PMID- 21265912 TI - Topiramate and the question of dosage. PMID- 21265914 TI - A simple derivation and classification of common probability distributions based on information symmetry and measurement scale. AB - Commonly observed patterns typically follow a few distinct families of probability distributions. Over one hundred years ago, Karl Pearson provided a systematic derivation and classification of the common continuous distributions. His approach was phenomenological: a differential equation that generated common distributions without any underlying conceptual basis for why common distributions have particular forms and what explains the familial relations. Pearson's system and its descendants remain the most popular systematic classification of probability distributions. Here, we unify the disparate forms of common distributions into a single system based on two meaningful and justifiable propositions. First, distributions follow maximum entropy subject to constraints, where maximum entropy is equivalent to minimum information. Second, different problems associate magnitude to information in different ways, an association we describe in terms of the relation between information invariance and measurement scale. Our framework relates the different continuous probability distributions through the variations in measurement scale that change each family of maximum entropy distributions into a distinct family. From our framework, future work in biology can consider the genesis of common patterns in a new and more general way. Particular biological processes set the relation between the information in observations and magnitude, the basis for information invariance, symmetry and measurement scale. The measurement scale, in turn, determines the most likely probability distributions and observed patterns associated with particular processes. This view presents a fundamentally derived alternative to the largely unproductive debates about neutrality in ecology and evolution. PMID- 21265915 TI - Measurement scale in maximum entropy models of species abundance. AB - The consistency of the species abundance distribution across diverse communities has attracted widespread attention. In this paper, I argue that the consistency of pattern arises because diverse ecological mechanisms share a common symmetry with regard to measurement scale. By symmetry, I mean that different ecological processes preserve the same measure of information and lose all other information in the aggregation of various perturbations. I frame these explanations of symmetry, measurement, and aggregation in terms of a recently developed extension to the theory of maximum entropy. I show that the natural measurement scale for the species abundance distribution is log-linear: the information in observations at small population sizes scales logarithmically and, as population size increases, the scaling of information grades from logarithmic to linear. Such log linear scaling leads naturally to a gamma distribution for species abundance, which matches well with the observed patterns. Much of the variation between samples can be explained by the magnitude at which the measurement scale grades from logarithmic to linear. This measurement approach can be applied to the similar problem of allelic diversity in population genetics and to a wide variety of other patterns in biology. PMID- 21265916 TI - After careful consideration. PMID- 21265918 TI - As death approaches: a retrospective survey of the care of adults dying in Alice Springs Hospital. AB - OBJECTIVE: Australians are more likely to die in a hospital than anywhere else, and most of these deaths are 'expected'. The aims of this survey were to identify if specific end-of-life issues were documented in clinical records of a regional hospital serving remote Australia. DESIGN: A retrospective consecutive case-note audit covering 18 months from 1 January 2006. SETTING: Alice Springs Hospital. PARTICIPANTS: Adult deaths in Alice Springs Hospital. During this period there were 128 deaths. OUTCOME MEASURES: Demographic, process (diagnosis of dying documented, 'not for resuscitation' documentation, intensive care unit (ICU) admission, social worker referral and specialised palliative care service referral) and outcome data ('comfort at end of life') were surveyed. RESULTS: Of the 128 admissions, 55 cases were excluded: 10 were children under 18, 33 died in < 48 hours, nine were coroner's cases and three files could no't be found. Of the 73 deaths surveyed (33 men), 47 (64%) were Aboriginal. A diagnosis of dying was made in 84%, 88% had an 'not for resuscitation' order, 48% were admitted to ICU during their last admission, 66% were referred to social workers, 68% were referred to palliative care and 85% of people were documented to be 'comfortable' during the dying process with no differential outcomes for Aboriginal and non Aboriginal decedents except age (P < 0.0001). CONCLUSION: This survey highlights the continuing need to diagnose dying, understand optimal use of intensive care and improve comfort care at the end of life. PMID- 21265919 TI - Stress and anxiety associated with lack of access to maternity services for rural parturient women. AB - OBJECTIVE: The objective of this study is to compare the level of stress and anxiety between women resident in communities with different degrees of access to local maternity services. DESIGN: Cross-sectional survey. SETTING: Fifty-two communities across rural British Columbia with different levels of access to maternity care services (ranging from no services to local specialist obstetrician). PARTICIPANTS: A total of 187 women, 40 of whom were from communities with no local access to services. MAIN OUTCOME MEASURES: Stress score on the R ural Pregnancy Experience Scale including financial and continuity of care subscales. RESULTS: Parturient women who had to travel more than one hour to access services were 7.4 times more likely to experience moderate or severe stress when compared to women who had local access to maternity services. CONCLUSIONS: Lack of access is strongly associated with stress in rural parturient women. PMID- 21265920 TI - It's not just about the HbA1c, Doc! Understanding the psychosocial is also important in managing diabetes? AB - OBJECTIVE: Despite significant efforts at a primary care level, at least 35% of people with diabetes fail to meet health targets. It is assumed that these poor results are a consequence of the patient not understanding their disease or not caring. This study seeks to understand what really lies behind poor control. DESIGN SETTING AND PARTICIPANTS: A qualitative study using semistructured interviews was conducted in a primary care setting in rural Western Australia. People living with diabetes for at least two years were specifically selected on the basis of whether they had either 'good' (HbA1c < 7%) or 'poor' (HbA1c > 8%) control. RESULTS: Interviews revealed that people understood only too well their disease and their responsibilities. Frequently, either they did not choose to make diabetes a priority in their lives or were unable to make appropriate lifestyle changes which were demanded for good blood sugar control. Their life/social stresses often influenced their glucose control. CONCLUSION: Poor control in our study was not related to lack of knowledge but more to how diabetes was prioritised in their lives. Attention to the patients' priorities is required to accomplish improved glycaemic control. PMID- 21265921 TI - Rural men's subjective well-being and the role of social support and sense of community: evidence for the potential benefit of enhancing informal networks. AB - OBJECTIVE: To examine the effects of social support and sense of community on rural men's subjective well-being, considering the main effects and stress-buffer models. DESIGN: Cross-sectional population-based survey, non-probability sampling frame primarily convenience sampling. SETTING: Community-based setting. PARTICIPANTS: A total of 185 men aged 18+ years from rural South Australia. MAIN OUTCOME MEASURES: Subjective well-being, measured by the Satisfaction With Life Scale. RESULTS: Two-step hierarchical multiple regression analysis was conducted, with subjective well-being as the dependent variable, controlling for independent variables of age, living alone and farm employment. Social support was the most effective predictor of well-being, followed by stress, and only a very modest contribution from sense of community; total variance explained was 56% (F(6,178) = 37.77, P < 0.001, R2 =0.56, adjusted R2 = 0.55, R2 change = 0.07, P < 0.001). Stress partially mediated both the social support/well-being and sense of community/well-being relationships (mediation analysis). CONCLUSIONS: Results demonstrated the benefits of social support on well-being using the stress-buffer and main effects models, within a sample of rural men, and explored the relatively unexamined relationship between sense of community and well-being. Rural men have considerable stress impacting their well-being. This study identifies that it is critical for individuals, organisations and policy makers to be aware of the capacity of both social supports and sense of community to buffer stress and promote well-being within rural men. Furthermore, structural, community-based approaches might have greater capacity to cost-effectively provide this support, contrasting with the growing trend towards individual-based approaches for mental health. PMID- 21265922 TI - Psychological distress of rural parents: Family influence and the role of isolation. AB - OBJECTIVE: Research regarding psychological distress has often underestimated the importance of contextual social factors. This research aims to investigate patterns of psychological distress within the family system (parent dyads) across rural and remote communities and the influence of remoteness on such distress. DESIGN: Self-report survey data from the Australian Rural Mental Health Study was used to examine the distress levels of cohabitating parental figures in rural and remote Australia. SETTING: The survey was conducted across rural and remote communities within New South Wales. PARTICIPANTS: The sample consisted of 129 adult couples (mean age = 42.66 years, SD = 8.11), 43 from Inner Regional areas, 48 from Outer Regional areas, 24 from Remote areas and 14 from Very Remote areas. MAIN OUTCOME MEASURE: Distress levels (Kessler-10). RESULTS: A significant association was detected between the levels of psychological distress among parents within a household. The strength of this relationship increased with increasing remoteness of residence. CONCLUSIONS: Identifying the influence of spousal factors on mental health in rural and remote areas allows health services in such regions to be aware of the needs of rural couples and families. These results support the need to consider partner/spouse mental health in clinical assessment and support the importance of household factors especially in remote communities. PMID- 21265923 TI - Nursing workforce in very remote Australia, characteristics and key issues. AB - OBJECTIVE: To describe the nursing workforce in very remote Australia, characteristics and key issues. METHODS: Data were collected from four main sources: the refined CRANAplus database of remote health facilities; the 2006 census which provided population and percentage of Indigenous people in communities in very remote Australia; a national survey on occupational stress among nurses and an earlier study into violence and remote area nurses conducted in 1995. A descriptive analysis of the data was conducted. SETTING: Health facilities in very remote Australia. RESULTS: The registered nursing workforce in very remote Australia is mostly female (89%) and ageing, with 40.2% 50 years or over, compared to 33% nationally. Many (43%) are in remote Indigenous communities. Over the last decade, there has been a significant decrease in registered nurses with midwifery qualifications (55%) and in child health nurses (39%) in very remote Australia. Only 5% have postgraduate qualifications in remote health practice. CONCLUSION: The nursing workforce in very remote areas of Australia is in trouble. The workforce is ageing, the numbers of nurses per population has fallen and the numbers of midwives and child health nurses have dropped significantly over the last 15 years. As many of these nurses work in Indigenous communities, if these trends continue it is likely to have a negative effect on 'closing the gap' in Indigenous health outcomes. PMID- 21265924 TI - Survey of the rural allied health workforce in New South Wales to inform recruitment and retention. AB - OBJECTIVE: To investigate the demographics, employment, education and factors affecting recruitment and retention of New South Wales (NSW) rural allied health professionals. DESIGN: Descriptive study, cross-sectional survey. SETTING: Regional, rural and remote areas of NSW, Australia. PARTICIPANTS: The sample includes 1879 respondents from more than 21 different allied health occupations. MAIN OUTCOMES MEASURES: Variables included gender, age, marital status, employment sector, hours worked, community size, highest qualification, rural origin and continuing education, as well as others. Certain variables were compared for profession and gender. RESULTS: Women made up 70% of respondents, with a mean age of 42 years. Men were older, with more experience. Sixty per cent were of rural origin and 74% partnered, most with their partner also working. Eighty-four per cent worked in centres of 10,000 or more people. The public sector accounted for 46% of positions and the private sector 40%. Eleven per cent worked across multiple sectors and 18% were self-employed. Two-thirds worked 35 hours or more per week, although only 49% were employed full-time. Job satisfaction was high but 56% intended leaving within 10 years, 28% to retire. Over 90% of respondents qualified in Australia and more than 80% held a degree or higher qualification. Almost half were dissatisfied with access to continuing education. CONCLUSIONS: The NSW rural allied health workforce is strongly feminised, mature and experienced. Recruitment should target rural high school students and promote positive aspects of rural practice, such as diversity and autonomy. Retention strategies should include flexible employment options and career development opportunities. PMID- 21265925 TI - Teaching pathology via online digital microscopy: positive learning outcomes for rurally based medical students. AB - INTRODUCTION: Technology has revolutionised teaching. Teaching pathology via digital microscopy (DM) is needed to overcome increasing student numbers, a shortage of pathology academics in regional medical schools, and difficulties with teaching students on rural clinical placement. OBJECTIVE: To identify whether an online DM approach, combining digital pathology software, Web-based slides and classroom management software, delivers effective, practical pathology teaching sessions to medical students located both on campus and on rural placement. METHODS: An online survey collected feedback from fourth and fifth year undergraduate James Cook University medical students on the importance of 16 listed benefits and challenges of using online DM to teach pathology, via a structured five-point Likert survey. RESULTS: Fifty-three students returned the survey (response rate = 33%). Benefits of online DM to teach pathology rated as 'very important' or 'extremely important' by over 50% of students included: higher quality images; faster learning; more convenient; better technology; everyone sees the same image; greater accessibility; helpful annotations on slides; cost savings; and more opportunity for self-paced learning out-of-hours and for collaborative learning in class. Challenges of online DM rated as 'very important' or 'extremely important' by over 50% of students included: Internet availability in more remote locations and potential problems using online technology during class. CONCLUSIONS: Nearly all medical students welcomed learning pathology via online digital technology. DM should improve the quantity, quality, cost and accessibility of pathology teaching by regional medical schools, and has significant implications for the growing emphasis in Australia for decentralised medical education and rural clinical placements. PMID- 21265926 TI - Model for rural and remote speech pathology student placements: using non traditional sites and partnerships. PMID- 21265928 TI - Progressing the rural health agenda. PMID- 21265927 TI - Nurse practitioners for rural and remote Australia: creating opportunities for better health in the bush. PMID- 21265929 TI - Renal tubular dysgenesis and tubulointerstitial nephritis antigen in juvenile nephronophthisis. AB - AIM: The relationship between abnormalities of tubular architecture and tubulointerstitial nephritis antigen (TIN-ag) in juvenile nephronophthisis (J NPH) was evaluated. METHODS: Sixteen J-NPH patients were examined. Nephrocystin 1, TIN-ag, type IV collagen, Fas antigen and the C5b-9 complement complex were stained by immunohistochemical methods. RESULTS: Renal tubules of patients with J NPH showed morphological abnormalities of tubular basement membranes (TBM) and frequent apoptosis of tubular epithelial cells. Additionally, the C5b-9 complement complex was deposited within the TBM in the absence of immunoglobulin deposition, suggesting complement-dependent TBM injury. Localization of TIN-ag in the TBM of J-NPH patients disclosed a partial defect or discontinuity in 14 of the 16 patients, while type IV collagen immunoreactivity was relatively preserved. These findings suggest that tubulogenesis is disturbed during nephronogenesis in J-NPH patients because of a defect in nephrocystin, an NPHP gene product. TBM defects induce further morphological abnormalities such as cystic dilation of tubules; as tubular function impairment advances, the incomplete tubules may be injured by C5b-9 complement complexes, followed by apoptotic cell death. CONCLUSION: TIN-ag, which is important in early nephrogenesis, lacks normal activity, and vulnerable and incomplete tubules with deficient TIN-ag expression are formed. Removal of these defective tubules by apoptosis combined with the C5b-9 complement complex could be the primary reason for progression to end-stage renal disease in J-NPH patients. PMID- 21265930 TI - Fibroblast growth factor 23 in chronic kidney disease: New insights and clinical implications. AB - Fibroblast growth factor 23 (FGF-23) is a recently discovered regulator of phosphate and mineral metabolism. Its main physiological function is the enhancement of renal phosphate excretion. FGF-23 levels are inversely related to renal function and in patients with chronic kidney disease (CKD) elevation in FGF 23 precedes the rise of serum phosphate. Studies have demonstrated an important role for FGF-23 in the development of secondary hyperparathyroidism through an effect on parathyroid hormone and calcitriol. In cross-sectional studies FGF-23 has been associated with surrogate markers of cardiovascular disease such as endothelial dysfunction and arterial stiffness. FGF-23 has also been associated with both progression of CKD and mortality in dialysis patients. The discovery of FGF-23 has provided a profound new insight into bone and mineral metabolism, and it may become an important biomarker and therapeutic target in CKD. PMID- 21265931 TI - Urinary proteins, N-acetyl-beta-D-glucosaminidase activity and estimated glomerular filtration rate in hypertensive patients with normoalbuminuria and microalbuminuria. AB - BACKGROUND: The aim of the study was to assess novel candidate markers measured in the urine of normoalbuminuric and microalbuminuric patients (the urinary albumin-to-creatinine ratio < 30 mg/mmol) with essential hypertension to be used for early detection and assessment of progressive deterioration in renal function. METHODS: Albumin, alpha-1-antitrypsin, orosomucoid, transferrin, retinol-binding protein and alpha-1-microglobulin concentrations and the NAG (N acetyl-beta-D-glucosaminidase) activity in the urine were evaluated in 102 hypertensive subjects with urinary albumin-to-creatinine ratio (uACR) < 30 mg/mmol. The estimated glomerular filtration rate (e-GFR) was calculated using the Modification of Diet in Renal Disease Study equation. RESULTS: The decreasing e-GFR values in normo- and microalbuminuric patients with essential hypertension were accompanied by significant increases (P < 0.05) in the NAG activity and uACR value in the urine. The e-GFR significantly (P < 0.05) correlated with the NAG activity in the urine, but no association was observed with the urinary concentrations of any of the individual proteins (P > 0.05). CONCLUSIONS: In normoalbuminuric and microalbuminuric patients with essential hypertension renal impairment measured by e-GFR is related to the increased urinary NAG activity and uACR rather than elevated concentrations of individual proteins. Urinary NAG activity and uACR value seem independently promising candidate markers for use in assessing progression of early renal impairment in patients with hypertension. PMID- 21265934 TI - Pharmacogenomics of antipsychotics efficacy for schizophrenia. AB - Central nervous system disorders are the third greatest health problem in developed countries, and schizophrenia represents some of the most disabling ailments in young individuals. There is an abuse and/or misuse of antipsychotics, and recent advances in pharmacogenomics pose new challenges for the clinical management of this complex disorder. Schizophrenia is a multi-factorial/polygenic complex disorder in which hundreds of different genes are potentially involved, leading to the phenotypic expression of the disease in conjunction with epigenetic and environmental phenomena. Consequently, structural and functional genomic changes induce proteomic and metabolomic defects associated with the disease phenotype. Disease-related genomic profiles and genetic variants in genes involved in drug metabolism are responsible for drug efficacy and safety. About 20% of Caucasians are defective in CYP2D6 enzymes, which participate in the metabolism of 25-30% of central nervous system drugs. Approximately 40% of antipsychotics are substrates of CYP2D6 enzymes, 23% are substrates of CYP3A4, and 18% are substrates of CYP1A2. In order to achieve a mature discipline of pharmacogenomics of schizophrenia it would be effective to accelerate: (i) the education of physicians and the public in the use of genomic screening in daily clinical practice; (ii) the standardization of genetic testing for major categories of drugs; (iii) the validation of pharmacogenomic procedures according to drug category and pathology; (iv) the regulation of ethical, social, and economic issues; and (v) the incorporation of pharmacogenomic procedures of drugs in development and drugs on the market in order to optimize therapeutics. PMID- 21265932 TI - A review of utility-based allocation strategies to maximize graft years of deceased donor kidneys. AB - With the continuing shortage of deceased donor kidneys coupled with a growing number of older potential recipients, there has been a greater acceptance of using older donor kidneys, including increased utility of expanded criteria donor (ECD) kidneys. In this review, we will look at the impact of using ECD kidneys on graft and patient survival, and to identify modifiable factors that may improve transplant outcomes in recipients receiving ECD kidneys. In addition, we will discuss whether the implementation of utility-based allocation strategies to maximize graft outcomes is an appropriate way forward to provide a better balance between utility and equity in the distribution of deceased donor kidneys. PMID- 21265935 TI - Age-specific prevalence of metabolic syndrome in Italian patients with bipolar disorder. AB - AIM: Metabolic syndrome (MetS) is highly prevalent in patients with bipolar disorder (BD). Little research has evaluated the risk profile of MetS and cardiovascular disease in different gender and age groups in these patients. Our aim is to evaluate the prevalence of MetS in Italian patients with BD stratified by gender and age, and to determine the correlates of MetS. METHODS: Subjects with BD were included and stratified by sex and age according to the following age groups: <30; 30-39; 40-49; 50-59; >= 60 years. Socio-demographic and clinical characteristics, lifestyle information, and comorbidity for cardiovascular diseases and diabetes were collected. MetS was diagnosed according to National Cholesterol Education Program Adult Treatment Panel III modified criteria. RESULTS: MetS was evaluated in 200 patients, with a prevalence of 26.5%. Men had higher rates of hypertension and hypertriglyceridemia, women had more abdominal obesity. Women had a peak of prevalence in the >= 60 years group, while men displayed high rates even in the young age groups. In young patients, MetS was associated with Cluster B personality disorders and less physical exercise. CONCLUSION: Our paper highlights the importance of evaluating MetS even in young patients with bipolar disorder, especially males. The strong association with lack of physical exercise suggests that the implementation of healthy behaviors might be relevant in order to prevent MetS and future adverse cardiovascular outcomes. PMID- 21265936 TI - An open-label, dose-titration tolerability study of atomoxetine hydrochloride in Japanese adults with attention-deficit/hyperactivity disorder. AB - AIMS: The main purpose of this first atomoxetine study in Japanese adults with attention-deficit/hyperactivity disorder (ADHD) was to investigate the tolerability of an 8-week treatment regimen. METHODS: This was an open-label, dose escalation study conducted in 45 Japanese patients aged at least 18 years with DSM-IV-defined ADHD. Patients received atomoxetine orally for 8 weeks. Atomoxetine administration was started at 40 mg/day (7 days), and subsequently increased to a maximum dose of 120 mg/day. Tolerability was assessed by discontinuation rate due to adverse events. Adverse events, laboratory tests, vital signs and electrocardiograms were collected. In addition, ADHD symptoms were assessed by using the Japanese version of the Conners' Adult ADHD Rating Scale-Investigator Rated: Screening Version (CAARS-Inv:SV) scores. RESULTS: Thirty-nine patients completed the study period. Atomoxetine was well tolerated with a 6.7% (3/45) discontinuation rate due to nausea, malaise and anorexia. The most commonly reported adverse events were nausea, nasopharyngitis and headache; there were no unexpected safety concerns. No deaths or serious adverse events were reported. Mean CAARS-Inv:SV-J total ADHD symptom scores decreased in a time dependent manner; the mean change from baseline to endpoint was -15.0 (P<0.001). CONCLUSIONS: This study showed that atomoxetine was well tolerated in these patients and suggested that atomoxetine at a maximum dose of 120 mg/day would be safe in Japanese ADHD patients. PMID- 21265937 TI - Reliability and validity of the Japanese version of the Cognitive Therapy Awareness Scale: a scale to measure competencies in cognitive therapy. AB - AIM: This study aimed to test reliability and validity of the Japanese-version Cognitive Therapy Awareness Scale, a self-rating scale that measures basic knowledge of cognitive behavioral therapy (CBT) concepts and methodology. Furthermore, we explored optimal cutoff score to demonstrate required standard of CBT competency. METHODS: The reliability and validity of the scale was tested among 252 mental health professionals. The participants' number of readings relevant to CBT, as well as their experience in training and practice in CBT were used as external standards of competency. RESULTS: The scale has good internal consistency (the Kuder-Richardson formula 20=0.76). The total score of the scale was significantly correlated with experience in training and practice in cognitive behavioral therapy, and the number of relevant readings (Spearman's rho =0.27, 0.28 and 0.44, respectively, P<0.001). No significant correlation was found between the total score of the scale and experience in general psychosocial care (Spearman's rho = -0.02, P=0.76). The receiver operating characteristics curve analysis produced the area under curve (AUC) of 0.77 (SD=0.05, P<0.001), and a cutoff score of 31/32 produced sensitivity of 0.81 and specificity of 0.64 to discriminate trainees who have experience of 40 h or more of CBT training and five or more of relevant readings, from those who do not meet this standard. CONCLUSION: The Japanese-version Cognitive Therapy Awareness Scale was successfully validated. It has been demonstrated that the scale specifically assess knowledge in cognitive behavioral therapy. This scale would serve as a rough guide to assess competencies among beginner cognitive behavior therapists. PMID- 21265938 TI - Is a patient-administered depression rating scale valid for detecting cognitive deficits in patients with major depressive disorder? AB - AIMS: Although cognitive deficits are a common and potentially debilitating feature of major depressive disorder (MDD), such subjective declines in cognitive function are seldom validated by objective methods as a clinical routine. The aim of this study was to validate the Taiwanese Depression Questionnaire (TDQ) for detecting cognitive deficits in a sample of drug-free patients with MDD. METHODS: The subjects consisted of 40 well-characterized medication-free patients with MDD and 40 healthy controls. Clinical and neuropsychological assessments, including the Wisconsin Card Sorting Test, the Wechsler Memory Scale-Revised, the Continuous Performance Test, and the Finger-Tapping Test, were administered at the time of recruitment. RESULTS: Factor analyses of the TDQ yielded three factors. Memory, attention and psychomotor performance were significantly poorer in patients with MDD. The performances of verbal and delayed memory of the Wechsler Memory Scale-Revised were correlated with the cognitive domains of the TDQ. Generalization of our results must be undertaken with caution considering the relatively small sample size, which could lead to increased beta-error. CONCLUSION: Cognitive subdomains might be considered important for including in patient-administered questionnaires used to measure symptoms of MDD when developing a new scale. PMID- 21265939 TI - Chronic repetitive transcranial magnetic stimulation increases hippocampal neurogenesis in rats. AB - AIM: While the underlying therapeutic mechanisms of repetitive transcranial magnetic stimulation (rTMS) treatment for depression remain unclear, recent animal studies have suggested that hippocampal neurogenesis might be required for the effects of antidepressant treatments including antidepressant drugs and electroconvulsive therapy. The aim of this study was to examine chronic rTMS effects on hippocampal neurogenesis in rats. METHODS: Using a 70-mm figure-of eight coil, the stimulating parameters were set to 25 Hz and 70% of the rTMS device's maximum power. For 14 consecutive days, bromodeoxyuridine (BrdU) and 1000 pulses of rTMS were administered daily. Cell proliferation in the dentate gyrus was examined with immunohistochemistry. RESULTS: In the rTMS-treated group, BrdU-positive cells were significantly increased in the dentate gyrus. CONCLUSION: Our results suggest that hippocampal neurogenesis might be involved in the antidepressant effects of chronic rTMS. PMID- 21265940 TI - Prevalence of depressive symptoms in Japanese male patients with chronic obstructive pulmonary disease. AB - AIM: The objective of this study was to utilize commonly applied tools, the Hospital Anxiety and Depression Scale - Depression subscale (HADS-D) and the Center for Epidemiological Studies Depression Scale (CES-D), to screen for depressive symptoms in patients with stable chronic obstructive pulmonary disease (COPD). Furthermore, we sought to identify whether differences existed in the prevalence of depressive symptoms as assessed by CES-D and HADS-D, and predictors of depressive symptoms. METHODS: The presence of depressive symptoms in 80 outpatients and 51 inpatients with stable COPD was assessed using the CES-D and HADS-D. Data regarding sex, educational level, body mass index, smoking index and pulmonary function were obtained to evaluate their independent contribution as predictors of depressive symptoms. RESULTS: The prevalence of depressive symptoms was 29.8% based on CES-D and 40.5% based on HADS-D. A MacNemar test of COPD severity and analysis of the results of depressive symptoms based on CES-D and HADS-D revealed significant differences. Logistic regression analysis suggested that 'severity' is a predictor of depressive symptoms as assessed by CES-D, whereas 'body mass index', 'education level' and 'setting' were predictors of depressive symptoms as assessed by HADS-D. CONCLUSIONS: The prevalence of depressive symptoms differed when assessed with CES-D and HADS-D. The reasons behind this difference include the fact that HADS-D frequently detected depressive symptoms in patients with mild COPD as well as a tendency for HADS-D to be strongly influenced by education levels. In contrast, the severity of COPD was reflected in CES-D. It is possible that prevalence of depressive symptoms differs in accordance with the applied screening tool. PMID- 21265941 TI - Comparison of diagnostic names of mental illnesses in medical documents before and after the adoption of a new Japanese translation of 'schizophrenia'. AB - AIM: The name of a disease entered in medical documents often differs from the true diagnosis in psychiatric practice. We examined the effects of different translations of 'schizophrenia' into Japanese on the usage of disease names in documents. METHODS: We conducted a retrospective survey of the names of diseases used in the medical documents of 250 outpatients with schizophrenia or depression. These patients had attended our department of psychiatry between 1998 and 2000. We also investigated the names of the diseases of 226 outpatients who had first visited our department between 2003 and 2007. We defined the diagnosis (based on ICD-10) as the 'ICD-10 disease name' and the name of the disease written in medical documents as the 'disease name in documents'. We classified the documents that were used to apply for national psychiatric care and welfare services as 'official documents' and those submitted to others as 'private documents'. RESULTS: Prior to 2000, the term 'seishin-bunretsu-byo' ('split-mind disease'; old translation of 'schizophrenia') was used in 72.3% of official documents and 3.6% of private documents. In 2003 and later, the term 'togo shitcho-sho' ('integration disorder'; new translation of 'schizophrenia') was used in 98.0% of official documents and 21.7% of private documents. CONCLUSION: The use of 'togo-shitcho-sho' in official documents has become established. On the other hand, terms such as 'nervous breakdown' and 'depressive state' are still commonly used in private documents after the adoption of the new Japanese translation of schizophrenia. PMID- 21265944 TI - Delirium in the primary care setting. AB - Delirium is a complex multifactorial neuropsychiatric syndrome with a broad range of cognitive and neurobehavioral symptoms. It is associated with major adverse events and poor outcome. Little is known about delirium in the primary care setting. A retrospective chart review was carried out for the identification of ICD-10 delirium cases presented in the regional medical office of a rural area in central Greece. Nine cases of delirium, mostly the hyperactive subtype, had been recorded. The patients tended to be elderly and suffering from dementia; infections were the underlying cause in most cases. All but one patient had been successfully treated in the primary care setting. PMID- 21265942 TI - Improvement of serum prolactin and sexual function after switching to aripiprazole from risperidone in schizophrenia: a case series. AB - This study examined prolactin levels, sexual function and clinical improvement after switching to aripiprazole from risperidone. Nine schizophrenic male Chinese patients who reported risperidone-induced sexual dysfunction were studied. Clinical Global Impression Scale Scores for Severity (CGI-S), Clinical Global Impression Scale Scores for Improvement (CGI-I), Arizona Sexual Experience Scale results and serum prolactin concentrations were determined over 16 weeks. After treatment with aripiprazole, all patients showed reduced serum prolactin (26.54 +/- 17.03 ng/mL to 3.71 +/- 1.87 ng/mL, P=0.008) and five reported improved sexual function. Mean baseline CGI-S (5.11 +/- 0.93) decreased to 3.78 +/- 1.39 (P=0.010) by week 16. Compared to baseline (4.0), the mean CGI-I significantly declined by the end of the study (3.44 +/- 0.53, P=0.025). PMID- 21265943 TI - Reduced central white matter volume in autism: implications for long-range connectivity. AB - Cortical and central white matter (WM) volumes were measured to assess short- and long-range connectivity in autism, respectively. Subjects included 23 boys with autism and 23 matched controls, all without intellectual disability. Magnetic resonance imaging data obtained at 1.5 T were analyzed using BRAINS2 software (University of Iowa, Iowa City, IA, USA). Central WM volume was quantified by subtracting cortical from supratentorial WM volumes. Reduced central WM volume was observed in the autism group. IQ was higher in controls with no observed correlations between WM volumes and IQ. This preliminary evidence of reduced central WM volume in autism suggests abnormal long-range connectivity. PMID- 21265945 TI - Adult-type metachromatic leukodystrophy with compound heterozygous ARSA mutations: a case report and phenotypic comparison with a previously reported case. AB - Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by a deficiency of arylsulfatase A. MLD is a heterogeneous disease with variable age at onset and variable clinical features. We evaluated a 33-year old female patient who developed manifestations of disinhibitory behavior. She was diagnosed with MLD by genetic analysis, which revealed compound heterozygous ARSA missense mutations (p.G99D and p.T409I). The same combination of mutations was previously reported in a Japanese patient with similar symptoms. We performed additional, detailed neuropsychological tests with functional imaging on the current patient that demonstrated frontal lobe dysfunction. These results indicate that the mutations have important implications for genotype-phenotype correlation in MLD. PMID- 21265946 TI - Assessment of the Center for Epidemiological Studies Depression Scale factor structure among middle-aged workers in Japan. AB - Our aim was to assess the internal consistency and structural/construct validity of the Center for Epidemiological Studies Depression Scale among middle-aged employees in Japan. We conducted a cross-sectional study of 7284 workers, aged 49.0 +/- 6.3 (mean +/- SD) years old. Structural/construct validity was assessed by confirmatory factor analysis. The 4-factor structure reported in the general population was replicated, and a second-order model with an overarching depression factor fitted well. These findings indicate that the Center for Epidemiological Studies Depression Scale is a valid and reliable measure of depressive symptoms for middle-aged workers in Japan. PMID- 21265948 TI - Hypomanic episodes during menstrual periods: bipolar II disorder? PMID- 21265947 TI - Fluconazole-carbamazepine interaction in a patient with bipolar disorder. PMID- 21265949 TI - Musical creativity and mood bipolarity in Robert Schumann: a tribute on the 200th anniversary of the composer's birth. PMID- 21265950 TI - A novel single-chain-Fv antibody against connective tissue growth factor attenuates bleomycin-induced pulmonary fibrosis in mice. AB - BACKGROUND AND OBJECTIVE: Connective tissue growth factor (CTGF) has been identified as playing critical roles in fibrosis and is a promising therapeutic target. In a previous study, we used a phage display library to develop a humanized single-chain variable fragment antibody (scFv) against CTGF. In the present study, the protective effect of anti-CTGF scFv against bleomycin (BL) induced pulmonary fibrosis was investigated in mice. METHODS: The expression of alpha-smooth muscle actin in human embryonic lung fibroblast (HELF) cells was analysed by western blotting. A mouse model of pulmonary fibrosis was established by tracheal injection of BL (5 mg/kg). Mice received anti-CTGF scFv (4 mg/kg, three times a week) by i.v. injection. The effects of anti-CTGF scFv were evaluated by leukocyte counts in BAL fluid, hydroxyproline measurements in lung tissue and pathological examination. RESULTS: alpha-Smooth muscle actin expression was decreased in HELF cells treated with anti-CTGF scFv. Anti-CTGF scFv significantly reduced the numbers of inflammatory leukocytes (total and differential count) in BAL fluid, as well as the hydroxyproline content of lung tissue. The severity of alveolitis and fibrosis in the mouse model was markedly attenuated by treatment with anti-CTGF scFv. CONCLUSIONS: Anti-CTGF scFv may potentially be developed as a useful inhibitor of pulmonary fibrosis. PMID- 21265952 TI - Cellular prion protein promotes glucose uptake through the Fyn-HIF-2alpha-Glut1 pathway to support colorectal cancer cell survival. AB - Cellular prion protein (PrPc) is a glycosylphosphatidylinositol-anchored membrane protein that has various physical functions, including protection against apoptotic and oxidative stress, cellular uptake of copper ions, transmembrane signaling, and adhesion to the extracellular matrix. In this study, we show that PrPc is highly expressed in colorectal adenocarcinomas. Transcriptome profiling of PrPc-depleted DLD-1 cells revealed downregulation of glucose transporter 1 (Glut1). PrPc is shown to be involved in regulating Glut1 expression through the Fyn-HIF-2alpha pathway. As Glut1 is the natural transporter of glucose and is required for the high glycolytic rate seen in colorectal tumors, silencing of PrPc reduced the proliferation and survival rate of colorectal cancer cells in vitro. In vivo, knockdown of PrPc by hydrodynamic injection with a cocktail of PrPc-shRNA-encoding plasmids also inhibited tumorigenicity in a xenograft model in nude mice. In summary, our data characterize a novel molecular mechanism that links PrPc expression to the regulation of glycolysis. Targeting PrPc will therefore be a promising strategy to overcome the growth and survival advantage in colorectal tumors. PMID- 21265953 TI - Retraction: Curcumin targets Akt cell survival signaling pathway in HTLV-I infected T-cell lines. PMID- 21265954 TI - Retraction: Anti-adult T-cell leukemia effects of a novel synthetic retinoid, Am80 (Tamibarotene). PMID- 21265955 TI - Retraction: Epstein-Barr virus-encoded latent membrane protein 1 activates beta catenin signaling in B lymphocytes. PMID- 21265956 TI - Severe hypoglycemia in youth with T1DM: going, going ... but not yet gone. PMID- 21265958 TI - The journal in 2010. PMID- 21265960 TI - Severe sepsis: take care, take part. AB - Severe sepsis is defined as organ dysfunction in the setting of systemic inflammatory response due to infection. With changes in population age, comorbidity and the delivery of medical care, severe sepsis is increasingly common, and can present in every area of the hospital. The major obstacles to improved outcomes in severe sepsis are deficiencies in healthcare staffing and education, haphazard recognition and response to early clinical deterioration and deviation from optimal management as defined by international guidelines. Major treatment errors were identified in 30% of patients with bacteraemia in one recent investigation. Against this, substantial reductions in mortality can be achieved by improving recognition, urgent care and resuscitation. With a view to improving survival in sepsis, collaborative efforts are required to measure outcomes, implement guidelines and secure adequate funding for ongoing practice improvement, education and research. PMID- 21265961 TI - Left ventricular ejection fraction for the risk stratification of sudden cardiac death: friend or foe? AB - More than 450000 Americans die suddenly each year from sustained ventricular tachycardia or fibrillation. A correct identification of these patients is crucial for a rational clinical management, because the demonstrated effectiveness of implantable cardioverter-defibrillators (ICD) on the reduction of sudden cardiac death. Basing on the results of multiple clinical trials, left ventricular systolic function, measured as ejection fraction, is currently the only recommended tool to identify patients at higher risk of sudden death that would benefit from a prophylactic ICD. However, the systematic implementation of prophylactic ICD recommendations results in a substantial number of inappropriate ICD implantations, while failing to prevent the majority of sudden deaths occurring in the general population. That has been the case implementing arrhythmic risk stratification with a rough arrhythmic risk marker, such as ejection fraction, that lacks sensitivity and specificity in the prediction of sudden cardiac death. The aim of this viewpoint is to critically revise the value of ejection fraction in the identification of patients at risk of sudden cardiac death. PMID- 21265962 TI - Automated erythrocytapheresis for severe falciparum malaria. AB - We describe a case of severe falciparum malaria with hyperparasitaemia. Treatment with automated erythrocytapheresis, in conjunction with parenteral artesunate, produced a rapid and sustained fall in parasite burden. Several poor prognostic features were present at admission. Despite the development of a severe headache with abnormal cerebrospinal fluid parameters and transient pulmonary oedema, a complete recovery was observed. Erythrocytapheresis can be considered in selected cases where facilities exist and has theoretical and practical advantages over traditional methods of red cell exchange transfusion. The paucity of systematic or trial evidence convincingly demonstrating a benefit in terms of morbidity or mortality has limited its application. However, the lack of robust trial data should not in itself invalidate considering this therapeutic option in the appropriate context. PMID- 21265963 TI - 22q11.2 deletion presenting with severe hypocalcaemia, seizure and basal ganglia calcification in an adult man. AB - We report a 40-year-old man who was found to have profound hypocalcaemia and hypoparathyroidism when investigated for multiple, generalized, tonic/clonic seizures and a chest infection. Computed tomography scan of the brain revealed extensive symmetric bilateral calcification within the cerebellum, thalamus and basal ganglia. Molecular cytogenetic testing by fluorescent in situ hybridization using the commercial Vysis LSI DiGeorge/VCFS dual colour probe set showed a deletion of 22q11.2. The extraordinary feature of this case is the adult presentation of hypocalcaemia, hypoparathyroidism and basal ganglia calcification due to 22q11.2 deletion. PMID- 21265964 TI - Amyloidosis: clinical pentad. PMID- 21265965 TI - Giant atrial thrombus. PMID- 21265966 TI - The utility of adrenal and ovarian venous sampling in the investigation of androgen-secreting tumours. PMID- 21265967 TI - Treatment of gout. PMID- 21265968 TI - E-Health: what are we talking about? PMID- 21265969 TI - 2007 National Statement on Ethical Conduct in Human Research: not worth the paper it is written on? PMID- 21265970 TI - Physical and functional factors in activities of daily living that predict falls in community-dwelling older women. AB - AIM: In order to propose rehabilitation strategies for the reduction of falls risk, thereby preventing falls in older women, the present study was designed to explore the physical and functional factors related to actual incidence of falls. METHODS: Fifty-eight female patients aged 65 years and older (mean age +/- standard deviation, 80.5 +/- 5.7), who were attending a geriatric outpatient clinic participated. All the participants were assessed with their activities of daily living, gait and balance using various scales. Their handgrip strength and muscle strength of lower extremities were also measured using dynamometers. Falls of the participants during the 6 months follow-up period were recorded. RESULTS: Correlation analysis investigating associations between the scores of assessment scales and actual measurement of muscle strength and balance showed that there were significant correlations between handgrip strength and Falls Efficacy Scale, Functional Reach test, Timed Up and Go test, Berg Balance Scale, Motor Fitness Scale, motor Functional Independence Measure in fallers and non-fallers. A binary logistic stepwise regression analysis incorporating all the possible variables into the model revealed that only inability to "being able to go up and down the staircase" in the Motor Fitness Scale remained a significant variable to predict falls during the period of observation. CONCLUSION: The results confirmed that the sub-item in the Motor Fitness Scale has a possibility of being a significant predictor of falls in older women, and therefore might prove useful in considering specific rehabilitation program on falls prevention as well as screening this population at risk of falls. PMID- 21265971 TI - Relationship between interleukin-6 and cerebral deep white matter and periventricular hyperintensity in elderly women. AB - AIM: We evaluated the relationships between serum levels of high-sensitivity C reactive protein (hsCRP) and interleukin (IL)-6 with the severity of leukoaraiosis. METHODS: One hundred and thirty-seven elderly women who attended the Center for Comprehensive Care on Memory Disorders at Kyorin University Hospital were enrolled in this study. Leukoaraiosis was assessed by periventricular hyperintensity (PVH) score and deep white matter hyperintensity (DWMH) score. RESULTS: Serum log IL-6 level correlated with PVH and DWMH scores, but hsCRP did not. By multinomial logistic analysis, IL-6 was significantly related to DWMH score, independent of age and systolic blood pressure. CONCLUSION: IL-6 is presumably an important marker of leukoaraiosis, as is the case with silent cerebral infarction. PMID- 21265972 TI - Correlation between dental and nutritional status in community-dwelling elderly Japanese. AB - AIM: The purpose of this study was to clarify the correlation between dental and nutritional status among community-dwelling elderly Japanese people. METHODS: The subjects were 182 elderly individuals, aged 65-85 years, who voluntarily participated in a health seminar at Kyoto Prefectural University of Medicine. These subjects were divided into two groups according to the occlusion. The subjects in the retained contact group were those who had retained molar occlusion with natural teeth. The lost contact group were those who retained molar occlusion with removable partial dentures. Anthropometric variables such as body mass index (BMI) were collected and dietary intake was assessed using a brief self-administered diet history questionnaire (BDHQ). RESULTS: No statistical difference in BMI or intake of macronutrients was found between these two occlusal groups. The lost contact group reported significantly lower consumption of vegetables and higher consumption of confectionaries (foods rich in sugar) than did the retained contact group (P < 0.05), and therefore had significantly lower intake of vitamin C and dietary fiber (P < 0.05). CONCLUSION: It can be concluded that natural tooth contact loss in the posterior region affect the intake of vitamins and dietary fiber. . PMID- 21265973 TI - A graphical theory of competition on spatial resource gradients. AB - Resource competition is a fundamental interaction in natural communities. However, little remains known about competition in spatial environments where organisms are able to regulate resource distributions. Here, we analyse the competition of two consumers for two resources in a one-dimensional habitat in which the resources are supplied from opposite sides. We show that the success of an invading species crucially depends on the slope of the resource gradients shaped by the resident. Our analysis reveals that parameter combinations, which lead to coexistence in a uniform environment, may favour alternative stable states in a spatial system, and vice versa. Furthermore, differences in growth rate, mortality or dispersal abilities allow a consumer to coexist stationarily with - or even outcompete - a competitor with lower resource requirements. Applying our theory to a phytoplankton model, we explain shifts in the community structure that are induced by environmental changes. PMID- 21265974 TI - Distance-limited dispersal promotes coexistence at habitat boundaries: reconsidering the competitive exclusion principle. AB - Understanding the conditions for the stable coexistence of different alleles or species is a central topic in theoretical evolution and ecology. Different causes for stable polymorphism or species coexistence have already been identified but they can be grouped into a limited number of general processes. This article is devoted to the presentation and illustration of a new process, which we call 'habitat boundary polymorphism', and which relies on two key ingredients: habitat heterogeneity and distance-limited dispersal. Under direct competition and with fixed population densities, we show that this process allows for the equilibrium coexistence of more than n types in a n-habitat environment. Distance-limited dispersal indeed creates local maladaptation at habitat edges, which leaves room for the invasion of more generalist alleles or species. This mechanism provides a generic yet neglected process for the maintenance of polymorphism or species coexistence. PMID- 21265975 TI - Suppression of herbivory by macroalgal density: a critical feedback on coral reefs? AB - Coral reefs globally are in decline, with some reefs undergoing phase shifts from coral-dominance to degraded states dominated by large fleshy macroalgae. These shifts have been underpinned by the overharvesting of herbivorous fishes and represent a fundamental change in the physical structure of these reefs. Although the physical structure provided by corals is regarded as a key feature that facilitates herbivore activity, the influence of the physical structure of macroalgal stands is largely unknown. Using transplanted Sargassum, the largest coral reef macroalga, we created habitat patches of predetermined macroalgal density (0.25-6.23 kg m(-2)). Remote video cameras revealed both grazing and browsing fishes avoided high density patches, preferring relatively open areas with low macroalgal cover. This behaviour may provide a positive feedback leading to the growth and persistence of macroalgal stands; increasing the stability of phase shifts to macroalgae. PMID- 21265976 TI - Global patterns of leaf mechanical properties. AB - Leaf mechanical properties strongly influence leaf lifespan, plant-herbivore interactions, litter decomposition and nutrient cycling, but global patterns in their interspecific variation and underlying mechanisms remain poorly understood. We synthesize data across the three major measurement methods, permitting the first global analyses of leaf mechanics and associated traits, for 2819 species from 90 sites worldwide. Key measures of leaf mechanical resistance varied c. 500 800-fold among species. Contrary to a long-standing hypothesis, tropical leaves were not mechanically more resistant than temperate leaves. Leaf mechanical resistance was modestly related to rainfall and local light environment. By partitioning leaf mechanical resistance into three different components we discovered that toughness per density contributed a surprisingly large fraction to variation in mechanical resistance, larger than the fractions contributed by lamina thickness and tissue density. Higher toughness per density was associated with long leaf lifespan especially in forest understory. Seldom appreciated in the past, toughness per density is a key factor in leaf mechanical resistance, which itself influences plant-animal interactions and ecosystem functions across the globe. PMID- 21265977 TI - Antagonistic coevolution limits population persistence of a virus in a thermally deteriorating environment. AB - Understanding the conditions under which rapid evolutionary adaptation can prevent population extinction in deteriorating environments (i.e. evolutionary rescue) is a crucial aim in the face of global climate change. Despite a rapidly growing body of work in this area, little attention has been paid to the importance of interspecific coevolutionary interactions. Antagonistic coevolution commonly observed between hosts and parasites is likely to retard evolutionary rescue because it often reduces population sizes, and results in the evolution of costly host defence and parasite counter-defence. We used experimental populations of a bacterium Pseudomonas fluorescens SBW25 and a bacteriophage virus (SBW25Phi2), to study how host-parasite coevolution impacts viral population persistence in the face of gradually increasing temperature, an environmental stress for the virus but not the bacterium. The virus persisted much longer when it evolved in the presence of an evolutionarily constant host genotype (i.e. in the absence of coevolution) than when the bacterium and virus coevolved. Further experiments suggest that both a reduction in population size and costly infectivity strategies contributed to viral extinction as a result of coevolution. The results highlight the importance of interspecific evolutionary interactions for the evolutionary responses of populations to global climate change. PMID- 21265978 TI - Bacteria associated with an encrusting sponge (Terpios hoshinota) and the corals partially covered by the sponge. AB - Terpios hoshinota, a dark encrusting sponge, is known to be a competitor for space in coral reef environments, and facilitates the death of corals. Although numerous cyanobacteria have been detected in the sponge, little is known of the sponge-associated bacterial community. This study examined the sponge-associated bacterial community and the difference between the bacterial communities in the sponge and the coral partially covered by the sponge by analysis of 16S rRNA gene sequences of samples isolated from the sponge covering the corals Favia complanata, Isopora palifera, Millepora sp., Montipora efflorescens and Porites lutea. The sponge-associated bacterial community was mainly (61-98%) composed of cyanobacteria, with approximately 15% of these alphaproteobacteria and gammaproteobacteria, although the proportions varied in different sponge samples. The dominant cyanobacteria group was an isolated group closely related to Prochloron sp. The comparison of the bacterial communities isolated from sponge free and the sponge-covered P. lutea showed that covering by the sponge caused changes in the coral-associated bacterial communities, with the presence of bacteria similar to those detected in black-band disease, suggesting the sponge might benefit from the presence of bacteria associated with unhealthy coral, particularly in the parts of the coral closest to the margin of the sponge. PMID- 21265981 TI - In conversation with Edwin Darracott Vaughan, Jr, MD. Interviewed by John Fitzpatrick. PMID- 21265979 TI - Growth hormone axis treatments for HIV-associated lipodystrophy: a systematic review of placebo-controlled trials. AB - BACKGROUND: HIV-associated lipodystrophy is a disorder of fat metabolism that occurs in patients with HIV infection. It can cause metabolic derangements and negative self-perceptions of body image, and result in noncompliance with highly active antiretroviral therapy (HAART). Growth hormone (GH) axis drugs have been evaluated for treatment of this disorder, but no systematic review has been conducted previously. OBJECTIVES: The aim of the review was to compare the effects of GH axis drugs vs. placebo in changing visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and lean body mass (LBM) in patients with HIV associated lipodystrophy. SEARCH METHODS: We searched MEDLINE (1996-2009), CENTRAL (Issue 4, 2009), Web of Science, Summons, Google Scholar, the Food and Drug Administration (FDA) website, and Clinicaltrials.gov from 13 October 2009 to 7 June 2010. We excluded newspaper articles and book reviews from the Summons search; this was the only search limitation applied. We also manually reviewed references of included articles. SELECTION CRITERIA: Inclusion criteria were as follows: randomized placebo-controlled trial (RCT); study participants with HIV associated lipodystrophy; intervention consisting of GH, growth hormone releasing hormone (GHRH), tesamorelin or insulin-like growth factor-1 (IGF-1); study including at least one primary outcome of interest: change in VAT, SAT or LBM. DATA COLLECTION AND ANALYSIS: Two independent reviewers extracted data and assessed study quality using a standardized form. The authors of one study were contacted for missing information. The main effect was calculated as a summary of the mean differences in VAT, SAT and LBM between the intervention and placebo groups in the included studies. Subgroup analyses were performed to assess different GH axis drug classes. RESULTS: Ten RCTs including 1511 patients were included in the review. All had a low risk of bias and passed the test of heterogeneity for each primary outcome. Compared with placebo, GH axis treatments decreased VAT [weighted mean difference (WMD) -25.20 cm(2) ; 95% confidence interval (CI) -32.18 to -18.22 cm(2) ; P<0.001] and increased LBM (WMD 1.31 kg; 95% CI 1.00 to 1.61 kg; P<0.001], but had no significant effect on SAT mass (WMD 3.94 cm(2) ; 95% CI -10.88 to 3.00 cm(2) ; P=0.27]. Subgroup analyses showed that GH had the most significant effects on VAT and SAT, but none on LBM. The drugs were well tolerated but statistically significant side effects included arthralgias and oedema. CONCLUSIONS: Our review indicates that, based on the findings of the 10 included studies, GH axis treatments are effective in reducing VAT and increasing LBM in patients with HIV-associated lipodystrophy. However, clinicians must decide whether the attributed benefits are clinically significant, considering the costs and potential risks of GH axis treatments. A limitation of this study is the small number of studies available of each GH axis drug class. PMID- 21265982 TI - The tumour-node-metastasis staging of prostate cancer in transurethral resection of the prostate chips requires revision. PMID- 21265983 TI - Topiramate and the risk of urolithiasis. PMID- 21265984 TI - High-intensity focused ultrasound as salvage therapy for patients with recurrent prostate cancer after external beam radiation, brachytherapy or proton therapy. AB - OBJECTIVE: To investigate the use of high-intensity focused ultrasound (HIFU) as a salvage therapy in patients with recurrence of localized prostate cancer after external beam radiation (EBRT), brachytherapy, or proton therapy. PATIENTS AND METHODS: We retrospectively reviewed the charts of all patients who had undergone salvage HIFU for biopsy-proven prostate cancer after primary radiation therapy. Patient characteristics and oncological outcomes were assessed. RESULTS: Records of 22 patients with a median (range) follow-up of 24 (5-80) months were reviewed. Patients were men with presumed organ-confined disease who had been treated with salvage HIFU following recurrent disease after EBRT (fourteen patients), brachytherapy (five patients: four with high-dose brachytherapy using In(192) ; and one with low-dose brachytherapy using Au(98) ) or proton therapy (three patients). The median (range) age at salvage HIFU was 65 (52-80) years, with a median (range) prostate-specific antigen (PSA) level before radiation therapy of 14.3 (5.7-118) ng/mL and a median (range) PSA level of 4.0 (1.2-30.1) ng/mL before HIFU. The median (range) period to HIFU after radiation therapy was 36 (4 96) months. The biochemical disease-free survival (bDFS) rate in all patients at 5 years was 52%. Rates of bDFS in low-, intermediate- and high-risk groups were 100%, 86%, and 14%, respectively. One of the twelve patients who received post HIFU prostate biopsy showed malignancy. Side effects included urethral stricture in four patients, grade I urinary incontinence in four patients, rectourethral fistula and epididymitis in one of each patient. CONCLUSION: Salvage HIFU is a promising treatment option for local recurrence after radiation therapy, with morbidity comparable with other forms of salvage treatment. PMID- 21265985 TI - Impact of adjuvant androgen deprivation therapy after radical prostatectomy on the survival of patients with pathological T3b prostate cancer. AB - OBJECTIVE: To determine the impact of adjuvant androgen deprivation therapy (ADT) on survival in patients with seminal vesicle invasion (pT3b) at radical prostatectomy. PATIENTS AND METHODS: We reviewed 12,115 patients who underwent radical prostatectomy between 1987 and 2002 to identify patients with pT3bN0 prostate cancer who received adjuvant ADT (n= 191). These patients were matched by clinical and pathological variables to a group of patients with pT3b prostate cancer who did not receive adjuvant ADT. Median postoperative follow-up was 10 years. Clinical endpoints included biochemical progression-free survival (BPFS), local recurrence-free survival (LRFS), systemic progression-free survival (SPFS), cancer-specific survival (CSS) and overall survival. RESULTS: Patients who underwent adjuvant ADT experienced improved 10-year BPFS (60% vs 16%, P < 0.001), LRFS (87% vs 76%, P= 0.002), SPFS (91% vs 78%, P= 0.004) and CSS (94% vs 87%, P= 0.037). Overall survival was not significantly different between groups (75% vs 69%, P= 0.12). Both luteinizing hormone-releasing hormone agonists (hazard ratio, 0.26; 95% CI, 0.15-0.46; P < 0.001) and bilateral orchiectomy (hazard ratio, 0.13; 95% CI, 0.06-0.31; P < 0.001) improved BPFS. When stratified by type of ADT (hormonal therapy vs orchiectomy), there was no difference in survival outcomes. CONCLUSIONS: Adjuvant ADT improves local, and systemic control after radical prostatectomy for pT3b prostate cancer. There is no difference in survival between patients receiving medical hormonal therapy vs patients undergoing orchiectomy. Given the lack of improvement in overall survival, continued investigation is needed to identify the cohort of pT3b patients at highest risk for cancer progression and therefore most likely to benefit from a multimodal treatment approach. PMID- 21265987 TI - Do not get lost in the spaces of the spermatic cord during subinguinal microsurgical varicocelectomy. PMID- 21265989 TI - Laparoscopic sacrocolpopexy. PMID- 21265993 TI - Risk stratification for benign prostatic hyperplasia (BPH) treatment. AB - * Benign prostatic hyperplasia (BPH) is a common cause of bothersome lower urinary tract symptoms. In the past, the aim of drug treatment was to relieve symptoms until surgery became necessary, predominantly using an alpha-blocker or a 5alpha-reductase inhibitor (5ARI) as monotherapy. * Together with improving knowledge about the pathogenesis of BPH, there is now strong evidence from large randomized trials that risk stratification and appropriate treatment with combined alpha-blocker/5ARI therapy can significantly reduce the risk of disease progression and avoid long-term complications such as acute urinary retention and surgery. * BPH will increasingly be managed in primary care in the future and, if new management strategies based on this evidence are to be implemented cost effectively, there is a need to introduce shared care between the primary and secondary care sectors to optimise use of resources and expertise. PMID- 21265994 TI - Economic evaluation of new targeted therapies for the first-line treatment of patients with metastatic renal cell carcinoma. AB - OBJECTIVE: * To assess the economic value of targeted therapies as first-line metastatic renal cell carcinoma (mRCC) treatment in the US and Sweden by indirect comparison of survival data. METHODS: * A Markov model simulated disease progression, adverse events and survival with sunitinib vs sorafenib in the US and bevacizumab plus interferon-alpha (IFN-alpha) in both countries. * Results, in life-years (LYs), progression-free LYs (PFLYs), quality-adjusted LYs (QALYs) gained and treatment costs (2008 USD) were obtained through deterministic and probabilistic analyses over the patient's lifetime. RESULTS: * Sunitinib was more effective and less costly than sorafenib (gains of 0.52 PFLYs, 0.16 LYs and 0.17 QALYs and savings/patient of $13,576 in the US) and bevacizumab plus IFN-alpha (gains of 0.19 PFLYs, 0.23 LYs and 0.16 QALYs in both countries and savings/patient of $67,798 and $47,264 in the US and Sweden, respectively). * Results were most influenced by hazard ratios for progression-free and overall survival and treatment costs, making results generalizable across other countries if relative costs were to fall within the ranges of those in the US and Sweden. CONCLUSION: * The present analyses suggest that first-line mRCC treatment with sunitinib is a cost-effective alternative to sorafenib and bevacizumab plus IFN alpha. PMID- 21265995 TI - Trade-offs between biomass growth and inducible biosynthesis of polyhydroxybutyrate in transgenic poplar. AB - Polyhydroxybutyrate (PHB) is a bioplastic that can be produced in transgenic plants by the coexpression of three bacterial genes for its biosynthesis. PHB yields from plants have been constrained by the negative impacts on plant health that result from diversion of resources into PHB production; thus, we employed an ecdysone analogue-based system for induced gene expression. We characterized 49 insertion events in hybrid transgenic poplar (Populus tremula x alba) that were produced using Agrobacterium transformation and studied two high-producing events in detail. Regenerated plants contained up to 1-2% PHB (dry weight) in leaves after 6-8 weeks of induction. Strong induction was observed with 1-10 mm Intrepid and limited direct toxicity observed. Confocal fluorescence microscopy was used to visualize PHB granules in chloroplasts after chemical treatment to reduce autofluorescence. A greenhouse study indicated that there were no negative consequences of PHB production on growth unless the PHB content exceeded 1% of leaf weight; at PHB levels above 1%, growth (height, diameter and total mass) decreased by 10%-34%. PMID- 21265996 TI - Plant production of anti-beta-glucan antibodies for immunotherapy of fungal infections in humans. AB - There is an increasing interest in the development of therapeutic antibodies (Ab) to improve the control of fungal pathogens, but none of these reagents is available for clinical use. We previously described a murine monoclonal antibody (mAb 2G8) targeting beta-glucan, a cell wall polysaccharide common to most pathogenic fungi, which conferred significant protection against Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans in animal models. Transfer of this wide-spectrum, antifungal mAb into the clinical setting would allow the control of most frequent fungal infections in many different categories of patients. To this aim, two chimeric mouse-human Ab derivatives from mAb 2G8, in the format of complete IgG or scFv-Fc, were generated, transiently expressed in Nicotiana benthamiana plants and purified from leaves with high yields (approximately 50 mg Ab/kg of plant tissues). Both recombinant Abs fully retained the beta-glucan-binding specificity and the antifungal activities of the cognate murine mAb against C. albicans. In fact, they recognized preferentially beta1,3 linked glucan molecules present at the fungal cell surface and directly inhibited the growth of C. albicans and its adhesion to human epithelial cells in vitro. In addition, both the IgG and the scFv-Fc promoted C. albicans killing by isolated, human polymorphonuclear neutrophils in ex vivo assays and conferred significant antifungal protection in animal models of systemic or vulvovaginal C. albicans infection. These recombinant Abs represent valuable molecules for developing novel, plant-derived immunotherapeutics against candidiasis and, possibly, other fungal diseases. PMID- 21265997 TI - Temporal and spatial control of transgene expression using a heat-inducible promoter in transgenic wheat. AB - Constitutive promoters are widely used to functionally characterise plant genes in transgenic plants, but their lack of specificity and poor control over protein expression can be a major disadvantage. On the other hand, promoters that provide precise regulation of temporal or spatial transgene expression facilitate such studies by targeting over-expression or knockdown of target genes to specific tissues and/or at particular developmental stages. Here, we used the uidA (beta glucuronidase, GUS) reporter gene to demonstrate that the barley Hvhsp17 gene promoter can be induced by heat treatment of 38-40 degrees C for 1-2 h in transgenic wheat. The GUS enzyme was expressed only in those tissues directly exposed to heat and not in neighbouring leaf tissues. The induction of HSP::GUS was demonstrated in all organs and tissues tested, but expression in older tissues was lower. Generally, proximal root sections showed less GUS activity than in root tips. This heat-inducible promoter provides the ability to investigate the function of candidate genes by overexpression or by down regulation of target gene expression (for example by RNAi) in selected tissues or developmental stages of a transgenic plant, limited only by the ability to apply a heat shock to the selected tissues. It also allows the investigation of genes that would be lethal or reduce fertility if expressed constitutively. PMID- 21265998 TI - Virus-induced gene silencing can persist for more than 2 years and also be transmitted to progeny seedlings in Nicotiana benthamiana and tomato. AB - Virus-induced gene silencing (VIGS) is one of the commonly used RNA silencing methods in plant functional genomics. It is widely known that VIGS can occur for about 3 weeks. A few reports show that duration of VIGS can be prolonged for up to 3 months. Increasing the duration of endogenous gene silencing and developing a method for nonintegration-based persistent VIGS in progeny seedlings will widen the application of VIGS. We used three marker genes that provoke visible phenotypes in plants upon silencing to study persistence and transmittance of VIGS to progeny in two plant species, Nicotiana benthamiana and tomato. We used a Tobacco rattle virus (TRV)-based VIGS vector and showed that the duration of gene silencing by VIGS can occur for more than 2 years and that TRV is necessary for longer duration VIGS. Also, inoculation of TRV-VIGS constructs by both Agrodrench and leaf infiltration greatly increased the effectiveness and duration of VIGS. Our results also showed transmittance of VIGS to progeny seedlings via seeds. A longer silencing period will facilitate detailed study of target genes in plant development and stress tolerance. Further, the transmittance of VIGS to progeny will be useful in studying the effect of gene silencing in young seedlings. Our results provide a new dimension for the application of VIGS in plants. PMID- 21265999 TI - Maternal obesity and labour complications following induction of labour in prolonged pregnancy. AB - OBJECTIVE: To investigate the effect of maternal obesity on mode of delivery following induction of labour (IOL) for prolonged pregnancy and subsequent intrapartum and neonatal complications. DESIGN: Retrospective (historical) cohort study. SETTING: Liverpool Women's Hospital NHS Foundation Trust, UK. POPULATION: A total of 29, 224 women with singleton pregnancies between 2004 and 2008 of whom 3076 had a prolonged pregnancy (defined as >=290 days or 41(+3) weeks of gestation) and received IOL. METHODS: Kruskal-Wallis test, chi-square test and multivariable logistic regression. MAIN OUTCOME MEASURES: Mode of delivery and risk of delivery and neonatal complications in obese verses non-obese women following IOL. RESULTS: Obese women had a significantly higher rate of IOL ending in caesarean section compared with women of normal weight following IOL (38.7% versus 23.8% primiparous; 9.9% versus 7.9% multiparous women, respectively); however, length of labour, incidence of postpartum haemorrhage and third-degree tear, rate of low cord blood pH, low Apgar scores and shoulder dystocia were similar in all body mass index categories. Complications included a higher incidence of fetal macrosomia and second-degree, but not third-degree, tear in primiparous women. CONCLUSIONS: Higher maternal body mass index at booking is associated with an increased risk of prolonged pregnancy and increased rate of IOL. Despite this, more than 60% of obese primiparous and 90% of multiparous women with prolonged pregnancies who were induced achieved vaginal delivery and labour complications in the obese women with prolonged pregnancies were largely comparable to those of normal weight women with prolonged pregnancies. Our data suggest that IOL for prolonged pregnancy in obese women is a reasonable and safe management option. PMID- 21266000 TI - Because we can: clashes of perspective over researcher obligation in the failed PrEP trials. AB - This article examines the relationship between bioethics and the therapeutic standards in HIV prevention research in the developing world, focusing on the closure of the pre-exposure prophylaxis (PrEP) trials in the early 2000s. I situate the PrEP trials in the historical context of the vertical transmission debates of the 1990s, where there was protracted debate over the use of placebos despite the existence of a proven intervention. I then discuss the dramatic improvement in the clinical management of HIV and the treatment access movement, and consider how these contexts have influenced research practice. I argue that as HIV prevention trials oblige researchers to observe the rate at which vulnerable people under their care acquire HIV, there is an obligation to provide antiretroviral treatment to seroconverters and other health care benefits that fall within the scope of researchers' entrustment, both to avoid exploitation and to enact reciprocal justice. I argue against propositions that the obligations to provide specific benefits are vague, fall only upon researchers and sponsors, and create injustices by privileging the few over the many. Finally, I contend that the realisation of a broader standard of care in HIV prevention research broadens the role of research from being a simple tool to produce knowledge to a complex intervention that can play a part in the reduction of health disparities. PMID- 21266002 TI - Reflection on family consent: based on a pregnant death in a Beijing hospital. AB - The 'family consent' process has been placed at the centre of Chinese clinical practice. Although there has been critical analysis of how the process functions in relation to the autonomy and rights of patients, there has been little examination of the perceptions and attitude of patients and their families and the medical professionals, in relation to moral dilemmas that arise in real cases in the bioethical discourse. When faced with a consent form in an emergency situation, the family member's capacity to act is reduced, as he/she becomes enmeshed in the hospital structure of tacit, socially-imposed rules. In a questionnaires based on a real death case in 2008, 70.9% of the surveyed medical professionals (n = 3,665) disagreed with performing surgery without the consent of the family even if the patient's life was in danger, while 36.6% of the surveyed patients (n = 1,198) hold the same position. This work demonstrates the weakness of the family consent process as a safeguard of patient's autonomy. Finally, I argue that saving the patient's life should be the overriding obligation rather than the respect for the surrogate's autonomous choice at such a decisive moment. PMID- 21266001 TI - The adequacy of informed consent forms in genetic research in Oman: a pilot study. AB - Genetic research presents ethical challenges to the achievement of valid informed consent, especially in developing countries with areas of low literacy. During the last several years, a number of genetic research proposals involving Omani nationals were submitted to the Department of Research and Studies, Ministry of Health, Oman. The objective of this paper is to report on the results of an internal quality assurance initiative to determine the extent of the information being provided in genetic research informed consent forms. In order to achieve this, we developed checklists to assess the inclusion of basic elements of informed consent as well as elements related to the collection and future storage of biological samples. Three of the authors independently evaluated and reached consensus on seven informed consent forms that were available for review. Of the seven consent forms, four had less than half of the basic elements of informed consent. None contained any information regarding whether genetic information relevant to health would be disclosed, whether participants may share in commercial products, the extent of confidentiality protections, and the inclusion of additional consent forms for future storage and use of tissue samples. Information regarding genetic risks and withdrawal of samples were rarely mentioned (1/7), whereas limits on future use of samples were mentioned in 3 of 7 consent forms. Ultimately, consent forms are not likely to address key issues regarding genetic research that have been recommended by research ethics guidelines. We recommend enhanced educational efforts to increase awareness, on the part of researchers, of information that should be included in consent forms. PMID- 21266003 TI - Does intrathecal morphine sulfate provide preemptive analgesia for patients undergoing stapled hemorrhoidopexy? AB - OBJECTIVE: Surgical excision of hemorrhoids is characterized by a prolonged and painful postoperative course. This double-blind, randomized, prospective, controlled trial was conducted to determine if morphine sulfate provides additional pain relief after stapled hemorrhoidopexy when added to a standard lidocaine spinal anesthetic. It was hypothesized that the addition of morphine sulfate to a spinal anesthetic would decrease postoperative pain. INTERVENTIONS: Thirty-four patients were randomized prospectively to receive a spinal block with either lidocaine or lidocaine plus morphine sulfate. Patients were followed postoperatively for 42 days to record Numeric Pain Scale (NPS) values and to record analgesic use. Patients also filled out a Short Form 36 (SF-36) Health Survey Questionnaire preoperatively and at days 3, 14, and 28 after their operation to assess physical and mental well-being. Longitudinal mixed models were used to determine whether there was a difference in maximum pain, average pain, narcotic analgesic use, and physical or mental well-being over time. RESULTS: No group differences were found in maximum or average NPS, analgesic use, mental well-being, or time to complete pain relief. There was a four-point difference in mean scores for physical well-being, favoring the lidocaine plus morphine group. CONCLUSIONS: This study provides evidence that intrathecal morphine sulfate does not significantly alter postoperative pain, narcotic use, or well-being when used as preemptive analgesia for patients undergoing stapled hemorrhoidopexy. PMID- 21266004 TI - Reduced opioid consumption and improved early rehabilitation with local and intraarticular cocktail analgesic injection in total hip arthroplasty: a randomized controlled clinical trial. AB - OBJECTIVE: Postoperative pain after total hip arthroplasty (THA) is not well tolerated. We assessed postoperative pain relief and the need for opioid use after using a cocktail of local and intraarticular analgesic injection (LIA) after THA. METHODS: Eighty patients undergoing THA under spinal anesthesia were randomly assigned to receive either LIA or placebo. The LIA was composed of 5 mg morphine, 30 mg bupivacaine (15 mg/1.5 mL), 1 mL betamethasone, and 0.5 mL epinephrine (1:1,000) intraoperatively. We compared three outcomes total morphine consumption, visual analog scale (VAS) at rest and during activity, and hip flexion angle while standing. RESULTS: When compared with placebo, opioid consumption was significantly reduced in the trial group, as well as VAS at rest and during mobilization. Earlier rehabilitation and better range of motion (ROM) were achieved in the trial group. There were no significant differences in side effects or postoperative wound healing between groups. CONCLUSION: In patients undergoing THA, LIA may reduce postoperative systemic opioid use and offer better pain control and earlier rehabilitation, without observable risks. PMID- 21266005 TI - Chronic pain and psychiatric morbidity: a comparison between patients attending specialist orthopedics clinic and multidisciplinary pain clinic. AB - OBJECTIVE: The objective of this study was to examine the associations between chronic pain and psychiatric morbidity using interview-based assessments of psychiatric symptomatology. We compared the prevalence of common mental disorder (CMD; consistent with neurotic and somatic symptoms, fatigue, and negative affect), depression, and anxiety disorder(s), and associated factors with these psychiatric illnesses among Chinese patients with chronic pain attending specialist orthopedics clinic and multidisciplinary pain clinic. METHODS: A total of 370 patients with chronic pain were recruited from an Orthopedics Clinic (N=185) and a Pain Clinic (N=185) in Hong Kong. Psychiatric morbidity was assessed using the Revised Clinical Interview Schedule. Individual scores for neurotic symptoms and neurotic disorders (including depression and four types of anxiety disorders) were also calculated. RESULTS: The reported lifetime prevalence rates of CMD were 35.3% and 75.3% for the Orthopedics and Pain Clinic samples, respectively. Rates of depression and anxiety disorders in the Pain Clinic (57.1% and 23.2%, respectively) were significantly higher than those in the Orthopedics sample (20.2% and 5.9%, respectively) (all P<0.001). Pain characteristics including number of pain sites, pain duration, pain intensity, and pain interference were all significantly associated with psychiatric morbidity after controlling for sociodemographic factors. Pain duration and litigation/compensation status consistently predicted concurrent pain intensity and disability. CONCLUSIONS: Chronic pain is associated with psychiatric morbidity. The higher rate of depression than anxiety disorder(s) among patients with chronic pain is consistent with previous studies that have found depression to be highly prevalent in chronic pain. PMID- 21266006 TI - What is the source of chronic low back pain and does age play a role? AB - OBJECTIVE: The objective of this study was to estimate the prevalence, mean age, and association of prevalence and age of lumbar internal disc disruption (IDD), facet joint pain (FJP), sacroiliac joint pain (SIJP), spinal and pelvic insufficiency fractures, interspinous ligament injury/Baastrup's Disease, and soft tissue irritation by fusion hardware. DESIGN: The study's design was a retrospective chart review. SETTING: The study was set in an academic spine center. PATIENTS: A total of 378 cases from 358 patients were reviewed of which 170 cases from 156 patients who underwent diagnostic procedures were included. INTERVENTIONS: Discography, dual diagnostic facet joint blocks, intra-articular sacroiliac joint injections, anesthetic injections of painful interspinous ligaments/opposing spinous processes/posterior fusion hardware, or percutaneous augmentation were performed. OUTCOME MEASURES: Prevalence and age were analyzed for each diagnosis group. METHODS: Patients with recalcitrant low back pain underwent diagnostic procedures based on their clinical presentation until the pain source was identified. RESULTS: The prevalence of internal disc disruption, facet joint pain and sacroiliac joint pain was 42%, 31%, and 18%, respectively. Patients with internal disc disruption were significantly younger than those with facet joint pain or sacroiliac joint pain. Increased age was associated with a decreased probability of internal disc disruption and increased probabilities of facet joint pain and sacroiliac joint pain as the source of low back pain until approximately age 70. CONCLUSION: Our data confirm the intervertebral disc as the most common etiology of chronic low back pain in adults. Based on our sample, the younger the patient, the more likely low back pain is discogenic in origin. Facetogenic or sacroiliac joint pain is more likely in older patients. PMID- 21266007 TI - Central post stroke pain: clinical, MRI, and SPECT correlation. AB - OBJECTIVE: The objective of this study was to report clinical spectrum of central post stroke pain (CPSP) and correlate these with magnetic resonance imaging (MRI) and single photon emission computed tomography (SPECT) findings. DESIGN: The study was designed as a prospective study. SETTING: The study was set in a tertiary care teaching hospital. SUBJECT AND METHOD: Twenty-three consecutive CPSP patients were included and their severity of pain, sensory threshold, allodynia, hyperalgesia, and temporal summation were assessed by quantitative sensory testing (QST). Cranial MRI and (99)Tc ethylene cystine dimmer SPECT findings correlated with QST. RESULTS: The duration of CPSP was 5 months (0.25 108). Allodynia was present in 12 patients, punctuate hyperalgesia in 11, and temporal summation in 12. SPECT was abnormal on visual analysis in 17 patients; hypoperfusion in corresponding thalamus in nine, and parietal cortex in 11 patients. Semiquantitative analysis revealed hyperperfusion of thalamus in four and parietal cortex in five patients. MRI revealed infarction in 14 and hematoma in nine patients. The QST findings were similar in thalamic and extrathalamic CPSP. The MRI and SPECT findings were also not different in CPSP patients with and without allodynia. CONCLUSION: The QST findings in patients with CPSP were similar in patients with thalami and extrathalamic lesions. SPECT and MRI findings were also not different in CPSP patients with and without allodynia. PMID- 21266008 TI - Correlations between fibromyalgia symptom and function domains and patient global impression of change: a pooled analysis of three randomized, placebo-controlled trials of pregabalin. AB - OBJECTIVE: The objective of the study was to conduct an analysis of pooled data from pregabalin fibromyalgia clinical trials to determine which fibromyalgia symptom and function domains drive patient perception of improvement. DESIGN: Data from three double-blind, placebo-controlled trials of pregabalin in fibromyalgia patients were pooled for this analysis. Changes in independent variables, including the Medical Outcomes Study 36-item Short-Form Health Survey, Medical Outcomes Study-Sleep Scale, sleep quality score from the daily sleep diary, pain score from the daily pain diary, Fibromyalgia Impact Questionnaire, and Multidimensional Assessment of Fatigue were analyzed as predictors of outcome on the dependent variable, Patient Global Impression of Change (PGIC). Correlation analysis assessed relationships between the independent variables and PGIC. Cluster analysis identified dependencies among variables, and a shrinkage and selection method and stepwise logistic regression determined rank order of variables. RESULTS: Improvement in PGIC at endpoint showed highest correlation with pain improvement, fatigue, sleep, and work and physical function (0.4 < r < 0.6). Cluster analysis identified three main clusters of symptoms at endpoint: mood (anxiety and depression), pain and sleep, and function and fatigue. Pain was ranked as the most important outcome explaining variability in PGIC, followed by fatigue and sleep. CONCLUSIONS: Pain, fatigue, and sleep associate most strongly with improvement in PGIC. Physical- and work-related function also correlated with patients' overall assessment of improvement. These domains and their respective outcome measures can be used to improve assessment of patients' response to treatment. PMID- 21266009 TI - Surgical debridement with VERSAJET: an analysis of bacteria load of the wound bed pre- and post-treatment and skin graft taken. A preliminary pilot study. AB - Surgical debridement, which is used for the removal of necrotic tissue from a wound, is becoming more and more important in the treatment of skin injuries. VERSAJET (VERSAJETTM, Versajet Hydrosurgery System, Smith and Nephew, Hull, UK) is one of the techniques used for wound debridement. Medical literature does not present either analytical or comparative data correlating the bacterial load with the VERSAJET treatment. For this reason, we have decided to carry out a study to evaluate the level of bacterial contamination before and after the surgical debridement treatment with VERSAJET and, in connection with this, the correlation between the bacterial load and the successful healing of the skin graft. We took a total of 100 bacteriological swabs, 50 before and 50 from 27 selected patients after the treatment with VERSAJET, with which the wound bed was prepared to receive the skin graft or Integra graft in order to acquire data about the level of bacterial contamination. After analysing all those data we can assume that reducing the bacterial load is not the only variable which the successful healing of the skin graft depends on. In conclusion, there is still many data to analyse and study in order to better understand the qualitative and quantitative presence of bacteria and the success of this future surgical procedure. We remind that the performance of this study was not sponsored by any company. PMID- 21266010 TI - The 'Step by Step' Diabetic Foot Project in Tanzania: a model for improving patient outcomes in less-developed countries. AB - Foot complications cause substantial morbidity in Tanzania, where 70% of leg amputations occur in diabetic patients. The Step by Step Foot Project was initiated to train healthcare personnel in diabetic foot management, facilitate transfer of knowledge and expertise, and improve patient education. The project comprised a 3-day basic course with an interim period 1-year of for screening, followed by an advanced course and evaluation of activities. Fifteen centres from across Tanzania participated during 2004-2006 and 12 during 2004-2007. Of 11,714 patients screened in 2005, 4335 (37%) had high-risk feet. Of 461 (11%) with ulcers, 45 (9.8%) underwent major amputation. Of 3860 patients screened during 2006-2007, there was a significant increase in the proportion with ulcers and amputations compared with 2005 (P < 0.001), likely a result of enhanced case finding. During 2005-2008, there was a fall in the incidence of foot ulcers in patient referrals to the main tertiary care centre in Dar es Salaam and a parallel fall in amputation among these referrals. In conclusion, the Step by Step Foot Project in Tanzania improved foot ulcer management for persons with diabetes and resulted in permanent, operational foot clinics across the country. This programme is an effective model for improving outcomes in other less developed countries. PMID- 21266011 TI - Effects of carbon black nanoparticles on elastase-induced emphysematous lung injury in mice. AB - Although adverse health effects of particulate matter with a diameter of <100 nm (nanoparticles) have been proposed, biological evidence supporting their promotion of the inflammatory lung response in vivo is limited. This study investigated the impact of pulmonary exposure to carbon black nanoparticles (CBNP) on emphysematous lung injury induced by porcine pancreatic elastase (PPE) in mice. Vehicle, two sizes (14 and 56 nm) of CBNP (50 MUg/body: 4 mg/kg), PPE (0.03 U/body: 1 U/kg) or PPE + CBNP was administered intratracheally; thereafter, parameters of inflammatory lung changes were evaluated at several time-points. CBNP of 14 nm significantly induced acute lung inflammation in non-elicited subjects and aggravated PPE-elicited airway neutrophilic inflammation at an early stage (day 1), which was concomitant with the enhanced lung expression of pro inflammatory cytokines such as interleukin-1beta and chemokine such as keratinocyte-derived chemoattractant. Further, 14-nm CBNP exaggerated emphysematous lung structural changes at a delayed stage (day 14). On the other hand, 56-nm CBNP induced lung inflammation but did not influence PPE-elicited pathophysiology in the lung. Taken together, CBNP at an optimal size and dose can exacerbate PPE-induced pulmonary inflammation and emphysema. This enhancement may be mediated, at least partly, via the increased local expression of pro inflammatory molecules. PMID- 21266012 TI - In vivo antigenotoxicity of baccharin, an important constituent of Baccharis dracunculifolia DC (Asteraceae). AB - Baccharin (3-prenyl-4-(dihydrocinnamoyloxy)cinnamic acid) is an important chemical compound isolated from the aerial parts of Baccharis dracunculifolia DC (Asteraceae), a native plant of South America, and the most important plant source of Brazilian green propolis. The present study was designed to investigate the ability of baccharin to modulate the genotoxic effects induced by doxorubicin and methyl methanesulphonate in male Swiss mice using the micronucleus and comet assays, respectively. The different doses of baccharin [0.12, 0.24 and 0.48 mg/kg body-weight (b.w.)] were administered simultaneously to doxorubicin (micronucleus test; 15 mg/kg b.w.) and to methyl methanesulphonate (comet assay; 40 mg/kg b.w.). The results showed a significant decrease in the frequency of micronucleated polychromatic erythrocytes in animals treated with baccharin and doxorubicin compared to animals that received only doxorubicin. This reduction ranged from 39.8% to 50.7% in the micronucleus test. The extent of DNA damage in liver cells was significantly lower in animals treated with different concentrations of baccharin combined with methyl methanesulphonate in comparison with the damage observed for animals treated only with methyl methanesulphonate. These differences resulted in a significant reduction in the extent of DNA damage, which ranged from 47.8% to 60.6%. PMID- 21266014 TI - Antimicrobial beta-peptides and alpha-peptoids. AB - The field of drug discovery and development has seen tremendous activity over the past decade to better tackle the increasing occurrence of drug-resistant bacterial infections and to alleviate some of the pressure we put on the last resort drugs on the market. One of the new and promising drug candidates is derived from naturally occurring antimicrobial peptides. However, despite promising results in early-stage clinical trials, these molecules have faced some difficulties securing FDA approval, which can be linked to their poor metabolic stability. Hence, mimetics of these antimicrobial peptides have been suggested as new templates for antibacterial compound design, because these mimetics are resistant against degradation by proteases. This review will discuss the structural features of two different types of mimetics, beta-peptides and alpha peptoids, in relation to their antibacterial activity and conclude on their potential as new candidates for bacterial intervention. PMID- 21266015 TI - From Zn to Mn: the study of novel manganese-binding groups in the search for new drugs against tuberculosis. AB - In most eubacteria, apicomplexans, and most plants, including the causal agents for diseases such as malaria, leprosy, and tuberculosis, the methylerythritol phosphate pathway is the route for the biosynthesis of the C(5) precursors to the essential isoprenoid class of compounds. Owing to their absence in humans, the enzymes of the methylerythritol phosphate pathway have become attractive targets for drug discovery. This work investigates a new class of inhibitors against the second enzyme of the pathway, 1-deoxy-D-xylulose 5-phosphate reductoisomerase. Inhibition of this enzyme may involve the chelation of a crucial active site Mn ion, and the metal-chelating moieties studied here have previously been shown to be successful in application to the zinc-dependent metalloproteinases. Quantum mechanics and docking calculations presented in this work suggest the transferability of these metal-chelating compounds to Mn-containing 1-deoxy-D xylulose 5-phosphate reductoisomerase enzyme, as a promising starting point to the development of potent inhibitors. PMID- 21266017 TI - Analysis of HIV protease binding pockets based on 3D shape and electrostatic potential descriptors. AB - Using a shape analysis technique, a Dataset of 79 (19 wild-type and 60 mutated) HIV-1 protease crystal structures was analyzed for the shape changes in their binding pockets. The structures are reported with different bound inhibitors and consist of a variety of mutations. Several 3D-shape descriptors based on the volumetric shape function are calculated, in addition to the electrostatic potential (EP)-based descriptors. A cluster analysis is performed using the calculated descriptors of the binding pocket of the proteins to investigate the effect of mutations or bound inhibitors on the shape of the binding pocket of proteins. We observed that mutations and/or bound ligands influence the 3D shape of the binding pocket of these HIV proteases. This study shows that the shape changes in the binding pocket caused by mutations or bound ligands can be quantitatively captured using 3D shape- and EP-based descriptors. PMID- 21266016 TI - A D-peptide analog of the second extracellular loop of claudin-3 and -4 leads to mislocalized claudin and cellular apoptosis in mammary epithelial cells. AB - Claudins are cell adhesion proteins thought to mediate cell-cell contacts at the tight junction. Although a major role of claudins is to control paracellular diffusion, increasing evidence suggests that they may also function in tumor progression. To examine the role of the second extracellular loop in cell adhesion, a small peptide was designed, which mimics a conserved sequence, DFYNP, within specific 'classic' claudin subtypes. Using fluorescent indicators with mammary epithelial cells, treatment with both the L- and D-forms of this peptide showed mislocalization of claudin-4 and claudin-3 and activation of caspase-8 and caspase-3, indicating apoptosis. To test specificity, peptides were made both with various end-groups and with glycine substitutions at each of the five residues. Changing end-groups did not influence the activity of the peptide. Amino acid substitutions at F147, Y148, N149, or P150, however, prevented peptide activity. A fluorescent-labeled peptide was shown to associate with the tight junction at 4 degrees C and cause apoptosis when the cultures were warmed to 37 degrees C. In conclusion, both the D- and L-forms of a small peptide that mimics a sequence in the second extracellular loop of claudins can target and disrupt claudin proteins in an epithelial monolayer and initiate apoptosis. PMID- 21266018 TI - A novel series of 2,5-disubstituted 1,3,4-oxadiazoles: synthesis and SAR study for their anticonvulsant activity. AB - In search for a better anticonvulsant drug and the importance of semicarbazones and 2,5-disubstituted 1,3,4-oxadiazoles as anticonvulsant pharmacophore, a series of novel substituted semicarbazones were designed, synthesized, and evaluated for their anticonvulsant activity. The chemical structures of the synthesized molecules were confirmed by elemental and spectral (IR, (1) H NMR, (13) C NMR and MS) analysis. The anticonvulsant activities of the compounds were investigated using maximal electroshock seizure and subcutaneous pentylenetetrazole (scPTZ) models. Efforts were also made to establish structure-activity relationships among synthesized compounds. The results of the present study validated that the pharmacophore model with four binding sites is essential for anticonvulsant activity. PMID- 21266019 TI - Haemoglobin (Hb) G-Philadelphia, Hb Stanleyville-II, Hb G-Norfolk, Hb Matsue-Oki and Hb Mizushi can form a panel of alpha-chain variants that overlap in their phenotype: the novel use of StyI to screen for Hb G-Philadelphia. AB - INTRODUCTION: Haemoglobin (Hb) G-Philadelphia mutation is a common alpha-globin chain variant [alpha68(E17)Asn > Lys]. Combined high performance liquid chromatography (HPLC) and isoelectric focusing (IEF) can be used in a presumptive diagnosis of Hb G-Philadelphia, but there are other alpha-chain variants with a similar phenotype that cannot be excluded. Our aim was to develop a novel StyI restriction enzyme assay to diagnose the common Hb G-Philadelphia mutation and to identify any other variants with a similar phenotype by DNA sequencing. METHODS: Thirty-one cases given a presumptive diagnosis as Hb G-Philadelphia by HPLC and IEF were subjected to DNA analysis by restriction enzyme digestion using StyI. Negative cases were then subjected to DNA sequencing. RESULTS: Twenty-two cases (78.6%) of 28 cases amplified were tested positive for Hb G-Philadelphia by StyI restriction digestion. Sequencing of the six negative cases revealed two cases of Hb G-Philadelphia with C->A mutation in codon 68 in alpha2 globin gene, plus one case each of Hb G-Norfolk Hb Stanleyville-II, Hb Matsue-Oki and Hb Mizushi. CONCLUSION: A novel StyI restriction enzyme can be used to confirm the commonest type of Hb G-Philadelphia. DNA sequencing identified four other alpha-chain variants with a similar HPLC and IEF phenotype. PMID- 21266020 TI - Three novel alternative splicing mutations in BCR-ABL1 detected in CML patients with resistance to kinase inhibitors. AB - INTRODUCTION: Multiple types of mutations in the BCR-ABL1 kinase domain have been reported. We previously reported a common alternatively spliced BCR-ABL mRNA with a 35-nucleotide insertion (35INS). We report three novel alternative splicing mutants expressed as the dominant transcripts in patient with chronic myelogenous leukemia and resistance to kinase inhibitors. METHODS: We screened RNA from more than 200 patients with resistance to more than one of the three kinase inhibitors for ABL1 kinase domain mutations by direct sequencing. RESULTS: We found three not previously described splice mutants. All three showed >90% mutant transcript. The first resulted from the insertion of 79 nucleotides into the ABL1 exon 8-9 junction. The inserted sequence contained a sequence from regions of intron 8, located 120 bp apart: the 35-nucleotide sequence previously described, and an additional 44-nucleotide segment downstream from 35INS. The combined 79 nucleotide insertion splice mutant showed the same protein change as 35INS (p C475YfsX11). The second splice mutation comprised an 84-nucleotide sequence from intron 7 inserted into the ABL1 exon7-8 junction, also causing a frameshift and protein truncation (p A424EfsX18). The third splice derived from a 231-nucleotide sequence from intron 4 retained in the ABL1 exon 4-5 junction adding 40 intron encoded amino acids and leading to a frameshift and early termination (p E275LfsX41). CONCLUSION: These findings, when combined with the data on 35INS, support the concept that loss of the C-terminus of BCR-ABL1 is associated with significant resistance to kinase inhibitors; this mechanism appears to be a major source of resistance to kinase inhibitors. PMID- 21266021 TI - Performance evaluation of the Celltac F haematology analyser. AB - INTRODUCTION: Performance of the Celltac F haematology analyser (MEK-8222) which provides 22 parameters, including a 5-part differential, was compared with the Sysmex XE-2100. METHODS: 242 EDTA samples were investigated. Differential results from both instruments were compared with the reference microscopic count. Flagging performance was compared with cell morphology seen in the blood films. RESULTS: Precision met or exceeded manufacturer's specifications, carryover was minimal (<=1.37%) and linearity was excellent (R >= 0.99). Results were stable for at least 8 h at room temperature and for 24 h at 4 degrees C. Comparisons were excellent for white blood cells, red cell count, Hb, HCT and platelets (R >= 0.98). All other red cell and platelet parameters showed good correlation with the XE-2100 (R >= 0.93) except for mean cell haemoglobin concentration. The differential was comparable to the XE-2100 for neutrophils, lymphocytes and eosinophils and acceptable for monocytes. Correlation of automated differentials with manual reference counts and the efficiency of flagging of blasts, immature granulocytes and platelet clumps were similar for both instruments. Celltac F demonstrated better efficiency for atypical lymphocyte and platelet clumps. CONCLUSION: The Celltac F shows broadly comparable analytical performance to the XE-2100 for the parameters assessed. The Celltac F is recommendable for medium sized laboratories or as a back-up instrument in larger laboratories. PMID- 21266022 TI - Safety, efficacy, predictability and stability of laser in situ keratomileusis (LASIK) with a 1000-Hz scanning spot excimer laser. AB - PURPOSE: To evaluate the safety, efficacy, predictability and stability of laser in situ keratomileusis (LASIK) with a 1000-Hz scanning spot excimer laser (Concept System 1000; WaveLight GmbH, Erlangen, Germany). METHODS: LASIK was performed on twenty eyes with myopia or myopic astigmatism (mean spherical equivalent refraction: -3.97+/-1.72 dioptres (D); mean cylinder: -0.84+/-0.77 D) using a microkeratome for flap creation and the Concept System 1000 for photoablation. Patients were examined preoperatively as well as 1, 3 and 6 months after the treatment. Manifest sphere and cylinder, uncorrected (UCDVA) and best corrected (BCDVA) distance visual acuity, corneal topography and pachymetry were analysed. RESULTS: We observed no adverse events that might have been associated with the use of a repetition rate of 1000 Hz. All eyes maintained or had improved BCDVA at 6 months after treatment when compared to preoperative values. Six months after LASIK, UCDVA was 20/20 or better in 85% and 20/25 or better in 100% of the eyes. The spherical equivalent refraction was within +/-0.50 D in 95% of the eyes at 6 months after surgery. The refraction stayed stable over time; 95% of the eyes changed<0.5 D postoperatively. CONCLUSION: LASIK with the prototype 1000-Hz excimer laser was safe, efficient and predictable. The postoperative refraction was stable over time. There were no specific clinical side-effects that might be associated with the use of such a high repetition rate. PMID- 21266023 TI - 54th annual meeting of the society for research into hydrocephalus and spina bifida vancouver, Canada. 7-10 july 2010. Abstracts. PMID- 21266024 TI - Dimeticone 4% liquid gel found to kill all lice and eggs with a single 15 minute application. AB - BACKGROUND: Dimeticone 4% lotion is an effective and widely accepted treatment for head louse infestation. However, it is a highly mobile fluid that some people find difficult to apply and is mainly left on the hair for 8 hours or overnight. User preference is for a more manageable and viscous product that can be used with a short application time. FINDINGS: This proof of concept study in 41 people investigated dimeticone 4% liquid gel, a product that is easier to apply than the lotion, applied for 15 minutes on two occasions a week apart. We found that head lice were eliminated from all participants following the first application of product. We did not find lice of any stage on any participant during four post treatment assessments and particularly, unlike other treatments, no young nymphs on days 1 and 6 prior to the second treatment, indicating ovicidal as well as pediculicidal activity. CONCLUSIONS: Dimeticone 4% liquid gel has demonstrated efficacy greater than other similar products and the evidence obtained indicates elimination of head louse infestation with a single 15 minute application. TRIAL REGISTRATION: Current Controlled Trials ISRCTN59227204. PMID- 21266025 TI - Measurement of ventilation and cardiac related impedance changes with electrical impedance tomography. AB - INTRODUCTION: Electrical impedance tomography (EIT) has been shown to be able to distinguish both ventilation and perfusion. With adequate filtering the regional distributions of both ventilation and perfusion and their relationships could be analysed. Several methods of separation have been suggested previously, including breath holding, electrocardiograph (ECG) gating and frequency filtering. Many of these methods require interventions inappropriate in a clinical setting. This study therefore aims to extend a previously reported frequency filtering technique to a spontaneously breathing cohort and assess the regional distributions of ventilation and perfusion and their relationship. METHODS: Ten healthy adults were measured during a breath hold and while spontaneously breathing in supine, prone, left and right lateral positions. EIT data were analysed with and without filtering at the respiratory and heart rate. Profiles of ventilation, perfusion and ventilation/perfusion related impedance change were generated and regions of ventilation and pulmonary perfusion were identified and compared. RESULTS: Analysis of the filtration technique demonstrated its ability to separate the ventilation and cardiac related impedance signals without negative impact. It was, therefore, deemed suitable for use in this spontaneously breathing cohort.Regional distributions of ventilation, perfusion and the combined DeltaZV/DeltaZQ were calculated along the gravity axis and anatomically in each position. Along the gravity axis, gravity dependence was seen only in the lateral positions in ventilation distribution, with the dependent lung being better ventilated regardless of position. This gravity dependence was not seen in perfusion.When looking anatomically, differences were only apparent in the lateral positions. The lateral position ventilation distributions showed a difference in the left lung, with the right lung maintaining a similar distribution in both lateral positions. This is likely caused by more pronounced anatomical changes in the left lung when changing positions. CONCLUSIONS: The modified filtration technique was demonstrated to be effective in separating the ventilation and perfusion signals in spontaneously breathing subjects. Gravity dependence was seen only in ventilation distribution in the left lung in lateral positions, suggesting gravity based shifts in anatomical structures. Gravity dependence was not seen in any perfusion distributions. PMID- 21266026 TI - Structural insights into the membrane-extracted dimeric form of the ATPase TraB from the Escherichia coli pKM101 conjugation system. AB - BACKGROUND: Type IV secretion (T4S) systems are involved in secretion of virulence factors such as toxins or transforming molecules, or bacterial conjugation. T4S systems are composed of 12 proteins named VirB1-B11 and VirD4. Among them, three ATPases are involved in the assembly of the T4S system and/or provide energy for substrate transfer, VirB4, VirB11 and VirD4. The X-ray crystal structures of VirB11 and VirD4 have already been solved but VirB4 has proven to be reluctant to any structural investigation so far. RESULTS: Here, we have used small-angle X-ray scattering to obtain the first structural models for the membrane-extracted, dimeric form of the TraB protein, the VirB4 homolog encoded by the E. coli pKM101 plasmid, and for the monomeric soluble form of the LvhB4 protein, the VirB4 homolog of the T4S system encoded by the Legionella pneumophila lvh operon. We have obtained the low resolution structures of the full-length TraB and of its N- and C-terminal halves. From these SAXS models, we derive the internal organisation of TraB. We also show that the two TraB N- and C terminal domains are independently involved in the dimerisation of the full length protein. CONCLUSIONS: These models provide the first structural insights into the architecture of VirB4 proteins. In particular, our results highlight the modular arrangement and functional relevance of the dimeric-membrane-bound form of TraB. PMID- 21266027 TI - Bimanual training in stroke: How do coupling and symmetry-breaking matter? AB - BACKGROUND: The dramatic consequences of stroke on patient autonomy in daily living activities urged the need for new reliable therapeutic strategies. Recently, bimanual training has emerged as a promising tool to improve the functional recovery of upper-limbs in stroke patients. However, who could benefit from bimanual therapy and how it could be used as a part of a more complete rehabilitation protocol remain largely unknown. A possible reason explaining this situation is that coupling and symmetry-breaking mechanisms, two fundamental principles governing bimanual behaviour, have been largely under-explored in both research and rehabilitation in stroke. DISCUSSION: Bimanual coordination emerges as an active, task-specific assembling process where the limbs are constrained to act as a single unit by virtue of mutual coupling. Consequently, exploring, assessing, re-establishing and exploiting functional bimanual synergies following stroke, require moving beyond the classical characterization of performance of each limb in separate and isolated fashion, to study coupling signatures at both neural and behavioural levels. Grounded on the conceptual framework of the dynamic system approach to bimanual coordination, we debated on two main assumptions: 1) stroke-induced impairment of bimanual coordination might be anticipated/understood by comparing, in join protocols, changes in coupling strength and asymmetry of bimanual discrete movements observed in healthy people and those observed in stroke; 2) understanding/predicting behavioural manifestations of decrease in bimanual coupling strength and/or increase in interlimb asymmetry might constitute an operational prerequisite to adapt therapy and better target training at the specific needs of each patient. We believe that these statements draw new directions for experimental and clinical studies and contribute in promoting bimanual training as an efficient and adequate tool to facilitate the paretic upper-limb recovery and to restore spontaneous bimanual synergies. SUMMARY: Since bimanual control deficits have scarcely been systematically investigated, the eventual benefits of bimanual coordination practice in stroke rehabilitation remains poorly understood. In the present paper we argued that a better understanding of coupling and symmetry-breaking mechanisms in both the undamaged and stroke-lesioned neuro-behavioral system should provide a better understanding of stroke-related alterations of bimanual synergies, and help clinicians to adapt therapy in order to maximize rehabilitation benefits. PMID- 21266028 TI - mPGES-1 null mice are resistant to bleomycin-induced skin fibrosis. AB - INTRODUCTION: Microsomal prostaglandin E2 synthase-1 (mPGES-1) is an inducible enzyme that acts downstream of cyclooxygenase (COX) to specifically catalyze the conversion of prostaglandin (PG) H2 to PGE2. mPGES-1 plays a key role in inflammation, pain and arthritis; however, the role of mPGES-1 in fibrogenesis is largely unknown. Herein, we examine the role of mPGES-1 in a mouse model of skin scleroderma using mice deficient in mPGES-1. METHODS: Wild type (WT) and mPGES-1 null mice were subjected to the bleomycin model of cutaneous skin scleroderma. mPGES-1 expressions in scleroderma fibroblasts and in fibroblasts derived from bleomycin-exposed mice were assessed by Western blot analysis. Degree of fibrosis, dermal thickness, inflammation, collagen content and the number of alpha-smooth muscle actin (alpha-SMA)-positive cells were determined by histological analyses. The quantity of the collagen-specific amino acid hydroxyproline was also measured. RESULTS: Compared to normal skin fibroblasts, mPGES-1 protein expression was elevated in systemic sclerosis (SSc) fibroblasts and in bleomycin-exposed mice. Compared to WT mice, mPGES-1-null mice were resistant to bleomycin-induced inflammation, cutaneous thickening, collagen production and myofibroblast formation. CONCLUSIONS: mPGES-1 expression is required for bleomycin-induced skin fibrogenesis. Inhibition of mPGES-1 may be a viable method to alleviate the development of cutaneous sclerosis and is a potential therapeutic target to control the onset of fibrogenesis. PMID- 21266029 TI - Dysregulation of chemo-cytokine production in schizophrenic patients versus healthy controls. AB - BACKGROUND: The exact cause of schizophrenia is not known, although several aetiological theories have been proposed for the disease, including developmental or neurodegenerative processes, neurotransmitter abnormalities, viral infection and immune dysfunction or autoimmune mechanisms. Growing evidence suggests that specific cytokines and chemokines play a role in signalling the brain to produce neurochemical, neuroendocrine, neuroimmune and behavioural changes. A relationship between inflammation and schizophrenia was supported by abnormal cytokines production, abnormal concentrations of cytokines and cytokine receptors in the blood and cerebrospinal fluid in schizophrenia. Since the neuropathology of schizophrenia has recently been reported to be closely associated with microglial activation we aimed to determined whether spontaneous or LPS-induced peripheral blood mononuclear cell chemokines and cytokines production is dysregulated in schizophrenic patients compared to healthy subjects. We enrolled 51 untreated first-episode schizophrenics (SC) and 40 healthy subjects (HC) and the levels of MCP-1, MIP-1alpha, IL-8, IL-18, IFN-gamma and RANTES were determined by Elisa method in cell-free supernatants of PBMC cultures. RESULTS: In the simultaneous quantification we found significantly higher levels of constitutively and LPS-induced MCP-1, MIP-1alpha, IL-8 and IL-18, and lower RANTES and IFNgamma levels released by PBMC of SC patients compared with HC. In ten SC patients receiving therapy with risperidone, olanzapine or clozapine basal and LPS-induced production of RANTES and IL-18 was increased, while both basal and LPS-induced MCP-1 production was decreased. No statistically significant differences were detected in serum levels after therapy. CONCLUSION: The observation that in schizophrenic patients the PBMC production of selected chemo cytokines is dysregulated reinforces the hypothesis that the peripheral cyto chemokine network is involved in the pathophysiology of schizophrenia. These preliminary, but promising data are supportive of the application of wider profiling approaches to the identification of biomarker as diagnostic tools for the analysis of psychiatric diseases. PMID- 21266030 TI - Bilateral adrenocortical carcinoma in a patient with multiple endocrine neoplasia type 1 (MEN1) and a novel mutation in the MEN1 gene. AB - The incidence of adrenal involvement in MEN1 syndrome has been reported between 9 and 45%, while the incidence of adrenocortical carcinoma (ACC) in MEN1 patients has been reported between 2.6 and 6%. In the literature data only unilateral development of ACCs in MEN1 patients has been reported. We report a 31 years-old female MEN1-patient, in whom hyperplasia of the parathyroid glands, prolactinoma, non functioning pancreatic endocrine carcinoma and functioning bilateral adrenal carcinomas were diagnosed. Interestingly, a not previously described in the literature data, novel germline mutation (p.E45V) in exon 2 of MEN1 gene, was detected. The association of exon 2 mutation of the MEN1 gene with bilateral adrenal carcinomas in MEN1 syndrome, should be further investigated. PMID- 21266031 TI - Early diagnosis of Gorlin-Goltz syndrome: case report. AB - The Gorlin-Goltz syndrome, also known as nevoid basal cell carcinoma syndrome (NBCCS), is an infrequent multisystemic disease inherited in a dominant autosomal way, which shows a high level of penetrance and variable expressiveness. It is characterized by keratocystic odontogenic tumors (KCOT) in the jaw, multiple basal cell nevi carcinomas and skeletal abnormities. This syndrome may be diagnosed early by a dentist by routine radiographic exams in the first decade of life, since the KCOTs are usually one of the first manifestations of the syndrome. This article paper reports the case of a patient, a 10-year-old boy with NBCCS, emphasizing its clinical and radiographic manifestations. This study highlights the importance of health professionals in the early diagnosis of NBCCS and in a preventive multidisciplinary approach to provide a better prognosis for the patient. PMID- 21266032 TI - Genetic variances, heritabilities and maternal effects on body weight, breast meat yield, meat quality traits and the shape of the growth curve in turkey birds. AB - BACKGROUND: Turkey is an important agricultural species and is largely used as a meat bird. In 2004, turkey represented 6.5% of the world poultry meat production. The world-wide turkey population has rapidly grown due to increased commercial farming. Due to the high demand for turkey meat from both consumers and industry global turkey stocks increased from 100 million in 1970 to over 276 million in 2004. This rapidly increasing importance of turkeys was a reason to design this study for the estimation of genetic parameters that control body weight, body composition, meat quality traits and parameters that shape the growth curve in turkey birds. RESULTS: The average heritability estimate for body weight traits was 0.38, except for early weights that were strongly affected by maternal effects. This study showed that body weight traits, upper asymptote (a growth curve trait), percent breast meat and redness of meat had high heritability whereas heritabilities of breast length, breast width, percent drip loss, ultimate pH, lightness and yellowness of meat were medium to low. We found high positive genetic and phenotypic correlations between body weight, upper asymptote, most breast meat yield traits and percent drip loss but percent drip loss was found strongly negatively correlated with ultimate pH. Percent breast meat, however, showed genetic correlations close to zero with body weight traits and upper asymptote. CONCLUSION: The results of this analysis and the growth curve from the studied population of turkey birds suggest that the turkey birds could be selected for breeding between 60 and 80 days of age in order to improve overall production and the production of desirable cuts of meat. The continuous selection of birds within this age range could promote high growth rates but specific attention to meat quality would be needed to avoid a negative impact on the quality of meat. PMID- 21266033 TI - A living cell quartz crystal microbalance biosensor for continuous monitoring of cytotoxic responses of macrophages to single-walled carbon nanotubes. AB - BACKGROUND: Numerous engineered nanomaterials (ENMs) exist and new ENMs are being developed. A challenge to nanotoxicology and environmental health and safety is evaluating toxicity of ENMs before they become widely utilized. Cellular assays remain the predominant test platform yet these methods are limited by using discrete time endpoints and reliance on organic dyes, vulnerable to interference from ENMs. Label-free, continuous, rapid response systems with biologically meaningful endpoints are needed. We have developed a device to detect and monitor in real time responses of living cells to ENMs. The device, a living cell quartz crystal microbalance biosensor (QCMB), uses macrophages adherent to a quartz crystal. The communal response of macrophages to treatments is monitored continuously as changes in crystal oscillation frequency (Deltaf). We report the ability of this QCMB to distinguish benign from toxic exposures and reveal unique kinetic information about cellular responses to varying doses of single-walled carbon nanotubes (SWCNTs). RESULTS: We analyzed macrophage responses to additions of Zymosan A, polystyrene beads (PBs) (benign substances) or SWCNT (3-150 MUg/ml) in the QCMB over 18 hrs. In parallel, toxicity was monitored over 24/48 hrs using conventional viability assays and histological stains to detect apoptosis. In the QCMB, a stable unchanging oscillation frequency occurred when cells alone, Zymosan A alone, PBs alone or SWCNTs without cells at the highest dose alone were used. With living cells in the QCMB, when Zymosan A, PBs or SWCNTs were added, a significant decrease in frequency occurred from 1-6 hrs. For SWCNTs, this Deltaf was dose-dependent. From 6-18 hrs, benign substances or low dose SWCNT (3-30 MUg/ml) treatments showed a reversal of the decrease of oscillation frequency, returning to or exceeding pre-treatment levels. Cell recovery was confirmed in conventional assays. The lag time to see the Deltaf reversal in QCMB plots was linearly SWCNT-dose dependent. Lastly, the frequency never reversed at high dose SWCNT (100-150 MUg/ml), and apoptosis/necrosis was documented in conventional 24 and 48 hr-assays. CONCLUSION: These data suggest that the new QCMB detects and provides unique information about peak, sub-lethal and toxic exposures of living cells to ENMs before they are detected using conventional cell assays. PMID- 21266034 TI - The function and mechanism of COX-2 in angiogenesis of gastric cancer cells. AB - BACKGROUND: Here we aimed to investigate the effect of COX-2 siRNA on proliferation and angiogenesis of gastric cancer cells. METHODS: The gastric cancer cell line SGC7901 was transfected with COX-2 siRNA, then the growth and angiogenesis of cells were detected by in vitro and in vivo assay. Human microarray, RT-PCR and western blot were used to identify differentially expressed angiogenesis-related molecules in cells with decreased expression of COX-2. RESULTS: Down-regulation of COX-2 could significantly inhibit the in vitro and in vivo growth of gastric cancer cells, and suppress the migration and tube formation of human umbilical vein endothelial cells. Totally 23 angiogenesis related molecules were found involved in COX-2-induced angiogenesis suppression. The results of RT-PCR and western blot showed that down-regulation of COX-2 might inhibit VEGF, Flt-1, Flk-1/KDR, angiopoietin-1, tie-2, MMP2 and OPN. CONCLUSIONS: COX-2 might mediate tumor angiogenesis and growth, and could be considered as a target for gastric cancer therapy. PMID- 21266035 TI - Self-rated health, ethnicity and social position in a deprived neighbourhood in Denmark. AB - BACKGROUND: In recent years the close connection between SES and differences in health between ethnic groups have been subject to growing interest among researchers, and some studies have found an association between ethnicity and long term illness and poor health. However, there is limited research-based knowledge about health and illness in ethnic groups in Denmark and about ethnic Danes living in deprived neighbourhoods. The purpose of this study is to investigate associations between self-rated health and ethnicity and social position in a deprived neighbourhood in Denmark in which a relatively largely proportion of the residents are immigrants. METHODS: This study investigates the association between self-rated health used as dependent variable and ethnicity and social position (defined as index for life resources) as the independent variables. The analyses are based on data collected in a survey in a geographically bounded and social deprived neighbourhood, Korskaerparken, located in the municipality of Fredericia in Denmark. The sample consisted of 31% of the residents in Korskaerparken and of these 29% have an ethnic background other than Danish.The analyses were conducted using logistic regression adjusting for confounding variables. RESULTS: This study indicates no significant association between ethnicity and having poor/very poor self-rated health.On the other hand the study confirms that a strong and significant association between the number of residents' life resources and their self-rated health does indeed exist. The results clearly suggest that the more life resources an individual has, the lower is the risk of that individual reporting poor health. CONCLUSION: The results show a strong association between the residents' number of life resources and their self-rated health. In this study, we were not able to identify any association between ethnicity and self-rated health, i.e. our results suggest that ethnicity does not constitute an explanation to differences in self- rated health. PMID- 21266036 TI - ZINC-INDUCED FACILITATOR-LIKE family in plants: lineage-specific expansion in monocotyledons and conserved genomic and expression features among rice (Oryza sativa) paralogs. AB - BACKGROUND: Duplications are very common in the evolution of plant genomes, explaining the high number of members in plant gene families. New genes born after duplication can undergo pseudogenization, neofunctionalization or subfunctionalization. Rice is a model for functional genomics research, an important crop for human nutrition and a target for biofortification. Increased zinc and iron content in the rice grain could be achieved by manipulation of metal transporters. Here, we describe the ZINC-INDUCED FACILITATOR-LIKE (ZIFL) gene family in plants, and characterize the genomic structure and expression of rice paralogs, which are highly affected by segmental duplication. RESULTS: Sequences of sixty-eight ZIFL genes, from nine plant species, were comparatively analyzed. Although related to MSF_1 proteins, ZIFL protein sequences consistently grouped separately. Specific ZIFL sequence signatures were identified. Monocots harbor a larger number of ZIFL genes in their genomes than dicots, probably a result of a lineage-specific expansion. The rice ZIFL paralogs were named OsZIFL1 to OsZIFL13 and characterized. The genomic organization of the rice ZIFL genes seems to be highly influenced by segmental and tandem duplications and concerted evolution, as rice genome contains five highly similar ZIFL gene pairs. Most rice ZIFL promoters are enriched for the core sequence of the Fe-deficiency-related box IDE1. Gene expression analyses of different plant organs, growth stages and treatments, both from our qPCR data and from microarray databases, revealed that the duplicated ZIFL gene pairs are mostly co-expressed. Transcripts of OsZIFL4, OsZIFL5, OsZIFL7, and OsZIFL12 accumulate in response to Zn-excess and Fe deficiency in roots, two stresses with partially overlapping responses. CONCLUSIONS: We suggest that ZIFL genes have different evolutionary histories in monocot and dicot lineages. In rice, concerted evolution affected ZIFL duplicated genes, possibly maintaining similar expression patterns between pairs. The enrichment for IDE1 boxes in rice ZIFL gene promoters suggests a role in Zn excess and Fe-deficiency up-regulation of ZIFL transcripts. Moreover, this is the first description of the ZIFL gene family in plants and the basis for functional studies on this family, which may play important roles in Zn and Fe homeostasis in plants. PMID- 21266037 TI - Chlorfenapyr: a new insecticide with novel mode of action can control pyrethroid resistant malaria vectors. AB - BACKGROUND: Malaria vectors have acquired widespread resistance to many of the currently used insecticides, including synthetic pyrethroids. Hence, there is an urgent need to develop alternative insecticides for effective management of insecticide resistance in malaria vectors. In the present study, chlorfenapyr was evaluated against Anopheles culicifacies and Anopheles stephensi for its possible use in vector control. METHODS: Efficacy of chlorfenapyr against An. culicifacies and An. stephensi was assessed using adult bioassay tests. In the laboratory, determination of diagnostic dose, assessment of residual activity on different substrates, cross-resistance pattern with different insecticides and potentiation studies using piperonyl butoxide were undertaken by following standard procedures. Potential cross-resistance patterns were assessed on field populations of An. culicifacies. RESULTS: A dose of 5.0% chlorfenapyr was determined as the diagnostic concentration for assessing susceptibility applying the WHO tube test method in anopheline mosquitoes with 2 h exposure and 48 h holding period. The DDT-resistant/malathion-deltamethrin-susceptible strain of An. culicifacies species C showed higher LD50 and LD99 (0.67 and 2.39% respectively) values than the DDT-malathion-deltamethrin susceptible An. culicifacies species A (0.41 and 2.0% respectively) and An. stephensi strains (0.43 and 2.13% respectively) and there was no statistically significant difference in mortalities among the three mosquito species tested (p > 0.05). Residual activity of chlorfenapyr a.i. of 400 mg/m2 on five fabricated substrates, namely wood, mud, mud+lime, cement and cement + distemper was found to be effective up to 24 weeks against An. culicifacies and up to 34 weeks against An. stephensi. No cross-resistance to DDT, malathion, bendiocarb and deltamethrin was observed with chlorfenapyr in laboratory-reared strains of An. stephensi and field-caught An. culicifacies. Potentiation studies demonstrated the antagonistic effect of PBO. CONCLUSION: Laboratory studies with susceptible and resistant strains of An. culicifacies and An. stephensi, coupled with limited field studies with multiple insecticide-resistant An. culicifacies have shown that chlorfenapyr can be a suitable insecticide for malaria vector control, in multiple-insecticide-resistant mosquitoes especially in areas with pyrethroid resistant mosquitoes. PMID- 21266038 TI - Cognitive performance measures in bioelectromagnetic research--critical evaluation and recommendations. AB - BACKGROUND: The steady increase of mobile phone usage has led to a rising concern about possible adverse health effects of radio frequency electromagnetic field (RF EMF) exposure at intensities even below the existing safety limits. Accumulating evidence suggests that pulse-modulated RF EMF may alter brain physiology. Yet, whereas effects on the human electroencephalogram in waking and sleep have repeatedly been shown in recent years, results on cognitive performance are inconsistent. METHODS: This review compares 41 provocation studies regarding the effects of RF EMF exposure similar to mobile telephones on cognitive performance measures in humans. The studies were identified via systematic searches of the databases Pub Med and ISI Web of Science and were published in peer-reviewed journals between 1998 and the end of 2009. RESULTS: Based on a critical discussion within the scope of methodological standards it is concluded that state-of-the-art-methods in bio-electromagnetic research on RF EMF effects and cognition have neither been specified nor fully implemented over the last 10-11 years. The lack of a validated tool, which reliably assesses changes in cognitive performance caused by RF EMF exposure, may contribute to the current inconsistencies in outcomes. The high variety of findings may also be due to methodological issues such as differences in sample size and the composition of study groups, experimental design, exposure setup as well as the exposure conditions, and emphasizes the need for a standardized protocol in bioelectromagnetic research. CONCLUSIONS: At present, no underlying biological mechanism has been identified which mediates the effects on brain functioning as observed in electroencephalographic (EEG) studies. A future aim must be to identify this mechanism as well as a reliable exposure protocol in order to gain more insights into possible behavioral and related health consequences of high frequency EMF exposure. PMID- 21266039 TI - Work related musculoskeletal disorders amongst therapists in physically demanding roles: qualitative analysis of risk factors and strategies for prevention. AB - BACKGROUND: Physiotherapy and occupational therapy are two professions at high risk of work related musculoskeletal disorders (WRMD). This investigation aimed to identify risk factors for WRMD as perceived by the health professionals working in these roles (Aim 1), as well as current and future strategies they perceive will allow them to continue to work in physically demanding clinical roles (Aim 2). METHODS: A two phase exploratory investigation was undertaken. The first phase included a survey administered via a web based platform with qualitative open response items. The second phase involved four focus group sessions which explored topics obtained from the survey. Thematic analysis of qualitative data from the survey and focus groups was undertaken. RESULTS: Overall 112 (34.3%) of invited health professionals completed the survey; 66 (58.9%) were physiotherapists and 46 (41.1%) were occupational therapists. Twenty four health professionals participated in one of four focus groups. The risk factors most frequently perceived by health professionals included: work postures and movements, lifting or carrying, patient related factors and repetitive tasks. The six primary themes for strategies to allow therapists to continue to work in physically demanding clinical roles included: organisational strategies, workload or work allocation, work practices, work environment and equipment, physical condition and capacity, and education and training. CONCLUSIONS: Risk factors as well as current and potential strategies for reducing WRMD amongst these health professionals working in clinically demanding roles have been identified and discussed. Further investigation regarding the relative effectiveness of these strategies is warranted. PMID- 21266040 TI - Analysis of machine perfusion benefits in kidney grafts: a preclinical study. AB - BACKGROUND: Machine perfusion (MP) has potential benefits for marginal organs such as from deceased from cardiac death donors (DCD). However, there is still no consensus on MP benefits. We aimed to determine machine perfusion benefits on kidney grafts. METHODS: We evaluated kidney grafts preserved in ViaspanUW or KPS solutions either by CS or MP, in a DCD pig model (60 min warm ischemia+24 h hypothermic preservation). Endpoints were: function recovery, quality of function during follow up (3 month), inflammation, fibrosis, animal survival. RESULTS: ViaspanUW-CS animals did not recover function, while in other groups early follow up showed similar values for kidney function. Alanine peptidase and beta-NAG activities in the urine were higher in CS than in MP groups. Oxydative stress was lower in KPS-MP animals. Histology was improved by MP over CS. Survival was 0% in ViaspanUW-CS and 60% in other groups. Chronic inflammation, epithelial-to mesenchymal transition and fibrosis were lowest in KPS-MP, followed by KPS-CS and ViaspanUW-MP. CONCLUSIONS: With ViaspanUW, effects of MP are obvious as only MP kidney recovered function and allowed survival. With KPS, the benefits of MP over CS are not directly obvious in the early follow up period and only histological analysis, urinary tubular enzymes and red/ox status was discriminating. Chronic follow-up was more conclusive, with a clear superiority of MP over CS, independently of the solution used. KPS was proven superior to ViaspanUW in each preservation method in terms of function and outcome. In our pre-clinical animal model of DCD transplantation, MP offers critical benefits. PMID- 21266041 TI - Lung cancer risk and pollution in an industrial region of Northern Spain: a hospital-based case-control study. AB - BACKGROUND: Asturias, an Autonomous Region in Northern Spain with a large industrial area, registers high lung cancer incidence and mortality. While this excess risk of lung cancer might be partially attributable to smoking habit and occupational exposure, the role of industrial and urban pollution also needs to be assessed. The objective was to ascertain the possible effect of air pollution, both urban and industrial, on lung cancer risk in Asturias. METHODS: This was a hospital-based case-control study covering 626 lung cancer patients and 626 controls recruited in Asturias and matched by ethnicity, hospital, age, and sex. Distances from the respective participants' residential locations to industrial facilities and city centers were computed. Using logistic regression, odds ratios (ORs) and 95% confidence intervals (95%CIs) for categories of distance to urban and industrial pollution sources were calculated, with adjustment for sex, age, hospital area, tobacco consumption, family history of cancer, and occupation. RESULTS: Whereas individuals living near industries displayed an excess risk of lung cancer (OR = 1.49; 95%CI = 0.93-2.39), which attained statistical significance for small cell carcinomas (OR = 2.23; 95%CI = 1.01-4.92), residents in urban areas showed a statistically significant increased risk for adenocarcinoma (OR = 1.92; 95%CI = 1.09-3.38). In the Gijon health area, residents in the urban area registered a statistically significant increased risk of lung cancer (OR = 2.17; 95%CI = 1.25-3.76), whereas in the Aviles health area, no differences in risk were found by area of exposure. CONCLUSIONS: This study provides further evidence that air pollution is a moderate risk factor for lung cancer. PMID- 21266042 TI - Reduced clinical and postmortem measures of cardiac pathology in subjects with advanced Alzheimer's Disease. AB - BACKGROUND: Epidemiological studies indicate a statistical linkage between atherosclerotic vascular disease (ATH) and Alzheimer's disease (AD). Autopsy studies of cardiac disease in AD have been few and inconclusive. In this report, clinical and gross anatomic measures of cardiac disease were compared in deceased human subjects with and without AD. METHODS: Clinically documented cardiovascular conditions from AD (n = 35) and elderly non-demented control subjects (n = 22) were obtained by review of medical records. Coronary artery stenosis and other gross anatomical measures, including heart weight, ventricular wall thickness, valvular circumferences, valvular calcifications and myocardial infarct number and volume were determined at autopsy. RESULTS: Compared to non-demented age similar control subjects, those with AD had significantly fewer total diagnosed clinical conditions (2.91 vs 4.18), decreased coronary artery stenosis (70.8 vs 74.8%), heart weight (402 vs 489 g for males; 319 vs 412 g for females) and valvular circumferences. Carriage of the Apolipoprotein E-epsilon4 allele did not influence the degree of coronary stenosis. Group differences in heart weight remained significant after adjustment for age, gender, body mass index and apolipoprotein E genotype while differences in coronary artery stenosis were significantly associated with body mass index alone. CONCLUSIONS: The results are in agreement with an emerging understanding that, while midlife risk factors for ATH increase the risk for the later development of AD, once dementia begins, both risk factors and manifest disease diminish, possibly due to progressive weight loss with increasing dementia as well as disease involvement of the brain's vasomotor centers. PMID- 21266043 TI - Macrophage colony-stimulating factor and its receptor signaling augment glycated albumin-induced retinal microglial inflammation in vitro. AB - BACKGROUND: Microglial activation and the proinflammatory response are controlled by a complex regulatory network. Among the various candidates, macrophage colony stimulating factor (M-CSF) is considered an important cytokine. The up-regulation of M-CSF and its receptor CSF-1R has been reported in brain disease, as well as in diabetic complications; however, the mechanism is unclear. An elevated level of glycated albumin (GA) is a characteristic of diabetes; thus, it may be involved in monocyte/macrophage-associated diabetic complications. RESULTS: The basal level of expression of M-CSF/CSF-1R was examined in retinal microglial cells in vitro. Immunofluorescence, real-time PCR, immunoprecipitation, and Western blot analyses revealed the up-regulation of CSF-1R in GA-treated microglial cells. We also detected increased expression and release of M-CSF, suggesting that the cytokine is produced by activated microglia via autocrine signaling. Using an enzyme-linked immunosorbent assay, we found that GA affects microglial activation by stimulating the release of tumor necrosis factor-alpha and interleukin-1beta. Furthermore, the neutralization of M-CSF or CSF-1R with antibodies suppressed the proinflammatory response. Conversely, this proinflammatory response was augmented by the administration of M-CSF. CONCLUSIONS: We conclude that GA induces microglial activation via the release of proinflammatory cytokines, which may contribute to the inflammatory pathogenesis of diabetic retinopathy. The increased microglial expression of M-CSF/CSF-1R not only is a response to microglial activation in diabetic retinopathy but also augments the microglial inflammation responsible for the diabetic microenvironment. PMID- 21266044 TI - The logic of kinetic regulation in the thioredoxin system. AB - BACKGROUND: The thioredoxin system consisting of NADP(H), thioredoxin reductase and thioredoxin provides reducing equivalents to a large and diverse array of cellular processes. Despite a great deal of information on the kinetics of individual thioredoxin-dependent reactions, the kinetic regulation of this system as an integrated whole is not known. We address this by using kinetic modeling to identify and describe kinetic behavioral motifs found within the system. RESULTS: Analysis of a realistic computational model of the Escherichia coli thioredoxin system revealed several modes of kinetic regulation in the system. In keeping with published findings, the model showed that thioredoxin-dependent reactions were adaptable (i.e. changes to the thioredoxin system affected the kinetic profiles of these reactions). Further and in contrast to other systems-level descriptions, analysis of the model showed that apparently unrelated thioredoxin oxidation reactions can affect each other via their combined effects on the thioredoxin redox cycle. However, the scale of these effects depended on the kinetics of the individual thioredoxin oxidation reactions with some reactions more sensitive to changes in the thioredoxin cycle and others, such as the Tpx dependent reduction of hydrogen peroxide, less sensitive to these changes. The coupling of the thioredoxin and Tpx redox cycles also allowed for ultrasensitive changes in the thioredoxin concentration in response to changes in the thioredoxin reductase concentration. We were able to describe the kinetic mechanisms underlying these behaviors precisely with analytical solutions and core models. CONCLUSIONS: Using kinetic modeling we have revealed the logic that underlies the functional organization and kinetic behavior of the thioredoxin system. The thioredoxin redox cycle and associated reactions allows for a system that is adaptable, interconnected and able to display differential sensitivities to changes in this redox cycle. This work provides a theoretical, systems biological basis for an experimental analysis of the thioredoxin system and its associated reactions. PMID- 21266045 TI - Concurrent insulinoma and pancreatic adenocarcinoma: report of a rare case and review of the literature. AB - Pancreatic adenocarcinoma is the 5th leading cause of cancer-related death in Western countries and insulinomas are rare endocrine neoplasms of the pancreas. The concurrent appearance of pancreatic adenocarcinoma and insulinoma is very rare and to the best of our knowledge has never been reported again. Herein, we present such an occurrence in a 74-year-old man. Resection of a mass in the uncinate process of the pancreas revealed pancreatic adenocarcinoma with severe desmoplastic reaction. Two years later, due to symptomatology persistence the patient was re-examined and a new 2 cm mass in the uncinate process was found leading to surgery, which demonstrated a 2 cm endocrine islet-cell tumor. Establishing a diagnosis in patients with insulinoma is difficult and the imaging studies still have low sensitivity and specificity except for intra-operative ultrasonography, which is the most accurate method detecting 90% of these lesions. PMID- 21266046 TI - Epidermal Growth Factor Receptor (EGFR) mutation analysis, gene expression profiling and EGFR protein expression in primary prostate cancer. AB - BACKGROUND: Activating mutations of the epidermal growth factor receptor (EGFR) confer sensitivity to the tyrosine kinase inhibitors (TKi), gefitinib and erlotinib. We analysed EGFR expression, EGFR mutation status and gene expression profiles of prostate cancer (PC) to supply a rationale for EGFR targeted therapies in this disease. METHODS: Mutational analysis of EGFR TK domain (exons from 18 to 21) and immunohistochemistry for EGFR were performed on tumour tissues derived from radical prostatectomy from 100 PC patients. Gene expression profiling using oligo-microarrays was also carried out in 51 of the PC samples. RESULTS: EGFR protein overexpression (EGFRhigh) was found in 36% of the tumour samples, and mutations were found in 13% of samples. Patients with EGFRhigh tumours experienced a significantly increased risk of biochemical relapse (hazard ratio-HR 2.52, p=0.02) compared with patients with tumours expressing low levels of EGFR (EGFRlow). Microarray analysis did not reveal any differences in gene expression between EGFRhigh and EGFRlow tumours. Conversely, in EGFRhigh tumours, we were able to identify a 79 gene signature distinguishing mutated from non mutated tumours. Additionally, 29 genes were found to be differentially expressed between mutated/EGFRhigh (n=3) and mutated/EGFRlow tumours (n=5). Four of the down-regulated genes, U19/EAF2, ABCC4, KLK3 and ANXA3 and one of the up-regulated genes, FOXC1, are involved in PC progression. CONCLUSIONS: Based on our findings, we hypothesize that accurate definition of the EGFR status could improve prognostic stratification and we suggest a possible role for EGFR-directed therapies in PC patients. Having been generated in a relatively small sample of patients, our results warrant confirmation in larger series. PMID- 21266047 TI - Lin4Neuro: a customized Linux distribution ready for neuroimaging analysis. AB - BACKGROUND: A variety of neuroimaging software packages have been released from various laboratories worldwide, and many researchers use these packages in combination. Though most of these software packages are freely available, some people find them difficult to install and configure because they are mostly based on UNIX-like operating systems. We developed a live USB-bootable Linux package named "Lin4Neuro." This system includes popular neuroimaging analysis tools. The user interface is customized so that even Windows users can use it intuitively. RESULTS: The boot time of this system was only around 40 seconds. We performed a benchmark test of inhomogeneity correction on 10 subjects of three-dimensional T1 weighted MRI scans. The processing speed of USB-booted Lin4Neuro was as fast as that of the package installed on the hard disk drive. We also installed Lin4Neuro on a virtualization software package that emulates the Linux environment on a Windows-based operation system. Although the processing speed was slower than that under other conditions, it remained comparable. CONCLUSIONS: With Lin4Neuro in one's hand, one can access neuroimaging software packages easily, and immediately focus on analyzing data. Lin4Neuro can be a good primer for beginners of neuroimaging analysis or students who are interested in neuroimaging analysis. It also provides a practical means of sharing analysis environments across sites. PMID- 21266048 TI - Placenta growth factor and vascular endothelial growth factor B expression in the hypoxic lung. AB - BACKGROUND: Chronic alveolar hypoxia, due to residence at high altitude or chronic obstructive lung diseases, leads to pulmonary hypertension, which may be further complicated by right heart failure, increasing morbidity and mortality. In the non-diseased lung, angiogenesis occurs in chronic hypoxia and may act in a protective, adaptive manner. To date, little is known about the behaviour of individual vascular endothelial growth factor (VEGF) family ligands in hypoxia induced pulmonary angiogenesis. The aim of this study was to examine the expression of placenta growth factor (PlGF) and VEGFB during the development of hypoxic pulmonary angiogenesis and their functional effects on the pulmonary endothelium. METHODS: Male Sprague Dawley rats were exposed to conditions of normoxia (21% O2) or hypoxia (10% O2) for 1-21 days. Stereological analysis of vascular structure, real-time PCR analysis of vascular endothelial growth factor A (VEGFA), VEGFB, placenta growth factor (PlGF), VEGF receptor 1 (VEGFR1) and VEGFR2, immunohistochemistry and western blots were completed. The effects of VEGF ligands on human pulmonary microvascular endothelial cells were determined using a wound-healing assay. RESULTS: Typical vascular remodelling and angiogenesis were observed in the hypoxic lung. PlGF and VEGFB mRNA expression were significantly increased in the hypoxic lung. Immunohistochemical analysis showed reduced expression of VEGFB protein in hypoxia although PlGF protein was unchanged. The expression of VEGFA mRNA and protein was unchanged. In vitro PlGF at high concentration mimicked the wound-healing actions of VEGFA on pulmonary microvascular endothelial monolayers. Low concentrations of PlGF potentiated the wound-healing actions of VEGFA while higher concentrations of PlGF were without this effect. VEGFB inhibited the wound-healing actions of VEGFA while VEGFB and PlGF together were mutually antagonistic. CONCLUSIONS: VEGFB and PlGF can either inhibit or potentiate the actions of VEGFA, depending on their relative concentrations, which change in the hypoxic lung. Thus their actions in vivo depend on their specific concentrations within the microenvironment of the alveolar wall during the course of adaptation to pulmonary hypoxia. PMID- 21266049 TI - Human neutrophil migration and activation by BJcuL, a galactose binding lectin purified from Bothrops jararacussu venom. AB - BACKGROUND: Neutrophil migration to an inflamed site constitutes the first line of the innate immune response against invading microorganisms. Given the crucial role of endogenous lectins in neutrophil mobilization and activation, lectins from exogenous sources have often been considered as putative modulators of leukocyte function. Lectins purified from snake venom have been described as galactoside ligands that induce erythrocyte agglutination and platelet aggregation. This study evaluated human neutrophil migration and activation by C type lectin BJcuL purified from Bothrops jararacussu venom. RESULTS: Utilizing fluorescence microscopy, we observed that biotinylated-BJcuL was evenly distributed on the neutrophil surface, selectively inhibited by D-galactose. Lectin was able to induce modification in the neutrophil morphology in a spherical shape for a polarized observed by optical microscopy and exposure to BJcuL in a Boyden chamber assay resulted in cell migration. After 30 minutes of incubation with BJcuL we found enhanced neutrophil functions, such as respiratory burst, zymozan phagocytosis and an increase in lissosomal volume. In addition, BJcuL delays late apoptosis neutrophils. CONCLUSION: These results demonstrate that BJcuL can be implicated in a wide variety of immunological functions including first-line defense against pathogens, cell trafficking and induction of the innate immune response since lectin was capable of inducing potent neutrophil activation. PMID- 21266050 TI - Hydrogenated fat intake during pregnancy and lactation caused increase in TRAF-6 and reduced AdipoR1 in white adipose tissue, but not in muscle of 21 days old offspring rats. AB - BACKGROUND: Although lipids transfer through placenta is very limited, modification in dietary fatty acids can lead to implications in fetal and postnatal development. Trans fatty acid (TFA) intake during gestation and lactation have been reported to promote dyslipidemia and increase in pro- inflammatory adipokines in offspring. The aim of this study was to evaluate whether the alterations on pro-inflammatory cytokines and dyslipidemia observed previously in 21-d-old offspring of rats fed a diet containing hydrogenated vegetable fat during gestation and lactation were related to alterations in TLR 4, TRAF-6 and adipo-R1 receptor in white adipose tissue and muscle. On the first day of gestation, rats were randomly divided into two groups: (C) received a control diet, and (T) received a diet enriched with hydrogenated vegetable fat, rich in trans fatty acids. The diets were maintained throughout gestation and lactation. Each mother was given eight male pups. On the 21st day of life the offspring were killed. Blood, soleus and extensor digital longus (EDL) muscles, and retroperitoneal (RET) white adipose tissue were collected. RESULTS: 21-d-old of T rats had higher serum triacylglycerols, cholesterol, and insulin. The Adipo R1 protein expression was lower in RET and higher in EDL of T group than C. TLR-4 protein content in all studied tissues were similar between groups, the same was verified in TRAF-6 protein expression in soleus and EDL. However, TRAF-6 protein expression in RET was higher in T than C. CONCLUSION: These results demonstrated that maternal ingestion of hydrogenated vegetable fat rich in TFAs during gestation and lactation decrease in Adipo R1 protein expression and increase in TRAF-6 protein expression in retroperitoneal adipose tissue, but not in skeletal muscle, which could contributed for hyperinsulinemia and dyslipidemia observed in their 21-d-old offspring. PMID- 21266051 TI - Three models of community mental health services In low-income countries. AB - OBJECTIVE: To compare and contrast three models of community mental health services in low-income settings. DATA SOURCES/STUDY SETTING: Primary and secondary data collected before, during, and after site visits to mental health programs in Nigeria, the Philippines, and India. STUDY DESIGN: Qualitative case study methodology. DATA COLLECTION: Data were collected through interviews and observations during site visits to the programs, as well as from reviews of documentary evidence. PRINCIPAL FINDINGS: A set of narrative topics and program indicators were used to compare and contrast three community mental health programs in low-income countries. This allowed us to identify a diversity of service delivery models, common challenges, and the strengths and weaknesses of each program. More definitive evaluations will require the establishment of data collection methods and information systems that provide data about the clinical and social outcomes of clients, as well as their use of services. CONCLUSIONS: Community mental health programs in low-income countries face a number of challenges. Using a case study methodology developed for this purpose, it is possible to compare programs and begin to assess the effectiveness of diverse service delivery models. PMID- 21266052 TI - Bacillus pumilus laccase: a heat stable enzyme with a wide substrate spectrum. AB - BACKGROUND: Laccases are multi-copper oxidases that catalyze the one electron oxidation of a broad range of compounds. Laccase substrates include substituted phenols, arylamines and aromatic thiols. Such compounds are activated by the enzyme to the corresponding radicals. Owing to their broad substrate range laccases are considered to be versatile biocatalysts which are capable of oxidizing natural and non-natural industrial compounds, with water as sole by product. RESULTS: A novel CotA-type laccase from Bacillus pumilus was cloned, expressed and purified and its biochemical characteristics are presented here. The molecular weight of the purified laccase was estimated to be 58 kDa and the enzyme was found to be associated with four copper atoms. Its catalytic activity towards 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS), 2,6 dimethoxyphenol (2,6-DMP) and syringaldazine (SGZ) was investigated. The kinetic parameters KM and kcat for ABTS were 80 +/- 4 MUM and 291 +/- 2.7 s(-1), for 2,6 DMP 680 +/- 27 MUM and 11 +/- 0.1 s(-1) and for SGZ only kcat could be estimated to be 66 +/- 1.5 s(-1). The pH optimum for ABTS was 4, for 2,6-DMP 7 and for SGZ 6.5 and temperature optima for ABTS and 2,6-DMP were found to be around 70 degrees C. The screening of 37 natural and non-natural compounds as substrates for B. pumilus laccase revealed 18 suitable compounds. Three of them served as redox mediators in the laccase-catalyzed decolorization of the dye indigocarmine (IC), thus assessing the new enzyme's biotechnological potential. CONCLUSIONS: The fully copper loaded, thermostable CotA laccase from Bacillus pumilus is a versatile laccase with potential applications as an industrial biocatalyst. PMID- 21266053 TI - In vitro secretion and activity profiles of matrix metalloproteinases, MMP-9 and MMP-2, in human term extra-placental membranes after exposure to Escherichia coli. AB - BACKGROUND: Premature rupture of fetal membranes (PROM) complicated with intrauterine infection has been associated to alterations of the extracellular matrix (ECM) homeostasis. The aim of this work was to evaluate the integral/functional response of the amnion (AMN) and choriodecidua (CHD) to synthesis, secretion, and activity of MMP-2 and MMP-9 and of their inhibitors TIMP-1, -2, and -4, after stimulation with Escherichia coli. METHODS: Full thickness membranes were mounted on a Transwell device, constituting two independent chambers, Escherichia coli (1*10 (6) CFU/mL) were added to either the amniotic or the choriodecidual face or to both. Secretion profiles of MMP-2, MMP 9, TIMP-1, TIMP-2, and TIMP-4 were quantified by ELISA and gelatinolytic activity by zymography. Immunoreactivity for MMP-2 and MMP-9 was revealed by immunohistochemistry and the collagen content was assessed by the hydroxyproline assay. RESULTS: Levels of MMP-9 in CHD and AMN increased 4- and 8-fold, respectively, after simultaneous infection. MMP-2 secreted to the medium by CHD increased a mean of 3 times after direct stimulation. Secretion profiles of TIMP 1, TIMP-2, and TIMP-4 remained without significant changes. Collagen content was significantly decreased (4-fold) in infected membranes, and was associated with loss of structural continuity and co-localization with immunoreactive forms of MMP-2 and MMP-9. CONCLUSIONS: Infection of chorioamniotic membranes with E. coli induces an increase in the secretion of inactive forms and an association to ECM of active forms of MMP-2 and MMP-9 without changes in TIMP-1, -2, and -4. These changes could explain the significant decrease of collagen content and loss of structural continuity. PMID- 21266054 TI - Ketamine inhibits tumor necrosis factor secretion by RAW264.7 murine macrophages stimulated with antibiotic-exposed strains of community-associated, methicillin resistant Staphylococcus aureus. AB - BACKGROUND: Infections caused by community-associated strains of methicillin resistant Staphylococcus aureus (CA-MRSA) are associated with a marked and prolonged host inflammatory response. In a sepsis simulation model, we tested whether the anesthetic ketamine inhibits the macrophage TNF response to antibiotic-exposed CA-MRSA bacteria via its antagonism of N-methyl-D-aspartate (NMDA) receptors. RAW264.7 cells were stimulated for 18 hrs with 105 to 107 CFU/mL inocula of either of two prototypical CA-MRSA isolates, USA300 strain LAC and USA400 strain MW2, in the presence of either vancomycin or daptomycin. One hour before bacterial stimulation, ketamine was added with or without MK-801 (dizocilpine, a chemically unrelated non-competitive NMDA receptor antagonist), APV (D-2-amino-5-phosphono-valerate, a competitive NMDA receptor antagonist), NMDA, or combinations of these agents. Supernatants were collected and assayed for TNF concentration by ELISA. RESULTS: RAW264.7 cells exposed to either LAC or MW2 in the presence of daptomycin secreted less TNF than in the presence of vancomycin. The addition of ketamine inhibited macrophage TNF secretion after stimulation with either of the CA-MRSA isolates (LAC, MW2) in the presence of either antibiotic. The NMDA inhibitors, MK-801 and APV, also suppressed macrophage TNF secretion after stimulation with either of the antibiotic-exposed CA-MRSA isolates, and the effect was not additive or synergistic with ketamine. The addition of NMDA substrate augmented TNF secretion in response to the CA-MRSA bacteria, and the addition of APV suppressed the effect of NMDA in a dose dependent fashion. CONCLUSIONS: Ketamine inhibits TNF secretion by MRSA stimulated RAW264.7 macrophages and the mechanism likely involves NMDA receptor antagonism. These findings may have therapeutic significance in MRSA sepsis. PMID- 21266055 TI - Focusing on fast food restaurants alone underestimates the relationship between neighborhood deprivation and exposure to fast food in a large rural area. AB - BACKGROUND: Individuals and families are relying more on food prepared outside the home as a source for at-home and away-from-home consumption. Restricting the estimation of fast-food access to fast-food restaurants alone may underestimate potential spatial access to fast food. METHODS: The study used data from the 2006 Brazos Valley Food Environment Project (BVFEP) and the 2000 U.S. Census Summary File 3 for six rural counties in the Texas Brazos Valley region. BVFEP ground truthed data included identification and geocoding of all fast-food restaurants, convenience stores, supermarkets, and grocery stores in study area and on-site assessment of the availability and variety of fast-food lunch/dinner entrees and side dishes. Network distance was calculated from the population-weighted centroid of each census block group to all retail locations that marketed fast food (n = 205 fast-food opportunities). RESULTS: Spatial access to fast-food opportunities (FFO) was significantly better than to traditional fast-food restaurants (FFR). The median distance to the nearest FFO was 2.7 miles, compared with 4.5 miles to the nearest FFR. Residents of high deprivation neighborhoods had better spatial access to a variety of healthier fast-food entree and side dish options than residents of low deprivation neighborhoods. CONCLUSIONS: Our analyses revealed that identifying fast-food restaurants as the sole source of fast-food entrees and side dishes underestimated neighborhood exposure to fast food, in terms of both neighborhood proximity and coverage. Potential interventions must consider all retail opportunities for fast food, and not just traditional FFR. PMID- 21266056 TI - var gene transcription and PfEMP1 expression in the rosetting and cytoadhesive Plasmodium falciparum clone FCR3S1.2. AB - BACKGROUND: The pathogenicity of Plasmodium falciparum is in part due to the ability of the parasitized red blood cell (pRBC) to adhere to intra-vascular host cell receptors and serum-proteins. Binding of the pRBC is mediated by Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), a large multi-variant molecule encoded by a family of ~60 var genes. METHODS: The study of var gene transcription in the parasite clone FCR3S1.2 was performed by semi-quantitative PCR and quantitative PCR (qPCR). The expression of the major PfEMP1 in FCR3S1.2 pRBC was analysed with polyclonal sera in rosette disruption assays and immunofluorescence. RESULTS: Transcripts from var1 (FCR3S1.2(var1); IT4var21) and other var genes were detected by semi-quantitative PCR but results from qPCR showed that one var gene transcript dominated over the others (FCR3S1.2(var2); IT4var60). Antibodies raised in rats to the recombinant NTS-DBL1alpha of var2 produced in E. coli completely and dose-dependently disrupted rosettes (~95% at a dilution of 1/5). The sera reacted with the Maurer's clefts in trophozoite stages (IFA) and to the infected erythrocyte surface (FACS) indicating that FCR3S1.2(var2) encodes the dominant PfEMP1 expressed in this parasite. CONCLUSION: The major transcript in the rosetting model parasite FCR3S1.2 is FCR3S1.2(var2) (IT4var60). The results suggest that this gene encodes the PfEMP1 species responsible for the rosetting phenotype of this parasite. The activity of previously raised antibodies to the NTS-DBL1alpha of FCR3S1.2(var1) is likely due to cross-reactivity with NTS-DBL1alpha of the var2 encoded PfEMP1. PMID- 21266058 TI - Fecal pancreatic elastase-1 levels in older individuals without known gastrointestinal diseases or diabetes mellitus. AB - BACKGROUND: Structural changes occur in the pancreas as a part of the natural aging process. With aging, also the incidence of maldigestive symptoms and malnutrition increases, raising the possibility that these might be caused at least in part by inadequate pancreatic enzyme secretion due to degenerative processes and damage of the gland. Fecal elastase-1 is a good marker of pancreatic exocrine secretion. The aim of this study was to investigate the fecal elastase-1 levels among over 60 years old Finnish and Polish healthy individuals without any special diet, known gastrointestinal disease, surgery or diabetes mellitus. METHODS: A total of 159 patients participated in this cross-sectional study. 106 older individuals (aged 60-92 years) were recruited from outpatient clinics and elderly homes. They were divided to three age groups: 60-69 years old (n = 31); 70-79 years old (n = 38) and over 80 years old (n = 37). 53 young subjects (20-28 years old) were investigated as controls. Inclusion criteria were age over 60 years, normal status and competence. Exclusion criteria were any special diet, diabetes mellitus, any known gastrointestinal disease or prior gastrointestinal surgery. Fecal elastase-1 concentration was measured from stool samples with an ELISA that uses two monoclonal antibodies against different epitopes of human elastase-1. RESULTS: Fecal elastase-1 concentrations correlated negatively with age (Pearson r = -0,3531, P < 0.001) and were significantly lower among subjects over 70 years old compared to controls (controls vs. 70-79 years old and controls vs. over 80 years old, both P < 0.001). Among the over 60 years old subjects, the fecal elastase-1 concentrations were below the cut off level of 200 MUg/g in 23 of 106 (21.7%) individuals [mean 112 (86-138) MUg/g] indicating pancreatic exocrine insufficiency. Of those, 9 subjects had fecal elastase-1 level below 100 MUg/g as a marker of severe pancreatic insufficiency. CONCLUSION: In our study one fifth of healthy older individuals without any gastrointestinal disorder, surgery or diabetes mellitus suffer from pancreatic exocrine insufficiency and might benefit from enzyme supplementation therapy. PMID- 21266057 TI - Design, baseline characteristics, and retention of African American light smokers into a randomized trial involving biological data. AB - BACKGROUND: African Americans experience significant tobacco-related health disparities despite the fact that over half of African American smokers are light smokers (use <= 10 cigarettes per day). African Americans have been under represented in smoking cessation research, and few studies have evaluated treatment for light smokers. This paper describes the study design, measures, and baseline characteristics from Kick It at Swope III (KIS-III), the first treatment study of bupropion for African American light smokers. METHODS: Five hundred forty African American light smokers were randomly assigned to receive bupropion (150 mg bid) (n = 270) or placebo (n = 270) for 7 weeks. All participants received written materials and health education counseling. Participants responded to survey items and provided blood samples for evaluation of phenotype and genotype of CYP2A6 and CYP2B6 enzymes involved in nicotine and bupropion metabolism. Primary outcome was cotinine-verified 7-day point prevalence smoking abstinence at Week 26 follow-up. RESULTS: Of 2,628 individuals screened, 540 were eligible, consented, and randomized to treatment. Participants had a mean age of 46.5 years and 66.1% were women. Participants smoked an average of 8.0 cigarettes per day, had a mean exhaled carbon monoxide of 16.4 ppm (range 1-55) and a mean serum cotinine of 275.8 ng/ml. The mean Fagerstrom Test for Nicotine Dependence was 3.2, and 72.2% of participants smoked within 30 minutes of waking. The average number of quit attempts in the past year was 3.7 and 24.2% reported using pharmacotherapy in their most recent quit attempt. Motivation and confidence to quit were high. CONCLUSION: KIS-III is the first study designed to examine both nicotine and bupropion metabolism, evaluating CYP2A6 and CYP2B6 phenotype and genotype in conjunction with psychosocial factors, in the context of treatment of African American light smokers. Of 1629 smokers screened for study participation, only 18 (1.1%) were ineligible to participate in the study because they refused blood draws, demonstrating the feasibility of recruiting and enrolling African American light smokers into a clinical treatment trial involving biological data collection and genetic analyses. Future evaluation of individual factors associated with treatment outcome will contribute to advancing tailored tobacco use treatment with the goal of enhancing treatment and reducing health disparities for African American light smokers. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00666978. PMID- 21266059 TI - Tumor-suppressor activity of RRIG1 in breast cancer. AB - BACKGROUND: Retinoid receptor-induced gene-1 (RRIG1) is a novel gene that has been lost in several types of human cancers. The aim of this study was to determine whether RRIG1 plays a role in breast cancer, such as in the suppression of breast cancer cell growth and invasion. METHODS: Immunohistochemistry was used to detect RRIG1 expression in breast tissue specimens. Gene transfection was used to restore or knock down RRIG1 expression in breast cancer cell lines for analysis of cell viability, colony formation, and migration/invasion potential. Reverse-transcription polymerase chain reaction and western blot assays were used to detect the changes in gene expression. The RhoA activation assay was used to assess RRIG1-induced inhibition of RhoA activity. RESULTS: The immunohistochemical data showed that RRIG1 expression was reduced in breast cancer tissues compared with normal and atypical hyperplastic breast tissues. RRIG1 expression was inversely correlated with lymph node metastasis of breast cancer but was not associated with the status of hormone receptors, such as estrogen receptor, progesterone receptor, or HER2. Furthermore, restoration of RRIG1 expression inhibited proliferation, colony formation, migration, and invasion of breast cancer cells. Expression of RRIG1 also reduced phosphorylated Erk1/2 and Akt levels; c-Jun, MMP9, and Akt expressions; and RhoA activity. In contrast, knockdown of RRIG1 expression promoted breast cancer cell proliferation, colony formation, migration, and invasion potential. CONCLUSION: The data from the current study indicated that RRIG1 expression was reduced or lost in breast cancer and that restoration of RRIG1 expression suppressed breast cancer cell growth and invasion capacity. Future studies will determine the underlying molecular mechanisms and define RRIG1 as a tumor-suppressor gene in breast cancer. PMID- 21266060 TI - SciReader enables reading of medical content with instantaneous definitions. AB - BACKGROUND: A major problem patients encounter when reading about health related issues is document interpretation, which limits reading comprehension and therefore negatively impacts health care. Currently, searching for medical definitions from an external source is time consuming, distracting, and negatively impacts reading comprehension and memory of the material. METHODS: SciReader was built as a Java application with a Flex-based front-end client. The dictionary used by SciReader was built by consolidating data from several sources and generating new definitions with a standardized syntax. The application was evaluated by measuring the percentage of words defined in different documents. A survey was used to test the perceived effect of SciReader on reading time and comprehension. RESULTS: We present SciReader, a web-application that simplifies document interpretation by allowing users to instantaneously view medical, English, and scientific definitions as they read any document. This tool reveals the definitions of any selected word in a small frame at the top of the application. SciReader relies on a dictionary of ~750,000 unique Biomedical and English word definitions. Evaluation of the application shows that it maps ~98% of words in several different types of documents and that most users tested in a survey indicate that the application decreases reading time and increases comprehension. CONCLUSIONS: SciReader is a web application useful for reading medical and scientific documents. The program makes jargon-laden content more accessible to patients, educators, health care professionals, and the general public. PMID- 21266061 TI - Annotation-based genome-wide SNP discovery in the large and complex Aegilops tauschii genome using next-generation sequencing without a reference genome sequence. AB - BACKGROUND: Many plants have large and complex genomes with an abundance of repeated sequences. Many plants are also polyploid. Both of these attributes typify the genome architecture in the tribe Triticeae, whose members include economically important wheat, rye and barley. Large genome sizes, an abundance of repeated sequences, and polyploidy present challenges to genome-wide SNP discovery using next-generation sequencing (NGS) of total genomic DNA by making alignment and clustering of short reads generated by the NGS platforms difficult, particularly in the absence of a reference genome sequence. RESULTS: An annotation-based, genome-wide SNP discovery pipeline is reported using NGS data for large and complex genomes without a reference genome sequence. Roche 454 shotgun reads with low genome coverage of one genotype are annotated in order to distinguish single-copy sequences and repeat junctions from repetitive sequences and sequences shared by paralogous genes. Multiple genome equivalents of shotgun reads of another genotype generated with SOLiD or Solexa are then mapped to the annotated Roche 454 reads to identify putative SNPs. A pipeline program package, AGSNP, was developed and used for genome-wide SNP discovery in Aegilops tauschii the diploid source of the wheat D genome, and with a genome size of 4.02 Gb, of which 90% is repetitive sequences. Genomic DNA of Ae. tauschii accession AL8/78 was sequenced with the Roche 454 NGS platform. Genomic DNA and cDNA of Ae. tauschii accession AS75 was sequenced primarily with SOLiD, although some Solexa and Roche 454 genomic sequences were also generated. A total of 195,631 putative SNPs were discovered in gene sequences, 155,580 putative SNPs were discovered in uncharacterized single-copy regions, and another 145,907 putative SNPs were discovered in repeat junctions. These SNPs were dispersed across the entire Ae. tauschii genome. To assess the false positive SNP discovery rate, DNA containing putative SNPs was amplified by PCR from AL8/78 and AS75 and resequenced with the ABI 3730 xl. In a sample of 302 randomly selected putative SNPs, 84.0% in gene regions, 88.0% in repeat junctions, and 81.3% in uncharacterized regions were validated. CONCLUSION: An annotation-based genome-wide SNP discovery pipeline for NGS platforms was developed. The pipeline is suitable for SNP discovery in genomic libraries of complex genomes and does not require a reference genome sequence. The pipeline is applicable to all current NGS platforms, provided that at least one such platform generates relatively long reads. The pipeline package, AGSNP, and the discovered 497,118 Ae. tauschii SNPs can be accessed at (http://avena.pw.usda.gov/wheatD/agsnp.shtml). PMID- 21266062 TI - Responses of photosynthetic capacity to soil moisture gradient in perennial rhizome grass and perennial bunchgrass. AB - BACKGROUND: Changing water condition represents a dramatic impact on global terrestrial ecosystem productivity, mainly by limiting plant functions, including growth and photosynthesis, particularly in arid and semiarid areas. However, responses of the potential photosynthetic capacity to soil water status in a wide range of soil moisture levels, and determination of their thresholds are poorly understood. This study examined the response patterns of plant photosynthetic capacity and their thresholds to a soil moisture gradient in a perennial rhizome grass, Leymus chinensis, and a perennial bunchgrass, Stipa grandis, both dominant in the Eurasian Steppe. RESULTS: Severe water deficit produced negative effects on light-saturated net CO2 assimilation rate (A(sat)), stomatal conductance (g(s)), mesophyll conductance (g(m)), maximum carboxylation velocity (V(c,max)), and maximal efficiency of PSII photochemistry (F(v)/F(m)). Photosynthetic activity was enhanced under moderate soil moisture with reductions under both severe water deficit and excessive water conditions, which may represent the response patterns of plant growth and photosynthetic capacity to the soil water gradient. Our results also showed that S. grandis had lower productivity and photosynthetic potentials under moderate water status, although it demonstrated generally similar relationship patterns between photosynthetic potentials and water status relative to L. chinensis. CONCLUSIONS: The experiments tested and confirmed the hypothesis that responsive threshold points appear when plants are exposed to a broad water status range, with different responses between the two key species. It is suggested that vegetation structure and function may be shifted when a turning point of soil moisture occurs, which translates to terms of future climatic change prediction in semiarid grasslands. PMID- 21266063 TI - Nickel and low CO2-controlled motility in Chlamydomonas through complementation of a paralyzed flagella mutant with chemically regulated promoters. AB - BACKGROUND: Chlamydomonas reinhardtii is a model system for the biology of unicellular green algae. Chemically regulated promoters, such as the nickel inducible CYC6 or the low CO2-inducible CAH1 promoter, may prove useful for expressing, at precise times during its cell cycle, proteins with relevant biological functions, or complementing mutants in genes encoding such proteins. To this date, this has not been reported for the above promoters. RESULTS: We fused the CYC6 and CAH1 promoters to an HA-tagged RSP3 gene, encoding a protein of the flagellar radial spoke complex. The constructs were used for chemically regulated complementation of the pf14 mutant, carrying an ochre mutation in the RSP3 gene. 7 to 8% of the transformants showed cells with restored motility after induction with nickel or transfer to low CO2 conditions, but not in non-inducing conditions. Maximum complementation (5% motile cells) was reached with very different kinetics (5-6 hours for CAH1, 48 hours for CYC6). The two inducible promoters drive much lower levels of RSP3 protein expression than the constitutive PSAD promoter, which shows almost complete rescue of motility. CONCLUSIONS: To our knowledge, this is the first example of the use of the CYC6 or CAH1 promoters to perform a chemically regulated complementation of a Chlamydomonas mutant. Based on our data, the CYC6 and CAH1 promoters should be capable of fully complementing mutants in genes whose products exert their biological activity at low concentrations. PMID- 21266065 TI - Development and implementation of a performance improvement project in adult intensive care units: overview of the Improving Medicine Through Pathway Assessment of Critical Therapy in Hospital-Acquired Pneumonia (IMPACT-HAP) study. AB - INTRODUCTION: In 2005 the American Thoracic Society and Infectious Diseases Society of America (ATS/IDSA) published guidelines for managing hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), and healthcare-associated pneumonia (HCAP). Although recommendations were evidence based, collective guidelines had not been validated in clinical practice and did not provide specific tools for local implementation. We initiated a performance improvement project designated Improving Medicine Through Pathway Assessment of Critical Therapy in Hospital-Acquired Pneumonia (IMPACT-HAP) at four academic centers in the United States. Our objectives were to develop and implement the project, and to assess compliance with quality indicators in adults admitted to intensive care units (ICUs) with HAP, VAP, or HCAP. METHODS: The project was conducted in three phases over 18 consecutive months beginning 1 February 2006: 1) a three-month planning period for literature review to create the consensus pathway for managing nosocomial pneumonia in these ICUs, a data collection form, quality performance indicators, and internet-based repository; 2) a six-month implementation period for customizing ATS/IDSA guidelines into center-specific guidelines via educational forums; and 3) a nine-month post-implementation period for continuing education and data collection. Data from the first two phases were combined (pre-implementation period) and compared with data from the post implementation period. RESULTS: We developed a consensus pathway based on ATS/IDSA guidelines and customized it at the local level to accommodate formulary and microbiologic considerations. We implemented multimodal educational activities to teach ICU staff about the guidelines and continued education throughout post-implementation. We registered 432 patients (pre- vs post implementation, 274 vs 158). Diagnostic criteria for nosocomial pneumonia were more likely to be met during post-implementation (247/257 (96.1%) vs 150/151 (99.3%); P = 0.06). Similarly, empiric antibiotics were more likely to be compliant with ATS/IDSA guidelines during post-implementation (79/257 (30.7%) vs 66/151 (43.7%); P = 0.01), an effect that was sustained over quarterly intervals (P = 0.0008). Between-period differences in compliance with obtaining cultures and use of de-escalation were not statistically significant. CONCLUSIONS: Developing a multi-center performance improvement project to operationalize ATS/IDSA guidelines for HAP, VAP, and HCAP is feasible with local consensus pathway directives for implementation and with quality indicators for monitoring compliance with guidelines. PMID- 21266064 TI - Pathophysiology, treatment, and animal and cellular models of human ischemic stroke. AB - Stroke is the world's second leading cause of mortality, with a high incidence of severe morbidity in surviving victims. There are currently relatively few treatment options available to minimize tissue death following a stroke. As such, there is a pressing need to explore, at a molecular, cellular, tissue, and whole body level, the mechanisms leading to damage and death of CNS tissue following an ischemic brain event. This review explores the etiology and pathogenesis of ischemic stroke, and provides a general model of such. The pathophysiology of cerebral ischemic injury is explained, and experimental animal models of global and focal ischemic stroke, and in vitro cellular stroke models, are described in detail along with experimental strategies to analyze the injuries. In particular, the technical aspects of these stroke models are assessed and critically evaluated, along with detailed descriptions of the current best-practice murine models of ischemic stroke. Finally, we review preclinical studies using different strategies in experimental models, followed by an evaluation of results of recent, and failed attempts of neuroprotection in human clinical trials. We also explore new and emerging approaches for the prevention and treatment of stroke. In this regard, we note that single-target drug therapies for stroke therapy, have thus far universally failed in clinical trials. The need to investigate new targets for stroke treatments, which have pleiotropic therapeutic effects in the brain, is explored as an alternate strategy, and some such possible targets are elaborated. Developing therapeutic treatments for ischemic stroke is an intrinsically difficult endeavour. The heterogeneity of the causes, the anatomical complexity of the brain, and the practicalities of the victim receiving both timely and effective treatment, conspire against developing effective drug therapies. This should in no way be a disincentive to research, but instead, a clarion call to intensify efforts to ameliorate suffering and death from this common health catastrophe. This review aims to summarize both the present experimental and clinical state-of-the art, and to guide future research directions. PMID- 21266066 TI - Hip abductor moment arm--a mathematical analysis for proximal femoral replacement. AB - BACKGROUND: Patients undergoing proximal femoral replacement for tumor resection often have compromised hip abductor muscles resulting in a Trendelenberg limp and hip instability. Commercially available proximal femoral prostheses offer several designs with varying sites of attachment for the abductor muscles, however, no analyses of these configurations have been performed to determine which design provides the longest moment arm for the hip abductor muscles during normal function. METHODS: This study analyzed hip abductor moment arm through hip adduction and abduction with a trigonometric mathematical model to evaluate the effects of alterations in anatomy and proximal femoral prosthesis design. Prosthesis dimensions were taken from technical schematics that were obtained from the prosthesis manufacturers. Manufacturers who contributed schematics for this investigation were Stryker Orthopaedics and Biomet. RESULTS: Superior and lateral displacement of the greater trochanter increased the hip abductor mechanical advantage for single-leg stance and adduction and preserved moment arm in the setting of Trendelenberg gait. Hip joint medialization resulted in less variance of the abductor moment arm through coronal motion. The Stryker GMRS endoprosthesis provided the longest moment arm in single-leg stance. CONCLUSIONS: Hip abductor moment arm varies substantially throughout the hip's range of motion in the coronal plane. Selection of a proximal femur endoprosthesis with an abductor muscle insertion that is located superiorly and laterally will optimize hip abductor moment arm in single-leg stance compared to one located inferiorly or medially. PMID- 21266067 TI - Evolutionary patterns of two major reproduction candidate genes (Zp2 and Zp3) reveal no contribution to reproductive isolation between bovine species. AB - BACKGROUND: It has been established that mammalian egg zona pellucida (ZP) glycoproteins are responsible for species-restricted binding of sperm to unfertilized eggs, inducing the sperm acrosome reaction, and preventing polyspermy. In mammals, ZP apparently represents a barrier to heterospecific fertilization and thus probably contributes to reproductive isolation between species. The evolutionary relationships between some members of the tribe Bovini are complex and highly debatable, particularly, those involving Bos and Bison species for which interspecific hybridization is extensively documented. Because reproductive isolation is known to be a major precursor of species divergence, testing evolutionary patterns of ZP glycoproteins may shed some light into the speciation process of these species. To this end, we have examined intraspecific and interspecific genetic variation of two ZP genes (Zp2 and Zp3) for seven representative species (111 individuals) from the Bovini tribe, including five species from Bos and Bison, and two species each from genera Bubalus and Syncerus. RESULTS: A pattern of low levels of intraspecific polymorphism and interspecific divergence was detected for the two sequenced fragments each for Zp2 and Zp3. At intraspecific level, none of neutrality tests detected deviations from neutral equilibrium expectations for the two genes. Several haplotypes in both genes were shared by multiple species from Bos and Bison. CONCLUSIONS: Here we argue that neither ancestral polymorphism nor introgressive hybridization alone can fully account for haplotype sharing among species from Bos and Bison, and that both scenarios have contributed to such a pattern of haplotype sharing observed here. Additionally, codon-based tests revealed strong evidence for purifying selection in the Zp3 coding haplotype sequences and weak evidence for purifying selection in the Zp2 coding haplotype sequences. Contrary to a general genetic pattern that genes or genomic regions contributing to reproductive isolation between species often evolve rapidly and show little or no gene flow between species, these results demonstrate that, particularly, those sequenced exons of the Zp2 and the Zp3 did not show any contribution to reproductive isolation between the bovine species studied here. PMID- 21266069 TI - Larval migration in PERL chambers as an in vitro model for percutaneous infection stimulates feeding in the canine hookworm Ancylostoma caninum. AB - BACKGROUND: Ancylostoma caninum third-stage larvae are the non-feeding infective stage of this parasite and are able to infect potential hosts via different infection routes. Since percutaneous infection is one of the most important routes and skin penetration is the first step into parasitic life, an existing in vitro model for percutaneous migration was modified and evaluated. The main parameter used to evaluate migration was the migration ratio (migrated larvae as a percentage of total number of larvae recovered). Additionally, the skin lag was calculated, expressing the percentage of larvae remaining in the skin and therefore not being recovered. Since initiation of feeding is proposed to be an important step in the transition from free-living to parasitic A. caninum larvae, feeding assays were performed with in vitro percutaneously migrated larvae. Additionally, infective larvae of A. caninum were activated via serum-stimulation and feeding behaviour was analysed and compared between percutaneously migrated and serum-stimulated larvae. RESULTS: Maximum skin migration levels of infective larvae were observed at temperatures above 32 degrees C when larvae were placed on the epidermal side of skin for more than 12 hours. The medium beneath the skin had no effect on migration ratio, and no significant difference between the migration ratios through fresh and frozen/thawed skin was observed. Maximum feeding levels of 93.2% were observed for percutaneously migrated larvae after 48 h incubation, whereas serum-stimulated larvae reached the maximum of 91.0% feeding larvae after 24 h. CONCLUSIONS: The PERL chamber system was optimised and standardised as an in vitro model for percutaneous migration. The larvae recovered after percutaneous migration showed characteristic signs of activation similar to that of serum-stimulated larvae. The observed difference in time course of resumption of feeding indicates that percutaneously migrated larvae are not identical to serum-stimulated larvae, which are currently representing the model for early parasitic stages. PMID- 21266070 TI - Participating in a Community of Learners enhances resident perceptions of learning in an e-mentoring program: proof of concept. AB - BACKGROUND: Community learning and e-mentoring, learning methods used in higher education, are not used to any extent in residency education. Yet both have the potential to enhance resident learning and, in the case of community learning, introduce residents to basic lifelong learning skills. We set out to determine whether residents participating in an Internet based e-mentoring program would, with appropriate facilitation, form a community of learners (CoL) and hold regular community meetings. We also determined resident and faculty perceptions of CoL and Internet sessions as effective learning experiences. METHODS: A six month e-mentoring pilot was offered to 10 Radiology residents in the Aga Khan University Postgraduate Medical Education Program in Nairobi, Kenya (AKUHN) with a Professor of Radiology, located at University of Virginia, USA, acting as the e mentor. Monthly Internet case-based teaching sessions were facilitated by the e mentor. In addition, residents were coached by a community facilitator to form CoL and collectively work through clinical cases at weekly face-to-face CoL sessions.Event logs described observed resident activity at CoL sessions; exit survey and interviews were used to elicit perceptions of CoL and Internet sessions as effective learning experiences. RESULTS: Resident adoption of CoL behaviors was observed, including self-regulation, peer mentoring and collaborative problem solving. Analysis revealed high resident enthusiasm and value for CoL. Surveys and interviews indicated high levels of acceptance of Internet learning experiences, although there was room for improvement in audio visual transmission technologies. Faculty indicated there was a need for a larger multi-specialty study. CONCLUSIONS: The pilot demonstrated resident acceptance of community building and collaborative learning as valued learning experiences, addressing one barrier to its formal adoption in residency education curricula. It also highlighted the potential of e-mentoring as a means of expanding faculty and teaching materials in residency programs in developing countries. PMID- 21266068 TI - Long-term CD4+ T-cell count evolution after switching from regimens including HIV nucleoside reverse transcriptase inhibitors (NRTI) plus protease inhibitors to regimens containing NRTI plus non-NRTI or only NRTI. AB - BACKGROUND: Data regarding CD4+ recovery after switching from protease inhibitor (PI)-based regimens to regimens not containing PI are scarce. METHODS: Subjects with virological success on first-PI-regimens who switched to NNRTI therapy (NNRTI group) or to nucleoside reverse transcriptase (NRTI)-only (NRTI group) were studied. The effect of the switch on the ongoing CD4+ trend was assessed by two-phase linear regression (TPLR), allowing us to evaluate whether a change in the CD4+ trend (hinge) occurred and the time of its occurrence. Furthermore, we described the evolution of the frequencies in CD4-count classes across four relevant time-points (baseline, before and immediately after the switch, and last visit). Finally, we explored whether the CD4+ counts evolved differently in patients who switched to NNRTI or NRTI-only regimens by considering: the overall CD4+ trends, the time to CD4+>= 500/mm3 after the switch, and the area-under-the curve (AUC) of the CD4+ after the switch. RESULTS: Eight hundred and ninety-six patients, followed for a median of 2,121 days, were included. At TPLR, hinges occurred in 581/844 (68.9%), but in only 40/581 (6.9%) within a time interval (180 days) compatible with a possible relationship to the switch; furthermore, in 19/40 cases, CD4+ counts appeared to decrease after the hinges. In comparison with the NNRTI group, the NRTI group showed CD4+ count greater at baseline (P = 0.0234) and before the switch (P <= 0.0001), superior CD4+ T-cell increases after HAART was started, lower probability of not achieving CD4+ >= 500/mm3 (P = 0.0024), and, finally, no significant differences in the CD4+ T-cell AUC after the switch after adjusting for possible confounders (propensity score and pre switch AUC). Persistence at CD4+ < 200/mm3 was observed in 34/435 (7.5%) patients, and a decrease below this level was found in only 10/259 (3.9%) with baseline CD4+ >= 350/mm3. CONCLUSIONS: Switching from first-line PI to NNRTI- or NRTI-based regimens did not seem to impair CD4+ trend over long-term follow-up. Although the greater CD4+ increases in patients who switched to the NRTI-only regimen was due to higher CD4+ counts before the switch, several statistical analyses consistently showed that switching to this regimen did not damage the ongoing immune-reconstitution. Lastly, the observation that CD4+ T-cell counts remained low or decreased in the long term despite virological success merits further investigation. PMID- 21266071 TI - Characterization of the Conus bullatus genome and its venom-duct transcriptome. AB - BACKGROUND: The venomous marine gastropods, cone snails (genus Conus), inject prey with a lethal cocktail of conopeptides, small cysteine-rich peptides, each with a high affinity for its molecular target, generally an ion channel, receptor or transporter. Over the last decade, conopeptides have proven indispensable reagents for the study of vertebrate neurotransmission. Conus bullatus belongs to a clade of Conus species called Textilia, whose pharmacology is still poorly characterized. Thus the genomics analyses presented here provide the first step toward a better understanding the enigmatic Textilia clade. RESULTS: We have carried out a sequencing survey of the Conus bullatus genome and venom-duct transcriptome. We find that conopeptides are highly expressed within the venom duct, and describe an in silico pipeline for their discovery and characterization using RNA-seq data. We have also carried out low-coverage shotgun sequencing of the genome, and have used these data to determine its size, genome-wide base composition, simple repeat, and mobile element densities. CONCLUSIONS: Our results provide the first global view of venom-duct transcription in any cone snail. A notable feature of Conus bullatus venoms is the breadth of A-superfamily peptides expressed in the venom duct, which are unprecedented in their structural diversity. We also find SNP rates within conopeptides are higher compared to the remainder of C. bullatus transcriptome, consistent with the hypothesis that conopeptides are under diversifying selection. PMID- 21266072 TI - Reverse Delta-wave as a possible sign in electrocardiography to diagnose mitral valve prolapse. AB - BACKGROUND: Mitral valve prolapse (MVP) is defined as superior displacement of the mitral valve leaflets more than 2 mm into the left atrium during systole. Easier and cheaper assessment of this common disease is a priority in cardiac health care facilities. PRESENTATION OF THE HYPOTHESIS: In this study I addressed electrocardiographic presentation in 300 patients with MVP compared with 100 healthy individuals. I faced a novel finding in electrocardiogram (ECG) examination of these patients. It was a notch (reverse Delta-wave) in descending arm of QRS observed in 79% (237/300) of patients, consisting of 58% (174/300) in inferior leads and 21% (63/300) in I and aVL leads. The notch was identified only in 6 men in control group. TESTING THE HYPOTHESIS: Considering the relatively higher prevalence of disease, a population-based diagnostic clinical trial study is appropriate to test the hypothesis. IMPLICATIONS OF THE HYPOTHESIS: The hypothesis on diagnostic value of reverse Delta-wave in MVP may help in decreasing the rate of unnessessary echocardiography in some patients. PMID- 21266073 TI - Nanosilver induces minimal lung toxicity or inflammation in a subacute murine inhalation model. AB - BACKGROUND: There is increasing interest in the environmental and health consequences of silver nanoparticles as the use of this material becomes widespread. Although human exposure to nanosilver is increasing, only a few studies address possible toxic effect of inhaled nanosilver. The objective of this study was to determine whether very small commercially available nanosilver induces pulmonary toxicity in mice following inhalation exposure. RESULTS: In this study, mice were exposed sub-acutely by inhalation to well-characterized nanosilver (3.3 mg/m3, 4 hours/day, 10 days, 5 +/- 2 nm primary size). Toxicity was assessed by enumeration of total and differential cells, determination of total protein, lactate dehydrogenase activity and inflammatory cytokines in bronchoalveolar lavage fluid. Lungs were evaluated for histopathologic changes and the presence of silver. In contrast to published in vitro studies, minimal inflammatory response or toxicity was found following exposure to nanosilver in our in vivo study. The median retained dose of nanosilver in the lungs measured by inductively coupled plasma-optical emission spectroscopy (ICP-OES) was 31 MUg/g lung (dry weight) immediately after the final exposure, 10 MUg/g following exposure and a 3-wk rest period and zero in sham-exposed controls. Dissolution studies showed that nanosilver did not dissolve in solutions mimicking the intracellular or extracellular milieu. CONCLUSIONS: Mice exposed to nanosilver showed minimal pulmonary inflammation or cytotoxicity following sub-acute exposures. However, longer term exposures with higher lung burdens of nanosilver are needed to ensure that there are no chronic effects and to evaluate possible translocation to other organs. PMID- 21266074 TI - Delivering high-resolution landmarks using inkjet micropatterning for spatial monitoring of leaf expansion. AB - BACKGROUND: Inkjet micropatterning is a versatile deposition technique with broad applications in numerous fields. However, its application in plant science is largely unexplored. Leaf expansion is one of the most important parameters in the field of plant science and many methods have been developed to examine differential expansion rates of different parts of the leaf lamina. Among them, methods based on the tracking of natural landmarks through digital imaging require a complicated setup in which the leaf must remain fixed and under tension. Furthermore, the resolution is limited to that of the natural landmarks, which are often difficult to find, particularly in young leaves. To study the fine scale expansion dynamics of the leaf lamina using artificial landmarks it is necessary to place small, noninvasive marks on a leaf surface and then recover the location of those marks after a period of time. RESULTS: To monitor leaf expansion in two dimensions, at very fine scales, we used a custom designed inkjet micropatterning system to print a grid composed of c. 0.19 mm2 cells on small developing leaves of ivy (Hedera helix) using 40 MUm dots at a spacing of c. 91 MUm. The leaves in different growing stages were imaged under magnification to extract the coordinates of the marks which were then used in subsequent computer-assisted leaf expansion analyses. As an example we obtained quantified global and local expansion information and created expansion maps over the entire leaf surface. The results reveal a striking pattern of fine-scale expansion differences over short periods of time. In these experiments, the base of the leaf is a "cold spot" for expansion, while the leaf sinuses are "hot spots" for expansion. We have also measured a strong shading effect on leaf expansion. We discuss the features required to build an inkjet printing apparatus optimized for use in plant science, which will further maximize the range of tissues that can be printed at these scales. CONCLUSIONS: To apply inkjet micropatterning to plant studies, we have successfully delivered landmarks on ivy leaf surfaces and achieved high-resolution, two-dimensional monitoring of leaf expansion at different growing stages. The measurement is capable of reliably identifying the fine scale changes during plant growth. As well as delivering landmarks, this technology may be used to deliver microscale targeted biological components such as growth hormones, and possibly be used to pattern sensors directly on the leaves. PMID- 21266075 TI - Mathematical model of uptake and metabolism of arsenic(III) in human hepatocytes Incorporation of cellular antioxidant response and threshold-dependent behavior. AB - BACKGROUND: Arsenic is an environmental pollutant, potent human toxicant, and oxidative stress agent with a multiplicity of health effects associated with both acute and chronic exposures. A semi-mechanistic cellular-level toxicokinetic (TK) model was developed in order to describe the uptake, biotransformation and clearance of arsenical species in human hepatocytes. Notable features of this model are the incorporation of arsenic-glutathione complex formation and a "switch-like" formulation to describe the antioxidant response of hepatocytes to arsenic exposure. RESULTS: The cellular-level TK model applies mass action kinetics in order to predict the concentrations of trivalent and pentavalent arsenicals in hepatocytes. The model simulates uptake of arsenite (iAsIII) via aquaporin isozymes 9 (AQP9s), glutathione (GSH) conjugation, methylation by arsenic methyltransferase (AS3MT), efflux through multidrug resistant proteins (MRPs) and the induced antioxidant response via thioredoxin reductase (TR) activity. The model was parameterized by optimization of model estimates for arsenite (iAsIII), monomethylated (MMA) and dimethylated (DMA) arsenicals concentrations with time-course experimental data in human hepatocytes for a time span of 48 hours, and dose-response data at 24 hours for a range of arsenite concentrations from 0.1 to 10 MUM. Global sensitivity analysis of the model showed that at low doses the transport parameters had a dominant role, whereas at higher doses the biotransformation parameters were the most significant. A parametric comparison of the TK model with an analogous model developed for rat hepatocytes from the literature demonstrated that the biotransformation of arsenite (e.g. GSH conjugation) has a large role in explaining the variation in methylation between rats and humans. CONCLUSIONS: The cellular-level TK model captures the temporal modes of arsenical accumulation in human hepatocytes. It highlighted the key biological processes that influence arsenic metabolism by explicitly modelling the metabolic network of GSH-adducts formation. The parametric comparison with the TK model developed for rats suggests that the variability in GSH conjugation could have an important role in inter-species variability of arsenical methylation. The TK model can be incorporated into larger-scale physiologically based toxicokinetic (PBTK) models of arsenic for improving the estimates of PBTK model parameters. PMID- 21266076 TI - Access and use of human tissues from the developing world: ethical challenges and a way forward using a tissue trust. AB - BACKGROUND: Scientists engaged in global health research are increasingly faced with barriers to access and use of human tissues from the developing world communities where much of their research is targeted. In part, the problem can be traced to distrust of researchers from affluent countries, given the history of 'scientific-imperialism' and 'biocolonialism' reflected in past well publicized cases of exploitation of research participants from low to middle income countries. DISCUSSION: To a considerable extent, the failure to adequately engage host communities, the opacity of informed consent, and the lack of fair benefit sharing have played a significant role in eroding trust. These ethical considerations are central to biomedical research in low to middle income countries and failure to attend to them can inadvertently contribute to exploitation and erode trust. A 'tissue trust' may be a plausible means for enabling access to human tissues for research in a manner that is responsive to the ethical challenges considered. SUMMARY: Preventing exploitation and restoring trust while simultaneously promoting global health research calls for innovative approaches to human tissues research. A tissue trust can reduce the risk of exploitation and promote host capacity as a key benefit. PMID- 21266077 TI - MicroRNA-34a is a potent tumor suppressor molecule in vivo in neuroblastoma. AB - BACKGROUND: Neuroblastoma is a paediatric cancer which originates from precursor cells of the sympathetic nervous system and accounts for 15% of childhood cancer mortalities. With regards to the role of miRNAs in neuroblastoma, miR-34a, mapping to a chromosome 1p36 region that is commonly deleted, has been found to act as a tumor suppressor through targeting of numerous genes associated with cell proliferation and apoptosis. METHODS: A synthetic miR-34a (or negative control) precursor molecule was transfected into NB1691luc and SK-N-ASluc neuroblastoma cells. Quantitative PCR was used to verify increased miR-34a levels in NB1691luc and SK-N-ASluc cell lines prior to in vitro and in vivo analysis. In vitro analysis of the effects of miR-34a over expression on cell growth, cell cycle and phosphoprotein activation in signal transduction pathways was performed. Neuroblastoma cells over expressing miR-34a were injected retroperitoneally into immunocompromised CB17-SCID mice and tumor burden was assessed over a 21 day period by measuring bioluminescence (photons/sec/cm2). RESULTS: Over expression of miR-34a in both NB1691luc and SK-N-ASluc neuroblastoma cell lines led to a significant decrease in cell number relative to premiR-negative control treated cells over a 72 hour period. Flow cytometry results indicated that miR-34a induced cell cycle arrest and subsequent apoptosis activation. Phosphoprotein analysis highlighted key elements involved in signal transduction, whose activation was dysregulated as a result of miR-34a introduction into cells. As a potential mechanism of miR-34a action on phosphoprotein levels, we demonstrate that miR-34a over-expression results in a significant reduction of MAP3K9 mRNA and protein levels. Although MAP3K9 is a predicted target of miR-34a, direct targeting could not be validated with luciferase reporter assays. Despite this fact, any functional effects of reduced MAP3K9 expression as a result of miR-34a would be expected to be similar regardless of the mechanism involved. Most notably, in vivo studies showed that tumor growth was significantly repressed after exogenous miR-34a administration in retroperitoneal neuroblastoma tumors. CONCLUSION: We demonstrate for the first time that miR-34a significantly reduces tumor growth in an in vivo orthotopic murine model of neuroblastoma and identified novel effects that miR-34a has on phospho-activation of key proteins involved with apoptosis. PMID- 21266078 TI - The combination of the entomopathogenic fungus Metarhizium anisopliae with the insecticide Imidacloprid increases virulence against the dengue vector Aedes aegypti (Diptera: Culicidae). AB - BACKGROUND: Dengue fever transmitted by the mosquito Aedes aegypti, is one of the most rapidly spreading insect borne diseases, stimulating the search for alternatives to current control measures. The dengue vector A. aegypti has received less attention than anophelene species, although more than 2.5 billion people are at risk of infection worldwide. Entomopathogenic fungi are emerging as potential candidates for the control of mosquitoes. Here we continue our studies on the pathogenicity of the entomopathogenic fungus Metarhizium anisopliae against adult A. aegypti females. With the aim of further reducing mean survival times of A. aegypti exposed to fungus impregnated surfaces, a sub-lethal concentration of the neonicotinoid insecticide Imidacloprid (IMI) was added to fungal suspensions. RESULTS: A sub-lethal concentration of IMI that did not significantly alter the daily survival rates or mean survival percentages of mosquitoes was identified to be 0.1 ppm. This sub-lethal concentration was combined with M. anisopliae conidia (1 * 10(9) conidia mL(-1)). Both the combined treatment and the conidia alone were able to reduce the survival of A. aegypti compared with untreated or IMI treated mosquitoes. Importantly, mosquito survival following exposure to the combined treatment for 6 and 12 hrs was significantly reduced when compared with mosquitoes exposed to conidia alone. CONCLUSIONS: This is the first time that a combination of an insecticide and an entomopathogenic fungus has been tested against A. aegypti. Firstly, the study showed the potential of IMI as an alternative to the currently employed pyrethroid adulticides. Secondly, as an alternative to applications of high concentrations of chemical insecticides, we suggest that adult A. aegypti could be controlled by surface application of entomopathogenic fungi and that the efficiency of these fungi could be increased by combining the fungi with ultra-low concentrations of insecticides, resulting in higher mortality following relatively short exposure times. PMID- 21266079 TI - Distribution of Leishmania major zymodemes in relation to populations of Phlebotomus papatasi sand flies. AB - Phlebotomus papatasi (Scopoli) (Diptera: Psychodidae) is the main vector of Leishmania major Yakimoff & Schokhor (Kinetoplastida: Trypanosomatidae), the causative agent of zoonotic cutaneous leishmaniasis in the Old World. Multilocus enzyme electrophoresis (MLEE) was extensively used to type different L. major stocks all over the world. Multilocus microsatellite typing (MLMT) has been recently used to investigate P. papatasi sand flies at population and subpopulation levels. In this article, the association between geographical distribution of L. major zymodemes and the distribution of populations and subpopulations of L. major vector; P. papatasi are discussed. PMID- 21266080 TI - An uncommon cause of seizures in children living in developed countries: neurocysticercosis--a case report. AB - Neurocysticercosis represents an important cause of seizures in children in endemic countries, such as Latin America, Asia and sub-Saharan Africa, while in Europe, especially in Italy, the cases of neurocysticercosis are anectodal. We report the case of a 6 year old boy, born and lived for four years in Cameroon, who presented a right emiconvulsion. The diagnosis was neurocysticercosis. This case accentuates the need to consider neurocysticercosis in a child presenting with non febrile seizures, mainly if he emigrated from an area of high prevalence or if he had long-term stay in endemic regions. PMID- 21266081 TI - The hylEfm gene in pHylEfm of Enterococcus faecium is not required in pathogenesis of murine peritonitis. AB - BACKGROUND: Plasmids containing hylEfm (pHylEfm) were previously shown to increase gastrointestinal colonization and lethality of Enterococcus faecium in experimental peritonitis. The hylEfm gene, predicting a glycosyl hydrolase, has been considered as a virulence determinant of hospital-associated E. faecium, although its direct contribution to virulence has not been investigated. Here, we constructed mutants of the hylEfm-region and we evaluated their effect on virulence using a murine peritonitis model. RESULTS: Five mutants of the hylEfm region of pHylEfmTX16 from the sequenced endocarditis strain (TX16 [DO]) were obtained using an adaptation of the PheS* system and were evaluated in a commensal strain TX1330RF to which pHylEfmTX16 was transferred by mating; these include i) deletion of hylEfm only; ii) deletion of the gene downstream of hylEfm (down) of unknown function; iii) deletion of hylEfm plus down; iv) deletion of hylEfm-down and two adjacent genes; and v) a 7,534 bp deletion including these four genes plus partial deletion of two others, with replacement by cat. The 7,534 bp deletion did not affect virulence of TX16 in peritonitis but, when pHylEfmTX16Delta7,534 was transferred to the TX1330RF background, the transconjugant was affected in in vitro growth versus TX1330RF(pHylEfmTX16) and was attenuated in virulence; however, neither hylEfm nor hylEfm-down restored wild type function. We did not observe any in vivo effect on virulence of the other deletions of the hylEfm-region CONCLUSIONS: The four genes of the hylEfm region (including hylEfm) do not mediate the increased virulence conferred by pHylEfmTX16 in murine peritonitis. The use of the markerless counterselection system PheS* should facilitate the genetic manipulation of E. faecium in the future. PMID- 21266082 TI - CX3CL1 reduces neurotoxicity and microglial activation in a rat model of Parkinson's disease. AB - BACKGROUND: Parkinson's disease is characterized by a progressive loss of dopaminergic neurons in the substantia nigra. The cause of the neurodegeneration is unknown. Neuroinflammation has been clearly shown in Parkinson's disease and may be involved in the progressive nature of the disease. Microglia are capable of producing neuronal damage through the production of bioactive molecules such as cytokines, as well as reactive oxygen species (ROS), and nitric oxide (NO). The inflammatory response in the brain is tightly regulated at multiple levels. One form of immune regulation occurs via neurons. Fractalkine (CX3CL1), produced by neurons, suppresses the activation of microglia. CX3CL1 is constitutively expressed. It is not known if addition of exogenous CX3CL1 beyond otherwise physiologically normal levels could decrease microglia activation and thereby minimize the secondary neurodegeneration following a neurotoxic insult. METHODS: The intrastriatal 6-hydroxydopamine (6-OHDA) rat model of Parkinson disease, was used to test the hypothesis that exogenous CX3CL1 could be neuroprotective. Treatment with recombinant CX3CL1 was delivered to the striatum by an osmotic minipump for 28 days beginning 7 days after the initial insult. Unbiased stereological methods were used to quantify the lesion size in the striatum, the amount of neuronal loss in the substantia nigra, and the amount of microglia activation. RESULTS: As hypothesized, CX3CL1 was able to suppress this microglia activation. The reduced microglia activation was found to be neuroprotective as the CX3CL1 treated rats had a smaller lesion volume in the striatum and importantly significantly fewer neurons were lost in the CX3CL1 treated rats. CONCLUSION: These findings demonstrated that CX3CL1 plays a neuroprotective role in 6-OHDA-induced dopaminergic lesion and it might be an effective therapeutic target for many neurodegenerative diseases, including Parkinson disease and Alzheimer disease, where inflammation plays an important role. PMID- 21266083 TI - The maternal and early embryonic transcriptome of the milkweed bug Oncopeltus fasciatus. AB - BACKGROUND: Most evolutionary developmental biology ("evo-devo") studies of emerging model organisms focus on small numbers of candidate genes cloned individually using degenerate PCR. However, newly available sequencing technologies such as 454 pyrosequencing have recently begun to allow for massive gene discovery in animals without sequenced genomes. Within insects, although large volumes of sequence data are available for holometabolous insects, developmental studies of basally branching hemimetabolous insects typically suffer from low rates of gene discovery. RESULTS: We used 454 pyrosequencing to sequence over 500 million bases of cDNA from the ovaries and embryos of the milkweed bug Oncopeltus fasciatus, which lacks a sequenced genome. This indirectly developing insect occupies an important phylogenetic position, branching basal to Diptera (including fruit flies) and Hymenoptera (including honeybees), and is an experimentally tractable model for short-germ development. 2,087,410 reads from both normalized and non-normalized cDNA assembled into 21,097 sequences (isotigs) and 112,531 singletons. The assembled sequences fell into 16,617 unique gene models, and included predictions of splicing isoforms, which we examined experimentally. Discovery of new genes plateaued after assembly of ~1.5 million reads, suggesting that we have sequenced nearly all transcripts present in the cDNA sampled. Many transcripts have been assembled at close to full length, and there is a net gain of sequence data for over half of the pre existing O. fasciatus accessions for developmental genes in GenBank. We identified 10,775 unique genes, including members of all major conserved metazoan signaling pathways and genes involved in several major categories of early developmental processes. We also specifically address the effects of cDNA normalization on gene discovery in de novo transcriptome analyses. CONCLUSIONS: Our sequencing, assembly and annotation framework provide a simple and effective way to achieve high-throughput gene discovery for organisms lacking a sequenced genome. These data will have applications to the study of the evolution of arthropod genes and genetic pathways, and to the wider evolution, development and genomics communities working with emerging model organisms.[The sequence data from this study have been submitted to GenBank under study accession number SRP002610 (http://www.ncbi.nlm.nih.gov/sra?term=SRP002610). Custom scripts generated are available at http://www.extavourlab.com/protocols/index.html. Seven Additional files are available.]. PMID- 21266084 TI - Effectiveness of Cheneau brace treatment for idiopathic scoliosis: prospective study in 79 patients followed to skeletal maturity. AB - BACKGROUND: Progressive idiopathic scoliosis can negatively influence the development and functioning of 2-3% of adolescents, with health consequences and economic costs, placing the disease in the centre of interest of the developmental medicine. The aim of this study was to evaluate the effectiveness of Cheneau brace in the management of idiopathic scoliosis. METHODS: A prospective observational study according to SOSORT and SRS recommendations comprised 79 patients (58 girls and 21 boys) with progressive idiopathic scoliosis, treated with Cheneau brace and physiotherapy, with initial Cobb angle between 20 and 45 degrees, no previous brace treatment, Risser 4 or more at the final evaluation and minimum one year follow-up after weaning the brace. Achieving 50 degrees of Cobb angle was considered surgical recommendation. RESULTS: At follow-up 20 patients (25.3%) improved, 18 patients (22.8%) were stable, 31 patients (39.2%) progressed below 50 degrees and 10 patients (12.7%) progressed beyond 50 degrees (2 of these 10 patients progressed beyond 60 degrees). Progression concerned the younger and less skeletally mature patients. CONCLUSION: Conservative treatment with Cheneau orthosis and physiotherapy was effective in halting scoliosis progression in 48.1% of patients. The results of this study suggest that bracing is effective in reducing the incidence of surgery in comparison with natural history. PMID- 21266085 TI - Knowledge and attitudes of healthcare workers in Chinese intensive care units regarding 2009 H1N1 influenza pandemic. AB - BACKGROUND: To describe the knowledge and attitudes of critical care clinicians during the 2009 H1N1 influenza pandemic. METHODS: A survey conducted in 21 intensive care units in 17 provinces in China. RESULTS: Out of 733 questionnaires distributed, 695 were completed. Three hundred and fifty-six respondents (51.2%) reported their experience of caring for H1N1 patients. Despite the fact that 88.5% of all respondents ultimately finished an H1N1 training program, only 41.9% admitted that they had the knowledge of 2009 H1N1 influenza. A total of 572 respondents (82.3%) expressed willingness to care for H1N1 patients. Independent variables associated with increasing likelihood to care for patients in the logistic regression analysis were physicians or nurses rather than other professionals (odds ratio 4.056 and 3.235, p = 0.002 and 0.007, respectively), knowledge training prior to patient care (odds ratio 1.531, p = 0.044), and the confidence to know how to protect themselves and their patients (odds ratio 2.109, p = 0.001). CONCLUSION: Critical care clinicians reported poor knowledge of H1N1 influenza, even though most finished a relevant knowledge training program. Implementation of appropriate education program might improve compliance to infection control measures, and willingness to work in a pandemic. PMID- 21266086 TI - Hemangioma in a pulmonary hilar lymph node: case report. AB - BACKGROUND: Different types of vascular proliferation may occur in lymph nodes, but hemangiomas in lymph nodes are extremely rare. CASE PRESENTATION: A 73-year old man was found to have a 15-mm nodular shadow in the left lung on computed tomography, and bronchoscopic brush cytology yielded a diagnosis of squamous cell carcinoma. Chest computed tomography showed no evidence of hilar or mediastinal lymphadenopathy. Left lower lobectomy with hilar and mediastinal lymph node dissection was performed. Postoperative histopathological examination revealed squamous cell carcinoma and no lymph node metastasis. On the other hand, a lobar bronchial lymph node presented a small lesion showing the dense proliferation of capillary blood vessels with elastic change. Immunohistochemically, the lesion was positive for factor VIII and CD34, leading to a diagnosis of primary hemangioma of the lymph node. CONCLUSION: To our knowledge, this is the first case reported in the literature of hemangioma in a pulmonary hilar lymph node. Intranodal hemangioma needs to be differentiated from malignant vascular tumors. PMID- 21266087 TI - Burden of disease in Thailand: changes in health gap between 1999 and 2004. AB - BACKGROUND: Continuing comprehensive assessment of population health gap is essential for effective health planning. This paper assessed changes in the magnitude and pattern of disease burden in Thailand between 1999 and 2004. It further drew lessons learned from applying the global burden of disease (GBD) methods to the Thai context for other developing country settings. METHODS: Multiple sources of mortality and morbidity data for both years were assessed and used to estimate Disability-Adjusted Life Years (DALYs) loss for 110 specific diseases and conditions relevant to the country's health problems. Causes of death from national vital registration were adjusted for misclassification from a verbal autopsy study. RESULTS: Between 1999 and 2004, DALYs loss per 1,000 population in 2004 slightly decreased in men but a minor increase in women was observed. HIV/AIDS maintained the highest burden for men in both 1999 and 2004 while in 2004, stroke took over the 1999 first rank of HIV/AIDS in women. Among the top twenty diseases, there was a slight increase of the proportion of non communicable diseases and two out of three infectious diseases revealed a decrease burden except for lower respiratory tract infections. CONCLUSION: The study highlights unique pattern of disease burden in Thailand whereby epidemiological transition have occurred as non-communicable diseases were on the rise but burden from HIV/AIDS resulting from the epidemic in the 1990s remains high and injuries show negligent change. Lessons point that assessing DALY over time critically requires continuing improvement in data sources particularly on cause of death statistics, institutional capacity and long term commitments. PMID- 21266088 TI - The boron-oxygen core of borinate esters is responsible for the store-operated calcium entry potentiation ability. AB - BACKGROUND: Store-Operated Calcium Entry (SOCE) is the major Ca2+ ion entry pathway in lymphocytes and is responsible of a severe combined immunodeficiency (SCID) when deficient. It has recently been observed or highlighted in other cell types such as myoblasts and neurons, suggesting a wider physiological role of this pathway. Whereas Orai1 protein is considered to be the channel allowing the SOCE in T cells, it is hypothesized that other proteins like TRPC could associate with Orai1 to form SOCE with different pharmacology and kinetics in other cell types. Unraveling SOCE cell functions requires specific effectors to be identified, just as dihydropyridines were crucial for the study of Ca2+ voltage gated channels, or spider/snake toxins for other ion channel classes. To identify novel SOCE effectors, we analyzed the effects of 2-aminoethyl diphenylborinate (2 APB) and its analogues. 2-APB is a molecule known to both potentiate and inhibit T cell SOCE, but it is also an effector of TRP channels and endoplasmic reticulum Ca2+-ATPase. RESULTS: A structure-function analysis allowed to discover that the boron-oxygen core present in 2-APB and in the borinate ester analogues is absolutely required for the dual effects on SOCE. Indeed, a 2-APB analogue where the boron-oxygen core is replaced by a carbon-phosphorus core is devoid of potentiating capacity (while retaining inhibition capacity), highlighting the key role of the boron-oxygen core present in borinate esters for the potentiation function. However, dimesityl borinate ester, a 2-APB analogue with a terminal B OH group showed an efficient inhibitory ability, without any potentiating capacity. The removal or addition of phenyl groups respectively decrease or increase the efficiency of the borinate esters to potentiate and inhibit the SOCE. mRNA expression revealed that Jurkat T cells mainly expressed Orai1, and were the more sensitive to 2-APB modulation of SOCE. CONCLUSIONS: This study allows the discovery of new boron-oxygen core containing compounds with the same ability as 2-APB to both potentiate and inhibit the SOCE of different leukocyte cell lines. These compounds could represent new tools to characterize the different types of SOCE and the first step in the development of new immunomodulators. PMID- 21266089 TI - Characterisation and expression of microRNAs in developing wings of the neotropical butterfly Heliconius melpomene. AB - BACKGROUND: Heliconius butterflies are an excellent system for studies of adaptive convergent and divergent phenotypic traits. Wing colour patterns are used as signals to both predators and potential mates and are inherited in a Mendelian manner. The underlying genetic mechanisms of pattern formation have been studied for many years and shed light on broad issues, such as the repeatability of evolution. In Heliconius melpomene, the yellow hindwing bar is controlled by the HmYb locus. MicroRNAs (miRNAs) are important post transcriptional regulators of gene expression that have key roles in many biological processes, including development. miRNAs could act as regulators of genes involved in wing development, patterning and pigmentation. For this reason we characterised miRNAs in developing butterfly wings and examined differences in their expression between colour pattern races. RESULTS: We sequenced small RNA libraries from two colour pattern races and detected 142 Heliconius miRNAs with homology to others found in miRBase. Several highly abundant miRNAs were differentially represented in the libraries between colour pattern races. These candidates were tested further using Northern blots, showing that differences in expression were primarily due to developmental stage rather than colour pattern. Assembly of sequenced reads to the HmYb region identified hme-miR-193 and hme-miR 2788; located 2380 bp apart in an intergenic region. These two miRNAs are expressed in wings and show an upregulation between 24 and 72 hours post pupation, indicating a potential role in butterfly wing development. A search for miRNAs in all available H. melpomene BAC sequences (~2.5 Mb) did not reveal any other miRNAs and no novel miRNAs were predicted. CONCLUSIONS: Here we describe the first butterfly miRNAs and characterise their expression in developing wings. Some show differences in expression across developing pupal stages and may have important functions in butterfly wing development. Two miRNAs were located in the HmYb region and were expressed in developing pupal wings. Future work will examine the expression of these miRNAs in different colour pattern races and identify miRNA targets among wing patterning genes. PMID- 21266091 TI - Morbidity, life style and psychosocial situation in cancer survivors aged 60-69 years: results from the Nord-Trondelag health study (the HUNT-II study). AB - BACKGROUND: Due to considerable health status differences in the elderly population, research limited to narrow age-spans might be an advantage. In this population-based controlled study we compare short-term (<5 years) (STS) and long term (>= 5 years) (LTS) cancer survivors and cancer-free controls aged 60-69 years from two Norwegian health registers; the Health Survey of North-Trondelag County (HUNT-2 study) and the Cancer Registry of Norway (CRN). We examined possible factors associated with being cancer survivor. METHODS: Among 9,089 individuals aged 60-69 who participated in HUNT-2, 334 had been diagnosed with invasive primary cancer from 1 month to 42 years before HUNT-2 according to CRN and self-report. An overall random sample of controls without cancer five times larger than the sample of cases (N = 1,670) were drawn from the parent cohort. RESULTS: The cancer sample comprised 128 STS and 206 LTS. For most variables no significant differences were observed between LTS and STS. LTS were significantly more women, and cases with gynaecological cancer, with physical impairment and more thyroid diseases compared to STS. When comparing all the survivors with controls, the survivors showed significantly higher rate of pensioning, decreased self-rated health, more physical impairment and thyroid diseases, daily use of medication and psychotropics and higher level of anxiety and Framingham Risk score. Multivariate logistic regression analysis showed that increasing age, being female, physical impairment and thyroid diseases all were significantly associated with being survivor versus controls. CONCLUSION: STS and LTS showed mostly similar situation. Compared to controls, the survivors reported somewhat poorer physical and mental health, but these differences were of doubtful clinical significance. PMID- 21266092 TI - Nutrition communication: consumer perceptions and predicting intentions. AB - Health claims on food products, which aim at informing the public about the health benefits of the product, represent one type of nutrition communication; the use of these is regulated by the European Union. This paper provides an overview of the research on health claims, including consumers' perceptions of such claims and their intention to buy products that carry health-related claims. This is followed by a discussion on the results from some recent studies investigating public perceptions and willingness to use products with health claims. In these studies, claims are presented in the form of messages of different lengths, types, framing, with and without qualifying words and symbols. They also investigate how perceptions and intentions are affected by individual needs and product characteristics. Results show that adding health claims to products does increase their perceived healthiness. Claim structure was found to make a difference to perceptions, but its influence depended on the level of relevance, familiarity and individuals' need for information. Further, the type of health benefit proposed and the base product used also affected perceptions of healthiness. The paper concludes that while healthiness perceptions relating to products with health claims may vary between men and women, old and young and between countries, the main factor influencing perceived healthiness and intention to buy a product with health claim is personal relevance. PMID- 21266090 TI - A general scenario of Hox gene inventory variation among major sarcopterygian lineages. AB - BACKGROUND: Hox genes are known to play a key role in shaping the body plan of metazoans. Evolutionary dynamics of these genes is therefore essential in explaining patterns of evolutionary diversity. Among extant sarcopterygians comprising both lobe-finned fishes and tetrapods, our knowledge of the Hox genes and clusters has largely been restricted in several model organisms such as frogs, birds and mammals. Some evolutionary gaps still exist, especially for those groups with derived body morphology or occupying key positions on the tree of life, hindering our understanding of how Hox gene inventory varied along the sarcopterygian lineage. RESULTS: We determined the Hox gene inventory for six sarcopterygian groups: lungfishes, caecilians, salamanders, snakes, turtles and crocodiles by comprehensive PCR survey and genome walking. Variable Hox genes in each of the six sarcopterygian group representatives, compared to the human Hox gene inventory, were further validated for their presence/absence by PCR survey in a number of related species representing a broad evolutionary coverage of the group. Turtles, crocodiles, birds and placental mammals possess the same 39 Hox genes. HoxD12 is absent in snakes, amphibians and probably lungfishes. HoxB13 is lost in frogs and caecilians. Lobe-finned fishes, amphibians and squamate reptiles possess HoxC3. HoxC1 is only present in caecilians and lobe-finned fishes. Similar to coelacanths, lungfishes also possess HoxA14, which is only found in lobe-finned fishes to date. Our Hox gene variation data favor the lungfish-tetrapod, turtle-archosaur and frog-salamander relationships and imply that the loss of HoxD12 is not directly related to digit reduction. CONCLUSIONS: Our newly determined Hox inventory data provide a more complete scenario for evolutionary dynamics of Hox genes along the sarcopterygian lineage. Limbless, worm-like caecilians and snakes possess similar Hox gene inventories to animals with less derived body morphology, suggesting changes to their body morphology are likely due to other modifications rather than changes to Hox gene numbers. Furthermore, our results provide basis for future sequencing of the entire Hox clusters of these animals. PMID- 21266093 TI - Effect of maternal diet on the epigenome: implications for human metabolic disease. AB - The rapid increase in the incidence of chronic non-communicable diseases over the past two decades cannot be explained solely by genetic and adult lifestyle factors. There is now considerable evidence that the fetal and early postnatal environment also strongly influences the risk of developing such diseases in later life. Human studies have shown that low birth weight is associated with an increased risk of CVD, type II diabetes, obesity and hypertension, although recent studies have shown that over-nutrition in early life can also increase susceptibility to future metabolic disease. These findings have been replicated in a variety of animal models, which have shown that both maternal under- and over-nutrition can induce persistent changes in gene expression and metabolism within the offspring. The mechanism by which the maternal nutritional environment induces such changes is beginning to be understood and involves the altered epigenetic regulation of specific genes. The demonstration of a role for altered epigenetic regulation of genes in the developmental induction of chronic diseases raises the possibility that nutritional or pharmaceutical interventions may be used to modify long-term cardio-metabolic disease risk and combat this rapid rise in chronic non-communicable diseases. PMID- 21266094 TI - Do SCFA have a role in appetite regulation? AB - The recently discovered SCFA-activated G-coupled protein receptors FFA receptor 2 and FFA receptor 3 are co-localised in l-cells with the anorexigenic 'ileal brake' gut hormone peptide YY, and also in adipocytes, with activation stimulating leptin release. Thus, SCFA such as acetate and propionate show promise as a candidate to increase satiety-enhancing properties of food. We therefore postulate SCFA may have a role in appetite regulation and energy homeostasis. SCFA can be delivered either directly within food, or indirectly via the colon by the provision of fermentable non-digestible carbohydrates. A review of studies investigating the effects of oral SCFA ingestion on appetite suggests that while oral SCFA ingestion is associated with enhanced satiety, this may be explained by product palatability rather than a physiological effect of SCFA. Colon-derived SCFA generated during microfloral fermentation have also been suggested to explain satiety-enhancing properties of non-digestible carbohydrates. However, findings are mixed from investigations into the effects of the prebiotic inulin-type fructans on appetite. Overall, data presented in this review do not support a role for SCFA in appetite regulation. PMID- 21266095 TI - Maternal fish consumption, fetal growth and the risks of neonatal complications: the Generation R Study. AB - Maternal fish consumption during pregnancy has been suggested to affect birth outcomes. Previous studies mainly focused on birth outcomes and did not study fetal growth during pregnancy. In a prospective cohort study from early pregnancy onwards in The Netherlands, we assessed the associations of first-trimester maternal total-fish, lean-fish, fatty-fish and shellfish consumption with fetal growth characteristics in the second and third trimesters, growth characteristics at birth and the risks of neonatal complications, including pre-term birth, low birth weight and small for gestational age. In total, 3380 mothers completed a 293-item semi-quantitative FFQ to obtain information about fish consumption during the first trimester of pregnancy. Head circumference, femur length and fetal weight were estimated in the second and third trimesters by ultrasound. Information about birth anthropometrics and neonatal complications was available from hospital and midwife registries. Maternal older age, higher educational level, folic acid supplement use, alcohol use and not smoking were associated with higher fish consumption (P < 0.01). After adjustment, we observed no consistent associations of maternal total-fish consumption or specific consumption of lean fish, fatty fish or shellfish with fetal growth characteristics in the second and third trimesters and at birth. Likewise, total fish consumption or specific consumption of any type of fish was not consistently associated with the risks of neonatal complications. These findings suggest that in a population with a relatively low fish intake, consumption of lean fish, fatty fish or shellfish in the first trimester is not associated with fetal growth or the risks of neonatal complications. PMID- 21266096 TI - Influence of dietary spices on the in vivo absorption of ingested beta-carotene in experimental rats. AB - Animal studies were conducted to evaluate the influence of dietary spice compounds, piperine, capsaicin and ginger, on the absorption of orally administered beta-carotene and its conversion to vitamin A. In rats maintained on these spice-containing diets for 8 weeks, concentrations of beta-carotene and retinol were determined in the serum, liver and intestine 4 h after a single oral administration of beta-carotene. beta-Carotene concentration was significantly increased in the serum, liver and intestine of piperine- and ginger-fed rats, suggesting improved absorption of beta-carotene. However, retinol concentration was not significantly changed in these animals, suggesting that the bioconversion of beta-carotene to vitamin A was not similarly influenced. Between the two enzymes involved in the bioconversion of beta-carotene to vitamin A, the activity of intestinal and hepatic beta-carotene 15,15'-dioxygenase was either unaffected or lowered by these spice treatments. The activity of intestinal and hepatic retinal reductase was unaffected by the dietary spices. Activities of these two enzymes involved in the bioconversion of beta-carotene to retinal were inhibited by the test spices in vitro, thus corroborating with the in vivo observation. Although the bioconversion of beta-carotene was not promoted, increased absorption and tissue levels of beta-carotene by the dietary spices may contribute to a higher antioxidant protection. PMID- 21266097 TI - Publication bias in clinical trials. PMID- 21266098 TI - An unusual case of gingival swelling in a 43-year-old man. PMID- 21266099 TI - Prognosis in implant dentistry: a system for classifying the degree of peri implant mucosal inflammation. AB - Disease related to peri-implant mucosal inflammation (PIMI) has been reported as one of the major factors leading to failure of dental implants. Many authors have suggested options for treatment of these lesions, ranging from simple mechanical debridement and regenerative surgical techniques to removal of the implant. Prognostic classification systems have become an integral part of dental practice because they provide direct guidance in planning treatment. However, there is limited evidence to support the appropriate classification of PIMI and the corresponding treatments, and a more specific prognostic system is required. Because the number of patients with implants is increasing, clinicians must be aware of PIMI as an entity with specific management requirements. This report describes a simple prognostic system to help clinicians to foresee the outcomes of PIMI treatment. PMID- 21266101 TI - Small RNA biology is systems biology. AB - During the last decade small regulatory RNA (srRNA) emerged as central players in the regulation of gene expression in all kingdoms of life. Multiple pathways for srRNA biogenesis and diverse mechanisms of gene regulation may indicate that srRNA regulation evolved independently multiple times. However, small RNA pathways share numerous properties, including the ability of a single srRNA to regulate multiple targets. Some of the mechanisms of gene regulation by srRNAs have significant effect on the abundance of free srRNAs that are ready to interact with new targets. This results in indirect interactions among seemingly unrelated genes, as well as in a crosstalk between different srRNA pathways. Here we briefly review and compare the major srRNA pathways, and argue that the impact of srRNA is always at the system level. We demonstrate how a simple mathematical model can ease the discussion of governing principles. To demonstrate these points we review a few examples from bacteria and animals. PMID- 21266100 TI - Microbial linguistics: perspectives and applications of microbial cell-to-cell communication. AB - Inter-cellular communication via diffusible small molecules is a defining character not only of multicellular forms of life but also of single-celled organisms. A large number of bacterial genes are regulated by the change of chemical milieu mediated by the local population density of its own species or others. The cell density-dependent "autoinducer" molecules regulate the expression of those genes involved in genetic competence, biofilm formation and persistence, virulence, sporulation, bioluminescence, antibiotic production, and many others. Recent innovations in recombinant DNA technology and micro-/nano fluidics systems render the genetic circuitry responsible for cell-to-cell communication feasible to and malleable via synthetic biological approaches. Here we review the current understanding of the molecular biology of bacterial intercellular communication and the novel experimental protocols and platforms used to investigate this phenomenon. A particular emphasis is given to the genetic regulatory circuits that provide the standard building blocks which constitute the syntax of the biochemical communication network. Thus, this review gives focus to the engineering principles necessary for rewiring bacterial chemo communication for various applications, ranging from population-level gene expression control to the study of host-pathogen interactions. PMID- 21266102 TI - Contribution of lysine-containing cationic domains to thermally-induced phase transition of elastin-like proteins and their sensitivity to different stimuli. AB - A series of elastin-like proteins, SKGPG[V(VKG)(3)VKVPG](n)-(ELP1-90)WP (n = 1, 2, 3, and 4), were biosynthesized based on the hydrophobic and lysine linkage domains of tropoelastin. The formation of self-assembled hydrophobic aggregates was monitored in order to determine the influence of cationic segments on phase transition properties as well as the sensitivity to changes in salt and pH. The thermal transition profiles of the proteins fused with only one or two cationic blocks (n = 1 or 2) were similar to that of the counterpart ELP1-90. In contrast, diblock proteins that contain 3 and 4 cationic blocks displayed a triphasic profile and no transition, respectively. Upon increasing the salt concentration and pH, a stimulus-induced phase transition from a soluble conformation to an insoluble aggregate was observed. The effects of cationic segments on the stimuli sensitivity of cationic bimodal ELPs were interpreted in terms of their structural and molecular characteristics. PMID- 21266103 TI - The microRNA expression profiles of mouse mesenchymal stem cell during chondrogenic differentiation. AB - MicroRNAs are potential key regulators in mesenchymal stem cells chondrogenic differentiation. However, there were few reports about the accurate effects of miRNAs on chondrogenic differentiation. To investigate the mechanisms of miRNAs mediated regulation during the process, we performed miRNAs microarray in MSCs at four different stages of TGF-beta3-induced chondrogenic differentiation. We observed that eight miRNAs were significantly up-regulated and five miRNAs were downregulated. Interestingly, we found two miRNAs clusters, miR-143/145 and miR 132/212, kept on down-regulation in the process. Using bioinformatics approaches, we analyzed the target genes of these differentially expressed miRNAs and found a series of them correlated with the process of chondrogenesis. Furthermore, the qPCR results showed that the up-regulated (or down-regulated) expression of miRNAs were inversely associated with the expression of predicted target genes. Our results first revealed the expression profiles of miRNAs in chondrogenic differentiation of MSCs and provided a new insight on complicated regulation mechanisms of chondrogenesis. PMID- 21266104 TI - A novel variant of t-PA resistant to plasminogen activator inhibitor-1; expression in CHO cells based on in silico experiments. AB - Resistance to PAI-1 is a factor which confers clinical benefits in thrombolytic therapy. The only US FDA approved PAI-1 resistant drug is Tenecteplase(r). Deletion variants of t-PA have the advantage of fewer disulfide bonds in addition to higher plasma half lives. A new variant was developed by deletion of the first three domains in t-PA in addition to substitution of KHRR 128-131 amino acids with AAAA in truncated t-PA. The specific activity of this new variant, 570 IU/MUg, was found to be similar to those found in full length t-PA (Alteplase(r)), 580 IU/MUg. A 65% and 85% residual activity after inhibition by rPAI-1 was observed for full length and truncated-mutant form, respectively. This new variant as the first PAI-1 resistant truncated t-PA may offer more advantages in clinical conditions in which high PAI-1 levels makes the thrombolytic system prone to re-occlusion. PMID- 21266105 TI - Inactive extracellular superoxide dismutase disrupts secretion and function of active extracellular superoxide dismutase. AB - Extracellular superoxide dismutase (EC-SOD) is an antioxidant enzyme that protects cells and tissues from extracellular damage by eliminating superoxide anion radicals produced during metabolism. Two different forms of EC-SOD exist, and their different enzyme activities are a result of different disulfide bond patterns. Although only two folding variants have been discovered so far, five folding variants are theoretically possible. Therefore, we constructed five different mutant EC-SOD expression vectors by substituting cysteine residues with serine residues and evaluated their expression levels and enzyme activities. The mutant EC-SODs were expressed at lower levels than that of wild-type EC-SOD, and all of the mutants exhibited inhibited extracellular secretion, except for C195S ECSOD. Finally, we demonstrated that co-expression of wild-type EC-SOD and any one of the mutant EC-SODs resulted in reduced secretion of wild-type EC-SOD. We speculate that mutant EC-SOD causes malfunctions in systems such as antioxidant systems and sensitizes tissues to ROS-mediated diseases. PMID- 21266106 TI - Depletion of Neuroguidin/CANu1 sensitizes human osteosarcoma U2OS cells to doxorubicin. AB - Osteosarcoma is a primary bone cancer which occurs mainly in children. Neuroguidin/CANu1 is a nucleolar protein involved in the maintenance of ribosomal structure. In this study, we investigated the effect of Neuroguidin/CANu1 depletion on the response of osteosarcoma cells to doxorubicin. In normal circumstances, Neuroguidin/CANu1 is localized at nucleoli, which translocates to nuclear foci in the presence of doxorubicin. shRNA knockdown of Neuroguidin/CANu1 did not affect cell viability in the absence of doxorubicin, but led to enhanced cytotoxicity in doxorubicin-treated cells. Doxorubicin increased the population of apoptotic cells by 3-fold in Neuroguidin/CANu1-depleted cells compared to that in control cells. Depletion of Neuroguidin/CANu1 mRNA induced the expression of p21 and the cleavage of PARP, leading to increased caspase-3/7 activity. Together, these results suggest that Neuroguidin/CANu1 is required for maintaining cellular homeostasis and may contribute to the improved efficiency of chemotherapy. PMID- 21266107 TI - Molecular cloning, expression and characterization of a novel feruloyl esterase enzyme from the symbionts of termite(Coptotermes formosanus) gut. AB - Termites play an important role in the degradation of dead plant materials and have acquired endogenous and symbiotic cellulose digestion capabilities. The feruloyl esterase enzyme (FAE) gene amplified from the metagenomic DNA of Coptotermes formosanus gut was cloned in the TA cloning vector and subcloned into a pET32a expression vector. The Ft3-7 gene has 84% sequence identity with Clostridium saccharolyticum and shows amino acid sequence identity with predicted xylanase/chitin deacetylase and endo-1,4-beta-xylanase. The sequence analysis reveals that probably Ft3-7 could be a new gene and that its molecular mass was 18.5 kDa. The activity of the recombinant enzyme (Ft3-7) produced in Escherichia coli (E.coli) was 21.4 U with substrate ethyl ferulate and its specific activity was 24.6 U/mg protein. The optimum pH and temperature for enzyme activity were 7.0 and 37oC, respectively. The substrate utilization preferences and sequence similarity of the Ft3-7 place it in the type-D sub-class of FAE. PMID- 21266108 TI - A novel human KRAB-related zinc finger gene ZNF425 inhibits mitogen-activated protein kinase signaling pathway. AB - Zinc finger (ZNF) proteins play a critical role in cell growth, proliferation, apoptosis, and intracellular signal transduction. In this paper, we cloned and characterized a novel human KRAB-related zinc finger gene, ZNF425, which encodes a protein of 752 amino acids. ZNF425 is strongly expressed in the three month old human embryos and then is almost undetectable in six month old embryos and in adult tissues. An EGFP-ZNF425 fusion protein can be found in both the nucleus and the cytoplasm. ZNF425 appears to act as a transcription repressor. Over expression of ZNF425 inhibits the transcriptional activities of SRE, AP-1, and SRF. Deletion analysis indicates that the C2H2 domain is the main region responsible for the repression. Our results suggest that the ZNF425 gene is a new transcriptional inhibitor that functions in the MAPK signaling pathway. PMID- 21266109 TI - Purification and enzymatic properties of a peroxidase from leaves of Phytolacca dioica L. (Ombu tree). AB - A peroxidase (PD-cP; 0.47 mg/100 g leaves) was purified from autumn leaves of Phytolacca dioica L. and characterized. PD-cP was obtained by acid precipitation followed by gel-filtration and cation exchange chromatography. Amino acid composition and N-terminal sequence of PD-cP up to residue 15 were similar to that of Spinacia oleracea (N-terminal pairwise comparison showing four amino acid differences). PD-cP showed a molecular mass of approx. 36 kDa by SDS-PAGE, pH and temperature optima at 3.0 and 50.0 degrees C, respectively and seasonal variation. The Michaelis-Menten constant (K(M)) for H(2)O(2) was 5.27 mM, and the velocity maximum (V(max)) 1.31 nmol min(-1), while the enzyme turnover was 0.148 s(-1). Finally, the presence of Ca(2+) and Mg(2+) enhanced the PD-cP activity, with Mg(2+) 1.4-fold more effective than Ca(2+) PMID- 21266110 TI - Identification of nucleolar and coiled-body phosphoprotein 1 (NOLC1) minimal promoter regulated by NF-kappaB and CREB. AB - Nucleolar and coiled-body phosphoprotein 1 (NOLC1) is a phosphoprotein that transiently associates with the mature nucleolar H/ACA and C/D box small nucleolar ribonucleoproteins (snoRNPs). Several lines of evidence indicate that NOLC1 plays an important role in the synthesis of rRNA and the biosynthesis of ribosomes. In the present study, we examined the transcriptional regulation mechanisms that govern the expression of NOLC1. We first performed functional dissection of the NOLC1 promoter. We demonstrated that transcription factors NF kappaB and CREB could bind to the minimal NOLC1 promoter. This was demonstrated by electrophoretic mobility shift assays and chromatin immunoprecipitation. Mutagenesis and overexpression assays revealed that NF-kappaB and CREB positively regulated the NOLC1 promoter. These findings may provide new insight into the mechanisms that regulate NOLC1 expression. PMID- 21266111 TI - [Construction of adenoviral vector carrying Smad3D or Smad7]. AB - BACKGROUND: To construct recombinant adenoviral vector carrying Smad3D or Smad7 by a simplified means. METHODS: Based on AdEasy System, adenoviral backbone plasmid vector and shuttle vector carrying the gene of interest were transferred into E.coli BJ5183 by chemical transformation methods in special order. The homologous recombination was performed. RESULTS: Recombinant adenoviral vector pAd-Smad3D and pAd-Smad7 were constructed successfully, which were confirmed by restriction enzyme digesting. CONCLUSIONS: Recombinant adenoviral vector may be constructed quickly and efficiently in E.coli by sequential chemical transformation methods. PMID- 21266112 TI - [Effect of exogenous wild type p53 expression on sensitization of lung cancer cell line to cisplatin and cloning of the corresponding genes]. AB - BACKGROUND: To isolate and clone the cisplatin genes in 801-D cell line, a kind of lung cancer cell line, with the emphasis of the objective genes regulated by wild type p53 (wtp53). METHODS: Total RNA was extracted from transfected 801-D wtp53, 801-D-vector cells which were both treated by cisplatin and 801-D-wtp53 cells. Using mRNA differential display, the DNA bands on gel were displayed by silver stain method. The DNA bands obtained from differential display were recovered and reamplified by PCR. The isolated genes were further proved by reverse Northern dot blot and were cloned to pGEMT easy vector. RESULTS: Six positive genes were identified and cloned. Out of them, 2 related fragments were found to have an open reading frame. One was partly homologous to ribonucleoside diphosphate reductase A, and the other was no homologous to the known genes. CONCLUSIONS: There are obvious differences in gene expression in 801-D-wtp53 after induced by cisplatin than two other controls. It is possible for p53 to regulate the sensitization of lung cancer cells to cisplatin through its downstream target genes. PMID- 21266113 TI - [Angiogenesis and blood supply during the course of pulmonary carcinogenesis in experimental rat]. AB - BACKGROUND: To investigate the origin of tumor blood vessel and blood supply during pulmonary carcinogenesis, and the relationship between vascular endothelial growth factor (VEGF), its receptor Flk-1 and angiogenesis. METHODS: One hundred Wistar rats were instilled with 3-methylcholanthrene (MCA) and diethylinitrosamine (DEN) to induce pulmonary squamous cell carcinoma through left lower lobe bronchus. To acquire different pathological phase during the carcinogenesis, rats were killed in 15, 35, 55, 65, 75 days after instillation. Yellow and green silastics were respectively injected into the bronchial and pulmonary arteries of 30 rats in 55, 65, 75 days after instillation. Intertumor microvessel density (MVD) was marked by anti-von Willebrand factor monoantibody. VEGF and Flk-1 expression were examined by immunohistochemistry. RESULTS: In the tumor area the tumor blood vessels were yellow and connected with distorted bronchial artery and very few green incomplete branches of pulmonary artery were seen. Silastic particles could be seen in the disordered tumor blood vessels by microscope after bronchial artery perfusion. There was no silastic particles in the carcinoma interstitial blood vessels after pulmonary artery perfusion. MVD count significantly increased in carcinoma in situ (39.50+/-12.60) and infiltrative carcinoma (61.05+/-19.92) as compared to atypical hyperplasia (8.92+/-3.80)(both P < 0.01), and the increased vessels originated from bronchial artery, but not pulmonary artery. The expression of VEGF and Flk-1 increased during pulmonary carcinogenesis. The positive coefficients of VEGF and FLK-1 expressions became higher and higher from epithelial proliferation to squamous metaplasia, to atypical hyperplasia, to carcinoma in situ and finally to infiltrative carcinoma. There was significant correlation between MVD and VEGF expression (r=0.979 8, P < 0.005), as well as between MVD and Flk-1 expression (r=0.907 8, P < 0.05). CONCLUSIONS: Angiogenesis is the important phenomenon of the rat pulmonary carcinogenesis and the newly formed blood vessels in tumor connect with the branches of bronchial artery, but not pulmonary artery. This confirms that the blood supply of pulmonary carcinoma is from bronchial artery, not from pulmonary artery. VEGF and Flk-1 are closely related to angiogenesis of tumor. PMID- 21266114 TI - [Studies on proliferation inhibition and anti-invasion of retinoic acid and 18beta-glycyrrhetinic acid in highly metastasized human lung cancer cell line]. AB - BACKGROUND: To study the proliferation inhibition and anti-invasion of retinoic acid (RA) and 18beta-glycyrrhetinic acid (GA) in highly metastasized lung cancer cell line (PGCL3), and to observe the combined effects of RA and GA. METHODS: The proliferation inhibitive rate, the colony-formation rate in semi-solid agar, the invasive ability to reconstituted basement membrane, the chemotatic migration ability, the laminin adhesion ability, and the activity of cathepsin B (CB) were tested. RESULTS: Treated with RA and GA, the proliferation of PGCL3 cells were inhibited obviously, and the inhibition degree was related to the dosage of the drugs. IC50 of the proliferation inhibition were 12.58 MUmol/L and 145.3 MUmol/L respectively. Treated with 5.0 MUmol/L RA, 25 MUmol/L and 50 MUmol/L GA, the invasive ability was decreased significantly (P < 0.01 and P < 0.001), and the inhibition was in a dose dependent manner. In combined treatment with 5.0 MUmol/L RA and 25 MUmol/L GA, the inhibition of invasion was greater than the sum of them used alone. Treated with GA of above concentrations and 10 MUmol/L RA, the adhesion and migration ability and the secretion of CB of the PGCL3 cells were decreased significantly (P < 0.001). Treated with GA of above concentation, the colony formation rate in semi-solid agar was decreased significantly (P < 0.001).. CONCLUSIONS: RA and GA can inhibit the proliferation and invasion of the PGCL3 human lung cancer cells and have the anti-invasion synergism. The mechanism of anti-invasion of RA and GA is to inhibit many points of invasive process. PMID- 21266115 TI - [Level of DNA adduct in lung cancer tissues and its influencing factors]. AB - BACKGROUND: To detect DNA adduct in lung cancer tissues and analyze the factors influencing formation of DNA adduct. METHODS: DNA was extracted from the tumor tissues derived from 34 patients with lung cancer. DNA adducts were analyzed using 32P-postlabeling method with P 1 nuclear modification. RESULTS: DNA adduct level was significantly higher in smoking patients than that in non smoking patients(P < 0.05). DNA adduct level was related to the histological classification, degree of cell differentiation and lymph node metastasis, but not to age and sex. CONCLUSIONS: DNA adduct level might be used as a potential marker to estimate malignant degree for lung cancer. PMID- 21266116 TI - [Tracheo-bronchoplasty and/or cardiovascular reconstruction in the treatment of centrally located lung cancer]. AB - BACKGROUND: To explore the feasibility of extended resection in selective patients with centrally located lung cancer. METHODS: From January, 1987 to December, 2001, lobectomy or pneumonectomy combined with extended resection of trachea, bronchus, heart or great vessels were carried out in 134 patients with centrally located lung cancer. The operations included bronchoplastic procedures in 80 cases, extended resection and reconstruction of left atrium and/or great vessels in 54 cases (32 cases with contemporary bronchoplasty). RESULTS: Operative death occurred in one case. Postoperative complications happened in 16 cases (11.9%). One hundred and seventeen cases (94.4%) were followed up. The 1-, 3-, 5-year survival rate was 84.7% (61/72), 56.7% (34/60) and 45.7% (21/46) respectively, while of those combined with tracheo bronchoplasty and/or cardiovascular reconstruction, the 1-, 3-, 5-year survival rate was 69.2% (36/52), 46.8% (22/47) and 22.2% (8/36) respectively. (P < 0.05), while expression of KAI1 mRNA did not relate to mutant P53 protein expression (P > 0.05). CONCLUSIONS: Extended resection combined with tracheo-bronchoplasty and/or cardiovascular reconstruction is feasible for selected patients with centrally located lung cancer and could improve the survival and life quality of patients. PMID- 21266117 TI - [Preoperative hyperfractionated accelerated irradiation-induced apoptosis in non small cell lung cancer]. AB - BACKGROUND: To study the apoptosis inducing effect of preoperative hyperfractionated accelerated radiation therapy (HART) and expression of Bcl-2, Bax proteins in non-small cell lung cancer. METHODS: From October 1999 to March 2001, 81 patients with non-small cell lung cancer were prospectively divided into preoperative HART group (20 patients) and surgical group (61 patients). The patients in preoperative HART group were given preoperative irradiation with 2.5 Gy/fraction, twice a day to a total dose of 25 Gy/10 fractions/5-7 days using anterior-posterior opposing parallel fields, then operation would be performed within 2 weeks. The patients in surgical group only received surgical treatment. Apoptotic index (AI), cell cycle distribution and expression of Bcl-2, Bax proteins were quantitatively analyzed by indirect-immunofluorescene and flow cytometry. RESULTS: AI was 4.6%+/-2.3% in surgical group and 12.8%+/-4.3% in preoperative HART group, respectively ( P < 0.001). There was no difference in S phase fraction (SPF) between the two groups ( P > 0.05). The fluorescence index (FI) for Bcl-2, Bax proteins and the ratio of Bcl-2/Bax were 1.33+/-0.21, 1.05+/ 0.13 and 1.29+/-0.23 in surgical group, and 1.14+/-0.26, 1.19+/-0.16 and 0.96+/ 0.23 in preoperative HART group respectively ( P < 0.01, P < 0.001 and P < 0.001 respectively). AI showed a positive correlation to Bax protein ( P < 0.001) and a negative correlation to the ratio of Bcl-2/Bax ( P < 0.01). CONCLUSIONS: Preoperative HART may induce a high-level apoptosis by decreasing the expression of Bcl-2 protein and increasing the expression of Bax protein. However, it is still necessary to further observe whether it can improve the long-term survival of patients with NSCLC. PMID- 21266118 TI - [A prospective randomized trial comparing mitomycin C and vindesine and cisplatin versus pirarubicin and vindesine and cisplatin in the treatment of advanced non small cell lung cancer]. AB - BACKGROUND: To evaluate the response, adverse effects and survival of MVP regimen and TVP regimen. METHODS: Sixty six patients with advanced non-small cell lung cancer were randomized into two groups:MVP arm (32 patients, mitomycin C 6-8 mg/m2 d1, vindesine 2-3 mg/m2 d1 and d8, cisplatin 70-80 mg/m2 d1) and TVP arm (34 patients, pirarubicin 40-50 mg/m2 d1, vindesine and cisplatin were the same as arm MVP). Characteristics of the patients were similar in two arms. All patients received two to four cycles of chemotherapy. RESULTS: The overall responses were 34% (11/32) in the MVP arm and 56% (19/34) in the TVP arm. There were 1 complete response, 10 partial responses in the MVP arm and 1 complete response, 18 partial responses in the TVP arm. TVP regimen appeared to have a higher objective response, but no statistically significant difference in the response was observed between two regimens (Chi-square=2.269, P=0.132). Main side effects were hematological toxicities. Grade III+IV hematological toxicities were significantly higher in the patients of arm TVP than arm MVP, especially neutropenia (79% vs 44%, Chi-square=7.458, P=0.006). Median survival time was 12 months vs 8 months, and 1-, 2-, 3-year survival rates were 53% vs 24% (Chi square=4.943, P=0.026), 17% vs 6%, 6% vs 0, for arm TVP and arm MVP, respectively.. CONCLUSIONS: MVP regimen has a lower response rate and longer survival time but less hematological toxicities than TVP regimen. The results suggest MVP regimen is a safe and active regimen for advanced non-small cell lung cancer. PMID- 21266119 TI - [Value of FDG PET for mediastinal lymph node staging in non-small cell lung cancer]. AB - BACKGROUND: To evaluate the diagnostic significance of FDG PET in preoperative mediastinal lymph node staging for NSCLC. METHODS: Whole-body FDG PET imaging was performed in 70 patients with NSCLC. All patients received thoracic CT examination 2 weeks before PET scan or 1 week after PET scan, and then were given thoracotomy with hilar and mediastinal lymph nodes dissection. After intravenous administration of 18F-FDG (150MUCi/kg), PET scan was performed in 3-7 bed positions with 2D acquisition and OSEM reconstruction. For quantitative evaluation, a region of interest (ROI) was placed over the mediastinal lymph node which had abnormal uptake of radiation activity, then the standardized uptake value (SUV) were calculated. If SUV>=2.5 or uptake activity was higher than the blood pool of mediastinal on the basis of visual inspection, it was considered to be positive. RESULTS: The sensitivity, specificity and accuracy of PET were 100%, 93% and 94%, respectively. The positive lymph nodes diagnosed by PET correctly corresponded to pathological results. PET changed the clinical staging of 12 patients. The sensitivity, specificity and accuracy of CT were 70%, 77% and 76%, respectively. CONCLUSIONS: PET is an effective modality for accurate mediastinal lymph node staging in patients with NSCLC. It is valuable for determining clinical treatment. PMID- 21266120 TI - [Long-term results of chemotherapy alone or combined with radiation therapy for limited-stage small cell lung cancer]. AB - BACKGROUND: To evaluate therapeutic outcome of limited stage small cell lung cancer treated with chemotherapy alone or combined with radiation therapy with different doses. METHODS: A retrospective analysis was performed in 128 limited stage small cell lung cancer patients who were treated with three different ways of treatment, from February 1988 to March 1998 in Heilongjiang Cancer Hospital. All patients were pathologically proved. Forty-two patients received chemotherapy alone (C), 48 patients were treated by interdigitating chemoradiotherapy (IDG) and other 38 patients received concurrent chemoradiotherapy (CON). For thoracic radiation, 20 patients received a dose of <=45 Gy, 23 >=60 Gy, and 43 > 45 Gy but < 60 Gy . RESULTS: The 3-year survival rates were 23.7%, 20.8% and 4.8% in the CON, the IDG and the C groups respectively. There was a significant difference between the CON and the C groups ( P < 0.05), as well as between the IDG and the C groups ( P < 0.05). There was no remarkable difference between the CON and the IDG groups ( P > 0.05). Loco-regional recurrence rate was significantly higher in <=45 Gy group (55.0%) than that in >=60 Gy group (8.7%)( P < 0.01). CONCLUSIONS: The chemotherapy combined radiotherapy may improve the survival of patients with limited-stage small cell lung cancer. Dose of thoracic radiation might be related to the loco-regional recurrence. PMID- 21266121 TI - [The clinical analysis of lung cancer with paraneoplastic syndrome as initial symptom]. AB - BACKGROUND: To investigate the clinical characteristics and diagnosis of lung cancer with paraneoplastic syndrome as initial symptom. METHODS: The clinical data of 168 cases of lung cancer with paraneoplastic syndrome as initial symptom were analysed from Jan. 1990, to Nov. 2002, in the hospital. RESULTS: (1) Among the patients with lung cancer in the hospital, 11.8% (168/1 426) had paraneoplastic syndrome as initial symptom. The ratio of male to female was 4.25:1. There were 138 cases aged above 45 (82.1%) and 116 with smoking history (69.0%). (2)There were 62 cases of small cell lung cancer (36.9%) and 102 non small cell lung cancer (60.7%) and 4 carcinoid (2.4%). Thirty-three cases (37.5%) were central type and 82 (48.8%) peripheral type and 23 (13.7%) diffuse type. (3) The patients with paraneoplastic syndrome included: 48 cases of osteoarthopathy (28.6%), 27 cachexia (16.1%), 23 cancerous fever (13.7%), 14 myasthenia (8.3%), 12 vegetative nerve hyperfunction (7.1%), 11 cerebellar cortex degeneration (6.5%), 9 acanthosis nigricans (5.4%), 8 cutaneous pigmentation (4.8%), 7 dermatomyositis (4.2%), 5 encephalopathy (3.0%), and 4 gynecomastia (2.4%). (4)The misdiagnosis rate of the first consultation was 44.6% (75/168). (5)Initial chest X-ray positive rate was 61.9% (104/168); initial CT positive rate was 78.6% (132/168). (6)One hundred and thirty-two cases accepted the treatment of lung cancer: 32 cases accepted pure operation, 8 cases accepted pure chemotherapy, 35 cases accepted operation and chemotherapy, 39 cases accepted chemotherapy and radiotherapy, 18 cases accepted operation and chemotherapy and radiotherapy. Totally 8 cases were dead and 17 cases had abandoned treatment. One hundred and seven cases had improvement after complex treatment of lung cancer, including 83 cases with improvement or disappearance of paraneoplastic syndrome, 18 cases with no change, and 6 cases exacerbated. CONCLUSIONS: The lung cancer with paraneoplastic syndrome as initial symptom is difficult to diagnose because of its latent onset. The knowledge of paraneoplastic syndrome should be improved, chst X-ray or CT examination should be done for the high risk group of lung cancer with paraneoplastic syndrome, and these strategies could decrease misdiagnosis rate and increase diagnosis rate of lung cancer in early stage. PMID- 21266122 TI - [Diagnostic and prognostic values of serum CA125, NSE, CT levels in patients with lung cancer]. AB - BACKGROUND: To explore the clinical and prognostic values of serum carbohydrate antigen (CA125), neuron-specific enolase (NSE), calcitonin (CT) levels in patients with lung cancer before operation. METHODS: Ninety two untreated patients with lung cancer confirmed histologically were studied. Serum CA125, NSE, and CT were detected in 92 lung cancer patients by ELISA before operation. Thirty healthy volunteers were chosen as controls. RESULTS: The sensitivity of CA125, NSE, and CT for the diagnosis of lung cancer were 48.9%, 21.7%, and 7.6% respectively. The level of CA125 in lung cancer patients was significantly higher than that of control (P < 0.05). The level of NSE in patients with small cell lung cancer was significantly higher than that of control (P < 0.01). The level of CT in lung cancer patients was higher than that of control, but without significant difference. The 3-year survival rate of patients with increased serum CA125 level before operation was 44.4% (20/45), whereas that of patients with normal CA125 level was 66.0% (31/47) (P < 0.05). The 3-year survival rate of patients with increased serum NSE and CT levels was 45.0% (9/20) and 42.8% (3/7) respectively, whereas that of patients with normal serum NSE and CT level was 58.3% (42/72) and 56.5% (48/85) respectively. The 3-year survival rate of patients with increased serum NSE or CT level had no significant difference with that of patients with normal level (P > 0.05). CONCLUSIONS: The diagnostic values of CA125, NSE and CT are limited. CA125 can be used as an prognostic parameter in patients with lung cancer after operation. PMID- 21266123 TI - [A clinical study of ProGRP as a new tumor marker for small cell lung cancer]. AB - BACKGROUND: To evaluate the significance of progastrin-releasing peptide (ProGRP) as a new tumor marker for small cell lung cancer (SCLC).. METHODS: Fifty-five patients with pathologically proved SCLC were initially treated and retrospectively studied, in which the level of serum ProGRP was tesed in various situations and its relationship with tumor stage and therapeutic effects was observed. RESULTS: The diagnostic sensitivity and specificity of ProGRP to SCLC were 80.0% and 97.0% respectively. The average ProGRP level in extensive disease of SCLC patients was 820.00 ng/L, significantly higher than 205.86 ng/L in limited disease of SCLC patients (P=0.000 3). In chemotherapy sensitive cases, the ProGRP level had a significant decrease after treatment, while there was no change in failure cases. CONCLUSIONS: ProGRP is a new SCLC tumor marker with high specificity and sensitivity. It has a close relationship with SCLC stage and can be used as a predictor of SCLC to chemotherapy response. PMID- 21266124 TI - [Efficacy comparison between hyperfractionated and conventional fractionated radiotherapy for non-small cell lung cancer]. AB - BACKGROUND: To investigate the efficacy of hyperfractionated radiotherapy (HRT) for non small cell lung cancer (NSCLC). METHODS: Fifty patients with stage I-III NSCLC were treated in our department from Oct. 1995 to Jan. 2000. All patients had the pathological diagnosis. The patients were divided into two groups according to their entrance sequence: 25 patients were treated by HRT as the treatment group given the tumor doses (DT) 68.9-74.6 Gy/6-6.5 weeks, mean DT 70.3 Gy/6-6.5 weeks; 25 patients were irradiated by conventional fractionation (CF) as the control group given DT 64.2-70.4 Gy/6-7 weeks, mean DT 68.6 Gy/6-7 weeks. No patients received chemotherapy or immunotherapy before this treatment. RESULTS: The effective rate after the radiotherapy was 80% (20/25) in the HRT group and 48% (12/25) in the CF group (Chi-square=5.56,P < 0.05 ). The 1-, 2-, 3-year survival rate of the HRT group was 68% (17/25), 60% (15/25) and 36% (9/25) respectively. The 1-, 2-, 3-year survival rate of the CF group was 52% (13/25), 32% (8/25) and 20% (5/25) respectively. The 2-year survival rate was significantly different between two groups (Chi-square=3.95,P < 0.05 ). The 1-, 2 , 3-year local progression free-rate of the HRT group was 72% (18/25), 60% (15/25) and 44% (11/25) respectively. The 1 , 2 , 3 year local progression free rate of the CF group was 64% (16/25), 48% (12/25) and 32% (8/25) respectively. CONCLUSIONS: According to the direct calculation, the efficacy of HRT for NSCLC is higher than that of CF. It is necessary to follow up the long term survival for the patients treated with HRT. PMID- 21266127 TI - [Assessment of competence: literature review and project research]. AB - The authors propose a research project aimed at developing a system for evaluating and codifying nursing competencies. The purpose of the project is to improve the outcome of care and the way nurses perceive their profession, by introducing a new concept of professional roles that allows innovation, creativity, methodological flexibility and functionality in group working. Although reference models for evaluating nursing competencies have been devised, in Italy they but have not yet been become operative and nurses are evaluated by the single health authorities. PMID- 21266125 TI - Differential brain glucose metabolic patterns in antipsychotic-naive first episode schizophrenia with and without auditory verbal hallucinations. AB - BACKGROUND: Auditory verbal hallucinations (AVHs) are a core symptom of schizophrenia. Previous reports on neural activity patterns associated with AVHs are inconsistent, arguably owing to the lack of an adequate control group (i.e., patients with similar characteristics but without AVHs) and neglect of the potential confounding effects of medication. METHODS: The current study was conducted in a homogeneous group of patients with schizophrenia to assess whether the presence or absence of AVHs was associated with differential regional cerebral glucose metabolic patterns. We investigated differences between patients with commenting AVHs and patients without AVHs among a group of dextral antipsychotic-naive inpatients with acute first-episode schizophrenia examined with [(18)F]fluoro-deoxyglucose positron emission tomography (FDG-PET) at rest. Univariate and multivariate approaches were used to establish between-group differences. RESULTS: We included 9 patients with AVHs and 7 patients without AVHs in this study. Patients experiencing AVHs during FDG uptake had significantly higher metabolic rates in the left superior and middle temporal cortices, bilateral superior medial frontal cortex and left caudate nucleus (cluster level p < 0.005, family wise error-corrected, and bootstrap ratio > 3.3, respectively). Additionally, the multivariate method identified hippocampal parahippocampal, cerebellar and parietal relative hypoactivity during AVHs in both hemispheres (bootstrap ratio < -3.3). LIMITATIONS: The FDG-PET imaging technique does not provide information regarding the temporal course of neural activity. The limited sample size may have increased the risk of false-negative findings. CONCLUSION: Our results indicate that AVHs in patients with schizophrenia may be mediated by an alteration of neural pathways responsible for normal language function. Our findings also point to the potential role of the dominant caudate nucleus and the parahippocampal gyri in the pathophysiology of AVHs. We discuss the relevance of phenomenology-based grouping in the study of AVHs. PMID- 21266126 TI - Reduced prepulse inhibition in adolescents at risk for psychosis: a 2-year follow up study. AB - BACKGROUND: Reduced prepulse inhibition (PPI) of the auditory startle reflex is a hallmark feature of attention-processing deficits in patients with schizophrenia and other psychotic disorders. Recent evidence suggests that these deficits may also be present before the onset of psychosis in individuals at ultra-high risk (UHR) and become progressively worse as psychosis develops. We conducted a longitudinal follow-up study to observe the development of PPI over time in UHR adolescents and healthy controls. METHODS: Two-year follow-up data of PPI measures were compared between UHR adolescents and a matched control group of typically developing individuals. RESULTS: We included 42 UHR adolescents and 32 matched controls in our study. Compared with controls, UHR individuals showed reduced PPI at both assessments. Clinical improvement in UHR individuals was associated with an increase in PPI parameters. LIMITATIONS: A developmental increase in startle magnitude partially confined the interpretation of the association between clinical status and PPI. Furthermore, post hoc analyses for UHR individuals who became psychotic between assessments had limited power owing to a low transition rate (14%). CONCLUSION: Deficits in PPI are present before the onset of psychosis and represent a stable vulnerability marker over time in UHR individuals. The magnitude of this marker may partially depend on the severity of clinical symptoms. PMID- 21266128 TI - [A system for evaluating nursing competencies: definition of operative instruments]. AB - Assessment of competencies is an essential element of staff management. Many approaches have been suggested at international level but their application is not always straightforward due to cultural interference. The system for monitoring nursing competencies merges the concepts of Advanced Practice Nursing and the Learning Organization model. This study addresses the introduction of a system of for assessing nursing competencies by modules for evaluation and self assessment as well as outcome indicators The first phase of the study has made it possible to define the areas , variables and contexts to be evaluated together with the relevant indicators and methodology, as established in 2009. PMID- 21266129 TI - [Nursing outcomes: instruments for visualizing the effectiveness of nursing care]. AB - Literature reports several definitions of outcomes sensitive to nursing care. Van Der Bruggen and Groen defined nursing outcomes as observable and measurable aspects in individuals, groups and population that should be objective for clinicians and researchers and subjective for patients and families. Johnson and Maas defined nursing outcomes as variable behaviors or perceptions of family or caregiver after the caring intervention. According to the International Classification for Nursing Practice (ICNP), nursing outcomes are the status of a nursing diagnosis after the intervention. In the IowaOutcome Project, where Nursing Outcomes Classification (NOC) system has been elaborated, nursing outcome is a measurable condition, behavior or perception of the person or family conceptualized as sensitive variable to nursing care. Outcomes of NOC system are focused on individuals, families and community and refers to status, behavior or perceptions. Elements to be considered in nursing outcome definition are four: specific aspects of nursing care, the illness, general aspects of care, patient typology. It is important to identify which system for nursing evaluation outcomes are more suitable for Italy, where the field of action of nurses has faded edge with functions that mix and confuse with other professionals. Studies on the application of NOC taxonomy in Italy could be a starting point for defining and adapting an outcome evaluation system that will allow the objective visibility that nursing care gives to the global improvement of the cared person. PMID- 21266130 TI - [Awareness and respect of procedures for hand hygiene: review of the literature]. AB - The procedures necessary to ensure hand hygiene are simple and non-expensive but are extremely important for the patient and the quality of care he receives. It is therefore fundamental that health workers are aware of these procedures and how they should be performed to reduce the risks of care-related infections. The authors selected 195 articles from a review of the abundance of published reports in international journals, which deal with the awareness and respect of guidelines regarding hand hygiene on which to base their discussion. PMID- 21266131 TI - [Nursing workload in Day Surgery]. AB - The "workload" is defined as the whole of the activities completed by a group of professionals in a period of time. The different conceptualization of nursing workload has determined different methods and tools of evaluation. The aim of this study is to evaluate the nursing workload in a Day Surgery Unit with a quantitative (time in activities) and qualitative approach (perceived complexity). We want analyze also every correlation with the time in the activities. The study design is observational. We have analyzed 147 patients admitted to the Day Surgery Unit of a University Hospital in Italy. The nurses have dedicated the average of 164,8 minutes in care. The nursing care time is correlated to anesthesiological risk class and to the general surgery procedure. The patients in specialistic surgery are considered more complexes from the nurses then the general surgery patients. Another indicator associated to the high perceived complexity is the "comorbidity management". This study will help to manage nursing resources and the admission of the patients. PMID- 21266132 TI - [Nursing care of osteogenesis imperfecta child: implications for nursing practice. A review of the literature]. AB - This work provides a systematic review of literature, a careful analysis, synthesis and critical review, gathering the relevant findings and results of 20 clinical studies on Osteogenesis Imperfecta all with the ultimate goal of generating an overview of nursing assistance addressed to the child with this rare chronic disease. The works come from texts considered scientifically validated. The review will serve as a stimulus to improve nursing care and lead nurses to care conscious choices based on scientific evidence, as it is only by an experienced and experimental evidence that can rise to the optimal treatment for each patient (R. Iovine, 2000). PMID- 21266133 TI - [Dental evaluation in the disabled: case-control study]. AB - Impaired dental status in the mentally retarded is one of the principal secondary conditions limiting daily activities such as eating and talking, causing pain, loss of sleep and function, and low self-esteem. Little information is available regarding the dental status of the mentally retarded disable attending day centers in Italy. The aim of this study was to provide such information, enrolling 6 day centers in the Veneto region comprising a total number of 65 mentally retarded subjects aged between 19 and 44 years of age. Data were collected using 2 different instruments. Results showed a significantly higher number of teeth missing in the mentally disabled (9.2) in comparison to the control group (2.3), although this figure is lower than the international one. PMID- 21266134 TI - [Behavioural problems in adolescents who are in adoption, residential care, and grandparent fostering]. AB - The aim of this research is to identify the severity and type of behavioural problems found in a sample of 181 Spanish adolescents, aged 11 and 18, who have been, or still are in the protective system and to provide give up-to-date figures about behavioural problem situations of children are living under protective measures, and to determine the existence of diverse behavioural problems concerning the kind of care the adolescents are receiving (adoption, residential care, or with grandparent fostering). The Child Behavior Checklist (CBCL) was used in this study. The results show that most of the adolescents scored within the normal range and only a small percentage of them had important behavioural problems and were therefore situated within the clinical range of the trial. The adopted adolescents scored higher than the adolescents who were either fostered by their extended families or in residential care. The main problems identified in each section are discussed, along with the results, in the context of modernising the Spanish protection system. PMID- 21266135 TI - [Self-concept and psychosocial adjustment in adolescence]. AB - This study analyses the relationship between a multidimensional measure of self concept, Self-concept Form-5 Questionnaire (AF5), and a broad set of adolescents' psychosocial adjustment indicators. From the responses of 1,281 participants (53.7% females) aged 12 to 17 years ( M = 14.98 years, SD = 1.74 years), results indicated that higher self-concept scores corresponded to better psychological adjustment, good personal skills and fewer behavioral problems. Although a positive relationship between social self-concept and drug use was found, this significant relationship disappeared once the adolescent's age and sex was controlled for. These results support the idea that the self-concept is a basic theoretical construct closely related to the psychosocial adjustment in adolescence. Also this study helps explain some contradictory results reported in the literature (i.e., a positive relationship between social self-concept and drug use), by showing how the statistical control of a third variable effect (i.e., age) avoids reaching conclusions based on spurious relationships. PMID- 21266136 TI - [Relationships among empathy, prosocial behavior, aggressiveness, self-efficacy and pupils' personal and social responsibility]. AB - The aim of this study was, on the one hand, to present/display the Spanish version of diverse instruments that assess Empathy, Prosocial behavior, Aggressiveness, Self-efficacy and Personal and social responsibility, and, on the other hand, to analyze which of these variables could predict responsibility. Participants were 822 pupils, ages 8 to 15 years, who studied in 11 educational centres of the Valencian Community. Measures include Spanish versions of the Index of Empathy for Children and Adolescents, Prosocial Behaviour, and Physical and Verbal Aggression, the Multidimensional Scale of Perceived Self-Efficacy, and the Contextual Self-Responsibility Questionnaire. Through structural equation modelling (SEM), the results showed positive relationships between Prosocial behaviour, Empathy, Self-efficacy, and Responsibility; and negative relationships between Aggressiveness and Responsibility. The results and implications for education are discussed. PMID- 21266137 TI - [Conflicts between parents and aggressive and delinquent behavior in children]. AB - The exposure of children to their parents' conflicts are a factor of substantial risk for the development of behavior problems in children. This study examines the relationship between marital conflicts and children's aggressive and delinquent behavior. The sample consisted of a total of 332 children, aged 7 to 17 years, and their mothers. The children completed the Children's Perceptions of Interparental Conflict Scale, providing information on the dimensions of the marital conflicts: frequency, intensity, no resolution, and content. The mothers completed the O'Leary Porter Scale, providing information about the frequency of conflicts, and the Child Behavior Checklist, about the aggressive and delinquent behavior problems in their children. The results indicate that parental conflicts affect sons and daughters equally, and they affect adolescents more than younger children when they are perceived by the children. However, conflicts affect all groups when the mothers perceive them. PMID- 21266138 TI - Knowledge and question asking. AB - The ability and the motivation for question asking are, or should be, some of the most important aims of education. Unfortunately, students neither ask many questions, nor good ones. The present paper is about the capacity of secondary school pupils for asking questions and how this activity depends on prior knowledge. To examine this, we use texts containing different levels of information about a specific topic: biodiversity. We found a positive relationship between the amount of information provided and the number of questions asked about the texts, supporting the idea that more knowledgeable people ask more questions. Some students were warned that there would be an exam after the reading, and this led to a diminishing number of questions asked, and yet this still did not significantly improve their exam scores. In such a case, it seems that reading was more concerned with immediacy, hindering critical thinking and the dialog between their previous ideas and the new information. Thus, question asking seems to be influenced not only by the amount of knowledge, but also by the reader's attitude towards the information. PMID- 21266139 TI - [Generalization of money-handling though training in equivalence relationships]. AB - This research used a matching-to-sample procedure and equivalence learning process with language and verbal tasks. In the study, an application of the equivalence relationship of money was used with several kinds of euro coins presented. The sample consisted of 16 children (8 in the experimental group and 8 in the control group) aged 5 years. The prerequisite behaviors, the identification of coins and the practical use of different euro coins, were assessed in the pre and post phases for both groups. The children in the experimental group performed an equivalence task using the matching-to-sample procedure. This consisted of a stimulus sample and four matching stimuli, using a series of euro coins with equivalent value in each set. The children in the control group did not undergo this training process. The results showed a large variability in the children's data of the equivalence tests. The experimental group showed the greatest pre and post changes in the statistically significant data. They also showed a greater generalization in the identification of money and in the use of euro coins than the control group. The implications for educational training and the characteristics of the procedure used here for coin equivalence are discussed. PMID- 21266140 TI - [Reciprocal teaching and self-monitoring of strategy use: effects on reading comprehension]. AB - Reciprocal teaching (RT) is an instructional procedure to teach students cognitive strategies that might lead to improved reading comprehension. However, self-monitoring (SM) strategy use can optimize instruction of comprehension. Thus, the present study analyzed: (a) the efficacy of RT in regular classes and (b) the efficacy of RT + SM of strategy use. A sample of 59 students in the fourth year of primary education was selected: 19 children were selected as an RT condition, 18 as an RT + SM condition, while the remaining 22 made up the comparison group. Two types of comprehension measures were used: tasks of specific effects (getting the main idea, writing a summary, comprehension monitoring test) and transfer effect measures (standardised tests, word meaning inference, and free recall). Thus, the results show that both the RT condition and the RT + SM condition benefited from the instruction, performing better than the comparison group in measures of specific effects and in some of the transfer effect measures. This result shows that SM is not a necessary component in the instruction of reading comprehension with RT. PMID- 21266141 TI - [Efficacy of cognitive training programs based on new software technologies in patients with Alzheimer-type dementia]. AB - The study aims to assess the efficacy of the Big Brain Academy (BBA), a computerized cognitive training program (CT) based on video games, compared to the Integrated Psychostimulation Program (IPP), a classical CT tool for patients with Alzheimer's disease (AD). A total of 45 patients with AD at the mild stage were randomly assigned to three experimental conditions. Two treatment groups were established, in which patients received either a stimulation program with BBA (EABB) or a traditional stimulation program (EAPI), based on paper-and-pencil tasks, for twelve weeks. A third group, the control group (EANT), did not receive any treatment during this period. The differential effectiveness of the programs was evaluated through pre-post design, considering neuropsychological, behavioral, and functional standard measures as outcome variables. The EABB group showed significantly slower rates of cognitive decline compared to the EAPI and EANT groups. Furthermore, the EABB group reported significantly greater decrease in depressive symptoms in comparison with the EAPI and EANT groups. The BBA program was more effective than IPP to reduce cognitive decline and depressive symptoms in patients with AD. PMID- 21266142 TI - Achievement goals, social goals, and motivational regulations in physical education settings. AB - This study examined the relationship between achievement and social goals, and explored how both goals affect students' level of informed self-determination in Physical Education. Participants were 395 high school students. Three scales were used to assess achievement, social goals, and motivation. Several hierarchical regression analyses revealed that mastery-approach goals were the greatest contributors to the individuals' levels of self-determination. Achievement and social goals were found to be separate predictors of students' levels of self determination, and this highlights the importance of separating mastery and performance goals into avoidance and approach profiles. Girls reported significantly higher values than boys on responsibility, relationship, and mastery-avoidance goals, whereas boys scored higher on performance-approach goals. Researchers could use achievement and social goals to study students' motivation and achievement in Physical Education settings. PMID- 21266143 TI - [Impact of a training program in full consciousness (mindfulness) in the measure of growth and personal self-realization]. AB - This research focused on the impact of a full awareness (mindfulness) program on the sense of growth and personal self-realization in a sample of secondary school students. A randomized controlled design with an experimental group and waiting list group was implemented. The Self-concept and Self-actualization Questionnaire (AURE) was used as dependent variable and was administrated before and after running the mindfulness program. The results show a statistically significant difference between pre-test and post-test scores on all factors and subfactors of the AURE. It is concluded that a program of meditation, focused on mindfulness training, may be a valid and appropriate instrument to improve a personal sense of self-realization and growth. It is also suggested that the use of such a program could be complementary with the Instructional-Emotive Program for Personal Growth and Self-realization (PIECAP) psycho-educational program. PMID- 21266144 TI - [A model of the effects of child sexual abuse on post-traumatic stress: the mediating role of attributions of blame and avoidance coping]. AB - Employing structural equation modeling, the direct and indirect effects of the severity of Child Sexual Abuse (CSA), attributions of blame for the abuse, and coping strategies on Post-traumatic Stress Disorder (PTSD) symptomatology are analyzed. The effects of other types of child maltreatment on PTSD were also controlled. The sample comprised 163 female college students who were victims of CSA. The results suggested that victims of more severe abuse showed higher levels of avoidant coping, self blame, and family blame. Having suffered other kinds of abuse or neglect was also related to higher family blame attributions. Lastly, both attributions of blame scales were indirectly related to PTSD symptomatology through avoidant coping. The strong relationships between attributions of blame, coping strategies, and PTSD suggest that it might be useful to intervene early with children who have suffered CSA in an effort to modify the attributions they make about the abuse and the way they cope with it. PMID- 21266145 TI - Coping strategies and quality of life among liver transplantation candidates. AB - The maintenance of self-reported quality of life (QL) among people on the liver transplantation waiting list is one of the priority objectives of transplantation teams. Although there are different determinant factors of QL, results are not conclusive. In our study, the goal was to evaluate both the influence of cirrhosis etiology (ethylic and non-ethylic) and the coping strategies used concerning QL. A sample of 93 patients was selected, divided into two groups: ethylic cirrhosis (EC) and non-ethylic cirrhosis (NEC). QL was evaluated through the SF-36 Health Survey, and coping strategies through the Medical Coping Modes Questionnaire (MCMQ). Our results indicated that subjects with EC obtained similar QL levels to subjects with NEC, on all the SF-36 and MCMQ subscales. Furthermore, negative correlations were found between avoidance and acceptance resignation coping strategies with the SF-36 components. Consequently, the acceptance-resignation strategy was associated with a worse perception of physical functioning, general and mental health, and vitality and role-emotional. Overall, these results suggest that cirrhosis etiology is not a determinant factor of QL, whereas the acceptance-resignation coping strategy might lead to lower self-perception of QL. PMID- 21266146 TI - Schizotypy and pathological personality profile in siblings of patients with psychosis. AB - Schizotypy has been proposed to be the expression of the genetic vulnerability to schizophrenia. Schizotypal features have been associated with personality dimensions found in patients with psychosis. In this study, we compared the Dimensional Assessment of Personality Pathology - Basic Questionnaire (DAPP-BQ) scores of patients with psychosis, siblings scoring higher on schizotypy (SSHS), and siblings scoring lower (SSLS). The SSHSs displayed a DAPP-BQ profile characterized by high scores in the dimensions of affective lability, anxiousness, submissiveness, social avoidance, identity problems, oppositionality, narcissism, and restricted expression, distinguishing them from the SSLS. Due to these dimensions, SSHSs are more similar to the patients' DAPP BQ profile. The results suggest that this pathological personality profile might contribute to increase the risk of developing psychosis in siblings who have more schizotypal features. PMID- 21266147 TI - Early psychopathological features in Spanish adolescents. AB - Schizotypal experiences and depressive symptoms are quite common among adolescents, and have been considered as risk markers for schizophrenia-spectrum and mood disorders. The main goal of the present study was to analyze the relationship between schizotypal experiences and depressive symptoms in a community sample of non-clinical adolescents. The sample comprised a total of 1653 participants, 794 male (48%), with an average age of 15.94 years (SD = 1.23). Results showed that schizotypal traits and depressive symptoms were closely related at a subclinical level. Canonical correlation analysis indicated that the two sets of variables shared approximately 48% of the variance. The study of the dimensionality underlying the subscales of the self-reports revealed the presence of three components, namely: Depressive, Anhedonia and Reality Distortion. These results are convergent with previous studies conducted in both clinical and non-clinical samples, indicating overlap between schizotypal experiences and depressive symptoms. PMID- 21266148 TI - [Emotional processing in people with obsessive-compulsive symptomatology]. AB - The present study was aimed at assessing obsessive-compulsive symptomatology based on visualization of affective pictures, elaborated following Peter Lang's dimensional model of emotion. Participants were 370 psychology students at Malaga University, selecting those with high and low scores in obsessive-compulsive symptomatology. All participants assessed a set of pictures containing obsessive compulsive cues using the three scales of the Self-Assessment Manikin: affective valence, arousal, and control/dominance. The results show that participants with high scores in obsessive-compulsive symptomatology experience reduced control over the affective pictures and rate as more unpleasant the neutral and obsessive compulsive pictures. PMID- 21266149 TI - [Personality differences between alcohol abusers and matched controls: Relation to frontal symptoms and subtypes of addicts]. AB - Epidemiological studies usually show a link between personality disorders and addictions. Dimensional models of personality, such as that of Cloninger, are able to diagnose and discriminate between transient dysfunctional behavior styles and relatively more stable traits. Certain brain areas have been proposed, as trait locations, based on their activation. This paper explores differences in personality traits among a sample of alcohol abusers (N= 95) and a control group of non-clinical population (N= 95), matched in sociodemographic variables, using the TCI-R-67 and the FrSBe-Sp. It is hypothesized that such differences are associated with frontal symptomatology. The existence of different subgroups of addicts based on certain combinations of traits is also analyzed. Results showed significant differences in two temperament traits (Novelty Seeking and Harm Avoidance) and a characterial trait (Self-Direction). We also found a correlation with a large effect size between these traits and frontal symptomatology. Cluster analysis classified the participants into several subtypes with different combinations of traits that matched diverse frontal symptomatology. Possible neurobiological explanations of these differences and their importance in the clinical practice are discussed. PMID- 21266150 TI - [Ambulatory group treatment for cocaine dependent patients combining cognitive behavioral therapy and motivational interviewing]. AB - Psychological interventions in cocaine dependent patients have demonstrated efficacy. Remarkable approaches are Contingency Management (CM) and Cognitive Behavioral Therapy (CBT). Lack of treatment adherence is the most important limitation. Motivational Interview (MI) has been shown to be an adherence enhancer. The objective of this study is to evaluate retention and abstinence in a combined CM and CBT group treatment in patients who have reached maintenance stage according to Prochaska and DiClemente's transtheoretical model (1982). Therefore, a longitudinal study was carried out with cocaine dependent patients with or without concomitant mental health disease. A 12-session open group was conducted weekly. Nineteen patients were included (78.9% men, mean age 36.6 years), 95% consumed intranasally and 47% had another psychiatric comorbidity. Treatment retention was 84%. During treatment and the first month of follow-up, all patients remained abstinent whereas at three months, 3 patients relapsed. These data confirm that using combined CM and CBT group therapy in cocaine dependents undergoing maintenance treatment enhances adherence and is effective to achieve abstinence. PMID- 21266151 TI - Individual characteristics and response to Contingency Management treatment for cocaine addiction. AB - Voucher-based contingency management (CM) research has demonstrated efficacy for treating cocaine addiction, but few studies have examined associations between individual baseline characteristics and response to CM treatments. The aim of this study, involving 50 cocaine outpatients receiving CM for cocaine addiction, was to assess the impact of baseline characteristics on abstinence outcomes after six months of treatment. Patients who were abstinent after six months of treatment accounted for 58% of the sample. Patients with higher scores on the Alcohol area of the EuropASI and patients that were non-abstinent during the first month of treatment were less likely to achieve abstinence. These outcome predictors have implications both for treatment research and for clinical practice. Patients who do not respond early to treatment may need a more intensive intervention, and concomitant problematic alcohol use should be detected and treated. The remaining baseline variables examined were not statistically significant predictors of abstinence. This finding is important for the generalizability of CM across the range of individual characteristics of treatment-seeking cocaine abusers. PMID- 21266152 TI - [The effects of the Demand-Support-Control model on construction workers' health]. AB - This work takes as reference the Demand-Control-Support model and analyzes the relation of job control and social support and some job demands and physical well being in a sample of 285 construction workers. In general, job demands, exposure to harmful conditions, social support, and job control were found to be related to physical well-being. The modulator effects of job control and social support were verified. Job control modulates the negative effects of stress, mainly in situations of high demand. Moreover, social support modulates the negative effects of stress in situations of high exposure to harmful conditions. A three way interaction effect was found but the increase in explained variance was not significant. Thus, the results do not reveal empirical evidence of the Demand Control-Support model. The limitations and practical implications of this study are discussed. PMID- 21266153 TI - [The Short Nicotine Dependence Syndrome Scale (NDSS-S) in Spanish smokers]. AB - We present a brief scale derived from the Nicotine Dependence Syndrome Scale (NDSS). We used a sample of 1.061 daily smokers, which was obtained from five Primary Care Health Centers, a Unit of Alcoholism, and a Smoking Cessation Unit. All smokers were evaluated with the NDSS and the SCID to assess nicotine dependence according to DSM-IV criteria. The results indicate the existence of a general factor of nicotine dependence according to the NDSS. We selected the items with a higher factor loading (>.50), obtaining a short scale of 6 items. With this brief scale, we obtained results similar to those of the total scale in the diverse variables (sociodemographic and smoking) of the study. Scale reliability is satisfactory (a= .79), the correlation between the short and the total scale is very high (r=.95, p<.001) and the short scale discriminates the smokers in terms of cigarette consumption and nicotine dependence, as assessed with the SCID. The operation under the ROC curve is excellent (area under the curve .84). The data indicate the usefulness of this brief scale (NDSS-S) to assess nicotine dependence in smokers. PMID- 21266154 TI - Psychometric properties of the Spanish version of the Frost Multidimensional Perfectionism Scale in women. AB - This instrumental study was designed to analyze the psychometric properties of the Spanish version of the Frost Multidimensional Perfectionism Scale (FMPS). The total sample was made up of 582 female college students, with a mean age of 21.68 (SD= 4.45). The results of confirmatory factor analysis identified the six-factor solution proposed by the original authors as the best factor structure, with acceptable fit indices. Cronbach's alpha coefficient was .93 for the FMPS total score and ranged from .74 to .91 for the subscales. Test-retest reliability suggested a good temporal stability of the FMPS total score [ICC= .89 (95% CI= .80-.94)] and its subscales. Results showed moderate to high associations between the Spanish version of the FMPS and other measures of perfectionism. The Spanish version of FMPS has shown satisfactory psychometric properties to be used in women. Future research should replicate these findings in broader samples, in clinical populations, and use longitudinal designs to determine whether perfectionism is a risk factor for psychopathology in women. PMID- 21266155 TI - [Psychometric examination of the School Social Climate Questionnaire in Chileans students]. AB - The School Social Climate Questionnaire (CECSCE) was adapted and applied. Subsequently, its psychometric proprieties were analyzed. The 1075 Chilean students who participated were assessed with the CECSCE and the School Violence Scale. The results showed that the CECSCE has a bifactorial structure, although there was also the possibility of a unifactorial structure. The CECSCE achieved satisfactory reliability and homogeneity indexes. The CECSCES scores were inversely related to the school violence rate. Lastly, differences by gender and educational level were analyzed. Given that there are differences in school climate perceptions in favor of girls, Chilean standards are presented in percentiles by gender. It can therefore be concluded that the CECSCE is sufficiently valid and reliable to be applied in Chile. PMID- 21266156 TI - Assessing indirect aggression in aggressors and targets: Spanish adaptation of the Indirect Aggression Scales. AB - In recent years, there has been increasing interest in indirect aggression as the most common aggressive behaviour in adulthood. Despite this interest, there are not a great many instruments for measuring this behaviour in adults. The aim of our study was to develop the Spanish adaptation of one of the few instruments that does exist: the Indirect Aggression Scale, in its aggressor and target versions. The analysis of these scales in a sample of 935 university students showed that the aggressor and target versions of the scales had good reliabilities, but that a one-factor structure seemed more feasible than the three-factor structure initially proposed. Taking this one-dimensionality, we developed short versions of the scales, which also showed good reliabilities. The aggressor version presented good convergent validity with direct aggression and impulsivity measures. Finally, none of the scales showed differences associated with sex. PMID- 21266157 TI - [Development and validation of a scale to assess positive youth development values]. AB - This paper describes the development of a self-report scale for adolescents to assess positive youth development values. It presents a substantial number of psychometric results performed on a sample of 2,400 adolescents (1,068 boys and 1,332 girls) from 12 to 17 years ( M = 14.73, SD = 1.25), who were studying secondary education in Western Andalusia. The results provide evidence of the psychometric quality of items, cross-validity of a structure of eight first-order factors and three second-order factors, obtained through exploratory and confirmatory factor analysis, and adequate reliability. This study concludes that the scale presents adequate evidence of validity and reliability that allows assessment, especially in school contexts, of a broad set of values of particular relevance to positive youth development. PMID- 21266158 TI - [Spanish adaptation of the EAS Temperament Survey for the assessment of child temperament]. AB - Better understanding of child temperament is essential, as it may predict subsequent development of psychopathology. Questionnaires which have been adapted to Spanish population include a rather restricted age range. The Emotionality Sociability and Activity (EAS) Temperament Survey has been widely used in child temperament genetic research. A Spanish version of the scale was administered to a sample of 229 mothers and to their children at 18 and 42 months of age. Its psychometric features were examined. Results showed accuracy indices akin to that obtained in prior studies. Findings suggest a three-factor structure for the assessment of temperament. PMID- 21266159 TI - MAVARIC - a comparison of automation-assisted and manual cervical screening: a randomised controlled trial. AB - OBJECTIVES: The principal objective was to compare automation-assisted reading of cervical cytology with manual reading using the histological end point of cervical intraepithelial neoplasia grade II (CIN2) or worse (CIN2+). Secondary objectives included (i) an assessment of the slide ranking facility of the Becton Dickinson (BD) FocalPointTM Slide Profiler (Becton Dickinson, Franklin Lakes, NJ, USA), especially 'No Further Review', (ii) a comparison of the two approved automated systems, the ThinPrep(r) Imaging System (Hologic, Bedford, MA, USA) and the BD FocalPoint Guided Screener Imaging System, and (iii) automated versus manual in terms of productivity and cost-effectiveness. DESIGN: A 1 : 2 randomised allocation of slides to either manual reading or automation-assisted paired with manual reading. Cytoscreeners were blinded to whether samples would be read only manually or manually paired with automated. Slide reading procedures followed real-life laboratory protocol to produce a final result and, for paired readings, the worse result determined the management. Costs per event were estimated and combined with productivity to produce a cost per slide, per woman and per CIN2+ and cervical intraepithelial neoplasia grade III (CIN3) or worse (CIN3+) lesion detected. Cost-effectiveness was estimated using cost per CIN2+ detected. Lifetime cost-effectiveness in terms of life-years and quality-adjusted life-years was estimated using a mathematical model. SETTING: Liquid-based cytology samples were obtained in primary care, and a small number of abnormal samples were obtained from local colposcopy clinics, from different women, in order to enrich the proportion of abnormals. All of the samples were read in a single large service laboratory. Liquid residues used for human papillomavirus (HPV) triage were tested (with Hybrid Capture 2, Qiagen, Crawley, UK) in a specialist virology laboratory in Edinburgh, UK. Histopathology was read by a specialist gynaecological pathology team blinded to HPV results and type of reading. PARTICIPANTS: Samples were obtained from women aged 25-64 years undergoing primary cervical screening in Greater Manchester, UK, with small proportions from women outside this age range and from women undergoing colposcopy. INTERVENTIONS: The principal intervention was automation-assisted reading of cervical cytology slides which was paired with a manual reading of the same slide. Low-grade cytological abnormalities (borderline and mild dyskaryosis) were triaged with HPV testing to direct colposcopy referral. Women with high grade cytology were referred for colposcopy and those with negative cytology were returned to recall. MAIN OUTCOME MEASURES: The principal outcome measure was the sensitivity of automation-assisted reading relative to manual for the detection of CIN2+. A secondary outcome measure was cost-effectiveness of each type of reading to detect CIN2+. The study was powered to detect a relative sensitivity difference equivalent to an absolute difference of 5%. RESULTS: The principal finding was that automated reading was 8% less sensitive relative to manual, 6.3% in absolute terms. 'No further review' was very reliable and, if restricted to routine screening samples, < 1% of CIN2+ would have been missed. Automated and manual were very similar in terms of cost-effectiveness despite a 60%-80% increase in productivity for automation-assisted reading. CONCLUSIONS: The significantly reduced sensitivity of automated reading, combined with uncertainty over cost-effectiveness, suggests no justification at present to recommend its introduction. The reliability of 'no further review' warrants further consideration as a means of saving staff time. TRIAL REGISTRATION: Current Controlled Trials ISRCTN66377374. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 15, No. 3. See the HTA programme website for further project information. PMID- 21266160 TI - Thermodynamic, enzymatic and structural effects of removing a salt bridge at the base of loop 4 in (pro)caspase-3. AB - Interactions between loops 2, 2' and 4, known as the loop bundle, stabilize the active site of caspase-3. Loop 4 (L4) is of particular interest due to its location between the active site and the dimer interface. We have disrupted a salt bridge between K242 and E246 at the base of L4 to determine its role in overall conformational stability and in maintaining the active site environment. Stability measurements show that only the K242A single mutant decreases stability of the dimer, whereas both single mutants and the double mutant demonstrate much lower activity compared to wild-type caspase-3. Structural studies of the caspase 3 variants show the involvement of K242 in hydrophobic interactions that stabilize helix 5, near the dimer interface, and the role of E246 appears to be to neutralize the positive charge of K242 within the hydrophobic cluster. Overall, the results suggest E246 and K242 are important in procaspase-3 for their interaction with neighboring residues, not with one another. Conversely, formation of the K242-E246 salt bridge in caspase-3 is needed for an accurate, stable conformation of loop L4 and proper active site formation in the mature enzyme. PMID- 21266161 TI - Mechanism involved in enhancement of osteoblast differentiation by hyaluronic acid. AB - OBJECTIVES: Bone morphogenetic protein-2 (BMP-2) is expected to be utilized to fill bone defects and promote healing of fractures. However, it is unable to generate an adequate clinical response for use in bone regeneration. Recently, it was reported that glycosaminoglycans, including heparin, heparan sulfate, keratan sulfate, dermatan sulfate, chondroitin-4-sulfate, chondroitin-6-sulfate, and hyaluronic acid (HA), regulate BMP-2 activity, though the mechanism by which HA regulates osteogenic activities has not been fully elucidated. The aim of this study was to investigate the effects of HA on osteoblast differentiation induced by BMP-2. MATERIALS AND METHODS: Monolayer cultures of osteoblastic lineage MG63 cells were incubated with BMP-2 and HA for various time periods. To determine osteoblastic differentiation, alkaline phosphatase (ALP) activity in the cell lysates was quantified. Phosphorylation of Smad 1/5/8, p38, and ERK proteins was determined by Western blot analysis. To elucidate the nuclear translocation of phosphorylated Smad 1/5/8, stimulated cells were subjected to immunofluorescence microscopy. To further elucidate the role of HA in enhancement of BMP-2-induced Smad signaling, mRNA expressions of the BMP-2 receptor antagonists noggin and follistatin were detected using real-time RT-PCR. RESULTS: BMP-2-induced ALP activation, Smad 1/5/8 phosphorylation, and nuclear translocation were up regulated when MG63 cells were cultured with both BMP-2 and HA. Western blot analysis revealed that phosphorylation of ERK protein was diminished by HA. Furthermore, the mRNA expressions of noggin and follistatin induced by BMP-2 were preferentially blocked by HA. CONCLUSIONS: These results indicate that HA enhanced BMP-2 induces osteoblastic differentiation in MG63 cells via down regulation of BMP-2 antagonists and ERK phosphorylation. PMID- 21266162 TI - Uncoupling of the ERalpha regulated morphological phenotype from the cancer stem cell phenotype in human breast cancer cell lines. AB - The CD24(low/-)CD44(+)EpCAM(+) phenotype is associated with breast cancer initiating cells. To investigate if these putative breast cancer stem cell markers are regulated by estrogen receptor alpha (ERalpha) we have determined the expression levels of EpCAM, CD44 and CD24 in several well characterized breast cancer cell lines. The expression levels of the three adhesion proteins were quantitatively different in the cell lines but the composite CD24(low/ )CD44(+)EpCAM(+) breast cancer stem cell phenotype was shown to exist as a small fraction, between 0.1% and 1.2%, in all breast cancer cell lines tested. Experimental silencing of ERalpha resulted in a reduced epithelial appearance and partial reduction of CD24 mRNA, while levels of CD44 and EpCAM were unaltered. Moreover, knockdown of ERalpha led to a change in the morphology of the cells similar to the epithelial to mesenchymal transition phenotype and was associated with decreased E-cadherin expression. Our findings offer new insights into the regulation of the breast cancer stem cell phenotype by ERalpha and suggest that treatments targeting the breast cancer stem cell adhesion molecules and the ERalpha pathway may be complementary. PMID- 21266163 TI - Adaptation of Clostridium difficile toxin A for use as a protein translocation system. AB - A cellular delivery system is a useful biotechnology tool, with many possible applications. Two derivatives of Clostridium difficile toxin A (TcdA) have been constructed (GFP-TcdA and Luc-TcdA), by fusing reporter genes to functional domains of TcdA, and evaluated for their ability to translocate their cargo into mammalian cells. The cysteine protease and receptor binding domains of TcdA have been examined and found to be functional when expressed in the chimeric construct. Whereas GFP failed to internalize in the context of the TcdA fusion, significant cellular luciferase activity was detected in vero cell lysates after treatment with Luc-TcdA. Treatment with bafilomycin A1, which inhibits endosomal acidification, traps the luciferase activity within endosomes. To further understand these results, clarified lysates were subjected to molecular weight sieving, demonstrating that active luciferase was released from Luc-TcdA after translocation and internal processing. PMID- 21266164 TI - Studies on substrate specificity of Jmjd2a-c histone demethylases. AB - Jumonji domain containing iron (II), 2-oxoglutarate (2OG)-dependent dioxygenases from Jmjd2 family demethylate trimethylated histone3-lysine 9 (H3-K9me3), and also H3-K9me2 and H3-K36me3, albeit at lower rates. Recently, we have identified the first non-histone substrates of JmjD2 demethylases. Here, we studied the substrate specificity of Jmjd2a-c demethylases using site-directed mutagenesis and novel non-histone substrates. We identified preference of Arg at -1 position and a smaller amino acid at -2 position using both singly and doubly mutated peptide substrates by Jmjd2a-c demethylases. Our results also identified similarities in substrate selectivity by H3-K9 methyltransferase, G9a and Jmjd2 demethylases despite their distinct reaction mechanisms. PMID- 21266165 TI - The melatonin action on stromal stem cells within pericryptal area in colon cancer model under constant light. AB - Constant light (LL) is associated with high incidence of colon cancer. MLT supplementation was related to the significant control of preneoplastic patterns. We sought to analyze preneoplastic patterns in colon tissue from animals exposed to LL environment (14 days; 300 lx), MLT-supplementation (10mg/kg/day) and DMH treatment (1,2 dimethylhydrazine; 125 mg/kg). Rodents were sacrificed and MLT serum levels were measured by radioimmunoassay. Our results indicated that LL induced ACF development (p < 0.001) with a great potential to increase the number of CD133(+) and CD68(+) cells (p < 0.05 and p < 0.001). LL also increased the proliferative process (PCNA-Li; p < 0.001) as well as decreased caspase-3 protein (p < 0.001), related to higher COX-2 protein expression (p < 0.001) within pericryptal colonic stroma (PCCS). However, MLT-supplementation controlled the development of dysplastic ACF (p < 0.001) diminishing preneoplastic patterns into PCCS as CD133 and CD68 (p < 0.05 and p < 0.001). These events were relative to decreased PCNA-Li index and higher expression of caspase-3 protein. Thus, MLT showed a great potential to control the preneoplastic patterns induced by LL. PMID- 21266166 TI - Ataxia telangiectasia mutated influences cytochrome c oxidase activity. AB - Cells lacking ataxia telangiectasia mutated (ATM) have impaired mitochondrial function. Furthermore, mammalian cells lacking ATM have increased levels of reactive oxygen species (ROS) as well as mitochondrial DNA (mtDNA) deletions in the region encoding for cytochrome c oxidase (COX). We hypothesized that ATM specifically influences COX activity in skeletal muscle. COX activity was ~40% lower in tibialis anterior from ATM-deficient mice than for wild-type mice (P < 0.01, n = 9/group). However, there were no ATM-related differences in activity of succinate dehydrogenase, isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, mitochondrial glycerol 3-phosphate dehydrogenase, or complex III. Incubation of wild-type extensor digitorum longus muscles for 1h with the ATM inhibitor KU55933 caused a ~50% reduction (P<0.05, n = 5/group) in COX activity compared to muscles incubated with vehicle alone. Among the control muscles and muscles treated with the ATM inhibitor, COX activity was correlated (r = 0.61, P<0.05) with activity of glucose 6-phosphate dehydrogenase, a key determinant of antioxidant defense through production of NADPH. Overall, the findings suggest that ATM has a protective role for COX activity. PMID- 21266167 TI - Rose odor can innately counteract predator odor. AB - When animals smell a predator odor such as 2,5-Dihydro-2,4,5-trimethylthiazoline (TMT), even if it is a novel substance, the hypothalamo-pituitary-adrenal (HPA) axis is activated, causing stress-like behaviors. Although the medial part of the bed nucleus of stria terminalis (mBST) is known to be involved in this process, the mechanism remains unclear. Moreover, it is unknown whether there is any odor that can counteract the predator odor, even when the odorants are novel substances for the animals. In this study, we assessed whether rose odor can counteract by counting the number of activated neurons in mice brain following the presentation of rose odor with or without TMT for 30 min. The number of activated cells in the mBST and in the ventrorostral part of the anterior piriform cortex (APC) was significantly reduced by a mixture of TMT and rose odor; however, no significant differences were noted in the dorsal part of the APC and in the olfactory bulb (OB) following TMT presentation with or without rose odor. The results suggest that rose odor may counteract the TMT-induced stress response in the OB and/or APC and suppress the neural circuit to the mBST. It also indicates that there are some odors that can innately counteract predator odor, even when they have not been experienced before. PMID- 21266168 TI - Relationship of neutrophil-lymphocyte ratio with arterial stiffness and coronary calcium score. AB - BACKGROUND: Emerging evidence suggests that the neutrophil/lymphocyte ratio (NLR) may be a useful marker of cardiovascular disease and a more powerful predictor than any other leukocyte subtypes. We determined whether NLR is related to atherosclerosis measured by brachial-ankle pulse wave velocity (baPWV) and coronary calcium score (CCS). METHODS: We examined the relationship of NLR with baPWV and CCS in 849 Korean adults in a health examination program. The odds ratios for a high baPWV or a high CCS were calculated using multivariate logistic regression analysis across NLR quartiles. A high baPWV was defined as >1500 cm/s (>75th percentile) and a high CCS was defined as over 100 (at least moderate atherosclerotic plaque burden). RESULTS: The ORs (95% CIs) for a high baPWV by NLR quartiles were 1.00, 0.76 (0.41-1.39), 1.08 (0.61-1.90), and 2.12 (1.18-3.83) after adjusting for confounding variables. Similarly, positive associations between NLR and a high CCS were also observed after adjusting for the same co variables. CONCLUSION: A higher NLR was independently associated with arterial stiffness and CCS. Accordingly, a higher NLR may be a useful additional measure in assessing cardiovascular risks in clinical practice. PMID- 21266169 TI - Development of an economic and efficient strategy to detect HBsAg: application of "gray-zones" in ELISA and combined use of several detection assays. AB - BACKGROUND: ELISA and CMIA are commonly used for detection of HBsAg. However, few investigations have been performed to evaluate their value in clinical practice, especially when jointly used. A reasonable and economic HBsAg testing algorithm is in great need. METHODS: A total of 161,426 specimens in China were tested for 5 serum HBV markers with commonly used ELISA kits. 498 of these specimens were further tested for HBsAg by another ELISA kit, a CMIA kit and an HBsAg confirmatory assay. RESULTS: The sensitivities of the 2 ELISA kits were 76.21% and 88.42%, respectively. However, when using "gray-zones", the sensitivities were significantly improved to 97.43% and 96.43%. Furthermore, the combined use of the 2 ELISA kits and their "gray-zones" improved the sensitivity to 99.04%. Nevertheless, 2.91% of the samples with S/CO values below the lower "gray-zone" limits were reactive by the CMIA kit and then confirmed as HBsAg positive. However, 71.43% of the samples with HBsAg values within 0.05 and 0.10 IU/ml detected by the CMIA kit could not be confirmed. CONCLUSIONS: As a rational and economic strategy, combined use of "gray-zones" in ELISA and several different detection assays can significantly increase the efficiency of HBsAg detection. PMID- 21266170 TI - Stimulation of chondrogenesis in ATDC5 chondroprogenitor cells and hypertrophy in mouse by Genkwadaphnin. AB - The growth in height of the bone plate is a result of endochondral proliferation in epiphyseal growth plates and the conversion of chondrocytes into new bone. The control of chondrogenic differentiation and hypertrophy is critical for these processes. The present study was aimed to demonstrate the chondromodulating activity of Genkwadaphnin. ATDC5 cultures treated with Genkwadaphnin produced cartilaginous nodules that were greater in number and larger in size than control cultures. Genkwadaphnin treated ATDC5 cells also stained more intensely with Alcian blue than control cells, suggesting greater synthesis of matrix proteoglycans in the former. Genkwadaphnin markedly induced the activation of alkaline phosphatase, as well as the expression of chondrogenic marker genes such as type II collagen, aggrecan, type I collagen, type X collagen, osteocalcin, and bone sialoprotein in ATDC5 cells. The expression of signaling molecules involved in chondrogenesis including Smad4, Sox9, and beta-catenin was also induced by treatment of ATDC5 cells with Genkwadaphnin. Furthermore, Genkwadaphnin induced the activation of extracellular signal-regulated kinase (ERK) and c-Jun N terminal kinase (JNK). To analyze the role of Genkwadaphnin in growth plate chondrocyte in vivo, we analyzed chondrogenesis in mice treated with Genkwadaphnin. The significant expansion in growth plate and hypertrophic zone and numerous numbers of chondrocyte positive cells in hypertrophic and proliferative bone areas were observed. These observations provide the first evidence that Genkwadaphnin has chondromodulating activity and may open new therapeutic avenues to treat a variety of skeletal diseases, such as dwarfism. PMID- 21266171 TI - Inhibition of isoflurane-induced increase of cell-surface redistribution and activity of glutamate transporter type 3 by serine 465 sequence-specific peptides. AB - Excitatory amino acid transporters (EAAT) transport glutamate into cells to regulate glutamate neurotransmission and to maintain nontoxic extracellular glutamate levels for neurons. We showed previously that the commonly used volatile anesthetic isoflurane increases the transporting activity of EAAT3, the major neuronal EAAT. This effect requires a protein kinase C (PKC) alpha-mediated and S465-dependent EAAT3 redistribution to the plasma membrane. Thus, we hypothesize that specific peptides can be designed to block this effect. We conjugated a 10-amino acid synthetic peptide with a sequence identical to that of EAAT3 around the S465 to a peptide that can facilitate permeation of the plasma membrane. This fusion peptide inhibited the isoflurane-increased EAAT3 activity and redistribution to the plasma membrane in C6 cells and hippocampus. It did not affect the basal EAAT3 activity. This peptide also attenuated isoflurane-induced increase of PKCalpha in the immunoprecipitates produced by an anti-EAAT3 antibody. A scrambled peptide that has the same amino acid composition as the S465 sequence-specific peptide but has a random sequence did not change the effects of isoflurane on EAAT3. The S465 sequence-specific peptide, but not the scrambled peptide, is a good PKCalpha substrate in in vitro assay. These peptides did not affect cell viability. These results, along with our previous findings, strongly suggest that PKCalpha interacts with EAAT3 to regulate its functions. The S465 sequence-specific peptide may interrupt this interaction and is an effective inhibitor for the regulation of EAAT3 activity and trafficking by PKCalpha and isoflurane. PMID- 21266172 TI - Allyl isothiocyanates and cinnamaldehyde potentiate miniature excitatory postsynaptic inputs in the supraoptic nucleus in rats. AB - Allyl isothiocyanates (AITC) and cinnamaldehyde are pungent compounds present in mustard oil and cinnamon oil, respectively. These compounds are well known as transient receptor potential ankyrin 1 (TRPA1) agonists. TRPA1 is activated by low temperature stimuli, mechanosensation and pungent irritants such as AITC and cinnamaldehyde. TRPA1 is often co-expressed in TRPV1. Recent study showed that hypertonic solution activated TRPA1 as well as TRPV1. TRPV1 is involved in excitatory synaptic inputs to the magnocellular neurosecretory cells (MNCs) that produce vasopressin in the supraoptic nucleus (SON). However, it remains unclear whether TRPA1 may be involved in this activation. In the present study, we examined the role of TRPA1 on the synaptic inputs to the MNCs in in vitro rat brain slice preparations, using whole-cell patch-clamp recordings. In the presence of tetrodotoxin, AITC (50MUM) and cinnamaldehyde (30MUM) increased the frequency of miniature excitatory postsynaptic currents without affecting the amplitude. This effect was significantly attenuated by previous exposure to ruthenium red (10MUM), non-specific TRP channels blocker, high concentration of menthol (300MUM) and HC-030031 (10MUM), which are known to antagonize the effects of TRPA1 agonists. These results suggest that TRPA1 may exist at presynaptic terminals to the MNCs and enhance glutamate release in the SON. PMID- 21266173 TI - Cannabinoids inhibit the synaptic uptake of adenosine and dopamine in the rat and mouse striatum. AB - Adenosine, dopamine and endocannabinoids strictly modulate the release of one another in the dorsolateral striatum thereby controlling synaptic plasticity. As a second level of interaction, they regulate the action of one another via receptor heteromer formation. Here we investigated a putative third level of interaction, i.e. the possible control by cannabinoids of synaptic dopamine and adenosine reuptake. We found that a large number of endo- and exogenous cannabinoid ligands inhibit the uptake of [(3)H]adenosine and [(3)H]dopamine in rat sriatal nerve terminals. Maximal effects were often comparable to those of the dopamine transporter inhibitor, GBR12783 and the equilibrative nucleoside transporter inhibitor, dipyridamole. Cannabinoid ligands were generally more potent to inhibit the uptake of adenosine than that of dopamine. The inhibitory effect was: (1) unrelated to the pharmacological profile(s) of the ligands at the cannabinoid CB(1), CB(2), GPR55 and at the vanilloid TRPV(1) receptors; (2) not prevented by the cannabinoid CB(1) receptor antagonist/inverse agonist, LY320135; and (3) maintained in the cannabinoid CB(1) receptor knockout mice. In the same experiments, only O-2050, cannabidiol, and WIN55212-3 inhibited the simultaneously measured DL-TBOA-sensitive uptake of [(14)C]glutamate. In summary, many cannabinoid ligands are able to inhibit the synaptic uptake of adenosine and dopamine. These effects are not mediated by cannabinoid CB(1) receptors, and should be an additional mechanism to consider when interpreting synaptic effects of cannabinoids. PMID- 21266174 TI - Effects of antidiabetic drugs in high-fat diet and streptozotocin-nicotinamide induced type 2 diabetic mice. AB - Based on previously established methods, we developed an easily available type 2 diabetic mouse model that exhibits obesity and insulin resistance. We investigated the effects of several antidiabetic drugs on this new model, which was induced by a high-fat diet in combination with streptozotocin and nicotinamide injection. Male ICR mice were fed a high-fat diet (45% of calories as fat) for 3weeks and then intraperitoneally administered with nicotinamide (1000mg/kg) and streptozotocin (150mg/kg). These diabetic mice exhibited hyperglycemia and glucose intolerance as a result of the loss of early-phase insulin secretion. The mice also developed significant insulin resistance, hyperlipidemia and obesity. A single dose of mitiglinide, glibenclamide, sitagliptin, insulin, metformin and voglibose significantly improved glucose tolerance during a liquid meal tolerance test. Repeated administration of sitagliptin and rosiglitazone also improved hyperglycemia and insulin resistance. These results demonstrate that a high-fat diet combined with nicotinamide and streptozotocin injection induces a diabetic mouse model that replicates the metabolic characteristics of human type 2 diabetes. This diabetic model, which exhibits impaired insulin secretion, glucose intolerance, insulin resistance, and obesity, may be suitable to evaluate antidiabetic agents for the treatment of type 2 diabetes. PMID- 21266175 TI - Crystal structure of constitutively monomeric E. coli Hsp33 mutant with chaperone activity. AB - Heat shock protein 33 (Hsp33) from Escherichia coli is a redox-regulated molecular chaperone that protects cells from oxidative stress. To understand the molecular basis for the monomer-dimer switch in the functional regulation of E. coli Hsp33, we generated a constitutively monomeric Hsp33 by introducing the Q151E mutation in the dimeric interface and determined its crystal structure. The overall scaffold of the monomeric Hsp33(1-235) (Q151E) mutant is virtually the same as that of the dimeric form, except that there is no domain swapping. The measurement of chaperone activity to thermally denatured luciferase showed that the constitutively monomeric Hsp33 mutant still retains chaperone activity similar to that of wild-type Hsp33(1-235), suggesting that a Hsp33 monomer is sufficient to interact with slowly unfolded substrate. PMID- 21266176 TI - Linker length dependent binding of a focal adhesion kinase derived peptide to the Src SH3-SH2 domains. AB - The interaction between a peptide encompassing the SH3 and SH2 binding motifs of focal adhesion kinase (FAK) and the Src SH3-SH2 domains has been investigated with NMR spectroscopy and calorimetry. The binding to both motifs is anti cooperative. Reduction of the long linker connecting the motifs does not lead to cooperativity. Short linkers that do not allow simultaneous intramolecular binding of the peptide to both motifs cause peptide-mediated dimerisation, even with a linker of only three amino acids. The role of the SH3 binding motif is discussed in view of the independent nature of the SH interactions. PMID- 21266177 TI - Control of RNA processing by a large non-coding RNA over-expressed in carcinomas. AB - RNA processing is vital for the high fidelity and diversity of eukaryotic transcriptomes and the encoded proteomes. However, control of RNA processing is not fully established. Sigma RNA is a class of conserved large non-coding RNAs (murine Hepcarcin; human MALAT-1) up-regulated in carcinomas. Using antisense technology, we identified that RNA post-transcriptional modification is the most significant global function of Sigma RNA. Specifically, processing of the pre mRNAs of genes including Tissue Factor and Endoglin was altered by hydrolysis of Sigma RNA/MALAT-1. These results support the hypothesis that Sigma RNA/MALAT-1 is a regulatory molecule exerting roles in RNA post-transcriptional modification. PMID- 21266178 TI - Central injection of des-acyl chicken ghrelin does not affect food intake in chicks. AB - In rodents and goldfish, ghrelin is well known as an orexigenic peptide, and des acyl ghrelin, which is a ghrelin gene-derived peptide lacking Ser-3 acylation, affects feeding behavior when injected with or without ghrelin. Intracerebroventricular (i.c.v.) injection of ghrelin inhibits food intake in chicks (Gallus gallus), but has the opposite effect in rodents and goldfish. The aim of the present study was to investigate the effect of chicken des-acyl ghrelin on feeding in chicks. I.c.v. injection of des-acyl ghrelin alone at doses from 4 to 1000 pmol did not affect food intake in fed and 12-h fasted chicks. Co injection of des-acyl ghrelin with ghrelin tended to attenuate ghrelin-induced anorexia. In an in vitro study, only the highest concentration (10(-6) M) of des acyl ghrelin increased intracellular calcium ion concentration in chicken GHS-R1a expressing cells. Des-acyl ghrelin (10(-6) M) slightly but significantly decreased intracellular calcium ion influx induced by 1 or 3 nM ghrelin. The present results demonstrate that des-acyl ghrelin is not positively involved in the central regulation of feeding in chicks. The feeding regulatory network between ghrelin and des-acyl ghrelin in chicks would be different from those in rodents and goldfish. PMID- 21266179 TI - Changes in vasoactive intestinal peptide and tyrosine hydroxylase immunoreactivity in the brain of nest-deprived native Thai hen. AB - Hyperprolactinemia is associated with incubation behavior and ovarian regression in birds. To investigate the association of prolactin (PRL), vasoactive intestinal peptide (VIP), and dopamine (DA) with the neuroendocrine regulation of incubation behavior, changes in the number of visible VIP-immunoreactive (VIP-ir) neurons in the nucleus inferioris hypothalami (IH) and nucleus infundibuli hypothalami (IN) and tyrosine hydroxylase-immunoreactive (TH-ir) neurons in the nucleus intramedialis (nI) and nucleus mamillaris lateralis (ML) of incubating native Thai hens were compared with those of nest-deprived hens. TH was used as a marker for dopaminergic (DAergic) neurons. Blood samples were collected to determine PRL levels. The localization and the number of visible VIP-ir and TH-ir neurons were determined by immunohistochemistry. Disruption of incubation behavior was accompanied by a precipitous decline in plasma PRL levels. The number of visible VIP-ir neurons in the IH-IN and TH-ir neurons in the nI and ML were high during incubation and decreased when hens were deprived of their nests. This study indicated an association between VIP neurons in the IH-IN and DA neurons in the nI and ML with the degree of hyperprolactinemia, suggesting that the expression of incubation behavior in birds might be, in part, regulated by the DAergic input from the nI and ML to VIP neurons in the IH-IN and subsequent PRL release. PMID- 21266180 TI - Match probabilities in a finite, subdivided population. AB - We generalize a recently introduced graphical framework to compute the probability that haplotypes or genotypes of two individuals drawn from a finite, subdivided population match. As in the previous work, we assume an infinite alleles model. We focus on the case of a population divided into two subpopulations, but the underlying framework can be applied to a general model of population subdivision. We examine the effect of population subdivision on the match probabilities and the accuracy of the product rule which approximates multi locus match probabilities as a product of one-locus match probabilities. We quantify the deviation from predictions of the product rule by R, the ratio of the multi-locus match probability to the product of the one-locus match probabilities. We carry out the computation for two loci and find that ignoring subdivision can lead to underestimation of the match probabilities if the population under consideration actually has subdivision structure and the individuals originate from the same subpopulation. On the other hand, under a given model of population subdivision, we find that the ratio R for two loci is only slightly greater than 1 for a large range of symmetric and asymmetric migration rates. Keeping in mind that the infinite-alleles model is not the appropriate mutation model for STR loci, we conclude that, for two loci and biologically reasonable parameter values, population subdivision may lead to results that disfavor innocent suspects because of an increase in identity-by descent in finite populations. On the other hand, for the same range of parameters, population subdivision does not lead to a substantial increase in linkage disequilibrium between loci. Those results are consistent with established practice. PMID- 21266181 TI - Attention modulates spatio-temporal grouping. AB - Dynamic stimuli are ubiquitous in natural viewing conditions implying that grouping operations need to operate, not only in space, but also jointly in space and time. Moreover, in natural viewing, attention plays an important role in controlling how resources are allocated. We investigated how attention interacts with spatio-temporal perceptual grouping by using a bistable stimulus, called the Ternus-Pikler display. Ternus-Pikler displays can give rise to two different motion percepts, called Element Motion (EM) and Group Motion (GM), the former dominating at short Inter-Stimulus Intervals (ISIs) and the latter at long ISIs. Our results indicate that GM grouping requires more attentional resources than EM grouping. Different theoretical accounts of perceptual grouping and attention are discussed and evaluated in the light of the current results. PMID- 21266184 TI - Developmental toxicity of copaiba tree (Copaifera reticulata Ducke, Fabaceae) oleoresin in rat. AB - The oleoresin of the copaiba tree (Copaifera sp., Fabaceae) is traditionally used in Brazilian herbal medicine to treat a variety of illnesses and symptoms. This study, conducted according to the OECD Guideline 414, provides data on the developmental toxicity of oleoresin from C. reticulata (COPA-R) in rats. Pregnant Wistar rats (25 per dose group) were treated by gavage with COPA-R (0, 500, 1000 and 1250 mg/kg bw/day) on gestation days (GD) 6-19 and Caesarean sections performed on GD20. Implantations, living and dead fetuses and resorptions were recorded. Half of the fetuses from each litter were examined for visceral abnormalities and the remaining were cleared and stained for skeleton evaluation. COPA-R was maternally toxic (reduced food intake and weight gain) and embryotoxic (lower fetal body weight and increased occurrence of fetal skeleton variations) at the two highest doses, but did not cause embryo deaths or fetal malformations at any dose level. The study derived an oral no-observed-adverse-effect-level (NOAEL) for maternal and developmental toxicity induced by COPA-R of 500 mg/kg bw/day. The results suggest that copaiba oleoresin does not pose a health risk to pregnant women when used according to the recommended doses (up to five drops, three times a day). PMID- 21266183 TI - Down-regulation of intra-hepatic T-cell signaling associated with GB virus C in a HCV/HIV co-infected group with reduced liver disease. AB - BACKGROUND & AIMS: Studies have shown that GB virus C (GBV-C) infection leads to reduced liver disease in hepatitis C virus (HCV)/human immunodeficiency virus (HIV) co-infection. Considering that the underlying mechanism(s) are unknown, we aim to identify differential gene and protein expression associated with GBV-C in HCV/HIV co-infection that may be responsible for reduced liver disease. METHODS: Liver, peripheral blood mononuclear cells (PBMCs), and plasma samples were collected from 43 HCV/HIV patients. Plasma was tested for GBV-C RNA by RT-PCR with NS5B gene primers. A microarray was performed on the liver and RT-qPCRs on the liver/PBMC samples. Hepatic protein expression was measured by immunohistochemistry. RESULTS: Sixteen out of 43 patients had GBV-C RNA. GBV-C was associated with reduced hepatic fibrosis (p=0.005) and inflammation (p=0.007). The microarray analysis of the liver samples (n=10) showed down regulation of genes critical to intra-hepatic T-cell signaling associated with GBV-C. Quantitative RT-PCR of the liver samples (n=13) confirmed the down regulation of lymphocyte-specific protein tyrosine kinase (LCK) (p=0.02) and docking protein 2 (DOK2) (p=0.04). No differences in the expression levels of these genes were observed in PBMCs (n=22) according to the GBV-C status. The hepatic expression of the LCK protein, measured by immunohistochemistry (n=36), was decreased in CD3-positive T-cells within portal tracts associated with GBV-C (p=0.003). This remained significant in multivariate analysis controlling for hepatic fibrosis and inflammation (p=0.027). No differences were observed in plasma cytokine concentrations (n=25) or ex-vivo peripheral T-cell responses (n=13) versus GBV-C status. CONCLUSIONS: GBV-C infection is associated with down regulation of critical genes involved in intra-hepatic T-cell signaling in HCV/HIV co-infection. This may be relevant to the pathogenesis of reduced HCV related liver disease in HIV co-infection. PMID- 21266185 TI - Effects of chloroacetaldehyde in 2-chloroethanol-induced cardiotoxicity. AB - Cardiovascular effects have often been found in 2-chloroethanol (2-CE) intoxicated patients, but the 2-CE elicits cardiovascular toxicity mechanism is not clear. Recently, we have found that chloroacetaldehyde (CAA) accumulation in 2-CE-intoxicated rat's blood and play an important role in 2-CE intoxication. In this study, we used an isolated rat atrium model to examine the cardiotoxicity of 2-CE and CAA. Results indicated that 2-CE did not cause tension arrest in isolated rat right atria, but CAA did. 2-CE caused tension inhibition in the isolated rat left atria. In addition, CAA caused significant tension inhibition and contracture in the isolated rat left atria. Nifedipine, an L-type calcium channel blocker, decreased CAA-induced tension inhibition and contracture. Meanwhile, atrial nNOS and calmodulin (CaM) had significantly greater expression in the 2-CE group and the CAA group than control group. Nifedipine could decrease CAA-induced nNOS and CaM expression. 2-CE-induced cardiovascular toxicity might be due to its metabolite CAA. CAA-induced cardiovascular toxicity might be mediated by calcium channel and nifedipine protected against nNOS-triggered cardiovascular effects. PMID- 21266186 TI - Evaluation of the potential protective effects of ad libitum black grape juice against liver oxidative damage in whole-body acute X-irradiated rats. AB - AIMS: The aim of this study was to evaluate the potential protective effects of ad libitum black grape (Vitis labrusca) juice against liver oxidative damage in whole-body acute X-irradiated rats. MAIN METHODS: Animals were fed ad libitum and drank voluntarily black grape juice or placebo (isocaloric glucose and fructose solution) for 6 days before and 15 days following a 6 Gy X-irradiation from a 200 kV machine. KEY FINDINGS: Irradiated animals receiving placebo showed a significant increase in the concentration of thiobarbituric acid-reactive substances (TBARS), a marker of lipid peroxidation, as well as a significant decrease in both Cu/Zn superoxide dismutase (Cu/ZnSOD) and glutathione peroxidase (GPx) activity and reduced glutathione concentration (GSH). Black grape juice supplementation resulted in a reversal of lipid peroxidation, Cu/ZnSOD activity, and GSH concentration, towards values not significantly differing from those in non-irradiated, placebo-supplemented rats. Poly(ADP-ribose) polymerase (PARP-1) and Cu/ZnSOD changes in protein expression were observed for irradiated rats. No change in p53 expression or DNA fragmentation was found. SIGNIFICANCE: Ad libitum black grape juice intake is able to restore the liver primary antioxidant system against adverse effects due to whole-body acute X-irradiation in rats after 15 days post-irradiation. The results support using antioxidant supplements as a preventive tool against radiation-induced harm. PMID- 21266187 TI - Two generation reproduction and teratogenicity studies of feeding cyadox in Wistar rats. AB - To investigate the teratogenic potential and reproductive toxicity of cyadox, a growth promoting agent, Wistar rats (F(0)) were fed with diets containing cyadox (0, 50, 150 and 2500 mg/kg) or olaquindox (150 mg/kg), approximately equivalent to cyadox 5, 15, 250 or olaquindox 15 mg/kg b.w./day across two generations. Half of the pregnant rats (F(0), F(1b)) were subjected to caesarean section on gestational day 20 for teratogenic examination and the other half produced pups F(1a) and F(2a), respectively. At the 250 mg/kg b.w./day cyadox group, body weights of F(1b) pregnant rats and F(2a) on day 21 after birth decreased; fetal body lengths and tail lengths decreased; the number of fetal resorptions increased significantly; litter weights, number of viable fetuses decreased; number of embryo resorptions increased significantly; number of liveborn F(1a), F(1b) and F(2a) decreased. No macroscopic or microscopic change of any significance was found in the reproductive organs. Significant increases in the incidence of cervical ribs or lumbar ribs in F(2a) pups and significant increases of relative organ weight of testis and epididymis in F(1b) were observed at the 250 mg/kg b.w./day cyadox group. The NOAEL for reproduction/development of cyadox for rats was estimated to be 150 mg/kg diet, which was equivalent to approximately 15 mg/kg b.w./day. PMID- 21266188 TI - PAMPA permeability, plasma protein binding, blood partition, pharmacokinetics and metabolism of formononetin, a methoxylated isoflavone. AB - Formononetin (FMN) is a methoxylated isoflavone which is the major constituent in red clover and in commercially available extracts of this plant. In this study, we investigated the parallel artificial membrane permeability assay (PAMPA) permeability, protein binding, blood uptake characteristics, pharmacokinetics and metabolism of FMN. The permeability study samples were analyzed by HPLC-PDA method; whereas the pharmacokinetic study, protein binding and whole blood partitioning samples were analyzed by LC-MS/MS method. The PAMPA permeability of FMN was found to be high at pH 4.0 and 7.0. Plasma protein binding of FMN was found to be 93.61+/-0.44% and 96.14+/-0.15% at the tested concentration of 50 and 150 ng/mL, respectively. FMN reached equilibrium fast between red blood cells (RBCs) and plasma, and the partition coefficients between RBCs and plasma (K(RBC/PL)) were independent of the initial rat blood concentrations of FMN. The bioavailability of unchanged/free FMN was found to be poor, i.e. approximately 3%. FMN was found to have a high clearance (5.13 L/h/kg) and a large apparent volume of distribution (14.16L/kg). Circulating conjugates (glucuronides/sulfates) of FMN and daidzein (DZN) were quantified using enzymatic hydrolysis of plasma samples. The levels of isoflavone glucuronides/sulfates were found to be much greater than that of the corresponding aglycones. PMID- 21266189 TI - Hexahydro-beta-acids induce apoptosis through mitochondrial pathway, GADD153 expression, and caspase activation in human leukemia cells. AB - Hexahydro-beta-acids (HBA) and beta-acids (BA) displayed strong growth inhibitory effects against human leukemia HL-60 cells and were able to induce apoptosis in a concentration- and time-dependent manner and the morphological changes associated with apoptotic cell death; however, BA was less effective. Treatment with HBA caused a rapid loss of mitochondrial trans-membrane potential, release of mitochondrial cytochrome c into cytosol. The levels of Bad and Bax were dramatically increased in cells treated with HBA. In addition, the results showed that HBA promoted the up-regulation of Fas prior to the processing and activation of pro-caspase-8 and cleavage of Bid, suggesting the involvement of a Fas mediated pathway in HBA-induced cells. Moreover, the changes occurred after single breaks in DNA were detected, suggesting that HBA induced irreparable DNA damage, which in turn triggered the process of apoptosis. HBA markedly enhanced the growth arrest DNA damage-inducible gene 153 (GADD153) protein in a concentration- and time-dependent manner. These findings suggest that HBA creates an oxidative cellular environment that induces DNA damage and GADD153 gene activation, which in turn triggers apoptosis in HL-60 cells. Our study identified the novel mechanisms of HBA-induced apoptosis and indicated that HBA may be used as a potential chemopreventive and chemotherapeutic agent. PMID- 21266190 TI - Protein phosphorylation in bacterial signal transduction. AB - BACKGROUND: Protein phosphorylation has emerged as one of the major post translational modifications in bacteria, involved in regulating a myriad of physiological processes. In a complex and dynamic system such as the bacterial cell, connectivity of its components accounts for a number of emergent properties. This article is part of a Special Issue entitled: Systems Biology of Microorganisms. SCOPE OF REVIEW: This review focuses on the implications of bacterial protein phosphorylation in cell signaling and regulation and highlights the connections and cross talk between various signaling pathways: bacterial two component systems and serine/threonine kinases, but also the interference between phosphorylation and other post-translational modifications (methylation and acetylation). MAJOR CONCLUSIONS: Recent technical developments in high accuracy mass spectrometry have profoundly transformed proteomics, and today exhaustive site-specific phosphoproteomes are available for a number of bacterial species. Nevertheless, prediction of phosphorylation sites remains the main guide for many researchers, so we discuss the characteristics, limits and advantages of available phosphorylation predictors. GENERAL SIGNIFICANCE: The advent of quantitative phosphoproteomics has brought the field on the doorstep of systems biology, but a number of challenges remain before the bacterial phosphorylation networks can be efficiently modeled and their physiological role understood. This article is part of a Special Issue entitled: Systems Biology of Microorganisms. PMID- 21266192 TI - Norcantharidin induces apoptosis of breast cancer cells: involvement of activities of mitogen activated protein kinases and signal transducers and activators of transcription. AB - Involvement of activities of mitogen-activated protein kinases (MAPKs) and signal transducers and activators of transcription (STATs) remains unsolved in norcantharidin-associated breast cancer cell apoptosis. This study investigated the anti-cancer effect of norcantharidin and its underlying mechanism in two human breast cancer cell lines, estrogen receptor (ER)- HS-578T and ER+ MCF-7 cells. Norcantharidin induced potent cytotoxicity and arrested cell growth through increasing phosphorylation of Chk1, Chk2 and total p21(Waf1/Cip1) and reducing cyclin B and cdc25c expression. It also induced apoptosis through extrinsic death receptor and intrinsic mitochondrial pathways by cytochrome c release, caspase activation, oligonucleosome appearance, PARP cleavage, and aberration of Bcl-2 family protein expression and phosphorylation. Although norcantharidin did not affect STAT1, STAT3, and STAT5 protein expression, it suppressed STAT3 and STAT5 phosphorylation in HS-578T cells, whereas it up regulated STAT1 phosphorylation and down-regulated STAT5 phosphorylation in MCF-7 cells. Moreover, norcantharidin activated MAPK family member proteins, extracellular signal-regulated kinase (ERK), p38(MAPK) and c-Jun N-terminal kinase (JNK), were all phosphorylated by treatment. Pretreatment with selective kinase inhibitors significantly attenuated the norcantharidin-induced cytotoxicity in breast cancer cells. These findings suggest the potential involvement of MAPK and STAT pathways in norcantharidin-induced apoptogenesis. Norcantharidin may be an effective anti-cancer drug against breast cancer. PMID- 21266191 TI - Endoplasmic reticulum stress mediates withaferin A-induced apoptosis in human renal carcinoma cells. AB - The accumulation of misfolded proteins in the lumen of the endoplasmic reticulum (ER) results in cellular stress that initiates a specialized response designated as the unfolded protein response. ER stress has been implicated in a variety of common diseases, such as diabetes, ischemia and neurodegenerative disorders. Withaferin A, a major chemical constituent of Withania somnifera, has been reported to inhibit tumor cell growth. We show that withaferin A induced a dose dependent apoptotic cell death in several types of human cancer cells, as measured by FACS analysis and PARP cleavage. Treatment of Caki cells with withaferin A induced a number of signature ER stress markers, including phosphorylation of eukaryotic initiation factor-2alpha (eIF-2 alpha), ER stress specific XBP1 splicing, and up-regulation of glucose-regulated protein (GRP)-78. In addition, withaferin A caused up-regulation of CAAT/enhancer-binding protein homologous protein (CHOP), suggesting the induction of ER stress. Pretreatment with N-acetyl cysteine (NAC) significantly inhibited withaferin A-mediated ER stress proteins and cell death, suggesting that reactive oxygen species (ROS) mediate withaferin A-induced ER stress. Furthermore, CHOP siRNA or inhibition of caspase-4 activity attenuated withaferin A-induced apoptosis. Taken together, the present study provides strong evidence supporting an important role of the ER stress response in mediating withaferin A-induced apoptosis. PMID- 21266193 TI - Differential expression of immune-associated cancer regulatory genes in low- versus high-dose-rate irradiated AKR/J mice. AB - AKR/J mice carrying leukemia viral inserts develop thymic lymphoma. Recently, we demonstrated that the incidence of thymic lymphoma was decreased when these mice were raised in a low-dose-rate gamma-irradiation facility. In contrast, mice irradiated at a high-dose rate developed severe thymic lymphoma and died much earlier. To understand the genetic changes occurred by low- versus high-dose-rate gamma-irradiation whole genome microarray was performed. Both groups of mice demonstrated up-regulation of Ifng, Igbp1, and IL7 in their thymuses, however, mice exposed to high-dose-rate gamma-irradiation exhibited marked down-regulation of Sp3, Il15, Traf6, IL2ra, Pik3r1, and Hells. In contrast, low-dose-rate irradiated mice demonstrated up-regulation of Il15 and Jag2. These gene expression profiles imply the impaired immune signaling pathways by high-dose rate gamma-irradiation while the facilitation of anti-tumor immune responses by low-dose-rate gamma-irradiation. Therefore, our data delineate common and distinct immune-associated pathways downstream of low- versus high-dose-rate irradiation in the process of cancer progression in AKR/J mice. PMID- 21266195 TI - LIM domains regulate protein kinase C activity: a novel molecular function. AB - Enigma homolog protein 1 (ENH1) acts as a scaffold that selectively associates protein kinases and transcription factors with cytoskeletal elements. ENH1 comprises an N-terminal PDZ domain and three C-terminal LIM domains. Through the LIM domains ENH1 interacts with the N-terminal region of protein kinase C betaI (PKCbetaI). Here, we show that when ENH1 is co-expressed, PKCbetaI is translocated from the cytoplasm to the plasma membrane in the absence of any other stimulation. Moreover expression of ENH1 markedly increases PKCbetaI activity in the absence of PKC activators. A similar activation of PKCbetaI was observed with co-expression of Cypher1 or Enigma, but not other LIM proteins. The region including the three LIM domains of ENH1 (residues 415-591) appears to be sufficient for this PKCbetaI activation. Finally, interaction with ENH1 also increases the activity of PKCalpha and PKCgamma, whereas it reduces PKCzeta activity. These findings provide strong evidence that ENH1 activates conventional PKCs by directly binding through its LIM domains. Thus, LIM domains have a novel molecular function: the regulation of PKC activities in a PKC isoform-specific manner. PMID- 21266194 TI - Activation of inflammatory signaling by lipopolysaccharide produces a prolonged increase of voluntary alcohol intake in mice. AB - Previous studies showed that mice with genetic predisposition for high alcohol consumption as well as human alcoholics show changes in brain expression of genes related to immune signaling. In addition, mutant mice lacking genes related to immune function show decreased alcohol consumption (Blednov et al., 2011), suggesting that immune signaling promotes alcohol consumption. To test the possibility that activation of immune signaling will increase alcohol consumption, we treated mice with lipopolysaccaride (LPS; 1mg/kg, i.p.) and tested alcohol consumption in the continuous two-bottle choice test. To take advantage of the long-lasting activation of brain immune signaling by LPS, we measured drinking beginning one week or one month after LPS treatment and continued the studies for several months. LPS produced persistent increases in alcohol consumption in C57BL/6J (B6) inbred mice, FVBxB6F1 and B6xNZBF1 hybrid mice, but not in FVB inbred mice. To determine if this effect of LPS is mediated through binding to TLR4, we tested mice lacking CD14, a key component of TLR4 signaling. These null mutants showed no increase of alcohol intake after treatment with LPS. LPS treatment decreased ethanol-conditioned taste aversion but did not alter ethanol-conditioned place preference (B6xNZBF1 mice). Electrophysiological studies of dopamine neurons in the ventral tegmental area showed that pretreatment of mice with LPS decreased the neuronal firing rate. These results suggest that activation of immune signaling promotes alcohol consumption and alters certain aspects of alcohol reward/aversion. PMID- 21266196 TI - SNX25 regulates TGF-beta signaling by enhancing the receptor degradation. AB - SNXs (sorting nexin), a family of proteins playing roles in cargo sorting and signaling from compartments within the endocytic network, regulate traffic of membrane proteins including TGF-beta receptors. Here we report that the full length human and mouse SNX25, a SNX member with PX, PXA and RGS domains, co localizes with TGF-beta receptors, and forms internalized cytosolic punctae upon treatment with TGF-beta. While overexpression of SNX25 inhibits TGF-beta induced luciferase reporter activity, knocking down endogenous SNX25 by siRNA in NIH3T3 cells elevates the TGF-beta receptor levels and facilitates TGF-beta signaling. Immunoprecipitation experiments demonstrate that SNX25 interacts with TbetaRI. Western blot analyses indicate that SNX25 enhances the degradation of TGF-beta receptors. SNX25 induced TGF-beta receptor degradation is shown via the clathrin dependent endocytosis pathway into lysosome. We have characterized that PXA domain of SNX25 is required for the degradation of TbetaRI. Our findings demonstrate that SNX25 negatively regulates TGF-beta signaling by enhancing the receptor degradation through lysosome pathway. PMID- 21266197 TI - State of the art of nanocrystals--special features, production, nanotoxicology aspects and intracellular delivery. AB - Drug nanocrystals are the latest, broadly introduced nanoparticulate carrier to the pharmaceutical market from the year 2000 onwards. The special features of nanocrystals for the delivery of poorly soluble drugs are briefly reviewed (saturation solubility, dissolution velocity, adhesiveness). The industrially relevant bottom up (precipitation) and top down production technologies (pearl milling, high pressure homogenization, combination technologies) are presented. As nanotoxicological aspects, the effect of size, degradability versus biopersistency and intracellular uptake are discussed, classifying the nanocrystals in the low/non-risk group. Intracellular uptake plays a minor or no role for dermal and oral nanocrystals, but it plays a key role for intravenously injected nanocrystals (e.g. nevirapine, paclitaxel, itraconazole). Uptake by the macrophages of the mononuclear phagocytic system (MPS, liver spleen) can modify/optimize blood profiles via prolonged release from the MPS (itraconazole), but also target toxicity by too high organ concentrations and thus cause nanotoxicity. The balance in the competitive intracellular uptake by MPS and the target cells (e.g. blood-brain barrier) decides about therapeutic efficiency. The concept of "differential protein adsorption" to modulate this balance is shown for its applicability to nanocrystals for intracellular delivery to the cells of the blood-brain barrier (atovaquone). PMID- 21266198 TI - Expression of Human papillomavirus 16 E7ggg oncoprotein on N- and C-terminus of Potato virus X coat protein in bacterial and plant cells. AB - The E7 oncoprotein from Human papillomavirus type 16 (HPV16) is an attractive candidate for anti-cancer therapeutical vaccine development. In this study, we engineered different fusions of mutagenized coding sequence of E7 oncoprotein (E7ggg) with coat protein of Potato virus X (PVX CP) both on 5'- and 3'-terminus of PVX CP and evaluated the influence of the length of linker (no linker, 4, 15aa) connecting PVX CP and E7ggg on their production. At first the expression in Escherichia coli was conducted to assess the characteristics of the recombinant protein prior to be further produced in plants, that is, resultant proteins were used for screening of their immunological reactivity with antibodies against PVX CP and E7. Fusion proteins successfully expressed in bacteria and plants were partially purified and their reactivity and ability to form virus-like particles were evaluated with anti-E7 antibodies. PMID- 21266199 TI - Plasma corticosterone of city and desert Curve-billed Thrashers, Toxostoma curvirostre, in response to stress-related peptide administration. AB - We compared the activity and responsiveness of the hypothalamo-pituitary-adrenal (HPA) axis of an urban (Phoenix, Arizona) and desert population of a male songbird species (Curve-billed Thrasher, Toxostoma curvirostre), by measuring plasma corticosterone in response to acute administration of corticotropin releasing factor, arginine vasotocin, or adrenocorticotropin hormone. Urban adult male thrashers showed greater responsiveness than desert birds to an injection of arginine vasotocin or adrenocorticotropin hormone, suggesting a population difference in pituitary and adrenal gland sensitivity. Plasma corticosterone in response to corticotropin-releasing factor injection did, however, not differ between populations. The differential corticosterone response to arginine vasotocin and corticotropin-releasing factor may reflect effects of chronic stress or habituation, which are known to favor arginine vasotocin over corticotropin-releasing factor sensitivity. Efficacy of HPA negative feedback by glucocorticoids was determined by measuring plasma corticosterone in response to acute administration of the synthetic glucocorticoid dexamethasone. This administration decreased plasma corticosterone similarly in urban and desert thrashers, suggesting that the negative feedback of glucocorticoids on the HPA axis in the two populations was equally effective. The higher sensitivity of urban than desert thrashers to adrenocorticotropin hormone and arginine vasotocin may result from up-regulation of the HPA axis in urban birds. This up-regulation may in turn make it easier for city birds to cope with urban environment associated stressors. PMID- 21266200 TI - Intra- and inter-specific variation in metabolic gene expression in relationship to environmental hypoxia. AB - In this study, we explored how environmental oxygen levels affect the metabolic phenotype of sympatric sunfish known to differ in their hypoxia tolerance. We examined bluegill (Lepomis macrochirus) and pumpkinseed (Lepomis gibbosus), two species commonly found in the same water bodies, though pumpkinseed are considered more hypoxia tolerant, and survive in hypoxic lakes that exclude bluegill. Freshly caught Lake Opinicon pumpkinseed possessed significantly higher glycolytic enzyme activities (PGI, ALD, GAPDH, ENO, and LDH) than bluegill, but after holding the fish in an oxygenated environment for 7days, pumpkinseed glycolytic enzymes (PGI, ALD, and LDH) and mRNA (LDHA and HIF1alpha) declined to bluegill's levels. When glycolytic enzymes and mRNA were compared in pumpkinseed populations from seven lakes, only Penyck Lake pumpkinseed had significantly elevated glycolytic enzyme activity that did not diminish with normoxic holding. The levels of mRNA for LDHA and HIF1alpha did not differ between lakes and did not change in response to normoxic holding in the Penyck Lake fish. Collectively, these studies on sunfish show that hypoxia tolerance contributes to ecological niche specialization between species, and provides an example of a population that has adapted chronically elevated glycolytic enzyme activity independent of current dissolved oxygen in the water. PMID- 21266202 TI - An analysis of the impact of FDA's guidelines for addressing cardiovascular risk of drugs for type 2 diabetes on clinical development. AB - We examined the impact of FDA's 2008 guidelines for addressing cardiovascular risks of new therapies for type 2 diabetes on clinical trials. We focused on the new class of incretin-modulating drugs, exenatide, sitagliptin, saxagliptin and liraglutide, which were approved in 2005-2010. We contrasted these findings with those from 2 different groups: 1. diabetes drugs approved in the same timeframe but with a non-incretin mechanism of action (colesevelam HCl and bromocriptine mesylate) and 2. diabetes drugs with NDAs delayed and not yet approved within the same time frame (vildagliptin, alogliptin, insulin inhalation powder, and exenatide long acting release). The new guidelines have had an important impact on clinical development. Review time has increased over 2-fold. The increase is seen even if a drug with the same mechanism of action has been already approved. Whereas exenatide (approved in 2005) required 10 months of regulatory review, the approval of liraglutide in 2010 required more than twice as long (21 months). In contrast, the marketing authorization of liraglutide in the EU required 14 months. Additionally, the manufacturer of vildagliptin announced in June 2008, 30 months after the NDA was filed, that a re-submission to meet FDA's demands was not planned. The drug however received marketing authorization in the EU in 2007. The number of randomized patients and patient-years in NDAs increased more than 2.5 and 4 fold, respectively since the guidelines. The significant cost increases and negative publicity because of rare adverse reactions will adversely affect future clinical research in type 2 diabetes and not address its burgeoning health care impact. PMID- 21266201 TI - Molecular characterization and functions of zebrafish ABCC2 in cellular efflux of heavy metals. AB - Multidrug-resistance associated protein 2 (MRP2/ABCC2) plays crucial roles in bile formation and detoxification by transporting a wide variety of endogenous compounds and xenobiotics, but its functions in zebrafish (Danio rerio) remain to be characterized. In this study, we obtained the full-length cDNA of zebrafish abcc2, analyzed its expression in developing embryos and adult tissues, investigated its transcriptional response to heavy metals, and evaluated its roles in efflux of heavy metals including cadmium, mercury and lead. Zebrafish abcc2 gene is located on chromosome 13 and composed of 32 exons. The deduced polypeptide of zebrafish ABCC2 consists of 1567 amino acids and possesses most of functional domains and critical residues defined in human ABCC2. Zebrafish abcc2 gene is not maternally expressed and its earliest expression was detected in embryos at 72hpf. In larval zebrafish, abcc2 gene was found to be exclusively expressed in liver, intestine and pronephric tubules. In adult zebrafish, the highest expression of abcc2 gene was found in intestine followed by those in liver and kidney, while relative low expression was detected in brain and muscle. Expression of abcc2 in excretory organs including kidney, liver and intestine of zebrafish larvae was induced by exposure to 0.5MUM mercury or 5MUM lead. Moreover, exposure to 0.125-1MUM of mercury or lead also significantly induced abcc2 expression in these excretory organs of adult zebrafish. Furthermore, overexpression of zebrafish ABCC2 in ZF4 cells and zebrafish embryos decreased the cellular accumulation of heavy metals including cadmium, mercury and lead as determined by MRE (metal responsive element)- or EPRE (electrophile response element)-driven luciferase reporters and atomic absorption spectrometry. These results suggest that zebrafish ABCC2/MRP2 is capable of effluxing heavy metals from cells and may play important roles in the detoxification of toxic metals. PMID- 21266203 TI - Analysis of tumor burden versus progression-free survival for Phase II decision making. AB - PURPOSE: There have been recent recommendations to use percentage change in tumor burden (dTB) as a primary endpoint in randomized Phase II trials. We assessed whether dTB is better for the decision to start a Phase III trial than is progression-free survival (PFS). METHODS: We repeatedly sampled patients from six large randomized trials to obtain simulated Phase II trials. We derived PFS and dTB endpoints on the trial patients and determined the fraction of simulated trials with positive results for each endpoint. We supplemented these analyses with regression analyses to assess the ability of PFS and dTB to predict overall survival (OS). RESULTS: The best PFS endpoint included tumor assessments through 6 months after the last patient enrolled. With 70 patients in each simulated Phase II trial, the estimated rate of a correct 'Phase III go' decision ranged from 0.74 to 0.91 across the six parent studies. The best dTB endpoint was the last dTB through 6 months after the last patient enrolled, with corresponding rates of 0.54 to 0.81. The PFS rate was better than the dTB rate in five studies. PFS and dTB are individually statistically significant predictors of OS (p < 0.05). In all six studies PFS added significantly to the regression models with dTB included, while in only two studies did dTB add significantly to the regression model with PFS included. CONCLUSION: Analysis of PFS in randomized Phase II trials generally leads to better 'Phase III go' decisions than does analysis of dTB. Tumor burden analyses should be used in supportive analyses to a primary PFS analysis. PMID- 21266205 TI - Creb and Sp/Kruppel response elements cooperate to control rat TRH gene transcription in response to cAMP. AB - Expression of hypophysiotropic TRH, that controls thyroid axis activity, is increased by cold exposure; this effect is mimicked in rat hypothalamic cells incubated with norepinephrine or cAMP analogs. TRH proximal promoter contains three putative CRE: Site-4 or CRE-1 that overlaps an element recognized by thyroid hormone receptors, CRE-2 with adjacent sequences GC box or CACCC recognized by Sp/Kruppel factors (extended CRE-2), and AP-1 sites flanking a GRE(1/2). To evaluate the role of each element in the cAMP response, these sites were mutated or deleted in rat TRH promoter linked to luciferase gene (TRH-luc) and co-transfected with beta-gal expression vector in various cell lines; C6 cells gave the highest response to forskolin. Basal activity was most affected by mutations or deletion of CRE-2 site, or CACCC (50-75% of wild type-WT). Forskolin induced 3* stimulation in WT which decreased 25% with CRE-1 or AP-1 deletions, but 50% when CRE-2 or its 5' adjacent GC box was altered. SH-SY5Y cells co transfected with CREB-expression vector increased dB-cAMP response in the wild type but not in the CRE-2 mutated plasmid; cotransfecting CREB-A (a dominant negative expression vector) strongly diminished basal or cAMP response. Primary cultures of hypothalamic cells transfected with plasmids containing deletions of CRE-1, CRE-2, or extended CRE-2 failed to respond to forskolin when CRE-2 was modified. These results corroborate the CRE-2 site as the main cAMP-response element of rat TRH promoter, not exclusive of transcription factors of hypothalamic cells, and stress the relevance of adjacent Sp-1 sites, important mediators of some metabolic hormones. PMID- 21266204 TI - Effect of statin therapy on disease progression in pediatric ADPKD: design and baseline characteristics of participants. AB - Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney condition and is associated with important renal and cardiovascular manifestations in childhood. Renal cystic disease can be documented in some cases as early as in utero. Early intervention is critical if the long-term complications of this condition, including end-stage renal disease, are to be ameliorated. Here we describe our ongoing randomized double-blind placebo controlled phase III clinical trial to assess the effect of pravastatin treatment on renal and cardiovascular disease progression in 107 children and young adults age 8-22 years with ADPKD who are receiving the angiotensin converting enzyme inhibitor lisinopril. Baseline demographic and laboratory data are provided. Results of this study could markedly impact the standard of care for evaluation and treatment of ADPKD in this population. PMID- 21266206 TI - Association of apolipoprotein E promoter polymorphisms with bone structural traits is modified by dietary saturated fat intake - the Cardiovascular Risk in Young Finns study. AB - Association of apolipoprotein E (APOE) epsilon4 allele with peripheral quantitative computed tomography (pQCT) bone traits at the distal and shaft sites of the radius and tibia was evaluated in the Young Finns Cohort (n=1777). We also analyzed the interactions of the APOE promoter polymorphisms (-219G/T rs405509 and +113G/C rs440446) and bone traits within the APOE epsilon3/epsilon3 genotype (n=1025 and n=1013, respectively), and investigated the gene-environment interactions on bone traits with longitudinal saturated fatty acids (SAFA) intake. Differences between the epsilon4 allele carriers and noncarriers were modest and mostly nonsignificant. Within the APOE promoter -219G/T polymorphism, cortical strength index (CSI) and compressive bone strength index (BSI) at the distal radius (linear, P=0.003 and P=0.05, respectively) and tibia (linear, P=0.01 and P=0.03, respectively), and CSI at the tibial shaft (linear, P=0.04) decreased towards the -219T/T genotype in women. In men, total cross-sectional areas at the radial site and stress-strain index (SSI) at the radial shaft (linear, P=0.03 and P=0.04 and P=0.05, respectively) increased, and conversely cortical bone density and CSI at the radial shaft (linear, P=0.005 and P=0.05, respectively) and CSI at the tibial shaft (linear, P=0.03) decreased towards the 219T/T genotype. In the highest SAFA tertile, women with the -219T/T genotype had the smallest total area and SSI at the radial shaft (P=0.01 and P=0.02, respectively). Subjects with the APOE +113C/C genotype shared similar bone traits as subjects with the APOE -219T/T genotype. In conclusion, APOE genotypes -219T/T and +113C/C could be genetic markers for cortical bone strength. Furthermore, high longitudinal SAFA intake seems to be more detrimental to bone in women with the -219T/T and +133C/C genotypes than others. PMID- 21266208 TI - A rare cause of acute pancreatitis in an adolescent. Juxtapapillary duodenal duplication cyst as a rare cause of acute pancreatitis in an adolescent. PMID- 21266209 TI - Proton pump inhibitor co-therapy with clopidogrel: is there GI benefit or cardiovascular harm? PMID- 21266210 TI - Mesenchymal stem cells: therapeutic potential for acute pancreatitis. PMID- 21266212 TI - Leiomyosarcoma of the infra-renal inferior vena cava. AB - Leiomyosarcoma of the inferior vena cava (IVC) is a rare slow-growing retroperitoneal tumor. Two percent of leiomyosarcomas are vascular in origin, and tumors of the IVC account for the majority of the cases. The diagnosis is frequently delayed, because affected patients remain asymptomatic for a long period. It has an extremely poor prognosis, with 5-year actuarial malignancy-free survival rates of 30% to 50% after a wide surgical resection. The authors present the case of a patient with IVC leiomyosarcoma who underwent en bloc resection of the tumor along with the involved segment of the infrarenal IVC without caval reconstruction. Complete surgical resection offers the only potential of long term survival, but survival of unresected patients is generally measured in months. Palliative resections may temporarily improve symptoms but do not offer long-term survival. PMID- 21266213 TI - Small bowel obstruction caused by appendiceal tourniquet. AB - True mechanical small bowel obstruction because of appendicitis is extremely rare. A case is presented, and diagnosis and treatment principles are discussed. PMID- 21266211 TI - Abnormalities of angiotensin regulation in postural tachycardia syndrome. AB - BACKGROUND: Postural tachycardia syndrome (POTS) is a disorder characterized by excessive orthostatic tachycardia and significant functional disability. We previously reported that POTS patients have low blood volume and inappropriately low plasma renin activity (PRA) and aldosterone. In this study, we sought to more fully characterize the renin-angiotensin-aldosterone system (RAAS) to gain a better understanding of the pathophysiology of POTS. OBJECTIVE: The purpose of this study was to prospectively assess the plasma levels of angiotensin (Ang) peptides and their relationship to other RAAS components in patients with POTS compared with healthy controls. METHODS: Heart rate, PRA, Ang I, Ang II, Ang (1 7), and aldosterone were measured in POTS patients (n = 38) and healthy controls (n = 13) while they were consuming a sodium-controlled diet. RESULTS: POTS patients had larger orthostatic increases in heart rate than did controls (52 +/- 3 [mean +/- SEM] bpm vs 27 +/- 6 bpm, P = .001). Plasma Ang II was significantly higher in POTS patients (43 +/- 3 pg/mL vs 28 +/- 3 pg/mL, P = .006), whereas plasma Ang I and angiotensin 1-7 [Ang-(1-7)] were similar between groups. Despite the twofold increase of Ang II, POTS patients trended to lower PRA levels than did controls (0.9 +/- 0.1 ng/mL/h vs 1.6 +/- 0.5 ng/mL/h, P = .268) and lower aldosterone levels (4.6 +/- 0.8 pg/mL vs 10.0 +/- 3.0 pg/mL, P = .111). Estimated angiotensin-converting enzyme-2 (ACE2) activity was significantly lower in POTS patients than in controls (0.25 +/- 0.02 vs 0.33 +/- 0.03, P = .038). CONCLUSION: Some patients with POTS have inappropriately high plasma Ang II levels, with low estimated ACE2 activity. We propose that these abnormalities in Ang regulation may play a key role in the pathophysiology of POTS in some patients. PMID- 21266214 TI - The morbidity of Clostridium difficile infection after elective colonic resection results from a national population database. AB - BACKGROUND: Clostridium difficile (CD), a gram-positive rod bacterium, resides normally within the human colon. Antibiotic treatment alters normal colonic flora, potentiating abnormal overgrowth of CD. METHODS: This study examined the 2004 to 2006 Nationwide Inpatient Sample to determine outcomes of CD colitis after 695,010 elective colonic resections. RESULTS: CD infection, occurring in 1.4% of patients, was associated with higher pulmonary (12.1% vs 6.4%) and gastrointestinal (12.8% vs 10.5%) complications as well as an increased length of stay (22.6 vs 10.9 days) and mortality (16.2% vs 4.9%; all P < .001). CD colitis patients more frequently held Medicare insurance (68% vs 51%) and underwent small segmental colonic resection as opposed to a defined anatomic resection (20.0% vs 9.9%; P < .001). An underlying diagnosis of colon cancer was associated with a lower incidence of CD colitis (odds ratio, .71; 95% confidence interval, .59-.84; P < .001). CONCLUSIONS: CD colitis is associated with worse outcomes after elective colonic resection. PMID- 21266215 TI - Randomized clinical trial comparing ambulatory and inpatient care after inguinal hernia repair in patients aged 65 years or older. AB - BACKGROUND: There is a lack of evidence from randomized studies of the feasibility of ambulatory surgery in patients aged 65 years and older. METHODS: Medically stable patients scheduled for open inguinal hernia repair, with postoperative care available at home, were randomized to receive treatment either as outpatients or inpatients. Younger patients undergoing the same procedure served as a reference group. Outcome measures during the 2 weeks after surgery were complications, unplanned admissions, visits to the hospital, unplanned visits to primary health care, and patients' acceptance of the type of provided care. RESULTS: Of 151 patients, 89 were included. Main reasons for exclusion were lack of postoperative company (16%), unwillingness to participate (13%), and medical conditions (10%). All outpatients were discharged home as planned, and none of the study patients were readmitted to the hospital. Patient satisfaction was high with no differences between the groups. CONCLUSIONS: Ambulatory surgery was safe and well accepted by older, medically stable patients. PMID- 21266216 TI - Sensitivity of detection of radiofrequency surgical sponges: a prospective, cross over study. AB - BACKGROUND: A retained surgical sponge is a serious medical error that results in negative patient outcomes. Radiofrequency (RF) technology has recently been introduced to evaluate for the presence of a retained sponge. The aim of this study was to evaluate the sensitivity and specificity of the detection of surgical sponges embedded with an RF chip through the torsos of subjects of varying body habitus, including the morbidly obese. METHODS: A prospective, crossover, and observer blinded study design was used. Subjects served as their own controls. With the subject supine, 4 surgical sponges were sequentially placed behind the subject's torso in locations approximating abdominal quadrants. RESULTS: Two hundred ten subjects were enrolled in the study. Nearly half (n = 101) were morbidly obese. Eight hundred forty readings were taken. There were no false-positive or false-negative readings. The sensitivity and specificity of detection of the RF sponges through the torsos of subjects of varying body habitus were 100%. CONCLUSIONS: The sensitivity and specificity of RF sponge technology are much higher than published reports of surgical counts or published findings of intraoperative radiographs for retained sponges. PMID- 21266217 TI - Impact of concomitant arterial injury on the outcome of laparoscopic bile duct injury. AB - BACKGROUND: Concomitant injury to the bile duct and hepatic artery is an increasingly recognized complication of laparoscopic cholecystectomy (LC). The impact of a concomitant arterial injury in patients with a bile duct injury (BDI) remains debatable. Early reports described a high incidence of septic complications, difficulty of biliary repair, and increased the risk of recurrent stricture. DATA SOURCES: A literature search on the clinical significance and management of a concomitant hepatic artery injury (HAI) to the outcome of biliary enteric reconstruction following BDI was reviewed. Relevant articles were extracted through MEDLINE, with secondary references obtained from key articles. CONCLUSIONS: The association between failure of biliary repair and concomitant arterial injuries is not confirmed by the largest studies, which showed no difference in anastomotic stricture rate between patients who had an isolated BDI and those who had a combined HAI and BDI. However, right arterial injury associated with liver necrosis or damage to the right hepatic duct may require right hepatectomy. PMID- 21266218 TI - Bariatric surgery. AB - Bariatric surgery is a growing segment of minimally invasive surgery. Laparoscopic bariatric procedures are considered some of the most technically challenging surgeries, requiring advanced surgical skills. Successful care of the morbidly obese patient requires a multidisciplinary team approach. These unique requirements are difficult to meet during residency and surgeons interested in bariatric surgery should pursue fellowship training in bariatric surgery. PMID- 21266219 TI - Vascular surgery career resource. AB - Vascular surgery has undergone a minimally invasive revolution in the past 15 years. The subspecialty emerged with many changes to its training paradigms that have made this field more attractive to both medical student and general surgery resident candidates. Commitment to diagnosis and treatment of arterial, venous, and lymphatic systems disorders remains the cornerstone of this profession, but an entirely new generation of endovascular treatments has been added to the staple of open surgical procedures used to treat these diseases. A wide variety of practice options are available, ranging from high-stress, technologically demanding complex arterial repairs to low-risk, outpatient, venous insufficiency treatment and all combinations in-between. Many online resources are available to allow an interested candidate to stay current with all the exciting changes in the field. This information is maintained by strong national organizations of vascular surgeons. PMID- 21266220 TI - The unfolded protein response and cellular stress, Part A.. Preface. PMID- 21266221 TI - The unfolded protein response in mouse cerebral cortex. AB - The unfolded protein response (UPR) is important for normal cellular homeostasis, development, and physiology. Endoplasmic reticulum stress and the UPR have also been implicated in a variety of diseases and pathologies. Thus the UPR is being studied in many model systems. We describe in this chapter methods for studying the UPR in a mouse model, specifically the cerebral cortex of mouse brain. PMID- 21266222 TI - Immunohistochemical detection of the unfolded protein response in atherosclerotic plaques. AB - It is well established that activation of the unfolded protein response (UPR) occurs during all stages of plaque development and progression. Mouse models of atherosclerosis have allowed the study of the UPR in the complex environment of lesions which are composed of different cell types, abundant extracellular matrix, as well as necrotic and apoptotic areas. For proper evaluation of the UPR, the processing, sectioning, and staining of lesions have to be performed in a consistent and reproducible manner. In this chapter, we describe in detail how to embed aortic roots in paraffin, cut serial sections through the aortic root, measure lesion size, and stain paraffin sections by immunohistochemistry, immunofluorescence, and the terminal dUTP nick-end-labeling (TUNEL) technique, with special attention to the proteins involved in the UPR. PMID- 21266223 TI - The role of PDI as a survival factor in cardiomyocyte ischemia. AB - Acute myocardial infarction (AMI) leads to activation of unfolded protein response (UPR) following endoplasmic reticulum (ER) stress. Failing in the restoration of the proper folding activity in the ER can lead to apoptosis and cell death. While it can be easy to detect transcripts and proteins expression alterations during a pathological state, it can be difficult to address the importance of changes in protein expression in the physiopathological context. We found protein disulfide isomerase (PDI) increased expression in human autoptic heart samples correlating with cell survival following AMI. PDI enzymatic activity resulted to be important to achieve cardiomyocyte protection from hypoxic stress, dependent on its ability to relieve ER stress preventing accumulation of nonfolded proteins in the ER, and to enhance superoxide dismutase 1 (SOD-1) activity. Furthermore, adenoviral-mediated PDI overexpression in an in vivo mouse model of AMI prevented adverse cardiac remodeling reducing cardiomyocyte apoptosis. Finally, we suggest a method to detect alterations in normal redox state in PDI (and eventually in the PDI family's proteins) during pathologies in which ER stress is induced. Diabetes pathology correlates with increased risk of AMI and worse cardiac remodeling. We found an alteration in PDI redox state in the diabetic heart and suggest using this system for the detection of the redox state alteration to screen for therapies able to restore the proper redox state. PMID- 21266224 TI - Measurement of the increase in endoplasmic reticulum stress-related proteins and genes in adipose tissue of obese, insulin-resistant individuals. AB - Here, we provide a detailed description of proteomic, Western blot and RT-PCR analyses performed to examine fat biopsy samples from lean insulin-sensitive and obese insulin-resistant nondiabetic individuals for evidence of endoplasmic reticulum (ER) stress. Subcutaneous fat biopsies were obtained from the upper thighs of six lean and six obese nondiabetic subjects. Fat homogenates were used for proteomic (two-dimensional gel (2DE) and MALDI-TOF/TOF), Western blot, and RT PCR analysis. Proteomic analysis revealed 19 differentially upregulated proteins in fat of obese subjects. Three of these proteins were the ER stress-related unfolded protein response (UPR) proteins calreticulin, protein disulfide isomerase A3, and glutathione-S-transferase P; Western blotting revealed upregulation of several other UPR stress-related proteins, including calnexin, a membrane-bound chaperone, and phospho c-jun NH(2)-terminal kinase (JNK)-1, a downstream effector protein of ER stress; RT-PCR analysis revealed upregulation of the spliced form of X-box-binding protein-1s, a potent transcription factor and part of the proximal ER stress sensor inositol-requiring enzyme-1 pathway. These findings demonstrate of UPR activation in subcutaneous adipose tissue of obese human subjects. As JNK can inhibit insulin action and activate proinflammatory pathways, ER stress activation of JNK may be a link between obesity, insulin resistance, and inflammation. PMID- 21266225 TI - Measurement of the unfolded protein response (UPR) in monocytes. AB - In mammalian cells, the primary function of the endoplasmic reticulum (ER) is to synthesize and assemble membrane and secreted proteins. As the main site of protein folding and posttranslational modification in the cell, the ER operates a highly conserved quality control system to ensure only correctly assembled proteins exit the ER and misfolded and unfolded proteins are retained for disposal. Any disruption in the equilibrium of the ER engages a multifaceted intracellular signaling pathway termed the unfolded protein response (UPR) to restore normal conditions in the cell. A variety of pathological conditions can induce activation of the UPR, including neurodegenerative disorders such as Parkinson's disease, metabolic disorders such as atherosclerosis, and conformational disorders such as cystic fibrosis. Conformational disorders are characterized by mutations that modify the final structure of a protein and any cells that express abnormal protein risk functional impairment. The monocyte is an important and long-lived immune cell and acts as a key immunological orchestrator, dictating the intensity and duration of the host immune response. Monocytes expressing misfolded or unfolded protein may exhibit UPR activation and this can compromise the host immune system. Here, we describe in detail methods and protocols for the examination of UPR activation in peripheral blood monocytes. This guide should provide new investigators to the field with a broad understanding of the tools required to investigate the UPR in the monocyte. PMID- 21266226 TI - Assessment of endurance exercise training in hepatic endoplasmic reticulum stress. AB - Hepatic endoplasmic reticulum (ER) stress has recently been associated with several health complications such as obesity, type 2 diabetes, and hepatic steatosis. Exercise training has been recognized for many years to have important beneficial effects in these metabolic complications, however much remains unknown regarding the effects of exercise training on ER stress in the liver. A better understanding of the effects of exercise training on hepatic ER stress response requires studies in which the exercise training protocol is well assessed. Therefore, the purpose of this chapter is to provide detailed description of an endurance-training program and suggest a dietary approach in order to help induce and study changes in ER stress molecular markers expression levels in the liver of rats in response to exercise training. PMID- 21266227 TI - Discovery approaches to UPR in athero-susceptible endothelium in vivo. AB - The endothelium is a monolayer of cells that lines the entire inner surface of the cardiovascular and lymphatic circulations where it controls normal physiological functions through both systemic and local regulation. Endothelial phenotypes are heterogeneous, dynamic and malleable, properties that in large- and medium-sized arteries lead to a central role in the development of focal and regional atherosclerosis. The endothelial phenotype in athero-susceptible sites is different from that in nearby athero-resistant regions. Understanding the in vivo gene, protein, and metabolic expression profiles of susceptible endothelium is, therefore, an important spatiotemporal challenge in atherosclerosis research. Recent studies have demonstrated that endoplasmic reticulum (ER) stress and the UPR are characteristics of susceptible endothelium. Here, we outline global genomic profiling, pathway analyses, and gene connectivity approaches to the identification of UPR and associated pathways as discrete markers of athero susceptibility in arterial endothelium. PMID- 21266228 TI - Assessment of endoplasmic reticulum stress and the unfolded protein response in endothelial cells. AB - In the vascular wall, the most inner cell layer that separates the blood from organelles is comprised of only a single layer of endothelial cells (ECs). This cell type is fundamental to a large variety of processes, ranging from blood coagulation and interaction with inflammatory cells to cardiovascular diseases such as hypertension, diabetes, and atherosclerosis. Dysfunction of ECs is often causally linked to these processes such that research exploring such events attracted much attention. Damage of ECs and subsequent disruption of the intact endothelial barrier can result not only from oxidative stress, but also from conditions that stress the endoplasmic reticulum (ER) and induce a signaling pathway termed unfolded protein response (UPR). While its primary goal is to alleviate ER stress, the UPR can also induce cell death. Cultured ECs are often used in in vitro approaches to understand various pathophysiological events, but they behave differently from many other cell types such that cell-type-specific procedures are needed. Here, we describe how ER stress can be induced and assessed in cultured ECs and demonstrate their specific responses to classical ER stress conditions. PMID- 21266229 TI - Measuring the impact of cigarette smoke on the UPR. AB - The unfolded protein response (UPR) is a set of pathways activated by the accumulation of improperly folded proteins. It can be triggered by a broad range of stressful conditions which disrupt successful maturation of proteins in the endoplasmic reticulum (ER) by interfering with proper folding, assembly, and posttranslational modification. Recent studies have demonstrated the induction of ER stress and activation of elements of the UPR in human lung cells exposed to diesel exhaust particles, airborne particulate matter, and tobacco smoke. ER stress has been found to play a role in a variety of lung maladies, including cancer, infections, idiopathic pulmonary fibrosis, and chronic obstructive pulmonary disease. Lung cancer is one of the few diseases where the etiological agent, cigarette smoke (CS), is well known. It is, therefore, desirable to measure dysregulation of the UPR pathway in samples representing both the earliest events (cells exposed to CS in vitro) and in clinical samples from healthy smokers and individuals with smoking-related lung diseases. We hereby provide a detailed description of methods for assessing the degree and timing of cellular response to CS with respect to the three major UPR pathways. PMID- 21266230 TI - Induction and measurement of UPR and osmotic stress in the yeast Pichia pastoris. AB - Unfolded protein response (UPR) is a major reaction to intrinsic stress of eukaryotic organisms and is also related to environmental stress reactions. Among yeasts, stress regulation has mainly been investigated in Saccharomyces cerevisiae, while other species with biotechnological or medical interest are less well understood. Pichia pastoris as one example has emerged as a favorite production platform for recombinant proteins during the last two decades. UPR and environmental stress are well known to interfere with the production of recombinant proteins as well as other technologically relevant processes, so that the demand for well-documented protocols to measure such stress reactions has strongly increased. Here, we describe protocols for the induction of UPR and osmotic stress, as well as for the quantitative measurement of cellular stress reactions at the levels of transcripts, proteins, and metabolites. As such protocols need to be adapted for a new species of interest, the guidelines presented here should enable researchers to study P. pastoris directly without the hassle to modify standard protocols designed for the model organism S. cerevisiae first. PMID- 21266231 TI - Induction of ER stress response leading to programmed cell death in Trypanosoma brucei. AB - Trypanosomes are parasitic protozoans that include several medically and a variety of economically important parasites, such as Trypanosoma brucei, the causative agent of sleeping sickness. This parasite cycles between the insect host (procyclic form) and mammalian host (bloodstream form). These parasites lack transcription regulation, including factors that govern the unfolded protein response (UPR) in other eukaryotes. Gene expression is controlled posttranscriptionally by unique mechanisms such as trans-splicing and RNA editing and by mRNA stability. In trans-splicing, a common exon, the spliced leader (SL) is donated to all mRNAs from a small RNA, the SL RNA. The SL RNA is transcribed from a defined promoter assisted by the tSNAP complex. Despite the lack of transcriptional regulation, induction of ER stress elicits changes in the transcriptome similar to those induced by conventional UPR found in other eukaryotes. The mechanism of upregulation under UPR is dependent on differential stabilization of mRNAs. The transcriptome changes result in ER expansion and elevation in the ER chaperone, BiP. Prolonged ER stress induces the spliced leader RNA silencing (SLS) pathway. SLS is the trypanosome-specific stress response mechanism that elicits the shut-off of SL RNA transcription by perturbing the binding of the transcription factor tSNAP42 to its cognate promoter, eliminating trans-splicing of all mRNAs. SLS was discovered in the RNAi silenced cells depleted for functions that mediate translocation of proteins to the ER such as the signal recognition particle receptor SRalpha, SEC63- a factor that participates in protein translocation across the ER membrane, or SEC61- the translocation channel. Induction of SLS, either by prolonged ER stress or silencing of the genes associated with the ER membrane that function in ER protein translocation led to programmed cell death (PCD), evident by the exposure of phosphatidyl serine, DNA laddering, increase in ROS production, increase in cytoplasmic Ca(2+), and decrease in mitochondrial membrane potential. Here, we describe the protocols to induce ER stress and to observe the resulting morphological changes by transmission electron microscopy (TEM), changes in cytoplasmic Ca(2+), and DNA fragmentation which are the hallmarks of programmed cell death. PMID- 21266232 TI - Measurement of activation of the endoplasmic reticulum stress response in autoimmune myositis. AB - Evidence suggests that both immune (cell-mediated and humoral) and nonadaptive immune (endoplasmic reticulum (ER) stress and autophagy) mechanisms play a role in muscle fiber damage and dysfunction in idiopathic inflammatory myopathies (IIM). More recently, the ER stress response pathway, the activation of unfolded protein response, and the ER overload response are being studied to understand their contribution in the progression of IIM. A variety of qualitative and quantitative techniques are used to measure the activation of the endoplasmic reticulum stress response in myopathy. Accurately assessing the activation of ER stress response pathway would not only help in the understanding of disease pathogenesis but would also help to assess the response to therapy. Here, we describe common techniques such as western blotting, immunohistochemistry, immunofluorescence, and determination of mRNA levels for the gene of interest to monitor the ER stress in skeletal muscle tissues. PMID- 21266233 TI - Activation of the unfolded protein response in human acute myeloid leukemia. AB - There is accumulating evidence for the involvement of the unfolded protein response (UPR) in the pathogenesis of many tumor types in humans. This is particularly the case in rapidly growing solid tumors in which the demand for oxygen and nutrients can exceed the supply until new tumor-initiated blood vessels are formed. In contrast, the role of the UPR during leukemogenesis remains largely unknown. Acute myeloid leukemia (AML) is a genetically heterogeneous clonal disorder characterized by the accumulation of somatic mutations in hematopoietic progenitor cells that alter the physiological regulation of self-renewal, survival, proliferation, or differentiation. The CCAAT/enhancer-binding protein alpha (CEBPA) gene is a key myeloid transcription factor and a frequent target for disruption in AML. In particular, translation of CEBPA mRNA can be specifically blocked by binding of the chaperone calreticulin (CALR), a well-established effector of the UPR, to a stem loop structure within the 5' region of the CEBPA mRNA. The relevance of this mechanism was first elucidated in certain AML subtypes carrying the gene rearrangements t(3;21) or inv(16). In our recent work, we could demonstrate the induction of key effectors of the UPR in leukemic cells of AML patients comprising all subtypes (according to the French-American-British (FAB) classification for human AML). The formation of the spliced variant of the X-box binding protein (XBP1s) was detectable in 17.4% (17 of 105) of AML patients. Consistent with an activated UPR, this group had significantly increased expression of the UPR target genes CALR, the 78 kDa glucose-regulated protein (GRP78), and the CCAAT/enhancer-binding protein homologous protein (CHOP). Consistently, in vitro studies confirmed that calreticulin expression was upregulated via activation of the ATF6 pathway in myeloid leukemic cells. As a consequence, CEBPA protein expression was inhibited in vitro as well as in leukemic cells from patients with activated UPR. We therefore propose a model of the UPR being involved in leukemogenesis through induction of calreticulin along the ATF6 pathway, thereby ultimately suppressing CEBPA translation and contributing to the block in myeloid differentiation and cell-cycle deregulation which represent key features of the leukemic phenotype. From a more clinical point of view, the presence of activated UPR in AML patient samples was found to be associated with a favorable disease course. PMID- 21266234 TI - Modulation of the unfolded protein response by GRP78 in prostate cancer. AB - The unfolded protein response (UPR) is an adaptive survival mechanism through which cells can weather the stress of misfolded protein accumulation induced by a wide variety of pathophysiologic and pharmacologic insults. The ER chaperone GRP78 is a central modulator of the UPR both through its protein-binding capacity and its direct regulation of the UPR signaling molecules IRE1alpha, PERK, and ATF6. Recent reports have revealed the presence of GRP78 on the surface of cancer cells. Biological roles for cell-surface GRP78 include competing NH(2)-domain and COOH-domain agonist receptor activities that induce opposite effects on proliferation and apoptosis. Modulation of the UPR impacts both of these processes directly and indirectly. Here, we outline methods that we use to investigate UPR modulation via direct ligation of cell-surface GRP78. Specifically, we review methods of cell culture, cell-signaling analysis with emphasis on UPR components, and ultimately, the impact that these have on cell proliferation, survival, and apoptosis. PMID- 21266235 TI - Endoplasmic reticulum stress in brain damage. AB - The efficient functioning of the ER is indispensable for most of the cellular activities and survival. Disturbances in the physiological functions of the ER result in the activation of a complex set of signaling pathways from the ER to the cytosol and nucleus, and these are collectively known as unfolded protein response (UPR), which is aimed to compensate damage and can eventually trigger cell death if ER stress is severe or persists for a longer period. The precise molecular mechanisms that facilitate this switch in brain damage have yet to be understood completely with multiple potential participants involved. The ER stress-associated cell death pathways have been recognized in the numerous pathophysiological conditions, such as diabetes, hypoxia, ischemia/reperfusion injury, and neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and bipolar disorder. Hence, there is an emerging need to study the basic molecular mechanisms of ER stress-mediating multiple cell survival/death signaling pathways. These molecules that regulate the ER stress response would be potential drug targets in brain diseases. PMID- 21266236 TI - Methods and models for monitoring UPR-associated macrophage death during advanced atherosclerosis. AB - During advanced atherosclerosis, chronic activation of the endoplasmic reticulum (ER) stress pathway, otherwise known as the unfolded protein response (UPR), is strongly associated with atherosclerotic plaque destabilization, the precursor to acute myocardial infarction and sudden death. Destabilized or vulnerable plaques are characterized by features that include thinning of a protective collagenous cap at the interface between the plaque and the vascular lumen and expansion of the necrotic core, a lipid-rich graveyard of dead macrophages. The cell biology of advanced plaque progression is complex and includes multiple cellular stressors that combine to promote chronic inflammation and progressive plaque deterioration. Several of these stressors converge at the ER, leading to activation of the UPR in multiple cell types. In macrophages, prolonged UPR activation triggers apoptosis, which when coupled to defective phagocytic clearance of these dying cells, leads to secondary necrosis and expansion of the plaque necrotic core. Though much insight has been gained recently on the role of the UPR in atherosclerosis, future studies are warranted to determine the cell type specific contributions of ER stress to athero-progression and the therapeutic potential of UPR modulation. For such objectives to be met, reliable and standardized methodology must be utilized and developed. This chapter summarizes our current understanding of ER stress-induced macrophage apoptosis in atheromata and outlines both in vitro and in vivo methodologies to quantify the UPR in the context of experimental murine-advanced atherosclerosis. PMID- 21266237 TI - Detecting autophagy in response to ER stress signals in cancer. AB - Different physiological and pathological situations that produce alterations in the endoplasmic reticulum, lead to a condition known as ER stress. ER stress activates a complex intracellular signal transduction pathway, called unfolded protein response (UPR). UPR is tailored essentially to reestablish ER homeostasis. However, when persistent, ER stress can switch the cytoprotective functions of UPR into cell death promoting mechanisms. One of the cellular mechanisms that are regulated by ER stress is autophagy. Autophagy is a cellular process by which different cytoplasmic components including organelles are targeted for degradation to the autophagosomes. Interestingly, like ER stress, autophagy can be a protective or a cell death promoting mechanism. Recently, a variety of anticancer therapies (including those that stimulate ER stress) have been shown to activate autophagy in tumor cells, which has been proposed to either enhance cancer cell death or act as a mechanism of resistance to chemotherapy. In this chapter, we will describe some of the procedures that are currently used to analyze autophagy as well as some of the experimental approaches that can be undertaken to investigate the connection between ER stress and autophagy in cancer. PMID- 21266238 TI - The unfolded protein response induced by salt stress in Arabidopsis. AB - Salt stress has a major impact on plant growth and crop production, pointing to the importance of understanding the mechanism of salt tolerance in plants. Disruption of the protein-folding capacity in the endoplasmic reticulum (ER) induces the accumulation of unfolded protein and ER stress, which activates an "unfolded protein response" (UPR). Although reports show that salt stress leads to UPR in various organisms, including plants, it remains to be determined how salt stress induces UPR. Zinc deficiency also induces UPR in a wide range of organisms. Here we provide a detailed description of the role of zinc in initiating UPR in the plant response to salt stress along with details of the methodology required for its investigation. PMID- 21266240 TI - Methods in Enzymology. Preface. PMID- 21266239 TI - Measurement of ER stress response and inflammation in the mouse model of nonalcoholic fatty liver disease. AB - In eukaryotic cells, the endoplasmic reticulum (ER) is the organelle that is responsible for protein folding and assembly, lipid and sterol biosynthesis, and intracellular calcium storage. Biochemical or pathophysiological stimuli that disrupt protein-folding reaction or increase protein-folding load can cause accumulation of unfolded or misfolded proteins in the ER lumen, a condition called "ER stress". As an adaptive intracellular stress response initiated from the ER, unfolded protein response (UPR) alleviates the accumulation of unfolded or misfolded proteins in the ER. It has been demonstrated that the UPR is a fundamental intracellular signal transduction response that is critical for health and disease. ER stress and other cellular stress responses, such as inflammation and oxidative stress, are integrated in many pathophysiological processes. Particularly, recent research demonstrated that ER stress and the UPR signaling are critically involved in the initiation and progression of nonalcoholic fatty liver disease (NAFLD). Under metabolic stress conditions, the UPR regulates transcriptional and translational programs that are associated with hepatic steatosis and inflammation, the major characteristics of NAFLD. In this chapter, we summarize reliable methods to quantitatively analyze the UPR and hepatic inflammation in the mouse model of NAFLD. PMID- 21266241 TI - Methods for investigating the UPR in filamentous fungi. AB - Filamentous fungi have a high-capacity secretory system and are therefore widely exploited for the industrial production of native and heterologous proteins. However, in most cases, the yields of nonfungal proteins are significantly lower than those obtained for fungal proteins. One well-studied bottleneck appears to be the result of slow or aberrant folding of heterologous proteins in the ER during the early stages of secretion within the endoplasmic reticulum, leading to stress responses in the host, including the unfolded protein response (UPR). Most of the key elements constituting the signal transduction pathway of the UPR in Saccharomyces cerevisiae have been identified in filamentous fungi, including the central activation mechanism of the pathway, that is, the stress-induced splicing of an unconventional (nonspliceosomal) intron in orthologs of the HAC1 mRNA. This splicing event relieves a translational block in the HAC1 mRNA, allowing for the translation of the bZIP transcription factor Hac1p that regulates the expression of UPR target genes. The UPR is involved in regulating the folding, yield, and delivery of secretory proteins and that has consequences for fungal lifestyles, including virulence and biotechnology. The recent releases of genome sequences of several species of filamentous fungi and the availability of DNA arrays, GeneChips, and deep sequencing methodologies have provided an unprecedented resource for exploring expression profiles in response to secretion stresses. Furthermore, genome-wide investigation of translation profiles through polysome analyses is possible, and here, we outline methods for the use of such techniques with filamentous fungi and, principally, Aspergillus niger. We also describe methods for the batch and controlled cultivation of A. niger and for the replacement and study of its hacA gene, which provides either a UPR-deficient strain or a constitutively activated UPR strain for comparative analysis with its wild type. Although we focus on A. niger, the utility of the hacA-deletion strategy is also described for use in investigating the virulence of the plant pathogen Alternaria brassicicola. PMID- 21266242 TI - Assays for detecting the unfolded protein response. AB - The endoplasmic reticulum (ER) is the site for folding of membrane and secreted proteins in the cell. Physiological or pathological processes that disturb protein folding in the ER cause ER stress and activate a set of signaling pathways termed the unfolded protein response (UPR). The UPR leads to transcriptional activation of genes encoding ER-resident chaperones, oxidoreductases, and ER-associated degradation (ERAD) components. Thus, UPR promotes cellular repair and adaptation by enhancing protein-folding capacity, reducing the secretory protein load, and promoting degradation of misfolded proteins. In mammalian cells, the UPR also triggers apoptosis, perhaps when adaptive responses fail. Research into ER stress and the UPR continues to grow at a rapid rate as many new investigators are entering the field. Here, we describe the experimental methods that we have used to study UPR in tissue culture cells. These methods can be used by researchers to plan and interpret experiments aimed at evaluating whether the UPR and related processes are activated or not. It is important to note that these are general guidelines for monitoring the UPR and not all assays will be appropriate for every model system. PMID- 21266243 TI - Analysis of the role of nerve growth factor in promoting cell survival during endoplasmic reticulum stress in PC12 cells. AB - Nerve growth factor (NGF) was first described by Rita Levi-Montalcini in the early 1960s from her studies of peripheral neurons. It has since been reported that NGF has the potential to elongate neurites or to prevent apoptosis via specific intracellular mechanisms. It has further been reported that as a component of these mechanisms, NGF binds to a specific receptor, TrkA, and thereby contributes to peripheral nerve cell functions or neuronal functions. It is noteworthy in this regard that pheochromocytoma 12 (PC12) cells express TrkA and respond to neurite outgrowth or anti-apoptotic signals by binding to NGF. Hence, PC12 cells have been used as an in vitro model system for the study of neuronal functions. It has been reported that endoplasmic reticulum (ER) stress is involved in neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's disease. The common link with regard to ER stress is that the neuronal cells die in these pathologies via specific intracellular mechanisms. This type of cell death, if it is apoptotic in nature, is termed ER stress mediated apoptosis. In the process of ER stress-mediated apoptosis, the cleavage of pro-caspase-12 residing on the ER and the expression of glucose-regulated protein 78 (GRP78) can be observed. The expression of GRP78 protein is a characteristic of an unfolded protein response (UPR) via specific signal transduction pathways mediated by the unfolded protein response element (UPRE) in the upstream region of the grp78 gene so on. In ER stress-mediated apoptosis, a caspase cascade is also observed. To further clarify the mechanisms underlying ER stress-mediated apoptosis, a better understanding of the UPR is therefore important. In our current study, we describe a method for detecting gene induction via the UPR, focusing on GRP78 and caspase activities as the measurement end-points. The information generated by our method will accelerate our understanding of the pathophysiological processes leading to ER stress mediated apoptosis. PMID- 21266244 TI - Measuring ER stress and the unfolded protein response using mammalian tissue culture system. AB - The endoplasmic reticulum (ER) functions to properly fold and process secreted and transmembrane proteins. Environmental and genetic factors that disrupt ER function cause an accumulation of misfolded and unfolded proteins in the ER lumen, a condition termed ER stress. ER stress activates a signaling network called the Unfolded Protein Response (UPR) to alleviate this stress and restore ER homeostasis, promoting cell survival and adaptation. However, under unresolvable ER stress conditions, the UPR promotes apoptosis. Here, we discuss the current methods to measure ER stress levels, UPR activation, and subsequent pathways in mammalian cells. These methods will assist us in understanding the UPR and its contribution to ER stress-related disorders such as diabetes and neurodegeneration. PMID- 21266245 TI - Real-time monitoring of ER stress in living cells and animals using ESTRAP assay. AB - Endoplasmic reticulum (ER) stress is involved in a wide range of pathologies. Detection and monitoring of the unfolded protein response are required to disclose the link between ER stress and diseases. Assessment of ER stress is also essential for evaluation of therapeutic drugs in vitro and in vivo; that is, their therapeutic utility as well as adverse effects. For detection and monitoring of ER stress in living cells and animals, ER stress-responsive alkaline phosphatase (ESTRAP), also called secreted alkaline phosphatase (SEAP), serves as a useful indicator. In cells genetically engineered to express SEAP, secretion of SEAP is quickly downregulated in response to ER stress. This phenomenon is observed in a wide range of cell types triggered by various ER stress inducers. The magnitude of the decrease in extracellular SEAP is proportional to the intensity of ER stress, which is inversely correlated with the induction of endogenous ER stress markers. In contrast to SEAP, the activity of intracellular luciferase is not affected by ER stress. ER stress causes a decrease in SEAP activity not via transcriptional suppression but via abnormal posttranslational modification, accelerated degradation, and reduced secretion of SEAP protein. In mice constitutively producing SEAP, in vivo induction of ER stress similarly causes rapid reduction in serum SEAP activity. Using SEAP as an indicator, real-time monitoring of ER stress in living cells and animals is feasible. The ESTRAP method provides a powerful tool to investigate the pathogenesis of ER stress-associated diseases, to assess toxicity and the adverse effects of drugs, and to develop therapeutic agents for the treatment of ER stress-related disorders. PMID- 21266246 TI - HIV protease inhibitors induce endoplasmic reticulum stress and disrupt barrier integrity in intestinal epithelial cells. AB - The integrity of the intestinal epithelial barrier plays a crucial role in maintaining symbiotic homeostasis between microbes in the gut lumen and eukaryotic cells. Disruption of intestinal epithelial barrier function occurs commonly under various pathological conditions, including trauma, inflammatory bowel disease, and drug-induced gastrointestinal toxicity, exhibiting increased intestinal epithelial paracellular permeability or "leakiness" of the intestinal mucosa. Endoplasmic reticulum (ER) stress has recently been linked to various pathological conditions, including intestinal inflammation. Our previous studies have shown that HIV protease inhibitors (PIs) induce ER stress and activate the unfolded protein response (UPR) in different types of cells, and HIV PI-induced UPR activation contributes to the disruption of barrier function in intestinal epithelial cells and the increase of intestinal permeability. This chapter will discuss the commonly used methods for analysis of ER stress activation and epithelial barrier function. Both in vitro cell culture models and in vivo animal models are useful tools to examine general drug-induced ER stress and intestinal barrier dysfunction. PMID- 21266247 TI - Dexamethasone induction of a heat stress response. AB - Dexamethasone is a potent, synthetic member of the glucocorticoid class of steroid drugs with pleiotropic effects on multiple signaling pathways, and has been widely used in many disorders during the last 50 years. Recent studies sustain a role of this drug in the heat stress response, increasing the levels of heat-shock proteins, particularly under certain stress conditions. More conflictive is the role of dexamethasone on the levels of endoplasmic reticulum chaperons. However, these effects may certainly contribute to explain the therapeutic benefits of dexamethasone in cardiac transplant, sepsis, cancer, and other pathologic disorders associated with stress affecting the folding of proteins. In this chapter, we review the methods that can be used to evaluate the effect of dexamethasone in the heat stress response both in patients and animal and cellular models. PMID- 21266248 TI - Detecting and quantitating physiological endoplasmic reticulum stress. AB - Unfolded protein response (UPR) is a key cellular defense mechanism associated with many human "conformational" diseases, including heart diseases, neurodegeneration, and metabolic syndrome. One of the major obstacles that have hindered our further understanding of physiological UPR and its future therapeutic potential is our inability to detect and quantitate ER stress and UPR activation under physiological and pathological conditions, where ER stress is perceivably very mild. Here, we describe a Phos-tag-based Western blot approach that allows for direct visualization and quantitative assessment of mild ER stress and UPR signaling, directly at the levels of UPR sensors, in various in vivo conditions. This method will likely pave the foundation for future studies on physiological UPR, aid in the diagnosis of ER-associated diseases, and facilitate therapeutic strategies targeting UPR in vivo. PMID- 21266249 TI - PI 3-kinase regulatory subunits as regulators of the unfolded protein response. AB - The endoplasmic reticulum (ER) consists of an interconnected, membranous network that is the major site for the synthesis and folding of integral membrane and secretory proteins. Within the ER lumen, protein folding is facilitated by molecular chaperones and a variety of enzymes that ensure that polypeptides obtain their appropriate, tertiary conformation (Dobson, C. M. (2004). Principles of protein folding, misfolding and aggregation. Semin. Cell Dev. Biol. 15, 3-16; Ni, M., and Lee, A. S. (2007). ER chaperones in mammalian development and human diseases. FEBS Lett. 581, 3641-3651.). Physiological conditions that increase protein synthesis or stimuli that disturb the processes by which proteins obtain their native conformation, create an imbalance between the protein-folding demand and capacity of the ER. This results in the accumulation of unfolded or improperly folded proteins in the ER lumen and a state of ER stress. The cellular response, referred to as the unfolded protein response (UPR), results in activation of three linked signal transduction pathways: PKR-like kinase (PERK), inositol requiring 1 alpha (IRE1alpha), and activating transcription factor 6alpha (ATF6alpha) (Ron, D., and Walter, P. (2007). Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell. Biol. 8, 519-529; Schroder, M., and Kaufman, R. (2005). ER stress and the unfolded protein response. Mutat. Res./Fundam. Mol. Mech. Mutagen. 569, 29-63.). Collectively, the combined actions of these signaling cascades serve to reduce ER stress through attenuation of translation to reduce protein synthesis and through activation of transcriptional programs that ultimately serve to increase ER protein-folding capacity. Recently, we and Park et al. have characterized a novel function for the p85alpha and p85beta subunits as modulators of the UPR by virtue of their ability to facilitate the nuclear entry of XBP-1s following induction of ER stress (Park, S. W., Zhou, Y., Lee, J., Lu, A., Sun, C., Chung, J., Ueki, K., and Ozcan, U. (2010). Regulatory subunits of PI3K, p85alpha and p85 beta, interact with XBP1 and increase its nuclear translocation. Nat. Med. 16, 429-437; Winnay, J. N., Boucher, J., Mori, M. A., Ueki, K., and Kahn, C. R. (2010). A regulatory subunit of phosphoinositide 3-kinase increases the nuclear accumulation of X-box binding protein-1 to modulate the unfolded protein response. Nat. Med. 16, 438 445.). This chapter describes the recently elucidated role for the regulatory subunits of PI 3-kinase as modulators of the UPR and provides methods to measure UPR pathway activation. PMID- 21266250 TI - The emerging role of histone deacetylases (HDACs) in UPR regulation. AB - Although the function of histone deacetylases (HDACs) have primarily been associated with influencing transcription through chromatin remodeling, the capacity of these enzymes to interface with a diverse array of biologic processes by modulating a growing list of nonhistone substrates has gained recent attention. Recent investigations have demonstrated the potential of HDACs to directly regulate the unfolded protein response (UPR) through acetylation of its central regulatory protein, Grp78. Further, this appears to be an important mechanism underlying the anti-tumor activity of HDAC inhibitors. Herein, we provide a summary of the literature supporting the role HDACs play in regulating the UPR and a detailed description of methods to allow for the study of both acetylation of nonhistone proteins and UPR pathway activation following HDAC inhibition. PMID- 21266252 TI - Experimental approaches for elucidation of stress-sensing mechanisms of the IRE1 family proteins. AB - Endoplasmic reticulum (ER) stress, which is often regarded as the accumulation of unfolded proteins in the ER, triggers cellular protective events including the unfolded protein response (UPR). In the yeast S. cerevisiae, the UPR signaling pathway starts from the ER-located transmembrane protein Ire1, the activation of which eventually leads to transcriptional induction of various genes including those encoding ER-located molecular chaperones. Mammals have two Ire1 paralogues, of which IRE1alpha exhibits ubiquitous tissue expression. Here, we show how we have approached study of the molecular mechanisms by which ER stress activates the Ire1 family proteins. Immunoprecipitation analyses indicated that the ER located chaperone BiP associates with IRE1alpha and yeast Ire1, while ER stress dissociates these complexes. We also devised experimental systems for exogenous expression of wild-type or mutant versions of IRE1alpha and yeast Ire1 at appropriate levels, in order to monitor correctly their activity in evoking downstream events. An IRE1alpha partial deletion mutant with which BiP poorly associates showed considerable activity even under nonstress conditions, whereas a BiP-nonbinding mutant of yeast Ire1 was almost normally regulated in an ER stress dependent manner. This finding suggests that the dissociation of BiP is the principal determinant of IRE1alpha's activation upon ER stress, while yeast Ire1 is largely controlled by another factor(s). Based on in vitro ability to inhibit aggregation of denatured proteins, we deduce that the luminal domain of yeast Ire1, but not that of IRE1alpha, is capable of direct interaction with unfolded proteins. Since this ability of yeast Ire1 was abolished by a mutation impairing its cellular activity, we propose that yeast Ire1 is fully activated by its direct interaction with unfolded proteins. PMID- 21266251 TI - Immunohistochemical detection of activating transcription factor 3, a hub of the cellular adaptive-response network. AB - Activating transcription factor 3 (ATF3) gene encodes a member of the ATF family of transcription factors and is induced by various stress signals, including many of those that induce the unfolded protein response (UPR). Emerging evidence suggests that ATF3 is a hub of the cellular adaptive-response network and studies using various mouse models indicate that ATF3 plays a role in the pathogenesis of various diseases. One way to investigate the potential relevance of ATF3 to human diseases is to determine its expression in patient samples and test whether it correlates with disease progression or clinical outcomes. Due to the scarcity and preciousness of patient samples, methods that can detect ATF3 on archival tissue sections would greatly facilitate this research. In this chapter, we briefly review the roles of ATF3 in cellular adaptive-response and UPR, and then describe the detailed steps and tips that we developed based on general immunohistochemistry (IHC) protocols to detect ATF3 on paraffin embedded sections. PMID- 21266253 TI - Measurement and modification of the expression level of the chaperone protein and signaling regulator GRP78/BiP in mammalian cells. AB - GRP78/BiP is a major endoplasmic reticulum (ER) chaperone protein essential for protein quality control in the ER as well as a central regulator of unfolded protein response (UPR). The induction of GRP78 is well established as a marker for ER stress. Recently, mouse models targeting the Grp78 allele indicate that GRP78 has critical roles in cancer progression, drug resistance, angiogenesis, neurological diseases, and diabetes. The discovery of a cytosolic GRP78 isoform and cell surface GRP78 adds new insights to its function beyond the ER compartment in regulating growth factor signaling and cell viability. Here, we summarize and update several approaches for the detection and quantitation of total GRP78, cytosolic GRP78 isoform, and cell surface GRP78, and the use of small interfering RNA to knockdown GRP78 expression. These techniques can be applied to culture cells as well as tissues. PMID- 21266254 TI - The endoplasmic reticulum-associated degradation and disulfide reductase ERdj5. AB - The endoplasmic reticulum (ER) is an organelle where secretory or membrane proteins are correctly folded with the aid of various molecular chaperones and oxidoreductases. Only correctly folded and assembled proteins are enabled to reach their final destinations, which are called as ER quality control (ERQC) mechanisms. ER-associated degradation (ERAD) is one of the ERQC mechanisms for maintaining the ER homeostasis and facilitates the elimination of misfolded or malfolded proteins accumulated in the ER. ERAD is mainly consisting of three processes: recognition of misfolded proteins for degradation in the ER, retrotranslocation of (possibly) unfolded substrates from the ER to the cytosol through dislocation channel, and their degradation in the cytosol via ubiquitin protesome system. After briefly mentioned on productive folding of nascent polypeptides in the ER, we here overview the above three processes in ERAD system by highlighting on novel ERAD factors such as EDEM and ERdj5 in mammals and yeasts. PMID- 21266255 TI - Structural insight into the protective role of P58(IPK) during unfolded protein response. AB - P58(IPK) has been identified as an ER molecular chaperone to maintain protein folding homeostasis. P58(IPK) expression can be significantly upregulated during unfolded protein responses (UPR), and it may play important roles in suppressing the ER protein aggregations. To investigate the mechanism how P58(IPK) functions to promote protein folding within ER, we have determined the crystal structure of P58(IPK) TPR domain at 2.5A resolution. P58(IPK) contains nine TPR motifs and a C terminal J domain within its primary sequence. The crystal structure of P58(IPK) revealed three subdomains (I, II, and III) with similar folds and each domain contains three TPR motifs. Our data also showed that P58(IPK) acts as a molecular chaperone by interacting with the unfolded proteins such as luciferase, rhodanese, and insulin. The P58(IPK) structure reveals a conserved hydrophobic patch located in subdomain I that may be involved in binding the misfolded polypeptides. We have proposed a working model for P58(IPK) to act together with Bip to prevent protein aggregations and promote protein foldings within ER. PMID- 21266256 TI - Principles of IRE1 modulation using chemical tools. AB - Perturbations that derail the proper folding and assembly of proteins in the endoplasmic reticulum (ER) lead to misfolded protein accrual in the ER-a toxic condition known as ER stress. The unfolded protein response (UPR) is a signaling system evolved to detect and rectify ER stress. IRE1 is the most ancient member of the ER stress transducers and is conserved in all eukaryotes. In response to ER stress, IRE1 activates a UPR-dedicated transcription factor called X-box binding protein 1 (XBP1) in metazoans (or HAC1 in yeast) to bolster the productive capacity of the ER and purge misfolded proteins from the ER. To activate XBP1/HAC1, IRE1 cleaves XBP1/HAC1 mRNA twice to eliminate an inhibitory intron using a dormant nuclease function in its cytoplasmic effector region (IRE1(cyto)). Recent structural, molecular, and chemical biological approaches have greatly advanced our molecular understanding of how IRE1 transduces ER stress. Here we highlight a sampling of these advances with a bias toward structure and the insights they provide. We also propose a set of principles for IRE1 chemical modulation that may assist in the development of tools to better understand how IRE1 function contributes to health and disease and perhaps ultimately the development of new methods of therapeutic intervention. PMID- 21266257 TI - Methods to study stromal-cell derived factor 2 in the context of ER stress and the unfolded protein response in Arabidopsis thaliana. AB - The accumulation of misfolded or unfolded polypeptides in the endoplasmic reticulum (ER) provokes ER stress and triggers protective signaling pathways termed the unfolded protein response (UPR). Stromal cell-derived factor 2 (SDF2) type proteins are conserved throughout the animal and plant kingdoms. Upon UPR activation transcription of SDF2-type genes is significantly enhanced in metazoan and plants, suggesting an evolutionarily conserved role. However, the precise molecular function of SDF2-type proteins still needs to be established. Most eukaryotes have two SDF2 homologous, whereas the model plant Arabidopsis thaliana has a single SDF2, thus representing an ideal model system to study the functional role of SDF2-type proteins. This chapter provides techniques to study SDF2 in the context of ER stress in Arabidopsis. We describe available sdf2 mutants, and methods to evaluate ER stress sensitivity of seedlings. Further, we summarize tools and methods that are helpful to monitor UPR induction in general (e.g., SDF2 promoter-reporter fusion constructs and SDF2-specific antibodies). In Section 6, we provide protocols for the expression and purification of recombinant SDF2 protein that can be used for further biochemical studies. PMID- 21266259 TI - Methods for analyzing eIF2 kinases and translational control in the unfolded protein response. AB - Endoplasmic reticulum (ER) stress induces a program of translational and transcriptional regulation, designated the unfolded protein response (UPR), that collectively remedies stress damage and restores ER homeostasis. The protein kinase PERK facilitates the translational control arm of the UPR by phosphorylation of eIF2, a translation initiation factor that combines with GTP to escort initiator Met-tRNA(i)(Met) to the ribosomal machinery during the initiation of protein synthesis. Phosphorylation of the alpha subunit of eIF2 on serine-51 inhibits global translation initiation, which reduces the influx of nascent polypeptides into the overloaded ER. eIF2 phosphorylation also facilitates the preferential translation of stress-related mRNAs, such as ATF4 which in turn activates the transcription of UPR genes. In this chapter, we present experimental strategies and methods for establishing and characterizing global and gene-specific translation control induced by eIF2 phosphorylation (eIF2alpha~P) during ER stress. These methods include assays for the detection of eIF2alpha~P and its target genes. We also discuss strategies to address whether a given ER stress condition triggers eIF2alpha~P through PERK, as opposed to other stress conditions activating alternative members of the eIF2 kinase family. Additionally, experimental descriptions are provided for detecting and quantifying a repression in global translation initiation, and identifying stress induced preferential translation, such as that described for ATF4. Together, these experimental descriptions will provide a useful molecular "toolkit" to study each feature of the translational control processes invoked during ER stress. PMID- 21266258 TI - Nitrosative stress-induced S-glutathionylation of protein disulfide isomerase. AB - Oxidative and nitrosative stress result in the accumulation of reactive oxygen and nitrogen species (ROS/RNS) which trigger redox-mediated signaling cascades through posttranslational modifications on cysteine residues, including S nitrosylation (P-SNO) and S-glutathionylation (P-SSG). Protein disulfide isomerase (PDI) is the most abundant chaperone in the endoplasmic reticulum and facilitates protein folding via oxidoreductase activity. Prolonged or acute nitrosative stress blunts the activity of PDI through the formation of PDI-SNO and PDI-SSG. The functional implication is that reduced activity for the period of time leads to an accumulation of misfolded or unfolded proteins and activation of the unfolded protein response. Redox regulation of PDI and downstream signaling events provides an integration point for the functional determination of cell survival pathways. Herein, we describe the methodologies to globally identify S-glutathionylated targets of ROS/RNS; validate and identify the specific cysteine targets and characterize the structural and functional consequences. PMID- 21266260 TI - Hypertension and kidney disease in pregnancy: introduction. PMID- 21266261 TI - The kidney in normal pregnancy and preeclampsia. AB - Complicating up to 8% of pregnancies, preeclampsia is, in fact, the most common glomerular disease worldwide. In this article, we review the effect of normal pregnancy on the kidney as well as the role of the kidney in preeclampsia. We discuss blood pressure in pregnancy and preeclampsia, followed by the physiology of hyperfiltration in normal pregnancy as well as the pathophysiology of hypofiltration and proteinuria in preeclampsia. Recent studies have suggested that the clinical syndrome of preeclampsia, which recovers rapidly after delivery of the placenta, is caused by impaired vascular endothelial growth factor signaling that disturbs the status of vascular dilatation as well as the symbiosis between the glomerular endothelium and the podocytes. Finally, we discuss the intriguing association between chronic kidney disease (CKD) and preeclampsia. We hypothesize that the imbalance between angiogenic and anti angiogenic factors, which may be common to both preeclampsia and CKD, might explain why CKD predisposes pregnant women to develop preeclampsia. PMID- 21266262 TI - Emerging role of relaxin in the maternal adaptations to normal pregnancy: implications for preeclampsia. AB - Relaxin is an approximately 6-kilodalton peptide hormone secreted by the corpus luteum, and circulates in the maternal blood during pregnancy. Relaxin administration to awake, chronically instrumented, nonpregnant rats mimics the vasodilatory phenomena of pregnancy. Furthermore, immunoneutralization of relaxin or its elimination from the circulation during midterm pregnancy in awake rats prevents maternal systemic and renal vasodilation, and the increase in global arterial compliance. Human investigation, albeit limited through 2010, also reveals vasodilatory effects of relaxin in the nonpregnant condition and observations consistent with a role for relaxin in gestational renal hyperfiltration. Evidence suggests that the vasodilatory responses of relaxin are mediated by its major receptor, the relaxin/insulin-like family peptide 1 receptor, RFXP1. The molecular mechanisms of relaxin vasodilation depend on the duration of hormone exposure (ie, there are rapid and sustained vasodilatory responses). Newly emerging data support the role of Galpha(i/o) protein coupling to phosphatidylinositol-3 kinase/Akt (protein kinase B)-dependent phosphorylation and activation of endothelial nitric oxide synthase in the rapid vasodilatory responses of relaxin. Sustained vasodilatory responses critically depend on vascular endothelial and placental growth factors, and increases in arterial gelatinase(s) activity. Gelatinases hydrolyze big endothelin (ET) at a gly-leu bond to form ET(1-32), which activates the endothelial ET(B)/nitric oxide vasodilatory pathway. Although the relevance of relaxin biology to preeclampsia is largely speculative at this time, there are potential tantalizing links that are discussed in the context of our current understanding of the etiology and pathophysiology of the disease. PMID- 21266263 TI - Angiogenic factors and preeclampsia. AB - Preeclampsia, a hypertensive disorder peculiar to pregnancy, is a systemic syndrome that appears to originate in the placenta and is characterized by widespread maternal endothelial dysfunction. Until recently, the molecular pathogenesis of phenotypic preeclampsia was largely unknown, but recent observations support the hypothesis that altered expression of placental anti angiogenic factors are responsible for the clinical manifestations of the disease. Soluble Flt1 and soluble endoglin, secreted by the placenta, are increased in the maternal circulation weeks before the onset of preeclampsia. These anti-angiogenic factors produce systemic endothelial dysfunction, resulting in hypertension, proteinuria, and the other systemic manifestations of preeclampsia. The molecular basis for placental dysregulation of these pathogenic factors remains unknown, and as of 2011 the role of angiogenic proteins in early placental vascular development was starting to be explored. The data linking angiogenic factors to preeclampsia have exciting clinical implications, and likely will transform the detection and treatment of preeclampsia. PMID- 21266265 TI - Diabetes and the kidney in pregnancy. AB - The prevalence of diabetes in pregnant women is increasing, with 4% of deliveries in the United States occurring in women with pregestational or gestational diabetes. The proteinuria of late pregnancy is exaggerated in women with diabetes. However, diabetic women with preserved renal function before pregnancy appear to have little risk of deterioration of kidney function during pregnancy. Women with impaired renal function before pregnancy may be at risk for permanent decline of renal function during pregnancy, although it is unclear whether this represents the effect of pregnancy or the natural history of their diabetic renal disease. Preeclampsia, which is more common in women with diabetes, may be difficult to diagnose in this group of women. From the currently available literature, there appears to be no negative effect of pregnancy on the long-term progression of diabetic renal disease if renal function is normal and marked proteinuria is absent, but in light of recent findings in which preeclampsia appears to be associated with an increased risk of end-stage renal disease, large cohort studies will be necessary before this question can be definitively answered. PMID- 21266266 TI - Antihypertensive drugs in pregnancy. AB - Blood pressure targets and medications that are safe differ in pregnant women compared with nonpregnant individuals. The principles of treatment for mild, moderate, and severe hypertension in pregnancy, chronic versus gestational versus preeclampsia, and women hypertensive at term versus remote from term are reviewed. The choice of antihypertensive drugs also is discussed; methyldopa, labetalol, and nifedipine, among others, appear safe for use in pregnancy, whereas angiotensin converting enzyme inhibitors and angiotensin receptor blockers should be avoided. The management of increased blood pressure in the postpartum period, and agents to use in lactation, are also discussed. PMID- 21266264 TI - Renin angiotensin signaling in normal pregnancy and preeclampsia. AB - Many reports indicate that there is an increase in almost all of the components of the renin-angiotensin system (RAS) during an uncomplicated pregnancy, but renin activity, angiotensin II, and aldosterone decrease in preeclampsia (PE) for reasons that are unclear. PE is a life-threatening disorder of late pregnancy characterized by hypertension, proteinuria, increased soluble fms-like tyrosine kinase-1, as well as renal and placental morphologic abnormalities. Although a leading cause of maternal and perinatal morbidity and mortality, the pathogenic mechanisms of PE remain largely undefined. Immunologic mechanisms and aberrations of the RAS have been long considered contributors to the disorder. Bridging these two concepts, numerous studies report the presence of the angiotensin II type I receptor agonistic autoantibody (AT(1)-AA) found circulating in preeclamptic women. This autoantibody induces many key features of the disorder through AT(1) receptor signaling, and has been implicated in the pathogenesis of PE. Here we review the functions of the RAS during normal pregnancy and PE, and highlight the role of AT(1)-AA in both animal models and in the human disorder. PMID- 21266267 TI - Pregnancy and chronic kidney disease. AB - This article reviews the association of chronic renal disease and pregnancy. Included are discussions of guidelines for counseling pregnant women with underlying chronic renal disease who are considering conceiving as well as management of those already pregnant. Specifically highlighted are recent studies that question the validity of using estimated glomerular filtration rate and other formulae and questions of whether we should strive to replace the classic counseling approaches based primarily on serum creatinine levels with guidelines based on chronic kidney disease classification. The article concludes with a review as well as a critique of recent research on the prevalence of preeclampsia in women with underlying chronic renal disease, as well as if women with preeclampsia and underlying kidney disease have accelerated courses toward end stage renal disease. PMID- 21266268 TI - Pregnancy and kidney transplantation. AB - Despite decades of experience with child bearing in women with kidney transplants, these pregnancies remain high risk with an increased prevalence of hypertension and pre-eclampsia. Infertility, common in women with end-stage renal disease, is rapidly restored after transplant although pregnancy rates appear lower in transplant recipients than the general public. Many unanswered questions exist, some old questions such as what is the optimal timing of pregnancy after transplant, whether breast feeding is safe, the long-term impact if any on the offspring, and whether pregnancy negatively affects the kidney graft; and some new questions such as whether to modify immunosuppression in a patient taking a mycophenolic acid-containing drug, whether kidney donation has a deleterious impact on future pregnancies, whether to use erythropoietin-stimulating agents, and the role of BK virus. Counseling about contraception and pregnancy after transplant should be initiated during the pretransplant evaluation process. It is important because of the rapid restoration of fertility that occurs after transplant as well as the many risks and unanswered questions that remain. PMID- 21266269 TI - Long-term complications of preeclampsia. AB - SUMMARY: Preeclampsia is a multi-organ syndrome of pregnancy, defined by the new onset of hypertension and proteinuria after 20 weeks' gestation. This working definition ignores the variable multi-organ involvement of a syndrome that can include seizures in the absence of hypertension, or fulminating hepatic necrosis in the absence of proteinuria. These disparate clinical features are akin to an accelerated metabolic syndrome with widespread maternal endothelial dysfunction in the presence of a relatively underperfused placenta. Delivery of the placenta remains the only cure, but years after a pregnancy complicated by preeclampsia, women are at increased risk of chronic hypertension, diabetes mellitus, ischemic heart disease, cerebrovascular disease, kidney disease, thromboembolism, hypothyroidism, and even impaired memory. This article describes how pregnancy propels vulnerable women toward preeclampsia and how a brief, usually single, episode of this acute pregnancy syndrome defines those vulnerable to chronic disease in later life. PMID- 21266270 TI - Musculoskeletal mnemonics: differentiating features. AB - Mnemonics are often used in musculoskeletal radiology to help radiologists remember long differential diagnoses. However, unless the specific appearance of each entity on a differential is also recalled, mnemonics become useless. This article presents 8 mnemonics with their corresponding differential diagnoses and distinguishing features. Bubbly lucent lesions of bone are recalled with the FEGNOMASHIC mnemonic, but when only lucent lesions of the diaphysis are included, a more appropriate mnemonic is FEMALE. The lucent lesions of bone differentials often can be narrowed based on specific characteristics of the lesion but radiographic findings elsewhere and clinical information often help. Osseous metastases may present as lucent or sclerotic lesions; when sclerotic, the differential is best remembered with the mnemonic 5 "BEES" Like Pollen. The mnemonic for Wormian bones is PORKCHOPS. The Wormian bones in most of these entities are indistinguishable, so one must rely on radiographic findings outside the skull for diagnosis. By contrast, differentiating causes of acro-osteolysis is often possible with findings seen only on the hand radiographs; the mnemonic for acro-osteolysis is RADSHIP. In skeletally immature patients with frayed metaphyses, the mnemonic is CHARMS. Although the appearance of the fraying is seldom diagnostic, findings in the adjacent portions of the long bones may be characteristic. FETISH is the mnemonic used to remember the entities for the differential diagnosis of vertebra plana. Age of the patient, clinical history, and findings in the adjacent spine often help to provide the specific diagnosis. Nearly all the entities on the differential diagnosis for distal clavicle erosion (mnemonic: SHIRT Pocket) are included in other differentials in this article. PMID- 21266271 TI - Cardiac aneurysms and diverticula: magnetic resonance and computed tomography appearances. AB - Echocardiography is the first-line imaging modality for assessment of structural heart disease but magnetic resonance imaging and multi-detector computed tomography are being increasingly used for cardiac morphologic assessment. Aneurysms and diverticulae of the cardiac chambers and related structures represent a diverse group of conditions with varying etiologies and clinical manifestations. This article reviews the magnetic resonance imaging and multi detector computed tomography features of these lesions with consideration of the emerging role that cross-sectional imaging has to play in their evaluation. Radiologists should be familiar with the salient imaging appearances of these conditions to facilitate optimal patient management. PMID- 21266272 TI - Implications of new (seventh) TNM classification of lung cancer on general radiologists--a pictorial review. AB - The new TNM (seventh) classification of lung cancer, published by Union Internationale Centre le Cancer, has been in use since January 2010. It is vital for general radiologists to be well versed with this system and be aware of the impact of these changes on patient management and prognosis. It is also important that radiologists appreciate the implications of the new system on reporting different imaging modalities and its limitations. This pictorial essay outlines the proposed changes, its limitations, and implications for radiologists. PMID- 21266273 TI - Prompt operative intervention reduces long-term osteoarthritis after knee anterior cruciate ligament tear. PMID- 21266274 TI - Comments on glenohumeral joint preservation. PMID- 21266276 TI - Comparative systematic review of the open dislocation, mini-open, and arthroscopic surgeries for femoroacetabular impingement. AB - PURPOSE: To analyze the current approaches to the surgical management of symptomatic femoroacetabular impingement (FAI). METHODS: Thirteen relevant queries were used in four search engines (PubMed, EMBASE, Ovid, and the Cochrane Review) with a resultant 5,856 articles. Eighteen peer-reviewed treatment outcome studies met the inclusion criteria with minimum 1-year follow-up of the surgical treatment of skeletal pathoanatomy and associated chondrolabral pathology in skeletally mature patients with FAI. RESULTS: There were 6 open surgical dislocation, 4 mini-open, and 8 arthroscopic studies, all with Levels of Evidence III or IV. The only prospective studies were in the arthroscopic category. Outcome data were extracted and analyzed with respect to surgical efficacy, failure rates, and complications. CONCLUSIONS: The open dislocation, mini-open, and arthroscopic methods for treating symptomatic FAI are effective in improving pain and function in short-term to midterm studies and are relatively safe procedures. The historical gold standard of open dislocation surgery had a comparatively high major complication rate primarily because of trochanteric osteotomy-related issues. The mini-open method showed comparable efficacy but a significant incidence of iatrogenic injury to the lateral femoral cutaneous nerve in some studies. The arthroscopic method had surgical outcomes equal to or better than the other methods with a lower rate of major complications when performed by experienced surgeons. PMID- 21266277 TI - Open surgical dislocation versus arthroscopy for femoroacetabular impingement: a comparison of clinical outcomes. AB - PURPOSE: Over the last decade, the surgical treatment of femoroacetabular impingement (FAI) has evolved as surgical techniques through arthroscopy, open surgical dislocation, and combined approaches have been developed. The purpose of this systematic review was to evaluate and compare the clinical results of available surgical approaches for FAI. METHODS: A review of the literature was performed through the PubMed database and related articles' reference lists. Inclusion criteria were (1) all patients treated for FAI, (2) Level I, II, III, or IV study design, and (3) written in the English language. Case reports and studies involving patients with acetabular dysplasia were excluded. RESULTS: Overall, 1,299 articles fit our keyword search criteria. Of these, 26 articles reported clinical outcomes, using 3 surgical modalities: open surgical dislocation, arthroscopic, and combined approaches. In compiling the data in these articles, we analyzed the outcomes of a total 1,462 hips in 1,409 patients. The most published surgical method was arthroscopy, which included 62% of the patients. Labral repair was performed more frequently in open surgical dislocation (45%) and combined approach (41%) procedures than in arthroscopies (23%). Mean improvement in the modified Harris hip score after surgery was 26.4 for arthroscopy, 20.5 for open surgical dislocation, and 12.3 for the combined approach. A higher rate of return to sport was reported for arthroscopy in professional athletes than for open surgical dislocation. Overall complication rates were 1.7% for the arthroscopic group, 9.2% for the open surgical dislocation group, and 16% in the combined approach group. CONCLUSIONS: All 3 surgical approaches led to consistent improvements in patient outcomes. Because a wide variety of subjective hip questionnaires were used, direct comparisons could not be made in many cases, and none of the approaches could be clearly shown to be superior to the others. However, it seems that, overall, the arthroscopic method had the lowest complication and fastest rehabilitation rate. PMID- 21266278 TI - Arthroscopic-assisted minimally invasive total knee arthroplasty. AB - This technical note describes an arthroscopic technique to enhance visualization during minimally invasive total knee arthroplasty. The arthroscope is used, with the aid of balloon catheter retractors, to allow intraoperative identification of potentially adverse findings, including retained bone and cement fragments. This technique has been used successfully to identify and treat knees with these findings. Although further study and refinement are needed, this technique shows promise in reducing postoperative complications and improving outcomes in total knee arthroplasty. PMID- 21266279 TI - Suture rupture in acromioclavicular joint dislocations treated with flip buttons. AB - Acute acromioclavicular joint dislocations (ACDs) may be treated arthroscopically with flip buttons. This extra-articular fixation is easy to implant and is well tolerated. Between 2007 and 2009, 20 ACD patients (2 women and 18 men; mean age, 32 years) had surgery by the arthroscopic TightRope technique (Arthrex, Naples, FL). The main complication of this technique that has been reported is the partial loss of reduction at follow-up due to clavicular osteolysis under the superior flip button. We describe 4 cases with loss of reduction due to rupture of the sutures running across the buttons: 2 women with joint hyperlaxity and acute Rockwood grade IV ACD and 2 men, heavy manual workers, with joint hyperlaxity and acute Rockwood grade IV ACD. The use of flip buttons might not be indicated in patients with joint hyperlaxity because they are able to obtain immediate stability only on the vertical plane and not on the horizontal plane. Anteroposterior movements of the acromioclavicular joint might rub the suture against the bone tunnels leading to wear and cutting. PMID- 21266280 TI - End-of-life care in the nursing home. PMID- 21266281 TI - End of life in the nursing home: redefining roles. PMID- 21266282 TI - Improving end-of-life care for patients with noncancer illnesses: The time is now. PMID- 21266283 TI - Hospice providers in nursing homes: why is a negative study important? PMID- 21266284 TI - Strategies and innovative models for delivering palliative care in nursing homes. AB - The goals of palliative care address critical issues for individuals with complex and serious illness residing in nursing homes, including pain and symptom management, communication, preparation for death, decisions about treatment preferences, and caregiver support. Because of the uncertain prognosis associated with chronic nonmalignant diseases such as dementia, many nursing home residents are either not referred to hospice or have very short or very long hospice stays. The integration of palliative care into nursing homes offers a potential solution to the challenges relating to hospice eligibility, staffing, training, and obtaining adequate reimbursement for care that aligns with resident and surrogate's preferences and needs. However, the delivery of palliative care in nursing homes is hindered by both regulatory and staffing barriers and, as a result, is rare. In this article, we draw on interviews with nursing home executives, practitioners, and researchers to describe the barriers to nursing home palliative care. We then describe 3 existing and successful models for providing nonhospice palliative care to nursing home residents and discuss their ongoing strengths and challenges. We conclude with specific policy proposals to expedite the integration of palliative care into the nursing home setting. PMID- 21266285 TI - Severe Alzheimer's disease: treatment effects on function and care requirements. AB - The number and age of patients with Alzheimer's disease (AD) continues to increase dramatically with more patients requiring long-term skilled care. The care of patients with AD, particularly those with severe AD, is a challenge that long-term care administrators are facing with increasing frequency. The therapeutic approach to patients in the moderate to severe stages of AD is a combination of pharmacologic agents to maximize patient function and independence and is cost effective for the nursing home facility and the patient. Here we review the use of drug therapy in patients with severe AD, focusing on function and long-term care perspectives. PMID- 21266286 TI - Evaluation of a continuous quality improvement initiative for end-of-life care for older noncancer patients. AB - OBJECTIVES: The burden of suffering among patients with end-stage chronic diseases may be greater than those of cancer patients, as a result of longer duration of illness trajectory and high prevalence of symptoms, yet they may be less likely to receive palliative care services. To improve the quality of care of these patients, we carried out a continuous quality improvement initiative among medical and nursing staff of a convalescent facility. DESIGN: Evaluation of a quality improvement initiative. SETTING: Nonacute institution in Hong Kong SAR, China. PARTICIPANTS: The participants were patients with advanced chronic diseases not opting for active treatment. INTERVENTION: The intervention was a continuous quality improvement process carried out over a 3-month period, consisting of service reengineering, provision of guidelines and educational material, and interactive sessions to achieve culture change among staff. Evaluation before and after the intervention included patient symptoms checklist and quality-of-life measures for patients; quality-of-life and cost-of-care index for family members; quality-of-life and carer burden for staff; and use of various health care services. RESULTS: There were 80 and 89 participants in the pre- and post-intervention phase. The initiative resulted in shorter duration of stay, fewer investigations, fewer transfers back to the affiliated acute care hospital, and more follow-up by the outreach team, with no significant difference in mortality after adjusting for age and comorbidity. Symptoms of pain and cough were reduced, while there was a trend toward more constipation but less dizziness. Family members' satisfaction improved. CONCLUSIONS: It is possible to improve quality-of-life care for elderly patients with end-stage chronic diseases by staff education, and culture and system change, not only without additional resources, but likely savings were achieved in terms of reduced use of health care resources. PMID- 21266287 TI - The transition from routine care to end-of-life care in a nursing home: exploring staff perspectives. AB - OBJECTIVES: The objective of this study was to explore how nursing home staff members manage the transition from routine care to end-of-life care when a resident is dying. DESIGN: The exploratory descriptive study used qualitative methods. SETTING: A 122-bed nursing home on a continuum of long-term care campus. PARTICIPANTS: Participants were 35 nursing home professionals (21 nurses, 9 CNAs, and 5 social workers). MEASUREMENTS: In-depth interviews that involved open-ended questions about the transition to end-of-life care were audiotaped, transcribed, and submitted to qualitative data analysis for the development of emergent themes. RESULTS: Three emergent themes characterize the central aspects of the transition in care as the management of (1) physical changes, (2) emotions, and (3) overlapping systems of care. CONCLUSION: In balancing the sometimes conflicting expectations of routine, restorative, and end-of-life care needs, nursing home professionals have developed ways of managing the transition that can be important in developing specific end-of-life protocols. This study has 3 implications for practice: (1) focused end-of-life education and planning can help frontline staff prepare for the inevitable numbers of residents who will die in the nursing homes, (2) mechanisms for helping staff manage the intense emotional responses that accompany loss of long-term residents are important for long-term well-being of frontline staff, and (3) focused attention on the unique dynamics of "home" and "family" can assist nursing home professionals with ongoing losses and cumulative grief. PMID- 21266288 TI - Attitudes and approaches to decision making about antihypertensive treatment in elderly patients. AB - OBJECTIVE: Optimal antihypertensive therapy in very old subjects requires their understanding and acceptance. We investigated elderly patients' willingness to accept antihypertensive therapy and their desire for information and for participation in medical decisions. METHODS: After standardized explanations about hypertension and its treatment, 120 patients (mean age 83.8 +/- 7.4 years) were asked whether they would accept hypertension treatment in 15 hypothetical scenarios with different outcomes (myocardial infarction/heart failure, stroke, and death), absolute risks/risk reductions, and risk of side effects. RESULTS: Fifty percent to 60% of patients accepted treatment in all scenarios; only 4% to 7% clearly refused it, and 30% to 40% were unsure. Paradoxically, the Autonomy Preference Index (API) indicated a variable, overall low desire for participation in medical decisions (mean score 58.9 +/- 13.9 mean +/- SD, on 100), including about hypertension, but patients wanted to receive extensive medical information (mean score 69.6 +/- 17.2). CONCLUSIONS: Our data indicate that many patients prefer to delegate the final decision to their physician, although most want to receive extensive information. Although the decision to treat belongs to the physician, initial acceptance of antihypertensive therapy does not imply that patients really understand and adhere to it. True understanding and acceptance of treatment requires attention to patients' preferences and repeated explanations during follow-up. PMID- 21266289 TI - Opioids, survival, and advanced cancer in the hospice setting. AB - OBJECTIVE: Although pain is common among advanced cancer patients, it can be controlled in a large proportion of patients. Several barriers hinder this, including the concern that opioids hasten death. We examined whether opioids influence survival among advanced cancer patients. DESIGN: Retrospective observational study from September 2006 to October 2007. SETTING: In-patient hospice unit. PARTICIPANTS: Participants were 114 consecutive hospice patients (mean age 71.7 +/- 13.9 years). OUTCOME MEASUREMENT: Analysis of survival (days) following admission, according to opioid usage. Standardized Oral Morphine Equivalents (OME mg/d) were calculated. RESULTS: On admission 74.6% received opioids, rising to 92.1% at death. Mean opioid dosage was OME of 146 +/- 245 mg/d, and mean survival was 12.3 +/- 12.15 days. Mean survival, according to opioid dosage of 0, 1 to 119, and greater than or equal to 120 OME mg/d respectively at admission, was 16.7 +/- 13.4, 11.2 +/- 12.1, 10.0 +/- 10.2 (P = .009), and according to dose at death was 17.0 +/- 15.1, 12.3 +/- 12.1, 11.1 +/- 11.3 (P = ns). Increasing overall opioid dosage was associated with improved survival compared with no change or decreasing overall dosage (mean survival 14.0 +/- 12.7 days versus 9.3 +/- 9.8 versus 9.1 +/- 11.4, days respectively, P = .01). Adjusting for clinical variables in Cox proportional hazards models, no significant association was found between mortality and of the following aspects of opioid usage: (1) dose on admission (Hazard Ratio [HR] 1.009, 95% confidence interval [CI] 0.999-1.019); (2) dose at death (HR 1.004, 95% CI 0.996-1.013); (3) mean dose (HR 1.006, 95% CI 0.997-1.016); (4) overall dose increase (HR 0.733, 95% CI 0.417-1.288) and decrease (HR 0.967, 95% CI 0.472-1.984); (5) day-by-day dosage changes (HR 1.005, 95% CI 0.996-1.013). CONCLUSIONS: Opioid usage, even at high dosages, had no effect on survival among advanced cancer patients in a hospice setting. PMID- 21266290 TI - A pilot study to explore next of kin's perspectives on end-of-life care in the nursing home. AB - OBJECTIVES: To explore next-of-kin's (NOK's) perceptions of end-of-life (EOL) care in the nursing home setting and to compare these perceptions for residents receiving hospice care plus usual care versus usual care only. DESIGN: Mailed survey. SETTING: Three nursing homes in central Massachusetts. PARTICIPANTS: Nursing home decedents' NOK MEASUREMENTS: Nursing home decedents' NOK were identified from nursing home records. Survey data were collected on NOK demographics and perceptions of decedents' EOL care. This care included nursing home care and services received by decedents, pain and symptom management, communication about decedents' care, and advance directives. RESULTS: Of 164 surveys mailed, 114 surveys were returned (70% response rate) with 100 completed (61% used for analysis). NOK reported that nursing home decedents had a high symptom burden, with at least 70% experiencing pain, agitation, and/or anxiety, and 60% having shortness of breath or depression. Most NOK reported good-to excellent symptom control for decedents (88%), feeling well informed about the decedent's condition (91%), satisfaction with medical and nursing care (90%), and the decedent having advance directives in place (89%). Respondents' impressions of decedents' symptom control, communication about decedents' care, level of care, or advance directives did not differ significantly between the hospice plus usual care and usual care only groups. CONCLUSION: In this pilot study, NOK perceived that decedents' EOL care in the nursing home was of similarly good quality under hospice care plus usual care and usual care only. Our study provides an approach to assessing quality of EOL care in the nursing home setting. PMID- 21266291 TI - Advance directive and end-of-life care preferences among Chinese nursing home residents in Hong Kong. AB - OBJECTIVES: The objectives of the present study were to describe the knowledge and preferences of Hong Kong Chinese older adults regarding advance directives and end-of-life care decisions, and to investigate the predictors of preferences for advance directive and community end-of-life care in nursing homes. METHODS: This was a cross-sectional survey conducted in 140 nursing homes in Hong Kong. A total of 1600 cognitively normal Chinese older adults were recruited. Information on demographics, social, medical diseases, preferences of end-of-life care decisions, and advance directives were collected by face-to-face questionnaire interviews. RESULTS: The mean age of the participants was 82.4 years; 94.2% of them would prefer to be informed of the diagnosis if they had terminal diseases and 88.0% preferred to have their advance directives regarding medical treatment in the future. Approximately 35% would prefer to die in their nursing homes. The significant independent predictors for the preference of advance directive included asking for relatives' advice, wishing to be informed of their terminal illness diagnoses, absence of stroke, and having no problems in self-care in European Quality of Life-5 Dimensions. For the preference for community end-of life care and dying in nursing homes, the independent predictors included older age, not having siblings in Hong Kong, Catholic religion, nonbeliever of traditional Chinese religion, not receiving any old age allowance, lower Geriatric Depression Scale score, and being residents of government-subsidized nursing homes. CONCLUSIONS: Most of our cognitively normal Chinese nursing home older adults prefer having an advance directive, and one-third of them would prefer to die in nursing homes. PMID- 21266292 TI - Onco-geriatric approach for the management of older patients with cancer. AB - INTRODUCTION AND RATIONALE: The number of older cancer patients is increasing with global aging of the population. A close interaction between oncologists and geriatricians becomes necessary to (1) better evaluate the elders' health status, (2) determine their residual clinical/biological reserves, and (3) optimize the provided medical care. In fact, aggressive antineoplastic managements are often denied to older patients, possibly because of the common misconception suggesting older age and/or clinical complexity as absolute contraindications to advanced treatments. METHODS: The primary aim of the presented project is to assess whether assigning a geriatrician to provide daily medical care to older cancer patients (aged 65 years and older) admitted to an oncology ward increases the number of patients eligible for a chemotherapeutic and/or surgical intervention. The project is articulated in 2 phases: (1) a retrospective phase based on analysis of data collected over the 2 years before the beginning of the study, and (2) a prospective 2-year intervention. Additional information about clinical conditions, biological parameters, adverse drug reactions, body composition, physical function, and 1-year health-related events will also be recorded. OUTCOMES: The combination of expertise from oncologists and geriatricians is likely to result in (1) an improved selection of candidates for interventions aimed at increasing disability-free life expectancy and/or overall survival, and (2) a more rational exclusion of patients at higher risk of toxicity or with poor prognosis. In this article, the development of an onco-geriatric unit aimed at the evaluation, management, and treatment of older women with gynecological cancer is also described. PMID- 21266293 TI - Removal of copper by oxygenated pyrolytic tire char: kinetics and mechanistic insights. AB - The kinetics of copper ion (Cu(II)) removal from aqueous solution by pyrolytic tire char was modeled using five different conventional models. A modification to these models was also developed through a modified equation that accounts for precipitation. Conventional first- and second-order reaction models did not fit the copper sorption kinetics well, indicating a lack of simple rate-order dependency on solute concentration. Instead, a reversible first-order rate reaction showed the best fit to the data, indicating a dependence on surface functional groups. Due to the varying solution pH during the sorption process, modified external and internal mass transfer models were employed. Results showed that the sorption of copper onto oxygenated chars was limited by external mass transfer and internal resistance with and without the modification. However, the modification of the sorption process produced very different results for unoxygenated chars, which showed neither internal nor external limitation to sorption. Instead, its slow sorption rate indicates a lack of surface functional groups. The sorption of Cu(II) by oxygenated and unoxygenated chars was also found to occur via three and two distinct stages, respectively. PMID- 21266294 TI - Sodium niobate adsorbents doped with tantalum (TaV) for the removal of bivalent radioactive ions in waste waters. AB - Sodium niobates doped with different amounts of tantalum (Ta(V)) were prepared via a thermal reaction process. It was found that pure nanofibrils and bar like solids can be obtained when tantalum is introduced into the reaction system. For the well crystallized fibril solids, the Na(+) ions are difficult to exchange, and the radioactive ions such as Sr(2+) and Ra(2+) just deposit on the surface of the fibers during the sorption process, resulting in lower sorption capacity and distribution coefficients (K(d)). However, the bar like solids are poorly crystallized and have many exchangeable Na(+) ions. They are able to remove highly hazardous bivalent radioactive isotopes such as Sr(2+) and Ra(2+) ions. Even in the presence of many Na(+) ions, they also have higher K(d). More importantly, such sorption finally intelligently triggers considerable collapse of the structure, resulting in permanent entrapment of the toxic bivalent cations in the solids, so that they can be safely disposed of. This study highlights new opportunities for the preparation of Nb-based adsorbents to efficiently remove toxic radioactive ions from contaminated water. PMID- 21266295 TI - MicroRNA-155 regulates lipid uptake, adhesion/chemokine marker secretion and SCG2 expression in oxLDL-stimulated dendritic cells/macrophages. PMID- 21266296 TI - Comparing the structural properties of human and rat islet amyloid polypeptide by MD computer simulations. AB - Conformational properties of the full-length human and rat islet amyloid polypeptide 1-37 (amyloidogenic hIAPP and non-amyloidogenic rIAPP, respectively) were studied at 310 and 330 K by MD simulations both for the cysteine (reduced IAPP) and cystine (oxidized IAPP) moieties. At all temperatures studied, IAPP does not adopt a well-defined conformation and is essentially random coil in solution, although transient helices appear forming along the peptide between residues 8 and 22, particularly in the reduced form. Above the water percolation transition (at 320 K), the reduced hIAPP moiety presents a considerably diminished helical content remaining unstructured, while the natural cystine moiety reaches a rather compact state, presenting a radius of gyration that is almost 10% smaller and characterized by intrapeptide H-bonds that form many beta bridges in the C-terminal region. This compact conformation presents a short end to-end distance and seems to form through the formation of beta-sheet conformations in the C-terminal region with a minimization of the Y/F distances in a two-step mechanism: the first step taking place when the Y37/F23 distance is ~1.1 nm, and subsequently Y37/F15 reaches its minimum of ~0.86 nm. rIAPP, which does not aggregate, also presents transient helical conformations. A particularly stable helix is located in proximity of the C-terminal region, starting from residues L27 and P28. Our MD simulations show that P28 in rIAPP influences the secondary structure of IAPP by stabilizing the peptide in helical conformations. When this helix is not present, the peptide presents bends or H-bonded turns at P28 that seem to inhibit the formation of the beta-bridges seen in hIAPP. Conversely, hIAPP is highly disordered in the C-terminal region, presenting transient isolated beta-strand conformations, particularly at higher temperatures and when the natural disulfide bond is present. Such conformational differences found in our simulations could be responsible for the different aggregational propensities of the two different homologues. In fact, the fragment 30-37, which is identical in both homologues, is known to aggregate in vitro, hence the overall sequence must be responsible for the amyloidogenicity of hIAPP. The increased helicity in rIAPP induced by the serine-to-proline variation at residue 28 seems to be a plausible inhibitor of its aggregation. PMID- 21266297 TI - Emergency physician diagnosis of pediatric infective endocarditis by point-of care echocardiography. PMID- 21266298 TI - Current protocol for initial anticoagulants in pulmonary embolism: one size fits all? PMID- 21266299 TI - Letter for Killip classification and glucose level in patients with acute myocardial infarction. PMID- 21266300 TI - Anaphylactic shock due to intravenous amiodarone. AB - A 24-year-old male patient was admitted to the coronary intensive care unit with atrial fibrillation with rapid ventricular response. He was given amiodarone (Cordarone 150 mg i.v., Sanofi-Aventis) intravenous loading dose of 300 mg in 100 mL dextrose 5% in water (D5W) over 1 hour, followed by a maintenance dose of 900 mg in 500 mL D5W for infusion up to 24 hours. At the emergency department, the patient was conscious and cooperative; his pretreatment arterial blood pressure was 120/80 mm Hg, and the arrhythmic tachycardia was 145 per minute. After intravenous amiodarone loading and half an hour into maintenance infusion, extreme perspiration, hypotension (blood pressure immeasurable), and mild cyanosis developed. The patient was conscious; his auscultation and pulse were normal. He was given physiologic serum and dopamine support. Approximately an hour later, the blood pressure was measurable. Infusion was terminated because of suspicion of an allergic reaction to acetylsalicylic acid or amiodarone. The allergic reaction observed was attributed to acetylsalicylic acid and amiodarone; infusion was resumed when the clinical situation worsened during the maintenance infusion. Once again, the patient was given physiologic serum (2000 mL), dopamine (20 mg/kg per minute), and, additionally, 250 mg of methyprednisolone sodium succinate intravenous, whereby the clinical condition improved within 20 minutes. Anaphylactic shock cases due to amiodarone are rare; it is important to take a history of drug-mediated anaphylaxis before prescribing amiodarone. An addition to a review of the literature regarding treatment of amiodarone-related anaphylactic shock cases had not been reported before. PMID- 21266301 TI - A randomized controlled trial of fluoxetine in the treatment of cocaine dependence among methadone-maintained patients. AB - BACKGROUND: Cocaine abuse and dependence continue to be widespread. Currently, there are no pharmacotherapies shown to be effective in the treatment of cocaine dependence. METHODS: A 33-week outpatient clinical trial of fluoxetine (60 mg/day, po) for cocaine dependence that incorporated abstinence-contingent voucher incentives was conducted. Participants (N = 145) were both cocaine and opioid dependent and treated with methadone. A stratified randomization procedure assigned subjects to one of four conditions: fluoxetine plus voucher incentives (FV), placebo plus voucher incentives (PV), fluoxetine without vouchers (F), and placebo without vouchers (P). Dosing of fluoxetine/placebo was double blind. Primary outcomes were treatment retention and cocaine use based on thrice-weekly urine testing. RESULTS: The PV group had the longest treatment retention (M = 165 days) and lowest probability of cocaine use. The adjusted predicted probabilities of cocaine use were 65% in the P group, 60% in the F group, 56% in the FV group, and 31% in the PV group. CONCLUSIONS: Fluoxetine was not efficacious in reducing cocaine use in patients dually dependent on cocaine and opioids. PMID- 21266303 TI - Perioperative diagnosis of the positive axilla in breast cancer: a safe, time efficient algorithm. AB - BACKGROUND: This study evaluates the combined role of axillary ultrasound (Ax US), fine needle aspiration (FNAC) and intraoperative frozen section analysis of the sentinel node (FS SN) in a practical, time efficient algorithm to reduce the requirement for reoperation for axillary clearance in breast cancer in a busy tertiary unit. METHODS: Between October 2007 and June 2009 188 women underwent Ax US as a first investigation for nodal status. Suspicious nodes were biopsied, negative axillae proceeded to FS SN at time of primary breast surgery. All confirmed positive cases proceeded to immediate axillary clearance. RESULTS: 93 women had positive axillary nodes at final histology. Ax US + FNAC identified 59 positive axillae and had a sensitivity of 63.4% and specificity of 100%. FS SN identified a further 26 cases with a sensitivity of 76.5% and specificity of 100%. Overall, only 8 women required reoperation for axillary clearance. Sensitivity for the combined procedures was 91.4%. Commencement of adjuvant therapy was significantly less in those women identified earlier compared to those requiring a second operation (23.3 days vs 49.0 days, p < 0.005). CONCLUSION: 95.7% of cases were diagnosed accurately in the perioperative period, preventing delay to triage to definitive oncological care and reducing requirement for costly reoperation. PMID- 21266302 TI - Gender and treatment response in substance use treatment-mandated parolees. AB - Well-controlled, randomized studies of correctional interventions examining gender effects are rare. This study examined gender main effects and gender * treatment interactions in a multisite randomized trial (N = 431) comparing a new form of correctional supervision for drug-involved offenders (collaborative behavioral management [CBM]) to standard parole. Outcomes included repeated measures of yes/no use of primary drug, alcohol use, and recidivism during 9 months postrelease. Generalized estimating equation analyses indicated that despite using harder drugs at baseline, women were less likely than men to use their primary drug and to use alcohol during the follow-up period. No gender related differences in recidivism were found. Treatment interacted with gender to predict alcohol use, with women in CBM reporting the best alcohol outcomes (only 5% of women used alcohol during the follow-up period). The clear expectations, positive reinforcement, recognition of successes, fairness, and support present in CBM may be particularly important for women parolees. PMID- 21266304 TI - Natural orifice total mesorectal excision using transanal port and laparoscopic assistance. AB - Natural Orifice Transluminal Endoscopic Surgery (NOTES) is an emerging concept which has been recently applied to the field of rectal excision. The authors describe a case of total mesorectal excision using a transanal port and laparoscopic assistance. We described a procedure performed in a 45-year-old for a rectal adenocarcinoma (1 cm wide, T1sm3) 3 cm above the dentate line. The procedure is described in the text and in a didactic video. PMID- 21266305 TI - Midterm results of 506 solid trispiked reflection cementless acetabular components for primary total hip arthroplasty. AB - The purpose of this prospective study was to evaluate the outcomes and survivorship of a trispiked, sintered bead-coated titanium shell with a polished inner surface, no screw holes, and an improved locking mechanism. A total of 506 total hip arthroplasties with a minimum 5-year follow-up were available for review at a mean of 7 years (range, 5-11 years). Three sockets (0.6%) were revised for reasons other than aseptic loosening, and 14 (2.8%) polyethylene liners were exchanged. There was no difference in revision rate between non-cross linked and highly cross-linked liners (P = .4). There were no cases of radiographic loosening. Retroacetabular osteolysis was identified in 2%. The overall 5-year and 10-year Kaplan-Meier survivorship was 97.5% and 97.4%, respectively, whereas survivorship of the shell was 99.8%. PMID- 21266306 TI - Retroperitoneal migration of a septically loose femoral component. AB - Migration of total hip arthroplasty components is generally associated with a medial acetabular wall defect and may cause various intrapelvic complications. This is often a result of the destructive bone loss that takes place with infection. To our knowledge, this is the first report that presents complete intrapelvic migration of a femoral stem of total hip arthroplasty due to septic loosening with an intact medial acetabular wall. PMID- 21266307 TI - LC-MS and NMR characterization of the purple chromophore formed in the o aminobenzaldehyde assay of dihydrodipicolinate synthase. AB - The enzyme dihydrodipicolinate synthase (DHDPS) has been widely investigated as a target for new antibiotics. The o-aminobenzaldehyde (o-ABA) assay is routinely used as a highly specific, if qualitative, tool for DHDPS purification, whereby fractions containing active DHDPS appear purple upon addition of o-ABA. The purple adduct absorbs in the visible region (540 nm) but has never been characterized in the 50 years since it was first reported. Structural characterization of this purple compound has been performed by UV spectrophotometry, NMR spectroscopy and tandem mass spectrometry. The extinction coefficient of this chromophore was also determined. PMID- 21266308 TI - Distinct, gene-specific effect of heat shock on heat shock factor-1 recruitment and gene expression of CXC chemokine genes. AB - The heat shock (HS) response, a phylogenetically conserved ubiquitous response to stress, is generally characterized by the induced expression of heat shock protein (HSP) genes. Our earlier studies showed that the stress-activated transcription factor, heat shock factor-1 (HSF1), activated at febrile range or HS temperatures also modified expression of non-HSP genes including cytokine and chemokine genes. We also showed by in silico analysis that 28 among 29 human and mouse CXC chemokine genes had multiple putative heat shock response elements (HSEs) present in their gene promoters. To further determine whether these potential HSEs were functional and bound HSF1, we analyzed the recruitment of HSF1 to promoters of 5 human CXC chemokine genes (CXCL-1, 2, 3, 5 and 8) by chromatin immunoprecipitation (ChIP) assay and analyzed the effect of HS exposure on tumor necrosis factor-alpha (TNFalpha)-induced expression of these genes in human lung epithelial-like A549 cells. HSF1 ChIP analysis showed that HSF1 was recruited to all but one of these CXC chemokine genes (CXCL-3) and HS caused a significant increase in recruitment of HSF1 to one or multiple HSEs present in the promoters of CXCL-1, 2, 5 and 8 genes. However, the effect of HS exposure on expression of these genes showed a variable gene-specific effect. For example, CXCL8 expression was markedly enhanced (p<0.05) whereas CXCL5 expression was significantly repressed (p<0.05) in cells exposed to HS coincident with TNFalpha stimulation. In contrast, expression of CXCL1 and CXCL2, despite HSF1 recruitment to their promoters, was not affected by HS exposure. Our results indicate that some, if not all, putative HSEs present in the CXC chemokine gene promoters are functional and recruit HSF1 in vivo but the effects on gene expression are variable and gene specific. We speculate, the physical proximity and interactions of other transcription factors and co-regulators with HSF1 could be critical to determining the effects of HS on the expression of these genes. PMID- 21266309 TI - Insulin-like growth factor-1 overexpression in cardiomyocytes diminishes ex vivo heart functional recovery after acute ischemia. AB - BACKGROUND: Acute insulin-like growth factor-1 administration has been shown to have beneficial effects in cardiac pathological conditions. The aim of the present study was to assess the structural and ex vivo functional impacts of long term cardiomyocyte-specific insulin-like growth factor-1 overexpression in hearts of transgenic alphaMHC-IGF-1 Ea mice. METHODS: Performance of isolated transgenic alphaMHC-IGF-1 Ea and littermate wild-type control hearts was compared under baseline conditions and in response to 20-min ischemic insult. Cardiac desmin and laminin expression patterns were determined histologically, and myocardial hydroxyproline was measured to assess collagen content. RESULTS: Overexpression of insulin-like growth factor-1 did not modify expression patterns of desmin or laminin but was associated with a pronounced increase (~30%) in cardiac collagen content (from ~3.7 to 4.8 MUg/mg). Baseline myocardial contractile function and coronary flow were unaltered by insulin-like growth factor-1 overexpression. In contrast to prior evidence of acute cardiac protection, insulin-like growth factor-1 overexpression was associated with significant impairment of acute functional response to ischemia-reperfusion. Insulin-like growth factor-1 overexpression did not modify ischemic contracture development, but postischemic diastolic dysfunction was aggravated (51+/-5 vs. 22+/-6 mmHg in nontransgenic littermates). Compared with wild-type control, recovery of pressure development and relaxation indices relative to baseline performance were significantly reduced in transgenic alphaMHC-IGF-1 Ea after 60-min reperfusion (34+/-7% vs. 62+/-7% recovery of +dP/dt; 35+/-11% vs. 57+/-8% recovery of -dP/dt). CONCLUSIONS: Chronic insulin-like growth factor-1 overexpression is associated with reduced functional recovery after acute ischemic insult. Collagen deposition is elevated in transgenic alphaMHC-IGF-1 Ea hearts, but there is no change in expression of the myocardial structural proteins desmin and laminin. These findings suggest that sustained cardiac elevation of insulin-like growth factor-1 may not be beneficial in the setting of an acute ischemic insult. PMID- 21266310 TI - Combining one-dimensional stray-field micro-imaging with mechanical field-cycling NMR: a new spectrometer design. AB - A new spectrometer design combining stray-field micro-imaging with mechanical field-cycling Nuclear Magnetic Resonance (FC-NMR), allowing for one dimensional spatial resolution in the order of 10 MUm is described. The field-cycle is implemented by moving the probe in the stray-field of a superconducting gradient magnet. In this way a field range between 10 mT and 6.3 T is covered. The maximum transfer time is less than 5 s. Further, methods to correct for some of the imaging artefacts found in previous studies are implemented. The main objective of this design is a depth- and field-dependent investigation of the defect structure caused by heavy-ion irradiation of ionic crystals. PMID- 21266311 TI - Protein functional sites prediction using modified bio-basis function and quantitative indices. AB - The prediction of functional sites in proteins is an important issue in protein function studies and drug design. To apply the kernel based pattern recognition algorithms such as support vector machines for protein functional sites prediction, a new string kernel function, termed as the modified bio-basis function, is proposed recently. The bio-basis strings for the new kernel function are selected by an efficient method that integrates the Fisher ratio and the concept of degree of resemblance. In this regard, this paper introduces some quantitative indices for evaluating the quality of selected bio-basis strings. Moreover, the effectiveness of the new string kernel function and bio-basis string selection method, along with a comparison with existing bio-basis function and related bio-basis string selection methods, is demonstrated on different protein data sets using the proposed quantitative indices and support vector machines. PMID- 21266312 TI - Novel tunable dynamic tweezers using dark-bright soliton collision control in an optical add/drop filter. AB - We propose a novel system of the dynamic optical tweezers generated by a dark soliton in the fiber optic loop. A dark soliton known as an optical tweezer is amplified and tuned within the microring resonator system. The required tunable tweezers with different widths and powers can be controlled. The analysis of dark bright soliton conversion using a dark soliton pulse propagating within a microring resonator system is analyzed. The dynamic behaviors of soliton conversion in add/drop filter is also analyzed. The control dark soliton is input into the system via the add port of the add/drop filter. The dynamic behavior of the dark-bright soliton conversion is observed. The required stable signal is obtained via a drop and throughput ports of the add/drop filter with some suitable parameters. In application, the trapped light/atom and transportation can be realized by using the proposed system. PMID- 21266313 TI - Incremental Mountain Clustering Method to find building blocks for constructing structures of proteins. AB - In this paper we propose an algorithm named Incremental Structural Mountain Clustering Method (ISMCM) with a view to finding a library of building blocks for reconstruction of 3-D structures of proteins/peptides. The building blocks are short structural motifs that are identified based on an estimate of local "density" of 3-D fragments computed using a measure of structural similarity. The structural similarity is computed after the best-molecular-fit alignment of pairs of fragments. The algorithm is tested on two well known benchmark data sets. Following the protocols used by other researchers, for the first data set we reconstruct a set of 71 test peptides (up to first 60 residues) whereas for the second data set we reconstruct all 143 test peptides. The ISMCM algorithm is found to successfully reconstruct the test peptides in terms of both global-fit root-mean-square (RMS) error and local-fit RMS error. The low values of local-fit RMS errors suggest that these building blocks extracted by ISMCM are good quantizers, which can represent nearby fragments quite accurately. To further assess the quality of building blocks we use two alternative graphical ways. We also use Shannon's entropy to show the structural similarity of the clusters found by our algorithm. This is important as building blocks that represent clusters with structurally similar fragments will be very effective in reconstruction. The entropic analysis reveals a very interesting fact that the secondary structure of the central residue of the fragments in a cluster is most strongly conserved (minimum entropy) over the cluster, which might be an indicator that central residue of the structural motif plays a dominant role in local folding. PMID- 21266314 TI - Dynamic Robust Games in MIMO Systems. AB - In this paper, we study dynamic robust power-allocation games in multiple-input multiple-output systems under the imperfectness of the channel-state information at the transmitters. Using a robust pseudopotential-game approach, we show the existence of robust solutions in both discrete and continuous action spaces under suitable conditions. Considering the imperfectness in terms of the payoff measurement at the transmitters, we propose a COmbined fully DIstributed Payoff and Strategy Reinforcement Learning (CODIPAS-RL) in which each transmitter learns its payoff function, as well as the associated optimal covariance matrix strategies. Under the heterogeneous CODIPAS-RL, the transmitters can use different learning patterns (heterogeneous learning) and different learning rates. We provide sufficient conditions for the almost-sure convergence of the heterogeneous learning to ordinary differential equations. Extensions of the CODIPAS-RL to Ito's stochastic differential equations are discussed. PMID- 21266315 TI - Spatial Markov Kernels for Image Categorization and Annotation. AB - This paper presents a novel discriminative stochastic method for image categorization and annotation. We first divide the images into blocks on a regular grid and then generate visual keywords through quantizing the features of image blocks. The traditional Markov chain model is generalized to capture 2-D spatial dependence between visual keywords by defining the notion of "past" as what we have observed in a row-wise raster scan. The proposed spatial Markov chain model can be trained via maximum-likelihood estimation and then be used directly for image categorization. Since this is completely a generative method, we can further improve it through developing new discriminative learning. Hence, spatial dependence between visual keywords is incorporated into kernels in two different ways, for use with a support vector machine in a discriminative approach to the image categorization problem. Moreover, a kernel combination is used to handle rotation and multiscale issues. Experiments on several image databases demonstrate that our spatial Markov kernel method for image categorization can achieve promising results. When applied to image annotation, which can be considered as a multilabel image categorization process, our method also outperforms state-of-the-art techniques. PMID- 21266316 TI - Finite-Time Attitude Tracking Control for Spacecraft Using Terminal Sliding Mode and Chebyshev Neural Network. AB - A finite-time attitude tracking control scheme is proposed for spacecraft using terminal sliding mode and Chebyshev neural network (NN) (CNN). The four-parameter representations (quaternion) are used to describe the spacecraft attitude for global representation without singularities. The attitude state (i.e., attitude and velocity) error dynamics is transformed to a double integrator dynamics with a constraint on the spacecraft attitude. With consideration of this constraint, a novel terminal sliding manifold is proposed for the spacecraft. In order to guarantee that the output of the NN used in the controller is bounded by the corresponding bound of the approximated unknown function, a switch function is applied to generate a switching between the adaptive NN control and the robust controller. Meanwhile, a CNN, whose basis functions are implemented using only desired signals, is introduced to approximate the desired nonlinear function and bounded external disturbances online, and the robust term based on the hyperbolic tangent function is applied to counteract NN approximation errors in the adaptive neural control scheme. Most importantly, the finite-time stability in both the reaching phase and the sliding phase can be guaranteed by a Lyapunov-based approach. Finally, numerical simulations on the attitude tracking control of spacecraft in the presence of an unknown mass moment of inertia matrix, bounded external disturbances, and control input constraints are presented to demonstrate the performance of the proposed controller. PMID- 21266317 TI - [Immunization coverage of children aged 0 to 5 years in Libreville (Gabon)]. AB - The strategies recently implemented in Gabon have been effective in improving immunization coverage. These include, in particular, the integration of the Expanded Programme on Immunization (EPI) in primary health care centers, the integration of immunization outside of EPI, immunization by peripheral health centers according to pre-set advanced strategies, and awareness and catch-up campaigns. This descriptive, cross-sectional survey was conducted from 1 October 2007 through 30 January 2008, throughout public- and private-sector health care centers in the town of Libreville. In the public sector, where health care is free, the study took place at the largest health facility in the country, the Hospital Center of Libreville (HCL), at Estuary Melen Hospital (on the outskirts of Libreville), at Nkembo Hospital, which houses the EPI offices, and the 5 Maternal and Child Health centers (MCH) where vaccine monitoring is done. Monitoring in the private sector covered only the three largest clinics, where vaccine monitoring is done, all of which agreed to participate. After obtaining informed consent from the parents or guardian accompanying the child, a semi structured interview according to a standardised questionnaire was conducted to collect socioeconomic and demographic data, including age, sex, recruitment site, place of residence, number of siblings, parental origin, ethnicity of head of household, type of family (couple or single parent), mother's age, level of education, employment and socio-economic status, as determined by the head of household's monthly income (in three categories: 1) low income, at or below the minimum wage, set at 80 000 FCFA (120 euros); 2) average income, from more than 80 000 FCFA to 300 000 FCFA (458 euros); and 3) high income over 300 000 FCFA. After the interview, the child's vaccination booklet was carefully examined to identify the types of antigen, number of doses administered, age at vaccination, and the regularity of the monitoring. Parents were asked to explain the reasons for any delays in or absences of vaccinations. EPI vaccines administered to children aged 0 to 11 months include: BCG (Calmette-Guerin bacillus); DPT3 (3rd combination dose for Diphtheria-Tetanus-Pertussis); Hib3 (3rdd dose of Haemophilus influenza b); OPV3 (3rd dose of oral polio vaccine); IPV3 (3rd dose of injectable polio vaccine, often in combination); HEB3 (3rd dose of Hepatitis B); yellow fever vaccine; and measles vaccine. The non-EPV vaccines for children aged 12 to 59 months included: HiB4; DPT4; HEB4; IPV4; MMR (combined Measles Mumps-Rubella); meningococcal vaccine A and C; Typhim Vi (typhoid polysaccharide vaccine); and Pneumo 23 (pneumococcal vaccine.) RESULTS: The study included 1001 children: 533 boys (53.2%) and 468 girls (46.8%), for a sex ratio of 1.1. The mean age of the sample was 12.0 +/- 13.1 months, distributed as follows: 64.5% aged 0 to 11 months; 20.1% aged 12 to 24 months; and 15.4% aged 25 to 59 months. In all, 175 children (17.5%) came from the private sector, and 826 children (82.5%) from the public sector. Both parents lived with 696 children (69.5%), while the remaining 305 children (30.5%) lived with their mother. The mothers' mean age was 26 years (min/max: 15/49 years); 61.3% had completed secondary education, 19.1% superior level, 10.6% primary level and 9.0% had no education at all. Almost 37% of mothers had some sort of paid employment. Household income was distributed as follows: low income for 18.6%, average income for 47.2%, and high income for 34.3% of the families interviewed. The average number of children under the age of 15 in a household was 3 (+/-2). Among children aged 0 to 11 months, the EPI antigens had the highest vaccination coverage rates, and these rates were higher in the private sector (more than 80% to 99% for some). Overall, the BCG scar was seen in 98.5% of all children; in the private sector 90.2% had received the third dose of the DTC/VPO-IPV vaccine, and in the public sector, 74.5%. The measles vaccination rate in the private sector was 82.5% compared with 64.4% in the public sector. The rates of coverage for antigens not included in the EPI varied from 50.8% to 74.2% in the private sector and from 6.2% to 32.5% in the public sector. The vaccine with the least coverage was the pneumococcal: only 3.2% and were vaccinated against this in the private sector and 0.8% in the public sector. The principal reasons for non-immunization were lack of financial resources (n = 283, 28.3%), in particular, for booster up vaccines and those recommended by the EPI, lack of information (n = 259, 25.9%), forgetfulness (n = 217, 21.7%), neglect (n = 113, 11.3%), sick child (n = 80, 8%), vaccine not available (n = 19, 1.9%), wrong information (n = 15, 1.5%), travel (n = 14, 1.4%), mother sick (n = 12, 1.2%) and lack of time (n = 18, 1.8%). Finally, the direct cost of good vaccination coverage for boosters was 42,245 FCFA (74 euros) in the public sector and 54,800 FCFA (84 euros) in the private sector. PMID- 21266318 TI - Use of an online community to develop patient-reported outcome instruments: the Multiple Sclerosis Treatment Adherence Questionnaire (MS-TAQ). AB - BACKGROUND: Patients with multiple sclerosis (MS) may face barriers, such as treatment fatigue, memory problems, or side effects, that may influence their adherence to medication. OBJECTIVE: The objective of our study was to use an online community to develop a self-report questionnaire to quantify adherence and barriers to achieving adherence, that is specific to MS disease-modifying treatments (DMTs) and predictive of missed doses. METHODS: A review of the scientific literature and analysis of discussions between MS patients on PatientsLikeMe.com were used to generate survey items salient to patients. Cognitive debriefing was used to refine the items. The Multiple Sclerosis Treatment Adherence Questionnaire (MS-TAQ) contains 30 questions in three subscales: Barriers, Side Effects, and Coping Strategies. RESULTS: MS patients completed an online survey (response rate: 431 of 1209 invited, 35.7%). Between 16% (14/86) and 51% (51/100) of MS patients missed at least 1 dose of their DMT in the previous 28 days, with significant between-treatment differences. The MS TAQ Barriers scale was positively correlated with the proportion of doses missed (r = .5), demonstrating a stronger relationship between adherence and perceived barriers than was found with clinical or demographic variables (r ~ .3). The Coping Strategies subscale was negatively correlated with missed doses (r = -.3), suggesting that use of more coping strategies is associated with higher adherence. CONCLUSIONS: Online communities can provide domains of interest and psychometric data to more rapidly develop and prototype patient-reported outcome instruments. The MS-TAQ offers patients and clinicians a simple method for identifying barriers to adherence, which may then be targeted through interventions. PMID- 21266319 TI - Single-Boosted Protease Inhibitor versus Double-Boosted Protease Inhibitors for the Salvage Therapy in HIV-Infected Patients. AB - OBJECTIVE: To compare treatment outcomes between the regimens of single-boosted protease inhibitor (PI) and double-boosted PIs for the salvage therapy in patients who failed nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens. METHODS: A total of 64 patients from 2 cohorts, 40 in twice daily ritonavir-boosted lopinavir (LPV/r) at 400/100 mg plus lamivudine (3TC) and 24 in once daily ritonavir-boosted atazanavir and saquinavir (ATV/SQV/r) at 300/1600/100 mg/d, were studied. RESULTS: At 48 weeks, 30 (75%) patients in LPV/r group and 20 (83%) patients in ATV/SQV/r group achieved HIV-1 RNA at <400 copies/mL (P = .790). In all, 24 (60%) and 16 (67%) achieved HIV-1 RNA at <50 copies/mL (P = .541). Low-level viral rebound (51-400 copies/mL) was found in 6 (15%) in LPV/r group and 4 (17%) in ATV/SQV/r group (P = 1.000). Medians CD4 counts were 336 cells/mm(3) and 330 cells/mm(3) in the corresponding groups (P = 0.937). CONCLUSION: No additional benefit is found with double-boosted PIs compared to single-boosted PI in terms of treatment responses in HIV-infected patients failing NNRTI-based regimen. PMID- 21266320 TI - Safety, Tolerability, and Efficacy of Second-Line Generic Protease Inhibitor Containing HAART after First-Line Failure among South Indian HIV-Infected Patients. AB - INTRODUCTION: We describe the safety, tolerability, and efficacy of protease inhibitor (PI) containing highly active antiretroviral therapy (HAART) among patients switching from nonnucleoside reverse transcriptase inhibitor (NNRTI) based HAART from a clinical setting in South India. METHODS: We assessed a prospective cohort of 91 HIV-infected patients with at least 12 months of clinical follow-up on second-line ritonavir-boosted PI-based therapy between August 2003 and December 2008. RESULTS: More than three fourths of patients met the World Health Organization (WHO) criteria for immunological failure at the time of switch. The median time to switch was 758 days. Patients demonstrated consistent increases in their CD4 counts during the first 12 months, by which time the median CD4 count was 322 cells/mm(3). The most common adverse events within the first year after switch were nausea (14.8%), lipodystrophy (10.4%), and peripheral neuropathy (7.0%). Patients switching to atazanavir (ATV)-based regimens compared to those switching to indinavir (IDV)-based regimens had similar immunological and clinical outcomes. CONCLUSIONS: Given the therapeutic success of using second-line PI-containing HAART after experiencing treatment failure, further efforts must be taken to expand access to second-line HAART so that more patients can benefit from these drugs. PMID- 21266321 TI - Morbidity Profiles of People Living With HIV/AIDS in Urban and Rural Inpatient and Outpatient Settings in Karnataka, South India. AB - We examined the morbidity profiles associated with people living with HIV infection in an urban HIV inpatient treatment site near the city of Bangalore, in southern Karnataka state, south India, and in a rural outpatient site in northern Karnataka. Data from March 2007 until July 2008 were analyzed. The urban cohort comprised 432 patients, and the most common comorbid conditions were unexplained prolonged fever (50.2%) and oral candidiasis (42.6%). The rural cohort comprised 2374 patients, and the most common comorbid conditions were unexplained prolonged fever (58.8%), minor mucocutaneous infections (58.4%), and recurrent upper respiratory tract infections (52.3%). With less than 1% of patients in rural areas on treatment for tuberculosis (vs over one third in the urban cohort), tuberculosis is likely significantly underdiagnosed in rural areas. In addition, only 2.6% of rural outpatients who were eligible for antiretroviral treatment (ART), per Government of India guidelines, were actually on ART, compared to 31.6% of the urban population. PMID- 21266322 TI - Percentages, Process, and Patterns of HIV Disclosure Among the Spouses of HIV Infected Men in South India. AB - Most studies have described the outcome of HIV status disclosure rather than the process of disclosure. Hence, a study was conducted among 201 women who accompanied their spouses and children to 3 hospitals at Chennai and Vellore, Tamil Nadu, India, during January to June 2007. Majority of the respondents were sero-positive (69%) and marriage was the only risk factor for them. Of 201 women, 49% did not know the reason for their husbands' HIV infection. Confidentiality of the patient was often breached during disclosure as family members were drawn into the process without consulting the patient. Only for 117 (50%) respondents, HIV diagnosis was disclosed directly by the health providers. There was a considerable delay for men in disclosing their HIV status to their spouses. Apart from the spouses, 122 (61%) shared their diagnosis with other family members. Disgrace to self and family (54%), fear of discrimination (27%), and fear of rejection (9%) were reported for nondisclosure. PMID- 21266323 TI - Initial Experience with Topical Fluorouracil for Treatment of HIV-Associated Anal Intraepithelial Neoplasia. AB - Exposure to high-risk strains of human papillomavirus (HPV) promotes cellular dysplasia of the anal canal epithelium, potentially leading to anal intraepithelial neoplasia (AIN), which is in turn a precursor to invasive squamous cell carcinoma of the anus (SCCA). People with HIV infection who engage in anoreceptive intercourse are at heightened risk for acquiring HPV, AIN, and SCCA. Although intravenous 5-fluorouracil (5-FU) is commonly used for treatment of invasive SCCA, there has been little experience with the use of topical 5-FU as therapy for AIN. We retrospectively reviewed records of the first 11 HIV positive patients treated with topical 5-FU in our anal dysplasia clinic. Six (55%) patients had clinical improvement with reduction in area of dysplasia seen on high-resolution anoscopy (HRA). Three (27%) patients had improvement in AIN pathologic grade. Eight (73%) patients reported mild-to-moderate perianal irritation, which led six to reduce the frequency of 5-FU application. Further study of topical 5-FU for treatment of HIV-associated AIN is warranted. PMID- 21266324 TI - Bilateral in utero cerebellar infarction. AB - We report a case of complete bilateral cerebellar infarction diagnosed in utero by routine prenatal ultrasound and magnetic resonance imaging in a 26-week-old fetus. This posterior fossa ischemic stroke with secondary hemorrhage caused transient obstructive hydrocephalus and likely occurred subsequent to vertebrobasilar artery thrombosis. Such posterior fossa ischemic insults diagnosed in utero are rare with scarce clinical reports. The serial imaging characteristics, clinical, and developmental implications of this case are reviewed. PMID- 21266325 TI - Deletion of Lkb1 in pro-opiomelanocortin neurons impairs peripheral glucose homeostasis in mice. AB - OBJECTIVE: AMP-activated protein kinase (AMPK) signaling acts as a sensor of nutrients and hormones in the hypothalamus, thereby regulating whole-body energy homeostasis. Deletion of Ampkalpha2 in pro-opiomelanocortin (POMC) neurons causes obesity and defective neuronal glucose sensing. LKB1, the Peutz-Jeghers syndrome gene product, and Ca(2+)-calmodulin-dependent protein kinase kinase beta (CaMKKbeta) are key upstream activators of AMPK. This study aimed to determine their role in POMC neurons upon energy and glucose homeostasis regulation. RESEARCH DESIGN AND METHODS: Mice lacking either Camkkbeta or Lkb1 in POMC neurons were generated, and physiological, electrophysiological, and molecular biology studies were performed. RESULTS: Deletion of Camkkbeta in POMC neurons does not alter energy homeostasis or glucose metabolism. In contrast, female mice lacking Lkb1 in POMC neurons (PomcLkb1KO) display glucose intolerance, insulin resistance, impaired suppression of hepatic glucose production, and altered expression of hepatic metabolic genes. The underlying cellular defect in PomcLkb1KO mice involves a reduction in melanocortin tone caused by decreased alpha-melanocyte-stimulating hormone secretion. However, Lkb1-deficient POMC neurons showed normal glucose sensing, and body weight was unchanged in PomcLkb1KO mice. CONCLUSIONS: Our findings demonstrate that LKB1 in hypothalamic POMC neurons plays a key role in the central regulation of peripheral glucose metabolism but not body-weight control. This phenotype contrasts with that seen in mice lacking AMPK in POMC neurons with defects in body-weight regulation but not glucose homeostasis, which suggests that LKB1 plays additional functions distinct from activating AMPK in POMC neurons. PMID- 21266326 TI - Increased whole-body and sustained liver cortisol regeneration by 11beta hydroxysteroid dehydrogenase type 1 in obese men with type 2 diabetes provides a target for enzyme inhibition. AB - OBJECTIVE: The cortisol-regenerating enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) amplifies glucocorticoid levels in liver and adipose tissue. 11beta-HSD1 inhibitors are being developed to treat type 2 diabetes. In obesity, 11beta-HSD1 is increased in adipose tissue but decreased in liver. The benefits of pharmacological inhibition may be reduced if hepatic 11beta-HSD1 is similarly decreased in obese patients with type 2 diabetes. To examine this, we quantified in vivo whole-body, splanchnic, and hepatic 11beta-HSD1 activity in obese type 2 diabetic subjects. RESEARCH DESIGN AND METHODS: Ten obese men with type 2 diabetes and seven normal-weight control subjects were infused with 9,11,12,12 [(2)H](4)cortisol (40%) and cortisol (60%) at 1.74 mg/h. Adrenal cortisol secretion was suppressed with dexamethasone. Samples were obtained from the hepatic vein and an arterialized hand vein at steady state and after oral administration of cortisone (5 mg) to estimate whole-body and liver 11beta-HSD1 activity using tracer dilution. RESULTS: In obese type 2 diabetic subjects, the appearance rate of 9,12,12-[(2)H](3)cortisol in arterialized blood was increased (35 +/- 2 vs. 29 +/- 1 nmol/min, P < 0.05), splanchnic 9,12,12-[(2)H](3)cortisol production was not reduced (29 +/- 6 vs. 29 +/- 6 nmol/min), and cortisol appearance in the hepatic vein after oral cortisone was unchanged. CONCLUSIONS: Whole-body 11beta-HSD1 activity is increased in obese men with type 2 diabetes, whereas liver 11beta-HSD1 activity is sustained, unlike in euglycemic obesity. This supports the concept that inhibitors of 11beta-HSD1 are likely to be most effective in obese type 2 diabetic subjects. PMID- 21266327 TI - Rictor/mTORC2 is essential for maintaining a balance between beta-cell proliferation and cell size. AB - OBJECTIVE: We examined the role of Rictor/mammalian target of rapamycin complex 2 (mTORC2), a key component of the phosphotidylinositol-3-kinase (PI3K)/mTORC2/AKT signaling pathway, in regulating both beta-cell mass and function. RESEARCH DESIGN AND METHODS: Mice with beta-cell-specific deletions of Rictor or Pten were studied to determine the effects of deleting either or both genes on beta-cell mass and glucose homeostasis. RESULTS: Rictor null mice exhibited mild hyperglycemia and glucose intolerance caused by a reduction in beta-cell mass, beta-cell proliferation, pancreatic insulin content, and glucose-stimulated insulin secretion. Islets from these mice exhibited decreased AKT-S473 phosphorylation and increased abundance of FoxO1 and p27 proteins. Conversely, Pten null (betaPtenKO) mice exhibited an increase in beta-cell mass caused by increased cellular proliferation and size. Although beta-cell mass was normal in mice lacking both Rictor and Pten (betaDKO), their beta-cells were larger than those in the betaPtenKO mice. Even though the beta-cell proliferation rate in the betaDKO mice was lower than in the betaPtenKO mice, there was a 12-fold increase the phosphorylation of AKT-T308. CONCLUSIONS: PI3K/AKT signaling through mTORC2/pAKT-S473 plays a key role in maintaining normal beta-cell mass. The phosphorylation of AKT-S473, by negatively regulating that of AKT-T308, is essential for maintaining a balance between beta-cell proliferation and cell size in response to proliferative stimuli. PMID- 21266328 TI - Diabetes in mice with selective impairment of insulin action in Glut4-expressing tissues. AB - OBJECTIVE: Impaired insulin-dependent glucose disposal in muscle and fat is a harbinger of type 2 diabetes, but murine models of selective insulin resistance at these two sites are conspicuous by their failure to cause hyperglycemia. A defining feature of muscle and fat vis-a-vis insulin signaling is that they both express the insulin-sensitive glucose transporter Glut4. We hypothesized that diabetes is the result of impaired insulin signaling in all Glut4-expressing tissues. RESEARCH DESIGN AND METHODS: To test the hypothesis, we generated mice lacking insulin receptors at these sites ("GIRKO" mice), including muscle, fat, and a subset of Glut4-positive neurons scattered throughout the central nervous system. RESULTS: GIRKO mice develop diabetes with high frequency because of reduced glucose uptake in peripheral organs, excessive hepatic glucose production, and beta-cell failure. CONCLUSIONS: The conceptual advance of the present findings lies in the identification of a tissue constellation that melds cell-autonomous mechanisms of insulin resistance (in muscle/fat) with cell nonautonomous mechanisms (in liver and beta-cell) to cause overt diabetes. The data are consistent with the identification of Glut4 neurons as a distinct neuroanatomic entity with a likely metabolic role. PMID- 21266329 TI - Tests for genetic interactions in type 1 diabetes: linkage and stratification analyses of 4,422 affected sib-pairs. AB - OBJECTIVE: Interactions between genetic and environmental factors lead to immune dysregulation causing type 1 diabetes and other autoimmune disorders. Recently, many common genetic variants have been associated with type 1 diabetes risk, but each has modest individual effects. Familial clustering of type 1 diabetes has not been explained fully and could arise from many factors, including undetected genetic variation and gene interactions. RESEARCH DESIGN AND METHODS: To address this issue, the Type 1 Diabetes Genetics Consortium recruited 3,892 families, including 4,422 affected sib-pairs. After genotyping 6,090 markers, linkage analyses of these families were performed, using a novel method and taking into account factors such as genotype at known susceptibility loci. RESULTS: Evidence for linkage was robust at the HLA and INS loci, with logarithm of odds (LOD) scores of 398.6 and 5.5, respectively. There was suggestive support for five other loci. Stratification by other risk factors (including HLA and age at diagnosis) identified one convincing region on chromosome 6q14 showing linkage in male subjects (corrected LOD = 4.49; replication P = 0.0002), a locus on chromosome 19q in HLA identical siblings (replication P = 0.006), and four other suggestive loci. CONCLUSIONS: This is the largest linkage study reported for any disease. Our data indicate there are no major type 1 diabetes subtypes definable by linkage analyses; susceptibility is caused by actions of HLA and an apparently random selection from a large number of modest-effect loci; and apart from HLA and INS, there is no important susceptibility factor discoverable by linkage methods. PMID- 21266330 TI - Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice. AB - OBJECTIVE: Obesity-associated insulin resistance is characterized by a state of chronic, low-grade inflammation that is associated with the accumulation of M1 proinflammatory macrophages in adipose tissue. Although different evidence explains the mechanisms linking the expansion of adipose tissue and adipose tissue macrophage (ATM) polarization, in the current study we investigated the concept of lipid-induced toxicity as the pathogenic link that could explain the trigger of this response. RESEARCH DESIGN AND METHODS: We addressed this question using isolated ATMs and adipocytes from genetic and diet-induced murine models of obesity. Through transcriptomic and lipidomic analysis, we created a model integrating transcript and lipid species networks simultaneously occurring in adipocytes and ATMs and their reversibility by thiazolidinedione treatment. RESULTS: We show that polarization of ATMs is associated with lipid accumulation and the consequent formation of foam cell-like cells in adipose tissue. Our study reveals that early stages of adipose tissue expansion are characterized by M2 polarized ATMs and that progressive lipid accumulation within ATMs heralds the M1 polarization, a macrophage phenotype associated with severe obesity and insulin resistance. Furthermore, rosiglitazone treatment, which promotes redistribution of lipids toward adipocytes and extends the M2 ATM polarization state, prevents the lipid alterations associated with M1 ATM polarization. CONCLUSIONS: Our data indicate that the M1 ATM polarization in obesity might be a macrophage-specific manifestation of a more general lipotoxic pathogenic mechanism. This indicates that strategies to optimize fat deposition and repartitioning toward adipocytes might improve insulin sensitivity by preventing ATM lipotoxicity and M1 polarization. PMID- 21266331 TI - Global gene expression profiles of subcutaneous adipose and muscle from glucose tolerant, insulin-sensitive, and insulin-resistant individuals matched for BMI. AB - OBJECTIVE: To determine altered gene expression profiles in subcutaneous adipose and skeletal muscle from nondiabetic, insulin-resistant individuals compared with insulin-sensitive individuals matched for BMI. RESEARCH DESIGN AND METHODS: A total of 62 nondiabetic individuals were chosen for extremes of insulin sensitivity (31 insulin-resistant and 31 insulin-sensitive subjects; 40 were European American and 22 were African American) and matched for age and obesity measures. Global gene expression profiles were determined and compared between ethnic groups and between insulin-resistant and insulin-sensitive participants individually and using gene-set enrichment analysis. RESULTS: African American and European American subjects differed in 58 muscle and 140 adipose genes, including many inflammatory and metabolically important genes. Peroxisome proliferator-activated receptor gamma cofactor 1A (PPARGC1A) was 1.75-fold reduced with insulin resistance in muscle, and fatty acid and lipid metabolism and oxidoreductase activity also were downregulated. Unexpected categories included ubiquitination, citrullination, and protein degradation. In adipose, highly represented categories included lipid and fatty acid metabolism, insulin action, and cell-cycle regulation. Inflammatory genes were increased in European American subjects and were among the top Kyoto Encyclopedia of Genes and Genomes pathways on gene-set enrichment analysis. FADS1, VEGFA, PTPN3, KLF15, PER3, STEAP4, and AGTR1 were among genes expressed differentially in both adipose and muscle. CONCLUSIONS: Adipose tissue gene expression showed more differences between insulin-resistant versus insulin-sensitive groups than the expression of genes in muscle. We confirm the role of PPARGC1A in muscle and show some support for inflammation in adipose from European American subjects but find prominent roles for lipid metabolism in insulin sensitivity independent of obesity in both tissues. PMID- 21266333 TI - Indications of possible brain-tumour risk in mobile-phone studies: should we be concerned? PMID- 21266332 TI - SUMOylation regulates insulin exocytosis downstream of secretory granule docking in rodents and humans. AB - OBJECTIVE: The reversible attachment of small ubiquitin-like modifier (SUMO) proteins controls target localization and function. We examined an acute role for the SUMOylation pathway in downstream events mediating insulin secretion. RESEARCH DESIGN AND METHODS: We studied islets and beta-cells from mice and human donors, as well as INS-1 832/13 cells. Insulin secretion, intracellular Ca(2+), and beta-cell exocytosis were monitored after manipulation of the SUMOylation machinery. Granule localization was imaged by total internal reflection fluorescence and electron microscopy; immunoprecipitation and Western blotting were used to examine the soluble NSF attachment receptor (SNARE) complex formation and SUMO1 interaction with synaptotagmin VII. RESULTS: SUMO1 impairs glucose-stimulated insulin secretion by blunting the beta-cell exocytotic response to Ca(2+). The effect of SUMO1 to impair insulin secretion and beta-cell exocytosis is rapid and does not require altered gene expression or insulin content, is downstream of granule docking at the plasma membrane, and is dependent on SUMO-conjugation because the deSUMOylating enzyme, sentrin/SUMO specific protease (SENP)-1, rescues exocytosis. SUMO1 coimmunoprecipitates with the Ca(2+) sensor synaptotagmin VII, and this is transiently lost upon glucose stimulation. SENP1 overexpression also disrupts the association of SUMO1 with synaptotagmin VII and mimics the effect of glucose to enhance exocytosis. Conversely, SENP1 knockdown impairs exocytosis at stimulatory glucose levels and blunts glucose-dependent insulin secretion from mouse and human islets. CONCLUSIONS: SUMOylation acutely regulates insulin secretion by the direct and reversible inhibition of beta-cell exocytosis in response to intracellular Ca(2+) elevation. The SUMO protease, SENP1, is required for glucose-dependent insulin secretion. PMID- 21266335 TI - Manipulation effects of prior exercise intensity feedback by the Borg scale during open-loop cycling. AB - OBJECTIVE: To verify the effects of exercise intensity deception by the Borg scale on the ratings of perceived exertion (RPE), heart rate (HR) and performance responses during a constant power output open-loop exercise. METHODS: Eight healthy men underwent a maximal incremental test on a cycle ergometer to identify the peak power output (PPO) and heart rate deflection point (HRDP). Subsequently, they performed a constant power output trial to exhaustion set at the HRDP intensity, in deception (DEC) and informed (INF) conditions: DEC--subjects were told that they would be cycling at an intensity corresponding to two categories below the RPE quantified at the HRDP; INF--subjects were told that they would cycle at the exact intensity corresponding to the RPE quantified at the HRDP. RESULTS: The PPO and power output at the HRDP obtained in maximal incremental tests were 247.5 +/- 32.1 W and 208.1 +/- 27.1 W, respectively. No significant difference in the time to exhaustion was found between DEC (525 +/- 244 s) or INF (499 +/- 224 s) trials. The slope and the first and second measurements of the RPE and HR parameters showed no significant difference between trials. CONCLUSIONS: Psychophysiological variables such as RPE and HR as well as performance were not affected when exercise intensity was deceptively manipulated via RPE scores. This may suggest that unaltered RPE during exercise is a regulator of performance in this open-loop exercise. PMID- 21266336 TI - The effect of the neonatal Continuous Negative Extrathoracic Pressure (CNEP) trial enquiries on research in the UK. PMID- 21266337 TI - Probiotics and the immunological response to infant vaccinations: a prospective, placebo controlled pilot study. AB - BACKGROUND: Probiotics have been shown to be immunomodulatory and can affect antibody responses following vaccination. Several immunisations are associated with suboptimal seroconversion rates leaving a substantial part of the population exposed to infection. OBJECTIVES: To evaluate the influence of probiotic supplementation on the immune response of infants following mumps, measles, rubella and varicella vaccination. METHODS: A randomised, placebo-controlled, double blinded prospective trial was performed in a cohort of healthy infants. Study subjects were randomly assigned to receive probiotics or placebo for a total of 5 months, starting 2 months prior to vaccination. Antibody levels against vaccine components were measured 3 months after immunisation. Treatment related and vaccine-related adverse events were recorded. FINDINGS: 47 infants completed the study, 25 in the probiotic group and 22 in the placebo group. There was no statistically significant difference in the number of infants failing to reach protective antibody titres against the different vaccine components (three infants in the placebo group against one in the treatment group for rubella, two each for mumps, four children vs two for measles). When combining all results in both groups, a larger percentage of failures to seroconvert occurred in the placebo group (17% vs 8%, p=0.052), a result of borderline significance. The number of infants needed to treat in order to prevent one failed vaccine component was 12. There was no difference in the rate of treatment related adverse effects between the two groups. There was a significant trend toward fewer vaccine related adverse effects in the treatment group. CONCLUSIONS: Oral probiotics given to infants during the period of immunisation do not interfere with the immune response to mumps, measles, rubella and varicella vaccine, and may improve seroconversion rates. PMID- 21266338 TI - Oral montelukast may have a role in severe and in life-threatening acute asthma. PMID- 21266340 TI - EWTD: incompatible with subspecialty training? PMID- 21266339 TI - Prevalence, profile and predictors of malnutrition in children with congenital heart defects: a case-control observational study. AB - OBJECTIVE: To investigate the prevalence, profile and predictors of severe malnutrition in children with congenital heart defects (CHDs). DESIGN: Case control, observational study. SETTING: Tertiary teaching hospital in Lagos, Nigeria (March 2006 to March 2008). PARTICIPANTS: Children aged 3-192 months with uncorrected symptomatic CHD and healthy controls, frequency matched for age and sex. MAIN OUTCOME MEASURES: Prevalence of malnutrition based on WHO/National Center for Health Statistics/Centers for Disease Control and Prevention z score <=-2; weight for age, weight for height/length and height for age; proportions of underweight, wasting and stunting in cases and controls, and in acyanotic and cyanotic CHD; and predictors of malnutrition using multivariate logistic analysis. RESULTS: 90.4% of cases and 21.1% of controls had malnutrition (p=0.0001), and 61.2% and 2.6%, respectively, had severe malnutrition (p=0.0001). Wasting, stunting and underweight were identified in 41.1%, 28.8% and 20.5%, and 2.6%, 3.9% and 14.5% of cases and controls, respectively. Wasting was significantly higher (58.3%) in acyanotic CHD (p=0.0001), and stunting (68.0%) in cyanotic CHD (p=0.0001). Age at weaning was significantly lower in cases than controls (3.24+/-0.88 and 7.04+/-3.04 months, respectively; p=0.0001) and in acyanotic than cyanotic CHD (2.14+/-0.33 and 5.33+/-1.22 months, respectively; p=0.004). Predictors of malnutrition in CHD were anaemia, moderate to severe congestive heart failure (CHF), poor dietary intake of fat and prolonged unoperated disease. CONCLUSION: Severe malnutrition in association with anaemia and moderate to severe CHF is highly prevalent in CHD preoperatively in these children. Early weaning may be a marker of feeding difficulties in heart failure. PMID- 21266341 TI - Risk score to stratify children with suspected serious bacterial infection: observational cohort study. AB - OBJECTIVES: To derive and validate a clinical score to risk stratify children presenting with acute infection. STUDY DESIGN AND PARTICIPANTS: Observational cohort study of children presenting with suspected infection to an emergency department in England. Detailed data were collected prospectively on presenting clinical features, laboratory investigations and outcome. Clinical predictors of serious bacterial infection (SBI) were explored in multivariate logistic regression models using part of the dataset, each model was then validated in an independent part of the dataset, and the best model was chosen for derivation of a clinical risk score for SBI. The ability of this score to risk stratify children with SBI was then assessed in the entire dataset. MAIN OUTCOME MEASURE: Final diagnosis of SBI according to criteria defined by the Royal College of Paediatrics and Child Health working group on Recognising Acute Illness in Children. RESULTS: Data from 1951 children were analysed. 74 (3.8%) had SBI. The sensitivity of individual clinical signs was poor, although some were highly specific for SBI. A score was derived with reasonable ability to discriminate SBI (area under the receiver operator characteristics curve 0.77, 95% CI 0.71 to 0.83) and risk stratify children with suspected SBI. CONCLUSIONS: This study demonstrates the potential utility of a clinical score in risk stratifying children with suspected SBI. Further work should aim to validate the score and its impact on clinical decision making in different settings, and ideally incorporate it into a broader management algorithm including additional investigations to further stratify a child's risk. PMID- 21266342 TI - Not NICE: a better way forward? PMID- 21266343 TI - Adapting functional genomic tools to metagenomic analyses: investigating the role of gut bacteria in relation to obesity. AB - With the expanding availability of sequencing technologies, research previously centered on the human genome can now afford to include the study of humans' internal ecosystem (human microbiome). Given the scale of the data involved in this metagenomic research (two orders of magnitude larger than the human genome) and their importance in relation to human health, it is crucial to guarantee (along with the appropriate data collection and taxonomy) proper tools for data analysis. We propose to adapt the approaches defined for the analysis of gene expression microarray in order to infer information in metagenomics. In particular, we applied SAM, a broadly used tool for the identification of differentially expressed genes among different samples classes, to a reported dataset on a research model with mice of two genotypes (a high density lipoprotein knockout mouse and its wild-type counterpart). The data contain two different diets (high-fat or normal-chow) to ensure the onset of obesity, prodrome of metabolic syndromes (MS). By using 16S rRNA gene as a genomic diversity marker, we illustrate how this approach can identify bacterial populations differentially enriched among different genetic and dietary conditions of the host. This approach faithfully reproduces highly-relevant results from phylogenetic and standard statistical analyses, used to explain the role of the gut microbiome in relation to obesity. This represents a promising proof-of-principle for using functional genomic approaches in the fast growing area of metagenomics, and warrants the availability of a large body of thoroughly tested and theoretically sound methodologies to this exciting new field. PMID- 21266344 TI - RADSeq: next-generation population genetics. AB - Next-generation sequencing technologies are making a substantial impact on many areas of biology, including the analysis of genetic diversity in populations. However, genome-scale population genetic studies have been accessible only to well-funded model systems. Restriction-site associated DNA sequencing, a method that samples at reduced complexity across target genomes, promises to deliver high resolution population genomic data-thousands of sequenced markers across many individuals-for any organism at reasonable costs. It has found application in wild populations and non-traditional study species, and promises to become an important technology for ecological population genomics. PMID- 21266345 TI - The era of epigenetics. PMID- 21266346 TI - Chatting histone modifications in mammals. AB - Eukaryotic chromatin can be highly dynamic and can continuously exchange between an open transcriptionally active conformation and a compacted silenced one. Post translational modifications of histones have a pivotal role in regulating chromatin states, thus influencing all chromatin dependent processes. Methylation is currently one of the best characterized histone modification and occurs on arginine and lysine residues. Histone methylation can regulate other modifications (e.g. acetylation, phosphorylation and ubiquitination) in order to define a precise functional chromatin environment. In this review we focus on histone methylation and demethylation, as well as on the enzymes responsible for setting these marks. In particular we are describing novel concepts on the interdependence of histone modifications marks and discussing the molecular mechanisms governing this cross-talks. PMID- 21266347 TI - Next generation sequencing based approaches to epigenomics. AB - Next generation sequencing has brought epigenomic studies to the forefront of current research. The power of massively parallel sequencing coupled to innovative molecular and computational techniques has allowed researchers to profile the epigenome at resolutions that were unimaginable only a few years ago. With early proof of concept studies published, the field is now moving into the next phase where the importance of method standardization and rigorous quality control are becoming paramount. In this review we will describe methodologies that have been developed to profile the epigenome using next generation sequencing platforms. We will discuss these in terms of library preparation, sequence platforms and analysis techniques. PMID- 21266348 TI - HSulf-1 modulates FGF2- and hypoxia-mediated migration and invasion of breast cancer cells. AB - HSulf-1 modulates the sulfation states of heparan sulfate proteoglycans critical for heparin binding growth factor signaling. In the present study, we show that HSulf-1 is transcriptionally deregulated under hypoxia in breast cancer cell lines. Knockdown of HIF-1alpha rescued HSulf-1 downregulation imposed by hypoxia, both at the RNA and protein levels. Chromatin immunoprecipitation with HIF-1alpha and HIF-2alpha antibodies confirmed recruitment of HIF-alpha proteins to the two functional hypoxia-responsive elements on the native HSulf-1 promoter. HSulf-1 depletion in breast cancer cells resulted in an increased and sustained bFGF2 (basic fibroblast growth factor) signaling and promoted cell migration and invasion under hypoxic conditions. In addition, FGFR2 (fibroblast growth factor receptor 2) depletion in HSulf-1-silenced breast cancer cells attenuated hypoxia mediated cell invasion. Immunohistochemical analysis of 53 invasive ductal carcinomas and their autologous metastatic lesions revealed an inverse correlation for the expression of HSulf-1 to CAIX in both the primary tumors (P >= 0.0198) and metastatic lesions (P >= 0.0067), respectively, by chi(2) test. Finally, HSulf-1 expression levels in breast tumors by RNA in situ hybridization showed that high HSulf-1 expression is associated with increased disease-free and overall survival (P >= 0.03 and P >= 0.0001, respectively). Collectively, these results reveal an important link between loss of HSulf-1 under hypoxic microenvironment and increased growth factor signaling, cell migration, and invasion. PMID- 21266349 TI - EGFR nuclear translocation modulates DNA repair following cisplatin and ionizing radiation treatment. AB - Epidermal growth factor receptor (EGFR) overexpression is associated with resistance to chemotherapy and radiotherapy. It modulates DNA repair after radiation-induced damage through association with the catalytic subunit of DNA protein kinase (DNA-PKcs). We investigated the role of EGFR nuclear import and its association with DNA-PKcs on DNA repair after exposure to cisplatin or ionizing radiation (IR). The model system was based on EGFR-null murine NIH3T3 fibroblasts in which EGFR expression was restored with isoforms that were wild type (wt), derived from human cancers (L858R, EGFRvIII), or mutated in the nuclear localization signal (NLS) sequence. In cells expressing wtEGFR or EGFRvIII, there was complete unhooking of cisplatin-induced interstrand cross links and repair of IR-induced strand breaks. In contrast, cells expressing L858R or NLS mutations showed reduced unhooking of interstrand cross-links and repair of strand breaks. Immunoprecipitation showed wtEGFR and EGFRvIII binding to DNA PKcs, increasing 2-fold 18 hours after cisplatin therapy. Confocal microscopy and proximity ligation assay showed that this interaction in the cytoplasm and nucleus was associated with increased DNA protein kinase complex (DNA-PK) activity. Cells expressing the EGFR L858R mutation, which has constitutive kinase activity, exhibited reduced DNA repair without nuclear localization. EGFR-NLS mutants showed impaired nuclear localization and DNA-PKcs association with reduced DNA repair and DNA-PK kinase activity. In summary, EGFR nuclear localization was required for modulation of cisplatin and IR-induced repair of DNA damage. EGFR-DNA-PKcs binding was induced by cisplatin or IR but not by EGFR nuclear translocation per se. Our findings show that EGFR subcellular distribution can modulate DNA repair kinetics, with implications for design of EGFR-targeted combinational therapies. PMID- 21266351 TI - hPuf-A/KIAA0020 modulates PARP-1 cleavage upon genotoxic stress. AB - Human hPuf-A/KIAA0020 was first identified as a new minor histocompatibility antigen in 2001. Its zebrafish orthologue contains six Pumilio-homology RNA binding domains and has been shown to participate in the development of eyes and primordial germ cells, but the cellular function of hPuf-A remains unclear. In this report, we showed that hPuf-A predominantly localized in the nucleoli with minor punctate signals in the nucleoplasm. The nucleolar localization of hPuf-A would redistribute to the nucleoplasm after the treatment of RNA polymerase inhibitors (actinomycin D and 5,6-dichlorobenzimidazole riboside) and topoisomerase inhibitors [camptothecin (CPT) and etoposide]. Interestingly, knockdown of hPuf-A sensitized cells to CPT and UV treatment and cells constitutively overexpressing hPuf-A became more resistant to genotoxic exposure. Affinity gel pull-down coupled with mass spectrometric analysis identified PARP-1 as one of the hPuf-A interacting proteins. hPuf-A specifically interacts with the catalytic domain of PARP-1 and inhibits poly(ADP-ribosyl)ation of PARP-1 in vitro. Depletion of hPuf-A increased the cleaved PARP-1 and overexpression of hPuf-A lessened PARP-1 cleavage when cells were exposed to CPT and UV light. Collectively, hPuf-A may regulate cellular response to genotoxic stress by inhibiting PARP-1 activity and thus preventing PARP-1 degradation by caspase-3. PMID- 21266350 TI - Phosphorylation regulates c-Myc's oncogenic activity in the mammary gland. AB - Expression of the c-Myc oncoprotein is affected by conserved threonine 58 (T58) and serine 62 (S62) phosphorylation sites that help to regulate c-Myc protein stability, and altered ratios of T58 and S62 phosphorylation have been observed in human cancer. Here, we report the development of 3 unique c-myc knock-in mice that conditionally express either c-Myc(WT) or the c-Myc(T58A) or c-Myc(S62A) phosphorylation mutant from the constitutively active ROSA26 locus in response to Cre recombinase to study the role of these phosphorylation sites in vivo. Using a mammary-specific Cre model, we found that expression of c-Myc(WT) resulted in increased mammary gland density, but normal morphology and no tumors at the level expressed from the ROSA promoter. In contrast, c-Myc(T58A) expression yielded enhanced mammary gland density, hyperplastic foci, cellular dysplasia, and mammary carcinoma, associated with increased genomic instability and suppressed apoptosis relative to c-Myc(WT). Alternatively, c-Myc(S62A) expression reduced mammary gland density relative to control glands, and this was associated with increased genomic instability and normal apoptotic function. Our results indicate that specific activities of c-Myc are differentially affected by T58 and S62 phosphorylation. This model provides a robust platform to interrogate the role that these phosphorylation sites play in c-Myc function during development and tumorigenesis. PMID- 21266352 TI - EphB3 is overexpressed in non-small-cell lung cancer and promotes tumor metastasis by enhancing cell survival and migration. AB - Eph receptors, the largest subfamily of transmembrane tyrosine kinase receptors, have been increasingly implicated in various physiologic and pathologic processes, and the roles of the Eph family members during tumorigenesis have recently attracted growing attention. Until now, research on EphB3 function in cancer is limited to focusing on tumor suppression by EphB receptors in colorectal cancer. However, its function in other types of cancer remains poorly investigated. In this study, we explored the function of EphB3 in non-small-cell lung cancer (NSCLC). We found that the expression of EphB3 was significantly upregulated in clinical samples and cell lines, and the expression level correlated with the patient pathologic characteristics, including tumor size, differentiation, and metastasis. Overexpression of EphB3 in NSCLC cell lines accelerated cell growth and migration and promoted tumorigenicity in xenografts in a kinase-independent manner. In contrast, downregulation of EphB3 inhibited cell proliferation and migration and suppressed in vivo tumor growth and metastasis. Furthermore, we showed that silencing of EphB3 inhibited cell growth by reducing DNA synthesis and caspase-8-mediated apoptosis and suppressed cell migration by increasing accumulation of focal adhesion formation. Taken together, our findings suggest that EphB3 provides critical support to the development and progression of NSCLC by stimulating cell growth, migration, and survival, thereby implicating EphB3 as a potential therapeutic target in NSCLC. PMID- 21266353 TI - PTEN level in tumor suppression: how much is too little? AB - The importance of PTEN (phosphatase and tensin homolog located on chromosome 10) in cancer has surpassed all predictions and expectations from the time it was discovered and has qualified this gene as one of the most commonly mutated and deleted tumor suppressors in human cancer. PTEN levels are frequently found downregulated in cancer, even in the absence of genetic loss or mutation. PTEN is heavily regulated by transcription factors, microRNAs, competitive endogenous RNAs (such as the PTEN pseudogene), and methylation, whereas the tumor suppressive activity of the PTEN protein can be altered at multiple levels through aberrant phosphorylation, ubiquitination, and acetylation. These regulatory cues are presumed to play a key role in tumorigenesis through the alteration of the appropriate levels, localization, and activity of PTEN. The identification of all these levels of PTEN regulation raises, in turn, a key corollary question: How low should PTEN level(s) or activity drop in order to confer cancer susceptibility at the organismal level? Our laboratory and others have approached this question through the genetic manipulation of Pten in the mouse. This work has highlighted the exquisite and tissue-specific sensitivity to subtle reductions in Pten levels toward tumor initiation and progression with important implications for cancer prevention and therapy. PMID- 21266356 TI - Cancer stem cell niche: the place to be. AB - Tumors are being increasingly perceived as abnormal organs that, in many respects, recapitulate the outgrowth and differentiation patterns of normal tissues. In line with this idea is the observation that only a small fraction of tumor cells is capable of initiating a new tumor. Because of the features that these cells share with somatic stem cells, they have been termed cancer stem cells (CSC). Normal stem cells reside in a "stem cell niche" that maintains them in a stem-like state. Recent data suggest that CSCs also rely on a similar niche, dubbed the "CSC niche," which controls their self-renewal and differentiation. Moreover, CSCs can be generated by the microenvironment through induction of CSC features in more differentiated tumor cells. In addition to a role in CSC maintenance, the microenvironment is hypothesized to be involved in metastasis by induction of the epithelial-mesenchymal transition, leading to dissemination and invasion of tumor cells. The localization of secondary tumors also seems to be orchestrated by the microenvironment, which is suggested to form a premetastatic niche. Thus, the microenvironment seems to be of crucial importance for primary tumor growth as well as metastasis formation. Combined with its role in the protection of CSCs against genotoxic insults, these data strongly put forward the niche as an important target for novel therapies. PMID- 21266355 TI - In vivo profiling of hypoxic gene expression in gliomas using the hypoxia marker EF5 and laser-capture microdissection. AB - Hypoxia is a key determinant of tumor aggressiveness, yet little is known regarding hypoxic global gene regulation in vivo. We used the hypoxia marker EF5 coupled with laser-capture microdissection to isolate RNA from viable hypoxic and normoxic regions of 9L experimental gliomas. Through microarray analysis, we identified several mRNAs (including the HIF targets Vegf, Glut-1, and Hsp27) with increased levels under hypoxia compared with normoxia both in vitro and in vivo. However, we also found striking differences between the global in vitro and in vivo hypoxic mRNA profiles. Intriguingly, the mRNA levels of a substantial number of immunomodulatory and DNA repair proteins including CXCL9, CD3D, and RAD51 were found to be downregulated in hypoxic areas in vivo, consistent with a protumorigenic role of hypoxia in solid tumors. Immunohistochemical staining verified increased HSP27 and decreased RAD51 protein levels in hypoxic versus normoxic tumor regions. Moreover, CD8(+) T cells, which are recruited to tumors upon stimulation by CXCL9 and CXCL10, were largely excluded from viable hypoxic areas in vivo. This is the first study to analyze the influence of hypoxia on mRNA levels in vivo and can be readily adapted to obtain a comprehensive picture of hypoxic regulation of gene expression and its influence on biological functions in solid tumors. PMID- 21266354 TI - Spatial regulation of RhoA activity during pancreatic cancer cell invasion driven by mutant p53. AB - The ability to observe changes in molecular behavior during cancer cell invasion in vivo remains a major challenge to our understanding of the metastatic process. Here, we demonstrate for the first time, an analysis of RhoA activity at a subcellular level using FLIM-FRET (fluorescence lifetime imaging microscopy fluorescence resonance energy transfer) imaging in a live animal model of pancreatic cancer. In invasive mouse pancreatic ductal adenocarcinoma (PDAC) cells driven by mutant p53 (p53(R172H)), we observed a discrete fraction of high RhoA activity at both the leading edge and rear of cells in vivo which was absent in two-dimensional in vitro cultures. Notably, this pool of active RhoA was absent in noninvasive p53(fl) knockout PDAC cells, correlating with their poor invasive potential in vivo. We used dasatanib, a clinically approved anti invasive agent that is active in this model, to illustrate the functional importance of spatially regulated RhoA. Dasatanib inhibited the activity of RhoA at the poles of p53(R172H) cells in vivo and this effect was independent of basal RhoA activity within the cell body. Taken together, quantitative in vivo fluorescence lifetime imaging illustrated that RhoA is not only necessary for invasion, but also that subcellular spatial regulation of RhoA activity, as opposed to its global activity, is likely to govern invasion efficiency in vivo. Our findings reveal the utility of FLIM-FRET in analyzing dynamic biomarkers during drug treatment in living animals, and they also show how discrete intracellular molecular pools might be differentially manipulated by future anti invasive therapies. PMID- 21266358 TI - Agonist anti-CD137 mAb act on tumor endothelial cells to enhance recruitment of activated T lymphocytes. AB - Agonist monoclonal antibodies (mAb) to the immune costimulatory molecule CD137, also known as 4-1BB, are presently in clinical trials for cancer treatment on the basis of their costimulatory effects on primed T cells and perhaps other cells of the immune system. Here we provide evidence that CD137 is selectively expressed on the surface of tumor endothelial cells. Hypoxia upregulated CD137 on murine endothelial cells. Treatment of tumor-bearing immunocompromised Rag(-/-) mice with agonist CD137 mAb did not elicit any measurable antiangiogenic effects. In contrast, agonist mAb stimulated tumor endothelial cells, increasing cell surface expression of the adhesion molecules intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E-selectin. When adoptively transferred into mice, activated T lymphocytes derived from CD137-deficient animals entered more avidly into tumor tissue after treatment with agonist mAb. This effect could be neutralized with anti-ICAM-1 and anti-VCAM-1 blocking antibodies. Thus, stimulation of CD137 not only enhanced T-cell activation but also augmented their trafficking into malignant tissue, through direct actions on the blood vessels that irrigate the tumor. Our findings identify an additional mechanism of action that can explain the immunotherapeutic effects of agonist CD137 antibodies. PMID- 21266357 TI - Multiple mutations and bypass mechanisms can contribute to development of acquired resistance to MET inhibitors. AB - Therapies targeting receptor tyrosine kinases have shown efficacy in molecularly defined subsets of cancers. Unfortunately, cancers invariably develop resistance, and overcoming or preventing resistance will ultimately be key to unleashing their full therapeutic potential. In this study, we examined how cancers become resistant to MET inhibitors, a class of drugs currently under clinical development. We utilized the highly sensitive gastric carcinoma cell line, SNU638, and two related MET inhibitors PHA-665752 and PF-2341066. To our surprise, we observed at least two mechanisms of resistance that arose simultaneously. Both resulted in maintenance of downstream PI3K (phosphoinositide 3-kinase)-AKT and MEK (MAP/ERK kinase)-ERK signaling in the presence of inhibitor. One mechanism, observed by modeling resistance both in vitro and in vivo, involved the acquisition of a mutation in the MET activation loop (Y1230). Structural analysis indicates that this mutation destabilizes the autoinhibitory conformation of MET and abrogates an important aromatic stacking interaction with the inhibitor. The other cause of resistance was activation of the epidermal growth factor receptor (EGFR) pathway due to increased expression of transforming growth factor alpha. Activation of EGFR bypassed the need for MET signaling to activate downstream signaling in these cells. This resistance could be overcome by combined EGFR and MET inhibition. Thus, therapeutic strategies that combine MET inhibitors capable of inhibiting Y1230 mutant MET in combination with anti EGFR-based therapies may enhance clinical benefit for patients with MET-addicted cancers. Importantly, these results also underscore the notion that a single cancer can simultaneously develop resistance induced by several mechanisms and highlight the daunting challenges associated with preventing or overcoming resistance. PMID- 21266359 TI - MicroRNA-1258 suppresses breast cancer brain metastasis by targeting heparanase. AB - Heparanase (HPSE) is a potent protumorigenic, proangiogenic, and prometastatic enzyme that is overexpressed in brain metastatic breast cancer (BMBC). However, little is known about the regulation of this potential therapeutic target in BMBC, which remains very poorly managed in the clinic. We hypothesized that HPSE gene expression might be regulated by micro RNA that might be exploited therapeutically. Using miRanda and RNAhybrid, we identified miR-1258 as a candidate micro RNA that may directly target HPSE and suppress BMBC. In support of our hypothesis, we found that miR-1258 levels inversely correlated with heparanase expression, enzymatic activity, and cancer cell metastatic propensities, being lowest in highly aggressive BMBC cell variants compared with either nontumorigenic or nonmetastatic human mammary epithelial cells. These findings were validated by analyses of miR-1258 and heparanase content in paired clinical specimens of normal mammary gland versus invasive ductal carcinoma, and primary breast cancer versus BMBC. In regulatory experiments, miR-1258 inhibited the expression and activity of heparanase in BMBC cells, whereas modulating heparanase blocked the phenotypic effects of miR-1258. In functional experiments, stable expression of miR-1258 in BMBC cells inhibited heparanase in vitro cell invasion and experimental brain metastasis. Together, our findings illustrate how micro RNA mechanisms are linked to brain metastatic breast cancer through heparanase control, and they offer a strong rationale to develop heparanase-based therapeutics for treatment of cancer patients with brain metastases, BMBC in particular. PMID- 21266361 TI - Intracellular CD24 inhibits cell invasion by posttranscriptional regulation of BART through interaction with G3BP. AB - We report a novel function for the CD24 molecule in pancreatic cancer cells. Intracellular CD24 is associated with stress granules that contain specific mRNAs and RNA-binding proteins that regulate mRNA stability and translation. Intracellular CD24 in stress granules is associated with G3BP, a phosphorylation dependent endoribonuclease. The vesicles in which the CD24/G3BP complex localizes are transported toward cell protrusions in migrating cells. We show that G3BP binds to and degrades Binder of Arl Two (BART) mRNA. BART was originally identified as a binding partner of ARL2, a small G-protein implicated as a regulator of microtubule dynamics and folding. Intracellular CD24 inhibits the specific endoribonuclease activity of G3BP toward BART mRNA in stress granules. We show that knockdown of CD24 increases retroperitoneal invasion and liver metastasis of pancreatic cancer cells in an orthotopic xenograft model, and that BART also prevents retroperitoneal invasion and liver metastasis of pancreatic cancer cells. Our results imply that surface CD24 may play a role in the inhibition of cell invasion and metastasis, and that intracellular CD24 inhibits invasiveness and metastasis through its influence on the posttranscriptional regulation of BART mRNA levels via G3BP RNase activity. PMID- 21266360 TI - DeltaNp63alpha confers tumor cell resistance to cisplatin through the AKT1 transcriptional regulation. AB - Strategies to address resistance to platin drugs are greatly needed in human epithelial cancers (e.g., ovarian, head/neck, and lung) where platins are used widely and resistance occurs commonly. We found that upon DeltaNp63alpha overexpression, AKT1 and phospho-AKT1 levels are upregulated in cancer cells. Investigations using gel-shift, chromatin immunoprecipitation and functional reporter assays implicated DeltaNp63alpha in positive regulation of AKT1 transcription. Importantly, we found that DeltaNp63alpha, AKT1, and phospho-AKT levels are greater in 2008CI3 CDDP-resistant ovarian cancer cells than in 2008 CDDP-sensitive cells. siRNA-mediated knockdown of DeltaNp63alpha expression dramatically decreased AKT1 expression, whereas knockdown of either DeltaNp63alpha or AKT1 decreased cell proliferation and increased death of ovarian and head/neck cancer cells. Conversely, enforced expression of DeltaNp63alpha increased cancer cell proliferation and reduced apoptosis. Together, our findings define a novel DeltaNp63alpha-dependent regulatory mechanism for AKT1 expression and its role in chemotherapeutic resistance of ovarian and head/neck cancer cells. PMID- 21266362 TI - Hydrophilic agarose macrobead cultures select for outgrowth of carcinoma cell populations that can restrict tumor growth. AB - Cancer cells and their associated tumors have long been considered to exhibit unregulated proliferation or growth. However, a substantial body of evidence indicates that tumor growth is subject to both positive and negative regulatory controls. Here, we describe a novel property of tumor growth regulation that is neither species nor tumor-type specific. This property, functionally a type of feedback control, is triggered by the encapsulation of neoplastic cells in a growth-restricting hydrogel composed of an agarose matrix with a second coating of agarose to form 6- to 8-mm diameter macrobeads. In a mouse cell model of renal adenocarcinoma (RENCA cells), this process resulted in selection for a stem cell like subpopulation which together with at least one other cell subpopulation drove colony formation in the macrobeads. Cells in these colonies produced diffusible substances that markedly inhibited in vitro and in vivo proliferation of epithelial-derived tumor cells outside the macrobeads. RENCA cells in monolayer culture that were exposed to RENCA macrobead-conditioned media exhibited cell-cycle accumulation in S phase due to activation of a G(2)/M checkpoint. At least 10 proteins with known tumor suppression functions were identified by analysis of RENCA macrobead-conditioned media, the properties of which offer opportunities to further dissect the molecular basis for tumor growth control. More generally, macrobead culture may permit the isolation of cancer stem cells and other cells of the stem cell niche, perhaps providing strategies to define more effective biologically based clinical approaches to treat neoplastic disease. PMID- 21266363 TI - Three-dimensional culture of mouse renal carcinoma cells in agarose macrobeads selects for a subpopulation of cells with cancer stem cell or cancer progenitor properties. AB - The culture of tumor cell lines in three-dimensional scaffolds is considered to more closely replicate the in vivo tumor microenvironment than the standard method of two-dimensional cell culture. We hypothesized that our method of encapsulating and maintaining viable and functional pancreatic islets in agarose agarose macrobeads (diameter 6-8 mm) might provide a novel method for the culture of tumor cell lines. In this report we describe and characterize tumor colonies that form within macrobeads seeded with mouse renal adenocarcinoma cells. Approximately 1% of seeded tumor cells survive in the macrobead and over several months form discrete elliptical colonies appearing as tumor cell niches with increasing metabolic activity in parallel to colony size. The tumor colonies demonstrate ongoing cell turnover as shown by BrdU incorporation and activated caspase-3 and TUNEL staining. Genes upregulated in the tumor colonies of the macrobead are likely adaptations to this novel environment, as well as an amplification of G(1)/S cell-cycle checkpoints. The data presented, including SCA 1 and Oct4 positivity and the upregulation of stem cell-like genes such as those associated with the Wnt pathway, support the notion that the macrobead selects for a subpopulation of cells with cancer stem cell or cancer progenitor properties. PMID- 21266364 TI - Insulin sensitivity is not associated with palmitoleate availability in obese humans. AB - We evaluated whether insulin resistance in obese people is associated with decreased plasma palmitoleate availability. Palmitoleate content (percentage and absolute concentrations) in FFA and VLDL was measured in obese subjects who were either insulin resistant (IR) or insulin sensitive (IS), based on assessment of multiorgan (skeletal muscle, liver, and adipose tissue) insulin sensitivity by using the hyperinsulinemic-euglycemic clamp procedure in conjunction with infusion of stable isotopically labeled tracers. Plasma palmitoleate concentration and the relative contribution of palmitoleate to total plasma FFA concentration in the IS group (0.018 +/- 0.002 mmol/l and 4.4% +/- 0.2%, respectively) were not significantly different than values in the IR group (0.023 +/- 0.003 mmol/l and 4.4% +/- 0.4%, respectively). Plasma VLDL-triglyceride palmitoleate concentration and the proportion of VLDL fatty acids as palmitoleate in the IS group (0.09 +/- 0.02 mmol/l and 5.7 +/- 0.3%, respectively) were also not significantly different than those in the IR group (0.16 +/- 0.04 mmol/l and 5.0% +/- 0.4%, respectively). These data demonstrate that decreased palmitoleate in plasma and in VLDL is not associated with insulin resistance in skeletal muscle, liver, or adipose tissue in obese people. PMID- 21266366 TI - Branch retinal artery occlusion following elective percutaneous coronary intervention. PMID- 21266365 TI - A simple desalting method for direct MALDI mass spectrometry profiling of tissue lipids. AB - Direct MALDI-mass spectrometry (MALDI-MS) profiling of tissue lipids often observes isobaric phosphatidylcholine (PC) species caused by the endogenous alkali metal ions that bias the relative abundance of tissue lipids. Fresh rat brain cryosections were washed with 70% ethanol (EtOH), water (H2O), or 150 mM ammonium acetate (NH4Ac), and the desalting effectiveness of each fluid was evaluated by MALDI-MS profiling of PC and sphingomyelin (SM) species in tissue and in the washing runoff. The results indicated that EtOH and H2O only partially desalted the tissue lipids, yet both substantially displaced the tissue lipids to the washing runoffs. On the other hand, NH4Ac effectively desalted the tissue lipids and produced a runoff containing no detectable PCs or SMs. NH4Ac wash also unveiled the underlying changes of PCs and SMs in the infarcted rat cortex previously masked by edema-caused increase of tissue sodium. The MS/MS of an isobaric PC in the infarcted cortex revealed the precursor change as the result of NH4Ac wash and confirmed the desalting effectiveness of such wash. Other than desalting, NH4Ac wash also removes contaminants in tissue, enhances the overall spectral quality, and benefits additionally in profiling of biological molecules in tissue. PMID- 21266367 TI - Circulatory support in severe aortic stenosis. PMID- 21266368 TI - Cardiac amyloidosis in full glory. PMID- 21266369 TI - Simulating Makrofol as a detector for neutron-induced recoils. AB - The response of solid-state nuclear track detector is extremely dependent on incident angles of neutrons, which determine the angular distribution of secondary particles. In this paper, the authors present a method to investigate the angular response of Makrofol detectors. Using the C++-based Monte-Carlo tool kit Geant4 in combination with SRIM and our MATLAB codes, we simulated the angular response of Makrofol. The simulations were based on the restricted energy loss model, and the concept of energy threshold and critical angle. Experiments were carried out with (252)Cf neutrons to verify the simulation results. PMID- 21266370 TI - Relative radiological risks derived from different TENORM wastes in Malaysia. AB - In Malaysia technologically enhanced naturally occurring radioactive materials (TENORM) wastes are mainly the product of the oil and gas industry and mineral processing. Among these TENORM wastes are tin tailing, tin slag, gypsum and oil sludge. Mineral processing and oil and gas industries produce large volume of TENORM wastes that has become a radiological concern to the authorities. A study was carried out to assess the radiological risk related to workers working at these disposal sites and landfills as well as to the members of the public should these areas be developed for future land use. Radiological risk was assessed based on the magnitude of radiation hazard, effective dose rates and excess cancer risks. Effective dose rates and excess cancer risks were estimated using RESRAD 6.4 computer code. All data on the activity concentrations of NORM in wastes and sludges used in this study were obtained from the Atomic Energy Licensing Board, Malaysia, and they were collected over a period of between 5 and 10 y. Results obtained showed that there was a wide range in the total activity concentrations (TAC) of nuclides in the TENORM wastes. With the exception of tin slag and tin tailing-based TENORM wastes, all other TENORM wastes have TAC values comparable to that of Malaysia's soil. Occupational Effective Dose Rates estimated in all landfill areas were lower than the 20 mSv y(-1) permissible dose limit. The average Excess Cancer Risk Coefficient was estimated to be 2.77*10(-3) risk per mSv. The effective dose rates for residents living on gypsum and oil sludge-based TENORM wastes landfills were estimated to be lower than the permissible dose limit for members of the public, and was also comparable to that of the average Malaysia's ordinary soils. The average excess cancer risk coefficient was estimated to be 3.19*10(-3) risk per mSv. Results obtained suggest that gypsum and oil sludge-based TENORM wastes should be exempted from any radiological regulatory control and should be considered radiologically safe for future land use. PMID- 21266371 TI - Questionnaire of executive function for dancers: an ecological approach. AB - There is a current debate about the ecological validity of executive function (EF) tests. Consistent with the verisimilitude approach, this research proposes the ballet executive scale (BES), a self-rating questionnaire that assimilates idiosyncratic executive behaviors of classical dance community. The BES was administrated to 149 adolescents, students of the Cuban Ballet School. Results present a Cronbach's alpha coefficient of .80 and a split-half Spearman-Brown coefficient r (SB) = .81. An exploratory factor analysis describes a bifactorial pattern of EF dimensions, with a self-regulation component, which explains more than 40% of variance, and a Developmental component, which accounts for more than 20% of variance. The questionnaire's total scores fit linear regression models with two external criteria of academic records, confirming concurrent validity. These findings support the hypothesis that the internalization of specific contextual cultural meanings has a mediating influence in the development of EF. PMID- 21266372 TI - Introducing English and German versions of the Adolescent Time Attitude Scale. AB - In this study, the authors report on the development of English and German versions of the Adolescent Time Attitude Scale (ATAS). The ATAS consists of six subscales assessing Past Positive, Past Negative, Present Positive, Present Negative, Future Positive, and Future Negative time attitudes. The authors describe the development of the scales and present data on the reliability and structural validity of ATAS scores in samples of American (N = 300) and German (N = 316) adolescents. Internal consistency estimates for scores on the English and German versions of the ATAS were in the .70 to .80 range. Confirmatory factor analyses indicated that a six-factor structure yielded the best fit for scores and that the scores were invariant across samples. PMID- 21266373 TI - Environment and women's reproductive health. AB - BACKGROUND: There is significant evidence that continuous and prolonged exposure to several endocrine disrupting chemicals (EDC) is a risk factor for reduced fertility and fecundity in women. There is also evidence that ED exposure has trans-generational effects. In this systematic review, we evaluate the evidence for an association between EDC exposure and women's reproductive health. METHODS: Studies were found by searching the PubMed database for articles published up to 2010. Associations between ED exposure and women's reproductive health reported in the PubMed database are summarized and classified as fertility and fecundity, pregnancy outcomes, transgenerational exposure and effects. RESULTS: Epidemiological studies on EDCs are not always consistent, in part due to limitations imposed by practical constraints. In order to make progress in this field, we recommend taking advantage of biomonitoring and biobanks, including the development of appropriate biomarkers, and taking into greater consideration modulating factors such as genetic polymorphisms and dietary habits. Further human studies are warranted with particular focus on impaired fertility/fecundity associated with currently widespread ED (e.g. bisphenol A, phthalates and polybrominated flame retardants). CONCLUSIONS: A detailed appraisal of compounds specifically related to adverse reproductive outcomes is very important for prevention and risk-communication strategies. Besides research needs, the current evidence is sufficient to prompt precautionary actions to protect women's reproductive health. PMID- 21266374 TI - Road traffic noise and stroke: a prospective cohort study. AB - AIMS: Epidemiological studies suggest that long-term exposure to road traffic noise increases the risk of cardiovascular disorders. The aim of this study was to investigate the relation between exposure to road traffic noise and risk for stroke, which has not been studied before. METHODS AND RESULTS: In a population based cohort of 57,053 people, we identified 1881 cases of first-ever stroke in a national hospital register between 1993-1997 and 2006. Exposure to road traffic noise and air pollution during the same period was estimated for all cohort members from residential address history. Associations between exposure to road traffic noise and stroke incidence were analysed in a Cox regression model with stratification for gender and calendar-year and adjustment for air pollution and other potential confounders. We found an incidence rate ratio (IRR) of 1.14 for stroke [95% confidence interval (CI): 1.03-1.25] per 10 dB higher level of road traffic noise (L(den)). There was a statistically significant interaction with age (P < 0.001), with a strong association between road traffic noise and stroke among cases over 64.5 years (IRR: 1.27; 95% CI: 1.13-1.43) and no association for those under 64.5 years (IRR: 1.02; 95% CI: 0.91-1.14). CONCLUSION: Exposure to residential road traffic noise was associated with a higher risk for stroke among people older than 64.5 years of age. PMID- 21266375 TI - Acute coronary syndrome and cocaine use: 8-year prevalence and inhospital outcomes. AB - AIMS: The use of cocaine as a recreational drug has increased in recent years. The aims of this study were to analyse the prevalence and in-hospital evolution of acute coronary syndrome (ACS) associated with cocaine consumption (ACS-ACC). METHODS AND RESULTS: Prospective analysis of ACS patients admitted to a coronary care unit from January 2001 to December 2008. During the study period, 2752 patients were admitted for ACS, and among these 479 were <=50 years of age. Fifty six (11.7%) patients had a medical history of cocaine use with an increase in prevalence from 6.8% in 2001 to 21.7% in 2008 (P = 0.035). Among patients younger than 30 years of age, 25% admitted to being users compared with 5.5% of those aged 45-50 years (P = 0.007). Similarly, the prevalence of positive urine tests for cocaine was four times higher in the younger patients (18.2 vs. 4.1%, P = 0.035). Acute coronary syndrome associated with cocaine consumption patients (n = 24; those who had a positive urine test for cocaine or who admitted to being users upon admission) had larger myocardial infarcts as indicated by troponin I levels (52.9 vs. 23.4 ng/mL, P < 0.001), lower the left ventricular ejection fraction (44.5 vs. 52.2%, P = 0.049), and increased in-hospital mortality (8.3 vs. 0.8%, P = 0.030). CONCLUSIONS: The association between cocaine use and ACS has increased significantly over the past few years. Young adults with ACS-ACC that require admission to the coronary care unit have greater myocardial damage and more frequent complications. PMID- 21266376 TI - Increased serum high-mobility group box-1 and cleaved receptor for advanced glycation endproducts levels and decreased endogenous secretory receptor for advanced glycation endproducts levels in diabetic and non-diabetic patients with heart failure. AB - AIMS: High-mobility group box-1 (HMGB1) is a ligand for the receptor for advanced glycation endproducts (RAGE). An HMGB1-RAGE interaction has been implicated in cardiac dysfunction. We assessed the association of HMGB1 and RAGE isoforms with heart failure (HF) in diabetic and non-diabetic patients. METHODS AND RESULTS: We assayed serum levels of HMGB1, cleaved RAGE (cRAGE), endogenous secretory RAGE (esRAGE), high-sensitivity C-reactive protein (hsCRP), and N-terminal pro-brain natriuretic peptide (NT-proBNP) in parallel with assessment of left ventricular volumes and function in 125 diabetic and 222 non-diabetic Chinese patients with chronic HF. Of the total, 79 diabetic patients without HF and 220 normal subjects served as diabetic and normal controls, respectively. Serum HMGB1, cRAGE, hsCRP, and NT-proBNP levels were higher and, in contrast, esRAGE levels lower in HF patients than in subjects without HF (for all; P < 0.01), with higher levels of cRAGE and hsCRP in diabetic HF vs. non-diabetic HF patients (P < 0.01). For HF patients-with or without diabetes-HMGB1 levels correlated positively with left ventricular end-diastolic and end-systolic volumes (r = 0.267 and r = 0.321, respectively) and NT-proBNP values (r = 0.497), and were inversely related to ejection fraction (r = -0.461; all P < 0.001). Serum cRAGE levels correlated with NT-proBNP values (r = 0.451) and New York Heart Association functional class (r = 0.402; both P < 0.001). Multivariable regression analysis revealed that HMGB1, cRAGE, and esRAGE were consistently associated with HF in diabetic and non diabetic patients. CONCLUSION: Heart failure patients have increased serum HMGB1 and cRAGE and decreased esRAGE levels, and these are related to the severity of HF in both diabetic and non-diabetic patients. Such associations are worth further investigation. PMID- 21266378 TI - Preventive effect of renin-angiotensin system inhibitor on left atrial remodelling in patients with chronic atrial fibrillation: long-term echocardiographic study. AB - AIMS: Left atrium (LA) gradually enlarges with the time course of atrial fibrillation (AF). The aim of this study was to examine whether the renin angiotensin system (RAS) inhibitor could prevent LA remodelling in patients with chronic AF. METHODS AND RESULTS: Forty-one patients with chronic non-valvular AF were enrolled and divided into the following two groups: the RAS group taking an RAS inhibitor and the non-RAS group not taking it. We compared echocardiographic parameters including LA volume at the beginning and the end of follow-up. Percent change of these parameters was calculated from the value at the end of follow-up divided by the value at the beginning of follow-up. An enlargement of LA volume index and a decrease in LA expansion fraction was significantly prevented in the RAS group. Administration of RAS inhibitors was significantly associated with the prevention of increasing LA volume in multivariate analysis. CONCLUSION: RAS inhibitors may prevent structural and functional degradation of LA in chronic non valvular AF. PMID- 21266377 TI - Predictors for the efficacy of naltrexone treatment in alcohol dependence: sweet preference. AB - AIMS: To analyse the possible associations between sweet preference and the efficacy of naltrexone treatment of alcohol dependence. METHODS: The preference for different concentrations of sucrose was evaluated in 78 participants diagnosed with alcohol dependence after treatment for 32 weeks with naltrexone or placebo without prior detoxification. RESULTS: A significant difference between naltrexone and placebo groups was found in the association between the preference for higher sucrose concentrations and relapses to heavy drinking. Higher sweet preference was significantly related to successful treatment measures in the naltrexone group but not in the placebo group. CONCLUSION: Sweet preference has a strong correlation to treatment outcomes with naltrexone, and sweet preference might be used as a predictor for better treatment results in alcoholics. Our study offers one possible new explanation of the clinical observation that naltrexone is not effective for every patient. PMID- 21266379 TI - Comparison of mitral valve area by pressure half-time and proximal isovelocity surface area method in patients with mitral stenosis: effect of net atrioventricular compliance. AB - AIMS: The aim of this study was to test the hypothesis that, unlike calculation of the mitral valve area (MVA) with the pressure half-time method (PHT), the proximal isovelocity surface area method (PISA) is not affected by changes in net atrioventricular compliance (C(n)). METHODS AND RESULTS: We studied 51 patients with mitral stenosis (MS) from two centres. MVA was assessed with the PISA (MVA(PISA)), PHT (MVA(PHT)), and planimetry (MVA(PLN), serving as the gold standard) method. C(n) was calculated with a previously validated equation using 2D echocardiography. MVA(PISA) closely correlated with MVA(PLN) (r = 0.96, P < 0.0001), while MVA(PHT) and MVA(PLN) showed a weaker but still good correlation (r = 0.69, P < 0.0001). The correlation between MVA(PHT) and MVA(PLN) for patients with C(n) between 4 and 6 mL/mmHg (considered to be normal) was excellent (r = 0.93, P < 0.0001), but that for patients with C(n) of less than 4 or more than 6 mL/mmHg was not as good (r = 0.64, P < 0.0001). Importantly, a significant inverse correlation was detected between the percentage difference among MVA(PHT), MVA(PLN), and C(n) (r = -0.77, P < 0.0001), but the line of fit was nearly flat for the percentage difference among MVA(PISA), MVA(PLN), and C(n) (r = 0.1, P = 0.388). CONCLUSION: MVA calculated with both the PISA and PHT methods correlated well with MVA calculated with the planimetry method. However, the PISA rather than PHT is recommended for patients with MS and extreme C(n) values because PISA, unlike PHT, is not affected by changes in C(n). PMID- 21266380 TI - Usefulness of real-time three-dimensional transoesophageal echocardiography in the assessment of chronic aortic dissection. AB - AIMS: To assess the usefulness of three-dimensional transoesophageal echocardiography (3D-TOE) vs. two-dimensional (2D)-TOE in the evaluation of morphological and dynamic findings of aortic dissection, and compare the results with those obtained by multi-slice computed tomography (CT). METHODS AND RESULTS: Twenty-six patients (21 men and 5 women, median age: 67 years, range: 28-74 years) diagnosed of chronic aortic dissection with patent false lumen were studied. A comprehensive 2D-TOE and a real-time 3D-TOE study targeted at assessing dissection variables were performed and compared with CT within 3 months. Both 3D-TOE and 2D-TOE visualized the intimal flap extension and presence of flow in aortic dissection lumina in the same aortic segments. Three dimensional TOE correctly identified true lumen in all cases, being superior to 2D-TOE in three cases with a spiroidal course of the dissection in descending aorta. Maximum entry tear diameter measured by 3D-TOE showed a better correlation with CT than 2D-TOE (0.96 and 0.87, P< 0.001, respectively). Compared with CT, 2D TOE underestimated maximum entry tear diameter (-1.75 +/- 3.28 mm, P< 0.01) but 3D-TOE did not (-0.20 +/- 1.92 mm, P: n.s.). However, entry tear area measured by 3D-TOE and CT showed the best correlation (r: 0.97) and agreement (0.05 +/- 0.20 cm(2), P: n.s.). CONCLUSION: Three-dimensional TOE provides additional information to 2D-TOE in aortic dissection assessment, particularly in entry tear size quantification. Agreement between entry tear area defined by 3D-TOE and CT was excellent. Three-dimensional TOE permits better morphological and dynamic understanding of aortic dissection when the flap is spiroidal. PMID- 21266381 TI - Rapid identification of mutations in GJC2 in primary lymphoedema using whole exome sequencing combined with linkage analysis with delineation of the phenotype. AB - BACKGROUND: Primary lymphoedema describes a chronic, frequently progressive, failure of lymphatic drainage. This disorder is frequently genetic in origin, and a multigenerational family in which eight individuals developed postnatal lymphoedema of all four limbs was ascertained from the joint Lymphoedema/Genetic clinic at St George's Hospital. METHODS: Linkage analysis was used to determine a locus, and exome sequencing was employed to look for causative variants. RESULTS: Linkage analysis revealed cosegregation of a 16.1 Mb haplotype on chromosome 1q42 that contained 173 known or predicted genes. Whole exome sequencing in a single affected individual was undertaken, and the search for the causative variant was focused to within the linkage interval. This approach revealed two novel non synonymous single nucleotide substitutions within the chromosome 1 locus, in NVL and GJC2. NVL and GJC2 were sequenced in an additional cohort of individuals with a similar phenotype and non-synonymous variants were found in GJC2 in four additional families. CONCLUSION: This report demonstrates the power of exome sequencing efficiently applied to a traditional positional cloning pipeline in disease gene discovery, and suggests that the phenotype produced by GJC2 mutations is predominantly one of 4 limb lymphoedema. PMID- 21266382 TI - LRPPRC mutations cause a phenotypically distinct form of Leigh syndrome with cytochrome c oxidase deficiency. AB - BACKGROUND: The natural history of all known patients with French-Canadian Leigh disease (Saguenay-Lac-St-Jean cytochrome c oxidase deficiency, MIM220111, SLSJ COX), the largest known cohort of patients with a genetically homogeneous, nuclear encoded congenital lactic acidosis, was studied. RESULTS: 55 of 56 patients were homozygous for the A354V mutation in LRPPRC. One was a genetic compound (A354V/C1277Xdel8). Clinical features included developmental delay, failure to thrive, characteristic facial appearance and, in 90% of patients, acute crises that have not previously been detailed, either metabolic (fulminant lactic acidosis) and/or neurological (Leigh syndrome and/or stroke-like episodes). Survival ranged from 5 days to >30 years. 46/56 patients (82%) died, at a median age of 1.6 years. Of 73 crises, 38 (52%) were fatal. The immediate causes of death were multiple organ failure and/or Leigh disease. Major predictors of mortality during crises (p<0.005) were hyperglycaemia, hepatic cytolysis, and altered consciousness at admission. Compared to a group of SURF1 deficient Leigh syndrome patients assembled from the literature, SLSJ-COX is distinct by the occurrence of metabolic crises, leading to earlier and higher mortality (p=0.001). CONCLUSION: SLSJ-COX is clinically distinct, with acute fatal acidotic crises on a backdrop of chronic moderate developmental delay and hyperlactataemia. Leigh syndrome is common. Stroke-like episodes can occur. The Leigh syndrome of SLSJ-COX differs from that of SURF1-related COX deficiency. SLSJ-COX has a different spectrum of associated abnormalities, acidotic crises being particularly suggestive of LRPPRC related Leigh syndrome. Even among A354V homozygotes, pronounced differences in survival and severity occur, showing that other genetic and/or environmental factors can influence outcome. PMID- 21266384 TI - DICER1 syndrome: clarifying the diagnosis, clinical features and management implications of a pleiotropic tumour predisposition syndrome. AB - BACKGROUND: Constitutional DICER1 mutations were recently reported to cause familial pleuropulmonary blastoma (PPB). AIM: To investigate the contribution and phenotypic spectrum of constitutional and somatic DICER1 mutations to cancer. METHODS AND RESULTS: The authors sequenced DICER1 in constitutional DNA from 823 unrelated patients with a variety of tumours and in 781 cancer cell lines. Constitutional DICER1 mutations were identified in 19 families including 11/14 with PPB, 2/3 with cystic nephroma, 4/7 with ovarian Sertoli-Leydig-type tumours, 1/243 with Wilms tumour (this patient also had a Sertoli-Leydig tumour), 1/1 with intraocular medulloepithelioma (this patient also had PPB), 1/86 with medulloblastoma/infratentorial primitive neuroectodermal tumour, and 1/172 with germ cell tumour. The inheritance was investigated in 17 families. DICER1 mutations were identified in 25 relatives: 17 were unaffected, one mother had ovarian Sertoli-Leydig tumour, one half-sibling had cystic nephroma, and six relatives had non-toxic thyroid cysts/goitre. Analysis of eight tumours from DICER1 mutation-positive patients showed universal retention of the wild-type allele. DICER1 truncating mutations were identified in 4/781 cancer cell lines; all were in microsatellite unstable lines and therefore unlikely to be driver mutations. CONCLUSION: Constitutional DICER1 haploinsufficiency predisposes to a broad range of tumours, making a substantial contribution to PPB, cystic nephroma and ovarian Sertoli-Leydig tumours, but a smaller contribution to other tumours. Most mutation carriers are unaffected, indicating that tumour risk is modest. The authors define the clinical contexts in which DICER1 mutation testing should be considered, the associated tumour risks, and the implications for at-risk individuals. They have termed this condition 'DICER1 syndrome'. ACCESSION NUMBERS: The cDNA Genbank accession number for the DICER1 sequence reported in this paper is NM_030621.2. PMID- 21266383 TI - Clinical features distinguish childhood chordoma associated with tuberous sclerosis complex (TSC) from chordoma in the general paediatric population. AB - BACKGROUND: Chordoma, an age-dependent rare cancer, arises from notochordal remnants. Fewer than 5% of chordomas occur in children. Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous syndrome characterised by abnormal tissue growths in multiple organ systems. Reports of chordoma in children with TSC suggest that TSC1 and TSC2 mutations may contribute to chordoma aetiology. METHODS: To determine whether the 10 TSC-associated childhood chordomas reported in the literature are representative of chordoma in the general paediatric population, the authors compared age at diagnosis, primary site and outcome in them with results from a systematic assessment of 65 paediatric chordoma cases reported to the US population-based cancer registries contributing to the SEER Program of the National Cancer Institute. RESULTS: TSC associated paediatric chordomas differed from chordomas in the general paediatric population: median age at diagnosis (6.2 months, TSC, vs 12.5 years, SEER); anatomical site (40% sacral, TSC, vs 9.4% sacral, SEER); and site-specific age at diagnosis (all four sacral chordomas diagnosed during the fetal or neonatal period, TSC, vs all six sacral chordomas diagnosed at >15 years, SEER). Finally, three of four patients with TSC-associated sacral chordoma were alive and tumour free at 2.2, 8 and 19 years after diagnosis versus a median survival of 36 months among paediatric patients with sacral chordoma in SEER. CONCLUSIONS: These results strengthen the association between paediatric chordoma and TSC. Future clinical and molecular studies documenting the magnitude and clinical spectrum of the joint occurrence of these two diseases should provide the basis for delineating the biological relationship between them. PMID- 21266385 TI - Ethical issues related to the access to orphan drugs in Brazil: the case of mucopolysaccharidosis type I. AB - BACKGROUND/AIMS: Mucopolysaccharidosis type I (MPS I) is a rare lysosomal storage disorder treated with bone marrow transplantation or enzyme replacement therapy with laronidase, a high-cost orphan drug. Laronidase was approved by the US Food and Drug Administration and the European Medicines Agency in 2003 and by the Brazilian National Health Surveillance Agency in 2005. Many Brazilian MPS I patients have been receiving laronidase despite the absence of a governmental policy regulating access to the drug. Epidemiological and treatment data concerning MPS I are scarce. This study aims to present a demographic profile of Brazilian patients with MPS I, describe the routes of access to laronidase in Brazil, and discuss associated ethical issues relating to public funding of orphan drugs. METHODS: In this cross-sectional observational study, data were collected nationwide between January and September 2008 from physicians, public institutions and non-governmental organisations involved with diagnosis and treatment of MPS I, using two data collection instruments specifically designed for this purpose. RESULTS: The minimum prevalence of MPS I in Brazil was estimated at 1/2,700,000. Most patients (69.8%) were younger than 15 years; 60 (88.2%) received laronidase. The most common route of access to the drug was through lawsuits (86.6%). CONCLUSIONS: In Brazil, MPS I is predominantly a paediatric illness. Even though the cost of laronidase treatment is not officially covered by the Brazilian government, most MPS I patients receive the drug, usually through litigation. This gives rise to major ethical conflicts concerning drug access in a low-resource context. The Brazilian health policy framework lacks evidence-based clinical protocols for the distribution of orphan drugs. PMID- 21266386 TI - Effect of ethnicity, gender and drug use history on achieving high rates of affirmative informed consent for genetics research: impact of sharing with a national repository. AB - AIM: Genetic research representative of the population is crucial to understanding the underlying causes of many diseases. In a prospective evaluation of informed consent we assessed the willingness of individuals of different ethnicities, gender and drug dependence history to participate in genetic studies in which their genetic sample could be shared with a repository at the National Institutes of Health. METHODS: Potential subjects were recruited from the general population through the use of flyers and referrals from previous participants and clinicians with knowledge of our study. They could consent to 11 separate choices so that they could specify how and with whom their genetic sample could be shared. Rates of affirmative consent were then analysed by gender, ethnicity and drug dependence history. RESULTS: Of 1416 volunteers enrolled, 99.7% gave affirmative informed consent for studies of addiction conducted in our laboratory. No significant difference was found for participation in genetic studies conducted in our laboratory by gender, ethnicity or drug dependence history. Over all 11 questions, individuals with a history of drug use were more likely to agree to consent to participate in our study than were healthy volunteers. CONCLUSION: A high percentage of each category of gender, ethnicity and drug history, gave affirmative consent at all levels. The level of detail in and the amount of time spent reviewing the informed consent, and a relationship of trust with the clinical investigator may contribute to this outcome. PMID- 21266387 TI - Authorship policies of bioethics journals. AB - Inappropriate authorship is a common problem in biomedical research and may be becoming one in bioethics, due to the increase in multiple authorship. This paper investigates the authorship policies of bioethics journals to determine whether they provide adequate guidance for researchers who submit articles for publication, which can help deter inappropriate authorship. It was found that 63.3% of bioethics journals provide no guidance on authorship; 36.7% provide guidance on which contributions merit authorship, 23.3% provide guidance on which contributions do not merit authorship, 23.3% require authors to take responsibility for their contributions or for the article as a whole, 20% provide guidance on which contributions merit an acknowledgement but not authorship, 6.7% require authors to describe their contributions, and only 3.3% distinguish between authorship in empirical and conceptual research. To provide authors with effective guidance and promote integrity in bioethics research, bioethics journals should adopt authorship policies that address several important topics, such as the qualifications for authorship, describing authorship contributions, taking responsibility for the research and the difference between authorship in empirical and conceptual research. PMID- 21266388 TI - Parents' experiences of newborn screening for genetic susceptibility to type 1 diabetes. AB - Advances in genomic medicine have lead to debate about the potential inclusion of genetic tests for susceptibility to common complex disorders in newborn screening programmes. Empirical evidence concerning psychosocial reactions to genetic testing is a crucial component of both ethical debate and policy development, but while there has been much speculation concerning the possible psychosocial impact of screening newborns for genetic susceptibilities, there remains a paucity of data. The aim of the study reported here is to provide some of this missing empirical evidence, using type 1 diabetes as an example of a common disorder with multiple significant genetic contributors to its aetiology. Semi-structured interviews were conducted with 11 parents of babies who had received increased risk results in a study that involved newborn screening for genetic susceptibility to type 1 diabetes. Interpretative phenomenological analysis was used to evaluate the data. The interview data suggest that the probabilistic nature of results of genetic susceptibility tests impacts upon all aspects of parents' psychosocial reactions, resulting in a complex and dynamic process quite different to that described in relation to current newborn screening programmes. While parents generally reported fairly minor levels of concern in response to news of their child's increased genetic risk, these worries frequently recurred, and perception of risk also varied and fluctuated over time. Both individual and contextual factors appeared to interact with the inherent uncertainty of the test result to contribute to the dynamic nature of parental reactions, and their behavioural responses. The implications of these findings for future research and for the debate concerning potential expansion of newborn screening are discussed. PMID- 21266389 TI - Rethinking scientific responsibility. AB - Researchers should be made co-responsible for the wider consequences of their research focus and the application of their findings. This paper describes a meta reflection procedure that can be used as a tool to enhance scientific responsibility and reflective practice. The point of departure is that scientific practice is situated in power relations, has direction and, consequently, power implications. The contextual preconditions and implications of research should be stated and discussed openly. The reflection method aims at revealing both upstream elements, such as for instance preconceptions, and downstream elements, for example, public consequences of research. The validity of research might improve from such discussions. Validity should preferably be understood as a broader concept than the methodological concerns in science. PMID- 21266390 TI - Veterinary surgeons' attitudes towards physician-assisted suicide: an empirical study of Swedish experts on euthanasia. AB - AIM: To examine the hypothesis that knowledge about physician-assisted suicide (PAS) and euthanasia is associated with a more restrictive attitude towards PAS. DESIGN: A questionnaire about attitudes towards PAS, including prioritization of arguments pro and contra, was sent to Swedish veterinary surgeons. The results were compared with those from similar surveys of attitudes among the general public and physicians. PARTICIPANTS: All veterinary surgeons who were members of the Swedish Veterinary Association and had provided an email address (n=2421). MAIN OUTCOME MEASURES: Similarities or differences in response pattern between veterinary surgeons, physicians and the general public. RESULTS: The response pattern among veterinary surgeons and the general public was almost similar in all relevant aspects. Of the veterinarians 75% (95% CI 72% to 78%) were in favour of PAS, compared with 73% (95% CI 69% to 77%) among the general public. Only 10% (95% CI 5% to 15%) of the veterinary surgeons were against PAS, compared with 12% (95% CI 5% to 19%) among the general public. Finally, 15% (95% CI 10% to 21%) of veterinarians were undecided, compared with 15% (95% CI 8% to 22%) among the general public. Physicians had a more restrictive attitude to PAS than the general public. CONCLUSIONS: Since veterinary surgeons have frequent practical experience of euthanasia in animals, they do have knowledge about what euthanasia really is. Veterinary surgeons and the general public had an almost similar response pattern. Accordingly it seems difficult to maintain that knowledge about euthanasia is unambiguously associated with a restrictive attitude towards PAS. PMID- 21266391 TI - Child-friendly healthcare: delivering on the right to be heard. PMID- 21266392 TI - Trafficking of persons for the removal of organs and the admission of guilt of a South African hospital. PMID- 21266393 TI - Negligent antenatal disclosure and management of labour. PMID- 21266394 TI - A population-based cohort study of HRT use and breast cancer in Korea. AB - The incidence of breast cancer has recently been ranked first in Korea. This is a population-based cohort study that aims to evaluate the risk of breast cancer from the use of hormone replacement therapy (HRT). A total of 9579 participants were observed between January 1998 and June 2004; 6108 women who took HRT constituted the HRT group, and 3471 women who did not take HRT constituted the non-HRT group. Using the database from the Korea Central Cancer Registry, the authors examined the incidence of breast cancer from HRT. A total of 26 cases of breast cancer developed in the HRT group as compared with the 13 cases in the non HRT group, during the follow-up period. The relative risk of developing breast cancer in the HRT group was 1.16 times higher than in the non-HRT group, with a population attributable risk of 29.9%. The risk of breast cancer in the HRT group increased when the risk factors were adjusted in the model. PMID- 21266395 TI - Preparedness against an influenza pandemic of the frontline health facilities in southern Thailand: factor and cluster analyses. AB - Preparedness at the frontline health level is essential for early detection, response, and prevention of the spread of an influenza pandemic in a community. This study aimed to assess and document patterns of basic preparedness for a threat of an influenza pandemic of the frontline health facilities in southern Thailand. A cross-sectional assessment was conducted among health centers. Key staffs were asked to complete a checklist consisting of facility access plan, surveillance, infection control, risk communication and health information dissemination, and health alert network and information technology. RESULTS: showed that the frontline health facilities were not well prepared for the threat in the early stages of a pandemic. Using cluster analysis, 6 variation patterns of preparedness were identified, with infection control being the weakest. Grassroots healthcare should be encouraged and supported to increase capacities in preparedness against influenza pandemics. Periodical monitoring by higher levels is needed. PMID- 21266396 TI - Socioeconomic correlates of reproductive morbidity among adolescent girls in Sikkim, India. AB - The present study investigates the prevalence of reproductive health morbidities, treatment-seeking behavior, and its association with sociodemographic correlates among unmarried and married adolescent girls of Sikkim. The study sample includes 1250 adolescent girls randomly selected from both urban and rural blocks of the State. Information on socioeconomic and demographic characteristics, prevalence of reproductive health morbidities, and treatment-seeking behavior was collected using standard pretested questionnaires. RESULTS: of the study indicate that the prevalence of reproductive health morbidities among both married and unmarried girls is quite high. Age, media exposure, and economic status emerged as significant correlates of treatment-seeking practices among both married and unmarried girls. High prevalence of reproductive health morbidity in this vulnerable group, particularly in rural settings, requires urgent intervention of health planners. This study reinforces an indirect and mediatory role of socioeconomic and demographic factors in the prevalence of reproductive health morbidities and associated treatment-seeking behaviors. PMID- 21266397 TI - Pulsed brachytherapy: a modelled consideration of repair parameter uncertainties and their influence on treatment duration extension and daytime-only "block schemes". AB - OBJECTIVES: The radiobiological modelling of all types of protracted brachytherapy is susceptible to uncertainties in the values of tissue repair parameters. Although this effect has been explored for many aspects of pulsed brachytherapy (PB), it is usually considered within the constraint of a fixed brachytherapy treatment time. Here the impact of repair parameter uncertainty is assessed for PB treatments of variable duration. The potential use of "block schemes" (blocks of PB pulses separated by night-time gaps) is also investigated. METHODS: PB schedule constraints are based on the cervical cancer protocols of the Royal Marsden Hospital (RMH), but the methodology is applicable to any combination of starting schedule and treatment constraint. Calculations are performed using the biologically effective dose (BED) as a tissue-specific comparison metric. The ratio of normal tissue BED to tumour BED is considered for PB regimens with varying total pulse numbers and/or "block-schemes". RESULTS: For matched brachytherapy duration, PB has a good "window of opportunity" relative to the existing RMH continuous low dose rate (CLDR) practice for all modelled repair half-times. The most clear-cut route to radiobiological optimisation of PB is via modest temporal extension of the PB regimen relative to the CLDR reference. This option may be practicable for those centres with scope to extend their relatively short CLDR treatment durations. CONCLUSION: Although daytime-only "block-scheme" PB for cervical cancer has not yet been employed clinically, the possibilities appear to be theoretically promising, providing the overall (external beam plus brachytherapy) treatment duration is not extended relative to current practice, such that additional tumour repopulation becomes a concern. PMID- 21266398 TI - Repair kinetic considerations in particle beam radiotherapy. AB - OBJECTIVES: A second-order repair kinetics model is developed to predict damage repair rates following low or high linear energy transfer (LET) irradiations and to assess the amount of unrepairable damage produced by such radiations. The model is a further development of an earlier version designed to test if low-LET radiation repair processes could be quantified in terms of second-order kinetics. The newer version allows calculation of both the repair rate of the proportion of DNA damages that repair according to second-order kinetics and the proportion of DNA damages that do not repair. METHODS: The original and present models are intercompared in terms of their goodness-of-fit to a number of data sets obtained from different ion beams. The analysis demonstrates that the present model provides a better fit to the data in all cases studied. RESULTS: The proportions of unrepairable damage created by radiations of different LET predicted by the new model correspond well with previous studies on the increased effectiveness of high-LET radiations in inducing reproductive cell death. The results show that the original model may underestimate the proportion of unrepaired damage at any given time after its creation as well as failing to predict very slow or unrepairable damage components, which may result from high-LET irradiation. CONCLUSION: It is suggested that the second-order model presented here offers a more realistic view of the patterns of repair in cell lines or tissues exposed to high-LET radiation. PMID- 21266399 TI - Adult patient radiation doses from non-cardiac CT examinations: a review of published results. AB - OBJECTIVES: CT is a valuable tool in diagnostic radiology but it is also associated with higher patient radiation doses compared with planar radiography. The aim of this article is to review patient dose for the most common types of CT examinations reported during the past 19 years. METHODS: Reported dosimetric quantities were compared with the European diagnostic reference levels (DRLs). Effective doses were assessed with respect to the publication year and scanner technology (i.e. single-slice vs multislice). RESULTS: Considerable variation of reported values among studies was attributed to variations in both examination protocol and scanner design. Median weighted CT dose index (CTDI(w)) and dose length product (DLP) are below the proposed DRLs; however, for individual studies the DRLs are exceeded. Median reported effective doses for the most frequent CT examinations were: head, 1.9 mSv (0.3-8.2 mSv); chest, 7.5 mSv (0.3-26.0 mSv); abdomen, 7.9 mSv (1.4-31.2 mSv); and pelvis, 7.6 mSv (2.5-36.5 mSv). CONCLUSION: The introduction of mechanisms for dose reduction resulted in significantly lower patient effective doses for CT examinations of the head, chest and abdomen reported by studies published after 1995. Owing to the limited number of studies reporting patient doses for multislice CT examinations the statistical power to detect differences with single-slice scanners is not yet adequate. PMID- 21266400 TI - Does the breast cancer age at diagnosis differ by ethnicity? A study on immigrants to Sweden. AB - BACKGROUND: Age-specific incidence rates for breast cancer in low-risk and high risk ethnic populations differ by age at which the incidence maximum is reached: around 50 years in low-risk populations and over 60 years in high-risk populations. The interpretation of these differences remains unsettled, one line primarily referring to biological differences, the second one to cohort effects of rapidly increasing rates in young populations, and the third one to incomplete registration of cancer in the elderly. METHODS: The nationwide Family-Cancer Database was used to analyze standardized incidence ratios (SIRs) and age at diagnosis of breast cancer in female immigrants to Sweden by their region of origin compared with women native to Sweden matched on birth year and other relevant factors. RESULTS: We showed first that the SIRs for breast cancer were lower in many immigrant groups compared with natives of Sweden; women from Turkey had the lowest SIR of 0.45, followed by those from Chile (0.54) and Southeast Asia (0.57). Women from nine regions showed an earlier mean age at diagnosis than their matched Swedish controls, the largest differences being 5.5 years for women from Turkey, 5.1 years for those from Asian Arab and "Other African" countries, 4.3 years for those from Iran, and 4.0 years for those from Iraq. CONCLUSIONS: The results show that in many immigrant groups, the diagnostic age is earlier (<50 years) than in natives of Sweden (>50 years), suggesting that true biological factors underlie the differences. These factors may explain much of the international variation in breast cancer incidence. Identifying these factors should advance understanding of breast cancer etiology and prevention. PMID- 21266401 TI - Treatment outcome and prognostic factors for patients with bone-only metastases of breast cancer: a single-institution retrospective analysis. AB - PURPOSE: Limited information is available about the optimal management and clinical outcome of bone-only metastases in breast cancer patients. The objective of this study was to define prognostic factors for patients with bone-only metastases. Our second objective was to compare progression-free survival (PFS) and overall survival (OS) between patients with hormone receptor (HR)(+) tumors and bone-only metastases who received combinatory therapy (chemotherapy followed by endocrine therapy, or endocrine therapy combined with molecular targeted therapy) and those treated with endocrine or chemotherapy alone. PATIENTS AND METHODS: We retrospectively identified 351 breast cancer patients diagnosed with bone-only metastasis in 1997-2008 at our institution. RESULTS: Patients with metastasis detected at the time of their primary breast cancer diagnosis (rather than at recurrence), a single metastasis, or asymptomatic bone disease had a longer PFS interval, and patients with a performance status of 0-1, a single metastasis, or asymptomatic bone disease had a longer OS time. Among patients with HR(+) human epidermal growth factor receptor (HER)-2(-) disease, combinatory therapy was associated with longer PFS and OS times than with endocrine therapy. In multivariate analyses, combinatory therapy was not associated with longer PFS or OS times than with endocrine therapy. Among patients with HER-2(+) disease, trastuzumab led to a longer PFS interval but no difference in the OS time. CONCLUSION: Our results indicate that, for HR(+) disease, a prospective trial of chemotherapy followed by endocrine therapy is warranted to determine whether it prolongs survival more than endocrine therapy alone in patients with bone-only metastases. PMID- 21266402 TI - Neonatal outcomes of preterm infants in breech presentation according to mode of birth in Canadian NICUs. AB - BACKGROUND: Many medical practitioners have adopted the practice of caesarean section for preterm infants in breech presentation based on term infant data. Some studies have highlighted deleterious effects on survival, such as intraventricular haemorrhage and periventricular leucomalacia, while others have reported no difference from the outcomes after vaginal delivery. OBJECTIVE: To compare outcomes of preterm infants of <=32 weeks' gestational age who were in breech position at the time of birth according to mode of birth in Canadian neonatal intensive care units (NICUs). SETTINGS: 29 Canadian NICUs. DESIGN: Neonates admitted to participating NICUs in the Canadian Neonatal Network between 2003 and 2007 were included in this retrospective study. Infants who were in breech position at the time of birth were divided into two groups: vaginal birth (VB) and caesarean section (CS). Data on common neonatal outcomes were compared using univariate and multivariate logistic regression. MAIN OUTCOME MEASURES: Neonatal mortality and other neonatal morbidities. RESULTS: Of 3552 preterm infants in breech position at birth, 2937 (83%) were delivered by CS and 615 (17%) by VB. Multivariate regression analysis with adjustment for perinatal risk factors indicated that VB was associated with an increased risk of death (OR 1.7; 95% CI 1.3 to 2.3), chronic lung disease (OR 1.5; 95% CI 1.1 to 1.9) and severe retinopathy of prematurity (OR 1.6; 95% CI 1.1 to 2.3). CONCLUSION: Vaginal birth for preterm infants in breech presentation is possibly associated with a higher risk of adverse neonatal outcomes compared with caesarean birth in Canadian NICUs. It is not clear whether adverse outcomes are due to the mode of delivery or whether breech birth is associated with other risk factors, an issue that can only be resolved by a randomised controlled trial. PMID- 21266403 TI - An interview with Margaret Buckingham: President of the French Society of Developmental Biology. [Interviewed by Eva Amsen]. PMID- 21266404 TI - What's all the noise about developmental stochasticity? AB - In October 2010, researchers from diverse backgrounds collided at the historic Cumberland Lodge (Windsor, UK) to discuss the role of randomness in cell and developmental biology. Organized by James Briscoe and Alfonso Marinez-Arias, The Company of Biologists' workshop was the latest in a series of meetings aimed at encouraging interdisciplinary interactions between biologists. This aim was reflected in talks at this workshop that ranged from the tissue to the cellular scale, and that integrated experimental and theoretical approaches to examining stochastic behavior in diverse systems. PMID- 21266405 TI - Sox9+ ductal cells are multipotent progenitors throughout development but do not produce new endocrine cells in the normal or injured adult pancreas. AB - One major unresolved question in the field of pancreas biology is whether ductal cells have the ability to generate insulin-producing beta-cells. Conclusive examination of this question has been limited by the lack of appropriate tools to efficiently and specifically label ductal cells in vivo. We generated Sox9CreER(T2) mice, which, during adulthood, allow for labeling of an average of 70% of pancreatic ductal cells, including terminal duct/centroacinar cells. Fate mapping studies of the Sox9(+) domain revealed endocrine and acinar cell neogenesis from Sox9(+) cells throughout embryogenesis. Very small numbers of non beta endocrine cells continue to arise from Sox9(+) cells in early postnatal life, but no endocrine or acinar cell neogenesis from Sox9(+) cells occurs during adulthood. In the adult pancreas, pancreatic injury by partial duct ligation (PDL) has been suggested to induce beta-cell regeneration from a transient Ngn3(+) endocrine progenitor cell population. Here, we identify ductal cells as a cell of origin for PDL-induced Ngn3(+) cells, but fail to observe beta-cell neogenesis from duct-derived cells. Therefore, although PDL leads to activation of Ngn3 expression in ducts, PDL does not induce appropriate cues to allow for completion of the entire beta-cell neogenesis program. In conclusion, although endocrine cells arise from the Sox9(+) ductal domain throughout embryogenesis and the early postnatal period, Sox9(+) ductal cells of the adult pancreas no longer give rise to endocrine cells under both normal conditions and in response to PDL. PMID- 21266407 TI - Feedback regulation of Drosophila BMP signaling by the novel extracellular protein larval translucida. AB - The cellular response to the Drosophila BMP 2/4-like ligand Decapentaplegic (DPP) serves as one of the best-studied models for understanding the long-range control of tissue growth and pattern formation during animal development. Nevertheless, fundamental questions remain unanswered regarding extracellular regulation of the ligand itself, as well as the nature of the downstream transcriptional response to BMP pathway activation. Here, we report the identification of larval translucida (ltl), a novel target of BMP activity in Drosophila. Both gain- and loss-of-function analyses implicate LTL, a leucine-rich repeat protein, in the regulation of wing growth and vein patterning. At the molecular level, we demonstrate that LTL is a secreted protein that antagonizes BMP-dependent MAD phosphorylation, indicating that it regulates DPP/BMP signaling at or above the level of ligand-receptor interactions. Furthermore, based on genetic interactions with the DPP-binding protein Crossveinless 2 and biochemical interactions with the glypican Dally-like, we propose that LTL acts in the extracellular space where it completes a novel auto-regulatory loop that modulates BMP activity. PMID- 21266406 TI - Specification of ion transport cells in the Xenopus larval skin. AB - Specialized epithelial cells in the amphibian skin play important roles in ion transport, but how they arise developmentally is largely unknown. Here we show that proton-secreting cells (PSCs) differentiate in the X. laevis larval skin soon after gastrulation, based on the expression of a 'kidney-specific' form of the H(+)v-ATPase that localizes to the plasma membrane, orthologs of the Cl( )/HCO(-)(3) antiporters ae1 and pendrin, and two isoforms of carbonic anhydrase. Like PSCs in other species, we show that the expression of these genes is likely to be driven by an ortholog of foxi1, which is also sufficient to promote the formation of PSC precursors. Strikingly, the PSCs form in the skin as two distinct subtypes that resemble the alpha- and beta-intercalated cells of the kidney. The alpha-subtype expresses ae1 and localizes H(+)v-ATPases to the apical plasma membrane, whereas the beta-subtype expresses pendrin and localizes the H(+)v-ATPase cytosolically or basolaterally. These two subtypes are specified during early PSC differentiation by a binary switch that can be regulated by Notch signaling and by the expression of ubp1, a transcription factor of the grainyhead family. These results have implications for how PSCs are specified in vertebrates and become functionally heterogeneous. PMID- 21266408 TI - Gbx2 and Fgf8 are sequentially required for formation of the midbrain-hindbrain compartment boundary. AB - In vertebrates, the common expression border of two homeobox genes, Otx2 and Gbx2, demarcates the prospective midbrain-hindbrain border (MHB) in the neural plate at the end of gastrulation. The presence of a compartment boundary at the MHB has been demonstrated, but the mechanism and timing of its formation remain unclear. We show by genetic inducible fate mapping using a Gbx2(CreER) knock-in mouse line that descendants of Gbx2(+) cells as early as embryonic day (E) 7.5 do not cross the MHB. Without Gbx2, hindbrain-born cells abnormally populate the entire midbrain, demonstrating that Gbx2 is essential for specifying hindbrain fate. Gbx2(+) and Otx2(+) cells segregate from each other, suggesting that mutually exclusive expression of Otx2 and Gbx2 in midbrain and hindbrain progenitors is responsible for cell sorting in establishing the MHB. The MHB organizer gene Fgf8, which is expressed as a sharp transverse band immediately posterior to the lineage boundary at the MHB, is crucial in maintaining the lineage-restricted boundary after E7.5. Partial deletion of Fgf8 disrupts MHB lineage separation. Activation of FGF pathways has a cell-autonomous effect on cell sorting in midbrain progenitors. Therefore, Fgf8 from the MHB may signal the nearby mesencephalic cells to impart distinct cell surface characteristics or induce local cell-cell signaling, which consequently prevents cell movements across the MHB. Our findings reveal the distinct function of Gbx2 and Fgf8 in a stepwise process in the development of the compartment boundary at the MHB and that Fgf8, in addition to its organizer function, plays a crucial role in maintaining the lineage boundary at the MHB by restricting cell movement. PMID- 21266409 TI - Jagged 1 regulates the restriction of Sox2 expression in the developing chicken inner ear: a mechanism for sensory organ specification. AB - Hair cells of the inner ear sensory organs originate from progenitor cells located at specific domains of the otic vesicle: the prosensory patches. Notch signalling is necessary for sensory development and loss of function of the Notch ligand jagged 1 (Jag1, also known as serrate 1) results in impaired sensory organs. However, the underlying mechanism of Notch function is unknown. Our results show that in the chicken otic vesicle, the Sox2 expression domain initially contains the nascent patches of Jag1 expression but, later on, Sox2 is only maintained in the Jag1-positive domains. Ectopic human JAG1 (hJag1) is able to induce Sox2 expression and enlarged sensory organs. The competence to respond to hJag1, however, is confined to the regions that expressed Sox2 early in development, suggesting that hJag1 maintains Sox2 expression rather than inducing it de novo. The effect is non-cell-autonomous and requires Notch signalling. hJag1 activates Notch, induces Hes/Hey genes and endogenous Jag1 in a non-cell autonomous manner, which is consistent with lateral induction. The effects of hJag1 are mimicked by Jag2 but not by Dl1. Sox2 is sufficient to activate the Atoh1 enhancer and to ectopically induce sensory cell fate outside neurosensory competent domains. We suggest that the prosensory function of Jag1 resides in its ability to generate discrete domains of Notch activity that maintain Sox2 expression within restricted areas of an extended neurosensory-competent domain. This provides a mechanism to couple patterning and cell fate specification during the development of sensory organs. PMID- 21266411 TI - Integration of Hedgehog and BMP signalling by the engrailed2a gene in the zebrafish myotome. AB - Different levels and timing of Hedgehog (Hh) signalling activity have been proposed to specify three distinct cell types in the zebrafish myotome. Two of these, the medial fast-twitch fibres (MFFs) and the slow-twitch muscle pioneers (MPs) are characterised by expression of eng1a, -1b and -2a and require the highest levels of Hh for their specification. We have defined a minimal eng2a element sufficient to drive reporter expression specifically in MPs and MFFs. This element binds both Gli2a, a mediator of Hh signalling, and activated Smads (pSmads), mediators of bone morphogenic protein (BMP) signalling, in vivo. We found a strict negative correlation between nuclear accumulation of pSmad, and eng2a expression in myotomal cells and show that abrogation of pSmad accumulation results in activation of eng2a, even when Hh signalling is attenuated. Conversely, driving nuclear accumulation of pSmad suppresses the induction of eng expression even when Hh pathway activity is maximal. Nuclear accumulation of pSmads is depleted by maximal Hh pathway activation. We show that a synthetic form of the Gli2 repressor interacts with Smad1 specifically in the nuclei of myotomal cells in the developing embryo and that this interaction depends upon BMP signalling activity. Our results demonstrate that the eng2a promoter integrates repressive and activating signals from the BMP and Hh pathways, respectively, to limit its expression to MPs and MFFs. We suggest a novel basis for crosstalk between the Hh and BMP pathways, whereby BMP-mediated repression of Hh target genes is promoted by a direct interaction between Smads and truncated Glis, an interaction that is abrogated by Hh induced depletion of the latter. PMID- 21266410 TI - Age-dependent fate and lineage restriction of single NG2 cells. AB - NG2-expressing glia (NG2 cells, polydendrocytes) appear in the embryonic brain, expand perinatally, and persist widely throughout the gray and white matter of the mature central nervous system. We have previously reported that NG2 cells generate oligodendrocytes in both gray and white matter and a subset of protoplasmic astrocytes in the gray matter of the ventral forebrain and spinal cord. To investigate the temporal changes in NG2 cell fate, we generated NG2creERTMBAC transgenic mice, in which tamoxifen-inducible Cre is expressed in NG2 cells. Cre induction at embryonic day 16.5, postnatal day (P) 2, P30 and P60 in mice that were double transgenic for NG2creERTMBAC and the Cre reporter revealed that NG2 cells in the postnatal brain generate only NG2 cells or oligodendrocytes, whereas NG2 cells in the embryonic brain generate protoplasmic astrocytes in the gray matter of the ventral forebrain in addition to oligodendrocytes and NG2 cells. Analysis of cell clusters from single NG2 cells revealed that more than 80% of the NG2 cells in the P2 brain give rise to clusters consisting exclusively of oligodendrocytes, whereas the majority of the NG2 cells in the P60 brain generate clusters that contain only NG2 cells or a mixture of oligodendrocytes and NG2 cells. Furthermore, live cell imaging of single NG2 cells from early postnatal brain slices revealed that NG2 cells initially divide symmetrically to produce two daughter NG2 cells and that differentiation into oligodendrocytes occurred after 2-3 days. PMID- 21266413 TI - Role of IGF signaling in catch-up growth and accelerated temporal development in zebrafish embryos in response to oxygen availability. AB - Animals respond to adverse environments by slowing down or arresting growth and development. Upon returning to normal conditions, they often show compensatory acceleration in growth and developmental rate. This phenomenon, known as 'catch up' growth, is widely documented in the animal kingdom. The underlying molecular mechanisms, however, are poorly understood. Using the zebrafish embryo as an experimental model system, we tested the hypothesis that changes in IGF signaling activities play an important role in the accelerated growth and temporal development resulting from re-oxygenation following hypoxia. We show that chronic hypoxia reduced, and re-oxygenation accelerated, embryonic growth and developmental rate. Whereas hypoxia repressed the Igf1 receptor and its downstream Erk1/2 and Akt signaling activities, re-oxygenation restored their activities. Specific inhibition of Igf1 receptor signaling during re-oxygenation by genetic and pharmacological approaches attenuated catch-up growth. Further analysis showed that whereas PI3K-Akt is required in both normal and catch-up growth, Mek1/2-Erk1/2 activation induced by elevated IGF signaling during re oxygenation is particularly crucial for catch-up growth. These results suggest that the evolutionarily conserved IGF signaling pathway coordinates growth and temporal development in zebrafish embryos in response to oxygen availability. PMID- 21266412 TI - Disruption of reelin signaling alters mammary gland morphogenesis. AB - Reelin signaling is required for appropriate cell migration and ductal patterning during mammary gland morphogenesis. Dab1, an intracellular adaptor protein activated in response to reelin signaling, is expressed in the developing mammary bud and in luminal epithelial cells in the adult gland. Reelin protein is expressed in a complementary pattern, first in the epithelium overlying the mammary bud during embryogenesis and then in the myoepithelium and periductal stroma in the adult. Deletion in mouse of either reelin or Dab1 induced alterations in the development of the ductal network, including significant retardation in ductal elongation, decreased terminal branching, and thickening and disorganization of the luminal wall. At later stages, some mutant glands overcame these early delays, but went on to exhibit enlarged and chaotic ductal morphologies and decreased terminal branching: these phenotypes are suggestive of a role for reelin in spatial patterning or structural organization of the mammary epithelium. Isolated mammary epithelial cells exhibited decreased migration in response to exogenous reelin in vitro, a response that required Dab1. These observations highlight a role for reelin signaling in the directed migration of mammary epithelial cells driving ductal elongation into the mammary fat pad and provide the first evidence that reelin signaling may be crucial for regulating the migration and organization of non-neural tissues. PMID- 21266415 TI - Primary prevention of cardiovascular disease. PMID- 21266414 TI - Embryonic mesoderm and endoderm induction requires the actions of non-embryonic Nodal-related ligands and Mxtx2. AB - Vertebrate mesoderm and endoderm formation requires signaling by Nodal-related ligands from the TGFbeta superfamily. The factors that initiate Nodal-related gene transcription are unknown in most species and the relative contributions of Nodal-related ligands from embryonic, extraembryonic and maternal sources remain uncertain. In zebrafish, signals from the yolk syncytial layer (YSL), an extraembryonic domain, are required for mesoderm and endoderm induction, and YSL expression of nodal-related 1 (ndr1) and ndr2 accounts for a portion of this activity. A variable requirement of maternally derived Ndr1 for dorsal and anterior axis formation has also been documented. Here we show that Mxtx2 directly activates expression of ndr2 via binding to its first intron and is required for ndr2 expression in the YSL. Mxtx2 is also required for the Nodal signaling-independent expression component of the no tail a (ntla) gene, which is required for posterior (tail) mesoderm formation. Therefore, Mxtx2 defines a new pathway upstream of Nodal signaling and posterior mesoderm formation. We further show that the co-disruption of extraembryonic Ndr2, extraembryonic Ndr1 and maternal Ndr1 eliminates endoderm and anterior (head and trunk) mesoderm, recapitulating the loss of Nodal signaling phenotype. Therefore, non-embryonic sources of Nodal-related ligands account for the complete spectrum of early Nodal signaling requirements. In summary, the induction of mesoderm and endoderm depends upon the combined actions of Mxtx2 and Nodal-related ligands from non embryonic sources. PMID- 21266416 TI - Vaccination programme to protect children against pneumonia and diarrhoea needs more funds. PMID- 21266417 TI - Hospital closures are inevitable under health reforms, conference hears. PMID- 21266419 TI - Vitamin D and bone health in children. PMID- 21266418 TI - Effects of vitamin D supplementation on bone density in healthy children: systematic review and meta-analysis. AB - OBJECTIVE: To determine the effectiveness of vitamin D supplementation for improving bone mineral density in children and adolescents and if effects vary with factors such as vitamin D dose and vitamin D status. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Cochrane Central Register of Controlled Trials, Medline (1966 to present), Embase (1980 to present), CINAHL (1982 to present), AMED (1985 to present), and ISI Web of Science (1945 to present), last updated on 9 August 2009, and hand searching of conference abstracts from key journals. Study selection Placebo controlled randomised controlled trials of vitamin D supplementation for at least three months in healthy children and adolescents (aged 1 month to <20 years) with bone density outcomes. Two authors independently assessed references for inclusion and study quality and extracted data. DATA SYNTHESIS: Standardised mean differences of the percentage change from baseline in bone mineral density of the forearm, hip, and lumbar spine and total body bone mineral content in treatment and control groups. Subgroup analyses were carried out by sex, pubertal stage, dose of vitamin D, and baseline serum vitamin D concentration. Compliance and allocation concealment were also considered as possible sources of heterogeneity. RESULTS: From 1653 potential references, six studies, totalling 343 participants receiving placebo and 541 receiving vitamin D, contributed data to meta-analyses. Vitamin D supplementation had no statistically significant effects on total body bone mineral content or on bone mineral density of the hip or forearm. There was a trend to a small effect on lumbar spine bone mineral density (standardised mean difference 0.15, 95% confidence interval -0.01 to 0.31; P=0.07). Effects were similar in studies of participants with high compared with low serum vitamin D levels, although there was a trend towards a larger effect with low vitamin D for total body bone mineral content (P=0.09 for difference). In studies with low serum vitamin D, significant effects on total body bone mineral content and lumbar spine bone mineral density were roughly equivalent to a 2.6% and 1.7% percentage point greater change from baseline in the supplemented group. CONCLUSIONS: It is unlikely that vitamin D supplements are beneficial in children and adolescents with normal vitamin D levels. The planned subgroup analyses by baseline serum vitamin D level suggest that vitamin D supplementation of deficient children and adolescents could result in clinically useful improvements, particularly in lumbar spine bone mineral density and total body bone mineral content, but this requires confirmation. PMID- 21266420 TI - Competing interests: When do your politics become a competing interest? PMID- 21266421 TI - Portrayal of caesarean section in Brazilian women's magazines: 20 year review. AB - OBJECTIVE: To assess the quality and comprehensiveness of the information on caesarean section provided in Brazilian women's magazines. DESIGN: Review of articles published during 1988-2008 in top selling women's magazines. SETTING: Brazil, one of the countries with the highest caesarean section rates in the world. DATA SOURCES: Women's magazines with the largest distribution during the study period, identified through the official national media indexing organisations. SELECTION CRITERIA: Articles with objective scientific information or advice, comments, opinions, or the experience of ordinary women or celebrities on delivery by caesarean section. MAIN OUTCOME MEASURES: Sources of information mentioned by the author of the article, the accuracy and completeness of data presented on caesarean section, and alleged reasons why women would prefer to deliver though caesarean section. RESULTS: 118 articles were included. The main cited sources of information were health professionals (78% (n=92) of the articles). 71% (n=84) of the articles reported at least one benefit of caesarean section, and 82% (n=97) reported at least one short term maternal risk of caesarean section. The benefits most often attributed to delivery by caesarean section were reduction of pain and convenience for family or health professionals. The most frequently reported short term maternal risks of caesarean section were increased time to recover and that it is a less natural way of giving birth. Only one third of the articles mentioned any long term maternal risks or perinatal complications associated with caesarean section. Fear of pain was the main reported reason why women would prefer to deliver by caesarean section. CONCLUSIONS: Most of the articles published in Brazilian women's magazines do not use optimal sources of information. The portrayal of caesarean section is mostly balanced, not explicitly in favour of one or another route of delivery, but incomplete and may be leading women to underestimate the maternal/perinatal risks associated with this route of delivery. PMID- 21266423 TI - Embryology: New life for the HFEA? PMID- 21266422 TI - Carbamazepine in pregnancy: Levetiracetam and lamotrigine are better options. PMID- 21266424 TI - Reference intakes of vitamin D: Need to be implemented in UK. PMID- 21266425 TI - Treatment abroad: A long journey to healing. PMID- 21266426 TI - Febrile neutropenia: national guidelines are urgently needed. PMID- 21266427 TI - Assisted dying debate: Try another approach, BMJ. PMID- 21266428 TI - Assisted dying debate: Put everything out in the open. PMID- 21266429 TI - MMR scare: UCL's response. PMID- 21266430 TI - Assisted dying debate: Let's get the words right too. PMID- 21266431 TI - Assisted dying debate: What of virtue and integrity? PMID- 21266432 TI - MMR scare: Piltdown--hoax or fraud? PMID- 21266433 TI - Insulin manufacture: Marketing insulins. PMID- 21266434 TI - Industry sponsored bias: NICE may be biased too. PMID- 21266435 TI - Yankee Doodling: Guns don't kill crowds, people with semi-automatics do. PMID- 21266436 TI - Philadelphia doctor who ran "baby charnel house" is charged with murder. PMID- 21266437 TI - Hong Kong's murky skyline is linked with excess deaths. PMID- 21266438 TI - WHO calls for action to restrict marketing of unhealthy foods and drinks to children. PMID- 21266439 TI - Rich countries dominate cancer league table. PMID- 21266441 TI - Judging nudging: can nudging improve population health? PMID- 21266440 TI - Effect of pay for performance on the management and outcomes of hypertension in the United Kingdom: interrupted time series study. AB - OBJECTIVE: To assess the impact of a pay for performance incentive on quality of care and outcomes among UK patients with hypertension in primary care. DESIGN: Interrupted time series. SETTING: The Health Improvement Network (THIN) database, United Kingdom. PARTICIPANTS: 470 725 patients with hypertension diagnosed between January 2000 and August 2007. INTERVENTION: The UK pay for performance incentive (the Quality and Outcomes Framework), which was implemented in April 2004 and included specific targets for general practitioners to show high quality care for patients with hypertension (and other diseases). MAIN OUTCOME MEASURES: Centiles of systolic and diastolic blood pressures over time, rates of blood pressure monitoring, blood pressure control, and treatment intensity at monthly intervals for baseline (48 months) and 36 months after the implementation of pay for performance. Cumulative incidence of major hypertension related outcomes and all cause mortality for subgroups of newly treated (treatment started six months before pay for performance) and treatment experienced (started treatment in year before January 2001) patients to examine different stages of illness. RESULTS: After accounting for secular trends, no changes in blood pressure monitoring (level change 0.85, 95% confidence interval -3.04 to 4.74, P=0.669 and trend change -0.01, -0.24 to 0.21, P=0.615), control (-1.19, -2.06 to 1.09, P=0.109 and -0.01, -0.06 to 0.03, P=0.569), or treatment intensity (0.67, -1.27 to 2.81, P=0.412 and 0.02, -0.23 to 0.19, P=0.706) were attributable to pay for performance. Pay for performance had no effect on the cumulative incidence of stroke, myocardial infarction, renal failure, heart failure, or all cause mortality in both treatment experienced and newly treated subgroups. CONCLUSIONS: Good quality of care for hypertension was stable or improving before pay for performance was introduced. Pay for performance had no discernible effects on processes of care or on hypertension related clinical outcomes. Generous financial incentives, as designed in the UK pay for performance policy, may not be sufficient to improve quality of care and outcomes for hypertension and other common chronic conditions. PMID- 21266442 TI - One nudge forward, two steps back. PMID- 21266443 TI - An efficient hierarchical generalized linear mixed model for pathway analysis of genome-wide association studies. AB - MOTIVATION: In genome-wide association studies (GWAS) of complex diseases, genetic variants having real but weak associations often fail to be detected at the stringent genome-wide significance level. Pathway analysis, which tests disease association with combined association signals from a group of variants in the same pathway, has become increasingly popular. However, because of the complexities in genetic data and the large sample sizes in typical GWAS, pathway analysis remains to be challenging. We propose a new statistical model for pathway analysis of GWAS. This model includes a fixed effects component that models mean disease association for a group of genes, and a random effects component that models how each gene's association with disease varies about the gene group mean, thus belongs to the class of mixed effects models. RESULTS: The proposed model is computationally efficient and uses only summary statistics. In addition, it corrects for the presence of overlapping genes and linkage disequilibrium (LD). Via simulated and real GWAS data, we showed our model improved power over currently available pathway analysis methods while preserving type I error rate. Furthermore, using the WTCCC Type 1 Diabetes (T1D) dataset, we demonstrated mixed model analysis identified meaningful biological processes that agreed well with previous reports on T1D. Therefore, the proposed methodology provides an efficient statistical modeling framework for systems analysis of GWAS. AVAILABILITY: The software code for mixed models analysis is freely available at http://biostat.mc.vanderbilt.edu/LilyWang. PMID- 21266444 TI - Classifying short gene expression time-courses with Bayesian estimation of piecewise constant functions. AB - MOTIVATION: Analyzing short time-courses is a frequent and relevant problem in molecular biology, as, for example, 90% of gene expression time-course experiments span at most nine time-points. The biological or clinical questions addressed are elucidating gene regulation by identification of co-expressed genes, predicting response to treatment in clinical, trial-like settings or classifying novel toxic compounds based on similarity of gene expression time courses to those of known toxic compounds. The latter problem is characterized by irregular and infrequent sample times and a total lack of prior assumptions about the incoming query, which comes in stark contrast to clinical settings and requires to implicitly perform a local, gapped alignment of time series. The current state-of-the-art method (SCOW) uses a variant of dynamic time warping and models time series as higher order polynomials (splines). RESULTS: We suggest to model time-courses monitoring response to toxins by piecewise constant functions, which are modeled as left-right Hidden Markov Models. A Bayesian approach to parameter estimation and inference helps to cope with the short, but highly multivariate time-courses. We improve prediction accuracy by 7% and 4%, respectively, when classifying toxicology and stress response data. We also reduce running times by at least a factor of 140; note that reasonable running times are crucial when classifying response to toxins. In conclusion, we have demonstrated that appropriate reduction of model complexity can result in substantial improvements both in classification performance and running time. AVAILABILITY: A Python package implementing the methods described is freely available under the GPL from http://bioinformatics.rutgers.edu/Software/MVQueries/. PMID- 21266445 TI - Inter-observer reliability of ultrasound detection of tendon abnormalities at the wrist and ankle in patients with rheumatoid arthritis. AB - OBJECTIVE: To assess inter-observer reliability in US detection of tendon inflammatory and structural changes at wrists and ankles in RA patients. METHODS: Fourteen consecutive RA patients underwent bilateral US assessment of the extensor carpi ulnaris (ECUT) and tibialis posterior tendons (TPTs) by two blinded rheumatologists, with different level of experience in musculoskeletal (MS) US. Grey scale and power Doppler (PD) US assessment was focused on detection of tenosynovitis, tenosynovial and intra-tendon PD signal and structural lesions (i.e. tendinosis, tendon erosion, partial or total rupture). RESULTS: The frequency of US findings detected by Investigator 1 was 28.6% for inflammatory changes and 51.8% for structural damage changes while Investigator 2 detected 34 and 53.6% for the corresponding abnormalities. A high overall agreement (82.7%) was found for inflammatory pathology and 89.7% for structural lesions in all tendons. Mean kappa (kappa) values for all tendons and pathology was moderate (kappa = 0.42), with fair level of agreement for the wrist region (0.27-0.34) and moderate to good values for the ankle region (kappa = 0.47-0.62). Subclinical abnormalities were detected in 37.5% of the tendons by Investigator 1 and 28.6% of the tendons by Investigator 2. CONCLUSIONS: MSUS showed high overall agreement and fair to moderate inter-observer kappa-values between investigators with different levels of experience in detection of tendon pathology at the wrist and ankle in RA patients. Further standardization of scanning method and pathology definitions may improve MSUS reproducibility. PMID- 21266446 TI - Eotaxin-3 in Churg-Strauss syndrome: a clinical and immunogenetic study. AB - OBJECTIVES: To determine the potential of eotaxin-3 as a diagnostic marker for active disease and genetic susceptibility factor for Churg-Strauss syndrome (CSS). METHODS: A total of 37 patients with active, relapsed or inactive CSS, 123 healthy controls and 138 disease controls were studied. Clinical data were collected and serum levels of eotaxin-3 were determined. Ex vivo stability of eotaxin-3 in serum samples was tested. Furthermore, the association of single nucleotide polymorphisms (SNPs) in the eotaxin-3 gene with CSS was determined in 161 CSS patients and 124 healthy controls. RESULTS: Serum eotaxin-3 was highly elevated in active CSS patients. Neither eosinophilic diseases nor other small vessel vasculitides were associated with high serum eotaxin-3 levels. Receiver operating characteristic curve analysis determined a sensitivity and specificity of 87.5 and 98.6% at a cut-off level of 80 pg/ml. None of the tested SNPs within the eotaxin-3 gene influenced the susceptibility to develop CSS. CONCLUSIONS: Serum eotaxin-3 is a sensitive and specific marker for the diagnosis of active CSS suitable for routine clinical practice. Previously described SNPs in the eotaxin-3 gene do not predict the risk of developing CSS. PMID- 21266447 TI - A double-blind, randomized, placebo-controlled study to explore the efficacy of a dietary plant-derived polysaccharide supplement in patients with rheumatoid arthritis. AB - OBJECTIVES: There is increased interest in the potential benefits of complementary therapies, of which dietary plant-derived polysaccharides (dPPs) are an important component. We examined the impact of oral ingestion of a pre biotic dPP supplement active compound (AC) on serum glycosylation and clinical variables associated with inflammation and general health in patients with RA. METHODS: A double-blind, placebo-controlled, parallel-group clinical trial was used. Participants were randomly assigned to receive AC (n = 33) or placebo (n = 36) for 6 months. Serum protein N-glycosylation was determined by mass spectrometry. Patient outcomes were assessed by validated clinical trial health questionnaires. The primary clinical efficacy variable was DAS-28. RESULTS: The groups had comparable baseline clinical characteristics. AC was well tolerated with low drop-out rates. Supplementation resulted in a 12% significant drop in the levels of the agalactosylated (G0F) glycans [8.10 (0.89) to 7.16 (0.60); P = 0.03], but had no significant overall effect on patient outcomes. The placebo treated group showed no change in G0F but exhibited a reduction in the levels of fully digalactosylated (G2) glycans (11%; P = 0.03). Although not clinically significant, DAS scores were, however, marginally lower in the placebo group [difference = 0.63 (0.23) s.e.; 95% CI 0.17, 1.10; P = 0.009], as were two of the secondary variables. CONCLUSIONS: Short-term dietary supplementation with AC resulted in a moderate, but significant, reduction in G0F levels, but did not result in any clinically significant improvement in disease activity when assessing the study group as a whole. PMID- 21266448 TI - Translation and validation of EORTC QLQ-C30 into Indonesian version for cancer patients in Indonesia. AB - OBJECTIVE: Quality of life studies in Indonesia are still uncommon. This research was aimed to validate the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 in Indonesian version. The standard procedure of forward-backward translation was adhered to in the translation procedures. The validity procedure included reliability, convergent and discriminant validity, known-groups validity, factor analysis and external convergent validity. METHODS: Data were collected from cancer patients in the Oncology Department of Sardjito Hospital, Yogyakarta, Indonesia, who were treated with cisplatin at the dosage >=50 mg/m(2) as monotherapy or in combinations. The Short Form-36 was used to assess the external convergent validity of our translated questionnaire. RESULTS: One hundred and twenty-eight patients were recruited from March 2009 to November 2009. The internal consistency with values of >0.70 was observed in the Indonesian version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 scales. All items in the questionnaire met the criteria of convergent and discriminant validity, except for items 5. Both of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 and the Short Form-36 showed that different diagnoses were associated with a similar impact on quality of life. Factor analysis showed that only the role function and social function loaded onto the second factor together. Correlations between the Indonesian versions of both questionnaires were moderate: between 0.18 and 0.48 for the physical, emotional, social, fatigue and pain domains. CONCLUSIONS: The Indonesian version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 can be used as a questionnaire to assess quality of life in Indonesian cancer patients with high-emetogenic treatments. PMID- 21266449 TI - JMY is required for asymmetric division and cytokinesis in mouse oocytes. AB - JMY is a transcriptional co-factor of p53. Latest work has revealed that JMY is also an actin nucleation factor that regulates new filament assembly and activates Arp2/3 complex in somatic cells; however, roles of JMY in mouse oocyte are unknown. Here we showed the expression and functions of JMY during mouse oocyte meiotic maturation. JMY mRNA is expressed largely from germinal vesicle to metaphase I stage, and gradually decreased during anaphase I, telophase I (TI) and metaphase II (MII) stages. Immunostaining results showed that JMY localized at the spindle and cytoplasm of oocytes. Depletion of JMY by RNAi resulted in symmetric division, failure of spindle migration and cytokinesis during oocyte meiotic maturation, showing a 2-cell-like MII oocyte and TI stage arrest. Actin cap and cortical granules-free domain formation were also disrupted after JMY RNAi, indicating the failure of spindle migration. JMY antibody injection results were consistent with those of JMY RNAi, further confirming the involvement of JMY in oocyte polarity. Our data indicate that JMY is required for spindle migration, asymmetric division and cytokinesis during mouse oocyte maturation. PMID- 21266450 TI - Prevalence of thinness among early adolescent in rural school girls of Paschim Medinipur, West Bengal, India. PMID- 21266451 TI - Adolescents speak: why do we smoke? AB - OBJECTIVES: To assess the role of different factors that are associated with initiation and continuation of adolescent smoking. MATERIALS AND METHODS: A total of 2535 students (1465 males and 1070 females) between the age groups of 14 and 19 years were selected from four schools and two colleges of the city by two stage cluster sampling design for this cross-sectional study. RESULTS: The prevalence of cigarette smoking was 21.58%. Smoking was found to be considerably influenced with having seen best friend, father, sibling and favorite movie star smoke and also with receiving pocket money. CONCLUSION: Experimentation of substance use, motivated by family members, peer groups and the surrounding environment is common among adolescents and starts early in life. Therefore, it is necessary to come up with health promotion programs directed toward students which encourage attitude shaping among them toward self-confidence and healthy life style. PMID- 21266452 TI - Assessment of impact on health of children working in the garbage dumping site in Dhaka, Bangladesh. AB - Waste dumping is one of the major causes of environment pollution in Bangladesh. This study was designed to assess the impact on health of children working in one of the garbage dumping sites in Dhaka. Blood samples were collected from exposed (n = 20, aged: 8-15 years, exposed to dumped garbage from 6 months to 6 years) and control subjects (n = 15, age matched and never worked in the garbage dumping site). Oxidative stress markers like lipid hydroperoxides, thiobarbituric acid reactive substances and protein carbonyl content were measured. Alkaline comet assay was performed to assess the possible damage in DNA. To check the consequences of possible toxic exposure, we performed liver function tests of the study subjects. Oxidative stress-mediated damage of macromolecules was found to be significantly increased in the exposed children. Liver function tests were found normal. Thus, the children working in garbage dumping site are in severe health risk. PMID- 21266453 TI - Do polymorphic variants of chromosomes affect the outcome of in vitro fertilization and embryo transfer treatment? AB - BACKGROUND The aim of this study was to investigate the effect of chromosomal polymorphic variations on the outcome of IVF and embryo transfer (IVF-embryo transfer) treatment for infertile couples. METHODS During the period from October 2006 to December 2009, 1978 infertile couples who had received their first IVF embryo transfer treatment cycle in our hospital were selected for this retrospective study, and the frequency of chromosomal polymorphic variations was calculated. From these, 1671 couples were selected and divided into three groups: 1402 couples with normal chromosomes (Group 1/control group), 82 couples with chromosomal polymorphic variations in only females (Group 2) and 187 couples with chromosomal polymorphic variations in only males (Group 3). The clinical pregnancy rates (CPR), early miscarriage rates and ongoing pregnancy rates after IVF-embryo transfer treatment were compared. RESULTS There were no statistically significant differences among the three groups in implantation rates (29.37% in the control group, 29.70% in Group 2 and 31.41% in Group 3, P > 0.05) and CPR (45.86, 46.34 and 51.87%, respectively, P > 0.05). Although there was a trend toward higher first trimester pregnancy loss rates in Group 3 (male chromosomal polymorphic variations), but not in Group 2, compared with normal karyotype couples (10.31 versus 6.84%), the difference did not reach significance (P > 0.05). CONCLUSIONS Chromosomal polymorphic variations appear to have no adverse effects on the outcome of IVF-embryo transfer treatment. PMID- 21266454 TI - Commentary: violent child disciplinary practices in low- and middle-income households. PMID- 21266455 TI - Vitamin D and all-cause mortality among adults in USA: findings from the National Health and Nutrition Examination Survey Linked Mortality Study. AB - BACKGROUND: Whether concentrations of vitamin D are related to mortality remains unresolved. Our objective was to examine the relationship between serum concentrations of 25-hydroxyvitamin D and all-cause mortality in a national sample of US adults. METHODS: We used data from the National Health and Nutrition Examination Survey Mortality Study from 2001 to 2004 with mortality compiled through 2006. Mortality status was established through a match to the National Death Index. RESULTS: Of the 7531 participants, 347 died. Median follow-up was 3.8 years. The mean unadjusted concentrations of vitamin D were 54.1 nmol/l (21.7 ng/ml) among participants who died and 60.7 nmol/l (24.3 ng/ml) among participants who survived (P = 0.002). After adjustment for socio-demographic factors, the hazard ratios (HR) for all-cause mortality were 1.65 [95% confidence interval (CI): 95% CI: 1.13-2.40] for participants with a concentration <50 nmol/l (<20 ng/ml) and 1.02 (95% CI: 0.74-1.41) for participants with a concentration of 50 to <75 nmol/l (20 to <30 ng/ml) compared with participants who had a concentration of >= 75 nmol/l (>= 30 ng/ml). After more extensive adjustment, the HRs were 1.28 (95% CI: 0.86-1.90) and 0.91 (95% CI: 0.63-1.33), respectively. The fully adjusted HR per 10 nmol/l of vitamin D was 0.93 (95% CI: 0.86-1.01). The HRs did not vary by gender (P = 0.80) or among the three major racial or ethnic groups (P = 0.46). CONCLUSIONS: Concentrations of vitamin D were weakly and inversely related to all-cause mortality in this sample of US adults. PMID- 21266456 TI - APP-dependent up-regulation of Ptch1 underlies proliferation impairment of neural precursors in Down syndrome. AB - Mental retardation in Down syndrome (DS) appears to be related to severe neurogenesis impairment during critical phases of brain development. Recent lines of evidence in the cerebellum of a mouse model for DS (the Ts65Dn mouse) have shown a defective responsiveness to Sonic Hedgehog (Shh), a potent mitogen that controls cell division during brain development, suggesting involvement of the Shh pathway in the neurogenesis defects of DS. Based on these premises, we sought to identify the molecular mechanisms underlying derangement of the Shh pathway in neural precursor cells (NPCs) from Ts65Dn mice. By using an in vitro model of NPCs obtained from the subventricular zone and hippocampus, we found that trisomic NPCs had an increased expression of the Shh receptor Patched1 (Ptch1), a membrane protein that suppresses the action of a second receptor, Smoothened (Smo), thereby maintaining the pathway in a repressed state. Partial silencing of Ptch1 expression in trisomic NPCs restored cell proliferation, indicating that proliferation impairment was due to Ptch1 overexpression. The overexpression of Ptch1 in trisomic NPCs resulted from increased levels of AICD [a transcription promoting fragment of amyloid precursor protein (APP)] and increased AICD binding to the Ptch1 promoter. Our data provide novel evidence that Ptch1 overexpression underlies derangement of the Shh pathway in trisomic NPCs with consequent proliferation impairment. The demonstration that Ptch1 overexpression in trisomic NPCs is due to an APP fragment provides a link between this trisomic gene and the defective neuronal production that characterizes the DS brain. PMID- 21266458 TI - Natural selection and functional genetic variation in the p53 pathway. AB - The allele frequencies of two functional single-nucleotide polymorphisms (SNPs) in the p53 pathway, the MDM2 SNP309 and TP53 Arg72Pro, vary dramatically among populations. That the frequencies of the TP53 SNP follow a clinal distribution may suggest that selective pressure from environmental variables correlated with latitude contributed to these observed population differences. Recently, winter temperature and UV radiation were found to be significantly correlated with the TP53 and the MDM2 SNPs, respectively, in East Asians; whether these correlations are more extreme than expected based upon nonselective factors such as patterns of human migration remains unclear. Here, we genotyped these two SNPs in 971 unrelated individuals from 52 unique populations worldwide and tested for correlations with both latitude and a number of climate-related environmental variables on a global scale, controlling for these neutral processes. The TP53 SNP was associated with a significant selection signal for a few climate variables, such as short-wave radiation flux in the winter, but these signals were no longer significant after correction for multiple tests. The MDM2 SNP did not exhibit a significant signal with any climate variable. Therefore, these SNPs are unlikely to be under selective pressure driven by these variables. Thus, these data underscore the need to incorporate population history when assessing signatures of selection. PMID- 21266457 TI - Partial recessive IFN-gammaR1 deficiency: genetic, immunological and clinical features of 14 patients from 11 kindreds. AB - We report a series of 14 patients from 11 kindreds with recessive partial (RP) interferon (IFN)-gammaR1 deficiency. The I87T mutation was found in nine homozygous patients from Chile, Portugal and Poland, and the V63G mutation was found in five homozygous patients from the Canary Islands. Founder effects accounted for the recurrence of both mutations. The most recent common ancestors of the patients with the I87T and V63G mutations probably lived 1600 (875-2950) and 500 (200-1275) years ago, respectively. The two alleles confer phenotypes that are similar but differ in terms of IFN-gammaR1 levels and residual response to IFN-gamma. The patients suffered from bacillus Calmette-Guerin-osis (n= 6), environmental mycobacteriosis (n= 6) or tuberculosis (n= 1). One patient did not suffer from mycobacterial infections but had disseminated salmonellosis, which was also present in two other patients. Age at onset of the first environmental mycobacterial disease differed widely between patients, with a mean value of 11.25 +/- 9.13 years. Thirteen patients survived until the age of 14.82 +/- 11.2 years, and one patient died at the age of 7 years, 9 days after the diagnosis of long-term Mycobacterium avium infection and the initiation of antimycobacterial treatment. Up to 10 patients are currently free of infection with no prophylaxis. The clinical heterogeneity of the 14 patients was not clearly related to either IFNGR1 genotype or the resulting cellular phenotype. RP-IFN-gammaR1 deficiency is, thus, more common than initially thought and should be considered in both children and adults with mild or severe mycobacterial diseases. PMID- 21266459 TI - Isolation and characterization of a barley yellow stripe-like gene, HvYSL5. AB - Yellow stripe-like (YSL) family transporters, belonging to a novel subfamily of oligopeptide transporter (OPT), has been proposed to be involved in metal uptake and long-distance transport, but only a few of them have been functionally characterized so far. In the present study, we isolated an uncharacterized member of the YSL family, HvYSL5, in barley based on expressed sequence tag (EST) information. HvYSL5 shared 50% identity with HvYS1, a transporter for the ferric mugineic acid complex, at the amino acid level. Promoter analysis showed that the HvYSL5 upstream sequence contains both iron deficiency response element 1 and 2 (IDE1 and 2). HvYSL5 was expressed in the roots and the expression was greatly induced by Fe deficiency, but not by deficiency of other metals including Zn, Cu and Mn. Spatial investigation showed that much higher expression of HvYSL5 was found in the mature zones of the roots, but not in the root tips. Furthermore, the expression showed a diurnal rhythm, being the highest in the morning, but with no expression in the afternoon. HvYSL5 was localized in all root cells, and subcellular localization analysis showed that HvYSL5 is likely to be localized in the vesicles. Knockdown of HvYSL5 did not result in any detectable phenotype changes. Although the exact role of HvYSL5 remains to be examined, our results suggest that it is involved in the transient storage of Fe or phytosiderophores. PMID- 21266460 TI - In vivo studies on the roles of two closely related Arabidopsis Tic20 proteins, AtTic20-I and AtTic20-IV. AB - Protein translocation across the inner envelope of plastids is mediated by the TIC (translocon at the inner envelope membrane of chloroplasts) protein translocation machinery. Tic20 has been shown to function as a central component of TIC machinery. The Arabidopsis genome encodes four Tic20 homologous proteins, AtTic20-I, AtTic20-II, AtTIC20-IV and AtTic20-V, among which only AtTic20-I has been extensively characterized and demonstrated to be essential for protein import into chloroplasts. AtTic20-I is more closely related to AtTic20-IV than to AtTic20-II or AtTic20-V, whereas AtTic20-II and AtTic20-V show higher similarities to each other than to AtTic20-I or AtTic20-IV. Here, we show that AtTic20-IV is expressed mainly in roots whereas AtTic20-I is more abundant in shoots than in roots. Although AtTic20-IV is dispensable for viability in the wild-type background, interestingly, expression of AtTic20-IV is markedly elevated in both shoots and roots in the tic20-I knockout mutant that exhibits severe albino and seedling-lethal phenotypes. The albino tic20-I seedlings do not accumulate any of the photosynthetic proteins analyzed, but the plastids can still import non-photosynthetic housekeeping proteins. This residual import ability of the tic20-I mutant can be attributed to partial compensation by the elevated expression of AtTic20-IV, since a double knockout mutant of AtTic20-I and AtTic20-IV exhibits more severe embryonic lethality. Further overexpression of AtTic20-IV in the tic20-I mutant can only marginally rescue the accumulation of photosynthetic proteins in the albino seedlings. These data demonstrate an absolute requirement of at least one of the two closely related Tic20 proteins in protein translocation across the inner envelope of plastids and also suggest their distinct substrate preferences. PMID- 21266461 TI - Distal transport of exogenously applied jasmonoyl-isoleucine with wounding stress. AB - Determining the mobile signal used by plants to defend against biotic and abiotic stresses has proved elusive, but jasmonic acid (JA) and its derivatives appear to be involved. Using deuterium-labeled analogs, we investigated the distal transport of JA and jasmonoyl-isoleucine (JA-Ile) in response to leaf wounding in tobacco (Nicotiana tabacum) and tomato (Solanum lycopersicum) plants. We recovered [(2)H(2)-2]JA ([(2)H(2)]JA) and [(2)H(3)-12]JA-Ile ([(2)H(3)]JA-Ile) in distal leaves of N. tabacum and S. lycopersicum after treating wounded leaves with [(2)H(2)]JA or [(2)H(3)]JA-Ile. We found that JA-Ile had a greater mobility than JA, despite its lower polarity, and that application of exogenous JA-Ile to wounded leaves of N. tabacum led to a higher accumulation of JA and JA-Ile in distal leaves compared with wounded control plants. We also found that exudates from the stem of S. lycopersicum plants with damaged leaflets contained JA and JA Ile at higher levels than in an undamaged plant, and a significant difference in the levels of JA-Ile was observed 30 min after wounding. Based on these results, it was found that JA-Ile is a transportable compound, which suggests that JA-Ile is a signaling cue involved in the resistance to biotic and abiotic stresses in plants. PMID- 21266462 TI - Existential neuroscience: a functional magnetic resonance imaging investigation of neural responses to reminders of one's mortality. AB - A considerable body of evidence derived from terror management theory indicates that the awareness of mortality represents a potent psychological threat engendering various forms of psychological defense. However, extant research has yet to examine the neurological correlates of cognitions about one's inevitable death. The present study thus investigated in 17 male participants patterns of neural activation elicited by mortality threat. To induce mortality threat, participants answered questions arranged in trial blocks that referred to fear of death and dying. In the control condition participants answered questions about fear of dental pain. Neural responses to mortality threat were greater than to pain threat in right amygdala, left rostral anterior cingulate cortex, and right caudate nucleus. We discuss implications of these findings for stimulating further research into the neurological correlates of managing existential fear. PMID- 21266463 TI - An RNA-zipcode-independent mechanism that localizes Dia1 mRNA to the perinuclear ER through interactions between Dia1 nascent peptide and Rho-GTP. AB - Signal-peptide-mediated ER localization of mRNAs encoding for membrane and secreted proteins, and RNA-zipcode-mediated intracellular targeting of mRNAs encoding for cytosolic proteins are two well-known mechanisms for mRNA localization. Here, we report a previously unidentified mechanism by which mRNA encoding for Dia1, a cytosolic protein without the signal peptide, is localized to the perinuclear ER in an RNA-zipcode-independent manner in fibroblasts. Dia1 mRNA localization is also independent of the actin and microtubule cytoskeleton but requires translation and the association of Dia1 nascent peptide with the ribosome-mRNA complex. Sequence mapping suggests that interactions of the GTPase binding domain of Dia1 peptide with active Rho are important for Dia1 mRNA localization. This mechanism can override the beta-actin RNA zipcode and redirect beta-actin mRNA to the perinuclear region, providing a new way to manipulate intracellular mRNA localization. PMID- 21266464 TI - Centriolar satellites are assembly points for proteins implicated in human ciliopathies, including oral-facial-digital syndrome 1. AB - Ciliopathies are caused by mutations in genes encoding proteins required for cilia organization or function. We show through colocalization with PCM-1, that OFD1 (the product of the gene mutated in oral-facial-digital syndrome 1) as well as BBS4 and CEP290 (proteins encoded by other ciliopathy genes) are primarily components of centriolar satellites, the particles surrounding centrosomes and basal bodies. RNA interference experiments reveal that satellite integrity is mutually dependent upon each of these proteins. Upon satellite dispersal, through mitosis or forced microtubule depolymerization, OFD1 and CEP290 remain centrosomal, whereas BBS4 and PCM-1 do not. OFD1 interacts via its fifth coiled coil motif with the N-terminal coiled-coil domain of PCM-1, which itself interacts via its C-terminal non-coiled-coil region with BBS4. OFD1 localization to satellites requires its N-terminal region, encompassing the LisH motif, whereas expression of OFD1 C-terminal constructs causes PCM-1 and CEP290 mislocalization. Moreover, in embryonic zebrafish, OFD1 and BBS4 functionally synergize, determining morphogenesis. Our observation that satellites are assembly points for several mutually dependent ciliopathy proteins provides a further possible explanation as to why the clinical spectrum of OFD1, Bardet Biedl and Joubert syndromes overlap. Furthermore, definition of how OFD1 and PCM 1 interact helps explain why different OFD1 mutations lead to clinically variable phenotypes. PMID- 21266465 TI - Mutation in the betaA3/A1-crystallin gene impairs phagosome degradation in the retinal pigmented epithelium of the rat. AB - Phagocytosis of the shed outer segment discs of photoreceptors is a major function of the retinal pigmented epithelium (RPE). We demonstrate for the first time that betaA3/A1-crystallin, a major structural protein of the ocular lens, is expressed in RPE cells. Further, by utilizing the Nuc1 rat, in which the betaA3/A1-crystallin gene is mutated, we show that this protein is required by RPE cells for proper degradation of outer segment discs that have been internalized in phagosomes. We also demonstrate that in wild-type RPE, betaA3/A1 crystallin is localized to the lysosomes. However, in the Nuc1 RPE, betaA3/A1 crystallin fails to translocate to the lysosomes, perhaps because misfolding of the mutant protein masks sorting signals required for proper trafficking. The digestion of phagocytized outer segments requires a high level of lysosomal enzyme activity, and cathepsin D, the major enzyme responsible for proteolysis of the outer segments, is decreased in mutant RPE cells. Interestingly, our results also indicate a defect in the autophagy process in the Nuc1 RPE, which is probably also linked to impaired lysosomal function, because phagocytosis and autophagy might share common mechanisms in degradation of their targets. betaA3/A1-crystallin is a novel lysosomal protein in RPE, essential for degradation of phagocytosed material. PMID- 21266466 TI - Punctuated actin contractions during convergent extension and their permissive regulation by the non-canonical Wnt-signaling pathway. AB - Actomyosin networks linked to the micro-environment through the plasma membrane are thought to be key players in regulating cell behaviors within multicellular tissues, such as converging and extending mesoderm. Here, we observe the dynamics of actin contractions called 'punctuated actin contractions' in the mid-cell body of embryonic mesenchymal cells in the mesoderm. These contraction dynamics are a common feature of Xenopus embryonic tissues and are important for cell shape changes during morphogenesis. Quantitative morphological analysis of these F actin dynamics indicates that frequent and aligned movements of multiple actin contractions accompany mesoderm cells as they intercalate and elongate. Using inhibitors combined with fluorescence recovery after photobleaching (FRAP) analysis, we find that the dynamics of actin contractions are regulated by both myosin contractility and F-actin polymerization. Furthermore, we find that the non-canonical Wnt-signaling pathway permissively regulates levels of punctuated actin contractions. Overexpression of Xfz7 (Fzd7) can induce early maturation of actin contractions in mesoderm and produce mesoderm-like actin contractions in ectoderm cells. By contrast, expression of the dominant-negative Xenopus disheveled construct Xdd1 blocks the progression of actin contractions into their late mesoderm dynamics but has no effect in ectoderm. Our study reveals punctuated actin contractions within converging and extending mesoderm and uncovers a permissive role for non-canonical Wnt-signaling, myosin contractility and F-actin polymerization in regulating these dynamics. PMID- 21266467 TI - Temporal changes in Hec1 phosphorylation control kinetochore-microtubule attachment stability during mitosis. AB - Precise control of the attachment strength between kinetochores and spindle microtubules is essential to preserve genomic stability. Aurora B kinase has been implicated in regulating the stability of kinetochore-microtubule attachments but its relevant kinetochore targets in cells remain unclear. Here, we identify multiple serine residues within the N-terminus of the kinetochore protein Hec1 that are phosphorylated in an Aurora-B-kinase-dependent manner during mitosis. On all identified target sites, Hec1 phosphorylation at kinetochores is high in early mitosis and decreases significantly as chromosomes bi-orient. Furthermore, once dephosphorylated, Hec1 is not highly rephosphorylated in response to loss of kinetochore-microtubule attachment or tension. We find that a subpopulation of Aurora B kinase remains localized at the outer kinetochore even upon Hec1 dephosphorylation, suggesting that Hec1 phosphorylation by Aurora B might not be regulated wholly by spatial positioning of the kinase. Our results define a role for Hec1 phosphorylation in kinetochore-microtubule destabilization and error correction in early mitosis and for Hec1 dephosphorylation in maintaining stable attachments in late mitosis. PMID- 21266468 TI - Purinergic P2X7 receptor regulates lung surfactant secretion in a paracrine manner. AB - Alveolar epithelium is composed of alveolar epithelial cells of type I (AEC I) and type II (AEC II). AEC II secrete lung surfactant by means of exocytosis. P2X(7) receptor (P2X(7)R), a P2 purinergic receptor, has been implicated in the regulation of synaptic transmission and inflammation. Here, we report that P2X(7)R, which is expressed in AEC I but not AEC II, is a novel mediator for the paracrine regulation of surfactant secretion in AEC II. In primary co-cultures of AEC I and AEC II benzoyl ATP (BzATP; an agonist of P2X(7)R) increased surfactant secretion, which was blocked by the P2X(7)R antagonist Brilliant Blue G. This effect was observed in AEC II co-cultured with human embryonic kidney HEK-293 cells stably expressing rat P2X(7)R, but not when co-cultured with AEC I in which P2X(7)R was knocked down or in co-cultures of AEC I and AEC II isolated from P2X(7)R(-/-) mice. BzATP-mediated secretion involved P2Y(2) receptor signaling because it was reduced by the addition of the ATP scavengers apyrase and adenosine deaminase and the P2Y(2) receptor antagonist suramin. However, the stimulation with BzATP might also release other substances that potentially increase surfactant secretion as a greater stimulation of secretion was observed in AEC II incubated with BzATP when co-cultured with E10 or HEK-293-P2X(7)R cells than with ATP alone. P2X(7)R(-/-) mice failed to increase surfactant secretion in response to hyperventilation, pointing to the physiological relevance of P2X(7)R in maintaining surfactant homeostasis in the lung. These results suggest that the activation of P2X(7)R increases surfactant secretion by releasing ATP from AEC I and subsequently stimulating P2Y(2) receptors in AEC II. PMID- 21266470 TI - TNFalpha induced noncanonical NF-kappaB activation is attenuated by RIP1 through stabilization of TRAF2. AB - The current paradigm of noncanonical NF-kappaB signaling suggests that the loss of TRAF2, TRAF3 or cIAP1 and cIAP2 leads to stabilization of NF-kappaB-inducing kinase (NIK) to activate the noncanonical pathway. Although a crucial role of RIP1 in the TNFalpha-induced canonical NF-kappaB pathway has been well established, its involvement in noncanonical activation of NF-kappaB through the TNFR1 receptor, is unknown. Here we show that TNFalpha is capable of activating the noncanonical NF-kappaB pathway, but that activation of this pathway is negatively regulated by RIP1. In the absence of RIP1, TNFR1 stimulation leads to activation of the noncanonical NF-kappaB pathway through TRAF2 degradation, leading to NIK stabilization, IKKalpha phosphorylation and the processing of p100 to generate p52. Thus although RIP1(-/-) mouse embryonic fibroblasts are sensitive at early time points to cell death induced by TNFalpha, probably as a result of lack of canonical NF-kappaB activation, the late activation of the noncanonical NF-kappaB pathway protects the remaining cells from further cell death. The TNFR1-dependent noncanonical NF-kappaB activation in RIP1(-/-) cells suggests that there is functional interplay between the two NF-kappaB pathways during TNFR1 signaling, which might regulate the number and kinds of NF-kappaB transcription factors and thus finely control NF-kappaB-dependent gene transcription. PMID- 21266469 TI - Multivesicular bodies in the enigmatic amoeboflagellate Breviata anathema and the evolution of ESCRT 0. AB - Endosomal sorting complexes required for transport (ESCRTs) are heteromeric protein complexes required for multivesicular body (MVB) morphogenesis. ESCRTs I, II, III and III-associated are ubiquitous in eukaryotes and presumably ancient in origin. ESCRT 0 recruits cargo to the MVB and appears to be opisthokont-specific, bringing into question aspects of the current model of ESCRT mechanism. One caveat to the restricted distribution of ESCRT 0 was the previous limited availability of amoebozoan genomes, the supergroup closest to opisthokonts. Here, we significantly expand the sampling of ESCRTs in Amoebozoa. Our electron micrographic and bioinformatics evidence confirm the presence of MVBs in the amoeboflagellate Breviata anathema. Searches of genomic databases of amoebozoans confirm the ubiquitous nature of ESCRTs I-III-associated and the restriction of ESCRT 0 to opisthokonts. Recently, an alternate ESCRT 0 complex, centering on Tom1 proteins, has been proposed. We determine the distribution of Tom1 family proteins across eukaryotes and show that the Tom1, Tom1L1 and Tom1L2 proteins are a vertebrate-specific expansion of the single Tom1 family ancestor, which has indeed been identified in at least one member of each of the major eukaryotic supergroups. This implies a more widely conserved and ancient role for the Tom1 family in endocytosis than previously suspected. PMID- 21266471 TI - A novel compression tool for efficient storage of genome resequencing data. AB - With the advent of DNA sequencing technologies, more and more reference genome sequences are available for many organisms. Analyzing sequence variation and understanding its biological importance are becoming a major research aim. However, how to store and process the huge amount of eukaryotic genome data, such as those of the human, mouse and rice, has become a challenge to biologists. Currently available bioinformatics tools used to compress genome sequence data have some limitations, such as the requirement of the reference single nucleotide polymorphisms (SNPs) map and information on deletions and insertions. Here, we present a novel compression tool for storing and analyzing Genome ReSequencing data, named GRS. GRS is able to process the genome sequence data without the use of the reference SNPs and other sequence variation information and automatically rebuild the individual genome sequence data using the reference genome sequence. When its performance was tested on the first Korean personal genome sequence data set, GRS was able to achieve ~159-fold compression, reducing the size of the data from 2986.8 to 18.8 MB. While being tested against the sequencing data from rice and Arabidopsis thaliana, GRS compressed the 361.0 MB rice genome data to 4.4 MB, and the A. thaliana genome data from 115.1 MB to 6.5 KB. This de novo compression tool is available at http://gmdd.shgmo.org/Computational-Biology/GRS. PMID- 21266472 TI - Identification of evolutionarily conserved non-AUG-initiated N-terminal extensions in human coding sequences. AB - In eukaryotes, it is generally assumed that translation initiation occurs at the AUG codon closest to the messenger RNA 5' cap. However, in certain cases, initiation can occur at codons differing from AUG by a single nucleotide, especially the codons CUG, UUG, GUG, ACG, AUA and AUU. While non-AUG initiation has been experimentally verified for a handful of human genes, the full extent to which this phenomenon is utilized--both for increased coding capacity and potentially also for novel regulatory mechanisms--remains unclear. To address this issue, and hence to improve the quality of existing coding sequence annotations, we developed a methodology based on phylogenetic analysis of predicted 5' untranslated regions from orthologous genes. We use evolutionary signatures of protein-coding sequences as an indicator of translation initiation upstream of annotated coding sequences. Our search identified novel conserved potential non-AUG-initiated N-terminal extensions in 42 human genes including VANGL2, FGFR1, KCNN4, TRPV6, HDGF, CITED2, EIF4G3 and NTF3, and also affirmed the conservation of known non-AUG-initiated extensions in 17 other genes. In several instances, we have been able to obtain independent experimental evidence of the expression of non-AUG-initiated products from the previously published literature and ribosome profiling data. PMID- 21266473 TI - Evolution of linear chromosomes and multipartite genomes in yeast mitochondria. AB - Mitochondrial genome diversity in closely related species provides an excellent platform for investigation of chromosome architecture and its evolution by means of comparative genomics. In this study, we determined the complete mitochondrial DNA sequences of eight Candida species and analyzed their molecular architectures. Our survey revealed a puzzling variability of genome architecture, including circular- and linear-mapping and multipartite linear forms. We propose that the arrangement of large inverted repeats identified in these genomes plays a crucial role in alterations of their molecular architectures. In specific arrangements, the inverted repeats appear to function as resolution elements, allowing genome conversion among different topologies, eventually leading to genome fragmentation into multiple linear DNA molecules. We suggest that molecular transactions generating linear mitochondrial DNA molecules with defined telomeric structures may parallel the evolutionary emergence of linear chromosomes and multipartite genomes in general and may provide clues for the origin of telomeres and pathways implicated in their maintenance. PMID- 21266474 TI - Controlled interplay between trigger loop and Gre factor in the RNA polymerase active centre. AB - The highly processive transcription by multi-subunit RNA polymerases (RNAP) can be interrupted by misincorporation or backtracking events that may stall transcription or lead to erroneous transcripts. Backtracked/misincorporated complexes can be resolved via hydrolysis of the transcript. Here, we show that, in response to misincorporation and/or backtracking, the catalytic domain of RNAP active centre, the trigger loop (TL), is substituted by transcription factor Gre. This substitution turns off the intrinsic TL-dependent hydrolytic activity of RNAP active centre, and exchanges it to a far more efficient Gre-dependent mechanism of RNA hydrolysis. Replacement of the TL by Gre factor occurs only in backtracked/misincorporated complexes, and not in correctly elongating complexes. This controlled switching of RNAP activities allows the processivity of elongation to be unaffected by the hydrolytic activity of Gre, while ensuring efficient proofreading of transcription and resolution of backtracked complexes. PMID- 21266475 TI - Use of RecA fusion proteins to induce genomic modifications in zebrafish. AB - The bacterial recombinase RecA forms a nucleic acid-protein filament on single stranded (ss) DNA during the repair of double-strand breaks (DSBs) that efficiently undergoes a homology search and engages in pairing with the complementary DNA sequence. We utilized the pairing activity of RecA-DNA filaments to tether biochemical activities to specific chromosomal sites. Different filaments with chimeric RecA proteins were tested for the ability to induce loss of heterozygosity at the golden locus in zebrafish after injection at the one-cell stage. A fusion protein between RecA containing a nuclear localization signal (NLS) and the DNA-binding domain of Gal4 (NLS-RecA-Gal4) displayed the most activity. Our results demonstrate that complementary ssDNA filaments as short as 60 nucleotides coated with NLS-RecA-Gal4 protein are able to cause loss of heterozygosity in ~3% of the injected embryos. We demonstrate that lesions in ~9% of the F0 zebrafish are transmitted to subsequent generations as large chromosomal deletions. Co-injection of linear DNA with the NLS-RecA-Gal4 DNA filaments promotes the insertion of the DNA into targeted genomic locations. Our data support a model whereby NLS-RecA-Gal4 DNA filaments bind to complementary target sites on chromatin and stall DNA replication forks, resulting in a DNA DSB. PMID- 21266476 TI - PDGF induced microRNA alterations in cancer cells. AB - Platelet derived growth factor (PDGF) regulates gene transcription by binding to specific receptors. PDGF plays a critical role in oncogenesis in brain and other tumors, regulates angiogenesis, and remodels the stroma in physiologic conditions. Here, we show by using microRNA (miR) arrays that PDGFs regulate the expression and function of miRs in glioblastoma and ovarian cancer cells. The two PDGF ligands AA and BB affect expression of several miRs in ligand-specific manner; the most robust changes consisting of let-7d repression by PDGF-AA and miR-146b induction by PDGF-BB. Induction of miR-146b by PDGF-BB is modulated via MAPK-dependent induction of c-fos. We demonstrate that PDGF regulates expression of some of its known targets (e.g. cyclin D1) through miR alterations and identify the epidermal growth factor receptor (EGFR) as a new PDGF-BB target. We show that its expression and function are repressed by PDGF-induced miR-146b and that mir-146b and EGFR correlate inversely in human glioblastomas. We propose that PDGF-regulated gene transcription involves alterations in non-coding RNAs and provide evidence for a miR-dependent feedback mechanism balancing growth factor receptor signaling in cancer cells. PMID- 21266477 TI - Combinatorial chromatin modification patterns in the human genome revealed by subspace clustering. AB - Chromatin modifications, such as post-translational modification of histone proteins and incorporation of histone variants, play an important role in regulating gene expression. Joint analyses of multiple histone modification maps are starting to reveal combinatorial patterns of modifications that are associated with functional DNA elements, providing support to the 'histone code' hypothesis. However, due to the lack of analytical methods, only a small number of chromatin modification patterns have been discovered so far. Here, we introduce a scalable subspace clustering algorithm, coherent and shifted bicluster identification (CoSBI), to exhaustively identify the set of combinatorial modification patterns across a given epigenome. Performance comparisons demonstrate that CoSBI can generate biclusters with higher intra cluster coherency and biological relevance. We apply our algorithm to a compendium of 39 genome-wide chromatin modification maps in human CD4(+) T cells. We identify 843 combinatorial patterns that recur at >0.1% of the genome. A total of 19 chromatin modifications are observed in the combinatorial patterns, 10 of which occur in more than half of the patterns. We also identify combinatorial modification signatures for eight classes of functional DNA elements. Application of CoSBI to epigenome maps of different cells and developmental stages will aid in understanding how chromatin structure helps regulate gene expression. PMID- 21266478 TI - Real-time detection of cruciform extrusion by single-molecule DNA nanomanipulation. AB - During cruciform extrusion, a DNA inverted repeat unwinds and forms a four-way junction in which two of the branches consist of hairpin structures obtained by self-pairing of the inverted repeats. Here, we use single-molecule DNA nanomanipulation to monitor in real-time cruciform extrusion and rewinding. This allows us to determine the size of the cruciform to nearly base pair accuracy and its kinetics with second-scale time resolution. We present data obtained with two different inverted repeats, one perfect and one imperfect, and extend single molecule force spectroscopy to measure the torque dependence of cruciform extrusion and rewinding kinetics. Using mutational analysis and a simple two state model, we find that in the transition state intermediate only the B-DNA located between the inverted repeats (and corresponding to the unpaired apical loop) is unwound, implying that initial stabilization of the four-way (or Holliday) junction is rate-limiting. We thus find that cruciform extrusion is kinetically regulated by features of the hairpin loop, while rewinding is kinetically regulated by features of the stem. These results provide mechanistic insight into cruciform extrusion and help understand the structural features that determine the relative stability of the cruciform and B-form states. PMID- 21266479 TI - Yeast H2A.Z, FACT complex and RSC regulate transcription of tRNA gene through differential dynamics of flanking nucleosomes. AB - FACT complex is involved in elongation and ensures fidelity in the initiation step of transcription by RNA polymerase (pol) II. Histone variant H2A.Z is found in nucleosomes at the 5'-end of many genes. We report here H2A.Z-chaperone activity of the yeast FACT complex on the short, nucleosome-free, non-coding, pol III-transcribed yeast tRNA genes. On a prototype gene, yeast SUP4, chromatin remodeler RSC and FACT regulate its transcription through novel mechanisms, wherein the two gene-flanking nucleosomes containing H2A.Z, play different roles. Nhp6, which ensures transcription fidelity and helps load yFACT onto the gene flanking nucleosomes, has inhibitory role. RSC maintains a nucleosome abutting the gene terminator downstream, which results in reduced transcription rate in active state while H2A.Z probably helps RSC in keeping the gene nucleosome-free and serves as stress-sensor. All these factors maintain an epigenetic state which allows the gene to return quickly from repressed to active state and tones down the expression from the active SUP4 gene, required probably to maintain the balance in cellular tRNA pool. PMID- 21266480 TI - WDHD1 modulates the post-transcriptional step of the centromeric silencing pathway. AB - The centromere is a highly specialized chromosomal element that is essential for chromosome segregation during mitosis. Centromere integrity must therefore be properly preserved and is strictly dependent upon the establishment and maintenance of surrounding chromatin structure. Here we identify WDHD1, a WD40 domain and HMG-domain containing protein, as a key regulator of centromere function. We show that WDHD1 associates with centromeres in a cell cycle dependent manner, coinciding with mid-to-late S phase. WDHD1 down-regulation compromises HP1alpha localization to pericentric heterochromatin and leads to altered expression of epigenetic markers associated with this chromatin region. As a consequence, such reduced epigenetic silencing is manifested in disrupted heterochromatic state of the centromere and a defective mitosis. Moreover, we demonstrate that a possible underlying mechanism of WDHD1's involvement lies in the proper generation of the small non-coding RNAs encoded by the centromeric satellite repeats. This role is mediated at the post-transcriptional level and likely through stabilizing Dicer association with centromeric RNA. Collectively, these findings suggest that WDHD1 may be a critical component of the RNA dependent epigenetic control mechanism that sustains centromere integrity and genomic stability. PMID- 21266481 TI - A simple and efficient method to search for selected primary transcripts: non coding and antisense RNAs in the human pathogen Enterococcus faecalis. AB - Enterococcus faecalis is a commensal bacterium and a major opportunistic human pathogen. In this study, we combined in silico predictions with a novel 5'RACE derivative method coined '5'tagRACE', to perform the first search for non-coding RNAs (ncRNAs) encoded on the E. faecalis chromosome. We used the 5'tagRACE to simultaneously probe and characterize primary transcripts, and demonstrate here the simplicity, the reliability and the sensitivity of the method. The 5'tagRACE is complementary to tiling arrays or RNA-sequencing methods, and is also directly applicable to deep RNA sequencing and should significantly improve functional studies of bacterial RNA landscapes. From 45 selected loci of the E. faecalis chromosome, we discovered and mapped 29 novel ncRNAs, 10 putative novel mRNAs and 16 antisense transcriptional organizations. We describe in more detail the oxygen dependent expression of one ncRNA located in an E. faecalis pathogenicity island, the existence of an ncRNA that is antisense to the ncRNA modulator of the RNA polymerase, SsrS and provide evidences for the functional interplay between two distinct toxin-antitoxin modules. PMID- 21266482 TI - Structural and biochemical studies of human lysine methyltransferase Smyd3 reveal the important functional roles of its post-SET and TPR domains and the regulation of its activity by DNA binding. AB - The SET- and MYND-domain containing (Smyd) proteins constitute a special subfamily of the SET-containing lysine methyltransferases. Here we present the structure of full-length human Smyd3 in complex with S-adenosyl-L-homocysteine at 2.8 A resolution. Smyd3 affords the first example that other region(s) besides the SET domain and its flanking regions participate in the formation of the active site. Structural analysis shows that the previously uncharacterized C terminal domain of Smyd3 contains a tetratrico-peptide repeat (TPR) domain which together with the SET and post-SET domains forms a deep, narrow substrate binding pocket. Our data demonstrate the important roles of both TPR and post-SET domains in the histone lysine methyltransferase (HKMT) activity of Smyd3, and show that the hydroxyl group of Tyr239 is critical for the enzymatic activity. The characteristic MYND domain is located nearby to the substrate binding pocket and exhibits a largely positively charged surface. Further biochemical assays show that DNA binding of Smyd3 can stimulate its HKMT activity and the process may be mediated via the MYND domain through direct DNA binding. PMID- 21266483 TI - NMR structure of the A730 loop of the Neurospora VS ribozyme: insights into the formation of the active site. AB - The Neurospora VS ribozyme is a small nucleolytic ribozyme with unique primary, secondary and global tertiary structures, which displays mechanistic similarities to the hairpin ribozyme. Here, we determined the high-resolution NMR structure of a stem-loop VI fragment containing the A730 internal loop, which forms part of the active site. In the presence of magnesium ions, the A730 loop adopts a structure that is consistent with existing biochemical data and most likely reflects its conformation in the VS ribozyme prior to docking with the cleavage site internal loop. Interestingly, the A730 loop adopts an S-turn motif that is also present in loop B within the hairpin ribozyme active site. The S-turn appears necessary to expose the Watson-Crick edge of a catalytically important residue (A756) so that it can fulfill its role in catalysis. The A730 loop and the cleavage site loop of the VS ribozyme display structural similarities to internal loops found in the active site of the hairpin ribozyme. These similarities provided a rationale to build a model of the VS ribozyme active site based on the crystal structure of the hairpin ribozyme. PMID- 21266484 TI - A high-throughput DNA methylation analysis of a single cell. AB - In recent years, the field of epigenetics has grown dramatically and has become one of the most dynamic and fast-growing branches of molecular biology. The amount of diseases suspected of being influenced by DNA methylation is rising steadily and includes common diseases such as schizophrenia, bipolar disorder, Alzheimer's disease, diabetes, atherosclerosis, cancer, major psychosis, lupus and Parkinson's disease. Due to cellular heterogeneity of methylation patterns, epigenetic analyses of single cells become a necessity. One rationale is that DNA methylation profiles are highly variable across individual cells, even in the same organ, dependent on the function of the gene, disease state, exposure to environmental factors (e.g. radiation, drugs or nutrition), stochastic fluctuations and various other causes. Using a polymerase chain reaction (PCR) slide microreaction system, we present here a methylation-sensitive PCR analysis, the restriction enzyme-based single-cell methylation assay (RSMA), in the analysis of DNA methylation patterns in single cells. This method addresses the problems of cell heterogeneity in epigenetics research; it is comparably affordable, avoids complicated microfluidic systems and offers the opportunity for high-throughput screening, as many single cells can be screened in parallel. In addition to this study, critical principles and caveats of single cell methylation analyses are discussed. PMID- 21266485 TI - Induced topological changes in DNA complexes: influence of DNA sequences and small molecule structures. AB - Heterocyclic diamidines are compounds with antiparasitic properties that target the minor groove of kinetoplast DNA. The mechanism of action of these compounds is unknown, but topological changes to DNA structures are likely to be involved. In this study, we have developed a polyacrylamide gel electrophoresis-based screening method to determine topological effects of heterocyclic diamidines on four minor groove target sequences: AAAAA, TTTAA, AAATT and ATATA. The AAAAA and AAATT sequences have the largest intrinsic bend, whereas the TTTAA and ATATA sequences are relatively straight. The changes caused by binding of the compounds are sequence dependent, but generally the topological effects on AAAAA and AAATT are similar as are the effects on TTTAA and ATATA. A total of 13 compounds with a variety of structural differences were evaluated for topological changes to DNA. All compounds decrease the mobility of the ATATA sequence that is consistent with decreased minor groove width and bending of the relatively straight DNA into the minor groove. Similar, but generally smaller, effects are seen with TTTAA. The intrinsically bent AAAAA and AAATT sequences, which have more narrow minor grooves, have smaller mobility changes on binding that are consistent with increased or decreased bending depending on compound structure. PMID- 21266486 TI - The natural history of treated and untreated primary hyperparathyroidism: the parathyroid epidemiology and audit research study. AB - BACKGROUND: Primary hyperparathyroidism (PHPT) is a common endocrine disorder with the majority of cases being mild and untreated. AIM: To provide an update on the natural history of treated and untreated PHPT. DESIGN: Retrospective population-based observational study. METHODS: From 1997 to 2006, a well-defined cohort of PHPT patients was established in Tayside, Scotland. Subsequent cohorts of 'mild untreated' and 'surgically treated' PHPT patients were selected for the present study. Their serum calcium (S-Ca) and PTH concentrations were followed until September 2009. Surgical outcomes were evaluated using hospital admission data. RESULTS: A total of 904 'mild untreated' patients were identified (median follow-up=4.7 years), with a baseline median S-Ca of 2.62 mmol/l. A general decreased trend was observed in the S-Ca concentration for up to 12 years but an increasing trend in PTH (P<0.001 in both instances). Disease progression, defined as an increase in S-Ca concentration, was observed in 121 patients (13.4%). Twenty-six (2.9%) patients had undergone surgery during the subsequent follow-up period. Baseline age and PTH concentration were the only significant risk factors for disease progression. In comparison, there were 200 'surgically treated' patients (median follow-up=5.8 years). S-Ca was normalised after surgery, in 196 patients (98%). Hospital admissions for renal complications were reduced after surgery. In conclusion, most untreated patients with mild PHPT had no progression of S-Ca but approximately 15% did show some evidence of progression. Parathyroidectomy, with a high success rate, normalized the S-Ca in patients with PHPT. PMID- 21266488 TI - Paradoxical stimulatory effects of the "standard" histamine H4-receptor antagonist JNJ7777120: the H4 receptor joins the club of 7 transmembrane domain receptors exhibiting functional selectivity. AB - The histamine H(4) receptor (H(4)R) is expressed in several cell types of the immune system and is assumed to play an important pro-inflammatory role in various diseases, including bronchial asthma, atopic dermatitis, and pruritus. Accordingly, H(4)R antagonists have been suggested to provide valuable drugs for the treatment of these diseases. Over the past decade, the indole derivative 1 [(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine (JNJ7777120) has become the "standard" H(4)R antagonist and has been extensively used to assess the pathophysiological role of the H(4)R. However, the situation has now become more complicated by recent data (p. 749 and Naunyn Schmiedebergs Arch Pharmacol doi: 10.1007/s00210-011-0612-3) showing that JNJ7777120 can also activate beta arrestin in a supposedly G(i)-protein-independent (pertussis toxin-insensitive) manner and that at certain H(4)R species orthologs, JNJ7777120 exhibits partial agonist efficacy with respect to G(i)-protein activation (steady-state high affinity GTPase activity). These novel findings can be explained within the concept of functional selectivity or biased signaling, assuming unique ligand specific receptor conformations with distinct signal transduction capabilities. Thus, great caution must be exerted when interpreting in vivo effects of JNJ7777120 as H(4)R antagonism. We discuss future directions to get out of the current dilemma in which there is no "standard" H(4)R antagonist available to the scientific community. PMID- 21266487 TI - A cation-pi interaction at a phenylalanine residue in the glycine receptor binding site is conserved for different agonists. AB - Cation-pi interactions have been demonstrated to play a major role in agonist binding in Cys-loop receptors. However, neither the aromatic amino acid contributing to this interaction nor its location is conserved among Cys-loop receptors. Likewise, it is not clear how many different agonists of a given receptor form a cation-pi interaction or, if they do, whether it is with the same aromatic amino acid as the major physiological agonist. We demonstrated previously that Phe159 in the glycine receptor (GlyR) alpha1 subunit forms a strong cation-pi interaction with the principal agonist, glycine. In the current study, we investigated whether the lower efficacy agonists of the human GlyR beta alanine and taurine also form cation-pi interactions with Phe159. By incorporating a series of unnatural amino acids, we found cation-pi interactions between Phe159 and the amino groups of beta-alanine and taurine. The strengths of these interactions were significantly weaker than for glycine. Modeling studies suggest that beta-alanine and taurine are orientated subtly differently in the binding pocket, with their amino groups further from Phe159 than that of glycine. These data therefore show that similar agonists can have similar but not identical orientations and interactions in the binding pocket and provide a possible explanation for the lower potencies of beta-alanine and taurine. PMID- 21266489 TI - An X-linked haplotype of Neandertal origin is present among all non-African populations. AB - Recent work on the Neandertal genome has raised the possibility of admixture between Neandertals and the expanding population of Homo sapiens who left Africa between 80 and 50 Kya (thousand years ago) to colonize the rest of the world. Here, we provide evidence of a notable presence (9% overall) of a Neandertal derived X chromosome segment among all contemporary human populations outside Africa. Our analysis of 6,092 X-chromosomes from all inhabited continents supports earlier contentions that a mosaic of lineages of different time depths and different geographic provenance could have contributed to the genetic constitution of modern humans. It indicates a very early admixture between expanding African migrants and Neandertals prior to or very early on the route of the out-of-Africa expansion that led to the successful colonization of the planet. PMID- 21266490 TI - Video-assisted thoracic lobectomy with bronchoplasty for lung cancer, with special reference to methodology. AB - Few studies have described video-assisted thoracic surgery (VATS) to bronchoplasty with pulmonary resection. Here, we report the successful implementation of VATS bronchoplasty, as determined retrospectively. Between 2005 and 2010, 362 patients underwent elective lung resection for malignant or benign lung tumors. Of these patients, VATS lobectomy with bronchoplasty was performed in seven patients (four men, three women; median age, 72.9 years). The medical records were retrospectively reviewed. Of the seven patients, six had primary lung cancer (PLC), and one had metastatic cancer of the lung. The surgical procedures were lobectomy with wedge bronchoplasty. The patients with PLC also underwent mediastinal or hilar lymph node dissection. The median total operating time was 230 min, and the median blood loss was 152 ml. The median postoperative hospital stay was seven days, without major postoperative complications. The most important feature of the described method is that the surgeon mainly observes the operative field directly, through a working wound; the surgical team observes via a monitor. An advantage for the surgeon is the ability to use the same instruments in VATS as are used in conventional thoracotomy, as well as the same suturing techniques in vascular reconstruction, especially involving the pulmonary artery. PMID- 21266491 TI - Is prophylactic minitracheostomy beneficial in high-risk patients undergoing thoracotomy and lung resection? AB - A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was whether prophylactic minitracheostomy (PM) is beneficial in high-risk patients undergoing thoracotomy and lung resection. Altogether, 115 papers were found using the reported search, of which four represented the best evidence to answer the question. Three randomised controlled trials (RCT) compared a total of 161 patients who underwent thoracotomy and received either PM or standard postoperative treatment alone. Another non-RCT of 144 patients observed the reduction of toilet bronchoscopy with the increased use of PM. These are summarised in the Table. The studies assessed the benefit of PM inserted immediately after lung resection surgery in patients perceived as at high-risk of developing pulmonary complications. High-risk defined patients as those who smoked, have poor lung function, ischaemic heart disease, chronic obstructive pulmonary disease, absence/failure of regional analgesia, and/or cerebrovascular accident. In the largest randomised study (102 patients), Bonde et al. [Bonde P, Papachristos I, McCraith A, Kelly B, Wilson C, McGuigan JA, McManus K. Sputum retention after lung operation: prospective randomized trial shows superiority of prophylactic minitracheostomy in high-risk patients. Ann Thorac Surg 2002;74:196-202] concluded that the PM group had a significant reduction in sputum retention and postoperative atelectasis. The authors also reported a reduction in the incidence of pneumonia and toilet bronchoscopy but this did not achieve statistical significance. Issa et al. [Issa MM, Healy DM, Maghur HA, Luke DA. Prophylactic minitracheotomy in lung resection. A randomized controlled study. J Thorac Cardiovasc Surg 1991;101:895-900] were able to demonstrate a significant reduction in the rate of pneumonia in the PM group and Randell et al. [Randell TT, Tierala E, Lepantalo MJ, Lindgren L. Prophylactic minitracheostomy: a prospective, random control, clinical trial. Eur J Surg 1991;157:501-504] showed a significant reduction in postoperative atelectasis and toilet bronchoscopy in their PM group. Au et al. [Au J, Walker WS, Inglis D, Cameron EW. Percutaneous cricothyroidostomy (minitracheostomy) for bronchial toilet: results of therapeutic and prophylactic use. Ann Thorac Surg 1989;48:850 852] observed a reduction in toilet bronchoscopy from 9% to 4% in a four-year period; however, the authors could not directly relate this to the use of PM but believed it was likely. None of the studies demonstrated a statistical difference in mortality or intensive care unit or hospital length of 38 stay. All the studies reported some complications associated with minitracheostomy (MT) insertion, the incidence of which ranged from 5.6% to 57%. One percent of 227 patients who received MT in the studies experienced a life-threatening complication, the rest were minor and easily controlled. None of the complications resulted in death. PMID- 21266492 TI - Open door approach by partial sternotomy and sterno-costo-chondroplasty for annuloaortic ectasia with pectus excavatum. AB - A 32-year-old female patient with Marfan syndrome was admitted for repair of annuloaortic ectasia and severe pectus excavatum. Because the chest cage deformity was severe, concomitant reparative surgery of the chest wall was performed. Partial median sternotomy and left second-fifth rib division was made to obtain good surgical field. The patient underwent valve-sparing aortic root remodeling successfully. After complete neutralization of heparin, additional division of the right ribs was performed and each rib and the sternum was reshaped. Pectus excavatum was completely repaired by this method. We believe this approach is efficacious for intracardiac repair with severe pectus excavatum. PMID- 21266493 TI - Does positron emission tomography offer prognostic information in malignant pleural mesothelioma? AB - A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was whether positron emission tomography is useful in the diagnosis and prognosis of malignant pleural mesothelioma (MPM). Altogether 136 papers were found using the reported search, of which 15 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. We conclude that fluorodeoxyglucose-positron emission tomography (FDG-PET) accurately differentiates benign from malignant pleural disease, helps detect recurrence and provides prognostic information in terms of staging, survival and mortality. Eleven studies evaluated the role of FDG-PET in the diagnosis and prognosis of MPM. Malignant disease had a higher standardised uptake value (SUV) (6.5 +/- 3.4 vs. 0.8 +/- 0.6; P < 0.001) than benign pleural disease. Shorter median survival (9.7 vs. 21 months; P = 0.02) was associated with high SUV (>10) than low SUV (<10). PET accurately upstaged 13% and downstaged 27% of cases initially staged with computed tomography (CT). In patients undergoing chemotherapy, higher total glycolytic volume led to a lower median survival (4.9 vs. 11.5 months; P = 0.09), while a decline in FDG uptake was associated with a longer time to tumour progression (14 vs. 7 months; P = 0.02). Four studies observed the role of FDG PET-CT in the diagnosis and prognosis of MPM. SUV was found to be higher in MPM compared to benign pleural disease (6.5 vs. 0.8; P < 0.001). A higher SUV(max) was observed in primary pleural lesions of metastatic (7.1 vs. 4.7; P = 0.003) compared to non-metastatic disease. Patients who underwent surgery had equivalent survival to those excluded based on scan results (20 vs. 12 months; P = 0.3813). One study compared the utility of PET and PET-CT in the diagnosis and prognosis of mesothelioma. PET-CT was found to be more accurate than PET in terms of staging (P < 0.05) disease. Overall, PET accurately diagnoses MPM, predicts survival and disease recurrence. It can guide further management by predicting the response to chemotherapy and excluding surgery in patients with extrathoracic disease. Combined PET-CT has additional benefits in accurately staging disease. PMID- 21266494 TI - Computational models of VEGF-associated angiogenic processes in cancer. AB - Tumour angiogenesis allows a growing mass of cancer cells to overcome oxygen diffusion limitation and to increase cell survival. The growth of capillaries from pre-existing blood vessels is the result of numerous signalling cascades involving different molecules and of cellular events involving multiple cell and tissue types. Computational models offer insight into the mechanisms governing angiogenesis and provide quantitative information on parameters difficult to assess by experiments alone. In this article, we summarize results from computational models of tumour angiogenic processes with a focus on the molecular detailed vascular endothelial growth factor-associated models that have been developed in our laboratory, spanning multiple scales from the molecular to whole body. PMID- 21266495 TI - Dynamic imaging of glucose flux impedance using FRET sensors in wild-type Arabidopsis plants. AB - Quantitative and dynamic analysis of metabolites and signalling molecules is limited by technical challenges in obtaining temporally resolved information at the cellular and compartmental level. Real-time information on signalling and metabolite levels with subcellular granularity can be obtained with the help of genetically encoded FRET (Forster resonance energy transfer) nanosensors. FRET nanosensors represent powerful tools for gene discovery, and analysis of regulatory networks, for example by screening mutants. However, RNA silencing has impaired our ability to express FRET nanosensors functionally in Arabidopsis plants. This drawback was overcome here by expressing the nanosensors in RNA silencing mutants. However, the use of silencing mutants requires the generation of homozygous lines deficient in RNA silencing as well as the mutation of interest and co-expression of the nanosensor. Here it is shown that dynamic changes in cytosolic glucose levels can readily be quantified in wild-type Arabidopsis plants at early stages of development (7-15 d) before silencing had a major effect on fluorescence intensity. A detailed protocol for screening 10-20 mutant seedlings per day is provided. The detailed imaging protocol provided here is suitable for analysing sugar flux in young wild-type plants as well as mutants affected in sugar signalling, metabolism, or transport using a wide spectrum of FRET nanosensors. PMID- 21266496 TI - Independent effects of leaf growth and light on the development of the plastid and its DNA content in Zea species. AB - In maize (Zea mays L.), chloroplast development progresses from the basal meristem to the mature leaf tip, and light is required for maturation to photosynthetic competence. During chloroplast greening, it was found that chloroplast DNA (cpDNA) is extensively degraded, falling to undetectable levels in many individual chloroplasts for three maize cultivars, as well as Zea mexicana (the ancestor of cultivated maize) and the perennial species Zea diploperennis. In dark-grown maize seedlings, the proplastid-to-etioplast transition is characterized by plastid enlargement, cpDNA replication, and the retention of high levels of cpDNA. When dark-grown seedlings are transferred to white light, the DNA content per plastid increases slightly during the first 4 h of illumination and then declines rapidly to a minimum at 24 h during the etioplast-to-chloroplast transition. Plastid autofluorescence (from chlorophyll) continues to increase as cpDNA declines, whereas plastid size remains constant. It is concluded that the increase in cpDNA that accompanies plastid enlargement is a consequence of cell and leaf growth, rather than illumination, whereas light stimulates photosynthetic capacity and cpDNA instability. When cpDNA from total tissue was monitored by blot hybridization and real-time quantitative PCR, no decline following transfer from dark to light was observed. The lack of agreement between DNA per plastid and cpDNA per cell may be attributed to nupts (nuclear sequences of plastid origin). PMID- 21266497 TI - The auxin receptor homologue in Solanum lycopersicum stimulates tomato fruit set and leaf morphogenesis. AB - TIR1 and its homologues act as auxin receptors and play a crucial role in auxin mediated plant development. While the functions of auxin receptor genes have been widely studied in Arabidopsis thaliana, there has been no report on the consequences of TIR1 overexpression in plants that regulate fruit development. Here a putative tomato auxin receptor gene, homologous to Arabidopsis AtTIR1, is reported. This gene, designated as Solanum lycopersicum TIR1 (SlTIR1), was found to be expressed in all the parts of floral buds and flowers at anthesis stages. From bud to anthesis, SlTIR1 expression increases slightly in sepal tissue and decreases dramatically in stamen. From anthesis to post-anthesis when fruit set is expected to occur, the expression of SlTIR1 declines in the ovary and sepal. Overexpression of SlTIR1 results in a pleiotropic phenotype including parthenocarpic fruit formation and leaf morphology. Furthermore, SlTIR1 overexpression altered transcript levels of a number of auxin-responsive genes. The present data demonstrate that the tomato SlTIR1 gene plays an important role at the stages of flower-to-fruit transition and leaf formation. PMID- 21266498 TI - Education about HIV/AIDS--theoretical underpinnings for a practical response. AB - Human immunodeficiency virus (HIV)- and acquired immunodeficiency syndrome (AIDS) related education is seen by many as central to increasing young people's awareness of, as well as decreasing their vulnerability to, HIV. There is less agreement, however, on the central goals of HIV- and AIDS-related education and the form it might best take. This paper offers a conceptual framework for understanding some of the main approaches to HIV- and AIDS-related education being implemented today, drawing a distinction between approaches which are 'scientifically' informed; those that draw upon notions of 'rights' and those which are overtly 'moralistic' in the sense that they promote conservative moral positions concerning sexuality and sexual acts. In outlining these three approaches, we examine different ways in which the terms 'science', 'rights' and 'moral values' are conceptualized and some of the key assumptions underpinning different forms of HIV- and AIDS-related education. Findings will be useful for those desiring to develop a typology of approaches to HIV- and AIDS-related education and their potential effects. PMID- 21266499 TI - Fas (CD95/APO-1) limits the expansion of T lymphocytes in an environment of limited T-cell antigen receptor/MHC contacts. AB - Fas-deficient mice (Fas(lpr/lpr)) and humans have profoundly dysregulated T lymphocyte homeostasis, which manifests as an accumulation of CD4(+) and CD8(+) T cells as well as an unusual population of CD4(-)CD8(-)TCRalphabeta(+) T cells. To date, no unifying model has explained both the increased T-cell numbers and the origin of the CD4(-)CD8(-)TCRalphabeta(+) T cells. As Fas(lpr/lpr) mice raised in a germ-free environment still manifest lymphadenopathy, we considered that this process is primarily driven by recurrent low-avidity TCR signaling in response to self-peptide/MHC as occurs during homeostatic proliferation. In these studies, we developed two independent systems to decrease the number of self-peptide/MHC contacts. First, expression of MHC class I was reduced in OT-I TCR transgenic mice. Although OT-I Fas(lpr/lpr) mice did not develop lymphadenopathy characteristic of Fas(lpr/lpr) mice, in the absence of MHC class I, OT-I Fas(lpr/lpr) T cells accumulated as both CD8(+) and CD4(-)CD8(-) T cells. In the second system, re-expression of beta(2)m limited to thymic cortical epithelial cells of Fas(lpr/lpr) beta(2)m-deficient mice yielded a model in which polyclonal CD8(+) thymocytes entered a peripheral environment devoid of MHC class I. These mice accumulated significantly greater numbers of CD4(-)CD8(-)TCRalphabeta(+) T cells than conventional Fas(lpr/lpr) mice. Thus, Fas shapes the peripheral T-cell repertoire by regulating the survival of a subset of T cells proliferating in response to limited self-peptide/MHC contacts. PMID- 21266500 TI - SERCA2a superinhibition by human phospholamban triggers electrical and structural remodeling in mouse hearts. AB - Phospholamban (PLN), the reversible inhibitor of the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a), is a key regulator of myocyte Ca(2+) cycling with a significant role in heart failure. We previously showed that the single amino acid difference between human and mouse PLN results in increased inhibition of Ca(2+) cycling and cardiac remodeling and attenuated stress responses in transgenic mice expressing the human PLN (hPLN) in the null background. Here we dissect the molecular and electrophysiological processes triggered by the superinhibitory hPLN in the mouse. Using a multidisciplinary approach, we performed global gene expression analysis, electrophysiology, and mathematical simulations on hPLN mice. We identified significant changes in a series of Na(+) and K(+) homeostasis genes/proteins (including Kcnd2, Scn9a, Slc8a1) and ionic conductance (including L-type Ca(2+) current, Na(+)/Ca(2+) exchanger, transient outward K(+) current). Simulation analysis suggests that this electrical remodeling has a critical role in rescuing cardiac function by improving sarcoplasmic reticulum Ca(2+) load and overall Ca(2+) dynamics. Furthermore, multiple structural and transcription factor gene expression changes indicate an ongoing structural remodeling process, favoring hypertrophy and myogenesis while suppressing apoptosis and progression to heart failure. Our findings expand current understanding of the hPLN function and provide additional insights into the downstream implications of SERCA2a superinhibition in the mammalian heart. PMID- 21266501 TI - Comprehensive microRNA analysis in bleomycin-induced pulmonary fibrosis identifies multiple sites of molecular regulation. AB - The molecular mechanisms of lung injury and fibrosis are incompletely understood. MicroRNAs (miRNAs) are crucial biological regulators that act by suppressing their target genes and are involved in a variety of pathophysiological processes. To gain insight into miRNAs in the regulation of lung fibrosis, total RNA was isolated from mouse lungs harvested at different days after bleomycin treatment, and miRNA array with 1,810 miRNA probes was performed thereafter. MiRNAs expressed in lungs with bleomycin treatment at different time points were compared with miRNAs expressed in lungs without bleomycin treatment, resulting in 161 miRNAs differentially expressed. Furthermore, miRNA expression patterns regulated in initial and late periods after bleomycin were identified. Target genes were predicted in silico for differentially expressed miRNAs, including let 7f, let-7g, miR-196b, miR-16, miR-195, miR-25, miR-144, miR-351, miR-153, miR 468, miR-449b, miR-361, miR-700, miR-704, miR-717, miR-10a, miR-211, miR-34a, miR 367, and miR-21. Target genes were then cross-referenced to the molecular pathways, suggesting that the differentially expressed miRNAs regulate apoptosis, Wnt, Toll-like receptor, and TGF-beta signaling. Our study demonstrated a relative abundance of miRNA levels in bleomycin-induced lung fibrosis. The miRNAs and their potential target genes identified may contribute to the understanding of the complex transcriptional program of lung fibrosis. PMID- 21266502 TI - Gene expression profiling of skeletal muscles treated with a soluble activin type IIB receptor. AB - Inhibition of the myostatin signaling pathway is emerging as a promising therapeutic means to treat muscle wasting and degenerative disorders. Activin type IIB receptor (ActRIIB) is the putative myostatin receptor, and a soluble activin receptor (ActRIIB-Fc) has been demonstrated to potently inhibit a subset of transforming growth factor (TGF)-beta family members including myostatin. To determine reliable and valid biomarkers for ActRIIB-Fc treatment, we assessed gene expression profiles for quadriceps muscles from mice treated with ActRIIB-Fc compared with mice genetically lacking myostatin and control mice. Expression of 134 genes was significantly altered in mice treated with ActRIIB-Fc over a 2-wk period relative to control mice (fold change > 1.5, P < 0.001), whereas the number of significantly altered genes in mice treated for 2 days was 38, demonstrating a time-dependent response to ActRIIB-Fc in overall muscle gene expression. The number of significantly altered genes in Mstn(-/-) mice relative to control mice was substantially higher (360), but for most of these genes the expression levels in the 2-wk treated mice were closer to the levels in the Mstn( /-) mice than in control mice (P < 10-30). Expression levels of 30 selected genes were further validated with quantitative real-time polymerase chain reaction (qPCR), and a correlation of >= 0.89 was observed between the fold changes from the microarray analysis and the qPCR analysis. These data suggest that treatment with ActRIIB-Fc results in overlapping but distinct gene expression signatures compared with myostatin genetic mutation. Differentially expressed genes identified in this study can be used as potential biomarkers for ActRIIB-Fc treatment, which is currently in clinical trials as a therapeutic agent for muscle wasting and degenerative disorders. PMID- 21266503 TI - Gene expression profiling in peripheral blood cells of patients with rheumatoid arthritis in response to anti-TNF-alpha treatments. AB - The efficacy of anti-TNF-alpha therapies highlights the role of TNF-alpha in the pathogenesis of rheumatoid arthritis (RA). However, the mechanism of action of these agents is poorly understood at the molecular level. The aim of this study was to characterize the effects of anti-TNF-alpha treatment on the global gene expression profile in peripheral blood mononuclear cells (PBMCs) of responder RA patients. Changes in gene expression were determined using oligonucleotide microarrays (25,341 genes) in PBMCs obtained before and after 12 wk of treatment with either etanercept or adalimumab from responder RA patients. Two hundred fifty-one genes displayed significant changes (false discovery rate < 0.1%) in expression level (178 upregulations with mean fold change = 1.5 and 73 downregulations with mean fold change = -1.50) after 12 wk of treatment. Importantly, the expression of several genes, including those coding for the calcium binding proteins S100A12 and A8, CD14 antigen, Selectin P, or ribosomal protein L39, reported to be upregulated in RA patients, were found to be decreased after anti-TNF-alpha treatment. Globally, inflammation, immune response, apoptosis, protein synthesis, and mitochondrial oxido-reduction were the most affected pathways in response to anti-TNF-alpha treatment. The obtained gene expression signature in PBMCs provides new information to better understand the mechanisms of action of anti-TNF-alpha treatment in RA patients. PMID- 21266504 TI - Blood gene expression signatures associate with heart failure outcomes. AB - Gene expression signatures in blood correlate with specific diseases. Such signatures may serve as valuable diagnostic and prognostic tools in disease management. Blood gene expression signatures associated with heart failure may be applied to predict prognosis, monitor disease progression, and optimize treatment. Blood gene expression profiles were generated for 71 subjects with heart failure and 15 controls without heart failure, using the Affymetrix GeneChip U133Plus2.0. Survival analysis identified 197 "mortality genes" that were significantly associated with patient outcome. Functional categorization showed that genes associated with T cell receptor signaling were most significantly overpresented. Cluster analysis of these T cell receptor signaling genes significantly categorized heart failure patients into three risk groups (P = 0.031) that were distinct from the three risk groups categorized by New York Heart Association (NYHA) Classification (P = 0.0002). By combining the analysis of clinical assessment (NYHA class) with T cell receptor signaling gene expression, we proposed a model that demonstrated an even greater differentiation of patients at risk (P = 0.0001). In this discovery study, we identified blood expression signatures associated with heart failure patient outcomes. Characterization of these mortality genes helped identify a set of T cell receptor signaling genes that may be of utility in predicting survival of heart failure patients. These data raise the possibility of prospectively risk stratifying patients with heart failure by integrating blood gene expression signatures with current clinical assessment. PMID- 21266506 TI - Identification of S100A16 as a novel adipogenesis promoting factor in 3T3-L1 cells. AB - S100A16 is a member of S100 protein super family that carries calcium-binding EF hand motifs. Its expression is ubiquitous and elevated in various types of tumors. The functions of S100 proteins are still being defined, although many members of S100 protein family are traditionally considered as markers of tumor tissues. Using 3T3-L1 preadipocyte model, we investigated the expression and function of S100A16 during differentiation into adipocytes as well as the potential roles of S100A16 in the regulation of insulin sensitivity. We found that the expression of S100A16 was increased during differentiation and that elevation of intracellular Ca(2+) via calcium ionophores led to its nucleus exclusion. Overexpression of S100A16 in 3T3-L1 preadipocytes increased their proliferation and markedly enhanced adipogenesis but resulted in significant reduction of insulin-stimulated glucose uptake and phosphorylation of AKT. In contrast, suppression of S100A16 expression with two different types of RNA interference significantly inhibited adipogenesis and preadipocyte proliferation. Immunoprecipitation analysis revealed that S100A16 could physically interact with tumor suppressor protein p53, also a known inhibitor of adipogenesis. Overexpression or RNA interference-initiated reduction of S100A16 led to the inhibition or activation of the expression of p53-responsive genes, respectively. Interestingly, Western blot assays showed that S100A16 protein levels were markedly higher in the adipose tissues of diet-induced obese mice and the ob/ob mice than that in control lean mice. Thus, we reveal for the first time that S100A16 protein is a novel adipogenesis-promoting factor and that increased expression of S100A16 in 3T3-L1 adipocytes can have a negative impact on insulin sensitivity. PMID- 21266505 TI - Hormone-related risk factors and postmenopausal breast cancer among nulliparous versus parous women: An aggregated study. AB - Nulliparity is an established breast cancer risk factor, particularly when compared with parity at young ages. The authors aggregated data from 4 US prospective studies (1979-2006) including 32,641 nulliparous (1,612 breast cancers) and 204,270 parous (8,180 breast cancers) women to examine the hypothesis that nulliparity may increase susceptibility to established postmenopausal breast cancer risk factors. The aggregated hazard ratio for nulliparous versus all parous women = 1.27 (95% confidence interval: 1.21, 1.34), and that for nulliparous versus women <25 years of age at first birth = 1.38 (95% confidence interval: 1.30, 1.46). Among nulliparous women, the hazard ratios for current menopausal hormone therapy use (vs. never use), body mass index >=30 kg/m(2) (vs. <25 kg/m(2)), and weekly consumption of >=7 alcoholic drinks (vs. none) ranged from 1.3 to 1.6. The hazard ratios did not differ by parity. In a model including all women, the joint association for each of these factors and nulliparity combined compared with first birth before age 25 years was an approximately 2-fold increased breast cancer risk. Although the baseline risk is higher for nulliparous women compared with parous women, these results suggest that the associations between hormone-related factors and breast cancer do not differ by parity. PMID- 21266507 TI - Role of EphA4 receptor signaling in thyroid development: regulation of folliculogenesis and propagation of the C-cell lineage. AB - Transcriptome analysis revealed that the tyrosine kinase receptor EphA4 is enriched in the thyroid bud in mouse embryos. We used heterozygous EphA4-EGFP knock-in mice in which enhanced green fluorescent protein (EGFP) replaced the intracellular receptor domain (EphA4(+/EGFP)) to localize EphA4 protein in thyroid primordial tissues. This showed that thyroid progenitors originating in the pharyngeal floor express EphA4 at all embryonic stages and when follicles are formed in late development. Also, the ultimobranchial bodies developed from the pharyngeal pouch endoderm express EphA4, but the ultimobranchial epithelium loses the EGFP signal before it merges with the median thyroid primordium. Embryonic C cells invading the thyroid are exclusively EphA4-negative. EphA4 expression continues in the adult thyroid. EphA4 knock-out mice and EphA4-EGFP homozygous mutants are euthyroid and have a normal thyroid anatomy but display subtle histological alterations regarding number, size, and shape of follicles. Of particular interest, the pattern of follicular abnormality differs between EphA4( /-) and EphA4(EGFP/EGFP) thyroids. In addition, the number of C cells is reduced by >50% exclusively in animals lacking EphA4 forward signaling (EphA4(EGFP/EGFP)). Heterozygous EphA4 mutants have no apparent thyroid phenotype. We conclude that EphA4 is a novel regulator of thyroid morphogenesis that impacts on postnatal development of the two endocrine cell lineages of the differentiating gland. In this process both EphA4 forward signaling (in the follicular epithelium) and reverse signaling mediated by its cognate ligand(s) (A and/or B-ephrins expressed in follicular cells and C cells, respectively) are probably functionally important. PMID- 21266508 TI - Subacute endotoxemia induces adipose inflammation and changes in lipid and lipoprotein metabolism in cats. AB - Acute inflammation in humans is associated with transient insulin resistance (IR) and dyslipidemia. Chronic low-grade inflammation is a pathogenic component of IR and adipose tissue dysfunction in obesity-induced type 2 diabetes. Because feline diabetes closely resembles human type 2 diabetes, we studied whether lipopolysaccharide (LPS)-induced subacute inflammation, in the absence of obesity, is the potential primary cause of IR and metabolic disorders. Cats received increasing iv doses (10-1000 ng/kg(-1) . h(-1)) of LPS (n = 5) or saline (n = 5) for 10 d. Body temperature, proinflammatory and metabolic markers, and insulin sensitivity were measured daily. Tissue mRNA and protein expression were quantified on d 10. LPS infusion increased circulating and tissue markers of inflammation. Based on the homeostasis model assessment, endotoxemia induced transient IR and beta-cell dysfunction. At the whole-body level, IR reverted after the 10-d treatment; however, tissue-specific indications of IR were observed, such as down-regulation of adipose glucose transporter 4, hepatic peroxisome proliferative activated receptor-gamma1 and -2, and muscle insulin receptor substrate-1. In adipose tissue, increased hormone-sensitive lipase activity led to reduced adipocyte size, concomitant with increased plasma and hepatic triglyceride content and decreased total and high-density lipoprotein cholesterol levels. Prolonged LPS-induced inflammation caused acute IR, followed by long-lasting tissue-specific dysfunctions of lipid-, glucose-, and insulin metabolism-related targets; this ultimately resulted in dyslipidemia but not whole-body IR. Endotoxemia in cats may provide a promising model to study the cross talk between metabolic and inflammatory responses in the development of adipose tissue dysfunction and IR. PMID- 21266509 TI - Fetal programming of gene expression in growth-restricted rats depends on the cause of low birth weight. AB - Low birth weight and intrauterine growth restriction (IUGR) can be caused by numerous different conditions. In many experimental settings, however, these different causes are not accounted for. This study aimed at comparing the impact of two frequent causes of IUGR (low utero-placental blood flow vs. malnutrition) on fetal programming of gene expression. We studied offspring of dams treated by uterine artery ligation or sham operation compared with untreated controls and offspring of dams that were fed either a low protein or normal protein diet. After Cesarean section at term, placental and fetal hepatic expression of key "metabolic" and "vasoregulative" genes was investigated by quantitative RT-PCR. Ligation neonates showed IUGR, reduced expression of placental leptin, placental and hepatic IGF-I, hepatic inducible nitric oxide synthase, and increased expression of placental IGF binding protein 1, hepatic IGF-II receptor and erythropoietin (EPO). Low protein offspring also showed IUGR but increased expression of placental leptin; IGF-I; placental and hepatic inducible nitric oxide synthase; hepatic insulin, IGF-I, and IGF-II receptors; and reduced expression of placental IGF binding protein 1, IGF-II, leptin-receptor type A, placental and hepatic leptin receptor type B, and EPO. Expression was independent of sex, birth weight, fetal intrauterine position, and EPO expression. In conclusion, the impact of IUGR on fetal and placental gene expression depends on the cause of low birth weight. Therefore, morbidity after IUGR should be analyzed referring to its pathophysiological cause rather than referring to low birth weight itself. Fetal hypoxia as estimated by hepatic EPO expression does not seem to be a key regulator of transcriptional activity in our models. PMID- 21266510 TI - beta2-Adrenergic receptor signaling in osteoblasts contributes to the catabolic effect of glucocorticoids on bone. AB - The sympathetic nervous system is a physiological regulator of bone homeostasis. Autonomic nerves are indeed present in bone, bone cells express the beta2 adrenergic receptors (beta2AR), and pharmacological or genetic disruption of sympathetic outflow to bone induces bone gain in rodents. These recent findings implied that conditions that affect beta2AR signaling in osteoblasts and/or sympathetic drive to bone may contribute to bone diseases. In this study, we show that dexamethasone stimulates the expression of the beta2AR in differentiated primary calvarial osteoblasts, as measured by an increase in Adrbeta2 mRNA and beta2AR protein level after short-term dexamethasone treatment. Isoproterenol induced cAMP accumulation and the expression of the beta2AR target gene Rankl were also significantly increased after dexamethasone pretreatment, indicating that dexamethasone promotes the responsiveness of differentiated osteoblasts to adrenergic stimulation. These in vitro results led to the hypothesis that glucocorticoid-induced bone loss, provoked by increased endogenous or high-dose exogenous glucocorticoids given for the treatment of inflammatory diseases, might, at least in part, be mediated by increased sensitivity of bone-forming cells to the tonic inhibitory effect of sympathetic nerves on bone formation or their stimulatory effect on bone resorption. Supporting this hypothesis, both pharmacological and genetic beta2AR blockade in mice significantly reduced the bone catabolic effect of high-dose prednisolone in vivo. This study emphasizes the importance of sympathetic nerves in the regulation of bone homeostasis and indicates that this neuroskeletal signaling axis can be modulated by hormones or drugs and contribute to enhance pathological bone loss. PMID- 21266511 TI - Low-grade hypothalamic inflammation leads to defective thermogenesis, insulin resistance, and impaired insulin secretion. AB - Hypothalamic inflammation is present in animal models of obesity, and the intracerebroventricular injection of TNFalpha can reproduce a number of features of the hypothalamus of obese animals. Because obesity is a risk factor for type 2 diabetes (DM2) we hypothesized that, by inducing hypothalamic inflammation, we could reproduce some clinical features of DM2. Lean Wistar rats and TNF receptor 1-knockout mice were employed to determine the effects of hypothalamic actions of TNFalpha on thermogenesis and metabolic parameters. Signal transduction and protein expression were evaluated by immunoblot and real-time PCR. Thermogenesis was evaluated in living rats, and respirometry was determined in isolated muscle fiber. In Wistar rats, hypothalamic TNFalpha blunts the anorexigenic effect of leptin, which is accompanied by reduced leptin signaling and increased expression of suppressor of cytokine signaling 3. In addition, hypothalamic TNFalpha reduces O(2) consumption and the expression of thermogenic proteins in brown adipose tissue and skeletal muscle. Furthermore, hypothalamic inflammation increases base line plasma insulin and insulin secretion by isolated pancreatic islets, which is accompanied by an impaired insulin signal transduction in liver and skeletal muscle. Hypothalamic inflammation induced by stearic acid also reduces O(2) consumption and blunts peripheral insulin signal transduction. The use of intracerebroventricular infliximab restores O(2) consumption in obese rats, whereas TNF receptor 1-knockout mice are protected from diet-induced reduced thermogenesis and defective insulin signal transduction. Thus, low-grade inflammation of the hypothalamus is sufficient to induce changes in a number of parameters commonly impaired in obesity and DM2, and TNFalpha is an important mediator of this process. PMID- 21266512 TI - Thyroid hormone and COUP-TF1 regulate kallikrein-binding protein (KBP) gene expression. AB - Kallikrein-binding protein (KBP) is a component of the kallikrein-kinin system that mediates vasodilation and inhibits tumor growth by antagonizing vascular endothelial growth factor-mediated angiogenesis. We demonstrate that KBP gene expression is repressed by T(3) and modulated by the orphan nuclear receptor, chicken ovalbumin upstream promoter transcription factor 1 (COUP-TF1). In hypothyroid mice, KBP mRNA expression in the testis was increased 2.1-fold compared with euthyroid mice. We have identified two negative thyroid hormone response elements (nTREs) in the mouse KBP gene, nTRE1 located in the 5' flanking region (-53 to -29) and nTRE2, located in the first intron (104-132). We used functional assays, cofactor knockdown, and chromatin immunoprecipitation assays to characterize nTRE1 and nTRE2 in hepatic (HepG2) and testes (GC-1spg) cell lines. Reporter expression directed by both elements was enhanced with addition of thyroid hormone receptor and repressed with the addition of T(3). COUP-TF1 enhanced basal expression of both elements but blunted unliganded thyroid hormone receptor enhancement and T(3) repression of nTRE1 but not nTRE2. Both nTREs bound nuclear corepressor and binding increased in response to T(3). Nuclear corepressor knockdown resulted in loss of T(3) repression of both nTRE1 and nTRE2. COUP-TF1, which usually represses T(3) induction of positive thyroid hormone response elements, reverses T(3) repression mediated by nTRE1 in the mouse KBP gene. Endogenous KBP expression is repressed by T(3) and two functional nTREs, both of which are required, have been characterized in the KBP gene. COUP TF1 may be an important factor to modulate expression of genes that are repressed by T(3). PMID- 21266513 TI - A randomized controlled study of accelerated versus standard hepatitis B vaccination in HIV-positive patients. AB - BACKGROUND: In human immunodeficiency virus (HIV)-infected patients, the immunogenicity of hepatitis B vaccines is impaired. The primary and secondary aims of our study were to investigate the effectiveness and compliance of 2 different vaccination regimen in an HIV-infected population. METHODS: A noninferiority trial with a 10% response margin was designed. Included were patients >= 18 years old, with negative HBsAg/anti-HBc serology, and not previously vaccinated against hepatitis B. Patients were stratified according to CD4(+) cell count: <200, 200-500, >500. Participants received 10 MUg HBvaxPRO intramuscularly according to a 0-1-3 week schedule or the standard 0-4-24 week schedule. Anti-HBs levels were measured at week 28, considered protective >= 10 IU/L. RESULTS: Modified intention to treat analysis in 761 patients was performed. Overall response difference was 50%(standard arm) versus 38.7% (accelerated arm) =11.3% (95% confidence interval [CI], [4.3, 18.3]), close to the 10% response margin. In CD4(+) cell count group 200-500 cells/mm(3,) the response difference was 20.8% (95% CI [10.9, 30.7]). However, the response difference in CD4(+)cell count group >500 cells/mm(3) was -1.8% (95% CI [ 13.4,+9.7]). Compliance was significantly superior with the accelerated schedule, 91.8% versus 82.7% (P <= .001). CONCLUSION: In HIV-infected patients, compliance with an accelerated hepatitis B vaccination schedule is significantly better. The efficacy of an accelerated schedule proved to be non-inferior in CD4(+) cell count group >500 cells/mm(3). CLINICAL TRIALS REGISTRATION: CT00230061. PMID- 21266514 TI - Statins as anti-inflammatory therapy in HIV disease? PMID- 21266515 TI - Differential mRNA expression of genes in the porcine adrenal gland associated with psychosocial stress. AB - To gain insight into the adrenal stress response, we analysed differential mRNA expression of genes associated with psychosocial stress in the pig (Sus scrofa domestica). Various levels of psychosocial stress were induced by mixing groups of unfamiliar pigs with different aggressiveness. We selected two experimental groups for comparison, each comprising eight animals, which differed significantly in aggressive behaviour and plasma cortisol levels. To identify differentially expressed genes, we compared the adrenal transcriptome of these two groups of pigs, using the Affymetrix GeneChip porcine Genome Array. Bioinformatic analysis revealed that psychosocial stress induced upregulation of transcripts enriched for functions associated with cholesterol accumulation and downregulation of transcripts enriched for functions associated with cell growth and death. These responses are similar to those induced by ACTH stimulation. Nevertheless, the majority of the differentially expressed genes were so far not described as ACTH responsive. Some, such as GAL and GALP, may have responded to sympathoadrenal stimulation. Several of the differentially expressed transcripts, such as AGT, are associated with processes modulating steroidogenic response of adrenocortical cells to ACTH. One of the most significant findings was upregulation of LOC100039095, comprising a precursor of the microRNA miR-202, pointing to a previously unrecognised layer of regulation of adrenal steroidogenesis by microRNA. Our study, performed under entirely physiological conditions, complements previous studies focusing either on a single adrenal tissue and/or on a single stimulus, and contributes to understanding of the fine tuning of adrenal stress response. PMID- 21266516 TI - A German multicenter, randomized phase III trial comparing irinotecan-carboplatin with etoposide-carboplatin as first-line therapy for extensive-disease small-cell lung cancer. AB - BACKGROUND: This trial was designed to prove superiority of irinotecan over etoposide combined with carboplatin in extensive-disease small-cell lung cancer. PATIENTS AND METHODS: Patients were randomly assigned to receive carboplatin area under the curve 5 mg x min/ml either in combination with irinotecan 50 mg/m2 on days 1, 8, and 15 (IP) or etoposide 140 mg/m2 on days 1-3 (EP). Primary end point was progression-free survival (PFS) at 6 months. Secondary end points were overall survival (OS), response rate, and toxicity. RESULTS: Of 226 patients, 216 were eligible. Median PFS was 6.0 months [95% confidence interval (CI) 5.0-7.0] in the IP arm and 6.0 months (95% CI 5.2-6.8) in EP arm (P = 0.07). Median survival was 10.0 months (95% CI 8.4-11.6) and 9.0 months (95% CI 7.6-10.4) in the IP and EP arm (P = 0.06), respectively. Hazard ratios for disease progression and OS were 1.29 (95% CI 0.96-1.73, P = 0.095) and 1.34 (95% CI 0.97-1.85, P = 0.072), respectively. No difference in response rates was observed. Grade 3 and 4 hematologic toxicity favored the IP arm, whereas diarrhea was significantly more frequent in the IP arm. CONCLUSION: This trial failed to show superiority of irinotecan over etoposide in combination with carboplatin. PMID- 21266517 TI - EORTC workshop on clinical trial methodology in older individuals with a diagnosis of solid tumors. AB - BACKGROUND: Due to the aging of the population, the number of older patients diagnosed with a malignant disease is increasing. A multidisciplinary approach to the senior adult cancer patient is mandatory, to assure optimal diagnosis and therapeutic management. DESIGN: European Organisation for Research and Treatment of Cancer (EORTC) has currently defined senior adult oncology as one of its priorities and has established an active Elderly Task Force (ETF). Under the auspices of the EORTC, the ETF organized a workshop on clinical trial methodology in older cancer patients and in this article, we present the conclusions of this workshop. RESULTS: Besides the 'classical' efficacy end points, quality of life, functional status and independence of the patient should be assessed in clinical trials in older patients. The participants of the workshop agreed on the use of a minimum dataset for the assessment of global health and functional status in older cancer patients. The panel also recommended that optimization of collaboration with pharmaceutical industry requires reporting of age-related data (subgroup analyses of clinical trials, age-related pooled analyses and obligatory post-marketing studies in vulnerable and frail older patients). CONCLUSION: The identification of proper clinical outcomes and the validation of geriatric screening tools are needed for conducting sound and comparable clinical trials. PMID- 21266519 TI - Identification of potential surrogate end points in randomized clinical trials of aggressive and indolent non-Hodgkin's lymphoma: correlation of complete response, time-to-event and overall survival end points. AB - BACKGROUND: The correlation between efficacy end points in randomized controlled trials (RCTs) of systemic therapy for non-Hodgkin's lymphoma (NHL) was investigated to identify an appropriate surrogate end point for overall survival (OS). METHODS: RCTs of previously untreated NHL published from 1990 to 2009 were identified. Associations between absolute differences in efficacy end points were determined using nonparametric Spearman's rank correlation coefficients (r(s)). RESULTS: Thirty-eight RCTs representing 85 treatment arms for aggressive NHL and 20 RCTs representing 42 arms for indolent NHL were included. For aggressive NHL, differences in 3-year progression-free survival (PFS)/event-free survival (EFS) were high correlated with differences in 5-year OS {r(s) of 0.90 [95% confidence interval (CI) 0.73-0.96]} and linear regression determined that a 10% improvement in 3-year EFS or PFS would predict for a 7% +/- 1% improvement in 5-year OS. For indolent histology disease, differences in complete response were strongly correlated with differences in 3-year EFS [r(s) 0.86 (95% CI 0.35-0.97)], but there was no correlation between 3-year time-to-event end points and 5-year OS. CONCLUSIONS: Improvements in 3-year EFS/PFS are highly correlated with improvements in 5-year OS in aggressive NHL and should be explored as a candidate surrogate end point. Definition of these relationships may inform future clinical trial design and interpretation of interim trial data. PMID- 21266520 TI - Obesity and thyroid cancer risk among U.S. men and women: a pooled analysis of five prospective studies. AB - BACKGROUND: Thyroid cancer incidence has risen dramatically in the United States since the early 1980s. Although the prevalence of obesity has doubled during this time period, the relationship between obesity and thyroid cancer is uncertain. METHODS: We examined the association between body mass index (BMI) and thyroid cancer risk in a pooled analysis of five prospective U.S. studies, including 413,979 women and 434,953 men. Proportional hazards models with attained age as the time metric were adjusted for education, race, marital status, smoking, alcohol intake, and (where appropriate) cohort and sex. RESULTS: Over follow-up (mean=10.3 years), 768 women and 388 men were diagnosed with thyroid cancer. The risk of thyroid cancer was greater with increasing BMI [per 5 kg/m2: HR in women, 1.16 (95% CI, 1.08-1.24); HR in men, 1.21 (95% CI, 0.97-1.49)]. There was no significant heterogeneity between studies (both P>0.05). For women and men combined, the HRs for overweight (25.0-29.9 kg/m2) and obesity (>=30 kg/m2) compared with normal-weight (18.5-24.9 kg/m2) were 1.20 (95% CI, 1.04-1.38) and 1.53 (95% CI, 1.31-1.79), respectively. We found no significant effect modification by other factors, and the results did not differ significantly by histologic type. A significant positive association for BMI in young adulthood (ages 18-20) with thyroid cancer risk was also observed [per 5-kg/m2 increase: HR, 1.18 (95% CI, 1.03-1.35)]. CONCLUSION: BMI was positively associated with thyroid cancer risk in both men and women. IMPACT: Our study provides strong evidence that obesity is an independent risk factor for thyroid cancer. PMID- 21266521 TI - Menopausal hormone therapy does not influence lung cancer risk: results from the California Teachers Study. AB - BACKGROUND: Results from studies examining the association between hormone therapy (HT) and lung cancer risk disagree. METHODS: We examined the associations between HT use and lung cancer risk among 60,592 postmenopausal women enrolled in the prospective California Teachers Study cohort. Between 1995 and 2007, a total of 727 women had a diagnosis of lung cancer. Multivariable Cox proportional hazards regression models were fit using age as the time metric. RESULTS: No measure of HT use was associated with lung cancer risk (all P(trend) values >=0.4). In addition, no variations in risk by smoking status (never, ever, former, current), type of HT [estrogen (E)-alone, E + progestin (P) use], type of menopause, or lung cancer histology were observed. CONCLUSIONS: Our findings do not support an association between HT and lung cancer. IMPACT: This large-scale, prospective study, which capitalizes on the detailed hormone use, smoking history, and type of menopause information available within this unique cohort, was unable to find any association between intake of HT and lung cancer risk. PMID- 21266522 TI - U.S. geographic distribution of prevaccine era cervical cancer screening, incidence, stage, and mortality. AB - BACKGROUND: Cervical cancer prevention programs are being reconfigured to incorporate human papillomavirus (HPV) testing and vaccination. To define priority areas for prevention efforts, we examined the geographic distribution of cervical cancer screening, incidence, stage, and mortality in the United States, prior to the introduction of HPV-based prevention technologies. METHODS: County level cervical cancer incidence data from 37 central registries were obtained from Surveillance, Epidemiology, and End Results and North American Association of Central Cancer Registries. A spatial-temporal model that accounted for demographic and behavioral attributes was used to generate a complete view of county-level incidence from 1995 to 2004, including counties with missing data. Distribution of stage at diagnosis was examined by registry. Counties with high mortality and infrequent screening were identified using vital statistics and newly available county-level screening estimates. RESULTS: Compared with non Hispanic whites and Asian and Pacific Islanders, incidence rates were higher among non-Hispanic black, American Indian and Alaska Native, and Hispanic women. Counties with infrequent screening often experienced elevated incidence and mortality rates and were located in states with suboptimal stage at diagnosis profiles. Affected areas included Appalachia, the southeastern Atlantic states, and the lower Mississippi Valley. Elevated death rates were experienced in central counties of large metropolitan areas. CONCLUSIONS: Geographic and racial/ethnic variability were evident in cervical cancer incidence and mortality. Women living in areas with endemic poverty would benefit from access to HPV-based prevention technologies. IMPACT: These findings provide a baseline for monitoring progress in cervical cancer control in the era of HPV-based prevention. PMID- 21266523 TI - Expression of SLCO transport genes in castration-resistant prostate cancer and impact of genetic variation in SLCO1B3 and SLCO2B1 on prostate cancer outcomes. AB - BACKGROUND: Metastases from men with castration-resistant prostate cancer (CRPC) harbor increased tumoral androgens versus untreated prostate cancers. This may reflect steroid uptake by OATP (organic anion transporting polypeptide)/SLCO transporters. We evaluated SLCO gene expression in CRPC metastases and determined whether prostate cancer outcomes are associated with single nucleotide polymorphisms (SNP) in SLCO2B1 and SLCO1B3, transporters previously shown to mediate androgen uptake. METHODS: Transcripts encoding eleven SLCO genes were analyzed in untreated prostate cancer and in metastatic CRPC tumors obtained by rapid autopsy. SNPs in SLCO2B1 and SLCO1B3 were genotyped in a population-based cohort of 1,309 Caucasian prostate cancer patients. Median survival follow-up was 7.0 years (0.77-16.4). The risk of prostate cancer recurrence/progression and prostate cancer-specific mortality (PCSM) was estimated with Cox proportional hazards analysis. RESULTS: Six SLCO genes were highly expressed in CRPC metastases versus untreated prostate cancer, including SLCO1B3 (3.6-fold; P = 0.0517) and SLCO2B1 (5.5-fold; P = 0.0034). Carriers of the variant alleles SLCO2B1 SNP rs12422149 (HR: 1.99; 95% CI: 1.11-3.55) or SLCO1B3 SNP rs4149117 (HR: 1.76; 95% CI: 1.00-3.08) had an increased risk of PCSM. CONCLUSIONS: CRPC metastases show increased expression of SLCO genes versus primary prostate cancer. Genetic variants of SLCO1B3 and SLCO2B1 are associated with PCSM. Expression and genetic variation of SLCO genes which alter androgen uptake may be important in prostate cancer outcomes. IMPACT: OATP/SLCO genes may be potential biomarkers for assessing risk of PCSM. Expression and genetic variation in these genes may allow stratification of patients to more aggressive hormonal therapy or earlier incorporation of nonhormonal-based treatment strategies. PMID- 21266524 TI - Fumonisin B1 as a urinary biomarker of exposure in a maize intervention study among South African subsistence farmers. AB - BACKGROUND: The consumption of maize highly contaminated with carcinogenic fumonisins has been linked to high oesophageal cancer rates. The aim of this study was to validate a urinary fumonisin B1 (UFB1) biomarker as a measure of fumonisin exposure and to investigate the reduction in exposure following a simple and culturally acceptable intervention. METHODS: At baseline home-grown maize, maize-based porridge, and first-void urine samples were collected from female participants (n=22), following their traditional food practices in Centane, South Africa. During intervention the participants were trained to recognize and remove visibly infected kernels, and to wash the remaining kernels. Participants consumed the porridge prepared from the sorted and washed maize on each day of the two-day intervention. Porridge, maize, and urine samples were collected for FB1 analyses. RESULTS: The geometric mean (95% confidence interval) for FB1 exposure based on porridge (dry weight) consumption at baseline and following intervention was 4.84 (2.87-8.14) and 1.87 (1.40-2.51) MUg FB1/kg body weight/day, respectively, (62% reduction, P<0.05). UFB1C, UFB1 normalized for creatinine, was reduced from 470 (295-750) at baseline to 279 (202-386) pg/mg creatinine following intervention (41% reduction, P=0.06). The UFB1C biomarker was positively correlated with FB1 intake at the individual level (r=0.4972, P<0.01). Urinary excretion of FB1 was estimated to be 0.075% (0.054%-0.104%) of the FB1 intake. CONCLUSION: UFB1 reflects individual FB1 exposure and thus represents a valuable biomarker for future fumonisin risk assessment. IMPACT: The simple intervention method, hand sorting and washing, could positively impact on food safety and health in communities exposed to fumonisins. PMID- 21266526 TI - A20, ABIN-1/2, and CARD11 mutations and their prognostic value in gastrointestinal diffuse large B-cell lymphoma. AB - PURPOSE: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of aggressive lymphomas with the activated B-cell-like subtype characterized by constitutive NF-kappaB activation. Activating mutations of CARD11 and inactivating mutations of A20 are frequent events in DLBCL. However, the full extent of genetic alterations in the NF-kappaB pathway regulators and their potential prognostic value in DLBCL remain to be investigated. We investigated the genetic abnormalities of CARD11, A20, and ABIN-1/2/3 (the A20 binding inhibitor of NF-kappaB) and their clinicopathologic correlation in gastrointestinal DLBCL. EXPERIMENTAL DESIGN: The somatic mutation and copy number changes of CARD11, A20, and ABIN-1/2/3 were investigated in 71 gastrointestinal DLBCLs by PCR/sequencing, and interphase FISH/array comparative genomic hybridization, respectively. The mutations identified were functionally characterized by NF-kappaB reporter assays and immunoprecipitation experiments. RESULTS: Recurrent somatic mutations were found in CARD11 (10%), A20 (17%), ABIN 1 (4%), and ABIN-2 (3%), but not in ABIN-3. In comparison with the wild-type, all CARD11 mutants were potent NF-kappaB activators in vitro. On the basis of the destructive nature of the observed mutations, and the findings by reporter assays and immunoprecipitation studies, most if not all of the somatic mutations that were seen in A20, ABIN-1, and ABIN-2 could impair their normal functions. Among these genetic abnormalities, A20 somatic mutation was significantly associated with both poor overall survival and event-free survival. CONCLUSIONS: We show further evidence of NF-kappaB pathway genetic abnormalities in DLBCL, which are potentially valuable in the prognosis and design of future therapeutic strategies. PMID- 21266525 TI - Epigenetic mechanisms in diabetic vascular complications. AB - There has been a rapid increase in the incidence of diabetes as well the associated vascular complications. Both genetic and environmental factors have been implicated in these pathologies. Increasing evidence suggests that epigenetic factors play a key role in the complex interplay between genes and the environment. Actions of major pathological mediators of diabetes and its complications such as hyperglycaemia, oxidant stress, and inflammatory factors can lead to dysregulated epigenetic mechanisms that affect chromatin structure and gene expression. Furthermore, persistence of this altered state of the epigenome may be the underlying mechanism contributing to a 'metabolic memory' that results in chronic inflammation and vascular dysfunction in diabetes even after achieving glycaemic control. Further examination of epigenetic mechanisms by also taking advantage of recently developed next-generation sequencing technologies can provide novel insights into the pathology of diabetes and its complications and lead to the discovery of much needed new drug targets for these diseases. In this review, we highlight the role of epigenetics in diabetes and its vascular complications, and recent technological advances that have significantly accelerated the field. PMID- 21266527 TI - Cyst fluid interleukin-1beta (IL1beta) levels predict the risk of carcinoma in intraductal papillary mucinous neoplasms of the pancreas. AB - PURPOSE: Biomarkers for high-grade dysplasia in patients with radiographically identified intraductal papillary mucinous neoplasms (IPMN) have not been described. We hypothesized that dysplasia in IPMN invokes an immunogenic/proinflammatory microenvironment that can be identified by cyst fluid cytokine levels. EXPERIMENTAL DESIGN: Pancreatic cyst fluid aspirates were collected at resection (2005-2009). Samples were grouped into low-risk [low-grade (n = 6) or moderate dysplasia (n = 15)] and high-risk groups [high-grade dysplasia (n = 13) or carcinoma (n = 6)]. Cytokine expression was determined using a multiplex sandwich immunoassay. Differences in cytokine expression were evaluated using the 2-sample t test. Sample classification was performed using a logistic regression adjusting for sample covariates. RESULTS: IL5 and IL8 concentrations were higher in the cyst fluid from patients in the high-risk group than the low-risk group. Interleukin (IL)-1beta concentrations were also higher in the cyst fluid from patients with high-grade dysplasia or cancer (n = 19) than those with low- or moderate-grade dysplasia (n = 21, 539 +/- 255 pg/mL vs. 0.2 +/ 0.1 pg/mL; P < 0.0001). IL1beta remained a significant predictor of high-risk cysts after multivariate analysis. There was no significant difference in levels of IL2, IL4, IL10, IL12, IL13, TNF-alpha, or IFN-gamma between the groups. That IL1beta levels identified cysts at a high risk of malignancy was confirmed in an independent validation set. CONCLUSIONS: Cyst fluid levels of IL1beta can differentiate low- from high-risk IPMN. This study introduces IL1beta as a potential biomarker for validation in larger clinical studies. PMID- 21266528 TI - A unique spectrum of somatic PIK3CA (p110alpha) mutations within primary endometrial carcinomas. AB - PURPOSE: The goal of this study was to comprehensively define the incidence of mutations in all exons of PIK3CA in both endometrioid endometrial cancer (EEC) and nonendometrioid endometrial cancer (NEEC). EXPERIMENTAL DESIGN: We resequenced all coding exons of PIK3CA and PTEN, and exons 1 and 2 of KRAS, from 108 primary endometrial tumors. Somatic mutations were confirmed by sequencing matched normal DNAs. The biochemical properties of a subset of novel PIK3CA mutations were determined by exogenously expressing wild type and mutant constructs in U2OS cells and measuring levels of AKT(Ser473) phosphorylation. RESULTS: Somatic PIK3CA mutations were detected in 52.4% of 42 EECs and 33.3% of 66 NEECs. Half (29 of 58) of all nonsynonymous PIK3CA mutations were in exons 1-7 and half were in exons 9 and 20. The exons 1-7 mutations localized to the ABD, ABD-RBD linker and C2 domains of p110alpha. Within these regions, Arg88, Arg93, Gly106, Lys111, Glu365, and Glu453, were recurrently mutated; Arg88, Arg93, and Lys111 formed mutation hotspots. The p110alpha-R93W, -G106R, -G106V, -K111E, delP449-L455, and -E453K mutants led to increased levels of phospho-AKT(Ser473) compared to wild-type p110alpha. Overall, 62% of exons 1-7 PIK3CA mutants and 64% of exons 9-20 PIK3CA mutants were activating; 72% of exon 1-7 mutations have not previously been reported in endometrial cancer. CONCLUSIONS: Our study identified a new subgroup of endometrial cancer patients with activating mutations in the amino-terminal domains of p110alpha; these patients might be appropriate for consideration in clinical trials of targeted therapies directed against the PI3K pathway. PMID- 21266529 TI - Combined blockade of Src kinase and epidermal growth factor receptor with gemcitabine overcomes STAT3-mediated resistance of inhibition of pancreatic tumor growth. AB - PURPOSE: We previously established a mechanistic rationale for Src inhibition as a novel therapeutic target in pancreatic cancer and have identified activated STAT3 as a potential biomarker of resistance to Src inhibition. The purpose of this study was to translate the current understanding of complementary activated tyrosine kinase signaling pathways by targeting Src kinase and epidermal growth factor receptor (EGFR). EXPERIMENTAL DESIGN: IC(50) values for dasatinib, a Src kinase inhibitor, erlotinib, an EGFR tyrosine kinase inhibitor and gemcitabine were determined and sensitive and resistant pancreatic cancer cell lines were identified. The in vitro and in vivo effects of these agents on multiple signaling pathways and tumorigenicity in pancreatic cancer were investigated. RESULTS: The combination of dasatinib, erlotinib, and gemcitabine resulted in cooperative inhibition of cell migration and invasion of both sensitive and resistant pancreatic cancer cells as well as cooperative inhibition of multiple signaling pathways including FAK, AKT, ERK, JNK, MAPK, and STAT3 at concentrations that were ineffective as individual agents or as double combinations of agents. The triple combination of agents was also most effective at inhibiting the growth of xenografts of both sensitive and resistant pancreatic cancer cells in vivo without increasing toxicity. Furthermore, combined inhibition of Src and EGFR with gemcitabine inhibited constitutively activated STAT3 in vitro and in vivo. CONCLUSIONS: These results provide evidence that combined targeted biological therapy in addition to cytotoxic chemotherapy can overcome treatment resistance. Such treatment strategies may be used to tailor therapy based on identified biomarkers of resistance to targeted monotherapy. PMID- 21266530 TI - Response to combined molecular targeting: defining the role of P-STAT3. AB - Src family kinase (SFK)-targeting agents are currently undergoing clinical investigation for treatment of solid malignancies. Epidermal growth factor receptor (EGFR)-independent phosphorylation of STAT3 (P-STAT3) has been identified as a mechanism of tumor resistance to agents targeting SFK. Tumor P STAT3 levels may be an important indicator of EGFR- and SKF-targeted antitumor treatment efficacy. PMID- 21266532 TI - Exposure to the widely used fungicide mancozeb causes thyroid hormone disruption in rat dams but no behavioral effects in the offspring. AB - The widely used fungicide mancozeb has been shown to cause hypothyroxinemia and other adverse effects on the thyroid hormone system in adult experimental animals. In humans, hypothyroxinemia early in pregnancy is associated with adverse effects on the developing nervous system and can lead to impaired cognitive function and motor development in children. The aim of the present study was therefore to assess whether perinatal mancozeb exposure would cause developmental neurotoxicity in rats. Groups of 9-21 time-mated Wistar rats were dosed with 0, 50, 100, or 150 mg mancozeb/kg body weight (bw)/day by gavage from gestation day (GD) 7 to postnatal day (PND) 16, and total thyroxine (T(4)) levels were measured in dams during gestation. On PND 16, hormone levels and several organ weights were measured in the offspring, whereas motor activity, startle response, and cognitive function were assessed in the adult offspring. The dose of 150 mg/kg/day caused neurotoxicity in the pregnant dams and was therefore reduced to 100 mg/kg bw/day in mid study. T(4) levels showed a dose-dependent and significant decrease in dams from all three dose groups on GD 15, whereas offspring T(4) levels, thyroid weights, and histology were unaffected on PND 16. No effects on reproductive organ weights were seen, and no behavioral changes were observed. Taken together, these results indicate that in rats, moderate maternal hypothyroxinemia during gestation does not necessarily lead to hyperactivity or reduced special learning abilities in the offspring. Mancozeb exposure did, however, reduce T(4) levels in dams and may therefore still be a potential contributor to thyroid disruption in humans and in result adversely affects the developing brain. PMID- 21266531 TI - The ATP-binding cassette transporter ABCB6 is induced by arsenic and protects against arsenic cytotoxicity. AB - Arsenic, an environmental carcinogen, remains a major public health problem. Arsenic damages biological systems through multiple mechanisms, including the generation of reactive oxygen species. ABCB6 is an ATP-binding cassette transporter that is highly expressed in cells resistant to arsenic. We have recently demonstrated that ABCB6 expression protects against cellular stressors. In the present study, we evaluated the significance of ABCB6 expression to arsenic toxicity both in mice and in cell culture. We show that sodium arsenite induces ABCB6 expression in a dose-dependent manner both in mice fed sodium arsenite in drinking water and in cells exposed to sodium arsenite in vitro. Arsenite-induced ABCB6 expression was transcriptionally regulated, but this induction was not mediated by the redox-sensitive transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2). We demonstrate that, in HepG2 and Hep3B cells, knockdown of ABCB6 expression using ABCB6-specific small interfering RNA sensitized the cells to arsenite toxicity. In contrast, stable overexpression of ABCB6 conferred a strong survival advantage toward arsenite-induced oxidative stress. Collectively, these results, obtained by both loss of function and gain of function analysis, suggest that ABCB6 expression in response to sodium arsenite might be an endogenous protective mechanism activated to protect cells against arsenite-induced oxidative stress. PMID- 21266533 TI - Species-specific dibutyl phthalate fetal testis endocrine disruption correlates with inhibition of SREBP2-dependent gene expression pathways. AB - Fetal rat phthalate exposure produces a spectrum of male reproductive tract malformations downstream of reduced Leydig cell testosterone production, but the molecular mechanism of phthalate perturbation of Leydig cell function is not well understood. By bioinformatically examining fetal testis expression microarray data sets from susceptible (rat) and resistant (mouse) species after dibutyl phthalate (DBP) exposure, we identified decreased expression of several metabolic pathways in both species. However, lipid metabolism pathways transcriptionally regulated by sterol regulatory element-binding protein (SREBP) were inhibited in the rat but induced in the mouse, and this differential species response corresponded with repression of the steroidogenic pathway. In rats exposed to 100 or 500 mg/kg DBP from gestational days (GD) 16 to 20, a correlation was observed between GD20 testis steroidogenic inhibition and reductions of testis cholesterol synthesis endpoints including testis total cholesterol levels, Srebf2 gene expression, and cholesterol synthesis pathway gene expression. SREBP2 expression was detected in all fetal rat testis cells but was highest in Leydig cells. Quantification of SREBP2 immunostaining showed that 500 mg/kg DBP exposure significantly reduced SREBP2 expression in rat fetal Leydig cells but not in seminiferous cords. By Western analysis, total rat testis SREBP2 levels were not altered by DBP exposure. Together, these data suggest that phthalate-induced inhibition of fetal testis steroidogenesis is closely associated with reduced activity of several lipid metabolism pathways and SREBP2-dependent cholesterologenesis in Leydig cells. PMID- 21266534 TI - Motion discrimination under uncertainty and ambiguity. AB - Speed and accuracy of visual motion discrimination depend systematically on motion strength. This behavior is traditionally explained by diffusion models that assume accumulation of sensory evidence over time to a decision bound. However, how does the brain decide when sensory evidence is ambiguous, such as in binocular rivalry? Theories on bistable vision propose that such a conflict is resolved through competitive interactions between adapting units encoding the alternative stimulus interpretations. Thus, distinctly different theoretical frameworks have been proposed for deciding under uncertainty and ambiguity; a discrepancy overlooked so far. Here, we studied motion discrimination at stimulus onset under both conditions. In Experiment 1, speed and accuracy were similar when observers viewed noisy, unambiguous motion patterns in which signal dots were either at identical or at different, uncorrelated locations for the two eyes. This result is compatible with a race between two monocular discrimination processes. However, Experiments 2 and 3 showed that reaction times increase under rivalry conditions and that this increase cannot be explained by motion transparency. The data thus reveal competitive rivalry interactions. We discuss a model that can account for the accuracy and latencies observed under both ambiguous and unambiguous conditions, by combining key elements from diffusion and rivalry models. PMID- 21266535 TI - IRF3 regulates cardiac fibrosis but not hypertrophy in mice during angiotensin II induced hypertension. AB - Hypertension is a typical modern lifestyle-related disease that is closely associated with the development of cardiovascular disorders. Elevation of angiotensin II (ANG II) is one of several critical factors for hypertension and heart failure; however, the mechanisms underlying the ANG II-mediated pathogenesis are still poorly understood. Here, we show that ANG II-mediated cardiac fibrosis, but not hypertrophy, is regulated by interferon regulatory factor 3 (IRF3), which until now has been exclusively studied in the innate immune system. In a ANG II-infusion mouse model (3.0 mg/kg/d), we compared IRF3 deficient mice (Irf3(-/-)/Bcl2l12(-/-)) with matched wild-type (WT) controls. The development of cardiac fibrosis [3.95 +/- 0.62% (WT) vs. 1.41 +/- 0.46% (Irf3(-/ )/Bcl2l12(-/-)); P<0.01] and accompanied reduction in left ventricle end diastolic dimension [2.89 +/- 0.10 mm (WT) vs. 3.51 +/- 0.15 mm (Irf3(-/ )/Bcl2l12(-/-)); P=0.012] are strongly suppressed in Irf3(-/-)/Bcl2l12(-/-) mice, whereas hypertrophy still develops. Further, we provide evidence for the activation of IRF3 by ANG II signaling in mouse cardiac fibroblasts. Unlike the activation of IRF3 by innate immune receptors, IRF3 activation by ANG II is unique in that it is activated through the canonical ERK signaling pathway. Thus, our present study reveals a hitherto unrecognized function of IRF3 in cardiac remodeling, providing new insight into the progression of hypertension-induced cardiac pathogenesis. PMID- 21266536 TI - The Nodal inhibitor Lefty is negatively modulated by the microRNA miR-302 in human embryonic stem cells. AB - MicroRNAs (miRNAs) have been shown to be important in early development and maintenance of human embryonic stem cells (hESCs). The miRNA miR-302-367 is specifically expressed in hESCs, and its expression decays on differentiation. We previously identified the structure of the gene coding for the human miR-302-367 cluster and characterized its promoter. The promoter activity was functionally validated in hESCs, opening up new avenues to further investigate how these miRNA molecules fit in the complex molecular network conferring "stemness" properties to hESCs. The physiological roles of specific miRNA-mRNA interactions remain largely unknown. Here, we investigated putative miR-302-367 mRNA targets in hESCs, potentially relevant for ESC biology. We found that the Nodal inhibitors Lefty1 and Lefty2 are post-transcriptionally targeted by miR-302s in hESCs. Functional analyses indicate that miR-302s negatively modulate the level of lefties, and become upstream regulators of the TGFbeta/Nodal pathway, functioning via Smad-2/3 signaling. Overexpression of the miR-302-367 cluster in hESCs causes a delay in early hESC differentiation, as measured by enhanced levels of ESC specific transcription factors, coupled to a faster teratoma formation in mice transplanted with miR-302-367-expressing hESCs and a concomitant impairment of germ layer specification, displaying robust decreased levels of early mesodermal, endodermal, and ectodermal specific markers. These findings suggest that Lefty is negatively modulated by miR-302s in hESCs, which plays an important role in maintaining the balance between pluripotency and germ layer specification. PMID- 21266537 TI - OxLDL up-regulates microRNA-29b, leading to epigenetic modifications of MMP-2/MMP 9 genes: a novel mechanism for cardiovascular diseases. AB - MicroRNAs (miRNAs), small noncoding RNAs, can control gene expression by binding to their target genes for degradation and/or translational repression. Epigenetic mechanisms are defined as heritable changes in gene expression that do not involve coding sequence modifications. Both mechanisms play an important role in maintaining physiological functions and are also related to disease development. However, few studies report that miRNA-mediated epigenetic regulations are involved in atherosclerosis. In the present study, oxidized low-density lipoprotein (oxLDL) significantly increased primary human aortic smooth muscle cell (HASMC) migration through MMP-2/MMP-9 up-regulation associated with decreased DNA methylation levels. Either mRNA or protein level of DNA methyltransferase 3b (DNMT3b) showed a dose-dependent down-regulation in oxLDL mediated HASMCs. Knockdown DNMT3b expression enhanced oxLDL-induced DNA demethylation levels of MMP-2/MMP-9. The expression of miRNA-29b (miR-29b), directly targeting DNMT3b, was up-regulated by oxLDL treatment in a dose dependent manner. OxLDL-mediated MMP-2/MMP-9 up-regulation, DNMT3b down regulation, and DNA demethylation were all attenuated after knockdown miR-29b expression by antagomiR-29b. We find that oxLDL can up-regulate miR-29b expression, resulting in DNMT3b down-regulation in HASMCs and epigenetically regulated MMP-2/MMP-9 genes involved in cell migration. These results show that miRNA-mediated epigenetic regulation may be a novel mechanism in atherosclerosis. PMID- 21266538 TI - High ability of apolipoprotein E4 to stabilize amyloid-beta peptide oligomers, the pathological entities responsible for Alzheimer's disease. AB - Nowadays, the emerging role of amyloid-beta peptide (Abeta) oligomers in Alzheimer's disease (AD) is widely accepted, putting aside the old idea that fibrils are the primary entities responsible for the onset of the disease. Besides, carrying the E4 isoform of apolipoprotein E (apoE) represents the highest risk of developing AD. Nevertheless, the involvement of apoE4 in AD remains confusing. The goal of this study was to bring new insights into the role of apoE4 in Abeta aggregation. We used infrared spectroscopy, thioflavin T fluorescence, and Western blots to evaluate the influence of apoE isoforms on Abeta aggregation in vitro. Comparing Abeta controls with Abeta incubated either with the apoE3 or apoE4 isoform, we report a 30% reduction of the Abeta fibrillar content, whereas the oligomeric content is 2 times higher on incubation with the pathological isoform apoE4. ApoE4 would bind and block Abeta in its oligomeric conformation, inhibiting further formation of less toxic fibrillar forms of Abeta. While previous studies mostly correlated E4 with fibrils, our report underlines a link between apoE4 and Abeta oligomers and therefore reconciles apoE4 with the new amyloid cascade hypothesis. Our observations suggest that apoE4 strongly stabilizes Abeta oligomers, the pathological species responsible for Alzheimer's disease. PMID- 21266539 TI - HIV proteinase inhibitors target the Ddi1-like protein of Leishmania parasites. AB - HIV proteinase inhibitors reduce the levels of Leishmania parasites in vivo and in vitro, but their biochemical target is unknown. We have identified an ortholog of the yeast Ddi1 protein as the only member of the aspartic proteinase family in Leishmania parasites, and in this study we investigate this protein as a potential target for the drugs. To date, no enzyme assay has been developed for the Ddi1 proteins, but Saccharomyces cerevisiae lacking the DDI1 gene secrete high levels of protein into the medium. We developed an assay in which these knockout yeast were functionally complemented to low secretion by introduction of genes encoding Ddi1 orthologs from Leishmania major or humans. Plasmid alone controls gave no complementation. Treatment of the Ddi1 transformants with HIV proteinase inhibitors showed differential effects dependent on the origin of the Ddi1. Dose responses allowed calculation of IC(50) values; e.g., for nelfinavir, of 3.4 MUM (human Ddi1) and 0.44 MUM (Leishmania Ddi1). IC(50) values with Leishmania constructs mirror the potency of inhibitors against parasites. Our results show that Ddi1 proteins are targets of HIV proteinase inhibitors and indicates the Leishmania Ddi1 as the likely target for these drugs and a potential target for antiparasitic therapy. PMID- 21266540 TI - Massive genomic decay in Serratia symbiotica, a recently evolved symbiont of aphids. AB - All vertically transmitted bacterial symbionts undergo a process of genome reduction over time, resulting in tiny, gene-dense genomes. Comparison of genomes of ancient bacterial symbionts gives only limited information about the early stages in the transition from a free-living to symbiotic lifestyle because many changes become obscured over time. Here, we present the genome sequence for the recently evolved aphid symbiont Serratia symbiotica. The S. symbiotica genome exhibits several of the hallmarks of genome evolution observed in more ancient symbionts, including elevated rates of evolution and reduction in genome size. The genome also shows evidence for massive genomic decay compared with free living relatives in the same genus of bacteria, including large deletions, many pseudogenes, and a slew of rearrangements, perhaps promoted by mobile DNA. Annotation of pseudogenes allowed examination of the past and current metabolic capabilities of S. symbiotica and revealed a somewhat random process of gene inactivation with respect to function. Analysis of mutational patterns showed that deletions are more common in neutral DNA. The S. symbiotica genome provides a rare opportunity to study genome evolution in a recently derived heritable symbiont. PMID- 21266541 TI - Expression, purification, and functional characterization of recombinant PTD SARA. AB - The Smad anchor for receptor activation (SARA) protein is a binding partner for Smad2/3 that plays an important role in the fibrotic promoting signaling pathway initiated by transforming growth factor-beta1 (TGF-beta1). The C-terminal 665-750 aa of SARA comprises the Smad-binding domain (SBD). By direct interaction through the SBD, SARA inhibits Smad2/3 phosphorylation and blocks the interaction between Smad2/3 and Smad4, thereby restrains the process of fibrosis. In this study, we constructed a SARA peptide aptamer based on the SBD sequence. The recombinant SARA aptamer, fused with a protein transduction domain (PTD-SARA), was cloned, purified from E. coli, and characterized for the first time. The full-length PTD SARA coding sequence, created with E. coli favored codons, was cloned into a pQE 30 vector, and the recombinant plasmid was transformed into an M15 strain. After Isopropyl beta-D-1-Thiogalactopyranoside (IPTG) induction and Ni(2+) affinity purification, recombinant PTD-SARA was further identified by immunoblotting and protein N-terminal sequencing. Epifluorescence microscopy revealed that the recombinant PTD-SARA was transferred into the cytoplasm and nucleus more efficiently than SARA. Moreover, the recombinant PTD-SARA was found to up regulate the level of E-cadherin and down-regulate the levels of alpha-SMA and phospho-Smad3 more efficiently than SARA (P < 0.05). Our work explored a method to obtain recombinant PTD-SARA protein. The recombinant PTD-SARA fusion protein could enter HK2 cells (an immortalized proximal tubule epithelial cell line) more efficiently than the SARA protein and reverse the renal epithelial-to-mesenchymal transdifferentiation process that was induced by TGF-beta1 more effectively than the SARA protein. Recombinant PDT-SARA is likely to be a potential candidate for clinical prevention and treatment of renal fibrosis. PMID- 21266542 TI - Humoral immune response induced by an engineered cell-based neuroblastoma vaccine with or without CD25 blockade. AB - Neuroblastoma is the most common extracranial solid cancer in childhood and it can develop in the nerve tissue of the adrenal gland, neck, chest, or spinal cord. A number of tumor-associated antigens (TAAs), which can elicit humoral immunity, have been identified in cancer patients. To investigate the humoral immunity during neuroblastoma development, we treated A/J mice with an aggressive clone of neuroblastoma (AGN2a) cells, then vaccinated the mice with cells expressing AGN2a-CD80/CD137L under the conditions with or without regulatory T cell blockade. Strong humoral immunity was induced by AGN2a-CD80/CD137L immunization in the context of regulatory T cell blockade. Sera from treated mice were used to screen an AGN2a cDNA expression library for identifying TAAs by SEREX (serological analysis of recombinant cDNA expression libraries). Clones were identified by sequencing and comparative analysis of gene pools. Further investigation of these gene products revealed that most of them play a role in the neuronal differentiation, cell metabolism, and are highly expressed in other types of malignancy. Asz1 (ankyrin repeat, SAM, and basic leucine zipper domain containing protein) was found in all tumor-bearing groups. These results implicated that these candidates identified from tumor-bearing mice may be neuroblastoma-associated antigens, which can be used as biomarkers in early diagnosis of neuroblastoma, whereas those identified from vaccinated mice may be the potential therapeutic targets. PMID- 21266543 TI - Human mesenchymal stem cells are sensitive to abnormal gravity and exhibit classic apoptotic features. AB - The aim of the present study was to investigate the effects of abnormal gravity on human mesenchymal stem cells (hMSCs). Strong magnetic field and magnetic field gradient generate a magnetic force that can add to or subtract from the gravitational force. In this study, this is defined as a high-magneto gravitational environment (HMGE). The HMGE provides three apparent gravity levels, i.e. hypogravity (MUg), hypergravity (2g) and normal gravity with strong magnetic field (1g) conditions. After hMSCs were subject to HMGE for 12 h, the proliferation, morphology, structure and apoptosis were investigated. Results showed that the proliferation of hMSCs was inhibited under MUg condition. The abnormal gravity induced morphologic characteristics of apoptosis cells, such as cell shrinkage, membrane blebbing, nuclear chromatin condensation and margination, decreased cell viability, and increased caspase-3/7 activity. The rate of apoptosis under MUg condition is up to 56.95%. The F-actin stress fibers and microtubules were disrupted under abnormal gravity condition. Under MUg condition, the expression of p53 at mRNA and protein levels was up-regulated more than 9- and 6 folds, respectively. The Pifithrin-alpha, an specific inhibitor of p53, inhibited the apoptosis and prevented the disruption of cytoskeleton induced by abnormal gravity. These results implied that hMSCs were sensitive to abnormal gravity and exhibited classic apoptotic features, which might be associated with p53 signaling. PMID- 21266544 TI - Evaluation of chylomicron effect on ASP production in 3T3-L1 adipocytes. AB - In the past few years, there has been increasing interest in the production and physiological role of acylation-stimulating protein (ASP), identical to C3adesArg, a product of the alternative complement pathway generated through C3 cleavage. Recent studies in C3 (-/-) mice that are ASP deficient have demonstrated a role for ASP in postprandial triglyceride clearance and fat storage. The aim of the present study was to establish a cell model and sensitive ELISA assay for the evaluation of ASP production using 3T3-L1 adipocytes. 3T3-L1 preadipocytes were differentiated into adipocytes, then cultured in different media such as serum-free (SF), Dulbecco's modified Eagle's medium (DMEM)/F12 + 10% fetal calf serum (FBS), and at varying concentrations of chylomicrons and insulin + chylomicrons up to 48 h. ASP production in SF and DMEM/F12 + 10% FBS was compared. Chylomicrons stimulated ASP production in a concentration- and time dependent manner. By contrast, chylomicron treatment had no effect on the production of C3, the precursor protein of ASP, which was constant over 48 h. Addition of insulin (100 nM) to a low-dose of chylomicrons (100 ug TG/ml) significantly increased ASP production compared with chylomicrons alone at 48 h (P < 0.001). Furthermore, addition of insulin significantly increased C3 secretion at both 18 and 48 h of incubation (P < 0.05, P < 0.001, respectively). Overall, the proportion of ASP to C3 remained constant, indicating no change in the ratio of C3 cleaved to generate ASP. This study demonstrated that 3T3-L1 adipocyte is a useful model for the evaluation of C3 secretion and ASP production by using a sensitive mouse-specific ELISA assay. The stimulation of ASP production with chylomicrons demonstrates a physiologically relevant response, and provides a strategy for further studies on ASP production and function. PMID- 21266545 TI - Changes in 24-nt siRNA levels in Arabidopsis hybrids suggest an epigenetic contribution to hybrid vigor. AB - Intraspecific hybrids between the Arabidopsis thaliana accessions C24 and Landsberg erecta have strong heterosis. The reciprocal hybrids show a decreased level of 24-nt small RNA (sRNA) relative to the parents with the decrease greatest for those loci where the parents had markedly different 24-nt sRNA levels. The genomic regions with reduced 24-nt sRNA levels were largely associated with genes and their flanking regions indicating a potential effect on gene expression. We identified several examples of genes with altered 24-nt sRNA levels that showed correlated changes in DNA methylation and expression levels. We suggest that such epigenetically generated differences in gene activity may contribute to hybrid vigor and that the epigenetic diversity between ecotypes provides increased allelic (epi-allelic) variability that could contribute to heterosis. PMID- 21266546 TI - Unfolding and translocation pathway of substrate protein controlled by structure in repetitive allosteric cycles of the ClpY ATPase. AB - Clp ATPases are ring-shaped AAA+ motors in the degradation pathway that perform critical actions of unfolding and translocating substrate proteins (SPs) through narrow pores to deliver them to peptidase components. These actions are effected by conserved diaphragm-forming loops found in the central channel of the Clp ATPase hexamer. Conformational changes, that take place in the course of repetitive ATP-driven cycles, result in mechanical forces applied by the central channel loops onto the SP. We use coarse-grained simulations to elucidate allostery-driven mechanisms of unfolding and translocation of a tagged four-helix bundle protein by the ClpY ATPase. Unfolding is initiated at the tagged C terminal region via an obligatory intermediate. The resulting nonnative conformation is competent for translocation, which proceeds on a different time scale than unfolding and involves sharp stepped transitions. Completion of the translocation process requires assistance from the ClpQ peptidase. These mechanisms contrast nonallosteric mechanical unfolding of the SP. In atomic force microscopy experiments, multiple unfolding pathways are available and large mechanical forces are required to unravel the SP relative to those exerted by the central channel loops of ClpY. SP threading through a nonallosteric ClpY nanopore involves simultaneous unfolding and translocation effected by strong pulling forces. PMID- 21266548 TI - Molecular basis for ubiquitin and ISG15 cross-reactivity in viral ovarian tumor domains. AB - Crimean Congo hemorrhagic fever virus (CCHFV) is a deadly human pathogen that evades innate immune responses by efficiently interfering with antiviral signaling pathways mediated by NF-kappaB, IRF3, and IFNalpha/beta. These pathways rely on protein ubiquitination for their activation, and one outcome is the modification of proteins with the ubiquitin (Ub)-like modifier interferon stimulated gene (ISG)15. CCHFV and related viruses encode a deubiquitinase (DUB) of the ovarian tumor (OTU) family, which unlike eukaryotic OTU DUBs also targets ISG15 modifications. Here we characterized the viral OTU domain of CCHFV (vOTU) biochemically and structurally, revealing that it hydrolyzes four out of six tested Ub linkages, but lacks activity against linear and K29-linked Ub chains. vOTU cleaved Ub and ISG15 with similar kinetics, and we were able to understand vOTU cross-reactivity at the molecular level from crystal structures of vOTU in complex with Ub and ISG15. An N-terminal extension in vOTU not present in eukaryotic OTU binds to the hydrophobic Ile44 patch of Ub, which results in a dramatically different Ub orientation compared to a eukaryotic OTU-Ub complex. The C-terminal Ub-like fold of ISG15 (ISG15-C) adopts an equivalent binding orientation. Interestingly, ISG15-C contains an additional second hydrophobic surface that is specifically contacted by vOTU. These subtle differences in Ub/ISG15 binding allowed the design of vOTU variants specific for either Ub or ISG15, which will be useful tools to understand the relative contribution of ubiquitination vs. ISGylation in viral infection. Furthermore, the crystal structures will allow structure-based design of antiviral agents targeting this enzyme. PMID- 21266547 TI - Allostery in the ferredoxin protein motif does not involve a conformational switch. AB - Regulation of protein function via cracking, or local unfolding and refolding of substructures, is becoming a widely recognized mechanism of functional control. Oftentimes, cracking events are localized to secondary and tertiary structure interactions between domains that control the optimal position for catalysis and/or the formation of protein complexes. Small changes in free energy associated with ligand binding, phosphorylation, etc., can tip the balance and provide a regulatory functional switch. However, understanding the factors controlling function in single-domain proteins is still a significant challenge to structural biologists. We investigated the functional landscape of a single domain plant-type ferredoxin protein and the effect of a distal loop on the electron-transfer center. We find the global stability and structure are minimally perturbed with mutation, whereas the functional properties are altered. Specifically, truncating the L1,2 loop does not lead to large-scale changes in the structure, determined via X-ray crystallography. Further, the overall thermal stability of the protein is only marginally perturbed by the mutation. However, even though the mutation is distal to the iron-sulfur cluster (~20 A), it leads to a significant change in the redox potential of the iron-sulfur cluster (57 mV). Structure-based all-atom simulations indicate correlated dynamical changes between the surface-exposed loop and the iron-sulfur cluster-binding region. Our results suggest intrinsic communication channels within the ferredoxin fold, composed of many short-range interactions, lead to the propagation of long-range signals. Accordingly, protein interface interactions that involve L1,2 could potentially signal functional changes in distal regions, similar to what is observed in other allosteric systems. PMID- 21266549 TI - A long-term follow-up study of mortality in transsexuals receiving treatment with cross-sex hormones. AB - OBJECTIVE: Adverse effects of long-term cross-sex hormone administration to transsexuals are not well documented. We assessed mortality rates in transsexual subjects receiving long-term cross-sex hormones. DESIGN: A cohort study with a median follow-up of 18.5 years at a university gender clinic. Methods Mortality data and the standardized mortality rate were compared with the general population in 966 male-to-female (MtF) and 365 female-to-male (FtM) transsexuals, who started cross-sex hormones before July 1, 1997. Follow-up was at least 1 year. MtF transsexuals received treatment with different high-dose estrogen regimens and cyproterone acetate 100 mg/day. FtM transsexuals received parenteral/oral testosterone esters or testosterone gel. After surgical sex reassignment, hormonal treatment was continued with lower doses. RESULTS: In the MtF group, total mortality was 51% higher than in the general population, mainly from increased mortality rates due to suicide, acquired immunodeficiency syndrome, cardiovascular disease, drug abuse, and unknown cause. No increase was observed in total cancer mortality, but lung and hematological cancer mortality rates were elevated. Current, but not past ethinyl estradiol use was associated with an independent threefold increased risk of cardiovascular death. In FtM transsexuals, total mortality and cause-specific mortality were not significantly different from those of the general population. CONCLUSIONS: The increased mortality in hormone-treated MtF transsexuals was mainly due to non-hormone related causes, but ethinyl estradiol may increase the risk of cardiovascular death. In the FtM transsexuals, use of testosterone in doses used for hypogonadal men seemed safe. PMID- 21266550 TI - Observing pretibial myxedema in patients with Graves' disease using digital infrared thermal imaging and high-resolution ultrasonography: for better records, early detection, and further investigation. AB - OBJECTIVE: Pretibial myxedema (PM) is a manifestation of Graves' disease (GD). Currently, its diagnosis depends on physicians' observation and biopsy. No satisfactory, objective, and non-invasive tool is available to record and investigate lesions. Digital infrared thermal imaging (DITI) detects surface temperature, and sonography reflects composition changes in soft tissue. This study was aimed to observe changes in DITI and sonography in PM, and to evaluate their clinical usefulness. METHODS: Nineteen GD patients with PM, 22 GD patients with mild diffuse non-pitting edema over lower legs, 46 GD patients with normal appearance of lower legs, and 14 normal volunteers were recruited for observation with DITI; 8, 21, 21, and 11 of them respectively also received soft tissue sonography for investigating the pathogenesis of DITI change. RESULTS: Lower leg temperatures of normal volunteers decreased gradually from proximal to distal parts. In all 19 patients with PM, DITI showed abnormally low focal temperatures over the lesions. In GD patients with mild diffuse non-pitting edema and GD patients with normal appearance of lower legs, DITI showed abnormally low focal temperature in 90.9 and 65.2% of the patients respectively. Areas of clinically visible PM and low focal temperature detected by DITI were sonographically characterized with increased skin thickness, hypoechoic substance deposition in the cutaneous tissue, and blurred boundary lines between dermis and subcutaneous tissue. TSH receptor antibody level correlated positively and significantly with skin thickness change and adjusted temperature difference between the center of temperature defect and the surrounding skin (P=0.046 and 0.033 respectively). CONCLUSIONS: By using DITI and sonography, we detected characteristic changes in PM. These techniques are helpful in recording and may be useful tools to detect early changes of PM. PMID- 21266551 TI - HDL measures, particle heterogeneity, proposed nomenclature, and relation to atherosclerotic cardiovascular events. AB - BACKGROUND: A growing body of evidence from epidemiological data, animal studies, and clinical trials supports HDL as the next target to reduce residual cardiovascular risk in statin-treated, high-risk patients. For more than 3 decades, HDL cholesterol has been employed as the principal clinical measure of HDL and cardiovascular risk associated with low HDL-cholesterol concentrations. The physicochemical and functional heterogeneity of HDL present important challenges to investigators in the cardiovascular field who are seeking to identify more effective laboratory and clinical methods to develop a measurement method to quantify HDL that has predictive value in assessing cardiovascular risk. CONTENT: In this report, we critically evaluate the diverse physical and chemical methods that have been employed to characterize plasma HDL. To facilitate future characterization of HDL subfractions, we propose the development of a new nomenclature based on physical properties for the subfractions of HDL that includes very large HDL particles (VL-HDL), large HDL particles (L-HDL), medium HDL particles (M-HDL), small HDL particles (S-HDL), and very-small HDL particles (VS-HDL). This nomenclature also includes an entry for the pre-beta-1 HDL subclass that participates in macrophage cholesterol efflux. SUMMARY: We anticipate that adoption of a uniform nomenclature system for HDL subfractions that integrates terminology from several methods will enhance our ability not only to compare findings with different approaches for HDL fractionation, but also to assess the clinical effects of different agents that modulate HDL particle structure, metabolism, and function, and in turn, cardiovascular risk prediction within these HDL subfractions. PMID- 21266553 TI - Doppler criteria for identifying proximal vertebral artery stenosis of 50% or more. AB - OBJECTIVES: The proximal segment of the vertebral artery is a frequent site of obstructive atherosclerosis. The purpose of this study was to determine Doppler criteria for identifying proximal vertebral artery stenosis of 50% or more by comparison with digital subtraction angiography. METHODS: Forty-eight patients with vertebral artery stenosis were examined prospectively with color Doppler sonography and digital subtraction angiography. The peak systolic velocity (PSV), end-diastolic velocity (EDV), peak systolic velocity ratio (PSVr), and end diastolic velocity ratio (EDVr) were evaluated by receiver operating characteristic curve analysis for their ability to detect vertebral artery stenosis of 50% or more. The optimal criteria for identifying proximal vertebral artery stenosis of 50% or more were determined. RESULTS: For identifying vertebral artery stenosis, the parameter with the highest accuracy was the PSVr (area under the receiver operating characteristic curve, 0.967 [95% confidence interval, 0.899-0.994]). A PSVr of greater than 2.2 was found to be the optimal criterion for identifying proximal vertebral artery stenosis of 50% or more, with sensitivity and specificity of 96% and 89%, respectively. The optimal thresholds for the other Doppler parameters in identifying proximal vertebral artery stenosis of 50% or more were as follows: PSV, greater than 108 cm/s; EDV, greater than 36 cm/s; and EDVr, greater than 1.7. CONCLUSIONS: Color Doppler sonography is an accurate method for identifying proximal vertebral artery stenosis. The PSVr is superior to other Doppler parameters for detecting vertebral artery stenosis. PMID- 21266552 TI - S-adenosylmethionine decreases lipopolysaccharide-induced phosphodiesterase 4B2 and attenuates tumor necrosis factor expression via cAMP/protein kinase A pathway. AB - S-Adenosylmethionine (SAM) treatment has anti-inflammatory, cytoprotective effects against endotoxin-induced organ injury. An important component of the anti-inflammatory action of SAM involves down-regulation of the lipopolysaccharide (LPS)-induced transcriptional induction of tumor necrosis factor-alpha (TNF) expression by monocytes/macrophages. We examined the effect of SAM on expression and activity of LPS-induced up-regulation of phosphodiesterase 4 (PDE4), which regulates cellular cAMP levels and TNF expression. LPS treatment of RAW 264.7, a mouse macrophage cell line, led to the induction of Pde4b2 mRNA expression with no effect on Pde4a or Pde4d. SAM pretreatment led to a significant decrease in LPS-induced up-regulation of Pde4b2 expression in both RAW 264.7 cells and primary human CD14(+) monocytes. Of note, the decreased Pde4b2 mRNA expression correlated with the SAM-dependent increase in the transcriptionally repressive histone H3 lysine 9 trimethylation on the Pde4b2 intronic promoter region. The SAM-mediated decrease in LPS-inducible Pde4b2 up regulation resulted in an increase in cellular cAMP levels and activation of cAMP dependent protein kinase A (PKA), which plays an inhibitory role in LPS-induced TNF production. In addition, SAM did not affect LPS-inducible inhibitor of nuclear factor-kappaB degradation or nuclear factor-kappaB (NF-kappaB)-p65 translocation into the nucleus but rather inhibited NF-kappaB transcriptional activity. These results demonstrate for the first time that inhibition of LPS induced PDE4B2 up-regulation and increased cAMP-dependent PKA activation are significant mechanisms contributing to the anti-TNF effect of SAM. Moreover, these data also suggest that SAM may be used as an effective PDE4B inhibitor in the treatment of chronic inflammatory disorders in which TNF expression plays a significant pathogenic role. PMID- 21266554 TI - Doppler parameters in renal transplant dysfunction: correlations with histopathologic changes. AB - OBJECTIVES: The aim of this study was to assess the relationship between intrarenal Doppler parameters and histopathologic changes shown on kidney biopsy in renal transplant dysfunction. METHODS: We retrospectively reviewed the records of 113 patients (61 men and 52 women; age range, 22-76 years; mean age +/- SD, 50.9 +/- 12.7 years) who underwent both transplanted kidney sonography and biopsy from May 1, 2007, to May 31, 2009. Doppler parameters of the interlobar arteries, including the peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistive index (RI), were compared with kidney biopsy findings. According to histopathologic findings, the 113 patients were divided into two groups: 1, interstitial fibrosis/tubular atrophy and vascular/glomerular sclerosis (n = 79); and 2, edematous changes in glomeruli without fibrosis (n = 34). The correlations between Doppler parameters and histopathologic findings were statistically analyzed. RESULTS: There were statistically significant differences in the PSV and EDV of the interlobar arteries between groups 1 and 2. Both the PSV and EDV in group 1 were significantly lower than those in group 2 (P < .001). There was no significant difference in the RI of the interlobar arteries between the two groups (P > .05). There were no significant differences in the PSV, EDV, and RI of the main renal artery between the two groups (all P > .05). CONCLUSIONS: The PSV and EDV of the interlobar artery have statistical correlations with histopathologic types in renal transplant dysfunction. Both the PSV and EDV in interstitial fibrosis/tubular atrophy and vascular/glomerular sclerosis seem lower than those in glomerulopathy without fibrosis. Hence, the PSV and EDV of the interlobar artery may potentially be used as hemodynamic indicators for monitoring the progress of renal transplants. PMID- 21266555 TI - Qualitative and semiquantitative evaluations of solid breast lesions by sonoelastography. AB - OBJECTIVES: Our purpose was to determine whether the combination of a qualitative elasticity scoring method and a semiquantitative strain index method by sonoelastography is useful for differentiating between benign and malignant breast masses. METHODS: Seventy-eight lesions in 71 consecutive patients with solid breast masses (62 benign and 16 malignant) were prospectively included in this study. For each lesion, B-mode sonographic and sonoelastographic images were obtained. After elasticity scores had been determined with a 5-point scoring method, strain indices of the lesions were calculated using a same-level and normal-appearing breast region as an internal reference by means of strain ratio measurement. The findings were compared with histopathologic findings. With the use of receiver operating characteristic curves, the diagnostic performances of the elasticity scoring and strain index methods were determined. RESULTS: The mean scores +/- SD on sonoelastography were 2.69 +/- 0.59 for benign lesions and 3.75 +/- 0.68 for malignant lesions. The mean stiffness index values were 2.03 +/ 2.67 for benign lesions and 5.97 +/- 4.45 for malignant lesions. The areas under the curves were 0.864 for 5-point scoring and 0.840 for the strain index. Sensitivity and specificity were 80% and 95%, respectively, for 5-point scoring, 87.5% and 72.6% for B-mode sonography, and 80% and 93% for the strain index when a cutoff point of 3.52 was used. A semiquantitative evaluation using the strain index did not contribute to the qualitative scoring evaluation. CONCLUSIONS: After 5-point scoring with sonoelastography, additional measurement with the strain index is not mandatory for differentiating between benign and malignant breast masses. PMID- 21266557 TI - Sonographically guided tendon sheath injections are more accurate than blind injections: implications for trigger finger treatment. AB - OBJECTIVES: Trigger finger is frequently treated with tendon sheath injections. This cadaveric study evaluated the accuracy and safety of blind and sonographically guided tendon sheath injections. To our knowledge, a study that precisely mapped the locations of material injected into the tendon sheath has not been reported previously. METHODS: A total of 40 fingers (excluding thumbs) of 5 fresh cadavers were used. Methylene blue dye was injected into the flexor tendon sheath using either a blind or sonographically guided injection technique (20 fingers for each technique). The location of the dye was then determined via dissection. RESULTS: Dye was observed only in the tendon sheath (ie, optimal outcome) in 70% of sonographically guided injections and 15% of blind injections (P = .001). Dye was observed in the tendon proper (ie, unsafe outcome) in 30% of blind injections and 0% of sonographically guided injections (P = .02). CONCLUSIONS: We found that sonographically guided tendon sheath injections were more accurate and may be potentially safer than blind injections. These findings suggest that sonographically guided injections should be considered over blind injections when treating trigger finger. PMID- 21266556 TI - Flow velocity vector fields by ultrasound particle imaging velocimetry: in vitro comparison with optical flow velocimetry. AB - OBJECTIVES: We performed an in vitro study to assess the precision and accuracy of particle imaging velocimetry (PIV) data acquired using a clinically available portable ultrasound system via comparison with stereo optical PIV. METHODS: The performance of ultrasound PIV was compared with optical PIV on a benchmark problem involving vortical flow with a substantial out-of-plane velocity component. Optical PIV is capable of stereo image acquisition, thus measuring out of-plane velocity components. This allowed us to quantify the accuracy of ultrasound PIV, which is limited to in-plane acquisition. The system performance was assessed by considering the instantaneous velocity fields without extracting velocity profiles by spatial averaging. RESULTS: Within the 2-dimensional correlation window, using 7 time-averaged frames, the vector fields were found to have correlations of 0.867 in the direction along the ultrasound beam and 0.738 in the perpendicular direction. Out-of-plane motion of greater than 20% of the in plane vector magnitude was found to increase the SD by 11% for the vectors parallel to the ultrasound beam direction and 8.6% for the vectors perpendicular to the beam. CONCLUSIONS: The results show a close correlation and agreement of individual velocity vectors generated by ultrasound PIV compared with optical PIV. Most of the measurement distortions were caused by out-of-plane velocity components. PMID- 21266558 TI - Noninvasive analysis of portal pressure by contrast-enhanced sonography in patients with cirrhosis. AB - OBJECTIVES: Free portal pressure measurement is a reliable method for assessment of portal pressure in patients with cirrhosis. Intrahepatic circulatory time analysis of a sonographic contrast agent can assess liver fibrosis and its severity. The purposes of this pilot study were to assess the correlation between the intrahepatic circulatory time and free portal pressure and to assess whether intrahepatic circulatory time analysis can be used to predict portal venous pressure severity. METHODS: The intrahepatic circulatory time and free portal pressure were measured in 31 patients with hepatitis B virus-related liver disease. Pearson correlation analysis was used to assess the correlation between the intrahepatic circulatory time and free portal pressure. RESULTS: The hepatic vein-hepatic artery interval times were significantly shorter in the portal hypertension group than the non-portal hypertension group (mean +/- SD, 8.26 +/- 1.94 and 13.83 +/- 1.17 seconds, respectively; P < .001). The portal vein-hepatic artery interval times were significantly longer in the portal hypertension group than the nonportal hypertension group (13.13 +/- 2.25 and 7.25 +/- 1.81 seconds; P < .001). Considering the whole patient population, there were statistically significant correlations between free portal pressure and the hepatic vein hepatic artery interval time (r = -0.900; P < .001) and portal vein-hepatic artery interval time (r = 0.808; P < .001). In patients with portal hypertension, there was a statistically significant correlation between free portal pressure and the hepatic vein-hepatic artery interval time (r = -0.804; P = .009) and a weak correlation between free portal pressure and the portal vein-hepatic artery interval time (r = 0.506; P = .036). CONCLUSIONS: Intrahepatic circulatory time measurement is correlated with free portal pressure and has the potential capability to evaluate portal pressure noninvasively in patients with hepatitis B virus-related liver disease. PMID- 21266559 TI - Sepsis rates after ultrasound-guided prostate biopsy using a bowel preparation protocol in a community hospital. AB - OBJECTIVES: The purpose of this study was to determine whether the addition of disposable enemas and a 24-hour diet of clear fluids to the bowel preparation protocol before transrectal ultrasound-guided prostate biopsy decreases the rate of postbiopsy sepsis. METHODS: Sepsis rates of patients who underwent transrectal ultrasound-guided prostate biopsies at a community hospital were analyzed before and after a new bowel preparation protocol was introduced in our department. All patients received the antibiotic ciprofloxacin both before and after the biopsy. The first group (190 patients) had a preparation protocol that only asked the patients to stop eating by midnight (clear fluids only) on the day before the biopsy. The second group involved 217 patients and followed a bowel-cleansing biopsy preparation protocol. This protocol included the use of 2 disposable enemas and a diet of clear fluids for 24 hours preceding the biopsy. A systematic chart review was then performed to determine which patients had required treatment for postbiopsy sepsis. RESULTS: Sepsis occurred in 4 patients (2.11%) in group 1 and 1 patient (0.46%) in group 2. After performing a 2-sided Fisher exact test, it was found that there was no significant difference between the groups at a 95% confidence level (P = .189). CONCLUSIONS: The 24-hour clear-fluid diet and the use of disposable enemas combined with a regimen of ciprofloxacin decreased the rate of postbiopsy sepsis in patients who underwent transrectal ultrasound-guided prostate biopsy, but the results were not significantly different. PMID- 21266560 TI - Sonographic assessment of hypopharyngeal carcinoma: preliminary study. AB - OBJECTIVES: This study investigated the ability of sonography for diagnosis of hypopharyngeal carcinoma. METHODS: Between November 2008 and January 2010, 34 consecutive patients with hypopharyngeal carcinoma (34 tumors) were examined by sonography. The visualization capability of sonography was evaluated by grading criteria of "excellent," "good," "moderate," and "poor" in comparison with computed tomography (CT). Localization of the primary tumor foci and intrahypopharyngeal and extrahypopharyngeal invasion were initially assessed by sonography and confirmed with surgical and pathologic findings. Laryngeal movement was observed on real-time sonography and compared with endoscopic findings. RESULTS: On sonography, 29 of the 34 lesions (85.3%) were graded excellent, similar to the shapes and dimensions of the tumors on CT. Localization was correctly undertaken in 26 of the 28 foci resected (92.9%), with excellent agreement between sonography and surgical and pathologic findings (kappa = 0.823; P < .001). In evaluating intrahypopharyngeal and extrahypopharyngeal invasion with sonography, the sensitivity and specificity were 90.9% and 82.4%, respectively, for intrahypopharyngeal intersubsite spreading, 50.0% and 96.2% for diagnosis of thyroid cartilage destruction, both 100% for evaluation of cervical esophagus, neck soft tissue, and thyroid gland involvement, and 76.9% and 100% for assessment of hemilarynx fixation. CONCLUSIONS: Sonography has a similar role in visualization of hypopharyngeal carcinoma as CT and is satisfactory in localization of the primary focus and assessment of tumor extension inside and outside the hypopharynx. PMID- 21266561 TI - Effect of membrane sweeping on cervical length by transvaginal ultrasonography and impact of cervical shortening on cesarean delivery. AB - OBJECTIVES: The purpose of this study was to evaluate cervical length changes after membrane sweeping and the effect of cervical shortening on pregnancy outcomes. METHODS: Low-risk women at 40 weeks' gestation undergoing membrane sweeping to expedite labor were recruited. Participants were scheduled for labor induction at 41 weeks' gestation. Transvaginal ultrasonography was performed immediately before and after membrane sweeping to measure the cervical length. Three presweep and postsweep cervical lengths were measured. The shortest lengths before and after the sweep were taken as the representative lengths. The effect of membrane sweeping on cervical length was analyzed. Multivariable logistic regression analysis was performed to evaluate the effect of cervical shortening on labor induction and the mode of delivery. RESULTS: For the 160 participants, the mean presweep cervical length +/- SD was 21.0 +/- 10.0 mm; the postsweep length was 23.8 +/- 10.9 mm, an average increase of 2.8 +/- 0.6 mm (P < .001). Cervical shortening after membrane sweeping was noted in 53 of 160 cases (33%). Cervical shortening was associated with a reduction in all-cause cesarean delivery but not labor induction on bivariate analysis. After adjustment for maternal age, parity, presweep Bishop score, postsweep cervical length, oxytocin augmentation, epidural analgesia, and meconium-stained fluid, cervical shortening after membrane sweeping was independently predictive of a reduction in cesarean deliveries (adjusted odds ratio, 0.24; 95% confidence interval, 0.06-0.90; P = .034). CONCLUSIONS: Membrane sweeping was associated with lengthening of the cervix. A shortened cervix after sweeping was independently predictive of vaginal delivery. PMID- 21266562 TI - Measurement of the fetal umbilical cord insertion-to-genital tubercle length in early gestation: in utero sonographic study. AB - OBJECTIVES: The purpose of this study was to establish in utero reference ranges for the fetal umbilical cord insertion-to-genital tubercle length in early gestation. METHODS: A prospective cross-sectional study was performed on 140 normal low-risk singleton pregnancies between 12 and 18 weeks' gestation. The umbilical cord insertion-to-genital tubercle length was measured in a midsagittal section with high-resolution transvaginal or transabdominal sonography. The mean and 95% prediction limits were defined for each gestational week and analyzed by regression equations and correlation coefficients. RESULTS: Adequate measurements were obtained in 134 patients. The umbilical cord insertion-to-genital tubercle length as a function of gestational age was expressed by the following regression equation: umbilical cord insertion-to-genital tubercle length = -3.079452 + 1.09 * week (R(2) = 0.7117). The correlation R(2) = 0.7117 was found to be highly statistically significant (P < .001). The normal mean and 95% prediction limits were defined for each gestational week. During the study period, 2 cases were referred to our unit because of nonvisualization of the urinary bladder. The umbilical cord insertion-to-genital tubercle lengths in these cases were below the 95th percentile, confirming the diagnosis of bladder exstrophy. CONCLUSIONS: The normative data established in this study may be helpful for early pre-natal diagnosis congenital bladder exstrophy. PMID- 21266563 TI - Real-time interpolation for true 3-dimensional ultrasound image volumes. AB - We compared trilinear interpolation to voxel nearest neighbor and distance weighted algorithms for fast and accurate processing of true 3-dimensional ultrasound (3DUS) image volumes. In this study, the computational efficiency and interpolation accuracy of the 3 methods were compared on the basis of a simulated 3DUS image volume, 34 clinical 3DUS image volumes from 5 patients, and 2 experimental phantom image volumes. We show that trilinear interpolation improves interpolation accuracy over both the voxel nearest neighbor and distance-weighted algorithms yet achieves real-time computational performance that is comparable to the voxel nearest neighbor algrorithm (1-2 orders of magnitude faster than the distance-weighted algorithm) as well as the fastest pixel-based algorithms for processing tracked 2-dimensional ultrasound images (0.035 seconds per 2 dimesional cross-sectional image [76,800 pixels interpolated, or 0.46 ms/1000 pixels] and 1.05 seconds per full volume with a 1-mm(3) voxel size [4.6 million voxels interpolated, or 0.23 ms/1000 voxels]). On the basis of these results, trilinear interpolation is recommended as a fast and accurate interpolation method for rectilinear sampling of 3DUS image acquisitions, which is required to facilitate subsequent processing and display during operating room procedures such as image-guided neurosurgery. PMID- 21266564 TI - Real-time sonography with electromagnetic tracking navigation for biopsy of a hepatic neoplasm seen only on arterial phase computed tomography. AB - This case illustrates the ability of electromagnetic tracking navigation to localize difficult targets in real time during biopsy or ablation of lesions that are only transiently apparent on arterial phase computed tomography and may be unapparent on sonography. Readily available technology enabling multimodality registration to sonography allows for the use of positron emission tomographic, magnetic resonance imaging, and computed tomographic information during sonographically guided procedures and examinations. PMID- 21266565 TI - Sonographically guided therapeutic injection for primary medial (tibial) collateral bursitis. AB - The purpose of this article is to describe a sonographically guided technique to perform therapeutic injection into the medial collateral ligament bursa. Scans are performed using a high-frequency linear transducer with the scan plane corresponding to the anatomic coronal plane. The transducer is positioned along the medial aspect of the knee; a 25-gauge needle is placed along the inferior border of the bursa; and a standardized therapeutic mixture (anesthetic and long active corticosteroid) is injected. Distention of the bursa is the determining factor for a successful injection. Sonography allows confirmation of correct injection placement, resulting in increased accuracy and more successful patient outcomes. PMID- 21266566 TI - Gelatin-agar lumbosacral spine phantom: a simple model for learning the basic skills required to perform real-time sonographically guided central neuraxial blocks. AB - This report describes the preparation of a gelatin-agar spine phantom that was used for spinal sonography and to practice the hand-eye coordination skills required to perform sonographically guided central neuraxial blocks. The phantom was prepared by embedding a lumbosacral spine model into a mixture of gelatin and agar in a plastic box. Cellulose powder and chlorhexidine were also added to the mixture, after which it was allowed to solidify. Sonography of the osseous elements of the lumbosacral spine in the phantom was then performed, and their sonographic appearances were compared to those in volunteers. Simulated real-time sonographically guided paramedian spinal needle insertions were also performed in the phantom. The texture and echogenicity of the phantom were subjectively comparable to those of tissue in vivo. The osseous elements of the spine in the phantom were clearly delineated, and their sonographic appearances were comparable to those seen in vivo in the volunteers. During the simulated sonographically guided spinal injections, the needle could be clearly visualized, but the phantom provided little tactile feedback. In conclusion, the gelatin-agar spine phantom is a simple and inexpensive sonographic spine model that has a tissuelike texture and echogenicity. It can be used to study the osseous anatomy of the lumbar spine and practice the skills required to perform sonographically guided central neuraxial blocks. PMID- 21266567 TI - Isolated fetal intra-abdominal umbilical vein varix: clinical importance and recommendations. AB - This series describes a single center's experience in follow-up and management of fetuses with an isolated fetal intra-abdominal umbilical vein varix. All cases with a fetal intra-abdominal umbilical vein varix that were diagnosed or referred to our medical center over 15 years were followed and managed. The definition of a fetal intra-abdominal umbilical vein varix used was a segment dilated to 9 mm or greater or at least 50% wider than the diameter of the adjacent umbilical vein. Over the 15-year period, our center had approximately 65,000 births with 28 cases of isolated fetal intra-abdominal umbilical vein varices: a prevalence rate of 1 case per 2300 births. Three of the 28 cases (10.7%) had intrauterine growth restriction. Five of 30 fetuses (17%) showed turbulent flow in the varix. We had no cases of intrauterine fetal death, and 27 of the 28 neonates had good outcomes. In contrary to earlier reports, we found that when a fetal intra abdominal umbilical vein varix is isolated, a good fetal outcome is expected. On the basis of our experience, we have changed our policy and do not recommend inducing preterm labor. Nevertheless, close fetal surveillance until delivery is warranted. PMID- 21266568 TI - Prenatal diagnosis of a unilateral hypoplastic vertebral arch by 2- and 3 dimensional sonography. PMID- 21266569 TI - Paratesticular solitary fibrous tumor: a rare cause of a hypervascular extratesticular mass. PMID- 21266570 TI - Unusual presentation of a sacral parasitic conjoined twin. PMID- 21266571 TI - Current guidelines for fetal echocardiography: time to raise the bar. PMID- 21266572 TI - Direct activation of human phospholipase C by its well known inhibitor u73122. AB - Phospholipase C (PLC) enzymes are an important family of regulatory proteins involved in numerous cellular functions, primarily through hydrolysis of the polar head group from inositol-containing membrane phospholipids. U73122 (1-(6 ((17beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione), one of only a few small molecules reported to inhibit the activity of these enzymes, has been broadly applied as a pharmacological tool to implicate PLCs in diverse experimental phenotypes. The purpose of this study was to develop a better understanding of molecular interactions between U73122 and PLCs. Hence, the effects of U73122 on human PLCbeta3 (hPLCbeta3) were evaluated in a cell-free micellar system. Surprisingly, U73122 increased the activity of hPLCbeta3 in a concentration- and time-dependent manner; up to an 8-fold increase in enzyme activity was observed with an EC50=13.6+/-5 MUm. Activation of hPLCbeta3 by U73122 required covalent modification of cysteines as evidenced by the observation that enzyme activation was attenuated by thiol-containing nucleophiles, l-cysteine and glutathione. Mass spectrometric analysis confirmed covalent reaction with U73122 at eight cysteines, although maximum activation was achieved without complete alkylation; the modified residues were identified by LC/MS/MS peptide sequencing. Interestingly, U73122 (10 MUm) also activated hPLCgamma1 (>10-fold) and hPLCbeta2 (~2-fold); PLCdelta1 was neither activated nor inhibited. Therefore, in contrast to its reported inhibitory potential, U73122 failed to inhibit several purified PLCs. Most of these PLCs were directly activated by U73122, and a simple mechanism for the activation is proposed. These results strongly suggest a need to re-evaluate the use of U73122 as a general inhibitor of PLC isozymes. PMID- 21266573 TI - Naturally secreted amyloid-beta increases mammalian target of rapamycin (mTOR) activity via a PRAS40-mediated mechanism. AB - Reducing the mammalian target of rapamycin (mTOR) activity increases lifespan and health span in a variety of organisms. Alterations in protein homeostasis and mTOR activity and signaling have been reported in several neurodegenerative disorders, including Alzheimer disease (AD); however, the causes of such deregulations remain elusive. Here, we show that mTOR activity and signaling are increased in cell lines stably transfected with mutant amyloid precursor protein (APP) and in brains of 3xTg-AD mice, an animal model of AD. In addition, we show that in the 3xTg-AD mice, mTOR activity can be reduced to wild type levels by genetically preventing Abeta accumulation. Similarly, intrahippocampal injections of an anti-Abeta antibody reduced Abeta levels and normalized mTOR activity, indicating that high Abeta levels are necessary for mTOR hyperactivity in 3xTg-AD mice. We also show that the intrahippocampal injection of naturally secreted Abeta is sufficient to increase mTOR signaling in the brains of wild type mice. The mechanism behind the Abeta-induced mTOR hyperactivity is mediated by the proline-rich Akt substrate 40 (PRAS40) as we show that the activation of PRAS40 plays a key role in the Abeta-induced mTOR hyperactivity. Taken together, our data show that Abeta accumulation, which has been suggested to be the culprit of AD pathogenesis, causes mTOR hyperactivity by regulating PRAS40 phosphorylation. These data further indicate that the mTOR pathway is one of the pathways by which Abeta exerts its toxicity and further support the idea that reducing mTOR signaling in AD may be a valid therapeutic approach. PMID- 21266574 TI - A single tyrosine residue in the amyloid precursor protein intracellular domain is essential for developmental function. AB - The Abeta-precursor protein (APP) intracellular domain is highly conserved and contains many potentially important residues, in particular the (682)YENPTY(687) motif. To dissect the functions of this sequence in vivo, we created an APP knock in allele mutating Tyr(682) to Gly (Y682G). Crossing this allele to APP-like protein 2 (APLP2) knock-out background showed that mutation of Tyr(682) results in postnatal lethality and neuromuscular synapse defects similar to doubly deficient APP/APLP2 mice. Our results demonstrate that a single residue in the APP intracellular region, Tyr(682), is indispensable for the essential function of APP in developmental regulation. PMID- 21266575 TI - Purification and characterization of OleA from Xanthomonas campestris and demonstration of a non-decarboxylative Claisen condensation reaction. AB - OleA catalyzes the condensation of fatty acyl groups in the first step of bacterial long-chain olefin biosynthesis, but the mechanism of the condensation reaction is controversial. In this study, OleA from Xanthomonas campestris was expressed in Escherichia coli and purified to homogeneity. The purified protein was shown to be active with fatty acyl-CoA substrates that ranged from C(8) to C(16) in length. With limiting myristoyl-CoA (C(14)), 1 mol of the free coenzyme A was released/mol of myristoyl-CoA consumed. Using [(14)C]myristoyl-CoA, the other products were identified as myristic acid, 2-myristoylmyristic acid, and 14 heptacosanone. 2-Myristoylmyristic acid was indicated to be the physiologically relevant product of OleA in several ways. First, 2-myristoylmyristic acid was the major condensed product in short incubations, but over time, it decreased with the concomitant increase of 14-heptacosanone. Second, synthetic 2 myristoylmyristic acid showed similar decarboxylation kinetics in the absence of OleA. Third, 2-myristoylmyristic acid was shown to be reactive with purified OleC and OleD to generate the olefin 14-heptacosene, a product seen in previous in vivo studies. The decarboxylation product, 14-heptacosanone, did not react with OleC and OleD to produce any demonstrable product. Substantial hydrolysis of fatty acyl-CoA substrates to the corresponding fatty acids was observed, but it is currently unclear if this occurs in vivo. In total, these data are consistent with OleA catalyzing a non-decarboxylative Claisen condensation reaction in the first step of the olefin biosynthetic pathway previously found to be present in at least 70 different bacterial strains. PMID- 21266576 TI - The G protein-coupled receptor 30 is up-regulated by hypoxia-inducible factor 1alpha (HIF-1alpha) in breast cancer cells and cardiomyocytes. AB - GPR30, also known as GPER, has been suggested to mediate rapid effects induced by estrogens in diverse normal and cancer tissues. Hypoxia is a common feature of solid tumors involved in apoptosis, cell survival, and proliferation. The response to low oxygen environment is mainly mediated by the hypoxia-inducible factor named HIF-1alpha, which activates signaling pathways leading to adaptive mechanisms in tumor cells. Here, we demonstrate that the hypoxia induces HIF 1alpha expression, which in turn mediates the up-regulation of GPER and its downstream target CTGF in estrogen receptor-negative SkBr3 breast cancer cells and in HL-1 cardiomyocytes. Moreover, we show that HIF-1alpha-responsive elements located within the promoter region of GPER are involved in hypoxia-dependent transcription of GPER, which requires the ROS-induced activation of EGFR/ERK signaling in both SkBr3 and HL-1 and cells. Interestingly, the apoptotic response to hypoxia was prevented by estrogens through GPER in SkBr3 cells. Taken together, our data suggest that the hypoxia-induced expression of GPER may be included among the mechanisms involved in the anti-apoptotic effects elicited by estrogens, particularly in a low oxygen microenvironment. PMID- 21266577 TI - Urate as a physiological substrate for myeloperoxidase: implications for hyperuricemia and inflammation. AB - Urate and myeloperoxidase (MPO) are associated with adverse outcomes in cardiovascular disease. In this study, we assessed whether urate is a likely physiological substrate for MPO and if the products of their interaction have the potential to exacerbate inflammation. Urate was readily oxidized by MPO and hydrogen peroxide to 5-hydroxyisourate, which decayed to predominantly allantoin. The redox intermediates of MPO were reduced by urate with rate constants of 4.6 * 10(5) M(-1) s(-1) for compound I and 1.7 * 10(4) M(-1) s(-1) for compound II. Urate competed with chloride for oxidation by MPO and at hyperuricemic levels is expected to be a substantive substrate for the enzyme. Oxidation of urate promoted super-stoichiometric consumption of glutathione, which indicates that it is converted to a free radical intermediate. In combination with superoxide and hydrogen peroxide, MPO oxidized urate to a reactive hydroperoxide. This would form by addition of superoxide to the urate radical. Urate also enhanced MPO dependent consumption of nitric oxide. In human plasma, stimulated neutrophils produced allantoin in a reaction dependent on the NADPH oxidase, MPO and superoxide. We propose that urate is a physiological substrate for MPO that is oxidized to the urate radical. The reactions of this radical with superoxide and nitric oxide provide a plausible link between urate and MPO in cardiovascular disease. PMID- 21266579 TI - Raftlin is involved in the nucleocapture complex to induce poly(I:C)-mediated TLR3 activation. AB - The double-stranded RNA analog, poly(I:C), extracellularly activates both the endosomal Toll-like receptor (TLR) 3 and the cytoplasmic RNA helicase, melanoma differentiation-associated gene 5, leading to the production of type I interferons (IFNs) and inflammatory cytokines. The mechanism by which extracellular poly(I:C) is delivered to TLR3-positive organelles and the cytoplasm remains to be elucidated. Here, we show that the cytoplasmic lipid raft protein, Raftlin, is essential for poly(I:C) cellular uptake in human myeloid dendritic cells and epithelial cells. When Raftlin was silenced, poly(I:C) failed to enter cells and induction of IFN-beta production was inhibited. In addition, cellular uptake of B-type oligodeoxynucleotide that shares its uptake receptor with poly(I:C) was suppressed in Raftlin knockdown cells. Upon poly(I:C) stimulation, Raftlin was translocated from the cytoplasm to the plasma membrane where it colocalized with poly(I:C), and thereafter moved to TLR3-positive endosomes. Thus, Raftlin cooperates with the uptake receptor to mediate cell entry of poly(I:C), which is critical for activation of TLR3. PMID- 21266578 TI - Loss of subcellular lipid transport due to ARV1 deficiency disrupts organelle homeostasis and activates the unfolded protein response. AB - The ARV1-encoded protein mediates sterol transport from the endoplasmic reticulum (ER) to the plasma membrane. Yeast ARV1 mutants accumulate multiple lipids in the ER and are sensitive to pharmacological modulators of both sterol and sphingolipid metabolism. Using fluorescent and electron microscopy, we demonstrate sterol accumulation, subcellular membrane expansion, elevated lipid droplet formation, and vacuolar fragmentation in ARV1 mutants. Motif-based regression analysis of ARV1 deletion transcription profiles indicates activation of Hac1p, an integral component of the unfolded protein response (UPR). Accordingly, we show constitutive splicing of HAC1 transcripts, induction of a UPR reporter, and elevated expression of UPR targets in ARV1 mutants. IRE1, encoding the unfolded protein sensor in the ER lumen, exhibits a lethal genetic interaction with ARV1, indicating a viability requirement for the UPR in cells lacking ARV1. Surprisingly, ARV1 mutants expressing a variant of Ire1p defective in sensing unfolded proteins are viable. Moreover, these strains also exhibit constitutive HAC1 splicing that interacts with DTT-mediated perturbation of protein folding. These data suggest that a component of UPR induction in arv1Delta strains is distinct from protein misfolding. Decreased ARV1 expression in murine macrophages also results in UPR induction, particularly up-regulation of activating transcription factor-4, CHOP (C/EBP homologous protein), and apoptosis. Cholesterol loading or inhibition of cholesterol esterification further elevated CHOP expression in ARV1 knockdown cells. Thus, loss or down regulation of ARV1 disturbs membrane and lipid homeostasis, resulting in a disruption of ER integrity, one consequence of which is induction of the UPR. PMID- 21266580 TI - Thrombin induces NF-kappaB activation and IL-8/CXCL8 expression in lung epithelial cells by a Rac1-dependent PI3K/Akt pathway. AB - We previously showed that thrombin induces interleukin (IL)-8/CXCL8 expression via the protein kinase C (PKC)alpha/c-Src-dependent IkappaB kinase alpha/beta (IKKalpha/beta)/NF-kappaB signaling pathway in human lung epithelial cells. In this study, we further investigated the roles of Rac1, phosphoinositide 3-kinase (PI3K), and Akt in thrombin-induced NF-kappaB activation and IL-8/CXCL8 expression. Thrombin-induced IL-8/CXCL8 release and IL-8/CXCL8-luciferase activity were attenuated by a PI3K inhibitor (LY294002), an Akt inhibitor (1-L-6 hydroxymethyl-chiro-inositol-2-((R)-2-O-methyl-3-O-octadecylcarbonate)), and the dominant negative mutants of Rac1 (RacN17) and Akt (AktDN). Treatment of cells with thrombin caused activation of Rac and Akt. The thrombin-induced increase in Akt activation was inhibited by RacN17 and LY294002. Stimulation of cells with thrombin resulted in increases in IKKalpha/beta activation and kappaB-luciferase activity; these effects were inhibited by RacN17, LY294002, an Akt inhibitor, and AktDN. Treatment of cells with thrombin induced Gbetagamma, p85alpha, and Rac1 complex formation in a time-dependent manner. These results imply that thrombin activates the Rac1/PI3K/Akt pathway through formation of the Gbetagamma, Rac1, and p85alpha complex to induce IKKalpha/beta activation, NF-kappaB transactivation, and IL-8/CXCL8 expression in human lung epithelial cells. PMID- 21266581 TI - Physiological roles of group X-secreted phospholipase A2 in reproduction, gastrointestinal phospholipid digestion, and neuronal function. AB - Although the secreted phospholipase A(2) (sPLA(2)) family has been generally thought to participate in pathologic events such as inflammation and atherosclerosis, relatively high and constitutive expression of group X sPLA(2) (sPLA(2)-X) in restricted sites such as reproductive organs, the gastrointestinal tract, and peripheral neurons raises a question as to the roles played by this enzyme in the physiology of reproduction, digestion, and the nervous system. Herein we used mice with gene disruption or transgenic overexpression of sPLA(2) X to clarify the homeostatic functions of this enzyme at these locations. Our results suggest that sPLA(2)-X regulates 1) the fertility of spermatozoa, not oocytes, beyond the step of flagellar motility, 2) gastrointestinal phospholipid digestion, perturbation of which is eventually linked to delayed onset of a lean phenotype with reduced adiposity, decreased plasma leptin, and improved muscle insulin tolerance, and 3) neuritogenesis of dorsal root ganglia and the duration of peripheral pain nociception. Thus, besides its inflammatory action proposed previously, sPLA(2)-X participates in physiologic processes including male fertility, gastrointestinal phospholipid digestion linked to adiposity, and neuronal outgrowth and sensing. PMID- 21266582 TI - Nitroarachidonic acid, a novel peroxidase inhibitor of prostaglandin endoperoxide H synthases 1 and 2. AB - Prostaglandin endoperoxide H synthase (PGHS) catalyzes the oxidation of arachidonate to prostaglandin H(2). We have previously synthesized and chemically characterized nitroarachidonic acid (AANO(2)), a novel anti-inflammatory signaling mediator. Herein, the interaction of AANO(2) with PGHS was analyzed. AANO(2) inhibited oxygenase activity of PGHS-1 but not PGHS-2. AANO(2) exhibited time- and concentration-dependent inhibition of peroxidase activity in both PGHS 1 and -2. The plot of k(obs) versus AANO(2) concentrations showed a hyperbolic function with k(inact) = 0.045 s(-1) and K(i)(*app) = 0.019 MUM for PGHS-1 and k(inact) = 0.057 s(-1) and K(i)(*app) = 0.020 MUM for PGHS-2. Kinetic analysis suggests that inactivation of PGHS by AANO(2) involves two sequential steps: an initial reversible binding event (described by K(i)) followed by a practically irreversible event (K(i)(*app)) leading to an inactivated enzyme. Inactivation was associated with irreversible disruption of heme binding to the protein. The inhibitory effects of AANO(2) were selective because other nitro-fatty acids tested, such as nitrooleic acid and nitrolinoleic acid, were unable to inhibit enzyme activity. In activated human platelets, AANO(2) significantly decreased PGHS-1-dependent thromboxane B(2) formation in parallel with a decrease in platelet aggregation, thus confirming the biological relevance of this novel inhibitory pathway. PMID- 21266583 TI - Hair follicular expression and function of group X secreted phospholipase A2 in mouse skin. AB - Although perturbed lipid metabolism can often lead to skin abnormality, the role of phospholipase A(2) (PLA(2)) in skin homeostasis is poorly understood. In the present study we found that group X-secreted PLA(2) (sPLA(2)-X) was expressed in the outermost epithelium of hair follicles in synchrony with the anagen phase of hair cycling. Transgenic mice overexpressing sPLA(2)-X (PLA2G10-Tg) displayed alopecia, which was accompanied by hair follicle distortion with reduced expression of genes related to hair development, during a postnatal hair cycle. Additionally, the epidermis and sebaceous glands of PLA2G10-Tg skin were hyperplasic. Proteolytic activation of sPLA(2)-X in PLA2G10-Tg skin was accompanied by preferential hydrolysis of phosphatidylethanolamine species with polyunsaturated fatty acids as well as elevated production of some if not all eicosanoids. Importantly, the skin of Pla2g10-deficient mice had abnormal hair follicles with noticeable reduction in a subset of hair genes, a hypoplasic outer root sheath, a reduced number of melanin granules, and unexpected up-regulation of prostanoid synthesis. Collectively, our study highlights the spatiotemporal expression of sPLA(2)-X in hair follicles, the presence of skin-specific machinery leading to sPLA(2)-X activation, a functional link of sPLA(2)-X with hair follicle homeostasis, and compartmentalization of the prostanoid pathway in hair follicles and epidermis. PMID- 21266586 TI - 4th European Public Health Conference 2011 in Copenhagen: Public Health and Welfare--Welfare Development and Health . PMID- 21266584 TI - Distinct molecular regulation of glycogen synthase kinase-3alpha isozyme controlled by its N-terminal region: functional role in calcium/calpain signaling. AB - Glycogen synthase kinase-3 (GSK-3) is expressed as two isozymes alpha and beta. They share high similarity in their catalytic domains but differ in their N- and C-terminal regions, with GSK-3alpha having an extended glycine-rich N terminus. Here, we undertook live cell imaging combined with molecular and bioinformatic studies to understand the distinct functions of the GSK-3 isozymes focusing on GSK-3alpha N-terminal region. We found that unlike GSK-3beta, which shuttles between the nucleus and cytoplasm, GSK-3alpha was excluded from the nucleus. Deletion of the N-terminal region of GSK-3alpha resulted in nuclear localization, and treatment with leptomycin B resulted in GSK-3alpha accumulation in the nucleus. GSK-3alpha rapidly accumulated in the nucleus in response to calcium or serum deprivation, and accumulation was strongly inhibited by the calpain inhibitor calpeptin. This nuclear accumulation was not mediated by cleavage of the N-terminal region or phosphorylation of GSK-3alpha. Rather, we show that calcium-induced GSK-3alpha nuclear accumulation was governed by GSK-3alpha binding with as yet unknown calpain-sensitive protein or proteins; this binding was mediated by the N-terminal region. Bioinformatic and experimental analyses indicated that nuclear exclusion of GSK-3alpha was likely an exclusive characteristic of mammalian GSK-3alpha. Finally, we show that nuclear localization of GSK-3alpha reduced the nuclear pool of beta-catenin and its target cyclin D1. Taken together, these data suggest that the N-terminal region of GSK-3alpha is responsible for its nuclear exclusion and that binding with a calcium/calpain-sensitive product enables GSK-3alpha nuclear retention. We further uncovered a novel link between calcium and nuclear GSK-3alpha-mediated inhibition of the canonical Wnt/beta-catenin pathway. PMID- 21266585 TI - A novel putrescine importer required for type 1 pili-driven surface motility induced by extracellular putrescine in Escherichia coli K-12. AB - Recently, many studies have reported that polyamines play a role in bacterial cell-to-cell signaling processes. The present study describes a novel putrescine importer required for induction of type 1 pili-driven surface motility. The surface motility of the Escherichia coli DeltaspeAB DeltaspeC DeltapotABCD strain, which cannot produce putrescine and cannot import spermidine from the medium, was induced by extracellular putrescine. Introduction of the gene deletions for known polyamine importers (DeltapotE, DeltapotFGHI, and DeltapuuP) or a putative polyamine importer (DeltaydcSTUV) into the DeltaspeAB DeltaspeC DeltapotABCD strain did not affect putrescine-induced surface motility. The deletion of yeeF, an annotated putative putrescine importer, in the DeltaspeAB DeltaspeC DeltapotABCD DeltaydcSTUV strain abolished surface motility in putrescine-supplemented medium. Complementation of yeeF by a plasmid vector restored surface motility. The surface motility observed in the present study was abolished by the deletion of fimA, suggesting that the surface motility is type 1 pili-driven. A transport assay using the yeeF(+) or DeltayeeF strains revealed that YeeF is a novel putrescine importer. The K(m) of YeeF (155 MUM) is 40 to 300 times higher than that of other importers reported previously. On the other hand, the V(max) of YeeF (9.3 nmol/min/mg) is comparable to that of PotABCD, PotFGHI, and PuuP. The low affinity of YeeF for putrescine may allow E. coli to sense the cell density depending on the concentration of extracellular putrescine. PMID- 21266587 TI - Is participation in labour market programmes related to mental health? Results from a 14-year follow-up of the Northern Swedish Cohort. AB - AIMS: There is a lack of empirical studies assessing the possible impact of active labour market programmes (ALMP) on health. The aim of this study was to analyze whether participation in ALMP, in contrast to being unemployed and not participating in ALMP (UNALMP), was related to mental health at different ages. METHODS: The study was carried out in a medium-sized industrial town in the north of Sweden. The cohort, consisting of all 1,083 pupils who attended or should have attended the last year of compulsory school in 1981, was followed up at the ages of 16, 18, 21 and 30. Data on 381 individuals at age 21, and 281 at age 30 were used in the study. The main health measurement was psychological symptoms among participants of ALMP in contrast to UNALMP at ages 21 and 30, and was analyzed by propensity score matching method (PSM) and multivariate logistic regression. RESULTS: Generally, ALMP had higher scores of psychological symptoms than UNALMP. Nevertheless, participation in ALMP was not related to mental health. Due to methodological shortages our results have to be interpreted with caution. Adjustment for either all background selection variables or the propensity score in multivariate logistic regression showed similar associations, suggesting that propensity score could be used to adjust for background selection variables. CONCLUSIONS: There is a need for more well-designed studies, using a theoretical framework, within the field, that are based on larger samples. PMID- 21266588 TI - Norm compliance and self-reported health among Swedish adolescents. AB - AIMS: This study examines the relationship between norm compliance and self reported health in adolescents, and how this differs between genders. Our specific aim was to investigate if extremely high norm compliance revealed any particular health patterns. METHODS: This empirical study used a web-based survey from 2005, which was distributed to all students (n = 5,066) in years 7-9 of compulsory school within six municipalities in northern Sweden. The respondents answered questions about their general health as well as specific health problems such as headaches, stomach ache, sleeping difficulties and stress. Compliance was measured according to different norm-related behaviour, such as truancy, crime and use of tobacco, alcohol and narcotics. RESULTS: The majority of respondents reported good health and norm-compliant behaviour. Girls reported more health problems than boys, a difference that increased with age. Those who were more norm compliant reported better health, fewer somatic complaints and less stress, which goes against our initial hypothesis that extremely high norm compliance and self-reported ill-health are related. There seemed to be a stronger relationship between self-reported health and norm compliance for girls than boys, in absolute terms. CONCLUSIONS: The results clearly show a relationship between norm compliance and health, and suggest inequalities between genders. PMID- 21266589 TI - Vacations to sunny destinations, sunburn, and intention to tan: a cross-sectional study in Denmark, 2007-2009. AB - BACKGROUND: Denmark has experienced an increase in melanoma incidence since the 1960s. Exposure to ultraviolet radiation is the main preventable cause of this cancer. We examined current travel to, and sun-related behaviour of Danes at, sunny destinations in relation to their risk for sunburn. METHOD: A population based sample of 11,158 respondents aged 15-59 years completed three questionnaires in 2007-2009 that included items on exposure to ultraviolet radiation. Using logistic regression analysis we examined the relations between sunny vacations, sun-related behaviour, demographic factors and risk for sunburn. RESULTS: During 2007-2009, 44.8-45.8% of the respondents travelled to a sunny destination at least once a year; 24% became sunburnt, and 69% tanned intentionally. The odds ratio for sunburn in general for people who went on a sunny vacation as compared with those who did not was 1.6 (1.5-1.7). Sunscreen use (1.9; 1.4-2.6) and intentional tanning (3.4; 2.8-4.1) were positively associated with sunburn on vacation. CONCLUSIONS: Taking a vacation in a sunny place is a risk factor for sunburn, especially for young people. The recommendation for sunscreen use should be re-evaluated, as intention to tan is the most important factor in sunburn on vacation and should be targeted more strategically. PMID- 21266590 TI - Group treatment of obesity in primary care practice: a qualitative study of patients' perspectives. AB - AIMS: To explore patients' experiences of very low calorie diet (VLCD) and subsequent corset treatment of obesity in a primary care setting, and to explore their perceptions of factors influencing weight control. METHODS: In western Sweden, five focus group sessions were carried out. The main themes for the discussions were the informants' perceptions of the treatment they had received and their experiences of living with obesity. The analysis was based on the Grounded Theory methodology. RESULTS: The outcomes reflect obese individuals' struggle to handle the demands of their life situation and to recognize their own resources. The core category generated was labelled ''Achieving a balance in life and adjusting one's identity''. Three categories related to the process of weight reduction were identified: living with obesity, reducing weight and developing self-management. The group treatment with VLCD was positively perceived by the participants, but the corset treatment was considered to be of less value. CONCLUSIONS: Maintenance after weight reduction was demanding and the findings indicate a need for extended support. For some individuals the corset treatment could be a psychological support. Follow-up after weight reduction programmes should focus on long-term self-help strategies. PMID- 21266591 TI - The Swedish National Institute of Public Health: public health policy report 2010. PMID- 21266594 TI - Identification of the metabolites of the antioxidant flavonoid 7-mono-O-(beta hydroxyethyl)-rutoside in mice. AB - The clinical use of the anticancer drug doxorubicin is limited by severe cardiotoxicity. In mice, the semisynthetic antioxidant flavonoid 7-mono-O-(beta hydroxyethyl)-rutoside (monoHER) has been successfully used as a protector against doxorubicin-induced cardiotoxicity. However, most monoHER has already been cleared from the body at the time that doxorubicin concentrations are still high. This result suggests that not only the parent compound monoHER itself but also monoHER metabolites could be responsible for the observed cardioprotective effects in mice. Therefore, in the present study, we investigated the metabolism of monoHER in mice. Mice were administered 500 mg/kg monoHER intraperitoneally. At different time points after monoHER administration, bile was collected and analyzed for the presence of monoHER metabolites. The formed metabolites were identified by liquid chromatography-diode array detection-time of flight-mass spectrometry. Thirteen different metabolites were identified. The observed routes of monoHER metabolism are methylation, glucuronidation, oxidation of its hydroxyethyl group, GSH conjugation, and hydrolysis of its disaccharide. In line with other flavonoids, methylated monoHER and the monoHER glucosides are expected to have relatively high cellular uptake and low clearance from the body. Therefore, these metabolites might contribute to the observed protection of monoHER against doxorubicin-induced cardiotoxicity. PMID- 21266593 TI - The development of UDP-glucuronosyltransferases 1A1 and 1A6 in the pediatric liver. AB - UDP-glucuronosyltransferases (UGTs) are critical for the metabolism and clearance of drugs, chemicals, and hormones. The development of UGT1A1 and 1A6 was studied in 50 pediatric liver samples using bilirubin, serotonin activity assays, and Western blot as well as pharmacokinetic scaling. UGT activity developed age dependently in pediatric liver. Maximal activity of 0.7690 nmol . min . (-1) mg protein(-1) was observed for UGT1A1 at 3.8 months. For UGT1A6, activity matured at 14 months (4.737 nmol . min . (-1)mg protein(-1)). Protein expression was not age-dependent, and activities did not correlate to protein levels for either enzyme. The in vitro activities were used to calculate normalized hepatic clearances using both allometric scaling and a physiologically based pharmacokinetic model. For UGT1A1, allometry predicted normalized adult clearances of 0.0070 l . h(-1) . kg(-1) at 3.0 (well stirred) and 2.8 years (parallel tube), whereas the Simcyp model showed normalized clearances of 0.0079 l . h(-1) . kg(-1) at 2.6 (well stirred) and 2.5 years (parallel tube). For UGT1A6, only the Simcyp well stirred model converged at 0.3524 l . h(-1) . kg(-1) at 12.6 months. These data imply independent regulation of UGT1A1 and 1A6 where activity has matured after 6 months to 1 year. Total hepatic clearance of substances mediated by these enzymes may mature concurrently or take longer because of other physiological factors. Late development of UGT enzymes may contribute to chemical, drug, and environmental toxicity. PMID- 21266595 TI - Sorafenib and sunitinib, two anticancer drugs, inhibit CYP3A4-mediated and activate CY3A5-mediated midazolam 1'-hydroxylation. AB - Sorafenib and sunitinib are novel small-molecule molecularly targeted anticancer drugs that inhibit multiple tyrosine kinases. These medicines have shown survival benefits in advanced renal cell carcinomas as well as in advanced hepatocellular carcinomas and gastrointestinal stromal tumors, respectively. The effects of sorafenib and sunitinib on midazolam 1'-hydroxylation catalyzed by human CYP3A4 or CYP3A5 were investigated. Sorafenib and sunitinib inhibited metabolic reactions catalyzed by recombinant CYP3A4. Midazolam hydroxylation was also inhibited in human liver microsomes harboring the CYP3A5*3/*3 genotype (poor CYP3A5 expressor). In contrast, midazolam 1'-hydroxylation catalyzed by recombinant CYP3A5 was enhanced by the coexistence of sorafenib or sunitinib in a concentration-dependent manner, with saturation occurring at approximately 10 MUM. Midazolam hydroxylation was also enhanced in human liver microsomal samples harboring the CYP3A5*1/*1 genotype (extensive CYP3A5 expressor). Sorafenib N oxidation and sunitinib N-deethylation, the primary routes of metabolism, were predominantly catalyzed by CYP3A4 but not by CYP3A5. The preincubation period of sorafenib and sunitinib before the midazolam addition in the reaction mixture did not affect the enhancement of CYP3A5-catalyzed midazolam hydroxylation, indicating that the enhancement was caused by parent sorafenib and sunitinib. Docking studies with a CYP3A5 homology model based on the structure of CYP3A4 revealed that midazolam closely docked to the heme of CYP3A5 compared with sorafenib or sunitinib, suggesting that these anticancer drugs act as enhancers, not as substrates. Our results thus showed that sorafenib and sunitinib activated midazolam 1'-hydroxylation by CYP3A5 but inhibited that by CYP3A4. Unexpected drug interactions involving sorafenib and sunitinib might occur via heterotropic cooperativity of CYP3A5. PMID- 21266596 TI - Electronic medical records are not associated with improved documentation in community primary care practices. AB - The adoption of electronic medical records (EMRs) in ambulatory settings has been widely recommended. It is hoped that EMRs will improve care; however, little is known about the effect of EMR use on care quality in this setting. This study compares EMR versus paper medical record documentation of basic health history and preventive service indicators in 47 community-based practices. Differences in practice-level documentation rates between practices that did and did not use an EMR were examined using the Kruskal-Wallis nonparametric test and robust regression, adjusting for practice-level covariates. Frequency of documentation of health history and preventive service indicator items were similar in the 2 groups of practices. Although EMRs provide the capacity for more robust record keeping, the community-based practices here do not use EMRs to their full capacity. EMR usage does not guarantee more systematic record keeping and thus may not lead to improved quality in the community practice setting. PMID- 21266597 TI - Using online learning collaboratives to facilitate practice improvement for COPD: an ACPNet pilot study. AB - The purpose of this pilot study was to (1) understand the attitudes, knowledge, and beliefs of internists who manage patients with chronic obstructive pulmonary disease (COPD) and (2) evaluate the impact of a multifaceted approach to quality improvement (QI) work involving the management of COPD patients. This pilot study used a pre-post intervention design. The intervention included an online educational toolkit, QI coaching calls led by faculty, and the use of individual physician feedback reports to act as motivators for change. Data were collected using a practice pattern survey and a chart abstraction tool to identify discrepancies between perceived and actual care. Results from the pilot study showed a statistically significant improvement in quality indicators postintervention, suggesting a causal relationship with the multifaceted intervention. Discrepancies were identified between perceived and actual care in the areas of spirometry, pulse oximetry (exertion and resting), influenza and pneumococcal vaccinations, peak flow assessment, and inhaler use instruction. PMID- 21266598 TI - White matter hyperintensities are associated with an increased risk of stroke, dementia and mortality. PMID- 21266599 TI - Conventional antiepileptic drugs are not associated with an increased risk of suicidal behaviour or self-harm. PMID- 21266600 TI - Current use of antiepileptic drugs is associated with an increased risk of suicidality in people with depression but not in people with epilepsy or bipolar disorder. PMID- 21266601 TI - Confusion Assessment Method is the most appropriate tool to quickly detect delirium in hospitalised patients at the bedside. PMID- 21266602 TI - A quarter of people with Parkinson's disease without dementia have mild cognitive impairment. PMID- 21266603 TI - Young black females in three UK cities have higher rates of self-harm than other ethnic groups but are less likely to be referred for psychiatric care. PMID- 21266604 TI - Suicide attempts more common in offspring of depressed parents exposed to suicidal behaviour than unexposed offspring. PMID- 21266605 TI - Attachment-based family therapy reduces suicidal ideation in adolescents. PMID- 21266606 TI - Association between recent stressful life events and prevalence of depression, anxiety and PTSD differs according to exposure to childhood adversity. PMID- 21266607 TI - Generalised anxiety disorder doubles risk of cardiovascular events in people with stable coronary heart disease. PMID- 21266608 TI - Early term, preterm and post-term gestation births increase the risk of special educational needs during schooling. PMID- 21266609 TI - Veterans with post-traumatic stress disorder are at increased risk of developing dementia. PMID- 21266610 TI - Rapid discontinuation of antidepressants reduces time to recurrence of depression and panic. PMID- 21266611 TI - Exposure to statins in early old age but not in late old age may be associated with a lower risk of developing Alzheimer's disease. PMID- 21266612 TI - Young children with ADHD are at increased risk of depression and suicidal behaviour in adolescence. PMID- 21266613 TI - Method used in an unsuccessful suicide attempt predicts likelihood of future completed suicide. PMID- 21266614 TI - People with bipolar disorder and comorbid substance abuse are six times more likely to be convicted of violent crime than the general population. PMID- 21266615 TI - Parent-child CBT reduces anxiety disorders among children aged 4-7 years. PMID- 21266616 TI - Type I diabetes: motivational enhancement therapy delivered with CBT by nurse therapists to people with type I diabetes leads to lowering of HbA1C values. PMID- 21266617 TI - Brief intervention in an emergency department reduces violence in the short term but not alcohol misuse in at-risk adolescents. PMID- 21266618 TI - Fluoxetine, trazodone and ritanserin are more effective than placebo when used as add-on therapies for negative symptoms of schizophrenia. PMID- 21266619 TI - Acamprosate reduces risk of return to drinking after detoxification, but is similarly effective to naltrexone. PMID- 21266620 TI - A personality-based intervention moderately reduces risk of drinking in at-risk 13-14-year-old British school children. PMID- 21266621 TI - Adding a psychosocial intervention to antipsychotic medication reduces treatment discontinuation and relapse. PMID- 21266622 TI - No differences in efficacy of atypical and typical antipsychotics in early psychosis, but side effects differ. PMID- 21266623 TI - Droperidol and midazolam, alone or combined, have similar effects on duration of violent and acute behaviour disturbance in emergency department patients. PMID- 21266624 TI - Family-based treatment increases full remission at 1-year follow-up compared with adolescent-focused individual therapy in adolescents with anorexia nervosa. PMID- 21266625 TI - CBT is effective in reducing symptoms in adults with ADHD whose symptoms persist following pharmacotherapy. PMID- 21266626 TI - Intense case management for severe mental health problems reduces time in hospital and loss to follow-up compared with standard care, but benefits over non ICM are less clear. PMID- 21266627 TI - Adding buprenorphine implants to counselling reduces opioid use over 6 months in opioid-dependent adults. PMID- 21266628 TI - Review: teratogenicity of first- and second-generation antipsychotics in pregnancy is unclear. PMID- 21266629 TI - Yersinia Enterocolitica Bacteremia in a Chronic, Mildly Iron-Overloaded Dialysis Patient. AB - OBJECTIVE: To report an unusual case of Yersinia enterocolitica in a chronic, mildly iron-overloaded dialysis patient lacking other typical risk factors for bacteremia, who was treated successfully with a third-generation cephalosporin as monotherapy for a short duration of treatment. CASE SUMMARY: A 76-year-old dialysis-dependent man developed Y. enterocolitica bacteremia after 8 days of hospitalization. One month prior to presentation, his ferritin level was mildly elevated at 571.5 ng/mL, while receiving both intravenous and oral iron supplements. On day 14 of hospitalization, his ferritin level was acutely increased to 885.8 ng/mL. No risk factors commonly associated with Yersinia were present. He was treated successfully with a 14-day course of intravenous ceftriaxone, with negative surveillance blood cultures 2 months after treatment. One year after the infection, there was no evidence of recurrence, despite reinitiation of intravenous iron therapy, albeit with lower ferritin levels. DISCUSSION: Y. enterocolitica is most commonly associated with patients receiving deferoxamine mesylate or those with iron overload, as the bacteria thrive in the presence of chelated iron. There has been limited experience with the use of third-generation cephalosporins as monotherapy for the treatment of Y. enterocolitica bacteremia; most of the data are from in vitro studies. Historical treatment choices have included aminoglycosides, doxycycline, trimethoprim/ sulfamethoxazole, and ciprofloxacin. Ceftriaxone was used in our patient because of the once-daily ease of administration, with complete resolution of bacteremia. Reinitiation of intravenous iron therapy, while keeping the ferritin levels below 300 ng/mL, allowed for treatment of his anemia without recurrence of infection. CONCLUSIONS: This is the first English-language case of a dialysis patient with mild iron overload leading to Y. enterocolitica, despite having no known risk factors for the infection. Treatment success was obtained after a 14-day course of intravenous ceftriaxone. Intravenous iron was restarted without recurrence of infection, underscoring the importance of monitoring iron status in chronic dialysis patients. PMID- 21266630 TI - The First Description of Docetaxel-Induced Recall Inflammatory Skin Reaction After Previous Drug Extravasation. AB - OBJECTIVE: To describe a cutaneous recall soft tissue injury at the site of previous extravasation of docetaxel. CASE SUMMARY: A 65-year-old white female with an invasive ductal carcinoma of the right breast was treated with carboplatin AUC 2 and docetaxel 30 mg/m(2) weekly via a peripheral vein access. During the 14th cycle, drug extravasation of docetaxel occurred in the left antecubital fossa characterized by a mild erythema without edema. A severe erythema developed in the former area of extravasation after the 15th cycle of carboplatin/docetaxel. The recall dermatitis continued to exacerbate after each course of systemic docetaxel chemotherapy and finally led to termination of this therapy. DISCUSSION: In general, extravasation of docetaxel causes only mild local skin reactions without further necessity of intervention. For pegylated liposomal doxorubicin and paclitaxel, inflammatory recall phenomena at sites of previous drug extravasation are rare and often occur as single events following administration of the same cytotoxic drug. According to the Naranjo probability scale, the administration of docetaxel in this case probably led to the cutaneous soft tissue injury as a result of extravasation. CONCLUSIONS: Caution is needed after an episode of docetaxel extravasation. Even after a therapy interruption of several weeks, resumption of chemotherapy with docetaxel might lead to recrudescence of the inflammatory skin reaction. PMID- 21266631 TI - mzResults: an interactive viewer for interrogation and distribution of proteomics results. AB - The growing use of mass spectrometry in the context of biomedical research has been accompanied by an increased demand for distribution of results in a format that facilitates rapid and efficient validation of claims by reviewers and other interested parties. However, the continued evolution of mass spectrometry hardware, sample preparation methods, and peptide identification algorithms complicates standardization and creates hurdles related to compliance with journal submission requirements. Moreover, the recently announced Philadelphia Guidelines (1, 2) suggest that authors provide native mass spectrometry data files in support of their peer-reviewed research articles. These trends highlight the need for data viewers and other tools that work independently of manufacturers' proprietary data systems and seamlessly connect proteomics results with original data files to support user-driven data validation and review. Based upon our recently described API(1)-based framework for mass spectrometry data analysis (3, 4), we created an interactive viewer (mzResults) that is built on established database standards and enables efficient distribution and interrogation of results associated with proteomics experiments, while also providing a convenient mechanism for authors to comply with data submission standards as described in the Philadelphia Guidelines. In addition, the architecture of mzResults supports in-depth queries of the native mass spectrometry files through our multiplierz software environment. We use phosphoproteomics data to illustrate the features and capabilities of mzResults. PMID- 21266632 TI - mzServer: web-based programmatic access for mass spectrometry data analysis. AB - Continued progress toward systematic generation of large-scale and comprehensive proteomics data in the context of biomedical research will create project-level data sets of unprecedented size and ultimately overwhelm current practices for results validation that are based on distribution of native or surrogate mass spectrometry files. Moreover, the majority of proteomics studies leverage discovery-mode MS/MS analyses, rendering associated data-reduction efforts incomplete at best, and essentially ensuring future demand for re-analysis of data as new biological and technical information become available. Based on these observations, we propose to move beyond the sharing of interpreted spectra, or even the distribution of data at the individual file or project level, to a system much like that used in high-energy physics and astronomy, whereby raw data are made programmatically accessible at the site of acquisition. Toward this end we have developed a web-based server (mzServer), which exposes our common API (mzAPI) through very intuitive (RESTful) uniform resource locators (URL) and provides remote data access and analysis capabilities to the research community. Our prototype mzServer provides a model for lab-based and community-wide data access and analysis. PMID- 21266633 TI - Commentary on an article by Alpesh A. Patel, MD, et al.: "Evidence for an Inherited Predisposition to Lumbar Disc Disease". PMID- 21266634 TI - Commentary on an article by Matthew D. Milewski, MD, et al.: "Lyme Arthritis in Children Presenting with Joint Effusions". PMID- 21266636 TI - Assessment of a new undergraduate module in musculoskeletal medicine. AB - BACKGROUND: Despite the high prevalence of musculoskeletal disorders seen by primary care physicians, numerous studies have demonstrated deficiencies in the adequacy of musculoskeletal education at multiple stages of medical education. The aim of this study was to assess a newly developed module in musculoskeletal medicine for use at European undergraduate level (i.e., the medical-school level). METHODS: A two-week module in musculoskeletal medicine was designed to cover common musculoskeletal disorders that are typically seen in primary care. The module incorporated an integrated approach, including core lectures, bedside clinical examination, and demonstration of basic practical procedures. A previously validated examination in musculoskeletal medicine was used to assess the cognitive knowledge of ninety-two students on completion of the module. A historical control group (seventy-two students) from a prior course was used for comparison. RESULTS: The new module group (2009) performed significantly better than the historical (2006) control group in terms of score (62.3% versus 54.3%, respectively; p < 0.001) and pass rate (38.4% versus 12.5%, respectively; p = 0.0002). In a subgroup analysis of the new module group, students who enrolled in the graduate entry program (an accelerated four-year curriculum consisting of students who have already completed an undergraduate university degree) were more likely to perform better in terms of average score (72.2% versus 57%, respectively; p < 0.001) and pass rates (70.9% versus 21.4%, respectively; p < 0.001) compared with students who had enrolled via the traditional undergraduate route. In terms of satisfaction rates, the new module group reported a significantly higher satisfaction rate than that reported by the historical control group (63% versus 15%, respectively; p < 0.001). CONCLUSIONS: In conclusion, the musculoskeletal module described in this paper represents an educational advance at undergraduate (i.e., medical-school) level as demonstrated by the improvement in scores in a validated examination. As pressure on medical curricula grows to accommodate advancing medical knowledge, it is important to continue to improve, assess, and consolidate the position of musculoskeletal medicine in contemporary medical education. PMID- 21266635 TI - Is a subgroup claim believable? A user's guide to subgroup analyses in the surgical literature. PMID- 21266637 TI - Evidence for an inherited predisposition to lumbar disc disease. AB - BACKGROUND: A genetic predisposition for the development of symptomatic lumbar disc disease has been suggested by several twin sibling studies and subsequent genetic marker studies. The purpose of the present study was to define population based familial clustering among individuals with a diagnosis of, or treated for, lumbar disc herniation or disc degeneration. METHODS: The Utah Population Database allows analysis of combined health and genealogic data for over one million Utah residents. We used the International Classification of Diseases, Ninth Revision, diagnosis codes entered in patient records to identify patients with a diagnosis of either lumbar disc herniation or lumbar disc degeneration and genealogic data. The hypothesis of excess relatedness (familial clustering) was tested with use of the Genealogical Index of Familiality, which compares the average relatedness of affected individuals with expected population relatedness. Relative risks in relatives were estimated by comparing rates of disease in relatives with expected population rates (estimated from the relatives of matched controls). This methodology has been previously reported for other disease conditions but not for spinal diseases. RESULTS: The Genealogical Index of Familiality test for 1264 patients with lumbar disc disease showed a significant excess relatedness (p < 0.001). Relative risk in relatives was significantly elevated in both first-degree (relative risk, 4.15; p < 0.001) and third-degree relatives (relative risk, 1.46; p = 0.027). CONCLUSIONS: Excess relatedness of affected individuals and elevated risks to both near and distant relatives was observed, strongly supporting a heritable contribution to the development of symptomatic lumbar disc disease. PMID- 21266638 TI - Associations of anatomical measures from MRI with radiographically defined knee osteoarthritis score, pain, and physical functioning. AB - BACKGROUND: The prevalence of knee osteoarthritis is traditionally based on radiographic findings, but magnetic resonance imaging is now being used to provide better visualization of bone, cartilage, and soft tissues as well as the patellar compartment. The goal of this study was to estimate the prevalences of knee features defined on magnetic resonance imaging in a population and to relate these abnormalities to knee osteoarthritis severity scores based on radiographic findings, physical functioning, and reported knee pain in middle-aged women. METHODS: Magnetic resonance images of the knee were evaluated for the location and severity of cartilage defects, bone marrow lesions, osteophytes, subchondral cysts, meniscal and/or ligamentous tears, effusion, and synovitis among 363 middle-aged women (724 knees) from the Michigan Study of Women's Health Across the Nation. These findings were related to Kellgren-Lawrence osteoarthritis severity scores from radiographs, self-reported knee pain, self-reported knee injury, perception of physical functioning, and physical performance measures to assess mobility. Radiographs, physical performance assessment, and interviews were undertaken at the 1996 study baseline and again (with the addition of magnetic resonance imaging assessment) at the follow-up visit during 2007 to 2008. RESULTS: The prevalence of moderate-to-severe knee osteoarthritis changed from 3.7% at the baseline assessment to 26.7% at the follow-up visit eleven years later. Full-thickness cartilage defects of the medial, lateral, and patellofemoral compartments were present in 14.5% (105 knees), 4.6% (thirty-three knees), and 26.2% (190 knees), respectively. Synovitis was identified in 24.7% (179) of the knees, and joint effusions were observed in 70% (507 knees); 21.7% (157) of the knees had complex or macerated meniscal tears. Large osteophytes, marked synovitis, macerated meniscal tears, and full-thickness tibial cartilage defects were associated with increased odds of knee pain and with 30% to 40% slower walking and stair-climbing times. CONCLUSIONS: Middle-aged women have a high prevalence of moderate-to-severe knee osteoarthritis corroborated by strong associations with cartilage defects, complex and macerated meniscal tears, osteophytes and synovitis, knee pain, and lower mobility levels. PMID- 21266639 TI - Lyme arthritis in children presenting with joint effusions. AB - BACKGROUND: The present study was designed to evaluate the prevalence of Lyme arthritis in children who had a joint aspiration at a tertiary care children's hospital in an endemic area and to identify clinical factors useful to differentiate Lyme arthritis from septic arthritis at the time of the initial presentation. METHODS: The records of all children with an age of eighteen years or less who were managed with aspiration for joint effusions at our institution from 1992 to 2009 were reviewed. Data collection included a review of aspirates; an analysis of cell count, culture results, and hematological inflammatory markers; and a review of surgical intervention. RESULTS: A total of 506 joint aspirations were analyzed. One hundred and fifteen aspirations were excluded. In the remaining group of 391 patients, 123 (31%) were subsequently diagnosed with Lyme arthritis. Fifty-one patients had culture-positive septic arthritis. The two cohorts were significantly different in terms of the presence of a fever of >101.5 degrees F (>40.6 degrees C) at the time of presentation, the refusal to bear weight, the peripheral white blood-cell count, and joint fluid cell count. The erythrocyte sedimentation rate and the C-reactive protein level were not significantly different between the two cohorts. Multivariate analysis demonstrated that refusal to bear weight was the strongest predictor of the diagnosis of septic arthritis over Lyme arthritis. CONCLUSIONS: For any child presenting with a joint effusion in a Lyme-endemic area of the Northeastern United States, the likely prevalence of Lyme arthritis is 31% overall and 45% in the presence of knee effusion. Children with joint effusions resulting from Lyme disease are more likely to have knee involvement, a lower peripheral white blood cell count, and a lower joint fluid cell count, and they are less likely to have fever or complete refusal to bear weight, when compared with children with septic arthritis. PMID- 21266641 TI - Comparison of necrotizing fasciitis and sepsis caused by Vibrio vulnificus and Staphylococcus aureus. AB - BACKGROUND: Vibrio vulnificus can cause a rapidly progressive fatal soft-tissue infection. Staphylococcus aureus is the most common cause of skin and soft-tissue infections reported worldwide, and, in particular, methicillin-resistant Staphylococcus aureus has emerged as the most common isolate in emergency departments. The purposes of the present study were to compare the specific characteristics of Vibrio vulnificus and Staphylococcus aureus infections and to compare the clinical outcomes of Vibrio vulnificus, methicillin-resistant Staphylococcus aureus, and methicillin-sensitive Staphylococcus aureus necrotizing infections. METHODS: One hundred and fifteen patients with necrotizing fasciitis caused by Vibrio vulnificus (sixty patients) or Staphylococcus aureus (fifty-five patients) were retrospectively reviewed over a six-year period. Differences in mortality, patient characteristics, clinical presentations, laboratory data, and hospital course were compared between the Vibrio vulnificus and Staphylococcus aureus groups. RESULTS: Nineteen patients (including eleven in the Vibrio vulnificus group and eight in the Staphylococcus aureus group) died, resulting in a mortality rate of 16.5%. We found significant differences between the two groups with regard to hypotension, fever, the interval between contact and admission, the interval between the diagnosis of necrotizing fasciitis and the first operation, and admission to the intensive care unit. The patients in the Vibrio vulnificus group had significantly lower total white blood-cell counts, higher banded white blood-cell counts, and lower platelet counts as compared with those in the Staphylococcus aureus group. The proportion of patients who were hypotensive (as indicated by a systolic blood pressure of <= 90 mm Hg) was significantly greater in the methicillin-resistant Staphylococcus aureus subgroup than in the methicillin-sensitive Staphylococcus aureus subgroup. Patients with hepatic dysfunction were significantly more likely to have Vibrio vulnificus infection, and those with diabetes mellitus were significantly more likely to have Staphylococcus aureus infection. CONCLUSIONS: Necrotizing fasciitis caused by Vibrio vulnificus and Staphylococcus aureus is a surgical emergency. Vibrio vulnificus infection progresses more rapidly and the clinical characteristics are more fulminant than either methicillin-resistant Staphylococcus aureus or methicillin-sensitive Staphylococcus aureus infection. PMID- 21266642 TI - Comparison of paper and computer-based questionnaire modes for measuring health outcomes in patients undergoing total hip arthroplasty. AB - BACKGROUND: Health status questionnaires are important, especially with the growing interest in outcome studies. However, these questionnaires continue to be administered in their original paper format. We hypothesized that total hip arthroplasty outcome data derived with computer-based questionnaires do not differ significantly from those derived with established paper-based formats. METHODS: From January 2006 to January 2007, the clinic schedules of four attending arthroplasty surgeons were screened weekly to identify patients who could potentially be included in the study. Charts were reviewed for subjects who were scheduled for or had received primary total hip arthroplasty. Patients were recruited during their office visit or when they attended a preoperative educational class, and five health status questionnaires (the Harris hip score, WOMAC [Western Ontario and McMaster Universities Osteoarthritis Index], SF-36 [Short Form-36], EQ-5D [EuroQol-5D], and UCLA [University of California at Los Angeles] activity score) were administered in three formats: paper, touch screen, and web-based. Repeated-measures analysis of variance and Pearson correlations were used to compare the questionnaire modes for the Harris hip score (normally distributed data), and the Friedman test and Spearman correlations were used to compare the modes for the other health status scores (non-normally distributed data). The study was designed with 90% power for detecting 10% differences between modes in the entire series of sixty-one patients and with 82% and 87% power in preoperative and postoperative subgroups, respectively. RESULTS: The mean age was sixty-three years, with thirty-seven male and twenty-four female patients in the study. Forty-seven hips (77%) had osteoarthritis as the primary diagnosis. No significant differences were detected, for any of the five health outcome systems, among the paper, touch screen, and web-based modes, and there were highly significant correlations among all questionnaire modes in the entire series of patients and in the preoperative and postoperative subgroups (p < 0.001). CONCLUSIONS: The scores obtained with the paper, touch screen, and web based modes of the five questionnaires demonstrated excellent agreement. Thus, touch screen and web-based formats can be used to collect and track patient outcome data. Use of electronic formats of these questionnaires will facilitate a more efficient and reliable data collection process. PMID- 21266640 TI - Living bone allotransplants survive by surgical angiogenesis alone: development of a novel method of composite tissue allotransplantation. AB - BACKGROUND: Segmental bone defects pose reconstructive challenges. Composite tissue allotransplantation offers a potential solution but requires long-term immunosuppression with attendant health risks. This study demonstrates a novel method of composite-tissue allotransplantation, permitting long-term drug-free survival, with use of therapeutic angiogenesis of autogenous vessels to maintain circulation. METHODS: Ninety-three rats underwent femoral allotransplantation, isotransplantation, or allografting. Group-1 femora were transplanted across a major histocompatibility complex barrier, with microsurgical pedicle anastomoses. The contralateral saphenous artery and vein (termed the AV bundle) of the recipient animal were implanted within the medullary canal to allow development of an autogenous circulation. In Group 2, allotransplantation was also performed, but with AV bundle ligation. Group 3 bones were frozen allografts rather than composite-tissue allotransplantation femora, and Group 4 bones were isotransplants. Paired comparison allowed evaluation of AV bundle effect, bone allogenicity (isogeneic or allogeneic), and initial circulation and viability (allotransplant versus allograft). Two weeks of immunosuppression therapy maintained blood flow initially, during development of a neoangiogenic autogenous blood supply from the AV bundle in patent groups. At eighteen weeks, skin grafts from donor, recipient, and third-party rats were tested for immunocompetence and donor-specific tolerance. At twenty-one weeks, bone circulation was quantified and new bone formation was measured. RESULTS: Final circulatory status depended on both the initial viability of the graft and the successful development of neoangiogenic circulation. Median cortical blood flow was highest in Group 1 (4.6 mL/min/100 g), intermediate in Group 4 isotransplants (0.4 mL/min/100 g), and absent in others. Capillary proliferation and new bone formation were generally highest in allotransplants (15.0%, 6.4 MUm3/MUm2/yr) and isotransplants with patent AV bundles (16.6%, 50.3 MUm3/MUm2/yr) and less in allotransplants with ligated AV bundles (4.4%, 0.0 MUm3/MUm2/yr) or allografts (8.1%, 24.1 MUm3/MUm2/yr). Donor and third-party-type skin grafts were rejected, indicating immunocompetence without donor-specific tolerance. CONCLUSIONS: In the rat model, microvascular allogeneic bone transplantation in combination with short-term immunosuppression and AV bundle implantation creates an autogenous neoangiogenic circulation, permitting long-term allotransplant survival with measurable blood flow. PMID- 21266643 TI - Ankle valgus deformity secondary to proximal migration of the fibula in tibial lengthening with use of the Ilizarov external fixator. AB - BACKGROUND: Ankle valgus deformity secondary to proximal migration of the fibula following an Ilizarov tibial lengthening has not been discussed in detail in the literature. The purposes of this study were to determine the underlying mechanism of and to identify factors associated with proximal migration of the fibula that caused ankle valgus deformity after an Ilizarov tibial lengthening. METHODS: We reviewed the outcome of seventy-four bilateral Ilizarov tibial lengthenings for short stature in thirty-seven patients. The mean age at the time of surgery was 21.7 years (range, thirteen to thirty-one years), and the mean duration of follow up was forty-five months. Proximal migration of the fibula was assessed with changes in the malleolar tip distance. A valgus change of >= 5 degrees in the tibiotalar angle was regarded as ankle valgus deformity following tibial lengthening. RESULTS: The average length gain was 6.9 cm (range, 4.7 to 11.5 cm), and the average lengthening index was 1.5 mo/cm. Valgus deformity developed in six ankles (8%) and fibular nonunion developed in ten (14%). Proximal migration of the lateral malleolus of >= 5 mm was related to valgus talar tilting. Bifocal tibial lengthening, rapid distraction rate of the fibula (>1 mm per day), and development of a fibular nonunion were factors associated with proximal migration of the distal end of the fibula of >= 5 mm, which suggests that regenerated bone of poor quality in the distraction gap may cause proximal migration of the distal end of the fibula following tibial lengthening. CONCLUSIONS: Proximal migration of the distal end of the fibula following tibial lengthening may occur even with the use of an Ilizarov ring fixator. This migration seems to be caused by collapse of regenerated bone of poor quality or fibular nonunion. Proximal migration of >= 5 mm is associated with the risk of valgus talar tilting. Surgeons should consider earlier intervention with bone-grafting if there are conditions that compromise regenerated bone formation in the fibular distraction gap, such as can occur with extensive tibial lengthening by bifocal corticotomy. PMID- 21266644 TI - Joint space widening in synovial chondromatosis of the hip. AB - BACKGROUND: One of the radiographic findings in synovial chondromatosis of the hip is widening of the joint space between the femoral head and the acetabulum, although the cause and sequelae of the widening are unclear. METHODS: Between May 1991 and June 2005, twenty-one patients with synovial chondromatosis of the hip were treated with open synovectomy and removal of osteochondral fragments. Joint space widening was assessed on radiographs made preoperatively, immediately after surgery, and at the time of follow-up. The changes of the radiographic joint space width were evaluated during the mean follow-up period of 5.9 years (range, 2.3 to 12.3 years). RESULTS: Twelve patients had joint space widening on preoperative radiographs of the hip. Medial joint space widening was seen in three patients, and both medial and superior joint space widening was evident in nine patients. Compared with the medial and superior joint spaces in the unaffected, contralateral hip, those in the affected hip were wider by an average of 44.7% and 35.9%, respectively. The medial joint space widths of the affected hip decreased slightly during the early postoperative period; however, widened joint spaces were persistent at the final follow-up visit, without other important changes. The superior joint space widths did not show substantial changes throughout the postoperative follow-up period. CONCLUSIONS: Joint space widening is a recognized radiographic finding in primary synovial chondromatosis of the hip. Although there was persistence of joint space widening after synovectomy in all patients, this joint space widening did not influence the clinical results at the time of follow-up. PMID- 21266645 TI - Femoral shaft fracture fixation and chest injury after polytrauma. PMID- 21266646 TI - Lifestyle interaction with fat mass and obesity-associated (FTO) genotype and risk of obesity in apparently healthy U.S. women. AB - OBJECTIVE: Variation in the fat mass and obesity-associated (FTO) gene is associated with obesity. The extent to which separate and combined effects of physical activity and caloric intake modify this association remains unclear. RESEARCH DESIGN AND METHODS: FTO polymorphism rs8050136 was measured, and physical activity, caloric intake, and anthropometrics were self-reported in 21,675 apparently healthy Caucasian women. RESULTS: The effect of the risk allele (A) on BMI was larger among inactive or higher intake women, with additive effects of inactivity and high intake on the associated genetic risk. Specifically, each A allele was associated with mean BMI difference of +0.73 (SE 0.08) kg/m(2) among inactive women (<= median, 8.8 MET-hours/week), compared with +0.31 (0.06) kg/m(2), P < 0.0001, among active women (>8.8 MET-hours/week). Similarly, each A allele was associated with mean BMI difference of +0.65 (0.07) among high intake women (>median, 1,679 kcals/day), compared with +0.38 (0.07) kg/m(2), P = 0.005, among low intake women (<= 1,679 kcals/day). Among inactive/high intake women, each A allele was associated with mean BMI difference of +0.97 (0.11) kg/m(2) vs. +0.22 (0.08) kg/m(2) among inactive/low intake women, P < 0.0001. Among inactive/high intake women, each A allele carried increased risk of obesity (odds ratio 1.39, 95% CI 1.27-1.52) and diabetes (odds ratio 1.36, 95% CI 1.07-1.73). CONCLUSIONS: In this study, lifestyle factors modified the genetic risk of FTO on obesity phenotypes, particularly among women who were both inactive and had high intake. Healthier lifestyle patterns blunted but did not completely eliminate the associated genetic risk. PMID- 21266648 TI - The Diabeo software enabling individualized insulin dose adjustments combined with telemedicine support improves HbA1c in poorly controlled type 1 diabetic patients: a 6-month, randomized, open-label, parallel-group, multicenter trial (TeleDiab 1 Study). AB - OBJECTIVE: To demonstrate that Diabeo software enabling individualized insulin dose adjustments combined with telemedicine support significantly improves HbA(1c) in poorly controlled type 1 diabetic patients. RESEARCH DESIGN AND METHODS: In a six-month open-label parallel-group, multicenter study, adult patients (n = 180) with type 1 diabetes (>1 year), on a basal-bolus insulin regimen (>6 months), with HbA(1c) >= 8%, were randomized to usual quarterly follow-up (G1), home use of a smartphone recommending insulin doses with quarterly visits (G2), or use of the smartphone with short teleconsultations every 2 weeks but no visit until point end (G3). RESULTS: Six-month mean HbA(1c) in G3 (8.41 +/- 1.04%) was lower than in G1 (9.10 +/- 1.16%; P = 0.0019). G2 displayed intermediate results (8.63 +/- 1.07%). The Diabeo system gave a 0.91% (0.60; 1.21) improvement in HbA(1c) over controls and a 0.67% (0.35; 0.99) reduction when used without teleconsultation. There was no difference in the frequency of hypoglycemic episodes or in medical time spent for hospital or telephone consultations. However, patients in G1 and G2 spent nearly 5 h more than G3 patients attending hospital visits. CONCLUSIONS: The Diabeo system gives a substantial improvement to metabolic control in chronic, poorly controlled type 1 diabetic patients without requiring more medical time and at a lower overall cost for the patient than usual care. PMID- 21266649 TI - Maternal glucose concentration during pregnancy predicts fat and lean mass of prepubertal offspring. AB - OBJECTIVE: Intrauterine exposure to high maternal glucose is associated with excess weight gain during childhood, but it is not clear whether the excess weight represents increased fat or lean mass. The purpose of this study was to examine the relationship between maternal glucose concentrations during pregnancy and offspring body composition. A secondary goal was to examine whether the association between maternal glucose and children's body fat was independent of energy intake, energy expenditure, or physical activity. RESEARCH DESIGN AND METHODS: Children aged 5-10 years and their biological mothers (n = 27) were recruited. Maternal glucose concentration 1 h after a 50-g oral glucose load, used to screen for gestational diabetes mellitus at 24-28 weeks gestation, was retrieved from medical records. Children underwent dual-energy X-ray absorptiometry to measure body composition, indirect calorimetry to measure resting energy expenditure (REE), accelerometry to measure physical activity, and three 24-h diet recalls to measure energy intake. RESULTS: Maternal glucose concentration during pregnancy was positively associated with children's lean mass (P < 0.05) and adiposity (fat mass adjusted for lean mass; P < 0.05). The association between maternal glucose and children's adiposity was independent of children's REE, percent of time spent physically active, and energy intake (P < 0.001). CONCLUSIONS: Intrauterine exposure to relatively high maternal glucose is associated with greater lean mass and adiposity among prepubertal offspring. Further research is needed to examine the mechanisms by which maternal glucose concentrations during pregnancy influence children's body composition. PMID- 21266647 TI - Hemoglobin A1c and mean glucose in patients with type 1 diabetes: analysis of data from the Juvenile Diabetes Research Foundation continuous glucose monitoring randomized trial. AB - OBJECTIVE: To determine the relationship between mean sensor glucose concentrations and hemoglobin A(1c) (HbA(1c)) values measured in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications laboratory at the University of Minnesota in a cohort of subjects with type 1 diabetes from the Juvenile Diabetes Research Foundation continuous glucose monitoring randomized trial. RESEARCH DESIGN AND METHODS: Near-continuous glucose sensor data (>= 4 days/week) were collected for 3 months before a central laboratory-measured HbA(1c) was performed for 252 subjects aged 8-74 years, the majority of whom had stable HbA(1c) values (77% within +/- 0.4% of the patient mean). RESULTS: The slope (95% CI) for mean sensor glucose concentration (area under the curve) versus a centrally measured HbA(1c) was 24.4 mg/dL (22.0-26.7) for each 1% change in HbA(1c), with an intercept of -16.2 mg/dL (-32.9 to 0.6). Although the slope did not vary with age or sex, there was substantial individual variability, with mean sensor glucose concentrations ranging from 128 to 187 mg/dL for an HbA(1c) of 6.9-7.1%. The root mean square of the errors between the actual mean sensor glucose concentration versus the value calculated using the regression equation was 14.3 mg/dL, whereas the median absolute difference was 10.1 mg/dL. CONCLUSIONS: There is substantial individual variability between the measured versus calculated mean glucose concentrations. Consequently, estimated average glucose concentrations calculated from measured HbA(1c) values should be used with caution. PMID- 21266650 TI - No loss of chance of diabetic retinopathy screening by endocrinologists with a digital fundus camera. AB - OBJECTIVE: To compare the efficacy of the diabetic retinopathy (DR) screening with digital camera by endocrinologists with that by specialist and resident ophthalmologists in terms of sensitivity, specificity, and level of "loss of chance." RESEARCH DESIGN AND METHODS: In a cross-sectional study, 500 adult diabetic patients (1,000 eyes) underwent three-field retinal photography with a digital fundus camera following pupillary dilatation. Five endocrinologists and two ophthalmology residents underwent 40 h of training on screening and grading of DR and detection of associated retinal findings. A kappa test compared the accuracy of endocrinologist and ophthalmology resident screening with that performed by experienced ophthalmologists. Screening efficiency of endocrinologists was evaluated in terms of "loss of chance," i.e., missed diagnoses that required ophthalmologist referrals. RESULTS: The mean weighted kappa of DR screening performed by endocronologists was similar to that of ophthalmology residents (0.65 vs. 0.73). Out of 456 DR eyes, both endocrinologists and ophthalmology residents misdiagnosed only stage 1 DR (36 and 14, respectively), which did not require ophthalmologist referral. There were no significant differences between endocrinologists and ophthalmology residents in terms of diabetic maculopathy and incidental findings except for papillary cupping and choroidal lesions, which were not the main purpose of the study or of the training. CONCLUSIONS: The endocrinologist with specific training for DR detection using a three-field digital fundus camera with pupillary dilatation can perform a reliable DR screening without any loss of chance for the patients when compared with identical evaluation performed by experienced ophthalmologists. PMID- 21266652 TI - Proximal neuropathic lesions in distal symmetric diabetic polyneuropathy: findings of high-resolution magnetic resonance neurography. AB - OBJECTIVE: This study investigated high-resolution magnetic resonance neurography (MRN) in distal symmetric diabetic polyneuropathy (dPNP). RESEARCH DESIGN AND METHODS: MRN comprised high-resolution transaxial imaging of peripheral nerves of the lower limbs in 20 patients with type 2 diabetes (10 with dPNP, type 2/dPNP[+], and 10 without dPNP, type 2/dPNP[-]), seven patients with type 1 diabetes (two with dPNP, type 1/dPNP[+], five without dPNP, type 1/dPNP[-]), and 10 nondiabetic control subjects. Intraneural T2 lesions, as the main diagnostic criterion of MRN, were detected visually by two independent observers and quantitatively by analysis of T2 contrast ratios. RESULTS: Multifocal fascicular, symmetric intraneural T2 lesions occurred in the proximal trunks of sciatic nerves in four patients (three with type 2/dPNP[+] and one with type 1/dPNP[+]) but not in control subjects (type 2/dPNP[-], type 1/dPNP[-], nondiabetic control subjects), which was confirmed by quantitative analysis. Clinical severity was higher in patients with T2 lesions (neuropathy deficit score: 10 vs. 7.8; P = 0.05). CONCLUSIONS: For the first time, proximal neuropathic lesions of dPNP are reported in vivo. This supports that accumulation of proximal, multifocal fascicular injury may be important in disease progression. PMID- 21266651 TI - Factors predictive of severe hypoglycemia in type 1 diabetes: analysis from the Juvenile Diabetes Research Foundation continuous glucose monitoring randomized control trial dataset. AB - OBJECTIVE: Identify factors predictive of severe hypoglycemia (SH) and assess the clinical utility of continuous glucose monitoring (CGM) to warn of impending SH. RESEARCH DESIGN AND METHODS: In a multicenter randomized clinical trial, 436 children and adults with type 1 diabetes were randomized to a treatment group that used CGM (N = 224), or a control group that used standard home blood glucose monitoring (N = 212) and completed 12 months of follow-up. After 6 months, the original control group initiated CGM while the treatment group continued use of CGM for 6 months. Baseline risk factors for SH were evaluated over 12 months of follow-up using proportional hazards regression. CGM-derived indices of hypoglycemia were used to predict episodes of SH over a 24-h time horizon. RESULTS: The SH rate was 17.9 per 100 person-years, and a higher rate was associated with the occurrence of SH in the prior 6 months and female sex. SH frequency increased eightfold when 30% of CGM values were <= 70 mg/dL on the prior day (4.5 vs. 0.5%; P < 0.001), but the positive predictive value (PPV) was low (<5%). Results were similar for hypoglycemic area under the curve and the low blood glucose index calculated by CGM. CONCLUSIONS: SH in the 6 months prior to the study was the strongest predictor of SH during the study. CGM-measured hypoglycemia over a 24-h span is highly associated with SH the following day (P < 0.001), but the PPV is low. PMID- 21266653 TI - Improvement and emergence of insulin restriction in women with type 1 diabetes. AB - OBJECTIVE: To determine the distinguishing characteristics of women who report stopping insulin restriction at 11 years of follow-up from those continuing to endorse insulin restriction as well as those characteristics differing in patients who continue to use insulin appropriately from new insulin restrictors. RESEARCH DESIGN AND METHODS: This is an 11-year follow-up study of 207 women with type 1 diabetes. Insulin restriction, diabetes self-care behaviors, diabetes specific distress, and psychiatric and eating disorder symptoms were assessed using self-report surveys. RESULTS: Of the original sample, 57% participated in the follow-up study. Mean age was 44 +/- 12 years, diabetes duration was 28 +/- 11 years, and A1C was 7.9 +/- 1.3%. At follow-up, 20 of 60 baseline insulin restrictors had stopped restriction. Women who stopped reported improved diabetes self-care and distress, fewer problems with diabetes self-management, and lower levels of psychologic distress and eating disorder symptoms. Logistic regression indicated that lower levels of fear of weight gain with improved blood glucose and fewer problems with diabetes self-management predicted stopping restriction. At follow-up, 34 women (23%) reported new restriction, and a larger proportion of new insulin restrictors, relative to nonrestrictors, endorsed fear of weight gain with improved blood glucose. CONCLUSIONS: Findings indicate that fear of weight gain associated with improved blood glucose and problems with diabetes self-care are core issues related to both the emergence and resolution of insulin restriction. Greater attention to these concerns may help treatment teams to better meet the unique treatment needs of women struggling with insulin restriction. PMID- 21266654 TI - Monitoring of Individual Needs in Diabetes (MIND): baseline data from the Cross National Diabetes Attitudes, Wishes, and Needs (DAWN) MIND study. AB - OBJECTIVE: To test the feasibility and impact of implementing the computer assisted Monitoring of Individual Needs in Diabetes (MIND) procedure, which is aimed at improving recognition and management of the psychological needs of diabetic patients in routine care. RESEARCH DESIGN AND METHODS: The MIND study was implemented in diabetes clinics across eight countries as part of the annual review. The computerized assessment covered emotional well-being (World Health Organization 5 Well-Being Index), diabetes-related distress (Problem Areas in Diabetes), life events, and the patient's agenda. Medical data were retrieved from the charts, and agreed-upon actions were recorded. RESULTS: Of 1,567 patients monitored using the MIND, 24.9% had either likely depression or high diabetes-related distress; 5.4% had both. Over 80% of these patients were newly identified cases, and 41% of patients with depression were referred to a mental health professional. CONCLUSIONS: Monitoring of well-being and diabetes-related distress as part of routine diabetes care is feasible and helps to identify and discuss unmet psychosocial needs. PMID- 21266655 TI - Heart rate recovery after exercise is a predictor of silent myocardial ischemia in patients with type 2 diabetes. AB - OBJECTIVE: Slow heart rate recovery (HRR) predicts all-cause mortality. This study investigated the relationship between silent myocardial ischemia (SMI) and HRR in type 2 diabetes. RESEARCH DESIGN AND METHODS: The study enrolled 87 consecutive patients with type 2 diabetes and no chest symptoms. They underwent treadmill exercise testing and single-photon emission computed tomography imaging with thallium scintigraphy. Patients with abnormal myocardial perfusion images also underwent coronary angiography. RESULTS: SMI was diagnosed in 41 patients (47%). The SMI group showed slower HRR than the non-SMI group (18 +/- 6 vs. 30 +/ 12 bpm; P < 0.0001). HRR was significantly associated with SMI (odds ratio 0.83 [95% CI 0.75-0.92]; P = 0.0006), even after adjustment for maximal exercise workload, resting heart rate, maximum heart rate, rate pressure product, HbA(1c), use of sulfonamides, and a history of cardiovascular disease. CONCLUSIONS: HRR can predict SMI in patients with type 2 diabetes. PMID- 21266656 TI - Target of rapamycin regulates development and ribosomal RNA expression through kinase domain in Arabidopsis. AB - Target of rapamycin (TOR) is a central regulator of cell growth, cell death, nutrition, starvation, hormone, and stress responses in diverse eukaryotes. However, very little is known about TOR signaling and the associated functional domains in plants. We have taken a genetic approach to dissect TOR functions in Arabidopsis (Arabidopsis thaliana) and report here that the kinase domain is essential for the role of TOR in embryogenesis and 45S rRNA expression. Twelve new T-DNA insertion mutants, spanning 14.2 kb of TOR-encoding genomic region, have been characterized. Nine of these share expression of defective kinase domain and embryo arrest at 16 to 32 cell stage. However, three T-DNA insertion lines affecting FATC domain displayed normal embryo development, indicating that FATC domain was dispensable in Arabidopsis. Genetic complementation showed that the TOR kinase domain alone in tor-10/tor-10 mutant background can rescue early embryo lethality and restore normal development. Overexpression of full-length TOR or kinase domain in Arabidopsis displayed developmental abnormalities in meristem, leaf, root, stem, flowering time, and senescence. We further show that TOR, especially the kinase domain, plays a role in ribosome biogenesis by activating 45S rRNA production. Of the six putative nuclear localization sequences in the kinase domain, nuclear localization sequence 6 was identified to confer TOR nuclear targeting in transient expression assays. Chromatin immunoprecipitation studies revealed that the HEAT repeat domain binds to 45S rRNA promoter and the 5' external transcribed spacer elements motif. Together, these results show that TOR controls the embryogenesis, postembryonic development, and 45S rRNA production through its kinase domain in Arabidopsis. PMID- 21266658 TI - Assembly of the chloroplast ATP-dependent Clp protease in Arabidopsis is regulated by the ClpT accessory proteins. AB - The ATP-dependent caseinolytic protease (Clp) is an essential housekeeping enzyme in plant chloroplasts. It is by far the most complex of all known Clp proteases, with a proteolytic core consisting of multiple catalytic ClpP and noncatalytic ClpR subunits. It also includes a unique form of Clp protein of unknown function designated ClpT, two of which exist in the model species Arabidopsis thaliana. Inactivation of ClpT1 or ClpT2 significantly reduces the amount of Clp proteolytic core, whereas loss of both proves seedling lethal under autotrophic conditions. During assembly of the Clp proteolytic core, ClpT1 first binds to the P-ring (consisting of ClpP3-6 subunits) followed by ClpT2, and only then does the P-ring combine with the R-ring (ClpP1, ClpR1-4 subunits). Most of the ClpT proteins in chloroplasts exist in vivo as homodimers, which then apparently monomerize prior to association with the P-ring. Despite their relative abundance, however, the availability of both ClpT proteins is rate limiting for the core assembly, with the addition of recombinant ClpT1 and ClpT2 increasing core content up to fourfold. Overall, ClpT appears to regulate the assembly of the chloroplast Clp protease, revealing a new and sophisticated control mechanism on the activity of this vital protease in plants. PMID- 21266657 TI - Two distinct roles of ARABIDOPSIS HOMOLOG OF TRITHORAX1 (ATX1) at promoters and within transcribed regions of ATX1-regulated genes. AB - The Arabidopsis thaliana trithorax-like protein, ATX1, shares common structural domains, has similar histone methyltransferase (HMT) activity, and belongs in the same phylogenetic subgroup as its animal counterparts. Most of our knowledge of the role of HMTs in trimethylating lysine 4 of histone H3 (H3K4me3) in transcriptional regulation comes from studies of yeast and mammalian homologs. Little is known about the mechanism by which ATX1, or any other HMT of plant origin, affects transcription. Here, we provide insights into how ATX1 influences transcription at regulated genes, playing two distinct roles. At promoters, ATX1 is required for TATA binding protein (TBP) and RNA Polymerase II (Pol II) recruitment. In a subsequent event, ATX1 is recruited by a phosphorylated form of Pol II to the +300-bp region of transcribed sequences, where it trimethylates nucleosomes. In support of this model, inhibition of phosphorylation of the C terminal domain of Pol II reduced the amounts of H3K4me3 and ATX1 bound at the +300-nucleotide region. Importantly, these changes did not reduce the occupancy of ATX1, TBP, or Pol II at promoters. Our results indicate that ATX1 affects transcription at target genes by a mechanism distinct from its ability to trimethylate H3K4 within genes. PMID- 21266659 TI - Seventy million years of concerted evolution of a homoeologous chromosome pair, in parallel, in major Poaceae lineages. AB - Whole genome duplication ~70 million years ago provided raw material for Poaceae (grass) diversification. Comparison of rice (Oryza sativa), sorghum (Sorghum bicolor), maize (Zea mays), and Brachypodium distachyon genomes revealed that one paleo-duplicated chromosome pair has experienced very different evolution than all the others. For tens of millions of years, the two chromosomes have experienced illegitimate recombination that has been temporally restricted in a stepwise manner, producing structural stratification in the chromosomes. These strata formed independently in different grass lineages, with their similarities (low sequence divergence between paleo-duplicated genes) preserved in parallel for millions of years since the divergence of these lineages. The pericentromeric region of this homeologous chromosome pair accounts for two-thirds of the gene content differences between the modern chromosomes. Both intriguing and perplexing is a distal chromosomal region with the greatest DNA similarity between surviving duplicated genes but also with the highest concentration of lineage-specific gene pairs found anywhere in these genomes and with a significantly elevated gene evolutionary rate. Intragenomic similarity near this chromosomal terminus may be important in hom(e)ologous chromosome pairing. Chromosome structural stratification, together with enrichment of autoimmune response-related (nucleotide binding site-leucine-rich repeat) genes and accelerated DNA rearrangement and gene loss, confer a striking resemblance of this grass chromosome pair to the sex chromosomes of other taxa. PMID- 21266660 TI - Space toxicology: protecting human health during space operations. AB - Space toxicology is a unique and targeted discipline for spaceflight, space habitation, and occupation of celestial bodies including planets, moons, and asteroids. Astronaut explorers face distinctive health challenges and limited resources for rescue and medical care during space operation. A central goal of space toxicology is to protect the health of the astronaut by assessing potential chemical exposures during spaceflight and setting safe limits that will protect the astronaut against chemical exposures while in a physiologically altered state. In order to maintain sustained occupation in space on the International Space Station (ISS), toxicological risks must be assessed and managed within the context of isolation, continuous exposures, reuse of air and water, limited rescue options, and the need to use highly toxic compounds for propulsion and other purposes. As we begin to explore other celestial bodies, in situ toxicological risks, such as inhalation of reactive mineral dusts, must also be managed. PMID- 21266661 TI - Neurobehavioral effects of acute exposure to normal (n-) paraffins. AB - This article reports the results of neurobehavioral tests on C(5)-C(10) normal paraffinic constituents (n-paraffins). Shortly after exposure, effects were evaluated in several domains including clinical effects, motor activity, functional observations, and visual discrimination performance. The representative C(5) n-paraffin, n-pentane, did not produce any evidence of acute central nervous system (CNS) effects at levels up to 20 000 mg/m(3). Similarly, there was no compelling evidence that n-octane (C(8)) produced CNS effects at 14 000 mg/m(3), the highest concentration tested. n-decane (C(10)) produced minor, reversible acute CNS effects at 5000 mg/m(3), with 1500 mg/m(3) as the no-effect level. Consistent with literature data, there seemed to be a relationship between increasing molecular weight up to C(10) and acute CNS effects. However, the CNS effects were reversible. Repeated exposures did not provide evidence of metabolic induction. PMID- 21266662 TI - Cryopreservation of human embryonic stem cells derived-cardiomyocytes induced by BMP2 in serum-free condition. AB - Although previous studies showed that cardiomyocytes (CMs) can be generated from human embryonic stem cells (hESCs), the protocols for cryopreservation of hESC derived CMs is not available to date. Here, we report on the efficient generation of hESC-derived CMs by direct differentiation using BMP2 in a serum-free condition, along with successful cryopreservation of derived CMs using Rho associated kinase (ROCK) inhibitor. To induce differentiation, hESCs were treated with activin A and BMP2 for 5 days. A mesodermal gene, Brachyury, was expressed from day 3, and cardiac-specific markers such as Nkx2.5 and cTnI were detected at day 14. Furthermore, these cardiac progenitors expressed ion channel-related transcripts such as HCN1 and HCN2 from day 10. Beating clusters were observed from 14 days of differentiation for up to 35 days. Using mass cryopreservation, we froze hESC-derived CMs at 2 stages, at day 12 and 16 (prebeating and postbeating), after treating with ROCK inhibitor, Y-27632. Postthaw survival of CMs was higher in day 12 group compared to day 16, and some cell clusters from day 12 group recovered their contraction. From transmission electron microscope (TEM) analysis, less ultrastructural alterations were observed in day 12 group. Our results provide an insight into the use of BMP2 for cardiac lineage differentiation in a serum-free condition and a possibility of long-term storage of hESC-derived CMs. PMID- 21266663 TI - The associations between maternal and fetal angiotensinogen M235T polymorphism and pregnancy-induced hypertension in Chinese women. AB - This study was to investigate whether the maternal and fetal angiotensinogen (AGT) M235T polymorphism were associated with the risk of pregnancy-induced hypertension (PIH) in Chinese Han ethnic women. Using a case-control mother-baby dyads study, a total of 226 maternal/offspring pairs were recruited at Anyang Maternal and Child Health Hospital from January 2008 to December 2009. Genomic DNA was extracted from maternal venous and cord blood. We genotyped the AGT M235T polymorphism by using PCR-RFLP assay and examined the association with PIH using logistic regression analysis. In the current study, the maternal AGT M235T polymorphism showed no effect on the risk of PIH (P = .786) while the fetal AGT M235T polymorphism is significantly associated with PIH in Chinese Han ethnic women (P = .004). The fetus carrying TT genotype is a protective factor in developing PIH in the study population (OR = .28, 95% CI = .14-0.59). PMID- 21266664 TI - Effect of vascular endothelial growth factor inhibition on endometrial implant development in a murine model of endometriosis. AB - The main factor involved in neovascularization of ectopic endometrial tissue in endometriosis is the vascular endothelial growth factor (VEGF), which is produced both by the endometrial implant and by peritoneal macrophages. On the other hand, bevacizumab is an antiangiogenic agent used in the treatment of different tumors, like colorectal, pulmonary, and recently mammary. We evaluated the effect of the inhibition of VEGF activity with bevacizumab (Avastin) on ectopic endometrial growth in a murine model of endometriosis. Two months old female BALB/c mice had surgery performed to induce endometriotic-like lesions. Treatment with bevacizumab started on post-surgery day 15 and continued during 2 weeks. Then, animals were sacrificed, peritoneal fluid was collected, and endometriotic-like lesions were counted, measured, and removed. Cell proliferation, vascular density, and apoptosis were assessed by immunohistochemistry for proliferating cell nuclear antigen (PCNA), immunohistochemistry for CD34, and Terminal Deoxynucleotidil Transferase-Mediated dUTP Nick End Labeling (TUNEL), respectively. Vascular endothelial growth factor levels were evaluated in the peritoneal fluid by enzyme-linked immunoassay (ELISA). Treatment with bevacizumab significantly inhibited endometriotic lesion development (P < .05). Consistently, bevacizumab significantly inhibited cell proliferation in lesions (P < .01), reduced vascular density (P < .001), as well as increased the apoptotic cell percentage (P < .001). In addition, bevacizumab reduced VEGF levels in peritoneal fluid of endometriosis-induced animals (P < .05). In conclusion, this study suggests a direct effect of bevacizumab on the reduction of endometrial implant growth and supports further research on VEGF inhibition as a novel therapeutic modality in endometriosis. PMID- 21266665 TI - Effect of gestational diabetes on maternal artery function. AB - Endothelial dysfunction has been observed systemically in women with gestational diabetes (GDM). Important cardiovascular adaptations occur during pregnancy, including enhanced endothelium-dependent vasodilation in systemic and uterine arteries, which are necessary to ensure the health of both mother and fetus. The effects of GDM, however, on uterine artery function and the possible mechanisms that mediate endothelial dysfunction remain unknown. The aim of this study was to utilize a mouse model of GDM to investigate (a) effects on uteroplacental flow, (b) endothelial function of uterine and mesenteric arteries, and (c) possible mechanisms of any dysfunction observed. Pregnant mice heterozygous for a leptin receptor mutation (Lepr(db) (/+); He) spontaneously develop GDM and were compared to wild-type (WT) mice at day 18.5 of gestation. Uterine artery flow was assessed using ultrasound biomicroscopy. Uterine and mesenteric artery function was assessed using wire myography. Arterial superoxide production was measured using oxidative fluorescence microphotography. In vivo uteroplacental perfusion was impaired in mice with GDM, indicated by a significant increase in uterine artery resistance index. Maximal endothelium-dependent relaxation to methacholine was significantly impaired in mesenteric arteries from mice with GDM, while sensitivity was significantly reduced in uterine arteries. Both uterine and mesenteric arteries from mice with GDM exhibited a greater dependence on nitric oxide and increased superoxide production compared with those from mice with a healthy pregnancy. A significant source of superoxide in GDM mice was uncoupled nitric oxide synthase. These changes may contribute to the development of some of the fetal and maternal complication associated with GDM. PMID- 21266666 TI - Association between a 45-bp 3'untranslated insertion/deletion polymorphism in exon 8 of UCP2 gene and neural tube defects in a high-risk area of China. AB - Uncoupling protein 2(UCP2) is an attractive candidate gene for screening neural tube defects (NTDs) risk. In this study, polymerase chain reaction and agarose gel electrophoresis were used to determine the distribution of the polymorphism in a case group of 140 deliveries with NTDs, and a control group of 251 normal newborns. We found that the frequencies of allele I and genotypes ID + II were higher in the case group than in the control group (P = .167, OR = 1.4, 95% CI, 0.9-2.1; P = .132, OR = 1.44, 95% CI, 0.89-2.33, respectively); and at low maternal educational level, the frequency of ID + II genotypes was significantly higher in the NTD case group (P < .05, OR = 1.7, 95% CI, 1.01-2.79). The result suggested that the polymorphism in UCP2 may be a potential genetic risk factor for NTDs in a high-risk area of China, and the association was influenced by maternal education. PMID- 21266667 TI - Single-nucleotide polymorphisms in the KCNN3 gene associate with preterm birth. AB - The objectives were to determine whether single-nucleotide polymorphisms (SNPs) in KCNN3 (encodes the small conductance calcium-activated potassium channel subfamily N, member 3), associate with preterm birth (PTB). In all, 602 preterm families with at least 1 preterm (<37 weeks gestation) infant were studied: DNA from the infant and one or both parents were genotyped for 16 SNPs in KCNN3. A region of interest within KCNN3 was sequenced in 512 Caucasian non-Hispanic mothers (412 with preterm deliveries;100 who delivered at term). Family-based association testing was used for genotyping analysis; Fisher exact test was used for sequencing analysis. Six SNPs (rs1218585, rs4845396, rs12058931, rs1218568, rs6426985, and rs4845394) were associated with PTB (all Ps < .05). These variations were all located within the intronic region between exons 1 and 2. Maternal sequencing revealed an association of 3 SNPs with spontaneous PTB; rs1218585 (P = .007), rs1218584 (P = .05), and a novel SNP at chromosome1:153099353 (P = .02). Polymorphisms in KCNN3 are associated with PTB and investigation into the functional significance of these allelic changes is warranted. PMID- 21266668 TI - Soluble epoxide hydrolase in the generation and maintenance of high blood pressure in spontaneously hypertensive rats. AB - We hypothesized that perinatal inhibition of soluble epoxide hydrolase (SEH), which metabolizes epoxyeicosatrienoic acids in the arachidonic acid (AA) cascade, with an orally active SEH inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), would persistently reduce blood pressure (BP) in adult SHR despite discontinuation of AUDA at 4 wk of age. Renal cytoplasmic epoxide hydrolase-2 (Ephx2) gene expression was enhanced in SHR vs. WKY from 2 days to 24 wk. Effects of perinatal treatment with AUDA, supplied to SHR dams until 4 wk after birth, on BP in female and male offspring and renal oxylipin metabolome in female offspring were observed and contrasted to female SHR for direct effects of AUDA (8-12 wk). Briefly, inhibition of SEH was effective in persistently reducing BP in female SHR when applied during the perinatal phase. This was accompanied by marked increases in major renal AA epoxides and decreases in renal lipoxygenase products of AA. Early inhibition of SEH induced a delayed increase in renal 5-HETE at 24 wk, in contrast to a decrease at 2 wk. Inhibition of SEH in female SHR from 8 to 12 wk did not reduce BP but caused profound decreases in renal 15(S)-HETrE, LTB4, TBX2, 5-HETE, and 20-HETE and increases in TriHOMEs. In male SHR, BP reduction after perinatal AUDA was transient. Thus, Ephx2 transcription and SEH activity in early life may initiate mechanisms that eventually contribute to high BP in adult female SHR. However, programmed BP-lowering effects of perinatal SEH inhibition in female SHR cannot be simply explained by persistent reduction in renal SEH activity but rather by more complex and temporally dynamic interactions between the renal SEH, lipoxygenase, and cyclooxygenase pathways. PMID- 21266669 TI - Acipimox reduces circulating levels of insulin and associated neutrophilic inflammation in metabolic syndrome. AB - Metabolic syndrome is a proatherosclerotic condition clustering cardiovascular risk factors, including glucose and lipid profile alterations. The pathophysiological mechanisms favoring atherosclerotic inflammation in the metabolic syndrome remain elusive. Here, we investigated the potential role of the antilipolytic drug acipimox on neutrophil- and monocyte-mediated inflammation in the metabolic syndrome. Acipimox (500 mg) was orally administered to metabolic syndrome patients (n = 11) or healthy controls (n = 8). Serum and plasma was collected before acipimox administration (time 0) as well as 2-5 h afterward to assess metabolic and hematologic parameters. In vitro, the effects of the incubation with metabolic syndrome serum were assessed on human neutrophil and monocyte migration toward the proatherosclerotic chemokine CCL3. Two to five hours after acipimox administration, a significant reduction in circulating levels of insulin and nonesterified fatty acid (NEFA) was shown in metabolic syndrome patients. At time 0 and 2 h after acipimox administration, metabolic syndrome serum increased neutrophil migration to CCL3 compared with healthy controls. No effect was shown in human monocytes. At these time points, serum induced neutrophil migration positively correlated with serum levels of insulin and NEFA. Metabolic syndrome serum or recombinant insulin did not upregulate CCR5 expression on neutrophil surface membrane, but it increased intracellular JNK1/2 phosphorylation. Insulin immunodepletion blocked serum-induced neutrophil migration and associated JNK1/2 phosphorylation. Although mRNA expression of acipimox receptor (GPR109) was shown in human neutrophils, 5-500 MUM acipimox did not affect insulin-induced neutrophil migration. In conclusion, results suggest that acipimox inhibited neutrophil proatherosclerotic functions in the metabolic syndrome through the reduction in circulating levels of insulin. PMID- 21266670 TI - 17beta-Hydroxyestra-4,9,11-trien-3-one (trenbolone) exhibits tissue selective anabolic activity: effects on muscle, bone, adiposity, hemoglobin, and prostate. AB - Selective androgen receptor modulators (SARMs) now under development can protect against muscle and bone loss without causing prostate growth or polycythemia. 17beta-Hydroxyestra-4,9,11-trien-3-one (trenbolone), a potent testosterone analog, may have SARM-like actions because, unlike testosterone, trenbolone does not undergo tissue-specific 5alpha-reduction to form more potent androgens. We tested the hypothesis that trenbolone-enanthate (TREN) might prevent orchiectomy induced losses in muscle and bone and visceral fat accumulation without increasing prostate mass or resulting in adverse hemoglobin elevations. Male F344 rats aged 3 mo underwent orchiectomy or remained intact and were administered graded doses of TREN, supraphysiological testosterone-enanthate, or vehicle for 29 days. In both intact and orchiectomized animals, all TREN doses and supraphysiological testosterone-enanthate augmented androgen-sensitive levator ani/bulbocavernosus muscle mass by 35-40% above shams (P <= 0.001) and produced a dose-dependent partial protection against orchiectomy-induced total and trabecular bone mineral density losses (P < 0.05) and visceral fat accumulation (P < 0.05). The lowest doses of TREN successfully maintained prostate mass and hemoglobin concentrations at sham levels in both intact and orchiectomized animals, whereas supraphysiological testosterone-enanthate and high-dose TREN elevated prostate mass by 84 and 68%, respectively (P < 0.01). In summary, low dose administration of the non-5alpha-reducible androgen TREN maintains prostate mass and hemoglobin concentrations near the level of shams while producing potent myotrophic actions in skeletal muscle and partial protection against orchiectomy induced bone loss and visceral fat accumulation. Our findings indicate that TREN has advantages over supraphysiological testosterone and supports the need for future preclinical studies examining the viability of TREN as an option for androgen replacement therapy. PMID- 21266672 TI - Modulation of palmitate-induced endoplasmic reticulum stress and apoptosis in pancreatic beta-cells by stearoyl-CoA desaturase and Elovl6. AB - Induction of endoplasmic reticulum (ER) stress and apoptosis by elevated exogenous saturated fatty acids (FAs) plays a role in the pathogenesis of beta cell dysfunction and loss of islet mass in type 2 diabetes. Regulation of monounsaturated FA (MUFA) synthesis through FA desaturases and elongases may alter the susceptibility of beta-cells to saturated FA-induced ER stress and apoptosis. Herein, stearoyl-CoA desaturase (SCD)1 and SCD2 mRNA expression were shown to be induced in islets from prediabetic hyperinsulinemic Zucker diabetic fatty (ZDF) rats, whereas SCD1, SCD2, and fatty acid elongase 6 (Elovl6) mRNA levels were markedly reduced in diabetic ZDF rat islets. Knockdown of SCD in INS 1 beta-cells decreased desaturation of palmitate to MUFA, lowered FA partitioning into complex neutral lipids, and increased palmitate-induced ER stress and apoptosis. Overexpression of SCD2 increased desaturation of palmitate to MUFA and attenuated palmitate-induced ER stress and apoptosis. Knockdown of Elovl6 limited palmitate elongation to stearate, increasing palmitoleate production and attenuating palmitate-induced ER stress and apoptosis, whereas overexpression of Elovl6 increased palmitate elongation to stearate and palmitate-induced ER stress and apoptosis. Overall, these data support the hypothesis that enhanced MUFA synthesis via upregulation of SCD2 activity can protect beta-cells from elevated saturated FAs, as occurs in prediabetic states. Overt type 2 diabetes is associated with diminished islet expression of SCD and Elovl6, and this can disrupt desaturation of saturated FAs to MUFAs, rendering beta-cells more susceptible to saturated FA-induced ER stress and apoptosis. PMID- 21266674 TI - The cover. Paquebot "Paris". PMID- 21266673 TI - The "high" risk of energy drinks. PMID- 21266675 TI - A piece of my mind. The tyranny of reality. PMID- 21266671 TI - Template to improve glycemic control without reducing adiposity or dietary fat. AB - Drugs that improve chronic hyperglycemia independently of insulin signaling or reduction of adiposity or dietary fat intake may be highly desirable. Ad36, a human adenovirus, promotes glucose uptake in vitro independently of adiposity or proximal insulin signaling. We tested the ability of Ad36 to improve glycemic control in vivo and determined if the natural Ad36 infection in humans is associated with better glycemic control. C57BL/6J mice fed a chow diet or made diabetic with a high-fat (HF) diet were mock infected or infected with Ad36 or adenovirus Ad2 as a control for infection. Postinfection (pi), systemic glycemic control, hepatic lipid content, and cell signaling in tissues pertinent to glucose metabolism were determined. Next, sera of 1,507 adults and children were screened for Ad36 antibodies as an indicator of past natural infection. In chow fed mice, Ad36 significantly improved glycemic control for 12 wk pi. In HF-fed mice, Ad36 improved glycemic control and hepatic steatosis up to 20 wk pi. In adipose tissue (AT), skeletal muscle (SM), and liver, Ad36 upregulated distal insulin signaling without recruiting the proximal insulin signaling. Cell signaling suggested that Ad36 increases AT and SM glucose uptake and reduces hepatic glucose release. In humans, Ad36 infection predicted better glycemic control and lower hepatic lipid content independently of age, sex, or adiposity. We conclude that Ad36 offers a novel tool to understand the pathways to improve hyperglycemia and hepatic steatosis independently of proximal insulin signaling, and despite a HF diet. This metabolic engineering by Ad36 appears relevant to humans for developing more practical and effective antidiabetic approaches. PMID- 21266676 TI - Scientists find promising therapies for fragile X and Down syndromes. PMID- 21266677 TI - Studies hint at benefits of imaging as a screening tool to detect coronary risk. PMID- 21266678 TI - CDC advises pregnancy lead screening that targets populations at risk. PMID- 21266679 TI - Blood transfusion and cardiac surgery. PMID- 21266680 TI - Blood transfusion and cardiac surgery. PMID- 21266681 TI - Maternal depression and child development after prenatal DHA supplementation. PMID- 21266682 TI - Maternal depression and child development after prenatal DHA supplementation. PMID- 21266683 TI - Industry response to the obesity threat. PMID- 21266684 TI - Association between stroke center hospitalization for acute ischemic stroke and mortality. AB - CONTEXT: Although stroke centers are widely accepted and supported, little is known about their effect on patient outcomes. OBJECTIVE: To examine the association between admission to stroke centers for acute ischemic stroke and mortality. DESIGN, SETTING, AND PARTICIPANTS: Observational study using data from the New York Statewide Planning and Research Cooperative System. We compared mortality for patients admitted with acute ischemic stroke (n = 30,947) between 2005 and 2006 at designated stroke centers and nondesignated hospitals using differential distance to hospitals as an instrumental variable to adjust for potential prehospital selection bias. Patients were followed up for mortality for 1 year after the index hospitalization through 2007. To assess whether our findings were specific to stroke, we also compared mortality for patients admitted with gastrointestinal hemorrhage (n = 39,409) or acute myocardial infarction (n = 40,024) at designated stroke centers and nondesignated hospitals. MAIN OUTCOME MEASURE: Thirty-day all-cause mortality. RESULTS: Among 30,947 patients with acute ischemic stroke, 15,297 (49.4%) were admitted to designated stroke centers. Using the instrumental variable analysis, admission to designated stroke centers was associated with lower 30-day all-cause mortality (10.1% vs 12.5%; adjusted mortality difference, -2.5%; 95% confidence interval [CI], -3.6% to -1.4%; P < .001) and greater use of thrombolytic therapy (4.8% vs 1.7%; adjusted difference, 2.2%; 95% CI, 1.6% to 2.8%; P < .001). Differences in mortality also were observed at 1-day, 7-day, and 1-year follow-up. The outcome differences were specific for stroke, as stroke centers and nondesignated hospitals had similar 30-day all-cause mortality rates among those with gastrointestinal hemorrhage (5.0% vs 5.8%; adjusted mortality difference, +0.3%; 95% CI, -0.5% to 1.0%; P = .50) or acute myocardial infarction (10.5% vs 12.7%; adjusted mortality difference, +0.1%; 95% CI, -0.9% to 1.1%; P = .83). CONCLUSION: Among patients with acute ischemic stroke, admission to a designated stroke center was associated with modestly lower mortality and more frequent use of thrombolytic therapy. PMID- 21266685 TI - Temporal onset, risk factors, and outcomes associated with stroke after coronary artery bypass grafting. AB - CONTEXT: Stroke is a devastating and potentially preventable complication of coronary artery bypass graft (CABG) surgery. Better understanding of the timing and risk factors for stroke associated with CABG are needed. OBJECTIVES: To investigate temporal trends in stroke after CABG and to identify stroke risk factors and association with longitudinal outcomes. DESIGN, SETTING, AND PATIENTS: Prospective study conducted from 1982 through 2009 at a single US academic medical center among 45,432 consecutive patients (mean age, 63 [SD, 10] years) undergoing isolated primary or reoperative CABG surgery. Strokes occurring following CABG were recorded prospectively and classified as having occurred intraoperatively or postoperatively. Complications and survival after stroke were assessed in propensity-matched groups. INTERVENTION: CABG performed using 4 different operative strategies (off-pump, on-pump with beating heart, on-pump with arrested heart, on-pump with hypothermic circulatory arrest). MAIN OUTCOME MEASURES: Hospital complications; late survival. RESULTS: Among 45,432 patients undergoing CABG surgery, 705 (1.6% [95% confidence interval {CI}, 1.4%-1.7%]) experienced a stroke. The prevalence of stroke peaked in 1988 at 2.6% (95% CI, 1.9%-3.4%), then declined at 4.69% (95% CI, 4.68%-4.70%) per year (P = .04), despite increasing patient comorbidity. Overall, 279 strokes (40%) occurred intraoperatively and 409 (58%) occurred postoperatively (timing indeterminate in 17 patients). Postoperative stroke peaked at 40 hours, decreasing to 0.055%/d (95% CI, 0.047%-0.065%) by day 6. Risk factors for both intraoperative and postoperative stroke included older age (odds ratio, 8.5 [95% CI, 3.2-22]) and variables representing arteriosclerotic burden. Intraoperative stroke rates were lowest in off-pump CABG (0.14% [95% CI, 0.029%-0.40%]) and on-pump beating-heart CABG (0% [95% CI, 0%-1.6%]), intermediate with on-pump arrested-heart CABG (0.50% [95% CI, 0.41%-0.61%]), and highest with on-pump CABG with hypothermic circulatory arrest (5.3% [95% CI, 2.0%-11%]). Patients with stroke had worse adjusted hospital outcomes, longer intensive care and postoperative stays, and worse downstream survival (mean, 11 [SD, 8.6] years). CONCLUSION: Among patients undergoing CABG surgery at a single center over the past 30 years, the occurrence of stroke declined despite an increasing patient risk profile, and more than half of strokes occurred postoperatively rather than intraoperatively. PMID- 21266686 TI - Sarcoidosis: clinical presentation, immunopathogenesis, and therapeutics. AB - Sarcoidosis is a multisystem granulomatous disorder that most often affects the lungs and may cause significant morbidity. Sarcoidosis can manifest as neurological disease, uveitis, blindness, end-stage pulmonary fibrosis, pulmonary hypertension, dysrhythmias, cardiomyopathy, hypercalcemia, and renal failure. Sarcoidosis persists as chronic disease in approximately one-third of those affected. Clinical pitfalls and misconceptions about the course of disease place this population at risk for delayed or inadequate care. While noncaseating granulomas are the histopathological hallmark of sarcoidosis, they also are nonspecific. No pathognomonic diagnostic test exists for sarcoidosis, so the diagnosis remains one of exclusion. While the etiology of sarcoidosis is still unknown, recent insights into its immunopathogenesis have moved investigators closer to finding more effective treatments. Corticosteroids remain the standard of care when treatment is indicated, despite their adverse effect profile. Clinical investigations of novel drugs and biological agents targeting mechanisms involving CD4 type 1 helper T cells may provide more effective, better tolerated therapies. PMID- 21266687 TI - The promise of comparative effectiveness research. PMID- 21266688 TI - A "prosthetic" approach for individuals with dementia? PMID- 21266689 TI - Meaningful disparities reduction through research and translation programs. PMID- 21266690 TI - Preventing death one stroke at a time. PMID- 21266691 TI - JAMA patient page. Sarcoidosis. PMID- 21266692 TI - Nutrition support in critical illness. Editor's note. PMID- 21266693 TI - Nutrition support for the acute lung injury/adult respiratory distress syndrome patient: a review. AB - Support for Acute Lung Injury (ALI) and Adult Respiratory Distress Syndrome (ARDS) in many ways represents the summation of all intensive care unit nutrition modalities. Basic tenets of management are based on those established for the general population of mechanically ventilated patients. As a marker of critical illness however, patients with ALI/ARDS suffer from other organ dysfunctions that require advanced support. Specific issues to be considered in this population include carbon dioxide production, prevention of aspiration, and modulation of the inflammatory response. These particular areas, with special attention paid to the role of lipids in ALI/ARDS, will be reviewed. PMID- 21266694 TI - Acute respiratory distress syndrome: use of specialized nutrients in pediatric patients and infants. AB - With a high rate of mortality, acute respiratory distress syndrome (ARDS) has limited treatments options. Immune-enhanced formulas, containing eicosapentaenoic acid, borage oil, and antioxidants, have shown to be beneficial in adults patients with ARDS, decreasing mortality, length of mechanical ventilation, and new organ dysfunction. There is promising research in pediatric patients with improvement in oxygenation status found, but further trials are needed to realize these benefits in pediatric and infant populations. PMID- 21266695 TI - Glucose control in the intensive care unit: a nutrition support perspective. AB - Hyperglycemia commonly occurs in acutely ill patients who receive nutrition support, even in patients without a history of diabetes. The traditional view that stress hyperglycemia may be a beneficial adaptive response has been replaced by data linking hyperglycemia with increased morbidity and mortality in critically ill populations. Initial randomized studies to control stress hyperglycemia with intensive insulin infusion reported dramatic decreases in infectious complications and decreased mortality. However, recent large multicenter trials have reported that intensive insulin therapy designed to normalize blood glucose resulted in an unacceptable increase in the incidence of hypoglycemia. Review of the methods, protocols, and nutrition provided during these randomized studies is crucial to understanding the different conclusions reached and how these results may be used to influence protocols in intensive care units today. Evidence is reviewed and practical considerations are provided for nutrition support regimens to minimize stress hypoglycemia and assist glucose management. PMID- 21266696 TI - Effect of glutamine-supplemented parenteral nutrition on mortality in critically ill patients. AB - Glutamine is recognized as a critical amino acid involved in immunity, intestinal health, and nitrogen transport between organs. Prior to the pivotal study by Griffiths and colleagues in 1997, no clinical trials had demonstrated a positive effect from glutamine supplementation on improving long-term survival in critically ill intensive care unit patients receiving parenteral nutrition. Subsequent investigations have confirmed these findings, but further data are needed to determine the optimal dose and timing of glutamine as well as the form of glutamine (ie, free vs dipeptide) that produces the most significant improvement in outcome parameters. PMID- 21266697 TI - Optimal caloric intake for critically ill patients: first, do no harm. AB - Despite considerable efforts to define energy requirements for critically ill patients, no single method has been found to be precise and unbiased for all patients. As a result, clinicians have used various methods that may overestimate energy requirements for some patients. Provision of target caloric intake without regard to the complications of overfeeding, such as hyperglycemia, hypercapnia, or gastric feeding intolerance, could result in overall detrimental clinical outcome. Inadequate nutrition support is also associated with adverse clinical outcomes that necessitate optimization of delivery and tolerance of the nutrition regimen. A pivotal paper by Krishnan and colleagues published in 2003 brought these issues to the forefront of clinical practice. Key papers that support or refute the practice of "permissive underfeeding" are reviewed. Further research is necessary to determine the minimum amount of nutrition required to achieve a therapeutic benefit as well as to ascertain at what amount of additional nutrition intake offers no further improvement in clinical outcome. PMID- 21266698 TI - Subjective global assessment in patients with pulmonary tuberculosis. AB - BACKGROUND: Malnutrition is observed frequently in patients with pulmonary tuberculosis (TB). Subjective global assessment (SGA) is a subjective method of measuring nutrition status. Few studies have investigated the prognostic role of SGA in patients with pulmonary TB. METHODS: The authors evaluated 39 patients with pulmonary TB. The SGA classification technique was performed; patients were classified as well nourished (A), moderately malnourished (B), or severely malnourished (C). RESULTS: The mean patient age was 67.7 +/- 19.0 years, and the majority of patients were male (64.1% ). Twelve patients (30.1% ) were categorized as SGA class A, 14 patients (35.9% ) as class B, and 13 patients (33.3% ) as class C. The SGA-A group had a median survival of 438 days (95% confidence interval, 366-509), the median survival of the SGA-B group was 344 days (251-436), and the median survival of the SGA-C group was 118 days (37-198); these survival rates were significantly different (P < .001). CONCLUSION: SGA appears to be a useful tool for nutrition assessment of patients with pulmonary TB. In addition, SGA may be a prognostic indicator of survival in patients with pulmonary TB. PMID- 21266699 TI - Olive oil-based fat emulsion versus soy oil-based fat emulsion in abdominal oncologic surgery. AB - In parenteral nutrition (PN), essential fatty acids are provided by soy oil-based fat emulsions, which may exert adverse effects on the immune system and lipid peroxidation. Olive oil -based fat emulsions have been said to prevent these undesired effects. This study compares effects of olive oil - and soy oil -based fat emulsions in 22 patients who underwent abdominal surgery for cancer. The first group (n = 10) received soy oil -based fat emulsion; the second group (n = 10) received olive oil -based fat emulsion. Body temperature, body mass index, (BMI) and biochemical variables were measured on days 0 and 7. There were no differences between the groups with regard to BMI or temperature. On day 7, the first group (compared with day 0) had significant increases in plasma alkaline phosphatase (81.70 +/- 16.03 vs 117.60 +/- 11.1), gamma-glutamyl transferase (39.90 +/- 15.40 vs 137.70 +/- 24.09), and mean body temperature (36.72 degrees C +/- 0.14 degrees C vs 37.20 degrees C +/- 0.17 degrees C) (P < .01). Second group had increases in alkaline phosphatase (85.80 +/- 13.46 vs 147.20 +/- 34.17), gamma-glutamyl transferase (48.40 +/- 12.86 vs 129.40 +/- 42.03), total protein (5.14 +/- 0.19 vs 6.06 +/- 0.49), and albumin (2.62 +/- 0.14 vs 3.00 +/- 0.18) (P < .05). Changes in thiobutyric acid levels were not statistically significant in either group. In postoperative cancer patients, olive oil-based fat emulsion had similar effects on BMI, body temperature, biochemical values, and thiobutyric acid levels as soy oil-based fat emulsions. PMID- 21266700 TI - Early-onset copper deficiency following Roux-en-Y gastric bypass. AB - Weight loss surgery can provide many health benefits to those suffering from morbid obesity. The surgery, however, is not without potential complications. This clinical observation describes a patient who experienced gait disturbances, lower extremity weakness, and neuropathy which led to a diagnosis of copper deficiency less than 2 years following a Roux-en-Y gastric bypass. Neurological symptoms were improved within 2 months of copper supplementation. The need to monitor patients for less common micronutrient deficiencies such as copper following Roux-en-Y gastric bypass is reinforced by this case. PMID- 21266701 TI - The feeding tube bridle: one inexpensive, safe, and effective method to prevent inadvertent feeding tube dislodgement. AB - Nasally placed feeding tubes are heavily relied on in healthcare. Inadvertent tube removal not only poses safety hazards and discomfort for the patient, but also causes strain on valuable healthcare resources. Because use of restraints can agitate patients, increase safety hazards, and create a sense of depersonalization, alternative methods to prevent inadvertent tube removal are desirable. This article describes a feeding tube bridle constructed with supplies that are inexpensive and readily available to most patient care units. This method has been successfully utilized for patients at significant risk for self initiated feeding tube removal in one Midwestern facility for many years without adverse effects. The method of bridling feeding tubes described here is effective, safe, and relatively comfortable as well as minimally noticeable to the patient and others. PMID- 21266702 TI - Percutaneous endoscopic gastrojejunostomy tube feeding in children. AB - Managing infants and children with difficult feeding problems, such as intractable vomiting and dysmotility, can be challenging. Maintaining sufficient enteral feeding is the ultimate goal. However, the options for establishing this goal may be limited. One option is gastrojejunostomy tube feeding, a technique developed in 1984. This review discusses indications and limitations of gastrojejunostomy tube feeding in children. It also discusses alternative options for gastrojejunostomy tube feeding in view of the available evidence. PMID- 21266703 TI - Folate: is too much of a good thing harmful? PMID- 21266704 TI - Abstracts of Clinical Nutrition Week. Vancouver, British Columbia, Canada. January 29-February 1, 2011. PMID- 21266705 TI - Being a qualitative researcher. AB - This article, from a keynote address, is the result of some of the things which I learned about qualitative research during my many years of doing and teaching it. The main point I make is that qualitative researchers should present a good story which is based on evidence but focused on meaning rather than measurement. In qualitative inquiry, the researchers' selves are involved, their experiences become a resource. Researchers cannot distance themselves from the other participants, although they cannot fully present their meaning and experience. I also discuss voice, paradigm, and innovation as potentially problematic issues in qualitative research. These are terms often used but not always examined for their meaning in qualitative inquiry. If researchers are aware and sensitive, rather than overemotional or self-absorbed, qualitative research can be enlightening, person-centered, and humanistic. PMID- 21266706 TI - The role of brothels in reducing HIV risk in Sonagachi, India. AB - High rates of empowerment, HIV-related knowledge, and condom use among sex workers in Sonagachi, India have been attributed to a community-led intervention called the Sonagachi HIV/AIDS Intervention Program (SHIP). In this research we examined the crucial role of brothels in the success of the intervention. In depth, semistructured interviews were conducted with 55 participants of SHIP. The results indicate that brothels help sex workers reduce HIV risk by (a) serving as targeted sites for SHIP's HIV intervention efforts, (b) being operated by madams (women managers of brothels) who participate in SHIP's intervention efforts and promote healthy regimes, (c) structuring the economic transactions and sexual performances related to sex work, thus standardizing sex-related behavior, and (d) promoting community empowerment among brothel residents. Implications of these results are discussed for future efforts to replicate SHIP's success in other sex work communities. PMID- 21266707 TI - Mechanisms of in-stent restenosis after drug-eluting stent implantation: intravascular ultrasound analysis. AB - BACKGROUND: We used intravascular ultrasound (IVUS) to (1) clarify the mechanisms of luminal loss after drug-eluting stent (DES) implantation and (2) classify morphological patterns of in-stent restenosis (ISR). METHODS AND RESULTS: On the basis of IVUS-identified luminal narrowing (in-stent minimum lumen area <4 mm(2)), IVUS-defined ISR was classified as focal (luminal narrowing <=10 mm in length), multifocal (>=1 focal lesions), and diffuse (luminal narrowing >10 mm in length) with or without stent edge involvement. Significant intimal hyperplasia (IH) was defined as IH area >50% of stent. Overall, 76 lesions had IVUS-defined ISR; 32 (42%) had stent underexpansion (minimal stent area <5 mm(2)); and 71 (93%) had IH area >50% of stent. Total stent length negatively correlated with minimal stent area (r=-0.613, P<0.001) as well as with stent area at the minimum lumen site (r=-0.436, P<0.001) but not with minimum lumen area (r=-0.084, P=0.472). Underexpansion was present at the minimum lumen site in 15 of 43 (35%) lesions with stent length >28 mm, even though there was significant IH in 34 (79%) lesions; conversely, in 32 of 33 (97%) lesions with stent length <=28 mm, the minimum lumen site was not associated with stent underexpansion but significant IH. IVUS-defined focal ISR was most common (47%). Compared with focal ISR, normalized vessel, stent, lumen, and plaque volumes were smaller in diffuse and multifocal than focal ISR, with no difference in IH extent. CONCLUSIONS: In most DES restenosis, IH was the dominant mechanism of ISR. Nevertheless, underexpansion associated with longer stent length remained an important preventable mechanism of ISR. PMID- 21266708 TI - Validation of intravascular ultrasound-derived parameters with fractional flow reserve for assessment of coronary stenosis severity. AB - BACKGROUND: We assessed optimal intravascular ultrasound (IVUS) criteria for predicting functional significance of intermediate coronary lesions. METHODS AND RESULTS: Overall, 201 patients with 236 coronary lesions underwent IVUS and invasive physiological assessment before intervention. Fractional flow reserve (FFR) was measured at maximal hyperemia induced by intravenous adenosine infusion. FFR <0.80 at maximum hyperemia was seen in 49 (21%) of the overall 236 lesions. The independent determinants of FFR were minimal lumen area (MLA; beta=0.020; 95% confidence interval [CI], 0.008 to 0.031; P=0.032), plaque burden (beta=-0.002; 95% CI, -0.003 to 0.001; P=0.001), lesion length with a lumen area <3.0 mm(2) (beta=-0.003; 95% CI, -0.005 to -0.001; P=0.005), and left anterior descending artery location (beta=-0.035; 95% CI, -0.055 to -0.016; P=0.001). The best cutoff value (with a maximal accuracy) of the MLA to predict FFR <0.80 was <2.4 mm(2), with a diagnostic accuracy of 68% (90% sensitivity, 60% specificity, and area under the curve=0.800; 95% CI, 0.742 to 0.848; P<0.001). The cutoff value of plaque burden to predict FFR <0.80 was >=79% (69% sensitivity, 72% specificity, and area under the curve=0.756; 95% CI, 0.696 to 0.810; P<0.001). The cutoff value of lesion length with a lumen area <3.0 mm(2) was 3.1 mm (84%sensitivity, 63%specificity, and area under the curve=0.765; 95% CI, 0.706 to 0.818; P<0.001). Among 117 lesions with an MLA >=2.4 mm(2), 112 (96%) had an FFR >=0.80,; and all but 1 showed FFR >=0.75. Conversely, 44 (37%) lesions with an MLA <2.4 mm(2) had an FFR <0.80. CONCLUSIONS: IVUS-derived MLA >=2.4 mm(2) may be useful to exclude FFR <0.80, but poor specificity limits its value for physiological assessment of lesions with MLA <2.4 mm(2). Thus, FFR or stress tests may be necessary to accurately identify ischemia-inducible intermediate stenoses. PMID- 21266709 TI - Dynamics of trust in medical decision making: an experimental investigation into underlying processes. AB - BACKGROUND: Patient trust in medical decision makers is a crucial facilitator of effective health care. Greater patient involvement in decision making requires improved understanding of how such trust is built, maintained, and lost in medical contexts. OBJECTIVE: The study investigates how trust in clinicians is affected by the 4 main diagnostic outcomes proposed by signal detection theory: true positives, true negatives, false positives, and false negatives. Cognitive appraisals of, and affective reactions to, the decisions were measured to investigate the psychological mechanisms underpinning effects on trust. DESIGN: Members of an Internet research panel (N = 1162) participated in a between participant experimental study using hypothetical cancer diagnosis scenarios. RESULTS: Overall, correct diagnoses bolstered trust as much as incorrect ones undermined it. Consistent with recent findings in other decision-making domains, trust was not as precarious as generally believed. The influence of decisions and outcomes on trust was mediated through cognitive assessments and affective responses in line with current appraisal theories in psychology. Prior levels of trust in clinicians affected sympathy for doctors, highlighting the role that trust plays in responding to new information. CONCLUSIONS: Trust in (hypothetical) clinicians is sensitive to information about their past diagnostic performance. Greater understanding of the cognitive and affective mechanisms by which this occurs may help maintain current high levels of trust. Further research is needed to examine whether findings generalize to real medical decision-making contexts. Clinicians may want to consider the impact their diagnoses have on trust alongside medical and financial considerations. PMID- 21266710 TI - Applying the transtheoretical model to health care proxy completion. AB - BACKGROUND: For many, an important health decision is whether or not to document end-of-life wishes using an advance directive (e.g., health care proxy). To date, interventions targeting this health behavior have had little effect on increasing advance directive completion rates. Health behavior models, such as the transtheoretical model (TTM) could be useful for understanding the health decision-making processes used along a continuum, from no intention to complete an advance directive to completing one and discussing it with an appointed advocate. PURPOSE: To explore the applicability of the TTM for a previously understudied health behavior-completing a health care proxy (HCP). METHOD: Four established TTM measures for completing a HCP (stages of change, processes of change, decisional balance, and self-efficacy) were administered to 566 adults with coverage from 1 of 2 health insurance companies. Separate analyses of variance were used to test the relationships between the independent variable (stages of change) and dependent variables (processes of change, decisional balance, self-efficacy scores). RESULTS: Consistent with other TTM research both the experiential and the behavioral processes of change revealed the lowest scores in the precontemplation stage peaking in the preparation stage. The pattern of pros and cons was replicated from previous TTM studies, with the 2 scores crossing over just prior to the preparation stage. Self-efficacy scores incrementally increased across the stages of change with the largest effect evident from the precontemplation to preparation stage. CONCLUSION: The models developed from this study can be used to guide the development of stage-based interventions for promoting health care proxy completion. PMID- 21266711 TI - The role of L(u)ck in T cell triggering. AB - T cells use a highly complex signaling apparatus to discriminate between a diverse array of foreign antigens and a myriad of self molecules. The precise mechanism whereby signals are communicated from the antigen-binding T cell receptor to the intracellular signal transduction machinery remains a source of intense debate. This Journal Club article highlights recent research elucidating the role of the Src family kinase Lck in T cell triggering. Resting T cells contain a newly described form of preactivated Lck that is both necessary and sufficient for T cell activation but remains uncoupled from the T cell receptor in the absence of antigen. This research allows a reappraisal of the mechanisms underlying T cell triggering. PMID- 21266712 TI - Dependence receptors: from basic research to drug development. AB - The fourth meeting on dependence receptors featured descriptions of previously unknown dependence receptors. New mechanistic data were presented on the switch between the trophic, antiapoptotic response with the proapoptotic response that occurs with loss of trophic support. The possibility that the loss of trophic support may also involve the binding of an active antitrophin was also discussed. New in vivo data were presented on the roles of dependence receptors in development, angiogenesis, oncogenesis, and neurodegeneration, as well as new therapeutic approaches based on dependence receptor function. The next meeting on dependence receptors is scheduled for 2012. PMID- 21266713 TI - Control of DNMT1 abundance in epigenetic inheritance by acetylation, ubiquitylation, and the histone code. AB - Inheritance of DNA methylation patterns is a key mechanism involved in epigenetic cell memory transmission from mother cell to daughter cell. This occurs due to cooperation between the DNA methyltransferase DNMT1 and the ubiquitin ligase UHRF1 (ubiquitin-like, containing plant homeo domain and RING finger 1) in a macromolecular complex. Newly identified members of this complex are the acetyltransferase Tip60 (Tat-interactive protein) and the deubiquitinase HAUSP (herpes virus-associated ubiquitin specific protease), which exert tight regulation of DNMT1 abundance through a ubiquitylation-dependent process. It is important to determine how all of these actors communicate with each other and what signals coordinate their communication. In the case of DNMT1, the balance of UHRF1 and HAUSP activities might be influenced by the local environment, such as histone code, cell-cycle status, and local DNA methylation status. PMID- 21266714 TI - Rho and Rho-kinase activity in adipocytes contributes to a vicious cycle in obesity that may involve mechanical stretch. AB - The development of obesity involves multiple mechanisms. Here, we identify adipocyte signaling through the guanosine triphosphatase Rho and its effector Rho kinase as one such mechanism. Mice fed a high-fat diet (HFD) showed increased Rho kinase activity in adipose tissue compared to mice fed a low-fat diet. Treatment with the Rho-kinase inhibitor fasudil attenuated weight gain and insulin resistance in mice on a HFD. Transgenic mice overexpressing an adipocyte specific, dominant-negative form of RhoA (DN-RhoA TG mice) showed decreased Rho kinase activity in adipocytes, decreased HFD-induced weight gain, and improved glucose metabolism compared to wild-type littermates. Furthermore, compared to HFD-fed wild-type littermates, DN-RhoA TG mice on a HFD showed decreased adipocyte hypertrophy, reduced macrophage recruitment to adipose tissue, and lower expression of mRNAs encoding various adipocytokines. Lipid accumulation in cultured adipocytes was associated with increased Rho-kinase activity and increased abundance of adipocytokine transcripts, which was reversed by a Rho kinase inhibitor. Direct application of mechanical stretch to mature adipocytes increased Rho-kinase activity and stress fiber formation. Stress fiber formation, which was also observed in adipocytes from HFD-fed mice, was prevented by Rho kinase inhibition and in DN-RhoA TG mice. Our findings indicate that lipid accumulation in adipocytes activates Rho to Rho-kinase (Rho-Rho-kinase) signaling at least in part through mechanical stretch and implicate Rho-Rho-kinase signaling in inflammatory changes in adipose tissue in obesity. Thus, inhibition of Rho-Rho-kinase signaling may provide a therapeutic strategy for disrupting a vicious cycle of adipocyte stretch, Rho-Rho-kinase signaling, and inflammation of adipose tissue that contributes to and aggravates obesity. PMID- 21266715 TI - Genome-wide RNAi screen reveals disease-associated genes that are common to Hedgehog and Wnt signaling. AB - The Hedgehog (Hh) and Wnt signal transduction pathways are master regulators of embryogenesis and tissue renewal and represent anticancer therapeutic targets. Using genome-wide RNA interference screening in murine cultured cells, we established previously unknown associations between these signaling pathways and genes linked to developmental malformations, diseases of premature tissue degeneration, and cancer. We identified functions in both pathways for the multitasking kinase Stk11 (also known as Lkb1), a tumor suppressor implicated in lung and cervical cancers. We found that Stk11 loss resulted in disassembly of the primary cilium, a cellular organizing center for Hh pathway components, thus dampening Hh signaling. Loss of Stk11 also induced aberrant signaling through the Wnt pathway. Chemicals that targeted the Wnt acyltransferase Porcupine or that restored primary cilia length by inhibiting the tubulin deacetylase HDAC6 (histone deacetylase 6) countered deviant pathway activities driven by Stk11 loss. Our study demonstrates that Stk11 is a critical mediator in both the Hh and the Wnt pathways, and our approach provides a platform to support the development of targeted therapeutic strategies. PMID- 21266716 TI - V2 receptor-mediated autocrine role of somatodendritic release of AVP in rat vasopressin neurons under hypo-osmotic conditions. AB - Arginine vasopressin (AVP) neurons in the hypothalamus are osmosensory neurons that respond to increased or decreased plasma osmolarity by releasing more or less AVP, respectively, from their axon terminals. Here, we found that, in contrast, hypo-osmotic stress enhanced somatodendritic AVP secretion from isolated rat AVP neurons, and this somatodendritic release depended on actin depolymerization. In AVP neurons identified by transgenic expression of green fluorescent protein, hypo-osmotic stimulation led to activation of anion currents and a slow regulatory volume decrease (RVD). Bath application of AVP increased the volume-sensitive anion current and accelerated RVD; these effects were abolished by inhibition of adenylate cyclase or by a specific antagonist of the V(2)-type vasopressin receptor. The V(2) receptor antagonist slowed the RVD rate of AVP neurons even in the absence of exogenous AVP when the volume of bath solution was reduced. Reverse transcription polymerase chain reaction and immunostaining both indicated that the V(2) receptor was present in AVP neurons. We conclude that somatodendritic release of AVP under hypo-osmotic conditions acts through the V(2) receptor as an autocrine signal to enhance volume-sensitive anion channel activity and thereby facilitate cell volume regulation. PMID- 21266717 TI - The clinical utility and prognostic value of multiparameter flow cytometry immunophenotyping in light-chain amyloidosis. AB - The clinical value of multiparameter flow cytometry (MFC) immunophenotyping in primary or light chain amyloidosis (AL) remains unknown. We studied 44 consecutive bone marrow samples from newly diagnosed patients with amyloidosis; 35 patients with AL and 9 with other forms of amyloidosis. Monoclonal plasma cells (PCs) were identifiable by MFC immunophenotyping in 34 of 35 (97%) patients with AL, whereas it was absent from all but 1 of the 9 (11%) patients with other forms of amyloidosis. Quantification of bone marrow plasma cells (BMPCs) by MFC immunophenotyping was a significant prognostic factor for overall survival (OS) (<= 1% vs > 1% BMPC cutoff; 2-year OS rates of 90% vs 44%, P = .02). Moreover, detecting persistent normal PCs at diagnosis identifies a subgroup of patients with AL with prolonged OS (> 5% vs <= 5% normal PC within all BMPC cutoff, 2-year rates of 88% vs 37%, P = .01). MFC immunophenotyping could be clinically useful for the demonstration of PC clonality in AL and for the prognostication of patients with AL. PMID- 21266718 TI - The genetics of Richter syndrome reveals disease heterogeneity and predicts survival after transformation. AB - Richter syndrome (RS) represents the development of diffuse large B-cell lymphoma in the context of chronic lymphocytic leukemia. The scarcity of biologic information about RS has hampered the identification of molecular predictors of RS outcome. We addressed this issue by performing a comprehensive molecular characterization of 86 pathologically proven RS. TP53 disruption (47.1%) and c MYC abnormalities (26.2%) were the most frequent alterations, whereas common genetic lesions of de novo diffuse large B-cell lymphoma were rare or absent. By multivariate analysis, lack of TP53 disruption (hazard ratio, 0.43; P = .003) translated into significant survival advantage with 57% reduction in risk of death. An algorithm based on TP53 disruption, response to RS treatment, and Eastern Cooperative Oncology Group performance status had 80.9% probability of correctly discriminating RS survival (c-index = .809). RS that were clonally unrelated to the paired chronic lymphocytic leukemia phase were clinically and biologically different from clonally related RS because of significantly longer survival (median, 62.5 months vs 14.2 months; P = .017) and lower prevalence of TP53 disruption (23.1% vs 60.0%; P = .018) and B-cell receptor stereotypy (7.6% vs 50.0%; P = .009). The molecular dissection of RS into biologically distinct categories highlights the genetic heterogeneity of this disorder and provides clinically relevant information for refining the prognostic stratification of patients. PMID- 21266720 TI - Special focus: Diagnosis and prognosis of neoplastic diseases in companion animals. PMID- 21266719 TI - Functional architecture of Weibel-Palade bodies. AB - Weibel-Palade bodies (WPBs) are elongated secretory organelles specific to endothelial cells that contain von Willebrand factor (VWF) and a variety of other proteins that contribute to inflammation, angiogenesis, and tissue repair. The remarkable architecture of WPBs is because of the unique properties of their major constituent VWF. VWF is stored inside WPBs as tubules, but on its release, forms strikingly long strings that arrest bleeding by recruiting blood platelets to sites of vascular injury. In recent years considerable progress has been made regarding the molecular events that underlie the packaging of VWF multimers into tubules and the processes leading to the formation of elongated WPBs. Mechanisms directing the conversion of tightly packaged VWF tubules into VWF strings on the surface of endothelial cells are starting to be unraveled. Several modes of exocytosis have now been described for WPBs, emphasizing the plasticity of these organelles. WPB exocytosis plays a role in the pathophysiology and treatment of von Willebrand disease and may have impact on common hematologic and cardiovascular disorders. This review summarizes the major advances made on the biogenesis and exocytosis of WPBs and places these recent discoveries in the context of von Willebrand disease. PMID- 21266721 TI - Prognostic markers for canine melanocytic neoplasms: a comparative review of the literature and goals for future investigation. AB - Many studies have evaluated various prognostic markers for canine melanocytic neoplasms either as primary or secondary goals; however, design, methodology, and statistical validation vary widely across these studies. The goal of this article was to evaluate and compare published canine melanocytic neoplasm studies in relation to the principals established in the Recommended Guidelines for the Conduct and Evaluation of Prognostic Studies in Veterinary Oncology. Based on this evaluation, we determined which parameters currently have the most statistically supported validity for prognostic use in canine melanocytic neoplasia. This information can also be used as part of evidence-based prospective evaluations of treatment regimens. Additionally, we highlight areas in which the current data are incomplete and that warrant further evaluation. This article represents an initiative of the American College of Veterinary Pathologists' Oncology Committee and has been reviewed and endorsed by the World Small Animal Veterinary Association. PMID- 21266722 TI - Classification and grading of canine mammary tumors. AB - Mammary neoplasms are the most common neoplasm in female dogs. Two histologic classification systems for canine mammary tumors and dysplasias have been published: the first in 1974 and a modification in 1999. This article provides a brief overview of the two histologic classification systems. Since the publication of the second system, several new histologic subtypes of canine mammary neoplasms have been described. These have been incorporated into the proposed new classification system. This article also compares the grading systems for canine mammary carcinomas and their use for prognosis, along with the histologic classification. PMID- 21266723 TI - Accuracy of computed tomographic colonography in a nationwide multicentre trial, and its relation to radiologist expertise. AB - OBJECTIVE: Reports on the accuracy of computed tomographic colonography (CTC) mainly involve series from expert institutions. The aims of this study were to assess CTC accuracy in a nationwide population and to relate it to radiologist performance in their initial training. DESIGN: Nationwide multicentre trial. SETTING: Twenty-eight radiologists, working in 26 mostly academic clinical units, were involved in the study after having attended a formal specialised 2-day training session on CTC. They worked through a training set of 52 cases with automatic feedback after an attempt at each case. PATIENTS: The study enrolled 845 patients with average and high risk of colorectal cancer, 737 of whom had both complete CTC and videocolonoscopy data, which constituted the dataset. INTERVENTIONS: Patients underwent same-day CTC followed by videocolonoscopy with segmental unblinding of CTC results. MAIN OUTCOME MEASURES: Sensitivity, specificity and positive and negative predictive values for detection of polyps >= 6 mm in per-patient and per-lesion analyses of CTC without computer-aided detection. RESULTS: Sensitivity, specificity and positive and negative predictive values for patients with polyps >= 6 mm were 69% (95% CI 61% to 77%), 91% (95% CI 89% to 94%), 67% (95% CI 59% to 74%) and 92% (95% CI 90% to 94%), respectively. Univariate analysis showed that the detection rate for polyps >= 6 mm was linked to neither radiologist case volume nor number of polyps, but was related to sensitivity achieved in the training set. Pooled sensitivity was 72% (95% CI 63% to 80%) versus 51% (95% CI 40% to 60%) for radiologists achieving above and below median sensitivity in the training set (61%), respectively. Multivariate analysis showed that sensitivity for polyps >= 6 mm in the training set was the only remaining significant predictive factor for subsequent performance. CONCLUSIONS: Radiologist sensitivity CTC for detection of polyps >= 6 mm in training was the sole independent predictor for subsequent sensitivity in detection of such polyps. PMID- 21266724 TI - Lessons from type I interferons in ulcerative colitis. PMID- 21266725 TI - Long-term peptic ulcer rebleeding risk estimation in patients undergoing haemodialysis: a 10-year nationwide cohort study. AB - OBJECTIVE: We aimed to study 1-, 5- and 10-year risks of peptic ulcer rebleeding among end-stage renal disease (ESRD) patients with regular haemodialysis, to identify the high-risk subpopulation, and to estimate the number needed to harm (NNH) to increase a peptic ulcer rebleeding in different periods. DESIGN: A nationwide cohort study. SETTING: Data from the Taiwan National Health Insurance Research Database. PATIENTS: Uraemic cohort and matched controls were selected from among hospitalised patients with a primary diagnosis of peptic ulcer bleeding. In total, 6447 uraemic patients and 25,788 age-, gender- and gastroprotective agent use-matched controls were selected. Intervention No. Main outcome measures Cumulative incidences and HRs. RESULTS: The cumulative incidences of ESRD patients were significantly higher than the cumulative incidences of matched controls (1 year: 18.8% vs 14.2%; 5 years: 38.5% vs 31.4%; and 10 years: 46.3% vs 39.4%; all p<0.001). The NNH to increase a peptic ulcer rebleeding by ESRD at 1, 5 and 10 years were 22, 15 and 15, respectively. On multivariate analysis, ESRD (HR=1.38, p<0.0001) was an independent risk factor for rebleeding. Compared with matched controls, ESRD was associated with higher risk of rebleeding especially in patients using ulcerogenic agents (HR=1.33 1.45), indication to prescribe gastroprotective agents (HR=1.44) and with liver cirrhosis (HR=1.45). CONCLUSIONS: ESRD patients had higher long-term risk of peptic ulcer rebleeding, especially in certain populations. The enhanced risk gradually decreased after the first year and stabilised after the fifth year. PMID- 21266726 TI - Diarrhoea and massive duodenal round cell infiltration in a 27-year-old HIV positive female. PMID- 21266728 TI - Effectiveness of polarized training for rowing performance. PMID- 21266727 TI - Evidence for subpopulations of Listeria monocytogenes with enhanced invasion of cardiac cells. AB - Cardiac infections caused by the foodborne bacterium Listeria monocytogenes represent a significant but poorly studied facet of disease. It is not known whether L. monocytogenes cardiac infections stem solely from host susceptibility, or whether bacterial isolates exist that exhibit a tropism for cardiac tissue. Here we examine the cardio-invasive capacity of a recent L. monocytogenes cardiac case strain (07PF0776) as well as nine additional outbreak and clinical isolates. Mice infected with the cardiac isolate 07PF0776 had 10-fold more bacteria recovered from heart tissue than those infected with L. monocytogenes strain 10403S, a well-characterized clinical isolate originally obtained from a human skin lesion. Additional L. monocytogenes isolates exhibited varied capacities to colonize the hearts of mice; however, those with the highest efficiency of mouse cardiac invasion also demonstrated the highest levels of bacterial invasion in cultured myoblast cells. Our findings strongly suggest that subpopulations of L. monocytogenes strains have acquired an enhanced ability to target and invade the myocardium. PMID- 21266729 TI - Value of the application of the heart rate performance curve in sports. AB - The heart rate performance curve (HRPC) has been shown to be nonlinearly related to work load. This phenomenon has been used to determine a deflection point and to be related to the lactate anaerobic threshold. The original method was heavily criticized, and the method was challenged by several authors. However, some authors also demonstrated a high value for this method's application in various sports conditions. Unfortunately, the HRPC was shown to be not uniform and three different patterns were found. Basic investigations have shown a dependence of the HR-deflection on beta1-receptor sensitivity, which gave a plausible explanation of the phenomenon. Important details regarding the testing protocol and the method of turn point determination are given in this review. As a conclusion, we may state that based on numerous studies the method is plausible and valid to determine aerobic exercise performance in various laboratory ergometer and specific sports-related field conditions. Standard protocol conditions adjusted to the exercise performance level of subjects and a computer supported determination of turn points are necessary to obtain reliable results. Large-scale investigations to validate the heart rate turn point with maximal lactate steady state are still needed. However, from the available literature, the application of this noninvasive method can be recommended to determine aerobic exercise performance in various sports. This noninvasive test is easy to perform repeatedly, which gives interesting possibilities for the monitoring of training adaptation in the short term, such as altitude training or specific taper forms. PMID- 21266730 TI - The validity and reliability of 1-Hz and 5-Hz global positioning systems for linear, multidirectional, and soccer-specific activities. AB - PURPOSE: The study aimed to analyze the validity and reliability of commercially available nondifferential Global Positioning System (NdGPS) devices for measures of total distance during linear, multidirectional and soccer-specific motion at 1 Hz and 5-Hz sampling frequencies. METHODS: Linear (32 trials), multidirectional (192 trials) and soccer-specific courses (40 trials) were created to test the validity (mean +/- 90% confidence intervals), reliability (mean +/- 90% confidence intervals) and bias (mean +/- 90% confidence intervals) of the NdGPS devices against measured distance. Standard error of the estimate established validity, reliability was determined using typical error and percentage bias was established. RESULTS: The 1-Hz and 5-Hz data ranged from 1.3% +/- 0.76 to 3.1% +/ 1.37 for validity and 2.03% +/- 1.31 to 5.31% +/- 1.2 for reliability for measures of linear and soccer-specific motion. For multidirectional activity, data ranged from 1.8% +/- 0.8 to 6.88% +/- 2.99 for validity and from 3.08% +/- 1.34 to 7.71% +/- 1.65 for reliability. The 1-Hz underestimated some complex courses by up to 11%. CONCLUSIONS: 1-Hz and 5-Hz NdGPS could be used to quantify distance in soccer and similar field-based team sports. Both 1-Hz and 5-Hz have a threshold beyond which reliability is compromised. 1-Hz also underestimates distance and is less valid in more complex courses. PMID- 21266731 TI - The influence of elliptical chainrings on 10 km cycling time trial performance. AB - The use of elliptical chainrings (also called chainwheels or sprockets) has gained considerable interest in the amateur and professional cycling community. Nevertheless, we are unaware of any scientific studies that have examined the performance benefits of using elliptical chainrings during an actual performance trial. Therefore, this study examined the influence of elliptical chainring use on physiological and performance parameters during a 10 km cycling time trial. Nine male cyclists completed, in a counterbalanced order, three 10 km cycling time trials using either a standard chainring or an elliptical chainring at two distinct settings. An attempt was made to blind the cyclists to the type of chainring used until the completion of the study. During the 10 km time trial, power output and heart rate were recorded at a frequency of 1 Hz and RPE was measured at 3, 6, and 8.5 km. Total power output was not different (P = .40) between the circular (340 +/- 30 W) or either elliptical chainring condition (342 +/- 29 W and 341 +/- 31 W). Similarly, no differences (P = .73) in 2 km mean power output were observed between conditions. Further, no differences in RPE were observed between conditions measured at 3, 6, and 8.5 km. Heart rate was significantly greater (P = .02) using the less aggressive elliptical setting (174 +/- 10 bpm) compared with the circular setting (171 +/- 9 bpm). Elliptical chainrings do not appear to provide a performance benefit over traditional circular chainrings during a mid-distance time trial. PMID- 21266732 TI - Kinematic comparison of team handball throwing with two different arm positions. AB - PURPOSE: The aims of the present study were: (1) to compare the differences in the ball release speed and throwing accuracy between the ABOVE and SIDE throw; (2) to analyze kinematic differences of these two throwing techniques; and (3) to give practical applications to team handball coaches and players. METHODS: Ball release speed, throwing accuracy, and kinematics were measured via the Vicon MX 13 (Vicon Peak, Oxford, UK) from 12 male elite right-handed team handball players. RESULTS: Results of our study suggest that the two throwing techniques differ significantly (P < .0073) in the angles and/or angular velocities of the trunk (flexion, left tilt and rotation) and shoulder (flexion and abduction) of the throwing arm that result in a significantly different ball release speed (1.4 +/- 0.8 m/s; P < .001) and that throwing accuracy was not significantly different. CONCLUSION: Our results indicated that the different position of the hand at ball release of the ABOVE and SIDE throws is primarily caused by different trunk flexion and tilt angles that lead to differences in ball release speed but not in throwing accuracy, and that the participants try to move their throwing arm similarly in both throwing techniques. PMID- 21266733 TI - Relationship between relative net vertical impulse and jump height in jump squats performed to various squat depths and with various loads. AB - PURPOSE: The purpose of the current investigation was to determine the relationship between relative net vertical impulse (net vertical impulse (VI)) and jump height in the jump squat (JS) going to different squat depths and utilizing various loads. METHODS: Ten males with two years of jumping experience participated in this investigation (Age: 21.8 +/- 1.9 y; Height: 176.9 +/- 5.2 cm; Body Mass: 79.0 +/- 7.1 kg, 1RM: 131.8 +/- 29.5 kg, 1RM/BM: 1.66 +/- 0.27). Subjects performed a series of static jumps (SJS) and countermovement jumps (CMJJS) with various loads (Body Mass, 20% of 1RM, 40% of 1RM) in a randomized fashion to a depth of 0.15, 0.30, 0.45, 0.60, and 0.75 m and a self-selected depth. During the concentric phase of each JS, peak force (PF), peak power (PP), jump height (JH) and relative VI were recorded and analyzed. RESULTS: Increasing squat depth corresponded to a decrease in PF and an increase in JH, relative VI for both SJS and CMJJS during all loads. Across all squat depths and loading conditions relative VI was statistically significantly correlated to JH in the SJS (r = .8956, P < .0001, power = 1.000) and CMJJS (r = .6007, P < .0001, power = 1.000). Across all squat depths and loading conditions PF was statistically nonsignificantly correlated to JH in the SJS (r = -0.1010, P = .2095, power = 0.2401) and CMJJS (r = -0.0594, P = .4527, power = 0.1131). Across all squat depths and loading conditions peak power (PP) was significantly correlated with JH during both the SJS (r = .6605, P < .0001, power = 1.000) and the CMJJS (r = .6631, P < .0001, power = 1.000). PP was statistically significantly higher at BM in comparison with 20% of 1RM and 40% of 1RM in the SJS and CMJJS across all squat depths. CONCLUSIONS: Results indicate that relative VI and PP can be used to predict JS performance, regardless of squat depth and loading condition. However, relative VI may be the best predictor of JS performance with PF being the worst predictor of JS performance. PMID- 21266734 TI - Hypoxia increases muscle hypertrophy induced by resistance training. AB - PURPOSE: Recent studies have shown that low-intensity resistance training with vascular occlusion (kaatsu training) induces muscle hypertrophy. A local hypoxic environment facilitates muscle hypertrophy during kaatsu training. We postulated that muscle hypertrophy can be more efficiently induced by placing the entire body in a hypoxic environment to induce muscle hypoxia followed by resistance training. METHODS: Fourteen male university students were randomly assigned to hypoxia (Hyp) and normoxia (Norm) groups (n = 7 per group). Each training session proceeded at an exercise intensity of 70% of 1 repetition maximum (RM), and comprised four sets of 10 repetitions of elbow extension and flexion. Students exercised twice weekly for 6 wk and then muscle hypertrophy was assessed by magnetic resonance imaging and muscle strength was evaluated based on 1RM. RESULTS: Muscle hypertrophy was significantly greater for the Hyp-Ex (exercised flexor of the hypoxia group) than for the Hyp-N (nonexercised flexor of the hypoxia group) or Norm-Ex flexor (P < .05, Bonferroni correction). Muscle hypertrophy was significantly greater for the Hyp-Ex than the Hyp-N extensor. Muscle strength was significantly increased early (by week 3) in the Hyp-Ex, but not in the Norm-Ex group. CONCLUSION: This study suggests that resistance training under hypoxic conditions improves muscle strength and induces muscle hypertrophy faster than under normoxic conditions, thus representing a promising new training technique. PMID- 21266735 TI - Anthropometric profiling of elite junior and senior Australian football players. AB - PURPOSE: Body structure and physical development must be addressed when preparing junior athletes for their first season in a senior competition. The aim of this preliminary study was to measure the extent of the assumption that final year junior Australian Football (AF) athletes are at a physical mismatch to their senior counterparts. METHODS: Twenty-one male participants (17.71 +/- 0.27 y) were recruited from one state based elite junior AF competition and forty-one male participants (22.80 +/- 4.24 y) were recruited from one club competing in the senior elite Australian Football League (AFL), who were subsequently divided into two groups; professional rookies aged 18-20 y (19.44 +/- 0.70 y; n = 18) and professional seniors aged 21+ y (25.43 +/- 3.98 y; n = 23). Dual energy X-ray absorptiometry (DEXA) scans of all participants were completed. RESULTS: Despite being an average 6.0% and 6.1% lighter in total weight and lean mass respectively, no significant difference was found between the elite junior athletes and their professional AFL rookie counterparts. However, significant differences were demonstrated in comparison with the professional AFL senior athletes (P < .01). Both professional AFL groups demonstrated greater than 0.3 kg total bone mineral content (BMC) than the elite junior athletes (P < .01) and significantly greater segmental BMC and bone mineral density (BMD) results (P < .05). CONCLUSION: While the results identify the differences in body composition of the elite junior athletes, development in a linear fashion is noted, providing useful information for the creation of age appropriate expectations and training programs. PMID- 21266736 TI - An attempt to quantify the placebo effect from a three-week simulated altitude training camp in elite race walkers. AB - PURPOSE: To quantify physiological and performance effects of hypoxic exposure, a training camp, the placebo effect, and a combination of these factors. METHODS: Elite Australian and International race walkers (n = 17) were recruited, including men and women. Three groups were assigned: 1) Live High:Train Low (LHTL, n = 6) of 14 h/d at 3000 m simulated altitude; 2) Placebo (n = 6) of 14 h/d of normoxic exposure (600 m); and 3) Nocebo (n = 5) living in normoxia. All groups undertook similar training during the intervention. Physiological and performance measures included 10-min maximal treadmill distance, peak oxygen uptake (VO2peak), walking economy, and hemoglobin mass (Hbmass). RESULTS: Blinding failed, so the Placebo group was a second control group aware of the treatment. All three groups improved treadmill performance by approx. 4%. Compared with Placebo, LHTL increased Hbmass by 8.6% (90% CI: 3.5 to 14.0%; P = .01, very likely), VO2peak by 2.7% (-2.2 to 7.9%; P = .34, possibly), but had no additional improvement in treadmill distance (-0.8%, -4.6 to 3.8%; P = .75, unlikely) or economy (-8.2%, -24.1 to 5.7%; P = .31, unlikely). Compared with Nocebo, LHTL increased Hbmass by 5.5% (2.5 to 8.7%; P = .01, very likely), VO2peak by 5.8% (2.3 to 9.4%; P = .02, very likely), but had no additional improvement in treadmill distance (0.3%, -1.9 to 2.5%; P = .75, possibly) and had a decrease in walking economy (-16.5%, -30.5 to 3.9%; P = .04, very likely). CONCLUSION: Overall, 3-wk LHTL simulated altitude training for 14 h/d increased Hbmass and VO2peak, but the improvement in treadmill performance was not greater than the training camp effect. PMID- 21266737 TI - Partial heat acclimation in cricketers using a 4-day high intensity cycling protocol. AB - Cricketers are often required to play in hot/humid environments with little time for heat adaptation. PURPOSE: We examined the effect of a short 4-d hot/humid acclimation program on classical physiological indicators of heat acclimation. METHODS: Male club cricketers were randomly assigned into heat acclimation (ACC, n = 6) or control (CON, n = 6) groups, and 30 min treadmill trials (10 km/h, approx. 30 +/- 1.0 degrees C, approx. 65 +/- 6% RH) were conducted at baseline and postacclimation. The ACC group completed four high intensity (30-45 min) acclimation sessions on consecutive days at approx. 30 degrees C and approx. 60% RH using a cycle ergometer. The CON group completed matched cycle training in moderate conditions (approx. 20 degrees C, approx. 60% RH). Physiological measures during each treadmill trial included heart rate; core and skin temperatures; sweat Na+, K+ and Cl- electrolyte concentrations; and sweat rate. RESULTS: After the 4-d intervention, the ACC group had a moderate decrease of -11 (3 to -24 beats/min; mean and 90% CI) in the 30 min heart rate, and moderate to large reductions in electrolyte concentrations: Na+ -18% (-4 to -31%), K+ -15% (0 to -27%), Cl- -22% (-9 to -33%). Both ACC and CON groups had only trivial changes in core and skin temperatures and sweat rate. After the intervention, both groups perceived they were more comfortable exercising in the heat. The 4-d heat intervention had no detrimental effect on performance. CONCLUSIONS: Four 30-45 min high intensity cycle sessions in hot/humid conditions elicited partial heat acclimation. For full heat acclimation a more intensive and extensive (and modality-specific) acclimation intervention is needed for cricket players. PMID- 21266738 TI - Sources of variability in iso-inertial jump assessments. AB - PURPOSE: This investigation aimed to quantify the typical variation for kinetic and kinematic variables measured during loaded jump squats. METHODS: Thirteen professional athletes performed six maximal effort countermovement jumps on four occasions. Testing occurred over 2 d, twice per day (8 AM and 2 PM) separated by 7 d, with the same procedures replicated on each occasion. Jump height, peak power (PP), relative peak power (RPP), mean power (MP), peak velocity (PV), peak force (PF), mean force (MF), and peak rate of force development (RFD) measurements were obtained from a linear optical encoder attached to a 40 kg barbell. RESULTS: A diurnal variation in performance was observed with afternoon values displaying an average increase of 1.5-5.6% for PP, RPP, MP, PV, PF, and MF when compared with morning values (effect sizes ranging from 0.2-0.5). Day to day reliability was estimated by comparing the morning trials (AM reliability) and the afternoon trials (PM reliability). In both AM and PM conditions, all variables except RFD demonstrated coefficients of variations ranging between 0.8 6.2%. However, for a number of variables (RPP, MP, PV and height), AM reliability was substantially better than PM. PF and MF were the only variables to exhibit a coefficient of variation less than the smallest worthwhile change in both conditions. DISCUSSION: Results suggest that power output and associated variables exhibit a diurnal rhythm, with improved performance in the afternoon. Morning testing may be preferable when practitioners are seeking to conduct regular monitoring of an athlete's performance due to smaller variability. PMID- 21266739 TI - How hot is too hot?: Some considerations regarding temperature and performance. AB - The regulation of temperature during exercise is a widely debated topic. Two primary views exist, with one embracing a peripheral approach and the other adopting a more integrative and central explanation of the physiology. Especially in the past 10 years, several investigators have published increasingly elegant interpretations that have moved the debate forward. PMID- 21266740 TI - Variability of GPS units for measuring distance in team sport movements. AB - PURPOSE: To examine the difference in distance measured by two global positioning system (GPS) units of the same model worn by the same player while performing movements common to team sports. METHODS: Twenty elite Australian football players completed two trials of the straight line movement (10, 20, 40 m) at four speeds (walk, jog, stride, sprint), two trials of the changes of direction (COD) courses of two different frequencies (gradual and tight), and five trials of a team sport running simulation circuit. To assess inter-unit variability for total and high intensity running (HIR) distance measured in matches, data from eight field players were collected in three Australian Hockey League (AHL) matches during the 2009 season. Each subject wore two GPS devices (MinimaxX v2.5, Catapult, Australia) that collected position data at 5 Hz for each movement and match trial. The percentage difference +/-90% confidence interval (CI) was used to determine differences between units. RESULTS: Differences (+/-90% CI) between the units ranged from 9.9 +/- 4.7% to 11.9 +/- 19.5% for straight line running movements and from 9.5 +/- 7.2% to 10.7 +/- 7.9% in the COD courses. Similar results were exhibited in the team sport circuit (11.1 +/- 4.2%). Total distance (10.3 +/- 6.2%) and HIR distance (10.3 +/- 15.6) measured during the match play displayed similar variability. CONCLUSION: It is recommended that players wear the same GPS unit for each exercise session to reduce measurement error. The level of between-unit measurement error should be considered when comparing results from players wearing different GPS units. PMID- 21266741 TI - Metabolic profile of the Ironman World Championships: a case study. AB - PURPOSE: The purpose of this study was to determine the metabolic profile during the 2006 Ironman World Championship in Kailua-Kona, Hawaii. METHODS: One recreational male triathlete completed the race in 10:40:16. Before the race, linear regression models were established from both laboratory and field measures to estimate energy expenditure and substrate utilization. The subject was provided with an oral dose of 2H2(18)O approximately 64 h before the race to calculate total energy expenditure (TEE) and water turnover with the doubly labeled water (DLW) technique. Body weight, blood sodium and hematocrit, and muscle glycogen (via muscle biopsy) were analyzed pre-and postrace. RESULTS: The TEE from DLW and indirect calorimetry was similar: 37.3 MJ (8,926 kcal) and 37.8 MJ (9,029 kcal), respectively. Total body water turnover was 16.6 L, and body weight decreased 5.9 kg. Hematocrit increased from 46 to 51% PCV. Muscle glycogen decreased from 152 to 48 mmoL/kg wet weight pre- to postrace. CONCLUSION: These data demonstrate the unique physiological demands of the Ironman World Championship and should be considered by athletes and coaches to prepare sufficient nutritional and hydration plans. PMID- 21266742 TI - The glyoxalase system as an example of a cellular maintenance pathway with relevance to aging. PMID- 21266743 TI - Manipulating ovarian aging: a new frontier in fertility preservation. PMID- 21266744 TI - p53 governs telomere regulation feedback too, via TRF2. AB - p53 takes critical part in a number of positive and negative feedback loops to regulate carcinogenesis, aging and other biological processes. Uncapped or dysfunctional telomeres are an endogenous DNA damage that activates ATM kinase (ataxia telangiectasia mutated) and then p53 to induce cellular senescence or apoptosis. Our recent study shows that p53, a downstream effector of the telomere damage signaling, also functions upstream of the telomere-capping protein complex by inhibiting one of its components, TRF2 (telomeric repeat binding factor 2). Since TRF2 inhibition leads to ATM activation, a novel positive feedback loop exists to amplify uncapped telomere-induced, p53-mediated cellular responses. Siah1 (seven in absentia homolog 1), a p53-inducible E3 ubiquitin ligase, plays a key role in this feedback regulation by targeting TRF2 for ubiquitination and proteasomal degradation. Biological significance and therapeutic implications of this study are discussed. PMID- 21266746 TI - Nanosecond pulse electrical fields used in conjunction with multi-wall carbon nanotubes as a potential tumor treatment. AB - The objectives of this communication were to fabricate pure samples of multi walled carbon nanotubes (MWCNTs) and to determine their toxicity in tumor cell lines. MWCNTs were dispersed in a concentration of the surfactant T80 that was minimally toxic. Cell-type variation in toxicity to MWCNTs was observed but was not significantly different to unexposed controls. Additionally, we investigated the increased cell killing of the pancreatic cancer cell line PANC1 when exposed to ultrashort (nanosecond) pulsed electrical fields (nsPEF) in the presence of MWCNTs as a potential form of cancer therapy. We hypothesized that the unique electronic properties of MWCNTs disrupt cell function, leading to cell death, when cells are exposed to nsPEF. We observed a 2.3-fold reduction in cell survival in cells pulsed in the presence of MWCNTs compared to pulsed controls. This study demonstrates that ultrashort pulse electrical field applications have enhanced killing effects when cells are previously grown in the presence of MWCNTs, suggesting that the electrical properties of MWCNTs play a vital role in this process and is suggestive of a synergistic interaction between these nanomaterials and electrical fields. PMID- 21266745 TI - Biomechanical properties of Achilles tendon repair augmented with a bioadhesive coated scaffold. AB - The Achilles tendon is the most frequently ruptured tendon. Both acute and chronic (neglected) tendon ruptures can dramatically affect a patient's quality of life, and require a prolonged period of recovery before return to pre-injury activity levels. This paper describes the use of an adhesive-coated biologic scaffold to augment primary suture repair of transected Achilles tendons. The adhesive portion consisted of a synthetic mimic of mussel adhesive proteins that can adhere to various surfaces in a wet environment, including biologic tissues. When combined with biologic scaffolds such as bovine pericardium or porcine dermal tissues, these adhesive constructs demonstrated lap shear adhesive strengths significantly greater than that of fibrin glue, while reaching up to 60% of the strength of a cyanoacrylate-based adhesive. These adhesive constructs were wrapped around transected cadaveric porcine Achilles tendons repaired with a combination of parallel and three-loop suture patterns. Tensile mechanical testing of the augmented repairs exhibited significantly higher stiffness (22 34%), failure load (24-44%), and energy to failure (27-63%) when compared to control tendons with suture repair alone. Potential clinical implications of this novel adhesive biomaterial are discussed. PMID- 21266747 TI - Influence of menstruation on the microbiota of healthy women's labia minora as analyzed using a 16S rRNA gene-based clone library method. AB - The aim of this study was to determine the influence of menstruation on the bacterial population of healthy Japanese women's vulvas, especially the labia minora. Labia minora swabs were obtained from 10 premenopausal, nonpregnant Japanese women at premenstruation and on day 2 of menstruation. Vaginal swabs were also obtained from 3 out of the 10 women. No significant difference was found in the average bacterial cell count between the menstruation and premenstruation samples. Molecular analysis using a 16S rRNA gene-based clone library method detected 22 genera from the labia minora swabs (total 20), with the genus Lactobacillus being predominant at both premenstruation and during menstruation in 7 out of the 10 women. Of the other 3 women, 2 showed various kinds of bacterial species, including oral and fecal bacteria, with Atopobium vaginae and Gardnerella vaginalis predominating in the remaining woman's vulva in both conditions. In total, 6 out of 10 cases (60%) showed significantly different microbiota of the labia minora between the two conditions. These results imply that menstruation may promote a distortion of the bacterial flora around the vulva, although it causes no significant increase of the bacterial count. PMID- 21266748 TI - A personal recollection of smallpox eradication with the benefit of hindsight: in commemoration of 30th anniversary. AB - This year 2010 marks the 30th anniversary of smallpox eradication, as declared by the WHO Assembly in 1980. As someone who worked for this program for many years, I would like to present my recollection of how it succeeded and what lessons can be learnt, with the added benefit of hindsight. The program achieved the global unification of mankind despite differences in race, nationality, religion, and politics, and research contributed significantly to building the effective strategy that ultimately led to success. These lessons should be useful in a designing a planning solution for many of the problems we face in today's changing world, including problems regarding health security and even those in current and future socioeconomic regions. PMID- 21266749 TI - Phenotypic and genotypic characterization of Vibrio cholerae clinically isolated in Surabaya, Indonesia. AB - The phenotypic and genotypic characteristics of 6 clinical strains of Vibrio cholerae isolated in Surabaya, Indonesia in 2009 were examined. The DNA fingerprints obtained suggested that these isolates were not from a single clone. Furthermore, all isolates produced cholera toxin and possessed the classical type of toxin B subunit gene, thus meaning that this is the first report of the occurrence of El Tor variants of V. cholerae in Indonesia. Although all isolates were sensitive to almost all antibiotics tested, including ampicillin, chloramphenicol, ciprofloxacin, gentamicin, levofloxacin, kanamycin, nalidixic acid, norfloxacin, streptomycin, trimethoprim-sulfamethoxazole, and tetracycline, and had no mutation in the gyrA and parC genes, they nevertheless possessed the class 1 integron that is a molecular vehicle for the acquisition of antibiotic resistance genes, suggesting that they have the potential to acquire the genetic element for drug resistance. PMID- 21266750 TI - An enterovirus 71 epidemic in Guangdong Province of China, 2008: epidemiological, clinical, and virogenic manifestations. AB - Enterovirus 71 (EV71) is shown to be a major causative agent in outbreaks of hand, foot, and mouth disease (HFMD) reported in Guangdong (GD) Province of China in 2008. A total of 48,876 HFMD cases (131 severe and 21 fatal) were reported to the GD HFMD web-based surveillance system, which covers 871 clinics. The main causes of death included central nervous system damage, heart failure, and pulmonary edema. The incidence rate was 52 per 100,000, and the epidemic peak appeared in May and June. EV71 was found in 59% and coxsackievirus A16 in 26% of 936 laboratory-confirmed cases. Other viruses are likely to be responsible for the remaining 15% of cases. Of the 185 EV71 cases collected, 62% were mild, 27% were severe, and the remaining 11% were fatal. A total of 17 EV71 isolates were subjected to nucleotide sequencing of the entire VP1 gene. Phylogenetic analysis showed that the GD EV71 strains belonged to the C4 subgenotype and that EV71 circulates at a national rather than a regional level. A Comparison with the VP1 gene from a different clinical case showed that there was no obvious virulence determinant in this locus. Furthermore, this study found that most deaths occurred in rural areas, thereby indicating that delayed diagnosis and incorrect treatment may play an important role. PMID- 21266751 TI - Evaluation of a cytolethal distending toxin (cdt) gene-based species-specific multiplex PCR assay for the identification of Campylobacter strains isolated from diarrheal patients in Japan. AB - We have developed a cytolethal distending toxin (cdt) gene-based species-specific multiplex PCR assay for the detection and identification of Campylobacter jejuni, C. coli, and C. fetus. The applicability of this assay was evaluated with 325 Campylobacter strains isolated from diarrheal patients in Japan and the results were compared with those obtained by other genetic methods, including hipO gene detection and 16S rRNA gene sequencing. Of the 325 strains analyzed, 314 and 11 were identified as C. jejuni and C. coli, respectively, by combination of hipO gene detection and 16S rRNA gene sequencing. When the multiplex PCR assay was employed, 309, 310, and 314 strains were identified as C. jejuni on the basis of cdtA, cdtB, and cdtC gene-specific primers, respectively. Similarly, 11, 11, and 10 strains were identified as C. coli on the basis of cdtA, cdtB, and cdtC gene specific primers, respectively. Sequence analysis of the cdt gene region of 6 strains (5 C. jejuni and 1 C. coli) which did not yield specific PCR products in any of the cdt gene-based multiplex PCR assays revealed deletions or mutations of the cdt genes. Pulsed-field gel electrophoresis indicated that C. jejuni and C. coli strains were genetically diverse. Taken together, these findings suggest that the cdtC gene-based multiplex PCR seems to be a particularly simple and rapid method for differentiating between species of Campylobacter strains, such as C. jejuni and C. coli. However, combination of these multiplex PCR assays will allow more accurate identification. PMID- 21266752 TI - Characterization of SCCmec types and antibacterial susceptibility patterns of methicillin-resistant Staphylococcus aureus in Southern Iran. AB - A total of 156 methicillin-resistant Staphylococcus aureus (MRSA) isolates from patients hospitalized in southern Iran were tested for staphylococcal cassette chromosome mec (SCCmec) types and antibacterial susceptibility patterns between May 2008 and May 2009. Type III SCCmec was the most prevalent (116, 74.3%), followed by mec types A (147 bp only; 11, 7.1%), IVa (8, 5.1%), IVc (7, 4.5%), IVd and V (4, 2.6%), and II (1, 0.6%). Class A mec and type III ccr and mec complexes were also predominant. All isolates were found to be sensitive to vancomycin, teicoplanin, linezolid, quinupristin-dalfopristin, mupirocin, and fusidic acid. However, reduced sensitivity of these MRSA isolates to other antibiotics, including rifampin, co-trimoxazole, clindamycin, cephalexin, tetracycline, ciprofloxacin, erythromycin, and gentamicin, was also observed. The predomination of type III SCCmec could be due to the antibiotic pressure which facilitated its clonal selection and dissemination. The present findings are indicative of the existence of community-acquired types (IV, V) in the hospitals studied, therefore comprehensive and periodic control measures and rational prescription of appropriate antibiotics are highly recommended to reduce antibiotic resistance. PMID- 21266753 TI - Oral and cervical human papillomavirus infection among female sex workers in Japan. AB - It has been reported recently that oral human papillomavirus (HPV) infection is associated with oropharyngeal squamous cell carcinomas. The aim of this study was to determine the prevalence of HPV infection and HPV types in the oral cavity and cervix of female sex workers in Japan. Oral and cervical swabs were taken from 196 female sex workers who visited a clinic for regular medical checkups in 2007, and genomic DNA was extracted from those specimens. The HPV L1 gene was amplified by polymerase chain reaction (PCR) using original and modified GP5(+)/6(+) primers, and genotyping was performed using the Kurabo GeneSquare Microarray or by sequencing cloned PCR products. HPV DNA was detected in the oral cavity of 12 (6.1%) women, with HPV-56 being the most common type (7/12). Likewise, HPV DNA was detected in the cervix of 103 (52.6%) women, with HPV-52 (30/103, 29.1%), followed by HPV-16 (24.3%) and HPV-56 (18.4%), being the most common. Of the 12 women with oral HPV infection, only two were infected with the concordant HPV genotype in the cervix. These findings suggest that oral HPV infection occurs independently of cervical HPV infection in this population, and that oral HPV infection may play a role in HPV transmission in Japan. PMID- 21266754 TI - Passive immune-prophylaxis against influenza virus infection by the expression of neutralizing anti-hemagglutinin monoclonal antibodies from plasmids. AB - The genetic delivery of therapeutic monoclonal antibodies (mAbs) by in vivo production may offer a new solution to the current problems in the mAb therapy for microbial diseases. Herein, plasmids encoding the neutralizing mAb against hemagglutinin (HA) of A/PR/8/34 influenza virus (IFV) were electro-transferred into mouse muscle and the relationship between serum recombinant anti-HA mAb (rHA mAb) levels and the prophylactic efficacy against lethal IFV infection were analyzed. Pretreatment of the muscle with hyaluronidase before electroporation and gene transfer into 3 muscles resulted in a marked enhancement of the mAb expression. After single gene transfer, peak serum concentrations were reached around 20 days after the gene transfer following sustained expression of >10 ug/ml of rHA mAbs. This level of rHA mAb expression was sufficient to protect all mice against a lethal IFV infection. Furthermore, a significant rHA mAb expression level sufficient to protect the host against lethal IFV infection was maintained for at least 130 days. Passive immune-prophylaxis with gene transfer using the plasmid encoding neutralizing mAbs may therefore provide effective protection against viral infections, including IFV. PMID- 21266755 TI - Experimental transmission of bovine spongiform encephalopathy (BSE) to cynomolgus macaques, a non-human primate. AB - Bovine spongiform encephalopathy (BSE) was transmitted to three macaques by intracerebral inoculation of a brain homogenate from affected cattle detected in Japan. All monkeys developed abnormal behavioral signs, such as intermittent anorexia and hyperekplexia, around 24 months after inoculation. Neuronal symptoms, such as tremor, myoclonic jerking, and paralysis, appeared 27-44 months after inoculation. These symptoms worsened and total paralysis ensued within a year after onset. The disease duration was approximately 8-12 months. Both the incubation period and the duration of disease were shortened in the secondary transmission experiment to macaques. Heavy accumulation of disease-causing conformer(s) of prion protein (PrP(Sc)), with a similar glycoform profile to the PrP(Sc) contained in the inoculum, and severe spongiform changes in the histology of the brain, confirmed the successful transmission of BSE to monkeys. Florid plaques, a characteristic histological hallmark of variant Creutzfeldt-Jakob disease, were prominent in the cerebral cortex, in which a prion antigen was detected by immunohistochemistry (IHC). PrP(Sc) was mostly confined to the central nervous system, although small amounts of PrP(Sc) accumulated in the peripheral nerves of monkeys, as detected by Western blotting (WB). Neither IHC nor WB detected PrP(Sc) in the lymphatic organs/tissues, such as the tonsils, spleen, and appendix. PMID- 21266756 TI - Prevalence of plasmid-mediated quinolone resistance in Escherichia coli isolates in Wenzhou, Southern China, 2002-2008. AB - A total of 514 consecutive clinical Escherichia coli isolates, irrespective of resistance background, were collected in the period 2002-2008 in Wenzhou, southern China, to investigate the prevalence of plasmid-mediated quinolone resistance (PMQR). The dominant PMQR gene was aac(6')-Ib-cr, followed by qnr, whereas qepA was absent. A total of 253 (49.2%) of these isolates were aac(6')-Ib positive. Subsequently, 134 of these isolates were sequenced and 42 (31.3%) found to harbor aac(6')-Ib-cr, 18 to harbor new aac(6')-Ib mutants, and 74 to harbor wild-type aac(6')-Ib. The genes qnrA, qnrB, and qnrS were found in 2 (0.4%), 6 (1.2%), and 14 (2.7%) of 514 isolates, respectively, with 2 isolates co-harboring qnrB and qnrS genes. Sequencing allowed us to identify qnrA1, qnrB4, qnrB6, and qnrS1 in 20 qnr-positive isolates, with qnrS1 being the most prevalent allele. The genes qnrC and qnrD were not found in any isolates. Interestingly, 35% of qnr positive isolates and 16.7% of aac(6')-Ib-cr-positive isolates were susceptible to ciprofloxacin. PMQR genes are therefore present in both quinolone-resistant and -susceptible isolates and can also be transferred by conjugation experiments, thus suggesting a likely future increase in quinolone resistance. PMID- 21266757 TI - Fatal necrotizing pneumonia caused by Panton-Valentine leukocidin-producing hospital-acquired Staphylococcus aureus: a case report. AB - Panton-Valentine leukocidin (PVL) is a cytotoxin which causes leukocyte destruction and tissue necrosis. Although it is produced by fewer than 5% of Staphylococcus aureus strains, PVL-producing S. aureus is emerging as a serious problem worldwide. There has been a marked increase in the incidence of necrotizing lung infections with a very high mortality associated with these strains. This report describes a fatal case of hospital-acquired necrotizing pneumonia caused by PVL-positive methicillin-susceptible S. aureus in a patient with a brain tumor. PMID- 21266758 TI - A case of sepsis and meningitis caused by probable travel-related Neisseria meningitidis serogroup B infection: the first report of N. meningitidis ST-4893 in Japan. AB - Herein we present a case of Neisseria meningitidis-related sepsis and meningitis in a 60-year-old woman. The N. meningitidis strain was identified as serogroup B and sequence type (ST)-4893 by multilocus sequence typing (MLST). The patient in this case had visited France prior to development of symptoms. No meningococcal isolate belonging to ST-4893 has been identified in Japan previously, whereas an ST-4893 strain from France has been reported in the MLST database. These results strongly suggest that this case is likely to have been imported from France. PMID- 21266759 TI - Application of a multilocus variable number of tandem repeats analysis to regional outbreak surveillance of Enterohemorrhagic Escherichia coli O157:H7 infections. AB - A total of 18 strains of EHEC O157:H7 were isolated from distinct cases in Akita Prefecture, Japan from July to September 2007. The genetic relatedness of these isolates was investigated by performing a multilocus variable number of tandem repeats analysis (MLVA) and a pulsed-field gel electrophoresis (PFGE) analysis using XbaI. The PFGE analyses allowed us to group these 18 isolates into three major clusters. The MLVA results correlated closely with those obtained by PFGE, although some variants were found within the clusters obtained by PFGE, thus highlighting the utility of this technique for determining a precise classification when it is difficult to differentiate between isolates with indistinguishable or very similar PFGE patterns. In addition, MLVA is a much easier and more rapid method than PFGE for analysis of the genetic relatedness of strains. Thus, as a second molecular epidemiological subtyping method, MLVA is useful for the regional outbreak surveillance of EHEC O157:H7 infections. PMID- 21266760 TI - Biotyping, capsular typing, and antibiotic resistance pattern of Haemophilus influenzae strains in Iran. AB - The aim of this study was to determine the capsular types of Haemophilus influenzae isolated from clinical specimens by slide agglutination serotyping (SAST) and PCR capsule typing methods. All the isolates were biotyped and their antibiotic resistance patterns also determined. Thirteen isolates of serotype b, 2 of serotype e, 4 of serotype f, and 19 nontypeable (NT) isolates were identified by SAST method in 38 H. influenzae culture-positive samples. Capsule typing by PCR increased the proportion of all invasive cases from 34.2% (by SAST) to 60.5%, and 6 culture-negative samples were identified as invasive H. influenzae (Hib) by this method. The discrepancy rate between SAST and PCR results were 41%. Biotypes I, II, and III were the prevalent biotypes whereas biotypes VI and VII were not found. The majority of capsule type b belonged to biotype II. The isolates were resistant to cotrimoxazole (47.1%) and ampicillin (43.6%). Multidrug resistance was observed in 7 of the isolates. PMID- 21266761 TI - High prevalence of metallo-beta-lactamase-producing acinetobacter baumannii in a teaching hospital in Tabriz, Iran. AB - Metallo-beta-lactamase (MBL)-producing Acinetobacter baumannii has become a growing therapeutic concern worldwide. The aims of this study were to evaluate the antimicrobial susceptibility of A. baumannii isolates and to determine the prevalence of MBL genes among carbapenem non-susceptible isolates. During a period of 16 months (March 2008-June 2009), 100 isolates of A. baumannii were collected from different clinical specimens of inpatients admitted to the largest teaching hospital in the northwest of Iran. All isolates were tested for antimicrobial susceptibility by Kirby-Bauer disk diffusion method. Carbapenem non susceptible isolates were further screened for production of MBL by Etest and were then subjected to PCR for detection of MBL genes of types bla(IMP) and bla(VIM). Among 63 carbapenem (imipenem and meropenem) non-susceptible isolates of A. baumannii, 31 (49%) were found to be MBL producers. Of 31 MBL-producing isolates, 19 (61%) carried the bla(IMP) gene and 9 (29%) carried the bla(VIM) gene. All MBL-producing isolates were multidrug resistant. This is the first report of IMP and VIM types among MBL-producing A. baumannii in Iran. PMID- 21266762 TI - Serological evidence of Thailand virus-related hantavirus infection among suspected leptospirosis patients in Kandy, Sri Lanka. AB - A cross-sectional study was undertaken to determine the current prevalence of leptospirosis and hantaviral infections, and the socio-demographic characteristics and risk factors of infected patients, in Kandy, Sri Lanka. This report discusses the serological evidence of hantavirus infections among 105 suspected leptospirosis patients, 8 of whom had hantavirus antibodies. Serotyping ELISA showed that these 8 patients had high optical density values for Thailand virus. Most of the sera showed that the focus reduction neutralization test titer against Thailand virus was higher than that against Seoul virus, thereby suggesting that the hantaviral antibodies found in Sri Lanka are different from Seoul virus but closely related to Thailand virus. These findings imply that the hantaviral infection found in Kandy, Sri Lanka appears to be due to a virus similar to Thailand virus. Epidemiological analysis revealed that the association between hantavirus infection and socio-demographic characteristics was not statistically significant. PMID- 21266764 TI - Detection of human metapneumovirus genomes during an outbreak of bronchitis and pneumonia in a geriatric care home in Shimane, Japan, in autumn 2009. PMID- 21266763 TI - Atypical L-type bovine spongiform encephalopathy (L-BSE) transmission to cynomolgus macaques, a non-human primate. AB - A low molecular weight type of atypical bovine spongiform encephalopathy (L-BSE) was transmitted to two cynomolgus macaques by intracerebral inoculation of a brain homogenate of cattle with atypical BSE detected in Japan. They developed neurological signs and symptoms at 19 or 20 months post-inoculation and were euthanized 6 months after the onset of total paralysis. Both the incubation period and duration of the disease were shorter than those for experimental transmission of classical BSE (C-BSE) into macaques. Although the clinical manifestations, such as tremor, myoclonic jerking, and paralysis, were similar to those induced upon C-BSE transmission, no premonitory symptoms, such as hyperekplexia and depression, were evident. Most of the abnormal prion protein (PrP(Sc)) was confined to the tissues of the central nervous system, as determined by immunohistochemistry and Western blotting. The PrP(Sc) glycoform that accumulated in the monkey brain showed a similar profile to that of L-BSE and consistent with that in the cattle brain used as the inoculant. PrP(Sc) staining in the cerebral cortex showed a diffuse synaptic pattern by immunohistochemistry, whereas it accumulated as fine and coarse granules and/or small plaques in the cerebellar cortex and brain stem. Severe spongiosis spread widely in the cerebral cortex, whereas florid plaques, a hallmark of variant Creutzfeldt-Jakob disease in humans, were observed in macaques inoculated with C BSE but not in those inoculated with L-BSE. PMID- 21266765 TI - Detection of various respiratory viruses in patients with influenza-like illness before and after emergence of the 2009 pandemic H1N1 influenza virus in Okinawa. PMID- 21266766 TI - Virus-related lower respiratory inflammation: detection of human metapneumovirus from severe pneumonia cases with A/H1N1pdm virus. PMID- 21266767 TI - A new method for monitoring and forecasting the case-fatality rate in ongoing epidemics and its evaluation using published data of SARS in 2003, H1N1 pandemic in 2009/2010, hand-foot-mouth disease in China in 2009/2010, and cholera in Haiti in 2010. PMID- 21266768 TI - Nuclear receptors take center stage in Th17 cell-mediated autoimmunity. AB - Liver X receptors (LXRs) are nuclear receptors involved in cholesterol homeostasis. Notably, they are also expressed by T cells and are involved in regulating T cell proliferation and differentiation. In this issue of the JCI, Cui et al. have elucidated the molecular mechanism underlying the effects of LXR activation on a subset of T cells known as Th17 cells in mice and humans. Specifically, they showed that LXR-induced Srebp-1 inhibits Il17 transcription by binding to the Il17 promoter through interaction with the aryl hydrocarbon receptor (Ahr), a transcription factor known to enhance Th17 cell responses. PMID- 21266769 TI - The cautionary tale of side effects of chronic Notch1 inhibition. AB - Aberrant Notch1 signaling is implicated in several types of cancer. Therefore, Notch signaling pathways are important anticancer targets. Pan-Notch receptor inhibition is associated with numerous complications; thus, selective Notch receptor inhibition has been pursued. Studies have shown minimal side effects with short-term blockade of either Notch1 or its ligand Delta-like 4, but long term side effects were not investigated. In this issue of the JCI, Liu et al. use mouse models to demonstrate the consequence of long-term Notch1 inhibition. They present evidence that chronic Notch1 inhibition leads to vascular tumors in the liver and decreased survival, which suggests that Notch1 therapies should be reevaluated. PMID- 21266770 TI - Growing a tumor stroma: a role for granulin and the bone marrow. AB - The tumor stroma is critical in cancer progression; understanding its formation is therefore important biologically and therapeutically. In this issue of the JCI, Elkabets et al. report on the generation of data in mice that lead them to propose that certain tumors can stimulate the growth of a second otherwise quiescent or indolent tumor in the same animal by stimulating stromal formation. Granulin-expressing Sca+Kit- hematopoietic progenitor cells in the bone marrow of the tumor host were required to mediate this effect. These data shed new light on the importance of the bone marrow in tumor growth and the role of granulin in carcinogenesis. PMID- 21266771 TI - Navigational error in the heart leads to premature ventricular excitation. AB - In the normal heart, an insulating barrier separates the atria and ventricles. The only way in which electrical impulses can cross this barrier is via the atrioventricular (AV) node, which delays impulse conduction to ensure the forward flow of the blood. However, in some individuals, additional muscular bundles (accessory pathways) allow rapid conduction of electrical impulses from the atria to the ventricles, resulting in premature ventricular excitation and contraction. In this issue of the JCI, two independent research groups demonstrate that erroneous development of the embryonic AV canal, which performs a similar function to that of the adult AV node, is a novel mechanism by which accessory pathways can form. PMID- 21266772 TI - Thrombotic thrombocytopenic purpura: reducing the risk? AB - von Willebrand factor (vWF) has a key role in initiating platelet aggregation, and thereby thrombus formation, that is dependent on its ability to form appropriately sized multimers. Ultralarge multimers promote the formation of the microvascular thrombi that are hallmarks of the life-threatening condition thrombotic thrombocytopenic purpura (TTP). In this issue of the JCI, Chen et al. show that the drug N-acetylcysteine (NAC) can decrease the size of vWF multimers in vitro and in vivo, resolving thrombi in mice. These data suggest that NAC could potentially be used to treat thrombotic conditions such as TTP. PMID- 21266773 TI - The perplexing case of the geranylgeranyl transferase-deficient mouse. AB - Proteins that end with a CAAX sequence are targeted to cellular membranes by a series of posttranslational modifications that include prenylation, proteolysis, and carboxyl methylation. Two prenyltransferases modify CAAX proteins: farnesyltransferase and geranylgeranyltransferase type I (GGTase-I). Rho family GTPases that control the actin cytoskeleton and are therefore critical to inflammatory cell function are substrates for GGTase-I. In this issue of the JCI, Khan et al. examined mice in which GGTase-I was conditionally deleted in macrophages. Rather than obtunded cells, the authors found activated Rho proteins in fully functional macrophages that hypersecreted inflammatory cytokines and induced an erosive, inflammatory arthritis. This surprising result calls into question the role of protein geranylgeranylation in inflammatory cell signaling. PMID- 21266774 TI - Notch1 loss of heterozygosity causes vascular tumors and lethal hemorrhage in mice. AB - The role of the Notch signaling pathway in tumor development is complex, with Notch1 functioning either as an oncogene or as a tumor suppressor in a context dependent manner. To further define the role of Notch1 in tumor development, we systematically surveyed for tumor suppressor activity of Notch1 in vivo. We combined the previously described Notch1 intramembrane proteolysis-Cre (Nip1::Cre) allele with a floxed Notch1 allele to create a mouse model for sporadic, low-frequency loss of Notch1 heterozygosity. Through this approach, we determined the cell types most affected by Notch1 loss. We report that the loss of Notch1 caused widespread vascular tumors and organism lethality secondary to massive hemorrhage. These findings reflected a cell-autonomous role for Notch1 in suppressing neoplasia in the vascular system and provide a model by which to explore the mechanism of neoplastic transformation of endothelial cells. Importantly, these results raise concerns regarding the safety of chronic application of drugs targeting the Notch pathway, specifically those targeting Notch1, because of mechanism-based toxicity in the endothelium. Our strategy also can be broadly applied to induce sporadic in vivo loss of heterozygosity of any conditional alleles in progenitors that experience Notch1 activation. PMID- 21266775 TI - Defective Tbx2-dependent patterning of the atrioventricular canal myocardium causes accessory pathway formation in mice. AB - Ventricular preexcitation, a feature of Wolff-Parkinson-White syndrome, is caused by accessory myocardial pathways that bypass the annulus fibrosus. This condition increases the risk of atrioventricular tachycardia and, in the presence of atrial fibrillation, sudden death. The developmental mechanisms underlying accessory pathway formation are poorly understood but are thought to primarily involve malformation of the annulus fibrosus. Before birth, slowly conducting atrioventricular myocardium causes a functional atrioventricular activation delay in the absence of the annulus fibrosus. This myocardium remains present after birth, suggesting that the disturbed development of the atrioventricular canal myocardium may mediate the formation of rapidly conducting accessory pathways. Here we show that myocardium-specific inactivation of T-box 2 (Tbx2), a transcription factor essential for atrioventricular canal patterning, leads to the formation of fast-conducting accessory pathways, malformation of the annulus fibrosus, and ventricular preexcitation in mice. The accessory pathways ectopically express proteins required for fast conduction (connexin-40 [Cx40], Cx43, and sodium channel, voltage-gated, type V, alpha [Scn5a]). Additional inactivation of Cx30.2, a subunit for gap junctions with low conductance expressed in the atrioventricular canal and unaffected by the loss of Tbx2, did not affect the functionality of the accessory pathways. Our results suggest that malformation of the annulus fibrosus and preexcitation arise from the disturbed development of the atrioventricular myocardium. PMID- 21266776 TI - Liver X receptor (LXR) mediates negative regulation of mouse and human Th17 differentiation. AB - Th17 cells are a subset of CD4+ T cells with an important role in clearing certain bacterial and fungal pathogens. However, they have also been implicated in autoimmune diseases such as multiple sclerosis. Exposure of naive CD4+ T cells to IL-6 and TGF-beta leads to Th17 cell differentiation through a process in which many proteins have been implicated. We report here that ectopic expression of liver X receptor (LXR) inhibits Th17 polarization of mouse CD4+ T cells, while LXR deficiency promotes Th17 differentiation in vitro. LXR activation in mice ameliorated disease in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis, whereas LXR deficiency exacerbated disease. Further analysis revealed that Srebp-1, which is encoded by an LXR target gene, mediated the suppression of Th17 differentiation by binding to the E-box element on the Il17 promoter, physically interacting with aryl hydrocarbon receptor (Ahr) and inhibiting Ahr-controlled Il17 transcription. The putative active site (PAS) domain of Ahr and the N-terminal acidic region of Srebp-1 were essential for this interaction. Additional analyses suggested that similar LXR-dependent mechanisms were operational during human Th17 differentiation in vitro. This study reports what we believe to be a novel signaling pathway underlying LXR-mediated regulation of Th17 cell differentiation and autoimmunity. PMID- 21266777 TI - N-acetylcysteine reduces the size and activity of von Willebrand factor in human plasma and mice. AB - Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease characterized by systemic microvascular thrombosis caused by adhesion of platelets to ultra-large vWF (ULVWF) multimers. These multimers accumulate because of a deficiency of the processing enzyme ADAMTS13. vWF protein forms long multimers from homodimers that first form through C-terminal disulfide bonds and then join through their N termini by further disulfide bonding. N-acetylcysteine (NAC) is an FDA-approved drug that has long been used to treat chronic obstructive lung disease and acetaminophen toxicity and is known to function in the former disorder by reducing mucin multimers. Here, we examined whether NAC could reduce vWF multimers, which polymerize in a manner similar to mucins. In vitro, NAC reduced soluble plasma-type vWF multimers in a concentration-dependent manner and rapidly degraded ULVWF multimer strings extruded from activated ECs. The effect was preceded by reduction of the intrachain disulfide bond encompassing the platelet-binding A1 domain. NAC also inhibited vWF-dependent platelet aggregation and collagen binding. Injection of NAC into ADAMTS13 deficient mice led to the rapid resolution of thrombi produced by ionophore treatment of the mesenteric venules and reduced plasma vWF multimers. These results suggest that NAC may be a rapid and effective treatment for patients with TTP. PMID- 21266778 TI - Notch signaling regulates murine atrioventricular conduction and the formation of accessory pathways. AB - Ventricular preexcitation, which characterizes Wolff-Parkinson-White syndrome, is caused by the presence of accessory pathways that can rapidly conduct electrical impulses from atria to ventricles, without the intrinsic delay characteristic of the atrioventricular (AV) node. Preexcitation is associated with an increased risk of tachyarrhythmia, palpitations, syncope, and sudden death. Although the pathology and electrophysiology of preexcitation syndromes are well characterized, the developmental mechanisms are poorly understood, and few animal models that faithfully recapitulate the human disorder have been described. Here we show that activation of Notch signaling in the developing myocardium of mice can produce fully penetrant accessory pathways and ventricular preexcitation. Conversely, inhibition of Notch signaling in the developing myocardium resulted in a hypoplastic AV node, with specific loss of slow-conducting cells expressing connexin-30.2 (Cx30.2) and a resulting loss of physiologic AV conduction delay. Taken together, our results suggest that Notch regulates the functional maturation of AV canal embryonic myocardium during the development of the specialized conduction system. Our results also show that ventricular preexcitation can arise from inappropriate patterning of the AV canal-derived myocardium. PMID- 21266781 TI - Identification of the catalytic residues of carboxylesterase from Arthrobacter globiformis by diisopropyl fluorophosphate-labeling and site-directed mutagenesis. AB - The role of amino acid residues in the enzymatic activity of carboxylesterase from Arthrobacter globiformis was analyzed by diisopropyl fluorophosphate (DFP) labeling and site-directed mutagenesis. The electrospray ionization mass spectrometric (ESI-MS) analysis of the esterase, covalently labeled by DFP, showed stoichiometric incorporation of the inhibitor into the enzyme. The further comparison of endopeptidase-digested fragments between native and DFP-labeled esterase by fast atom bombardment mass spectrometric (FAB-MS) analysis as well as site-directed mutagenesis indicated that Ser59 in the consensus sequence Ser-X-X Lys, which is conserved exclusively in penicillin-binding proteins and some esterases, served as a catalytic nucleophile. In addition, the results obtained from analysis of the mutants at position 62 suggested the importance of the basic amino acid side chain at this position, and suggested the significance of this residue acting directly as a general base rather than its involvement in the maintenance of the optimum hydrogen-bonding network at the active site. PMID- 21266779 TI - Human tumors instigate granulin-expressing hematopoietic cells that promote malignancy by activating stromal fibroblasts in mice. AB - Systemic instigation is a process by which endocrine signals sent from certain tumors (instigators) stimulate BM cells (BMCs), which are mobilized into the circulation and subsequently foster the growth of otherwise indolent carcinoma cells (responders) residing at distant anatomical sites. The identity of the BMCs and their specific contribution or contributions to responder tumor growth have been elusive. Here, we have demonstrated that Sca1+ cKit- hematopoietic BMCs of mouse hosts bearing instigating tumors promote the growth of responding tumors that form with a myofibroblast-rich, desmoplastic stroma. Such stroma is almost always observed in malignant human adenocarcinomas and is an indicator of poor prognosis. We then identified granulin (GRN) as the most upregulated gene in instigating Sca1+ cKit- BMCs relative to counterpart control cells. The GRN+ BMCs that were recruited to the responding tumors induced resident tissue fibroblasts to express genes that promoted malignant tumor progression; indeed, treatment with recombinant GRN alone was sufficient to promote desmoplastic responding tumor growth. Further, analysis of tumor tissues from a cohort of breast cancer patients revealed that high GRN expression correlated with the most aggressive triple-negative, basal-like tumor subtype and reduced patient survival. Our data suggest that GRN and the unique hematopoietic BMCs that produce it might serve as novel therapeutic targets. PMID- 21266780 TI - Geranylgeranyltransferase type I (GGTase-I) deficiency hyperactivates macrophages and induces erosive arthritis in mice. AB - RHO family proteins are important for the function of inflammatory cells. They are modified with a 20-carbon geranylgeranyl lipid in a process catalyzed by protein geranylgeranyltransferase type I (GGTase-I). Geranylgeranylation is viewed as essential for the membrane targeting and activity of RHO proteins. Consequently, inhibiting GGTase-I to interfere with RHO protein activity has been proposed as a strategy to treat inflammatory disorders. However, here we show that mice lacking GGTase-I in macrophages develop severe joint inflammation resembling erosive rheumatoid arthritis. The disease was initiated by the GGTase I-deficient macrophages and was transplantable and reversible in bone marrow transplantation experiments. The cells accumulated high levels of active GTP bound RAC1, CDC42, and RHOA, and RAC1 remained associated with the plasma membrane. Moreover, GGTase-I deficiency activated p38 and NF-kappaB and increased the production of proinflammatory cytokines. The results challenge the view that geranylgeranylation is essential for the activity and localization of RHO family proteins and suggest that reduced geranylgeranylation in macrophages can initiate erosive arthritis. PMID- 21266783 TI - Restrictive mitral annuloplasty for functional mitral regurgitation in patients with end-stage cardiomyopathy. PMID- 21266784 TI - Costarring statins with ARBs: going to be a smash hit? PMID- 21266785 TI - Short-term prognosis of adaptive servo-ventilation therapy in patients with heart failure. AB - BACKGROUND: This study tested the hypothesis that adaptive servo-ventilation (ASV) therapy improves the prognosis of heart failure (HF) patients, regardless of the severity of sleep-disordered breathing (SDB). METHODS AND RESULTS: 88 consecutive patients were divided into 4 groups based on ASV therapy and SDB severity. The incidence of HF, brain natriuretic peptide (BNP) levels, and left ventricular ejection fraction (LVEF) were followed for 12 months. Fewer HF events, together with an increase in LVEF and a decrease in BNP, occurred in ASV treated patients with both non-to-mild and moderate-to-severe SDB. CONCLUSIONS: ASV therapy improves the short-term prognosis in HF-patients, regardless SDB severity. PMID- 21266786 TI - Improvement of cardiac function by intracoronary freshly isolated bone marrow cells transplantation in patients with acute myocardial infarction. AB - BACKGROUND: We analyzed in the present study the influence of intracoronary autologous freshly isolated bone marrow cells transplantation (BMCs-Tx) on cardiac function in patients with acute myocardial infarction (AMI). METHODS AND RESULTS: The 32 patients with AMI were enrolled in this prospective nonrandomized study to either freshly isolated BMC-Tx or to a control group without cell therapy. Global left ventricular ejection fraction (LVEF) and the size of infarct area were determined by left ventriculography. We observed in patients with autologous freshly isolated BMCs-Tx at 6 months follow up a significant reduction of infarct size as compared to control group. Moreover, we found a significant increase of LVEF as well as infarct wall movement velocity at 6 months follow up in cell therapy group as compared to control group. In the control group there was no significant difference of LVEF, infarct size and infarct wall movement velocity between baseline and 6 months after AMI. CONCLUSIONS: These results demonstrate for the first time that intracoronary transplantation of autologous freshly isolated BMCs by use of a point of care system is safe, and may lead to improvement of cardiac function in patients with AMI. PMID- 21266787 TI - Early intervention with rosuvastatin decreases the lipid components of the plaque in acute coronary syndrome: analysis using integrated backscatter IVUS (ELAN study). AB - BACKGROUND: It has recently become possible to analyze coronary plaque characteristics by using integrated backscatter intravascular ultrasound (IB IVUS). The aim of this study was to use this modality to evaluate the impact of early intervention with rosuvastatin on both the volume and tissue characteristics of non-culprit plaques in acute coronary syndrome (ACS). METHODS AND RESULTS: Patients with ACS underwent IB-IVUS after percutaneous coronary intervention procedure and were administered rosuvastatin. Follow-up IB-IVUS was recorded 6 months later. We analyzed the changes in plaque burden and tissue characteristics in these patients. Plaque components were classified as calcified, fibrous, and lipid according IB-IVUS. We comprehensively analyzed 20 ACS patients. The low-density lipoprotein-cholesterol levels decreased significantly from 117 +/- 34 mg/dl to 73 +/- 19 mg/dl (P<0.001) after statin therapy. Comparing the baseline images with the follow-up ones revealed a significant reduction in the plaque burden from 98.4 +/- 42.1mm(3)/10mm to 80.2 +/- 35.8 mm(3)/10mm (P<0.001) and in the lipid volume from 44.1 +/- 29.6 mm(3)/10mm to 28.6 +/- 17.8 mm(3)/10mm (P<0.001). With respect to the % lipid volume, the reduction rate at follow-up showed a significant correlation with its baseline value (r=-0.498, P=0.024). CONCLUSIONS: Early intervention with rosuvastatin in ACS patients enabled significant reduction of the non-culprit plaque during 6 months. This regression was mainly due to the decrease in the lipid component of the plaque. PMID- 21266788 TI - Vascular smooth muscle cell proliferation is influenced by let-7d microRNA and its interaction with KRAS. AB - BACKGROUND: Several microRNAs (miRNAs) have been reported to regulate cardiovascular biological and pathological processes through inhibiting the translation of certain RNA transcripts. However, little is known about the association between miRNAs and vascular smooth muscle cell (VSMC) proliferation. The aim was to investigate the role of miRNAs in VSMC growth and the potential mechanism. METHODS AND RESULTS: Primary VSMCs were isolated from the medial layer of the thoracic aorta obtained from spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY). miRNA microarrays were used to analyze the difference in miRNA expression between VSMCs of SHR and WKY rats and were validated using TaqMan real-time PCR. Of the potentially related genes under the influence of let 7d identified through literature search, KRAS was verified by western blot and functionally analyzed using miRNA mimics transfection and analysis of transfectants by cell enumeration was made using CCK-8 and flow cytometric analysis of cell cycle progression. let-7d-transfected VSMCs from SHR, WKY and human coronary arteries expressed significantly lower amounts of KRAS protein, displayed reduced cell growth and led to a greater number of cells in the G1 phase than the G2/M phases of the cell cycle. CONCLUSIONS: let-7d was significantly downregulated in VSMCs as an important regulator of cell proliferation. RAS might be involved in the proliferation regulation by let-7d. PMID- 21266789 TI - Plant sterols increased IL-6 and TNF-alpha secretion from macrophages, but to a lesser extent than cholesterol. AB - AIM: Phytosterolemia is an inherited disorder characterized by hypercholesterolemia and premature atherosclerosis, together with increased inflammatory states in some cases. The underlying mechanisms of atherogenesis in phytosterolemia, however, have not been completely elucidated. In this study, we investigated whether phytosterols would affect inflammatory reactions in macrophages and macrophage cell lines. METHODS: We incubated RAW264.7 cells (RAW) and mouse peritoneal macrophages (MPMs) with sitosterol (Sito), campesterol (Camp) or cholesterol (Chol) at low (8 uM, 16 uM) or high (160 uM) concentrations, and investigated their effects on LPS-induced secretion of IL-6 and TNF-alpha. We also analyzed their effects on endoplasmic reticulum (ER) stress in both cells, and on the cell proliferation of RAW. RESULTS: At low sterol concentrations, only Chol resulted in a tendency toward the increased secretion of TNF-alpha from MPMs. At high concentrations, Chol induced a significant increase in TNF-alpha secretions from both cells; however, Sito resulted in a non-significant increase in TNF-alpha secretion. The effects on IL 6 secretions of Sito were also significantly less than those of Chol. Camp increased the secretions of both cytokines from MPMs; however, the extent of these increases was less pronounced than that of Chol. Augmentation of ER stress was greatest with Chol among the sterols, and the proliferation of RAW cells was inhibited only with Chol. CONCLUSION: The lesser degree of inflammatory reactions and toxicity in macrophages with phytosterols than with cholesterol suggests that plant sterols themselves might not be primarily responsible for atherogenesis in phytosterolemia. PMID- 21266790 TI - Identification of three factors influencing trail making test performance using multichannel near-infrared spectroscopy. AB - Recent advances in medical care have facilitated the survival of patients with stroke or traffic-related injuries. However, such patients may suffer from higher brain dysfunction; i.e., an impaired ability to plan and perform behaviors based on prior knowledge. The Trail Making Test (TMT) is a cognitive task that is used to evaluate higher brain dysfunction caused by frontal lobe injury. TMT consists of two tasks; TMT-A involves connecting consecutive numbers, and TMT-B involves connecting numbers and letters alternately. In this study, using near-infrared spectroscopy (NIRS) and the achievement value (TMT score), we investigated the effects of three factors on TMT performance: knowledge of the TMT, the order of TMT-A and TMT-B performance, and gender. The subjects were 48 healthy adults, consisting of college graduates and undergraduates (age: 22.8 +/- 2.5 years, education: 16.0 +/- 1.2 years, 24 males and 24 females). We measured the changes in oxygenated hemoglobin (oxy-Hb) levels using NIRS, showing that the increase in oxy-Hb was higher in subjects who had no knowledge of the TMT than those who had prior knowledge. In both TMT-A and TMT-B, the subjects who performed their first task displayed higher oxy-Hb levels. Moreover, the oxy-Hb level in males was higher than that in females. In contrast, only the order of TMT performance showed noticeable effect on the TMT score. In the present study, using NIRS we have shown that either knowledge of the TMT, the order of the TMT, or gender affects TMT performance, providing invaluable information for interpreting TMT results. PMID- 21266791 TI - Trophoblast apoptosis in placentas from pregnancies complicated by preeclampsia. AB - AIMS: To assess trophoblast apoptosis separately in the cytotrophoblast, syncytiotrophoblast, total villous trophoblast, syncytial knots and syncytial knot formation, and to investigate the expression of apoptotic factors Fas ligand (FasL), Bcl-2 and proliferation marker Ki-67 in the trophoblast of placentas from preeclamptic patients. METHODS: The study included placental samples from 25 preeclamptic and 25 normal pregnancies. For the detection of apoptosis and proliferation, antibody M30 and antibody against Ki-67 antigen were used. Expression of FasL and Bcl-2 was assessed using semi-quantitative HSCORE method. Syncytial knots were expressed as the number of syncytial knots per individual villus and as the total number of syncytial knots in each placental sample. RESULTS: Trophoblast apoptosis, number of syncytial knots per individual villus and the total number of syncytial knots in each placental sample were significantly higher in preeclamptic placentas than in control group placentas. FasL expression was significantly less, and Bcl-2 expression significantly greater in the villus trophoblast among the study subjects compared with controls. There was no difference in the trophoblast proliferation between groups. CONCLUSION: Our findings might suggest that increased apoptosis and syncytial knot formation combined with reduced FasL expression could be involved in pathophysiological mechanisms of preeclampsia. PMID- 21266792 TI - Comparison of the efficacy of three progestins in the treatment of simple endometrial hyperplasia without atypia. AB - AIM: To evaluate the treatment of endometrial hyperplasia (EH) with different progestins. METHODS: Eighty-two women with simple EH without atypia were included. Patients were offered oral progestagens and were randomized to one of three options for 3 months: medroxyprogesterone acetate (MPA, 10 mg/day), lynestrenol (LYN, 15 mg/day) and norethisterone (NET, 15 mg/day) for 10 days per cycle. Patients were reevaluated after treatment. Women diagnosed with proliferative and nonatypical EH at the second curettage were offered the same progestins for another 3 months. The primary outcome of the study was the proportion of women requiring further treatment. RESULTS: Of the 82 women, 46 (56.1%) received MPA (23.2%), LYN (13.4%) and NET (19.5%) therapy for another 3 months at the end of the first 3 months of treatment. The patients receiving MPA showed resolution in 36.7% of the cases versus 37% in the NET group. The highest resolution rate (56%) was observed in the LYN group, although there was no statistically significant difference between progestins regarding the proportion of women requiring further treatment (chi(2) = 2.608; p = 0.271). CONCLUSION: It seems that the efficacies of oral progestins are similar at these dosages in simple EH without atypia. PMID- 21266793 TI - Maternal serum adiponectin at 11-13 weeks of gestation in preeclampsia. AB - OBJECTIVE: To determine whether the maternal serum levels of adiponectin in the first trimester of pregnancy are altered in cases that develop preeclampsia (PE) and whether the levels are related to pregnancy-associated plasma protein-A (PAPP A) and uterine artery pulsatility index (PI). METHODS: Serum adiponectin, PAPP-A and uterine artery PI were measured at 11-13 weeks in 90 cases that developed PE, including 30 that required delivery before 34 weeks (early PE) and 300 unaffected controls. The median adiponectin, PAPP-A and uterine artery PI multiple of the unaffected median (MoM) in the outcome groups were compared. RESULTS: In both early PE and late PE, compared to controls, uterine artery PI MoM was increased (1.32 and 1.05 vs. 1.02) and PAPP-A MoM was decreased (0.61 and 0.84 vs. 1.00), whereas adiponectin MoM was increased in early PE but not in late PE (1.32 and 1.05 vs. 1.02). In the PE group, there was no significant association between adiponectin and PAPP-A or uterine artery PI. Serum adiponectin did not improve the performance of screening for PE provided by a combination of the maternal factors, uterine artery PI and serum PAPP-A. CONCLUSION: Serum adiponectin levels at 11-13 weeks are increased in women that develop early PE by a mechanism unrelated to impaired placentation. PMID- 21266794 TI - Initial experience with temsirolimus in 2nd-, 3rd- and 4th-line therapy for metastatic renal cell cancer: good clinical response. AB - PURPOSE: To report our experience with temsirolimus in 2nd-, 3rd- and 4th-line therapy for patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: In our prospectively maintained tumor registry, we identified 6 mRCC patients with temsirolimus in >1st-line systemic therapy. Patients were followed by weekly clinical and laboratory examination during admission of temsirolimus. Re-staging with chest CT and abdominal MRI was performed every 3 months. RESULTS: We observed excellent response rates. Progression-free survival (PFS) ranged from 6 to 40 months with a median of 15 months. Treatment was generally well tolerated. However, pneumonitis was observed in 4 of 6 patients. Drug-related pneumonitis led to severe dyspnea, with the result that treatment with temsirolimus had to be interrupted for a short period of time in 2 patients and discontinued in 1 patient. CONCLUSIONS: Temsirolimus proved to be a very good treatment option in 2nd- to 4th-line therapy with excellent response rates and manageable side effects. The incidence of pneumonitis must not be underestimated. PMID- 21266795 TI - Bronchoscopic long-term palliation of a recurrent atypical carcinoid tumor. AB - Bronchial carcinoid tumors account for 1-2% of all primary lung tumors and are separated into 2 subgroups: typical and atypical carcinoids. Atypical carcinoids as intermediate-grade malignancies can metastasize more frequently, thus exhibiting poorer prognosis than the low-grade typical carcinoid tumors. Surgical resection remains the mainstay of treatment for pulmonary carcinoids. Bronchoscopic treatment using ablation techniques is an effective alternative to surgery in selected patients with typical carcinoid tumors. However, evidence is lacking regarding the effect of bronchoscopic resection of atypical carcinoid tumor and its recurrences. We report the case of a 73-year-old male with frequent endobronchial recurrences of a previously surgically resected atypical carcinoid tumor successfully treated using Nd:YAG laser photoresection. Furthermore, the therapeutic and local staging aspects of the disease are discussed emphasizing the efficacy of bronchoscopic resection strategies and the value of novel bronchoscopic imaging techniques in detailed inspection of the structures of the bronchial wall. PMID- 21266796 TI - Is radical oncosurgery justified for the treatment of primary malignant fibrous histiocytoma of the urinary bladder? Report of two cases and analyses of disease specific survival rates based on a review of the literature. AB - Disease-specific survival (DSS) rates were evaluated in 20 patients with primary malignant fibrous histiocytoma (MFH) of the bladder. The most common pathologic finding was the pleomorphic subtype of MFH (55%) with a mean tumor size of 6.8 cm. 10 patients underwent surgery without and 6 patients with adjuvant therapy. Local and systemic rates of progression were 30 and 60% after surgery only compared with 16.7 and 50% after surgery with adjuvant therapy. Although none of the patients showed metastatic dissemination at the time of diagnosis, overall 1- and 2-year DSS rates of only 47.8 and 31.9% were observed. Hence, after the onset of clinical symptoms, the disease runs a very aggressive course regardless of the therapeutic options employed. Although distant dissemination seems to be rare at the time of diagnosis, the prognostic outcome is dismal. The rarity and inconsistency of the currently available case reports on MFH of the bladder hampers the development of therapeutic guidelines. Advanced studies enrolling a larger number of patients with appropriate clinical and pathological data are needed to compare the beneficial effects of various treatment options. PMID- 21266798 TI - Cutting edge without cutting corners: bronchoscopic treatment for bronchial carcinoids. PMID- 21266797 TI - Evoluting the invaginated--one step closer to the perfect valve? Modified serosal lined tapered ileum (Kalble's procedure) as a continence mechanism for catheterizable pouches. AB - INTRODUCTION: A sufficient and easily catheterizable continence mechanism is essential in continent cutaneous pouches. Kalble embedded a tapered ileum as efferent segment into a serosal lined tunnel formed by an ileal 'U' according to the principle of Abol-Enein and Ghoneim. We report a modified technique applied in a series of 12 patients who had undergone different urinary diversions. METHODS: All patients received a modified Kalble procedure (first-line urinary diversion, n = 8; revision/undiversion, n = 4) for different forms of continent pouches. To alleviate embedding of the efferent segment, ileal detubularization was performed asymmetrically. Mean follow-up was 9.5 months. RESULTS: All patients were continent and performed self-catheterization easily. Of 12 patients, 2 underwent endoscopic incision for stomal stenosis 8 and 12 months postoperatively. CONCLUSIONS: Subject to our short follow-up, Kalble's technique is a promising alternative in patients undergoing a continent cutaneous urinary diversion but offers an inapplicable or missing appendix. PMID- 21266799 TI - Ustekinumab and herpes zoster. AB - BACKGROUND: TNF-alpha antagonists may increase the risk of herpes zoster (HZ), as well as the duration and severity. Recently, the monoclonal antibody ustekinumab, blocking the p40 subunit of IL-12 and IL-23, has been introduced for treating moderate to severe plaque psoriasis. There are no PubMed reports of HZ occurring in people receiving ustekinumab treatment. Common HZ was reported in clinical trials. OBSERVATION: Two patients with severe psoriasis treated with ustekinumab developed severe contiguous multidermatomal HZ 1 and 9 months after treatment initiation. DISCUSSION: The occurrence of HZ after the instauration of ustekinumab suggests a causal relationship. Indeed, the inhibition of the p40 subunit of IL-12 shifts the immune response towards a Th1 profile with diminished IFN-gamma and TNF-alpha expression, decreasing the antiviral immune response. CONCLUSION: Ustekinumab is probably a risk factor for developing HZ. Anti-HZ vaccination prior to ustekinumab treatment should be considered. PMID- 21266800 TI - Clinical characteristics, biological profile, and outcome of biphenotypic acute leukemia: a case series. AB - BACKGROUND: Biphenotypic acute leukemia (BAL) is a rare type of acute leukemia that presents with a high degree of heterogeneity and is not well defined. METHODS: We identified 51 cases (3%) of BAL from 1,693 newly diagnosed acute leukemia patients according to the EGIL scoring system. The immunophenotyping, cytogenetics, treatment, and outcome of 39 BAL patients were retrospectively analyzed. RESULTS: There were 23 (59%) cases of the myeloid and B-lymphoid phenotype, 14 (36%) cases of the myeloid and T-lymphoid phenotype, and 1 case (3%) of the trilineage phenotype or B/T phenotype. Abnormal karyotypes were detected in 76% of the 37 validated patients and displayed a high degree of heterogeneity. Combined regimens for both acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL), as well as ALL type regimens, appeared to achieve a better complete remission rate than AML type regimens (71 and 64 vs. 33%, respectively). BAL patients with complex karyotypes or a rearrangement of chromosome 11 had a significantly reduced survival rate in comparison to patients with normal, t(8; 21), or t(9; 22) karyotypes. The probability of overall survival and disease-free survival at 2 years was 26 and 18%, respectively. CONCLUSIONS: Our findings indicate that BAL shows a high incidence of abnormal karyotypes and a poor prognosis. Combined-type regimens or ALL-based protocols are effective for the treatment of BAL. PMID- 21266801 TI - Oral iron chelator deferasirox in the treatment of secondary hemochromatosis following bone marrow transplantation in a patient with severe aplastic anemia. AB - Iron overload sometimes complicates the clinical course of bone marrow transplantation and can cause damage to liver and heart function. A patient with post-transplantation secondary hemochromatosis was treated with deferasirox, which not only normalized ferritin levels, but also reduced hepatic iron to normal values as measured by biosusceptometry with a superconducting quantum interference device. Side effects were minimal. The use of deferasirox to reduce post-transplant iron burden merits evaluation in a larger patient population. PMID- 21266802 TI - The mitochondrial connection in auditory neuropathy. AB - 'Auditory neuropathy' (AN), the term used to codify a primary degeneration of the auditory nerve, can be linked directly or indirectly to mitochondrial dysfunction. These observations are based on the expression of AN in known mitochondrial-based neurological diseases (Friedreich's ataxia, Mohr-Tranebjaerg syndrome), in conditions where defects in axonal transport, protein trafficking, and fusion processes perturb and/or disrupt mitochondrial dynamics (Charcot-Marie Tooth disease, autosomal dominant optic atrophy), in a common neonatal condition known to be toxic to mitochondria (hyperbilirubinemia), and where respiratory chain deficiencies produce reductions in oxidative phosphorylation that adversely affect peripheral auditory mechanisms. This body of evidence is solidified by data derived from temporal bone and genetic studies, biochemical, molecular biologic, behavioral, electroacoustic, and electrophysiological investigations. PMID- 21266803 TI - Development of tectal connectivity across metamorphosis in the bullfrog (Rana catesbeiana). AB - In the bullfrog (Rana catesbeiana), the process of metamorphosis culminates in the appearance of new visual and visuomotor behaviors reflective of the emergence of binocular vision and visually-guided prey capture behaviors as the animal transitions to life on land. Using several different neuroanatomical tracers, we examined the substrates that may underlie these behavioral changes by tracing the afferent and efferent connectivity of the midbrain optic tectum across metamorphic development. Intratectal, tectotoral, tectotegmental, tectobulbar, and tecto-thalamic tracts exhibit similar trajectories of neurobiotin fiber label across the developmental span from early larval tadpoles to adults. Developmental variability was apparent primarily in intensity and distribution of cell and puncta label in target nuclei. Combined injections of cholera toxin subunit beta and Phaseolus vulgaris leucoagglutinin consistently label cell bodies, puncta, or fiber segments bilaterally in midbrain targets including the pretectal gray, laminar nucleus of the torus semicircularis, and the nucleus of the medial longitudinal fasciculus. Developmentally stable label was observed bilaterally in medullary targets including the medial vestibular nucleus, lateral vestibular nucleus, and reticular gray, and in forebrain targets including the posterior and ventromedial nuclei of the thalamus. The nucleus isthmi, cerebellum, lateral line nuclei, medial septum, ventral striatum, and medial pallium show more developmentally variable patterns of connectivity. Our results suggest that even during larval development, the optic tectum contains substrates for integration of visual with auditory, vestibular, and somatosensory cues, as well as for guidance of motivated behaviors. PMID- 21266804 TI - Standardized antipyretic treatment in stroke: a pilot study. AB - BACKGROUND: Fever after acute cerebral injury is associated with unfavorable functional outcome and increased mortality, but there is controversy about the optimal antipyretic treatment. This study investigated an institutional standard operating procedure (SOP) for fever treatment in stroke patients including a sequence of pharmacologic and physical interventions. METHODS: A 4-step antipyretic SOP was established for patients with acute cerebral ischemia or hemorrhage and a body temperature >=37.5 degrees C within the first 6 days after admission. Data on the course of body temperature, duration of fever and achievement of normothermia were recorded. Results were compared to a historic control group that underwent conventional treatment. RESULTS: A total of 77 patients (mean age 70.4 +/- 14.2 years) received 331 antipyretic interventions. Sequential administration of paracetamol (n = 219), metamizole (n = 71) and calf packing (n = 24) resulted in a significant drop in body temperature after 60 min in each instance. In 5 of 9 cases which were refractory to previous attempts, normothermia followed the infusion of ice-cooled saline. In more than 90% of cases treated per protocol, normothermia was achieved within 120 min. Compared to conventional treatment, fever burden was significantly lower within the first 4 days after admission (p < 0.001). CONCLUSION: This SOP may help to optimize antipyretic treatment for stroke patients. PMID- 21266805 TI - Effective fever control in acute stroke: still wanted! PMID- 21266807 TI - Visceral obesity and the risk of Barrett's esophagus. AB - It still remains controversial whether simple obesity, as measured by the body mass index (BMI), is an independent risk factor for Barrett's esophagus (BE). Recent studies have shown abdominal obesity, as defined by the waist circumference (WC) and the waist-to-hip ratio (WHR), to be a risk factor for BE, independent of the BMI, with the association between BMI and BE being no longer observed after adjustment for the WC and WHR. Moreover, visceral obesity, as directly measured by the surface area of the visceral adipose tissue (VAT) on abdominal CT images, has also been reported to have an association with the risk of BE. In addition to the mechanical effects of abdominal obesity, that is, increase of the intra- abdominal pressure by the large amount of adipose tissue, circulating factors secreted from the VAT, such as tumor necrosis factor-alpha, interleukin-6, leptin, and adiponectin, have also been proposed to be pathogenetically linked to BE and esophageal adenocarcinoma. Obesity is associated with the risk of BE, and this risk appeared to be mediated for the most part by abdominal obesity, especially visceral obesity. This raises several questions regarding the pathogenesis of obesity-related BE. Larger studies with prospective enrollment of patients are required for further examination of this issue. PMID- 21266808 TI - Induction chemotherapy with docetaxel/cisplatin/5-fluorouracil for patients with node-positive esophageal cancer. AB - BACKGROUND: Despite improvements in the surgical management of esophageal cancer, the prognosis of patients with lymph node metastases is still unsatisfactory. Recently, survival benefit of neoadjuvant or induction chemotherapy for patients with esophageal cancer has been highlighted. METHODS: Efficacy and toxicity of induction chemotherapy for esophageal cancer were reviewed. In addition, our experience on modified docetaxel/cisplatin/5-FU (DCF) as induction chemotherapy was also demonstrated. The modified DCF consisted of 60 mg/m2 of docetaxel on day 1, and 350 mg/m2 of 5-FU and 6 mg/m2 of cisplatin on days 1-5. Two courses have been administered as induction chemotherapy in 51 patients with node-positive esophageal cancer. Response was evaluated by RECIST v1.0 and changes in standardized uptake value by 18F-fluorodeoxyglucose positron emission tomography. RESULTS: Induction chemotherapy may be beneficial for node-positive esophageal cancer, although the consensus has not yet been established. A regimen of induction chemotherapy should have a high response rate and cisplatin/5-FU may be underpowered as an induction setting. DCF can be a candidate for the regimen of induction chemotherapy for esophageal cancer, although severe adverse events have been reported. Several modified regimens to reduce the toxicity have been reported. The response rate of our series was 61% and a significant decrease in standardized uptake values was observed after the induction chemotherapy. Although high-grade neutropenia was still observed with this regimen, neither treatment-related death nor delay in the following treatment was observed. CONCLUSIONS: Modified DCF can be a regimen of induction chemotherapy for node positive esophageal cancer because of its high efficacy, although an adequate care for severe neutropenia is needed. PMID- 21266809 TI - Gastrointestinal bleeding after percutaneous coronary intervention. AB - Percutaneous coronary intervention (PCI) is now performed in a wide range of patients with coronary artery disease. Complications of PCI include in-stent re stenosis and in-stent thrombosis. According to the recent 2005 guidelines of the American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions, dual antiplatelet therapy with low dose aspirin and thienopyridine derivatives such as ticlopidine and clopidogrel should be used in patients who have undergone PCI. A serious complication of dual antiplatelet therapy is bleeding, most of which arise from the gastrointestinal (GI) tract. In this article we review published studies about GI bleeding in patients who have undergone PCI. The prevalence of GI bleeding in patients who are administered dual antiplatelet therapy following PCI is approximately 2%, and GI bleeding after PCI is associated with increased morbidity, mortality, duration of hospitalization and cost. Advanced age, a history of peptic ulcer disease, co administration of non-steroidal anti-inflammatory drugs, co-administration of anticoagulants, and physiological stress are considered to be the major risk factors for GI bleeding in patients undergoing antiplatelet therapy following PCI. Recent clinical and experimental studies indicate that administration of low dose aspirin may also increase the risk of adverse events in the small intestine. Although some prophylactic strategies such as proton-pump inhibitor, H2 receptor antagonist and eradication of Helicobacter pylori are proposed, there are few randomized controlled trials assessing the best strategy for the prevention of GI bleeding after PCI. Further extensive studies are required to ascertain the beneficial effect of prophylactic agents for dual antiplatelet therapy following PCI. PMID- 21266810 TI - Usefulness of magnifying narrow-band imaging endoscopy in the Helicobacter pylori related chronic gastritis. AB - Combining the narrow-band imaging (NBI) system and magnifying endoscopy allows simple and clear visualization of microscopic structures of the superficial mucosa and its capillary patterns, which may be useful for precise endoscopic diagnosis in the gastrointestinal tract, being more closely to histopathological diagnosis. In the non-neoplastic gastric mucosa, there have been reports showing a potential usefulness of magnifying NBI for the diagnosis of Helicobacter pylori infection, degree of histological gastritis, and intestinal metaplasia. We have shown that magnifying NBI appearances in the non-neoplastic gastric mucosa also predicts pepsinogen levels, which indicates extension of gastric atrophy in the entire stomach, and gastric cancer occurrence. Furthermore, we have shown that magnifying NBI appearances predicts the result of H. pylori treatment. Clear visualization of fine mucosal and capillary patterns, obtained by magnifying NBI, allows prediction of the histological condition, more in detail without biopsy, and it may also be useful for less invasive, and cost-effective endoscopic gastric cancer surveillance, and prediction of H. pylori eradication. PMID- 21266811 TI - Current status of narrow-band imaging magnifying colonoscopy for colorectal neoplasia in Japan. AB - The narrow-band imaging system can be used to examine the microvascular architecture and surface pattern on the mucosal surface with high sensitivity. The clinical significance of NBI observation is summarized as follows: (1) differential diagnosis of hyperplasia, adenoma, and carcinoma; (2) diagnosis according to the presence of a surface pattern as an alternative to magnifying endoscopic observation with dye spraying, and (3) determination of the invasion depth of an early colorectal carcinoma. However, at present, many NBI magnifying observation classifications for colorectal tumor exist in Japan. To internationally standardize the NBI observation criteria, a simple classification system is required. On the basis of these backgrounds, an international cooperative group (Colon Tumor NBI Interest Group - CTNIG) has developed a simple category classification (NICE classification: NBI International Colorectal Endoscopic Classification) which classifies NBI findings into types 1-3. PMID- 21266812 TI - Daikenchuto ameliorates muscle hypercontractility in a murine T-cell-mediated persistent gut motor dysfunction model. AB - BACKGROUND AND AIMS: Low-grade inflammation and immunological alterations are evident in functional gastrointestinal disorders such as irritable bowel syndrome (IBS). We evaluated the effects of daikenchuto (DKT), a pharmaceutical grade Japanese herbal medicine, on the hypercontractility of intestinal smooth muscle persisting after acute inflammation induced by a T-cell-activating anti-CD3 antibody (alphaCD3). METHODS: BALB/c mice were injected with alphaCD3 (12.5 MUg, i.p.), and DKT (2.7 g/kg) was administered orally once daily for 1 week. The contraction of isolated small intestinal muscle strips and muscle cells was examined on day 7 after alphaCD3 injection. The gene and protein expressions in the small intestines were evaluated by real-time PCR and multiplex immunoassays, respectively, on days 1, 3 and 7 after alphaCD3 injection. RESULTS: alphaCD3 injection resulted in significant increases in carbachol-evoked contractility in the muscle strips and isolated smooth muscle cells on day 7. DKT ameliorated the alphaCD3-induced muscle hypercontractility on day 7 in both the muscle strips and smooth muscle cells. alphaCD3 injection rapidly up- and downregulated the mRNA and protein expressions of pro- and anti-inflammatory cytokines, respectively. Although the influence of DKT on the mRNA expressions was moderate, the protein expressions of IL-13 and IL-17 were significantly decreased. CONCLUSIONS: We observed changes in the intestinal muscle contractility in muscle strips and muscle cells following resolution of inflammation in a T-cell-mediated model of enteropathy. The observed modulation of cytokine expression and function by DKT may lead to the development of new pharmacotherapeutic strategies aimed at a wide variety of gut motor dysfunction disorders. PMID- 21266813 TI - FGF19 protects colonic epithelial cells against hydrogen peroxide. AB - BACKGROUND/AIMS: The apoptosis induced by hydrogen peroxide (H2O2) in colonic epithelial cells is very important for the pathogenesis of inflammatory bowel disease (IBD). Fibroblast growth factor (FGF) 15, the human ortholog of FGF19, is reported to be secreted from colonic myofibroblasts and enhances colonic epithelial restitution, but little is known about the function of FGF19 to colonic epithelial cells. In the present study, we investigate the anti-apoptosis effect of FGF19 in colonic epithelial cells treated with H2O2. METHODS: Young adult mouse colonic epithelial (YAMC) cells are used to investigate the protective role of FGF19. Cellular viability was determined by WST-8 assay, and apoptosis was measured by Hoechst staining and Western blotting of cleaved caspase-3. YAMC cells were pretreated by FGF19 and H2O2 was used for cellular damage. RESULTS: We demonstrated that pretreatment of FGF19 (50 ng/ml) significantly protects YAMC cells treated with H2O2 assessed by WST-8. We also demonstrated Hoechst staining of YAMC cells and that H2O2-induced apoptosis is significantly reduced by FGF19 treatment via inhibition of the caspase-3 pathway. CONCLUSION: These results indicate FGF19 protects YAMC cells against H2O2 and might be related to the pathogenesis of IBD. Even further studies are needed - FGF19 may be one of the possible therapeutic strategies of IBD. PMID- 21266814 TI - Clinical outcome and clinicopathological characteristics of recurrence after laparoscopic gastrectomy for advanced gastric cancer. AB - BACKGROUND: Although laparoscopic gastrectomy has been recognized as a treatment of early gastric cancer, the indication for laparoscopic gastrectomy with D2 lymph node dissection has remained controversial. D2 lymph node dissection is considered to be feasible for advanced gastric cancer in some high-volume institutions specifically trained for the laparoscopic procedure. This study was undertaken to determine the clinical outcome and clinicopathological characteristics of patients who showed recurrence following laparoscopic gastrectomy for advanced gastric cancer. METHODS: From August 1999 through February 2009, among 805 patients who underwent laparoscopic gastrectomy associated with regional lymph node dissection, a total of 209 patients undergoing gastrectomy associated with lymph node dissection who consequently obtained complete resection for advanced gastric cancer were subjected to the retrospective analysis to evaluate clinical outcome. RESULTS: The mean period of postoperative observation was 1,068 days. The final stages of the 209 cases were as follows: 83 in IB, 56 in II, 46 in IIIA, and 24 in IIIB. The 5-year survival rate was 89.1% in stage IB, 93.1% in stage II, 52.5% in stage IIIA, and 46.5% in stage IIIB, respectively. A total of 27 patients (12.9%) had recurrence. Postoperative recurrence of gastric carcinoma occurred in peritoneal dissemination in 13 patients, liver in 7, distant lymph nodes in 6, ovary in 3, lung in 2, skin in 1, and meninges in 1 patient. There were neither port-site metastases nor locoregional recurrence. CONCLUSION: The characteristics and the rate of postoperative recurrence after laparoscopic gastrectomy for advanced gastric cancer were not greatly different from those of the open conventional procedure. Although further observation is required to finally conclude long-term survival, laparoscopic radical gastrectomy may possibly be indicated for patients with advanced gastric cancer. PMID- 21266815 TI - Clinical features of gastrointestinal follicular lymphoma: comparison with nodal follicular lymphoma and gastrointestinal MALT lymphoma. AB - We retrospectively compared the clinicopathological features of primary intestinal follicular lymphomas (FL-GIs), nodal follicular lymphomas (FL-LNs) and gastrointestinal MALT lymphomas (MALT-GIs), and investigated the distribution and the endoscopic appearances of FL-GI to evaluate the effectiveness of treatment modality. The subjects were 28 FL-GI patients, 135 FL-LN patients and 70 MALT-GI patients. In FL-LNs the clinical stage III-IV was 83%, while in FL-GIs clinical stage I-II was 68%. In MALT-GIs clinical stage I-II was 87%. The overall survival was significantly better in MALT-GI patients than in FL-LN patients. All FL-GI patients were alive at the time of evaluation. Regarding the histological grade (WHO), grade 1 was 81% in FL-GI, whereas in FL-LN grade 2 was 28% and grade 3 was 11%. The Follicular Lymphoma International Prognostic Index was low in 61% of FL GIs, while in FL-LNs it was equally distributed to low, intermediate and high, suggesting that the prognosis is better in FL-GIs than in FL-LNs. The clinicopathological studies revealed the FL-GI has intermediate characteristics between FL-LN and MALT-GI. We recommend a 'watch-and-wait' policy or chemotherapy with rituximab for the therapy of FL-GIs because the lesions are often located in broader areas from the lower duodenum to the small intestine. PMID- 21266816 TI - Antibiotic combination therapy for steroid withdrawal in steroid-dependent ulcerative colitis. AB - BACKGROUND AND AIM: Immunosuppressive drugs are recommended for use as replacements of steroid therapy in sustaining remission of steroid-dependent ulcerative colitis (UC). However, discontinuation of these therapeutic agents leads to a high relapse, and their long-term administration has not been proven safe. A newly introduced antibiotic combination therapy led to improvement and remission of active UC. The aim of this study is to examine whether this new therapy can replace immunosuppressive agents and allow discontinuation of steroids in steroid-dependent UC remission. METHODS: 48 patients with steroid dependent UC were recruited for a 2-week treatment with amoxicillin, tetracycline, and metronidazole (ATM). Examination of clinical symptoms, endoscopy, and histological evaluation were performed before and 6 and 12 months after treatment. RESULTS: The proportion of patients who showed clinical improvement at 6 and 12 months after treatment was 54.2% (26/48) and 75.0% (36/48), respectively. The rate of clinical remission at 6 and 12 months was 31.3% (15/48) and 37.5% (18/48), respectively. Steroid withdrawal was attained in 64.6% (31/48) and 70.8% (34/48) of patients at 6 and 12 months, respectively. Endoscopic improvement was detected in 56.3% (27/48), and histological improvement was detected in 52.1% (25/48) at the final observation point for each patient. CONCLUSION: The triple antibiotic therapy resulted in improvement, remission, and steroid withdrawal in steroid-dependent UC patients. PMID- 21266817 TI - Immunohistochemical analysis of REG Ialpha expression in ulcerative colitis associated neoplastic lesions. AB - BACKGROUND AND AIMS: The regenerating gene (REG)Ialpha has been identified by microarray analysis as a gene that is distinctly overexpressed in ulcerative colitis (UC), and its protein product is suggested to play a pivotal role in the development of UC-associated carcinoma. In the present study, we investigated the significance of REG Ialpha expression as a diagnostic marker of UC-associated neoplasia. METHODS: Tissue samples were obtained from colectomy specimens from 31 patients with long-standing UC (mean disease duration 17.2 years, range 5-29). The lesions were evaluated according to the International Classification for Dysplasia in Inflammatory Bowel Diseases, and the sections were examined using immunohistochemistry for REG Ialpha and p53. RESULTS: In the 'regenerating atypia' group, REG Ialpha immunoreactivity was restricted to the lower third of the UC mucosa (grade 1). Lesions classified as 'indefinite for dysplasia' also showed predominantly basal-type staining for REG Ialpha. However, in 'low-grade dysplasia' and 'high-grade dysplasia' lesions, the localization of REG Ialpha immunoreactivity expanded to the middle (grade 2) and upper (grade 3) third of the UC mucosa, respectively. The REG Ialpha immunostaining pattern differed significantly (p < 0.0001) between non-neoplastic and neoplastic lesions, and was significantly (p < 0.0001) associated with p53 overexpression. CONCLUSIONS: Immunohistochemical analysis of REG Ialpha expression is useful for differential diagnosis of non-neoplastic and neoplastic lesions in UC tissues. PMID- 21266818 TI - Colonoscopic findings and pathologic characteristics of Strongyloides colitis: a case series. AB - BACKGROUND/AIMS: Strongyloidiasis, which is caused by Strongyloides stercoralis, is one of the prevalent infections in the tropical and subtropical regions worldwide. The larvae mainly infect the small intestine and cause serious disseminated strongyloidiasis. Although upper gastrointestinal features in strongyloidiasis are well known, colonoscopic evaluation has not been established yet. The aim of this study is to clarify the characteristic findings on colonic lesions in strongyloidiasis. METHOD: From January 2005 to December 2009, 10 cases with strongyloidiasis underwent colonoscopy at a single center on an endemic island of Japan. The clinical and colonoscopic findings were analyzed retrospectively. RESULTS: Six (60%) cases had an immunocompromised condition, including human T lymphotropic virus type 1 infection, corticosteroids, and chemotherapy. Hyperinfection or disseminated strongyloidiasis was not presented. Endoscopic features included yellowish-white nodules, erythema, and loss of vascular pattern, which were mainly observed in the right colon. Pathological examination revealed the filariform Strongyloides larvae and the eosinophilic infiltration of the lamina propria. CONCLUSION: This study demonstrates that colonoscopic observation and biopsies are very useful to diagnose strongyloidiasis. Asymptomatic cases with strongyloidiasis can have colonic involvement. Yellowish-white nodules may be a characteristic finding of colonic lesions in strongyloidiasis and can be a cautious marker to prevent fatal disseminated strongyloidiasis in endemic regions. PMID- 21266823 TI - Maxillary dental arch dimensions in 6-year-old children with articulatory speech disorders. AB - AIMS: To evaluate maxillary dental arch dimensions in 6-year-old children with articulatory speech disorders and to compare their dental arch dimensions with age- and sex-matched controls without speech disorders. METHODS: Fifty-two children (15 girls) with errors in the articulation of the sounds /r/, /s/ or /l/ were compared retrospectively with age- and sex-matched controls from dental casts taken at a mean age of 6.4 years (range 5.0-8.4). All children with articulatory speech disorders had been referred to City of Helsinki Health Care, Dental Care Department by a phoniatrician or a speech therapist in order to get oral-motor activators (removable palatal plates) to be used in their speech therapy. A chi2-test and paired Student's t tests were used in the statistical analyses. RESULTS: The children with articulatory speech disorders had similar maxillary dental arch widths but smaller maxillary dental arch length than the controls. CONCLUSION: This small series suggests that 6-year-old children with articulatory speech disorders may have decreased maxillary dental arch length. PMID- 21266824 TI - Evidence for dietary niche separation based on infraorbital foramen size variation among subfossil lemurs. AB - The size of the infraorbital foramen (IOF) has been used in drawing both phylogenetic and ecological inferences regarding fossil taxa. Within the order Primates, frugivores have relatively larger IOFs than folivores or insectivores. This study uses relative IOF size in lemurs to test prior trophic inferences for subfossil lemurs and to explore the pattern of variation within and across lemur families. The IOFs of individuals belonging to 12 extinct lemur species were measured and compared to those of extant Malagasy strepsirhines. Observations matched expectations drawn from more traditional approaches (e.g. dental morphology and microwear, stable isotope analysis) remarkably well. We confirm that extinct lemurs belonging to the families Megaladapidae and Palaeopropithecidae were predominantly folivorous and that species belonging to the genus Pachylemur (Lemuridae) were frugivores. Very high values for relative IOF area in Archaeolemur support frugivory but are also consistent with omnivory, as certain omnivores use facial touch cues while feeding. These results provide additional evidence that the IOF can be used as an informative osteological feature in both phylogenetic and paleoecological interpretations of the fossil record. PMID- 21266825 TI - Impact of diabetes mellitus on survival in patients with end-stage renal disease: a three-year follow-up. AB - BACKGROUND/AIMS: To assess the impact of diabetes mellitus (DM) on clinical outcome in patients with end-stage renal disease (ESRD) on a 3-year follow-up. METHODS: 58 ESRD patients were divided into 2 groups according to the presence of DM. We analyzed following end points: death, cardiac arrest, myocardial infarction, stroke, hospitalizations due to cardiovascular causes, revascularization, and combined end point. RESULTS: Among diabetics, 14 (77.8%) had significant atherosclerotic changes, in the group without DM only 8 (38.1%), p = 0.01. In the group without DM, 14 (46.7%) patients reached combined end point, while in the group with DM 16 (53.3%) patients, p = 0.0013. There were no statistical differences in mortality (p = 0.423). CONCLUSION: Survival of hemodialyzed diabetic patients is not inferior to nondiabetics; however, morbidity is significantly higher due to adverse cardiac events. PMID- 21266826 TI - Nanog is highly expressed in ovarian serous cystadenocarcinoma and correlated with clinical stage and pathological grade. AB - OBJECTIVE: Nanog is overexpressed in embryonic stem cells for cell self-renewal and differentiation. We investigated whether the Nanog expression is associated with the occurrence and development of ovarian cancer. METHODS: Immunohistochemistry was used to examine the expression of Nanog in 43 normal ovarian epithelia, 110 serous cystadenomas, 80 borderline serous cystadenomas, and 107 serous cystadenocarcinomas. In the meantime, their association with various clinicopathologic features was assessed. RESULTS: The expression intensity of Nanog in normal ovarian tissue, benign, borderline, and malignant tumors showed a gradual rising trend. Among the serous cystadenocarcinomas, 42.86% were detected to be positive for stage I, 70.97% for stage II, 95.31% for stage III, and 100% for stage IV. There was a strong correlation between Nanog and clinical stage (r = 0.418, p = 0.000). Besides, there was a 55.56% positive expression of grade I, 73.68% of grade II, and 96.67% of grade III. The correlation between Nanog and differentiation grade was dramatic (r = 0.692, p = 0.000). CONCLUSIONS: Nanog was highly expressed in ovarian serous cystadenocarcinoma, and showed a positive correlation with clinical stage and grade. Nanog may play an important role in the development of dedifferentiation and progression of serous ovarian carcinoma. PMID- 21266827 TI - Alteration of REDD1-mediated mammalian target of rapamycin pathway and hypoxia inducible factor-1alpha regulation in human breast cancer. AB - OBJECTIVE: The purpose of this study is to investigate REDD1-(regulated in development and DNA damage response 1) mediated regulation of the mammalian target of rapamycin (mTOR) pathway in breast cancer. METHODS: A tissue microarray included samples from 224 patients with breast cancer, and 30 patients with papilloma were used as a control group. An immunohistochemistry (IHC) including estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), epithelial growth factor receptor, cytokeratin 5/6, glucose transporter 1 (Glut-1), hypoxia-inducible factor (HIF)-1alpha, REDD1, AMPK (5' adenosine-monophosphate-activated protein kinase) alpha(1), 14-3-3sigma, phosphatase and tensin homolog, phospho-Akt, phospho-mTOR, phospho-S6, and Ki-67 was conducted. The phenotypic classification of breast cancer was performed based on the results of the IHC for ER, PR and HER2: luminal A, luminal B, HER2 overexpression and triple-negative breast cancer (TNBC). RESULTS: Glut-1 and HIF 1alpha were more highly expressed in TNBC, the HER2 overexpression type and papilloma than in the luminal A and B phenotypes (p = 0.000). REDD1 expression was higher in papilloma than in breast cancer (p = 0.000), but no difference was found among the 4 breast cancer phenotypes (p = 0.307). CONCLUSION: In the HER2 overexpression type and TNBC, tumor cell proliferation and survival in the hypoxic tumor environment could possibly be due to disinhibition of the mTOR pathway and HIF-1alpha stabilization by downregulation of REDD1. PMID- 21266828 TI - Refined prognostic role of CD68-positive tumor macrophages in the context of the cellular micromilieu of classical Hodgkin lymphoma. AB - OBJECTIVE: Classical Hodgkin lymphoma (HL) consists of neoplastic Hodgkin and Reed-Sternberg cells (HRSC) and a nonneoplastic micromilieu that greatly outnumbers the HRSC. Studies on HRSC-related prognostic biomarkers have been unsuccessful, but the microenvironmental composition is of prognostic importance. Recently, the number of CD68-positive macrophages was correlated with adverse survival in HL, and there was a call to validate these results. METHODS: We utilized immunohistochemistry to analyze the prognostic importance of the CD68 positive macrophage number compared to other cellular environmental components in an unselected series of 105 HLs in tissue microarrays. RESULTS: Applying a cutoff score of >0.82% tumor macrophages, cases with increased numbers showed worse overall survival (mean 185 months, median 192) compared to cases with lower numbers (mean 285 months, median not reached). Eleven of 62 patients with <=0.82% tumor macrophages died, compared to 19 of 43 with >0.82% (p < 0.001). The number of macrophages correlated with a low FOXP3-/high granzyme B-/high PD-1-positive micromilieu and patient age, but did not have independent prognostic significance. A combination background score taking into consideration all negative prognostic microenvironmental components (CD68-, PD-1- and granzyme B positive cells) was of independent prognostic significance (p = 0.002). CONCLUSION: Increased numbers of CD68-positive tumor macrophages indicate an adverse overall outcome in HL. PMID- 21266829 TI - Different expressions and DNA methylation patterns of lysophosphatidic acid receptor genes in mouse tumor cells. AB - OBJECTIVE: Lysophosphatidic acid (LPA) receptors act as several biological effectors through LPA, which is a bioactive phospholipid. Recently, aberrant expressions of LPA receptor genes due to DNA methylation have been detected in several tumor cells. In this study, we measured expression levels and DNA methylation status of LPA receptor genes in mouse tumor cells, LL/2 lung carcinoma, B16F0 melanoma, FM3A mammary carcinoma and L1210 leukemia cells, compared with normal tissues. METHODS: Total RNAs were extracted and RT-PCR analysis was performed. For DNA methylation status, bisulfite sequencing analysis was carried out, comparing outcomes with other tumor cells and normal tissues. RESULTS: The expressions of LPA1 gene were shown in LL/2, but not in B16F0, FM3A and L1210 cells. While the LPA2 gene was expressed in all 4 tumor cells, the LPA3 gene was unexpressed in them. The LPA1 and LPA3 unexpressed cells were highly methylated, although normal tissues were all unmethylated. The DNA methylation status was correlated with gene expression levels in cancer cells. CONCLUSION: The present results demonstrate that DNA methylation patterns of LPA receptor genes are dependent on cancer cell types, suggesting that LPA receptors may be new molecular targets for therapeutic approaches and chemoprevention. PMID- 21266830 TI - Validation of glomerular basement membrane thickness changes with aging in minimal change disease. AB - Measurement of the normal range of glomerular basement membrane (GBM) thickness by electron microscopy is required for the diagnosis of thin basement membrane disease or diabetic nephropathy; however, this measurement is influenced by aging. The aim of this study was to introduce a simple histogram plotting method for the validation of the results of the GBM thickness measurements by the accepted arithmetic mean +/- SD method. We examined renal biopsy specimens obtained from 19 patients (10 males and 9 females) with minimal change disease, ranging in age from 3 to 70 years. Renal tissue samples obtained at autopsy from a male baby (3 months old) with no renal disease were also examined. For each case, GBM thicknesses at 10-15 evenly distributed points per glomerular loop were directly measured and the arithmetic mean +/- SD was calculated. Subsequently, the arithmetic mean +/- SD for each group of cases classified by age into 4 groups, i.e. babyhood (3 months old), childhood (3-11 years old), adulthood (12 57 years old), and old age (60-70 years old), was determined. On the other hand, a histogram of the frequency of GBM points measured against thickness was plotted to determine the distribution pattern and the range of measurements in each age group. The histogram plot showed 4 clearly divided modes for GBM thickness. Comparison of the results obtained by the 2 methods revealed a significant correlation indicating the feasibility of the histogram plotting method as a useful adjunct to validate GBM thickness measurements. PMID- 21266831 TI - Caspase-9-dependent nuclear translocation of cytochrome c in hypoxic injury. AB - OBJECTIVE: Hypoxia signals the release of cytochrome c from mitochondria as well as sequential activation of caspase-9 and caspase-3 in the pathway to apoptosis. In this report, we describe novel mechanisms governing the nuclear translocation of cytochrome c during hypoxia-induced apoptosis in neuroepithelioma, SK-N-MC cells. METHODS: This work focuses on an investigation of the mechanism of cytochrome c translocation by means of immunocytochemistry, cell fractionation, Western blot and caspase assay. RESULTS: Using immunocytochemistry and subcellular fractionation, we found that caspase-9 activation precedes cytochrome c release and translocation. Inhibition of caspase-9 activity blocked these responses to hypoxia. Previous studies suggest a key role for c-Jun N-terminal kinase (JNK) in apoptosis regulation and accordingly we found that JNK activation was essential for caspase-9 activation and nuclear translocation of cytochrome c. CONCLUSIONS: In this report, we describe novel mechanisms of caspase-9-dependent nuclear translocation of cytochrome c in hypoxic injury. PMID- 21266832 TI - FOXP3 expression in duodenal mucosa in pediatric patients with celiac disease. AB - OBJECTIVE: It was the aim of this study to evaluate the number of 2 lymphoid subpopulations, CD8(+) cells and FOXP3(+), in the duodenum mucosa from pediatric celiac patients. METHODS: Tissue sections prepared from paraffin-embedded biopsies of the descending duodenum of 61 celiac patients with Marsh grade 1 (M1), M2 and M3 disease and biopsies from 21 age-matched non-celiac (NC) patients were immunohistostained with anti-CD8 or FOXP3 antibodies. RESULTS: The histological Marsh grade correlated with the mean number of FOXP3(+) cells in the lamina propria (LP) mucosa (8.9 +/- 1.1, 6.8 +/- 2.4, 24.5 +/- 2.6 and 31.1 +/- 2.8 for NC, M1, M2 and M3 biopsies, respectively; p < 0.001). Using a cutoff point of 15 cells, 95% of NC and 88% of M1 biopsies had a mean of <15 FOXP3(+) cells compared with 14% for M2 and 13% for M3 biopsies. The number of FOXP3(+) cells in the epithelial mucosa also correlated with transglutaminase type 2 serum levels from the celiac patients. Unlike the FOXP3(+) cells, CD8(+) lymphocytes were present in both LP and surface epithelial mucosa and significantly different only in the LP mucosa of the M2 and M3 groups. CONCLUSION: The number of FOXP3(+) cells is substantially increased in the mucosa of celiac patients at advanced stages. Characterization of the activity of these cells in celiac and in other inflammatory bowel diseases will enable us to understand the significance of these cells in celiac disease. PMID- 21266833 TI - Today's understanding about bone aging. AB - Patient's age is an important factor in orthodontic treatment. There are many studies about bone aging from the aspects of osteoporosis and other bone diseases. Both, aging and osteoporosis are associated problems and have a great importance in relation to their incidence. But not only osteoporosis or other bone related diseases are issue for many studies, because the knowledge of bone pathophysiology and diagnostics with signaling molecules makes it possible to predict treatment outcome and specific cell targeted pharmacology. In recent years immunohistological studies had become very popular in all fields of medicine including orthodontics, too. The question we tried to answer in this literature mini-review was--what kind of immunohistological studies were done from the aspect of bone aging in relation to patient's age and orthodontic treatment? Search on Cochrane Library, PubMed, Science Direct, and DynaMed data bases by keywords: Alveolar bone aging, RANK, RANKL, OPG, MMP-1, MMP-8, IL-1, IL 6, TNF-alpha, TNF-beta, and BM, resulted with 147 full-text articles; from them 90 met the criteria, 30 were reviews, and only in 22 articles from 60 bone aging from the aspect of signaling molecules were discussed. Interestingly, only 2 articles (Cei 2006 and Zhang 2003) were related to alveolar bone, and none studied it from the orthodontic point of view. Patient's age plays an important role in orthodontic treatment, because of the bone response to mechanical loading. It is in accordance to clinical studies, or alike, that tooth movement in younger patient occurs much faster than in adults, but the question which factors are responsible for the process still remains. PMID- 21266834 TI - Epidemiologic factors causing cleft lip and palate and their regularities of occurrence in Estonia. AB - OBJECTIVES: To study epidemiological factors causing development of cleft lip and palate and their occurrence regularities. MATERIALS AND METHODS: This study included 583 cleft lip and palate patients and the information for statistical analyses was gathered from Tartu University Hospital. RESULTS: 19% of the patients had a cleft lip (CL), 39% of the patients had a cleft palate (CP), and 42 % of the patients had a cleft lip and palate (CLP). The ratio for different cleft types CL: CLP: CP was 1:2:2. In unilateral CLP and CL cases, the left side was affected 2.2 times more frequently than the right side. Boys had a CLP nearly 2.1 times more often than girls. CP was more common for girls (60%) than for boys (40%). 30% of children had multiple malformations. 2.6% of children with clefts were born premature, half of which had accompanying developmental anomalies. The average birth weight for cleft child was ~3400 grams. 6.8% of children with clefts had a birth weight below 2.5 kg. In case of children with clefts, the mother's age exceeded 30 years in 1/4 of cases and father's age in 1/3 of cases. Both parents were older than 30 years in 66% of the cases. 1/5 of both parents were older than 30 years. 1/3 of mothers of children with clefts had suffered psychological stress, 1/5 of mothers had done hard physical work. 1/5 of mothers had an exposure to teratogenic toxic substances. 15% of them received medications during the first trimester of pregnancy. 15% of mothers had experienced hormonal disorders. CONCLUSIONS: As a result of the study we found a high occurrence rate of CP (CL: CLP: CP--1:2:2), which is similar to the studies conducted in Finland and Sweden. The reasons for this ratio need further research. PMID- 21266835 TI - Analysis of the crown fractures and factors affecting pulp survival due to dental trauma. AB - OBJECTIVES: The aim of the present study was to investigate pulp survival following crown fracture with and without pulp exposure as well as with and without associated subluxation and in relation to stage of root development and type of enamel-dentine fracture. MATERIALS AND METHODS: This study consisted of 83 patients with 116 crown fractured incisors without pulp exposure and 35 patients with 44 complicated crown fractures. The effect of variables on the maintenance of tooth vitality were explored using the Linear Regression analysis , which assumes the effects of different factors on the pulp vitality such as (age, stage of the root development, contaminant subluxation, fracture depth, emergency treatment). RESULTS: The general distribution was 59 (71%) boys and 24 (29%) girls with uncomplicated crown fractures aged 7-17 years, mean 10.7 years +/-2.83SD and 24 (68.5%) boys and 11 (31%) girls with complicated crown fracture. From 78 uncomplicated crown fractures without subluxation PN (pulp necrosis) was evaluated in 4 (4.88%) cases but from 20 uncomplicated crown fractures with subluxation PN was 14 (56.52%) cases. Univariate analysis showed that stage of root development p<0.05, subluxation p<0.001, fracture depth p<0.001 were significantly related to the pulp survival. CONCLUSIONS: The primary factors related to pulp healing events after crown fracture appears to be compromised pulp circulation due to concomitant subluxation as well as the stage of root development and fracture depth. For incisors with complicated crown fractures there were two more factors related to pulpal healing-time interval from injury until initial treatment and appropriate emergency treatment. PMID- 21266836 TI - Microflora of root filled teeth with apical periodontitis in Latvian patients. AB - OBJECTIVE: The aim of the present study was to investigate the microbial flora of root filled teeth with apical periodontitis and to determine the prevalence of beta-lactamase producing strains in isolated bacteria in Latvian patients. MATERIALS AND METHODS: 33 root filled teeth with asymptomatic persisting periapical lesions were selected for the present study. During nonsurgical endodontic retreatment, the root filling material was removed and canals were sampled. Determination of microbial species was based on series of biochemical tests using identification kits. All strains of bacteria were tested for beta lactamase production by using chromogenic nitrocefin-impregnated slides. RESULTS: Bacteria were found in 32 (97%) of initial specimens from the teeth. The number of isolated microbial strains in the specimens ranged from one to six (mean 2.7). 79% of the isolated microbial species were Gram-positive bacteria. The most common isolates were Streptococcus (27%), Actinomyces (27%), Staphylococcus (18%), Enterococcus (18%) and Lactobacillus (18%) spp. Yeasts were found as four isolates in 3 cases (9%). beta-lactamase-producing bacterial strains were detected in 12 specimens, 36% of the patients. The most common enzyme-producing bacteria belonged to Actinomyces and Staphylococcus spp. CONCLUSIONS: The microbial flora in previously treated root canals with apical periodontitis is limited to a small number of predominantly Gram-positive microbial species. The most common isolates are Streptococcus, Actinomyces, Staphylococcus, Enterococcus and Lactobacillus spp. A moderately high prevalence of beta-lactamase producing bacterial strains was detected in patients with root filled teeth with apical periodontitis. PMID- 21266837 TI - An expanded odontogenic myxoma in maxilla. AB - Odontogenic myxomas are considered to be a benign odontogenic tumor with locally aggressive behavior, non-metastasizing neoplasm of the jaw bones. It derives from the dental mesenchyme or periodontal ligament. Despite the benign nature of these lesions, there is a high rate of local recurrence after curettage alone and in certain cases requires adequate resection. This paper describes a case of a large odontogenic myxoma in the maxilla, emphasizing a discussion on the differential diagnosis related to radiological findings and the surgical treatment. PMID- 21266838 TI - MicroRNA-dependent regulation of the microenvironment and the epithelial stromal cell interactions in the mouse mammary gland. PMID- 21266839 TI - Towards an AIDS vaccine: the transmembrane envelope protein as target for broadly neutralizing antibodies. AB - Although the development of an effective vaccine is the main goal in the fight against AIDS, all attempts by numerous laboratories to develop a vaccine have failed so far. In addition, it is still unclear whether cytotoxic T cells or neutralizing antibodies or both should be induced. The major advantage of neutralizing antibodies is their ability to prevent infection and subsequent integration of the provirus into the cellular genome where it may persist in a form invisible to the immune system. Broadly neutralizing antibodies have been found in HIV infected individuals, including antibodies directed against a highly conserved region in the membrane proximal external region (MPER) of the transmembrane envelope (TM) protein gp41 of HIV-1. We successfully induced neutralizing antibodies against different gammaretroviruses by immunization with their respective TM proteins. These antibodies recognized epitopes not only in the MPER but also in the fusion peptide proximal region of the TM protein. In the case of feline leukaemia virus (FeLV), these antibodies protected cats from antigenemia following challenge. To understand the mechanism of neutralization, the interactions between neutralizing antibodies and their corresponding epitopes in the TM protein of gammaretroviruses and HIV-1 were analysed. These data may help to design antigens able to induce specific broadly neutralizing antibodies. PMID- 21266841 TI - Mutants of plant genes for developing cancer vaccines. AB - Preventive Human Papillomavirus (HPV) vaccination is an expensive practice and it may be an insufficient tool to tackle cervical cancer worldwide. Therapeutic intervention is seeking for safe/effective vaccines inducing the activation of CD8+ cytotoxic T lymphocytes (CTLs) that is required to clear the tumor. Linking a tumor-specific antigen (i.e. the E7 oncoprotein of the 'high risk' HPVs) to molecules able to increase its immune 'visibility' represents a strategy to force the immune system to fight cancer. We focused on plants as sources of innovative immunostimulatory sequences. We have already shown the anti-cancer activity obtained by fusing E7GGG (a mutagenized E7 gene from the high risk HPV type 16) to the coat protein of a plant virus, the Potato Virus X. We are now investigating plant-derived carriers, such as the 'Ribosome inactivating proteins' (RIPs), so far used to develop immunotoxins for targeted cancer therapy. Beside toxicity, RIPs have other features (i.e. immunogenicity, ability to modulate immune functions and apoptosis induction) that could be useful tools to use in tumor immunotherapy. A non toxic mutant of saporin (SAP-KQ) was used as a carrier for the E7GGG gene in the context of a DNA-based vaccine. We show here that fusion constructs of SAP-KQ with E7GGG can induce E7-specific Immunoglobulins (IgGs), CTLs and Delayed-Type Hypersensitivity (DTH) affecting the growth of E7-expressing tumors in mice. These data demonstrate that mutant plant genes hold promise to improve the poor immunogenicity of tumor-associated cancer antigens and could contribute to the evolution of new cancer immunotherapy. PMID- 21266840 TI - Campylobacter capsule and lipooligosaccharide confer resistance to serum and cationic antimicrobials. AB - The innate immune system plays a critical role in host defense against mucosal bacteria. Campylobacter jejuni is a major cause of human gastroenteritis that usually resolves spontaneously within several days, suggesting that innate mechanisms are important to control the infection. However, the specific means by which this occurs is not well understood. While diarrheal isolates of C. jejuni usually are susceptible to human serum, we found that a systemic strain of C. jejuni, isolated from the cerebrospinal fluid of an infant with meningitis, is relatively more resistant to human serum, the Bactericidal/Permeability Increasing Protein (BPI), an endogenous cationic antimicrobial protein, and the cationic peptide antibiotic polymyxin B. To test the hypothesis that the surface properties of this strain contributed to its ability to withstand these innate host defenses, we constructed isogenic mutants in capsule (kpsM) and lipooligosaccharide (waaF) and complemented these mutants by insertion of the complementation construct in trans into hipO, a chromosomal locus. We found that capsule expression was essential for serum resistance, whereas lipooligosaccharide played no substantial role. In contrast, the lipooligosaccharide mutant showed increased sensitivity to polymyxin B, alpha defensins, cathelicidins, and BPI. These findings suggest that the polysaccharides of C. jejuni strains contribute differently to resistance against host innate immunity; whereby capsule is more important for resisting human complement and lipooligosaccharide is more important for protection against killing mediated by cationic antimicrobial peptides and proteins. PMID- 21266842 TI - Safety and tolerability of bivalent HPV vaccine: an Italian post-licensure study. AB - One of the most important scientific discoveries of the last century was that persistent infection by some types of HPV is a precondition for the development of cervical cancer. The oncogenic types of HPV are also associated with other tumours (vaginal, vulvar and anal carcinomas, tumours of the head and neck, urethra and penis). Two preventive vaccines are currently available (Cervarix and Gardasil). Both have shown very good efficacy, safety and tolerability profiles. Nonetheless, extensive vaccination requires long-term monitoring of safety and tolerability. The aim of our study was to evaluate the safety and tolerability of the bivalent vaccine Cervarix in Italy. Every participant in the study completed a questionnaire after each dose of vaccine received, with a view to recording adverse events during the first 7 days after vaccination. We registered local (pain, redness, swelling) and systemic symptoms (fever, headache, myalgia, fatigue, arthralgia, itching, gastrointestinal disorders, rash and urticaria). A total of 4,643 subjects were recruited. In all, 7,107 questionnaires were collected: 3,064 after the first dose, 2,367 after the second and 1,676 after the third. No serious adverse events were observed. The most frequent local symptom was pain at the injection site, while fatigue, headache and myalgia were the most common systemic reactions. Pain was reported more frequently after the first dose than after the others, while all the other local and general symptoms were reported most frequently after the third dose. Almost all of the local and general reactions proved to be of negligible intensity and duration and required no medical intervention. Our results show better tolerability of the vaccine in comparison with the data from some controlled clinical studies and from other surveillance programmes conducted internationally. That tolerability proved to be better than in clinical studies could be explained by the absence of the typical apprehension felt by subjects involved in clinical experimentation. PMID- 21266843 TI - Autophagy and Akt promote survival in glioma. AB - Signaling through phosphatidylinositol 3-kinase (PtdIns3K)-Akt-mTOR is frequently activated in cancers including glioblastoma multiforme (GBM), where this kinase network regulates survival. It is thus surprising that inhibitors of these pathways induce minimal cell death in glioma. We showed that the dual PtdIns3K mTOR inhibitor PI-103 induces autophagy in therapy-resistant, PTEN-mutant glioma, with blockade of mTOR complex 1 (mTORC1) and complex 2 (mTORC2) contributing independently to autophagy. Inhibition of autophagosome maturation synergizes with PI-103 to induce apoptosis through the Bax-dependent intrinsic mitochondrial pathway, indicating that PI-103 induces autophagy as a survival pathway in this setting. Not all inhibitors of PtdIns3K-Akt-mTOR signaling synergize with inhibitors of autophagy. The allosteric mTORC1 inhibitor rapamycin fails to induce apoptosis in conjunction with blockade of autophagy, due to feedback activation of Akt. Apoptosis in the setting of rapamycin therapy requires concurrent inhibition of both autophagy and of PtdIns3K-Akt. Moreover, the clinical PtdIns3K-mTOR inhibitor NVP-BEZ235 cooperates with the clinical lysosomotropic autophagy inhibitor chloroquine to induce apoptosis in PTEN-mutant glioma xenografts in vivo, offering a therapeutic approach translatable to patients. PMID- 21266844 TI - Survival of an islet beta-cell in type-2 diabetes: curbing the effects of amyloid cytotoxicity. AB - Type 2 diabetes mellitus is a chronic hyperglycaemic disorder caused by defective action and secretion of insulin. It is characterized by a progressive decline in pancreatic beta-cell function and mass and the occurrence of insoluble amyloid deposits within the islets of Langerhans. These amyloid deposits comprise predominantly of fibrillar aggregates of the 37-amino acid human amylin (hA) monomer, also known as islet amyloid polypeptide (IAPP), which is co-secreted with insulin from pancreatic islet beta-cells via the regulated secretory pathway. hA has a propensity to aggregate in vitro into fibrillar structures through the self-association of monomers that is largely mediated by an amyloidogenic region spanning amino acids 20-29 (reviewed in ref. 8). PMID- 21266845 TI - Pancreatic cancer with Nest-in tendencies. PMID- 21266846 TI - Plant-based rapid production of recombinant subunit hemagglutinin vaccines targeting H1N1 and H5N1 influenza. AB - In 2009, a novel H1N1 swine influenza virus was isolated from infected humans in Mexico and the United States, and rapidly spread around the world. Another virus, a highly pathogenic avian influenza virus of the H5N1 subtype, identified by the World Health Organization as a potential pandemic threat in 1997, continues to be a significant risk. While vaccination is the preferred strategy for the prevention and control of influenza infections, the traditional egg-based approach to producing influenza vaccines does not provide sufficient capacity and adequate speed to satisfy global needs to combat newly emerging strains, seasonal or potentially pandemic. Significant efforts are underway to develop and implement new cell substrates with improved efficiency for influenza vaccine development and manufacturing. In recent years, plants have been used to produce recombinant proteins including subunit vaccines and antibodies. The main advantages of using plant systems for the production of vaccine antigens against influenza are their independence from pathogenic viruses, and cost and time efficiency. Here, we describe the large-scale production of recombinant hemagglutinin proteins from A/California/04/09 (H1N1) and A/Indonesia/05/05 (H5N1) strains of influenza virus in Nicotiana benthamiana plants, and their immunogenicity (serum hemagglutination inhibition and virus neutralizing antibodies), and safety in animal models. These results support the testing of these candidate vaccines in human volunteers and also the utility of our plant expression system for large-scale recombinant influenza vaccine production. PMID- 21266847 TI - Antibodies to plant-produced Plasmodium falciparum sexual stage protein Pfs25 exhibit transmission blocking activity. AB - Malaria is a serious and sometimes fatal mosquito-borne disease caused by a protozoan parasite. Each year, it is estimated that over one million people are killed by malaria, yet the disease is preventable and treatable. Developing vaccines against the parasite is a critical component in the fight against malaria and these vaccines can target different stages of the pathogen's life cycle. We are targeting sexual stage proteins of P. falciparum which are found on the surface of the parasite reproductive cells present in the mosquito gut. Antibodies against these proteins block the progression of the parasite's life cycle in the mosquito, and thus block transmission to the next human host. Transmission blocking vaccines are essential to the malaria eradication program to ease the disease burden at the population level. We have successfully produced multiple versions of the Pfs25 antigen in a plant virus-based transient expression system and have evaluated these vaccine candidates in an animal model. The targets are expressed in plants at a high level, are soluble and most importantly, generate strong transmission blocking activity as determined by a standard membrane feeding assay. These data demonstrate the feasibility of expressing Plasmodium antigens in a plant-based system for the economic production of a transmission blocking vaccine against malaria. PMID- 21266849 TI - Co-delivery of PSA and PSMA DNA vaccines with electroporation induces potent immune responses. AB - Prostate cancer (PCa) remains a significant public health problem. Current treatment modalities for PCa can be useful, but may be accompanied by deleterious side effects and often do not confer long-term control. Accordingly, additional modalities, such as immunotherapy, may represent an important approach for PCa treatment. The identification of tissue-specific antigens engenders PCa an attractive target for immunotherapeutic approaches. Delivery of DNA vaccines with electroporation has shown promising results for prophylactic and therapeutic targets in a variety of species including humans. Application of this technology for PCa immunotherapy strategies has been limited to single antigen and epitope targets. We sought to test the hypothesis that a broader collection of antigens would improve the breadth and effectiveness of a PCa immune therapy approach. We therefore developed highly optimized DNA vaccines encoding prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) as a dual antigen approach to immune therapy of PCa. PSA-and PSMA-specific cellular immunogenicity was evaluated in a mouse model for co-delivery and single antigen vaccination. Mice received 2 immunizations spaced 2 weeks apart and immunogenicity was evaluated 1 week after the second vaccination. Both the PSA and PSMA vaccines induced robust antigen-specific IFNgamma responses by ELISpot. Further characterization of cellular immunogenicity by flow cytometry indicated strong antigen-specific TNFalpha production by CD4+ T cells and IFNgamma and IL-2 secretion by both CD4+ and CD8+ T cells. There was also a strong humoral response as determined by PSA-specific seroconversion. These data support further study of this novel approach to immune therapy of PCa. PMID- 21266851 TI - DNA methylation: A source of random variation in natural populations. AB - Epigenetic processes (e.g., DNA methylation) have been proposed as potentially important evolutionary mechanisms. However, before drawing conclusions about their evolutionary relevance, we need to evaluate the independence of epigenetic variation from genetic variation, as well as the extent of methylation polymorphism in nature. We evaluated these in natural populations of a clonal fish, Chrosomus eos-neogaeus, for which genetically identical individuals may be found in distinct environments. A genomic survey confirms the genetic uniformity of individuals, whereas a substantial level of inter-individual variation results in DNA methylation. Survey of the methylation status of the CpG dinucleotides of a fragment of a retrotransposon confirmed a marked difference in epiallelic composition among tissues, as well as among individuals. This study provides further evidence of epigenetic variation in the absence of genetic variation and demonstrates that this process can be a source of random variation in natural populations. PMID- 21266850 TI - A novel fluorescence imaging approach for comparative measurements of pancreatic islet function in vitro. AB - Pancreatic islet dysfunction is a key element in the development of type 2 diabetes. Determining possible early warning signs of dysfunction is thus important to determining the underlying causes of diabetes. We describe an improved fluorescent imaging approach to detect potential islet dysfunction. Using Cell Tracker Red (CTR, a mildly thiol-reactive fluorescent probe) to positively label particular islets, we measured intracellular free calcium with fura-2 AM in both CTR-labeled and unlabeled sets of pancreatic islets simultaneously in vitro. This approach enhances sensitivity by controlling for differences in background fluorescence, temperature, and perifusion dynamics. We confirmed that 200 nM CTR produced no spectral overlap with fura-2 and no significant physiological effects in selective tests of islet function. To demonstrate the utility of dual-labeling, we compared untreated islets with islets pretreated with low-dose pro-inflammatory cytokines (IL-6 + IL-1B) to induce mild dysfunction. We alternated CTR-labeling between control and test islets and identified consistent reductions in the amplitude and trajectory of glucose-stimulated calcium responses (GSCa) among cytokine-treated islets that were independent of labeling. Observations were verified using a MATLAB program specifically designed to identify key features in the GSCa. Our findings thus demonstrate the utility of CTR-labeling in identifying islet dysfunction and propose that this technique can be adapted for other cells and tissues. PMID- 21266852 TI - Early epigenetic events regulate the adaptive immune response gene CIITA. AB - Precise regulation of Major Histocompatibility class II (MHC II) genes plays important roles in initiation, propagation and termination of adaptive immune responses by controlling antigen presentation to CD4+ T cells. MHC II genes are constitutively expressed in only a few cell types and are inducibly expressed by the inflammatory response cytokine interferon gamma (IFNgamma) in all nucleated cells. The regulation of MHC II is tightly controlled by a Master Regulator, the class II transactivator (CIITA), which is a general regulator of both constitutive and inducible MHC II expression. Although much is known about the transcription factors necessary for CIITA expression, less is known about the epigenetic modifications and the requisite enzymes needed to provide these transcription factors access to DNA. We show here that multiple epigenetic changes occur at the IFNgamma inducible CIITA promoter within 20' of IFNgamma stimulation and that these changes correlate with the opening of the promoter and the initiation of transcription. Our study links these rapidly occurring epigenetic events at the inducible CIITA promoter to decreased promoter binding of the histone methyltransferase EZH2, and shows that decreased promoter binding of EZH2 transforms this previously tightly regulated and cytokine inducible promoter into a constitutively active and dysregulated gene. PMID- 21266853 TI - Methylome analysis reveals Jak-STAT pathway deregulation in putative breast cancer stem cells. AB - Growing evidence supports the existence of a subpopulation of cancer cells with stem cell characteristics within breast tumors. In spite of its potential clinical implications, an understanding of the mechanisms responsible for retaining the stem cell characteristics in these cells is still lacking. Here, we used the mammosphere model combined with DNA methylation bead arrays and quantitative gene expression to characterize the epigenetic mechanisms involved in the regulation of developmental pathways in putative breast cancer stem cells. Our results revealed that MCF7-derived mammospheres exhibit distinct CpG promoter methylation profiles in a specific set of genes, including those involved in Jak STAT signaling pathway. Hypomethylation of several gene components of the Jak STAT pathway was correlated with an increased expression in mammospheres relative to parental cells. Remarkably, cell sorting of the cells with a putative cancer stem cell phenotype (CD44+/CD24 low) suggests a constitutive activation of Jak STAT pathway in these cells. These results show that Jak-STAT activation may represent a characteristic of putative breast cancer stem cells. In addition, they favor the concept that the expression of cancer stem-like pathways and the establishment and maintenance of defining properties of cancer stem cells are orchestrated by epigenetic mechanisms. PMID- 21266854 TI - ERbeta and PEA3 co-activate IL-8 expression and promote the invasion of breast cancer cells. AB - Metastasis represents the major remaining cause of mortality in human breast cancer. Interleukin-8 (IL-8), a proinflammatory chemokine, plays an important role during tumor angiogenesis and metastasis. In this study, we found that IL-8 and ERbeta showed positive association. Overexpression of ERbeta or PEA3 could up regulate IL-8 promoter activity, mRNA and secretion; silencing of ERbeta or PEA3 decreased IL-8 mRNA and secretion. ERbeta and PEA3 increased IL-8 expression through binding to the IL-8 promoter and increased cell invasion. HER2 could increase ERbeta and PEA3 expression and their binding to the IL-8 promoter. We conclude that ERbeta and PEA3 play important roles in tumor invasion by regulating IL-8 expression, and HER2 maybe the upstream of ERbeta and PEA3 - IL-8 pathway. PMID- 21266855 TI - Large human islets secrete less insulin per islet equivalent than smaller islets in vitro. AB - Islet yield is a critical parameter to determine clinical use of isolated islets. Because islet equivalent (IEQ) is used to evaluate islet yield, it is important to know the function per IEQ. In this study, we assessed insulin secretion per IEQ by our newly developed single islet glucose-stimulated insulin release test (SI-GSIRT). For SI-GSIRT, an individual islet was classified by its diameter from the area of a digital image and calculated IEQ. Each single islet was incubated with low glucose followed by high glucose solutions. Insulin secretions by SI GSIRT were compared based on diameter of islets. There was a significantly strong correlation between insulin secretion stimulated by high glucose solution and low glucose solution (R(2) =0.90, p< 0.001) confirming our technical applicability for SI-GSIRT. Insulin secretion stimulated by high glucose per IEQ was significantly lower in larger islets compared to smaller islets. This means that one IEQ from a large islet secretes less insulin than one IEQ from a small islet. In conclusion, we developed SI-GSIRT to evaluate single islets. This method revealed that large human islets secrete less insulin per IEQ. Thus the distribution of islet size must be monitored when the glucose stimulation test is conducted. PMID- 21266856 TI - 13-valent pneumococcal conjugate vaccine immune sera protects against pneumococcal serotype 1, 3, and 5 bacteremia in a neonatal rat challenge model. AB - PCV7 was first licensed in the United States in 2000 based on clinical efficacy studies. Since the introduction, PCV7 has demonstrated protective effectiveness for each of the vaccine serotypes. More recently, PCV13 has been licensed in more than 60 countries based on serological noninferiority to PCV7 for the shared serotypes and noninferiority to the least immunogenic serotypes of PCV7 for the additional 6 serotypes in PCV13. To evaluate whether the functional antibody responses to serotypes 1, 3, and 5 were sufficient to protect animals challenged with virulent strains of these serotypes, rhesus macaques were immunized with three clinical doses of PCV13. The macaques mounted robust anti-capsular polysaccharide IgG and opsonophagocytic killing (OPA) responses to each serotype contained in the vaccine. Pooled pre-immunization sera and post-immunization serum pools were tested in a neonatal rat bacteremia model. Passive transfer of pooled post-immunization sera, but not pre-immunization sera, protected neonatal rats from lethal IP challenge with serotype 1, 3, or 5 strains. The functional activity of PCV13 immune sera against a virulent type 3 strain was further evaluated using sera from human children immunized with 4 doses of PCV7 or PCV13. Pooled sera from children immunized with PCV13, but not pooled sera from children immunized with PCV7, which does not contain the serotype 3 polysaccharide conjugate, protected neonatal rats from lethal IP challenge with a highly encapsulated and virulent serotype 3 strain. These data suggest that PCV13 will provide protection against pneumococcal serotype 1, 3, and 5 disease in human populations, even at relatively low OPA titers. PMID- 21266857 TI - Arrested Plasmodium liver stages as experimental anti-malaria vaccines. AB - Eukaryotic pathogens typically follow a complex life cycle, including host switch and morphologically distinct forms. Parasite stage conversion offers exceptional opportunities for whole organism vaccine development. In case of Plasmodium, the causative agent of malaria, disease is exclusively caused by asexual blood stages that invade and replicate within erythrocytes. Pathogenic blood stage infections are preceded by a silent parasite growth phase inside the liver. Two alternative experimental whole organisms vaccine strategies that lead to arrested Plasmodium liver stages elicit potent, lasting immunity against re-infection. Live irradiation- or genetically arrested parasites are metabolically active and correspond to classical attenuated vaccines. Specific antimalarial treatment during experimental natural sporozoite infections prevents a febrile malaria episode and, simultaneously, induces effective anti-liver stage immunity. Translation of these strategies into a safe, affordable, and accessible pediatric anti-malaria vaccine requires major bioengineering and pharmaceutical improvements, respectively, but holds promise for a truly effective immunization scheme against the most prevalent and fatal vector-borne disease. PMID- 21266858 TI - Periodontal disease and hypertension: a chicken and egg story? PMID- 21266859 TI - Can exercise prevent preeclampsia? PMID- 21266860 TI - Issues in the development of new combinations of blood pressure lowering drugs. PMID- 21266863 TI - The Boston anesthesia system. PMID- 21266864 TI - Liebig on the 100 reichsmark banknote. PMID- 21266865 TI - Combination of EuroSCORE and cardiac troponin I improves the prediction of adverse outcome after cardiac surgery. AB - BACKGROUND: Reclassification tables have never been used to compare concentrations of cardiac troponin I (cTnI) with predictive models of risk in the perioperative setting. The current study aimed to evaluate the prognostic value of pre- and/or postoperative serum cTnI when combined with The European System for Cardiac Operative Risk Evaluation (EuroSCORE) in predicting adverse outcome after cardiac surgery. METHODS: Nine hundred five consecutive patients were included. Standard EuroSCORE as well as preoperative and 24-h postoperative cTnI were measured in all patients. Major adverse cardiac events and in-hospital mortality were chosen as study endpoints. The performance of EuroSCORE with and without pre- and/or postoperative cTnI were assessed by means of receiver operating characteristic curves, net reclassification index, and integrated discrimination improvement analyses. Data are expressed as +/-SD. RESULTS: Death occurred in 28 of 905 (3%) patients and major adverse cardiac events in 202/905 (22%) patients. Models including EuroSCORE alone were characterized by a low discriminative power (c-index = 0.60 +/- 0.05) in predicting major adverse cardiac events. The c-index increased to 0.61 +/- 0.05 (P = 0.46), 0.70 +/- 0.04 (P < 0.001), and 0.71 +/- 0.04 (P < 0.001) when preoperative, postoperative, and pre/postoperative cTnI were included, respectively. The better predictive ability was confirmed by net reclassification index (0.41 +/- 0.08, P < 0.001; 0.67 +/- 0.08, P < 0.001; and 0.68 +/- 0.08, P < 0.001, respectively) and integrated discrimination improvement (0.003 +/- 0.002, P = 0.12; 0.099 +/- 0.015, P < 0.001; and 0.094 +/- 0.016, P < 0.001, respectively). Similar results were observed for in-hospital mortality. CONCLUSIONS: The combination of EuroSCORE and postoperative cTnI provides the best discriminative power and performance in predicting adverse outcome after cardiac surgery and is suggested as being an effective model that improves early identification of high-risk patients. PMID- 21266866 TI - The barn by vandam. PMID- 21266867 TI - Annie oakley guns down "cocaine libel". PMID- 21266868 TI - Acute postoperative negative-pressure pulmonary edema. PMID- 21266869 TI - Questioning diuretic use in acute negative-pressure pulmonary edema. PMID- 21266870 TI - Face mask ventilation using a lower lip face mask placement in edentulous patients. PMID- 21266873 TI - Another way to eliminate an air leak during mask ventilation in edentulous patients. PMID- 21266874 TI - Why do similar studies conclude differently when they are performed with nearly the same protocol and the same skin conductance technology and on the same population of patients? PMID- 21266876 TI - Supersized suites. PMID- 21266877 TI - American Society of Anesthesiologists P5: "with or without" definition? PMID- 21266880 TI - Ergonomics in healthcare facility design, part 1: patient care areas. AB - There are many ergonomic considerations during design that can enhance nurse and other provider safety in the built healthcare environment. This facility design department aims to expand nurse leaders' knowledge and competencies in health facility design and enables them to take leadership roles in design efforts. Part 1 in this 2-part series focuses on ergonomic designs for patient care areas to enhance patient and nurse safety. Part 2 discusses ergonomic designs for centralized and decentralized nursing stations. PMID- 21266881 TI - Staying afloat in a sea of digital waves. AB - As systems evolve over time, their natural tendency is to become increasingly more complex. Studies in the field of complex systems have generated new perspectives on management in social organizations such as hospitals. Much of this research appears as a natural extension of the cross-disciplinary field of systems theory. This is the 17th in a series of articles applying complex systems science to the traditional management concepts of planning, organizing, directing, coordinating, and controlling. In this article, Dr Clancy further discusses the similarity in complex system behavior observed between the financial markets and healthcare systems. PMID- 21266882 TI - The emergence of nurse executive influence in practice: an interview with Joyce Clifford. Interview by Jeffrey M. Adams. AB - This department highlights nursing leaders who have demonstrated the ability to inspire and lead change. This competency is seen in the ability to create, structure, and implement organizational change through strategic vision, risk taking, and effective communication. In this article, the author showcases the work of Joyce Clifford, PhD, RN, FAAN. PMID- 21266883 TI - Sustaining a successful RN compensation model through transparency and communication. AB - In the March 2005 issue of The Journal of Nursing Administration, authors from an academic medical center outlined a new RN salary program that addressed recruitment and retention of valued resources and established an approach for pay and pay practices for staff RNs across an integrated practice. This follow-up article describes experiences in implementing the program and the successful outcomes achieved. PMID- 21266884 TI - The association of shift-level nurse staffing with adverse patient events. AB - OBJECTIVE: The objective of this study was to demonstrate the association between nurse staffing and adverse events at the shift level. BACKGROUND: Despite a growing body of research linking nurse staffing and patient outcomes, the relationship of staffing to patient falls and medication errors remains equivocal, possibly due to dependence on aggregated data. METHODS: Thirteen military hospitals participated in creating a longitudinal nursing outcomes database to monitor nurse staffing, patient falls and medication errors, and other outcomes. Unit types were analyzed separately to stratify patient and nurse staffing characteristics. Bayesian hierarchical logistic regression modeling was used to examine associations between staffing and adverse events. RESULTS: RN skill mix, total nursing care hours, and experience, measured by a proxy variable, were associated with shift-level adverse events. CONCLUSIONS: Consideration must be given to nurse staffing and experience levels on every shift. PMID- 21266885 TI - Work-related burnout, job satisfaction, intent to leave, and nurse-assessed quality of care among travel nurses. AB - OBJECTIVE: This research study examines work-related burnout, job satisfaction, nurse-assessed quality of care, and intent to leave in travel nurses, a population that has not been studied previously. BACKGROUND: Travel nurses are frequently used to supplement nursing staff in acute care hospitals, especially in times of shortage--understanding their satisfaction with the job may further illuminate the problem of nurse job dissatisfaction in general. METHODS: Ordinary least-squares regression analyses were used to examine the influence of nurse and workplace characteristics on work-related burnout, job satisfaction, intent to leave, and perceived quality of care. RESULTS: Quality of care and job satisfaction were significantly influenced by whether a hospital held Magnet designation. As the number of patients cared for increases, there was a significant increase in work-related burnout. Work-related burnout was also significantly lower for nurses working in California. CONCLUSION: The results of this study suggest that different workplace characteristics influence the perceptions of quality of care provided at a hospital facility and the degree to which a nurse is either burned out or satisfied with his/her job. PMID- 21266886 TI - Feasibility of a multi-institution collaborative to improve patient-nurse relationship quality. AB - OBJECTIVE: The objective of the study was to assess the feasibility of a multi institution quality improvement collaborative to improve patient-nurse relationship quality. BACKGROUND: Patient-nurse relationships provide the foundation for nursing services and are linked to patient outcomes. Measuring the quality of these relationships is important for ongoing practice changes. METHODS: A prospective evaluation approach was used. Patients from 12 hospitals in 4 distinct areas of the United States comprised the sample. RESULTS: All 12 hospitals submitted patient data on a quarterly basis, yielding a reliable database for performance improvement. The Caring Assessment Tool (CAT) performed well, and individual hospitals used the results to improve their performance. Inconsistencies in labeling, differing sample sizes, and administrative burden limited the results. CONCLUSIONS: Adult patients were willing to provide feedback about their care during hospitalization and multiple institutions successfully participated in the project. An electronic version of the CAT with real-time analysis would decrease burden and provide more timely and accurate results for actionable practice changes. PMID- 21266887 TI - Decreasing pressure ulcers across a healthcare system: moving beneath the tip of the iceberg. AB - The authors describe a pressure ulcer prevention program implemented across a large healthcare system in Minnesota. An interprofessional team of representatives from 10 hospitals developed a bundle of interventions directed at measurement standardization, provider education, patient/family education and point-of-care resources for providers, timely nutritional assessment, and a novel Skin Day event intended to increase awareness. The number of pressure ulcers reported to the State of Minnesota decreased 33% after implementation of the program with a potential cost savings of up to $430,000. PMID- 21266889 TI - The passage of time. PMID- 21266888 TI - Use of outsourced nurses in long-term acute care hospitals: outcomes and leadership preferences. AB - When staffing effectiveness is not maintained over time, the likelihood of negative outcomes increases. This challenge is particularly problematic in long term acute care hospitals (LTACHs) where use of outsourced temporary nurses is common when providing safe, sufficient care to medically complex patients who require longer hospital stays than normally would occur. To assess this issue, the authors discuss the outcomes of their survey of LTACH chief nursing officers that demonstrated LTACH quality indicators and overall patient satisfaction were within nationally accepted benchmarks even with higher levels of outsourced nurses used in this post-acute care setting. PMID- 21266891 TI - Treatment-disrupting behaviors during psychotherapy of patients with personality disorders: the predictive power of psychodynamic personality diagnosis. AB - BACKGROUND: Behavioral dyscontrol and violations of treatment contracts are serious clinical problems during psychotherapy, especially in treating patients with personality disorders. However, little is known about predictors of these treatment-interfering phenomena. OBJECTIVE: To identify psychodynamic personality characteristics that can interfere with the psychotherapy process as indicated by treatment-disrupting behaviors. METHODS: Sociodemographic characteristics, descriptive psychiatric diagnoses, and psycho-dynamic characteristics were assessed in 89 inpatients with personality disorders in psychotherapeutic treatment. Psychodynamic characteristics were assessed with the Develop mental Profile (DP). DP variables were used to predict impulsive acts, anger outbursts, para-suicidal behaviors, and contract violations. Incremental value was established. RESULTS: In this sample, 4 out of 5 patients engaged in treatment interfering behaviors during the first 3 months of therapy. In general, treatment disrupting behaviors were not predicted by baseline DSM-IV Axis I or II disorders. In contrast, impulsive behaviors, anger outbursts, and contract violations were significantly predicted by psychodynamic variables, especially the DP levels Fragmentation and Egocentricity. DP variables accounted for an incremental predictive value of 23% for treatment-disrupting behaviors, over and above demographics and descriptive diagnoses. Para-suicidal gestures were not predicted by either DSM-IV diagnoses or psychodynamic variables. CONCLUSION: Psychodynamic personality variables significantly predicted impulsive behaviors, outbursts of anger, and treatment contract violations during psychotherapeutic treatment. The amount of explained variance and incremental value was substantial. These findings support the relevance of psychodynamic assessment in clinical practice. (Journal of Psychiatric Practice. 2011;17:21-34). PMID- 21266892 TI - Carnitine and metabolic correlates in hospitalized psychiatric patients: a follow through report. AB - BACKGROUND: Carnitine deficiency may be encountered in the context of chronic psychiatric illness, particularly with the chronic use of valproic acid. Despite the importance of carnitine in lipid metabolism and mitochondrial function, its metabolic effects have not been studied in a psychiatric population. OBJECTIVE: To raise awareness regarding the possible metabolic implications of carnitine homeostasis in psychiatric patients. METHOD: Retrospective database review in a subgroup of 23 patients with documented hypo carnitinemia. RESULTS: Statistical analysis revealed a negative correlation between serum carnitine levels and lipid levels. Initial fasting plasma glucose levels correlated positively with acylcarnitine/free carnitine ratios, suggesting unfavorable secondary effects of carnitine insufficiency, which resolved once carnitine was supplemented. CONCLUSION: Carnitine is a plausible substrate for future investigations of metabolic status in psychiatric patients. Further studies are needed to evaluate whether serum carnitine levels may be useful as a marker for psychiatric patients at risk for developing metabolic syndrome, and whether carnitine supplementation may reduce that risk. (Journal of Psychiatric Practice 2011;17:35-40). PMID- 21266893 TI - Learning from losing: ethical, psychoanalytic, and spiritual perspectives on managing the incremental losses of the distributed self in dementia. AB - The author describes his experiences making decisions about the care of his mother, who was suffering from dementia, and the profound effect this process had on him as a psychotherapist. As background, he first presents an overview of writings from Jerry M. Lewis, George Pollock, and George Vaillant on issues related to attachment, death, loss, and mourning. The author equates his experiences caring for his mother with a type of involuntary "continuing education" and describes the lessons he learned as he was faced with decisions about his mother's level of care and as he mourned the slow, piecemeal loss of her distributed self. A case vignette is presented to illustrate how the author applied the lessons he had learned in psychotherapy with a distressed patient caring for her aging mother. The article concludes with a summary of the clinical and ethical questions raised by this case and the author's experience with his mother and a discussion of principles that can help psychotherapists provide treatment for patients who are caring for family members with dementia. (Journal of Psychiatric Practice. 2011;17:41-48). PMID- 21266890 TI - Improving treatment adherence in patients with bipolar disorder and substance abuse: rationale and initial development of a novel psychosocial approach. AB - Patients with comorbid bipolar and substance use disorders are at particularly high risk for treatment nonadherence and a host of negative consequences. However, no previous interventions have been designed specifically to address this problem. In the current study, we describe the rationale for and initial development of an adjunctive psychosocial intervention that targets adherence in patients with bipolar disorder who are substance abusers. The intervention involves brief in-person sessions and follow-up phone contacts with the patient and a significant other/family member. We describe the effects of this novel intervention on adherence and other psychiatric outcomes in a series of cases treated as part of our initial development work. Results suggest that the intervention is feasible and acceptable to patients and could be helpful in enhancing the effects of existing treatments. Given these promising results, we plan to test the intervention further in a randomized clinical trial. PMID- 21266894 TI - CNS drug development: part III: future directions. AB - This column, the third in a series on central nervous system (CNS) drug development, discusses advances during the first decade of the 21st century and directions the field may take in the next 10 years. By identifying many possible new drug targets, the human genome project has created the potential to develop novel central nervous system (CNS) drugs with new mechanisms of action. At the same time, this proliferation of possible new targets has complicated the drug development process, since research has not yet provided guidance as to which targets may be most fruitful. This and other factors (eg, increasing regulatory requirements) have increased the cost and complexity of the drug development process. In addition, as more is learned about the biology of psychiatric illnesses, syndromes may be subdivided into more specific entities that are better understood from a pathophysiological and pathoetiological perspective. This is likely to lead to development of more targeted treatments focused on underlying causes of illness as well as prevention. The development of drugs for Alzheimer's disease is discussed as a possible model for future CNS drug development. We are at the beginning of an era when it is likely that the way in which CNS drugs are developed will need to be rethought, which will call for flexibility and creativity on the part of both drug developers and clinical researchers. PMID- 21266895 TI - Addressing impairment in a colleague. AB - It is an anguishing experience for a professional community to deal with a colleague's impairment. This column is the outgrowth of a recent workshop in a multidisciplinary psychoanalytic center focused on the ethical, technical, and humane dimensions of that situation. A hypothetical case history was used to stimulate discussion of issues related to clinical evidence of impairment, protection of patients/clients, the role of aging in observers as well as the observed, denial and wishful thinking that may delay intervention, how to intervene, and duties imposed by the various health professional licensing boards. The discussion also focused on the effects of impairment and intervention on confidential psychotherapeutic relationships and process as well as on personal friendships, monitoring colleagues dealing with impairments, and the resources for response within the professional community such as assistance and ethics committees. (Journal of Psychiatric Practice 2011;17:53-56). PMID- 21266896 TI - Statistics for the clinician: diagnostic questionnaires. AB - The goal of this column is to help working clinicians understand the statistical calculations involved in interpreting the results of diagnostic questionnaires. Using the Patient Health Questionnaire-9 as an example, the author explains how to determine the most appropriate cutoffs to choose, depending on the population involved, the probabilities of error (a and {), and the expected losses associated with each kind of error in the context in which the test is being administered. (Journal of Psychiatric Practice. 2011;17:57-60). PMID- 21266897 TI - Electroconvulsive therapy for the treatment of refractory mania. AB - We present the case of a patient with treatment-refractory mania. The patient had been tried on numerous medications, to which she either did not respond well or on which she developed severe side effects, However, the patient improved rapidly when treated with unilateral electropercussive therapy (ECT) following a court order. We outline the legal barriers that have been raised against the use of ECT in patients with mania, who often refuse treatment, and the irony that ECT can be safer than medications for some patients. ECT is underutilized in mania but deserves more frequent consideration. (Journal of Psychiatric Practice. 2011;17:61-66). PMID- 21266898 TI - Clinical characteristics of patients with major depressive disorder with and without hypothyroidism: a comparative study. AB - INTRODUCTION: Differentiating major depressive disorder (MDD) without hypothyroidism from MDD associated with hypothyroidism can be challenging. Therefore some authors have suggested that thyroid function should be tested in all depressed patients. This study compared the clinical characteristics of patients with MDD associated with hypothyroidism with those of patients with MDD without hypothyroidism. METHOD: Thyroid function tests were administered to 75 patients (60 female and 15 male) who met DSM-IV criteria for MDD. The 15 patients with hypothyroidism (8 with subclinical hypothyroidism and 7 with overt hypothyroidism) were compared with the other 60 patients with regard to depressive characteristics. The primary measure of depressive signs and symptoms used to assess depression severity and symptoms was the Hamilton Rating Scale for Depression, first 17 items (Ham-D-17). Baseline demographic data, including age and sex, were also compared. RESULT: The two groups did not differ significantly in severity of overall depression at baseline, as measured by total score on the Ham-D-17 (P=0.471, Z=0.970). Patients with MDD without hypothyroidism had worse scores on item 1 (depressed mood), item 2 (feelings of guilt), item 3 (suicidality), item 6 (late insomnia), and item 16 (loss of weight). In contrast, depressed patients with hypothyroidism had more severe anxiety symptoms and greater agitation (items 9, 10, and 11). CONCLUSION: Our results may help clinicians differentiate MDD associated with hypothyroidism from MDD without hypothyroidism. Depressed patients with hypothyroidism had more anxiety symptoms and greater agitation, but they had fewer severe core depressive symptoms and biological signs of MDD. (Journal of Psychiatric Practice. 2011;17:67-71). PMID- 21266900 TI - Adult interleukin-6 knockout mice show compromised neurogenesis. AB - Interleukin-6 (IL-6) is a proinflammatory cytokine known to modulate neurogenesis. We presently evaluated neural progenitor proliferation, survival, and phenotypic maturation in the hippocampal dentate gyrus, subventricular zone, and the posterior periventricle in the brains of IL-6 knockout mice and their wild-type littermates. In all the three neurogenic regions of the IL-6 mice there was a significant decrease in the number of 5-bromo-2-deoxyuridine positive (BrdU) proliferating progenitors compared with the IL-6 mice. The IL-6 mice also showed a significantly lower progenitor cell survival in the dentate gyrus and subventricular zone compared with the IL-6 mice. In conclusion, a complete lack of IL-6 might be detrimental to neurogenesis in the adult brain. PMID- 21266901 TI - The continuing evolution of somatostatin receptor imaging in neuroendocrine tumours. PMID- 21266904 TI - The scope is not limited. PMID- 21266906 TI - Do miniaturized extracorporeal circuits confer significant clinical benefit without compromising safety? A meta-analysis of randomized controlled trials. AB - Miniaturized extracorporeal circulation (mECC) attempts to reduce the adverse effects of conventional extracorporeal circulation (CECC) bypass. However, the potential benefits remain unclear and safety concerns persist. A systematic literature review identified 29 studies incorporating 2,355 patients: 1,181 (50.1%) who underwent cardiac surgery with CECC and 1,174 (49.9%) with mECC. These were meta-analyzed using random effects modeling. Heterogeneity, subgroup analysis, and risk of bias were assessed. Primary endpoints were 30-day mortality, neurovascular compromise, and end organ dysfunction. Secondary endpoints were length of stay and transfusion burden. Miniaturized extracorporeal circulation significantly reduced postoperative arrhythmias (p = 0.03), but no significant difference in 30-day mortality, neurocognitive disturbance, cerebrovascular events, renal failure, or myocardial infarction was identified. Miniaturized extracorporeal circulation also significantly reduced mean blood loss (p < 0.00001) and number of patients transfused (p < 0.00001); however, duration of hospitalization, units transfused per patient, chest tube drainage, and revision for rebleeding remained unchanged. Subgroup analysis of larger studies (10 studies, n >= 31) showed mECC to significantly reduce ventilation period, hospital stay, and intensive care unit (ICU) stay. Similarly, a significant reduction in neurocognitive disturbance was seen in studies with closely matched demographic groups. Miniaturized extracorporeal circulation is not associated with increased cerebrovascular injury and may confer an advantage, reducing postoperative arrhythmia, blood loss, and transfusion burden. PMID- 21266907 TI - The effect on hemolysis of the raceway profile of roller pumps used in cardiopulmonary bypass. AB - This study aims at the influence on hemolysis of the differences between the maximum and minimum amplitudes of pressure in the outlet of three roller pump models adjusted by dynamic calibration method. Tests were performed with silicone tubes (1/2 * (3)/(16) inches) in fluid analogous to blood and fresh bovine blood from slaughterhouse. Tests with analogous solution to blood were performed varying the dynamic calibration pressure between 78 and 500 mm Hg. Tests with fresh bovine blood were performed with the three pumps simultaneously, and pressure differences and free hemoglobin in the plasma were measured during 360 minutes. Tests with both analogous solution to blood and fresh bovine blood showed differences of mean pressures of pump 2 related to pumps 1 and 3 (p < 0.01). The different models of roller pumps analyzed presented differences in pressure amplitudes (p < 0.01) and hemolysis (p < 0.01) adjusted for the same dynamic calibration pressure. Raceway profile of pump 2 resulted in smaller pressure amplitude, implying lower hemolysis rate compared with pumps 1 and 3. PMID- 21266908 TI - Factors associated with decreased kidney function in HIV-infected adults enrolled in the MTCT-Plus Initiative in sub-Saharan Africa. AB - BACKGROUND: Pre-existing kidney disease in HIV-infected patients may necessitate dose modification of antiretroviral therapy (ART). Despite increasing ART availability, there are few prevalence studies of chronic kidney disease in HIV infected individuals across multiple African countries. METHODS: Routine laboratory data obtained before ART initiation were used to evaluate prevalence and predictors of decreased creatinine clearance (CrCl) in participants of the MTCT-Plus Initiative from 7 sub-Saharan countries. Cockcroft-Gault equation was used to estimate CrCl and logistic regression modeling to identify factors associated with CrCl <50 mL/min. RESULTS: Of 2495 individuals evaluated, median age was 30 years (interquartile range: 27-35); 70% were women. Median CD4+ cell count was 295 (interquartile range: 173-450); 78% were World Health Organization stage 1/2. Median CrCl was 95 mL/min. Overall, 3.4% [95% confidence interval (CI): 2.7 to 4.1] of patients had a CrCl <50 mL/min. Age >30 years (odds ratio = 2.06; 95% CI: 1.23 to 3.45) and CD4+ count <50 cells per cubic millimeter (odds ratio = 5.4 for CD4+ <50, 95% CI: 2.5 to 11.9) were associated with CrCl <50 mL/min. CONCLUSIONS: The prevalence of clinically significant kidney disease was low in this relatively healthy population of HIV-infected adults, and few participants would have required ART dose reductions. These findings support recent World Health Organization guidelines to initiate ART without routine laboratory screening. Our findings suggest that available laboratory resources could be targeted to older persons and those with very low CD4+ cell count. PMID- 21266909 TI - Bacterial translocation in HIV-infected patients with HCV cirrhosis: implication in hemodynamic alterations and mortality. AB - OBJECTIVE: Analysis of the influence of portal hypertension on intestinal permeability in HIV-infected patients with hepatitis C virus (HCV)-related cirrhosis and of the prognostic significance of consequent macrophage activation. METHODS: Twenty HIV-monoinfected patients, 70 patients with HIV-HCV coinfection, 20 of them with compensated and 50 with decompensated cirrhosis, and 20 healthy controls were evaluated for intestinal permeability [measured by lipopolysaccharide-binding protein (LBP) serum levels], macrophage activation [soluble CD14, soluble tumour necrosis factor receptor 55 Kd, and interleukin 6 (IL-6)], and activation of the rennin-angiotensin-aldosterone axis. Patients with decompensated cirrhosis were monitored for a median period of 429 days to analyze the prognostic factors implicated in survival. RESULTS: Patients with decompensated cirrhosis show increased LBP levels compared with HIV-monoinfected patients. Patients with increased LBP concentration showed elevated soluble CD14, soluble tumour necrosis factor receptor 55 Kd, and IL-6 levels. Twenty-two patients died, from liver-related causes, during the follow-up, and 2 more underwent liver transplantation. Child-Pugh index, CD4 T-cell count, plasma aldosterone and serum IL-6 concentrations independently predicted liver-related mortality. CONCLUSIONS: Increased intestinal permeability, as measured by serum LBP levels, observed in patients with HIV infection is significantly higher in patients with decompensated liver cirrhosis. Proinflammatory cytokines (IL-6) are prognostic markers of HIV-HCV-coinfected patients with decompensated cirrhosis. PMID- 21266910 TI - Increased risk of severe infant anemia after exposure to maternal HAART, Botswana. AB - BACKGROUND: Maternal highly-active antiretroviral therapy (HAART) reduces mother to-child HIV transmission but may increase the risk for infant anemia. METHODS: The incidence of first severe anemia (grade 3 or 4, Division of AIDS 2004 Toxicity Table) was assessed among HIV-uninfected infants in the Mashi and Mma Bana mother-to-child HIV transmission prevention trials in Botswana. Severe anemia rates were compared between 3 groups: infants exposed to maternal HAART in utero and during breastfeeding (BF) and 1 month of postnatal zidovudine (ZDV) (HAART-BF); infants exposed to maternal ZDV in utero, 6 months of postnatal ZDV, and BF (ZDV-BF); and infants exposed to maternal ZDV in utero, 1 month of postnatal ZDV, and formula-feeding (ZDV-FF). RESULTS: A total of 1719 infants were analyzed-691 HAART-BF, 503 ZDV-BF, and 525 ZDV-FF. Severe anemia was detected in 118 infants (7.4%). By 6 months, 12.5% of HAART-BF infants experienced severe anemia, compared with 5.3% of ZDV-BF (P < 0.001) and 2.5% of ZDV-FF infants (P < 0.001). In adjusted analysis, HAART-BF infants were at greater risk of severe anemia than ZDV-BF or ZDV-FF infants (adjusted odds ratios 2.6 and 5.8, respectively; P < 0.001). Most anemias were asymptomatic and improved with iron/multivitamin supplementation and cessation of ZDV exposure. However, 11 infants (0.6% of all infants) required transfusion for symptomatic anemia. Microcytosis and hypochromia were common among infants with severe anemia. CONCLUSIONS: Exposure to maternal HAART starting in utero was associated with severe infant anemia. Confirmation of this finding and possible strategies to mitigate hematologic toxicity warrant further study. PMID- 21266911 TI - Medical encounter characteristics of HIV seroconverters in the US Army and Air Force, 2000-2004. AB - BACKGROUND AND METHODS: Active duty US Army and Air Force military personnel undergo mandatory biennial HIV antibody screening. We compared pre- and post-HIV seroconversion health status by conducting a case-control study, which evaluated all medical encounters and sociodemographic factors among incident HIV seroconverters and HIV-negative controls from June 2000 through February 2004. RESULTS: A total of 274 HIV seroconverters and 6205 HIV-negative personnel were included. In multivariate analysis restricted to male personnel (cases = 261, controls = 5801), single marital status (adjusted odds ratio [AOR] = 14.37), clinical indicators or symptoms within four years of HIV diagnosis (AOR = 6.22), black race (AOR = 5.88), nonindicator clinical syndromes within 2 years of HIV diagnosis (AOR = 3.31), any mental disorder within 4 years of HIV diagnosis (AOR = 3.04), increasing service-connected time (AOR = 1.69), and older age (AOR = 1.12) were associated with HIV diagnosis among males. A prior history of a sexually transmitted infection (STI) was associated with post-HIV seroconversion STI (OR(M-H) = 4.10). Similarly, a prior history of mental disorder was associated with post-HIV seroconversion mental disorder (OR(M-H) = 4.98). Forty seven (18%) male cases were hospitalized at least once after HIV diagnosis; infectious diseases, and mental disorders made up 53% of initial admissions. CONCLUSIONS: HIV seroconversion was associated with increased health care-seeking behavior, STIs, and mental disorders, some of which may be amenable to screening. The higher STI rate after HIV diagnosis may partially be a consequence of monitoring, but secondary transmission of STI and possibly HIV require further definition and subsequent tailored preventive interventions. PMID- 21266913 TI - Visfatin and cardio-cerebro-vascular disease. AB - Nicotinamide phosphoribosyltransferase is the rate-limiting enzyme that catalyzes the first step in the biosynthesis of nicotinamide adenine dinucleotide from nicotinamide. This protein was originally cloned as a putative pre-B cell colony enhancing factor and also found to be a visceral fat-derived adipokine (visfatin). As a multifunctional protein, visfatin plays an important role in immunity, metabolism, aging, inflammation, and responses to stress. Visfatin also participates in several pathophysiological processes contributing to cardio cerebro-vascular diseases, including hypertension, atherosclerosis, ischemic heart disease, and ischemic stroke. However, whether visfatin is a friend or a foe in these diseases remains uncertain. This brief review focuses on the current understanding of the complex role of visfatin in the cardio-cerebro-vascular system under normal and pathophysiological conditions. PMID- 21266912 TI - Predictors of successful early infant diagnosis of HIV in a rural district hospital in Zambezia, Mozambique. AB - BACKGROUND: A key challenge inhibiting the timely initiation of pediatric antiretroviral treatment is the loss to follow-up of mothers and their infants between the time of mothers' HIV diagnoses in pregnancy and return after delivery for early infant diagnosis of HIV. We sought to identify barriers to follow-up of HIV-exposed infants in rural Zambezia Province, Mozambique. METHODS: We determined follow-up rates for early infant diagnosis and age at first test in a retrospective cohort of 443 HIV-infected mothers and their infants. Multivariable logistic regression models were used to identify factors associated with successful follow-up. RESULTS: Of the 443 mother-infant pairs, 217 (49%) mothers enrolled in the adult HIV care clinic, and only 110 (25%) infants were brought for early infant diagnosis. The predictors of follow-up for early infant diagnosis were larger household size (odds ratio [OR], 1.29; 95% confidence interval [CI], 1.09-1.53), independent maternal source of income (OR, 10.8; 95% CI, 3.42-34.0), greater distance from the hospital (OR, 2.14; 95% CI, 1.01-4.51), and maternal receipt of antiretroviral therapy (OR, 3.15; 95% CI, 1.02-9.73). The median age at first test among 105 infants was 5 months (interquartile range, 2 7); 16% of the tested infants were infected. CONCLUSIONS: Three of four HIV infected women in rural Mozambique did not bring their children for early infant HIV diagnosis. Maternal receipt of antiretroviral therapy has favorable implications for maternal health that will increase the likelihood of early infant diagnosis. We are working with local health authorities to improve the linkage of HIV-infected women to HIV care to maximize early infant diagnosis and care. PMID- 21266914 TI - Physiological and pharmacological roles of vascular nucleoside transporters. AB - Adenosine modulates various vascular functions such as vasodilatation and anti inflammation. The local concentration of adenosine in the vicinity of adenosine receptors is fine tuned by 2 classes of nucleoside transporters: equilibrative nucleoside transporters (ENTs) and concentrative nucleoside transporters (CNTs). In vascular smooth muscle cells, 95% of adenosine transport is mediated by ENT-1 and the rest by ENT-2. In endothelial cells, 60%, 10%, and 30% of adenosine transport are mediated by ENT-1, ENT-2, and CNT-2, respectively. In vitro studies show that glucose per se increases the expression level of ENT-1 via mitogen activating protein kinase-dependent pathways. Similar results have been demonstrated in diabetic animal models. Hypertension is associated with the increased expression of CNT-2. It has been speculated that the increase in the activities of ENT-1 and CNT-2 may reduce the availability of adenosine to adenosine receptors, thereby weakening the vascular functions of adenosine. This may explain why patients with diabetes and hypertension suffer greater morbidity from ischemia and atherosclerosis. No oral hypoglycemic agents can inhibit ENTs, but an exception is troglitazone (a thiazolidinedione that has been withdrawn from the market). ENTs are also sensitive to dihydropyridine-type calcium-channel blockers, particularly nimodipine, which can inhibit ENT-1 in the nanomolar range. Those calcium-channel blockers are noncompetitive inhibitors of ENTs, probably working through the reversible interactions with allosteric sites. The nonsteroidal anti-inflammatory drug sulindac sulfide is a competitive inhibitor of ENT-1. In addition to their original pharmacological actions, it is believed that the drugs mentioned above may regulate vascular functions through potentiation of the effects of adenosine. PMID- 21266915 TI - Synergism of telmisartan and amlodipine on blood pressure reduction and cardiorenal protection in hypertensive rats. AB - AIM: This study was designed to investigate the effects of telmisartan and amlodipine on reduction of blood pressure (BP), myocardial hypertrophy, and renal injury in hypertensive rats. METHOD: In acute experiments, the BP was measured in conscious freely moving rats. Spontaneously hypertensive rats were treated with intragastric administration of amlodipine (1, 2, 4 mg/kg), telmisartan (4, 8, 12, 16, 20 mg/kg), and their different combinations (4 + 4, 2 + 4, 4 + 8, 4 + 12, 1 + 4, 2 + 8, 4 + 16, 2 + 12, 1 + 8, 2 + 16, 2 + 20, 1 + 12, 1 + 16, 1 + 20 mg/kg). The probability sum test (q test) was used to evaluate the synergistic action on BP reduction. In two-kidney, one-clip rats, the effects of amlodipine (1 mg/kg), telmisartan (6 mg/kg) and their combination on BP reduction were observed. In the chronic study, spontaneously hypertensive rats were treated with amlodipine (1 mg/kg), telmisartan (6 mg/kg), and their combination for 4 months. Histopathologic examinations were performed after the determination of BP and BP variability. RESULTS: There is a synergistic interaction between amlodipine and telmisartan on BP reduction. The optimal dose ratio was found at 1:6. The synergistic effect of this dose ratio (1:6) was also seen in two-kidney, one-clip rats. Long-term treatment with this combination results in a beneficial effect on the reduction of BP and BP variability. The end-organ damage, including myocardial hypertrophy, glomerular atrophy, and fibrosis, was significantly attenuated by this combination. CONCLUSION: The optimal dose ratio of amlodipine and telmisartan on BP was 1:6. This combination is beneficial for the BP and BP variability reduction and end-organ damage prevention. PMID- 21266916 TI - The onset of inhibition of platelet aggregation with prasugrel compared with clopidogrel loading doses using gatekeeping analysis of integrated clinical pharmacology data. AB - The purpose of this analysis was to determine the time by which a prasugrel 60-mg loading dose (LD) achieved significantly greater inhibition of platelet aggregation (IPA) than the peak IPA after a clopidogrel 300-mg LD or 600-mg LD. Data were pooled from nine studies representing 587 individuals: 274 healthy subjects and 313 patients with stable coronary artery disease. The primary pharmacodynamic measure was IPA using 20 [mu]M adenosine-5'-diphosphate as the agonist. Gatekeeping analysis compared the peak IPA at 4, 6, and 24 hours after a clopidogrel 300-mg or 600-mg LD with IPA at various prior time points backwards after a prasugrel LD until a statistically nonsignificant difference was reached. Prasugrel 60-mg LD produced greater IPA by 30 minutes than the peak IPA after a clopidogrel 300-mg LD (P < 0.0001). Significantly greater IPA was achieved at 1 hour after prasugrel 60-mg LD compared with the peak IPA after 600-mg clopidogrel LD (P < 0.0001), regardless of sex, body weight, or age and as early as 30 minutes in the diabetic subgroup. A prasugrel 60-mg LD produces significantly faster onset and greater IPA compared with a clopidogrel 300-mg LD or 600-mg LD. PMID- 21266917 TI - Vernakalant selectively prolongs atrial refractoriness with no effect on ventricular refractoriness or defibrillation threshold in pigs. AB - Vernakalant is a novel antiarrhythmic agent that has demonstrated clinical efficacy for the treatment of atrial fibrillation. Vernakalant blocks, to various degrees, cardiac sodium and potassium channels with a pattern that suggests atrial selectivity. We hypothesized, therefore, that vernakalant would affect atrial more than ventricular effective refractory period (ERP) and have little or no effect on ventricular defibrillation threshold (DFT). Atrial and ventricular ERP and ventricular DFT were determined before and after treatment with vernakalant or vehicle in 23 anesthetized male mixed-breed pigs. Vernakalant was infused at a rate designed to achieve stable plasma levels similar to those in human clinical trials. Atrial and ventricular ERP were determined by endocardial extrastimuli delivered to the right atria or right ventricle. Defibrillation was achieved using external biphasic shocks delivered through adhesive defibrillation patches placed on the thorax after 10 seconds of electrically induced ventricular fibrillation. The DFT was estimated using the Dixon "up-and-down" method. Vernakalant significantly increased atrial ERP compared with vehicle controls (34 +/- 8 versus 9 +/- 7 msec, respectively) without significantly affecting ventricular ERP or DFT. This is consistent with atrial selective actions and supports the conclusion that vernakalant does not alter the efficacy of electrical defibrillation. PMID- 21266918 TI - 20-Hydroxyeicosatetraenoic acid induces apoptosis in neonatal rat cardiomyocytes through mitochondrial-dependent pathways. AB - OBJECTIVE: 20-Hydroxyeicosatetraenoic acid (20-HETE), a [omega]-hydroxylation product of arachidonic acid catalyzed by cytochrome P450 4A, may play a role in the cardiovascular system. It is well known that cytochrome P450 [omega] hydroxylase inhibitors markedly reduced the cardiac ischemia reperfusion injury. However, the direct effect of 20-HETE on cardiomyocytes is still poorly investigated. Here, we studied the effect of 20-HETE on cardiomyocyte apoptosis and the apoptosis-associated signaling pathways. METHODS AND RESULTS: The cardiomyocyte apoptosis was measured by fluorescein isothiocyanate conjugated annexin V/propidium iodide double staining cytometry, indicating that the percentage of early apoptotic cells increased from 15.6% +/- 2.6% to 25.5% +/- 2.5% in control and 20-HETE-treated cells, respectively. The mitochondrial membrane potential ([DELTA][PSI]m) was measured by detecting the ratio of JC-1 green/red emission intensity. A significant decrease in the ratio was observed after treatment with 20-HETE for 24 hours in comparison with control group, suggesting the disruptive effect of 20-HETE on mitochondrial [DELTA][PSI]m. In addition, 20-HETE stimulated caspase-3 activity and Bax mRNA expression in cardiomyocytes. In contrast, the Bcl-2 mRNA levels were significantly decreased by 20-HETE treatment. CONCLUSION: These results demonstrate that 20-HETE induces cardiomyocyte apoptosis by activation of several intrinsic apoptotic pathways. The 20-HETE-induced apoptosis could contribute to the cytochrome P450 [omega] hydroxylase-dependent cardiac injure during cardiac ischemia-reperfusion. PMID- 21266919 TI - Accuracy of diagnostic biopsy for the histological subtype of malignant pleural mesothelioma. AB - INTRODUCTION: Histological subtype is an established prognostic factor in malignant pleural mesothelioma (MPM). We retrospectively investigated the accuracy of classifying histological subtype on diagnostic biopsies and examined the impact of different diagnostic procedures on the outcome. METHODS: Consecutive patients with histologically confirmed MPM who underwent extrapleural pneumonectomy (EPP) from 1994 to 2009 were included. Patient records were reviewed, and the initial diagnoses of histological subtype were obtained. The archival EPP specimens were reviewed by a panel of pathologists. The histological subtype obtained at review was compared with the initial diagnosis. RESULTS: Eighty-five patients underwent EPP. Two patients achieved a pathological complete response after neoadjuvant chemotherapy, leaving 83 patients to be included in this review. Different diagnostic methods were used before EPP: 81% thoracoscopy; 7% thoracotomy; 11% computed tomography-guided procedure; and 1% other. Patients determined to have an epithelial subtype (n = 64) at EPP were diagnosed correctly at initial diagnostic biopsy in 84% of cases, whereas patients considered to have a biphasic subtype (n = 19) at EPP were diagnosed correctly at diagnostic biopsy in 26% of cases. The sensitivity and specificity of diagnostic biopsy for epithelial MPM was 93% and 31%, respectively. The overall subtype misclassification rate was 20%. Biopsy by thoracotomy was most accurate in subtype classification (83%) compared with thoracoscopy (74%) and computed tomography-guided procedure (44%). CONCLUSIONS: The determination of histological subtype from a diagnostic biopsy is difficult due to sampling error, but an adequate specimen obtained from surgical biopsy increases the accuracy of subtype classification compared with radiological-guided biopsies. PMID- 21266920 TI - The impact of superior mediastinal lymph node metastases on prognosis in non small cell lung cancer located in the right middle lobe. AB - BACKGROUND: We aimed to assess hilar and mediastinal lymph node involvement and its impact on prognosis in patients with right middle lobe lung cancer. METHODS: The records of 170 patients undergoing surgery for right middle lobe non-small cell lung cancer from 1980 to December 2007 were retrospectively examined. There were 45 patients found to have hilar or mediastinal lymph nodes metastases. This subgroup included 31 N2 patients and 14 N1 patients, and included 23 women and 22 men, whose ages ranged from 32 to 83 years (median = 61 years). The status of mediastinal, hilar, and interlobar lymph nodes was assessed according to the seventh edition of the TNM classification for lung cancer. Patient records were examined for age, gender, preoperative nodal status, surgical procedure, metastatic status of lymph nodes (distribution and numbers), tumor size, and histologic features (cell type and differentiation degree). Survival duration was defined as the interval between surgery and death from the tumor or the most recent follow-up. RESULTS: For N1 cases (n = 14), the most frequent metastatic site was #12m (lymph nodes adjacent to the middle lobe bronchus), which occurred in 11 cases; there was one case with metastases in #11s (lymph nodes between the upper lobe bronchus and bronchus intermedius), and no case with #11i metastases (lymph nodes between the right middle and lower lobe bronchi). The most frequent metastatic mediastinal zone was the subcarinal zone (25/31), and the superior mediastinal zone also had a high incidence of metastases (22/31). Sixteen cases had metastases to both the superior and subcarinal zones, and six cases had metastasis to superior mediastinal zone without subcarinal zone metastasis. When #11s or #11i was involved, eight of nine or five of five, respectively, were N2 cases. Univariate analyses revealed that tumor diameter, cN, status of lymph node metastases, and operative procedure (pneumonectomy) were significant prognostic factors in N2 cases. Regarding status of lymph node metastases, superior mediastinal zone metastases, both superior and inferior (subcarinal) zone metastases, and #11i were significant prognostic factors. Because #11i metastases and superior mediastinal lymph nodes metastases were highly correlated with each other (p = 0.02), two separate models were used in multivariate analyses. Superior mediastinal metastases (p = 0.03) and #11i metastases (p = 0.015) were revealed to be significant independent prognostic factors, whereas multiple-zone metastases only tended toward significance as an adverse prognostic factor (p = 0.054). CONCLUSIONS: Superior mediastinal lymph node metastases and #11i metastases were significant adverse prognostic factors in patients with middle lobe lung cancer, and they were associated with each other. PMID- 21266921 TI - Management of thymic tumors: a survey of current practice among members of the European Society of Thoracic Surgeons. AB - INTRODUCTION: Management of thymoma has largely been based on single-institution retrospective, observational studies. The European Society of Thoracic Surgeons (ESTS) Thymic Working Group has investigated the current practice among ESTS members. METHODS: A questionnaire divided into seven sections with 24 questions was designed, and it was delivered to ESTS members. RESULTS: Forty-four centers replied to the questionnaire. The results indicate that there is a general agreement concerning (1) the value of computed tomography scan for preoperative assessment; (2) the uselessness of a routine histologic confirmation before surgery; (3) the role of the World Health Organization classification; (4) the importance of complete and extended resection; (5) the role of surgery for recurrent disease; and (6) the need of a multidisciplinary team, including thoracic surgeons, pathologists, medical, and radiation oncologists. On the other hand, there is still a considerable debate about (1) the role of positron emission tomography scan for preoperative assessment; (2) a consistent and reliable staging system; (3) the usefulness of postoperative treatments for stages II and III diseases; (4) the management of type C thymoma; and (5) the role of extrapleural pneumonectomy for stage IVA thymoma. CONCLUSIONS: The survey provides a large, multiinstitutional overview of the clinical practice in the management of thymic tumors by ESTS members. Responses show some areas of agreement along with several areas of controversy. It is conceivable that a consequent step forward will be the creation of a collaborative effort within the ESTS and with other organizations for the creation of standard recommendations and guidelines for the management of thymic malignancies. PMID- 21266922 TI - Suitability of thoracic cytology for new therapeutic paradigms in non-small cell lung carcinoma: high accuracy of tumor subtyping and feasibility of EGFR and KRAS molecular testing. AB - INTRODUCTION: The two essential requirements for pathologic specimens in the era of personalized therapies for non-small cell lung carcinoma (NSCLC) are accurate subtyping as adenocarcinoma (ADC) versus squamous cell carcinoma (SqCC) and suitability for EGFR and KRAS molecular testing. The aim of this study was to comprehensively review the performance of cytologic specimens for the above two goals in a high-volume clinical practice. METHODS: Subtyping of primary lung carcinomas by preoperative cytology was correlated with subsequent resection diagnoses during a 1-year period (n = 192). The contribution of various clinicopathologic parameters to subtyping accuracy and utilization of immunohistochemistry (IHC) for NSCLC subtyping were analyzed. In addition, the performance of cytologic specimens submitted for EGFR/KRAS molecular testing during a 1-year period (n = 128) was reviewed. RESULTS: Of the 192 preoperative cytology diagnoses, tumor subtype was definitive versus favored versus unclassified in 169 (88%) versus 15 (8%) versus 8 (4%) cases, respectively. Overall accuracy of cytologic tumor subtyping (concordance with histology) was 93% and accuracy of definitive diagnoses 96%. For a group of patients with ADC and SqCC (n = 165), the rate of unclassified cytologic diagnoses was 3% and overall accuracy 96%. IHC was used for subtyping of 9% of those cases, yielding 100% accuracy. The strongest predictors of difficulty in subtyping of ADC and SqCC were poor differentiation (p = 0.0004), low specimen cellularity (p = 0.019), and squamous histology (p = 0.003). Of 128 cytologic specimens submitted for molecular testing, 126 (98%) were suitable for analysis, revealing EGFR and KRAS mutations in 31 (25%) and 25 (20%) cases, respectively. CONCLUSIONS: Cytologic subtyping of NSCLC is feasible and accurate, particularly when morphologic assessment is combined with IHC. Furthermore, routine cytologic specimens can be successfully used for EGFR/KRAS mutation analysis. Our data strongly support the suitability of cytologic specimens for the new therapeutic paradigms in NSCLC. PMID- 21266923 TI - The outcome of medical intensive care for lung cancer patients: the case for optimism. AB - In recent years, there have been significant advances in the management of patients with lung cancer. This progress is associated with increased use of medical intensive care units (ICUs) for the management of a variety of complications related to cancer, its treatment, or comorbid illnesses. At the same time, there are advances in the care of critically ill patients in general. Over the last decade, there are several studies that report progressive improvement in the outcome of lung cancer patients admitted to the medical ICUs. On average, the ICU and hospital mortality rates of lung cancer patients are 36% and 51%, respectively. These rates are approaching those of critically ill general population. However, it is clear that not all lung cancer patients will benefit from this aggressive care. Although there are no absolute predictors, the current evidence suggests that advanced refractory cancer, poor baseline performance status, the need for mechanical ventilation, and multiple organ system failures are factors associated with worse ICU outcome. Further studies are needed to better triage patients who are going to benefit from ICU care; determine the optimal duration of this care; and assess the impact of this therapy on the long-term survival, cancer treatment, and quality of life of these patients. PMID- 21266924 TI - Amylin and selective glucoregulatory peptide alterations during prolonged exercise. AB - Amylin is a pancreatic beta-cell peptide that facilitates the regulation of blood glucose concentration by inhibiting release of glucagon and modulating gastric emptying. Prolonged exercise may alter amylin and aid in the maintenance of blood glucose concentration; however, no studies have investigated the effects of prolonged exercise on amylin. PURPOSE: This study aimed to determine the effects of 90 min of treadmill exercise on amylin and other glucoregulatory hormone responses in a postprandial state. METHODS: Eight young healthy males completed a preliminary trial for VO2max and body composition determination and subsequent experimental and control trials in a counterbalanced manner. The experimental trial subjects arrived at the laboratory at 8:00 a.m., 1 h after consumption of a standard nutrient beverage (Ensure Plus(r)). At 9:50 a.m., subjects initiated 90 min of treadmill exercise at 60% of VO2max. Blood samples were collected twice before exercise, every 18 min during exercise, and every 20 min during 1 h of recovery. A resting control trial was conducted in an identical manner without VO2 assessment. RESULTS: Plasma glucose and leptin concentrations remained stable across exercise, whereas lactate significantly increased to peak at 18 min of exercise then gradually declined. Amylin, insulin, and C-peptide values significantly declined over the trials, with no difference between exercise and control days. Glucagon area-under-the-curve concentrations were significantly greater during the exercise than the control trials. There was a significant time effect and trial effect for cortisol with a higher concentration during the experimental trial than during the control trial. CONCLUSIONS: In a postprandial state, prolonged exercise stimulates glucagon and cortisol increases that are associated with stable blood glucose and leptin concentrations; however, similar to postprandial state control condition, insulin, C-peptide, and amylin concentrations decline. PMID- 21266925 TI - Spatiotemporal volumetric analysis of dynamic plantar pressure data. AB - PURPOSE: The purposes of this study were (i) to develop a three-dimensional interactive visualization tool for exploring plantar pressure time series and spatiotemporal statistical volumes and (ii) to demonstrate the benefits of volumetric analyses using various running and walking data sets. METHODS: A data exploration tool was developed in Python using the open-source Visualization Toolkit. Multiple-pressure isosurfaces were computed and were then rendered with interactive rotation and adjustable thresholds and transparencies. Plantar pressure data were collected: (i) from two running subjects, one with a heel loading pattern and one with a forefoot-loading pattern; (ii) from one individual while running straight and then while performing a cutting maneuver; and (iii) from one subject walking at three different speeds. All data were spatiotemporally aligned, and mean volumes were computed. Statistical volumes were also computed for the walking data set, and significance was assessed topologically using techniques from three-dimensional brain imaging. RESULTS: After converting raw plantar pressure data into a rapidly readable format, volumetric renderings were presented in ~50 ms, a negligible time lag for interactive data exploration. We observed that consideration of only spatial two dimensional variables yielded "impulse illusions" that could be resolved most effectively with three-dimensional renderings. For all data sets, we found that dynamic foot behavior was clearest through interactive three-dimensional exploration. CONCLUSIONS: Plantar pressure data contain high-quality biomechanical information in their original three-dimensional form. The main benefit of the proposed visualization technique is that it affords qualitatively rich and unique holistic explorations of dynamic foot behavior. PMID- 21266926 TI - Movement variability in the golf swing of male and female skilled golfers. AB - BACKGROUND: Despite the complexity of movement, the swings of skilled golfers are considered to be highly consistent. Interestingly, no direct investigation of movement variability or coupling variability during the swings of skilled golfers has occurred. PURPOSE: To determine whether differences in movement variability exist between male and female skilled golfers during the downswing of the full golf swing. METHODS: Three-dimensional thorax, pelvis, hand, and clubhead data were collected from 19 male (mean +/- SD: age = 26 +/- 7 yr) and 19 female (age = 25 +/- 7 yr) skilled golfers. Variability of segmental movement and clubhead trajectory were examined at three phases of the downswing using discrete (SD) and continuous analyses (spanning set), whereas variability of intersegment coupling was examined using average coefficient of correspondence. RESULTS: Compared with males, females exhibited higher thorax and pelvis variability for axial rotation at the midpoint of the downswing and ball contact (BC). Similarly, thorax-pelvis coupling variability was higher for females than males at both the midpoint of the downswing and BC. Regardless of thorax and pelvis motion, the variability of hand and clubhead trajectory sequentially decreased from the top of the backswing to BC for both males and females. CONCLUSIONS: Male and female skilled golfers use different upper body movement strategies during the downswing while achieving similarly low levels of clubhead trajectory variability at BC. It is apparent that the priority of skilled golfers is to progressively minimize hand and clubhead trajectory variability toward BC, despite the individual motion or coupling of the thorax and pelvis. PMID- 21266927 TI - Changes in functional magnetic resonance imaging cortical activation with cross education to an immobilized limb. AB - PURPOSE: The purpose of this study was to assess cortical activation associated with the cross-education effect to an immobilized limb, using functional magnetic resonance imaging. METHODS: Fourteen right-handed participants were assigned to two groups. One group (n = 7) wore a cast and strength trained the free arm (CAST TRAIN). The second group (n = 7) wore a cast and did not strength train (CAST). Casts were applied to the nondominant (left) wrist and hand. Strength training was maximal isometric handgrip contractions (right hand) 5 d.wk(-1). Peak force (handgrip dynamometer), muscle thickness (ultrasound), EMG, and cortical activation (functional magnetic resonance imaging) were assessed before and after the intervention. RESULTS: CAST-TRAIN improved right handgrip strength by 10.7% (P < 0.01) with no change in muscle thickness. There was a significant group * time interaction for strength of the immobilized arm (P < 0.05). Handgrip strength of the immobilized arm of CAST-TRAIN was maintained, whereas the immobilized arm of CAST significantly decreased by 11% (P < 0.05). Muscle thickness of the immobilized arm decreased by an average of 3.3% (P < 0.05) for all participants and was not different between groups after adjusting for baseline differences. There was a significant group * time interaction for EMG activation (P < 0.05), where CAST-TRAIN showed an increasing trend and CAST showed a decreasing trend, pooled across arms. For the immobilized arm of CAST TRAIN, there was a significant increase in contralateral motor cortex activation after training (P < 0.05). For the immobilized arm of CAST, there was no change in motor cortex activation. CONCLUSIONS: Handgrip strength training of the free limb attenuated strength loss during unilateral immobilization. The maintenance of strength in the immobilized limb via the cross-education effect may be associated with increased motor cortex activation. PMID- 21266928 TI - Association of military training with oxidative stress and overreaching. AB - We hypothesized that increased oxidative stress and disrupted redox balance may be predisposing factors and markers for overreaching (OR). PURPOSE: The study's purpose was to examine whether oxidative stress markers and antioxidant status and physical fitness are related to OR during an 8-wk military basic training (BT) period. METHODS: Oxidative stress and antioxidant status were evaluated in the beginning and after 4 and 7 wk of training in 35 males (age = 19.7 +/- 0.3 yr) at rest and immediately after a 45-min submaximal exercise. Physical activity (PA) was monitored by an accelerometer throughout BT. Indicators of OR were also examined. RESULTS: From baseline to week 4, increased daytime moderate to vigorous PA led to concomitant decreases in the ratio of oxidized to total glutathione (GSSG/TGSH) and GSSG. After 4 wk of BT, GSSG/TGSH and GSSG returned to the baseline values at rest, whereas PA remained unchanged. At every time point, acute exercise decreased TGSH and increased GSSG and GSSG/TGSH, whereas a decrease was observed in antioxidant capacity after 4 wk of training. In the beginning of BT, OR subjects (11 of the 35 males) had higher GSSG, GSSG/TGSH, and malondialdehyde (a marker of lipid peroxidation) at rest (P < 0.01-0.05) and lower response of GSSG and GSSG/TGSH ratio (P < 0.01) to exercise than non-OR subjects. Moreover, OR subjects had higher PA during BT than non-OR (P < 0.05). CONCLUSIONS: The sustained training load during the last 4 wk of BT led to oxidative stress observable both at rest and after submaximal exercise. Increased oxidative stress may be a marker of insufficient recovery leading possibly to OR. PMID- 21266929 TI - Effect of caffeine on reactive agility time when fresh and fatigued. AB - PURPOSE: This study examined the effects of acute caffeine ingestion on agility performance and decision-making accuracy after simulated team-sport exercise. METHODS: Using a randomized, double-blinded, counterbalanced design, 10 moderately trained male team-sport athletes ingested either caffeine (6 mg.kg( 1)) or placebo (dextrose) 60 min before completing an 80-min (4 * 20 min) simulated team-game, intermittent running protocol. Interspersed between each exercise quarter was a reactive agility test (RAT) consisting of five trials where measures of total time (TT), reactive agility (RA) time, decision time (DT), movement time (MT), and decision-making accuracy were obtained. RESULTS: Although there were no significant differences between trials for TT (P = 0.54), RA time (P = 0.84), MT (P = 0.89), or DT (P = 0.91), caffeine ingestion resulted in consistently faster TT (2.3%), RA time (3.9%), MT (2.7%), and DT (9.3%) scores compared with placebo (significant main effect for condition for RA time, TT, DT, and MT; P < 0.05). These faster times were supported by qualitative analyses of "almost certain benefit" and large effect size (ES) for RA (quarter 3) and "likely" to "very likely benefits" and moderate to large ES for TT (precircuit and quarters 1, 2, and 4) and RA time (precircuit and quarters 1, 2 and 4). A "likely benefit" and moderate ES was found for MT (quarters 1 and 3), but the effect of caffeine on DT was largely "unclear," with small ES and only a "likely" chance of benefit (quarters 2 and 3). Improved decision-making accuracy (3.8%) after caffeine ingestion was supported by a "likely benefit" (quarter 1) and large ES (quarters 1 and 4). CONCLUSION: Caffeine ingestion may be beneficial to RA performance when athletes are fresh and fatigued. PMID- 21266930 TI - Tendon length and joint flexibility are related to running economy. AB - PURPOSE: The purpose of study was to determine whether quadriceps/patella and Achilles tendon length and flexibility of the knee extensors and plantar flexors are related to walking and running economy. METHODS: Twenty-one male distance runners were subjects. Quadriceps/patella and Achilles tendon length were measured by magnetic resonance imaging; body composition was measured DXA; oxygen uptake at rest while seated, walking (3 mph), and running (6 and 7 mph) were measured by indirect calorimetry; knee and ankle joint flexibility were measured by goniometry; and leg lengths were measured by anthropometry while seated. Correlations were used to identify relationships between variables of interest. RESULTS: Net VO2 (exercise VO2 - rest VO2) for walking (NVOWK) and running at 6 and 7 mph (NVO6 and NVO7, respectively) was significantly related to Achilles tendon length (r varying from -0.40 to -0.51, P all < 0.04). Achilles tendon cross section was not related to walking or running economy. Quadriceps/patella tendon length was significantly related to NVO7 (r = -0.43, P = 0.03) and approached significance for NVO6 (r = -0.36, P = 0.06). Flexibility of the plantar flexors was related to NVO7 (+0.38, P = 0.05). Multiple regression showed that Achilles tendon length was independently related to NVO6 and NVO7 (partial r varying from -0.53 to -0.64, all P < 0.02) independent of lower leg length, upper leg length, quadriceps/patella tendon length, knee extension flexibility, or plantarflexion flexibility. CONCLUSIONS: These data support the premise that longer lower limb tendons (especially Achilles tendon) and less flexible lower limb joints are associated with improved running economy. PMID- 21266931 TI - Current analysis of women athletes with pelvic pain. AB - BACKGROUND AND METHODS: Accurate diagnosis and effective management of pelvic pain in women have become more challenging now that the number of women athletes and the number of diagnostic possibilities are increasing. We conducted a prospective study of women athletes with pelvic pain seen during a 2-yr period within a large well-defined clinical practice to clarify some of the current causes and treatment possibilities. RESULTS: One hundred fourteen females, 14% of the total male/female cohort, were referred for treatment of suspected musculoskeletal injury. On the basis of history and physical and radiological examinations, 74 (64.9% of females) turned out to have injuries of the hip (group A) and/or soft tissues surrounding the hip (group B), and 40 (35.1%) had other sometimes more threatening diagnoses. In groups A and B, 40 (90.1%) of 44 patients who chose surgery achieved previous performance levels within 1 yr compared with only 4 (13.8%) of 29 who did not have surgery. Factors such as sport type, competitive status, and age did not affect the outcomes. Most diagnoses in group C, e.g., inflammatory bowel disease, reflex sympathetic dystrophy, and malignancy, usually eclipsed the potential musculoskeletal diagnoses in terms of long-term importance. CONCLUSIONS: In this series of patients, most pelvic pain in women athletes was identifiable and treatable. Most had benign musculoskeletal causes, and surgery played an important role in treatment of those causes. Still, we found a large number of other causes that required longer specialized care. Health care professionals seeing such patients need to be alert to the new concepts of pelvic injury and the various roles for surgery and the broad list of other considerations. PMID- 21266932 TI - Practicing a functional task improves steadiness with hand muscles in older adults. AB - INTRODUCTION: Improvements in steadiness with practice have been associated with enhanced performance on a functional task in old adults. PURPOSE: The aims of the study were to examine the specificity of the association between steadiness and a functional task and to assess the influence of practicing a functional task on force steadiness of hand muscles. METHODS: Twenty-three older adults (>=70 yr) participated in the study and were assigned to either a practice group (n = 15) or a control group (n = 8). Subjects completed two testing sessions that were 2 wk apart. The practice group completed six additional sessions to practice a functional task (Grooved Pegboard). Tests included maximal voluntary contractions (MVC), force steadiness (precision pinch and index finger abduction) at three target forces (5%, 15%, and 25% MVC), and the Grooved Pegboard test. The associations between strength, steadiness, and the time needed to complete the Grooved Pegboard test were examined. In addition, MVC force, steadiness, and pegboard time were compared between the two testing sessions. RESULTS: The time needed to complete the Grooved Pegboard test was associated with index finger abduction steadiness for two of the three target forces (15% and 25% MVC) but was not associated with pinch steadiness. Practice significantly reduced the time needed to complete the Grooved Pegboard test and improved steadiness in both tasks. CONCLUSIONS: Force steadiness provides an appropriate index of hand function, especially when measured at low forces. PMID- 21266933 TI - Attenuation of muscle deoxygenation precedes EMG threshold in normoxia and hypoxia. AB - PURPOSE: The aim of this study was to investigate the relationship between the attenuation point of muscle deoxygenation (APMD) and the EMG threshold (EMGT) during incremental cycling exercise under different fractions of inspired O2 (FIO2). METHODS: Nine male subjects performed ramp cycling exercise tests (20 W.min(-1)) to exhaustion under normoxic and hypoxic conditions (FIO2 = 0.12). Pulmonary O2 uptake (VO2), muscle deoxygenation, and EMG activity in the vastus lateralis muscle were simultaneously measured during the tests, and both APMD and EMGT were calculated. RESULTS: Hypoxia significantly reduced peak VO2 (VO2peak). At the same absolute exercise intensity and at VO2peak, muscle deoxygenation, but not EMG activity, was significantly greater in hypoxia. VO2 at APMD was significantly decreased in hypoxia (P < 0.01). Similarly, VO2 at EMGT was significantly lower in hypoxia than in normoxia (P < 0.01). In addition, VO2 was lower at APMD than at EMGT under both conditions (P < 0.01). However, the relationships between APMD and EMGT were significant under both normoxic (r = 0.95, P < 0.01) and hypoxic (r = 0.89, P < 0.01) conditions. CONCLUSIONS: These results suggest that the attenuation of muscle deoxygenation near VO2peak is related to and precedes changes in neuromuscular activity under normoxic and hypoxic conditions. PMID- 21266934 TI - Valgus plus internal rotation moments increase anterior cruciate ligament strain more than either alone. AB - PURPOSE: To test the influence of combined knee valgus and internal tibial rotation moment on anterior cruciate ligament (ACL) strain during single-leg landing. We tested the following hypotheses: the combination of the valgus and internal rotation moments observed during single-leg landing produces a higher ACL strain than either moment applied individually, the combined rotational moments at the physiological levels observed could theoretically increase strain in the ACL high enough to rupture the ACL, and the location of the peak contact force was at the posterior-lateral side for combined loading. METHODS: The study was conducted by applying in vivo human loading data to a validated simulation model of the three-dimensional dynamic knee joint to predict ACL strains. RESULTS: The peak ACL strain increased nonlinearly when either applied valgus moment or internal rotation moment was increased in the model. When the two rotational moments were applied individually, neither caused ACL strain >0.077. However, when applied in combination, the two rotational moments had a much larger effect, and the predicted peak ACL strain increased up to 0.105. During landing, the peak contact force occurred at the posterior-lateral side of the tibial cartilage in the model when the combined maximum valgus moment and tibial internal rotation moments were applied. CONCLUSIONS: Combined knee valgus and internal rotation moments increases ACL strain more than either alone. The combination of a valgus and internal rotational moment at magnitudes that occurs in vivo during landing can cause ACL strains that may be high enough to cause ACL rupture. This predicted high ACL strain and the contact force location suggest that combined valgus and internal tibial rotational moments during single-leg landing are relevant to ACL injuries. PMID- 21266935 TI - The impact of premature ovarian insufficiency on sexual function. PMID- 21266936 TI - Menopausal vasomotor symptoms and cardiovascular disease. PMID- 21266937 TI - Estimating the number of births to hepatitis B virus-infected women in 22 states, 2006. AB - BACKGROUND: Estimating the annual number of births to hepatitis B virus (HBV) infected women is essential for monitoring efforts to prevent perinatal HBV transmission. We describe a method for estimating births to HBV-infected women in 22 states during 2006. METHODS: The number of births to HBV-infected women was calculated by (1) multiplying the number of US/Canadian-born mothers stratified by US race/ethnicity-specific HBV prevalence estimates, and (2) adding the number of foreign-born mothers stratified by their region of birth and multiplied by region-specific HBV prevalence estimates. RESULTS: Of 2,359,912 births, an estimated 16,608 (0.7%) were to HBV-infected women. Foreign-born women, who represented 25.3% of all mothers, accounted for 80.6% of estimated HBV-infected mothers. Estimated foreign-born HBV-infected mothers were from Southeast Asia (31.2%), East Asia (21.2%), and Africa (13.8%). Non-Hispanic blacks represented 55.1% of US/Canadian-born HBV-infected mothers. Compared with a previous estimate, which considers foreign-born status only for Asian/Pacific Islander mothers, this method estimated an additional 3000 births to HBV-infected women. CONCLUSIONS: Incorporating maternal country of birth and region-specific HBV infection prevalence likely enhances estimation of births to HBV-infected women in the United States. According to our estimate, approximately 10,000 births to HBV-infected women were not identified by state and local health departments in 22 states. PMID- 21266938 TI - Laboratory-based, 2-year surveillance of pediatric parapneumonic pneumococcal empyema following heptavalent pneumococcal conjugate vaccine universal vaccination in Madrid. AB - BACKGROUND: In October 2006, the heptavalent pneumococcal conjugate vaccine was included in the Madrid vaccination calendar, warranting serotype (St) surveillances in pneumococcal pediatric parapneumonic empyema (PPE). METHODS: A prospective 2-year (May 2007-April 2009) laboratory-confirmed PPE surveillance was performed in 22 hospitals. All isolates (for serotyping) and culture-negative pleural fluids were sent to the reference laboratory for polymerase chain reaction (PCR) analysis. RESULTS: We identified 138 PPEs. Pneumococcal etiology was confirmed in 100 cases: 38 by culture, 62 by PCR. Mean age was 44.64 +/- 26.64 months; 51.0% were male. Similar pneumococcal PPE distribution was found by age: 21% to 28% in <24, >=24-<36, >=36-<60, and >=60 months. PPE-associated Sts were St 1 (38%), St 5 (15%), St 19A (11%), St 7F (9%), St 3 (8%), and others (19%). St 1 was the most common in >36 months, with similar rates to St 19A in <24 months (~30%). In >=24-<=36 months, St 3 (21.7%), St 1 and St 5 (17.4% each) were the most frequent. No differences in demographic data, vaccination status, length of hospitalization, and outcome were found between culture-negative (PCR positive) and culture-positive PPE patients, with significantly higher percentages of St 1 and St 5 in culture-positive PPEs. Total rates of St 1 (38%), St 5 (15%), and St 7F (9%) would have been over-represented considering only positive-culture PPEs (n = 38), by increasing to 52.6% (St 1), 23.7% (St 5), and 10.5% (St 7F). The 13-valent pneumococcal conjugate vaccine would cover 84.0% of Sts causing PPEs. CONCLUSIONS: PCR is essential for determining the specific etiology of PPE. PMID- 21266939 TI - Evaluation of 4 weeks' neonatal antiretroviral prophylaxis as a component of a prevention of mother-to-child transmission program in a resource-rich setting. AB - BACKGROUND: In resource-rich settings, universal adoption of a 4- rather than 6 week neonatal antiretroviral (ARV) prophylaxis regimen could reduce toxicity and results in cost savings, provided prevention of mother-to-child transmission program effectiveness is not compromised. METHODS: Between January 1999 and December 2008, a 10-year study of the observational database of the Irish prevention of mother-to-child transmission program that uses a 4- rather than 6 week neonatal ARV prophylaxis regimen was undertaken. Maternal and infant data were analyzed to determine the vertical transmission rate (VTR) and infant outcome. Infants were categorized as uninfected if, off ARVs, they had 2 negative human immunodeficiency virus (HIV) polymerase chain reaction (PCR) tests, the second at 3 months of age or older. RESULTS: Between January 1999 and December 2008, there were 964 HIV-exposed live births. Excluding 7 early neonatal deaths, 4 weeks of ARV prophylaxis was prescribed for 957 infants: 61% received mono, 32% triple, and 7% dual therapy. Of 957 infants, 906 were uninfected, 10 infected, and 41 of indeterminate status. Twenty-four of the indeterminate status infants had at least one negative HIV PCR test at >= 6 weeks and 17 were lost to follow up before 6 weeks of age. On the basis of 916 infants of known outcome, the VTR was 1.09% (95% confidence interval, 1.07-1.11). If restricted to 910 infants whose mothers received at least 4 weeks of antiretroviral therapy (ART), the VTR was 0.4%. CONCLUSIONS: This study provides evidence to support the current clinical practice toward use of a 4-week neonatal ARV prophylaxis regimen. PMID- 21266940 TI - Impact of enhanced sensory input on treadmill step frequency: infants born with myelomeningocele. AB - PURPOSE: To determine the effect of enhanced sensory input on the step frequency of infants with myelomeningocele (MMC) when supported on a motorized treadmill. METHODS: Twenty-seven infants aged 2 to 10 months with MMC lesions at, or caudal to, L1 participated. We supported infants upright on the treadmill for 2 sets of 6 trials, each 30 seconds long. Enhanced sensory inputs within each set were presented in random order and included baseline, visual flow, unloading, weights, Velcro, and friction. RESULTS: Overall friction and visual flow significantly increased step rate, particularly for the older subjects. Friction and Velcro increased stance-phase duration. Enhanced sensory input had minimal effect on leg activity when infants were not stepping. CONCLUSIONS: : Increased friction via Dycem and enhancing visual flow via a checkerboard pattern on the treadmill belt appear to be more effective than the traditional smooth black belt surface for eliciting stepping patterns in infants with MMC. PMID- 21266941 TI - Evaluation of QMS everolimus assay using Hitachi 917 Analyzer: comparison with liquid chromatography/mass spectrometry. AB - Everolimus is an immunosuppressant requiring routine monitoring in whole blood. We evaluated the analytical performance of a new immunoassay for everolimus, Quantitative Microsphere System (QMS) everolimus (Thermo Fisher Scientific), which is CE marked and currently under review by Food and Drug Administration of the United States by comparing results with values obtained by using liquid chromatography/mass spectrometry. The total coefficient of variations (CVs) were 8.3% for low control (mean: 3.8 ng/mL), 6.1% for the medium control (mean: 8.0 ng/mL), and 7.5% for the high control (mean: 14.4 ng/mL) (n = 80 for each control, run over 20 nonconsecutive days). The respective total CVs for patients' pool were 13.3% (mean: 4.0 ng/mL), 7.5% (mean: 8.2 ng/mL), and 8.7% (mean: 11.7 ng/mL) (n = 80 for each patient pool). The assay was linear from a whole-blood everolimus level between 1.5 and 20 ng/mL, and the limit of quantitation was 1.3 ng/mL. Comparison was carried out using 90 renal transplant patient samples, and we observed the following Passing and Bablok linear regression plot: y = 1.11, slope = -0.005 (R = 0.92). This assay was not affected by commonly used 70 drugs, but sirolimus, a drug structurally similar to everolimus, showed 46% cross reactivity. We conclude that QMS everolimus immunoassay has adequate sensitivity and specificity for the determination of whole-blood everolimus and can be used for routine therapeutic drug monitoring. PMID- 21266942 TI - Relationship between oversulfation and conformation of low and high molecular weight fucoidans and evaluation of their in vitro anticancer activity. AB - Low and high molecular weight fucoidans (F(5-30K) and F(>30K)) were chemically modified through the addition of sulfate groups, and the effect of oversulfation on the in vitro anticancer activity was investigated. After the addition of sulfate groups, a considerable increase of 35.5 to 56.8% was observed in the sulfate content of the F(5-30K) fraction, while the sulfate content of the F(>30K) fraction increased to a lesser extent (from 31.7 to 41.2%). Significant differences in anticancer activity were observed between the oversulfated F(5 30K) and F(>30K) fractions, with activities of 37.3-68.0% and 20.6-35.8%, respectively. This variation in the anticancer activity of oversulfated fucoidan derivatives was likely due to differences in their sulfate content. The results suggest that the molecular conformation of these molecules is closely related to the extent of sulfation in the fucan backbones and that the sulfates are preferably substituted when the fucoidan polymers are in a loose molecular conformation. PMID- 21266943 TI - A route to dicyanomethylene pyridines and substituted benzonitriles utilizing malononitrile dimer as a precursor. AB - The conditions of the reaction of malononitrile dimer with enaminones and arylidenemalononitrile could be adapted to yield either pyridines or benzene derivatives. A new synthesis of pyrido[1,2-a]pyrimidines from the reaction of malononitrile dimer 1 and 2-phenyl-3-piperidin-1-yl-acrylonitrile (11) is described. Compound 1 condensed with DMFDMA to yield an enaminonitrile that reacted with hydrazine hydrate to yield N',4,6-triamino-2H-pyrazolo[3,4 b]pyridine-5-carboxamidine (17). PMID- 21266944 TI - Synthesis, reactions and biological evaluation of some new naphtho[2,1-b]furan derivatives bearing a pyrazole nucleus. AB - Vilsmeier formylation of 2-(1-phenylhydrazonoethyl)naphtho[2,1-b]furan (2) gave 3 naphtho[2,1-b]furan-2-yl-1-phenyl-1H-pyrazole-4-carbaldehyde (3), which was reacted with C- and N-nucleophiles to afford naphthofuranpyrazol derivatives 4-8. Treatment of 2-[(3-(naphtho[2,1-b]furan-2-yl)-1-phenyl-1H-pyrazol-4-yl)methylene] malononitrile (4a) with reactants having active hydrogen and Et3N gave the corresponding pyrazoline, pyran and chromene addition product derivatives 10, 12 and 13, consisting of three different connected heterocyclic moieties. Reaction of 1-((3-(naphtho[2,1-b]furan-2-yl)-1-phenyl-1H-pyrazol-4-yl) methylene)-2 phenylhydrazone (6b) with AcONa and ethyl bromoacetate or chloroacetone afforded the thiazolidinone and methylthiazole derivatives 14 and 15, respectively. In addition, intramolecular cyclization of 6d with Ac2O afford the corresponding 1,3,4-thiadiazol-2-yl acetamide derivative 16. The structures of the synthesized compounds were confirmed by IR, 1H-NMR/13C-NMR and mass spectral studies. Compound 14 showed promising effects against the tested Gram positive and negative bacteria and fungi. PMID- 21266945 TI - Synthesis, molecular structure, spectral properties and antifungal activity of polymethylene-alpha,omega-bis(N,N- dimethyl-N-dodecyloammonium bromides). AB - Hexamethylene-1,6-bis-(N,N-dimethyl-N-dodecylammonium bromide), pentamethylene 1,5-bis(N,N-dimethyl-N-dodecylammonium bromide), tetramethylene-1,4-bis(N,N dimethyl-N-dodecylammonium bromide), trimethylene-1,3-bis(N,N-dimethyl-N dodecylammonium bromide) and ethylene-1,2-bis(N,N-dimethyl-N-dodecylammonium bromide) have been obtained and characterized by FTIR and NMR spectroscopy. DFT calculations have also been carried out. The optimized bond lengths, bond angles and torsion angles calculated by Hartree-Fock/3-21G(d,p) approach have been presented. MIC values for A. niger, P. chrysogenum, C. albicans have been determined and the relationship between MIC and spacer length has been discussed. PMID- 21266946 TI - Association study of cannabinoid receptor 1 (CNR1) gene in tardive dyskinesia. AB - Tardive dyskinesia (TD) is a severe, debilitating movement disorder observed in 25-30% of the patients treated with typical antipsychotics. Cannabinoid receptor 1 (CNR1) activators tend to inhibit movement, an effect prevented by rimonabant and other selective CNR1 antagonists. Furthermore, CNR1 receptor is downregulated in Huntington's disease and upregulated in Parkinson's disease. Twenty tagSNPs spanning the CNR1 gene were analyzed in schizophrenia patients of European ancestry (n=191; 74 with TD). Significant genotypic (P=0.012) and allelic (P=0.012) association was observed with rs806374 (T>C). Carriers of the CC genotype were more likely to be TD positive (CC vs TT+TC, odds ratio=3.4 (1.5 7.8), P=0.003) and had more severe TD (CC vs TT+TC; 9.52+/-9.2 vs 5.62+/-6.9, P=0.046). These results indicate a possible role of CNR1 in the development of TD in our patient population. However, these observations are marginal after correcting for multiple testing and need to be replicated in a larger patient population. PMID- 21266948 TI - Impact of weight change, secular trends and ageing on cardiovascular risk factors: 10-year experiences from the SOS study. AB - OBJECTIVE: Many short-term studies indicate that 5% weight loss in the obese is enough to induce significant improvements of cardiovascular risk factors. However, it is not known what degree of weight loss is required to improve risk factors over a more extended period of time or how ageing and secular trends per se are influencing risk factors during long-term follow-up. METHODS: Patients examined after 10 years in the intervention study Swedish Obese Subjects were used for the current analysis. Surgically treated subjects (n=959) and conventionally treated obese controls (n=842) were pooled to obtain a study group with a large range of weight changes. The patients were divided in 11 groups based on the amount of weight change. Analysis of covariance was used to determine the necessary weight change over 10 years for a significant alteration of a risk factor. In a linear regression of risk factor change by weight change, the y intercept was interpreted as the effect of 10 years ageing and secular trends on a given risk factor in the absence of weight change. RESULTS: The necessary weight loss for significant improvement of risk factors ranged from 10 to 44 kg. At zero weight change, 10 years of ageing was associated with significant increases in systolic blood pressure, pulse pressure, high-density lipoprotein cholesterol and glucose, and with significant decreases in diastolic blood pressure, total cholesterol, triglycerides and insulin. CONCLUSIONS: The necessary weight loss to maintain a favourable effect on risk factors in an obese population is larger than previously indicated by short-term studies. Treatment effects are influenced by non-weight change-dependant shifts in risk factor levels. PMID- 21266947 TI - Native human adipose stromal cells: localization, morphology and phenotype. AB - OBJECTIVES: Beside having roles in energy homeostasis and endocrine modulation, adipose tissue (AT) is now considered a promising source of mesenchymal stromal cells (adipose-derived stromal cells or ASCs) for regenerative medicine. Despite numerous studies on cultured ASCs, native human ASCs are rarely investigated. Indeed, the phenotype of ASCs in their native state, their localization within AT and comparison with bone marrow-derived mesenchymal stromal cells (BM-MSCs) has been poorly investigated. DESIGN: To address these issues, the stroma vascular fraction (SVF) of human AT was extracted and native cell subtypes were isolated by immunoselection to study their clonogenic potential in culture. Immunohistology on samples of human AT in combination with reconstruction of confocal sections were performed in order to localize ASCs. RESULTS: Compared with BM-MNCs, all native ASCs were found in the CD34(+) cell fraction of the AT SVF. Native ASCs expressed classical mesenchymal markers described for BM-MSCs. Interestingly, CD34 expression decreased during ASC cell culture and was negatively correlated with cell proliferation rate. Immunohistological analysis revealed that native ASCs exhibited specific morphological features with protrusions. They were found scattered in AT stroma and did not express in vivo pericytic markers such as NG2, CD140b or alpha-smooth muscle actin, which appeared during the culture process. Finally, ASCs spontaneous commitment to adipocytic lineage was enhanced in AT from obese humans. CONCLUSIONS: The use of complementary methodological approaches to study native human ASCs revealed their immunophenotype, their specific morphology, their location within AT and their stemness. Furthermore, our data strongly suggest that human ASCs participate in adipogenesis during AT development. PMID- 21266949 TI - Oedema in obesity; role of structural lymphatic abnormalities. AB - Oedema is a common finding in obesity and its cause is not always clear. Possible causes include impairment of cardiac, respiratory and/or renal function, chronic venous insufficiency and lymphatic problems. Lymphoscintigraphy is the best method to detect structural lymphatic abnormalities that can cause lymphoedema. We reviewed 49 female subjects with pitting oedema who had undergone lymphoscintigraphy, divided in three groups. The first group was comprised of severely obese patients in whom cardiorespiratory causes for oedema had been excluded. The second group consisted of non-obese patients with recognized causes for oedema and the third group was non-obese patients with 'idiopathic' oedema. A standard classification was used to interpret lymphoscintigraphy results. The frequency and severity of lymphoscintigraphic abnormalities was greatest in patients with clinical diagnoses of oedema related to 'recognized causes' (any abnormality in 50% of legs with obstruction in 22%). Obese patients and those with 'idiopathic'oedema had fewer (P=0.02 for both) and milder lymphoscintographic abnormalities (any abnormality 32 and 25%, respectively, obstruction 5 and 3%, respectively), and although the clinical oedema was invariably bilateral, the lymphoscintigraphy abnormalities were usually unilateral. In conclusion, structural lymphoscintigraphic abnormalities are uncommon in obesity and do not closely correlate with the clinical pattern of oedema. PMID- 21266950 TI - Prognostic impact of abdominal adiposity, waist circumference and body mass index in patients with intermediate-risk prostate cancer treated with radiotherapy. AB - OBJECTIVE: We tested the potential role of abdominal visceral (VAT) and subcutaneous (SAT) adipose tissues, waist circumference (WC) and body mass index (BMI) as prognostic factors in patients with intermediate-risk prostate cancer (clinical stage T1b-2b, and Gleason Score (GS)=7 and prostate-specific antigen PSA level <15 ng ml(-1), or GS <= 6 and PSA between 10 and 20 ng ml(-1)) treated with ultrasound-based image-guided radiotherapy. METHODS: VAT, SAT and WC (measured from planning abdominal computed tomography) and BMI were compared with clinical and pathologic factors using univariate analyses. Cox regression analyses were performed to evaluate whether obesity indices significantly predicted biochemical disease free-survival (bDFS). RESULTS: Of the 112 eligible patients, 30 (27%) were obese. Median BMI at baseline was 27.5 kg m(-2) (range, 19.2-51.5 kg m(-2)). Greater abdominal adiposity, WC and BMI were significantly associated with younger age at diagnosis and increased prostate volume (P=0.003 and P=0.002, respectively). No significant correlation between obesity measures and T-stage, GS, PSA or percentage of positive cores at biopsy was found. On Cox regression analyses, none of the obesity measures predicted for bDFS. No association was observed between obesity indices and surrogate markers of biochemical failure as PSA nadir (nPSA) or time to nPSA. CONCLUSIONS: Abdominal adiposity, WC and BMI are associated with younger age at diagnosis and greater prostate volume but not with an increased risk of biochemical failure in patients with intermediate-risk prostate cancer. PMID- 21266951 TI - PTPIP51 interaction with PTP1B and 14-3-3beta in adipose tissue of insulin resistant mice. AB - OBJECTIVE: We investigated the expression of protein tyrosine phosphatase interacting protein 51 (PTPIP51) and its interaction with protein tyrosine phosphatase 1B (PTP1B) and 14-3-3beta in mice exhibiting insulin resistance and obesity. DESIGN: A total of 20 mice were included in the study. Eight control animals were fed a normal standard diet, six animals were fed a high-fat diet and six animals were submitted to a treadmill training parallel to the feeding of a high-fat diet. After 10 weeks, a glucose tolerance test was performed and abdominal adipose tissue samples of the animals were collected. RESULTS: PTPIP51 protein was identified in the adipocytes of all samples. PTPIP51 interacted with PTP1B and with 14-3-3beta protein. Compared with untrained mice fed a standard diet, the interaction of PTPIP51 with PTP1B was reduced in high-fat diet-fed animals. The highest interaction of PTPIP51 with 14-3-3beta was seen in trained animals on high-fat diet, whereas untrained animals on high-fat diet displayed lowest values. CONCLUSION: PTPIP51 is expressed in adipose tissue of humans, rats and mice. Obesity with enhanced insulin resistance resulted in a reduction of PTPIP51 levels in adipocytes and influenced the interactions with PTP1B and 14-3 3beta. The interaction of PTPIP51 with PTP1B suggests a regulatory function of PTPIP51 in insulin receptor signal transduction. The interaction of PTPIP51 with 14-3-3beta, especially in trained individuals, hints to an involvement of PTPIP51 in the downstream regulation of insulin action. PMID- 21266952 TI - High- and persistent- body-weight misperception levels in overweight and obese Swiss adults, 1997-2007. PMID- 21266953 TI - The impact of obesity on physiological responses during prolonged exercise. AB - BACKGROUND: Prolonged, moderate-intensity exercise training is routinely prescribed to subjects with obesity. In the general population, this type of exercise can lead to fluid and sodium imbalance. However, little is known whether obesity alters the risk of fluid and sodium imbalances. OBJECTIVE: This study examined physiological responses, such as core body temperature, fluid and sodium balance, in lean (BMI<25), overweight (2530) subjects during prolonged moderate-intensity exercise. SUBJECTS: A total of 93 volunteers (24-80 years), stratified for BMI, participated in the Nijmegen Marches and walked 30-50 km at a self-selected pace. Heart rate and core body temperature were recorded every 5 km. Subjects reported fluid intake, while urine output was measured and sweat rate was calculated. Baseline and post-exercise plasma sodium levels were determined, and urinary specific gravity levels were assessed before and after exercise. RESULTS: BMI groups did not differ in training status preceding the experiment. Exercise duration (8 h 41 +/- 1 h 36 min) and intensity (72 +/- 9% HR(max)) were comparable across groups, whereas obese subjects tended to have a higher maximum core body temperature than lean controls (P=0.06). Obese subjects demonstrated a significantly higher fluid intake (P<0.001) and sweat rate (P<0.001), but lower urine output (P<0.05) compared with lean subjects. In addition, higher urine specific gravity levels were observed in obese versus lean subjects after exercise (P<0.05). Furthermore, plasma-sodium concentration did not change in lean subjects after exercise, whereas plasma-sodium levels increased significantly (P<0.001) in overweight and obese subjects. Also, overweight and obese subjects demonstrated a significantly larger decrease in body mass after exercise than lean controls (P<0.05). CONCLUSION: Obese subjects demonstrate a larger deviation in markers of fluid and sodium balance than their lean counterparts during prolonged moderate-intensity exercise. These findings suggest that overweight and obese subjects, especially under strenuous environmental conditions, have an increased risk to develop fluid and sodium imbalances. PMID- 21266954 TI - Opiates, overeating and obesity: a psychogenetic analysis. AB - OBJECTIVE: This study provides an original perspective on the associations among endogenous opiates, overeating and obesity. The aim was to assess whether variability in the OPRM1 gene, as assessed by seven single-nucleotide polymorphisms, relates to individual differences in the preference for sweet and fatty foods. We also anticipated that these food preferences would be positively associated with binge eating, hedonic eating and emotionally driven eating patterns of overeating that would, in turn, predict higher body mass index (BMI). DESIGN: Analysis of variance procedures examined genotype differences in food preferences; bivariate correlation coefficients examined the relationships among food preferences and the overeating variables; and a regression analysis tested the combined influences of the overeating variables on BMI. DNA was extracted from whole blood for the genotyping, and measures of food preferences and eating behaviours were obtained from well-validated self-report questionnaires. SUBJECTS: Participants were 300 healthy adult men and women recruited from the community. RESULTS: All the predicted associations were supported by statistically significant results. In particular, the G/G genotype group of the functional A118G marker of the OPRM1 gene reported higher preferences for sweet and fatty foods compared with the other two groups. Food preferences were also related to all overeating measures, which in turn accounted for a substantial proportion of the variance in BMI. CONCLUSIONS: Our findings suggest that some of the diversity in the preference for highly palatable foods can be explained by genotypic differences in the regulation of mu opioid receptors. The associations reported in this paper are important from a public-health perspective because of the abuse potential of sweet-fat foods and their strong relationship with obesity. PMID- 21266955 TI - Serum visfatin and vaspin levels in prepubertal children: effect of obesity and weight loss after behavior modifications on their secretion and relationship with glucose metabolism. AB - OBJECTIVE: To investigate the impact of obesity, weight loss and oral glucose ingestion on serum visfatin and vaspin levels in prepubertal children. SUBJECTS AND METHODS: A total of 100 prepubertal obese Caucasian children (OB) and 42 controls (C) were studied. The OB group was studied at baseline and after moderate (n=46) and extensive (n=14) body mass index (BMI) reduction by conservative treatment, undergoing body composition studies (dual-energy X-ray absorptiometry) and oral glucose tolerance tests (OGTTs). Serum visfatin and vaspin levels were studied throughout the OGTT, as were their relationships with insulin, leptin, leptin soluble receptor (sOB-R), adiponectin (total and high molecular weight), resistin, interleukin-6 (IL-6) and tumor necrosis factor-alpha levels at every time point. RESULTS: OB had higher visfatin (P<0.001), but similar vaspin than C. BMI reduction decreased visfatin levels (P<0.001), with BMI, waist circumference and the surrogate markers of body fat (leptin and sOB-R) showing significant correlations (P<0.05) with this peptide, but not with vaspin. Visfatin and vaspin decreased during the OGTT (P<0.001). Weight reduction did not alter visfatin dynamics in the OGTT, but decreased the area under the curve (AUC) for vaspin (P<0.001), with a correlation between the AUCs for vaspin and insulin after weight loss (P<0.05). Visfatin levels were positively correlated with resistin and IL-6, after controlling for BMI and HOMA (homeostatic model assessment) index at every time point in the study. CONCLUSION: Serum visfatin, but not vaspin, levels are influenced by body fat content in obese children, whereas both adipokines are modulated by glucose intake in a BMI-dependent manner. PMID- 21266956 TI - Modular assembly of yeast mitochondrial ATP synthase. AB - The mitochondrial ATP synthase (F(1)-F(0) complex) of Saccharomces cerevisiae is a composite of different structural and functional units that jointly couple ATP synthesis and hydrolysis to proton transfer across the inner membrane. In organello, pulse labelling and pulse-chase experiments have enabled us to track the mitochondrially encoded Atp6p, Atp8p and Atp9p subunits of F(0) and to identify different assembly intermediates into which they are assimilated. Surprisingly, these core subunits of F(0) segregated into two different assembly intermediates one of which is composed of Atp6p, Atp8p, at least two stator subunits, and the Atp10p chaperone while the second consists of the F(1) ATPase and Atp9p ring. These studies show that assembly of the ATP synthase is not a single linear process, as previously thought, but rather involves two separate but coordinately regulated pathways that converge at the end stage. PMID- 21266957 TI - Functionalized scaffold-mediated interleukin 10 gene delivery significantly improves survival rates of stem cells in vivo. AB - While stem cell transplantation could potentially treat a variety of disorders, clinical studies have not yet demonstrated conclusive benefits. This may be partly because transplanted stem cells have low survival rates, potentially due to host inflammation. The system described herein used two different gene therapy techniques to improve retention of rat mesenchymal stem cells. In the first, stem cells were transfected with interleukin-10 (IL-10) before being loaded into a collagen scaffold. In the second, unmodified stem cells were loaded into a collagen scaffold along with polymer-complexed IL-10 plasmids. The scaffolds were surgically implanted into the dorsum of syngeneic rats. At each endpoint, the scaffolds were explanted and cell retention, IL-10 level and inflammatory response were quantified. All treatment groups had statistically significant increases in cell retention after 7 days, but the group treated with 2 ug of IL 10 polyplexes had a significant improvement even at 21 days. This cell retention was associated with increased IL-10 and decreased levels of proinflammatory cytokines and apoptosis. The primary effect on the inflammatory response appeared to be on macrophage differentiation, encouraging the regulatory phenotype over the cytotoxic lineage. Improving cell survival may be an important step toward realization of the therapeutic potential of stem cells. PMID- 21266958 TI - Transcription factor rational design improves directed differentiation of human mesenchymal stem cells into skeletal myocytes. AB - There is great interest in transdifferentiating cells from one lineage into those of another and in dedifferentiating mature cells back into a stem/progenitor cell state by deploying naturally occurring transcription factors (TFs). Often, however, steering cellular differentiation pathways in a predictable and efficient manner remains challenging. Here, we investigated the principle of combining domains from different lineage-specific TFs to improve directed cellular differentiation. As proof-of-concept, we engineered the whole-human TF MyoDCD, which has the NH(2)-terminal transcription activation domain (TAD) and adjacent DNA-binding motif of MyoD COOH-terminally fused to the TAD of myocardin (MyoCD). We found via reporter gene and marker protein assays as well as by a cell fusion readout system that, targeting the TAD of MyoCD to genes normally responsive to the skeletal muscle-specific TF MyoD enforces more robust myogenic reprogramming of nonmuscle cells than that achieved by the parental, prototypic master TF, MyoD. Human mesenchymal stem cells (hMSCs) transduced with a codon optimized microdystrophin gene linked to a synthetic striated muscle-specific promoter and/or with MyoD or MyoDCD were evaluated for complementing the genetic defect in Duchenne muscular dystrophy (DMD) myocytes through heterotypic cell fusion. Cotransduction of hMSCs with MyoDCD and microdystrophin led to chimeric myotubes containing the highest dystrophin levels. PMID- 21266959 TI - Chemokine expression from oncolytic vaccinia virus enhances vaccine therapies of cancer. AB - Tumor vaccines can induce robust immune responses targeting tumor antigens in the clinic, but antitumor effects have been disappointing. One reason for this is ineffective tumor infiltration of the cytotoxic T lymphocytes (CTLs) produced. Oncolytic viruses are capable of selectively replicating within tumor tissue and can induce a strong immune response. We therefore sought to determine whether these therapies could be rationally combined such that modulation of the tumor microenvironment by the viral therapy could help direct beneficial CTLs induced by the vaccine. As such, we examined the effects of expressing chemokines from oncolytic vaccinia virus, including CCL5 (RANTES), whose receptors are expressed on CTLs induced by different vaccines, including type-1-polarized dendritic cells (DC1). vvCCL5, an oncolytic vaccinia virus expressing CCL5, induced chemotaxis of lymphocyte populations in vitro and in vivo, and displayed improved safety in vivo. Interestingly, enhanced therapeutic benefits with vvCCL5 in vivo correlated with increased persistence of the viral agent exclusively within the tumor. When tumor-bearing mice were both vaccinated with DC1 and treated with vvCCL5 a further significant enhancement in tumor response was achieved which correlated with increased levels of tumor infiltrating lymphocytes. This approach therefore represents a novel means of combining biological therapies for cancer treatment. PMID- 21266960 TI - Translumbar and transsacral motor-evoked potentials: a novel test for spino anorectal neuropathy in spinal cord injury. AB - OBJECTIVES: Spinal cord injury (SCI) causes anorectal problems, whose pathophysiology remains poorly characterized. A comprehensive method of evaluating spino-anorectal function is lacking. The aim of this study was to investigate the neuropathophysiology of bowel dysfunction in SCI by evaluating motor-evoked potentials (MEP) of anus and rectum following transspinal magnetic stimulation and anorectal physiology. METHODS: Translumbar and transsacral magnetic stimulations, anorectal manometry, and pudendal nerve terminal motor latency (PNTML) were performed in 39 subjects with SCI and anorectal problems and in 14 healthy controls, and data were compared. MEPs were recorded with an anorectal probe containing bipolar ring electrodes. RESULTS: The MEPs were significantly prolonged (P<0.05) bilaterally, and at lumbar and sacral levels, as well as at rectal and anal sites in SCI subjects compared with controls. A total of 95% of SCI subjects had abnormal MEPs and 53% had abnormal PNTML. All subjects with abnormal PNTML also demonstrated abnormal MEP, but 16/17 subjects with normal PNTML had abnormal MEP. Overall, SCI patients had weaker anal sphincters (P<0.05), higher prevalence of dyssynergia (85%), and altered rectal sensation (82%). CONCLUSIONS: Translumbar and transsacral MEPs revealed significant and hitherto undetected lumbosacral neuropathy in 90% of SCI subjects. Test was safe and provided neuropathophysiological information that could explain bowel dysfunction in SCI subjects. PMID- 21266961 TI - Location in the right hemi-colon is an independent risk factor for delayed post polypectomy hemorrhage: a multi-center case-control study. AB - OBJECTIVES: Delayed hemorrhage is an infrequent, but serious complication of colonoscopic polypectomy. Large size is the only polyp-related factor that has been unequivocally proven to increase the risk of delayed bleeding. It has been suggested that location in the right hemi-colon is also a risk factor. The objective of this study was to determine whether polyp location is an independent risk factor for delayed post-polypectomy hemorrhage. METHODS: A retrospective case-control study was conducted in two university hospitals and two community hospitals. RESULTS: Thirty-nine cases and 117 controls were identified. In multivariate analysis, size and location were found to be independent polyp related risk factors for delayed type hemorrhage. The risk increased by 13% for every 1 mm increase in polyp diameter (odds ratio (OR) 1.13, 95% confidence interval (CI) 1.05-1.20, P<0.001). Polyps located in the right hemi-colon had an OR of 4.67 (1.88-11.61, P=0.001) for delayed hemorrhage. Polyps in the cecum seemed to be especially at high risk in univariate analysis (OR 13.82, 95% CI 2.66-71.73), but this could not be assessed in multivariate analysis as the number of cases was too small. Polyp type (sessile or pedunculated) was not a risk factor. CONCLUSIONS: Polyp location in the right hemi-colon seems to be an independent and substantial risk factor for delayed post-polypectomy hemorrhage. A low threshold for preventive hemostatic measures is advised when removing polyps from this region. PMID- 21266962 TI - The American College of Gastroenterology Emily Couric Lecture--the adenoma carcinoma sequence revisited: has the era of genetic tailoring finally arrived? AB - Colorectal cancer (CRC) remains a common and often lethal disease. The classic adenoma-carcinoma sequence was defined on histologic grounds but over the last 25 years, the molecular basis of this process has been progressively clarified. There are at least three distinct molecular pathways to CRC: the chromosomal instability (CIN) pathway is thought to be largely driven by mutational events in oncogenes and tumor suppressor genes, the microsatellite instability pathway is responsible for Lynch syndrome CRCs and is driven by mutations in one of the DNA mismatch repair genes, and the epigenetic pathway is thought to be driven in large part by hypermethylation-induced silencing of tumor suppressor-like genes. The molecular understanding of this sequence has had a profound impact on our understanding of the process(s) of colonic carcinogenesis and this understanding has begun to change the clinical care of patients with colonic polyps and cancer including changes in therapy of established CRCs (anti-epidermal growth factor receptor antibody therapy is no longer offered to patients with mutant KRAS CRCs), identification of high-risk groups (diagnosis of Lynch syndrome by molecular analysis of CRCs) and the management of precursor lesions (identification of the serrated polyp pathway to CRC). PMID- 21266963 TI - Ancient origins determine global biogeography of hot and cold desert cyanobacteria. AB - Factors governing large-scale spatio-temporal distribution of microorganisms remain unresolved, yet are pivotal to understanding ecosystem value and function. Molecular genetic analyses have focused on the influence of niche and neutral processes in determining spatial patterns without considering the temporal scale. Here, we use temporal phylogenetic analysis calibrated using microfossil data for a globally sampled desert cyanobacterium, Chroococcidiopsis, to investigate spatio-temporal patterns in microbial biogeography and evolution. Multilocus phylogenetic associations were dependent on contemporary climate with no evidence for distance-related patterns. Massively parallel pyrosequencing of environmental samples confirmed that Chroococcidiopsis variants were specific to either hot or cold deserts. Temporally scaled phylogenetic analyses showed no evidence of recent inter-regional gene flow, indicating populations have not shared common ancestry since before the formation of modern continents. These results indicate that global distribution of desert cyanobacteria has not resulted from widespread contemporary dispersal but is an ancient evolutionary legacy. This highlights the importance of considering temporal scales in microbial biogeography. PMID- 21266964 TI - An adaptive explanation for the horse-like shape of seahorses. AB - The body shape of seahorses resembles the head and neck of horses because of their curved trunk, their ventrally bent head and their long snout. Seahorses evolved from ancestral, pipefish-like species, which have a straight body. Here, we use a biomechanical analysis and show that the seahorse's peculiar head, neck and trunk posture allows for the capture of small shrimps at larger distances from the eyes compared with pipefish. The results from the mathematical modelling were confirmed by kinematic data of prey-capturing syngnathids: compared with straight-bodied pipefish, all seahorse species studied consistently show an additional forward-reaching component in the path travelled by the mouth during their strikes at prey. This increased strike distance enlarges the volume of water they can probe for food, which is especially useful for tail-attached, sit and-wait predators like seahorses. The biomechanics of prey capture thus provides a putative selective advantage that may explain the bending of the trunk into a horse-like shape. PMID- 21266965 TI - Development and host cell modifications of Plasmodium falciparum blood stages in four dimensions. AB - Blood stages of Plasmodium falciparum cause the pathology of malaria; however, the progression of the parasite through this complex part of the life cycle has never been visualized. In this study, we use four-dimensional imaging to show for the first time the development of individual parasites in erythrocytes and the concomitant host cell modifications. Our data visualize an unexpectedly dynamic parasite, provide a reference for this life cycle stage and challenge the model that protein export in P. falciparum is linked to the biogenesis of host cell modifications termed Maurer's clefts. Our results provide a novel view of the blood-stage development, Maurer's cleft development and protein export in malaria parasites, and open the door to study dynamic processes, drug effects and the phenotype of mutants. PMID- 21266966 TI - A hybrid bioorganic interface for neuronal photoactivation. AB - A key issue in the realization of retinal prosthetic devices is reliable transduction of information carried by light into specific patterns of electrical activity in visual information processing networks. Soft organic materials can be used to couple artificial sensors with neuronal tissues. Here, we interface a network of primary neurons with an organic blend. We show that primary neurons can be successfully grown onto the polymer layer without affecting the optoelectronic properties of the active material or the biological functionality of neuronal network. Moreover, action potentials can be triggered in a temporally reliable and spatially selective manner with short pulses of visible light. Our results may lead to new neuronal communication and photo manipulation techniques, thus paving way to the development of artificial retinas and other neuroprosthetic interfaces based on organic photodetectors. PMID- 21266967 TI - An optimized small molecule inhibitor cocktail supports long-term maintenance of human embryonic stem cells. AB - A major challenge in stem cell-mediated regenerative medicine is the development of defined culture systems for the maintenance of clinical-grade human embryonic stem (hES) cells. Here, we identify, using a feedback system control scheme, a unique combination of three small molecule inhibitors that enables the maintenance of hES cells on a fibronectin-coated surface through single cell passaging. After 20 passages, the undifferentiated state of the hES cells was confirmed by OCT4, SSEA4 and NANOG expressions, whereas their pluripotent potential and genetic integrity were demonstrated by teratoma formation and normal karyotype, respectively. Our study attests to the power of the feedback system control scheme to quickly pinpoint optimal conditions for desired biological activities, and provides a chemically defined, scalable and single cell passaging culture system for hES cells. PMID- 21266968 TI - Experimental magic state distillation for fault-tolerant quantum computing. AB - Any physical quantum device for quantum information processing (QIP) is subject to errors in implementation. In order to be reliable and efficient, quantum computers will need error-correcting or error-avoiding methods. Fault-tolerance achieved through quantum error correction will be an integral part of quantum computers. Of the many methods that have been discovered to implement it, a highly successful approach has been to use transversal gates and specific initial states. A critical element for its implementation is the availability of high fidelity initial states, such as |0> and the 'magic state'. Here, we report an experiment, performed in a nuclear magnetic resonance (NMR) quantum processor, showing sufficient quantum control to improve the fidelity of imperfect initial magic states by distilling five of them into one with higher fidelity. PMID- 21266969 TI - Rescuing ecosystems from extinction cascades through compensatory perturbations. AB - Food-web perturbations stemming from climate change, overexploitation, invasive species and habitat degradation often cause an initial loss of species that results in a cascade of secondary extinctions, posing considerable challenges to ecosystem conservation efforts. Here, we devise a systematic network-based approach to reduce the number of secondary extinctions using a predictive modelling framework. We show that the extinction of one species can often be compensated by the concurrent removal or population suppression of other specific species, a counterintuitive effect not previously tested in complex food webs. These compensatory perturbations frequently involve long-range interactions that are not evident from local predator-prey relationships. In numerous cases, even the early removal of a species that would eventually go extinct is found to significantly reduce the number of cascading extinctions. These compensatory perturbations only exploit resources available in the system, and illustrate the potential of human intervention combined with predictive modelling for ecosystem management. PMID- 21266970 TI - Comprehensive catecholaminergic projectome analysis reveals single-neuron integration of zebrafish ascending and descending dopaminergic systems. AB - Essential components of animal behaviour are modulated by dopaminergic (DA) and noradrenergic circuitry. In this study, we reveal at cellular resolution the complete set of projections ('projectome') of every single type of DA and noradrenergio neurons in the central nervous system of zebrafish larvae. The most extensive DA projections are established by posterior tubercular otp-dependent neurons, with individual somata integrating the ascending DA system, the descending diencephalospinal, as well as the endohypothalamic circuitry. These findings suggest a major role in the modulation of physiology and behaviour for otp-dependent DA neurons, which correlate with the mammalian A11 group. We further identified an endogenous subpallial DA system that not only provides most of the local DA projections, but also connects to the ventral diencephalon. The catecholaminergic projectome map provides a framework to understand the evolution and function of these neuromodulatory systems. PMID- 21266971 TI - Molecular decoding using luminescence from an entangled porous framework. AB - Chemosensors detect a single target molecule from among several molecules, but cannot differentiate targets from one another. In this study, we report a molecular decoding strategy in which a single host domain accommodates a class of molecules and distinguishes between them with a corresponding readout. We synthesized the decoding host by embedding naphthalenediimide into the scaffold of an entangled porous framework that exhibited structural dynamics due to the dislocation of two chemically non-interconnected frameworks. An intense turn-on emission was observed on incorporation of a class of aromatic compounds, and the resulting luminescent colour was dependent on the chemical substituent of the aromatic guest. This unprecedented chemoresponsive, multicolour luminescence originates from an enhanced naphthalenediimide-aromatic guest interaction because of the induced-fit structural transformation of the entangled framework. We demonstrate that the cooperative structural transition in mesoscopic crystal domains results in a nonlinear sensor response to the guest concentration. PMID- 21266972 TI - Development and evaluation of human AP endonuclease inhibitors in melanoma and glioma cell lines. AB - AIMS: Modulation of DNA base excision repair (BER) has the potential to enhance response to chemotherapy and improve outcomes in tumours such as melanoma and glioma. APE1, a critical protein in BER that processes potentially cytotoxic abasic sites (AP sites), is a promising new target in cancer. In the current study, we aimed to develop small molecule inhibitors of APE1 for cancer therapy. METHODS: An industry-standard high throughput virtual screening strategy was adopted. The Sybyl8.0 (Tripos, St Louis, MO, USA) molecular modelling software suite was used to build inhibitor templates. Similarity searching strategies were then applied using ROCS 2.3 (Open Eye Scientific, Santa Fe, NM, USA) to extract pharmacophorically related subsets of compounds from a chemically diverse database of 2.6 million compounds. The compounds in these subsets were subjected to docking against the active site of the APE1 model, using the genetic algorithm based programme GOLD2.7 (CCDC, Cambridge, UK). Predicted ligand poses were ranked on the basis of several scoring functions. The top virtual hits with promising pharmaceutical properties underwent detailed in vitro analyses using fluorescence based APE1 cleavage assays and counter screened using endonuclease IV cleavage assays, fluorescence quenching assays and radiolabelled oligonucleotide assays. Biochemical APE1 inhibitors were then subjected to detailed cytotoxicity analyses. RESULTS: Several specific APE1 inhibitors were isolated by this approach. The IC(50) for APE1 inhibition ranged between 30 nM and 50 MUM. We demonstrated that APE1 inhibitors lead to accumulation of AP sites in genomic DNA and potentiated the cytotoxicity of alkylating agents in melanoma and glioma cell lines. CONCLUSIONS: Our study provides evidence that APE1 is an emerging drug target and could have therapeutic application in patients with melanoma and glioma. PMID- 21266974 TI - An inflammation-based prognostic score (mGPS) predicts cancer survival independent of tumour site: a Glasgow Inflammation Outcome Study. AB - INTRODUCTION: A selective combination of C-reactive protein and albumin (termed the modified Glasgow Prognostic Score, mGPS) has been shown to have prognostic value, independent of tumour stage, in lung, gastrointestinal and renal cancers. It is also of interest that liver function tests such as bilirubin, alkaline phosphatase and gamma-glutamyl transferase, as well as serum calcium, have also been reported to predict cancer survival. The aim of the present study was to examine the relationship between an inflammation-based prognostic score (mGPS), biochemical parameters, tumour site and survival in a large cohort of patients with cancer. METHODS: Patients (n=21,669) who had an incidental blood sample taken between 2000 and 2006 for C-reactive protein, albumin and calcium (and liver function tests where available) and a diagnosis of cancer were identified. Of this group 9608 patients who had an ongoing malignant process were studied (sampled within 2 years before diagnosis). Also a subgroup of 5397 sampled at the time of diagnosis (sampled within 2 months prior to diagnosis) were examined. Cancers were grouped by tumour site in accordance with International Classification of Diseases 10 (ICD 10). RESULTS: On follow up, there were 6005 (63%) deaths of which 5122 (53%) were cancer deaths. The median time from blood sampling to diagnosis was 1.4 months. Increasing age, male gender and increasing deprivation was associated with a reduced 5-year overall and cancer-specific survival (all P<0.001). An elevated mGPS, adjusted calcium, bilirubin, alkaline phosphatase, aspartate transaminase, alanine transaminase and gamma-glutamyl transferase were associated with a reduced 5-year overall and cancer-specific survival (independent of age, sex and deprivation in all patients sampled), as well as within the time of diagnosis subgroup (all P<0.001). An increasing mGPS was predictive of a reduced cancer-specific survival in all cancers (all P<0.001). CONCLUSION: The results of the present study indicate that the mGPS is a powerful prognostic factor when compared with other biochemical parameters and independent of tumour site in patients with cancer. PMID- 21266973 TI - Human prostate cell lines from normal and tumourigenic epithelia differ in the pattern and control of choline lipid headgroups released into the medium on stimulation of protein kinase C. AB - BACKGROUND: Expression of protein kinase C alpha (PKCalpha) is elevated in prostate cancer (PCa); thus, we have studied whether the development of tumourigenesis in prostate epithelial cell lines modifies the normal pattern of choline (Cho) metabolite release on PKC activation. METHODS: Normal and tumourigenic human prostate epithelial cell lines were incubated with [(3)H]-Cho to label choline phospholipids. Protein kinase C was activated with phorbol ester and blocked with inhibitors. Choline metabolites were resolved by ion-exchange chromatography. Phospholipase D (PLD) activity was measured by transphosphatidylation. Protein expression was detected by western blotting and/or RT-PCR. Choline uptake was measured on cells in monolayers over 60 min. RESULTS: Normal prostate epithelial cell lines principally released phosphocholine (PCho) in contrast to tumourigenic lines, which released Cho. In addition, only with normal cell lines did PKC activation stimulate Cho metabolite release. Protein kinase C alpha expression varied between normal and tumourigenic cell lines but all showed a PKCalpha link to myristoylated alanine-rich C kinase substrate (MARCKS) protein. The five cell lines differed in Cho uptake levels, with normal PNT2C2 line cells showing highest uptake over 60 min incubation. Normal and tumourigenic cell lines expressed mRNA for PLD1 and PLD2, and showed similar levels of basal and PKC-activated PLD activity. CONCLUSIONS: The transition to tumourigenesis in prostate epithelial cell lines results in major changes to Cho metabolite release into the medium and PKC signalling to phosphatidylcholine turnover. The changes, which reflect the metabolic and proliferative needs of tumourigenic cells compared with untransformed cells, could be significant for both diagnosis and treatment. PMID- 21266975 TI - Sunitinib and other targeted therapies for renal cell carcinoma. AB - Targeted therapy has radically altered the way metastatic renal cancer is treated. Six drugs are now licensed in this setting, with several other agents under evaluation. Sunitinib is currently the most widely used in the first line setting with impressive efficacy and an established toxicity profile. However, as further randomised studies report and as newer drugs become available this may change. In this review, we address our current understanding of targeted therapy in renal cancer. We also discuss areas in which our knowledge is incomplete, including the identification of correlative biomarkers and mechanisms of drug resistance. Finally, we will describe the major areas of clinical research that will report over the next few years. PMID- 21266976 TI - Cytology history preceding cervical cancer diagnosis: a regional analysis of 286 cases. AB - BACKGROUND: Despite programmed screening in the Netherlands, the decrease in incidence of cervical carcinoma lags behind. We analysed screening results preceding carcinoma cases, timeliness in case of follow-up, and FIGO (International Federation of Gynaecology and Obstetrics) stages as efficiency parameters for screening were taken. METHODS: We analysed 286 women with cervical cancer between 2005 and 2007 for cytology history preceding carcinoma, hierarchically arranging cytology history (if present) into three groups: 'screened', 'work-up', and 'underscreened' (>6 yrs before diagnosis). For screen- and work-up smears, we analysed timeliness. FIGO stage was measured in relation to cytology history. RESULTS: A total of 105 out of 286 (36.7%) women with cervical carcinoma were screened preceding the diagnosis. Delayed time intervals in case of abnormal cytology were 43.5% for borderline/mild dyskaryosis (BMD) and 38.0% for BMD (moderate dyskaryosis or worse; P=0.51). A total of 108 out of 286 (36.4%) women were underscreened, and 73 out of 286 (25.5%) were unscreened. Advanced carcinoma or FIGO stage >=2B in screened women was 16.0 vs 48.7% in work up, underscreened, or unscreened (P<0.001). CONCLUSION: Women with cervical cancer are underscreened and have poor timeliness in case of abnormal cytology. Being un- or underscreened correlates significantly with higher cervical cancer stages, especially in older women (aged >=49 years; P<0.001). Improvement of attendancy is needed to meet the standard of quality for screening programmes. PMID- 21266977 TI - ERK5 signalling in prostate cancer promotes an invasive phenotype. AB - BACKGROUND: Aberrant mitogen/extracellular signal-regulated kinase 5 (MEK5) extracellular signal-regulated protein kinase 5 (ERK5)-mediated signalling has been implicated in a number of tumour types including prostate cancer (PCa). The molecular basis of ERK5-driven carcinogenesis and its clinical relevance remain to be fully characterised. METHODS: Modulation of ERK5 expression or function in human PCa PC3 and PC3-ERK5 (stably transfected with ERK5) cells was performed using siRNA-mediated knockdown or the MEK inhibitor PD18435 respectively. In vitro significance of ERK5 signalling was assessed by assays for proliferation, motility, invasion and invadopodia. Expression of matrix metalloproteinases/tissue inhibitors of metalloproteases was determined by Q-RT PCR. Extracellular signal-regulated protein kinase 5 expression in primary and metastatic PCa was examined using immunohistochemistry. RESULTS: Reduction of ERK5 expression or signalling significantly inhibited the motility and invasive capability of PC3 cells. Extracellular signal-regulated protein kinase 5-mediated signalling significantly promoted formation of in vivo metastasis in an orthotopic PCa model (P<0.05). Invadopodia formation was also enhanced by forced ERK5 expression in PC3 cells. Furthermore, in metastatic PCa, nuclear ERK5 immunoreactivity was significantly upregulated when compared with benign prostatic hyperplasia and primary PCa (P=0.013 and P<0.0001, respectively). CONCLUSION: Our in vitro, in vivo and clinical data support an important role for the MEK5-ERK5 signalling pathway in invasive PCa, which represents a potential target for therapy in primary and metastatic PCa. PMID- 21266978 TI - Association of obesity with prostate cancer: a case-control study within the population-based PSA testing phase of the ProtecT study. AB - BACKGROUND: Obesity has been inconsistently linked to prostate cancer, mainly with mortality rather than incidence. Few large-scale studies exist assessing obesity in relation to prostate-specific antigen (PSA)-detected prostate cancer. METHODS: We used cases and stratum-matched controls from the population-based PSA testing phase of the Prostate testing for cancer and Treatment study to examine the hypothesis that obesity as measured by body mass index (BMI), waist circumference and waist-to-hip ratio (WHR) is associated with increased prostate cancer risk, and with higher tumour stage and grade. In all, 2167 eligible cases and 11 638 randomly selected eligible controls with PSA values were recruited between 2001 and 2008. A maximum of 960 cases and 4156 controls had measurement data, and also complete data on age and family history, and were included in the final analysis. BMI was categorised as <25.0, 25.0-29.9, >= 30.0 in kg m(-2). RESULTS: Following adjustment for age and family history of prostate cancer, we found little evidence that BMI was associated with total prostate cancer (odds ratio (OR): 0.83, 95% confidence interval (CI): 0.67, 1.03; highest vs lowest tertile; P-trend 0.1). A weak inverse association was evident for low-grade (OR: 0.76, 95% CI: 0.59, 0.97; highest vs lowest tertile; P-trend 0.045) prostate cancer. We found no association of either waist circumference (OR: 0.94, 95% CI: 0.80, 1.12; highest vs lowest tertile) or waist-to-hip ratio (WHR; OR: 0.93, 95% CI: 0.77, 1.11; highest vs lowest tertile) with total prostate cancer, and in analyses stratified by disease stage (all P-trend>0.35) or grade (all P trend>0.16). CONCLUSION: General adiposity, as measured by BMI, was associated with a decreased risk of low-grade PSA-detected prostate cancer. However, effects were small and the confidence intervals had limits very close to one. Abdominal obesity (as measured by WHR/waist circumference) was not associated with PSA detected prostate cancer. PMID- 21266979 TI - Development of a questionnaire (EORTC module) to measure quality of life in patients with cholangiocarcinoma and gallbladder cancer, the EORTC QLQ-BIL21. AB - BACKGROUND: Quality of life measurement in cholangiocarcinoma and gallbladder cancer involves the assessment of patient-reported issues related to the symptoms, disease and treatment of these tumours. This study describes the development of the disease-specific quality of life (QoL) questionnaire for patients with cholangiocarcinoma and gallbladder cancer to supplement the European Organization for Research and Treatment of Cancer (EORTC)-QLQ C30 core cancer questionnaire. METHODS: Phases 1-3 of the guidelines for module development published by the EORTC were followed, with adaptations for incorporation of questions from existing modules. RESULTS: A total of 47 QoL issues (questions) were identified; 44 questions from the two related validated questionnaires, the EORTC QLQ-PAN26 (pancreatic module) and the EORTC QLQ-LMC21 (liver metastases module), two from the Functional Assessment of Cancer Therapy hepatobiliary module questionnaire in the literature search and one from healthcare professional interviews. Following phase 1 and 2 interviews with patients (n=101) and health care professionals (n=6), a 23-question provisional questionnaire was formulated. There were five questions from PAN26, 15 from LMC21 and three extra questions. In phase 3, the provisional item list was pre-tested in 52 patients in four languages and this resulted in a 21-item module. CONCLUSION: This is the only disease-specific QoL questionnaire for patients with cholangiocarcinoma and gallbladder cancer, and initial assessments show it to be accurate and acceptable to patients in reflecting QoL in these diseases. PMID- 21266981 TI - Diet quality and the influence of social and physical factors on food consumption and nutrient intake in materially deprived older people. AB - BACKGROUND/OBJECTIVES: To investigate the influence of social and physical factors on diet quality in materially deprived (low income) older people in the United Kingdom. SUBJECTS/METHODS: A diet quality index was obtained for 222 men and 440 women aged 65 and over living alone or with other adults of retirement age from the United Kingdom Low Income Diet and Nutrition Survey (2003-2005). The association between diet quality and social and physical factors was investigated by logistic regression analysis. RESULTS: Analysis revealed several barriers to an adequate diet in the older low-income population. For both men and women, having the best quality diet was inversely associated with usually eating meals on one's lap as opposed to at the table (Adjusted odds ratio (ORs)=0.3, 95% confidence interval: 0.12-0.77 (men), 0.3, 0.17-0.56 (women)). For men, difficulty chewing was inversely associated with the best quality diet (OR=0.4; 0.13-0.99), whereas for women, current smoking and being 75 years or over were inversely associated with the best quality diet (OR=0.2; 0.06-0.42 and 0.5; 0.27 0.87, respectively); P value for all associations was <0.05. CONCLUSIONS: Results suggest that the social setting is an important determinant of diet quality in this group and future studies should collect details on where and with whom meals are taken to fully investigate the extent of this influence. PMID- 21266980 TI - Comparison of methods for handling missing data on immunohistochemical markers in survival analysis of breast cancer. AB - BACKGROUND: Tissue micro-arrays (TMAs) are increasingly used to generate data of the molecular phenotype of tumours in clinical epidemiology studies, such as studies of disease prognosis. However, TMA data are particularly prone to missingness. A variety of methods to deal with missing data are available. However, the validity of the various approaches is dependent on the structure of the missing data and there are few empirical studies dealing with missing data from molecular pathology. The purpose of this study was to investigate the results of four commonly used approaches to handling missing data from a large, multi-centre study of the molecular pathological determinants of prognosis in breast cancer. PATIENTS AND METHODS: We pooled data from over 11,000 cases of invasive breast cancer from five studies that collected information on seven prognostic indicators together with survival time data. We compared the results of a multi-variate Cox regression using four approaches to handling missing data complete case analysis (CCA), mean substitution (MS) and multiple imputation without inclusion of the outcome (MI-) and multiple imputation with inclusion of the outcome (MI+). We also performed an analysis in which missing data were simulated under different assumptions and the results of the four methods were compared. RESULTS: Over half the cases had missing data on at least one of the seven variables and 11 percent had missing data on 4 or more. The multi-variate hazard ratio estimates based on multiple imputation models were very similar to those derived after using MS, with similar standard errors. Hazard ratio estimates based on the CCA were only slightly different, but the estimates were less precise as the standard errors were large. However, in data simulated to be missing completely at random (MCAR) or missing at random (MAR), estimates for MI+ were least biased and most accurate, whereas estimates for CCA were most biased and least accurate. CONCLUSION: In this study, empirical results from analyses using CCA, MS, MI- and MI+ were similar, although results from CCA were less precise. The results from simulations suggest that in general MI+ is likely to be the best. Given the ease of implementing MI in standard statistical software, the results of MI+ and CCA should be compared in any multi-variate analysis where missing data are a problem. PMID- 21266982 TI - The metabolomic profile during isoflurane anesthesia differs from propofol anesthesia in the live rodent brain. AB - Development of noninvasive techniques to discover new biomarkers in the live brain is important to further understand the underlying metabolic pathways of significance for processes such as anesthesia-induced apoptosis and cognitive dysfunction observed in the undeveloped brain. We used in vivo proton magnetic resonance spectroscopy and two different signal processing approaches to test the hypothesis that volatile (isoflurane) and intravenous (propofol) anesthetics at equipotent doses produce distinct metabolomic profiles in the hippocampus and parietal cortex of the live rodent. For both brain regions, prolonged isoflurane anesthesia was characterized by higher levels of lactate (Lac) and glutamate compared with long-lasting propofol. In contrast, propofol anesthesia was characterized by very low concentrations of Lac ([lac]) as well as glucose. Quantitative analysis revealed that the [lac] was fivefold higher with isoflurane compared with propofol anesthesia and independent of [lac] in blood. The metabolomic profiling further demonstrated that for both brain regions, Lac was the most important metabolite for the observed differences, suggesting activation of distinct metabolic pathways that may impact mechanisms of action, background cellular functions, and possible agent-specific neurotoxicity. PMID- 21266983 TI - Neuroprotection by glutamate oxaloacetate transaminase in ischemic stroke: an experimental study. AB - As ischemic stroke is associated with an excessive release of glutamate into the neuronal extracellular space, a decrease in blood glutamate levels could provide a mechanism to remove it from the brain tissue, by increasing the brain-blood gradient. In this regard, the ability of glutamate oxaloacetate transaminase (GOT) to metabolize glutamate in blood could represent a potential neuroprotective tool for ischemic stroke. This study aimed to determine the neuroprotective effects of GOT in an animal model of cerebral ischemia by means of a middle cerebral arterial occlusion (MCAO) following the Stroke Therapy Academic Industry Roundtable (STAIR) group guidelines. In this animal model, oxaloacetate-mediated GOT activation inhibited the increase of blood and cerebral glutamate after MCAO. This effect is reflected in a reduction of infarct size, smaller edema volume, and lower sensorimotor deficits with respect to controls. Magnetic resonance spectroscopy confirmed that the increase of glutamate levels in the brain parenchyma after MCAO is inhibited after oxaloacetate-mediated GOT activation. These findings show the capacity of the GOT to remove glutamate from the brain by means of blood glutamate degradation, and suggest the applicability of this enzyme as an efficient and novel neuroprotective tool against ischemic stroke. PMID- 21266984 TI - High blood glutamate oxaloacetate transaminase levels are associated with good functional outcome in acute ischemic stroke. AB - The capacity of the blood enzyme glutamate oxaloacetate transaminase (GOT) to remove glutamate from the brain by means of blood glutamate degradation has been shown in experimental models to be an efficient and novel neuroprotective tool against ischemic stroke; however, the beneficial effects of this enzyme should be tested in patients with stroke to validate these results. This study aims to investigate the association of GOT levels in blood with clinical outcome in patients with acute ischemic stroke. In two clinical independent studies, we found that patients with poor outcome show higher glutamate and lower GOT levels in blood at the time of admission. Lower GOT levels and higher glutamate levels were independently associated with poorer functional outcome at 3 months and higher infarct volume. These findings show a clear association between high blood glutamate levels and worse outcome and vice versa for GOT, presumably explained by the capacity of this enzyme to metabolize blood glutamate. PMID- 21266986 TI - Macroscopically local correlations can violate information causality. AB - Although quantum mechanics is a very successful theory, its foundations are still a subject of intense debate. One of the main problems is that quantum mechanics is based on abstract mathematical axioms, rather than on physical principles. Quantum information theory has recently provided new ideas from which one could obtain physical axioms constraining the resulting statistics one can obtain in experiments. Information causality (IC) and macroscopic locality (ML) are two principles recently proposed to solve this problem. However, none of them were proven to define the set of correlations one can observe. In this study, we show an extension of IC and study its consequences. It is shown that the two above mentioned principles are inequivalent: if the correlations allowed by nature were the ones satisfying ML, IC would be violated. This gives more confidence in IC as a physical principle, defining the possible correlation allowed by nature. PMID- 21266985 TI - Contrasting responses to selection in class I and class IIalpha major histocompatibility-linked markers in salmon. AB - Comparison of levels and patterns of genetic variation in natural populations either across loci or against neutral expectation can yield insight into locus specific differences in the strength and direction of evolutionary forces. We used both approaches to test the hypotheses on patterns of selection on major histocompatibility (MH)-linked markers. We performed temporal analyses of class I and class IIalpha MH-linked markers and eight microsatellite loci in two Atlantic salmon populations in Ireland on two temporal scales: over six decades and 9 years in the rivers Burrishoole and Delphi, respectively. We also compared contemporary Burrishoole and Delphi samples with nearby populations for the same loci. On comparing patterns of temporal and spatial differentiation among classes of loci, the class IIalpha MH-linked marker was consistently identified as an outlier compared with patterns at the other microsatellite loci or neutral expectation. We found higher levels of temporal and spatial heterogeneity in heterozygosity (but not in allelic richness) for the class IIalpha MH-linked marker compared with microsatellites. Tests on both within- and among-population differentiation are consistent with directional selection acting on the class IIalpha-linked marker in both temporal and spatial comparisons, but only in temporal comparisons for the class I-linked marker. Our results indicate a complex pattern of selection on MH-linked markers in natural populations of Atlantic salmon. These findings highlight the importance of considering selection on MH-linked markers when using these markers for management and conservation purposes. PMID- 21266987 TI - Systems-wide temporal proteomic profiling in glucose-starved Bacillus subtilis. AB - Functional genomics of the Gram-positive model organism Bacillus subtilis reveals valuable insights into basic concepts of cell physiology. In this study, we monitor temporal changes in the proteome, transcriptome and extracellular metabolome of B. subtilis caused by glucose starvation. For proteomic profiling, a combination of in vivo metabolic labelling and shotgun mass spectrometric analysis was carried out for five different proteomic subfractions (cytosolic, integral membrane, membrane, surface and extracellular proteome fraction), leading to the identification of ~52% of the predicted proteome of B. subtilis. Quantitative proteomic and corresponding transcriptomic data were analysed with Voronoi treemaps linking functional classification and relative expression changes of gene products according to their fate in the stationary phase. The obtained data comprise the first comprehensive profiling of changes in the membrane subfraction and allow in-depth analysis of major physiological processes, including monitoring of protein degradation. PMID- 21266988 TI - Single-molecule identification via electric current noise. AB - Label-free and real-time single-molecule detection may aid the development of high-throughput biosensing platforms. Molecular fluctuations are a source of noise that often hinders single-molecule identification by obscuring the fine details of molecular identity. In this study, we report molecular identification through direct observation of quantum-fluctuation-induced inelastic noise in single organic molecules. We investigated current fluctuations flowing through a single molecule that is chemically connected to two electrodes. We found increased current oscillations synchronous to electric field excitations of characteristic molecular vibrational modes that contribute to inelastic electron tunnelling. This finding demonstrates a large contribution of charge interaction with nuclear dynamics on noise properties of single-molecule bridges and suggests a potential use of inelastic noise as a valuable molecular signature for single molecule identification. PMID- 21266989 TI - High rates of photobiological H2 production by a cyanobacterium under aerobic conditions. AB - Among the emerging renewable and green energy sources, biohydrogen stands out as an appealing choice. Hydrogen can be produced by certain groups of microorganisms that possess functional nitrogenase and/or bidirectional hydrogenases. In particular, the potential of photobiological hydrogen production by oxygenic photosynthetic microbes has attracted significant interest. However, nitrogenase and hydrogenase are generally oxygen sensitive, and require protective mechanisms to function in an aerobic extracellular environment. Here, we describe Cyanothece sp. ATCC 51142, a unicellular, diazotrophic cyanobacterium with the capacity to generate high levels of hydrogen under aerobic conditions. Wild-type Cyanothece 51142 can produce hydrogen at rates as high as 465 MUmol per mg of chlorophyll per hour in the presence of glycerol. Hydrogen production in this strain is mediated by an efficient nitrogenase system, which can be manipulated to convert solar energy into hydrogen at rates that are several fold higher, compared with any previously described wild-type hydrogen-producing photosynthetic microbe. PMID- 21266990 TI - Pseudogap in a thin film of a conventional superconductor. AB - A superconducting state is characterized by the gap in the electronic density of states, which vanishes at the superconducting transition temperature T(c). It was discovered that in high-temperature superconductors, a noticeable depression in the density of states, the pseudogap, still remains even at temperatures above T(c). Here, we show that a pseudogap exists in a conventional superconductor, ultrathin titanium nitride films, over a wide range of temperatures above T(c). Our study reveals that this pseudogap state is induced by superconducting fluctuations and favoured by two-dimensionality and by the proximity to the transition to the insulating state. A general character of the observed phenomenon provides a powerful tool to discriminate between fluctuations as the origin of the pseudogap state and other contributions in the layered high temperature superconductor compounds. PMID- 21266991 TI - All-linear time reversal by a dynamic artificial crystal. AB - The time reversal of pulsed signals or propagating wave packets has long been recognized to have profound scientific and technological significance. Until now, all experimentally verified time-reversal mechanisms have been reliant upon nonlinear phenomena such as four-wave mixing. In this paper, we report the experimental realization of all-linear time reversal. The time-reversal mechanism we propose is based on the dynamic control of an artificial crystal structure, and is demonstrated in a spin-wave system using a dynamic magnonic crystal. The crystal is switched from an homogeneous state to one in which its properties vary with spatial period a, while a propagating wave packet is inside. As a result, a linear coupling between wave components with wave vectors k~pi/a and k'=k-2pi/a~ pi/a is produced, which leads to spectral inversion, and thus to the formation of a time-reversed wave packet. The reversal mechanism is entirely general and so applicable to artificial crystal systems of any physical nature. PMID- 21266993 TI - Spherical hyperlens for two-dimensional sub-diffractional imaging at visible frequencies. AB - Hyperlenses have generated much interest recently, not only because of their intriguing physics but also for their ability to achieve sub-diffraction imaging in the far field in real time. All previous efforts have been limited to sub wavelength confinement in one dimension only and at ultraviolet frequencies, hindering the use of hyperlenses in practical applications. Here, we report the first experimental demonstration of far-field imaging at a visible wavelength, with resolution beyond the diffraction limit in two lateral dimensions. The spherical hyperlens is designed with flat hyperbolic dispersion that supports wave propagation with very large spatial frequency and yet same phase speed. This allows us to resolve features down to 160 nm, much smaller than the diffraction limit at visible wavelengths, that is, 410 nm. The hyperlens can be integrated into conventional microscopes, expanding their capabilities beyond the diffraction limit and opening a new realm in real-time nanoscopic optical imaging. PMID- 21266992 TI - The phospholipase D1 pathway modulates macroautophagy. AB - Although macroautophagy is known to be an essential degradative process whereby autophagosomes mediate the engulfment and delivery of cytoplasmic components into lysosomes, the lipid changes underlying autophagosomal membrane dynamics are undetermined. Here, we show that phospholipase D1 (PLD1), which is primarily associated with the endosomal system, partially relocalizes to the outer membrane of autophagosome-like structures upon nutrient starvation. The localization of PLD1, as well as the starvation-induced increase in PLD activity, are altered by wortmannin, a phosphatidylinositol 3-kinase inhibitor, suggesting PLD1 may act downstream of Vps34. Pharmacological inhibition of PLD and genetic ablation of PLD1 in mouse cells decreased the starvation-induced expansion of LC3-positive compartments, consistent with a role of PLD1 in the regulation of autophagy. Furthermore, inhibition of PLD results in higher levels of Tau and p62 aggregates in organotypic brain slices. Our in vitro and in vivo findings establish a role for PLD1 in autophagy. PMID- 21266994 TI - Discrete plasticity in sub-10-nm-sized gold crystals. AB - Although deformation processes in submicron-sized metallic crystals are well documented, the direct observation of deformation mechanisms in crystals with dimensions below the sub-10-nm range is currently lacking. Here, through in situ high-resolution transmission electron microscopy (HRTEM) observations, we show that (1) in sharp contrast to what happens in bulk materials, in which plasticity is mediated by dislocation emission from Frank-Read sources and multiplication, partial dislocations emitted from free surfaces dominate the deformation of gold (Au) nanocrystals; (2) the crystallographic orientation (Schmid factor) is not the only factor in determining the deformation mechanism of nanometre-sized Au; and (3) the Au nanocrystal exhibits a phase transformation from a face-centered cubic to a body-centered tetragonal structure after failure. These findings provide direct experimental evidence for the vast amount of theoretical modelling on the deformation mechanisms of nanomaterials that have appeared in recent years. PMID- 21266995 TI - Integrated multilaboratory systems biology reveals differences in protein metabolism between two reference yeast strains. AB - The field of systems biology is often held back by difficulties in obtaining comprehensive, high-quality, quantitative data sets. In this paper, we undertook an interlaboratory effort to generate such a data set for a very large number of cellular components in the yeast Saccharomyces cerevisiae, a widely used model organism that is also used in the production of fuels, chemicals, food ingredients and pharmaceuticals. With the current focus on biofuels and sustainability, there is much interest in harnessing this species as a general cell factory. In this study, we characterized two yeast strains, under two standard growth conditions. We ensured the high quality of the experimental data by evaluating a wide range of sampling and analytical techniques. Here we show significant differences in the maximum specific growth rate and biomass yield between the two strains. On the basis of the integrated analysis of the high throughput data, we hypothesize that differences in phenotype are due to differences in protein metabolism. PMID- 21266996 TI - Herpesviruses carrying a Brainbow cassette reveal replication and expression of limited numbers of incoming genomes. AB - Whether all the infectious herpesvirus particles entering a cell are able to replicate and/or express their genomes is not known. Here, we developed a general method to determine the number of viral genomes expressed in an infected cell. We constructed and analysed fluorophore expression from a recombinant pseudorabies virus (PRV263) carrying a Brainbow cassette (Cre-conditional expression of different fluorophores). Using three isogenic strains derived from PRV263, each expressing a single fluorophore, we analysed the colour composition of cells infected with these three viruses at different multiplicities. We estimate that fewer than seven incoming genomes are expressed per cell. In addition, those templates that are expressed are the genomes selected for replication and packaging into virions. This finite limit on the number of viral genomes that can be expressed is an intrinsic property of the infected cell and may be influenced by viral and cellular factors. PMID- 21266997 TI - Cryptic prophages help bacteria cope with adverse environments. AB - Phages are the most abundant entity in the biosphere and outnumber bacteria by a factor of 10. Phage DNA may also constitute 20% of bacterial genomes; however, its role is ill defined. Here, we explore the impact of cryptic prophages on cell physiology by precisely deleting all nine prophage elements (166 kbp) using Escherichia coli. We find that cryptic prophages contribute significantly to resistance to sub-lethal concentrations of quinolone and beta-lactam antibiotics primarily through proteins that inhibit cell division (for example, KilR of rac and DicB of Qin). Moreover, the prophages are beneficial for withstanding osmotic, oxidative and acid stresses, for increasing growth, and for influencing biofilm formation. Prophage CPS-53 proteins YfdK, YfdO and YfdS enhanced resistance to oxidative stress, prophages e14, CPS-53 and CP4-57 increased resistance to acid, and e14 and rac proteins increased early biofilm formation. Therefore, cryptic prophages provide multiple benefits to the host for surviving adverse environmental conditions. PMID- 21266998 TI - Crystallographic observation of 'induced fit' in a cryptophane host-guest model system. AB - Cryptophane-A, comprised of two cyclotriguaiacylenes joined by three ethylene linkers, is a prototypal organic host molecule that binds reversibly to neutral small molecules via London forces. Of note are trifunctionalized, water-soluble cryptophane-A derivatives, which exhibit exceptional affinity for xenon in aqueous solution. In this paper, we report high-resolution X-ray structures of cryptophane-A and trifunctionalized derivatives in crown-crown and crown-saddle conformations, as well as in complexes with water, methanol, xenon or chloroform. Cryptophane internal volume varied by more than 20% across this series, which exemplifies 'induced fit' in a model host-guest system. PMID- 21266999 TI - Efficient quantum state tomography. AB - Quantum state tomography--deducing quantum states from measured data--is the gold standard for verification and benchmarking of quantum devices. It has been realized in systems with few components, but for larger systems it becomes unfeasible because the number of measurements and the amount of computation required to process them grows exponentially in the system size. Here, we present two tomography schemes that scale much more favourably than direct tomography with system size. One of them requires unitary operations on a constant number of subsystems, whereas the other requires only local measurements together with more elaborate post-processing. Both rely only on a linear number of experimental operations and post-processing that is polynomial in the system size. These schemes can be applied to a wide range of quantum states, in particular those that are well approximated by matrix product states. The accuracy of the reconstructed states can be rigorously certified without any a priori assumptions. PMID- 21267000 TI - Atomically flat single-crystalline gold nanostructures for plasmonic nanocircuitry. AB - Deep subwavelength integration of high-definition plasmonic nanostructures is of key importance in the development of future optical nanocircuitry for high-speed communication, quantum computation and lab-on-a-chip applications. To date, the experimental realization of proposed extended plasmonic networks consisting of multiple functional elements remains challenging, mainly because of the multi crystallinity of commonly used thermally evaporated gold layers. This can produce structural imperfections in individual circuit elements that drastically reduce the yield of functional integrated nanocircuits. In this paper we demonstrate the use of large (>100 MUm(2)) but thin (<80 nm) chemically grown single-crystalline gold flakes that, after immobilization, serve as an ideal basis for focused ion beam milling and other top-down nanofabrication techniques on any desired substrate. Using this methodology we obtain high-definition ultrasmooth gold nanostructures with superior optical properties and reproducible nano-sized features over micrometre-length scales. Our approach provides a possible solution to overcome the current fabrication bottleneck and realize high-definition plasmonic nanocircuitry. PMID- 21267001 TI - Clinical utility gene card for: achromatopsia. PMID- 21267002 TI - Dexamethasone normalizes aberrant elastic fiber production and collagen 1 secretion by Loeys-Dietz syndrome fibroblasts: a possible treatment? AB - Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder characterized by facial dysmorphism, cleft palate, dilation of the aortic arch, blood vessel tortuosity and a high risk of aortic dissection. It is caused by mutations in the transforming growth factor beta-receptor 1 and 2 (TGFbeta-R1 and TGFbeta-R2) genes. Fibroblasts derived from 12 Loeys-Dietz syndrome patients, six with TGFB-R1 mutations and six with TGFB-R2 mutations, were analyzed using RT PCR, biochemical assays, immunohistochemistry and electron microscopy for production of elastin, fibrillin 1, fibulin 1 and fibulin 4 and deposition of collagen type I. All LDS fibroblasts with TGFbeta-R1 mutations demonstrated decreased expression of elastin and fibulin 1 genes and impaired deposition of elastic fibers. In contrast, fibroblasts with TGFbeta-R2 mutations consistently demonstrated intracellular accumulation of collagen type I in the presence of otherwise normal elastic fiber production. Treatment of the cell cultures with dexamethasone induced remarkable upregulation in the expression of tropoelastin, fibulin 1- and fibulin 4-encoding mRNAs, leading to normalization of elastic fiber production in fibroblasts with TGFbeta-R1 mutations. Treatment with dexamethasone also corrected the abnormal secretion of collagen type I from fibroblasts with TGFbeta-R2 gene mutations. As the organogenesis-relevant elastic fiber production occurs exclusively in late fetal and early neonatal life, these findings may have implications for treatment in early life. Further studies are required to determine if dexamethasone treatment of fetuses prenatally diagnosed with LDS would prevent or alleviate the connective tissue and vascular defects seen in this syndrome. PMID- 21267003 TI - Does the new HapMap throw the baby out with the bath water? PMID- 21267005 TI - The 12q14 microdeletion syndrome: six new cases confirming the role of HMGA2 in growth. AB - We report six patients with array deletions encompassing 12q14. Out of a total of 2538 array investigations carried out on children with developmental delay and dysmorphism in three diagnostic testing centres, six positive cases yielded a frequency of 1 in 423 for this deletion syndrome. The deleted region in each of the six cases overlaps significantly with previously reported cases with microdeletions of this region. The chromosomal range of the deletions extends from 12q13.3q15. In the current study, we report overlapping deletions of variable extent and size but primarily comprising chromosomal bands 12q13.3q14.1. Four of the six deletions were confirmed as de novo events. Two cases had deletions that included HMGA2, and both children had significant short stature. Neither case had osteopoikilosis despite both being deleted for LEMD3. Four cases had deletions that ended proximal to HMGA2 and all of these had much better growth. Five cases had congenital heart defects, including two with atrial septal defects, one each with pulmonary stenosis, sub-aortic stenosis and a patent ductus. Four cases had moderate delay, two had severe developmental delay and a further two had a diagnosis of autism. All six cases had significant speech delay with subtle facial dysmorphism. PMID- 21267004 TI - Type B mandibuloacral dysplasia with congenital myopathy due to homozygous ZMPSTE24 missense mutation. AB - Mutation in ZMPSTE24 gene, encoding a major metalloprotease, leads to defective prelamin A processing and causes type B mandibuloacral dysplasia, as well as the lethal neonatal restrictive dermopathy syndrome. Phenotype severity is correlated with the residual enzyme activity of ZMPSTE24 and accumulation of prelamin A. We had previously demonstrated that a complete loss of function in ZMPSTE24 was lethal in the neonatal period, whereas compound heterozygous mutations including one PTC and one missense mutation were associated with type B mandibuloacral dysplasia. In this study, we report a 30-year longitudinal clinical survey of a patient harboring a novel severe and complex phenotype, combining an early-onset progeroid syndrome and a congenital myopathy with fiber-type disproportion. A unique homozygous missense ZMPSTE24 mutation (c.281T>C, p.Leu94Pro) was identified and predicted to produce two possible ZMPSTE24 conformations, leading to a partial loss of function. Western blot analysis revealed a major reduction of ZMPSTE24, together with the presence of unprocessed prelamin A and decreased levels of lamin A, in the patient's primary skin fibroblasts. These cells exhibited significant reductions in lifespan associated with major abnormalities of the nuclear shape and structure. This is the first report of MAD presenting with confirmed myopathic abnormalities associated with ZMPSTE24 defects, extending the clinical spectrum of ZMPSTE24 gene mutations. Moreover, our results suggest that defective prelamin A processing affects muscle regeneration and development, thus providing new insights into the disease mechanism of prelamin A defective associated syndromes in general. PMID- 21267006 TI - Hybridisation-based resequencing of 17 X-linked intellectual disability genes in 135 patients reveals novel mutations in ATRX, SLC6A8 and PQBP1. AB - X-linked intellectual disability (XLID), also known as X-linked mental retardation, is a highly genetically heterogeneous condition for which mutations in >90 different genes have been identified. In this study, we used a custom-made sequencing array based on the Affymetrix 50k platform for mutation screening in 17 known XLID genes in patients from 135 families and found eight single nucleotide changes that were absent in controls. For four mutations affecting ATRX (p.1761M>T), PQBP1 (p.155R>X) and SLC6A8 (p.390P>L and p.477S>L), we provide evidence for a functional involvement of these changes in the aetiology of intellectual disability. PMID- 21267007 TI - A nonsense mutation in FMR1 causing fragile X syndrome. AB - Fragile X syndrome is a common cause of inherited intellectual disability. It is caused by lack of the FMR1 gene product FMRP. The most frequent cause is the expansion of a CGG repeat located in the 5'UTR of FMR1. Alleles with 200 or more repeats become hypermethylated and transcriptionally silent. Only few patients with intragenic point mutations in FMR1 have been reported and, currently, routine analysis of patients referred for fragile X syndrome includes solely analysis for repeat expansion and methylation status. We identified a substitution in exon 2 of FMR1, c.80C>A, causing a nonsense mutation p.Ser27X, in a patient with classical clinical symptoms of fragile X syndrome. The mother who carried the mutation in heterozygous form presented with mild intellectual impairment. We conclude that further studies including western blot and DNA sequence analysis of the FMR1 gene should be performed in patients with typical symptoms of fragile X syndrome in whom no CGG repeat expansion is detected. PMID- 21267008 TI - The effect of genome-wide association scan quality control on imputation outcome for common variants. AB - Imputation is an extremely valuable tool in conducting and synthesising genome wide association studies (GWASs). Directly typed SNP quality control (QC) is thought to affect imputation quality. It is, therefore, common practise to use quality-controlled (QCed) data as an input for imputing genotypes. This study aims to determine the effect of commonly applied QC steps on imputation outcomes. We performed several iterations of imputing SNPs across chromosome 22 in a dataset consisting of 3177 samples with Illumina 610 k (Illumina, San Diego, CA, USA) GWAS data, applying different QC steps each time. The imputed genotypes were compared with the directly typed genotypes. In addition, we investigated the correlation between alternatively QCed data. We also applied a series of post imputation QC steps balancing elimination of poorly imputed SNPs and information loss. We found that the difference between the unQCed data and the fully QCed data on imputation outcome was minimal. Our study shows that imputation of common variants is generally very accurate and robust to GWAS QC, which is not a major factor affecting imputation outcome. A minority of common-frequency SNPs with particular properties cannot be accurately imputed regardless of QC stringency. These findings may not generalise to the imputation of low frequency and rare variants. PMID- 21267009 TI - Genetic testing and common disorders in a public health framework. PMID- 21267010 TI - Clinical utility gene card for: hypertrophic cardiomyopathy (type 1-14). PMID- 21267011 TI - Clinical utility gene card for: blue cone monochromatism. PMID- 21267012 TI - Cancer risk management strategies and perceptions of unaffected women 5 years after predictive genetic testing for BRCA1/2 mutations. AB - In a French national cohort of unaffected females carriers/non-carriers of a BRCA1/2 mutation, long-term preventive strategies and breast/ovarian cancer risk perceptions were followed up to 5 years after test result disclosure, using self administered questionnaires. Response rate was 74%. Carriers (N=101) were younger (average age +/- SD=37 +/- 10) than non-carriers (N=145; 42 +/- 12). There were four management strategies that comprised 88% of the decisions made by the unaffected carriers: 50% opted for breast surveillance alone, based on either magnetic resonance imaging (MRI) and other imaging (31%) or mammography alone (19%); 38% opted for either risk reducing salpingo-oophorectomy (RRSO) and breast surveillance, based on MRI and other imaging (28%) or mammography alone (10%). The other three strategies were: risk reducing mastectomy (RRM) and RRSO (5%), RRM alone (2%) and neither RRM/RRSO nor surveillance (6%). The results obtained for various age groups are presented here. Non-carriers often opted for screening despite their low cancer risk. Result disclosure increased carriers' short-term high breast/ovarian cancer risk perceptions (P <= 0.02) and decreased non carriers' short- and long-term perceptions (P<0.001). During follow-up, high breast cancer risk perceptions increased with time among those who had no RRM and decreased in the opposite case; high ovarian cancer risk perceptions increased further with time among those who had no RRSO and decreased in the opposite case; RRSO did not affect breast cancer risk perceptions. Informed decision-making involves letting women know whether opting for RRSO and breast MRI surveillance is as effective in terms of survival as RRM and RRSO. PMID- 21267013 TI - Phenotypical and functional specialization of FOXP3+ regulatory T cells. AB - Forkhead box P3 (FOXP3)(+) regulatory T (T(Reg)) cells prevent autoimmune disease, maintain immune homeostasis and modulate immune responses during infection. To accomplish these tasks, T(Reg) cell activity is precisely controlled, and this requires T(Reg) cells to alter their migratory, functional and homeostatic properties in response to specific cues in the immune environment. We review progress in understanding the diversity of T(Reg) cells, T(Reg) cell function in different anatomical and inflammatory settings, and the influence of the immune environment on T(Reg) cell activity. We also consider how these factors affect immune-mediated disease in the contexts of infection, autoimmunity, cancer and transplantation. PMID- 21267014 TI - Presumed guilty: natural killer T cell defects and human disease. AB - Natural killer T (NKT) cells are important regulatory lymphocytes that have been shown in mouse studies, to have a crucial role in promoting immunity to tumours, bacteria and viruses, and in suppressing cell-mediated autoimmunity. Many clinical studies have indicated that NKT cell deficiencies and functional defects might also contribute to similar human diseases, although there is no real consensus about the nature of the NKT cell defects or whether NKT cells could be important for the diagnosis and/or treatment of these conditions. In this Review, we describe the approaches that have been used to analyse the NKT cell populations of various patient groups, suggest new strategies to determine how (or indeed, if) NKT cell defects contribute to human disease, and discuss the prospects for using NKT cells for therapeutic benefit. PMID- 21267016 TI - [We must do something with this!]. PMID- 21267017 TI - [Clinical ethics committees--time for changes?]. PMID- 21267015 TI - Recognition of herpesviruses by the innate immune system. AB - Advances in innate immunity over the past decade have revealed distinct classes of pattern recognition receptors (PRRs) that detect pathogens at the cell surface and in intracellular compartments. This has shed light on how herpesviruses, which are large disease-causing DNA viruses that replicate in the nucleus, are initially recognized during cellular infection. Surprisingly, this involves multiple PRRs both on the cell surface and within endosomes and the cytosol. In this article we describe recent advances in our understanding of innate detection of herpesviruses, how this innate detection translates into anti-herpesvirus host defence, and how the viruses seek to evade this innate detection to establish persistent infections. PMID- 21267018 TI - [Cause of or consequence of?]. PMID- 21267019 TI - [Wrongly informed about influenza serology]. PMID- 21267021 TI - [More meaningless about whiplash]. PMID- 21267022 TI - [Elderly physicians and licence]. PMID- 21267023 TI - [Child psychiatry challenges]. PMID- 21267024 TI - [Dermatology with and without professor]. PMID- 21267025 TI - [Infectious endocarditis in a Norwegian hospital 1997-2006]. AB - BACKGROUND: Infective endocarditis is a serious disease with high morbidity and mortality. The causative microorganism and predisposing factors have changed over time. Four retrospective studies of this condition have been published in Norway; the most recent in 1998. Aetiology, treatment and mortality have been reviewed for such patients admitted to a Norwegian hospital in a 10-year period. MATERIAL AND METHODS: Medical records were reviewed for all patients >= 18 years admitted to Aalesund hospital, and diagnosed with infective endocarditis (as primary or secondary diagnosis) according to relevant ICD 9 and ICD 10 codes, in the period 01.01.1997-31.12.2006. Demographical, clinical, and laboratory data were recorded. RESULTS: 57 patients were diagnosed with infective endocarditis; the average age was 66 years and 37 were men. The average annual incidence was 6.3/100000 pr year. The average length of treatment was six weeks, and the first choice of antibiotics was usually a combination of penicillin and aminoglycosides (46%). The most common causative microorganism was S.aureus (21%). 42 (74%) patients had one or more complications. Nine (16%) patients died during their hospital stay. INTERPRETATION: The incidence of infective endocarditis in Aalesund hospital was in the upper range of previous reports. In accordance with previous studies, we found that staphylococcus is currently the most common causative micro-organism. The age of onset has increased compared to earlier Norwegian studies. PMID- 21267026 TI - Is the discussion of patient cases in clinical ethics-committees useful? AB - BACKGROUND: All health enterprises in Norway today have at least one clinical ethics committee (CEC). One of the aims is to give advice and to counsel the hospital staff on ethical issues. As part of the quality assurance of this work, we wanted to find out if clinicians have benefited from these committees in individual cases. MATERIAL AND METHODOLOGY: The local committees were requested to distribute a questionnaire to all clinicians who had submitted a case to the committee during the previous 18 months. The survey was anonymous. Out of the 86 questionnaires that were distributed, 43 (50%) were returned to the Centre for Medical Ethics. RESULTS: The majority of clinicians had a number of reasons for contacting the committee. The most usual reason was the desire to have a broad consultation on a case (70%), which was regarded as useful. The most common issue discussed was limiting the treatment of a seriously ill patient (56%), the will/wishes of the next-of-kin (40%) and patient autonomy (37%). The committee gave advice in 50% of the cases. Thirty-eight percent of the consultations resulted in practical consequences, including the discontinuation of treatment in six cases. INTERPRETATION: Because of the low response percentage, the results must be interpreted with caution. The work of the committees is generally evaluated as useful, and the consultations can have practical consequences. However, it is challenging to make this work better known among clinicians and to conduct quality assurance. PMID- 21267027 TI - How much sick leave is work-related? AB - BACKGROUND: Sick leave is a topical subject, particularly following the revision of the Agreement on a More Inclusive Working Life (the IA agreement). However, there has been little discussion about the extent to which sick leave may be related to work. MATERIAL AND METHODS: The paper is based on a non-systematic literature search using PubMed combined with personal research and experience. RESULTS: Various studies indicate that a significant proportion of all sick leaves may be due to illness caused by working conditions. Heavy physical work, awkward work postures and low job control are particularly important factors. People who suffer from work-related illnesses have a greater need for absence from work than people with similar illnesses caused by factors other than their work. Workplace interventions designed to prevent work-related illness may also prevent sick leave. Sick leaves which are due to an imbalance between an individual's resources and his/her job demands, may often be prevented or shortened by workplace interventions, irrespective of what causes the imbalance. INTERPRETATION: It is my view that more importance should be attached to primary preventive measures to reduce work-related illness, combined with workplace interventions to accommodate people who carry a higher risk of sick leave. However, this is not given sufficient attention in the current IA agreement. PMID- 21267028 TI - [Treatment of bipolar disorder during pregnancy and in the postpartum period]. AB - BACKGROUND: Pharmacological treatment and prophylaxis of bipolar disorders during pregnancy and in the postpartum period imply complicated clinical assessments. MATERIAL AND METHOD: This article is based on a non-systematic search in PubMed and the authors' clinical experience. RESULTS: If a woman is already using a prophylactic drug at the time of pregnancy, she can in general continue to do so during pregnancy, with the exception of valproate. If the disorder starts during pregnancy; lithium, lamotrigine or second generation antipsychotic drugs are suitable alternatives. In general, drugs used during pregnancy can also be used in the postpartum period, although some require special precautions if the mother wishes to breast-feed. If treatment is initiated after delivery, the mother's wish to breast-feed should be taken into consideration when choosing a drug. INTERPRETATION: Although existing studies have weaknesses, there is sufficient evidence to give qualified advice regarding choice of medication for bipolar disorder during pregnancy and in the postpartum period. PMID- 21267029 TI - [Patient participation in hospital wards--health personnel's experience]. AB - BACKGROUND: Users of the Norwegian health services have a legal right to influence the services through user committees, and also to assess the treatment they are being subject to on an individual basis. The aim of this study was to investigate the experience health personnel have with patient participation in hospital wards. MATERIAL AND METHODS: Qualitative interview study with 18 health workers from 12 hospital wards in Central Norway Regional Health Authority. RESULTS: Health personnel stated that they took the initiative to patient participation in the hospital ward. User representatives were either appointed by the user committee or chosen because of personal characteristics that suited the ward's needs. Health personnel were positively surprised by the user representatives' qualifications. It was still a challenge to achieve equality between health personnel and user representatives. Health personnel limited patient participation, especially regarding medical issues. INTERPRETATION: Patient participation in hospital wards seems to be regulated by health personnel, who initiate and limit such participation. PMID- 21267030 TI - [Paramyotonia]. PMID- 21267031 TI - Systemic treatment of acne. PMID- 21267032 TI - [A woman with recurrent urticaria, joint pain and fever]. AB - A middle-aged woman suffered from chronic recurrent urticarial rash and fever. After 13 years of skin disease, she developed monoclonal IgM gammopathy, myalgia and joint pain. She was diagnosed with Schnitzler's syndrome and successfully treated with the IL-1 receptor antagonist anakinra. PMID- 21267033 TI - [Effective treatment of rare diagnosis]. PMID- 21267034 TI - A spiritual dimension is important for many patients. PMID- 21267037 TI - Cardiovascular effects of spinal cord stimulation in hypertensive patients. AB - BACKGROUND: Several animal and clinical studies have shown that thoracic spinal cord stimulation (SCS) may decrease mean arterial pressure (MAP). A previous study in normotensive participants demonstrated a small reduction in MAP during SCS at the T5-T6 spinal level. It has also been demonstrated that chronic SCS at the subthreshold stimulation level significantly improved angina attacks and 6 minute hall walk distance in drug refractory angina patients. OBJECTIVES: To determine if thoracic SCS at 2 different stimulation strengths would decrease blood pressure (BP) and heart rate (HR) during baseline conditions and during activation of the sympathetic system by the cold pressor test (CPT). METHODS: Six hypertensive participants and 9 normotensive participants were evaluated. The SCS leads were implanted under sedation (midazolam and fentanyl) 3 days prior to the study. The SCS device was not implanted at the time of lead implantation; the exteriorized leads were connected to an external programmer at the time of the study. MAP was measured at the finger using beat-to-beat photoplethysmographic recordings at rest and during CPT with a Finometer (Model 1, Finapress Medical Systems, Amsterdam, The Netherlands). SCS at threshold (100%, SCS100) and subthreshold (80%, SCS80) intensities were randomly performed in the T5-T6 region of the spinal cord during normal conditions as well as during CPT. Each participant had 3 CPTs with the placebo (control, no SCS) CPT always performed first. CPT was performed by immersing the right hand into ice water for 90 seconds. Thirty seconds of beat-to-beat data prior to starting each CPT (baseline) was analyzed. During the 90 second CPT, the median values of the last 30 seconds of data were used for analysis. Heart rate variability (HRV) during baseline and SCS was computed using Kubios HRV Version 2.0 software (University of Kuopio, Kuopio, Finland). Since the median values of HR, MAP and their changes did not follow a normal distribution, groups were compared with a non-parametric Friedman's or Wilcoxon's signed rank test. The HRV data were normally distributed and a repeated measures analysis of variance (ANOVA) was used. RESULTS: SCS did not significantly alter MAP or HR at baseline nor did it appear to blunt changes in MAP or HR in response to CPT. In the normotensive group, MAP was significantly elevated by a median value of 16 mmHg (P<0.001) during the placebo phase, and by 18 and 10.5 mmHg during the SCS80 and SCS100 phases, respectively. In the hypertensive group, an enhanced response to the CPT was observed. In these participants, the MAP was significantly elevated by a median value of 26.8 mmHg (P<0.001) during the placebo phase, and by 20 and 17 mmHg during the SCS80 and SCS100 phases, respectively. There was a non-significant trend for the CPT induced increase in BP to be attenuated during SCS80. HRV tended to decrease in both the time and frequency domain in hypertensive participants, although this decrease was not statistically significant. LIMITATIONS: This was a pilot study including a limited number of participants CONCLUSIONS: Acute SCS at the T5-T6 region did not significantly alter MAP or HR compared to baseline (no SCS) in participants without sedation, supporting our previous findings in sedated patients. Hypertensive participants had a heightened response to transient cold stress, consistent with the literature. The observation of the tendency for a reduction in HRV in both the time and frequency domain in hypertensive participants is also consistent with the literature. In contrast to acute SCS, the hemodynamic effects of chronic SCS should be explored in the future. PMID- 21267038 TI - Italian registry on long-term intrathecal ziconotide treatment. AB - BACKGROUND: Ziconotide is commonly used for intrathecal (IT) therapy of chronic pain, and has been recently indicated as a first-line IT drug. It is also extremely useful for patients intolerant or refractory to the common IT drugs (such as morphine). The literature, excluding registration studies, mostly includes small samples, and gives only fragmentary evidence on the long-term risks and benefits of ziconotide. OBJECTIVE: To collect data on safety and efficacy of long-term ziconotide IT infusion in Italian pain centers. STUDY DESIGN: Retrospective cohort study on the use of ziconotide in Italy. The study was designed and coordinated by the Foundation ISAL (Algological Sciences Research and Training Institute). Patients treated with ziconotide from several pain therapy and neurosurgery units were included in the study, allowing the creation of the first Italian Registry of Ziconotide. SETTING: Seventeen Italian public and private pain and neurosurgery centers. METHODS: Patients suffering from cancer or non-cancer intractable chronic pain who had been treated with ziconotide IT infusion for at least one month. Efficacy was analyzed considering changes on the visual analog scale of pain intensity from baseline observation. Safety was assessed by monitoring the number and intensity of adverse events. RESULTS: Currently, 104 patients are included in the Italian Registry of Ziconotide. Ziconotide was administered as the first IT drug choice to 55 patients. Seventy-two patients reported at least a 30% pain intensity reduction with a mean dose of 4.36 ug/d. The sustained analgesic effect (P < 0.001) of the ziconotide IT therapy was observed in a group of 45 patients who remained in the study over 6 months without treatment interruptions and with relatively stable doses. Sixty-six patients reported at least one side effect related to ziconotide. However, adverse events have not always been decisive for treatment interruptions. LIMITATIONS: Data were collected retrospectively from different pain centers that used different methods for ziconotide treatment and clinical forms for its data collection; for this reason there is an absence of standardized methodologies and a placebo-controlled group, and some data were missing. CONCLUSIONS: Ziconotide IT therapy is a treatment option commonly used for clinical practice in 17 Italian pain therapy and neurosurgery units. It might give relief to patients with refractory chronic pain, and it seems to have a safe profile. Long-term studies and controlled trials are required. PMID- 21267039 TI - One-year results of a randomized, double-blind, active controlled trial of fluoroscopic caudal epidural injections with or without steroids in managing chronic discogenic low back pain without disc herniation or radiculitis. AB - BACKGROUND: Lumbar radicular pain pathophysiology continues to be the subject of research and debate as discogenic pain is increasingly seen as a cause of non specific low back pain. Among non-surgical methods used to manage chronic low back pain with or without disc herniation, epidural injections are one of the most common modalities. However, there is little evidence utilizing contemporary methodology for using epidural injections in patients with discogenic pain. STUDY DESIGN: A randomized, double-blind, active-controlled trial. SETTING: An interventional pain management practice, a specialty referral center, a private practice setting in the United States. OBJECTIVES: To evaluate the effectiveness of caudal epidural injections with local anesthetic, with or without steroids, in managing chronic low back pain without disc herniation or radiculitis. METHODS: A total of 120 patients were assigned to one of 2 groups. Group I patients received caudal epidural injections with local anesthetic (lidocaine 0.5% 10 mL); Group II patients received caudal epidural injections with 9 mL of 0.5% lidocaine mixed with 1 mL of steroid (either brand name or non-particulate betamethasone [6 mg] or methylprednisolone [40 mg]). Computer-generated randomization and random allocation sequence by simple randomization were the randomization techniques utilized. OUTCOMES ASSESSMENT: Multiple outcome measures were utilized which included the Numeric Rating Scale (NRS), the Oswestry Disability Index 2.0 (ODI), employment status, functional status, and opioid intake at 3, 6, and 12 months post treatment. Significant pain relief and functional status improvement were described as a 50% or more reduction in scores from baseline. RESULTS: Significant pain relief and functional status improvement were observed in 55% of the patients in Group I and 68% of the patients in Group II. In contrast, 84% of patients in Group I and 85% in Group II saw significant pain relief and functional status improvement in the successful group (62% in Group I and 68% in Group II). The average procedures per year were 3.8 +/- 0.9 for Group I and 4.3 +/- 0.9 for Group II. Average pain scores decreased from 8.0 +/- 0.9 to 4.3 +/- 1.79 for Group I and from 7.9 +/- 1.0 to 3.8 +/- 1.59 for Group II. There were no differences among the patients receiving one of the 3 steroids. LIMITATIONS: The results of this study are limited by lack of a placebo group. CONCLUSION: Caudal epidural injections with local anesthetic with or without steroids are effective in patients with chronic low back pain of discogenic origin without facet joint pain, disc herniation, and/or radiculitis. PMID- 21267040 TI - Feasibility of combined epicranial temporal and occipital neurostimulation: treatment of a challenging case of headache. AB - BACKGROUND: Evidence of a paradigm shift towards epicranial neurostimulation treatment techniques aimed at the site of headache pain is beginning to populate the literature. This is most apparent by 2 recently published reports describing alternative approaches to peripheral nerve stimulation techniques for refractory migraine, including hemiplegic migraine. OBJECTIVES: To contribute to the emerging literature on epicranial-based neuroaugmentative approaches which target site-specific areas of distinct, but relatively diffuse, headache pain. Specifically, we describe the feasibility of a novel neurostimulation technique: occipital nerve stimulation, combined with bilateral subcutaneous electrical stimulation over the temporal region, to treat a patient dually diagnosed with "complicated migraine" and occipital neuralgia. Integral to this report, key stimulation programming data are also presented to better distinguish the role of this form of therapy in migraine, or other headache forms, from both the clinical and biomedical perspectives. METHODS: Case presentation with literature review. RESULTS: At 24-month follow-up, headache onset had been reduced by more than 50%, including cessation of neurologic deficits that accompanied the patient's migraines. No complications or adverse side effects are reported. The programming data reported here supports a proposed mechanism of action concerning stimulation of the auriculotemporal nerve distribution/anterior temporal region for management of refractory pain in migraine. LIMITATIONS: Case presentation provides only initial assessment of treatment safety, not conclusive evidence of treatment effectiveness. Future studies which consider "follow-the-path" epicranial approaches to peripheral nerve stimulation techniques for refractory headache pain are needed to better quantify outcomes and mechanisms of action. CONCLUSIONS: In the single case reported here, the feasibility of a novel neurostimulation technique (occipital nerve stimulation/bilateral subcutaneous temporal region stimulation) to treat headache is presented. At the 24-month follow-up, no complications (such as loss of coverage due to lead displacement or lead fracture or erosion) or adverse side effects were reported. Finally, inclusion of fundamental programming data in reports on neuroaugmentative approaches to headache care will complement initiatives in research from the clinical and biomedical communities involved in this field. PMID- 21267041 TI - Alternative approach to needle placement in spinal cord stimulator trial/implantation. AB - Neuromodulation with spinal cord stimulation is a proven, cost effective treatment for the management of chronic radicular low back pain from failed low back surgery syndrome and other neuropathic pain conditions. The traditionally instructed method for percutaneous spinal cord stimulator lead placement promotes the use of a "loss of resistance" technique under anteroposterior fluoroscopic guidance to assure midline lead placement and proper entry into the epidural space. Loss of resistance is a reliable method to locate the epidural space in most clinical situations. However, in certain circumstances such as a congenital underdeveloped ligamentum flavum or defects of the ligamentum flavum, sometimes occurring after lumbar spine surgery, it might become difficult to use a loss of resistance technique to locate the epidural space. In this case, the level of resistance might not be clear. Further, a false loss of resistance might occur between changes in fascial planes that might lead to the uncertainty of needle depth. This paper introduces an alternative method for needle placement for spinal cord stimulator (SCS) trials and implantation without using the traditional loss of resistance technique. The technique allows for precise visual monitoring of the Tuohy needle tip under fluoroscopy to gauge needle depth as it enters into the tissue and the epidural space based on anatomic structural landmarks. This method allows for multiple lead placement or single lead insertion multiple times in the same interlaminar space. This is an alternative approach to the loss of resistance technique based on the fluoroscopic landmarks. Theoretically, this should be a safer approach for accessing the epidural space; however, further studies are needed to evaluate its safety. PMID- 21267042 TI - Spinal cord stimulation for the treatment of chronic renal pain secondary to uretero-pelvic junction obstruction. AB - BACKGROUND: Chronic renal pain secondary to uretero-pelvic junction obstruction (UPJO) is common but remains poorly understood. Patients with UPJO experience frequent infections, renal calculi and pain. Management options for patients with this condition are traditionally limited to surgical interventions to eliminate the obstruction. Spinal Cord Stimulation (SCS) has gained widespread popularity for the treatment of numerous conditions from complex regional pain syndrome to failed back syndrome. With continued success, the possible use of SCS has steadily increased. Although a significant number of patients with severe chronic renal pain will transiently respond to analgesics and physical interventions such as autonomic sympathetic blocks, substantial long-term pain relief is usually lacking. SCS therefore might be a welcome addition to the treatment of moderate to severe chronic renal pain. OBJECTIVE: This article presents a case of using spinal cord stimulation in the management of chronic renal pain secondary to uretero-pelvic junction obstruction. DESIGN: Case report. SETTING: Academic University Pain Management Center METHODS: A 38-year old female presented with a 15-year history of persistent right sided flank pain secondary to congenital uretero-pelvic junction obstruction. After failing to respond adequately to stenting, medications and nerve blocks, a trial of spinal cord stimulation and subsequent permanent implantation of a spinal cord stimulator (SCS) were performed. RESULTS: The patient reported significant improvement in pain, overall functioning and no consumption of opioids during the SCS trial and following system implant. LIMITATIONS: A case report. CONCLUSION: Spinal cord stimulation might be an option in the management of chronic renal pain secondary to uretero pelvic junction obstruction. PMID- 21267043 TI - Reliability and validity of the Global Pain Scale with chronic pain sufferers. AB - BACKGROUND: Many pain scales exist today; however, a comprehensive, easy-to analyze test has yet to be available to evaluate a patient's pain and understand the sociocultural, cognitive, and affective factors contributing to a patient's overall pain experience. Many scales have attempted to create an all-encompassing pain assessment but remain incomplete in their assessment of pain and the contributing aspects of pain. OBJECTIVE: To present the Global Pain Scale (GPS) as an alternative to current pain assessments and evaluate the reliability and construct validity of the GPS. METHODS: Two hundred sixty-two undergraduates with chronic pain at a large midwestern university participated in this survey study. Participants reported in which of 14 specific body regions they have pain, the frequency of pain, and treatment history for their pain. Participants completed 4 scales--GPS, the West Haven Yale Scale (WHY), the Perceived Stress Scale (PSS), and the short form McGill (SF-MPQ)--in a randomized order. RESULTS: The GPS demonstrated high criterion validity and high construct validity (including both convergent and discriminant validity). The total GPS scale and each of the subscales were reliable. The total GPS score was significantly correlated with all other subscales, excluding those for which there is a theoretical reason for them to not be correlated with our participant population. LIMITATIONS: A sample of college students was used, thus decreasing the generalizability of these findings to patients approximating our sample. CONCLUSIONS: The GPS is a valid scale that is concise and easily interpreted. The GPS is a comprehensive assessment of pain evaluating pain, emotions, clinical outcomes, and daily activities. This may be a valuable tool for evaluation and treatment planning for interventional pain management physicians. PMID- 21267045 TI - Neurotoxicity of subarachnoid preservative-free S(+)-ketamine in dogs. AB - BACKGROUND: Subarachnoid S(+)-ketamine is a matter of much debate as the results regarding its toxicity are contradictory. OBJECTIVES: Our objective was to investigate possible histopathological alterations after subarachnoid administration of different doses of preservative-free S(+)-ketamine to dogs. STUDY DESIGN: A randomized, blind, prospective experimental study. SETTING: Center for Research on Pain at the Federal University of Maranhao, Brazil. METHODS: Sixteen adult mongrel dogs of both sexes, each weighing 11 to 20 kg were divided into 3 groups: Group I (n=6), 0.7 mg/kg-1 S(+)-ketamine; Group II (n=6), 0.5 mg/kg-1 S(+)-ketamine, and a control group, Group III, (n=4), 0.9% NaCl. All substances were administered in one mL volume doses. The animals were kept in captivity for 2 weeks; after this period, they were put down and lumbar and sacral portions of the spinal cords were removed for histological examination using conventional light microscopy. RESULTS: There were histological alterations in the spinal cords of the test subjects in the control group. Comparison showed significant histological abnormalities in Groups I and II when compared to the control group, including gliosis, axonal edema, central chromatolysis, lymphocyte infiltration and fibrous thickening of the dura mater. LIMITATIONS: Test subjects received only a single dose each. The observation period was not very long, less than a month. CONCLUSIONS: Subarachnoid administration of S(+)-ketamine without preservative caused histological lesions on the spinal cord and meninges in the dogs studied. S(+)-ketamine should not be given to clinical patients in this way until further evaluation of the significance of this toxicity has been conducted. PMID- 21267044 TI - Feasibility study of rapid opioid rotation and titration. AB - BACKGROUND: Opioid guidelines recommend opioid rotation and switching for patients who do not achieve adequate pain relief or who experience intolerable adverse events (AEs) with their current opioid. However, specific recommendations and protocols for opioid rotation are lacking, making the practice time consuming and difficult for primary care physicians to accomplish independently or coordinate with a pain specialist. OBJECTIVES: To assess the safety and feasibility of using 24-hour intravenous patient-controlled analgesia (IV-PCA) to achieve rapid opioid rotation and titration (RORT). STUDY DESIGN: Open-label pilot study. SETTING: Hospital research center. METHODS: At admission, patients (aged >= 18 years) with treatment-refractory chronic pain who were taking morphine or oxycodone for >= 3 months and had pain scores >= 4 on a 10-point scale, underwent opioid rotation to oral oxymorphone extended release (ER). They also received IV-PCA oxymorphone for 24 hours as needed. At discharge, the participants were taking oral oxymorphone ER with oxymorphone immediate release (IR) as needed based on their total 24-hour oral plus IV-PCA oxymorphone use. During a 2-week follow-up, their oxymorphone usage was titrated as needed. Main outcome measures were AEs, Patient Global Impression of Change (PGIC), Brief Pain Inventory (0 = no pain/interference, 10 = worst pain/complete interference), treatment satisfaction, and change in oxymorphone dose. RESULTS: Twelve patients enrolled and completed the 24-hour IV-PCA; 10 completed the 2-week follow-up post 24-hour IV-PCA. PGIC status improved by 12 hours (odds ratio [OR], 0.19, 95% CI, 0.08 - 0.44; P < 0.001), and both PGIC status and activity scores improved by 24 hours (OR, 0.23, 95% CI, 0.09 - 0.55; P = 0.001; OR, 0.49, 95% CI, 0.25 - 0.96; P = 0.04, respectively) and 2 weeks (OR, 0.14, 95% CI, 0.04 - 0.46; P = 0.001; OR, 0.21, 95% CI, 0.06 - 0.72; P = 0.01) versus 6 hours. During the 24-hour IV-PCA time period, 6 of 10 patients accomplished >= 50% of their overall dose titration. At 2 weeks, 8 of 10 participants were Greatly Satisfied or Somewhat Satisfied with the overall RORT procedure. RORT was well tolerated, with no serious AEs. LIMITATIONS: This was a pilot open-label study in a small number of participants. A larger randomized study with long-term follow-up and comparison to traditional protocols is necessary. CONCLUSIONS: Preliminary data suggest that RORT can be performed safely and effectively by incorporating IV-PCA during the first 24 hours. Further investigations are needed to determine whether RORT can become an ambulatory treatment intervention in pain practice. PMID- 21267046 TI - Smoking-induced nociception. PMID- 21267047 TI - Patient Protection and Affordable Care Act of 2010: reforming the health care reform for the new decade. AB - The Patient Protection and Affordable Care Act (the ACA, for short) became law with President Obama's signature on March 23, 2010. It represents the most significant transformation of the American health care system since Medicare and Medicaid. It is argued that it will fundamentally change nearly every aspect of health care, from insurance to the final delivery of care. The length and complexity of the legislation and divisive and heated debates have led to massive confusion about the impact of ACA. It also became one of the centerpieces of 2010 congressional campaigns. Essentials of ACA include: 1) a mandate for individuals and businesses requiring as a matter of law that nearly every American have an approved level of health insurance or pay a penalty; 2) a system of federal subsidies to completely or partially pay for the now required health insurance for about 34 million Americans who are currently uninsured - subsidized through Medicaid and exchanges; 3) extensive new requirements on the health insurance industry; and 4) numerous regulations on the practice of medicine. The act is divided into 10 titles. It contains provisions that went into effect starting on June 21, 2010, with the majority of provisions going into effect in 2014 and later. The perceived major impact on practicing physicians in the ACA is related to growing regulatory authority with the Independent Payment Advisory Board (IPAB) and the Patient Centered Outcomes Research Institute (PCORI). In addition to these specifics is a growth of the regulatory regime in association with further discounts in physician reimbursement. With regards to cost controls and projections, many believe that the ACA does not fix the finances of our health care system - neither public nor private. It has been suggested that the Congressional Budget Office (CBO) and the administration have used creative accounting to arrive at an alleged deficit reduction; however, if everything is included appropriately and accounted for, we will be facing a significant increase in deficits rather than a reduction. When posed as a global question, polls suggest that public opinion continues to be against the health insurance reform. The newly elected Republican congress is poised to pass a bill aimed at repealing health care reform. However, advocates of the repeal of health care reform have been criticized for not providing a meaningful alternative approach. Those criticisms make clear that it is not sufficient to provide vague arguments against the ACA without addressing core issues embedded in health care reform. It is the opinion of the authors that while some parts of the ACA may be reformed, it is unlikely to be repealed. Indeed, the ACA already is growing roots. Consequently, it will be extremely difficult to repeal. In this manuscript, we look at reducing the regulatory burden on the public and providers and elimination of IPAB and PCORI. The major solution lies in controlling the drug and durable medical supply costs with appropriate negotiating capacity for Medicare, and consequently for other insurers. PMID- 21267048 TI - Medicare physician payment systems: impact of 2011 schedule on interventional pain management. AB - Physicians in the United States have been affected by significant changes in the patterns of medical practice evolving over the last several decades. The recently passed affordable health care law, termed the Patient Protection and Affordable Care Act of 2010 (the ACA, for short) affects physicians more than any other law. Physician services are an integral part of health care. Physicians are paid in the United States for their personal services. This payment also includes the overhead expenses for maintaining an office and providing services. The payment system is highly variable in the private insurance market; however, governmental systems have a formula-based payment, mostly based on the Medicare payment system. Physician services are billed under Part B. Since the inception of the Medicare program in 1965, several methods have been used to determine the amounts paid to physicians for each covered service. Initially, the payment systems compensated physicians on the basis of their charges. In 1975, just over 10 years after the inception of the Medicare program, payments changed so as not to exceed the increase in the Medical Economic Index (MEI). Nevertheless, the policy failed to curb increases in costs, leading to the determination of a yearly change in fees by legislation from 1984 to 1991. In 1992, the fee schedule essentially replaced the prior payment system that was based on the physician's charges, which also failed to live up to expectations for operational success. Then, in 1998, the sustainable growth rate (SGR) system was introduced. In 2009, multiple attempts were made by Congress to repeal the formula - rather unsuccessfully. Consequently, the SGR formula continues to hamper physician payments. The mechanism of the SGR includes 3 components that are incorporated into a statutory formula: expenditure targets, growth rate period, and annual adjustments of payment rates for physician services. Further, the relative value of a physician fee schedule is based on 3 components: physician work, practice expense (PE), and malpractice expense that are used to determine a value ranking for each service to which it is applied. On average, the work component represents 53.5% of a service's relative value, the fee component represents 43.6%, and the malpractice component represents 3.9%. The final schedule for physician payment was issued on November 24, 2010. This was based on a total cut of 30.8% with 24.9% of the cut attributed to SGR. However, as usual, with patchwork efficiency, Congress passed a one-year extension of the 0% update, effective through December 2011. Consequently, CMS issued an emergency update of the 2011 Medicare fee schedule, with multiple revisions, resulting in a reduction of the conversion factor of $36.8729 from December 2010 to $33.9764 for 2011. PMID- 21267049 TI - Critiquing the critiques: the American Pain Society guideline and the American Society of Interventional Pain Physicians' response to it. PMID- 21267052 TI - Truly a critical review: root cause analysis of paraplegia following transforaminal epidural steroid injections: "unsafe" triangle. PMID- 21267054 TI - Modeling robustness tradeoffs in yeast cell polarization induced by spatial gradients. AB - Cells localize (polarize) internal components to specific locations in response to external signals such as spatial gradients. For example, yeast cells form a mating projection toward the source of mating pheromone. There are specific challenges associated with cell polarization including amplification of shallow external gradients of ligand to produce steep internal gradients of protein components (e.g. localized distribution), response over a broad range of ligand concentrations, and tracking of moving signal sources. In this work, we investigated the tradeoffs among these performance objectives using a generic model that captures the basic spatial dynamics of polarization in yeast cells, which are small. We varied the positive feedback, cooperativity, and diffusion coefficients in the model to explore the nature of this tradeoff. Increasing the positive feedback gain resulted in better amplification, but also produced multiple steady-states and hysteresis that prevented the tracking of directional changes of the gradient. Feedforward/feedback coincidence detection in the positive feedback loop and multi-stage amplification both improved tracking with only a modest loss of amplification. Surprisingly, we found that introducing lateral surface diffusion increased the robustness of polarization and collapsed the multiple steady-states to a single steady-state at the cost of a reduction in polarization. Finally, in a more mechanistic model of yeast cell polarization, a surface diffusion coefficient between 0.01 and 0.001 um(2)/s produced the best polarization performance, and this range is close to the measured value. The model also showed good gradient-sensitivity and dynamic range. This research is significant because it provides an in-depth analysis of the performance tradeoffs that confront biological systems that sense and respond to chemical spatial gradients, proposes strategies for balancing this tradeoff, highlights the critical role of lateral diffusion of proteins in the membrane on the robustness of polarization, and furnishes a framework for future spatial models of yeast cell polarization. PMID- 21267055 TI - Ecological modeling of Aedes aegypti (L.) pupal production in rural Kamphaeng Phet, Thailand. AB - BACKGROUND: Aedes aegypti (L.) is the primary vector of dengue, the most important arboviral infection globally. Until an effective vaccine is licensed and rigorously administered, Ae. aegypti control remains the principal tool in preventing and curtailing dengue transmission. Accurate predictions of vector populations are required to assess control methods and develop effective population reduction strategies. Ae. aegypti develops primarily in artificial water holding containers. Release recapture studies indicate that most adult Ae. aegypti do not disperse over long distances. We expect, therefore, that containers in an area of high development site density are more likely to be oviposition sites and to be more frequently used as oviposition sites than containers that are relatively isolated from other development sites. After accounting for individual container characteristics, containers more frequently used as oviposition sites are likely to produce adult mosquitoes consistently and at a higher rate. To this point, most studies of Ae. aegypti populations ignore the spatial density of larval development sites. METHODOLOGY: Pupal surveys were carried out from 2004 to 2007 in rural Kamphaeng Phet, Thailand. In total, 84,840 samples of water holding containers were used to estimate model parameters. Regression modeling was used to assess the effect of larval development site density, access to piped water, and seasonal variation on container productivity. A varying-coefficients model was employed to account for the large differences in productivity between container types. A two-part modeling structure, called a hurdle model, accounts for the large number of zeroes and overdispersion present in pupal population counts. FINDINGS: The number of suitable larval development sites and their density in the environment were the primary determinants of the distribution and abundance of Ae. aegypti pupae. The productivity of most container types increased significantly as habitat density increased. An ecological approach, accounting for development site density, is appropriate for predicting Ae. aegypti population levels and developing efficient vector control programs. PMID- 21267056 TI - Using the game of Mastermind to teach, practice, and discuss scientific reasoning skills. PMID- 21267057 TI - Correcting mortality for loss to follow-up: a nomogram applied to antiretroviral treatment programmes in sub-Saharan Africa. AB - BACKGROUND: The World Health Organization estimates that in sub-Saharan Africa about 4 million HIV-infected patients had started antiretroviral therapy (ART) by the end of 2008. Loss of patients to follow-up and care is an important problem for treatment programmes in this region. As mortality is high in these patients compared to patients remaining in care, ART programmes with high rates of loss to follow-up may substantially underestimate mortality of all patients starting ART. METHODS AND FINDINGS: We developed a nomogram to correct mortality estimates for loss to follow-up, based on the fact that mortality of all patients starting ART in a treatment programme is a weighted average of mortality among patients lost to follow-up and patients remaining in care. The nomogram gives a correction factor based on the percentage of patients lost to follow-up at a given point in time, and the estimated ratio of mortality between patients lost and not lost to follow-up. The mortality observed among patients retained in care is then multiplied by the correction factor to obtain an estimate of programme-level mortality that takes all deaths into account. A web calculator directly calculates the corrected, programme-level mortality with 95% confidence intervals (CIs). We applied the method to 11 ART programmes in sub-Saharan Africa. Patients retained in care had a mortality at 1 year of 1.4% to 12.0%; loss to follow-up ranged from 2.8% to 28.7%; and the correction factor from 1.2 to 8.0. The absolute difference between uncorrected and corrected mortality at 1 year ranged from 1.6% to 9.8%, and was above 5% in four programmes. The largest difference in mortality was in a programme with 28.7% of patients lost to follow-up at 1 year. CONCLUSIONS: The amount of bias in mortality estimates can be large in ART programmes with substantial loss to follow-up. Programmes should routinely report mortality among patients retained in care and the proportion of patients lost. A simple nomogram can then be used to estimate mortality among all patients who started ART, for a range of plausible mortality rates among patients lost to follow-up. PMID- 21267058 TI - The impact of eHealth on the quality and safety of health care: a systematic overview. AB - BACKGROUND: There is considerable international interest in exploiting the potential of digital solutions to enhance the quality and safety of health care. Implementations of transformative eHealth technologies are underway globally, often at very considerable cost. In order to assess the impact of eHealth solutions on the quality and safety of health care, and to inform policy decisions on eHealth deployments, we undertook a systematic review of systematic reviews assessing the effectiveness and consequences of various eHealth technologies on the quality and safety of care. METHODS AND FINDINGS: We developed novel search strategies, conceptual maps of health care quality, safety, and eHealth interventions, and then systematically identified, scrutinised, and synthesised the systematic review literature. Major biomedical databases were searched to identify systematic reviews published between 1997 and 2010. Related theoretical, methodological, and technical material was also reviewed. We identified 53 systematic reviews that focused on assessing the impact of eHealth interventions on the quality and/or safety of health care and 55 supplementary systematic reviews providing relevant supportive information. This systematic review literature was found to be generally of substandard quality with regards to methodology, reporting, and utility. We thematically categorised eHealth technologies into three main areas: (1) storing, managing, and transmission of data; (2) clinical decision support; and (3) facilitating care from a distance. We found that despite support from policymakers, there was relatively little empirical evidence to substantiate many of the claims made in relation to these technologies. Whether the success of those relatively few solutions identified to improve quality and safety would continue if these were deployed beyond the contexts in which they were originally developed, has yet to be established. Importantly, best practice guidelines in effective development and deployment strategies are lacking. CONCLUSIONS: There is a large gap between the postulated and empirically demonstrated benefits of eHealth technologies. In addition, there is a lack of robust research on the risks of implementing these technologies and their cost-effectiveness has yet to be demonstrated, despite being frequently promoted by policymakers and "techno-enthusiasts" as if this was a given. In the light of the paucity of evidence in relation to improvements in patient outcomes, as well as the lack of evidence on their cost-effectiveness, it is vital that future eHealth technologies are evaluated against a comprehensive set of measures, ideally throughout all stages of the technology's life cycle. Such evaluation should be characterised by careful attention to socio-technical factors to maximise the likelihood of successful implementation and adoption. PMID- 21267059 TI - Development of a standardized screening rule for tuberculosis in people living with HIV in resource-constrained settings: individual participant data meta analysis of observational studies. AB - BACKGROUND: The World Health Organization recommends the screening of all people living with HIV for tuberculosis (TB) disease, followed by TB treatment, or isoniazid preventive therapy (IPT) when TB is excluded. However, the difficulty of reliably excluding TB disease has severely limited TB screening and IPT uptake in resource-limited settings. We conducted an individual participant data meta analysis of primary studies, aiming to identify a sensitive TB screening rule. METHODS AND FINDINGS: We identified 12 studies that had systematically collected sputum specimens regardless of signs or symptoms, at least one mycobacterial culture, clinical symptoms, and HIV and TB disease status. Bivariate random effects meta-analysis and the hierarchical summary relative operating characteristic curves were used to evaluate the screening performance of all combinations of variables of interest. TB disease was diagnosed in 557 (5.8%) of 9,626 people living with HIV. The primary analysis included 8,148 people living with HIV who could be evaluated on five symptoms from nine of the 12 studies. The median age was 34 years. The best performing rule was the presence of any one of: current cough (any duration), fever, night sweats, or weight loss. The overall sensitivity of this rule was 78.9% (95% confidence interval [CI] 58.3%-90.9%) and specificity was 49.6% (95% CI 29.2%-70.1%). Its sensitivity increased to 90.1% (95% CI 76.3%-96.2%) among participants selected from clinical settings and to 88.0% (95% CI 76.1%-94.4%) among those who were not previously screened for TB. Negative predictive value was 97.7% (95% CI 97.4%-98.0%) and 90.0% (95% CI 88.6% 91.3%) at 5% and 20% prevalence of TB among people living with HIV, respectively. Abnormal chest radiographic findings increased the sensitivity of the rule by 11.7% (90.6% versus 78.9%) with a reduction of specificity by 10.7% (49.6% versus 38.9%). CONCLUSIONS: Absence of all of current cough, fever, night sweats, and weight loss can identify a subset of people living with HIV who have a very low probability of having TB disease. A simplified screening rule using any one of these symptoms can be used in resource-constrained settings to identify people living with HIV in need of further diagnostic assessment for TB. Use of this algorithm should result in earlier TB diagnosis and treatment, and should allow for substantial scale-up of IPT. PMID- 21267061 TI - Synthetic associations created by rare variants do not explain most GWAS results. PMID- 21267060 TI - Analysis of LhcSR3, a protein essential for feedback de-excitation in the green alga Chlamydomonas reinhardtii. AB - In photosynthetic organisms, feedback dissipation of excess absorbed light energy balances harvesting of light with metabolic energy consumption. This mechanism prevents photodamage caused by reactive oxygen species produced by the reaction of chlorophyll (Chl) triplet states with O2. Plants have been found to perform the heat dissipation in specific proteins, binding Chls and carotenoids (Cars), that belong to the Lhc family, while triggering of the process is performed by the PsbS subunit, needed for lumenal pH detection. PsbS is not found in algae, suggesting important differences in energy-dependent quenching (qE) machinery. Consistent with this suggestion, a different Lhc-like gene product, called LhcSR3 (formerly known as LI818) has been found to be essential for qE in Chlamydomonas reinhardtii. In this work, we report the production of two recombinant LhcSR isoforms from C. reinhardtii and their biochemical and spectroscopic characterization. We found the following: (i) LhcSR isoforms are Chl a/b- and xanthophyll-binding proteins, contrary to higher plant PsbS; (ii) the LhcSR3 isoform, accumulating in high light, is a strong quencher of Chl excited states, exhibiting a very fast fluorescence decay, with lifetimes below 100 ps, capable of dissipating excitation energy from neighbor antenna proteins; (iii) the LhcSR3 isoform is highly active in the transient formation of Car radical cation, a species proposed to act as a quencher in the heat dissipation process. Remarkably, the radical cation signal is detected at wavelengths corresponding to the Car lutein, rather than to zeaxanthin, implying that the latter, predominant in plants, is not essential; (iv) LhcSR3 is responsive to low pH, the trigger of non-photochemical quenching, since it binds the non-photochemical quenching inhibitor dicyclohexylcarbodiimide, and increases its energy dissipation properties upon acidification. This is the first report of an isolated Lhc protein constitutively active in energy dissipation in its purified form, opening the way to detailed molecular analysis. Owing to its protonatable residues and constitutive excitation energy dissipation, this protein appears to merge both pH sensing and energy-quenching functions, accomplished respectively by PsbS and monomeric Lhcb proteins in plants. PMID- 21267062 TI - Synthetic associations are unlikely to account for many common disease genome wide association signals. PMID- 21267063 TI - SecM-stalled ribosomes adopt an altered geometry at the peptidyl transferase center. AB - As nascent polypeptide chains are synthesized, they pass through a tunnel in the large ribosomal subunit. Interaction between specific nascent chains and the ribosomal tunnel is used to induce translational stalling for the regulation of gene expression. One well-characterized example is the Escherichia coli SecM (secretion monitor) gene product, which induces stalling to up-regulate translation initiation of the downstream secA gene, which is needed for protein export. Although many of the key components of SecM and the ribosomal tunnel have been identified, understanding of the mechanism by which the peptidyl transferase center of the ribosome is inactivated has been lacking. Here we present a cryo electron microscopy reconstruction of a SecM-stalled ribosome nascent chain complex at 5.6 A. While no cascade of rRNA conformational changes is evident, this structure reveals the direct interaction between critical residues of SecM and the ribosomal tunnel. Moreover, a shift in the position of the tRNA-nascent peptide linkage of the SecM-tRNA provides a rationale for peptidyl transferase center silencing, conditional on the simultaneous presence of a Pro-tRNA(Pro) in the ribosomal A-site. These results suggest a distinct allosteric mechanism of regulating translational elongation by the SecM stalling peptide. PMID- 21267064 TI - A simple novel method for determining mortality rates in HIV treatment programs worldwide. AB - In this Perspective, Gregory Bisson discusses a new article by Matthias Egger and colleagues that introduces a simple method for HIV treatment programs to more accurately estimate the proportion of patients dying in the first year after ART initiation. PMID- 21267065 TI - Evaluation of immunoassays for the diagnosis of Schistosoma japonicum infection using archived sera. AB - BACKGROUND: With a national program initiated recently to reduce transmission of Schistosoma japonicum in the People's Republic of China (P.R. China), there is an urgent need for accessible, quality-assured diagnostics for case detection, surveillance, and program monitoring of chemotherapy efficacy and other control interventions in areas of low endemicity. We compared the performance of nine immunodiagnostic tests developed in P.R. China for detection of antibodies against S. japonicum and established their priority for further assessment in field settings. METHODOLOGY/PRINCIPAL FINDINGS: Using the Kato-Katz technique as the reference standard, 240 well-characterized archived serum specimens (100 positive and 140 negative) were evaluated in nine immunological tests developed in P.R. China. The enzyme-linked immunoelectrotransfer blot assay (EITB), which uses an adult worm extract of S. japonicum, supplied by the Center of Disease Control and Prevention, USA, was also evaluated. The sensitivity and specificity of each test were determined and the reproducibility of each test was assessed by evaluating operator-to-operator and run-to-run variation. In addition the simplicity of use for the end-user was evaluated. All tests showed good sensitivities ranging from 92.0% (95% confidence interval (CI): 86.7-97.3%) to 98.0% (95% CI: 95.3-100.0%). The test specificities varied from 70.0% (95% CI: 62.4-77.6%) to 97.1% (95% CI: 94.4-99.9%). All tests showed excellent reproducibility with a discordant rate in the range of 0-10.0% for operator-to operator variation and run-to-run variation. All tests, except one magnetic particle-based enzyme-linked immunosorbent assay, were found to be easy to use, especially the dot immunogold filtration assays. CONCLUSIONS/SIGNIFICANCE: Most evaluated tests had acceptable performance characteristics and could make an impact on the schistosomiasis control programs in P.R. China. Three tests with the highest sensitivity, specificity and greatest ease of use, were selected for further evaluation in field settings. PMID- 21267066 TI - The importance of synthetic associations will only be resolved empirically. PMID- 21267067 TI - Common disease: are causative alleles common or rare? PMID- 21267068 TI - A high-resolution anatomical atlas of the transcriptome in the mouse embryo. AB - Ascertaining when and where genes are expressed is of crucial importance to understanding or predicting the physiological role of genes and proteins and how they interact to form the complex networks that underlie organ development and function. It is, therefore, crucial to determine on a genome-wide level, the spatio-temporal gene expression profiles at cellular resolution. This information is provided by colorimetric RNA in situ hybridization that can elucidate expression of genes in their native context and does so at cellular resolution. We generated what is to our knowledge the first genome-wide transcriptome atlas by RNA in situ hybridization of an entire mammalian organism, the developing mouse at embryonic day 14.5. This digital transcriptome atlas, the Eurexpress atlas (http://www.eurexpress.org), consists of a searchable database of annotated images that can be interactively viewed. We generated anatomy-based expression profiles for over 18,000 coding genes and over 400 microRNAs. We identified 1,002 tissue-specific genes that are a source of novel tissue-specific markers for 37 different anatomical structures. The quality and the resolution of the data revealed novel molecular domains for several developing structures, such as the telencephalon, a novel organization for the hypothalamus, and insight on the Wnt network involved in renal epithelial differentiation during kidney development. The digital transcriptome atlas is a powerful resource to determine co-expression of genes, to identify cell populations and lineages, and to identify functional associations between genes relevant to development and disease. PMID- 21267069 TI - Evidence for OTUD-6B participation in B lymphocytes cell cycle after cytokine stimulation. AB - Deubiquitinating enzymes (DUBs) are important regulators of cell proliferation. Here we identified a functional deubiquitinating enzyme, ovarian tumor domain containing 6B (OTUD-6B). Mutation of the conserved Cys residue abolished its deubiquitinating activity in vitro. Otud-6b expression was induced with cytokine stimulation in both mouse Ba/F3 cells and primary B lymphocytes followed a rapid decrease. This rapid decrease was partially facilitated by tristetraprolin (TTP) destabilization of Otud-6b mRNA through AU-rich motifs. Enforced expression of OTUD-6B in Ba/F3 cells could block cell proliferation by arresting cells in G1 phase. In addition, cyclin D2 level was down-regulated when OTUD-6B WT was overexpressed. Therefore, down-regulation of Otud-6b expression after prolonged cytokine stimulation may be required for cell proliferation in B lymphocytes. PMID- 21267070 TI - Robust organizational principles of protrusive biopolymer networks in migrating living cells. AB - Cell migration is associated with the dynamic protrusion of a thin actin-based cytoskeletal extension at the cell front, which has been shown to consist of two different substructures, the leading lamellipodium and the subsequent lamellum. While the formation of the lamellipodium is increasingly well understood, organizational principles underlying the emergence of the lamellum are just beginning to be unraveled. We report here on a 1D mathematical model which describes the reaction-diffusion processes of a polarized actin network in steady state, and reproduces essential characteristics of the lamellipodium-lamellum system. We observe a steep gradient in filament lengths at the protruding edge, a local depolymerization maximum a few microns behind the edge, as well as a differential dominance of the network destabilizer ADF/cofilin and the stabilizer tropomyosin. We identify simple and robust organizational principles giving rise to the derived network characteristics, uncoupled from the specifics of any molecular implementation, and thus plausibly valid across cell types. An analysis of network length dependence on physico-chemical system parameters implies that to limit array treadmilling to cellular dimensions, network growth has to be truncated by mechanisms other than aging-induced depolymerization, e.g., by myosin-associated network dissociation at the transition to the cell body. Our work contributes to the analytical understanding of the cytoskeletal extension's bisection into lamellipodium and lamellum and sheds light on how cells organize their molecular machinery to achieve motility. PMID- 21267071 TI - MAP4K3 is a component of the TORC1 signalling complex that modulates cell growth and viability in Drosophila melanogaster. AB - BACKGROUND: MAP4K3 is a conserved Ser/Thr kinase that has being found in connection with several signalling pathways, including the Imd, EGFR, TORC1 and JNK modules, in different organisms and experimental assays. We have analyzed the consequences of changing the levels of MAP4K3 expression in the development of the Drosophila wing, a convenient model system to characterize gene function during epithelial development. METHODOLOGY AND PRINCIPAL FINDINGS: Using loss-of function mutants and over-expression conditions we find that MAP4K3 activity affects cell growth and viability in the Drosophila wing. These requirements are related to the modulation of the TORC1 and JNK signalling pathways, and are best detected when the larvae grow in a medium with low protein concentration (TORC1) or are exposed to irradiation (JNK). We also show that MAP4K3 display strong genetic interactions with different components of the InR/Tor signalling pathway, and can interact directly with the GTPases RagA and RagC and with the multi domain kinase Tor. CONCLUSIONS AND SIGNIFICANCE: We suggest that MAP4K3 has two independent functions during wing development, one related to the activation of the JNK pathway in response to stress and other in the assembling or activation of the TORC1 complex, being critical to modulate cellular responses to changes in nutrient availability. PMID- 21267072 TI - Pyronaridine-artesunate versus chloroquine in patients with acute Plasmodium vivax malaria: a randomized, double-blind, non-inferiority trial. AB - BACKGROUND: New antimalarials are needed for P. vivax and P. falciparum malaria. This study compared the efficacy and safety of pyronaridine-artesunate with that of chloroquine for the treatment of uncomplicated P. vivax malaria. METHODS AND FINDINGS: This phase III randomized, double-blind, non-inferiority trial included five centers across Cambodia, Thailand, India, and Indonesia. In a double-dummy design, patients (aged >3-<= 60 years) with microscopically confirmed P. vivax mono-infection were randomized (1:1) to receive pyronaridine-artesunate (target dose 7.2:2.4 mg/kg to 13.8:4.6 mg/kg) or chloroquine (standard dose) once daily for three days. Each treatment group included 228 randomized patients. Outcomes for the primary endpoint, Day-14 cure rate in the per-protocol population, were 99.5%, (217/218; 95%CI 97.5, 100) with pyronaridine-artesunate and 100% (209/209; 95%CI 98.3, 100) with chloroquine. Pyronaridine was non-inferior to chloroquine: treatment difference -0.5% (95%CI -2.6, 1.4), i.e., the lower limit of the 2 sided 95%CI for the treatment difference was greater than -10%. Pyronaridine artesunate cure rates were non-inferior to chloroquine for Days 21, 28, 35 and 42. Parasite clearance time was shorter with pyronaridine-artesunate (median 23.0 h) versus chloroquine (32.0 h; p<0.0001), as was fever clearance time (median 15.9 h and 23.8 h, respectively; p = 0.0017). Kaplan-Meier estimates of post baseline P. falciparum infection incidence until Day 42 were 2.5% with pyronaridine-artesunate, 6.1% with chloroquine (p = 0.048, log-rank test). Post baseline P. vivax or P. falciparum infection incidence until Day 42 was 6.8% and 12.4%, respectively (p = 0.022, log rank test). There were no deaths. Adverse events occurred in 92/228 (40.4%) patients with pyronaridine-artesunate and 72/228 (31.6%) with chloroquine. Mild and transient increases in hepatic enzymes were observed for pyronaridine-artesunate. CONCLUSION: Pyronaridine-artesunate efficacy in acute uncomplicated P. vivax malaria was at least that of chloroquine. As pyronaridine-artesunate is also efficacious against P. falciparum malaria, this combination has potential utility as a global antimalarial drug. TRIAL REGISTRATION: Clinicaltrials.gov NCT00440999. PMID- 21267073 TI - Influenza virus-like particles containing M2 induce broadly cross protective immunity. AB - BACKGROUND: Current influenza vaccines based on the hemagglutinin protein are strain specific and do not provide good protection against drifted viruses or emergence of new pandemic strains. An influenza vaccine that can confer cross protection against antigenically different influenza A strains is highly desirable for improving public health. METHODOLOGY/PRINCIPAL FINDINGS: To develop a cross protective vaccine, we generated influenza virus-like particles containing the highly conserved M2 protein in a membrane-anchored form (M2 VLPs), and investigated their immunogenicity and breadth of cross protection. Immunization of mice with M2 VLPs induced anti-M2 antibodies binding to virions of various strains, M2 specific T cell responses, and conferred long-lasting cross protection against heterologous and heterosubtypic influenza viruses. M2 immune sera were found to play an important role in providing cross protection against heterosubtypic virus and an antigenically distinct 2009 pandemic H1N1 virus, and depletion of dendritic and macrophage cells abolished this cross protection, providing new insight into cross-protective immune mechanisms. CONCLUSIONS/SIGNIFICANCE: These results suggest that presenting M2 on VLPs in a membrane-anchored form is a promising approach for developing broadly cross protective influenza vaccines. PMID- 21267074 TI - Nodes of ranvier and paranodes in chronic acquired neuropathies. AB - Chronic acquired neuropathies of unknown origin are classified as chronic inflammatory demyelinating polyneuropathies (CIDP) and chronic idiopathic axonal polyneuropathies (CIAP). The diagnosis can be very difficult, although it has important therapeutic implications since CIDP can be improved by immunomodulating treatment. The aim of this study was to examine the possible abnormalities of nodal and paranodal regions in these two types of neuropathies. Longitudinal sections of superficial peroneal nerves were obtained from biopsy material from 12 patients with CIDP and 10 patients with CIAP and studied by immunofluorescence and in some cases electron microscopy. Electron microscopy revealed multiple alterations in the nodal and paranodal regions which predominated in Schwann cells in CIDP and in axons in CIAP. In CIDP paranodin/Caspr immunofluorescence was more widespread than in control nerves, extending along the axon in internodes where it appeared intense. Nodal channels Nav and KCNQ2 were less altered but were also detected in the internodes. In CIAP paranodes, paranodin labeling was irregular and/or decreased. To test the consequences of acquired primary Schwann cells alteration on axonal proteins, we used a mouse model based on induced deletion of the transcription factor Krox-20 gene. In the demyelinated sciatic nerves of these mice we observed alterations similar to those found in CIDP by immunofluorescence, and immunoblotting demonstrated increased levels of paranodin. Finally we examined whether the alterations in paranodin immunoreactivity could have a diagnosis value. In a sample of 16 biopsies, the study of paranodin immunofluorescence by blind evaluators led to correct diagnosis in 70 +/- 4% of the cases. This study characterizes for the first time the abnormalities of nodes of Ranvier in CIAP and CIDP, and the altered expression and distribution of nodal and paranodal proteins. Marked differences were observed between CIDP and CIAP and the alterations in paranodin immunofluorescence may be an interesting tool for their differential diagnosis. PMID- 21267075 TI - A novel HURRAH protocol reveals high numbers of monomorphic MHC class II loci and two asymmetric multi-locus haplotypes in the Pere David's deer. AB - The Pere David's deer is a highly inbred, but recovered, species, making it interesting to consider their adaptive molecular evolution from an immunological perspective. Prior to this study, genomic sequencing was the only method for isolating all functional MHC genes within a certain species. Here, we report a novel protocol for isolating MHC class II loci from a species, and its use to investigate the adaptive evolution of this endangered deer at the level of multi locus haplotypes. This protocol was designated "HURRAH" based on its various steps and used to estimate the total number of MHC class II loci. We confirmed the validity of this novel protocol in the giant panda and then used it to examine the Pere David's deer. Our results revealed that the Pere David's deer possesses nine MHC class II loci and therefore has more functional MHC class II loci than the eight genome-sequenced mammals for which full MHC data are currently available. This could potentially account at least in part for the strong survival ability of this species in the face of severe bottlenecking. The results from the HURRAH protocol also revealed that: (1) All of the identified MHC class II loci were monomorphic at their antigen-binding regions, although DRA was dimorphic at its cytoplasmic tail; and (2) these genes constituted two asymmetric functional MHC class II multi-locus haplotypes: DRA1*01 ~ DRB1 ~ DRB3 ~ DQA1 ~ DQB2 (H1) and DRA1*02 ~ DRB2 ~ DRB4 ~ DQA2 ~ DQB1 (H2). The latter finding indicates that the current members of the deer species have lost the powerful ancestral MHC class II haplotypes of nine or more loci, and have instead fixed two relatively weak haplotypes containing five genes. As a result, the Pere David's deer are currently at risk for increased susceptibility to infectious pathogens. PMID- 21267076 TI - DNA methylation of the first exon is tightly linked to transcriptional silencing. AB - Tissue specific patterns of methylated cytosine residues vary with age, can be altered by environmental factors, and are often abnormal in human disease yet the cellular consequences of DNA methylation are incompletely understood. Although the bodies of highly expressed genes are often extensively methylated in plants, the relationship between intragenic methylation and expression is less clear in mammalian cells. We performed genome-wide analyses of DNA methylation and gene expression to determine how the pattern of intragenic methylation correlates with transcription and to assess the relationship between methylation of exonic and intronic portions of the gene body. We found that dense exonic methylation is far more common than previously recognized or expected statistically, yet first exons are relatively spared compared to more downstream exons and introns. Dense methylation surrounding the transcription start site (TSS) is uncoupled from methylation within more downstream regions suggesting that there are at least two classes of intragenic methylation. Whereas methylation surrounding the TSS is tightly linked to transcriptional silencing, methylation of more downstream regions is unassociated with the magnitude of gene expression. Notably, we found that DNA methylation downstream of the TSS, in the region of the first exon, is much more tightly linked to transcriptional silencing than is methylation in the upstream promoter region. These data provide direct evidence that DNA methylation is interpreted dissimilarly in different regions of the gene body and suggest that first exon methylation blocks transcript initiation, or vice versa. Our data also show that once initiated, downstream methylation is not a significant impediment to polymerase extension. Thus, the consequences of most intragenic DNA methylation must extend beyond the modulation of transcription magnitude.Sequencing data and gene expression microarray data have been submitted to the GEO online database (accession number SRA012081.1). Supporting information including expanded methods and ten additional figures in support of the manuscript is provided. PMID- 21267077 TI - QAPgrid: a two level QAP-based approach for large-scale data analysis and visualization. AB - BACKGROUND: The visualization of large volumes of data is a computationally challenging task that often promises rewarding new insights. There is great potential in the application of new algorithms and models from combinatorial optimisation. Datasets often contain "hidden regularities" and a combined identification and visualization method should reveal these structures and present them in a way that helps analysis. While several methodologies exist, including those that use non-linear optimization algorithms, severe limitations exist even when working with only a few hundred objects. METHODOLOGY/PRINCIPAL FINDINGS: We present a new data visualization approach (QAPgrid) that reveals patterns of similarities and differences in large datasets of objects for which a similarity measure can be computed. Objects are assigned to positions on an underlying square grid in a two-dimensional space. We use the Quadratic Assignment Problem (QAP) as a mathematical model to provide an objective function for assignment of objects to positions on the grid. We employ a Memetic Algorithm (a powerful metaheuristic) to tackle the large instances of this NP-hard combinatorial optimization problem, and we show its performance on the visualization of real data sets. CONCLUSIONS/SIGNIFICANCE: Overall, the results show that QAPgrid algorithm is able to produce a layout that represents the relationships between objects in the data set. Furthermore, it also represents the relationships between clusters that are feed into the algorithm. We apply the QAPgrid on the 84 Indo-European languages instance, producing a near-optimal layout. Next, we produce a layout of 470 world universities with an observed high degree of correlation with the score used by the Academic Ranking of World Universities compiled in the The Shanghai Jiao Tong University Academic Ranking of World Universities without the need of an ad hoc weighting of attributes. Finally, our Gene Ontology-based study on Saccharomyces cerevisiae fully demonstrates the scalability and precision of our method as a novel alternative tool for functional genomics. PMID- 21267078 TI - Distribution of the octopamine receptor AmOA1 in the honey bee brain. AB - Octopamine plays an important role in many behaviors in invertebrates. It acts via binding to G protein coupled receptors located on the plasma membrane of responsive cells. Several distinct subtypes of octopamine receptors have been found in invertebrates, yet little is known about the expression pattern of these different receptor subtypes and how each subtype may contribute to different behaviors. One honey bee (Apis mellifera) octopamine receptor, AmOA1, was recently cloned and characterized. Here we continue to characterize the AmOA1 receptor by investigating its distribution in the honey bee brain. We used two independent antibodies produced against two distinct peptides in the carboxyl terminus to study the distribution of the AmOA1 receptor in the honey bee brain. We found that both anti-AmOA1 antibodies revealed labeling of cell body clusters throughout the brain and within the following brain neuropils: the antennal lobes; the calyces, pedunculus, vertical (alpha, gamma) and medial (beta) lobes of the mushroom body; the optic lobes; the subesophageal ganglion; and the central complex. Double immunofluorescence staining using anti-GABA and anti AmOA1 receptor antibodies revealed that a population of inhibitory GABAergic local interneurons in the antennal lobes express the AmOA1 receptor in the cell bodies, axons and their endings in the glomeruli. In the mushroom bodies, AmOA1 receptors are expressed in a subpopulation of inhibitory GABAergic feedback neurons that ends in the visual (outer half of basal ring and collar regions) and olfactory (lip and inner basal ring region) calyx neuropils, as well as in the collar and lip zones of the vertical and medial lobes. The data suggest that one effect of octopamine via AmOA1 in the antennal lobe and mushroom body is to modulate inhibitory neurons. PMID- 21267079 TI - The physiological link between metabolic rate depression and tau phosphorylation in mammalian hibernation. AB - Abnormal phosphorylation and aggregation of tau protein are hallmarks of a variety of neurological disorders, including Alzheimer's disease (AD). Increased tau phosphorylation is assumed to represent an early event in pathogenesis and a pivotal aspect for aggregation and formation of neurofibrillary tangles. However, the regulation of tau phosphorylation in vivo and the causes for its increased stage of phosphorylation in AD are still not well understood, a fact that is primarily based on the lack of adequate animal models. Recently we described the reversible formation of highly phosphorylated tau protein in hibernating European ground squirrels. Hence, mammalian hibernation represents a model system very well suited to study molecular mechanisms of both tau phosphorylation and dephosphorylation under in vivo physiological conditions. Here, we analysed the extent and kinetics of hibernation-state dependent tau phosphorylation in various brain regions of three species of hibernating mammals: arctic ground squirrels, Syrian hamsters and black bears. Overall, tau protein was highly phosphorylated in torpor states and phosphorylation levels decreased after arousal in all species. Differences between brain regions, hibernation-states and phosphosites were observed with respect to degree and kinetics of tau phosphorylation. Furthermore, we tested the phosphate net turnover of tau protein to analyse potential alterations in kinase and/or phosphatase activities during hibernation. Our results demonstrate that the hibernation-state dependent phosphorylation of tau protein is specifically regulated but involves, in addition, passive, temperature driven regulatory mechanisms. By determining the activity-state profile for key enzymes of tau phosphorylation we could identify kinases potentially involved in the differentially regulated, reversible tau phosphorylation that occurs during hibernation. We show that in black bears hibernation is associated with conformational changes of highly phosphorylated tau protein that are typically related to neuropathological alterations. The particular hibernation characteristics of black bears with a continuous torpor period and an only slightly decreased body temperature, therefore, potentially reflects the limitations of this adaptive reaction pattern and, thus, might indicate a transitional state of a physiological process. PMID- 21267082 TI - Current distribution measurements inside an electromagnetic plasma gun operated in a gas-puff mode. AB - Measurements are presented of the time-dependent current distribution inside a coaxial electromagnetic plasma gun. The measurements are carried out using an array of six axially distributed dual-Rogowski coils in a balanced circuit configuration. The radial current distributions indicate that operation in the gas-puff mode, i.e., the mode in which the electrode voltage is applied before injection of the gas, results in a stationary ionization front consistent with the presence of a plasma deflagration. The effects of varying the bank capacitance, transmission line inductance, and applied electrode voltage were studied over the range from 14 to 112 MUF, 50 to 200 nH, and 1 to 3 kV, respectively. PMID- 21267081 TI - Steady-state visual evoked potentials can be explained by temporal superposition of transient event-related responses. AB - BACKGROUND: One common criterion for classifying electrophysiological brain responses is based on the distinction between transient (i.e. event-related potentials, ERPs) and steady-state responses (SSRs). The generation of SSRs is usually attributed to the entrainment of a neural rhythm driven by the stimulus train. However, a more parsimonious account suggests that SSRs might result from the linear addition of the transient responses elicited by each stimulus. This study aimed to investigate this possibility. METHODOLOGY/PRINCIPAL FINDINGS: We recorded brain potentials elicited by a checkerboard stimulus reversing at different rates. We modeled SSRs by sequentially shifting and linearly adding rate-specific ERPs. Our results show a strong resemblance between recorded and synthetic SSRs, supporting the superposition hypothesis. Furthermore, we did not find evidence of entrainment of a neural oscillation at the stimulation frequency. CONCLUSIONS/SIGNIFICANCE: This study provides evidence that visual SSRs can be explained as a superposition of transient ERPs. These findings have critical implications in our current understanding of brain oscillations. Contrary to the idea that neural networks can be tuned to a wide range of frequencies, our findings rather suggest that the oscillatory response of a given neural network is constrained within its natural frequency range. PMID- 21267080 TI - Perceptual load-dependent neural correlates of distractor interference inhibition. AB - BACKGROUND: The load theory of selective attention hypothesizes that distractor interference is suppressed after perceptual processing (i.e., in the later stage of central processing) at low perceptual load of the central task, but in the early stage of perceptual processing at high perceptual load. Consistently, studies on the neural correlates of attention have found a smaller distractor related activation in the sensory cortex at high relative to low perceptual load. However, it is not clear whether the distractor-related activation in brain regions linked to later stages of central processing (e.g., in the frontostriatal circuits) is also smaller at high rather than low perceptual load, as might be predicted based on the load theory. METHODOLOGY/PRINCIPAL FINDINGS: We studied 24 healthy participants using functional magnetic resonance imaging (fMRI) during a visual target identification task with two perceptual loads (low vs. high). Participants showed distractor-related increases in activation in the midbrain, striatum, occipital and medial and lateral prefrontal cortices at low load, but distractor-related decreases in activation in the midbrain ventral tegmental area and substantia nigra (VTA/SN), striatum, thalamus, and extensive sensory cortices at high load. CONCLUSIONS: Multiple levels of central processing involving midbrain and frontostriatal circuits participate in suppressing distractor interference at either low or high perceptual load. For suppressing distractor interference, the processing of sensory inputs in both early and late stages of central processing are enhanced at low load but inhibited at high load. PMID- 21267083 TI - Exploring the limits of ultrafast polymerase chain reaction using liquid for thermal heat exchange: A proof of principle. AB - Thermal ramp rate is a major limiting factor in using real-time polymerase chain reaction (PCR) for routine diagnostics. We explored the limits of speed by using liquid for thermal exchange rather than metal as in traditional devices, and by testing different polymerases. In a clinical setting, our system equaled or surpassed state-of-the-art devices for accuracy in amplifying DNA/RNA of avian influenza, cytomegalovirus, and human immunodeficiency virus. Using Thermococcus kodakaraensis polymerase and optimizing both electrical and chemical systems, we obtained an accurate, 35 cycle amplification of an 85-base pair fragment of E. coli O157:H7 Shiga toxin gene in as little as 94.1 s, a significant improvement over a typical 1 h PCR amplification. PMID- 21267084 TI - Three-dimensional multiexcitation magnetoacoustic tomography with magnetic induction. AB - Magnetoacoustic tomography with magnetic induction (MAT-MI) is a hybrid imaging modality proposed to image electrical conductivity contrast of biological tissue with high spatial resolution. This modality combines magnetic excitations with ultrasound detection through the Lorentz force based coupling mechanism. However, previous studies have shown that MAT-MI method with single type of magnetic excitation can only reconstruct the conductivity boundaries of a sample. In order to achieve more complete conductivity contrast reconstruction, we proposed a multiexcitation MAT-MI approach. In this approach, multiple magnetic excitations using different coil configurations are applied to the object sequentially and ultrasonic signals corresponding to each excitation are collected for conductivity image reconstruction. In this study, we validate the new multiexcitation MAT-MI method for three-dimensional (3D) conductivity imaging through both computer simulations and phantom experiments. 3D volume data are obtained by utilizing acoustic focusing and cylindrical scanning under each magnetic excitation. It is shown in our simulation and experiment results that with a common ultrasound probe that has limited bandwidth we are able to correctly reconstruct the 3D relative conductivity contrast of the imaging object. As compared to those conductivity boundary images generated by previous single-excitation MAT-MI, the new multiexcitation MAT-MI method provides more complete conductivity contrast reconstruction, and therefore, more valuable information in possible clinical and research applications. PMID- 21267085 TI - Optofluidic refractometer using resonant optical tunneling effect. AB - This paper presents the design and analysis of a liquid refractive index sensor that utilizes a unique physical mechanism of resonant optical tunneling effect (ROTE). The sensor consists of two hemicylindrical prisms, two air gaps, and a microfluidic channel. All parts can be microfabricated using an optical resin NOA81. Theoretical study shows that this ROTE sensor has extremely sharp transmission peak and achieves a sensitivity of 760 nm/refractive index unit (RIU) and a detectivity of 85 000 RIU(-1). Although the sensitivity is smaller than that of a typical surface plasmon resonance (SPR) sensor (3200 nm/RIU) and is comparable to a 95% reflectivity Fabry-Perot (FP) etalon (440 nm/RIU), the detectivity is 17 000 times larger than that of the SPR sensor and 85 times larger than that of the FP etalon. Such ROTE sensor could potentially achieve an ultrahigh sensitivity of 10(-9) RIU, two orders higher than the best results of current methods. PMID- 21267086 TI - Release monitoring of single cells on a microfluidic device coupled with fluorescence microscopy and electrochemistry. AB - A method for monitoring the biological exocytotic phenomena on a microfluidic system was proposed. A microfluidic device coupled with functionalities of fluorescence imaging and amperometric detection has been developed to enable the real-time monitoring of the exocytotic events. Exocytotic release of single SH SY5Y neuroblastoma cells was studied. By staining the cells located on integrated microelectrodes with naphthalene-2,3-dicarboxaldehyde, punctuate fluorescence consistent with localization of neurotransmitters stored in vesicles was obtained. The stimulated exocytotic release was successfully observed at the surface of SH-SY5Y cells without refitting the commercial inverted fluorescence microscope. Spatially and temporally resolved exocytotic events from single cells on a microfluidic device were visualized in real time using fluorescence microscopy and were amperometrically recorded by the electrochemical system simultaneously. This coupled technique is simple and is hoped to provide new insights into the mechanisms responsible for the kinetics of exocytosis. PMID- 21267087 TI - Optical manipulation and binding of microrods with multiple traps enabled in an inclined dual-fiber system. AB - We present experimental demonstrations of optical manipulation and optical binding of microscopic glass rods using the multiple traps created by a dual fiber optical trapping system. Trapping, alignment, rotation, and stacking of glass rods were realized. To the best of our knowledge, this is the first time that cylindrical particles are optically trapped and bound by an optical fiber based system. The optical manipulation of rods is also investigated through numerical simulations, which are used to quantitatively explain the experimental results. The ability of manipulating multiple particles of different shapes, as well as the integrable nature of the fiber-based setup, bestows the system the potential to be used in microfluidic systems for versatile particle manipulations. PMID- 21267088 TI - Transmittance tuning by particle chain polarization in electrowetting-driven droplets. AB - A tiny droplet containing nano/microparticles commonly handled in digital microfluidic lab-on-a-chip is regarded as a micro-optical component with tunable transmittance at programmable positions for the application of micro-opto-fluidic systems. Cross-scale electric manipulations of droplets on a millimeter scale as well as suspended particles on a micrometer scale are demonstrated by electrowetting-on-dielectric (EWOD) and particle chain polarization, respectively. By applying electric fields at proper frequency ranges, EWOD and polarization can be selectively achieved in designed and fabricated parallel plate devices. At low frequencies, the applied signal generates EWOD to pump suspension droplets. The evenly dispersed particles reflect and/or absorb the incident light to exhibit a reflective or dark droplet. When sufficiently high frequencies are used on to the nonsegmented parallel electrodes, a uniform electric field is established across the liquid to polarize the dispersed neutral particles. The induced dipole moments attract the particles each other to form particle chains and increase the transmittance of the suspension, demonstrating a transmissive or bright droplet. In addition, the reflectance of the droplet is measured at various frequencies with different amplitudes. PMID- 21267089 TI - Optofluidic tweezer on a chip. AB - A novel method to realize an optical tweezer involving optofluidic operation in a microchannel is proposed. To manipulate the optical tweezer, light from an optical fiber is passed through both PDMS (polydimethylsiloxane)-air surface lenses and an optofluidic region, which is located in a control channel. Two liquids with different refractive indices (RIs) are introduced into the control channel to form two different flow patterns (i.e., laminar and segmented flows), depending on the liquid compositions, the channel geometry, and the flow rates. By altering the shapes of the interface of the two liquids in the optofluidic region, we can continuously or intermittently control the optical paths of the light. To demonstrate the functionality of the proposed method, optical tweezer operations on a chip are performed. Changing the flow pattern of two liquids with different RIs in the optofluidic region results in successful trapping of a 25 MUm diameter microsphere and its displacement by 15 MUm. PMID- 21267090 TI - Tunable visual color filter using microfluidic grating. AB - This paper reports a tunable visual color filter based on a microfluidic transmission grating. The grating lines are formed by the microflows in an array of evenly spaced straight microchannels. In experimental study, the transmission of white light measures a shift of visual color from red to blue in the zeroth order diffraction in response to a change of the refractive index from 1.3290 to 1.3782 in the microflows. The merit of large tunability of transmission peak (Deltalambda=408 nm) makes this grating potential for various applications in biological and chemical measurements, such as space- and time-resolving micropattern spectrophotometers and separation of the fluorescence from the excitation. PMID- 21267091 TI - Optofluidic in situ maskless lithography of charge selective nanoporous hydrogel for DNA preconcentration. AB - An optofluidic maskless photopolymerization process was developed for in situ negatively charged nanoporous hydrogel [poly-AMPS (2-acrylamido-2-methyl-1 propanesulfonic acid)] fabrication. The optofluidic maskless lithography system, which combines a high power UV source and digital mirror device, enables fast polymerization of arbitrary shaped hydrogels in a microfluidic device. The poly AMPS hydrogel structures were positioned near the intersections of two microchannels, and were used as a cation-selective filter for biological sample preconcentration. Preconcentration dynamics as well as the fabricated polymer shape were analyzed in three-dimensions using fluorescein sample and a confocal microscope. Finally, single-stranded DNA preconcentration was demonstrated for polymerase chain reaction-free signal enhancement. PMID- 21267093 TI - WONCA and World Nutrition: A Positive Approach. PMID- 21267092 TI - Polyelectrolyte multilayer surface functionalization of poly(dimethylsiloxane) (PDMS) for reduction of yeast cell adhesion in microfluidic devices. AB - Polyelectrolyte multilayers (PEMs) based on the combinations poly(diallyldimethylammonium chloride)/poly(acrylic acid) (PDADMAC/PAA) and poly(allylamine hydrochloride)/PAA (PAH/PAA) were adsorbed on poly(dimethylsiloxane) (PDMS) and tested for nonspecific surface attachment of hydrophobic yeast cells using a parallel plate flow chamber. A custom-made graft copolymer containing poly(ethylene glycol) (PEG) side chains (PAA-g-PEG) was additionally adsorbed on the PEMs as a terminal layer. A suitable PEM modification effectively decreased the adhesion strength of Saccharomyces cerevisiae DSM 2155 to the channel walls. However, a further decrease in initial cell attachment and adhesion strength was observed after adsorption of PAA-g-PEG copolymer onto PEMs from aqueous solution. The results demonstrate that a facile layer-by-layer surface functionalization from aqueous solutions can be successfully applied to reduce cell adhesion strength of S. cerevisiae by at least two orders of magnitude compared to bare PDMS. Therefore, this method is potentially suitable to promote planktonic growth inside capped PDMS-based microfluidic devices if the PEM deposition is completed by a dynamic flow-through process. PMID- 21267094 TI - [Not Available]. PMID- 21267095 TI - WONCA 1986: A Personal Impression. PMID- 21267096 TI - Hypertension screening in a primary care clinic. AB - A chart audit of 250 randomly selected adult patients at a university-based family practice unit showed that 91.9% had attended the clinic during a five-year period (89.0% for males and 94.5% for females). Overall, 80.6% of the patients had their blood pressure recorded on the office chart in the five-year period (75.3% for males and 85.0% for females). For males 30-39 years old, however, the rate was only 54.5%. Flow sheets are suggested as a practical method for recording health maintenance items in an effort for the primary care physician to follow the recommended guidelines for hypertension screening. PMID- 21267097 TI - Ocular trauma: emergency care and management. AB - The emergency care and management of patients with ocular trauma can often be handled completely by the family physician, whose goal should be recognizing the nature and circumstance of the injury and subsequent decision making based on the initial management steps. Obtaining a careful and thorough patient history is vital, as unsuspected trauma may be looked for based on historical clues. The initial examination is similarly crucial for determining the extent of the injury and for formulating the treatment plan. Very often, early and effective first-aid care can prevent future complications, which could otherwise lead to subsequent deterioration of the eye. PMID- 21267098 TI - The medical check-up for potentially serious diabetic retinopathy. AB - In developed countries diabetic retinopathy is a major cause of visual impairment and the leading cause of blindness in the population aged 20-65 years. Serious retinopathy has a presymptomatic phase which underscores the importance of ophthalmoscopy in screening patients to detect microvascular abnormalities that are early and late predictors of increasing severity. The diagnosis of "high risk characteristics" for visual loss and "clinically significant macular edema" is essential, as photocoagulation treatment has been shown conclusively to reduce the rate of blindness and slow the rate of progression of retinopathy. The complete medical check-up and early referral for diagnostic work-up should lead to less disability. PMID- 21267099 TI - Changing concepts of primary open-angle glaucoma and early detection. AB - The understanding of primary open-angle glaucoma has changed over the past 20 years and recommendations on early detection are being revised. In this paper the use of Shiotz tonometry is critically examined, and the problems encountered in instituting alternative screening techniques are reviewed. PMID- 21267100 TI - Eye protection. AB - Eye injuries frequently occur in the home, at work and at play. Many result in legally blind eyes, and most are preventable. Awareness of potential hazards is essential to preventing eye injuries, particularly in children. In addition, protective devices must be used appropriately. We have developed eye protectors that have proved effective in reducing both the overall incidence and the severity of sports eye injuries. PMID- 21267101 TI - Modern concepts of the diagnosis and treatment of chronic open-angle glaucoma. AB - Chronic open-angle glaucoma is an important cause of blindness in North America. It consists of the triad of elevated intraocular pressure, pathological cupping of the optic nerve head, and visual field loss. Sophisticated techniques have been developed to determine more accurately the health of the optic nerve head and the status of the visual field. Therapy is aimed at lowering intraocular pressure. This includes topical and systemic therapy followed by laser therapy if necessary. Surgery is indicated if laser and medical treatment fail. The family practitioner has an important role to play in screening individuals to detect this disease. The family practitioner should be aware of the systemic and topical side effects of anti-glaucoma medications. PMID- 21267102 TI - Refractive surgery: new options for visual correction. AB - Refractive surgery is now at the forefront of ophthalmological development and has proved to be a safe and effective method of correcting refractive errors. The incisions performed during radial keratotomy flatten the cornea to reduce or eliminate myopia. In keratomileusis, resecting and reshaping a portion of the cornea can correct either myopia or hyperopia when the cornea is sutured back into position. In epikeratophakia, donor corneas become "living contact lenses". They have the potential for correcting high degrees of myopia and hyperopia. Although there are controversial aspects to refractive surgery, most informed people consider that the benefits outweigh the risks for suitable candidates. PMID- 21267103 TI - Lasers in ophthalmology. AB - Lasers provide a convenient source of focused light energy that can be delivered to a target and, specifically, can do one of two things in the eye. Lasers can create a thermal lesion, that is, a burn, in the same way that light from the sun that is focused with a magnifying glass will burn paper. This thermal lesion can create a scar or hole in the target tissue. In photocoagulation techniques depend on the thermal effect, i.e., the absorption characteristics of the tissues to be coagulated indicate the wavelength to be chosen. The three important ocular light absorbers are melanin, hemoglobin and xanthophyll. For anterior segment work, melanin in the iris and trabecular meshwork is the most important absorber and hemoglobin in blood is the second most important. In retinal work, hemoglobin and xanthophyll absorption are the most important absorbers. The second type of laser effect is achieved with very short duration, high-powered lasers such as the Q switched neodymium YAG. Non-thermal effects cause disruption of any target tissue either transparent or opaque. PMID- 21267104 TI - Hirschsprung's Disease: A Review. AB - Constipation is a common symptom in infants and young children who are seen by primary care physicians. If a patient fails to respond to the appropriate medical therapy for constipation, then the physician should consider the possibility of Hirschsprung's disease, a congenital disease in which ganglion cells are absent from the distal gastrointestinal tract, and which results in a functional colonic obstruction. Early diagnosis and prompt treatment of Hirschsprung's disease will result in a significantly improved quality of life for the patient, and may alleviate potentially life-threatening complications. This article describes a case of Hirschsprung's disease and reviews the most current literature on the topic. Clinical features that distinguish Hirschsprung's disease from other causes of constipation are emphasized. PMID- 21267105 TI - "The Moon's a Balloon"? PMID- 21267106 TI - The Chelsea Physic Garden-London's and the World's. PMID- 21267107 TI - WONCA et la nutrition dans le monde: Une approche positive. PMID- 21267108 TI - Let's Hear it for Housecalls. PMID- 21267110 TI - "Just a GP!". PMID- 21267109 TI - The Anglophone GP in Quebec: Requiescat in Pace? PMID- 21267111 TI - Kudos for CFP. PMID- 21267112 TI - The Use of the Cavity-Rim Cervical Cap in a Family Physician's Office. AB - This paper describes a retrospective study which looked at the effectiveness of the Prentif cavity-rim cervical cap, cap usage, cap-associated problems and acceptability for 95 women fitted with a cervical cap at a family physician's office. The pregnancy rate of this group was 12.28/100 years of exposure. Data on cap usage, cap-associated problems and acceptability are presented and briefly discussed. The authors believe that although cap fitting and teaching are time consuming, and that the reported pregnancy rate is relatively high, the cervical cap does remain a valuable alternative method of contraception for some women. PMID- 21267113 TI - Unexplained fatigue and hemoglobin: a primary care study. AB - The authors of this article investigated the relation between unexplained fatigue and the hemoglobin concentration in a general practice setting. They determined the hematologic parameters of 174 patients with unexplained fatigue in whom the general practitioners established an indication for hemoglobin measuring; a control group of 148 patients was used. Taking gender into consideration, the same distributions were found in both groups. This pattern was not influenced by the duration and severity of the symptom, the presence of other "anemic" symptoms, nor the opinion of the physicians about the likelihood of a low hemoglobin level. Hemoglobin levels below 7.0 mmol/l were not found. Obviously, in patients with unexplained fatigue the hypothesis "anemia" will rarely be confirmed. PMID- 21267114 TI - Sexuality and contraception for developmentally handicapped persons. AB - Marked changes are occurring in the manner in which developmentally handicapped persons are being incorporated into society. These changes necessitate careful planning and review of the consequences of social interactions, including those of sexual development and fertility. Physicians and other health care workers should familiarize themselves with the current techniques of contraception as they apply to the developmentally handicapped and the current status of consent as it applies to therapeutic and non-therapeutic interventions, including advice about temporary and permanent contraception. PMID- 21267115 TI - Female tubal sterilization. AB - Tubal ligation has become the second most popular method of contraception in Canada, after oral contraception. Refinement of techniques has resulted in sterilization procedures which have minimal potential for failure and high potential for reversibility. Laparoscopic and minilaparatomy techniques allow outpatient "Band-Aid" sterilizations with less risk of complications than more destructive procedures. Laparoscopic application of tubal clips or rings is highly effective, with minimal tubal destruction. Tubal ligation following a pregnancy is more often regretted than is interval sterilization. The search continues for a satisfactory transcervical sterilization procedure. PMID- 21267116 TI - Contraception for the older woman. AB - Women over the age of 35 are at higher risk for the rare, but serious, cardiovascular complications associated with the oral contraceptive. Thus, alternative methods are preferable choices for the older woman. Careful individual counselling will provide the patient with an effective choice of birth control methods. PMID- 21267117 TI - Infertility: a review of physical and emotional aspects. AB - Infertility affects 15% of couples. The primary causes are poor sperm production, ovulation defects, and fallopian tube obstruction, which can be detected by a simple, logical investigation. Infertility and its investigation precipitate characteristic emotional responses that require care by an informed, sensitive physician. PMID- 21267118 TI - What to Tell Patients about Vasectomy. AB - All elective surgery causes patients anxiety. Operations involving the genital tract are associated with even larger fears. Patients need information in order to make a realistic choice about vasectomy as a method of birth control, as well as an opportunity to discuss the question with their doctor.This tear-out sheet can be copied and distributed to patients considering vasectomy. Patients' fears decrease when the surgery has been adequately explained, and an informed decision can be made. PMID- 21267119 TI - Oral contraception for younger woman: the benefits of the low-dose pill. AB - Oral contraceptives provide the woman under 35 with the most effective and safest reversible method of birth control. As the estrogen content of oral contraceptives has gradually been lowered during the past 20 years, there has been a lessening of the side-effects first reported by the Royal College of General Practice in 1967. The research of two decades has brought about changes in "the pill". The most recent change has been the introduction of biphasic and triphasic pills with lower hormone dosages and fewer side-effects, but the same overall effectiveness and cycle control. Nevertheless, the percentage of women using OCs drops dramatically for those over the age of 25. Today's pills, with their lower hormone content, offer the physician a more flexible means of prescribing effectively for the individual patient. PMID- 21267120 TI - Familial endometriosis. AB - Although it has been suspected that endometriosis has familial tendencies, systemic studies have not been conducted until relatively recently. The inheritence is not a monogenic, but rather a polygenic multi-factorial process. A case is presented and the clinical significance of the familial endometriosis is discussed. PMID- 21267121 TI - First impressions. PMID- 21267122 TI - The canadian association of internes and residents committee on family medicine. AB - Family medicine residents across Canada represent a unique body of physicians with exciting and different training experiences. Some 30 residents from each of the 16 university-administered Canadian family medicine programs meet twice annually as a subcommittee of the Canadian Association of Internes and Residents (CAIR), to exchange ideas and discuss issues of relevance to family medicine programs. The CAIR Committee on Family Medicine (CAIR-CFM) has direct liaison with the College of Family Physicians of Canada through its Board of Directors and various educational committees. CAIR-CFM has also been actively involved in other independent projects directly affecting the training of family medicine residents, including a review of every family medicine program, accreditation of programs, and policy recommendations. PMID- 21267124 TI - Don'T forget ipecac in first aid kit. PMID- 21267123 TI - What constitutes elevated cholesterol? PMID- 21267125 TI - Organ donor awareness week. PMID- 21267126 TI - Cephradine in the prophylactic treatment of dog bites. AB - Four hundred and twenty patients with one or more open dog bite wounds were studied. Cephradine or no antibiotic was used for treatment. The wounds were debrided, irrigated, and dressed; 3.6% required suturing. Six patients treated prophylactically with cephradine developed wound infections and three of these had to be hospitalized in order to receive parenteral antibiotics. Five of the wounds grew Enterobacter species, and the sixth grew Pseudomonas aeruginosa. In the control group, only two patients developed infections, one with Staphylococcus aureus, and the other with Bacillus subtilis. Both were treated as outpatients with oral antibiotics after wound treatment. Although there is no statistically significant difference between the prophylactic and control groups, there was a trend toward more serious infections in those treated with cephradine. This investigation demonstrates that prophylactic cephradine is not useful in cases of uninfected dog bite wounds. PMID- 21267127 TI - Priorities in managing pediatric emergencies. AB - The accidents and infections which cause the majority of pediatric emergencies are characteristically sudden in onset and often complicated by rapid deterioration. The immediate objective, as with any age group, is to preserve life by providing a patent airway, effective breathing, and adequate circulation; however, in managing a pediatric emergency, the ABCs of resuscitation are not enough. Anticipation and intervention are also needed to identify and treat the child's special needs and potential complications. These requirements are size dependent, age related and disease specific. The management of serious respiratory illnesses, infections and convulsions is discussed. PMID- 21267128 TI - The Family Physician's Role During Disasters. AB - Family physicians can encourage disaster planning and mock disaster exercises in their community. If involved in an actual disaster, the family physician can be helpful as a triage officer in emergency, in initial resuscitation, in minor treatment, in discharging stable patients, and in counselling victims of post traumatic shock syndrome. The key to effective performance is being prepared beforehand to cope with the stress and confusion of the incident. Use of laboratory and diagnostic imaging must be curtailed until all severely injured patients are treated. PMID- 21267129 TI - Emergency treatment of acute asthma. AB - In assessing acute asthma, the physician must seek specific historical features, symptoms and physical findings. Recent work has shown, however, that while these features are associated with severity, their absence does not imply benignity. Objective measures of pulmonary function are required for accurate assessment of severity. A sequential treatment regimen using nebulized bronchodilators, vigorous rehydration, aminophylline, and corticosteroids should be employed. Status asthmaticus may require intubation and assisted ventilation and, as a last resort, inhalation anesthesia. PMID- 21267130 TI - Dealing with sudden death of the emergency patient. AB - A sudden, unexpected death or impending death is a crisis for the patient, family and emergency department staff. The emergency physician has several responsibilities. These include attempting to stabilize the patient's condition, relieving pain and discomfort, and deciding whether to initiate resuscitation for patients suffering cardiac arrest or terminal illness. The physician must also be sensitive to the psychological needs of the patient and family. It is important for emergency physicians to understand their own emotional reactions, as well as those of other emergency team members. PMID- 21267131 TI - Management of outpatient burns. AB - The severity of burns depends on the depth and extent of body surface involved. The total body surface area (TBSA) involved can be estimated by the 'rule of nines'; body locations are 9% of body surface or multiples of nine. Depth and TBSA can be used to classify burns as minor, moderate, or critical. Diagnosis depends on history and physical examination. Most burns can be treated in an outpatient setting. Treatment should include debriding necrotic tissue, preventing infection and encouraging healing. Specific treatment of burns of the face, hands, trunk and feet is described. Follow-up should include assessing healed wounds for the development of hypertrophic scars, and preventing such scars if possible. PMID- 21267132 TI - Foreign bodies in the aerodigestive tract. AB - Foreign bodies in the aerodigestive tract are common. They may cause minimal disturbance of function, severe morbidity or even sudden death. They enter the aerodigestive tract because of haste during eating, disturbances in physical function, impairments due to extreme youth or age, or contamination of food with foreign bodies. Common symptoms are pain, dysphagia, odynophagia, cough, airway distress, hemoptysis and hematemesis. Signs include point tenderness, respiratory distress and surgical emphysema. Clinical, radiological and endoscopic investigations are described, as are principles of crisis and elective management. PMID- 21267133 TI - Impact of Lay-Administered CPR on Survival Rates. AB - Sudden death accounts for between 20%-25% of all "new" coronary events. Until prevention is better understood, the best and most effective treatment is the rapid provision of resuscitative measures which "buy time" until definitive care can be provided. Factors positively associated with length of survival are: age, time from collapse to CPR; and time from collapse to CPR, combined with time to definitive care. Preliminary reports on the functional status of survivors are also promising. Canadians should readdress CPR as a vital factor influencing out of-hospital cardiac arrest survival rates and necessitating administration by lay persons. PMID- 21267134 TI - A clinical approach to the diagnosis of Acid-base disorders. AB - The ability to diagnose and manage acid-base disorders rapidly and effectively is essential to the care of critically ill patients. This article presents an approach to the diagnosis of pure and mixed acid-base disorders, metabolic or respiratory. The approach taken is based on using the law of mass-action equation as it applies to the bicarbonate buffer system (Henderson equation), using sub classifications for diagnostic purposes of causes of metabolic acidosis and metabolic alkalosis, and using a knowledge of the well-defined and predictable compensatory responses that attempt to limit the change in pH in each of the primary acid-base disorders. PMID- 21267135 TI - Medical management of premenstrual syndrome. AB - Premenstrual syndrome (PMS) is characterized by a wide variety of symptoms occurring over several days before menstruation. In the differential diagnosis, family physicians should consider other conditions such as chronic yeast infection, allergy, stress, hypoglycemia and primary dysmenorrhea. Each patient should complete a daily menstrual diary for two to three monthly cycles. This diary may help the physician to determine the cyclical nature of PMS and specific symptoms. For most PMS sufferers, initial treatment involves the physician's acknowledgement of the problem and advice about lifestyle, dietary modification and vitamin supplements (e.g., pyridoxine). Seven steps are recommended to assist the family physician in the practical office management of most women with PMS. The potential role of progesterone and other agents in the treatment of PMS is described. Referral to a psychiatrist or psychologist, or the use of drugs such as lithium, danazol or bromocriptine may be required for women suffering from severe PMS. PMID- 21267136 TI - Screening homosexual men for hepatitis B. AB - Homosexual men have been routinely screened for hepatitis B in an infectious diseases clinic since 1982. Of 159 patients, 65.4% were susceptible to the disease on initial screening, but only 10.6% underwent vaccination. Of the 159 patients, 7.5% are currently carriers of hepatitis B. The risks of long-term sequelae in terms of morbidity, mortality, and cost to the health care system must be balanced against the cost of promoting and funding preventive measures. In the interest of public health, screening and vaccination of susceptible homosexual men for hepatitis B should be provided free by government health-care agencies. PMID- 21267137 TI - Serum vitamin b(12) and folate levels in women taking oral contraceptives. AB - Serum vitamin B(12) and erythrocyte folate levels were determined in a group of healthy women eating a balanced diet. Approximately 50% were using oral contraceptives. Vitamin B(12) levels were lower in the oral contraceptive users. However, their folate levels were no different from those of non-users. Age had no effect on either vitamin B(12) or folate levels. Oral contraceptive users taking multiple vitamin tablets containing vitamin B(12) and folate had slightly higher folate levels, but their vitamin B(12) levels were no different from those of OC users who were not taking vitamin tablets. Hemoglobin and hematocrit levels were not affected by oral contraceptive steroids. No case of megaloblastosis was found. Regular folate supplementation is not required for OC users. In fact, such supplementation may be dangerous. PMID- 21267138 TI - Office management of diabetes in children part 1: general principles. AB - In order to manage diabetes mellitus in children, the physician must understand the principles of insulin action and dosage adjustment, meal planning, growth assessment, and the effects of exercise. The objectives of office supervision include ongoing education of the patient and family, excellent control of the diabetes, and the maintenance of normal growth and development, emotionally as well as physically. PMID- 21267139 TI - Office management of diabetes in children part 2: common problems. AB - A problem-solving approach is used to illustrate principles of managing diabetes mellitus in children. Situations discussed include adjustments for hypo- and hyperglycemia and vigorous activity, and care of the diabetic child who has another illness. The usefulness of referral to a diabetes education centre is emphasized. PMID- 21267140 TI - Estrogen replacement therapy for postmenopausal osteoporosis. AB - In postmenopausal women, inevitable longitudinal loss of bone mass is increased in association with reduced levels of endogenous estrogen. A review of the health care literature on therapy for postmenopausal osteoporosis provides strong evidence for prevention and treatment with estrogen/progestogen replacement therapy. This therapy was not associated with endometrial carcinoma. PMID- 21267142 TI - [Not Available]. PMID- 21267141 TI - Certificate of special competence in emergency medicine: college of family physicians of Canada. PMID- 21267143 TI - Midwives or family physicians? PMID- 21267144 TI - A profile of female family physicians. AB - One hundred and thirty-five women family physicians were surveyed to obtain a profile of their lifestyles, practice patterns, and stresses. The majority were married (81%), with a large percentage (45%) married to physicians. Fifty-three percent had children and assumed the major responsibility for domestic organization. Most (97%) were working; of these 60% were working full-time. Over half (63%) had interrupted their careers, usually for maternity leave (79%) with a relatively short absence (average 12.3 weeks). Most reported good to excellent health over their lifetime. Overall, medicine was viewed very positively, with most (88%) reporting a high level of confidence in their career choice. However, conflict between career and family needs was identified as a major area of stress. Results are compared with those found in other demographic studies of female physicians. To date, no comparable survey of family physicians exists. PMID- 21267145 TI - The 'one-write' prescribing method: applications for patient monitoring and research. AB - This article examines a method called 'one-write prescribing', designed for use by family physicians. The method produces three copies. The original is issued to the patient who takes it to the pharmacist, the second copy is attached to the inside cover of the patient's medical record, and the third copy is retained for research purposes. The findings of a two-year comparative study, conducted by a solo family physician who developed the method, are presented. Based on the results of this study, a modified version of the method is recommended as a convenient system which physicians can use to assess their own prescribing behaviors. This method will enable physicians to monitor their own patients better as well as to compare prescribing patterns between practices. PMID- 21267146 TI - A survey of chronic pain in an elderly population. AB - Elderly nursing home residents and those attending a day hospital program for six hours a week at the same home were surveyed to determine the prevalence of chronic pain. Of the 132 subjects, 83% reported having pain problems, mostly due to connective tissue disorders. Eighty-four percent of these patients were receiving analgesics for their pain, but the other 16% were receiving no treatment. Fifty percent of subjects report low levels of pain, 32% moderate levels, and 18% high to intolerable levels. For many patients, the pain has been present for several years. A relationship was also found between pain levels and depression. None of these patients was being actively treated for depression. There may be an inclination to underestimate the prevalence and intensity of pain in the elderly. PMID- 21267147 TI - The canadian family practice accoucheur. AB - Family practice obstetrics is strongly influenced by demography and marketing. The falling birth rate is leading to a surplus of caregivers who may inappropriately apply their technical skills to a population of low-risk pregnant women. This in turn may lead to a 'cascade' of negative consequences for the normal, child-bearing public. The family practice accoucheur has a key role to play as an advocate of high quality, humanistic maternity care. Training programs must address the academic base of family practice obstetrics through direct teaching, role modelling, research, and quality assurance. PMID- 21267149 TI - Diagnosing wife assault. AB - With the prevalence of wife assault quite high, family doctors will see battered women and their families in the office. However, the identification of the problem is often missed due to women's reluctance to explain their problem and physicians' hesitancy in exploring the possibility and lack of awareness of the prevalence of abuse. The importance of the family doctor's role in identifying the problem and referring the family to appropriate community resources is discussed. Possible explanations for the physician's difficulty in making the diagnosis are considered. PMID- 21267150 TI - [Not Available]. AB - The use of Pap smears for screening of carcionma of cervix uteri was evaluated in a family medicine unit. The charts of all women aged 18-34 were first reviewed then, over a month, a questionnaire was administered to all women consulting at the unit. For about 40% of the eligible women, no evidence was found that at least one Pap smear had been done over a three-year period. Most of them did not report being followed by a gynecologist. Women consulting for anxiety or depression were less likely to have a Pap smear done at the unit, in spite of the greater number of visits. Nearly 60% of the smears are not done at the unit but by a gynecologist, although only 15% of the women interviewed considered having a regular gynecologist. PMID- 21267148 TI - Supporting the Breast-feeding Dyad. AB - Although there has been a resurgence of breast-feeding in the last decade, 50% of women discontinue exclusive breast-feeding by the third month postpartum. Practices known to interfere with breast-feeding are often begun in hospital and continued at home. The physiology of lactation, the need for interaction between mother and infant during breast-feeding, and research findings indicate that scheduled feeds, feeds of limited duration, supplementation, and separation of mothers and infants interfere with the success of breast-feeding. Health care providers can promote breast-feeding duration by advising unlimited feeds, promoting 'rooming-in' at hospitals, and providing support and information. PMID- 21267151 TI - Pap smear practice patterns of family physicians. AB - London, Ontario family physicians were surveyed, to compare the frequency of their Pap smear screening and their management of the abnormal smear with the recommendations of the 1982 Task Force report on cervical cancer screening. Considerable variation was observed between the Task Force recommendations and frequency of screening 36-60-year-old women, and the management of mild, recurrent mild, and moderate dysplasia. Many family physicians appeared to rely heavily on the cytopathologist's recommendations. More uniformity is required, both in cytopathologists' recommendations and in the practice of family physicians, if cervical cancer screening programs are to achieve their maximum effectiveness. PMID- 21267152 TI - Management of cervical dysplasia. AB - Since the 1982 Revised Task Force Report on Cervical Cancer Screening, controversy has developed over the management of mild dysplasia. Recent developments have led some investigators to recommend colposcopy for any degree of cervical dysplasia because of significant false-negative factors in Pap smear reporting and the observation that some patients have lesions more severe than suggested by the cytology. Over a four-year period, all patients with dysplastic smears in the practice were evaluated by colposcopic examination and biopsy. In 20 cases of mild dysplasia, five cases of cancer in situ were found. Considerable variation from the Task Force's report was noted in cytopathologists' recommendations for cytological smears. Judging from the results of this audit, colposcopic evaluation of all dysplastic smears should be considered. PMID- 21267153 TI - Breast-feeding: The Problem of 'Not Enough Milk'. AB - 'Not enough milk' is the most common cause for early weaning to a bottle. However, it is almost always a non-problem, which is partly iatrogenic, and partly due to ignorance of normal breast-feeding in our society. For a woman who desires to breast-feed, recourse to bottle feeding is almost never necessary. For most babies who are 'not getting enough milk', only simple measures are required: feeding on demand; banning formula or water supplements, pacifiers, and nipple shields; and proper positioning. For the few babies who fail to thrive on breast milk, supplementation may be given with a lactation aid. Two case studies illustrate successful management of the problem of 'not enough milk'. PMID- 21267154 TI - A Well Doctor's Family: The Struggle for Intimacy. AB - For married people, mental health depends on a sound marriage and family life. Intimacy is a major requirement for a healthy marriage. One of the biggest problems among physicians is failure to develop intimate relationships within their families. Intimacy may be inhibited because the characteristics of a good physician are not always characteristics of a good spouse and parent. For example, a physician should be able to control feelings, while a spouse and parent should be able to express feelings. Also, the pressure of practice may mean physicians do not spend enough time with their families. Or, confronted by tensions at home, doctors may retreat into their work, where they feel competent and appreciated. However, physicians must realize that self-esteem and intimacy through family relationships are just as important as professional esteem. PMID- 21267155 TI - Antidepressants: which one? AB - There are now 15 effective antidepressant medicines marketed in Canada (eight tricyclic antidepressants, three monoamine oxidase inhibitors, and four medicines with novel chemical structures). The tricyclics remain the drug of first choice for major depressions, because of their proven efficacy over three decades, their known side effect profiles, and the cheaper cost of imipramine and amitriptyline compared to other tricyclics and the new antidepressants. The monoamine oxidase inhibitors are an excellent alternative, and are far safer than earlier reports suggested. Maprotiline offers few advantages over the tricyclics and costs significantly more. Trazodone may be a second- or third-line drug with the advantage of minimal anticholinergic properties. Adequate clinical evaluation of nomifensine has not yet occurred. Neuroleptic and cardiotoxic properties of amoxapine suggest other medicines should be tried first. PMID- 21267156 TI - Managing human bite infections of the hand. AB - Human bite injuries of the hand may become complicated and therefore demand an organized approach to management. Thirty-two patients with human bites to the hand, admitted to Toronto's Wellesley Hospital between 1981 and 1985, were analyzed. The history and etiology, delay before presentation, microbiology results versus time from injury, and treatment regimens were reviewed. Streptococci appeared to be early pathogens and staphylococci later pathogens. However, a prospective study with serial aerobic, anaerobic, and 10% CO(2) cultures is needed to confirm these findings. Lack of organization in management was the most notable finding. Inpatient therapy with intravenous antibiotics usually is required. Treatment should revolve around the mnemonic 'ODD BITES': open treatment; debridement; drugs (antibiotics); bloodwork (leukocyte count); irrigation; tetanus prophylaxis; exploration (including X-rays); and swab (for culture and sensitivity). PMID- 21267157 TI - Parents Experiencing Perinatal Loss: The Physician's Role. AB - The three cases presented in this article highlight some of the problems that family physicians encounter when their patients experience perinatal loss. By understanding the process of normal grieving, the family physician can help prevent pathological grief reactions. With cooperation from other members of the perinatal support team, the family doctor can keep parents informed, teach them about the grieving process, support them in seeing and touching the infant, arrange for photographs of the infant, discuss autopsy and funeral arrangements, and help them inform siblings. PMID- 21267158 TI - Managing disability from stroke. AB - Strokes are the single greatest neurological cause of disability, yet many stroke patients do not ever reach a specialized stroke rehabilitation unit. For those remaining in the hospital to which they were first admitted, active medical involvement may decline dramatically once the diagnosis has been made. However, the family physician can play an active role in managing post-stroke patients, enhancing their functional recovery and achieving successful discharge back into the community. This article describes post-diagnosis management of stroke, discharge planning, and post-discharge follow-up. PMID- 21267159 TI - An approach to difficult clinical problems. AB - Often physicians use an intuitive approach to treatment, based on years of clinical experience and discussion with colleagues. However, some complex clinical problems in family practice require a formal, structured, rational apprach to decision making. This article describes how clinical decision analysis was used in a family practice unit, for a patient with a suspected loose hip prosthesis. The use of probabilities and working through a 'decision tree' assisted in the formation of a successful treatment plan. PMID- 21267161 TI - Taking the helm. PMID- 21267160 TI - The microcomputer as a tool for literature searches. AB - Within the past several decades, computerized databases have been created for physicians. Technology now allows any physician who has access to a microcomputer to do computer literature searches. This article describes some of the hardware, software, and databases available to computer searchers. Two useful database providers, Dialog and Bibliographic Retrieval Services, are described. Two examples are given to illustrate the technique of literature search by computer. Basic skills needed to conduct searches are outlined, as are the advantages and disadvantages to physicians doing their own computer searches. PMID- 21267162 TI - [Not Available]. PMID- 21267163 TI - Physicians as mothers. PMID- 21267164 TI - College aiding in defining midwives' role. PMID- 21267165 TI - Will the real family physicians please stand up! (A medical manpower report). AB - Recent government studies have reported an oversupply of family physicians and recommended reductions in their numbers. Believing these recommendations to be based on overestimates, as the unfounded assumption is made that all non specialists are family physicians in active practice, we attempted to determine how many physicians were actually in general practice in Edmonton, Alberta, in 1984. Using screening procedures followed by a mailed questionnaire to confirm our results and obtain further information about family practice, we identified only 309 general practitioners of 662 non-specialists. Only 45% of the total number of physicians who are not practising a specialty other than family medicine, and who are registered with the College of Physicians and Surgeons of Alberta, could be positively identified as family physicians. We therefore recommend that information on actual numbers of family physicians, rather than non-specialists as a whole, be made available to policy makers determining personnel requirements. Questionnaire results indicated certain problem areas in family practice, particularly long work weeks, inadequate coverage for practices, and lack of hospital privileges and obstetrical care. We suggest that professionals in family medicine address these problems. PMID- 21267166 TI - Patients' Desires as Compared to Expectations for Psychosocial Intervention by their Family Physician. AB - The purpose of this study was to challenge previous studies on defining a behavioural science curriculum for family physicians. Schwenk's original questionnaire was reworded to ask patients what they desire ideally from their family physician as compared to what they have come to expect that their physician would do to manage 45 psychosocial problems. We found equivalence between the expectations and preferences in two family practice units with diverse patient populations. Patients wanted significantly more involvement than they expected in problems of overweight; lack of exercise; difficulty sleeping; adjustment to a family move; hospitalization of a family member; long-term physical illness; and abortion. The majority of problems fell in the some help/concern category (level 3). Expert help (level 4) was wanted in the areas of childhood illness, long-term physical illness, and pregnancy. A suggested behavioural science curriculum is outlined. PMID- 21267167 TI - The Family Physician as Peacemonger: How to Talk to Your Patients about the Threat of Nuclear War. AB - The threat of nuclear war concerns most Canadians. Many family physicians may consider the issue important as a topic of preventive medicine, but feel uncomfortable discussing it. Physicians must first inform themselves and deal with their own feelings and psychological defense mechanisms before they can help their patients through the same stages. PMID- 21267168 TI - Identifying concerns of parents of young children. AB - A survey was conducted to ascertain parenting concerns and willingness to participate in parenting groups as a means of addressing concerns. Questionnaires were sent to 121 families with a child aged three years or under. Mothers and fathers were asked to complete separate questionnaires. Analysis of the 85 sets of questionnaires returned indicates that more mothers (51.8%) than fathers (24.9%) had at least five parental concerns. The top five concerns of mothers were "discipline", "childhood illness", "impatience with terrible two's and three's", "lack of time for myself and my child" and "whether or not the child should attend nursery school". Fathers ranked three of these concerns among the top five they expressed; "nursery school attendance" and "impatience" were not major concerns but "working and being a parent" and "whether the child was eating properly" were in the top group. Guilt about leaving the child concerned almost one-quarter of the mothers, but it was the least important concern of fathers. Discipline was the primary concern of both mothers and fathers whether or not they were first-time parents or had two or more children. Couples willing to participate in parenting groups (41%) identified more concerns than those couples of whom only the mother was interested (35%). These results could be used to develop parenting groups in a family practice setting. PMID- 21267169 TI - Working with families in primary care: guidelines for the family physician. AB - Specific strategies for working with families in a busy office practice are described. Since the family provides an important context in which illness occurs, the physician should gather family data when seeing individual patients or entire families. Knowledge about the family's structure, development and functioning can enhance diagnosis, treatment and prevention. The physician attempting to promote adaptation or lessen distress might provide education or information. During certain medical and life crises, he/she might choose to offer brief support or enhance the family's problem-solving capacities. In other situations, referral may be the most appropriate intervention. PMID- 21267170 TI - Treating alcoholics and their spouses: a family-systems centred approach. AB - The need and rationale for an expanded focus in the treatment of alcoholism are outlined in this paper. The inadequacy of a treatment regime which treats alcoholics in isolation from their families is demonstrated. The author describes the Couples Treatment Program in Regina, which illustrates a new and innovative approach to dealing with underlying issues related to drinking behaviour. This approach recognizes that marital and family issues and perpetuation of drinking are highly interrelated. Recovery involves addressing not only the drinking problem, but also relationship issues that reinforce drinking. The role of the spouse of the alcoholic in treatment and the need for treatment of the entire nuclear family are also mentioned. PMID- 21267171 TI - [Not Available]. AB - Family history as a screening technique has received little attention from epidemiologists as a means of early detection of disorders. In this paper, we present several every-day family cases that will prepare the family physician to make use, at will, of this special investigative tool. We deal primarily with Down's syndrome, defects of the central nervous system, infertility, metabolic disorders and, finally, marriage of close relations. For each case, the role to be played by the physician dealing with a positive family history involving a problem is detailed in terms of risks of occurrence and recurrence of the condition; particular aspects of the counselling process are presented, especially the logistic, psychological, ethical and social aspects. We conclude that the family physician should routinely take a complete, detailed and accurate family history of the patients whom he/she sees, both in the course of obsterical care and during routine check-ups, in order to help identify cases of family related chronic diseases. PMID- 21267172 TI - Mental health and immigration. AB - The author reviews the psychosocial implications of immigration. Immigration is a complex, emotionally charged process which involves leaving behind old values, relationships, security, and resettling in an unknown culture with a new set of norms and boundaries. Some studies report a higher incidence of psychiatric illness in a migrant population than among the native born. Preventive and early therapeutic intervention is mandatory. In order to facilitate acculturation and eventual adaptation, the host society should promote easy access to the health care systems, educational facilities, housing requirements and community organizations. PMID- 21267173 TI - The art of cross-cultural care. AB - The art of cross-cultural care concerns learning how to transcend one's own culture in order to form a positive therapeutic alliance with patients from other cultures. Since the illness experience varies between cultures, communication difficulties are common between doctors and patients from divergent cultures. Family physicians can minimize these difficulties by sharing in the community life of patients, by listening analytically to patients' use of language and metaphor, and by using problem-solving skills to learn cultural codes. Examination of other cultures leads to increased self-awareness, which may be painful. Understanding one's own culture is a prerequisite to providing effective cross-cultural care. PMID- 21267174 TI - Adoption: implications for family physicians. AB - In the following article, the author discusses common myths which impede accurate understanding of the adoption process and of the individuals involved in that process. This overview of adoption procedures includes discussion of the input of family physicians, the need for patient education, and supportive counselling for all members of the adoption triangle. The family physician is in an important position to identify and assess problems arising from adoption after the formal agency involvement is complete. PMID- 21267175 TI - The pharmacological management of depression. AB - Antidepressants, given in the correct dosage and for an adequate period of time, are very effective in the treatment of the majority of cases of primary depressive illness. In this review, a rational approach to the pharmacological management of depression is discussed. The relative advantages and problems associated with the various types of antidepressants are reviewed. The role of benzodiazepines in the management of depression is considered. PMID- 21267177 TI - A CFP information section to help healthy patients stay healthy. PMID- 21267176 TI - Brief psychotherapy in family practice. AB - A large number of patients with psychosocial or psychiatric disorders present to family physicians, and the family physician needs a model of psychotherapy with which to cope with their problems. A model of brief psychotherapy is presented which is time limited, goal directed and easy to learn. It consists of four facets drawn from established areas of psychotherapy: characteristics of the therapist; characteristics of the patient; Eriksonian developmental stages; and the process of therapy as described by Carkhuff. These facets fit together in a way which is useful to the family physician in managing those patient problems for which brief psychotherapy is indicated. PMID- 21267178 TI - The newly released prisoner. AB - This paper deals with the problems faced by offenders in a category of short term, bit-term and long-term incarceration. Each group has characteristics which mitigate against unassisted rehabilitation. In a country burdened by unemployment of skilled and well-educated people, the criminal releasee is at a great disadvantage and often finds the freedom of prison more comfortable than the captivity of society. The bleak and forlorn futures of offenders vary in intensity. Certain recommendations are made in this paper which could prevent future criminal involvement. PMID- 21267179 TI - Meet CFPC's New President: Dr. Don Watt. PMID- 21267181 TI - What would you have done? Outcome of the elderly, suicidal patient. PMID- 21267180 TI - Left-vs. Right-Handedness: A Preliminary Survey of Health Status and Health Care Utilization. AB - Left-handedness has been linked to dyslexia, migraines, autoimmune disease and early-onset dementia. A pilot study to investigate further the association among handedness, health status and health-care utilization was carried out in a group family practice setting. Variables included frequency of types of medical problems, frequency of visits to the physician, number of referrals to specialists, and number of laboratory and radiographical investigations. A short questionnaire assessing handedness was distributed to 613 randomly selected patients visiting the family practice clinic over a one-month period. Twenty eight left-handers were identified among 520 patients. These were matched with 28 controls, after which charts for all subjects were reviewed to evaluate the study variables. No statistical differences were found between the two groups. Methodological problems included determining true handedness (as distinct from mixed), reviewing of charts for data, and coding and assessing the data. Suggestions are made for improving and facilitating further research in this area for family practice. PMID- 21267182 TI - Medical imaging: how to get the best radiological consult in 1986. PMID- 21267183 TI - [Not Available]. PMID- 21267184 TI - Chaucer described the consummate college member. PMID- 21267185 TI - The problems of illiteracy. PMID- 21267186 TI - A new jet-lag prescription. PMID- 21267187 TI - Jet lag or jet jag? PMID- 21267188 TI - Time and stress management. PMID- 21267189 TI - Stress can be positive. PMID- 21267190 TI - Nationalize all the professions. PMID- 21267192 TI - Allow private medical insurance. PMID- 21267191 TI - Make MDs Salaried Public Servants. PMID- 21267193 TI - Dietary preparation: an objection. PMID- 21267194 TI - Alcohol and drug problems in ontario physicians: characteristics of the physician sample. AB - Thirty-six Ontario physicians who entered a treatment process for alcohol and drug problems were systematically assessed prior to treatment. The demographic and medical practice characteristics of this sample are delineated and, where possible, are compared to those of all Ontario physicians. Physicians with alcohol and drug problems were both similar to and different from all Ontario physicians. Further study is needed to explore the similarities and differences between the two groups, with a view to improving treatment, prevention and professional goverance. PMID- 21267195 TI - Chest imaging. AB - Numerous imaging modalities may be utilized in the assessment of patients with pulmonary or cardiac disease. Because of their high cost and possible morbidity, only those investigations essential to establish the diagnosis should be ordered. This article reviews the imaging procedures most helpful in the evaluation of patients with solitary lung nodules, dyspnea, chest pain and cardiomegaly. PMID- 21267196 TI - Alimentary tract imaging. AB - Plain abdominal radiographs and barium studies are no longer the only available radiological methods for investigating alimentary tract disease. These basic procedures still retain their importance because of their cheapness, wide availability, and ease of performance. The newer modalities such as ultrasound, nuclear medicine, and computed tomography, however, have had a dramatic impact on the way in which common alimentary tract problems are routinely investigated in 1986. This presentation offers guidance in the investigation of acute abdomen, abdominal mass, peptic ulcer disease, right upper-quadrant pain, jaundice, altered bowel habit, and suspected pancreatic abnormality. PMID- 21267197 TI - Urinary tract imaging. AB - This article reviews the current imaging investigations usually required in the work-up of common urinary tract problems such as urinary tract infection, colic, trauma, hematuria and renal failure. Radiological therapeutic techniques such as percutaneous nephrostomy for drainage of obstructed systems and percutaneous nephrolithotomy for treatment of renal calculi are briefly mentioned. The virtual elimination of percutaneous or open surgery for renal and upper urinary tract stones, resulting from the installation of the first and only Canadian extracorporeal shock wave lithotripter in the Department of Radiology at the Vancouver General Hospital is also discussed. PMID- 21267198 TI - Musculoskeletal imaging. AB - Musculoskeletal problems account for a significant portion of primary care medicine. Increase in the public awareness of physical fitness has led to an increase in both the incidence and appreciation of musculoskeletal disorders. This discussion considers the investigation of disorders involving the shoulder, wrist, foot, knee and pelvis. Emphasis is placed on new imaging techniques and their place in the investigation of these problems, as well as on their relationship to the more traditional modalities. PMID- 21267199 TI - Neuroradiological imaging. AB - CT scan has become the primary imaging modality in assessement of patients with neurological problems. Angiography and myelography are useful in specific situations. The role of these modalities, as well as plain film radiography, is reviewed in this article with reference to particular clinical problems. PMID- 21267200 TI - Pediatric radiologic imaging. AB - Medical imaging in the pediatric age group presents special problems. The modern pediatric radiology department is a specialized area, and ensuring an adequate examination requires meticulous care from technician, radiologist and referring clinician. Radiation dose must be kept to a minimum, and constant modifications are being made to the "routine" methods of investigating common problems. These modifications include the introduction and rational integration of all the newer modalities. This presentation offers a modern diagnostic approach to a variety of common pediatric clinical problems. PMID- 21267201 TI - Breast imaging. AB - Breast lumps are extremely common. The high prevalence of breast cancer in our society and increasing public awareness of screening methods make a review of breast imaging for family physicians topical. Mammography and xeromammography remain the basic tools, supplemented by sonography, guided biopsy and diaphanography, for investigating breast lumps. Galactography is the major additional investigation where nipple discharge is present. Screening programs are gaining acceptance and can significantly affect cancer mortality rates. This article discusses these issues from a primary physician's perspective. PMID- 21267202 TI - Imaging by ultrasound. AB - Imaging by ultrasound has dramatically changed the investigation and management of many clinical problems. It is useful in many different parts of the body. In this brief discussion, the following topics are considered: hepatic lesions, bleeding in early pregnancy, gynecological pathology (adnexal lesions), aortic aneurysms, thyroid nodules and scrotal masses. The usefulness of duplex carotid sonography, which combines ultrasonic imaging and Doppler studies, is also discussed. Other topics (gallstones, biliary obstruction, renal calculi, hydronephrosis) are discussed in the appropriate sections. PMID- 21267203 TI - Nuclear medicine. AB - Nuclear medicine utilizes radioisotopes to diagnose and in some cases treat disease. Modern instruments can image their accumulation in an organ and provide quantitative data when indicated. The strength of these procedures is in the unique physiologic information they provide, rather than the presentation of precise anatomic detail. PMID- 21267204 TI - Angiographic imaging. AB - Angiographic imaging in 1986 employs not only conventional film arteriography and venography, but also digital subtraction angiography (DSA). Arteriography is still the best method of demonstrating pathology in patients with peripheral vascular disease. Transluminal angioplasty, its indications and results are discussed. Patients with suspected renovascular hypertension should be given intravenous DSA and, if pathology is demonstrated, renin sampling as well. Patients with severe, acute, life-threatening hemorrhage may have angiography not only to localize bleeding sites, but also to treat them by transcatheter embolization techniques. Various other angiographic techniques including venous sampling are discussed briefly. PMID- 21267205 TI - Magnetic resonance imaging. AB - Magnetic resonance imaging (MRI) is an important new imaging modality just arriving on the clinical scene in Canada. MRI uses no ionizing radiation; images are derived from the interaction of hydrogen nuclei, a powerful magnetic field, and radio waves. Images are displayed as tomographic slices, much like CT. Direct transverse, sagittal, coronal or oblique slices can be obtained. Unlike CT, the MRI image does not reflect varying tissue densities. In MRI, tissues are differentiated by variation in the amount of hydrogen they contain and by differences in the magnetic environment at a molecular level. All parts of the body can be examined with MRI, although the CNS is particularly well visualized. In addition to providing high resolution images, MRI has the potential for performing non-invasive angiography and biochemical analysis through spectroscopy. To date, there are no known harmful effects of MRI. PMID- 21267206 TI - Cigaret smoking and lifestyle modification: patients' views on physicians' roles. AB - Six hundred and twenty-eight patients completed a Health Habits Questionnaire in family practice waiting rooms. The questions covered lifestyle and health habits, how to improve health, and what the family physician could do to help. Current smokers believed they should quit smoking, and some thought the physician could help by providing advice and encouragement. Physicians should continue to educate their patients about the health risks of smoking, to advise patients repeatedly, if necessary, to quit and to reinforce abstinence on a continuing basis. More research is needed, however, to assess the effectiveness of these recommendations in relation to long-term abstinence from cigarets. PMID- 21267207 TI - The therapeutic use of local heat and cold. AB - Thermotherapy and cryotherapy are often valuable in the treatment of pain, inflammation and muscle spasm. Safe use of available modalities depends on specific knowledge of their contraindications. The choice of method requires an understanding of the physiological effects of heat and cold. The choice of any individual thermal modality depends on several factors including size of the area to be treated, ease of application, affordability, duration of application and depth of penetration. PMID- 21267208 TI - Screening for hypertension in family practice. AB - Although family doctors may be reasonably effective in screening their patients for hypertension, some patients are missed. We examined the characteristics of patients screened and not screened for hypertension in a teaching family practice. Office visits were sampled during a one-month period. For non hypertensives, the overall rate of patients whose blood pressure was taken was 32%. However 89% of patients had a blood pressure measurement taken on that visit or had had one taken within the past two years. Blood pressure was taken less often in younger patients, patients with acute problems, drop-ins, and patients with orthopedic, dermatologic, traumatic or infectious diseases. PMID- 21267209 TI - Chronic mononucleosis syndrome. AB - Debilitating illness in patients with only vague symptoms and minimal findings from physical examination and routine laboratory tests is frustrating for both patient and physician. A case of chronic mononucleosis is presented, and the literature describing the clinical and laboratory features of the syndrome is reviewed, with reference to four recent studies. Guidelines for diagnosis are suggested. PMID- 21267210 TI - The Words of the Prophets are Written on the Subway Walls. PMID- 21267211 TI - [Not Available]. PMID- 21267212 TI - Matiere a Discussion. PMID- 21267213 TI - Manpower study, 1986. PMID- 21267214 TI - Dealing with difficult demands from patients. PMID- 21267215 TI - Management of low-back pain. PMID- 21267216 TI - Consent to treatment of the adolescent patient. AB - Patient consent to medical treatment plays a significant role in doctor-patient interactions. A physician cannot examine or treat a patient unless the patient, or someone who is legally responsible for the patient, has given permission. A patient's consent is valid only if the patient is able to understand what is being proposed and the associated risks and available alternatives. A family physician may face a dilemma when dealing with a patient who is a minor, and whose parent or guardian cannot or will not consent to medical treatment on behalf of the patient, or a patient who prohibits the family physician from involving an adult who is legally responsible for him/her. Decisions that relate to certain aspects of treating adolescents, especially the provision of contraceptive advice, must be made carefully, bearing in mind the patient's ability to understand the medical and social or moral issues involved. PMID- 21267217 TI - The dillman total design survey method. AB - The Total Design Method (TDM) as offered by D.A. Dillman promises "guaranteed" 80% return rates for mail and telephone surveys. In a survey conducted in London, Ontario, a booklet-type questionnaire, introductory letter, return postcard and return stamped envelope were mailed to 185 family physicians. Non-responders were followed up one week after the initial mail-out with a reminder postcard, and three and seven weeks after the initial mail-out with replacement questionnaires. A return rate of 92.8% proved that the method was highly successful. The TDM is based on sound research principles and confirms that when attention is paid to administrative detail, high response rates can be achieved from difficult subjects. PMID- 21267218 TI - Enhancing adolescent compliance with medical regimens. AB - Factors influencing compliance with medical regimens among adolescents have been the subject of few studies. Much current knowledge is either the product of conventional wisdom or the subject of debate. Direct and indirect methods are available to measure compliance. Models used to study patient compliance include the individualistic model, the health-belief model, and the physician-patient relationship model. This article itemizes a host of characteristics influencing poor compliance and describes a series of interventions to enhance compliance. Overall, it is important that the physician assess the adolescent's level of psychosocial development and the environmental factors that can influence compliance. PMID- 21267219 TI - Common problems of adolescents encountered in schools. AB - Some adolescents present in school with problems of poor academic performance and unacceptable behaviour. A physician's evaluation of such a problem requires a careful history and consideration of emotional factors. A neuro-developmental assessment should reveal a pattern of strengths as well as any areas of delay. Management includes demystifying the problem to the student and counselling parents, as well as providing an explanation to the school staff. Stimulant medication, when the primary problem is one of attention-deficit disorder, can be a useful part of the therapeutic program. Long-term follow up, counselling and support are essential. Working within the school gives the counsellor access to teachers and other staff to ensure that understanding of, and help with, the problem continues. PMID- 21267220 TI - Teenage Concerns about the Physical Examination. AB - A study of teenagers' thoughts about doctor/patient relationships revealed a high level of discomfort deriving from the physical examination. Our report attempts to clarify the indications for genital and breast examination and techniques for performing these exams in a manner least distressing to teenagers. PMID- 21267221 TI - Detecting and managing anorexia nervosa and bulimia in adolescents. AB - This paper suggests a diagnostic process for anorexic nervosa and/or bulimia in adolescents. A complete history guided by an understanding of the symptomatology and family conflicts associated with these disorders is the single best tool for their diagnosis. Lengthy investigations are not warranted in most cases. Following an information-giving phase with the patient and her/his family, the treatment plan should be tailored to the patient's individual needs. A biopsychosocial model is suggested consisting of a nutritional rehabilitation program; individual, group and family therapy; and the use of self-help support groups as necessary or available. Working with these patients can be challenging, but rewarding. PMID- 21267222 TI - Assessment of growth problems in adolescents. AB - Investigation of an adolescent growth problem consists of taking an adequate history and doing a complete physical examination. This procedure, along with a calculation of bone age and height/weight age, will allow family physicians to decide on the cause of the growth variance in most patients. Relatively simple studies can be done in the family physician's office to delineate the major causes of growth problems; the majority will be unrelated to the endocrine system. Further studies may be needed in a hospital-based setting. PMID- 21267223 TI - Adolescent athletic injuries: diagnosis and management. AB - Adolescents are becoming involved in athletic activities at an ever-increasing rate, with the result that more adolescents are presenting to the family physician with athletic injuries. The most frequent type of sports injury involves the soft tissues. This paper discusses the diagnosis and management of soft-tissue injuries and identifies some of the behavioural characteristics of the injured adolescent athlete. PMID- 21267224 TI - Adolescent Skin: How to Keep it Healthy. AB - In order to identify and successfully treat the age-specific problems of adolescence, the physician must have knowledge of the physiologic skin changes of adolescence. The physician should provide practical advice on the basics of skin care, including face-washing technique, cosmetic use and sun exposure, since other sources of this information may be misleading. Acne, warts, scabies, tinea versicolor and molluscum contagiosum represent common skin disorders that require an organized treatment strategy. Most teenage patients will comply with even the most complex treatment regimens if reasons for, and mechanisms of, therapy have been adequately explained. PMID- 21267225 TI - Suicide in adolescence. AB - The recent trend in suicide mortality has made it the second-most-common cause of death in adolescence. The recognition of depressed adolescents, especially males, is made difficult by their low utilization of health services and by the variety of modes of presentation. The family physician's ability to play an effective role in helping the depressed adolescent and preventing the occurrence of suicide depends on the establishment of rapport, obtaining a detailed history, and being prepared to offer continuity of care. In most depressed adolescents there is limited need for hospitalization, medication or psychiatric treatment. PMID- 21267226 TI - Treating teens tactfully. AB - Providing medical care for young adults is both demanding and rewarding. Young adults are past the age when congenital defects are lethal or crippling and not yet at the stage where degenerative diseases are clinically significant. Tact, discretion, empathy and humour are necessary to deal with the issues of autonomy, sexuality, urgency and immediacy, privacy and confidentiality, and the inappropriate use of health-care resources which accompany young adults' health care needs. The rewards are the opportunities to practise preventive medicine and exert a beneficial influence on the lifestyles of young people who are going to be society's leaders of the future. PMID- 21267227 TI - Preventing teenage pregnancy: a team approach. AB - By age 16 one in three adolescents have experienced sexual intercourse. Because one-third of these sexually active teens never use contraception, they have a five-times greater risk of pregnancy than teenagers who take contraceptive measures. In 1982, one in 23 Canadian teenage girls became pregnant. Teenagers' reasons for not using contraceptives include fear of parents learning about their sexual activity, lack of knowledge about contraception, and lack of self-esteem. Parents, educators and health-care providers can all play important parts in helping to decrease the incidence of unwanted teenage pregnancy. In the past decade teenage pregnancy rates have dropped. At the same time, more schools have begun to offer sexuality-education classes, and more public clinics have begun to offer teens ready access to information and advice on contraception. PMID- 21267228 TI - A school-based outreach program in adolescent health. AB - Teenagers are often in a medical care vacuum. They avoid institutions and often see the family physician as part of the family setting of which they are striving to achieve independence. This article describes a school-based outreach program which has resulted in the creation of a Teenage Health Unit within a family practice centre. PMID- 21267229 TI - The disabled young adult: ready to leave home? AB - The disabled young adult strives to be independent when preparing to leave home and family. This article provides a checklist that can help the disabled young adult and his/her family to make this transition. In some cases, a transitional rehabilitation program may also be of help. The family physician who is familiar with the issues that pertain to adolescent development can play a central part in addressing patient and family problems that present at this time. PMID- 21267230 TI - Affective disorders (depression and mania) in adolescents. AB - Affective disorders in adolescents are common and can be clearly differentiated from the "growing up process". Basic questions about etiology, pathophysiology, psychobiology and treatment of these disorders remain to be answered. Current knowledge suggests that close co-operation between primary care physicians and psychiatrists with specialized training in adolescent psychiatry is necessary for optimum identification and management of these disorders. PMID- 21267231 TI - Leaving home: crisis and opportunity. AB - "Gaudeamus igitur, juvenes dum sumus!" Young people have not quite completed the developmental tasks of adolescence by the time they leave home to attend university. Geographical separation from family offers an opportunity for learning and personal growth, with the ultimate objective the acquisition of an education in the broadest sense of the word. University life with its peer pressures and academic stresses offers its own challenges and rewards. Unless there is close co-operation between family doctors and student-health physicians, the medical care of young adults degenerates into crisis management with loss of all the benefits of continuity of care. PMID- 21267232 TI - The Child's Eye Examination in Family Practice. AB - In view of the tragic results of undiagnosed and untreated visual problems in childhood, it is important for the family physician to have at her or his disposal a number of simple tests to detect problems at their earliest stages. Visual problems must be sought in the routine childhood physical examination because, unlike adults, children will not draw our attention to them. This article attempts to present several such tests as well as to discuss the mechanism of loss of sight through deprivation of clear visual stimuli, known as amblyopia. Other common childhood ophthalmic problems will also be discussed in the context of the child's eye examination. PMID- 21267233 TI - AIDS: Psychosocial Dimensions. AB - In order to provide comprehensive care to patients who have AIDS, it is important for the family physician to understand the psychosocial elements of the disease. Homosexual men who have AIDS face particular problems, such as the disclosure of sexual orientation to family and friends. Issues discussed in this article include the reactions of the patient, family and friends to the diagnosis, the stigma of AIDS, the patient's support network, and preparations for disability and death. The facts about AIDS are discussed briefly, and the psychosocial implications of the illness for patients and their "significant others" are examined. The role of the family physician is highlighted. PMID- 21267234 TI - An approach to somatization in family medicine. AB - Family physicians frequently encounter patients who somatize psychosocial turmoil. In this article, three cases are presented, and the recognition, classification and management of these often difficult patients are discussed. PMID- 21267235 TI - Reflections on the postgraduate experience. PMID- 21267236 TI - [Not Available]. PMID- 21267237 TI - Chloroquine dose for malaria prevention. PMID- 21267238 TI - Group formed to help brain tumor victims. PMID- 21267239 TI - Discrimination! PMID- 21267240 TI - Causes of Jogger's Toe. PMID- 21267241 TI - What is a Midwife? PMID- 21267242 TI - Baby walkers: 'useless gadgets'. PMID- 21267243 TI - Being an FP: No Apologies! PMID- 21267244 TI - The Editor's Craft. PMID- 21267245 TI - Jet-lagged? Take a pill. PMID- 21267247 TI - Most FPs Against Smoking on Airplanes. PMID- 21267246 TI - Polluted air affects everyone. PMID- 21267248 TI - Social pressure is showing results. PMID- 21267249 TI - First, ban in all public places. PMID- 21267250 TI - All passengers breathe in the air. PMID- 21267252 TI - They'll Smoke In the Washroom. PMID- 21267251 TI - In-flight Movies To Distract Smokers. PMID- 21267253 TI - Ban in all public places. PMID- 21267254 TI - No doubt in their minds. PMID- 21267255 TI - Nonsmokers' rights should come first. PMID- 21267257 TI - Cater to smokers but let them pay. PMID- 21267256 TI - Poor ventilation necessitates ban. PMID- 21267258 TI - Why does 'supermom' feel so guilty? PMID- 21267259 TI - How do sit ups cause backache? PMID- 21267260 TI - Help for the chemically dependent physician: a treatment program and its outcomes. AB - The Donwood Institute in Toronto is a public hospital dedicated to the treatment of chemical dependency. The standard program consists of three phases: detoxification and orientation to the program; active hospital treatment which includes individual, group, and family therapy, relaxation training, nutrition counselling and education; and a continuing education program after discharge. In this study, 125 chemically dependent physicians were treated at the institute. After inpatient treatment, 62% were in remission six months later. Those dependent on alcohol only had the best outcomes (72.5% remission rate), followed by those dependent on drugs only (66.7% remission rate), while the poorest outcome was for those dependent on both alcohol and drugs (48.1% remission rate). The findings of this study are encouraging when compared with other treatment programs for chemically dependent physicians. PMID- 21267261 TI - Referrals and investigation patterns in a family physician group: questions for teaching cost containment. AB - Analysis of laboratory use and referrals within a family practice teaching group showed large differences in physicians' behavior. There were three- to four-fold differences between physicians, both for the number and the costs of laboratory use and X-ray services. There were equally large variations in the types of referrals (to medical, dermatologic, obstetric and gynecologic, surgical, ophthalmological and psychological services). There was no consistent pattern for any physician: that is, if a physician used laboratory investigations often, that physician might seldom use X-ray services or might refer fewer patients to specialists. These results have major implications for teachers and for teaching cost containment. PMID- 21267262 TI - Hemoccult II Screening for Bowel Cancer: Will Family Practice Patients Accept It? AB - Acceptability to patients of Hemoccult II(r) screening for bowel cancer will be a major determinant of whether such screening programs can be successfully implemented. In order to evaluate the screening test's acceptability to patients, compliance rates were assessed in 17 family practices in London, Ontario. Patients' reactions to the test were assessed by both a retrospective questionnaire and a similar prospective questionnaire. Respondents indicated the test's unpleasantness, dietary preparation, and forgetfulness were the most prominent factors associated with non-compliance. The concurrent use of other medications was also identified as a limiting factor. Knowledge of these factors may assist the family physician in improving patients' acceptance of the test. PMID- 21267263 TI - Stress in family practice residents. AB - Sources and levels of stress, as well as coping mechanisms, perceived by residents in both years of a two-year family practice residency program in Toronto are described. In addition, differences between first- and second-year residents, and between women and men residents, regardless of year, are examined. Results of the survey indicate that the levels of stress are relatively high throughout the two years of residency training. The three most stressful aspects of being a resident are time pressures, fatigue, and lack of self-confidence. Female residents appear to report a higher level of stress than males, especially in trying to combine a personal and a professional life. Specific coping mechanisms include talking to others, adjusting attitudes and feelings, or strategic use of time. Recommendations aimed at helping family medicine residency programs deal with the problem of stress in residents are suggested. A current major province-wide research study including all interns and residents in Ontario is described. PMID- 21267264 TI - Doctors' spouses and doctors as spouses. AB - The personal and working lives of physicians and their spouses have changed markedly over the past ten to 15 years. Dual career marriages are now quite common. Spouses often have concerns about their physician spouses' overwork, depression, alcohol and drug use, parenting, difficulty in communicating, sexuality, attitude towards money, and about marital separation. Physicians have similar concerns about their spouses' mood changes and drug use, communication problems, dependency, needs for understanding and affection, and about separation. Marital therapy is an effective, time-efficient, and humane way to treat physicians and their spouses during times of marital distress. PMID- 21267265 TI - Medical manpower projections and proposals: the federal/provincial/territorial report and its implications for family physicians. AB - The Federal/Provincial/Territorial Advisory Committee on Health Manpower has projected a surplus of 4,870 family physicians in Canada by the year 2000. Among the committee's recommendations are proposals to reduce the number of family physicians in the future, and to decrease the undergraduate enrollment in Canadian medical schools by 17%. Too many physicians could lead to excessive costs for the government, and to overservicing, underemployment, low morale, and decreased incomes for physicians themselves. A shortfall in physician supply is easily overcome by opening the doors to immigrant physicians. However, quality of care may be sacrificed. The status and quality of family practice will be directly affected by the action ensuing from the advisory committee's report. PMID- 21267266 TI - Women as doctors, wives, and mothers. AB - The number of women choosing medicine as a career has increased significantly over the last 20 years. However, unlike their male colleagues, married women physicians also carry and seem to expect to carry the major responsibility for household and child care. As a result, they suffer role conflict in trying to be superdocs, superwives, and supermoms, and role strain in combining their multiple roles. More networking among women physicians; seminars for dual career couples; reduced hour training programs for both men and women; paternity as well as maternity leave; effective on-call sharing; housekeeping agencies for professionals; and a crisis hotline for female doctors are suggested as ways to ease their role overload. PMID- 21267267 TI - Physician at Risk Committees Re-evaluated. AB - Physician at risk committees have existed in some provinces for close to a decade. The major concern originally was that addicted physicians denied they suffered from an addictive illness, and so failed to seek treatment. Many provinces, including Manitoba, chose to develop an at risk committee so that an advocacy program was separate from the traditional disciplinary bodies. The rationale for the existence of such advocacy programs and the terms of reference of the physician at risk committees are reexamined in the light of eight years' experience. PMID- 21267268 TI - Continuing medical education and the competent family physician. AB - Several principles of adult education are explored in terms of how they relate to current practices in developing continuing medical education (CME) programs. The key to effective CME is its link with clinical competence. This entails reviewing how individual learning needs are determined, and how these needs are translated into programs. Ultimately, the success of CME depends on evaluating improvements in areas of physician knowledge, skills, and attitudes which will have a positive impact on health care delivery. PMID- 21267269 TI - On retirement of physicians. AB - This article takes a look at retirement in general, and the implications for physicians in particular. The recent application of the principles in the Canadian Charter of Rights has raised some unresolved issues for those doctors with contractual employment. They may no longer have mandatory retirement at age 65. Problems can and do arise when self-employed physicians defer retirement from active practice indefinitely. The evaluation of older physicians' competence is explored, and some suggestions offered. PMID- 21267270 TI - Marriage and medicine: the physician as partner, parent, and person. AB - Physicians are beginning to see the need to heal themselves, and to change the statistics on their morbidity, mortality, and marital distress. Stress for physicians comes from five sources: the nature of the work, their training, their public image, their families, and themselves. Medical school stress as an 'initiation rite' is discussed. Three theoretical frameworks are described which will enable family physicians to take a closer look at their own marriages and families as well as those of patients. A systems orientation will help avoid blame of self or partner or parents; object relations theory clarifies the human tendency to repeat history; a theory connecting self-esteem and communication styles will allow physicians to be more open at work and with their families. The importance of developing priorities and meaningful interests outside medicine is also discussed. PMID- 21267271 TI - Restrain infants, secure kids: a community program to teach parents to buckle up their children. AB - In 1981, the Council on Road Trauma developed an education program for the Hamilton-Wentworth area of Ontario, aimed at groups responsible for patient care and/or education. The program's purpose was to increase use of infants' car restraints. A questionnaire was developed to collect data from women hospitalized at the birth of a baby. The women were questioned about their education on car restraints and whether they had a car seat for the new baby. Of the 723 who completed questionnaires, 90% reported having a car seat. Eighty-three percent of those who attended prenatal classes received information about car safety from their prenatal teachers. Only 18% of the mothers reported that physicians discussed car safety. Judging from the survey results, all prenatal education programs, physicians providing prenatal and pediatric care, and public health nurses should give parents information about all aspects of infant safety. PMID- 21267272 TI - The effects of cultural differences on the physician-patient relationship. AB - Differences between patients' and physicians' perceptions of illness can result in poor communication and unsatisfactory treatment results. These differences are more likely when the patient's cultural background is different from the physician's. This article provides a case history of a cultural conflict between a patient, the patient's family, and the medical care system. The beliefs and practices of people unfamiliar with the North American health care system are discussed, and physicians' assumptions about how patients should behave are explored. Ways of preventing cultural conflict with patients are suggested. PMID- 21267274 TI - What would you have done? An elderly, suicidal patient. PMID- 21267273 TI - Physicians in literature: three portrayals. AB - Literature can provide an objective glimpse of how the public perceives physicians. Physicians have been recipients of the full range of human response in literature, from contempt to veneration. This article examines the impressions of three authors: Mark Twain, Sir Arthur Conan Doyle, and Arthur Hailey. Their descriptions provide insight into the complex relationship physicians have with their colleagues and patients. PMID- 21267275 TI - What can physicians do to help prevent nuclear war? PMID- 21267276 TI - The view from olympus. PMID- 21267277 TI - Paper to Print: Why Does it Take so Long? PMID- 21267278 TI - A pragmatic approach to quitting smoking. PMID- 21267280 TI - Le chelsea physic garden. PMID- 21267279 TI - " La lune est un ballon "? PMID- 21267281 TI - Screening homosexuals: support for dr. Jaczek. PMID- 21267282 TI - Unilac: a canadian infant formula. PMID- 21267283 TI - MRI Technology: Doubts about its Safety. PMID- 21267284 TI - Mnemonics, anyone? PMID- 21267285 TI - How to expedite rehabilitation without jeopardizing litigation. AB - Where litigation and rehabilitation become enmeshed, doctors may have to face problems both complex and stressful. When disabling injuries occur, law and medicine must work together in the best interests of the client/patient. This paper offers specific advice to doctors who are called upon to give evidence concerning the state of health or prognosis of patients involved in litigation arising from disabling injury. PMID- 21267286 TI - Atenolol in the treatment of essential hypertension. AB - In a large, open-label study of 522 patients diagnosed as essential hypertensives, atenolol was both effective and well tolerated. In 392 patients whose blood pressure was measured at the initial visit and after at least four weeks of atenolol therapy, average reductions of 21 mm Hg and 14 mm Hg, were noted in the systolic and diastolic blood pressure respectively. Forty-three patients stopped taking atenolol because of side-effects. The incidence of CNS side-effects was particularly low, and the drug was well tolerated by diabetic patients. Among eight asthmatics who took atenolol, asthma worsened in two. By virtue of its hydrophilicity, cardioselectivity and long half-life, atenolol appears to be a suitable and well-tolerated beta-blocker in the majority of patients. PMID- 21267287 TI - Rehabilitation after myocardial infarction. AB - The family physician plays an important role in rehabilitating a patient following a heart attack. Knowing the factors which influence the prognosis allows the therapeutic regimen to be individualized. Careful medical assessment is required throughout the program, and familiarity with medications to reduce the risk of complications is essential. The patient and his family should be educated to assist the patient to enjoy a lifestyle and attitude which should be healthier than it was before the acute cardiac event. PMID- 21267288 TI - Coronary rehabilitation. AB - This paper describes a team approach to coronary rehabilitation in a tertiary care hospital and the unique role of the family physician in a shared, multi disciplinary service for in- and out-patients. Primary care physicians facilitate and supplement the work of the coronary-unit team in establishing an optimal rehabilitative program for MI patients and their families. PMID- 21267289 TI - Sexual rehabilitation. AB - Sexual rehabilitation begins with an awareness of the potential for sex difficulties following any disruption in health. A thorough sex-functioning history and an exploration of the patient's (and partner's) expectations, limitations and potentials will enable the professional to understand the reasons why sex activity has not resumed after illness, accident or surgery and to offer appropriate therapy. Acceptance, validation, appropriate reassurance, accurate information and specific suggestion: these forms of "sex therapy" fall within the capabilities of every family physician. When applied early in the course of an illness, such interventions will initiate the process of sexual rehabilitation and may well prevent more severe dysfunction. PMID- 21267290 TI - Recovery and rehabilitation after stroke. AB - The incidence of stroke is about 1.5 to 2.5 per 1000 population per year. Stroke is among the commonest diagnoses on the list of yearly bed-days in Canadian hospitals. Recovery after stroke is often a lengthy and complex process in which doctors, nurses, therapists and family members are closely involved, yet little information is available about the use of therapy in stroke rehabilitation. This article discusses the mechanisms of recovery, the natural history of recovery of physical and social function, and the role of rehabilitation in treating acute stroke patients. PMID- 21267291 TI - Management of low-back pain in family practice: a critical review. AB - There is a profusion of both orthodox and unorthodox treatments for low-back pain, many of which have been inadequately evaluated. Conflicting claims exist for nearly all of these treatments. To assess the evidence supporting these commonly used conservative therapies in family practice, a set of methodological criteria for evaluating the validity and usefulness of the results was applied to original articles which described trials of bed rest, exercises, manipulation, drug therapy, advice/education, and other therapies such as traction, corsets and transcutaneous nerve stimulation (TNS). Guidelines for managing acute back pain and acute back pain with sciatica are indicated. Key questions and certain physical signs which suggest a functional overlay in a patient with chronic back pain are also outlined. PMID- 21267292 TI - Rehabilitation of the amateur athlete. AB - A prompt, effective and comprehensive rehabilitation program may often be just as important to the injured amateur athlete as it is to the elite or professional one. By focusing on three representative case files, this author will attempt to give a broader perspective of the psychological and social, as well as the physical, role that sports participation plays in the lives of many of today's athlete patients.Only through our understanding of this phenomenon can we effectively deal with the potentially profound and wide-ranging adverse effects that an injury may have on these patients. PMID- 21267293 TI - Cervical whiplash: considerations in the rehabilitation of cervical myofascial injury. AB - Cervical whiplash, usually the result of impact injuries at high speed, is a typically 20th-century problem. This article describes the biomechanical stresses that result in whiplash and outlines the treatment programs that can be expected to help the patient through the four stages of recovery to achieve functional rehabilitation. PMID- 21267294 TI - Toward a cost/benefit analysis of physical fitness. AB - This article, which is based, in part, on a paper presented to the Canadian Association of Sport Sciences, Quebec City, in November 1985, evaluates the principles of cost/benefit and cost-effectiveness analysis in the specific context of fitness programming. Because of difficulties in valuing all aspects of fitness and health-particularly survival after retirement-cost-effectiveness analysis is generally preferred. Allowance must be made for inflation, the discount rate (except in a "steady state" analysis), marginal costs of program expansion, opportunity costs incurred by participants, the changing fabric of society, the economic multiplication of investment in fitness, and anticipated participation rates. Benefits may be observed by the individual (improved health), the corporation (reduced turnover and absenteeism, increased productivity, fewer injuries), and the state (reduced direct and indirect costs of illness, improved lifestyle, reduced demand for geriatric services). Program costs vary widely with the activity that is undertaken, but even daily walking involves the participant in some expense. Employee programs often cost $500-$750 per participant/year, while, depending on the sport and local speculation by land "developers", community programs may cost $175-$1,000 per participant/year. Cost/effectiveness analyses allow governments to reach informed decisions, but they cannot always answer associated ethical problems such as determining the value of human life, and the rights of the individual as opposed to those of society. PMID- 21267295 TI - Working with the difficult patient. AB - Patients who evoke emotional reactions in the family physician tend to be labelled "difficult". The difficult patient might be one who "yes . . . but" 's every suggestion, or who demands that the physician provide something inappropriate, like drugs or an unjustifiable letter. Whenever such an interaction occurs, the family physician can expect aggravation, frustration and, often, anger, and the results are likely to be unsatisfactory for both doctor and patient. This article describes an approach which will help the doctor to decide what actually to say or do in response to a difficult patient, especially within the time frame of the short office visit. PMID- 21267296 TI - Natural family planning: an update. AB - Natural Family Planning (NFP) is defined by the World Health Organization (WHO) as "methods for planning or avoiding pregnancies by observation of the natural signs and symptoms of the fertile and infertile phase of the menstrual cycle. It is implicit in the definition of natural family planning, when used to avoid conception that drugs, devices and surgical procedures are not used, there is abstinence from sexual intercourse during the fertile phase of the menstrual cycle, and the act of intercourse, when it occurs, is complete."(1) The fertile period may be determined by using Rhythm, a calculation based on previous cycles, basal body temperature (BBT) charting alone, mucus secretion alone (Billings or Ovulation method), or symptothermal charting (Serena method), which includes observation of both mucus and BBT. The effectiveness of each method is discussed, and the social and psychological profile of couples who use NFP is reviewed. Nfp methods can be used not only to avoid pregnancy, but also to achieve pregnancy and thus are particularly useful in investigating and treating infertility. The function of the Family Life Clinic at St. Michael's Hospital in Toronto is described. PMID- 21267297 TI - Common dermatoses of infancy. AB - Within the pediatric population of their practices, family physicians frequently encounter infants with skin rashes. This article discusses several of the more common rashes of infancy: atopic dermatitis, cradle cap, diaper dermatitis and miliaria. Etiology, clinical picture and possible approaches to treatment are presented. PMID- 21267298 TI - A Review of Fatalities Reported as Associated with NSAID Treatment in Ontario. AB - This article reviews reports of 61 deaths associated with non-steroidal anti inflammatory drugs (NSAIDs). These fatalities occurred in Ontario, between February 1, 1981 and January 1, 1986. The average age of these patients at death was 78.6 years, and 59% were female. One or more gastro-intestinal hemorrhages preceded death in 48 patients (79%), and perforation of ulcers with peritonitis and shock were reported in five cases. Other reports indicated that edema and renal failure had occurred in three patients, and bone-marrow depression in another three. The NSAIDs most frequently implicated in these deaths were piroxicam and naproxen, but without data on the numbers of patients taking the various NSAIDs, no conclusions can be drawn about the relative frequencies of severe reactions. PMID- 21267299 TI - Liver disease in the alcoholic. AB - The problem of liver damage in alcoholic patients is widespread. This review discusses hepatic damage on the basis of a histologic classification of increasing severity. In the early stages, or with compensated cirrhosis, clinical and laboratory findings may not accurately reflect hepatic involvement. Furthermore, there exists a group of alcoholic patients in whom liver disease may be caused by factors other than alcohol. Nevertheless, in most patients with liver disease, certain biochemical features help to establish an alcoholic etiology. These features and the use of liver biopsy are discussed, and a practical guideline for diagnosis and follow-up is offered. PMID- 21267300 TI - Quinine-induced thrombocytopenia. AB - Severe drug-induced thrombocytopenia (DIT) is a relatively rare, but potentially lethal, complication of pharmacological therapy. Quinine, a drug commonly used for the treatment of leg cramps, is one of the most frequent causes of DIT. This article reports a case of quinine-induced thrombocytopenia (QIT) and reviews the literature on the subject. PMID- 21267301 TI - Myofascial trigger-point acupuncture in relieving chronic pain after endarterectomy. AB - Acute pain is common following surgery; however, post-operative pain occasionally evolves into chronic pain. If untreated, this pain may become intractable and untreatable. A case of chronic myofascial pain is presented which developed after an endarterectomy was performed, and which was eliminated by using acupuncture in the myofascial trigger points. PMID- 21267303 TI - Something to talk about . . . PMID- 21267302 TI - Obstetric distress signals. PMID- 21267304 TI - [Not Available]. PMID- 21267305 TI - [Not Available]. PMID- 21267306 TI - Congratulations, "family"! PMID- 21267307 TI - Keeping your ear glued . . .? PMID- 21267308 TI - Removing Intra-ocular Foreign Bodies. PMID- 21267309 TI - Fetal surgery. AB - Fetal surgery has come of age. For decades experimental fetal surgery proved essential in studying normal fetal physiology and development, and pathophysiology of congenital defects. Clinical fetal surgery started in the 1960s with intrauterine transfusions. In the 1970s, the advent of ultrasonography revolutionized fetal diagnosis and created a therapeutic vacuum. Fetal treatment, medical and surgical, is slowly trying to fill the gap. Most defects detected are best treated after birth, some requiring a modification in the time, mode and place of delivery for optimal obstetrical and neonatal care. Surgical intervention in utero should be considered for malformations that cause progressive damage to the fetus, leading to death or severe morbidity; that can be corrected or palliated in utero with a reasonable expectation of normal postnatal development; that cannot wait to be corrected after birth, even considering pre-term delivery; that are not accompanied by chromosomal or other major anomalies. At present, congenital hydronephrosis is the most common indication for fetal surgery, followed by obstructive hydrocephalus. Congenital diaphragmatic hernia also fulfills the criteria, but its correction poses more problems, and no clinical attempts have been reported so far. In the future many other malformations or diseases may become best treated in utero. The ethical and moral issues are complex and need to be discussed as clinical and experimental progress is made. PMID- 21267310 TI - Antenatal assessment of the fetus. AB - There is now a complex array of genetic, biochemical, and biophysical parameters to use in our assessment of the unborn. This article reviews these various parameters and discusses the indication for their use, as well as their limitations. PMID- 21267311 TI - The role of standardized risk assessment in the provision of prenatal care. AB - Errors in the provision of prenatal care are more likely to be the result of mental saturation than of inadequacies in the physician's fund of knowledge. To eliminate medical errors the physician should commit more time to the processing of clinical data. There are, however, limits to the physician's ability to handle large amounts of information in a busy clinic. This article outlines the benefits and limitations of risk scoring, and recommends the use of standardized risk assessment as a screening device to detect those pregnancies in need of further investigation or consultation with a specialist. PMID- 21267312 TI - VBAC: Is It Safe for Your Patients? AB - Vaginal birth after caesarean section (VBAC) is being increasingly considered as an alternative to elective repeat section, in order to help reduce overall caesarean rates and achieve improved perinatal outcomes. This review examines the evidence for the safety of VBAC compared to the traditional practice of "Once a caesarean, always a caesarean." It appears that the incidence of uterine rupture is much lower than previously thought (less than 1%), and that the rates of overall fetal and maternal mortality improve with the use of VBAC. A number of associated treatments such as epidural anesthesia and oxytocin use are also examined. PMID- 21267313 TI - The management of labour in the primiparous patient. AB - Dystocia continues to be the leading indication for caesarean birth. The active management of labour as developed in Dublin is one approach that could be applied to the problem. It is not generally appreciated, however, that the word 'active' describes the active involvement of the consultant obstetrician and not medical intervention with oxytocin infusions. In this article, the Dublin protocol is reviewed in broad perspective and is compared to more traditional North American methods of dealing with dysfunctional labour. PMID- 21267314 TI - The case for small rural hospital obstetrics. AB - Small obstetrical units can offer a very competitive quality of service as compared to large centres. They achieved this quality of service by transferring all high-risk deliveries to specialized regional centres with neonatal intensive care facilities (perinatal regionalization). The significant decrease in perinatal mortality over the past 20 years is a result of the superior care of low birth-weight infants, available in these large centres. It is not surprising that some people might project this superior performance to all weight categories. A review of the literature, however, shows that overall, small (level I) hospitals are as safe as larger centres. The authors discuss the means by which small, and often isolated, centres do as well as better equipped and more extensive centres with larger staffs. PMID- 21267315 TI - Referral pattern and rate of intervention in a small rural obstetrical practice. AB - This article describes an obstetrical chart review that covered a seven-year period from April 30, 1978 to March 31, 1984. This review includes both pre- and intra partum transfers and involves two main topics: referral pattern and rate of intervention during labour. The practice was involved in 60% of all pregnancies (344) of the catchment area. Seventeen per cent were transferred in their pre partum period, and 11% were transferred intra partum. The rates of intervention for forceps, induction, episiotomy and analgesia are presented, and they confirm the non-interventionist attitude of general practice obstetricians. PMID- 21267316 TI - Prenatal genetic counselling. AB - Genetic concerns and indications for prenatal diagnosis are first recognized by the family physician. Review of personal, pregnancy and family history may indicate concerns beyond that of advanced maternal age. Amniocentesis is still the most frequently used modality for prenatal diagnosis, but detailed ultrasound is valuable for structural abnormalities, and chorionic villus sampling is now being tested as an alternative to amniocentesis. PMID- 21267317 TI - The use of psychotropic drugs in pregnancy and lactation. AB - The decision to use drugs during pregnancy can be complicated by many factors. The concerns of congenital malformation, the effects of drugs during labour, withdrawal effects on the newborn, and the exposure of the breast-fed newborn to drugs are some of the issues every physician is faced with when treating a pregnant woman. Drugs should be used during pregnancy only in situations where anticipated benefits far outweigh the possible risks. Approximately 20%-30% of women of childbearing age reportedly use antidepressants. It is absolutely essential that physicians know the effects of psychotropics on pregnancy and lactation before they issue a prescription. In this paper I have reviewed the effects of different classes of psychotropics on women during pregnancy and lactation. PMID- 21267318 TI - The Family Physician's Role in Preventing Early Termination of Breastfeeding. AB - Despite the high rate of breastfeeding among mothers as they leave the hospital, early termination of breastfeeding continues to be a problem. A new mother needs considerable education, support and, often, early intervention, not only to initiate breastfeeding successfully, but also to prevent breastfeeding problems occurring and to continue breastfeeding successfully for several months. Knowledgeable health-care providers are the key to promoting and protecting breastfeeding, yet in the community, many of these mothers, lacking the support of such knowledgeable advisers, often terminate early. Family physicians are in a key position to help the nursing dyad. This article looks at the role that family physicians can play in advising and helping mothers, and discusses the management of common breastfeeding difficulties. PMID- 21267319 TI - Management of post-Date Pregnancy. AB - The problems of prolonged gestation place the modern obstetrical care giver in a delicate situation between increasing consumer pressures for non-interventionist approaches to obstetrical care and more active management with the potential pitfalls of failed induction, caesarean section, and other hazards. This paper will briefly discuss the definition, etiology and pathophysiology of prolonged gestation, but will focus on appropriate use of antepartum monitoring methods with the determination of fetal well-being, and methods of labour induction as well as intrapartum management. PMID- 21267320 TI - Sexuality during and after Pregnancy. AB - Most standard obstetrical and gynecological textbooks ignore the subject of sexuality during and after pregnancy, and physicians who practise obstetrics tend to pay scant attention to this aspect of their patients' well-being. Since 1966, when Masters and Johnson's studies were published, relatively little information about pregnancy and sexuality has appeared in the medical literature. A comprehensive survey of the feelings and opinions of some 300 couples, published in 1977, indicates patients' desire and need to discuss sexual concerns with their doctor during and after pregnancy. This article summarizes the relevant literature and discusses the author's own experience of counselling his maternity patients. It also addresses problems which may develop in the marital relationship when a baby enters the pre-existing marital dyad. PMID- 21267321 TI - A Family Physician's Approach to the Obstetric Patient. AB - This article describes a record for the physician to use for patients during pregnancy and the post-partum period. This record was designed to supplement the prenatal records in general use. Its purpose was to assist the family physician both to obtain relevant information and also to provide consistent and appropriate counselling to all pregnant patients. PMID- 21267322 TI - Childbirth Education: A Consumer's Viewpoint. AB - This article describes a series of classes for expectant parents and siblings and outlines how differences of opinion by health-care providers in the perinatal period can adversely affect a mother's undertsanding of, and satisfaction with, the birth process. It comments on concepts that family physicians should consider before suggesting prenatal classes to their patients. Family physicians must know what is being taught in prenatal classes, either directly through dialogue with the instructors or indirectly through conversation with their patients. There should be open dialogue between family physicians, expectant couples and childbirth educators in order to ensure supportive co-operation among all parties. Such co-operation will lead to maximum satisfaction with the experience of childbirth. PMID- 21267323 TI - Case studies in electronic fetal heart rate monitoring. AB - Subtle changes in the characteristics of the fetal heart rate are currently used to assess the condition of the fetus in late pregnancy and during labour. The authors present three case studies of fetal heart rate monitoring. PMID- 21267324 TI - Work and reproduction. AB - This article presents a short overview of the area of work effects on reproduction. Much speculation and confusion exist in this area of the relationship between the physical and social effects of work and the health of the elements of reproduction. Fulfilling the need for increased resources for research in this challenging and interesting area is most desirable. PMID- 21267325 TI - A library for family physicians. PMID- 21267326 TI - PCBs and the Family Physician. AB - Pcbs are widespread environmental contaminants present in virtually every mammal on earth. Great controversy and debate has been evoked over the past two decades concerning their potential toxicity. They, along with other organochlorine compounds such as DDT, have been reasonably well studied in field and experimental situations.In general, PCBs are not very toxic, especially in concentrations to which most people are exposed, even those who work in the industrial setting or who eat contaminated fish. In terms of environmental hazards to health, PCBs should be considered as relatively low on the list. The public cannot depend on media information as a source of objective knowledge on controversial compounds like PCBs. The family physician should be able to provide to concerned individuals objective information on the definition, sources and relative toxicity of PCBs. PMID- 21267327 TI - Maternal Phenylketonuria (MPKU). AB - Untreated maternal phenylketonuria (MPKU) is a major cause of microcephaly, congenital heart disease, intrauterine growth retardation and mental retardation in the offspring of mothers who have the disease. There is evidence, however, that dietary restriction of phenylalanine in the mother before conception and throughout the pregnancy will reduce the risk of these congenital anomalies in the fetus. It is important to be alert to this preventable cause of developmental retardation and congenital abnormalities in all pregnancies until the stage is reached where every woman of child-bearing age has been through the neonatal PKU screening program. Family physicians are advised to consider prenatal or premarital screening for PKU of all female patients of child-bearing age for the next generation. PMID- 21267328 TI - The challenge of teaching obstetrics to family practice residents. AB - Physicians who incorporate maternity care into family practice experience an increase in job satisfaction and enjoy a more favourable practice profile. Yet many family physicians are opting out of the obstetrical care of their patients. This development presents a major challenge to the teachers of family medicine. In many teaching programs the response of staff has been to move significant portions of residency training in obstetrics to smaller community hospitals. At Mount Sinai Hospital in Toronto, we believe that an integrated program in the tertiary care centre offers definite advantages. Our obstetrical training program integrates four elements: the community, the hospital, the Department of Family and Community Medicine, and the training program offered by that Department. We expect that family practice residents, by participating in this multifaceted, integrated program, will make a better-informed choice about practising obstetrics. PMID- 21267329 TI - Prevention: beliefs and behaviour. PMID- 21267331 TI - The problem of pain. PMID- 21267330 TI - The pitfalls of prevention. PMID- 21267332 TI - "Primary care" or "family practice". PMID- 21267333 TI - [Not Available]. PMID- 21267334 TI - [Not Available]. PMID- 21267335 TI - Cow's Milk and Breast-Milk Substitutes. PMID- 21267337 TI - A medical education survey. PMID- 21267336 TI - The future of family practice. PMID- 21267338 TI - The "living will": legal background and effects. AB - Living wills are made by those who wish to resist terminal care that involves use of mechanical means and other invasive life-sustaining treatments. This article reviews the legal right to natural death and the extent to which living wills can be legally effective. It considers the limitations of living wills and alternatives such as Natural Death Acts and "durable" powers of attorney. PMID- 21267339 TI - Family physicians' perspective of patient care at the london regional cancer clinic. AB - This article describes a survey of the opinions of family physicians practising in the London, Ontario, area concerning the management of doctor/patient relationships and patient treatment in cases referred by family physicians to the London Regional Cancer Clinic. Findings clearly identified a need for better communication between Clinic staff and referring family physicians, greater continuity of care for patients at the clinic, continuing family physician support of patients during periods of hospitalization at the Clinic, and some administrative adjustments in Clinic routines that would reduce patient stress and discomfort and improve morale. PMID- 21267340 TI - Survey of Physicians' Attitudes to the Haemophilus Influenzae Type-b Vaccine. AB - A survey was conducted in nine centres across Canada to determine the attitudes of Canadian physicians to the recommended Haemophilus Influenzae type-b vaccine program. The questionnaire was distributed to 448 family physicians and 315 pediatricians, with response rates of 42% and 64% respectively. Only 42% of the family physicians and 57% of the primary care pediatricians expressed their intent to recommend the vaccine to all indicated patients. Their responses emphasize the need for: appropriately packaged material (in single-dose vials); government funding to ensure universal patient accessibility and to relieve physicians of an unwelcome financial burden; development of a Haemophilus influenzae type-b vaccine suitable for the major target population (i.e., children under 24 months old); and public health education. An effective Haemophilus influenzae type-b immunization program will be seen only when these goals are met. PMID- 21267341 TI - Early detection of child abuse. AB - Child abuse, neglect and deprivation are more common than was previously thought. Family physicians are in a unique position to help abusers and abused because of their knowledge of patients from the cradle to the grave. They should use this knowledge to observe clues about parenting potential and should make a thorough family history a routine part of history taking in potential parents. They should also observe patients carefully during pregnancy and early childhood to detect parenting problems and to try to prevent all types of abuse, physical, mental and sexual. PMID- 21267342 TI - Rubella screening and immunization: its history and future-an ongoing challenge. AB - The Congenital Rubella Syndrome (CRS) continues to be a serious threat to the unborn child, since a significant number of women of childbearing age are susceptible to rubella. Vaccines and immunization programs, since their inception, have given us a false sense of security in our assumption that they have provided adequate protection. The ultimate purpose of immunization is the eradication of CRS; but to achieve this, an understanding of the evolution of vaccines and immunization programs is essential, in order to provide appropriate immunization today.This paper provides a review of rubella vaccines; immunization programs; current recommendations for screening and immunization; and the report of a five-year surveillance study of women of childbearing age, which found 17% of the subjects to be susceptible to rubella. PMID- 21267343 TI - Motor vehicle trauma: an unnecessary disease. AB - The motor vehicle accident kills and maims more of our young people than any other affliction. Yet prevention of injuries and deaths from MVA receives less emphasis in medical education, medical publications and collective political action than the problem merits. In daily practice, there are numerous opportunities for prevention counselling, alcoholic driver case finding, and critical assessment of the privilege of driving. Within their community, family physicians can have input into some preventive programs. At government level, physicians should increase their pressure for legislative action to reduce MVA injuries and deaths. PMID- 21267344 TI - Man's Closest Companions. AB - THE AUTHORS DESCRIBE FOUR COMMON PARASITES THAT INFEST HUMANS: the head louse, the pubic louse, and the body louse, as well as the human mite. They review the life cycle of these insects, advise on diagnosis of an infestation, and recommend various types of treatment for their human hosts that will put an end to these unwelcome pests. PMID- 21267345 TI - The pap smear and cervical cancer screening. AB - While the effectiveness of cervical cancer-screening programs is well accepted, further decreases in incidence and mortality rates of cervical cancer may require a changing role for the family physician. Especially important will be the use of computerized call-recall systems to ensure that all eligible women are screened at least once, and that appropriate follow-up is made for those with positive test results. Since concern is growing over false negative results, it will also be important to ensure that the Pap smear is done adequately. PMID- 21267346 TI - Immunization: primary prevention par excellence. AB - Immunizing agents and vaccination programs have had a major impact on the health and longevity of our population. The continuation of established programs and the introduction of new programs will undoubtedly remain an integral part of our primary prevention activities. Decisions on the universal need for earlier immunizing agents were relatively straightforward, since most were directed at agents which were extremely communicable, and all were active against agents to which the population was fairly uniformly exposed. Because several of the "newer" vaccines do not meet these criteria, decisions on their use must be reviewed and may need to be based on other criteria. All decisions must take into account the risks and benefits of the vaccines. It must also be accepted that not all beneficial vaccines will necessarily become a part of universal immunization programs. PMID- 21267347 TI - Perspectives on the prevention of anorexia nervosa and bulimia. AB - Ample evidence suggests a rising incidence of anorexia nervosa and bulimia over the past few decades. Correspondingly, medical knowledge about the etiology, symptomatology and treatment of these eating disorders has increased. Often the front line health-care workers who treat these disorders, family physicians are in a key position for early detection and prevention of these eating disorders. An adequate understanding of relevant risk factors, symptoms and signs may allow the physician to prevent the onset of an eating disorder in some patients or to minimize the severity of the illness in others. PMID- 21267348 TI - Osteoporosis: prevention and management strategies. AB - Osteoporosis is a major cause of morbidity in post-menopausal women. Strategies to prevent or delay bone loss in normal post-menopausal women and to reduce the risk of fractures in women with osteoporosis are within the scope of family practice. Certain factors, such as inadequate calcium intake, estrogen deficiency, cigarette smoking and lack of physical activity can be modified in peri- and post-menopausal women. For patients with osteoporosis, there is potential for lowering the risk of fractures by means of calcium supplements or other therapies, physical training and rehabilitation, and modification of factors associated with risk of falling. PMID- 21267349 TI - Geriatric Medicine in the United Kingdom: Lessons to be Learned. AB - Geriatrics in the United Kingdom, through its long history, has created an integrated and co-ordinated system through the development of solid home-care organization centred around the family doctor, and of available and efficient specialized geriatric services based in the geriatric unit. Even if we might not wish to transpose the British system to our country, the lessons to be learned from that system can help to stimulate the debate on the organization of geriatric services in Canada. PMID- 21267350 TI - Transforming Theory into Preventive Genetics in rural Communities. AB - Family physicians are at the frontier in health promotion. They have opportunity to identify many familial genetic risks prior to health crises. Early diagnosis allows time to discuss choices: schedules for screening, change of diet, preventive drug treatment, and/or reproductive alternatives. Investigation of risk is less time consuming when families already have a general awareness of how genetic disease is inherited. In geographic areas underserved by genetics clinic staff, we are using CEIC job-development monies to train laypeople to organize community workshops on health and "family trees". Family physicians, together with informed laypeople, succeed in transforming genetic theory into practice. PMID- 21267351 TI - Eco-maps: a systems tool for family physicians. AB - Family physicians are often faced with multi-factorial problems which are difficult to understand and document. Patients are not isolated beings; rather, they are participants in environmental systems. Recognizing this, the assessment of patients using a linear reductionist approach is limiting and incomplete. A systems approach, on the other hand, is congruent with the dynamic nature of the individual and the task. The Eco-map is a pictorial representation of the elements of a patient's environment and of the nature and quality of the interactions between those elements. Examples of the construction and usefulness of Eco-maps are given. PMID- 21267352 TI - Advising your elderly patients concerning safe exercising. AB - With the emergence of physical activity programs geared specifically to senior citizens, family physicians will increasingly be called on to provide advice or approval concerning their patients' suitability for participation. In addition, family physicians have been identified as having a key role to play in the promotion of exercise for sedentary older adults. To assist the family practitioner in advising elderly patients concerning safe exercise patterns, this article discusses the documented benefits, as well as the medical considerations, associated with exercising for this target group. PMID- 21267353 TI - "... As my own brothers...". AB - The author describes the aftermath of a serious motor vehicle accident in which her husband, a family practitioner, sustained a life-threatening brain injury just over two years ago. The period of rehabilitation was long and painful for everyone involved, and made the more distressing by lack of a rehabilitative program for profoundly injured physicians who wish to return to practice. The author argues strongly that it is the obligation of the medical profession to implement the promises of the Hippocratic Oath by developing such a protocol. PMID- 21267354 TI - An approach to limiting the adverse effects of therapy for hypertension in the elderly. AB - This paper raises questions pertaining to the possible benefits and undesirable side-effects of drug treatment for high blood pressure in the elderly. The importance of careful monitoring of elderly patients on hypotensive medication is emphasized, and recent findings in this area of treatment are reviewed. Decisions about the use of hypotensive medication in the elderly patient should be made jointly by a knowledgeable physician and an informed patient. PMID- 21267355 TI - The use of lorcaserin in the management of obesity: a critical appraisal. AB - Obesity is a chronic disease with a high prevalence in both developed and developing countries. Effective management of this worldwide epidemic will have a significant impact on the health care system globally. Lifestyle interventions, such as restricting calorie consumption and increasing physical activity, remain a major component of weight-reduction programs. The development of pharmacotherapy for the management of obesity is still at the infancy stage. Side effects have been the key issue for anti-obesity drugs previously withdrawn from the market. The focus of this review, lorcaserin, is a selective serotonin receptor agonist that is currently undergoing Phase III evaluations. The efficacy of this drug in reducing body weight and improving metabolic parameters of obese patients has been demonstrated in two recent clinical trials. The available evidence indicates that this drug does not show unwanted effects on heart valves or pulmonary artery pressure, and the treatment improves the risk factors for type 2 diabetes and cardiovascular diseases. Despite these promising results, additional experimental and clinical studies are critical for the approval of lorcaserin as a new anti-obesity monodrug therapy by the US Food and Drug Administration. PMID- 21267357 TI - Dronedarone: current evidence for its safety and efficacy in the management of atrial fibrillation. AB - Atrial fibrillation (AF) is the most common sustained arrhythmia. Management of AF includes rate control, rhythm control if necessary, prevention of thromboembolic events, and treatment of the underlying disease. Rate control is usually achieved by pharmacological suppression of calcium currents or by applying beta-blockers or digitalis compounds. In contrast, the number of compounds available for rhythm control is still limited. Class Ic agents increase mortality in patients with structural heart disease, and amiodarone harbors an extensive side effect profile despite its efficacy in maintaining sinus rhythm. Furthermore, rhythm control by these compounds has not been shown to reduce patient mortality. Dronedarone is a new anti-arrhythmic drug that has been developed to provide rhythm and rate control in AF patients with fewer side effects compared with amiodarone. This review primarily focuses on clinical trials evaluating efficacy and safety of the novel drug. Conclusions from these studies are critically reviewed, and recommendations for clinical practice are discussed. Dronedarone significantly reduced the incidence of hospitalization due to cardiovascular events or death in high-risk patients with atrial fibrillation (ATHENA trial). However, dronedarone was less efficient than amiodarone in maintaining normal sinus rhythm (DIONYSOS trial) and is contraindicated in severe or deteriorating heart failure (ANDROMEDA trial). In summary, dronedarone represents a valuable addition to the limited spectrum of antiarrhythmic drugs and is currently recommended in patients with paroxysmal and persistent AF to achieve rate and rhythm control, excluding cases of severe or unstable congestive heart failure. PMID- 21267356 TI - Current progress in the development of a prophylactic vaccine for HIV-1. AB - Since its discovery and characterization in the early 1980s as a virus that attacks the immune system, there has been some success for the treatment of human immunodeficiency virus-1 (HIV-1) infection. However, due to the overwhelming public health impact of this virus, a vaccine is needed urgently. Despite the tireless efforts of scientist and clinicians, there is still no safe and effective vaccine that provides sterilizing immunity. A vaccine that provides sterilizing immunity against HIV infection remains elusive in part due to the following reasons: 1) degree of diversity of the virus, 2) ability of the virus to evade the hosts' immunity, and 3) lack of appropriate animal models in which to test vaccine candidates. There have been several attempts to stimulate the immune system to provide protection against HIV-infection. Here, we will discuss attempts that have been made to induce sterilizing immunity, including traditional vaccination attempts, induction of broadly neutralizing antibody production, DNA vaccines, and use of viral vectors. Some of these attempts show promise pending continued research efforts. PMID- 21267358 TI - Comparative assessment of biologics in treatment of psoriasis: drug design and clinical effectiveness of ustekinumab. AB - The development of psoriasis and psoriatic arthritis is a multistep process that leads to chronic or recurrent inflammation. Recent studies have suggested the importance of T helper (TH)1 and TH17 cells, accessory cells, and proinflammatory cytokines in the pathogenesis of the enthesis, synovium, and skin involvement in psoriasis in the presence of susceptibility genes that remain quiescent until triggered. Biologics, such as soluble CTLA-4 immunoglobulin, tumor necrosis factor (TNF) inhibitors, and ustekinumab, inhibit T cell activation which eventually leads to further stimulation of the interleukin 12, 17, and 23 axis, TNF-alpha, and lymphotoxin-alpha. Treatment with TNF-alpha blockers has been effective in refractory psoriasis and psoriatic arthritis, but there is still a subgroup of patients who do not respond to TNF inhibitors and, paradoxically, when treated, may develop TNF-induced psoriasis. Ustekinumab, because of its different mechanism of action at the level of the interleukin 12, 17, and 23 pathways, is an alternative treatment for this group of patients. PMID- 21267360 TI - Work, family or personal life: Why not all three? PMID- 21267361 TI - Old-age insecurity: How far does the "Parents and Senior Citizen's Act of 2007" address the problem? PMID- 21267359 TI - Drug-induced psychosis: how to avoid star gazing in schizophrenia research by looking at more obvious sources of light. AB - The prevalent view today is that schizophrenia is a syndrome rather than a specific disease. Liability to schizophrenia is highly heritable. It appears that multiple genetic and environmental factors operate together to push individuals over a threshold into expressing the characteristic clinical picture. One environmental factor which has been curiously neglected is the evidence that certain drugs can induce schizophrenia-like psychosis. In the last 60 years, improved understanding of the relationship between drug abuse and psychosis has contributed substantially to our modern view of the disorder suggesting that liability to psychosis in general, and to schizophrenia in particular, is distributed trough the general population in a similar continuous way to liability to medical disorders such as hypertension and diabetes. In this review we examine the main hypotheses resulting from the link observed between the most common psychotomimetic drugs (lysergic acid diethylamide, amphetamines, cannabis, phencyclidine) and schizophrenia. PMID- 21267362 TI - Biological basis of tobacco addiction: Implications for smoking-cessation treatment. AB - Tobacco use became common all over the world after discovery of Americas. Tobacco, a plant carries in its leaves an alkaloid called nicotine, which is responsible not only for several pathophysiological changes in the body but also develops tolerance to its own action with repeated use. Studies suggest that the alpha-4 beta-2 nicotine acetylcholine receptor subtype is the main receptor that mediates nicotine dependence. Nicotine acts on these receptors to facilitate neurotransmitter release (dopamine and others), producing pleasure and mood modulation. Repeated exposure to nicotine develops neuroadaptation of the receptors, resulting in tolerance to many of the effects of nicotine. Withdrawal symptoms appear on stoppage of tobacco use, which are characterized by irritability, anxiety, increased eating, dysphoria, and hedonic dysregulation, among others. Smoking is also reinforced by conditioning. Pharmacotherapies for smoking cessation should reduce withdrawal symptoms and block the reinforcing effects of nicotine obtained from smoking without causing excessive adverse effects. PMID- 21267364 TI - The Global Mental Health Assessment Tool-validation in Hindi: A validity and feasibility study. AB - BACKGROUND: A computer-assisted interview, the Global Mental Health Assessment Tool-validation (GMHAT/PC) has been developed to assist general practitioners and other health professionals to make a quick, convenient, yet reasonably comprehensive standardized mental health assessment. GMHAT/PC has been translated into various languages including Hindi. This is the first study conducted in India, using the Hindi version GMHAT/PC of the series of studies assessing its validity in different cultures. AIM: The study aims to assess the feasibility of using a computer assisted diagnostic interview by health professionals and to examine the level of agreement between the Hindi version GMHAT/PC diagnosis and psychiatrists' ICD-10 based clinical diagnosis. DESIGN: Cross-sectional validation study. SETTING: Psychiatric clinic of a General Hospital and an out patient (Neurology) clinic in the Teaching General Hospital in Jaipur, India. MATERIALS AND METHODS: All consecutive patients attending the psychiatric out patient clinic were interviewed using GMHAT/PC and psychiatrists made a diagnosis applying ICD-10 criteria for a period of six weeks. A small sample of subjects was interviewed in a similar way in a Neurology clinic for four weeks. RESULTS: The mean duration of interview was under 17 minutes. Most patients were pleased that they were asked about every aspect of their mental health. The agreement between psychologists' GMHAT/PC interview diagnoses and psychiatrists' clinical diagnoses was excellent (Kappa 0.96, sensitivity 1.00, and specificity 0.94). CONCLUSION: GMHAT/PC Hindi version detected mental disorders accurately and it was feasible to use GMHAT/PC in Indian settings. PMID- 21267363 TI - A functional Magnetic Resonance Imaging study of neurohemodynamic abnormalities during emotion processing in subjects at high risk for schizophrenia. AB - BACKGROUND: Emotion processing abnormalities are considered among the core deficits in schizophrenia. Subjects at high risk (HR) for schizophrenia also show these deficits. Structural neuroimaging studies examining unaffected relatives at high risk for schizophrenia have demonstrated neuroanatomical abnormalities involving neo-cortical and sub-cortical brain regions related to emotion processing. The brain functional correlates of emotion processing in these HR subjects in the context of ecologically valid, real-life dynamic images using functional Magnetic Resonance Imaging (fMRI) has not been examined previously. AIM: To examine the neurohemodynamic abnormalities during emotion processing in unaffected subjects at high risk for schizophrenia in comparison with age-, sex-, handedness- and education-matched healthy controls, using fMRI. MATERIALS AND METHODS: HR subjects for schizophrenia (n=17) and matched healthy controls (n=16) were examined. The emotion processing of fearful facial expression was examined using a culturally appropriate and valid tool for Indian subjects. The fMRI was performed in a 1.5-T scanner during an implicit emotion processing paradigm. The fMRI analyses were performed using the Statistical Parametric Mapping 2 (SPM2) software. RESULTS: HR subjects had significantly reduced brain activations in left insula, left medial frontal gyrus, left inferior frontal gyrus, right cingulate gyrus, right precentral gyrus and right inferior parietal lobule. Hypothesis-driven region-of-interest analysis revealed hypoactivation of right amygdala in HR subjects. CONCLUSIONS: Study findings suggest that neurohemodynamic abnormalities involving limbic and frontal cortices could be potential indicators for increased vulnerability toward schizophrenia. The clinical utility of these novel findings in predicting the development of psychosis needs to be evaluated. PMID- 21267365 TI - Predictors of long-term outcome of first-episode schizophrenia: A ten-year follow up study. AB - OBJECTIVE: Schizophrenia is a severe mental disorder for which final outcomes continue to be unfavorable. The main objectives of this research were to examine and determine the baseline predictors of outcome status of first-episode schizophrenia in a long-term follow-up of ten years and of recovery ten years later. MATERIALS AND METHODS: The study was carried out in a non-governmental, psychiatric hospital and participants consisted of patients available for assessment ten years following their initial diagnosis. Outcome was assessed on clinical and social parameters. Clinical measures of outcome included psychopathology, hospitalization, and suicidality. Social parameters included quality of life functioning, employability, interpersonal functioning, and the ability to live independently. RESULTS: In our sample, mean positive symptoms' score were reduced by more than 65% between baseline and endpoint. The percentage of reduction in scores of negative symptoms is much less than reduction in positive symptoms. It was observed that only 23-25% patients showed social recovery on two or three different parameters. Additionally, fewer negative symptoms, lower depression scores, and low levels of aggression at baseline predicted good outcome. A higher level of positive symptoms at baseline also predicted recovery. The two social variables that predicted later outcomes were initially high levels of work performance and the ability to live independently at baseline. CONCLUSIONS: Clinical information is not sufficient to make an accurate prediction of outcome status; rather, outcome depends upon multiple factors (including social parameters). A major implication of this research is the argument for moving toward a comprehensive assessment of outcome and to plan management accordingly. Bringing social outcome measures to the forefront and into the communities will allow for a more patient-centric approach. It also opens newer vistas for addressing the complex interaction of clinical and social parameters. PMID- 21267366 TI - Psychiatric morbidity in outpatients of gynecological oncology clinic in a tertiary care hospital. AB - BACKGROUND: Psychiatric morbidity in gynecological oncology patients is relatively less studied. AIMS: This cross-sectional observational study was undertaken to assess the common psychiatric disorders in women who consult the gynecological oncology outpatients' department. MATERIALS AND METHODS: We assessed a total of 101 outpatients who were recruited by convenience method of sampling. The main outcome measures were PRIME-MD PHQ diagnoses, gynecological and sociodemographic profiles. RESULTS: Psychiatric disorders as detected by PRIME -MD PHQ were diagnosed in 44% of the patients. Mood disorders were most common. Major depression was present in 25.7% of patients. Anxiety disorders were diagnosed in 16.8% of the patients. Among 44 patients with a psychiatric diagnosis only one patient was on psychiatric treatment. Major depression was much more common (34.4%) in cancer patients than in women with benign conditions (16.6%). CONCLUSION: The findings of our study reveal a high rate of psychiatric morbidity in the gynecological oncology outpatients. PMID- 21267367 TI - Pathway of care among psychiatric patients attending a mental health institution in central India. AB - INTRODUCTION: Only a limited proportion of patients with psychiatric disorders attend the healthcare facilities, and that too when the condition becomes severe. Treatment from unqualified medical practitioners and faith healers is a common practice, and is attributable to the delay in proper treatment. MATERIALS AND METHODS: A cross-sectional study was conducted to understand the pathway of care adopted by psychiatric patients and its relationship with the socio-demographic determinants in the study population. The subjects were selected from urban specialty psychiatric hospitals and interviewed using a pre-tested, semi structured interview schedule. The data was analyzed using SPSS v10.0 software. The Chi square test, T test, and Kruskall Wallis Test were used, as needed. RESULTS: A total of 295 patients (203 males) were included in this study. The majority of the patients (45%) were suffering from Bipolar affective disorders (45%), followed by schizophrenia (36%). The majority, 203 (68%), were from the rural area, with 94 patients being illiterate. The mean distance traveled for treatment was 249 km. The majority of these (69%) had first contacted faith healers and a qualified psychiatrist was the first contacted person for only 9.2% of the patients. CONCLUSION: A large proportion of psychiatric patients do not attend any health facility due to a lack of awareness about treatment services, the distance, and due to the fear of the stigma associated with treatment. The psychiatric patients first seek the help of various sources prior to attending a psychiatric health facility. The pathway adopted by these patients need to be kept in mind at the time of preparation of the mental health program. PMID- 21267368 TI - Problem alcohol drinking in rural women of Telangana region, Andhra Pradesh. AB - BACKGROUND: This is the first ever study conducted to assess the prevalence of problem alcohol use in the rural women of Telangana region of Andhra Pradesh. AIMS: To evaluate the prevalence of dependence and problem drinking, observe the factors that led to it and to monitor the effect of intervention in the form of psycho-education on their treatment seeking attitude. MATERIALS AND METHODS: Cases were referred by the registrar from the Medicine Out-Patient Department using a three-item questionnaire for history of alcohol intake. Consecutive consenting female patients fulfilling the inclusion-exclusion criteria formed the sample. ICD-10 criteria and CAGE Questionnaire were used to assess dependence, problem drinking and co-morbid psychiatric illnesses. The socio-demographic data and the details regarding the nature and pattern of drinking and its complications were recorded using a semi-structured proforma. All patients were instructed to report at the end of 1 and 3 weeks for follow-up after a brief psycho-education regarding the problems of alcohol use. RESULTS: Dependence was seen in 4.1% and problem drinking in 1%. Physical complications possibly due to alcohol were seen in 4.1% and psychiatric co-morbidity in 1%. Pregnancy drinking was recorded in 4.4%. Only 0.2% came for follow-up. CONCLUSION: To conclude, there is a perceptible degree of problematic use of alcohol in the rural women of this region. Yet, none of them were seeking psychiatric help. The soaring number of pregnancy drinking needs further exploration. The poor psychiatric follow-up leads us to conclude that in this sample the perception of alcohol problem is very low. PMID- 21267369 TI - Empowering adolescents with life skills education in schools - School mental health program: Does it work? AB - AIM: Mental Health Promotion among adolescents in schools using life skills education (LSE) and teachers as life skill educators is a novel idea. Implementation and impact of the NIMHANS model of life skills education program studied. MATERIALS AND METHODS: The impact of the program is evaluated at the end of 1 year in 605 adolescents from two secondary schools in comparison to 423 age, sex, socioeconomic status-matched adolescents from nearby schools not in the program. RESULTS: The adolescents in the program had significantly better self esteem (P=0.002), perceived adequate coping (P=0.000), better adjustment generally (P=0.000), specifically with teachers (P=0.000), in school (P=0.001), and prosocial behavior (P=0.001). There was no difference between the two groups in psychopathology (P - and adjustment at home and with peers (P=0.088 and 0.921). Randomly selected 100 life skill educator-teachers also perceived positive changes in the students in the program in class room behavior and interaction. LSE integrated into the school mental health program using available resources of schools and teachers is seen as an effective way of empowering adolescents. PMID- 21267370 TI - Postgraduate trainees as simulated patients in psychiatric training: Role players and interviewers perceptions. AB - BACKGROUND: Teaching skills to enhance competence in clinical settings need to have a focus on learning how to do. This paper describes the subjective experiences and feedback of trainees who participated in a teaching technique using postgraduate trainees as simulated patients. MATERIALS AND METHODS: The Objective Structured Clinical Assessment and Feedback was employed for training using trainees as simulated patients and interviewers. This exercise is performed in front of consultants and peers who subsequently provide feedback about the content and process using a structured format. In order to assess the subjective experience of the interviewer and the role players they were requested to provide structured feedback on several aspects. The trainee role player provided feedback on comfort in playing the role, need for further inputs, satisfaction regarding role play, satisfaction with the interview, and the overall effect of the activity. The trainee interviewer gave feedback on his/her level of comfort performing in front of a peer group, being watched, and evaluated in a group. RESULTS: The feedback forms from 15 sessions were analyzed. Only two of the role players indicated that they felt very uncomfortable while the rest reported comfort. Twelve of the 15 trainees who simulated patients felt they needed more inputs to improve the clarity of the role play; however they all reported feeling satisfied with the role play or interview. The feedback from the interviewers indicated that most were comfortable in all aspects, i.e. conducting the interview, performing in front of a group, being evaluated, and given feedback in front of a group. CONCLUSION: The trainees report indicates that those simulating patients need more clarity on their roles and majority had no discomfort performing in front of a group. Interviewers were satisfied and comfortable with all aspects. On the whole, simulated interviews and role plays were found to be an acceptable teaching method by postgraduate psychiatry trainees. PMID- 21267371 TI - Awareness on psychosomatic health among adolescent girls of three schools in north Kolkata. AB - INTRODUCTION: Psychosomatic health of adolescent girls at crossroads of childhood and mature adulthood, may lead to various health problems in future. OBJECTIVE: To determine the improvement in the knowledge and attitude on health among adolescent girl students of Kolkata after the health education intervention. MATERIALS AND METHODS: This 'Health Education Intervention Study' was conducted in October and November 2006, in three senior secondary schools of North Kolkata. The Simple Random Sampling Technique was applied to select three schools from the spot map of North Kolkata for this study, and 282 girl students in the adolescent age group of 13 to 19 years were selected from the completed updated list of students from the enrollment registers in these schools. RESULTS: The mean age of the participants was 15.7 years (+/-1.8 years). This health education intervention showed a significant improvement in their knowledge on adolescent health, in the aspects of sex differences in pubertal spurts, probable causes of health problems during adolescence, physical changes in adolescent boys and girls, and psychological problems of adolescence. A significant improvement in positive attitude was observed, with regard to their opinion on substance abuse in the adolescent period and importance of sex education for adolescents. CONCLUSION: This study revealed some unknown parts of psychosomatic health among adolescent girls, in this part of India. PMID- 21267372 TI - Children of men with alcohol dependence: Psychopathology, neurodevelopment and family environment. AB - BACKGROUND: Children of people with alcohol dependence (COAs) are at high risk for behavioral and cognitive problems. AIM: Aim of this study was to compare the nature and extent of these problems in children of men with and without alcohol dependence. MATERIALS AND METHODS: 32 children (17 in study group and 15 controls) were evaluated for psychopathology, neurodevelopment, cognitive functioning and family environment. Tools used were: Socio-demographic data sheet, Malin's Intelligence Scale for Indian Children (MISIC), Child Behavior Checklist, Trail Making Test, Neurodevelopment Scale and the Family Environment Scale. RESULTS: Children of men with alcohol dependence had higher externalizing than internalizing scores. Children of alcohol-dependent fathers had higher scores on the neurodevelopment scale and lower scores on the performance scale of the MISIC than the children in control group. These children also made more errors on the Trail Making Test. The family environment of COAs was characterized by lack of independence for its members, greater perceived control and lack of adequate cultural and intellectual activities. CONCLUSION: Our findings suggest that children of men with alcohol dependence have difficulties with frontal lobe functions and neurodevelopmental tasks. There are also difficulties in the family, which are related to alcohol consumption by the father. PMID- 21267373 TI - Subsyndromal states in bipolar disorder. AB - BACKGROUND: Despite adequate treatment, patients with bipolar disorder suffer from subsyndromal symptoms. This study has been done to see the association of subsyndromal symptoms with age of onset, duration of illness, duration of episodes, and number of episodes. AIMS: To know the prevalence of subsyndromal symptoms and their relationship with age of onset, total duration of illness, number of episodes, and duration of episodes in patients with bipolar disorder in remission. MATERIALS AND METHODS: The study was cross sectional and hospital based. One hundred patients, aged between 18 and 65 years, diagnosed as bipolar disorder according to Research Diagnostic Criteria of ICD-10, and with good compliance with the prophylactic medications, score of <=5 on Beck's Mania Rating Scale (BMRS) and score <=8 on Hamilton Depression Rating Scale (HDRS) were recruited by the purposive sampling method. Descriptive statistics were used to describe various sample characteristics. Group differences for categorical variables were examined with the chi-square test, whereas an independent 't' test was used for continuous variables. RESULTS: The most common manic symptom was a decrease in sleep (49%), followed by an increase in verbal activity (39%), hostility (37%), and increase in motor activity (33.33%). The subsyndromal manic group had a lower age of onset (58.8%), males (82.4%), unemployed (23.5%), educated (80.4%). There was no significant difference between with and without subsyndromal mania groups with respect to age, age of onset, duration of illness, number of episode, and average duration of episode. CONCLUSION: Subsyndromal manic symptoms are prevalent and have no relationship with current age, age of onset of illness, duration of illness, number of episode, and average duration of illness in patient with bipolar disorder in remission. PMID- 21267374 TI - Dose-dependent galactorrhea with quetiapine. AB - Quetiapine is an atypical antipsychotic agent with minimal propensity to induce hyperprolactinemia in standard therapeutic dosages. Despite that quetiapine is considered to be a prolactin-sparing atypical antipsychotic, hyperprolactinemia with related side effects may rarely be encountered in susceptible individuals. We report a case of quetiapine-induced hyperprolactinemia and galactorrhea in an adult female, which was dose-dependent. PMID- 21267375 TI - The assessment of insight across cultures. AB - The assessment of insight is a part of the routine clinical examination for people with mental illness. Such assessment, by psychiatrists, is based on the current definitions of insight, which rely on western notions of health and illness. This paper discusses the recent findings of illness perspectives of people with a variety of physical diseases and mental disorders from India. Studies on insight in schizophrenia and bipolar disorders also examined explanatory models of illness among patients, relatives, and the general population. The findings argue for the fact that the assessment of insight should be against the local cultural standards rather than universal yardsticks. The assessment of insight should evaluate awareness, attribution, and action. People with psychosis who are able to re-label their psychotic experience, offer non delusional explanations for changes in themselves, which correspond to beliefs about illness held by the subculture, admit to the need for restitution, and seek locally available help, can be said to possess insight. The results recommend the use of universal conventions to assess insight in people with psychosis rather than the use of uniform criteria. PMID- 21267376 TI - How antidepressant drugs act: A primer on neuroplasticity as the eventual mediator of antidepressant efficacy. AB - Depression is conventionally viewed as a state of chemical imbalance, and antidepressants are suggested to act through increasing monoaminergic neurotransmission. These views are currently considered simplistic. This article examines the animal and human literature on the neurohistological mechanisms underlying stress, depression and antidepressant treatment. Pathological stress and depression are associated with changes such as loss of dendritic spines, shrinkage of the dendritic tree and loss of synapses in the hippocampus and prefrontal cortex. There is also a decrease in glia. Apoptosis may occur under extreme circumstances. In contrast, there is increased dendritic arborization and synaptogenesis in the amygdala. Antidepressant treatment protects against and even reverses some but not all of these stress-induced neurohistological changes. Pathological stress results in an aberrant neuroplasticity response characterized by abnormally increased activity in the amygdala and by impaired functioning of the hippocampus, prefrontal cortex and downstream structures. This aberrant neuroplasticity response directly explains most of the clinical symptoms of depression. Antidepressant treatment protects against stress-induced pathoplastic neurohistological and neurocognitive changes. Antidepressant treatment also restores functional neuroplasticity in stressed organisms and, thereby, presumably, facilitates re-adaptation through learning and memory mechanisms. Thus, the stress-depression syndrome and the therapeutic and prophylactic efficacy of antidepressant treatments can be explained through a hardwiring analogy. In this context, glutamate is an important neurotransmitter. PMID- 21267377 TI - Fee-based open-access journals: A fertile or slippery ground? PMID- 21267378 TI - Need of a formal psychotherapist-delivered counseling as a part of management of bony deformities, with emphasis on clubfoot. PMID- 21267379 TI - Differences in perceptions of family functioning among adolescents with internalizing and externalizing disorders. PMID- 21267380 TI - Preserve and strengthen family to promote mental health. PMID- 21267381 TI - Infective endocarditis and phlebotomies may have killed mozart. AB - Thirty-five year-old Amadeus Mozart died in Vienna after an acute illness that lasted only 15 days but no consensus has been reached on the cause of his death. From many letters written by his farther it is almost certain that he experienced at least three episodes of acute rheumatic fever attack in his childhood, and a relapse of rheumatic fever was suggested to have killed Mozart, although death from acute rheumatic fever is very rare in adults. His last illness was characterized by high fever, massive edema, vomiting and skin rash. His last illness can be explained by infectious endocarditis and heart failure. During his last hours, he was given phlebotomy, possibly for the third time in two weeks, and soon after he became unconscious and died. As such, phlebotomy performed on a man dehydrated by high fever and vomiting may have caused systemic shock. In summary, Mozart probably died from chronic rheumatic heart disease complicated by infective endocarditis and heart failure, and repeated phlebotomy-induced hypovolemic shock. PMID- 21267382 TI - Acute myocardial infarction in the evening has a worse prognosis. Circadian rhythm, does it matter? PMID- 21267383 TI - The impact of circadian variation on 12-month mortality in patients with acute myocardial infarction. AB - BACKGROUND AND OBJECTIVES: Although circadian variation in the onset of acute myocardial infarction (AMI) has been reported in a number of studies, not much is known about the impact of circadian variation on 12-month mortality. The aim of this study was to investigate the impact of circadian variation on 12-month mortality in patients with AMI. SUBJECTS AND METHODS: Eight hundred ninety two patients (mean age 67+/-12; 66.1% men) with AMI who visited Kyungpook National University Hospital from November 2005 to December 2007 were included in this study. Patients were divided into groups based on four 6-hours intervals: overnight (00:00-05:59); morning (06:00-11:59); afternoon (12:00-17:59) and evening (18:00-23:59). RESULTS: Kaplan-Meier survival curves showed 12-month mortality rates of 9.6%, 9.1%, 12.1%, and 16.7% in the overnight, morning, afternoon, evening-onset groups, respectively (p=0.012). Compared with the morning-onset AMI group, the serum creatinine levels (p=0.002), frequency of Killip class >=3 (p=0.004), and prescription rate of diuretics (p=0.011) were significantly higher in the evening-onset AMI group, while the left ventricular ejection fraction (p=0.012) was significantly lower. The proportion of patients who arrived in the emergency room during routine duty hours was significantly lower in evening-onset groups irrespective of the presence or absence of ST segment elevation (p<0.001). According to univariate analysis, the 12-month mortality rate in the evening group was significantly higher compared to the morning group (hazard ratio 1.998, 95% confidence interval 1.196 to 3.338, p=0.008). CONCLUSION: Patients with evening-onset AMI had poorer baseline clinical characteristics, and this might affect the circadian impact on 12-month mortality. Further studies are needed to clarify the role of circadian variation on the long-term outcome of AMI. PMID- 21267384 TI - The effects of pioglitazone in reducing atherosclerosis progression and neointima volume in type 2 diabetic patients: prospective randomized study with volumetric intravascular ultrasonography analysis. AB - BACKGROUND AND OBJECTIVES: Pioglitazone has been known for its anti-atherogenic effects. We compared the effects of pioglitazone in reducing atherosclerosis progression and neointima volume in type 2 diabetic patients. SUBJECTS AND METHODS: This was a prospective, randomized single-blinded, 8-month follow-up study. Patients with significant coronary artery stenosis were randomly assigned to either pioglitazone (n=19) or placebo (n=18) following zotarolimus-eluting stent (ZES) implantation. Intravascular ultrasonography of the culprit vessel was performed from 20 mm distal and proximal to the stent at baseline. and at 8 month, and volumetric analysis was performed. Changes in inflammation markers, insulin resistance and lipid profile were compared. RESULTS: Changes in atherosclerosis progression from baseline in the pioglitazone group was significantly lower than that of the placebo group (0.06+/-0.73 vs. 1.16+/-1.41 mm(3)/mm, p=0.024, respectively), and neointima volume was significantly lower in the pioglitazone group compared to the placebo group (1.74+/-0.93 vs. 2.42+/-1.98 mm(3)/mm, p=0.007, respectively). Homeostatic model assessment-index, interleukin 6, and tumor necrosis factor-alpha levels were significantly lower in the pioglitazone group at 8 months. Adiponectin levels increased significantly only in the pioglitazone group. No significant differences in retinol binding protein 4 levels between the 2 groups were seen during the 8-month follow-up period. CONCLUSION: Compared to placebo, pioglitazone was associated with significant reduction in atherosclerosis progression and neointima formation in type 2 diabetic patients with ZES implantation. PMID- 21267385 TI - Effect of Lacidipine on Blood Pressure and Endothelial Function in Mild-to Moderate Essential Hypertension Patients With Diabetes in Korea. AB - BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the efficacy of lacidipine in reducing blood pressure (BP) and to determine its effect on endothelial function in mild-to-moderate hypertensive patients with type 2 diabetes mellitus (DM). SUBJECTS AND METHODS: This was a prospective, multicenter, open-label, single-arm study, enrolling 290 patients with mild-to moderate hypertension and type 2 DM. Patients were initially treated with 2 mg lacidipine orally once daily for 4 weeks, which was then increased as necessary every 4 weeks to a maximal dose of 6 mg daily. The primary endpoint was the mean change in systolic blood pressure (SBP) from baseline after 12 weeks of treatment. Secondary endpoints included mean changes in diastolic blood pressure (DBP), flow-mediated vasodilatation (FMD), and serum concentrations of biochemical markers such as high-sensitivity C-reactive protein (hs-CRP), monocyte chemo-attractant protein-1 (MCP-1), matrix metalloproteinase-9 (MMP-9), and plasminogen activator inhibitor-1 (PAI-1). RESULTS: Lacidipine treatment significantly reduced SBP by -13.4+/-13.0 mmHg (p<0.001) and DBP by -6.2+/-9.3 mmHg (p<0.001). Lacidipine treatment did not improve endothelial-dependent vasodilatation, despite significantly improved nitroglycerin-induced, endothelial independent vasodilatation. MCP-1 levels significantly decreased from 283.66+/ 110.08 pg/mL to 257.83+/-100.23 pg/mL (p<0.001); whereas there were no significant changes in the levels of hs-CRP, MMP-9, or PAI-1. CONCLUSION: Twelve weeks of treatment with lacidipine was effective and well tolerated in mild-to moderate hypertensive patients with type 2 DM. In spite of inducing a significant reduction in MCP-1 levels, lacidipine did not improve endothelial function. PMID- 21267386 TI - Predicting myocardial functional recovery after acute myocardial infarction: relationship between myocardial strain and coronary flow reserve. AB - BACKGROUND AND OBJECTIVES: The purpose of this study was to evaluate the relationship between myocardial strain and coronary flow reserve (CFR) in the prediction of myocardial functional recovery after acute myocardial infarction (AMI). SUBJECTS AND METHODS: Consecutive patients with anterior ST elevation AMI were analyzed. Left ventricular (LV) strain, determined by 2-dimensional speckle tracking imaging and CFR, determined by intracoronary flow measurement, were obtained on the same day, 3-5 days after primary percutaneous coronary intervention. A-strain was defined as the mean systolic longitudinal strain of 11 LV segments (out of 18) assumed to be supplied by the left anterior descending coronary artery (LAD). Functional recovery was defined as improved wall motion >1 grade seen in at least 2 contiguous dysfunctional segments by echocardiography at the 6-month follow-up. RESULTS: Of 20 patients, 8 patients had preserved CFR (>2.0) and 12 patients had impaired CFR (<=2.0). There were no differences between the 2 CFR groups in LV ejection fractions and wall motion score indices in the LAD territory. However, A-strain was greater in patients with preserved CFR than in patients with impaired CFR (-6.4+/-2.0% vs. -4.6+/-1.4%, p=0.03). A strain and CFR correlated well with each other (r=-0.49, p=0.03). Ten of 20 patients showed functional recovery at 6 months. Of clinical and echocardiographic parameters, A-strain was the only predictor of recovery (odds ratio 2.02, 95% confidence interval=1.03-3.97, p=0.04). For predicting recovery, the sensitivity and specificity were 80.0% and 80.0%, respectively, for CFR (cutoff=1.60), and 60.0% and 90.0%, respectively, for A-strain (cutoff=-6.13%). CONCLUSION: Myocardial strain correlates well with the extent of microvascular integrity and can be used as a noninvasive method for predicting recovery after AMI. PMID- 21267387 TI - N-Terminal Pro-B-type Natriuretic Peptide Levels in the Korean General Population. AB - BACKGROUND AND OBJECTIVES: B-type natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP) levels may serve as a useful marker of cardiovascular risk for screening of the general population. We evaluated reference levels and distribution of NT-proBNP in the Korean general population based on a large cohort study. SUBJECTS AND METHODS: We included 1,518 adult subjects (ages 40-69) of a community-based cohort from the Korea Rural Genomic Cohort (KRGC) Study. Thorough biochemical and clinical data were recorded for all subjects. Levels of NT-proBNP from all participants were determined. In order to determine normal reference levels, subjects with factors known to influence NT-proBNP levels were excluded. RESULTS: The characteristics of the cohort are described below; subjects were 41.2% male, and the mean age was 54.8+/-8.4 years. The distribution of risk factors for cardiovascular disease in the cohort included hypertension (25%), left ventricular hypertrophy by electrocardiography (ECG-LVH) (15%), hypercholestolemia (4.5%), smoking (32%), diabetes (10.9%), history of coronary heart disease (4.9%), history of heart failure (0.9%), symptoms of heart failure (6.1%), elevated serum creatinine (>=1.5, 3.7%), and severe obesity (body mass index >30 kg/m(2), 4.6%). The levels of NT-proBNP of all subjects are shown below; the mean was 60.1+/-42.1, and the median was 36.5 pg/mL. In addition, the levels of NT-proBNP of normal subjects (which did not have any risk factors, n=224) are shown below; the mean was 40.8, and the median was 32.1 pg/mL. In normal subjects, the NT-proBNP level was slightly higher in females (25.7+/-24.8 vs. 46.9+/-35.4, p<0.001). NT-proBNP level increased with age in both the normal population and the total population. There were no significant differences in NT proBNP levels in subjects who smoked, or had diabetes mellitus, hypertension or ECG-LVH. However, in subjects with a history of congestive heart failure (CHF) (58.5+/-103.29 vs. 213.8+/-258.8, p<0.005), elevated serum creatinine levels (>=1.5 mg/dL, 146.2+/-98.2 vs. 54.3+/-38.1, p<0.001), or who were older (>=60, 48.4 vs. 84.2+/-139.5 pg/mL, p<0.05), the BNP level was higher. In addition, patients with more than 3 risk factors for CHF had higher BNP levels (risk 0: 40.8+/-34.0, 1-2: 57.4+/-93.2, >=3: 85.0+/-152.9 pg/mL). NT-proBNP levels were also related with age, sex, urine albumin, serum Cr, and high sensitivity C reactive protein (p<0.05). CONCLUSION: We determined the reference value and distribution of NT-proBNP in the Korean adult general population. We also found that adjustments for the independent effects of age, sex and renal function appear necessary when determining cardiac risk based on proBNP levels. PMID- 21267388 TI - Expression pattern of the thioredoxin system in human endothelial progenitor cells and endothelial cells under hypoxic injury. AB - BACKGROUND AND OBJECTIVES: The thioredoxin (TRx) system is a ubiquitous thiol oxidoreductase pathway that regulates cellular reduction/oxidation status. Although endothelial cell (EC) hypoxic damage is one of the important pathophysiologic mechanisms of ischemic heart disease, its relationship to the temporal expression pattern of the TRx system has not yet been elucidated well. The work presented here was performed to define the expression pattern of the TRx system and its correlation with cellular apoptosis in EC lines in hypoxic stress. These results should provide basic clues for applying aspects of the TRx system as a therapeutic molecule in cardiovascular diseases. SUBJECTS AND METHODS: Hypoxia was induced with 1% O(2), generated in a BBL GasPak Pouch (Becton Dickinson, Franklin Lakes, NJ, USA) in human endothelial progenitor cells (hEPC) and human umbilical vein endothelial cells (HUVEC). Apoptosis of these cells was confirmed by Annexin-V: Phycoerythrin flow cytometry. Expression patterns of TRx; TRx reductase; TRx interacting protein; and survival signals, such as Bcl-2 and Bax, in ECs under hypoxia were checked. RESULTS: Apoptosis was evident after hypoxia in the two cell types. Higher TRx expression was observed at 12 hours after hypoxia in hEPCs and 12, 36, 72 hours of hypoxia in HUVECs. The expression patterns of the TRx system components showed correlation with EC apoptosis and cell survival markers. CONCLUSION: Hypoxia induced significant apoptosis and its related active changes of the TRx system were evident in human EC lines. If the cellular impact of TRx expression pattern in various cardiovascular tissues under hypoxia or oxidative stress was studied meticulously, the TRx system could be applied as a new therapeutic target in cardiovascular diseases, such as ischemic heart disease or atherosclerosis. PMID- 21267389 TI - Simvastatin, sildenafil and their combination in monocrotaline induced pulmonary arterial hypertension. AB - BACKGROUND AND OBJECTIVES: Pulmonary arterial hypertension (PAH) is a life threatening disease characterized by progressive pulmonary arterial occlusion which may ultimately result in death. Currently, the available treatments are diverse, but no therapy alone can reverse the disease process although they may have some clinical benefits. This study was designed to investigate single and combination therapy of simvastatin and sildenafil, which have different mechanisms of action, in monocrotaline (MCT)-induced PAH. MATERIALS AND METHODS: [corrected] Rats were randomized to receive saline (control, n=8) or MCT treatment (n=32). MCT treated rats were randomized to vehicle, simvastatin (2 mg/kg/day), sildenafil (25 mg/kg/day) and a combination simvastatin and sildenafil (n=8, respectively). Three weeks later, hemodynamic study and histologic changes of pulmonary arterioles were measured. Proliferating cell nuclear antigen (PCNA) as well as Western blot for endothelial nitric oxide synthase (eNOS) were performed. RESULTS: Systolic right ventricular pressure was significantly decreased in monotherapy groups (simvastatin and sildenafil) and the combination group compared to MCT group (p<0.05). Right ventricular hypertrophy and medial wall thickness of pulmonary arterioles were significantly attenuated with sole and combination therapy (p<0.05). However, combination therapy did not confer additive benefits over monotherapy. Altered PCNA or eNOS in lung tissue was normalized by either monotherapy or combination therapy. CONCLUSION: The results suggest that either simvastatin or sildenafil has the therapeutic potential in MCT-induced PAH, although combination therapy of these two drugs has failed to show greater benefits in the study. PMID- 21267390 TI - Carotid intima-media thickness and plaque as a predictor for ischemic etiology in patients with severe left ventricular systolic dysfunction. AB - BACKGROUND AND OBJECTIVES: Coronary artery disease (CAD) is a major cause of heart failure associated with left ventricular systolic dysfunction (LVSD). The prognosis of LVSD is significantly influenced by the etiology of heart failure and therefore, differentiation of significant CAD from other etiologies is important. Carotid intima-media thickness (IMT) and plaque are useful predictors for cardiovascular events, including stroke and CAD. The purpose of this study was to evaluate the predictive value of carotid IMT and plaque for the diagnosis of CAD in LVSD patients. SUBJECTS AND METHODS: Seventy-three (n= 73, 47 male, 67.6+/-12.4 years) patients hospitalized for heart failure with severe LVSD were retrospectively enrolled. The severity of CAD was analyzed by the Duke Jeopardy Score system, and carotid IMT and plaque were measured according to the Mannheim Carotid IMT Consensus. RESULTS: Significant CAD was found in 41 patients (56.1%, CAD group) on coronary angiography. Mean common carotid artery (CCA) IMT (0.74+/ 0.05 mm vs. 1.04+/-0.04 mm, p<0.01) was significantly higher in the CAD group. Plaque in CCA (6.25% vs. 19.5%, p<0.01) and plaque in bulb (25.0% vs. 60.9%, p<0.001) were significantly higher in the CAD group. Mean CCA IMT {odds ratio (OR) 2.61, 95% confidence interval (CI) 1.134-4.469, p<0.01} and plaque in bulb (OR 4.69, 95% CI 1.702-12.965, p<0.01) were significant predictors for the diagnosis of CAD according to multivariate logistic regression analysis. CONCLUSION: In patients with severe LVSD, mean CCA IMT and bulb plaque can be useful additional predictors for the diagnosis of CAD. PMID- 21267391 TI - A case of cardiac amyloidosis with diuretic-refractory pleural effusions treated with bevacizumab. AB - Cardiac amyloidosis describes a clinical disorder caused by infiltration of abnormal insoluble fibrils in the heart, characterized by progressive heart failure and a grave prognosis. Pleural effusion in cardiac amyloidosis may represent a sign of heart failure, but it can also result from pleural infiltration of amyloid, manifested by recurrent large fluid accumulations. Recently, the role of vascular endothelial growth factor (VEGF) has been implicated in the pathogenesis of refractory pleural effusion. We report a case of a 53 year-old female patient with cardiac amyloidosis who presented with recurrent accumulation of large pleural effusions. She was initially treated with high dose loop diuretics, but the pleural effusion persisted, with the daily amount of drainage averaging 1 L/day. Accumulation of pleural fluid did not subside after 3 cycles of melphalan/prednisolone therapy. After the introduction of bevacizumab, an anti-VEGF antibody, the amount of pleural effusion decreased significantly. Efficacy of anti-VEGF therapy for refractory pleural effusions needs to be defined through further studies. PMID- 21267392 TI - A rare case of radial arteriovenous fistula after coronary angiography. AB - The percutaneous transfemoral approach has been routinely used for cardiac catheterization and coronary angioplasty. Local vascular complications following angioplasty are seen in 5% to 10% of patients, especially in those who need prolonged anticoagulation. Transradial access for coronary procedures dramatically reduces access site complications. We report a rare case of radial arteriovenous fistula, which developed after coronary angiography perfomed using the transradial approach. PMID- 21267393 TI - A Case of Cogan's Syndrome With Angina. AB - Cogan's syndrome is a rare systemic inflammatory disease and can be diagnosed on the basis of typical inner ear and ocular involvement with the presence of large vessel vasculitis. We report a case of Cogan's syndrome with stable angina resulting from coronary ostial stenosis caused by aortitis. PMID- 21267394 TI - A Case of a Pulmonary Arteriovenous Malformation With Ebstein's Anomaly. AB - A pulmonary arteriovenous malformation (PAVM) is a rare pulmonary vascular anomaly presenting as dyspnea or recurrent epistaxis. Ebstein's anomaly (EA), a congenital cardiac malformation, is also a rare condition. There have been no reports concerning the co-existence of PAVM with hereditary hemorrhagic telangiectasia (HHT) and EA. A 40-year-old woman was admitted with a 2-month history of increasing dyspnea and several years of recurrent epistaxis. On transthoracic echocardiography, she was diagnosed with EA and agreed to undergo surgical treatment. A chest CT angiography showed a 12-mm serpiginous vascular structure suspicious for a PAVM and a liver CT suggested HTT. Although it is unclear whether or not a concurrent PAVM and EA have an embryologic or genetic relationship, we report a case of a PAVM with EA. Further genetic and embryonic studies are needed to identify a possible relationship of the two medical conditions. PMID- 21267395 TI - It's about Time. AB - The purpose of this review/opinion paper is to argue that human cognitive neuroscience has focused too little attention on how the brain may use time and time-based coding schemes to represent, process, and transfer information within and across brain regions. Instead, the majority of cognitive neuroscience studies rest on the assumption of functional localization. Although the functional localization approach has brought us a long way toward a basic characterization of brain functional organization, there are methodological and theoretical limitations of this approach. Further advances in our understanding of neurocognitive function may come from examining how the brain performs computations and forms transient functional neural networks using the rich multi dimensional information available in time. This approach rests on the assumption that information is coded precisely in time but distributed in space; therefore, measures of rapid neuroelectrophysiological dynamics may provide insights into brain function that cannot be revealed using localization-based approaches and assumptions. Space is not an irrelevant dimension for brain organization; rather, a more complete understanding of how brain dynamics lead to behavior dynamics must incorporate how the brain uses time-based coding and processing schemes. PMID- 21267396 TI - Mechanisms Gating the Flow of Information in the Cortex: What They Might Look Like and What Their Uses may be. AB - The notion of gating as a mechanism capable of controlling the flow of information from one set of neurons to another, has been studied in many regions of the central nervous system. In the nucleus accumbens, where evidence is especially clear, gating seems to rely on the action of bistable neurons, i.e., of neurons that oscillate between a quiescent "down" state and a firing "up" state, and that act as AND-gates relative to their entries. Independently from these observations, a growing body of evidence now indicates that bistable neurons are also quite abundant in the cortex, although their exact functions in the dynamics of the brain remain to be determined. Here, we propose that at least some of these bistable cortical neurons are part of circuits devoted to gating information flow within the cortex. We also suggest that currently available structural, electrophysiological, and imaging data support the existence of at least three different types of gating architectures. The first architecture involves gating directly by the cortex itself. The second architecture features circuits spanning the cortex and the thalamus. The third architecture extends itself through the cortex, the basal ganglia, and the thalamus. These propositions highlight the variety of mechanisms that could regulate the passage of action potentials between cortical neurons sets. They also suggest that gating mechanisms require larger-scale neural circuitry to control the state of the gates themselves, in order to fit in the overall wiring of the brain and complement its dynamics. PMID- 21267398 TI - Gastric cancer: Where is the place for the surgeon, the oncologist and the endoscopist today? AB - Gastric cancer remains a major health issue and a leading cause of death worldwide. While the incidence is decreasing in western countries, there has been a shift to more proximal cancers of the diffuse type, which are usually more aggressive and associated with a worse prognosis. Radical surgery still offers the only chance of long term survival, but surgery has reached a plateau of effectiveness and more aggressive approaches like "ultraradical" lymphadenectomy have not improved prognosis. There are three options to improve the situation: Earlier detection, neoadjuvant chemotherapy and adjuvant therapy. Whilst systematic gastroscopic screening makes sense in countries with a high incidence of gastric cancer, in other regions targeted investigation of risk groups including first-degree relatives of cancer patients, patients with a chronic corpus-dominant gastritis or with defined genetic abnormalities may help to detect cancer at an earlier stage. Neoadjuvant chemotherapy has meanwhile proved to significantly improve the prognosis not only in patients with a locally advanced cancer who cannot be resected for cure but but also in those who are potentially amenable to curative resection. In the largest randomised study so far reported, perioperative chemotherapy raised overall survival after 5 years from 23% to 36%. The role of adjuvant chemotherapy has been discussed for over 30 years. Meta-analyses demonstrate a small but significant effect which, however, seems to be restricted to Asian patients. In a large US-study, adjuvant radiochemotherapy appeared to significantly improve outcomes. However, less than 50% of the study patients underwent a systematic lymphadenectomy and so the results of the therapy group were not better to those of "only resected" patients in two large European studies. Thus, the indication of adjuvant (radio )chemotherapy in gastric cancer currently remains uncertain. Endoscopists have found a therapeutic role through endoscopic resection of early cancers, introduced mainly by Japanese authors. With the development of high resolution endoscopy, endosonography and adequate equipment, the endoscopic curative resection of T1a-tumors (restricted to the mucosal layer) has been established. PMID- 21267397 TI - Surgical treatment of hepatic metastases from colorectal cancer. AB - Colorectal carcinoma is one of the most frequent cancers in Western societies with an incidence of around 700 per million people. About half of the patients develop metastases from the primary tumor and liver is the primary metastatic site. Improved survival rates after hepatectomy for metastatic colorectal cancer have been reported in the last few years and these may be the result of a variety of factors, such as advances in systemic chemotherapy, radiographic imaging techniques that permit more accurate determination of the extent and location of the metastatic burden, local ablation methods, and in surgical techniques of hepatic resection. These have led to a more aggressive approach towards liver metastatic disease, resulting in longer survival. The goal of this paper is to review the role of various forms of surgery in the treatment of hepatic metastases from colorectal cancer. PMID- 21267399 TI - Primary colorectal lymphoma: An overview. AB - Lymphomas represent common hematological malignancies with increasing incidence in recent years. The major site of extranodal non-Hodgkin lymphoma is the gastrointestinal tract. Involvement of the large intestine is rare in comparison to the stomach or small bowel. The disease appears later in life, predominantly in the male population. Complaints are nonspecific, requiring a high index of suspicion in order to establish the diagnosis. The treatment varies from chemotherapy alone to multimodal therapies combining surgery, chemotherapy and radiotherapy. The small number of patients with various histological subtypes and different stage at presentation results in unclear protocol for the treatment of primary colorectal lymphoma. The purpose of this paper is to review current data on primary lymphoma of the colon and rectum while analyzing reported case series and published material on the subject. PMID- 21267401 TI - Greek anatomist herophilus: the father of anatomy. AB - One of the most stirring controversies in the history of Anatomy is that Herophilus, an ancient Greek anatomist and his younger contemporary, Erasistratus, were accused of performing vivisections of living humans. However, this does not detract from the fact that Herophilus has made phenomenal anatomical observations of the human body which have contributed significantly towards the understanding of the brain, eye, liver, reproductive organs and nervous system. It is notable that he was the first person to perform systematic dissection of the human body and is widely acknowledged as the Father of Anatomy. He has been hailed as one of the greatest anatomists that ever lived, rivaled only by Andreas Vesalius who is regarded as the founder of modern human anatomy. PMID- 21267402 TI - HOXB13 is co-localized with androgen receptor to suppress androgen-stimulated prostate-specific antigen expression. AB - During the prostate cancer (PCa) development and its progression into hormone independency, androgen receptor (AR) signals play a central role by triggering the regulation of target genes, including prostate-specific antigen. However, the regulation of these AR-mediated target genes is not fully understood. We have previously demonstrated a unique role of HOXB13 homeodomain protein as an AR repressor. Expression of HOXB13 was highly restricted to the prostate and its suppression dramatically increased hormone-activated AR transactivation, suggesting that prostate-specific HOXB13 was a highly potent transcriptional regulator. In this report, we demonstrated the action mechanism of HOXB13 as an AR repressor. HOXB13 suppressed androgen-stimulated AR activity by interacting with AR. HOXB13 did neither bind to AR responsive elements nor disturb nuclear translocation of AR in response to androgen. In PCa specimen, we also observed mutual expression pattern of HOXB13 and AR. These results suggest that HOXB13 not only serve as a DNA-bound transcription factor but play an important role as an AR-interacting repressor to modulate hormone-activated androgen receptor signals. Further extensive studies will uncover a novel mechanism for regulating AR signaling pathway to lead to expose new role of HOXB13 as a non-DNA-binding transcriptional repressor. PMID- 21267400 TI - Control of neuronal migration through rostral migration stream in mice. AB - During the nervous system development, immature neuroblasts have a strong potential to migrate toward their destination. In the adult brain, new neurons are continuously generated in the neurogenic niche located near the ventricle, and the newly generated cells actively migrate toward their destination, olfactory bulb, via highly specialized migratory route called rostral migratory stream (RMS). Neuroblasts in the RMS form chains by their homophilic interactions, and the neuroblasts in chains continually migrate through the tunnels formed by meshwork of astrocytes, glial tube. This review focuses on the development and structure of RMS and the regulation of neuroblast migration in the RMS. Better understanding of RMS migration may be crucial for improving functional replacement therapy by supplying endogenous neuronal cells to the injury sites more efficiently. PMID- 21267403 TI - Mega-dose vitamin C attenuated lung inflammation in mouse asthma model. AB - Asthma is a Th2-dependent disease mediated by IgE and Th2 cytokines, and asthmatic patients suffer from oxidative stresses from abnormal airway inflammation. Vitamin C is a micro-nutrient functioning as an antioxidant. When administered at a mega-dose, vitamin C has been reported to shift immune responses toward Th1. Thus, we tried to determine whether vitamin C exerted beneficial effects in asthma animal model. Asthma was induced in mice by sensitizing and challenging with ovalbumin. At the time of challenge, 3~5 mg of vitamin C was administered and the effects were evaluated. Vitamin C did not modulate Th1/Th2 balance in asthma model. However, it decreased airway hyperreactivity to methacholine, decreased inflammatory cell numbers in brochoalveolar lavage fluid, and moderate reduction of perivascular and peribronchiolar inflammatory cell infiltration. These results suggest that vitamin C administered at the time of antigen challenge exerted anti-inflammatory effects. Further studies based on chronic asthma model are needed to evaluate a long-term effect of vitamin C in asthma. In conclusion, even though vitamin C did not show any Th1/Th2 shifting effects in this experiment, it still exerted moderate anti-inflammatory effects. Considering other beneficial effects and inexpensiveness of vitamin C, mega-dose usage of vitamin C could be a potential supplementary modality for the management of asthma. PMID- 21267404 TI - Downregulation of NFAT2 promotes melanogenesis in B16 melanoma cells. AB - Nuclear factor of activated T-cells (NFAT) proteins are, calcium-regulated transcription factors, key regulator of stimulation-dependent gene activation. In our microarray analysis for the genes expressed in human black and white hairs, NFAT2 was significantly upregulated in the white hair, compared to the black hair. The aim of this study was to investigate functional role of NFAT2 in melanogenesis. Western blot analysis was performed to investigate the expression of NFAT2 protein in B16 melanoma cells. Our data showed that NFAT2 expression was increased in the hypopigmented B16 cells, while tyrosinase and MITF expression was decreased. To investigate the potential role of NFAT2, the recombinant adenovirus expressing microRNA specific for NFAT2 was transduced into the cultured B16 melanoma cells. Consistently, inhibition of NFAT2 enhanced tyrosinase activity and melanin content. Moreover, cyclosporine A, which is known as a calcineurin inhibitor blocking NFAT activation, enhanced tyrosinase activity and melanin content. These data suggest that NFAT2 may play an important role in regulation of melanogenesis in melanocyte. PMID- 21267405 TI - Amorphigenin inhibits Osteoclast differentiation by suppressing c-Fos and nuclear factor of activated T cells. AB - Among the several rotenoids, amorphigenin is isolated from the leaves of Amopha Fruticosa and it is known that has anti-proliferative effects and anti-cnacer effects in many cell types. The main aim of this study was to investigate the effects of amorphigenin on osteoclast differentiation in vitro and on LPS treated inflammatory bone loss model in vivo. We show here that amorphigenin inhibited RANKL-induced osteoclast differentiation from bone marrow macrophages in a dose dependent manner without cellular toxicity. Anti-osteoclastogenic properties of amorphigenin were based on a down-regulation of c-fos and NFATc1. Amorphigenin markedly inhibited RANKL-induced p38 and NF-kappaB pathways, but other pathways were not affected. Micro-CT analysis of the femurs showed that amorphigenin protected the LPS-induced bone loss. We concluded that amorphigenin can prevent inflammation-induced bone loss. Thus we expect that amorphigenin could be a treatment option for bone erosion caused by inflammation. PMID- 21267406 TI - Lipoic acid suppresses compound 48/80-induced anaphylaxis-like reaction. AB - Alpha-lipoic acid (LA), a naturally occurring dithiol compound, is an essential cofactor in metabolic reactions involved in energy utilization. LA improves glycemic control, reduces diabetic polyneuropathies, atherosclerosis, and allergic inflammation. The effects of LA on mast cell-mediated anaphylactic reactions, however, are unknown. LA dose-dependently inhibited systemic and passive cutaneous anaphylaxis-like reactions in mice induced by compound 48/80, a condensation product of N-methyl-p-methoxyphenethylamine and formaldehyde. Pretreatment with LA, prior to induction of the systemic anaphylaxis-like reaction with compound 48/80, reduced plasma histamine levels in a dose-dependent manner. In our in vitro study, LA decreased histamine release from rat peritoneal mast cells (RPMCs) triggered by compound 48/80. Moreover, an increase in calcium uptake activated by compound 48/80 was inhibited by LA. LA also significantly elevated intracellular cyclic adenosine-3',5' monophosphate (cAMP) levels in RPMCs. This inhibition of mediator release from RPMCs may be due to inhibition of calcium uptake and augmentation of intracellular cAMP levels. Based on these results, we suggest that LA may be a potential remedy for allergy-related diseases. PMID- 21267407 TI - Direct protection of cultured neurons from ischemia-like injury by minocycline. AB - Minocycline, a tetracycline antibiotic, is now known to protect cells via an anti inflammatory mechanism. We further explored this effect using an in vitro model of ischemia-like injury to neurons. Coculturing neurons with microglia, the brain's resident immune cell, modestly increased cell death due to oxygen and glucose deprivation (OGD), compared to neurons alone. Treatment of cocultures with minocycline decreased cell death to a level significantly lower than that of neurons alone. Treatment of cocultures with minocycline or inhibitors of various immune mediators, also led to decreased cell death. Importantly, treatment of neuron cultures without added microglia with these same inhibitors of tissue plasminogen activator, matrix metalloproteinases, TNF-alpha and inducible nitric oxide synthase as well as minocycline also led to decreased cell death. Thus, anti-inflammatory treatments appear to be directly protective of neurons from in vitro ischemia. PMID- 21267408 TI - Expression of ErbB4 in the apoptotic neurons of Alzheimer's disease brain. AB - Neuregulin-1 (NRG1) signaling participates in the synaptic plasticity, maintenance or regulation of adult brain. Although ErbB4, a key NRG1 receptor, is expressed in multiple regions in the adult animal brain, little is known about its localization in Alzheimer's disease (AD) brains. We previously reported that ErbB4 immunoreactivity showed regional difference in the hippocampus of age matched control. In the present paper, immunohistochemical characterization of the distribution of ErbB4 receptor in the hippocampus relative to pathology staging were performed in age-matched control (Braak stage 0, n=6) and AD (Braak stage I/V, n=10). Here, we found that ErbB4 immunoreactivity was significantly increased in apoptotic hippocampal pyramidal neurons in the brains of AD patients, compared to those of age-matched control subjects. In AD brains, ErbB4 immunoreactivity was demonstrated to colocalize with the apoptotic signal Bax in apoptotic hippocampal pyramidal neurons. These results suggest that up-regulation of ErbB4 immunoreactivity in apoptotic neuron may involve in the progression of pathology of AD. PMID- 21267409 TI - Ultrastructural analysis of low-threshold mechanoreceptive vibrissa afferent boutons in the cat trigeminal caudal nucleus. AB - Ultrastructural parameters related to synaptic release and their correlation with synaptic connectivity were analyzed in the low-threshold mechanoreceptive vibrissa afferent boutons in laminae III and IV of the trigeminal caudal nucleus (Vc). Rapidly adapting vibrissa afferents were intra-axonally labeled, and quantitative ultrastructural analyses with serial sections were performed on the labeled boutons and their presynaptic endings (p-endings). The volume of the labeled boutons was widely distributed from small to large ones (0.8~12.3 um(3)), whereas the p-endings were small and uniform in size. The volume of the labeled boutons was positively correlated with the ultrastructural parameters such as mitochondrial volume (correlation coefficient, r=0.96), active zone area (r=0.82) and apposed surface area (r=0.79). Vesicle density (r=-0.18) showed little correlation to the volume of labeled boutons, suggesting that the total vesicle number of a bouton is proportional to its volume. In addition, the bouton volume was positively correlated with the number of p-endings (r=0.52) and with the number of dendrites postsynaptic to the labeled bouton (r=0.83). These findings suggest that low-threshold mechanoreception conveyed through vibrissa afferents is processed in a bouton size-dependent manner in the Vc, which may contribute to the sensory-motor function of laminae III/IV in Vc. PMID- 21267410 TI - Point mutations in Abeta result in the formation of distinct polymorphic aggregates in the presence of lipid bilayers. AB - A hallmark of Alzheimer's disease (AD) is the rearrangement of the beta-amyloid (Abeta) peptide to a non-native conformation that promotes the formation of toxic, nanoscale aggregates. Recent studies have pointed to the role of sample preparation in creating polymorphic fibrillar species. One of many potential pathways for Abeta toxicity may be modulation of lipid membrane function on cellular surfaces. There are several mutations clustered around the central hydrophobic core of Abeta near the alpha-secretase cleavage site (E22G Arctic mutation, E22K Italian mutation, D23N Iowa mutation, and A21G Flemish mutation). These point mutations are associated with hereditary diseases ranging from almost pure cerebral amyloid angiopathy (CAA) to typical Alzheimer's disease pathology with plaques and tangles. We investigated how these point mutations alter Abeta aggregation in the presence of supported lipid membranes comprised of total brain lipid extract. Brain lipid extract bilayers were used as a physiologically relevant model of a neuronal cell surface. Intact lipid bilayers were exposed to predominantly monomeric preparations of Wild Type or different mutant forms of Abeta, and atomic force microscopy was used to monitor aggregate formation and morphology as well as bilayer integrity over a 12 hour period. The goal of this study was to determine how point mutations in Abeta, which alter peptide charge and hydrophobic character, influence interactions between Abeta and the lipid surface. While fibril morphology did not appear to be significantly altered when mutants were prepped similarly and incubated under free solution conditions, aggregation in the lipid membranes resulted in a variety of polymorphic aggregates in a mutation dependent manner. The mutant peptides also had a variable ability to disrupt bilayer integrity. PMID- 21267411 TI - Good genes and sexual selection in dung beetles (Onthophagus taurus): genetic variance in egg-to-adult and adult viability. AB - Whether species exhibit significant heritable variation in fitness is central for sexual selection. According to good genes models there must be genetic variation in males leading to variation in offspring fitness if females are to obtain genetic benefits from exercising mate preferences, or by mating multiply. However, sexual selection based on genetic benefits is controversial, and there is limited unambiguous support for the notion that choosy or polyandrous females can increase the chances of producing offspring with high viability. Here we examine the levels of additive genetic variance in two fitness components in the dung beetle Onthophagus taurus. We found significant sire effects on egg-to-adult viability and on son, but not daughter, survival to sexual maturity, as well as moderate coefficients of additive variance in these traits. Moreover, we do not find evidence for sexual antagonism influencing genetic variation for fitness. Our results are consistent with good genes sexual selection, and suggest that both pre- and postcopulatory mate choice, and male competition could provide indirect benefits to females. PMID- 21267412 TI - Laboratory-evolved mutants of an exogenous global regulator, IrrE from Deinococcus radiodurans, enhance stress tolerances of Escherichia coli. AB - BACKGROUND: The tolerance of cells toward different stresses is very important for industrial strains of microbes, but difficult to improve by the manipulation of single genes. Traditional methods for enhancing cellular tolerances are inefficient and time-consuming. Recently, approaches employing global transcriptional or translational engineering methods have been increasingly explored. We found that an exogenous global regulator, irrE from an extremely radiation-resistant bacterium, Deinococcus radiodurans, has the potential to act as a global regulator in Escherichia coli, and that laboratory-evolution might be applied to alter this regulator to elicit different phenotypes for E. coli. METHODOLOGY/PRINCIPAL FINDINGS: To extend the methodology for strain improvement and to obtain higher tolerances toward different stresses, we here describe an approach of engineering irrE gene in E. coli. An irrE library was constructed by randomly mutating the gene, and this library was then selected for tolerance to ethanol, butanol and acetate stresses. Several mutants showing significant tolerances were obtained and characterized. The tolerances of E. coli cells containing these mutants were enhanced 2 to 50-fold, based on cell growth tests using different concentrations of alcohols or acetate, and enhanced 10 to 100 fold based on ethanol or butanol shock experiments. Intracellular reactive oxygen species (ROS) assays showed that intracellular ROS levels were sharply reduced for cells containing the irrE mutants. Sequence analysis of the mutants revealed that the mutations distribute cross all three domains of the protein. CONCLUSIONS: To our knowledge, this is the first time that an exogenous global regulator has been artificially evolved to suit its new host. The successes suggest the possibility of improving tolerances of industrial strains by introducing and engineering exogenous global regulators, such as those from extremophiles. This new approach can be applied alone or in combination with other global methods, such as global transcriptional machinery engineering (gTME) for strain improvements. PMID- 21267413 TI - TPL2/COT/MAP3K8 (TPL2) activation promotes androgen depletion-independent (ADI) prostate cancer growth. AB - BACKGROUND: Despite its initial positive response to hormone ablation therapy, prostate cancers invariably recur in more aggressive, treatment resistant forms. The lack of our understanding of underlying genetic alterations for the transition from androgen-dependent (AD) to ADI prostate cancer growth hampers our ability to develop target-driven therapeutic strategies for the efficient treatment of ADI prostate cancer. METHODOLOGY/PRINCIPAL FINDINGS: By screening a library of activated human kinases, we have identified TPL2, encoding a serine/threonine kinase, as driving ADI prostate cancer growth. TPL2 activation by over-expressing either wild-type or a constitutively activated form of TPL2 induced ADI growth, whereas the suppression of TPL2 expression and its kinase activity in ADI prostate cancer cells inhibited cell proliferation under androgen depleted conditions. Most importantly, TPL2 is upregulated in ADI prostate cancers of both the Pten deletion mouse model and the clinical prostate cancer specimens. CONCLUSIONS/SIGNIFICANCE: Together these data suggest that TPL2 kinase plays a critical role in the promotion of ADI prostate cancer progression. Furthermore, the suppression of TPL2 diminishes ADI prostate cancer growth and a high frequency of TPL2 overexpression in human ADI prostate cancer samples validates TPL2 as a target for the treatment of this deadly disease. PMID- 21267414 TI - Gender in facial representations: a contrast-based study of adaptation within and between the sexes. AB - Face aftereffects are proving to be an effective means of examining the properties of face-specific processes in the human visual system. We examined the role of gender in the neural representation of faces using a contrast-based adaptation method. If faces of different genders share the same representational face space, then adaptation to a face of one gender should affect both same- and different-gender faces. Further, if these aftereffects differ in magnitude, this may indicate distinct gender-related factors in the organization of this face space. To control for a potential confound between physical similarity and gender, we used a Bayesian ideal observer and human discrimination data to construct a stimulus set in which pairs of different-gender faces were equally dissimilar as same-gender pairs. We found that the recognition of both same gender and different-gender faces was suppressed following a brief exposure of 100 ms. Moreover, recognition was more suppressed for test faces of a different gender than those of the same-gender as the adaptor, despite the equivalence in physical and psychophysical similarity. Our results suggest that male and female faces likely occupy the same face space, allowing transfer of aftereffects between the genders, but that there are special properties that emerge along gender-defining dimensions of this space. PMID- 21267415 TI - Dispersed activity during passive movement in the globus pallidus of the 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primate. AB - Parkinson's disease is a neurodegenerative disorder manifesting in debilitating motor symptoms. This disorder is characterized by abnormal activity throughout the cortico-basal ganglia loop at both the single neuron and network levels. Previous neurophysiological studies have suggested that the encoding of movement in the parkinsonian state involves correlated activity and synchronized firing patterns. In this study, we used multi-electrode recordings to directly explore the activity of neurons from the globus pallidus of parkinsonian primates during passive limb movements and to determine the extent to which they interact and synchronize. The vast majority (80/103) of the recorded pallidal neurons responded to periodic flexion-extension movements of the elbow. The response pattern was sinusoidal-like and the timing of the peak response of the neurons was uniformly distributed around the movement cycle. The interaction between the neuronal activities was analyzed for 123 simultaneously recorded pairs of neurons. Movement-based signal correlation values were diverse and their mean was not significantly different from zero, demonstrating that the neurons were not activated synchronously in response to movement. Additionally, the difference in the peak responses phase of pairs of neurons was uniformly distributed, showing their independent firing relative to the movement cycle. Our results indicate that despite the widely distributed activity in the globus pallidus of the parkinsonian primate, movement encoding is dispersed and independent rather than correlated and synchronized, thus contradicting current views that posit synchronous activation during Parkinson's disease. PMID- 21267416 TI - Ultradian cortisol pulsatility encodes a distinct, biologically important signal. AB - CONTEXT: Cortisol is released in ultradian pulses. The biological relevance of the resulting fluctuating cortisol concentration has not been explored. OBJECTIVE: Determination of the biological consequences of ultradian cortisol pulsatility. DESIGN: A novel flow through cell culture system was developed to deliver ultradian pulsed or continuous cortisol to cells. The effects of cortisol dynamics on cell proliferation and survival, and on gene expression were determined. In addition, effects on glucocorticoid receptor (GR) expression levels and phosphorylation, as a potential mediator, were measured. RESULTS: Pulsatile cortisol caused a significant reduction in cell survival compared to continuous exposure of the same cumulative dose, due to increased apoptosis. Comprehensive analysis of the transcriptome response by microarray identified genes with a differential response to pulsatile versus continuous glucocorticoid delivery. These were confirmed with qRT-PCR. Several transcription factor binding sites were enriched in these differentially regulated target genes, including CCAAT-displacement protein (CDP). A CDP regulated reporter gene (MMTV-luc) was, as predicted, also differentially regulated by pulsatile compared to continuous cortisol delivery. Importantly there was no effect of cortisol delivery kinetics on either GR expression, or activation (GR phosphoSer(211)). CONCLUSIONS: Cortisol oscillations exert important effects on target cell gene expression, and phenotype. This is not due to differences in cumulative cortisol exposure, or either expression, or activation of the GR. This suggests a novel means to regulate GR function. PMID- 21267419 TI - Category-Specific Visual Responses: An Intracranial Study Comparing Gamma, Beta, Alpha, and ERP Response Selectivity. AB - The specificity of neural responses to visual objects is a major topic in visual neuroscience. In humans, functional magnetic resonance imaging (fMRI) studies have identified several regions of the occipital and temporal lobe that appear specific to faces, letter strings, scenes, or tools. Direct electrophysiological recordings in the visual cortical areas of epileptic patients have largely confirmed this modular organization, using either single-neuron peri-stimulus time-histogram or intracerebral event-related potentials (iERP). In parallel, a new research stream has emerged using high-frequency gamma-band activity (50-150 Hz) (GBR) and low-frequency alpha/beta activity (8-24 Hz) (ABR) to map functional networks in humans. An obvious question is now whether the functional organization of the visual cortex revealed by fMRI, ERP, GBR, and ABR coincide. We used direct intracerebral recordings in 18 epileptic patients to directly compare GBR, ABR, and ERP elicited by the presentation of seven major visual object categories (faces, scenes, houses, consonants, pseudowords, tools, and animals), in relation to previous fMRI studies. Remarkably both GBR and iERP showed strong category-specificity that was in many cases sufficient to infer stimulus object category from the neural response at single-trial level. However, we also found a strong discrepancy between the selectivity of GBR, ABR, and ERP with less than 10% of spatial overlap between sites eliciting the same category specificity. Overall, we found that selective neural responses to visual objects were broadly distributed in the brain with a prominent spatial cluster located in the posterior temporal cortex. Moreover, the different neural markers (GBR, ABR, and iERP) that elicit selectivity toward specific visual object categories present little spatial overlap suggesting that the information content of each marker can uniquely characterize high-level visual information in the brain. PMID- 21267420 TI - The Me31B DEAD-Box Helicase Localizes to Postsynaptic Foci and Regulates Expression of a CaMKII Reporter mRNA in Dendrites of Drosophila Olfactory Projection Neurons. AB - mRNP granules at adult central synapses are postulated to regulate local mRNA translation and synapse plasticity. However, they are very poorly characterized in vivo. Here, in Drosophila olfactory synapses, we present early observations and characterization of candidate synaptic mRNP particles, one of which contains a widely conserved, DEAD-box helicase, Me31B. In Drosophila, Me31B is required for translational repression of maternal and miRNA-target mRNAs. A role in neuronal translational control is primarily suggested by Me31B's localization, in cultured primary neurons, to neuritic mRNP granules that contain: (i) various translational regulators; (ii) CaMKII mRNA; and (iii) several P-body markers including the mRNA hydrolases, Dcp1, and Pcm/Xrn-1. In adult neurons, Me31B localizes to P-body like cytoplasmic foci/particles in neuronal soma. In addition it is present to synaptic foci that may lack RNA degradative enzymes and localize predominantly to dendritic elements of olfactory sensory and projection neurons (PNs). MARCM clones of PNs mutant for Me31B show loss of both Me31B and Dcp1 positive dendritic puncta, suggesting potential interactions between these granule types. In PNs, expression of validated hairpin-RNAi constructs against Me31B causes visible knockdown of endogenous protein, as assessed by the brightness and number of Me31B puncta. Knockdown of Me31B also causes a substantial elevation in observed levels of a translational reporter of CaMKII, a postsynaptic protein whose mRNA has been shown to be localized to PN dendrites and to be translationally regulated, at least in part through the miRNA pathway. Thus, neuronal Me31B is present in dendritic particles in vivo and is required for repression of a translationally regulated synaptic mRNA. PMID- 21267421 TI - Economic value biases uncertain perceptual choices in the parietal and prefrontal cortices. AB - An observer detecting a noisy sensory signal is biased by the costs and benefits associated with its presence or absence. When these costs and benefits are asymmetric, sensory, and economic information must be integrated to inform the final choice. However, it remains unknown how this information is combined at the neural or computational levels. To address this question, we asked healthy human observers to judge the presence or absence of a noisy sensory signal under economic conditions that favored yes responses (liberal blocks), no responses (conservative blocks), or neither response (neutral blocks). Economic information biased fast choices more than slow choices, suggesting that value and sensory information are integrated early in the decision epoch. More formal simulation analyses using an Ornstein-Uhlenbeck process demonstrated that the influence of economic information was best captured by shifting the origin of evidence accumulation toward the more valuable bound. We then used the computational model to generate trial-by-trial estimates of decision-related evidence that were based on combined sensory and economic information (the decision variable or DV), and regressed these against fMRI activity recorded whilst participants performed the task. Extrastriate visual regions responded to the level of sensory input (momentary evidence), but fMRI signals in the parietal and prefrontal cortices responded to the decision variable. These findings support recent single-neuron data suggesting that economic information biases decision-related signals in higher cortical regions. PMID- 21267422 TI - High-throughput microarray detection of vomeronasal receptor gene expression in rodents. AB - We performed comprehensive data mining to explore the vomeronasal receptor (V1R and V2R) repertoires in mouse and rat using the mm5 and rn3 genome, respectively. This bioinformatic analysis was followed by investigation of gene expression using a custom designed high-density oligonucleotide array containing all of these receptors and other selected genes of interest. This array enabled us to detect the specific expression of V1R and V2Rs which were previously identified solely based on computational prediction from gene sequence data, thereby establishing that these genes are indeed part of the vomeronasal system, especially the V2Rs. One hundred sixty-eight V1Rs and 98 V2Rs were detected to be highly enriched in mouse vomeronasal organ (VNO), and 108 V1Rs and 87 V2Rs in rat VNO. We monitored the expression profile of mouse VR genes in other non-VNO tissues with the result that some VR genes were re-designated as VR-like genes based on their non-olfactory expression pattern. Temporal expression profiles for mouse VR genes were characterized and their patterns were classified, revealing the developmental dynamics of these so-called pheromone receptors. We found numerous patterns of temporal expression which indicate possible behavior-related functions. The uneven composition of VR genes in certain patterns suggests a functional differentiation between the two types of VR genes. We found the coherence between VR genes and transcription factors in terms of their temporal expression patterns. In situ hybridization experiments were performed to evaluate the cell number change over time for selected receptor genes. PMID- 21267423 TI - A Simple, Highly Efficient Method for Heterologous Expression in Mammalian Primary Neurons Using Cationic Lipid-mediated mRNA Transfection. AB - Expression of heterologous proteins in adult mammalian neurons is a valuable technique for the study of neuronal function. The post-mitotic nature of mature neurons prevents effective DNA transfection using simple, cationic lipid-based methods. Adequate heterologous protein expression is often only achievable using complex techniques that, in many cases, are associated with substantial toxicity. Here, a simple method for high efficiency transfection of mammalian primary neurons using in vitro transcribed mRNA and the cationic lipid transfection reagent LipofectamineTM 2000 is described. Optimal transfection conditions were established in adult mouse dissociated dorsal root ganglion (DRG) neurons using a 96-well based luciferase activity assay. Using these conditions, a transfection efficiency of 25% was achieved in DRG neurons transfected with EGFP mRNA. High transfection efficiencies were also obtained in dissociated rat superior cervical ganglion (SCG) neurons and mouse cortical and hippocampal cultures. Endogenous Ca(2+) currents in EGFP mRNA-transfected SCG neurons were not significantly different from untransfected neurons, which suggested that this technique is well suited for heterologous expression in patch clamp recording experiments. Functional expression of a cannabinoid receptor (CB1R), a G protein inwardly rectifying K(+) channel (GIRK4) and a dominant-negative G protein alpha-subunit mutant (G(oA) G203T) indicate that the levels of heterologous protein expression attainable using mRNA transfection are suitable for most functional protein studies. This study demonstrates that mRNA transfection is a straightforward and effective method for heterologous expression in neurons and is likely to have many applications in neuroscience research. PMID- 21267424 TI - Visual evoked responses during standing and walking. AB - Human cognition has been shaped both by our body structure and by its complex interactions with its environment. Our cognition is thus inextricably linked to our own and others' motor behavior. To model brain activity associated with natural cognition, we propose recording the concurrent brain dynamics and body movements of human subjects performing normal actions. Here we tested the feasibility of such a mobile brain/body (MoBI) imaging approach by recording high density electroencephalographic (EEG) activity and body movements of subjects standing or walking on a treadmill while performing a visual oddball response task. Independent component analysis of the EEG data revealed visual event related potentials that during standing, slow walking, and fast walking did not differ across movement conditions, demonstrating the viability of recording brain activity accompanying cognitive processes during whole body movement. Non invasive and relatively low-cost MoBI studies of normal, motivated actions might improve understanding of interactions between brain and body dynamics leading to more complete biological models of cognition. PMID- 21267417 TI - Rosuvastatin, inflammation, C-reactive protein, JUPITER, and primary prevention of cardiovascular disease--a perspective. AB - The major public health concern worldwide is coronary heart disease, with dyslipidemia as a major risk factor. Statin drugs are recommended by several guidelines for both primary and secondary prevention. Rosuvastatin has been widely accepted because of its efficacy, potency, and superior safety profile. Inflammation is involved in all phases of atherosclerosis, with the process beginning in early youth and advancing relentlessly for decades throughout life. C-reactive protein (CRP) is a well-studied, nonspecific marker of inflammation which may reflect general health risk. Considerable evidence suggests CRP is an independent predictor of future cardiovascular events, but direct involvement in atherosclerosis remains controversial. Rosuvastatin is a synthetic, hydrophilic statin with unique stereochemistry. A large proportion of patients achieve evidence-based lipid targets while using the drug, and it slows progression and induces regression of atherosclerotic coronary lesions. Rosuvastatin lowers CRP levels significantly. The Justification for Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial was designed after the observation that when both low density lipoprotein and CRP were reduced, patients fared better than when only LDL was lowered. Advocates and critics alike acknowledge that the benefits of rosuvastatin in JUPITER were real. After a review, the US Food and Drug Administration extended the indications for rosuvastatin to include asymptomatic JUPITER-eligible individuals with one additional risk factor. The American Heart Association and Centers of Disease Control and Prevention had previously recognized the use of CRP in persons with "intermediate risk" as defined by global risk scores. The Canadian Cardiovascular Society guidelines went further and recommended use of statins in persons with low LDL and high CRP levels at intermediate risk. The JUPITER study focused attention on ostensibly healthy individuals with "normal" lipid profiles and high CRP values who benefited from statin therapy. The backdrop to JUPITER during this period was an increasing awareness of a rising cardiovascular risk burden and imperfect methods of risk evaluation, so that a significant number of individuals were being denied beneficial therapies. Other concerns have been a high level of residual risk in those who are treated, poor patient adherence, a need to follow guidelines more closely, a dual global epidemic of obesity and diabetes, and a progressively deteriorating level of physical activity in the population. Calls for new and more effective means of reducing risk for coronary heart disease are intensifying. In view of compelling evidence supporting earlier and aggressive therapy in people with high risk burdens, JUPITER simply offers another choice for stratification and earlier risk reduction in primary prevention patients. When indicated, and in individuals unwilling or unable to change their diet and lifestyles sufficiently, the benefits of statins greatly exceed the risks. Two side effects of interest are myotoxicity and an increase in the incidence of diabetes. PMID- 21267425 TI - Native language experience influences the topography of the mismatch negativity to speech. AB - The ability to learn second language speech sound categories declines during development. We examined this phenomenon by studying the mismatch negativity (MMN) to the /r/ - /l/ distinction in native English speakers and learners of English as a second language who are native speakers of Japanese. Previous studies have suggested that the MMN is remarkably plastic when evaluated as a waveform at a central electrode. We replicated this finding: analyses of the MMN at a typical electrode location (Fz) revealed only small, non-significant differences between groups, despite large behavioral differences in the ability to discriminate these sounds from one another. Topographic analyses, however, revealed reliable differences in lateralization of the MMN, such that native English speakers' responses were left-lateralized relative to native Japanese speakers' responses. PMID- 21267426 TI - Activity Modes in Thalamocortical Relay Neurons are Modulated by G(q)/G(11) Family G-proteins - Serotonergic and Glutamatergic Signaling. AB - In thalamocortical relay (TC) neurons, G-protein-coupled receptors play an important part in the control of activity modes. A conditional Galpha(q) knockout on the background of a constitutive Galpha(11) knockout (Galpha(q)/Galpha(11) (-/ )) was used to determine the contribution of Gq/G11 family G-proteins to metabotropic serotonin (5-HT) and glutamate (Glu) function in the dorsal part of the lateral geniculate nucleus (dLGN). In control mice, current clamp recordings showed that alpha-m-5-HT induced a depolarization of V(rest) which was sufficient to suppress burst firing. This depolarization was concentration-dependent (100 MUM: +6 +/- 1 mV, n = 10; 200 MUM: +10 +/- 1 mV, n = 7) and had a conditioning effect on the activation of other Galpha(q)-mediated pathways. The depolarization was significantly reduced in Galpha(q)/Galpha(11) (-/-) (100 MUM: 3 +/- 1 mV, n = 11; 200 MUM: 5 +/- 1 mV, n = 6) and was apparently insufficient to suppress burst firing. Activating Galpha(q)-coupled muscarinic receptors affected the magnitude of alpha-m-5-HT-induced effects in a reciprocal manner. Furthermore, the depolarizing effect of mGluR1 agonists was significantly reduced in Galpha(q)/Galpha(11) (-/-) mice. Immunohistochemical stainings revealed binding of 5-HT(2C)R- and mGluR1alpha-, but not of 5-HT(2A)R-specific antibodies in the dLGN of Galpha(q)/Galpha(11) (-/-) mice. In conclusion, these findings demonstrate that transmitters of ascending brainstem fibers and corticofugal fibers both signal via a central element in the form of Gq/G11-mediated pathways to control activity modes in the TC system. PMID- 21267427 TI - Associative learning changes the organization of functional excitatory circuits targeting the supragranular layers of mouse barrel cortex. AB - In primary sensory cortices, neuronal circuits change throughout life as a function of learning. During associative learning a neutral sensory stimulus acquires the emotional valence of an aversive event or a reward after repetitive contingent pairing. One important consequence is the enlargement of the representational area of the conditioned stimulus in the cortical map of its sensory modality. The details of this phenomenon at the circuit level are still largely unknown. Here, mice were trained in a differential conditioning paradigm where the deflections of one whisker row were paired with tail shocks and the deflections of two others were not. Changes occurring in excitatory circuits of barrel cortex were then examined in brain slices with laser scanning photostimulation mapping. We found that learning affected the projections targeting the supragranular layers in the columns of unpaired whiskers: Pyramidal cells located in layer (L) 3 received enhanced inputs from L5A cells located in their home column and new inputs from L2/3 and L4 cells located in the neighboring column of the paired whisker. In contrast, the excitatory projections impinging onto L2/3 cells in the column of the paired whisker were not altered. Together, these data reveal that associative learning alters the canonical columnar organization of functional ascending L4 projections and strengthens transcolumnar excitatory projections in barrel cortex. These phenomena could participate to the transformation of the whisker somatotopic map induced by associative learning. PMID- 21267428 TI - Cardiorespiratory fitness and attentional control in the aging brain. AB - A growing body of literature provides evidence for the prophylactic influence of cardiorespiratory fitness on cognitive decline in older adults. This study examined the association between cardiorespiratory fitness and recruitment of the neural circuits involved in an attentional control task in a group of healthy older adults. Employing a version of the Stroop task, we examined whether higher levels of cardiorespiratory fitness were associated with an increase in activation in cortical regions responsible for imposing attentional control along with an up-regulation of activity in sensory brain regions that process task relevant representations. Higher fitness levels were associated with better behavioral performance and an increase in the recruitment of prefrontal and parietal cortices in the most challenging condition, thus providing evidence that cardiorespiratory fitness is associated with an increase in the recruitment of the anterior processing regions. There was a top-down modulation of extrastriate visual areas that process both task-relevant and task-irrelevant attributes relative to the baseline. However, fitness was not associated with differential activation in the posterior processing regions, suggesting that fitness enhances attentional function by primarily influencing the neural circuitry of anterior cortical regions. This study provides novel evidence of a differential association of fitness with anterior and posterior brain regions, shedding further light onto the neural changes accompanying cardiorespiratory fitness. PMID- 21267429 TI - Abnormal speech spectrum and increased pitch variability in young autistic children. AB - Children with autism spectrum disorder (ASD) who can speak often exhibit abnormal voice quality and speech prosody, but the exact nature and underlying mechanisms of these abnormalities, as well as their diagnostic power are currently unknown. Here we quantified speech abnormalities in terms of the properties of the long term average spectrum (LTAS) and pitch variability in speech samples of 83 children (41 with ASD, 42 controls) ages 4-6.5 years, recorded while they named a sequence of daily life pictures for 60 s. We found a significant difference in the group's average spectra, with ASD spectra being shallower and exhibiting less harmonic structure. Contrary to the common impression of monotonic speech in autism, the ASD children had a significantly larger pitch range and variability across time. A measure of this variability, optimally tuned for the sample, yielded 86% success (90% specificity, 80% sensitivity) in classifying ASD in the sample. These results indicate that speech abnormalities in ASD are reflected in its spectral content and pitch variability. This variability could imply abnormal processing of auditory feedback or elevated noise and instability in the mechanisms that control pitch. The current results are a first step toward developing speech spectrum-based bio-markers for early diagnosis of ASD. PMID- 21267430 TI - Aberrant Effective Connectivity in Schizophrenia Patients during Appetitive Conditioning. AB - It has recently been suggested that schizophrenia involves dysfunction in brain connectivity at a neural level, and a dysfunction in reward processing at a behavioral level. The purpose of the present study was to link these two levels of analyses by examining effective connectivity patterns between brain regions mediating reward learning in patients with schizophrenia and healthy, age-matched controls. To this aim, we used functional magnetic resonance imaging and galvanic skin recordings (GSR) while patients and controls performed an appetitive conditioning experiment with visual cues as the conditioned (CS) stimuli, and monetary reward as the appetitive unconditioned stimulus (US). Based on explicit stimulus contingency ratings, conditioning occurred in both groups; however, based on implicit, physiological GSR measures, patients failed to show differences between CS+ and CS- conditions. Healthy controls exhibited increased blood-oxygen-level dependent (BOLD) activity across striatal, hippocampal, and prefrontal regions and increased effective connectivity from the ventral striatum to the orbitofrontal cortex (OFC BA 11) in the CS+ compared to the CS- condition. Compared to controls, patients showed increased BOLD activity across a similar network of brain regions, and increased effective connectivity from the striatum to hippocampus and prefrontal regions in the CS- compared to the CS+ condition. The findings of increased BOLD activity and effective connectivity in response to the CS- in patients with schizophrenia offer insight into the aberrant assignment of motivational salience to non-reinforced stimuli during conditioning that is thought to accompany schizophrenia. PMID- 21267431 TI - Effects of Initial Eye Position on Saccades Evoked by Microstimulation in the Primate Superior Colliculus: Implications for Models of the SC Read-Out Process. AB - The motor layers of the superior colliculus (SC) are thought to specify saccade amplitude and direction, independent of initial eye position. However, recent evidence suggests that eye position can modulate the level of activity of SC motor neurons. In this study, we tested whether initial eye position has an effect on microstimulation-evoked saccade amplitude. High (>300 Hz) and low (<300 Hz) frequency microstimulation was applied to 30 sites in the rostral part of the SC of two monkeys while they fixated one of six different locations. We found that the amplitude of the evoked saccades decreased with more contralateral initial eye positions. This effect was more pronounced in low frequency- compared to high frequency-evoked saccades, although it was present for both. Replication of these findings in head-free experiments showed that the effect of initial eye position was not due to physical constraints imposed by the oculomotor range. In addition to the effect of eye position on saccade amplitude, we also observed an increase in saccade latency and a decrease in the probability that microstimulation would evoke a saccade for low frequency stimulation at more contralateral eye positions. These findings suggest that an eye position signal can contribute to the read-out of the SC. Models of the saccadic pulse-step generator may need revision to incorporate an eye position modulation at the input stage. PMID- 21267433 TI - Preface to special topic: optofluidics. AB - This Special Topic section of Biomicrofluidics is on optofluidics or micro optofluidic systems (MOFS), a burgeoning technology that aims to manipulate light and fluid at microscale and exploits their interaction to create highly versatile devices and integrated systems. This special issue puts together various contributed articles focusing on optofluidics or MOFS, which help inspire new research ideas and innovation in the microfluidics and nanofluidics community. PMID- 21267432 TI - Holistic face categorization in higher order visual areas of the normal and prosopagnosic brain: toward a non-hierarchical view of face perception. AB - How a visual stimulus is initially categorized as a face in a network of human brain areas remains largely unclear. Hierarchical neuro-computational models of face perception assume that the visual stimulus is first decomposed in local parts in lower order visual areas. These parts would then be combined into a global representation in higher order face-sensitive areas of the occipito temporal cortex. Here we tested this view in fMRI with visual stimuli that are categorized as faces based on their global configuration rather than their local parts (two-tones Mooney figures and Arcimboldo's facelike paintings). Compared to the same inverted visual stimuli that are not categorized as faces, these stimuli activated the right middle fusiform gyrus ("Fusiform face area") and superior temporal sulcus (pSTS), with no significant activation in the posteriorly located inferior occipital gyrus (i.e., no "occipital face area"). This observation is strengthened by behavioral and neural evidence for normal face categorization of these stimuli in a brain-damaged prosopagnosic patient whose intact right middle fusiform gyrus and superior temporal sulcus are devoid of any potential face sensitive inputs from the lesioned right inferior occipital cortex. Together, these observations indicate that face-preferential activation may emerge in higher order visual areas of the right hemisphere without any face-preferential inputs from lower order visual areas, supporting a non-hierarchical view of face perception in the visual cortex. PMID- 21267434 TI - Review Article: Recent advancements in optofluidic flow cytometer. AB - There is an increasing need to develop optofluidic flow cytometers. Optofluidics, where optics and microfluidics work together to create novel functionalities on a small chip, holds great promise for lab-on-a-chip flow cytometry. The development of a low-cost, compact, handheld flow cytometer and microfluorescence-activated cell sorter system could have a significant impact on the field of point-of-care diagnostics, improving health care in, for example, underserved areas of Africa and Asia, that struggle with epidemics such as HIV/AIDS. In this paper, we review recent advancements in microfluidics, on-chip optics, novel detection architectures, and integrated sorting mechanisms. PMID- 21267435 TI - Cell rotation using optoelectronic tweezers. AB - A cell rotation method by using optoelectronic tweezers (OET) is reported. The binary image of a typical OET device, whose light and dark sides act as two sets of parallel plates with different ac voltages, was used to create a rotating electric field. Its feasibility for application to electrorotation of cells was demonstrated by rotating Ramos and yeast cells in their pitch axes. The electrorotation by using OET devices is dependent on the medium and cells' electrical properties, the cells' positions, and the OET device's geometrical dimension, as well as the frequency of the electric field. PMID- 21267436 TI - Optofluidic planar reactors for photocatalytic water treatment using solar energy. AB - Optofluidics may hold the key to greater success of photocatalytic water treatment. This is evidenced by our findings in this paper that the planar microfluidic reactor can overcome the limitations of mass transfer and photon transfer in the previous photocatalytic reactors and improve the photoreaction efficiency by more than 100 times. The microreactor has a planar chamber (5 cm*1.8 cm*100 MUm) enclosed by two TiO(2)-coated glass slides as the top cover and bottom substrate and a microstructured UV-cured NOA81 layer as the sealant and flow input/output. In experiment, the microreactor achieves 30% degradation of 3 ml 3*10(-5)M methylene blue within 5 min and shows a reaction rate constant two orders higher than the bulk reactor. Under optimized conditions, a reaction rate of 8% s(-1) is achieved under solar irradiation. The average apparent quantum efficiency is found to be only 0.25%, but the effective apparent quantum efficiency reaches as high as 25%. Optofluidic reactors inherit the merits of microfluidics, such as large surface/volume ratio, easy flow control, and rapid fabrication and offer a promising prospect for large-volume photocatalytic water treatment. PMID- 21267437 TI - Characterization of a microflow cytometer with an integrated three-dimensional optofluidic lens system. AB - Flow cytometry is a standard analytical method in cell biology and clinical diagnostics and is widely distributed for the experimental investigation of microparticle characteristics. In this work, the design, realization, and measurement results of a novel planar optofluidic flow cytometric device with an integrated three-dimensional (3D) adjustable optofluidic lens system for forward scattering/extinction-based biochemical analysis fabricated by silicon micromachining are presented. To our knowledge, this is the first planar cytometric system with the ability to focus light three-dimensionally on cells/particles by the application of fluidic lenses. The single layer microfluidic platform enables versatile 3D hydrodynamic sample focusing to an arbitrary position in the channel and incorporates integrated fiber grooves for the insertion of glass fibers. To confirm the fluid dynamics and raytracing simulations and to characterize the sensor, different cell lines and sets of microparticles were investigated by detecting the extinction (axial light loss) signal, demonstrating the high sensitivity and sample discrimination capability of this analysis system. The unique features of this planar microdevice enable new biotechnological analysis techniques due to the highly increased sensitivity. PMID- 21267438 TI - Miniaturization of dielectric liquid microlens in package. AB - This study presents packaged microscale liquid lenses actuated with liquid droplets of 300-700 MUm in diameter using the dielectric force manipulation. The liquid microlens demonstrated function focal length tunability in a plastic package. The focal length of the liquid lens with a lens droplet of 500 MUm in diameter is shortened from 4.4 to 2.2 mm when voltages applied change from 0 to 79 V(rms). Dynamic responses that are analyzed using 2000 frames/s high speed motion cameras show that the advancing and receding times are measured to be 90 and 60 ms, respectively. The size effect of dielectric liquid microlens is characterized for a lens droplet of 300-700 MUm in diameter in an aspect of focal length. PMID- 21267439 TI - Optofluidic tunable microlens by manipulating the liquid meniscus using a flared microfluidic structure. AB - We have designed, demonstrated, and characterized a simple, novel in-plane tunable optofluidic microlens. The microlens is realized by utilizing the interface properties between two different fluids: CaCl(2)solution and air. A constant contact angle of ~90 degrees is the pivotal factor resulting in the outward bowing and convex shape of the CaCl(2) solution-air interface. The contact angle at the CaCl(2) solution-air interface is maintained by a flared structure in the polydimethylsiloxane channel. The resulting bowing interface, coupled with the refractive index difference between the two fluids, results in effective in-plane focusing. The versatility of such a design is confirmed by characterizing the intensity of a traced beam experimentally and comparing the observed focal points with those obtained via ray-tracing simulations. With the radius of curvature conveniently controlled via fluid injection, the resulting microlens has a readily tunable focal length. This ease of operation, outstandingly low fluid usage, large range tunable focal length, and in-plane focusing ability make this lens suitable for many potential lab-on-a-chip applications such as particle manipulation, flow cytometry, and in-plane optical trapping. PMID- 21267440 TI - Central line bundle implementation in US intensive care units and impact on bloodstream infections. AB - BACKGROUND: Central line-associated bloodstream infections (CLABSI) represent a serious patient safety issue. To prevent these infections, bundled interventions are increasingly recommended. We examine the extent of adoption of Central Line (CL) Bundle elements throughout US intensive care units (ICU) and determine their effectiveness in preventing CLABSIs. METHODOLOGY/PRINCIPAL FINDINGS: In this cross-sectional study, National Healthcare Safety Network (NHSN) hospitals provided the following: ICU-specific NHSN-reported rates of CLABSI/1,000 central line days; policies and compliance rates regarding bundle components; and other setting characteristics. In 250 hospitals the mean CLABSI rate was 2.1 per 1000 central line days and 49% reported having a written CL Bundle policy. However, of those that monitored compliance, only 38% reported very high compliance with the CL Bundle. Only when an ICU had a policy, monitored compliance, and had >= 95% compliance did CLABSI rates decrease. Complying with any one of three CL Bundle elements resulted in decreased CLABSI rates (beta = -1.029, p = 0.015). If an ICU without good bundle compliance achieved high compliance with any one bundle element, we estimated that its CLABSI rate would decrease by 38%. CONCLUSIONS/SIGNIFICANCE: In NHSN hospitals across the US, the CL Bundle is associated with lower infection rates only when compliance is high. Hospitals must target improving bundle implementation and compliance as opposed to simply instituting policies. PMID- 21267441 TI - Serological evidence of subclinical transmission of the 2009 pandemic H1N1 influenza virus outside of Mexico. AB - BACKGROUND: Relying on surveillance of clinical cases limits the ability to understand the full impact and severity of an epidemic, especially when subclinical cases are more likely to be present in the early stages. Little is known of the infection and transmissibility of the 2009 H1N1 pandemic influenza (pH1N1) virus outside of Mexico prior to clinical cases being reported, and of the knowledge pertaining to immunity and incidence of infection during April June, which is essential for understanding the nature of viral transmissibility as well as for planning surveillance and intervention of future pandemics. METHODOLOGY/PRINCIPAL FINDINGS: Starting in the fall of 2008, 306 persons from households with schoolchildren in central Taiwan were followed sequentially and serum samples were taken in three sampling periods for haemagglutination inhibition (HI) assay. Age-specific incidence rates were calculated based on seroconversion of antibodies to the pH1N1 virus with an HI titre of 1:40 or more during two periods: April-June and September-October in 2009. The earliest time period with HI titer greater than 40, as well as a four-fold increase of the neutralization titer, was during April 26-May 3. The incidence rates during the pre-epidemic phase (April-June) and the first wave (July-October) of the pandemic were 14.1% and 29.7%, respectively. The transmissibility of the pH1N1 virus during the early phase of the epidemic, as measured by the effective reproductive number R(0), was 1.16 (95% confidence interval (CI): 0.98-1.34). CONCLUSIONS: Approximately one in every ten persons was infected with the 2009 pH1N1 virus during the pre-epidemic phase in April-June. The lack of age-pattern in seropositivity is unexpected, perhaps highlighting the importance of children as asymptomatic transmitters of influenza in households. Although without virological confirmation, our data raise the question of whether there was substantial pH1N1 transmission in Taiwan before June, when clinical cases were first detected by the surveillance network. PMID- 21267442 TI - Serum apolipoproteins C-I and C-III are reduced in stomach cancer patients: results from MALDI-based peptidome and immuno-based clinical assays. AB - Finding new peptide biomarkers for stomach cancer in human sera that can be implemented into a clinically practicable prediction method for monitoring of stomach cancer. We studied the serum peptidome from two different biorepositories. We first employed a C8-reverse phase liquid chromatography approach for sample purification, followed by mass-spectrometry analysis. These were applied onto serum samples from cancer-free controls and stomach cancer patients at various clinical stages. We then created a bioinformatics analysis pipeline and identified peptide signature discriminating stomach adenocarcinoma patients from cancer-free controls. Matrix Assisted Laser Desorption/Ionization Time of Flight (MALDI-TOF) results from 103 samples revealed 9 signature peptides; with prediction accuracy of 89% in the training set and 88% in the validation set. Three of the discriminating peptides discovered were fragments of Apolipoproteins C-I and C-III (apoC-I and C-III); we further quantified their serum levels, as well as CA19-9 and CRP, employing quantitative commercial clinical assays in 142 samples. ApoC-I and apoC-III quantitative results correlated with the MS results. We then employed apoB-100-normalized apoC-I and apoC-III, CA19-9 and CRP levels to generate rules set for stomach cancer prediction. For training, we used sera from one repository, and for validation, we used sera from the second repository. Prediction accuracies of 88.4% and 74.4% were obtained in the training and validation sets, respectively. Serum levels of apoC-I and apoC-III combined with other clinical parameters can serve as a basis for the formulation of a diagnostic score for stomach cancer patients. PMID- 21267443 TI - Comparison of proliferation and genomic instability responses to WRN silencing in hematopoietic HL60 and TK6 cells. AB - BACKGROUND: Werner syndrome (WS) results from defects in the RecQ helicase (WRN) and is characterized by premature aging and accelerated tumorigenesis. Contradictorily, WRN deficient human fibroblasts derived from WS patients show a characteristically slower cell proliferation rate, as do primary fibroblasts and human cancer cell lines with WRN depletion. Previous studies reported that WRN silencing in combination with deficiency in other genes led to significantly accelerated cellular proliferation and tumorigenesis. The aim of the present study was to examine the effects of silencing WRN in p53 deficient HL60 and p53 wild-type TK6 hematopoietic cells, in order to further the understanding of WRN associated tumorigenesis. METHODOLOGY/PRINCIPAL FINDINGS: We found that silencing WRN accelerated the proliferation of HL60 cells and decreased the cell growth rate of TK6 cells. Loss of WRN increased DNA damage in both cell types as measured by COMET assay, but elicited different responses in each cell line. In HL60 cells, but not in TK6 cells, the loss of WRN led to significant increases in levels of phosphorylated RB and numbers of cells progressing from G1 phase to S phase as shown by cell cycle analysis. Moreover, WRN depletion in HL60 cells led to the hyper-activation of homologous recombination repair via up-regulation of RAD51 and BLM protein levels. This resulted in DNA damage disrepair, apparent by the increased frequencies of both spontaneous and chemically induced structural chromosomal aberrations and sister chromatid exchanges. CONCLUSIONS/SIGNIFICANCE: Together, our data suggest that the effects of WRN silencing on cell proliferation and genomic instability are modulated probably by other genetic factors, including p53, which might play a role in the carcinogenesis induced by WRN deficiency. PMID- 21267444 TI - Stunned silence: gene expression programs in human cells infected with monkeypox or vaccinia virus. AB - Poxviruses use an arsenal of molecular weapons to evade detection and disarm host immune responses. We used DNA microarrays to investigate the gene expression responses to infection by monkeypox virus (MPV), an emerging human pathogen, and Vaccinia virus (VAC), a widely used model and vaccine organism, in primary human macrophages, primary human fibroblasts and HeLa cells. Even as the overwhelmingly infected cells approached their demise, with extensive cytopathic changes, their gene expression programs appeared almost oblivious to poxvirus infection. Although killed (gamma-irradiated) MPV potently induced a transcriptional program characteristic of the interferon response, no such response was observed during infection with either live MPV or VAC. Moreover, while the gene expression response of infected cells to stimulation with ionomycin plus phorbol 12 myristate 13-acetate (PMA), or poly (I-C) was largely unimpaired by infection with MPV, a cluster of pro-inflammatory genes were a notable exception. Poly(I-C) induction of genes involved in alerting the innate immune system to the infectious threat, including TNF-alpha, IL-1 alpha and beta, CCL5 and IL-6, were suppressed by infection with live MPV. Thus, MPV selectively inhibits expression of genes with critical roles in cell-signaling pathways that activate innate immune responses, as part of its strategy for stealthy infection. PMID- 21267446 TI - Presence of p24-antigen associated to erythrocyte in HIV-positive individuals even in patients with undetectable plasma viral load. AB - BACKGROUND: HIV adherence to erythrocytes has been demonstrated in vitro, and it has been suggested that erythrocytes may be carriers of the virus. However, the association between HIV particles or viral proteins and erythrocytes in HIV infected individuals is still to be elucidated. METHODOLOGY/PRINCIPAL FINDINGS: HIV-positive participants (n =112) were classified into two groups according to values of three plasma viral loads (pVL) determined during the 12-month period prior to the study. The first group included 71 individuals with detectable pVL, whereas the second group included 41 individuals with undetectable pVL. Plasma viral load, erythrocyte-associated p24-antigen and p24-antigen in plasma were determined at the moment of the study. A total of 51 out of the 71 patients with detectable pVL showed erythrocyte-associated p24-antigen whereas 13 showed p24 antigen in plasma. Twenty-two out of the 51 patients with erythrocyte-associated p24-antigen showed pVL<10,000 copies/ml and undetectable p24-antigen in plasma. The data indicates that the amount of erythrocyte-associated p24-antigen was not related to p24-antigen in plasma or pVL levels in this group. Among the 41 patients with prior undetectable pVL, eight presented detectable pVL and erythrocyte-associated p24-antigen at the moment of the study. The other 33 showed undetectable pVL and five of these presented erythrocyte-associated p24 antigen. A positive relationship was found between the presence of erythrocyte associated p24-antigen and the detectable pVL at the moment of the study (p<0.00001). Even more, in another series of assays, a detectable viral load associated to erythrocytes was determined and it was always accompanied by erythrocyte-associated p24-antigen detection. CONCLUSIONS/SIGNIFICANCE: This study demonstrates the presence of erythrocyte-associated p24-antigen in HIV infected individuals. Since erythrocyte-associated p24-antigen is not always related to pVL or p24-antigen in plasma, erythrocyte-associated p24-antigen showed viral expression not represented in plasma. Therefore, the determination of erythrocyte-associated p24-antigen may contribute to better understand the kinetics and/or evolution of HIV infection. PMID- 21267445 TI - Gene Expression Profiling via Multigene Concatemers. AB - We established a novel method, Gene Expression Profiling via Multigene Concatemers (MgC-GEP), to study multigene expression patterns simultaneously. This method consists of the following steps: (1) cDNA was obtained using specific reverse primers containing an adaptor. (2) During the initial 1-3 cycles of polymerase chain reaction (PCR), the products containing universal adaptors with digestion sites at both termini were amplified using specific forward and reverse primers containing the adaptors. (3) In the subsequent 4-28 cycles, the universal adaptors were used as primers to yield products. (4) The products were digested and ligated to produce concatemers. (5) The concatemers were cloned into the vector and sequenced. Then, the occurrence of each gene tag was determined. To validate MgC-GEP, we analyzed 20 genes in Saccharomyces cerevisiae induced by weak acid using MgC-GEP combined with real-time reverse transcription (RT)-PCR. Compared with the results of real-time RT-PCR and the previous reports of microarray analysis, MgC-GEP can precisely determine the transcript levels of multigenes simultaneously. Importantly, MgC-GEP is a cost effective strategy that can be widely used in most laboratories without specific equipment. MgC-GEP is a potentially powerful tool for multigene expression profiling, particularly for moderate-throughput analysis. PMID- 21267447 TI - Suspected motor problems and low preference for active play in childhood are associated with physical inactivity and low fitness in adolescence. AB - BACKGROUND: This prospective longitudinal study investigates whether suspected motor problems and low preference for active play in childhood are associated with physical inactivity and low cardiorespiratory fitness in adolescence. METHODOLOGY/PRINCIPAL FINDINGS: The study sample consisted of the Northern Finland Birth Cohort 1986 (NFBC 1986) composed of 5,767 children whose parents responded to a postal inquiry concerning their children's motor skills at age 8 years and who themselves reported their physical activity at age 16 years. Cardiorespiratory fitness was measured with a cycle ergometer test at age 16 years. Odds ratios (OR) and their 95% confidence intervals (95% CI) for the level of physical activity and fitness were obtained from multinomial logistic regression and adjusted for socio-economic position and body mass index. Low preference for active play in childhood was associated with physical inactivity (boys: OR 3.31, 95% CI 2.42-4.53; girls: OR 1.79, 95% CI 1.36-2.36) and low cardiorespiratory fitness (boys: OR 1.87, 95% CI 1.27-2.74; girls: OR 1.52, 95% CI 1.09-2.11) in adolescence. Suspected gross (OR 2.16, 95% CI 1.33-3.49) and fine (OR 1.88, 95% CI 1.35-2.60) motor problems were associated with physical inactivity among boys. Children with suspected motor problems and low preference for active play tended to have an even higher risk of physical inactivity in adolescence. CONCLUSIONS/SIGNIFICANCE: Low preference for active play in childhood was associated with physical inactivity and low cardiorespiratory fitness in adolescence. Furthermore, children with suspected motor problems and low preference for active play tended to have an even higher risk of physical inactivity in adolescence. Identification of children who do not prefer active play and who have motor problems may allow targeted interventions to support their motor learning and participation in active play and thereby promote their physical activity and fitness in later life. PMID- 21267448 TI - Perifosine and CCI 779 co-operate to induce cell death and decrease proliferation in PTEN-intact and PTEN-deficient PDGF-driven murine glioblastoma. AB - BACKGROUND: Platelet derived growth factor receptor (PDGFR) activity is deregulated in human GBM due to amplification and rearrangement of the PDGFR alpha gene locus or overexpression of the PDGF ligand, resulting in the activation of downstream kinases such as phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR). Aberrant PDGFR signaling is observed in approximately 25-30% of human GBMs, which are frequently molecularly classified as the proneural subclass. It would be valuable to understand how PDGFR driven GBMs respond to Akt and mTOR inhibition. METHODOLOGY/PRINCIPAL FINDINGS: Using genetically engineered PTEN-intact and PTEN-deficient PDGF-driven mouse models of GBM that closely mimic the histology and genetics of the human PDGF subgroup, we investigated the effect of inhibiting Akt and mTOR alone or in combination in vitro and in vivo. We used perifosine and CCI-779 to inhibit Akt and mTOR, respectively. Here, we show in vitro data demonstrating that the most effective inhibition of Akt and mTOR activity in both PTEN-intact and PTEN-null primary glioma cell cultures is obtained when using both inhibitors in combination. We next investigated if the effects we observed in culture could be duplicated in vivo by treating mice with gliomas for 5 days. The in vivo treatments with the combination of CCI-779 and perifosine resulted in decreased Akt and mTOR signaling, which correlated to decreased proliferation and increased cell death independent of PTEN status, as monitored by immunoblot analysis, histology and MRI. CONCLUSIONS/SIGNIFICANCE: These findings underline the importance of simultaneously targeting Akt and mTOR to achieve significant down regulation of the PI3K pathway and support the rationale for testing the perifosine and CCI-779 combination in the human PDGF-subgroup of GBM. PMID- 21267449 TI - Characterization of Burkholderia rhizoxinica and B. endofungorum isolated from clinical specimens. AB - Eight isolates submitted to CDC from 1989 to 2006 from clinical specimens were initially identified as members of the genus Burkholderia based on preliminary cellular fatty acid analysis and/or 16S rRNA gene sequencing. With the recent descriptions of the new species B. rhizoxinica and B. endofungorum, which are considered endosymbiotic bacteria in Rhizopus microsporus fungi, we now identify seven of these clinical isolates as B. rhizoxinica and one as B. endofungorum based on biochemical testing, 16s rRNA, and DNA-DNA hybridization results. We also further characterize these isolates by assessing toxin production and/or by multiple locus sequence typing. PMID- 21267450 TI - Race, ethnicity, language, social class, and health communication inequalities: a nationally-representative cross-sectional study. AB - BACKGROUND: While mass media communications can be an important source of health information, there are substantial social disparities in health knowledge that may be related to media use. The purpose of this study is to investigate how the use of cancer-related health communications is patterned by race, ethnicity, language, and social class. METHODOLOGY/PRINCIPAL FINDINGS: In a nationally representative cross-sectional telephone survey, 5,187 U.S. adults provided information about demographic characteristics, cancer information seeking, and attention to and trust in health information from television, radio, newspaper, magazines, and the Internet. Cancer information seeking was lowest among Spanish speaking Hispanics (odds ratio: 0.42; 95% confidence interval: 0.28-0.63) compared to non-Hispanic whites. Spanish-speaking Hispanics were more likely than non-Hispanic whites to pay attention to (odds ratio: 3.10; 95% confidence interval: 2.07-4.66) and trust (odds ratio: 2.61; 95% confidence interval: 1.53 4.47) health messages from the radio. Non-Hispanic blacks were more likely than non-Hispanic whites to pay attention to (odds ratio: 2.39; 95% confidence interval: 1.88-3.04) and trust (odds ratio: 2.16; 95% confidence interval: 1.61 2.90) health messages on television. Those who were college graduates tended to pay more attention to health information from newspapers (odds ratio: 1.98; 95% confidence interval: 1.42-2.75), magazines (odds ratio: 1.86; 95% confidence interval: 1.32-2.60), and the Internet (odds ratio: 4.74; 95% confidence interval: 2.70-8.31) and had less trust in cancer-related health information from television (odds ratio: 0.44; 95% confidence interval: 0.32-0.62) and radio (odds ratio: 0.54; 95% confidence interval: 0.34-0.86) compared to those who were not high school graduates. CONCLUSIONS/SIGNIFICANCE: Health media use is patterned by race, ethnicity, language and social class. Providing greater access to and enhancing the quality of health media by taking into account factors associated with social determinants may contribute to addressing social disparities in health. PMID- 21267451 TI - Sounds scary? Lack of habituation following the presentation of novel sounds. AB - BACKGROUND: Animals typically show less habituation to biologically meaningful sounds than to novel signals. We might therefore expect that acoustic deterrents should be based on natural sounds. METHODOLOGY: We investigated responses by western grey kangaroos (Macropus fulignosus) towards playback of natural sounds (alarm foot stomps and Australian raven (Corvus coronoides) calls) and artificial sounds (faux snake hiss and bull whip crack). We then increased rate of presentation to examine whether animals would habituate. Finally, we varied frequency of playback to investigate optimal rates of delivery. PRINCIPAL FINDINGS: Nine behaviors clustered into five Principal Components. PC factors 1 and 2 (animals alert or looking, or hopping and moving out of area) accounted for 36% of variance. PC factor 3 (eating cessation, taking flight, movement out of area) accounted for 13% of variance. Factors 4 and 5 (relaxing, grooming and walking; 12 and 11% of variation, respectively) discontinued upon playback. The whip crack was most evocative; eating was reduced from 75% of time spent prior to playback to 6% following playback (post alarm stomp: 32%, raven call: 49%, hiss: 75%). Additionally, 24% of individuals took flight and moved out of area (50 m radius) in response to the whip crack (foot stomp: 0%, raven call: 8% and 4%, hiss: 6%). Increasing rate of presentation (12x/min *2 min) caused 71% of animals to move out of the area. CONCLUSIONS/SIGNIFICANCE: The bull whip crack, an artificial sound, was as effective as the alarm stomp at eliciting aversive behaviors. Kangaroos did not fully habituate despite hearing the signal up to 20x/min. Highest rates of playback did not elicit the greatest responses, suggesting that 'more is not always better'. Ultimately, by utilizing both artificial and biological sounds, predictability may be masked or offset, so that habituation is delayed and more effective deterrents may be produced. PMID- 21267452 TI - A qualitative assessment of participation in a rapid scale-up, diagonally integrated MDG-related disease prevention campaign in Rural Kenya. AB - BACKGROUND: Many countries face severe scale-up barriers toward achievement of MDGs. We ascertained motivational and experiential dimensions of participation in a novel, rapid, "diagonal" Integrated Prevention Campaign (IPC) in rural Kenya that provided prevention goods and services to 47,000 people within one week, aimed at rapidly moving the region toward MDG achievement. Specifically, the IPC provided interventions and commodities targeting disease burden reduction in HIV/AIDS, malaria, and water-borne illness. METHODS: Qualitative in-depth interviews (IDI) were conducted with 34 people (18 living with HIV/AIDS and 16 not HIV-infected) randomly selected from IPC attendees consenting to participate. Interviews were examined for themes and patterns to elucidate participant experience and motivation with IPC. FINDINGS: Participants report being primarily motivated to attend IPC to learn of their HIV status (through voluntary counseling and testing), and with receipt of prevention commodities (bednets, water filters, and condoms) providing further incentive. Participants reported that they were satisfied with the IPC experience and offered suggestions to improve future campaigns. INTERPRETATION: Learning their HIV status motivated participants along with the incentive of a wider set of commodities that were rapidly deployed through IPC in this challenging region. The critical role of wanting to know their HIV status combined with commodity incentives may offer a new model for rapid scaled-up of prevention strategies that are wider in scope in rural Africa. PMID- 21267453 TI - Estrogen induced metastatic modulators MMP-2 and MMP-9 are targets of 3,3' diindolylmethane in thyroid cancer. AB - BACKGROUND: Thyroid cancer is the most common endocrine related cancer with increasing incidences during the past five years. Current treatments for thyroid cancer, such as surgery or radioactive iodine therapy, often require patients to be on lifelong thyroid hormone replacement therapy and given the significant recurrence rates of thyroid cancer, new preventive modalities are needed. The present study investigates the property of a natural dietary compound found in cruciferous vegetables, 3,3'-diindolylmethane (DIM), to target the metastatic phenotype of thyroid cancer cells through a functional estrogen receptor. METHODOLOGY/PRINCIPAL FINDINGS: Thyroid cancer cell lines were treated with estrogen and/or DIM and subjected to in vitro adhesion, migration and invasion assays to investigate the anti-metastatic and anti-estrogenic effects of DIM. We observed that DIM inhibits estrogen mediated increase in thyroid cell migration, adhesion and invasion, which is also supported by ER-alpha downregulation (siRNA) studies. Western blot and zymography analyses provided direct evidence for this DIM mediated inhibition of E(2) enhanced metastasis associated events by virtue of targeting essential proteolytic enzymes, namely MMP-2 and MMP-9. CONCLUSION/SIGNIFICANCE: Our data reports for the first time that DIM displays anti-estrogenic like activity by inhibiting estradiol enhanced thyroid cancer cell proliferation and in vitro metastasis associated events, namely adhesion, migration and invasion. Most significantly, MMP-2 and MMP-9, which are known to promote and enhance metastasis, were determined to be targets of DIM. This anti estrogen like property of DIM may lead to the development of a novel preventive and/or therapeutic dietary supplement for thyroid cancer patients by targeting progression of the disease. PMID- 21267454 TI - Gender differences in plasma biomarker levels in a cohort of COPD patients: a pilot study. AB - RATIONALE: Little is known about gender differences in plasma biomarker levels in patients with chronic obstructive pulmonary disease (COPD). HYPOTHESIS: There are differences in serum biomarker levels between women and men with COPD. OBJECTIVE: Explore gender differences in plasma biomarker levels in patients with COPD and smokers without COPD. METHODS: We measured plasma levels of IL-6, IL-8, IL-16, MCP-1, MMP-9, PARC and VEGF in 80 smokers without COPD (40 males, 40 females) and 152 stable COPD patients (76 males, 76 females) with similar airflow obstruction. We determined anthropometrics, smoking history, lung function, exercise tolerance, body composition, BODE index, co-morbidities and quality of life. We then explored associations between plasma biomarkers levels and the clinical characteristics of the patients and also with the clinical and physiological variables known to predict outcome in COPD. RESULTS: The plasma biomarkers level explored were similar in men and women without COPD. In contrast, in patients with COPD the median value in pg/mL of IL-6 (6.26 vs 8.0, p = 0.03), IL-16 (390 vs 321, p = 0.009) and VEGF (50 vs 87, p = 0.02) differed between women and men. Adjusted for smoking history, gender was independently associated with IL-16, PARC and VEGF levels. There were also gender differences in the associations between IL-6, IL-16 and VEGF and physiologic variables that predict outcomes. CONCLUSIONS: In stable COPD patients with similar airflow obstruction, there are gender differences in plasma biomarker levels and in the association between biomarker levels and important clinical or physiological variables. Further studies should confirm our findings. PMID- 21267455 TI - Contribution of cell elongation to the biofilm formation of Pseudomonas aeruginosa during anaerobic respiration. AB - Pseudomonas aeruginosa, a gram-negative bacterium of clinical importance, forms more robust biofilm during anaerobic respiration, a mode of growth presumed to occur in abnormally thickened mucus layer lining the cystic fibrosis (CF) patient airway. However, molecular basis behind this anaerobiosis-triggered robust biofilm formation is not clearly defined yet. Here, we identified a morphological change naturally accompanied by anaerobic respiration in P. aeruginosa and investigated its effect on the biofilm formation in vitro. A standard laboratory strain, PAO1 was highly elongated during anaerobic respiration compared with bacteria grown aerobically. Microscopic analysis demonstrated that cell elongation likely occurred as a consequence of defective cell division. Cell elongation was dependent on the presence of nitrite reductase (NIR) that reduces nitrite (NO(2) (-)) to nitric oxide (NO) and was repressed in PAO1 in the presence of carboxy-PTIO, a NO antagonist, demonstrating that cell elongation involves a process to respond to NO, a spontaneous byproduct of the anaerobic respiration. Importantly, the non-elongated NIR-deficient mutant failed to form biofilm, while a mutant of nitrate reductase (NAR) and wild type PAO1, both of which were highly elongated, formed robust biofilm. Taken together, our data reveal a role of previously undescribed cell biological event in P. aeruginosa biofilm formation and suggest NIR as a key player involved in such process. PMID- 21267456 TI - Schizotypal perceptual aberrations of time: correlation between score, behavior and brain activity. AB - A fundamental trait of the human self is its continuum experience of space and time. Perceptual aberrations of this spatial and temporal continuity is a major characteristic of schizophrenia spectrum disturbances--including schizophrenia, schizotypal personality disorder and schizotypy. We have previously found the classical Perceptual Aberration Scale (PAS) scores, related to body and space, to be positively correlated with both behavior and temporo-parietal activation in healthy participants performing a task involving self-projection in space. However, not much is known about the relationship between temporal perceptual aberration, behavior and brain activity. To this aim, we composed a temporal Perceptual Aberration Scale (tPAS) similar to the traditional PAS. Testing on 170 participants suggested similar performance for PAS and tPAS. We then correlated tPAS and PAS scores to participants' performance and neural activity in a task of self-projection in time. tPAS scores correlated positively with reaction times across task conditions, as did PAS scores. Evoked potential mapping and electrical neuroimaging showed self-projection in time to recruit a network of brain regions at the left anterior temporal cortex, right temporo-parietal junction, and occipito-temporal cortex, and duration of activation in this network positively correlated with tPAS and PAS scores. These data demonstrate that schizotypal perceptual aberrations of both time and space, as reflected by tPAS and PAS scores, are positively correlated with performance and brain activation during self-projection in time in healthy individuals along the schizophrenia spectrum. PMID- 21267457 TI - Saccharomyces cerevisiae Bat1 and Bat2 aminotransferases have functionally diverged from the ancestral-like Kluyveromyces lactis orthologous enzyme. AB - BACKGROUND: Gene duplication is a key evolutionary mechanism providing material for the generation of genes with new or modified functions. The fate of duplicated gene copies has been amply discussed and several models have been put forward to account for duplicate conservation. The specialization model considers that duplication of a bifunctional ancestral gene could result in the preservation of both copies through subfunctionalization, resulting in the distribution of the two ancestral functions between the gene duplicates. Here we investigate whether the presumed bifunctional character displayed by the single branched chain amino acid aminotransferase present in K. lactis has been distributed in the two paralogous genes present in S. cerevisiae, and whether this conservation has impacted S. cerevisiae metabolism. PRINCIPAL FINDINGS: Our results show that the KlBat1 orthologous BCAT is a bifunctional enzyme, which participates in the biosynthesis and catabolism of branched chain aminoacids (BCAAs). This dual role has been distributed in S. cerevisiae Bat1 and Bat2 paralogous proteins, supporting the specialization model posed to explain the evolution of gene duplications. BAT1 is highly expressed under biosynthetic conditions, while BAT2 expression is highest under catabolic conditions. Bat1 and Bat2 differential relocalization has favored their physiological function, since biosynthetic precursors are generated in the mitochondria (Bat1), while catabolic substrates are accumulated in the cytosol (Bat2). Under respiratory conditions, in the presence of ammonium and BCAAs the bat1Delta bat2Delta double mutant shows impaired growth, indicating that Bat1 and Bat2 could play redundant roles. In K. lactis wild type growth is independent of BCAA degradation, since a Klbat1Delta mutant grows under this condition. CONCLUSIONS: Our study shows that BAT1 and BAT2 differential expression and subcellular relocalization has resulted in the distribution of the biosynthetic and catabolic roles of the ancestral BCAT in two isozymes improving BCAAs metabolism and constituting an adaptation to facultative metabolism. PMID- 21267458 TI - Notch signaling regulates late-stage epidermal differentiation and maintains postnatal hair cycle homeostasis. AB - BACKGROUND: Notch signaling involves ligand-receptor interactions through direct cell-cell contact. Multiple Notch receptors and ligands are expressed in the epidermis and hair follicles during embryonic development and the adult stage. Although Notch signaling plays an important role in regulating differentiation of the epidermis and hair follicles, it remains unclear how Notch signaling participates in late-stage epidermal differentiation and postnatal hair cycle homeostasis. METHODOLOGY AND PRINCIPAL FINDINGS: We applied Cre/loxP system to generate conditional gene targeted mice that allow inactivation of critical components of Notch signaling pathway in the skin. Rbpj, the core component of all four Notch receptors, and Pofut1, an essential factor for ligand-receptor interactions, were inactivated in hair follicle lineages and suprabasal layer of the epidermis using the Tgfb3-Cre mouse line. Rbpj conditional inactivation resulted in granular parakeratosis and reactive epidermal hyperplasia. Pofut1 conditional inactivation led to ultrastructural abnormalities in the granular layer and altered filaggrin processing in the epidermis, suggesting a perturbation of the granular layer differentiation. Disruption of Pofut1 in hair follicle lineages resulted in aberrant telogen morphology, a decrease of bulge stem cell markers, and a concomitant increase of K14-positive keratinocytes in the isthmus of mutant hair follicles. Pofut1-deficent hair follicles displayed a delay in anagen re-entry and dysregulation of proliferation and apoptosis during the hair cycle transition. Moreover, increased DNA double stand breaks were detected in Pofut1-deficent hair follicles, and real time PCR analyses on bulge keratinocytes isolated by FACS revealed an induction of DNA damage response and a paucity of DNA repair machinery in mutant bulge keratinocytes. SIGNIFICANCE: our data reveal a role for Notch signaling in regulating late-stage epidermal differentiation. Notch signaling is required for postnatal hair cycle homeostasis by maintaining proper proliferation and differentiation of hair follicle stem cells. PMID- 21267459 TI - The burden of common infectious disease syndromes at the clinic and household level from population-based surveillance in rural and urban Kenya. AB - BACKGROUND: Characterizing infectious disease burden in Africa is important for prioritizing and targeting limited resources for curative and preventive services and monitoring the impact of interventions. METHODS: From June 1, 2006 to May 31, 2008, we estimated rates of acute lower respiratory tract illness (ALRI), diarrhea and acute febrile illness (AFI) among >50,000 persons participating in population-based surveillance in impoverished, rural western Kenya (Asembo) and an informal settlement in Nairobi, Kenya (Kibera). Field workers visited households every two weeks, collecting recent illness information and performing limited exams. Participants could access free high-quality care in a designated referral clinic in each site. Incidence and longitudinal prevalence were calculated and compared using Poisson regression. RESULTS: INCIDENCE RATES RESULTING IN CLINIC VISITATION WERE THE FOLLOWING: ALRI--0.36 and 0.51 episodes per year for children <5 years and 0.067 and 0.026 for persons >= 5 years in Asembo and Kibera, respectively; diarrhea--0.40 and 0.71 episodes per year for children <5 years and 0.09 and 0.062 for persons >= 5 years in Asembo and Kibera, respectively; AFI--0.17 and 0.09 episodes per year for children <5 years and 0.03 and 0.015 for persons >= 5 years in Asembo and Kibera, respectively. Annually, based on household visits, children <5 years in Asembo and Kibera had 60 and 27 cough days, 10 and 8 diarrhea days, and 37 and 11 fever days, respectively. Household-based rates were higher than clinic rates for diarrhea and AFI, this difference being several-fold greater in the rural than urban site. CONCLUSIONS: Individuals in poor Kenyan communities still suffer from a high burden of infectious diseases, which likely hampers their development. Urban slum and rural disease incidence and clinic utilization are sufficiently disparate in Africa to warrant data from both settings for estimating burden and focusing interventions. PMID- 21267460 TI - A new approach for heparin standardization: combination of scanning UV spectroscopy, nuclear magnetic resonance and principal component analysis. AB - The year 2007 was marked by widespread adverse clinical responses to heparin use, leading to a global recall of potentially affected heparin batches in 2008. Several analytical methods have since been developed to detect impurities in heparin preparations; however, many are costly and dependent on instrumentation with only limited accessibility. A method based on a simple UV-scanning assay, combined with principal component analysis (PCA), was developed to detect impurities, such as glycosaminoglycans, other complex polysaccharides and aromatic compounds, in heparin preparations. Results were confirmed by NMR spectroscopy. This approach provides an additional, sensitive tool to determine heparin purity and safety, even when NMR spectroscopy failed, requiring only standard laboratory equipment and computing facilities. PMID- 21267461 TI - Genetic variation of the serotonin 2a receptor affects hippocampal novelty processing in humans. AB - Serotonin (5-hydroxytryptamine, 5-HT) is an important neuromodulator in learning and memory processes. A functional genetic polymorphism of the 5-HT 2a receptor (5-HTR2a His452Tyr), which leads to blunted intracellular signaling, has previously been associated with explicit memory performance in several independent cohorts, but the underlying neural mechanisms are thus far unclear. The human hippocampus plays a critical role in memory, particularly in the detection and encoding of novel information. Here we investigated the relationship of 5-HTR2a His452Tyr and hippocampal novelty processing in 41 young, healthy subjects using functional magnetic resonance imaging (fMRI). Participants performed a novelty/familiarity task with complex scene stimuli, which was followed by a delayed recognition memory test 24 hours later. Compared to His homozygotes, Tyr carriers exhibited a diminished hippocampal response to novel stimuli and a higher tendency to judge novel stimuli as familiar during delayed recognition. Across the cohort, the false alarm rate during delayed recognition correlated negatively with the hippocampal novelty response. Our results suggest that previously reported effects of 5-HTR2a on explicit memory performance may, at least in part, be mediated by alterations of hippocampal novelty processing. PMID- 21267462 TI - Mutation and selection on the wobble nucleotide in tRNA anticodons in marine bivalve mitochondrial genomes. AB - BACKGROUND: Animal mitochondrial genomes typically encode one tRNA for each synonymous codon family, so that each tRNA anticodon essentially has to wobble to recognize two or four synonymous codons. Several factors have been hypothesized to determine the nucleotide at the wobble site of a tRNA anticodon in mitochondrial genomes, such as the codon-anticodon adaptation hypothesis, the wobble versatility hypothesis, the translation initiation and elongation conflict hypothesis, and the wobble cost hypothesis. PRINCIPAL FINDINGS: In this study, we analyzed codon usage and tRNA anticodon wobble sites of 29 marine bivalve mitochondrial genomes to evaluate features of the wobble nucleotides in tRNA anticodons. The strand-specific mutation bias favors G and T on the H strand in all the 29 marine bivalve mitochondrial genomes. A bias favoring G and T is also visible in the third codon positions of protein-coding genes and the wobble sites of anticodons, rejecting that codon usage bias drives the wobble sites of tRNA anticodons or tRNA anticodon bias drives the evolution of codon usage. Almost all codon families (98.9%) from marine bivalve mitogenomes support the wobble versatility hypothesis. There are a few interesting exceptions involving tRNA(Trp) with an anticodon CCA fixed in Pectinoida species, tRNA(Ser) with a GCU anticodon fixed in Mytiloida mitogenomes, and the uniform anticodon CAU of tRNA(Met) translating the AUR codon family. CONCLUSIONS/SIGNIFICANCE: These results demonstrate that most of the nucleotides at the wobble sites of tRNA anticodons in marine bivalve mitogenomes are determined by wobble versatility. Other factors such as the translation initiation and elongation conflict, and the cost of wobble translation may contribute to the determination of the wobble nucleotide in tRNA anticodons. The finding presented here provides valuable insights into the previous hypotheses of the wobble nucleotide in tRNA anticodons by adding some new evidence. PMID- 21267463 TI - Substrate profiling of tobacco etch virus protease using a novel fluorescence assisted whole-cell assay. AB - Site-specific proteolysis of proteins plays an important role in many cellular functions and is often key to the virulence of infectious organisms. Efficient methods for characterization of proteases and their substrates will therefore help us understand these fundamental processes and thereby hopefully point towards new therapeutic strategies. Here, a novel whole-cell in vivo method was used to investigate the substrate preference of the sequence specific tobacco etch virus protease (TEVp). The assay, which utilizes protease-mediated intracellular rescue of genetically encoded short-lived fluorescent substrate reporters to enhance the fluorescence of the entire cell, allowed subtle differences in the processing efficiency of closely related substrate peptides to be detected. Quantitative screening of large combinatorial substrate libraries, through flow cytometry analysis and cell sorting, enabled identification of optimal substrates for TEVp. The peptide, ENLYFQG, identical to the protease's natural substrate peptide, emerged as a strong consensus cleavage sequence, and position P3 (tyrosine, Y) and P1 (glutamine, Q) within the substrate peptide were confirmed as being the most important specificity determinants. In position P1', glycine (G), serine (S), cysteine (C), alanine (A) and arginine (R) were among the most prevalent residues observed, all known to generate functional TEVp substrates and largely in line with other published studies stating that there is a strong preference for short aliphatic residues in this position. Interestingly, given the complex hydrogen-bonding network that the P6 glutamate (E) is engaged in within the substrate-enzyme complex, an unexpectedly relaxed residue preference was revealed for this position, which has not been reported earlier. Thus, in the light of our results, we believe that our assay, besides enabling protease substrate profiling, also may serve as a highly competitive platform for directed evolution of proteases and their substrates. PMID- 21267464 TI - The spatial architecture of Bacillus subtilis biofilms deciphered using a surface associated model and in situ imaging. AB - The formation of multicellular communities known as biofilms is the part of bacterial life cycle in which bacteria display cooperative behaviour and differentiated phenotypes leading to specific functions. Bacillus subtilis is a Gram-positive bacterium that has served for a decade as a model to study the molecular pathways that control biofilm formation. Most of the data on B. subtilis biofilms have come from studies on the formation of pellicles at the air liquid interface, or on the complex macrocolonies that develop on semi-solid nutritive agar. Here, using confocal laser scanning microcopy, we show that B. subtilis strains of different origins are capable of forming biofilms on immersed surfaces with dramatically protruding "beanstalk-like" structures with certain strains. Indeed, these structures can reach a height of more than 300 um with one undomesticated strain from a medical environment. Using 14 GFP-labeled mutants previously described as affecting pellicle or complex colony formation, we have identified four genes whose inactivation significantly impeded immersed biofilm development, and one mutation triggering hyperbiofilm formation. We also identified mutations causing the three-dimensional architecture of the biofilm to be altered. Taken together, our results reveal that B. subtilis is able to form specific biofilm features on immersed surfaces, and that the development of these multicellular surface-associated communities involves regulation pathways that are common to those governing the formation of pellicle and/or complex colonies, and also some specific mechanisms. Finally, we propose the submerged surface associated biofilm as another relevant model for the study of B. subtilis multicellular communities. PMID- 21267465 TI - Reduced rate of neural differentiation in the dentate gyrus of adult dysbindin null (sandy) mouse. AB - Genetic variations in the gene encoding dysbindin has consistently been associated with schizophrenia and bipolar disorder, although little is known about the neural functions carried out by dysbindin. To gain some insight into this area, we took advantage of the readily available dysbindin-null mouse sandy (sdy-/-) and studied hippocampal neurogenesis using thymidine analogue bromodeoxuridine (BrdU). No significant differences were found in the proliferation (4 hours) or survival (1, 4 and 8 weeks after the last BrdU injection) of progenitors in the subgranular regions of the dentate gyrus between sdy-/- and sdy+/+ (control) mice. However, 4 weeks after the last BrdU injection, a significant reduction was observed in the ratio of neuronal differentiation in sdy-/- when compared to that of sdy+/+ (sdy+/+ = 87.0 +/- 5.3% vs. sdy-/- = 71.3 +/- 8.3%, p = 0.01). These findings suggest that dysbindin plays a role during differentiation process in the adult hippocampal neurogenesis and that its deficit may negatively affect neurogenesis-related functions such as cognition and mood. PMID- 21267466 TI - Effects of androgen receptor and androgen on gene expression in prostate stromal fibroblasts and paracrine signaling to prostate cancer cells. AB - The androgen receptor (AR) is expressed in a subset of prostate stromal cells and functional stromal cell AR is required for normal prostate developmental and influences the growth of prostate tumors. Although we are broadly aware of the specifics of the genomic actions of AR in prostate cancer cells, relatively little is known regarding the gene targets of functional AR in prostate stromal cells. Here, we describe a novel human prostate stromal cell model that enabled us to study the effects of AR on gene expression in these cells. The model involves a genetically manipulated variant of immortalized human WPMY-1 prostate stromal cells that overexpresses wildtype AR (WPMY-AR) at a level comparable to LNCaP cells and is responsive to dihydrotestosterone (DHT) stimulation. Use of WPMY-AR cells for gene expression profiling showed that the presence of AR, even in the absence of DHT, significantly altered the gene expression pattern of the cells compared to control (WPMY-Vec) cells. Treatment of WPMY-AR cells, but not WPMY-Vec control cells, with DHT resulted in further changes that affected the expression of 141 genes by 2-fold or greater compared to vehicle treated WPMY-AR cells. Remarkably, DHT significantly downregulated more genes than were upregulated but many of these changes reversed the initial effects of AR overexpression alone on individual genes. The genes most highly effected by DHT treatment were categorized based upon their role in cancer pathways or in cell signaling pathways (transforming growth factor-beta, Wnt, Hedgehog and MAP Kinase) thought to be involved in stromal-epithelial crosstalk during prostate or prostate cancer development. DHT treatment of WPMY-AR cells was also sufficient to alter their paracrine potential for prostate cancer cells as conditioned medium from DHT-treated WPMY-AR significantly increased growth of LNCaP cells compared to DHT-treated WPMY-Vec cell conditioned medium. PMID- 21267467 TI - Sexual violence toward children and youth in war-torn eastern Democratic Republic of Congo. AB - BACKGROUND: The epidemic of gender-based violence in the Democratic Republic of the Congo (DRC) has garnered popular media attention, but is incompletely described in the medical literature to date. In particular, the relative importance of militarized compared to civilian rape and the impact on vulnerable populations merits further study. We describe a retrospective case series of sexual abuse among children and youth in eastern DRC. METHODS: Medical records of patients treated for sexual assault at HEAL Africa Hospital, Goma, DRC between 2006 and 2008 were reviewed. Information extracted from the chart record was summarized using descriptive statistics, with comparative statistics to examine differences between pediatric (<= 18 yrs) and adult patients. FINDINGS: 440 pediatric and 54 adult sexual abuse cases were identified. Children and youth were more often assaulted by someone known to the family (74% vs 30%, OR 6.7 [95%CI 3.6-12], p<0.001), and less frequently by military personnel (13% vs 48%, OR 0.14 [95%CI 0.075-0.26], p<0.001). Delayed presentation for medical care (>72 hours after the assault) was more common in pediatric patients (53% vs 33%, OR 2.2 [95%CI 1.2-4.0], p = 0.007). Physical signs of sexual abuse, including lesions of the posterior fourchette, hymeneal tears, and anal lesions, were more commonly observed in children and youth (84% vs 69%, OR 2.3 [95%CI 1.3-4.4], p = 0.006). Nine (2.9%) pediatrics patients were HIV-positive at presentation, compared to 5.3% of adults (p = 0.34). INTERPRETATION: World media attention has focused on violent rape as a weapon of war in the DRC. Our data highlight some neglected but important and distinct aspects of the ongoing epidemic of sexual violence: sexual abuse of children and youth. PMID- 21267469 TI - Stability in ecosystem functioning across a climatic threshold and contrasting forest regimes. AB - Classical ecological theory predicts that changes in the availability of essential resources such as nitrogen should lead to changes in plant community composition due to differences in species-specific nutrient requirements. What remains unknown, however, is the extent to which climate change will alter the relationship between plant communities and the nitrogen cycle. During intervals of climate change, do changes in nitrogen cycling lead to vegetation change or do changes in community composition alter the nitrogen dynamics? We used long-term ecological data to determine the role of nitrogen availability in changes of forest species composition under a rapidly changing climate during the early Holocene (16k to 8k cal. yrs. BP). A statistical computational analysis of ecological data spanning 8,000 years showed that secondary succession from a coniferous to deciduous forest occurred independently of changes in the nitrogen cycle. As oak replaced pine under a warming climate, nitrogen cycling rates increased. Interestingly, the mechanism by which the species interacted with nitrogen remained stable across this threshold change in climate and in the dominant tree species. This suggests that changes in tree population density over successional time scales are not driven by nitrogen availability. Thus, current models of forest succession that incorporate the effects of available nitrogen may be over-estimating tree population responses to changes in this resource, which may result in biased predictions of future forest dynamics under climate warming. PMID- 21267468 TI - HP1 recruits activity-dependent neuroprotective protein to H3K9me3 marked pericentromeric heterochromatin for silencing of major satellite repeats. AB - H3 lysine 9 trimethylation (H3K9me3) is a histone posttranslational modification (PTM) that has emerged as hallmark of pericentromeric heterochromatin. This constitutive chromatin domain is composed of repetitive DNA elements, whose transcription is differentially regulated. Mammalian cells contain three HP1 proteins, HP1alpha, HP1beta and HP1gamma These have been shown to bind to H3K9me3 and are thought to mediate the effects of this histone PTM. However, the mechanisms of HP1 chromatin regulation and the exact functional role at pericentromeric heterochromatin are still unclear. Here, we identify activity dependent neuroprotective protein (ADNP) as an H3K9me3 associated factor. We show that ADNP does not bind H3K9me3 directly, but that interaction is mediated by all three HP1 isoforms in vitro. However, in cells ADNP localization to areas of pericentromeric heterochromatin is only dependent on HP1alpha and HP1beta. Besides a PGVLL sequence patch we uncovered an ARKS motif within the ADNP homeodomain involved in HP1 dependent H3K9me3 association and localization to pericentromeric heterochromatin. While knockdown of ADNP had no effect on HP1 distribution and heterochromatic histone and DNA modifications, we found ADNP silencing major satellite repeats. Our results identify a novel factor in the translation of H3K9me3 at pericentromeric heterochromatin that regulates transcription. PMID- 21267470 TI - Evaluation of apparent non-specific protein loss due to adsorption on sample tube surfaces and/or altered immunogenicity. AB - The non-specific loss of protein analytes can have a major effect on assay results particularly where the concentrations of such analytes are extremely low and the matrix is complex. This report assesses how the protein incubated in sample tubes may be lost due to adsorption. Use of proteins, such as bovine serum albumin (BSA), may be used to pre-treat tubes to reduce such losses. However, such losses may also be associated with structural perturbations leading to changes in immunogenicity (as a result of alterations in specific epitope-related conformations). This can lead to erroneous results or lack of comparability with a range of methodologies such as the bicinchoninic protein assay and immunoassays or when surface plasmon resonance (SPR)-based approaches are used. A model system to evaluate these phenomena is proposed. PMID- 21267471 TI - Ultrafast photoinduced intramolecular charge transfer in push-pull distyryl furan and benzofuran: solvent and molecular structure effect. AB - The excited state deactivation pathways of push-pull distyryl furan and benzofuran derivatives in several organic solvents were investigated in detail by using time-resolved transient absorption and fluorescence spectroscopies, with nano- and femto-second time resolution. Solvent polarity was found to play a key role in determining the efficiencies of fluorescence, intersystem crossing and internal conversion. The triplet yield gradually decreased, while the internal conversion increased upon increasing the solvent dielectric constant. However the fluorescence showed a different solvent polarity effect in the low and high solvent polarity region, with a reversal of the trend of fluorescence properties (quantum yield and lifetime). This fact points to an emitting state of a different nature (smaller and larger dipole moments) in the two cases, as also suggested by the huge fluorosolvatochromism. In fact the ultrafast spectroscopic investigation evidenced the presence of two transients characterized by peculiar spectral shapes assigned to a locally excited (LE) and a charge transfer (CT) state. In the more polar solvents the CT state was the longer lived, fluorescent one and an intramolecular charge transfer process was found to be operative and to become faster (up to ~200-250 fs) in the higher polarity media. On the contrary, distyrylfuran, which exhibits the same molecular skeleton without the push-pull character showed a similar excited state dynamics in solvents of different polarities. PMID- 21267472 TI - Regioselective deacetylation based on teicoplanin-complexed Orf2* crystal structures. AB - Lipoglycopeptide antibiotics are more effective than vancomycin against MRSA as they carry an extra aliphatic acyl side chain on glucosamine (Glm) at residue 4 (r4). The biosynthesis of the r4 N-acyl Glc moiety at teicoplanin (Tei) or A40926 has been elucidated, in which the primary amine nucleophile of Glm is freed from the r4 GlcNac pseudo-Tei precursor by Orf2* for the subsequent acylation reaction to occur. In this report, two Orf2* structures in complex with beta-D-octyl glucoside or Tei were solved. Of the complexed structures, the substrate binding site and a previously unknown hydrophobic cavity were revealed, wherein r4 GlcNac acts as the key signature for molecular recognition and the cavity allows substrates carrying longer acyl side chains in addition to the acetyl group. On the basis of the complexed structures, a triple-mutation mutant S98A/V121A/F193Y is able to regioselectively deacetylate r6 GlcNac pseudo-Tei instead of that at r4. Thereby, novel analogs can be made at the r6 sugar moiety. PMID- 21267473 TI - TiO2 and ZnO nanoparticles negatively affect wheat growth and soil enzyme activities in agricultural soil. AB - The properties of nanoparticles and their increased use have raised concerns about their possible harmful effects within the environment. Most studies on their effects have been in aqueous systems. Here we investigated the effect of TiO(2) and ZnO nanoparticles on wheat growth and soil enzyme activities under field conditions. Both of the nanoparticles reduced the biomass of wheat. The TiO(2) nanoparticles were retained in the soil for long periods and primarily adhered to cell walls of wheat. The ZnO nanoparticles dissolved in the soil, thereby enhancing the uptake of toxic Zn by wheat. The nanoparticles also induced significant changes in soil enzyme activities, which are bioindicators of soil quality and health. Soil protease, catalase, and peroxidase activities were inhibited in the presence of the nanoparticles; urease activity was unaffected. The nanoparticles themselves or their dissolved ions were clearly toxic for the soil ecosystem. PMID- 21267477 TI - Zirconia nanoparticles-coated column for the capillary electrochromatographic separation of iron-binding- and phosphorylated-proteins. AB - A ZrO(2) nanoparticles (ZrO(2)NPs)-coated column was prepared through a sol-gel process using zirconium(iv) oxychloride, which reacted with silanol groups of the fused-silica capillary. The condensation reaction was carried out at 350 degrees C for 8 h. Electroosmotic flow (EOF) measurements and scanning electron microscopy (SEM) images were used to characterize the ZrO(2)NPs fabricated on the inner wall of the capillary. Below the pI value (pH 5-6), cathodic EOF elucidated that the phosphate buffer adsorbs tightly on the zirconia surface, resulting in a negatively charged surface. In this work, iron-binding proteins, phosphorylated proteins and glycoproteins were selected as the model compounds. The effects of pH, concentration, buffer type and the organic modifier were studied to optimize the separation efficiency. Iron-binding proteins exhibited a retention time for myoglobin (Mb) < hemoglobin (Hb), which corresponded to the binding constants for ZrO(2)NPs. The alpha- and beta-subunit of Hb could be separated in borate buffer (20 mM, pH 9.0) with MeOH (20%, v/v). Greater affinity of alpha-casein and bovine serum albumin (BSA) for the stationary phase as the pH decreased was found by comparison with that of conalbumin (ConA) and transferrin (Tf). Interestingly, 14 peaks for glycoisoforms of ovalbumin (OVA) were observed using borate buffer (40 mM, pH 9.0). The established method was also applied to the determination of analytes in the egg whites of chicken and duck eggs. PMID- 21267478 TI - Occurrence of organochlorine pesticides in indoor dust. AB - Organochlorine pesticides are present in the environment and suspected of causing serious health effects. Diet has been the main exposure source, but indoor source release is gaining focus. Within a monitoring study of polychlorinated biphenyls of Danish buildings built during the 1960s and 1970s, we coincidently determined extreme levels of dichlorodiphenyltrichloroethane (DDT) levels in two of ten random samples. This raises concern and further large scale investigations are warranted to confirm this. PMID- 21267479 TI - Hydrophilic polycarbonate for generation of oil in water emulsions in microfluidic devices. AB - This report details the method for rendering hydrophilic surfaces of microchannels fabricated in polycarbonate (PC). We characterize the wetting properties and stability of the hydrophilic character of two coatings--one formed by a layer of poly(allylamine) (PAH*) and the second including an additional layer of poly(styrene-sulfonate) (PSS). This second (PC-PAH/PSS) coating yields highly hydrophilic surface that is stable against weeks of exposure to various fluids including organic oils. This coating allows for stable generation of oil in-water emulsions of hydrocarbon, silicone and fluorinated oils without the use of surfactants and over days of continuous use. PMID- 21267480 TI - Techniques for recording reconstituted ion channels. AB - This review describes and discusses techniques useful for monitoring the activity of protein ion channels in vitro. In the first section the biological importance and the classification of ion channels are outlined in order to justify the strong motivation for dealing with this important class of membrane proteins. The expression, reconstitution and integration of recombinant proteins into lipid bilayers are crucial steps to obtain consistent data when working with ion channels. In the second section recording techniques used in research are presented. Since this review focuses on analytical systems bearing reconstituted ion channels the industrial most important patch-clamp techniques of cells are only briefly mentioned. In section three, artificial systems developed in the last decades are described while the emerging technologies using nanostructured supports or microfluidic systems are presented in section four. Finally, the remaining challenges of membrane protein analysis and its potential applications are briefly outlined. PMID- 21267481 TI - Surface-enhanced Raman spectroscopy analysis of house paint and wallpaper samples from an 18th century historic property. AB - Conservation efforts for heritage buildings require a substantial knowledge of the chemical makeup of materials that were used throughout the lifetime of the property. In particular, conservators are often concerned with the identification of colorants used in both interior and exterior wall treatments (paint, wallpaper, etc.) in order to gain perspective into how the building may have appeared during a certain time period in its existence. Ideally, such an analysis requires a technique that provides molecular level information as to the identity of the colorant as well as other sample components (binders, fillers, etc.), which is useful for dating purposes. In addition, the technique should be easily applied to paint layer samples which can be extremely thin and fragile. Herein we report the surface-enhanced Raman spectroscopy (SERS) analysis of paint and wallpaper samples taken from exterior and interior surfaces of a historic building. Several pigments were identified in the samples, which ranged from early inorganic pigments (lead white, barium sulfate, calcium carbonate, anhydrous chromium(III) oxide) which have been used in house paints for centuries, to a more modern pigment (phthalocyanine blue), developed in the middle of the 20th century. This analysis highlights the usefulness of SERS in such a conservation effort, and demonstrates for the first time pigment identification in house paints and wallpaper using SERS, which has far-reaching implications not only in the field of conservation, but also in forensics, industrial process control, and environmental health and safety. PMID- 21267482 TI - Extended nanospace chemical systems on a chip for new analytical technology. AB - Integration of chemical processes on a microchemical chip has gained much attention in the past decade, and the basic concepts of micro-integration and the supporting technologies have been intensively developed. As a result, many analytical and chemical synthesis applications were demonstrated. The superior performances were verified including shortening analysis time, decrease of sample and reagent volume, and easy chemical operations. Now, the micro-technologies are moving toward practical applications by establishing the systems in which the microchemical chip works as chemical central processing unit. Recently, as a new research field, integration is further proceeding to the 10(1)-10(3) nm scale, which we call extended nanospace. The extended nanospace locates the gap between the targets of conventional nanotechnology (10(0)-10(1) nm) and micro-technology (>1 MUm), and the fluidics and chemistry have not been explored well due to a lack of fundamental technologies. For these purposes, many methodologies were established in recent years. Unique liquid properties were reported, which were quite different from those in microspace. Some properties can be expected by considering the characteristics of microspace and the downscaling, and the others are unexpected or are difficult to predict. These properties enabled new chemical operations which will be quite important as the next analytical technologies. Now, chemistry and fluidics in the extended nanospace are forming a new research field. In this review, we survey the fundamental technologies for extended nanospace researches and introduce several unique liquid properties. Finally, unique chemical operations are also illustrated leading to new analytical operations. PMID- 21267483 TI - Protein A-conjugated luminescent gold nanodots as a label-free assay for immunoglobulin G in plasma. AB - We have employed protein A-modified gold nanodots (PA-Au NDs) as a luminescence sensor for the detection of human immunoglobulin G (hIgG) in homogeneous solutions. The luminescent PA-Au NDs were prepared simply by mixing protein A with the luminescent Au NDs (average diameter: ca. 1.8 nm). The specific interactions that occur between protein A and hIgG allowed us to use the PA-Au NDs to detect hIgG selectively. Under optimal conditions [10 nM PA-Au NDs (two protein A molecules per Au ND), 5.0 mM phosphate buffer solution, pH 7.4], the PA Au ND probe detected hIgG with high sensitivity (limit of detection = 10 nM) and remarkable selectivity (>50-fold) over other proteins. In an assay that took advantage of the competition between protein G and the PA-Au NDs for IgG, we detected protein G at concentrations as low as 85 nM. This PA-Au ND probe allowed determination of the hIgG concentration in plasma samples without any need for sample pretreatment. Our results exhibited a good linear correlation (R(2)=0.97) with those obtained using an enzyme-linked immunosorbent assay. Our simple, sensitive, and selective approach appears to hold practical potential for use in the clinical diagnosis of immune diseases associated with changes in hIgG levels. PMID- 21267484 TI - The Zintl ion [As7]2-: an example of an electron-deficient As(x) radical anion. AB - [K(2,2,2-crypt)](2)[As(7)].THF, 1 (2,2,2-crypt = 4,7,13,16,21,24-hexaoxa-1,10 diazabicyclo[8.8.8]hexacosane) is the first well characterized seven-atom radical anion of group 15. UV-Vis spectroscopy confirms the presence and electronic structure of [As(7)](2-). Cyclic voltammetry in DMF solution shows the As(7)(3 )/As(7)(2-) redox couple as a one-electron reversible process. Theoretical investigations explore the bonding and properties of compound 1. PMID- 21267485 TI - Novel C-H functionalization of arenes: palladium-catalyzed synthesis of diaryl sulfides. AB - A novel protocol for the direct arylthiolation of electron-rich arenes is described. Applying arylsulfonyl cyanides in the presence of catalytic amounts of Pd allows for a straightforward synthesis of diaryl sulfides. PMID- 21267486 TI - Copper-catalyzed synthesis of alkynylphosphine derivatives: unprecedented use of nucleophilic phosphorus compounds. AB - A new and smooth approach towards alkynylphosphine derivatives is described. It relies on the unprecedented catalytic coupling of secondary phosphine boranes with alkynyl bromides using the CuI/1,10-phenanthroline couple. PMID- 21267487 TI - Label-free detection of telomerase activity in HeLa cells using electrochemical impedance spectroscopy. AB - A simple assay based on electrochemical impedance spectroscopy (EIS) for detection of telomerase activity is developed, and it is demonstrated that the label-free EIS method is capable of detecting the telomerase activity in HeLa cells with a detection limit of 1000 HeLa cells without using any amplification technique. PMID- 21267488 TI - Photon-driven charge transfer and photocatalysis of p-aminothiophenol in metal nanogaps: a DFT study of SERS. AB - When p-aminothiophenol (PATP) is used as a probe molecule and adsorbs on silver and gold nanogaps, a significant change of relative SERS intensities can be observed. Our DFT calculations show that surface photocatalytic coupling reactions yield a new surface species of p,p'-dimercaptoazobenzene (DMAB) causing the significant change in the SERS spectra. PMID- 21267489 TI - Surface-enhanced Raman scattering with silver nanostructures generated in situ in a sporopollenin biopolymer matrix. AB - Silver nanoparticles were generated based on citrate reduction in the ultrastructure of the sporopollenin biopolymer of Ambrosia artemisiifolia (ragweed) and Secale cereale (rye). The nanoparticles enable the acquisition of SERS spectra and thereby a vibrational characterization of the local molecular structure of sporopollenin. PMID- 21267490 TI - The impact of protonation and deprotonation of 3-methyl-2'-deoxyadenosine on N glycosidic bond cleavage. AB - The enzyme-substrate contacts that are believed to be involved in depurination by proton transfer have been modelled by protonation and deprotonation of 3-methyl 2'-deoxyadenosine (3-MDA) using quantum mechanical calculations in the gas-phase and solution media. The change in the charge distribution on the sugar ring and nucleobase that is introduced by the protonation and deprotonation strongly affects the N-glycosidic bond length. The unimolecular cleavage and hydrolysis of the N-glycosidic bond, involving D(N)*A(N) and A(N)D(N) pathways, have been considered at several levels of theory. The trend in the energy barriers is A(N)D(N) > cleavage > D(N)*A(N). All probable proton transfer reactions resulting from enzyme-substrate contacts do not facilitate the N-glycosidic bond cleavage of 3-MDA. The deprotonation of 3-MDA that may result from the interaction between H6 and enzyme do not facilitate bond cleavage. The protonation at N7 induces more positive charge on the sugar ring and further facilitates the depurination relative to the protonation at N1. The changes in the charges calculated on the ribose and nucleobase are in good relationship with the C1'-C2', C1'-O4', and N glycosidic bond lengths along the cleavage. The change in energy barrier DeltaE of glycosidic bond cleavage from the gas-phase to solution media strongly depends on the charge of the species. PMID- 21267491 TI - Multiscale modelling of mesoscopic phenomena triggered by quantum events: light driven azo-materials and beyond. AB - The macroscopic functionality of soft (bio-)materials is often triggered by quantum-mechanical events which are highly local in space and time. In order to arrive at the resulting macroscopically observable phenomena, many orders of magnitude need to be bridged on both the time and the length scale. In the present paper, we first introduce a range of simulation methods at different scales as well as theoretical approaches to form bridges between them. We then outline a strategy to develop an adaptive multiscale simulation approach which connects the quantum to the mesoscopic level by bringing together ab initio molecular dynamics (QM), classical (force field) molecular dynamics (MM), and coarse grained (CG) simulation techniques. With a multitude of photoactive materials in mind, we apply our methodology to a prototypical test case-light induced phase transitions in a liquid crystal containing the azobenzene photoswitch. PMID- 21267492 TI - Metal use in ribonucleotide reductase R2, di-iron, di-manganese and heterodinuclear--an intricate bioinorganic workaround to use different metals for the same reaction. AB - The ferritin-like superfamily comprises of several protein groups that utilize dinuclear metal sites for various functions, from iron storage to challenging oxidations of substrates. Ribonucleotide reductase R2 proteins use the metal site for the generation of a free radical required for the reduction of ribonucleotides to deoxyriboinucleotides, the building blocks of DNA. This ubiquitous and essential reaction has been studied for over four decades and the R2 proteins were, until recently, generally believed to employ the same cofactor and mechanism for radical generation. In this reaction, a stable tyrosyl radical is produced following activation and cleavage of molecular oxygen at a dinuclear iron site in the protein. Discoveries in the last few years have now firmly established that the radical generating reaction is not conserved among the R2 proteins but that different subgroups, that are structurally very similar, instead employ di-manganese or heterodinuclear Mn-Fe cofactors as radical generators. This is remarkable considering that the protein must exercise a strict control over oxygen activation, reactive metal-oxygen intermediate species and the resulting redox potential of the produced radical equivalent. Given the differences in redox properties between Mn and Fe, use of a different metal for this reaction requires associated adaptations of the R2 protein scaffold and the activation mechanism. Further analysis of the differences in protein sequence between R2 subgroups have also led to the discovery of new groups of R2-like proteins with completely different functions, expanding the chemical repertoire of the ferritin-like superfamily. This review describes the discoveries leading up to the identification of the different Mn-containing R2 protein groups and our current understanding of them. Hypotheses regarding the biochemical rationale to develop these chemically complex alternative solutions are also discussed. PMID- 21267493 TI - Isothiazolones; thiol-reactive inhibitors of cysteine protease cathepsin B and histone acetyltransferase PCAF. AB - Isothiazolones and 5-chloroisothiazolones react chemoselectively with thiols by cleavage of the weak nitrogen-sulfur bond to form disulfides. They show selectivity for inhibition of the thiol-dependent cysteine protease cathepsin B and the histone acetyltransferase p300/CBP associated factor (PCAF) based on their substitution pattern. Furthermore, enzyme kinetics and mass spectroscopy indicate covalent binding of a 5-chloroisothiazolone to cathepsin B, which demonstrates their potential utility as probes for activity-based protein profiling. PMID- 21267494 TI - A one-pot asymmetric organocatalytic tandem reaction for the synthesis of oxazine derivatives. AB - An easy one-pot tandem reaction catalyzed by a chiral secondary amine for the synthesis of optically active oxazine derivatives has been performed and the corresponding substituted benzo[d]pyrido[2,1-b][1,3]oxazine derivatives were afforded in generally high yields (up to 99%) and excellent enantioselectivities (up to >99%). PMID- 21267496 TI - Photoinduced decarboxylation of 3-(N-phthalimido)adamantane-1-carboxylic acid and radical addition to electron deficient alkenes. AB - Direct and sensitized excitation of 3-(N-phthalimido)adamantane-1-carboxylic acid (1) leads to the population of the triplet state that, in the presence of a base, decarboxylates, giving N-(1-adamantyl)phthalimide (2) cleanly and efficiently (Phi = 0.11). The radical initially formed by decarboxylation adds regiospecifically to electron deficient alkenes, whereas radical addition was not observed for electron rich alkenes. The radical addition can also be applied to molecules not bearing adamantanes wherein the electron donor (carboxylate) and the acceptor (phthalimide) are separated by a rigid spacer. The photodecarboxylation induced radical addition of phthalimide derivative 1 to alkenes takes place in good to excellent yields and represents a mild and efficient method for C-C bond formation. PMID- 21267495 TI - Is the photoactive yellow protein a UV-B/blue light photoreceptor? AB - UV light below 300 nm is shown to generate the first photocycle intermediate in the blue light photoreceptor Photoactive Yellow Protein. Fluorescence and ultrafast transient absorption measurements indicate two excitation pathways: UV B absorption by the chromophore and Fluorescence Resonant Energy Transfer (FRET) from tryptophan and tyrosine residues. PMID- 21267497 TI - Dielectrophoresis-Raman spectroscopy system for analysing suspended nanoparticles. AB - A microfluidic dielectrophoresis platform consisting of curved microelectrodes was developed and integrated with a Raman spectroscopy system. The electrodes were patterned on a quartz substrate, which has insignificant Raman response, and integrated with a microfluidic channel that was imprinted in poly dimethylsiloxane (PDMS). We will show that this novel integrated system can be efficiently used for the determination of suspended particle types and the direct mapping of their spatial concentrations. We will also illustrate the system's unique advantages over conventional optical systems. Nanoparticles of tungsten trioxide (WO(3)) and polystyrene were used in the investigations, as they are Raman active and can be homogeneously suspended in water. PMID- 21267498 TI - Geochemical characteristics of inorganic sulfur in Shijing River, South China. AB - Different inorganic sulfur species distributed in overlying water, pore water and sediment in a heavily polluted river were determined. The concentrations of S(2-) and SO(4)(2-) in the overlying water were much more than those in the pore water. This result perhaps indicates the S(2-) was mainly from discharged wastewater, not from sediment resuspension. In the sediments, acid-volatile sulfide, chromium(ii)-reducible sulfide, and elemental sulfur were determined by a modified diffusion method. The results indicate that acid-volatile sulfide was the dominant component of the reduced inorganic sulfur, making up about 62% of the total reduced inorganic sulfur. PMID- 21267499 TI - Synthesis of gold nanoparticles by laser ablation of an Au foil inside and outside ionic liquids. AB - Stable gold nanoparticles (AuNPs) were prepared by simple laser ablation of an Au foil placed inside or outside four ionic liquids (ILs), without the addition of any external chemical reagent. Irregular spherical AuNPs with a diameter range of 5 to 20 nm were produced after laser ablation of an Au foil located inside or outside the ILs 1-n-butyl-3-methylimidazolium tetrafluoroborate (BMI.BF4), 1-n butyl-3-methylimidazolium hexafluorophosphate (BMI.PF6) and 1-(3-cyanopropyl)-3 methylimidazolium bis(trifluoromethylsulfonyl)imide ((BCN)MI.NTf2). Additionally, whereas laser ablation inside the IL 1-n-butyl-3-methylimidazolium dicyanamide BMI.N(CN)2 produced flower-like shaped nanoparticles of about 50 nm in size, ablation outside this IL presented similar results to the others ILs studied, as determined by TEM and UV-Vis. The size and shape of the prepared NPs were related to where NP nucleation and growth occurred, i.e., at the IL surface or within the IL. Indeed, the chemical composition of the IL/air interface and surface ion orientation played important roles in the stabilization of the AuNPs formed by laser ablation outside the ILs. PMID- 21267500 TI - Exploring Leishmania major inositol phosphorylceramide synthase (LmjIPCS): insights into the ceramide binding domain. AB - The synthesis of set of ceramide analogues exploring hydrophobicity in the acyl chains and the degree and nature of hydroxylation is described. These have been assayed against the parasitic protozoan enzyme LmjIPCS. These studies showed that whilst the C-3 hydroxyl group was not essential for turnover it provided enhanced affinity. Reflecting the membrane bound nature of the enzyme a long (C(13)) hydrocarbon ceramide tail was necessary for both high affinity and turnover. Whilst the N-acyl chain also contributed to affinity, analogues lacking the amide linkage functioned as competitive inhibitors in both enzyme and cell-based assays. A model that accounts for this observation is proposed. PMID- 21267501 TI - Atroposelective formation of dibenz[c,e]azepines via intramolecular direct arylation with centre-axis chirality transfer. AB - 5-Substituted 6,7-dihydrodibenz[c,e]azepines, a class of secondary amine incorporating a centre-axis chirality relay, are accessible from 1-substituted N (2-bromobenzyl)-1-phenylmethanamines via N-acylation and ring-closing intramolecular direct arylation. The ring closure proceeds with high atropodiastereoselectivity due to strain effects that are induced by trigonalisation of the nitrogen atom, as predicted using molecular mechanics calculations. PMID- 21267502 TI - Binuclear (salen)osmium phosphinidine and phosphiniminato complexes. AB - The preparation of a number of binuclear (salen)osmium phosphinidine and phosphiniminato complexes using various strategies are described. Treatment of [Os(VI)(N)(L(1))(sol)](X) (sol = H(2)O or MeOH) with PPh(3) affords an osmium(IV) phosphinidine complex [Os(IV){N(H)PPh(3)}(L(1))(OMe)](X) (X = PF(6)1a, ClO(4)1b). If the reaction is carried out in CH(2)Cl(2) in the presence of excess pyrazine the osmium(III) phosphinidine species [Os(III){N(H)PPh(3)}(L(1))(pz)](PF(6)) 2 can be generated. On the other hand, if the reaction is carried out in CH(2)Cl(2) in the presence of a small amount of H(2)O, a MU-oxo osmium(IV) phosphinidine complex is obtained, [(L(1)){PPh(3)N(H)}Os(IV)-O Os(IV){N(H)PPh(3)}(L(1))](PF(6))(2)3. Furthermore, if the reaction of [Os(VI)(N)(L(1))(OH(2))]PF(6) with PPh(3) is done in the presence of 2, the MU pyrazine species, [(L(1)){PPh(3)N(H)}Os(III)-pz Os(III){N(H)PPh(3)}(L(1))](PF(6))(2)4 can be isolated. Novel binuclear osmium(IV) complexes can be prepared by the use of a diphosphine ligand to attack two Os(VI)=N. Reaction of [Os(VI)(N)(L(1))(OH(2))](PF(6)) with PPh(2)-C=C-PPh(2) or PPh(2)-(CH(2))(3)-PPh(2) in MeOH affords the binuclear complexes [(MeO)(L(1))Os(IV){N(H)PPh(2)-R-PPh(2)N(H)}Os(IV)(L(1))(OMe)](PF(6))(2) (R = C=C 5, (CH(2))(3)6). Reaction of [Os(VI)(N)(L(2))Cl] with PPh(2)FcPPh(2) generates a novel trimetallic complex, [Cl(L(2))Os(IV){NPPh(2)-Fc-PPh(2)N}Os(IV)(L(2))Cl] 7. The structures of 1b, 2, 3, 4, 5 and 7 have been determined by X-ray crystallography. PMID- 21267503 TI - Pre-processing of ultraviolet resonance Raman spectra. AB - The application of UV excitation sources coupled with resonance Raman have the potential to offer information unavailable with the current inventory of commonly used structural techniques including X-ray, NMR and IR analysis. However, for ultraviolet resonance Raman (UVRR) spectroscopy to become a mainstream method for the determination of protein secondary structure content and monitoring protein dynamics, the application of multivariate data analysis methodologies must be made routine. Typically, the application of higher order data analysis methods requires robust pre-processing methods in order to standardize the data arrays. The application of such methods can be problematic in UVRR datasets due to spectral shifts arising from day-to-day fluctuations in the instrument response. Additionally, the non-linear increases in spectral resolution in wavenumbers (increasing spectral data points for the same spectral region) that results from increasing excitation wavelengths can make the alignment of multi-excitation datasets problematic. Last, a uniform and standardized methodology for the subtraction of the water band has also been a systematic issue for multivariate data analysis as the water band overlaps the amide I mode. Here we present a two pronged preprocessing approach using correlation optimized warping (COW) to alleviate spectra-to-spectra and day-to-day alignment errors coupled with a method whereby the relative intensity of the water band is determined through a least-squares determination of the signal intensity between 1750 and 1900 cm(-1) to make complex multi-excitation datasets more homogeneous and usable with multivariate analysis methods. PMID- 21267504 TI - Mn(II) complexes of novel hexadentate AAZTA-like chelators: a solution thermodynamics and relaxometric study. AB - Three novel chelators based on the 6-amino-6-methylperhydro-1,4-diazepine scaffold and possessing three pendant N-acetic or N-alpha-methylacetic acid have been synthesised. The ligands contain six donor atoms for complexation of Mn(II) ions and thus potentially leave an additional site for coordination of a water molecule. The protonation constants of the ligands and the stability constants of their complexes formed with Mn(II) ion were determined by pH-potentiometric titrations in 0.15 M NaCl solution at 25 degrees C and compared to those of the parent AAZTA ligand (AAZTA = 6-amino-6-methylperhydro-1,4-diazepine tetraacetic acid). In spite of the similar value of the total basicity (Sigmalog K), the values of the stability constants of the Mn(II)AAZTA-like complexes are more than three orders of magnitude lower than that of MnAAZTA (log K(MnL) = 14.19). A detailed (1)H and (17)O NMR relaxometric study was carried out on the Mn(II) complexes in aqueous solution as a function of pH, temperature and magnetic field strength. The (1)H NMRD profiles of all the complexes show a similar shape, typical of low-molecular weight systems, but amplitudes that markedly differ to indicate a different degree of hydration. A similar behaviour is shown by the (17)O NMR transverse relaxation rates and chemical shift data as a function of temperature. The experimental data can be rationalised by considering the presence in solution of a mixture of two isomeric species differing in coordination number (7 and 6) and in the number (1 and 0) of bound water molecules. Whereas this type of coordination equilibrium has been previously reported for lanthanide(III) complexes, it is observed for the first time on Mn(II) chelates. PMID- 21267505 TI - The first C-glycosidic analogue of a novel galactosyltransferase inhibitor. AB - Structural analogues and mimics of the natural sugar-nucleotide UDP-galactose (UDP-Gal) are sought after as chemical tools for glycobiology and drug discovery. We have recently developed a novel class of galactosyltransferase (GalT) inhibitors derived from UDP-Gal, bearing an additional substituent at the 5 position of the uracil base. Herein we report the first C-glycosidic derivative of this new class of GalT inhibitors. We describe a practical convergent synthesis of the new UDP-C-Gal derivative, including a systematic study into the use of radical chemistry for the preparation of galactosyl ethylphosphonate, a key synthetic intermediate. The new inhibitor showed activity against a bacterial UDP-Gal 4'-epimerase at micromolar concentrations. This is the first example of a base-modified UDP-sugar as an inhibitor of a UDP-sugar-dependent enzyme which is not a glycosyltransferase, and these results may therefore have implications for the design of inhibitors of these enzymes in the future. PMID- 21267506 TI - One-pot double functionalisation of pi-deficient heterocyclic lithium reagents. AB - Herein, we report an efficient method for the double functionalisation of lithiated halogenopyridines, -pyrazines or -furopyridines through a convenient one-pot electrophilic trapping/nucleophilic substitution sequence. PMID- 21267507 TI - Design, synthesis, and cyclization of 4-aminobutyric acid derivatives: potential candidates as self-immolative spacers. AB - Self-immolative spacers have gained significant interest in recent years due to their utility in numerous prodrug, sensor and drug delivery systems. However, there are a very limited number of spacers that are capable of undergoing spontaneous and rapid reactions under mild conditions. To address this need, 4 aminobutyric acid derivatives were explored as a potential class of self immolative spacers. Using a modular approach, eleven N- and alpha-substituted derivatives of 4-aminobutyric acid were synthesized, and their intramolecular cyclizations to gamma-lactams were studied. Kinetics experiments were carried out at physiological pH and temperature, and the observed half-lives for the spacers ranged from 2 to 39 s, depending on the molecular structure. In addition, the pH dependence of the cyclization rate was also explored and it was found that cyclization still occurred rapidly at mildly acidic pH. Therefore, this class of compounds exhibits promise for incorporation into a variety of self-immolative systems where rapid cyclization reactions are desired. PMID- 21267508 TI - Raman and computational study of solvation and chemisorption of thiazole in silver hydrosol. AB - A SERS investigation combined with ab initio computational analysis involving Car Parrinello molecular dynamics simulations and Density Functional Theory approach allows fundamental information to be obtained on the behaviour of thiazole in silver aqueous suspension where solvation and chemisorption processes competitively occur. PMID- 21267509 TI - Insulin protects against hepatic damage postburn. AB - Burn injury causes hepatic dysfunction associated with endoplasmic reticulum (ER) stress and induction of the unfolded protein response (UPR). ER stress/UPR leads to hepatic apoptosis and activation of the Jun-N-terminal kinase (JNK) signaling pathway, leading to vast metabolic alterations. Insulin has been shown to attenuate hepatic damage and to improve liver function. We therefore hypothesized that insulin administration exerts its effects by attenuating postburn hepatic ER stress and subsequent apoptosis. Male Sprague Dawley rats received a 60% total body surface area (TBSA) burn injury. Animals were randomized to receive saline (controls) or insulin (2.5 IU/kg q. 24 h) and euthanized at 24 and 48 h postburn. Burn injury induced dramatic changes in liver structure and function, including induction of the ER stress response, mitochondrial dysfunction, hepatocyte apoptosis, and up-regulation of inflammatory mediators. Insulin decreased hepatocyte caspase-3 activation and apoptosis significantly at 24 and 48 h postburn. Furthermore, insulin administration decreased ER stress significantly and reversed structural and functional changes in hepatocyte mitochondria. Finally, insulin attenuated the expression of inflammatory mediators IL-6, MCP-1, and CINC-1. Insulin alleviates burn-induced ER stress, hepatocyte apoptosis, mitochondrial abnormalities, and inflammation leading to improved hepatic structure and function significantly. These results support the use of insulin therapy after traumatic injury to improve patient outcomes. PMID- 21267510 TI - Targeting inflammation in heart failure with histone deacetylase inhibitors. AB - Cardiovascular insults such as myocardial infarction and chronic hypertension can trigger the heart to undergo a remodeling process characterized by myocyte hypertrophy, myocyte death and fibrosis, often resulting in impaired cardiac function and heart failure. Pathological cardiac remodeling is associated with inflammation, and therapeutic approaches targeting inflammatory cascades have shown promise in patients with heart failure. Small molecule histone deacetylase (HDAC) inhibitors block adverse cardiac remodeling in animal models, suggesting unforeseen potential for this class of compounds for the treatment of heart failure. In addition to their beneficial effects on myocardial cells, HDAC inhibitors have potent antiinflammatory actions. This review highlights the roles of HDACs in the heart and the potential for using HDAC inhibitors as broad-based immunomodulators for the treatment of human heart failure. PMID- 21267511 TI - Peptide-based inhibition of NF-kappaB rescues diaphragm muscle contractile dysfunction in a murine model of Duchenne muscular dystrophy. AB - Deterioration of diaphragm function is one of the prominent factors that contributes to the susceptibility of serious respiratory infections and development of respiratory failure in patients with Duchenne Muscular Dystrophy (DMD). The NF-kappaB signaling pathway has been implicated as a contributing factor of dystrophic pathology, making it a potential therapeutic target. Previously, we demonstrated that pharmacological inhibition of NF-kappaB via a small NEMO Binding Domain (NBD) peptide was beneficial for reducing pathological features of mdx mice. Now, we stringently test the effectiveness and clinical potential of NBD by treating mdx mice with various formulations of NBD and use diaphragm function as our primary outcome criteria. We found that administering DMSO-soluble NBD rescued 78% of the contractile deficit between mdx and wild-type (WT) diaphragm. Interestingly, synthesis of a GLP NBD peptide as an acetate salt permitted its solubility in water, but as a negative consequence, also greatly attenuated functional efficacy. However, replacing the acetic acid counterion of the NBD peptide with trifluoroacetic acid retained the peptide's water solubility and significantly restored mdx diaphragm contractile function and improved histopathological indices of disease in both diaphragm and limb muscle. Together, these results support the feasibility of using a mass-produced, water-soluble NBD peptide for clinical use. PMID- 21267512 TI - Involvement of leptin receptor long isoform (LepRb)-STAT3 signaling pathway in brain fat mass- and obesity-associated (FTO) downregulation during energy restriction. AB - Obesity is an important risk factor for cardiovascular disease, diabetes and certain cancers. The fat mass- and obesity-associated (FTO) gene is tightly associated with the pathophysiology of obesity, whereas the exact role of FTO remains poorly understood. Here, we investigated the alternations of FTO mRNA and protein expression in the peripheral metabolic tissues and the brain upon energy restriction (ER) and explored the involvement of the leptin signaling pathway in FTO regulation under ER status. ER decreased the FTO mRNA and protein expression in hypothalamus and brainstem but not in periphery. Using double immunofluorescence staining, FTO was found to be colocalized with the leptin receptor long isoform (LepRb) in arcuate nucleus of hypothalamus and the nucleus of the solitary tract. In LepRb mutant db/db mice, the FTO downregulation in brain and body weight reduction induced by ER were completely abolished. The enhanced phosphorylation of signal transducer and activator of transcription 3 (STAT3) induced by ER was also impaired in db/db mice. Moreover, leptin directly activated the STAT3 signaling pathway and downregulated FTO in in vitro arcuate nucleus of hypothalamus cultures and in vivo wild-type mice but not db/db mice. Thus, our results provide the first evidence that the LepRb-STAT3 signaling pathway is involved in the brain FTO downregulation during ER. PMID- 21267513 TI - Autonomic contribution to endothelin-1 increase during laboratory anger-recall stress in patients with coronary artery disease. AB - In coronary artery disease (CAD), endothelin-1 (ET-1) is released by activated macrophages and thereby contributes to coronary plaque rupture and triggered cardiac events. The multifactorial regulation of ET-1 includes stimulated release by cytokines and autonomic factors. Laboratory stress provokes alteration in autonomic tone and prolonged ET-1 mediated endothelial dysfunction. The objective of the study is to determine the autonomic contribution to an increase in ET-1 in response to laboratory stress in patients with CAD. Patients (n = 88) with chronic stable CAD instrumented with hemodynamic monitor, digital electrocardiogram (ECG) monitor and indwelling catheter for blood sampling completed a laboratory protocol that included initial rest (30 min), baseline (BL: 10 min), and anger recall stress (AR: 8 min). Change from BL to AR was determined for (a) parasympathetic activity (by spectral analysis of ECG); (b) sympathetic activity (by circulating catecholamines); and (c) ET-1. AR provoked increases from BL in catecholamines, and a decrease in parasympathetic activity. Multivariate analysis with change in parasympathetic activity and catecholamines, while controlling for age and use of beta-blockers, revealed a significant odds ratio (OR = 3.27, 95% CI 1.03, 10.41 P = 0.04) for an increase in ET-1 associated with parasympathetic withdrawal; no other variables were significant. The predominant influence of parasympathetic activity on anger/stress-provoked increase in ET-1 is consistent with the cholinergic antiinflammatory pathway. Future examination of autonomic influences on atherosclerotic leukocytes, endothelial cell function and the dynamics of ET-1 are warranted. PMID- 21267514 TI - Depressive symptoms are associated with food insufficiency and nutritional deficiencies in poor community-dwelling elderly people. AB - Depression is associated with nutritional deterioration in older persons and is highly prevalent among people of low socioeconomic status (LSES). OBJECTIVES: To determine the prevalence of depressive symptoms and food insufficiency, and to examine the relationship between dietary intake, food insufficiency and depression, in LSES community dwelling elderly. DESIGN: Cross-sectional study. SETTING: Lod, a town in the central Israel. PARTICIPANTS: Community-dwelling welfare recipients aged 60 to 92. MEASUREMENTS: Depression was assessed by 15 item Geriatric Depression Scale (GDS-short version), using a score >= 10 as the cut off point for clinically important depressive symptoms. Dietary intake was evaluated using a 24-hour dietary recall. Food insufficiency was defined by participants reporting that they did not have enough food to eat " sometimes " or " often " . RESULTS: This study reports on 112 persons aged 60 years and above (27.1% men). The prevalence of depression in this population was 47%; 25% of the study sample was classified as " food insufficient " . Macronutrients intake was similar for depressed and non-depressed persons, except for polyunsaturated fats which was lower among the depressed group (7.9 +/- 4.9 vs.11.0 +/- 7.5 g/day in the non-depressed, p=0.03). Vitamins and minerals intake was lower than recommended for both groups; vitamin E intake was associated with depression. In regression models controlling for confounding variables, an increase of 1 mg in vitamin E intake and 1 gram in polyunsaturated fatty acids (PUFA) intake was associated with lower risk for depression (OR=0.73, p=0.008 and OR=0.86, p=0.007 respectively) Participants who reported food insufficiency were 10 times more likely to be depressed compared with those who reported sufficient food. CONCLUSIONS: Given the evaluated adverse association between depressive symptoms and food insufficiency, more efforts are needed to guarantee adequate food intake, particularly foods rich in vitamin E and PUFA, in poor elderly people. Further studies are needed to clarify the temporal relationship between the emotional and nutritional domains in this vulnerable population. PMID- 21267515 TI - The feasibility and acceptability of muscle biopsy in epidemiological studies: findings from the Hertfordshire Sarcopenia Study (HSS). AB - BACKGROUND: Sarcopenia, the loss of muscle mass and strength, is associated adversely with disability, morbidity and mortality. Epidemiological findings suggest influences operating across the life course may be important. Our aim was to ascertain the feasibility and acceptability of obtaining muscle tissue from healthy older people in order to ultimately identify cellular mechanisms underlying life course influences on sarcopenia. METHODS: 105 men with documented birth weight consented to detailed assessment of muscle mass and strength, and a biopsy of the vastus lateralis using the Weil-Blakesley conchotome. Acceptability was ascertained by questionnaire and a 100 mm pain Visual Analogue Scale (VAS). 100 mm indicated severe pain. RESULTS: Muscle biopsy was successfully carried out in 102 out of 105 participants, mean yield 107 mg (range 20-290 mg). There were no serious wound complications. Ninety-three participants completed feedback questionnaires. The median pain VAS score during the procedure was 7 mm (Interquartile range [IQR] 1-34), 4 mm (IQR 0-16) one day after the procedure and 1mm (IQR 0-4) 7 days after the procedure. 60 (65%) participants were back to their normal levels of activity one day after the procedure. 85 (91%) found this procedure acceptable and would have the procedure again. CONCLUSION: Muscle biopsy using a Weil-Blakesley conchotome is both feasible and acceptable in community dwelling older men participating in epidemiological research. The excellent yield of biopsy tissue will allow morphological and molecular studies of muscle to be integrated into an epidemiological study facilitating investigation of the mechanisms underpinning sarcopenia that could potentially be altered by life course influences. PMID- 21267516 TI - Anthropometric indexes of obesity and hypertension in elderly from Cuba and Barbados. AB - OBJECTIVE: To investigate the association between various anthropometric indexes of obesity with arterial hypertension in elderly from Barbados (Bridgetown) and Cuba (Havana). DESIGN: Cross-sectional data were extracted from the Survey on Health, Aging and Well being in Latin America and the Caribbean (SABE). SAMPLE SIZE: In Bridgetown and Havana, respectively, 1508 and 1905 subjects ( >= 60 years) were examined, and were selected by a controlled sampling design. MEASUREMENTS: The occurrence of hypertension was assessed by self-report. Multiple measurements of adiposity were used including body mass index (BMI >= 28 kg/m(2)), waist hip ratio (WHR = > 0.95 men; > 0.80 women), waist to height ratio (W/ht. = > 0.50) and waist circumference - WC(L) ( > 88 cm, women; > 102 cm, men) e WC(OK) ( > 90.3 cm, women; > 91.3 cm, men). Binary logistic regression analyses (Odds Ratio) were used to measure strengths of relationships. RESULTS: In the elderly of Bridgetown, the final design (adjusted for age, education, race, smoking, regular physical activity and diabetes) shows that, in men, WC(OK) and W/Ht were associated with hypertension, and in women, WCL and WCOK were the indexes associated. In the Cuban elderly, the final design shows that, with the exception of WHR, all indicators were associated with hypertension. WCOK and W/ht were the indexes most strongly associated with the outcome. CONCLUSION: The explanatory power of anthropometric indicators when determining the outcome differed between men and women, as well as between cultural groups living in relative proximity (Barbadians and Cubans). PMID- 21267517 TI - Designing clinical trials for early (pre-dementia) Alzheimer's disease: determining the appropriate population for treatment. AB - Treatments that are designed to reduce Alzheimer's disease (AD) pathology may be most useful when given to subjects prior to a diagnosis of AD using current diagnostic criteria. These earlier patients may have early cognitive losses consistent with mild cognitive impairment (MCI) or may be completely asymptomatic. Screening and treatment programs for other disease states have been explored previously; these include cholesterol screening for cardiovascular disease, genetic screening for Huntington ' s disease and screening for some types of cancer. Cancer screening and treatment programs have been developed for colon cancer, breast cancer and prostate cancer. Screening programs for these other disease states are briefly reviewed and are compared to preliminary modeling data describing a hypothetical screening and treatment program for AD. While primary prevention based on screening of asymptomatic individuals using biomarkers has broad appeal, secondary prevention employing treatment of patients with MCI may be more easily implemented. PMID- 21267518 TI - High dietary and plasma levels of the omega-3 fatty acid docosahexaenoic acid are associated with decreased dementia risk: the Rancho Bernardo study. AB - OBJECTIVE: This study examined the association of plasma DHA, dietary DHA, and fish intake with dementia and Alzheimer's Disease (AD) in older adults. DESIGN: Case-cohort study. SETTING: Clinic visit in 1991-93. PARTICIPANTS: 266 community dwelling men and women aged 67-100 years (mean=80.2). MEASUREMENTS: Participants had neurological and neuropsychological evaluations for dementia in 1991-93. Plasma DHA was measured in blood samples obtained at that visit. Dietary intakes of DHA and fish were obtained from an earlier (1988-91) visit. Three DHA exposure variables were used in separate analyses; plasma DHA, dietary DHA, and consumption of cold-water fish. All-cause dementia included AD and other types of possible or probable dementia. RESULTS: Among these 266 participants, 42 had dementia and 30 had possible or probable AD. Plasma DHA in the highest tertile was associated with a 65% reduced odds of all-cause dementia (95% CI: 0.17, 0.92) and a 60% reduced odds of AD (95% CI: 0.15, 1.10). Dietary DHA in the highest tertile was associated with a 73% reduced odds of all-cause dementia (95% CI: 0.09, 0.79) and a 72% reduced odds of AD (95% CI: 0.09, 0.93). Fish intake had similar, though not significant, reduced odds of dementia (OR = 0.51; 95% CI: 0.20, 1.32) and AD (OR = 0.55; 95% CI: 0.20, 1.48). CONCLUSIONS: Plasma and dietary DHA appear to protect against dementia. Increasing DHA intake from marine sources may be recommended for reducing dementia risk. PMID- 21267519 TI - Omega-3 polyunsaturated fatty acid supplements and cognitive decline: Singapore Longitudinal Aging Studies. AB - OBJECTIVE: To determine the association between long chain omega-3 polyunsaturated fatty acid (n-3 PUFA) supplements intake and cognitive decline in an older Chinese population. DESIGN: Prospective cohort study. SETTING: The Singapore Longitudinal Aging Studies (SLAS), a community-based study in urban region of Singapore. PARTICIPANTS: 1,475 Chinese adults aged >= 55 years. MEASUREMENT: Omega-3 PUFA supplements intake and Mini-Mental State Examination (MMSE) were assessed at baseline. MMSE was re-assessed at a median of 1.5 years after baseline and cognitive decline was defined as at least 2-points drop in MMSE score from baseline to follow-up. Odds ratios (ORs) of association between n 3 PUFA supplements intake and cognitive decline were calculated in logistic regression models controlling for baseline confounding variables. RESULTS: Daily n-3 PUFA supplements intake was significantly (p=0.024) associated with lower risk of cognitive decline (OR=0.37, 95% C.I. 0.16-0.87) after controlling for age, gender, education, number of medical comorbidity, the presence of vascular risk factors/diseases, smoking, alcohol drinking, depression, APOE e4 allele carrier status, nutritional status, level of leisure activities, baseline MMSE and length of follow-up. The association remained significant (p=0.015) after excluding participants with baseline cognitive impairment (MMSE < 24), diabetes, stroke, and cardiac diseases (OR=0.23, 95% C.I. 0.07-0.75). No statistically significant association (OR=1.02, 95% C.I. 0.81-1.27) of fish consumption with cognitive decline was found. CONCLUSION: Daily n-3 PUFA supplements consumption was independently associated with less cognitive decline in elderly Chinese. PMID- 21267521 TI - The perception of the benefits of herbal medicine consumption among the Thai elderly. AB - OBJECTIVES: To determine how the Thai elderly perceived the benefits of herbal medicine consumption and to study related variables influencing their perception. DESIGN: A cross-sectional study was used. PARTICIPANTS/SETTINGS: 419 participants were chosen by systematic stratified sampling; people between 60-96 years of age (mean age 70.2 years); 68.3 % female, and 31.7% male of Chonburi Province (Thailand). MEASUREMENTS: To determine the elderly perception about the benefits of herbal medicine consumption, a scale from one to four based upon 12 simply worded item check lists was used among the others. The questionnaires were conducted in June to August 2008 in 3 different regions (urban, suburban and rural areas). RESULTS: 97.4% having used herbal medicines in many ways. Most of the elderly used the local herbals together with conventional medicines. They believed that herbals could reduce expenses (51%), cure diseases (41.9%), relieve symptoms (35.4%), and provide good health (33.6%). A 16.7% of the elderly had the strongest opinion regarding the use of herbal medicines as substitutes for conventional medicines. They also strongly agreed on using them as nutrients (39.8%). The study found significant correlation among levels of education, stress levels, happiness levels, and perception of benefits of herbal medicine consumption. CONCLUSIONS: This study indicated that levels of education, happiness, and stress could influence the perception of herbal medicine consumption. Knowing how people perceive herbal medicine, its use, and local culture can help practicing health professionals, among other things, to avoid side effects from prescriptions and so maintain or promote the elderly health status. PMID- 21267522 TI - A practical approach to lipid management in the elderly. AB - Cardiovascular disease (CVD) increases in a curvilinear fashion after 65 years in men and 75 years in women and the majority of all cardiovascular events occur in individuals older then 65 years. There are notable differences in the clinical assessment of hyperlipidaemia, cardiovascular risk estimation as well as the safety and tolerability profiles in the elderly compared to younger individuals. Clinical trial data have now demonstrated the benefits of statin treatment in the elderly in both the primary and secondary prevention settings. There is however limited data for individuals older than 80 years. Little data is available on other lipid modifying medication in the elderly. With continuing increases in average life expectancy, preventive efforts will become increasingly important for preventing morbidity, improving quality of life, and reducing healthcare expenditures for older persons. This emphasizes the importance of clinical decision-making and weighing up the risks and benefits of treatment. PMID- 21267520 TI - Progress in the development of new drugs in Alzheimer's disease. AB - Alzheimer's disease (AD) is an age-related neurodegenerative disease with a global prevalence estimated at 26.55 million in 2006. During the past decades, several agents have been approved that enhance cognition of AD patients. However, the effectiveness of these treatments are limited or controversial and they do not modify disease progression. Recent advances in understanding AD pathogenesis have led to the development of numerous compounds that might modify the disease process. AD is mainly characterized neuropathologically by the presence of two kinds of protein aggregates: extracellular plaques of Abeta-peptide and intracellular neurofibrillary tangles. Abeta and tau could interfere in an original way contributing to a cascade of events leading to neuronal death and transmitter deficits. Investigation for novel therapeutic approaches targeting the presumed underlying pathogenic mechanisms is major focus of research. Antiamyloid agents targeting production, accumulation, clearance, or toxicity associated with Abeta peptide, are some approaches under investigation to limit extracellular plaques of Abeta-peptide accumulation. We can state as an example: Abeta passive and active immunization, secretases modulation, Abeta degradation enhancement, or antiaggregation and antifibrillization agents. Tau-related therapies are also under clinical investigation but few compounds are available. Another alternative approach under development is neuroprotective agents such as antioxidants, anti-inflammatory drugs, compounds acting against glutamate mediated neurotoxicity. Neurorestorative approaches through neurotrophin or cell therapy also represent a minor avenue in AD research. Finally, statins, receptor for advanced glycation end products inhibitors, thiazolidinediones, insulin, and hormonal therapies are some other ways of research for a therapeutic approach of Alzheimer's disease. Taking into account AD complexity, it becomes clear that polypharmacology with drugs targeting different sites could be the future treatment approach and a majority of the recent drugs under evaluation seems to act on multiple targets. This article exposes general classes of disease modifying therapies under investigation. PMID- 21267523 TI - Association between benzodiazepines and recurrent falls: a cross-sectional elderly population-based study. AB - BACKGROUND: While the association between benzodiazepines (BZD) and single fall is long-known, the association between BZD and recurrent falls has been few studied. OBJECTIVE: The aims of this study were 1) to examine whether BZD were associated with recurrent falls while taking into account the effect of potential confounders, and 2) to determine whether there was an interaction in terms of risk of falls between BZD and balance impairment in a community-dwelling population-based adults aged 65 and older. STUDY DESIGN: Cross-sectional. SETTING: Three health centers in North-East of France. POPULATION: 7643 community dwelling volunteers aged 65 and older. OUTCOME MEASURES: The use of BZD, the Mini Mental State Examination (MMSE) score, the Clock Drawing Test (CDT), the One Leg Balance (OLB) test, the Five Times Sit-To-Stand test (FTSS), and a history of falls were recorded. Subjects were separated into 4 groups based on the number of falls: 0, 1, 2 and >= 3 falls. RESULTS: Among the 1456 (19.2%) fallers, 994 (13.0%) were single fallers and 462 (6.1%) were recurrent fallers (i.e., > 2 falls). The number of falls increased significantly with age (Incident Rate Ratio (IRR)=1.04, P < 0.001), female gender (IRR=2.24, P < 0.001), the use of benzodiazepine (IRR=1.65 P < 0.001) and especially while subjects used bromazepam (IRR=1.44, P=0.006), clobazam (IRR=3.01, P=0.014) and prazepam (IRR=2.29, P < 0.001). A low MMSE score (IRR=0.96, P < 0.001), an impaired CDT (IRR=0.91, P < 0.001), and a bad performance at OLB and FTSS (respectively IRR=1.85, P < 0.001 and IRR=1.26, P < 0.001) were related to the recurrence of falls. After adjustment only the advance in age (IRR=1.02, P < 0.001), female gender (IRR=2.15, P < 0.001), clobazam (IRR=2.54, P=0.04), prazepam (IRR=1.63, P=0.03) and OLB (IRR=1.55, P < 0.001) were still significantly related to the number of falls. CONCLUSION: The current study shows that the age, the female gender, the use of clobazam or prazepam and a low score at OLB are related to the recurrence of falls. PMID- 21267524 TI - How to manage recurrent falls in clinical practice: guidelines of the French Society of Geriatrics and Gerontology. AB - BACKGROUND: Health care professionals need a simple and pragmatic clinical approach for the management of recurrent fallers in clinical routine. OBJECTIVE: To develop clinical practice recommendations with the aim to assist health care professionals, especially in primary care in the management of recurrent falls. METHODS: A systematic English and French review was conducted using Medline, Embase, Pascal and Cochrane literature. Search included systematic reviews, meta analyses, controlled trials, cohort studies, case-control studies and transversal studies published until July 31, 2008. The following Medical Subject Heading (MeSH) terms were used: "aged OR aged, 80 and over", "frail elderly", "Accidental Fall", "Mental Recall", and "Recurrent falls". The guidelines were elaborated according the Haute Autorite de Sante methods by a multidisciplinary working group comprising experts and practitioners. RESULTS: A fall is an event that results in a person coming to rest inadvertently on the ground or floor or other lower level and should be considered as a recurrent event as soon as a subject reported at least two falls in a 12-month period. Recurrent falls impose a prompt and appropriate management with the first aim to systematically evaluate the severity of falls. The evaluation of fall severity should be based on a standardized questionnaire and physical examination. It is recommended not to perform cerebral imaging in the absence of specific indication based on the clinical examination and to reevaluate the subject within a week after the fall. Prior to any intervention and after an evaluation of signs of severity, it is recommended to systematically assess the risk factors for falls. This evaluation should be based on the use of validated and standardized tests. The education of recurrent fallers and their care givers is required in order to implement appropriate intervention. In the event of a gait and/or balance disorders, it is recommended to prescribe physiotherapy. A regular physical activity should be performed with low to moderate intensity exercise. It is recommended to perform rehabilitation exercises with a professional, between therapy sessions and after each session, in order to extend rehabilitation benefits to the daily life. CONCLUSION: The clinical guidelines focused on management (i.e., diagnosis, assessment and treatment) of recurrent falls in clinical routine. They provide answers to the following clinical questions: 1) How to define recurrent falls? 2) How to identify severe falls? 3) How to assess recurrent falls? and 4) How to treat recurrent falls? PMID- 21267526 TI - Return to work and job retention--increasingly important outcomes in occupational health research. PMID- 21267525 TI - Long chain omega 3 polyunsaturated fatty acids supplementation in the treatment of elderly depression: effects on depressive symptoms, on phospholipids fatty acids profile and on health-related quality of life. AB - OBJECTIVE: Recent observations showed that long chain omega 3 polyunsaturated fatty acids (n-3 LCPUFA) could represent a potential treatment for elderly depression. To determine if a n-3 LCPUFA containing supplement improves depressive symptoms, changes phospholipids acids profile and ameliorates Health related quality of life (HRQoL) in depressed elderly patients. DESIGN: Two months, randomized, double-blind, placebo-controlled trial. SETTING: Nursing home in Pavia, Italy. SUBJECTS: Forty-six depressed females, aged 66-95 years. INTERVENTION: 22 depressed females were included in the intervention group (n-3 group, that received 2.5 g/day of n-3 LCPUFA, with 1.67 grams of EPA and 0.83 grams of DHA), and 24 patients in the placebo group. The primary endpoint was the improvement of depressive symptoms as evaluated by Geriatric Depression Scale (GDS). Secondary endpoints were the evaluation of modifications of erythrocyte membrane phospholipids fatty acid profile and of of HRQoL, by using the Short Form 36-Item Health Survey (SF-36). All parameters were assessed before and after the treatment period of 8 weeks. RESULTS: The mean GDS at 2 months was significantly lowered only for the n-3 group. SF-36 physical and mental components were significantly increased in the intervention group. Compliance was good, as confirmed by erythrocyte membrane phospholipid FA concentrations, with significant increase of EPA and DHA in the intervention group. CONCLUSION: The supplementation of n-3 LCPUFA in elderly female patients reduces the occurrence of depressive symptoms, improves phospholipids fatty acids profile and health related quality of life. PMID- 21267527 TI - Properties of the International Classification for Functioning, Disability and Health in assessing hand outcomes in patients with rheumatoid arthritis. AB - OBJECTIVES: Variables from a study of patients with rheumatoid arthritis were linked to the International Classification of Functioning, Disability and Health (ICF) Core Set for rheumatoid arthritis. The purpose of this analysis was to evaluate the ICF Core Sets for rheumatoid arthritis for assessing the functional outcomes of the rheumatoid hand. DESIGN: Prospective cohort. SUBJECTS: A total of 142 subjects with rheumatoid arthritis. METHODS: Patients who elected to have or not have arthroplasty were linked with the ICF Core Sets. Study variables were assigned into one of the Core Set blocks that compose the ICF model. The blocks were then entered into multiple regression models to determine the contribution of each block in explaining the variation in hand outcome at enrollment, as well as the change in hand outcome after one year. RESULTS: Seventy percent of the reported hand outcome at enrollment was explained by the ICF Core Set blocks. For change in hand outcome at one year, the ICF Core Set blocks measured at enrollment explained 18% of the variance. CONCLUSION: The components of the ICF Core Set for rheumatoid arthritis explained much of the variation in hand functioning for patients with rheumatoid arthritis, but were not predictive of the change in hand functioning after one year. PMID- 21267528 TI - Clinical tests performed in acute stroke identify the risk of falling during the first year: postural stroke study in Gothenburg (POSTGOT). AB - OBJECTIVE: To assess the likelihood of clinical tests for postural balance, walking and motor skills, performed during the first week after stroke, identifying the risk of falling. DESIGN: Prospective study. SUBJECTS: Patients with first stroke. METHODS: Assessments were carried out during the first week, and the occurrence of falls was recorded 3, 6 and 12 months after stroke onset. The tests used were: 10-Metre Walking Test (10MWT), Timed Up & Go, Swedish Postural Assessment Scale for Stroke Patients, Berg Balance Scale and Modified Motor Assessment Scale. Cut-off levels were obtained by receiver operation characteristic curves, and odds ratios were used to assess cut-off levels for falling. RESULTS: The analyses were based on 96 patients. Forty-eight percent had at least one fall during the first year. All tests were associated with the risk of falling. The highest predictive values were found for the 10MWT (positive predictive value 64%, negative predictive value 76%). Those subjects who were unable to perform the 10MWT had the highest odds ratio, 6.06 (95% confidence interval 2.66-13.84, p<0.001) of falling. CONCLUSION: Clinical tests used during the first week after stroke onset can, to some extent, identify those patients at risk of falling during the first year after stroke. PMID- 21267529 TI - [In house]. PMID- 21267530 TI - Optimizing the quality of breast cancer care at certified german breast centers: a benchmarking analysis for 2003-2009 with a particular focus on the interdisciplinary specialty of radiation oncology. AB - PURPOSE: A voluntary, external, science-based benchmarking program was established in Germany in 2003 to analyze and improve the quality of breast cancer (BC) care. Based on recent data from 2009, we aim to show that such analyses can also be performed for individual interdisciplinary specialties, such as radiation oncology (RO). METHODS: Breast centers were invited to participate in the benchmarking program. Nine guideline-based quality indicators (QIs) were initially defined, reviewed annually, and modified, expanded, or abandoned accordingly. QI changes over time were analyzed descriptively, with particular emphasis on relevance to radiation oncology. RESULTS: During the 2003-2009 study period, there were marked increases in breast center participation and postoperatively confirmed primary BCs. Starting from 9 process QIs, 15 QIs were developed by 2009 as surrogate indicators of long-term outcome. During 2003-2009, 2/7 RO-relevant QIs (radiotherapy after breast-conserving surgery or after mastectomy) showed considerable increases (from 20 to 85% and 8 to 70%, respectively). Another three, initially high QIs practically reached the required levels. CONCLUSION: The current data confirm proof-of-concept for the established benchmarking program, which allows participating institutions to be compared and changes in quality of BC care to be tracked over time. Overall, marked QI increases suggest that BC care in Germany improved from 2003-2009. Moreover, it has become possible for the first time to demonstrate improvements in the quality of BC care longitudinally for individual breast centers. In addition, subgroups of relevant QIs can be used to demonstrate the progress achieved, but also the need for further improvement, in specific interdisciplinary specialties. PMID- 21267532 TI - Omega-3 fatty acid supplementation in cancer therapy : does eicosapentanoic acid influence the radiosensitivity of tumor cells? AB - PURPOSE: The aim of this study was to evaluate whether the omega-3 polyunsaturated fatty acid cis-5,8,11,14,17-eicosapentanoic acid (EPA) can enhance the radiosensitivity of different human tumor cell lines. MATERIALS AND METHODS: Colon adenocarcinoma cells HT-29, and two glioblastoma multiforme tumor cells T98G and U251 were cultured under standard conditions. Cell growth was observed during administration with different concentrations of EPA, using it as the free fatty acid dissolved in ethanol or bound to bovine serum albumin. To investigate the influence of EPA (free and bound) on radiosensitivity, tumor cells were pretreated 30 minutes or 24 hours prior to irradiation with the fatty acid. Cell survival was measured by colony-forming assays. RESULTS: When combined with irradiation, incubation with EPA was found to result in enhanced radiosensitivity with substantial variation: while there was strong radiosensitization for HT-29 and U251 cells, almost no effect for T98G cells was observed. A marked radiosensitization was clearly dependent on the treatment schedule. CONCLUSION: The observations suggest that EPA is not only a nutritional adjuvant but also may be a potential candidate to enhance the efficacy of irradiation on human cancer cells. PMID- 21267531 TI - Preoperative oxaliplatin, capecitabine, and external beam radiotherapy in patients with newly diagnosed, primary operable, cT3NxM0, low rectal cancer: a phase II study. AB - PURPOSE: In patients with locally advanced rectal cancer (LARC), preoperative chemoradiation is known to improve local control, and down-staging of the tumor serves as a surrogate for survival. Intensification of the systemic therapy may lead to higher downstaging rates and, thus, enhance survival. This phase II study investigated the efficacy and safety of preoperative capecitabine and oxaliplatin in combination with radiotherapy. PATIENTS AND METHODS: Patients with LARC of the mid and lower rectum, T3NxM0 staged by MRI received radiotherapy (total dose 45 Gy) in combination with oral capecitabine (825 mg/m2 twice a day on radiotherapy days; weeks 1-4) and oxaliplatin 50 mg/m2 intravenously (days 1, 8, 15, and 22). Efficacy was evaluated as rate of tumor down-categorization at the T level. RESULTS: A total of 59 patients were enrolled (19 women, 40 men; median age of 61 years) and all were evaluable for efficacy and toxicity. Down-categorization at the T level was observed in 53% with pathological complete response in 6 patients (10%). Actual total radiotherapy, oxaliplatin and capecitabine doses received were 97%, 90%, and 93% of the protocol-specified preplanned doses, respectively. Grade 3/4 toxicity was observed in 15 patients (25%). The most frequent was diarrhea (12%). CONCLUSIONS: Preoperative chemoradiation with capecitabine and oxaliplatin is feasible in patients with MRI-proven cT3 LARC. The only clinically relevant toxicity was diarrhea. Overall, efficacy of the multimodality treatment was good, but not markedly exceeding that of 5-FU- or capecitabine-based chemoradiation approaches. PMID- 21267533 TI - [Interdisciplinary treatment of non-small cell lung cancer]. AB - At the time of diagnosis of non-small cell lung cancer, about two thirds of the patients manifest tumor disease limited to the lungs without distant metastases. In this group localized tumor spread (stages I and II) can be distinguished from locally advanced spread including lymph node metastases (stages IIIA and B). In stages I and II with sufficient cardiopulmonary function, surgical resection is considered the standard treatment approach. If lobe resection is not possible due to comorbidities or limited pulmonary function, parenchyma-sparing resection or definitive radiotherapy is advocated. Postoperative adjuvant chemotherapy is recommended for individual cases in stage IB and as the standard treatment in stage II. In stages IIIA and IIIB interdisciplinary consultation involving pneumologists/oncologists, surgeons, and radiation oncologists is necessary to reach decisions on treatment recommendations. Generally multiple treatment modalities are employed in these stages, such as induction chemotherapy followed by surgery and subsequent irradiation or simultaneous chemoradiotherapy. These treatment combinations with curative intent should be differentiated from the numerous treatment methods with palliative intent. PMID- 21267534 TI - [Cystic gastric tumor with calcifications]. AB - In imaging techniques was seen a thickness of the gastric wall in a patient with pain for several months and loss of weight. Biopsies taken out of the tumor mass by gastroscopy and laparoscopy have not been ground-breaking. For this disease pattern is it not unusual that the diagnosis of heterotopic pancreatic tissue with pancreatitis is not confirmed until a resection of the stomach. PMID- 21267535 TI - Type 2 diabetes risk allele near CENTD2 is associated with decreased glucose stimulated insulin release. AB - AIMS/HYPOTHESIS: By combining multiple genome-wide association (GWA) studies and comprehensive replication efforts, 12 novel type 2 diabetes associated loci have recently been discovered. Here we evaluate the effect of lead variants of these loci on estimates of insulin release and insulin resistance derived from an oral glucose tolerance test. METHODS: We examined 12 lead variants in or near HMGA2, CENTD2 (also known as ARAP1), KLF14, PRC1, TP53INP1, ZBED3, ZFAND6, CHCHD9, DUSP9, KCNQ1, BCL11A and HNF1A in 5,722 middle-aged people from the population based Inter99 sample. RESULTS: Carriers of the major diabetogenic allele of rs1552224 in CENTD2 had increased 30-min plasma glucose values (2.0%, p = 2 * 10( 5)) as well as 4.2% reduced insulin release 30 min after an oral glucose load (p = 0.001). Risk allele carriers also had decreased BIGTT-acute insulin release (AIR), which is a surrogate measure of insulin release where sex, BMI, plasma glucose and serum insulin are integrated (5.3%, p = 8 * 10(-7)). In addition, a decreased corrected insulin response (CIR; 9.9%, p = 3 * 10(-8)) was observed. For rs5945326 near DUSP9 on the X-chromosome we stratified according to sex. Male carriers of the risk allele showed nominally decreased BIGTT-AIR (2.6%, p = 0.01). No associations with intermediate metabolic traits were found in women. For the remaining ten lead variants no consistent associations were demonstrated. CONCLUSIONS/INTERPRETATION: Of the lead variants from 12 novel type 2 diabetes associated loci, CENTD2 significantly associated with increased plasma glucose values and decreased glucose-stimulated insulin release, suggesting that the diabetogenic effect of this locus is mediated through an impaired pancreatic beta cell function. PMID- 21267536 TI - Co-transplantation of mesenchymal stem cells maintains islet organisation and morphology in mice. AB - AIMS/HYPOTHESIS: Recent studies have shown that mesenchymal stem cells (MSCs) secrete several factors that improve survival and function of transplanted islets. Implantation of islets beneath the kidney capsule results in morphological changes, due to interactions of the graft with the host, thus impairing islet function. We co-transplanted MSCs with islets to determine their effects on the remodelling process and studied graft function in a mouse model of minimal islet mass. METHODS: Islets were syngeneically transplanted, either alone or with kidney-derived MSCs, underneath the kidney capsule of streptozotocin induced diabetic C57Bl/6 mice. Blood glucose levels were monitored and intraperitoneal glucose tolerance tests carried out. Hormone contents of grafts and pancreas were assessed by radioimmunoassay. Graft morphology and vascularisation were evaluated by immunohistochemistry. RESULTS: MSCs improved the capacity of islet grafts to reverse hyperglycaemia, with 92% of mice co transplanted with MSCs reverting to normoglycaemia, compared with 42% of those transplanted with islets alone. Average blood glucose concentrations were lower throughout the 1 month monitoring period in MSC co-transplanted mice. MSCs did not alter graft hormone content. Islets co-transplanted with MSCs maintained a morphology that more closely resembled that of islets in the endogenous pancreas, both in terms of size, and of endocrine and endothelial cell distribution. Vascular engraftment was superior in MSC co-transplanted mice, as shown by increased endothelial cell numbers within the endocrine tissue. CONCLUSIONS/INTERPRETATION: Co-transplantation of islets with MSCs had a profound impact on the remodelling process, maintaining islet organisation and improving islet revascularisation. MSCs also improved the capacity of islets to reverse hyperglycaemia. PMID- 21267537 TI - Serum C-reactive protein level and prediabetes in two Asian populations. AB - AIMS/HYPOTHESIS: Prediabetes, an early stage in the hyperglycaemic continuum, increases the future risk of developing diabetes and cardiovascular disease (CVD). C-reactive protein (CRP), a marker of inflammation, is associated with diabetes and CVD. However, studies examining the association between CRP and prediabetes among participants without diabetes are limited. METHODS: We analysed data from two large population-based studies in Singapore: the Singapore Prospective Study Programme (SP2, n = 4,252 Chinese, Malay and Indians aged >= 24 years) and the Singapore Malay Eye Study (SiMES, n = 2,337 Malays aged 40-80 years), participants of which were free of diabetes mellitus. Prediabetes was defined as glycated haemoglobin of 5.7-6.4% in SiMES (n = 1,231); fasting plasma glucose of 5.6-6.9 mmol/l in SP2 (n = 386). RESULTS: Elevated high sensitivity CRP (hsCRP) levels were found to be associated with prediabetes after adjusting for age, sex, race-ethnicity, education, smoking, alcohol consumption, hypertension, BMI and total cholesterol. Comparing those with hsCRP <1 mg/l (referent), the OR (95% confidence interval) of prediabetes in persons with hsCRP 1-3 mg/l and >3 mg/l was 1.31 (0.99-1.74) and 2.17 (1.61-2.92), p (trend) < 0.0001 in SP2; 1.23 (1.00-1.52) and 1.31 (1.06-1.64), p (trend) = 0.02 in SiMES. In subgroup analysis, the association was stronger in women, Chinese and Malays, and participants with BMI < 25 kg/m(2). CONCLUSIONS: Data from two population based Asian cohorts suggest that elevated serum hsCRP levels are associated with prediabetes. PMID- 21267538 TI - Glucose metabolism-related protein 1 (GMRP1) regulates pancreatic beta cell proliferation and apoptosis via activation of Akt signalling pathway in rats and mice. AB - AIMS/HYPOTHESIS: We attempted to elucidate the impacts on and possible mechanisms by which glucose metabolism-related protein 1 (GMRP1) affects beta cell survival. METHODS: Adenovirus-mediated GMRP1 overproduction and siRNA-mediated knockdown were performed in INS-1E cells and rat islets, after which cell proliferation or apoptosis were determined, and phosphorylation of Akt and BCL2-associated agonist of cell death (BAD) investigated. INS-1E cells and rat islets were cultured at 5.6 (low) or 25 mmol/l (high) glucose for 24 or 48 h, and cell proliferation or apoptosis and GMRP1 levels were investigated. INS-1E cells were treated for 24 h with 0, 10, 50 and 100 nmol/l insulin, and GMRP1 levels were determined. After INS-1E cells were transfected with siRNA for 72 h, high glucose-induced cell proliferation and insulin-stimulated Akt phosphorylation were investigated. Glucose-infused rat models were established and beta cell proliferation and mass were evaluated. Levels of GMRP1, and phosphorylation of Akt and BAD were determined in glucose-infused islets. The GMRP1-mediated Akt pathway was also investigated in db/db mice. RESULTS: Overproduction of GMRP1 promoted beta cell proliferation via increased phosphorylation of Akt. Knockdown of Gmrp1 (also known as Btbd10) reduced phosphorylation of Akt with enhanced beta cell apoptosis. High glucose increased GMRP1 levels and cell proliferation in INS-1E cells and islet cells. Knockdown of Gmrp1 decreased high glucose-induced cell proliferation and insulin-stimulated Akt phosphorylation. Increased GMRP1 levels were involved in the enhancement of beta cell proliferation and mass in glucose infused islets. Decreased GMRP1 levels may participate in beta cell apoptosis of db/db mice. CONCLUSIONS/INTERPRETATION: GMRP1 regulates pancreatic beta cell proliferation and apoptosis via activation of Akt signalling pathway. PMID- 21267539 TI - Genetic deficiency of aldose reductase counteracts the development of diabetic nephropathy in C57BL/6 mice. AB - AIMS/HYPOTHESIS: The aim of the study was to investigate the effects of genetic deficiency of aldose reductase in mice on the development of key endpoints of diabetic nephropathy. METHODS: A line of Ar (also known as Akr1b3)-knockout (KO) mice, a line of Ar-bitransgenic mice and control C57BL/6 mice were used in the study. The KO and bitransgenic mice were deficient for Ar in the renal glomeruli and all other tissues, with the exception of, in the bitransgenic mice, a human AR cDNA knockin-transgene that directed collecting-tubule epithelial-cell specific AR expression. Diabetes was induced in 8-week-old male mice with streptozotocin. Mice were further maintained for 17 weeks then killed. A number of serum and urinary variables were determined for these 25-week-old mice. Periodic acid-Schiff staining, western blots, immunohistochemistry and protein kinase C (PKC) activity assays were performed for histological analyses, and to determine the levels of collagen IV and TGF-beta1 and PKC activities in renal cortical tissues. RESULTS: Diabetes-induced extracellular matrix accumulation and collagen IV overproduction were completely prevented in diabetic Ar-KO and bitransgenic mice. Ar deficiency also completely or partially prevented diabetes induced activation of renal cortical PKC, TGF-beta1 and glomerular hypertrophy. Loss of Ar results in a 43% reduction in urine albumin excretion in the diabetic Ar-KO mice and a 48% reduction in the diabetic bitransgenic mice (p < 0.01). CONCLUSIONS/INTERPRETATION: Genetic deficiency of Ar significantly ameliorated development of key endpoints linked with early diabetic nephropathy in vivo. Robust and specific inhibition of aldose reductase might be an effective strategy for the prevention and treatment of diabetic nephropathy. PMID- 21267540 TI - Genetic predisposition to obesity leads to increased risk of type 2 diabetes. AB - AIMS/HYPOTHESIS: Obesity is a major risk factor for type 2 diabetes. Recent genome-wide association (GWA) studies have identified multiple loci robustly associated with BMI and risk of obesity. However, information on their associations with type 2 diabetes is limited. Such information could help increase our understanding of the link between obesity and type 2 diabetes. We examined the associations of 12 obesity susceptibility loci, individually and in combination, with risk of type 2 diabetes in the population-based European Prospective Investigation of Cancer (EPIC) Norfolk cohort. METHODS: We genotyped 12 SNPs, identified by GWA studies of BMI, in 20,428 individuals (aged 39-79 years at baseline) with an average follow-up of 12.9 years, during which 729 individuals developed type 2 diabetes. A genetic predisposition score was calculated by adding the BMI-increasing alleles across the 12 SNPs. Associations with incidence of type 2 diabetes were examined by logistic regression models. RESULTS: Of the 12 SNPs, eight showed a trend with increased risk of type 2 diabetes, consistent with their BMI-increasing effects. Each additional BMI increasing allele in the genetic predisposition score was associated with a 4% increased odds of developing type 2 diabetes (OR 1.041, 95% CI 1.005-1.078; p = 0.02). Adjustment for BMI completely abolished the association with incident type 2 diabetes (OR 1.003, 95% CI 0.967-1.039; p = 0.89). CONCLUSIONS/INTERPRETATION: The genetic predisposition to obesity leads to increased risk of developing type 2 diabetes, which is completely mediated by its obesity-predisposing effect. PMID- 21267541 TI - Macrophage gene expression is related to obesity and the metabolic syndrome in human subcutaneous fat as well as in visceral fat. AB - AIMS/HYPOTHESIS: Our goal was to identify a set of human adipose tissue macrophage (ATM)-specific markers and investigate whether their gene expression in subcutaneous adipose tissue (SAT) as well as in visceral adipose tissue (VAT) is related to obesity and to the occurrence of the metabolic syndrome. METHODS: ATM-specific markers were identified by DNA microarray analysis of adipose tissue cell types isolated from SAT of lean and obese individuals. We then analysed gene expression of these markers by reverse transcription quantitative PCR in paired samples of SAT and VAT from 53 women stratified into four groups (lean, overweight, obese and obese with the metabolic syndrome). Anthropometric measurements, euglycaemic-hyperinsulinaemic clamp, blood analysis and computed tomography scans were performed. RESULTS: A panel of 24 genes was selected as ATM specific markers based on overexpression in ATM compared with other adipose tissue cell types. In SAT and VAT, gene expression of ATM markers was lowest in lean and highest in the metabolic syndrome group. mRNA levels in the two fat depots were negatively correlated with glucose disposal rate and positively associated with indices of adiposity and the metabolic syndrome. CONCLUSIONS/INTERPRETATION: In humans, expression of ATM-specific genes increases with the degree of adiposity and correlates with markers of insulin resistance and the metabolic syndrome to a similar degree in SAT and in VAT. PMID- 21267542 TI - Donor conversion rates depend on the assessment tools used in the evaluation of potential organ donors. AB - PURPOSE: It is desirable to identify a potential organ donor (POD) as early as possible to achieve a donor conversion rate (DCR) as high as possible which is defined as the actual number of organ donors divided by the number of patients who are regarded as a potential organ donor. The DCR is calculated with different assessment tools to identify a POD. Obviously, with different assessment tools, one may calculate different DCRs, which make comparison difficult. Our aim was to determine which assessment tool can be used for a realistic estimation of a POD pool and how they compare to each other with regard to DCR. METHODS: Retrospective chart review of patients diagnosed with a subarachnoid haemorrhage, traumatic brain injury or intracerebral haemorrhage. We applied three different assessment tools on this cohort of patients. RESULTS: We identified a cohort of 564 patients diagnosed with a subarachnoid haemorrhage, traumatic brain injury or intracerebral haemorrhage of whom 179/564 (31.7%) died. After applying the three different assessment tools the number of patients, before exclusion of medical reasons or age, was 76 for the IBD-FOUR definition, 104 patients for the IBD-GCS definition and 107 patients based on the OPTN definition of imminent neurological death. We noted the highest DCR (36.5%) in the IBD-FOUR definition. CONCLUSION: The definition of imminent brain death based on the FOUR-score is the most practical tool to identify patients with a realistic chance to become brain dead and therefore to identify the patients most likely to become POD. PMID- 21267543 TI - Physiotherapy-guided versus home-based, unsupervised rehabilitation in isolated anterior cruciate injuries following surgical reconstruction. AB - PURPOSE: The aim of this study was to investigate the outcome after ACL reconstruction between a group of patients receiving a standardized, supervised, physiotherapy-guided rehabilitation programme and a group of patients who followed an unsupervised, home-based rehabilitation programme. METHODS: Forty patients with isolated anterior cruciate ligament injuries were allocated to either a supervised physiotherapy intervention group or home-based exercise group. Patients were investigated by an independent examiner pre-operative, 3, 6, 9 and 12 months post-surgery using the following outcome measures: Lysholm Score and Tegner Activity Scale, functional hopping tests, and isometric and isokinetic strength assessments. RESULTS: Both groups improved significantly (P = 0.01-0.04) following 12 months after surgery. The median Lysholm score increased from 57 (34 90) to 94 (90-100) in the supervised group and 60 (41-87) to 97 (95-100) in the unsupervised group. The median Tegner Activity Scale increased from 3 (2-8) to 6 (3-8) in the supervised group and 4 (2-8) to 5 (3-10) in the unsupervised group. The combined mean symmetry indices for the hopping tests improved from 77.3 +/- 18.7 to 86.8 +/- 11.1 (supervised) and from 78.1 +/- 30.5 to 88.3 +/- 10.9 (unsupervised). Isometric and isokinetic strength symmetry indices for knee extension improved from 68.9 +/- 23.5 to 82.8 +/- 11.9, respectively, 63.7 + 22.8 to 82.7 + 15.1 in the supervised group and from 73.6 +/- 20.5 to 76.5 +/- 17.9, respectively, 69.5 +/- 24.3 to 76.9 +/- 16.9 in the unsupervised group. Eccentric strength symmetry indices for knee extension improved from 67.9 +/- 27.7 to 87.8 +/- 6.8 in the supervised group and from 71.3 +/- 17.8 to 82.6 +/- 15.6 in the unsupervised group. CONCLUSION: This study could not demonstrate a benefit in a rehabilitation programme supervised by a physiotherapist in our population compared to an unsupervised cohort. PMID- 21267545 TI - Skeletal mineralization defects in adult hypophosphatasia--a clinical and histological analysis. AB - Histomorphometry and quantitative backscattered electron microscopy of iliac crest biopsies from patients with adult hypophosphatasia not only confirmed the expected enrichment of non-mineralized osteoid, but also demonstrated an altered trabecular microarchitecture, an increased number of osteoblasts, and an impaired calcium distribution within the mineralized bone matrix. INTRODUCTION: Adult hypophosphatasia is an inherited disorder of bone metabolism caused by inactivating mutations of the ALPL gene, encoding tissue non-specific alkaline phosphatase. While it is commonly accepted that the increased fracture risk of the patients is the consequence of osteomalacia, there are only few studies describing a complete histomorphometric analysis of bone biopsies from affected individuals. Therefore, we analyzed iliac crest biopsies from eight patients and set them in direct comparison to biopsies from healthy donors or from individuals with other types of osteomalacia. METHODS: Histomorphometric analysis was performed on non-decalcified sections stained either after von Kossa/van Gieson or with toluidine blue. Bone mineral density distribution was quantified by backscattered electron microscopy. RESULTS: Besides the well-documented enrichment of non-mineralized bone matrix in individuals suffering from adult hypophosphatasia, our histomorphometric analysis revealed alterations of the trabecular microarchitecture and an increased number of osteoblasts compared to healthy controls or to individuals with other types of osteomalacia. Moreover, the analysis of the mineralized bone matrix revealed significantly decreased calcium content in patients with adult hypophosphatasia. CONCLUSIONS: Taken together, our data show that adult hypophosphatasia does not solely result in an enrichment of osteoid, but also in a considerable degradation of bone quality, which might contribute to the increased fracture risk of the affected individuals. PMID- 21267546 TI - Carcinogenicity of deoxycholate, a secondary bile acid. AB - High dietary fat causes increased bile acid secretion into the gastrointestinal tract and is associated with colon cancer. Since the bile acid deoxycholic acid (DOC) is suggested to be important in colon cancer etiology, this study investigated whether DOC, at a high physiologic level, could be a colon carcinogen. Addition of 0.2% DOC for 8-10 months to the diet of 18 wild-type mice induced colonic tumors in 17 mice, including 10 with cancers. Addition of the antioxidant chlorogenic acid at 0.007% to the DOC-supplemented diet significantly reduced tumor formation. These results indicate that a high fat diet in humans, associated with increased risk of colon cancer, may have its carcinogenic potential mediated through the action of bile acids, and that some dietary anti oxidants may ameliorate this carcinogenicity. PMID- 21267547 TI - Prevention of benzene-induced genotoxicity in bone marrow and lung cells: superiority of polyphenolic acetates to polyphenols. AB - Previous investigations carried out in our laboratory have highlighted that 7,8 diacetoxy-4-methylcoumarin demonstrates a mechanism-based inhibition of cytochrome P450 (Cyt-P450) activities such as microsome-mediated aflatoxin B1 (AFB1) epoxidation, dealkylation of alkylated resorufin, and toxicokinetics of benzene. 7,8-Diacetoxy-4-methylcoumarin, quercetin pentaacetate, and ellagic acid peracetate were also found to be effective in giving the protection of AFB1 induced genotoxicity in rat's bone marrow and lung cells possibly due to acetylation of Cyt-P450 apoprotein mediated by acetoxy drug: protein transacetylase. Later, this transacetylase was identified as calreticulin, and the acetyltransferase function of calreticulin was appropriately termed calreticulin transacetylase. In this communication, we have focused on the superiority of several classes of polyphenolic acetates to polyphenols in the modification of Cyt-P450-linked mixed function oxidases (MFOs) such as 7 ethoxyresorufin O-deethylase (EROD) and pentoxyresorufin O-dealkylase (PROD). Special attention has also been focused on benzene-induced genotoxicity in bone marrow and lung cells. Results clearly indicated that polyphenolic acetates demonstrated time-dependent inhibition of Cyt-P450-linked MFOs, while parent polyphenols failed to demonstrate the same. Polyphenolic acetates were found to be more superior to polyphenols in preventing benzene-induced micronuclei formation. The pattern of inhibition of Cyt-P450-dependent MFOs and benzene induced micronuclei formation by polyphenolic acetates was found in tune with their specificities to calreticulin transacetylase. These results further substantiated that inhibition of Cyt-P450-linked MFOs and benzene-induced genotoxicity in bone marrow and lung cells by polyphenolic acetates are mediated by the action of calreticulin transacetylase that catalyzes the acetylation of concerned proteins. PMID- 21267548 TI - Nonrenewal spike train statistics: causes and functional consequences on neural coding. AB - Many neurons display significant patterning in their spike trains (e.g. oscillations, bursting), and there is accumulating evidence that information is contained in these patterns. In many cases, this patterning is caused by intrinsic mechanisms rather than external signals. In this review, we focus on spiking activity that displays nonrenewal statistics (i.e. memory that persists from one firing to the next). Such statistics are seen in both peripheral and central neurons and appear to be ubiquitous in the CNS. We review the principal mechanisms that can give rise to nonrenewal spike train statistics. These are separated into intrinsic mechanisms such as relative refractoriness and network mechanisms such as coupling with delayed inhibitory feedback. Next, we focus on the functional roles for nonrenewal spike train statistics. These can either increase or decrease information transmission. We also focus on how such statistics can give rise to an optimal integration timescale at which spike train variability is minimal and how this might be exploited by sensory systems to maximize the detection of weak signals. We finish by pointing out some interesting future directions for research in this area. In particular, we explore the interesting possibility that synaptic dynamics might be matched with the nonrenewal spiking statistics of presynaptic spike trains in order to further improve information transmission. PMID- 21267549 TI - Long-interval intracortical inhibition in a human hand muscle. AB - When two motor cortical stimuli are delivered with an interstimulus interval of 50-200 ms, the response (motor evoked potential; MEP) to the second stimulus is typically suppressed. This phenomenon is termed long-interval intracortical inhibition (LICI), although data from one subject suggest that facilitation is possible. Moreover, we recently showed that suppression can be mediated at a spinal level. We characterized LICI more fully by exploring a broad range of contraction strengths and test stimulus intensities. MEPs were evoked in first dorsal interosseous by transcranial magnetic stimulation over the motor cortex. Single test and paired (conditioning-test interval of 100 ms) stimuli at intensities of 100-160% resting motor threshold were delivered at rest or during brief contractions of 10, 25, or 100% maximal voluntary force. Inhibition or facilitation was quantified with the standard ratio in which conditioned MEPs were expressed as a percentage of unconditioned MEPs. Inhibition was greatest at weak-moderate contraction strengths and least at rest and during maximal efforts. Both at rest and during maximal efforts, MEPs evoked by strong stimuli were facilitated. In a subset of subjects, cervicomedullary stimulation was used to activate the corticospinal tract to identify possible spinal influences on changes to MEPs. Contraction strength and test stimulus intensity each had different effects on unconditioned and conditioned MEP size, and hence, LICI is highly dependent on both factors. Further, because motoneurons are facilitated during contraction but disfacilitated after a strong conditioning stimulus, the standard ratio of LICI is of questionable validity during voluntary contractions. PMID- 21267550 TI - Role of the rostral ventrolateral medulla (RVLM) in the patterning of vestibular system influences on sympathetic nervous system outflow to the upper and lower body. AB - Research on animal models as well as human subjects has demonstrated that the vestibular system contributes to regulating the distribution of blood in the body through effects on the sympathetic nervous system. Elimination of vestibular inputs results in increased blood flow to the hindlimbs during vestibular stimulation, because it attenuates the increase in vascular resistance that ordinarily occurs in the lower body during head-up tilts. Additionally, the changes in vascular resistance produced by vestibular stimulation differ between body regions. Electrical stimulation of vestibular afferents produces an inhibition of most hindlimb vasoconstrictor fibers and a decrease in hindlimb vascular resistance, but an initial excitation of most upper body vasoconstrictor fibers accompanied by an increase in upper body vascular resistance. The present study tested the hypothesis that neurons in the principal vasomotor region of the brainstem, the rostral ventrolateral medulla (RVLM), whose projections extended past the T10 segment, to spinal levels containing sympathetic preganglionic neurons regulating lower body blood flow, respond differently to electrical stimulation of the vestibular nerve than RVLM neurons whose axons terminate rostral to T10. Contrary to our hypothesis, the majority of RVLM neurons were excited by vestibular stimulation, despite their level of projection in the spinal cord. These findings indicate that the RVLM is not solely responsible for establishing the patterning of vestibular-sympathetic responses. This patterning apparently requires the integration by spinal circuitry of labyrinthine signals transmitted from the brainstem, likely from regions in addition to the RVLM. PMID- 21267551 TI - How do illusions constrain goal-directed movement: perceptual and visuomotor influences on speed/accuracy trade-off. AB - Recent research shows that visual processing influences the speed/accuracy trade off people use when performing goal-directed movement. This raises the question of how this influence is produced in visual cognition. Visual influences on speed/accuracy trade-off could be produced in conscious visual perception, in non conscious visuomotor transformation, or by some interaction of conscious perceptual and non-conscious visuomotor processes. There is independent evidence showing that both perceptual and visuomotor processes are involved in trading off speed and accuracy; however, the interaction between these processes has yet to be investigated. We present an experiment in which we show that a change in visual consciousness induced by a perceptual illusion affects the speed and accuracy of goal-directed movements, suggesting that perceptual and visuomotor processes do interact in speed/accuracy trade-off. We discuss the consequences of these results for theories of visual function more generally. PMID- 21267552 TI - Reaching strategies of very preterm infants at 8 months corrected age. AB - Reaching strategies and kinematics for a group of very preterm infants were investigated and compared with a group of full-term infants when reaching for a moving object. Eight-month-old (corrected-age) infants were presented with small toys moving on a semicircular path in the vertical plane. The trajectories of the target and the hands of the infants were measured using a 3D motion analysis system. No differences were found in how often the infants encountered the target. The very preterm group, however, used bimanual strategies more often and had more curved reaching paths than the full-term group. These results suggest that very preterm infants are equally successful as healthy full-term infants in catching a moving object but their reaching strategies are less efficient compared with full-term infants at 8 months (corrected age). PMID- 21267553 TI - Action and attentional load can influence aperture effects on motion perception. AB - When a moving featureless contour is viewed through a stationary circular aperture that occludes the contour's endpoints and the contour moves in a direction non-parallel to its orientation, observers report the contour's direction of motion as perpendicular to the contour's orientation regardless of its actual direction. In typical studies of this aperture effect on motion perception, observers made perceptual judgments of the line's motion. The aperture effect was not measured when observers actively controlled the line's motion. In addition, effects of attentional load on the aperture effect were not measured. Here, we demonstrated that attentional load influenced the aperture effect. Active control reduced the aperture effect, but did not eliminate it. Results have theoretical implications for motion perception and practical implications for the design of technologies that limit an observer's field-of view such as surgical cameras. PMID- 21267554 TI - Reach adaptation to online target error. AB - Magescas et al. (Exp Brain Res 193:337-350, 2009) recently suggested that online error, unlike terminal error, does not lead to reach adaptation. The present study re-examines adaptation to online target error, but uses a small target perturbation and eliminates online vision of the limb, factors that may affect adaptation. We compared 3 groups: terminal error, online error, and control. All groups completed a pretest, exposure, and posttest phase. Participants made look and-point movements to a target, and we examined how repeated rightward target perturbations during the exposure phases of the experimental groups influenced reaches to a stationary target in the posttest. Exposure phases of each group contained an equal number of interleaved look-and-point and look-only trials, the latter of which were designed to inhibit build-up of saccadic adaptation in the online error group. On look-and-point trials the target either disappeared at saccade onset and then re-appeared 3.75 cm to the right when the hand landed (terminal error group), immediately jumped right by 3.75 cm at saccade onset and remained lit throughout the saccade and reach (online error group), or remained lit but stationary throughout the saccade and reach (control group). In all groups, vision of the limb was only provided at the start and end of the reach. Our results show that both the terminal error and the online error groups developed significant aftereffects. It appears, therefore, that online error can produce reach adaptation. PMID- 21267555 TI - Identification and characterization of gene expression involved in the coloration of cichlid fish using microarray and qRT-PCR approaches. AB - It has been suggested that speciation on the basis of sexual selection is an important mechanism for the generation of new species for East African cichlids, where male body coloration is one of the major discriminatory factors used by females in mate choice. To gain insight into the molecular basis of cichlid coloration, we studied the Lake Malawi cichlid Pseudotropheus saulosi, comparing transcription in the bright blue skin of males to the yellow skin of females. Our cDNA microarray experiments identified 46 clones that exhibited expression differences between the two sexes, of which five were confirmed to be differentially expressed by relative quantitative real-time PCR (qRT-PCR). This gene list includes a representative from the endosomal-to-Golgi vesicle trafficking pathway, Coatomer protein complex, subunit zeta-1 (Copz-1), which is known to be a critical determinant of pigmentation in humans and zebrafish. With the support of microscopic images of the skin of these specimens, we interpret the transcriptional differences between the blue males and yellow females. Here, we provide insight into the putative functional diversification of genes involved in the coloration of cichlids and by extension, on the evolution of coloration in teleost fish. PMID- 21267556 TI - Pediatric sellar and suprasellar lesions. AB - Masses arising in the sella turcica and the suprasellar region are common in children. The type and frequency of the various lesions encountered in childhood differ from the adult presentation. This article reviews the embryology of the pituitary gland and its normal appearance in childhood as well as the imaging and clinical findings of the common and some of the uncommon lesions arising in the sella turcica, the pituitary stalk, the suprasellar cistern and the lower third ventricle in the pediatric population. PMID- 21267557 TI - The effect of membrane curvature on the conformation of antimicrobial peptides: implications for binding and the mechanism of action. AB - Short cationic antimicrobial peptides (AMPs) are believed to act either by inducing transmembrane pores or disrupting membranes in a detergent-like manner. For example, the antimicrobial peptides aurein 1.2, citropin 1.1, maculatin 1.1 and caerin 1.1, despite being closely related, appear to act by fundamentally different mechanisms depending on their length. Using molecular dynamics simulations, the structural properties of these four peptides have been examined in solution as well as in a variety of membrane environments. It is shown that each of the peptides has a strong preference for binding to regions of high membrane curvature and that the structure of the peptides is dependent on the degree of local curvature. This suggests that the shorter peptides aurein 1.2 and citropin 1.1 act via a detergent-like mechanism because they can induce high local, but not long-range curvature, whereas the longer peptides maculatin 1.1 and caerin 1.1 require longer range curvature to fold and thus bind to and stabilize transmembrane pores. PMID- 21267558 TI - Disruption of beta-oxidation pathway in Pseudomonas putida KT2442 to produce new functionalized PHAs with thioester groups. AB - This work describes the generation of novel PHAs (named PHACOS) with a new monomer composition containing thioester groups in the side chain, which confers new properties and made them suitable for chemical modifications after their biosynthesis. We have analyzed the PHACOS production abilities of the wild-type strain Pseudomonas putida KT2442 vs. its derived strain P. putida KT42FadB, mutated in the fadB gene from the central metabolic beta-oxidation pathway involved in the synthesis of medium-chain-length PHA (mcl-PHA). Different fermentation strategies based on one- or two-stage cultures have been tested resulting in PHACOS with different monomer composition. Using decanoic acid as inducer of the growth and polymer synthesis and 6-acetylthiohexanoic acid as PHA precursor in a two-stage strategy, the maximum yield was obtained by culturing the strain KT42FadB. Nuclear magnetic resonance and gas chromatography coupled to mass spectrometry showed that polymers obtained from the wild-type and KT42FadB strains, included 6-acetylthio-3-hydroxyhexanoic acid (OH-6ATH) and the shorter derivative 4-acetylthio-3-hydroxybutanoic acid (OH-4ATB) in their composition, although in different ratios. While the polymer obtained from KT42FadB strain contained mainly OH-6ATH monomer units, mcl-PHA produced by the wild-type strain contained OH-6ATH and OH-4ATB. Furthermore, polyesters showed differences in the OH-alkyl derivates moiety. The strain KT42FadB overproduced PHACOS when compared to the production rate of the control strain in one- and two-stage cultures. Thermal properties obtained by differential scanning calorimetry indicated that both polymers have different glass transition temperatures related to their composition. PMID- 21267559 TI - Pursuing an underdiagnosed disease: a simple imaging test for increasing suspicion of cardiac amyloidosis. PMID- 21267560 TI - Hepatocarcinogenesis: imaging-pathologic correlation. AB - Rapid advances in liver surgery, including liver transplantation, radiology, and pathology, have created a need for clinically relevant nomenclature for premalignant and early lesions of hepatocellular carcinoma (HCC). Precancerous lesions include dysplastic foci and dysplastic nodules (DNs) characterized by cytologic or structural atypia. Although imaging diagnosis is playing a crucial role in the evaluation of hepatocarcinogenesis and early diagnosis of HCC, it is still challenging to accurately characterize borderline nodules such as small arterially enhancing lesions or hypovascular nodules. This article discusses pathological and radiological features of these small nodular lesions and offers insights into the multistep process of hepatocarcinogenesis by describing the progression of pathologic change linking DNs to HCC. PMID- 21267561 TI - Hepatocellular nodules in liver cirrhosis: contrast-enhanced MR. AB - Nowadays, the diagnosis of hepatocellular carcinoma (HCC) is increasingly demanded to imaging techniques. Anyway, imaging cirrhotic patients still remains a challenging issue, since pre-neoplastic hepatocellular lesions, as dysplastic nodules (DNs), may frequently mimic small neoplasms. Differently from other imaging modalities, magnetic resonance (MR) can give an accurate evaluation of both intracellular and vascular changes occurring during the carcinogenetic pathway from dysplasia to full malignancy. Both DNs and HCC may in fact show a large variety of signal intensities, strictly reflecting nodules' characteristics, such as lesion architecture, grading, stromal components, as well as intracellular contents. In these last years, the introduction of dedicated contrast media has increased MR diagnostic efficacy, permitting to explore both vascular as well as the pathological changes occurring in the biliary and reticuloendothelial systems during the carcinogenetic process. MR performed with tissue specific contrast agents (hepatobiliary and reticulo endothelial) may thus give an insight on this "gray area", in whom significant histological changes are already present without an evident nodule arterial supply. This peculiar MR prerogative permits to give predictive information about the evolution trend in a cirrhotic parenchyma and to identify patients at high risk for developing carcinoma who would benefit from well-timed treatments. PMID- 21267562 TI - Hepatocelluar nodules in liver cirrhosis: hemodynamic evaluation (angiography assisted CT) with special reference to multi-step hepatocarcinogenesis. AB - To understand the hemodynamics of hepatocellular carcinoma (HCC) is important for the precise imaging diagnosis and treatment, because there is an intense correlation between their hemodynamics and pathophysiology. Angiogenesis such as sinusoidal capillarization and unpaired arteries shows gradual increase during multi-step hepatocarcinogenesis from high-grade dysplastic nodule to classic hypervascular HCC. In accordance with this angiogenesis, the intranodular portal supply is decreased, whereas the intranodular arterial supply is first decreased during the early stage of hepatocarcinogenesis and then increased in parallel with increasing grade of malignancy of the nodules. On the other hand, the main drainage vessels of hepatocellular nodules change from hepatic veins to hepatic sinusoids and then to portal veins during multi-step hepatocarcinogenesis, mainly due to disappearance of the hepatic veins from the nodules. Therefore, in early HCC, no perinodular corona enhancement is seen on portal to equilibrium phase CT, but it is definite in hypervascular classical HCC. Corona enhancement is thicker in encapsulated HCC and thin in HCC without pseudocapsule. To understand these hemodynamic changes during multi-step hepatocarcinogenesis is important, especially for early diagnosis and treatment of HCCs. PMID- 21267563 TI - Hepatocellular nodules in liver cirrhosis: state of the art CT evaluation (perfusion CT/volume helical shuttle scan/dual-energy CT, etc.). AB - The purpose of this article is to explain the role of advanced liver CT imaging, including perfusion CT, dual-energy CT, and volume helical shuttle (VHS) scanning, with regard to its clinical applications. Perfusion CT is a promising method for calculating hepatic blood flow and portal blood flow, including microcirculation, using a color-encoded display of parameters obtained from the liver time-density curve, with iodine contrast agent. Tumor angiogenesis and assessment of the response to antiangiogenesis treatment (e.g., Sorafenib) can be analyzed by perfusion CT of the liver. VHS scan has very high temporal resolution due to the reciprocating movement employed during scanning, enabling the acquisition of 24 scans of the whole liver in the arterial dominant phase during a 40-s breath hold, and a reduction in radiation dose. Dual-energy CT enables differentiation of materials and tissues based on their CT density values, using two different energy spectra. This method includes a low tube voltage CT technique that increases the contrast enhancement of vascular structures while simultaneously reducing radiation dose. Images obtained at the preferred settings of low tube voltage and high tube current, with dose reduction in the hepatic arterial phase, are useful for detecting hypervascular hepatocellular carcinoma. PMID- 21267564 TI - Guest editor's introduction: hepatocellular nodules in liver cirrhosis: imaging update 2011. AB - These review articles will enhance the knowledge of radiologists about current imaging modalities and various contrast agents for the detection and characterization hepatocellular nodules including hepatocellular carcinoma (HCC) in liver cirrhosis, and new concepts of imaging findings, and enable to understand these nodules more completely and thus accurately diagnose HCC. PMID- 21267565 TI - Influence of intraoperative neuromonitoring on surgeons' technique during thyroidectomy. AB - BACKGROUND: When assessing the value of intraoperative nerve monitoring (IONM) during routine thyroidectomy, it is necessary to consider its influence on the surgeon's dissection technique. We investigated the effect of IONM on individual surgeon performance by determining the learning curve associated with this tool. METHODS: A one-year prospective study was conducted between May 2008 and April 2009 within a team of three experienced endocrine surgeons. The measure of surgical performance was based on the detection of immediate postoperative recurrent laryngeal nerve palsy by laryngoscopy. Individual learning curves associated with IONM acquisition were drawn with the cumulative sum (CUSUM) chart. Each surgeon was questioned about possible changes he had experienced in his own surgical technique after the introduction of IONM. RESULTS: A total of 475 consecutive patients who underwent thyroid surgery with IONM were included. The pattern of learning curves varied among surgeons and ranged from 35 to 304 procedures required for complete IONM acquisition. The surgeon with the longest learning curve also described a drastic modification of his technique related to nerve dissection. CONCLUSIONS: Intraoperative nerve monitoring can induce changes in surgical practice. The different learning curve patterns among surgeons may reflect the variable degree to which surgeons will modify their own dissection technique. Such an effect on learning must be considered when assessing the impact of using IONM on patient safety. PMID- 21267566 TI - Implementing sentinel lymph node biopsy programs in developing countries: challenges and opportunities. AB - BACKGROUND: Sentinel lymph node biopsy (SLNB) is the accepted standard of care in early-stage breast cancer and cutaneous melanoma. This technology is accurate for nodal staging and determining the prognosis of these patients. There are several randomized controlled trials confirming the accuracy of this technique and confirming its role in reducing morbidity and improving quality of life. It is also gaining increased acceptance in the management of other solid tumors. Despite the established benefits of SLNB as a minimally invasive approach for nodal staging, the procedure is still underutilized in many developing countries. METHODS: The Human Health Division of the International Atomic Energy Agency (IAEA) convened advisory meetings with panels of multidisciplinary experts from different backgrounds with the remit to analyze the difficulties encountered by developing countries in establishing a successful SLNB program. The other remit of the panel was to recommend an effective program based on existing evidence that can be adapted and implemented in developing countries. The experience of some members of the panel in the training for this technique in Asia, Latin America, and Africa provided the insight required for the development of a comprehensive and structured program. The panel included recommendations on the technical aspects of the procedure, as well as a comprehensive training program, including theoretical teaching, practical training in surgical skills, laboratories, and hands-on proctored learning. Particular emphasis was placed on in-built quality assurance requirements to ensure that this powerful staging investigation is implemented with the highest possible standard in the management of cancer patients, with the lowest false negative rate. CONCLUSIONS: It is hoped that this article will be a useful resource for our colleagues planning to establish a SLNB program. PMID- 21267567 TI - Changes in the localization of perforated peptic ulcer and its relation to gender and age of the patients throughout the last 45 years. AB - BACKGROUND: Throughout recent decades there has been noticeable change in the incidence of peptic ulcer disease and its complications. The aim of the present study was to determine the character of changes over the last 45 years in the localization of perforation, in patient age, and in patient gender. METHODS: A group of 881 patients admitted to the Second Department of General Surgery in Krakow, Poland, from 1962 to 2006 were included in the study and constituted the material for the analysis. The study was divided into three time periods (1962 1976, 1977-1991, and 1992-2006) to allow statistical analysis of trends. RESULTS: The general incidence of perforations of peptic ulcer did not show changes; however, the percentage of women with perforated duodenal ulcer markedly increased. Patients with perforated stomach ulcer--regardless of gender--and females suffering from perforated duodenal ulcer were, on the average, about 10 years older than males with perforated duodenal ulcers. The mean age of male and female patients with perforated duodenal ulcer over the last 45 years showed an insignificant upward trend. CONCLUSIONS: (1) The percentage of women with perforated duodenal ulcer continuously and statistically significantly rose. (2) Men with perforated duodenal ulcer were significantly younger than other patients. (3) The mean ages of male and female patients with perforated duodenal ulcer over the last 45 years showed an insignificant upward trend. PMID- 21267570 TI - Anti-PAD4 autoantibodies in rheumatoid arthritis: levels in serum over time and impact on PAD4 activity as measured with a small synthetic substrate. AB - Isoform 4 of the human peptidylarginine deiminase (hPAD4) enzyme may be responsible for the citrullination of antigens in rheumatoid arthritis (RA) and has been shown to be itself the target of disease-specific autoantibodies. Here, we have tested whether the level of serum anti-hPAD4 antibodies in RA patients is stable over a period of 10 years and whether the antibodies influence hPAD4 mediated deimination of the small substrate N-alpha-benzoyl-L-arginine ethyl ester. RA sera (n = 128) obtained at baseline and after 10 years were assessed for anti-hPAD4 antibodies by a specific immunoassay. For 118 RA patients, serum anti-hPAD4 IgG levels were stable over 10 years. Seven patients who were negative for anti-PAD4 IgG at baseline had become positive after 10 years. Further, total IgG from selected RA patients and controls were purified, and a fraction was depleted for anti-hPAD4 antibodies. Kinetic deimination assays were performed with total IgG and depleted fractions. The k ( cat ) and K ( m ) values of hPAD4 mediated deimination of N-alpha-benzoyl-L-arginine ethyl ester were not affected by the depletion of the anti-hPAD4 antibodies from the total IgG pool. In conclusion, RA patients remain positive for anti-hPAD4 antibodies over time and some patients who are initially anti-hPAD4 negative become positive later in the disease course. The anti-hPAD4 antibodies did not affect the enzymatic activity of hPAD4 when the small substrate N-alpha-benzoyl-L-arginine ethyl ester was used. However, this finding may not exclude an effect of these autoantibodies on citrullination of protein substrates in RA. PMID- 21267569 TI - Polyethylene and metal wear particles: characteristics and biological effects. AB - This paper first presents a brief overview about the mechanism of wear particle formation as well as wear particle characteristics in metal-on-polyethylene and metal-on-metal artificial hip joints. The biological effects of such particles are then described, focusing on the inflammatory response induced by each type of particles as well as on how metal wear products may be the source of a T lymphocyte-mediated specific immune response, early adverse tissue responses, and genotoxicity. Finally, some of the current in vivo models used for the analysis of tissue response to various wear particles are presented. PMID- 21267571 TI - Pain intensity and quality of life perception in children with hypermobility syndrome. AB - Hypermobility syndrome (HMS) is a major source of morbidity in children. Impaired quality of life (QoL) has been observed recently in adults with HMS; however, this issue is yet to be investigated in children with this condition. This study compared pain intensity and QoL in children with HMS with healthy controls. It also examined the relationship between pain intensity and QoL in children with HMS. Following ethical approval, 29 children diagnosed with HMS and 37 healthy children aged 8-15 years participated. Informed written consent was obtained from participants and their parents/guardians. Average knee pain over the past week was examined using the Coloured Analogue Scale. QoL was measured via the Pediatric Quality of Life Inventory. Mann-Whitney U tests were performed to compare pain and QoL scores between the two groups. Spearman Rho correlation analysis was performed to examine the relationship between pain and QoL. Overall QoL scores in each domain were significantly lower in children with HMS (all p < 0.001) compared with the controls. Pain intensity was significantly higher in children with HMS compared with their healthy counterparts (p < 0.001). A strong negative correlation was observed between pain intensity and overall QoL and all the domains (r range = -0.614 to -0.717; all p < 0.001). In conclusion, the findings of the present study imply that pain and QoL assessment might form important components of clinical examination for children diagnosed with HMS. These children may benefit from appropriate treatment programmes to alleviate pain intensity and improve QoL. PMID- 21267572 TI - Rheumatoid arthritis risk associates with DNA repair gene XRCC1 Arg399Gln polymorphism in Turkish patients. AB - Rheumatoid arthritis (RA) is an autoinflammatory disease with a genetic background. The synoviocytes in RA shows cellular transformation with tumor-like features, and RA patients have genomic instability and relaxation of DNA repair mechanisms. The polymorphisms in BER repair pathway genes, XRCC1 and OGG1, may change the response to inflammation via altered DNA repair capacity. In this study, we aimed to investigate the relationship between the risk of RA and XRCC1 Arg194Trp, Arg399Gln, and OGG1 Ser326Cys polymorphisms in a group of Turkish RA patients. XRCC1 Arg194Trp, Arg399Gln, and OGG1 Ser326Cys polymorphisms were investigated by PCR-RFLP method in 100 RA patients and 158 healthy control subjects. The results were statistically analyzed by calculating the odds ratios (OR) and their 95% confidence intervals (95% CI) using the chi(2)-tests. RA patients in this study had significantly higher frequencies of XRCC1 Arg399Gln polymorphism in both homozygote (GG) (35%, OR: 7.78 [95% CI: 3.65-16.59], P < 0.001) and heterozygote (AG) forms (41%, OR: 2.17 [95% CI: 1.19-3.96], P < 0.01) and also increased frequency of 399Gln (G) allele (55%, OR:2.99 [95% CI: 1.67 5.37], P < 0.001). We conclude that XRCC1 Arg194Trp, and OGG1 Ser326Cys polymorphisms are not associated with RA; however, Arg399Gln polymorphism is a significant risk factor of RA, and carriers of 399Gln (G) allele have greater risk of RA. PMID- 21267573 TI - Patients with relapsing polychondritis and previous cartilage trauma present more autoimmunity phenomena. AB - Relapsing polychondritis (RP) is an autoimmune disease characterized by inflammation and destruction of all type of body cartilage, and the cartilage trauma may be a trigger of the disease in a susceptible person. We describe the clinical and laboratory findings in a group of 18 patients with RP with (7 cases) or without (11 cases) anteceding cartilage trauma. The mean age was 41 years in the group with cartilage trauma and 55 years in the group without cartilage trauma. For both groups, female gender was predominant. All patients presented with auricular chondritis. Systemic manifestations and autoimmunity were more common in patients with anteceding trauma. PMID- 21267574 TI - Tears at the rotator cuff footprint: prevalence and imaging characteristics in 305 MR arthrograms of the shoulder. AB - OBJECTIVES: To evaluate the prevalence, imaging characteristics and anatomical distribution of tears at the rotator cuff (RC) footprint with MR arthrography (MR A) of the shoulder. METHODS: MR arthrograms obtained in 305 patients were retrospectively reviewed. Partial articular-sided supraspinatus tendon avulsions (PASTA), concealed interstitial delaminations (CID), reverse PASTA lesions and full-thickness tears (FT) at the humeral tendon insertion were depicted. Anatomical locations were determined and depths of tears were classified. RESULTS: 112/305 patients showed RC tears, including 63 patients with 68 footprint tears. 34 PASTA lesions were detected with 20/34 involving the anterior supraspinatus (SSP) tendon and 17/34 PASTA lesions were grade I lesions. Most CID lesions (14/23) occurred at the posterior SSP and 20/23 were classified as grade I or II. 9 FT and 2 reverse PASTA lesions were found. Statistical analysis revealed no difference in anatomical location (p = 0.903) and no correlation with overhead sports activity (p = 0.300) or history of trauma (p = 0.928). There were significantly more PASTA lesions in patients < 40 years of age (p = 0.029). CONCLUSIONS: Most RC tears detected with MR-A involve the SSP footprint and are articular-sided with predominance in younger patients, but concealed lesions are not as uncommon as previously thought. PMID- 21267575 TI - Elastosonography: a possible new tool for diagnosis of adenomyosis? AB - OBJECTIVES: Adenomyosis is a disorder defined by the presence of ectopic endometrial glands and stroma within the myometrium. Transvaginal ultrasound (TVU) is currently the first-line examination for this condition and the aim of this paper is to relate a pilot experience that was conducted using TVU to evaluate adenomyosis and which started from the assumption that tissues with anatomopathological differences show different elasticity values. METHODS: Using standard B-mode analysis and elastosonography, we evaluated 30 consecutive women with suspected uterine adenomyosis. In 15 cases the diagnosis was confirmed by histology. RESULTS: The adenomyotic area presented more softness (red and green) compared with the surrounding uterine tissue (blue); the borders of the adenomyotic area corresponded to the borders of the green area. CONCLUSIONS: These preliminary results suggest that elastosonography could be considered a useful tool in the diagnosis of adenomyosis because it is non-invasive, easy to understand, easy to perform, and has a short learning curve towards becoming skilled at the procedure. PMID- 21267576 TI - MRI differentiates femoral condylar ossification evolution from osteochondritis dissecans. A new sign. AB - OBJECTIVE: To determine if MRI (magnetic resonance imaging) of the femoral condyles in children can differentiate variations in ossification from osteochondritis dissecans (OCD). METHODS: MRI studies of the knee of 315 patients demonstrated ossification defects of the femoral condyles involving the subchondral bone plate. MRI features categorized the defects as ossification variability (N = 150) or OCD (N = 165). Both groups were compared for age, residual physeal cartilage, site, configuration, 'lesion angle' and associated findings. RESULTS: (a) Ossification variability did not occur in girls >10 year. and boys >13 year., OCD did not occur in children younger than 8 year. (b) Ossification variability was not seen in patients with 10% or less residual physeal cartilage, OCD was rare in patients with 30% or greater residual physeal cartilage. (c) Ossification variability was located in the posterior third of the femoral condyle, OCD occurred most commonly in the middle third. (d) Intracondylar extension was seen in OCD and not in ossification variability. (e) Perilesional oedema was very common with OCD and absent with ossification variability. (f) Lesion angle <105 degrees was a feature of ossification variability. CONCLUSION: MRI may help differentiate variations in ossification of the femoral condyles from OCD. PMID- 21267577 TI - Correlation of atherosclerosis between different topographic sites is highly dependent on the type of hyperlipidemia. AB - There is a surprising paucity of studies that provide quantitative correlative data on the extent of atherosclerosis between different topographic sites. The impact of cardiovascular risk factors is dependent on the vascular bed, which underlies site-selective effects on progression of atherosclerosis. Therefore, the intraindividual correlation of atherosclerosis between different topographic sites may be dependent on the specific cardiovascular risk profile. The focused objective of the current study is to evaluate whether the correlation of the extent of atherosclerosis between different topographic sites is dependent on the type of hyperlipidemia. Atherosclerosis was quantified at four different topographic locations in the aorta of rabbits with type II or type III hyperlipidemia. Correlation coefficients and semi-partial correlation coefficients adjusted for plasma lipoproteins and sex were determined to compare the degree of atherosclerosis at different topographic sites. Semi-partial correlations adjusted for total plasma cholesterol, plasma triglycerides, and sex of the intima/media ratio between different topographic sites were highly dependent on the type of hyperlipidemia. E.g., the semi-partial correlation coefficient between the intima/media ratio at the level of the ascending aorta and at the level of the descending thoracic aorta was 0.87 (p < 0.0001) in the model of type II hyperlipidemia and was only 0.10 (p = NS) in the model of type III hyperlipidemia. This divergent pattern was also observed for other intersite correlations. Semi-partial Pearson correlation coefficients were very similar to unadjusted Pearson correlation coefficients. Correlation of atherosclerosis between different topographic sites may vary importantly in relation to the type of hyperlipidemia. PMID- 21267578 TI - Prognostic significance of blood pressure response to exercise in patients with systolic heart failure. AB - High systolic blood pressure (SBP) has been linked to worse cardiovascular outcomes. However, emerging data suggest that in patients with heart failure (HF), low SBP correlates with increased mortality. The purpose was to examine the impact of baseline and post-exercise systolic and diastolic blood pressure (DBP), as well as pulse pressure (PP), on cardiac mortality in patients with systolic HF. One hundred sixty patients with systolic HF (left ventricular ejection fraction 33 +/- 8) were studied. Blood pressure (BP) levels were determined at rest and at peak exercise during a cardiopulmonary exercise test. Patients were followed up for a period of 2.5 +/- 0.8 years. During this period 22 patients died and 5 subjects underwent heart transplantation. Patients with higher SBP and DBP at rest, and patients with SBP >=160 mmHg and PP >=75 mmHg at peak exercise had the most favorable prognosis. There was a fourfold increase in cardiac mortality risk for patients with SBP <160 mmHg at peak exercise (hazard ratio: 3.97, 95% confidence interval: 1.60-9.84) and a threefold increase for patients with PP <75 mmHg at peak exercise (hazard ratio: 2.96, 95% confidence interval: 1.29-6.82). There is an inverse relationship between SBP and cardiac mortality in patients with systolic HF. BP response to exercise could serve as a simple risk stratification model in HF patients. PMID- 21267579 TI - Role of ischemia-modified albumin in estimating the extent and scope of cardiac ischemia in patients with ST elevation myocardial infarction. AB - Ischemia-modified albumin (IMA) is a laboratory biomarker of cardiac ischemia. Our study aims to determine whether IMA can estimate or represent to any degree the extent of myocardial ischemia. We expect that the higher the marker of cardiac necrosis (maximum value after serial measurements) the greater the preceding cardiac ischemia, indicated by IMA in patients diagnosed with STEMI prior to direct percutaneous coronary intervention (PCI). We studied 216 patients indicated for direct PCI with a diagnosis of ST elevation myocardial infarction. Biochemical analysis of IMA was carried out using the albumin cobalt binding (ACB(r)) test. We also obtained relevant values for markers of myocardial necrosis (CK, CK-MB, cTnT). In all patients, there was an increased level of IMA prior to the procedure (116 +/- 16.9 kU/l); also raised were levels of CK (17.32 MUkat/l), CK-MB (4.85 MUkat/l) and cTnT (2.97 MUg/l) taken as the maximum values obtained after serial measurements at 12, 18, and 24 h after the procedure. We observed that there was no significant association between increase in IMA and cTnT (R2 = 0.0068, p = 0.483). This was also the case for CK-MB (R2 = 0.0011, p = 0.637). IMA does not estimate the extent of ischemia in patients with ST elevation myocardial infarction. However, its absence can be used qualitatively to rule out cardiac ischemia. PMID- 21267580 TI - Endovascular treatment combined with stratified surgery is effective in the management of venous thoracic outlet syndrome complications: a long term ultrasound follow-up study in patients with thrombotic events due to venous thoracic outlet syndrome. AB - Thoracic outlet syndrome (TOS) is caused by compression of peripheral nerves and vascular structures along their course through the upper thoracic aperture to the axilla. The aim of our study was to analyze long-term outcomes of different treatments stratified by symptom severity. We performed a retrospective analysis of a cohort of 73 consecutive patients treated at our institution presenting with TOS-associated venous thrombotic events. Treatment strategies and immediate outcome analysis were completed by long-term follow-up with duplex ultrasound controls 6-12 months after the initial clinical event. Conservative therapy was started in mildly symptomatic patients (n = 32), of which 12 required endovascular procedures because of treatment failure. Endovascular treatment was attempted in all highly symptomatic patients and in those with conservative treatment failure (n = 53), of which 12 required acute surgical intervention. Elective surgical treatment was indicated in 30 other patients because of persistent symptoms. Surgery was associated with a significantly lower rate of the ultrasound-detected signs of persisting vascular compression. However, the rate of persisting clinical symptoms was comparable to those treated only by endovascular or conservative therapy. Our data demonstrate that initial endovascular treatment proposed as first line therapy to highly symptomatic subjects and in those with conservative treatment failure improves the symptoms in 77% of patients avoiding the need of acute surgery. Acute and elective surgical decompression leads to lower rates of vascular compression signs without significant amelioration of persisting clinical symptoms as compared to endovascular or conservative therapy. PMID- 21267581 TI - In patients with idiopathic venous thrombosis, interleukin-10 is decreased and related to endothelial dysfunction. AB - The aim of this study was to evaluate the levels of anti-inflammatory interleukin 10 and pro-inflammatory cytokines and their relationship to endothelial function in patients with idiopathic venous thrombosis. Forty-nine eligible patients of both sexes with idiopathic venous thrombosis and 48 matched control subjects were studied. Levels of inflammatory markers were determined. Endothelial function was evaluated by ultrasound measurement of the flow mediated dilatation (FMD) of the brachial artery. Compared to the control group, patients with idiopathic venous thrombosis had significantly lower levels of interleukin-10 1.81 pg/ml (1.53 2.21) versus 2.71 pg/ml (1.84-3.65), p < 0.001. Patients also had increased levels of pro-inflammatory cytokines: interleukin-6 2.37 pg/ml (1.59-4.09) versus 2.03 pg/ml (1.49-2.59), p = 0.025, interleukin-8 3.53 pg/ml (2.94-5.30) versus 2.25 pg/ml (1.77-2.90), p < 0.001. Furthermore, decreased FMD was observed in patients: 5.0% (3.9-6.9) versus 12.7% (10.8-15.6), p < 0.001. FMD was related to levels of interleukin-10 (r = 0.33, p = 0.001) and was inversely related to pro inflammatory cytokines interleukin-6 (r = -0.34, p = 0.001) and interleukin-8 (r = -0.43, p < 0.001). Patients with idiopathic venous thrombosis have decreased levels of IL-10 and increased levels of pro-inflammatory cytokines. This imbalance indicates that in the stable phase of the disease, patients have an increased systemic inflammatory response. This inflammatory response could be the consequence of the disease, but most probably is involved in the pathogenesis of venous thrombosis. PMID- 21267583 TI - Melanotic medulloblastoma in children. AB - PURPOSE: We report a case of melanotic medulloblastoma in a child. Reviewing the literature, we discuss the characteristics, therapeutic method, and prognosis of melanotic medulloblastoma in children. MATERIALS AND METHODS: A 2-year-old girl was admitted with a mass located in the pineal region and presented obstructive hydrocephalus. The mass was subtotally resected through a slit-corpus-fornix approach. Thereafter, intraoperative direct third ventriculostomy was performed. The histopathological diagnosis of the mass suggested melanotic medulloblastoma. RESULTS: The MRI done at 4 days after surgery showed that the lateral ventricle normalized and the hydrocephalus was resolved. Thereafter, the patient underwent a Gamma Knife. The patient recovered well during the 8-month follow-up. CONCLUSIONS: Melanotic medulloblastoma is a malignant tumor of childhood. It usually occurs at young age and might involve the vermis cerebelli, the fourth ventricle, and the pineal region. Surgery combined with radiotherapy and chemotherapy is recommended for children. But, it still requires observation to determine their long-term prognosis. PMID- 21267582 TI - Efficacy of paclitaxel-eluting stent implantation in hemodialysis patients. AB - Hemodialysis patients were recognized as a high-risk group for restenosis after percutaneous coronary intervention in the era of the bare-metal stent. Recently, sirolimus-eluting stents (SES) have reduced restenosis and target lesion revascularization (TLR); however, it has been reported that their efficacy in hemodialysis patients is limited. The purpose of this study was to investigate whether paclitaxel-eluting stents (PES) improved angiographic outcomes of hemodialysis patients compared with SES. This study is a retrospective cohort study. We analyzed 54 hemodialysis patients with 87 lesions implanted with PES from February 2007 to September 2008, and 49 hemodialysis patients with 68 lesions implanted with SES from August 2004 to January 2007. Angiographic follow up after 8-10 months was obtained for 59 lesions (67.8%) in the PES group and 43 lesions (63.2%) in the SES group. At baseline, the PES patients had more peripheral artery disease compared with the SES group (66.7 vs. 34.7%; p = 0.0012). There were no significant differences in the angiographic characteristics or procedural index. The binary restenosis rate was lower in lesions implanted with PES than in those with SES (13.6 vs. 39.5%; p = 0.034). Accordingly, the TLR rate was lower in lesions implanted with PES than with SES (9.3 vs. 26.5%; p = 0.041). Our results suggest that PES is more effective than SES in reducing restenosis and TLR in hemodialysis patients. PMID- 21267584 TI - Early experience with thoracoscopic repair of congenital diaphragmatic hernias in pediatric age group: results and lessons learned. AB - PURPOSE: To describe the surgical technique, initial results, and overview indications of thoracoscopic repair of congenital diaphragmatic hernia. PATIENTS AND METHODS: A retrospective review was undertaken of patients with CDH who underwent thoracoscopic repair from January 2006 to July 2010, in department of pediatric surgery in a tertiary care institute in India. Patients underwent surgery under general anesthesia. Reduction of the hernia contents was carried out using one trocar for telescope and two operating trocars. Pleural insufflation with carbon dioxide was maintained at a pressure of 6-10 mmHg. The hernia defect was repaired using nonabsorbable interrupted sutures. RESULTS: There were 17 patients, including 12 boys and 5 girls. Among 12 infants, there were 6 patients younger than 30 days. The other 5 patients were older than 1 year. The hernia was located in the left side in 14 patients and in the right side in 3 patients. The mean operative time was 110 min. Conversion was required in three patients. There were one recurrence and one postoperative death. CONCLUSIONS: Thoracoscopic repair is feasible and safe for children with CDH, including selective newborn. The technique causes minimal trauma, results in good respiratory function, and promotes early recovery. PMID- 21267585 TI - Laparoscopic complete/partial nephroureterectomy in children in a single institution-nearly a decade of experience: what have we learned? AB - PURPOSE: To review our experience of laparoscopic nephroureterectomy and hemi nephroureterectomy over a 10-year period. METHODS: Forty patients had surgery between December 2000 and April 2010. Case notes were reviewed for clinical data, intraoperative time, complications, postoperative management, outcome and follow up. RESULTS: Mean age was 5.2 years. Thirty patients underwent nephroureterectomy. There were complications in five. Four required conversion. Two had bleeding from an adherent upper pole. One had adhesions from previous pyeloplasty. The fourth had a staghorn calculus secondary to xanthogranulomatous pyelonephritis. There were extensive inflammatory adhesions and despite early conversion, operating time was 9 h. Excluding this, mean operating time was 159 min. Nine patients underwent hemi-nephroureterectomy. There were complications in two; a hilar bleed and a peritoneal tear (neither required conversion). Mean operating time was 177 min. One patient with MCDK was for nephroureterectomy, but no renal tissue was found at laparoscopy and the procedure was abandoned. CONCLUSIONS: Laparoscopic nephroureterectomy/hemi-nephroureterectomy is well tolerated in children and should be the preferred option. Operative time is acceptable. There are few complications. Patients with MCDK should have an ultrasound before surgery to confirm ongoing presence of renal tissue. In patients with xanthogranulomatous disease, laparoscopy should be avoided. PMID- 21267586 TI - Medulloblastoma: clinicopathological correlates of SHH, WNT, and non-SHH/WNT molecular subgroups. AB - Medulloblastoma is heterogeneous, being characterized by molecular subgroups that demonstrate distinct gene expression profiles. Activation of the WNT or SHH signaling pathway characterizes two of these molecular subgroups, the former associated with low-risk disease and the latter potentially targeted by novel SHH pathway inhibitors. This manuscript reports the validation of a novel diagnostic immunohistochemical method to distinguish SHH, WNT, and non-SHH/WNT tumors and details their associations with clinical, pathological and cytogenetic variables. A cohort (n = 235) of medulloblastomas from patients aged 0.4-52 years was studied for expression of four immunohistochemical markers: GAB1, beta-catenin, filamin A, and YAP1. Immunoreactivity (IR) for GAB1 characterizes only SHH tumors and nuclear IR for beta-catenin only WNT tumors. IRs for filamin A and YAP1 identify SHH and WNT tumors. SHH, WNT, and non-SHH/WNT tumors contributed 31, 14, and 55% to the series. All desmoplastic/nodular (D/N) medulloblastomas were SHH tumors, while most WNT tumors (94%) had a classic phenotype. Monosomy 6 was strongly associated with WNT tumors, while PTCH1 loss occurred almost exclusively among SHH tumors. MYC or MYCN amplification and chromosome 17 imbalance occurred predominantly among non-SHH/WNT tumors. Among patients aged 3-16 years and entered onto the SIOP PNET3 trial, outcome was significantly better for children with WNT tumors, when compared to SHH or non-SHH/WNT tumors, which showed similar survival curves. However, high-risk factors (M+ disease, LC/A pathology, MYC amplification) significantly influenced survival in both SHH and non-SHH/WNT groups. We describe a robust method for detecting SHH, WNT, and non-SHH/WNT molecular subgroups in formalin-fixed medulloblastoma samples. In corroborating other studies that indicate the value of combining clinical, pathological, and molecular variables in therapeutic stratification schemes for medulloblastoma, we also provide the first outcome data based on a clinical trial cohort and novel data on how molecular subgroups are distributed across the range of disease. PMID- 21267587 TI - Developing a mouse model of acute bacterial rhinosinusitis. AB - The objective of this study is to establish a mouse model of acute bacterial rhinosinusitis. 179 healthy male BALB/c mice were divided into four groups in this randomized and controlled study. Sponge slivers impregnated with methicillin resistant Staphylococcus aureus (MRSA COL) suspension were inserted into the right nasal cavities for group A; sponge slivers impregnated with sterile saline were inserted into the right nasal cavities for group B; group C mice were inoculated with MRSA COL suspension in right nasal cavities; group D was control group without any treatment. Mice were killed on days 1, 4, 7 and 14, respectively. Nasal lavage fluid was prepared for microbiological culture. Histological examinations of nasal specimens were performed to observe the severity of inflammatory reaction. Acute bacterial rhinosinusitis was induced in all group A mice. Less severe inflammation was seen in partial group B mice compared with that in group A mice (P <= 0.05). No inflammatory reaction was found in group C and D mice. In conclusion, a mouse model of acute bacterial rhinosinusitis has been developed successfully using an easier, less invasive and potentially more reversible technique than those used in previous studies. PMID- 21267588 TI - Comparison of different tympanic membrane reconstruction techniques in type I tympanoplasty. AB - The objective of the study was to assess the functional results after type I tympanoplasty with temporal muscle fascia, perichondrium/cartilage island and cartilage palisades. The records of 120 patients who underwent type I tympanoplasty operation between January 2003 and June 2007 were retrospectively reviewed. This study aimed to comprise a homogeneous group of patients to make the comparisons as accurate as possible. For this purpose, primary tympanoplasty cases with subtotal perforations, intact ossicular chain, dry ear for a period of at least 1 month, and normal middle ear mucosa were included in the study. Patients younger than 15 years of age and patients with cholesteatoma were excluded. Temporal muscle fascia was used in 67 (55.8%), perichondrium/cartilage island flap was used in 34 (28.3%), and cartilage palisades were used in 19 (15.8%) of the patients. Pre- and postoperative otoscopic examinations, pure-tone averages, and air-bone gaps were compared pre and postoperatively. Concerning all of the cases, the graft take rate was 85% (102/120). In the perichondrium/cartilage island flap group, the graft take rate was 97.7%, whereas the graft take rates for the fascia group and cartilage palisades group were 80.6 and 79.0%, respectively. In the perichondrium/cartilage island flap group, the pure-tone average was 36.36 dB, whereas the pure-tone averages for the fascia group and cartilage palisades group were 36.07 and 39.79 dB, preoperatively. The postoperative pure-tone averages were 24.54 dB fort he perichondrium/cartilage island flap group, 24.51 dB for the fascia group and 23.23 dB for the cartilage palisades group. Cartilage grafting is not only more enduring against infection and negative middle ear pressure but also it has low re-perforation rates on long term follow-up. Thus, cartilage may be preferred more often for primary tympanoplasties with high graft rate and hearing improvement. PMID- 21267589 TI - Charles Bell (1774-1842). PMID- 21267590 TI - A novel mutation of the SGCE-gene in a German family with myoclonus-dystonia syndrome. PMID- 21267591 TI - Two dominantly inherited ataxias linked to chromosome 16q22.1: SCA4 and SCA31 are not allelic. AB - Autosomal dominant spinocerebellar ataxias (SCAs) are heterogeneous neurological disorders characterised by cerebellar dysfunction mostly due to Purkinje cell degeneration. Genetically, 30 different loci have been identified so far whereas the corresponding gene has not yet been determined for 12 of them. The chromosomal location for the spinocerebellar ataxia type 31 (SCA31) has been mapped to chromosome 16q22.1. This region is located within the candidate interval for the spinocerebellar ataxia type 4 (SCA4), for which the underlying mutation still has to be discovered. Recently, a complex (TGGAA)(n) containing repeat insertion within the SCA31 critical region was reported to be causative for SCA31. Although the presence of the pentanucleotide repeat component (TGGAA)(n) seems to be a specific feature of SCA31 patients' insertions, it is still unclear whether a large insertion lacking any (TGGAA) sequence remains nonpathogenic. In order to check whether the German SCA4 patients, belonging to one of the two currently known SCA4 families worldwide, exhibit a potential pathogenic mutation at the SCA31 locus, we performed molecular genetic analyses for affected as well as unaffected family members. Based on a nested-PCR approach and direct sequencing, a disease causing mutation at the SCA31 locus could be excluded for the German SCA4 kindred. However, our data impressively demonstrate the genetic instability in this chromosomal region. PMID- 21267592 TI - Localisation of the applause sign in a patient with acute bilateral lenticular infarction. PMID- 21267593 TI - Hemifacial presentation of mitochondrial myopathy. PMID- 21267594 TI - Assessment of limbus and central cornea in patients with keratolimbal allograft transplantation using in vivo laser scanning confocal microscopy: an observational study. AB - BACKGROUND: Keratolimbal allograft (KLAL) transplantation has been proved to be a useful surgical procedure for limbal stem cell deficiency patients. However, information about in vivo ocular surface changes in those patients is limited, due to the lack of a reliable and non-invasive technique for closely monitoring the changes of KLAL grafts. The aim of this study is to characterize the cellular changes in the limbus and central cornea after KLAL in patients with severe ocular chemical injury, using in vivo laser scanning confocal microscopy (LSCM). METHODS: This is a prospective, noncomparative, observational case series. Twenty three patients (23 eyes) with total limbal stem cell deficiency due to ocular chemical injury were recruited. KLAL with or without other concurrent surgery were performed. LSCM and slit-lamp examination were performed on the limbus and the central cornea before surgery and at 6 and 12 months postoperatively. Presence of palisades of Vogt, limbal basal epithelial cell density within the palisades of Vogt (LEC), limbal dendritic cells (DC) density, and central corneal basal epithelial cell (CEC) density were assessed by LSCM. RESULTS: All patients completed 12 months of follow-up. Twenty-one patients were male and two were female, with a mean age of 39.5 +/- 12.5 years. Six cases were due to acid burns, and the others were alkali burns. Palisades of Vogt were observed in all surviving grafts but were absent in graft failure. The epithelial cells in the central cornea of the failed graft had lost the classic polygonal morphology of the normal corneal basal epithelial cells. The cell density of LEC and CEC decreased significantly, whereas DC density increased in the failed grafts over time. CONCLUSIONS: In vivo LSCM is a useful tool for monitoring the cellular changes in KLAL grafts, and has the potential to diagnose the failure of KLAL grafts at the cellular level. PMID- 21267595 TI - Work-family conflict and prolonged fatigue among Japanese married male physicians. AB - PURPOSE: Fatigue experienced by physicians may not only endanger their own health but may also affect the safety of patients. Such fatigue may be associated with the work environment and personal factors such as work-family conflict (WFC). This study aimed to determine the association between WFC and prolonged fatigue among Japanese married male physicians. METHODS: Physicians who graduated from a Japanese medical school answered a mailed anonymous self-report questionnaire. For assessment of WFC and prolonged fatigue, the Japanese versions of the WFC scale and the Checklist of Individual Strength questionnaire (CIS) were used. Prolonged fatigue was defined as the upper quartile of total CIS scores. The WFC scale comprises six dimensions. Total scores were divided into tertiles: low, intermediate, and high levels of WFC. A multiple logistic regression analysis was performed to examine the association between WFC and prolonged fatigue. RESULTS: A total of 540 male physicians answered the questionnaire, and the data of 444 married male physicians were analyzed. The data were then adjusted for age and work condition factors. Prolonged fatigue was significantly associated with high strain-based work interference with family (WIF; corrected odds ratio, 5.56; 95% confidence interval, 2.55-12.1), intermediate strain-based WIF (2.53, 1.25-5.10), high time-based family interference with work (FIW; 1.92, 1.08-3.40), and there was a weak association with high strain-based FIW (1.93, 0.98-3.83). CONCLUSIONS: Employers should take measures to improve working conditions in hospitals, and give physicians the opportunity to learn how to cope with WFC. These measures could ultimately help prevent prolonged fatigue. PMID- 21267596 TI - Rapid top-down regulation of plant C:N:P stoichiometry by grasshoppers in an Inner Mongolia grassland ecosystem. AB - Understanding how food web interactions alter the processing of limiting nutrient elements is an important goal of ecosystem ecology. An experiment manipulating densities of the grasshopper Oedaleus asiaticus was performed to assess top-down effects of grasshoppers on C:N:P stoichiometry of plants and soil in a grassland ecosystem in Inner Mongolia (China). With increased grasshopper feeding, plant biomass declined fourfold, litter abundance increased 30%, and the plant community became dominated by non-host plant taxa. Plant stoichiometric response depended on whether or not the plant was a grasshopper host food species: C:N and C:P ratios increased with increasing grasshopper density (GD) for host plants but decreased in non-host plants. These data suggest either a direct transfer of grasshopper-recycled nutrients from host to non-host plants or a release of non host plants from nutrient competition with heavily grazed host plants. Litterfall C:N and C:P decreased across moderate levels of grasshopper density but no effects on C:N:P stoichiometry in the surface soil were observed, possibly due to the short experimental period. Our observations of divergent C:N:P stoichiometric response among plant species highlight the important role of grasshopper herbivory in regulating plant community structure and nutrient cycling in grassland ecosystems. PMID- 21267597 TI - Optimization of process variables by central composite design for the immobilization of urease enzyme on functionalized gold nanoparticles for various applications. AB - In the present study, enzyme urease has been immobilized on amine-functionalized gold nanoparticles (AuNPs). AuNPs were synthesized using natural precursor, i.e., clove extract and amine functionalized through 0.004 M L: -cysteine. Enzyme (urease) was extracted and purified from the vegetable waste, i.e., seeds of pumpkin to apparent homogeneity (sp. activity 353 U/mg protein). FTIR spectroscopy and transmission electron microscopy was used to characterize the immobilized enzyme. The immobilized enzyme exhibited enhanced activity as compared with the enzyme in the solution, especially, at lower enzyme concentration. Based on the evaluation of activity assay of the immobilized enzyme, it was found that the immobilized enzyme was quite stable for about a month and could successfully be used even after eight cycles having enzyme activity of about 47%. In addition to this central composite design (CCD) with the help of MINITAB version 15 Software was utilized to optimize the process variables viz., pH and temperature affecting the enzyme activity upon immobilization on AuNPs. The results predicted by the design were found in good agreement (R2 = 96.38%) with the experimental results indicating the applicability of proposed model. The multiple regression analysis and ANOVA showed the individual and cumulative effect of pH and temperature on enzyme activity indicating that the activity increased with the increase of pH up to 7.5 and temperature 75 degrees C. The effects of each variables represented by main effect plot, 3D surface plot, isoresponse contour plot and optimized plot were helpful in predicting results by performing a limited set of experiments. PMID- 21267598 TI - Pericardial tamponade in a child with nephrotic syndrome. PMID- 21267599 TI - Nocturnal enuresis-theoretic background and practical guidelines. AB - Nocturnal polyuria, nocturnal detrusor overactivity and high arousal thresholds are central in the pathogenesis of enuresis. An underlying mechanism on the brainstem level is probably common to these mechanisms. Enuretic children have an increased risk for psychosocial comorbidity. The primary evaluation of the enuretic child is usually straightforward, with no radiology or invasive procedures required, and can be carried out by any adequately educated nurse or physician. The first-line treatment, once the few cases with underlying disorders, such as diabetes, kidney disease or urogenital malformations, have been ruled out, is the enuresis alarm, which has a definite curative potential but requires much work and motivation. For families not able to comply with the alarm, desmopressin should be the treatment of choice. In therapy-resistant cases, occult constipation needs to be ruled out, and then anticholinergic treatment-often combined with desmopressin-can be tried. In situations when all other treatments have failed, imipramine treatment is warranted, provided the cardiac risks are taken into account. PMID- 21267600 TI - Can bisphosphonates play a role in the treatment of children with chronic kidney disease? AB - In patients with chronic kidney disease (CKD) renal osteodystrophy, in the form of either low- or high-turnover bone disease, is quite common. While renal transplantation is expected to reverse renal osteodystrophy, long-term treatment with glucocorticoids before and/or after transplantation may lead to osteoporosis instead. Osteoporosis is defined as a skeletal disease with low bone mineral density, microarchitectural deterioration, and concomitant fragility. In adults, bisphosphonates are widely used to treat osteoporosis and other diseases associated with excessive bone resorption. In pediatric CKD patients the efficacy and safety of these drugs have not yet been addressed adequately and thus no evidence-based recommendations regarding the optimal type of bisphosphonate, dosage, or duration of therapy are available. Furthermore, while in adults the determination of areal bone mineral density is sufficient to diagnose osteoporosis, this is not the case in children. Instead, in pediatric patients, careful morphological assessment of bone structure and formation is required. Indeed, data from studies with uremic rats indicated that bisphosphonates, via a deceleration of bone turnover, have the potential not only to aggravate pre existing adynamic bone disease, but also to impair longitudinal growth. Thus, the widespread use of bisphosphonates in children with CKD should be discouraged until the risks and benefits have been carefully elucidated in clinical trials. PMID- 21267601 TI - Weather conditions and visits to the medical wing of emergency rooms in a metropolitan area during the warm season in Israel: a predictive model. AB - Global climate changes affect health and present new challenges to healthcare systems. The aim of the present study was to analyze the pattern of visits to the medical wing of emergency rooms (ERs) in public hospitals during warm seasons, and to develop a predictive model that will forecast the number of visits to ERs 2 days ahead. Data on daily visits to the ERs of the four largest medical centers in the Tel-Aviv metropolitan area during the warm months of the year (April October, 2001-2004), the corresponding daily meteorological data, daily electrical power consumption (a surrogate marker for air-conditioning), air pollution parameters, and calendar information were obtained and used in the analyses. The predictive model employed a time series analysis with transitional Poisson regression. The concise multivariable model was highly accurate (r (2) = 0.819). The contribution of mean daily temperature was small but significant: an increase of 1 degrees C in ambient temperature was associated with a 1.47% increase in the number of ER visits (P < 0.001). An increase in electrical power consumption significantly attenuated the effect of weather conditions on ER visits by 4% per 1,000 MWh (P < 0.001). Higher daily mean SO(2) concentrations were associated with a greater number of ER visits (1% per 1 ppb increment; P = 0.017). Calendar data were the main predictors of ER visits (r (2) = 0.794). The predictive model was highly accurate in forecasting the number of visits to ERs 2 days ahead. The marginal effect of temperature on the number of ER visits can be attributed to behavioral adaptations, including the use of air-conditioning. PMID- 21267602 TI - The effects of simulated rainfall on immature population dynamics of Aedes albopictus and female oviposition. AB - Larvae of Aedes albopictus Skuse typically inhabit natural and artificial containers. Since these larval habitats are replenished by rainfall, Ae. albopictus may experience increased loss of immature stages in areas with high levels of rainfall. In this study, we investigated the effects of rainfall and container water level on population density, and oviposition activity of Ae. albopictus. In field and laboratory experiments, we found that rainfall resulted in the flushing of breeding habitats. Excess rain negatively impacted larval and pupal retention, especially in small habitats. When filled with water to overflowing, container habitats were significantly repellent to ovipositing females. Taken together, these data suggest that rainfall triggers population loss of Ae. albopictus and related species through a direct detrimental effect (flushing out) and an indirect effect (ovipositional repellency). PMID- 21267603 TI - Climate and heat-related emergencies in Chicago, Illinois (2003-2006). AB - Extreme heat events are responsible for more deaths in the United States than floods, hurricanes and tornados combined. Yet, highly publicized events, such as the 2003 heat wave in Europe which caused in excess of 35,000 deaths, and the Chicago heat wave of 1995 that produced over 500 deaths, draw attention away from the countless thousands who, each year, fall victim to nonfatal health emergencies and illnesses directly attributed to heat. The health impact of heat waves and excessive heat are well known. Cities worldwide are seeking to better understand heat-related illnesses with respect to the specifics of climate, social demographics and spatial distributions. This information can support better preparation for heat-related emergency situations with regards to planning for response capacity and placement of emergency resources and personnel. This study deals specifically with the relationship between climate and heat-related dispatches (HRD, emergency 911 calls) in Chicago, Illinois, between 2003 and 2006. It is part of a larger, more in-depth, study that includes urban morphology and social factors that impact heat-related emergency dispatch calls in Chicago. The highest occurrences of HRD are located in the central business district, but are generally scattered across the city. Though temperature can be a very good predictor of high HRD, heat index is a better indicator. We determined temperature and heat index thresholds for high HRD. We were also able to identify a lag in HRD as well as other situations that triggered higher (or lower) HRD than would typically be generated for the temperature and humidity levels, such as early afternoon rainfall and special events. PMID- 21267604 TI - Mood state profile and coping strategies after BRCA-1/2 genetic test disclosure: a retrospective study in Italy. PMID- 21267605 TI - Art therapy in psycho-oncology--recruitment of participants and gender differences in usage. AB - PURPOSE: Over the last years, there has been increasing focus on the effect of art therapy for oncological patients. The small sample sizes of these studies show that recruiting participants is difficult and has been poorly investigated. It is also apparent that women participate in art therapy more often than men. The question remains why this difference exists and if participating men benefit from these courses more, less or in a different way than women do. METHODS: We developed and tested an outpatient art intervention for cancer patients, whereby different recruitment strategies were documented. Participants were questioned about their mental health (HADS), coping strategies (FKV), and quality of life (EORTC QLQ-C30) at the beginning and end of the intervention. RESULTS: The recruitment strategies included personal letters, referrals from the "Information Center For Cancer Patients", press releases and leaflets/posters distributed to hospitals and medical practices. About half of the participants (N=35), especially the male ones, took part in response to receiving a personal letter. All in all, 14 men and 60 women took part in the intervention whereby all 18 drop outs were female. There were no significant gender differences regarding distress and quality of life before and after the intervention (men=14; women=41). CONCLUSIONS: A variety of approaches and intense public relations are necessary to recruit patients for art therapy. Describing recruitment strategies more in detail is suggested for upcoming art therapy studies. First gender specific differences were found in recruitment and usage. Exploring further questions in this area referring to quality of life and distress larger and uniformly distributed samples are desirable. PMID- 21267606 TI - Evaluation of early visual recovery in pituitary macroadenomas after endoscopic endonasal transphenoidal surgery: Quantitative assessment with diffusion tensor imaging (DTI). AB - BACKGROUND: Visual field analyses reflect the degree of the compression to the optic nerve that results the structural damage of the nerve. These structural damages can be evaluated by diffusion tensor imaging (DTI), which assesses the structural integrity of white matter tracts. Thus, we evaluated the quantitative assessment of early visual recovery in patients with pituitary macroadenomas, corresponding DTI with visual field analyses. METHODS: Seventy-two patients who had pituitary macroadenomas with visual field defects were included in the study retrospectively. All patients were operated on by pure endoscopic transphenoidal approach. Visual field assessment using Humphrey field analyzer and DTI with 3T magnet were performed in the preoperative and postoperative second day and sixth month. FINDINGS: Mean symptom duration was 14.7 +/- 10.5 weeks in the full recovery group patients, 50.1 +/- 29.1 weeks in partial recovery patients, and 92.4 +/- 15.4 weeks in the ones with no recovery. There was a significant difference at p < 0.001 among the groups. On visual field analysis, the visual lost was mostly recognized at upper temporal levels preoperatively. Visual field findings of both eyes were improved in 80% of the patients. Among these, 25% revealed full recovery, 55.6% partial recovery, and 19.4% did not demonstrate significant changes. DTI assessments of affected sides revealed preoperative fractional anisotropy (FA) values below 0.400 and mean diffusivity (MD) values over 1,400 * 10(-6) mm(2) s(-1) were related with no visual improvement in the postoperative 6 months period. The percentage increase of mean FA values of the affected areas postoperatively were found to be 21.9% in totally responded patients, 20.6% in partial responded patients, and 9.8% in patients that did not respond. CONCLUSIONS: There is a correlation between DTI-derived FA values of the optic nerves and visual parameters. DTI assessments of the affected sides with FA and MD values may help to estimate the response of visual improvement to the surgical therapy in the early postoperative period. PMID- 21267607 TI - Role of bacterioferritin comigratory protein and glutathione peroxidase-reductase system in promoting bentazone tolerance in a mutant of Synechococcus elongatus PCC7942. AB - In this article, we describe the modifications in the antioxidant system of Synechococcus elongatus PCC7942 mutant Mu2 capable of growing at five times higher concentration of bentazone than wild type. Nevertheless, in both the strains, bentazone almost identically induced light-dependent H(2)O(2) production and its extracellular release. However unlike the wild type, peroxide produced upon prolong bentazone incubation was immediately degraded in Mu2. Consequently, the lipid peroxidation activity was also kept low. With prolong incubation of bentazone the mutant displayed a steady increase in glutathione peroxidase reductase enzyme activities and reduced glutathione content, respectively, by 60% and 130%, favoring an efficient detoxification of bentazone-produced H(2)O(2). Catalase-peroxidase and glutathione S-transferase, though present, remained ineffective in rendering bentazone tolerance. In-gel assays of glutathione S transferase and glutathione reductase revealed presence of between four and five oligomeric states with mobility shifts. One oligomeric form each enzyme in wild type strain disappeared upon bentazone treatment. Upon two-dimensional electrophoresis and MALDI-TOF/TOF, a bacterioferritin comigratory protein (peroxiredoxin Q) was found to be already highly expressed in Mu2; whereas in wild type, its level increased only upon bentazone exposure. The bcp transcript pool in WT was relatively low but increased with bentazone, whereas Mu2 exhibited high bcp mRNA even without herbicide. Bacterioferritin comigratory protein and glutathione peroxidase-reductase appear to be responsible for detoxification of bentazone-derived peroxide in Mu2. PMID- 21267608 TI - ER disruption and GFP degradation during non-regenerable transformation of flax with Agrobacterium tumefaciens. AB - Flax is considered as plant species susceptible to Agrobacterium-mediated genetic transformation. In this study, stability of flax transformation by Agrobacterium rhizogenes versus Agrobacterium tumefaciens was tested by using combined selection for antibiotic resistance and visual selection of green fluorescent protein (GFP)-fusion reporter targeted to the endoplasmic reticulum (ER). Transformation with A. rhizogenes was stable for over 2 years, whereas transformation by A. tumefaciens resulted in non-regenerable stable transformation which was restricted solely to transgenic callus and lasted only 6 8 weeks. However, shoots regenerated from this callus appeared to be non transgenic. Importantly, callus and root cells stably transformed with A. rhizogenes showed typical regular organization and dynamics of ER as visualized by GFP-ER marker. On the other hand, callus cells transformed with A. tumefaciens showed disintegrated ER structure and impaired dynamics which was accompanied with developmental degradation of GFP. Consequently, shoots which regenerated from such callus were all non-transgenic. Possible reasons for this non regenerable flax transformation by A. tumefaciens are discussed. PMID- 21267610 TI - Structural and kinetic studies of imidazole binding to two members of the cytochrome c (6) family reveal an important role for a conserved heme pocket residue. AB - The amino acid at position 51 in the cytochrome c(6) family is responsible for modulating over 100 mV of heme midpoint redox potential. As part of the present work, the X-ray structure of the imidazole adduct of the photosynthetic cytochrome c(6) Q51V variant from Phormidium laminosum has been determined. The structure reveals the axial Met ligand is dissociated from the heme iron but remains inside the heme pocket and the Omega-loop housing the Met ligand is stabilized through polar interactions with the imidazole and heme propionate-6. The latter is possible owing to a 180 degrees rotation of both heme propionates upon imidazole binding. From equilibrium and kinetic studies, a Val residue at position 51 increases the stability of the Fe-S(Met) interaction and also affects the dynamics associated with imidazole binding. In this respect, the k (obs) for imidazole binding to Arabidopsis thaliana cytochrome c(6A), which has a Val at the position equivalent to position 51 in photosynthetic cytochrome c(6), was found to be independent of imidazole concentration, indicating that the binding process is limited by the Met dissociation rate constant (about 1 s(-1)). For the cytochrome c(6) Q51V variant, imidazole binding was suppressed in comparison with the wild-type protein and the V52Q variant of cytochrome c(6A) was found to bind imidazole readily. We conclude that the residue type at position 51/52 in the cytochrome c(6) family is additionally responsible for tuning the stability of the heme iron-Met bond and the dynamic properties of the ferric protein fold associated with endogenous ligand binding. PMID- 21267611 TI - Gadolinium exposure disrupts iron homeostasis in cultured cells. AB - Human exposure to gadolinium-based contrast agents can be complicated by nephrogenic systemic fibrosis (NSF). Demonstration of significant quantities of insoluble gadolinium in the skin of NSF patients suggested transmetallation as a mechanism of toxicity of this injury. An alternative pathway for the biological effect of gadolinium is a disruption of iron homeostasis. We tested the postulate that cell exposure to gadolinium increases iron uptake to disrupt intracellular metal homeostasis and impact inflammatory events. Alveolar macrophages, THP1 cells, NHBE cells, and BEAS-2B cells all demonstrated a capacity to import gadolinium from both GdCl(3) and Omniscan. All four cell types similarly imported iron following exposure to ferric ammonium citrate (FAC). Exposure of all cell types to gadolinium and iron resulted in increased iron import relative to cell concentrations following incubation with FAC alone. To analyze for further evidence of changes in iron homeostasis, cell ferritin concentration was determined. Relative to incubation with FAC alone, co-incubation of BEAS-2B cells with gadolinium and FAC resulted in significant increases in ferritin level. Finally, potential effects of gadolinium uptake and associated changes in iron homeostasis on the inflammatory response were evaluated by measuring IL-8. Co incubation of BEAS-2B cells with both gadolinium and iron resulted in diminished release of IL-8 relative to levels of the cytokine following incubation with gadolinium alone. We conclude that gadolinium impacts cell iron homeostasis to change import and storage of the metal and biological effects of exposure. PMID- 21267612 TI - A validation study of the Brief Scale for Psychiatric problems in Orthopaedic Patients (BS-POP) for patients with chronic low back pain (verification of reliability, validity, and reproducibility). AB - INTRODUCTION: We developed the Brief Scale for Psychiatric problems in Orthopaedic Patients (BS-POP) (doctor and patient versions). The present study aimed to proactively verify the factorial validity, internal consistency, criterion-related validity and reproducibility of the BS-POP with regard to chronic low back pain patients. METHODS: Subjects comprised 193 chronic low back pain patients. During the first test, the BS-POP, Minnesota Multiphasic Personality Inventory (MMPI), Profile of Mood States (POMS) and 36-Item Short Form Health Survey version 2 (SF-36 v2) were conducted. In the second test, patients were asked to complete the BS-POP in order to verify BS-POP reproducibility. RESULTS: Factor analysis demonstrated the factorial validity of the BS-POP, including 1-factor structure. Internal consistency was confirmed by Cronbach's alpha reliability coefficients of 0.794 (doctor version) and 0.750 (patient version). Criterion-related validity was confirmed through association with the psychosocial factors of the SF-36, the MMPI, and the POMS. The correlation coefficients for the retests were r = 0.654 (doctor version) and r = 0.719 (patient version), showing reproducibility. DISCUSSION: The present findings indicate that the BS-POP possesses sufficient reliability regarding computational psychology. The BS-POP constitutes a tool enabling orthopaedists themselves to easily identify psychiatric problems in orthopaedic patients. Further study is required regarding responsiveness. PMID- 21267613 TI - On the way to DSM-V. PMID- 21267614 TI - Indirect hernial sac containing the uterus, ovary, and fallopian tube in association with a giant intraabdominal lipoma: report of a case. AB - Presence of the ovary, fallopian tube, and uterus within an inguinal hernia is a rare condition. In this report, we describe the case of a 47-year-old female, multiparous patient with a giant omental lipoma (18 * 8 * 7 cm, 422 g) and left inguinal hernia. The uterus, left ovary, and fallopian tube were in the hernial sac. The presence of the uterus within the hernial sac accompanies mullerian anomalies, although, in this case, there was no such anomaly. To our knowledge, there have been no cases in the literature of a giant intraabdominal lipoma and a hernial sac containing the uterus, ovary, and fallopian tube, but a few cases of inguinal hernia involving the ovary, fallopian tube, and uterus have been reported. The aim of this case report was to call attention to the observation that the inguinal hernia seen in female patients may involve the ovary, fallopian tube, and uterus. PMID- 21267615 TI - Mortality after groin hernia surgery: delay of treatment and cause of death. AB - BACKGROUND: Emergency hernia surgery, in contrast to elective hernia surgery, is associated with appreciable mortality. Incarcerated hernia is the second most common cause of small bowel obstruction after adhesions, and the leading cause of bowel strangulation. METHODS: Information on patients who died within 30 days of groin hernia surgery was retrieved from the Swedish Hernia Register, from the Cause-of-Death Register, and from hospital notes. RESULTS: Of 103,710 groin hernia operations between 1992 and 2004, 292 patients died within 30 days of surgery. Hospital notes and cause of death were retrieved for 242 cases (82%). In 5 of these patients, the hernia operation was done in addition to more urgent surgery and therefore excluded from further analyses; 152 patients were admitted as emergency cases and 55 of these patients underwent bowel resection. A total of 107 patients had signs of bowel obstruction when admitted. For 37% of these patients, physical examination of the groin was not documented. Patients with bowel obstruction without a note on a palpable groin lump were more likely to undergo imaging investigation preoperatively (P < 0.001) and they had an increased time to surgery compared to patients with a palpable lump. Women and patients with femoral hernia were significantly less likely to undergo a groin examination compared to other patients. Local anaesthesia was used in 7% of all patients who died postoperatively, and in 3% of emergency cases. Pulmonary disease, sepsis and malignant disease were more common as causes of death after emergency surgery than after elective surgery. CONCLUSIONS: Groin examination of patients presenting with bowel obstruction is of utmost importance in order to minimise delay to hernia surgery. PMID- 21267616 TI - The characteristics of inguinal hernia recurrence in the modern era and the long term outcomes after re-operation. AB - BACKGROUND: Re-operative hernia surgery has become more technically challenging due to the use of mesh. In addition, there has been a paucity of clinical studies. A common recommendation has been to avoid the previous site and to use a different approach. METHODS: In this study of 218 patients, the anatomical characteristics of inguinal hernia recurrences were studied in relation to the previous technique of repair, including Mesh (n = 100), Laparoscopic (n = 61) and Shouldice (n = 57). RESULTS: The most common site of recurrence was direct (58.5%) in all three groups. Femoral recurrences were significantly lower in the Laparoscopic group. Indirect and multiple recurrences were significantly lower in the Shouldice group. The operative time in the Mesh group was significantly longer due to the dissection required of the previous mesh. A pro-peritoneal mesh repair was performed for the re-operation in 13.8%, while a Shouldice repair was performed in the others. The overall follow-up rate was 75.2% for a mean of 4.8 years. The re-recurrence rate was 1.8%. CONCLUSION: The distinct patterns of recurrence reflect the relative strengths and weaknesses of the different techniques of repair and present the anatomical and technical basis for future improvements. A safe and durable repair of an inguinal hernia recurrence can be achieved through an anterior trans-inguinal approach. PMID- 21267618 TI - Posterior column ataxia with retinitis pigmentosa in a Japanese family with a novel mutation in FLVCR1. AB - Posterior column ataxia with retinitis pigmentosa (PCARP) is an autosomal recessive neurodegenerative disorder characterized by retinitis pigmentosa and sensory ataxia. Previous studies of PCARP in two families showed a linkage to 1q31-q32. However, detailed investigations on the clinical presentations as well as molecular genetics of PCARP have been limited. Here, we describe a Japanese consanguineous family with PCARP. Two affected siblings suffered from childhood onset retinitis pigmentosa and slowly progressive sensory ataxia. They also showed mild mental retardation, which has not been described in patients with PCARP. Parametric linkage analysis using high-density single nucleotide polymorphism arrays supported a linkage to the same locus. Target capture and high-throughput sequencing technologies revealed a novel homozygous c.1477G>C (G493R) mutation in FLVCR1, which cosegregated with the disease. A recent study has identified three independent mutations in FLVCR1 in the original and other families. Our results further confirmed that PCARP is caused by mutations in FLVCR1. PMID- 21267619 TI - The cohort of the multiple sclerosis center of Cagliari. AB - We report our experience in long-term treatment of relapsing remitting multiple sclerosis patients with natalizumab (N). In November 2009 we evaluated 141 patients (126 AIFA criterion A, 15 AIFA criterion B). We paid particular attention to the treatment period and the patients follow-up; during the whole therapeutic program, they undergone to clinical and radiological evaluation for every 3 months. The compliance was optimal and we found no significant side effects. 26 patients completed the 24 monthly doses. After 24 months 51% of patients were free from disease activity. We found a reduction in relapses and EDSS, moreover the clinical improvement was also confirmed by radiological examinations. Our results show that the best therapeutic results are achieved by early initiation of treatment. PMID- 21267617 TI - Investigating the genetics of visual processing, function and behaviour in zebrafish. AB - Over the past three decades, the zebrafish has been proven to be an excellent model to investigate the genetic control of vertebrate embryonic development, and it is now also increasingly used to study behaviour and adult physiology. Moreover, mutagenesis approaches have resulted in large collections of mutants with phenotypes that resemble human pathologies, suggesting that these lines can be used to model diseases and screen drug candidates. With the recent development of new methods for gene targeting and manipulating or monitoring gene expression, the range of genetic modifications now possible in zebrafish is increasing rapidly. Combined with the classical strengths of the zebrafish as a model organism, these advances are set to substantially expand the type of biological questions that can be addressed in this species. In this review, we outline how the potential of the zebrafish can be harvested in the context of eye development and visual function. We review recent technological advances used to study the formation of the eyes and visual areas of the brain, visual processing on the cellular, subcellular and molecular level, and the genetics of visual behaviour in vertebrates. PMID- 21267620 TI - Enrichment culture of CSF is of limited value in the diagnosis of neonatal meningitis. PMID- 21267621 TI - The effect of empiric antibiotic therapy on mortality in debilitated patients with dementia. AB - The purpose of this investigation was to assess the effect of empirical antibiotic treatment on 30-day mortality among debilitated inpatients with dementia and Gram-negative bacteremia. A retrospective cohort study in the years 2005-2007 was undertaken. Data were collected through patient chart review. The association between individual variables and 30-day mortality was assessed through univariate analysis. Variables significantly associated with mortality (p < 0.05) were entered into a logistic regression analysis. Adjusted odds ratios (ORs) for mortality with 95% confidence intervals (CIs) are shown. Subgroup analysis of patients with and without decubitus ulcers was performed. In our cohort of 378 patients with dementia and Gram-negative bacteremia, the 30-day mortality was 39% overall and 61% in the subgroup of patients with decubitus ulcers. Inappropriate empirical therapy was associated with higher mortality, although this effect was not statistically significant (OR 1.41, 95% CI 0.86 2.29). Inappropriate empirical therapy did not affect mortality in the subgroup of patients with decubitus ulcers (OR 0.37, 95% CI 0.11-1.28). Other factors found to independently affect mortality included age, co-morbidities, source of infection, sepsis severity, and hospital-acquired infection. Appropriate empirical antibiotic therapy for patients with dementia and severe bacterial infection did not have a clear advantage, especially in the sickest group of patients with decubitus ulcers. PMID- 21267622 TI - Evaluating adaptation and olivocochlear efferent feedback as potential explanations of psychophysical overshoot. AB - Masked detection threshold for a short tone in noise improves as the tone's onset is delayed from the masker's onset. This improvement, known as "overshoot," is maximal at mid-masker levels and is reduced by temporary and permanent cochlear hearing loss. Computational modeling was used in the present study to evaluate proposed physiological mechanisms of overshoot, including classic firing rate adaptation and medial olivocochlear (MOC) feedback, for both normal hearing and cochlear hearing loss conditions. These theories were tested using an established model of the auditory periphery and signal detection theory techniques. The influence of several analysis variables on predicted tone-pip detection in broadband noise was evaluated, including: auditory nerve fiber spontaneous-rate (SR) pooling, range of characteristic frequencies, number of synapses per characteristic frequency, analysis window duration, and detection rule. The results revealed that overshoot similar to perceptual data in terms of both magnitude and level dependence could be predicted when the effects of MOC efferent feedback were included in the auditory nerve model. Conversely, simulations without MOC feedback effects never produced overshoot despite the model's ability to account for classic firing rate adaptation and dynamic range adaptation in auditory nerve responses. Cochlear hearing loss was predicted to reduce the size of overshoot only for model versions that included the effects of MOC efferent feedback. These findings suggest that overshoot in normal and hearing-impaired listeners is mediated by some form of dynamic range adaptation other than what is observed in the auditory nerve of anesthetized animals. Mechanisms for this adaptation may occur at several levels along the auditory pathway. Among these mechanisms, the MOC reflex may play a leading role. PMID- 21267623 TI - To model or not to model: lessons from two vaccinations. PMID- 21267624 TI - Relative effectiveness and the European pharmaceutical market. PMID- 21267625 TI - A determination of the minimum sizes of representative volume elements for the prediction of cortical bone elastic properties. AB - At its highest level of microstructural organization-the mesoscale or millimeter scale-cortical bone exhibits a heterogeneous distribution of pores (Haversian canals, resorption cavities). Multi-scale mechanical models rely on the definition of a representative volume element (RVE). Analytical homogenization techniques are usually based on an idealized RVE microstructure, while finite element homogenization using high-resolution images is based on a realistic RVE of finite size. The objective of this paper was to quantify the size and content of possible cortical bone mesoscale RVEs. RVE size was defined as the minimum size: (1) for which the apparent (homogenized) stiffness tensor becomes independent of the applied boundary conditions or (2) for which the variance of elastic properties for a set of microstructure realizations is sufficiently small. The field of elastic coefficients and microstructure in RVEs was derived from one acoustic microscopy image of a human femur cortical bone sample with an overall porosity of 8.5%. The homogenized properties of RVEs were computed with a finite element technique. It was found that the size of the RVE representative of the overall tissue is about 1.5 mm. Smaller RVEs (~0.5 mm) can also be considered to estimate local mesoscopic properties that strongly depend on the local pores volume fraction. This result provides a sound basis for the application of homogenization techniques to model the heterogeneity of cortical microstructures. An application of the findings to estimate elastic properties in the case of a porosity gradient is briefly presented. PMID- 21267626 TI - Flying over an infected landscape: distribution of highly pathogenic avian influenza H5N1 risk in South Asia and satellite tracking of wild waterfowl. AB - Highly pathogenic avian influenza (HPAI) H5N1 virus persists in Asia, posing a threat to poultry, wild birds, and humans. Previous work in Southeast Asia demonstrated that HPAI H5N1 risk is related to domestic ducks and people. Other studies discussed the role of migratory birds in the long distance spread of HPAI H5N1. However, the interplay between local persistence and long-distance dispersal has never been studied. We expand previous geospatial risk analysis to include South and Southeast Asia, and integrate the analysis with migration data of satellite-tracked wild waterfowl along the Central Asia flyway. We find that the population of domestic duck is the main factor delineating areas at risk of HPAI H5N1 spread in domestic poultry in South Asia, and that other risk factors, such as human population and chicken density, are associated with HPAI H5N1 risk within those areas. We also find that satellite tracked birds (Ruddy Shelduck and two Bar-headed Geese) reveal a direct spatio-temporal link between the HPAI H5N1 hot-spots identified in India and Bangladesh through our risk model, and the wild bird outbreaks in May-June-July 2009 in China (Qinghai Lake), Mongolia, and Russia. This suggests that the continental-scale dynamics of HPAI H5N1 are structured as a number of persistence areas delineated by domestic ducks, connected by rare transmission through migratory waterfowl. PMID- 21267627 TI - On and off responses of the photopic fullfield ERG in normal subjects and glaucoma patients. AB - Recent studies suggest a diagnostic value of the photopic negative response (PhNR) with a long-duration stimulus. The aim of this study was to record the on and off responses of the photopic fullfield electroretinogram (ERG) in normal subjects and glaucoma patients. We focused on different waves of the responses after onset and offset of the long-duration stimulus ERG. Photopic fullfield ERGs were recorded in response to a white bright LED flash on a white 20 cd/m(2) background. Stimulus luminances were 40, 60 and 80 cd/m(2). Responses were averaged using a flash duration of 240 ms and an offset period of 500 ms. We examined 19 healthy subjects, 27 patients with glaucomatous optic disc atrophy and 7 ocular hypertensive patients. The amplitudes and implicit times of the on and off responses of the human ERG depended on flash luminance. Comparing patients with glaucoma and healthy subjects for the 60 cd/m2 flash, there was a significant change in the PhNRs (at onset: P < 0.01, at offset: P < 0.001) of the d-wave and of the i-wave at offset (P < 0.01). No significant difference was found for peak times of the fullfield ERG and for a- and b-wave amplitudes. PhNR amplitudes were significantly correlated with mean thickness of retinal nerve fibre layer as measured with OCT. In comparison with the normal photopic long flash ERG, glaucoma patients showed changes in the PhNR amplitude following stimulus onset and in waves following stimulus offset. PMID- 21267628 TI - Unusual retinal manifestations of cat scratch disease. AB - We report on 2 patients with unusual retinal manifestations of cat scratch disease (CSD), caused by Bartonella henselae. Case 1. A 42-year-old farmer presented with a 5-day history of blurred vision in his right eye. Right visual acuity was 20/25. Fundus examination of the right eye revealed mild vitreous hemorrhage and diffuse retinal hemorrhages in the mid-peripheral retina. Fluorescein angiography showed multiple vasculitic occlusions in the same area. A blood sample taken on the day of examination revealed the presence of immunoglobulin (Ig)M and IgG to B. henselae. Oral azithromycin was given for 8 days. One month later, right visual acuity was 20/20, the vitreous and retinal hemorrhages resolved, and arteriolar attenuation and sclerosis was observed in the peripheral temporal retina. Case 2. A 66-year-old craftsman with systemic hypertension and hypercholesterolemia complained of sudden visual loss (light perception) in his left eye. Fundus evaluation and fluorescein angiography revealed central retinal artery occlusion (CRAO) in the affected eye. About 2 weeks earlier, he had been bitten and scratched on his right hand by a stray cat. Serologic testing detected the presence of IgM to B. henselae. Oral azithromycin was given for 6 days. One month later, left visual acuity was hand motion. Ophthalmologists should be aware that unusual ocular complications associated with CSD include vitreous hemorrhage with retinal vasculitis and isolated CRAO. Vitreous hemorrhage and retinal vasculitis may be the only clinical manifestation of CSD. PMID- 21267629 TI - Orbital dermoid cyst of childhood: clinical pathologic findings, classification and management. AB - To analyze the characteristics and treatment outcomes of pediatric orbital dermoid cysts. Chart review of consecutive pediatric biopsy-proven dermoid cysts surgically removed at the Department of Ophthalmology, Maggiore Hospital, between 2000 and 2007. We excised dermoid cysts from 30 children (30 eyes) whose mean age at the time of surgery was 24 months (range 6-84). The most common presentation of the cyst was a palpable or partially palpable mass (100%), followed by a superior lid ptosis (10%). Twenty patients (67%) had superficial cysts with margins well-definable by palpation, and 10 patients (33%) had deep cysts that extended beyond the orbital rim with an incomplete palpation of margins requiring imaging studies. The most frequent localization of the cysts was the superior temporal zygomatico-frontal suture (86.6%), followed by the superior nasal frontal suture (10%). Complete removal of the cysts was achieved and confirmed histopathologically, and there were no recurrences among the patients at a mean follow-up of 28 months (range 6-73). One child, however, developed a temporary orbital hematoma. The superficial cysts had an anatomic mean diameter of 10 mm (range 2.5-15), and the mean age of the patients at surgery was 19 months (range 6-31). The deep cysts had a larger diameter with a mean of 14 mm (range 10-30) (P = 0.008), and the children were older at presentation with a mean age of 34 months (range 15-84) (P = 0.03). There was a statistically significant difference (P < 0.05) between the two groups (superficial and deep) when comparing age and diameter. Cysts with palpably distinct margins (superficial) can be easily and completely excised with no recurrence. Cysts with indistinct margins need detailed computed tomography or magnetic resonance imaging investigation because they may require deep orbital dissection. Complete excision of the cyst's capsule may be difficult as a result. In our review we have not found cysts with intracranial extension. PMID- 21267630 TI - Lipoid proteinosis of Urbach and Weithe: case report and a brief review of the literature. AB - Lipoid proteinosis is a rare disorder involving multiple organ systems. The ocular manifestations are usually trivial, but greatly aid in the diagnosis. We describe a patient who presented to us with typical moniliform blepharosis. A brief description of relevance to the ophthalmologist and review of the literature follows. PMID- 21267631 TI - A case of Behcet's disease complicated by bilateral posterior ischemic optic neuropathy. AB - We report a case involving bilateral posterior ischemic optic neuropathy with Behcet's disease in a 49-year-old woman. The patient presented because of abrupt visual disturbances. An ophthalmic examination, including fluorescein angiography, visual field testing, and visual-evoked potentials, was performed. Her visual acuity was 20/100 bilaterally and posterior ischemic optic neuropathy was suspected. She was treated with systemic methylprednisolone; however, disc pallor developed and the visual acuity remained 20/200 bilaterally. Optic neuropathy can be bilateral, affect both eyes simultaneously, and lead to severe visual loss despite high doses of systemic steroid treatment. Optic neuropathy in Behcet's disease is very rare. This case provides clinical insight into the neuro ophthalmologic manifestations of Behcet's disease. PMID- 21267632 TI - The impact of penetrating keratoplasty in patients with keratoconus using the VF 14 questionnaire. AB - To assess the visual function of patients with keratoconus who underwent penetrating keratoplasty with the use of the VF-14 questionnaire. Fourteen patients (9 male and 5 female) with a mean age of 38 years (SD 13.59) participated in the study. All patients had keratoconus, confirmed by corneal topography, and all had previously undergone penetrating keratoplasty in one eye. Their mean best-corrected visual acuity (BCVA) binocularly was 0.185 (SD 0.077) LogMAR. None of the grafted eyes had a BCVA < 0.300 LogMAR. Fourteen healthy volunteers, age- and sex-matched, also participated in the study as control subjects. The VF-14 questionnaire was used to evaluate the effect of the ocular status in the daily life activities of the patients. The mean VF-14 result for the grafted patients with keratoconus was 62.37% (SD 22.60) and for the control group it was 100% (P < 0.001). There was only a weak correlation between the VF 14 score and the binocular BCVA (r = -0.394, P = 0.163). The mean VF-14 result in grafted patients with keratoconus is indicative of low functional ability despite the satisfactory postoperative BCVA. The absence of a significant correlation between the VF-14 score and the mean BCVA indicates that the low functional visual ability in these patients is probably associated more with the 'perceived by themselves' difficulty due to their ophthalmological condition. PMID- 21267633 TI - The many faces of the octahedral ferritin protein. AB - Iron is an essential trace nutrient required for the active sites of many enzymes, electron transfer and oxygen transport proteins. In contrast, to its important biological roles, iron is a catalyst for reactive oxygen species (ROS). Organisms must acquire iron but must protect against oxidative damage. Biology has evolved siderophores, hormones, membrane transporters, and iron transport and storage proteins to acquire sufficient iron but maintain iron levels at safe concentrations that prevent iron from catalyzing the formation of ROS. Ferritin is an important hub for iron metabolism because it sequesters iron during times of iron excess and releases iron during iron paucity. Ferritin is expressed in response to oxidative stress and is secreted into the extracellular matrix and into the serum. The iron sequestering ability of ferritin is believed to be the source of the anti-oxidant properties of ferritin. In fact, ferritin has been used as a biomarker for disease because it is synthesized in response to oxidative damage and inflammation. The function of serum ferritin is poorly understood, however serum ferritin concentrations seem to correlate with total iron stores. Under certain conditions, ferritin is also associated with pro oxidant activity. The source of this switch from anti-oxidant to pro-oxidant has not been established but may be associated with unregulated iron release from ferritin. Recent reports demonstrate that ferritin is involved in other aspects of biology such as cell activation, development, immunity and angiogenesis. This review examines ferritin expression and secretion in correlation with anti oxidant activity and with respect to these new functions. In addition, conditions that lead to pro-oxidant conditions are considered. PMID- 21267634 TI - Contrasting cDNA-AFLP profiles between crown and leaf tissues of cold-acclimated wheat plants indicate differing regulatory circuitries for low temperature tolerance. AB - Low-temperature (LT) tolerance in winter wheat (Triticum aestivum L.) is an economically important but complex trait. Four selected wheat genotypes, a winter hardy cultivar, Norstar, a tender spring cultivar, Manitou and two near-isogenic lines with Vrn-A1 (spring Norstar) and vrn-A1 (winter Manitou) alleles of Manitou and Norstar were cold-acclimated at 6 degrees C and crown and leaf tissues were collected at 0, 2, 14, 21, 35, 42, 56 and 70 days of cold acclimation. cDNA-AFLP profiling was used to determine temporal expression profiles of transcripts during cold-acclimation in crown and leaf tissues, separately to determine if LT regulatory circuitries in crown and leaf tissues could be delineated using this approach. Screening 64 primer combinations identified 4,074 and 2,757 differentially expressed transcript-derived fragments (TDFs) out of which 38 and 16% were up-regulated as compared to 3 and 6% that were down-regulated in crown and leaf tissues, respectively. DNA sequencing of TDFs revealed sequences common to both tissues including genes coding for DEAD-box RNA helicase, choline phosphate cytidylyltransferase and delta-1-pyrroline carboxylate synthetase. TDF specific to crown tissues included genes coding for phospahtidylinositol kinase, auxin response factor protein and brassinosteroid insensitive 1-associated receptor kinase. In leaf, genes such as methylene tetrahydrofolate reductase, NADH-cytochrome b5 reductase and malate dehydrogenase were identified. However, 30 and 14% of the DNA sequences from the crown and leaf tissues, respectively, were hypothetical or unknown proteins. Cluster analysis of up-, down-regulated and unique TDFs, DNA sequence and real-time PCR validation, infer that mechanisms operating in crown and leaf tissue in response to LT are differently regulated and warrant further studies. PMID- 21267635 TI - Evolutionary dynamics of heterochromatin in the genome of Dichotomius beetles based on chromosomal analysis. AB - We comparatively analyzed six Dichotomius species (Coleoptera: Scarabainae) through cytogenetic methods and mitochondrial genes sequencing in the aim to identify patterns of chromosomal evolution and heterochromatin differentiation in the group. The chromosomal data were accessed through the classical analysis of heterochromatin and mapping of high and moderately repeated DNAs (C (0) t-1 DNA fraction). Mitochondrial data were obtained from nucleotide sequences of the cytochrome oxidase I (COI) and 16S rRNA genes. The heterochromatin distribution was conserved but revealed variability in the base pair richness and repetitive DNA content, and an intense turnover of heterochromatic associated sequences seems to have occurred during Dichotomius speciation. Specifically for D. bos, an interesting pattern was observed, indicating apparently the presence of heterochromatic sequences composed of low copy-number sequences. Moreover, highly conserved terminal/sub-terminal sequences that could act as a telomeric or telomere-associated DNA were observed. The heterochromatin diversification patterns observed in Dichotomius were not accomplished by the diversification of the species studied, which may be a consequence of the intense dynamics that drive the evolution of repeated DNA clusters in the genome. Finally our findings also suggest that the use of C (0) t-1 DNA fraction represents a powerful, inexpensive and not time consuming tool to be applied in understanding heterochromatin and repetitive DNA organization. PMID- 21267636 TI - Vertebrate endothelial lipase: comparative studies of an ancient gene and protein in vertebrate evolution. AB - Endothelial lipase (gene: LIPG; enzyme: EL) is one of three members of the triglyceride lipase family that contributes to lipoprotein degradation within the circulation system and plays a major role in HDL metabolism in the body. In this study, in silico methods were used to predict the amino acid sequences, secondary and tertiary structures, and gene locations for LIPG genes and encoded proteins using data from several vertebrate genome projects. LIPG is located on human chromosome 18 and is distinct from other human 'neutral lipase' genes, hepatic lipase (gene: LIPC; enzyme: HL) and lipoprotein lipase (gene: LPL; enzyme: LPL) examined. Vertebrate LIPG genes usually contained 10 coding exons located on the positive strand for most primates, as well as for horse, bovine, opossum, platypus and frog genomes. The rat LIPG gene however contained only 9 coding exons apparently due to the presence of a 'stop' codon' within exon 9. Vertebrate EL protein subunits shared 58-97% sequence identity as compared with 38-45% sequence identities with human HL and LPL. Four previously reported human EL N glycosylation sites were predominantly conserved among the 10 potential N glycosylation sites observed for the vertebrate EL sequences examined. Sequence alignments and identities for key EL amino acid residues were observed as well as conservation of predicted secondary and tertiary structures with those previously reported for horse pancreatic lipase (PL) (Bourne et al. 1994). Several potential sites for regulating LIPG gene expression were observed including CpG islands near the LIPG gene promoter and a predicted microRNA binding site near the 3' untranslated region. Promoter regions containing functional polymorphisms that regulate HDL cholesterol in baboons were conserved among primates but not retained between primates and rodents. Phylogenetic analyses examined the relationships and potential evolutionary origins of the vertebrate LIPG gene subfamily with other neutral triglyceride lipase gene families, LIPC and LPL. It is apparent that the triglyceride lipase ancestral gene for the vertebrate LIPG gene predated the appearance of fish during vertebrate evolution >500 million years ago. PMID- 21267637 TI - The association between alcohol consumption and mortality: the Swedish women's lifestyle and health study. AB - Although light to moderate alcohol intake may reduce cardiovascular disease (CVD) mortality, the effect on total mortality requires further study, particularly among young and middle-aged women. We studied the association between alcohol consumption and mortality from all causes, from cancer, and from CVD in the Swedish Women's Lifestyle and Health Study, a cohort of 47,921 female residents of Sweden aged 30-49 years at baseline in 1991/1992 and followed up to 2006. We estimated the relative risk (RR) of mortality associated with alcohol intake using Cox regression adjusted for age, smoking, BMI, saturated fat intake, physical activity, and education. During 713,295 person-years of follow-up, 1,119 deaths occurred, including 158 deaths from CVD, 673 deaths from cancer, and 288 deaths from other causes. Compared with non-drinking, light to moderate drinking (0.1-19.9 g of alcohol per day) showed a statistically significant inverse association with total mortality (RR = 0.83, 95% CI = 0.71-0.98). Analyses of cause-specific mortality revealed an RR for CVD mortality of 0.69 (95% CI = 0.46 1.01) and an RR for cancer mortality of 0.92 (95% CI = 0.75-1.15). These results suggest that in younger women, a possibly beneficial effect of light to moderate drinking on future risk of mortality is limited to a prevention of CVD mortality but not cancer mortality. PMID- 21267638 TI - Ischemic preconditioning requires opening of pannexin-1/P2X(7) channels not only during preconditioning but again after index ischemia at full reperfusion. AB - Protection of the ex vivo rat heart from ischemia/reperfusion injury can be provided by ischemic preconditioning (IPC). Previous studies revealed that a complex of pannexin-1 with the P2X7 receptor forms a channel during IPC that results in the release of cardioprotectants such as adenosine and sphingosine 1 phosphate (S1P) that bind to G-protein-coupled cell surface receptors triggering cardioprotective cell signaling pathways. Antagonists of both pannexin-1 (carbenoxolone and mefloquine) and P2X7 receptors (brilliant blue G) are known to block IPC when administered at the time of preconditioning (Vessey et al. J Cardiovasc Pharmacol Ther 15:190, 2010). We now demonstrate that these same antagonists also block the cardioprotective effects of IPC when added after the index ischemia during full reperfusion. Likewise, addition at full reperfusion of binding antagonists to the endogenous cardioprotectants S1P (VPC) or adenosine (8 SPT) reduced the effectiveness of IPC. These data suggest that IPC has a component that requires the release of cardioprotectants via pannexin-1/P2X7 channels not only during preconditioning phase but again during the early stages of reperfusion following the index ischemia. It was found that the level of cardioprotectant release required at reperfusion to achieve cardioprotection was lower when hearts had been preconditioned. Further, pharmacologic preconditioning with S1P or adenosine was also blocked at reperfusion by antagonists of the pannexin-1/P2X7 channels indicating that pharmacologic preconditioning also requires opening of the channel at full reperfusion. In untreated hearts, key components of the PI3 kinase/Akt signaling pathway were revealed by western analysis to be lost during ischemia. This correlates with an inability to generate phospho-Akt at reperfusion. IPC prevents this loss and thereby primes the cell for response to cardioprotectants released at full reperfusion. PMID- 21267639 TI - Time and distance barriers to mammography facilities in the Atlanta metropolitan area. AB - To a great extent, research on geographic accessibility to mammography facilities has focused on urban-rural differences. Spatial accessibility within urban areas can nonetheless pose a challenge, especially for minorities and low-income urban residents who are more likely to depend on public transportation. To examine spatial and temporal accessibility to mammography facilities in the Atlanta metropolitan area by public and private transportation, we built a multimodal transportation network model including bus and rail routes, bus and rail stops, transfers, walk times, and wait times. Our analysis of travel times from the population-weighted centroids of the 282 census tracts in the 2-county area to the nearest facility found that the median public transportation time was almost 51 minutes. We further examined public transportation travel times by levels of household access to a private vehicle. Residents in tracts with the lowest household access to a private vehicle had the shortest travel times, suggesting that facilities were favorably located for women who have to use public transportation. However, census tracts with majority non-Hispanic black populations had the longest travel times for all levels of vehicle availability. Time to the nearest mammography facility would not pose a barrier to women who had access to a private vehicle. This study adds to the literature demonstrating differences in spatial accessibility to health services by race/ethnicity and socioeconomic characteristics. Ameliorating spatial inaccessibility represents an opportunity for intervention that operates at the population level. PMID- 21267640 TI - Results of a community-university partnership to reduce deadly hazards in hardwood floor finishing. AB - A community-university partnership used community-based participatory research (CBPR) to design, implement, and evaluate a multi-cultural public health campaign to eliminate flammable products and reduce use of products high in volatile organic compounds (VOCs) in hardwood floor finishing in Massachusetts. Leading participants were Vietnamese-American organizations and businesses. Following the public health campaign, a multi-lingual survey of self-reported experiences with fires, product use, exposure to outreach activities, and changes made, was conducted with floor finishers. One hundred nine floor finishers responded. Over 40% reported fires at their companies' jobs, mostly caused by lacquer sealers. Over one third had heard radio or TV shows about health and safety in floor finishing, and over half reported making changes as a result of outreach. Exposure to various outreach activities was associated with reducing use of flammable products, increasing use of low-VOC products, and greater knowledge about product flammability. However, most respondents still reported using flammable products. Outreach led by community partners reached large proportions of floor finishers, was associated with use of safer products, and adds to recent work on CBPR with immigrant workers. Continued use of flammable products supports the belief that an enforceable ban was ultimately necessary to eradicate them. PMID- 21267641 TI - Characterization of a single-stranded DNA binding protein from Salmonella enterica serovar Typhimurium LT2. AB - Single-stranded DNA-binding protein (SSB) plays an important role in DNA metabolism, such as DNA replication, repair, and recombination, and is essential for cell survival. We characterized the single-stranded DNA (ssDNA)-binding properties of Salmonella enterica serovar Typhimurium LT2 SSB (StSSB) by using fluorescence quenching measurements and electrophoretic mobility shift analysis (EMSA). Analysis of purified StSSB by gel filtration chromatography showed a stable tetramer in solution. In fluorescence titrations, StSSB bound to 21-38 nucleotides (nt) per tetramer depending on the salt concentration. Using EMSA, we characterized the stoichiometry of StSSB complexed with a series of ssDNA homopolymers, and the size of the binding site was determined to be 22 +/- 1 nt. Furthermore, EMSA results indicated that the dissociation constants of StSSB for the first tetramer were less than that for the second tetramer. On the basis of these biophysical analyses, the ssDNA binding-mode of StSSB is expected to be noncooperative. PMID- 21267642 TI - Reliability of eye tracking and pupillometry measures in individuals with fragile X syndrome. AB - Recent insight into the underlying molecular and cellular mechanisms of fragile X syndrome (FXS) has led to the proposal and development of new pharmaceutical treatment strategies, and the initiation of clinical trials aimed at correcting core symptoms of the developmental disorder. Consequently, there is an urgent and critical need for outcome measures that are valid for quantifying specific symptoms of FXS and that are consistent across time. We used eye tracking to evaluate test-retest reliability of gaze and pupillometry measures in individuals with FXS and we demonstrate that these measures are viable options for assessing treatment-specific outcomes related to a core behavioral feature of the disorder. PMID- 21267643 TI - Preference for facial self-resemblance and attractiveness in human mate choice. AB - Empirical studies present considerably consistent data about human mate choice, from which we may infer that it tends to be homogamous for various traits. However, different experiments on facial resemblance led to contradictory results. To obtain additional data about the preference for self-resembling potential mates, male and female composite faces were modified in a manner to resemble subjects. Volunteers were asked to choose a potential partner from three images in different situations: self-resembling faces, non-resembling faces (both with the same degree of other-rated attractiveness), and images which were rated by others as more attractive than the self-resembling faces. Women did not show any preference for similarity; they preferred the most attractive male and female faces. In contrast, men preferred the most attractive images of the opposite sex to self-resembling faces and the self-resembling to non-resembling faces. The self-resemblance of same-sex faces was preferred by neither men nor women. Our results support the hypothesis that both facial similarity (i.e., cues of shared genes) and observer-independent features of attractiveness (i.e., honest signals of genetic quality) play an important role in males' mate choice. The lack of choice for self-resemblance on the female side in this particular study might reflect their more complex decision-making rules that are probably based on other cues beside visual stimuli. PMID- 21267644 TI - Sexual satisfaction and relationship happiness in midlife and older couples in five countries. AB - Sexuality research focuses almost exclusively on individuals rather than couples, though ongoing relationships are very important for most people and cultures. The present study was the first to examine sexual and relationship parameters of middle-aged and older couples in committed relationships of 1-51 years duration. Survey research was conducted in Brazil, Germany, Japan, Spain, and the U.S. targeting 200 men aged 40-70 and their female partners in each country, with 1,009 couples in the final sample. Key demographic, health, physical intimacy, sexual behavior, sexual function, and sexual history variables were used to model relationship happiness and sexual satisfaction. The median ages were 55 for men and 52 for women; median relationship duration was 25 years. Relationship satisfaction in men depended on health, physical intimacy, and sexual functioning, while in women only sexual functioning predicted relationship satisfaction. Models predicting sexual satisfaction included significant physical intimacy and sexual functioning for both genders and, for men, more frequent recent sexual activity and fewer lifetime partners. Longer relationship duration predicted greater relationship happiness and sexual satisfaction for men. However, women in relationships of 20 to 40 years were significantly less likely than men to report relationship happiness. Compared to men, women showed lower sexual satisfaction early in the relationship and greater sexual satisfaction later. Within the long-term committed relationship context, there were significant gender differences in correlates of sexual and relationship satisfaction, with sexual functioning a common predictor of both types of satisfaction and physical intimacy a more consistent and salient predictor for men. PMID- 21267645 TI - Development of 19 dinucleotide microsatellite markers from the enriched library of Platysternon megacephalum. PMID- 21267646 TI - Soy consumption and breast cancer risk: four recent meta-analyses. PMID- 21267647 TI - Implication of two in-stream processes in the fate of nutrients discharged by sewage system into a temporary river. AB - The aim of this study was to better understand the fate of nutrients discharged by sewage treatment plants into an intermittent Mediterranean river, during a low flow period. Many pollutants stored in the riverbed during the low-flow period can be transferred to the downstream environments during flood events. The study focused on two processes that affect the fate and the transport of nutrients, a physical process (retention in the riverbed sediments) and a biological process (denitrification). A spatial campaign was carried out during a low-flow period to characterize the nutrient contents of both water and sediments in the Vene River. The results showed high nutrient concentrations in the water column downstream of the treated wastewater disposal (up to 13,315 MUg N/L for ammonium and 2,901 MUg P/L for total phosphorus). Nutrient concentrations decreased rapidly downstream of the disposal whereas nutrient contents in the sediments increased (up to 1,898 and 784 MUg/g for total phosphorus and Kjeldahl nitrogen, respectively). According to an in situ experiment using sediment boxes placed in the riverbed for 85 days, we estimated that the proportion of nutrients trapped in the sediments represents 25% (respectively 10%) of phosphorus (respectively nitrogen) loads lost from the water column. In parallel, laboratory tests indicated that denitrification occurred in the Vene River, and we estimated that denitrification likely coupled to nitrification processes during the 85 days of the experiment was significantly involved in the removal of nitrogen loads (up to 38%) from the water column and was greater than accumulation processes. PMID- 21267648 TI - Effects of malathion and carbendazim on Amazonian freshwater organisms: comparison of tropical and temperate species sensitivity distributions. AB - The risk assessment of pesticides for freshwater ecosystems in the Amazon has relied on the use of toxicity data and water quality criteria derived for temperate regions due to a lack of ecotoxicological studies performed with indigenous species. This leaves an unknown margin of uncertainty for the protection of Amazonian ecosystems, as differences in environmental conditions and species sensitivity are not taken into account. To address this issue, the acute toxic effects of malathion (an organophosphorus insecticide) and carbendazim (a benzimidazole fungicide) were assessed on five fish and five freshwater invertebrates endemic to the Amazonian region. Subsequently, the intrinsic sensitivity of Amazonian and temperate freshwater species was compared using the species sensitivity distribution (SSD) concept. Amazonian species sensitivity to malathion was found to be similar to that of their temperate counterparts, with LC50 values ranging between 111 and 1507 MUg/l for fish species and 2.1-426 MUg/l for arthropod species. However, Amazonian fish appeared to be slightly less sensitive for carbendazim than temperate fish with LC50 values ranging between 1648 and 4238 MUg/l, and Amazonian invertebrates were found to be significantly more resistant than their temperate counterparts, with LC50 values higher than 16000 MUg/l. The results of this study suggest that for these compounds, the use of water quality criteria derived with laboratory toxicity data for temperate species will result in a sufficient protection level for Amazonian freshwater organisms. Recommendations for further research include the validation of threshold concentrations derived with temperate standard test species and with the SSD model with semi-field experiments considering larger assemblages of indigenous species under local environmental conditions. PMID- 21267649 TI - Population response to ozone application in wastewater: an on-site microcosm study with Gammarus fossarum (Crustacea: Amphipoda). AB - We assessed possible ecotoxicological implications of ozone application to secondary treated wastewater from a municipal wastewater treatment plant on Gammarus fossarum, an aquatic leaf shredding amphipod. Our 10-week study exposed G. fossarum populations to ozone-treated, non-ozone treated wastewater, or tap water in replicated outdoor flow-through stream microcosms. Feeding activity, an indicator for organic matter decomposition, of amphipod populations exposed to ozone treated wastewater was significantly higher compared to those exposed to non-ozone treated wastewater (repeated measure ANOVA, p = 0.0002, df = 44). Also the population size was at the end of the experiment with approximately 150% significantly (t-test, p = 0.0059, n = 4) increased in ozone treated wastewater compared to non-ozone treated wastewater. Additionally, chlorophyll-a concentration, an indicator for algal biomass, was significantly higher in ozone treated wastewater (repeated measure ANOVA, p = 0.0404, df = 65). Thus, from an ecotoxicological viewpoint, we conclude that ozonation may improve wastewater quality, which should translate into positive ecological outcomes in the receiving waters. However, because ozonation also can cause toxic transformation products, the process may best be considered on a case-by-case basis. PMID- 21267650 TI - Honeybee tracking with microchips: a new methodology to measure the effects of pesticides. AB - Losses of foraging bees are sometimes attributed to altered flight pattern between a meliferous plant treated with an insecticide and the hive. Only a limited number of studies has investigated the impact of pesticides on homing flight due to the difficulty of measuring the flight time between the food source and the hive. Monitoring the flights of the foraging bees needs their individual identification. The number of bees monitored simultaneously and the time span during which observations can be made limit most of the monitoring techniques. However, techniques of automatic tracking and identification of individuals have the potential to revolutionize the study of the ecotoxicological effects of xenobiotics on the bee behaviors. Radio Frequency Identification (RFID) offer numerous advantages such as an unlimited number of codes, a large number of simultaneous recording, and a quick reading, especially through materials (e.g., wood). The aim of this study was to show how the RFID device can be used to study the effects of pesticides on both the behavioral traits and the lifespan of bees. In this context, we have developed a method under tunnel to automatically record the displacements of foragers individualized with RFID tags and to detect the alteration of the flight pattern between an artificial feeder and the hive. Fipronil was selected as test substance due to the lack of information on the effects of this insecticide on the foraging behavior of free-flying bees. We showed that oral treatment of 0.3 ng of fipronil per bee (LD50/20) reduced the number of foraging trips. The strengths of our approach were briefly discussed. PMID- 21267651 TI - A novel approach for characterization of cathepsin D protease and its effect on tau and beta-amyloid proteins. AB - Cathepsin D is the lysosomal protease abundantly expressed in the brain. It plays an important role in the regulation of cellular apoptosis. In addition, cathepsin D has been shown to be involved in the pathogenesis of Alzheimer disease and autism. In this study, we developed a novel approach for the preparation of highly purified cathepsin D from the calf brain. This high grade purification is achieved by using DEAE-Sephacel Chromatography before the final step of applying to the Pepstatin-Sepharose 4B column. The properties of cathepsin D have also been studied. We show that cathepsin D cleaves both tau and beta-amyloid precursor protein (APP). Both tau and APP are involved in the pathogenesis of Alzheimer's disease. Our findings strongly suggest a link between the lysosomal dysfunction of cathepsin D and the etiology of Alzheimer's disease. Our findings also indicate that cathepsin D could be a new approach to treating Alzheimer's disease. PMID- 21267652 TI - Synthesis and in vitro inhibition properties of siRNA conjugates carrying glucose and galactose with different presentations. AB - Oligoribonucleotide conjugates and the corresponding siRNA duplexes against tumor necrosis factor carrying one, two, or four glucose and galactose residues at the 5'-end have been prepared using phosphoramidite chemistry. Carbohydrate-modified siRNA duplexes have similar inhibitory properties than unmodified RNA duplexes in HeLa cells transfected with oligofectamine. When HeLa cells were treated with siRNA carrying one, two, or four glucose residues without oligofectamine, no inhibition was observed. The inhibitory properties of siRNA carrying galactose residues without transfecting agent were tested on HuH-7 cells that have abundant asialoglycoprotein receptors. In these cells siRNA carrying galactose residues have slight anti-TNF inhibitory properties (25% in the best case) that are eliminated if the receptors are blocked with a competitor. These results demonstrate receptor-mediated uptake of siRNA carrying galactose residues, although the efficacy of the process is not enough for efficient RNA interference experiments. PMID- 21267653 TI - Barriers and facilitators of treatment for depression in a latino community: a focus group study. AB - We conducted focus groups with Latinos enrolled in a Medicaid health plan in order to ask about the barriers to and facilitators of depression treatment in general as well as barriers to participation in depression telephone care management. Telephone care management has been designed for and tested in primary care settings as a way of assisting physicians with caring for their depressed patients. It consists of regular brief contacts between the care manager and the patient; the care manager educates, tracks, and monitors patients with depression, coordinates care between the patient and primary care physician, and may provide short-term psychotherapy. We conducted qualitative analyses of four focus groups (n = 30 participants) composed of Latinos who endorsed having been depressed themselves or having had a close friend or family member with depression, stress, nervios, or worries. Within the area of barriers and facilitators of receiving care for depression, we identified the following themes: vulnerability, social connection and engagement, language, culture, insurance/money, stigma, disengagement, information, and family. Participants discussed attitudes toward: importance of seeking help for depression, specific types of treatments, healthcare providers, continuity and coordination of care, and phone calls. Improved understanding of barriers and facilitators of depression treatment in general and depression care management in particular for Latinos enrolled in Medicaid should lead to interventions better able to meet the needs of this particular group. PMID- 21267655 TI - Nutritional vulnerability seen within asylum seekers in Australia. AB - To examine the extent of nutritional vulnerability seen in a cohort of asylum seekers in Australia. Twenty-one asylum seekers (15 males, 6 females) that used a food bank were interviewed over a 6 week period at the Melbourne based Asylum Seeker Resource Centre about foods consumed in the previous 24-h and any non food bank foods obtained. A basket audit was conducted after participants accessed the food bank on the day of interview, Participants obtained significantly less than the minimum requirements for the Australian Guide to Healthy Eating in the vegetables and legumes (P < .001, 95% CI -3.5, -1.7) fruits (P < .001, 95% CI 1.7, -.1.2), dairy (P < .001, 95% CI -1.8, -1.5) and meat and meat alternatives core food groups (P = .001, 95% CI -0.8, -0.3) using foods accessed from the food bank, their primary or sole food source. A high level of nutritional vulnerability was seen in this cohort due to their inability to meet minimum nutritional requirements from their primary food access point. Health professionals working with asylum seeker populations need to be aware of this issue and the resulting potential for longer term ill health as a consequence. PMID- 21267654 TI - A model of therapist competencies for the empirically supported cognitive behavioral treatment of child and adolescent anxiety and depressive disorders. AB - While a plethora of cognitive behavioral empirically supported treatments (ESTs) are available for treating child and adolescent anxiety and depressive disorders, research has shown that these are not as effective when implemented in routine practice settings. Research is now indicating that is partly due to ineffective EST training methods, resulting in a lack of therapist competence. However, at present, the specific competencies that are required for the effective implementation of ESTs for this population are unknown, making the development of more effective EST training difficult. This study therefore aimed to develop a model of therapist competencies for the empirically supported cognitive behavioral treatment of child and adolescent anxiety and depressive disorders using a version of the well-established Delphi technique. In doing so, the authors: (1) identified and reviewed cognitive behavioral ESTs for child and adolescent anxiety and depressive disorders, (2) extracted therapist competencies required to implement each treatment effectively, (3) validated these competency lists with EST authors, (4) consulted with a panel of relevant local experts to generate an overall model of therapist competence for the empirically supported cognitive behavioral treatment of child and adolescent anxiety and depressive disorders, and (5) validated the overall model with EST manual authors and relevant international experts. The resultant model offers an empirically derived set of competencies necessary for effectively treating children and adolescents with anxiety and depressive disorders and has wide implications for the development of therapist training, competence assessment measures, and evidence based practice guidelines for working with this population. This model thus brings us one step closer to bridging the gap between science and practice when treating child and adolescent anxiety and depression. PMID- 21267656 TI - Exploring factors influencing patient request for epidural analgesia on admission to labor and delivery in a predominantly Latino population. AB - Ethnic disparities in labor pain management exist. Our purpose is to identify patients' attitudes and beliefs about epidural analgesia in order to develop a culturally competent educational intervention. A prospective observational study was conducted in patients admitted for vaginal delivery between July 1st-31st, 2009. Inclusion criteria were: singleton, term, cephalic, normal fetal heart tracing and no contraindications for epidural. Patients were surveyed regarding their wishes for analgesia, and their reasons for declining epidural. The obstetrics physician performed pain management counseling as is usually done. Patients were asked again about their choice for analgesia. Likert scale questionnaires were used. Wilcoxon signed ranked test was used for categorical variables. Logistic regression was performed to look for predictors of epidural request. Fifty patients were interviewed. Average age was (27.9 +/- 6.7), gestational age (39.3 +/- 1.3), and a median parity of 2 (range 0-6). 72% declined epidural upon admission, and 61% after counseling (P = 0.14). Most common reasons for declined epidural were 'women should cope with labor pain' (57%), 'fear of back pain' (54%) and 'family/friends advise against epidural' (36%). Acculturation was assessed by years living in the US (10 +/- 6.3), preferred language (Spanish 80%) and ethnic self-identification (Hispanic 98%). 38% were high school graduates. In multivariate logistic regression, graduation from high school was the only variable associated to request for epidural in labor (OR 4.94, 95% CI 1.6-15.1). Educational level is associated to requesting an epidural in labor. Knowledge of patients' fears and expectations is essential to develop adequate counseling interventions. PMID- 21267657 TI - Toward a model-based predictive controller design in brain-computer interfaces. AB - A first step in designing a robust and optimal model-based predictive controller (MPC) for brain-computer interface (BCI) applications is presented in this article. An MPC has the potential to achieve improved BCI performance compared to the performance achieved by current ad hoc, nonmodel-based filter applications. The parameters in designing the controller were extracted as model-based features from motor imagery task-related human scalp electroencephalography. Although the parameters can be generated from any model-linear or non-linear, we here adopted a simple autoregressive model that has well-established applications in BCI task discriminations. It was shown that the parameters generated for the controller design can as well be used for motor imagery task discriminations with performance (with 8-23% task discrimination errors) comparable to the discrimination performance of the commonly used features such as frequency specific band powers and the AR model parameters directly used. An optimal MPC has significant implications for high performance BCI applications. PMID- 21267658 TI - The evil eye: a cautious look. AB - This article analyzes the superstition of the evil eye from a psychosocial perspective. The commonly employed antidotes to the evil eye are discussed. These include knock on wood, kenehora, and various other culturally prescribed protective measures. The sin of envy, the role of God, Scripture, and Satan are examined. The author concludes with a statement of his own way of dealing with the evil eye and its underlying essence. PMID- 21267659 TI - The doctor and the market: about the influence of market reforms on the professional medical ethics of surgeons and general practitioners in the Netherlands. AB - To explore whether market reforms in a health care system affect medical professional ethics of hospital-based specialists on the one hand and physicians in independent practices on the other. Qualitative interviews with 27 surgeons and 28 general practitioners in The Netherlands, held 2-3 years after a major overhaul of the Dutch health care system involving several market reforms. Surgeons now regularly advertise their work (while this was forbidden in the past) and pay more attention to patients with relatively minor afflictions, thus deviating from codes of ethics that oblige physicians to treat each other as brothers and to treat patients according to medical need. Dutch GPs have abandoned their traditional reticence and their fear of medicalization. They now seem to treat more in accordance with patients' preferences and less in accordance with medical need. Market reforms do affect medical professional principles, and it is doubtful whether these changes were intended when Dutch policy makers decided to introduce market elements in the health care system. Policy makers in other countries considering similar reforms should pay attention to these results. PMID- 21267660 TI - Deep hope: a song without words. AB - Hope helps alleviate suffering. In the case of terminal illness, recent experience in palliative medicine has taught physicians that hope is durable and often thrives even in the face of imminent death. In this article, I examine the perspectives of philosophers, theologians, psychologists, clinicians, neuroscientists, and poets, and provide a series of observations, connections, and gestures about hope, particularly about what I call "deep hope." I end with some proposals about how such hope can be sustained and enhanced at the end of life. Studies of terminally ill patients have revealed clusters of personal and situational factors associated with enhancement or suppression of hope at the end of life. Interpersonal connectedness, attainable goals, spiritual beliefs and practices, personal attributes of determination, courage, and serenity, lightheartedness, uplifting memories, and affirmation of personal worth enhance hope, while uncontrollable pain and discomfort, abandonment and isolation, and devaluation of personhood suppress hope. I suggest that most of these factors can be modulated by good medical care, utilizing basic interpersonal techniques that demonstrate kindness, humanity, and respect. PMID- 21267661 TI - Non-invasive bioluminescence imaging of myoblast-mediated hypoxia-inducible factor-1 alpha gene transfer. AB - PURPOSE: We tested a novel imaging strategy, in which both the survival of transplanted myoblasts and their therapeutic transgene expression, a recombinant hypoxia-inducible factor-1alpha (HIF-1alpha-VP2), can be monitored using firefly luciferase (fluc) and Renilla luciferase (hrl) bioluminescence reporter genes, respectively. PROCEDURES: The plasmid pUbi-hrl-pUbi-HIF-1alpha-VP2, which expresses both hrl and HIF-1alpha-VP2 using two ubiquitin promoters, was characterized in vitro. C2c12 myoblasts stably expressing fluc and transiently transfected with pUbi-hrl-pUbi-HIF-1alpha-VP2 were injected into the mouse hindlimb. Both hrl and fluc expression were monitored using bioluminescence imaging (BLI). RESULTS: Strong correlations existed between the expression of hRL and each of HIF-1alpha-VP2, VEGF, and PlGF (r(2) > 0.83, r(2) > 0.82, and r(2) > 0.97, respectively). In vivo, both transplanted cells and HIF-1alpha-VP2 transgene expression were successfully imaged using BLI. CONCLUSIONS: An objective evaluation of myoblast-mediated gene transfer in living mice can be performed by monitoring both the survival and the transgene expression of transplanted myoblasts using the techniques developed herein. PMID- 21267662 TI - Fully automated preparation and conjugation of N-succinimidyl 4 [18F]fluorobenzoate ([18F]SFB) with RGD peptide using a GE FASTlabTM synthesizer. AB - PURPOSE: The aim of this work was to automate the radiosynthesis of [(18)F]SFB, a widely used reagent for the labeling of biomolecules with (18)F on a new generation commercial synthesis module (FASTLabTM, GE Healthcare). PROCEDURES: Two synthesis approaches were implemented on this module: the classical "two-pot radiosynthesis" and the more recently described "one-pot" method. RESULTS: The "two-pot" approach affords [(18)F]SFB with a 42% decay-corrected yield in 57 min (n = 24) with a chemical purity sufficient to avoid an intermediate HPLC purification. The recently established "one-pot" method, afforded a product with a lower chemical purity, in the conditions used in this report. The lower d.c. yield obtained (32% (n = 15)) was related to the low (18)F labeling yields obtained in MeCN compared with DMSO. The subsequent conjugation step with a RGD (PRGD2) peptide was also successfully automated. CONCLUSIONS: The formulated [(18)F]FPRGD2 was obtained without any operator manipulation with a d.c. yield of 13% +/- 3% (n = 13) in 130 min, a radiochemical purity >98% and a specific activity of 140 +/- 40 TBq/mmol. PMID- 21267663 TI - Correlation of clinical profiles with obstructive sleep apnea and metabolic syndrome. AB - BACKGROUND: Obstructive sleep apnea (OSA) is a common condition being increasingly recognized and is associated with many diseases. Few data are available for Indian patients and public health hazard of the condition continues to be seriously underestimated in this country. The objective of this study was to evaluate the prevalence of obesity, hypertension, diabetes mellitus, and hyperlipidemia (HLP) in a South Indian population with proven OSA. METHODS: A retrospective analysis of data accrued in patients undergoing polysomnography (PSG) was undertaken. Two hundred thirty-four patients of either sex in the age of 54 +/- 11 years who tested positive for OSA were compared with control group. An apnea-hypopnea index (AHI) of >5 in the presence of snoring and daytime somnolence was taken to define sleep apnea. RESULTS: The mean AHI among the study group with OSA was 31.3 +/- 18.6 as compared with 1.2 +/- 0.5 in the control group. The BMI among patients with OSA was 36 +/- 6 as compared with 29 +/- 4 in comparison group (p < 0.001). Among the patients with OSA, 31% were having HLP, 59% were diabetics, and 86% were hypertensive. Subjects with PSG-proven OSA had significant levels of day time sleepiness, lack of concentration, changes in mood, morning headache, and dry mouth. Nonrestorative sleep, awakening with choking, nocturnal dyspnea, insomnia with frequent awakenings, nocturia, and diaphoresis were observed in (>80%) patients. A significant difference in the sleep efficiency (16%), sleep onset (14%), and mean saturation (9%) was observed in the study group as compared to the control group. CONCLUSIONS: The risk of obesity, hypertension, diabetes mellitus, and HLP in OSA syndrome patients was almost three times more than that of the comparing group. PMID- 21267664 TI - Total antioxidant status in patients with obstructive sleep apnea without comorbidities: the role of the severity of the disease. AB - OBJECTIVE: Several studies suggest that obstructive sleep apnea syndrome (OSAS) is associated with oxidative stress. However, there are also contrary observations and the role of antioxidant mechanisms has not been fully explored. PATIENTS AND METHODS: The present study evaluated serum total antioxidant status (TAS) in 32 OSAS patients without comorbidities, before and after a diagnostic sleep study and at a second sleep study after continuous positive airway pressure (CPAP) application. RESULTS: Lower TAS values were found in the morning, immediately after the first sleep study, compared with those before sleep (1.68 +/- 0.11 vs. 1.61 +/- 0.10 mmol/l, p < 0.01); this was evident in patients with less severe syndrome [apnea-hypopnea index (AHI) <30; 1.73 +/- 0.08 vs. 1.65 +/- 0.09 mmol/l, p = 0.01] but not in severe syndrome (AHI >=30; 1.64 +/- 0.12 vs. 1.58 +/- 0.10 mmol/l, p = 0.07). After CPAP application, a statistically significant decrease in TAS values was observed in patients with less severe syndrome (1.72 +/- 0.05 vs. 1.63 +/- 0.04 mmol/l, p = 0.003). On the contrary, no statistically significant changes in TAS were observed in patients with severe syndrome. CONCLUSIONS: The present study supports a reduction in antioxidant capacity during sleep in otherwise healthy patients with OSAS. This reduction was evident in less severe syndrome. However, a single night of CPAP application seems to ameliorate this antioxidant disturbance only in less severe syndrome. PMID- 21267665 TI - Appendix A: Additional peer-reviewed CAACP publications. PMID- 21267666 TI - Quasi real-time gait event detection using shank-attached gyroscopes. AB - This article describes an ambulatory gait event detection method for long-term monitoring of walking. Aminian et al. [2] have developed an automatic gait event detection algorithm based on shank-attached gyroscope signals. However, this algorithm has a drawback in that it is post-processed. We propose a modified algorithm which detects foot initial and end contact timings using the same concept as in [2], but in quasi real-time. The utilization of the knowledge on gait sequence and peak angular acceleration realizes the quasi real-time detection. Furthermore, to be practical, the algorithm has been developed to ensure the robustness of detection (i.e., without missing the gait events in various speed conditions). Validation of the algorithm using footswitches shows that the algorithm detected the end contacts earlier (-8 ms) and the initial contacts later (19 ms) than the footswitch-based method. PMID- 21267667 TI - Identification and expression of amphioxus AmphiSmad1/5/8 and AmphiSmad4. AB - Smad family proteins are identified as intracellular signal mediators of the TGF beta superfamily. In this study, we identified two novel members of the Smad family, termed as AmphiSmad1/5/8 and AmphiSmad4, from Chinese amphioxus. Both AmphiSmad1/5/8 and AmphiSmad4 showed a typical domain structure of Smad proteins consisting of conserved MH1 and MH2 domains. Phylogenetic analysis placed AmphiSmad1/5/8 in the Smad1, 5 and 8 subgroup of the R-Smad subfamily, and AmphiSmad4 in the Co-Smad subfamily. The spatial and temporal gene expression patterns of AmphiSmad1/5/8 and AmphiSmad4 showed that they may be involved in the embryonic development of notochord, myotome and alimentary canal, and may help to establish the specification of dorsal-ventral axis of amphioxus. Moreover, AmphiSmad1/5/8 and AmphiSmad4 showed extensive distribution in all adult tissues examined, suggesting that these two genes may play important roles in the morphogenesis of a variety of tissues especially notochord and gonad. PMID- 21267668 TI - Genes and regulatory networks involved in persistence of Mycobacterium tuberculosis. AB - The causative agent of tuberculosis, Mycobacterium tuberculosis, is one of the most successful of human pathogens. It can evade the host immune response and establish a persistent infection or enter a dormant state within the host which can be reactivated if the host becomes immuno-compromised. Both of these features are major obstacles to tuberculosis eradication. Dormancy and reactivation of M. tuberculosis are tightly coordinated dynamic processes involving numerous genes and their products. Molecular mechanisms underlying M. tuberculosis persistence may provide an opportunity for the discovery of effective drug targets for tuberculosis control. Here, we review the genes required for M. tuberculosis persistence and propose a regulatory network for the action of these genes using text mining. This should provide fresh insights into the persistence mechanisms of M. tuberculosis and suggest candidates for new drug targets and immune intervention. PMID- 21267669 TI - Hepatitis B--more treatments, more testing, not enough data. PMID- 21267670 TI - Systematic review of delayed postoperative hemorrhage after pancreatic resection. AB - INTRODUCTION: This review assesses the presentation, management, and outcome of delayed postpancreatectomy hemorrhage (PPH) and suggests a novel algorithm as possible standard of care. METHODS: An electronic search of Medline and Embase databases from January 1990 to February 2010 was undertaken. A random-effect meta analysis for success rate and mortality of laparotomy vs. interventional radiology after delayed PPH was performed. RESULTS: Fifteen studies comprising of 248 patients with delayed PPH were included. Its incidence was of 3.3%. A sentinel bleed heralding a delayed PPH was observed in 45% of cases. Pancreatic leaks or intraabdominal abscesses were found in 62%. Interventional radiology was attempted in 41%, and laparotomy was undertaken in 49%. On meta-analysis comparing laparotomy vs. interventional radiology, no significant difference could be found in terms of complete hemostasis (76% vs. 80%; P = 0.35). A statistically significant difference favored interventional radiology vs. laparotomy in term of mortality (22% vs. 47%; P = 0.02). CONCLUSIONS: Proper management of postoperative complications, such as pancreatic leak and intraabdominal abscess, minimizes the risk of delayed PPH. Sentinel bleeding needs to be thoroughly investigated. If a pseudoaneurysm is detected, it has to be treated by interventional angiography, in order to prevent a further delayed PPH. Early angiography and embolization or stenting is safe and should be the procedure of choice. Surgery remains a therapeutic option if no interventional radiology is available, or patients cannot be resuscitated for an interventional treatment. PMID- 21267671 TI - Effect of copper on the expression of TGF-beta in incubated chondrocytes of newborn pigs. AB - This experiment was conducted to measure the effect of copper supplementation on TGF-beta gene expression in chondrocytes of newborn pigs. Chondrocytes were cultured in media containing 15% fetal calf serum supplemented with 0, 15.6, 31.2, and 62.5 MUmol/L copper in 90-mm culture plate. Total RNA was isolated from chondrocytes, and TGF-beta cDNA was synthesized, amplified, and sequenced. The expression level of TGF-beta was examined by reverse transcription polymerase chain reaction. The results showed that the sequence of the cloned TGF-beta gene was 99.4% identical to that in GenBank. The expression of TGF-beta increased in culture media added with final concentration of 15.6, 31.2, and 62.5 MUmol/L copper. In this study, the optimal copper concentration and optimal culture time for the highest level of TGF-beta expression were 31.2 MUmol/L and 48 h, respectively. PMID- 21267672 TI - Distribution of calcium, iron, copper, and zinc in two portions of placenta of teenager and adult women. AB - The placenta is fundamental for fetal development. The aim of this study was to determine Ca, Fe, Cu, and Zn content in the fetal and maternal portions of the placentas of teenage and adult women. Measurement of the minerals was conducted using Synchrotron radiation total reflection X-ray fluorescence. Forty samples from the fetal portion of teenagers and adults and 40 samples from the maternal portion of teenagers and adults were analyzed. There were significant differences in the Ca and Cu concentrations of the placenta's maternal portion when compared to the fetal portion, for both teenagers and adults. There were differences in Fe and Zn concentrations only when comparing the maternal portion of placenta with the fetal portion of the adults. These results suggest important differences in mineral content based on the placental portion. No significant difference was observed between the minerals studied of the maternal portion of teenagers and adults; however, in the fetal portion, mineral concentrations were greater in adults than in teenagers. Therefore, the mineral concentration of the fetal portion of the placenta is influenced by the mother's age. If there is mineral's competition between the mother and fetus during pregnancy in adolescence due to the importance of these minerals in growth and development, then the mechanism and reason for it should be elucidated in future research. In addition, we believe that further research should be carried out on transporters of these minerals in the same portions of the placentas analyzed by our group, in teenagers and adults. PMID- 21267673 TI - Is critical illness neuromyopathy and duration of mechanical ventilation decreased by strict glucose control? AB - Strict glycemic control (SGC) is reported to have a beneficial effect on critical illness polyneuropathy/myopathy (CINM) and the duration of mechanical ventilation. The methodology used to diagnose CINM differs substantially in studies on this topic. This may influence the reported treatment effect. We reviewed literature on the effect of SGC on CINM and duration of ventilation by conducting a OVID Medline systematic electronic search of literature describing effects of SGC on occurrence of CINM and the effect of SGC on the duration of mechanical ventilation. A beneficial effect of SGC on CINM, diagnosed by needle myography, was reported in three studies. One of these studies showed that the incidence of weakness or failure to wean did not decrease by SGC, as the number of electrophysiological studies (EMG) ordered for these problems remained the same. Another study reported no improvement of muscle strength due to SGC. SGC reduced the duration of mechanical ventilation in three studies while six other studies did not report this beneficial effect. SGC seems to have a beneficial effect on CINM, but the reported risk reduction is likely to be an overestimation of the treatment effect due to the diagnostic methods used. Duration of mechanical ventilation may not be a reliable surrogate marker for CINM and a beneficial effect of SGC on this parameter has not been proven. We propose to use the recently developed diagnostic criteria for ICU-acquired weakness and critical illness neuromyopathy in future studies. PMID- 21267674 TI - Cardiac stunning as a manifestation of ATRA differentiation syndrome in acute promyelocytic leukemia. PMID- 21267675 TI - miR-153 sensitized the K562 cells to As2O3-induced apoptosis. AB - Relapse remains the biggest hurdle of leukemia therapy, while elucidating the molecular mechanism holds promise for the solution. Recently, microRNAs are emerging as an important regulator of cell function. In this study, we for the first time found that miR-153 was downregulated in As2O3-induced drug-resistant K562 cells. In the CD34+ K562 subpopulation, which is characteristic of leukemia stem cell and resembles the drug-resistant subgroup, miR-153 expression level was also much lower than that in the bulk. Forced expression of miR-153 only in K562 cells has no significant effects on cell growth and apoptosis. However, when cells were additionally treated with As2O3, significant greater apoptosis was observed in the miR-153 overexpressed group. Our data here suggest that strategies increasing the endogenous miR-153 might hold promise for an alternative adjuvant therapy of leukemia. PMID- 21267676 TI - Down-regulation of vascular endothelial growth factor expression by anti-Her2/neu single chain antibodies. AB - HER-2/neu is overexpressed in 25-30% of breast tumors. Signaling through HER 2/neu leads to an increase in the production of vascular endothelial growth factor (VEGF) and enhances angiogenesis. We evaluated the effects of three specific anti-HER2/neu single chain-Fv (scFv) antibodies on the expression level of VEGF in HER2/neu-expressing breast cancer cell lines. A nonimmunized human scFv library was panned against three epitopes of HER2/neu. BT-474 human breast cancer cell line was treated with three specific anti-HER2/neu scFv antibodies and the amount of VEGF gene transcript was determined by quantitative real-time PCR. The expression of VEGF protein was analyzed by western blot. All three scFv antibodies along with their combination inhibited VEGF expression at both the gene and protein levels. Our results show that anti-HER2/neu recombinant antibodies can be considered as anti-angiogenic agents in HER2/neu-positive breast cancers. PMID- 21267677 TI - Nicotine inhibits cisplatin-induced apoptosis in NCI-H446 cells. AB - Nicotine is not only a major component in tobacco but is also a survival agonist that inhibits apoptosis induced by certain agents including chemotherapeutic drugs. Here, we first showed that nicotine inhibits cisplatin-induced apoptosis in NCI-H446 cells. An MTT assay, Annexin V-FITC staining, RT-PCR, and Western blot were applied to identify the viability of cells, stages of apoptosis, mRNA and signaling proteins expression, respectively. First, we observed that nicotine induced no significant apoptosis when used alone and promoted cell proliferation at a low concentration or for a short time, but the opposite was observed at a high concentration or for a long time. In addition, an increase in XIAP and Survivin mRNA or protein was observed. Next, when combined with cisplatin, growth inhibition rates were concentration dependent, decreased to the lowest level at first, but later climbed to the highest point. Furthermore, nicotine inhibited apoptosis induced by cisplatin and caused a concentration-dependent increase in both XIAP and Survivin mRNA or protein. Moreover, the apoptotic effect of the combination group was obviously higher than that of nicotine used alone at the same nicotine concentration and lower than that of cisplatin used alone at the same cisplatin concentration. These studies suggest that exposure to nicotine might negatively impact the apoptotic potential of chemotherapeutics. PMID- 21267678 TI - Catastrophizing and pain in military personnel. AB - Combat-related injuries have been well documented for centuries. More recently, injuries suffered by US service members in Iraq and Afghanistan have resulted in a high number of survivable conditions. Polytrauma care in this setting must take into account both the physical and psychological injuries suffered by returning wounded warriors. Catastrophizing may occur when previously healthy individuals are faced with impairment and disfigurement. This is compounded with repeated operative procedures. Early detection and treatment of catastrophizing contributes to improved care of the wounded warrior. This article describes our experiences at Walter Reed Army Medical Center with catastrophizing in US service members returning from the current military operations in Iraq and Afghanistan. PMID- 21267679 TI - Concerns over participant suicides prematurely abort a clinical trial of potentially significant impact on public health: how will we make progress in timid times? PMID- 21267680 TI - Television viewing and its impact on childhood behaviors. AB - Despite the emergence of new media technologies, television remains the most widely used screen media format. Unfortunately, concerns have arisen about its effects on the health and well-being of children and adolescents. This article reviews television usage trends and television's impact on sleep, attention, and interpersonal relationships. American Academy of Pediatrics recommendations on television use are also discussed. Many studies on television viewing have cross sectional designs, and longitudinal research is limited. However, research to date suggests that excessive television viewing is associated with negative effects on sleep, attention, and interpersonal relationships. As use of different media formats escalates, research across multiple specialties (including child psychiatry) will need to incorporate evaluation of media use into its assessments. More research and education are needed on the appropriate use of media in youth. Information on the health effects of television may also increase awareness of potential issues with less well-studied media formats. PMID- 21267681 TI - Approach to smoking cessation in the patient with vascular disease. AB - OPINION STATEMENT: In the patient with vascular disease, cigarette smoking is particularly perilous; the benefits of smoking cessation greatly exceed any risks associated with pharmacologic treatment. The patient with claudication is often uniquely motivated to quit smoking because 1) there is a chance that the leg pain will improve and 2) smoking cessation may prevent disease progression and thus invasive procedures. The first step toward success is a systematic approach with focus on the 5 A's (Ask, Advise, Assess, Assist, and Arrange). Multiple clinical trials have demonstrated the efficacy of pharmacologic therapy for smoking cessation. The most effective medications available are bupropion and varenicline. If the patient is ready to quit, varenicline is typically first-line unless contraindicated. If the patient has concomitant signs or symptoms of depression, bupropion in combination with nicotine replacement therapy is preferred. In parallel with aggressive counseling and pharmacotherapy for smoking cessation, cardiovascular risk reduction is critical. Established atherosclerotic vascular disease (including peripheral artery disease, abdominal aortic aneurysm, or carotid artery disease) plus poorly controlled risk factors, including current smoking, place the patient in the "very high-risk" category, which favors reducing the low-density lipoprotein level to less than 70 mg/dL. The increased cardiovascular risk associated with smoking is tremendous, particularly in the vascular patient. Smoking cessation is critical, and no other health intervention offers such a large potential benefit. PMID- 21267682 TI - The role of radiation in the perioperative treatment of esophagogastric cancer. AB - Cancers of the esophagus, stomach, and the esophagogastric junction (EGJ) remain a global health problem. There has been a dramatic increase in the incidence of adenocarcinoma of the distal esophagus and EGJ in the past two decades with little change in the poor prognosis associated with these cancers. Previously surgery alone was the mainstay of therapeutic intervention, but high rates of local and systemic failure have prompted investigation into neoadjuvant and adjuvant therapy. Treatment paradigms differ across continents, but the unifying theme that has emerged in the past decade implies that surgery alone can no longer be considered the standard of care. The multi-disciplinary management of patients with locally advanced esophagogastric carcinomas using trimodality therapy with radiotherapy, chemotherapy, and surgery confers the greatest opportunity for margin negative resection, improved loco-regional control and cure, and should be the accepted treatment paradigm. The traditional backbone of platinum plus fluorouracil concurrent with radiotherapy may be supplanted by more modern, easier-to-administer regimens incorporating taxanes and irinotecan. The current generation of clinical trials in this heterogeneous group of diseases is examining targeted therapy, newer methods of radiotherapy, and predictors of response to therapy aiming to tailor management to an individual patient. PMID- 21267683 TI - How affordable are targeted therapies in non-small cell lung cancer? AB - As the treatment of non-small cell lung cancer (NSCLC) evolves to include more targeted therapies, costs of treatment have increased significantly. Advances in NSCLC treatment include longer survival duration, and in some cases, better progression-free survival and quality of life, and the potential for decreased toxicity. Through pharmacoeconomic analyses, payors seek to value the improvements in outcomes from novel therapies, and relate these improvements to their costs. In NSCLC, three categories of novel agents have been introduced into clinical practice: (1) agents targeting the epidermal growth factor receptor (EGFR); (2) agents targeting the vascular endothelial growth factor (VEGF) and (3) novel chemotherapy agents, specifically pemetrexed. Here we review published economic analyses for these agents in lung cancer, and their potential impact on treatment decisions. PMID- 21267684 TI - A novel injection-molded capsular device for oral pulsatile delivery based on swellable/erodible polymers. AB - The feasibility of injection molding was explored in the preparation of a novel capsular device for oral pulsatile/delayed delivery based on swellable/erodible polymers. For this purpose, a mold intended to be coupled with a bench-top injection-molding press was designed. This was expected to enable the preparation of matching capsule cap and body items within a single manufacturing cycle and the selection of differing shell thicknesses (300, 600, and 900 MUm). Hydroxypropylcellulose (Klucel((r)) EF, LF, and GF) was employed as the release controlling polymer in admixture with polyethylene glycol 1500 (10%, w/w) as the plasticizer. After preliminary trials aimed at the setup of operating conditions, Klucel((r)) EF and LF capsule shells with satisfactory technological properties were manufactured. The performance of capsular devices filled with a tracer drug powder was studied by means of a modified USP31 disintegration apparatus. Typical in vitro delayed release patterns were thereby obtained, with lag time increasing as a function of the wall thickness. A good correlation was found between the latter parameter and t (10%), i.e., the time to 10% release, for both polymer grades employed. On the basis of the overall results, the investigated technique was proven suitable for the manufacturing of an innovative pulsatile release platform. PMID- 21267685 TI - Estrogen receptor negative and progesterone receptor positive breast carcinomas how frequent are they? AB - Estrogen receptor (ER) testing has become an important part of breast cancer reporting as the ER status is a predictor of hormonal treatment efficacy. Progesteron receptors (PR) are often tested in parallel, and the best response to hormonal manipulations can be expected in tumors positive for both receptors. The existence of breast cancers with an ER negative and PR positive phenotype is controversial. A series of cases with this phenotype were reevaluated to clarify the existence and the frequency of this entity. A total of 205/6587 (3.1%; range of the rate per department: 0.3-7.1%.) cases reported to have the ER-negative and PR-positive status by immunohistochemistry were collected from 9 Hungarian departments. After careful reevaluation of the tumor slides and control tissues with a 1% cut-off for positivity and restaining of the questionable cases, all but 1 of the reevaluable 182 cases changed their original phenotype. Most cases converted to dual positives (n = 124) or dual negatives (n = 31) or unassessable / questionable. ER-negative and PR-positive breast cancers are very rare if existing. Such a phenotype should prompt reassessment. PMID- 21267686 TI - Expression of 11beta-hydroxysteroid dehydrogenase type 1 in breast cancer and adjacent non-malignant tissue. An immunocytochemical study. AB - Intratumoral biosynthesis of hormone steroids is thought to play a role in the pathogenesis and development of human breast cancer. There is evidence that glucocorticoids may inhibit the development and progression of breast cancer. 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1 is the enzyme which converts inactive cortisone to active cortisol. In order to study the expression of 11beta-HSD type 1 in breast cancer and non-cancerous breast tissue, we have developed specific antibodies to 11beta-HSD type 1 and proceeded to localization of the enzyme in 84 specimens of breast carcinoma and adjacent non-malignant tissues by immnohistochemistry. The results were correlated with the expression of androgen receptor, estrogen receptor, progesterone receptor, glucocorticoid receptor and CDC47, a cell division marker, as well as the tumor stage, tumor size, nodal status and menopausal status. The expression of 11beta-HSD type 1 in 64% of breast cancer specimens appeared significantly lower than that observed in normal adjacent tissues (97% of cases being positive). There was no significant correlation between 11beta-HSD type 1 expression and the clinicopathological parameters studied. The decrease in 11beta-HSD type 1 expression in breast cancer as compared to that observed in the adjacent normal tissues may play a role in the development and/or progression of the cancer by modifying the intratumoral levels of glucocorticoids. PMID- 21267687 TI - The evaluation of CD99 immunoreactivity and EWS/FLI1 translocation by fluorescence in situ hybridization in central PNETs and Ewing's sarcoma family of tumors. AB - Ewing's sarcoma family of tumors (ESFTs) are indicated by malignant, small, round and blue cell tumors of the bone and soft tissue. Gene rearrangements between EWS gene on chromosome 22q12 and members of the ETS gene family are common in and specific to ESFTs. Another defining characteristic of ESFTs is their membranous expression of the CD99. In contrast, such translocations and immunoreactivity are not found in central primitive neuroectodermal tumors (cPNETs). The aim of this study was to investigate the detection of EWS/FLI1 translocations and CD99 immunoreactivity in order to evaluate their clinicopathological features and their roles in the differential diagnosis of these tumors. In this study, we investigated CD99 immunoreactivity using immunohistochemistry and Ewing's sarcoma / Friend leukaemia virus integration 1 (EWS/FLI1) translocation using the fluorescence in situ hybridization (FISH) method in 23 cases. CD99 expression was detected in 10/11 (90%) ESFT cases and 2/7 cPNET cases. In 18 cases EWS/FLI1 translocation was examined using the FISH method. The EWS/FLI1 translocations were detected in 7/8 (87.5%) ESFTs cases, whereas non of 8 cPNET cases were detected with this translocation. One case could not be classified as either central or peripheral, showed EWS/FLI1 translocation. There was a statistically significant difference in CD99 expression (p = 0.0013) and EWS/FLI1 translocation (p = 0,002) between cPNETs and ESFTs cases. In conclusion, CD99 expression and EWS/FLI1 translocation are specific and sensitive markers in the diagnosis of ESFTs. However, these were often not found in cases of cPNET. Therefore, in the diagnosis of ESFTs, clinical, radiological, histopathological and immunohistochemical parameters should always be evaluated together. PMID- 21267688 TI - The influence of methylated septin 9 gene on RNA and protein level in colorectal cancer. AB - Colorectal cancer is one of the leading death causes in the world. Specificity and sensitivity of the present screening methods are unsuitable and their compliance is too low. Nowadays the most effective method is the colonoscopy, because it gives not only macroscopic diagnosis but therapeutic possibility as well, however the compliance of the patients is very low. Hence development of new diagnostic methods is needed. Altered expression of septin 9 was found in several tumor types including colorectal cancer. The aim of this study was to detect the methylation related mRNA and protein expression changes of septin 9 in colorectal adenoma-dysplasia-carcinoma sequence and to analyze its reversibility by demethylation treatment. Septin 9 protein expression showed significant difference between normal and colorectal cancer (CRC) samples (p < 0,001). According to biopsy microarray results, septin 9 mRNA expression decreased in the progression of colon neoplastic disease (p < 0,001). In laser microdissected epithelial cells, septin 9 significantly underexpressed in CRC compared to healthy controls (p < 0,001). The expression of septin9_v1 region was higher in the healthy samples, while septin9_v2, v4, v4*, v5 overexpression were detected in cancer epithelial cells compared to normal. The septin 9 mRNA and protein levels of HT29 cells increased after demethylation treatment. The increasing methylation of septin 9 gene during colorectal adenoma-dysplasia-carcinoma sequence progression is reflected in the decreasing mRNA and protein expression, especially in the epithelium. These changes can be reversed by demethylation agents converting this screening marker gene into therapeutic target. PMID- 21267689 TI - The beginning of the calcium transient in rat embryonic heart. AB - Although many researchers have tried to observe the beginning of the heartbeat, no study has shown the beginning of the calcium transient. Here, we evaluate the beginning of the calcium transient in the Wistar rat heart. We first tried to reveal when the heart of the Wistar rat begins to contract because no previous study has evaluated the beginning of the heartbeat in Wistar rats. Observation of embryos transferred to a small incubator mounted on a microscope revealed that the heart primordium, the so-called cardiac crescent, began to contract at embryonic day 9.99-10.13. Observation of embryos loaded with fluo-3 AM revealed that the beginning of the calcium transient precedes the initiation of contraction which precedes the appearance of the linear heart tube. Nifedipine (1 MUM), but not ryanodine (1 MUM), abolished the calcium transients. These results indicate that calcium transients in the early embryonic period involve exclusively calcium entry through L-type calcium channels in contrast to the situation in mature hearts. This study provides the first demonstration of the relationship between morphological changes in the heart primordium and the beginning of the calcium transient and contraction. PMID- 21267691 TI - Single access cholecystectomy using standard laparoscopic instruments. AB - The aim of this study was to verify feasibility and safety of single incision laparoscopic cholecystectomy using conventional surgical instruments. Twenty patients underwent single incision laparoscopic cholecystectomy. Indications for cholecystectomy were symptomatic cholelithiasis. Operative time, postoperative length of stay, intraoperative and postoperative complications, postoperative pain (by visual analogue scale), and patient cosmetic satisfaction were considered. All 20 procedures were successfully concluded without additional skin incisions. The mean operative time was 69 +/- 16 min with a trend toward a reduction in operating time with increasing surgical experience. Intraoperative bile leakages for gallbladder rupture were observed in only three cases. No postoperative complications were recorded. The median pain scale value was 3 and the median value of cosmetic satisfaction was 3. The mean postoperative length of stay was 1.3 +/- 0.9 days. Single incision laparoscopic cholecystectomy with conventional surgical instruments is a feasible and safe procedure, but additional studies in larger series are needed to confirm our results. PMID- 21267690 TI - Patients with Helicobacter pylori infection have less severe gastroesophageal reflux disease: a study using endoscopy, 24-hour gastric and esophageal pH metry. AB - BACKGROUND AND AIM: The relationship between gastroesophageal reflux disease (GERD) and Helicobacter pylori is controversial. We evaluated endoscopic, 24-h gastric and esophageal acid profile among patients with GERD in relation to H. pylori, as the latter might alter gastric acid secretion. METHODS: Patients with GERD (n = 123), who were not on acid-suppressive drugs, and had not received anti H. pylori therapy, underwent gastroduodenoscopy and tests for H. pylori detection. Esophageal manometry, 24-h pH metry, serum pepsinogen-I (PG-I), PG-II and gastrin-17 ELISA were done in all these patients. Univariate and multivariate analyses were performed to assess independent predictors for erosive esophagitis (EE). RESULTS: Of 123 patients (mean age 40.5 [13.1] years, 85 [69.1%] men), 59 (47.9%) had H. pylori infection. EE was more common in H. pylori non-infected than infected (49 vs. 32, p < 0.001). Among patients older than 40 years, absence of H. pylori was associated with lower esophageal pH and longer reflux (p = 0.02 and p < 0.001, respectively). PG-I/PG-II ratio was lower in H. pylori infected subjects (p < 0.001). In patients with higher LA grade of esophagitis, elevated PG-I levels and PG-I/PG-II ratio were associated with more acidic stomach (p = 0.04 and p = 0.01, respectively). Multivariate analyses showed low gastrin-17 (p = 0.016), higher age (p = 0.013), hiatus hernia (p = 0.004) and absence of H. pylori (p = 0.03) were independent predictors for risk of EE. CONCLUSION: H. pylori infection is associated with less acidic stomach and less severe GERD. Low gastrin-17, higher age, hiatus hernia and absence of H. pylori were the best predictors for EE risk. PMID- 21267692 TI - Giant esophageal lipoma. AB - A case of a giant esophageal pedunculated lipoma diagnosed in a 67-year-old male patient with recent onset of dysphagia is reported. Following the initial endoscopic and radiologic evaluation, the diagnosis was suspected by endo ultrasonography and confirmed by histopathology. The treatment consisted of an esophagotomy with submucosal resection, through a left sided cervical incision. The review of the literature confirmed the rarity of this neoplasm, and the difficulty of a correct preoperative diagnosis, since a possible progression to squamous carcinoma has been demonstrated. PMID- 21267693 TI - Interactions of numerical and temporal stimulus characteristics on the control of response location by brief flashes of light. AB - Pigeons pecked on three keys, responses to one of which could be reinforced after 3 flashes of the houselight, to a second key after 6, and to a third key after 12. The flashes were arranged according to variable-interval schedules. Response allocation among the keys was a function of the number of flashes. When flashes were omitted, transitions occurred very late. Increasing flash duration produced a leftward shift in the transitions along a number axis. Increasing reinforcement probability produced a leftward shift, and decreasing reinforcement probability produced a rightward shift. Intermixing different flash rates within sessions separated allocations: Faster flash rates shifted the functions sooner in real time, but later in terms of flash count, and conversely for slower flash rates. A model of control by fading memories of number and time was proposed. PMID- 21267694 TI - Mechanisms of estrogen receptor-alpha upregulation in breast cancers. AB - The most critical step for initiation and progression of estrogen receptor-alpha (ERalpha)-positive breast cancers is thought to be upregulation of ERalpha expression. There are several factors involved in this mechanism, i.e., increased promoter activity of the ERalpha gene (ESR1) at the transcriptional level, ESR1 gene amplification, and diminished degradation of ERalpha protein through ubiquitination and proteasomal pathways. Mediating these factors, ERalpha protein levels seem to be controlled, although the details of the mechanism remain to be clarified. In addition, for upregulation of estrogen signaling, functional changes in its action in cancer cells originating from normal epithelial cells, i.e., estrogen stimulation, which then leads to proliferation of ERalpha-positive cancer cells, has been recognized, but this action has not been observed in normal epithelial cells. These alterations are therefore likely to contribute to the pathogenesis of ERalpha-positive breast cancers. PMID- 21267695 TI - Immunohistochemical analysis of 17beta-hydroxysteroid dehydrogenase isozymes in human ovarian surface epithelium and epithelial ovarian carcinoma. AB - Epidemiological studies have indicated a relationship between gonadal steroid hormones, primarily estrogens, and epithelial ovarian carcinoma. In situ estrogen metabolism and synthesis have been considered to play important roles in the development of the progression of epithelial ovarian carcinoma. 17beta Hydroxysteroid dehydrogenases (17beta-HSDs) are a group of intracellular isozymes catalyzing interconversions between estradiol (E2) and estrone (E1). In the last step of steroidogenesis, 17beta-HSD type 1 catalyzes the 17beta-reduction and produces E2 from E1. The oxidative enzymes known as types 2, 4, and 8 are potent estrogen-inactivating enzymes that convert E2 to E1. Here we report the immunoexpression of 17beta-HSD types 1, 2, 4, and 8 in normal human ovarian surface epithelium (OSE) and epithelial ovarian carcinoma. For this study, novel polyclonal antibodies were generated against each type of 17beta-HSD. Of the six normal OSE cases investigated, 17beta-HSD types 1, 4, and 8, but not type 2, were found in the cytoplasm of epithelial cells. In 58 cases of epithelial ovarian carcinoma (45 serous, 4 endometrioid, 4 mucinous, and 5 clear cell), estrogen inactivating 17beta-HSDs were commonly found (type 2, 84.5%; type 4, 82.8%; type 8, 86.2%), whereas type 1 was detected in only 10 cases (17.2%). These results indicate that 17beta-HSDs may be involved in the protective and/or suppressive effects against the estrogen-dependent proliferation of epithelial ovarian carcinoma. PMID- 21267696 TI - Nicotine induces upregulated expression of beta defensin-2 via the p38MAPK pathway in the HaCaT human keratinocyte cell line. AB - Human beta-defensins (hBDs), a group of antimicrobial peptides, are involved in the protective barrier of the oral epithelium. Nicotine induces periodontal and oral epithelial diseases. The purpose of the present study was to investigate the effect of nicotine on the expression pattern of hBD-2 in keratinocytes. HaCaT cells, a keratinocyte cell line, were incubated with 8, 15, 30, or 80 MUM nicotine for 24 h. Expression of hBD-2 was observed by RT-PCR, qRTPCR, and ELISA assay. The cells were treated with inhibitors for intracellular pathways (p38MAP kinase, NF-kappaB, JNK, MAPK-ERK) and with nicotinic acetylcholine receptor (nAChR) inhibitors in a series of experiments. Data were analyzed using Student's t test. qRT-PCR revealed that the expression level of hBD-2 mRNA was significantly higher at 30 and 80 MUM nicotine than the control without nicotine (P < 0.05). The 80 MUM cell extraction contained significantly higher hBD-2 peptide levels than the control (P < 0.05). The p38MAP kinase inhibitor abolished the upregulated expression of hBD-2 by nicotine. Both nAChR inhibitors also abolished the upregulation of hBD-2 by nicotine. The present study demonstrated that nicotine causes upregulated expression of hBD-2 via the p38MAP kinase pathway in keratinocytes. PMID- 21267697 TI - Morphological and cytoskeletal changes of pancreatic cancer cells in three dimensional spheroidal culture. AB - Three-dimensional (3D) cell cultures are expected to mimic in vivo environments. We used a NanoCulture plate to determine the spheroid-forming ability of pancreatic ductal adenocarcinoma (PDAC) cell lines and compared the morphology and expression of cytoskeletal proteins of PDAC cells to those in two-dimensional (2D) cultures. All examined PDAC cells grew as monolayers in 2D culture. PANC-1 and KLM-1 formed spheroids in 3D culture, but PK-45H and MIAPaCa-2 did not. Strong expression of F-actin was observed in the cells attached to the surface of the plate, which formed cell projections in 3D culture. F-actin was detected on the grids of the NanoCulture plate in PANC-1 cells but not in PK-45H. The levels of tubulin expression in cells were higher in 3D culture than in 2D culture. The expression level of E-cadherin mRNA in PANC-1 and KLM-1 was higher than that in PK-45H and MIAPaCa-2. In conclusion, PDAC cells showed morphological changes, spheroid formation, and alterations of cytoskeletal proteins in 3D culture. E cadherin might be one of the key molecules involved in spheroid formation of PDAC cells. The 3D spheroidal culture system was a useful method for cell imaging with contrast-phase microscopy and confocal microscopy. PMID- 21267698 TI - Silver-enhanced immunogold scanning electron microscopy using vibratome sections of rat kidneys: detection of albumin filtration and reabsorption. AB - To show the three-dimensional distribution of proteins in renal cells, we applied the immunogold scanning electron microscopy method using vibratome slices. Kidney specimens from puromycin aminonucleoside (PAN) nephrotic rats and controls were obtained after intravenous infusion of human serum albumin and fixed in periodate lysine-paraformaldehyde solution. Vibratome slices were incubated with anti-human albumin antibody and 25-nm gold-labeled secondary antibody. After silver enhancement, the immunogold particles were clearly observed by backscatter electron imaging, whereas they were ambiguous in the secondary electron image. The images showed a higher resolution of the tissues at an acceleration voltage of 5 mV than at 10 mV. Immunogold-labeled albumin was observed in the lumen and endocytotic vesicles of the proximal tubules, and on the podocyte surface in the PAN nephrotic rats, whereas only a few particles were observed in the controls. In conclusion, silver-enhanced immunogold scanning electron microscopy at low acceleration voltages using vibratome sections can be applicable for detecting the intracellular/extracellular localization of molecules in solid tissues. We succeeded in visualizing the enhanced albumin endocytosis of the proximal tubules and the exocytosis of albumin from podocytes in the nephrotic rats. PMID- 21267699 TI - Hybrid sclerosing adenosis and basal cell hyperplasia of the prostate. AB - Hybrid sclerosing adenosis and basal cell hyperplasia of the prostate is a rare lesion. Here we report the seventh case of such lesions. Histological examination of the transurethral resection of the prostate of a 83-year-old Japanese man showed a small lesion consisted of sclerosing adenosis and basal cell hyperplasia, in addition to the diffuse glandular and fibromuscular hyperplasia. Immunohistochemically, many basal cells in sclerosing adenosis and basal cell hyperplasia areas showed a positive reaction for p63, cytokeratin 5, and D2-40. Additionally, many basal cells in the sclerosing adenosis area and some basal cells in the basal cell hyperplasia area were positive for S-100 protein and alpha-smooth muscle actin, which are myoepithelial cell markers. Finally, we suggest that hybrid sclerosing adenosis and basal cell hyperplasia may be actually a special form of hyperplastic lesion of all components of prostatic tissue, reflecting the unbalanced distribution of glandular, stromal (sclerosing adenosis), and basal cell hyperplasia with the differentiation toward myoepithelial cells predominantly occurring in a sclerosing adenosis area. Additionally, this case showed that D2-40 is a useful marker of basal cells. PMID- 21267700 TI - Acquired cystic disease-associated renal cell carcinoma with gain of chromosomes 3, 7, and 16, gain of chromosome X, and loss of chromosome Y. AB - Acquired cystic disease (ACD)-associated renal cell carcinoma (RCC) has been recently described. To date, there are no reports on genetic findings of G-band karyotype of ACD-associated RCC. In this article, we report the first report of G band karyotype of ACD-associated RCC. A 66-year-old Japanese man was found to have a left renal tumor during the follow-up of hemodialysis consequent to chronic renal failure. Left nephrectomy was performed. Histological examination of three tumors in the left kidney showed the cribriform or microcystic growth pattern of neoplastic cells with eosinophilic cytoplasm, and many oxalate crystals were observed. The G-band karyotype of ACD-associated RCC showed 49, X, +X, -Y, +3, +7, +16. These chromosomal abnormalities resemble those of sporadic papillary RCC that has been previously reported. Finally, we suggest that this tumor may show a close relationship between ACD-associated RCC and papillary RCC, but a large-scale study will be needed to clarify the relationship between ACD associated RCC and papillary RCC. PMID- 21267701 TI - A case of splenic low-grade mucinous cystadenocarcinoma resulting in pseudomyxoma peritonei. AB - Primary splenic mucinous cystadenocarcinoma (MCCa) is extremely rare, and only six cases appear to have been reported previously. We present herein a case of primary splenic MCCa resulting in pseudomyxoma peritonei (PMP). A 66-year-old Japanese woman presented to a hospital with a chief complaint of upper abdominal pain and a 7-year history of splenic cyst. Cyst rupture was noted on computed tomography, and splenectomy was performed. The abdominal cavity was filled with a large amount of gelatinous ascites, with the appearance of PMP. On the cut surface, multiple cysts containing mucinous material were found within and outside the spleen. Microscopically, splenic parenchyma was occupied by large mucinous pools focally lined with mucinous epithelial cells and mesothelial cell like cells, which were considered benign. Outside the spleen, a low-grade MCCa component was found. No ectopic pancreatic or intestinal tissue was identified. Although most PMP cases are known to be caused by low-grade mucinous appendiceal tumor, the present case represents the first report of a splenic MCCa resulting in PMP. PMID- 21267702 TI - Chondroid chordoma of the skull base: immunohistochemical and ultrastructural study of two cases with special reference to microtubules within rough-surfaced endoplasmic reticulum. AB - Two cases of skull base chordoma (case 1, a 57-year-old woman; case 2, a 69-year old woman) were investigated immunohistochemically and ultrastructurally. The tumors showed histopathological features typical of chondroid chordoma and contained both classical chordomatous and hyaline cartilaginous components. Tumor cells were immunoreactive for cytokeratin, vimentin, and S-100 protein, but negative for microtubule-associated protein 2 and class III beta-tubulin (tub B3). Tumor cells of case 2 were immunoreactive for tau-protein and class II beta tubulin (tub-B2), whereas those of case 1 were negative. Ultrastructurally, tumor cells in both cases showed the presence of abundant glycogen granules, well developed intracellular organelles, and desmosome-like junctions. In case 2, several microtubules were closely packed and ran parallel or in random directions within the dilated cisterns of rough-surfaced endoplasmic reticulum (rough ER). "Microtubules within rough ER" has been described in several neoplasms, including classical and chondroid chordomas. Although previous reports documented the tub B3 immunoreactivity in chordomas, our results suggested that, in our case 2, the predominant isoform of beta-tubulin in microtubules within rough ER was not tub B3 but tub-B2. PMID- 21267703 TI - Primary sebaceous carcinoma of the tongue. AB - Sebaceous carcinoma is the rarest type of oral malignancies. We report a case of primary sebaceous carcinoma of the tongue. Systemic imaging studies revealed that the patient had a T2N2cM0 (International Union Against Cancer guidelines) primary lingual tumor. Histopathological examination revealed neoplastic sebocytic and basaloid cells, and Sudan III staining and electron microscopy revealed intracytoplasmic lipid droplets. The neoplastic cells stained positive for adipophilin; epithelial membrane antigen; epithelial antigen; and cytokeratins 7, 8, and 15, but negative for cytokeratins 5/6, 18, 19, and 20; the androgen receptor; and carcinoembryonic antigen. Superselective intraarterial chemotherapy was administered via the superficial temporal artery concurrent with daily radiotherapy. Multiple biopsies confirmed a complete response of the primary lesion. The patient then underwent neck dissection followed by pathological examination, which revealed lymph nodes metastases. After postoperative radiotherapy to the neck, distant metastases were identified in the mediastinal lymph nodes and the lung. The patient died 17 months after completing the initial course of chemoradiotherapy. Our case demonstrates that superselective intraarterial chemotherapy combined with concurrent radiotherapy can be effective in treating the primary lesion of patients with a sebaceous carcinoma of the tongue. However, an effective strategy to eradicate metastases has yet to be established. PMID- 21267704 TI - Inaccurate summary of peripheral nerve sheath tumors in extradigital sites. Comment on "Hybrid peripheral nerve sheath tumor of the nasal cavity showing schwannomatous, neurofibromatus, and perineuriomatous areas. Med Mol Morphol (2010) 43:82-85". PMID- 21267706 TI - Surface-induced breakout crystallization in cylinder-forming P(I-b-EO) diblock copolymer thin films. AB - We have found very slow crystallization in thin films of cylinder-forming poly(isoprene-b-ethyleneoxide) (P(I-b -EO)) diblock copolymers with PEO being the minority block. The film was crystallized at room temperature after melting at 62 degrees C. Imaging methods were combined with X-ray reflectometry and grazing incidence small-angle X-ray scattering and diffraction. Initially, hexagonally packed, amorphous PEO cylinders lie in the film plane. After 148 days, crystallized, finger-like terraces were observed over the entire film surface. The terrace height is 20% higher than the repeat distance in the as-prepared film. Thus, at the film surface, the cylinders have been destroyed by crystalline lamellae lying in the film plane. The PEO chain stems are perpendicular to the substrate surface and are once-folded and fully interdigitated. The substrate near layers still consist of the hexagonally packed, amorphous PEO cylinders within the PI matrix. PMID- 21267707 TI - Intradermal rabies vaccination: the evolution and future of pre- and post exposure prophylaxis. AB - Inactivated rabies vaccines have been used to pioneer the immunological and economical advantages of intradermal (ID) administration over 35 years. Vaccine shortages or its prohibitive cost stimulated studies of various doses, frequency and sites of injection. An economical regimen for pre-exposure prophylaxis requires one-tenth of an intramuscular dose, but the early popularity of the method has been stifled by pharmaceutical regulations. There has also been reluctance to use multiple-site post-exposure ID regimens, except in a very few Asian counties. A new four-site ID regimen could overcome many of the problems encountered to date. The time is ripe to make dramatic progress towards efficient use of the current excellent vaccines globally, wherever there is a shortage of vaccine or funds. PMID- 21267708 TI - Control of NF-kappaB activity by proteolysis. AB - NF-kappaB transcription factors are critical regulators of many biological processes such as innate and adaptive immune responses, inflammation, cell proliferation and programmed cell death. This versatility necessitates a highly complex and tightly coordinated control of the signaling pathways leading to their activation. Here, we review the role of proteolysis in the regulation of NF kappaB activity, more specifically the contribution of the well-known ubiquitin proteasome system and the involvement of proteolytic activity of caspases and calpains. PMID- 21267709 TI - Combining genetical genomics and bulked segregant analysis-based differential expression: an approach to gene localization. AB - Positional gene isolation in unsequenced species generally requires either a reference genome sequence or an inference of gene content based on conservation of synteny with a genomic model. In the large unsequenced genomes of the Triticeae cereals the latter, i.e. conservation of synteny with the rice and Brachypodium genomes, provides a powerful proxy for establishing local gene content and order. However, efficient exploitation of conservation of synteny requires 'homology bridges' between the model genome and the target region that contains a gene of interest. As effective homology bridges are generally the sequences of genetically mapped genes, increasing the density of these genes around a target locus is an important step in the process. We used bulked segregant analysis (BSA) of transcript abundance data to identify genes located in a specific region of the barley genome. The approach is valuable because only a relatively small proportion of barley genes are currently placed on a genetic map. We analyzed eQTL datasets from the reference Steptoe * Morex doubled haploid population and showed a strong association between differential gene expression and cis-regulation, with 83% of differentially expressed genes co-locating with their eQTL. We then performed BSA by assembling allele-specific pools based on the genotypes of individuals at the partial resistance QTL Rphq11. BSA identified a total of 411 genes as differentially expressed, including HvPHGPx, a gene previously identified as a promising candidate for Rphq11. The genetic location of 276 of these genes could be determined from both eQTL datasets and conservation of synteny, and 254 (92%) of these were located on the target chromosome. We conclude that the identification of differential expression by BSA constitutes a novel method to identify genes located in specific regions of interest. The datasets obtained from such studies provide a robust set of candidate genes for the analysis and serve as valuable resources for targeted marker development and comparative mapping with other grass species. PMID- 21267710 TI - Primary menouria due to a congenital vesico-vaginal fistula with distal vaginal agenesis: a rarity. AB - We present the case of a female aged 16 years, suffering from cyclical menouria for the last 3 years. Clinical examination revealed the absence of a vagina. Cystoscopy performed while the patient was having menouria revealed an orifice (10 * 8 mm) in the supratrigonal region; blood clots were entering the urinary bladder through this orifice. Magnetic resonance imaging of the pelvis depicted a fluid-filled longitudinal tract distal to the uterus (which was the upper vagina), between the cervix and the bladder. Diagnostic laparoscopy confirmed the presence of a uterus, both ovaries, and the tubal structures. Exploratory laparotomy, correction of the fistulous tract, and sigmoid vaginoplasty were performed. The distal part of the fistulous tract (urinary bladder end) was anastomosed to the proximal end of the sigmoid neo-vagina. The patient is doing well as per her last follow-up at 6 months. She has started menstruating per neo vagina. PMID- 21267712 TI - Down-regulation of interleukin-16 in human mast cells HMC-1 by Clostridium difficile toxins A and B. AB - Toxin A (TcdA) and toxin B (TcdB) are the major virulence factors of Clostridium difficile and are the causative agents for clinical symptoms, such as secretory diarrhoea and pseudomembranous colitis. Mast cells are essentially involved in the toxin-induced colonic inflammatory processes. To study the direct effects of these toxins on the expression of inflammatory genes, a DNA microarray containing evaluated probes of 90 selected inflammatory genes was applied to the immature mast cell line HMC-1. TcdA and TcdB induced up-regulation of only a limited number of genes within the early phase of cell treatment. Interleukin-8 (IL-8), transcription factor c-jun and heme oxygenase-1 messenger RNA (mRNA) increased more than 2-fold. In contrast, IL-16, known as a CD4(+) T-cell chemoattractant factor and the chemokine receptor cKit were down-regulated. Stimulation of HMC-1 cells with IL-8 had no effect on IL-16 mRNA level, indicating that both cytokines were independently affected by the toxins. Regulation of both cytokines, however, depended on glucosylation of Rho GTPases as tested by application of enzyme deficient TcdA or TcdB. Down-regulation of total and secreted IL-16 protein was checked by enzyme-linked immunosorbent assay. The data implicate that TcdA and TcdB affect lymphocyte migration by modulating release of the chemoattractant factor IL-16 from mast cells. In addition, this is the first report showing that Rho GTPases are involved in the regulation of IL-16 expression. PMID- 21267713 TI - Label-free detection of nucleic acids by turn-on and turn-off G-quadruplex mediated fluorescence. AB - In this study we have used two fluorescent probes, tetrakis(diisopropylguanidino) zinc-phthalocyanine (Zn-DIGP) and N-methylmesoporphyrin IX (NMM), to monitor the reassembly of "split" G-quadruplex probes on hybridization with an arbitrary "target" DNA. According to this approach, each split probe is designed to contain half of a G-quadruplex-forming sequence fused to a variable sequence that is complementary to the target DNA. Upon mixing the individual components, both base pairing interactions and G-quadruplex fragment reassembly result in a duplex quadruplex three-way junction that can bind to fluorescent dyes in a G-quadruplex specific way. The overall fluorescence intensities of the resulting complexes were dependent on the formation of proper base-pairing interactions in the duplex regions, and on the exact identity of the fluorescent probe. Compared with samples lacking any "target" DNA, the fluorescence intensities of Zn-DIGP containing samples were lower, and the fluorescence intensities of NMM-containing samples were higher on addition of the target DNA. The resulting biosensors based on Zn-DIGP are therefore termed "turn-off" whereas the biosensors containing NMM are defined as "turn-on". Both of these biosensors can detect target DNAs with a limit of detection in the nanomolar range, and can discriminate mismatched from perfectly matched target DNAs. In contrast with previous biosensors based on the peroxidase activity of heme-bound split G-quadruplex probes, the use of fluorescent dyes eliminates the need for unstable sensing components (H(2)O(2), hemin, and ABTS). Our approach is direct, easy to conduct, and fully compatible with the detection of specific DNA sequences in biological fluids. Having two different types of probe was highly valuable in the context of applied studies, because Zn-DIGP was found to be compatible with samples containing both serum and urine whereas NMM was compatible with urine, but not with serum-containing samples. PMID- 21267711 TI - Argirein alleviates diabetic nephropathy through attenuating NADPH oxidase, Cx43, and PERK in renal tissue. AB - Diabetic nephropathy (DN) due to microvascular complication is a serious status characterized by continuously progressive until occurrence of the end stage of renal disease. It is attractive to investigate further mechanisms underlying the entity of DN and new drug discovery. We hypothesized that the entity of DN is inflammatory and is characterized by upregulated inflammatory/pro-inflammatory factors such as peroxisome proliferator-activated receptor alpha, NADPH oxidase, endoplasmic reticulum stress (ER stress), and endothelin receptor A (ET(A)) and downregulated connexin 43 (Cx43) in the kidney. Aminoguanidine is a special blocker to advanced glycation end products and argirein, a new compound contains a molecule of rhein linked to L: -arginine by a hydrogen bond. Rhein possesses anti-inflammatory activity and has been chemically modified to produce a new compound diacerein launched in European market for treating osteoarthritis. Argirein with two active molecules rhein and L: -arginine may be effective in suppressing the inflammatory cytokines contributing to the pathogenesis of DN. With a single injection of streptozotocin 65 mg/kg, ip in rats, early diabetic nephropathy was produced and revealed as an increased microalbuminuria, elevated creatinine and urea in serum, associated with upregulation of mRNA and protein of NADPH oxidase p22phox, p47phox, and p67phox and ET(A), upregulated PKR-like eukaryotic initiation factor 2alpha kinase (PERK), and downregulated Cx43 in the renal tissue. Upregulation of PERK suggested that there is an ER stress involved in the diabetic kidney, along with an increase in inflammatory/pro-inflammatory factors indicating an entity of chronic inflammation. Abnormalities of biomarkers were blunted by either aminoguanidine or argirein significantly. The new compound argirein is potential in alleviating and retarding microvascular complications of diabetes such as DN in clinical settings. PMID- 21267714 TI - Capillary electrophoretic separation of nanoparticles. AB - In the present work, CdSe nanocrystals (NCs) synthesized with a trioctylphosphine surface passivation layer were modified using amphiphilic molecules to form a surface bilayer capable of providing stable NCs aqueous solutions. Such modified nanocrystals were used as a test solute in order to analyze new electrophoretic phenomena, by applying a micellar plug as a separation tool for discriminating nanocrystals between micellar and micelle-free zones during electrophoresis. The distribution of NCs between both zones depended on the affinity of nanocrystals towards the micellar zone, and this relies on the kind of surface ligands attached to the NCs, as well as electrophoretic conditions applied. In this case, the NCs that migrated within a micellar zone can be focused using a preconcentration mechanism. By modifying electrophoretic conditions, NCs were forced to migrate outside the micellar zone in the form of a typical CZE peak. In this situation, a two-order difference in separation efficiencies, in terms of theoretical plates, was observed between focused NCs (N ~ 10(7)) and a typical CZE peak for NCs (N ~ 10(5)). By applying the amino-functionalized NCs the preconcentration of NCs, using a micellar plug, was examined, with the conclusion that preconcentration efficiency, in terms of the enhancement factor for peak height (SEF(height)) can be, at least 20. The distribution effect was applied to separate CdSe/ZnS NCs encapsulated in silica, as well as surface-modified with DNA, which allows the estimation of the yield of conjugation of biologically active molecules to a particle surface. PMID- 21267715 TI - Atrioventricular block in an infant with an atrioventricular septal aneurysm. AB - A case of atrioventricular (AV) septal aneurysm presenting in late fetal life with AV block is reported. In the neonatal period, second-degree AV block occurred, which progressed during infancy to complete block. This report includes ante- and postnatal echocardiograms demonstrating the anatomy. Only three other reports of AV septal aneurysm are found in the literature, none of which describe heart rhythm disturbance. PMID- 21267716 TI - Molecular genetics and pathogenesis of arrhythmogenic right ventricular cardiomyopathy: a disease of cardiac stem cells. AB - Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an uncommon cardiomyopathy characterized by fibroadiposis replacing cardiac myocytes, predominantly in the right ventricle. The clinical phenotype is characterized by cardiac arrhythmias, sudden cardiac death, and heart failure. The molecular genetic basis of ARVC is partially known. Mutations in DSP (desmoplakin), JUP (plakoglobin), PKP2 (plakophilin 2), DSG2 (desmoglein 2), and DSC2 (desmocollin 2) are responsible for approximately half of the cases. Mutations in TMEM43 and TGFB3, encoding transmembrane protein 43 and transforming growth factor beta3, respectively, also have been associated with ARVC. The molecular pathogenesis of ARVC has at least two components. The first component is fibroadiposis, which is the characteristics hallmark of the disease. The second is cardiac dysfunction, which is primarily due to impaired myocyte-to-myocyte attachment. The pathogenesis of fibroadiposis involves partial nuclear translocation of plakoglobin (PG) and subsequent suppression of canonical Wnt signaling, which is involved in the development of the right ventricle and its outflow tract, the predominant sites of involvement in ARVC. Suppression of the canonical Wnt signaling results in a switch to adipogenesis in the second heart field progenitor cells. Accordingly, ARVC is a disease of cardiac progenitor cells that have gone awry and differentiated to adipocytes. PMID- 21267717 TI - Pericarditis constrictiva in a 10-year-old boy after influenza A virus infection. AB - Pericarditis constrictiva is caused by fibrotic degeneration of the pericardium and leads to impaired diastolic ventricular filling. The diagnosis of constrictive pericarditis in children remains challenging and often requires a multimodal approach. We present a case of a pericarditis constrictiva in a 10 year old boy after influenza A virus infection. Clinicians should be aware of this complication, especially in patients with symptoms of exertional dyspnea and congestive heart failure. PMID- 21267718 TI - Perspective: skeletal complications of space flight. PMID- 21267719 TI - Impact of minimal tumor burden on antibody response to vaccination. AB - Four randomized phase III trials conducted recently in melanoma patients in the adjuvant setting have been based in part on the correlation between antibody responses in immunized patients and improved survival. Each of these randomized trials demonstrated no clinical benefit, although again there was a significant correlation between antibody response after vaccination and disease free and overall survival. To better understand this paradox, we established a surgical adjuvant model targeting GD2 ganglioside on EL4 lymphoma cells injected into the foot pad followed by amputation at variable intervals. Our findings are (1) comparable strong therapeutic benefit resulted from treatment of mice after amputation with a GD2-KLH conjugate vaccine or with anti-GD2 monoclonal antibody 3F8. (2) The strongest correlation was between antibody induction in response to vaccination and prolonged survival. (3) Antibody titers in response to vaccination in tumor challenged mice as compared to unchallenged mice were far lower despite the absence of detectable recurrences at the time. (4) The half life of administered 3F8 monoclonal antibody (but not control antibody) in challenged mice administered was significantly shorter than the half life of 3F8 antibody in unchallenged controls. The correlation between vaccine-induced antibody titers and prolonged survival may reflect, at least in part, increased tumor burden in antibody-negative mice. Absorption of vaccine-induced antibodies by increased, although not detected tumor burden may also explain the correlation between vaccine-induced antibody titers and survival in the adjuvant clinical trials described above. PMID- 21267720 TI - Enantiospecific adjuvant activity of cationic lipid DOTAP in cancer vaccine. AB - Commercially available DOTAP is a racemic mixture of two enantiomers. The adjuvanticity of each isomer was examined using a peptide/lipid complex as a therapeutic vaccine in an established murine cervical cancer model. This simple vaccine consists of a cationic lipid (DOTAP) and a major histocompatibility complex (MHC) class I-restricted epitope of the Human Papillomavirus (HPV) 16 protein E7. Dose-dependent tumor regression experiments have been completed for racemic DOTAP/E7, (R)-DOTAP/E7 and (S)-DOTAP/E7. Tumor-bearing mice treated with (R)-DOTAP/E7 complexes have shown tumor regression in a dose-dependent manner comparable to those mice treated with a racemic DOTAP with E7 peptide. These data are supported by IFN-gamma production by CD8(+) splenocytes, in vivo cytotoxic T lymphocytes (CTL) response, CD8(+) tumor-infiltrating lymphocytes (TIL), and IFN gamma production by CD8(+) TIL in (R)-DOTAP/E7-vaccinated mice. When (S)-DOTAP/E7 is delivered, tumor progression is delayed. While IFN-gamma production is absent from CD8(+) splenocytes in mice vaccinated with (S)-DOTAP/E7, IFN-gamma production by CD8(+) TIL is present, supporting our hypothesis that (S)-DOTAP has limited activity. Activation of bone marrow-derived dendritic cells by the enantiomeric formulations has also been evaluated, as well as cytokine production and toxicity with no considerable differences between the groups. The results show the DOTAP enantiomers act differently as adjuvants in vivo, with (R)-DOTAP being more effective at stimulating a CD8(+) anti-tumor response. PMID- 21267721 TI - 2011: the immune hallmarks of cancer. AB - Ten years after the publication of the position paper "The hallmarks of cancer" (Hanahan and Weinberg Cell 100:57-70, 2000), it has become increasingly clear that mutated cells on their way to giving rise to a tumor have also to learn how to thrive in a chronically inflamed microenvironment, evade immune recognition, and suppress immune reactivity. Genetic and molecular definition of these three immune hallmarks of cancer offers the opportunity to learn how to deploy specific countermeasures to reverse the situation in favor of the immune system and, eventually, the patient. This new information could be channeled to address what seem to be the three major hallmarks for the immune control of cancer progression: effective procedures to activate immune reactivity; characterization of not-disposable oncoantigens; and counteraction of immune suppression. PMID- 21267722 TI - The intestinal bacterial community in the food waste-reducing larvae of Hermetia illucens. AB - As it is known that food waste can be reduced by the larvae of Hermetia illucens (Black soldier fly, BSF), the scientific and commercial value of BSF larvae has increased recently. We hypothesised that the ability of catabolic degradation by BSF larvae might be due to intestinal microorganisms. Herein, we analysed the bacterial communities in the gut of BSF larvae by pyrosequencing of extracting intestinal metagenomic DNA from larvae that had been fed three different diets. The 16S rRNA sequencing results produced 9737, 9723 and 5985 PCR products from larval samples fed food waste, cooked rice and calf forage, respectively. A BLAST search using the EzTaxon program showed that the bacterial community in the gut of larvae fed three different diets was mainly composed of the four phyla with dissimilar proportions. Although the composition of the bacterial communities depended on the different nutrient sources, the identified bacterial strains in the gut of BSF larvae represented unique bacterial species that were unlike the intestinal microflora of other insects. Thus, our study analysed the structure of the bacterial communities in the gut of BSF larvae after three different feedings and assessed the application of particular bacteria for the efficient degradation of organic compounds. PMID- 21267723 TI - [Maculopathy with subretinal yellow deposits]. AB - We present the case of a 52-year-old female patient who presented with bilateral loss of vision over the course of several years. Funduscopy revealed multiple drusen in a "honeycomb"-like configuration at the entire posterior pole and in the peripapillary region. Autofluorescence and fluorescence angiography (FLA) showed multiple hyperfluorescent defects which show no leakage due to staining of the drusen-like lesions. Optical coherence tomography (OCT) revealed a marked irregularity of the photoreceptor-retinal pigment epithelium complex. Electroretinography (ERG) was without pathological findings, while the electrooculography (EOG) was abnormal, reflecting a functional disturbance of the retinal pigment epithelium. In consideration of all clinical findings, our patient suffered from Doyne honeycomb retinal dystrophy (DHRD) which is a rare autosomal dominant inherited retinal disease with full penetrance. Patients with DHRD are usually asymptomatic until the age of 30-40 years. In the later stages of this disease, central vision deteriorates as a result of geographic atrophy or choroidal neovascularization. PMID- 21267724 TI - [Diagnostic evaluation of retinal vein occlusion]. PMID- 21267725 TI - [Obituary for Prof. Dr. med. Christine Uhlemann]. PMID- 21267726 TI - [Rare viral infections during immunosuppressive therapy: a "normal" side effect?]. AB - The use of biologicals in the therapy of rheumatic diseases allows more effective treatment of patients with very active disease. Such regimens, however, can induce a more severe treatment-related immunosuppression and, as a consequence, opportunistic infections that are rarely seen with conventional immunosuppressive therapy appear to occur more frequently. The majority of these opportunistic infections are common viral infections which become latent and only cause severe disease if they are reactivated in a severely immunocompromised host. However, some of the newer biologicals, especially natalizumab, efalizumab or rituximab, appear to carry a special risk for the reactivation of JC polyoma virus manifesting as progressive multifocal leukoencephalopathy, a severe, untreatable and often fatal encephalitis. Therefore, such treatments should be used with caution in patients who have been or are being treated with combined immunosuppressive therapy including corticosteroids. Elderly patients are specifically at risk for this "normal" side effect. PMID- 21267727 TI - [Web-based learning in musculoskeletal ultrasound]. AB - Education and training in musculoskeletal ultrasound (MSUS) comprises attendance at theoretical and practical courses and independent study. Web-based learning as a novel teaching method has previously been described. The present study summarizes normal and pathological findings in a web-based approach using widely accepted guidelines. In a prospective study over a period of 3 years normal and pathological images of the musculoskeletal system have been documented and catalogued. Overall 1240 ultrasound images and 183 ultrasound videos were collected. A total of 14.4% were normal and 85.6% were pathological MSUS findings; 61% concerned the upper extremity, while 39% were images and videos of the lower limbs. The most captured conditions included synovitis (33.3%), pathologies of the tendons e.g., tenosynovitis or tendinosis (19.6%) and normal findings (14.4%). The most represented diseases were rheumatoid arthritis (20%), calcium deposition disease (8.2%), gout (7.1%) and osteoarthritis (6.9%). The images and videos were edited and integrated in a web-based tool. PMID- 21267728 TI - [Immune senescence and autoimmunity. Does the immune system really age, or just the organs which supply it?]. AB - Degenerative ageing processes are to a great extent responsible for organ specific morbidity and mortality among our population. The incidence of many autoimmune diseases also increases significantly with age, as is evident with rheumatoid arthritis (RA) for example. From an immunological and pathogenetic perspective, that the changes in the immune system of RA patients is comparable to the physiological ageing process seen in healthy individuals approximately 20 years later is of great interest. Despite the manifold functional changes seen in the immune system of older people, the incidence of infection in very elderly patients with RA is only marginally increased, such that immune suppression in older RA patients should be carried out just as consequently as in younger patients. Age-related changes and diseases in other organ systems should receive particular attention, since such complications can have a negative effect on the course of the autoimmune disease as well as the rate of side effects. PMID- 21267729 TI - [The future of methotrexate therapy and other folate inhibitors]. AB - Because of its good effectiveness and tolerability, methotrexate (MTX) has been the most important DMARD for the treatment of rheumatoid arthritis (RA) worldwide for many years. Thus the treatment of this disease is strongly based on the principle of folate inhibition. Recent years have brought new insights into the pharmacology and mechanisms of action of MTX. As a result, it now appears possible to further develop folate inhibitors to increase effectiveness and specificity. Polyglutamation of the drug, a metabolic step which appears to play a role both in terms of therapeutic effects and hepatic side effects, might be a possible starting point. Moreover, methods of targeted drug delivery intended to increase drug accumulation at the site of inflammation can increase the effectiveness of treatment and reduce toxicity. Albumin-coupled and liposomally conjugated MTX, both of which inhibit inflammation in animal models more potently than MTX, are undergoing preclinical evaluation. It was recognized that activated synovial macrophages upregulate folate receptor beta (FR-beta) expression and that MTX can become active by this pathway. This finding makes it possible to develop new FR-beta-specific folate inhibitors with specificity for this pathophysiologically important cell population. PMID- 21267730 TI - [Methotrexate toxicity. Myths and facts]. AB - Methotrexate (MTX) is a safe and well-tolerated drug for the treatment of rheumatic diseases, even if the strictest safety standards are considered. Initial apprehension as to severe pulmonary or hepatic side-effects has not been confirmed. The risk of infection is not elevated compared with other disease modifying antirheumatic drugs. In addition, a mutagenic potential could not be demonstrated even after long-term application. Therefore, MTX will maintain its significant role in antirheumatic therapy also in the near future. PMID- 21267731 TI - [Pharmacogenetics and pharmacogenomics of methotrexate. Current status and novel aspects]. AB - Since its introduction as a disease-modifying drug, methotrexate (MTX), a folate antagonist, is regarded as a major pillar of anti-rheumatic pharmacotherapy. This has not been changed in the current era of biologicals based on recombinant proteins. Despite most promising therapeutic progress about half of rheumatoid arthritis patients still display insufficient response to anti-rheumatic drugs. Specifically, about one in four patients on MTX shows lack of sufficient therapeutic efficacy which may lead to drug discontinuation. In addition, adjustment of therapy may be necessary due to individual drug toxicity. In this context and in light of recent advances concerning the use of genetic analysis in clinical practice, the development of novel strategies which implement individualized pharmacotherapy has become a major issue for translational and clinical research. Accordingly, numerous studies have been performed in recent years analyzing genetic polymorphisms of cellular parameters which relate to MTX efficacy and toxicity. Data currently available demonstrate the potential and the limitations of clinical genetic polymorphism analyses. PMID- 21267732 TI - [Current "off label use" of methotrexate for chronic inflammatory rheumatic diseases]. AB - Methotrexate (MTX) is probably the most commonly used off-label drug in rheumatology. It is used as an immunosuppressant for a wide range of chronic inflammatory rheumatic diseases. In most cases there is limited evidence from controlled studies for the efficacy of MTX in this off-label scenario. Only a few controlled clinical trials exist for different types of connective tissue diseases and vasculitis. In most indications, however, MTX could help to avoid using steroids and/or to prevent relapses. Thus, there is a great deal of experience with MTX in an off-label use and MTX is employed in the daily practice by most rheumatologists with success. A commonly used register indexing the off label use of MTX and also of other disease-modifying antirheumatic drugs (DMARDs) and biologicals would help to improve the acceptance and the safety of MTX as an orphan drug. PMID- 21267733 TI - [Combination therapy using methotrexate with DMARDs or biologics--current status]. AB - Methotrexate (MTX) is the most frequently used drug in combination treatment with disease-modifying antirheumatic drugs (DMARDs) and biologics in rheumatoid arthritis. DMARD combinations are usually the second step after unsuccessful MTX monotherapy. Evidence-based combinations of MTX+leflunomide, MTX+cyclosporine and triple combination MTX+sulphasalazine+hydroxychloroquine (complemented by glucocorticoids) showed the best results.In the case of insufficient response to the DMARD combination, MTX should be used in combination with a biologic. To date, the most frequent biologic treatment is with TNF inhibitors, but studies have shown that all biologics (with the exception of Anakinra) have comparable success rates. The combination of MTX plus abatacept, MTX plus rituximab and MTX plus tocilizumab are very promising, both clinically and in terms of blocking radiological progression. The efficacy of biological therapy is generally better using MTX combination than monotherapy.The safety of MTX combination treatment with DMARDs is not significantly lower than that of the individual substances; therefore, the required safety controls are also the same. PMID- 21267734 TI - [Elective rheumatology surgery from the perspective of the rheumatoid orthopaedist and the rheumatologist]. PMID- 21267735 TI - [Large-joint synovectomy in the era of biological therapies]. AB - Since the mid 1980s, a global decrease in surgical procedures related to rheumatoid arthritis (RA) has been documented for joint-preserving procedures such as synovectomy as well as joint replacement surgery. This reflects improvements in the early management of rheumatoid arthritis and availability of more effective medical treatment. The present review summarizes the recent literature on the frequency of orthopaedic surgery in RA patients as well as the role of synovectomy in the rheumatoid hip, knee and shoulder in times of biological RA therapy. PMID- 21267737 TI - [Hand and wrist surgery]. AB - Despite improved medical treatment of rheumatoid arthritis, carpal tunnel compression, caput ulnae syndrome and palmar and dorsal tenosynovitis with potential tendon rupture represent urgent surgical indications. While diagnostic and therapeutic synovectomy may guide medical treatment, it should be performed before joint instability and destructive arthritis are established. Swan-neck and Boutonniere deformities as well as ulnar or radial drift of metacarpophalangeal (MCP) joints or the wrist can only be corrected when the involved joints are supple and intact. In the presence of destructive arthritis, partial and total wrist fusion, arthroplasties of the MCP joints and arthrodeses of the distal interphalangeal joints are recommended. PMID- 21267736 TI - [Perioperative use of biologicals in rheumatoid arthritis]. AB - The high prevalence of patients with rheumatoid arthritis (RA) treated with biologics and the high proportion of RA patients requiring elective orthopaedic surgery indicates that the question of whether to continue or to interrupt biologic therapy in the context of a surgical procedure is a clinically relevant problem. Few data are available and the quality of the studies performed is somewhat limited. Thus, a straightforward recommendation on how this problem should be handled cannot be given on this basis. Therefore, individualized management based on risk stratification for postoperative complications seems currently to be the best solution. PMID- 21267738 TI - [Foot and ankle surgery]. AB - Rheumatoid arthritis is a systemic disease that often affects the foot and ankle (85%-100% of patients). There are characteristic deformities in relation to the stage of disease. Clinical assessment of both lower limbs is important, since factors such as valgus deformity of the knee can cause malposition of the foot and ankle. In the early stages, patients present with joint effusion which causes destruction of the cartilage ("stiff type") and distends ligaments and capsules ("loose type"). Medial and lateral ankle tendons are destroyed and become insufficient. A reduction in walking distance, pain, instability and difficulties with footwear lead to reduced quality of life. The talonavicular joint and rheumatoid forefoot destruction are in most cases the central problem in the foot deformity. Adequate medical therapy of the rheumatic disease is mandatory. Conservative treatment such as orthotic shoe devices should be used in the early stages and are concomitantly used after surgical treatment. Rheumatoid arthritis is a systemic disease requiring careful, stage-specific perioperative management. PMID- 21267739 TI - [The indication for radiosynoviorthesis. From the perspective of the nuclear medicine expert, rheumatic orthopedist and internist]. AB - Radiosynovectomy or radiosynoviorthesis (RSO), the intra-articular injection of beta-emitting radionuclides (e.g. colloidal preparations of 90-Yttrium, 186 Rhenium or 169-Erbium), is an approved, reliable and easily performed therapy for the treatment of chronic synovitis without harmful side effects. The best clinical results have been obtained in patients with predominantly inflammatory joint disease such as rheumatoid arthritis or reactive arthritis. But RSO is also established to treat pain and persistent effusions after total knee replacement. It also represents an adjuvant therapy in patients with pigmented villonodular synovitis to protect against recurrence following synovectomy. In patients with hemophilia and arthropathy a reduction in joint bleeding is seen and the use of coagulation factor is reduced. The indication for RSO should be made in close cooperation between the referring physician, the rheumatologist and the nuclear medicine expert in the context of a multimodal therapy concept. In this way, success rates of over 80%, with only few side effects, can be achieved, particularly in rheumatoid arthritis, reactive arthritis and hemophilic arthropathy. PMID- 21267740 TI - [Surgical therapy of osteoporotic vertebral body fractures]. AB - Osteoporosis is an age-related systemic disease leading to increased bone fragility. The vertebral bodies of the transitional area between the thoracic and lumbar spine are often involved. A large number of unreported or late-diagnosed fractures have to be assumed. If risk factors such as advanced age or comorbidities are present in the case of new-onset back pain, an osteoporotic vertebral body fracture as a possible cause has to be considered. This sets the diagnostic workup in motion, consisting of clinical and radiological examinations. In addition to conservative treatment, minimal invasive cement augmentation of the fracture via vertebroplasty or kyphoplasty is an option. Open surgical procedures, feared by older patients and their physicians, are rarely necessary. Of utmost importance after dealing with the fracture is the subsequent treatment of the underlying osteoporotic disease to prevent the occurrence of further fractures. PMID- 21267744 TI - Decreasing the minimum length criterion for an episode of hypomania: evaluation using self-reported data from patients with bipolar disorder. AB - Brief hypomania lasting less than 4 days may impair functioning and help to detect bipolarity. This study analyzed brief hypomania that occurred in patients with bipolar disorder who were diagnosed according to the DSM-IV criteria. Daily self-reported mood ratings were obtained from 393 patients (247 bipolar I and 146 bipolar II) for 6 months (75,284 days of data, mean 191.6 days). Episodes of hypomania were calculated using a 4, 3, 2, and single day length criterion. Brief hypomania occurred frequently. With a decrease in the minimum criterion from 4 days to 2 days, there were almost twice as many patients with an episode of hypomania (102 vs. 190), and more than twice as many episodes (305 vs. 863). Single days of hypomania were experienced by 271 (69%) of the sample. With a 2 day episode length, 33% of all hypomania remained outside of an episode. There was no significant difference in the percent of hypomanic days outside of an episode between patients with bipolar I and II disorders. There were no significant differences in the demographic characteristics of patients who met the 4-day minimum as compared with those who only experienced episodes of hypomania using a shortened length criterion. Decreasing the minimum length criterion for an episode of hypomania will cause a large increase in the number of patients who experience an episode and in the aggregate number of episodes, but will not distinguish subgroups within a sample who meet the DSM-IV criteria for bipolar disorder. Frequency may be an important dimensional aspect of brief hypomania. Clinicians should regularly probe for brief hypomania. PMID- 21267743 TI - Excessive cannabis use is associated with earlier age at onset in bipolar disorder. AB - The aim of the study was to investigate which factors are associated with age at onset in bipolar disorder with a specific focus on excessive alcohol and cannabis use, and the sequence of the onsets of excessive substance use and bipolar disorder. We investigated a naturalistic sample of 151 patients with bipolar I and II disorder receiving psychiatric treatment. Whether the presence of excessive substance use prior to bipolar disorder onset or the type of substance used (alcohol or cannabis) was associated with differences in age at onset was investigated using hierarchical and multiple linear regression analyses, adjusting for potential confounders. Patients with excessive alcohol use had a significantly later onset compared with patients with excessive cannabis use. Excessive general substance use prior to bipolar disorder onset was associated with a later onset. However, excessive cannabis use was associated with an earlier onset whether it preceded or followed bipolar disorder onset, also after adjusting for possible confounders. Excessive use of alcohol or other substances was not independently associated with age at onset in multivariate analyses. Alcohol use was associated with a later onset compared with cannabis use, suggesting different relationships to the onset of bipolar disorder. Lifetime use of cannabis predicted an earlier onset, independent of the sequence of onsets. This indicates that an early onset may increase the risk of cannabis use and that cannabis use may trigger bipolar disorder in vulnerable individuals. PMID- 21267745 TI - Impact of heat and pollution on oxidative stress and CC16 secretion after 8 km run. AB - To investigate the acute effect of a hot, humid and ozone-polluted (O(3)) environment on lung inflammation and oxidative tress of runners performing 8 km time trial run. Using a single-blinded randomized design, 10 male athletes (mean[Formula: see text]= 64.4 mlO(2) kg(-1) min(-1), SD = 4.4) took part in a time trial run in four different environmental conditions: 20 degrees C + 50% relative humidity (rh) (Control); 20 degrees C + 50% rh + 0.10 ppm O(3) (Control + O(3)); 31 degrees C + 70% rh (Heat); 31 degrees C + 70% rh + 0.10 ppm O(3) (Heat + O(3)). Blood samples and nasal lavage were collected post-exercise and analyzed for inflammatory, epithelial damage and oxidative stress markers. Data were analyzed using repeated measures ANOVA with Tukey's post hoc test. A significant increase in CC16 concentration (P < 0.05) and GSH/protein concentration (P < 0.05) in the upper respiratory airways was observed following the 8 km run in the Heat + O(3) trial compared with the control trial. There were no differences in the neutrophil counts between trials. No differences were observed for the other antioxidants analyzed. A hot, humid and ozone-polluted environment (0.1 ppm) elicits an early epithelial damage and antioxidant protection process in the upper respiratory airways of athletes immediately after performing 8 km time trial run. PMID- 21267746 TI - Comparing the effects of rehabilitation swallowing therapy vs. functional neuromuscular electrical stimulation therapy in an encephalitis patient: a case study. AB - A 49-year-old man with pharyngeal dysphagia after encephalitis is presented in this case study. Sixteen months earlier the patient experienced a sudden severe fever which resulted in encephalitis, leading to liquid dysphagia. Despite receiving an initial treatment of swallowing therapy, the patient's liquid dysphagia did not improve. Functional neuromuscular electrical stimulation, which is a new treatment method, was then applied to the patient. The patient showed improvement in the pharyngeal phase of swallowing. Clinical and treatment observations are reported. PMID- 21267747 TI - Kinematic analysis of dysphagia: significant parameters of aspiration related to bolus viscosity. AB - The purpose of this study was to investigate the mechanisms of aspiration with respect to the viscosity of ingested material in patients with dysphagia. Seventy patients with dysphagia underwent videofluoroscopic swallow studies (VFSS) between May 1, 2009 and September 30, 2009. Based on the findings of the VFSS, patients were divided into three groups: a thick-fluid aspiration group, a thin fluid aspiration group, and a no-aspiration group. Kinematic analyses were performed during thick-fluid swallowing. Among our 70 patients, 23 had thick fluid aspiration, 20 had thin-fluid aspiration, and 27 had no aspiration. A shortened duration of upper esophageal sphincter (UES) opening, a shorter interval between UES opening and peak pharyngeal constriction, and a diminished extent of laryngeal elevation were all significant risk factors for thick-fluid aspiration. A prolonged latency of the swallowing reflex, pharyngeal transit time, and the interval between bolus arrival at the vallecula and laryngeal elevation were all significant risk factors for thin-fluid aspiration. Our kinematic analysis of dysphagia employing the VFSS indicated that the mechanisms relevant to aspiration differed with respect to food viscosity. PMID- 21267748 TI - Clinical characteristics of de novo nonalcoholic fatty liver disease following pancreaticoduodenectomy. AB - BACKGROUND: Hepatic steatosis may develop after pancreatic resection, but its clinicopathological features remain unclear. We explored the clinical characteristics of newly appearing nonalcoholic fatty liver disease (NAFLD) after pancreaticoduodenectomy (PD), designated as de novo NAFLD after PD. METHODS: Of 83 patients who underwent PD between 2001 and 2006, the patients with regular alcohol consumption after PD (n = 3), those who were unavailable for regular abdominal computed tomography follow-up (n = 12), and those who died within 6 months of PD (n = 8) were excluded from the study. In the remaining 60 patients, the prevalence and clinical features of de novo NAFLD after PD were examined. RESULTS: NAFLD developed after PD in 14 (23%) patients in our cohort. Liver biopsy was performed in 8 patients and all showed typical steatohepatitis. Compared with the patients who had conventional nonalcoholic steatohepatitis (NASH), patients with post-PD de novo NASH demonstrated significant decreases in body mass index and lower levels of serum albumin, cholesterol, apolipoprotein B, and homeostasis model assessment for insulin resistance. Multivariate logistic regression analysis revealed that pancreatic head cancer was associated with an increased risk of developing NAFLD after PD (odds ratio 12.0, 95% confidence interval 2.0-71.4, P = 0.006). Increased dosage of oral pancreatic enzymes significantly ameliorated the steatosis, as well as leading to the recovery of body weight loss and resolution of the biochemical abnormalities. CONCLUSIONS: De novo NAFLD/NASH after PD is characterized by non-obesity and lack of hyperlipidemia and insulin resistance and is associated with pancreatic exocrine insufficiency. In such patients, intensifying pancreatic enzyme supplementation may be useful. PMID- 21267749 TI - Prediction of lysine ubiquitination with mRMR feature selection and analysis. AB - Ubiquitination, one of the most important post-translational modifications of proteins, occurs when ubiquitin (a small 76-amino acid protein) is attached to lysine on a target protein. It often commits the labeled protein to degradation and plays important roles in regulating many cellular processes implicated in a variety of diseases. Since ubiquitination is rapid and reversible, it is time consuming and labor-intensive to identify ubiquitination sites using conventional experimental approaches. To efficiently discover lysine-ubiquitination sites, a sequence-based predictor of ubiquitination site was developed based on nearest neighbor algorithm. We used the maximum relevance and minimum redundancy principle to identify the key features and the incremental feature selection procedure to optimize the prediction engine. PSSM conservation scores, amino acid factors and disorder scores of the surrounding sequence formed the optimized 456 features. The Mathew's correlation coefficient (MCC) of our ubiquitination site predictor achieved 0.142 by jackknife cross-validation test on a large benchmark dataset. In independent test, the MCC of our method was 0.139, higher than the existing ubiquitination site predictor UbiPred and UbPred. The MCCs of UbiPred and UbPred on the same test set were 0.135 and 0.117, respectively. Our analysis shows that the conservation of amino acids at and around lysine plays an important role in ubiquitination site prediction. What's more, disorder and ubiquitination have a strong relevance. These findings might provide useful insights for studying the mechanisms of ubiquitination and modulating the ubiquitination pathway, potentially leading to potential therapeutic strategies in the future. PMID- 21267751 TI - Crystal and electronic structures and high-pressure behavior of AgSO4, a unique narrow band gap antiferromagnetic semiconductor: LDA(+U) picture. AB - We demonstrate that DFT calculations performed with the local density approximation (LDA) allow for significantly better reproduction of lattice constants, the unit cell volume and the density of Ag(II)SO(4) than those done with generalized gradient approximation (GGA). The LDA+U scheme, which accounts for electronic correlation effects, enables the accurate prediction of the magnetic superexchange constant of this strongly correlated material and its band gap at the Fermi level. The character of the band gap places the compound on the borderline between a Mott insulator and a charge transfer insulator. The size of the band gap (0.82 eV) indicates that AgSO(4) is a ferrimagnetic semiconductor, and possibly an attractive material for spintronics. A bulk modulus of 27.0 GPa and a compressibility of 0.037 GPa(-1) were determined for AgSO(4) from the third order Birch-Murnaghan isothermal equation of state up to 20 GPa. Several polymorphic types compete with the ambient pressure P-1 phase as the external pressure is increased. The P-1 phase is predicted to resist pressure-induced metallization up to at least 20 GPa. PMID- 21267750 TI - Studies on filarial GST as a target for antifilarial drug development-in silico and in vitro inhibition of filarial GST by substituted 1,4-naphthoquinones. AB - Eleven 1,4-naphthoquinone analogues with different amino substitutions at position 3 of the quinone ring earlier reported for macrofilaricidal activity were selected and screened against purified cytosolic GST isolated from the bovine filarial worm Setaria digitata and IC(50) values were determined. Of the 11 compounds tested, 8 showed good inhibition against S. digitata GST. The IC(50) values of the most effective macrofilaricidal compounds-11 [2-(4-methylpiperazin 1-yl)naphthalene-1,4-dione] and 9 {2-[(1,3-dimethylbutyl)amino]naphthalene -1,4 dione}-were 0.872 and 0.994 mM, respectively. Compounds 9 and 11 were further studied for type of enzyme inhibition and found to exhibit competitive and uncompetitive inhibition kinetics, respectively, with respect to substrate GSH. All 11 compounds were in agreement with Lipinski's rule of five and passed through the FAFDrugs ADME/tox filter. Molecular docking was carried out using the modeled 3D structure of wbGST PDB ID:1SFM as receptor and substituted naphthoquinones as ligands using AutoDock 4.0. The binding energy of nine compounds varied from -9.15 to -6.58 Kcal mol(-1), whereas compounds 8 and 10 did not show any binding to the receptor. Among the compounds studied, compound 7 {2 [3-(diethylamino) propyl]aminonaphthalene-1,4-dione} showed maximum affinity towards wbGST as it exhibited the lowest binding energy, followed by compounds 11 and 9. However compound 7 was not macrofilaricidal while 11 and 9 exhibited macrofilaricidal activity. The results of in silico and in vitro studies with the synthesized 1,4 -naphthoquinone analogues on filarial GST and in vitro macrofilaricidal activity against adult bovine filarial worm S. digitata open up a promising biochemical target for antifilarial drug development. PMID- 21267752 TI - Trajectory NG: portable, compressed, general molecular dynamics trajectories. AB - We present general algorithms for the compression of molecular dynamics trajectories. The standard ways to store MD trajectories as text or as raw binary floating point numbers result in very large files when efficient simulation programs are used on supercomputers. Our algorithms are based on the observation that differences in atomic coordinates/velocities, in either time or space, are generally smaller than the absolute values of the coordinates/velocities. Also, it is often possible to store values at a lower precision. We apply several compression schemes to compress the resulting differences further. The most efficient algorithms developed here use a block sorting algorithm in combination with Huffman coding. Depending on the frequency of storage of frames in the trajectory, either space, time, or combinations of space and time differences are usually the most efficient. We compare the efficiency of our algorithms with each other and with other algorithms present in the literature for various systems: liquid argon, water, a virus capsid solvated in 15 mM aqueous NaCl, and solid magnesium oxide. We perform tests to determine how much precision is necessary to obtain accurate structural and dynamic properties, as well as benchmark a parallelized implementation of the algorithms. We obtain compression ratios (compared to single precision floating point) of 1:3.3-1:35 depending on the frequency of storage of frames and the system studied. PMID- 21267753 TI - Density functional theory study of the potassium complexation of an unsymmetrical 1,3-alternate calix[4]-crown-5-N-azacrown-5 bearing two different crown rings. AB - Theoretical studies of an unsymmetrical calix[4]-crown-5-N-azacrown-5 (1) in a fixed 1,3-alternate conformation and the complexes 1.K(+)(a), 1.K(+)(b), 1.K(+)(c) and 1.K(+)K(+) were performed using density functional theory (DFT) at the B3LYP/6-31G level. The fully optimized geometric structures of the free macroligand and its 1:1 and 1:2 complexes, as obtained from DFT calculations, were used to perform natural bond orbital (NBO) analysis. The two main types of driving force metal-ligand and cation-pi interactions were investigated. NBO analysis indicated that the stabilization interaction energies (E (2)) for O...K(+) and N...K(+) are larger than the other intermolecular interactions in each complex. The significant increase in electron density in the RY or LP orbitals of K(+) results in strong host-guest interactions. In addition, the intermolecular interaction thermal energies (DeltaE, DeltaH, DeltaG) were calculated by frequency analysis at the B3LYP/6-31G level. For all structures, the most pronounced changes in the geometric parameters upon interaction are observed in the calix[4]arene molecule. The results indicate that both the intermolecular electrostatic interactions and the cation-pi interactions between the metal ion and pi orbitals of the two pairs that face the inverted benzene rings play a significant role. PMID- 21267754 TI - Estimation of formamide harmonic and anharmonic modes in the Kohn-Sham limit using the polarization consistent basis sets. AB - Formamide harmonic and anharmonic frequencies of fundamental vibrations in the gas phase and in several solvents were successfully estimated in the B3LYP Kohn Sham complete basis set limit (KS CBS). CBS results were obtained by extrapolating a power function (two-parameter formula) to the results calculated with polarization-consistent basis sets. Anharmonic corrections using the second order perturbation treatment (PT2) and hybrid B3LYP functional combined with polarization consistent pc-n (n=0, 1, 2, 3, 4) and several Pople's basis sets were analyzed for all fundamental formamide vibrational modes in the gas phase and solution. Solvent effects were modeled within a PCM method. The anharmonic frequency of diagnostic amide vibration C=O in the gas phase and the CCl(4) solution calculated with the VPT2 method was significantly closer to experimental data than the corresponding harmonic frequency. Both harmonic and anharmonic frequencies of C=O stretching mode decreased linearly with solvent polarity, expressed by relative environment permittivity (epsilon) ratio (epsilon 1)/(2epsilon+1). However, an unphysical behavior of solvent dependence of some low frequency anharmonic amide modes of formamide (e.g., CN stretch, NH(2) scissoring, and NH(2) in plane bend) was observed, probably due to the presence of severe anharmonicity and Fermi resonance. PMID- 21267755 TI - Impact of natural disasters on the functional and health status of patients with rheumatoid arthritis. AB - To examine the effects of natural disasters on rheumatoid arthritis (RA) patients we conducted a questionnaire survey targeted to 1,477 members of a nationwide RA patient group in Japan who lived in the municipalities affected by natural disasters between 2004 and 2006. Functional statuses measured by the modified Health Assessment Questionnaire and self-rated health statuses before and after the events were retrospectively examined. The associations between the changes in functional and health status and socio-demographics, direct damage, and preparedness status were statistically analyzed. Of the 665 individuals who responded, the data on 192 women RA patients were analyzed. The values at 1 and 6 months post-event were the same, with 14% experiencing deteriorations of functional status, while 22% experienced a worsening of self-rated health status. Those in poorer functional status before the events were more likely to experience deteriorations of functional [odds ratio (OR) 4.4, 95% confidence interval (CI) 1.5-13.6] and health (OR 2.8, 95% CI 1.2-6.7) status at both 1 month and 6 months (OR 3.9, 95% CI 1.3-12.0, and OR 2.8, 95% CI 1.2-6.7, respectively) after the events. Based on these results, we conclude that the functional and health status of women RA patients could worsen due to the consequences of a natural disaster, with a disproportionately large impact upon those with a poorer functional status. PMID- 21267757 TI - A labile point in mutant amphotericin polyketide synthases. AB - Streptomyces nodosus produces the antifungal polyene amphotericin B. Numerous modifications of the amphotericin polyketide synthase have yielded new analogues. However, previous inactivation of the ketoreductase in module 10 resulted in biosynthesis of truncated polyketides. Here we show that modules downstream of this domain remain intact. Therefore, loss of ketoreductase-10 activity is sufficient to cause early chain termination. This modification creates a labile point in cycle 11 of the polyketide biosynthetic pathway. Non-extendable intermediates are released to accumulate as polyenyl-pyrones. PMID- 21267758 TI - Surface display of human lactoferrin using a glycosylphosphatidylinositol anchored protein of Saccharomyces cerevisiae in Pichia pastoris. AB - A cell surface display system was developed in Pichia pastoris using the gene TIP1, encoding the glycosylphosphatidylinositol (GPI)-anchored protein of Saccharomyces cerevisiae (ScTIP). Human lactoferrin cDNA (hLf) was fused to a full-length TIP1 DNA (ScTIP ( 630 )) or a short-TIP1 fragment (ScTIP ( 120 )) encoding the 40 C-terminal amino acids of ScTIP. Both hLf-ScTIP fusion genes were expressed in P. pastoris SMD 1168. The fused protein was detected by western blotting after extraction of the lysed recombinant cells with Triton X-100, urea, and Triton X-100 plus urea, suggesting that the hLf is associated with the membrane. The localization of surface-displayed hLf was confirmed by immunofluorescence confocal microscopy and flow cytometric analysis using FITC labeled anti-hLf antibody, suggesting that hLf was successfully located at the surface of P. pastoris. The intact recombinant cells and cell lysates showed antibacterial activity against target microorganisms, meaning that the expressed hLf was biologically active. The results indicated that the ScTIP anchoring motif is useful for cell surface display of foreign proteins in P. pastoris. PMID- 21267759 TI - Candida tropicalis: characterization of a strain capable of degrading high concentrations of phenol. AB - PURPOSE OF WORK: This study was to demonstrate the degradation effectiveness and application potential of Candida tropicalis JH8. A phenol-degrading yeast was isolated from activated sludge and was identified as C. tropicalis. It used phenol as the sole source of carbon at up to 1,800 mg l(-1). The optimal conditions for phenol degradation were pH 6 at 37 degrees C with a 2% (v/v) inoculum. Complete degradation of 1,800 mg phenol l(-1) was achieved after 62 h. PMID- 21267760 TI - Self-cleaving fusion tags for recombinant protein production. AB - Fusion expression is a common practice for recombinant protein production. Some fusion tags confer solubility on the target protein whereas others provide affinity handles that facilitate purification. However, the tag usually needs to be removed from the final product, which involves using expensive proteases or hazardous chemicals and requires additional chromatography steps. Self-cleaving tags are a special group of fusion tags that possess inducible proteolytic activity. Combined with appropriate affinity tags, they enable fusion purification, cleavage and target separation to be achieved in a single step, which saves time, labor and cost. This paper reviews currently available self cleaving fusion tags for recombinant protein production. For each system, an introduction of its key characteristics and a brief discussion of its advantages and disadvantages is given. PMID- 21267761 TI - A modified electro-transformation method for Bacillus subtilis and its application in the production of antimicrobial lipopeptides. AB - A modified electroporation method using trehalose is presented for the transformation of Bacillus subtilis. The new method improved the transformation efficiency of B. subtilis nearly 2,000-fold compared with the usual method, giving 4*10(5) transformants/MUg DNA. Using this method, B. subtilis was engineered to improve production of antimicrobial lipopeptides and produced 1.8 fold more surfactin and 2.9-fold more fengycin. PMID- 21267762 TI - Chemoenzymatic synthesis of diverse thiohydroximates from glucosinolate-utilizing enzymes from Helix pomatia and Caldicellulosiruptor saccharolyticus. AB - Thiohydroximates comprise a diverse class of compounds important in both biological and industrial chemistry. Their syntheses are generally limited to simple alkyl and aryl compounds with few stereocenters and a narrow range of functional groups. We hypothesized that sequential action of two recombinant enzymes, a sulfatase from Helix pomatia and a beta-O-glucosidase from Caldicellulosiruptor saccharolyticus, on glucosinolates would allow synthesis of thiohydroximates from a structurally broad array of abundant precursors. We report successful synthesis of thiohydroximates of varied chemical classes, including from homochiral compounds of demonstrated biological activity. The chemoenzymatic synthetic route reported here should allow access to many, if not all, of the thiohydroximate core structures of the ~200 known naturally occurring glucosinolates. The enrichment of this group for compounds with possible pharmacological potential is discussed. PMID- 21267763 TI - IGF-II inhibitory DNAzymes inhibit the invasion and migration of hepatocarcinoma cells. AB - Metastasis and recurrence are the biggest obstacles to enhance the efficacy of surgical resection as a cure for hepatocellular carcinoma which is the second most deadly cancer in China. Here, we had showed that two DNAzymes (DRz1 and DRz2) targeted to IGF-II could inhibit invasion, motility and migration of SMMC 7721 cells in vitro. DRz1 was transfected into SMMC-7721 cells and the results were shown that IGF-II expression level dramatically reduced. Meanwhile, DRz1 effectively inhibited adhesion between SMMC-7721 cells with the extracellular matrix and Fb cells comparing to those untreated or transfected with inactive DRz (P<0.05, ANOVA). Furthermore, vascular endothelial growth factor and matrix metalloproteinases were down-regulated in DRz1 treated cells. These results may help to identify novel therapeutic molecules targeting hepatocellular carcinomas. PMID- 21267764 TI - Lipopolysaccharide-stimulated activation of murine DC2.4 cells is attenuated by n butylidenephthalide through suppression of the NF-kappaB pathway. AB - Modulation of dendritic cell (DC) fate and function may be one approach for the treatment of inflammatory and autoimmune diseases. n-Butylidenephthalide (BP), derived from Angelica sinensis, at 40 MUg/ml significantly decreased the secretion of interleukin-6 and tumor necrosis factor-alpha by lipopolysaccharide (LPS)-stimulated activation of cultured murine DC2.4 cells (P<0.01). LPS-induced major histocompatibility complex class II (P<0.05), CD86 (P<0.01) and CD40 (P<0.01) expression on DC2.4 cells was also inhibited by BP. The endocytic capacity of LPS-stimulated DC2.4 cells was increased by BP (P<0.01). The antigen presenting capacity of LPS-stimulated DC2.4 cells was decreased by BP (P<0.05). Moreover, we confirmed BP attenuates the responses of LPS-stimulated activation of DCs via suppression of NF-kappaB-dependent pathways. PMID- 21267765 TI - TubeSpin bioreactor 50 for the high-density cultivation of Sf-9 insect cells in suspension. AB - Here we present the TubeSpin bioreactor 50 (TubeSpins) as a simple and disposable culture system for Sf-9 insect cells in suspension. Sf-9 cells had substantially better growth in TubeSpins than in spinner flasks. After inoculation with 10(6) cells/ml, maximal cell densities of 16*10(6) and 6*10(6) cells/ml were reached in TubeSpins and spinner flasks, respectively. In addition the cell viability in these batch cultures remained above 90% for 10 days in TubeSpins but only for 4 days in spinner flasks. Inoculation at even higher cell densities reduced the duration of the lag phase. After inoculation at 2.5*10(6) cells/ml, the culture reached the maximum cell density within 3 days instead of 7 days as observed for inoculation with 10(6) cells/ml. Infection of Sf-9 cells in TubeSpins or spinner flasks with a recombinant baculovirus coding for green fluorescent protein (GFP) resulted in similar GFP-specific fluorescence levels. TubeSpins are thus an attractive option for the small-scale cultivation of Sf-9 cells in suspension and for baculovirus-mediated recombinant protein production. PMID- 21267766 TI - Morphine and tumor growth and metastasis. AB - Morphine is an analgesic widely used to alleviate cancer pain. In addition, the perioperative management of pain in cancer surgery patients most often includes opioids. However, there are reports that these drugs may alter cancer recurrence or metastasis. Several mechanisms have been proposed, such as the modulation of the immune response or cellular pathways that control the survival and migratory behavior of cancer cells. The published literature, however, presents some discrepancies, with reports suggesting that opioids may either promote or prevent the spread of cancer. It is of great importance to determine whether opioids, in particular the most widely used, morphine, may increase the risk of metastasis when used in cancer surgery. This review examines the available data on the effects of morphine which influence cancer metastasis or recurrence, including immunomodulation, tumor cell aggressiveness, and angiogenesis, with special emphasis on recently published clinical and laboratory based studies. We further discuss the parameters that may explain the difference between reports on the effects of morphine on cancer. PMID- 21267767 TI - Modulation of tumor immunity by therapeutic monoclonal antibodies. AB - The surveillance of tumors by the immune system of cancer patients and its impact on disease progression and patient survival have been largely documented over the last years. In parallel, the use of therapeutic monoclonal antibodies (mAbs) in oncology has gained a widespread recognition as it has made it possible to increase patient survival and to ameliorate the quality of life in a number of cancers. However, the clinical responses observed following mAb treatment remain largely heterogeneous and their duration is still highly unpredictable. Recently, the concept that the injection of therapeutic antibodies not only triggers early anti-tumor events such as receptor blockade, cytostasis, apoptosis, complement dependent cytotoxicity and/or antibody-dependent cytotoxicity but also allows the host immune system to fight tumor cells through the development of a long-lasting adaptive immunity has emerged. In the present review, we will examine the arguments that support this concept by detailing the cellular and molecular events likely to underlie the induction of an efficient anti-tumor adaptive immune response by mAbs. We will also discuss the consequences of this induction on the way therapeutic antibodies can be used and inserted in a more global immunotherapeutic approach aiming at strengthening the adaptive anti-tumor immune response developed by cancer patients. PMID- 21267768 TI - The power of NGS technologies to delineate the genome organization in cancer: from mutations to structural variations and epigenetic alterations. AB - The development of cancer is characterized by the joined occurrence of alterations on different levels--from single nucleotide changes via structural and copy number variations to epigenetic alterations. With the advent of advanced technologies such as next generation sequencing, we have now the tools in hands to put some light on complex processes and recognize systematic patterns that develop throughout cancer progression. The combination of single hypothesis driven experiments with a system-wide genetic view enables us to prove so far not addressable questions such as the influence of DNA methylation on gene expression or the disruption of genome homeostasis by structural variations and miRNA expression patterns. Out of this enormous amount of information, specific biomarkers for cancer progression have been discovered, which pave the way for the development of new therapeutic strategies. Here, we will review the status quo of integrative cancer genomic approaches, give an overview over the power of next generation sequencing technologies in oncology, and outline future perspective. Both sides--clinical as well as basic research aspects--will be considered. PMID- 21267769 TI - Mast cell: insight into remodeling a tumor microenvironment. AB - Mast cells are of paramount importance to allergies, pathogen immune responses during infections, and angiogenesis, as well as innate and adaptive immune regulations. Beyond all these roles, mast cells are now more and more being recognized as modulators of tumor microenvironment. Notwithstanding mounting evidences of mast cell accumulation in tumors, their exact role in tumor microenvironment is still incompletely understood. In this review, we discuss the significant role of mast cells in the remodeling of tumor microenvironment by either releasing various factors after activation or interacting with other cells within tumor and, as a result, the possible role of mast cell in cancer invasion and metastasis. We also discuss recent findings that mast cells actively release microparticles, which account for the transfer of membrane-type receptor signal and regulatory molecules such as microRNAs to tumor cells and immune cells. These findings on mast cells provide further insights into the complexity of tumor microenvironment remodeling. PMID- 21267770 TI - True local recurrences do not metastasize. AB - Generally, the limits of local tumor control are in part connected with the term "field cancerization" and are known from oral, lung, prostate, or mammary cancer. With the example of breast cancer (BC), the problem of ipsilateral breast tumor recurrences (IBTR) after breast-conserving surgery will be reviewed. Three types of local recurrences are distinguished: true recurrences, new primaries, or residual tumors. Good data for BC allow the description of the time-dependent risk of these three types, relative to the diagnosis of the primary tumor, because the time of initiation and the growth duration of the IBTR can be estimated. Two hypotheses explain the data: first, local recurrences may be initiated years before the diagnosis of a primary tumor (PT) and can then appear as multifocal PT at diagnosis, and second, true local recurrences probably do not metastasize. The generalizability of these hypotheses for other tumors will be discussed. PMID- 21267772 TI - Myeloid cell diversification and complexity: an old concept with new turns in oncology. AB - Tumour development is accompanied by an enhanced haematopoiesis. This is not a widespread activation since only cells belonging to the myelo-monocytic compartment are expanded and mobilized from primary sites of haematopoiesis to other organs, reaching also the tumour stroma. This process occurs early during tumour formation but becomes more evident in advanced disease. Far from being a simple, unwanted consequence of cancer development, accumulation of myelo monocytitc cells plays a role in tumour vascularization, local spreading, establishment of metastasis at distant sites, and contribute to create an environment unfavourable for the adoptive immunity against tumour-associated antigens. Myeloid populations involved in these process are likely different but many cells, expanded in primary and secondary lymphoid organs of tumour-bearing mice, share various levels of the CD11b and Gr-1 (Ly6C/G) markers. CD11b(+)Gr 1(+) cells are currently named myeloid-derived suppressor cells for their ability to inhibit T lymphocyte responses in tumour-bearing hosts. In this manuscript, we review the recent literature on tumour-conditioned myeloid subsets that assist tumour growth, both in mice and humans. PMID- 21267773 TI - Automatic quantification of spinal curvature in scoliotic radiograph using image processing. AB - Choosing the most suitable treatment for the scoliosis relies heavily on accurate and reproducible spinal curvature measurement from radiographs. Our objective is to reduce the variability in spinal curvature measurement by reducing the user intervention and bias. In order to determine the reliability of the spinal curvature measurement as it is in the clinical measurement of scoliosis a methodological survey has been carried out that concludes with inter and intra observer error variation. The proposed method list out horizontal inclination of all the vertebrae's in terms of slopes using active contour models and morphological operators. This facilitates the radiologist to decide end vertebrae and hence inter/intra observer variation is completely eliminated. Tables 1 and 2 shows the observer error variation between manual and proposed methods in terms of mean and standard deviation. PMID- 21267774 TI - Health effects and safety of magnetic resonance imaging. PMID- 21267775 TI - Validation of a self-concept scale for Lynch syndrome in different nationalities. AB - Learning about hereditary cancer may influence an individual's self-concept, which otherwise represents a complex but stable cognitive structure. Recently, a 20-statement self-concept scale, with subscales related to stigma-vulnerability and bowel symptom-related anxiety, was developed for Lynch syndrome. We compared the performance of this scale in 591 mutation carriers from Denmark, Sweden and Canada. Principal component analysis identified two sets of linked statements-the first related to feeling different, isolated and labeled, and the second to concern and worry about bowel changes. The scale performed consistently in the three countries. Minor differences were identified, with guilt about passing on a defective gene and feelings of losing one's privacy being more pronounced among Canadians, whereas Danes more often expressed worries about cancer. Validation of the Lynch syndrome self-concept scale supports its basic structure, identifies dependence between the statements in the subscales and demonstrates its applicability in different Western populations. PMID- 21267776 TI - Quality improvement as a tool for translating evidence based interventions into practice: what the youth violence prevention community can learn from healthcare. AB - Health care has been working for the past 2 decades to improve the translation of evidence based practice (EBPs) into care. The strategies used to facilitate this, and lessons learned, can provide useful models for similar work taking place in youth violence prevention. This article discusses the history of evidence translation in health care, reviews key strategies used to support translation of evidence based practice into care, and suggests lessons learned that may be useful to similar efforts in youth violence prevention and intervention services. PMID- 21267777 TI - A tool for examining the role of the zinc finger myelin transcription factor 1 (Myt1) in neural development: Myt1 knock-in mice. AB - The Myt1 family of transcription factors is unique among the many classes of zinc finger proteins in how the zinc-stabilized fingers contact the DNA helix. To examine the function of Myt1 in the developing nervous system, we generated mice in which Myt1 expression was replaced by an enhanced Green Fluorescent Protein fused to a Codon-improved Cre recombinase as a protein reporter. Myt1 knock-in mice die at birth, apparently due to improper innervation of their lungs. Elimination of Myt1 did not significantly affect the number or distribution of neural precursor cells that normally express Myt1 in the embryonic spinal cord. Nor was the general pattern of differentiated neurons altered in the embryonic spinal cord. The Myt1 knock-in mice should provide an important tool for identifying the in vivo targets of Myt1 action and unraveling the role of this structurally distinct zinc finger protein in neural development. PMID- 21267778 TI - Esophageal adenocarcinoma presenting as pseudo-achalasia in a patient with juvenile polyposis syndrome: an enemy out of the blue. PMID- 21267779 TI - Reversal of hepatic and renal failure from sickle cell intrahepatic cholestasis. PMID- 21267780 TI - Women's health training in gastroenterology fellowship: a national survey of fellows and program directors. AB - BACKGROUND AND AIMS: The Gastroenterology Core Curriculum requires training in women's digestive disorders; however, requirements do not necessarily produce knowledge and competence. Our study goals were: (1) to compare perceptions of education, fellow-reported levels of competence, and attitudes towards training in women's gastrointestinal (GI) health issues during fellowship between gastroenterology fellows and program directors, and (2) to determine the barriers for meeting training requirements. METHODS: A national survey assessing four domains of training was conducted. All GI program directors in the United States (n = 153) and a random sample of gastroenterology fellows (n = 769) were mailed surveys. Mixed effects linear modeling was used to estimate all mean scores and to assess differences between the groups. Cronbach's alpha was used to assess the consistency of the measures which make up the means. RESULTS: Responses were received from 61% of program directors and 31% of fellows. Mean scores in perceived didactic education, clinical experiences, and competence in women's GI health were low and significantly differed between the groups (P < 0.0001). Fellows' attitudes towards women's GI health issues were more positive compared to program directors' (P = 0.004). Barriers to training were: continuity clinic at a Veteran's Administration hospital, low number of pregnant patients treated, low number of referrals from obstetrics and gynecology, and lack of faculty interest in women's health. CONCLUSIONS: (1) Fellows more so than program directors perceive training in women's GI health issues to be low. (2) Program directors more so than fellows rate fellows to be competent in women's GI health. (3) Multiple barriers to women's health training exist. PMID- 21267783 TI - Carica papaya lipase: a naturally immobilized enzyme with interesting biochemical properties. AB - Triacylglycerol (TAG) lipases have been thoroughly characterized in mammals and microorganisms, whereas very little is known about plant TAG lipases. The lipolytic activity occurring in all the laticies is known to be associated with sedimentable particles, and all attempts to solubilize the lipolytic activity of Carica papaya latex have been unsuccessful so far. However, some of the biochemical properties of the lipase from Carica papaya latex (CPL) were determined from the insoluble fraction of the latex. The activity was optimum at a temperature of 37 degrees C and a pH of 9.0, and the specific activities of CPL were found to be 2,000 +/- 185 and 256 +/- 8 U/g when tributyrin and olive oil were used as substrates, respectively. CPL was found to be active in the absence of any detergent, whereas many lipases require detergent to prevent the occurrence of interfacial denaturation. CPL was inactive in the presence of micellar concentrations of Triton X-100, sodium dodecyl sulfate (SDS) and tetradecyl trimethylammonium bromide (TTAB), and still showed high levels of activity in the presence of sodium taurodeoxycholate (NaTDC) and the zwitterionic Chaps detergent. The effects of various proteases on the lipolytic activity of CPL were studied, and CPL was found to be resistant to treatment with various enzymes, except in the presence of trypsin. All these properties suggest that CPL may be a good candidate for various biotechnological applications. PMID- 21267784 TI - Salinomycin selectively targets 'CD133+' cell subpopulations and decreases malignant traits in colorectal cancer lines. AB - BACKGROUND: Cancer stem-like cells (CSCs) in colorectal cancers (CRC) may account for the failure of treatments because they are resistant to many current anticancer therapies. Salinomycin, a potassium ionophore, was recently identified as a selective inhibitor of breast CSCs. METHODS: The human CRC cell lines HT29 and SW480 were treated with salinomycin and oxaliplatin. Cell viability was determined with cell counting kit 8. Fraction of CD133+ cell subpopulations was assessed by Flow Cytometric analysis. Clonogenecity and migration were determined with soft agar and Boyden chamber assays. Molecular changes were assessed by immunofluorescence staining, RT-PCR, and Western blot analysis. RESULTS: We report that salinomycin reduces the proportion of CD133+ subpopulations in human CRC HT29 and SW480 cells. Furthermore, salinomycin treatment decreases colony forming ability and cell motility in HT29 cells. Moreover, salinomycin downregulates the expression of vimentin and induces the E-cadherin expression in HT29 cells. CONCLUSIONS: This study demonstrates the ability of salinomycin to selectively target "CD133+" cell subpopulations and decrease the malignant traits in colorectal cancer lines. PMID- 21267785 TI - A prospective comparison of the prognostic value of tumor- and patient-related factors in patients undergoing potentially curative surgery for pancreatic ductal adenocarcinoma. AB - BACKGROUND: Outcome prediction after resection with curative intent for pancreatic ductal adenocarcinoma remains a challenge. There is increasing evidence that the presence of an ongoing systemic inflammatory response is associated with poor outcome in patients undergoing resection for a variety of common solid tumors. Our aim was to prospectively evaluate the prognostic value of tumor- and patient-related factors including the systemic inflammatory response in patients undergoing potentially curative surgery for pancreatic ductal adenocarcinoma of the head of pancreas. METHODS: The prognostic impact of tumor factors such as stage and host factors, including the systemic inflammatory response (modified Glasgow Prognostic Score [mGPS]), were evaluated in a prospective study of 135 patients who underwent elective pancreaticoduodenectomy for pancreatic ductal adenocarcinoma from January 2002 to April 2009. RESULTS: In addition to the established tumor-related pathological factors (in particular margin involvement; hazard ratio [HR] 2.82, 95% confidence interval [CI] 1.65 4.84, P < 0.001), an elevated mGPS (HR 2.26, 95% CI 1.43-3.57, P < 0.001) was independently associated with lower overall survival after pancreaticoduodenectomy. Additionally, in an adjuvant therapy subgroup of 74 patients, both margin involvement and an elevated mGPS remained independently associated with reduced overall survival. CONCLUSIONS: We have prospectively validated the influence of tumor-related and patient-related factors. Margin involvement and the preoperative mGPS were the most important determinants of overall survival in patients undergoing potentially curative pancreaticoduodenectomy. Furthermore, both had independent prognostic value in those patients receiving adjuvant chemotherapy. In the future, this may be considered a stratification factor for entry onto therapeutic trials. PMID- 21267786 TI - Senescence-associated gene YPEL3 is downregulated in human colon tumors. AB - BACKGROUND: Previous work has demonstrated YPEL3 to be a growth-suppressive protein that acts through a pathway of cellular senescence. We set out to determine whether human colon tumors demonstrated downregulation of YPEL3. METHODS: We collected colon tumor samples with matched normal control samples and analyzed them for YPEL3 gene expression by reverse transcriptase-polymerase chain reaction and CpG hypermethylation of the YPEL3 promoter by base-specific polymerase chain reaction analysis. Colon cancer cell lines (Caco-2 and HCT116(-/ ) p53) were used to assess YPEL3 gene expression after treatment with 5 azadeoxycytidine or trichostatin A. RESULTS: Reverse transcriptase-polymerase chain reaction analysis demonstrated a decrease in YPEL3 expression in tumor samples when compared to their patient-matched normal tissue. We determined that DNA methylation of the YPEL3 promoter CpG island does not play a role in YPEL3 regulation in human colon tumors or colon cancer cells lines, consistent with the inability of 5-azadeoxycytidine treatment to induce YPEL3 expression in colon cancer cell lines. In contrast, colon cell line results suggest that histone acetylation may play a role in YPEL3 regulation in colon cancer. CONCLUSIONS: YPEL3 is preferentially downregulated in human colon adenocarcinomas. DNA hypermethylation does not appear to be the mechanism of YPEL3 downregulation in this subset of collected patient samples or in colon cell lines. Histone acetylation may be a relevant epigenetic modulator of YPEL3 in colon adenocarcinomas. Future investigation of YPEL3 and its role in colon cancer signaling and development may lead to increased understanding and alternative treatment options for this disease. PMID- 21267787 TI - The "tipping point" for breast cancer mortality decline has resulted from size reductions due to mammographic screening. PMID- 21267788 TI - Minimal extrathyroidal extension in patients with papillary thyroid microcarcinoma: is it a real prognostic factor? AB - BACKGROUND: The clinical impact of minimal extrathyroidal extension (ETE) in patients with conventional papillary thyroid microcarcinoma (PTMC) is still controversial. The clinicopathologic characteristics of patients with or without minimal ETE or recurrence and the clinical impact of minimal ETE were investigated. METHODS: This study included 288 patients with conventional PTMC (mean age, 46.6 years; 262 female and 26 male subjects) and more than 5 years of follow-up. Patients were divided into two groups according to ETE and recurrence, and clinicopathologic characteristics between two groups were investigated. Disease-free survival was calculated to compare the clinical impact of minimal ETE between patients with and without ETE. RESULTS: Mean size (6.9 mm) of PTMCs in patients with minimal ETE (n = 89) was significantly larger than that in those (5.8 mm) without (n = 199) (P < 0.001). Tumor size [odds ratio (OR) = 1.185; 95% confidence interval (CI) 1.052-1.334], central lymph node (LN) metastasis at diagnosis (OR 2.105; 95% CI 1.182-3.750), and not well-defined margin on ultrasound (OR 3.808; 95% CI 1.055-13.736) were significantly associated with minimal ETE. Twelve patients (4.2%) had recurrence. No clinicopathologic factor was associated with recurrence. Disease-free survival was not significantly different between patients with and without minimal ETE (P = 0.671). CONCLUSIONS: Minimal ETE was statistically significantly associated with tumor size, central LN metastasis, and not well-defined margin on ultrasound. Minimal ETE had no impact on recurrence in patients with conventional PTMC. PMID- 21267789 TI - Secondary maxillofacial reconstruction with the radial forearm free flap: a standard operating procedure for the venous microanastomoses. AB - BACKGROUND: The radial forearm free flap (RFFF) is commonly used in reconstructive surgery. With respect to the maxillofacial region, several venous anastomotic techniques (e.g., single or double anastomoses) have been described, but the debate as to which alternative is preferable is ongoing. A complicating factor is the unpredictable anatomical situation in patients undergoing secondary operation. No recommendations are available for the surgical strategy in such cases. We present a standard operating procedure (SOP) applicable for secondary reconstructions, postulating double anastomoses as the method of choice, and evaluate its efficacy. METHODS: The following parameters were retrospectively analyzed for 120 patients with secondary (41; 34.2%) or primary (79; 65.8%) reconstruction following the instructions of SOP and compared between the study groups: age; sex; history of radiotherapy; side of the donor arm; flap size; preparation and use of the cephalic vein and reasons for its non-inclusion; included venae comitantes; recipient veins; arterial anastomoses; revisions, flap survival, and mortality within thirty days after operation. RESULTS: The method of choice was applicable in 26 (63.4%) secondary and 52 (65.8%) primary reconstructions (no difference; P = 0.841), resulting in 100% flap viability in both groups. In the remaining cases, single venous anastomoses were performed, resulting in 73.3% flap viability in secondary and 100% in primary reconstructions. Flap survival in secondary reconstructions was significantly higher when double anastomoses were conducted (P = 0.012). CONCLUSIONS: The results suggest the necessity of double venous anastomoses in secondary maxillofacial reconstructions with RFFF. PMID- 21267790 TI - Her-2/neu gene amplification in esophageal adenocarcinoma and its influence on survival. AB - BACKGROUND: HER-2/neu (c-erbB-2, HER2) gene amplification and protein overexpression have been associated with poor prognosis in several solid tumors, including breast and gastric cancer. Its incidence and significance in esophageal adenocarcinoma is unknown. MATERIALS AND METHODS: Tissue microarrays were successfully constructed from 89 paraffin-embedded archival specimens of esophageal adenocarcinomas for HER2 gene amplification by silver-enhanced in situ hybridization (SISH). No patients had undergone neoadjuvant therapy. Protein overexpression was tested with immunohistochemistry (IHC) using automated immunostaining (Ventana Benchmark). Incidence of HER2 positivity, correlation to clinicopathological variables in esophageal cancer patients, and concordance between SISH and IHC were determined. RESULTS: True HER2 gene amplification was detected in 14 esophageal cancer specimens (16%), and 92% of those with high level HER2 amplification showed positive HER2 protein overexpression. No significant associations were found among gene amplification and clinicopathological factors. The 5-year survival rates were 57% for esophageal cancer patients with HER2 amplification compared with 32% without, but the difference in overall survival was not significant (P = .37). The correlation between SISH and IHC was statistically significant (P < .0001). CONCLUSION: While molecular targeting may be possible for approximately 16% of esophageal adenocarcinoma patients, HER2 oncogene amplification did not influence survival in this study. PMID- 21267791 TI - Prognosis of hepatocellular carcinoma in relation to treatment across BCLC stages. AB - BACKGROUND: The Barcelona Clinic Liver Cancer (BCLC) staging system recommends first-line therapy for each tumor stage. We evaluated the effect of compliance with BCLC treatment allocation on the prognosis of patients with hepatocellular carcinoma (HCC). METHODS: We retrospectively analyzed 359 consecutive, newly diagnosed HCC patients treated in our Liver Unit during a 14-year period. For each stage, survival was compared according to whether treatment matched the BCLC recommendation. We also compared the survival of patients in the same BCLC stage who received different treatments, and patients in different BCLC stages receiving the same treatment. RESULTS: BCLC-A patients treated with radical therapies (66%) survived longer (117 vs. 20 months; p < 0.001) than patients (33%) who received locoregional or systemic therapies. Survival of BCLC-B patients treated with locoregional treatments (57%) was shorter (24 vs. 71 months; p < 0.001) than that of patients receiving radical therapies (32%). BCLC C patients treated with systemic therapy or supportive care survived shorter (6 vs. 11 months; p = 0.003) than those receiving locoregional therapies (39%). Survival of BCLC-D patients receiving systemic therapies or supportive care was significantly lower than that of patients treated by liver transplantation (5 vs. 137 months; p < 0.001). CONCLUSIONS: In addition to BCLC stage, actual treatment determines survival in patients with HCC. PMID- 21267792 TI - High accuracy of multislices computed tomography (MSCT) for para-aortic lymph node metastases from gastric cancer: a prospective single-center study. AB - BACKGROUND: The purpose of this study is to analyze the diagnostic accuracy of MSCT in the identification of para-aortic lymph node metastases from gastric cancer. METHODS: A total of 92 consecutive patients with primary gastric cancer were prospectively submitted to preoperative MSCT staging according to a standard protocol in the period 2003-2010. All diagnostic procedures were performed by dedicated radiologists who were unaware of the final pathological nodal status. Subsequently all patients underwent potentially curative (R0) resection with extended lymphadenectomy plus para-aortic nodal dissection. Lymph node mapping in different stations and retrieval of single lymph nodes were performed by the surgeon on the fresh specimen and then submitted for pathological examination. Clinical, radiological, and pathological data were prospectively stored on database. RESULTS: A median number of 47 (range: 18-114) total lymph nodes and 7 (range: 3-29) para-aortic lymph nodes were removed. In 13 of 92 included patients (14%), histological examination demonstrated para-aortic nodal metastases; MSCT was correctly positive in 11 of these cases (sensitivity: 85%). In 79 patients para-aortic nodes were not involved, and MSCT resulted correctly negative in 75 of these patients (specificity: 95%). Positive (PPV) and negative (NPV) predictive values were 73 and 97%, with a global accuracy of 93%. CONCLUSIONS: MSCT performed according to a standard protocol by dedicated radiologists demonstrated high accuracy in preoperative identification of para-aortic nodal metastases from gastric cancer. These results may be useful in planning surgical approach or during clinical staging before neoadjuvant chemotherapy. PMID- 21267794 TI - Modulation of triterpene saponin production: in vitro cultures, elicitation, and metabolic engineering. AB - Saponins are secondary metabolites that are widely distributed in the plant kingdom and are often the active components in medicinal herbs. Hence, saponins have a potential for the pharmaceutical industry as antibacterial, virucidal, anti-inflammatory, and anti-leishmanial drugs. However, their commercial application is often hindered because of practical problems, such as low and variable yields and limited availability of natural resources. In vitro cultures provide an alternative to avoid problems associated with field production; they offer a system in which plants are clonally propagated and yield is not affected by environmental changes. Additionally, treatment of in vitro cultures with elicitors such as methyl jasmonate may increase the production of saponins up to six times. In vitro cultures are amenable to metabolic engineering by targeting specific genes to enhance saponin production or drive production towards one specific class of saponins. Hitherto, this approach is not yet fully explored because only a limited number of saponin biosynthesis genes are identified. In this paper, we review recent studies on in vitro cultures of saponin-producing plants. The effect of elicitation on saponin production and saponin biosynthesis genes is discussed. Finally, recent research efforts on metabolic engineering of saponins will also be presented. PMID- 21267793 TI - CD46 plasticity and its inflammatory bias in multiple sclerosis. AB - Known as a link to the adaptive immune system, a complement regulator, a "pathogen magnet" and more recently as an inducer of autophagy, CD46 is the human receptor that refuses to be put in a box. This review summarizes the current roles of CD46 during immune responses and highlights the role of CD46 as both a promoter and attenuator of the immune response. In patients with multiple sclerosis (MS), CD46 responses are overwhelmingly pro-inflammatory with notable defects in cytokine and chemokine production. Understanding the role of CD46 as an inflammatory regulator is a distant goal considering the darkness in which its regulatory mechanisms reside. Further research into the regulation of CD46 expression through its internalization and processing will undoubtedly extend our knowledge of how the balance is tipped in favor of inflammation in MS patients. PMID- 21267795 TI - Accidental endosulfan ingestion in a toddler. PMID- 21267796 TI - Childhood tuberculosis challenges and way forward. PMID- 21267797 TI - Determinants of health related quality of life in school-going adolescents in Northern India. AB - OBJECTIVE: To identify determinants of good Health Related Quality of Life (HRQoL) in school going adolescents. METHODS: This Cross-sectional study was conducted in public and private schools in Lucknow, Northern India after obtaining institutional ethical clearance. Children aged 10 to 19 years were included after obtaining parental written informed consent. HRQoL was assessed using culturally appropriate WHOQOL-BREF version. RESULTS: From 1900 schools in Lucknow, 10 public and 10 private schools were selected. Within schools, random selection of the subjects was done. Dropout rate was 7.2% (525/566). Mean age of participants was 14.04 +/- 2.09 years, of which 52.4% (275/525) were boys and 48.5% (255/525) were from private schools. Good HRQoL was a score >=83, which corresponded to third quartile, and 33.7% and 16.6% of subjects, from private and public schools, respectively, fell in this category (p-value <0.0001). Determinants of good HRQoL on multivariate analysis were age <14 years (OR: 2.11, 95%CI 1.39-3.02, p < 0.0001) and studying in private school (OR = 2.04, 95%CI 1.18-3.51, p < 0.0001). CONCLUSIONS: Younger adolescent age and enrolment in private schools are determinants of good HRQoL in school-going adolescents. Further research is needed to identify measures to improve HRQoL among older adolescents and those studying in public schools. PMID- 21267798 TI - Selection of a port for use in laparoendoscopic single-site surgery. AB - Laparoendoscopic single-site surgery (LESS) is a novel technique that aims to perform abdominal surgery through a single incision. Various access techniques and ports exist. This review will attempt to describe the currently available ports as well as highlight their advantages and disadvantages. PMID- 21267799 TI - Implant survival, knee function, and pain relief after TKA: are there differences between men and women? AB - BACKGROUND: As efforts continue to improve the results of TKA, the potential influence of sex and gender on long-term survival of implants, knee function, pain relief, and patient satisfaction remains relevant, particularly given the increased incidence of osteoarthritis of the knee in women and reports that women derive equal benefit from TKA. QUESTIONS/PURPOSES: This article reviews the literature pertinent to the question of whether long-term survival, knee function, pain relief, and patient satisfaction after TKA differ between men and women. METHODS: Large clinical series (> 1000 patients) published in the last 10 years were identified in PubMed and reviewed. RESULTS: Men may be at higher risk of revision surgery than women. Sex/gender has been consistently shown to impact both function and pain relief both before and after TKA. Although women achieve at least the same degree of functional improvement as men, women have worse preoperative physical function and do not reach the same final level of physical function as men. Likewise women may have similar or even greater improvement in pain after arthroplasty than men but still have final pain scores that are less favorable. CONCLUSIONS: Further research is required to understand the sex and gender differences contributing to implant survival, physical function, and pain relief after TKA. Strategies need to be developed to identify any patient who is at higher risk of implant failure, suboptimal postoperative function, and incomplete pain relief. PMID- 21267800 TI - Coculture of engineered cartilage with primary chondrocytes induces expedited growth. AB - BACKGROUND: Soluble factors released from chondrocytes can both enhance and induce chondrocyte-like behavior in cocultured dedifferentiated cells. The ability to similarly prime and modulate biosynthetic activity of differentiated cells encapsulated in a three-dimensional environment is unknown. QUESTIONS/PURPOSES: To understand the effect of coculture on engineered cartilage, we posed three hypotheses: (1) coculturing with a monolayer of chondrocytes ("chondrocyte feeder layer") expedites and increases engineered tissue growth; (2) expedited growth arises from paracrine effects; and (3) these effects are dependent on the specific morphology and expression of the two dimensional feeder cells. METHODS: In three separate studies, chondrocyte-laden hydrogels were cocultured with chondrocyte feeder layers. Mechanical properties and biochemical content were quantified to evaluate tissue properties. Histology and immunohistochemistry stains were observed to visualize each constituent's distribution and organization. RESULTS: Coculture with a chondrocyte feeder layer led to stiffer tissue constructs (Young's modulus and dynamic modulus) with greater amounts of glycosaminoglycan and collagen. This was dependent on paracrine signaling between the two populations of cells and was directly modulated by the rounded morphology and expression of the feeder cell monolayer. CONCLUSIONS: These findings suggest a potential need to prime and modulate tissues before implantation and present novel strategies for enhancing medium formulations using soluble factors released by feeder cells. CLINICAL RELEVANCE: Determining the soluble factors present in the coculture system can enhance a chondrogenic medium formulation for improved growth of cartilage substitutes. The feeder layer strategy described here may also be used to prime donor cartilage allografts before implantation to increase their success in vivo. PMID- 21267801 TI - Dynamic regulation of mitochondrial network and oxidative functions during 3T3-L1 fat cell differentiation. AB - Mitochondria have been shown to be impaired in insulin resistance-related diseases but have not been extensively studied during the first steps of adipose cell development. This study was designed to determine the sequence of changes of the mitochondrial network and function during the first days of adipogenesis. 3T3 L1 preadipocytes were differentiated into adipocytes without using glitazone compounds. At days 0, 3, 6, 9, and 12, mitochondrial network imaging, mitochondrial oxygen consumption, membrane potential, and oxidative phosphorylation efficiency were assessed in permeabilized cells. Gene and protein expressions related to fatty acid metabolism and mitochondrial network were also determined. Compared to preadipocytes (day 0), new adipocytes (days 6 and 9) displayed profound changes of their mitochondrial network that underwent fragmentation and redistribution around lipid droplets. Drp1 and mitofusin 2 displayed a progressive increase in their gene expression and protein content during the first 9 days of differentiation. In parallel with the mitochondrial network redistribution, mitochondria switched to uncoupled respiration with a tendency towards decreased membrane potential, with no variation of mtTFA and NRF1 gene expression. The expression of PGC1alpha and NRF2 genes and genes involved in lipid oxidation (UCP2, CD36, and CPT1) was increased. Reactive oxygen species (ROS) production displayed a nadir at day 6 with a concomitant increase in antioxidant enzyme gene expression. This 3T3-L1-based in vitro model of adipogenesis showed that mitochondria adapted to the increased number of lipid droplets by network redistribution and uncoupling respiration. The timing and regulation of lipid oxidation-associated ROS production appeared to play an important role in these changes. PMID- 21267802 TI - Slow and steady: sustained effects of lexico-semantic associations can mediate referential impairments in schizophrenia. AB - The present study investigated the contribution of lexico-semantic associations to impairments in establishing reference in schizophrenia. We examined event related potentials as schizophrenia patients and healthy, demographically matched controls read five-sentence scenarios. Sentence 4 introduced a noun that referred back to three possible referents introduced in Sentences 1-3. These referents were contextually appropriate, contextually inappropriate but lexico-semantically associated, and contextually inappropriate and lexico-semantically nonassociated. In order to determine whether participants had correctly linked the anaphor to its referent, the final sentence reintroduced each referent, and participants indicated whether the last two sentences referred to the same entity. Results indicated that between 300 and 400 ms, patients, like healthy controls, used discourse context to link the noun with its preceding referent. However, between 400 and 500 ms, neural activity in patients was modulated only by lexico-semantic associations, rather than by discourse context. Moreover, patients were also more likely than controls to incorrectly link the noun with contextually inappropriate but lexico-semantically associated referents. These results suggest that at least some types of referential impairments may be driven by sustained activation of contextually inappropriate lexico-semantic associations. PMID- 21267803 TI - [Uncomplicated urinary tract infection and treatment]. AB - Urinary tract infections (UTI) are frequent infections in the outpatient and hospital setting. With respect to treatment options, UTI can generally be stratified into uncomplicated and complicated / nosocomial infections. Uncomplicated UTI are represented by the acute uncomplicated cystitis and the uncomplicated pyelonephritis. They are mainly caused by E. coli. There are, however, also increasing resistance rates found in uncomplicated UTI, e. g., against aminopenicillins, cotrimoxazole and increasingly also fluoroquinolones. This development has called for a new evaluation of the treatment recommendations in uncomplicated UTI. As an empirical therapy for uncomplicated cystitis fosfomycin trometamol, nitrofurantoin or pivmecillinam are recommended as first line agents. As the oral first line therapy for uncomplicated pyelonephritis fluroquinolones in high dosages are recommended. The frequent asymptomatic bacteriuria does not need to be treated, with only a few exceptions. Due to the increasing antibiotic resistance and the emergence of multiresistant uropathogens, empirical antibiotic treatment becomes more difficult. Therefore the results of susceptibility testing should be awaited whenever possible. PMID- 21267804 TI - [Perioperative antibiotic prophylaxis in radical retropubic prostatectomy: a randomised pilot study of perioperative and postoperative administration]. AB - PURPOSE: A standard protocol for perioperative antibiotic prophylaxis in radical retropubic prostatectomy has not been established until now. The present pilot study compared the perioperative single-dose of piperacillin/tazobactam to the administration of ciprofloxacin or cotrimoxazol for 5 days with regard to postoperative infections. For the first time these antibiotic regimes were described in radical retropubic prostatectomy. MATERIAL AND METHODS: The patients were divided into three groups, each consisting of 17 patients: group 1: a single dose of piperacillin / tazobactam 4.5 g i. v., group 2: ciprofloxacin 500 mg or cotrimoxazol 960 mg i. v. / p. o. and group 3: varying administration and duration of different kinds of antibiotics as control group. The basic characteristics of the patients such as age, body-mass-index, risk factors, diseases, former surgeries and medication were similar between all three groups. Also there were no significant differences in intraoperative parameters such as operation time, blood loss and other postoperative complications. RESULTS: The piperacillin / tazobactam group showed a significantly lower body temperature on postoperative days (POD) 1-3. The laboratory values were not significantly different among the groups, except the piperacillin / tazobactam group showed a significantly lower CRP level on POD 1-3 than group 3. All antibiotic regimes could afford an efficient protection: None of the patients died and there were no cases of serious consequences such as pneumonia, urosepsis or bacteriuria. Although not statistically significant, the piperacillin / tazobactam group showed better clinical outcomes: here the length of hospitalisation was two days less than in the other groups, no cases of wound infection occurred, the antimicrobial resistance rates were lower and fewer patients were treated with antibiotics in the postoperative course. CONCLUSIONS: Comparable to similar studies with a larger number of patients our pilot study demonstrated, although statistically not significant, better clinical results overall. We therefore conclude that a single-dose of piperacillin / tazobactam appears to be an efficient antibiotic prophylaxis in radical retropubic prostatectomy and even in some clinical parameters piperacillin / tazobactam seems to be equivalent or better than the usual 5-day administration of antimicrobial prophylaxis. PMID- 21267805 TI - [Reifensteiner pouch: A simplified ileum-colon pouch with umbilical-stoma based on the Mainz pouch I]. AB - Continent urinary diversion after radical cystectomy is the method of choice for suitable patients. For patients, in whom orthotopic bladder replacement with connection to the urethra stump is not possible, different pouches have been developed mostly with anastomosis to the umbilicus. These pouches have to be constructed with regard to three major principles: First, it has to be built as a low-pressure reservoir which does not interfere with high-pressure peaks during filling. Second, a direct transmission of the pressure by reflux from the pouch to the urinary system of the kidney has to be avoided. Finally, a sufficient continence mechanism has to be built to avoid urinary leakage. The standard procedure is the Mainz I pouch. This method is technically challenging and burdened with multiple complications regarding the continence mechanism, which is made by submucous placement of the appendix. Therefore, this operation is mostly performed in specialised centres. In this paper a simplified version of the continent umbilical pouch is, which has been applied in 11 patients. Instead of building the continence mechanism by using the appendix, the continent umbilical pouch acts as a natural valve. To prevent pressure transmission to the upper urinary tract, a part of the terminal ileum is connected proximally, which is built like an ileum conduit. Thereby it is possible to protect the upper urinary tract, as the pressure transmission from the pouch is not reduced by a static antireflux mechanism but by an air-chamber-like-mechanism. By means of the combination of urological standard procedures (like the ileum conduit) and a pouch, which is less challenging to construct, this method is technically simplified and therefore reduces operating time. Stoma stenosis, which had occurred in the first operated patients, was avoidable by a minimal change in technique in the following patients. Other complications that we saw (hernia, mucous tamponades), were not related to the used urinary diversion method. Therefore, this procedure is practical, technically simple and the results for patients are satisfying. This kind of continent pouch with umbilical stoma offers the opportunity for more patients to be operated on with this method. Further observation of the operated patients, possibly with with urodynamic examination, is necessary. PMID- 21267806 TI - [Clinical utility of an antimicrobial blocking solution in patients with an indwelling catheter]. AB - OBJECTIVE: Patients with indwelling catheters have a substantial long-term risk for catheter incrustation and blockage. Chronic bacteriuria is regarded as a risk factor for this complication. Until today, there are no effective prophylactic measures. We evaluated the effect of a triclosan-containing fluid for inflation of the catheter balloons (Farco-fill(r) Protect) on the extent of bacteriuria in a clinical setting. PATIENTS AND METHODS: In a prospective multicentre study, between 7 / 2009 and 3 / 2010, the effect of Farco-fill(r) Protect on urine culture was evaluated in 62 patients with indwelling catheters. RESULTS: 55 patients could be completely evaluated. With use of Farco-fill(r) Protect, urinary pH, and urine volume / 24 hours remained unchanged. The number of patients with > 10 (5) colony forming units / mL was reduced from 70.9 % to 45.5 %. In 34.5 % the extent of catheter incrustations could be reduced. CONCLUSION: This study is the first to demonstrate a marked reduction of bacteriuria and catheter incrustations with the help of a triclosan-containing fluid in a clinical setting. Long-term studies are necessary to determine whether or not the afore-mentioned effect leads to less catheter occlusions.This finding would have positive medical as well as economic aspects. PMID- 21267807 TI - [Thrombectomy in kidney tumors]. PMID- 21267808 TI - Plasma rich in quercetin metabolites induces G2/M arrest by upregulating PPAR gamma expression in human A549 lung cancer cells. AB - In this study, we incubated human A549 lung cancer cells with quercetin metabolite-enriched plasma (QMP) obtained from Mongolian gerbils 2 h after quercetin feeding (100 mg/kg body wt/week). We investigated the effects of QMP on the growth of A549 cells and the possible mechanisms for these effects. We found that QMP but not control plasma (CP) reduced the cell growth in A549 cells. QMP led to cell cycle arrest at the G (2)/M phase by downregulating the expression of cdk1 and cyclin B. QMP but not CP or quercetin itself significantly increased PPAR- gamma expression (p < 0.05), which was accompanied by an increase of phosphatase and tensin homologue deleted on the chromosome ten level and a decrease of phosphorylation of Akt. Furthermore, quercetin-3-glucuronide and quercetin-3'-sulfate also significantly increased PPAR- gamma expression in A549 cells. GW9662, a PPAR- gamma antagonist, significantly suppressed the effects of 10 % QMP on cell proliferation and on the expression of cyclin B and cdk1. Taken together, these data suggest that the activation of PPAR- gamma plays an important role, at least in part, in the antiproliferative effects of quercetin metabolites. PMID- 21267809 TI - Chemotype-dependent metabolic response to methyl jasmonate elicitation in Artemisia annua. AB - Considerable difference in artemisinin and its direct precursors, artemisinic acid and dihydroartemisinic acid, was detected between two chemotypes within the species Artemisia annua (A. annua). These two chemotypes showed differential metabolic response to methyl jasmonate (MeJA) elicitation. Exogenous application of MeJA resulted in an accumulation of dihydroartemisinic acid and artemisinin in Type I plants. In Type II plants, however, artemisinic acid and artemisinin level decreased dramatically under MeJA elicitation. Squalene and other sesquiterpenes, (e.g., caryophyllene, germacrene D), were stimulated by MeJA in both chemotypes. The effect of MeJA elicitation was also studied at the transcription level. Real time RT-PCR analysis showed a coordinated activation of most artemisinin pathway genes by MeJA in Type I plants. The lack of change in cytochrome P450 reductase (CPR) transcript in Type I plants indicates that the rate-limiting enzymes in artemisinin biosynthesis have yet to be identified. Other chemotype-specific electron donor proteins likely exist in A. annua to meet the demand for P450 mediated reactions in MeJA-mediated cellular processes. In Type II plants, mRNA expression patterns of most pathway genes were consistent with the reduced artemisinin level. Intriguingly, the mRNA transcript of aldehyde dehydrogenase1 (ADHL1), an enzyme which catalyzes the oxidation of artemisinic and dihydroartemisinic aldehydes, was upregulated by MeJA. The differential metabolic response to MeJA suggests a chemotype-dependent metabolic flux control towards artemisinin and sterol production in the species A. annua. PMID- 21267810 TI - Effect on the wound healing process and in vitro cell proliferation by the medicinal Mexican plant Ageratina pichinchensis. AB - The species Ageratina pichinchensis (Asteraceae) has been used for a long time in Mexican traditional medicine for the treatment of different skin conditions and injuries. In this study, the healing capacity of the plant extracts obtained was evaluated and, in order to understand the mechanism of healing, we also analyzed its effect on cell proliferation IN VITRO, cytotoxicity, and skin irritation. Different extracts obtained from the aerial parts of A. pichinchensis, topically administrated, were evaluated in a healing model by scalpel-blade incision on the rat. The extracts, at 10 % concentrations, were administrated daily during an eight-day period. A control group, to which the vehicle was administered, was used; while fibrinolysin (Fibrase SA(r)) was administered for positive control purposes. Reduction in wound size and the histological characteristics of the skin at the end of the treatment were evaluated. Cytotoxicity was evaluated in cell lines KB (nasopharyngeal carcinoma), UISO (squamous cell carcinoma of the cervix), OVCAR (ovarian carcinoma), and HCT-15 (colon carcinoma). In addition, the effect on cell proliferation of cell line MRC-5 (normal cells from human fetal lung) was measured, and skin irritation was evaluated. The results showed an important healing capacity of A. pichinchensis extract in noninfected wounds; the aqueous extract was found to be the most efficient. The extracts exhibited no cytotoxic effect; however, there was an effect that promoted cell proliferation in cell line MRC-5. The products tested demonstrated no skin irritant effects. PMID- 21267811 TI - Stilbenoids from the melinjo (Gnetum gnemon L.) fruit modulate cytokine production in murine Peyer's patch cells ex vivo. AB - Melinjo fruit ( Gnetum gnemon L.) has been used as a food in Southeast Asia. To investigate if this fruit has regulatory actions on ileal immune responses, we measured T-helper (Th) cytokine production, i.e., interleukin-2 (IL-2), IL-4, IL 5, and interferon-gamma (IFN- gamma), in cultured Peyer's patch (PP) cells from mice orally treated with a methanol extract of melinjo fruit. Oral administration of the 50 % ethanol extract at 100 mg/kg/day significantly enhanced the production of the Th1 cytokines IL-2 and IFN- gamma irrespective of concanavalin A stimulation, whereas the production of the Th2 cytokines IL-4 and IL-5 was not affected. We also isolated seven active constituents accompanied with two new stilbenoids from the ethylacetate fraction of the extracts. The structure of the new stilbene glucosides gnemonoside L (5) and gnemonoside M (7) was determined by 1D and 2D NMR and MS analyses. Five known stilbenoids were identified as resveratrol (1), isorhapontigenin (2), gnemonoside D (4), gnetins C (3) and E (6). Among these tested compounds, only new stilbenoid 7 strongly enhanced Th1 cytokine production in cultured PP cells at 10 mg/kg/day. These results indicated that this melinjo extract and its active constituent 7 potentiated T-cell dependent immune responses in the ileal mucosa. PMID- 21267812 TI - Vascular protection by natural product-derived polyphenols: in vitro and in vivo evidence. AB - Epidemiological studies have indicated that regular intake of fruit and vegetables and beverages such as red wine and tea, which contain high levels of polyphenols, is associated with a reduced risk of cardiovascular diseases. The beneficial effect of polyphenol-rich natural products has been attributable, at least in part, to their direct effect on blood vessels, and in particular on endothelial cells. Indeed, polyphenols from tea, grapes, berries, and plants have been shown to activate endothelial cells to increase the formation of potent vasoprotective factors including nitric oxide (NO) and endothelium-derived hyperpolarizing factor. Experimental and clinical studies have also indicated that chronic intake of several polyphenol-rich natural products is able to improve endothelial dysfunction and to decrease vascular oxidative stress associated with major cardiovascular diseases such as hypertension. Altogether, these observations suggest that polyphenol-rich sources of natural products have the potential to improve the function of blood vessels and, hence, to protect the vascular system. PMID- 21267813 TI - [Paraneoplastic syndromes in lung cancer]. AB - Paraneoplastic syndromes occur in approximately 10% of all patients with lung cancer. They can be the first manifestation of the disease or of a recurrence. Endocrine, haematological, neuromuscular, dermatological, renal, and metabolic syndromes as well as syndromes involving the connective tissue and constitutional syndromes can be distinguished based on their clinical symptoms. In this review, the epidemiology, pathogenesis, clinical signs and treatment options for the clinically important paraneoplastic syndromes in lung cancer are discussed. PMID- 21267814 TI - [Analysis of treatment outcomes in two patient cohorts (2004-2005 and 2007-2008) with limited and extensive disease small-cell lung cancer]. AB - PURPOSE: The aim of this retrospective study was to compare patient characteristics, treatment patterns and treatment results in two groups of patients with limited disease (LD) and extensive disease (ED) small-cell lung cancer (SCLC) in 2004 - 2005 vs. 2007 - 2008. PATIENTS AND METHODS: We included all patients with LD or ED SCLC in this retrospective analysis who were diagnosed in our department in the periods 2004 - 2005 and 2007 - 2008. We collected data on patient characteristics, chemotherapy, radiotherapy, treatment response and median survival. Statistical analyses were separately performed for patients in LD and ED SCLC. RESULTS: 109 patients had LD SCLC. The response rate on first line therapy was 74 %. More than half of the cases had recurrent disease. Second line treatment was given to about two thirds of these patients. Third-line therapy was administered in around 15 % of all cases. Prophylactic cranial irradiation was performed more frequently from 2007 - 2008. The median survival was 17 months. There were no statistically significant differences regarding patient characteristics and treatment results. ED SCLC was present in 188 patients. The response rate was around 68 %. All patients relapsed, second-line therapy was administered in half of these cases; third-line therapy in 10 % of all cases. No statistically significant differences were detected between the two time frames. Median survival was 10 months. CONCLUSION: Overall, no statistically significant differences were present for patients with LD and ED SCLC in 2004 - 2005 vs. 2007 - 2008. Prophylactic cranial irradiation was employed more frequently in LD SCLC from 2007. PMID- 21267815 TI - [How can the impact of Health Technology Assessment (HTA) in the Austrian healthcare system be assessed? Design of a conceptual framework]. AB - INTRODUCTION: In Austria research in Health Technology Assessment (HTA) has been conducted since the 1990s. Research in HTA aims at supporting an adequate and efficient use of health care resources in order to sustain a publicly financed and solidary health care system. Ultimately, HTA research should result in better health of the population. Research results should provide independent information for decision makers. For legitimizing further research resources and for prioritizing future HTA research and guaranteeing the value of future research, HTA research needs itself to undergo evaluation. Aim of the study is to design a conceptual framework for evaluating the impact of HTA research in Austria on the basis of the existing literature. METHODS: An already existing review which presents methods and concepts how to evaluate HTA-impact was updated by a systematic research including literature of the years 2004-January 2010. Results were analysed in regard to 4 categories: definition of the term impact, target groups and system levels, operationalisation of indicators and evaluation methods. RESULTS: Overall, 19 publications were included. Referring to the 4 categories, an explanation of impact has to take into account HTAs multidisciplinary setting and needs a context related definition. Target groups, system levels, indicators and methods depend on the impact defined. Studies investigated direct and indirect impact and were focused on different target groups like physicians, nurses and decision makers on the micro-, and meso level, as well as politicians and reimbursement institutions on the macro level. Except for one reference all studies applied already known and mostly qualitative methods for measuring the impact of HTA research. Thus, an appropriate pool of instruments seems to be available. There is a lack of information about validity of applied methods and indicators. By adapting adequate methods and concepts a conceptual framework for the Austrian HTA-Impact evaluation has been designed. CONCLUSIONS: The paper presents an overview of existing methods for the evaluation of the HTA research. This has been used to identify useful approaches for measuring the HTA-impact in Austria. By providing a context sensitive framework for impact evaluation in Austria the Austrian HTA-research contributes to the international trend of impact-evaluation. PMID- 21267816 TI - [Children of single mothers: health risks and environmental stress]. AB - BACKGROUND AND AIM: In Germany the risk for relative poverty has increased profoundly during the last 15 years, especially among single parent families. As poverty is often associated with bad health we examined the physical and mental health as well as health-related behaviour, housing and environmental conditions in children with lone mothers versus children in couple families. STUDY POPULATION AND METHODS: In 3 cross-sectional surveys conducted during 2004-2007 in 3 cities and 3 rural areas in Bavaria data on 19 039 pre-school children (47% female) were collected. Health, behaviour and exposure assessment was based on parental reports. The 18 327 cases with complete information on family status were analysed. 10% of the children grew up with single mothers. RESULTS: Single mothers evaluated the general state of health of their children more often as moderate to very poor than couple parents (OR [95% CI]: male: 1.37 [1.07-1.77], female 1.77 [1.33-2.35]). Sons with single mothers were more often obese (1.44 [1.09-1.90]). They scored significantly higher in the SDQ total difficulties score (1.94 [1.44-2.62]), on the emotional problem scale (1.91 [1.40-2.59]) as well as on the hyperactivity scale (1.82 [1.35-2.47]) compared to boys from couple families. No difference was found in prosocial behaviour. Girls with single mothers revealed more often conduct problems 1.36 [1.02-1.81] compared to those from couple families. They also showed a significantly higher prevalence of asthma (2.06 [1.29-3.30]). Children living with their single mothers were less often members of sports clubs and the boys were less physical active. No difference was found regarding the consumption of fruits and vegetables. Single mother family was associated with children's environmental tobacco smoke exposure at home (2.03 [1.79-2.29]). Single mothers perceived higher environmental exposures to noise and air pollution, suffered more often from a lack of accessible green spaces in the neighbourhood and reported a higher traffic load on the residential street. CONCLUSION: Children with single mothers reveal increased health risks and live under significantly poorer housing and environmental conditions. Further analyses are necessary to identify the mediating factors. PMID- 21267817 TI - [Health and life satisfaction in north-east German rural communities in 1973, 1994 and 2004/08]. AB - The development of the perceived state of health, the lifetime prevalence of chronic heart disease, hypertension and diabetes mellitus, and the life satisfaction of residents in rural communities in north-eastern Germany were analysed over the years 1973, 1994 and 2004/08 with reference to age and sex, and evaluated in comparison with nationally representative data. The analyses are based on data of surveys of the adult residential population of 14 rural communities in north-eastern Germany carried out in 1973 (N=3,603), 1994 (N=2,155) and 2004/08 (N=1,246). While there was an increase over time in the proportion of the population who assessed their health status as very good or good, the prevalence of hypertension and diabetes mellitus also rose successively. Life satisfaction was lower in 2004/08 than in 1994 in terms of almost all factors. A comparison with the results of nationally representative surveys shows that the illness burden of the population in the region we investigated was higher than average, while the perceived health status was considerably below average, as was the satisfaction with the work situation and the financial situation in particular. The development of health and illness parameters in accordance with the general trend is assessed as an expression of the modernisation of the working and living conditions in the region over this period, whereas the observed differences in levels are interpreted as a consequence of the rural nature of the region and peripherisation. PMID- 21267818 TI - [Evolution of Urology in Maghreb]. PMID- 21267819 TI - [Management of balanitis]. AB - Balanitis set in practice an aetiological and therapeutical problem. The clinical aspect is not specific except for the pustules which evoke a candidiasis. The mycological and bacteriological cultures should be performed in accordance with the clinical context. The biopsy is useful in case of chronic balanitis resistant to the treatment. Irritation and candidal infection are the main causes. Herpes and primary syphilis should be systematically ruled out. The treatment should not be aggressive and must take into account the possible psychological impact. PMID- 21267820 TI - [Renal failure in Tunisian patients with type 2 diabetes: frequency and related factors]. AB - BACKGROUND: Frequent screening of renal failure and good glycaemic control in diabetic patients can avoid this severe complication. AIM: To evaluate the frequency of renal failure and the associated risk factors among type 2 diabetic Tunisian in-patients. Glomerular filtration rate was estimated using the Cockcroft-Gault formula. Renal failure was diagnosed on figure of glomerular filtration rate inferior than 60 ml/min. RESULTS: Six hundred eighty-nine patients were included. The sex ratio was 0.65. The mean age was 60 +/- 11 years. The frequency of renal failure was 19.8% (137 patients) with dominance of a moderate form defined by a glomerular filtration rate between 30 and 59 ml/min (82.5% of patients). Patients with renal failure were older and less obese than diabetic patients without this complication (p<0.00001 and 0.02 respectively). The duration of both diabetes and hypertension was higher in presence of renal failure (p=0.0001 and p<0.001 respectively). Patients with renal failure had more often hypertension and dyslipidemia than patients with normal renal function (p<0.001 and p=0.01 respectively). A personal history of severe retinopathy treated by laser, of coronary disease or of stroke was significantly associated to renal failure (p=0.002, p<0.0001 and p=0.001 respectively). CONCLUSION: The frequency of renal failure observed in Tunisian patients diagnosed with type 2 diabetes is high. Hypertension and dyslipidemia should be carefully treated to prevent or delay the evolution to the renal failure. PMID- 21267821 TI - Is the rapid whole blood test useful for diagnosis and monitoring celiac disease in children? AB - AIM: To evaluate a new whole blood rapid test for the detection of IgA anti transglutaminase (ATG) for diagnosis and diet survey of celiac disease (CD). METHODS: 57 children, 20 of them were CD patients on a gluten-free diet and 37 were under suspicion of CD were enrolled. IgAATG was detected by the conventional ELISA test and the new rapid whole blood test. RESULTS: Concordance between the 2 tests was 96.4%. All patients positive with ELISA were also positive by the rapid test. Only 2 patients were slightly positive by the rapid test and negative by ELISA. CONCLUSION: Whole blood rapid test seems to be as performant as ELISA test for IgAATG detection. PMID- 21267822 TI - Dermatomyositis and breast cancer: a multicenter Tunisian retrospective study of 13 cases. AB - AIM: To evaluate the epidemiological, clinical, biological features and prognostic factors in patients presenting an association of dermatomyositis (DM) and breast cancer (BC). METHODS: Medical records of 13 patients with DM and BC among 210 DM collected from January 1982 to march 2009 were retrospectively reviewed. RESULTS: Mean age was 47 +/- 18 years. DM preceded BC in 3 patients, was concurrent with BC in 2 cases and followed it in 8 cases. Clinically, ulcerative and bullous lesions predominating on limbs were observed in 2 patients. A severe proximal muscular weakness was observed in 4 cases and one patient has presented an amyopathic dermatomyositis. BC was staged IV in 3 pts, IIIA in 2 cases while 3 had stage IIB, 3 stage IIA and 2 stage I according to TNM classification. Nine out of 13 patients had parallel improvement of DM symptoms after treatment of BC. Five patients died of recurrence or distant metastasis (mortality 41.66%). Median survival was 35 months (3-177) after DM diagnostic. CONCLUSION: In Tunisia, DM is associated with an increased incidence of BC. A paraneoplastic course of DM is noted in 70% of patients. In view of the increased risk of BC in our country, in addition to routine examination and laboratory screening, mammography, chest ultrasound, and gynaecological examination, are indicated in women with DM older than 40 years, particularly in case of previous personal or familial history of breast neoplasm. PMID- 21267823 TI - [Management of thyroid microcarcinoma. Report of 13 cases]. AB - BACKGROUND: Thyroid microcarcinoma is defined as a tumour of one centimeter or less in its greater diameter. Prognoses and therapeutic modalities remain controversial therapeutic guidelines for surgical treatment. AIM: To analyse the anatomical and clinical characteristics and discuss the modalities of care and therapeutic indications of these microcarcinoma. METHODS: We report a retrospective study concerning 13 cases of thyroid microcarcinoma, diagnosted and treated at the ENT department of Military Hospital of Tunis from 1998 to 2007. RESULTS: The mean age was 41 years and sex-ratio was 0.18. Clinical investigation by cervical ultrasonography found an isolated nodule in 30.7% and a multinodal goiter in 69.2%. Lymph node metastasis was precessiving in two cases. Five patients underwent loboisthmectomy and higt patients had a total thyroidectomy. Surgical lymph node removal was practiced for both cases with preceding cervical node involvement. Iodine 131 ablation was necessary every time when total thyroidectomy was practiced. A six years mean follow-up revealed no recurrence or death. CONCLUSION: Thyroid microcarcinoma is favorable long-term prognosis. Therapeutic modalities are closely depending on risk factors such as histology type, tumor size, lymph node involvement and extra thyroid extension. PMID- 21267824 TI - [Early infections in children following renal transplantation]. AB - BACKGROUND: Infections following renal transplantation in children are a major cause of severe morbidity and mortality. Surgery is complex and performed in a subject whose immunological mechanisms are impaired by end stage renal failure and immunosuppressive drugs. AIM: To evaluate the incidence and the risk factors of early infectious following renal transplantation in children. METHODS: Infectious complications were retrospectively monitored in 37 children receiving renal transplantation at our center from 1992 to 2008. RESULTS: Infectious complications identified were dominated by urinary tract infections occurred in 12 patients. The clinical symptomatology is dominated by fever and decrease in health. In 4 patients the urinary infection was asymptomatic. Three patients had pneumonia; the diagnosis was suspected clinically and confirmed by the chest radiography. Three other patients developed sepsis. In one of them, the etiology was a peritonitis related to dialysis catheter. Two transplant showed a herpetic cheilitis and one patient developed a parvovirus infection that evolved well after two transfusions. In all cases, the outcome was favourable with no deaths or impact on graft function. CONCLUSION: After renal transplantation, the disturbance of inflammatory reactions explains the often latent or delayed infectious process making early diagnosis difficult. It is imperative to monitor infectious to minimize morbidity and mortality. PMID- 21267825 TI - [Bardet - Biedl syndrome in the child. A study of 11 cases]. AB - BACKGROUND: The syndrome of Bardet-Biedl is definite clinically by the association of obesity, polydactyly, pigmentary retinopathy, hypogonadism and backwardness. AIM: To study the epidemiologic, clinical, biological, genetic, therapeutic and evolutionary characteristic of our patients. METHODS: We carried out a retrospective study concerning 11 hospitalized children and/or follow-ups with the service of pediatry of the CHU Hedi Chaker of Sfax for syndrome of Bardet-Biedl during a period of 21 years (1987-2007). RESULTS: The obesity was constant among all patients, polydactyly was found in 9 cases, the fall of night vision in 7 cases. The hypogonadism was constant among all our boys. The bottom of eye was practised among 9 patients, it showed a pigmentary aspect of retinopathy among 8 patients. The electroretinogram was done in 10 patients, it showed a pigmentary retinopathy in all the cases. The radiological exploration of the urinary tract made it possible to identify morphological anomalies in 3 cases. The genetic study concerned the families of one of our patients and it allowed the identification of a new gene BBS8 at one of the families. Treatment was only symptomatic. After 6 years an average retreat, we noted an aggravation of obesity (9cas) and visual deficit (7cas). Only one patient evolved to the chronic renal insufficiency. CONCLUSION: The syndrome of Bardet-Biedl is a hereditary disease characterized by a genetic heterogeneity. The diversity of the systemic attacks defining this syndrome is a source of several handicaps: blindness, backwardness and obesity. The forecast is conditioned by the renal attack of or the interest of an early tracking and genetic council. PMID- 21267826 TI - [Target-controlled intravenous anesthesia during laparoscopic surgery for obesity]. AB - BACKGROUND: The TCI is a mode of administration that provides greater security by allowing more accurate titration of the anesthetic agent. It leads to a better adaptation to the desired effects, and provide a great interest for the realization of anesthetic induction and the prediction of waking for a well- determined population. OBJECTIVE: The aim of our prospective study was to evaluate the feasibility of TCI in patients with morbid obesity undergoing laparoscopic surgery for obesity. METHODS: Thirty patients were included in this study. Age and BMI means were 32 years and 49.31 kg / m2. Our protocol was proposed to associate an hypnotic agent (propofol) to an opioid one (remifentanil) using the technique of the TCI, with respectively Schnider and Minto models. RESULTS: The induction protocol has brought good conditions for laryngoscopy with no hypertensive peak or desaturation episode. The period of unconsciousness was 89 seconds with an average target concentration of propofol of 5.1 mg / ml. We also noted hemodynamic stability in 79% of patients at induction. During both preparation phase and final installation of the patients, a low ERC to 2 hg / ml was consistent with a suitable hemodynami profile. We obtained hemodynamic stability by adapting target concentration of remifentanil at different operating times (Surgical incision: 3.64 hg / ml, insufflation of the peritoneum: 5.37 hg / ml, jejuno-jejunal resection anastomosis: 9 hg / ml, gastric resection and gastrojejunal anastomosis: 14.2 hg / ml). During this period, no episodes of bradycardia or hypotension were noticed. During the recovery phase and while doing the distribution of CEP and CER according to the BMI of patients, we identified two groups: Group 1 (BMI <49 kg / m2): fast time extubation (11 min) and target concentrations of propofol and remifentanil respectively at 1.3 mg / ml and 1.25 hg / ml which is similar to most publications on this subject and Group 2 (BMI> 49 kg / m2): time-delayed extubation (23 min) with very low values of CEP and CER inconsistent with the literature data. PMID- 21267827 TI - [Granulosa cell tumors: a study of 7 cases]. AB - BACKGROUND: The granulosa tumors have been described for the first time in 1855 by Rokitansky. AIMS: To investigate the epidemiological and pathological characteristics of granulosa tumors, and the prognostic factors to determine therapy management. METHODS: Our study is retrospective about 7 cases of granulosa cells tumors treated and monitored at the department C of Gynecology and Obstetrics in the Center of Maternity and Neonatology of Tunis. RESULTS: The average age of our patients was 40 years. The circumstances of discovery are dominated by pelvic pain (3 cases); menometrorrhagia and post-menopausal bleeding (2 cases) and secondary amenorrhea (2 cases). The sonographic most frequent aspect was solido-cystic (3 cases). The final pathologic examination revealed 6 cases of granulosa adult type tumor and one juvenile type. Five tumors were classified as stage Ia, one tumor was stage Ic and one stage IIa. The treatment was conservative in most cases. An ilioobturator and para-aortic lymphadenectomy was performed in 3 cases. Two patients had adjuvant chemotherapy. Six patients were in complete remission at the last inspection. There were two cases of pregnancies carried till birth after surgical treatment. CONCLUSION: The granulosa tumors are characterized by their natural history with a slow and indolent character and their secretion of sex hormones. PMID- 21267828 TI - Management of perineal ectopic testes. AB - BACKGROUND: Perineal ectopic testis (PET) is a rare congenital anomaly in which the testis is abnormally situated between the penoscrotal raphe and the genitofemoral fold. AIM: we report six patients treated for PET. The epidemiological, clinical, radiological and therapeutic aspects of this rare entity are discussed in light of data of the literature. RESULTS: Between 2000 and 2009, six patients (0, 2%) treated for PET were diagnosed among 2156 patients operated upon for undescended testes in unity of paediatric surgery in Tunis children's hospital. The mean age was 21+/- 25 months. The abnormality was associated with an inguinal hernia in two cases. The diagnosis was based on the presence of an empty scrotum or perineal swelling. In all, orchidopexy in a dartos pouch was easily performed through an inguinal skin crease incision.The length of the testicular vessels and vas deferens was adequate with a favourable course in every case. Although the complications of undescended testes are the same as for PET, the timing of surgery should be different. CONCLUSION: It is generally accepted that children must not be below 6 months of age for surgical correction of undescended testes, but there is no need to delay surgery in PET, which can easily be diagnosed by physical examination in the neonatal period. Surgery is indicated even if there is no hernia present. The functional prognosis, always difficult to define, appears to be identical to that of other sites. PMID- 21267829 TI - Prevalence and risk factors of overweight and obesity in elementary schoolchildren in the metropolitan region of Tunis, Tunisia. AB - BACKGROUND: Local data about prevalence of obesity in emerging countries are rather scarce. Risk factors for obesity, well known in most industrialized countries, are poorly understood in Tunisia. AIMS: To assess prevalence of overweight and obesity and to investigate associations with possible risk factors in a group of 6-12 year- old schoolchildren in Tunis, Tunisia. METHODS: A descriptive transversal study including a sample of 1335 schoolchildren (6-12 years; mean: 9.7 +/- 1.5 years) was conducted in Tunis. Personal and parental data were collected by questionnaires completed by parents. Height and weight were measured and body mass index was calculated. Prevalence of overweight and obesity was defined based on international agreed cut-off points. RESULTS: Prevalence of overweight and obesity was 19.7% and 5.7%, respectively. Risk factors associated with overweight were: high degree- educated mother and father: 17.3% vs 11.7% (p=.01) (OR (95%CI): 1.58; 1.09-2.29) and 26% vs 17.4% (p=.002) (OR: 1.66; 1.21-2.29), respectively; mother, father high in occupational hierarchy: 7.2% vs 3.6% (p=0.009) (OR: 2.1; 1.2-3.7) and 14% vs 9% (p=.014) (OR: 1.6; 1.1-2.48), respectively. Overweight children had a significantly higher consumption of bread (p=.044), of snack intake (p=0.046) and of soft drink consumption (p=.035). CONCLUSIONS: Prevalence of overweight and obesity in this cohort are 19.7% and 5.7%, respectively. Substantial differences in food choices in families with the highest socio-economic status are among risk factors contributing to obesity development. PMID- 21267830 TI - Congenital cystic adenomatoid malformation of the lung: two case reports. AB - BACKGROUND: Congenital cystic adenomatoid malformation (CCAM) is a rare embryonic developmental abnormality with an incidence of one in 25 000 to 35 000 pregnancies. With advances in antenatal ultrasonographia (USG), CCAM has been increasingly diagnosed. After birth, the clinical appearance of CCAM can vary from immediately postnatal respiratory distress, to an incidental finding on chest radiography. AIM: To report two additional cases with CCAM different in clinical features. CASE REPORTS: The first case was a boy in witch diagnosis was suspected by antenatal USG; he was born at 37 weeks of gestation by cesarean section because of severe toxemia, and presented immediately respiratory distress. The chest x ray and computed tomography scan (CT scan) revealed a right CCAM. The second case was also a boy of an inducted threefold pregnancy, born at 30 weeks by cesarean section. He presented immediately respiratory distress. The diagnosis of a right CCAM was confirmed by clinical and radiological findings in postnatal period. CONCLUSION: The two cases described in this report show the disparity in clinical features of CCAM. Nowadays, antenatal echotomography can establish the diagnosis allowing optimum management. PMID- 21267831 TI - Multifocal atrial tachycardia: an unusual cause of cardiogenic shock in a newborn. AB - BACKGROUND: Chaotic or multifocal atrial tachycardia (MAT) is a rare tachyarrhythmia in children, accounting for less than 1% of supraventricular tachycardia seen in childhood. The majority of children with MAT are healthy; a few may exhibit mild to life threatening cardiorespiratory disease. AIM: To report a new case of MAT revealed by a severe respiratory distress and cardiogenic shock. CASE REPORT: We report a rare case of MAT revealed by a severe respiratory distress and cardiogenic shock in a 12-day-old newborn. The echocardiogram demonstrated an isolated secundum-type atrial septal defect with a decreased left ventricular function. He was successfully treated with intravenous amiodarone. A relay by oral amiodarone and digoxine was made. Four months later, he had no recurrence of arrhythmia and left ventricular function returned to normal. CONCLUSION: Our case is original by its association to an isolated ostium secondum-type atrial septal defect and by the occurrence of a congestive heart failure revealing the arrhythmia and the structural heart disease during the neonatal period. PMID- 21267832 TI - [Tomodensitometric diagnosis of internal herniation: report of 3 cases]. AB - AIMS: To study the value of the CT scan in the diagnosis of internal herniation and to evaluate its performance comparing its features to preoperative data. CASES: We report 3 cases of patients with internal hernias (two men and one woman whose age is 23, 45 and 60 years) hospitalised in emergency for a small bowel obstruction. There were no previous abdominal surgeries or trauma, The three patients underwent CT scan. Signs of tranmesenteric hernias and hernia through the falciform ligament were diagnosed preoperatively and confirmed at laparotomy. CONCLUSION: The internal hernia is rare cause of small bowel obstruction. The CT scan is an important way to make diagnosis and to choose the surgical strategy. PMID- 21267833 TI - [Superior vena cava syndrome and internal mammary nodes in breast cancer: two cases]. AB - BACKGROUND: The association of superior vena cava syndrome with involvement of the internal mammary lymph nodes in breast cancer has not been reported in the literature. AIM: To report two cases of association of superior vena cava with involvement of the internal mammary lymph nodes in breast cancer. CASES REPORT: We report two observations in two patients 45 and 52 years with breast cancer classified T4N2M0 and T3N2M0 treated. Both patients had clinical features compatible with the diagnosis of superior vena cava confirmed by the initial clinical appearance (observation 1) and after treatment (observation 2) to the CT scan. CONCLUSION: The combination of superior vena cava with the achievement of the internal mammary chain in breast cancer worse prognosis. PMID- 21267834 TI - [Hemophagocytic syndrome: report of 4 cases]. AB - BACKGROUND: Hemophagocytic syndrome (HPS) is a rare but potentially fatal disease. The diagnosis is based on the combination of clinical and biological signs, requiring histological or cytological research hemophagocytosis and exhaustive etiological investigation. AIM: To report four cases of the HPS in an internal medicine department. CASES REPORT: We report four cases of HPS associated with Still's disease in two cases, with Sjogren syndrome in one case and a severe sepsis in one case. There are three women and one man. The mean age was 34.75 years, with extremes of 21 to 50 years. In all cases, patients were hospitalized for fever of unknown origin. The etiologic research of this fever remained negative. In all cases, patients validated criteria of HPS confirmed by cytological studies. The treatment was based on corticosteroids in all cases and immunosuppressant in one case. The evolution was favorable in two cases and fatal in two cases. CONCLUSION: HPS is a serious, often overlooked, may affect the prognosis and complicating various infectious, neoplastic or autoimmune diseases. PMID- 21267835 TI - [A rare costal tumor]. AB - BACKGROUND: Costal primary tumors are rare and dominated by malignant tumors. Hemangioma of the bone represents only 1% of the bone tumors. Costal localization accounts only for 1% of the cases and only about fifty cases have been reported in the literature. AIM: To describe a rare costal tumor, its histological features and the main differential diagnoses. OBSERVATION: The authors describe the case of a 46 - year-old woman who present with chest pain. Radiological findings didn't allow to rule out a malignant tumor and the treatment consisted in the resection of the posterior arch of the rib. Microscopic examination concluded to a costal hemangioma and the patient didn't present recurrences after 6 years of follow up. CONCLUSION: Costal hemangioma is an exceptional tumor with a debated etiology. Some radiological features may be specific but the diagnosis is based on histological findings. These tumours have a good prognosis and no case of recurrence have been reported in the literature. PMID- 21267836 TI - [Myocardial infarction as complication of Von Recklinghaussen disease]. PMID- 21267837 TI - [Anal gland adenocarcinoma]. PMID- 21267838 TI - [Association of Behcet's disease and celiac disease]. PMID- 21267839 TI - [Cardiac arrest associated with sulprostone use during cesarean section]. PMID- 21267840 TI - [Chronic pancreatitis rising in an ectopic pancreas]. PMID- 21267943 TI - Focal sparing of iron and fat in liver tissue in patients with hemosiderosis: diagnosis with combination of R2* relaxometry and proton density fat fraction calculation by MRI. AB - PURPOSE: To demonstrate magnetic resonance imaging (MRI) findings of the focal sparing of iron and fat in liver tissue in patients with hepatic iron overload. MATERIALS AND METHODS: We retrospectively reviewed 48 liver MRIs performed in patients with hemosiderosis from 2007-2009. We selected five (10%) of these patients based on the observation of focal signal abnormalities in the posterior aspect of segment 4, anterior to the portal vein, on in- and out-of-phase T1 weighted gradient-echo images. To further characterize this signal abnormality in segment 4, we calculated the simultaneous proton density fat fraction and R2* relaxometry using the investigational version of a quantitative chemical shift based water-fat separation method known as IDEAL-IQ with a multiecho gradient echo sequence. Visual assessment and objective measurements were performed for the focal sparing of iron and fat. RESULTS: The diagnoses of the five patients included thalassemia (n=3), aplastic anemia (n=1), and myelodosysplastic syndrome (n=1). The focal sparing of iron was hypointense on R2* relaxometry compared to the rest of the liver. Fat fraction images failed to demonstrate a heterogeneous fat distribution. The focal sparing of fat in the liver with iron overload appeared as a reduced fat-containing area (fat fraction, 4%) in segment 4 compared to the remainder of the left lobe (fat fraction, 12%). The R2* map revealed no difference between the focal fat-sparing area and the rest of the liver. Areas in which focal fat and iron sparing occurred were not visible on post-contrast and diffusion-weighted images. CONCLUSION: Focal fat and iron sparing in patients with liver siderosis can mimic a lesion. Quantitative MRI techniques can help to characterize abnormal signal changes in segment 4 of the liver in patients with hepatic iron overload and can eliminate the need for biopsy of pseudolesions. PMID- 21267944 TI - Development of an osteoblast/osteoclast co-culture derived by human bone marrow stromal cells and human monocytes for biomaterials testing. AB - The communication of bone-forming osteoblasts and bone-resorbing osteoclasts is a fundamental requirement for balanced bone remodelling. For biomaterial research, development of in vitro models is necessary to investigate this communication. In the present study human bone marrow stromal cells and human monocytes were cultivated in order to differentiate into osteoblasts and osteoclasts, respectively. Finally, a cultivation regime was identified which firstly induces the differentiation of the human bone marrow stromal cells followed by the induction of osteoclastogenesis through the osteoblasts formed--without the external addition of the factors RANKL and M-CSF. As a feedback on osteoblasts enhanced gene expression of BSP II was detected for modifications which facilitated the formation of large multinuclear osteoclasts. Phenotype characterization was performed by biochemical methods (DNA, LDH, ALP, TRAP 5b), gene expression analysis (ALP, BSP II, RANKL, IL-6, VTNR, CTSK, TRAP, OSCAR, CALCR) as well as light microscopy, confocal laser scanning microscopy, and scanning electron microscopy. After establishing this model on polystyrene, similar positive results were obtained for cultivation on a relevant bone substitution material--a composite xerogel of silica, collagen, and calcium phosphate. PMID- 21267945 TI - Impact of alginate type and bead diameter on mass transfers and the metabolic activities of encapsulated C3A cells in bioartificial liver applications. AB - Liver-assist devices have been developed in the last few decades to support patients with liver failure on the road to recovery or transplantation. Fluidised bed bio-artificial livers--where liver cells are encapsulated within alginate beads--appear to be a valuable alternative to hollow fibre devices for improving mass transfers and enhancing treatment efficacy. This approach nevertheless deserves optimization in terms of bead production. The aim of this study was to investigate the impact of alginate type and of two bead diameters (1000 um and 600 um) on mass transfers within beads and on the biological functions of encapsulated C3A cells. After assessing the effect of the encapsulation process on bead quality, we investigated cell viability and metabolic activities (ammonia, albumin, alpha-fetoprotein synthesis and glucose consumption). They were successfully maintained over 48 h within fluidised bed bioreactors, independently of alginate type and bead diameter. Mass transfers were not significantly influenced by the latter parameters. Finally, suggestions are made for improving the entrapment process as a means of enhancing the treatment efficiency of the fluidised bed bioartificial liver. PMID- 21267946 TI - Cardiogel supports adhesion, proliferation and differentiation of stem cells with increased oxidative stress protection. AB - Cultured murine bone marrow derived mesenchymal stem cells (BMSC) when grown along with cardiogel derived from mouse cardiac fibroblast, exhibited increased cell proliferation and differentiation and enhanced survival under oxidative stress induced by the exposure of H2O2 in vitro (similar to in vivo ischemia like condition). Adhesion of BMSC to the cardiogel occurred at a faster rate when compared to the cells grown on normal surface. BMSC attached to cardiogel showed an increased resistance to proteolytic (enzymatic) disassociation. This is the first report on an attempt to use an in house biomaterial for the growth of BMSC that led to their heightened resistance towards oxidative stress. These studies support that cardiogel is an efficient biodegradable three-dimensional extracellular matrix which supports better growth of BMSC and can be used as a scaffold for stem cell delivery, with potential therapeutic applications in cardiac tissue regeneration. PMID- 21267947 TI - [Epidemiological data on personality dimensions in the psychopathy of adolescent boys and girls - results of the Cologne GAP study]. AB - OBJECTIVE: This paper evaluates epidemiological data on psychopathy dimensions among adolescents. METHOD: The Psychopathy Checklist Youth Version (PCL:YV) was administered to a forensic sample of 169 boys and 172 girls, to a clinical sample of 30 boys and 63 girls, and to a community sample of 119 male and 116 female pupils. Analysis was based on three different conceptualizations of psychopathy. In total 669 youths between 14 to 19 years were included in the study. RESULTS: Depending on the cutoff used, we found a psychopathy prevalence between 27 % and 63 % among the incarcerated boys, and from 7 % and 24 % among the incarcerated girls. The clinical and the community samples showed higher scores on the behavior and lower scores on the core personality dimensions. All samples indicated significantly more psychopathy dimensions in boys than in girls. CONCLUSIONS: Varying rates of prevalence are found when using different models for analyzing the PCL:YV. The extent of age-typical adolescent and antisocial behavioral dimensions represented by the Lifestyle and the Antisocial Factor inflates the total PCL:YV score without presenting increased scores in the psychopathy core dimensions. Prospectively, the two core personality dimensions of psychopathy should be studied more closely. PMID- 21267948 TI - [VIA--an intensive therapeutic treatment program for conduct disorders]. AB - OBJECTIVES: Behavioral multimodal therapeutic approaches have proven effective in the treatment of conduct disorders. Yet there are hardly any findings regarding the effectiveness of outpatient treatment approaches. This article introduces an intensive behavioral therapeutic program for the reduction of aggressive behaviors (VIA - Verhaltenstherapeutisches Intensivprogramm zur Reduktion von Aggression). VIA combines a intensive outpatient group program for children, aged 8 to 14 years, with accompanying parent training. This study investigates the effectiveness of the VIA approach in reducing aggressive and comorbid symptoms. Furthermore, it pursues the question of the differential therapy effectiveness. METHODS: We evaluated the treatment program within the framework of a waitlist group study design. Pre-post changes and predictors of treatment efficacy were assessed via multivariate analyses of variance and a linear regression model, respectively. RESULTS: A group of 36 boys and their caregivers took part in the study. The between-groups comparison revealed a significantly greater reduction of oppositional behavior problems and co-morbid symptoms of ADHD in the intervention group (IG, n = 18) compared to the waitlist group (WG, n = 18). In addition, age and degree of dissocial-aggressive behavioral symptoms were identified as crucial predictors. CONCLUSIONS: This study shows that the VIA intensive therapeutic treatment program is effective in reducing aggressive behaviour and comorbid ADHD symptoms in patients with conduct disorder. PMID- 21267949 TI - [Multisystemic Therapy (MST) for adolescents with severe conduct disorders in German-speaking Switzerland - implementation and first results]. AB - OBJECTIVE: To determine the extent to which MST can be applied in German-speaking Switzerland, and the extent to which respectable international treatment outcomes can be replicated. METHOD: A sample of 70 adolescents was treated for an average of 155 days. Of these adolescents, 60 (85.5 %) remained in the study until the conclusion of treatment. The results of the parent version of the Strengths and Difficulties Questionnaire (SDQ) are available for 38 (63.3 %) of the completers. For 52 patients (86.7 %), the therapist ratings for Values for Clinical Global Impression (CGI) and for Global Assessment of Functioning (GAF) are available. RESULTS: The overall problem score of the parent version of the SDQ was reduced from 20 at the beginning of treatment to 14.6 at the conclusion of treatment. The overall score of the GAF improved from 55.4 to 70.3, and the CGI improved from 3.6 to 2.7 points. These results are statistically highly significant. The 6 month follow-up interview revealed treatment success rates of 91 % for "adolescent remains in his family of origin," 94 % for "adolescent remains in school or vocational training," and 91 % for "adolescent does not commit chargeable offences." The 18-month follow-up interviews show success rates of 80 %, 86 %, and 86 %, respectively. CONCLUSIONS: Multisystemic Therapy is a complex treatment program that is clearly applicable in the cultural environment of Switzerland. Respectable international results were replicated in this sample. PMID- 21267950 TI - [Multisystemic Therapy (MST) for youths with severe conduct disorders - economic evaluation of the implementation in a German-speaking environment]. AB - OBJECTIVE: Multisystemic Therapy (MST) was adapted for implementation in a German speaking environment. The study evaluates the possible economic effects of MST. METHOD: Professionals who recommended MST for youths with severe conduct disorders were asked to evaluate the probability of other forms of interventions if MST had not been used. We investigated the costs of those other forms of treatment and compared them to the costs that had actually been incurred with MST. RESULTS: Implementation of MST in a German-speaking environment showed a significant potential of cost savings compared to other intervention methods. The costs of MST per case were between 40 % and 64 % lower than these of standard interventions. CONCLUSIONS: MST is not only an effective, but also a cost efficient form of evidence-based treatment for youths with severe conduct disorders. PMID- 21267951 TI - [The meaning of anxiety in the phenotyping of children and adolescents with conduct disorder - a path toward more consistent neurobiological findings?]. AB - In recent years, neurobiological markers of antisocial behavior have frequently been identified in children of the early-starter subtype of conduct disorder (CD, according DSM-IV). Some studies, however, produced inconsistent findings. The present review argues that, given the existing methodological opportunities, we need a more detailed phenotyping of children with CD. In particular, establishing comorbid anxiety in neuroendocrinological studies might constitute an important factor. There also seem to be associations between trait anxiety and alterations of brain function and brain structure. Finally, the impact of trait anxiety on different subtypes of aggressive behavior as well as on prognosis is emphasized. In sum, a more detailed characterization of children with CD might help to improve our understanding of antisocial development and enhance therapeutic options. PMID- 21267954 TI - Direct comparison of the diagnostic value of point-of-care tests detecting heart type fatty acid binding protein or glycogen phosphorylase isoenzyme BB in patients with acute coronary syndromes with persistent ST-segment elevation. AB - BACKGROUND: Myocardial infarction (MI) with its complications is one of the most serious challenges in contemporary cardiology. Among biochemical markers of myocardial necrosis, heart-type specific fatty acid binding protein (h-FABP) showed excellent sensitivity and specificity for the early diagnosis of an acute MI. The h-FABP is released rapidly (after 30 min) from the cardiomiocyte to the circulation in response to myocardial injury and may be useful for rapid confirmation or exclusion of MI. In recent years, glycogen phosphorylase BB (GP BB) also emerged as a promising early specific marker of myocardial necrosis. Rapid, qualitative "point of care" tests (POCT) detecting h-FABP (Cardio Detect med) and GP-BB (Diacordon) have recently become available. AIM: To evaluate and compare qualitative POCTs detecting h-FABP and GP-BB in patients with an acute coronary syndrome (ACS). METHODS: We studied 52 patients with a strong suspicion of ACS with persistent ST-segment elevation and chest pain lasting less than 6 hours. The ultimate diagnosis of ST-segment elevation MI (STEMI) was confirmed in case of a second (6 h after admission) positive quantitative result of a cardiac troponin T (cTnT) test. On admission, POCTs to detect both h-FABP and GP-BB were performed. The study population was divided into two groups, with chest pain lasting < 3 h (n = 20) or 4-6 h (n = 32). All patients underwent coronary angiography and angioplasty if indicated. The sensitivity of the analysed biomarkers of myocardial necrosis was calculated. RESULTS: The sensitivity of h FABP (84%) was superior in comparison to the other biomarkers, GP-BB and cTnT, which had sensitivity of 64% and 50%, respectively. Comparison of typical parameters of the diagnostic value of a test (sensitivity, predictive values and accuracy) in both time periods demonstrated that h-FABP was superior to GP-BB. In particular, sensitivity and accuracy of h-FABP was excellent in the group of patients with chest pain lasting < 3 h, with sensitivity of 79% for h-FABP and only 47% for GP-BB. Sensitivity and accuracy of cTnT were significantly lower (32% and 35%, respectively). CONCLUSIONS: The h-FABP seems to be an excellent early biomarker of cardiac necrosis in the group of patients with chest pain lasting < 3 h. The GP-BB can be also used as a biomarker of myocardic necrosis, but its sensitivity in the early phase of MI is limited. PMID- 21267955 TI - [New hope for markers-h-FABP and GPBB as fast tests for acute myocardial infarction]. PMID- 21267956 TI - Usefulness of echocardiography in the identification of an excessive increase in pulmonary arterial pressure in patients with systemic sclerosis. AB - BACKGROUND: In systemic sclerosis (SSc), changes in the lungs and pulmonary hypertension (PH) are complications most adversely affecting the prognosis. Given the availability of specific treatment, early diagnosis of PH is very important. Exercise echocardiography, by increasing the patient's cardiac output, makes it possible to identify patients with elevated pulmonary artery pressure (PAP) during exercise. The diagnostic role of exercise echocardiography is still unclear, mainly because of the lack of prospective studies. AIM: To identify SSc patients with abnormally elevated PAP at rest or with a significant increase PAP during exercise, subsequently verified by right heart catheterisation (RHC). METHODS: A total of 71 consecutive patients (67 females and 4 males, mean age 56.9 +/- 17.1 years) with SSc diagnosed according to the American College of Rheumatology criteria were enrolled in this prospective study. The patients underwent transthoracic echocardiography (Philips iE33) with the measurement of tricuspid regurgitation peak gradient (TRPG) and an exercise test involving the standard treadmill exercise according to the Bruce protocol with the evaluation of TRPG at 1 min following the completion of exercise. The PH was suspected when TRPG at rest was > 31 mm Hg (V(max) > 2.8 m/s) or increased by at least 20 mm Hg from baseline following exercise. Patients with suspected PH were referred for resting and exercise RHC. RESULTS: The exercise testing was performed in 67 patients revealing normal left ventricular (LV) systolic function in all of them. The mean LV ejection fraction was 66.1% +/- 3.9%. The TRPG at rest could be recorded in 65 (97%) patients with the mean value of 26.9 +/- +/- 7.6 mm Hg (range 17-57 mm Hg). A resting TRPG of > 31 mm Hg, suggestive of possible PH, was demonstrated in 14 (21%) patients. During exercise test 56 (84%) patients achieved the maximum heart rate. A Doppler spectrum enabling the measurement of TRPG following the exercise was obtained in 66 (98.5%) patients. The gradient following the exercise could not be measured in one patient with a resting TRPG of 30 mm Hg. The mean post-exercise TRPG was 40.3 +/- 4.1 mm Hg (range 17-70) and the mean post-exercise increase in TRPG was 12.9 +/- 8.5 mm Hg (range 2-38). A TRPG increase of > 20 mm Hg was found in 11 (16%) patients (including 4 patients with resting values exceeding 31 mm Hg and 7 patients with normal resting values). Twenty-one (31%) patients with echocardiographic suspicion of PH (TRPG > 31 mm Hg at rest and/or a post-exercise increase in TRPG of more than 20 mm Hg) were referred for RHC with 16 patients actually undergoing the procedure. Four out of these 16 patients were qualified because of the "positive" exercise echocardiography in the presence of normal TRPG values. During catheterisation arterial PH was found in 2 patients, and an excessive precapillary PAP elevation in 2 further patients. Resting venous PH was found in 1 patient and an excessive postcapillary PAP elevation at rest was demonstrated in 11 patients. CONCLUSIONS: Exercise echocardiography is a safe and useful screening tool for PH diagnosis in patients with SSc. It enables to identify patients with normal systolic PAP at rest but a significant increase during exercise. The final confirmation of PH and differentiation between precapillary arterial and postcapillary venous PH requires RHC. PMID- 21267957 TI - [What does exertion echocardiography reveal in patients with systemic sclerosis?]. PMID- 21267958 TI - Predictors of sinus rhythm return during defibrillation testing in patients with permanent atrial fibrillation undergoing implantation of a cardioverter defibrillator. AB - BACKGROUND: Atrial fibrillation (AF) is present in a significant proportion of patients treated with an implantable cardioverter-defibrillator (ICD). Defibrillation testing may lead to sinus rhythm (SR) restoration which may be hazardous due to the increased risk of thromboembolic complications in these patients. AIM: To identify predictors of SR restoration during defibrillation testing in patients with permanent AF undergoing ICD implantation. METHODS: Permanent AF was present in 79 (12%) of 671 consecutive patients who received ICD in our institution between 2005 and 2010. In this group, 47 patients (mean age 64 +/- 12 years, 38 males) underwent defibrillation testing during the implantation procedure and in the remaining 32 patients defibrillation testing was not performed due to various contraindications. Sinus rhythm was restored in 17 (36%) patients, while AF was still present after defibrillation testing in the remaining 30 patients. We analysed demographic, clinical, echocardiographic and electrophysiological parameters which could identify those patients in whom SR was restored, using univariate and multivariate analysis as well as constructing ROC curves. RESULTS: Demographic parameters and clinical history were similar in both groups. Patients in whom SR was restored had smaller left atrial diameter (49.9 +/- 5.9 vs 59.4 +/- 6.1 mm, p < 0.001), more often received a double-coil defibrillation lead (83% vs 10%, p < 0.001), had less advanced heart failure as assessed using NYHA classification (p < 0.05), and were more frequently treated with amiodarone (47% vs 23%, p < 0.025). The chance of SR return was increased 11 times in patients receiving amiodarone, 6 times in patients with a double-coil lead, 2 times in patients with lower NYHA class, and 1.36 times in patients with smaller left atrium diameter (for each 1 mm increase). The ROC curves showed that using the cut-off value for the left atrial diameter of 47 mm, patients prone to SR restoration were identified with a sensitivity of 65%, specificity of 100%, positive predictive value of 83%, and negative predictive value of 90% (area under curve 0.904, 95% CI 0.809-1.0). Multivariate analysis showed that NYHA class, amiodarone usage, type of defibrillating lead and left atrial diameter were independent predictors of SR restoration. CONCLUSIONS: Atrial fibrillation was present in 12% of consecutive patients undergoing ICD implantation and was terminated by defibrillation testing in 36% of those who underwent this test. The NYHA class, amiodarone usage, type of defibrillating lead and left atrial diameter were independent predictors of SR restoration. PMID- 21267959 TI - [Moderation of atrial fibrillation by ICD]. PMID- 21267960 TI - Characteristics of the heart failure population in Poland: ZOPAN, a multicentre national programme. AB - BACKGROUND: It is difficult to define the optimal management of elderly heart failure (HF) patients with complex comorbidities. Thus, comprehensive characterisation of HF patients constitutes a crucial pre-condition for the successful management of this fragile population. AIM: To analyse the 'real life' HF patients, including the evaluation of their health conditions, management and their use of public health resources. METHODS AND RESULTS: We examined 822 consecutive patients diagnosed with HF in NYHA classes II-IV in primary care practices. The mean age was 68.5 years, and 56% were male. Only 23% of the patients who were of pre-retirement age remained professionally active. Ischaemic or hypertension aetiology was found in 90% of participants. Nearly all patients had multiple comorbidities. Most patients received converting enzyme inhibitors (88%) and beta-blockers (77%), 60% of them both, although dosing was frequently inadequate. During the six months preceding the study, 31% had cardiovascular hospitalisation and 66% required unscheduled surgery visits. CONCLUSIONS: The real life HF population differs from trial populations. Most of the real life patients who had not yet reached retirement age were professionally inactive, mainly due to a disability caused by cardiovascular conditions. Moreover, extremely few participants were free from any comorbidity. Compared to 20th century Polish data, there has been an improvement in the overall quality of HF recommended pharmacotherapy. It must be stressed, however, that the percentage of those on optimal dosage remains unsatisfactory. PMID- 21267961 TI - [Primary care physician and heart failure]. PMID- 21267962 TI - The significance of anaemia in patients with acute ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. AB - BACKGROUND: The effects of pre-existing anaemia on the occurrence and course of an acute coronary syndrome has recently become a topic of extensive research. The data on the significance of anaemia in patients with ST-elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI) are less abundant and the conclusions equivocal. AIM: To evaluate the incidence of anaemia and its impact on early outcomes in patients undergoing primary PCI for STEMI. METHODS: Based on a retrospective review of the medical records of hospitalised patients we selected a study group comprising 551 consecutive patients with STEMI, including 164 females, mean age 63.4 +/- 12 years, undergoing primary PCI within the first 12 hours after the onset of chest pain. Anaemia was diagnosed according to the World Health Organisation criteria based on haemoglobin (Hb) values on admission (< 12 g/dL for females, < 13 g/dL for males). RESULTS: Anaemia was diagnosed in 61 (11%) patients (in 13% of females and 10% of males). The anaemic patients were older (71 vs 63 years, p < 0.001), had a lower body mass (70 vs 80 kg, p < 0.003) and a higher TIMI risk score for STEMI (5 vs 3, p < 0.0001). Their laboratory results showed a greater renal impairment (GFR 66.8 vs 75.8 mL/min, p < 0.008) and higher C-reactive protein levels (24.8 vs 14.4 mg/L, p < 0.001). There were no significant differences in post-infarction myocardial damage as estimated on the basis of ejection fraction and the baseline and peak CK-MB levels. During treatment, in both groups, there was a significant decrease in Hb levels from 11.9 to 11.0 g/dL in the anaemic patients (p < 0.0004) and from 14.3 to 13.3 g/dL in the non-anaemic patients (p < 0.001). While GFR did not change significantly in the anaemic patients, there was a significant increase in the non-anaemic patients from 75.8 to 80.9 mL/min (p < 0.001). The in-hospital mortality was low with a total of 8 (1.3%) patients dying: 5 (8.2%) in the anaemic group and 3 (0.6%) in the non-anaemic group (p < 0.001). The anaemic patients were also characterised by a higher incidence of cardiovascular complications (33% vs 17%, p = 0.003). In the multivariate analysis, older age, systolic blood pressure on admission and elevated white blood count were independently associated with a higher risk of death and cardiovascular complications, whereas baseline Hb level was a significant prognostic factor only in the univariate analysis. CONCLUSIONS: Patients with anaemia who develop STEMI are, right from the admission, a separate, higher-risk population of patients with considerably increased risk of death and in-hospital cardiovascular complications. The unfavourable impact of anaemia on outcomes in patients with acute MI undergoing PCI is complex and cannot be explained by the increased extend of post-infarction myocardial damage. In patients with STEMI, anaemia on admission should be treated as an additional risk factor. PMID- 21267963 TI - [Anemia as a risk factor in patients with heart attack after interventional treatment]. PMID- 21267964 TI - Cardiac rehabilitation after cardiac surgery is limited by gender and length of hospitalisation. AB - BACKGROUND: Cardiac rehabilitation (CR) is recommended after cardiac surgery. Secondary prevention through exercise training is one of the best scientifically proven ways of decreasing mortality and enhancing quality of life in cardiovascular disorders. Studies into the use of CR in different groups of patients after cardiac surgery are limited. AIM: To find the factors determining the reasons for the lack of CR in cardiac surgery patients. METHODS: The study group consisted of 82 patients (mean age 58.6 years, 80.7% male) in stable II/III NYHA class, who had undergone coronary artery bypass graft surgery, valvular surgery, or both. The following were analysed: age, gender, body mass index, basic laboratory results such as serum lipids level, cholesterol ratio LDL/HDL, creatinine and glucose levels, results of electrocardiography, echocardiography and coronary arteriography, presence of hypertension, diabetes, coronary artery disease, renal failure, previous stroke, obliteration of peripheral arteries, EuroSCORE and length of hospitalisation. Patients were divided into two groups: those referred for CR (n = 46, the CR group) and those referred for CR but who did not receive it (n = 36, non-CR group). RESULTS: From multiple logistic regression analysis with backward stepwise, only female gender (p = 0.0208, OR = 0.07) and length of hospitalisation (p = 0.0198, OR = 1.17) were significant for non-CR patients. CONCLUSIONS: We found a lower rate of use of CR after cardiac surgery in those patients hospitalised for longer periods, and in women. PMID- 21267965 TI - [Who benefits from cardiologic rehabilitation?]. PMID- 21267966 TI - [Mild type of the Ebstein anomaly]. AB - Ebstein anomaly is a congenital malformation of the heart that is characterised by apical displacement of the septal and posterior tricuspid valve leaflets, leading to atrialisation of the right ventricle with a variable degree of malformation and displacement of the anterior leaflet. We present a case of a mild type Ebstein anomaly leading to moderate tricuspid valve regurgitation and some degree of right ventricular dysfunction. PMID- 21267967 TI - Heart transplantation in a highly sensitised patient. AB - Some patients awaiting heart transplantation may develop positive panel reactive antibodies (PRA). Several reports have demonstrated that pre-transplant sensitisation is associated with decreased survival and a higher rejection rate, and leads to the development of cardiac allograft vasculopathy. We describe our experience with a highly sensitised transplant recipient. To reduce sensitisation, three courses of immunoadsorption were administered. The PRA level decreased effectively and actual cross-match was negative. The patient underwent successful heart transplantation, and desensitisation treatment continued with immunoadsorption and intravenous immunoglobulin for five courses. Graft function remains normal at 12 months post-operatively and the clinical status of the patient is stable. PMID- 21267968 TI - Ventricular fibrillation associated with occult eating disorder - a clinical puzzle. AB - Eating disorders are not infrequent in adolescents, and associated cardiac arrhythmias (CA) are well described in these patients. However, CA in adult eating disorders have been reported only rarely. We report a case of ventricular fibrillation in a patient presenting with fatigue and a recent history of vomiting. PMID- 21267969 TI - Treatment of saddle pulmonary embolism with streptokinase in an 83 year-old man - a case report. AB - Saddle pulmonary embolism (PE) is an embolus at the level of the bifurcation of the pulmonary trunk that extends into both main pulmonary arteries. Because of the unstable, large clot burden in the pulmonary artery and the risk of sudden haemodynamic collapse and sudden death, identifying a saddle embolus is extremely important. In this report, we describe successful treatment with streptokinase of a saddle PE in an elderly patient. PMID- 21267970 TI - [Chronic thromboembolic pulmonary embolism not preceded by clinical thromboembolic event - clinical, echocardiographic and haemodynamic course]. AB - Chronic thromboembolic pulmonary embolism not preceded by clinical thromboembolic event(s) in a 50 year-old male with a history of three-year dyspnea on exertion was detected. Proximal chronic pulmonary embolism, mean pulmonary artery pressure 32 mm Hg, and pulmonary vascular resistance of 444 dyn x s(-1) x cm(-5) were found. We describe a 11-year clinical course of anticoagulated patient with monitoring of functional status and echocardiography and with control of pulmonary haemodynamics at the end of follow-up. PMID- 21267971 TI - [Severe, thromboembolic pulmonary hypertension with recurrent pulmonary embolism and right heart thrombi in a patient with past myocardial infarction, cerebral ischaemic stroke and small intestine necrosis]. AB - Chronic thromboembolic pulmonary hypertension (CTEPH) is a chronic progressive disease of pulmonary circulation characterised by indistinct ethiopathogenesis. We present a case of a 50 year-old male with thrombophilia of unknown origin leading to the formation of multiple thrombi within venous circulation followed by episodes of acute pulmonary embolism resulting ultimately in acute heart failure in the course of developing CTEPH. Unfortunately, despite the wide range of haemostasis laboratory tests we were not able to define the type of coagulation abnormality. Owing to the efficient cooperation between cardiologists and cardiosurgeons it was possible to save patient's life. PMID- 21267973 TI - [Chronic ischaemic mitral regurgitation. Part I: epidemiology, pathogenesis and diagnosis]. PMID- 21267974 TI - [Chronic ischaemic mitral regurgitation. Part II: pharmacological and invasive treatment]. PMID- 21267975 TI - [Pseudo-Wellens syndrome in a patient with vasospastic angina]. AB - Wellens syndrome is characterised by negative or biphasic T waves in V2-V4 leads and critical stenosis of proximal part of the left descending coronary artery. These ECG changes without atherosclerotic changes in coronary angiography, i.e. coronary artery spasm are called pseudo-Wellens syndrome. We describe a patient with acute coronary syndrome and pseudo-Wellens syndrome as a cause of vasospastic angina. These ECG abnormalities need differentiation with acute pulmonary embolism. PMID- 21267977 TI - [Echocardiogram of the month. Giant left atrial appendage]. AB - Aneurysmal left atrial appendage (LAA) is a rare congenital anomaly. It may result in supraventricular arrhythmias and embolic complications. We present a case of a 33 year-old female in whom echocardiography showed a giant LAA (6 x 3 cm), confirmed by computed tomography. PMID- 21267978 TI - [Left atrial appendage elimination using Amplatzer Cardiac Plug in patients with atrial fibrillation - report of two cases]. AB - Percutaneous left atrial appendage device closure is currently under evaluation as a method for reducing stroke risk in patients with atrial fibrillation and contraindications for long-term oral anticoagulation therapy. We present two cases of successful implantation of new left atrial appendage occluder - Amplatzer Cardiac Plug. PMID- 21267980 TI - [Ventricular fibrillation effectively treated by wearable automatic defibrillator - a case report]. AB - We present a patient at risk of sudden cardiac death in whom ventricular fibrillation was effectively treated by wearable automatic defibrillator. We discuss the technical aspects of the device, current indications for this therapy and outcomes. PMID- 21267981 TI - [Commentary to the article: Kaiser C, Galatius S, Erne P et al. Drug-eluting versus bare-metal stents in large coronary arteries. N Engl J Med, 2010; 363: 2310-2319]. PMID- 21267982 TI - [Not Available]. PMID- 21267983 TI - [Statement on the diagnosis and treatment of tobacco dependence in patients with cardiovascular diseases]. PMID- 21267984 TI - [Selective thrombolysis for the treatment of the central retinal artery oclusion a new challenge for a stand-by cardiac catheterisation laboratory]. PMID- 21267985 TI - [Report from the conference "Adults with Congenital Heart Defects: compendium", Poznan, November 20, 2010]. PMID- 21267989 TI - Effect of the circumferential resection margin on survival following rectal cancer surgery. AB - BACKGROUND: The aim was to determine the effect of the circumferential resection margin (CRM) on overall survival following surgical excision of rectal cancer. METHODS: The effect of CRM on survival was examined by case mix-adjusted analysis of patients undergoing potentially curative excision of a rectal cancer between 1998 and 2002. RESULTS: Of 1896 patients, 1561 (82.3 per cent) had recorded data on the CRM. In 232 patients (14.9 per cent) tumour was found 1 mm or less from the CRM. In 370 patients (23.7 per cent) it was over 1 mm but no more than 5 mm from the CRM, and in 288 (18.4 per cent) it was over 5 mm but no more than 10 mm from the CRM. The remaining 671 patients (43.0 per cent) had a CRM exceeding 10 mm. Overall 5-year survival rates for these groups were 43.2, 51.7, 66.6 and 66.0 per cent respectively. Compared with patients with a CRM exceeding 10 mm, the adjusted risk of death was significantly increased for patients with a CRM of 1 mm or less (hazard ratio (HR) 1.61, P < 0.001) and those with a margin greater than 1 mm but no larger than 5 mm (HR 1.35, P = 0.005). There was no added risk for patients with tumour more than 5 mm but 10 mm or less from the CRM (HR 1.02, P = 0.873). The adverse effect of a CRM greater than 1 mm but no larger than 5 mm was found particularly in mid-rectal cancers. CONCLUSION: A predicted CRM of 5 mm or less on preoperative staging should be considered for neoadjuvant treatment. PMID- 21267988 TI - Forcing a connection: impacts of single-molecule force spectroscopy on in vivo tension sensing. AB - Mechanical tension plays a large role in cell development ranging from morphology to gene expression. On the molecular level, the effects of tension can be seen in the dynamic arrangement of membrane proteins as well as the recruitment and activation of intracellular proteins. Forces applied to biopolymers during in vitro force measurements offer greater understanding of the effects of tension on molecules in live cells, and experimental techniques involving test tubes and live cells can often overlap. Indeed, when forces exerted on cellular components can be calibrated ex vivo with force spectroscopy, a powerful tool is available for researchers in probing cellular mechanotransduction on the molecular scale. This review will discuss the techniques used in measuring both cellular traction forces and single-molecule force spectroscopy. Emphasis will be placed on the use of fluorescence reporter systems for the development of in vivo tension sensors that can be used for calibration with single molecule force methods. PMID- 21267990 TI - Recurrence-free survival more than 10 years after liver resection for hepatocellular carcinoma. AB - BACKGROUND: High recurrence rates after liver resection with curative intent for hepatocellular carcinoma (HCC) remain a problem. The characterization of long term survivors without recurrence after liver resection may help improve the therapeutic strategy for HCC. METHODS: A nationwide Japanese database was used to analyse 20 811 patients with HCC who underwent liver resection with curative intent. RESULTS: The 10-year recurrence-free survival rate after liver resection for HCC with curative intent was 22.4 per cent. Some 281 patients were recurrence free after more than 10 years. The HCCs measured less than 5 cm in 83.2 per cent, a single lesion was present in 91.7 per cent, and a simple nodular macroscopic appearance was found in 73.3 per cent of these patients; histologically, most HCCs showed no vascular invasion or intrahepatic metastases. Multivariable analysis revealed tumour differentiation as the strongest predictor of death from recurrent HCC within 5 years. CONCLUSION: Long-term recurrence-free survival is possible after liver resection for HCC, particularly in patients with a single lesion measuring less than 5 cm with a simple nodular appearance and low tumour marker levels. PMID- 21267994 TI - 1st EFIS-EJI intensive course in clinical immunology: towards a new era in immunology. PMID- 21267995 TI - IL-22 in antifungal immunity. AB - Deciphering cellular and molecular mechanisms that maintain host immune homeostasis with fungi and the breakdown of this homeostatic tolerance during fungal infections disease is a challenge in medical mycology. In fact, the virulence of fungi may be determined by the interaction between fungi and the host immune status and its classification as a commensal microorganism or a pathogen may shift depending on the balance. In addition to the central role of the IL-12/IFN-gamma-dependent Th1 responses in cell-mediated immune protection against fungi, Th17 cells provide protection and inflammation at mucosal surfaces, and Tregs fine-tune immune responses to prevent damage to the host. Recent evidence indicates that IL-22-producing cells, employing primitive antifungal effector mechanisms, contribute to antifungal resistance at mucosal surfaces under conditions of defective adaptive immunity. The fact that IL-22 production is driven by commensals points to the need of an integrated, systems biology approach to improve our understanding of the inherent and intimate mechanisms underlying multilevel host-fungus interactions. PMID- 21267996 TI - The role of Syk/CARD9 coupled C-type lectins in antifungal immunity. AB - Fungal infections are affecting an increasing number of people, and the failure of current therapies in treating systemic infection has resulted in an unacceptably high mortality rate. It is therefore of importance that we understand immune mechanisms operating during fungal infections, in order to facilitate development of adjunctive immunotherapies for the treatment of these diseases. C-type lectin receptors (CLRs) are pattern recognition receptors (PRRs) that are critical for immune responses to fungi. Many of these receptors are coupled to Syk kinase, which allows these receptors to signal via CARD9 leading to NF-kappaB activation, which in turn contributes to the induction of both innate and adaptive immunity. Dectin-1, Dectin-2 and Mincle are all CLRs that share this common signalling mechanism and have been shown to play key roles in antifungal immunity. This review aims to update existing paradigms and summarise the most recent findings on these CLRs, their signal transduction mechanisms and the collaborations between these CLRs and other PRRs. PMID- 21267997 TI - Co-stimulation by dendritic cells maintains the peripheral pool of Tregs. AB - Many aspects of an immune response are regulated by dendritic cells (DCs). DCs play key proinflammatory roles by sensing microbial invaders and promoting the activation of innate immune cells such as NK cells. In addition, DCs are required for the initiation and maintenance of adaptive T-cell responses against invading pathogens. Moreover, DCs also fulfill important anti-inflammatory functions: they induce peripheral T-cell tolerance by silencing self-reactive T cells and supporting the homeostasis of regulatory T cells (Tregs). A study in this issue of the European Journal of Immunology reveals that CD80/CD86 expression on DCs contributes to the maintenance of the peripheral pool of Tregs. This Commentary discusses current findings on this topic, focusing on the role of DCs in the homeostatic control of Tregs and myeloid cells, and the potential consequences for T-cell activation. PMID- 21267998 TI - The STATus of PD-L1 (B7-H1) on tolerogenic APCs. AB - Expression by DCs of co-inhibitory molecules such as programmed death ligand-1 (PD-L1/B7-H1/CD274), a member of the B7 superfamily, is crucial for the downregulation of T-cell responses and the maintenance of immune homeostasis. Exposure of immature DCs to danger-associated molecular patterns (DAMPS) or pathogen-associated molecular patterns (PAMPs) generally results in their maturation and acquisition of immunostimulatory function. However, exposure of DCs to TLR ligands early during their differentiation can inhibit further differentiation and confer tolerogenic properties on these APCs. A report in this issue of The European Journal of Immunology reveals that early inhibition of human DC differentiation from blood monocytes by TLR agonists is associated with a tolerogenic phenotype and Treg generation. The tolerogenic function of these APCs is dependent on MAPK-induced IL-6 and IL-10 production, which drives STAT-3 mediated PD-L1 expression. These observations link IL-10 and IL-6 to PD-L1 expression, providing a new dimension to the anti-inflammatory properties of these cytokines. These findings also have implications for understanding the inherent function of DCs in non-lymphoid tissues such as the liver and lung, where they are exposed to PAMPs that are found constitutively in the local microenvironment. PMID- 21267999 TI - Dendritic cell-restricted CD80/86 deficiency results in peripheral regulatory T cell reduction but is not associated with lymphocyte hyperactivation. AB - Classical DC (cDC) are required for efficient protective T-cell immunity. Moreover, recent data indicate that cDC also play a critical role in mediating homeostatic proliferation and maintenance of peripheral Treg. Here, we corroborate these findings by defining CD80/CD86 costimulation as an essential molecular component required for the cDC-Treg interactions. In contrast to earlier reports, the reduced Treg compartment of mice lacking cDC or selective CD80/86 expression on cDC, as such, did not render the respective animals prone to systemic lymphocyte hyperactivation or autoimmunity. Rather, we provide evidence that elevated immunoglobulin titers, as well as changes in T-cell subset prevalence and activation status are strictly associated with the nonmalignant myeloproliferative disorder triggered by the absence of cDC. PMID- 21268000 TI - A natural protective function of invariant NKT cells in a mouse model of innate cell-driven lung inflammation. AB - Activation of invariant natural killer T (iNKT) cells by treatment with their alpha-galactosyl ceramide ligand provides therapeutic benefits in several immune inflammatory settings. Given the artificial nature of this stimulation, the natural regulatory functions of iNKT remain uncertain. Addressing this issue in a mouse model of innate-cell-driven lung inflammation induced by the cytokine/alarmin IL-33 that targets iNKT cells, we found that eosinophil and neutrophil recruitment was markedly increased in treated iNKT cell-deficient (Jalpha18 KO) mice, as was the local production of eotaxin and keratinocyte chemoattractant chemokines. By contrast, lung inflammation decreased after adoptive transfer of iNKT cells, which restored the WT inflammatory response in Jalpha18 KO mice. Finally, we established that this natural anti-inflammatory function of iNKT cells depends on their IFN-gamma production and on endogenous IL 12. Our study provides the first evidence of a protective role of iNKT cells during lung inflammation that does not require pharmacological TCR engagement. PMID- 21268001 TI - Human CD4+ FOXP3+ regulatory T cells produce CXCL8 and recruit neutrophils. AB - One of the defining features of the majority of FOXP3(+) Tregs is their inability to produce typical T-cell-derived cytokines. Little is known, however, about their capacity to produce chemokines. As Tregs are constitutively present in, and rapidly traffic to, non-lymphoid tissues, we hypothesized that they may produce chemokines to direct the composition of cells that infiltrate inflamed tissues. Surprisingly, we found that Tregs produce high amounts of CXCL8 (IL-8), a potent neutrophil chemoattractant. Tregs also produced other CC and CXC family chemokines, including CCL2-5, CCL7, and CXCL10. Whereas ectopic expression of FOXP3 suppressed cytokine production, it significantly induced CXCL8. Moreover, supernatants from Tregs attracted neutrophils via a CXCL8-dependent mechanism. These data provide the first evidence that although classical Tregs are defined by their lack of proinflammatory cytokine production, they secrete significant quantities of chemokines and thus may have an unappreciated role in directing the recruitment of immune cells. PMID- 21268002 TI - Active immunization using a single dose immunotherapeutic abates established EAE via IL-10 and regulatory T cells. AB - Stimulation of Ag-specific inducible Treg can enhance resolution of autoimmune disease. Conventional methods to induce Treg often require induction of autoimmune disease or subjection to infection. Reovirus adhesin, protein sigma1 (psigma1), can successfully facilitate tolerance when fused to a tolerogen. We tested whether myelin oligodendrocyte glycoprotein (MOG) fused to psigma1 (MOG psigma1) can stimulate Ag-specific Treg. We show that C57BL/6 mice treated nasally with MOG-psigma1 fail to induce MOG-specific Abs and delayed-type hypersensitivity (DTH) responses and resist EAE. Such resistance was attributed to stimulation of Foxp3(+) Treg, as well as Th2 cells. MOG-psigma1's protective capacity was abrogated in IL-10(-/-) mice, but restored when adoptively transferred with MOG-psigma1-induced Treg. As a therapeutic, MOG-psigma1 diminished EAE within 24 h of nasal application, unlike recombinant MOG (rMOG), psigma1, or psigma1+rMOG, implicating the importance of Ag specificity by psigma1 based therapeutics. MOG-psigma1-treated mice showed elevated IL-4, IL-10, and IL 28 production by CD4(+) T cells, unlike rMOG treated or control mice that produced elevated IFN-gamma or IL-17, respectively. These data show the feasibility of using psigma1 as a tolerogen platform for Ag-specific tolerance induction and highlight its potential use as an immunotherapeutic for autoimmunity. PMID- 21268003 TI - Threshold levels of Flt3-ligand are required for the generation and survival of lymphoid progenitors and B-cell precursors. AB - The generation of B-cell precursors (BCP) from lymphohematopoietic progenitors (LHP) in bone marrow is dependent on signals provided by the receptor tyrosine kinase Flt3 and its ligand, Flt3-ligand (FL). Mice deficient in FL exhibit striking reductions in LHP and BCP. Currently, the mechanism by which Flt3 regulates lymphoid lineage/B-cell development is unknown. Here, we show that haploinsufficiency of FL (FL(+/) (-) ) reduced the numbers of LHP, common lymphoid progenitors, and pro-B cells, suggesting that FL levels set a threshold for B lymphopoiesis. Limiting dilution analysis confirmed reduced BCP frequency in FL(+/) (-) mice. Real-time PCR of LHP from FL(+/) (-) animals showed increased transcripts of the B lineage inhibitor id1. However, targeted deletion of id1 did not restore the lymphoid/B lineage deficiencies in FL(-/-) mice, supporting Id1 independent mechanisms. BrdU incorporation studies established that FL is not essential for the proliferation of Flt3(+) multipotential progenitors. Analysis of FL(-/-) progenitors expressing low levels of Flt3 revealed decreased levels of the pro-survival factor Mcl1. Consequently, the Flt3(+) LHP progeny of Flt3(low) LSK(+) cells exhibited increased Annexin V staining. Together, these data suggest that Flt3 signaling initiates a cascade of events in Flt3(low) precursors that promote the survival of LHP from which BCP are derived. PMID- 21268004 TI - TNFR1 delivers pro-survival signals that are required for limiting TNFR2 dependent activation-induced cell death (AICD) in CD8+ T cells. AB - Members of the TNF and TNF receptor (TNFR) superfamily play important roles in the maintenance of homeostasis of the immune system. Furthermore, several members of the TNFR family participate in T-cell activation and sustaining T-cell responses. We have shown that TNFR2 regulates T-cell activation by lowering the activation threshold and providing costimulatory signaling. Furthermore, activated TNFR2(-/-) CD8(+) T cells are highly resistant to activation-induced cell death (AICD). Here, we showed that using anti-TNFR2 antibodies to block TNFR2 on activated WT CD8(+) T cells rendered them resistant to AICD. This resistance of activated TNFR2(-/-) CD8(+) T cells to AICD correlated with the accumulation of TNF receptor-associated factor 2 (TRAF2). Overexpression of TRAF2 by retroviral transfection and knockdown of TRAF2 by small interfering RNA also support this conclusion. Furthermore, neutralizing TNF-alpha reduced TRAF2 accumulation in activated TNFR2(-/-) CD8(+) T cells and increased their susceptibility to AICD. AICD-resistant TNFR2(-/-) CD8(+) T cells expressed elevated levels of phosphorylated IkappaBalpha and higher DNA-binding activity of the p65 NK-kappaB subunit and neutralization of TNF-alpha blocked this increase. Therefore, in activated TNFR2(-/-) CD8(+) T cells, TNFR1 functions as a survival receptor by utilizing high intracellular levels of TRAF2 to promote IkappaBalpha phosphorylation and NF-kappaB activation. PMID- 21268005 TI - Expression and function of PD-1 in human gammadelta T cells that recognize phosphoantigens. AB - Programmed cell death-1 (PD-1) is an inhibitory receptor and plays an important role in the regulation of alphabeta T cells. Little is known, however, about the role of PD-1 in gammadelta T cells. In this study, we investigated the expression and function of PD-1 in human gammadelta T cells. Expression of PD-1 was rapidly induced in primary gammadelta T cells following antigenic stimulation, and the PD 1(+) gammadelta T cells produced IL-2. When PD-1(+) gammadelta T cells were stimulated with Daudi cells with and without programmed cell death ligand-1 (PD L1) expression, the levels of IFN-gamma production and cytotoxicity in response to PD-L1(+) Daudi cells were diminished compared to the levels seen in response to PD-L1(-) Daudi cells. The attenuated effector functions were reversed by anti PD-L1 mAb. When PD-1(+) gammadelta T cells were challenged by PD-L1(+) tumors pretreated with zoledronate (Zol), which induced gammadelta TCR-mediated signaling, the resulting reduction in cytokine production was only slight to moderate compared to the reduction seen when PD-1(+) gammadelta T cells were challenged by PD-L1(-) tumors. In addition, cytotoxic activity of PD-1(+) gammadelta T cells against Zol-treated PD-L1(+) tumors was comparable to that against Zol-treated PD-L1(-) tumors. These results suggest that TCR triggering may partially overcome the inhibitory effect of PD-1 in gammadelta T cells. PMID- 21268006 TI - Hoxb8 conditionally immortalised macrophage lines model inflammatory monocytic cells with important similarity to dendritic cells. AB - We have examined the potential to generate bona fide macrophages (MO) from conditionally immortalised murine bone marrow precursors. MO can be derived from Hoxb8 conditionally immortalised macrophage precursor cell lines (MOP) using either M-CSF or GM-CSF. When differentiated in GM-CSF (GM-MOP) the resultant cells resemble GM-CSF bone marrow-derived dendritic cells (BMDC) in morphological phenotype, antigen phenotype and functional responses to microbial stimuli. In spite of this high similarity between the two cell types and the ability of GM MOP to effectively present antigen to a T-cell hybridoma, these cells are comparatively poor at priming the expansion of IFN-gamma responses from naive CD4(+) T cells. The generation of MOP from transgenic or genetically aberrant mice provides an excellent opportunity to study the inflammatory role of GM-MOP, and reduces the need for mouse colonies in many studies. Hence differentiation of conditionally immortalised MOPs in GM-CSF represents a unique in vitro model of inflammatory monocyte-like cells, with important differences from bone marrow derived dendritic cells, which will facilitate functional studies relating to the many 'sub-phenotypes' of inflammatory monocytes. PMID- 21268007 TI - Saturated-efferocytosis generates pro-resolving CD11b low macrophages: modulation by resolvins and glucocorticoids. AB - During the resolution phase of inflammation, apoptotic leukocytes are efferocytosed by macrophages in a nonphlogistic fashion that results in diminished responses to bacterial moieties and production of anti-inflammatory cytokines. Complement receptor 3 and pro-resolving lipid mediators promote the engulfment of apoptotic leukocytes by macrophages. Here, we present evidence for the emergence of pro-resolving, CD11b(low) macrophages in vivo during the resolution of murine peritonitis. These macrophages are distinct from the majority of peritoneal macrophages in terms of their functional protein expression profile, as well as pro-resolving properties, such as apoptotic leukocyte engulfment, indifference to TLR ligands, and emigration to lymphoid organs. Notably, we also found macrophages convert from the CD11b(high) to the CD11b(low) phenotype upon interaction with apoptotic cells ex vivo. In addition, we found that the pro-resolving lipid mediators resolvin E1 and D1, and the glucocorticoid dexamethasone regulated pro-resolving macrophage functions in vivo. This regulation culminated in a novel pro-resolving function, namely reducing the apoptotic leukocyte ingestion requirement for CD11b(low) macrophage generation. These new phenotype and molecular pathway markers define the new satiated macrophage. Thus, we suggest that satisfying efferocytosis generates CD11b(low) macrophages that are essential for complete nonphlogistic containment of inflammatory agents and the termination of acute inflammation. PMID- 21268008 TI - ADAM-8, a metalloproteinase, drives acute allergen-induced airway inflammation. AB - Asthma is a complex disease linked to various pathophysiological events including the activity of proteinases. The multifunctional A disintegrin and metalloproteinases (ADAMs) displaying the ability to cleave membrane-bound mediators or cytokines appear to be key mediators in various inflammatory processes. In the present study, we investigated ADAM-8 expression and production in a mouse model of allergen-induced airway inflammation. In allergen-exposed animals, increased expression of ADAM-8 was found in the lung parenchyma and in DC purified from the lungs. The potential role of ADAM-8 in the development of allergen-induced airway inflammation was further investigated by the use of an anti-ADAM-8 antibody and ADAM-8 knockout animals. We observed a decrease in allergen-induced acute inflammation both in BALF and the peribronchial area in anti-ADAM-8 antibody-treated mice and in ADAM-8-deficient mice (ADAM-8(-/-) ) after allergen exposure. ADAM-8 depletion led to a significant decrease of the CD11c(+) lung DC. We also report lower levels of CCL11 and CCL22 production in antibody-treated mice and ADAM-8- deficient mice that might be explained by decreased eosinophilic inflammation and lower numbers of DC, respectively. In conclusion, ADAM-8 appears to favour allergen-induced acute airway inflammation by promoting DC recruitment and CCL11 and CCL22 production. PMID- 21268009 TI - Invariant NKT cells regulate experimental autoimmune uveitis through inhibition of Th17 differentiation. AB - Although NKT cells have been implicated in diverse immunomodulatory responses, the effector mechanisms underlying the NKT cell-mediated regulation of pathogenic T helper cells are not well understood. Here, we show that invariant NKT cells inhibited the differentiation of CD4(+) T cells into Th17 cells both in vitro and in vivo. The number of IL-17-producing CD4(+) T cells was reduced following co culture with purified NK1.1(+) TCR(+) cells from WT, but not from CD1d(-/-) or Jalpha18(-/-) , mice. Co-cultured NKT cells from either cytokine-deficient (IL-4( /-) , IL-10(-/-) , or IFN-gamma(-/-) ) or WT mice efficiently inhibited Th17 differentiation. The contact-dependent mechanisms of NKT cell-mediated regulation of Th17 differentiation were confirmed using transwell co-culture experiments. On the contrary, the suppression of Th1 differentiation was dependent on IL-4 derived from the NKT cells. The in vivo regulatory capacity of NKT cells on Th17 cells was confirmed using an experimental autoimmune uveitis model induced with human IRBP(1-20) (IRBP, interphotoreceptor retinoid-binding protein) peptide. NKT cell-deficient mice (CD1d(-/-) or Jalpha18(-/-) ) demonstrated an increased disease severity, which was reversed by the transfer of WT or cytokine-deficient (IL-4(-/-) , IL-10(-/-) , or IFN-gamma(-/-) ) NKT cells. Our results indicate that invariant NKT cells inhibited autoimmune uveitis predominantly through the cytokine-independent inhibition of Th17 differentiation. PMID- 21268010 TI - CD68-expressing cells can prime T cells and initiate autoimmune arthritis in the absence of reactive oxygen species. AB - It is widely believed that DC, but not macrophages, prime naive T cells in vivo. Here, we investigated the ability of CD68-expressing cells (commonly defined as macrophages) in priming autoreactive T cells and initiating collagen-induced arthritis (CIA) in the mouse. For this purpose, a transgenic mouse was developed (MBQ mouse) where macrophages exclusively expressed the MHC class II H2-A(q) (A(q)) on an H2-A(p) (A(p)) background. A(q), but not A(p) expression mediates susceptibility to CIA through presentation of type II collagen (CII) to T cells. CIA severity is enhanced by a mutation in the Ncf1 gene, impairing reactive oxygen species (ROS) production by the phagocyte NADPH oxidase (NOX2) complex. Expression of functional Ncf1 on macrophages was previously shown to protect from severe CIA. To study the effect of ROS on macrophage-mediated priming of T cells, the Ncf1 mutation was introduced in the MBQ mouse. Upon CII immunization, Ncf1 mutated MBQ mice, but not Ncf1 wild-type MBQ mice nor Ncf1-mutated A(p) mice, activated autoreactive T cells and developed CIA. These findings demonstrate for the first time that macrophages can initiate arthritis and that the process is negatively regulated by ROS produced via the NOX2 complex. PMID- 21268011 TI - PD-L1 expression on tolerogenic APCs is controlled by STAT-3. AB - During infection, TLR agonists are released and trigger mature as well as differentiating innate immune cells. Early encounter with TLR agonists (R848; LPS) blocks conventional differentiation of CD14(+) monocytes into immature dendritic cells (iDCs) resulting in a deviated phenotype. We and others characterized these APCs (TLR-APC) by a retained expression of CD14 and a lack of CD1a. Here, we show in addition, expression of programmed death ligand-1 (PD-L1). TLR-APCs failed to induce T-cell proliferation and furthermore were able to induce CD25(+) Foxp3(+) T regulatory cells (Tregs). Since PD-L1 is described as a key negative regulator and inducer of tolerance, we further analyzed its regulation. PD-L1 expression was regulated in a MAPK/cytokine/STAT-3-dependent manner: high levels of IL-6 and IL-10 that signal via STAT-3 were produced by TLR APCs. Blocking of STAT-3 activation prevented PD-L1 expression. Moreover, chromatin immunoprecipitation revealed direct binding of STAT-3 to the PD-L1 promoter. Those findings indicate a pivotal role of STAT-3 in regulating PD-L1 expression. MAPKs were indirectly engaged, as blocking of p38 and p44/42 MAPKs decreased IL-6 and IL-10 thus reducing STAT-3 activation and subsequent PD-L1 expression. Hence, during DC differentiation TLR agonists induce a STAT-3 mediated expression of PD-L1 and favor the development of tolerogenic APCs. PMID- 21268012 TI - 5'-Phosphate oligodeoxynucleotides enhance the phosphodiester-CpG DNA-induced inflammatory response in macrophages. AB - Dying cells release genomic DNA into the surroundings where the DNA is first degraded to oligodeoxynucleotides, then to nucleotides, nucleosides and so on. Given that the unmethylated CpG dinucleotide (CpG motif), which is characteristic of bacterial DNA, is also contained in mammalian DNA and has been reported to be involved in the exacerbation of DNA-associated autoimmune diseases, we investigated whether nucleotides and nucleosides affect immune responses to phosphodiester (PO)-CpG DNA. Addition of non-CpG DNA to RAW264.7, murine macrophage-like cells, induced no significant TNF-alpha production irrespective of treatment with DNase I; however, DNase I-treated, but not untreated, non-CpG DNA increased the PO-CpG DNA-mediated TNF-alpha production. This increase was not observed with phosphorothioate-CpG DNA or ligands for TLR3, TLR4 or TLR7. Deoxynucleotides with a 5'-phosphate showed similar effects to those of DNase I treated non-CpG DNA, but DNase II-treated DNA or deoxynucleosides did not. Subcutaneous injection of PO-CpG DNA into the mouse footpad induced little swelling of the paw; however, significant swelling was observed when DNase I treated DNA was co-injected with PO-CpG DNA. These results imply that PO-CpG DNA dependent inflammatory responses are increased by DNA molecules with a 5' phosphate; such molecules could therefore be considered as exacerbating factors for CpG motif-related inflammation. PMID- 21268013 TI - Serglycin inhibits the classical and lectin pathways of complement via its glycosaminoglycan chains: implications for multiple myeloma. AB - Serglycin (SG) is a proteoglycan expressed by hematopoietic cells and is constitutively secreted by multiple myeloma (MM) cells. SG participates in the regulation of various inflammatory events. We found that SG secreted by human MM cell lines inhibits both the classical and lectin pathways of complement, without influencing alternative pathway activity. The inhibitory effect of SG is due to direct interactions with C1q and mannose-binding lectin (MBL). C1q-binding is mediated through the glycosaminoglycan moieties of SG, whereas MBL binds additionally to SG protein core. Interactions between SG and C1q as well as MBL are diminished in the presence of chondroitin sulfate type E. In addition, we localized the SG-binding site to the collagen-like stalk of C1q. Interactions between SG and C1q as well as MBL are ionic in character and only the interaction with MBL was found to be partially dependent on the presence of calcium. We found the serum levels of SG to be elevated in patients with MM compared to healthy controls. Moreover, we found that SG expressed from myeloma plasma cells protects these cells from complement activation induced by treatment with anti-thymocyte immunoglobulins. This might protect myeloma cells during immunotherapy and promote survival of malignant cells. PMID- 21268014 TI - Molecular structure of the Mycobacterium tuberculosis virulence factor, mycolic acid, determines the elicited inflammatory pattern. AB - Mycolic acids (MAs) occur in the cell wall of Mycobacterium tuberculosis as variable mixtures of different classes and chain lengths. Here, we address the relationship between the structure and its inflammatory function of this virulence factor using single synthetic MA isomers, differing in oxygenation class and cis- versus alpha-methyl-trans proximal cyclopropane orientation. Analysis of bronchoalveolar inflammation, lung histopathology and alveolar macrophage transcription revealed a strong dependence on these meromycolic chemistries of mouse pulmonary inflammation in response to intratracheal treatments with MAs. Whereas alpha-MA was inert, oxygenated methoxy- and keto-MA with cis-cyclopropane stereochemistry elicited solid to mild inflammatory responses respectively. In trans-cyclopropane orientation, methoxy-MA partially lost its inflammatory activity and keto-MA exerted anti-inflammatory alternative activation of alveolar macrophages and counteracted cis-methoxy-MA induced airway inflammation. The differential innate immune activities of MAs demonstrated here, dependent on oxygenation class and cis versus alpha-methyl-trans cyclopropane chemistry, identify a novel means for M. tuberculosis to steer host immune responses during infection. PMID- 21268015 TI - Counter-regulation mechanism of IL-4 and IFN-alpha signal transduction through cytosolic retention of the pY-STAT6:pY-STAT2:p48 complex. AB - IFN-alpha and IL-4 induce Th1 and Th2 responses, respectively, and often display antagonistic actions against each other. To elucidate the molecular mechanism of counter-regulation, we have investigated the signal interception by IFN-alpha and IL-4, employing a human B-cell line Ramos, sensitive to both cytokines. In these cells, IFN-alpha effectively inhibited IL-4-induced Fc epsilon receptor II (CD23) expression, whereas IL-4 suppressed IFN-alpha-mediated IRF7 expression. The counter-regulatory action by IL-4 and IFN-alpha proceeded with a delayed kinetics requiring 4 h. Notably, IFN-alpha did not affect the IL-4-induced tyrosine phosphorylation of STAT6, but induced a time-dependent cytoplasmic accumulation of phosphotyrosine(pY)-STAT6 and a corresponding decrease in nuclear pY-STAT6. By confocal analysis and co-immunoprecipitation assays, we demonstrated the colocalization and molecular interaction of IL-4-induced pY-STAT6 with IFN-alpha induced pY-STAT2:p48 in the cytosol. In addition, the over-expression of STAT2 or STAT6 induced the concomitant cytosolic accumulation of pY-STAT6 or pY-STAT2, leading to the suppression of IL-4-induced CD23 or IFN-alpha-induced IRF7 gene expression, respectively. Our data suggest that the signals ensued by IFN-alpha and IL-4 induce cytoplasmic sequestration of IL-4-activated STAT6 and IFN-alpha activated STAT2:p48 in B cells through the formation of pY-STAT6:pY-STAT2:p48 complex, which provides a novel mechanism by which IFN-alpha and IL-4 cross regulate their signaling into the nucleus. PMID- 21268016 TI - Critical role of the calpain/calpastatin balance in acute allograft rejection. AB - Rejection of solid organ allograft involves alloreactive T-cell expansion. The importance of NF-kappaB and NFAT in this process is underscored by the therapeutic efficacy of immunosuppressive agents, which target the two transcription factors. Since calpains, calcium-activated proteases, are involved in the activation of NF-kappaB and NFAT, we investigated the role of calpains in allograft rejection. In human transplant kidneys undergoing acute or chronic rejection, we show an increased expression of CAPN 1 gene encoding MU-calpain, associated with a marked expression of MU-calpain, mainly in infiltrating T cells. To address the role of calpain in rejection, we used a skin transplant model in transgenic mice expressing high levels of calpastatin, a calpain specific inhibitor. We show that calpain inhibition extended skin allograft survival, from 11 to 20 days. This delay was associated with a limitation in allograft infiltration by T cells. In vitro, calpain inhibition by calpastatin transgene expression limited dramatically T-cell migration but, unexpectedly, increased slightly T-cell proliferation. Amplification of IL-2 signaling via the stabilization of IL-2R common gamma-chain provided an explanation for the proliferation response. This is the first study establishing that calpain inhibition delays allograft rejection by slowing down T-cell migration rather than proliferation. PMID- 21268017 TI - The dependence of Ig class-switching on the nuclear export sequence of AID likely reflects interaction with factors additional to Crm1 exportin. AB - Activation-induced deaminase (AID) is a B lymphocyte-specific DNA deaminase that triggers Ig class-switch recombination (CSR) and somatic hypermutation. It shuttles between cytoplasm and nucleus, containing a nuclear export sequence (NES) at its carboxyterminus. Intriguingly, the precise nature of this NES is critical to AID's function in CSR, though not in somatic hypermutation. Many alterations to the NES, while preserving its nuclear export function, destroy CSR ability. We have previously speculated that AID's ability to potentiate CSR may critically depend on the affinity of interaction between its NES and Crm1 exportin. Here, however, by comparing multiple AID NES mutants, we find that - beyond a requirement for threshold Crm1 binding - there is little correlation between CSR and Crm1 binding affinity. The results suggest that CSR, as well as the stabilisation of AID, depend on an interaction between the AID C-terminal decapeptide and factor(s) additional to Crm1. PMID- 21268018 TI - Protein synthesis in plasma cells is regulated by crosstalk between endoplasmic reticulum stress and mTOR signaling. AB - Plasma cells (PCs) secrete copious levels of immunoglobulins. To achieve this, their endoplasmic reticulum (ER) undergoes expansion in a process that requires continuous ER stress and activation of the unfolded protein response. It is important that protein synthesis, the driver of ER stress, is regulated in a manner that does not induce apoptosis. We followed protein synthesis in murine splenic B cells activated in vitro with LPS. Total protein synthesis levels increased and then steeply decreased when the cells acquired a secretory phenotype. We explored the involvement of two mechanisms in controlling protein synthesis levels, namely ER stress-mediated phosphorylation of eukaryote initiation factor 2alpha (eIF2alpha) and the mammalian target of rapamycin (mTOR) pathway, which attenuate or activate mRNA translation, respectively. We show that induction of ER stress in activated B cells counter-intuitively led to dephosphorylation of eIF2alpha. Despite the reduction in phosphorylated eIF2alpha, expression of activating transcription factor 4, an effector of hyper eIF2alpha phosphorylation, was induced. In addition, ER stress attenuated the mTOR pathway, which ultimately reduced protein synthesis. Finally, B cells engineered to overactivate the mTOR pathway exhibited higher apoptosis in the course of LPS stimulation. We conclude that protein synthesis in PCs is controlled by an ER stress-mediated mTOR regulation, which is needed for optimal cell viability. PMID- 21268019 TI - CD28 costimulation regulates FOXP3 in a RelA/NF-kappaB-dependent mechanism. AB - The molecular mechanisms whereby CD28 alone or associated with TCR can regulate FOXP3 expression are not understood, although the importance of CD28 as a pivotal regulator of CD4(+) CD25(+) FOXP3(+) T cells is well recognized. We previously demonstrated that unique CD28-induced, NF-kappaB-dependent signals were sufficient to activate FOXP3 transcription in human CD4(+) CD25(-) T cells; however, the exact mechanisms are currently unknown. In this study, we have identified novel kappaB-binding sites on FOXP3 gene and demonstrated that CD28 signals mediated FOXP3 trans activation by nuclear translocation of RelA/NF kappaB and not of c-Rel. The occupancy of FOXP3 kappaB-binding sites by RelA dimers that correlated with histone acetylation and recruitment of Pol II were required both to initiate FOXP3 transcription and to control the promoter occupancy by NFAT. Interestingly, knockdown of RelA in CD4(+) CD25(-) T cells stimulated through TCR and CD28 significantly affected FOXP3 expression, confirming that also the transcriptional activation of FOXP3 gene by TCR in the presence of CD28-costimulatory signals is RelA-dependent. In conclusion, these data suggest a new mechanism by which FOXP3 is activated and supports the critical role of CD28 in the regulation of peripheral tolerance. PMID- 21268020 TI - IL-17-producing T cells contribute to acute graft-versus-host disease in patients undergoing unmanipulated blood and marrow transplantation. AB - The aim of this study was to investigate the effects of IL-17-producing T cells, including Th17 and Tc17 cells, on acute graft-versus-host disease (aGVHD) in patients who had undergone granulocyte colony-stimulating factor (G-CSF) mobilised peripheral blood progenitor cell (PBPC) and G-CSF-primed bone marrow (G BM) transplantation. Allografts from forty-one patients were analysed for IL-17 producing T cells with respect to aGVHD. Furthermore, ten patients with aGVHD onset were monitored for the presence of Th17 cells in the peripheral blood by flow cytometry. Patients who received a higher dose of Th17 cells in the G-BM (>8.5 * 10(4) /kg, p=0.005) or a higher dose of Tc17 cells in PBPC (>16.8 * 10(4) /kg, p=0.001) exhibited a higher incidence of aGVHD. An increased Th17 population (up to 4.99% CD4(+) T lymphocytes) was observed in patients with aGVHD onset. In contrast, the percentage of Th17 population decreased drastically in aGVHD patients following treatment to achieve partial and complete remission (p=0.013 and p=0.008, respectively). All percentages of Th17 and Tc17 cells were significantly reduced after in vivo G-CSF application. Our results suggested that IL-17-producing T cells contributed to aGVHD. The application of G-CSF in vivo aided in reducing the occurrence of aGVHD through a decrease in IL-17 secretion by T cells. PMID- 21268021 TI - An intrinsic B-cell defect supports autoimmunity in New Zealand black chromosome 13 congenic mice. AB - Introgression of a New Zealand Black (NZB) chromosome 13 interval onto a C57BL/6 (B6) background (B6.NZBc13) is sufficient to produce many hallmarks of lupus, including high-titre anti-chromatin antibody production, abnormal B- and T-cell activation, and renal disease. In this study we sought to characterize the immune defects leading to these abnormalities. By generating hematopoietic chimeras and BCR transgenic mice, we show that the congenic autoimmune phenotype can be transferred by BM cells and requires the presence of autoreactive B cells. Using the hen egg white lysozyme immunoglobulin transgenic mouse model, we demonstrate that B-cell anergy, deletion, and receptor editing are intact. Nevertheless, congenic B cells exhibit altered peripheral B-cell selection, as demonstrated by enhanced survival and activation of endogenous B cells with autoreactivity to chromatin and Sm/ribonucleoprotein. Given the autoantibody specificities to nuclear antigens, TLR signalling was assessed. B6.NZBc13 B cells were hyper responsive to poly(I:C), a TLR3 ligand, demonstrating enhanced proliferation and survival as compared to B6 B cells. Our findings indicate the presence of an intrinsic B-cell defect on NZB chromosome 13 that results in hyper-responsiveness to a dsRNA analogue and implicates its potential supporting role in the generation of autoimmunity in B6.NZBc13 mice. PMID- 21268022 TI - Serum and organ-associated anti-hemoglobin humoral autoreactivity: association with anti-Sm responses and inflammation. AB - The release of hemoglobin (Hb) occurs in some infectious and autoimmune diseases characterized by inflammation. As levels of haptoglobin (Hp) fall, free Hb can cause pathology. Humoral autoreactivity to human Hb was demonstrated in the sera of systemic lupus erythematosus (SLE), leishmania and malaria patients. Serum anti-murine Hb antibody levels in lupus-prone mice also exhibited an age dependent increase, with progressive organ sequestration; significant isotypic correlation was observed with anti-dsDNA antibodies. A suggestive link between anti-Hb and anti-Sm responses was observed: Human lupus sera expressing anti-Sm antibody reactivity preferentially contained heightened levels of anti-Hb autoantibodies, and immunization of lupus-prone mice with Sm led to enhanced anti murine Hb reactivity. Human and murine anti-Hb monoclonal antibodies were generated, some of which were preferentially reactive toward disease-associated methemoglobin. Epitope-mapping studies revealed evidence of intra-molecular cross reactivity. One such autoantibody synergized with Hb to enhance the secretion of pro-inflammatory cytokines while eliciting the increased production of monocyte migratory signals from endothelial cells. Preferential usage of specific variable region gene segments was not observed, although somatic mutations were documented. These studies reveal that, while the etiology, specificity and sequences of anti-Hb autoreactive antibodies can vary, they occur quite frequently and can have inflammatory consequences. PMID- 21268023 TI - A facile method to increase titers of miRNA-encoding retroviruses by inhibition of the RNaseIII enzyme Drosha. PMID- 21268024 TI - Sustained torpidity following multi-dose administration of 3-iodothyronamine in mice. AB - Despite significant medical benefits as in space exploration or emergency care, prolonged torpidity of non-hibernator mammals remains unexplored to date. Here, we report that male Institute of Cancer Research mice could sustain two separate 2-day torpor bouts and maintain body temperature of 28-33 degrees C following repeated treatments of 3-iodothyronamine (T(1) AM), a natural derivative of thyroid hormone. A 1-day interbout arousal period, adopted to mimic the behavior of true hibernators, seemed critical for the subjects to restore physiological homeostasis. Molecular studies of neuron-specific enolase, S100 calcium binding protein B and heat shock protein 72 suggested that the brain maintains functional and cytoprotective activities during sustained torpidity. Together, the results of this study propose a practical protocol using a torpor-arousal cycle that can be applied to the extreme medical situations. PMID- 21268025 TI - Phenylboronic acid grafted chitosan as a glucose-sensitive vehicle for controlled insulin release. AB - To develop self-regulated insulin delivery system, the glucose-sensitive copolymers with a fraction of phenylboronic acid group were prepared by the coupling reaction of -COOH of N-(carboxyacyl) chitosan and -NH(2) of 3 aminophenylboronic acid. A sufficient glucose sensitivity of the copolymer was accomplished by the glucose-induced volume changes of the nanoparticles and release profiles of insulin in phosphate buffered saline (PBS, pH 7.4) with different glucose concentrations, which occurred in a remarkable glucose concentration-dependent manner. Furthermore, circular dichroism spectroscopy demonstrates that the overall tertiary structure of the released insulin was not altered compared with that of the standard insulin. The analysis of relative cell proliferation suggests that the copolymer showed good cytocompatibility. The glucose-sensitive copolymers have a potential use in self-regulated drug releasing systems. PMID- 21268026 TI - Improved aerosolization performance of salbutamol sulfate formulated with lactose crystallized from binary mixtures of ethanol-acetone. AB - It has been shown that dry powder inhaler (DPI) formulations typically achieve low fine particle fractions (poor performance). A commonly held theory is that this is due, at least in part, to low levels of detachment of drug from lactose during aerosolization as a result of strong adhesion of drug particles to the carrier surfaces. Therefore, the purpose of the present study is to overcome poor aerosolization performance of DPI formulation by modification of lactose particles. Lactose particles were crystallized by adding solution in water to different ratios of binary mixtures of ethanol-acetone. The results showed that modified lactose particles had exceptional aerosolization performance that makes them superior to commercial lactose particles. Morphology assessment showed that crystallized lactose particles were less elongated, more irregular in shape, and composed of smaller primary lactose particles compared with commercial lactose. Solid-state characterization showed that commercial lactose particles were alpha lactose monohydrate, whereas crystallized lactose particles were a mixture of alpha-lactose monohydrate and beta-lactose according to the ratio of ethanol acetone used during crystallization process. The enhanced performance could be mainly due to rougher surface and/or higher amounts of fines compared with the lactose crystallized from pure ethanol or commercial lactose. PMID- 21268027 TI - Evaluation of a non-Arrhenius model for therapeutic monoclonal antibody aggregation. AB - Understanding antibody aggregation is of great significance for the pharmaceutical industry. We studied the aggregation of five different therapeutic monoclonal antibodies (mAbs) with size-exclusion chromatography-high-performance liquid chromatography (SEC-HPLC), fluorescence spectroscopy, electron microscopy, and light scattering methods at various temperatures with the aim of gaining insight into the aggregation process and developing models of it. In particular, we find that the kinetics can be described by a second-order model and are non Arrhenius. Thus, we develop a non-Arrhenius model to connect accelerated aggregation experiments at high temperature to long-term storage experiments at low temperature. We evaluate our model by predicting mAb aggregation and comparing it with long-term behavior. Our results suggest that the number of monomers and mAb conformations within aggregates vary with the size and age of the aggregates, and that only certain sizes of aggregates are populated in the solution. We also propose a kinetic model based on conformational changes of proteins and monomer peak loss kinetics from SEC-HPLC. This model could be employed for a detail analysis of mAb aggregation kinetics. PMID- 21268028 TI - Macro electromyography and motor unit number index in the tibialis anterior muscle: differences and similarities in characterizing motor unit properties in prior polio. AB - Our objective was to establish the usefulness of the noninvasive method of the motor unit number index (MUNIX) in a large muscle and to study how macro electromyography (EMG) and MUNIX complement each other in describing the motor units (MUs) in prior polio. MUNIX and macro EMG were performed in 48 tibialis anterior muscles in 33 prior polio patients. In addition, the reproducibility of MUNIX was investigated. It is shown that MUNIX can be used to characterize MUs with high reproducibility, even in a large muscle. As judged by MUNIX values, the patients had a 25% reduction of motor neurons, whereas the macro EMG indicated a loss of 60% of the neurons. Macro EMG showed more pronounced changes compared with control material than the MUNIX. One of the reasons for this finding may be the difference in MU populations studied with the two methods. PMID- 21268029 TI - Giant metastatic alveolar soft part sarcoma in the left ventricle: appearance in echocardiography, magnetic resonance imaging, and histopathology. AB - Alveolar soft part sarcoma is a rare soft-tissue neoplasm that accounts for <1% of all soft-tissue sarcomas. Most cases arise in the extremities and head and neck region of young adults. The common sites of metastasis are lung, brain, and bone. Cardiac metastasis is extremely rare, in particular. Here we present the diagnostic evaluation and successful surgical resection of such a cardiac tumor in a patient aged 50 years with a histology-confirmed diagnosis of metastatic alveolar soft part sarcoma. PMID- 21268030 TI - Prediction of gestational diabetes mellitus by maternal factors and biomarkers at 11 to 13 weeks. AB - OBJECTIVE: To develop a model for the prediction of gestational diabetes mellitus (GDM) from maternal characteristics and biochemical markers at 11 to 13 weeks' gestation. METHODS: A prospective screening study on early prediction of pregnancy complications (n = 11, 464), including 297 (2.6%) cases of GDM was used to create the predictive model of GDM based on maternal characteristics. Maternal serum concentrations of adiponectin, follistatin-like-3 (FSTL3) and sex hormone binding globulin (SHBG) were measured in a case-control study of 80 women who developed GDM and 300 controls. RESULTS: In the screening study, maternal age, body mass index, racial origin, previous history of GDM and macrosomic neonate were significant independent predictors of future GDM. In the GDM group, compared to controls, the median multiple of the normal median adiponectin (0.66; IQR: 0.5 0.9 vs 1.02; IQR: 0.7-1.29) and SHBG (0.81; IQR: 0.6-1.04 vs 1.02; IQR: 0.8-1.2) was lower (p < 0.05), but FSTL3 was not significantly different. In screening for GDM by maternal characteristics, the detection rate was 61.6% at a false-positive rate of 20% and the detection increased to 74.1% by the addition of adiponectin and SHBG. CONCLUSION: First-trimester screening for GDM can be provided by a combination of maternal characteristics and biomarkers. PMID- 21268031 TI - Perinatal outcome of prenatally diagnosed congenital talipes equinovarus. AB - OBJECTIVE: The purpose of this study was to investigate the perinatal outcome of prenatally diagnosed congenital talipes equinovarus. METHODS: This was a retrospective observational study of all cases of prenatally diagnosed congenital talipes equinovarus referred to a major tertiary fetal medicine unit. Cases were identified from the fetal medicine and obstetric databases and pregnancy details and delivery outcome data obtained. Details of termination of pregnancy, number of patients undergoing karyotyping as well as details of prenatal classification of severity were recorded. RESULTS: A total of 174 cases were identified. Of these, outcome data was available for 88.5% (154/174) of the pregnancies. Eighty three (47.7%) of cases were isolated and 91 cases (52.3%) were associated with additional abnormalities. There was a significant difference in birth weights between the two cohorts. Bilateral abnormality tended to be more severe. A high caesarean section rate was noted overall and a high preterm delivery rate seen in the isolated group. CONCLUSION: This study is important because it provides contemporary data that can be used to counsel women prenatally. In particular, the raised risk of preterm delivery and caesarean section as well as the increased severity of the condition when both feet are affected should be discussed. The poor perinatal outcome when additional anomalies are present and the increased risk of aneuploidy are also important factors. PMID- 21268032 TI - Fetal micrognathia: objective assessment and associated anomalies on prenatal sonogram. AB - OBJECTIVE: To determine the accuracy and characteristics of prenatally detected fetal micrognathia. METHODS: A retrospective analysis of all pregnancies with the suspicion of fetal micrognathia was performed. The affected fetuses were reassessed by estimation of the inferior facial angle (IFA) and the frontal nasomental angle on stored gray scale images to objectively establish the diagnosis. RESULTS: Of the 28.935 ultrasounds (USs) reviewed, 58 cases were eligible and 4 were excluded because of inconclusive data. The mean values for IFA and frontal nasomental angle were 44.8 degrees and 123.3 degrees , respectively. In 33 cases, the pregnancy was terminated. Four fetuses died sub partu or immediately after birth, five were stillborn. Invasive testing in 40/54 cases revealed aneuploidies in 35%. Associated anomalies comprised musculoskeletal disorders (43%) and non-skeletal anomalies (15%). Less than one fifth (9/54) were alive beyond postnatal period. Four fetuses had an isolated micrognathia, one of which was found to have a cleft palate postnatally. CONCLUSION: The diagnosis of micrognathia has a crucial impact on both prenatal and postnatal outcomes of affected individuals due to its association with additional abnormalities. A detailed sonographic survey using objective criteria for defining micrognathia is mandatory. Once the diagnosis is confirmed, an intensive interdisciplinary counseling of the parents is needed. PMID- 21268033 TI - Cytogenetic analysis of 355 cases of fetal loss in different trimesters. AB - OBJECTIVE: We estimated the success rates of cytogenetic analyses in different tissue samples after intrauterine fetal deaths and analyzed the value of cytogenetic testing for determining the causes. METHODS: Women with intrauterine fetal deaths (occurring at > 10 weeks of gestation) were offered either invasive testing before medical induction of labor, or solid tissue biopsy diagnosis after delivery. RESULTS: A total cohort of 355 intrauterine fetal deaths was studied. During antepartum examinations, invasive procedures included amniocentesis (AMC), chorionic villus sampling (CVS) and umbilical cord (UBC) sampling. During postpartum examinations, samples were taken from unfixed specimens of fetal skin, placenta and other tissues. Chromosomal abnormalities were observed in 22 fetal deaths for which cytogenetic analyses were successful. Logistic regression analysis identified antepartum invasive sampling [P = 0.000, odds ratio (OR) 31.125, 95% confidence interval (CI) 14.265-67.908] to be associated with a high cytogenetic success rate and older age with fetal deaths (P = 0.104, OR 0.487, 95% CI 0.204-1.160) not to be associated with a high chromosomal abnormality. In the patients with recurrent pregnancy loss, the chromosomal abnormality rate of 18.6% of spontaneous abortions has not been significantly more than that of fetal deaths 11.5% (P = 0.437). CONCLUSION: Parents should be counseled on all aspects of cytogenetic analysis after fetal death. Antepartum testing after pregnancy loss is recommended. PMID- 21268034 TI - Aberrant lymphatic development in euploid fetuses with increased nuchal translucency including Noonan syndrome. AB - OBJECTIVE: Increased nuchal translucency in the human fetus is associated with aneuploidy, structural malformations and several syndromes such as Noonan syndrome. In 60-70% of the Noonan syndrome cases, a gene mutation can be demonstrated. Previous research showed that aneuploid fetuses with increased nuchal translucency (NT) demonstrate an aberrant lymphatic endothelial differentiation. METHOD: Fetuses with increased NT and normal karyotype (n = 7) were compared with euploid controls having normal NT (n = 5). A Noonan syndrome gene mutation was found in three out of seven fetuses with increased NT. Endothelial differentiation was evaluated by immunohistochemistry using lymphatic markers (PROX-1, Podoplanin, LYVE-1) and blood vessel markers vascular endothelial growth factor-A (VEGF-A), Neuropilin-1 (NP-1), Sonic hedgehog, von Willebrand factor, and the smooth muscle cell marker, smooth muscle actin. RESULTS: Nuchal edema and enlarged jugular lymphatic sacs (JLSs) were observed in fetuses with increased NT, together with abnormal lymphatic endothelial differentiation i.e. the presence of blood vessel characteristics, including high levels of VEGF-A and NP-1 expression. The enlarged JLSs contained erythrocytes and were surrounded by smooth muscle cells. CONCLUSION: This study shows an aberrant lymphatic endothelial differentiation in fetuses with increased NT and a normal karyotype (including Noonan syndrome fetuses), as was previously reported before in aneuploid fetuses. PMID- 21268035 TI - Evaluation of normal fetal atrio-ventricular septum dimensions during pregnancy. AB - OBJECTIVES: Ebstein anomaly and atrio-ventricular septal defect involve a profound change in the appearance of the atrio-ventricular septum (AVS). AVS is the area between the insertion of the mitral valve and the tricuspid valve leaflets to the ventricular septum. In normal fetuses, the tricuspid valve has an apical displacement relative to the mitral valve. We aimed to create a nomogram of its normal dimensions, beginning in the 11th gestational week. METHODS: Measurement of the length of the AVS was performed during ultrasonographic fetal echocardiography, in the four-chamber view from 11 to 34 gestational weeks in otherwise normal pregnancies. In addition, standard fetal biometry was measured. Linear regression analysis was used to evaluate the correlation between variables. RESULTS: Two hundred and ninety-two examinations of normal fetuses were included. A positive correlation was found between AVS length and gestational age (r(2) = 0.96, P < 0.001), each week adding 0.165 mm (beta = 0.165, P < 0.001). AVS length was also proportional to inter-ventricular septum (IVS) length with increasing gestational age (r(2) = 0.882, beta = 0.94, P < 0.001). Positive linear correlation was obtained between AVS length and fetal biometry (P < 0.001). CONCLUSION: We provide a nomogram for AVS length which can be used as a reference when either Ebstein anomaly or atrio-ventricular septal defects are suspected. PMID- 21268036 TI - PAPP-A and free beta-hCG measured prior to 10 weeks is associated with preterm delivery and small-for-gestational-age infants. AB - OBJECTIVE: To evaluate whether measuring pregnancy-associated plasma protein A (PAPP-A) and free beta-human chorionic gonadotrophin (beta-hCG) before 10 weeks of gestation affect the association between these biomarkers and adverse pregnancy outcomes. METHODS: Singleton pregnant women (9450) who attended the prenatal screening program, Aarhus University Hospital, Denmark, were included. Maternal serum levels of PAPP-A and free beta-hCG were measured between week 8 and 13 weeks and 6 days. The risk of preterm delivery (<37 weeks) and small for gestational age (SGA) (= 10 weeks) biochemical testing. RESULTS: A stronger association between low PAPP-A and SGA was found with early serum sampling compared to late, but the difference was not statistically significant [odds ratio (OR) 3.2 vs 1.8; P value = 0.11]. This difference did not apply to PAPP-A and preterm delivery. For free beta-hCG, a stronger association with preterm delivery was found with early testing (OR 1.9 vs 1.1; P value = 0.31), whereas this difference was not found regarding SGA. CONCLUSION: Biochemical testing before 10 weeks does not affect the association between low PAPP-A and free beta hCG and adverse pregnancy outcomes. Whether the association is actually stronger with early testing, requires further study. PMID- 21268037 TI - Changes in the recipient fetal Tei index in the peri-operative period after laser photocoagulation of placental anastomoses for twin-twin transfusion syndrome. AB - OBJECTIVE: To assess serial changes in the Tei index of the recipient fetus secondary to fetoscopic laser photocoagulation of placental anastomoses (FLP) for twin-twin transfusion syndrome (TTTS) during the peri-operative period. STUDY DESIGN: A prospective study of cases that underwent FLP at the Texas Children's Fetal Center was performed. Mean and individual changes in the Tei index measurements were obtained during the pre-operative, intra-operative and the post operative (12-h and 24-h) periods after surgery and were compared using paired t test. A p-value of < 0.05 was considered as significant. RESULTS: A total of 20 patients were included in the study. In both the right and the left side, the mean Tei indices appeared to be increased from baseline during the intra operative period, with a subsequent decrease to pre-operative values within 24 h of laser surgery. These changes were also noted when individualized patient results were analyzed in a serial fashion. CONCLUSION: FLP results in a transient increase in the intra-operative myocardial performance index in the recipient fetus. These changes appear to resolve in the post-operative period. PMID- 21268038 TI - Gene expression in chorionic villous samples at 11 weeks of gestation in women who develop pre-eclampsia later in pregnancy: implications for screening. AB - OBJECTIVES: To determine the gene expression profile in chorionic villous samples (CVSs) of women destined to develop pre-eclampsia (PE). METHOD: Case-control study encompassing five women destined to develop PE [cases matched for gestational age with 30 controls]. We quantified mRNA expression on tissue samples from CVS of normal and PE patients. We then assessed mRNA expressions of cathepsin (CTSD), angiopoietin 2 (ANGPT2), interleukin 8, chemokine (C-X-C motif) ligand 10, neurokinin B (NKB), matrix metallopeptidase 9, major histocompatibility complex, class I, C (HLA-C)and human leukocyte antigen-G (HLA G). Data were analyzed by nonparametric rank analysis. RESULTS: For all the mRNA species considered in this study, except CTSD and ANGPT2, all the mean observed ranks in the PE group were significantly altered compared with the rank expectation among controls. mRNA for NKB and HLA-C were the markers with the highest degree of aberration in PE, compared with those in controls. CONCLUSION: Our study has directly showed that gene expressions relating to trophoblastic cell invasion or utero-placental hemodynamic adaptation are altered in the first trimester trophoblasts that go on to develop PE later. These results posit the use of residual CVS as a possible screening method for PE. PMID- 21268039 TI - Prenatal diagnosis of non-immune hydrops fetalis: what do we tell the parents? AB - OBJECTIVE: The aim of this study is to outline the aetiology and outcome of a series of fetuses with non-immune hydrops (NIH), detected prenatally. The findings are compared with a comprehensive review of recent reports. METHODS: This is a retrospective study reviewing all pregnancies complicated by NIH in the fetus and continued after 20 weeks of pregnancy over a period of 10 years. Outcome was obtained from postmortem reports, discharge summaries, communication with the clinicians or information from the parents. A literature search was also performed to identify all reports on NIH in the last 10 years. RESULTS: Seventy one fetuses affected by NIH were included in this study. The aetiology of the NIH was identified prenatally in 40 cases. The most common causes of NIH were thoracic disorders, infections and cardiovascular disorders. Forty-four of the 71 (62%) fetuses were live-born. There were 10 neonatal deaths. Of the remaining 34 babies, 17 infants survived without morbidity. CONCLUSION: The survival rate of NIH is at least 48% in this study. Prenatal identification of the cause is possible in 56% of cases. The risk of neurodevelopmental delay in those that survive is 3 of 28 (11%). PMID- 21268040 TI - Maternal serum insulin-like growth factor-binding protein-1 (IGFBP-1) at 11-13 weeks in pre-eclampsia. AB - OBJECTIVE: The aim of this study was to determine the maternal serum concentration of insulin-like growth factor-binding protein-1 (IGFBP-1) at 11-13 weeks' gestation in pregnancies that subsequently develop pre-eclampsia (PE) and to examine the possible association with uterine artery pulsatility index (PI). METHODS: Maternal serum concentration of IGFBP-1 and uterine artery PI were measured in 60 cases that developed PE, including 20 that required delivery before 34 weeks (early-PE) and 120 unaffected controls. The measured IGFBP-1 concentration and uterine artery PI were converted into a multiple of the expected median (MoM) in unaffected pregnancies and median MoM values were compared in the outcome groups. Regression analysis was used to determine the significance of association of IGFBP-1 MoM with uterine artery PI MoM. RESULTS: In the early- and late-PE groups, the median IGFBP-1 was decreased (0.63 and 0.67 MoM, respectively) and uterine artery PI was increased (1.31 and 1.19 MoM, respectively). In the group that developed PE there were no significant associations between serum IGFBP-1 with uterine artery PI (p = 0.210). CONCLUSION: In pregnancies that develop PE, the serum IGFBP-1 is decreased from the first trimester suggesting that IGFBP-1 may be implicated in the pathogenesis of PE in a mechanism unrelated to impaired placental perfusion. PMID- 21268041 TI - A predictive model of short cervix at 20-24 weeks using first-trimester cervical length measurement and maternal history. AB - OBJECTIVES: To develop a model for the prediction of short cervix ( <= 15 mm) at 20-24 weeks by combining maternal history and transvaginal ultrasonographic measurement of cervical length at 11-14 weeks. To explore the value of an additional ultrasound examination of the cervix at about 17 weeks. METHODS: Longitudinal prospective study in 800 unselected pregnant women presenting for first-trimester ultrasound assessment by nuchal translucency and serum biochemistry. Cervical length was evaluated transvaginally between 11 weeks and 13 weeks and 6 days (cx1), at 16-19 weeks (cx2) and 20-24 weeks (cx3). Backward multiple logistic regression analysis with cx3 <= 15 mm as the dependent variable was used to identify the predictors of a short cervix at 20-24 weeks. RESULTS: Cx1 and history of preterm delivery were significant independent contributors of a short cervix at 20-24 weeks [area under the curve (AUC 0.808, p < 0.001, Model) 1]. Furthermore, the cx1/cx2 ratio was a significant independent predictor of a short cervix at 20-24 weeks (odds ratio = 58.325 p = 0.012). The addition of the cx1/cx2 ratio improved the model (AUC = 0.878, p < 0.001, Model 2). CONCLUSIONS: A short cervix at 20-24 weeks can be predicted at the 11-14 weeks scan. The addition of a cervical measurement at about 17 weeks can improve the prediction model. PMID- 21268042 TI - Hypomethylated DSCR4 is a placenta-derived epigenetic marker for trisomy 21. AB - BACKGROUND: Trisomy 21 is the most common chromosomal aberration in live births. Some efforts have been made to develop noninvasive prenatal detection of trisomy 21 by using fetal DNA in maternal plasma. Due to the maternal DNA background, a distinguishable marker between maternal DNA and fetal DNA must be used, such as DNA methylation. The objective of this study was to search for fetal-specific methylation markers on chromosome 21. METHODS: We chose six genes highly or specifically expressed in placenta and screened the methylation status of these gene promoter regions by combination of methylated-DNA precipitation and methylation-sensitive restriction enzymes assay (COMPARE-MS). We further determined the methylation status of each CpG site within selected gene fragments by bisulfite sequencing. At last, we detected the placenta-derived methylation marker in the first-trimester maternal plasma by real-time methylation-specific PCR (MSP). RESULTS: Down syndrome (DS) critical region gene 4 (DSCR4) promoter region was found to be hypomethylated in placental tissues and densely methylated in maternal blood cells. Unmethylated DSCR4 (Down syndrome) sequence can be detected in the first-trimester maternal plasma. CONCLUSION: DSCR4 promoter DNA is a candidate fetal epigenetic marker for noninvasive prenatal detection of trisomy 21. PMID- 21268043 TI - Pericardial effusion in the first trimester of pregnancy. PMID- 21268044 TI - Detection of the S252W mutation in fibroblast growth factor receptor 2 (FGFR2) in fetal DNA from maternal plasma in a pregnancy affected by Apert syndrome. PMID- 21268045 TI - Non-invasive prenatal diagnosis: improved detection rates. PMID- 21268046 TI - Prenatal screening for Down syndrome: a survey of willingness in women and family physicians to engage in shared decision-making. AB - OBJECTIVE: To assess the willingness of women and their family physicians (FPs) to engage in shared decision-making (SDM) as regards prenatal Down-syndrome screening and the factors that might influence their willingness to do so. METHODS: We conducted a survey of participants in Quebec City, Canada, using the theory of planned behavior. We used a general linear model and multilevel approach that took the fact that some women consulted the same FP into account. RESULTS: This study comprised 109 pregnant women and 41 FPs. On a scale of - 3 to + 3, the pregnant women's and FPs' response scores were, respectively, 2.11 +/- 1.38 and 2.66 +/- 0.40. In women, attitude, significant others, self-efficacy, perceived moral correctness, and their FP's attitude influenced their willingness to engage in SDM. However, women without a post-secondary education were less likely to engage in SDM than women with a post-secondary education, mostly because the former lacked a sense of self-efficacy. In FPs, only attitude and significant others influenced their willingness to engage in SDM. CONCLUSION: Overall, the women and their FPs wished to engage in SDM as regards prenatal Down syndrome screening. Only a few factors influenced this desire which therefore may be modifiable. PMID- 21268047 TI - A hevein-like protein and a class I chitinase with antifungal activity from leaves of the paper mulberry. AB - Paper mulberry (Broussonetia papyrifera, syn. Morus papyrifera L.) is a Chinese traditional medicine and its low-molecular-weight extracts are reported to have antifungal activity. In this study, two proteins (PMAPI and PMAPII) with activity against Trichoderma viride were obtained from paper mulberry leaves with a fast protein liquid chromatography (FPLC) unit. The purification protocol employed (NH(4))(2)SO(4) precipitation, ion-exchange chromatography and hydrophobic interaction chromatography on FPLC. Molecular masses were 18,798 Da for PMAPI, and 31,178 Da for PMAPII determined by Matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Peptide mapping fingerprint analysis showed that PMAPI has no peptides similar to PMAPII. N-terminal amino acid sequencing revealed that PMAPI is a hevein-like protein, and PMAPII is a class I chitinase. They both had a half-maximal inhibitory concentration (IC50) of 0.1 ug/uL against T. viride. This is the first report of high-molecular-weight extracts with antifungal activity from paper mulberry. PMID- 21268048 TI - Development and validation of a highly sensitive LC-MS/MS method for simultaneous quantitation of ethionamide and ethionamide sulfoxide in human plasma: application to a human pharmacokinetic study. AB - A highly sensitive and specific LC-MS/MS method has been developed for simultaneous quantification of ethionamide and ethionamide sulfoxide in human plasma (300 uL) using prothionamide as an internal standard (IS). Solid-phase extraction was used to extract ethionamide, ethionamide sulfoxide and IS from human plasma. The chromatographic separation of ethionamide, ethionamide sulfoxide and IS was achieved with a mobile phase consisting of 0.1% acetic acid : acetonitrile (20:80, v/v) at a flow rate of 0.50 mL/min on a Peerless Basic C(18) column. The total run time was 3.5 min and the elution of ethionamide, ethionamide sulfoxide and IS occurred at 2.50, 2.18 and 2.68 min, respectively. A linear response function was established for the range of concentrations 25.7 6120 ng/mL (r > 0.998) for ethionamide and 50.5-3030 ng/mL (r > 0.998) for ethionamide sulfoxide. The intra- and inter-day precision values for ethionamide and ethionamide sulfoxide met the acceptance as per FDA guidelines. Ethionamide and ethionamide sulfoxide were stable in battery of stability studies, viz. bench top, autosampler and freeze-thaw cycles. The developed assay was applied to a pharmacokinetic study in humans. PMID- 21268049 TI - Simultaneous estimation of E- and Z-isomers of guggulsterone in rabbit plasma using liquid chromatography tandem mass spectrometry and its application to pharmacokinetic study. AB - A sensitive and selective liquid chromatography/tandem mass spectrometric method was developed for simultaneous determination of E- and Z-guggulsterone isomers (antihyperlipidemic drug) in rabbit plasma. Both the isomers were resolved on a Symmetry-Shield C(18) (5 um, 4.6 * 150 mm) column, using gradient elution comprising a mobile phase of methanol, 0.5% v/v formic acid and acetonitrile. With dexamethasone as internal standard, plasma samples were extracted by an automated solid-phase extraction method using C(18) cartridges. Detection was performed by electrospray ionization in multiple reaction monitoring (MRM) in positive mode. The calibration curve was linear over the concentration range of 1.56-200 ng/mL (r(2) >= 0.998) for both analytes. The intra-day and inter-day accuracy and precision were within -0.96 to 4.12 (%bias) and 2.73 to 8.00 (%RSD) respectively. The analytes were stable after three freeze-thaw cycles. The method was successfully applied to study steriospecific pharmacokinetics of E- and Z guggulsterone in NZ rabbit. PMID- 21268050 TI - Simultaneous determination of fimasartan, a novel antihypertensive agent, and its active metabolite in rat plasma by liquid chromatography-tandem mass spectrometry. AB - Fimasartan, 2-butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2'-(1H tetrazol -5-yl)biphenyl-4-yl]methyl]pyrimidin-4(3H)-one (BR-A-657), is a novel angiotensin II receptor blocker exhibiting potent and selective AT1 receptor blocking activity. This study reports the liquid chromatography-tandem mass spectrometry assay for the simultaneous determination of fimasartan and its active metabolite, BR-A-557, in rat plasma. The assay was validated to demonstrate the specificity, linearity, recovery, lower limit of quantification, accuracy, precision and stability. The multiple reaction monitoring was based on the transition of m/z 502.1 -> 207.1 for fimasartan, 486.2 -> 207.1 for BR-A-557 and 526.1 -> 207.1 for BR-A-563 (internal standard). The assay utilized a simple precipitation procedure with acetonitrile and isocratic elution. The LLOQ was 0.2 ng/mL for fimasartan and BR-A-557 using 50 MUL plasma samples. The assay was linear over a concentration range from 0.2 to 500 ng/mL for fimasartan and BR-A 557, with correlation coefficients >0.9995. The intra- and inter-day assay accuracies were 93.6-108.0 and 90.8-101.4% for fimasartan and 102.2-107.1 and 99.6-103.3% for BR-A-557, respectively. The intra- and inter-day precision were 2.4-4.4 and 3.0-13.4% for fimasartan and 3.1-5.2 and 2.8-9.8% for BR-A-557, respectively. The developed assay may be used to study the metabolism and mechanistic pharmacokinetics of fimasartan in future studies. PMID- 21268051 TI - Health impact of pneumoconiosis in Mongolia: estimation of losses in life expectancy and quality adjusted life expectancy. AB - OBJECTIVE: To estimate the life expectancy (LE), quality-adjusted life expectancy (QALE), and their losses, in patients with pneumoconiosis in Mongolia. METHODS AND MATERIALS: All patients (n = 432) diagnosed with occupational pneumoconiosis during 1986-2006 were recruited from the registry of the National Research Center of Occupational Diseases, which was linked to the National Mortality Registry of Mongolia to obtain the survival function. We simulated age and gender matched referents group based on the life table in 2000. The survival ratio between patients and referents was used to extrapolate and calculate the LE. The average expected years of life loss (EYLL) of pneumoconiosis were calculated as the mean survival difference between patients and referents. We adopted utility values for workers with pneumoconiosis and multiplied them with the survival function to estimate the QALE, which was then used to calculate the loss of QALE. RESULTS: The life expectancy and EYLL of a patient with pneumoconiosis were 18.1 and 9.5 years respectively. QALE and loss of QALE were 15.1 and 12.5 QALYs (quality adjusted life years), respectively, indicating a health gap of 45%. CONCLUSION: The health inequality suffered by miners in Mongolia must be addressed through prevention, including exposure monitoring and control, early diagnosis and case management and rehabilitation of pneumoconiosis. PMID- 21268052 TI - Multivariate meta-analysis: potential and promise. AB - The multivariate random effects model is a generalization of the standard univariate model. Multivariate meta-analysis is becoming more commonly used and the techniques and related computer software, although continually under development, are now in place. In order to raise awareness of the multivariate methods, and discuss their advantages and disadvantages, we organized a one day 'Multivariate meta-analysis' event at the Royal Statistical Society. In addition to disseminating the most recent developments, we also received an abundance of comments, concerns, insights, critiques and encouragement. This article provides a balanced account of the day's discourse. By giving others the opportunity to respond to our assessment, we hope to ensure that the various view points and opinions are aired before multivariate meta-analysis simply becomes another widely used de facto method without any proper consideration of it by the medical statistics community. We describe the areas of application that multivariate meta analysis has found, the methods available, the difficulties typically encountered and the arguments for and against the multivariate methods, using four representative but contrasting examples. We conclude that the multivariate methods can be useful, and in particular can provide estimates with better statistical properties, but also that these benefits come at the price of making more assumptions which do not result in better inference in every case. Although there is evidence that multivariate meta-analysis has considerable potential, it must be even more carefully applied than its univariate counterpart in practice. PMID- 21268053 TI - A stochastic multicriteria model for evidence-based decision making in drug benefit-risk analysis. AB - Drug benefit-risk (BR) analysis is based on firm clinical evidence regarding various safety and efficacy outcomes. In this paper, we propose a new and more formal approach for constructing a supporting multi-criteria model that fully takes into account the evidence on efficacy and adverse drug reactions. Our approach is based on the stochastic multi-criteria acceptability analysis methodology, which allows us to compute the typical value judgments that support a decision, to quantify decision uncertainty, and to compute a comprehensive BR profile. We construct a multi-criteria model for the therapeutic group of second generation antidepressants. We assess fluoxetine and venlafaxine together with placebo according to incidence of treatment response and three common adverse drug reactions by using data from a published study. Our model shows that there are clear trade-offs among the treatment alternatives. PMID- 21268054 TI - Strengthening ancient mtDNA equid sequences from Pompeii. PMID- 21268055 TI - Neuronal chromatin dynamics of imprinting in development and disease. AB - Epigenetic mechanisms play essential roles in mammalian neurodevelopment and genetic mutations or chromosomal deletions or duplications of epigenetically regulated loci or pathways result in several important human neurodevelopmental disorders. Postnatal mammalian neurons have among the most structured and dynamic nuclear organization of any cell type. Human chromosome 15q11-13 is an imprinted locus required for normal neurodevelopment and is regulated by a plethora of epigenetic mechanisms in neurons, including multiple noncoding RNAs, parentally imprinted transcription and histone modifications, large-scale chromatin decondensation, and homologous pairing in mature neurons of the mammalian brain. Here, we describe the multiple epigenetic layers regulating 15q11-13 gene expression and chromatin dynamics in neurons and propose a model of how noncoding RNAs may influence the unusual neuronal chromatin structure and dynamics at this locus. We also discuss the need for improved neuronal cell culture systems that model human 15q11-13 and other neurodevelopmental disorders with epigenetic bases in order to test the mechanisms of chromatin dynamics and nuclear organization in neurons. Induced pluripotent stem cells and other stem cell technologies hold promise for improved understanding of and therapeutic interventions for multiple human neurodevelopmental disorders. PMID- 21268056 TI - Stem and progenitor cells for neurological repair: minor issues, major hurdles, and exciting opportunities for paracrine-based therapeutics. AB - The transplantation of cultured stem and progenitor cells is a key element in the rapidly growing field of regenerative medicine. Based on their ability to rescue and/or repair injured tissue and partially restore organ function, multiple types of stem/progenitor cells have already entered into clinical trials. However, despite several decades of intense research, the goal to apply culture-expanded stem/progenitor cells in a manner that can effectively replace cells after injury has yet to be realized. Many sources of potentially useful cells are available, but something is clearly missing. In addition, recent studies suggest that paracrine effects of secreted or released factors are responsible for most of the benefits observed after cell transplantation, rather than direct cell replacement. These data call into question the need for cell transplantation for many types of therapy, in particular for acute injuries such as myocardial infarction and stroke. In this review, we examine current progress in the area of cell transplantation and minor issues and major hurdles regarding the clinical application of different cell types. We discuss the "paracrine hypothesis" for the action of transplanted stem/progenitor cells as an opportunity to identify defined combinations of biomolecules to rescue and/or repair tissues after injury. Although many of the concepts in this review will apply to multiple injury/repair systems, we will focus primarily on stem/progenitor cell-based treatments for neurological disorders and stroke. PMID- 21268057 TI - New insights into the inactivation of gastric tumor suppressor RUNX3: the role of H. pylori infection. AB - Runt-related transcription factor 3, or RUNX3, is a tumor suppressor in gastric cancer. Inactivation of RUNX3 is causally associated with the genesis of gastric cancer, since RUNX3 is frequently inactivated in gastric cancers by hemizygous deletion, hypermethylation of its promoter, or protein mislocalization. Infection with Helicobacter pylori is the strongest risk factor for the development of gastric cancer. Recent studies have indicated that H. pylori infection plays an important role in the inactivation of RUNX3, and that this inactivation contributes to the pathogenesis of H. pylori. Here we summarize these recent advances and discuss their significances in understanding the initiation and development of gastric cancer. PMID- 21268058 TI - Oncogenic role of RUNX3 in head and neck cancer. AB - Cumulative evidences show that Runt-related transcription factor 3 (RUNX3) has a tumor suppressive role in various cancers. In particular, RUNX3 appears to be an important component of the transforming growth factor-beta (TGF-beta)-induced tumor suppression pathway. Contrary to reports on this tumor suppressive role of RUNX3, RUNX3 can also function as an oncogene when overexpressed. Recently, we found that RUNX3 overexpression was frequently observed and was well correlated with malignant behaviors in head and neck cancer, which is one of the most common types of human cancer. Moreover, it has been revealed that RUNX3 overexpression promoted cell growth and inhibited apoptosis in head and neck cancer cells. This review introduces the oncogenic role of RUNX3 in certain types of cancer including head and neck cancer. PMID- 21268059 TI - Control of RUNX3 by histone methyltransferases. AB - Runt-related (RUNX) family proteins function as context-dependent transcription factors during developmental processes such as hematopoiesis, neurogenesis, and osteogenesis. RUNX3 is involved in a variety of physiological processes including neurogenesis, thymopoiesis, and dendritic cell maturation. A large amount of information indicates that RUNX3 may be a tumor suppressor. Recent data suggest that the molecular mechanism responsible for RUNX3 deficiency in numerous cancers is a primarily epigenetic silencing. The present review focuses on the regulation of RUNX3 gene expression by histone modification, emphasizing histone methylation at the RUNX3 promoter and inactivation of protein itself. Inactivation of the promoter and protein can be the results of various chemical modifications, including methylation by histone methyltransferase. Inactivation of RUNX3 may contribute to the tumor initiation, progression and pathogenesis in specific microenvironmental contexts. Finally, this review describes the reactivation of RUNX3 by epigenetic regulatory agents. PMID- 21268061 TI - Functions of Runx in IgA class switch recombination. AB - Runt-related (Runx) transcriptional regulators play essential roles in various cell fate determination processes, and dysfunction of these regulators causes many human diseases. Considerable insight into the functions of Runx proteins was provided mainly by studies of hematopoietic and skeletal disorders. Recently, extensive investigations have revealed new functions of these transcription factors in immune cell differentiation and functioning. In the present review, we discuss the mechanisms of selective IgA production in the intestine and report the involvement of Runx proteins in this process. PMID- 21268060 TI - Direct transcriptional targets of sex steroid hormones in bone. AB - The sex steroid hormones, androgens and estrogens, via their respective nuclear receptors, regulate bone mineral density in humans and mice. Very little is known about the direct targets of the androgen and estrogen receptors in bone cells. First, models of hormone and receptor deficiency in mouse and human bone are discussed. This review then focuses on the direct targets of the receptors in osteoblasts and osteoclasts. A direct target of a NR is defined here as a gene that is regulated by NR binding to the DNA (either through DNA binding or association with a DNA binding protein) at an enhancer or promoter of that gene. The experimental evidence that illustrates androgen and estrogen gene regulation in osteoblasts and osteoclasts will be summarized and compared with the phenotype of the hormones in vivo. PMID- 21268062 TI - Key roles of histone methyltransferase and demethylase in leukemogenesis. AB - A growing body of evidence has underlined the involvement of histone methyltransferases and demethylases in leukemia development. These findings can be roughly classified into two categories according to their association with leukemia. On the one hand, these histone modifiers are recruited to DNA by specific affinities of aberrantly expressed transcription factors or fusion proteins, and induce chromatin modifications to regulate target gene expression. Epigenetic regulators may function as oncogenes in this context. On the other hand, recent studies have identified inactivating mutations of some key histone modulators in myeloid malignancies and these results suggest that they act as tumor suppressors. Profound understanding of these findings in the two categories will help us consider clinical applications of epigenetic drugs. In this prospect we will review the leukemogenic mechanisms clarified by the epigenetic approach and the current findings on genetic aberrations in each methyltransferase or demethylase, and discuss the potential of medical intervention in leukemia or leukemia stem cells targeting histone modifiers. PMID- 21268063 TI - Molecular mechanisms that produce secondary MDS/AML by RUNX1/AML1 point mutations. AB - RUNX1/AML1 point mutations have been identified in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients. A heterozygous germline mutation of the RUNX1 gene causes a familial platelet disorder with a predisposition to AML. RUNX1 mutations have also been detected with high frequency in minimally differentiated AML M0 subtypes and myelodysplastic/myeloproliferative neoplasms. Here we propose a new disease category of myelodysplastic neoplasms (MDN) consisting of MDS refractory anemia with excess blasts and AML with myelodysplasia-related changes, including therapy-related cases. RUNX1 mutations have been detected in about 20% of patients with "MDN". Among the MDN cases, histories of radiation exposure, therapy-related myeloid neoplasms after successful treatment for acute promyelocytic leukemia, and leukemic transformation of myeloproliferative neoplasms have been reported to have a strong association with RUNX1 mutations. The mutations occur in a normal, a receptive, or a disease-committed hematopoietic stem cell. It is suspected that the "MDN" phenotypes are defined by the RUNX1 mutations in addition to some other abnormalities. PMID- 21268064 TI - Per-1 is a specific clock gene regulated by parathyroid hormone (PTH) signaling in osteoblasts and is functional for the transcriptional events induced by PTH. AB - Per-1 is one of the clock genes and is known to regulate various biological events including bone mass determination. Parathyroid hormone is anabolic to bone while the mechanism of its action is not fully understood. Here, we examined the role of PTH on Per-1 gene expression under osteoblast specific PTH signaling. Constitutively active PTH receptor (caPPR) expressed specifically in osteoblasts in transgenic mice activates Per-1 gene expression in bone. This is specific as expression of other clock gene Bmal-1 is not affected by caPPR over-expression. Per-1 is also expressed in osteoblastic cell line. Interestingly, Per-1 expression is required for PTH signaling-induced CRE dependent transcription. This is forming a positive feed back loop in the anabolic action of PTH signaling and Per-1 in bone. These data indicate that PTH singling in osteoblasts activates Per-1 gene expression in vivo in association with its anabolic action in bone at least in part through the regulation of transcriptional events. PMID- 21268065 TI - Usp7 and Uhrf1 control ubiquitination and stability of the maintenance DNA methyltransferase Dnmt1. AB - In mammals Dnmt1 is the DNA methyltransferase chiefly responsible for maintaining genomic methylation patterns through DNA replication cycles, but how its maintenance activity is controlled is still not well understood. Interestingly, Uhrf1, a crucial cofactor for maintenance of DNA methylation by Dnmt1, is endowed with E3 ubiquitin ligase activity. Here, we show that both Dnmt1 and Uhrf1 coprecipitate with ubiquitin specific peptidase 7 (Usp7), a de-ubiquitinating enzyme. Overexpression of Uhrf1 and Usp7 resulted in opposite changes in the ubiquitination status and stability of Dnmt1. Our findings suggest that, by balancing Dnmt1 ubiquitination, Usp7 and Uhrf1 fine tune Dnmt1 stability. PMID- 21268067 TI - FPTB, a novel CA-4 derivative, induces cell apoptosis of human chondrosarcoma cells through mitochondrial dysfunction and endoplasmic reticulum stress pathways. AB - Chondrosarcoma is a malignant primary bone tumor that responds poorly to both chemotherapy and radiation therapy. The aim of this study was to elucidate the mechanism of the novel Combretastatin A-4 derivative, 2-(furanyl)-5 (pyrrolidinyl)-1-(3,4,5-trimethoxybenzyl)benzoimidazole (FPTB)-induced human chondrosarcoma cells apoptosis. FPTB induced cell apoptosis in human chondrosarcoma cell line but not primary chondrocytes. FPTB induced up-regulation of Bax and Bak, down-regulation of Bcl-2 and Bcl-XL and dysfunction of mitochondria in chondrosarcoma. FPTB also triggered endoplasmic reticulum (ER) stress, as indicated by changes in cytosol-calcium levels. We found that FPTB increased glucose-regulated proteins (GRP)78 but not GRP94 expression. In addition, treatment of cells with FPTB induced calpain expression and activity. Transfection of cells with GRP78 or calpain siRNA reduced FPTB-mediated cell apoptosis. Therefore, FPTB-induced apoptosis in chondrosarcoma cells through the mitochondria dysfunction and involves caspase-9 and caspase-3-mediated mechanism. FPTB also induced cell death mediated by increasing ER stress, GPR78 activation, and Ca(2+) release, which subsequently triggers calpain, caspase-12 and caspase-3 activity, resulting in apoptosis. PMID- 21268066 TI - SUMOylation of DLX3 by SUMO1 promotes its transcriptional activity. AB - Small ubiquitin-like modifiers (SUMO) are post-translational modifiers that regulate target protein activity in diverse ways. The most common group of SUMO substrates is transcription factors, whose transcriptional activity can be altered positively or negatively as a result of SUMOylation. DLX3 is a homeodomain transcription factor involved in placental development, in the differentiation of structures involving epithelial-mesenchymal interactions, such as hair, teeth and nails, and in bone mineralization. We identified two potential SUMOylation sites in the N-terminal domain of DLX3 at positions K83 and K112. Among the six members of the Distal-less family, DLX3 is the only member containing these sites, which are highly conserved among vertebrates. Co expression experiments demonstrated that DLX3 can be SUMOylated by SUMO1. Site directed mutagenesis of lysines 83 and 112 to arginines (K83R and K112R) demonstrated that only K112 is involved in SUMOylation. Immunocytochemical analysis determined that SUMOylation does not affect DLX3 translocation to the nucleus and favors perinuclear localization. Moreover, using electrophoresis mobility shift assay (EMSA), we found that DLX3 is still able to bind DNA when SUMOylated. Using luciferase reporter assays, we showed that DLX3(K112R) exhibits a significantly lower transcriptional activity compared to DLX3(WT), suggesting that SUMOylation has a positive effect on DLX3 activity. We identified a new level of regulation in the activity of DLX3 that may play a crucial role in the regulation of hair, teeth, and bone development. PMID- 21268068 TI - Suppression of the proinflammatory response of metastatic melanoma cells increases TRAIL-induced apoptosis. AB - Melanoma is the most lethal form of human skin cancer. However, only limited chemotherapy is currently available for the metastatic stage of the disease. Since chemotherapy, radiation and sodium arsenite treatment operate mainly through induction of the intrinsic mitochondrial pathway, a strongly decreased mitochondrial function in metastatic melanoma cells, could be responsible for low efficacy of the conventional therapy of melanoma. Another feature of metastatic melanoma cells is their proinflammatory phenotype, linked to endogenous expression of the inflammatory cytokines, such as TNFalpha IL6 and IL8, their receptors, and constitutive NF-kappaB- and STAT3-dependent gene expression, including cyclooxygenase-2 (PTGS2/COX2). In the present study, we treated melanoma cells with immunological (monoclonal antibody against TNFalpha or IL6), pharmacological (small molecular inhibitors of IKKbeta-NF-kappaB and JAK2-STAT3) or genetic (specific RNAi for COX-2) agents that suppressed the inflammatory response in combination with induction of apoptosis via TRAIL. As a result of these combined treatments, exogenous TRAIL via interactions with TRAIL-R2/R1 strongly increased levels of apoptosis in resistant melanoma cells. The present study provides new understanding of the regulation of TRAIL-mediated apoptosis in melanoma and will serve as the foundation for the potential development of a novel approach for a therapy of resistant melanomas. PMID- 21268069 TI - Phytoestrogens directly inhibit TNF-alpha-induced bone resorption in RAW264.7 cells by suppressing c-fos-induced NFATc1 expression. AB - TNF-alpha-induced osteoclastogenesis is central to post-menopausal and inflammatory bone loss, however, the effect of phytoestrogens on TNF-alpha induced bone resorption has not been studied. The phytoestrogens genistein, daidzein, and coumestrol directly suppressed TNF-alpha-induced osteoclastogenesis and bone resorption. TRAP positive osteoclast formation and resorption area were significantly reduced by genistein (10(-7) M), daidzein (10(-5) M), and coumestrol (10(-7) M), which was prevented by the estrogen antagonist ICI 182,780. TRAP expression in mature TNF-alpha-induced osteoclasts was also significantly reduced by these phytoestrogen concentrations. In addition, in the presence of ICI 182,780 genistein and coumestrol (10(-5) -10(-6) M) augmented TNF-alpha-induced osteoclast formation and resorption. However, this effect was not observed in the absence of estrogen antagonist indicating that genistein's and coumestrol's ER-dependent anti-osteoclastic action normally negates this pro osteoclastic effect. To determine the mechanism mediating the anti-osteoclastic action we examined the effect of genistein, coumestrol, and daidzein on caspase 3/7 activity, cell viability and expression of key genes regulating osteoclast differentiation and fusion. While anti-osteoclastic phytoestrogen concentrations had no effect on caspase 3/7 activity or cell viability they did significantly reduce TNF-alpha-induced c-fos and NFATc1 expression in an ER dependent manner and also inhibited NFATc1 nuclear translocation. Significant decreases in NFkappaB and DC-STAMP levels were also noted. Interestingly, constitutive c-fos expression prevented the anti-osteoclastic action of phytoestrogens on differentiation, resorption and NFATc1. This suggests that phytoestrogens suppress TNF-alpha-induced osteoclastogenesis via inhibition of c-fos-dependent NFATc1 expression. Our data provides further evidence that phytoestrogens have a potential role in the treatment of post-menopausal and inflammatory bone loss directly inhibiting TNF-alpha-induced resorption. PMID- 21268070 TI - JAK2/STAT3 pathway is involved in the early stage of adipogenesis through regulating C/EBPbeta transcription. AB - Signal transducer and activator of transcription 3 (STAT3) was reported to be involved in adipogenesis. However, the regulating mechanism of STAT3 remains unclear. The present results showed that STAT3 was activated within 2-h adipogenic induction, in which the phosphorylated STAT3 translocated from cytoplasm to the nucleus. In addition, we detected Janus kinase2 (JAK2) acted upstream of the STAT3 activation at the early stage of adipogenesis. Accordingly, the JAK2 inhibitor AG490 and siRNAs led to the partial inhibition of the STAT3 activation, and the inhibition of 3T3-L1 adipocyte differentiation. Furthermore, the results based on luciferase, chromatin immunoprecipitation, and gel shift approaches indicated that STAT3 could regulate the transcription of C/EBPbeta by binding the distal region of C/EBPbeta promoter at the early stage of adipogenesis. Collectively, our findings reveal that JAK2/STAT3 pathway is involved in the early stage of 3T3-L1 adipocyte differentiation though regulating the C/EBPbeta transcription. PMID- 21268071 TI - Protein stability of mitochondrial superoxide dismutase SOD2 is regulated by USP36. AB - SOD2 is a key mitochondrial antioxidant enzyme and its perturbation leads to oxidative cell death, which results in various disorders. In this study, we identified a deubiquitinating enzyme USP36 that regulates the protein stability of SOD2. The regulatory effect of USP36 on SOD2 was initially identified by 2-DE and MALDI-TOF/MS analyses. In addition, endogenous USP36 and SOD2 were shown to interact in an immunoprecipitation assay, which was verified using the yeast two hybrid system. Furthermore, we demonstrated that SOD2 binds with ubiquitin molecules to form polyubiquitination chains and undergoes degradation through the ubiquitin-proteasomal pathway. Finally, USP36 was shown to be a specific deubiquitinating enzyme that reduces the ubiquitination level of SOD2 and was involved in SOD2 protein stability by extending its half-life. PMID- 21268072 TI - Gambogic acid-induced degradation of mutant p53 is mediated by proteasome and related to CHIP. AB - As an oncoprotein, mutant p53 is a potential tumor-specific target for cancer therapy. Most mutated forms of the protein are largely accumulated in cancer cells due to their increased stability. In the present study, we demonstrate that mutant p53 protein stability is regulated by gambogic acid (GA). Following GA exposure, protein levels of mutant p53 decreased while the mRNA levels were not affected in MDA-MB-435 cells, which indicate that GA down-regulates mutant p53 at post-transcription level. Co-treatment with GA and cycloheximide, a protein synthesis inhibitor, induced a decrease of half-life of mutant p53 protein. These findings indicated that the reduction of mutant p53 by GA was due to the destabilization and degradation of the protein. Furthermore, inhibition of proteasome activity by MG132 blocked GA-induced down-regulation of mutant p53, causing mutant p53 accumulation in detergent-insoluble cellular fractions. Further studies revealed that mutant p53 was ubiquitinated and it was chaperones related ubiquitin ligase carboxy terminus of Hsp70-interacting protein (CHIP) rather than MDM2 involved in the degradation of mutant p53. In addition, GA prevented Hsp90/mutant p53 complex formation and enhanced interaction of mutant p53 with Hsp70. Depletion of CHIP stabilized mutant p53 in GA treated cells. In conclusion, mutant p53 may be down-regulated by GA through chaperones-assisted ubiquitin/proteasome degradation pathway in cancer cells. PMID- 21268073 TI - Examining rhodopsin retention in endoplasmic reticulum and intracellular localization in vitro and in vivo by using truncated rhodopsin fragments. AB - More than 100 mutations of rhodopsin have been identified to be associated with retinitis pigmentosa (RP), and mostly autosomal-dominant RP (ADRP). The majority of rhodopsin-associated ADRP is caused by protein misfolding and ER retention. In this study, we aimed to evaluate rhodopsin folding, exiting the ER and intracellular localization through expression of the rhodopsin fragments in COS-1 cells as well as in the transgenic zebrafish. We cloned human rhodopsin cDNA, which was then divided into the N-terminal domain, the C-terminal domain, and the fragment between the N- and C-terminal domains, and examine their intracellular expression in vitro and in vivo. We introduced a point mutation, either F45L or G51V, into this fragment and observed the intracellular localization of these mutants in COS-1 cells and in the zebrafish. The results revealed all of the truncated rhodopsin fragments except for the C-terminal domain and the full length rhodopsin which had some plasma membrane localization, formed aggregates nearby or within the ER in COS-1 cells; however, the N-terminally truncated rhodopsin fragment, the C-terminal domain, and the full-length rhodopsin could traffic to the ROS in the zebrafish. Besides, the F45L mutation and the G51Vmutation in the rhodopsin fragment between the N- and C-terminal domains produced different effects on the aggresome formation and the intracellular distribution of the mutants both in vivo and in vitro. This current study provides new information about the mutant rhodopsin as well as in treatment of the RP in humans in the future. PMID- 21268074 TI - Cell-type-specific organization of nuclear DNA into structural looped domains. AB - In the interphase nucleus of metazoan cells the DNA is organized in supercoiled loops anchored to a proteinaceous substructure known as the nuclear matrix (NM). The DNA is anchored to the NM by means of non-coding sequences of variable length known as matrix attachment regions or MARs operationally classified in structural constitutive, resistant to high-salt extraction and transient-functional, non resistant to high-salt extraction. The former are also known as true loop attachment regions or LARs that determine structural DNA loops. The DNA-NM interactions define a higher order structure within the cell nucleus (NHOS). We studied in a comparative fashion the NHOS in two primary cell types from the rat: hepatocytes and naive B lymphocytes, by analyzing the topological relationships between the NM and a set of eight short gene sequences located in six separate chromosomes and as such representing a coarse-grained, large-scale sample of the actual organization of nuclear DNA into structural loop domains. Our results indicate that such an organization is cell-type specific since most of the gene sequences studied showed significant differences in their relative position to the NM according to cell type. Such cell-type specific differences in the NHOS have no obvious correlation with the tissue-specific transcriptional activity of the corresponding genes, supporting the notion that permanent, structural DNA loops are different from transient, functional DNA loops that may be associated with transcription. PMID- 21268075 TI - The procollagen type III, alpha 1 (COL3A1) gene first intron expresses poly-A+ RNA corresponding to multiple ESTs and putative miRNAs. AB - The mouse COL3A1 first intron is 9684 bp. RNA's of approximately 1.6 and 3.0 kb were detected by Northern hybridization analysis of poly-A RNA from fetal mice and total RNA from suckling and adult mouse intestine using (32)P-labeled, anti sense RNA synthesized from a mouse COL3A1 first intron, 5 prime region, 5.4 kb Xba I fragment (1655-7030 bp), recombinant plasmid (pPI5.4x). Expression of the 1.6 and 3.0 kb RNA's was significantly reduced in adult mouse intestine, indicating that these RNAs are developmentally regulated. "BLAST" analysis indicated that the mouse first intron 5 prime sequence has 94-100% identity to 13 mouse ESTs. These mouse first intron EST's lie within the 5.4 Xba I fragment of the mouse COL3A1 first intron. Two of the mouse first intron EST's have significant identity to known miRNA, mature sequences, mmu-miR-466f-3P, mmu-miR 1187, and mmu-miR-574-5P as well as others. Predicted targets for mmu-miR-466f-3P include COL1A1, COL19A1, COL11A2, COL4A1, and COL4A5 indicating that COL3A1 intronic miRNAs may regulate the expression of other collagen genes in development. PMID- 21268076 TI - Stercurensin inhibits nuclear factor-kappaB-dependent inflammatory signals through attenuation of TAK1-TAB1 complex formation. AB - We identified a chalcone, 2',4'-dihydroxy-6'-methoxy-3'-methylchalcone (stercurensin), as an active compound isolated from the leaves of Syzygium samarangense. In the present study, the anti-inflammatory effects and underlying mechanisms of stercurensin were examined using lipopolysaccharide (LPS) stimulated RAW264.7 cells and mice. To determine the effects of stercurensin in vitro, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression were analyzed by RT-PCR and immunoblotting. Nuclear factor-kappaB (NF kappaB) activation and its upstream signaling cascades were also investigated using a dual-luciferase reporter assay, electrophoretic mobility shift assay, immunoblotting, immunofluorescence, and immunoprecipitation. To verify the effects of stercurensin in vivo, the mRNA expression levels of iNOS and COX-2 were evaluated in isolated mouse peritoneal macrophages by quantitative real-time PCR, and the production of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and IL-1beta were assessed in serum samples from mice using a Luminex system. Pretreatment with stercurensin reduced LPS-induced iNOS and COX-2 expression, thereby inhibiting nitric oxide (NO) and prostaglandin E(2) production, respectively. In addition, an inhibitory effect of stercurensin on NF kappaB activation was shown by the recovery of LPS-induced inhibitor of kappaB (I kappaB) degradation after blocking the transforming growth factor-beta-activated kinase 1 (TAK1)/I-kappaB kinase signaling pathway. In mouse models, stercurensin negatively regulated NF-kappaB-dependent pro-inflammatory mediators and cytokines. These results demonstrate that stercurensin modulates NF-kappaB dependent inflammatory pathways through the attenuation of TAK1-TAB1 complex formation. Our findings demonstrating the anti-inflammatory effects of stercurensin in vitro and in vivo will aid in understanding the pharmacology and mode of action of stercurensin. PMID- 21268077 TI - Enterovirus 71 modulates a COX-2/PGE2/cAMP-dependent viral replication in human neuroblastoma cells: role of the c-Src/EGFR/p42/p44 MAPK/CREB signaling pathway. AB - Enterovirus 71 (EV71) has been shown to induce cyclooxygenase-2 (COX-2) expression in human neuroblastoma SK-N-SH cells through the action of MAPKs, NF kappaB, and AP-1. On the other hand, the transcription factor CREB has also been implicated in the expression of COX-2 in other cell lines. Here, we report that EV71-induced COX-2 expression and PGE(2) production were both inhibited by pretreatment with the PKA inhibitor H89 or by transfection with CREB siRNA. In addition, EV71-induced COX-2 expression and c-Src/EGFR phosphorylation were both attenuated by transfection with c-Src siRNA or pretreatment with the inhibitors of c-Src (PP1) or EGF receptor (EGFR) (AG1478 and EGFR-neutralizing antibody). We also observed that EV71-induced p42/p44 MAPK phosphorylation was decreased following pretreatment with AG1478. Moreover, EV71-induced COX-2 expression was blocked by pretreatment with the p300 inhibitor GR343 or by transfection with p300 siRNA. Using immunoprecipitation and chromatin immunoprecipitation assays, we observed that EV71 stimulated the association of CREB and p300 with the COX-2 promoter region. Notably, we also demonstrated that EV71-induced COX-2 expression and PGE(2) production promoted viral replication via cAMP signaling. In summary, this study demonstrates that EV71 activates the c-Src/EGFR/p42/p44 MAPK pathway in human SK-N-SH cell, which leads to the activation of CREB/p300, and stimulates COX-2 expression and PGE(2) release. PMID- 21268078 TI - Nuclear translocation of calpain-2 regulates propensity toward apoptosis in cardiomyocytes of tail-suspended rats. AB - The compensatory increase in catecholamine release does not reverse orthostatic intolerance after returning from a long-term spaceflight, but it is unclear whether high dose of catecholamine induces cardiac damage. The tail-suspended rat model was used to simulate the effects of weightlessness on the heart. Apoptotic rates in the left ventricular myocardium did not increase in 4-week of tail suspended rats compared with the synchronous control. On the contrary, isoproterenol (intraperitoneal injection) and 1-day recovery from the 4-week tail suspension increased apoptotic rates in the myocardium. Propranolol and PD150606 inhibited cardiomyocyte apoptosis in the recovery group. PD150606 and calpain-2 knockdown also blocked isoproterenol-induced cardiomyocyte apoptosis in tail suspended rats. The activity and nuclear translocation of calpain-2 increased, but the expression of calpain-1, calpain-2, and calpastatin was unchanged in the myocardium of tail-suspended rats. The Ser-16-phosphorylated phospholamban of the nuclear envelope was higher in tail-suspended rats than in the control rats under isoproterenol stimulation. Isoproterenol treatment also induced a large intranuclear Ca(2+) transient of cardiomyocytes in tail-suspended rats. These results suggest that high-dose isoproterenol phosphorylates phospholamban of the nuclear envelope and increases intranuclear Ca(2+) transient. Larger intranuclear Ca(2+) further activates nuclear calpain-2 and hence induces cardiomyocyte apoptosis. PMID- 21268079 TI - Oxidized low-density lipoprotein promotes osteoblast differentiation in primary cultures of vascular smooth muscle cells by up-regulating Osterix expression in an Msx2-dependent manner. AB - We have previously shown that oxidized low-density lipoproteins (oxLDLs) act synergistically with beta-glycerophosphate to induce the osteogenic differentiation of primary bovine aortic smooth muscle cells (BASMCs). In the present study, we attempt to resolve the mechanism responsible for this effect by examining the expression of several osteoblast-specific transcription factors. Thus, by culturing BASMCs in the absence or presence of beta-glycerophosphate and/or oxLDL, we demonstrate that beta-glycerophosphate induces both Runx2 and Osterix (Osx) expression. In contrast, oxLDL has no effect on Runx2 expression but rather it enhances beta-glycerophosphate-induced osteoblast differentiation by further up-regulating Osx expression. In an attempt to elucidate the mechanism responsible for this latter effect, we examined the ability of oxLDL to affect Msh homeobox 2 (Msx2) expression. Similar to its effect on Osx expression, oxLDL was found to synergistically enhance beta-glycerophosphate-induced Msx2 expression in an extracellular signal-regulated kinase 1 and 2 (Erk 1 and 2) dependent manner. Furthermore, oxLDL's ability to enhance both beta glycerophosphate-induced Osx expression and alkaline phosphatase activity was prevented when the BASMCs were first transfected with Msx2-specific siRNA. Taken together, these findings suggest a plausible mechanism by which oxLDL may promote osteoblast differentiation and vascular calcification in vivo. PMID- 21268080 TI - Cigarette smoke extract regulates cytosolic phospholipase A2 expression via NADPH oxidase/MAPKs/AP-1 and p300 in human tracheal smooth muscle cells. AB - Up-regulation of cytosolic phospholipase A(2) (cPLA(2)) by cigarette smoke extract (CSE) may play a critical role in airway inflammatory diseases. However, the mechanisms underlying CSE-induced cPLA(2) expression in human tracheal smooth muscle cells (HTSMCs) were not completely understood. Here, we demonstrated that CSE-induced cPLA(2) protein and mRNA expression was inhibited by pretreatment with the inhibitors of AP-1 (tanshinone IIA) and p300 (garcinol) or transfection with siRNAs of c-Jun, c-Fos, and p300. Moreover, CSE also induced c-Jun and c-Fos expression, which were inhibited by pretreatment with the inhibitors of NADPH oxidase (diphenyleneiodonium chloride and apocynin) and the ROS scavenger (N acetyl-L-cysteine) or transfection with siRNAs of p47(phox) and NADPH oxidase (NOX)2. CSE-induced c-Fos expression was inhibited by pretreatment with the inhibitors of MEK1 (U0126) and p38 MAPK (SB202190) or transfection with siRNAs of p42 and p38. CSE-induced c-Jun expression and phosphorylation were inhibited by pretreatment with the inhibitor of JNK1/2 (SP600125) or transfection with JNK2 siRNA. CSE-stimulated p300 phosphorylation was inhibited by pretreatment with the inhibitors of NADPH oxidase and JNK1/2. Furthermore, CSE-induced p300 and c-Jun complex formation was inhibited by pretreatment with diphenyleneiodonium chloride, apocynin, N-acetyl-L-cysteine or SP600125. These results demonstrated that CSE-induced cPLA(2) expression was mediated through NOX2-dependent p42/p44 MAPK and p38 MAPK/c-Fos and JNK1/2/c-Jun/p300 pathways in HTSMCs. PMID- 21268081 TI - Rho GTPase-mediated cytoskeletal organization in Schlemm's canal cells play a critical role in the regulation of aqueous humor outflow facility. AB - The increased intraocular pressure (IOP) has been considered to be an increased resistance of the aqueous humor outflow through the inner wall of Schlemm's canal (SC) and/or the juxtacanalicular tissue (JCT). The Rho GTPase-regulated actomyosin organization appears to be an important mechanistic determinant of aqueous humor outflow facility. Therefore, in this study, we have evaluated the effects of modulating Rho GTPase activity on actomyosin cytoskeletal organization, monolayer permeability/barrier function of human SC cells, and aqueous humor outflow facility in enucleated porcine eyes ex vivo. Human SC cells, isolated from cadaver eyes, were treated with either Rho GTPase activators such as thrombin and lysophosphatidic acid (LPA), or a specific inhibitor (C3 exoenzyme) of Rho GTPases. Treatment of SC cells with thrombin and LPA led to increased formation of stress fibers, focal adhesion, and increased myosin light chain phosphorylation, whereas treatment with C3-exoenzyme showed the opposite effects like H-7 and ECA, known for increasing the outflow facility in porcine eyes. The findings presented here suggest that LPA and thrombin, presumably through activation of Rho GTPase-mediated actomyosin cytoskeletal reorganization in SC cells, cause a decrease in monolayer permeability of SC cells as well as a decrease in outflow facility of porcine eyes in ex vivo. Our results suggest that decrease in aqueous humor outflow may be correlated better with the changes in cytoskeletal organizations of SC, which could be the prime locus of the outflow resistance. PMID- 21268082 TI - Changes in matrix protein gene expression associated with mineralization in the differentiating chick limb-bud micromass culture system. AB - Chick limb-bud mesenchymal stem cells plated in high density culture in the presence of 4 mM inorganic phosphate and vitamin C differentiate and form a mineralizable matrix, resembling that of the chick growth plate. To further elucidate the mechanism that allows these cultures to form physiologic hydroxyapatite deposits, and how the process can be manipulated to gain insight into mineralization mechanisms, we compared gene expression in mineralizing (with 4 mM inorganic phosphate) and non-mineralizing cultures (containing only 1 mM inorganic phosphate) at the start of mineralization (day 11) and after mineralization reached a plateau (day 17) using a chick specific microarray. Based on replicate microarray experiments and K-cluster analysis, several genes associated with the mineralization process were identified, and their expression patterns confirmed throughout the culture period by quantitative RT-PCR. The functions of bone morphogenetic protein 1, BMP1, dentin matrix protein 1, DMP1, the sodium phosphate co-transporter, NaPi IIb, matrix metalloprotease 13. MMP-13, and alkaline phosphatase, along with matrix protein genes (type X collagen, bone sialoprotein, and osteopontin) usually associated with initiation of mineralization are discussed. PMID- 21268083 TI - Role of endogenous TGF-beta family in myogenic differentiation of C2C12 cells. AB - The present study evaluated endogenous activities and the role of BMP and transforming growth factor-beta (TGF-beta), representative members of the TGF beta family, during myotube differentiation in C2C12 cells. Smad phosphorylation at the C-terminal serines was monitored, since TGF-beta family members signal via the phosphorylation of Smads in a ligand-dependent manner. Expression of phosphorylated Smad1/5/8, which is an indicator of BMP activity, was higher before differentiation, and rapidly decreased after differentiation stimulation. Differentiation-related changes were consistent with those in the expression of Ids, well-known BMP-responsive genes. Treatment with inhibitors of BMP type I receptors or noggin in C2C12 myoblasts down-regulated the expression of myogenic regulatory factors, such as Myf5 and MyoD, leading to impaired myotube formation. Addition of BMP-2 during the myoblast phase also inhibited myotube differentiation through the down-regulation of Myf5 and MyoD. In contrast to endogenous BMP activity, the phosphorylation of Smad2, a TGF-beta-responsive Smad, was higher 8-16 days after differentiation stimulation. A-83-01, an inhibitor of TGF-beta type I receptor, increased the expression of Myf5 and MyoD, and enhanced myotube formation. The present results reveal that endogenous activities of the TGF-beta family are changed during myogenesis in a pathway specific manner, and that the activities are required for myogenesis. PMID- 21268084 TI - The effects of estrogen receptors alpha- and beta-specific agonists and antagonists on cell proliferation and energy metabolism in human bone cell line. AB - In cultured human osteoblasts estradiol-17beta (E2) modulated DNA synthesis, the specific activity of creatine kinase BB (CK), 12 and 15 lipoxygenase (LO) mRNA expression and formation of 12- and 15-hydroxyeicosatetraenoic acid (HETE). We now investigate the response of human bone cell line (SaOS2) to phytoestrogens and estrogen receptors (ER)-specific agonists and antagonists. Treatment of SaSO2 with E2, 2,3-bis (4-hydroxyphenyl)-propionitrile (DPN; ERbeta-specific agonist), 4,4',4"-[4-propyl-(1H)-pyrazol-1,3,5-triyl] tris-phenol (PPT; ERalpha-specific agonist), biochainin A (BA), daidzein (D), genistein (G) and raloxifene (Ral) showed increased DNA synthesis and CK. Ral inhibited completely all stimulations except DPN and to some extent D. The ERalpha-specific antagonist methyl piperidino-pyrazole (MPP) and the ERbeta-specific antagonist 4-[2-phenyl-5,7-bis (tri-fluoro-methyl) pyrazolo [1,5-a]pyrimidin-3-yl] phenol (PTHPP) inhibited DNA synthesis, CK and reactive oxygen species (ROS) formation induced by estrogens according to their receptors affinity. The LO inhibitor baicaleine inhibited only E2, DPN and G's effects. E2 and Ral unlike all other compounds had no effect on ERalpha mRNA expression, while ERbeta mRNA expression was stimulated by all compounds. All compounds modulated the expression of 12LO and 15LO mRNA, except E2, PPT and Ral for 12LO, and 12- and 15-HETE productions and stimulated ROS formation which was inhibited by NADPH oxidase inhibitors diphenyleneiodonium chloride (DPI) and N-acetyl cysteine and the estrogen inhibitor ICI. DPI did not affect hormonal-induced DNA and CK. In conclusion, we provide evidence for the separation of mediation via ERalpha and ERbeta pathways in the effects of estrogenic compounds on osteoblasts, but the role of LO/HETE/ROS is unclear. PMID- 21268085 TI - Phosphoproteome profiling for cold temperature perception. AB - Temperature sensation initiates from the activation of cellular receptors when the cell is exposed to a decrease in temperature. Here, we applied a phosphoproteome profiling approach to the human lung epithelial cell line BEAS-2B to elucidate cellular cold-responsive processes. The primary aim of this study was to determine which intracellular changes of phosphorylation are accompanied by cold sensation. Eighteen protein spots that exhibited differentially phosphorylated changes in cells were identified. Most of the proteins that were phosphorylated after 5 or 10 min were returned to control levels after 30 or 60 min. Identified proteins were mainly RNA-related (i.e., they were involved in RNA binding and splicing). Temperature (18 and 10 degrees C) stimuli showed homologies that were detected for time course changes in phosphoproteome. The data indicated a time-shift between two temperatures. The phosphorylation of putative cold responsive markers, such as ribosomal protein large P0 and heterochromatin-associated proteins 1, were verified by Western blotting in cells transfected with TRPM8 or TRPA1. PMID- 21268086 TI - Phloroglucinol derivative MCPP induces cell apoptosis in human colon cancer. AB - This study is the first to investigate the anticancer effects of the new phloroglucinol derivative (3,6-bis(3-chlorophenylacetyl)phloroglucinol; MCPP) in human colon cancer cells. MCPP induced cell death and antiproliferation in three human colon cancer, HCT-116, SW480, and Caco-2 cells, but not in primary human dermal fibroblast cells. MCPP-induced concentration-dependent apoptotic cell death in colon cancer cells was measured by fluorescence-activated cell sorter (FACS) analysis. Treatment of HCT-116 human colon cancer cells with MCPP was found to induce a number of signature endoplasmic reticulum (ER) stress markers; and up-regulation of CCAAT/enhancer-binding protein homologous protein (CHOP) and glucose-regulated protein (GRP)-78, phosphorylation of eukaryotic initiation factor-2alpha (eIF-2alpha), suggesting the induction of ER stress. MCPP also increased GSK3alpha/beta(Tyr270/216) phosphorylation and reduced GSK3alpha/beta(Ser21/9) phosphorylation time-dependently. Transfection of cells with GRP78 or CHOP siRNA, or treatment of GSK3 inhibitor SB216163 reduced MCPP mediated cell apoptosis. Treatment of MCPP also increased caspase-7, caspase-9, and caspase-3 activity. The inhibition of caspase activity by z-DEVE-FMK or z-VAD FMK significantly reduced MCPP-induced apoptosis. Furthermore, treatment of GSK3 inhibitor SB216763 also dramatically reversed MCPP-induced GRP and CHOP up regulation, and pro-caspase-3 and pro-caspase-9 degradation. Taken together, the present study provides evidences to support that GRP78 and CHOP expression, and GSK3alpha/beta activation in mediating the MCPP-induced human colon cancer cell apoptosis. PMID- 21268087 TI - Inducible expression of Runx2 results in multiorgan abnormalities in mice. AB - Runx2 is a transcription factor controlling skeletal development, and is also expressed in extraskeletal tissues where its function is not well understood. Existing Runx2 mutant and transgenic mouse models do not allow the necessary control of Runx2 expression to understand its functions in different tissues. We generated conditional, doxycyline-inducible, triple transgenic mice (CMV Cre;ROSA26-neo(flox/+)-rtTA;Tet-O-Runx2) to investigate the effects of wide spread overexpression of Runx2. Osteoblasts isolated from CMV-Cre;ROSA26 neo(flox/+)-rtTA; Tet-O-Runx2 mice demonstrated a dose-dependent effect of doxycycline to stimulate Runx2 transgene expression. Doxycycline administration to CMV-Cre;ROSA26-neo(flox/+)-rtTA;Tet-O-Runx2 mice induced Runx2 transgene expression in all tissues tested, with the highest levels observed in kidney, ovary, and bone. Runx2 overexpression resulted in deceased body size and reduced viability. With regard to bone, Runx2 overexpressing mice paradoxically displayed profound osteopenia and diminished osteogenesis. Induced expression of Runx2 in extraskeletal tissues resulted in ectopic calcification and induction of the osteogenic program in a limited number of tissues, including lung and muscle. In addition, the triple transgenic mice showed evidence of a myeloproliferative disorder and an apparent inhibition of lymphocyte development. Thus, overexpression of Runx2 both within and outside of the skeleton can have diverse biological effects. Use of tissue specific Cre mice will allow this model to be used to conditionally and inducibly overexpress Runx2 in different tissues and provide a means to study the post-natal tissue- and cell context-dependent functions of Runx2. PMID- 21268088 TI - An autonomous BMP2 regulatory element in mesenchymal cells. AB - BMP2 is a morphogen that controls mesenchymal cell differentiation and behavior. For example, BMP2 concentration controls the differentiation of mesenchymal precursors into myocytes, adipocytes, chondrocytes, and osteoblasts. Sequences within the 3'untranslated region (UTR) of the Bmp2 mRNA mediate a post transcriptional block of protein synthesis. Interaction of cell and developmental stage-specific trans-regulatory factors with the 3'UTR is a nimble and versatile mechanism for modulating this potent morphogen in different cell types. We show here, that an ultra-conserved sequence in the 3'UTR functions independently of promoter, coding region, and 3'UTR context in primary and immortalized tissue culture cells and in transgenic mice. Our findings indicate that the ultra conserved sequence is an autonomously functioning post-transcriptional element that may be used to modulate the level of BMP2 and other proteins while retaining tissue specific regulatory elements. PMID- 21268089 TI - Molecular mechanisms underlying the inhibition of IFN-gamma-induced, STAT1 mediated gene transcription in human macrophages by simvastatin and agonists of PPARs and LXRs. AB - PPARs and LXRs are ligand-activated transcription factors that are emerging as promising therapeutic targets for limiting atherosclerosis, an inflammatory disorder orchestrated by cytokines. The potent anti-atherogenic actions of these nuclear receptors involve the regulation of glucose and lipid metabolism along with attenuation of the inflammatory response. Similarly, cholesterol-lowering drugs, statins, inhibit inflammation. Unfortunately, the mechanisms underlying such inhibitory actions of these agents in human macrophages are poorly understood and were therefore investigated in relation to IFN-gamma, a key pro atherogenic cytokine, which mediates its cellular effects mainly through STAT1. Simvastatin and PPAR agonists had no effect on the IFN-gamma-induced, phosphorylation-mediated activation of STAT1 and its DNA binding but attenuated its ability to activate gene transcription. On the other hand, LXR activators attenuated both DNA binding and trans-activation potential of STAT1 induced by IFN-gamma. These studies reveal differences in the mechanism of action of agonists of PPARs (and simvastatin) and LXRs on the IFN-gamma-induced, STAT1 mediated gene transcription in human macrophages. PMID- 21268090 TI - Effect of three-dimensional culture and incubator gas concentration on phenotype and differentiation capability of human mesenchymal stem cells. AB - To obtain sufficient numbers of cells for tissue engineering applications, human bone marrow-derived mesenchymal stem cells (hBM-MSC) are commonly cultured as monolayers in incubators containing room air. In this study, we investigated whether three-dimensional (3D) culture conditions and incubator gas concentrations more similar to those observed in vivo impacted on cell expansion, differentiation capability, or phenotype of hBM-MSC. We found that 3D culture alone increased the expression of some molecules involved in osteogenic and adipogenic differentiation. In contrast, 3D culture did not induce chondrogenic differentiation, but enhanced the response to the chondrogenic differentiation medium. Changing the oxygen concentration to 6% and the carbon dioxide concentration to 7.5% did not impact on the results of any of our assays, showing that the hyperoxia of room air is not detrimental to hBM-MSC proliferation, differentiation, or phenotype. PMID- 21268091 TI - Preventive effect of phytoglycoprotein (27 kDa) on inflammatory factors at liver injury in cadmium chloride-exposed ICR mice. AB - Cadmium is one of the inflammation-related xenobiotics and has been regarded as a potent carcinogen. Gardenia jasminoides Ellis (GJE) has been used to cure inflammation in Korean folk medicine for a long time. The purpose of present study is the inhibitory effect of glycoprotein isolated from GJE (27 kDa) on inflammation mechanism in cadmium chloride-exposed ICR mice. We evaluated the activities of lactate dehydrogenase (LDH), alanine aminotransferase (ALT), and thiobarbituric acid-reactive substances (TBARS), activities of anti-oxidative enzymes [superoxide dismutase (SOD) and gluthathione peroxidase (GPx)], activities of c-Jun N-terminal protein kinase (JNK), heat shock protein 27 (Hsp27), activator protein (AP)-1, nuclear factor (NF)-kappaB and expression of inflammation-related mediators including tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 in cadmium chloride-exposed ICR mice using immunoblot analysis, EMSA and RT-PCR. It notes that mice plasma was used to measure ALT, LDH, and TBARS after treatment with cadmium chloride alone or cadmium chloride under the pretreatment with GJE glycoprotein. Liver tissues were used to assess activities of anti-oxidant enzymes, SAPK/JNK, Hsp27, AP-1, NF-kappaB, TNF-alpha, and IL-6 in this study. The results obtained from this study revealed that GJE glycoprotein (10 mg/kg) decreased the levels of LDH, ALT and TBARS, whereas increased the activity of hepatic anti-oxidant enzymes (SOD and GPx) in cadmium chloride-exposed ICR mice. Moreover, it decreased the activity of JNK/AP-1, NF kappaB, Hsp27, and pro-inflammatory cytokines (TNF-alpha and IL-6). Taken together, the results in this study suggest that GJE glycoprotein inhibits the expression of inflammation-related cytokines (TNF-alpha and IL-6) in cadmium chloride-exposed ICR mice. PMID- 21268092 TI - Effect of desacyl ghrelin, obestatin and related peptides on triglyceride storage, metabolism and GHSR signaling in 3T3-L1 adipocytes. AB - Acyl-ghrelin (AG), desacyl-ghrelin (DAG) and obestatin are all derived from the same gene transcript; however their plasma levels do not necessarily change in parallel. The influence of these peptides towards the development of obesity and their direct effects on adipocyte physiology has not been thoroughly investigated. This study was designed to evaluate the direct effects of peptides of the ghrelin family on preadipocyte proliferation, differentiation and adipocyte lipid and glucose metabolism in 3T3-L1 cells. 3T3 cells were treated with physiological peptide concentrations for 1 h to 9 days, and the relevant assays measured. In preadipocytes, AG, GHRP-6 and DAG stimulated proliferation, measured as (3)H-thymidine incorporation (up to 200%, P < 0.05), while all peptides stimulated differentiation (up to 300%, P < 0.01) as compared to standard differentiation conditions. In adipocytes, FA uptake was increased in a concentration-dependent manner especially with obestatin (three- to fourfold, P < 0.001) and DAG (three- to fivefold, P < 0.001). By contrast, glucose transport was unchanged. DAG and obestatin significantly decreased lipolysis measured as non-esterified fatty acid and glycerol release by 50%, P < 0.05-0.01 and 51%, P < 0.01, respectively. Interestingly, DAG stimulation of FA uptake was blocked with GHSR1 antagonist (D-lys(3))-GHRP-6 (P < 0.05), phospholipase C inhibitor U73122 and phosphatidylinositol-3-kinase inhibitor wortmannin (P < 0.001). Finally, in omental but not subcutaneous human adipose tissue, GHSR1 correlated with BMI (r = 0.549, P < 0.05) and insulin (r = 0.681, P < 0.01). Taken together, these results suggest that ghrelin-related peptides may directly affect adipose tissue metabolism. PMID- 21268093 TI - Nephroblastoma overexpressed (Nov) induces gremlin in ST-2 stromal cell lines by post-transcriptional mechanisms. AB - Nephroblastoma overexpressed (Nov) inhibits osteoblastogenesis in part because it binds bone morphogenetic protein (BMP)-2. In the present study, we investigated whether Nov regulated the expression of the BMP antagonist gremlin. Overexpression of Nov increased gremlin mRNA levels in ST-2 cells, and its downregulation by RNA interference decreased gremlin mRNA. Nov did not affect Grem1 transcription, but prolonged the half-life of gremlin mRNA in ST-2 cells, demonstrating that Nov acts by post-transcriptional mechanisms. This was confirmed by demonstrating that downregulation of Nov destabilizes gremlin transcripts. To assess whether the 3'-untranslated region (UTR) of gremlin mRNA mediated the effect of Nov, the decay of a chimeric cfos gremlin 3'-UTR construct was compared to that of cfos in ST-2 cells. The presence of the gremlin 3'-UTR prolonged the half-life of cfos and was responsible for the effect of Nov. To examine the binding of the gremlin 3'-UTR to ribonucleoproteins, radiolabeled gremlin RNA fragments were incubated with cytosolic extracts from Nov overexpressing and control cells. RNA electrophoretic mobility analysis revealed that Nov enhanced the binding of cytosolic proteins to the fragments spanning the 3'-UTR of gremlin between bases 1,358-1,557 and 1,158-1,357 from the transcriptional start. Mutations of AU-rich elements in these two RNA fragments prevented the formation of RNA-protein complexes induced by Nov. Nov did not alter the binding of cytosolic extracts to sequences present in the 5'-UTR or coding region of gremlin. In conclusion, Nov stabilizes gremlin transcripts, and this effect is possibly mediated by AU-rich elements present in the 3'-UTR of gremlin. PMID- 21268094 TI - Positive regulation of inositol 1,4,5-trisphosphate-induced Ca2+ release by mammalian target of rapamycin (mTOR) in RINm5F cells. AB - The inositol 1,4,5-trisphosphate receptor (IP(3)R), a ligand-gated Ca(2+) channel, is the main regulator of intracellular Ca(2+) mobilization in non excitable cells. An emerging body of evidence suggests that specific regulatory control of the Ca(2+) signaling pathway is modulated by the activation of additional signaling pathways. In the present study, we investigated the influence of the PI3-kinase/mammalian target of rapamycin (mTOR) pathway on the activity of the IP(3)R/Ca(2+) signaling pathway in RINm5F cells. We used a co immunoprecipitation approach to show that mTOR physically interacts with IP(3)R-3 in an mTOR activity-dependent manner. We also showed that IP(3)R is phosphorylated by mTOR in cellulo. All the conditions known to modulate mTOR activity (IGF-1, wortmannin, rapamycin, PP242, and nutrient starvation) were shown to modify carbachol-induced Ca(2+) signaling in RINm5F cells. Lastly, we used an assay that directly measures the activity of IP(3)R, to show that mTOR increases the apparent affinity of IP(3)R. Given that mTOR controls cell proliferation and cell homeostasis, and that Ca(2+) plays a key role in these two phenomena, it follows that mTOR facilitates IP(3)R-mediated Ca(2+) release when the nutritional status of cells requires it. PMID- 21268095 TI - Donor survey to assess facial flushing during automated red cell collections and medication use. AB - BACKGROUND: We conducted a donor survey to assess the occurrence of facial flushing and other symptoms during automated 2-U red cell collections (2RBC) and plateletpheresis (PLT) procedures and evaluated the possible association of the reactions with angiotensin-converting enzyme (ACE) inhibitors or with the collection technology. METHODS: An online survey was developed using Zoomerang to capture details of the donors' experience and medication use after 2RBC or PLT donations in regional blood centers of the American Red Cross. RESULTS: Between 12/16/09 and 4/19/10, 1,299 donors in five American Red Cross blood center regions completed an online survey (739 2RBC, 4.2% total registrations; 560 PLT, 2.3% total registrations). Facial flushing was reported by 29 donors, and was more likely associated with 2RBC than PLT procedures (3.0% vs. 1.3%, P = 0.03). Facial flushing with 2RBC donation was reported by eight of 72 (11%) donors on ACE inhibitors; and 14 of 667 (2%) donors who were not taking ACE inhibitors (P = 0.001). The incidence of facial flushing reactions with PLT donation was less than 2% whether donors reported ACEI inhibitor use or not. More than 95% of the donors reported their intent to donate again, regardless of symptoms. CONCLUSION: Facial flushing was more often reported by 2RBC donors taking ACE inhibitors than other donors [11% vs. 2%; P = 0.001]; and was uncommon among PLT donors, irrespective of ACE inhibitor use (<2%). All blood donors should be informed of the potential for common, minor side effects of the collection procedure and the possible but rare occurrence of more medically serious complications. PMID- 21268096 TI - Manual color monitoring to optimize hematopoietic progenitor cell collection on the Fenwal Amicus. AB - A technique was developed to improve consistency of MNC transfers from the centrifuge to the collection bag in the Fenwal Amicus. The operator assures that RBCs completely fill the cassette by the end of the transfer by adjusting the RBC offset in succeeding cycles. We compared yields and crosscellular content before and after implementation of the monitoring technique. Retrospective data from 400 consecutive HPC collection procedures (200 for each technique) were compared. In 40 monitored collections, the RBC offset was adjusted to 6-9 mL to ensure that RBCs completely filled the cassette. Collections requiring these adjustments were not associated with a specific diagnosis. Median values were compared between the 40 collections requiring offset adjustment and those performed before implementation of monitoring. Baseline peripheral CD34+ cell (17 vs. 14 cells MUL(-1)), lymphocytes (2 vs. 1.3 * 10(9) /L), WBCs, HCT, and PLTs were significantly higher in the group requiring offset changes. The group requiring offset changes had significantly more CD34+ cells per collection (190.8 * 10(6) or 2.04 * 10(6) /kg vs. 84.3 * 10(6) or 0.89 * 10(6) /kg) and more lymphocytes per collection (16.9 * 10(9) vs. 11.6 * 10(9)). Crosscellular content of the group requiring offset changes was significantly higher for WBCs (41.8 vs. 33.1 * 10(9)), granulocytes (9.6 vs. 7.2 * 10(9)), RBCs (23 vs. 17 mL), and PLTs (2.1 vs. 1.2 * 10(11)). Manual monitoring is a simple, inexpensive method to optimize each HPC collection to maximize CD34+ cell and lymphocyte yields. PMID- 21268097 TI - Successful preoperative treatment of a Graves' disease patient with agranulocytosis and hemophagocytosis using double filtration plasmapheresis. AB - Agranulocytosis is an uncommon but serious complication of Graves' disease under thionamide therapy. In some patients removal of circulating thyroid hormones and thyroid antibodies by plasmapheresis is an effective adjunctive therapeutic option. In perioperative settings, however, plasmapheresis may cause excess bleeding intraoperatively due to coagulation factor depletion unless fresh frozen plasma (FFP) products are used in the replacement fluid mix. Double filtration plasmapheresis (DFPP) in which only a small amount of albumin supplementation is used may be a potential alternative to conventional apheresis interventions where clotting factor depletion is problematic. We report a case of a patient with Graves' disease complicated with intravenous immunoglobulin responsive methimazole-induced agranulocytosis/hemophagocytosis who underwent successful preoperative DFPP treatment in preparation for thyriodectomy. In addition to conventional apheresis using FFP replacement, DFPP may offer an effective adjunct option in the management of hyperthyroid patients needing emergent surgical interventions. PMID- 21268098 TI - Rectal distension: the effect on bladder function. AB - AIMS: To assess how rectal distension affects urodynamics parameters and diagnosis. METHODS: Thirty women underwent filling cystometry with a rectal balloon inserted and filled with 150 ml of normal saline and repeated without the balloon distended. The volume at which first desire, strong desire and bladder capacity were reported by the women was recorded as well as urodynamics diagnosis. Women were randomized, using the closed envelope method, into having the rectal balloon distended during the first or during the second filling phase. Women with any bowel disease, history of bleeding per rectum were excluded, or women with any contraindication to undergoing urodynamics, or insertion of a device per rectum. All women of a reproductive age underwent pregnancy test and excluded if found to be pregnant. RESULTS: Thirty patients were recruited, 16 reported mixed urinary incontinence (53%), 5 (17%) had isolated overactive bladder (OAB) symptoms and 9 (30%) reported isolated stress urinary incontinence. Patients with distended rectum had statistically significant lower bladder volumes at which first (46% reduction) and strong desire (33% reduction) was felt and reduced maximum bladder capacity (26% reduction) when compared to the rectum being undistended. In four patients (13%) with a history of OAB a diagnosis of detrusor overactivity was found with the rectum was distended but not when the rectum was empty. CONCLUSION: Rectal distension alters bladder sensation and in some cases urodynamics diagnosis. PMID- 21268099 TI - A comprehensive anatomical view on pelvic floor disturbances. PMID- 21268100 TI - How well informed are women who undergo urodynamic testing? AB - AIMS: Urodynamic studies (UDS) are complex, invasive and may be emotionally and physically distressing. Inadequate information may heighten distress. Prior to UDS, our patients receive written and verbal information, yet concerns remains that some women may not be adequately informed. This study examined how informed women believe they are to undergo UDS in our clinic. METHODS: This was a before after questionnaire-based study. Data were collected from a convenience sample of 200 women prior to UD testing, and within 3 days of completion. Participants rated their level of agreement/disagreement with the following statements: I understand why I am having the test; I have been given enough information about the test; I understand what the test will involve. Women also reported their perceived levels of distress (anxiety, embarrassment, and discomfort). RESULTS: One hundred fifty-one women returned both pre- and post-UD questionnaires. Most (88.9%) had read the information sheet and agreed that they understood the indications for the testing (78.1%). Fewer agreed that they understood what the tests would involve (68.2%), or that they had been given enough information about the test (64.9%). The overall distress score (anxiety, embarrassment, and discomfort) was 6 (IQR 5-7; possible range 3-9). CONCLUSIONS: Urodynamic testing remains an invasive yet prevalent form of urogynecological assessment. One-third of our patients may not understand what UD testing involves and may not feel adequately informed about the tests. Additional research to explore informational needs is important. PMID- 21268101 TI - Once-daily administration of trospium chloride extended release provides 24-hr coverage of nocturnal and diurnal symptoms of overactive bladder: an integrated analysis of two phase III trials. AB - AIMS: Once-daily extended release (XR) trospium chloride, which provides therapeutic trospium plasma concentrations over 24 hours, has demonstrated efficacy in treating overactive bladder (OAB) symptoms as evaluated over a 24-hr period. This analysis examined the effects of trospium XR on diurnal and nocturnal OAB symptoms. METHODS: Pooled data were analyzed from two identically designed Phase III trials in which patients with OAB were randomized to receive trospium XR 60 mg or placebo once daily in the morning for 12 weeks. Efficacy was assessed using 3-day urinary diaries. Diurnal events were those occurring from arising from bed in the morning until retiring in the evening; nocturnal events were those occurring from retiring until arising. RESULTS: In total, 1,165 patients received trospium XR (N = 578) or placebo (N = 587). At Week 12 comparison of trospium XR versus placebo, a significantly greater mean reduction from baseline in nocturnal voids (-0.8 vs. -0.6; P = 0.006) and diurnal voids ( 1.9 vs. -1.4; P < 0.0001) was noted. At Week 12, the mean percent reduction from baseline with trospium XR versus placebo in nocturnal urge urinary incontinence (UUI) episodes (-60.2% vs. -48.3%; P = 0.003) and mean absolute reduction in diurnal UUI episodes (-2.0 vs. -1.5; P < 0.0001) was significantly greater. Predictors of nocturnal response were duration (weeks) and type of therapy (trospium XR vs. placebo). Reductions in nocturnal toilet voids were accompanied by significant improvements in sleep-related quality of life (QoL) domains. CONCLUSIONS: Trospium XR significantly improved both nocturnal and diurnal OAB symptoms. Nocturnal improvements were associated with sleep-related QoL benefits. These results indicate that the XR formulation of trospium chloride provides effective 24-hr coverage of OAB symptoms. PMID- 21268102 TI - L-carnitine improves oxidative stress and suppressed energy metabolism but not renal dysfunction following release of acute unilateral ureteral obstruction in rat. AB - BACKGROUND AND AIM: We recently showed that L-carnitine reduced oxidative stress and suppressed energy metabolism, while alpha-tocopherol only prevented redox imbalance, in the obstructed kidney of rats subjected to 24-hr of unilateral ureteral obstruction (UUO). The present study was undertaken to investigate the effects of both compounds on disturbed renal hemodynamics, solutes-excretion, and urine-concentrating ability as well as renal oxidative stress and suppressed metabolism at early hours following release of 24-hr UUO. METHODS: UUO was induced in anaesthetized rats that received L-carnitine, alpha-tocopherol or their vehicles in four different groups. Each rat was re-anaesthetized, prepared for renal functional measurements, and its ureteral obstruction was released at 24-hr. Then, urines of both kidneys were separately collected during 30-90 min of post-release, with taking blood samples at beginning and end of it. Finally, both kidneys were removed and preserved at -80 degrees C for future measuring their levels of ATP and ADP as well as malondialdehyde (MDA) and ferric reducing/antioxidant power (FRAP). There were also sham and control groups. RESULTS: Post-obstructed kidney (POK) of vehicle-treated groups compared to equivalent kidney of sham group had lower ATP, ATP/ADP, FRAP, creatinine clearance, absolute Na(+)- and K(+)-excretion, and effective free-water reabsorption, but higher MDA and ADP. L-carnitine could improve oxidative stress and suppressed energy metabolism and alpha-tocopherol normalized redox state, but both compounds did not have any effects on altered functional variables of the POK. CONCLUSION: Oxidative stress and suppressed energy metabolism may not be involved in the development of renal dysfunction during acute ureteral obstruction. PMID- 21268103 TI - Coital incontinence: relation to detrusor overactivity and stress incontinence. AB - AIMS: The aim was to assess functional (demographic, clinical, and urodynamic) and anatomical (described by MRI) abnormalities associated with coital incontinence (CI). METHODS: All consecutive sexually active women with urinary incontinence (UI) were invited. Women were asked if they experience urine leakage during sex; and its timing: during penetration (CIAP) versus during orgasm (CIAO). All women were studied with urodynamics. Pelvic MRI was done for selected group of women. MRI examination was done using 1.5 T superconducting magnet, supine, and during two phases: static and dynamic, using multiplanar T2-weighted turbo spin-echo and single short T2-wighted images. RESULTS: Ninety women with UI; 60 had CI while 30 had no CI. Prevalence of CI was significantly higher among women with stress incontinence (SUI) (89.4%) compared to those with detrusor overactivity (DOA) (33.3%); P = 0.000. Factors significantly associated with CI were parity, prolapse, and SUI. Among studied MRI variables, no factor was significantly associated with CI. CI showed significant positive correlation with severity of SUI (r = 0.327, P = 0.05) and significant negative correlation with Abdominal leak point pressure (r = -0.362, P = 0.01). Amplitude of unstable detrusor contraction as measured by urodynamics did not correlate with severity of CI. CONCLUSIONS: CI seems to be in the spectrum of SUI and POP. CI is almost invariably a symptom of SUI with urethral sphincter incompetence, even when it occurs during orgasm. Many women with DOA leak during sex; however, the potential role of associated urethral incompetence should be considered. PMID- 21268104 TI - Bladder storage and emptying disorder frequencies may change according to the post-stroke interval. PMID- 21268105 TI - Perineoscrotal reconstruction using a medial circumflex femoral artery perforator flap. AB - Major scrotal defects may result from infection due to Fournier's gangrene, excision of scrotal skin diseases, traumatic avulsion of scrotal and penile skin, and genital burns. The wide spectrum of bacterial flora of the perineum, difficulty in providing immobilisation, and obtaining a natural contour of the testes make testicular cover very difficult. Various methods have been reported to cover the penoscrotal area, including skin grafting, transposing them to medial thigh skin, and use of local fasciocutaneous or musculocutaneous flaps. In this report, reconstruction using six local medial circumflex femoral artery perforator (MCFAP) flaps was undertaken in five male patients (mean age, 47 years) with complex penoscrotal or perineal wounds. The cause of the wounds in four patients was Fournier's gangrene, and was a wide papillomateous lesion in the other patient. Flap width was 6-10 cm and flap length was 10-18 cm. The results showed that a MCFAP flap provided the testes with a pliable local flap without being bulky and also protected the testicle without increasing the temperature. The other advantage of the MCFAP flap was that the donor-site scar could be concealed in the gluteal crease. Our results demonstrated that the MCFAP flap is an ideal local flap for covering penoscrotal defects. PMID- 21268106 TI - Helicoid end-to-side and oblique attachment technique in repair of the musculocutaneous nerve injury with the phrenic nerve as a donor: an experimental study in rats. AB - The purpose of this study was to identify if a modified end-to-side repair can achieve equal results of nerve regeneration compared to an end-to-end repair using donor phrenic nerves in repair of the musculocutaneous nerve and also pulmonary protection. Eighteen rats were divided into three groups of six each comparing two nerve graft techniques: helicoid end-to-side plus distal oblique repair vs. traditional end-to-end repair, using a donor phrenic nerve. The saphenous nerve was used as a graft between the phrenic nerve and the musculocutaneous nerve. The third group was used as control; the musculocutaneous nerve was transected without any repair. Three months postoperatively, electrophysiology, tetanic force, moist muscle weight, histology, nerve fiber counting, and chest X-ray were evaluated. All results have shown that this modified end-to-side repair was superior to the end-to-end repair. The former did not compromise the diaphragm function, but the latter showed an elevation of the diaphragm. Little recovery was seen in the third group. The conclusion is that this modified end-to-side repair can replace the traditional end-to-end repair using donor phrenic nerves with better results of nerve regeneration without diaphragm compromise. PMID- 21268107 TI - Reconstruction of the weight-bearing surface of the foot with integra-grafted latissimus dorsi muscle flap. PMID- 21268108 TI - Vascularized medial femoral condyle corticoperiosteal flaps for the treatment of recalcitrant humeral nonunions. AB - BACKGROUND: Several methods have been used in the management of humeral nonunions. With the advent of modern microsurgical techniques, vascularized bone grafting is becoming increasingly used to improve local biology. We report our experience in the use of a vascularized corticoperiosteal bone flap from the medial femoral supracondylar region in the treatment of recalcitrant humeral nonunions. METHODS: A retrospective review was performed of all patients treated with this technique over a 4-year period within our institution. Patient demographics, nonunion characteristics, complications, and long-term outcomes were analyzed. RESULTS: Six patients underwent vascularized periosteal graft reconstruction. Prior to this, all had failed an average of three procedures with the length of nonunion ranging from 6 to 68 months. All six nonunions healed by an average of 6.8 months (range 2-12 months). Two patients required additional secondary procedures. Functional outcome improved in all patients as adjudged by disabilities of the arm, shoulder, and hand, Mayo elbow performance, and Constant Murley scores. CONCLUSIONS: The vascularized medial femoral condyle corticoperiosteal flap provides an additional treatment option for the management of humeral nonunions. PMID- 21268109 TI - Facial reanimation with gracilis muscle transplantation and obturator nerve coaptation to the motor nerve of masseter muscle as a salvage procedure in an unreliable cross-face nerve graft. PMID- 21268110 TI - Repair of bone defect with vascularized tissue engineered bone graft seeded with mesenchymal stem cells in rabbits. AB - This study evaluated the results of repair of the radius defect with a vascularized tissue engineered bone graft composed by implanting mesenchymal stem cells (MSCs) and a vascular bundle into the xenogeneic deproteinized cancellous bone (XDCB) scaffold in a rabbit model. Sixty-four rabbits were used in the study. Among them, four rabbits were used as the MSCs donor. Other 57 rabbits were divided into five groups. In group one (n = 9), a 1.5 cm bone defect was created with no repair. In group two (n = 12), the bone defect was repaired by a XDCB graft alone. In group three (n = 12), the defect was repaired by a XDCB graft that included a vascular bundle. In group four (n = 12), the defect was repaired by a XDCB graft seeded with MSCs. In group five (n = 12), the defect was repaired by a XDCB graft including a vascular bundle and MSCs implantation. The rest three rabbits were used as the normal control for the biomechanical test. The results of X-ray and histology at postoperative intervals (4, 8, and 12 weeks) and biomechanical examinations at 12 weeks showed that combining MSCs and a vascular bundle implantation resulted in promoting vascularization and osteogenesis in the XDCB graft, and improving new bone formation and mechanical property in repair of radius defect with this tissue engineered bone graft. These findings suggested that the vascularized tissue engineered bone graft may be a valuable alternative for repair of large bone defect and deserves further investigations. PMID- 21268111 TI - Hyaluronic acid biodegradable material for reconstruction of vascular wall: a preliminary study in rats. AB - The objective of this preliminary study was to develop a reabsorbable vascular patch that did not require in vitro cell or biochemical preconditioning for vascular wall repair. Patches were composed only of hyaluronic acid (HA). Twenty male Wistar rats weighing 250-350 g were used. The abdominal aorta was exposed and isolated. A rectangular breach (1 mm * 5 mm) was made on vessel wall and arterial defect was repaired with HA made patch. Performance was assessed at 1, 2, 4, 8, and 16 weeks after surgery by histology and immunohistochemistry. Extracellular matrix components were evaluated by molecular biological methods. After 16 weeks, the biomaterial was almost completely degraded and replaced by a neoartery wall composed of endothelial cells, smooth muscle cells, collagen, and elastin fibers organized in layers. In conclusion, HA patches provide a provisional three-dimensional support to interact with cells for the control of their function, guiding the spatially and temporally multicellular processes of artery regeneration. PMID- 21268112 TI - Learning generative models for protein fold families. AB - We introduce a new approach to learning statistical models from multiple sequence alignments (MSA) of proteins. Our method, called GREMLIN (Generative REgularized ModeLs of proteINs), learns an undirected probabilistic graphical model of the amino acid composition within the MSA. The resulting model encodes both the position-specific conservation statistics and the correlated mutation statistics between sequential and long-range pairs of residues. Existing techniques for learning graphical models from MSA either make strong, and often inappropriate assumptions about the conditional independencies within the MSA (e.g., Hidden Markov Models), or else use suboptimal algorithms to learn the parameters of the model. In contrast, GREMLIN makes no a priori assumptions about the conditional independencies within the MSA. We formulate and solve a convex optimization problem, thus guaranteeing that we find a globally optimal model at convergence. The resulting model is also generative, allowing for the design of new protein sequences that have the same statistical properties as those in the MSA. We perform a detailed analysis of covariation statistics on the extensively studied WW and PDZ domains and show that our method out-performs an existing algorithm for learning undirected probabilistic graphical models from MSA. We then apply our approach to 71 additional families from the PFAM database and demonstrate that the resulting models significantly out-perform Hidden Markov Models in terms of predictive accuracy. PMID- 21268113 TI - Crystal structure and substrate-binding mode of cellulase 12A from Thermotoga maritima. AB - Cellulases have been used in many applications to treat various carbohydrate containing materials. Thermotoga maritima cellulase 12A (TmCel12A) belongs to the GH12 family of glycoside hydrolases. It is a beta-1,4-endoglucanase that degrades cellulose molecules into smaller fragments, facilitating further utilization of the carbohydrate. Because of its hyperthermophilic nature, the enzyme is especially suitable for industrial applications. Here the crystal structure of TmCel12A was determined by using an active-site mutant E134C and its mercury containing derivatives. It adopts a beta-jellyroll protein fold typical of the GH12-family enzymes, with two curved beta-sheets A and B and a central active site cleft. Structural comparison with other GH12 enzymes shows significant differences, as found in two longer and highly twisted beta-strands B8 and B9 and several loops. A unique Loop A3-B3 that contains Arg60 and Tyr61 stabilizes the substrate by hydrogen bonding and stacking, as observed in the complex crystals with cellotetraose and cellobiose. The high-resolution structures allow clear elucidation of the network of interactions between the enzyme and its substrate. The sugar residues bound to the enzyme appear to be more ordered in the -2 and -1 subsites than in the +1, +2 and -3 subsites. In the E134C crystals the bound -1 sugar at the cleavage site consistently show the alpha-anomeric configuration, implicating an intermediate-like structure. PMID- 21268114 TI - Prediction of RNA-binding residues in proteins from primary sequence using an enriched random forest model with a novel hybrid feature. AB - The identification of RNA-binding residues in proteins is important in several areas such as protein function, posttranscriptional regulation and drug design. We have developed PRBR (Prediction of RNA Binding Residues), a novel method for identifying RNA-binding residues from amino acid sequences. Our method combines a hybrid feature with the enriched random forest (ERF) algorithm. The hybrid feature is composed of predicted secondary structure information and three novel features: evolutionary information combined with conservation information of the physicochemical properties of amino acids and the information about dependency of amino acids with regards to polarity-charge and hydrophobicity in the protein sequences. Our results demonstrate that the PRBR model achieves 0.5637 Matthew's correlation coefficient (MCC) and 88.63% overall accuracy (ACC) with 53.70% sensitivity (SE) and 96.97% specificity (SP). By comparing the performance of each feature we found that all three novel features contribute to the improved predictions. Area under the curve (AUC) statistics from receiver operating characteristic curve analysis was compared between PRBR model and other models. The results show that PRBR achieves the highest AUC value (0.8675) which represents that PRBR attains excellent performance on predicting the RNA-binding residues in proteins. The PRBR web-server implementation is freely available at http://www.cbi.seu.edu.cn/PRBR/. PMID- 21268115 TI - Topology-based modeling of intrinsically disordered proteins: balancing intrinsic folding and intermolecular interactions. AB - Coupled binding and folding is frequently involved in specific recognition of so called intrinsically disordered proteins (IDPs), a newly recognized class of proteins that rely on a lack of stable tertiary fold for function. Here, we exploit topology-based Go-like modeling as an effective tool for the mechanism of IDP recognition within the theoretical framework of minimally frustrated energy landscape. Importantly, substantial differences exist between IDPs and globular proteins in both amino acid sequence and binding interface characteristics. We demonstrate that established Go-like models designed for folded proteins tend to over-estimate the level of residual structures in unbound IDPs, whereas under estimating the strength of intermolecular interactions. Such systematic biases have important consequences in the predicted mechanism of interaction. A strategy is proposed to recalibrate topology-derived models to balance intrinsic folding propensities and intermolecular interactions, based on experimental knowledge of the overall residual structure level and binding affinity. Applied to pKID/KIX, the calibrated Go-like model predicts a dominant multistep sequential pathway for binding-induced folding of pKID that is initiated by KIX binding via the C terminus in disordered conformations, followed by binding and folding of the rest of C-terminal helix and finally the N-terminal helix. This novel mechanism is consistent with key observations derived from a recent NMR titration and relaxation dispersion study and provides a molecular-level interpretation of kinetic rates derived from dispersion curve analysis. These case studies provide important insight into the applicability and potential pitfalls of topology-based modeling for studying IDP folding and interaction in general. PMID- 21268116 TI - Crystal structure of the pyrimidine 5'-nucleotidase SDT1 from Saccharomyces cerevisiae complexed with uridine 5'-monophosphate provides further insight into ligand binding. PMID- 21268117 TI - Effects of media exposure on adolescents traumatized in a school shooting. AB - This study analyzes the impact of the media on adolescents traumatized in a school shooting. Participants were trauma-exposed students (n = 231) and comparison students (n = 526), aged 13-19 years. A questionnaire that included the Impact of Event Scale and a 36-item General Health Questionnaire was administered 4 months after the shooting. Being interviewed was associated with higher scores on the Impact of Event Scale (p = .005), but posttraumatic symptoms did not differ between those who refused to be interviewed and those not approached by reporters. Following a higher number of media outlets did not affect symptoms. PMID- 21268118 TI - Cognitive processing, rumination, and posttraumatic growth. AB - Intrusive thoughts about traumatic events are an important factor in determining the development of posttraumatic growth, although research has focused on the frequency rather than the type of intrusions. Based on cognitive processing models of posttraumatic growth, the authors present two cross-sectional studies exploring different types of intrusive ruminations about trauma and their associations with posttraumatic growth. Study 1 examines brooding and reflection; Study 2 uses measures of both deliberate and intrusive rumination regarding a past trauma. The results indicate that intrusive reexperiencing and ruminative brooding are not significantly associated with posttraumatic growth, whereas deliberate rumination is significantly positively associated with posttraumatic growth (beta = .44, p < .001) and reflection (partial r = .20, p = .003) is positively associated with posttraumatic growth in the context of low brooding. PMID- 21268119 TI - The familial influence of loss and trauma on refugee mental health: a multilevel path analysis. AB - Although the impact of human rights violations on the mental health of refugees has been well documented, little is known about these effects at a family level. In this study the authors examined the relationships among loss, trauma, and mental health at the individual and family levels in resettled Mandaean refugees (N = 315). Trauma, loss, posttraumatic stress disorder, depression, complicated grief, and mental health-related quality of life were assessed. A multilevel path analysis revealed that loss and trauma significantly impacted on psychological outcomes at both the individual and family levels. Effect sizes ranged from .21 to .68 at the individual level, and .38 to .99 at the family level, highlighting the importance of the family when considering the psychological impact of refugee related trauma. PMID- 21268120 TI - Patterns of motor branching of the musculocutaneous nerve in human fetuses and clinical significance. AB - The purpose of this morphologic study is to investigate the course and the branching pattern of motor branches of musculocutaneous nerve (MCN) in human fetuses. Twenty upper limbs (10 right, 10 left) of spontaneously aborted formalin fixed fetuses were dissected under a stereomicroscope to determine motor branches for the biceps brachii and brachialis and the communicating branches between the MCN and median nerve (MN). The MCN entered the proximal and middle part of coracobrachialis in 13/20 and 5/20 of arms, respectively, and the remaining 2/20 did not pierce coracobrachialis. The communication between MCN and MN was observed in 5/20 of the arms and detected only in the distal part of the coracobrachialis. The most frequently observed innervation is the type wherein a single branch to biceps brachii, which bifurcated for supplying the short and long heads (12/20). For the innervation of brachialis, the most frequent type was a single branch from the main trunk of the MCN (15/20). During the dissections, the distance between the acromion and the emerging point of the motor branches was measured. The mean distance between the acromion and the emerging point of the all motor branches for biceps brachii in all types of specimens was 33.8 +/- 6.1% of acromion-lateral epicondyle length and for brachialis was 50.6 +/- 11.5% of acromion-lateral epicondyle length. The data of the MCN variations in the human fetus may be useful for the clinicians and pediatric surgery. PMID- 21268121 TI - Intussusception: an anatomical perspective with review of the literature. AB - Originally described over 300 years ago, the clinical scenario of intussusception remains incompletely understood. Intussusception is now one of the conditions that can be, most of the time, preoperatively diagnosed and treated with success. This article reviews the literature regarding this pathological state of the abdomen and discusses what is known regarding the presentation, diagnosis, embryology, and anatomy of intussusception. PMID- 21268122 TI - Chest impact experiments aimed at producing aortic rupture. AB - There are a number of proposed mechanisms of traumatic aortic rupture. These experiments involved three different chest impacts that may be associated with aortic rupture. Eleven unembalmed cadavers were repressurized and impacted by a 24-34 kg mass at 8.6-14.9 m/sec. Three impact orientations were studied with the torso axis: (1) 30-45 degrees up from horizontal and impact 28-45 degrees clockwise of the midsagittal axis, (2) 105-130 degrees up from horizontal and impact 15 degrees counterclockwise, and (3) 75 degrees up from horizontal and impact 15 degrees counterclockwise. Spinal acceleration was measured at T1, T8, and T12 and chest compression was determined by high-speed video. Detailed autopsy determined injuries. Impact loads averaged 9.65 +/- 2.45 kN and resulted in 52.8 +/- 5.4% chest compression and 3.53 +/- 0.94 m/sec Viscous response. The resultant spinal acceleration was 124.5 +/- 105.4 g at T1, 141.3 +/- 80.5 g at T8 and 89.3 +/- 39.1 g at T12. The severity of impact resulted in multiple rib fractures and severe chest injury averaging AIS = 4.2 +/- 1.0. There were four cases of heart laceration and one transection of the ascending aorta 20 mm from the cusp of the aortic valve. The impacts were severe enough that aortic rupture was expected; however, only one occurred. In retrospect, the position of the heart and aorta in the upright cadaver may not have been representative of the position during human injury, thus reducing the incidence of aortic rupture in these experiments. PMID- 21268123 TI - Polymorphisms in prostate stem cell antigen gene rs2294008 increase gastric cancer risk in Chinese. AB - A recent genome-wide study identified a strong association between polymorphisms in the prostate stem cell antigen (PSCA) gene and the risk of diffuse-type of gastric cancer in Japanese and Korean population. In this case-control study, we aimed to investigate the possible association between PSCA rs2294008 C/T with clinicopathological features and the prognosis of gastric cancer in a Southern Chinese population. Genotypes of 460 gastric cancer patients and 549 controls were determined by PCR-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing. We found that individuals with at least one copy of the rs2294008T allele (CT or TT genotype) had an increased risk for gastric cancer compared with CC genotype (OR = 1.42, 95% CI = 1.10-1.82, P = 0.006). Further stratification analyses indicated that the effect of PSCA rs2294008T carriers was noteworthy in intestinal type (OR = 1.55, 95% CI = 1.18-2.04, P = 0.002), poorly differentiated (OR = 1.59, 95% CI = 1.19-2.13, P = 0.002), noncardia (OR = 1.55, 95% CI = 1.17-2.04, P = 0.002) subtypes of gastric cancer. Cox proportional hazards analyses demonstrated that TT genotype (HR = 2.12, 95% CI = 1.22-3.69, P = 0.008) as well as TNM staging were prognostic factors of gastric cancer patients. In conclusion, The T allele of PSCA rs2294008 is associated with increased risk of gastric cancer, especially intestinal type, poorly differentiated, early onset, and noncardia gastric cancer in Chinese population. TNM staging and TT genotype might be involved in the prognosis of gastric cancer patients. PMID- 21268124 TI - MDM2 SNP309 contributes to non-small cell lung cancer survival in Chinese. AB - Murine double minute 2 (MDM2) is a negative regulator of the tumor suppressor gene p53. Single nucleotide polymorphisms in MDM2 and p53 can affect patient's response to chemotherapy as well as overall survival of many cancers. This study aimed to assess the associations between polymorphisms in MDM2 and p53 and survival of non-small cell lung cancer (NSCLC) patients in Chinese. We selected and genotyped both potentially functional SNPs and tagging SNPs in MDM2 and p53 using Illumina Golden Gate platform in a cohort of 568 NSCLC patients. Associations between genotypes and NSCLC median survival time (MST) were assessed using the Kaplan-Meier method. Cox proportional hazard models were performed with the adjustment for age, stage, smoking, histology, surgical operation, and chemo- or radiotherapy status. We found that the MDM2 SNP309 (rs2279744) GT/TT genotypes were associated with a significantly worse survival (MST: 23.0 mo for GT/TT vs. 33.0 mo for GG; log-rank P = 0.028). In the multivariate Cox regression analyses, the MDM2 SNP309GT/TT genotypes were associated with a 1.42-fold [HR = 1.42, 95% confidence interval (CI), 1.09-1.84] increased risk of death of NSCLC, compared with SNP309GG genotype. MDM2 SNP309 may be used as one of the candidate biomarkers to predict NSCLC survival. PMID- 21268125 TI - The prostaglandin E2 receptor, EP2, regulates survivin expression via an EGFR/STAT3 pathway in UVB-exposed mouse skin. AB - We previously reported that cycloogenase (COX)-2-generated prostaglandin E2 (PGE2) had anti-apoptotic effects in UVB-exposed mouse skin that involved EP2 mediated signaling (Chun et al., Cancer Res. 2007; 67: 2015). Because survivin is a regulator of cell survival, the possible involvement of COX-2 and EP2 in survivin expression following UVB exposure of mouse skin was investigated. In wild type mice, UVB exposure time-dependently increased the levels of survivin and phosphorylated-signal transducer and activator of transcription 3 (p-STAT3), a transcription factor that regulates survivin expression; and COX-2- or EP2 deficiency significantly reduced their induction. Topical application of the COX 2 inhibitor, celecoxib, also reduced UVB-induced survivin levels. To further investigate the roles of PGE2 and EP2 in the regulation of survivin, indomethacin was used to inhibit UVB-induced endogenous PG production. UVB-induced survivin levels were reduced by indomethacin, and PGE2 and the EP2 agonist, butaprost, partially restored survivin levels. The epidermal growth factor receptor (EGFR) is a downstream effector of EP2 and EGFR inhibition (AG1478) significantly reduced UVB activation of STAT3 and survivin levels. UVB-induced epidermal apoptosis in COX-2-/- mice was reduced by butaprost and EGFR inhibition blocked butaprost's protective effects. Furthermore, butaprost in the absence of UVB exposure time-dependently increased p-EGFR, p-STAT3, and survivin levels in naive mouse skin, whereas the EP4 agonist, PGE1 alcohol, did not significantly increase p-STAT3 or survivin levels. These data suggest that COX-2-generated PGE2 regulates survivin expression in mouse skin, in part, via an EP2-mediated EGFR/STAT3 pathway. Therefore, targeting the EP2/survivin pathway may provide a strategy for the chemoprevention/chemotherapy of skin cancer. PMID- 21268126 TI - Wnt antagonist DICKKOPF-3 (Dkk-3) induces apoptosis in human renal cell carcinoma. AB - The Wnt signaling pathway is activated in most cancers while Wnt antagonist genes are inactivated. However, the functional significance and mechanisms of inactivation of Wnt antagonist Dkk-3 gene in renal cell carcinoma (RCC) has not been reported. In this study, we examined potential epigenetic mechanisms regulating Dkk-3 expression in RCC cells and whether Dkk-3 expression affects cell growth and apoptosis. The expression of Dkk-3 is regulated by histone modification rather than CpG island DNA methylation in renal cancer cells. Renal cancer cell proliferation was significantly inhibited and apoptosis was promoted in Dkk-3 transfected renal cancer cells. Dkk-3 did not inhibit the Wnt/beta catenin signaling pathway but induced apoptosis via the noncanonical JNK pathway in renal cancer cells. Expression of p21, MDM-2, and Puma genes were increased after transfecting RCC cell lines with a Dkk-3 expression plasmid. Overexpression of Dkk-3 induced G(0)/G(1) arrest together with an increase in p21 expression. Growth of stable Dkk-3 transfected cells in nude mice was decreased compared to controls. Our data show for the first time that mRNA expression of Dkk-3 is regulated by histone modification and that Dkk-3 inhibits renal cancer growth through modulation of cell cycle and apoptotic pathways. PMID- 21268127 TI - Upregulation of the EP1 receptor for prostaglandin E2 promotes skin tumor progression. AB - Prostaglandin E(2) (PGE(2) ) has been shown to promote the development of murine skin tumors. EP1 is 1 of the 4 PGE(2) G-protein-coupled membrane receptors expressed by murine keratinocytes. EP1 mRNA levels were increased ~2-fold after topical treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) or exposure to ultraviolet (UV) light, as well as increased ~3- to 12-fold in tumors induced by 7,12-dimethyl-benz[a]anthracene (DMBA) initiation/TPA promotion or by UV exposure. To determine the effect of EP1 levels on tumor development, we generated BK5.EP1 transgenic mice that overexpress EP1 in the basal layer of the epidermis. Skins of these mice were histologically indistinguishable from wild type (WT) mice and had similar levels of proliferation after TPA treatment. Using a DMBA/TPA carcinogenesis protocol, BK5.EP1 mice had a reduced tumor multiplicity compared to WT mice, likely due to the observed down-regulation of protein kinase C (PKC). However, the BK5.EP1 mice had an ~8-fold higher papilloma to carcinoma conversion rate. When DMBA/anthralin was used, BK5.EP1 mice produced more tumors than WT mice, as well as a ninefold increase in carcinomas, indicating that the tumor response is dependent on the type of tumor promoter agent used. Additionally, although almost undetectable in WT mice, cyclooxygenase-2 (COX-2) was expressed in the untreated epidermis of BK5.EP1 mice. While TPA highly induced COX-2 in WT mice, COX-2 expression in the BK5.EP1 mice did not change after TPA treatment; PGE(2) levels were likewise affected. These data indicate that EP1 is more important in tumor progression than in tumor promotion and that it indirectly regulates COX-2 expression. PMID- 21268128 TI - Loss of imprinting and abnormal expression of the insulin-like growth factor 2 gene in gastric cancer. AB - This study examined the frequency of loss of imprinting (LOI) and expression of the insulin-like growth factor 2 (IGF2) gene, and their relationship to selected clinical and pathological factors, in a well defined series of 90 Chinese patients with gastric cancer (GC) and 90 matched patients (controls) diagnosed with nonmalignant conditions. Using peripheral blood and gastric tissue samples, polymerase chain reaction-based assays and restriction endonuclease (Apa I) digestion revealed 33 GC patients and 21 controls to be Apa I informative. LOI of IGF2 was positive in 48.5% (16/33) of primary GC tumor tissues, in 21.2% (7/33) of histologically normal adjacent gastric mucosa (AM) and in 12.1% (4/33) of distant gastric mucosa (DM), and in 15.2% (5/33) of peripheral blood lymphocytes (PBLs). The prevalence of IGF2 LOI in PBL was not statistically different between GC patients (5/33, 15.2%) and control subjects (2/21, 9.5%), P = 0.69. Although patients who were found to have LOI of IGF2 were more likely to have advanced stage gastric tumors (P = 0.04), no statistically significant differences in survival were found based on imprinting status. IGF2 LOI was associated with an increased expression of IGF2 level in both tumors (P < 0.01) and blood (P < 0.01). The results of this study implicate IGF2 LOI in the molecular pathogenesis of GC, most likely through increased IGF2 expression. Although the precise molecular mechanisms by which LOI of IGF2 increases GC risk require further study, LOI of IGF2 may be a potentially important clinical epigenetic marker to identify individuals at increased risk for gastric malignancy. PMID- 21268129 TI - Association of cyclin D1 gene polymorphisms with risk of esophageal squamous cell carcinoma in Kashmir Valley: a high risk area. AB - Investigation of potential association of SNPs (G870A, rs9344; G1722C, rs678653) of cyclin D1 gene (CCND1) with susceptibility to esophageal squamous cell carcinoma (ESCC) in Kashmir valley (India). The study included 302 subjects comprising 151 ESCC cases and 151 controls. PCR-RFLP and direct sequencing were employed for genotyping. The G870A polymorphism, the individuals carrying GA + AA genotype was having 2.80-fold increased risk for development of ESCC (OR 2.8, 95% CI = 1.77-4.4; P = 0.0001) compared to GG genotype. Further a significantly higher risk was observed in individuals who consume >3 cups per day of salted tea (OR = 5.1; 95% CI = 1.6-16.7; P = 0.0016) and had smoking habits (OR = 6.3; 95% CI = 2.9-13.9; P = 0.0005). We also demonstrate for the first time in CCND1 1722 locus, the CC genotype was strongly associated with increased risk of developing ESCC (OR = 2.58; 95% CI = 1.61-4.15; P = 0.0001). In addition, the frequency of polymorphic C allele was also found to be higher in cases (OR = 1.92; 95% CI = 1.37-2.69; P = 0.0002). There appears to be an influence of CCND1 G870A/G1772C genotypes on genetic susceptibility to ESCC. PMID- 21268130 TI - Activation and up-regulation of translation initiation factor 4B contribute to arsenic-induced transformation. AB - Arsenic is a known human carcinogen. However, the mechanism of how arsenic induces cell transformation remains unclear. In this study, we demonstrated that long-term exposure to sodium arsenite at low-dose (2 uM) increases cell proliferation and neoplastic transformation in a mouse epidermal cell model, JB6 promotion-susceptible cells. The phosphorylation of AKT and its downstream targets, 70-kDa ribosomal protein S6 kinase (p70S6K) and translation initiation factor 4B (eIF4B), are increased in the arsenite treated cells, indicating that long-term arsenite treatment activates AKT-p70S6K signaling pathway. In addition, long-term exposure to arsenite up-regulates eIF4B expression and increases the rate of translation. Knockdown of eIF4B expression resulted in inhibition of arsenic-induced cell proliferation, transformation, and translation. Moreover, the expression of c-Myc which is up-regulated by long-term arsenite treatment is inhibited by eIF4B knockdown. Taken together, these results indicate that activation and up-regulation of eIF4B contributes to arsenic-induced transformation in JB6 cells. PMID- 21268131 TI - p38 MAP kinase plays a functional role in UVB-induced mouse skin carcinogenesis. AB - UVB irradiation of epidermal keratinocytes results in the activation of the p38 mitogen-activated protein kinase (MAPK) pathway and subsequently activator protein-1 (AP-1) transcription factor activation and cyclooxygenase-2 (COX-2) expression. AP-1 and COX-2 have been shown to play functional roles in UVB induced mouse skin carcinogenesis. In this study, the experimental approach was to express a dominant negative p38alpha MAPK (p38DN) in the epidermis of SKH-1 hairless mice and assess UVB-induced AP-1 activation, COX-2 expression, and the skin carcinogenesis response in these mice compared to wild-type littermates. We observed a significant inhibition of UVB-induced AP-1 activation and COX-2 expression in p38DN transgenic mice, leading to a significant reduction of UVB induced tumor number and growth compared to wild-type littermates in a chronic UVB skin carcinogenesis model. A potential mechanism for this reduction in tumor number and growth rate is an inhibition of chronic epidermal proliferation, observed as reduced Ki-67 staining in p38DN mice compared to wild-type. Although we detected no difference in chronic apoptotic rates between transgenic and nontransgenic mice, analysis of acutely irradiated mice demonstrated that expression of the p38DN transgene significantly inhibited UVB-induced apoptosis of keratinocytes. These results counter the concerns that inhibition of p38 MAPK in a chronic situation could compromise the ability of the skin to eliminate potentially tumorigenic cells. Our data indicate that p38 MAPK is a good target for pharmacological intervention for UV-induced skin cancer in patients with sun damaged skin, and suggest that inhibition of p38 signaling reduces skin carcinogenesis by inhibiting COX-2 expression and proliferation of UVB-irradiated cells. PMID- 21268132 TI - Promoter hypermethylation of fibulin 1 gene is associated with tumor progression in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common cancers world-wide but the molecular mechanisms that underlie hepatocarcinogenesis are not fully determined. On the same surgical sample with HCC, we performed microarray-based gene expression profiling and karyotype analysis using a single nucleotide polymorphism (SNP) array. In addition, quantitative real-time reverse transcription polymerase chain reaction (PCR), methylation specific PCR (MSP) and immunohistochemical staining were conducted using specimens from 48 patients with HCC. Gene expression profiling showed the expression of fibulin 1 (FBLN1), located on 22q13, to be decreased in tumor tissue. Karyotype analysis revealed no loss of heterozygosity (LOH) since deletions were not detected in 22q, and one of the SNPs on 22q13 showed AB genotype in both cancerous tissue and in corresponding noncancerous tissue, indicating retention of heterozygosity. Quantitative real-time PCR showed FBLN1 mRNA levels in cancerous tissues to be significantly decreased compared with that in corresponding noncancerous tissues. The immunohistochemical staining results were consistent with both gene expression profiling and quantitative PCR data. Twenty-four out of 48 HCCs gave a positive result in MSP. Moreover, promoter hypermethylation of FBLN1 was significantly associated with advanced stage HCC, multiple tumors and increased tumor size. Our results indicated that FBLN1 is a novel candidate of tumor suppressor gene and that promoter hypermethylation of FBLN1 is associated with tumor progression in HCC. (c) 2011 Wiley-Liss, Inc. PMID- 21268133 TI - Diclofenac, a selective COX-2 inhibitor, inhibits DMH-induced colon tumorigenesis through suppression of MCP-1, MIP-1alpha and VEGF. AB - Angiogenesis is a physiological process involving growth of new blood vessels from pre-existing ones; however, it also plays a critical role in tumor progression. It favors the transition from hyperplasia to neoplasia, that is, from a state of cellular multiplication to uncontrolled proliferation. Therefore targeting angiogenesis will be profitable as a mechanism to inhibit tumor's lifeline. Further, it is important to understand the cross-communication between vascular endothelial growth factor (VEGF)-master switch in angiogenesis and other molecules in the neoplastic and pro-inflammatory milieu. We studied the role of two important chemokines [monocyte chemoattractant protein (MCP)-1 and macrophage inflammatory protein (MIP)-lalpha] alongwith VEGF and matrix metalloproteinases (MMPs) in non-steroidal anti-inflammatory drugs (NSAIDs)-induced chemopreventive effect in experimental colon cancer in rat. 1,2-Dimethylhydrazine (DMH, 30 mg/kg body weight, subcutaneously (s.c.) once-a-week) for 18 wk was used as pro carcinogen and diclofenac (8 mg/kg body weight, orally daily) as the preferential cyclooxygenase-2 (COX-2) inhibitor. Expression of COX-2 and VEGF was found to be significantly elevated in the DMH-treated group as compared to the control, which was lowered notably by Diclofenac co-administration with DMH. Gelatin zymography showed prominent MMP-9 activity in the DMH-treated rats, while the activity was nearly absent in all the other groups. Expression of MCP-1 was found to be markedly increased whereas MIP-1alpha expression was found to be decreased in colonic mucosa from DMH-treated rats, which was reversed in the DMH + Diclofenac group. Our results indicate potential role of chemokines alongwith VEGF in angiogenesis in DMH-induced cancer and its chemoprevention with diclofenac. PMID- 21268134 TI - CacyBP/SIP protein promotes proliferation and G1/S transition of human pancreatic cancer cells. AB - Calcyclin-binding protein or Siah-1-interacting protein (CacyBP/SIP), a component of the ubiquitin-mediated proteolysis, could participate in beta-catenin degradation, which was found to be related to the malignant phenotypes of pancreatic cancer previously. However, the role of CacyBP/SIP itself in pancreatic cancer has not been investigated. In the present study, CacyBP/SIP expression was assayed and manipulated to reveal the potential mechanism in pancreatic cancer carcinogenesis. Here, we show that CacyBP/SIP is over-expressed in pancreatic cancer cells. Down-regulation of CacyBP/SIP by small interference RNA (siRNA) severely suppresses the proliferation and tumorigenesis in pancreatic cancer. G1/S transition arrest induced by inhibition of CacyBP/SIP is at least partly mediated by down-regulation of Cyclin E and CDK2 as well as up-regulation of p27 and Rb. Collectively, CacyBP/SIP as an enhancer of pancreatic cancer malignance might develop into another possible therapeutic target. PMID- 21268135 TI - Inhibition of pituitary tumor-transforming gene-1 in thyroid cancer cells by drugs that decrease specificity proteins. AB - Methyl 2-cyano-3,11-dioxo-18beta-olean-1,12-dien-30-oate (CDODA-Me) and the corresponding 2-trifluoromethyl analog (CF(3)DODA-Me) are derived synthetically from the triterpenoid glycyrrhetinic acid, a major component of licorice. CDODA Me and CF(3)DODA-Me inhibited growth of highly invasive ARO, DRO, K-18, and HTh 74 thyroid cancer cells and this was due, in part, to decreased expression of specificity protein (Sp) transcription factors Sp1, Sp3, and Sp4 that are overexpressed in these cells. CDODA-Me and CF(3)DODA-Me also decreased expression of Sp-dependent genes, such as survivin and vascular endothelial growth factor (VEGF), and induced apoptosis. In addition, pituitary tumor-transforming gene-1 (PTTG-1) protein and mRNA levels were also decreased in thyroid cancer cells treated with CDODA-Me or CF(3)DODA-Me and this was accompanied by decreased expression of PTTG-1-dependent c-Myc and fibroblast growth factor-2 (FGF-2) genes. RNA interference studies against Sp1, Sp3, and Sp4 proteins showed that in thyroid cancer cells, PTTG-1 was an Sp-dependent gene. This study demonstrates for the first time that drugs, such as CDODA-Me and CF(3)DODA-Me, that decrease Sp protein expression also downregulate PTTG-1 in thyroid cancer cells and therefore have potential for clinical treatment of thyroid cancer and other endocrine neoplasias where PTTG-1 is a major pro-oncogenic factor. PMID- 21268136 TI - Grape seed extract upregulates p21 (Cip1) through redox-mediated activation of ERK1/2 and posttranscriptional regulation leading to cell cycle arrest in colon carcinoma HT29 cells. AB - Abnormalities in cell cycle progression provide unlimited replicative potential to cancer cells, and therefore targeting of key cell cycle regulators could be a sound cancer chemopreventive strategy. Earlier, we found that grape seed extract (GSE) increases Cip/p21 protein level and inhibits growth and induces apoptosis in human colon carcinoma HT29 cells both in vitro and in vivo. However, the mechanism of GSE-induced p21 upregulation and its role in biological efficacy of GSE are not known, which were investigated here. GSE treatment of HT29 cells resulted in a strong dose- and time-dependent phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2), consistent with p21 induction. The inhibition of sustained ERK1/2 activation by GSE using pharmacological inhibitors abrogated GSE-induced p21 upregulation. Furthermore, pretreatment of cells with N acetylcysteine inhibited GSE-induced ERK1/2 phosphorylation as well as p21 upregulation, suggesting the involvement of GSE-induced oxidative stress as an upstream event. Consistent with this, GSE also decreased intracellular level of reduced glutathione. Next, we determined whether GSE-induced signaling regulates p21 expression at transcriptional and/or translational levels. GSE was found to increase the stability of p21 message with resultant increase in p21 protein level, but it did not alter the protein stability to a great extent. Importantly, knock-down of p21 abrogated GSE-induced G(1) arrest suggesting that p21 induction by GSE is essential for its G(1) arrest effect. Together, our results for the first time identify a central role of p21 induction and associated mechanism in GSE-induced cell cycle arrest in HT29 cells. PMID- 21268138 TI - Structure, bioactivity and synthesis of natural products with hexahydropyrrolo[2,3-b]indole. AB - Research on natural products containing hexahydropyrrolo[2,3-b]indole (HPI) has dramatically increased during the past few years. Newly discovered natural products with complex structures and important biological activities have recently been isolated and synthesized. This review summarizes the structures, biological activities, and synthetic routes for natural compounds containing HPI, emphasizing the different strategies for assembling this motif. It covers a broad range of molecules, from small alkaloids to complex peptides. PMID- 21268139 TI - Highly selective visible and near-IR sensing of Cu2+ based on thiourea salicylaldehyde coordination in aqueous media. PMID- 21268140 TI - Labile diazo chemistry for efficient silencing of metallic carbon nanotubes. PMID- 21268141 TI - {[1.1.1]Cryptand/imidazole}: a prototype composite kinetic molecular device for automatic NMR variable pH reaction monitoring. PMID- 21268142 TI - Hierarchical structures of single-crystalline anatase TiO2 nanosheets dominated by {001} facets. PMID- 21268143 TI - Enantioselective synthesis of axially chiral 1-arylisoquinolines by rhodium catalyzed [2+2+2] cycloaddition. PMID- 21268144 TI - Gold(I)-catalyzed access to tetrahydropyran-4-ones from 4-(alkoxyalkyl)oxy-1 butynes: formal catalytic Petasis-Ferrier rearrangement. PMID- 21268145 TI - Gold-catalyzed tandem intramolecular heterocyclization/Petasis-Ferrier rearrangement of 2-(prop-2-ynyloxy)benzaldehydes as an expedient route to benzo[b]oxepin-3(2 H)-ones. PMID- 21268146 TI - Investigation of a series of silver-N-heterocyclic carbenes as antibacterial agents: activity, synergistic effects, and cytotoxicity. PMID- 21268147 TI - Liquid-phase epitaxy of multicomponent layer-based porous coordination polymer thin films of [M(L)(P)0.5] type: importance of deposition sequence on the oriented growth. AB - The progressive liquid-phase layer-by-layer (LbL) growth of anisotropic multicomponent layer-based porous coordination polymers (PCPs) of the general formula [M(L)(P)(0.5)] (M: Cu(2+), Zn(2+); L: dicarboxylate linker; P: dinitrogen pillar ligand) was investigated by using either pyridyl- or carboxyl-terminated self-assembled monolayers (SAMs) on gold substrates as templates. It was found that the deposition of smooth, highly crystalline, and oriented multilayer films of these PCPs depends on the conditions at the early growth cycles. In the case of a two-step process with an equimolar mixture of L and P, growth along the [001] direction is strongly preferred. However, employing a three-step scheme with full separation of all components allows deposition along the [100] direction on carboxyl-terminated SAMs. Interestingly, the growth of additional layers on top of previously grown oriented seeding layers proved to be insensitive to the particular growth scheme and full retention of the initial orientation, either along the [001] or [100] direction, was observed. This homo- and heteroepitaxial LbL growth allows full control over the orientation and the layer sequence, including introduction of functionalized linkers and pillars. PMID- 21268148 TI - Metal-free dehydration of glucose to 5-(hydroxymethyl)furfural in ionic liquids with boric acid as a promoter. AB - The dehydration of glucose and other hexose carbohydrates to 5 (hydroxymethyl)furfural (HMF) was investigated in imidazolium-based ionic liquids with boric acid as a promoter. A yield of up to 42% from glucose and as much as 66% from sucrose was obtained. The yield of HMF decreased as the concentration of boric acid exceeded one equivalent, most likely as a consequence of stronger fructose-borate chelate complexes being formed. Computational modeling with DFT calculations confirmed that the formation of 1:1 glucose-borate complexes facilitated the conversion pathway from glucose to fructose. Deuterium-labeling studies elucidated that the isomerization proceeded via an ene-diol mechanism, which is different to that of the enzyme-catalyzed isomerization of glucose to fructose. The introduced non-metal system containing boric acid provides a new direction in the search for catalyst systems allowing efficient HMF formation from biorenewable sources. PMID- 21268149 TI - Controllable synthesis of organic-inorganic hybrid MoOx/polyaniline nanowires and nanotubes. AB - A novel chemical oxidative polymerization approach has been proposed for the controllable preparation of organic-inorganic hybrid MoO(x)/polyaniline (PANI) nanocomposites based on the nanowire precursor of Mo(3)O(10)(C(6)H(8)N)(2).2H(2)O with sub-nanometer periodic structures. The nanotubes, nanowires, and rambutan like nanoparticles of MoO(x)/PANI were successfully obtained through simply modulating the pH values to 2.5-3.5, ~2.0 and ~1.0, respectively. Through systematic physicochemical characterization, such as scanning electron microscopy, transmission electron microscopy, X-ray photoelectron spectroscopy, Raman spectroscopy, and so forth, the composition and structure of MoO(x)/PANI hybrid nanocomposites are well confirmed. It is found that the nanowire morphology of the precursor is the key to achieve the one-dimensional (1D) structures of final products. A new polymerization-dissolution mechanism is proposed to explain the formation of such products with different morphologies, in which the match between polymerization and dissolution processes of the precursor plays the important role. This approach will find a new way to controllably prepare various organic-inorganic hybrid 1D nanomaterials especially for polymer-hybrid nanostructures. PMID- 21268150 TI - Designing structural motifs for clickamers: exploiting the 1,2,3-triazole moiety to generate conformationally restricted molecular architectures. AB - Noncovalent interactions, especially hydrogen-bonding interactions as well as electrostatic forces, confined within one macromolecule are the key to designing foldamers that adopt well-defined conformations in solution. In the context of significant recent activities in the area of triazole-connected foldamers, so called clickamers, we present a fundamental study that compares various model compounds that bear adjacent N-, O-, or F-heteroatom substituents. The interplay of attractive and repulsive interactions leads to rotational constraints around the single bonds attached to both the 1- and 4-positions of the 1,2,3-triazole moiety and should therefore be able to induce well-defined conformational preferences in higher oligomers and polymers, that is, foldamers. Various compounds were synthesized and characterized with regard to their preferred conformations in all three aggregation states--that is, in the gas phase, in solution as well as in the solid state--by employing DFT calculations, NMR spectroscopic experiments, and X-ray crystallography, respectively. On the basis of the thus-obtained general understanding of the conformational behavior of the individual connection motifs, heterostructures were prepared from different motifs without affecting their distinct folding characteristics. Therefore, this work provides a kind of foldamer construction kit, which should enable the design of various clickamers with specific shape and incorporated functionality. PMID- 21268151 TI - From helix to macrocycle: anion-driven conformation control of pi-conjugated acyclic oligopyrroles. AB - Anion-responsive pyrrole-based linear receptor oligomers were newly synthesized and their anion-driven dynamic conformation changes were investigated. Phenylene bridged dimers and a tetramer of dipyrrolyldiketone boron complexes as pi conjugated acyclic anion receptors formed anion-driven helical structures in the solid and solution states. In fact, single-crystal X-ray analyses of the receptor anion complexes exhibited various helical structures, such as [1+1]- and [1+2] type single helices and a [2+2]-type double helix according to the lengths of oligomers and the existence of terminal aryl substituents. Anion-binding modes and behaviors of the oligomers in solution state were also examined by (1)H NMR and UV/Vis spectra along with ESI-TOF MS. Differences in the binding modes were observed in the solid and solution states. The oligomers showed augmented anion binding constants and anion-tunable electronic and optical properties in comparison with the monomer receptor. A negative cooperative effect in the tetramer was observed in the second anion binding of the [1+2]-type single helix due to electrostatic repulsion between two anions captured in the helix. Further, an anion-template coupling reaction from the linear dimer provided a receptor macrocycle, which was obtained as a Cl(-) complex with distinct electronic and optical properties. The macrocycle exhibited extremely high anion-binding constants (>10(10) m(-1) in CH(2)Cl(2)) through multiple hydrogen bonding. PMID- 21268152 TI - Role of steric effects in protein-directed enediyne cycloaromatization of neocarzinostatin. AB - The antibiotic neocarzinostatin comprises a carrier protein with a well-defined cavity for accommodating an active enediyne chromophore. The protein has two disulfides, one (Cys(37)-Cys(47)) lies on the cavity bottom and the other (Cys(88)-Cys(93)) in a constrained short loop. When the chromophore is not bound to the protein, a thiol-induced cycloaromatization of the enediyne into a tetrahydroindacene derivative is responsible for the potent antitumor activity. When it is protein-bound, the protein diverts the cycloaromatization pathway to form a distinct hydroxyisochromene-type product. How the protein directs the enediyne chemistry is an interesting puzzle, and various suggestions have been proposed in the past. We screened more than fifty thiols and manipulated conditions to locate reaction features and search for factors that could influence the protein directing strength. Thiol- and oxygen-concentration dependence studies suggested that disulfides, which maintain the steric rigidity of the protein, could play a key role in diverting the cycloaromatization pathway. For direct proofs, we made mutations at each of the two disulfides by replacing sulfur atoms with oxygen. Circular dichroism and two-dimensional NMR spectroscopy studies suggested that the mutations changed neither the protein conformation nor the ligand interactions. Analyses of the thiol-induced cycloaromatization revealed that rupture of Cys(37)-Cys(47) made the protein almost completely lose its chemical directing ability, whereas rupture of Cys(88) Cys(93) had only a minor influence. The results demonstrated that the steric rigidity of the binding cavity, but not necessary the whole protein, played an important role in the protein-directed mechanism. PMID- 21268153 TI - Dendritic oligothiophenes terminated with tris(alkyloxy)phenylethynyl tails: synthesis, physical properties, and self-assembly. AB - Three-dimensional (3D) pi-conjugated dendritic oligothiophenes up to a third generation have been functionalized with tris(decyloxy)phenylethynyl tails at the periphery. The first-generation compounds (3 T-p-Ph-C10 and 6 T-p-Ph-C10) were synthesized by palladium-catalyzed Sonogashira coupling reactions, whereas the higher generation products were synthesized by palladium-catalyzed Suzuki coupling reactions in a divergent approach. The optical and electrochemical properties were investigated by UV/Vis absorption, fluorescence spectroscopy, and cyclic voltammetry. The results revealed that the terminal tris(alkyloxy)phenylethynyl groups are conjugated to the branched oligothiophene core, yielding redshifted absorption and fluorescence spectra and reduced optical band gaps relative to the dendritic oligothiophene core. A structural study revealed a close relationship between the type of supramolecular organization and the size of the oligothiophene core. The first-generation compounds 3 T-p-Ph-C10 and 6 T-p-Ph-C10 displayed columnar phases in the bulk state, which was confirmed by two-dimensional wide-angle X-ray scattering (2D WAXS) measurements. The self assembly into columnar stacks has mainly been attributed to phase separation between the rigid thiophene cores and the flexible side-chains assisted by minor pi-stacking interactions between the conjugated dendritic oligothiophene units. The high-generation compounds, however, showed less ordered structures in the solid state. PMID- 21268154 TI - Structural and binding study of modified siRNAs with the Argonaute 2 PAZ domain by NMR spectroscopy. AB - By using high-resolution NMR spectroscopy, the structures of a natural short interfering RNA (siRNA) and of several altritol nucleic acid (ANA)-modified siRNAs were determined. The interaction of modified siRNAs with the PAZ domain of the Argonaute 2 protein of Drosophila melanogaster was also studied. The structures show that the modified siRNA duplexes (ANA/RNA) adopt a geometry very similar to the naturally occurring A-type siRNA duplex. All ribose residues, except for the 3' overhang, show 3'-endo conformation. The six-membered altritol sugar in ANA occurs in a chair conformation with the nucleobase in an axial position. In all siRNA duplexes, two overhanging nucleotides at the 3' end enhance the stability of the first neighboring base pair by a stacking interaction. The first overhanging nucleotide has a rather fixed position, whereas the second overhanging nucleotide shows larger flexibility. NMR binding studies of the PAZ domain with ANA-modified siRNAs demonstrate that modifications in the double-stranded region of the antisense strand have some small effects on the binding affinity as compared with the unmodified siRNA. Modification of the 3' overhang with thymidine (dTdT) residues shows a sixfold increase in the binding affinity compared with the unmodified siRNA (relative binding affinity of 17% compared with dTdT-modified overhang), whereas modification of the 3' overhang with ANA largely decreases the binding affinity. PMID- 21268155 TI - Critical in vitro evaluation of responsive MRI contrast agents for calcium and zinc. AB - The synthesis of two gadolinium(III) complexes that exhibit an increase in proton relaxivity in the presence of added Ca(2+) or Zn(2+) ions is reported. The complexes increase their hydration state from zero to one following metal-ion binding, confirmed by spectral measurements on the corresponding Eu(III) complexes. At a field of 1.4 T and 310 K, modulation of relaxivity of the order of 30-40% was observed in mouse serum in each case. The dissociation constants for Ca(2+) and Zn(2+) binding were sensitive to the presence of added bicarbonate, and were 450 MUM (Ca(2+)) and 200 MUM (Zn(2+)) in serum. Such systems may, therefore, be considered for use as magnetic resonance imaging (MRI) contrast agents to track the restoration of changes in metal-ion concentration in the cerebrospinal fluid of the brain, following neural stimulation. PMID- 21268156 TI - Nitrogen-rich salts based on energetic nitroaminodiazido[1,3,5]triazine and guanazine. AB - Highly dense nitrogen-rich ionic compounds are potential high-performance energetic materials for use in military and industrial venues. Guanazinium salts with promising energetic anions and a family of energetic salts based on nitrogen rich cations and the 6-nitroamino-2,4-diazido[1,3,5]triazine anion (NADAT) were prepared and fully characterized by elemental analysis, IR spectroscopy, (1)H NMR and (13)C NMR spectroscopy, and differential scanning calorimetry (DSC). The crystal structures of neutral NADAT (2) and its biguanidinium salt 5 were determined by single-crystal X-ray diffraction (2: orthorhombic, Pnma; 5: monoclinic, P2(1)). Additionally, the isomerization behavior of 2 in solution was investigated by proton-decoupled (13)C and (15)N NMR spectroscopy. All the new salts exhibit desirable physical properties, such as relatively high densities (1.63-1.78 g cm(-3)) and moderate thermal stabilities (T(d) = 130-196 degrees C for 3-10 and 209-257 degrees C for 11-15). Theoretical performance calculations (Gaussian 03 and Cheetah 5.0) gave detonation pressures and velocities for the ionic compounds 3-15 in the range of 21.0-30.3 GPa and 7675-9048 m s(-1), respectively, which makes them competitive energetic materials. PMID- 21268157 TI - A solution NMR study of the interactions of oligomannosides and the anti-HIV-1 2G12 antibody reveals distinct binding modes for branched ligands. AB - The structural and affinity details of the interactions of synthetic oligomannosides, linear (di-, tri-, and tetra-) and branched (penta- and hepta-), with the broadly neutralizing anti-HIV-1 antibody 2G12 (HIV=human immunodeficiency virus) have been investigated in solution by using ligand-based NMR techniques, specifically saturation transfer difference (STD) NMR spectroscopy and transferred NOE experiments. Linear oligomannosides show similar binding modes to the antibody, with the nonreducing terminal disaccharide Manalpha(1->2)Man (Man=mannose) making the closest protein/ligand contacts in the bound state. In contrast, the branched pentamannoside shows two alternate binding modes, involving both ligand arms (D2- and D3-like), a dual binding description of the molecular recognition of this ligand by 2G12 in solution that differs from the single binding mode deduced from X-ray studies. On the contrary, the antibody shows an unexpected selectivity for one arm (D1-like) of the other branched ligand (heptamannoside). This result explains the previously reported lack of affinity enhancement relative to that of the D1-like tetramannoside. Single ligand STD NMR titration experiments revealed noticeable differences in binding affinities among the linear and branched ligands in solution, with the latter showing decreased affinity. Among the analyzed series of ligands, the strongest 2G12 binders were the linear tri- and tetramannosides because both show similar affinity for the antibody. These results demonstrate that NMR spectroscopic techniques can deliver abundant structural, dynamics, and affinity information for the characterization of oligomannose-2G12 binding in solution, thus complementing, and, as in the case of the pentamannoside, extending, the structural view from X-ray crystallography. This information is of key importance for the development of multivalent synthetic gp120 high-mannose glycoconjugate mimics in the context of vaccine development. PMID- 21268158 TI - Efficient charge separation in TiO2 films sensitized with ruthenium(II) polypyridyl complexes: hole stabilization by ligand-localized charge-transfer states. AB - We have studied the interfacial electron-transfer dynamics on TiO(2) film sensitized with synthesized ruthenium(II)-polypyridyl complexes- [Ru(II)(bpy)(2)(L(1))] (1) and [Ru(II)(bpy)(L(1))(L(2))] (2), in which bpy=2,2' bipyridyl, L(1)=4-[2-(4'-methyl-2,2'-bipyridinyl-4-yl)vinyl]benzene-1,2-diol, and L(2)=4-(N,N-dimethylaminophenyl)-2,2'-bipyridine-by using femtosecond transient absorption spectroscopy. The presence of electron-donor L(2) and electron acceptor L(1) ligands in complex 2 introduces lower energetic ligand-to-ligand charge-transfer (LLCT) excited states in addition to metal-to-ligand (ML) CT manifolds of complex 2. On photoexcitation, a pulse-width-limited (<100 fs) electron injection from populating LLCT and MLCT states are observed on account of strong catecholate binding on the TiO(2) surface. The hole is transferred directly or stepwise to the electron-donor ligand (L(2)) as a consequence of electron injection from LLCT and MLCT states, respectively. This results an increased spatial charge separation between the hole residing at the electron donor (L(2)) ligand and the electron injected in TiO(2) nanoparticles (NPs). Thus, we observed a significant slow back-electron-transfer (BET) process in the 2/TiO(2) system relative to the 1/TiO(2) system. Our results suggest that Ru(II) polypyridyl complexes comprising LLCT states can be a better photosensitizer for improved electron injection yield and slow BET processes in comparison with Ru(II)-polypyridyl complexes comprising MLCT states only. PMID- 21268159 TI - Crystallographic analysis of metal-ion binding to human ubiquitin. AB - The metal-binding ability of human ubiquitin (hUb) towards a selection of biologically relevant metal ions and complexes has been probed. Different techniques have been used to obtain crystals suitable for crystallographic analysis. In the first type of experiments, crystals of hUb have been soaked in solutions containing copper(II) acetate and two metallodrugs, Zeise salt (K[PtCl(3)(eta(2)-C(2)H(4))].H(2)O) and cisplatin (cis-[PtCl(2)(NH(3))(2)]). The Zeise salt is used in a test for hepatitis, whereas cisplatin is one of the most powerful anticancer drugs in clinical use. The Zeise salt readily reacts with hUb crystals to afford an adduct with three platinum residues per protein molecule, Pt(3)-hUb. In contrast, copper(II) acetate and cisplatin were found to be unreactive for contact times up to one hour and to cause degradation of the hUb crystals for longer times. In the second type of experiments, hUb was cocrystallized with a solution of copper(II) or zinc(II) acetate or cisplatin. Zinc(II) acetate gives, at low metal-to-protein molar ratios (8:1), crystals containing one metal ion per three molecules of protein, Zn-hUb(3) (already reported in previous work), whereas at high metal-to-protein ratios (70:1) gives crystals containing three Zn(II) ions per protein molecule, Zn(3)-hUb. In contrast, once again, copper(II) acetate and cisplatin, even at low metal-to protein ratios, do not give crystalline material. In the soaking experiment, the Zeise anion leads to simultaneous platination of His68, Met1, and Lys6. Present and previous results of cocrystallization experiments performed with Zn(II) and other Group 12 metal ions allow a comprehensive understanding of the metal-ion binding properties of hUb with His68 as the main anchoring site, followed by Met1 and carboxylic groups of Glu16, Glu18, Glu64, Asp21, and Asp32, to be reached. In the case of platinum, Lys6 can also be a binding site. The amount of bound metal ion, with respect to that of the protein, appears to be a relevant parameter influencing crystal packing. PMID- 21268160 TI - Regiocontrolled halohydroxylations of bicyclic vinylidenecyclopropanes: a versatile strategy for the construction of diverse highly functionalized carbocyclic scaffolds. AB - Highly regioselective halohydroxylations of bicyclic vinylidenecyclopropanes that lead to four types of products 2, 3, 4, and 6 were developed. The halohydroxylation reaction occurs at room temperature to give rise to ring keeping products vinylbicyclo[(n+2).1.0]alkanols 2 in 55-90% yields with excellent regio- and diastereoselectivity; the reaction of bicyclic vinylidenecyclopropanes with 2.0 equiv of N-bromosuccinimide (NBS) at 100 degrees C affords alkylidenebicyclo[(n+2).2.0]alkanones 3 in 48-75% yields by means of further proximal cleavage of the cyclopropane ring. The structures of both types of compounds 2 and 3 have been elucidated by X-ray crystal diffraction. An interesting sequential reaction that consists of a couple electrophilic addition and elimination reactions was developed when the reaction of bicyclic vinylidenecyclopropanes with N-halosuccinimide (NXS; 3.0 equiv) was performed under the specified conditions to furnish a variety of divinyl ketones 4 by means of proximal cleavage of the cyclopropane ring. In addition, vinylidenecyclopropanes that bore one aryl group at the cyclopropyl ring reacted with NBS or I(2) at room temperature, thereby producing the corresponding divinyl ketones 4 in moderate to good yields with excellent E selectivity. Unexpectedly, 2-vinylic cyclohex-2-enols 6 were generated through a very different distal C-C bond cleavage of the cyclopropane due to the significant ring-size effect. Possible mechanisms are proposed on the basis of the obtained intermediates. PMID- 21268161 TI - Spin-trapping evidence for the formation of alkyl, alkoxyl, and alkylperoxyl radicals in the reactions of dialkylzincs with oxygen. AB - The reactions of dialkylzincs (Me(2)Zn, Et(2)Zn, and nBu(2)Zn) with oxygen have been investigated by EPR spectroscopy using spin-trapping techniques. The use of 5-diethoxyphosphoryl-5-methyl-1-pyrrroline N-oxide (DEPMPO) as a spin-trap has allowed the involvement of alkyl, alkylperoxyl, and alkoxyl radicals in this process to be probed for the first time. The relative ratio of the corresponding spin-adducts depends strongly on the nature of the R group, which controls the C Zn bond dissociation enthalpy, and on the experimental conditions (excess of spin trap compared with R(2)Zn and vice versa). The results have demonstrated that Et(2)Zn and, to a lesser extent, nBu(2)Zn are much better traps for oxygen centered species than Me(2)Zn. When the dialkylzincs were used in excess with respect to the spin-trap, the concentration of the oxygen-centered radical adducts of DEPMPO was much lower for Et(2)Zn and nBu(2)Zn than for Me(2)Zn. A detailed reaction mechanism is discussed and C-Zn, O-Zn, and O-O bond dissociation enthalpies for the proposed reaction intermediates were calculated at the UB3LYP/6-311++G(3df,3pd)//UB3LYP/6-31G(d,p) level of theory to support the rationale. PMID- 21268162 TI - Topochemical synthesis of cobalt oxide-based porous nanostructures for high performance lithium-ion batteries. AB - Two kinds of topochemical conversion routes from cobalt hydroxide precursors to cobalt oxide-based porous nanostructures are presented: pyrolysis in air and hydrothermal treatment by the Kirkendall diffusion effect. These cobalt hydroxide precursors were synthesized by a simple hydrothermal approach with sodium acetate as mineralizer at 200 degrees C. Detailed proof indicates that the process of cobalt hydroxide precursor growth is dominated by a nucleation, dissolution, renucleation, growth, and exfoliation mechanism. By the topochemical conversion processes several Co(3)O(4) nanostructures, such as cobalt oxide-coated cobalt hydroxide carbonate nanowires, cobalt oxide nanotubes, hollow cobalt oxide spheres, and porous cobalt oxide nanowires, have been synthesized. The obtained Co(3)O(4) nanostructures have also been evaluated as the anode materials in lithium-ion batteries. It was found that the as-prepared Co(3)O(4) nanostructures exhibited high reversible capacity and good cycle performance due to their porous structure and small size. PMID- 21268163 TI - Mimicking photosynthetic antenna-reaction-center complexes with a (boron dipyrromethene)3-porphyrin-C60 pentad. AB - A highly efficient functional mimic of the photosynthetic antenna-reaction-center complexes has been designed and synthesized. The model contains a zinc(II) porphyrin (ZnP) core, which is connected to three boron dipyrromethene (BDP) units by click chemistry, and to a C(60) moiety using the Prato procedure. The compound has been characterized using various spectroscopic methods. The intramolecular photoinduced processes of this pentad have also been studied in detail with steady-state and time-resolved absorption and emission spectroscopic methods, both in polar benzonitrile and nonpolar toluene. The BDP units serve as the antennae, which upon excitation undergo singlet-singlet energy transfer to the porphyrin core. This is then followed by an efficient electron transfer to the C(60) moiety, resulting in the formation of the singlet charge-separated state (BDP)(3)-ZnP(.+) -C(60)(.-) , which has a lifetime of 476 and 1000 ps in benzonitrile and toluene, respectively. Interestingly, a slow charge recombination process (k(CR)(t)=2.6*10(6) s(-1)) and a long-lived triplet charge separated state (tau(CS)(T)=385 ns) were detected in polar benzonitrile by nanosecond transient measurements. PMID- 21268164 TI - Density functional calculations on the distribution, acidity, and catalysis of Ti(IV) and Ti(III) ions in MCM-22 zeolite. AB - Isolated Ti species in zeolites show unique catalytic activities for a variety of chemical reactions. In this work, density functional calculations were used to explore three current concerns: 1) the distributions of Ti(IV) and Ti(III) ions in the MCM-22 zeolite; 2) the Lewis acidity of the Ti(IV) and Ti(III) sites; and 3) activation of alkane C-H bonds by photocatalysis with Ti-doped zeolites. Neither the Ti(IV) nor Ti(III) ions are randomly distributed in the MCM-22 zeolite. The orders of relative stability are very close for the eight Ti(IV) and Ti(III) sites, and the T3 site is the most probable in both cases. The wavelengths for Ti(IV)-Ti(III) excitations were calculated to lie in the range lambda=246.9-290.2 nm. The Ti3(IV) site shows Lewis acidity toward NH(3) in two different modes, and these two modes can coexist with each other. The calculated Ti(IV) coordination numbers, Ti(IV)-O bond elongations, and charge transfers caused by NH(3) adsorption are in good agreement with previous results. Similarly, two different NH(3) adsorption modes exist for the Ti3(III) site; the site that exhibits radical transfer from the lattice O to N atoms is preferred due to the higher adsorption energy. This indicates that the Ti3(III) site does not show Lewis acidity, in contrast to the Ti3(IV) site. At the Ti3(III) site, the energy barrier for activating the methane C-H bond was calculated to be 33.3 kJ mol(-1) and is greatly reduced by replacing the hydrogen atoms with methyl groups. In addition, the reactivity is improved when switching from MCM-22 to TS 1 zeolite. The studies on the various Ti species reveal that lattice O atoms rather than Ti(III) radicals are crucial to the activation of alkane C-H bonds. This work provides new insights into and aids understanding of the catalysis by isolated Ti species in zeolites. PMID- 21268166 TI - A label-free, quadruplex-based functional molecular beacon (LFG4-MB) for fluorescence turn-on detection of DNA and nuclease. AB - We demonstrate a novel concept for the construction of a label-free, quadruplex based functional molecular beacon (LFG4-MB) by using G-quadruplex motif as a substitute for Watson-Crick base pairing in the MB stem and a specific G quadruplex binder, N-methyl mesoporphyrin IX (NMM) as a reporter. It shows high sensitivity in assays for UDG activity/inhibition and detection of DNA sequence based on the unique fluorescence increase that occurs as a result of the strong interaction between NMM and the folded quadruplex upon removal of uracil by UDG or displacement of block sequence by target DNA. The LFG4-MB is simple in design, fast in operation and could be easily transposed to other biological relevant target analysis by simply changing the recognition portion. The LFG4-MB does not require any chemical modification for DNA, which offers the advantages of simplicity and cost efficiency and obviates the possible interference with the affinity and specificity of the MB as well as the kinetic behavior of the catalysts caused by the bulky fluorescent groups. More importantly, the LFG4-MB offers great extent of freedom to tune the experimental conditions for the general applicability in bioanalysis. PMID- 21268165 TI - Modeling the cis-oxo-labile binding site motif of non-heme iron oxygenases: water exchange and oxidation reactivity of a non-heme iron(IV)-oxo compound bearing a tripodal tetradentate ligand. AB - The spectroscopic and chemical characterization of a new synthetic non-heme iron(IV)-oxo species [Fe(IV)(O)((Me,H) Pytacn)(S)](2+) (2, (Me,H)Pytacn=1-(2' pyridylmethyl)-4,7-dimethyl-1,4,7-triazacyclononane, S=CH(3)CN or H(2)O) is described. Complex 2 was prepared by reaction of [Fe(II)(CF(3)SO(3))(2)((Me,H) Pytacn)] (1) with peracetic acid. Complex 2 bears a tetradentate N(4) ligand that leaves two cis sites available for binding an oxo group and a second external ligand but, unlike the related iron(IV)-oxo species with tetradentate ligands, it is remarkably stable at room temperature (t(1/2)>2 h at 288 K). Its ability to exchange the oxygen atom of the oxo ligand with water has been analyzed in detail by means of kinetic studies, and a mechanism is proposed on the basis of DFT calculations. Hydrogen-atom abstraction from C-H bonds and oxygen-atom transfer to sulfides by 2 have also been studied. Despite its thermal stability, 2 proves to be a very powerful oxidant that is capable of breaking the strong C-H bond of cyclohexane (bond dissociation energy=99.3 kcal mol(-1)). PMID- 21268167 TI - A sensitive, label-free, aptamer-based biosensor using a gold nanoparticle initiated chemiluminescence system. AB - We report a label-free, aptamer-based chemiluminescent biosensor. The biosensor relies upon the catalytic activity of unmodified gold nanoparticles (AuNPs) on the luminol-H(2)O(2) chemiluminescence (CL) reaction, and the interaction of unmodified AuNPs with the aptamer. The unmodified AuNPs can effectively differentiate unstructured and folded aptamer. The binding of the aptamer with the target can induce the AuNP aggregation in the presence of 0.5 M NaCl, and after aggregation the catalytic activity of the AuNPs on the luminol-H(2)O(2) CL reaction is greatly enhanced. During the assay, no covalent functionalization of the AuNPs or aptamer is required. The detection limit of thrombin was estimated to be as low as 26 fM, and the sensitivity was more than 4 orders of magnitude better than that of known AuNP-based colorimetric methods for the detection of thrombin. This aptamer-based biosensor offers the advantages of being simple, cheap, rapid, and sensitive. PMID- 21268168 TI - Diastereoselective synthesis of cyclosaligenyl-nucleosyl-phosphotriesters. AB - A diastereoselective synthesis of cycloSal-phosphotriesters (cycloSal=cycloSaligenyl) based on chiral auxiliaries has been developed that allows the synthesis of single diastereomers of the cycloSal-pronucleotides. In previously described synthesis routes, the cycloSal-compounds were always obtained as 1:1 diastereomeric mixtures that could be separated in only rare cases. However, it was shown that the diastereomers have different antiviral activity, toxicity, and hydrolysis stabilities. Here, first a chiral thiazoline derivative was used to prepare nonsubstituted and 5-methyl-cycloSal phosphotriesters in 48 and >=95% de (de=diastereomeric excess). However, this approach failed to give the important group of 3-substituted cycloSal nucleotides. Therefore, two other chiral groups were discovered that allowed the synthesis of (R(P))- and (S(P))-3-methyl-cycloSal-phosphotriesters as well. The antiviral activity was found to be five- to 20-fold different between the two individual diastereomers, which proved the importance of this approach. PMID- 21268169 TI - Luminescent organic 1D nanomaterials based on bis(beta-diketone)carbazole derivatives. AB - A series of new triphenylamine-functionalized bis(beta-diketone)s bridged by a carbazole (CnBDKC, n=1, 4, 8, 16) with twisted intramolecular charge-transfer emission in polar solvents has been synthesized. The length of the carbon chains has a significant effect on the self-assembling properties of the compounds. Well defined 1D nanowires were easily generated from C1BDKC with a methyl group by a reprecipitation approach directed by pi-stacking interaction, and the molecules packed into J-aggregates in the nanowires. In addition, 1D nanofibers based on C16BDKC bearing a long hexadecyl chain were prepared through the organogelation process, and H-aggregates were formed driven by the synergistic effect of pi stacking interaction and van der Waals force in the gel phase. C4BDKC and C8BDKC containing butyl and octyl side chains, respectively, cannot arrange into dispersed nanostructures, probably because pi-pi interaction between conjugated moieties might be disturbed by the interaction between the side chains, which is, however, not strong enough to dominate the self-assembling process. Notably, the nanowires based on C1BDKC and the gel nanofibers from C16BDKC can emit strong green light under irradiation, which suggests that these 1D nanomaterials may have potential applications in emitting materials as well as photonic devices. PMID- 21268170 TI - A macrocyclic ligand as receptor and Zn(II)-complex receptor for anions in water: binding properties and crystal structures. AB - Binding properties of 24,29-dimethyl-6,7,15,16 tetraoxotetracyclo[19.5.5.0(5,8).0(14,17)]-1,4,9,13,18,21,24,29 octaazaenatriaconta-Delta(5,8),Delta(14,17)-diene ligand L towards Zn(II) and anions, such as the halide series and inorganic oxoanions (phosphate (Pi), sulfate, pyrophosphate (PPi), and others), were investigated in aqueous solution; in addition, the Zn(II)/L system was tested as a metal-ion-based receptor for the halide series. Ligand L is a cryptand receptor incorporating two squaramide functions in an over-structured chain that connects two opposite nitrogen atoms of the Me(2)[12]aneN(4) polyaza macrocyclic base. It binds Zn(II) to form mononuclear species in which the metal ion, coordinated by the Me(2)[12]aneN(4) moiety, lodges inside the three-dimensional cavity. Zn(II)-containing species are able to bind chloride and fluoride at the physiologically important pH value of 7.4; the anion is coordinated to the metal center but the squaramide units play the key role in stabilizing the anion through a hydrogen-bonding network; two crystal structures reported here clearly show this aspect. Free L is able to bind fluoride, chloride, bromide, sulfate, Pi, and PPi in aqueous solution. The halides are bound at acidic pH, whereas the oxoanions are bound in a wide range of pH values ranging from acidic to basic. The cryptand cavity, abundant in hydrogen-bonding sites at all pH values, allows excellent selectivity towards Pi to be achieved mainly at physiological pH 7.4. By joining amine and squaramide moieties and using this preorganized topology, it was possible, with preservation of the solubility of the receptor, to achieve a very wide pH range in which oxoanions can be bound. The good selectivity towards Pi allows its discrimination in a manner not easily obtainable with nonmetallic systems in aqueous environment. PMID- 21268171 TI - Energetic salts of the binary 5-cyanotetrazolate anion ([C2N5]-) with nitrogen rich cations. AB - The reaction of cyanogen (NC-CN) with MN(3) (M=Na, K) in liquid SO(2) leads to the formation of the 5-cyanotetrazolate anion as the monohemihydrate sodium (1.1.5 H(2)O) and potassium (2) salts, respectively. Both 1.1.5 H(2)O and 2 were used as starting materials for the synthesis of a new family of nitrogen-rich salts containing the 5-cyanotetrazolate anion and nitrogen-rich cations, namely ammonium (3), hydrazinium (4), semicarbazidium (5), guanidinium (6), aminoguanidinium (7), diaminoguanidinium (8), and triaminoguanidinium (9). Compounds 1-9 were synthesised in good yields and characterised by using analytical and spectroscopic methods. In addition, the crystal structures of 1.1.5 H(2)O, 2, 3, 5, 6, and 9.H(2)O were determined by using low-temperature single-crystal X-ray diffraction. An insight into the hydrogen bonding in the solid state is described in terms of graph-set analysis. Differential scanning calorimetry and sensitivity tests were used to assess the thermal stability and sensitivity against impact and friction of the materials, respectively. For the assessment of the energetic character of the nitrogen-rich salts 3-9, quantum chemical methods were used to determine the constant volume energies of combustion, and these values were used to calculate the detonation velocity and pressure of the salts using the EXPLO5 computer code. Additionally, the performances of formulations of the new compounds with ammonium nitrate and ammonium dinitramide were also predicted. Lastly, the ICT code was used to determine the gases and heats of explosion released upon decomposition of the 5 cyanotetrazolate salts. PMID- 21268175 TI - The yellow body. PMID- 21268172 TI - A thermosensitive monolithic column as an artificial antibody for the on-line selective separation of the protein. AB - The main objective of this study was to develop a new methodology for the preparation of a protein (antigen) that is a molecularly imprinted polymer (MIP, an artificial antibody) modified onto the surface of a silica skeleton in which the resulting stationary phase is thermosensitive. The silica monolithic skeleton with vinyl groups was synthesized in a stainless-steel column by using a mild one step sol-gel process with two types of precursor: methyltrimethoxysilane (MTMS) and gamma-methacryloxypropyltrimethoxysilane (gamma-MAPS). Subsequently, three types of the thermosensitive protein MIP were anchored onto the surface of the silica skeleton to prepare the MIP monoliths, which were systematically investigated for back pressure and separation ability at different temperatures to establish good imprinting conditions. Under the optimized imprinting conditions, the chromatographic behavior of the thermosensitive MIP monolith exhibited strong retention ability for the lysozyme template (target antigen) in relation to the nonimprinting monolith (NIP monolith). The imprinting factor (IF) for lysozyme reached 3.48 at 20 degrees C. Moreover, this new type of artificial antibody displayed favorable binding characteristics for lysozyme over competitive proteins and was further evaluated to selectively separate lysozyme in a real sample by using an on-line method. The run-to-run and column-to-column repeatability measurements of the thermosensitive MIP monoliths were also satisfactory. PMID- 21268177 TI - X-ray of fertilization. PMID- 21268178 TI - Gene targeting with zinc finger nucleases to produce cloned eGFP knockout pigs. PMID- 21268179 TI - Polar bodies--more a lack of understanding than a lack of respect. AB - Polar bodies are as diverse as the organisms that produce them. Although in many animals these cells often die following meiotic maturation of the oocyte, in other organisms they are an essential and diverse part of embryonic development. Here we highlight some of this diversity and summarize the evolutionary basis for their utility. PMID- 21268180 TI - cables1 is required for embryonic neural development: molecular, cellular, and behavioral evidence from the zebrafish. AB - In vitro studies have suggested that the Cables1 gene regulates epithelial cell proliferation, whereas other studies suggest a role in promoting neural differentiation. In efforts to clarify the functions of Cables1 in vivo, we conducted gain- and loss-of-function studies targeting its ortholog (cables1) in the zebrafish embryo. Similar to rodents, zebrafish cables1 mRNA expression is detected most robustly in embryonic neural tissues. Antisense knockdown of cables1 leads to increased numbers of apoptotic cells, particularly in brain tissue, in addition to a distinct behavioral phenotype, characterized by hyperactivity in response to stimulation. Apoptosis and the behavioral abnormality could be rescued by co-expression of a morpholino-resistant cables1 construct. Suppression of p53 expression in cables1 morphants partially rescued both apoptosis and the behavioral phenotype, suggesting that the phenotype of cables1 morphants is due in part to p53-dependent apoptosis. Alterations in the expression patterns of several neural transcription factors were observed in cables1 morphants during early neurulation, suggesting that cables1 is required for early neural differentiation. Ectopic overexpression of cables1 strongly disrupted embryonic morphogenesis, while overexpression of a cables1 mutant lacking the C-terminal cyclin box had little effect, suggesting functional importance of the cyclin box. Lastly, marked reductions in p35, but not Cdk5, were observed in cables1 morphants. Collectively, these data suggest that cables1 is important for neural differentiation during embryogenesis, in a mechanism that likely involves interactions with the Cdk5/p35 kinase pathway. PMID- 21268181 TI - Fer tyrosine kinase is required for germinal vesicle breakdown and meiosis-I in mouse oocytes. AB - The control of microtubule and actin-mediated events that direct the physical arrangement and separation of chromosomes during meiosis is critical since failure to maintain chromosome organization can lead to germ cell aneuploidy. Our previous studies demonstrated a role for FYN tyrosine kinase in chromosome and spindle organization and in cortical polarity of the mature mammalian oocyte. In addition to Fyn, mammalian oocytes express the protein tyrosine kinase Fer at high levels relative to other tissues. The objective of the present study was to determine the function of this kinase in the oocyte. Feline encephalitis virus (FES)-related kinase (FER) protein was uniformly distributed in the ooplasm of small oocytes, but became concentrated in the germinal vesicle (GV) during oocyte growth. After germinal vesicle breakdown (GVBD), FER associated with the metaphase-I (MI) and metaphase-II (MII) spindles. Suppression of Fer expression by siRNA knockdown in GV stage oocytes did not prevent activation of cyclin dependent kinase 1 activity or chromosome condensation during in vitro maturation, but did arrest oocytes prior to GVBD or during MI. The resultant phenotype displayed condensed chromosomes trapped in the GV, or condensed chromosomes poorly arranged in a metaphase plate but with an underdeveloped spindle microtubule structure or chromosomes compacted into a tight sphere. The results demonstrate that FER kinase plays a critical role in oocyte meiotic spindle microtubule dynamics and may have an additional function in GVBD. PMID- 21268182 TI - Identification and functional analysis of an ovarian form of the egg activation factor phospholipase C zeta (PLCzeta) in pufferfish. AB - Recent studies suggest that egg activation in mammals is triggered by a sperm specific phospholipase C, PLCzeta. In other vertebrate species such as medaka fish, chickens, and quail, PLCzeta is also expressed as a testis-specific mRNA. Functional studies suggest that PLCzeta plays a similar role as a trigger of egg activation in these species. Here, we report the identification of PLCzeta orthologues in pufferfish species Takifugu rubripes (Fugu) and Tetraodon nigroviridis (Tetraodon). Unexpectedly in these species PLCzeta is expressed not in the testis, but in ovary and brain. Injection of pufferfish PLCzeta copy ribonucleic acid (cRNA) into mouse eggs failed to trigger calcium oscillations, unlike medaka PLCzeta cRNA. Our findings provide the first evidence that PLCzeta may be expressed in the egg, rather than the sperm, in some vertebrate species, and that its mechanism of action and physiologic role at fertilization may differ in different vertebrate species. PMID- 21268183 TI - Novel conserved structural domains of acrosome reaction-inducing substance are widespread in invertebrates. AB - In the starfish Asterias amurensis, acrosome reaction inducing substance (ARIS) is the main factor responsible for allowing sperm to recognize the egg jelly and begin the acrosome reaction (AR). ARIS is a large proteoglycan-like molecule, and its pentasaccharide repeat, Fragment 1 (Fr. 1), is responsible for inducing AR. Here, we investigated the primary structure of ARIS for the first time in order to improve our understanding of its functionality. Electrophoretic analysis revealed that ARIS is a complex of three proteins, all of which are modified by the Fr. 1 sugar chain. Sequencing indicated that there are two novel, conserved domains in all three ARIS proteins: ARIS N-terminus (AR-N) and ARIS C-terminus (AR-C) domains. We also found that other echinoderms possess ARIS proteins that are capable of inducing the AR for homologous sperm, indicating that ARIS proteins may be a ubiquitous component for echinoderm fertilization. Moreover, we identified ARIS-like genes from Ctenophora to Protochordata. PMID- 21268184 TI - Aggression and risk of future violence in forensic psychiatric patients with and without dyslexia. AB - Dyslexia does not cause criminal behaviour, but it may worsen aggressive behaviour tendencies. In this study, aggressive behaviour and risk of future violence were compared between forensic psychiatric patients with and without dyslexia. Dyslexia was assessed using the Swedish phonological processing battery 'The Pigeon'. The patients filled in the Aggression Questionnaire, and trained assessors performed the risk assessments using HCR-20 version 2. Patients with dyslexia self-reported more aggressive behaviour compared with those without dyslexia. There was only a nearly significant tendency (p = 0.06) for the patients with dyslexia to receive higher scores in the HCR-20 compared with the patients without dyslexia, and phonological processing skills did not significantly predict aggression or risk of future violence. However, regression analyses demonstrated that poor phonological processing skills are a significant predictor of anger, which in turn significantly predicts risk of future violence. PMID- 21268188 TI - Selective epitaxial growth of silver nanoplates. PMID- 21268189 TI - Allylic alcohols: sustainable sources for catalytic enantioselective alkylation reactions. PMID- 21268190 TI - Nanoporous organics enter the cage age. PMID- 21268191 TI - A salicylbisimine cage compound with high surface area and selective CO2/CH4 adsorption. PMID- 21268192 TI - Specific recognition of proteins by array-bound hexanucleotides. PMID- 21268193 TI - Recognition of the GM3 ganglioside glycan by Rhesus rotavirus particles. PMID- 21268194 TI - A Ritter-type reaction: direct electrophilic trifluoromethylation at nitrogen atoms using hypervalent iodine reagents. PMID- 21268195 TI - Rhodium-catalyzed oxidative olefination of C-H bonds in acetophenones and benzamides. PMID- 21268196 TI - Biocatalytic enantioselective oxidative C-C coupling by aerobic C-H activation. PMID- 21268197 TI - Metal-organic conjugated microporous polymers. PMID- 21268198 TI - Palladium(II)-catalyzed C-H bond arylation of electron-deficient arenes at room temperature. PMID- 21268199 TI - Synthesis of highly enantioenriched C-tertiary amines from boronic esters: application to the synthesis of igmesine. PMID- 21268200 TI - Design and application of a mevalonate-responsive regulatory protein. PMID- 21268201 TI - The hydrogen-enriched Al-B-N system as an advanced solid hydrogen-storage candidate. PMID- 21268202 TI - Synthesis of a stable disilyne bisphosphine adduct and its non-metal-mediated CO2 reduction to CO. PMID- 21268203 TI - Ultrafast energy-transfer pathway in a purple-bacterial photosynthetic core antenna, as revealed by femtosecond time-resolved spectroscopy. PMID- 21268204 TI - Enantioselective cobalt-catalyzed preparation of trifluoromethyl-substituted cyclopropanes. PMID- 21268205 TI - Single-crystal-like titania mesocages. PMID- 21268206 TI - Direct cross-coupling of C-H bonds with Grignard reagents through cobalt catalysis. PMID- 21268207 TI - Coupling of N-tosylhydrazones with terminal alkynes catalyzed by copper(I): synthesis of trisubstituted allenes. PMID- 21268208 TI - Domino condensation/S-arylation/heterocyclization reactions: copper-catalyzed three-component synthesis of 2-N-substituted benzothiazoles. PMID- 21268209 TI - Metal-silicon triple bonds: nucleophilic addition and redox reactions of the silylidyne complex [Cp(CO)2 Mo=Si-R]. PMID- 21268210 TI - Indeno[1,2-b]fluorenes: fully conjugated antiaromatic analogues of acenes. PMID- 21268211 TI - Total synthesis of pederin and analogues. PMID- 21268212 TI - Highly enantioselective catalytic benzoyloxylation of 3-aryloxindoles using chiral VAPOL calcium phosphate. PMID- 21268213 TI - Total synthesis and biological evaluation of monorhizopodin and 16-epi monorhizopodin. PMID- 21268214 TI - Experimental detection of trinitramide, N(NO2)3. PMID- 21268215 TI - Protonation-triggered conversion between single- and triple-stranded helices with a visible fluorescence change. PMID- 21268216 TI - Bottom-up assembly from a helicate to homochiral micro- and mesoporous metal organic frameworks. PMID- 21268217 TI - The role of bridge-bonded adsorbed formate in the electrocatalytic oxidation of formic acid on platinum. PMID- 21268218 TI - Self-assembly of semiconducting photoluminescent peptide nanowires in the vapor phase. PMID- 21268219 TI - Proof of the existence of an unstable amino acid: pleurocybellaziridine in Pleurocybella porrigens. PMID- 21268220 TI - Microfluidic multicolor encoding of microspheres with nanoscopic surface complexity for multiplex immunoassays. PMID- 21268222 TI - Light-harvesting hybrid hydrogels: energy-transfer-induced amplified fluorescence in noncovalently assembled chromophore-organoclay composites. PMID- 21268221 TI - Attomolar detection of a cancer biomarker protein in serum by surface plasmon resonance using superparamagnetic particle labels. PMID- 21268223 TI - Synthesis and photocatalytic properties of a family of CdS-PdX hybrid nanoparticles. PMID- 21268224 TI - The continuous-flow synthesis of carboxylic acids using CO2 in a tube-in-tube gas permeable membrane reactor. PMID- 21268225 TI - Semiempirical rate constants for complex chemical kinetics: first-principles assessment and rational refinement. PMID- 21268227 TI - Investigation on the analytical application of cationic Gemini surfactant 12-4-12 and its interaction with DNA. AB - The quantitative determination of nucleic acids is of great importance in fundamental research and clinical diagnosis. In this work, the interaction between DNA and cationic Gemini surfactant 12-4-12, which changes the conformation of DNA, was investigated by UV-vis absorption, FT-IR spectra and steady-state fluorescence techniques. A hydrophobic pyrene probe was used to investigate the microenvironment change and calculate the critical micelle concentration (CMC) of Gemini surfactant 12-4-12 (0.69 mmol/L), which is close to the value obtained from the conductivity method (0.79 mmol/L). A new detection assay for DNA is proposed with Gemini surfactant 12-4-12, using the resonance light-scattering (RLS) technique. The formation of DNA-12-4-12 complex resulted in enhanced RLS signals at 368 nm, which is proportional to DNA concentration in the range 0.304-5.32 mg/L, with a detection limit of 35 ug/L. Most coexisting substances do not interfere in the detection and four synthetic samples were analyzed satisfactorily. PMID- 21268228 TI - Flow-injection chemiluminescent determination of estrogen benzoate using the tris(1,10-phenanthroline) ruthenium(II)-permanganate system. AB - Chemiluminescence (CL) detection for the determination of estrogen benzoate, using the reaction of tris(1,10-phenanthroline)ruthenium(II)-Na(2)SO(3) permanganate, is described. This method is based on the CL reaction of estrogen benzoate (EB) with acidic potassium permanganate and tris(1,10 phenanthroline)ruthenium(II). The CL intensity is greatly enhanced when Na(2)SO(3) is added. After optimization of the different experimental parameters, a calibration graph for estrogen benzoate is linear in the range 0.05-10 ug/mL. The 3 s limit of detection is 0.024 ug/mL and the relative standard deviation was 1.3% for 1.0 ug/mL estrogen benzoate (n = 11). This proposed method was successfully applied to commercial injection samples and emulsion cosmetics. The mechanism of CL reaction was also studied. PMID- 21268229 TI - Interaction of beta-cyclodextrin-capped CdSe quantum dots with inorganic anions and cations. AB - A facile method was developed for the preparation of water soluble beta Cyclodextrin (beta-CD)-modified CdSe quantum dots (QDs) (beta-CD-QDs) by directly replacing the oleic acid ligands on the QDs surface with beta-CD in an alkaline aqueous solution. The as-prepared QDs show good stability in aqueous solution for several months. Oxoanions, including phosphoric acid ion, sulphite acid ion and carbonic acid ion, affect the fluorescence of beta-CD-QDs. Among them, H(2)PO(4)( ) exhibited the largest quenching effect. For the polyprotic acids (HO)(3)AO, the effect of acidic anions on the fluorescence of beta-CD-QDs was in the order: monoanion (HO)(2)AO(2)(-) > dianion (HO)AO(3)(2-) >> trianion AO(4)(3-). After photoactivation for several days in the presence of anions at alkaline pH, the beta-CD-QDs exhibited strong fluorescence emission. The effect of various heavy and transition metal ions on the fluorescence properties of the beta-CD-QDs was investigated further. It was found that Ag(+), Hg(2+) and Co(2+) have significant quenching effect on the fluorescence of the beta-CD-QDs. The Stern-Volmer quenching constants increased in the order: Hg(2+) < Co(2+) jejunum>colon~duodenum>stomach. Most of emodin was absorbed in ileum, and the absorption amount was increased with prolonged retention of drug form in intestine, especially in ileum and jejunum. The developed UHPLC-ESI-MS/MS method was appropriate for determining the in vivo absorption of emodin in other herbal medicines or preparations containing this compound. PMID- 21268249 TI - Ultra-performance LC-photodiode array-elambda-ESI-MS/MS screening method for the detection of radical-scavenging natural antioxidants from radix et rhizoma Rhei. AB - A novel ultra-performance LC-photodiode array-el-ESI-MS/MS screening method was developed for the detection and identification of natural antioxidants from radix et rhizoma Rhei. Nine compounds were found to possess a potential antioxidant activity, and their free radical-scavenging capacities were investigated in detail. The nine compounds were identified as 1-O-galloyl-2-O-cinnamoylglucose, 6 hydroxymusizin-8-O-beta-D-glucopyranoside, (+)-catechin, gallic acid 3-O-beta-D glucopyranoside, trans-3,5,4'-trihydroxystilbene- 4'-O-beta-D-(2"-O-galloyl) glucopyranoside, sennoside A, 4-(4'-hydroxyphenyl)-2- butanone-4'-O-beta-D-(2"-O galloyl-6"-O-p-coumaroyl) glucopyranoside, emodin-8-O-(6'-Omalonyl) glucopyranoside, and physcion-8-O-beta-D-glucopyranoside. The reactivity and SC(50) values of those compounds were investigated, respectively. 1-O-Galloyl-2-O cinnamoylglucose showed the strongest capability for scavenging 1,1-diphenyl-2 picrylhydrazylfree radical; trans-3,5,4'-trihydroxystilbene-4'-O-beta-D-(2"-O galloyl) glucopyranoside showed the strongest capability for scavenging superoxide radical; 4-(4'-hydroxyphenyl)-2-butanone- 4'-O-2-D-(2"-O-galloyl-6"-O p-coumaroyl) glucopyranoside exhibited the highest reactivity in the lipid peroxidation processes. The use of the analytical screening method based on ultra performance LC-photodiode array-el-ESI-MS/MS would provide a new way for rapid detection of radical-scavenging natural compounds from radix et rhizoma Rhei or complex matrices. PMID- 21268250 TI - Preparative separation of quaternary ammonium alkaloids from Corydalis yanhusuo W. T. Wang by pH-zone-refining counter-current chromatography. AB - The optimal extraction condition for extracting quaternary ammonium alkaloid dehydrocorydaline from Corydalis yanhusuo W. T. Wang was investigated using orthogonal experimental design. pH-zone-refining counter-current chromatography (CCC) with normal phase elution was successfully applied to preparative separation of alkaloids from the crude extract of Corydalis yanhusuo. The separation was performed with a biphasic solvent system composed of chloroform (CHCl(3))-methanol (MeOH)-water (2:1:1, v/v), in which the lower organic phase containing 10 mM of triethylamine was used as the mobile phase, while the upper aqueous phase containing 10 mM of hydrochloric acid was used as the stationary phase. The separation mechanism of quaternary ammonium alkaloids using pH-zone refining CCC was discussed in comparison with standard high-speed CCC. In the present study, the separation of 1.200 g of crude sample yielded 129 mg of dehydrocorydaline and 12 mg of palmatine at a high purity of 94 and 92%, respectively. Recovery for dehydrocorydaline and palmatine was 85 and 86%, respectively. PMID- 21268251 TI - Simultaneous quantification of diterpenoids in Premna integrifolia using a validated HPTLC method. AB - A sensitive, selective and robust densitometric high-performance thin layer chromatographic method was developed and validated for the determination of diterpenoids in the root bark of Premna integrifolia. Diterpenoids 1beta,3alpha,8beta-trihydroxy-pimara-15-ene (A), 6alpha,11,12,16-tetrahydroxy-7 oxo-abieta-8,11,13-triene (B) and 2alpha,19-dihydroxy-pimara-7,15-diene (C) were used as chemical markers for the standardization of P. integrifolia plant extracts. The separation was performed on silica gel 60F(254) high-performance thin layer chromatography plates using hexane/acetone/ethylacetate (60:20:20 v/v) as mobile phase. The quantitation of diterpenoids was carried out using densitometric reflection/absorption mode at 475 nm after post-chromatographic derivatization using vanillin-sulfuric acid reagent. A precise and accurate quantification can be performed for compounds A, B and C in the linear working concentration range of 1-10 MUg/spot with good correlations (r(2) =0.9985, 0.9996 and 0.9992, respectively). The method was validated for peak purity, precision, robustness, limit of detection (LOD) and quantitation (LOQ) etc., as per the International Conference on Harmonization (ICH) guidelines. Specificity of quantitation was confirmed using retention factor (R(f)) and spectra correlation of markers in standard and sample tracks. The method reported here is simple and reproducible which may be applied for quantitative analysis of above diterpenoids in the root bark of P. integrifolia. PMID- 21268252 TI - Quantification of flavonoid glycosides in an aqueous extract from the traditional Mongolian medicinal plant Dianthus versicolor FISCH. AB - An HPLC-diode array detection (DAD) method was established in order to investigate dried aerial parts of Dianthus versicolor FISCH. (Caryophyllaceae), a plant used in traditional Mongolian medicine against liver impairment. Aqueous extracts were separated on an Aquasil((r)) C(18) column with a linear gradient of acetonitrile (ACN) and water (adjusted to pH 2.8 with formic acid) as the mobile phase. LC-IT-MS facilitated the assignment of 26 flavonoids, among them a series of rare C-glycosylated as well as O-glycosylated derivatives, which are assumed to be the active principles. Quantification was performed and validated using isovitexin-7-O-glucoside (saponarin) as the external standard. The method showed good linear behaviour (r(2) >=0.9999) over the investigated concentration range (0.007-3.5 mg/mL). The good precision of the method allowed the successful qualitative and quantitative analysis of flavonoid-glycosides in the aqueous extracts prepared from five different D. versicolor samples. Depending on the origin of the samples, the total flavonoid content was found to vary considerably from 0.41 to 3.30% in the aqueous extracts and from 0.07 to 0.57% in the crude drug. In addition, the relative composition of the various flavonoids was found to differ strongly. These results highlight the need for proper quality control for this herbal drug. PMID- 21268253 TI - Purification of compounds from Lignum Dalbergia Odorifera using two-dimensional preparative chromatography with Click oligo (ethylene glycol) and C18 column. AB - Purification of compounds from traditional Chinese medicines (TCMs) is an important task for understanding the chemical composition of TCMs. However, it is difficult to obtain compounds with high enough purity for identification by NMR due to the complexity of TCMs in chemical composition. In this study, a two dimensional purification method based on a Click oligo (ethylene glycol) column and a C18 column was developed to realize an orthogonal separation in preparative level for purifying compounds efficiently. The first dimensional preparation was performed on a Click oligo (ethylene glycol) column to simplify the sample into the fractions with good separation repeatability. On the first dimension, 7.2 g sample was separated into 11 fractions with a recovery of 86% within 6 h. A C18 column was taken as the second dimension to realize the high-performance separation and rapid preparation from the fractions collected from the first dimension. Eight compounds in fraction 6 and 2 compounds in fraction 8 were isolated and identified after optimizing the separation and collection parameters. This method is a high-efficient and orthogonal preparation method to improve the separation of a complex sample and increase the purity of the compounds, which benefits from the application of novel materials in the preparation and purification. PMID- 21268254 TI - Qualitative and quantitative determination of nine main active constituents in Pulsatilla cernua by high-performance liquid chromatography coupled to electrospray ionization tandem mass spectrometry. AB - A novel qualitative and quantitative method using high-performance liquid chromatography coupled to electrospray ionization tandem mass spectrometry (HPLC ESI-MS/MS) was developed for simultaneous determination of the nine major active constituents in Pulsatilla cernua (Thunb.) Bercht. et Opiz., namely anemoside A3 (1), anemoside B4 (2), 23-hydroxybetulinic acid (3), cirenshenoside S (4), pulsatilloside B (5), pulsatilloside C (6), oleanolic acid (7), ajugasterone C (8) and beta-ecdysterone (9), respectively. A Sapphire C18 column (250 mm * 4.6 mm, 5 MUm) and gradient elution were used during the analysis. The identification and quantification of the analytes were achieved on a hybrid quadrupole linear ion trap mass spectrometer. Multiple-reaction monitoring (MRM) scanning was employed for quantification with switching electrospray ion source polarity between positive and negative modes in a single run. All calibration curves showed good linearity (r(2) > 0.9948) within the test ranges. The intra and interday variations for nine analytes were less than 3.95 and 3.78%, respectively. The developed method was successfully applied to determine the investigated compounds in 15 batches of natural and cultured samples of P. cernua. The results indicated that the method was simple, rapid, specific and reliable, which is helpful to comprehensive evaluation of quality of P. cernua. PMID- 21268255 TI - Construction of a thermodesorption injector for gas chromatography. AB - A detailed description for the do-it-yourself construction of a high-performance thermodesorption GC injector (HPTI) is presented. The injector consists of a heated desorption chamber, a cooled loop for focusing the desorbed volatiles as well as a heating control for sample injection into the separation column. The gas flow is controlled by valve switching during the steps of the operation. Two versions of the injector function either for the injection of highly volatile compounds or for compounds with extremely low volatility, e.g. lubricants. The sophisticated gas flow management allows injection of highly concentrated samples without memory effects in a sample gas split mode, while traces may be injected with virtually 1:1 sample transfer. A wide range of adsorbents appropriate for the compounds can be chosen due to homemade adsorbent tubes and the achievability of high desorption temperature. Solutions may be injected from a carrier material after solvent evaporation. The HPTI fulfills all multipurpose GC injector requirements and with the support of downloadable instruction files can be built by anyone working with conventional GC devices. PMID- 21268256 TI - Determination of cypromazine and its metabolite melamine in milk by cation selective exhaustive injection and sweeping-capillary micellar electrokinetic chromatography. AB - In this study, we described a high-sensitive on-line preconcentration method for cypromazine (CYP) and melamine (MEL) analysis using cation-selective exhaustive injection (CSEI) combined with sweeping-MEKC. The optimum conditions of on-line concentration and separation were discussed. The BGE contained 100 mM SDS, 50 mM phosphoric acid (pH=2.0) and 15% acetonitrile (v/v). The sample was injected at 10 kV for 600 s, separated at -20 kV, and detected at 210 nm. The sensitivity enhancements were 6222 for CYP and 9179 for MEL. The linear dynamic ranges were 0.4-25 ng/mL for CYP (r=0.9995) and 0.2-12 ng/mL for MEL (r=0.9991). The LODs (signal-to-noise ratio, 3) were 43.7 and 23.4 pg/mL for CYP and MEL, respectively. The proposed method was applied to analyze CYP and MEL in dairy products pretreated using off-line SPE to minimize the influence of the matrix. The recoveries of CYP and MEL were satisfactory (ca. 74-83%). The experimental results suggest that the CSEI-sweeping-MEKC method is feasible for the application to simultaneously detect trace levels of CYP and its metabolite MEL in real milk samples. PMID- 21268257 TI - Preparation of novel polydimethylsiloxane solid-phase microextraction film and its application in liquid sample pretreatment. AB - In this paper, an extraction approach based on the use of a novel polydimethylsiloxane (PDMS) film as the extraction medium was described. Two kinds of PDMS films with smooth surface and frosted surface were prepared and were practically evaluated for extraction. A model analytical problem, the determination of organochlorine pesticides in water samples, was selected for practical evaluation of the film extraction procedure by direct extraction and solvent desorption, followed by gas chromatography (GC) analysis with electron capture detection (ECD). The main variables affecting the extraction process such as the extraction time, the extraction temperature, the elution conditions, etc. were studied. The method was characterized on the basis of its linearity, precision, and limits of detection. The novel approach was sensitive and precise enough for the detection of the target analytes in the low nanogram per liter range using 5 mL of sample. In fact, limits of detection ranging from 0.77 to 10.25 ng/L were obtained. Compared with the solid-phase microextraction (SPME) fiber, the robust extraction film has a large extraction capacity, low cost of preparation. Besides, owing to the simplicity of the extraction procedures, in site sample preparation for environmental monitor may be realized. PMID- 21268258 TI - Sorbent coatings for solid-phase microextraction based on mixtures of polymeric ionic liquids. AB - Four polymeric ionic liquids based on two different cations, poly(1-vinyl-3 hexylimidazolium) and poly(1-vinyl-3-hexadecylimidazolium), combined with two different anions, bis[(trifluoromethyl)sulfonyl]imide (NTf 2-) and chloride (Cl( )), were combined in various weight percentages and used as sorbent coatings for solid-phase microextraction gas chromatography (SPME-GC). The selectivity of the fiber coatings for 12 test analytes was examined. The extraction efficiency of n alcohols increased with an increase in the weight percentage of chloride ion in the sorbent coating. The ability to tune the interactions between the coating material and the analytes was exploited and resulted in distinct changes in the limits of detection for hydrogen-bonding analytes with varying chloride ion content in the sorbent coating. PMID- 21268259 TI - Novel isolation of phytochemical compositions by phase transition extraction with acetonitrile. AB - Based on the phenomenon that hydrophilic acetonitrile can be separated from water by adding a hydrophobic solvent, a phase transition extraction (PTE) method for isolation of phytochemical compositions was developed. The isolation efficiency of the proposed method was assessed in complete grouping of the constituents in three important traditional Chinese medicine plants. Further study of the PTE for Scutellaria bacalensis Georgi found that the constituents in the organic phase are all flavonoid aglycones while the ones in the aqueous phase are all flavonoid glycosides, revealing the property of high structure selectivity for the proposed PTE process. The effect of using different modifiers on the isolation efficiency was investigated. The results obtained by using non-oxygenated hydrophobic solvents are perfect while those by inorganic salts are acceptable, but those by oxygenated hydrophobic solvents are bad. Subsequent GC analysis revealed that the solvent composition difference between the two separated phases among PTE processes using different types of modifier is responsible for the different isolation results obtained. Finally, the proposed method was proved to be insensitive to both the acetonitrile concentration and the added amount of modifier. PMID- 21268260 TI - Analysis of active components of rhinoceros, water buffalo and yak horns using two-dimensional electrophoresis and ethnopharmacological evaluation. AB - Cornu Rhinoceri Asiatici (rhinoceros horn, RH), Cornu Bubali (water buffalo horn, WBH), and Cornu Bovis grunniens (yak horn, YH) are traditional Chinese medicine (TCM), and have been used in China for thousands of years. In this study, ethnopharmacological experiments were used to evaluate and verify the traditional efficacies of horns. Area under curve (AUC) was used to quantify the pharmacological efficacy strength of three horns. Two-dimensional electrophoresis (2-DE) was used to analyze the protein components in horns, as a result, 14 common protein spots in rhinoceros horn, water buffalo horn, and yak horn electrophoresis gels were found by image analysis. Then linear regression analysis was used to establish the correlation between pharmacological efficacies and components in the horns, and five potential active components were selected from the 14 common protein spots. Finally, two protein spots from five were identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). In this study, a simple method to construct correlation between components and efficacy strength was explored by linear regression analysis, which could be applied to screen potential active components of animal horns. PMID- 21268261 TI - Novel approach to improve the detection of colchicine via online coupling of ionic liquid-based single-drop microextraction with capillary electrophoresis. AB - A novel approach based on ionic liquid-single-drop microextraction (IL-SDME) online coupling with capillary electrophoresis (CE) was used to determine a toxic alkaloid--colchicine. The IL-SDME procedure was optimized by extraction solvent, drop volume controlling, sample volume and pH, extraction time, and ionic strength. Under optimum conditions, enrichment factor was as much as 41-fold with a relative standard deviation of 2.8% (n = 3). Linear range of response was observed from 1 to 100 MUg/mL, with detection limit of 0.25 MUg/mL and correlation coefficient (R(2) ) of 0.9994. The extraction of colchicine from spiked Lanzhou lily sample was performed and obtaining good result with an average recovery rate of 102.4 and 98.8% at 5 and 50 MUg/mL, respectively. Comparing with the previous methods, IL-SDME-CE is really a convenient, economical, and environmentally benign way for determining colchicine. PMID- 21268264 TI - Quantitative protein expression and cell surface characteristics of Escherichia coli MG1655 biofilms. AB - Cell surface physicochemical characterization techniques were combined with quantitative changes in protein expression, to investigate the biological and biophysical changes of Escherichia coli MG1655 cells when grown as a biofilm (BIO). The overall surface charge of BIO cells was found to be less negative, highlighting the need for a lower electrophoretic mobility for attachment to occur. Comparison of the chemical functional groups on the cell surface showed similar profiles, with the absorbance intensity higher for proteins and carbohydrates in the BIO cells. Quantitative proteomic analysis demonstrated that 3 proteins were significantly increased, and 9 proteins significantly decreased in abundance, in cells grown as a BIO compared to their planktonic counterparts, with 7 of these total 12 proteins unique to this study. Proteins showing significant increased or decreased abundance include proteins involved in acid resistance, DNA protection and binding and ABC transporters. Further predictive analysis of the metabolic pathways showed an increased abundance of the amino acid metabolism and tricarboxylic acid (TCA) cycle, with a decrease in expression within the pentose phosphate and glycolysis pathways. It is therefore hypothesized that cells grown as a BIO are still energetically viable potentially using amino acids as an indirect carbon backbone source into the TCA cycle. PMID- 21268265 TI - Proteomic analysis of mesenchymal stem-like cells derived from ovarian teratoma: potential role of glutathione S-transferase M2 in ovarian teratoma. AB - Ovarian teratoma is a dermoid cyst in the ovary that contains mature tissues such as hair, teeth, bone, thyroid, etc. To understand the molecular mechanisms of ovarian teratoma growth, a comparative proteomic analysis was undertaken using mesenchymal stem cell-like cells (MSCLCs) isolated from normal human ovarian or teratoma tissues. Both normal ovarian and teratoma MSCLCs expressed stem cell markers OCT4 and NANOG, and were negatively staining with the senescence associated (SA) beta-galactosidase. Furthermore, teratoma MSCLCs had higher proliferation and colony formation rates, with more angiogenic property than that of normal MSCLCs. Proteomic study revealed that 17 proteins had the expression changes over eightfold in ovarian teratoma MSCLCs compared with normal control. Interestingly, among them, GSTM2 was strongly expressed in teratoma MSCLCs. Moreover, overexpressed GSTM2 in the teratoma was associated with downregulation of p38 MAPK and activation of AKT and survivin. Taken together, these findings suggest that that ovarian teratoma MSCLCs have a higher potency for proliferation and angiogenesis and GSTM2 appears to be involved in the regulation of other survival genes. PMID- 21268266 TI - Characterisation of proteins extracted from the surface of Salmonella Typhimurium grown under SPI-2-inducing conditions by LC-ESI/MS/MS sequencing. AB - Salmonella enterica has two pathogenicity islands encoding separate type three secretion systems (T3SS). Proteins secreted through these systems facilitate invasion and survival. After entry, Salmonella reside within a membrane bound vacuole, the Salmonella containing vacuole (SCV), where translocation of a second set of effectors by the Salmonella pathogenicity island 2 (SPI-2) T3SS is initiated. SPI-2 secretion in vitro can be induced by conditions that mimic the Salmonella containing vacuole. Utilising high-throughput mass spectrometry, we mapped the surface-attached proteome of S. Typhimurium SL1344 grown in vitro under SPI-2-inducing conditions and identified 108 proteins; using secretion signal prediction software, 43% of proteins identified contained a signal sequence. Of these proteins, 13 were known secreted effector proteins including SPI-2 effector proteins SseB, SseC, SseD, SseL, PipB2 and SteC, although surprisingly five were SPI-1 proteins, SipA, SipB, SipC, SipD and SopD, while 2 proteins SteA and SlrP are secreted by both T3SSs. This is the first in vitro study to demonstrate dual secretion of SPI-1 and SPI-2 proteins by S. Typhimurium and demonstrates the potential of high-throughput LC-ESI/MS/MS sequencing for the identification of novel proteins, providing a platform for subsequent comparative proteomic analysis, which should greatly assist understanding of the pathogenesis and inherent variation between serovars of Salmonella and ultimately help towards development of novel control strategies. PMID- 21268267 TI - Proteomic analysis of peripheral layers during wheat (Triticum aestivum L.) grain development. AB - Grains of hexaploid wheat, Triticum aestivum (cv. Recital), were collected at 15 stages of development, from anthesis to physiological maturity, 0-700 degrees C days (degree days after anthesis). Two hundred and seven proteins of grain peripheral layers (inner pericarp, hyaline, testa and aleurone layer) were identified by 2-DE, MALDI-TOF MS and data mining, then were classified in 16 different functional categories. Study of the protein expression over time allowed identification of five main profiles and four distinct phases of development. Composite expression curves indicated that there was a shift from metabolic processes, translation, transcription and ATP interconversion towards storage and defence processes. Protein synthesis, protein turnover, signal transduction, membrane transport and biosynthesis of secondary metabolites were the mediating functions of this shift. A picture of the dynamic processes taking place in peripheral layers during grain development was obtained in this study. It should further help in the construction of proteome reference maps for the developing peripheral layers. PMID- 21268268 TI - Rab23 plays a role in the pathophysiology of mesangial cells--a proteomic analysis. AB - Rab23, a novel member of the Rab family of small GTPases, has recently been identified in mesangial cells (MCs). Although Rab23 levels in MCs are associated with glomerular nephropathies, the exact physiological and pathological roles of Rab23 in MCs are unknown. In the present study, its roles in MCs were explored by performing proteomics and systems biology analyses in MCs after knockdown or overexpression of Rab23. Knockdown of Rab23 was achieved by transfecting MCs with a plasmid expressing short hairpin RNA against Rab23, while overexpression of Rab23 was accomplished by transfection with the wild-type, dominant negative, and constitutively active Rab23 gene constructs. The effects of different levels of Rab23 activity on proteome of various biological pathways were investigated. Gel based proteomic approaches and systems biology tools, respectively, were used to identify the Rab23-regulated proteins and the functional pathways. Proteomic analysis revealed the potential roles for Rab23 in multiple processes, including G-protein signal transduction, transcription modulation, RNA stabilization, protein synthesis and degradation, cytoskeleton reorganization, anti-oxidation and detoxification, circadian rhythm regulation and phagocytosis. Bioinformatics analyses showed that Rab23 impacts on multiple biological networks in MCs. These data may shed light on the roles of Rab23 in mesangiopathy or MC damage. PMID- 21268270 TI - Comparative proteomic profiles of the marine cyanobacterium Trichodesmium erythraeum IMS101 under different nitrogen regimes. AB - Trichodesmium is a marine filamentous diazotrophic cyanobacterium and an important contributor of "new" nitrogen in the oligotrophic surface waters of the tropical and sub-tropical oceans. It is unique in that it exclusively fixes N(2) at daytime, although it belongs to the non-heterocystous filamentous segment of the cyanobacterial radiation. Here we present the first quantitative proteomic analysis of Trichodesmium erythraeum IMS101 when grown under different nitrogen regimes using 2-DE/MALDI-TOF-MS. Addition of combined nitrogen (NO3-) prevented development of the morphological characteristics of the N(2)-fixing cell type (diazocytes), inhibited expression of the nitrogenase enzyme subunits and consequently N(2) fixation activity. The diazotrophic regime (N(2) versus NO3- cultures) elicited the differential expression of more than 100 proteins, which represented 13.5% of the separated proteins. Besides proteins directly related to N(2) fixation, proteins involved in the synthesis of reducing equivalents and the generation of a micro-oxic environment were strongly up-regulated, as was in particular Dps, a protein related to iron acquisition and potentially other vital cellular processes. In contrast, proteins involved in the S-adenosylmethionine (SAM) cycle, synthesis of amino acids and production of carbon skeletons for storage and synthesis of amino acids were suppressed. The data are discussed in the context of Trichodesmium's unusual N(2)-fixing physiology. PMID- 21268269 TI - Resurrection of a clinical antibody: template proteogenomic de novo proteomic sequencing and reverse engineering of an anti-lymphotoxin-alpha antibody. AB - A mouse hybridoma antibody directed against a member of the tumour necrosis factor (TNF)-superfamily, lymphotoxin-alpha (LT-alpha), was isolated from stored mouse ascites and purified to homogeneity. After more than a decade of storage the genetic material was not available for cloning; however, biochemical assays with the ascites showed this antibody against LT-alpha (LT-3F12) to be a preclinical candidate for the treatment of several inflammatory pathologies. We have successfully rescued the LT-3F12 antibody by performing MS analysis, primary amino acid sequence determination by template proteogenomics, and synthesis of the corresponding recombinant DNA by reverse engineering. The resurrected antibody was expressed, purified and shown to demonstrate the desired specificity and binding properties in a panel of immuno-biochemical tests. The work described herein demonstrates the powerful combination of high-throughput informatic proteomic de novo sequencing with reverse engineering to reestablish monoclonal antibody-expressing cells from archived protein sample, exemplifying the development of novel therapeutics from cryptic protein sources. PMID- 21268271 TI - Mapping the glycoxidation product Nepsilon-carboxymethyllysine in the milk proteome. AB - Milk processing leads to severe protein damage caused by the formation of nonenzymatic posttranslational modifications (nePTMs), such as glycation and glycoxidation. As a result, the technological and nutritional function of milk proteins can be critically altered. The present study investigated the protein specific distribution of the glycoxidation product N(epsilon) carboxymethyllysine (CML) in the proteome of processed milk. For this purpose, raw milk and heated milk were separated by 1-D or 2-DE. The distribution of CML in the milk proteome was examined by immunoblotting. The changes in the protein composition that occurred during heating were monitored by Coomassie staining. Relative modification rates were measured for the major milk protein fractions after 30 and 60 min of heating at 120 degrees C and normalized to the content of the respective protein fraction in the samples. The highest glycoxidation rates were detected in the high molecular weight aggregates that are generated during heating. The casein fraction and the whey protein beta-lactoglobulin were affected in a similar manner. The relevance of the results for industrial milk processing was confirmed by analyzing several commercial milk products accordingly. The presented approach allows nonenzymatic posttranslational modification mapping of the entire milk proteome. PMID- 21268272 TI - Subcellular proteomics revealed the epithelial-mesenchymal transition phenotype in lung cancer. AB - Subcellular proteomics was used to compare the protein profiles between human lung adenocarcinoma A549 cells and human bronchial epithelial (HBE) cells. In total, 106 differential proteins were identified and the altered expression levels of partial identified proteins were confirmed by Western blot analysis. Importantly, pathway analysis and biological validation revealed epithelial mesenchymal transition (EMT) phenotype shift in A549 cells as compared with HBE cells. The EMT phenotype of A549 cells can be increased by self-producing TGF beta1 and significantly decreased by silencing heterogeneous nuclear ribonucleoprotein (hnRNPK) expression. As EMT has been considered as an important event during malignant tumor progression and metastasis, investigating EMT and deciphering the related pathways may lead to more efficient strategies to fight lung cancer progression. By integrating the subcellular proteomic data with EMT related functional studies, we revealed new insights into the EMT progress of lung carcinogenesis, providing clues for further investigations on the discovery of potential therapeutic targets. PMID- 21268273 TI - Gel-based and gel-free proteomic analysis of Nicotiana tabacum trichomes identifies proteins involved in secondary metabolism and in the (a)biotic stress response. AB - Nicotiana tabacum leaves are covered by trichomes involved in the secretion of large amounts of secondary metabolites, some of which play a major role in plant defense. However, little is known about the metabolic pathways that operate in these structures. We undertook a proteomic analysis of N. tabacum trichomes in order to identify their protein complement. Efficient trichome isolation was obtained by abrading frozen leaves. After homogenization, soluble proteins and a microsomal fraction were prepared by centrifugation. Gel-based and gel-free proteomic analyses were then performed. 2-DE analysis of soluble proteins led to the identification of 1373 protein spots, which were digested and analyzed by MS/MS, leading to 680 unique identifications. Both soluble proteins and microsomal fraction were analyzed by LC MALDI-MS/MS after trypsin digestion, leading to 858 identifications, many of which had not been identified after 2-DE, indicating that the two methods complement each other. Many enzymes putatively involved in secondary metabolism were identified, including enzymes involved in the synthesis of terpenoid precursors and in acyl sugar production. Several transporters were also identified, some of which might be involved in secondary metabolite transport. Various (a)biotic stress response proteins were also detected, supporting the role of trichomes in plant defense. PMID- 21268274 TI - Shotgun proteomic analysis for detecting differentially expressed proteins in the reduced culm number rice. AB - To survey protein expression patterns in the reduced culm number (RCN) rice, a comparative shotgun proteomic analysis was conducted. For large-scale protein identification, multidimensional protein identification technology (MudPIT) coupled with pre-fractionation of plant shoot proteins led to the identification of 3004 non-redundant rice proteins. By statistically comparing relative amounts of 1353 reproducibly identified proteins between the RCN rice and the wild-type rice, 44 differentially expressed proteins were detected, where 42 proteins were increased and 2 proteins were decreased in the RCN rice. These proteins appear to have roles in glycolysis, trichloroacetic acid cycle, secondary metabolism, nutrient recycling, and nucleotide metabolism and repair. Consequently, we hypothesized that the RCN rice might fail to maintain sugar nutrient homeostasis. This was confirmed with the observation that the sucrose concentration was increased significantly in the RCN rice compared with the wild-type rice. Also, the RCN rice showed a hypersensitive response to exogenous sucrose treatment. PMID- 21268275 TI - Comprehensive proteomic and transcriptomic characterization of hepatic expression signatures affected in p14 liver conditional knockout mice. AB - Scaffold proteins regulate intracellular MAP kinase signaling by providing critical spatial and temporal specificities. We have shown previously that the scaffold protein MEK1 partner (MP1) is localized to late endosomes by the adaptor protein p14. Using conditional gene disruption of p14 in livers of mice (p14(Deltahep) ) we analyzed protein and transcript signatures in tissue samples. Further biological network analysis predicted that the differentially expressed transcripts and proteins are involved in cell cycle progression and regulation of cellular proliferation. Although some of the here identified signatures were previously linked to phospho-ERK activity, most of them were novel targets of the late endosomal p14/MP1/MEK/ERK signaling module. Finally, the proliferation defect was confirmed in a chemically induced liver regeneration model in p14(Deltahep) knockout mice. PMID- 21268276 TI - Determination of in-gel protein concentration by a ninhydrin-based method. AB - Until now quantification of proteins in gel-based methods relies on the amount of protein loaded onto the gel. This does not, however, represent the amount of proteins in the gel and therefore determination of proteins within the gel is mandatory. A method to quantify proteins, both hydrophilic and hydrophobic, using in-gel digestion with proteases, subsequent acid hydrolysis and the use of the ninhydrin reaction is herein presented. PMID- 21268277 TI - Accurate mass comparison coupled with two endopeptidases enables identification of protein termini. AB - Protein termini play important roles in biological processes, but there have been few methods for comprehensive terminal proteomics. We have developed a new method that can identify both the amino and the carboxyl termini of proteins. The method independently uses two proteases, (lysyl endopeptidase) Lys-C and peptidyl-Lys metalloendopeptidase (Lys-N), to digest proteins, followed by LC-MS/MS analysis of the two digests. Terminal peptides can be identified by comparing the peptide masses in the two digests as follows: (i) the amino terminal peptide of a protein in Lys-C digest is one lysine residue mass heavier than that in Lys-N digest; (ii) the carboxyl terminal peptide in Lys-N digest is one lysine residue mass heavier than that in Lys-C digest; and (iii) all internal peptides give exactly the same molecular masses in both the Lys-C and the Lys-N digest, although amino acid sequences of Lys-C and Lys-N peptides are different (Lys-C peptides end with lysine, whereas Lys-N peptides begin with lysine). The identification of terminal peptides was further verified by examining their MS/MS spectra to avoid misidentifying pairs as termini. In this study, we investigated the usefulness of this method using several protein and peptide mixtures. Known protein termini were successfully identified. Acetylation on N-terminus and protein isoforms, which have different termini, was also determined. These results demonstrate that our new method can confidently identify terminal peptides in protein mixtures. PMID- 21268278 TI - One-source peptide/phosphopeptide standards for accurate phosphorylation degree determination. AB - Reversible protein phosphorylation is a key mediator for intracellular signal transduction. Here we report an innovative method for accurate, site-specific protein phosphorylation degree determination by nanoLC-ESI-MS/MS. A stable isotope-labeled pair of peptide/phosphopeptide standards with volumetrically defined molar ratio is used as reference, providing an internal standard for both the analyte peptide and the phosphopeptide. For the preparation of one-source peptide/phosphopeptide standards, an aliquot of the labeled phosphopeptide standard is quantitatively dephosphorylated, yielding an equimolar solution of the peptide standard. Subsequently, the two solutions are mixed at a 1:1 or other volumetric ratio, which equals the molar ratio. This procedure assures a defined concentration ratio of both components that is independent from their absolute concentration. We demonstrate the applicability of the one-source peptide/phosphopeptide standard method by determining the phosphorylation degree of the signalling proteins STAT5A/B and STAT6. PMID- 21268279 TI - Analysis of the human pituitary proteome by data independent label-free liquid chromatography tandem mass spectrometry. AB - Studies of pituitary-related disorders would be facilitated by enhanced knowledge of the pituitary proteome. To construct a data set of human pituitary proteins, separate protein extracts were prepared from 15 post-mortem pituitaries and analyzed by data independent label-free nanoflow liquid chromatography mass spectrometry (nLC-MS(E) ). The detected mass/time features were aligned and quantified using the Rosetta Elucidator((r)) system and annotated using results from ProteinLynx Global Server. The resulting data set comprised 1007 unique proteins, with stringent identification by a minimum of two distinct peptides. These proteins consisted predominantly of enzymes, transporters, transcription/translation factors, cell structure and secreted proteins. PMID- 21268280 TI - Comprehensive two-dimensional liquid chromatography mass spectrometric profiling of the rat hippocampal proteome. AB - In this study, we performed the first high-throughput and comprehensive proteomic profiling of the rat hippocampal proteome. Using a combination of 2-D LC-MS and data analysis with the Rosetta Elucidator((r)) system, we identified 1340 unique proteins. Functional classification showed that most of these were associated with synaptic function and comprised a high proportion of phosphorylated proteins and analytically challenging classes of membrane proteins such as ion channel receptor subunits. PMID- 21268281 TI - Staphylococcus aureus phenotype switching: an effective bacterial strategy to escape host immune response and establish a chronic infection. AB - Staphylococcus aureus is a frequent cause for serious, chronic and therapy refractive infections in spite of susceptibility to antibiotics in vitro. In chronic infections, altered bacterial phenotypes, such as small colony variants (SCVs), have been found. Yet, it is largely unclear whether the ability to interconvert from the wild-type to the SCV phenotype is only a rare clinical and/or just laboratory phenomenon or is essential to sustain an infection. Here, we performed different long-term in vitro and in vivo infection models with S. aureus and we show that viable bacteria can persist within host cells and/or tissues for several weeks. Persistence induced bacterial phenotypic diversity, including SCV phenotypes, accompanied by changes in virulence factor expression and auxotrophism. However, the recovered SCV phenotypes were highly dynamic and rapidly reverted to the fully virulent wild-type form when leaving the intracellular location and infecting new cells. Our findings demonstrate that bacterial phenotype switching is an integral part of the infection process that enables the bacteria to hide inside host cells, which can be a reservoir for chronic and therapy-refractive infections. PMID- 21268282 TI - Travels with ubiquitin: from protein degradation to DNA repair. PMID- 21268283 TI - Excellence in biomedical research: ubiquitin family proteins and grid cells. PMID- 21268284 TI - Crystals of the brain. PMID- 21268285 TI - Zinc-finger-based transcriptional repression of rhodopsin in a model of dominant retinitis pigmentosa. AB - Despite the recent success of gene-based complementation approaches for genetic recessive traits, the development of therapeutic strategies for gain-of-function mutations poses great challenges. General therapeutic principles to correct these genetic defects mostly rely on post-transcriptional gene regulation (RNA silencing). Engineered zinc-finger (ZF) protein-based repression of transcription may represent a novel approach for treating gain-of-function mutations, although proof-of-concept of this use is still lacking. Here, we generated a series of transcriptional repressors to silence human rhodopsin (hRHO), the gene most abundantly expressed in retinal photoreceptors. The strategy was designed to suppress both the mutated and the wild-type hRHO allele in a mutational independent fashion, to overcome mutational heterogeneity of autosomal dominant retinitis pigmentosa due to hRHO mutations. Here we demonstrate that ZF proteins promote a robust transcriptional repression of hRHO in a transgenic mouse model of autosomal dominant retinitis pigmentosa. Furthermore, we show that specifically decreasing the mutated human RHO transcript in conjunction with unaltered expression of the endogenous murine Rho gene results in amelioration of disease progression, as demonstrated by significant improvements in retinal morphology and function. This zinc-finger-based mutation-independent approach paves the way towards a 'repression-replacement' strategy, which is expected to facilitate widespread applications in the development of novel therapeutics for a variety of disorders that are due to gain-of-function mutations. PMID- 21268286 TI - A loss-of-function variant of the antiviral molecule MAVS is associated with a subset of systemic lupus patients. AB - Dysregulation of the antiviral immune response may contribute to autoimmune diseases. Here, we hypothesized that altered expression or function of MAVS, a key molecule downstream of the viral sensors RIG-I and MDA-5, may impair antiviral cell signalling and thereby influence the risk for systemic lupus erythematosus (SLE), the prototype autoimmune disease. We used molecular techniques to screen non-synonymous single nucleotide polymorphisms (SNPs) in the MAVS gene for functional significance in human cell lines and identified one critical loss-of-function variant (C79F, rs11905552). This SNP substantially reduced expression of type I interferon (IFN) and other proinflammatory mediators and was found almost exclusively in the African-American population. Importantly, in African-American SLE patients, the C79F allele was associated with low type I IFN production and absence of anti-RNA-binding protein autoantibodies. These serologic associations were not related to a distinct, functionally neutral, MAVS SNP Q198K. Hence, this is the first demonstration that an uncommon genetic variant in the MAVS gene has a functional impact upon the anti-viral IFN pathway in vivo in humans and is associated with a novel sub-phenotype in SLE. This study demonstrates the utility of functional data in selecting rare variants for genetic association studies, allowing for fewer comparisons requiring statistical correction and for alternate lines of evidence implicating the particular variant in disease. PMID- 21268287 TI - Rational design, synthesis and pharmacological evaluation of the (2R)- and (2S) stereoisomers of 3-(2-carboxypyrrolidinyl)-2-methyl acetic acid as ligands for the ionotropic glutamate receptors. AB - In this paper we describe the rational design, synthesis and pharmacological evaluation of two new stereoisomeric (S)-glutamate (Glu) analogues. The rational design was based on hybrid structures of the natural product kainic acid, a synthetic analogue CPAA and the high-affinity Glu analogue SYM2081. Pharmacological evaluation of the two stereoisomers revealed that one stereoisomer showed a subtype selectivity profile with low micromolar affinity for GluK1 and GluK3 and a 10- to 15-fold lower affinity for GluK2. The other stereoisomer displayed full selectivity for the KA over AMPA and NMDA receptors (GluK1-3: 0.39, 0.51 and 0.099 uM, respectively). PMID- 21268288 TI - A novel method for the isolation of subpopulations of rat adipose stem cells with different proliferation and osteogenic differentiation potentials. AB - Bone marrow has been the elected cell source of studies published so far concerning bone and cartilage tissue-engineering approaches. Recent studies indicate that adipose tissue presents significant advantages over bone marrow as a cell source for tissue engineering. Most of these studies report the use of adipose stem cells (ASCs) isolated by a method based on the enzymatic digestion of the adipose tissue and on the ability of stem cells to adhere to a cell culture plastic surface. Using this method, a heterogeneous population was obtained containing different cell types that have been shown to compromise the proliferation and differentiation potential of the stem cells. This paper reports the development and optimization of a new isolation method that enables purified cell populations to be obtained that exhibit higher osteogenic differentiation and/or proliferation potential. This method is based on the use of immunomagnetic beads coated with specific antibodies and it is compared with other methods described in the literature for the selection of stem cell populations, e.g. methods based on a gradient solution and enzymatic digestion. The results showed that the isolation method based on immunomagnetic beads allows distinct subpopulations of rat ASCs to be isolated, showing different stem cells marker expressions and different osteogenic differentiation potentials. Therefore, this method can be used to study niches in ASC populations and/or also allow adipose tissue to be used as a stem cell source in a more efficient manner, increasing the potential of this cell source in future clinical applications. PMID- 21268290 TI - An orthodontic success story. PMID- 21268289 TI - Modifying behavioral phenotypes in Fmr1KO mice: genetic background differences reveal autistic-like responses. AB - Fragile X syndrome (FXS) is the most common inherited form of intellectual disability in humans. In addition to cognitive impairment, patients may exhibit hyperactivity, attention deficits, social difficulties and anxiety, and autistic like behaviors. The degree to which patients display these behaviors varies considerably and is influenced by family history, suggesting that genetic modifiers play a role in the expression of behaviors in FXS. Several studies have examined behavior in a mouse model of FXS in which the Fmr1 gene has been ablated. Most of those studies were done in Fmr1 knockout mice on a pure C57BL/6 or FVB strain background. To gain a better understanding of the effects of genetic background on behaviors resulting from the loss of Fmr1 gene expression, we generated F1 hybrid lines from female Fmr1 heterozygous mice on a pure C57BL/6J background bred with male Fmr1 wild-type (WT) mice of various background strains (A/J, DBA/2J, FVB/NJ, 129S1/SvImJ and CD-1). Male Fmr1 knockout and WT littermates from each line were examined in an extensive behavioral test battery. Results clearly indicate that multiple behavioral responses are dependent on genetic background, including autistic-like traits that are present on limited genetic backgrounds. This approach has allowed us to identify improved models for different behavioral symptoms present in FXS including autistic-like traits. PMID- 21268291 TI - [Task-orientated therapy (target-therapy) directed to patients with renal cell carcinoma]. AB - Two main ways playing a cardinal role in the pathogenesis of metastatic renal cell carcinoma (mRCC) have been identified in recent years, they are following: 1) a way of the mutation of a gene suppressor VHL (Van-Hippel-Lindau), stimulating various types of tyrosine-kinases participating in the development of tumors; 2) mTOR way, where ramapycyn plays a leading role, which effect proliferation and angiogenesis of mRCC. This discovery enabled the development of a new generation of highly effective medications for target-therapy of mRCCC- tyrosine-kinases inhibitors (VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-alpha/PDGFR-beta, Raf-kinases, etc.) sunitimab, sorafenib, pazopanib, axitinib, etc. and mTOR inhibitors--everolimus and temsirolimus as well as monoclonal neutralising antibody VEGF (bevasizumab). The review is devoted to the analysis of antitumor activity, patient tolerance and side effect of these preparations in the system therapy of patients with mRCC. PMID- 21268292 TI - [Influence of low doses of ionizing irradiation on parameters of the non-specific immunologically-mediated resistance in persons working in the oil industry]. AB - The authors have determined blood parameters reflected condition of the non specific immunologically-mediated resistance (NIR) in workers of the oil industry, including persons directly participated in oil wells exploration and exposed for long period of time to low doses of ionizing radiation. The article presents obtained results of the percentage of neutrophils and natural killer cells as well as the level of alpha-interferon in the blood serum. Obtained results demonstrated that parameters of NIR of oil industry workers were not substantively different from analogous parameters of healthy person living in the same region. PMID- 21268293 TI - [Some clinical-pathogenetical characteristics of arrhythmias in patients with myocardial infarction and diabetes mellitus type 2]. AB - In spite of considerable success in the study of basic pathogenetic mechanisms of arrhythmias development in patients without diabetes mellitus 2 type (DM), the problem of impact of DM on disorders of the cardiac rhythm of patients with acute myocardial infarction is still not resolved. Disorders of the cardiac rhythm have been analyzed in all groups of patients. So, the first group of patients, for certain, had more patients with fibrillation and palpitation of auricles, i.e. hypoglycemia more frequent induced the development of supra ventricular disorders of cardiac rhythm. Fibrillation of auricles, for certain, was more frequently observed in the group of patients with Hba1c less than 7 mkmol/l (P < 0,001). Single VE (ventricular extra systoles) and SVE (supra ventricular extra systoles) prevailed in the 2nd group. Patients with Hba1c more than 9 mkmol/l and hyperglycemia episodes prevailed with ventricular disorders, namely ventricular extra systoles of high degree. Thus, hypoglycemia provokes the development of supra ventricular disorders of the cardiac rhythm in a greater degree, while hyperglycemia results in the development of ventricular disorders of the cardiac rhythm. PMID- 21268295 TI - Liver transplantation: Donation after cardiac death: risk factors identified. PMID- 21268294 TI - [Combination of antioxidants and a hepatoprotector in the treatment of patients with diabetic distal symmetric polyneuropathy]. AB - The complex open randomized clinical, instrumental and biochemical research with including 89 patients with type 2 diabetes mellitus (DM), complicated with distal symmetric polyneuropathy (DDSP) has been conducted. It is proved that the antioxidant "cocktail" application (Dialipon, Byocerulin, hepatoprotector with the antioxidant action Glutargin) contributes to the improvement of different levels of antioxidant defence, reduces free radical processes intensification, improves hepatocyte state which dysfunction is one of leading links of DDSP pathogenesis. These improves indirectly and directly the peripheral nerves functional state according electroneuromyography results, prevents DDSP progression and development of diabetic foot syndrome. Taking into account negative influence of Dialipon on the clinical parameters of DDSP with parallel intensification of free radical processes at decompensated DM in the early terms of treatment, Dialipon use is recommended after normalization of glycemia. At the same time the positive influence of Byocerulin has been noted regardless the compensation state of diabetes. PMID- 21268296 TI - Endoscopy: Safety and efficacy of colorectal endoscopic submucosal dissection. PMID- 21268297 TI - Functional gastrointestinal disorders: Link discovered between cow's-milk allergy and functional gastrointestinal disorders in children. PMID- 21268298 TI - Hepatitis: Cryoblobulinemia-a useful predictor of treatment response in patients with chronic HCV infection? PMID- 21268299 TI - Bernard Kouchner--founder of doctors without borders. PMID- 21268300 TI - Correlation between MR imaging and discography with provocative concordant pain in patients with low back pain. AB - OBJECTIVE: this study aimed to correlate magnetic resonance (MR) findings and discography with pain response at provocative discography in patients with low back pain. METHODS: ninety-three patients who underwent MR imaging of the lumbar spine and subsequent provocation discography as part of a clinical evaluation of low back pain were enrolled in the study. MR images were then evaluated for disc degeneration, high-intensity zone (HIZ), and endplate abnormalities. In the procedure of discography, concordant pain was denoted as positive, whereas discordant pain and no pain were denoted as negative. Finally, MR and discographic findings were analyzed by w2 test based on results of concordant pain. RESULTS: discography was conducted on 256 discs successfully, 116 discs of which presented with concordant pain, and the others presented with discordant pain. There were 141 discs we reevaluated as Grade I-III on MR images, 17 of which presented with concordant pain; 115 were evaluated as Grade IV-V, 99 of which presented with concordant pain. HIZ was found in 60 discs,52 of which had concordant pain. The endplate abnormalities we reobserved in 58 discs, 51 of which manifested concordant pain. Concordant pain was significant correlated with Type IV-V discs on discography (w2=144.08, r=0.60, P<0.01), Grade IV-V disc degeneration on MR image (w2=137.11, r=0.59, P<0.01), the presence of HIZ (w2=51.93, r=0.41, P<0.01), and endplate abnormalities (w2=52.76, r=0.41, P<0.01). DISCUSSION: disc degeneration grades on MR imaging showedan association with discographic grades. Type IV-V discs on discography, Grade IV-V disc on MR images, the presence of HIZ,and endplate abnormalities might indicate discogenic pain inpatients with chronic low back pain. PMID- 21268301 TI - Persistent pain outcomes and patient satisfaction with pain management after burn injury. AB - OBJECTIVES: acute burn pain management has advanced significantly, yet little is known about long-term pain outcomes after severe burn injury. Even less is known about patient satisfaction with pain management after burn injury. This study examined the long-term pain and psychological outcomes of burn survivors who were treated at the Burns Service of Western Australia between 1994 and 2005. METHODS: of 2114 burn survivors who were mailed standardized self-report measures of pain, depressive, and posttraumatic stress symptoms, 492 returned completed questionnaires. Of these, 18%reported persistent burn-related pain, and 27% and 14% reported clinically significant depressive and posttraumatic stress symptoms, respectively. Those with persistent pain reported significantly more severe depressive and posttraumatic stress symptoms compared with those with no pain. Interestingly, respondents with persistent burn-related pain recalled significantly higher levels of procedural and dressing change acute pain than those without pain symptoms. Linear multiple regression analyses revealed that the extent to which pain treatment expectations were met predicted overall satisfaction with pain treatment, beyond the effects of perceived pain improvement, current burn pain intensity, depression and posttraumatic stress symptoms, age, sex, and total burn surface area. DISCUSSION: collectively, these findings suggest a significant proportion of severely injured burn survivors continue to experience persistent pain and point to the need to identify and treat persistent pain more effectively. Moreover, assessing and managing pain treatment expectations during the early phase of recovery postburn may yield improved levels of patient satisfaction with treatment received PMID- 21268302 TI - Increased capsaicin-induced secondary hyperalgesia in patients with multiple chemical sensitivity. AB - OBJECTIVE: the underlying cause of pathophysiological mechanisms triggering multiple chemical sensitivity (MCS) remains disputed.Recently, alterations in the central nervous system, for example,central sensitization, similar to various chronic pain disorders, have been suggested. Capsaicin is used in experimental pain models to provoke peripheral and central sensitization. In patients with symptoms elicited by odorous chemicals capsaicin-induced secondary hyperalgesia and temporal summation were assessed as markers for abnormal central nociceptive processing together with neurogenic inflammation (flare). METHODS: sixteen patients fulfilling Cullen criteria for MCS and 15 eczema patients with airway symptoms induced by odorous chemicals (EC) were compared with 29 age-matched healthy controls.Participants underwent 2 intradermal injection of capsaicin (3.3 mM and 33 mM). Measurements included pain intensity, flare, pinprick hyperalgesia, temporal summation, and McGill Pain Questionnaire score. RESULTS: no difference was found in the flare area between the groups. The capsaicin evoked pain intensity was higher in MCS patients compared with controls (P<0.01, 33 mM). The area of secondary hyperalgesia was larger in both the patient groups compared with controls (P<0.05) at both capsaicin concentrations. Temporal summation was increased in MCS patients compared with controls(P<0.01). Further, in patients with comorbidity of fibromyalgia, pain and chronic fatigue, pain continued after end stimulation, and the stimulus response function was enhanced compared with patients without comorbidity, and significant to controls (P<0.05). CONCLUSION: this is the first study to show facilitated pain processing in MCS and EC patients with the most abnormal responses in MCS. PMID- 21268303 TI - Dermatomal skin rash after lumbar epidural steroid injection. AB - OBJECTIVES: the objective of this case is to report an occurrence of a skin rash in a dermatomal distribution subsequent to a lumbar transforaminal epidural steroid injection. METHODS: in this clinical report, a 54-year old woman performed a left L5 transforaminal epidural steroid injection to manage left thigh and foot pain and tingling. She developed a rash in left L5 dermatomal distribution following injection. RESULTS AND DISCUSSION: this is the first described case of a focal dermatomal rash occurring following lumbar transforaminal epidural steroid injection and we wish to remind pain practitioner's of the possibility of anaphylactic events. PMID- 21268304 TI - Re: "Muscle prolapse after harvesting autogenous fascia lata used for frontalis suspension in children". PMID- 21268305 TI - Re: "Sinus opacification associated with exacerbation of thyroid eye disease". PMID- 21268306 TI - Re: "Utilization patterns for diagnostic imaging in the evaluation of epiphora due to lacrimal obstruction: a national survey". PMID- 21268307 TI - Temporary ex vivo posterior tibial artery bypass for iliofemoral artery injury. AB - BACKGROUND: The objective of this study is to report a temporary, ex vivo, distal extremity revascularization technique providing distal perfusion and allowing for a staged repair of complex iliofemoral injury. In addition, the objective of this report is to provide outcome data after this novel procedure including mortality, limb salvage, and quality of limb assessment. METHODS: From February 1993 to December 2005, temporary ex vivo posterior tibial artery revascularization from the uninjured (donor) to the injured extremity was performed in 14 patients. All patients had blunt iliofemoral artery injury with class III or IV hemorrhagic shock. An end-to-end anastomosis between the two posterior tibial arteries was performed. Muscle strength of both legs was measured using the Medical Research Council scale and grade 5 means normal strength. RESULTS: The mean age at surgery was 35 years+/-7.4 years (mean+/-SD). All patients with ipsilateral legs survived. Patency of the bypass was achieved in all cases. At a mean time of 30 days+/-10 days after injury, the injured iliofemoral artery was reconstructed, and the bypass was transected 7 days later. At the final follow-up, the muscle strength of both legs was of grade 5 based on Medical Research Council scale. Static two-point discrimination test scores were similar on both feet. CONCLUSIONS: Temporary ex vivo revascularization of the posterior tibial artery is a feasible option in selecting patients with blunt iliofemoral artery injury with ischemia and severe physiologic derangements. This unconventional method provides extremity perfusion distal to the injury and maintains neuromuscular viability during an interval period, allowing for a staged, proximal revascularization after improvement in the patient's physiologic condition. PMID- 21268308 TI - Denervation dynamically regulates integrin alpha7 signaling pathways and microscopic structures in rats. AB - BACKGROUND: Peripheral nerve injury causes serious problems in orthopedic and plastic surgeries. Cell adhesion molecules such as integrin alpha7 provoke cell binding and signaling pathways within myofibers. Expression profiles of integrin alpha7 signaling pathways and the molecule's microscopic structure were assessed to investigate the long-term dynamic changes in denervated rat skeletal muscle. METHODS: A denervated rat skeletal muscle model was established by severing the sciatic nerve for 1 week, 2 weeks, 4 weeks, 8 weeks, 12 weeks, 20 weeks, and 26 weeks. Molecular expressions were investigated by mRNA and Western blot. The structural alterations were detected by immunohistochemistry, scanning electron microscopy, and transmission electron microscopy. RESULTS: The denervated muscle atrophy presented the following dynamic molecular alterations: an initial increase around postdenervation in week (PIW) 8 and then a subsequent decay of integrin alpha7, integrin downstream signaling pathway (Ras or Raf or, ERK1/2), Akt, cleaved caspase-3, fast myosin heavy chain (MHC), beta actin, and RhoA. We demonstrated that the expressions of multiple signaling molecules were highly upregulated at PIW 8 (p<0.01). Scanning electron microscopy findings of the surface textures of myofibers showed more severe damage at PIW 8 and subsequently became smoother. Inner structures of myofibers separated with discontinuity on transmission electron microscopy examinations. CONCLUSION: Our novel finding showed that time-series alterations of integrin alpha7 signaling molecules and surface microstructures in the long-term denervated rat skeletal muscle are biphasic and coherently dynamic. Persisted p-Akt elevation suggested that denervated muscle may regenerate if reinnervation or other treatment was performed. PMID- 21268309 TI - [Summary]. PMID- 21268310 TI - Photochemotherapy induces a faster apoptosis of alloreactive activated T cells than of nonalloreactive resting T cells in graft versus host disease. AB - BACKGROUND: Graft versus host disease (GvHD) is the main complication after hematopoietic stem-cell transplantation.Extracorporeal photochemotherapy (ECP) is a cell therapy currently used for the treatment of T-cell-mediated diseases and seems as a valuable second-line therapy for patients suffering from steroid refractory acute or chronic GvHD. ECP induces the apoptosis of treated cells and is believed to elicit a specific immune regulation of alloreactive T cells through repeated apoptotic T-cell infusions. However, its mechanisms of action have not yet been elucidated. In GvHD,alloreactive but not non alloreactive T cells are continuously activated by their environment. We hypothesized that ECP has a differential apoptotic effect on activated compared with resting T cells. METHOD: The ECP-induced apoptosis of resting and activated T cells from patients with chronic GvHD was assessed.The kinetic of apoptosis was also evaluated using several triggers of T-cell activation such as mitogenic or antigen specific activation. The influence of survival cytokines (interleukin-2, -7, and -15) was also evaluated. RESULTS: Activated T cells from patients with chronic GvHD underwent apoptosis faster than resting T cells. This phenomenon was confirmed using mitogenic and antigen-specific activated T cells from healthy donors and cannot be delayed by protective cytokines. CONCLUSIONS: ECP induces a faster apoptosis of alloreactive activated T cells than of non alloreactive resting T cells in GvHD and more generally of activated T cells than of resting T cells. These novel findings provide new insights about the ECP-induced specific control of pathogenic T cells in GvHD. PMID- 21268311 TI - The two largest parathyroid adenomas in the U.S. literature. PMID- 21268312 TI - Salaries are increasing, but so are CM responsibilities. PMID- 21268313 TI - What's new in early breast cancer treatment? It may be time to rethink traditional lymph node removal and radiation. PMID- 21268314 TI - Workout for arching hands. Stretching, strengthening, and range-of-motion exercises can help relieve pain and prevent injury. PMID- 21268315 TI - A doctor talks about radiation risk from medical imaging. PMID- 21268316 TI - Link between calcium supplements and heart attack risk unclear. PMID- 21268317 TI - Sitting can shorten your life. PMID- 21268319 TI - A report on World Congress on cancer of the thyroid gland (August 6-10, 2009, Toronto, Canada). PMID- 21268318 TI - By the way, doctor. I've been advised not to take my statin drug, simvastatin, with grapefruit juice. But is it safe to take the medication at night and then drink grapefruit juice in the morning? PMID- 21268320 TI - [New international classification of chronic pancreatitis (2007) M-ANNHEIM]. AB - Beginning in 1963, proposed various classifications of chronic pancreatitis. These classifications were based on the latest at the time the results of studies of the pancreas and to reflect the latest achievements pancreatology at the time, but not one of these classifications was not a simple unified classification system for chronic pancreatitis simultaneously etiology, clinical stage, severity of disease. The authors have developed a new classification that included all of the above listed characteristics. As a result, developed a multifactor classification of M-ANNHEIM, taking into account the many risk factors for CP. This classification allows to divide the patients with chronic pancreatitis into categories according to etiology, clinical stage and severity of CP. The severity of the disease is classified by the system of assessment, which takes into account the clinical symptoms and treatment options for CP. This new classification is optimal for the evaluation of various risk factors and their interactions. PMID- 21268321 TI - [Role of exocrine pancreatic insufficiency in reducing of the bone mineral density in patients with chronic pancreatitis]. PMID- 21268322 TI - [Autoimmune reaction component in chronic pancreatitis: clinical and experimental study]. AB - The study was undertaken to identify the relationship between inflammatory and autoimmune processes in chronic pancreatitis and to determine the prognostic significance of autoantibodies to antigens of acinar cells and hepatocytes, immunoglobulin G1-4. MATERIALS AND METHODS: In 85 patients with CP (43 men, 42 women) were studied autoantibodies to antigens of acinar and liver cells, IgG1-4. Of these, 43 patients HP was characterized by complications (cysts, calcification, pseudotumoral form), 40 patients--HP without complications, 2 patients were diagnosed chronic autoimmune pancreatitis (CAP), confirmed histologically. 20 people-- the control group. Experimental studies on animals, reproduction of acute and chronic pancreatitis. RESULTS: Maximize the level of autoantibodies--32.4 +/- 5.6 U / ml (control--10.5 +/- 2.5 U / ml) (p < or = 0.01), as well as IgG4--24 mg/ml in normal (0.8 +/- 0.08 mg/ml)--was recorded in patients with autoimmune pancreatitis. The average value of autoantibodies--in patients with CP complications: 24.2 +/- 3.8 U/ml (p < or = 0.01). The minimum value of autoantibodies--in patients with CP without complications: 18.6 +/- 2.6 U/ml (p < or = 0.05). CONCLUSION: The course of autoimmune pancreatitis accompanied by an increase of autoantibodies to antigens of acinar and liver cells, as well as serum IgG1-4, especially IgG4, which reflects the intensity of the autoimmune responses in this disease. In addition, the exacerbation of chronic pancreatitis with complications is clearly defined autoimmune component of disease. Experimental studies with preimmunization of animals allogeneic tissues have convincingly demonstrated that the formation of antibodies is not only to the antigens, reflecting the specific characteristics of these tissues, but also to general cell structures of other tissues. PMID- 21268323 TI - [Pancreatitis in intestinal diseases]. AB - In article review of the literature and own data about pathogenesis of pancreatitis and secondary pancreatic insufficiency in various diseases of small and large intestines is presented. The special attention is given to pancreatic insufficiency in celiac disease and in inflammatory bowel disease. The main directions of pancreatitis and exocrine pancreatic insufficiency therapy are grounded. PMID- 21268324 TI - [Evacuation activity of gastroduodenal complex as a digestive process]. AB - Literature data and the results of own examinations of speed and differentiation of stomach evacuation of test breakfasts consisted of different nutrients were presented. The relation of evacuation speed, antegrade and retrograde gastro duodenal passage to digestive fermentative potential of gastro-duodenal complex was shown. It was concluded about the possibility of it's system characterizing by the ultrasonographical examination of speed and character of test breakfast's evacuation from the stomach. PMID- 21268325 TI - [Treatment of postoperative pancreatitis, in patients undergoing cholecystectomy for cholelithiasis]. AB - In the prevention of exacerbations of chronic pancreatitis 28 patients in the early period and one month after cholecystectomy were appointed by octreotide. In assessing the effectiveness of treatment, along with the general clinical data, used a number of modern laboratory instrumentation, ultrasound and biochemical studies. Comprehensive studies have shown that octreotide has a positive impact on the rehabilitation of patients after cholecystectomy, prevents the progression of inflammation and systemic complications. PMID- 21268326 TI - [Dynamics of inflammatory periodontal diseases under the influence of gastroesophageal reflux disease therapy]. AB - Was made a comparative evaluation of the influence of treatment of gastroesophageal reflux disease (GERD) on the course of inflammatory periodontal diseases in patients with combined pathology of periodontal and GERD. Was performed an assessment of GERD symptom severity, the establishment of periodontal status of patients and analysis of the effects of GERD therapy on the course parodontopaty inflammatory genesis (chronic catarrhal gingivitis and chronic periodontitis mild). In patients with inflammatory periodontal diseases, coupled with GERD, was marked by a more pronounced therapeutic effect of combined treatment in comparison with isolated local treatment CDW (HKG and HGPI), which was reflected in the improvement of the parameters of the microcirculation system of periodontal tissues. This suggests the presence of pathogenic link between chronic inflammatory periodontal diseases (CDW) and the presence of pathological gastroesophageal reflux. PMID- 21268327 TI - [The experience of cryomodelling of the pancreas pathology]. AB - The purpose of the research is to determine the capabilities of cryomodelling of the pathology of the pancreas. Local cold influence of the pancreas of white rat was made with the help of cryosurgical complex KCH 3A/B (Chirana, Brno). Cooling was carried out intraoperatively, by the direct contact of the cryosurgical tip with the tissue of the pancreas. The relation of local morphological changes from the temperature of cooling is established. The modeling of the pathology of the pancreas on the basis of local cryoinfluence differs by high specificity and stability of reproduction and it can be recommended for studying mechanisms of the origin of given pathology and approbation of the ways of the treatment. PMID- 21268328 TI - [Diagnosis and treatment of cystic forms of duodenal dystrophia]. AB - Cystic dystrophy of duodenal wall and duodenal dystrophy (DD)--is a rare disease which is based on chronic inflammation of the pancreas tissue (PT), malrelated in the wall of the duodenum (DU). The principal method of surgical treatment of this disease is Pancreaticoduodenectomy (PRD), although it was presented several reports of successful use sandostatin or endoscopic treatment in some patients. Analysis of demographic, clinical and instrumental data, methods of surgical treatment of DD showed that all patients with persistent or recurrent abdominal pain was noted in all patients, weight loss--51%, vomiting--at 26%, jaundice--in 20% of patients. The most accurate diagnostic methods were CT, endo-ultrasound and MRI. The diagnosis of duodenal dystrophy installed in 35 patients. Operations were performed on 22 patients: Implemented PRD (10), removal of pancreatic head resection with a vertical branch of the PT and duodenoduodenoanastomosis (2), pancreatic head resection with excision of the cyst wall of the first portion of duodenum (2), gastric resection (1), resection of the vertical branch of the duodenum with duodenoduodenoanastomosus (2), duodenectomia (1) and resection of the vertical branch of the duodenum with reconstruction of the intestinal insert (2). Four patients fulfilled draining intervention on pancreatic ductal system- pankreatico and cystoenteroanastomoses. Postoperative and late mortality--0.77% of patients the disappearance of pain and 23%--a decrease in its intensity. In two cases, after the PRD against the background of pronounced chronic pancreatitis observed impaired glucose tolerance. Cystic dystrophy of duodenal wall without the expressed "orthotopic" pancreatitis clearly shows pathogenetic, clinical, diagnostic and therapeutic aspects of this disease, causing the possibility of an effective surgical treatment, only limited intervention by the KDP, without resection of the pancreas. PMID- 21268329 TI - [Endoscopic transpapillary operations on a pancreatic duct]. AB - Reports are continuing to accumulate rapidly on clinical outcomes of endoscopic interventions in patients with pancreatic disease. This review of the literature differs from previous all-inclusive reviews by excluding diagnostic ERCP, with the exception of recent reports on minimizing post-ERCP pancreatitis. This review is limited to studies including the treatment of strictures, recurrent pancreatitis, stones, and ductal disruption. The main goal was to determine potential directions of future research in the area of therapeutic pancreatic endoscopy. PMID- 21268330 TI - [Autoimmune pancreatitis: current theories]. PMID- 21268331 TI - [Pancreas at metabolic syndrome]. AB - Authors showed the possible role of the pancreas namely in chronic pancreatitis (CP) in development of metabolic syndrome (MS). Apportionment of the basic clinical syndromes which cause development, both MS, and CP is important. There was noticed that pathogenetic approach to therapy of MS should be cased on understanding of pathogenetic contribution of pancreas functional condition to metabolic changes. Careful studying of this problem will give an opportunity for working out clinico-diagnostic, morphological and laboratory criteria of diagnostics of MS in pancreatic pathology in the future. It will allow to control efficiency of treatment that should consist of two stages--corrections of MS and treatment of the damaged target organ, namely--the pancreas. PMID- 21268332 TI - [Diagnosis and treatment of chronic pancreatitis in children]. AB - The paper gives many years experience in following up children with chronic pancreatitis. It shows the clinical polymorphism of pancreatitis that in associated with the specific features of a pathological process in the gastroduodenocholedochopancreatis area. To recognize diseases of the pancreas and to evaluate its function, the authors have developed an effective complex of studies and substantiated adequate therapy for pancreatitis. Evidence is provided that patients can be effectively treated when rehabilitation is correctly organized and aimed at preventing degenerative processes in the pancreas and to preserve its secretory function. PMID- 21268333 TI - [Pancreas physiopathology in cystic fibrosis]. PMID- 21268334 TI - [Hypereosinophilic syndrome with the esophagus, stomach and small intestine pathology]. AB - In this article the differential diagnostic line of blood hypereosinophilia is analyzed and the complicated clinical case of severe eosinophilic esophagogastroenteritis with recurrent oedema associated with protein loss is represented. PMID- 21268335 TI - [Budesonide in treatment of patients with cross primary biliary cirrhosis and autoimmune hepatitis]. PMID- 21268336 TI - [Effect of enzyme supportive therapy of the Ermital' on a quality of life of patients with chronic pancreatitis]. AB - The purpose of the study was to evaluate the quality of life in patients with chronic pancreatitis with the presence of complications treated conservatively and surgical treatment. With the help of a questionnaire MOS SF-36 were asked 80 patients with CP, of whom 15 patients were after the operation, the PDR, 10 patients underwent draining operations, 15 patients had a history of pancreatic necrosis, in 20 patients with CP were characterized by complications (cyst calcification, kalkulez, pseudotumoral form of HP, diabetes) and surgical interventions were not performed in 20 CPs proceeded without complications. Were obtained significant differences on all scales of the questionnaire with the control group all CP patients. Assessment of coping with pain in long-terms after various operations was revealed significantly better results and got rid of persistent pain in patients with a complicated course, who underwent surgery. 23 CP patients with a complicated course, as enzyme replacement therapy received in ermital dose of 20,000 IU lipase 3-4 times a day for 3 weeks. The assessment of quality of life before and after therapy with ermital. The intensity of pain significant changes in the groups received. On the other hand the improvement in general health, physical and social functioning. PMID- 21268337 TI - [Congress of the European Pancreatic Club in Stockholm]. PMID- 21268338 TI - [Increasing the accuracy of the global alignment of amino acid sequences by constructing a set of alignment candidates]. AB - The accuracy of the global Smith-Waterman alignments and Pareto-optimal alignments depending on the degree of sequence similarity (percent of coincidence, % id, and the number of remote fragments NGap) has been examined. An algorithm for constructing a set of three to six alignments has been developed of which the accuracy of the best alignment exceeds on the average the accuracy of the best alignment that can be constructed using the Smith-Waterman algorithm. For weakly homologous sequences (% id 15, NGap 20), the increase in the accuracy is on the average about 8%, with the average accuracy of the global Smith Waterman alignments being about 38% (the accuracy was estimated on model test sets). PMID- 21268339 TI - [Asymmetry of the GC content in vicinity of transcription starts (with participation of polymerase PoII) and its correlation with location of adsorption sites of protein SP1 on DNA]. AB - Nucleotide DNA sequences within the clusters of transcription starts, determined by the method of cap analysis of gene expression, have some distinguishing features. The sequences of these clusters are rich in nucleotides C and G, and there is an asymmetry of the nucleotide content, which correlates with the choice of chain from which the transcription in the cluster occurs. On the coding chain, the concentration of guanine exceeds the concentration of cytosine. In the nucleotide sequence of the cluster on the coding chain, the frequency of the polynucleotide tracts of the avoided nucleotide (cytosine), normalized to the frequency expected based on the content of this nucleotide in the cluster, is significantly higher compared with the normalized frequency of the polynucleotide tracts of the other nucleotide (guanine). Similarly, the statistical significance of the C-rich variant of the site of specific binding of the transcription initiation factor Sp1 in the coding chain is higher than that of the G-rich variant. However, the assumption can hardly be confirmed that the choice of the variant of the binding region of protein Sp1 correlates with the choice of the transcription chain. It is more likely that both variants are more or less equally probable, and the binding region of protein Sp1 acts in this case as a factor of selection, which counteracts the mutations inducing the shift of the nucleotide content. PMID- 21268340 TI - [Purification of transducin betagamma-subunit complex from isotonic extracts of bovine retinal rod outer segments]. AB - A method for obtaining a free complex of transducin betagamma-subunits from bovine retinal rod outer segments in a highly purified state has been suggested. PMID- 21268341 TI - [Analysis of pro/antioxidant properties of water and water solutions]. AB - The ability of water preparations of different composition to affect the generation of superoxide radicals has been compared. The superoxygenating reaction of adrenaline autoxidation with some modifications was used as a model system, which makes it possible to reveal the pro/antioxidant properties of materials being tested. It was shown that samples of water from sources having different specific electroconductivity and, accordingly, ionic composition differ in the ability to affect reactions proceeding with the participation of ROS. The parameter measured, the pro/antioxidant activity of water, is a new informative indicator, and the approach proposed enables one to perform a comparative estimation of the quality of water and aqueous solutions. PMID- 21268342 TI - [Protein kinase LOSK regulates the network of microtubules and cell locomotion]. AB - It has been found that the inhibition of the activity of protein kinase LOSK reduces the ability of cells to the directed movement over the substrate and changes the parameters of the interaction of cells with the substrate. It is suggested that the chaotization of microtubules leads to the stabilization of cell contacts with the substrate and, consequently, to a slowing down of locomotion. PMID- 21268343 TI - [Involvement of guanine nucleotide exchange factor xLARG in epiboly of cells of the animal pole of Xenopus laevis embryos]. AB - The development of multicellular organisms is a complicated coordinated process of the movement of groups of embryonic cells, which is controlled by many regulatory systems. At present little is known about the regulation of the earliest manifestations of the movement in the embryogenesis: epiboly and radial intercalation. The coordinators of these processes may be small GTPases of the Rho family and their activators, the factors of exchange of guanylic nucleotides. It has been shown in this work that the overexpression of the factor of exchange of guanylic nucleotides xLARG in Xenopus laevis embryos leads to an increase in the amount of the active form of xLARG. In addition, an increase in the expression of xLARG disturbs the process of radial intercalation. The data obtained suggest that xLARG is involved in maintaining the xLARG activation level necessary for the occurrence of epiboly. PMID- 21268344 TI - [Novel peptide inhibitors of the myosin light chain kinase suppress hyperpermeability of vascular endothelium]. AB - The ability of novel cell-permeating peptide molecules derived from the peptide inhibitor of the myosin light chain kinase (MLCK) L-PIK (Arg-Lys-Lys-Tyr-Lys-Tyr Arg-Arg-Lys) to inhibit this kinase in vitro and attenuate the thrombin-induced hyperpermeability of endothelial cell monolayer in culture has been studied. It was found that the compounds [NalphaMeArg1]-L-PIK and [Cit1]-L-PIK possess the inhibitory activity towards MLCK comparable to that of L-PIK and the ability to suppress the hyperpermeability of endothelium, whereas other modifications of L PIK were less effective. Thus, among de novo synthesized peptides, [NalphaMeArg1] L-PIK and [Cit1]-L-PIK demonstrate the inhibitory properties of the original peptide L-PIK and additionally surpass it by stability in blood plasma. These peptides may be used in the design of novel antiedemic drugs. PMID- 21268345 TI - [Mechanoelectric potentials in synthetic hydrogels: possible relation to cytoskeleton]. AB - Mechanical and electrical properties of a synthetic polyelectrolyte hydrogel considered as a model of the cytoskeletal gel were studied. Hydrogels were synthesized from polymethacrylic acid by radical polymerization in aqueous solution. The electrical charge was introduced into the gel network by partial neutralization of monomer acids with magnesium (hydro)oxides. Through the use of a motor, triangular longitudinal (axial) deformations were applied to gel samples. Simultaneously, the electrochemical (Donnan) potential of the gel was measured using conventional microelectrodes. We found that: (1) the Young modulus of the gel was 0.53 kPa; (2) at a given deformation velocity, the extent of gel deformation closely correlates with the gel potential; and (3) at the same level of gel deformation, the lower the deformation velocity, the higher the relative change of gel potential. These findings show a striking similarity to the data obtained in living cells, particularly in cardiac myocytes. A hypothesis involving the deformation-induced solvent migration from the gel to the surrounding solution is considered. It is concluded that the physicochemical features of the cytoskeletal gel may play a role in determining the mechanoelectric properties of excited cells. PMID- 21268346 TI - [The Na+ pump and intracellular signaling mechanisms]. AB - The main properties of Na+ /K(+)-ATPase as a natural receptor for cardiotonic steroids have been discusses. Primary attention is focused on structural and functional differences between the alpha-subunit isoforms of Na+/K(+)-ATPase in different tissues. General information on the role of the Na pump in signaling cascades in kidney epithelial cells, cardiomyocytes and neurons is presented. The data obtained indicate that, in neurons, several alpha-isoforms of Na+/K(+) ATPase possessing different sensitivity to ouabain may have different signaling functions. PMID- 21268347 TI - [Age-related changes in the functioning of the mitochondrial potassium transporting system]. AB - Changes in the rate of respiration and functioning of the ATP-dependent potassium channel the liver and heart mitochondria of one-, three-, eight-, and twenty four month-old Wistar male rats have been investigated. It was shown that the activity of the channel in the mitochondria of both tissues in 24-months-old animals decreases more than three times, and the content of potassium, 1.5-2 times compared with young one-month-old rats. The changes occur against the background of age-related decrease of energy supply in mitochondria, the respiratory complex I underganig the greatest changes upon aging. The decrease of channel activity may be the result of changes in channel sensitivity to modulators and a decrease in the expression of mitochondrial K(+)-transporting channel-protein with a molecular mass of 5.5 kDa upon aging found in this work. As a result, the functioning of not only the mitoK(ATP) but also the whole mitochondrial potassium cycle is impaired. PMID- 21268348 TI - [Mitochondria and hepatotoxicity of ethanol]. AB - The current understanding of the effects of alcohol intoxication on the basic mitochondrial functions has been presented. Both, the direct toxic effect of ethanol on biological membranes and various cellular systems and the toxicity of acetaldehyde and reactive oxygen species (the products of ethanol oxidation) are discussed, with emphasis on the effect of ethanol on the basic functions of mitochondria and Ca(2+)-dependent mitochondrial permeability transition. Based on the available experimental data, it is demonstrated that acute alcohol intoxication causes a global mitochondrial dysfunction in the liver, resulting in considerable disturbance of the whole cellular metabolism. Alcohol poisoning of the liver leads to a decreased ability of cells to withstand oxidative stress, to support the synthesis of vital metabolic intermediates (e.g., methyl groups), as well as to produce urea from ammonia, due to a decreased permeability of the outer membrane and impaired exchange of substrates between the cytoplasm and the mitochondrial matrix. This review emphasizes the role of the voltage-dependent anion channels of the outer mitochondrial membrane in ethanol-mediated disturbances of basic mitochondrial functions and its consequences for the entire cell metabolism in the liver. PMID- 21268349 TI - [NADPH oxidase controls EGF-induced proliferation via the ERK1/2-independent mechanism]. AB - Using HyPer, a ratiometric GFP-based biosensor, the dynamics of H2O2 in living cells has been studied. It was found that activation of the receptor of the epidermal growth factor (EGF) in epithelial cells leads to sustained generation of intracellular H2O2, which is blocked by apocynin, an inhibitor of the assembly of plasma membrane NADPH oxidase. Apocynin also blocked HeLa cell proliferation induced by EGF, indicating that NADPH oxidase should be involved in the process. However, apocynin failed to alter the kinetics of the EGF-stimulated ERK1/2 activation. It was concluded that NADPH oxidase and intracellular H2O2 are the important downstream targets of the EGF receptor, which mediate the proliferation response by mechanisms distinct from the activation of the classical ERK1/2 MAP kinase pathway. PMID- 21268350 TI - [Effect of ethanol on synthesis of serine and exchange of methyl groups in hepatocytes by NMR spectroscopy]. AB - The method of NMR spectroscopy was used to investigate the role of voltage dependent anion channels in the outer mitochondrial membrane in the mechanism of ethanol hepatotoxicity using the synthesis of serine and exchange of methyl groups in hepatocytes metabolizing 13C-labeled glycine. Here we present and describe a methodological approach developed for the independent monitoring of the synthesis of serine in two intracellular compartments: the cytoplasm and mitochondria of intact hepatocytes, and quantification of different serine isotopomers synthesized in hepatocytes from 13C-labeled glycine. The data obtained indicate that the treatment of cells with ethanol as well as cysteamine (specific inhibitor of mitochondrial synthesis of serine) suppressed the level of mitochondria but not cytoplasmic serine isotopomers. It is concluded that the decrease in the production of mitochondrial serine isotopomers in hepatocytes exposed to ethanol can be caused not only by decreased permeability of the outer mitochondrial membrane due to the closure of voltage-dependent anion channels and suppression of the exchange of substrates of serine synthesis in mitochondria but also by the restoration of the cytoplasmic and/or mitochondrial pool of pyridine nucleotides (NADH) during the oxidation of ethanol. Our work reveals a new mechanism of action of ethanol (alcohol intoxication) in hepatocytes through the regulation of glycine metabolism and opens new possibilities in the treatment of alcohol poisoning. PMID- 21268351 TI - [Use of perfluorocarbon emulsions for administration of photosensitizing preparations into bone marrow stem cells]. AB - It has been shown that, upon incubation of mouse bone marrow stem cells (BMSC) in vitro with the nanoparticles of perfluorocarbon (PFC) emulsion stabilized by proxanol 268, these nanoparticles penetrate into cells and stay there for a long time (up to 20 days of observation). It has been found that, under in vitro conditions, mouse BMSC loaded with the nanoparticles of both the original emulsion and the emulsion preliminarily incubated with radachlorine do not differ from control stem cells in the rate of division, stretching on a plastic support, and the formation of a monolayer. It has been shown that the exposure to laser radiation of BMSC incubated with the nanoparticles of a PFC emulsion preliminarily incubated with radachlorine under in vitro conditions leads to the death of these cells due to the destruction of the cell membrane. The treatment with laser radiation of BMSC incubated with the nanoparticles of the starting PFC emulsion (without preliminarily incubation with radachlorine) causes no death of these cells. It has been shown in in vivo experiments that, when transplanted to the organism of a recipient mouse, BMSC of a donor mouse incubated with the nanoparticles of a PFC emulsion preliminarily incubated with radachlorine retain their functional activity, in particular the ability to migrate in the animal body. In this case, radachlorine contained in these stem cells retains its major function, to induce the death of stem cells by the action of laser radiation due to the destruction of the cell membrane. The observation period after the transplantation was 5-7 days. PMID- 21268352 TI - [Slow calcium waves in cultured postnatal rat skeletal myocytes]. AB - A variety of active agents increasing [Ca2+]i in cultivated skeletal myocytes have been investigated. It was shown that, out of the agents such as noradrenaline, carbacholine, caffeine, cyclopiazonic acid, and potassium solution, only the last caused the formation of slow calcium waves in skeletal myocytes. These waves propagated not only near the location of the cell nucleus but also along the whole length of myocytes. It is supposed that this wave process can be related to the modulation of excitation-relaxation processes in skeletal muscles. PMID- 21268353 TI - [Involvement of extracellular cAMP-specific phosphodiesterase in control of motile activity of Physarum polycephalum plasmodium]. AB - Possible involvement of extracellular cAMP-specific phosphodiesterase in the control of cell motile behavior has been investigated in Physarum polycephalum plasmodium, a multinuclear amoeboid cell with the autooscillatory mode of motility. It was found that the rate of the hydrolysis of 10 mM cAMP by a partially purified preparation of cAMP-specific phosphodiesterase secreted by the plasmodium in the course of migration decreases 20-30 times under the action of 1 mM dithiothreitol. In the presence of 1-5 mM of this strong reducing agent, the onset of the plasmodium spreading and the transition to the stage of migration were delayed in a concentration-dependent manner. In accordance with the morphological pattern of motile behavior, the duration of the maintenance of high frequency autooscillations, which normally precede the increase in the rate of the spreading and appear also in response to the application of attractants at spatially uniform concentrations, strongly increased by the action of dithiothreitol. The results obtained suggest that the autocrine production of cAMP and extracellular cAMP-specific phosphodiesterase is an important constituent of the mechanism controlling the motile behavior of the Physarum polycephalum plasmodium. PMID- 21268354 TI - [Cytomechanics of oscillatory contractions. Modeling the longitudinal dynamics of Physarum polycephalum protoplasmic strands]. AB - A mathematical model of the longitudinal dynamics of an isolated strand of the Physarum polycephalum plasmodium has been constructed. Its contractile system is considered as a continual viscoelastic medium with passive and active components. The mathematical description of the longitudinal dynamics of the plasmodial strand is reduced to a system of three first-order differential equations, whose variables are its active stress, deformation, and the intracellular concentration of calcium ions. The model is based on the hypothesis that there exists a feedback loop, which appears because of the influence of strand stretching on the rate of the release of calcium ions, which in turn controls the active contraction and deformation of the strand. Nonlinear interactions between the variables evoke a loss of the stationary state stability and a self-excitation of mechanochemical autooscillations when the external load exceeds some critical value. The results of numerical solutions of the model with the empirically determined viscoelastic parameters are in good agreement with the available experimental data and testify to the adequacy of the description of strand dynamics by the mathematical model in which the contractile apparatus is a part of the cellular control system. In particular, this model well simulates the form and duration of transient mechanochemical processes observed under isotonic and isometric conditions immediately after strand isolation, as well as the subsequent excitation of autooscillations of the contractile activity and their activation by strand stretching. PMID- 21268355 TI - [Changes in the shape of epithelial embryonic cells of the spur-toed frog upon deformation of the cell layer]. AB - A quantitative study of changes in the shape of cells of double explants of the tectum of gastrule blastocoele of the spur-toed frog within the first four hours after the artificial bending of explants has been performed. It was found that, on the concave (contracted) side of explants, epithelial cells stretch out, and the apical surface of many of these cells contracts, whereas on the convex (stretched) side they remain isodiometric. The maximal difference between the values of the apical index of epithelial cells located on the concave and convex sides was observed after 4 h of the cultivation of explants. It was shown that, by 2 h, the artificially produced curvature of the bent explant increases. The endocytosis on the concave side is more active than on the convex (stretched) side. The results of experiments with the use of inhibitors simulating the behavior of the actomyosin complex showed that the unimpeded functioning of myosin I is more important for the apical contraction and elongation of cells than the proper structural organization of the actin backbone. PMID- 21268356 TI - [Dinitrosyl complexes of iron with glutathione in the rat myocardial tissue during regional ischemia and postischemic reperfusion]. AB - The injection of dinitrosyliron iron complexes with glutathione at the onset of 40-min rat regional myocardial ischemia was shown to exert a clear cardioprotective action by decreasing the infarct size and suppressing the cardiac rhythm disturbance. After the introduction of the preparation, its effective accumulation with protein thiol-containing ligands in the myocardial tissue was registered be the EPR method. It was also found that, as a result of postischemic reperfusion, the rate of the decrease in the content of these complexes in the ischemic area increases, which demonstrates the effective scavenging of short-lived reactive oxygen species by molecules of dinitrosyl iron complexes. PMID- 21268357 TI - [Insulin-like growth factor 1 and the key markers of proteolysis during the acute period of readaptation of the muscle atrophied as a result of unloading]. AB - It has been shown that, after prolonged disuse, the accumulation of muscle mass and the recovery of soleus fibers volume are caused by water accumulation rather than protein synthesis intensification. At the same time, expression rate of the main markers of the activity of ubiquitin-proteasome system remained increased on the 3rd day of reloading and decreased to the control by the 7th day. Both the quantity of the insulin-like growth factor 1 and the number of satellite cells fused with muscle fibers and of myonuclei began to increase only on the 7th day of reloading. The data obtained evidenced a significant inertness of the postural muscle during its adaptation to the load (normal gravity) after prolonged disuse. PMID- 21268358 TI - [Comparative analysis of structural and functional characteristics of soleus muscle in rats and Mongolian gerbils during gravitational unloading of various duration]. AB - A comparative investigation of the dynamics of contractile properties of the whole soleus muscle and its fibers during 3- and 12-day-long hind limb suspension of Wistar rats and Mongolian gerbils (Meriones unguiculatus) has been performed. The data obtained indicate that the structural and functional changes caused by hypogravity in gerbils are slowed down compared with rats. A very intensive drop in water containment in gerbils was found, which can cause shifts in the ionic strength of the intracellular space of the muscle fiber. As a result, the photolytic activity of different enzymes may change, which can induce a less pronounced reduction in Z-disc and M-line stiffness and contractile capabilities in gerbils compared to rats. PMID- 21268359 TI - [The role of energy substrates in regulation of the force-frequency relationship in the rat myocardium: effect of ambiocor]. AB - The effect of ambiocor (15 mg/100 ml), which contains natural substrates of energy metabolism, on the contractility of papillary muscles (PM) of the right ventricle of the rat heart was studied at stimulation frequencies from 0.1 to 3.0 Hz at a temperature of 30 +/- 1 degrees C (n = 7). The effect was recorded 20 min after the addition of the preparation. It was demonstrated that ambiocor causes a significant (about 70%), independent of stimulation frequency, suppression of the amplitude of isometric contractions (negative inotropic effect), which is coupled with an increase in the relative value of the rest potentiation effect (a qualitative index of calcium content in sarcoplasmic reticulum). The influence of the mixture leads to significant alterations in the time parameters of the "contraction-relaxation" cycle: an increase in the duration of latent period; and a decrease in the time to peak tension and half-relaxation time (TR50%). The effect of the mixture is partially reversible. During the washing of the preparation with the control solution, the qualitative indicators of the contractile activity of papillary muscles are substantially improved in comparison with the initial ones. The character of alterations allows one to assume that the effect of ambiocor in the papillary muscles of the rat heart is realized partly through the suppression of the activity of sarcolemmal calcium channels. PMID- 21268360 TI - [Computer simulations of pacemaker shift in the sinoatrial node]. AB - The initiation and propagation of electrical pulses in the sinoatrial node under normal conditions and after the application of acetylcholine have been simulated. It has been found that normally a single or a few leading centers are formed in the tissue. When acetylcholine is applied, a temporary functional block of conduction may appear; the leading center migrates under these conditions. PMID- 21268361 TI - [Mathematical model of invasion of mysids (Mysidacea) into the Naroch Lake system]. AB - We present a mathematical model of the invasion of mysid into the Naroch Lake system. The model is parameterized with the use of field observation data. We show that the mysid invasion can lead to an increase in the time-averaged fish population size, and to a decrease in the time-averaged rotifer population size. PMID- 21268362 TI - [Compensation of the rectum muscle dysfunction]. AB - The possibility of compensating for the inborn pathology of the obturative apparatus of the rectum has been examined. An adequate experimental model of encopresis and a method of transplantological compensation of this pathological state have been developed. PMID- 21268363 TI - [Pioneer neurons: a basis or bottleneck of diversity of nervous systems of Lophotrochozoa?]. AB - In a case study on development of larvae of Trochozoa species of different systematic positions, it was shown that peripheral neurons differentiated firstly. According to the characters of early peripheral neurons, in particular their localization in parts that differed from known zones of appearance of central ganglia, the difficult periphery of processes used as a "frame" by differentiated neurons of definitive nervous system, and transient expression of specific markers, it is reputed that these cells are pioneer. On the one hand, pioneer neurons are the bottleneck of morphogenesis diversity in late stages of development which prepare, in early larvae, the framework of the further central nervous system. On the other hand, navigation and marking using pioneer neurons can be a mechanism of evolutionary lability of definitive neural structures. Functional adaptive significance of pioneer neurons of larvae of Trochozoa animals, probably, is in the maintenance of a fast change from larvae life-form to adult life-form in metamorphosis that decreases the time of animals at intermediate stages of morphogenesis, which are associated with a dramatic fall in adaptation. PMID- 21268364 TI - [Cross-regulation in development of neuroendocrine and immune systems]. AB - Cross-regulatory effects of immune and neuroendocrine systems on their appearance and functioning occur during a whole life period. At different stages of ontogenesis, the functions of these systems are diverse. In perinatal ontogenesis hormones, neuropeptides and neurotransmitters control the processes of growth and differentiation of various embryo tissues, particularly lymphoid. In the postnatal period, their functions are mostly in homeostasis maintaining of the immune system in response to changes of the environment. Conversely, transmitters of the immune system, such as cytokines, whose synthesis is increased in inflammation, and thymic peptides, program the development of the neuroendocrine system of the embryo. The perinatal period is crucial for final appearance of these systems. Changes in one of the interacting systems, caused by negative environmental factors at this stage, usually provoke changes in other developing systems for a long period. Plasticity of physiological systems in perinatal development allows the organism to adapt to changed conditions. However, these changes can limit physiological functions in interacting systems and induce the appearance of various pathologies in postnatal life. PMID- 21268365 TI - [From Vendian to Cambrian: the beginning of morphological disparity of modern Metazoan phyla]. AB - Continuity of the transition from Precambrian to the Phanerozoic metazoan fauna at the phylum level is analyzed. The discrete traces of feeding on bacterial mats by Dickinsonia and similar organisms are explained by extracorporeal digestion, characteristic ofa placozoan level of organization, as in the extant Trichoplax. The absence of a morphologically developed anterior end of the body, of food gathering appendages of any kind, and of appendages responsible for movement suggest that these animals were at this level of organization. Probably, an expanded placozoan level of organization can be assumed for most vendian animals. Against this background, new characters emerged in the Cambrian to be included in the body plan of extant animal phyla. The relationships between the morphological archetype (body plan) and morphogenetic archetype are considered. It is shown that major features of a morphogenetic archetype could be retained from the time the taxon was formed. PMID- 21268366 TI - [The role of the thyroid gland hormone in ontogenesis and morphological diversification of Barbus intermedius sensu of Lake Tana in Ethiopia]. AB - The role of thyroid gland hormone in the ontogenesis of the Large African Barb Barbus intermedius sensu Banister, 1973 (Teleostei; Cyprinidae)--the supposed ancestral species which produced the species flock of the large African Barbs of the Lake Tana (Ethiopia)--has been studied. It has been shown that the thyroid hormone influences the period of many morphological processes and a change in its level causes heterochrony, reflecting on the definitive morphology of fish. Thus, it can be assumed that even a slight change in activity of the thyroid axis in the process of ontogenesis can be the cause of wide variability of the morphological features of B. intermedius and is at the basis for the fast diversification of the species flock of Big African Barbs of Lake Tana. PMID- 21268367 TI - [Morphologic and molecular manifestations of hybrid dysgenesis in ontogenesis of Drosophila virilis]. AB - Disorders of germ track cell development that take place in crossbreeding of certain lines of Drosophila virilis and lead to hybrid dysgenesis (HD) syndrome have been studied. Polar cells and germ line cells were identified with specific antibodies against Vasa protein. It has been shown that abnormalities of formation of primary gonads takes place already at the 11-12 stage of embryo development and the consequences of germ line cell death lead to disorders of gonad development at the following stages of ontogenesis of dysgenic hybrids. The start point of germ line cell death in embryogenesis as well as initiation of transcription of Penelope retroelement, which is supposed to play a significant role in HD syndrome development in D. virilis, were estimated. PMID- 21268368 TI - [Integumenal embryony in CMS sunflower line]. AB - In ovules of cultural sunflower (Helianthus annuus L.) CMS line VIR 116, which were pollinated by wild perennial specie H. occidentalis, the integumentary embryos have been revealed. They are found out at 7-9 days after pollination in embryo sacs where there was no normal fertilization. The integumentary embryos arise from somatic cells of a parent organism and their occurrence can be one of the reasons matroclinal inheritances at interspecific hybrids. PMID- 21268369 TI - [The treatment of the glucocorticoids-induced osteoporosis: recent knowledge]. AB - Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fractures that affects both cortical bone and trabecular bone. Osteoporosis may be either primary or secondary. Among the secondary forms, the glucocorticoid-induced osteoporosis is most common form that occurs, regardless of age, sex, and even with low doses of glucocorticoid. PMID- 21268370 TI - [Dehydroepiandrosterone [DHEA(S)]: anabolic hormone?]. AB - The role of dehydroepiandrosterone (DHEA) and its sulphated form (DHEAS) as anabolic hormones is still debated in the literature. In this review we describe the fundamental steps of DHEA physiological secretion and its peripheral metabolism. Moreover we will list all the observational and intervention studies conducted in humans. Many observational studies have tested the relationship between low DHEA levels and age-related changes in skeletal muscle and bone, while intervention studies underline the positive and significant effects of DHEA treatment on several parameters of body composition. Surprisingly, observational studies are not consistent with different effects in men and women. There is recent evidence of a significant role of DHEA in frailty syndrome and as predictor of mortality. However a more complete approach of the problem suggests the opportunity to not focus only on one single hormonal derangement but to analyze the parallel dysregulation of anabolic hormones including sex steroids, GH-IGF-1 system and other catabolic hormones. PMID- 21268371 TI - [Antibiotic-prophylaxis in the minimally invasive pain surgical procedures]. AB - The minimally invasive pain surgical procedures are more and more frequently used in the treatment and management of the chronic pain. The patients will often have recourse to a higher infection's risk during the proceedings for acquired general conditions (like enterotomy, skin ulcers, bladder catheter).The analysis literature doesn't produce specific treatment guidelines about antibiotic prophylaxis in pain therapy. This document, drawn up with multidisciplinary approach, correspond to rational, efficacy and functional guide about the choice and management of the antibiotic prophylaxis during the minimally invasive pain surgical procedures. PMID- 21268372 TI - [Serological and clinical aspects in initial Wegener's disease. A case report]. AB - The clinical and biochemical features of an acute and initial Wegener's granulomatosis case were analysed in a young woman. A multifactorial aspects are evident. A chronic inflammation of the superior respiratory tract has been observed. Staphylococcus aureus has been isolated. An oligoclonal component constituted of high levels of anti-PR3 autoantibodies was detected: initial autoreactive B cell clone activation is probable. The chronological link with postpartum is present: our study excluded foetal microchimerism; the hormonal state can be a trigger factor. Serical IL-17 was negative. PMID- 21268373 TI - [Kawasaki's syndrome: recent advances in diagnosis and therapy]. AB - Kawasaki disease is an autoimmune disease that manifests as a multisystemic necrotizing medium vessel vasculitis that is largely seen in children under 5 years of age. It affects many organs, including the skin, lymph nodes, and blood vessel walls, but the most serious effect is on the heart where it can cause severe aneurysmal dilations in untreated children. The aim of this paper is to evidence the recent advances in the diagnosis and therapy of this disease. PMID- 21268374 TI - [Recent knowledge on the pathogenesis of nonalcoholic fatty liver disease. Role of genetic factors]. AB - The Non-Alcoholic Fatty Liver Disease (NAFLD) is the most frequent cause of chronic liver disease in West, potentially associated with an elevated morbidity and mortality. The search is busy in to identify genetic factors of progression in people with same environmental risk factors. Objective of this review is to analyze the data from association studies on the role of the genetic factors in NAFLD. The available studies are not conclusive in to identify candidate genes, because conducted on small populations and with not well-done designs. Identification of genetic risk profiles for NAFLD progression could help to individualize the patients treatment and follow-up. PMID- 21268375 TI - [Role of biomarkers in the detection of sub-clinical myocardial injury: H-FABP and radiofrequency ablation of ventricular arrhythmias]. AB - The importance of biomarker assay such as cardiac troponins and H-FABP is assuming a pivotal role not only in the diagnosis and follow-up of patients with acute coronary syndromes. Radiofrequency (RF) ablation represents a widely used method for the non pharmacologic treatment of arrhythmias.We report a case of a patient complaining of life-threatening arrhythmias treated by RF in whom temporal changes of cardiac biomarkers was determined after the procedure. PMID- 21268376 TI - [Asthma control. A gap between the patients' perceptions and reality]. PMID- 21268377 TI - [Manganese in the water: impact on children]. PMID- 21268378 TI - [Living with ... the pain clinic of Hotel-Dieu of CHUM. Interview by Francine Saint-Laurent]. PMID- 21268379 TI - [Haiti--it's been one year. A postoperative care nurse reports]. PMID- 21268380 TI - [Donation of organs after cardiocirculatory death: a developing practice in Quebec]. PMID- 21268381 TI - [Do the patients appreciate your care? Development of an evaluation questionnaire]. PMID- 21268382 TI - [Wound infection: local and systemic treatment]. PMID- 21268383 TI - [Alpine skiing and snow-boarding. From the mountain to the emergency room!]. PMID- 21268384 TI - [Blood pressure]. PMID- 21268386 TI - [Fructose and hypertension?]. PMID- 21268385 TI - [SATIN project: terminal care and sources of stress]. PMID- 21268387 TI - [Ivabradine]. PMID- 21268388 TI - [Thinking of getting a divorce?]. PMID- 21268389 TI - [The right tube for the right time]. PMID- 21268390 TI - [New guidelines on the prevention of infective endocarditis. Special aspects for dentists]. AB - Infective endocarditis (IE) is a disease with serious, even fatal complications, often requiring long-term and expensive treatment. Therefore, prophylaxis has emerging importance. Previous guidelines suggested the use of prophylactic treatment for a wide range of patients and procedures. The Working Group of the European Society of Cardiology accepted a new guideline on the prevention, diagnosis, and treatment of infective endocarditis in 2009. One of its major point is a radical decrease in the type of procedures requiring prophylaxis. These changes also affect dental and oral surgical procedures. It is important for dentists and oral surgeons to come to know the changes and to apply them in their everyday practice. PMID- 21268391 TI - [Surgical-orthodontic treatment of the upper canine retention]. AB - Combined surgical and orthodontic treatment of upper canine retention showed thorough development during the past decade. Depending on the axial position of the unerupted canine there are three methods for their alignment. When the axis of the unerupted canine is near vertical making a mucosal window is enough for deliberation of the crown. When the unerupted canine is covered by bone a palatinal or buccal corticotomy is necessary for the accessibility of the crown. When the unerupted tooth is positioned near horizontally redressment force or removal is advisable. Combined surgical and orthodontic method for alignment of unerupted canine may achieve excellent cosmetical and functional results. PMID- 21268392 TI - [Remnant of tooth root in the maxilla]. PMID- 21268393 TI - [The first printed textbook in dentistry]. AB - The first book focused solely on dentistry was published in Germany in 1530. Former scientific publications on dentistry were collected by an unknown author. The book presents 44 pages on the main issues of dentistry divided into 13 chapters. It was made by the Guttenberg method of printing. PMID- 21268394 TI - [Effect of being disabled, dental fear and anxiety on drawings]. AB - AIM: To investigate if there is an influence of being a disabled people (with disturbed body-image), dental fear and anxiety on several form/shape parameters of drawings. SUBJECTS: Disabled (46) and healthy (33) volunteers (n = 79; male 39, female 40; age: 18.16 +/- 3.01 yrs.) were investigated. METHODS: Collection of demographic data (gender, age, marital status, profession), and administration of the Hungarian versions of dental fear and anxiety related scales namely: DAS, DAQ, DASQ, DFS, DBS, STAI-S, STAI-T and Expectation scale. Free drawing test portraying a person, a mouth, and a tooth were also administered, and form/shape parameters were analyzed. RESULTS: Mean values of the scales were: DAS: 10.22 +/- 3.1; DAQ: 2.21 +/- 0.9; DASQ: 12.44 +/- 3.9; DFS: 40.98 +/- 14,0; Expectation Scale: 2.32 +/- 0.7, DBS: 34.50 +/- 9.0; STAI-S: 37.56 +/-10.7; STAI-T 42.41 +/ 10.2. Disables subjects scored higher in all of the scales but there was a significant difference (t-probe, p < 0.05) in the case of DBS scale only. Being a disabled influenced 2 of person-, 5 of tooth-, and 3 of mouth-drawing parameters significantly (chi2 probe, p < 0.05). Dental fear related scales influenced 5 of person-, 5 of tooth-, and 1 of mouth-drawing parameters significantly (one-way ANOVA, p < 0.05). Anxiety influenced 2 of person-, 1 of tooth-, and none of mouth drawing parameters significantly (one-way ANOVA, p < 0.05). CONCLUSION: Interestingly, the influence of being a disabled people was the strongest in case of tooth-drawings, and the influence of dental fear on drawing parameters was stronger than that of anxiety. PMID- 21268395 TI - [Plasminogen activator inhibitor type 1 activity in women with unexplained very early recurrent pregnancy loss]. AB - The aim of the study was to assess the independent role of polymorphism 4G/5G (PL 4G/5G)--genotype 4G/4G in plasminogen activator inhibitor type 1 (PAI-1) in the development of very early recurrent pregnancy loss (RPL)--before 10 weeks of gestation of pregnancy. The polymorphism 4G/5G as well as Factor V Leiden (FVL), prothrombin (FII) gene mutation 20210 G > A and polymorphism 677 C > T in methylentetrahydrofolat reductase (MTHFR) gene was investigated in 110 women with recurrent pregnancy loss before 10 weeks of gestation and in 97 healthy women with at least one uncomplicated full-term pregnancy. A significant prevalence of PL 4G/5G in women with RPL was found in comparison to prevalence of the polymorphism in controls (41.8% versus 26.8% respectively in patients and controls, OR: 1.96, 95% CI: 1.05 3.69, p = 0.034). The difference in prevalence of the polymorphism remains still significant after exclusion of patients and control carriers of FVL, FII 202010 G > A and 677 C > T in MTHFR (the prevalence of PL 4G/5G alone was 44.1% and 24% respectively in patients and controls, OR: 2,5, 95% CI: 1,15 5, 45, p = 0.018). The found association of PL 4G/5G in PAI-1 with early recurrent pregnancy loss encourage an extension of the list of inherited thrombophilic factors with this one. This result also could have had an implication for adjustment of further prophylactic low-molecular weight heparin implication in further pregnancy to prevent a poor foetal outcome. PMID- 21268396 TI - [Oral contraceptives increase deep venous thrombosis in smoking women]. AB - There is consistent evidence that the use of oral contraceptives and is associated with increased risk of deep vein thrombosis. The study objective was to assess age specific incidence of deep venous thrombosis and pulmonary embolism in women 20 to 50 years of age associated with the use of oral contraceptives, and smoking habit. A case-control study of vein thrombosis was conducted in National Heart Hospital in Sofia. The study consists of studies for vascular events (peripheral vascular disease) during hormonal therapy. We found that cigarette smoking aggravates venous thromboembolism and pulmonary embolism the in women using oral contraceptives, v. The effect of smoking alone on venous tromboembolism was not found significant. Most probably different factors that increase the incidence of vascular narrowing or occlusion might explain the association between deep venous thrombosis, complicated pulmonary thromboembolism oral contraceptives use and smoking in women in pre-menopausal age. PMID- 21268397 TI - [Empty renal fossa--a prenatal diagnostic dilemma]. AB - AIM: To assess the feasibility of ultrasound for the prenatal diagnosis and the evaluation of prognosis in cases with empty fetal renal fossa. METHODS: A prospective observational longitudinal study from September 2007 till May 2010 was performed with high-resolution ultrasound equipment at MC "MARKOVS" and State University Hospital of Ob/Gyne "Maichin dom", Sofia. Seventeen cases with empty fetal renal fossa (EFRF) were prenatally diagnosed. Renal ectopia or unilateral renal agenesis (URA) were the two major differential diagnoses. Cases with bilateral renal agenesis were excluded from further analysis. The following prognostic factors were analyzed: gestational age at diagnosis, type and location of the defect, obstruction of the urinary tract and presence of associated structural fetal abnormalities. Invasive prenatal diagnosis (genetic amniocentesis) and fetal karyotyping was offered if required. Termination of pregnancy was an option in cases diagnosed at earlier gestational age with pessimistic prognosis. All continuing pregnancies were followed-up sonographically, incl. with fetal echocardiography. Pregnancy outcome was ascertained from hospital records, referring physicians and/or the patients themselves. RESULTS: Overall 17 cases with EFRF were prenatally diagnosed during the study period. The mean gestational age at diagnosis was 22+3 w.g. Prenatal detection of EFRF before 24 w.g. was achieved in 82 (14/17). There were 9 cases of ectopic kidney: 7--pelvic, 1--iliac, 1--crossed fused ectopia. The remaining 8 cases had URA. Empty fetal renal fossa was an isolated finding in 16/17 cases. In the last 17th case the anomaly was part of a malformation complex associated with tetralogy of Fallot and single umbilical artery. No cases with urinary tract obstruction were observed. In 16/17 cases there was favorable perinatal outcome. The remaining pregnancy with associated anomalies was terminated. There was one case with missed diagnosis of URA, detected after birth during an abdominal scan performed for another reason. CONCLUSIONS: Ultrasound is the method of choice for prenatal diagnosis and prognostic evaluation in cases with EFRF. Early detection allows adequate consultation and pregnancy follow-up. In cases with associated anomalies termination of pregnancy is an option. All continuing pregnancies with EFRF generally have good prognosis and favorable perinatal outcome. PMID- 21268398 TI - [Clinical efficacy of a new method for LEEP conization with pistol-shaped electroknife]. AB - The aim of this study is to establish clinical efficacy of a new method for LEEP conization of uterine cervix. The study is open, retrospective, performed at Department of General and Oncogynecology - Military Medical Academy (Sofia, Bulgaria) for the duration from 2007 till Mar 2010. The study includes 37 women at age from 19-50 years with proved high grade CIN (included Ca coil uteri in situ) by abrasion or biopsy. Medical history was collected from all patients enrolled in the study as well as gynecological examination and colposcopy was performed to them. A LEEP with short intra venues anesthesia was performed to the patients. An innovation system for LEEP conization and generator for monopolar currency ERBE VIO 300D was used. The follow up visit was performed one month after the treatment procedure and included gynecological examination and colposcopy (positive/negative atypical colposcopy results). The clinical efficacy of the method was evaluated on the base of histological results. The patients whose histological results show negative endocervical margins were accepted for cured. From 37 patients in total with different stage of dysplasia and carcinoma in situ hospitalized at Clinic of surgical gynecology for surgical treatment, in 33 (89%) there are negative endocervical margins. These patients formed the cured group. In four patients (10.8%) were discovered histological evidences for positive endocervical margins. The LEEP was not the final operative procedure for them. They were included in the uncured group. The final results achieved from the study about the efficacy of the used method LEEP has statistical significance (d.f .= 1, X2 = 2.82, p < 0.05). The data shows that the LEEP eliminate completely the affected by malignant process areas of cervix uteri. The LEEP can be used as a common surgical method in the treatment of the women with high stage of pre-carcinoma and carcinoma in situ coli uteri. PMID- 21268399 TI - [Role of oocyte cytoplasmic factors in human IVF failure]. AB - Premature chromosome condensation (PCC) of the sperm chromatin and abnormal dispersion of oocyte chromosomes are independent indirect indicators for cytoplasmic immaturity and cytoskeletal anomalies in the oocyte affecting the normal zygote and embryo formation in human IVF-ET practice. In a group of 66 human unfertilized oocytes, two types of cytoplasmic factors were registered: PCC in 49 (74.24%) and cytoskeletal anomalies in 17 oocytes (25.76%). These data were analyzed according to the main stimulation regimen and female age as well as to the familial factor of infertility. Our results displayed a higher proportion of PCC if the stimulation regimen included gonadotrophins alone (77.55%) compared with the combined GnRH agonist and gonadotrophins administration (22.45%) and in the female age group of 36-40 years (63.33%). Cytoskeletal defects were predominant in the female age group of 31-35 years (46.06%). Remarkable was the significance of cytoplasmic factors in cases of unknown infertility factor- oocytes from these patients included 34.69% of all cells with PCC and 52.94% of all cells with cytoskeletal defects. Hence, these anomalies were probable causes for IVF failure in cases of unexplained infertility Conclusions: 1. The main regimen for hormonal stimulation and the female age influence the cytological status of studied oocytes (cytoplasmic immaturity causing PCC and polyspermy). 2. Cytoplasmic factors (immaturity and cytoskeletal anomalies) are a prognostic factor for the IVF success in cases of unknown infertility problem in the family. PMID- 21268400 TI - [The role of cytological examination in diagnosis of precancer and cancer of the uterine cervix]. AB - AIM AND GOALS: The aim of this study is to evaluate the efficiency of cytologic examination in the diagnosis of precancer and cancer lesions of the uterine cervix. MATERIALS AND METHODS: We made a retrospective study for the period 30.08.2007 to 30.12.2008 in clinic of Oncogynecology, Oncologic center to University Hospital of Pleven. We included 51 patients with inflammatory, dysplastic and microinvasive changes of uterine cervix. They all passed through a cytologic examination before the operation and followed by conization, 42 patients had PAP above III class and 9 had PAP up to II class--no correspondence is found in 17.64% between the PAP test and permanent histological results of the conization and 82.53% we found correspondence. CONCLUSION: Cytologic examination is a screening method for diagnosis of precancer and cancer lesion of the uterine cervix with proved efficiency, easy to perform and cheap, positive and negative predictive value is well. PMID- 21268401 TI - [Epidural analgesia for vaginal delivery]. AB - Epidural anaesthesia is the most efficient method of pain reduction. The effect of pain over physiological mother's and fetuse's process; indications, contraindications and conditions for epidural analgesia for vaginal delivery, as like as side effects and complications of epidural analgesia are established in this review. PMID- 21268402 TI - [Neonatal infections. Diagnostic markers of infection]. AB - Infections are highly prevalent in the neonatal period. Unfortunately the symptoms of infection are non-specific and are seen in other neonatal diseases as: respiratory distress syndrome, metabolic diseases, intracranial hemorrhages. Diagnosis is based on the clinics, microbiologic tests and laboratory markers of infection. Considering the high mortality and serious morbidity associated with neonatal sepsis, a diagnostic marker with a very high sensitivity and negative predictive value approaching 100% is desirable. Unfortunately there is no laboratory marker that has all of the characteristics of ideal infection marker. Procalcitonin, interleukins 6 and 8, CD 11b are early, sensitive markers of infection. C- reactive protein is a late specific marker of infection. CD 64 is the most sensitive marker of late, nosocomial infection. Serial measurement of infection markers will certainly improve the diagnostic sensitivity of these tests, because in most circumstances it is not certain at which stage of the infection the specimen should be taken for analysis. In addition, the use of multiple markers, in particular, combining an early sensitive marker with a late specific test will further enhance the diagnostic accuracy of these mediators in identifying infected cases. PMID- 21268403 TI - [Meiotic maturation of oocytes--interaction between chromatin and cytoskeletal elements]. PMID- 21268404 TI - [Precancerous and cancerous lesions of the uterine cervix--risks of the morphological diagnostics]. AB - In this article authors are analyzing the current state of the morphological macroscopic and microscopic diagnostics of precancerous and cancerous tumors and lesions of the uterine cervix it is made a brief, retrospective view of the development of the relevant questions, examining closely the routinely applied procedures and indicators leading to possible risks of erroneous diagnostics. The evaluation is focusing on diagnostic problems within the area of cytological, as well as, histological analyses. Some lesions in endocervical pathology have the potential to be misinterpreted and are discussed as sources of false-positive smears in cytological diagnostics. More emphasis is placed on those benign lesions which mimics malignancy: ectopias, metaplasias and hyperplasias (mesonephric remants, endometriosis: tunnel clusters, tubal metaplasia, microglandular hyperplasia etc.). PMID- 21268405 TI - [Case report of synchronous manifestation of two malignant tumors--cervical cancer and malignant lymphoma]. AB - According the morphological classification of tumors as metahronnic are defined tumors with more than two histological types in one anatomic region (one body), and as synchronous--these with two histological types in one anatomic area. Affected lymph nodes in cervical cancer is different and depends on the stage and histological type of tumor (squamous and adenocarcinoma) and is an important prognostic factor. Malignant non-Hodgkin's lymphoma populations (NHL) originale from the lymph organs and from their populations downstream lymphoid Stem cell to mature lymphocytes that have opportunities for transformation and proliferation. Recognition of different types of NHL is a complex diagnostic process, in which besides routine cytological and histological methods is requiring the use of immunohistological, imaging and invasive methods. We present the random case developed cervical cancer and malignant lymphoma. PMID- 21268406 TI - [In vitro and in vivo effects of a long-acting anti-influenza agent CS-8958 (laninamivir octanoate, Inavir) against pandemic (H1N1) 2009 influenza viruses]. AB - Laninamivir is a novel neuraminidase inhibitor of influenza viruses and it has been reported that its prodrug, CS-8958 shows a long-lasting characteristics. Using viruses isolated in Nagasaki of pandemic (H1N1) 2009 influenza virus which cause pandemic in 2009, it was shown that laninamivir has a strong inhibitory activities against their neuraminidases and virus replication in cultured cells, and strong binding stability to the virus NA. Furthermore, a single intranasal administration of CS-8958 showed a superior reduction of virus load in lungs in mouse infection model. These suggest that CS-8958 will work as a long-acting neuraminidase inhibitor to an infection with pandemic (H1N1) 2009 influenza viruses as well. PMID- 21268408 TI - [New Delhi-metallo-beta-lactamase 1 (NDM-1)-producing, multiple drug resistant Enterobacteriaceae]. PMID- 21268407 TI - [Retrospective investigation on the cases treated with liposomal amphotericin B]. AB - We have retrospectively investigated clinical profile, efficacy, and safety in 41 patients who were treated with liposomal amphotericin B (L-AMB) in Aichi Medical University Hospital between January 2008 and June 2009. It turned out that L-AMB was used for severe infectious diseases and 31.7% cases discontinued L-AMB therapy because of death. L-AMB was administered as the second-line therapy in 56.1% (23/41), and was not effective in 48.8% (20/41). L-AMB was administered as the first-line therapy in 43.9% (18/41); (1) 1 for cryptotoccal infection, (2) 7 for severe sepsis or septic shock, (3) 2 for the case which cannot remove medical device and might have biofilm formation, (4) 6 for the induction of step-down therapy concept, (5) 2 for febrile neutropenic patients who have needed aggressive empiric therapy. There was no significant difference in serum potassium level (p = 0.10) and serum creatinine level (p = 0.05) between pretreatment and posttreatment with L-AMB. The serum creatinine level before initial treatment with L-AMB was 1.31 +/- 1.30 mg/dL. The patients for 7.3% (3 cases) had dialyzed before initial treatment with L-AMB, however, there was no case who need dialysis after administration of L-AMB. As for the highest creatinine level in L-AMB administered cases, 29.3% (12/41) and 24.4% (10/41) were normal to abnormal, and abnormal to abnormal, respectively. This is the first investigational report when the serum creatinine level before initial administration of LAMB had been abnormal. The other antimicrobial agents, which might have influenced renal function, were administered to 51.2% cases (21/41). That means the cases administered L-AMB might have other bacterial infections. As for the serum creatinine level, we observed the changing cases and the cases which did not cause the change at all regardless of the administering period of LAMB. The serum potassium level before initial administration of L-AMB was 4.1 +/ 0.8 mEq/L, concomitant use of furosemide etc. was 31.7% (13/41), the lowest serum potassium level was 3.4 +/- 0.9 (1.9-6.2)mEq/L in during using L-AMB, the serum potassium was 34.1% (14/41) in replenish potassium during administration of L-AMB, and the total replenished potassium was 131.25 mEq. We did not observe the case who had died because of the low potassium. Since L-AMB was the only fungicidal drug, when we use L-AMB for the serious infectious diseases to make the best use of the characteristic, we have to pay attention to the concomitant medication, renal function and the serum potassium level. PMID- 21268409 TI - [Prevention and control of nosocomial infections for multi-drug resistant Acinetobacter baumannii]. PMID- 21268410 TI - [Systematic review on the role of neurocognitive deficits in first-degree relatives of schizophrenic patients]. AB - AIM: To systematically review studies exploring cognitive deficits in first degree relatives of schizophrenic patients as putative indicators of vulnerability for schizophrenia and identifying if some dysfunction may represent endophenotypic features with genetic liability to the disorder. METHODS: Studies focusing on cognitive performances of first-degree relatives of schizophrenic patients within three neuropsychological domains (i.e., attention, memory and executive functions) were included. Searches included MedLine, Embase, PsychINFO, and bibliographies. RESULTS: No clear-cut conclusions can be drawn from the published literature on the topic, since results of reviewed studies were biased by a number of limitations (e.g., low sample sizes, heterogeneity of samples, use of different assessment measures). However, some specific deficits in each of the investigated domains have been reported in both schizophrenic patients and, to a lesser degree, in their first degree relatives, thus suggesting that neurocognitive functions may be considered putative indicators of illness vulnerability. CONCLUSIONS: Further evidences are needed to obtain definitive conclusion on the role of neuropsychological functions of first-degree relatives of schizophrenic patients as a marker of illness vulnerability. Future studies should adopt more rigorous research methods and more specific and sophisticated measures of cognitive functions. PMID- 21268411 TI - [What are the differences between well-being therapy and anxiety management in the school setting?]. AB - BACKGROUND: In the last decade there has been increasing interest in the potential of early preventive interventions capable of promoting psychological well being in order to reduce the risk of childhood psychological distress. This study analyzes the differential effects of strategies for promotion of psychological well-being (Well-Being Therapy, WBT) and removal of distress (Anxiety Management, AM) in a non clinical school setting. METHODS: Our sample consisted of eight classes (N=162 students) attending middle schools in Northern Italy which were randomly assigned to a protocol derived from WBT (4 classes) and to an anxiety-management protocol (AM) (4 classes). Immediately before and after both school interventions students were assessed using the Psychological Well Being Scales (PWB), Kellner's Symptom Questionnaire (SQ) and the Revised Children's Manifest Anxiety Scale (R-CMAS). A six month follow-up was performed in the following school year, and students were re-assessed with the same psychometric instruments. RESULTS: Our results lend support to the possibility to change attitudes to psychological well-being and distress with brief interventions in school (both well-being improving and distress removing). CONCLUSIONS: Further investigations should determine whether the combined and sequential integration of well-being and symptom oriented strategies may yield more complete and lasting effects that each strategy alone. PMID- 21268412 TI - [Reward processing and psychopathology]. AB - Reward processing permits to establish if and how an environmental stimulus or a future goal is reinforcing or punishing for the subject. This process is at the basis of reinforcement learning and decision making; is principally based on the orbitofrontal cortex and its connections with the striatum and the limbic system. If a dysfunctional reward processing has been often reported in substance abusers or pathologic gamblers, recent studies reported a dysfunction of this process in patients with other psychiatric disorders, previously not assessed by this experimental perspective, for example attention deficit/hyperactivity disorder, mood disorders, eating behaviour disorders and cluster B personality disorders. Experimental findings on a dysfunctional reward processing in these disorders are reviewed and discussed, in order to trace directions for future studies, that need to clarify if different dysfunctions are associated to different psychiatric disorders. PMID- 21268413 TI - [Temperament and attachment in alcohol addicted patients of type 1 and 2]. AB - OBJECTIVES: Our study first objective is the evaluation of the attachment to partner and affective temperamental traits in alcohol addicted patients; the second objective is the evaluation of differences between alcohol addicted patients of type 1 and 2 according to Cloninger and Sullivan. METHODS: The sample is composed of 40 adult patients with a alcohol addiction diagnosis enrolled at the Alcoholic Service of the Viterbo "Villa Rosa" Nursing Home. Patients have been submitted the semistructured interviews SCID I and SCID II and the self submitted TCI-R test. Furthermore they have completed the TEMPS-A (Temperament Evaluation Memphis, Pisa, Paris and San Diego) and the ECR (Experiences in Close Relationships). RESULTS: The attachment profile shows that 50% of patients have an insecure type of attachment so distributed: 25.5% of patients show a preoccupied type of attachment, 17.5% appear dismissing and 7.5% fearful. As for the affective temperament we observed a major frequency of elevated scores of Hyperthymic TEMPS-A (OR = 1.68; p < 0.01) compared to controls. At last type 2 compared to type 1 is characterized by a more elevated mid scores presence at the Avoiding dimension of Scale ECR. CONCLUSIONS: The alcohol addicted patients sample mainly show an attachment of insecure type and, with major frequency, a hyperthymic temperament. Moreover in type 2 patients there is a prevalence of the avoiding dimension in intimate relationships. PMID- 21268414 TI - [A trial to measure the effectiveness of an intervention in the assessment and rehabilitation of cognitive functions in psychotic individuals]. AB - AIMS: The present study aims to evaluate the outcome of two different approach in rehabilitation: IPT Cognitive Training (Brenner's) administered in conjunction with Treatment As Usual (TAU) versus TAU as a sole intervention, on cognitive functions such as attention, memory, and executive functioning in a sample of participants with a diagnosis of a Schizophrenia Spectrum Disorder. Levels of problem-solving have been highlighted in participants not only in relation to the method used but also to the age, between 17-30 years with 1-3 years of mental illness and participants who are 30+ years with over 9 years of mental illness. METHOD: 77 participants completed the study and were matched according to diagnosis and severity of illness. 37 subjects (48%) received TAU and 40 subjects (52%) received IPT Cognitive Training+TAU. Each group have participants aged between 17-30 years with 1-3 years of mental illness and 30+ years with over 9 years of mental illness. A Neuropsychological Protocol particularly made allow assessments and was administered pre-intervention and 24 months post intervention. RESULTS AND CONCLUSIONS: Participants who received Cognitive Training IPT+TAU showed statistically significant improvements in Selective Attention (p < 0.05) instead of the others with only TAU. By both method significant improvements were also found in all considered outcome variables (p = 0.04-0.001) on working memory, short and long-term memory, semantic memory and logical-deductive ability. Neither rehabilitation treatment produced any improvement in problem solving once compromised. Logical-Deductive Ability showed improvements only in patients aged between 17-30 years with 1-3 years of mental illness in comparison with participants aged over 30 years with 9 or more years of illness. PMID- 21268415 TI - [Mental retardation and somatoform disorder with globus pharyngeus: a case study of comorbidity]. AB - AIM: The case study of a young woman affected by moderate mental retardation and somatoform disorder not otherwise specified, with globus pharyngeus, is reported. The purpose is to show how an articulated diagnosis and treatment of individuals with mental retardation and comorbid psychopathology may produce syndromal and functional recovery. METHODS: Psychometric testing of the patient was performed, in order to monitor the prescribed, duloxetine-based, treatment. RESULTS: After six weeks of treatment the patient underwent full remission. DISCUSSION: The correct identification of psychiatric comorbidity is the prerequisite for an appropriate complementary pharmacological intervention, aimed at improving the quality of life. PMID- 21268416 TI - [Some ideas facing the demographic crisis that threatens the intensive care.]. PMID- 21268417 TI - [Non invasive ventilation in the ICU for the neuromuscular patient: ethical issues]. AB - Non-invasive mechanical ventilation in patients with chronic neuromuscular disorders is an effective tool for treating dyspnea or sleep disturbances often observed in such patients. So, NIV has to be considered as a palliative treatment and it must systematically be offered to these patients. Mechanical ventilation, non-invasive or invasive (via a trachesotomy) have to be considered systematically with patients and families at an earlier stages of these diseases in order to design a strategy in case of acute respiratory failure. In a second parent paper of this issue, we discuss the medico-legal implications of mechanical ventilation in neuromuscular failure, particularly the end-of-life aspects. PMID- 21268418 TI - [Non invasive ventilation in the ICU for the neuromuscular patient: legal issues]. AB - The legal frame in which chronic mechanical ventilation is placed in Switzerland and France is discussed in this article. Safety of the patients and responsibility of caregivers are considered. We also discuss the ethical and legal aspects of the end-of-life of these patients, particularly when they decide that mechanical ventilation must be interrupted because they do not more tolerate their poor quality of life, and when they deliberately decide to die. PMID- 21268419 TI - [Resilience engineering in intensive care]. AB - The process of health care delivery in Intensive Care Units (ICUs) is subject to significant workload fluctuations and unpredictable events. Medical and nursing staff, while relying on protocols, must adjust to these "out of the routine" disturbances by displaying initiative and innovation. The aim is to maintain the ratio risk-performance in admissible margins for the institution despite severe disruptions of operation. The assumption is that this resilience ability may be intentionally built by a specific work organization. The theoretical framework of "resilience engineering" described here could be a powerful tool in organizational designing suited to the ICUs. PMID- 21268420 TI - [Pathophysiological mechanisms of organ dysfunction in sepsis]. AB - Sepsis is defined as the systemic inflammatory response to an infection. The occurrence of organ dysfunction increases the severity of sepsis. Complex interactions between multiple immunomodulating mediators and various cell populations, activated secondarily to the initial infectious insult, promote the development of organ dysfunction in sepsis. Although septic organ dysfunction has long been considered as the end result of chaotic, uncontrolled and deregulated inflammatory cascades, it might instead represent an adaptive response to avoid the occurrence of irreversible tissue damage and end-organ injury. In this article, we review the major mechanisms involved in organ dysfunction during sepsis, and also present the concept of organ dysfunction as an adaptive response to the septic process. PMID- 21268421 TI - [Pre- and intra-hospital over-resuscitation in burns: frequent and deleterious]. AB - Major burns are characterized by an initial capillary leak which requires fluid resuscitation for hemodynamic stabilisation. While under-resuscitation was the major cause of death until the 80ies, over-resuscitation has become an important source of complications: abdominal compartment syndrome, escharotomies, impaired gas exchange and prolonged mechanical ventilation and hospital stay. The fluid creep started in the 90ies with an increasing proportion of the first 24 hours' fluid delivery above the 4 ml/kg/% BSA Parkland prediction. The first alerts were published under the form of case reports of increased mortality due to abdominal compartment syndrome and respiratory failure. The paper analyses the causes of this fluid creep, and the ways to prevent it, which includes rationing prehospital fluid delivery, avoiding early colloids and permissive hypovolemia. PMID- 21268422 TI - [Neurally adjusted ventilatory assist: a revolution of mechanical ventilation?]. AB - Neurally adjusted ventilatory assist or NAVA is a new assisted ventilatory mode which, in comparison with pressure support, leads to improved patient-ventilator synchrony and a more variable ventilatory pattern. It also improves arterial oxygenation. With NAVA, the electrical activity of the diaphragm is recorded through a nasogastric tube equipped with electrodes. This electrical activity is then used to pilot the ventilator. With NAVA, the patient's respiratory pattern controls the ventilator's timing of triggering and cycling as well as the magnitude of pressurization, which is proportional to inspiratory demand. The effect of NAVA on patient outcome remains to be determined through well-designed prospective studies. PMID- 21268423 TI - [Assisted suicide in the EMS (Medico-Social Establishment): recommendations for ethics consultation of the FEGEMS (Geneva Federation of Medico-Social Establishment]. PMID- 21268424 TI - [Home visit]. PMID- 21268425 TI - [Benedict XVI and AIDS: first my fault?(1)]. PMID- 21268426 TI - [The funeral video recording is born]. PMID- 21268427 TI - [I love my job as a doctor]. PMID- 21268428 TI - [Cardiorenal syndrome and its pathophysiological implications]. AB - Cardiorenal syndrome is a pathophysiological condition in which combined cardiac and renal dysfunction amplifies individual organs failure progression. Therefore, morbidity and mortality is higher in this group patients. Its incidence has increased due to increased longevity and because patients survive more years with cardiac and/or renal dysfunction. The aim of the present paper is the revision of the most recent advances in this area. For a better comprehension and systematization of this syndrome it is suggested a classification in various subtypes (I-V). Type I reflects an abrupt worsening of cardiac function leading to acute kidney injury. Type II results from chronic abnormalities in cardiac function (chronic heart failure) causing progressive and potentially irreversible kidney disease. Type III consists of an abrupt worsening of renal function (acute kidney lesion) causing acute cardiac dysfunction (heart failure, arrhythmia or ischemia). Type IV describes a state of chronic kidney disease contributing to decrease cardiac function, ventricular hypertrophy, and/or increased risk of adverse cardiovascular events. Type V reflects a systemic condition causing both: cardiac and renal dysfunction. The clinical use of recently identified biomarkers can be an additional tool in the early diagnosis and stratification of this syndrome. This classification can be particularly useful in the identification of underlying abnormalities and in the establishment of an effective therapeutic approach. PMID- 21268429 TI - [Clopidogrel--proton pump inhibitors drug interaction: implications to clinical practice]. AB - Recent studies have raised the concern that proton pump inhibitors (PPIs) could potentially interfere with clopidogrel antiplatelet effect. This association is frequent in clinical practice and is recommended by recent consensus guidelines in patients taking dual antiplatelet therapy to prevent gastrointestinal (GI) bleeding. Clopidogrel is a pro-drug which needs to be metabolized into its active metabolite, by cytochrome P450, especially by CYP2C19 isoenzyme. Various PPIs can inhibit CYP2C19, which could possibly decrease clopidogrel bioactivation process and, therefore, its antiplatelet effect. Various platelet function studies have shown that omeprazol can significantly decrease clopidogrel inhibitory effect on platelet P2Y12 receptor, leading to an increase in the number of patients who are "nonresponders" to clopidogrel. These pharmacokinetic studies also shown that this is not probably a class effect of PPIs, because they are metabolized to varying degrees by CYP2C19. The clinical impact of these observations remains uncertain, because various observational studies have shown conflicting results, and remains to demonstrate if PPIs can really increase the risk of cardiovascular events in patients taking clopidogrel. In this review we will discuss the pharmacokinetic basis underlying this drug interaction, the effect of different PPIs on platelet function tests and we will analyze in detail the potential clinical implications of using this association, both on cardiovascular and gastrointestinal events. Until further data is available, some clinical strategies can be recommended: (1) individual gastrointestinal risk assessment, with PPIs administration only to patients on dual anti-platelet therapy with additional GI risk factors; (2) preferential use of PPIs that have shown less interference with clopidogrel efficacy; (3) wide separation of PPI and clopidogrel dosing to minimize the risk of interaction (PPI may be given before breakfast and clopidogrel at bedtime); (4) or alternative use of histamine-2 receptor antagonist therapy, in patients at low GI risk. PMID- 21268430 TI - The politics of memory: nation, individual and self. PMID- 21268431 TI - Collective memory divided and reunited: mothers, daughters and the Fascist experience in Germany. PMID- 21268432 TI - The return of science. PMID- 21268433 TI - Routine intraoperative cholangiography in elective laparoscopic cholecystectomy. PMID- 21268434 TI - Reporting disease control rates or clinical benefit rates in early clinical trials of anticancer agents: useful endpoint or hype? AB - Disease Control Rate (DCR) and Clinical Benefit Rate (CBR) are defined as the percentage of patients with advanced or metastatic cancer who have achieved complete response, partial response and stable disease to a therapeutic intervention in clinical trials of anticancer agents. DCR and CBR are commonly reported in many clinical trials in abstracts, papers, meeting presentations and media releases. The frequent use of these measures of drug activity presents the question of whether DCR and CBR are useful additional endpoints in early clinical trials, and if they can reasonably predict the success of an agent in subsequent, adequately powered, randomized trials. There are no comprehensive analyses to demonstrate that CBR and DCR add to the value of traditional response/activity endpoints in early clinical trials. Data from phase II clinical trials in which the DCR or CBR are reported suggest that DCR or CBR provides ambiguous information that likely exaggerates the anticancer activity of the therapy. The terms 'disease control' and 'clinical benefit' in the context of non-randomized trials are themselves disingenuous because neither tumor regression nor stable disease, defined without any consideration of duration of effect or reduction of symptoms appropriate for the specific patient population, are evidence of these endpoints in an individual patient. PMID- 21268439 TI - Yellow fever in Africa and Central and South America, 2008-2009. PMID- 21268441 TI - [Various functions of cytokines in metabolism of bones and cartilage]. PMID- 21268442 TI - Halogenated flame retardants: do the fire safety benefits justify the risks? AB - Since the 1970s, an increasing number of regulations have expanded the use of brominated and chlorinated flame retardants. Many of these chemicals are now recognized as global contaminants and are associated with adverse health effects in animals and humans, including endocrine and thyroid disruption, immunotoxicity, reproductive toxicity, cancer, and adverse effects on fetal and child development and neurologic function. Some flame retardants such as polybrominated diphenyl ethers (PBDEs) have been banned or voluntarily phased out by manufacturers because of their environmental persistence and toxicity, only to be replaced by other organohalogens of unknown toxicity. Despite restrictions on further production in some countries, consumer products previously treated with banned retardants are still in use and continue to release toxic chemicals into the environment, and the worldwide use of organohalogen retardants continues to increase. This paper examines major uses and known toxic effects of commonly-used organohalogen flame retardants, replacements for those that have been phased out, their combustion by-products, and their effectiveness at reducing fire hazard. Policy and other solutions to maintain fire safety while reducing toxicity are suggested. The major conclusions are: (1) Flammability regulations can cause greater adverse environmental and health impacts than fire safety benefits. (2) The current options for end-of-life disposal of products treated with organohalogens retardants are problematic. (3) Life-cycle analyses evaluating benefits and risks should consider the health and environmental effects of the chemicals, as well as their fire safety impacts. (4) Most fire deaths and most fire injuries result from inhaling carbon monoxide, irritant gases, and soot. The incorporation of organohalogens can increase the yield of these toxic by-products during combustion. (5) Fire-safe cigarettes, fire-safe candles, child-resistant lighters, sprinklers, and smoke detectors can prevent fires without the potential adverse effects of flame retardant chemicals. (6) Alternatives to organohalogen flame retardant chemicals include using less flammable materials, design changes, and safer chemicals. To date, before evaluating their health and environmental impacts, many flame retardant chemicals have been produced and used, resulting in high levels of human exposure. As a growing literature continues to find adverse impacts from such chemicals, a more systematic approach to their regulation is needed. Before implementing new flammability standards, decision-makers should evaluate the potential fire safety benefit versus the health and environmental impacts of the chemicals, materials, or technologies likely to be used to meet the standard. Reducing the use of toxic or untested flame retardant chemicals in consumer products can protect human and animal health and the global environment without compromising fire safety. PMID- 21268443 TI - Scientific panel on electromagnetic field health risks: consensus points, recommendations, and rationales. AB - In November, 2009, a scientific panel met in Seletun, Norway, for three days of intensive discussion on existing scientific evidence and public health implications of the unprecedented global exposures to artificial electromagnetic fields (EMF). EMF exposures (static to 300 GHz) result from the use of electric power and from wireless telecommunications technologies for voice and data transmission, energy, security, military and radar use in weather and transportation. The Scientific Panel recognizes that the body of evidence on EMF requires a new approach to protection of public health; the growth and development of the fetus, and of children; and argues for strong preventative actions. New, biologically-based public exposure standards are urgently needed to protect public health worldwide. PMID- 21268444 TI - Tragedy of the commons revisited: the high tech-high risk wireless world. AB - In 1968, Garrett Hardin, an eminent population ecologist from Santa Barbara, CA published an article in Science titled 'Tragedy of the Commons' that was immediately hailed as a landmark piece of thinking. This paper reshaped prevailing views about our place in the ecological network of the planet and was pivotal in defining how pursuit of our individual actions to maximize self interest will, across populations all doing the same thing, result in diminished and overused environmental resources. Before sustainability was even a buzzword, Hardin created a way of seeing the world that emphasized how individuals must learn to recognize and to act with more in mind than squeezing one more cow onto the common pasture. He gave us new ways to think about how we might better manage our resources in the face of new technologies. He was not a believer in the technological fix. Those lessons are highly relevant today to the unchecked proliferation of wireless radiofrequency signals, thought by many to cause serious health consequences. PMID- 21268445 TI - Health risk assessment of electromagnetic fields: a conflict between the precautionary principle and environmental medicine methodology. AB - The purpose of the precautionary principle is that legal requirements are to be made to safeguard against the possible health risks that have not yet been scientifically established. That a risk is not established cannot, therefore, be used as an excuse for not applying the principle. Yet, that rationale is exactly what is happening in the case of the possible health risks from exposure to electromagnetic fields (EMF). The scientists, representing both the World Health Organization and the European Commission, do not have at all the precautionary principle in mind when they report on health risks. Their starting point is instead to determine whether new research findings have been scientifically established and thus cannot be the basis for an amendment to the existing exposure limits. Uncertain indications of risk are ignored or played down. This approach is in conflict with European Union (EU) law, which requires that the degree of scientific uncertainty should be presented correctly. A thorough examination of the state of research shows many serious indications of possible health risks from exposure very far below existing limits for EMF. Case law, for other types of exposure, also shows that the precautionary principle can be applied on the basis of weaker evidence than that. Our investigation shows that the precautionary principle is not being used for its intended purpose in relation to exposure to EMF. The reason for this position is that decision-makers are being misled by inaccurate risk assessments. PMID- 21268446 TI - The environment and reproductive health. PMID- 21268447 TI - Effects of environmental estrogens on animals in Israel: implications for effects on humans. AB - In the last decade interest has increased in the possible effects of endocrine disruptor compounds. Numerous papers have appeared as to their possible effects on humans, but definitive effects are hard to demonstrate. In the field of animal husbandry, however, the effects of the endocrine disruptors are well documented. This paper discussed the effects of the endocrine disruptors seen in animals and the possible implications for humans. The areas considered are reproductive disorders, premature udder/breast development, prolapsed oviduct/uterus, scrotal atrophy, and skewed sex ratio. PMID- 21268448 TI - The environmental compartments of environmental hormones. AB - Compounds with estrogenic activity are ubiquitous in nature. Phytoestrogens and steroidal estrogens are found naturally in the food, in particular legumes and milk products. Naturally occurring steroidal estrogens and synthetic estrogens such as ethinylestradiol are constantly excreted into the environment as the result of the release of animal and human waste. As the result of this constant exposure, testosterone, estrogens, and ethinylestradiol are readily detectable in every stream examined in Israel. The concentrations observed of the estrogenic compounds are physiological, i.e., at these concentrations fish reproductive function can be affected. Estrogenic compounds do not usually reach the groundwater but testosterone percolates through the soil and is frequently found in the groundwater. In the dry season, there are no natural or synthetic steroids in the streams of the Jordan River watershed. However, at the beginning of the rainy season, both estrogen and testosterone reach the surface waters in the runoff from fields with manure, whereas ethinylestradiol reaches the streams in overflows from oxygenation ponds used to treat sewage prior to irrigation. PMID- 21268449 TI - Synergistic ecotoxicity of APEOs-PAHs in rivers and sediments: is there a potential health risk? AB - The occurrence and persistence of anthropogenic pollutants in the environment showing estrogenic-endocrine modulating effects in aquatic organisms is a 'hot' issue of major health- and environment-related concern worldwide. The population growth and the increasing scarcity of water in many regions of the world have led to a comprehensive reuse of treated wastewater that, ultimately, may cause a long term concentration buildup of many toxic persistent organic pollutants (POPs) in the closed cycle of water supply and wastewater treatment and reuse. The endocrinic/mutagenic potencies of the EDCs-branched chain alkylphenol ethoxylates (APEOs), polycyclic aromatic hydrocarbons (PAHs), and their metabolites are well documented. From approximately 5.5 x 108 m3/y of sewage produced in Israel, approximately 70% are reused, following a conventional, or advanced, activated sludge or sand aquifer treatment (SAT). A major related question is: Does this practice conform to sustainability? Our studies reveal that (a) the concentrations of APEOs and PAHs in Israel rivers and sediments do pose a potential health risk problem; and (b) the synergistic ecotoxicologic impact of environmentally relevant mixtures of these POPs, in WWTP effluents, constitutes an inconsistency, healthwise, with sustainability practice. PMID- 21268450 TI - Variability of phthalate monoester levels in daily first-morning urine from adult women: a pilot study. AB - Phthalate exposure is ubiquitous and may affect child and adolescent health through both in utero exposure and direct exposure during childhood. Variability in exposure within women is not well documented. We analyzed 90 first-morning urine samples collected by ten reproductive-age women for phthalate metabolites and creatinine. Monoethyl [122 ng/mL (geometric mean concentration = 139 microg/g creatinine)], monobutyl [85.4 ng/mL (97.0 microg/g creatinine)], monobenzyl [37.2 ng/mL (42.2 microg/g creatinine)], and mono-2-ethylhexyl phthalate [9.4 ng/mL (10.7 microg/g creatinine)] were detected in most (94.4%) samples. The concentrations ranged from 23.8-1090 ng/mL, 43-437 ng/mL, 12.4-186 ng/mL, and 1.3 31.1 ng/mL, respectively. We observed considerable variation in phthalate concentrations by day for individual women. The intraclass correlation coefficient, indicating the proportion of variance explained by differences between subjects, ranged from 0.40 (monobutyl) to 0.68 (monoethyl). Monobenzyl and monoethyl phthalates showed higher levels on weekends as compared with weekdays (p = .01 for both). We found no significant difference between monoester levels from different menstrual cycles. Phthalate concentrations vary considerably for an individual and may require multiple samples for accurate assessment PMID- 21268451 TI - Menstrual cycle variability and the likelihood of achieving pregnancy. AB - The menstrual cycle is an important indicator of underlying hormonal function. Although menstrual cycle variability (sometimes referred to as 'regularity') is associated with a variety of demographic, behavioral, occupational, and environmental factors, as well as with several chronic diseases, few studies have examined its association with fecundity. We investigated whether a woman's menstrual cycle variability was associated with the likelihood of her achieving pregnancy. In this prospective study, we analyzed 3,536 menstrual cycles from 401 women (aged 19-41) recruited from 1990-1994. The women provided daily diaries recording menstrual bleeding, intercourse, and birth control use. Urine samples were assayed for human chorionic gonadotropin to identify early pregnancies during each menstrual cycle. Each woman's menstrual cycle variability was defined by the standard deviation of her cycle lengths during followup. The median follow up was eight cycles. The outcome was her per-cycle probability of pregnancy. We found that women with high menstrual cycle variability had a reduced (51% lower) per cycle probability of pregnancy (fecundity ratio: 0.49; 95% confidence interval: 0.31, 0.77) compared with women with minimal variability. This relationship was independent of a woman's age and her mean cycle length. Thus, researchers and clinicians using menstrual cycle characteristics as indicators of endocrine or reproductive health should include measures of cycle variability in addition to the more commonly examined cycle length. PMID- 21268452 TI - Survival case of colchicine intoxication following ingestion of a lethal dose. AB - INTRODUCTION: There have been few reports of cases where the ingestion of colchicine was utilized as a method of suicide and accordingly, its effect on the human body is not fully understood. It has been reported that all individuals who ingested more than 0.8 mg/kg of colchicine died of shock within 72 hours. CASE REPORT: A 46-year-old man was sent to the hospital after ingesting a lethal amount of colchicine (total dose, 71 mg; body weight, about 70 kg) in a suicide attempt. On admission, his vital signs were stable and physical examination was unremarkable. Laboratory findings were normal. He was admitted to the intensive care unit, and severe diarrhea and vomiting commenced approximately 4 hours after ingestion, accompanied by electrolyte disturbance, coagulopathy and renal dysfunction. Bone marrow suppression, bradycardia, alopecia and myoneuropathy also occurred, these findings being the typical symptoms of colchicine poisoning. The symptoms were almost resolved after about 1 week and he was discharged on the 19th day of admission. CONCLUSION: Immediate and precise care for colchicine poisoning successfully saved the patient's life. PMID- 21268453 TI - The biggest evolutionary jump: restructuring of the genome and some consequences. AB - In this paper, the evolution of the cell is investigated till the level of complexity obtained by protists. Particular attention is paid to the genomic compartment and to the question: why has the genome of prokaryotes remained so small over more than 3 billion years and more than 3 trillion generations? Constraints on their genome evolution may be attributed mainly to: 1) the fact that repetitions of nucleotide sequences longer than 12 to 15 bp are forbidden according to Thomas' principle; 2) the high cost of the control of gene expression by means of regulatory proteins: this cost increases exponentially with chromosome elongation. The formation of chromatin, i. e. the wrapping of DNA around the nucleosomes, removed these constraints and allowed the increase of the genome and especially of the redundant sequences of DNA, whose role is discussed. The transformation and growth of the genome generated a trend towards separation of the various physiological functions and of their control. The formation of a nuclear envelope may have begun with the advent of mitosis, which replaced the simple but delicate device of pushing the newly formed DNA into the daughter prokaryotic cells. An increase of the O2 concentration in waters stimulated further evolution: the new cell established symbiosis with a bacterium capable of protecting against peroxides and performing aerobic respiration. The increased O2 concentration also led to the production of sterols, which became an important component of the cell membrane. The mutual adaptation of cells belonging to different domains involved further modifications, leading to the birth of proto eukaryotic cells and facilitating the establishment of further symbioses with photosynthetic cyanobacteria. Proto-eukaryotic cells were devoid of motility and contractility, as are the cells of red algae, fungi and Zygnematales today. Both these faculties evolved when the protist eukaryotic cell acquired flagella, cytoplasmic contractility and sensors to govern them. PMID- 21268454 TI - Seeking excellence. PMID- 21268455 TI - Routine practices to reduce the risk of infectious diseases. PMID- 21268456 TI - Post-exposure management of occupational exposure to blood/body fluids. PMID- 21268457 TI - Informatics is about patient care (not technology). PMID- 21268458 TI - Dos and don'ts of social networking...avoid a social networking nightmare. PMID- 21268459 TI - Follow ISMP guidelines to safeguard the design and use of automated dispensing cabinets. PMID- 21268460 TI - Lost in translation: nursing care delivery models and staff mix. PMID- 21268461 TI - The effects of opposition and gender on knee kinematics and ground reaction force during landing from volleyball block jumps. AB - The aim of this study was to examine the effect of opposition and gender on knee kinematics and ground reaction force during landing from a volleyball block jump. Six female and six male university volleyball players performed two landing tasks: (a) an unopposed and (b) an opposed volleyball block jump and landing. A 12-camera motion analysis system (120 Hz) was used to record knee kinematics, and a force platform (600 Hz) was used to record ground reaction force during landing. The results showed a significant effect for level of opposition in peak normalized ground reaction force (p = .04), knee flexion at ground contact (p = .003), maximum knee flexion (p = .001), and knee flexion range of motion (p = .003). There was a significant effect for gender in maximum knee flexion (p = .01), knee flexion range of motion (p = .001), maximum knee valgus angle (p = .001), and knee valgus range of motion (p = .001). The changes in landing biomechanics as a result of opposition suggest future research on landing mechanics should examine opposed exercises, because opposition may significantly alter neuromuscular responses. PMID- 21268462 TI - Seasonal variation in physical activity among preschool children in a northern Canadian city. AB - Little research has examined seasonal differences in physical activity (PA) levels among children. Proxy reports of PA were completed by 1,715 parents on their children in Edmonton, Alberta, Canada. Total PA (TPA) minutes were calculated, and each participant was classified as active, somewhat active, or inactive. Logistic regression models were conducted to examine associations between PA status and seasons. Significant seasonal differences were observed for TPA, weekday PA, weekend PA, and active play. Children were significantly more likely to be physically active in the summer and spring and somewhat physically active in the summer and fall, relative to winter Children living in cold climates are less likely to be physically active in the winter. PMID- 21268463 TI - A primer-test centered equating method for setting cut-off scores. AB - This study evaluated the use of a new primary field test method based on test equating to address inconsistent classification among field tests. We analyzed students' information on the Progressive Aerobic Cardiovascular Endurance Run (PACER), mile run (MR), and VO2max from three data sets (college: n = 94; middle school: n = 39; elementary school: n = 96). Using the college and elementary school data, the equivalent relationship between PACER and MR scores was first established by the Kernel equating method. This yielded MR scores derived from PACER (mile run PACER equated [MR PEQ]), which were used to predict maximal oxygen uptake (VO2max) and classify students according to the FITNESSGRAM Healthy Fitness Zones. We compared the results to the predictions and classifications based on measured VO2max, MR and PACER-predicted VO2max and cross-validated the relationships using the middle school data. We found the test conversion to be accurate and that the MR PEQ scores functioned similarly to the original MR scores. Both performed better than the original PACER scores in predicting VO2max and classifying students. The middle school data generally supported these results. The proposed method is accurate and effective in setting a new field test onto the same scale of a primary field test and determining its cut-off scores. PMID- 21268464 TI - Visual illusions and the control of ball placement in goal-directed hitting. AB - When hitting kicking, or throwing balls at targets, online control in the target area is impossible. We assumed this lack of late corrections in the target area would induce an effect of a single-winged Muller-Lyer illusion on ball placement. After extensive practice in hitting balls to different landing locations, participants (N = 9) had to hit a ball to a distant target specified by the vertex of a single-winged Muller-Lyer configuration. Impact velocity was not significantly "tricked" by the pictorial illusion, suggesting that, even when late corrections in the target area are absent, some motor behaviors are not susceptible to the influence of the visual environment surrounding the target. PMID- 21268465 TI - The influence of audience and monetary reward on the putting kinematics of expert and novice golfers. AB - We investigated changes in movement kinematics and attentional focus when expert and novice golfers performed a golf-putting task under pressure. Six male professional golfers and five male novice golfers performed 100 acquisition trials, followed by 10 trials in the pressure condition with a performance contingent cash reward and small audience. After the 10 trials in the pressure condition, participants answered a questionnaire concerning attentional focus during both types of trial, including such aspects as conscious control of movements and the effects of distraction. A pressure manipulation check revealed a modest increase in physiological arousal, in that heart rate increased by about 10 bpm although state anxiety did not increase. A two-dimensional analysis of movement kinematics revealed that the amplitudes of arm and club movements decreased on the backswing in the pressure condition. Arm and club movement speed decreased on the foreswing in both experts and novices. Furthermore, neither experts nor novices changed their attentional focus in the pressure condition. Whereas previous studies of "choking under pressure" focused on attentional changes, the kinematic changes found in the present study were possibly caused by the influences of strategy modification and/or emotional response. Choking phenomena can be explained by attentional changes, along with the influences of strategy modification and/or emotional response under pressure. PMID- 21268466 TI - Normative feedback effects on learning a timing task. AB - This study investigated the influence of normative feedback on learning a sequential timing task. In addition to feedback about their performance per trial, two groups of participants received bogus normative feedback about a peer group's average block-to-block improvement after each block of 10 trials. Scores indicated either greater (better group) or less (worse group) than the average improvement, respectively. On the transfer test 1 day later which required producing novel absolute movement times, the better group demonstrated more effective learning than the worse group. These findings add to the mounting evidence that motivational factors affect motor skill learning. PMID- 21268467 TI - Developmental gender differences for overhand throwing in Aboriginal Australian children. AB - In a review of 46 meta-analyses of gender differences, overhand throwing had the largest gender difference favoring boys (ES > 3.0). Expectations for gender specific performances may be less pronounced in female Australian Aborigines, because historical accounts state they threw for defense and hunting. Overhand throwing velocities and kinematics were recorded in 30 female and male Aboriginal Australian children 6-10 years old. Results indicated the Aboriginal girls and boys were more similar in horizontal ball velocities than U.S. girls and boys. Throwing kinematics between girls and boys were also more similar in Australian Aborigines than U.S. children. Aboriginal girls threw with greater velocities than U.S., German, Japanese, and Thai girls, while the boys were similar across cultures. PMID- 21268468 TI - Sport education and extracurricular sport participation: an examination using the trans-contextual model of motivation. AB - In this study, we used the trans-contextual model of motivation (TCM) to examine the effect of Sport Education (SE) on students' participation in a voluntary lunch recess sport club. A total of 192 participants (ages 9-14 years) completed measures of the TCM constructs before and after a 12-week SE intervention period. Participants had the opportunity to participate in weekly, voluntary lunch recess sport club sessions during the intervention period. SE elicited a moderate increase in autonomous motives in physical education. The TCM accounted for a significant proportion of the explained variance in lunch recess sport club intention and participation. Autonomy-supportive curricular models, such as SE, may have the potential to facilitate transfer of motivation and participation in physical activity from a physical education to an extracurricular context. PMID- 21268469 TI - How can perceived autonomy support influence enrollment in elective physical education? A prospective study. AB - This prospective study was designed to investigate the influence of high students' perceived teacher autonomy support in mandatory physical education on their intention and actual enrollment in elective physical education. Participants included 545 ninth-grade students enrolled in three suburban high schools in a major midwestern metropolitan area. A series of hypothesized models related to autonomy support within the Theory of Planned Behavior were tested. Structural equation modeling results demonstrated that perceived autonomy support provided by teachers in mandatory physical education could predict elective physical education enrollment indirectly via the mediation of attitudes and intention in the Theory of Planned Behavior Providing support for students' autonomy in physical education may hold potential promise for enhancing their future physical activity engagement. PMID- 21268470 TI - Evaluating the prediction of maximal heart rate in children and adolescents. AB - In this study, we compared measured maximal heart rate (HRmax) to two different HRmax prediction equations [22 - age and 208 - 0.7(age)] in 52 children ages 7-17 years. We determined the relationship of chronological age, maturational age, and resting HR to measured HRmax and assessed seated resting HR and HRmax during a graded exercise test. Maturational age was calculated as the maturity offset in years from the estimated age at peak height velocity. Measured HRmax was 201 +/- 10 bpm, whereas predicted HRmax ranged from 199 to 208 bpm. Measured HRmax and the predicted value from the 208 - 0.7(age) prediction were similar but lower (p < .05) than the 220 - age prediction. Absolute differences between measured and predicted HRmax were 8 +/- 5 and 10 +/- 8 bpm for the 208 - 0.7 (age) and 220 - age equations, respectively, and were greater than zero (p < .05). Regression equations using resting HR and maturity offset or chronological age significantly predicted HRmax, although the R2 < .30 and the standard error of estimation (8.2 8.5) limits the accuracy. The 208 - 0.7(age) equation can closely predict mean HRmax in children, but individual variation is still apparent. PMID- 21268471 TI - Effect of a prolonged altitude expedition on glucose tolerance and abdominal fatness. AB - In the present study, we investigated the effect of a long-term mountain expedition on glucose tolerance and insulin action. Twelve registered mountaineers ages 31 years (SD = 1.1) participated in a 25-day expedition at a 2,200-3,800-m altitude with an average duration of 8 hr per day. Arterial oxygen saturation (SaO2) was substantially reduced during hiking. Glucose tolerance and insulin responses were measured prior to and twice during the expedition period. Maximal oxygen consumption increased from 43.0 +/- 2.7 to 49.1 +/- 2.2 mL/kg/min. Percentage of body fat decreased from 19.4 +/- 6.8% to 16.9 +/- 5.9%. The area under the curves for insulin and glucose during the oral glucose tolerance test were also reduced in Days 3 and 25. The present study demonstrated that altitude hiking activity is an effective lifestyle intervention to improve insulin action. PMID- 21268472 TI - Who takes risks in high-risk sports? A typological personality approach. AB - We investigated the risk-taking behaviors of 302 men involved in high-risk sports (downhill skiing mountaineering rock climbing, paragliding, or skydiving). The sportsmen were classified using a typological approach to personality based on eight personality types, which were constructed from combinations of neuroticism, extraversion, and conscientiousness. Results showed that personality types with a configuration of low conscientiousness combined with high extraversion and/or high neuroticism (impulsive, hedonistic, insecure) were greater risk-takers. Conversely, personality types with a configuration of high conscientiousness combined with low extraversion and/or high extraversion (skeptic, brooder, entrepreneur) were lower risk-takers. Results are discussed in the context of typology and other approaches to understanding who takes risks in high-risk domains. PMID- 21268473 TI - A measurement and conceptual investigation of exercise imagery establishing construct validity. AB - We assessed the factor structure of a revised version of the Exercise Imagery Inventory (ELI; Giacobbi, Hausenblas, & Penfield, 2005), second-order interrelationships for cognitive and motivational forms of mental imagery, and associations with exercise behavior and barriers self-efficacy. A convenience sample of 358 (M age = 20.55 years, SD = 3.88) college students completed the EII revised (EII-R), a measure of barriers self-efficacy and the Leisure-Time Exercise Questionnaire. The EII-R demonstrated reliability and factorial validity with good model fit statistics. We observed second-order relationships among scale scores and discriminant validity evidence that distinguished cognitive (e.g., exercise technique, exercise routines) and motivational (e.g., appearance/health, exercise self-efficacy, exercise feelings) factors. The second order imagery factors were significantly and moderately associated with barriers self-efficacy and exercise behavior. PMID- 21268474 TI - A cross-cultural perspective of parental influence on female adolescents' achievement beliefs and behaviors in sport and school domains. AB - Little is known about parental socialization processes for youth participants from different cultural backgrounds. The purpose of this study was to examine parental influence on self-perceptions, task values, and achievement behaviors among female adolescents from two cultures using Eccles' expectancy-value theory (Eccles et al., 1983). Twelve Anglo Canadian and nine East Indian female adolescents were interviewed about perceptions of parental influence on expectancy-value constructs for sport and academic domains. Inductive and deductive content analyses were performed to identify lower and higher order themes from interview responses. Similarities and differences in perceived parental influence emerged for girls of both cultural groups and in both domains. Our findings support links among expectancy-value constructs and highlight cultural variations in parental socialization of achievement cognitions and behaviors in multiple domains. PMID- 21268475 TI - Bearing the burden of doubt: female coaches' experiences of gender relations. AB - Based on interview research, this study examined how master female coaches based in the United Kingdom experienced relations with men within their profession. Using a feminist cultural studies approach to examine how sport promotes and maintains a gender order unfavorable to women, we found that female coaches felt the need to continually prove themselves and often experienced coaching as a hostile and intimidating culture. Participants reported a gradual reduction in such unwelcoming behavior from men, seemingly because they had proved to be no threat to the existing patriarchal structure. A critical exploration of coaching is needed to understand how masculine hegemony leads to women's relative powerlessness as coaches. Furthermore, the findings present a case for a greater emphasis on sociocultural education within the UK coaching curricula. PMID- 21268476 TI - The relationship between motor skill proficiency and body mass index in children with and without dyslexia: a pilot study. PMID- 21268477 TI - Signal-to-noise ratio in physical education settings. PMID- 21268478 TI - Overcrowding: a global challenge. PMID- 21268480 TI - Invitation to emergency care staff. PMID- 21268479 TI - Emergency care provision in the age of information. PMID- 21268481 TI - Perceptions of a 'virtual' acute admission unit. AB - The Haaglanden Medical Centre, the Hague, Netherlands, has opened a 'virtual' acute admission unit (VAAU) to increase throughput of acute patients. The VAAU consists of 15 inpatient beds located on different wards that are set aside for patients from the emergency department (ED) when all of the beds on specialty wards are being used. A qualitative evaluation of the VAAU has revealed that it has reduced emergency nurses' workload and allowed them more time to see and treat patients. This suggests that the introduction of VAAUs may address similar problems of ED throughput in the U.K. PMID- 21268482 TI - Techniques for removing rings from injured fingers. AB - Staff in emergency departments or minor injury units are sometimes asked to remove rings from patients' fingers. This is often because their presence has become painful or is preventing treatment of injuries or illnesses. Practitioners must be able to identify the tourniquet effect of rings or bracelets, and understand why and how they should be removed. This article describes the procedures that can be used. PMID- 21268483 TI - Possible growth hormone deficiency: a case study. AB - When reviewing radiographs of the musculoskeletal system, variants such as ligament or tendon ossifications can be observed (Keats and Anderson 2006). X rays can also give first indications that patients have growth problems. This article explains how an unexpected x-ray finding indicated a condition that could affect the life of the patient involved. PMID- 21268484 TI - Risk assessment and treatment of venous thromboembolism. AB - This article argues that the number of deaths caused by venous thromboembolism (VTE) can be reduced if all patients in emergency departments are assessed to identify those who are most at risk of developing VTE. Such patients can be given the appropriate anticoagulant prophylaxis and educated on the importance of preventing VTE. PMID- 21268485 TI - Demographics of people who self-harm deliberately. AB - The suicide rate in the borough of Westminster is the third highest in London and higher than the national average. This is a pressing concern for local healthcare providers and, to begin to reduce the rate, they conducted a prospective audit of the incidence of self-harm, which is a strong predictor of suicide. This article discusses the method and results of the audit, which revealed that the number of people who self-harm is greater than had been estimated previously. PMID- 21268486 TI - Adverse effects of overcrowding on patient experience and care. AB - There has been much investigation into the causes and management of overcrowding, but little about how it affects care delivery. The author therefore undertook a systematic literature review of the subject. This revealed that diverse areas of care are affected by overcrowding, and confirmed its adverse effects on patient experience and care. PMID- 21268487 TI - Research reporting: clarity and accuracy improve quality. PMID- 21268488 TI - Nurse case management to improve risk reduction outcomes in a stroke prevention clinic. AB - Stroke prevention clinic health care professionals are mandated to provide early access to neurological consultation and treatment, diagnostic testing, and behavioural risk factor management for clients with transient ischemic attack or mild non-disabling stroke. Clinic nurses collaborate with clients and interprofessional teams to support risk factor reduction to prevent recurrent stroke events. Although hypertension is the most important modifiable risk factor for stroke, broader evidence indicates that adherence to prescribed medications may be less than 50%. One clinic identified a need to improve risk factor outcomes through identifying clients with uncontrolled hypertension, cognitive, self-eficacy and/or adherence characteristics predictive of non-achievement of blood pressure targets. To address this need, an expanded nurse case management care delivery model was pilot tested for feasibility in a participant sample of 20 clients. Motivational interviewing and self-management approaches were combined with interventions designed to improve adherence:facilitation of the simplification of medication routines, providing memory cues and home self monitoring equipment, counselling, and six-month nursing follow-up. Results demonstrated that an expanded nurse case management model of care delivery is feasible with only a modest impact on clinic resources. At six months, there were significant reductions in blood pressure and increases in medication self efficacy and adherence for selected clients identified with high risk for stroke and non-achievement of treatment outcomes. PMID- 21268489 TI - Examining the relationship between patient-centred care and outcomes. AB - PURPOSE: to examine the extent to which staff nurses provided patient-centred care (PCC), as perceived by staff nurses and patients, and to explore the relationships between implementation of PCC and patient outcomes. DESIGN: A descriptive correlational design with repeated measures was used. Descriptive statistics, correlations and t-tests were calculated. METHODS: Data were collected from 63 nurses and 44 patients admitted to cardiology, neurology/neurosurgery and orthopedic units. Nurses' and patients' perception of implementation of dimensions of PCC, and patient outcomes were measured with validated instruments. FINDINGS: Overall, nurses and patients reported implementation of PCC to a moderate extent. Provision of different aspects of PCC was associated with high levels of patient self-care. CONCLUSIONS: Implementation of PCC is expected to improve patient outcome by increasing patient self-care ability and improving satisfaction with care and quality of life. CLINICAL RELEVANCE: The findings will guide further improvement in the implementation of PCC to continuously enhance quality of nursing care, the patients' hospital experience and readiness for discharge. PMID- 21268491 TI - Physicians. With physician employment on the rise, new compensation models emerge. PMID- 21268492 TI - Staffing. How to hire employees whoe live the mission. PMID- 21268493 TI - Supply chain. Reprocessed medical devices letting a second look. PMID- 21268494 TI - 'An extraordinary story of faith, networking--you name it'. PMID- 21268495 TI - Infection control. Hand hygiene surveillance gets a 21st-century makeover. PMID- 21268496 TI - Patient care. Provider collaborations are the new wave in treating chronic illness. PMID- 21268497 TI - Emergency department. Efforts underway to bring more palliative care to the ED. PMID- 21268498 TI - For the rest of their lives. PMID- 21268499 TI - It's all about the outcomes. AB - CMS and quality organizations want hospitals to collect more data that focus on patients and results rather than on processes and payment. How to measure things like readmissions and whether data should be publicly reported remain knotty issues. PMID- 21268500 TI - Striving to capture the voice of the patient. PMID- 21268501 TI - The race for health reform enters a whole new stage. PMID- 21268502 TI - Optimal healing environments. PMID- 21268503 TI - The doctor (and his scribe) will see you now. PMID- 21268504 TI - A hospital imperative: enterprisewide IT security. PMID- 21268505 TI - Becoming a meaningful user of health IT. PMID- 21268507 TI - Lessons learned: A tribute to Dr. Gary Kielhofner. PMID- 21268508 TI - Power and confidence in professions: lessons for occupational therapy. AB - BACKGROUND: Powerful professions have the capacity to obtain leadership positions, advocate successfully in the policy arena, and secure the resources necessary to achieve their professional goals. Within the occupational therapy profession, cultivating power and confidence among our practitioners is essential to realize our full capacity for meeting society's occupational needs. PURPOSE AND KEY ISSUES: Drawing from a historical analysis of the medical and nursing professions, this paper discusses the implications of power and disempowerment among health professions for their practitioners, clients, and public image. Theoretical perspectives on power from social psychology, politics, organizational management, and post-structuralism are introduced and their relevance to the profession of occupational therapy is examined. IMPLICATIONS: The paper concludes with recommendations for occupational therapy practitioners to analyze their individual sources of power and evaluate opportunities to develop confidence and secure power for their professional work--in venues both in and outside the workplace. PMID- 21268509 TI - A scoping review of the use of theory in studies of knowledge translation. AB - BACKGROUND: Advancing the science of knowledge translation (KT) in occupational therapy is critical. Explicit application of theory can advance this science; yet, how theory is applied and the degree to which it can guide research remain poorly defined. PURPOSE: To understand how theory is applied within KT research. METHODS: A scoping review was conducted to examine and summarize the extent, range, and nature of the application of three specific KT theories: Diffusion of Innovations, Promoting Action on Research Implementation in Health Services framework, and Theory of Planned Behaviour. FINDINGS: Theory use was seen most frequently in medicine and nursing. Only 3 of 90 articles were in rehabilitation. Five approaches to theory application were found, the most common being the use of to predict success of KT (57/90). IMPLICATIONS: In-depth study of the importance and methods of theory application in KT research is needed, in particular in occupational therapy. PMID- 21268510 TI - Measuring occupational balance: a theoretical exploration of two approaches. AB - BACKGROUND: Occupational balance is a fundamental yet complex concept in occupational therapy requiring empirical study. PURPOSE: To advance the theoretical discussion of occupational balance, its measurement and relationship to well-being. METHODS: In part one of this 2-phase study, 122 adults completed a bipolar measure of occupational balance, the Cross Impact Matrix (CIM) of the Personal Project Analysis and two well-being measures: the Satisfaction with Life Scale (SWLS) and Positive and Negative Affect Scales (PANAS). In part two, 24 adults completed the Inter-goal Relations Questionnaire (IRQ), a unipolar measure of occupational balance (harmony) and imbalance (conflict), plus the SWLS and PANAS. FINDINGS: Neither the CIM scores nor IRQ occupational balance/harmony were associated with well-being whereas the IRQ occupational imbalance/conflict was significantly associated with SWLS. IMPLICATIONS: Dimensions of occupational balance (conflict and harmony) may be best measured separately. To promote well being attention can be given to reducing conflict across occupations. PMID- 21268511 TI - Content validation of the International Classification of Functioning, Disability and Health (ICF) Core Set for stroke: the perspective of occupational therapists. AB - BACKGROUND: The "ICF Core Set for stroke" is an application of the International Classification of Functioning, Disability and Health (ICF) and represents the typical spectrum of problems in the functioning of patients with stroke. PURPOSE: The objective of this study was to validate this ICF Core Set from the perspective of occupational therapists. METHODS: In a three-round electronic mail survey using the Delphi technique, occupational therapists experienced in stroke treatment were asked about patients'problems, patients' resources, and aspects of environment they take care of. Two health professionals linked responses to the ICF. FINDINGS: Sixty-nine occupational therapists in 21 countries named 1,747 concepts that occupational therapists treat in patients with stroke. These concepts were linked to 347 different ICF categories. Twenty-three concepts were linked to the ICF component Personal Factors. CONCLUSION: The content validity of the "ICF Core Set for stroke" was largely supported by occupational therapists. PMID- 21268512 TI - Finding and sustaining employment: a qualitative meta-synthesis of mental health consumer views. AB - BACKGROUND: The viewpoints of employed people experiencing mental ill-health receive limited attention in reviews of employment-related research. PURPOSE: To identify implications from studies investigating the employment-related views of people with persistent mental ill-health to guide the further development of employment supports available to this group. METHODS: Published qualitative studies between 1998 and 2008 were searched, resulting in 20 studies for qualitative metasynthesis. FINDINGS: Four themes were synthesized from the findings:(a) employment has varied meanings, benefits, and drawbacks to weigh up; (b) strategies for maintaining employment and mental health are important and both require ongoing, active self-management; (c) diverse supports within and beyond the workplace are helpful; and (d) systemic issues add to the employment barriers. IMPLICATIONS: Strategies based on these themes highlight how occupational therapists could initiate improvements in employment support and mental health services to increase their success in enabling satisfying and sustainable employment. PMID- 21268513 TI - The role of insulin-like growth factor in prediction and prevention of preterm delivery. AB - BACKGROUND/AIM: Prediction and prevention of preterm delivery remain great challenge. It is important to include in everyday medical practice determination of certain markers that could help identifying pregnant women with preterm delivery. Insulinlike growth factor (IGF) is involved in the control mechanism of fetal and placental growth and development. The aim of this study was to examine the presence of insulin-like growth factor binding protein 1 (IGFBP-1) in cervicovaginal secretion of pregnant women with symptoms of preterm labor, but with apparently intact fetal membranes and to point out a possible application of the strip test for detection of phlGFBP-1 in diagnosis of preterm premature rupture of total membranes (PPROM) in everyday medical practice. METHODS: The study was performed at the Department for Obstetrics and Gynecology, Clinical Center of Vojvodina between October 2008 and May 2009. The study included 54 pregnant women between 20-35 weeks of gestation (WG), divided into two groups: the study group (16 pregnant women with symptoms of preterm delivery that gave birth before 37 WG) and the control group (38 pregnant women with the normal course of pregnancy that gave birth on term). In cervicovaginal secretion of the examined pregnant women the level of IGFBP-1 was determined by the immunochromatographic assay with monoclonal antibodies 6303 as a detecting antibody (Actim PROM test, Medix Biochemica, Kauniainen, Finland). RESULTS: Gestational age (GA) at delivery in the study group was 32.6 WG and in the control group it was 38.4 WG. Weight of newborns in the study group was 2,021 g and in the control group 3,430 g. IGFBP test was positive in 15 women (93.75%) of the study group, while in the control group it was positive only in 1 woman (2.63%). CONCLUSION: Test on phIGFBP-1 in cervicovaginal mucus was positive in 93.75% women with preterm delivery, suggesting that this test could be used in diagnosis of silent rupture of fetal membranes and in prediction of preterm delivery. PMID- 21268514 TI - Kinetics of C-reactive protein, interleukin-6 and -10, and phospholipase A2-II in severely traumatized septic patients. AB - BACKGROUND/AIM: Injury-induced anergy is one of the key factors contributing to trauma victims' high susceptibility to sepsis. This group of patients is mostly of young age and it is therefore essential to be able to predict as accurately as possible the development of septic complications, so appropriate treatment could be provided. The aim of this study was to assess kinetics of interleukin (IL)-6 and -10, phospholipase A2-II and C-reactive protein (CRP) in severely traumatized patients and explore the possibilities for early detection of potentially septic patients. METHODS: This prospective study included 65 traumatized patients with injury severity score (ISS) > 18, requiring treatment at surgical intensive care units, divided into two groups: 24 patients without sepsis and 41 patients with sepsis. C-reactive protein, IL-6 and -10 and phospholipase A2 group II, were determined within the first 24 hours, and on the second, third and seventh day of hospitalization. RESULTS: Mean values of IL-6 and phospholipase A2-II in the patients with and without sepsis did not show a statistically significant difference on any assessed time points. In the septic patients with ISS 29-35 and > 35 on the days two and seven a statistically significantly lower level of IL-10 was found, compared with those without sepsis and with the same ISS. C-reactive protein levels were significantly higher in septic patients with ISS 18-28 on the first day. On the second, third and seventh day CRP levels were significantly lower in the groups of septic patients with ISS 29-35 and > 35, than in those with the same ISS but without sepsis. CONCLUSION: Mean levels of CRP on the first day after the injury may be useful predictor of sepsis development in traumatized patients with ISS score 18-28. Mean levels of CRP on the days two, three and seven after the injury may be a useful predictor of sepsis development in traumatized patients with ISS score more than 28. Mean levels of IL-10 on the second and seventh day after the injury may be a useful predictor of sepsis development in traumatized patients with ISS score > 28. PMID- 21268515 TI - Epidemiological characteristics and clinical manifestations of acute non-A-E hepatitis. AB - BACKGROUND/AIM: Acute non-A, non-B, non-C, non-D, non-E hepatitis (non-A-E AH) is an acute disease of the liver of unknown etiology for which one or more new, so far undetected, hepatotropic viruses may be responsible. The frequency of non-A-E AH ranges from 3.8% to 33.9%, and therefore it has a significant place within current infectology and hepatology. The aim of our study was to establish the frequency, clinical and biochemical characteristics, natural course and outcome of non-A-E AH and compare them with control groups affected by acute viral hepatitis A, B and C. METHODS: This descriptive-analytic prospective study included 31 patients with non-A-E AH treated at the Institute of Infectious and Tropical Diseases, Clinical Center of Serbia, Belgrade, from 2003 to 2008. They were followed up during the period not less than 6 months. The controls involved randomly selected patients, treated at the same time with a definite diagnosis of acute viral hepatitis A, B and C. Statistical data analysis used Mann-Whitney U test, Student's t-test and variance analysis. The value of p < 0.05 was considered statistically significant. RESULTS: The frequency of non-A-E AH was 7.6%. Almost no difference was found between sexes (male/female ratio was 1:1.07); it was developed in all age groups, with the highest incidence in the middle age (mean age was 38.32 +/- 15.3 years). It appeared equally throughout the whole year. Out of risk factors, inoculation risk was predominant (before all, dental interventions), mostly involving urban population living in comfortable conditions. The duration of incubation varied much ranging from 20 to 180 days (median 60 days). By clinical course, moderate and icteric forms were most common, mostly corresponding to acute hepatitis A and C. On the other hand, by duration of the disease (mean duration was 67.1 +/- 27.1) and chronic transformation, non-A-E AH resembled to acute hepatitis B. Progression to chronicity was recorded in 9.68% of the patients. There was no fulminant neither cholestatic form of the disease. CONCLUSION: Based on the results obtained in this study, it is probable that there are some so far undetected primary hepatotropic viruses in our environment. PMID- 21268516 TI - Carotid ultrasonographic parameters as markers of atherogenesis and mortality rate in patients on hemodialysis. AB - BACKGROUND/AIM: Vascular endothelium plays an important role in atherogenesis. The aim of this study was to estimate the correlation of endothelium malfunction and arteriosclerosis in patients on hemodialysis. METHODS: The investigation was designed as a clinical, non-randomized, five-year study in the "Kragujevac" Clinical Center and included 146 patients. We evaluated demographic characteristics, smoking, duration of dialysis, existence of tissue calcification and duplex ultrasound parameters of the carotid artery. All lethal outcomes, including the cause and time of death were recorded. RESULTS: The cumulative survival rate was 57.5%. Survival was short in patients with wider lumen diameter of the carotid arteries. Carotid artery lumen diameter in men was wider than in women. The area cross section was closely correlated with intima media thickness (r = 0.913; p < 0.0001), as well as with the lumen diameter of the carotid arteries (r = 0.527;p < 0.0001). Carotid artery lumen diameter was negatively associated with serum cholesterol (r = -0.278; p = 0.019), while serum triglycerides correlated negatively with the cross section of intima media (r = 0.261; p = 0.028). Positive correlations were found between the serum total protein level and carotid artery lumen diameter (r = 0.235; p = 0.047), cross section intima media (r = 0.269; p = 0.022) and cholesterol (r = 0.248; p = 0.037). Time on dialysis showed a negative correlation with carotid artery cross section (r = -0.241; p = 0.04), while age was positively correlated with intima media (r = 0.295; p = 0.013), lumen diameter (r = 0.296; p = 0.012) and intima media cross section (r = 0.347; p = 0.003). Regression analysis pointed to predictive importance of carotid artery lumen diameter for survival (Beta = 0.437; p = 0.011) of the examined patients. The cumulative rate of survival was 57%. CONCLUSION: In our study patient age correlated positively with all parameters of arteriosclerosis. The average duration of dialysis was negatively associated with carotid artery diameter, which was significantly higher in males. Regression correlation analyses indicated that the survival rate of the patients on hemodialysis was lower if the carotid artery diameter was larger. PMID- 21268517 TI - And pain shall have no dominion? PMID- 21268518 TI - A pilot study on the effectiveness of anticipatory grief therapy for elderly facing the end of life. AB - This pilot study evaluates the benefits of anticipatory grief therapy (AGT) for day hospice patients and long-term care (LTC) residents with cancer and non malignant chronic diseases. Twenty-six elderly people (69.2 percent female; average age 81.8 years) participated in experiential, expressive activities and discussions during AGT. The McGill Quality of Life Questionnaire-Hong Kong version and the 15-item Geriatrics Depression Scale (Chinese version) were administered immediately before and after AGT, and at a four-week follow-up. Focus groups were held to collect qualitative feedback. Significant post-AGT improvements were found in physical (Z = -2.12, p < 0.05), psychological (Z = 2.22, p < 0.05), and total quality of life measures (Z = -2.66, p < 0.01), and in depression levels (Z = -2.49, p < 0.05). Emergent qualitative themes included grief and existential concerns, pros and cons of reminiscence, reflection and affirmation of meaning through expressive art, perceived benefits of AGT, and comments and suggestions for improving AGT in the future. We conclude that AGT delivered in both day hospice and LTC settings could be acceptable, feasible, and useful for elderly people facing the end of life. PMID- 21268519 TI - How end-of-life home care services are used from admission to death: a population based cohort study. AB - AIM: Our goal was to describe the trajectories of end-of-life nursing and personal support worker (PSW) use from home care admission until death. METHODS: We studied a historical prospective cohort of end-of-life home care patients in Ontario, Canada, linking administrative databases. We calculated the odds of using any nursing or PSW hours and the incidence rate ratio of services used for each week approaching death, controlling for confounders. RESULTS: Among all patients (n = 11,867), the odds of using any nursing and PSW hours increased by 4 percent and 10 percent, respectively, each week closer to death. Among patients using services, the ratio of nursing and PSW hours increased 20 percent and 11 percent, respectively, in the last 4 weeks of life compared to use at 24 weeks before death. CONCLUSION: Use of nursing and PSW hours increases slightly each week before death and sharply in the last month of life. Understanding the trajectory of home care services use can help decision makers design better end of-life care. PMID- 21268520 TI - Determinants of place of death for recipients of home-based palliative care. AB - INTRODUCTION: Health system restructuring combined with the preferences of many terminally ill care recipients and their caregivers has led to an increase in home-based palliative care, yet many care recipients die within institutional settings such as hospitals. This study sought to determine the place of death and its predictors among palliative care patients with cancer. METHODS: Study participants were recruited from the Temmy Latner Centre for Palliative Care, a regional palliative care program based in Toronto, Canada. A total of 137 patients and their family caregivers participated in the study; application of various exclusion criteria restricted analysis to a sub-sample of 110. Bivariate (chi-square) and multivariate (logistic regression) analyses were conducted. RESULTS: 66 percent of participants died at home. Chi-square analysis indicated that women were more likely to die at home than men; multivariate analysis indicated that women and those living with others were significantly more likely to die at home than men or those who lived alone. CONCLUSION: Place of death is influenced by the socio-demographic characteristics of patients, the characteristics of their caregivers, and health service factors. Palliative care programs need to tailor services to men and those living alone in order to reduce institutional deaths. PMID- 21268521 TI - Learning to work with the "unsolvable": building capacity for working with refractory suffering. AB - This article reports on a preliminary study of the experiences and perceptions of palliative care clinicians in developing capacity for effective, sustainable practice in their work with people who have refractory suffering. Members of a purposive sample of 17 clinicians (10 nurses, 5 doctors, and 2 allied health professionals) were either interviewed (13) or responded to an online questionnaire (4). The study's findings provide insight into these palliative care clinicians' experiences and their perceptions of the capabilities they require, effective learning methods for developing these capabilities, and the supports that can facilitate this capacity building. PMID- 21268522 TI - Using critical reflection to support health promotion goals in palliative care. PMID- 21268523 TI - Dying under a cloud. PMID- 21268524 TI - Palliative care activity in the field of oncology in Turkey. PMID- 21268525 TI - Successful treatment of a seizure disorder with chronic high-dose chloral hydrate: a pediatric case report. PMID- 21268526 TI - Detection of tick blood parasites in Egypt using PCR assay II- Borrelia burgdorferi sensu lato. AB - The prevalence of Borrelia burgdorferi sensu lato (s.l.), the etiologic agent of Lyme borrelosis (LB), was determined for the first time in Egypt by using polymerase chain reaction (PCR). Questing 5243 hard and soft ticks were collected from animal farms throughout Giza Governorate. DNA from 500 individual tick species was extracted and PCR was performed. Primers verified from the sequence of German strain Pko of Borrelia afzelii were used. Fragments of 642 bp were generated and sequenced. The prevalence of B. burgdorferi sensu lato (s.l.) was 28% of examined soft and hard ticks. High infection rate (66%) of B. burgdorferi s.l. was observed in both nymph and adult soft ticks Ornithodoros savignyi. Beside, the role of hard ticks as potential vectors of Lyme disease in Egypt, where the infection rate was between 0.0-50.0%. Sequence analysis of PCR product of Borrelia burgdorferi sensu lato shares high degree of similarity in sequence compared to similar species in GenBank. PMID- 21268527 TI - The biological effects of the insect growth regulators; pyriproxyfen and diflubenzuron on the mosquito Aedes aegypti. AB - The biological effects of two insect growth regulators (IGRs), pyriproxyfen and diflubenzuron against larvae of the mosquito Aedes aegypti (L.) have been evaluated. Mosquitoes were collected from Jeddah governorate, west of the Kingdom of Saudi Arabia and maintained in the laboratory. According to IC50 values obtained (concentrations which inhibit the emergence of 50% of adults), diflubenzuron (0.00036 ppm) proved to be more effective by 11.4 fold of pyriproxyfen (0.0041 ppm). In addition to the delayed lethal action, larval treatment with the two IGRs, pyriproxyfen and diflubenzuron led to pronounced reduction in the reproductive potential of mosquito adults that emerged from these treatments. Pyriproxyfen caused a 33.2% decrease in egg production compared to 25.5% for diflubenzuron. The reduction in egg hatchability was by 40.6 and 36.2% for pyriproxyfen and diflubenzuron, respectively, with up to 4 fold higher reduction rates than in the control tests. These results shed light on the extended biological effects of IGRs on mosquitoes and encourage further testing of IGRs for wider use in the control of Ae. aegypti and other important disease vectors in Arabia and the world. PMID- 21268528 TI - The role of insects in mechanical transmission of zoonotic human parasites. AB - Arthropods can be found on human or animals as ecto-parasites as well as endo parasites. The ecto-parasites or vectors can contaminate stored foods and transmit illness, or introduced diseases in new area. Pet species facilitating infestations, and different risk factors related to infestation were identified. Insect prevention and control is necessary to prevent the transmission of pathogens that could affect animal and human health and the maintenance of good hygiene. We conclude that although biological control looks promising, more research should be done concerning its side effects. Currently, optimal monitoring and prevention seem to offer the best solution. PMID- 21268529 TI - Haematological side effect of Helicobacter pylori eradication. AB - The effect of Helicobacter pylori infection on systemic disorders is not well understood. This study was to evaluate the effect of H. pylori eradication on blood count, differential leucocytic count and RBCs indices. In this study, a total of 115 H. pylori positive patients underwent eradication triple therapy for one week, with cured 100 patients. Complete blood count, RBCs indices and differential leucocytic count were analyzed before 2 & 12 weeks after eradication for the cured patients. The results showed that two weeks after H. pylori eradication, platelets count significantly increased but total leucocytic counts and neutrophils were significantly reduced. After three months, RBCs count, Hb concentration, MCV and MCHC were significantly increased, but lymphocytic counts was significantly reduced. PMID- 21268530 TI - Zoonotic ectopic fascioliasis: review and discussion. AB - Ectopic fascioliasis (EF) has direct and indirect effects on both humans and animals. The phenomenon of EF was individual cases in the period from 1950 up to the end of last century. From the period of 2000 up to 2006, plenty of researches were on EF in the developed and undeveloped countries. Nineteen EF cases infected with the immature and few with the mature worms were 13 females and 6 males. Three cases of lymphatic, pleural and breast fascioliasis reached the adults and laid their eggs in a lymph node in the cervical region pleural cavity and breast tissues. Until recent, knowledge about the ectopic fascioliasis pathway is little. Fasciola hepatica was the commonest species in most cases. The effect of fascioliasis might be direct to liver as ectopic foci or indirect on other organs due to the metabolites and secretory excretory products. All ages and both sexes were EF infected. Watercress topped the list of water plants born encysted metacercariae followed by lettuce, mint, and alfalfa. Nearly 24 million Egyptians at risk and about 800,000 were infected. On the global scale, about 180 million are at risk of infection. PMID- 21268531 TI - Efficacy of two rodenticides against Leishmania reservoir host rat (Psammomys obesus) in the rural area of Al-Ahsa Oasis, Saudi Arabia. AB - Zoonotic cutaneous leishmaniasis (ZCL) is a serious and increasing public health problem in many parts of Saudi Arabia. Rodent control operations are effective in destroying rodents and reducing the incidence of disease. This study tested the efficacy of zinc phosphide and fenacoum against the reservoir host Psammomys obesus rat. The results showed that both the rodenticides were significantly (P < 0.01) effective in reducing the number of active holes during one year of application. PMID- 21268532 TI - A preliminary study on the prevalence of parasitic infections in immunocompromised children. AB - Parasitic infections might become life threatening in immuno-compromised children' The study assessed the parasites' prevalence in different groups of immuno-compromised children. It was conducted on 120 children of whom 90 were inpatients in Tanta University Pediatric Hospital and were divided into 6 groups. GI: malignant diseases, GII: renal diseases, GIII: aggressive corticosteroid therapy, GIV: malnourished, GV: diabetic & GVI: miscellaneous. GVII comprised healthy children as control. Each child was subjected to history taking, clinical examination and examination of 3 stool samples by direct wet smear and a concentration technique. Coproculture and smear staining by a special stain, as well as examination of one blood sample for anti-Toxoplasma antibodies were done. The diagnostic efficacy of an immuno-chromatographic test for Giardia/ Cryptosporidium coproantigen was also assessed. The results revealed parasitic infections in 62.2% of the children in the test groups. Cryptosporidium was the most prevalent (33.3%). Cryptosporidium and Microsporidia were significantly prevalent in GI, Giardia was significantly high in GII, and Strongyloides stercoralis was detected in GIII. Coproantigen detection test showed 100% sensitivity, 87.5% specificity and 95% accuracy for Giardia; and 13.3%, 100%, 35% for Cryptosporidium respectively. PMID- 21268533 TI - Response of predominant rodent borne diseases to difethialone anticoagulant rodenticide under laboratory conditions. AB - Susceptibility level to difethialone 0.0025% anticoagulant rodenticide by bioassay method were studied (during 2009 & 2010) to the Norway rat Rattus norvegicus and the roof rat Rattus rattus trapped from Giza and Menoufia Governorates (G) where anticoagulant rodenticides were used to control rodents for long periods. Complete mortality was obtained for both species at two Governorates within 3 days no-choice feeding test period, indicated to be susceptible to difethialone. The bait consumption and corresponding active ingredient intake was more in R. rattus than R. norvegicus. The mean intake values for R. rattus were 3.1 & 2.29 mg/kg at Giza G and 2.63 & 2.65 mg/kg at Menoufia G for males and females and for R. norvegicus 1.93 & 2.29 mg/kg at Giza and 2.14 & 2.09 mg/kg at Menoufia for males and females, respectively. Within 2 days no-choice feeding test period, difethialone caused mortality ranged between 70-80% for both species. The higher intake values of active ingredient for died animals was recorded for R. rattus males at Giza G (2.23 mg/kg), while the lower value was recorded for R. norvegicus females of at Menoufia G (1.37 mg/kg). Within one-day no-choice feeding test period, difethialone caused mortality ranged between 60-70% for R. norvegicus and 50-60% to R. rattus. The higher intake values for died animals were recorded for R. rattus males at Giza G (1.45 mg/kg), while the lower value was recorded for R. norvegicus males at Giza (0.75 mg/kg). PMID- 21268534 TI - The role of calprotectin and ghrelin in diagnosis of post ERCP pancreatitis. AB - Acute pancreatitis is a common and dreaded complication of endoscopic retrograde cholangiopancreatography (ERCP) patients. The study identified the incidence of post ERCP pancreatitis and role of serum calprotectin and ghrelin in its diagnosis. One hundred forty two patients underwent ERCP-related procedures were studied. Serum amylase, lipase, calprotectin and ghrelin concentrations were measured 24 hours after the procedure using ELISA, kinetic and colorimetric methods. Thirty two healthy controls were enrolled. In post ERCP group, mean level of amylase was 146.03 +/- 57.40 U/L, lipase 328.37 +/- 133.95 U/L, calprotectin 3.26 +/- 2.99 U/L and gherkin 2.56 +/- 1.76 mg/l. In controls mean level of amylase was 58.13 +/- 15.96U/L, lipase 181.63 +/- 51.94 U/L, calprotectin 0.49 +/- 0.17 U/L and ghrelin 2.59 +/- 0.19 mg/l. A statistical significant increase was reported (p < 0.001) in levels of amylase, lipase and calprotectin between the two groups without significant in ghrelin level. PMID- 21268535 TI - Anti-coccidial effect of Commiphora molmol in the domestic rabbit (Oryctolagus cuniculus domesticus L.). AB - This study investigated the effect of oleo-gum-resin of Commiphora monlmol Engler (Family: Burceraceae) known as Myrrh and the commercial extract known as Mirazid as a treatment against hepatic coccidiosis induced by the parasite Eimeria stiedae in domestic rabbits. Rabbits were infected with 1000 parasite sporulated oocysts and subjected to two treatment regimens, using crude myrrh suspension and the oleo-resin extract, mirazid, each administered at 500 mg/kg rabbit body weight. Treatments of infected rabbits resulted in significant reduction of the mean oocyst numbers in rabbit faeces by 52.38% in the crude-treated rabbits and by 90.90% mirazid-treated rabbits, compared to the untreated infected rabbits at day 21 post-infection (pi). At day 28 pi no oocysts parasite were observed in the faeces of rabbits. Both treatments resulted in significant recovery of infected rabbits from all symptoms of infection compared to the untreated infected group and healthy control groups. Histopathological examination of liver showed remarkable improvement in all histopathological parameters in G5 and G8 compared with the infected untreated G2. These included an almost complete healing of the hemorrhagic tissue and partial healing of the endothelial lining and hepatocytes encircling the central vein, the hepatocytes laminate regained their original radial shape and disappearance of fat vacuoles from the tissue and remarkable reduction in lymphocytes infiltration, decreased hyperplasia of the epithelial cells with significant decreasing of the parasite stage numbers. Results also indicate that mirazid was more effective than crude myrrh, probably due to higher content of purified active ingredients. PMID- 21268536 TI - Hematological changes in mice exposed to biting of the bedbug: Cimex lectularius L. (Hemiptera: Cimicidae). AB - The studies on hematologic changes in humans or animals as a result of bedbug bites are lacking. This study was undertaken to examine changes in the blood picture of mice (Mus musculus) exposed to Cimex lectularius biting. As compared to the check animals, mice exposed to bedbug bites either once or twice within 7 days showed insignificantly higher WBC's (1.6 and 2.8% increase, respectively) and lower HGB content (0.5 and 0.8% decrease, respectively) and significantly higher PLT's (P < 0.01) by 2.2% and 3.0%, respectively. Significantly higher (P < 0.01) RBC's counts in mice bitten once than those of normal animals or those exposed to twice bites (5.3 and 5.9% increase, respectively). Bedbug biting exerts its effects largely upon the differential WBC's. Mice bitten once or twice showed significantly lower number of neutrophils (1.2% & 12.1% decrease, respectively) than those for normal animals. Mice exposed to twice bites showed significantly (P < 0.01) higher numbers of lymphocyte (18.8%), monocyte (13.6%), eosinophil (200.0%) and basophil (500%) than those of normal mice. PMID- 21268537 TI - Role of parasites among chronic diarrheic patients. AB - This work studied the role of parasitic infection among 85 chronic diarrheic patients in Delta region and cross-matched 20 normal controls. They were subjected to thorough history taking and clinical examination and stool examination by direct smear, formol-ether concentration, simple sedimentation, simple floatation and Kato-katz thick smear. Questionnaire sheet was obtained for each case included personal history, complaint, present as well as past history and family history. The results showed that 67.1% of patients suffered from parasites versus 20% in controls. They included giardiasis mixed with hymenolepiasis nana, ameobiasis, ascariaisis, S. mansoni, heterophyiasis, B. homninis, Taenia spp and enterobiasis respectively. Single infection represented 54.2 %, while mixed ones were 12.9% of total chronic diarrhea cases and non parasitic causes were responsible for 32.9%. Mixed infection was common in A. lumbricoides with E. histolytica (18.18%) and H. nana with G. lambia (27.28%). The diarrhea duration was longer in mixed infections (3 months), E. histolytica (2 months) and H. nana (1.5 months). Commonest symptom other than diarrhea was abdominal pain mainly in mixed parasitosis. Parasitic diarrhea was more common in males than females (1.28: 1). Chronic parasitic diarrhea was most prevalent among low social class (49 or 57.6%) followed by very low social class (20 or 23.5%), middle social class (10 or 11.7%) and finally high social class (6 or 7.1%) with significant increase in low social class as compared to high one, and most prevalent among positive cases in rural area than in urban area. PMID- 21268538 TI - Efficacy of volatile oils (curzerene, furanoeudesma-1, 3-diene and lindestrene) on avian coccidiosis under laboratory conditions. AB - The coccidicidal efficacy of volatile oils (curzerene, furanoeudesma-1, 3-diene and lindestrene) against unsporulated and sporulated chicken Eimeria species oocysts was tested in three concentrations: 1, 2 & 3 microg/ml. Marked reduction in the number of living oocysts was recorded in exposed groups. The concentration of 3 microg/ml volatile oils induced the highest destructive effect. 58.1% of viable unsporulated oocysts were destroyed. A mean number of 153,800 oocysts was the difference between the total number of the produced oocysts per gram faeces in the group infected with exposed oocysts and that of the group infected with non exposed oocysts being less in the exposed group with more reduction in the vitality of shedding oocysts in the former group. At the meantime, the postmortem and histopathological microscopical examination of the intestine and caecum of the tested group revealed a reduction in the intestinal lesions in the group infected with the exposed oocysts. PMID- 21268539 TI - Clinical and parasitological study on scabies in Sirte, Libya. AB - The present work aimed to determine the risk factors, clinical and parasitological skin lesion features and effective drug regimens. Study was carried out on 200 patients referred to dermatology outpatient clinics in Sirte Libya. Each was subjected to detailed questionnaire, dermatological skin examination, parasitological skin scraping test (SST), burrow ink test (BIT), drug administration and follow up. Results revealed that females 59%, children 37.5% and military personnel 18% of immigrant families were particularly prone to scabies infestation. Effective risk factors included overcrowding, bed sharing, low hygienic and education levels. Commonest skin lesions included erythematous papules 93%, excoriated papules 77.5%, burrows 66%, pustulation 31%, vesicles 21.5 and nodules 3%. Predilection lesion sites were hand 86%, wrist 82%, abdomen 56%, male external genitalia 64.5% and female breast 28%. Specific SST was positive in 67.3% of cases, particularly sensitive in early cases with short itching duration. BIT was positive in 62%. Topical permethrin proved more effective than precipitated sulpher with cure rates of of 100% and 85.3% in 21% and 75% of cases, respectively. Ivermectin was 100% effective in 4% of cases. PMID- 21268540 TI - The effect of hemodialysis on Q-T interval on children with chronic renal failure. AB - The hemodialysis patients have a wide variety of electrocardiographic (ECG) abnormalities and, in certain instances; hemodialysis itself seems to be a cause of ECG changes and different kinds of dysrhythmias. The purpose of the study was to assess the effect of hemodialysis on QT and corrected QT (QTc) interval and QTc interval dispersion in patients with end-stage renal failure 10 min before (pre-HD) and 10 min after each hemodialysis (post-HD). An observational cross section study was conducted on 30 patients'admitted to the dialysis unit in Abou El Ressh pediatric hospital along a period of 6 months starting from October 2008. The total number of cases on regular hemodialysis throughout the year was: 60 cases. 30 cases were picked at random to be included in the present work. Clinical examination, history taking and laboratory analysis were offered to all patients, 12 lead ECG was done before and after hemodialysis. The results showed that after hemodialysis there were significant changes for the QTc and QT dispersion with 3.3% of cases had prolonged QT interval after hemodialysis and 43.3% had prolonged QTc after dialysis and 50% had abnormal QTd after dialysis. After dialysis there was significant negative correlation between Na level and QTc, also between K level and QTc. PMID- 21268541 TI - Portal vein parameters in Egyptian patients with spontaneous bacterial peritonitis. AB - Spontaneous bacterial peritonitis (SBP) is a severe complication of cirrhosis and the role of portal hypertension in the development of SBP has been suggested. This study assessed the portal vein (PV) haemodynamic changes in patients with SBP. The study was conducted on 20 ascitic patients with SBP (GI), 20 ascitic patients without SBP (GII), 20 cirrhotic patients without ascites (GIII) and 20 healthy cross-matched controls (GIV). All groups were subjected to complete clinical assessment and routine laboratory investigations. Portal vein diameter, velocity and congestion index (CI) were assessed by Doppler ultrasound. The results showed no significant difference between SBP patients and ascitic patients without SBP as regard PV diameter, velocity or CI. Portal vein diameter was significantly wider in patients with SBP (14.9 +/- 2.08 mm) and cirrhotic ascites (14.15 +/- 2.3) than normal persons (10.55 +/- 2.24 mm) or cirrhotic compensated patients (13.15 +/- 1.6 mm). The mean velocity of PV was significantly lower in patients with SBP (10.4 +/- 2.11) and ascites (10.7 +/- 2.22) than normal persons (15.35 +/- 2.08) or cirrhotic compensated patients (14 +/- 2.6), with no significant difference between controls and cirrhotic compensated patients. The CI of PV was significantly higher in patients with SBP (0.1825 +/- 0.036) and ascites (0.1743 +/- 0.051) than controls (0.05 +/- 0.050) or cirrhotic compensated patients (0.0955 +/- 0.091). Cirrhotic compensated patients showed significantly wider PV (13.15 +/- 1.6) and higher congestion index (0.0955 +/- 0.091) than normal persons (10.55 +/- 2.24 and 0.05 +/- 0.050 respectively). PMID- 21268542 TI - Efficacy of myrrh in controlling coccidioses in chickens. AB - Myrrh was used for controlling the infection with Eimeria species in chickens. A total of 120 one-day-old native breed chickens bought from commercial hatchery were used in the experiment. Birds were feed on starter balanced ration free from anticoccidial drugs. At age of 2 weeks the chickens were divided into 4 groups (1 4), 30 chicks each. Chickens of first group were inoculated by 50,000 sporulated oocysts of mixed local field isolated Eimneria species and served as infected non treated control group. Birds of the second group were infected similarly and received simultaneously 10 mg Myrrh / bird by oral route. Birds of group 3 was supplied with Myrrh 10 mg / bird one day before infection by coccidia (50000 oocyst/bird). Last chicken group was left as non infected non treated control group. Measurements to evaluate the efficacy of Myrrh as anticoccidial drug included; mortality percentage; lesion score at 5 day post infection and the total oocyst output/gm of fecal dropping. The results showed that the mortality rate reached 10% and 3.33% in groups 2&3 respectively, while it reached 26.66% in infected non treated control group. High lesion score was recorded in infected non treated group followed by infected treated chicken groups regardless the time of treatment. The feed conversion rates reached 3.14 in infected non treated chicken group against 2.47 & 2.21 in treated chickens groups, 2&3 respectively. Mean oocyst count per gram faecal dropping (OPG) was reduced significantly in group 3 when compared with other infected treated or infected non treated chicken groups. PMID- 21268543 TI - The role of plasma transforming growth factor beta-1 in the development of fibrosis in patient with HCV related steatohepatitis. AB - Hepatitis C virus (HCV) is a major public health problem worldwide, which causes high rate of chronic liver disease such as liver cirrhosis and hepatocellular carcinoma. Plasma transforming growth factor Beta-1 (TGFB-1) is a member of large family of peptides, which has a major regulatory role in hepatic fibrosis and cirrhosis. The study evaluated the role of transforming growth factor Beta-1 (TGFB-1) in induction of fibrosis in liver parasites-free HCV patients with related steatohepatitis. Thirty HCV patients who were clinically and serologically positive were selected. They were diagnosed as fatty liver by abdominal ultrasonography; steatohepatitis and confirmed by histopathological biopsies examination. ELISA evaluated plasma transforming growth factor Beta-1 (TGFB-1) level. Also, 12 cross-matched subjects clinically, parasitologically and serologically free were used as a controls. The level of plasma transforming growth factor Beta-1 (TGFB-1) was highly elevated in the patients versus controls with mean +/- SD 18739.86 +/- 18539.46 and 6465 +/- 1142 respectively (P < 0.001). The TGFB-1 level in HCV related steato-hepatitis was elevated in all grades in contrast to controls (P < 0.05), without relation between the TGFB-1 levels and steatohepatitis severity. The TGFB-1 level showed high significant difference in all stages of fibrosis in patients in contrast to controls and the TGFB-1 level was very high when fibrosis started in stage I (P < 0.01) and tended to decrease in fibrosis of stage 2 & 3 (P < 0.05). There was highly significant positive correlation between TGFB-1 and body mass index (BMI) r = 0.774. PMID- 21268544 TI - Imported malaria as a threat to Egypt. AB - This work evaluated the clinical and parasitic status of malaria as a cause of fever among patients admitted to the Military fever hospitals. Thirty six patients were included twenty already diagnosed as malarial patients, who were recruited from Peace Keeping Mission Forces in Africa and sixteen cases presented with prolonged fever coming from different locations in Egypt. The results showed that El-Gabal El-Ahmar area (Cairo) was the most extensively infested region (37.4%). This might be due to change of its ecolo-gical pattern since the year 2003 and the environmental conditions favoured by breeding and flaring mosquitoes. El-Sharkia and El-Fayoum Governorates (G.) were next in order (18.7%) and (12.5%) and this might be due to increased rural areas and agricultural projects and re-establishment. Plasmodiumn vivax was the main species among locally acquired patients (81.25%), while the imported patients coming back to Egypt from Africa especially (Sudan) had P. falciparumn (100%). However, P. falciparum was also present in 6.2% of cases from El Fayoum Governorate while P. ovale and P. malariae were not encountered. Of interest, was a case recruited from Ard-El-Golf, Heliopolis, an area with high social and hygienic standard, and the same condition applied to that from El-Nozha El-Gidida. Such cases included the "runway" or "airport" malaria, in which local transmission of disease has been attributed to an infected mosquito that was transported on a long haul flight. The two locally acquired cases were malaria positive by bone marrow smears and negative by peripheral blood examination. However, the thick blood film was the most sensitive (97.2%). The patients (75%) were clinically and parasitologically cured, but one patient died. The best therapeutic response for locally acquired malaria infection was the monotherapy-based one such as Chloroquine or Mefloquine. PMID- 21268545 TI - What happens if nothing happens?--History of an untreated urothelial carcinoma of the bladder. AB - Bladder cancer is controllable when adequately diagnosed and treated according to current recommendations. Radical cystectomy with urinary diversion is the standard therapy for muscle invasive tumors. In patients unfit or unwilling to get radical surgery, external beam or combined chemo-radiotherapy display alternative treatment options and can be safely performed. Every therapy implies the patient's disposition to cooperate. CASE PRESENTATION: This case report describes the clinical course over 31 months after initial diagnosis of a 56 years-old Caucasian, white man with an initial pT1G3 urothelial carcinoma of the bladder. The patient denied early radical cystectomy, radio-chemotherapy and almost all alternative treatment possibilities. He finally died 31 months after initial verification of the disease. PMID- 21268546 TI - Opportunistic parasitic infections among immunocompromised Egyptian patients. AB - The commonest opportunistic parasites causing morbidity and/or mortality in the immuno-compromised subjects are mainly the gastro-intestinal ones. This study clarified the prevalence of the opportunistic parasites among a group of immunocompromised patients selected from Al Azhar University Hospitals. One hundred immunocompromised patients (GI) were divided into GIa: 40 malignancy patients. GIb: 30 with diabetes mellitus. GIc: 30 with chronic renal failure. GII: included 20 cross-matched healthy subjects as controls. Sheets were filled out on each subject including all personal and medical history. Both groups were subjected to stool and blood examinations for parasites. The results showed opportunistic parasites in 30% of patients and in 10% of healthy controls. The highest group had parasitosis was patients suffering from malignancy (18%). The patients suffering from chronic renal failure or from diabetes mellitus were equally affected (6% each group). There was significant relation between malignant patients and diabetic or chronic renal failure ones, but without significant relation between diabetic and chronic renal failure patients. Giardia lamblia was the most common parasite found in the patients (10%) of which 5% were among patients suffering from malignancy. Others were Cryptospotidium parvum (7%) Cyclospora cayetanensis (3%) and Microsporidia species (2%). Mixed infection was detected in 2 cases that had C. parvum and Cyclospora. But, neither Isospora belli nor Strongyloides stercoralis were detected. Also, ELISA showed antibodies against Toxoplasma gondii in sex patients but none against Leishmania d. infantum. PMID- 21268547 TI - Sub-antibiotic doses of erythromycin as a prokinetic in abdominal surgeries: reviving the old. AB - All patients undergoing major abdominal procedures have some degree of gastricatony in the immediate postoperative period, presenting mainly with vomiting. Many prokinetic agents have been used in the past, but none is a universal remedy. Studies showed that subantibiotic doses of erythromycin, a macrolide antibiotic and motilin agonist, accelerates gastric emptying. This study investigated whether preoperative subantibiotic dose oral erythromycin (250 mg), altered residual gastric volume and postoperative adverse effects in patients scheduled for abdominal surgeries. Erythromycin was compared with the commonly used prokinetic metoclopramide and antiemetic ondansetron, in terms of prokinetic efficacy, cost and adverse effects. In a double-blind study, eighty patients (20 each) were allocated randomly to receive orally, either erythromycin 250 mg (E250) or erythromycin 500 mg (E500), or 10 mg metoclopramide (M), or 4 mg ondansetron (Z), an hour pre-induction of anesthesia. Preoperative oral erythromycin in subantibiotic dose 250 mg elicited a significntly lower residual gastric volume (P < 0.001) and a lower VAS for vomiting, compared with ondansetron. As for metoclopramide and erythromycin 500, residual gastric volume was comparable, but E 250 had a lower VAS for vomiting than both groups. Rescue remedy for vomiting was required for groups E500, M and Z (100, 10 and 10%) compared to 0% in group E250. Ultimately, subantibiotic oral dose of erythromycin (250 mg), given 1 hr preoperatively, is an inexpensive prokinetic alternative with a promising post-operative profile which may be superior to the inexpensive prokinetic metoclopramide with known adverse effects, and the expensive antiemetic ondansetron. PMID- 21268548 TI - HCV and community expectations. PMID- 21268549 TI - Revenue lost and found: debt buying and your bottom line. PMID- 21268550 TI - Taking notice of observation service opportunities and risks. PMID- 21268551 TI - Danbury Hospital. PMID- 21268552 TI - Strategies for simplifying your staff training. PMID- 21268553 TI - Significance of cephalosporin antibiotics in human healthcare. AB - Cephalosporins have been most frequently used antibiotics for the treatment of a wide variety of bacterial infections. The present article summarises general information on selected aspects of cephalosporin antibiotics viz. general features, uses and bacterial resistance. PMID- 21268554 TI - Purification and partial characterization of thermostable serine alkaline protease from a newly isolated Bacillus species HSRB08 from hotspring. AB - The purpose of the research was to study the purification and partial characterization of thermostable serine alkaline protease from a newly isolated Bacillus species HSRB08, which was isolated from hotspring. The enzyme was purified in a 2-step procedure involving ammonium sulfate precipitation and Sephadex G-200 chromatography. The enzyme was shown to have molecular weight of 66 kD by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and Gelatin Zymogram and was purified 15.3-fold with a yield of 7.5%. It was most active at 45 degrees C, pH 9.0, with casein as substrate. It was strongly activated by metal ions such as Ca2+, Mg2+, and Mn2+. Enzyme activity was inhibited strongly by phenylmethyl sulphonyl fluoride (PMSF) but was not inhibited by ethylene diamine tetra acetic acid (EDTA), while a slight inhibition was observed with beta-mercaptoethanol (beta-ME). The compatibility of the enzyme was studied with commercial and local detergents in the presence of 10 mM CaCl2. The addition of 10 mM CaCl2 individually and in combination, was found to be very effective in improving the enzyme stability. This enzyme improved the cleansing power of various detergents. It removed blood stains completely when used with detergents in the presence of 10 mM CaCl2. PMID- 21268555 TI - Media optimization studies for Serratiopeptidase production from Serratia marcescens ATCC 13880. AB - Production of an anti-inflammatory enzyme serratiopeptidase by fermentation with Serratia marcescens ATCC 13880 was studied to ascertain optimal nutritional conditions for large scale production. To study biosynthesis and production of serratiopeptidase by Serratia marcescens ATCC 13880, different physicochemical parameters were studied and optimized. The optimized medium contain, (g/l) glycerine 10.0, maltose 10.0 as carbon source, peptone 10.0 as organic nitrogen source, ammonium sulphate 10.0 as inorganic nitrogen source, dihydrogen phosphate 10.0, sodium bicarbonate 10.0, sodium acetate 10.0 as inorganic salt source, ascorbic acid 10.0 as stabilizer, distilled water 1000 ml and the optimized fermentation conditions were pH 7.0, temperature 37 degrees C and duration 24 hr. The modified fermentation medium produced 27.36 IU/ml of serratiopeptidase compared to 17.97 IU/ml in basal medium and the molecular weight of the purified serratiopeptidase was found to be 52 kD. PMID- 21268556 TI - Simultaneous spectrophotometric determination of Cefpodoxime proxetil and Potassium clavulanate. AB - Two accurate, precise, sensitive and economical procedures for simultaneous estimation of Cefpodoxime proxetil and Potassium clavulanate in tablet dosage form have been developed. The methods employed were absorbance correction method (I) and first order derivative spectroscopic method (II). The first method employs wavelength 288 nm for direct estimation of Cefpodoxime proxetil where Potassium clavulanate shows nil absorbance. Estimation of Potassium clavulanate is carried out after correction for absorbance of Cefpodoxime proxetil at 218 nm. The second method is based on first order derivative spectroscopy. Wavelengths 235.6 nm and 308.2 nm were selected for the estimation of the Potassium clavulanate and Cefpodoxime proxetil, respectively. Both the drugs obey Beer's law in the concentration range 5-50 microg/ml. The results of analysis have been validated statistically and by recovery studies. The percentage assay was found to be 99.54 +/- 0.285 for Cefpodoxime proxetil and 98.53 +/- 0.760 for Potassium clavulanate (Mean +/- SD) by method I and 99.93 +/- 0.270 for Cefpodoxime proxetil and 99.40 +/- 0.723 for Potassium clavulanate (Mean +/- S.D) by method II respectively. PMID- 21268557 TI - Simultaneous estimation of Cefixime and Erdosteine in capsule dosage form by spectrophotometric method. AB - Two accurate, precise, rapid and economical methods viz. Absorption correction method and Dual wavelength method were developed for the estimation of Cefixime (CEF) and Erdosteine (ERDO) in capsule dosage form. In both the methods linearity was observed in the concentration range of 2-25 microg/ml for Cefixime and 3-37.5 microg/ml for Erdosteine. The results of the analysis have been validated statistically and by recovery studies. The percentage assay was found to be 100.03 +/- 0.68 for Cefixime and 99.5 +/- 1.0 for Erdosteine (Mean +/- S.D) by method A and 99.54 +/- 0.84 for Cefixime and 100.54 +/- 1.3 for Erdosteine (Mean +/- S.D) by method B respectively. PMID- 21268558 TI - Simultaneous spectrophotometric estimation of Hydrochlorothiazide, Atenolol and Losartan potassium in tablet dosage form. AB - Two simple, accurate and reproducible spectrophotometric methods have been developed for the simultaneous estimation of Hydrochlorothiazide (Hctz), Atenolol (Atn) and Losartan potassium (Los) in combined tablet dosage forms. The first method involves determination using the simultaneous equation method, the sampling wavelengths selected are, 272.5 nm, 224 nm and 250 nm over the concentration ranges of 0.5-30 microg/ml, 1-50 microg/ ml and 1-60 microg/ml for Hctz, Atn and Los respectively. The second method is the First order derivative method, the sampling wavelengths selected for estimation of Hctz, Atn and Los are 280.5 nm, 233 nm and 244 nm with linearity in the concentration ranges of 0.5-30 microg/ ml, 1-50 microg/ml and 1-60 microg/ml respectively. The results of the analysis were validated statistically and recovery studies were carried out as per ICH guidelines. PMID- 21268559 TI - Effect of nutrients on production of Hamycin antibiotic by Streptomyces pimprina Thirum. PMID- 21268560 TI - 60 years of Acta Anaesthesiologica Belgica. PMID- 21268561 TI - The epidemiologic implications of perioperative anemia. PMID- 21268562 TI - Effects of anaemia on the myocardium. PMID- 21268563 TI - Efects of anaemia on the injured brain. PMID- 21268564 TI - New anticoagulants--how do they work? PMID- 21268565 TI - New antiplatelet agents. PMID- 21268566 TI - Place of Epoetin and Novo7 in Belgian anaesthesia & ICU practice: a clinical perspective. PMID- 21268567 TI - Periprocedural bridging of anticoagulation. AB - When deciding to preoperatively interrupt--and potentially substitute--a chronic treatment with antithrombotics or not, the surgical or anesthetic bleeding risk of continuing or substituting treatment should be balanced against the risk of thrombosis in case treatment is not interrupted or substituted. The decision will primarily be based upon the initial indication to antithrombotic treatment and the nature of the planned procedure. PMID- 21268568 TI - Antiplatelet therapy in the perioperative period. AB - Antiplatelet drugs are the cornerstone treatment in the secondary prevention of arterial thrombosis. Until recently, their intake was interrupted in the perioperative period because of fear for bleeding, but new insights have challenged this old habit: In patients at high risk for atherothrombotic events who need to undergo surgery or an invasive procedure, the risk for bleeding complications because of a treatment with low-dose acetylsalicylic acid (LD ASA) needs to be balanced against the risk of atherothrombotic events after treatment discontinuation. For patients at high risk of atherothrombotic complications recent guidelines do no longer advocate to interrupt LD ASA routinely. However, the likelihood of bleeding versus atherothrombotic complications should be considered on a case-by-case basis. When continued perioperatively, the bleeding risk associated with thienopyridines (ticlopidine, clopidogrel and prasugrel) is higher than that of LD ASA. It is recommended to stop their intake 1 week before the surgical intervention, except in patients with (recent) coronary stenting. PMID- 21268569 TI - Transfusion triggers: state of the art in 2010. PMID- 21268570 TI - Pleth variability index combined with passive leg raising-induced pulse pressure variation to detect hypovolemia in spontaneously breathing patients. AB - The combination of Pleth Variability Index (PVI) and passive leg raising (PLR) induced pulse pressure variation may help to diagnose hypovolemia in spontaneously breathing patients. In 44 subjects, PVI and Pulse Pressure (PP) variation after PLR were measured before and after induced hypovolemia (blood gift or hemodialysis session). PVI values were significantly greater after hemodialysis session or blood gift (22% vs 18%, P = 0.03); in contrast PP variation did not change significantly (7% vs 4%, P = 0.49). The accuracy of these parameters or of their combination to identify the "after hypovolemia induction" period was weak. In spontaneous ventilation, PVI value is greater after induced hypovolemia, whereas PP variation does not change significantly. The combination of PVI and PLR does not improve the accuracy of the detection of induced hypovolemia. PMID- 21268571 TI - Predictors of cardiac responsiveness to fluid therapy after cardiac surgery. AB - OBJECTIVES: Central venous pressure (CVP) and pulmonary capillary wedge pressure (PCWP) are insensitive preload markers and sometimes misleading. The introduction of the pulse contour method for monitoring of continuous cardiac output enabled the real-time quantification of stroke volume variation (SVV). Studies evaluating the accuracy of this parameter as a measure of preload responsiveness are still limited and conflicting results have been published in cardiac surgical patients. The aim of this study was to reevaluate the predictive value of SVV regarding cardiac responsiveness to fluid therapy and to compare it with the standard preload variables in a clinical setting in the ICU after cardiac surgery. METHODS: The assessment of cardiac responsiveness to fluid therapy (HAES-steril 6% 10 mL * Body Mass Index) was performed in 92 ventilated coronary artery surgical patients after arrival in the ICU. After the fluid load, detailed hemodynamic measurements were performed. A 'responder' was defined as a patient with a gain in stroke volume index (SVI) of 5% or more from baseline value to the volume challenge. RESULTS: Post hoc analysis showed that there were 47 responders to the fluid challenge and 45 non-responders. Hemodynamic data before the fluid therapy show that stroke volume variation in the responders group was significantly higher than in the non-responders groups (9.7 +/- 4.3% versus 7.6 +/- 3.0%, P = 0.01). The receiver operating characteristic curves for the baseline values of CVP, PCWP and SVV were constructed for illustrative purposes. The area under the curve for baseline values of SVV was significantly higher than random guess (area = 0.65, p < 0.05), indicative for the value of SVV as a marker of cardiac responsiveness to fluid therapy. The static preload parameters CVP and PCWP had no predictive value. CONCLUSION: SVV as measured with the LiDCO system is a better functional marker of cardiac responsiveness to fluid therapy than the static parameters CVP and PCWP. PMID- 21268572 TI - Combined spinal epidural anesthesia with epidural volume extension technique for hysterectomy in patient with unpalliated cyanotic heart disease--a case-report. AB - Adults with unrepaired cyanotic heart disease scheduled for a non-cardiac surgery present serious concerns for the anesthesiologists. Both general and regional anesthetic techniques have been safely reported in Eisenmenger's syndrome and adults with Tetralogy of Fallot (TOF) for non-cardiac surgery. The safety of low dose sequential combined spinal epidural (CSE) technique in high-risk cardiac cases has recently been emphasized in obstetric anesthetic practice but to our knowledge, this technique has not been reported for hysterectomy in cyanotic heart disease patients in anesthetic literature. We report the successful management of hysterectomy in a patient with ventricular septal defect and pulmonary atresia (VSD-PA) using CSE anesthesia with epidural volume extension (EVE) technique. PMID- 21268573 TI - Unpredicted neurological complications after robotic laparoscopic radical cystectomy and ileal conduit formation in steep trendelenburg position: two case reports. AB - Robotic surgery is becoming popular for minimally invasive surgical evolution as robotic devices allow unprecedented control and precision in minimally invasive procedures. Two cases of robotic radical cystectomy with ileal conduit urinary diversion surgeries having perioperative neurologic complications related to prolonged surgery in steep head down position are presented. In these patients, neurological deterioration occurred after extubation probably due to cerebral edema. We suggest the duration and positioning should be optimized for such prolonged surgery in steep head down position and some recommendations should be made. Moreover, in such surgeries a great vigilance has to be observed in the perioperative period. PMID- 21268574 TI - Osteoconductive and bioresorbable composites based on poly(L,L-lactide) and pseudowollastonite: from synthesis and interfacial compatibilization to in vitro bioactivity and in vivo osseointegration studies. AB - This contribution reports on the elaboration of novel bioresorbable composites consisting of pseudowollastonite (psW) (a silicate-based polycrystalline ceramic (alpha-CaSiO(3))) and poly(L,L-lactide) as a valuable polymeric candidate in bone guided regeneration. These composites were prepared by direct melt-blending to avoid the use of organic solvents harmful for biomedical applications. Amphiphilic poly(ethylene oxide-b-L,L-lactide) diblock copolymers synthesized by ring-opening polymerization were added to psW-based composites to modulate the bioactivity of the composites. The bioactivity of the composites was first evaluated by monitoring the release of bioactive Ca(2+) and (SiO(4))(4-) ions as well as the concomitant formation of hydroxyapatite on the material surface after soaking them in physiological fluid. Subsequently, the composites were studied in vitro to evaluate their cytotoxicity in the presence of SaOS-2 osteoblastic cells and in vivo to assess their osteoconductivity in an orthotopic rat tibia model. This study provides a first insight into the use of direct melt-blended psW poly(L,L-lactide) composites for bone-regeneration applications. PMID- 21268575 TI - Dendronized chitosan derivative as a biocompatible gene delivery carrier. AB - To improve the transfection efficiency of chitosan as a nonviral gene delivery vector, a dendronized chitosan derivative was prepared by a copper-catalyzed azide alkyne cyclization reaction of propargyl focal point poly(amidoamine) dendron with 6-azido-6-deoxy-chitosan. Its structure was characterized by (1)H NMR and FTIR analyses and its buffering capacity was evaluated by acid-base titration. In particular, its complexation with plasmid DNA was investigated by agarose gel electrophoresis, zeta potential, and particle size analyses as well as transmission electron microscopy observation. Compared to unmodified chitosan, such a chitosan derivative has better water solubility and buffering capacity. Compared to commonly used polyethyleneimine (PEI, 25 kDa), it could exhibit enhanced transfection efficiency in some cases and lower cell toxicity, as confirmed by in vitro transfection and cytotoxicity tests in human kidney 293T and human nasopharyngeal carcinoma CNE2 cell lines. In addition, the effect of serum on its transfection efficiency was also studied. PMID- 21268576 TI - Antiferromagnetism in a technetium oxide. Structure of CaTcO3. AB - The technetium perovskite CaTcO(3) has been synthesized. Combining synchrotron X ray and neutron diffraction, we found that CaTcO(3) is an antiferromagnetic with a surprisingly high Neel temperature of ~800 K. The transition to the magnetic state does not involve a structural change, but there is obvious magnetostriction. Electronic structure calculations confirm the experimental results. PMID- 21268577 TI - Pressure- and heat-induced insertion of CO2 into an auxetic small-pore zeolite. AB - When the small-pore zeolite natrolite is compressed at ca. 1.5 GPa and heated to ca. 110 degrees C in the presence of CO(2), the unit cell volume of natrolite expands by 6.8% and ca. 12 wt % of CO(2) is contained in the expanded elliptical channels. This CO(2) insertion into natrolite is found to be reversible upon pressure release. PMID- 21268578 TI - Enantioselective total syntheses of (-)-taiwaniaquinone H and (-)-taiwaniaquinol B by iridium-catalyzed borylation and palladium-catalyzed asymmetric alpha arylation. AB - We report a concise, enantioselective total synthesis of (-)-taiwaniaquinone H and the first enantioselective total synthesis of (-)-taiwaniaquinol B by a route that includes asymmetric palladium-catalyzed alpha-arylation of a ketone with an aryl bromide that was generated by sterically controlled halogenation via iridium catalyzed C-H borylation. This asymmetric alpha-arylation creates the benzylic quaternary stereogenic center present in the taiwaniaquinoids. The synthesis was completed efficiently by developing a Lewis acid-promoted cascade to construct the [6,5,6] tricyclic core of an intermediate common to the synthesis of a number of taiwaniaquinoids. Through the preparation of these compounds, we demonstrate the utility of constructing benzylic quaternary stereogenic centers, even those lacking a carbonyl group in the alpha-position, by asymmetric alpha-arylation. PMID- 21268579 TI - Monodisperse porous LiFePO4 microspheres for a high power Li-ion battery cathode. AB - A novel solvothermal approach combined with high-temperature calcinations was developed to synthesize on a large scale LiFePO(4) microspheres consisting of nanoplates or nanoparticles with an open three-dimensional (3D) porous microstructure. These micro/nanostructured LiFePO(4) microspheres have a high tap density and, as electrodes, show excellent rate capability and cycle stability. PMID- 21268580 TI - Mechanistic insights into the Brust-Schiffrin two-phase synthesis of organo chalcogenate-protected metal nanoparticles. AB - New insights into the formation chemistry of chalcogenate-protected metal nanoparticles (NPs) synthesized via the well-known Brust-Schiffrin two-phase method are presented here. On the basis of Raman, NMR, and surface plasmon resonance characterizations, it is concluded that, before the formation of any metal-chalcogen bonds, metal nucleation centers/NPs are first formed inside the inverse micelles of the tetrabutylammonium bromide in the organic solvent, where the metal ions are reduced by NaBH(4). The ensuing formation of the metal chalcogen bonds between the naked metal NPs inside the micelles and the organo chalcogen ligands in the organic solvent is the mechanism by which the further growth of the metal core can be controlled. This proposed mechanism is further examined in the formation of Ag and Cu NPs. PMID- 21268581 TI - Selective enhancement of nucleases by polyvalent DNA-functionalized gold nanoparticles. AB - We demonstrate that polyvalent DNA-functionalized gold nanoparticles (DNA-Au NPs) selectively enhance ribonuclease H (RNase H) activity while inhibiting most biologically relevant nucleases. This combination of properties is particularly interesting in the context of gene regulation, since high RNase H activity results in rapid mRNA degradation and general nuclease inhibition results in high biological stability. We have investigated the mechanism of selective RNase H activation and found that the high DNA density of DNA-Au NPs is responsible for this unusual behavior. This work adds to our understanding of polyvalent DNA-Au NPs as gene regulation agents and suggests a new model for selectively controlling protein-nanoparticle interactions. PMID- 21268582 TI - Efficient screening of a novel antimicrobial peptide from Jatropha curcas by cell membrane affinity chromatography. AB - A novel method named cell membrane affinity chromatography was used to screen antimicrobial peptides from Jatropha curcas . A cationic antimicrobial peptide (KVFLGLK, JCpep7) was successfully isolated and identified. Antimicrobial assays indicated that JCpep7 was active against the tested microorganisms ( Salmonella typhimurium ATCC 50013, Shigella dysenteriae ATCC 51302, Pseudomonas aeruginosa ATCC 27553, Staphylococcus aureus ATCC 25923, Bacillus subtilis ATCC 23631, and Streptococcus pneumoniae ATCC 49619) with minimal inhibitory concentration (MIC) values ranging from 24 to 64 MUg/mL. The antimicrobial mechanisms based on Fourier transform infrared (FTIR) spectroscopy and transmission electron microscopy (TEM) techniques showed that JCpep7 killed microbes principally via breaking of their cell walls and membranes, followed by cell lysis. The results indicated that cell membrane affinity chromatography could be a promising approach for high-throughput screening of antimicrobial peptides from J. curcas . PMID- 21268583 TI - A domino approach (hydrolysis/dehydrohalogenation/Heck coupling) for the synthesis of styrene sulfonate salts. AB - A domino approach of hydrolysis/dehydrohalogenation/Heck coupling was used to synthesize styrene sulfonate salts from iodoarenes and chloroethanesulfonyl chloride in good to excellent yields. Methodology was applicable for heterocyclic as well as disubstituted iodoarenes. Some of the key features of this synthetic methodology include the use of phosphine free catalytic system, water as an environmentally friendly solvent, short reaction times, and absence of additives. PMID- 21268584 TI - A kinetic aggregation assay allowing selective and sensitive amyloid-beta quantification in cells and tissues. AB - The process of amyloid-beta (Abeta) fibril formation is genetically and pathologically linked to Alzheimer's disease (AD). Thus, a selective and sensitive method for quantifying Abeta fibrils in complex biological samples allows a variety of hypotheses to be tested. Herein, we report the basis for a quantitative in vitro kinetic aggregation assay that detects seeding-competent Abeta aggregates in mammalian cell culture media, in Caenorhabditis elegans lysate, and in mouse brain homogenate. Sonicated, proteinase K-treated Abeta fibril-containing tissue homogenates or cell culture media were added to an initially monomeric Abeta(1-40) reporter peptide to seed an in vitro nucleated aggregation reaction. The reduction in the half-time (t(50)) of the amyloid growth phase is proportional to the quantity of seeding-competent Abeta aggregates present in the biological sample. An ion-exchange resin amyloid isolation strategy from complex biological samples is demonstrated as an alternative for improving the sensitivity and linearity of the kinetic aggregation assay. PMID- 21268586 TI - Structure of prokaryotic polyamine deacetylase reveals evolutionary functional relationships with eukaryotic histone deacetylases. AB - Polyamines are a ubiquitous class of polycationic small molecules that can influence gene expression by binding to nucleic acids. Reversible polyamine acetylation regulates nucleic acid binding and is required for normal cell cycle progression and proliferation. Here, we report the structures of Mycoplana ramosa acetylpolyamine amidohydrolase (APAH) complexed with a transition state analogue and a hydroxamate inhibitor and an inactive mutant complexed with two acetylpolyamine substrates. The structure of APAH is the first of a histone deacetylase-like oligomer and reveals that an 18-residue insert in the L2 loop promotes dimerization and the formation of an 18 A long "L"-shaped active site tunnel at the dimer interface, accessible only to narrow and flexible substrates. The importance of dimerization for polyamine deacetylase function leads to the suggestion that a comparable dimeric or double-domain histone deacetylase could catalyze polyamine deacetylation reactions in eukaryotes. PMID- 21268587 TI - Low-spin->high-spin relaxation dynamics in the highly diluted spin-crossover system [Fe(x)Zn(1-x)(bbtr)3](ClO4)2. AB - Whereas the neat polymeric iron(II) compound [Fe(bbtr)(3)](ClO(4))(2), bbtr = 1,4 di(1,2,3-triazol-1-yl)butane, shows a quantitative spin transition triggered by a crystallographic phase transition centered at 107 K with a 13 K wide hysteresis, the iron(II) complexes in the diluted mixed crystals [Fe(x)Zn(1 x)(bbtr)(3)](ClO(4))(2), x = 0.02 and 0.1, stay predominantly in the (5)T(2) high spin state down to cryogenic temperatures. However, the (1)A(1) low-spin state can be populated as metastable state via irradiation into the spin-allowed (5)T(2)->(5)E ligand-field transition of the high-spin species in the near infrared. The quantum efficiency of the light-induced conversion is approximately 10% at low temperatures and decreases rapidly above 160 K. The lifetime of the light-induced low-spin state decreases from 15 days at 40 K to 30 ns at 220 K, that is, by 14 orders of magnitude. In the high-temperature regime the activation energy for the low-spin->high-spin relaxation is 1840(20) cm(-1). PMID- 21268585 TI - Proline 96 of the copper ligand loop of amicyanin regulates electron transfer from methylamine dehydrogenase by positioning other residues at the protein protein interface. AB - Amicyanin is a type 1 copper protein that serves as an electron acceptor for methylamine dehydrogenase (MADH). The site of interaction with MADH is a "hydrophobic patch" of amino acid residues including those that comprise a "ligand loop" that provides three of the four copper ligands. Three prolines are present in this region. Pro94 of the ligand loop was previously shown to strongly influence the redox potential of amicyanin but not affinity for MADH or mechanism of electron transfer (ET). In this study Pro96 of the ligand loop was mutated. P96A and P96G mutations did not affect the spectroscopic or redox properties of amicyanin but increased the K(d) for complex formation with MADH and altered the kinetic mechanism for the interprotein ET reaction. Values of reorganization energy (lambda) and electronic coupling (H(AB)) for the ET reaction with MADH were both increased by the mutation, indicating that the true ET reaction observed with native amicyanin was now gated by or coupled to a reconfiguration of the proteins within the complex. The crystal structure of P96G amicyanin was very similar to that of native amicyanin, but notably, in addition to the change in Pro96, the side chains of residues Phe97 and Arg99 were oriented differently. These two residues were previously shown to make contacts with MADH that were important for stabilizing the amicyanin-MADH complex. The values of K(d), lambda, and H(AB) for the reactions of the Pro96 mutants with MADH are remarkably similar to those obtained previously for P52G amicyanin. Mutation of this proline, also in the hydrophobic patch, caused reorientation of the side chain of Met51, another reside that interacted with MADH and caused a change in the kinetic mechanism of ET from MADH. These results show that proline residues near the copper site play key roles in positioning other amino acid residues at the amicyanin-MADH interface not only for specific binding to the redox protein partner but also to optimize the orientation of proteins for interprotein ET. PMID- 21268588 TI - Kinetic consequences of replacing the internucleotide phosphorus atoms in DNA with arsenic. AB - It was claimed in a recent publication that a strain of Halomonadacea bacteria (GFAJ-1) isolated from the arsenic-rich waters of Mono Lake, California is able to substitute arsenic for phosphorus in its macromolecules and small molecule metabolites. In this short Perspective, we consider chemical and biochemical issues surrounding the central claim that Halomonadacea GFAJ-1 is able to survive while incorporating kinetically labile arsenodiester linkages into the backbone of its DNA. Chemical precedents suggest that arsenodiester linkages in the putative arsenic-containing DNA of GFAJ-1 would undergo very rapid hydrolytic cleavage in water at 25 degrees C with an estimated half-life of 0.06 s. In contrast, the phosphodiester linkages of native DNA undergo spontaneous hydrolysis with a half-life of approximately 30,000,000 y at 25 degrees C. Overcoming such dramatic kinetic instability in its genetic material would present serious challenges to Halomonadacea GFAJ-1. PMID- 21268589 TI - Unidirectional broadband light emission from supported plasmonic nanowires. AB - Metal nanowires are thought to become key elements in future nanophotonics applications. Here we show that single crystal silver nanowires supported on a dielectric interface behave similar to broadband unidirectional antennas for visible light. The degree of directionality can be controlled through the nanowire radius and its dielectric environment and the effect can be interpreted in terms of so-called leakage radiation from surface plasmons propagating in a single direction along a wire. We measure a forward-to-backward emission ratio exceeding 15 dB and an angular spread of 4 degrees for wires with radii of the order 150 nm on glass in air. These findings could pave the way for development of metal nanowires as subwavelength directors of light in solar, sensor, and spectroscopy applications. PMID- 21268591 TI - Synthesis and electrical characterization of magnetic bilayer graphene intercalate. AB - We report synthesis and transport properties of the minimal graphite intercalation compound, a ferric chloride (FeCl(3))(n) island monolayer inside bilayer graphene. Chemical doping by the intercalant is simultaneously probed by micro-Raman spectroscopy and Hall measurements. Quantum oscillations of conductivity originate from microscopic domains of intercalated and unintercalated regions. A slight upturn in resistance related to magnetic transition is observed. Two-dimensional intercalation in bilayer graphene opens new possibilities to engineer two-dimensional properties of intercalates. PMID- 21268592 TI - Endoprotease-mediated intracellular protein delivery using nanocapsules. AB - Proteins possess distinct intracellular roles allowing them to have vast therapeutic applications. However, due to poor cellular permeability and fragility of most proteins, intracellular delivery of native, active proteins is challenging. We describe a biomimetic protein delivery vehicle which is degradable upon the digestion by furin, a ubiquitous intracellular protease, to release encapsulated cargos. Proteins were encapsulated in a nanosized matrix prepared with monomers and a bisacrylated peptide cross-linker which can be specifically recognized and cleaved by furin. Release of encapsulated protein was confirmed in a cell-free system upon proteolytic degradation of nanocapsules. In vitro cell culture studies demonstrated successful intracellular delivery of both nuclear and cytosolic proteins and confirmed the importance of furin-degradable construction for native protein release. This endoprotease-mediated intracellular delivery system may be extended to effectively deliver various biological therapeutics. PMID- 21268593 TI - Photochemical eliminations involving zwitterionic intermediates generated via electrocyclic ring closure of benzothiophene carboxanilides. AB - Leaving groups such as carboxylate, thiolate, and phenolate are expelled via zwitterionic intermediates produced upon photochemical electrocyclic ring closure of benzothiophene carboxanilides in the triplet excited state. Chemical yields generally exceed 90%, while quantum yields vary with basicity of the released leaving group. PMID- 21268594 TI - Tandem reaction of propargylic alcohol, sulfonamide, and N-iodosuccinimide: synthesis of N-(2-iodoinden-1-yl)arenesulfonamide. AB - An efficient and straightforward strategy for the synthesis of N-(2-haloinden-1 yl)arenesulfonamides from propargylic alcohols and sulfonamides is described. Allenesulfonamide is postulated to be the key intermediate for this tandem transformation. PMID- 21268595 TI - Tetrahydroxanthones by sequential Pd-catalyzed C-O and C-C bond construction and use in the identification of the "antiausterity" pharmacophore of the kigamicins. AB - Readily available C-acylated cycloalkanones undergo efficient Pd catalyzed ring closure/cross-coupling providing 7-substituted tetrahydroxanthones in a single operation. One of the synthesized derivatives (depicted) is shown to selectively kill pancreatic cancer (PANC-1) cells under conditions of nutrient deprivation indicating that the tetrahydroxanthone is responsible, in part, for the "antiausterity" effects of the naturally occurring kigamicins. PMID- 21268596 TI - A heterowheel [3]pseudorotaxane by integrating beta-cyclodextrin and cucurbit[8]uril inclusion complexes. AB - A heterowheel [3]pseudorotaxane was prepared by integrating two binary inclusion complexes of beta-cyclodextrin-hydroxynaphthalene (beta-CD.3) with a cucurbit[8]uril-viologen derivative (CB[8].2), in which simultaneous molecular recognition of the adamantine moiety in 2 by beta-CD and the charge-transfer interaction of 3 with the viologen nucleus of 2 in the cavity of CB[8] are two crucial factors for the formation of the quaternary complex. PMID- 21268597 TI - Atomic scale growth dynamics of nanocrystals within carbon nanotubes. AB - The confined interior region of carbon nanotubes has proved to be an effective "nano-test-tube" to conduct chemical reactions in a restricted volume. It also benefits from being thin and relatively transparent to electrons, enabling structural characterization using high-resolution transmission electron microscopy. This permits real-time monitoring of chemical reactions with atomic resolution. Here, we have studied the dynamics of single Pr atoms released from Pr(2)@C(72) metallofullerenes. We show that the Pr atoms form small nanoclusters that subsequently coalesce to ordered, stable nanocrystals within the confines of a carbon nanotube. This process has been tracked in situ with atomic-resolution using low-voltage aberration-corrected high-resolution transmission electron microscopy. We reveal that nanocrystal formation within a nanotube does not generally occur by the addition of single atoms to one pre-existing cluster but rather through aggregation of several smaller clusters. These results provide some of the deepest insights into the dynamics of single-atom behavior in the solid state. PMID- 21268598 TI - Heteroaromatic synthesis via olefin cross-metathesis: entry to polysubstituted pyridines. AB - The olefin cross-metathesis reaction provides a rapid and efficient method for the synthesis of alpha,beta-unsaturated 1,5-dicarbonyl derivatives which then serve as effective precursors to mono-tetrasubstituted pyridines. Manipulation of the key 1,5-dicarbonyl intermediate allows access to pyridines with a wide range of substitution patterns. An extension of this methodology facilitates the preparation of pyridines embedded within macrocycles, as exemplified by an efficient synthesis of (R)-(+)-muscopyridine. High levels of regiocontrol, short reaction sequences, and facile substituent variation are all notable aspects of this methodology. PMID- 21268599 TI - Structural evolution of magnesium difluoride: from an amorphous deposit to a new polymorph. AB - The structural evolution of magnesium difluoride from an amorphous deposit has been investigated by in situ powder X-ray diffraction (XRPD) and transmission electron microscopy (TEM). Crystalline MgF(2) was evaporated at different temperatures, which define the vapor pressures in the range from 4.7 * 10(-3) to 1.6 * 10(-1) mbar, and deposited onto various substrates. The temperature of the substrate was systematically varied from -228 to 25 degrees C. Magnesium difluoride was obtained as an amorphous sample when deposited on a substrate kept at a temperature below -100 degrees C. Upon warming, the deposit transforms via the CaCl(2) type of structure (beta-MgF(2), at 70 degrees C) into the stable rutile type (alpha-MgF(2), 250 degrees C) by a displacive order-disorder phase transition. The new beta-MgF(2) polymorph was refined assuming the orthorhombic CaCl(2) type of structure (Pnnm, No. 58) with the lattice constants a = 4.592(1) A, b = 4.938(3) A, and c = 2.959(3) A. When deposited above -50 degrees C, samples crystallize directly in the rutile structure. PMID- 21268600 TI - Spectroscopic studies on tetracycline in room-temperature ionic liquids. AB - Circular dichroism and steady-state fluorescence of tetracycline (1) were investigated in a series of 1-butyl-3-methylimidazolium room-temperature ionic liquids. The identity of the anion of the ionic liquids was found to modulate the conformation as well as the emission intensity of tetracycline over a wide range. PMID- 21268601 TI - Pyrrole-based scaffolds for turn mimics. AB - Two amino acid derived synthons were combined to give homopropargylic amines 2. Platinum dichloride was used to cyclize these intermediates into pyrroles 3 which collapsed to the target secondary structure mimics 1 on treatment with base. Side chains of these compounds overlay with an idealized type 1 beta-turn and with an inverse gamma-turn. PMID- 21268602 TI - Theoretical insights into heme-catalyzed oxidation of cyclohexane to adipic acid. AB - Adipic acid is a key compound in the chemical industry, where it is mainly used in the production of polymers. The conventional process of its generation requires vast amounts of energy and, moreover, produces environmentally deleterious substances. Thus, there is interest in alternative ways to gain adequate amounts of adipic acid. Experimental reports on a one-pot iron-catalyzed conversion of cyclohexane to adipic acid motivated a theoretical investigation based on density functional theory calculations. The process investigated is interesting because it requires less energy than contemporary methods and does not produce environmentally harmful side products. The aim of the present contribution is to gain insight into the mechanism of the iron-catalyzed cyclohexane conversion to provide a basis for the further development of this process. The rate-limiting step of the process is discussed, but considering the accuracy of the calculations, it is difficult to ensure whether the rate-limiting step is in the substrate oxidation or in the generation of the catalytically active species. It is shown that the slowest step in the substrate oxidation is the conversion of cyclohexanol to cyclohexane-1,2-diol. Hydrogen-atom transfer from one of the OH groups of cyclohexane-1,2-diol makes the intradiol cleavage occur spontaneously. PMID- 21268603 TI - Catalytic enantioselective synthesis of naturally occurring butenolides via hetero-allylic alkylation and ring closing metathesis. AB - An efficient catalytic asymmetric synthesis of chiral gamma-butenolides was developed based on the hetero-allylic asymmetric alkylation (h-AAA) in combination with ring closing metathesis (RCM). The synthetic potential of the h AAA-RCM protocol was illustrated with the facile synthesis of (-)-whiskey lactone, (-)-cognac lactone, (-)-nephrosteranic acid, and (-)-roccellaric acid. PMID- 21268604 TI - Buckled layers in K0.66Mn2O4.0.28H2O and K0.99Mn3O6.1.25H2O synthesized at high pressure: implication for the mechanism of layer-to-tunnel transformation in manganese oxides. AB - A 2 * 2 layer-buckled manganese oxide, K(0.66)Mn(2)O(4).0.28H(2)O (I), has been synthesized under high pressure and retained at ambient pressure; it is metastable and will finally transform to a 2 * 1 layer-buckled K(0.99)Mn(3)O(6).1.25H(2)O (II) in 1 year. Both crystal structures were determined by single-crystal X-ray diffraction. On the basis of these buckled layers, which are a result of ordering of Mn(3+)/Mn(4+) in separate rows and cooperative Jahn-Teller distortion of Mn(3+)O(6) octahedra, a mechanism of structure transformation from birnessite to tunnel structures was proposed. PMID- 21268605 TI - Synthesis, structure elucidation, and redox properties of 99Tc complexes of lacunary Wells-Dawson polyoxometalates: insights into molecular 99Tc-metal oxide interactions. AB - The isotope (99)Tc (beta(max), 293.7; half-life, 2.1 * 10(5) years) is an abundant product of uranium-235 fission in nuclear reactors and is present throughout the radioactive waste stored in underground tanks at the Hanford and Savannah River sites. Understanding and controlling the extensive redox chemistry of (99)Tc is important in identifying tunable strategies to separate (99)Tc from spent fuel and from waste tanks and, once separated, to identify and develop an appropriately stable waste form for (99)Tc. Polyoxometalates (POMs), nanometer sized models for metal oxide solid-state materials, are used in this study to provide a molecular level understanding of the speciation and redox chemistry of incorporated (99)Tc. In this study, (99)Tc complexes of the (alpha(2) P(2)W(17)O(61))(10-) and (alpha(1)-P(2)W(17)O(61))(10-) isomers were prepared. Ethylene glycol was used as a "transfer ligand" to minimize the formation of TcO(2).xH(2)O. The solution structures, formulations, and purity of Tc(V)O(alpha(1)/alpha(2)-P(2)W(17)O(61))(7-) were determined by multinuclear NMR. X-ray absorption spectroscopy of the complexes is in agreement with the formulation and structures determined from (31)P and (183)W NMR. Preliminary electrochemistry results are consistent with the EXAFS results, showing a facile reduction of the Tc(V)O(alpha(1)-P(2)W(17)O(61))(7-) species compared to the Tc(V)O(alpha(2)-P(2)W(17)O(61))(7-) analog. The alpha(1) defect is unique in that a basic oxygen atom is positioned toward the alpha(1) site, and the Tc(V)O center appears to form a dative metal-metal bond with a framework W site. These attributes may lead to the assistance of protonation events that facilitate reduction. Electrochemistry comparison shows that the Re(V) analogs are about 200 mV more difficult to reduce in accordance with periodic trends. PMID- 21268606 TI - Chemical reactivity of the imidazole: a semblance of pyridine and pyrrole? AB - It has been suggested that pyridine and pyrrole could be patterns for imidazole reactivity studies due to the amine (-NH-) and aza (-N?) nitrogen atoms. The analyses of the local and global electronic indexes prove and quantify that imidazole has an intermediate analogy between pyrrole and pyridine. PMID- 21268607 TI - Monodispersed Pd-Ni nanoparticles: composition control synthesis and catalytic properties in the Miyaura-Suzuki reaction. AB - We have successfully prepared a series of magnetically separable "quasi homogeneous" Pd-Ni nanoalloy catalysts with tunable composition in a one-pot wet chemical route. We have evaluated the catalytic activity of these Pd-Ni alloy catalysts with different compositions through the Miyaura-Suzuki coupling reaction. These palladium/non-noble metal alloy catalysts show better catalytic activity than an equal amount of palladium nanoparticles. Furthermore, these catalysts exhibited excellent performance in superparamagnetism owing to its great advantage for reducing the usage of noble metal. PMID- 21268608 TI - GC/MS with post-column switching for large volume injection of headspace samples: sensitive determination of volatile organic compounds in human whole blood and urine. AB - When volatile or semivolatile compounds are measured by headspace (HS) gas chromatography (GC)/mass spectrometry (MS), the maximum gas volume to be injected is usually 0.5-1.0 mL; over the volume, the MS detector automatically shuts down due to impairment of the vacuum rate of the MS ionization chamber. To overcome the problem, we modified the gas flow routes of a new type of GC/MS instrument to create a postcolumn switching system, which can eliminate the large volume of gas before introduction of target compounds into the MS ionization chamber. Our HS GC/MS system enabled injection of as large as 5 mL of HS gas without any disturbance. As the first example analysis, we tried to establish the analysis of naphthalene and p-dichlorobenzene in human whole blood and urine by this method with large volume injection. The limits of detection for both compounds in whole blood and urine were as low as about 10 and 5 pg/mL, respectively. The validation data and actual measurements were also demonstrated. The new GC/MS system has great potential to analyze any type of volatile or semivolatile organic compounds in biological matrixes with very high sensitivity and full automation. PMID- 21268609 TI - Stable isotope labeling by essential nutrients in cell culture for preparation of labeled coenzyme A and its thioesters. AB - Stable isotope dilution mass spectrometry (MS) represents the gold standard for quantification of endogenously formed cellular metabolites. Although coenzyme A (CoA) and acyl-CoA thioester derivatives are central players in numerous metabolic pathways, the lack of a commercially available isotopically labeled CoA limits the development of rigorous MS-based methods. In this study, we adapted stable isotope labeling by amino acids in cell culture (SILAC) methodology to biosynthetically generate stable isotope labeled CoA and thioester analogues for use as internal standards in liquid chromatography/multiple reaction monitoring mass spectrometry (LC/MRM-MS) assays. This was accomplished by incubating murine hepatocytes (Hepa 1c1c7) in media in which pantothenate (a precursor of CoA) was replaced with [(13)C(3)(15)N(1)]-pantothenate. Efficient incorporation into various CoA species was optimized to >99% [(13)C(3)(15)N(1)]-pantothenate after three passages of the murine cells in culture. Charcoal-dextran-stripped fetal bovine serum (FBS) was found to be more efficient for serum supplementation than dialyzed or undialyzed FBS, due to lower contaminating unlabeled pantothenate content. Stable isotope labeled CoA species were extracted and utilized as internal standards for CoA thioester analysis in cell culture models. This methodology of stable isotope labeling by essential nutrients in cell culture (SILEC) can serve as a paradigm for using vitamins and other essential nutrients to generate stable isotope standards that cannot be readily synthesized. PMID- 21268610 TI - Analyte distribution at channel intersections of electro-fluid-dynamic devices. AB - Mass conservation is the guiding principle for analyte distribution at channel intersections of microfluidic devices, where analyte migration is mainly driven by an applied electric field, and in electro-fluid-dynamic (EFD) devices, where multiple fields and pressures can be applied simultaneously on the same channel network. This paper introduces another type of conservation, the conservation of effective volumetric flow rate, at channel intersections when the conductivity of the solution in the intersecting channels is maintained constant. This conservation principle provides an additional criterion needed to describe analyte migration in channels connecting to a common intersection and to predict how analyte is distributed into individual channels in the channel network of EFD devices, when multiple voltages and pressures are applied. The theoretical bases of effective volumetric flow rate balance are discussed, and the potential use of this principle in conjunction with the principle of mass conservation to predict the migration behavior of analytes is demonstrated. Junctions of different geometry in EFD devices are used to demonstrate the validity of these equations, and the measured velocities and numbers of microbeads in each channel agree with the predicted values. PMID- 21268611 TI - Interface architecture determined electrocatalytic activity of Pt on vertically oriented TiO(2) nanotubes. AB - The surface atomic structure and chemical state of Pt is consequential in a variety of surface-intensive devices. Herein we present the direct interrelationship between the growth scheme of Pt films, the resulting atomic and electronic structure of Pt species, and the consequent activity for methanol electro-oxidation in Pt/TiO(2) nanotube hybrid electrodes. X-ray photoelectron spectroscopy (XPS) and X-ray absorption spectroscopy (XAS) measurements were performed to relate the observed electrocatalytic activity to the oxidation state and the atomic structure of the deposited Pt species. The atomic structure as well as the oxidation state of the deposited Pt was found to depend on the pretreatment of the TiO(2) nanotube surfaces with electrodeposited Cu. Pt growth through Cu replacement increases Pt dispersion, and a separation of surface Pt atoms beyond a threshold distance from the TiO(2) substrate renders them metallic, rather than cationic. The increased dispersion and the metallic character of Pt results in strongly enhanced electrocatalytic activity toward methanol oxidation. This study points to a general phenomenon whereby the growth scheme and the substrate-to-surface-Pt distance dictates the chemical state of the surface Pt atoms, and thereby, the performance of Pt-based surface-intensive devices. PMID- 21268612 TI - Synthesis and reactivity of o-benzylphosphino- and o-alpha-methylbenzyl(N,N dimethyl)amine-boranes. AB - The series of o-benzylphosphino-boranes, o-(R(2)B)C(6)H(4)CH(2)PtBu(2) (R = Cl 3, Ph 4, Cy 6, C(6)F(5) 7, Mes 8) and o-(BBN)C(6)H(4)CH(2)PtBu(2) (5), were synthesized from reactions of the respective chloroboranes with the lithiated benzyl-phosphine. In an analogous fashion, the alpha-methylbenzyl(N,N dimethyl)amine-boranes o-(R(2)B)C(6)H(4)CH(Me)NMe(2) (R = Cl 10, Ph 11, Cy 12, C(6)F(5) 13, Mes 14) were prepared. While these species were inactive in the catalytic hydrogenation of tBuN?CHPh, compounds 7, 8, and 14 did react with H(2) at elevated temperatures (100 degrees C), resulting in the elimination of HC(6)F(5) and mesitylene, respectively. In the latter case, the species o ((Mes)HB)C(6)H(4)CH(Me)NMe(2) 15 was isolated. 14 was also shown to react with H(2)O to give the species o-((Mes)(HO)B)C(6)H(4)CH(Me)NMe(2) 16 with the loss of mesitylene. The structure of these compounds and the nature of these reactions were also probed spectroscopically, crystallographically, and computationally. The energies for the products of hydrogenation, the phosphonium and ammonium hydridoborates, were computed. In all cases, these products were endothermic with respect to the precursor phosphine-boranes and amine-boranes and H(2). The barriers to H(2) activation were found to be in the range of 24-38 kcal/mol. These theoretical studies also demonstrate that the steric bulk around the boron center dramatically affects the activation barrier for H(2) activation, while the Lewis acidity of the borane has the largest effect on the stabilization of the resulting onium-borohydride. In the case of the elimination reactions, the driving forces appear to be the loss of arene byproduct and formation of a strong donor-acceptor bond. PMID- 21268613 TI - Direct photochemical functionalization of Si(111) with undecenol. AB - Direct UV photochemical functionalization of H-terminated Si(111) with bifunctional 10-undecen-1-ol was achieved with selective attachment via its vinyl end, resulting in the formation of a compact monolayer with free terminal alcohol groups. This is due to the faster radical propagation mechanism in hydrosilylation with alkene compared to the nucleophilic attack mechanism of alcohol, which is impeded by intermolecular hydrogen bonding present at room temperature. Evidence from X-ray photoelectron spectroscopy, infrared spectroscopy, and resistance to fluoride etching shows that Si-C is the interfacial bond, and atomic force microscopy shows the presence of a smooth, uniform monolayer conforming to the atomic terraces of the Si(111) surface. The application of such a hydroxyl-terminated monolayer was demonstrated by tethering a bromoinitiator through surface esterification and thereafter subjecting the surface to the surface-initiated atom-transfer radical polymerization of butyl methacrylate. The poly(butyl methacrylate) brushes formed were found to be smooth (R(a) < 0.3 nm) and uniform even for a thin film of 4.0 nm. PMID- 21268614 TI - Cu2+-cyclen as probe to identify conformational states in guanine nucleotide binding proteins. AB - (31)P NMR spectroscopy is a suitable method for identifying conformational states in the active site of guanine nucleotide binding proteins detecting the nucleotide placed there. Because there is no labeling necessary, this method is gaining increasing interest. By (31)P NMR spectroscopy two major conformational states, namely state 1(T) and state 2(T), can be detected in active Ras protein characterized by different chemical shifts. Depending on the conformational state Ras shows clearly different physiological properties. Meanwhile analogous conformational equilibria could also be shown for other members of the Ras superfamily. It is often difficult to determine the conformational states of the proteins on the basis of chemical shift alone; therefore, direct detection would be a great advantage. With the use of Cu(2+)-cyclen which selectively interacts only with one of the major conformational states (state 1) one has a probe to distinguish between the two states, because only proteins existing in conformational state 1 interact with the Cu(2+)-cyclen at low millimolar concentrations. The suitability was proven using Ras(wt) and Ras mutants, Ras complexed with GTP, GppNHp, or GTPgammaS, as well as two further members of the Ras superfamily namely Arf1 and Ran. PMID- 21268615 TI - Copper-mediated intermolecular direct biaryl coupling. AB - Copper-mediated intermolecular direct biaryl coupling of arylazines and azoles via dual C-H bond cleavage proceeds even without palladium catalysts. The reaction system shows the high potential of copper salts in direct C-H arylation chemistry and provides a new approach to biaryl motifs, which are ubiquitous in pharmaceuticals and functional materials. PMID- 21268616 TI - Modified scaled hierarchical equation of motion approach for the study of quantum coherence in photosynthetic complexes. AB - We present a detailed theoretical study of the transfer of electronic excitation energy through the Fenna-Matthews-Olson (FMO) pigment-protein complex, using the newly developed modified scaled hierarchical approach (Shi, Q.; et al. J. Chem. Phys. 2009, 130, 084105). We show that this approach is computationally more efficient than the original hierarchical approach. The modified approach reduces the truncation levels of the auxiliary density operators and the correlation function. We provide a systematic study of how the number of auxiliary density operators and the higher-order correlation functions affect the exciton dynamics. The time scales of the coherent beating are consistent with experimental observations. Furthermore, our theoretical results exhibit population beating at physiological temperature. Additionally, the method does not require a low temperature correction to obtain the correct thermal equilibrium at long times. PMID- 21268617 TI - Temperature at small scales: a lower limit for a thermodynamic description. AB - We analyze the concept of equilibrium temperature in a set of interacting argon atoms, confined in a nanostructure, a zeolite with an intricate distribution of channels through which the atoms may move. The temperature is computed following two procedures: by averaging over the kinetic energy of the particles and over the forces acting on them. It is shown that for external surfaces and for regions which do not fall under the whole pattern of potential energy distribution, smaller than a quarter of a crystal unit cell, both temperatures, kinetic and configurational, show significant differences. The configurational temperature accounts for the different interactions on the particles in the different parts of the channels which makes them move in an energetically heterogeneous environment. The kinetic temperature is practically not affected by these inhomogeneities. The observed disparity between both temperatures disappears when averages are taken over larger regions of the zeolite. The size of these regions imposes a lower limit for a consistent thermodynamic description of a small-scale systems such as nanostructured materials, catalytic cells, and nano heat exchangers. PMID- 21268618 TI - Synthesis of the antiproliferative agent hippuristanol and its analogues via Suarez cyclizations and Hg(II)-catalyzed spiroketalizations. AB - A full account of the synthesis of hippuristanol and its analogues is described. Hecogenin acetate was identified as a suitable and economical starting material for this work, and substrate-controlled stereoselection was obtained throughout the construction of the key spiroketal unit. Suarez cyclization was first used, but Hg(II)-catalyzed spiroketalization of the 3-alkyne-1,7-diol motif was finally identified as the most convenient strategy. PMID- 21268619 TI - Double-tandem [4pi+2pi].[2pi+2pi].[4pi+2pi].[2pi+2pi] synthetic sequence with photoprotolytic oxametathesis and photoepoxidation in the chromone series. AB - Chromones are introduced into a double-tandem [4(pi)+2(pi)].[2(pi)+2(pi)].[4(pi)+2(pi)].[2(pi)+2(pi)] synthetic sequence, culminating in photoprotolytic oxametathesis, which leads to an expeditious growth of molecular complexity over a few experimentally simple steps. The overall reaction can potentially be utilized in diversity-oriented synthesis, as it allows for three or more diversity inputs furnishing novel unique polycyclic scaffolds decorated with a variety of functionalities and aromatic/heterocyclic pendants. The polycyclic alkenes, resulting from the oxametathesis step, were found to undergo efficient and clean photoinduced epoxidation when irradiated in the presence of molecular oxygen. PMID- 21268620 TI - A highly fluorescent hydrophilic ionic liquid as a potential probe for the sensing of biomacromolecules. AB - With respect to the conventional imidazolium ionic liquids which generally create very weak fluorescence with quantum yields at extremely low levels of 0.005-0.02, a symmetrical hydrophilic ionic liquid 1,3-butylimidazolium chloride (BBimCl) was found to be highly fluorescent with lambda(em) at 388 nm when excited at lambda(ex) < 340 nm. The very high quantum yield of BBimCl in aqueous medium, derived to be 0.523 when excited at 315 nm, was attributed to its symmetrical plane conjugating structure. In the presence of hemoglobin, the fluorescence of BBimCl could be significantly quenched, resulting from the coordinating interaction between the iron atom in the heme group of hemoglobin and the cationic imidazolium moiety. This feature of the present hydrophilic ionic liquid makes it a promising fluorescence probe candidate for the sensitive sensing of hemoglobin. A linear regression was observed within 3 * 10(-7) to 5 * 10(-6) mol L(-1) for hemoglobin, and a detection limit of 7.3 * 10(-8) mol L(-1) was derived. PMID- 21268621 TI - Structural properties of high and low density water in a supercooled aqueous solution of salt. AB - We consider and compare the structural properties of bulk TIP4P water and of a sodium chloride aqueous solution in TIP4P water with concentration c = 0.67 mol/kg, in the metastable supercooled region. In a previous paper (Corradini, D.; Rovere, M.; Gallo, P. J. Chem. Phys. 2010, 132, 134508) we found in both systems the presence of a liquid-liquid critical point (LLCP). The LLCP is believed to be the end point of the coexistence line between a high density liquid (HDL) and a low density liquid (LDL) phase of water. In the present paper we study the different features of water-water structure in HDL and LDL both in bulk water and in the solution. We find that the ions are able to modify the bulk LDL structure, rendering water-water structure more similar to the bulk HDL case. By the study of the hydration structure in HDL and LDL, a possible mechanism for the modification of the bulk LDL structure in the solution is identified in the substitution of the oxygen by the chloride ion in oxygen coordination shells. PMID- 21268622 TI - Spectroscopic characterization of oligoaniline microspheres obtained by an aniline-persulfate approach. AB - This paper investigates the structure of the products obtained from the polymerization of aniline with ammonium persulfate in a citrate/phosphate buffer solution at pH 3 by resonance Raman, NMR, FTIR, and UV-vis-NIR spectroscopies. All the spectroscopic data showed that the major product presented segments that were formed by a 1,4-Michael reaction between aniline and p-benzoquinone monoimine, ruling out the formation of polyazane structure that has been recently proposed. The characterization of samples obtained at different stages of the reaction indicated that, as the reaction progressed, phenazine units were formed and 1,4-Michael-type adducts were hydrolyzed/oxidized to yield benzoquinone. Raman mapping data suggested that phenazine-like segments could be related to the formation of the microspheres morphology. PMID- 21268623 TI - Rotational and rovibrational spectroscopy of CH3NC of the ground and nu4 = 1 vibrational states. AB - The parallel vibration-rotation band nu(4) of methyl isocyanide (CH(3)NC), with a band center at 944.9 cm(-1), was studied by FTIR spectroscopy between 890 and 980 cm(-1) in order to improve the ground-state rotational constants. Such improvement is essential for the scheduled studies of excited vibrational levels and their mutual anharmonic resonances occurring at higher values of the K rotational number. Ground-state combination differences generated from this band, spanning values of J/K from 0 to 85/13, were combined with rotational data from the literature and newly measured rotational transitions, extending the J/K range from 3/0 up to 31/14, and fitted simultaneously with a fully quantitative reproduction of the data. The infrared data of the nu(4) band were analyzed together with rotational data of the nu(4) = 1 level, spanning values of J/K from 4/0 to 14/12. The fit in the approximation of an isolated vibrational state, with the transitions perturbed by weak local resonances excluded, yields reproduction of the data within experimental uncertainties. PMID- 21268624 TI - Chemically modulating the photophysics of the GFP chromophore. AB - There is growing interest in engineering the properties of fluorescent proteins through modifications to the chromophore structure utilizing mutagenesis with either natural or unnatural amino acids. This entails an understanding of the photophysical and photochemical properties of the modified chromophore. In this work, a range of GFP chromophores with different alkyl substituents are synthesized and their electronic spectra, pH dependence, and ultrafast fluorescence decay kinetics are investigated. The weakly electron donating character of the alkyl substituents leads to dramatic red shifts in the electronic spectra of the anions, which are accompanied by increased fluorescence decay times. This high sensitivity of electronic structure to substitution is also characteristic of some fluorescent proteins. The solvent viscosity dependence of the decay kinetics are investigated, and found to be consistent with a bimodal radiationless relaxation coordinate. Some substituents are shown to distort the planar structure of the chromophore, which results in a blue shift in the electronic spectra and a strong enhancement of the radiationless decay. The significance of these data for the rational design of novel fluorescent proteins is discussed. PMID- 21268625 TI - Cluster-models for uranyl(VI) adsorption on alpha-alumina. AB - Aqueous complexation, adsorption, and redox chemistry of actinide species at mineral surfaces have a significant impact on their transport and reactive behavior in chemically and physically heterogeneous environments. The adsorption configurations and energies of microsolvated uranyl dication species, UO(2)(H(2)O)(n)(2+), were determined on fully hydroxylated and proton-deficient alpha-alumina(0001)-like finite cluster models. The significant size of the models provides faithful representations of features that have emerged from periodic calculations, but most importantly, they afford us a systematic study of the adsorption mechanism, the effect of secondary solvation shells and an explicit treatment of the total charge. Based on this cluster representation, the energetics computed from the difference between the optimized structures and the appropriate reference states point to a preference for an inner-sphere type complex. PMID- 21268626 TI - Photophysical study of bis(naphthalimide)-amine conjugates: toward molecular design of excimer emission switching. AB - The fluorescence properties of two bis(1,8-naphthalimides) with amino-containing spacers are investigated, giving special emphasis to the observation of excimer emission. It is found that a minor elongation of the spacer by two methylene units gives rise to a quantitative shut-down of the broad and red-shifted excimer emission. Furthermore, a switching of this emission is established through manipulation of a photoinduced electron transfer process, which involves the amino spacer. Protons as well as protic solvents lead to substantial excimer emission with lifetimes of 12 to 27 ns. The excimer quantum yield takes a maximum value of Phi(f) = 0.07 (acetonitrile with 1 equiv trifluoroacetic acid). The increased virtual Stokes shifts (ca. 150 nm) as compared to the fluorescence of monomeric 1,8-naphthalimides are an alternative approach to obtain colored, significant, and long-lived fluorescence from these chromophores. As an additional excited state pathway, the occurrence of homo-Forster resonance energy transfer (homo-FRET) is established by fluorescence polarization measurements and calculation of the corresponding critical Forster radius (R(0) ca. 13 A). The average interchromophore distance between the naphthalimides is estimated as 7.5 A and 9.5 A for the dyad with the shorter and the longer spacer, respectively. These observations and the absence of a rise time component for excimer emission are in agreement with the formation of a "loose" ground state dimer, which upon excitation undergoes a fast geometrical adjustment to the excimer structure where the chromophores are at contact distance. PMID- 21268627 TI - Formation of a hybrid compound composed of a saddle-distorted Tin(IV)-porphyrin and a Keggin-type heteropolyoxometalate to undergo intramolecular photoinduced electron transfer. AB - Nonplanar Sn(IV)-porphyrin complexes, [Sn(TMPP(Ph)(8))-Cl(2)] (1) and [Sn(TMPP(Ph)(8))(OMe)(2)] (2) (TMPP(Ph)(8): 5,10,15,20-tetrakis(4-methoxyphenyl) 2,3,7,8,12,13,17,18-octaphenylporphyrinato), were prepared and characterized by spectroscopic and electrochemical methods together with X-ray crystallography. Variable-temperature (1)H NMR study revealed that the coordination of the methoxo ligand of 2 is weak enough in solution to enhance the axial ligand exchange with a Keggin-type phosphotungstate (alpha-[PW(12)O(40)](3-)) due to the steric stress between the axial methoxo ligand and the peripheral phenyl groups of the porphyrin ligand. The formation of a novel 1:1 donor-acceptor complex, [Sn(TMPP(Ph)(8))(OMe)(alpha-[PW(12)O(40)])](2-) (4) was confirmed by (1)H NMR and UV-vis spectral titrations, and also by MALDI-TOF-MS measurements. Electrochemical measurements for the donor-acceptor complex in PhCN revealed that the Sn(IV)-TMPP(Ph)(8) moiety acts as an electron donor and the alpha [PW(12)O(40)](3-) moiety acts as an electron acceptor and that the energy level of the electron-transfer (ET) state of the 1:1 complex (1.17 eV) is lower than that of the triplet excited states of the SnTMPP(Ph)(8) complex (1.31 eV). Femtosecond and nanosecond laser flash photolysis measurements indicate that intersystem crossing from the singlet excited sate to the triplet excited state occurs followed by intramolecular photoinduced electron transfer from the triplet excited state of the Sn(IV)-TMPP(Ph)(8) moiety to the alpha-[PW(12)O(40)](3-) moiety in the 1:1 complex in benzonitrile. PMID- 21268628 TI - Spontaneous formation of bulk heterojunction nanostructures: multiple routes to equivalent morphologies. AB - Bulk heterojunction (BHJ) layers based on poly(3-hexylthiophene-2,5-diyl) (P3HT) and [6,6]-phenyl C61 butyric acid methyl ester (PCBM) were fabricated by two methods: codeposition of P3HT/PCBM from a common solvent (conventional BHJ) and by sequential, layer-by-layer deposition of P3HT/PCBM from separate solvents (layer-evolved BHJ). Thermally annealed layer-evolved BHJ solar cells show power conversion efficiencies and electron/hole mobilities comparable to conventional BHJ solar cells. The nanomorphology of both active layers is compared in situ by transmission electron microscopy (TEM) using a multilayer cross-sectional sample architecture. No significant difference is observed between the nanomorphology of the conventional BHJ and layer-evolved BHJ material implying that the bulk heterojunction forms spontaneously and that it is the lowest energy state of the two component system. PMID- 21268629 TI - Palaeosol control on groundwater flow and pollutant distribution: the example of arsenic. AB - The consumption of groundwater polluted by arsenic (As) has a severe and adverse effect on human health, particularly where, as happens in parts of SE Asia, groundwater is supplied largely from fluvial/deltaic aquifers. The lateral distribution of the As-pollution in such aquifers is heterogeneous. The cause of the heterogeneity is obscure. The location and severity of the As-pollution is therefore difficult to predict, despite the importance of such predictions to the protection of consumer health, aquifer remediation, and aquifer development. To explain the heterogeneity, we mapped As-pollution in groundwater using 659 wells across 102 km(2) of West Bengal, and logged 43 boreholes, to reveal that the distribution of As-pollution is governed by subsurface sedimentology. Across 47 km(2) of contiguous palaeo-interfluve, we found that the shallow aquifer (<70 mbgl) is unpolluted by As (<10 MUg/L) because it is capped by an impermeable palaeosol of red clay (the last glacial maximum palaeosol, or LGMP, of ref 1 ) at depths between 16 and 24 mbgl. The LGMP protects the aquifer from vertical recharge that might carry As-rich water or dissolved organic matter that might drive reduction of sedimentary iron oxides and so release As to groundwater. In 55 km(2) of flanking palaeo-channels, the palaeosol is absent, so invasion of the aquifer by As and dissolved organic matter can occur, so palaeo-channel groundwater is mostly polluted by As (>50 MUg/L). The role of palaeosols and, in particular, the LGMP, has been overlooked as a control on groundwater flow and pollutant movement in deltaic and coastal aquifers worldwide. Models of pollutant infiltration in such environments must include the appreciation that, where the LGMP (or other palaeosols) are present, recharge moves downward in palaeo-channel regions that are separated by palaeo-interfluvial regions where vertical recharge to underlying aquifers cannot occur and where horizontal flow occurs above the LGMP and any aquifer it caps. PMID- 21268630 TI - A thermodynamic approach for assessing the environmental exposure of chemicals absorbed to microplastic. AB - The environmental distribution and fate of microplastic in the marine environment represents a potential cause of concern. One aspect is the influence that microplastic may have on enhancing the transport and bioavailability of persistent, bioaccumulative, and toxic substances (PBT). In this study we assess these potential risks using a thermodynamic approach, aiming to prioritize the physicochemical properties of chemicals that are most likely absorbed by microplastic and therefore ingested by biota. Using a multimedia modeling approach, we define a chemical space aimed at improving our understanding of how chemicals partition in the marine environment with varying volume ratios of air/water/organic carbon/polyethylene, where polyethylene represents a main group of microplastic. Results suggest that chemicals with log KOW > 5 have the potential to partition >1% to polyethylene. Food-web model results suggest that reductions in body burden concentrations for nonpolar organic chemicals are likely to occur for chemicals with log KOW between 5.5 and 6.5. Thus the relative importance of microplastic as a vector of PBT substances to biological organisms is likely of limited importance, relative to other exposure pathways. Nevertheless, a number of data-gaps are identified, largely associated with improving our understanding of the physical fate of microplastic in the environment. PMID- 21268631 TI - A new prodrug-derived ratiometric fluorescent probe for hypoxia: high selectivity of nitroreductase and imaging in tumor cell. AB - Based on the hypoxia prodrug moiety of p-nitrobenzyl, a selective ratiometric fluorescent sensor (RHP) for the detection of microenvironment hypoxia was designed and synthesized. RHP can be selectively activated by bioreductive enzymes (NTR) and results in an evident blue to green fluorescent emission wavelength change in both solution phases and in cell lines, which might be the first fluorescent ratiometric probe for hypoxia in solid tumors. PMID- 21268632 TI - Nanoporous thermochromic VO(2) films with low optical constants, enhanced luminous transmittance and thermochromic properties. AB - Nanoporous thermochromic VO(2) films with low optical constants and tunable thicknesses have been prepared by polymer-assisted deposition. The film porosity and thickness change the interference relationship of light reflected from the film-substrate and the air-film interfaces, strongly influencing the optical properties of these VO(2) films. Our optimized single-layered VO(2) films exhibit high integrated luminous transmittance (T(lum,l) = 43.3%, T(lum,h) = 39.9%) and solar modulation (DeltaT(sol) = 14.1%, from T(sol,l) = 42.9% to T(sol,h) = 28.8%), which are comparable to those of five-layered TiO(2)/VO(2)/TiO(2)/VO(2)/TiO(2) films (T(lum,l) = 45%, T(lum,h) = 42% and DeltaT(sol) = 12%, from T(sol,l) = 52% to T(sol,h) = 40%, from Phys. Status Solidi A2009, 206, 2155-2160.). Optical calculations suggest that the performance could be further improved by increasing the porosity. PMID- 21268633 TI - Thermodynamic model for uranium release from hanford site tank residual waste. AB - A thermodynamic model of U solid-phase solubility and paragenesis was developed for Hanford Site tank residual waste that will remain in place after tank closure. The model was developed using a combination of waste composition data, waste leach test data, and thermodynamic modeling of the leach test data. The testing and analyses were conducted using actual Hanford Site tank residual waste. Positive identification of U phases by X-ray diffraction was generally not possible either because solids in the waste were amorphous or their concentrations were not detectable by XRD for both as-received and leached residual waste. Three leachant solutions were used in the studies: deionized water, CaCO3 saturated solution, and Ca(OH)2 saturated solution. Analysis of calculated saturation indices indicate that NaUO2PO4.xH2O and Na2U2O7(am) are present in the residual wastes initially. Leaching of the residual wastes with deionized water or CaCO3 saturated solution results in preferential dissolution Na2U2O7(am) and formation of schoepite. Leaching of the residual wastes with Ca(OH)2 saturated solution appears to result in transformation of both NaUO2PO4.xH2O and Na2U2O7(am) to CaUO4. Upon the basis of these results, the paragenetic sequence of secondary phases expected to occur as leaching of residual waste progresses for two tank closure scenarios was identified. PMID- 21268634 TI - Using rhodamine 6G-modified gold nanoparticles to detect organic mercury species in highly saline solutions. AB - We developed a gold nanoparticle (Au NP)-based fluorescence sensor for the detection of mercury ions in aqueous solutions. After introducing bovine serum albumin (BSA) to a solution of rhodamine 6G (R6G) and 3-mercaptopropionic acid (MPA)-modified Au NPs, the as-prepared BSA@R6G/MPA-Au NP probe could sense mercury ions under high salt conditions. This probe operated through a mechanism involving mercury species depositing onto the surfaces of the Au NPs and releasing R6G molecules into the solution, causing the fluorescence intensity of the BSA@R6G/MPA-AuNP solution to increase. We improved the selectivity of the nanosensor by adding masking agents (ethylenediamine tetraacetic acid (EDTA) and Na2S) or tellurium nanowires (Te NWs) to the sample solutions. In the presence of 1.0 mM EDTA and 10 MUM Na2S, the selectivities of this system toward phenylmercury (PhHg(I)) over other metal ions and mercury species were greater than 200- and 10-fold, respectively. The limit of detection (LOD), at a signal-to noise ratio of 3, for PhHg(I) was 20 nM. Selective detection of the total organic mercury (methylmercury (MeHg(I)), ethylmercury (EtHg(I)), and PhHg(I)) was possible when using the BSA@R6G/MPA-Au NPs in conjunction with Te NWs (3.0 nM). The selectivity of this nanosensor system for the total organic mercury over Hg(II) was remarkably high (100-fold) with an LOD for organic mercury of 10 nM. We also demonstrated the feasibility of using the developed nanosensor for rapid determination of mercury species in river, sea, and tap water as well as in fish samples. PMID- 21268635 TI - One-pot synthesis of luotonin A and its analogues. AB - Starting with inexpensive reagents, a self-directed chemical process with the aid of a single metal triflate was readily achieved to concomitantly construct quinazoline and pyrroloquinoline cores to afford the synthesis of luotonin A and its analogues. Among all compounds prepared, 2c, 2d, and 3b exhibit more potent inhibitory activity than luotonin A against human topoisomerase I. PMID- 21268636 TI - Bovine colostrum: determination of naturally occurring steroid hormones by Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS). AB - The aim of this study was to collect further data about levels of endogenous hormones in foodstuffs derived from animal production. Because of expected higher concentrations of especially estrogens in colostrum compared to other foodstuffs, our investigation focused on this matrix. For evaluation of endogenous steroid hormones in separated colostrum (fat and defatted fraction) and colostrum powder, the relevant free and conjugated estrogens (estradiol-17beta, estradiol-17alpha, estrone, and estriol) androgens (androstendione, 19nor-androstendione, 19nor testosterone-17beta, 19nor-testosterone-17alpha, testosterone-17beta, and testosterone-17alpha), and progesterone were determined by means of liquid chromatography-tandem mass spectrometry (LC-MS/MS). Upmost determined concentrations were found in the fat fraction, with 25.56 and 7.59 MUg/L for estrone and androstendione, respectively. In defatted milk and colostrum powder, conjugated estrogens dominated, whereas total (free and conjugated) estrone (5.51 MUg/L; 15.0 MUg/kg) exceeded estradiol-17alpha (2.66 MUg/L; 7.5 MUg/kg) and estradiol-17beta (2.28 MUg/L; 3.3 MUg/kg). Neither 19nor-steroids nor estriol were detected in colostrum fractions or processed colostrum. PMID- 21268637 TI - Phragmalin- and mexicanolide-type limonoids from the leaves of Trichilia connaroides. AB - Phytochemical investigation of the leaves of Trichilia connaroides afforded 12 new limonoids with phragmalin- (1-11) and mexicanolide-type skeletons (12). The structures of these limonoids, including the absolute configuration of 3, were determined by spectroscopic analysis. Compounds 6 and 8 showed moderate cytotoxicity against HL-60 cells. PMID- 21268638 TI - Toward the second generation synthesis of aplyronine A: stereocontrolled assembly of the C1-C19 segment by using an asymmetric Nozaki-Hiyama-Kishi coupling. AB - An efficient synthesis of the C1-C19 segment of aplyronine A is described. Stereoselective construction of the C14-C15 (E)-trisubstituted double bond and the C13 stereocenter was achieved by using an asymmetric Nozaki-Hiyama-Kishi coupling. PMID- 21268639 TI - Conductivity enhancement in carbon nanocone adhesive by electric field induced formation of aligned assemblies. AB - We show how an alternating electric field can be used to assemble carbon nanocones (CNCs) and align these assemblies into microscopic wires in a commercial two-component adhesive. The wires form continuous pathways that may electrically connect the alignment electrodes, which leads to directional conductivity (~10(-3) S/m) on a macroscopic scale. This procedure leads to conductivity enhancement of at least 2-3 orders of magnitude in the case where the CNC fraction (~0.2 vol %) is 1 order of magnitude below the percolation threshold (~2 vol %). The alignment and conductivity are maintained on curing that joins the alignment electrodes permanently together. If the aligned CNC wires are damaged before curing, they can be realigned by an extended alignment period. This concept has implications in areas such as electronic packaging technology. PMID- 21268640 TI - [3 + 2] cycloaddition on carbohydrate templates: stereoselective synthesis of pyrrolidines. AB - Pyrrolidine derivatives were prepared in high diastereoselectivities and good yields via a [3 + 2] cycloaddition of a tert-butyldimethylsilyl protected carbohydrate-based allene with a diverse range of imines. The subsequent removal of the carbohydrate auxiliary afforded a variety of pyrrolidines with excellent enantioselectivities (up to 99% ee). Selective reduction of the pyrrolidines further demonstrated the potential of this strategy. PMID- 21268641 TI - Remote toehold: a mechanism for flexible control of DNA hybridization kinetics. AB - Hybridization of DNA strands can be used to build molecular devices, and control of the kinetics of DNA hybridization is a crucial element in the design and construction of functional and autonomous devices. Toehold-mediated strand displacement has proved to be a powerful mechanism that allows programmable control of DNA hybridization. So far, attempts to control hybridization kinetics have mainly focused on the length and binding strength of toehold sequences. Here we show that insertion of a spacer between the toehold and displacement domains provides additional control: modulation of the nature and length of the spacer can be used to control strand-displacement rates over at least 3 orders of magnitude. We apply this mechanism to operate displacement reactions in potentially useful kinetic regimes: the kinetic proofreading and concentration robust regimes. PMID- 21268642 TI - A cast-mold approach to iron oxide and Pt/iron oxide nanocontainers and nanoparticles with a reactive concave surface. AB - We report the synthesis of various iron oxide nanocontainers and Pt-iron oxide nanoparticles based on a cast-mold approach, starting from nanoparticles having a metal core (either Au or AuPt) and an iron oxide shell. Upon annealing, the particles evolve to asymmetric core-shells and then to heterodimers. If iodine is used to leach Au out of these structures, asymmetric core-shells evolve into "nanocontainers", that is, iron oxide nanoparticles enclosing a cavity accessible through nanometer-sized pores, while heterodimers evolve into particles with a concave region. When starting from a metal domain made of AuPt, selective leaching of the Au atoms yields the same iron oxide nanoparticle morphologies but now encasing Pt domains (in their concave region or in their cavity). We found that the concave nanoparticles are capable of destabilizing Au nanocrystals of sizes matching that of the concave region. In addition, for the nanocontainers, we propose two different applications: (i) we demonstrate loading of the cavity region of the nanocontainers with the antitumoral drug cis-platin; and (ii) we show that nanocontainers encasing Pt domains can act as recoverable photocatalysts for the reduction of a model dye. PMID- 21268643 TI - Polymer vesicles with a colloidal armor of nanoparticles. AB - The fabrication of polymer vesicles with a colloidal armor made from a variety of nanoparticles is demonstrated. In addition, it is shown that the armored supracolloidal structure can be postmodified through film-formation of soft polymer latex particles on the surface of the polymersome, hereby effectively wrapping the polymersome in a plastic bag, as well as through formation of a hydrogel by disintegrating an assembled polymer latex made from poly(ethyl acrylate-co-methacrylic acid) upon increasing the pH. Furthermore, ordering and packing patterns are briefly addressed with the aid of Monte Carlo simulations, including patterns observed when polymersomes are exposed to a binary mixture of colloids of different size. PMID- 21268644 TI - Efficient light-driven carbon-free cobalt-based molecular catalyst for water oxidation. AB - The abundant-metal-based polyoxometalate complex [Co(4)(H(2)O)(2)(PW(9)O(34))(2)](10-) is a hydrolytically and oxidatively stable, homogeneous, and efficient molecular catalyst for the visible-light-driven catalytic oxidation of water. Using a sacrificial electron acceptor and photosensitizer, it exhibits a high (30%) photon-to-O(2) yield and a large turnover number (>220, limited solely by depletion of the sacrificial electron acceptor) at pH 8. The photocatalytic performance of this catalyst is superior to that of the previously reported precious-metal-based polyoxometalate water oxidation catalyst [{Ru(4)O(4)(OH)(2)(H(2)O)(4)}(gamma-SiW(10)O(36))(2)](10-). PMID- 21268645 TI - Reductive alkylation of indoles with alkynes and hydrosilanes under indium catalysis. AB - Under Indium catalysis, diverse alkylindoles were successfully prepared with a flexible combination of indoles and alkynes in the presence of hydrosilanes. In addition to the hydrosilane, carbon nucleophiles are also available. This new method generates alkylindoles in yields over 70% with a broad scope of functional group compatibility. PMID- 21268646 TI - CuBr-Catalyzed Coupling of N-Tosylhydrazones and Terminal Alkynes: Synthesis of Benzofurans and Indoles. AB - A new method for the synthesis of benzofurans or indoles via ligand-free CuBr catalyzed coupling/cyclization of terminal alkynes with N-tosylhydrazones derived from o-hydroxy- or o-aminobenzaldehydes has been developed. A wide range of functional groups were found that are able to tolerate the reaction conditions. PMID- 21268647 TI - Top-down process based on electrospinning, twisting, and heating for producing one-dimensional carbon nanotube assembly. AB - Multiwalled carbon nanotube (MWNT)/poly(vinyl butyral) (PVB) composite nanofibers were prepared by electrospinning, successive twisting and heat treatment. The MWNTs were highly oriented in an electrified thin jet during electrospinning. The heat treatment of the twisted electrospun nanofiber yarns produced the characteristics of the CNT in the composite nanofiber yarns and enhanced their electrical properties, mechanical properties, and thermal properties. The electrical conductivity of the heated yarn was significantly enhanced and showed the maximum value of 154 S cm(-1) for the yarn heated at 400 degrees C. It is an order of magnitude higher than other electrospun CNT composite materials. These results demonstrated that the novel top-down process based on electrospinning, twisting, and heat treatment provide a promising option for simple and large scale manufacture of CNT assemblies. PMID- 21268648 TI - Compositional mapping of the surface and interior of mammalian cells at submicrometer resolution. AB - We present progress toward imaging of chemical species within intact mammalian cells using secondary ion mass spectrometry, including the simultaneous mapping of subcellular elemental and molecular species along with intrinsic membrane specific cellular markers. Results from imaging both the cell surface and cell interior exposed by site-specific focused ion beam milling demonstrate that in plane resolutions of approximately 400-500 nm can be achieved. The results from mapping cell surface phosphatidylcholine and several other molecular ions present in the cells establish that spatially resolved chemical signatures of individual cells can be derived from novel multivariate analysis and classification of the molecular images obtained at different m/z ratios. The methods we present here for specimen preparation and chemical imaging of cell interiors provide the foundation for obtaining 3D molecular maps of unstained mammalian cells, with particular relevance for probing the subcellular distributions of small molecules, such as drugs and metabolites. PMID- 21268649 TI - A selective colorimetric Hg2+ probe featuring a styryl dithiaazacrown containing platinum (II) terpyridine complex through modulation of the relative strength of ICT and MLCT transitions. AB - A series of platinum(II) terpyridine complexes featuring an aminostilbene donor acceptor framework was synthesized. The complex with a dithiaazacrown moiety exhibits a highly sensitive and selective colorimetric response to a Hg(2+) cation through modulation of the relative strength of ICT and MLCT transitions. The results from (1)H NMR titration suggest the existence of a weak Pt(II)...Hg(II) metallophilic interaction at low Hg(2+) concentration. PMID- 21268650 TI - Vibronic enhancement of exciton sizes and energy transport in photosynthetic complexes. AB - Transport processes and spectroscopic phenomena in light harvesting proteins depend sensitively on the characteristics of electron-phonon couplings. Decoherence imposed by low-frequency nuclear motion generally suppresses the delocalization of electronic states, whereas the Franck-Condon progressions of high-frequency intramolecular modes underpin a hierarchy of vibronic Coulombic interactions between pigments. This Article investigates the impact of vibronic couplings on the electronic structures and relaxation mechanisms of two cyanobacterial light-harvesting proteins, allophycocyanin (APC) and C-phycocyanin (CPC). Both APC and CPC possess three pairs of pigments (i.e., dimers) that undergo electronic relaxation on the subpicosecond time scale. Electronic relaxation is ~10 times faster in APC than in CPC despite the nearly identical structures of their pigment dimers. We suggest that the distinct behaviors of these closely related proteins are understood on the same footing only in a basis of joint electronic-nuclear states (i.e., vibronic excitons). A vibronic exciton model predicts well-defined rate enhancements in APC at realistic values of the site reorganization energies, whereas a purely electronic exciton model points to faster dynamics in CPC. Calculated exciton sizes (i.e., participation ratios) show that wave function delocalization underlies the rate enhancement predicted by the vibronic exciton model. Strong vibronic coupling and heterogeneity in the pigment sites are the key ingredients of the vibronic delocalization mechanism. In contrast, commonly employed purely electronic exciton models see heterogeneity as only a localizing influence. This work raises the possibility that similar vibronic effects, which are often neglected, may generally have a significant influence on energy transport in molecular aggregates and photosynthetic complexes. PMID- 21268651 TI - Synthesis, structural, and photophysical investigation of diimine triscarbonyl Re(I) tetrazolato complexes. AB - The synthesis, structural, and photophysical properties of a novel family of neutral fac-[Re(N(?)N)(CO)(3)(L)] complexes, where N(?)N is either 2,2' bipyridine or 1,10-phenanthroline and L is a para functionalized 5 aryltetrazolate [namely, 5-phenyltetrazolate (Tph(-)), 4-(tetrazolate-5 yl)benzaldehyde (Tbdz(-)), 5-(4-acetylphenyl)tetrazolate (Tacy(-)), and methyl 4 (tetrazolate-5-yl)benzoate (Tmeb(-))] are reported. The complexes were prepared by direct addition of the corresponding tetrazolate anion to the acetonitrile solvated fac-[Re(N(?)N)(CO)(3)](+) precursor. NMR data demonstrate that the coordination of the metal fragment is regiospecific at the N2 atom of the tetrazolate ring. These conclusions are also supported by X-ray structural determinations. Photophysical data were obtained in diluted and deaerated dichloromethane solutions displaying broad and structureless profiles with emission maxima ranging from 566 to 578 nm. The absorption profiles indicate the presence of higher energy intraligand (IL) pi-pi* transitions and lower energies ligand-to-ligand charge transfer (LLCT) and metal-to-ligand charge transfer (MLCT). As the last two transitions are mixed, they are better described as a metal-ligand-to-ligand charge transfer (MLLCT), a result that is also supported by density functional theory (DFT) calculations. The complexes show excited state lifetime values ranging from 102 to 955 ns, with associated quantum yield between 0.012 and 0.099. Compared to the parent neutral chloro or bromo [Re(N(?)N)(CO)(3)X], the complexes show a slightly improved performance because of the pi accepting nature of the tetrazolato ligand. The metal-to-ligand backbonding is in fact depleting the Re center of electron density, thus widening the HOMO-LUMO gap and reducing the non-radiative decay mechanism in accordance with the energy gap law. Finally, the electron-withdrawing or donating nature of the substituent on the phenyltetrazolato ligand allows the fine-tuning of the photophysical properties. PMID- 21268652 TI - Aggregation of [Au(CN)4]- anions: examination by crystallography and 15N CP-MAS NMR and the structural factors influencing intermolecular Au...N interactions. AB - To investigate the factors influencing the formation of intermolecular Au...NC interactions between [Au(CN)(4)](-) units, a series of [cation](n+)[Au(CN)(4)](n) double salts was synthesized, structurally characterized and probed by IR and (15)N{(1)H} CP-MAS NMR spectroscopy. Thus, [(n)Bu(4)N][Au(CN)(4)], [AsPh(4)][Au(CN)(4)], [N(PPh(3))(2)][Au(CN)(4)], [Co(1,10 phenanthroline)(3)][Au(CN)(4)](2), and [Mn(2,2';6',2'' terpyridine)(2)][Au(CN)(4)](2) show [Au(CN)(4)](-) anions that are well-separated from one another; no Au-Au or Au...NC interactions are present. trans-[Co(1,2 diaminoethane)(2)Cl(2)][Au(CN)(4)] forms a supramolecular structure, where trans [Co(en)(2)Cl(2)](+) and [Au(CN)(4)](-) ions are found in separate layers connected by Au-CN...H-N hydrogen-bonding; weak Au...NC coordinate bonds complete octahedral Au(III) centers, and support a 2-D (4,4) network motif of [Au(CN)(4)]( )-units. A similar structure-type is formed by [Co(NH(3))(6)][Au(CN)(4)](3).(H(2)O)(4). In [Ni(1,2 diaminoethane)(3)][Au(CN)(4)](2), intermolecular Au...NC interactions facilitate formation of 1-D chains of [Au(CN)(4)](-) anions in the supramolecular structure, which are separated from one another by [Ni(en)(3)](2+) cations. In [1,4 diazabicyclo[2.2.2]octane-H][Au(CN)(4)], the monoprotonated amine cation forms a hydrogen-bond to the [Au(CN)(4)](-) unit on one side, while coordinating to the axial sites of the gold(III) center through the unprotonated amine on the other, thereby generating a 2-D (4,4) net of cations and anions; an additional, uncoordinated [Au(CN)(4)](-)-unit lies in the central space of each grid. This body of structural data indicates that cations with hydrogen-bonding groups can induce intermolecular Au...NC interactions, while the cationic charge, shape, size, and aromaticity have little effect. While the nu(CN) values are poor indicators of the presence or absence of N-cyano bridging between [Au(CN)(4)](-) units (partly because of the very low intensity of the observed bands), (15)N{(1)H} CP-MAS NMR reveals well-defined, ordered cyanide groups in the six diamagnetic compounds with chemical shifts between 250 and 275 ppm; the resonances between 260 and 275 ppm can be assigned to C-bound terminal ligands, while those subject to CN...H-N bonding resonate lower, around 250-257 ppm. The (15)N chemical shift also correlates with the intermolecular Au...N distances: the shortest Au-N distances also shift the (15)N peak to lower frequency. This provides a real, spectroscopically measurable electronic effect associated with the crystallographic observation of intermolecular Au...NC interactions, thereby lending support for their viability. PMID- 21268654 TI - Combining NMR of dynamic and paramagnetic molecules: fluxional high-spin nickel(II) complexes bearing bisguanidine ligands. AB - A detailed nuclear magnetic resonance (NMR) study was carried out on a series of paramagnetic, tetrahedrally coordinated nickel(II) dihalide complexes featuring chelating guanidine ligands. A complete assignment of the NMR signals for all complexes was achieved by sophisticated NMR experiments, including correlation spectra. The effects of halide exchange, as well as the variation in the guanidine-metal bite angles on the paramagnetic shifts, were assessed. The paramagnetic shift was derived with the aid of the diamagnetic NMR spectra of the analogous Zn complexes, which were synthesized for this purpose. The experimentally derived paramagnetic shift was then compared with the values obtained from quantum chemical (DFT) calculations. Furthermore, variable temperature NMR studies were recorded for all complexes. It is demonstrated that NMR spectroscopy can be applied to evaluate the rate constants of fast fluxional processes within paramagnetic and catalytically active metal complexes. PMID- 21268653 TI - Binding and "pKa" modulation of a polycyclic substrate analogue in a type II polyketide acyl carrier protein. AB - Type II polyketide synthases are biosynthetic enzymatic pathways responsible for the production of complex aromatic natural products with important biological activities. In these systems, biosynthetic intermediates are covalently bound to a small acyl carrier protein that associates with the synthase enzymes and delivers the bound intermediate to each active site. In the closely related fatty acid synthases of bacteria and plants, the acyl carrier protein acts to sequester and protect attached intermediates within its helices. Here we investigate the type II polyketide synthase acyl carrier protein from the actinorhodin biosynthetic pathway and demonstrate its ability to internalize the tricyclic, polar molecule emodic acid. Elucidating the interaction of acyl carrier proteins with bound analogues resembling late-stage intermediates in the actinorhodin pathway could prove valuable in efforts to engineer these systems toward rational design and biosynthesis of novel compounds. PMID- 21268655 TI - Tetrahedral-shaped anions as a template in the synthesis of high-nuclearity silver(I) dithiophosphate clusters. AB - Novel Ag(32) clusters, [Ag(16)(EO(4)){S(2)P(OEt)(2)}(12)](2) (PF(6))(4) (E = S, 1; Se, 2) and [Ag(16)(MO(4)){S(2)P(OEt)(2)}(12)](2)(PF(6))(4) (M = Cr, 3; Mo, 4), were prepared in situ from the addition of a tetrahedral-shaped anion as a template to the pentanuclear extended chain [Ag(5){S(2)P(OEt)(2)}(4)](n)(PF(6))(n). PMID- 21268656 TI - Conformational effects induced by guest encapsulation in an enantiopure water soluble cryptophane. AB - A new water-soluble cryptophane 1 derivative (penta-hydroxyl cryptophane-A) has been synthesized from cryptophanol-A and the chiroptical properties of its two enantiomers MM-1 and PP-1 have been studied by polarimetry, electronic circular dichroism (ECD), and vibrational circular dichroism (VCD). Cryptophane 1 shows specific circular dichroism responses upon complexation that depend on the size of the guest and on the nature of the counterion (Li(+), Na(+), K(+), Cs(+)) present in the solution. In LiOH and NaOH solutions, chiroptical changes induced by the encapsulation of guests and by the presence of cations in the vicinity of hosts can be interpreted from molecular dynamics (MD) and ab initio calculations by subtle conformational changes of the bridges. In KOH solution, the exchange dynamics is dependent on the size of the guest molecules, whereas in CsOH solution no encapsulation effect is observed whatever the size of the guest molecule. This last behavior comes from the fact that host 1 exhibits a very high affinity for cesium cations. PMID- 21268657 TI - Complexation, computational, magnetic, and structural studies of the Maillard reaction product isomaltol including investigation of an uncommon pi interaction with copper(II). AB - The metal complexation properties of the naturally occurring Maillard reaction product isomaltol HL(2) are investigated by measurement of its stability constants with copper(II), zinc(II), and iron(III) using potentiometric pH titrations in water, by structural and magnetic characterization of its crystalline complex, [Cu(L(2))(2)].8H(2)O, and by density functional theory calculations. Strong complexation is observed to form the bis(isomaltolato)copper(II) complex incorporating copper in a typical (pseudo )square-planar geometry. In the solid state, extensive intra- and intermolecular hydrogen bonding involving all three oxygen functions per ligand assembles the complexes into ribbons that interact to form two-dimensional arrays; further hydrogen bonds and pi interactions between the furan moiety of the anionic ligands and adjacent copper(II) centers connect the complexes in the third dimension, leading to a compact polymeric three-dimensional (3D) arrangement. The latter interactions involving copper(II), which represent an underappreciated aspect of copper(II) chemistry, are compared to similar interactions present in other copper(II) 3D structures showing interactions with benzene molecules; the results indicate that dispersion forces dominate in the pi system to chelated copper(II) ion interactions. PMID- 21268658 TI - Decoupling of the catalytic and transport activities of complex I from Rhodothermus marinus by sodium/proton antiporter inhibitor. AB - The energy transduction by complex I from Rhodothermusmarinus was addressed by studying the influence of 5-(N-ethyl-N-isopropyl)-amiloride (EIPA) on the activities of this enzyme. EIPA is an inhibitor of both Na(+)/H(+) antiporter and complex I NADH:quinone oxidoreductase activity. We performed studies of NADH:quinone oxidoreductase and H(+) and Na(+) translocation activities of complex I from R. marinus at different concentrations of EIPA, using inside-out membrane vesicles. We observed that the oxidoreductase activity and both H(+) and Na(+) transports are inhibited by EIPA. Most interestingly, the catalytic and the two transport activities showed different inhibition profiles. The transports are inhibited at concentrations of EIPA at which the catalytic activity is not affected. In this way the catalytic and transport activities were decoupled. Moreover, the inhibition of the catalytic activity was not influenced by the presence of Na(+), whereas the transport of H(+) showed different inhibition behaviors in the presence and absence of Na(+). Taken together our observations indicate that complex I from R. marinus performs energy transduction by two different processes: proton pumping and Na(+)/H(+) antiporting. The decoupling of the catalytic and transport activities suggests the involvement of an indirect coupling mechanism, possibly through conformational changes. PMID- 21268659 TI - Histidines in the octapeptide repeat of PrPC react with PrPSc at an acidic pH. AB - Cellular PrP is actively cycled between the cell surface and the endosomal pathway. The exact site and mechanism of conversion from PrP(C) to PrP(Sc) remain unknown. We have previously used recombinant antibodies containing grafts of PrP sequence to identify three regions of PrP(C) (aa23-27, 98-110, and 136-158) that react with PrP(Sc) at neutral pH. To determine if any regions of PrP(C) react with PrP(Sc) at an acidic pH similar to that of an endosomal compartment, we tested our panel of grafted antibodies for the ability to precipitate PrP(Sc) in a range of pH conditions. At pH near or lower than 6, PrP-grafted antibodies representing the octapeptide repeat react strongly with PrP(Sc) but not PrP(C). Modified grafts in which the histidines of the octarepeat were replaced with alanines did not react with PrP(Sc). PrP(Sc) precipitated by the octapeptide at pH 5.7 was able to seed conversion of normal PrP to PrP(Sc) in vitro. However, modified PrP containing histidine to alanine substitutions within the octapeptide repeats was still converted to PrP(Sc) in N2a cells. These results suggest that once PrP has entered the endosomal pathway, the acidic environment facilitates the binding of PrP(Sc) to the octarepeat of PrP(C) by the change in charge of the histidines within the octarepeat. PMID- 21268660 TI - One-pot multicomponent synthesis of diversely substituted 2-aminopyrroles. A short general synthesis of rigidins A, B, C, and D. AB - Privileged medicinal scaffolds based on the structures of tetra- and pentasubstituted 2-aminopyrroles were prepared via one-pot multicomponent reactions of structurally diverse aldehydes and N-(aryl-, hetaryl-, alkylsulfonamido)acetophenones with activated methylene compounds. This methodology was used in a four-step synthesis of alkaloids rigidins A, B, C, and D in overall yields of 61%, 58%, 60%, and 53%, respectively. Of these, rigidins B, C, and D were synthesized for the first time. PMID- 21268661 TI - Continuous flow ozonolysis in a laboratory scale reactor. AB - Several important types of ozonolysis reactions have been performed in a continuous flow device that is able to perform both the ozonolysis and quenching steps in flow mode. This technique allows safe and scalable ozonolysis reactions to be performed on a laboratory scale. PMID- 21268662 TI - Copper-free Sonogashira coupling of cyclopropyl iodides with terminal alkynes. AB - The substrate scope of the copper-free Sonogashira coupling has been successfully extended to cyclopropyl iodides, allowing an efficient access to a wide variety of functionalized alkynyl cyclopropanes. PMID- 21268663 TI - Excipient-mediated supersaturation stabilization in human intestinal fluids. AB - It was the purpose of this study to investigate excipient-mediated precipitation inhibition upon induction of supersaturation of poorly water-soluble drugs in aspirated human intestinal fluids (HIF) representing both the fasted and fed state. Etravirine, ritonavir, loviride, danazol and fenofibrate were selected as model compounds. For comparative purposes, precipitation inhibition was also evaluated in simple aqueous buffer, and in intestinal simulation media representative for the fasted and fed state (FaSSIF and FeSSIF, respectively). Supersaturation was induced in the test media containing predissolved excipient (HPMC-AS, HPMC-E5, HPMC-E50, HPMC-E4M, HPMC-P and PVP) at a defined degree of supersaturation (DS = 20) using the solvent shift method. The results illustrate that cellulosic polymers can reduce the precipitation rate and stabilize supersaturation in HIF. The extent of stabilization was compound and excipient dependent but independent of the nutritional state. Whenever excipient effects were observed, the predictive value of simple buffer or FaSSIF/FeSSIF was rather limited. In general, excipient-mediated precipitation inhibition was less pronounced in HIF compared to simple aqueous buffer or FaSSIF/FeSSIF. However, excipients showing no effect in simple aqueous buffer or FaSSIF/FeSSIF also proved to be ineffective in HIF, indicating the value of these simulation media in the elimination of excipients during formulation development. PMID- 21268664 TI - High performance dye-sensitized solar cells with alkylpyridinium iodide salts in electrolytes. AB - Pyridinium iodide salts, which are competitive to the conventional imidazolium iodide salts, have been used for dye-sensitized solar cells as iodide sources and ionic conductivities. Pyridinium iodide series are easy to prepare and less expensive than the imidazolium series salts. In this research, quite comparable efficiencies were obtained from electrolytes with pyridinium iodide salts. For the experiments, pyridinium salts with a few different alkyl chains are applied. When a pyridinium head is modified to picolinium, which has a methyl group on the pyridinium head, a noticeable V(oc) drop has been observed. However, the length of the alkyl chains on the pyridinium head does not affect V(oc) effectively. The odd-numbered alkyl chains showed slightly lower V(oc) compared to that of the even-numbered alkyl chains. Finally, the performances of the cells with pyridinium salts are compared to those of the conventional cells with imidazolium salts. PMID- 21268665 TI - Triplet excited states of cyclic disulfides and related compounds: electronic structures, geometries, energies, and decay. AB - We have performed a computational study on the properties of a series of heterocycles bearing two adjacent heteroatoms, focusing on the structures and electronic properties of their first excited triplet states. If the heteroatoms are both heavy chalcogens (S, Se, or Te) or isoelectronic species, then the lowest excited triplet state usually has (pi*, sigma*) character. The triplet energies are fairly low (30-50 kcal mol(-1)). The (pi*, sigma*) triplet states are characterized by a significantly lengthened bond between the two heteroatoms. Thus, in 1,2-dithiolane (1b), the S-S bond length is calculated to be 2.088 A in the singlet ground state and 2.568 A in the first triplet excited state. The spin density is predicted to be localized almost exclusively on the sulfur atoms. Replacing one heavy chalcogen atom by an oxygen atom or an NR group results in a significant destabilization of the (pi*, sigma*) triplet excited state, which then no longer is lower in energy than an open-chain biradical. The size of the heterocyclic ring also contributes to the stability of the (pi*, sigma*) triplet state, with five-membered rings being more favorable than six-membered rings. Benzoannulation, finally, usually lowers the energy of the (pi*, sigma*) triplet excited states. If one of the heteroatoms is an oxygen or nitrogen atom, however, the corresponding lowest triplet states are better described as sigma,pi biradicals. PMID- 21268666 TI - Network dynamics mediating ipsilateral motor cortex activity during unimanual actions. AB - Executing difficult actions with the left hand results in bilateral activity of motor areas along the precentral gyrus. Using TMS and fMRI, we explored the functional relationship between primary (M1) and premotor areas during unimanual actions, focusing on M1 activity in the ipsilateral hemisphere. Single-pulse TMS revealed that the amplitude of motor-evoked potentials (MEPs), elicited in the stationary right-hand muscles following left M1 stimulation, fluctuated with the state of homologous muscles in the moving left hand. This ipsilateral excitability was pronounced when the left-hand movements were more complex. We used fMRI to visualize the cortical dynamics during unimanual actions. Trial-by trial fluctuations in ipsilateral M1 activity were correlated with contralateral M1 responses and this correlation increased with movement complexity. Consistent with previous studies, the left caudal precentral premotor area (pcPM) was engaged during movements of either hand. Following low-frequency rTMS over left pcPM, the correlation between the activity level in the two M1s increased. This finding indicates that left pcPM may regulate the unintentional mirroring of motor commands in M1 during unilateral movement. PMID- 21268667 TI - Neural processing of what and who information in speech. AB - Human speech is composed of two types of information, related to content (lexical information, i.e., "what" is being said [e.g., words]) and to the speaker (indexical information, i.e., "who" is talking [e.g., voices]). The extent to which lexical versus indexical information is represented separately or integrally in the brain is unresolved. In the current experiment, we use short term fMRI adaptation to address this issue. Participants performed a loudness judgment task during which single or multiple sets of words/pseudowords were repeated with single (repeat) or multiple talkers (speaker-change) conditions while BOLD responses were collected. As reflected by adaptation fMRI, the left posterior middle temporal gyrus, a crucial component of the ventral auditory stream performing sound-to-meaning computations ("what" pathway), showed sensitivity to lexical as well as indexical information. Previous studies have suggested that speaker information is abstracted during this stage of auditory word processing. Here, we demonstrate that indexical information is strongly coupled with word information. These findings are consistent with a plethora of behavioral results that have demonstrated that changes to speaker-related information can influence lexical processing. PMID- 21268668 TI - The late positive potential predicts subsequent interference with target processing. AB - The current study investigated the association between neural engagement with task-irrelevant images and subsequent interference with target processing using the Emotional Interrupt paradigm [Mitchell, D., Richell, R., Leonard, A., & Blair, R. Emotion at the expense of cognition: Psychopathic individuals outperform controls on an operant response task. Journal of Abnormal Psychology, 115, 559, 2006]. Consistent with previous studies, PCA-derived factors corresponding to the early posterior negativity, P300, and late positive potential (LPP) were enhanced for emotional (i.e., both unpleasant and pleasant) compared with neutral distracters, and the P300 elicited by targets was smaller following emotional compared with neutral pictures. In addition, RTs were increased to targets that followed emotional pictures. Within-subject analyses demonstrated that slow trials were characterized by a smaller P300 and were preceded by pictures with a larger LPP. Additionally, between-subject analyses indicate that individuals with a larger LPP also demonstrated slower RTs to targets and reduced target-elicited P300s. All results were specific to the LPP and were not observed for either the early posterior negativity or the P300 elicited by task-irrelevant pictures. By relating the LPP to subsequent behavioral and ERP interference in both within- and between-subject analyses, the current study provides direct support for the notion that LPP indexes attentional engagement with visual stimuli that is uniquely associated with subsequent interference in terms of both RT slowing and P300 reduction to targets. PMID- 21268669 TI - The continuity illusion does not depend on attentional state: FMRI evidence from illusory vowels. AB - We investigate whether the neural correlates of the continuity illusion, as measured using fMRI, are modulated by attention. As we have shown previously, when two formants of a synthetic vowel are presented in an alternating pattern, the vowel can be identified if the gaps in each formant are filled with bursts of plausible masking noise, causing the illusory percept of a continuous vowel ("Illusion" condition). When the formant-to-noise ratio is increased so that noise no longer plausibly masks the formants, the formants are heard as interrupted ("Illusion Break" condition) and vowels are not identifiable. A region of the left middle temporal gyrus (MTG) is sensitive both to intact synthetic vowels (two formants present simultaneously) and to Illusion stimuli, compared to Illusion Break stimuli. Here, we compared these conditions in the presence and absence of attention. We examined fMRI signal for different sound types under three attentional conditions: full attention to the vowels; attention to a visual distracter; or attention to an auditory distracter. Crucially, although a robust main effect of attentional state was observed in many regions, the effect of attention did not differ systematically for the illusory vowels compared to either intact vowels or to the Illusion Break stimuli in the left STG/MTG vowel-sensitive region. This result suggests that illusory continuity of vowels is an obligatory perceptual process, and operates independently of attentional state. An additional finding was that the sensitivity of primary auditory cortex to the number of sound onsets in the stimulus was modulated by attention. PMID- 21268670 TI - Brain dynamics sustaining rapid rule extraction from speech. AB - Language acquisition is a complex process that requires the synergic involvement of different cognitive functions, which include extracting and storing the words of the language and their embedded rules for progressive acquisition of grammatical information. As has been shown in other fields that study learning processes, synchronization mechanisms between neuronal assemblies might have a key role during language learning. In particular, studying these dynamics may help uncover whether different oscillatory patterns sustain more item-based learning of words and rule-based learning from speech input. Therefore, we tracked the modulation of oscillatory neural activity during the initial exposure to an artificial language, which contained embedded rules. We analyzed both spectral power variations, as a measure of local neuronal ensemble synchronization, as well as phase coherence patterns, as an index of the long range coordination of these local groups of neurons. Synchronized activity in the gamma band (20-40 Hz), previously reported to be related to the engagement of selective attention, showed a clear dissociation of local power and phase coherence between distant regions. In this frequency range, local synchrony characterized the subjects who were focused on word identification and was accompanied by increased coherence in the theta band (4-8 Hz). Only those subjects who were able to learn the embedded rules showed increased gamma band phase coherence between frontal, temporal, and parietal regions. PMID- 21268671 TI - Puddles, parties, and professors: linking word categorization to neural patterns of visuospatial coding. AB - Behavioral evidence suggests that during word processing people spontaneously map object, valence, and power information to locations in vertical space. Specifically, whereas "overhead" (e.g., attic), positive (e.g., party), and powerful nouns (e.g., professor) are associated with "up," "underfoot" (e.g., carpet), negative (e.g., accident), and powerless nouns (e.g., assistant) are associated with "down." What has yet to be elucidated, however, is the precise nature of these effects. To explore this issue, an fMRI experiment was undertaken, during which participants were required to categorize the position in which geometrical shapes appeared on a computer screen (i.e., upper or lower part of the display). In addition, they also judged a series of words with regard to location (i.e., up vs. down), valence (i.e., good vs. bad), and power (i.e., powerful vs. powerless). Using multivoxel pattern analysis, it was found that classifiers that successfully distinguished between the positions of shapes in subregions of the inferior parietal lobe also provided discriminatory information to separate location and valence, but not power word judgments. Correlational analyses further revealed that, for location words, pattern transfer was more successful the stronger was participants' propensity to use visual imagery. These findings indicate that visual coding and conceptual processing can elicit common representations of verticality but that divergent mechanisms may support the reported effects. PMID- 21268672 TI - Differential impairment of remembering the past and imagining novel events after thalamic lesions. AB - Vividly remembering the past and imagining the future (mental time travel) seem to rely on common neural substrates and mental time travel impairments in patients with brain lesions seem to encompass both temporal domains. However, because future thinking-or more generally imagining novel events-involves the recombination of stored elements into a new event, it requires additional resources that are not shared by episodic memory. We aimed to demonstrate this asymmetry in an event generation task administered to two patients with lesions in the medial dorsal thalamus. Because of the dense connection with pFC, this nucleus of the thalamus is implicated in executive aspects of memory (strategic retrieval), which are presumably more important for future thinking than for episodic memory. Compared with groups of healthy matched control participants, both patients could only produce novel events with extensive help of the experimenter (prompting) in the absence of episodic memory problems. Impairments were most pronounced for imagining personal fictitious and impersonal events. More precisely, the patients' descriptions of novel events lacked content and spatio-temporal relations. The observed impairment is unlikely to trace back to disturbances in self-projection, scene construction, or time concept and could be explained by a recombination deficit. Thus, although memory and the imagination of novel events are tightly linked, they also partly rely on different processes. PMID- 21268673 TI - Error awareness revisited: accumulation of multimodal evidence from central and autonomic nervous systems. AB - The differences between erroneous actions that are consciously perceived as errors and those that go unnoticed have recently become an issue in the field of performance monitoring. In EEG studies, error awareness has been suggested to influence the error positivity (Pe) of the response-locked event-related brain potential, a positive voltage deflection prominent approximately 300 msec after error commission, whereas the preceding error-related negativity (ERN) seemed to be unaffected by error awareness. Erroneous actions, in general, have been shown to promote several changes in ongoing autonomic nervous system (ANS) activity, yet such investigations have only rarely taken into account the question of subjective error awareness. In the first part of this study, heart rate, pupillometry, and EEG were recorded during an antisaccade task to measure autonomic arousal and activity of the CNS separately for perceived and unperceived errors. Contrary to our expectations, we observed differences in both Pe and ERN with respect to subjective error awareness. This was replicated in a second experiment, using a modified version of the same task. In line with our predictions, only perceived errors provoke the previously established post-error heart rate deceleration. Also, pupil size yields a more prominent dilatory effect after an erroneous saccade, which is also significantly larger for perceived than unperceived errors. On the basis of the ERP and ANS results as well as brain behavior correlations, we suggest a novel interpretation of the implementation and emergence of error awareness in the brain. In our framework, several systems generate input signals (e.g., ERN, sensory input, proprioception) that influence the emergence of error awareness, which is then accumulated and presumably reflected in later potentials, such as the Pe. PMID- 21268676 TI - Retinal nerve fiber thickness measurements in choroideremia patients with spectral-domain optical coherence tomography. AB - PURPOSE: To evaluate the presence of peripapillary retinal nerve fiber layer (RNFL) defects in patients with choroideremia by using spectral-domain optical coherence tomography (SD-OCT). METHODS: Twenty-nine eyes of 16 patients with choroideremia underwent peripapillary RNFL thickness measurements by using SD OCT. RESULTS: The mean (+/-SD) age of the study population was 44.0 +/- 16.0 years (range, 13-63 years). Thirteen eyes (45%) showed a thinning of the peripapillary RNFL in at least 1 quadrant in either 1 or both eyes. Thinning was most commonly found in the superior (13 eyes) and inferior (10 eyes) quadrants. Twenty-one eyes (72%) showed a thickening of the peripapillary RNFL in at least 1 quadrant in either 1 or both eyes. Of these 21 eyes, all had thickening in the temporal quadrant. Additionally, 2 eyes in each of the other 3 quadrants were found to be abnormally thick. CONCLUSION: Our study demonstrated the presence of defects in the peripapillary RNFL thickness in patients with choroideremia by using SD-OCT. It would be clinically prudent that choroideremia patients considered for various treatment options be considered for RNFL thickness measurements. PMID- 21268677 TI - Why some photoreceptors die, while others remain dormant: lessons from RPE65 and LRAT associated retinal dystrophies. AB - PURPOSE: Why some photoreceptors die and other do not is not well understood, but is a fascinating and important emerging concept, now that gene and drug therapy have shown preliminary positive results in treatments for patients with gene specific retinal degenerations. RESULTS: This review discusses these concepts and a new study that shows that continuous activation of the phototransduction cascade activates Bcl-2 apoptotic pathways. Knockout out of Bax revealed rescue from apoptosis, indicating that bax inhibition may be an avenue for pharmocological intervention. PMID- 21268678 TI - Ubiquitin carboxyl-terminal esterase L1 (UCHL1) S18Y polymorphism in patients with cataracts. AB - BACKGROUND: Cataract is characterized by light-scattering protein aggregates. The ubiquitin-proteasome system has been proposed a role in proteolytic removal of these protein aggregates. Ubiquitin carboxyl-terminal esterase L1 (UCHL1) is a de-ubiquitinating enzyme with important functions in recycling of ubiquitin. A protective role of the p.S18Y polymorphism of the UCHL1 gene has been shown in Parkinson's disease. The current study aimed to examine possible effects on cataract formation. METHODS: Patients with cataract (n = 493) and controls (n = 142) were analyzed for the UCHL1 p.S18Y polymorphism using dynamic allele specific hybridization. RESULTS: Significant differences were observed in allele and genotype frequencies of the p.S18Y polymorphism between controls and cataract patients, where a positive UCHL1 allele A carrier status was associated with the cataract diagnosis (adjusted OR 1.7 [95% CI = 1.1-2.6] p = 0.02). No significant differences were seen in genotype distribution when stratifying for type of cataract. Nor did the mean age at cataract surgery differ between genotypes. CONCLUSION: The current study does not support a protective role for the UCHL1 S18Y polymorphism in cataract development, but may instead suggest a disease promoting effect. PMID- 21268679 TI - Oligocone trichromacy is part of the spectrum of CNGA3-related cone system disorders. AB - PURPOSE: To report the rare observation of CNGA3 mutation as a cause of oligocone trichromacy (OT) and present phenotypic characteristics. METHODS: A 20 year old male patient underwent ophthalmological evaluation including detailed color vision assessment using Ishihara pseudoisochromatic plates, American Optical Hardy Rand Rittler plates (HRR) and Mollon-Reffin Minimalist test (MRM). Optical coherence tomography (OCT), fundus autofluorescence (FAF), visual field assessment and electrophysiological testing was also performed. The patient's DNA was sequenced for mutations in the coding sequence of CNGA3 and CNGB3 genes. RESULTS: Best corrected visual acuity (BCVA) was 20/50 and 20/30 in the right and left eyes respectively. His color vision was normal to Ishihara, HRR and MRM tests. Fundus appearance, FAF, OCT and Goldmann visual fields (GVF) were all normal. Humphrey visual field analysis (HVF) demonstrated reduced sensitivity and paracentral scotomas (5-20 degrees ). The full-field electroretinogram (ERG) showed normal rod responses and severely reduced cone responses. The multifocal electroretinogram (mfERG) was non-recordable above noise. Compound heterozygous mutations in exon 8 of the CNGA3 coding sequence were identified; c.1070 A > G (Tyr357Cys; novel) and c.1694 C > T (Thr565Met). Allele-specific polymerase chain reaction confirmed that the mutations were located on separate alleles. No mutations were identified in CNGB3. CONCLUSION: This is the second reported case of CNGA3 associated OT. Mutations in CNGA3 have previously been associated with incomplete and complete achromatopsia. This report confirms that OT forms the mildest end of the spectrum of CNGA3 related diseases. PMID- 21268680 TI - Occurrence of class 1 and 2 integrons in resistant Enterobacteriaceae collected from a urban wastewater treatment plant: first report from central Italy. AB - The purpose of this study was to investigate the presence and distribution of integron-carrying isolates among Enterobacteriaceae resistant to beta-lactam antibiotics collected from a wastewater effluent of the city of L'Aquila (Italy). A total of 471 Enterobacteriaceae were collected during a period of 2 years (2005 2006). The presence and distribution of class 1 and 2 integrons was investigated by colony blot hybridization using specific probes labelled with dUTP fluoresceine kit. The variable region of class 1 and 2 integrons was analyzed by polymerase chain reaction and DNA sequencing in 24 isolates with different random amplified polymorphic DNA profile. The characterization of class 1 and 2 integrons gene cassettes of 24 nonrelated strains showed the presence of four different arrays: dfr17-aadA5; aadA10; dfr1-sat1; dfr1-sat1-aadA1. This is the first report from Italy in which the authors confirm the presence of Enterobacteriaceae carrying class 1 and 2 integrons in a wastewater treatment plant that collects the urban and hospital discharges. PMID- 21268681 TI - Meta-analysis of deinstitutionalisation adaptive behaviour outcomes: Research and clinical implications. AB - Background A meta-analysis examined the effects of deinstitutionalisation on adaptive behaviour outcomes in persons with intellectual disability. The need for an updated review in this area is reflected by recent policy shifts in community care practices and the international status of deinstitutionalisation efforts. Method Twenty-three studies were compared using standardised mean effect sizes across 5 demographic, 4 methodological, and 1 outcome variable. Results Moderate habilitative gains were found in 75% of adaptive behaviour domains. A weighted linear multiple regression revealed that larger effect sizes were significantly predicted by sample size and research design. Disability level also moderated the extent to which sample size affected the magnitude of effect sizes. Conclusions These results are discussed in relation to the implications they have for community services for persons with intellectual disability. The difficulties in accurately comparing studies with dissimilar procedures and contexts are also outlined. PMID- 21268690 TI - Is selective digestive decontamination useful in controlling aerobic gram negative bacilli producing extended spectrum beta-lactamases? AB - AIMS: To identify outbreak episodes of either carriage or infection due to extended spectrum beta-lactamases producing aerobic Gram-negative bacilli (AGNB ESBL); to establish whether AGNB-ESBL, sensitive to tobramycin, become resistant over time; and to evaluate the impact of selective decontamination of the digestive tract (SDD) on abnormal carriage of AGNB-ESBL. DESIGN AND SETTING: All children admitted to the pediatric intensive care unit (PICU) over a 12-month period had biweekly surveillance cultures of throat and rectum and diagnostic cultures when clinically indicated. All AGNB were tested for ESBL, and the positive isolates were sent for molecular typing. The PICU uses SDD (parenteral cefotaxime and enteral polymyxin E/tobramycin) to control abnormal carriage. Patients who had at least one AGNB-ESBL were included in the study. RESULTS: During the study period, 1,101 children were admitted to the PICU. There were 39 patients (3.5%) with a total of 236 cultures positive for AGNB-ESBL. Twenty-eight patients (2.5%) were carriers, and 11 (1%) had proven infections. Organisms isolated from the first culture were 14 patients with Klebsiella pneumoniae, 8 with Enterobacter cloacae, 7 with Citrobacter freundii, 5 with Klebsiella oxytoca, and 5 with Escherichia coli. In the first sample, 59% of isolates showed tobramycin resistance. Molecular typing confirmed that there were five different strains of K. pneumoniae and that similar strains were not isolated in the same period. CONCLUSIONS: SDD is an effective measure to control AGNB-ESBL and to avoid outbreak episodes of either carriage or infection. When tobramycin resistance is found, replacing it with another aminoglycoside based on antibiogram may be more effective in achieving AGNB clearance. PMID- 21268696 TI - Insecticidal activity of some reducing sugars against the sweet potato whitefly, Bemisia tabaci, Biotype B. AB - The effects of 16 sugars (arabinose, cellobiose, fructose, galactose, gentiobiose, glucose, inositol, lactose, maltose, mannitol (a sugar alcohol), mannose, melibiose, ribose, sorbitol, trehalose, and xylose) on sweet potato whitefly Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae) survival were determined using in vitro bioassays. Of these sugars, arabinose, mannose, ribose, and xylose were strongly inhibitory to both nymphal and adult survival. When 10% mannose was added to the nymphal diet, 10.5%, 1.0%, and 0% developed to the 2nd, 3rd, and 4th instars, respectively. When 10% arabinose was added, 10.8% and 0% of the nymphs molted to the 2nd and 3rd instars, respectively. Addition of 10% xylose or ribose completely terminated B. tabaci development, preventing the molt to the 2(nd) instar. With decreasing sugar concentrations the inhibitory effect was significantly reduced. In tests using adults, arabinose, galactose, inositol, lactose, maltose, mannitol, mannose, melibiose, ribose, sorbitol, trehalose, and xylose significantly reduced mean day survival. Mortality rates were highest when arabinose, mannitol, mannose, ribose, or xylose was added to the diet. Mean day survival was less than 2 days when adults were fed on diet containing 10% of any one of these five sugars. When lower concentrations of sugars were used there was a decrease in mortality. Mode of action studies revealed that toxicity was not due to the inhibition of alpha glucosidase (converts sucrose to glucose and fructose) and/or trehalulose synthase (converts sucrose to trehalulose) activity. The result of agarose gel electrophoresis of RT-PCR products of bacterial endosymbionts amplified from RNA isolated from whiteflies fed with 10% arabinose, mannose, or xylose indicated that the concentration of endosymbionts in mycetomes was not affected by the toxic sugars. Experiments in which B. tabaci were fed on diets that contained radio-labeled sucrose, methionine or inulin and one or none (control) of the highly toxic sugars showed that radioactivity (expressed in DPM) in the body, in excreted honeydew and/or carbon dioxide, was significantly reduced as compared to controls. Thus, it appears that the ability of insecticidal sugars to act as antifeedants is responsible for their toxicity to B. tabaci. PMID- 21268697 TI - An artificial light source influences mating and oviposition of black soldier flies, Hermetia illucens. AB - Current methods for mass-rearing black soldier flies, Hermetia illucens (L.) (Diptera: Stratiomyidae), in the laboratory are dependent on sunlight. Quartz iodine lamps and rare earth lamps were examined as artificial light sources for stimulating H. illucens to mate and lay eggs. Sunlight was used as the control. Adults in the quartz-iodine lamp treatment had a mating rate of 61% of those in the sunlight control. No mating occurred when the rare earth lamp was used as a substitute. Egg hatch for the quartz-iodine lamp and sunlight treatments occurred in approximately 4 days, and the hatch rate was similar between these two treatments. Larval and pupal development under these treatments required approximately 18 and 15 days at 28 degrees C, respectively. Development of methods for mass rearing of H. illucens using artificial light will enable production of this fly throughout the year without investing in greenhouse space or requiring sunlight. PMID- 21268698 TI - Stage-dependent tolerance of the German cockroach, Blattella germanica for dichlorvos and propoxur. AB - tage-dependent dichlorvos and propoxur tolerance in a field population of the German cockroach, Blattella germanica Linnaeus (Blatodea: Blattellidae), was investigated in the laboratory using a topical application bioassay. The results showed the 6 week-old nymphs were more tolerant to dichlorvos and propoxur than the other ages tested. LD50 values of dichlorvos and propoxur for the 6 week-old nymphs were 2.003 ug per insect and 5.296 ug per insect, respectively. Tolerance ratios of 18.55-fold and 4.98-fold for LD50 were obtained from 6-week-old nymphs compared to 4 week-old nymphs. The specific activity of acetylcholinesterase (AChE) from 1 week-old nymphs was the highest among all tested developmental stages of nymphs and adult males and females. The specific activity of AChE decreased significantly with increasing age. The sensitivity of AChE to dichlorvos was the highest with a k(i) value of 3.12 * 104 mol-1min-1 in the last nymphal stage of B. germanica (about 6 weeks-old). The AChE from 4 week-old nymphs was the most sensitive to propoxur, with the highest k(i) value being 2.63 * 105 mol-1 min-1. These results indicated that the different developmental stages and sexes of B. germanica affected the inhibition of AChE by dichlorvos and propoxur. PMID- 21268699 TI - Response of the gypsy moth, Lymantria dispar to transgenic poplar, Populus simonii x P. nigra, expressing fusion protein gene of the spider insecticidal peptide and Bt-toxin C-peptide. AB - The response of the Asian gypsy moth Lymantria dispar (L.) (Lepidoptera: Lymantriidae) to a fusion gene consisting of the spider, Atrax robustus Simon (Araneae: Hexanthelidae) omega-ACTX-Ar1 sequence coding for an omega-atracotoxin and a sequence coding for the Bt-toxin C-peptide, expressed in transgenic poplar Populus simonii x P. nigra L. (Malphigiales: Salicaceae) was investigated. Individual performance, feeding selection, midgut proteinase activity and nutrition utilization were monitored. The growth and development of L. dispar were significantly affected by continually feeding on the transgenic poplar, with the larval instars displaying significantly shorter developmental times than those fed on nontransgenic poplar, but pupation was delayed. Mortality was higher in populations fed transgenic poplar leaves, than for larvae fed nontransgenic poplar leaves. The cumulative mortality during all stages of larvae fed transgenic leaves was 92% compared to 16.7% of larvae on nontransgenic leaves. The highest mortality observed was 71.7% in the last larval instar stage. A two choice test showed that fifth-instar larvae preferred to feed on nontransgenic leaves at a ratio of 1:1.4. Feeding on transgenic leaves had highly significant negative effects on relative growth of larvae, and the efficiency of conversion of ingested and digested food. Activity of major midgut proteinases was measured using substrates TAME and BTEE showed significant increases in tryptase and chymotrypsinlike activity (9.2- and 9.0-fold, respectively) in fifth-instar larvae fed on transgenic leaves over control. These results suggest transgenic poplar is resistant to L. dispar, and the mature L. dispar may be weakened by the transgenic plants due to Bt protoxins activated by elevated major midgut proteinase activity. The new transgenic poplar expressing fusion protein genes of Bt and a new spider insecticidal peptide are good candidates for managing gypsy moth. PMID- 21268700 TI - Description of immature stages and life cycle of the treehopper, Guayaquila projecta. AB - Immature stages of the membracid Guayaquila projecta (Funkhouser) (Hemiptera: Cicadomorpha: Membracidae), collected in San Salvador de Jujuy, Argentina on Bougainvillea glabra Choisy (Caryophyllales: Nyctaginaceae), are described in detail based on specimens reared in the laboratory. Like other membracids, this species has five nymphal instars, not seven as previously reported. Morphological characters for identifying the different instars of G. projecta, determining the sex of later instars and distinguishing this species from other members of the Guayaquila pugnax group, are discussed. At 19 +/- 4 degrees C, RH 59 +/- 9%, and a 12:12 L:D photoperiod, the time required for development from egg to adult emergence was 73 +/- 5 days. PMID- 21268701 TI - The presence of flour affects the efficacy of aerosolized insecticides used to treat the red flour beetle, Tribolium castaneum. AB - Experiments were conducted in tightly sealed pilot scale warehouses to assess the efficacy of common aerosolized insecticides on all life stages of Tribolium castaneum (Herbst) (Coleoptera: Tenebrionidae) when exposed in dishes containing 0 to 2 g of wheat flour either under pallets or out in the open. Petri dishes containing 0, 0.1, 1, or 2 g of flour were prepared with 25 eggs, 3rd instars, pupae, or adults and then immediately treated with aerosolized solvent, Pyrethrins, or esfenvalerate. Twenty-four h after insecticide exposure, the dishes were brought to the laboratory and placed in a growth chamber and held for a 3 day moribund (knockdown) assessment and a 21 day mortality assessment. Mortality in untreated controls was generally less than 10%, with the exception of the 21 day counts of adults and eggs. Solvent-treated replications followed similar trends, except that additional mortality was observed in exposed larvae and pupae. In the insecticide-treated dishes, mortality of T. castaneum provisioned with flour generally showed a linear decrease with increasing flour deposits. Regardless of life stage, mortality did not exceed 60% when individuals were exposed in petri dishes containing 2 g of flour. Exposure location also made a significant difference in observed mortality. While mortality never exceeded 75% in dishes positioned under pallets, there was never less than 80% mortality in dishes exposed in the open. Although there was a perceptible increase in mortality with esfenvalerate compared to Pyrethrins, these differences were considerably less than the variation observed among flour deposits. The study suggests that sanitation and preparation prior to aerosol insecticide treatments were more important than choice of a particular insecticide. PMID- 21268702 TI - Pest status and distribution of the stem borer, Dectes texanus, in Kansas. AB - The Dectes stem borer, Dectes texanus LeConte (Coleoptera: Cerambycidae), is currently receiving increased attention as a pest of soybeans in the Great Plains of North America. Field surveys were conducted in 1999 and in 2008 to record the distribution of this pest in Kansas. These surveys documented an increase in the abundance of the pest and an expansion in the range of this insect westward and eastward. The percentage of fields with more than 50% of plants infested also increased from 4% in 1999 to 11% in 2008. The far eastern counties still had surprisingly few infested fields even though much of the Kansas soybean acreage is located in these counties. It is not clear if D. texanus simply haven't expanded into eastern Kansas yet or if there is an ecological barrier that keeps them from doing so. Field crop entomologists from across eastern North America were sent an email questionnaire and their responses indicate that this pest is now well established as a pest of soybeans in at least 14 states across eastern North America. PMID- 21268703 TI - Evaluation of a microbial inhibitor in artificial diets of a generalist caterpillar, Heliothis virescens. AB - Controlling microbial growth in artificial diets is a key component in the rearing of laboratory insects. In this study an antimicrobial agent, Diet Antimicrobial Agent (DAA), was tested for its ability to suppress microbial growth on a range of different diets, and for its effect on larval and pupal performance of individuals from two different strains of Heliothis virescens Fabricus (Lepidoptera: Noctuidae). In the first experiment, it was found that the presence of DAA in a pinto bean-based diet was highly effective at suppressing microbial growth relative to other methods, and that survival of caterpillars on diets with DAA was superior to other treatments. Caterpillars also performed best on diets with DAA, although this may have been the result of laboratory selection pressure as these caterpillars had been reared on pinto bean-based diets with DAA for several hundred generations. A second experiment was conducted, using different diets and a different strain of H. virescens to more fully evaluate DAA. Here it was found that DAA significantly suppressed microbial growth and development, particularly in synthetic diets. There was no significant effect of DAA on pupal development time or mass gain. There was a statistically significant effect of DAA on eclosion time for two of the diets, although the effect did not seem to be biologically meaningful. The findings suggest that DAA is an effective suppressor of microbial growth on artificial diets, and that its net effect on developing diet-reared insects is neutral. PMID- 21268704 TI - Serial monodomy in the gypsy ant, Aphaenogaster araneoides: does nest odor reduction influence colony relocation? AB - Serial monodomy is the nesting behavior in which a colony of animals maintains multiple nests for its exclusive use, occupying one nest at a time. Among serially monodomous ants, the availability of unoccupied nests reduces the probability and costs of army ant attacks. It has been proposed that nest odors mediate serial monodomy in the gypsy ant, Aphaenogaster araneoides Emery (Hymenoptera: Formicidae), and that colonies avoid returning to previously occupied nests that harbor colony odors. To evaluate this hypothesis, the odors inside the nests of A. araneoides colonies were experimentally reduced through ventilation; the nest movement behaviors of treatment and control colonies were compared. Odor reduction was found to have increased the frequency of movements into and out of the treated nest, without a change in the total occupation duration in the treated nest. Nests with a more open architecture that permitted natural flow of air were reoccupied more quickly than nests with smaller nest entrances. In summary, the openness of the architecture of A. araneoides nests and the ventilation of air through nests alters the use of these nests. These findings further support the working hypothesis that nest-bound odors mediate the pattern of serial monodomy in A. araneoides. PMID- 21268705 TI - The common swift louse fly, Crataerina pallida: an ideal species for studying host-parasite interactions. AB - Little is known of the life-history of many parasitic species. This hinders a full understanding of host-parasitic interactions. The common swift louse fly, Crataerina pallida Latreille (Diptera: Hippoboscidae), an obligate haematophagous parasite of the Common Swift, Apus apus Linnaeus 1758, is one such species. No detrimental effect of its parasitism upon the host has been found. This may be because too little is known about C. pallida ecology, and therefore detrimental effects are also unknown. This is a review of what is known about the life history of this parasite, with the aim of promoting understanding of its ecology. New, previously unreported observations about C. pallida made from personal observations at a nesting swift colony are described. Unanswered questions are highlighted, which may aid understanding of this host-parasite system. C. pallida may prove a suitable model species for the study of other host-parasite relationships. PMID- 21268706 TI - 50 years later: remembering the paper. PMID- 21268707 TI - A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. 1961. PMID- 21268708 TI - Sensitivity to low-dose/low-LET ionizing radiation in mammalian cells harboring mutations in succinate dehydrogenase subunit C is governed by mitochondria derived reactive oxygen species. AB - It has been hypothesized that ionizing radiation-induced disruptions in mitochondrial O2 metabolism lead to persistent heritable increases in steady state levels of intracellular superoxide (O2(*U+2212)) and hydrogen peroxide (H2O2) that contribute to the biological effects of radiation. Hamster fibroblasts (B9 cells) expressing a mutation in the gene coding for the mitochondrial electron transport chain protein succinate dehydrogenase subunit C (SDHC) demonstrate increases in steady-state levels of O2*- and H2O2. When B9 cells were exposed to low-dose/low-LET radiation (5-50 cGy), they displayed significantly increased clonogenic cell killing compared with parental cells. Clones derived from B9 cells overexpressing a wild-type human SDHC (T4, T8) demonstrated significantly increased surviving fractions after exposure to 5-50 cGy relative to B9 vector controls. In addition, pretreatment with polyethylene glycol-conjugated CuZn superoxide dismutase and catalase as well as adenoviral mediated overexpression of MnSOD and/or mitochondria-targeted catalase resulted in significantly increased survival of B9 cells exposed to 10 cGy ionizing radiation relative to vector controls. Adenoviral-mediated overexpression of either MnSOD or mitochondria-targeted catalase alone was equally as effective as when both were combined. These results show that mammalian cells over expressing mutations in SDHC demonstrate low-dose/low-LET radiation sensitization that is mediated by increased levels of O2*- and H2O2. These results also support the hypothesis that mitochondrial O2*- and H2O2 originating from SDH are capable of playing a role in low-dose ionizing radiation-induced biological responses. PMID- 21268709 TI - The role of mitochondria in the radiation-induced bystander effect in human lymphoblastoid cells. AB - Cells without intact mitochondrial DNA have been shown to lack the bystander effect, which is an energy-dependent process. We hypothesized that cells harboring mutations in mitochondrial genes responsible for ATP synthesis would show a decreased bystander effect compared to normal cells. Radiation-induced bystander effects were analyzed in two normal and four mitochondrial mutant human lymphoblastoid cells. Medium from previously irradiated cells (conditioned medium) was transferred to unirradiated cells from the respective cell lines and evaluated for the bystander effect using the cytokinesis-block micronucleus assay. Unlike normal cells that were used as a control, mitochondrial mutant cells neither generated nor responded to the bystander signals. The bystander effect was inhibited in normal cells by adding the mitochondrial inhibitors rotenone and oligomycin to the culture medium. Time-controlled blocking of the bystander effect by inhibitors was found to occur either for prolonged exposure to the inhibitor prior to irradiation with an immediate and subsequent removal of the inhibitors or immediate post-application of the inhibitor. Adding the inhibitors just prior to irradiation and removing them immediately after irradiation was uneventful. Fully functional mitochondrial metabolic capability may therefore be essential for the bystander effect. PMID- 21268710 TI - Identification of radiation-induced expression changes in nonimmortalized human T cells. AB - In the event of a radiation accident or attack, it will be imperative to quickly assess the amount of radiation exposure to accurately triage victims for appropriate care. RNA-based radiation dosimetry assays offer the potential to rapidly screen thousands of individuals in an efficient and cost-effective manner. However, prior to the development of these assays, it will be critical to identify those genes that will be most useful to delineate different radiation doses. Using global expression profiling, we examined expression changes in nonimmortalized T cells across a wide range of doses (0.15-12 Gy). Because many radiation responses are highly dependent on time, expression changes were examined at three different times (3, 8, and 24 h). Analyses identified 61, 512 and 1310 genes with significant linear dose-dependent expression changes at 3, 8 and 24 h, respectively. Using a stepwise regression procedure, a model was developed to estimate in vitro radiation exposures using the expression of three genes (CDKN1A, PSRC1 and TNFSF4) and validated in an independent test set with 86% accuracy. These findings suggest that RNA-based expression assays for a small subset of genes can be employed to develop clinical biodosimetry assays to be used in assessments of radiation exposure and toxicity. PMID- 21268711 TI - Low-dose/dose-rate gamma radiation depresses neural differentiation and alters protein expression profiles in neuroblastoma SH-SY5Y cells and C17.2 neural stem cells. AB - The effects of low doses of ionizing radiation on cellular development in the nervous system are presently unclear. The focus of the present study was to examine low-dose gamma-radiation-induced effects on the differentiation of neuronal cells and on the development of neural stem cells to glial cells. Human neuroblastoma SH-SY5Y cells were exposed to (137)Cs gamma rays at different stages of retinoic acid-induced neuronal differentiation, and neurite formation was determined 6 days after exposure. When SH-SY5Y cells were exposed to low-dose rate gamma rays at the onset of differentiation, the number of neurites formed per cell was significantly less after exposure to either 10, 30 or 100 mGy compared to control cells. Exposure to 10 and 30 mGy attenuated differentiation of immature C17.2 mouse-derived neural stem cells to glial cells, as verified by the diminished expression of glial fibrillary acidic protein. Proteomic analysis of the neuroblastoma cells by 2D-PAGE after 30 mGy irradiation showed that proteins involved in neuronal development were downregulated. Proteins involved in cell cycle and proliferation were altered in both cell lines after exposure to 30 mGy; however, the rate of cell proliferation was not affected in the low-dose range. The radiation-induced attenuation of differentiation and the persistent changes in protein expression is indicative of an epigenetic rather than a cytotoxic mechanism. PMID- 21268712 TI - P2Y6 receptors and ADAM17 mediate low-dose gamma-ray-induced focus formation (activation) of EGF receptor. AB - The EGF receptor (EGFR) is frequently expressed in tumors of epithelial origin. Although it is well known that ionizing radiation induces activation of EGFR, the mechanism remains unknown. Recently, we reported that activation of P2Y receptors is involved in gamma-radiation-induced activation of extracellular signal regulated kinase1/2 (ERK1/2), which is dependent on activation of EGFR. Here we focused on the mechanism of activation of EGFR in response to low-dose gamma radiation, mainly in terms of the activation-associated formation of EGFR foci in A549 cells. Irradiation of cells with 0.1 Gy gamma rays induced biphasic phosphorylation of EGFR and ERK1/2 as well as biphasic formation of EGFR foci. The radiation-induced focus formation of EGFR was abolished by ecto-nucleotidase, P2Y receptor antagonists and knockdown of P2Y6 receptor, suggesting the involvement of extracellular nucleotides and activation of P2Y6 receptors in this process. Further, a disintegrin and metalloprotease 17 (ADAM17) is expressed in A549 cells and an ADAM17 inhibitor significantly blocked the radiation-induced focus formation of EGFR. We conclude that activation of both P2Y6 receptors and ADAM17 mediates the low-dose gamma-radiation-induced activation of EGFR, as evaluated in terms of focus formation, in A549 cells. PMID- 21268713 TI - Induction of incomplete and complex chromosome aberrations by 30 kVp X rays. AB - X rays of 26-30 kVp are routinely used for mammography screening. For radioprotection purposes, a quality factor (Q) of 1 is assumed for all photon energies, but it is thought that the relative biological effectiveness (RBE) increases as the photon energy decreases. The analysis of radiation-induced chromosome aberrations is one of the most widely used methods to study the interaction between radiation and DNA. Here we present a FISH study on metaphases from peripheral blood samples irradiated with three different X-ray energies (30, 80 and 120 kVp). The study comprises two FISH approaches: one using pantelomeric and pancentromeric probes to evaluate the induction of incomplete chromosome aberrations and the other using mFISH to evaluate the induction of complex chromosome aberrations. The results indicate that exposure to 30 kVp X rays resulted in a modest increase in the induction of incomplete elements and complex aberrations compared to 80 and 120 kVp X rays. PMID- 21268714 TI - The dose response of chromosome aberrations in human lymphocytes induced in vitro by very low-dose gamma rays. AB - This paper considers the dose-effect relationship for unstable chromosome aberration yields in human lymphocytes in very low-dose range. Data are presented for (60)Co gamma-ray doses of 0, 10, 20, 40 and 1000 mGy. More than 5,000 metaphases were scored for each data point at the very low doses, and each cell was double-checked using a semi-automated metaphase finding/relocation system. Aberration yields of dicentrics plus centric rings followed an excellent linear dose response down to zero dose; the yields were significantly above the control frequency from 20 mGy. PMID- 21268715 TI - The mTOR inhibitor rapamycin suppresses DNA double-strand break repair. AB - mTOR (mammalian target of rapamycin) signaling plays a key role in the development of many tumor types. Therefore, mTOR is an attractive target for cancer therapeutics. Although mTOR inhibitors are thought to have radiosensitization activity, the molecular bases remain largely unknown. Here we show that treating MCF7 breast cancer cells with rapamycin (an mTOR inhibitor) results in significant suppression of homologous recombination (HR) and nonhomologous end joining (NHEJ), two major mechanisms required for repairing ionizing radiation-induced DNA DSBs. We observed that rapamycin impaired recruitment of BRCA1 and Rad51 to DNA repair foci, both essential for HR. Moreover, consistent with the suppressive role of rapamycin on both HR and NHEJ, persistent radiation-induced DSBs were detected in cells pretreated with rapamycin. Furthermore, the frequency of chromosome and chromatid breaks was increased in cells treated with rapamycin before and after irradiation. Thus our results show that radiosensitization by mTOR inhibitors occurs via disruption of the major two DNA DSB repair pathways. PMID- 21268716 TI - Effect of exposure to the edge signal on oxidative stress in brain cell models. AB - In this study we investigated the effect of the Enhanced Data rate for GSM Evolution (EDGE) signal on cells of three human brain cell lines, SH-SY5Y, U87 and CHME5, used as models of neurons, astrocytes and microglia, respectively, as well as on primary cortical neuron cultures. SXC-1800 waveguides (IT'IS Foundation, Zurich, Switzerland) were modified for in vitro exposure to the EDGE signal radiofrequency (RF) radiation at 1800 MHz. Four exposure conditions were tested: 2 and 10 W/kg for 1 and 24 h. The production of reactive oxygen species (ROS) was measured by flow cytometry using the dichlorofluorescein diacetate (DCFH-DA) probe at the end of the 24-h exposure or 24 h after the 1-h exposure. Rotenone treatment was used as a positive control. All cells tested responded to rotenone treatment by increasing ROS production. These findings indicate that exposure to the EDGE signal does not induce oxidative stress under these test conditions, including 10 W/kg. Our results are in agreement with earlier findings that RF radiation alone does not increase ROS production. PMID- 21268717 TI - Effects of 1 GeV/nucleon 56Fe particles on longevity, carcinogenesis and neuromotor ability in Atm-deficient mice. AB - As therapeutic uses of high-LET radiation become more prevalent and human space exploration continues to be a focus of NASA, it is important to understand the biological effects of high-LET radiation and the role of genetics in sensitivity to high-LET radiation. To study genetic susceptibility to radiation, we used mice deficient in Atm activity (AtmDeltaSRI). ATM is important in DNA repair, apoptosis and cell cycle regulation. Although homozygous mutations in ATM are rare, the prevalence of ATM heterozygosity is estimated to be 1% and results in an increased cancer risk. We found that the effects of 1 Gy 1 GeV/nucleon 56Fe particles on life span and tumorigenesis are genotype- and sex-specific. Significant effects of 1 Gy 1 GeV/nucleon 56Fe particles on incidence of non cancer end points were seen; however, 2 Gy 1 GeV/nucleon 56Fe particles significantly affected neuromotor ability. Our results represent an extensive investigation into the late effects of high-LET radiation exposure in a sex- and genotype-dependent manner and provide a baseline for understanding the long-term risks of high-LET radiation. PMID- 21268718 TI - DNA damage induced by low-energy electrons: conversion of thymine to 5,6 dihydrothymine in the oligonucleotide trimer TpTpT. AB - Low-energy electrons (LEE) induce single- and double-strand breaks in DNA. To investigate the mechanism of LEE-induced DNA damage, nucleotides and short oligonucleotide were irradiated with monoenergetic electrons in the solid state and the modifications were observed by chemical analyses. With 10 eV electrons and TpTpT as the target, approximately one-third of the total damage of TpTpT involves cleavage of the phosphodiester-sugar bond (C-O) and the N-glycosidic bond (C-N). Here we focus on the remaining two-thirds of the damage. The major products were observed to elute between TpT and TpTpT on the HPLC chromatogram. Of these products, three modifications were identified as XpTpT, TpXpT and TpTpX, where X = 5,6-dihydrothymine, on the basis of comparison with standard compounds using HPLC and mass spectrometry. These results suggest that 5,6 dihydrothymine is a major product of the reaction of LEE with DNA. PMID- 21268719 TI - Energy loss of hydrogen- and helium-ion beams in DNA: calculations based on a realistic energy-loss function of the target. AB - We have calculated the electronic energy loss of proton and alpha-particle beams in dry DNA using the dielectric formalism. The electronic response of DNA is described by the MELF-GOS model, in which the outer electron excitations of the target are accounted for by a linear combination of Mermin-type energy-loss functions that accurately matches the available experimental data for DNA obtained from optical measurements, whereas the inner-shell electron excitations are modeled by the generalized oscillator strengths of the constituent atoms. Using this procedure we have calculated the stopping power and the energy-loss straggling of DNA for hydrogen- and helium-ion beams at incident energies ranging from 10 keV/nucleon to 10 MeV/nucleon. The mean excitation energy of dry DNA is found to be I = 81.5 eV. Our present results are compared with available calculations for liquid water showing noticeable differences between these important biological materials. We have also evaluated the electron excitation probability of DNA as a function of the transferred energy by the swift projectile as well as the average energy of the target electronic excitations as a function of the projectile energy. Our results show that projectiles with energy ?100 keV/nucleon (i.e., around the stopping-power maximum) are more suitable for producing low-energy secondary electrons in DNA, which could be very effective for the biological damage of malignant cells. PMID- 21268720 TI - The states' next challenge--securing primary care for expanded Medicaid populations. PMID- 21268721 TI - Images in clinical medicine: Decreased skin turgor. PMID- 21268722 TI - Prevention of dialysis catheter malfunction with recombinant tissue plasminogen activator. AB - BACKGROUND: The effectiveness of various solutions instilled into the central venous catheter lumens after each hemodialysis session (catheter locking solutions) to decrease the risk of catheter malfunction and bacteremia in patients undergoing hemodialysis is unknown. METHODS: We randomly assigned 225 patients undergoing long-term hemodialysis in whom a central venous catheter had been newly inserted to a catheter-locking regimen of heparin (5000 U per milliliter) three times per week or recombinant tissue plasminogen activator (rt PA) (1 mg in each lumen) substituted for heparin at the midweek session (with heparin used in the other two sessions). The primary outcome was catheter malfunction, and the secondary outcome was catheter-related bacteremia. The treatment period was 6 months; treatment assignments were concealed from the patients, investigators, and trial personnel. RESULTS: A catheter malfunction occurred in 40 of the 115 patients assigned to heparin only (34.8%) and 22 of the 110 patients assigned to rt-PA (20.0%)--an increase in the risk of catheter malfunction by a factor of almost 2 among patients treated with heparin only as compared with those treated with rt-PA once weekly (hazard ratio, 1.91; 95% confidence interval [CI], 1.13 to 3.22; P = 0.02). Catheter-related bacteremia occurred in 15 patients (13.0%) assigned to heparin only, as compared with 5 (4.5%) assigned to rt-PA (corresponding to 1.37 and 0.40 episodes per 1000 patient-days in the heparin and rt-PA groups, respectively; P = 0.02). The risk of bacteremia from any cause was higher in the heparin group than in the rt-PA group by a factor of 3 (hazard ratio, 3.30; 95% CI, 1.18 to 9.22; P = 0.02). The risk of adverse events, including bleeding, was similar in the two groups. CONCLUSIONS: The use of rt-PA instead of heparin once weekly, as compared with the use of heparin three times a week, as a locking solution for central venous catheters significantly reduced the incidence of catheter malfunction and bacteremia. (Current Controlled Trials number, ISRCTN35253449.). PMID- 21268723 TI - Ventricular tachyarrhythmias after cardiac arrest in public versus at home. AB - BACKGROUND: The incidence of ventricular fibrillation or pulseless ventricular tachycardia as the first recorded rhythm after out-of-hospital cardiac arrest has unexpectedly declined. The success of bystander-deployed automated external defibrillators (AEDs) in public settings suggests that this may be the more common initial rhythm when out-of-hospital cardiac arrest occurs in public. We conducted a study to determine whether the location of the arrest, the type of arrhythmia, and the probability of survival are associated. METHODS: Between 2005 and 2007, we conducted a prospective cohort study of out-of-hospital cardiac arrest in adults in 10 North American communities. We assessed the frequencies of ventricular fibrillation or pulseless ventricular tachycardia and of survival to hospital discharge for arrests at home as compared with arrests in public. RESULTS: Of 12,930 evaluated out-of-hospital cardiac arrests, 2042 occurred in public and 9564 at home. For cardiac arrests at home, the incidence of ventricular fibrillation or pulseless ventricular tachycardia was 25% when the arrest was witnessed by emergency-medical-services (EMS) personnel, 35% when it was witnessed by a bystander, and 36% when a bystander applied an AED. For cardiac arrests in public, the corresponding rates were 38%, 60%, and 79%. The adjusted odds ratio for initial ventricular fibrillation or pulseless ventricular tachycardia in public versus at home was 2.28 (95% confidence interval [CI], 1.96 to 2.66; P < 0.001) for bystander-witnessed arrests and 4.48 (95% CI, 2.23 to 8.97; P<0.001) for arrests in which bystanders applied AEDs. The rate of survival to hospital discharge was 34% for arrests in public settings with AEDs applied by bystanders versus 12% for arrests at home (adjusted odds ratio, 2.49; 95% CI, 1.03 to 5.99; P = 0.04). CONCLUSIONS: Regardless of whether out-of-hospital cardiac arrests are witnessed by EMS personnel or bystanders and whether AEDs are applied by bystanders, the proportion of arrests with initial ventricular fibrillation or pulseless ventricular tachycardia is much greater in public settings than at home. The incremental value of resuscitation strategies, such as the ready availability of an AED, may be related to the place where the arrest occurs. PMID- 21268725 TI - Induced first-trimester abortion and risk of mental disorder. AB - BACKGROUND: Concern has been expressed about potential harm to women's mental health in association with having an induced abortion, but it remains unclear whether induced abortion is associated with an increased risk of subsequent psychiatric problems. METHODS: We conducted a population-based cohort study that involved linking information from the Danish Civil Registration system to the Danish Psychiatric Central Register and the Danish National Register of Patients. The information consisted of data for girls and women with no record of mental disorders during the 1995-2007 period who had a first-trimester induced abortion or a first childbirth during that period. We estimated the rates of first-time psychiatric contact (an inpatient admission or outpatient visit) for any type of mental disorder within the 12 months after the abortion or childbirth as compared with the 9-month period preceding the event. RESULTS: The incidence rates of first psychiatric contact per 1000 person-years among girls and women who had a first abortion were 14.6 (95% confidence interval [CI], 13.7 to 15.6) before abortion and 15.2 (95% CI, 14.4 to 16.1) after abortion. The corresponding rates among girls and women who had a first childbirth were 3.9 (95% CI, 3.7 to 4.2) before delivery and 6.7 (95% CI, 6.4 to 7.0) post partum. The relative risk of a psychiatric contact did not differ significantly after abortion as compared with before abortion (P = 0.19) but did increase after childbirth as compared with before childbirth (P < 0.001). CONCLUSIONS: The finding that the incidence rate of psychiatric contact was similar before and after a first-trimester abortion does not support the hypothesis that there is an increased risk of mental disorders after a first-trimester induced abortion. PMID- 21268724 TI - Peginterferon plus adefovir versus either drug alone for hepatitis delta. AB - BACKGROUND: Chronic infection with hepatitis B virus and hepatitis delta virus (HDV) results in the most severe form of viral hepatitis. There is no currently approved treatment. We investigated the safety and efficacy of 48 weeks of treatment with peginterferon alfa-2a plus adefovir dipivoxil, peginterferon alfa 2a alone, and adefovir dipivoxil alone. METHODS: We conducted a randomized trial in which 31 patients with HDV infection received treatment with 180 MUg of peginterferon alfa-2a weekly plus 10 mg of adefovir daily, 29 received 180 MUg of peginterferon alfa-2a weekly plus placebo, and 30 received 10 mg of adefovir alone weekly for 48 weeks. Follow-up was conducted for an additional 24 weeks. Efficacy end points included clearance of HDV RNA, normalization of alanine aminotransferase levels, and a decline in levels of hepatitis B surface antigen (HBsAg). RESULTS: The primary end point--normalization of alanine aminotransferase levels and clearance of HDV RNA at week 48--was achieved in two patients in the group receiving peginterferon alfa-2a plus adefovir and two patients in the group receiving peginterferon alfa-2a plus placebo but in none of the patients in the group receiving adefovir alone. At week 48, the test for HDV RNA was negative in 23% of patients in the first group, 24% of patients in the second, and none of those in the third (P = 0.006 for the comparison of the first and third groups; P = 0.004 for the comparison of the second and third). The efficacy of peginterferon alfa-2a was sustained for 24 weeks after treatment, with 28% of the patients receiving peginterferon alfa-2a plus adefovir or peginterferon alfa-2a alone having negative results on HDV-RNA tests; none of the patients receiving adefovir alone had negative results. A decline in HBsAg levels of more than 1 log(10) IU per milliliter from baseline to week 48 was observed in 10 patients in the first group, 2 in the second, and none in the third (P<0.001 for the comparison of the first and third groups and P = 0.01 for the comparison of the first and second). CONCLUSIONS: Treatment with peginterferon alfa-2a for 48 weeks, with or without adefovir, resulted in sustained HDV RNA clearance in about one quarter of patients with HDV infection. (Current Controlled Trials number, ISRCTN83587695.). PMID- 21268726 TI - Genomics and the continuum of cancer care. PMID- 21268727 TI - Chronic thromboembolic pulmonary hypertension. PMID- 21268728 TI - Images in clinical medicine: A photosensitive dermatitis in the intensive care unit. PMID- 21268729 TI - Case records of the Massachusetts General Hospital: Case 3-2011: a 58-year-old woman with a mass in the liver. PMID- 21268730 TI - Tackling the Achilles' heel of hemodialysis. PMID- 21268731 TI - A critic's assessment of our approach to cardiac arrest. PMID- 21268732 TI - Systems biology and red cells. PMID- 21268733 TI - Home monitoring of warfarin effects. PMID- 21268734 TI - Home monitoring of warfarin effects. PMID- 21268736 TI - Treatment of superficial thrombophlebitis. PMID- 21268737 TI - Treatment of superficial thrombophlebitis. PMID- 21268739 TI - Endobronchial valves for emphysema. PMID- 21268740 TI - Endobronchial valves for emphysema. PMID- 21268741 TI - Endobronchial valves for emphysema. PMID- 21268743 TI - Erythropoietin in kidney disease and type 2 diabetes. PMID- 21268744 TI - Erythropoietin in kidney disease and type 2 diabetes. PMID- 21268745 TI - Erythropoietin in kidney disease and type 2 diabetes. PMID- 21268746 TI - Erythropoietin in kidney disease and type 2 diabetes. PMID- 21268748 TI - Permethrin treatment of head lice with knockdown resistance-like gene. PMID- 21268749 TI - Nonmydriatic ocular fundus photography in the emergency department. PMID- 21268762 TI - The most commonly occurring papillary thyroid cancer in the United States is now a microcarcinoma in a patient older than 45 years. AB - BACKGROUND: The incidence of papillary thyroid cancer (PTC) is growing at a faster rate than any other malignancy. However, it is unknown what effect age is having on the changing PTC incidence rates. With the goal of understanding the role of age in thyroid cancer incidence, this study analyzes the changing demographics of patients with PTC over the past three decades. METHODS: This was a retrospective evaluation of the incidence rates of PTC from 1973 to 2006 reported by the National Cancer Institute's Surveillance, Epidemiology, and End Results database. RESULTS: From 1973-2006 the age group most commonly found to have PTC has shifted from patients in their 30s to patients in the 40-50-year-old age group. In 1973 60% of PTC cases were found in patients younger than 45, and the majority of cases continued to occur in younger patients until 1999. After 1999 PTC became more common in patients older than 45 years, and in 2006, 61% of PTC cases were in patients older than 45 years. From 1988 to 2003 there has been an increasing incidence of all sizes of PTC in all age groups with the largest increase in tumors <1 cm in patients older than 45. Forty-three percent of tumors in patients older than 45 are now <1 cm, whereas only 34% are <1 cm in patients younger than 45. Of the nearly 20,000 thyroid cancer cases in 2003, 24% were microcarcinomas in patients over the age of 45. CONCLUSIONS: The incidence of PTC is increasing disproportionally in patients older than 45 years. The number of PTC tumors smaller than 1 cm is increasing in all age groups, and now the most commonly found PTC tumor in the United States is a microcarcinoma in a patient older than 45 years. These changing patterns relating age and incidence have important prognostic and treatment implications for patients with PTC. PMID- 21268766 TI - [Computer--tomographic resecability criteria at cancer head of the pancreas]. AB - The aim of the study was to explore the possibilities of CT in evaluating resectability of pancreatic head adenocarcinoma, depending on the tumor. MATERIALS: The results of CT and intraoperative findings in 62 patients with cancer of the head of the pancreas. RESULTS: It was shown that the tumor localized in caudal glands, had higher resectability when compared with tumors of the cranial localization at tumor sizes of 3-4 cm in size tumor less than 3 cm, the probability that radical surgery was highest in patients with central localization of the tumor. PMID- 21268767 TI - [Autologous artificial tracheas were born]. PMID- 21268768 TI - Foreword. The progressive expansion of screening programmes. PMID- 21268769 TI - To register or not-that is the question. The case for collaboration and a National Cardiac Procedures Database. PMID- 21268770 TI - Proceedings of the University of Pennsylvania annual conference on statistical issues in clinical trials: statistical issues in developing targeted therapies. PMID- 21268771 TI - High-frequency percussive ventilation. PMID- 21268772 TI - In vitro fluid leak around the endotracheal tube cuff is easily remedied. PMID- 21268773 TI - Natural remodeling of onlay-patch arterial coronary bypass grafts. PMID- 21268774 TI - Exercise intolerance in chronic heart failure: mechanisms and therapies. Part I. AB - Muscular fatigue and dyspnoea on exertion are among the most common symptoms in chronic heart failure; however their origin is still poorly understood. Several studies have shown that cardiac dysfunction alone cannot fully explain their origin, but the contribution of the multiorgan failure present in this syndrome must be highlighted. In this study, divided in two parts (see part II: pp. 643 648), we aimed to summarize the existing evidence and the most controversial aspects of the complex interplay of different factors involved in symptom generation. In this first part of the review, six key factors are revised: the heart, the lung, the skeletal muscle, the hormonal changes, the O2 delivery to the periphery, the endothelium. In the second part, the role of the excitatory reflexes and the cardiac cachexia will be presented, and finally, the potential therapeutic implications are discussed. We believe that a better knowledge of the pathophysiology of this syndrome may contribute to the management of the patients and to the improvement in their stress tolerance and quality of life. PMID- 21268775 TI - Increased body fat is independently and negatively related with cardiorespiratory fitness levels in children and adolescents with normal weight. AB - BACKGROUND: Body mass index (BMI) is related with cardiorespiratory fitness (CRF), but less is known regarding the combined relationships between BMI and body fat (BF) on CRF. DESIGN: Cross-sectional study included 2361 girls and 2328 boys aged 10-18 years living in the area of Lisbon, Portugal. BMI was calculated by measuring height and weight, and obesity was assessed by international criteria. BF was assessed by bioimpedance. CRF was assessed by the 20-m shuttle run and the participants were classified as normal-to-high or low-CRF level according to Fitness gram criterion-referenced standards. RESULTS: The prevalence of low CRF was 47 and 39% in girls and boys, respectively. The corresponding values for the prevalence of obesity were 4.8 and 5.6% (not significant) and of excess BF of 12.1 and 25.1% (P <0.001), respectively. In both sexes, BMI and BF were inversely related with CRF: r = - 0.53 and - 0.45 for BMI and % BF, respectively, in boys and the corresponding values in girls were - 0.50 and - 0.33 (all P <0.01). When compared with a participant with normal BMI and BF, the odds ratios (95% confidence interval) for low CRF were 1.94 (1.46-2.58) for a participant with normal BMI and high BF, and 6.19 (5.02-7.63) for a participant with high BMI and high BF. CONCLUSION: The prevalence of low-CRF levels is high in Portuguese youths. BF negatively influences CRF levels among children/adolescents with normal BMI. PMID- 21268776 TI - Recollections of my friendship with Klaus Ruckpaul. AB - Klaus Ruckpaul was the leader of cytochrome P450 research in the "East" Germany when the world was politically divided into "East" and "West". Under strong political pressure during the "Cold War", the communication between the scientists in the "East" countries with those in the "West" countries was badly restricted. He wanted to improve the situation, and organized an international gathering of the biochemists studying cytochrome P450. The first meeting was held in 1976, and it developed later into a big international conference named "International Conference on Cytochrome P450, Biochemistry and Biophysics". He and his colleagues also contributed greatly to the elucidation of the mechanism of P450-catalyzed reactions. I respect him for his great contribution to the advancement of biochemical study on cytochrome P450, and feel happy that I have enjoyed a long friendship with him. PMID- 21268777 TI - Estimation of genetic distance based on RAPDs between 11 cotton accessions varying in heat tolerance. AB - The genetic distance of 11 cotton genotypes varying in heat tolerance was studied using RAPD markers. Fifty-three random decamer primers were used for the estimation of genetic distance. Among the 53 RAPD primers, which were custom synthesized by GeneLink Inc., UK, 32 were polymorphic and 21 were monomorphic. The 32 polymorphic primers produced 273 fragments, with a mean of 8.3 fragments per primer. The number of polymorphic bands produced in the 11 cotton accessions ranged from 1 to 31. Primer GLC-20 produced 31 polymorphic bands, while two primers, GLB-5 and GLC-12, produced one polymorphic band each. A range of 88.89 to 42.48% genetic similarity was observed among the 11 cotton accessions. The highest genetic similarity was observed between FH-945 and BH-160 (88.89%), whereas the lowest value was found between NIAB-801/2 and FH-945 (42.48%). Unique amplification profiles were produced by most of the cultivars; the differences were sufficient to distinguish them from other genotypes. This confirms the efficacy of RAPD markers for the identification of plant genotypes. An accumulative analysis of amplified products generated by RAPDs was sufficient to assess the genetic diversity among the genotypes. This information should be helpful for formulating breeding and genome mapping programs. PMID- 21268778 TI - Identification of sunflower (Helianthus annuus, Asteraceae) hybrids using simple sequence repeat markers. AB - Hybrid identification of 16 sunflower hybrids was confirmed using simple-sequence repeat methodology. Of 20 specific simple-sequence repeat primers, 18 authenticated the purity of these hybrids; the remaining two specific primer pairs gave ambiguous DNA fragments. The results indicate that simple-sequence repeat analysis for the identification of hybrids derived from the crossing of different inbred sunflower lines can improve the accuracy of selection, save time and reduce cost. PMID- 21268779 TI - A novel TSC1 mutation (c.1964delA) in a Chinese patient with tuberous sclerosis complex. AB - Tuberous sclerosis complex is an autosomal-dominant heritable disease caused by mutations in the TSC1 and TSC2 genes. We studied a Chinese patient with sporadic tuberous sclerosis complex. The clinical features of this patient included epilepsy, hypomelanotic macules and angiofibromas on his back; a cranial CT scan showed subependymal nodules along the lateral walls of the lateral ventricles. The TSC1 and TSC2 genes were studied by PCR and direct sequencing of the entire coding region and exon-intron boundaries of these genes. A novel deletion mutation (c.1964delA) in the TSC1 gene exon 15 was identified, which was not present in his parents or 100 unrelated normal controls. This is the first report of this c.1964delA mutation of the TSC1 gene, associated with tuberous sclerosis complex, expanding the spectrum of TSC1 mutations that cause this disease. PMID- 21268780 TI - New developments in CSF biomarkers for early detection and monitoring of Parkinson disease. PMID- 21268781 TI - Genetic diversity and differentiation in Dalbergia sissoo (Fabaceae) as revealed by RAPD. AB - Dalbergia sissoo, a wind-dispersed tropical tree, is one of the most preferred timber tree species of South Asia. Genetic diversity and differentiation among natural populations of D. sissoo were examined for the first time. We found a relatively high level of genetic diversity in D. sissoo, both at the species level (percentage of polymorphic bands = 89.11%; H = 0.2730; I = 0.4180) and the population level (percentage of polymorphic bands = 68.7%; H = 0.239; I = 0.358), along with a relatively low degree of differentiation among populations (GST = 0.1311; AMOVA = 14.69%). Strong gene flow among populations was estimated, N(m) = 3.3125. The Mantel test suggested that genetic distances between populations were weakly correlated with geographic distances (R = 0.3702, P = 0.1236). The high level of genetic diversity, low degree of differentiation, strong gene flow, and weak correlation between genetic and geographic distances can be explained by its biological character and wide-spread planting. This information will be useful for the introduction, conservation and further studies of D. sissoo and related species. PMID- 21268782 TI - Preventing epilepsy in malaria survivors. PMID- 21268783 TI - Stroke. Dabigatran and stroke prevention. PMID- 21268784 TI - cDNA, genomic sequence cloning and overexpression of the ribosomal protein S13 gene in the giant panda (Ailuropoda melanoleuca). AB - The cDNA and the genomic sequence of ribosomal protein S13 (RPS13) of the giant panda (Ailuropoda melanoleuca) was cloned using reverse transcription-polymerase chain reaction (RT-PCR) and touchdown-PCR, respectively. These two sequences were sequenced and analyzed, and the cDNA of the RPS13 gene was overexpressed in Escherichia coli BL21. We compared the nucleotide sequences of the coding region and the amino acid sequences with those of seven other mammalian species retrieved from GenBank. The cDNA fragment of the RPS13 cloned from the giant panda is 496 bp in size, containing an open-reading frame of 456 bp, encoding 151 amino acids. The length of the genomic sequence is 2277 bp, with five exons and four introns. The coding sequence shows a high degree of homology to those of Homo sapiens, Bos taurus, Canis lupus familiaris, Macaca mulatta, Mus musculus, Rattus norvegicus, and Pan troglodytes; the degree of homology was 91.23, 94.30, 94.74, 92.11, 87.94, 87.72, and 91.45%, respectively. The homologies for the deduced amino acid sequences reached as high as 99%. Primary structure analysis revealed that the molecular weight of the putative RPS13 protein is 17.22325 kDa, with a theoretical pI of 10.42. Based on topology prediction, there is one protein kinase C phosphorylation site, one casein kinase II phosphorylation site, two N-myristoylation sites, and one ribosomal protein S15 signature in the RPS13 protein of the giant panda. The RPS13 gene can be expressed in E. coli and the RPS13 protein fused with the N-terminally GST-tagged form, which gave rise to the addition of an expected 43-kDa polypeptide. PMID- 21268785 TI - Neurodegenerative disease. CSF biomarkers differentiate between two forms of frontotemporal lobar degeneration. PMID- 21268786 TI - Stroke. a new window of opportunity for stroke rehabilitation? PMID- 21268787 TI - Alzheimer disease. Frontal cortex biopsy samples can predict Alzheimer disease. PMID- 21268788 TI - Abstracts of Jasper's Basic Mechanisms of the Epilepsies Workshop. March 23-27, 2009. Yosemite National Park, California, USA. PMID- 21268789 TI - Reducing waiting times. PMID- 21268790 TI - First-aid training. PMID- 21268792 TI - Legal. Experts debate the impact of antitrust suit against Michigan Blues. PMID- 21268793 TI - The health benefits of strong relationships. Good connections can improve health and increase longevity. PMID- 21268794 TI - How to put your smartphone "on call." Applications that run on your cell phone put health and wellness aids just a touch away. PMID- 21268795 TI - Grip strength and other physical measures predict lifespan. PMID- 21268796 TI - FDA approves the first oral drug for reducing multiple sclerosis relapses. PMID- 21268797 TI - What to make of the new warning on bisphosphonates. Officials acknowledge a connection between the most popular bone drugs and rare thigh fractures. PMID- 21268798 TI - By the way, doctor. I keep hearing that aspirin can help prevent colon cancer, but I have no idea how much I should take. Can you help? I've had adenomatous polyps in the past. PMID- 21268799 TI - Salt and your health, Part I: the sodium connection. PMID- 21268800 TI - Blood in the urine: what does it mean for your health? PMID- 21268801 TI - On call. I've been taking Zocor since my heart attack in 2006. My cholesterol count has come way down, and I haven't had any heart problems. In the past few months, however, I've had some muscle aches. My blood tests don't show any muscle damage, but my doctor says Zocor may still be causing the problem. He wants me to stop Zocor for a while, but I'm worried about my heart. Is it safe for me to stop? PMID- 21268802 TI - [10th annual scientific-practical conference with international participation: "Wounds, wound infection, tissue suturing". Kiev, 2010. Abstracts]. PMID- 21268803 TI - [V seminar with international participation: "New trends in research of living soft tissues welding". Kiev, 2010. Abstracts]. PMID- 21268804 TI - [Efficacy of prostaglandin E1 and systemic antibacterial therapy application in patients with diabetes mellitus and purulent-necrotic lesions of the foot]. AB - The results of prostaglandin E1 et systemic antibacterial therapy use in 1836 patients, suffering purulent-necrotic affection of foot, were summarized. There was established, that cefuroxym constitutes the first line preparation for the ostheoarthropathy focus elimination, when the affection is limited and the patient state is stable, and meronem--for extended affection and unstable patient's state. In the pronounced ischemia of the foot the initial administration of cefepim is the most effective. For purulent-necrotic affection as a consequence of the foot wounding, erysipelas or operative intervention it is expedient to use carbapenem or meropenem. The systemic antibacterial therapy administration had promoted significant reduction of the treatment duration and improvement of its result. PMID- 21268805 TI - [Rational antibacterial therapy of acute surgical diseases of abdominal organs]. AB - Comparative analysis of medical documents, concerning 1055 patients, aged 18-92 yrs old, operated for an acute surgical diseases of abdominal organs in 2007-2009 yrs, was performed. Preoperative antibioticotherapy was performed in all the patients, in 877 of them ceftazidim (ceftadim) was administered as the main antibacterial preparation and in 178--other antibacterial preparations. Application of ceftadim, as a basic preparation in antibioticotherapy, had permitted to lower the purulent-septic complications rate by 61% and to reduce the stationary treatment duration of the patients. PMID- 21268806 TI - [Methods of surgical correction of the inferior vena cava syndrome in patients, suffering mediastinal compression syndrome]. AB - The experience of treatment of patients, suffering mediastinal compression syndrome, caused by syndrome of vena cava inferior, is presented. The types of affection of vena cava inferior in accordance with classification of clinic were delineated. The methods of operative treatment of the vena cava inferior syndrome, applied in the clinic, were adduced. PMID- 21268807 TI - [Simultaneous operations in laparoscopic surgery]. PMID- 21268808 TI - [Laparoscopic resection of the liver]. PMID- 21268809 TI - [Experience of Fournier's gangrene treatment]. PMID- 21268810 TI - [The injury of the common biliary duct in a blunt abdominal trauma]. PMID- 21268811 TI - [Concomitant injury of the extrahepatic biliary duct and right hepatic artery during performance of laparoscopic cholecystectomy]. PMID- 21268812 TI - [Rare observation of gastric diverticulum]. PMID- 21268813 TI - [The ways of improvement of the physicians-interns training for specialties "surgery" and "obstetrics and gynecology"]. PMID- 21268814 TI - [Trailing the footpath of Acanthamoeba keratitis]. PMID- 21268815 TI - [Effect of repeated intravitreal bevacizumab injections for secondary macular edema of branch retinal vein occlusion]. AB - PURPOSE: To evaluate the effects of intravitreal bevacizumab (IVB) injections for secondary macular edema of branch retinal vein occlusion (BRVO). SUBJECTS AND METHODS: We treated 91 patients (91 eyes) with IVB injections (1.25 mg/0.05 ml), including 27 eyes which received two injections. Visual acuity and central retinal thickness (CRT) were measured at 1, 4, 8 and 12 weeks after injection. RESULTS: The mean visual acuity and CRT improved from 0.25 (610.8 microm) at baseline to 0.47 (238.4 microm) 4 weeks after injection and 0.45 (368.7 microm) after 12 weeks. Twenty seven eyes among the total of 91 eyes had a second injection due to recurrence or worsened metamorphopsia. In these cases, mean visual acuity and CRT improved from 0.33 (483.7 microm) at baseline to 0.44 (234.3 microm) 4 weeks after injection and 0.42 (296.8 microm) after 12 weeks. Comparing the efficacy by the number of treatments, visual acuity and CRT improved more significantly in a first time treatment group. CONCLUSIONS: IVB injection is generally effective, but recurrence occurred in 26/47 eyes based on CRT. The second injection is effective, however, its effect is weak when compared with the first injection. PMID- 21268816 TI - [Frequency of classified forms in endogenous uveitis considering the anatomical location of the inflammation]. AB - PURPOSE: To investigate the frequency of classified forms in endogenous uveitis in Asahikawa Medical College considering the anatomical location of the inflammation. METHOD: 116 new uveitis patients, who visited our hospital between 2001 and 2008, were retrospectively analyzed. We reviewed medical charts of the patients' age at disease onset, unilateral or bilateral uveitis, anatomical location of inflammation and diagnosis of classified form of uveitis. RESULTS: Age ranged from 5 to 83 years and the distribution of age showed two peaks. Sarcoidosis was the most common form accounting for 33% of all uveitis, 40% of bilateral uveitis and 43% of panuveitis. Vogt-Koyanagi-Harada disease and Behcet's disease followed sarcoidosis. In the unilateral uveitis cases, herpes virus infectious uveitis was the most common form followed by Behcet's disease and ulcerative colitis. In anterior uveitis, herpes virus infectious uveitis was the most common form followed by sarcoidosis and HLA-B27-positive anterior uveitis. CONCLUSION: The most common form amang the entire endogenous uveitis patient's in our hospital was sarcoidosis, and it was also the commonest in panuveitis and bilateral uveitis. The high frequency of sarcoidosis was remarkable when compared with other studies from other facilities. PMID- 21268817 TI - [Demodex-related marginal blepharitis in Japan]. AB - PURPOSE: Some marginal blepharitis is related to demodex, but this has not yet been reported in Japan. In this study, patients with severe marginal blepharitis with cylindrical dandruff were studied to examine the number of demodex in their cilia. METHODS: Ten eyes of 10 patients (7 men and 3 women, mean age: 62.9 +/- 9.0 years) with unilateral marginal blepharitis which had cylindrical dandruff in their cilia were studied. Three cilia which had the most cylindrical dandruff were removed from the eyelids for microscopic examination. After cleaning the eyelid margins for 1 week, the examination was repeated. Scoring of itching and foreign body sensation of the patients was performed both before and after the treatment. RESULTS: Demodex folliculorum was detected in the cilia of 8 out of 10 eyes (80%), and 22 cilia out of 30 with cylindrical dandruff. The average number of demodex/cilia was 1.6 +/- 0.9. In all cases, the number of demodex/cillium decreased significantly with the improvement in symptoms and blepharitis. CONCLUSION: An Increase in the number of demodex might be the pathogen causing blepharitis with cylindrical dandruff, and cleaning of the eyelid margin is effective as a therapeutic method. PMID- 21268818 TI - [Characteristic appearance of early-stage Acanthamoeba keratitis]. AB - PURPOSE: To clarify the characteristic appearances of early-stage Acanthamoeba keratitis (AK) and to investigate the effects of topical steroids on those appearances. SUBJECT AND METHODS: This study involved 25 eyes of 24 patients diagnosed as early-stage AK at Kyoto Prefectural University of Medicine between October 2002 and June 2008. All patients were contact lens wearers, and 23 patients (96%) were referred from other hospitals. Clinical findings in the medical records of all patients were analyzed retrospectively. RESULTS: Radial keratoneuritis was observed in 20 of 25 eyes (80%), and pseudodendritic lesions were observed in 15 eyes (60%). Only 1 eye (4%) showed neither of these two findings. Of the 10 eyes treated with topical steroids until the first presentation at our hospital, 6 eyes manifested radial keratoneuritis and/or pseudodendritic lesions after the discontinuation of that treatment. The visual prognosis was good in both groups, with or without topical steroid treatment. CONCLUSIONS: We found that radial keratoneuritis and pseudodendritic lesions are characteristic appearances of early-stage AK, and that topical steroid treatment might mask these characteristic findings. PMID- 21268819 TI - [Pyogenic granuloma developing rapidly after excision of corneal/conjunctival intraepithelial neoplasia]. AB - BACKGROUND: Pyogenic granuloma is a benign tumor presenting with a smooth hemorrhagic surface that develops on the ocular surface after trauma or ophthalmic surgery. Abnormal wound healing due to physical and/or chemical stimulation may contribute to the pathogenesis of the tumor. We herein report the usefulness of brushing cytology for diagnosis of pyogenic granuloma, which rapidly developed after surgical resection of corneal/conjunctial intraepithelial neoplasia (CIN). CASE: A 70-year-old man presented with a flat tumor on the left lower conjunctiva in conjunction with the cornea. The patient underwent excision of the tumor and cryotherapy. The primary tumor was histologically diagnosed with CIN. A hemorrhagic mass developed on the conjunctiva one month after the excision. Brushing cytology demonstrated vascular endothelial cells with spindle shaped nuclei mixed with prominent neutrophils without abnormal squamous epithelial cells. The secondary tumor was diagnosed as pyogenic granuloma. CONCLUSIONS: It is possible to diagnose a secondary tumor based on information of the clinical course, slit-lamp examination and brushing cytology before the excision of CIN. PMID- 21268820 TI - [Case of alkaline esophagitis due to sodium hypochlorite ingestion]. AB - The severity of alkaline esophagitis due to sodium hypochlorite ingestion is variable and the findings of endoscope within 48 hours of ingestion are reported to be associated with its prognosis. We report a good recovery case of grade 2B of alkaline esophagitis, which was treated with close observation. The patient was 59-year old man. He was found lying on the bed by his wife, after drinking bactericidal agents (Jianok) and kitchen cleaner (Magiclean) for suicide attempt. After his trachea was intubated, he underwent upper gastrointestinal scope, which displayed circumferential ulcers at the lower esophagus. He was diagnosed as having a Grade 2B alkaline esophagitis, which was associated with a higher probability of stricture or perforation. On the 14th day of the admission, the 2nd endoscope was performed and no esophageal strictures were detected. He was extubated and started oral feeding on the 15th day. After that, his hospital course was uneventful and was discharged on the 18th day. 6 months have passed since he left hospital. No esophageal strictures were detected so far. PMID- 21268821 TI - [Case followed by delayed loss of consciousness after exposure to hydrogen sulfide that was treated with intermittent administration of sodium nitrite]. AB - A 49-year-old man lost consciousness after being accidentally exposed to what was probably hydrogen sulfide gas while performing maintenance on a machine producing feather meal. He was immediately taken to the hospital. Upon admission, his consciousness level was 14 (E4V4M6) on the Glasgow Coma Scale (GCS), but it subsequently decreased, and the patient was intubated when his respirations became depressed as well. About 5 hours after the initial incident, he was transferred to our department. His consciousness level was GCS 9 (E2V2M5), his blood pressure was 95/78 mmHg, and his heart rate was 90 beats per min. There was no metabolic acidosis. Mechanical ventilation was begun and 10% sodium nitrite was intermittently administered intravenously, with the goal of lowering arterial blood methemoglobin saturation to 20%. Two days following admission, the patient regained full consciousness and sodium nitrite administration was stopped. The following day mechanical ventilation was also discontinued. This patient exhibited severe recurring neurologic symptoms without metabolic acidosis; thus, the manifestations of toxicity in this case might have been due to the direct neurologic toxicity of hydrogen sulfide, hypoxia, or delayed post-ischemic cerebral hypoperfusion syndrome. The patient made a full recovery without any sequelae; therefore we would like to hypothesize that repetitive intravenous administration of sodium nitrite is effective in cases of hydrogen sulfide exposure. PMID- 21268822 TI - [Japan Poison Information Center]. PMID- 21268823 TI - [The Yamagata Prefectural Institute of Public Health]. PMID- 21268824 TI - [Clinical Toxicology, Department of Clinical Pharmacy, Center for Clinical Pharmacy and Clinical Sciences, School of Pharmacy, Kitasato University]. PMID- 21268825 TI - [Summary of current topics and problems in toxicology laboratories]. PMID- 21268826 TI - [Acute tebufenpyrad and tolfenpyrad poisoning in humans]. PMID- 21268827 TI - [Leptin and metabolic syndrome]. AB - Obesity is characterized by increased concentration of leptin and disturbance of the feedback between hyperleptinaemia and enhanced appetite. The hyperleptinaemia is often combined with hyperglycaemia and arterial hypertension and seems to be a predictor of acute cardiovascular events. Leptin inhibitors might be used in the future for therapy in case of the metabolic syndrome. PMID- 21268828 TI - [Disruption of latent inhibition in ISIAH rats with stress-sensitive arterial hypertension]. AB - Latent inhibition phenomenon is used in the study of processes of selective attention in the context reinforcing training. The purpose of this study was a comparative analysis of the ability to ignore irrelevant stimuli in hypertensive ISIAH rats and normotensive Wistar rats with different psychoemotional statuses. Latent inhibition was formed in the passive and active avoidance tasks the development of which was preceded by repeated presentation (pre-exposition) conditioned stimulus without reinforcement. In ISIAH rats, disruption of latent inhibition in both behavioural tasks was observed as compared with Wistar rats. These data suggest that the deficit of selection information in ISIAH rats is caused by congenital weakness of internal inhibition in the adaptation to anxiogenic stimuli. PMID- 21268829 TI - [Analysis of changes in heart rate variability during fast extracardial impulsation in the sinoatrial node]. AB - It is known that fast extracardial impulsation in the sinoatrial node modifies the degree of heart rare variability. The present study presents theoretical and experimental investigation of this effect. Theoretical investigation is based on the mathematical modelling of impulse conduction in the cardiac conduction system. Experimental investigation on dogs revealed quantitative correlations between the frequency of extracardial impulsation in the sinoatrial node and changes of heart rate variability. Computer simulation shows that the mathematical model can account for most principal properties of the heart rate disturbances during fast extracardial impulsation in the sinoatrial node: transitions between different regimens of heart rate dynamics; increase in the delay of atrio-ventricular conduction; Wenkebach's periodicity. PMID- 21268830 TI - [Effect of acetylcholine on coordination of spontaneous activities registered from different areas of uterus in rats]. AB - Spontaneous electrical activities of uterine corpus, periuterine part of horn and uterine cervix in response to intravenous injections of different concentrations of acetylcholine were observed. The changes of frequency and amplitude characteristics of rhythmogenesis in these conditions, both separately and with their co-active state were analysed. Acetylcholine in concentration of 10(-3) M in the blood of the animal creates the optimal conditions for synchronization and coordination of electrical activities in the above areas of the uterus. PMID- 21268831 TI - [Selective influence of dehydroepiandrosterone-sulphate on anxiety induced by corticotropin-releasing hormone injection]. AB - The objective of this study was to ascertain the effect of dehydroepiandrosterone sulphate (DHEA-S) on changes of anxiety level, induced by corticotropin-releasing hormone (CRH) injection. Active and passive rats were selected from Wistar rats on the basis of T-maze testing. Active rats were then divided into the groups with high (HA) and low anxiety (LA) level after testing in elevated-plus maze. Intranasal injection of CRH induced increase of anxiety level in the LA rats, while in HA rats it remained unchanged. DHEA-S exerted a moderate anxiolytic effect on the LA rats and sedative effect--on the HA rats. DHEA-S injection had no effect on anxiety level in passive rats that typically demonstrate high level of trait-anxiety and resistance to CRH. These results suggest that DHEA-S effect depends on the individual psycho-emotional status and responsiveness to CRH. PMID- 21268832 TI - [The effect of low-intensity red and infrared laser radiation on the rat arterial and deoxygenated blood]. AB - In vitro experiments the effect of low-intensity red or near-infrared laser irradiation on the blood samples (1.5 ml from abdominal aorta of Wistar rats) were studied. The diode laser light (lambda = 650 nm or 808 nm, power density 15.6 mW/cm2, duration 15 min) were used. In some experiments the deoxygenated blood as object for comparison with arterial blood was chosen. Under red laser irradiation we observed a significant increase of average volume of erythrocytes as well as mean amount of free (disaggregated) leukocytes especially in case of the deoxygenated blood. At the same time the concentration of Ca2+ and Na+ were decreased. The effects of infrared laser irradiation on indices mentioned above were not significant. We believe that red low-intensity laser irradiation on the blood is an important factor for theological properties in the field of microcirculation. PMID- 21268833 TI - [Interhemisphere asymmetry of the CSF dynamics and biomechanical properties of the skull]. AB - This investigation shows that both intracranial liquor circulation and skull biomechanical properties evaluated by its pliability (compliance) to intracranial pressure are characterised by marked interhemisphere asymmetry. The interhemisphere differences of cerebrospinal fluid mobility were evaluated by means of asymmetry coefficient (right/left ratio of liquor mobility) which was found to be 1.25-1.45 in healthy middle-age persons. For the skull pliability (compliance) the coefficient of hemispheric asymmetry was 0.75-0.95. These two hemisphere asymmetry coefficients are characterized by reciprocal relationships. These coefficients demonstrated no dominancy related to right/left hemisphere as well as no correlation with neurophysiological parameter. Functional tests (apnoea, hyperventilation, Stookey test) gave rise to significant changes of these coefficient values. At ageing, the magnitudes of these coefficients decreased. The spectral analysis of pulse waves of dopplerogram and rheoencephalogram reveals hemisphere asymmetry, too. It should be suggested that the interhemisphere asymmetry of the CSF dynamics and skull biomechanical properties is a special mechanism which contributes in the process of circulatory metabolic support of brain activity. PMID- 21268834 TI - [Nootropic and analgesic effects of Semax following different routes of administration]. AB - Heptapeptide Semax (MEHFPGP) is the fragment of ACTH(4-10) analogue with prolonged neurotropic activity. The aim of the present work was to study the Semax effects on learning capability and pain sensitivity in white rats following intraperitoneal and intranasal administration in different doses. Semax nootropic effects were studied in the test of acquisition of passive avoidance task. Pain sensitivity was estimated in Randall-Selitto paw-withdrawal test. It was shown that Semax exerts nootropic and analgesic activities following intraperitoneal administration. Analysis of dependence of these effects on dose resulted in different dose-response curves. Following intranasal administration, Semax was more potent in learning improvement compared to intraperitoneal administration. The peptide failed to affect the animal pain sensitivity following intranasal administration as opposed to intraperitoneal administration. The data obtained suggest different mechanisms and brain structures involved in realization of the nootropic and analgesic effects of Semax. PMID- 21268835 TI - [Interstrain differences in testicular responses to hCG: effects of a female exposition]. AB - It is known that among many animal species, including laboratory mice, a short time exposition to a female causes activation of the pituitary-testicular axis in males, which then rapidly decreases. Effects of a prolonged female exposition on the testicular testosterone output in response to hCG injections were investigated in adult males of two inbred mice strains CBA/Lac and PT. The males of both genotypes kept with females for 5 days were injected subcutaneously with 10 IU of hCG 120 minutes before decapitation. Males of the same genotype and similar age keeping alone were served as control. The serum testosterone concentration and its testicular content were measured with immune-enzyme assay. It has been shown that the hCG increased the testosterone concentration and its testicular content in control males of both strains, but the testosterone output was expressed more significantly in PT males in comparison with CBA/Lac. The prolonged exposition of a female itself did not influence the testosterone output in males of both strains. However, it increased significantly the testicular response to hCG in PT strain. The data obtained suggest that a long-term exposition of a female could reinforce the testicular reactivity to hCG in genotype-dependent manner. PMID- 21268836 TI - [Blood lactate dehydrogenase activity in newborn children]. AB - Arterial and venous blood samples from babies' umbilical cord vessels before lung breath beginning were used to measure arterial-venous difference between lactate dehydrogenase activity, pH and oxygen blood saturation (sO2). Enzyme activity was 735.4 +/- 90.8 U/L in venous blood and 672.0 +/- 108.1 U/L in arterial one, pH 7.21 +/- 0.06 and 7.32 +/- 0.06, sO2 32.9 +/- 12.7 and 56.5 +/- 18.3%, respectively. Reverse correlation between enzyme activity, pH and sO2 was found. PMID- 21268837 TI - [Morphological and functional heterogeneity of rat ascitic hepatoma Zajdela cells]. AB - This work is devoted to the study of molecular and cellular mechanisms of disdifferentiation during neoplastic transformation of cells by investigating the malignant tumor cell heterogeneity. We have revealed two cell fractions of hepatoma Zajdela which differ in patterns of growth in primary culture. The cells of one fraction were attached to the culture plastic and grew in a monolayer (S fraction), whereas cells of another fraction floated in the culture medium (F fraction). Using method of lifetime supervision of primary culture cells (1-2 passages) at the limit of the resolving power of DIC-microscopy it has been revealed, that both fractions contain cells of several types. Some of them were specific for one of the fractions, and others were found in both fractions, but their frequencies differed. It has been shown by the same method, that long separate cultivation of these fractions in vitro (more than 50 passage) change both cellular structure and the initial ratio of different types of cells in both fractions. According to DNA flow cytometry, the cells of both fractions were hypotetraploid and had insignificant differences in DNA contents. After adaptation to in vitro conditions, S-fraction cells raised their proliferative activity in comparison with the F-fraction cells, and after long cultivation showed 2.3 times higher DNA content. Greater amount of cell surface laminin, a hepatocellular carcinoma marker, was observed on F-fraction cells than on S fraction cells. Interfractional distinctions were confirmed also by immunologic assessment of hepatoma cells resistance to natural killer lyses: the sensitivity of S-fraction cells in primary culture was 2.4 times higher than F-fraction cells sensitivity, and, after long cultivation, F-fraction cells became practically resistant to cytotoxic action of natural killers. Based on the data obtained, the most probable paths of cell disdifferentiation during hepatoma Zajdela formation and during long cultivation of this tumor cells in vitro are discussed. PMID- 21268838 TI - [Detection and identification of the tumor-associated antigens in the fraction enriched with plasma membranes of the Zajdela hepatoma cells]. AB - Tumor-associated antigens 45, 57, 80 and 130 kDa were detected using tumor specific rabbit immune serum in the fraction enriched with plasma membrane of the rat Zajdela hepatoma cells and isolated on the immunosorbent. Revealed proteins were identified as integrin beta-1, ecto-nucleotide pyrophosphatase/phosphodiesterase-3 (E-NPP3), basigin, epithelial cell adhesion molecule (EpCAM), alpha-fetoprotein (AFP) and protein chaperones--glucose regulated protein 78 (GRP78) and protein disulfide-isomerase (PDI) A1 by mass spectrometry technique. Functions and characteristics of these proteins in tumor cells and some aspects of the Zajdela hepatoma cells origin are discussed. PMID- 21268839 TI - [The cultivation of cells on the porous titanium implants with the different structure]. AB - The data on human dermal fibroblasts and rabbit mesenchymal stromal cells cultivation on porous titanium implants are presented in given paper. Two types of implants were used: type 1--with irregular pores formed by pressed titanium particles and type 2--with regular pores formed by coalescence of one-size titanium particles into implant. The goal of this study was to choose the type of titanium implant porosity which ensures the tightest interaction of titanium implant with surrounding tissue cells after implantation in the body. Cells were cultivated on implants for 7 days and in both cases they formed confluent monolayer on the implants surfaces. That indicated adhesion, migration and proliferation of cells on such implants. Condition of cells cultured on titanium implants was controlled by scanning electron microscopy. The character of fibroblasts interaction with given implants was different depending on porosity type of implants. On implants with irregular pores, the cells were more spread and overlapped the pores spreading over neighbored particles. On implants with regular pores that formed by one-size particles into implant, the fibroblasts covered these particles not overlapping the pores and seldom interacted with neighbored particles by small outgrowths. There was no tight interaction of particles into implant. In implants formed by pressed particles, the cells grew not only on the surface but also in the depth of implant. Thereby, we suppose that more tight interaction of cells with titanium implant and, supposedly, tissues with implant in an organism will take place in the case of implant structure formed by pressed titanium particles. PMID- 21268840 TI - [Model in vivo to study the transdifferentiation of the somatic cell into urothelium]. AB - Development of reconstructive therapy of the urinary tract using pluripotent and somatic stem cells, for example mesenchymal stem cell (MSCs), recently goes through the stage of experimental studies. These studies include investigation of the main functions of MSCs and urothelium lining from inside the organs of the urinary tract. An important role in the regulation of proliferation and differentiation of urothelium belongs to EGF and Wnt-beta-catenin signaling pathways which activity may be accessed by the level of Her-4 and Tcf3,4, accordingly. We found here that MSCs labeled by transgenic green fluorescence protein (GFP) did not produce in vitro Her-4 and Tcf3,4 but activated their production after transfer into cryoinjured bladder of the syngenic mouse. After MSCs transplantation, GFP was detected in the bladder by RT-PCR and was colocalized with Her-4 or Tcf3,4 in a few urothelium cells detected by immunohistichemical staining with specific antibodies. These results suggest that MSCs labeled by GFP may be used as a good model to study transdifferentiation of somatic cells into urothelium. PMID- 21268841 TI - [Characteristic of tumors developed after transplantation of transgenic GFP positive C57BL/6 mice bone-marrow mesenchymal stem cells to mdx mice muscle]. AB - The purpose of the study was the morphological and histochemical characteristics of differentiation of tumors developed after transplantation of GFP-positive mesenchymal bone-marrow stem cells (MSC) of transgenic mice C57BL/6 into M. quadriceps femoris of mdx mice. The tumors occurred only after transplantation of MSCs of 43-45th passages and did not arise after transplantation of MSCs of the 15th passage. No tumors developed also after transplantation of MSCs of 43-45th passages into muscle of C57BL/6 mice. The average weight of tumors appeared in 4 mdx mice studied was 1.3 +/- 0.5 g. All four tumors were classified as mesenchymomas because they originated from mesenchymal stem cells. Most of the periphery of the tumors was classified as fibrosarcomas with mitotic index 0.9 +/ 0.1%. The central parts of tumors had areas with epithelial like morphology of cells. Such cells showed positive reactivity for alcyan blue staining at pH 2.5, which indicated chondrocyte nature of the cells. No mitosis was observed in epithelial like cells. In the tumors, there were also areas with bone trabeculae containing megacaryocytes and foci of myeloid and erythrocyte hematopoiesis. There were also areas with neuronal and glial cells, and accumulations of adipocytes. One of the tumors was classified as a round cells sarcoma. The observed types of tumor cell differentiation in vivo were in accordance with described in literature types of MSCs differentiation after induction in vitro with special inductors. The spectrum of in vivo differentiation of transgenic GFP positive MSCs after transplantation to mdx mice was broader than the spectrum of in vivo differentiation of transfected or transformed in vitro adult MSCs after transplantation to immunodeficient mice and mdx mice. PMID- 21268842 TI - [Variation of BM224 microsatellite in green frogs of the genus Rana]. AB - The variable microsatellite repeat BM224 has been discovered in the genomes of eight species of green frogs (Rana ridibunda, R. cf bedriagae, R. cretensis, R. esculenta, R. lessonae, R. shquiperica, R. saharica, R. nigromaculata). Earlier, this repeat had been observed in members of the genus Bufo. In this paper, a possibility of usage of this genetic marker for species identification is discussed. PMID- 21268843 TI - [Nuclear localization sequence of bovine gamma-interferon provides translocation of recombinant protein to yeast Pichia pastoris cell nucleus]. AB - It is known that heterologous protein production in microorganisms has negative influence upon a host cell. In this regard, of particular interest is to know the fate of recombinant proteins in a cell. In this study, it was shown that NLS of bovine gamma-interferon functions in yeast Pichia pastoris cells. The absence of the C-terminal NLS of bovine gamma-interferon leads to cytoplasmic localization of the recombinant protein. PMID- 21268844 TI - [Hyperthyreosis inhibits the ability of actin to form strong-binding with myosin]. AB - The effect of hyperthyreosis development induced by the increase in thyroid hormones in rats (during 2-4 weeks) on the orientation and mobility of fluorescent probe N-(iodoacetyl)-(1-naphtyl-5-sulpho-ethylenediamine) specifically bound to Cys 374 of actin in ghost muscle fibers isolated from fast (EDL) and slow (SOL) rat muscles was studied. It was found that the binding of myosin subfragment-1 (S1) to F-actin induced the typical for the formation of strong binding actomyosin decrease in mobility of actin subdomain 1 and its rotation towards thin filament periphery. Development of hyperthyreosis markedly inhibited these phenomena. The maximal effect was observed after 21 days of disease development. It is suggested that one of the reasons of the contractile deficit of muscle in hyperthyreosis is inhibition of the strong binding between actin and myosin during ATPase cycle. PMID- 21268845 TI - [Generation of dopamine neurons from human embryonic stem cells in vitro]. AB - The aim of the study was to generate dopaminergic (DA) neurons from human embryonic stem cells (ESC) in vitro. It was shown that human ESCs are able to differentiated into DA neurons without co-culture with stromal cells. Terminal differentiation into DA neurons was reached by successive application of noggin and bFGF growth factors on collagen and matrigel substrates during 3-4 weeks. Differentiation efficiency was evaluated by the number of colonies with cells expressing tyrosine hydroxylase (TH), a DA neuron marker, and by the number of TH positive cells in cell suspension using flow cytometry. No cells with pluripotent markers were detected in DA-differentiated cultures. It makes possible to propose that the protocol of human ESC differentiation might be applied to generate DA neurons for their transplantation into the animals modeling neurodegenerative (Parkinson) disease without the risk of tumor growth. PMID- 21268846 TI - [Cytogenetic characteristics of Stenochironomus gibbus (Fabricius, 1794) (Diptera, Chironomidae), an obligate miner of submerged wood]. AB - The karyotype of Stenochironomus gibbus F. (2n = 8) is described for the first time. Chromosomes: I(AB) > or = II(CD) > or = II(EF) > IV(G). Larvae of this species undermine submerged wood. Low degree of polyteny and poor development of active regions is characteristic of this species polytene chromosome structure, which is probably due to diminished function of salivary glands of the larvae that do not build web shelters. PMID- 21268847 TI - [Bjorn Ekwall and his contribution to modern cell toxicology]. AB - Dr. Bjorn Ekwall (1940-2000) was a prominent Swedish scientist--cell toxicologist, who made an outstanding contribution in the field of in vitro toxicology. In the early 80-ties Ekwall formulated so called basal cytotoxicity concept, which served as a basis for modern orientation in the field of cell toxicology: the use of tests on cells in culture for prediction of acute systemic toxicity in humans, instead of the use of tests on experimental animals. To be able to verify his theories, Ekwall organized and led the international toxicological project called MEIC: Multicentre Evaluation of In Vitro Cytotoxicity Programme (1989-1999). In this project, 50 selected chemicals were tested in 100 laboratories worldwide with more than 60 different in vitro tests (laboratories have chosen tests themselves). MEIC project was unique not only because its large scale, but, in particular, because, for the first time, the human peak blood concentrations after acute poisoning with chemicals were used as references, aiming to check predictability of the in vitro assays. The results of the MEIC project have clearly demonstrated a possibility to use in vitro tests for prediction of toxicity of chemicals in humans. PMID- 21268848 TI - [Heat shock proteins 90 kDa: diversity, structure, functions]. AB - The review presents data on diversity, structure, functions and gene expression of the high conserved family of heat shock proteins 90 kDa (Hsp90). They are specialized molecular chaperones that fulfill the folding, maintenance of structural integrity and conformational regulation of a subset of proteins involved in important cellular processes, such as transduction of signals, cell cycle control etc. A composition and functioning of the Hsp90 chaperone machine are considered. Hsp90s play a significant role in growth and development of organisms carrying out conformational regulation of many regulatory proteins and protecting cells under stress. The review summarizes the results of investigations of different organisms, mainly animals and yeasts, with emphasis on the facts on Hsp90s in plants. PMID- 21268849 TI - [Possible ways of MSCs influence on the ischemic tissue in the case of cardiovascular diseases]. AB - Mesenchymal stem cells (MSCs) therapy is a modern and promising approach to the treatment of cardiovascular diseases. The background of MSCs therapeutic usage was their ability to differentiate into cardiomyocytes and neuronal lineage cells. It has been experimentally proven that MSCs transplantation accelerates inflammation in the ischemic region, activates angiogenesis, prevents apoptosis and acts as a protective agent in the areas adjacent to infarction. This reduces the size of the scar and the volume of damaged tissue, restores the functioning of the injured organ, and returns the standard rates of behavioral and neurological reactions of the experimental animals. PMID- 21268850 TI - [Stem cells and cell therapy: on the eve of scientific approach]. AB - Cell therapy and the stem cells (SC) have become a popular topic during last time. The theme is cluttered with numerous publications of questionable reliability. Not all methods applied in praxis are founded on evidence-based research. In the abundant literature, there is a gap between the supposed SC's healing properties associated with their capability to migrate to and engraft in injured tissue, and lack of clear morphological evidence thereof. Accordingly, there is a gap between advertizing and the better part of professional literature: the former speaks about rejuvenation of tissues, and the latter explains sometimes questionable therapeutic effects by paracrine or immunomodulating mechanisms, secretion of cytokines and growth factors. However, a SC is an undifferentiated cell, and a specific and efficient paracrine function can hardly be awaited from it as compared to others, more differentiated cells. It should be noted in conclusion that the main problem with the SC and cell therapy is commercial influence. Probably, experience of some foreign countries should be studied, where moves have been made to stop the use of unproven treatments, including some stem cell therapy. PMID- 21268851 TI - [Left ventricular heart aneurism--a new source of resident cardiac stem cells]. AB - In the past few years it has been established that the heart contains a reservoir of stem and progenitor cells that have the ability to differentiate in vitro and in vivo toward vascular and cardiac lineages and that show cardiac regeneration potential in vivo following injection into the infracted myocardium. The aim of the present study was to characterize cardiac stem cells in the tissue of chronic left ventricular aneurism. It was shown that human c-kit positive cells were scattered in fibrous, muscle and adipose parts of aneurism tissue. C-kit positive cells localized mainly in fibrous tissue nearby large vessels, however, c-kit positive cells did not express endothelial, smooth muscle or cardiomyocyte cell markers. Co-localization experiments demonstrated that all c-kit positive cells were of non-hematopoietic origin, since they did not express markers such as CD34 and CD45. Majority of c-kit positive cells expressed MDR1, but showed no proliferation activity (Ki67). It thus appears that aneurism tissue could be an alternative source of autologous cardiac stem cells. However, their regeneration capacity should be further explored. PMID- 21268852 TI - [Chaotization of division spindle, phragmoplast, and telophase chromosome groups in wheat x wheatgrass F1 hybrids meiosis]. AB - The paper describes the phenomenon of disorganization of completely formed subcellular structures: division spindle, phragmoplast and chromosome telophase groups. These structures disintegrate into their elements (cytoskeletal fibers, chromosomes) that transform into chaotic system. Chaotization of cytoskeleton structures such as prophase spindle in mitosis or perinuclear ring in meiosis is a normal step of wild type plant cell division. Disintegration of division spindle and phragmoplast presumably indicate the abnormality of temporal regulation of cytoskeleton cycle during meiosis. Disintegration of telophase chromosome groups and the migration of the chromosomes backward to the equatorial area might mean the abnormal start of some prometaphase mechanisms, in particular, chromokinesins activation. PMID- 21268853 TI - [Oligomeric forms, functions and cellular localization of alpha-crystallin type protein from Acholeplasma laidlawii]. AB - Alpha-Crystallin type heat shock protein (alpha-HSP) IbpA from Acholeplasma laidlawii was expressed in Escherichia coil and isolated from cell extract on Ni sepharose column. Recombinant IbpA, like other alpha-HSPs, spontaneously formed oligomeres in vitro. High resolution electron microscopy revealed regular structures with 15 nm in diameter. Evaluation of molecular mass of IbpA oligomers was performed by gel filtration. Most of oligomers consist of 24 subunits. Recombinant IbpA prevents heat denaturation of soluble proteins in cell extract of E. coli and displays a mild positive effect on thermotolerance of E. coli cells during severe heat shock. We investigated a localization of IbpA in A. laidlawii cell by immunocytochemistry. We suppose that IbpA may protect various intracellular structures from damage during heat shock. PMID- 21268854 TI - [Interaction between non-histone chromatin protein HMGB1 and linker histone H1]. AB - The fundamental possibility of interaction between non-histone chromatin protein HMGB1 and linker histone H1 was studied in the solutions with different ionic strength by intrinsic UV-fluorescence, far and near-UV CD and spectrophotometry. The obtained data allow us to assume that the increase of histone H1 content in the HMGB1 solutions in a low ionic strength is accompanied by the destruction of HMGB1 associates. The interaction between proteins of HMGB1 and H1 causes the increase in the number of ordered regions in the protein molecules and the minor changes in their tertiary structure. PMID- 21268855 TI - [Stability of sugar-binding proteins: D-galactose/D-glucose-binding protein from Escherichia coli and trehalose/maltose-binding protein from Thermococcus litoralis]. AB - In this work we studied the structure and stability of sugar-binding proteins from mesophilic and thermophilic organisms which are of great importance for their possible use as sensing probe of biosensors aimed to glucose detection in the blood. The data obtained revealed the stabilizing effect of ligands on the structures of D-galactose/D-glucose-binding protein (GGBP) from Escherichia coli and trehalose/maltose-binding protein from thermophilic bacterium Thermococcus litoralis. It was found that TMBP possess an increased stability as its structure remains native even under heating up to 95 degrees C. PMID- 21268856 TI - [Thioflavin T interaction with amyloid fibrils as an instrument for their studying]. AB - Benzthiazole dye thioflavin T (ThT) is widely used to study the formation and structure of amyloid fibrils. Nevertheless, till now there is no common opinion concerning molecular mechanisms of ThT binding to amyloid fibrils and the reasons of dramatic increase in its fluorescence quantum yield on incorporation into amyloid fibrils. Our data prove that ThT molecules incorporate in the amyloid fibrils in the monomeric form and there is no ground to suppose the formation of ThT dimers, eximers, or micells. It was shown that the increase in the quantum yield of ThT incorporated in amyloid fibrils was caused by restriction of benzthiazole and aminobenzene rings torsion fluctuations relative to each other. The use of equilibrium microdialysis allowed determining the absorption spectrum, the number of binding modes of ThT with insulin amyloid fibrils and for each mode determining the binding constants and the number of binding sites for each mode. PMID- 21268857 TI - [Characteristics of rat ceruloplasmin from the serum of animals, which received salts of silver with food]. AB - Abiogenic Ag(I) ions have electronic structure, similar to Cu(I) ions and can compete with Cu(I) for binding sites of proteins which transport copper from extracellular media to sites of cuproenzyme formation in the cell. Rodents receiving Ag-salts with food develop extracellular deficiency of copper associated with ceruloplasmin (Cp, the major copper-transporting protein in blood serum of vertebrates). The present work focuses on the studies of biochemical and physicochemical properties of Cp, obtained from blood serum of rats, which received AgCl with food for 4 weeks (Ag-rats). Cp-fractions from blood serum of Ag-rats (Ag-Cp) were obtained by ion-exchange chromatography with stepped gradient of NaCl. Each fraction was tested for oxidase and ferroxidase activities by direct measurement of catalytic activity in the gel, and for specific activity in holo-Cp in oxidation of chromogenic substrate. Molecular mass, electrophoretic mobility and ratio of apo- and holo-forms in Ag-Cp fractions were evaluated by immunoblotting. Ag-Cp samples did not contain products of spontaneous partial proteolytic degradation, characteristic of holo-Cp samples. Fractions of Ag-Cp and holo-Cp (from blood serum of control rats) were compared by optical spectra, tertiary structure, susceptibility to thermal denaturation, and by atomic Cu and Ag content. Ag-Cp contained 1-2% Cp, which is similar by spectral and catalytic properties with holo-Cp. [Ag]:[Cu] ration in Ag-Cp samples was about 4:1. As evidenced by circular dichroism and differential scanning calorimetric studies, the major apo-fraction of Ag-Cp lacked tertiary structure of native Cp and was significantly misfolded, which might explain its resistance to spontaneous partial proteolytic degradation. PMID- 21268858 TI - [Functional characteristics of calcium-sensitive adenylyl cyclase of ciliate Tetrahymena pyriformis]. AB - Calcium-sensitive forms of adenylyl cyclase (AC) were revealed in most vertebrates and invertebrates and also in some unicellular organisms, in particular ciliates. We have shown for the first time that calcium cations influence the AC activity of ciliate Tetrahymena pyriformis. These cations at the concentrations of 0.2-20 microM stimulated the enzyme activity, and maximum of catalytic effect was observed at 2 microM Ca2+. Calcium cations at a concentrations of 100 microM or higher inhibited the AC activity. Calmodulin antagonists W-5 and W-7 at the concentrations of 20-100 microM inhibited the catalytic effect induced by 5 microM Ca2+ and blocked the effect at higher concentrations of Ca2+. Chloropromazine, another calmodulin antagonist, reduced Ca2+-stimulated AC activity only at the concentrations of 200-1000 microM. AC stimulating effects of serotonin, EGF and cAMP increased in the presence of 5 microM Ca2+. AC stimulating effects of EGF, cAMP and insulin decreased in the presence of 100 microM Ca2+, and AC stimulating effect of cAMP decreased also in the presence of calmodulin antagonists (1 mM). At the same time, stimulating effect of D-glucose in the presence of Ca2+ and calmodulin antagonists did not change essentially. The data obtained speak in favor of the presence of calcium sensitive forms of AC in ciliate T. pyriformis which mediate enzyme stimulation by EGF, cAMP, insulin, and serotonin. PMID- 21268859 TI - [Analyzing spatial-temporal dynamics of the ecological niche: a marten (Martes martes) population case study]. AB - A potential of discriminant analysis is demonstrated in a case study of the common marten (Martes martes L., 1758) ecological niche within the Central Forest Reserve and its buffer zone. The analysis is aimed at identifying how the probability to encounter a marten's footprint along a walking route depends on the relief and other parameters of the environment discerned by remote sensing. The analyses that were done individually for each of the eleven months from a three-year observation period have revealed the pattern of the species spatial distribution and a measure of its association with the environment to be dependent, to a large extent, on the weather conditions. In general, associations with the environment do increase under unfavorable conditions. The methods are suggested that integrate outcomes of the monthly analyses into a general map of habitat types. The technique presented has wide application opportunities in studying the ecology of populations and solving problems of practical ecology. PMID- 21268860 TI - [Charles Darwin and the problem of evolutionary progress]. AB - According to Ch. Darwin's evolutionary theory, evolutionary progress (interpreted as morpho-physiological progress or arogenesis in recent terminology) is one of logical results of natural selection. At the same time, natural selection does not hold any factors especially promoting evolutionary progress. Darwin emphasized that the pattern of evolutionary changes depends on organism nature more than on the pattern of environment changes. Arogenesis specificity is determined by organization of rigorous biological systems - integral organisms. Onward progressive development is determined by fundamental features of living organisms: metabolism and homeostasis. The concept of social Darwinism differs fundamentally from Darwin's ideas about the most important role of social instincts in progress of mankind. Competition and selection play secondary role in socio-cultural progress of human society. PMID- 21268861 TI - [Application of the group theory to description of biological objects pseudosymmetry]. AB - The application of the group theory to description of biological objects pseudosymmetry is introduced and substantiated by the example of rotatory symmetry of actinomorphic and zygomorphic flowers. Problems of biosymmetrics terminology are considered; point symmetry elements are characterized as being applied to description of flower symmetry; central constructs of the group theory are stated. Application of the Curie principle to biological objects is outlined. Algorithms for quantitative assessment of flower pseudosymmetry are given; the description is made of flower pseudosymmetry in the terms of the group theory, including evolutionary aspect. The conclusion is made that adaptation of the group theory to description of biological objects symmetry (biosymmetrics) is important not only in fundamental respect but also as a tool of inter disciplinary mutual understanding between biologists, physicists, crystallographers and other specialists whose communicative language is mathematics. PMID- 21268862 TI - [Morphoprocess and life cycles of organisms]. AB - In developing the ideas of V.N. Beklemishev about an organism as a form, existing in a process of determined transformation and matter/energy exchange, we consider different aspects of the term "morphoprocess" and introduce corresponding additional terms. Momentary morphoprocess characterizes an organism in the given moment of time. This term reflects a constancy of the form ("momentary form"), where the existence of an organism can be imagined as a sequence of "momentary forms". "First derivative" of this momentary characteristic is particular morphoprocess--an organism from its origin to fission/division or death. Compound particular morphoprocess is a determined and reiterating sequence of different particular morphoprocesses. And, at last, general morphoprocess--a "second derivative" of momentary morphoprocess--is rhythmical reiteration of a particular morphoprocess on the long-term scale, an ancestors/descendants lineage. To describe consecutive changes in this material system, the terms ontogenesis and life cycle are used. Ontogenesis characterizes a sequence of the morpho functional changes of an individual organism during its life, whereas life cycle reflects a sequence of changes during one complete segment of the general morphoprocess represented by a single or several particular morphoprocesses. We also discuss morphoprocess uniformity along with the phase nature of morphoprocesses, both particular and compound particular ones. PMID- 21268863 TI - [Dynamics of body mass and oxygen consumption in the Iberian ribbed newt Pleurodeles waltl ontogenesis: 1. Endotrophic development]. AB - The correlation between parameters of growth and energy metabolism in the example of embryonic and larval development of the Iberian ribbed newt Pleurodeles waltl has been studied. The wet body mass increases five times during this period due to water absorption by developing tissues and the yolk, and the dry mass decreases 1.18 times. The highest specific growth rate of developing tissues was noticed at the 33rd stage of embryogenesis (13th-14th day of development). These indexes decreased after the hatching, but increased after larvae switched to external nutrition. Comparison of the studied parameters has identified a similar features in alteration of the specific growth rate, intensity of oxygen consumption, and watering of developing tissues in early development of the Iberian ribbed newt. PMID- 21268864 TI - [Distribution of picocyanobacteria and virioplankton in mesotrophic and eutrophic reservoirs: the role of viruses in mortality of picocyanobacteria]. AB - The quantitative distribution and relationships of picocyanobacteria and viruses were studied in the mesotrophic Sheksna and mesoeutrophic Rybinsk reservoirs belonging to the system of the Volga-Baltic Waterway. The share of picocyanobacteria in the sum biomass and production of phytoplankton decreased along with increase in the productivity in the waterbody. However, the abundance of virioplankton increased in such conditions. The extent of infection by phages and virus-induced mortality of picocyanobacteria were two times higher on average in the mesoeutrophic reservoir compared to the mesotrophic one: 14 and 7% of the number of picocyanobacteria, 21 and 11% of daily production of picocyanobacteria, respectively. Mortality in picocyanobacteria resulted from lysis by viruses increased (up to 52% of daily production of picocyanobacteria) at the local parts where water was blooming with phytoplankton and at the parts affected by communal pollution. PMID- 21268865 TI - [Larch chromosomal mosaicism]. AB - Karyological study of larch population members from different parts of the Larix olgensis L. Henry areal in the Primorskii krai has been carried out. The main amount of chromosomes for larch as n = 12 (2n = 24) has been confirmed. Mixoploidy was observed in all studied populations. The difference of individuals from the larch areal based on the cell amount with a different level of ploidity has been found in the population of L. olgensis locus classicus and both L. sibirica and L. gmelinii, which is probably a consequence of their hybrid nature. PMID- 21268866 TI - [The relationship between cytokines and the amount of nitrogen in the wintering organs of herbaceous plants]. AB - The dynamics of cytokine content and the total protein and nonprotein forms of nitrogen in tissues of wintering organs of clary sage Salvia sclarea L. and cinquefoil Potentilla alba L. in abnormally cold (2005-2006 years) and abnormally warm (2006-2007 years) winters in Moscow have been studied. A direct correlation between the content of total cytokines and the total and protein nitrogen forms in tissues of wintering leaves and buds has been determined. A correlation link between the level of single cytokines and the protein nitrogen forms has been found. PMID- 21268867 TI - [Structure of the mushroom bodies in Scarabaeoidea (Coleoptera): II. Phytophagous Scarabaeidae and general discussion]. AB - The mushroom body structure is progressively more complicated within the superfamily Scarabaeoidea. In the basal families and coprophagous Scarabaeidae, the calyx region is asymmetrical and poorly developed but reaches the maximal degree of development in the phytophagous Scarabaeidae of the subfamilies Melolonthinae and Cetoniinae. These Scarabaeidae have two separate calyces; moreover, some species have additional regions of glomerular neuropile. The processes of different Kenyon cell types segregate into special subdivisions of vertical and medial lobes. It is assumed that a progressive development of the mushroom body in phytophagous Scarabaeidae is associated with the need to integrate olfactory and visual information. PMID- 21268868 TI - [Activity dynamics of proteinases and glycosidases of fish chymus with exposure in fresh and brackish water]. AB - Activity of proteinases of the content of intestines (chymus) of the benthos eater Carassius carassius fed different diets during prolonged exposure to water is studied. In the process of exposure of the chymus to water, the activity of proteinases decreases. Activity of glycosidases may increase, maximally during the first three days of exposure. This phenomenon suggests the important role of enzymes of the enteral microflora in processes of destruction of proteinaceous and carbohydrate components of the suspension and especially of organic detritus. PMID- 21268869 TI - [The effect of volatile antioxidants of plant origin on leukemogenesis in mice]. AB - The effect of savory essential oil added with drinking water (150 ng/ml) or with feed (2.5 microg/g) on the lifetime of AKR mice and the parameters of oxidative stress in animal blood were investigated. It was found for the first time that long-term administration of an essential oil in low doses increased the average lifetime of mice by 20-35% and was accompanied by a decrease in the hemolysis level and the content of lipid peroxidation products in erythrocytes of mice, as well as alteration in the structural state of their membranes and stabilization of polyunsaturated fatty acids level in mice liver cells. PMID- 21268870 TI - [Global climate change and carbon balance in forest ecosystems of boreal zones: imitating modeling as a forecast tool]. AB - The individually oriented system of the EFIMOD models simulating carbon and nitrogen flows in forest ecosystems has been used for forecasting the response of forest ecosystems to various forest exploitation regimes with climate change. As input data the forest management materials for the Manturovskii forestry of the Kostroma region were used. It has been shown that increase of mid-annual temperatures and rainfall influence the redistribution of carbon and nitrogen supply in organic form: supply increase of these elements in phytomass simultaneously with depletion of them in soil occurred. The most carbon and nitrogen accumulation in forest ecosystems occurs in the scenario without felling. In addition, in this scenario only the ecosystems of the modeling territory function as a carbon drain; in the other two scenarios (with selective and total felling) they function as a source of carbon. Climate changes greatly influence the decomposition rate of organic matter in soil, which leads to increased emission of carbonic acid. The second consequence of the increase in the destruction rate is nitrogen increase in the soil in a form available for plants that entails production increase of plantations. PMID- 21268871 TI - [Baikal whitefish Coregonus baicalensis Dybowski, 1874 parasite communities and host age]. AB - Data on the taxonomic diversity of Baikal whitefish parasites are summarized in the study. Significant correlations of some parasite species' relative abundance and parasite communities' (infracommunities and component communities) parameters with host age were found during the study of parasite distribution in the host's age groups in the Baikal whitefish population from Chivyrkui Bay of Lake Baikal. Study of morphobiological and genetic features which have arisen due to long-term geographic isolation allowed confirming the initial specific independence of lake whitefishes of Lake Baikal as Coregonus baicalensis Dybowski, 1874, i.e., the Baikal whitefish (Sukhanova et al., 2000). The main habitats of this Baikal endemic are Barguzin and Chivyrkui bays, Selenga shallow, and Little Sea strait (Pronin et al., 2007). Local populations from these habitats were previously considered to be independent stocks (Krogius, 1933). PMID- 21268872 TI - [Inhibitory effect of kappa/beta-carrageenan from red alga Tichocarpus crinitus on the development of a potato virus X infection in leaves of Datura stramonium L]. AB - The effect of kappa/beta-carrageenan from red alda Tichocarpus crinitus on the development of a potato virus X (PVX) infection in the leaves of Datura stramonium L. has been studied. The treatment of leaves with carrageenan stimulates a protein synthesis in the cells, causing an increase in the size of nucleoli and in the number of mitochondria and membranes of the granular endoplasmic reticulum. At the same time, such treatment slightly stimulates lytic processes, causing an increase in the number of agranular endoplasmic reticulum cisterns, dictyosomes, and cytoplasmic vacuoles and the formation of cytoplasmic zones, transparent to electron microscopy. The carrageenan-induced stimulation of lytic processes results in the destruction of viral particles and can be considered as one of the defense mechanisms, preventing the intracellular accumulation of viruses. The carrageenan-stimulated formation of PVX-specific laminar structures, able to bind viral particles and, therefore, prevent their intracellular translocation and reproduction, represents another carrageenan induced mechanism of the antiviral defense in plant cells. PMID- 21268873 TI - [Seasonal changes of steroid levels in blood plasma of three Phodopus species (Mammalia, Cricetinae)]. AB - Seasonal change of the base plasma level of testosterone and cortisol in males and progesterone, estradiol, and cortisol levels in females were analyzed in three Phodopus species: Ph. campbelli (Campbell's dwarf hamster), Ph. sungorus (Russian dwarf hamster), and Ph. roborovskii (Roborovski's dwarf hamster). Our results showed a significant difference in the seasonal plasma level of testosterone and cortisol in males and cortisol in females of all Phodopus species, though the rhythms of breeding activity were similar. The results are discussed in the context of adaptive differences between hormonal patterns of evolutionarily young species (Campbell's dwarf hamster and Russian dwarf hamster) and the evolutionarily old Roborovski's dwarf hamster, the phylogenic position of which is currently under discussion. PMID- 21268874 TI - [The history of development of evolutionary methods in St. Petersburg school of computer simulation in biology]. AB - The history of rise and development of evolutionary methods in Saint Petersburg school of biological modelling is traced and analyzed. Some pioneering works in simulation of ecological and evolutionary processes, performed in St.-Petersburg school became an exemplary ones for many followers in Russia and abroad. The individual-based approach became the crucial point in the history of the school as an adequate instrument for construction of models of biological evolution. This approach is natural for simulation of the evolution of life-history parameters and adaptive processes in populations and communities. In some cases simulated evolutionary process was used for solving a reverse problem, i. e., for estimation of uncertain life-history parameters of population. Evolutionary computations is one more aspect of this approach application in great many fields. The problems and vistas of ecological and evolutionary modelling in general are discussed. PMID- 21268875 TI - [History of some model]. AB - This paper refers us to the mid-1960s, when mechanisms of the animal rhythmic activity were vividly discussed and the concept of "generator of rhythm" was formulated. Since at than time the device of the generator of rhythm was understood very poorly, V. Menshutkin, V. Svidersky, and A. Umnov, by the example of an insect (locust), attempted to develop the first mathematical model generating rhythm of the flight. Why the interest in such model arose, how it was created, and what the result of it was has been described in this paper. PMID- 21268876 TI - [The model of development of science by the example of limnology]. AB - Limnology--the science about lakes is the young and relatively closed area of studies; its existence is owing to several hundreds of scientists. The International Society of Limnologists holds its meetings since 1922. We used materials of these meetings to find out the main stages of development of this science; among these stages there were both fast and relatively calm periods. Based on analysis of these data, we constructed a model of development of the science, the same data being used for tuning and verification of the model. We have suggested that the main regularities and of development of limnology can be extrapolated to other sciences. The main "acting person" in the model is population of scientists. Each scientist, with some probability, can propose new ideas as well as use in his elaborations some particular complex of the already accumulated knowledge and ideas. The model also takes into consideration how the scientific information is spreading, specifically some individual peculiarities of model scientists, such as age, experience, communicability. After the model parameters had been chosen in such a way that is described adequately the development of limnology, we performed a series of experiments by changing some of the characteristics and obtained rather unexpected results published preliminary in the short work (Levchenko V. F and Menshutkin V. V. Int. J. Comp. Anticip. Syst., 2008, vol. 22, p. 63-75) and discussed here in the greater detail. It is revealed, that the development of science is passing irregularly and sharply decelerated at low level of scientists communication and absence of scientific schools, and that the age of "scientific youth" of scientist begins usually only after 40 years. PMID- 21268877 TI - [Insect cholinesterases and irreversible inhibitors. Statistical treatment of the data]. AB - The data on sensitivity of cholinesterases (ChE) of different insects to reversible inhibitors, as well as the data on physico-chemical parameters of amino acids constituting their active centers, were treated by factor analysis and juxtaposed. It is shown that both these characteristics are related to taxonomical belonging of insects. It is revealed the "material substrate" of the factors determining inhibitor action specificity, which are specific sites in ChE active center. PMID- 21268878 TI - [How the various substrates activate the process of enzymatic hydrolysis by different cholinesterases]. AB - Kinetic analysis of the activating effect of substrate on the cholinesterase catalysis is performed. There are determined values of coefficient of activation A in the pH zone 5.0-7.5 for the process of hydrolysis of acetylcholine, indophenylacetate (IPA), and 2,6-dichlorophenolindophenylacetate (DIPA) by cholinesterase (ChE) of horse blood serum, as well as of IPA and DIPA by ChE of optical ganglia of the Pacific squid Todarodes pacificus. The phenomenon of activation has not been revealed at hydrolysis of phenylacetate by the horse blood serum ChE. The conclusion is made that the cause of the activating effect of substrate on the process of enzymatic hydrolysis by ChEs of different origin is the presence of the onium grouping in the structure of substrates. PMID- 21268879 TI - [Calcium-dependent proteinases of some invertebrates and fishes]. AB - In comparative-evolutionary aspect, the experimental data are considered about activity, biochemical properties, and peculiarities of structural organization of proteins of the calpain family in some invertebrates and fishes. Peculiarities of calpain-like proteins of invertebrates--the predecessors of calpains of higher animals are revealed. By the example of the studied taxons, there is traced complication of the structural organization and mechanisms of control of the calpain activities, which reflects stages of molecular evolution of the protein family. PMID- 21268880 TI - [Principles of organization and evolution of systems of regulation of functions]. AB - Evolution of living organisms is closely connected with evolution of structure of the system of regulations and its mechanisms. The functional ground of regulations is chemical signalization. As early as in unicellular organisms there is a set of signal mechanisms providing their life activity and orientation in space and time. Subsequent evolution of ways of chemical signalization followed the way of development of ways of delivery of chemical signal and development of mechanisms of its regulation. The mechanisms of chemical regulation of the signal interaction is discussed by the example of the specialized system of transduction of signal from neuron to neuron, of effect of hormone on the epithelial cell and modulation of this effect. These mechanisms are considered as the most important ways of the fine and precise adaptation of chemical signalization underlying functioning of physiological systems and organs of the living organism. PMID- 21268881 TI - [Longevity of animals in units of intrinsic time]. AB - We propose two different approaches to defining variable units of intrinsic time (physiological time units in a strict sense, or PTU). For continuously growing animals, we suggest the use of specific mass growth rates; and for animals that cease to grow at some point, we recommend specific metabolic rates. Longevity of animals in terms of PTU is equal to the total specific rate (per lifetime) of the respective processes. A method is proposed to describe age-related changes in respect of specific metabolic rates of non-growing constant-mass adult birds. Maximum intrinsic longevity values have been estimated for certain fish species (continuously growing animals), and birds (that cease growth). Estimates of the maximum PTU longevity across both passerine and non-passerine groups differ slightly and are actually estimates of the Rubner constant for birds. PMID- 21268882 TI - [Modeling of processes of specialization and integration as a basis for development of multicellularity]. AB - The formalized description of the procedure of division of labor as the most important invariant of progressing development is presented. The concept of histion is introduced--the element of the elementary unit that arises as a result of such division and represents the so far overlooked independent level of biological organization. Based on the division of labor there is proposed the theory of progressing development, which allows calculating the composition and structure of multitude of histions and constructing their model. It has been shown that development of these units obeys the periodic law and their classification looks like the periodic table whose parameters have biological meaning and are useful for measuring progressing development. The obtained results constitute the basis for the nomogenetic theory of the progressing development of multicellular organisms. PMID- 21268883 TI - [Components of the pigeon tectothalamic visual pathway, revealed with aid of study of cytochrome oxidase and immunoreactivity to calcium-binding proteins]. AB - Distribution of activity of cytochrome oxidase (CO) and immunoreactivity to parvalbumin (Pv) and calbindin (Cb) was studied in the optic tectum of the pigeon (Columba livia). In the first link of the tectofugal pathway in the central gray layer (SGC = layer 13), small amounts of the CO-active and Pv-immunoreactive (Pv ir) cellular bodies were revealed in its internal part (sublayer 13b). Some of these neurons located along the SGC lower boundary had long dendritic processes ascending into the superficial tectum layer (SGF). In the retinorecipient SGF sublayers and particularly in neuropil of the sublayers 4 and 7, the high CO activity correlating with Pv-immunoreactivity was found. It is suggested that a great contribution to metabolic activity of these sublayers is made by the largely branching dendritic processes of Pv-ir neurons of sublayer 13b. The projectional neurons SGC located in its external part (sublayer 13a) were CO inactive and contained Cb. They sent long dendrites into sublayer 5b; in its neuropil, the high density of Cb-immunoreactivity and a moderate CO activity were detected. Thus, the tectal link of the pigeon tectofugal visual channel consists of two components--the Pv-specific, highly metabolically active and the Cb specific, metabolically less active ones that transduce visual information from different retinorecipient SGF sublayers. The absence of the significant amount of CO-positive bodies of projectional neurons in SGC can be due to that metabolically more active are their dendritic arborizations in the SGF sublayers. PMID- 21268884 TI - [Levels of organization of living systems: cooperons]. AB - All creatures living on Earth are traditionally being considered in the context of structural-morphological approach, in frame of which there are considered various living systems (for instance, organisms and ecosystems) that have different sizes and organization and use different resources for their existence. These characteristics are sometimes added by some particular functional and ecological characteristics, but usually with respect to the structural ones. We believe that such traditional approach, although illustrating, but distracts from the circumstance that any living system is to be considered an integrated structural-functional complex, the maintenance of existence of this system being impossible without the processes occurring constantly in it and aimed at preserving this complex. This leads us to the concept of cooperons--the self preserved dynamic structures existing only as a result of various specifically organized cooperative processes (their intensities can vary depending on circumstances). From our point of view, all living systems are cooperons of different hierarchy levels. Some other systems, specifically the symbiotic ones, also are cooperons. In frame of this concept, it is possible to discuss functioning of living systems of different types of organization in a new context closer to physiologists, both for the case of "norm" and for the situation when the cooperative interrelations of parts of the system are impaired (for instance, in systemic diseases). PMID- 21268885 TI - [Application of rhizobia-legume symbiosis for remediation of heavy-metal contaminated soils]. AB - Heavy-metal pollution in soil is a major threat to human health and the entire ecosystem. Legumes and their associated rhizobial microorganisms are important for the biogeochemical cycles in agriculture and natural ecosystems. Legume rhizobia symbiosis is very important in restoration of heavy-metal contaminated soils because the fixation of atmospheric nitrogen by legume-rhizobium symbiosis can increase the accumulation of nitrogen and organic matter. We reviewed the importance of remediation of heavy-metal contamination in soil and the current situation of remediation techniques, analysed the advantages and disadvantages of each remedial techniques. We address especially the superiority, recent advances and potential application of the legume-rhizobium symbiosis in remediation of heavy-metal contaminated soils. PMID- 21268886 TI - [Transcriptional regulation of cellulases and hemicellulases gene in Hypocrea jecorina--a review]. AB - Hypocrea jecorina (anamorph: Trichoderma reesei) is the main industrial fungi that can produce large amounts of extracellular cellulases and hemicellulases. It also represents a model system to study the mechanism of transcriptional regulation in eukaryotes. The expression of these hydrolases genes in Hypocrea jecorina can be triggered rapidly in the presence of inducers, but differences in the inducing mode of various soluble inducers have been reported. At present, three models have been offered to explain the question of "how an insoluble inducer such as cellulose would initiate the transcription of cellulases?" Moreover, interactions between the identified positive (Xyr1, Ace2, Hap2/3/5) and negative transcriptional regulators (Ace1, Cre1), as well as the interactions between these proteins and the promoters of cellelase and hemicellulase genes have also been primarily characterized. This review focuses on the key factors and the current understanding on the regulation of expression of cellulase and hemicellulase genes in Hypocrea jecorina. PMID- 21268887 TI - [Advance in fungal diterpene cyclase--a review]. AB - Diterpenoid is a huge group of nature products isolated from plants and fungi. Diterpene cyclase, which is responsible for the diterpene carbon skeleton formation from geranylgeranyl diphosphate (GGPP), is a key enzyme in the biosynthetic pathway of diterpene. The specificity of diterpene cyclase in different species results in structural diversity and bioactivity variety of diterpenoid. Isolation and characterization of the diterpene cyclase in various species will facilitate studies on the biosynthesis and regulation of diterpenoid in future. Compared to plant diterpenoids, few fungal diterpenoid and diterpene cyclase were studied. This article reviews the research advancement of fungal diterpene cyclase in recent years, especially describes the biosynthesis pathway of diterpenoid, the characteristics and cloning strategies of fungal diterpene cyclase, and the metabolic engineering of diterpenoid. PMID- 21268888 TI - [Type three secretion system and pathogenesis of Shigella spp.--a review]. AB - The powerful weapon of Shigella spp. is Type Three Secretion System, which remains the focus of pathogenic research. The regulation and function of Type Three Secretion System of Shigella spp. are summarized in this review. PMID- 21268889 TI - [Diversity of halophilic and halotolerant bacteria isolated from non-saline soil collected from Xiaoxi National Natural Reserve, Hunan Province]. AB - OBJECTIVE: To investigate the diversity of cultivable halophilic and halotolerant bacteria isolated from ordinary non-saline soil samples collected from Xiaoxi National Natural Reserve (28 degrees 42' 15"-28 degrees 53' 15" N, 110 degrees 6' 50"-110 degrees 21' 35" E), Hunan Province, China. METHODS: Bacterial strains were isolated from the samples by using the conventional culture-dependent method and investigated by using phylogenetic analysis based on 16S rRNA gene sequence comparisons. RESULTS: We isolated 114 bacterial strains (8 moderately halophilic, 19 slightly halophilic, 87 halotolerant) from the samples on media (marine agar 2216, International Streptomyces Project medium 2 and 5, nutrient and humic acid agars) supplemented with 5% to 20% (w/v) NaCl. On the basis of morphological, physiological and biochemical characteristics, we selected 61 strains to perform a phylogenetic analysis based on 16S rRNA gene sequences. Results showed that 61 isolates represented 41 species, belonging to 18 genera (Actinomadura, Arthrobacter, Bacillus, Brachybacterium, Brevibacterium, Erwinia, Halobacillus, Jeotgalibacillus, Microbacterium, Microbulbifer, Nocardia, Pseudomonas, Rheinheimera, Rhodococcus, Sphingomonas, Staphylococcus, Streptomyces, Yaniella) of 16 families ( Alteromonadaceae, Bacillaceae, Brevibacteriaceae, Chromatiaceae, Dermabacteraceae, Enterobacteriaceae, Microbacteriaceae, Micrococcaceae, Nocardiaceae, Planococcaceae, Pseudomonadaceae, Sphingomonadaceae, Staphylococcaceae, Streptomycetaceae, Thermomonosporaceae, Yaniellaceae) in three phyla (Actinobacteria, Firmicutes, Proteobacteria). The most abundant and diverse isolates were within the phylum Firmicutes (38 strains; 62.3%) and the phylum Actinobacteria (18 strains; 29.5%). The phylogenetic distance matrix results suggested that there were obvious genetic divergences between most isolates and their closestly related type strains (16S rRNA gene sequence similarities ranged from 96.9% to 99.8%), and that, out of 61 isolates, at least 7 strains (JSM 070026, JSM 081004, JSM 081006, JSM 081008, JSM 083058, JSM 083085, JSM 084035) should represent 7 potential novel species within 6 characterized genera (Yaniella, Bacillus, Jeotgalibacillus, Sphingomonas, Rheinheimera, Microbulbifer). CONCLUSION: The results presented here showed that there is abundant diversity of halophilic and halotolerant bacteria, as well as a number of novel species in non-saline soil collected from Xiaoxi National Natural Reserve, Hunan Province, China. PMID- 21268890 TI - [Molecular and phenotypic characterization of a VGII genotype Cryptococcus gattii XH91 isolated in China]. AB - OBJECTIVE: To characterize the molecular and phenotypic traits of the VGII genotype of Cryptococcus gattii isolate XH91 firstly isolated in China. METHODS: The serotype was identified by molecular method; multi-locus sequence typing (MLST) was performed based on 16 gene fragments both of nuclear and mitochondria genomes; the abilities of haploid fruiting, same-sex mating and opposite sex mating were all evaluated; the phenotypic traits including melanin production, capsule size, and growth at 37 degrees C were characterized. RESULTS: The isolate XH91 firstly isolated in China was serotype B. The isolate shared the same MLST genotype with the minor outbreak genotype VGIIb from Vancouver islands. Strain XH91 could mate with the reference strain of opposite mating type and produced basidiospores, but could not mate with the reference strain of same mating type and had no ability of haploid fruiting. We did not observe obvious difference between XH91 and reference strains for melanin production, capsule size, and growth at 37 degrees C. CONCLUSION: Based on the results from MLST and phenotypic analysis, the Cryptococcus gattii strain XH91 is identical with the minor outbreak genotype VGIIb from Vancouver islands. This study will be critical to gain further insight into the emergence and molecular epidemiology of the VGII genotype of Cryptococcus gattii from China. PMID- 21268891 TI - [Genetic diversity and phylogeny of soybean rhizobia isolated from the regions of Loess Plateau in China]. AB - OBJECTIVE: We investigated the genetic diversity and phylogeny of soybean rhizobia isolated from the regions of Loess Plateau in China. METHODS: We analyzed 130 soybean rhizobia isolated from 15 regions in 4 provinces of Loess Plateau through BOX-PCR, 16S rDNA PCR- RFLP, 16S-23S IGS PCR-RFLP and 16S rRNA gene sequencing. RESULTS: BOX-PCR, 16S rDNA PCR- RFLP and 16S-23S IGS PCR-RFLP were in good agreement with the results which showed that all strains tested ascribed to two groups: the genus of Sinorhizobium and Bradyrhizobium phylogenetically. The analysis of 16S rRNA gene of 5 representative strains indicated that they were related to type strains S. fredii, B. japonicum and B. liaoningense, homology coefficient with type strains was 100% respectively. CONCLUSION: Soybean rhizobia isolated from the regions of Loess Plateau in China showed rich genetic diversity. S. fredii was the dominant species. Bradyrhizobium accounted for 10% of the strains tested only, of which, two strains were B. liaoningense. PMID- 21268892 TI - [Corynebacterium pekinense transketolase: gene cloning, sequence analysis and expression]. AB - OBJECTIVE: Transketolase (EC 2. 2. 1. 1; TK) is the key enzyme in non-oxidative phosphate pentose pathway. We cloned tkt gene from Corynebacterium pekinense AS 1.299 and its mutant PD-67 in order to investigate the effect of gene expression on physiological characteristics of C. pekinense. PD-67. METHODS: According to the homology between Corynebacterium glutamicum ATCC13032 and C. pekinense, we designed a pair of PCR primers to clone the tkt gene from wild-type C. pekinense AS1.299 and its mutant PD-67, then the mutant tkt gene was expressed in C. pekinense PD-67 by subcloning the PCR fragment into plasmid pAK6. The physiological characteristics of the recombinant C. pekinense PD-67 was investigated by fermentation. RESULTS: Analysis of PCR fragments reveals that, besides the regulatory sequence, they contain the whole structure of tkt gene. There is no base change all over the structure genes and regulatory sequences between C. pekinense AS1. 299 and PD-67. Comparing with Corynebacterium glutamicum ATCC 13032, there exist 5 amino acids change in amino acid sequence. Four of them were located in the motifs involved in thiamine pyrophosphate binding sites. The tkt gene from C. pekinense PD-67 was expressed homogenously, and the specific enzyme activity of TK in C. pekinense PD-67 (pTK3) is two times over that of the control strain C. pekinense PD-67 (pAK6). The recombinant C. pekinense PD-67 exhibits higher cell mass and accumulation of more tryptophan. CONCLUSION: The moderate amplification of TK activity resulted in increase of L tryptophan production without affecting the cell growth. PMID- 21268893 TI - [Improving heat and pH stability of nisin by site-directed mutagenesis]. AB - OBJECTIVE: The aim of this study was to optimize the property of nisin through altering its specific amino acid by site-directed mutagenesis method. METHODS: On the basis of M21K nisinZ, a former reported nisinZ mutant that exhibited antimicrobial activity against Gram-negative bacteria, the 29th amino acid of it was mutated from serine to lysine. The mutant M21K/S29K nisZ gene was cloned into vector pMG36e and the recombinant plasmid was introduced into Lacotococcus lactis NZ9800. The resulting M21K/S29K nisinZ was then isolated and purified, and its antibacterial activity, antibacterial spectrum and stability were analyzed and compared to those of M21K nisinZ and nisinZ. RESULTS: Compared with wild-type nisinZ and M21K nisinZ, the M21K/S29K nisinZ displayed reduced antimicrobial activity, but showed significantly increased stabilities to heat and pH stress. Moreover, M21K/S29K nisinZ also exhibited antimicrobial activity against Gram negative bacteria as M21K nisinZ did. CONCLUSION: By changing the 29th amino acid of nisin, we can optimize the property of nisin, especially its stability to heat and pH stress. PMID- 21268894 TI - [Isolation and identification of a polyhydroxyalkanoate producing strain]. AB - OBJECTIVE: We screened and isolated polyhydroxyalkanoate producing bacteria. METHODS: The strains were isolated from sludge from a beer brewery and screened by Sudan black B staining method. The isolated strains were identified according to their morphological features, physiological and biochemical analysis as well as 16S rRNA gene sequence analysis. The product extracted with hot chloroform from the isolated strain HG-B-1 was confirmed by Fourier transform infrared spectra. RESULTS: We isolated a bacterium, HG-B-1, from sludge collected from a beer brewery in Guangdong province, China. The yield of polyhydroxyalkanoates was 23.4% (w/w) based on dried weight of the bacterium cells when HG-B-1 grew in a medium containing saccharose. We analyzed 16S rRNA nucleotide sequence, and ascertained the phylogenetic position of the strain. CONCLUSION: Strain HG-B-1 with PHAs biosynthesis ability was identified as Stenotrophomonas maltophlia. PMID- 21268895 TI - [In vivo replacement of phosphatidylethanolamine by phosphatidylcholine affects biological function of E. coli]. AB - OBJECTIVE: We investigated differences in morphology, physiology, periplasmic proteins and phagocytosis by macrophage among E. coli strains AD93 (PE- PC-), AD93/ptac67 (PE- PC+), Top10/ptac66(PE+ PC+) and the wild types in order to understand if phosphatidylcholine (PC) can substitute phosphatidylethanolamine (PE) in vivo. METHODS: Bacterial cells were observed under microscope after staining with Gram-staining kit or by electron microscope. Bacterial growth under different conditions was monitored by measuring the absorbance at the wavelength of 600 nm. Periplasmic proteins were analyzed using SDS-PAGE and 2-D electrophoresis. Bacterial adherence and phagocytosis by macrophage were also examined by using murine RAW264.7 macrophage. RESULTS: 100% bacterial cells in AD93/pDD72 were bar-shaped but 25% AD93/ptac67 cells came out as long filaments. Different from AD93/ pDD72, AD93/ptac67 and AD93 required Mg2+ or Ca2+ for growth. Moreover, AD93/ptac67 displayed a different pattern of periplasmic proteins on a 2-D gel and a low relatively phagocytic efficiency in the phagocytosis test when compared to AD93/pDD72 and AD93. Both Top10/ptac66 and the wild-type Top10/ptac85 cells were bar-shaped under microscope, but the former showed noticeably difference in the outer-layer structure of cell wall, and its stress resistance and periplasmic protein composition were also different from those of the latter. CONCLUSION: Substitution of phosphatidylethanolamine with phosphatidylcholine in E. coli cells is unable to restore the phonotype of PE- mutant to the wild type. Biological functions of PE and PC are different, and phosphatidylcholine cannot substitute phosphatidylethanolamine in vivo. PMID- 21268896 TI - [Isolation, identification and characterization of ACC deaminase-containing endophytic bacteria from halophyte Suaeda salsa]. AB - OBJECTIVE: We Isolated and characterized 1-aminocyclopropane-1-carboxylate (ACC) deaminase-containing endophytic bacteria from halophyte Suaeda salsa to understand the interactions between endophytes and halophyte. METHODS: ACC deaminase-containing endophytic bacteria were isolated from root, stalk and leaf of Suaeda salsa and were identified based on morphological, physiological biochemical properties, API and 16S rRNA sequence analysis. Isolates were evaluated for their ACC deaminase, antifungal, protease activity, siderophores and phytohormones, such as indole-3-acetic acid, gibberellic acid and abscisic acid production, as well as atmospheric nitrogen fixation and phosphate solubilization. RESULTS: Four ACC deaminase-containing endophytic bacteria strains named as LP11, SS12, TW1 and TW2 were isolated and identified as Pseudomonas oryzihabitans, Pseudomonas sp., Pantoea agglomerans and Pseudomonas putida respectively. All the strains possessed the phosphate-solubilizing ability and could produce siderophores and phytohormones more or less. None of them could fix atmospheric nitrogen or produce protease. Only strain SS12 showed antagonism against two phytopathogenic fungi viz Fusarium oxysporum f. sp. conglutinans and F. oxysporum f. sp. cucumerinum. CONCLUSION: ACC deaminase-containing endophytic bacteria of Pseudomonas sp. and Pantoea sp. isolated from halophyte Suaeda salsa have abundant biological characteristics related to plant growth promotion, stress homeostasis regulation and biocontrol activity. PMID- 21268897 TI - [Prokaryotic microbial phylogenetic diversity of "Eryuan Niujie" hot spring in Yunnan province, China]. AB - OBJECTIVE: We analyzed the prokaryotic microbial diversity of Eryuan Niujie hot spring, in Yunnan Province, to enrich our knowledge about thermo-stable microbes. METHOD: We constructed bacterial and archaeal 16S rRNA gene libraries, analyzed the sequences and constructed phylogenetic trees to learn the prokaryotic microbial diversity. RESULT: The majority of the prokaryotic microbes in this hot spring were bacteria, while beta-Proteobacteria was the most abundant, next were Bacteroidetes and Chlorobi; the abundance and diversity of archaea were both less than that of bacteria, including Euryarchaeota and Crenarchaeota, while Euryarchaeota was the most abundant. PMID- 21268898 TI - [Effects of recycled water irrigation on bacterial community compositions in lawn soil]. AB - OBJECTIVE: In order to obtain the information about how irrigations with recycled water affecting the cultivable microbial population of the rhizosphere of turfgrasses. METHODS: We isolated strains from two irrigated areas with recycled water (RW) and drinking water (DW) in Taoranting Park in Beijing, China, by using diluting plate and counting method, and analyzing the 16S rDNA sequence of the isolates. RESULTS: We obtained 20 and 25 strains with different morphological character of colonies from the area irrigated with DW and area irrigated with RW, respectively. The sequence analysis of 16SrDNA showed that RW-irrigated system supported more complex communities of 18 genus and 24 species, whereas the DW irrigated system only supported 15 genus and 20 species. Both samples had similar microbial population. There were 9.7% or 13.4% alphaproteobacteria, 8.1% or 12.3% betaproteobacteria, 17.9% or 42.0% gammaproteobacteria, 13.0% or 2.9% bacteroidetes, 23.6% or 10.1% firmicutes, and 27.6% or 19.6% actinobacteria at the rhizosphere of turfgrasses irrigated with DW or RW respectively. The dominant bacteria in DW area were the genera Bacillus whereas that of RW area was the genera Acinetobacter. Other than the gammaproteobacteria, the dominant genera in other groups of two areas were similar. CONCLUSION: The result showed that the bacterial community composition of rhizosphere samples did not change, but the distribution of different types of bacteria does change after irrigation by reclaimed water, which were determined by the abundance increasing of the dominant species and the appearance or disappearance of non-dominant species. Finally, it is important that the control of the pathogen and metal should be enforced when using RW for irrigation. PMID- 21268899 TI - [Isolation and identification of a thermophilic anaerobic bacterium]. AB - OBJECTIVE: To find new microbial resources from a high-temperature oil reservoir. METHODS: Strain HL-3 was isolated by Hungate Anaerobic Technique from oil reservoir water sampled from Dagang oilfield, China. Through physiological, biochemical and phylogenetic analysis, the strain HL-3 was classified. RESULTS: Cells were Gram-positive. The temperature range for growth was 40 degrees C-75 degrees C (optimum at 60 degrees C) and the pH range was 5.0-8.0 (optimum at 6.5). The isolate could grow in the presence of 0%-3.2% NaCl (optimum at 0.25%). Glucose, ribose, mannose, xylose and cellobiose could be metabolized. Metabolites of glucose were ethanol, acetate, CO2 and trace amount of propionate and butanol. The G + C content of DNA was 33.9 mol%. Based on 16S rRNA studies,strain HL-3 was most close to T. uzonensis DSM 18761T (EF530067) with 98.8% similarity and to T. sulfurigignens DSM 17917T (AF234164) with the 98.1% similarity. Strain HL-3 tolerated to high sulfite (0. 1mol/L) ions and extremely high concentration of thiosulfate (0.8 mol/L). When the concentration of thiosulfate was higher than 0.075 mol/L, the cell would generate S element granular. The presence of H2S gas was detected inside of space at the top of serum bottle. Strain HL-3 together with T. uzonensis DSM 18761T differed greatly in toleration of thiosulfate and sulfite. The toleration of strain HL-3 to thiosulfate and sulfite was most close to T. sulfurigignens DSM 17917T (AF234164). In addition, strain HL-3 to metabolite thiosulfate and sulfite was also similar with T. sulfurigignens DSM 17917T (AF234164). However, it differs largely from both of them to metabolize glucose. CONCLUSION: Therefore, strain HL-3 may be a new spieces of the Thermoanaerobacter, and the definitive classification positioning is still awaiting for further verified with the method of determination of whole-genome DNA-DNA similarity PMID- 21268900 TI - [Identification of Legionella isolates from environmental water by using PCR combined with enzymatic digestion analysis]. AB - OBJECTIVE: To evaluate polymerase chain reaction (PCR) combined with enzymatic digestion for identification of Legionella, and investigate status of Legionella in environmental water systems in Guangzhou. METHODS: Forty-four water samples collected in Guangzhou were cultivated for Legionella, and Legionella isolates were identified by PCR-enzymatic digestion, 16S rDNA and mip gene sequencing analysis. RESULTS: Sixty-six strains of Legionella pneumophila and 46 Non-L. pneumophila were identified by PCR-enzymatic digestion and sequencing analysis. Forty-six strains of Non-L. pneumophila included 20 strains of L. feeilei, 17 L. gormanii, 7 L. oakridgensis and 2 L. longbeachae. CONCLUSION: PCR combined with enzymatic digestion is a simple, rapid, and specific method for the identification of Legionella. L. pneumophila was distributed widely, followed by L. feeilei, L. gormanii, L. oakridgensis and L. longbeachae, in environmental water in Guangzhou area. PMID- 21268901 TI - [sRNA (sraB) regulate the resistant ability of Salmonella enterica serovar enteritidis to egg albumen]. AB - OBJECTIVE: Salmonella species are important food-borne pathogens of human and animal. S. enterica serovar Enteritidis is the only serovar that routinely causes human infection through intact egg, the molecular basis of its ability to survive in egg is poorly understood. The importance of post-transcriptional regulation by small non-coding RNAs (sRNA) has recently been recognized. The sRNAs play diverse physiological roles in stress responses, regulation of metabolism, control of bacterial envelope composition and bacterial virulence. In this study, we studied regulatory function of salmonella sRNA sraB associated with survival ability of S. enterica serovar Enteritidis in egg albumen. METHODS: To study the contribution of sraB to the survival ability of S. Enteritidis in egg albumen, we constructed sraB deletion strain (SE2472 delta sraB) with wild type S. Enteritidis SE2472, using red recombination system. For complementation of sraB, complete fragment sraB was amplified from SE2472 and inserted into plasmid pHDB3 to overexpress sraB. We carried out the egg albumen bactericidal experiment with strains of SE2472, SE2472 delta sraB (sraB deletion), SE2472 delta sraB-comp (sraB complement) and control. To explore the regulatory role of sraB, we assayed the bactericidal activity of the two important antimicrobial components of egg albumen: lysozyme and transferrin. RESULTS: In the egg albumen bactericidal experiment, the survival rate of SE2472 delta sraB was only about 61%-70% of that of SE2472; while SE2472 delta sraB-comp improve the survival rate of SE2472 delta sraB by 10%-33% . In the transferrin bactericidal experiment, the survival rate of SE2472 delta sraB was 38% of that of SE2472 at 8 h incubation, and 23% at 24 h incubation. SE2472 delta sraB-comp played an important role in improving the survival rate rescued the defect by 14% than SE2472 delta sraB at 8 h of incubation, but failed to rescue the defect at 24 h incubation. In the Lysozyme experiment, the survival rate of SE2472 delta sraB was 41% of that of SE2472 at 8 h incubation, and 27% at 24 h incubation, compared with SE2472 delta sraB, the expression of sraB of SE2472 delta sraB-comp has improved the survival rate by 35% after 8 h of incubation and 23% after 24 h of incubation. CONCLUSION: Based on our results, we conclude that small RNA (sraB) plays important role during the survival of S. Enteritidis in egg albumen, and may contribute regulatory role in response to antimicrobial components of egg albumen such as lysozyme and transferrin. PMID- 21268902 TI - [Cloning and identification of ipaJ gene in Salmonella pullorum]. AB - OBJECTIVE: Cloning of ipaJ gene from Salmonella pullorum C79-13, and identification of expressed IpaJ protein as an immunogen of the pathogen. METHODS: With suppression subtractive hybridization (SSH) between Salmonella pullorum strain C79-13 (tester) and Salmonella enteritidis strain 50041 (driver), three subtracted fragments PEA3, PE31 and PE44 showed high homology with ipaJ in plasmid pSFD10 of Salmonella choleraesuis C500. The three subtracted sequences were spliced together into the whole sequence of ipaJ in Salmonella pullorum. Then the ipaJ gene was amplified from Salmonella pullorum by polymerase chain reaction (PCR) and cloned into prokaryotic expressive vector pET-30a(+). Western blot was used to identify it as an immunogen. The distribution of the gene was also detected in Salmonella pullorum isolates. RESULTS: The ipaJ gene cloned from Salmonella pullorum was 840 bp, and the expressed fusion protein was 37 kDa. Specific reaction was found between Salmonella pullorum positive serum and expressed protein by Western-blot assay, confirming its identification as an immunogen of Salmonella pullorum. The PCR results showed that the gene exists in all Salmonella pullorum strains. CONCLUSION: The ipaJ gene from Salmonella pullorum was first reported and cloned, and the expressed IpaJ protein was confirmed as an immunogen of Salmonella pullorum. PMID- 21268903 TI - [Effect of quorum sensing response regulator nprR deletion on expression of cry protein in Bacillus thuringiensis]. AB - OBJECTIVE: The role of Quroum Sensing response regulator nprR on the expression of Cry protein in B. thuringiensis HD-73 was studied. METHODS: The nprR gene deletion mutant HD73 (delta nprR) was constructed by using of homologous recombination. Beta-galactosidase assay of cry1Ac'-lacZ gene fusion and SDS-PAGE in both HD-73 and HD73 (delta nprR) strains were performed to analyze the effect of nprR gene deletion on expression of cry1lAc gene. RESULTS: Beta-galactosidase assay of nprR'-lacZ in both LB and Schaeffer' s sporulation medium showed nprR gene in B. thuringiensis was initially transcripted at TO (end of Logarithmic growth phase) and keeping expression in stationary phase. Beta-galactosidase assay of cry1Ac'-lacZ and SDS-PAGE indicated that expression of cry1Ac gene in HD73 (delta nprR) was stronger than that in HD-73 during transition phase and early stationary phase. However, Cry expressed product between HD-73 and HD73 (delta nprR) in LB medium has no significant difference when crystal and spore were released. CONCLUSION: The deletion of nprR increased expression and transcription activity of cry1Ac during transition and early stationary phase in rich media. PMID- 21268904 TI - [Effect of inorganic salts on the conjugation and heterologous expression of actinorhodin in Streptomyces avermitilis]. AB - OBJECTIVE: Streptomyces avermitilis NRRL8165 could serve as a good host for heterologous expression of antibiotics biosynthetic gene clusters. However, it needs to improve its conjugation frequency to accept large plasmids. METHODS: We chose MgCl2, NaCl, Ca(NO3)2 and CaCl2, to test whether they affected the conjugation frequency of large plasmids at salt concentration from 0-200 mmol/L. A complete random experiment was designed for optimization. RESULTS: We found that CaCl2 promoted conjugation dramatically, and MgCl2 did significantly too. The complete random experiment led to diclosure of an optimal combination of MgCl2 and CaCl2 by which the conjugation frequency was improved by 11 fold. In addition, a supplemented medium was found to lead to successful heterologous expression of actinorhodin in S. avermitilis. CONCLUSION: Some inorganic salts can not only significantly improve the conjugation frequency of Streptomyces avermitilis NRRL8165 but also promote the expression of actinorhodin in Streptomyces avermitilis NRRL8165. PMID- 21268905 TI - [The treatment of valvular heart disease]. AB - During the last few years, progress has been made in the diagnostics and treatment of valvular heart disease. Valvuloplasties have become more common in cases of valve leakage, whereby complications associated with artificial valves and anticoagulant therapy can be avoided. New less invasive catheter valve techniques seem to be as good as conventional ones. In the treatment of aortic valve stenosis, artificial valve replacement via catheter has become almost routine for patients having an excessive risk in open heart surgery. PMID- 21268906 TI - [Sperm DNA damage and male infertility]. AB - Conventional semen analysis is a poor predictor of reproductive outcome. There is a lot of evidence that sperm DNA fragmentation tests can differentiate fertile from infertile men. DNA damage can be due to intrinsic (e.g., protamine deficiency), or extrinsic factors (e.g., tobacco smoking, infections, testicular hyperthermia, varicocele). Seminal plasma leucocytes generate excess free oxygen radicals and can cause sperm DNA fragmentation. Couples in whom the husband has a high DNA damage have low potential to a natural pregnancy. Sperm DNA damage is also associated with a lower pregnancy rate and an increase of pregnancy loss in assisted reproduction treatments. PMID- 21268907 TI - [The possibilities of neuropsychological rehabilitation in multiple sclerosis]. AB - Cognitive deficits are common in multiple sclerosis (MS) occurring in over half of the patients. Deficits may have a multidimensional impact on patients' quality of life. The preliminary research evidence on the effectiveness of neuropsychological rehabilitation in MS so far is positive: rehabilitation may have favourable effects on patient's cognitive performance, mood, and fatigue symptoms. The patient's ability to manage with disease-related cognitive symptoms can be promoted by individually planned neuropsychological rehabilitation. In clinical work, the diagnostics and treatment of cognitive problems should be improved in patients with MS. Neuropsychological rehabilitation should be an important part of rehabilitation regimen in MS. PMID- 21268908 TI - [Obsessive-compulsive disorder (OCD) in childhood]. AB - The onset of OCD in a child is influenced by genetic and environmental factors. The most common obsessive thoughts are associated with getting dirty, fear of injury, as well as obsessions about symmetry and exactness. The most common compulsive acts include washing, repetition, checking, counting, touching, arranging and collecting. The majority of children with obsessive-compulsive symptoms also exhibit other concomitant disorders. Cognitive behavior therapy alone or combined with SSRI medication is the essential mode of treatment. Complete recovery from individual episodes of OCD may take place, but in some the disorder continues until adulthood. PMID- 21268909 TI - [Musicians consulting a hand surgeon having special competence in musician's medicine. A survey of 148 patients]. AB - 148 musicians (81 females, mean age 33.8 years) visited the senior hand surgeon's office due to disorder of an upper extremity. They had started playing at mean age of 8.6 years and did play mean 2.4 hours a day. One third were string players, and piano was the main instrument in 21%. The area of disorder was hand and wrist in 57%, forearm in 19%, and arm in 18%. Pain was the main complaint in 64%. Most of the musicians (87%) had consulted earlier another doctor and they already had a diagnosis, mostly some kind of tendonitis. However, in a half of them the diagnosis was changed. The most common diagnosis given by the hand surgeon was thoracic outlet syndrome, TOS. Those patients' earlier diagnosis was mostly tendinitis. Playing-related musculoskeletal disorders were counted in 14%, hypermobility syndrome in 8%, and focal dystonia in 5%. In 5 patients, hand surgeon was unable to make any relevant diagnosis. Only 16 patients (11%) needed surgical treatment. PMID- 21268910 TI - [Update on current care guidelines. Bacterial skin infections]. AB - Bacterial skin infections are common, and range from mild to serious, even life threatening infections. This guideline presents treatment options for erysipelas, cellulitis, impetigo, ecthyma, folliculitis, abscess, paronychia (nail infection) and early borreliosis as well as for erysipeloid, mycobacterial skin infections and tularemia. Recommended antibiotic and/or other treatments are described for children and adults. PMID- 21268911 TI - [Analysis of the nursing role in the care of patients with neuromuscular disorders]. AB - The nursing role in neuromuscular disorders has been shown as a promising solution in service organization. However, the role of neuromuscular nurses has scarcely been addressed in the literature. The present evaluation process was geared toward defining nursing role in relation to systematic follow-up of neuromuscular disorders and to assess its theoretical background. PMID- 21268912 TI - [Serum biomarkers in idiopathic pulmonary fibrosis]. AB - Idiopathic pulmonary fibrosis (IPF) is the most common of interstitial lung diseases and is characterised by a significant mortality rate. That is way both clinicists and patients are interested to identify factors that may influence outcome of disease. This factors are named biological markers or biomarkers. Their usefulness in diagnostic, monitoring and prognosis of interstitial pneumonia, and idiopathic pulmonary fibrosis was estimated in many researches. The most of them was concerned to serum biomarkers, such as surfactant proteins, mucin-connected proteins, Clara cells proteins, cytoceratines and cytokines. PMID- 21268913 TI - [European Antibiotic Awareness Day educational campaign--has it changed public attitudes to antibiotic use in Poland?]. AB - Widespread inappropriate antibiotic use is a global concern for public health care. That is why national and international antibiotic resistance control strategies recommend education of health-care professionals and the public to promote prudent antibiotic use. This paper show the effect of the 2009 public antibiotic campaign in Poland on the knowledge and social attitudes towards use of antibiotics. The aim of this study was to assess the level of knowledge and behaviour models of Polish people regarding antibiotics, recommendations for their use as well as sources of information on antibiotics. At the same time the study was aimed at assessing whether actions undertaken during educational campaigns resulted in growing knowledge on the subject of antibiotic use or a change in attitudes towards this group of medicines. MATERIAL AND METHODS: A two stage survey was carried out from October to December 2009 based on 14 self prepared questions. The survey was carried out by Millward Brown SMG/KRC on the representative sample of 1000 people using CATI - Computer Assisted Telephone Interviews. RESULTS: In Poland there is still a high percentage of people taking antibiotics. 37% of Polish people used an antibiotic in the last 12 months. Most Polish people--88% use an antibiotic prescribed by a doctor. At the same time Polish people receive antibiotics due to viral infections which should not be treated thus. The results of the survey show that almost half of adult Poles would expect to have an antibiotic prescribed in case of a flu. Over half of Polish people believe that antibiotics kill viruses. Over 1/3 of recipients, who have come across information on prudent use of antibiotics (mostly due to National Program for Antibiotics Protection) claimed to have changed their behavior model regarding this group of medicines. CONCLUSIONS: The results of this study show that further and systematic education regarding appropriate antibiotic use is needed. PMID- 21268914 TI - [Rational antibiotic therapy of acute upper respiratory tract infections]. AB - Overuse of antibiotics is a major cause of bacterial resistance. Inappropriate and unnecessary antibiotic therapies are particularly frequent in the treatment of respiratory tract infections, which are viral in origin in about 80% of cases. This review work presents the principles of rational antibiotic therapy of acute upper respiratory tract infections, namely pharyngotonsillitis, otitis media and sinusitis according to Polish Recommendations 2010. PMID- 21268915 TI - [Lipid peroxidation level in gastrointestinal tract tumors]. AB - Oxygen free radicals and their reactive derivatives participate in formation of chronic inflammation states, which facilitate development of gastrointestinal tract tumors. Oxidative stress is one of the main causes of damage to cell membranes in result of exacerbated lipid peroxidation process. End products of lipid peroxidation (aldehydes, organic peroxides) react with important biological macromolecules such as DNA and proteins, cause changes in cell membrane structure and properties leading to loss of its integrity. Intensification of the lipid peroxidation process is a factor which may also lead to a malfunction in the antioxidant barrier, which further weakens the defense of cells against oxygen free radicals and promotes the onset and development of cancer. The aim of the study was the determination of lipid peroxidation level in gastrointestinal tract tumors (stomach, liver, colon, and colorectal cancer to liver metastases). MATERIAL AND METHODS: Materials for studies were obtained from 150 patients with gastrointestinal tract tumors: 10 with stomach cancer, 30 with malignant and benign liver cancers, 60 with primary colorectal cancer, and 50 with metachronous colorectal cancer liver metastases. We also investigated 25 patients with liver cirrhosis, which was treated as a pre-cancerous condition. In total, 175 patients were examined. Tumor specimens, and normal adjacent tissues (6-7 cm from the edge of the tumor), which served as control tissue in studies, were collected from patients (with their consent) during surgery. Additionally, liver specimens were collected from patients with liver cirrhosis. Lipid peroxidation level was determined spectrophotometrically as a concentration of final lipid peroxidation products, which in reaction with tiobarbituric acid (TBA) form colour complex (thiobarbituric acid-reactive substances - TBARS). RESULTS: The study showed the highest concentration of TBARS in benign, and the lowest in malignant liver tumors. Other types of gastrointestinal tumors studied, were characterized by similar levels of lipid peroxidation. TBARS concentration in these tumors was approximately 2-fold higher than in malignant liver tumors and much lower than in benign tumors. In all cancers of the digestive tract with the exception of malignant liver tumors increased level of TBARS was found, comparing with control tissue. The concentration of TBARS in cirrhotic liver was lower than in control. The level of lipid peroxidation in liver cirrhosis and malignant liver tumors was similar. There were no significant differences in TBARS concentration in the tumors of particular sections of the intestine and normal colon. The highest concentration of TBARS was found in G1 grade of colorectal cancer. In subsequent grades of cells differentiation (G2 and G3) its concentration was lower. The highest level of lipid peroxidation, expressed as the concentration of TBARS was found in the I stage of colorectal cancer clinical advancement. The significantly lowest concentration of TBARS was shown for stage II (UICC). CONCLUSIONS: The level of lipid peroxidation in cancerous cells of gastrointestinal tract indicates increased oxidative stress. The changes of lipid peroxidation level--a marker of oxidative stress in gastrointestinal tumors appear to be closely associated with their development stages (liver cirrhosis/malignant liver cancer; colorectal cancer/colorectal cancer liver metastases) and are likely to create such conditions, in which cancerous cells may proliferate, undergo gradual dedifferentiation and malignancy, and generate metastases. PMID- 21268916 TI - [Vipera berus bite--a case report]. AB - Cases of bite by common viper (Vipera berus) are rare on the territory of Poland, and the mortality after bites is less than 1%. This paper describes a case of 81 year-old patient with massive swelling, redness and soreness of the right hand, which occurred shortly after the adder bite. In this paper we present composition and mechanisms of the venom's action, clinical symptoms and treatment of poisoning after a snake bite. Based on the reported case authors draw attention to hospital treatment and indications for administration of antivenom as the only causative method of treatment. PMID- 21268917 TI - [Actinomycosis associated with perforation of jejunum in patient after cholecystectomy--a case report]. AB - Actinomyces is endogenic infection with rare abdominal manifestations. Diagnosis is very difficult and not always taken into account in differential diagnosis. Disease is recurrent and treatment is mostly pharmacologic and takes a long time. The aim of the paper was to present a case of patient operated on acute cholecystitis with intraabdominal actinomycosis. The 66 years old patient 28 days after cholecystectomy appeared to have jejunal perforation in the course of actinomycosis. Patient regarded two interventions due to intraabdominal abscesses. Since last discharge, a year ago, we do not observe recurrence. Intraabdominal actinomycosis is often recurrent and should be considered in patients with purulent complications after surgical procedures. PMID- 21268918 TI - [Chronic fatigue syndrome with special focus on systemic lupus erythematosus]. AB - Chronic fatigue is an ailment frequently reported in the course of several pathologies. When fatigue clearly predominates over other symptoms, it is referred to as chronic fatigue syndrome (CFS). Initial CFS definition and diagnostic criteria were published in 1988, and have been several times modified since that time. In 1994, Fukuda et al. presented precise guidelines for the evaluation and study of CFS. The etiopathogenic mechanisms of CFS have not yet been satisfactorily clarified although immune and hormonal responses as well as a decline in neurotransmitter concentrations have been implicated in the development of the disorder. Systemic lupus erythematosus (SLE) is an autoimmune disease, with chronic fatigue as a very common symptom observed in as many as 80% of the patients. Owing to its obscure pathogenesis, therapy for CFS remains a difficult and complex issue consisting mostly of the treatment of the underlying disease. Appropriate lifestyle and physical activity should be emphasized. Medications include antidepressants and glucocorticosteroids. Psychological counseling has also been recommended. Complex etiopathogenesis and the involvement of the immune and neurohormonal systems suggest that CFS might be a primary and not secondary disorder. Hence a significant role of medical professionals in the diagnosis and treatment of chronic fatigue syndrome. PMID- 21268919 TI - [Paraoxonase--important enzyme of the lipid metabolism and potential ally in the antiatherosclerotic treatment]. AB - In composed process of atherogenesis take part different classes of lipoproteins. Atherogenic are low density lipoproteins (LDL), especially their modified, like oxidized, particles. Different role have high density lipoproteins (HDL): those molecules could protect arterial wall. This effect depends eg. on the presence paraoxonase 1 (PON 1) in HDL molecules. PON 1 is the enzyme with hydrolase activity. PON 1 protects lipoproteins against oxidative stress and makes possible to metabolize lipid peroxides. Several polymorphisms of the gene PON 1 have been identified. The most important for enzyme activity seem to be two polymorphisms: in the position 55 (L55M) and in the position 192 (R192Q). For instance the genotype PON 1 55 MM is connected with low enzyme serum level. Gene polymorphisms of PON could be one of the possibilities genetic conditioning of atherosclerosis. PMID- 21268920 TI - [Hemobilia of neoplastic origin]. AB - Haemobilia is a rare and difficult to diagnose cause of gastrointestinal tract bleeding. Actually the most frequent causes of haemobilia are iatrogenic traumas, due to development of different diagnostic and therapeutic procedures performed endoscopically or laparoscopically. On the other hand cancer disease is the rarest reason of haemobilia. Diagnosing and treatment of cancer disease resulting in haemobilia are still big challenge for up to date medicine. Typical symptoms can be observed only in 30% of patients. From among all diagnostic procedures angiography of branches of the coeliac trunk seems to be the most important due to it's potentially therapeutic value in case of performing TAE. Actually treatment of haemobilia depends on patient's general condition, tumor localization and size, and intensity of bleeding. TAE should be considered in all cases of haemobilia. Surgery should be performed in cases of haemobilia caused by small, resectable neoplastic tumors. Advanced cancer disease resulting in haemobilia is the indication for TAE and other endoscopic or surgical procedures stopping bleeding and opening the bile duct passage. PMID- 21268921 TI - [Empathy-building of physicians. Part III. Students exposure to literature, theatre, film and the arts]. AB - Literature, theatrical performances, films and the arts could be used to enhance empathy among students of medicine and residents. The use of these media enables them to learn how feelings are expressed. Through study of literature and the performing arts students can also gain new insights into their own emotional responses to illness and suffering as well as into the moral and ethical issues posed by medical practice. The objective of this paper is to describe ways in which literature, film, drama, and the arts are used in medical schools to enhance empathy in students of medicine. We also want to show the rational purpose for the inclusion of these media in medical school training. We searched PubMed, ProQuest, ERIC, MedLine, and Polish Medical Bibliography (Polska Bibliografia Lekarska) published from 1990 to the present--for studies that address use of literature, drama, film and the arts for teaching empathy to medical students. Analysis of papers reporting use of different forms of literary, artistic, and performing arts productions within the context of medical education indicates that exposure to these types of media, when used properly, may trigger attitude change, foster understanding of the illness experience and enhance empathy for the patients. PMID- 21268922 TI - [Report from International Stroke Conference 2010, San Antonio, USA]. AB - During the 35th International Stroke Conference held in February 2010, San Antonio, USA, the new definitions of transient ischemic attack, ischemic stroke, acute neurovascular syndrome, acute hypertensive reaction in stroke have been discussed. Data from recent clinical trials and meta-analysis covering different epidemiological, diagnostic and therapeutic aspects of cerebrovascular diseases discussed during conference has been presented. Results of new trials in primary and secondary stroke prevention assessing efficacy and safety of: stenting vs endarterectomy of carotid arteries (CREST), dabigatran in prevention of cardioembolic stroke in atrial fibrillation (RE-LY), cilostazole in secondary prevention of atherogenic stroke (CSPSS II) have been discussed. PMID- 21268923 TI - [The Nobel prize in physiology or medicine 2010]. PMID- 21268924 TI - [Simultaneous determination of amoxicillin and clavulanic acid in the human plasma by high performance liquid chromatography-mass spectrometry (UPLC/MS)]. AB - BACKGROUND/AIM: Quantitative analysis of amoxicillin and clavulanic acid in biological matrices requires sensitive and specific methods which allow determination of therapeutic concentration in 1 g/mL range. Analytical methods for determination of their concentrations in body fluids described in literature include high performance liquid chromatography coupled to UV detector (HPLC-UV) and liquid chromatography-mass spectrometry (LC-MS). The aim of this study was to develop sensitive and specific ultra performance liquid chromatography/mass spectrometry (UPLC/MS) method which could be used for the spectral identification and quantification of the low concentrations of amoxicillin and clavulanic acid in the human plasma. METHOD: A sensitive and specific UPLC/MS method for amoxicillin and clavulanic acid determination was developed in this study. The samples were taken from the adult healthy volunteers receiving per os one tablet of amoxicillin (875 mg) in combination with clavulanic acid (125 mg). RESULTS: Plasma samples were pretreated by direct deproteinization with perchloric acid. Quantification limit of 0.01 microg/ml for both amoxicillin and clavulanic acid was achieved. The method was reproducible day by day (RSD < 7%). Analytical recoveries for amoxicillin ranged from 98.82% to 100.9% (for concentrations of 1, 5 and 20 microg/mL), and recoveries for clavulanic acid were 99.89% to 100.1% (for concentrations of 1, 2 and 5 microg/mL). This assay was successfully applied to a pilot pharmacokinetic study in healthy volunteers after a single-oral administration of amoxicillin/clavulanic combination. The determined plasma concentrations of both amoxicillin and clavulanic acid were in the range of the expected values upon the literature data for HPLC-UV and LC-MS methods. CONCLUSION: The described method provided a few advantages comparing with LC/MS MS method. The method is faster using running time of 5 minute, has lower limit of quantification (LOQ) and it could be used in pharmacokinetic studies of both amoxicillin and clavulanic acid. PMID- 21268925 TI - [Association between clinical parameters and the presence of Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis in patients with progressive periodontal lesions]. AB - BACKGROUND/AIM: Periodontitis is a chronic inflammatory disease of periodontal tissues with consequential is bone loss as a result of host immunological reactions caused by periopathogens. The aim of the study was to investigate if there is a correlation between clinical parameters and the presence of two most aggressive periopathogens (Aggregatibacter actinomycetemcomitans--Aa and Porphyromonas gingivalis--Pg) in patients with progressive periodontal lesions. METHODS: A total of 34 systemic healthy people, 23 to 70 years old, were included in the study. The patients were clinically and radiologically examined, and after that, the representative pocket with greatest pocket depth was chosen and the sample was collected from that place. The measured clinic parameters were: gingival index, index of gingival bleeding, pocket depth and plaque indices. The multiplex Polymerase Chain Reaction (PCR) method was used for detection of periopathogens. After obtaining results, appropriate statistical tests were used to correlate the clinical and microbiological results. RESULTS: Aa and Pg were detected in the same percentage of samples. Aa and Pg were detected in 35.29% samples alone, and in 29.41% both were detected. The values of measured clinical parameters did not show a statistical significance between the groups. In analysis of correlations among clinical parameters inside the groups, a statistical significance was found only between gingival and plaque index in the group with Aa. CONCLUSION: Clinical course of periodontitis in the developed stage does not differ in relation to the presence of different periopathogens as the major inductors of immunologically guided destructive processes. PMID- 21268926 TI - [Use of linear radiofrequency device in liver resection]. AB - BACKGROUND/AIM: Linear radiofrequency device (LRFD) is disposable tool designed for liver parenchyma transection using controlled radiofrequency to "seal" blood vessels and bile ducts, making liver resection easier and safer compared to classical resectional techniques. The aim of this study was to determine real value of the LRFD compared to the standard "keliclasia" technique. METHODS: This prospective study analyzed the significant intraoperative parameters and postoperative results of the 200 patients who underwent surgery at the Surgery Clinic of Clinical Centre in Nis, between January 1, 2001, and January 1, 2009. The patients were divided into two groups: the control Keli group (144 patients) with the "keliclasia" resection technique and the control RF group (with resection performed using LRFD--Tissue Link / Dissection Sealer (DS-3.0) (56 patients). The following parameters were analyzed: duration of liver ischemia, liver parenchyma transection time, intraoperative blood loss, significant intraoperative and postoperative complication rate-duration of hospitalization and mortality. RESULTS: . LRFD was used in 56 liver resections. The average duration of liver ischemia in the RF group was shorter than in the Keli group (7 versus 22 minutes). Parenchymal liver transection was significantly slower in the RF group than in the Keli group (2.05 versus 4.34 cm2/minutes, respectively). There was less intraoperative bleeding using LRFD "Keliclasia" technique than in the control group (390 mL compared to 420 mL, respectively). After the use of LRFD two cases of biliary leak and 4 pleural effusions were registered. CONCLUSION: LRFD is simple device for safe liver transection with decreased need for liver ischemia and significant reducing of the intraoperative blood loss. High price for disposable device and slow parenchyma transection are disadvantages of this device. PMID- 21268927 TI - [Therapy of chronic hepatitis C--virologic response monitoring]. AB - BACKGROUND/AIM: Virological testing is considered to be essential in the management of hepatitis C virus (HCV) infection in order to diagnose infection, and, most importantly, as a guide for treatment decisions and assess the virological response to antiviral therapy. The aim of this study was to determine the rate of a sustained virological response (SVR) and various factors associated with response rates in chronic hepatitis C infected patients treated with peg interferon alpha (PEG-INF) and ribavirin (RBV) combination therapy. METHODS: A total of 34 patients, treated with PEG-IFN and RBV were studied. Serum HCV-RNA was measured before the treatment, 12 weeks following the start of the therapy and 6 weeks after the treatment cessation. SVR was defined as undetectable serum HCV-RNA 6 months of post-treatment follow-up, virologic relapse (VR) as relapse of HCV-RNA during the posttreatment follow-up. Serum HCV-RNA was measured with the Cobas Amplicor test. RESULTS: At the end of post-treatment follow-up 19 (55.8%) patients demonstrated a SVR. The majority of the patients were genotype 1 (27), and the other were genotype 3 (5 patients) and genotype 4 (2 patients). There was VR in 6 patients 6 months after the therapy. In 9 patients HCV-RNA was positive after 12 weeks. CONCLUSION: We demonstrated that patients with chronic HCV infection can be successfully treated with combination of PEG-INF and RBV. This result emphasizes also that post-treatment follow-up to identify patients with SVR or VR could be important. PMID- 21268928 TI - [Frequency of foot deformity in preschool girls]. AB - BACKGROUND/AIM: In order to determine the moment of creation of postural disorders, regardless of the causes of this problem, it is necessary to examine the moment of entry of children into a new environment, ie. in kindergarten or school. There is a weak evidence about the age period when foot deformity occurs, and the type of these deformities. The aim of this study was to establish the relationship between the occurrence of foot deformities and age characteristics of girls. METHODS: The research was conducted in preschools "Radosno detinjstvo" in the region of Novi Sad, using the method of random selection, on the sample of 272 girls, 4-7 years of age, classified into four strata according to the year of birth. To determine the foot deformities measurement technique using computerized digitized pedografy (CDP) was applied. RESULTS: In preschool population girls pes transversoplanus and calcanei valga deformities occured in a very high percentage (over 90%). Disturbed longitudinal instep ie flat feet also appeared in a high percentage, but we noted the improvement of this deformity according to increasing age. Namely, there was a statistically significant correlation between the age and this deformity. As a child grows older, the deformity is lower. CONCLUSION: This study confirmed that the formation of foot arches probably does not end at the age of 3-4 years but lasts until school age. PMID- 21268929 TI - [Agroterrorism as a current challenge]. PMID- 21268930 TI - [Functional magnetic resonance imaging of cortical changes in a low-grade glioma patient]. AB - INTRODUCTION: New methods for studying brain functions have provided the new insights into human brain. It is really possible to study a cortical adaptation in adults who have sustained injury. We reported cortical changes in a left frontal low-grade glioma patient during disease progression and after reoperation by functional magnetic resonance imaging (fMRI). CASE REPORT: The use of fMRI exams for localisation of eloquent motor and language areas were performed three times in a period of 15 months: seven years after initial tumor resection, eleven months later and three months after the reoperation. The first fMRI demonstrated cortical activation for motor tasks in the expected location of primary motor area while later examinations showed activations of both primary motor areas for right hand movement. The first exam language evaluation showed the left hemisphere dominance for both language tasks, while the second fMRI demonstrated the right hemisphere dominance for complex word generation task, but the left hemisphere remained dominant in simple language task. After the reoperation, language mapping revealed the left hemisphere dominance for both language tasks. CONCLUSION: fMRI evaluation of cortical changes in low-grade glioma patients may additionally optimize and individualize neurosurgical treatment. PMID- 21268931 TI - [Association of post-traumatic communication of endocranium and nasal cavity with recurrent meningoencephalitis without rhinorrhea]. AB - INTRODUCTION: A gunshot head injury, characterized by a huge intensity of mechanical force, in addition to the direct tissue damage at the location of direct impact, may cause a skull and skull base fracture, distant from the the point of direct impact, which could be further complicated by creating a communication between endocranium and nasal/paranasal cavities. Such cases pose a great diagnostic and therapeutic challenge for every clinician. CASE REPORT: The patient is presented with the history of a perforating gunshot head injury six years ago, with recurrent attacks of meningoencephalitis subsequently, without rhinorrhea. By using high resolution CT scans, previous traumatic skull injury was verified and a fissure in the frontoethmoidal region, far from the point of direct impact, was detected. The patient underwent transnasal endoscopic surgery, in order to seal the communication on skull basis. The patient did not suffer from meningoencephalitis during the next two years. CONCLUSION: In the cases with late occurrence of posttraumatic meningoencephalitis with no signs of rhinorrhea, a possibility of an existing communication between intracranial and nasal cavities should be considered, as well. By applying modern diagnostic and therapeutic procedures such communication should be precisely located and sealed. PMID- 21268932 TI - The keys to IBD 2010: treatment, diagnosis and pathophysiology. Proceedings of Falk Symposium 172. March 26-27, 2010. Miami, Florida, USA. PMID- 21268933 TI - Evolutionary theory and group selection: the question of warfare. PMID- 21268934 TI - Queer history. PMID- 21268935 TI - The Gay Oral History Project in Zimbabwe: black empowerment, human rights, and the research process. PMID- 21268936 TI - Ethnographic appropriations: German exploration and fieldwork in West-Central Africa. PMID- 21268939 TI - "Why is that white man pointing that thing at me?" Representing the Maasai. PMID- 21268941 TI - A child's eye view of New Zealand history: child welfare and family policy. PMID- 21268943 TI - Strategies of women teachers 1860-1920: feminization in Dutch elementary and secondary schools from a comparative perspective. PMID- 21268944 TI - Hard times, expedient measures: women teachers in Queensland rural schools, 1920 50. PMID- 21268946 TI - National identity, citizenship and education for displacement: Spanish refugee children in Cambridge, 1937. PMID- 21268947 TI - "Saving the nation's children": teachers, wartime evacuation in England and Wales and the construction of national identity. PMID- 21268948 TI - Whose country is it anyway? The construction of a new identity through schooling for Maori in Aotearoa/New Zealand. PMID- 21268949 TI - Magnetic resonance imaging in diagnosis, staging and radiotherapy planning for prostate cancer. AB - T2-weighted magnetic resonance imaging (MRI), preferably using an endorectal coil, is able to clearly depict the normal prostatic anatomy and to identify prostate cancer with fair diagnostic accuracy. The latter can be further increased by using functional techniques such as spectroscopy (assessment of prostatic metabolism), dynamic contrast-enhanced MRI (assessment of angiogenesis) and diffusion-weighted imaging (assessment of cellular density). T2-weighted MRI is an important tool for local staging of prostate cancer in patients clinically staged as cT1 or cT2, because of its high specificity for macroscopic capsular extension or seminal vesicle invasion. Compared to CT-imaging, MRI depicts the internal prostatic anatomy, prostatic margins and the extent of prostatic tumours much more clearly. This benefit can be exploited to improve the accuracy of target delineations in radiotherapy planning. PMID- 21268950 TI - Cancer-related fatigue. AB - Cancer-related fatigue (CRF) is the most commonly reported symptom in patients with cancer with a prevalence up to 100%. It has a significant negative impact on quality of life. An effective management of CRF could significantly reduce the disease burden associated with cancer and its treatment. Unfortunately, the underlying pathophysiology is very complex and not uniform. This article reviews the possible therapy of contributing factors, nonpharmacological treatment, such as exercise and psychosocial interventions, and pharmacologic approaches in managing CRF. Numerous drugs, such as psychostimulants (methylphenidate, dexamphetamines, modafinil and pemoline), antidepressants, corticosteroids, L carnitine, donepezil and guarana have been studied. Methylphenidate, modafinil and guarana show the most promising results so far. However, additional randomized, placebo-controlled trials are needed to determine the benefit of these and other drugs in the treatment of CRF. PMID- 21268951 TI - Prevalence of early postoperative arrhythmias in children with delayed open-heart surgery for severe congenital heart disease. AB - BACKGROUND; Our aim was to determine the incidence, risk factors and outcome of early postoperative arrhythmias in children with delayed treatment of severe congenital heart disease. METHODS: A prospective study was conducted in 141 consecutive children with delayed referral from emerging countries, who underwent open-heart surgery. RESULTS: Sinus node dysfunction was noted in 5 cases. Preoperative moderate extrasystoly was common and its incidence significantly increased in the postoperative phase. Overall, 9 patients required specific antiarrhythmic therapy: 6 for sustained atrioventricular reciprocating tachycardia, and 3 respectively for atrial flutter, atrial fibrillation and junctional ectopic tachycardia. Non-sustained atrioventricular and ventricular tachycardia required no therapy in respectively 6 and 1 case. Postoperative complete atrioventricular block was observed in 6 patients and remained permanent in 3. No major complications resulted from those arrhythmias. Preoperative low oxygen saturation, preoperative arrhythmias, as well as long cardiopulmonary bypass time and aortic cross-clamp time, were risk factors for early postoperative arrhythmias. CONCLUSIONS: Children with delayed surgery for congenital heart disease are at risk of developing early postoperative arrhythmias depending on the complexity of their disease and of its treatment. However, their prevalence (14%) is not higher than in the general population of cardiac children. PMID- 21268952 TI - Prevalence of chronic renal failure stage 3 or more in HIV-infected patients in Antwerp: an observational study. AB - The introduction of Highly Active Antiretroviral Therapy has transformed HIV infection from an inevitably lethal disease to a chronic condition with a life expectancy comparable to that of people with diabetes mellitus. In recent years it has become evident that people living with HIV/AIDS have an increased risk of developing cardiovascular disease and it is expected that the prevalence of chronic kidney disease will rise accordingly. To investigate the prevalence of chronic kidney disease in patients with HIV, we conducted a retrospective observational analysis using the clinical database of a large centre (Institute of Tropical Medicine) in the urban area of Antwerp, Belgium. The prevalence of chronic kidney disease among HIV infected subjects was found to be 3.0%. The development of chronic kidney disease was associated with age above 50 years, lower CD4 cell counts and Caucasian origin. Screening for chronic renal disorders and prevention of evolution toward chronic renal failure is a crucial challenge in the management of people living with HIV/AIDS. PMID- 21268953 TI - Abdominal decompression for abdominal compartment syndrome in critically ill patients: a retrospective study. AB - BACKGROUND: The abdominal compartment syndrome (ACS) refers to organ dysfunction that may occur as a result of increased intra-abdominal pressure (IAP). Successful management may require abdominal decompression and temporary abdominal closure (TAC). The aim of this study was to analyze the characteristics of patients requiring abdominal decompression, to describe the methods used for TAC, and to study the outcome of these patients. METHODS: A series of critically ill patients who required abdominal decompression for ACS between January 2000 and March 2007 were reviewed retrospectively. Age, gender, severity of organ dysfunction before decompression and the cause of ACS as well as the type of abdominal closure system and length of ICU-stay were recorded. Definitive abdominal closure and in-hospital mortality were the main outcome parameters. RESULTS: Eighteen patients with primary ACS and 6 with secondary ACS required decompressive Laparotomy. Patients' ages ranged from 18 to 89 years (mean 50.7). The median preoperative IAP was 26 mmHg, and IAP decreased to 13 mmHg after decompressive laparotomy. Organ function, as quantified by the SOFA scoring system, improved significantly after the intervention. Eight patients had immediate primary fascial closure after the decompressive procedure and 16 patients required TAC. The majority of the survivors underwent planned ventral hernia repair at a later stage. The mean length of stay in the ICU was 23 (+/- 16) days. Overall, fifteen patients survived (63%). CONCLUSIONS: Decompressive Laparotomy was effective in reducing IAP and was associated with an improvement in organ function. In most of the patients, the abdomen could not be closed after decompression, and fascial repair was delayed. PMID- 21268954 TI - A case series of embryonal rhabdomyosarcoma of the head and neck in adults. AB - Embryonal rhabdomyosarcoma (RMS) is a rare malignant mesenchymal tumour that is believed to arise from cells committed to a skeletal muscle lineage. The head and neck region is among the most frequent locations for embryonal RMS in adults. We present a retrospective review of seven patients treated in our institution between 2000 and 2008. The age at diagnosis ranged from 19 to 41 years. One patient received primary surgery followed by adjuvant radiotherapy. Six inoperable patients were treated along a single chemotherapy protocol: the VIA VIP regimen (a combination of vincristine, ifosfamide and doxorubicin (VIA) in alternation with etoposide, ifosfamide and cisplatin (VIP) administered in 3 weekly cycles), followed by local therapy, involving radiation therapy and/or surgery. An objective response to chemotherapy was observed in all six patients. Three out of seven patients remain disease-free with a median follow up of 4.5 years. Although the prognosis of head and neck embryonal RMS is worse in adults than in children, a multimodality treatment combining surgery, radiotherapy and intensive chemotherapy is feasible and effective in this population. PMID- 21268955 TI - Necrotizing fasciitis complicated by fatal multiple organ dysfunction due to Pasteurella multocida infection: a case report. AB - Necrotizing fasciitis is rarely caused by Pasteurella multocida, a facultative anaerobic gram-negative coccobacillus found in the flora of the oro gastrointestinal tract of many animals. We describe a rare case with overwhelming septicaemia resulting in multiple organ failure. PMID- 21268956 TI - Aspiration pneumonia: an underestimated cause of severe respiratory failure in patients with haematological malignancies and severe oral mucositis? AB - Aspiration pneumonia is rarely considered in the differential diagnosis of respiratory failure in patients suffering from haematologic malignancies in daily practice. We describe four patients who were admitted with severe respiratory failure in the ICU over a one-year-period prospective survey (a total of 72 patients with haematological malignancies of which 34 presented with respiratory failure). All of these patients had chemotherapy-induced severe oral mucositis (WHO grade ILL-IV) for which three of them received opioids. All had a history of cough after oral rinsing and two of them experienced sudden brief desaturation in the days before ICU referral. Two of these patients, both in allogeneic bone marrow transplant setting, died. With this data, we want to draw the attention to the diagnosis of aspiration pneumonia in this group of patients. PMID- 21268957 TI - Chyloma: an uncommon cause of supraclavicular swelling. AB - We report the case of a 46-year-old woman who noticed a swelling of the left supraclavicular fossa of rapid onset soon after a Mycoplasma Pneumoniae upper respiratory infection. On the basis of clinical history, physical examination and imaging findings, a diagnosis of chyloma due to intense non-productive coughing bouts was made. The supraclavicular swelling progressively disappeared after a few days. This observation prompted us to briefly review the pathophysiology of chylomas. PMID- 21268958 TI - Occurrence of pulmonary artery aneurysms and pulmonary artery thrombosis in a young man. AB - Behcet's disease (BD) is a multisystemic inflammatory disorder of unknown aetiology. Arterial involvement is uncommon but associated with important morbidity and mortality. We describe the clinical course of BD with severe pulmonary artery involvement in a 19-year-old man. He presented with massive haemoptysis related to pulmonary artery aneurysms. Initial treatment consisted in urgent right inferior lobectomy, corticosteroids and monthly intravenous cyclophosphamide. Subsequently, he developed pulmonary artery thrombosis at non aneurysmatic sites. Corticosteroid therapy was intensified, monthly intravenous cyclophosphamide was continued and an anticoagulant was added to the treatment with a favourable clinical and radiological response. Our case illustrates that timely initiation of highly potent immunosuppressive therapy is critical to obtain a favourable outcome. At present, a consensus regarding optimal management of vascular BD is lacking. ALthough anticoagulation is not generally recommended, our report encourages a patient-based decision after carefully tailoring potential risks and benefits. PMID- 21268959 TI - Nocardia asiatica visiting Belgium: nocardiosis in a immunocompetent patient. AB - We report the case of a 57-year-old lady presenting with a Nocardia asiatica infection in Belgium. No predisposing conditions were found except for an underlying asthma. We reviewed the literature and discussed the role of linezolid in the treatment of nocardiosis. PMID- 21268960 TI - Relapse of a renal inflammatory pseudotumour associated with Wegener's granulomatosis. AB - We report the case of a 32-year-old patient with Wegener's granulomatosis (WG) associated with a (biopsy - proven) renal inflammatory pseudotumour (IPT) of the left kidney treated by a partial nephrectomy, glucocorticoids and immunosuppressive drugs, in whom a relapse of renal IPT was found 6 years after the diagnosis of the first IPT. The originality of this observation lies in the fact that a relapse of IPT has never been described and also in the fact that complete regression of the IPT relapse was obtained with immunosuppressive treatment, while renal IPTs are currently treated by total or partial resection of the kidney. Finally, we discuss the potential benefits of an integrated 18fluorodeoxyglucose PET/CT for the follow-up of WG, since this imaging technique contributed to the management of the present case. PMID- 21268961 TI - Guidelines for colorectal cancer screening--a puzzle of tests and strategies. AB - Colorectal cancer (CRC) is a leading cause of cancer death around the World. An effective way to reduce colorectal cancer mortality is to screen for it and its precursor, the adenoma. In industrialized countries the mortality related to CRC is decreasing probably due to better screening programmes in average-risk individuals as well as changes in risk factors. Screening procedures are various including faecal screening tests--which primarily detect colon cancer--and structural tests (endoscopy--flexible sigmoidoscopy or colonoscopy--, Barium enema, Computed Tomography Colonography) that may detect not only cancer but also its precursors. Video-colon capsule is a new tool for exploring the colon but needs further studies before becoming a screening test. The choice of a screening test includes several factors as cost, invasiveness, acceptability, adherence to repeat testing and acceptance referral for colonoscopy for positive tests as well as local financial resources. Every screening programme has advantages and limitations. Enhancing use and quality of CRC screening programmes is mandatory. PMID- 21268962 TI - Management of hypotonic hyponatremia. PMID- 21268963 TI - Autosomal dominant polycystic kidney disease with cystic haemorrhage and infection. PMID- 21268964 TI - Grip myotonia. PMID- 21268965 TI - Comparison of the in vitro activity of meropenem and doripenem against Pseudomonas aeruginosa and multidrug-resistant Enterobacteriaceae. PMID- 21268966 TI - Opportunities for Tennessee nurses: crafting health care reform. PMID- 21268967 TI - To err is human. PMID- 21268968 TI - The Botswana "I am proud to be a nurse" campaign. PMID- 21268969 TI - Amphibian chytridiomycosis. AB - Amphibian chytridiomycosis is a fungal disease caused by the chytrid fungus Batrachochytrium dendrobatidis. It is arguably the most significant recorded infectious disease of any vertebrate class. The disease is reducing amphibian biodiversity across most continents and regions of the world, affecting the resilience of surviving populations and driving multiple species to extinction. It is now recognised by the World Organisation for Animal Health (OIE) as an internationally notifiable disease. Collaborative research in areas including the development of diagnostic assays, distribution and impact of the disease, and management (treatment and policy) has assisted in leading a paradigm shift in accepting infectious disease as a major factor influencing wildlife population stability and biodiversity. PMID- 21268970 TI - Amphibian decline and extinction: what we know and what we need to learn. AB - For over 350 million yr, thousands of amphibian species have lived on Earth. Since the 1980s, amphibians have been disappearing at an alarming rate, in many cases quite suddenly. What is causing these declines and extinctions? In the modern era (post 1500) there are 6 leading causes of biodiversity loss in general, and all of these acting alone or together are responsible for modern amphibian declines: commercial use; introduced/exotic species that compete with, prey on, and parasitize native frogs and salamanders; land use change; contaminants; climate change; and infectious disease. The first 3 causes are historical in the sense that they have been operating for hundreds of years, although the rate of change due to each accelerated greatly after about the mid 20th century. Contaminants, climate change, and emerging infectious diseases are modern causes suspected of being responsible for the so-called 'enigmatic decline' of amphibians in protected areas. Introduced/exotic pathogens, land use change, and infectious disease are the 3 causes with a clear role in amphibian decline as well as extinction; thus far, the other 3 causes are only implicated in decline and not extinction. The present work is a review of the 6 causes with a focus on pathogens and suggested areas where new research is needed. Batrachochytrium dendrobatidis (Bd) is a chytrid fungus that is an emerging infectious disease causing amphibian population decline and species extinction. Historically, pathogens have not been seen as a major cause of extinction, but Bd is an exception, which is why it is such an interesting, important pathogen to understand. The late 20th and early 21st century global biodiversity loss is characterized as a sixth extinction event. Amphibians are a striking example of these losses as they disappear at a rate that greatly exceeds historical levels. Consequently, modern amphibian decline and extinction is a lens through which we can view the larger story of biodiversity loss and its consequences. PMID- 21268971 TI - Two amphibian diseases, chytridiomycosis and ranaviral disease, are now globally notifiable to the World Organization for Animal Health (OIE): an assessment. AB - The global trade in amphibians entails the transport of tens of millions of live animals each year. In addition to the impact harvesting wild animals can have on amphibian populations, there is mounting evidence that the emerging pathogens Batrachochytrium dendrobatidis and ranaviruses, the aetiological agents of chytridiomycosis and ranaviral disease, respectively, are spread through this trade. The link between these pathogens and amphibian declines and extinctions suggests that the epidemiological impact of the trade is significant and may negatively affect conservation and trade economics. Here we present a brief assessment of the volume of the global trade in live amphibians, the risk of individuals harboring infection, and information on the recent listing by the World Organization for Animal Health (OIE) of chytridiomycosis and ranaviral disease in the OIE Aquatic Animal Health Code. This listing made chytridiomycosis and ranaviral disease internationally notifiable diseases and thus subject to OIE standards, which aim to assure the sanitary safety of international trade in live amphibians and their products. PMID- 21268972 TI - Batrachochytrium dendrobatidis: requirement for further isolate collection and archiving. AB - The fungal pathogen Batrachochytrium dendrobatidis (Bd) causes the disease chytridiomycosis, which is lethal to many species of amphibians worldwide. Many studies have investigated the epidemiology of chytridiomycosis in amphibian populations, but few have considered possible host-pathogen coevolution. More specifically, investigations focused on the evolution of Bd, and the link with Bd virulence, are needed. Such studies, which may be important for conservation management of amphibians, depend on access to Bd isolates. Here we provide a summary of known Bd isolates that have been collected and archived in various locations around the world. Of 257 Bd isolates, we found that 53% originate from ranids in the United States. In many cases, detailed information on isolate origin is unavailable, and it is unknown how many isolates are cryo-archived. We suggest the creation of a centralized database of isolate information, and we urge researchers and managers to isolate and archive Bd to facilitate future research on chytridiomycosis. PMID- 21268973 TI - BSA reduces inhibition in a TaqMan assay for the detection of Batrachochytrium dendrobatidis. AB - A TaqMan assay for the causative agent of chytridiomycosis in amphibians (Batrachochytrium dendrobatidis) can be inhibited by phenolic compounds, including humic and tannic acids, resulting in false negatives. Bovine serum albumin (BSA) is known to reduce inhibition of PCR when samples are contaminated with these inhibitors. We assessed the effect of BSA in reducing inhibition of the TaqMan assay when analyzing skin swabs for B. dendrobatidis. We found that the addition of BSA to the TaqMan reaction reduced inhibition to insignificant levels. BSA did not appreciably affect the efficiency or analytical sensitivity of the TaqMan reaction in the analysis of standard DNA solutions free from environmental inhibitors. We recommend the addition of 400 ng microl(-1) of BSA to the standard TaqMan assay to reduce inhibition associated with sampling wild amphibians. PMID- 21268974 TI - Application of the survey protocol for chytridiomycosis to Queensland, Australia. AB - Spread of the amphibian chytrid fungus Batrachochytrium dendrobatidis (Bd), which causes chytridiomycosis, has resulted in the extinction of frogs, but the distribution of Bd is incompletely known. We trialled the survey protocol for Bd by attempting to systematically map its distribution in Queensland, Australia. Bd was easily detected in known infected areas, such as the Wet Tropics and South East Queensland. It was not detected in bioregions adjacent to, but inland from or to the north of, infected regions: Einasleigh Uplands and Cape York adjacent to the infected Wet Tropics; and Brigalow Belt South adjacent to the infected South East Queensland bioregion. These regions where Bd was not detected have bordered infected regions for between 15 yr (in northern Queensland) and 30 yr (in southern Queensland), and so they define the geographical limits of Bd with regard to the long-term environmental conditions in Queensland. The Gulf Plains, a bioregion distant from infected bioregions, was also negative. Bd was confined to rainforest and bordering habitats, such as wet eucalypt forests. Infections were largely confined to permanent water-associated species, consistent with this being an important cause of this group having the greatest declines. Our data supports biogeographic climatic models that show much of inland and northern Australia to be too hot and dry to support Bd. As there is limited opportunity for Bd to spread further in Queensland, the priority for management is reducing the impact of Bd in affected populations and assisting frogs to disperse into their former distributions. Given that the survey protocol has been applied successfully in Australia it may be useful for mapping the distribution of Bd in other parts of the world. PMID- 21268975 TI - A molecular perspective: biology of the emerging pathogen Batrachochytrium dendrobatidis. AB - Ten years after the first discovery of the chytrid pathogen Batrachochytrium dendrobatidis (Bd), the catastrophic effect of Bd on wild amphibian populations is indisputable. However, a number of persistent questions remain about Bd's origin and mechanisms of pathogenicity. Here we discuss the promise of genetic and genomic tools for answering these previously intractable questions about the biology and evolutionary history of Bd. Full genomes of 2 Bd strains have recently been sequenced, and Bd research on this species using population genetics, phylogenetics, proteomics, comparative genomics and functional genomics is already underway. We review some of the insights gleaned from the first studies using these genome-scale approaches focusing particularly on Bd's genomic architecture, patterns of global genetic variation, virulence factors and genetic interactions with hosts. Avenues of future research promise to be particularly fruitful and highlight the need for integrative studies that unite genetic, ecological and spatial data in both Bd and its amphibian hosts. PMID- 21268976 TI - Identification and partial characterization of an elastolytic protease in the amphibian pathogen Batrachochytrium dendrobatidis. AB - Batrachochytrium dendrobatidis (Bd) is a fungus that causes chytridiomycosis, a disease that has been implicated as a cause of amphibian population declines worldwide. Infected animals experience hyperkeratosis and sloughing of the epidermis due to penetration of the keratinized tissues by the fungus. These symptoms have led us to postulate that Bd produces proteases that play a role in the infection process. Here, we show that Bd is capable of degrading elastin in vitro, a protein found in the extracellular matrix of the host animal. Elastolytic enzyme activity was partially purified using ion exchange chromatography and size-exclusion filtration from cultures grown in inducing media. The elastolytic activity of the purified fraction had a pH optimum of 8, was strongly inhibited by EDTA and phenylmethylsulfonyl fluoride (PMSF), and was partially inhibited by an elastase-specific inhibitor. This activity was also enhanced by the presence of Mg2+ and Ca2+ but not Zn2+. An antiserum directed against Aspergillus fumigatus serine protease (Alp) was found to react with a polypeptide of approximately 110 kDa from the purified material. Using immunofluorescence, this antiserum was also observed to react with zoospores and sporangia grown on toad skin. These observations suggest that Bd may produce proteases similar to those produced by other pathogenic fungi that are capable of degrading proteins found in the extracellular matrix. The proteolytic activity exhibited in vitro might aid the organism in its ability to colonize and destroy the epidermis of its amphibian host. PMID- 21268977 TI - Experimental infection of self-cured Leiopelma archeyi with the amphibian chytrid Batrachochytrium dendrobatidis. AB - The susceptibility of Archey's frog Leiopelma archeyi to Batrachochytrium dendrobatidis (Bd) is unknown, although one large population is thought to have declined sharply due to chytridiomycosis. As primary infection experiments were not permitted in this endangered New Zealand species, 6 wild-caught L. archeyi that naturally cleared infections with Bd while in captivity were exposed again to Bd to assess their immunity. These frogs were from an infected population at Whareorino, which has no known declines. All 6 L. archeyi became reinfected at low intensities, but rapidly self cured, most by 2 wk. Six Litoria ewingii were used as positive controls and developed heavier infections and clinical signs by 3 wk, demonstrating that the zoospore inoculum was virulent. Six negative controls of each species remained uninfected and healthy. Our results show that L. archeyi that have self cured have resistance to chytridiomycosis when exposed. The pattern is consistent with innate or acquired immunity to Bd, and immunological studies are needed to confirm this. PMID- 21268978 TI - Treatment of chytridiomycosis requires urgent clinical trials. AB - Effective and safe treatments of amphibian chytridiomycosis, caused by Batrachochytrium dendrobatidis (Bd), are needed to prevent mortality in captive programs, reduce the risk of disease spread, and better manage the disease in threatened wild populations. Bd is susceptible to a range of antifungal agents and low levels of heat (>30 degrees C) when tested in vitro, but there are few proven methods for clearing adult amphibians of Bd, and acute drug toxicity is a problem for tadpoles and juveniles. In postmetamorphic animals, heat (32 and 37 degrees C) is the only well-supported treatment. Antifungal drugs have not undergone rigorous testing--for example, trials were small or lacked controls and thorough post-treatment testing. In addition, pharmacokinetic studies have not been performed so there are no data on blood or tissue levels of antifungal agents. However, itraconazole baths have been widely used in amphibian rescue and conservation programs and anecdotal evidence suggests that they are effective for adults and subadults. In an experimental trial with tadpoles, a low dose of itraconazole cleared Bd but may have been associated with cutaneous depigmentation. Fluconazole appeared safe for tadpoles as it did not cause mortality, and future attempts to find an effective dose may be worthwhile. Palliative restoration of blood sodium and potassium levels by administration of electrolyte solutions appears useful in frogs with clinical chytridiomycosis. Randomised and blinded clinical trials, which include basic pharmacological studies, are urgently needed to provide comparable evidence for the safety and efficacy of treatment options which are likely to vary with amphibian species. Priorities are to validate and optimize the use of heat and itraconazole regimes. PMID- 21268979 TI - Minimising exposure of amphibians to pathogens during field studies. AB - Many of the recent global amphibian mass mortalities, declines and extinctions have been attributed to the emerging infectious disease chytridiomycosis. There have been mass mortalities due to ranaviral disease but no major declines or extinctions. Controlling the transmission and spread of disease is of utmost importance, especially where there is the potential for human involvement. We have reviewed current hygiene guidelines for working with wild frogs, identified potential flaws and recommended those most suitable and effective for the field environment. Our within-site hygiene measures aim to reduce the risk of transmission among individuals. These measures encompass the capture, handling and holding of amphibians, skin disinfection before and after invasive procedures, marking frogs, sealing open wounds and treatment of accessory equipment. Our between-site hygiene measures aim to mitigate the risk of pathogen spread among populations. We have designed a risk calculator to help simplify and standardise the decision-making process for determining the level of risk and appropriate risk mitigation strategies to reduce the risk of increasing pathogen spread above background levels. Calculation of an overall risk score for pathogen spread takes into account the prior activity of field workers, the proposed activity, remoteness of the site, presence of known pathogens and the consequences of increased pathogen spread for amphibians in a given area. PMID- 21268980 TI - Batrachochytrium dendrobatidis in the live frog trade of Telmatobius (Anura: Ceratophryidae) in the tropical Andes. AB - Species of frogs in the genus Telmatobius are traded and sold for human consumption in the Andes and in coastal cities of Peru and Bolivia. These frogs are harvested from wild populations. We report high prevalence of infection by the pathogenic fungus Batrachochytrium dendrobatidis in live frogs purchased at the main market in Cusco, Peru, from January 2008 to January 2010. We suggest that the transport of native anurans through the live frog trade could facilitate the spread of this fungus among Andean frogs. The tropical Andes are the most important biodiversity hotspot for amphibians. Because many neotropical taxa are known to be susceptible to chytridiomycosis, the presence of a large reservoir of infection in the frog trade poses a significant threat to amphibian conservation. PMID- 21268981 TI - Distribution and risk factors for spread of amphibian chytrid fungus Batrachochytrium dendrobatidis in the Tasmanian Wilderness World Heritage Area, Australia. AB - Chytridiomycosis is an emerging infectious disease caused by the pathogen Batrachochytrium dendrobatidis (Bd) and is the cause of the decline and extinction of amphibian species throughout the world. We surveyed the distribution of Bd within and around the Tasmanian Wilderness World Heritage Area (TWWHA), a 1.38 million ha area of significant fauna conservation value, which provides the majority of habitat for Tasmania's 3 endemic frog species (Litoria burrowsae, Bryobatrachus nimbus and Crinia tasmaniensis). Bd was detected at only 1 (3%) of the 33 sites surveyed within the TWWHA and at 15 (52%) of the 29 sites surveyed surrounding the TWWHA. The relatively low incidence of the disease within the TWWHA suggests that the majority of the TWWHA is currently free of the pathogen despite the fact that the region provides what appears to be optimal conditions for the persistence of Bd. For all survey sites within and around the TWWHA, the presence of Bd was strongly associated with the presence of gravel roads, forest and < 1000 m altitude--factors that in this study were associated with human-disturbed landscapes around the TWWHA. Conversely, the presence of walking tracks was strongly associated with the absence of Bd, suggesting an association of absence with relatively remote locations. The wide distribution of Bd in areas of Tasmania with high levels of human disturbance and its very limited occurrence in remote wilderness areas suggests that anthropogenic activities may facilitate the dissemination of the pathogen on a landscape scale in Tasmania. Because the majority of the TWWHA is not readily accessible and appears to be largely free of Bd, and because Tasmanian frogs reproduce in ponds rather than streams, it may be feasible to control the spread of the disease in the TWWHA. PMID- 21268982 TI - Future potential distribution of the emerging amphibian chytrid fungus under anthropogenic climate change. AB - Anthropogenic climate change poses a major threat to global biodiversity with a potential to alter biological interactions at all spatial scales. Amphibians are the most threatened vertebrates and have been subject to increasing conservation attention over the past decade. A particular concern is the pandemic emergence of the parasitic chytrid fungus Batrachochytrium dendrobatidis, which has been identified as the cause of extremely rapid large-scale declines and species extinctions. Experimental and observational studies have demonstrated that the host-pathogen system is strongly influenced by climatic parameters and thereby potentially affected by climate change. Herein we project a species distribution model of the pathogen onto future climatic scenarios generated by the IPCC to examine their potential implications on the pandemic. Results suggest that predicted anthropogenic climate change may reduce the geographic range of B. dendrobatidis and its potential influence on amphibian biodiversity. PMID- 21268983 TI - Presence of the amphibian chytrid fungus Batrachochytrium dendrobatidis in threatened corroboree frog populations in the Australian Alps. AB - Since the early 1980s, the southern corroboree frog Pseudophryne corroboree and northern corroboree frog P. pengilleyi have been in a state of decline from their sub-alpine and high montane bog environments on the southern tablelands of New South Wales, Australia. To date, there has been no adequate explanation as to what is causing the decline of these species. We investigated the possibility that a pathogen associated with other recent frog declines in Australia, the amphibian chytrid fungus Batrachochytrium dendrobatidis, may have been implicated in the decline of the corroboree frogs. We used histology of toe material and real-time PCR of skin swabs to investigate the presence and infection rates with B. dendrobatidis in historic and extant populations of both corroboree frog species. Using histology, we did not detect any B. dendrobatidis infections in corroboree frog populations prior to their decline. However, using the same technique, high rates of infection were observed in populations of both species after the onset of substantial population declines. The real-time PCR screening of skin swabs identified high overall infection rates in extant populations of P. corroboree (between 44 and 59%), while significantly lower rates of infection were observed in low-altitude P. pengilleyi populations (14%). These results suggest that the initial and continued decline of the corroboree frogs may well be attributed to the emergence of B. dendrobatidis in populations of these species. PMID- 21268984 TI - Batrachochytrium dendrobatidis in Darwin's frog Rhinoderma spp. in Chile. AB - The presence of the chytrid fungus Batrachochytrium dendrobatidis in Chile was evaluated in 2 endangered frog species of the genus Rhinoderma. Specimens from a captive rearing facility, wild populations and preserved collection material were analyzed using histological and molecular techniques. The fungus was identified in the rearing facility and in wild populations, but not in the archived frogs. This study confirms, for first time, the presence of chytridiomycosis in Rhinoderma darwinii in Chile. PMID- 21268985 TI - Batrachochytrium dendrobatidis infection dynamics in the Columbia spotted frog Rana luteiventris in north Idaho, USA. AB - The pathogenic chytrid fungus Batrachochytrium dendrobatidis (Bd) is contributing to amphibian declines worldwide. Temperature plays an important role in both pathogen growth and host immune function, but little is known about seasonal dynamics of Bd infection in north temperate regions. Our objective was to increase understanding of Bd disease ecology by investigating patterns of Bd infection of Columbia spotted frogs Rana luteiventris across seasons, age classes, and sexes in north Idaho, USA. We collected skin swabs from 223 R. luteiventris in spring, summer, and fall 2009 at 7 ponds in the Palouse region and quantified Bd zoospores for each sample using quantitative PCR. Across seasons, Bd prevalence of adults was higher in summer than in spring or fall, suggesting that individuals may be clearing low-level infections over the summer. Among age classes, all but one late stage tadpole (Gosner stage 43-45) tested negative for Bd. Conversely, 100% of metamorphs tested positive for Bd and had the highest Bd loads of all age classes, suggesting they may be the most vulnerable age class. Adult R. luteiventris had high infection prevalence (> 60%) in all seasons, indicating that Bd infection is maintained within populations and that adults likely serve as disease reservoirs across seasons. Among adults, we also found weak evidence for females having higher infection prevalence than males. Further laboratory and field studies are needed to determine whether there are individual and population impacts from Bd on R. luteiventris and other amphibians in north Idaho. PMID- 21268986 TI - Amphibian chytrid fungus and ranaviruses in the Northwest Territories, Canada. AB - Pathogens can cause serious declines in host species, and knowing where pathogens associated with host declines occur facilitates understanding host-pathogen ecology. Suspected drivers of global amphibian declines include infectious diseases, with 2 pathogens in particular, Batrachochytrium dendrobatidis (Bd) and ranaviruses, causing concern. We explored the host range and geographic distribution of Bd and ranaviruses in the Taiga Plains ecoregion of the Northwest Territories, Canada, in 2007 and 2008. Both pathogens were detected, greatly extending their known geographic distributions. Ranaviruses were widespread geographically, but found only in wood frogs. In contrast, Bd was found at a single site, but was detected in all 3 species of amphibians in the survey area (wood frogs, boreal chorus frogs, western toads). The presence of Bd in the Northwest Territories is not congruent with predicted distributions based on niche models, even though findings from other studies at northern latitudes are consistent with those same models. Unexpectedly, we also found evidence that swabs routinely used to collect samples for Bd screening detected fewer infections than toe clips. Our use and handling of the swabs was consistent with other studies, and the cause of the apparent lack of integrity of swabs is unknown. The ranaviruses detected in our study were confirmed to be Frog Virus 3 by sequence analysis of a diagnostic 500 bp region of the major capsid protein gene. It is unknown whether Bd or ranaviruses are recent arrivals to the Canadian north. However, the genetic analyses required to answer that question can inform larger debates about the origin of Bd in North America as well as the potential effects of climate change and industrial development on the distributions of these important amphibian pathogens. PMID- 21268987 TI - Early-spring survey for Batrachochytrium dendrobatidis in wild Rana dybowskii in Heilongjiang Province, China. AB - Batrachochytrium dendrobatidis has been investigated worldwide because of its importance in population declines in multiple species of amphibians; however, little is known regarding the disease status of all native amphibian species in China. The present study is the first survey of chytridiomycosis in free-ranging amphibian populations in China, and it examined the possible presence of B. dendrobatidis in Rana dybowskii in northeastern China (Heilongjiang Province). R. dybowskii is mainly distributed in the northeast part of China and is intensively hunted for human consumption, making populations vulnerable to extirpation in the event of additional stresses from disease epidemics. The survey was performed in early spring of 2008, using a PCR assay, histological examination of skin samples, and zoospore culture. In total, 191 frogs were examined; thus, a 95% confidence limit for prevalence of 1.57% was selected. Our results demonstrate that R. dybowskii is currently free from chytridiomycosis in Heilongjiang, even though the natural conditions of the sampling sites are suitable for the occurrence of B. dendrobatidis. Central and local governments should implement strict management measures to prevent the escape of non-native commercial amphibian species into this area, which might endanger local populations of native species. PMID- 21268988 TI - Amphibian chytrid fungus Batrachochytrium dendrobatidis in Cusuco National Park, Honduras. AB - Amphibian population declines in Honduras have long been attributed to habitat degradation and pollution, but an increasing number of declines are now being observed from within the boundaries of national parks in pristine montane environments. The amphibian chytrid fungus Batrachochytrium dendrobatidis has been implicated in these declines and was recently documented in Honduras from samples collected in Pico Bonito National Park in 2003. This report now confirms Cusuco National Park, a protected cloud forest reserve with reported amphibian declines, to be the second known site of infection for Honduras. B. dendrobatidis infection was detected in 5 amphibian species: Craugastor rostralis, Duellmanohyla soralia, Lithobates maculata, Plectrohyla dasypus, and Ptychohyla hypomykter. D. soralia, P. dasypus, and P. hypomykter are listed as critically endangered in the IUCN Red List of Threatened Species and have severely fragmented or restricted distributions. Further investigations are necessary to determine whether observed infection levels indicate an active B. dendrobatidis epizootic with the potential to cause further population declines and extinction. PMID- 21268989 TI - Seasonality of Batrachochytrium dendrobatidis infection in direct-developing frogs suggests a mechanism for persistence. AB - Batrachochytrium dendrobatidis (Bd), a disease-causing amphibian-specific fungus, is widely distributed in Puerto Rico, but is restricted to elevations above 600 m. The effect of this pathogen in the wild was studied by monitoring Eleutherodactylus coqui and E. portoricensis in 2 upland forests at El Yunque, a site characterized by historic population declines in the presence of chytridiomycosis. We tested a potential synergistic interaction between climate and Bd by measuring prevalence of infection and level of infection per individual sampled (number of zoospores), across the dry and wet seasons for 2 yr (between 2005 and 2007). Infection levels in adult frogs were significantly higher during the dry season in both species studied, suggesting a cyclic pattern of dry/ cool wet/warm climate-driven synergistic interaction. These results are consistent with ex situ experiments in which E. coqui infected with Bd were more susceptible to chytridiomycosis when subjected to limited water treatments resembling drought. Long-term data on the prevalence of Bd in the populations studied versus intensity of infection in individual frogs provided contradictory information. However, the conflicting nature of these data was essential to understand the status of Bd in the species and geographical area studied. We conclude that in Puerto Rico, Bd is enzootic, and vulnerability of eleutherodactylid frogs to this pathogen is related to seasonal climatic variables. Our data suggest a mechanism by which this disease can persist in tropical frog communities without decimation of its hosts, but that complex interactions during severe droughts may lead to population crashes. PMID- 21268990 TI - Celebrating the 550th anniversary of the University of Basel: centuries of excellence in chemistry. PMID- 21268991 TI - Bioorganic and bioinorganic chemistry. AB - The interdisciplinary projects in bioinorganic and bioorganic chemistry of the Department of Chemistry, University of Basel led to the preparation of new systems that mimic biologically important processes and to the discovery of compounds from natural sources which are very promising with respect to medical applications. The advances in these areas are reported here. PMID- 21268992 TI - Spectroscopy and chemical dynamics. AB - Chemical physics and molecular spectroscopy are topics with a traditionally strong emphasis in the department. Current research focuses on the spectroscopic characterization of transient molecules present in interstellar space and the preparation, control and chemistry of ultracold molecules and ions in the gas phase. PMID- 21268994 TI - Theoretical and computational chemistry. AB - Computer-based and theoretical approaches to chemical problems can provide atomistic understanding of complex processes at the molecular level. Examples ranging from rates of ligand-binding reactions in proteins to structural and energetic investigations of diastereomers relevant to organo-catalysis are discussed in the following. They highlight the range of application of theoretical and computational methods to current questions in chemical research. PMID- 21268993 TI - Synthesis and catalysis. AB - Research projects of the Department of Chemistry, University of Basel are reviewed ranging from the synthesis of complex natural products to the development of metalorganic catalysts and organocatalysts. PMID- 21268995 TI - Analytical sciences. AB - The research group for analytical and bioanalytical sciences at the Department of Chemistry of the University of Basel is working on miniaturization of analytical techniques, with special focus on detection. Downsizing is a challenge for quantitation and contributions have been made based on different techniques which encompass atomic and molecular spectroscopy as well as different electroanalytical methods. Particularly successful has been contactless conductivity detection and an introduction to this technique is given as an example of the activities of the research group. PMID- 21268996 TI - Biophysical chemistry. AB - Biophysical chemistry at the Department of Chemistry, University of Basel, covers the NMR analysis of protein-protein interaction using paramagnetic tags and sophisticated microscopy techniques investigating the dynamics of biological matter. PMID- 21268997 TI - Supramolecular and nanochemistry. AB - The following contributions describe various research activities of the Department of Chemistry, University of Basel in the area of nanochemistry and supramolecular chemistry. PMID- 21268998 TI - Reaction screening using a microreactor. AB - This article discusses the screening of chemical reactions using a microreactor equipped with infrared spectroscopy as online analytics. An esterification reaction has been optimized in continuous mode with the proposed setup. The esterification did not work well due to the material of the microreactor (stainless-steel 316Ti) that catalyzed the decomposition of formic acid. However, despite the occurrence of decomposition, an optimization could be achieved with this system. PMID- 21268999 TI - Defining clinical issues around tolerance, hyperalgesia, and addiction: a quantitative and qualitative outcome study of long-term opioid dosing in a chronic pain practice. AB - Treatment with opioid medications has grown over the past decades, but has been surrounded by some ongoing controversy and debate to whether it is causing more harm than good for patients. To this end, the field of pain management has suffered from a lack of clarity about some basic definitions on concepts such as tolerance and hyperalgesia. Some characterize these issues as inevitable parts of opioid therapy while other schools of thought look at these issues as relatively rare occurrences. Unfortunately, most of the rhetoric around these topics has occurred with very little in the realm of real world data. To this end, the authors have reviewed the charts of 197 patients treated by a pain specialist for at least 1 year to better illustrate whether notions of tolerance and hyperalgesia are common occurrences and, more importantly, whether they occur within any type of specified timeframe. A total of 197 patient charts were reviewed. The sample had an average age of 49.39 years (range = 19-87 years; standard deviation [SD] = 12.48) and comprised 66 men (33.5 percent) and 131 women (66.5 percent). The patients were seen in the pain practice for an average of 56.52 months (range = 12-155 months; SD = 31.26). On average, the patients maintained an average daily dose of 180 mg morphine equivalents for a period of 35.1 months (range = 3-101 months; SD = 21.3). Looking at the pattern of medication usage change over time, 34.5 percent experienced dose stabilization after the initial titration, 13.2 percent had early dose stabilization within one dose change, and an additional 14.7 percent actually had dose decreases after surgeries or other interventional procedures. Only 6.6 percent of the sample had to be discharged or weaned from controlled substances over time in the clinic. Thus, it appears that tolerance and hyperalgesia are not foregone conclusions when considering placing a patient on long-term opioid therapy. PMID- 21269001 TI - Neonatal abstinence scores in opioid-exposed and nonexposed neonates: a blinded comparison. AB - Twenty-nine opioid-exposed and 26 nonopioid-exposed neonates received neonatal abstinence syndrome (NAS) assessment by an examiner blinded to group status twice daily over the first two postnatal days. The opioid-exposed group had higher mean NAS scores than the nonopioid-exposed group. A 3-sign index, consisting of hyperactive moro reflex, mild tremors when undisturbed, and increased muscle tone, showed excellent discrimination between groups. The use of a 3-sign screening index in the days immediately after birth may provide a cost-effective mechanism for the identification of opioid-exposed infants, particularly in infants of women for whom identification of status as a substance user may not be immediately evident. Although a potentially useful screening tool, the 3-sign screening tool should not replace the full assessment of the opioid-exposed infant after birth. PMID- 21269000 TI - Comparison of postoperative analgesia with epidural butorphanol/bupivacaine versus fentanyl/bupivacaine following pediatric urological procedures. AB - BACKGROUND: The aim of this retrospective study is to compare safety and efficacy of postoperative epidural butorphanol/bupivacaine with the gold-standard epidural analgesic infusion fentanyl/bupivacaine in children. METHODS: With the Institutional Review Board's approval, the authors searched their Pain Management Database and divided children who received epidural analgesia into two groups. Each butorphanol group subject was matched with two fentanyl group subjects. Demographic data, pain scores, epidural interventions, epidural side effects, use of rescue opioid analgesia and adjuvant analgesics, causes of epidural failure, time of first oral intake and ambulation, and length of stay were statistically compared. RESULTS: A total of 191 patients were identified between 2000 and 2007; 58 in epidural butorphanol/bupivacaine and 133 in fentanyl/bupivacaine groups. Demographic data were comparable between the groups. The number of children with good pain control on postoperative days 1 and 2 in butorphanol (84 and 82 percent) and fentanyl (93 and 91 percent) groups were statistically similar (p = 0.06 and 0.13, respectively). Incidences of epidural side effects, especially pruritus, were significantly higher in the fentanyl group. Significantly more children in the butorphanol group required epidural rate changes when compared with those in the fentanyl group. Incidence of failed epidurals was significantly higher in the fentanyl group when compared with that in the butorphanol group. Clinically significant respiratory depression occurred in two children in the fentanyl group and in none of the children in the butorphanol group (p > 0.99). CONCLUSIONS: Epidural butorphanol provided similar analgesia to epidural fentanyl after urological procedures in children, but butorphanol caused less pruritus than fentanyl. IMPLICATION STATEMENT: Epidural analgesia with butorphanol/bupivacaine is effective in children undergoing urological procedures. When compared with epidural fentanyl, epidural butorphanol causes significantly less itching. PMID- 21269003 TI - Cerebral measurements and their correlation with the onset age and the duration of opioid abuse. AB - BACKGROUND: Opioid-dependent patients have been shown to have structural brain alterations. This study focuses on magnetic resonance imaging (MRI) measurements of brain and their correlation with the onset age and the duration of opioid abuse. METHODS: Brain MRI was obtained from 17 opioid-dependent patients (mean age 34 years, SD 7 years) and 17 controls. Compulsive opioid use had begun between ages 15 and 31 (mean 20) and had continued from 5 to 26 years. All patients were tobacco smokers, six had also abused amphetamines and 11 benzodiazepines. Relative volumes of cerebral white matter (WM), gray matter (GM), and cerebrospinal fluid (CSF) spaces were measured. In addition, Sylvian fissure ratio (SFR), bifrontal ratio, and midsagittal cerebellar vermian area were correlated with the onset age and the duration of opioid abuse. RESULTS: The total volume (GM + WM + CSF) of the cerebrum was significantly smaller in patients than in controls (Mann-Whitney U-test, p = 0.026) as well as the absolute volumes of GM and WM (p = 0.014 and p = 0.007, respectively). There was no significant difference in GM and WM volumes normalized with total cerebral volume. In contrast, the absolute volume of CSF did not significantly differ between the groups, but the relative volume of CSF was significantly higher in opioid dependents (p = 0.029). SFR and bifrontal ratio were larger in opioid dependents than in controls (p = 0.005 and p = 0.013). The SFR correlated negatively (p = 0.017, r = - 0.569) and the area of vermis cerebelli correlated positively (p = 0.043, r = 0.496) with the onset age of opioid abuse. The length of opioid abuse and the area of vermis cerebellum had a negative correlation (p = 0.038, r = - 0.523) even though the areas of cerebellar vermis did not significantly differ between opioid dependents and controls. The authors speculate that the onset of substance abuse in adolescence or early adulthood may have in part disturbed the late brain maturation process, as in normal development, the dorsolateral frontal cortex and superior parts of the temporal lobes are the last to maturate. Also, the cerebellar vermis may be affected by early onset substance abuse. It is possible that the brain is more vulnerable to substance abuse at a young age than later in life. PMID- 21269002 TI - Improved detection of ethyl glucuronide and ethyl sulfate in a pain management population using high-throughput LC-MS/MS. AB - BACKGROUND: Ethyl glucuronide (EtG) and ethyl sulfate (EtS) have been proposed as markers for detecting alcohol use because they exhibit extended excretion lifetimes when compared with ethanol; however, their presence is not considered as absolute proof of alcohol use. Two methods are currently used for the detection and quantitation of EtG: immunoassay and mass spectrometry. The purpose of this study was to provide more patient data to better compare the two methods. METHODS: A retrospective diagnostic accuracy study was performed to compare the methods. EtS was also measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) as an additional comparative analyte. The investigators examined 4,287 sequential urines from pain patients to determine the incidence of alcohol use and the corresponding presence of EtG by immunoassay at a cutoff of 500 ng/mL. EtG and EtS were subsequently quantitated in all the urines using LC-MS/MS. RESULTS: A total of 794 samples were found positive by immunoassay, and these results were compared at three distinct LC-MS/MS cutoffs of 100, 500, and 1,000 ng/mL. The incidence of ethanol use in this population was found to be at least 12 percent. CONCLUSIONS: Approximately 30 percent of the samples screened by immunoassay as positive were confirmed to be negative by LC-MS/MS. PMID- 21269004 TI - A retrospective chart review of opioid-induced nausea and somnolence on commencement for cancer pain treatment. AB - Morphine, oxycodone, and fentanyl are major opioids available as controlled release morphine (CRM), controlled-release oxycodone (CRO), and transdermal fentanyl (TDF), respectively, in Japan. The authors conducted a retrospective chart review to examine (1) nausea and somnolence on commencement of CRM, CRO, and TDF for cancer pain treatment, (2) the antiemetic effectiveness of prochlorperazine to prevent opioid-induced nausea, and (3) the side effect of prochlorperazine on somnolence in patients with cancer pain. Four hundred thirteen patients with cancer were prescribed with CRM (N = 66), CRO (N = 196), and TDF (N = 151). The incidence of nausea on commencement of the TDF group (6.8 percent) was significantly lower than that of both the CRM group (22.6 percent) and the CRO group (35.4 percent; p < 0.001). There was no significant difference in the incidence of nausea on commencement of all groups combined with prochlorperazine at dosage of 15 mg/d. The incidence of somnolence on commencement of the TDF group (9.0 percent) was significantly lower than that of both the CRM group (31.3 percent) and the CRO group (41.5 percent; p < 0.001). The incidence of somnolence on commencement of the CRO group combined with prochlorperazine was significantly higher than that of the CRO combined without prochlorperazine (p < 0.05). In conclusion, the incidence of nausea and somnolence on commencement of TDF are significantly lower than that of both CRM and CRO for cancer pain treatment. Prochlorperazine at a dosage of 15 mg/d may not be effective in preventing opioid-induced nausea and may cause somnolence in patients with cancer pain. PMID- 21269005 TI - Current concepts in the management of opioid-induced constipation. AB - Patients with chronic pain on daily opioid therapy are frequently burdened with symptoms of constipation. Opioid-induced constipation (OIC) contributes to an overall negative impact on the quality of life and may result in poor pain management outcomes. Laxative agents are crucial in opioid-related pain management. Following a careful assessment, a stepwise approach to OIC may provide comfort and relief to patients. This article reviews the pathophysiology, assessment, and pharmacological treatment of OIC. Novel approaches for OIC such as the peripheral opioid receptor antagonists and selective serotonin antagonists are also discussed. PMID- 21269007 TI - Neighbourhood variation in hospitalization for unintentional injury among children and teenagers. AB - BACKGROUND: Research suggests that living in more affluent neighbourhoods positively influences children's health. Relationships with injury are less clear. This study examines variations in rates of unintentional injury hospitalization by neighbourhood income for the population aged 0 to 19 in urban Canada. DATA AND METHODS: Acute-care inpatient hospitalization discharge records from 2001/2002 through 2004/2005 for 0-to 19-year-olds were examined. Injuries were classified using the International Classification of Diseases. Census Dissemination Areas were used as neighbourhood proxies; income quintiles were calculated from the 2001 Census. Age-standardized rates of hospitalization per 10,000 person-years at risk were calculated for each type of injury, by sex, age group and neighbourhood income quintile. RESULTS: Children and teenagers in the lowest neighbourhood income quintile generally had a higher rate of unintentional injury hospitalization than did those in the highest. The pattern was particularly evident among children aged 0 to 9 in lower-income neighbourhoods for injuries due to land transportation, poisoning, fire, drowning/ suffocation, being cut or pierced, and the natural environment. INTERPRETATION: Canadian children in lower-income neighbourhoods generally have higher rates of hospitalization due to unintentional injuries, compared with children in higher income neighbourhoods. PMID- 21269006 TI - The relationship between opioid and sugar intake: review of evidence and clinical applications. AB - Opioid dependence poses significant public health risks arising from associated morbidity and mortality caused by accidents, infectious diseases, and social ramifications of crime and unemployment, among other complications. Opioid use, acute and chronic, is also associated with weight gain, glycemic dysregulation, and dental pathology. The literature supporting the connection between opiate use and development of preference for sweet tastes is reviewed, and further association with dental pathology, weight gain, and loss of glycemic control are considered. Additionally, the impact of sweet tastes on the endogenous opioid system, as pertaining to analgesia, is also discussed. The authors discuss the clinical implications in relation to the aforementioned conditions while treating the opiate-dependent patient. PMID- 21269008 TI - Socio-economic status and vitamin/ mineral supplement use in Canada. AB - BACKGROUND: The link between diet quality and socio-economic status (SES) may extend to the use of vitamin/ mineral supplements. This article examines factors related to Canadians' use of such supplements, with emphasis on associations with household income and education. DATA AND METHODS: The data are from the 2004 Canadian Community Health Survey-Nutrition (n = 35,107). The prevalence of vitamin/mineral supplement consumption during the previous month was recorded. Supplement use at the national level was estimated by age/sex groups, SES and chronic conditions. Logistic regression was used to determine significant associations between socio-economic factors and vitamin/mineral supplement use. Estimates of usual calcium intake from food and from food plus supplements were obtained using SIDE-IML. RESULTS: The prevalence of supplement use was significantly higher in females than in males in all age groups 14 or older. Age, being female, high household income and education, and being food-secure were positively associated with supplement use. Supplement use substantially increased the percentage of the population, particularly older adults, meeting the Adequate Intake level for calcium. INTERPRETATION: The reported use of vitamin/mineral supplements varies by age, sex and SES. The relatively low prevalence of use among Canadians of low SES is similar to findings from American studies. These individuals, already at risk for inadequate intake from food, do not make up the difference with vitamin/ mineral supplements. PMID- 21269009 TI - Trends in long-term care staffing by facility ownership in British Columbia, 1996 to 2006. AB - BACKGROUND: Long-term care facilities (nursing homes) in British Columbia consist of a mix of for-profit, not-for-profit non-government, and not-for-profit health region-owned establishments. This study assesses the extent to which staffing levels have changed by facility ownership category. DATA AND METHODS: With data from Statistics Canada's Residential Care Facilities Survey, various types of care hours per resident-day were examined from 1996 through 2006 for the province of British Columbia. Random effects linear regression modeling was used to investigate the effect of year and ownership on total nursing hours per resident day, adjusting for resident demographics, case mix, and facility size. RESULTS: From 1996 to 2006, crude mean total nursing hours per resident-day rose from 1.95 to 2.13 hours in for-profit facilities (p = 0.06); from 1.99 to 2.48 hours in not for-profit non-government facilities (p < 0.001); and from 2.25 to 3.30 hours in not-for-profit health-region-owned facilities (p < 0.001). The adjusted rate of increase in total nursing hours per resident-day was significantly greater in not for-profit health-region-owned facilities. INTERPRETATION: While total nursing hours per resident-day have increased in all facility groups, the rate of increase was greater in not-for-profit facilities operated by health authorities. PMID- 21269010 TI - Asthma and school functioning. AB - BACKGROUND: The impact of asthma on school performance particularly compared with that of other chronic conditions, is relatively unexplored, and the results of analyses that have been conducted are inconclusive. This article examines associations between asthma and school functioning. DATA AND METHODS: The data are from the 1998/1999 National Longitudinal Survey of Children and Youth. The study pertains to a sample of 8,914 children aged 7 to 15. Descriptive and regression analyses were used to examine associations between asthma severity and scores on standardized math and reading tests, and maternal ratings of school performance. School absence and the use of educational services were considered as potential mediators. Comparisons were made with children who had other chronic conditions or no chronic conditions. RESULTS: Compared with children who did not have a chronic condition, children with asthma scored lower on standardized math and reading tests and had less favourable mother-reported school performance. Those with the most severe asthma had the poorest outcomes. These associations persisted when adjusting for child and family factors. The poorer scholastic outcomes were not mediated by school absence. However, the use of educational services appeared to mediate low math scores for children with severe asthma. INTERPRETATION: The relationship between asthma and children's school functioning may be of interest to physicians and educators. Educational support and remedial services may be beneficial. PMID- 21269011 TI - Recent trends in upper respiratory infections, ear infections and asthma among young Canadian children. AB - Upper respiratory (nose and throat) infections, ear infections and asthma are common among young children. This article uses data from the National Longitudinal Survey of Children and Youth (NLSCY) to trace trends in the prevalence of these conditions among young children in Canada from 1994/1995 to 2008/2009. Gender, age and regional differences in the occurrence of these conditions are examined, and possible links with exposure to cigarette smoke are considered. The prevalence of upper respiratory infections among children aged 2 to 3 remained constant or declined in most regions of Canada between 1994/1995 and 2008/2009, but rose significantly in Quebec. Ear infections declined significantly in all regions. The prevalence of asthma among children aged 2 to 7 rose steadily until 2000/2001 and then declined. A wide range of environmental factors, including reduced exposure to cigarette smoke, may have contributed to these trends. PMID- 21269012 TI - Chronic pain at ages 12 to 44. AB - According to results from the 2007/2008 Canadian Community Health Survey, about 1 in 10 Canadians aged 12 to 44-9% of males and 12% of females, an estimated 1.5 million people--experienced chronic pain. The prevalence of chronic pain increased with age and was significantly higher among people in households where the level of educational attainment was low and among the Aboriginal population. The most common pain-related chronic conditions at ages 12 to 44 were back problems and migraine headaches. Chronic pain prevented at least a few activities in the majority of sufferers. It was associated with activity limitations and needing help with everyday tasks, and had work-related implications. Individuals with chronic pain were frequent users of health care services, and were less likely than people without chronic pain to respond positively on measures of well being, including mood and anxiety disorders. PMID- 21269013 TI - H1N1 vaccination. AB - Early results (January to April) from the 2010 Canadian Community Health Survey show that an estimated 41% of Canadians (excluding those in the territories) aged 12 or older had been vaccinated for H1N1 by April 2010. The percentages were higher in the Atlantic provinces, Quebec and Saskatchewan than in Canada overall. Relatively high percentages of females and people aged 45 or older were vaccinated; the percentage of immigrants who had done so was relatively low. Being in a priority group (health-care worker, having children younger than 5 in the household, or having a chronic condition that could increase the risk for complications from H1N1) increased the likelihood of vaccination. A history of seasonal flu vaccination and having a regular doctor were also associated with H1N1 vaccination. Nearly three-quarters of those who had not been vaccinated reported that they did not think it was necessary. PMID- 21269014 TI - Combining nutrient intake from food/beverages and vitamin/mineral supplements. AB - BACKGROUND: To calculate total intake of a nutrient and estimate inadequate intake for a population, the amounts derived from food/beverages and from vitamin/mineral supplements must be combined. The two methods Statistics Canada has suggested present problems of interpretation. DATA AND METHODS: Data collected from 34,386 respondents to the 2004 Canadian Community Health Survey Nutrition were used to compare four methods of combining nutrient intake from food/beverages and vitamin/mineral supplements: adding average intake from supplements to the 24-hour food/beverage recall and estimating the usual distribution in the population (Method 1); estimating usual individual intake from food? beverages and adding intake from supplements (Method 2); and dividing the population into supplement users and non-users and applying Method 1 or Method 2 and combining the estimates based on the percentages of users and non users (Methods 3 and 4). RESULTS: Interpretation problems arise with Methods 1 and 2; for example, the percentage of the population with inadequate intake of vitamin C and folate equivalents falls outside the expected minimum-maximum range. These interpretation problems are not observed with Methods 3 and 4. INTERPRETATION: Interpretation problems that may arise in combining food and supplement intake of a given nutrient are overcome if the population is divided into supplement users and non-users before Method 1 or Method 2 is applied. PMID- 21269015 TI - Validation of cognitive functioning categories in the Canadian Community Health Survey--Healthy Aging. AB - BACKGROUND: The objective of this study was to validate categories of cognitive functioning using data from the 2009 Canadian Community Health Survey (CCHS)- Healthy Aging Cognition Module. DATA AND METHODS: Four measures of cognitive functioning--immediate and delayed recall (memory), and animal-naming and the Mental Alternation Test (executive functioning)--were coded into five categories for the Canadian household population aged 45 or older. The scores for each measure were standardized to t-scores that controlled for age, sex and education. Respondents were classified into five cognitive functioning categories. Cross tabulations, stratum-specific likelihood ratios and multinomial logit regression were used to assess associations between levels of cognitive functioning and various health outcomes: self-reported general and mental health status, memory and problem-solving ability, activities of daily living, life satisfaction, loneliness, depression, and chronic conditions. RESULTS: Results supported the use of five levels of cognitive functioning for all four outcomes on the CCHS- Healthy Aging sample overall and by age group (45 to 64, 65 or older) and language group (English, French). INTERPRETATION: These categories can be used in future work on cognitive functioning based on the CCHS--Healthy Aging. PMID- 21269016 TI - Urgent care: CIOs struggle with the ED systems integration issue. Will standalone systems stand a chance under the pressures of meaningful use data collection and reporting requirements? CIOs are of two minds. PMID- 21269017 TI - Is there a pharmacist house? When it comes to clinical IT implementations, healthcare IT leaders are turning to the 'third discipline' for leadership and involvement in clinical informatics. PMID- 21269018 TI - Healthcare IT superstars. A look at what makes this year's davies stars really shine. PMID- 21269019 TI - Performance personified. Why does Hill Physicians Medical Group keep winning quality awards? PMID- 21269020 TI - IT financing options. A growing range of financial vehicles has become available for hospital leaders looking to finance it implementations. PMID- 21269021 TI - Meaningful use marathon. Tackling meaningful use is not unlike training for a marathon. PMID- 21269022 TI - Comparative effectiveness Research: the horizon. Interview with Tom Hubbard, Senior Program Director, the New England Healthcare Institute. Interviews by Mark Hagland. PMID- 21269023 TI - Leveraging technology in your hiring practices. It's prime time for video conferencing. PMID- 21269024 TI - The hard reality of the payroll debacle. PMID- 21269025 TI - Should a better life include more risk for workers? PMID- 21269026 TI - Health reform: putting together the puzzle. PMID- 21269027 TI - New reporting obligations for nurses and midwives. PMID- 21269028 TI - NSW nurses and midwives strike for ratios. PMID- 21269030 TI - Professional boundary violations. PMID- 21269029 TI - Nambour mental health nurses take action for safe workloads. PMID- 21269031 TI - Nurses take action for safety on site. PMID- 21269032 TI - Better reporting on maternal mortality needed. PMID- 21269033 TI - Changing nature of private practice midwifer. PMID- 21269034 TI - Up to the challenge. PMID- 21269035 TI - QNU seminars--a professional tool kit for nurses and midwives. PMID- 21269036 TI - Superior management of plaque and gingivitis through the use of a triclosan/copolymer dentifrice. PMID- 21269037 TI - Evaluation of the antimicrobial activity of dentifrices on human oral bacteria. AB - OBJECTIVE: In vitro testing of antimicrobial agents is an important tool in the testing hierarchy, and may provide interesting insights into their potential clinical efficacy. Agents with demonstrable in vitro antimicrobial activity may be effective against the same microorganisms in vivo, whereas agents without demonstrable in vitro antimicrobial activity are unlikely to exhibit in vivo antimicrobial activity. In addition, these methods may also be useful in screening antimicrobial agents in product formulations because such agents with both in vitro and in vivo activity may have reduced antimicrobial effects when formulated into a dentifrice. Accordingly, this study examined the in vitro and ex vivo antimicrobial activity of three commercial dentifrices: one formulated with 0.243% sodium fluoride (Crest Cavity Protection Toothpaste-Regular); one with 0.454% stannous fluoride, sodium hexametaphosphate, and zinc lactate (Crest Pro-Health), and one with 0.3% triclosan, 2.0% PVM/MA copolymer, and 0.243% sodium fluoride (Colgate Total). METHODS: The minimum inhibitory concentration (MIC) of each dentifrice was determined for resident oral bacterial species, including bacteria that are associated with dental caries; periodontitis, and oral halitosis. Evaluations were performed on individual laboratory strains, and on oral bacteria from supragingival plaque samples obtained from 10 adults and from oral rinse samples obtained from 18 adults. RESULTS: The lowest MICs against the oral strains and human samples, i.e., greatest antimicrobial activity, were seen for the triclosan/ copolymer dentifrice. There was, in general, a four-fold difference in MICs between the triclosan/copolymer dentifrice and the stannous fluoride/sodium hexametaphosphate/zinc lactate dentifrice. The triclosan/copolymer dentifrice significantly inhibited periodontal pathogens, such as Aggregatibacter actinomycetemcomitans, Eikenella corrodens, and Fusobacterium nucleatum. In ex vivo tests measuring antimicrobial effects, the triclosan/copolymer dentifrice substantially inhibited bacterial growth after 30 , 60-, and 120-second exposures compared to the sodium fluoride or stannous fluoride/sodium hexametaphosphate/zinc lactate dentifrices. Similarly, in ex vivo tests measuring antimicrobial effects on supragingival plaque biofilms, the triclosan/copolymer dentifrice substantially inhibited bacterial growth compared to the other test dentifrices. CONCLUSION: Different in vitro and ex vivo analyses show that the triclosan/copolymer dentifrice has significant antimicrobial activity on oral bacteria, including species causing dental caries, periodontitis, and oral halitosis, and it provides superior efficacy compared to the stannous fluoride/sodium hexametaphosphate/zinc lactate dentifrice. PMID- 21269038 TI - Comparison of the short-term antiplaque/antibacterial efficacy of two commercial dentifrices. AB - OBJECTIVE: The objective of these three clinical trials was to compare the impact of two commercial products, Colgate Total and Crest Pro-Health, on the formation of dental plaque over a 24-hour period of time. The studies utilized the Modified Gingival Margin Plaque Index (MGMPI), a validated and reliable clinical method for assessing the efficacy of products in reducing plaque build-up. METHODS: Colgate Total and Crest Pro-Health were the test products for all three clinical trials. Colgate Great Regular Flavor (CR) was used as the universal washout product. Colgate Total, as the only toothpaste approved by the FDA under an NDA for antiplaque, antigingivitis, and anticaries benefits, contains 0.3% triclosan/2.0% PVM/MA copolymer for antigingivitis and antiplaque, as well as 0.243% sodium fluoride (NaF) for anticaries. Crest Pro-Health contains 0.454% stannous fluoride (SnF2) as both a monographed anticaries agent and a monographed antigingivitis agent, along with sodium hexametaphosphate and zinc lactate. Twenty-five healthy subjects meeting all study criteria were included into each of the double-blind studies. Product assignment was randomized and a crossover design was implemented. Informed consent was obtained from all subjects prior to commencement of each of the studies. The studies followed published MGMPI procedures, which require subjects to receive a dental scaling/prophylaxis followed by a one-week washout period prior to use of test products. A baseline MGMPI score was calculated following use of the test products in the dental clinic. Subjects refrained from all oral hygiene for 24 hours following use of each test product, and returned to the clinic for a 24-hour MGMPI score. Following a washout period, subjects repeated the procedure with the other test product as per the crossover design. The differences (delta) between baseline plaque scores and 24-hour plaque scores were independently calculated for each study, and the delta values were compared for the two test products in each of the studies. RESULTS: In all three clinical trials, Colgate Total significantly reduced plaque regrowth over a 24-hour time period (p < or = 0.05) compared to Crest Pro-Health. Existing differences were determined via a paired t-test, which confirmed that Colgate Total was statistically significantly different from Crest Pro-Health. CONCLUSION: These in vivo data support the antiplaque benefit of the 0.3% triclosan/2.0% PVM/MA copolymer/0.243% sodium fluoride dentifrice. Additionally, the results support that Colgate Total provides superior efficacy in inhibiting the formation of dental plaque compared to Crest Pro-Health. PMID- 21269039 TI - A clinical investigation of the efficacy of three commercially available dentifrices for controlling established gingivitis and supragingival plaque. AB - OBJECTIVE: To assess the efficacy ofa dentifrice containing 0.3% triclosan/2.0% PVM/MA copolymer/0.243% sodium fluoride for controlling established gingivitis and supragingival plaque relative to that of a dentifrice containing 0.454% stannous fluoride, sodium hexametaphosphate, and zinc lactate, and a dentifrice containing 0.243% sodium fluoride as a negative control. METHODS: Following a baseline examination for gingivitis and supragingival plaque, qualifying adult male and female subjects from the Piscataway, NJ, USA area were randomized into three dentifrice groups. Subjects were instructed to brush their teeth twice daily (morning and evening) for one minute with their assigned dentifrice and a soft-bristled toothbrush. Examinations for gingivitis and supragingival plaque were repeated after six weeks of product use. RESULTS: One-hundred and seventy one (171) subjects complied with the protocol and completed the study. Relative to the group using the dentifrice with 0.243% sodium fluoride alone, the 0.3% triclosan/2.0% PVM/MA copolymer/0.243% sodium fluoride group exhibited statistically significant reductions in gingival index and supragingival plaque index scores of 25.3% and 33.0%, respectively, after six weeks of product use. Similarly, relative to the group using the 0.243% sodium fluoride dentifrice, the 0.454% stannous fluoride, sodium hexametaphosphate, and zinc lactate dentifrice group exhibited statistically significant reductions in gingival index and plaque index scores of 8.1% and 14.1% after six weeks of product use. Further, relative to the 0.454% stannous fluoride, sodium hexametaphosphate, and zinc lactate dentifrice group, the 0.3% triclosan/2.0% PVM/MA copolymer/0.243% sodium fluoride dentifrice group exhibited statistically significant reductions in gingival index and plaque index scores of 18.7% and 22%, respectively. CONCLUSION: The overall results of this double-blind clinical study support the conclusion that a dentifrice containing 0.3% triclosan/2.0% PVM/MA copolymer/0.243% sodium fluoride is efficacious for the control of established gingivitis and supragingival plaque as compared to a regular fluoride dentifrice, and that it provides a greater level of efficacy for the control of gingivitis and supragingival plaque than does a dentifrice containing 0.454% stannous fluoride, sodium hexametaphosphate, and zinc lactate. PMID- 21269040 TI - A comparison of the efficacy of a triclosan/copolymer/sodium fluoride dentifrice, a stannous fluoride/sodium hexametaphosphate/zinc lactate dentifrice, and a sodium fluoride dentifrice for the control of established supragingival plaque and gingivitis: a six-week clinical study. AB - OBJECTIVE: To compare the efficacy ofa dentifrice containing 0.3% triclosan, 2.0% PVM/MA copolymer, and 0.243% sodium fluoride in controlling established gingivitis and supragingival plaque to that of a commercially available dentifrice containing 0.454% stannous fluoride, sodium hexametaphosphate, and zinc lactate, and a commercially available dentifrice containing 0.243% sodium fluoride. METHODS: Following a baseline examination for gingivitis and supragingival plaque, qualifying adult male and female subjects from the Mississauga, Ontario, Canada area were randomized into three dentifrice groups. Subjects were instructed to brush their teeth twice daily (morning and evening) for one minute with their assigned dentifrice and a soft-bristled toothbrush. Examinations for gingivitis and supragingival plaque were repeated after six weeks of product use. RESULTS: One-hundred eighty-two (182) subjects complied with the protocol and completed the study. Relative to the 0.243% sodium fluoride dentifrice group, the 0.3% triclosan/2.0% PVM/MA copolymer/0.243% sodium fluoride dentifrice group exhibited statistically significant reductions in gingival index and supragingival plaque index scores of 26.5% and 29.4%, respectively, after six weeks of product use. Similarly, relative to the 0.243% sodium fluoride dentifrice group, the 0.454% stannous fluoride/sodium hexametaphosphate/zinc lactate dentifrice group exhibited statistically significant reductions in gingival index and plaque index scores of 12.7% and 12.6%, respectively, after six weeks of product use. Further, relative to the 0.454% stannous fluoride/sodium hexametaphosphate/zinc lactate dentifrice group, the 0.3% triclosan/2.0% PVM/MA copolymer/0.243% sodium fluoride dentifrice group exhibited statistically significant reductions in gingival index and plaque index scores of 15.8% and 19.2%, respectively. CONCLUSION: The overall results of this double blind clinical study support the conclusion that a dentifrice containing 0.3% triclosan, 2.0% PVM/MA copolymer, and 0.243% sodium fluoride is efficacious for the control of established gingivitis and supragingival plaque, and that it provides a greater level of efficacy for the control of gingivitis and supragingival plaque than does a dentifrice containing 0.454% stannous fluoride, sodium hexametaphosphate, and zinc lactate. PMID- 21269041 TI - Comparative investigation of the efficacy of triclosan/copolymer/sodium fluoride and stannous fluoride/sodium hexametaphosphate/zinc lactate dentifrices for the control of established supragingival plaque and gingivitis in a six-month clinical study. AB - OBJECTIVE: This double-blind clinical study, conducted at the University of Puerto Rico, San Juan, Puerto Rico, was designed to compare the efficacy of two commercially available dentifrices for the control of supragingival plaque and gingivitis. METHODS: Qualifying adult male and female subjects from the San Juan, Puerto Rico area were randomly assigned to one of two treatment groups: 1) a commercially available dentifrice containing 0.3% triclosan, 2.0% PVM/MA copolymer, and 0.243% sodium fluoride (Colgate Total); and 2) a commercially available dentifrice containing 0.454% stannous fluoride, sodium hexametaphosphate, and zinc lactate (Crest Pro-Health). All subjects received an oral soft and hard tissue examination, and were dispensed their assigned dentifrice product, along with a soft-bristled adult toothbrush for home use. Subjects were instructed to brush their teeth for one minute, twice daily (morning and evening), using only the dentifrice provided. Examinations for supragingival plaque and gingivitis, and oral soft and hard tissue assessments were repeated after six weeks, three months, and six months of product use. RESULTS: One-hundred and nine (109) subjects complied with the protocol and completed the six-month examinations. At the six-month examination, both treatment groups exhibited statistically significant reductions from baseline with respect to supragingival plaque and gingivitis scores. Relative to the Crest Pro-Health Toothpaste group, the Colgate Total Toothpaste group exhibited statistically significant reductions in supragingival plaque index scores of 18.5%, 20.7%, and 25.8% after six weeks, three months, and six months of product use, respectively. For gingival index scores, statistically significant reductions of 20.5%, 18.9%, and 17.1% were exhibited after six weeks, three months, and six months of product use, respectively. CONCLUSION: The results of this double-blind clinical study support the conclusion that a dentifrice containing 0.3% triclosan, 2.0% PVM/MA copolymer, and 0.243% sodium fluoride provides a significant reduction in established supragingival plaque and gingivitis, as compared to a dentifrice containing 0.454% stannous fluoride, sodium hexametaphosphate, and zinc lactate when used over a period of six months. PMID- 21269046 TI - Individualized erlanger KS-impression trays for infants with cleft lip and palate. AB - OBJECTIVE: The use of individualized impression trays is required when taking impressions of the maxilla in infants with cleft lip and palate. Custom trays made of plastic such as polymethylmethacrylate, as well as generic, full-arch infant metal trays, have been used up to now. Given the increasing incidence of infectious diseases, the ability to sterilize impression trays for infants with cleft lip and palate is mandatory. Polymethylmethacrylate impression trays are altered in shape and consistency when autoclaved during the sterilization process. Therefore, they have to be fabricated afresh at regular intervals. METHODS: Based on modified mold patterns of the available plastic trays, 44 pieces were sorted into four groups of 11 trays in ascending order of size. On these plaster casts, which served as the male part of the template, a 1-mm layer of sheet wax was applied. An optimized ergonomic wax handle was then fitted to the wax plate. Realization in a chromium-cobalt-molybdenum alloy was performed according to the lost wax principle. CONCLUSIONS: The sterilizable Erlangen KS Impression tray (Erlanger KS-Abformloffel(r)) is now available in 11 sizes for each of four basic forms. They meet current hygiene guidelines. They can be recommended for routine use when taking impressions in infants with any form of cleft lip and palate without complications. PMID- 21269056 TI - Effect of antihypertensive treatment on cardiovascular events in elderly hypertensive patients: Japan's Benidipine Research on Antihypertensive Effects in the Elderly (J-BRAVE). AB - The achievement rate of blood pressure (BP) target and the relationship between on-treatment BP and development of cardiovascular events (i.e., stroke, myocardial infarction, and heart failure) were investigated in a total of 8,897 patients in the Japan's Benidipine Research on Antihypertensive Effects in the Elderly (J-BRAVE) study, a prospective, 3-year observational study of a calcium channel blocker-based treatment in hypertensive patients aged >=65 years as a post-marketing surveillance. Blood pressure decreased significantly from 164.8 +/ 14.1/88.2 +/- 10.3 mmHg to 137.0 +/- 13.5/75.6 +/- 9.5 mmHg and the percentage of patients who achieved BP <140/90 mmHg was 57.2% after 3 years. The incidence of cardiovascular events was 7.54/1,000 patient-years. Subgroups of patients stratified by on-treatment systolic blood pressure (SBP) were analyzed. Baseline BP, body mass index (BMI), the dose of benidipine, the mean number of anti hypertensive drugs, and the incidence of cardiovascular events were higher in patients with on-treatment SBP >=160 mmHg than in those with an SBP of <130 mmHg. In patients aged 65 to 74 years (n = 5,092) and patients aged >=75 years (n = 3,805), the percentages of patients who achieved the BP target of <140/90 mmHg were 57.5% and 56.6% after 3 years, respectively, and the incidence of cardiovascular events was higher in patients with on-treatment SBP >=160 mmHg in both age subgroups. The results of the J-BRAVE study show that on-treatment SBP >=160 mmHg is associated with a higher incidence of cardiovascular events in elderly hypertensive patients. PMID- 21269057 TI - Comparison of the hypotensive and bradycardic activity of ginkgo, garlic, and onion extracts. AB - The acute effect of ethanol extracts ginkgo (Ginkgo biloba L.), garlic (Allium sativum L.), and onion (Allium cepa L.) on arterial blood pressure (BP), and heart rate (HR) in anesthetized normotensive rats was examined and compared. Arterial BP was registered in the left carotid artery. The data showed that intravenous administration of the extracts produced dose-dependent and reversible hypotensive and bradycardic effects. The most effective in reducing arterial BP and HR is extract of garlic. There were statistically significant differences in bradycardic and hypotensive effects of the garlic and ginkgo extracts. PMID- 21269058 TI - Telmisartan lowers home blood pressure and improves insulin resistance without correlation between their changes. AB - Telmisartan is an angiotensin type 1 receptor blocker (ARB), which also partially activates liganding peroxisome proliferator-activated receptor gamma. However, the relationship between the effects of telmisartan on hemodynamics and metabolism has not sufficiently been elucidated in clinical settings. We examined the long-term effects of telmisartan on hemodynamics including home blood pressure (BP) and on insulin resistance representing as homeostasis model assessment (HOMA-R). Twenty-seven hypertensive patients were consecutively enrolled at our outpatient department. At entry, all of the participants were previously prescribed another ARB for more than 3 months and then the former ARB were replaced by telmisartan. Hemodynamic and metabolic parameters were measured before treatment and at points 1 and 3 months after treatment with telmisartan. Telmisartan significantly lowered home systolic blood pressure (SBP) and diastolic blood pressure (DBP) (DBP) and improved HOMA-R during the treatment period. However, the changes in home SBP and DBP were not correlated with that of HOMA-R. In conclusion, telmisartan lowers home BP and improves insulin resistance without correlation between their changes. PMID- 21269059 TI - Association of the human CYP11B2 gene and essential hypertension in southwest Han Chinese population: a haplotype-based case-control study. AB - Aldosterone synthase produces aldosterone, which regulates electrolytes and thereby blood pressure (BP). The aldosterone-synthase gene (CYP11B2) has been regarded as a candidate gene for essential hypertension. To address this issue, we carried out a haplotype-based, case-control study to explore the association between a human CYP11B2 gene and essential hypertension (EH) in the southwest Han population of China (n = 1020 individuals). Four tag single-nucleotide polymorphisms (SNPs) (rs4536, rs4545, rs3097, and rs3802230) and the C-344T polymorphism, as well as the K173R polymorphism in the CYP11B2 gene, were genotyped using the PCR-RFLP method. Single-locus analysis showed that the C allele of rs3802230 was significantly more prevalent in the EH subjects as compared to control subjects, adjusted for covariates. Haplotype analysis showed that the haplotype AAGC constructed by the tag SNPs (rs4536, rs4545, rs3097, and rs3802230), which carried the susceptible rs3802230 C allele, significantly increased the risk of essential hypertension with an odds ratios equal to 3.56 (P = 0.0001). The present results indicated that the rs3802230 C allele might be a risk marker for essential hypertension and haplotype AAGC might confer high genetic susceptibility to essential hypertension in a southwest Han Chinese population. PMID- 21269060 TI - Prognostic value of serum LP-PLA2 and hs-CRP in unstable atherosclerotic plaques. AB - To evaluate the prognostic value of LP-PLA2 and hs-CRP to the stability of atherosclerotic plaques. Forty-eight New Zealand White rabbits were randomly divided into control group, stable plaque group, P53 group, and P53 + drug group. Rabbits in the control group were fed a regular diet. Rabbits in stable plaque group, P53 group, and P53 + drug group underwent balloon-induced arterial wall injury and then were fed a diet of 1% cholesterol. Then the rabbits in the P53 group and P53 + drug group underwent Ad5-CMV P53 transfection in the 10th week; The P53 + drug group underwent pharmacologic triggering with Russell's viper venom (RVV) and histamine in 24 h and 48 h before euthanized. Intravascular ultrasound (IVUS) was used before sacrificing of the animal. In the 0 week and 12th week, rabbits underwent fast blood collection from the medium-sized artery of the ears, and the serum LP-PLA2 and hs-CRP level was determined. The animal altherosclerotic (AS) model was successfully gained and the rules of serum LP PLA2 and hs-CRP level in instable plaque were discovered: serum LP-PLA2 in P53 group and P53 + drug group were significantly different from the control group and the stable group, while hs-CRP failed to differ between the control group and the stable group and succeeded in different degrees of unstable plague. The relationship analysis of serum and IVUS results revealed LP-PLA2 might predict an instability of plaque. Combining serum Lp-PLA2 and hs-CRP has higher specificity in predicting the vulnerability of the plaque. PMID- 21269061 TI - Interaction of ACE and CYP11B2 genes on blood pressure response to hydrochlorothiazide in Han Chinese hypertensive patients. AB - To valuate whether angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and aldosterone synthase (CYP11B2) gene -344T/C polymorphism are associated with individual response to hydrochlorothiazide (HCTZ) in the Han Chinese population with essential hypertension. We enrolled 829 mild/moderate hypertensive patients and 12.5 mg of HCTZ was given daily. After 6 weeks, the results showed that the ACE I/D polymorphism, not the CYP11B2 -344T/C polymorphism, was associated with systolic blood pressure (SBP) response to HCTZ (P = 0.009) in the Han Chinese population with essential hypertension, with no interaction. PMID- 21269062 TI - Suppressive effects of valsartan on microalbuminuria and CRP in patients with metabolic syndrome (Val-Mets). AB - The presence of metabolic syndrome (Mets) increases the risk for cardiovascular disease. There is a significant correlation between the levels of urinary albumin to creatinine ratio (UACR) and high-sensitive C-reactive peptide (hs-CRP), and accumulation of each Mets component. Increasing evidence has shown the importance of blockade of renin-angiotensin-systems (RAS) for reducing urinary albumin excretion and hs-CRP levels in Mets patients. However, the impact of RAS blockade on these effects in hypertensive (HT) Mets patients without diabetes mellitus (DM) has not been evaluated. We prospectively measured the levels of UACR and hs CRP in 153 HT patients with and without Mets. Body weight; waist circumference; presence of dyslipidemia and DM, and levels of HOMA-R, UACR, and hs-CRP were significantly higher in HT patients with Mets than in those without Mets. After we treated these Mets patients with valsartan for 6 months, blood pressure (BP), UACR, and hs-CRP were decreased, whereas body weight, HOMR-R, and the lipid profile were not changed. In HT Mets patients without DM, 6 months after valsartan administration, levels of UACR and hs-CRP were also significantly decreased by 37.8% (-9.0-56.5%, p < 0.05) and 23.6% (-28.7-73.4%, p < 0.05), respectively. However, the percentage change of UACR and hs-CRP was not correlated with the reduction in BP. Valsartan administration lowered increased levels of chronic inflammation in both HT Mets patients with DM and in those without DM. These results indicate that the anti-inflammatory properties of valsartan might also have beneficial effects in Mets patients without DM. PMID- 21269063 TI - Resveratrol inhibits transforming growth factor-beta-induced proliferation and differentiation of ex vivo human lung fibroblasts into myofibroblasts through ERK/Akt inhibition and PTEN restoration. AB - The authors investigated the role of resveratrol (RV), a natural poliphenolic molecule with several biological activities, in transforming growth factor-beta (TGF-beta)-induced proliferation and differentiation of ex vivo human pulmonary fibroblasts into myofibroblasts. The effects of RV treatment were evaluated by analyzing TGF-beta-induced alpha-smooth muscle actin (alpha-SMA) expression and collagen production, as well as cell proliferation of both normal and idiopathic pulmonary fibrosis (IPF) lung fibroblasts. Results demonstrate that RV inhibits TGF-beta-induced cell proliferation of both normal and pathological lung fibroblasts, attenuates alpha-SMA expression at both the mRNA and protein levels, and also inhibits intracellular collagen deposition. In order to understand the molecular mechanisms, the authors also investigated the effects of RV treatment on signaling pathways involved in TGF-beta-induced fibrosis. The authors show that RV inhibited TGF-beta-induced phosphorylation of both extracellular signal regulated kinases (ERK1/2) and the serine/threonine kinase, Akt. Moreover, RV treatment blocked the TGF-beta-induced decrease in phosphatase and tensin homolog (PTEN) expression levels. PMID- 21269064 TI - Suppression of transforming growth factor beta1 in lung alveolar epithelium derived cells using adeno-associated virus type 2/5 vectors to carry short hairpin RNA. AB - Since the discovery of RNA interference, short interfering RNA (siRNA) has become a standard research tool. However, expression of siRNA in lung alveolar epithelial cells has remained a problem. Adeno-associated virus (AAV) vectors are known to have low toxicity, and AAV type 5 vectors transduce these cells efficiently. In this study, LacZ expression was higher using AAV2/5-LacZ and LA-4 cells compared with transfection of plasmid or transduction to 3T12-3 cells. The authors designed 10 different siRNAs against mouse transforming growth factor beta1 (Tgfbeta1), selected one with the highest knockdown efficiency, and transduced the AAV vectors carrying the short hairpin RNA (shRNA) to target cells. The AAV vectors transduced LA-4 cells 50 times more efficiently than 3T12 3 cells, and suppression of Tgfbeta1 protein expression was similar, at approximately 50%. Knockdown of mRNA was only seen in LA-4 cells. Inhibition of Tgfbeta1 resulted in higher number of LA-4 cells, lower number of 3T12-3 cells, and decreased procollagen expression in LA-4 cells. Higher transduction was seen in H23 cells than in H1975 cells, and low transduction was seen MH-S cells. This study shows that AAV2/5 can be used to carry shRNA and suppress gene function in lung alveolar epithelium-derived cells. PMID- 21269065 TI - Interleukin 2 and the treatment of leukemia and lymphoma. AB - As evidence has accumulated that allogeneic bone marrow transplantation provides therapeutic benefit by means of a graft versus malignancy effect, there has been a corresponding increase in interest in inducing or enhancing such an effect after chemotherapy and/or autologous bone marrow transplantation. Administration of Interleukin-2 may be one way of achieving this aim. Recent studies have shown the cytokine is tolerated after ABMT/chemotherapy in immunomodulatory doses and that the MHC unrestricted cytotoxic effector mechanisms induced can indeed discriminate between normal and malignant tissue. As always, larger scale randomized studies will be required before the therapeutic efficacy of this approach can been assessed. PMID- 21269066 TI - Ras protooncogene activation in acute myeloid leukemia and related disorders. PMID- 21269067 TI - Chromosomal abnormalities in malignant lymphoma and Hodgkin's disease. PMID- 21269068 TI - Spinal epidural involvement in haematological tumors: clinical features and therapeutic options. AB - Haematological malignancies that may cause epidural spinal cord compression (SCC) include plasma cell dyscrasias, lymphomas and infrequently leukemias. Bone lesions are the major clinicopathologic manifestations in plasma cell dyscrasias but are evident in less than 30% of patients with SCC due to lymphomas. The incidence of SCC in solitary plasmacytomas is between 43 to 71%, in contrast to 7.4 to 16% in multiple myeloma where vertebral involvement is always present. The incidence of SCC in Hodgkin's disease and in non-Hodgkin's lymphomas is about 4 and 2.5% respectively. Spinal computed tomography, myelography and magnetic resonance imaging serve for establishing a definite diagnosis, assessment of tumor location within the spinal canal, delineation of the involved spinal levels, evaluation of spinal stability and for detection of extraosseous paravertebral extension. Treatment planning is based on the information obtained above, combined with clinical considerations. The primary modalities of therapy are radio- and chemotherapy. Surgery is reserved for those cases presenting with SCC when tissue diagnosis is unavailable, recurrence of SCC after previous irradiation and for spinal instability or compression of the neural elements by impinging bone fragments. PMID- 21269069 TI - Mini-beam as salvage chemotherapy for refractory Hodgkin's disease and non Hodgkin's lymphoma. AB - Long-term disease-free survival after conventional dose salvage chemotherapy for relapsed or refractory non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD) is rare. Intensive chemotherapy and autologous bone marrow transplantation (ABMT) is regarded by many as the treatment of choice. For lymphoma, eligibility for transplant is frequently restricted to cases with chemotherapy-sensitive disease or minimal tumour bulk. We evaluated the mini-BEAM regimen as further treatment for patients unresponsive to initial salvage therapy and thus ineligible for ABMT at our centre. Carmustine 60 mg/m(2) I.V. day one, etoposide 75 mg/m(2) I.V. days 2-5, cytosine arabinoside 100 mg/m(2) I.V. q12h days 2-5 and melphalan 30 mg/m(2) day 6 (mini-BEAM) was administered to 24 patients with lymphoma, 22 of whom were refractory to at least first-line salvage chemotherapy. Eleven had HD and 13 NHL. The complete response (CR) rate was 21% and the overall response was 59%. Febrile neutropenia occurred in 48% of treatment episodes. There were two treatment related deaths. Thirteen patients underwent bone marrow transplantation (BMT), 11 received ABMT (8 HD, 3 NHL). Six patients did not achieve remission after transplant but 7 patients remain in continuous CR, with a follow-up of 6-17 months post-transplant. Consequently, 7 of 24 (29%) patients responded to mini BEAM and many achieve long-term disease-free survival after BMT. Further evaluation of mini-BEAM as a salvage regimen prior to BMT is indicated. PMID- 21269070 TI - Therapy related myelodysplastic syndrome and leukemia with no "unfavourable" cytogenetic findings have a good response to intensive chemotherapy: a report on 15 cases. AB - We treated 15 patients with therapy related acute nonlymphocytic leukemia (tANLL) or therapy related myelodysplastic syndrome (tMDS) who had no rearrangements of chromosomes 5 and/or 7 or complex cytogenetic rearrangements by intensive chemotherapy. The median age was 43 years. Seven patients had one of the "specific" rearrangements of de novo ANLL (inv(16), t(8;21), t(15;17)or t(9;11)). Eight patients had a normal karyotype (4 cases) or single cytogenetic rearrangements not involving chromosomes 5 and 7: trisomy 8 (2 cases), t(1,2)(1 case), 20q deletion (1 case). All 7 patients with "specific" rearrangements had tANLL at presentation, without a preceding myelodysplastic phase. Seven of the 8 patients with a normal karyotype or other single cytogenetic rearrangements presented with tMDS, and the remaining patient with tANLL. Twelve patients achieved complete remission (CR), 2 had hypoplastic death and 1 had resistant disease. Median actuarial disease free interval (DFI) was 30 months. No significant prognostic factor for achieving CR was found. Significantly longer DFI was found in patients with "specific" chromosome rearrangements, compared to other karyotypes, and in patients who presented with tANLL, compared to those who presented with tMDS. Those 2 prognostic factors strongly correlated. In contrast to tANLL and tMDS with rearrangements of chromosomes 5 and/or 7 or complex karyotypes, patients with tANLL or tMDS who had other abnormal cytogenetic findings seem to achieved a high CR rate with intensive chemotherapy. tANLL with "specific" rearrangements achieved prolonged CR in many cases, whereas tMDS with other abnormal karyotypes generally had short CR, like their de novo counterparts. PMID- 21269071 TI - Transplant related septicaemia in patients undergoing autologous bone marrow transplantation for lymphoma and acute leukaemia. AB - 193 consecutive adult patients undergoing autologous bone marrow transplantation (ABMT) for lymphomas and acute leukaemias were studied retrospectively to investigate the pattern of peri-transplant septicaemia. 80% of the early peri transplant septicaemia occurred between day 4 and day 10 after AMBT. Gram positive septicaemia was significantly more frequent than gram-negative septicaemia. The immediate mortality rate due to septicaemia during the early post-transplant period (< 72 hours from the development of first febrile episode), whether gram-negative or gram-positive was low (1%). Most infective deaths occurred in patients undergoing ABMT for primary refractory or resistant relapsed lymphomas and as a result of pulmonary complications presumed but not always confirmed to be of infective origin. PMID- 21269072 TI - Primary lymphoma of the parotid gland: a report of twelve cases with a review of the literature. AB - Primary extranodal lymphoma of the salivary gland is an extremely rare disease. In this report we describe twelve cases of primary lymphoma of the parotid gland seen at a single centre, and review the relevant literature. The 12 cases were treated in different departments and did not receive a uniform therapeutic approach. All three patients with Hodgkin's disease are still alive and two are in complete remission after initial radiotherapy. One of these cases developed stage 4 disease and had to receive combination chemotherapy subsequently. Of the 9 non-Hodgkin's lymphoma (NHL) patients, four had low grade NHL and 5 intermediate or high grade NHL. Of these, 2 died with disseminated disease. However, 6 are still alive and well from 1 to 5 years after therapy. These cases were treated with surgery alone, radiotherapy alone or combination chemotherapy with an anthracycline-bearing regimen. Consequently, we are unable to draw any conclusions relating the success of therapy in these cases, nor can we suggest therapeutic guidelines on the basis of this study alone. The treatment of parotid lymphoma is discussed briefly in the light of the available literature. In most cases, symptoms related to an enlarging mass in the parotid region, were evident. In the light of the above data, we suggest that, despite its rarity, lymphoma of the salivary gland should always be considered in the differential diagnosis of a parotid mass. No correlation between lymphoma and Sjogren's syndrome was noted in the present study. PMID- 21269073 TI - Myelomonocytic associated antigens in B-chronic lymphocytic leukemia: analysis of clinical significance. AB - The expression of myelomonocytic (My+) associated antigens on lymphocytes from B chronic lymphocytic leukemia (B-CLL) was studied in 62 patients. Most of them expressed at least a My(+) antigen: CD11b in 40 cases (64.2%), CD13 in 31 (50%), CD14 in 18 (29%), CD33 in 41 (66%), CD36 in 6 (9.6%). The relationship between the clinical features of the disease and My(+) antigen status was studied. No significant correlation was found between Rai's clinical stages and the average percent value of CD11b, CD13, CD33 and CD36. In contrast, patients in Rai's stage 0 had a significant lower value of CD14 positive cells than those with more advanced disease (P < 0.001). Interestingly, patients with a diffuse bone marrow histology had a higher average percent value of CD33-positive cells (76.3% +/- 29.3) than those with a non-diffuse one (50.4% +/- 37.5). Furthermore, 90% of My( ) patients fulfilled Montserrat's criteria of "smouldering" CLL while only 48.3% of My(+) cases did (P < 002). My(+) lineage antigens on B-CLL cells may provide another criterion to characterize patient subgroups with a poor prognosis. PMID- 21269074 TI - Oral idarubicin and low dose cytarabine as the initial treatment of acute myeloid leukemia in elderly patients. AB - Idarubicin (IDR) is an anthracycline that can be administered orally. Low dose cytarabine (LDARAC) has been commonly used in the treatment of acute myeloid leukemia (AML) in elderly patients. A comination of oral IDR (20 mg/m(2) for 3 days) and LDARAC (10 mg/m(2) q12 hours for 10 days) was given in 32 patients aged 65 to 82 years (median 76) with de novo AML. Eight patients whose marrow remained blastic by day 20 received a second course (IDR for 2 days and LDARAC for 5 days). Complete remission (CR) was achieved in 13 cases (40.5%), (one course 12, two courses 1). There was 1 early death, 3 deaths in aplasia, 2 partial remissions and 13 failures. All but 5 patients were entirely managed in hospital. The median duration of neutropenia was 18 days and only 1 patient obtained CR without therapeutic aplasia. The extrahematologic toxicity was mild with 3 reversible cardiac events. These results are comparable to those obtained with conventional chemotherapy and this regimen could be proposed as induction treatment of AML in elderly patients. PMID- 21269075 TI - The use of a commercially available immunoassay to determine the level of interleukin-6 in the serum of patients with myeloma. AB - Interleukin-6 (IL-6) is the B cell growth factor which stimulates the final differentiation of B cells to plasma cells and has been suggested to be an autocrine growth factor in patients with multiple myeloma. We have compared the concentration of IL-6 in the serum of patients with myeloma at diagnosis (n = 11), in plateau phase (n = 10) and with progressive disease (n = 13) using Intertest-6, a commercially available enzyme-linked immunoassay (ELISA). Longitudinal studies were performed with 6 patients. IL-6 levels were normal in all myeloma sera studied and did not change with disease progression. Serum IL-6 levels did not correlate with disease activity as determined by serum thymidine kinase (r = 0.07) nor did serum IL-6 provide any useful prognostic data. These results contradict previous studies using bioassays which reported that IL-6 levels increase significantly during progressive disease. Until this problem is resolved and these assays are validated, studies which attempt to quantitate IL-6 and other growth factors in serum should be treated with some caution. PMID- 21269076 TI - Surgery in primary gastric lymphoma: impact on clinical staging and long-term survival. AB - This study analyzes the value of surgery in the treatment, staging and long-term survival of 17 patients affected with primary gastric lymphoma. In 7 patients the neoplasm was localized to the lower third of the stomach, in three to the middle third, in two to the upper third, while in 5 patients there was involvement of the entire stomach. Patients were classified according to the Ann-Arbor classification. Nine patients were stage Ie, five stage Ile, and three stage IVe. A partial gastrectomy was carried out in ten patients and total gastrectomy in 7. In all cases surgical excision of the gastric lymphoma was performed together with intraoperative staging including bilateral hepatic biopsies, and exploration of all abdominal lymph nodes. Two postoperative deaths occurred among the 7 patients who underwent total gastrectomy but no major complications were observed in the remaining 5 patients. No deaths occurred among the 10 patients who underwent partial gastrectomy, but in one case an acute complication developed. Staging laparotomy permitted the correction of clinical staging, and showed that three cases were understaged and one overstaged. All patients received adjuvant chemio-radiotherapy. All but one patient are currently alive, well and free of disease. Survival was correlated significantly with the stage of the disease and extent of gastric involvement, but there was no correlation between survival, histological grade, and the type of gastrectomy performed. PMID- 21269077 TI - Activation of bcr-abl fusion gene and ras oncogenes in chronic myelogenous leukemia. AB - We attempted to detect the bcr-abl fusion gene and ras gene family in CML by the in vitro focus forming assay and the tumorigenicity assay. Eight of 14 chronic phase and both of two blastic phase cases showed transforming activity in the tumorigenicity assay. However, only one chronic phase sample was positive in the in vitro focus forming assay. Among these 10 transformants, we found N-ras activation in one chronic phase, and K-ras activation in another chronic phase case. The bcr-abl fusion gene was activated in one chronic phase and all of the blastic phase cases by the tumorigenicity assay. The present result showed that the bcr-abl fusion gene transfected N1H3T3 cells formed tumors in nude mice in contrast to the in vitro focus forming assay. The bcr-abl fusion gene may play important roles in the progression as well as the pathogenesis of CML. PMID- 21269078 TI - Comparison of chimerism of red cells with that of granulocytes, T-lymphocytes, and bone marrow cells in recipients of bone marrow grafts depleted of lymphocytes using counterflow centrifugation. AB - We analyzed the origin of red cells (using red cell phenotyping), T lymphocytes (using both cytogenetic analysis and restriction fragment length polymorphism studies), and of granulocytes and bone marrow cells (using restriction fragment length polymorphism studies) in 10 consecutive patients. All received bone marrow grafts depleted of lymphocytes using counterflow centrifugation. Analyses were performed on identically timed samples from 6 months after transplantation onward. After correction for the higher sensitivity of red cell phenotyping, results of red cell phenotyping were concordant with restriction fragment length polymorphism studies of granulocytes and bone marrow cells in all cases studied. Outcome of cytogenetic analysis and restriction fragment length polymorphism studies of T lymphocytes were concordant in all 10 cases. Two patients had only mixed chimerism in T lymphocytes but not in red cells nor in granulocytes; in one of these two patients the absence of mixed chimerism was confirmed with restriction fragment length polymorphism studies of bone marrow cells; bone marrow cells of the second patient were not available for analysis with restriction fragment length polymorphisms, but cytogenetic analysis of his bone marrow cells showed only metaphases of donor type. These data show that red cell phenotyping represents the hematopoietic chimeric state of granulocytes and nucleated bone marrow cells. Cytogenetic analysis or restriction fragment length polymorphism studies of T lymphocytes increases the number of instances of mixed chimerism, but this reflects the higher incidence of mixed chimerism in the clonogenic T cell population. These cells are less sensitive to radiochemotherapy than the hematopoietic stem cells and have retained the capacity for (limited) selfrenewal. PMID- 21269079 TI - Comparative effect of heme analogues on hematopoiesis in lymphoproliferative disorders. AB - Anemia is a common characteristic of lymphoproliferative disorders (LPD) and the impairment of blood formation in these disorders is not fully understood. Heme synthesis and the heme degradative enzyme heme oxygenase are critical to hematopoietic differentiation and disturbances may contribute to anemic states. Tin protoporphyrin (SnPP) is a potent inhibitor of heme oxygenase, and has proven to be a useful clinical agent. Bone marrow cells from seven patients with LPD were studied for their in vitro hemopoietic response to growth factors and SnPP. Heme oxygenase mRNA levels were determined by Northern blot analysis of bone marrow samples. Quantitation of hematopoiesis in cultures with erythropoietin or GM-CSF revealed adequate CFU-E, BFU-E and CFU-GM growth by LPD bone marrow. Inclusion of 10 MUM SnPP in cultures was found to significantly enhance CFU-E/BFU E growth by LPD marrows, whereas Zinc protoporphyrin had a marked inhibitory effect. Little or no effect by SnPP was seen on CFU-GM. In contrast, normal bone marrow cultures failed to show an enhanced response to 10 MUM SnPP. Analysis of heme oxygenase mRNA levels revealed that LPD marrows had elevated expression of heme oxygenase mRNA as contrasted with normals. Furthermore, measurements revealed that heme oxygenase activity was markedly suppressed by SnPP in the LPD bone marrow cultures. Results lend further support to the importance of heme oxygenase in the differentiation process. Although LPD bone marrow cells may respond to erythropoietin in vitro, in stressed conditions where heme oxygenase is elevated, suppression of heme oxygenase may potentiate the erythropoietic response in this disease. PMID- 21269080 TI - Therapeutic and prognostic value of chromosomal AP classification at the blastic phase of Ph-positive chronic myeloid leukemia: comparison of data from Nagasaki University, Japan and Roswell Park Memorial Institute, U.S.A. AB - To assess parameters of therapeutic response and survival after the onset of the blastic phase (BP) in 47 patients with Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML), a number of clinical hematologic, and cytogenetic data at the BP were evaluated. Among the eleven parameters examined, only the chromosomal findings correlated with the therapeutic response and survival after onset of the BP. The patients were divided into three groups on the basis of the chromosome findings in the bone marrow: one, with only a Ph (PP), another with two different clones, i.e., one clone with Ph only and another with additional karyotypic changes (AP), and a third group with only abnormal clones containing karyotypic abnormalities in addition to the Ph (AA). The number of patients with AA was 12, 18 with AP, and 17 with PP. The results were as follows: (1) The percentage of patients with a good therapeutic response was 25% (3/12) in AA, 22% (4/18) in AP, and 76% (13/17) in PP; (2) The median survival after the onset of the BP was 1.5 mo for AA, 2.4 mo for AP, and 7.3 mo for PP. Statistically, there was a significant difference between PP and the other two groups (p < 0.05). These data were reevaluated and compared to those of 64 patients with Ph-positive CML in Roswell Park Memorial Institute (RPMI) who had been reported earlier in 1983. PMID- 21269081 TI - Chromosome 1p abnormalities in B non Hodgkin's lymphoma. AB - Thirteen patients with B-non Hodgkin's lymphoma and abnormalities of the short arm of chromosome 1 were evaluated, to see if this cytogenetic anomaly was associated with a particular subgroup of lymphomas. Large cell lymphoma was found in seven patients (with an immunoblastic component in four cases). Six patients with diffuse small cleaved cell lymphoma of non follicle centre cell origin formed a second group. The chromosome 1 breakpoints in the second group were located between p34 and p36, suggesting that genes located here may be important in the initiation or progression of these lymphomas. PMID- 21269082 TI - Breakpoints of 11q25 in three similar cases of B non Hodgkin's lymphoma. AB - We report three cases of small B cell non Hodgkins lymphoma, two with plasmacytoid differentiation, presenting with a similar clinical picture and identical immunophenotype, who cytogenetically had breakpoints involving band 11q25. We suggest that this breakpoint may define a group of lymphomas closely related to the diffuse small cleaved cell lymphomas with t(11;14)(q13;q32). PMID- 21269083 TI - A unique case of three autografts for acute myelogenous leukaemia with subsequent long term survival in second remission. AB - We report here a patient with acute mycloid leukaemia who relapsed 20 months after undergoing a double autograft procedure in first remission. He was reinduced and subsequently underwent a third autologous bone marrow transplantation in second remission using bone marrow harvested in second remission and a Busulphan and Cyclophosphamide conditioning regimen. Although the engraftment was very slow, he has remained in second remission for 34+ months. This case demonstrates that durable disease-free survival can be attained by a second preparative therapy, even in second remission, for patients relapsed after autologous bone marrow transplantation. PMID- 21269084 TI - Pseudotumour cerebri and paraproteinaemia. AB - We describe two cases of haematological malignancy, lymphoma and myeloma, presenting with pseudotumour cerebri. A haematological disorder should be considered in the differential diagnosis of the cause of pseudotumour cerebri, and the treatment of pseudotumour cerebri should be considered in the management of haematological disease, especially in avoiding irreversible visual deficit. PMID- 21269085 TI - Chronic myeloid leukemia following radioactive iodine (131)I therapy of thyroid cancer. AB - We describe a 51 years old female patient who developed Ph(1) positive chronic myeloid leukemia 7 years following radioactive iodine therapy for follicular carcinoma of thyroid. Until now, only two patients have been reported to have developed CML after this kind of therapy. The underlying mechanisms are discussed and the need to study such patients at cytogenetic, molecular biologic and cell kinetic levels is stressed. PMID- 21269088 TI - Papers from ICPLA 1999. PMID- 21269089 TI - Patterns in the acquisition of the Welsh lateral fricative. PMID- 21269090 TI - A preliminary typology of initial clusters in acquisition. PMID- 21269091 TI - New insights from optimality theory for acquisition. PMID- 21269092 TI - A model of lexical diffusion in phonological acquisition. PMID- 21269093 TI - Conflicting phonologically based and phonetically based constraints in the analysis of liquid-nasal substitutions. PMID- 21269095 TI - Phonemic awareness of coda consonants and sonority in bilingual children. PMID- 21269094 TI - Promotion and demotion of phonological constraints in the acquisition of the Japanese liquid. PMID- 21269096 TI - Treatment for phonologically disordered children with variable substitution patterns. PMID- 21269097 TI - Influence of chronic otitis media on phonological acquisition. PMID- 21269098 TI - When is a cluster not a cluster? PMID- 21269099 TI - Phoneme discrimination and phoneme identification in French language-impaired and normally-developing children. PMID- 21269100 TI - Characteristics of mazes produced by SLI children. PMID- 21269101 TI - Compensatory strategies in SLI. PMID- 21269102 TI - Unconstrained oral naming abilities of right-hemisphere damaged individuals: A qualitative and time-course analysis. PMID- 21269103 TI - Context as a resource for the construction of turns at talk in aphasia. PMID- 21269104 TI - The processing of prosodic patterns in patients with unilateral brain lesions. PMID- 21269105 TI - Intelligibility and rehearsed sequences in conversations with a DAT patient. PMID- 21269106 TI - A preliminary study of the effects of sub thalamic nucleus (STN) deep brain stimulation (DBS) on voice and speech characteristics in Parkinson's Disease (PD). PMID- 21269107 TI - Phonetics versus phonology?-Voicing impairment in anterior aphasia: preliminary results of acoustic analyses. PMID- 21269109 TI - The role of attention in apraxic errors. PMID- 21269108 TI - A preliminary study of the effects of pallidotomy surgery upon voice onset time in persons with Parkinson's disease. PMID- 21269110 TI - Age and gender effects on measures of RMS nasalance. PMID- 21269111 TI - A stumbling block in the development of motor theories of speech: relating EMG to force-related changes in articulation. PMID- 21269112 TI - Speech rate in cleft lip and palate speakers with compensatory articulation. PMID- 21269113 TI - The realization of affricates in a group of individuals with atypical speech production: a perceptual and instrumental study. PMID- 21269114 TI - Coarticulation in fricative-vowel syllables produced by children and adults: a preliminary report. PMID- 21269115 TI - Coarticulation within and between syllables by children with developmental apraxia of speech. PMID- 21269116 TI - Acoustic correlates of phonetic correction. AB - The paper addresses the question of speech correction using the auditory-phonetic approach. This approach is based on developing good auditory perception of the spoken material, by manipulating the signal itself, and by various strategies including the use of the optimal sound context, word and sentence position, intonation and stress patterns, and movement accompanying speech production. The acoustic analysis and listening judgements of speech produced by the same subject before and after phonetic correction indicate significant improvement in pronunciation. This type of correction may be used from speech-hearing pathology to foreign language learning. PMID- 21269117 TI - Speech motor learning: preliminary data. PMID- 21269118 TI - Searching for the neural basis of stuttering treatment outcome: recent neuroimaging studies. PMID- 21269119 TI - The effect of speech clinician race and Afro-American students' cultural mistrust on clinician-child conversation. PMID- 21269124 TI - Auditory perceptual evaluation of rhythm-manipulated and resynthesized sentence utterances obtained from cerebellar patients and normal speakers: A preliminary report. AB - Alterations of the temporal structure of spoken utterances in terms of lengthened acoustic segments and increased syllabic isochrony seem to represent a salient feature of ataxic dysarthria. The present study addresses the question of whether systematic manipulations of the durational aspects of the acoustic speech signal yield an improvement of perceived dysarthric deficits. Different variants of speech rhythm were imposed on sentence utterances obtained from two patients with ataxic dysarthria and two normal control speakers. For the sake of comparability the pitch contours were standardized by means of linearly interpolated stylized versions. The introduced manipulations significantly influenced the ratings of perceived slowness, dysfluency, and rhythmic adequacy. With respect to estimates of overall intelligibility and naturalness, however, ataxic-dysarthric utterances did not benefit from any synthetic changes. By contrast, utterances of normal speakers were rated less intelligible and somewhat more unnatural when resynthesized with an ataxic rhythm. These results indicate that durational factors play a minor role with respect to the overall speech impairment of ataxic speakers. PMID- 21269125 TI - Formant transition duration and place perception in misarticulating children and adolescents. AB - The explanation of articulatory problems as an output speech disorder does not preclude the possibility that auditory processing problems are associated. Identification of brief auditory spectral cues in a place-of-articulation continuum was studied in children with articulation problems. First, it was shown that formant transition durations smaller than 20.0 ms dramatically decreased phonemic identification rates for alveolar stop consonants in control subjects. Identification tasks based on two place-of-articulation continua /palphak/ /talphak/ with F2/F3 transition durations of 52 and 20 ms were administered to groups of misarticulating children and adolescents and two control groups (children and adults). For all subject groups there was poorer phonetic processing with shorter transition durations of F2 and F3. The misarticulating subjects demonstrated poorer phonetic processing of formant transitions than did the control subjects. Shortening F2/F3 transition duration did not differentially influence perceptual behaviour between the experimental and the control groups. In determining the causal link between perception and production, an explanation of perception preceding production was favoured. It was argued that, in addition to assessing the specificity between perception and production mechanisms, assessment of perception of formant transitions may have potential as a clinical tool for evaluating phonetic processing. PMID- 21269126 TI - Joint productions as a conversational strategy in aphasia. AB - To address the longstanding question of the conversational ability of persons with aphasia, this study investigated the spontaneous occurrence of a specific type of conversational collaboration, joint production, that is known to occur in the conversation of ordinary speakers. A person with aphasia and his wife videorecorded eight of their naturally occurring conversations. These conversations were analysed and three types of joint productions were identified: word search, turn completion and appendor production. Additional sequential analysis revealed the linguistic, paralinguistic and contextual resources available to the interactants in designing their joint production. Results showed that, despite the presence of aphasia, this couple was able to successfully employ joint production as an interactive technique leading to conversational success. Implications of this study are discussed relative to the understanding of communicative ability of persons with aphasia and how aphasia is diagnostically and therapeutically approached. PMID- 21269127 TI - Natural domains of cyclicity in phonological acquisition. AB - This study expands and further validates cyclicity in the course of phonological development by exploring a potential relationship between the acquisition of singletons and clusters. The hypothesis is that children will acquire singletons followed by clusters in an alternating and recursive pattern, in complement to observed subsegmental cyclicity involving larnygeal and supralaryngeal distinctions. Six children with functional phonological disorders participated in one of three experimental conditions administered as a staggered multiple baseline, multiple-probe design: treatment of singletons only, clusters only, or the singleton-cluster cycle. Results indicated that a singleton-cluster cycle could be induced experimentally, but it was not generally sustained by a child in expansion of the phonological repertoire. In comparison, laryngeal-supralaryngeal cyclicity was consistently maintained by all children, independent of experimental condition. A theoretical implication of these findings is that cyclicity functions as a governing principle of phonological development, but only if it is inherent to the natural domain of language. The clinical application of cyclicity in structuring treatment is considered. PMID- 21269131 TI - Validating five questions of antiretroviral nonadherence in a public-sector treatment program in rural South Africa. AB - Simple questions are the most commonly used measures of antiretroviral treatment (ART) adherence in sub-Saharan Africa (SSA), but rarely validated. We administered five adherence questions in a public-sector primary care clinic in rural South Africa: 7-day recall of missed doses, 7-day recall of late doses, a six-level Likert item, a 30-day visual analogue scale of the proportion of doses missed, and recall of the time when an ART dose was last missed. We estimated question sensitivity and specificity in detecting immunologic (or virologic) failure assessed within 45 days of the adherence question date. Of 165 individuals, 7% had immunologic failure; 137 individuals had viral loads with 9% failure detected. The Likert item performed best for immunologic failure with sensitivity/specificity of 100%/5% (when defining nonadherence as self-reported adherence less than "excellent"), 42%/55% (less than "very good"), and 25%/95% (less than "good"). The remaining questions had sensitivities <=17%, even when the least strict cutoffs defined nonadherence. When we stratified the analysis by gender, age, or education, question performance was not substantially better in any of the subsamples in comparison to the total sample. Five commonly used adherence questions performed poorly in identifying patients with treatment failure in a public-sector ART program in SSA. Valid adherence measurement instruments are urgently required to identify patients needing treatment support and those most at risk of treatment failure. Available estimates of ART adherence in SSA are mostly based on studies using adherence questions. It is thus unlikely that our understanding of ART adherence in the region is correct. PMID- 21269138 TI - Changes in the nitric oxide system contribute to effect of procyanidins extracted from the lotus seedpod ameliorating memory impairment in cognitively impaired aged rats. AB - The major purpose of this study was to determine the effect of procyanidins extracted from the lotus seedpod (LSPC) on the nitric oxide (NO) system in the hippocampus and cerebral cortex in cognitively impaired aged rats. Using the Morris water maze, aged-unimpaired (AU) and aged-impaired (AI) rats were chosen from aged rats. All aged rats exhibited elevated inducible nitric oxide synthase (iNOS) activities and decreased neuronal nitric oxide synthase (nNOS) activities in the both brain regions. The changes were more pronounced in the brain of AI rats, especially in the hippocampus. Furthermore, AI rats greatly lowed the percentage of change of hippocampal nNOS activity in the presence of protein kinase inhibitors or phosphatase inhibitor, which meant that AI animals existed in a hardly modified nNOS dephosphorylated state in hippocampus. LSPC supplementation [50, 100 mg/kg of body weight (BW), per os (p.o.)] for 7 weeks significantly decreased iNOS activities and improved hippocampal nNOS phosphorylation status in AI animals. These results suggested that changes in the NO system may involve in the ameliorative effects of LSPC on cognitive deficits in AI animals. PMID- 21269146 TI - Specific treatment of Prader-Willi syndrome through cyclical rehabilitation programmes. AB - PURPOSE: To evaluate retrospectively the efficiency of our rehabilitation programme for patients with Prader-Willi Syndrome. In total, 49 patients were examined, 21 female and 28 male, the youngest in their late teens. Prader-Willi syndrome is generally characterised by cognitive impairment, behavioural abnormalities, and hyperphagia. Patients are usually considerably adverse to any form of physical exercise, and despite hormonal therapy, weight control in adult patients can be difficult. METHODS: Four times a year, disease-specific residential programmes were organised, each lasting 4 weeks. The patients were restricted to a 1500 Kcal diet. In addition, they were required to do 6.5 h of physical exercise daily, stamina being built up by using music therapy, psychomotor therapy, education and entertainment activities. RESULTS: BMI decreased by 2.1 average points in every residential session. For three patients who attended our treatments regularly, a reduction of 8.9 points over 6 years was recorded. An attendance of at least three sessions per year seemed to be necessary to substantially reduce weight. CONCLUSIONS: A multidisciplinary approach and a daily calorie-counted diet can lead to significant weight loss in teenage and adult PWS patients. This approach would also be suitable in treating patients with other obesity syndromes with mental retardation. PMID- 21269156 TI - Treatment efficiency as a function of target selection in the remediation of child language disorders. AB - A number of studies appearing in the recent literature examined the effectiveness of treating language impairments using indirect, conversationally based interventions. However, such studies have been difficult to interpret, due, in part, to a lack of direct comparisons of treatment types. The present study was designed to compare directly elicited imitation treatment and conversational treatment using linguistic targets matched for structural stage and assigned randomly to treatment condition. These treatments were applied to four specifically language-impaired children (age range 4;9 to 5;11) during a 16-week training period. Spontaneous productions occurred following significantly fewer presentations within the conversational treatment. Additionally, the results indicated that both kinds of treatments were effective and that certain individual targets were acquired more rapidly within the elicited imitation treatment. These findings are discussed in terms of the differing approaches to treatment and in terms of more general theories of language learning. PMID- 21269157 TI - Phonetic intelligibility testing in dysarthria for the use of French language clinicians. AB - Reduced intelligibility is a common characteristic of dysarthria. The object of this paper is to propose a word intelligibility test for the assessment of intelligibility in French language dysarthric speakers. Based on a phonetic intelligibility test previously developed for English by Kent et al. (1989), this test not only measures dysarthric severity but also serves to identify the intelligibility deficits. PMID- 21269158 TI - Teaching and learning /theta/: A non-confound. AB - The purpose of this study was to replicate and extend the findings on the effectiveness of homonymous versus non-homonymous treatment approaches for children with phonological disorders, following Gierut (1991b). The present study was motivated by a potential confound noted in the previous report; namely, the specific sounds /theta, theta/ treated in the presumably less effective homonymous condition may have inhibited degree of phonological change. It was thus necessary to teach these more difficult, late-acquired interdental fricatives in the more effective non-homonymous treatment condition using identical methods and procedures. Results indicated that a non-homonymous teaching approach again motivated greater phonological change than a homonymous approach, regardless of sounds that were taught. These findings have implications for the independence of linguistic structures of treatment in inducing sound change, and bear upon assumptions about ease of sound learning based on normative developmental sequences. PMID- 21269159 TI - Electropalatographic investigation of abnormal lingual-palatal contact patterns in cleft palate patients. AB - Lingual-palatal contact patterns and auditorily judged misarticulations, classed as palatalized misarticulation (PM), lateral misarticulation (LM), nasopharyngeal misarticulation (NM), and other distortions were compared in 53 Japanese cleft palate patients. Velopharyngeal function of these patients was considered within normal limits. Contact patterns were recorded by electropalatography (EPG) in an attempt to objectively categorize the misarticulations of cleft palate speakers including those previously reported in English. It is concluded that these lingual-palatal contact patterns are characterized by a broader and/or more posterior pattern than found in normal speakers, although considerable variability was noted. PMID- 21269160 TI - Uncovering phonological regularity in neologisms: Contributions of sonority theory. AB - The sonority sequencing principle suggests that the relative sonority rank among sounds can explain intrasyllabic phoneme ordering patterns in words produced by normal speakers. Some investigators have incorporated sonority into explanations of the phonemic paraphasias and syllable structure deficits often seen in aphasic language. However, little is known about the role of sonority in constructing the bizarre words characteristic of neologistic jargonaphasia. This study examined the syllabic structure of the neologistic (and legitimate) utterances produced by three English-speaking jargonaphasics in order to determine if sonority constraints governed construction of neologisms at the level of core phonology. Results revealed that the demisyllable shapes and intrasyllabic sonority profiles of the subjects' target-related neologisms, abstruse neologisms and English words were similar to those produced by normal English speakers, as described by the theory. Results suggest that (1) sonority may be a well-distributed and 'hard wired' component of normal phonological processing, (2) sonority analyses may capture the 'hidden' phonological regularity in neologisms, (3) sonority may constrain the operation of mechanisms that create neologisms. PMID- 21269161 TI - Speaking fundamental frequency characteristics of centenarian females. AB - Speaking fundamental frequency (F(0)) characteristics were determined for nine centenarian females and nine young adult females. Mean, maximum, and minimum F(0) values were obtained for each subject from a minimum of 20 s of continuous speech. Results indicated that female centenarians have significantly lower mean and minimum speaking F(0) values than young adult females, as well as significantly greater speaking F(0) ranges (in both Hz and semitones). The present results extend the investigation of the ageing continuum as it affects vocal F(0), and indicate that excessively low mean and minimum speaking F(0) values must be considered within the normal spectrum of voice characteristics for the female centenarian population. PMID- 21269163 TI - Recommended Phonetic Symbols: Extensions to the IPA. PMID- 21269226 TI - Expression of GPR30, ERalpha and ERbeta in endometrium during window of implantation in patients with polycystic ovary syndrome: a pilot study. AB - Women with polycystic ovary syndrome (PCOS) exhibit a lower pregnancy rate, which may be related to decreased estrogen receptor (ER) expression or endometrial receptivity. We measured expression of ERalpha, ERbeta and the novel G protein coupled ER (GPR30) in endometrium during window of implantation (WOI) in PCOS patients. Fifteen Chinese women with PCOS were compared to 15 normal subjects. Serial trans-vaginal ultrasonic scanner (TVUS) examinations detected follicular development, and endometrial thickness and pattern were assessed via TVUS on the day of ovulation. GPR30 expression was detected in the cytoplasm of endometrial epithelial cells, and was significantly lower in the PCOS group (p < 0.05). ERalpha and ERbeta expression was lower in the PCOS group, and was detected mainly in the nucleus of endometrial epithelial cells. There was no significant difference in endometrium thickness (p > 0.05), but there was a significant difference in the ultrasonic pattern (p < 0.05). Endometrial expression of GPR30, ERalpha and ERbeta was decreased during WOI in PCOS patients, and was accompanied by poor endometrial receptivity, low pregnancy rate and higher spontaneous abortions. We propose that restored receptor expression might improve endometrial receptivity and help lower infertility associated with PCOS. PMID- 21269234 TI - The impact of biologic response modifiers on hepatitis B virus infection. AB - INTRODUCTION: The biologic response modifiers are a diverse group of medications that have emerged over the last decade. They target pro-inflammatory cytokines or cell surface molecules that drive illnesses such as rheumatoid arthritis. Despite the greater control afforded they have also ushered in a new spectrum of side effects. As the same immunologic machinery that helps control infections such as HBV contributes to the pathogenesis of rheumatologic diseases, persistence or reactivation of the virus remains an evolving concern. AREAS COVERED: A systemic literature review was performed using the PubMed and Medline databases (1996 to January 2010) searching for the index term 'Hepatitis B' combined with the terms 'tumor necrosis factor', 'B cell', 'rituximab', 'IL-1', 'anakinra', 'IL-6', 'tocilizumab', 'CTLA-4', and 'abatacept'. All relevant articles in English were reviewed and secondary references of interest were also retrieved. This paper addresses the role of the various cytokines and cluster of differentiation molecules in controlling HBVinfection and the currently known effect that the biologic response modifiers have on viral control by the host immune response. EXPERT OPINION: The risk of HBV reactivation is greatest in HBsAg positive patients. These patients should start antiviral therapy one week before receiving a biologic response modifier. The risk of HBV reactivation in HBsAg negative patients appears very low but when HBsAb titers are low use of rituximab or TNF alpha antagonists may increase the risk of reactivation. PMID- 21269235 TI - Cytotoxic triplets plus a biologic: state-of-the-art in maximizing the potential of up-front medical treatment of metastatic colorectal cancer. AB - INTRODUCTION: Up-front treatment of metastatic colorectal cancer (mCRC) has progressively become more complex during last few years. Nowadays, treatment options range from monotherapies with biologics or traditional chemotherapeutic agents to intensive combinations of chemotherapy plus targeted drugs. AREAS COVERED: This review deals with the results of the most recent first-line trials in the medical treatment of mCRC, with a special focus on recently closed or ongoing trials of intensive concomitant combinations of all active cytotoxics plus a biologic agent. EXPERT OPINION: Combinations of three cytotoxic drugs plus a biologic are under clinical investigation and therefore should not be recommended for routine use, nevertheless preliminary results are promising. The main challenges for the future are not only to demonstrate the real clinical usefulness of intensive approaches, but also to gain the ability of defining prior to treatment which patients will benefit most on the basis of clinical and molecular elements. PMID- 21269236 TI - Novel adenosine 5'-triphosphate-sensitive potassium channel ligands: a patent overview (2005-2010). AB - INTRODUCTION: ATP-sensitive potassium channels are important metabolic regulators that link cellular metabolism to excitability. Their wide distribution in various tissues and organs makes them significant and topical targets in a large number of diseases. AREAS COVERED: This review summarizes the current understanding of the molecular biology and pharmacology of K(ATP) channels, and the pathological states that result from aberrant expression or function of these proteins. In particular, relevant research, patents and patent applications of the past 5 years are discussed. EXPERT OPINION: The tissue-specific K(ATP) channel modulation reflects an early discovery stage in drug design. The wide distribution of K(ATP) channels lets us consider them as valid targets for several pathologies, but on other hand the ubiquitous nature is a relevant drawback in developing an effective therapy because of the onset of side effects related to the lack of selectivity. On this basis, further investigations on both the structures and the localization of each receptor subtype should be carried out either exploring the structure-activity relationship of the already existing K(ATP) ligands or developing new selective fluorescent probes. To date, this research area still strives to design new tissue-targeted ligands that could pave the way to the development of innovative and effective drugs for clinical use. PMID- 21269237 TI - Donor lymphocyte infusion following allogeneic hematopoietic stem cell transplantation. AB - INTRODUCTION: Allogeneic hematopoietic stem cell transplantation (SCT) is the treatment of choice for many malignant hematological disorders. Following recent improvements in non-relapse-related mortality rates, relapse has become the commonest cause of treatment failure. Infusion of donor lymphocytes can potentially enhance immune-mediated antitumor activity and offers a salvage option for some patients. This paper reviews the current literature on the efficacy of this therapeutic strategy. AREAS COVERED: The biology of adoptive cellular therapy with allogeneic immune cells to treat relapse across a spectrum of diseases in both the full intensity and reduced intensity hematopoietic SCT settings is explored. The review discusses the current limitations of the approach and reviews several new experimental strategies which aim to segregate the desired graft-versus-tumor effect from the deleterious effects of more widespread graft-versus-host reactivity. EXPERT OPINION: Durable responses to DLI have been noted in chronic myeloid leukemia and responses have also been described in acute leukemia, multiple myeloma and chronic lymphoproliferative disorders. The new challenge in transplantation is to optimize DLI therapy in order to further improve patient outcomes. PMID- 21269241 TI - Management of varices in cirrhosis. AB - INTRODUCTION: Acute variceal bleeding is a medical emergency and one of the main causes of mortality in patients with cirrhosis. Timely and effective treatment of the acute bleeding episode results in increased survival, and appropriate prophylactic treatment can prevent bleeding or rebleeding from varices. AREAS COVERED: We discuss the prevention of development and growth of varices, the primary and secondary prophylaxis of bleeding, the treatment of acute bleeding, and the management of gastric varices. We systematically reviewed studies, without time limits, identified through Medline and searches of reference lists, and provide an overview of the evidence underlying the -treatment options in the management of varices in cirrhosis. EXPERT OPINION: The management of variceal hemorrhage relies on nonspecific interventions (e.g., adequate fluid resuscitation, airway protection) and on specific interventions. These are routine prophylactic antibiotics, vasoactive drugs and endoscopic treatment. Procedures such as the placement of a Sengstaken-Blakemore tube or a transjugular intrahepatic portosystemic shunt (TIPS) can be lifesaving. The primary and secondary prophylaxis of bleeding is based on nonselective beta-blockers and endoscopy, even though TIPS or, less frequently, surgery have a role in selected cases. PMID- 21269242 TI - New approaches in light/laser therapies and photodynamic treatment of acne. AB - Acne is a domain in which the technology and understanding of light/laser therapeutic procedures have advanced considerably. The aim of the paper was to revisit adjunctive physical treatments of acne, including light/laser treatments and photodynamic therapy. This review summarizes findings about such treatment modalities with particular emphasis on efficacy and safety. A number of laser/light-based modalities have been developed to meet the increasing demand for new acne treatments. The current devices correspond, on the one hand, to light-emitting diode therapy and, on the other hand, to the 532-nm potassium titanyl phosphate laser, the 585- and 595-nm pulsed dye laser, the 1450-nm diode laser, the 1320-nm Nd:YAG laser and intense pulsed light. Photodynamic therapy is also available. It is claimed that light/laser treatments might induce a faster response compared with the 1-3 months needed for response to traditional oral and topical treatments. In conclusion, pulsed dye laser shows efficacy in some patients with mild to moderate acne. The relative effectiveness compared with other treatments is unconfirmed; from the published information, evidence-based efficacy assessment of light/laser therapies in acne remains almost impossible. PMID- 21269246 TI - Fecal calprotectin: a selection tool for small bowel capsule endoscopy in suspected IBD with prior negative bi-directional endoscopy. AB - BACKGROUND AND AIM: Fecal calprotectin (FC) is a non-invasive marker of gastrointestinal inflammation with advocated diagnostic precision in distinguishing inflammatory bowel disease (IBD) from non-IBD diagnoses. FC correlates with abnormalities seen on small bowel barium radiology, but little data exist in relation with small bowel capsule endoscopy (SBCE). To investigate the value of FC as a selection tool for further investigation of the small bowel with SBCE, in a cohort of patients who had negative bi-directional endoscopies, but with continuing clinical suspicion of Crohn's disease (CD). METHODS: We retrospectively correlated the findings of SBCE with FC levels in patients referred with clinical suspicion of CD and negative bi-directional endoscopies. Only patients with FC results prior to the SBCE test were included; in cases of multiple FC determinations, the value closest to the SBCE date was selected. Medications history including usage of aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) was made available for all patients. SBCE findings were analyzed against final diagnosis and FC values. RESULTS: Seventy adult patients were studied (53 females, 17 males). Three cases were excluded, due to capsule retention in the stomach. Median time from FC measurement to SBCE was 62 days. Twenty-three patients had normal FC (<= 50 MUg/g) and in all those the SBCE was normal. Forty-four patients had FC >50 MUg/g; in this group, nine patients had FC between 51 and 100 MUg/g and all had a normal SBCE. Thirty-five patients had FC levels >100 MUg/g; of those, 15 (42.85%) had SBCE findings compatible with CD and mean FC levels 326 MUg/g (range 116-1430 MUg/g). A definitive clinical diagnosis of CD, based on subsequent follow-up, was made in 10/35 (28.5%) of patients. These 10 patients were within the subgroup of 15 patients with positive SBCE findings and had median FC levels 368 MUg/g (range 235-1430 MUg/g). CONCLUSIONS: Measurement of FC levels prior to referral for SBCE is a useful tool to select patients with possible small bowel CD. A FC >100 MUg/g is good predictor of positive SBCE findings, while FC >200 MUg/g was associated with higher SBCE yield (65%) and confirmed CD in 50% of cases. Patients with FC between 50 and 100 MUg/g had normal SBCE, despite symptoms suggestive of IBD. In all patients with clinical suspicion of CD and negative bi-directional endoscopies, FC assessment should be carried out prior to their referral for SBCE. Where FC is <100 MUg/g (NPV 1.0), SBCE is not indicated. PMID- 21269249 TI - Modulation of histone acetylation by garlic sulfur compounds. AB - Preclinical studies have shown that fresh garlic extracts, aged garlic, garlic oil and specific organosulfur compounds generated by processing garlic could alter carcinogen metabolism, inhibit tumor cell growth through induction of cell cycle arrest or apoptosis, or angiogenesis. In particular, recent studies have suggested that anticarcinogenic effects of certain garlic compounds may implicate at least in part a modulation of histone acetylation, a process involved in the regulation of gene expression, resulting from the inhibition of histone deacetylase activity. The aim of this review is to describe available data on sulfur compounds from garlic and histone acetylation and to discuss their potential for cancer prevention. Available data indicate that garlic compounds could inhibit histone deacetylase activity and induce histone hyperacetylation in vitro as well as in vivo. Sparse studies provide evidence of an involvement of histone acetylation in modulation of gene expression by diallyl disulfide and allyl mercaptan. These effects were observed at high concentrations. Further investigations are needed to determine if the HDAC inhibitory effects of garlic organosulfur compounds might play a role in primary cancer prevention at doses achievable by human diet. PMID- 21269251 TI - Anti-proliferation activity of synthetic ajoene analogues on cancer cell-lines. AB - The ability of garlic preparations to inhibit cancer cell-growth has been attributed to a group of structurally-related organosulfur compounds found in the crushed clove. Historically, interest has centred on three such compounds as allicin, diallyl disulfide and diallyl trisulfide, with less interest on E- and Z ajoene. A recently developed synthetic route from our laboratory for preparing ajoene analogues allows access to derivatives containing the sulfoxide / vinyl disulfide core whilst varying the terminal end-group functionality. A small library has been synthesized and an advanced lead with p-methoxybenzyl end groups (8) identified. Data on the in vitro anti-proliferation activity of compound (8) is presented here against six cancer cell-lines in comparison with that of Z- and E-ajoene to reveal an enhancement in activity of up to twelvefold. In addition, a modest selectivity is observed for tumour over normal cell-lines of up to threefold. Data on ajoene and its derivatives is presented in the context of chemosensitization in drug-resistance, and ideas on ajoene's mode of action at the molecular level are presented and discussed. PMID- 21269250 TI - Cilengitide: the first anti-angiogenic small molecule drug candidate design, synthesis and clinical evaluation. AB - Cilengitide, a cyclic RGD pentapeptide, is currently in clinical phase III for treatment of glioblastomas and in phase II for several other tumors. This drug is the first anti-angiogenic small molecule targeting the integrins alphavbeta3, alphavbeta5 and alphavbeta1. It was developed by us in the early 90s by a novel procedure, the spatial screening. This strategy resulted in c(RGDfV), the first superactive alphavbeta3 inhibitor (100 to 1000 times increased activity over the linear reference peptides), which in addition exhibited high selectivity against the platelet receptor alphaIIbbeta3. This cyclic peptide was later modified by N methylation of one peptide bond to yield an even greater antagonistic activity in c(RGDf(NMe)V). This peptide was then dubbed Cilengitide and is currently developed as drug by the company Merck-Serono (Germany). This article describes the chemical development of Cilengitide, the biochemical background of its activity and a short review about the present clinical trials. The positive anti angiogenic effects in cancer treatment can be further increased by combination with "classical" anti-cancer therapies. Several clinical trials in this direction are under investigation. PMID- 21269252 TI - Targeting focal adhesion kinase in neuroblastoma. AB - Neuroblastoma is the most common extracranial solid tumor encountered in children, and continues to carry a dismal prognosis. Focal adhesion kinase (FAK) has been shown to be upregulated in a number of human tumors and is related to tumor virulence and patient prognosis. We have demonstrated FAK expression in human neuroblastoma cell lines and tumors, and have shown that FAK is important for neuroblastoma tumor cell viability. We have also demonstrated that FAK inhibition through a number of different methods results in decreased neuroblastoma survival both in vitro and in vivo. The current review addresses the merit of further exploring FAK inhibition as a novel treatment for neuroblastoma. PMID- 21269253 TI - Evaluation of effect of triterpenes and limonoids on cell growth, cell cycle and apoptosis in human tumor cell line. AB - Six triterpenes and eight limonoids were evaluated for their capacity to inhibit the growth of three human tumour cell lines, breast adenocarcinoma (MCF-7), non small cell lung cancer (NCI-H460) and melanoma (A375-C5). The mechanisms involved in the observed cell growth arrest of the four most potent compounds were carried out by studying their effect in cell cycle profile and programmed cell death. The results showed that one triterpene (odoratol) and two limonoids (gedunin and cedrelone) caused cell cycle arrest while only the limonoids gedunin and cedrelone were found to be very potent inducers of apoptosis. PMID- 21269254 TI - Tumor promoters--microcystin-LR, nodularin and TNF-alpha and human cancer development. AB - Microcystin-LR and nodularin, along with okadaic acid, are potent inhibitors of protein phosphatases 1 and 2A (PP1 and PP2A). The mechanisms of action of microcystin-LR and nodularin in the liver and that of okadaic acid, a potent tumor promoter on mouse skin, have attracted the attention of the scientists. This paper reviews several topics: new inhibitors of PP1 and PP2A with new chemical structures, structure-function relationships for both receptor binding and inhibition of protein phosphatases, the crystal structure of PP1 or PP2A toxin complex, induction of gene expression and apoptosis. These subjects were studied by using in vitro and in vivo experimental systems. Two-stage carcinogenesis experiments with microcystin-LR and nodularin for the first time demonstrated that microcystin-LR is a new tumor promoter in rat liver initiated with diethylnitrosamine (DEN), and that nodularin is a potent tumor promoter associated with weak initiating activity in rat liver initiated with DEN. A working group of WHO (IARC) concluded that microcystin-LR is "possibly carcinogenic to humans" and that nodularin is "not classifiable as to carcinogenicity". Our studies revealed that chemical tumor promoters are inducers of TNF-alpha in the cells of target tissues and that TNF-alpha is an endogenous tumor promoter. This advance in carcinogenesis made it possible to look for the link between chemical tumor promoters and endogenous tumor promoters, such as TNF alpha and IL-1. The carcinogenic features of TNF-alpha are described in this review, and the TNF-alpha inducing protein (Tipalpha) of Helicobacter pylori genome is presented as an example of a tumor promoter of human stomach cancer development. PMID- 21269255 TI - Can we effectively degrade microcystins?--Implications on human health. AB - Microcystins are cyclic heptapeptide toxins produced by a number of genera of cyanobacteria. They are ubiquitous in bodies of water worldwide and pose significant hazard to human, plant, and animal health. Microcystins are primarily hepatotoxins known to inhibit serine-threonine phosphatases leading to the disruption of cascade of events important in the regulation and control of cellular processes. Covalent binding of microcystins with phosphatases is thought to be responsible for the cytotoxic and genotoxic effects of microcystins. In addition, microcystins can trigger oxidative stress in cells resulting in necrosis or apoptosis. Their cyclic structure and novel amino acids enhance their stability and persistence in the environment. Humans are primarily exposed to microcystins via drinking water consumption and accidental ingestion of recreational water. Recreational exposure by skin contact or inhalation to microcystins is now recognized to cause a wide range of acute illnesses which can be life-threatening. Microcystins are primarily degraded by microorganisms in the environment, while sunlight can cause the isomerization of the double bonds and hydroxylation in the presence of pigments. Attempts to utilize these organisms in sand and membrane filters to treat water contaminated with microcystins showed complete removal and detoxification. Conventional water treatment processes may not fully eliminate microcystins when there are high levels of organic compounds especially during harmful bloom events. Combination of conventional and advanced oxidation technologies can potentially remove 100% of microcystins in water even in turbid conditions. This review covers selected treatment technologies to degrade microcystins in water. PMID- 21269256 TI - In-gel protein phosphatase assays and other useful methods for the detection of protein phosphatase activities. AB - Intracellular signaling is governed by protein phosphorylation and dephosphorylation catalyzed by protein kinases and protein phosphatases, respectively. Since there is growing evidence that a variety of protein phosphatases are involved in the pathogenesis of various diseases, protein phosphatases have recently been the focus of intense research interest, not only in basic biology but also in clinical medicine. In the process of these studies, analytical methods for protein phosphatases will be of increasing importance. A major bottleneck in protein phosphatase assays is the selection and preparation of an efficient substrate for the phosphatase to be assayed. To circumvent this difficulty, a variety of protein phosphatase substrates have been devised during the development of novel assay techniques by which protein phosphatase activities can be readily detected. In this review, we focus on the methodology for detecting protein phosphatase activities, with special emphasis on in-gel protein phosphatase assays and related techniques. The utility and limitations of these methods are also discussed. PMID- 21269257 TI - Metal-based inhibitors of protein tyrosine phosphatases. AB - Protein tyrosine phosphatases (PTPs) are a large family of signaling enzymes playing critical role in signal transduction and regulation of cellular processes. Dysfunction of PTP activity is associated with diabetes, cancer, autoimmune disorders, and neural diseases. PTP inhibitors therefore emerged as promising therapeutic targets. Recent research indicates that besides small organic molecules, metal ions and metal complexes can also strongly inhibit PTPs both in vitro and in vivo, resulting in the increase of phosphorylation of corresponding substrates and the modulation of cellular process. Structure of metal complexes influences the potency and selectivity of PTP inhibition. Detailed studies on this subject are not only expected to yield metal-based drugs targeting individual PTPs, but also to support understanding the function of metals in organisms. This review focuses on recent advancements in this area of research. PMID- 21269258 TI - Focal adhesion kinase as a therapeutic target of bortezomib. AB - Bortezomib, a modified dipeptidyl boronic acid, is a selective potent proteasome inhibitor that has been approved for clinical treatment of multiple myeloma and mantel cell lymphoma. Results from a growing number of basic studies and clinical trials reveal that bortezomib could be used to treat diverse types of solid tumors alone or in combination with other chemotherapeutic drugs. It has been shown that bortezomib transcriptionally suppresses focal adhesion kinase (FAK) expression by interrupting the nuclear factor kappa B (NFkappaB) pathway, which suggests that FAK could be a potential molecular target for bortezomib. Analysis of FAK promoter sequences revealed that FAK promoter harbors the NFkappaB and p53 binding domains. Further studies of FAK promoter activity, real-time PCR, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay revealed that bortezomib inhibits NFkappaB binding on the FAK promoter, thereby reducing FAK expression. Thus, bortezomib could inhibit cancer cell growth and migration or invasion by repressing FAK expression. Since activation and overexpression of FAK has been implicated in the progression and invasion of malignant tumors, it is likely that targeting FAK with bortezomib is a potential strategy for preventing cancer metastasis. This review focuses on the molecular regulation of FAK and the potential clinical application of bortezomib. PMID- 21269259 TI - Anticancer effects of garlic and garlic-derived compounds for breast cancer control. AB - Garlic and garlic-derived compounds reduce the development of mammary cancer in animals and suppress the growth of human breast cancer cells in culture. Oil soluble compounds derived from garlic, such as diallyl disulfide (DADS), are more effective than water-soluble compounds in suppressing breast cancer. Mechanisms of action include the activation of metabolizing enzymes that detoxify carcinogens, the suppression of DNA adduct formation, the inhibition of the production of reactive oxygen species, the regulation of cell-cycle arrest and the induction of apoptosis. Selenium-enriched garlic or organoselenium compounds provide more potent protection against mammary carcinogenesis in rats and greater inhibition of breast cancer cells in culture than natural garlic or the respective organosulfur analogues. DADS synergizes the effect of eicosapentaenoic acid, a breast cancer suppressor, and antagonizes the effect of linoleic acid, a breast cancer enhancer. Moreover, garlic extract reduces the side effects caused by anti-cancer agents. Thus, garlic and garlic-derived compounds are promising candidates for breast cancer control. PMID- 21269260 TI - Chemical properties and mechanisms determining the anti-cancer action of garlic derived organic sulfur compounds. AB - Organic sulfur compounds (OSCs) derived from plants, fungi or bacteria can serve as chemopreventive and/or chemotherapeutic agents and have been attracting medical and research interest as a promising source for novel anti-cancer agents. Garlic, which has long been used as a medicinal plant in different cultures due to its multiple beneficial effects, contains a consistent number of OSCs, the majority of which are currently under investigation for their biological activities. Experimental animal and laboratory studies have shown strong evidence that garlic OSCs may affect cancer cells by promoting early mitotic arrest followed by apoptotic cell death without affecting healthy cells. The ability of OSCs to hinder cancer cell proliferation and viability tightly correlates with the length of the sulfur chain. Current data support a mechanism of mitotic arrest of cancer cells due to the alteration of the microtubule network, possibly as a consequence of the high reactivity of sulfur atoms against the thiol groups of different cellular macromolecules controlling crucial regulatory functions. Taken together, these findings indicate a promising potential for the use of garlic-derived sulfur compounds in chemoprevention and chemotherapy. PMID- 21269261 TI - Repressing the activity of protein kinase CK2 releases the brakes on mitochondria mediated apoptosis in cancer cells. AB - Execution of the mitochondrial death signaling is paramount to an effective response of cancer cells to chemotherapeutic intervention. Therefore, factors that inhibit the engagement of the mitochondrial amplification pathway, such as the expression of the anti-apoptotic proteins of the Bcl2 family or inactivation of inducers of mitochondrial permeability, play a critical role in the acquisition of the resistant phenotype. Protein kinase CK2 (CK2) is a ubiquitous serine/threonine kinase that is highly conserved in eukaryotic cells. This multifunctional protein kinase has been shown to impact cell growth and proliferation, as numerous growth-related proteins are substrates of CK2. More importantly, experimental evidence linking increased expression and activity of the kinase to human cancers, underscores the relevance of CK2 biology to cellular transformation and carcinogenesis. Of note, among the many cellular substrates of CK2 are proteins involved in the efficient execution of the mitochondria dependent cell death signaling, such as Bid, caspase-2, ARC and others. Supporting this, recent reports have demonstrated that genetic manipulation of CK2 expression as well as pharmacological inhibition of its enzymatic activity sensitizes cancer cells to apoptotic stimuli. Due to the critical regulatory role that this kinase plays in cell fate determination in cancer cells, there is a tremendous increase in activity geared at the development of CK2-specific therapies. Here we provide a brief review of CK2-mediated inhibition of mitochondrial death signaling in cancer cells and its implications for the design of novel target specific therapeutic strategies. PMID- 21269262 TI - The adenine nucleotide translocase 2, a mitochondrial target for anticancer biotherapy. AB - Apoptosis or programmed cell death is one of the most important signaling pathways, which controls the cell fate and is frequently impaired in cancer cells. The major consequences of apoptosis inhibition are the accumulation of mutated cells and their enhanced resistance to chemotherapeutic agents. More generally, intrinsic or acquired apoptosis resistance may favor tumor growth and dissemination of mutated cells, and this resistance can be responsible of treatment failure. Mitochondria are central organelles in the signaling pathway of apoptosis and have been proposed as favorite candidates for anticancer biotherapy because they accommodate potential biological targets. Indeed, although cancer cells are highly glycolytic and become energetically independent of oxidative phosphorylation. Mitochondrial proteins involved in the so-called mitochondrial membrane permeabilization (MMP), such as the adenine nucleotide translocase (ANT) can be instrumental to elicit cancer cell death. Thus, multiple pharmacological and molecular studies revealed ANT could be a promising therapeutic target for the following reasons: (i) ANT is a bi-functional protein, it mediates the vital exchange of cytosolic ADP and mitochondrial ATP and participates to MMP via its capacity to become a lethal pore in the mitochondrial inner membrane; (ii) both ANT functions are under the control of the (anti) oncogenes from the Bax/Bcl-2 family, (iii) several chemotherapeutic agents directly modulate the pore-forming activity of ANT and (iv) ANT2 isoform, which is anti-apoptotic, can be overexpressed in human cancers and its invalidation sensitize cells to apoptosis. In this review, we will introduce the knowledge of the role of ANT in MMP, illustrate the modulation of ANT by several strategies and propose the possibility to target preferentially the ANT2 isoform for induction of cancer cell apoptosis. PMID- 21269263 TI - Mitochondria in chronic liver disease. AB - Mitochondria are the main energy source in hepatocytes and play a major role in extensive oxidative metabolism and normal function of the liver. This key role also assigns mitochondria a gateway function in the center of signaling pathways that mediate hepatocyte injury, because impaired mitochondrial functions affect cell survival and contribute to the onset and perpetuation of liver diseases. Altered mitochondrial functions have indeed been documented in a variety of chronic liver diseases including alcohol-induced liver disease, nonalcoholic fatty liver disease, viral hepatitis, primary and secondary cholestasis, hemochromatosis, and Wilson's disease. Major changes include impairment of the electron transport chain and/or oxidative phosphorylation leading to decreased oxidative metabolism of various substrates, decreased ATP synthesis, and reduced hepatocyte tolerance towards stressing insults. Functional impairment of mitochondria is often accompanied by structural changes, resulting in organelle swelling and formation of inclusion in the mitochondrial matrix. Adequate mitochondrial functions in hepatocytes are maintained by mitochondrial proliferation and/or increased activity of critical enzymes. The assessment of mitochondrial functions in vivo can be a useful tool in liver diseases for diagnostic and prognostic purposes, and also for the evaluation of (novel) therapeutic interventions. PMID- 21269264 TI - Regulation of mitochondrial biogenesis in metabolic syndrome. AB - Insulin resistant individuals manifest multiple disturbances in free fatty acids metabolism and have excessive lipid accumulation in insulin-target tissues. A wide range of evidence suggests that defective muscle mitochondrial metabolism, and subsequent impaired ability to oxidize fatty acids, may be a causative factor in the accumulation of intramuscular lipid and the development of insulin resistance. Such mitochondrial dysfunction includes loss of mitochondria, defects in the mitochondrial OXPHOS system and decreased rate of ATP synthesis. Stimulation of mitochondrial biogenesis appears as a strategy for the clinical management of the metabolic syndrome, by enhancing mitochondrial activity and protecting the cell against the increased flux of reduced substrates to the electron transport chain and thus reducing metabolic inflammation. PMID- 21269265 TI - Mitochondria as a target for exercise-induced cardioprotection. AB - Cardiac damage is a major contributor to the morbidity and mortality particularly associated with coronary artery disease. Moreover, it is also related to some metabolic diseases such as diabetes and to some side effects of drug treatments. Regular exercise has been confirmed as a pragmatic countermeasure to protect against cardiac injury. Specifically, life-long physical activity and endurance exercise training have been proven to provide cardioprotection against cardiac insults in both young and old animals. It is suggested that the beneficial effects resulting from increased physical activity levels occur at different levels of cellular organization, being mitochondria preferential target organelles. At present, it remains unclear what the protective mechanisms that are essential for exercise-induced cardioprotection are. Proposed mechanisms to explain the cardioprotective effects of exercise are mediated, at least partially, by redox changes and include the up-regulation of mitochondrial chaperones, improved antioxidant capacity, and/or elevation of other protective molecules against cellular death. It is possible that under some conditions, exercise also diminishes the increased susceptibility of cardiac mitochondria to undergo permeability transition pore opening through the modulation of pore components or sensitizers. The role of physical exercise against the impairment of heart mitochondrial function that accompany ageing, diabetes, administration of the anti-cancer agent Doxorubicin and ischemia-reperfusion is analysed in the present review, which provides biochemical, functional and morphological data illustrating the cross tolerance effect of exercise in these conditions predisposing to cardiac "mitotoxicity". However, further work should be addressed in order to clarify the precise regulatory mechanisms by which physical exercise augments heart mitochondrial tolerance against many conditions predisposing to dysfunction. PMID- 21269266 TI - Berberine as a promising safe anti-cancer agent - is there a role for mitochondria? AB - Metabolic regulation is largely dependent on mitochondria, which play an important role in energy homeostasis. Imbalance between energy intake and expenditure leads to mitochondrial dysfunction, characterized by a reduced ratio of energy production (ATP production) to respiration. Due to the role of mitochondrial factors/events in several apoptotic pathways, the possibility of targeting that organelle in the tumor cell, leading to its elimination is very attractive, although the safety issue is problematic. Berberine, a benzyl-tetra isoquinoline alkaloid extracted from plants of the Berberidaceae family, has been extensively used for many centuries, especially in the traditional Chinese and Native American medicine. Several evidences suggest that berberine possesses several therapeutic uses, including anti-tumoral activity. The present review supplies evidence that berberine is a safe anti-cancer agent, exerting several effects on mitochondria, including inhibition of mitochondrial Complex I and interaction with the adenine nucleotide translocator which can explain several of the described effects on tumor cells. PMID- 21269267 TI - Mitochondrial tolerance to drugs and toxic agents in ageing and disease. AB - Better understanding of the effect of ageing on mitochondrial metabolism and of the mechanisms of action of various drugs is required to allow optimization of the treatment of many diseases with minimized risk of dangerous impairment of mitochondrial function. Numerous reports show that efficacy of medical treatment depends on the age of treated subjects. This applies particularly to the effect of drugs on various senescence-prone cellular pathways. In this review, we demonstrate how ageing affects various mitochondria-associated pathways and their response to a variety of factors. These factors include registered drugs and other chemicals, and account for diverse consequences which vary depending on the physiological condition. Pharmacological treatments aimed at improving mitochondrial function should thus have in mind the subject age. PMID- 21269268 TI - Mitochondrial-targeted plastoquinone derivatives. Effect on senescence and acute age-related pathologies. AB - Plastoquinone, a very effective electron carrier and antioxidant of chloroplasts, was conjugated with decyltriphenylphosphonium to obtain a cation easily penetrating through membranes. This cation, called SkQ1, is specifically targeted to mitochondria by electrophoresis in the electric field formed by the mitochondrial respiratory chain. The respiratory chain also regenerates reduced SkQ1H(2) from its oxidized form that appears as a result of the antioxidant activity of SkQ1H(2). SkQ1H(2) prevents oxidation of cardiolipin, a mitochondrial phospholipid that is especially sensitive to attack by reactive oxygen species (ROS). In cell cultures, SkQ1 and its analog plastoquinonyl decylrhodamine 19 (SkQR1) arrest H(2)O(2)-induced apoptosis. When tested in vivo, SkQs (i) prolong the lifespan of fungi, crustaceans, insects, fish, and mice, (ii) suppress appearance of a large number of traits typical for age-related senescence (cataract, retinopathies, achromotrichia, osteoporosis, lordokyphosis, decline of the immune system, myeloid shift of blood cells, activation of apoptosis, induction of beta-galactosidase, phosphorylation of H2AX histones, etc.) and (iii) lower tissue damage and save the lives of young animals after treatments resulting in kidney ischemia, rhabdomyolysis, heart attack, arrhythmia, and stroke. We suggest that the SkQs reduce mitochondrial ROS and, as a consequence, inhibit mitochondria-mediated apoptosis, an obligatory step of execution of programs responsible for both senescence and fast "biochemical suicide" of an organism after a severe metabolic crisis. PMID- 21269269 TI - Mitophagy in neurodegeneration: an opportunity for therapy? AB - Neurodegenerative disorders such as Alzheimer's and Parkinson's diseases are characterized by distinct clinical manifestations and neuropathological hallmarks, but they also share common features like mitochondrial dysfunction. As strategic organelles in several cellular pathways, including life/death decision, it is crucial to maintain a healthy mitochondrial pool to ensure cellular homeostasis. Macroautophagy is a pathway of lysosomal-dependent degradation of cytosolic portions, such as misfolded proteins or damaged organelles. In the last decade this process has gained new frontiers and is currently seen as a specific, rather than a random process. In this regard the term mitophagy came to describe the selective degradation of mitochondria by autophagy. This review is intended to discuss mitochondrial dysfunction in Alzheimer's and Parkinson's diseases. The recent developments on the molecular basis of mitophagy will be also argued. Finally, we will discuss mitophagy as a potential therapeutic target for neurodegenerative diseases. PMID- 21269270 TI - Evidence and significance of non-targeted effects of ionizing radiation. PMID- 21269271 TI - WT1 and its transcriptional cofactor BASP1 redirect the differentiation pathway of an established blood cell line. AB - The Wilms' tumour suppressor WT1 (Wilms' tumour 1) is a transcriptional regulator that plays a central role in organogenesis, and is mutated or aberrantly expressed in several childhood and adult malignancies. We previously identified BASP1 (brain acid-soluble protein 1) as a WT1 cofactor that suppresses the transcriptional activation function of WT1. In the present study we have analysed the dynamic between WT1 and BASP1 in the regulation of gene expression in myelogenous leukaemia K562 cells. Our findings reveal that BASP1 is a significant regulator of WT1 that is recruited to WT1-binding sites and suppresses WT1 mediated transcriptional activation at several WT1 target genes. We find that WT1 and BASP1 can divert the differentiation programme of K562 cells to a non-blood cell type following induction by the phorbol ester PMA. WT1 and BASP1 co-operate to induce the differentiation of K562 cells to a neuronal-like morphology that exhibits extensive arborization, and the expression of several genes involved in neurite outgrowth and synapse formation. Functional analysis revealed the relevance of the transcriptional reprogramming and morphological changes, in that the cells elicited a response to the neurotransmitter ATP. Taken together, the results of the present study reveal that WT1 and BASP1 can divert the lineage potential of an established blood cell line towards a cell with neuronal characteristics. PMID- 21269272 TI - Structure and kinetic characterization of human sperm-specific glyceraldehyde-3 phosphate dehydrogenase, GAPDS. AB - hGAPDS (human sperm-specific glyceraldehyde-3-phosphate dehydrogenase) is a glycolytic enzyme essential for the survival of spermatozoa, and constitutes a potential target for non-hormonal contraception. However, enzyme characterization of GAPDS has been hampered by the difficulty in producing soluble recombinant protein. In the present study, we have overexpressed in Escherichia coli a highly soluble form of hGAPDS truncated at the N-terminus (hGAPDSDeltaN), and crystallized the homotetrameric enzyme in two ligand complexes. The hGAPDSDeltaN NAD+-phosphate structure maps the two anion-recognition sites within the catalytic pocket that correspond to the conserved Ps site and the newly recognized Pi site identified in other organisms. The hGAPDSDeltaN-NAD+-glycerol structure shows serendipitous binding of glycerol at the Ps and new Pi sites, demonstrating the propensity of these anion-recognition sites to bind non physiologically relevant ligands. A comparison of kinetic profiles between hGAPDSDeltaN and its somatic equivalent reveals a 3-fold increase in catalytic efficiency for hGAPDSDeltaN. This may be attributable to subtle amino acid substitutions peripheral to the active centre that influence the charge properties and protonation states of catalytic residues. Our data therefore elucidate structural and kinetic features of hGAPDS that might provide insightful information towards inhibitor development. PMID- 21269273 TI - Counter-regulation in the IKK family. AB - The human IKK [IkappaB (inhibitor of NF-kappaB) kinase] family has four members; they are the central kinases of innate immunity. Two members, IKKalpha and IKKbeta, the so-called canonical members, phosphoryate IkappaBalpha, leading to activation of the transcription factor NF-kappaB (nuclear factor kappaB), which controls the expression of many immune and inflammatory genes. The IKK-related proteins TBK-1 (TANK-binding kinase 1) and IKKepsilon have a different substrate- IRF3 (interferon regulatory factor 3)--which regulates a different set of genes, the products of which include Type I interferons. Toll-like receptors (TLRs) such as the lipopolysaccharide receptor TLR4 or the poly(I:C) receptor TLR3 activate each of the IKKs, but the pro-inflammatory cytokine IL-1 (interleukin 1), which signals in a broadly similar way to the TLRs, has so far been shown to activate only the canonical IKKs. In this issue of the Biochemical Journal, Clark et al. bring new insights into the regulation of IKKs. They demonstrate that IL-1 is in fact able to activate IKKepsilon/TBK-1, which occurs via IKKalpha/IKKbeta. The consequence of this is not IRF3 activation, but a negative feedback effect on IKKalpha/IKKbeta. This provides us with yet another regulatory feedback loop in a system already replete with control mechanisms. It attests yet again to the importance of keeping these innate immune pathways in check, since if they proceed uncontrolled, inflammatory diseases can occur. Importantly, this study utilized new and specific inhibitors of these kinases, suggesting that the interpretation of any effects the compound might have in vivo may be complex, since for example the inhibition of IKKepsilon/TBK-1 might actually have a pro inflammatory effect. PMID- 21269274 TI - Smad7: not only a regulator, but also a cross-talk mediator of TGF-beta signalling. AB - TGF-beta (transforming growth factor-beta) is a pleiotropic cytokine regulating diverse cellular processes. It signals through membrane-bound receptors, downstream Smad proteins and/or other signalling mediators. Smad7 has been well established to be a key negative regulator of TGF-beta signalling. It antagonizes TGF-beta signalling through multiple mechanisms in the cytoplasm and in the nucleus. Smad7 can be transcriptionally induced by TGF-beta and other growth factors and serves as an important cross-talk mediator of the TGF-beta signalling pathway with other signalling pathways. Accordingly, it plays pivotal roles in embryonic development and adult homoeostasis, and altered expression of Smad7 is often associated with human diseases, such as cancer, tissue fibrosis and inflammatory diseases. PMID- 21269275 TI - Targeting chemokine receptors in allergic disease. AB - The directed migration of cells in response to chemical cues is known as chemoattraction, and plays a key role in the temporal and spatial positioning of cells in lower- and higher-order life forms. Key molecules in this process are the chemotactic cytokines, or chemokines, which, in humans, constitute a family of approx. 40 molecules. Chemokines exert their effects by binding to specific GPCRs (G-protein-coupled receptors) which are present on a wide variety of mature cells and their progenitors, notably leucocytes. The inappropriate or excessive generation of chemokines is a key component of the inflammatory response observed in several clinically important diseases, notably allergic diseases such as asthma. Consequently, much time and effort has been directed towards understanding which chemokine receptors and ligands are important in the allergic response with a view to therapeutic intervention. Such strategies can take several forms, although, as the superfamily of GPCRs has historically proved amenable to blockade by small molecules, the development of specific antagonists has been has been a major focus of several groups. In the present review, I detail the roles of chemokines and their receptors in allergic disease and also highlight current progress in the development of relevant chemokine receptor antagonists. PMID- 21269276 TI - Cardiomyocyte differentiation of pluripotent stem cells and their use as cardiac disease models. AB - More than 10 years after their first isolation, human embryonic stem cells are finally 'coming of age' in research and biotechnology applications as protocols for their differentiation and undifferentiated expansion in culture become robust and scalable, and validated commercial reagents become available. Production of human cardiomyocytes is now feasible on a daily basis for many laboratories with tissue culture expertise. An additional recent surge of interest resulting from the first production of human iPSCs (induced pluripotent stem cells) from somatic cells of patients now makes these technologies of even greater importance since it is likely that (genetic) cardiac disease phenotypes can be captured in the cardiac derivatives of these cells. Although cell therapy based on replacing cardiomyocytes lost or dysfunctional owing to cardiac disease are probably as far away as ever, biotechnology and pharmaceutical applications in safety pharmacology and drug discovery will probably impact this clinical area in the very near future. In the present paper, we review the cutting edge of this exciting area of translational research. PMID- 21269277 TI - Identification of regions responsible for the open conformation of S100A10 using chimaeric S100A11-S100A10 proteins. AB - S100A11 is a dimeric EF-hand calcium-binding protein. Calcium binding to S100A11 results in a large conformational change that uncovers a broad hydrophobic surface used to interact with phospholipid-binding proteins (annexins A1 and A2) and facilitate membrane vesiculation events. In contrast with other S100 proteins, S100A10 is unable to bind calcium due to deletion and substitution of calcium-ligating residues. Despite this, calcium-free S100A10 assumes an 'open' conformation that is very similar to S100A11 in its calcium-bound state. To understand how S100A10 is able to adopt an open conformation in the absence of calcium, seven chimaeric proteins were constructed where regions from calcium binding sites I and II, and helices II-IV in S100A11 were replaced with the corresponding regions of S100A10. The chimaeric proteins having substitutions in calcium-binding site II displayed increased hydrophobic surface exposure as assessed by bis-ANS (4,4'-dianilino-1,1'-binaphthyl-5,5'disulfonic acid, dipotassium salt) fluorescence and phenyl-Sepharose binding in the absence of calcium. This response is similar to that observed for Ca2+-S100A11 and calcium free S100A10. Further, this substitution resulted in calcium-insensitive binding to annexin A2 for one chimaeric protein. The results indicate that residues within site II are important in stabilizing the open conformation of S100A10 and presentation of its target binding site. In contrast, S100A11 chimaeric proteins with helical substitutions displayed poorer hydrophobic surface exposure and, consequently, unobservable annexin A2 binding. The present study represents a first attempt to systematically understand the molecular basis for the calcium insensitive open conformation of S100A10. PMID- 21269278 TI - Eszopiclone increases the respiratory arousal threshold and lowers the apnoea/hypopnoea index in obstructive sleep apnoea patients with a low arousal threshold. AB - Recent insights into sleep apnoea pathogenesis reveal that a low respiratory arousal threshold (awaken easily) is important for many patients. As most patients experience stable breathing periods mediated by upper-airway dilator muscle activation via accumulation of respiratory stimuli, premature awakening may prevent respiratory stimuli build up as well as the resulting stabilization of sleep and breathing. The aim of the present physiological study was to determine the effects of a non-benzodiazepine sedative, eszopiclone, on the arousal threshold and the AHI (apnoea/hypopnoea index) in obstructive sleep apnoea patients. We hypothesized that eszopiclone would increase the arousal threshold and lower the AHI in patients with a low arousal threshold (0 to -15 cm H(2)O). Following a baseline overnight polysomnogram with an epiglottic pressure catheter to quantify the arousal threshold, 17 obstructive sleep apnoea patients, without major hypoxaemia [nadir SaO(2) (arterial blood oxygen saturation) >70%], returned on two additional nights and received 3 mg of eszopiclone or placebo immediately prior to each study. Compared with placebo, eszopiclone significantly increased the arousal threshold [-14.0 (-19.9 to -10.9) compared with -18.0 ( 22.2 to -15.1) cm H(2)O; P<0.01], and sleep duration, improved sleep quality and lowered the AHI without respiratory event prolongation or worsening hypoxaemia. Among the eight patients identified as having a low arousal threshold, reductions in the AHI occurred invariably and were most pronounced (25+/-6 compared with 14+/-4 events/h of sleep; P<0.01). In conclusion, eszopiclone increases the arousal threshold and lowers the AHI in obstructive sleep apnoea patients that do not have marked overnight hypoxaemia. The greatest reductions in the AHI occurred in those with a low arousal threshold. The results of this single night physiological study suggest that certain sedatives may be of therapeutic benefit for a definable subgroup of patients. However, additional treatment strategies are probably required to achieve elimination of apnoea. PMID- 21269279 TI - Case studies are not sufficient. PMID- 21269281 TI - Factors determining response to antiepileptic drugs in randomized controlled trials. A systematic review and meta-analysis. AB - PURPOSE: Because of the lack of head-to-head adjunctive-therapy trials of antiepileptic drugs (AEDs) in refractory partial epilepsy, meta-analyses of placebo-controlled randomized controlled trials (RCTs) represent a potentially important source of evidence to guide treatment decisions. However, such indirect comparisons raise various methodologic issues that may hamper their relevance. METHODS: All RCTs in adult refractory partial epilepsy were analyzed to assess whether efficacy outcomes are influenced by: characteristics of patients and trials ; use of last observation carried forward (LOCF) analysis; evaluation period (entire period versus maintenance period); and year of publication. A meta analysis of these AEDs was then performed taking these factors into consideration. KEY FINDINGS: Sixty-three RCTs evaluating 20 AEDs were included. The following variables influenced efficacy estimates: (1) responder rates correlated positively with duration of the entire treatment period (p = 0.038); (2) response to placebo was significantly greater in the maintenance period than in the entire treatment period (p = 0.005); (3) responder rates increased over the years both for AEDs (p < 0.001) and for placebo (p = 0.001); (4) LOCF analysis overestimated responder rates for AEDs (p < 0.001) and for placebo (p = 0.001) compared with completer-based analysis, and the overestimation correlated positively with withdrawal rates (p < 0.001). A meta-analysis of available data showed large differences in efficacy ranking in relation to dose selection and type of analysis, but these were mostly nonsignificant due to statistical power limitations. SIGNIFICANCE: Several methodologic issues hamper the relevance of indirect comparisons of AEDs in the adjunctive-therapy of refractory partial epilepsy. Some of these issues could be overcome by improved standardization in the reporting of efficacy outcomes. PMID- 21269282 TI - Molecular alterations underlying epileptogenesis after prolonged febrile seizure and modulation by erythropoietin. AB - PURPOSE: Children who experience complex febrile seizures are at a higher risk of subsequent epileptic episodes, and they may require therapy. This issue can be resolved by interventional studies using molecular targets identified and defined in animal models. In the current study, the molecular changes in the rat brain after febrile seizures were examined throughout the latent period, and erythropoietin was administered as a potentially antiepileptogenic intervention. METHODS: The changes in the expressions of genes that were differentially regulated during the latent period after febrile seizures were categorized into the following four patterns: (1) continuously high (CH); (2) continuously low (CL); (3) rise and fall (RF); and (4) going-up (GU). Erythropoietin was administered immediately after seizure cessation and then once daily for at most 7 days, and spontaneous recurrent seizures and cellular and molecular changes were investigated. KEY FINDINGS: The CH genes were associated with cell cycle and adhesion, whereas the CL genes were related to energy metabolism. Within the category of RF, the largest changes were for genes involved in inflammation, apoptosis, and gamma-aminobutyric acid (GABA) signaling. The GU category included genes involved in ion transport and synaptogenesis. Along with an early rise in inflammatory genes, there were substantial increases in brain edema and activated microglia during the early latent period. Erythropoietin reduced the early inflammatory responses and modulated the molecular alterations after febrile seizures, thereby reducing the risk of subsequent spontaneous seizures. SIGNIFICANCE: Erythropoietin treatment may provide a new strategy for preventing epilepsy in susceptible individuals with atypical febrile seizures. PMID- 21269283 TI - Cognitive development in Dravet syndrome: a retrospective, multicenter study of 26 patients. AB - PURPOSE: To clarify the role of epilepsy and genetic background in determining the cognitive outcome of patients with Dravet syndrome. METHODS: In this retrospective study, we reviewed the clinical history and cognitive development of 26 patients who had been followed with standardized evaluations since seizure onset. The cognitive outcome was quantified as differential general quotient (dGQ) between ages 12 and 60 months. Statistical analysis correlated the dGQ with genotype and epilepsy course. KEY FINDINGS: Epilepsy started at the mean age of 5.6 months. All patients experienced prolonged convulsive seizures, whereas absences and myoclonus were reported in 17. Cognitive outcome was poor in almost all patients; the mean dGQ was 33 points, varying from 6-77 points. The analysis of individual cognitive profiles identified seven patients in whom the dGQ was <20 points; the main clinical characteristic in this subset of patients was lack of early absences and myoclonus. The statistical analysis of the whole series failed to reveal significant differences in cognitive outcome with regard to the presence of SCN1A mutations and their type. In particular, mutation-carrier patients with the best cognitive outcome harbored either missense or truncating mutations. SIGNIFICANCE: Dravet syndrome encompasses different epileptic and cognitive phenotypes that probably result from both genetic and epigenetic factors. In this series, early appearance of myoclonus and absences was associated with the worst cognitive outcome. PMID- 21269284 TI - Absence seizures in the first 3 years of life: an electroclinical study of 46 cases. AB - PURPOSE: Early onset absence seizures have been considered a rare heterogeneous group with a poor prognosis. Only few patients may be categorized into well-known syndromes. We have evaluated electroclinical features, evolution, and the nosologic boundaries of early onset absence seizures. METHODS: Forty-six neurologically normal patients with absence seizures associated with bilateral, synchronic, or asynchronic, and symmetric or asymmetric spike-and-wave paroxysms with onset in the first 3 years of life were included. Patients with abnormal neurologic examination and brain imaging were excluded from the study. KEY FINDINGS: In our study, 39 patients met the clinical and electroencephalography (EEG) criteria of well-defined epileptic syndromes. Childhood absence epilepsy was found in 11 patients, benign myoclonic epilepsy in infancy in 18 patients, eyelid myoclonic epilepsy in 4, and epilepsy with myoclonic absences in 6. We did not find clinical and EEG criteria of well-recognized epileptic syndromes in seven children. Nine of 11 patients with simple absence seizures became seizure free. All these patients had normal neurologic and neuropsychological evaluations. Of the 35 patients who had absence seizures associated with myoclonic seizures, 20 became seizure free. Fifteen of 35 children continue having seizures. At the last visit, 20 of these 35 patients had normal neurologic and neuropsychological evaluations, 11 presented with mild mental retardation, and 4 with severe mental retardation. SIGNIFICANCE: Epilepsies with absence seizures of early onset are relatively uncommon. Most of the patients had well defined epileptic syndromes with a variable evolution. The evolution depended on the epileptic syndromes. PMID- 21269285 TI - Comorbidities of epilepsy: results from the Epilepsy Comorbidities and Health (EPIC) survey. AB - PURPOSE: To estimate the prevalence of neuropsychiatric and pain disorders in adults with epilepsy in the United States. METHODS: In 2008, an 11-item survey including validated questions to screen for a lifetime history of epilepsy was mailed to 340,000 households from two national panels selected to be generally representative of the noninstitutionalized U.S. population. Information on epilepsy and other disorders was collected from 172,959 respondents aged 18 or older. Propensity scoring was used to match respondents with and without epilepsy on baseline characteristics and risk factors for epilepsy. Prevalence ratios (PRs) of comorbidities in respondents with epilepsy were calculated using log binomial generalized linear models. Comorbidities were categorized as neuropsychiatric (anxiety, depression, bipolar disorder, attention deficit/hyperactivity disorder, sleep disorder/apnea, and movement disorder/tremor), pain (migraine headache, chronic pain, fibromyalgia, neuropathic pain), and other (asthma, diabetes, and high blood pressure). KEY FINDINGS: Two percent (3,488) of respondents reported ever having been told they had epilepsy or a seizure disorder. Respondents with self-reported epilepsy were more likely (p < 0.001) than those without epilepsy to report all six neuropsychiatric disorders (PR from 1.27-2.39), all four pain disorders (PR 1.36 1.96), and asthma (PR 1.25). SIGNIFICANCE: Neuropsychiatric conditions and pain disorder comorbidities were reported more often in individuals with self-reported epilepsy than in those without epilepsy. Identification of these conditions is an important consideration in the clinical management of epilepsy. PMID- 21269286 TI - Bilateral hippocampal atrophy in temporal lobe epilepsy: effect of depressive symptoms and febrile seizures. AB - PURPOSE: Neuroimaging studies suggest a history of febrile seizures, and depression, are associated with hippocampal volume reductions in patients with temporal lobe epilepsy (TLE). METHODS: We used radial atrophy mapping (RAM), a three-dimensional (3D) surface modeling tool, to measure hippocampal atrophy in 40 patients with unilateral TLE, with or without a history of febrile seizures and symptoms of depression. Multiple linear regression was used to single out the effects of covariates on local atrophy. KEY FINDINGS: Subjects with a history of febrile seizures (n =15) had atrophy in regions corresponding to the CA1 and CA3 subfields of the hippocampus contralateral to seizure focus (CHC) compared to those without a history of febrile seizures (n = 25). Subjects with Beck Depression Inventory II (BDI-II) score >= 14 (n = 11) had atrophy in the superoanterior portion of the CHC compared to subjects with BDI-II <14 (n = 29). SIGNIFICANCE: Contralateral hippocampal atrophy in TLE may be related to febrile seizures or depression. PMID- 21269287 TI - Remission and relapse in a drug-resistant epilepsy population followed prospectively. AB - PURPOSE: We investigated the cumulative probability of seizure remission and relapse in an adult population with drug-resistant epilepsy and frequent seizures. In addition, we determined clinical predictors of remission and relapse in this population. METHODS: IN 2003, we identified 246 patients at a single center with drug-resistant epilepsy defined as at least one seizure per month and failure of at least two antiepileptic drugs. These patients were followed prospectively (cohort design). We examined the cumulative probability of seizure remission and relapse in this population using Kaplan-Meier methodology. Clinical predictors of remission and relapse were also evaluated using Cox regression analysis. KEY FINDINGS: The estimated cumulative probability of 12-month seizure remission was 34.6% at 7 years in the entire population and 33.4% when limited to those without surgery. The risk for relapse after a 12-month period of seizure remission was 71.2% at 5 years. Negative predictors of seizure remission included developmental delay, symptomatic generalized epilepsy syndrome, duration of intractability, and number of antiepileptic drugs failed. Localization-related epilepsy was the only negative predictor of relapse. SIGNIFICANCE: Among patients with drug-resistant epilepsy, 5% per year enter seizure remission even with a follow-up of 6 years. However, a substantial proportion of these patients relapse after the first year following a remission. The large proportion of patients entering a significant remission gives these patients hope; however, caution should be advised when discussing the likelihood of future seizures. PMID- 21269288 TI - Localized overexpression of FGF-2 and BDNF in hippocampus reduces mossy fiber sprouting and spontaneous seizures up to 4 weeks after pilocarpine-induced status epilepticus. AB - PURPOSE: We have recently reported that viral vector-mediated supplementation of fibroblast growth factor-2 (FGF-2) and brain-derived neurotrophic factor (BDNF) in a lesioned, epileptogenic rat hippocampus limits neuronal damage, favors neurogenesis, and reduces spontaneous recurrent seizures. To test if this treatment can also prevent hippocampal circuit reorganization, we examined here its effect on mossy fiber sprouting, the best studied form of axonal plasticity in epilepsy. METHODS: A herpes-based vector expressing FGF-2 and BDNF was injected into the rat hippocampus 3 days after an epileptogenic insult (pilocarpine-induced status epilepticus). Continuous video-electroencephalography (EEG) monitoring was initiated 7 days after status epilepticus, and animals were sacrificed at 28 days for analysis of cell loss (measured using NeuN immunofluorescence) and mossy fiber sprouting (measured using dynorphin A immunohistochemistry). KEY FINDINGS: The vector expressing FGF-2 and BDNF decreased both mossy fiber sprouting and the frequency and severity of spontaneous seizures. The effect on sprouting correlated strictly with the cell loss in the terminal fields of physiologic mossy fiber innervation (mossy cells in the dentate gyrus hilus and CA3 pyramidal neurons). SIGNIFICANCE: These data suggest that the supplementation of FGF-2 and BDNF in an epileptogenic hippocampus may prevent epileptogenesis by decreasing neuronal loss and mossy fiber sprouting, that is, reducing some forms of circuit reorganization. PMID- 21269289 TI - Identification of reproducible ictal patterns based on quantified frequency analysis of intracranial EEG signals. AB - PURPOSE: The identification of the epileptogenic zone (EZ) is crucial for planning epilepsy surgery in patients with drug-resistant partial epilepsy. This task may require intracerebral encephalography (EEG) monitoring, the results of which are usually interpreted by visual presurgical inspection. A computer assisted method for rapidly identifying reproducible ictal patterns based on the analysis of time, frequency, and spatial domains of stereo-EEG (SEEG) signals is described here. METHODS: A new method for EZ detection was tested on SEEG recordings performed by intracerebral electrodes in eight patients with pharmacoresistant partial epilepsy. SEEG data were exported to a program developed in LabView. KEY FINDINGS: Prevalent frequencies during seizure events were evaluated by Fourier transform and further integral algorithms. Different frequencies and the relative powers were simultaneously evaluated in all recording leads. Patterns characterized by specific and prevalent frequencies were identified in a subset of recording sites during both seizure onset and seizure development. Three-dimensional (3D) maps of the measurements obtained from each recording channel were reconstructed on magnetic resonance coordinates to visualize the spatial distribution of the EZ. With this method, the reproducibility of ictal patterns in the same patient was characterized. The boundaries of the EZ identified with this algorithm correlated well with the EZ recognized with the traditional approach (n = 8). The spatial distribution of specific SEEG signals associated with different types of seizures was also analyzed in two patients. SIGNIFICANCE: We describe a computer-assisted method to acquire information on EZ boundaries and to verify reproducibility of seizure patterns from intracerebral recordings performed in patients with pharmacoresistant partial epilepsies. PMID- 21269290 TI - Epilepsy and the new cytogenetics. AB - We set out to review the extent to which molecular karyotyping has overtaken conventional cytogenetics in applications related to epilepsy. Multiplex ligase dependent probe amplification (MLPA) targeted to predetermined regions such as SCN1A and KCNQ2 has been effectively applied over the last half a decade, and oligonucleotide array comparative genome hybridization (array CGH) is now well established for genome-wide exploration of microchromosomal variation. Array CGH is applicable to the characterization of lesions present in both sporadic and familial epilepsy, especially where clinical features of affected cases depart from established syndromes. Copy number variants (CNVs) associated with epilepsy and a range of other syndromes and conditions can be recurrent due to nonallelic homologous recombination in regions of segmental duplication. The most common of the recurrent microdeletions associated with generalized epilepsy are typically seen at a frequency of ~ 1% at 15q13.3, 16p13.11, and 15q11.2, sites that also confer susceptibility for intellectual disability, autism, and schizophrenia. Incomplete penetrance and variable expressivity confound the established rules of cytogenetics for determining the pathogenicity for novel CNVs; however, as knowledge is gained for each of the recurrent CNVs, this is translated to genetic counseling. CNVs play a significant role in the susceptibility profile for epilepsies, with complex genetics and their comorbidities both from the "hotspots" defined by segmental duplication and elsewhere in the genome where their location and size are often novel. PMID- 21269291 TI - Population pharmacokinetics of pregabalin in healthy subjects and patients with chronic pain or partial seizures. AB - PURPOSE: Pregabalin, a high-affinity ligand for alpha2delta subunits of voltage gated calcium channels, is a novel pharmacotherapy for chronic pain, partial seizures, and other disorders. The present study investigated the population pharmacokinetics of pregabalin following single and multiple doses in healthy volunteers and patient populations. METHODS: Using nonlinear mixed-effect modeling, 5,583 plasma pregabalin concentration-time samples from 1,723 subjects were analyzed: 2,868 samples from healthy volunteers or subjects with renal impairment (n = 123), 1,513 from patients with partial seizures (n = 626), and 1,202 from patients with chronic pain (n = 974). A one-compartment model with first-order elimination and absorption processes and absorption lag time was used. KEY FINDINGS: This pharmacostatistical model showed that: (1) pregabalin oral clearance (CL/F) was directly proportional to creatinine clearance (CLcr), but was independent of gender, race, age, female hormonal status, daily dose, and dosing regimen; (2) apparent volume of distribution was dependent on body weight and gender; (3) absorption rate was decreased when given with food; and (4) coadministration with marketed antiepileptic drugs (AEDs) had no significant effect on pregabalin CL/F. SIGNIFICANCE: Pregabalin CL/F is related to CLcr, and this relationship is similar among healthy volunteers and patients with either partial seizures or chronic pain disorders. The only factor having a clinically significant influence on steady-state plasma pregabalin concentrations is renal function. PMID- 21269292 TI - The nature and extent of cerebellar atrophy in chronic temporal lobe epilepsy. AB - PURPOSE: Research indicates that patients with chronic temporal lobe epilepsy (TLE) exhibit cerebellar atrophy compared to healthy controls, but the degree to which specific regions of the cerebellum are affected remains unclear. The purpose of this study was to characterize the extent and lateralization of atrophy in individual cerebellar lobes and subregions in unilateral TLE using advanced quantitative magnetic resonance imaging (MRI) techniques. METHODS: Study participants were 46 persons with TLE and 31 age- and gender- matched healthy controls. All participants underwent high-resolution MRI with manual tracing of the cerebellum yielding gray and white matter volumes of the right and left anterior lobes, superior posterior lobes, inferior posterior lobes, and corpus medullare. The degree to which asymmetric versus generalized abnormalities was evident in unilateral chronic TLE was determined and related to selected clinical seizure features (age of onset, duration of disorder). KEY FINDINGS: There were no lateralized abnormalities in cerebellar gray matter or white matter in patients with right or left TLE (all p's > 0.2). Compared with controls, unilateral TLE was associated with significant bilateral reductions in the superior (p = 0.032) and inferior (p = 0.023) posterior lobes, whereas volume was significantly increased in the anterior lobes (p = 0.002), especially in patients with early onset TLE, and not significantly different in the corpus medullare (p = 0.71). Total superior cerebellar tissue volumes were reduced in association with increasing duration of epilepsy. SIGNIFICANCE: Patients with unilateral TLE exhibit a pattern of bilateral cerebellar pathology characterized by atrophy of the superior and inferior posterior lobes, hypertrophy of the anterior lobe, and no effect on the corpus medullare. Cross-sectional analyses show that specific aspects of cerebellar pathology are associated with neurodevelopmental (anterior lobe) or chronicity-related (superior posterior lobe) features of the disorder. PMID- 21269293 TI - Functional connectivity in patients with idiopathic generalized epilepsy. AB - PURPOSE: Idiopathic generalized epilepsy (IGE) is characterized by electroencephalography (EEG) recordings with generalized spike wave discharges (GSWDs) arising from normal background activity. Although GSWDs are the result of highly synchronized activity in the thalamocortical network, EEG without GSWDs is believed to represent normal brain activity. The aim of this study was to investigate whether thalamocortical interactions are altered even during GSWD free EEG periods in patients with IGE. METHODS: A GSWD-related group analysis was performed in 12 IGE patients to define seeds in areas involved during GSWDs. EEG functional magnetic resonance imaging (fMRI) datasets from 22 IGE patients without GSWDs during the investigation and 30 age-matched healthy controls were then selected to investigate functional connectivity in GSWD-related areas. Blood oxygen level dependent (BOLD) signal changes were extracted from seeds defined by the GSWD-related group analysis. The averaged time course within each seed was used to detect brain regions with BOLD signal correlated with the seed. Group differences between patients and controls were estimated. KEY FINDINGS: The GSWD related group analysis showed BOLD activation in the thalamus, the frontomesial cortex, and the cerebellum and BOLD deactivation in default mode areas. For the connectivity analysis, eight seeds were placed bilaterally in the thalamus, mesial frontal cortex, precuneus, and cerebellum. The functional connectivity analysis of these seeds did not show clearly altered functional connectivity for patients versus controls. SIGNIFICANCE: The results underscore the paroxysmal nature of GSWDs: Although GSWDs are characterized by highly synchronized activity in the thalamocortical network, the functional connectivity in areas involved during GSWDs does not demonstrate abnormality in GSWD-free periods. PMID- 21269294 TI - Comparison of short- versus long-term ketogenic diet for intractable infantile spasms. AB - PURPOSE: To compare the prognoses between short-term (8 months) and conventional long-term (> 2 years) trials involving patients with refractory infantile spasms who successfully completed the ketogenic diet (KD). METHODS: Of 40 patients who achieved seizure-free outcomes and showed improvement in hypsarrhythmic patterns within 6 months of the KD, with a 3:1 fat to nonfat ratio as an add-on treatment, 16 patients were randomized into the short-term trial group and the diet was tapered throughout two additional months. Twenty-four patients were randomized into a long-term trial group, and 19 patients could successfully discontinue the diet after 2 years. Primary outcome measures included seizure relapse and frequency of 35 patients for > 12 months after successful completion of the KD. KEY FINDINGS: Of 16 patients in the short-term trial group, two patients relapsed with clusters of spasms, and one patient had recurrence of occasional focal seizures. Of 19 patients in the long-term trial group, two patients progressed to Lennox-Gastaut syndrome and one patient experienced recurrence of occasional focal seizures with secondary generalization. An early response to the KD, evidenced by short latency before seizure freedom and disappearance of hypsarrythmia and cryptogenic etiology, may indicate a successful early discontinuation of the KD. Significant growth failure was complicated only in conventional long-term trial group. SIGNIFICANCE: Use of the KD for only 8 months in children who become spasm-free appears to be justified, with similar outcomes, recurrence rate, and less growth disturbance than a longer-term, traditional use. PMID- 21269295 TI - Efficacy and tolerability of the modified Atkins diet in adults with pharmacoresistant epilepsy: a prospective observational study. AB - PURPOSE: Evidence from the pediatric population exists for the efficacy of ketogenic diets in reducing seizure frequency in patients with intractable epilepsy. Recent evidence suggests that a Modified Atkins Diet may be a beneficial form of cotherapy for adult patients with pharmacoresistant epilepsy. METHODS: A prospective, open-label study was performed of adults > 18 years of age with pharmacoresistant epilepsy. Carbohydrates were restricted to 20 g/day. Fluids and calories from protein and fat were allowed ad libitum. KEY FINDINGS: Eighteen patients, ages 18-55 years, were initially enrolled. Using an intent-to treat analysis, 12% had a >50% seizure reduction after 3 months; 28% after 6 months, and 21% after 12 months. Response at 3 months predicted response at 12 months in 79% of patients. The mean decrease in weight was 10.9 kg and the mean decrease in body mass index (BMI) was 3.8, p = 0.01. Fourteen of 18 patients (78%) completed 12 months of this diet. Patients experienced a decrease in triglycerides from (mean) 1.22 to 0.9 mm (p = 0.02). SIGNIFICANCE: The Modified Atkins Diet demonstrates modest efficacy as cotherapy for some adults with pharmacoresistant epilepsy and may be also helpful for weight loss. Financial and logistical barriers were significant factors for those who declined enrollment and for those who discontinued the study. PMID- 21269296 TI - L-Type calcium channel blockade reduces network activity in human epileptic hypothalamic hamartoma tissue. AB - PURPOSE: Human hypothalamic hamartomas (HHs) are associated with gelastic seizures, intrinsically epileptogenic, and notoriously refractory to medical therapy. We previously reported that the L-type calcium channel antagonist nifedipine blocks spontaneous firing and gamma-aminobutyric acid (GABA)(A) induced depolarization of single cells in HH tissue slices. In this study, we examined whether blocking L-type calcium channels attenuates emergent activity of HH neuronal networks. METHODS: A high-density multielectrode array was used to record extracellular signals from surgically resected HH tissue slices. High frequency oscillations (HFOs, ripples and fast ripples), field potentials, and multiunit activity (MUA) were studied (1) under normal and provoked [4 aminopyridine (4-AP)] conditions; and (2) following nifedipine treatment. KEY FINDINGS: Spontaneous activity occurred during normal artificial cerebrospinal fluid (aCSF) conditions. Nifedipine reduced the total number and duration of HFOs, abolished the association of HFOs with field potentials, and increased the inter-HFO burst intervals. Notably, the number of active regions was decreased by 45 +/- 9% (mean +/- SEM) after nifedipine treatment. When considering electrodes that detected activity, nifedipine increased MUA in 58% of electrodes and reduced the number of field potentials in 67% of electrodes. Provocation with 4-AP increased the number of events and, as the number of electrodes that detected activity increased 248 +/- 62%, promoted tissue-wide propagation of activity. During provocation with 4-AP, nifedipine effectively reduced HFOs, the association of HFOs with field potentials, field potentials, MUA, and the number of active regions, and limited propagation. SIGNIFICANCE: This is the first study to report (1) the presence of HFOs in human subcortical epileptic brain tissue in vitro; (2) the modulation of "pathologic" high-frequency oscillations (i.e., fast ripples) in human epileptic tissue by L-type calcium channel blockers; and (3) the modulation of network physiology and synchrony of emergent activity in human epileptic tissue following blockade of L-type calcium channels. Attenuation of activity in HH tissue during normal and provoked conditions supports a potential therapeutic usefulness of L-type calcium channel blockers in epileptic patients with HH. PMID- 21269297 TI - Outcome of status epilepticus in children treated in the intensive care unit: a study of 302 cases. AB - PURPOSE: The aim of the study was to evaluate the outcome of status epilepticus (SE) in children and to define predictors for morbidity, mortality, and SE recurrence. METHODS: The study included 302 children (age 2 months to less than 18 years; mean age +/- SD 4.7 +/- 4.2 years) with 489 episodes of SE. Etiology, treatment, and clinical and electroencephalography (EEG) features of SE and their impact on the outcome were analyzed. The outcome was classified into three categories: unchanged neurologic status, neurologic consequences, and lethal outcome. Univariate and multivariate Cox hazard regression analyses were used to define predictors of mortality, morbidity, and SE recurrence. KEY FINDINGS: Neurologic status was unchanged in 235 children (77.8%) and neurologic consequences occurred in 39 patients (12.9%); case-fatality ratio was 9.3% and recurrence rate was 21%. Mortality was related to progressive encephalopathy, preexisting neurologic abnormalities, specific EEG findings, and generalized convulsive type of SE. Neurologic consequences were associated with younger age, progressive encephalopathy, duration of SE >24 h, prior epilepsy, and specific EEG findings. Multivariate analyses showed that etiology of SE and prior neurologic abnormalities were independent predictors of mortality, whereas younger age, etiology, and very long duration of SE were predictors of morbidity. SIGNIFICANCE: Outcome of SE in children is favorable in most of the cases, but mortality and morbidity rates are still high. Etiology and prior neurologic abnormalities were the main predictors of mortality, whereas the main predictor of morbidity was underlying etiology. PMID- 21269298 TI - Frovatriptan as preemptive treatment for fasting-induced migraine. AB - OBJECTIVE: To examine frovatriptan's efficacy as preemptive treatment for fasting induced migraine. BACKGROUND: Fasting is a common migraine trigger that cannot always be avoided. The development of a short-term preemptive approach would be of benefit. Because of its longer half-life, frovatriptan has been effectively used for short-term daily use to prevent menstrually related migraines and might prove useful in the prevention of fasting-induced migraine. METHODS: This was a double-blind, placebo-controlled, randomized, parallel-group trial. SUBJECTS: With a history of fasting-induced episodic migraine were randomly assigned to receive either frovatriptan (5.0 mg) or placebo (ratio 1:1). SUBJECTS: Took a single dose of study medication at the start of their 20-hour fast. Information about headache intensity, associated symptoms, and use of rescue medication was captured at defined time points from the start of the fast through 20 hours post fast. RESULTS: Of the 75 subjects screened, 74 subjects were randomized and 71 subjects completed the study. Demographic characteristics of the placebo and frovatriptan treatment groups were not statistically different. Thirty-three subjects received active drug. Twelve (36.4%) developed a headache between 6 and 20 hours after the start of the fast (1/33 mild, 11/33 moderate or severe). In the placebo group, 18/34 (52.9%) developed a headache (4/34 mild, 14/34 moderate or severe). The difference between the 2 treatment groups did not achieve statistical significance; Pearson chi-square, P = .172. Kaplan-Meier survival analysis showed no difference between the 2 treatment groups with respect to the time of onset of headache of any intensity (log rank, P = .264) and for the time of onset of a moderate or severe intensity (log rank, P = .634). CONCLUSION: More subjects on placebo developed a headache than those on frovatriptan. Perhaps because of the small number of subjects involved, the differences in headache incidences observed did not achieve statistical significance. PMID- 21269299 TI - Cervicomedullary junction spinal cord stimulation for head and facial pain. AB - OBJECTIVE: To review our experience with cervicomedullary junction spinal cord stimulation (SCS), to alleviate head and facial pain. BACKGROUND: There is a dearth of literature regarding the use of spinal cord stimulation for treating head and facial pain. DESIGN: We performed a Boolean search of the electronic medical record (1990-2009) and identified 35 patients (9 men, 26 women) for whom the senior author (J.J.M) trialed paddle lead cervicomedullary junction stimulation (CMJ-S) for intractable head or facial pain. Twenty-five patients (71.4%) had a successful trial with subsequent implantation of SCS hardware and 10 patients (28.6%) experienced a failed trial. Pain syndromes were categorized into diagnostic groups: trigeminal deafferentation pain (TDP), trigeminal neuropathic pain (TNP), occipital pain/neuralgia, post-herpetic neuralgia (PHN), and post-stroke facial pain. Follow-up via structured telephone interview was obtained in 25 patients (71.4%). RESULTS: Among the 25 patients available for follow-up, 16 patients (64%) underwent implantation and 9 patients (36%) had a failed trial of CMJ-S. The mean patient age and length of follow-up was 47.3 years old (20-78 years old) and 53.4 months (2-120 months), respectively. On a 0 10 pain intensity scale (0 being no pain and 10 being the worst degree of pain), a mean pretrial pain level of 9.6 (range 7-10) had been reduced to a mean of 4.8 (0-10) at follow-up. Successful trial and subsequent implantation occurred in 7 patients with TDP (70%), 4 patients with TNP (80%), both patients with PHN (100%), and in the single patient with post-stroke facial pain (100%) but in only 2 patients (28.6%) with occipital neuralgia/pain. At the time of telephone interview, 4 of the implanted patents (25%) had their hardware removed because of loss of effectiveness (3) and infection (1). The other 12 implanted patients (75%) continue to use CMJ-S on a daily basis and insist that it has improved their quality of life. Six current users (50%) of CMJ-S have been able to decrease their use of oral pain medications. Complications in the implanted group included infection (1), uncomfortable paresthesias from breakdown of connecting wire insulation (1), and gradual loss of effectiveness (3). CONCLUSIONS: Our preliminary experience suggests that patients suffering from TDP, TNP, and PHN may respond favorably to CMJ-S whereas patients with occipital neuralgia/pain are rarely palliated by this neuromodulatory approach. PMID- 21269300 TI - Body mass index and adult weight gain among reproductive age women with migraine. AB - OBJECTIVE: To evaluate the cross-sectional relationship between migraine and pregravid obesity; and to assess the risk of adult weight gain among women with history of a pediatric diagnosis of migraine. BACKGROUND: Obesity, comorbid with pain disorders including migraine, shares common pathophysiological characteristics including systemic inflammation, and derangements in adipose tissue derived cytokines. Despite biochemical and epidemiological commonalities, obesity-migraine associations have been inconsistently observed. METHODS: A cohort of 3733 women was interviewed during early pregnancy. We ascertained participants' self-reported history of physician-diagnosed migraine and collected self-reported information about pregravid weight, adult height, and net weight change from age 18 to the 3-months period before pregnancy. Using pregravid body mass index, we categorized participants as follows: lean (< 18.5 kg/m2), normal (18.5-24.9 kg/m2), overweight (25-29.9 kg/m2), obese (30-34.9 kg/m2), severely obese (35-39.9 kg/m2), and morbidly obese (>= 40 kg/m2). Logistic regression procedures were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: After adjusting for confounders, relative to normal weight women, obese women had a 1.48-fold increased odds of migraine (OR = 1.48; 95% CI 1.12 1.96). Severely obese (OR = 2.07; 95% CI 1.27-3.39) and morbidly obese (OR = 2.75; 95% CI 1.60-4.70) had the highest odds of migraines. Women with a history of diagnosed pediatric migraine had a 1.67-fold higher odds of gaining >= 10.0 kg above their weight at age 18, as compared with non-migraineurs (OR = 1.67; 95% CI 1.13-2.47). CONCLUSION: These data support earlier observations of migraine obesity association among women, and extend the literature to include evidence of adult weight gain among women with a history of pediatric migraine. PMID- 21269301 TI - Pterin-based ornamental coloration predicts yolk antioxidant levels in female striped plateau lizards (Sceloporus virgatus). AB - 1. Maternal investment in egg quality can have important consequences for offspring fitness. For example, yolk antioxidants can affect embryonic development as well as juvenile and adult phenotype. Thus, females may be selected to advertise their yolk antioxidant deposition to discriminatory males via ornamental signals, perhaps depending on the reproductive costs associated with signal production. 2. Female striped plateau lizards (Sceloporus virgatus) develop pterin-based orange colour patches during the reproductive season that influence male behaviour and that are positively associated with the phenotypic quality of the female and her offspring. Here, we assessed one potential developmental mechanism underlying the relationship between offspring quality and female ornamentation in S. virgatus, by examining the relationship between ornament expression and yolk antioxidant levels. 3. As expected, concentrations of the yolk antioxidants vitamin A, vitamin E and carotenoids (lutein and zeaxanthin) were strongly positively intercorrelated. Eggs from larger clutches had fewer antioxidants than eggs from smaller clutches, suggesting that females may be limited in antioxidant availability or use. Fertilized and unfertilized eggs did not differ in yolk antioxidant levels. 4. The size of a female's ornament was positively related to both the concentration and total amount of yolk antioxidants, and ornament colour was positively related to yolk antioxidant concentration. Thus, in S. virgatus, female ornaments may advertise egg quality. In addition, these data suggest that more ornamented females may produce higher quality offspring, in part because their eggs contain more antioxidants. As the colour ornament of interest is derived from pterins, not carotenoids, direct resource trade-offs between ornaments and eggs may be eliminated, reducing reproductive costs associated with signalling. 5. This is the first example of a positive relationship between female ornamentation and yolk antioxidants in reptiles and may indicate the general importance of these patterns in oviparous vertebrates. PMID- 21269302 TI - Prospective randomized clinical study of arterial pumps used for routine on pump coronary bypass grafting. AB - In a number of studies, centrifugal blood pumps--in comparison with roller pumps- have been shown to attenuate trauma to blood components. Nevertheless, the impact of these results on the postoperative course needs to be discussed controversially. In a prospective randomized study, 240 consecutive adult patients underwent elective myocardial revascularization with cardiopulmonary bypass employing five different pumps (Roller, Avecor, Sarns, Rotaflow, Bio Medicus). We analyzed clinical course, blood loss, damage of blood components, and impairment of the hemostatic system. The study population was homogenous with respect to age, gender, myocardial function, and operative data. No differences were found with respect to time of ventilation, duration of intensive care stay, hospitalization, and laboratory data. The choice of arterial pump during standard extracorporeal bypass for elective coronary artery bypass grafting is no matter of concern. PMID- 21269305 TI - Efficacy of oral antibiotics on acne vulgaris and their effects on quality of life: a multicenter randomized controlled trial using minocycline, roxithromycin and faropenem. AB - There are few clinical studies which compare the efficacy and patient satisfaction for oral antibiotics to treat inflammatory acne. To clarify the difference between oral antibiotics, acne patients with moderate to severe inflammatory eruptions were randomized into three groups, and each patient was given minocycline (MINO), roxithromycin (RXM) or faropenem (FRPM) for 4 weeks, followed by 4 weeks of observation without any oral antibiotics. We estimated the reduction rate of inflammatory lesion counts, the scale of Skindex-16 which represents patient quality of life (QOL), and minimum inhibitory concentrations required to inhibit the growth of 90% of Propionibacterium acnes isolated from acne patients (MIC(90) ). In all three groups, inflammatory lesion counts, and emotional and total score of Skindex-16 were significantly improved (P<0.05) after 4 weeks treatment, and these effects were maintained for the following 4 weeks. Dizziness/nausea in two patients (4.1%) of the MINO group and diarrhea in three patients (5.9%) of the FRPM group were observed. There was no significant difference of percentage reduction in inflammatory lesion counts and incident rates of side-effects between these three oral antibiotics. MIC(90) of MINO was 0.25 MUg/mL before and after treatment, but MIC(90) of RXM had increased from 0.25 MUg/mL to more than 32 MUg/mL after treatment. MIC(90) of FRPM was 0.06 MUg/mL or less for all strains before and after treatment. Our randomized controlled clinical trial suggested that MINO, RXM and FRPM were efficient to improve inflammatory acne and patient QOL, and there was no significant difference between them. PMID- 21269306 TI - Screening of Herpes simplex virus 2 infection among pregnant women in southern China. AB - The aim was to investigate the prevalence of Herpes simplex virus (HSV)-2 infection among pregnant women in southern China and analyze the relationship between the HSV-2 infection and pregnancy outcome. We examined 1740 sera collected from pregnant women aged 21-39 years, using enzyme-linked immunosorbent assay for the detection of specific antibodies against HSV-2. The overall prevalence of HSV-2 infection was 23.56% (95% confidence interval [CI]=21.53 26.00). The prevalence of HSV-2 infection in the women with abnormal pregnancy was 35.93% (95% CI=26.23-42.44) (83/231), which was much higher than that in women who had been pregnant before but without abnormal pregnancy and that in the primipara group. (P<0.05). The presence of HSV-2 antibodies was also associated with status of education. The prevalence of HSV-2 infection in the 26-30-year age group (27.49%) (95% CI=24.53-30.33) was the highest among all age groups. The prevalence of HSV-2 infection in pregnant women in southern China is quite high. Women with asymptomatic or subclinical genital infection should be identified by examining the HSV-2 antibody, which would be helpful to reduce the abnormal pregnancy outcome. PMID- 21269307 TI - Syndromic nevoid hypermelanosis: description of seven cases with a 10-year follow up. AB - Skin lesions can often be the only sign of an underlying systemic abnormality which will require further investigation. Several syndromic conditions are diagnosed after their cutaneous marker, which is in most cases a nevus. We report a neurocutaneous condition which we named "syndromic nevoid hypermelanosis" (SNH). We studied seven patients who presented with hyperpigmented disseminated macules (melanotic or pigmented nevi) as a cardinal sign. Neurological abnormalities were detected in all cases and skeletal dysmorphism in four. In spite of the genetic alteration that may be the cause of this disease, dermatologists should be able to diagnose it based on its semiological features and distinguish it from other neurocutaneous conditions. We consider SNH to be a distinct clinical entity that has not been clearly defined until now. PMID- 21269308 TI - Beneficial effect of a diet containing heat-killed Lactobacillus paracasei K71 on adult type atopic dermatitis. AB - The purpose of this study was to investigate the clinical effect of a supplementary diet containing heat-killed lactic acid bacterium Lactobacillus paracasei K71 (LAB diet) on adult patients with atopic dermatitis (AD). A randomized, double-blind, placebo-controlled study was conducted in 34 adult type AD subjects who were treated with conventional topical corticosteroid and tacrolimus. LAB diet or placebo was added over 12 weeks. The primary end-point was the clinical severity of AD which was evaluated by a severity scoring system proposed by the guideline of the Japanese Dermatological Association. The effect was also secondarily evaluated by itch scores of visual analog scales (VAS), quality-of-life (QOL) impairment scores of Skindex 16 and consumption amounts of topical therapeutics. Data on these four assessment variables were collected at baseline and at week 4, 8 and 12. Within the study population, the skin severity scores were significantly decreased from baseline at week 8 (P<0.05) and at week 12 (P<0.01) in the LAB diet group but not in the placebo group. Influence of LAB diet on itch scores or QOL impairment scores was not evident. The consumption of topical therapeutics in the placebo group was 1.9-times greater in total amount compared with the corresponding value in the LAB diet group during the intervention period, although there was no significant difference. No LAB diet- or placebo-related adverse events were observed. We concluded that the LAB diet may have some benefits as a complementary therapy for adult AD patients who are managed with the conventional treatment. PMID- 21269309 TI - Aggravation of atopic dermatitis in breast-fed infants by tree nut-related foods and fermented foods in breast milk. AB - Ninety-two exclusively breast-fed Japanese infants with atopic dermatitis were studied to see whether tree nut-related foods (chocolate and coffee) and fermented foods (cheese, yogurt, bread, soy sauce, miso soup and fermented soy beans) eaten by their mothers affected their skin condition. Of the 92 infants, 67 (73%) showed improvement of skin lesions when their mothers avoided these foods and showed aggravation of skin lesions when these foods were reintroduced. The predominant offending foods were chocolate, yogurt, soy sauce and miso soup. A long-term maternal exclusion of the trigger foods brought about progressive improvement of skin lesions in the majority of the infants. These findings suggest that tree nut-related foods and fermented foods are important offending foods of atopic dermatitis in breast-fed infants. PMID- 21269310 TI - Langerhans cell histiocytosis treated with narrow-band ultraviolet B. AB - A 58-year-old man had widespread multiple erythemas that had been untreated for 20 years. The cutaneous lesions increased in size for a year. Histopathological examination revealed increased number of large, dysplastic, histiocytic cells in the dermis; most of these cells tested positive for Langelin, CD1a and S-100 staining. The patient was diagnosed with Langerhans cell histiocytosis (LCH) and treated with narrow-band ultraviolet B (NB-UVB) radiation. The erythema improved after treatment, but the tumor remained. Therefore, the tumor was surgically excised. NB-UVB therapy might be effective for the treatment of superficial lesions, but not tumoral lesions of LCH. PMID- 21269311 TI - Synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome with review of the relevant published work. AB - Synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome is characterized by various dermatological manifestations and osteoarthropathy frequently localized to the anterior chest wall. Dermatologists should be familiar with this syndrome. Its early diagnosis is important to avoid prolonged antibiotic treatments and unnecessary invasive procedures. We report a new case of this syndrome with review of the relevant published work. PMID- 21269312 TI - Intravascular large B-cell lymphoma of the cutaneous variant in Korea. AB - Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of diffuse large B cell lymphoma. It is characterized by proliferation of malignant lymphoid cells within the small vessels of various organs. The skin and central nervous system are commonly involved although it occurs in other organs such as the kidneys, adrenals, lung and liver. In Western patients, there is a cutaneous variant of IVLBCL, which involves only the skin. However, the Asian variant, which rarely involves the skin, is associated with hemophagocytosis. It was reported in the majority of Japanese patients. Here, we report a case of the cutaneous variant of IVLBCL in a Korean individual. PMID- 21269313 TI - Therapy-related myelodysplastic syndrome developed by dacarbazine, nimustine hydrochloride and vincristine sulfate (DAV) therapy for patient with malignant melanoma. AB - Therapy-related myelodysplastic syndrome (t-MDS) is mostly attributed to chemotherapeutic agents of alkylating agents. Few studies have evaluated the late effects of chemotherapy for malignant melanoma (MM). To evaluate whether dacarbazine, nimustine hydrochloride and vincristine sulfate (DAV) therapy for MM related to t-MDS or not, a retrospective analysis was performed. We conducted a retrospective case-control study in a cohort of the 217 patients diagnosed with MM from 1989-2007 in Aichi Medical University Department of Dermatology and Nagoya University Graduate School of Medicine Department of Dermatology. One hundred and fifty-five of the 217 patients with MM were prospectively followed after DAV therapy or with or without local injection of beta-interferon, of whom two patients developed t-MDS. Cytogenetic abnormalities were found in two of the 35 patients by chromosome banding method - leukemia (G-Banding). The karyotypes were found in the chromosome of -5, deletion (5), addition (7) and 7q-. In conclusion, DAV therapy should be used carefully for older patients with MM after satisfactory operation. PMID- 21269314 TI - Mucous membrane pemphigoid with immunoglobulin G autoantibodies against full length and 120-kDa ectodomain of BP180. AB - Mucous membrane pemphigoid (MMP) is a rare autoimmune, subepidermal, bullous disease characterized by erosive lesions on the mucous membranes and skin. MMP reacts with various target antigens including BP180, laminin-332, beta4 integrin, alpha6 integrin or type VII collagen. We present a 67-year-old male MMP patient who had lesions on the oral and ocular mucous membranes and facial skin. By immunoblot analyses, immunoglobulin G autoantibodies in the patient's sera reacted with full-length BP180 and the 120-kDa ectodomain of BP180 (LAD-1). PMID- 21269315 TI - Dystrophic epidermolysis bullosa pruriginosa of elderly onset. AB - A 71-year-old man with no family history of skin diseases presented with a 4 month history of recalcitrant pruritic papules and nodules on the lower extremities. He had prurigo-like eruptions with tense bullae on the extensor aspect of his lower extremities with multiple adjacent milia. Toenail dystrophy was observed. Mucous membranes were not affected. Skin biopsy from the shin showed a subepidermal blister with milium. Electron microscopy from lesional and perilesional skin of the leg showed scanty, hypoplastic anchoring fibrils. We detected a heterozygous mutation in the COL7A1 gene, a G-to-A substitution in exon 87 (c.6859G>A; p.Gly2287Arg). Thus, the clinicopathological and molecular findings supported a diagnosis of dystrophic epidermolysis bullosa pruriginosa. Assessment of other relatives was not feasible. To the best of our knowledge, this is the oldest clinical onset of this unusual variant of dystrophic epidermolysis bullosa reported to date. Why the onset of skin fragility should have occurred so late is not known, but the case serves as a reminder that this particular mechanobullous disease can have a delayed presentation. PMID- 21269316 TI - Clinical effect of tocoretinate on lichen and macular amyloidosis. AB - Lichen amyloidosis and macular amyloidosis are commonly therapy-resistant. Tocoretinate is a hybrid compound of retinoic acid and tocopherol that is commonly used for the treatment of skin ulcers. Although beneficial effect of oral retinoic acid on lichen amyloidosis is reported, tocoretinate has not been reported to be useful for the treatment of lichen amyloidosis or macular amyloidosis. We evaluated the effects of topical tocoretinate on lichen amyloidosis and macular amyloidosis lesions. Tocoretinate was topically applied daily to the lesions and clinical improvement and histological changes were evaluated. The outcome was very good for four, good for two, moderate for two and poor for two of 10 treated patients. Epidermal hypertrophy was reduced and expression of involucrin, keratin 1 and keratin 10 was decreased by tocoretinate treatment, suggesting the normalization of epidermal differentiation. Amyloid deposits remained histologically detectable, even in clinically responsive patients. Together, topical application of tocoretinate reduced the clinical symptoms of lichen amyloidosis and macular amyloidosis, and normalized disturbed epidermal differentiation. PMID- 21269317 TI - Imported tungiasis in a Japanese student returning from East Africa. AB - Ectoparastiosis by Tunga penetrans is becoming more common in non-tropical countries as people travel more to endemic areas. We present here a classic case of imported tungiasis including a history of visit to an endemic region and its typical presentation. Diagnosis with dermoscopy, treatment and prevention are discussed. PMID- 21269318 TI - Lichen planus-like dermatosis distributed along the lines of Blaschko. PMID- 21269319 TI - Erythema annulare centrifugum simulating erythema gyratum repens. PMID- 21269320 TI - Low sensitization rate but good clinical relevance of preservatives in Turkey: evaluation of 1256 patients over 10 years (1996-2006). PMID- 21269321 TI - Folliculosebaceous cystic hamartoma on the nipple. PMID- 21269322 TI - Large, papillomatous and pedunculated nevus sebaceus. PMID- 21269323 TI - Clinical and pathological changes in a long-term follow-up case of dermatofibrosarcoma protuberans. PMID- 21269324 TI - Primary cutaneous precursor B-cell lymphoblastic lymphoma in an elderly patient. PMID- 21269325 TI - En coup de sabre presenting as a port-wine stain initially treated with a pulsed dye laser. PMID- 21269326 TI - Cutaneous Mycobacterium chelonae infection successfully treated with faropenem. PMID- 21269327 TI - Human amniotic epithelial cells express melatonin receptor MT1, but not melatonin receptor MT2: a new perspective to neuroprotection. AB - Recent studies have demonstrated that the human placenta is a novel source of adult stem cells. We have provided laboratory evidence that transplantation of these human placenta-derived cells in vitro and in vivo stroke models promotes functional recovery. However, the mechanisms underlying these observed therapeutic benefits of human placenta-derived cells unfortunately remain poorly understood. Here, we examined the expression of two discrete types of melatonin receptors and their roles in proliferation and differentiation of cultured human amniotic epithelial cells (AECs). Cultured AECs express melatonin receptor type 1A (MT1), but not melatonin receptor type 1B (MT2). The proliferation of cultured AECs was increased in the melatonin-treated group in a dose-dependent manner, and the viability of cultured AECs could be further enhanced by melatonin. Moreover, the viability of AECs significantly decreased with H(2) O(2) exposure, which was reversed by pretreatment with melatonin, resulting in increased cell survival rate and cell proliferation. Immunocytochemically, administration of melatonin significantly suppressed nestin proliferation, but enhanced TUJ1 differentiation of MT1-expressing AECs. Additional experiments incorporating antibody blocking and synergistic AEC-melatonin treatments further showed AEC therapeutic benefits via MT1 modulation. Finally, analysis of trophic factors revealed cultured AECs secreted VEGF in the presence of melatonin. These data indicate that melatonin by stimulating MT1 increased cell proliferation and survival rate while enhancing neuronal differentiation of cultured AECs, which together with VEGF upregulation, rendered neuroprotection against experimental in vitro models of ischemic and oxidative stress injury. PMID- 21269328 TI - WT1-specific CTL cells of recipient origin may exist in the peripheral blood of patients achieving full donor chimerism soon after nonmyeloablative transplantation. AB - This study was performed to assay whether leukemia-associated antigen (LAA) specific CTLs of recipient origin existed in the blood of patients who achieved full donor chimerism (FDC) soon after nonmyeloablative transplantation (NST). In 15 patients who received haplo-identical NST, WT1(+) CD8(+) CTLs were detected with WT1/HLA-A*0201 pentamer, and the donor-recipient chimerism levels were analyzed by three methods. Results showed that WT1(+) CD8(+) CTLs could be detected in patients with HLA-A*0201 expressing only in recipient, and cells of recipient origin existed in the blood of patients who achieved FDC, which suggested that LAA-specific CTLs of recipient origin may exist in patients achieving FDC soon after NST. PMID- 21269329 TI - Social Adaptability Index predicts access to kidney transplantation. AB - Identifying the group of subjects prone to disparities in access to kidney transplantation is important for developing potential interventions. Data from the United States Renal Data System (January 1, 1990-September 1, 2007; n = 3407) were used to study association between the Social Adaptability Index (SAI; based upon employment, marital status, education, income, and substance abuse) and outcomes (time to being placed on the waiting list and time to being transplanted once listed). Patients were 56.9 +/- 16.1 yr old, 54.2% men, 64.2% white, and 50.4% had diabetes. SAI was higher in whites (7.4 +/- 2.4) than African Americans (6.5 +/- 2.6) [ANOVA, p < 0.001] and greater in men (7.4 +/- 2.4) than in women (6.7 +/- 2.5) [T-test, p < 0.001]. In multivariate model, greater SAI (range 0 12) was associated with increased likelihood of being placed on the waiting list (hazard ratio [HR] 1.19 [95% CI 1.15-1.23] per each point of increase in SAI, p < 0.001) and greater likelihood of receiving a transplant once listed (HR of 1.06 [95% CI 1.03-1.09] per point of increase in SAI, p < 0.001). Similar trends were observed in most of the subgroups (based upon race, sex, diabetic status, age, comorbidities, and donor type). SAI is associated with access to renal transplantation in patients with end-stage renal disease; it may be used to indentify individuals at risk of healthcare disparities. PMID- 21269330 TI - Post-transplant lymphoproliferative disorders: clinicopathological analysis of 43 cases in a single center, 1990-2009. AB - Post-transplant lymphoproliferative disorders (PTLDs) are a heterogeneous set of complications of organ transplantation associated with poor patient prognosis. We analyzed the clinicopathological features of PTLDs in 43 adult and pediatric recipients of solid organ or bone marrow transplantation at a large transplant service in the Republic of Korea between 1990 and 2009. Of 4545 solid organ and 747 bone marrow transplant recipients, 37 (0.81%) and 6 (0.8%), respectively, developed heterogeneous types of PTLDs. The cumulative incidences of PTLDs during this period were 1.79% (4/223) for heart transplant recipients, 0.78% (17/2192) for kidney transplant recipients, and 0.77% (16/2067) for liver transplant recipients. The patterns of disease onset, histology, and patient survival were associated with the types of organs transplanted. There is a trend for shorter overall survival (OS) in recipients with early-onset PTLDs and monomorphic PTLD histology, while kidney transplant recipients showed favorable OS. This study may be the first comprehensive analysis of the characteristics of PTLDs in Korean patients. PMID- 21269331 TI - An autopsied case of V180I Creutzfeldt-Jakob disease presenting with panencephalopathic-type pathology and a characteristic prion protein type. AB - A 73-year-old Japanese woman showed slowly progressive aphasia, apraxia and dementia. She had no family history of prion disease or dementia. One year later she showed parkinsonism and corticobasal degeneration was initially suspected. On MRI, the left temporal neocortex seemed swollen on T2-weighted images in the initial stage, and a later high-signal intensity region was observed in the cerebral cortex in diffusion-weighted images. The patient developed myoclonus and an akinetic mutism state 15 months and 22 months after onset, respectively. Consecutive electroencephalography revealed no periodic sharp-wave complexes. Prion protein (PrP) gene analysis revealed a valine to isoleucine point mutation at codon 180, and methionine homozygosity at codon 129. This patient's clinical symptoms and disease course were atypical for Creutzfeldt-Jakob disease (CJD), and a stable state with nasal tube-feeding lasted several years. She died of respiratory failure at the age of 81, 102 months after the onset. Autopsy revealed widespread spongiform degeneration with weak synaptic-type PrP deposition, confirming the diagnosis of genetic CJD. Neurons in the cerebral cortex were relatively preserved in number and hypertrophic astrocytosis was generally moderate for such long-term disease, but cerebral white matter showed diffuse severe myelin pallor with tissue rarefaction suggestive of panencephalopatic-type pathology. The cerebellar cortex was relatively well preserved with observation of mild spongiform change in the molecular layer, moderate neuron loss in the Purkinje neuron layer, and scattered small plaque like PrP deposition. Western blot analysis of protease-resistant PrP showed a characteristic pattern without a diglycoform band. V180I CJD is an interesting form of genetic CJD with regards to the clinicopathologic, molecular and genetic findings. PMID- 21269332 TI - An immunohistochemical study of the serotonin 1A receptor in the hippocampus of subjects with Alzheimer's disease. AB - Alzheimer's disease (AD) is associated with neuronal degeneration, synaptic loss and deficits in multiple neurotransmitter systems. Alterations in the serotonin 1A (5-HT1A) receptor can contribute to impaired cognitive function in AD, and both in vitro binding and Positron emission tomography (PET) imaging studies have demonstrated that 5-HT1A receptors in the hippocampus/medial temporal cortex are affected early in AD. This neuropathological study examined the localization and immunoreaction intensity of 5-HT1A receptor protein in AD hippocampus with the goal to determine whether neuronal receptor levels are influenced by the severity of NFT severity defined by Braaks' pathological staging and to provide immunohistochemical confirmation of the binding assays and PET imaging studies. Subjects included AD patients and non-AD controls (NC) stratified into three Braaks' stages (Braak 0-II, NC; Braak III/IV and V/VI, AD). In the Braak 0-II group, 5-HT1A-immunoreactivity (ir) was prominent in the neuropil of the CA1 and subiculum, moderate in the dentate gyrus molecular layer (DGml), and low in the CA3 and CA4. No changes in 5-HT1A-ir were observed in the hippocampus of AD subjects in the Braak III/IV group. Hippocampal 5-HT1A-ir intensity was markedly decreased in the CA1 region in 6/11 (54.5%) subjects in the Braak V/VI group. Across all three groups combined, there was a statistically significant association between reduced 5HT1A-ir and neuronal loss in the CA1, but not in the CA3. The present data demonstrate that hippocampal 5-HT1A receptors are mainly preserved until the end-stage of NFT progression in AD. Thus, the utility of PET imaging using a 5-HT1A-specific radiolabeled probe as a marker of hippocampal neuronal loss may be limited to the CA1 field in advanced stage AD cases. PMID- 21269333 TI - The presence of stem cell marker-expressing cells is not prognostically significant in glioblastomas. AB - Glioblastoma is one of the most frequent primary brain tumors and is characterized by aggressive clinical behavior and biologic heterogeneity. To evaluate the prognostic implication of cancer stem cell markers in glioblastoma, the expression of these markers was investigated in a large series of glioblastoma patients in relation to the survival rate. This series includes 88 cases of glioblastoma that were diagnosed at the Chonnam University Hwasun Hospital from 2004 to 2009. The expression of newly established stem cell markers (nestin, CD133 and CD15) was detected using immunohistochemical analysis. The presence of immunopositive tumor cells was evaluated and interpreted in comparison with the patients' survival data. The expression of nestin was high in 60 cases (68.2%). CD133 and CD15 were positive in 52 cases (59.1%) and 40 cases (45.5%), respectively. No statistically significant difference in patient survival according to stem cell marker expression was observed (P > 0.05). However, gross total resection or combined radiation therapy and chemotherapy significantly prolonged survival (P = 0.04 and P = 0.04). Cox's proportional hazards model showed that the gross total resection and combined radiation therapy and chemotherapy were independent prognostic factors. Although the correlation of stem cell marker expression with clinical outcome in glioma is of considerable interest, the data do not support their prognostic value in glioblastoma. Identification of the key cells in the glioblastoma population in the context of clinical outcomes will provide insight into the mechanism of brain tumorigenesis and will be of paramount importance in determining therapeutically appropriate targets. PMID- 21269334 TI - Induction of autophagy in temozolomide treated malignant gliomas. AB - Autophagy is a dynamic process of protein degradation. Induction of autophagy by temozolomide (TMZ) has been noted in glioma cell lines. Twenty-eight specimens, obtained from 14 patients before and after TMZ treatment, were analyzed to investigate whether induction of autophagy could be detected in surgical specimens by immunohistochemical analysis. Macroautophagy was monitored by immunohistochemical analysis employing anti-light chain 3 isoform B (LC3B) and anti-lysosome-associated membrane protein 1 (LAMP1) antibodies; chaperone mediated autophagy was monitored by anti-LAMP2A antibody immunostaining. Furthermore, detection of LC3B protein by Western blotting was performed on six specimens obtained from the preserved frozen tissues of three patients. All specimens showed dot-like staining for each immunostain in the cytoplasm of glioma cells, indicating induction of autophagy. LC3B, LAMP1 and LAMP2A immunostains were semiquantitatively scored from 1 to 3 points. Combination of the three scores after TMZ treatment (6.4 +/- 1.2) showed a significant increase (P = 0.020) compared to pre-treatment scores (5.2 +/- 1.5). Western blotting for LC3B showed increased LC3B-I and LC3B-II expression after TMZ treatment. The present study proved that autophagy monitoring by immunohistochemical staining of surgical specimens was feasible. These results suggest that autophagy is induced by TMZ. PMID- 21269336 TI - Does there always need to be brain pathology in brain pathology? PMID- 21269335 TI - Molecular and proteomic analyses highlight the importance of ubiquitination for the stress resistance, metabolic adaptation, morphogenetic regulation and virulence of Candida albicans. AB - Post-translational modifications of proteins play key roles in eukaryotic growth, differentiation and environmental adaptation. In model systems the ubiquitination of specific proteins contributes to the control of cell cycle progression, stress adaptation and metabolic reprogramming. We have combined molecular, cellular and proteomic approaches to examine the roles of ubiquitination in Candida albicans, because little is known about ubiquitination in this major fungal pathogen of humans. Independent null (ubi4/ubi4) and conditional (MET3p-UBI4/ubi4) mutations were constructed at the C. albicans polyubiquitin-encoding locus. These mutants displayed morphological and cell cycle defects, as well as sensitivity to thermal, oxidative and cell wall stresses. Furthermore, ubi4/ubi4 cells rapidly lost viability under starvation conditions. Consistent with these phenotypes, proteins with roles in stress responses (Gnd1, Pst2, Ssb1), metabolism (Acs2, Eno1, Fba1, Gpd2, Pdx3, Pgk1, Tkl1) and ubiquitination (Ubi4, Ubi3, Pre1, Pre3, Rpt5) were among the ubiquitination targets we identified, further indicating that ubiquitination plays key roles in growth, stress responses and metabolic adaptation in C. albicans. Clearly ubiquitination plays key roles in the regulation of fundamental cellular processes that underpin the pathogenicity of this medically important fungus. This was confirmed by the observation that the virulence of C. albicans ubi4/ubi4 cells is significantly attenuated. PMID- 21269337 TI - Neuroependymal denudation is in progress in full-term human foetal spina bifida aperta. AB - In human spina bifida aperta (SBA), cerebral pathogenesis [hydrocephalus, Sylvius aqueduct (SA) stenosis and heterotopias] is poorly understood. In animal models, loss of ventricular lining (ependymal denudation) causes SA stenosis and hydrocephalus. We aimed to investigate whether ependymal denudation also takes place in human foetal SBA. Considering that ependymal denudation would be related to alterations in junction proteins, sections through SA of five SBA and six control foetuses (gestational ages ranged between 37 and 40 weeks) were immunostained for markers of ependyma (caveolin 1, betaIV-tubulin, S100), junction proteins (N-cadherin, connexin-43, neural cell adhesion molecule (NCAM), blood vessels (Glut-1) and astrocytes [glial fibrillary acidic protein (GFAP)]. In control foetuses, ependymal denudation was absent. In SBA foetuses different stages of ependymal denudation were observed: (i) intact ependyma/neuroepithelium; (ii) imminent ependymal denudation (with abnormal subcellular location of junction proteins); (iii) ependymal denudation (with protrusion of neuropile into SA, formation of rosettes and macrophage invasion); (iv) astroglial reaction. It is suggested that abnormalities in the formation of gap and adherent junctions result in defective ependymal coupling, desynchronized ciliary beating and ependymal denudation, leading to hydrocephalus. The presence of various stages of ependymal denudation within the same full-term SBA foetuses suggests continuation of the process after birth. PMID- 21269338 TI - 56-year old woman with sphenoid wing tumor. PMID- 21269339 TI - 47-year-old man with frontal lobe tumor. PMID- 21269340 TI - Synaptic activation of mGluR1 generates persistent depression of a fast after depolarizing potential in CA3 pyramidal neurons. AB - Burst firing is an important property of hippocampal pyramidal neurons. Group I metabotropic glutamate receptors (mGluRs) produce a multitude of effects on both the synaptic and intrinsic properties of neurons. We investigated whether brief activation of these receptors results in persistent modifications to the intrinsic excitability of rat hippocampal CA3 pyramidal cells (CA3-PCs). In whole cell current-clamp recordings, current stimuli consisting of filtered, pseudo random noise produced action potential firing with a mean frequency of ~1.5-2 Hz. Analysis of spike intervals revealed that this firing included a substantial component (~20%) of high-frequency (~100 Hz) bursting activity. Activation of group I mGluRs with (S)-3,5-dihydroxyphenylglycine [(S)-DHPG] selectively eliminated the high-frequency bursts, an effect that persisted > 30 min after (S) DHPG washout. The fast after-depolarizing potential (ADP) of CA3-PCs is known to be important for generating high-frequency action potential bursting. This ADP was persistently depressed following a short application of (S)-DHPG. This effect was blocked by the mGluR1 antagonist, (S)-(+)-alpha-amino-4-carboxy-2 methylbenzeneacetic acid (LY367385). In contrast, the depression was resistant to the mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate, N-methyl D-aspartate (NMDA) and gamma-aminobutyric acid (GABA)(A) antagonists. Unlike other manipulations that generate persistent depression of the ADP in CA3-PCs, DHPG-mediated ADP depression was insensitive to the Kv7 channel inhibitor 10,10 bis(4-Pyridinylmethyl)-9(10H)-anthracenone dihydrochloride (XE991) and strong intracellular Ca(2+) buffering by 1,2-Bis(2-aminophenoxy)ethane-N,N,N',N' tetraacetic acid (BAPTA). Synaptic activation of mGluRs in the associational commissural pathway also resulted in persistent depression of the ADP in postsynaptic CA3-PCs, which was blocked by LY367385. These data represent the first evidence that synaptic activation of mGluR1 can modulate the intrinsic excitability properties of hippocampal neurons. PMID- 21269341 TI - The utility of pre-test clinical scoring for clinical diagnosis of heparin induced thrombocytopenia in cardiac surgery patients of a tertiary care centre in north India. AB - BACKGROUND: Heparin-induced thrombocytopenia (HIT) should be diagnosed clinically as well as by laboratory assays for timely recognition, prevention and management of complications. OBJECTIVE: To evaluate the clinical utility of pre-test clinical scoring system in combination with two immunoassays for the diagnosis of HIT in cardiac surgery patients. MATERIALS AND METHODS: A total of 100 consecutive patients undergoing cardiac surgery were studied. Pre-test clinical scoring was carried out in patients with thrombocytopenia and further tested by two immunoassays, i.e., Heparin platelet factor 4 (H-PF4) enzyme-linked immunosorbent assay (ELISA) and particle gel immunoassay (PaGIA). RESULTS: Of the 100 patients studied, 42 patients developed thrombocytopenia post-operatively. On pre-test clinical scoring, low T-score was observed in 6 patients, intermediate in 28 and high score in 8 patients, whereas 19 patients (45.2%) were positive by H-PF4 ELISA and 10 (23.8%) by PaGIA for H-PF4 antibody. The difference in the incidence of clinically significant HIT antibodies in the three categories was statistically significant. A good correlation was also observed with ELISA optical density, T-scoring and PaGIA. CONCLUSIONS: Pre-test clinical scoring correlates well with the development of H-PF4 antibodies which are incriminated in the causation of thrombotic complications in patients with HIT. We also propose a protocol for diagnosing patients with clinical suspicion of HIT using pre-test clinical scoring and immunoassay. PMID- 21269342 TI - Distribution of weak D types in the Croatian population. PMID- 21269343 TI - An integrative literature review of student retention in programmes of nursing and midwifery education: why do students stay? AB - AIMS AND OBJECTIVES: The purpose of the review was to identify student characteristics and strategies in research studies investigating retention (why students stay) as opposed to attrition (why students leave) nursing and midwifery preregistration programmes. BACKGROUND: Retention in nursing and midwifery programmes is a serious international problem. Many governments are committed to diversifying both the student population and the health care workforce. This has led to higher education institutes in some countries offering places on nursing and midwifery programmes to students with non-traditional entry qualifications. There are suggestions that the policy of widening access has contributed to the challenges of retention in nursing and midwifery programmes. DESIGN: Integrative literature review. METHOD: Undertaken using electronic databases and specific search terms, 15 articles were identified and reviewed. The critical appraisal tools produced by CASP (2009) were used to evaluate the quality of the data. Findings from the identified research literature were analysed using qualitative content analysis. RESULTS: Two broad themes emerged from the analysis: Programme and Personal. Subthemes were identified in these that give clues as to why students stay: profession, support, student characteristics and family. CONCLUSIONS: Personal commitment and good support seem to be essential for students to remain on undergraduate programmes of nursing and midwifery. The term 'support' is rarely explicit and requires to be more clearly defined. Furthermore, studies reviewed fail to indicate clearly how to identify when students are most vulnerable and which interventions are most appropriate in different situations in supporting retaining students on programmes. RELEVANCE TO CLINICAL PRACTICE: Nursing and midwifery student retention is a political and professional problem. Collaboration between clinical placement providers, academic institutions, students and their families is required to address the issue. Illumination of factors that help students stay may help us devise interventions that prevent future students leaving. PMID- 21269344 TI - Radiologic and pathologic images of mammary fibromatosis. PMID- 21269345 TI - Atypical fibroxanthoma: a review of the literature. AB - BACKGROUND: Atypical fibroxanthoma (AFX) is an uncommon superficial fibrohistiocytic tumor. It was originally described as a low-grade dermal tumor of atypical spindle cells, but this view has changed, and it is generally considered to be a tumor of intermediate malignant potential. OBJECTIVE: To review the current literature on AFX pertaining to epidemiology, pathogenesis and etiology, clinical presentation, histology, immunohistochemistry, prognosis and follow-up, and treatment. MATERIALS AND METHODS: Extensive literature review was conducted using OVID Medline and Pubmed searching for articles relating to AFX. RESULTS: AFX typically presents as a red or pink papule or nodule on the head or neck of an elderly man. The pathogenesis is most commonly related to ultraviolet radiation. It can clinically mimic other cutaneous malignancies and histologically can mimic squamous cell carcinoma, desmoplastic melanoma, and undifferentiated pleomorphic sarcoma. Immunohistochemistry is important in making the distinction. The prognosis is generally excellent, although there are rare cases of metastatic disease. There is a higher cure rate with Mohs' micrographic surgery than with wide local excision. CONCLUSIONS People with AFX generally have had significant ultraviolet radiation exposure. They should be examined at least every 6 months for recurrence, metastasis, and the development of additional skin cancers. PMID- 21269346 TI - Enhanced healing of surgical wounds of the lower leg using weekly zinc oxide compression dressings. AB - BACKGROUND: Management of lower extremity wounds after Mohs micrographic surgery can pose a challenge to the surgeon. Postoperative reactive edema and inflammation can lead to a painful and protracted healing course. Unna boots deliver zinc oxide to the wound bed and surrounding skin while providing compression and occlusion of the wound. OBJECTIVE: To evaluate the utility of weekly Unna boot therapy in decreasing postoperative edema, inflammation, and morbidity; minimizing postoperative wound care; and improving the rate of wound healing in patients with lower leg surgical defects. METHODS: Ten patients (6 men, 4 women) aged 72 to 91 with postoperative defects on the distal lower extremity were treated with weekly Unna boots until wounds had sufficiently granulated or re-epithelialized. RESULTS: In all 10 patients, weekly Unna boot therapy was well tolerated, with high satisfaction levels relating to minimal postoperative wound care, rapid granulation, minimal pain, and excellent esthetic outcome of postoperative wounds. No infections or other complications were noted during the healing process. LIMITATIONS This was not a randomized, controlled trial. CONCLUSIONS: In patients with postoperative wounds of the lower leg, weekly Unna boots significantly improve the healing process, decrease postoperative pain, and minimize wound care. PMID- 21269347 TI - Ear keloids as a primary candidate for the application of mitomycin C after shave excision: in vivo and in vitro study. AB - BACKGROUND: Although many methods have been developed to treat ear keloids, new therapeutic options are still needed. OBJECTIVE: To determine the effects of topical mitomycin C (MC) on shave-removed wounds and fibroblasts of ear keloids. METHODS: Fourteen ear keloids in 12 patients were shaved, and MC (1 mg/mL) was applied to the resected bed for 5 minutes. The application was repeated 3 weeks later. All patients were assessed 2, 4, and 6 months after the procedure to evaluate the cosmetic results, recurrence, and postsurgical complications. An in vitro study to determine the effects of MC on fibroblasts of the excised keloids was conducted using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, the measurement of total cell counts, and immunoassay of DNA synthesis. RESULTS: Only one recurrence occurred (on the ear helix), and the patients were satisfied with the cosmetic outcomes. The results of the MTT assay, total cell counts, and DNA synthesis immunoassay confirmed the suppressive effects of MC on the keloid fibroblasts. CONCLUSION: The application of topical MC to the resected bed of shave-removed ear keloids was successful in preventing recurrences and providing an acceptable cosmetic outcome. PMID- 21269348 TI - Autologous noncultured melanocyte transplantation for stable vitiligo: can suspending autologous melanocytes in the patients' own serum improve repigmentation and patient satisfaction? AB - BACKGROUND: Vitiligo is a cosmetically disfiguring acquired depigmenting disorder caused by the loss of functional melanocytes from the epidermis. Various approaches that have been used for the treatment of vitiligo can be classified as medical and surgical therapies. Noncultured autologous melanocyte transplantation is a new and effective surgical treatment for stable vitiligo. OBJECTIVES: To compare the repigmentation results in stable vitiligo of transplantation of autologous noncultured melanocytes suspended in normal saline with that of those suspended in the patient's own serum. METHODS AND MATERIALS: Twenty-five patients with 36 lesions of stable vitiligo were randomized into two groups for noncultured melanocyte transplantation. Patients in Group A received melanocytes suspended in normal saline, and those in Group B received melanocytes suspended in their own serum. RESULTS: Statistically significant difference in repigmentation results and reduction in Dermatology Life Quality Index (DLQI) score was observed between the two groups 16 weeks after surgery. Repigmentation results were excellent (>90%) and very good to excellent (>75%) in 44.4% and 66.7% of lesions, respectively, in Group A and 88.8% and 94.4% of lesions, respectively, in Group B. There was also a significant (p=.002) decline in DLQI score in both groups, with the mean reduction being significantly greater in Group B than Group A (p=.005). CONCLUSION: Results of noncultured melanocyte transplantation can be improved significantly more by suspending the melanocytes in the patients' autologous serum than in normal saline. This could be an important innovation in the surgical management of patients with stable vitiligo. PMID- 21269349 TI - Sequential treatment with triple combination cream and intense pulsed light is more efficacious than sequential treatment with an inactive (control) cream and intense pulsed light in patients with moderate to severe melasma. AB - BACKGROUND: Triple combination (TC) cream is a stable combination of fluocinolone acetonide 0.01%, hydroquinone 4%, and tretinoin 0.05% and is currently the only hydroquinone-containing drug approved by the Food and Drug Administration for the treatment of melasma. OBJECTIVE: To evaluate the safety and efficacy of TC cream when used sequentially with intense pulsed light (IPL) treatments in patients with moderate to severe melasma. MATERIALS & METHODS: This was a 10-week, split face study in which 56 patients with symmetrical melasma lesions were treated with TC cream on one side of the face and an inactive control cream on the other side of the face. Patients also had two IPL treatments at weeks 2 and 6. (Topical treatment was suspended during IPL treatments +/- 1 day.) RESULTS: Melasma severity was significantly less with TC cream and IPL than with inactive cream and IPL at weeks 6 (p=.007) and 10 (p=.002). Improvement in melasma was greater with TC cream and IPL than with inactive cream and IPL according to investigator and patient evaluations at weeks 6 and 10 (p<.001 for both time points). Treatment with TC cream and IPL was well tolerated. CONCLUSION: The results of this study suggest that TC cream and IPL treatment is an effective and safe treatment option for patients with melasma. PMID- 21269350 TI - Sclerosing squamous cell carcinoma of the skin, an underemphasized locally aggressive variant: a 20-year experience. AB - BACKGROUND: Desmoplastic (sclerosing) responses to a variety of neoplasms have been documented but rarely evaluated in association with primary cutaneous squamous cell carcinoma (SCC). We report a distinctive variant of SCC demonstrating an infiltrative growth pattern and stromal desmoplasia. METHODS: Cases were identified through a retrospective review of our dermatopathology and dermatologic surgery databases. After initiation of the study, additional cases were identified prospectively. Neoplasms were scored microscopically for specific histopathologic parameters and reactivity with selected histochemical and immunohistochemical stains. Clinical follow-up data were obtained through a review of medical records or contact with the patient's referring physicians. RESULTS: Seventy-three carcinomas from 72 patients were identified (46 men, 26 women; median age 76, range 45-91). The original pretreatment biopsies were available in 69 of 73 cases. All lesions developed on sun-damaged skin, with the cheek constituting the most common site. The clinical presentation was typically as a sclerotic plaque. All neoplasms extended into the reticular dermis or subcutaneous fat, and perineural invasion was identified in 53 cases (73%). Patients who underwent standard excisional surgery experienced a recurrence rate of 80%; 9% of those treated with micrographic surgery experienced postoperative recurrences. Metastasis or carcinoma-related death was not observed in any patient during the follow-up period (median 36 months). CONCLUSIONS: Our results suggest that desmoplasia is uncommonly found in association with cutaneous SCC but helps define a locally aggressive variant of carcinoma. In light of the infiltrative nature of desmoplastic SCC of the skin and the high incidence of perineural invasion, micrographic surgery is the surgical modality of choice. PMID- 21269351 TI - Percutaneous collagen induction versus full-concentration trichloroacetic acid in the treatment of atrophic acne scars. AB - BACKGROUND: Percutaneous collagen induction (PCI) promotes removal of damaged collagen and induces more collagen immediately under the epidermis. The chemical reconstruction of skin scars (CROSS) method is a focal application of full concentration trichloroacetic acid (TCA) to atrophic acne scars. The CROSS method has the advantage of reconstructing acne scars by increasing dermal thickening and collagen production. OBJECTIVE: To compare the safety and efficacy of PCI and the 100% TCA CROSS method for the treatment of atrophic acne scars. MATERIALS AND METHODS: Thirty participants were randomly equally divided into two groups; group 1 underwent four sessions (4 weeks apart) of PCI, and group 2 underwent four sessions (4 weeks apart) of 100% TCA CROSS. RESULTS: Acne scarring improved in 100% of patients. Scar severity scores improved by a mean of 68.3% (p<.001) in group 1 and a mean of 75.3% (p<.001) in group 2. The difference in the degree of improvement was not statistically significant between the groups (p=.47). CONCLUSIONS: PCI and 100% TCA CROSS were effective in the treatment of atrophic acne scars. PMID- 21269352 TI - Sentinel lymph node biopsy or nodal observation in melanoma: a prospective study of patient choices. AB - BACKGROUND: There is no consensus regarding the therapeutic utility of sentinel lymph node biopsy (SLNB) versus that of nodal observation (NO) in melanoma. OBJECTIVE: To prospectively evaluate a standardized counseling procedure and its effect on patient choices to undergo SLNB or NO. METHODS: In four centers, patients with melanoma eligible for SLNB or NO received a complete counseling procedure that included verbal information from dermatologists and surgeons, a detailed information sheet, and a written consent form. Data collected included patient and tumor characteristics, counseling conditions, and specialties of informing doctors. Factors influencing patients' choices were studied using multivariate analysis. RESULTS: Of 343 consecutive patients, 309 were offered SLNB and NO and received complete verbal and written information from a dermatologist alone (62%) or in association with a surgeon (38%). Approximately half took advice from trusted persons, and half asked for additional time before making a decision; 268 (86.7%) ultimately decided to undergo SLNB. Multivariate analysis showed that older patients, those with a head and neck melanoma, and those informed without a surgeon present were more likely to prefer NO. CONCLUSIONS: This counseling procedure was easily implemented in clinical practice. Patients favored SLNB but were able to understand uncertainties and express preferences. PMID- 21269353 TI - Identification and utilization of genes associated with beef qualities. AB - The fatty acid composition of adipose tissue in beef has been recognized as an important trait because of its relationship with beef quality, including favorable beef flavor and tenderness. Over the last decade, we have tried to identify the genes responsible for the fatty acid composition in cattle, and have found the following. (i) Genetic polymorphism of stearoyl-CoA desaturase (SCD) is one of the responsible genes associated with fatty acid composition. The average effects of gene substitution of the SCD type A gene on the monounsaturated fatty acid (MUFA) percentage and the melting point of intramuscular fat were approximately +1.0% and -1.0 degrees C, respectively. (ii) Intron polymorphism of sterol regulatory element binding protein-1 (SREBP-1) also affected MUFA. (iii) No effect of SCD or SREBP-1 genotypes on any representative carcass traits of Japanese Black in the field population was observed. (iv) Additional genetic markers adipocytes fatty acid binding protein 4 (FABP4) and liver X receptor alpha also affected the fatty acid composition. (v) SCD and FABP4 significantly affected fatty acid composition in Holstein steers. These findings will bring new insight into the fat-related carcass traits of beef cattle and will thus contribute to the beef industry. PMID- 21269354 TI - Development of novel intracytoplasmic sperm injection and somatic cell nuclear transfer techniques for animal reproduction. AB - Animal biotechnology has made new biological experiments possible and new discoveries are being made on an almost daily basis. Among these discoveries is a method for directly injecting a spermatozoa or somatic nucleus into an oocyte that has brought a revolution in the world of micromanipulators. Experiments that were unfeasible until now have become possible, and normal offspring can be generated from infertile cells, such as using dead sperm or a dead frozen body. In this review, I will introduce the progress of animal reproductive biotechnology, including our current research. PMID- 21269355 TI - Promotion of intramuscular fat accumulation in porcine muscle by nutritional regulation. AB - Recently, pork with marbling has received attention as good quality pork and scientists are required to develop methods to produce pork with reasonable amounts of intramuscular fat (IMF). The aim of this review is to describe studies relevant to promotion of IMF accumulation in porcine muscle by nutritional regulation. The main focus is on effect of dietary lysine levels. First, we found dietary low lysine up-regulated glucose transporter protein 4 messenger (m)RNA expression in Longissimus dorsi (L. dorsi) and Rhomboideus muscles. In addition, the proportion of oxidative fiber of both muscles was also enhanced by dietary low lysine. Because it has been observed that higher oxidative capacity is associated with higher IMF content, we hypothesized that dietary low lysine would promote IMF accumulation. Further, higher mRNA abundance of peroxisome proliferator-activated receptor gamma, a master regulator of adipogenesis, in both muscles induced by dietary low lysine, supported this hypothesis. Indeed, IMF content of L. dorsi muscle of finishing pigs given a low lysine diet for 2 months until reaching the market weight was twice that of pigs given a control diet. Possible underlying mechanisms of IMF accumulation in porcine muscle and future perspectives are also discussed in this review. PMID- 21269356 TI - Recent progress in the study of behavior and management in grazing cattle. AB - Recent progress in studies concerning behavior of, and management for, grazing cattle are reviewed. Since 1950, much study has been conducted on 'How', 'When', 'Where' and 'How long' regarding grazing. After the 1980s, grazing ecology introduced the concept of hierarchy at different spatial and temporal scales, and since then grazing behavior has been investigated on the foraging hierarchy of large grazing herbivores: bite, feeding station (FS), patch, feeding site, camp and home range. From the sequence of activities, FS is grouped within a feeding patch, and movement of grazing cattle has been studied between FSs, feeding patches, feeding sites and between camps. Grazing behavior and production relates closely with defoliation, and grazing management should control both grazing behavior and vegetation according to three rules: planning, operational and adaptation rules. Planning rules relate the stocking rate of cattle; operational rules relate to defoliation; and adaptation rules vary with regional situations. Recent studies on grazing have been carried out in the fields of animal diversity and welfare. Future studies in this field should be conducted on the ecology, neurophysiology and psychology of grazing. Nonlinear analysis will also be significant in this field. Grazing cattle production should also utilize supplementation by roughage and/or grains. PMID- 21269357 TI - Polymorphisms in the bovine hemoglobin-beta gene provide evidence for gene-flow between wild species of Bos (Bibos) and domestic cattle in Southeast Asia. AB - The electrophoretic variation in bovine hemoglobin-beta (HBB) is one of the most investigated genetic markers. The presence of a unique HBB variant, HBB(X), in Southeast Asian cattle has been reputed as a sign of gene-flow from wild bovine species. In this study, we analyzed the DNA sequences of HBB genes in domestic and wild bovine species to verify this belief. Isoelectric focusing of HBB chain revealed that the HBB(X) in domestic cattle had dimorphism and was separated into HBB(X1) and HBB(X2). The HBB(X1) had the same DNA sequence of the common HBB variant in gayal (Bos gaurus frontalis), while some of the HBB(X2) were identical with that of Cambodian banteng (Bos javanicus birmanicus). As a result, we confirmed that the bovine HBB variants can be a good indicator of introgression between wild and domestic cattle. The HBB(X1) was always predominant to HBB(X2) in the continental populations, suggesting that the gaur had contributed to the gene pool of domestic cattle in this region much more than the banteng. On the other hand, the mitochondrial DNA analysis could not detect gene-flow from wild species. Autosomal markers that can trace the phylogeny between alleles are suitable for the assessment of bovine interspecific introgression. PMID- 21269358 TI - Association of an SNP marker in exon 24 of a class 3 phosphoinositide-3-kinase (PIK3C3) gene with production traits in Duroc pigs. AB - A C<->T single nucleotide polymorphism (SNP) on exon 24 of the porcine class 3 phosphoinositide-3-kinase (PIK3C3) gene is considered a possible genetic marker for selecting backfat (BF) thickness and carcass fat, although only one study has published results on its effects by performing experiments on a single resource family. We analyzed the association of this PIK3C3 polymorphism with production traits in 739 Duroc pigs. The C allele frequency was 67.9% in our study population. PIK3C3 polymorphism showed significant effects on average daily weight gain (ADG), BF thickness, intermuscular fat content (IMF), and the size of the loin eye muscle area (EMA). The C alleles increased ADG, BF and IMF, and decreased EMA. The predicted differences in traits between the homozygous pigs of the C and T alleles were 40 g/day for DG, 1.2 mm for BF, 0.44% for IMF, and 1.6 cm(2) for EMA. Furthermore, the statistical models for estimating the breeding values of each trait had lower Akaike's information criterion values when adding PIK3C3 genotype information. We therefore confirmed that the polymorphism in PIK3C3 (C2604T) has the potential to be a genetic marker for production traits in Duroc pigs. PMID- 21269359 TI - Molecular phylogeny and diversity of Myanmar and Bhutan mithun based on mtDNA sequences. AB - The mithun (Bos frontalis), synonymous with mithan and gayal, is considered to be a domesticated form of gaur (B. gaurus). However, there has been a controversy concerning its origin. In an effort to address this issue, the mitochondrial cytochrome b (cytb) genes of 20 mithun from Myanmar and 13 from Bhutan were sequenced to trace its maternal origin. Seven cytb haplotypes were found in the 33 mithun, and the phylogenetic tree for these haplotypes clearly showed three embranchments involving five gaur types, a B. indicus type, and a B. taurus type. Sixteen Myanmar and 12 Bhutan mithun had gaur haplotypes, while a B. indicus haplotype was found in three Myanmar and one Bhutan mithun. The B. taurus haplotype was detected in a single Myanmar animal. These results demonstrated that the principal maternal origin of mithun was gaur and suggested that it was directly domesticated from gaur. However, some introgression of domestic cattle existed in current mithun populations. The presence of cattle mtDNA raised the question of how many cattle nuclear genes might have been integrated into the gene pool of mithun. PMID- 21269360 TI - Polymorphism of inhibin betaB gene and its relationship with litter size in sheep. AB - The inhibin beta(B) (INHBB) gene was studied as a candidate gene for the prolificacy of Small Tail Han and Hu sheep. According to the sequence of exon 1 and 2 of bovine INHBB gene, six pairs of primers were designed to detect single nucleotide polymorphisms of exon 1 and 2 of INHBB gene in both high (Small Tail Han and Hu sheep) and low prolificacy breeds (Dorset, Texel and German Mutton Merino sheep) by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). Three pairs of primers (primers 1-1, 1-2 and 1-3) were used to amplify the exon 1, and others (primers 2-1, 2-2 and 2-3) to the exon 2. Only the products amplified by primer 2-3 displayed polymorphism. For primer 2-3, three genotypes (AA, AB and BB) were detected in Hu sheep and only AA genotype in other breeds. In Hu sheep, frequency of AA, AB and BB genotypes was 0.636, 0.046 and 0.318, respectively. Sequencing revealed 276A > G mutation (based on the amplification region of primer 2-3) which did not cause any amino acid change because it lay in the 3' untranslated region. The ewes with genotype BB had 0.58 (P < 0.01) lambs more than those with AA in Hu sheep. PMID- 21269361 TI - Comparative genomic analysis of growth hormone gene in geese. AB - To explore the mutation characteristic of growth hormone (GH) gene in geese, all the exons and introns of the gene were amplified by 20 pairs of primers, and then single nucleotide polymorphisms (SNPs) were detected by single strand conformation polymorphism (SSCP) and subsequently confirmed by sequencing. There were six SNPs per 1000 nucleotides in exons compared to two SNPs per 1000 nucleotides in intron regions. The variant in exons contained only one non synonymous mutation and three synonymous mutations. The results show that its sequence identity with chicken and duck were 77.54% and 92.38%, respectively, which may be concluded that the GH gene was highly conservative in phylogenesis, although there were differences between waterfowls and chicken in their evolution process. PMID- 21269362 TI - Development of discrimination markers between Japanese domestic and imported beef. AB - In the meat industry, correct labeling of beef origins or breed is required to assure quality and safety. This paper describes the development of discrimination markers between Japanese domestic and imported beef from the United States (US) and Australia (AUS) based on a bovine 50K single nucleotide polymorphism (SNP) array using a total of 110 samples: Japanese Black (n = 50), Japanese Holstein (n = 50) and US cattle (n = 10). Genotyping information revealed 1081 SNPs as candidate markers that were polymorphic only in US cattle. The genotyping results by PCR-restriction length polymorphism in Japanese Black (n = 300) and Holstein cattle (n = 146) revealed that 11 SNPs had alleles specific to US cattle. Their allelic frequencies in US cattle (n = 108) ranged from 0.097 to 0.250 with an average of 0.178 and the combined identification probability of US cattle was 0.987. In addition, we also verified the applicability of these US-specific markers to AUS cattle. Their allelic frequencies in AUS cattle (n = 280) ranged from 0.063 to 0.224 with an average of 0.137 and the combined identification probability of AUS cattle was 0.963. In conclusion, a set of these markers could be useful for discriminating between Japanese domestic and imported beef and would contribute to identify origins and prevent falsified labeling of beef. PMID- 21269363 TI - Sex steroid hormones do not enhance the direct stimulatory effect of kisspetin-10 on the secretion of growth hormone from bovine anterior pituitary cells. AB - The aims of the present study were to clarify the effect of kisspeptin10 (Kp10) on the secretion of growth hormone (GH) from bovine anterior pituitary (AP) cells, and evaluate the ability of sex steroid hormones to enhance the sensitivity of somatotrophic cells to Kp10. AP cells prepared from 8-11-month-old castrated calves were incubated for 12 h with estradiol (E(2), 10(-8) mol/L),progesterone (P(4), 10(-8) mol/L), testosterone (T, 10(-8) mol/L), or vehicle only (control), and then for 2 h with Kp10. The amount of GH released in the medium was measured by a time-resolved fluoroimmunoassay. Kp10 (10(-6) or 10( 5) mol/L) significantly stimulated the secretion of GH from the AP cells regardless of steroid treatments (P < 0.05), and E(2), P(4), and T had no effect on this response. The GH-releasing response to growth hormone-releasing hormone (GHRH, 10(-8) mol/L) was significantly greater than that to Kp10 (P < 0.05). The present results suggest that Kp10 directly stimulates the release of GH from somatotrophic cells and sex steroid hormones do not enhance the sensitivity of these cells to Kp10. Furthermore, they suggest that the GH-releasing effect of Kp10 is less potent than that of GHRH. PMID- 21269364 TI - Effects of rice straw particle size on digesta particle size distribution, nitrogen metabolism, blood biochemical parameters, microbial amino acid composition and intestinal amino acid digestibility in goats. AB - Effects of rice straw particle size and physically effective neutral detergent fiber (peNDF) on particle size distribution of different digestive tract, nitrogen (N) metabolism, blood biochemical parameters, microbial amino acid (AA) composition and intestinal AA digestibility in goats were investigated. A 4 * 4 Latin square design was employed using four mature Liuyang black goats fitted with permanent ruminal, duodenal, and terminal ileal fistulae. During each of the four periods, goats were offered one of four diets that were similar in chemical composition, but varied in particle sizes and peNDF through alteration of the theoretical cut length of rice straw (10, 20, 40 and 80 mm, respectively). Dietary peNDF contents of four diets were 17.4, 20.9, 22.5 and 25.4%, respectively. Results showed that increasing particle size of rice straw and dietary peNDF significantly affected the particle size distributions of digesta in rumen, duodenum and ileum, except feces. However, increasing particle size of rice straw and peNDF did not affected N metabolism in goats, except the increased apparent N digestibility in rumen and large intestine, and the decreased apparent N digestibility in small intestine. Furthermore, increasing particle size of rice straw and peNDF showed little influence on the profile of blood biochemical parameters, microbial AA composition and intestinal AA digestibility in goats. PMID- 21269365 TI - Regulation of muscular glutamate metabolism by high-protein diet in broiler chicks. AB - The major taste active component, glutamate (Glu), improves the taste of meat. In this study, we investigated the effect of a short-term high-protein (HCP) diet on the intramuscular free Glu content to improve the taste of meat. Furthermore, we elucidated how the muscle free Glu content was controlled by the HCP diet. Chicks (14 days old) were fed the control diet or HCP diet for 10 days. Plasma and muscle free amino acid concentrations, and activity and messenger RNA (mRNA) expression of muscle enzymes related to Glu metabolism were determined. Muscle free Glu content was increased (P < 0.01) by 51%. Activity and mRNA expression of glutaminase (GA), which is one of the major Glu-related enzymes, were significantly decreased (P < 0.05) in the HCP group because of feedback inhibition. The mRNA expression of lysine alpha-ketoglutarate reductase (LKR), which is the enzyme involved in lysine (Lys) degradation and Glu production, was significantly increased (P < 0.001) in the HCP group. These results suggest that short-term dietary HCP feeding is an effective treatment for improving the taste of meat. Furthermore, our results suggest that the free Glu content in muscle is regulated by GA and LKR. PMID- 21269366 TI - Comparison of the peripheral blood leukocyte population between Japanese Black and Holstein calves. AB - Japanese black (JB) calves have greater susceptibility to infectious diseases compared to Holstein (Hol) calves. In order to clarify the differences in cellular immune status between JB and Hol calves, the leukocyte population and lymphocyte proliferative ability were analyzed. In total 200 healthy calves, 1 day to 14 weeks of age, were examined: 105 JB and 95 Hol calves. Lower numbers in peripheral blood and percentage in peripheral blood mononuclear cells of CD3(+)TcR1-N12(+) T cells and major histocompatibility complex class-II(+)CD14(-) B cells were observed in the JB compared to the Hol. The percentage of TcR1 N12(+)CD25(+) T cell in the JB was significantly lower than that of the Hol at 4 6, and 8-10 weeks. Interleukin (IL)-2 sensitivity in the JB was lower than that in the Hol, and significant differences were observed in age groups of 6-8 weeks and 10-14 weeks. These findings indicated that the lower numbers of gammadelta T cells and B cells in the JB compared to the Hol might be associated with the specificity of the immune systems in JB calves. PMID- 21269367 TI - Gene expression and hormonal regulation of adiponectin and its receptors in bovine mammary gland and mammary epithelial cells. AB - Although the functions of adiponectin, a differentiated adipocyte-derived hormone, in regulating glucose and fatty acid metabolism are regulated by two subtypes of adiponectin receptors (AdipoRs; AdipoR1 and AdipoR2), those in ruminants remain unclear. Therefore we examined the messenger RNA (mRNA) expression levels of adiponectin and its receptors in various bovine tissues and mammary glands among different lactation stages, and the effects of lactogenic hormones (insulin, dexamethasone and prolactin) and growth hormone (GH) on mRNA expression of the AdipoRs in cultured bovine mammary epithelial cells (BMEC). AdipoRs mRNAs were widely expressed in various bovine tissues, but adiponectin mRNA expression was significantly higher in adipose tissue than in other tissues. In the mammary gland, although adiponectin mRNA expression was significantly decreased at lactation, AdipoR1 mRNA expression was significantly higher at peak lactation than at the dry-off stage. In BMEC, lactogenic hormones and GH upregulated AdipoR2 mRNA expression but did not change that of AdipoR1. In conclusion, adiponectin and its receptor mRNA were expressed in various bovine tissues and the adiponectin mRNA level was decreased during lactation. These results suggest that adiponectin and its receptors ware changed in mammary glands by lactation and that AdipoRs mRNA expression was regulated by different pathways in BMEC. PMID- 21269368 TI - Ontogenesis of the rumen: a comparative analysis of the Merino sheep and Iberian red deer. AB - The aim of this study is to describe differences in the ontogenesis of the rumen in the sheep (domestic ruminant) and deer (wild ruminant). A total of 50 embryos and fetuses of Merino sheep and 50 of Iberian deer were used, from the first stages of prenatal life until birth. For the study, the animals were divided into five experimental groups according to the most relevant histological characteristics. The appearance of the rumen from the primitive gastric tube was earlier in the sheep (22% gestation, 33 days) than in the deer (25% gestation, 66 days). In both cases it displayed a primitive epithelium of a stratified, cylindrical, non-ciliary type. At around 28% gestation in the sheep (42 days) and 26% (67 days) in the deer, the rumen was configured of three clearly differentiated layers: internal or mucosal, middle or muscular and external or serosal. In both species the stratification of the epithelial layer was accompanied by modifications in its structure with the appearance of the ruminal pillars and papillae. The pillars appeared before the papillae and the appearance of both structures was always earlier in the deer (pillars: 70 days, 27% gestation; papillae: 97 days, 36% gestation) than in the sheep (pillars: 42 days, 28% gestation; papillae: 57 days, 38% gestation). The outlines of the ruminal papillae appeared as evaginations of the basal zone toward the ruminal lumen, dragging in their formation the basal membrane, the lamina propria and the submucosa. The tegumentary mucosa of the rumen was without secretion capability in the first embryonic phases. From 67 days (26% gestation) the neutral mucopolysaccharides appeared in the deer and at 46 days (30% gestation) in the sheep. In both cases they continued to decrease until birth, this diminution being more pronounced in the deer. Finally, the presence of neuroendocrine and glial cells was detected in the deer at earlier stages than in the sheep. PMID- 21269369 TI - Evaluation of the potential effects of abortion on the productive performance of Iranian Holstein dairy cows. AB - Calving records from the Animal Breeding Center of Iran collected from January 1983 to December 2007 and comprising 1,163,594 Holstein calving events from 2552 herds were used to evaluate the potential effect of abortion occurrence on 305 day milk yield, milk fat yield, fat percentage of milk and milk protein yield in Iranian Holsteins. Statistical analyses of production traits were performed using a linear mixed model procedure. Normal-calved cows had greater 305-day milk production, fat yield and protein yield of milk than abortive-calved cows (P < 0.05). However, abortive-calved cows had the greater milk fat percentage than normal calved cows (P < 0.05). The linear and quadratic effects of age of dam were significant on all of the studied traits (P < 0.05). The results of regression analysis showed that increase in the quadratic effect of age can cause an increase in the fat percentage of milk for all calvings including normal and abortive calvings. Because abortion is one of the most important conditions that limit a cow's ability to produce, maintaining the general health of cattle is important in minimizing the risk of abortion problems. PMID- 21269370 TI - Flavor evaluation of yak butter in Tsinghai-Tibet Plateau and isolation of microorganisms contributing flavor. AB - Yak butter in Tsinghai-Tibet Plateau possesses the characters of high energy, abundant alimentation and a special flavor with certain medical and health care functions. In this paper the organoleptic flavor of yak butter was estimated, and 28 kinds of substance with different flavors were identified with the technique of coupling gas chromatography to mass spectroscopy (GC-MS). The results showed that there are many microorganisms in yak butter with natural inoculation, which contribute to the formation of its special flavors. It was found that three of these 15 microorganisms, identified as Saccharomycetaceae, Penicillium and Asperillus separately, contributed the most to flavors. The microorganisms are expected to be applied in the food industry, especially to produce dairy food with the unique flavor of yak butter. PMID- 21269371 TI - Enhancement of viability of a probiotic Lactobacillus strain for poultry during freeze-drying and storage using the response surface methodology. AB - A rotatable central composite design (CCD) was used to study the effect of cryoprotectants (skim milk, sucrose and lactose) on the survival rate of a probiotic Lactobacillus strain, L. reuteri C10, for poultry, during freeze-drying and storage. Using response surface methodology, a quadratic polynomial equation was obtained for response value by multiple regression analyses: Y = 8.59546 0.01038 X(1)-0.09382 X(2)-0.07771 X(3)-0.054861 X(1)(2)-0.04603 X(3)(2)-0.10938 X(1)X(2). Based on the model predicted, sucrose exerted the strongest effect on the survival rate. At various combinations of cryoprotectants, the viability loss of the cells after freeze-drying was reduced from 1.65 log colony forming units (CFU)/mL to 0.26-0.66 log CFU/mL. The estimated optimum combination for enhancing the survival rate of L. reuteri C10 was 19.5% skim milk, 1% sucrose and 9% lactose. Verification experiments confirmed the validity of the predicted model. The storage life of freeze-dried L. reuteri C10 was markedly improved when cryoprotectants were used. At optimum combination of the cryoprotectants, the survival rates of freeze-dried L. reuteri C10 stored at 4 degrees C and 30 degrees C for 6 months were 96.4% and 73.8%, respectively. Total viability loss of cells which were not protected by cryoprotectants occurred after 12 and 8 weeks of storage at 4 degrees C and 30 degrees C, respectively. PMID- 21269372 TI - Simple method for isolation of glyceraldehyde 3-phosphate dehydrogenase and the improvement of myofibril gel properties. AB - Porcine glycolytic enzyme, glyceraldehyde 3-phosphate dehydrogenase (G3PD) was prepared effectively by a combination of ethylene diamine tetra-acetate (EDTA) pretreatment and affinity purification. After salting out of porcine sarcoplasmic proteins (SP) with ammonium sulfate at 75% saturation, the obtained supernatant (SP-f3) was treated with EDTA, leaving G3PD in the supernatant (G3PD-E) and most other SPs in the precipitate. At that time, the separation of G3PD-E required more than 20 mmol/L EDTA. G3PD-E was then subjected to affinity purification by batchwise method using blue-sepharose CL-6B, and purified G3PD (G3PD-AP) was obtained using 2 mol/L potassium chloride (KCl) as an eluent. Texture analysis showed that the hardness, adhesiveness and gumminess of the myofibril gel at 0.2 mol/L NaCl increased with the addition of G3PD-AP. Scanning electron microscopy revealed that the G3PD-AP reinforced the gel network of the myofibril. However, scanning electron micrograph analysis showed that the network-structure of the gel by the addition of G3PD-AP developed in a different manner from that by adding 0.6 mol/L NaCl. These results showed that glycolytic enzyme, G3PD, contributes to the improvement of the rheological properties of meat products. PMID- 21269373 TI - Cellularity of developing subcutaneous adipose tissue in Landrace and Meishan pigs: adipocyte size differences between two breeds. AB - Experiments were designed to compare the adipocyte cellularity of subcutaneous adipose tissue between growing Landrace (low backfat) and Meishan (high backfat) pigs at 1 week, 3 weeks, 6 weeks, 3 months and 5 months of age. As pigs aged, body weight and backfat thickness of both breeds significantly increased. When compared at equal ages, backfat thickness adjusted to equal body weight was greater for Meishan pigs. The mean diameter of fat cell size also increased with age, and by 6 weeks adipocytes from both outer and inner layers of subcutaneous adipose tissue were larger in Meishan pigs. At 5 months, approximately 80% of the adipose tissue mass in Meishan pigs was attributable to adipocytes measuring 95 165 um in diameter, whereas adipocytes of 75-145 um comprised most of the tissue mass in the Landrace. Although the contribution of smaller adipocytes (25-45 um) to the tissue volume was negligible, both breeds showed a biphasic diameter distribution at all ages, suggesting that adipocyte hyperplasia is still active. Our results demonstrate that cellularity differences exist between the subcutaneous adipose tissues of Landrace and Meishan pigs, and adipocyte hypertrophy is the most overwhelming contributor to the greater backfat deposition for Meishan pigs. PMID- 21269374 TI - Overall welfare assessment of laying hens: comparing science-based, environment based and animal-based assessments. AB - To increase the validity of evaluations and facilitate expansion and maintenance of assessment systems, we constructed a database of studies on the welfare of laying hens around the world. On the basis of this database, we devised a science based welfare assessment model. Our model includes measurements, levels and weightings based on the scientific studies in the database, and can clarify the advantages and disadvantages of housing systems for laying hens from the viewpoint of the five freedoms. We also evaluated the usefulness of our model by comparing it with environment-based Animal Needs Index (ANI), another science based model called FOWEL, and animal-based measurements. Our model showed that freedom from injury, pain and disease, and freedom from discomfort were more secure in the cage system, while non-cage systems scored better for natural behavior and freedom from fear and distress. A significant strong-positive correlation was found between the animal-based assessment and the total scores of ANI (rs = 0.94, P < 0.05), FOWEL (rs = 0.99, P < 0.05) or our model (rs = 0.99, P < 0.05), which indicate that these different approaches to welfare assessment may be used almost interchangeably to 'measure' a common property ('overall laying hen welfare'). However, assessments using our model and FOWEL were more sensitive than ANI and can be applied to cage systems, which suggest that our model and FOWEL may have added value. PMID- 21269375 TI - Behavioral indexes of piglet welfare: comparison of indoor and outdoor housing systems. AB - The purpose of this experiment was to establish behavioral indexes of piglet welfare. Forty-eight piglets were allocated to either four indoor pens or four outdoor pens (six piglets per pen). The indoor system was a commercial pen that consisted of a concrete floor and a slat floor. The outdoor system had a dirt paddock with a wooden hutch. Growth performance, salivary cortisol levels, skin lesions and behaviors of the piglets were monitored for 4 weeks. Sixteen types of behaviors were recorded by using 2-min instantaneous scan sampling for 8 h/day. Growth performance and salivary cortisol levels did not significantly differ between the two housing systems. On the other hand, skin lesions and behaviors were significantly affected by the housing system. The number of skin lesions was higher in the indoor system. In addition, piglets in the outdoor system showed more investigative and social-play behaviors than those in the indoor system. Piglets in the indoor system showed more resting, drinking, moving, fighting, and conflict behaviors than those in the outdoor system. We conclude that investigative, social-play and conflict behaviors may be effective indexes of the welfare level of piglets, especially investigative and conflict behaviors. PMID- 21269376 TI - Effect of lameness (hoof disorders) on productivity of Karan Fries crossbred cows. AB - In present study production performance of 96 lame cows was compared with 67 healthy cows. No significant effect of parity and year of calving on milk yield were observed but the effect of season of calving was significant (P < 0.01). Effect of lameness on milk yield at the second, third and fourth months and 305 days was highly significant (P < 0.01), and was also significant (P < 0.05) on lactation yield of the fifth and tenth months. The effect of lameness on monthly and 305-day milk yield was significant (P < 0.01) only for those cows diagnosed lame before calving and during the first month of lactation. The differences in mean monthly yield were highly significant (P < 0.01) at the second, third and fourth months; and significant (P < 0.05) in the first and fifth months. The loss in the first lactation month of cows which were diagnosed as lame in the second month, was found to be significant (P < 0.05). Thus the yield of the month previous to the diagnosis (sub-clinical stage) was also affected. A significant (P < 0.01) total loss of 498.95 kg of milk yield was observed during a period of 305 days. PMID- 21269377 TI - Impressions and purchasing intentions of Japanese consumers regarding pork produced by 'Ecofeed,' a trademark of food-waste or food co-product animal feed certified by the Japanese government. AB - Impressions and purchasing intentions of Japanese consumers regarding pork produced by 'Ecofeed', a trademark of food-waste or co-product animal feeds certified by the Japanese government, were investigated by a questionnaire on the Internet. 'Ecofeed' did not elicit specific impressions as compared to domestic, imported, Kurobuta (in Japan), and specific pathogen-free (SPF) pork. Purchasing intent for 'Ecofeed' pork was the second lowest of the five pork products. Knowledge and purchasing experience regarding 'Ecofeed' pork was the lowest of the five pork products. Respondents were classified into four categories according to their impressions of 'Ecofeed' pork. The largest category of respondents did not have any specific impression of 'Ecofeed' pork and had little knowledge of pork farming. A category that had a positive impression for 'Ecofeed' pork had high knowledge of the pork farming system. In order to establish 'Ecofeed' pork in Japan, our results suggest that information disclosure and education about 'Ecofeed', its certification system, environmental benefits and the current self-efficiency ratio of animal feed, are needed. PMID- 21269378 TI - Proteome analysis of whole and water-soluble proteins in masseter and semitendinosus muscles of Holstein cows. AB - To assess both quantitative and qualitative differences between the slow- and fast-type muscles, masseter (slow) and semitendinosus (fast) from four Holstein cows were analyzed by two-dimensional difference gel electrophoresis (2D DIGE) and mass spectrometry. The proteome analysis identified 27 spots as 20 proteins in the whole protein fraction extracted with 8 mol/L urea solution, and 16 spots were identified as 11 proteins in the water-soluble protein fraction. Two slow type myofibrillar proteins (myosin light chain-1 slow-b and myosin light chain-2 slow), and aconitase-2 mitochondria were present at higher levels in the masseter muscle (P < 0.05). Four fast-type myofibrillar proteins (myosin light chain-1 fast, myosin light chain-2 fast, myosin light chain-3 fast and tropomyosin-1), and three enzymes of glycolytic pathway (enolase-3, aldolase-A and triosephosphate isomerase), were present at higher levels in the semitendinosus muscle (P < 0.05). Our proteome analysis showed that the composition of sarcoplasmic proteins as well as myofibrillar proteins was clearly different between slow- and fast-type muscles. PMID- 21269379 TI - Person-centred medicine in the context of primary care: a view from the World Organization of Family Doctors (Wonca). AB - RATIONALE, AIMS AND OBJECTIVES: Most professional medical care is provided in the community, and this determines the importance of primary care for the health care system. As family doctors are involved in the care of different health problems over time to the same individual, the personal dimension is strong. This paper analyses the importance of person-centred medicine from the perspective of primary care and family medicine. METHODS: The views and opinions of the leadership of the World Organization of Family Doctors, Wonca, provided the background material. Wonca brings together national colleges and academies of family medicine around the world. RESULTS: The community, with its social, cultural and economic characteristics, is an important determinant of illness, health and disease. This shapes the personal relation between patient and family physician, with its basis of trust, and determines the effectiveness with which primary care functions. Continuity and integration of care are important person centred 'techniques'. CONCLUSIONS: As the effectiveness of primary care is a major factor for overall effective health care, it is important to come to a better understanding of how to address the personal context of care and the mechanisms through which this determines outcome of care. PMID- 21269380 TI - Hepatic ischemia-reperfusion injury and therapeutic strategies to alleviate cellular damage. AB - Warm hepatic ischemia-reperfusion injury is a significant medical problem in many clinical conditions such as liver transplantation, hepatic surgery for tumor excision, trauma and hepatic failure after hemorrhagic shock. Partial or, mostly, total interruption of hepatic blood flow is often necessary when liver surgery is performed. This interruption of blood flow is termed "warm ischemia" and upon revascularization, when molecular oxygen is reintroduced, the organ undergoes a process called "reperfusion injury" that causes deterioration of organ function. Ischemia reperfusion results in cellular damage and tissue injury associated with a complex series of events. Pathophysiological mechanisms leading to tissue injury following ischemia-reperfusion will be discussed and therapies targeted to reduce liver damage will be summarized within this review. PMID- 21269381 TI - Characterization of elevated alanine aminotransferase levels during pegylated interferon alpha-2b plus ribavirin treatment for chronic hepatitis C. AB - AIM: Elevation of alanine aminotransferase (ALT) levels during pegylated interferon (peg-IFN) plus ribavirin therapy in patients with chronic hepatitis C [CHC] is a problem that cannot be disregarded. The aim of this study is to assess the frequency and to characterize clinical parameters of this phenomenon. METHODS: Two hundred and thirty-five (235) CHC patients with genotype 1b receiving peg-IFN alpha-2b plus ribavirin therapy were analyzed. Clinical parameters that may be associated with abnormal ALT values during treatment and therapy outcomes were evaluated statistically. One hundred and sixteen (116) patients treated with peg-IFN alpha-2a plus ribavirin were also included for partial analysis. RESULTS: Abnormal ALT values during treatment were observed in 23.0% of patients. It was observed in 14.5% of those with sustained virological response (SVR) and 17.8% of those with relapse, in whom viral clearance was observed during therapy. Multivariate logistic regression analysis revealed that pretreatment ALT values, therapy outcome, and body mass index (BMI) were significant factors related to abnormal ALT values during treatment. Abnormal ALT values during treatment became normal in SVR patients at 6 months after the completion of treatment, but not in NR (non-response) patients. Mean ALT values were significantly higher at some time points during treatment in patients treated with alpha-2a when compared to those treated with alpha-2b. CONCLUSION: Abnormal ALT values during peg-IFN plus ribavirin treatment are observed relatively frequently, even in patients without detectable HCV RNA. Direct or indirect involvement of drugs is considered as one possible cause. PMID- 21269382 TI - Simple formula to predict response to peginterferon alpha2b and ribavirin combination therapy in genotype 1 chronic hepatitis C patients with high viral loads. AB - AIM: We advocate a simple formula which can conveniently predict the outcome of Peg-interferon (IFN) alpha2b and ribavirin (RBV) combination therapy for genotype 1 chronic hepatitis C (CH-C) with high viral load. METHODS: A total of 338 (group A: 230, Group B: 108) genotype 1 CH-C patients treated with Peg-IFN alfa 2b and RBV were enrolled. Clinical parameters differing significantly between sustained virological responders (SVRs) and non-SVRs in group A were categorized, then a simple formula to predict SVR was constructed and re-evaluated in group B. Another formula containing hepatitis C virus amino acid mutations/substitutions also was constructed. RESULTS: In group A, gender and HCV RNA load <1000 KIU were significant predictors of SVR by multivariate logistic regression analysis. A simple formula was constructed (formula A): male gender (point 2) + HCV RNA load <1000 KIU (3) + platelet counts >=15 * 10(4) /mm(3) (1) + age <60 (1). In group A, score (0-1) predicted SVR rate 23.8% (2-4): 48.1% and (5-7): 70.2%. According to this formula, score (0-1) predicted SVR rate 7.1% (2-4): 38.6%, and (5-7): 70.3% in group B. Information on HCV amino acid mutations/substitutions seemed to add some accuracy. CONCLUSIONS: This simple formula can be used to roughly determine, at the patients' first/second visit, the probability of response to Peg-IFN alpha2b and RBV combination therapy for genotype 1 CH-C with high viral load. PMID- 21269383 TI - Autoimmune fulminant liver failure in adults: Experience in a Japanese center. AB - AIM: After the establishment of the international criteria of autoimmune hepatitis (AIH) in 1999 and the recognition of acute onset AIH, the diagnosis of patients with fulminant type of AIH came to be made. We diagnosed autoimmune fulminant liver failure based on the criteria, and discussed the etiology of fulminant hepatitis (FH) and late onset hepatic failure (LOHF), and the characteristics of autoimmune fulminant liver failure. METHODS: We investigated the etiology of 95 consecutive adult patients with FH or LOHF admitted to our liver unit between 1990 and 2009. Clinical and biochemical features, therapies and outcomes were examined in patients with AIH after 2000. RESULTS: Of 95 patients, 85 were FH and 10 LOHF. The etiology was due to viral infections in 51.6% (hepatitis A virus in 7.4%, hepatitis B virus in 43.2% and hepatitis E virus in 1.1%), AIH in 15.8%, drug allergy-induced in 12.6%, and unknown causes in 20.0%. The rate of patients with AIH increased significantly between 2000 and 2009 compared to the rate between 1990 and 1999 (P = 0.002). In recovered patients with AIH without transplantation after 2000, coma grade was lower, alanine aminotransferase level, prothrombin time activity and alfa-fetoprotein level were higher than in the others with statistical significance. CONCLUSION: AIH is not a rare cause of FH and LOHF, and the number of patients with unknown causes would surely decrease in concert with the precise diagnosis of AIH. PMID- 21269384 TI - Clinical evaluation of liver injury in patients with acute ischemic brain stroke treated with edaravone. AB - AIM: To elucidate the etiologic factors and features of liver injury in patients with acute ischemic brain stroke who were treated with edaravone and reported by their attending physicians to have developed serious liver injury. METHODS: The present study investigated 123 patients with a verified episode of liver injury among 132 patients with serious liver injury that had been reported attributable to edaravone. RESULTS: Ischemic and/or congestive liver (70.7%) were most predominant among the etiologic factors for liver injury, and edaravone related liver injury accounted for 20.3% (25 patients). Evident liver injury (defined in the text) was found in 104 among 123 evaluated patients; 54 patients (51.9%) of the former subset showed severe liver injury (defined increases in serum aspartate and/or alanine aminotransferase levels of >=1000 IU/L and/or serum total bilirubin levels of >=5 mg/dL). Among 104 patients with evident liver injury, 65 showed recovery. Furthermore, 53 patients (51.0%) were complicated by renal disorders; all of these patients had ischemic and/or congestive liver, or severe infections. CONCLUSIONS: Edaravone was considered to be etiologic for liver injury in approximately 20% of evaluated patients. When a patient treated with edaravone developed liver injury therefore an investigation not only on edaravone but also on other potential etiologic factors (e.g. ischemic liver, congestive liver, and infection) and the quick implementation of appropriate treatments, especially for infections, revealed possible reductions in the incidences of severe liver injury and of complications by renal disorders. PMID- 21269385 TI - +49A/G polymorphism of cytotoxic T-lymphocyte antigen 4 gene in type 1 autoimmune hepatitis and primary biliary cirrhosis: A meta-analysis. AB - AIM: Recently, the associations of +49A/G polymorphisms of cytotoxic T lymphocyte antigen 4 (CTLA-4) gene with the susceptibility to type 1 autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) have been reported; however these associations are yet to be fully elucidated. This study aimed to identify the associations of CTLA-4 gene +49A/G polymorphisms with the susceptibility to type 1 AIH and PBC by using a meta-analysis. METHODS: PubMed was searched by using the following keywords: "autoimmune hepatitis AND (polymorphism OR polymorphisms)" or "primary biliary cirrhosis AND (polymorphism OR polymorphisms)". Meta-analyses of five studies including 526 patients with type 1 AIH and 631 controls and seven studies including 1500 patients with PBC and 2345 controls were performed. RESULTS: For type 1 AIH, the odds ratio (OR) of G allele was 1.26 [95% confidence interval (CI) 1.06-1.51] although G/G homozygosity was not associated with the susceptibility to type 1 AIH. On the other hand, the OR of A/A homozygosity for type 1 AIH was 0.66 (95% CI 0.50 0.86). For PBC, the OR of G allele was 1.20 (95% CI 1.06-1.34). Furthermore, G/G homozygosity was significantly associated with the susceptibility to PBC (OR 1.29, 95% CI 1.01-1.66). The OR of A/A homozygosity for PBC was 0.81 (95% CI 0.70 0.94). CONCLUSIONS: This study suggests that CTLA-4 gene +49A/G polymorphisms may be associated with the susceptibility to type 1 AIH and PBC. Especially, while G/G genotype may be associated with the susceptibility to PBC, A/A genotype may be protective against type 1 AIH and PBC. PMID- 21269386 TI - Expression profiles of miRNAs in human embryonic stem cells during hepatocyte differentiation. AB - AIM: Human embryonic stem cells (hESCs) are able to self-renew and differentiate into a variety of cell types. Although miRNAs have emerged as key regulators in the cellular process, a few studies have been reported about behaviors of miRNAs during differentiation of hESCs into a specialized cell type. Here, we demonstrate that different kinds of miRNAs may function in a lineage specific manner during the differentiation of human embryonic stem cells (hESCs). METHODS: hESCs were induced to definitive endoderm (DE) cells and further differentiated to hepatocytes. The expression levels of miRNAs were examined in hESCs, DE cells, and hepatocytes by miRNA array using 799 human miRNA probes. RESULTS: Among 387 miRNAs significantly detected, 13 and 56 miRNAs were downregulated and upregulated during transition of hESCs to DE cells, respectively, while 30 and 92 miRNAs were downregulated and upregulated during differentiation of DE cells to hepatocytes, respectively. In particular, 5, 4, and 86 miRNAs were enriched in hESCs, DE cells, and hepatocytes, respectively. Quantitative RT-PCR represented that miR-512-3p, miR-512-5p and miR-520c-3p were enriched in hESCs, miR-9*, miR-205 and miR-375 in hESC-derived DE cells, and miR 10a, miR-122 and miR-21 in hESC-derived hepatocytes. Expression patterns of lineage-specific miRNAs in the liver tissue were similar to those of hESC-derived hepatocytes. CONCLUSION: The results indicate that different kinds of miRNAs may function in a lineage-specific manner during differentiation of hESCs into a specialized cell type. PMID- 21269387 TI - Classification and characteristics of interferon-related diabetes mellitus in Japan. AB - AIM: The aim of this study was to assess the classification and clinical characteristics of interferon (IFN)-related diabetes. METHODS: Cases with IFN related diabetes in Japan were retrieved through web search engines for medical literature until July in 2009, and unreported data were obtained from the authors by letter or e-mail. RESULTS: We collected 143 cases with IFN-related diabetes consisting of 104 type 1 diabetes including 4 own cases, and 39 non-autoimmune type 2-like diabetes. We found a marked increase in IFN-related type 1 diabetes for these 3 years. In contrast, no increase was observed in IFN-related type 2 like diabetes in the literature. Polyethylene glycol (PEG)-IFN and ribavirin had been more frequently used in patients with type 1 diabetes than in patients with type 2-like diabetes. The age of diabetes onset was comparable between type 1 and type 2-like diabetes, while the ratio of male patients was higher and the latency before diabetes was shorter in type 2-like diabetes. Patients with IFN-related type 1 diabetes had HLA types susceptible to Japanese type 1 diabetic patients, and a high positive rate of GAD antibodies. CONCLUSION: Potent combination therapy with PEG-IFN and ribavirin is likely associated with the increase in IFN related type 1 diabetes. The combined measurement of GAD antibody and HLA-typing could be an effective strategy to predict the onset of type 1 diabetes associated with IFN therapy. PMID- 21269388 TI - Cowden syndrome complicated with hepatocellular carcinoma possibly originating from non-alcoholic steatohepatitis (NASH). AB - There is currently no report that has documented hepatocellular carcinoma (HCC) in a case of Cowden syndrome. Here, we present the first reported case of HCC in a 60-year-old female patient with Cowden syndrome. We diagnosed the patient using a pathognomonic criterion of the International Cowden Consortium Operational Diagnostic Criteria and performed genetic analysis. Enhanced computed tomography demonstrated a hypervascular tumor in segment VII of the liver. The patient was diagnosed with Cowden syndrome because her mucocutaneous lesions met the pathognomonic criterion. Mutational analysis confirmed a heterozygous germ line TGT->TAT transition at nucleotide 407 in exon 5 of the phosphatase and tensin homolog detected on the chromosome 10 (PTEN) gene. Needle biopsy showed a poorly differentiated HCC. We also diagnosed non-alcoholic steatohepatitis (NASH) from hepatic histological findings of Mallory's bodies and ballooning cells. PTEN deficient mice reportedly develop HCC through NASH. This is the first reported case of Cowden syndrome complicated with HCC possibly originating from NASH. PMID- 21269389 TI - Liver abscess caused by periodontal bacterial infection with Fusobacterium necrophorum. AB - Liver abscess is recognized as a life-threatening disease. However, even in recent years, approximately 50% of liver abscess cases are considered to be cryptogenic. Here, we report a case of liver abscess associated with periodontal bacterial infection by Fusobacterium necrophorum, which is commonly found in the oropharyngeal flora. A 36-year-old man presented with fever and contrast-enhanced abdominal computed tomography revealed multiple liver abscesses. F.necrophorum was isolated from oral smears, liver aspirates and blood samples. Liver abscesses caused by periodontal bacterial infection are rare, however, the incidence is expected to increase in the future, as periodontitis is extremely common and is on the rise as one of the most common chronic infections in the world. A systemic survey including periodontitis may be required for the exact diagnosis of the source of infection. PMID- 21269390 TI - Double filtration plasmapheresis in combination with interferon therapy for chronic hepatitis C. PMID- 21269391 TI - Reply from the author. PMID- 21269392 TI - What is the definition of a satisfactory erectile function after bilateral nerve sparing radical prostatectomy? AB - INTRODUCTION: Different cut-offs of the erectile function (EF) domain of the International Index of Erectile Function (IIEF) have been used as definition of postoperative EF recovery. AIM: To test the correlation between patient satisfaction and IIEF-EF domain score cut-offs. MAIN OUTCOME MEASURE: The IIEF was used to evaluate EF and satisfaction before and after bilateral nerve sparing radical prostatectomy (BNSRP). METHODS: The study included 165 consecutive patients treated with retropubic BNSRP at a single institution. All patients had normal preoperative EF (IIEF-EF >= 26) and reached an IIEF-EF >= 17 following surgery. Complete data included EF, intercourse (IS), and overall satisfaction (OS) assessed by the corresponding domains of the IIEF administered prior and after surgery. Patients were divided into three groups according to the highest IIEF-EF score reached postoperatively, namely 17-21 (group 1), 22-25 (group 2), and >= 26 (group 3). One-way analysis of variance was used to compare IIEF-OS and IIEF-IS domain scores at the time the EF end point was reached. The same analyses were repeated separately in those patients with a complete EF recovery after surgery (group 3). RESULTS: Mean preoperative IIEF-OS and IIEF-IS domain score was 8.4, 8.8, 8.7 and 11.6, 11.8, 11.9 in group 1, 2, 3, respectively (all P >= 0.3). After a mean follow-up of 26.7 months, mean postoperative IIEF-OS and IIEF IS domain scores assessed at the time of EF recovery were comparable for patients reaching an IIEF-EF of 22-25 and for patients scoring postoperatively >= 26 (8.1, 8.1, and 10.6, 11.4; all P >= 0.3). However, mean IIEF-OS and IIEF-IS domain scores of these patients were significantly higher as compared to patients reaching an IIEF-EF domain score < 22 (6.3 and 8.4, respectively; all P <= 0.006). Similar results were achieved considering only those patients (group 3) who had complete EF recovery after surgery. CONCLUSIONS: We demonstrated that in preoperatively fully potent patients treated with BNSRP a lower satisfaction is expected when an IIEF-EF cut-off of 17 is used. Conversely, no difference was found using a cut-off of 22 or 26. Therefore, our results support that a cut-off of IIEF-EF >= 22 might represent a reliable score for defining EF recovery after BNSRP. PMID- 21269393 TI - Silencing MaxiK activity in corporal smooth muscle cells initiates compensatory mechanisms to maintain calcium homeostasis. AB - INTRODUCTION: The MaxiK potassium channel is regulated by voltage and intracellular calcium, and plays a critical role in regulating intracellular calcium concentration ([Ca(2+) ](i)), which is the ultimate determinant of smooth muscle tone. Tight control of corpus cavernosum smooth muscle (CCSM) tone is critically important and misregulation can result in erectile dysfunction. AIM: Because of the tight functional linkage of MaxiK and calcium channel activity, the aim of this study was to determine the effects of silencing and pharmacological inhibition of MaxiK on calcium homeostasis and intercellular calcium signaling in CCSM cells. METHODS: We compared changes in the basal intracellular [Ca(2+) ](i) and parameters defining intercellular calcium wave (ICW) spread in 48 hours MaxiK silenced CCSM cells vs. acute blockade of the channel with iberiotoxin. To analyze changes occurring in gene expression we performed micro-array analysis following MaxiK silencing for 48 hours. MAIN OUTCOME MEASURES: Changes in Fura-2 fluorescence intensities were measured to evaluate basal [Ca(2+) ](i) levels and ICW parameters. Microarray analysis of global gene expression was performed. RESULTS: Forty-eight hours after MaxiK silencing the basal [Ca(2+) ](i) , the ICW amplitude and spread among CCSM cells were not markedly different in silenced compared to mock transfected controls, whereas short-term blockade significantly increased basal [Ca(2+) ](i) level and amplified Ca(2+) signaling among CCSM cells. Micro-array analysis showed that several genes within Ca(2+) homeostasis and smooth muscle tone regulation pathways had significantly altered expression. CONCLUSIONS: Our results indicate that while short-term blockade of the MaxiK channel is associated with an increase in basal [Ca(2+) ](i), Ca(2+) homeostasis is restored during the 48 hours period following silencing. We hypothesize that the different pathways regulating [Ca(2+) ](i) and CCSM tone are linked through molecular crosstalk and that their coordinated regulation is part of a compensatory mechanism aimed to maintain Ca(2+) homeostasis and CCSM tone. PMID- 21269394 TI - A survey of obesity and erectile dysfunction of men conscripted into the military in Taiwan. AB - INTRODUCTION: Obesity is receiving growing research attention. However, investigations concerning the potential impact of obesity and testosterone on erectile dysfunction (ED) in young men have not been completely clarified. AIM: To identify the relationship between ED, serum testosterone level, and obesity in draftees in Taiwan. METHODS: Data were obtained from a baseline survey of 364 young adult military conscripts (19-24 years old). Their demographic data, body mass index (BMI), serum testosterone, and ED status were assessed. Sixty-four subjects had ED, and 300 comprised the normal control group. MAIN OUTCOME MEASURES: The International Index of Erectile Function-5 (IIEF-5), Sexual Desire Inventory, and Sexual Behavior Scale were used to assess ED, sexual desire, and sexual function. RESULTS: Three hundred sixty-four men were available for analysis. The mean age of the sample was 21.66 +/- 0.92 years (19-24 years). The IIEF total score had a mean of 21.99 +/- 2.34 and median of 23; 64 (17.6%) subjects had ED, although mild. The results showed an increased risk of ED among obese men and subjects with lower serum testosterone. Among the predictors of ED, obesity (odds ratio =83.97, 95% CI = 16.17-436.03, degrees of freedom [d.f.] = 1, P < 0.001) and lower serum testosterone (odds ratio = 679.84, 95% CI = 108.48 4,260.58, d.f. = 1, P < 0.001) were significantly independent factors. Testosterone levels were lower in subjects with obesity (P < 0.001). CONCLUSION: This study supports the idea that BMI and serum testosterone may provide warning signs of ED and, at the same time, an opportunity for early intervention in young men. PMID- 21269395 TI - Neural supply to the clitoris: immunohistochemical study with three-dimensional reconstruction of cavernous nerve, spongious nerve, and dorsal clitoris nerve in human fetus. AB - INTRODUCTION: Little detailed information is available concerning autonomic and somatic nerve supply to the clitoris, potentially causing difficulties for nerve preservation during pelvic and perineal surgery. AIM: To identify the location and type (nitrergic, adrenergic, cholinergic and sensory) of nerve fibers in the clitoris and to provide a three-dimensional (3D) representation of their structural relationship in the human female fetus. METHODS: Serial transverse sections were obtained from five human female fetuses (18-31 weeks of gestation) and subjected to histological and immunohistochemical investigations; digitized serial sections were used to construct a 3D representation of the pelvis. MAIN OUTCOME MEASURES: Pelvic-perineal nerve location and type were evaluated qualitatively. RESULTS: The female neurovascular bundle (NVB) is the anteroinferior terminal portion of the inferior hypogastric plexus that runs along the postero-lateral then lateral face of the vagina and is rich in nNOS positive fibers. The cavernous nerve (CN) is a thin ventrocaudal collateral projection of the NVB, and this projection does not strictly follow the NVB course. The CN runs along the lateral surface of the vagina and urethra and penetrates the homolateral clitoral crus. The CN provides adrenergic, cholinergic, and nitrergic innervation to the clitoris, but not sensory innervation. The spongious nerve (SN) is the terminal and main projection of the NVB and provides nitrergic innervation to the vestibular bulbs. The dorsal clitoris nerve (DCN), somatic branche of the pudendal nerve, runs along the superior surface of the clitoral crus and body and has a segmental proerectile nitrergic activity related to communicating branches with the CN. CONCLUSIONS: "Computer-assisted anatomic dissection" allowed the identification of the precise location and distribution of the autonomic and somatic neural supply to female erectile bodies, providing an anatomical basis for nerve-sparing surgical techniques, and participating to the understanding of neurogenic female sexual dysfunction. PMID- 21269396 TI - The comparison of premature ejaculation assessment questionnaires and their sensitivity for the four premature ejaculation syndromes: results from the Turkish society of andrology sexual health survey. AB - INTRODUCTION: In addition to the previously defined "lifelong" and "acquired" premature ejaculation (PE), the existence of two more subtypes of PE, namely "natural variable PE" and "premature-like ejaculatory dysfunction," has been proposed. AIMS: To evaluate the diagnostic value of the Premature Ejaculation Diagnostic Tool (PEDT) and Arabic Index of Premature Ejaculation (AIPE) in a population-based study, in relation to their sensitivity across these four different PE syndromes and to assess the Premature Ejaculation Profile (PEP) scores of patients with lifelong, acquired, natural variable PE and premature like ejaculatory dysfunction. METHODS: Between June 2009 and December 2009, couples were randomly selected from 17 provinces of Turkey. Subjects with the complaint of ejaculating prematurely were classified as lifelong, acquired, natural variable PE, and premature-like ejaculatory dysfunction according to the medical and sexual history they described. PE status was also assessed with PEDT, AIPE and PEP. The sensitivity, specificity, positive predictive value and negative predictive value were calculated for PEDT and AIPE in the study population whereas detection rates of these two questionnaires were also compared among the four PE syndromes. Moreover, PEP scores of patients with lifelong, acquired, natural variable PE and premature-like ejaculatory dysfunction were compared. Significance level was considered as P < 0.05. MAIN OUTCOME MEASURES: Scores obtained from PEDT, AIPE, and PEP questionnaires. RESULTS: A total of 2,593 couples were enrolled where 512 (20.0%) male subjects reported PE. PEDT, AIPE, and PEP measures of the PE patients indicated worse sexual function (P < 0.001 each). Mean scores obtained from questionnaires were significantly better in patients with premature-like ejaculatory dysfunction and they were the worst in patients with acquired PE (P < 0.001 each). The sensitivity values of PEDT and AIPE were 89.3 and 89.5, whereas their specificity values were 50.5 and 39.1, respectively. There were statistically significant differences in detection rates of PEDT and AIPE among the four PE syndromes (P = 0.006 and P < 0.001). They were higher in acquired and lifelong PE and lower in premature-like ejaculatory dysfunction. CONCLUSION: PEDT and AIPE can diagnose PE with high sensitivity, especially in patients with lifelong and acquired PE. The complaint of patients with acquired PE seems to be more severe than those complaining of lifelong, natural variable PE and premature-like ejaculatory dysfunction patients. PMID- 21269397 TI - Impact of sacral neuromodulation on female sexual function and his correlation with clinical outcome and quality of life indexes: a monocentric experience. AB - INTRODUCTION: Lower urinary tract symptoms (LUTS) have a profound impact on physical, social, and sexual well-being. Sacral neuromodulation (SNM) may have a positive effect on sexuality, though few studies have so far evaluated its impact on female sexual function. AIM: To prospectively assess changes in sexual function, clinical outcome and quality of life after SNM in female patients with overactive bladder (OAB) and their possible correlation with improvement in urinary symptoms and quality of life indexes. MAIN OUTCOME MEASURES: Correlations between differences in Female Sexual Function Index (FSFI) scores and in clinical outcome and correlations between differences in FSFI, SF36, and IQoL scores were evaluated by Spearman's coefficient. Comparison between preoperative, midterm follow-up (MFU), and last follow-up (FFU) visits were performed by generalized linear model (GLM) for repeated measurements. METHODS: Between May 2003 and December 2008, 30 consecutive female patients (median age 53 years, range 35-79) with OAB underwent the two-stage procedure of SNM. Only 16 (53%) patients were considered eligible; these completed a bladder diary, the FSFI, the Status of Health questionnaire (SF36) and the Incontinence Quality of Life Index (IQoL) before implantation and on follow-up examinations. RESULTS: The results were analyzed before implantation, on MFU (median MFU 22.5 months) and on FFU (median FFU period 36.3 months). Regarding sexuality, the mean improvement in the total FSFI score was 27.9% on MFU and 29.3% on FFU. Only four patients (25%) showed a >50% improvement in global FSFI score on MFU, and 3 (25%) on FFU. A significant correlation was found between clinical improvement and improvement in sexual function. No significant correlation was found between differences in FSFI and quality of life indexes (IQoL and SF36). CONCLUSION: Our results demonstrate that improvement in the quality of sexual function in female patients with OAB correlates with improvement in urinary symptoms. PMID- 21269398 TI - Chronic paroxetine treatment does not affect sexual behavior in hormonally sub primed female rats despite 5-HT1(A) receptor desensitization. AB - INTRODUCTION: Selective serotonin reuptake inhibitors (SSRIs) cause sexual dysfunctions in humans. However, because SSRIs are used to treat depression, it is unclear whether the problems are caused by the drug, by the depression itself, or an interaction between both. AIM: The present study investigated the effects of chronic paroxetine treatment on sexual behavior in female rats. Furthermore, we tested whether 5-hydroxytryptamine (5-HT)1(A) receptors were desensitized in these females. METHODS: Ovariectomized female rats, either sub-primed with estradiol or fully primed with estradiol and progesterone, were tested in a paced mating test. Proceptive (darting and hopping), receptive (lordosis), and paced mating-related (percentages of exits and contact-return latencies) behaviors were quantified during the course of 56 days of chronic paroxetine treatment (10 mg/kg and 20 mg/kg per day). The 5-HT1(A) /5-HT7 receptor agonist (+/-)-8-hydroxy-2 (dipropylamino)tetralin hydrobromide ((+/-)8-OH-DPAT) alone and in combination with the selective 5-HT1(A) receptor antagonist WAY-100635 was administered to study putative 5-HT1(A) desensitization in the same females. MAIN OUTCOME MEASURES: Proceptive, receptive, and paced mating behaviors were quantified. RESULTS: Acute and chronic paroxetine treatment did not change proceptive and receptive behaviors in both sub-primed and fully primed female rats. In all groups, (+/-)8-OH-DPAT showed a clear dose-dependent inhibition of sexual behaviors in vehicle-treated females and a right-shifted dose-response effect in the paroxetine-treated rats. WAY-100635 attenuated the inhibiting effect of the 5 HT1(A) receptor agonist in all females. These data suggest 5-HT1(A) receptor desensitization after chronic paroxetine treatment. CONCLUSIONS: Chronic paroxetine treatment does not cause sexual side effects in sub- or fully hormonally primed female rats. Furthermore, chronic treatment causes adaptive changes in the serotonin system such as desensitization of 5-HT1(A) receptors, which may counteract the inhibiting effects of increased extracellular serotonin levels in the chronic paroxetine-treated rats. PMID- 21269399 TI - Vardenafil and resveratrol synergistically enhance the nitric oxide/cyclic guanosine monophosphate pathway in corpus cavernosal smooth muscle cells and its therapeutic potential for erectile dysfunction in the streptozotocin-induced diabetic rat: preliminary findings. AB - INTRODUCTION: Phosphodiesterase type 5 (PDE5) inhibitors are very effective agents for erectile dysfunction; however, specific patient populations are hard to treat. The efficacy of PDE5 inhibitors is limited because a minimum amount of nitric oxide (NO) is necessary. Resveratrol, a plant polyphenol, is reported to activate endothelial NO synthase (eNOS) through activation of sirtuin 1. We previously reported that human corpus cavernosal smooth muscle cells (CCSMCs) express eNOS and synthesize cyclic guanosine monophosphate (cGMP) via the NO/cGMP pathway. AIM: To investigate the ability of resveratrol and/or vardenafil to increase cGMP in an in vitro model using CCSMCs and to improve erectile function in an in vivo rat model of streptozotocin (STZ)-induced diabetes. METHODS: CCSMCs were treated with resveratrol and/or vardenafil. Twenty male Sprague-Dawley rats were randomly divided into five groups (N = 4 in each group): age-matched controls, diabetic controls, and diabetic rats treated with resveratrol, vardenafil, or both in combination for the last 4 weeks of an 8-week period of diabetes induction. MAIN OUTCOME MEASURES: Intracellular cGMP measurement, intracovernous pressure (ICP)/mean arterial pressure (MAP) ratio, and smooth muscle/collagen ratio. RESULTS: Intracellular cGMP level was elevated by resveratrol treatment in CCSMCs. The combination treatment of resveratrol and vardenafil had a synergistic effect. Diabetic rats showed impairment of erectile function. Treatment with either resveratrol or vardenafil improved ICP/MAP ratio, and combination therapy with resveratrol and vardenafil had a synergistic effect in improvement of ICP/MAP. CONCLUSIONS: Treatment with either resveratrol or vardenafil elevated cGMP level in CCSMCs and improved erectile function in STZ induced diabetic rats. Furthermore, a synergistic effect was observed in vitro and in vivo. Resveratrol or combination therapy of resveratrol and vardenafil can improve erectile function in which NO release is impaired, although further study is needed to confirm the results. PMID- 21269400 TI - Genital Chlamydia trachomatis infection is related to poor sexual quality of life in young sexually active women. AB - INTRODUCTION: Chlamydia trachomatis (Ct) genital infection has been related to several diseases in young sexually active women. It could be related to their sexual quality of life. AIM: To assess whether genital Ct infection can induce sexual function alterations in women. METHODS: Nine hundred ninety-eight women (mean age 29.4, range 18-43) attending our Sexually Transmitted Disease Centre were enrolled in this observational case-control study. All participants were clinically and microbiologically investigated due to their sexual relationships with a subject affected by chronic bacterial prostatitis. All participants underwent microbiological cultures, DNA and antibodies evaluation for common bacteria and Ct on vaginal swab and urine samples. They completed the Female Sexual Function Index [FSFI] questionnaire. On the basis of microbiological investigation results, all patients were split into three groups: Group A-genital Ct infection, Group B-genital common bacteria/yeast infection, and Group C negative for Ct and bacteria/yeast infection. MAIN OUTCOME MEASURES: FSFI questionnaire. RESULTS: Two hundred ninety-one women were classified in Group A, 276 in Group B, and 431 in Group C. Group A patients were statistically, significantly different from Group B and Group C patients in terms of pain during sexual intercourse and sexual satisfaction. Group C patients had significantly higher FSFI scores (27.1 +/- 1.3) (P < 0.001) for both desire (4.9 +/- 1.0) and lubrication domain (3.8 +/- 1.1) (P < 0.001, P < 0.003, respectively) when compared with Group A patients. Multivariate analysis demonstrated that negative Ct infection marker in female patients must be considered as an independent prognostic factor in predicting a subsequent optimal FSFI questionnaire score (P = 0.002). CONCLUSIONS: Positive values of Ct infection markers are associated with lower FSFI scores for sexual desire, lubrication, and overall sexual function. Genital Ct infection could induce pain during sexual intercourse, reducing sexual satisfaction and sexual quality of life in young sexually active women. PMID- 21269401 TI - Sildenafil promotes smooth muscle preservation and ameliorates fibrosis through modulation of extracellular matrix and tissue growth factor gene expression after bilateral cavernosal nerve resection in the rat. AB - INTRODUCTION: It has been shown that phosphodiesterase type 5 (PDE5) inhibitors preserve smooth muscle (SM) content and ameliorate the fibrotic degeneration normally seen in the corpora cavernosa after bilateral cavernosal nerve resection (BCNR). However, the downstream mechanisms by which these drugs protect the corpora cavernosa remain poorly understood. AIM: To provide insight into the mechanism, we aimed to determine the gene expression profile of angiogenesis related pathways within the penile tissue after BCNR with or without continuous sildenafil (SIL) treatment. METHODS: Five-month-old Fisher rats were subjected to BCNR or sham operation and treated with or without SIL (20 mg/kg/BW drinking water) for 3 days or 45 days (N = 8 rats per group). Total RNAs isolated from the denuded penile shaft and prostate were subjected to reverse transcription and to angiogenesis real-time-polymerase chain reaction arrays (84 genes). Changes in protein expression of selected genes such as epiregulin (EREG) and connective tissue growth factor (CTGF) were corroborated by Western blot and immunohistochemistry. MAIN OUTCOMES MEASURES: Genes modulated by BCNR and SIL treatment. RESULTS: A decreased expression of genes related to SM growth factors such as EREG, platelet-derived growth factor (PDGF), extracellular matrix regulators such as metalloproteinases 3 and 9, endothelial growth factors, together with an upregulation of pro-fibrotic genes such as CTGF and transforming growth factor beta 2 were found at both time points after BCNR. SIL treatment reversed this process by upregulating endothelial and SM growth factors and downregulating pro-fibrotic factors. SIL did not affect the expression of EREG, VEGF, and PDGF in the ventral prostate of BCNR animals. CONCLUSIONS: SIL treatment after BCNR activates genes related to SM preservation and downregulates genes related to fibrosis in the corpora cavernosa. These results provide a mechanistic justification for the use of SIL and other PDE5 inhibitors as protective therapy against corporal SM loss and fibrosis after radical prostatectomy. PMID- 21269402 TI - A phase IV prospective evaluation of the safety and efficacy of extended release testosterone pellets for the treatment of male hypogonadism. AB - INTRODUCTION: Men with hypogonadism exhibit decreased serum testosterone levels and may experience a constellation of clinical symptoms, including decrease in muscle mass, loss of sexual desire, impotence, and infertility. While previous studies have shown that implantation of extended release testosterone pellets can provide therapeutic levels of testosterone over several months, additional data are needed to establish this approach as the standard of care for male hypogonadism. AIM: To evaluate the safety and efficacy of testosterone pellets over 6 months as a treatment for male hypogonadism in a clinical practice setting. METHODS: A phase IV, single center, open-label study designed to assess the safety and efficacy of subcutaneous insertion of 8 to 12 testosterone 75 mg pellets (450 mg to 900 mg), during a single implantation procedure in hypogonadal men. Subjects who successfully completed the protocol were allowed to enroll in an extension study that included another implantation and 6 months of follow-up. MAIN OUTCOME MEASURES: Safety was determined by investigator-reported adverse events, changes in vital signs, physical exam findings, and laboratory tests. Efficacy was based on serum laboratory tests, physical exams, implantation site evaluations, and vital signs. Secondary objectives were to assess patient preference for testosterone pellets and to maintain optimal total testosterone. RESULTS: Mean testosterone significantly increased and luteinizing hormone (LH) levels significantly decreased from pre-implantation values at weeks 1, 4, and 12, and had returned to pre-implantation levels by week 24. Prostate-specific antigen levels remained unchanged for the duration of the study. Improvements in several symptoms of hypogonadism were determined with multiple questionnaires. Implanted testosterone pellets were generally well tolerated. CONCLUSION: Implanted testosterone pellets can normalize testosterone and LH levels and improve symptoms for at least 3 months and up to 6 months in men with hypogonadism, and should be considered as a therapeutic option for hypogonadal men. PMID- 21269403 TI - Versatility and HIV vulnerability: investigating the proportion of Australian gay men having both insertive and receptive anal intercourse. AB - INTRODUCTION: There is a lack of recent data on the extent to which gay men engage in insertive anal intercourse (IAI) and receptive anal intercourse (RAI). Accurate assessments of the overall risk of infection from HIV and other sexually transmitted infections (STIs) require such data because versatile men who engage in both roles have heightened vulnerability for becoming infected and infecting others. AIM: To investigate the extent to which gay men are versatile with regard to having IAI and RAI. MAIN OUTCOME MEASURES: Percentages of gay men who reported engaging in IAI, RAI, or both during the past 12 months and in their most recent sexual encounter. METHODS: Eight hundred fifty-six Australian gay men completed an online survey to retrospectively report on their sexual practices over the past 12 months. RESULTS: Of men who had anal intercourse in the past 12 months, 83% had both IAI and RAI, of whom 57% were highly versatile in that they had approximately equal numbers of partners for IAI and RAI. Of men who had anal intercourse in their most recent sexual encounter, as many as one in five (20%) had reciprocal anal intercourse, having both IAI and RAI with the same partner in a single encounter. Condom use was significantly less likely with reciprocal (38%) than nonreciprocal anal intercourse (50%; P = 0.04). While highly versatile men were less likely to know their HIV status, practices at most recent sexual encounter such as reciprocal anal intercourse and condom use were not significantly related to either their HIV status or that of their partner. CONCLUSIONS: Engaging in both IAI and RAI appears to be common among gay men. HIV/STI prevention strategies would benefit from paying attention to the implications of high rates of versatile sexual practices, particularly the tendency for condoms to be used less often when having reciprocal anal intercourse. PMID- 21269404 TI - Impact of cannabis use on male sexual health. AB - INTRODUCTION: Cannabis (marijuana) is the most widely used illicit drug globally. Given the prevalence of nonprescription illicit drug abuse, there is a growing interest in the study of its potential effects on male sexual health. In this review, we discuss the effects of cannabis on male sexual health. OBJECTIVE: In this review, we discuss the effects of cannabis on male sexual health. METHODS AND MAIN OUTCOME MEASURE: Critical review of scientific literature examining the impact of cannabis use on male sexual health. RESULTS: Studies examining the effects of cannabis use on male sexual function have been limited in both quality and quantity. Most results of these studies are conflicting and contradictory. While some did outline the beneficial effects of cannabis in enhancing erectile function, others did not. However, recent animal and in vitro studies have identified potential links between cannabis and sexual health. It appears that cannabis may actually have peripheral antagonizing effects on erectile function by stimulating specific receptors in the cavernous tissue. CONCLUSIONS: Given the prevalence of cannabis use, and the potential relationships between use and the development of potentially hazardous effects on male sexual function, we encourage renewed use of research resources to determine in-depth mechanistic knowledge, and new clinically oriented studies examining the effect of cannabis on male sexual function. PMID- 21269405 TI - A letter to the editor regarding the article by Panjari et al. PMID- 21269407 TI - Outcome of complex adult congenital heart surgery in the developing world. AB - BACKGROUND: There is scanty information on the outcome of adult congenital heart disease surgery from the developing world. METHODS: This was a retrospective chart review of the surgical outcome of 153 adults with congenital heart disease over a 5-year period. Surgical atrial septal defect closure was considered "simple" while all other surgeries were considered "complex." RESULTS: There were 102 patients in the "simple" group and 51 in the "complex" group. Only three (2%) patients had prior operations. The "complex" group had longer bypass time and cross clamp time. Intensive care unit stay, ventilation time, and inotrope administration were longer. Major complications were more common and there were two deaths in the "complex" group. Age more than 30 years, cyanosis, and New York Heart Association class more than II were predictors of longer stay in the intensive care unit. Surgical repair of Tetralogy of Fallot in adults tended to have a longer ventilation time and intensive care unit stay with a mortality of 4%. At follow up, all patients were in New York Heart Association class I or II. Improvement of the functional class with negligible adverse events was noted in both groups. CONCLUSIONS: A retrospective evaluation of 153 adults with congenital heart disease who underwent open heart surgery at a single center in India showed strikingly fewer reoperations compared with large European studies. There was a similar prevalence of complex lesions. Surgical mortality was low, and long-term functional outcome was gratifying. PMID- 21269409 TI - Children and adolescents with repaired tetralogy of fallot report quality of life similar to healthy peers. AB - OBJECTIVE: The study aims to evaluate and compare self-reported and parent proxy reported quality of life (QOL) in pediatric patients with repaired tetralogy of Fallot (TOF) and determine relationships with residual disease. DESIGN: QOL was prospectively evaluated in children/adolescents with repaired TOF and parents' proxy report using the Pediatric Quality of Life Inventory Generic Core and Cardiac Module scales. The scores were compared with published self and parent proxy-reported normative data for children considered healthy, chronically ill, and with congenital heart disease. Recent clinical data were reviewed for correlations between QOL and residual disease severity. RESULTS: Twenty child parent pairs were assessed at median age of 10.9 years (range 8.4-18.7 years). Self-report was higher than parent proxy report. Compared with peers, self reported QOL was higher than for chronically ill children (overall QOL 85 vs. 77, P= 0.007) and similar to healthy children (85 vs. 83, P= 0.44), while proxy report by parent was similar to parents of chronically ill children (overall QOL 77 vs. 74, P= 0.035). Despite moderate pulmonary regurgitation (mean 35%) and right ventricular dilation (mean 114 mL/m(2) ), 76% had a New York Heart Association class of 1, normal B-natriuretic peptide (24 pg/mL), reasonable exercise tolerance VO(2) max% predicted (mean 77%), and preserved right ventricular ejection fraction (mean 58%, range 44-80%). Overall QOL positively correlated with child's VO(2) max% predicted, when reported by child (r = 0.47, P < 0.05) and parent proxy (r = 0.63, P < 0.05). CONCLUSIONS: QOL in children/adolescents with repaired TOF is not proportional to the severity of their residual disease. Self-reported QOL appears similar to healthy peers while parent proxy reported lower QOL. For both children and parents, QOL positively correlated with the child's exercise capacity. Therefore, comprehensive follow-up should include cardiac rehabilitation and psychosocial evaluation to ensure an active lifestyle, improve health perception, and prevent later acquired heart disease. PMID- 21269408 TI - Clinical profile of the adolescent/adult Fontan survivor. AB - OBJECTIVES: The study aims to describe the clinical profile of the adult Fontan survivor and identify the worries, symptoms, and the impact of cardiac surveillance most commonly experienced. DESIGN: A descriptive, cross-sectional design was used. SETTING: The study was performed in outpatient adult and pediatric cardiology clinics in university-affiliated and private practice offices. PATIENTS: Fifty-four adolescent and adult patients with single ventricle congenital heart disease who have undergone the Fontan procedure participated in the study. The mean age was 26 +/- 9 years with 52% female and 63% Caucasian. OUTCOME MEASURES: Demographic and clinical data were obtained by a standard intake form and retrospective chart reviews. The Congenital Heart Disease TNO/AZL Adult Quality Of Life questionnaire was completed to assess worries, symptoms, and the impact of cardiac surveillance. RESULTS: The majority were single (73%), employed or full-time students (93%), with health insurance (94%), had a single left ventricle (78%), the diagnosis of tricuspid atresia or double inlet left ventricle (59%), lateral tunnel Fontan type (44%), history of arrhythmias (76%), left ventricle ejection fraction percentage >50 (66%), oxygen saturations >90% (70%), frequent headaches (50%), scoliosis (22%), varicose veins, ascites, and liver cirrhosis (46%), normal body mass index (59%), and New York Heart Association class I (48%) and II-III (52%). Primary worries related to current health (83%), job/employment (69%), ability to work, (61%) and living independently (54%). The most bothersome symptoms were shortness of breath with ambulation (69%), dizziness (61%), and palpitations (61%). CONCLUSIONS: Fontan survivors experience residua and sequelae from multiple surgical procedures and the natural disease course. Our results support the need for ongoing assessment of both physical symptoms and psychosocial concerns, and suggest the need for multiple risk factor intervention strategies that improve physical and emotional health in Fontan survivors. PMID- 21269410 TI - Congenital portosystemic venous connections and other abdominal venous abnormalities in patients with polysplenia and functionally univentricular heart disease: a case series and literature review. AB - OBJECTIVE: Published case reports suggest that congenital portosystemic venous connections (PSVC) and other abdominal venous anomalies may be relatively frequent and potentially important in patients with polysplenia syndrome. Our objective was to investigate the frequency and range of portal and other abdominal systemic venous anomalies in patients with polysplenia and inferior vena cava (IVC) interruption who underwent a cavopulmonary anastomosis procedure at our center, and to review the published literature on this topic and the potential clinical importance of such anomalies. DESIGN: Retrospective cohort study and literature review were used. RESULTS: Among 77 patients with heterotaxy, univentricular heart disease, and IVC interruption who underwent a bidirectional Glenn and/or modified Fontan procedure, pulmonary arteriovenous malformations were diagnosed in 33 (43%). Bilateral superior vena cavas were present in 42 patients (55%). Despite inadequate imaging in many patients, a partial PSVC, dual IVCs, and/or renal vein anomalies were detected in 15 patients (19%). A PSVC formed by a tortuous vessel running from the systemic venous system to the extrahepatic portal vein was found in six patients (8%). Abdominal venous anomalies other than PSVC were documented in 13 patients (16%), including nine (12%) with some form of duplicated IVC system, with a large azygous vein continuing to the superior vena cava and a parallel, contralateral IVC of similar or smaller size, and seven with renal vein anomalies. In patients with a partial PSVC or a duplicate IVC that connected to the atrium, the abnormal connection allowed right-to-left shunting. CONCLUSIONS: PSVC and other abdominal venous anomalies may be clinically important but under-recognized in patients with IVC interruption and univentricular heart disease. In such patients, preoperative evaluation of the abdominal systemic venous system may be valuable. More data are necessary to determine whether there is a pathophysiologic connection between the polysplenia variant of heterotaxy, PSVC, and cavopulmonary anastomosis-associated pulmonary arteriovenous malformations. PMID- 21269411 TI - Survival implications: hypertrophic cardiomyopathy in Noonan syndrome. AB - OBJECTIVES: To understand relationships and survival implications between structural heart disease and hypertrophic cardiomyopathy in Noonan syndrome (Noonan syndrome-HCM), we reviewed the clinical course of 138 children with Noonan syndrome diagnosed with cardiovascular abnormalities and compared survival with the 30 children with Noonan syndrome-HCM with 120 contemporaneous children with nonsyndromic HCM. METHODS: Study cohorts represent consecutive cases diagnosed at our institution 1966 through 2006. Outcomes were modeled using multiphase parametric techniques followed by multivariable regression with bagging. RESULTS: Cardiac abnormalities in Noonan syndrome: Cardiac abnormalities in the 138 Noonan syndrome children included pulmonary valve dysplasia (52%), hypertrophic cardiomyopathy (22%), atrial septal defect (20%), ventricular septal defect (10%), mitral valve dysplasia (6%), coarctation (3%), and Fallot's tetralogy (2%). Need for surgery was high but not different from children with structural defects coexisting with HCM. Overall, late survival in children with Noonan syndrome and cardiac defects was good (91 +/- 3% at 15 years), although significantly worse for those with Noonan syndrome-HCM (P < .01). Noonan syndrome HCM vs. nonsyndromic HCM: In the 30 children with Noonan syndrome-HCM, structural cardiac malformations coexisted in 18 (57%). The incidence of structural cardiac malformations in nonsyndromic HCM was instead 3/120 (2.5%, P < .001). Risk adjusted late survival was significantly worse for Noonan syndrome-HCM than for nonsyndromic HCM (P= .02). CONCLUSIONS: Noonan syndrome-HCM frequently coexists with structural cardiac malformations, whereas nonsyndromic HCM does not; their natural histories may therefore be different. Late survival is significantly worse for Noonan syndrome-HCM than nonsyndromic HCM. PMID- 21269412 TI - Diagnosis and repair of anomalous right coronary artery from pulmonary artery in a neonate. AB - We describe a case of an anomalous right coronary artery from the pulmonary artery that presented in the neonatal period with significant arrhythmias. The repair demonstrates that this can be performed safely and effectively in the neonate. PMID- 21269413 TI - Clinical features of the complete closure of the ductus arteriosus prenatally. AB - OBJECTIVE: Prenatal constriction of the ductus arteriosus associated with maternal drug ingestion was reported several decades ago. There are fewer reports of the complete closure of the ductus arteriosus; therefore, the clinical features of the latter are poorly understood. The aim of this study is to clarify the clinical features of complete ductal closure and postnatal pulmonary hypertension by performing echocardiography of the fetus. PATIENTS: We diagnosed four fetuses with complete ductal closure by performing fetal echocardiography and reviewed the prenatal and postnatal medical records of the mother and fetus. RESULTS: One mother each had bronchial asthma, ulcerative colitis, and idiopathic thrombocytopenic purpura, and they had received nonsteroidal anti-inflammatory drugs and/or corticosteroids during pregnancy. The fourth mother did not have basal disease and had not ingested any drugs. Fetal diagnosis was performed at 32 38 weeks of gestation. All fetuses had right heart dilatation with tricuspid regurgitation in the absence of any cardiac defects, and Doppler echocardiography indicated that the right ventricular pressure was elevated. Two of the fetuses had fetal hydrops, which suggested severe right heart dysfunction. All fetuses were delivered by emergent cesarean delivery. After birth, all the infants developed persistent pulmonary hypertension and required oxygen inhalation. Of these, three required mechanical ventilation, and two, nitric oxide inhalation. All infants improved within 2 weeks, and they had no neurological and cardiac complications after discharge. CONCLUSION: Right heart dilatation and severe tricuspid regurgitation in the absence of a cardiac defect in the fetus strongly suggested ductal dysfunction. Careful evaluation of ductal patency and right ventricular function can lead to precise early diagnosis and good prognosis. PMID- 21269415 TI - Residual VSD closure with an ADO II device in an infant. AB - Postoperative residual ventricular septal defects (VSDs) are often percutaneously closed using septal occluder devices. However, their use is not advisable in small infants, because of poor outcome. We describe the successful device closure of a residual muscular VSD with an Amplatzer Duct Occluder II (ADO II) device in a child weighing 4.5 kg. It appears that ADO II may be the preferable device for the closure of moderate defects in infants and small children because of its lower profile and trackability. PMID- 21269414 TI - Percutaneous edge-to-edge repair of tricuspid regurgitation in congenitally corrected transposition of the great arteries. AB - A 62-year-old woman presented with shortness of breath and NYHA III. Severe heart failure was due to reduced systolic function. The woman reported of lung edema at two times. Computed tomography scan and magnetic resonance imaging showed a congenitally corrected transposition of the great arteries (CC-TGA). Echocardiographic findings revealed a high grade tricuspid regurgitation. For treatment of the tricuspid regurgitation, we used a percutaneous approach. The Evalve MitraClip((r)) system has demonstrated feasibility and safety in the treatment of mitral regurgitation. Three months after successful tricuspid valve clipping, the patient is fine and NYHA score is reduced to grade I. PMID- 21269416 TI - Closure of tubular patent ductus arteriosus in infants and small children with the Amplatzer Vascular Plug II. AB - Percutaneous closure of a tubular patent ductus arteriosus can be challenging in the infant and small child. In this report, we describe the successful closure of tubular patent ductus arteriosus with the Amplatzer Vascular Plug II in two patients, ages 3 months and 13 months. PMID- 21269417 TI - A trileaflet "mitral valve" with three papillary muscles: brand new echocardiographic finding. AB - Congenital mitral valve malformations are rare, but are well known and described entities. Mitral valve malformations involve mitral valve apparatuses (leaflets and annulus) and subvalvar apparatuses (chordae and papillary muscle). Case reports of accessory mitral leaflets were already described, but were usually an appendix of the normal valve. We describe here a case report and present the images of a trileaflet mitral valve sustained by three papillary muscles in a young girl with subaortic stenosis. PMID- 21269418 TI - Silent double aortic arch coincidentally found during cardiac catheterization in elderly man. AB - We describe a case of an elderly man known for coronary artery disease (previous bypass surgery) hospitalized for ischemia in inferior wall. Since the operation, the patient underwent coronary angiographies. Due to the impossibility of selective engagement of left subclavian artery from femoral access, LIMA was always visualized through a right radial approach. Despite the suspicious of abnormal origin of left subclavian artery, aortic angiography was never performed. During the third angiography, the double aortic arch was coincidentally visualized by using a left Amplatz catheter. The diagnosis was confirmed by 64-slice computed tomography scan. PMID- 21269419 TI - Congenital anomalies of the mitral valve. PMID- 21269421 TI - Clinical and radiological outcome of conservative vs. surgical treatment of atraumatic degenerative rotator cuff rupture: design of a randomized controlled trial. AB - BACKGROUND: Subacromial impingement syndrome is a frequently observed disorder in orthopedic practice. Lasting symptoms and impairment may occur when a subsequent atraumatic rotator cuff rupture is also present. However, degenerative ruptures of the rotator cuff can also be observed in asymptomatic elderly individuals. Treatment of these symptomatic degenerative ruptures may be conservative or surgical. Acceptable results are reported for both treatment modalities. No evidence-based level-1 studies have been conducted so far to compare these treatment modalities. The objective of this study is to determine whether there is a difference in outcome between surgical reconstruction and conservative treatment of a degenerative atraumatic rotator cuff tendon rupture. METHODS/DESIGN: A randomized controlled trial will be conducted. Patients aged between 45 and 75 with a symptomatic atraumatic rotator cuff rupture as diagnosed by MRI will be included. Exclusion criteria are traumatic rotator cuff rupture, frozen shoulder and diabetes mellitus. Patients will be randomized into two groups. Conservative treatment includes physical therapy according to a standardized protocol, NSAIDs and, if indicated, subacromial infiltration with a local anesthetic and corticosteroids. Surgical reconstruction is performed under general anesthesia in combination with an interscalenus plexus block. An acromioplasty with reconstruction of the rotator cuff tendon is performed, as described by Rockwood et al. Measurements take place preoperatively and 6 weeks, 3 months, 6 months and 1 year postoperatively. The primary outcome measure is the Constant score. Secondary measures include both disease-specific and generic outcome measures, and an economic evaluation. Additionally, one year after inclusion a second MRI will be taken of all patients in order to determine whether extent and localization of the rupture as well as the amount of fatty degeneration are prognostic factors. DISCUSSION: Both surgical as conservative treatment of a symptomatic atraumatic rotator cuff tendon rupture is used in current practice. There is a lack of level-1 studies comparing surgical vs. conservative treatment. This randomized controlled trial has been designed to determine whether the surgical treatment of a degenerative atraumatic rotator cuff tendon rupture may lead to a better functional and radiological outcome than conservative treatment after one year of follow-up. TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NTR): NTRTC2343. PMID- 21269422 TI - Cutaneous infection by Mycobacterium haemophilum and kansasii in an IgA-deficient man. AB - BACKGROUND: The prevalence of infections by nontuberculous mycobacteria (NTM) has steadily increased over the past decades, especially in immunocompromised patients. CASE PRESENTATION: We present a patient with IgA-deficiency and mixed cutaneous infection by two slowly growing mycobacteria, Mycobacterium (M.) haemophilum and M. kansasii. CONCLUSIONS: Cutaneous M. haemophilum infections most often result from HIV or transplantation-associated immunosuppression. Rarely, M. haemophilum may also infect healthy patients or iatrogenically immunosuppressed patients without transplantation. M. kansasii is one of the most frequent NTM and large awareness exists about its involvement in human diseases. Mycobacterial diagnosis of cutaneous infections should be considered in long lasting skin lesions. PMID- 21269423 TI - Proteome sequence features carry signatures of the environmental niche of prokaryotes. AB - BACKGROUND: Prokaryotic environmental adaptations occur at different levels within cells to ensure the preservation of genome integrity, proper protein folding and function as well as membrane fluidity. Although specific composition and structure of cellular components suitable for the variety of extreme conditions has already been postulated, a systematic study describing such adaptations has not yet been performed. We therefore explored whether the environmental niche of a prokaryote could be deduced from the sequence of its proteome. Finally, we aimed at finding the precise differences between proteome sequences of prokaryotes from different environments. RESULTS: We analyzed the proteomes of 192 prokaryotes from different habitats. We collected detailed information about the optimal growth conditions of each microorganism. Furthermore, we selected 42 physico-chemical properties of amino acids and computed their values for each proteome. Further, on the same set of features we applied two fundamentally different machine learning methods, Support Vector Machines and Random Forests, to successfully classify between bacteria and archaea, halophiles and non-halophiles, as well as mesophiles, thermophiles and mesothermophiles. Finally, we performed feature selection by using Random Forests. CONCLUSIONS: To our knowledge, this is the first time that three different classification cases (domain of life, halophilicity and thermophilicity) of proteome adaptation are successfully performed with the same set of 42 features. The characteristic features of a specific adaptation constitute a signature that may help understanding the mechanisms of adaptation to extreme environments. PMID- 21269424 TI - Antimicrobial activities of the methanol extract, fractions and compounds from Ficus polita Vahl. (Moraceae). AB - BACKGROUND: Many plants of the family Moraceae are used in the treatment of infectious diseases. Ficus polita Vahl., an edible plant belonging to this family is used traditionally in case of dyspepsia, infectious diseases, abdominal pains and diarrhea. The present work was designed to assess the antimicrobial activity of the methanol extract from the roots of F. polita (FPR), as well as that of its fractions (FPR1-5) and two of the eight isolated compounds, namely euphol-3-O cinnamate (1) and (E)-3,5,4'-trihydroxy-stilbene-3,5-O-beta-D-diglucopyranoside (8). METHODS: The liquid microdilution assay was used in the determination of the minimal inhibitory concentration (MIC) and the minimal microbicidal concentration (MMC), against seven bacterial and one fungal species. RESULTS: The results of the MIC determination showed that the crude extract, fractions FPR1, FPR2 and compound 8 were able to prevent the growth of the eight tested microorganisms. Other samples showed selective activity. The lowest MIC value of 64 MUg/ml for the crude extract was recorded on 50% of the studied microbial species. The corresponding value for fractions of 32 MUg/ml was obtained on Salmonella typhi, Escherichia coli and Candida albicans ATCC strains. The MIC values recorded with compound 8 on the resistant Pseudomonas aeruginosa PA01 strain was equal to that of chloramphenicol used as reference antibiotic. CONCLUSION: The obtained results highlighted the interesting antimicrobial potency of F. polita as well as that of compound 8, and provided scientific basis for the traditional use of this taxon in the treatment of microbial infections. PMID- 21269425 TI - A patient presenting with intact sensory modalities in acute spinal cord ischemia syndrome: a case report. AB - INTRODUCTION: Acute spinal cord ischemia syndrome is a rare condition comprising a small fraction of neurovascular accidents, the majority of which occur within the cerebral circulation. The circulation of the spinal cord has several unique features that determine the clinical presentation. CASE PRESENTATION: In this case of a 67-year-old Caucasian man who came to our emergency department with sudden-onset, severe right-sided pain and bilateral upper limb weakness, an atypical pattern of sensory deficit was observed. In this case report, we review acute spinal cord ischemia syndrome and consider the pathophysiology, diagnostic measures and prognostic factors associated with patient recovery. CONCLUSION: Acute spinal cord ischemia syndrome with atypical patterns of sensory deficit is uncommon. Clinicians must consider acute spinal cord ischemia syndrome when assessing all patients with acute neck pain and focal neurological deficits; atypical presentations can present a diagnostic challenge. Current knowledge of the long-term outcome in patients with spinal cord ischemia is based on only a few small studies, some of which are discussed here. PMID- 21269426 TI - Determinants of generic drug substitution in Switzerland. AB - BACKGROUND: Since generic drugs have the same therapeutic effect as the original formulation but at generally lower costs, their use should be more heavily promoted. However, a considerable number of barriers to their wider use have been observed in many countries. The present study examines the influence of patients, physicians and certain characteristics of the generics' market on generic substitution in Switzerland. METHODS: We used reimbursement claims' data submitted to a large health insurer by insured individuals living in one of Switzerland's three linguistic regions during 2003. All dispensed drugs studied here were substitutable. The outcome (use of a generic or not) was modelled by logistic regression, adjusted for patients' characteristics (gender, age, treatment complexity, substitution groups) and with several variables describing reimbursement incentives (deductible, co-payments) and the generics' market (prices, packaging, co-branded original, number of available generics, etc.). RESULTS: The overall generics' substitution rate for 173,212 dispensed prescriptions was 31%, though this varied considerably across cantons. Poor health status (older patients, complex treatments) was associated with lower generic use. Higher rates were associated with higher out-of-pocket costs, greater price differences between the original and the generic, and with the number of generics on the market, while reformulation and repackaging were associated with lower rates. The substitution rate was 13% lower among hospital physicians. The adoption of the prescribing practices of the canton with the highest substitution rate would increase substitution in other cantons to as much as 26%. CONCLUSIONS: Patient health status explained a part of the reluctance to substitute an original formulation by a generic. Economic incentives were efficient, but with a moderate global effect. The huge interregional differences indicated that prescribing behaviours and beliefs are probably the main determinant of generic substitution. PMID- 21269428 TI - Actinomadura meyerae osteitis following wound contamination with hay in a woman in France: a case report. AB - INTRODUCTION: Mycetoma is a chronic granulomatous infection caused by environmental fungi or bacteria. It affects dermal and subcutaneous tissues, with putative contiguous extension to muscles or bones. While common in tropical and subtropical areas, mycetoma is rare in Europe. CASE PRESENTATION: We describe a case of Actinomadura meyerae osteitis in a 49-year-old Caucasian woman who suffered a tibia open fracture contaminated with hay; to the best of our knowledge the first case of autochthonous A. meyerae infection reported in France. The bacterium was cultivated from a bone biopsy. Following surgical osteosynthesis and six months of treatment with cotrimoxazole, our patient made a full recovery. CONCLUSION: Our case report suggests that A. meyerae is a potential agent of wound infection in farm workers in contact with hay. PMID- 21269430 TI - The impact of the National HIV Health Care Worker Hotline on patient care in South Africa. AB - BACKGROUND: South Africa has a huge burden of illness due to HIV infection. Many health care workers managing HIV infected patients, particularly those in rural areas and primary care health facilities, have minimal access to information resources and to advice and support from experienced clinicians. The Medicines Information Centre, based in the Division of Clinical Pharmacology at the University of Cape Town, has been running the National HIV Health Care Worker (HCW) Hotline since 2008, providing free information for HIV treatment-related queries via telephone, fax and e-mail. RESULTS: A questionnaire-based study showed that 224 (44%) of the 511 calls that were received by the hotline during the 2-month study period were patient-specific. Ninety-four completed questionnaires were included in the analysis. Of these, 72 (77%) were from doctors, 13 (14%) from pharmacists and 9 (10%) from nurses. 96% of the callers surveyed took an action based on the advice received from the National HIV HCW Hotline. The majority of actions concerned the start, dose adaption, change, or discontinuation of medicines. Less frequent actions taken were adherence and lifestyle counselling, further investigations, referring or admission of patients. CONCLUSIONS: The information provided by the National HIV HCW Hotline on patient-specific requests has a direct impact on the management of patients. PMID- 21269431 TI - Maternal thyroid function and the outcome of external cephalic version: a prospective cohort study. AB - BACKGROUND: To investigate the relation between maternal thyroid function and the outcome of external cephalic version (ECV) in breech presentation. METHODS: Prospective cohort study in 141 women (>= 35 weeks gestation) with a singleton fetus in breech. Blood samples for assessing thyroid function were taken prior to ECV. Main outcome measure was the relation between maternal thyroid function and ECV outcome indicated by post ECV ultrasound. RESULTS: ECV success rate was 77/141 (55%), 41/48 (85%) in multipara and 36/93 (39%) in primipara. Women with a failed ECV attempt had significantly higher TSH concentrations than women with a successful ECV (p < 0.001). Multiple logistic regression showed that TSH (OR: 0.52, 95% CI: 0.30-0.90), nulliparity (OR: 0.11, 95% CI: 0.03-0.36), frank breech (OR: 0.30, 95% CI: 0.10-0.93) and placenta anterior (OR: 0.31, 95% CI: 0.11-0.85) were independently related to ECV success. CONCLUSIONS: Higher TSH levels increase the risk of ECV failure. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT00516555. PMID- 21269432 TI - Refractory topiramate-induced angle-closure glaucoma in a man: a case report. AB - INTRODUCTION: Topiramate is a sulphonamide derivative indicated in the treatment of epilepsy and migraine. A known adverse affect is an idiosyncratic reaction that results in angle-closure glaucoma. We describe a patient with bilateral glaucoma related to topiramate that showed some unusual clinical features. CASE PRESENTATION: A 39-year-old Caucasian man presented with acute angle-closure glaucoma; he initially presented with intractable headaches after being treated with an escalating dose of topiramate. Clinical signs included elevated intraocular pressure that was initially refractory to treatment, shallow anterior chambers, and extensive bilateral choroidal effusions. After treatment with intravenous methylprednisolone, in conjunction with conventional glaucoma treatment, there was rapid reduction of intraocular pressure, gradual delayed resolution of the choroidal effusion and induced myopic shift; and eventually a good outcome without optic nerve damage. CONCLUSION: This case illustrates the importance of recognizing this entity in a non-ophthalmic setting and that intravenous methylprednisolone may be useful in the treatment of the condition when it is not responsive to conventional treatment. In addition, it is important to recognize that complete resolution of visual symptoms from the myopic shift may be delayed, despite normalization of intraocular pressure. PMID- 21269433 TI - Bisphenol A induces otolith malformations during vertebrate embryogenesis. AB - BACKGROUND: The plastic monomer and plasticizer bisphenol A (BPA), used for manufacturing polycarbonate plastic and epoxy resins, is produced at over 2.5 million metric tons per year. Concerns have been raised that BPA acts as an endocrine disruptor on both developmental and reproductive processes and a large body of evidence suggests that BPA interferes with estrogen and thyroid hormone signaling. Here, we investigated BPA effects during embryonic development using the zebrafish and Xenopus models. RESULTS: We report that BPA exposure leads to severe malformations of the otic vesicle. In zebrafish and in Xenopus embryos, exposure to BPA during the first developmental day resulted in dose-dependent defects in otolith formation. Defects included aggregation, multiplication and occasionally failure to form otoliths. As no effects on otolith development were seen with exposure to micromolar concentrations of thyroid hormone, 17-beta estradiol or of the estrogen receptor antagonist ICI 182,780 we conclude that the effects of BPA are independent of estrogen receptors or thyroid-hormone receptors. Na+/K+ ATPases are crucial for otolith formation in zebrafish. Pharmacological inhibition of the major Na+/K+ ATPase with ouabain can rescue the BPA-induced otolith phenotype. CONCLUSIONS: The data suggest that the spectrum of BPA action is wider than previously expected and argue for a systematic survey of the developmental effects of this endocrine disruptor. PMID- 21269434 TI - A genetic algorithm-Bayesian network approach for the analysis of metabolomics and spectroscopic data: application to the rapid identification of Bacillus spores and classification of Bacillus species. AB - BACKGROUND: The rapid identification of Bacillus spores and bacterial identification are paramount because of their implications in food poisoning, pathogenesis and their use as potential biowarfare agents. Many automated analytical techniques such as Curie-point pyrolysis mass spectrometry (Py-MS) have been used to identify bacterial spores giving use to large amounts of analytical data. This high number of features makes interpretation of the data extremely difficult We analysed Py-MS data from 36 different strains of aerobic endospore-forming bacteria encompassing seven different species. These bacteria were grown axenically on nutrient agar and vegetative biomass and spores were analyzed by Curie-point Py-MS. RESULTS: We develop a novel genetic algorithm Bayesian network algorithm that accurately identifies sand selects a small subset of key relevant mass spectra (biomarkers) to be further analysed. Once identified, this subset of relevant biomarkers was then used to identify Bacillus spores successfully and to identify Bacillus species via a Bayesian network model specifically built for this reduced set of features. CONCLUSIONS: This final compact Bayesian network classification model is parsimonious, computationally fast to run and its graphical visualization allows easy interpretation of the probabilistic relationships among selected biomarkers. In addition, we compare the features selected by the genetic algorithm-Bayesian network approach with the features selected by partial least squares-discriminant analysis (PLS-DA). The classification accuracy results show that the set of features selected by the GA BN is far superior to PLS-DA. PMID- 21269435 TI - Immunologically reactive M. leprae antigens with relevance to diagnosis and vaccine development. AB - BACKGROUND: Leprosy is a chronic infectious disease caused by Mycobacterium leprae that can manifest a wide variety of immunological and clinical outcomes ranging from potent humoral responses among borderline lepromatous (BL) and lepromatous (LL) patients to strong cellular responses among tuberculoid (TT) and borderline tuberculoid (BT) patients. Until recently, relatively little has been known about the immune responses to individual proteins of M. leprae recognized during leprosy. METHODS: The immune reactivity to a panel of 33 M. leprae recombinant proteins was evaluated among leprosy patients and controls from a high endemic area for leprosy (Goiania/GO, Central Brazil). Serum IgG responses were measured by ELISA (45 participants/group) and T cell responses (20 participants/group) were evaluated by IFN-gamma production in 24 hours whole blood cultures with antigen (whole blood assay-WBA). Study groups were newly diagnosed, untreated TT/BT and BL/LL leprosy patients classified by Ridley Jopling criteria and household contacts of BL/LL patients (HHC). Control groups were HIV-1 negative pulmonary tuberculosis patients (TB) and healthy individuals from the same endemic area (EC). In silico predictions indicated the level of identity of M. leprae proteins with homologues in other mycobacteria and the presence of T cell and B cell epitopes. RESULTS: Despite the prediction that all proteins would be reactive, 16 of 33 (48%) of the single proteins tested were immunogenic (recognized in WBA or ELISA) and seventeen were non-immunogenic (not recognized in either assay). Among the 16 immunogenic proteins, 9 were considered leprosy specific in WBA inducing cell-mediated IFN-gamma secretion from TT/BT patients and HHC. Three of these proteins were also leprosy specific in serology being recognized by serum IgG from LL/BL patients. Seven of the immunogenic proteins were not leprosy specific. CONCLUSIONS: New M. leprae antigens recognized by antibody responses of BL/LL patients and cellular responses of TT/BT leprosy patients were identified. An improved serological diagnostic test for leprosy could be developed by incorporating these IgG-reactive antigens to the current PGL-I based tests. Moreover our data indicate that the WBA is a robust, relatively simple and user friendly format for a T cell based diagnostic test. The field use of these test formats in leprosy endemic countries could contribute to early leprosy diagnosis before the development of deformities and disabilities. PMID- 21269436 TI - Gepoclu: a software tool for identifying and analyzing gene positional clusters in large-scale gene expression analysis. AB - BACKGROUND: The notion that genes are non-randomly organized within the chromosomes of eukaryotic organisms has recently received strong experimental support. Clusters of co-expressed and co-localized genes have been recognized as playing key roles in a number of functional pathways and adaptive responses including organism development, differentiation, disease states and aging. The identification of genes arranged in close proximity with each other within a particular temporal and spatial transcriptional program is anticipated to unravel possible functional links and reciprocal interactions. RESULTS: We developed a novel software tool Gepoclu (Gene Positional Clustering) that automatically selects genes based on expression values from multiple sources, including microarray, EST and qRT-PCR, and performs positional clustering. Gepoclu provides expression-based gene selection from multiple experimental sources, position based gene clustering and cluster visualization functionalities, all as parts of the same fully integrated, and interactive, package. This means rapid iterations while exploring for emergent behavior, and full programmability of the filtering and clustering steps. CONCLUSIONS: Gepoclu is a useful data-mining tool for exploring relationships among transcriptional data deriving form different sources. It provides an easy interactive environment for analyzing positional clustering behavior of co-expressed genes, and at the same time it is fully programmable, so that it can be customized and extended to support specific analysis needs. PMID- 21269437 TI - Characterization of conserved combined T and B cell epitopes in Leptospira interrogans major outer membrane proteins OmpL1 and LipL41. AB - BACKGROUND: Leptospira interrogans are bacterial pathogens of animal that cause zoonotic infections in human. Outer membrane proteins of leptospire are among the most effective antigens which can stimulate remarkable immune responses during the infection processes, and thus are currently considered leading candidate vaccine antigens. The objective of the present study is to predict and confirm major combined B and T cell epitopes of leptospiral outer membrane proteins OmpL1 and LipL41, as well as to evaluate their capacity in the induction of immune responses in BALB/c mice. RESULTS: In this study, four epitopes from OmpL1 and four from LipL41 conserved regions were evaluated for their potential utilization in leptospire vaccines. Firstly, combined B and T cell epitopes were predicted by softwares and expressed using a phage display system. OmpL1 residues 87-98 and 173-191 (OmpL187-98 and OmpL1173-191) and LipL4130-48, LipL41233-256 of LipL41 were identified as immunodominant B cell epitopes by Western blot. Epitopes OmpL1173-191, OmpL1297-320 of OmpL1 and LipL41233-256, LipL41263-282 of LipL41 were identified as immunodominant CD4+ T cell epitopes through proliferation analysis of splenocytes from recombinant OmpL1 (rOmpL1) or recombinant LipL41 (rLipL41)-immunized BALB/c (H-2d) mice. These epitopes induced responses of CD4+ T cells and Th1 (T helper cells) type cytokine responses during the infection. CONCLUSION: This work identified combined T and B cell immunodominant epitopes in outer membrane proteins OmpL1 and LipL41 of Leptospira interrogans. OmpL1173-191 of OmpL1 and LipL41233-256 of LipL41 could be useful in a vaccine against Leptospira. The findings could also contribute to the development of effective cross-protective vaccine strategies for leptospirosis. PMID- 21269438 TI - A prospective registry of emergency department patients admitted with infection. AB - BACKGROUND: Patients with infections account for a significant proportion of Emergency Department (ED) workload, with many hospital patients admitted with severe sepsis initially investigated and resuscitated in the ED. The aim of this registry is to systematically collect quality observational clinical and microbiological data regarding emergency patients admitted with infection, in order to explore in detail the microbiological profile of these patients, and to provide the foundation for a significant programme of prospective observational studies and further clinical research. METHODS/DESIGN: ED patients admitted with infection will be identified through daily review of the computerised database of ED admissions, and clinical information such as site of infection, physiological status in the ED, and components of management abstracted from patients' charts. This information will be supplemented by further data regarding results of investigations, microbiological isolates, and length of stay (LOS) from hospital electronic databases. Outcome measures will be hospital and intensive care unit (ICU) LOS, and mortality endpoints derived from a national death registry. DISCUSSION: This database will provide substantial insights into the characteristics, microbiological profile, and outcomes of emergency patients admitted with infections. It will become the nidus for a programme of research into compliance with evidence-based guidelines, optimisation of empiric antimicrobial regimens, validation of clinical decision rules and identification of outcome determinants. The detailed observational data obtained will provide a solid baseline to inform the design of further controlled trials planned to optimise treatment and outcomes for emergency patients admitted with infections. PMID- 21269439 TI - Genomic value prediction for quantitative traits under the epistatic model. AB - BACKGROUND: Most quantitative traits are controlled by multiple quantitative trait loci (QTL). The contribution of each locus may be negligible but the collective contribution of all loci is usually significant. Genome selection that uses markers of the entire genome to predict the genomic values of individual plants or animals can be more efficient than selection on phenotypic values and pedigree information alone for genetic improvement. When a quantitative trait is contributed by epistatic effects, using all markers (main effects) and marker pairs (epistatic effects) to predict the genomic values of plants can achieve the maximum efficiency for genetic improvement. RESULTS: In this study, we created 126 recombinant inbred lines of soybean and genotyped 80 makers across the genome. We applied the genome selection technique to predict the genomic value of somatic embryo number (a quantitative trait) for each line. Cross validation analysis showed that the squared correlation coefficient between the observed and predicted embryo numbers was 0.33 when only main (additive) effects were used for prediction. When the interaction (epistatic) effects were also included in the model, the squared correlation coefficient reached 0.78. CONCLUSIONS: This study provided an excellent example for the application of genome selection to plant breeding. PMID- 21269440 TI - A blue native-PAGE analysis of membrane protein complexes in Clostridium thermocellum. AB - BACKGROUND: Clostridium thermocellum is a Gram-positive thermophilic anaerobic bacterium with the unusual capacity to convert cellulosic biomass into ethanol and hydrogen. Identification and characterization of protein complexes in C. thermocellum are important toward understanding its metabolism and physiology. RESULTS: A two dimensional blue native/SDS-PAGE procedure was developed to separate membrane protein complexes of C. thermocellum. Proteins spots were identified by MALDI-TOF/TOF Mass spectrometry. 24 proteins were identified representing 13 distinct protein complexes, including several putative intact complexes. Interestingly, subunits of both the F1-F0-ATP synthase and the V1-V0 ATP synthase were detected in the membrane sample, indicating C. thermocellum may use alternative mechanisms for ATP generation. CONCLUSION: Two dimensional blue native/SDS-PAGE was used to detect membrane protein complexes in C. thermocellum. More than a dozen putative protein complexes were identified, revealing the simultaneous expression of two sets of ATP synthase. The protocol developed in this work paves the way for further functional characterization of these protein complexes. PMID- 21269441 TI - Theoretical basis to measure the impact of short-lasting control of an infectious disease on the epidemic peak. AB - BACKGROUND: While many pandemic preparedness plans have promoted disease control effort to lower and delay an epidemic peak, analytical methods for determining the required control effort and making statistical inferences have yet to be sought. As a first step to address this issue, we present a theoretical basis on which to assess the impact of an early intervention on the epidemic peak, employing a simple epidemic model. METHODS: We focus on estimating the impact of an early control effort (e.g. unsuccessful containment), assuming that the transmission rate abruptly increases when control is discontinued. We provide analytical expressions for magnitude and time of the epidemic peak, employing approximate logistic and logarithmic-form solutions for the latter. Empirical influenza data (H1N1-2009) in Japan are analyzed to estimate the effect of the summer holiday period in lowering and delaying the peak in 2009. RESULTS: Our model estimates that the epidemic peak of the 2009 pandemic was delayed for 21 days due to summer holiday. Decline in peak appears to be a nonlinear function of control-associated reduction in the reproduction number. Peak delay is shown to critically depend on the fraction of initially immune individuals. CONCLUSIONS: The proposed modeling approaches offer methodological avenues to assess empirical data and to objectively estimate required control effort to lower and delay an epidemic peak. Analytical findings support a critical need to conduct population wide serological survey as a prior requirement for estimating the time of peak. PMID- 21269442 TI - Acute/subacute cerebral infarction (ASCI) in HIV-negative adults with cryptococcal meningoencephalitis (CM): a MRI-based follow-up study and a clinical comparison to HIV-negative CM adults without ASCI. AB - BACKGROUND: Acute/subacute cerebral infarction (ASCI) in HIV-negative cryptococcal meningoencephalitis (CM) adults has rarely been examined by a series of MRI-based follow-up study. We studied a series of MRI follow-up study of CM adults and compared the clinical characters of those with ASCI and those without ASCI. METHODS: The clinical characteristics and a series of brain MRI findings of seven CM adults with ASCI were enrolled for analysis. The clinical characteristics of another 30 HIV-negative CM adults who did not have ASCI were also included for a comparative analysis. RESULTS: The seven HIV-negative CM adults with ASCI were four men and three women, aged 46-78 years. Lacunar infarction was the type of ASCI, and 86% (6/7) of the ACSI were multiple infarctions distributed in both the anterior and posterior cerebrovascular territories. The seven CM patients with ASCI were significantly older and had a higher rate of DM and previous stroke than the other 30 CM adults without ASCI. They also had a higher incidence of consciousness disturbance at presentation and had a poor prognosis. CONCLUSION: ASCI was found in 18.9% (7/37) of HIV-negative CM adults. Serial MRI follow-up studies may allow a better delineation of ASCI in this specific group of infectious disease and multiple lacunar infarctions was the most common type. Older in age and presence of DM and previous stroke were the significant underlying conditions. CM patients with ASCI also had a poor therapeutic outcome. PMID- 21269443 TI - Peripheral blood and neuropsychological markers for the onset of action of antidepressant drugs in patients with Major Depressive Disorder. AB - BACKGROUND: In Major Depressive Disorder (MDD), treatment outcomes with currently available strategies are often disappointing. Therefore, it is sensible to develop new strategies to increase remission rates in acutely depressed patients. Many studies reported that true drug response can be observed within 14 days (early improvement) of antidepressant treatment. The identical time course of symptom amelioration after early improvement in patients treated with antidepressants of all classes or with placebo strongly suggests a common biological mechanism, which is not specific for a particular antidepressant medication. However, the biology underlying early improvement and final treatment response is not understood and there is no established biological marker as yet, which can predict treatment response for the individual patient before initiation or during the course of antidepressant treatment. Peripheral blood markers and executive functions are particularly promising candidates as markers for the onset of action and thus the prediction of final treatment outcome in MDD. METHODS/DESIGN: The present paper presents the rationales, objectives and methods of a multi-centre study applying close-meshed repetitive measurements of peripheral blood and neuropsychological parameters in patients with MDD and healthy controls during a study period of eight weeks for the identification of biomarkers for the onset of antidepressants' action in patients with MDD. Peripheral blood parameters and depression severity are assessed in weekly intervals from baseline to week 8, executive performance in bi-weekly intervals. Patients are participating in a randomized controlled multi-level clinical trial, healthy controls are matched according to mean age, sex and general intelligence. DISCUSSION: This investigation will help to identify a biomarker or a set of biomarkers with decision-making quality in the treatment of MDD in order to increase the currently disappointing remission rates of antidepressant treatment. PMID- 21269444 TI - In planta expression of A. cellulolyticus Cel5A endocellulase reduces cell wall recalcitrance in tobacco and maize. AB - The glycoside hydrolase family 5 endocellulase, E1 (Cel5A), from Acidothermus cellulolyticus was transformed into both Nicotiana tabacum and Zea mays with expression targeted to the cell wall under a constitutive promoter. Here we explore the possibility that in planta expression of endocellulases will allow these enzymes to access their substrates during cell wall construction, rendering cellulose more amenable to pretreatment and enzyme digestion. Tobacco and maize plants were healthy and developed normally compared with the wild type (WT). After thermochemical pretreatment and enzyme digestion, transformed plants were clearly more digestible than WT, requiring lower pretreatment severity to achieve comparable conversion levels. Furthermore, the decreased recalcitrance was not due to post-pretreatment residual E1 activity and could not be reproduced by the addition of exogenous E1 to the biomass prior to pretreatment, indicating that the expression of E1 during cell wall construction altered the inherent recalcitrance of the cell wall. PMID- 21269445 TI - Branch facial nerve trauma after superficial temporal artery biopsy: a case report. AB - INTRODUCTION: Giant cell arteritis is an emergency requiring prompt diagnosis and treatment. Superficial temporal artery biopsy is the gold diagnostic standard. Complications are few and infrequent; however, facial nerve injury has been reported, leaving an untoward cosmetic outcome. This case report is to the best of our knowledge only the fourth one presented in the available literature so far regarding facial nerve injury from superficial temporal artery biopsy. CASE PRESENTATION: A 73-year-old Caucasian woman presented for neurological evaluation regarding eyebrow and facial asymmetry after a superficial temporal artery biopsy for presumptive giant cell arteritis-induced cephalalgia. CONCLUSION: Damage to branches of the facial nerve may occur after superficial temporal artery biopsy, resulting in eyebrow droop. Although an uncommon and sparsely reported complication, all clinicians of various specialties involved in the care of these patients should be aware of this given the gravity of giant cell arteritis and the widespread use of temporal artery biopsy. PMID- 21269446 TI - Are the health messages in schoolbooks based on scientific evidence? A descriptive study. AB - BACKGROUND: Most textbooks contains messages relating to health. This profuse information requires analysis with regards to the quality of such information. The objective was to identify the scientific evidence on which the health messages in textbooks are based. METHODS: The degree of evidence on which such messages are based was identified and the messages were subsequently classified into three categories: Messages with high, medium or low levels of evidence; Messages with an unknown level of evidence; and Messages with no known evidence. RESULTS: 844 messages were studied. Of this total, 61% were classified as messages with an unknown level of evidence. Less than 15% fell into the category where the level of evidence was known and less than 6% were classified as possessing high levels of evidence. More than 70% of the messages relating to "Balanced Diets and Malnutrition", "Food Hygiene", "Tobacco", "Sexual behaviour and AIDS" and "Rest and ergonomics" are based on an unknown level of evidence. "Oral health" registered the highest percentage of messages based on a high level of evidence (37.5%), followed by "Pregnancy and newly born infants" (35%). Of the total, 24.6% are not based on any known evidence. Two of the messages appeared to contravene known evidence. CONCLUSION: Many of the messages included in school textbooks are not based on scientific evidence. Standards must be established to facilitate the production of texts that include messages that are based on the best available evidence and which can improve children's health more effectively. PMID- 21269447 TI - Thermostable endoglucanases in the liquefaction of hydrothermally pretreated wheat straw. AB - BACKGROUND: Thermostable enzymes have several benefits in lignocellulose processing. In particular, they potentially allow the use of increased substrate concentrations (because the substrate viscosity decreases as the temperature increases), resulting in improved product yields and reduced capital and processing costs. A short pre-hydrolysis step at an elevated temperature using thermostable enzymes aimed at rapid liquefaction of the feedstock is seen as an attractive way to overcome the technical problems (such as poor mixing and mass transfer properties) connected with high initial solid loadings in the lignocellulose to ethanol process. RESULTS: The capability of novel thermostable enzymes to reduce the viscosity of high-solid biomass suspensions using a real time viscometric measurement method was investigated. Heterologously expressed enzymes from various thermophilic organisms were compared for their ability to liquefy the lignocellulosic substrate, hydrothermally pretreated wheat straw. Once the best enzymes were identified, the optimal temperatures for these enzymes to decrease substrate viscosity were compared. The combined hydrolytic properties of the thermostable preparations were tested in hydrolysis experiments. The studied mixtures were primarily designed to have good liquefaction potential, and therefore contained an enhanced proportion of the key liquefying enzyme, EGII/Cel5A. CONCLUSIONS: Endoglucanases were shown to have a superior ability to rapidly reduce the viscosity of the 15% (w/w; dry matter) hydrothermally pretreated wheat straw. Based on temperature profiling studies, Thermoascus aurantiacus EGII/Cel5A was the most promising enzyme for biomass liquefaction. Even though they were not optimized for saccharification, many of the thermostable enzyme mixtures had superior hydrolytic properties compared with the commercial reference enzymes at 55 degrees C. PMID- 21269448 TI - Extensive central nervous system involvement in Merkel cell carcinoma: a case report and review of the literature. AB - INTRODUCTION: Merkel cell carcinoma is a rare malignant cutaneous neoplasm that is locally invasive and frequently metastasizes to lymph nodes, liver, lungs, bone and brain. The incidence of Merkel cell carcinoma has increased in the past three decades. CASE PRESENTATION: A 65-year-old Caucasian man presented with a sudden onset of severe headache and a three-month history of balance disturbance. Magnetic resonance imaging revealed a large meningeal metastasis. The radiologic workup showed retroperitoneal and inguinal lymph node metastases. Biopsy of the inguinal lymph nodes showed metastases of Merkel cell carcinoma. Biopsy from three different suspected skin lesions revealed no Merkel cell carcinoma, and the primary site of Merkel cell carcinoma remained unknown. Leptomeningeal metastases, new axillary lymph node metastases, and intraspinal (epidural and intradural) metastases were detected within six, seven and eight months, respectively, from the start of symptoms despite treating the intracranial metastasis with gamma knife and the abdominal metastases with surgical dissection and external radiotherapy. This indicates the aggressive nature of the disease. CONCLUSION: To the best of our knowledge, this is the first report in the literature of an intracranial meningeal metastasis of Merkel cell carcinoma treated with gamma knife and of intraspinal intradural metastases of Merkel cell carcinoma. Despite good initial response to radiotherapy, recurrence and occurrence of new metastases are common in Merkel cell carcinoma. PMID- 21269449 TI - In silico quantitative structure-activity relationship studies on P-gp modulators of tetrahydroisoquinoline-ethyl-phenylamine series. AB - BACKGROUND: Multidrug resistance (MDR) is a major obstacle in cancer chemotherapy. The drug efflux by a transport protein is the main reason for MDR. In humans, MDR mainly occurs when the ATP-binding cassette (ABC) family of proteins is overexpressed simultaneously. P-glycoprotein (P-gp) is most commonly associated with human MDR; it utilizes energy from adenosine triphosphate (ATP) to transport a number of substrates out of cells against concentration gradients. By the active transport of substrates against concentration gradients, intracellular concentrations of substrates are decreased. This leads to the cause of failure in cancer chemotherapy. RESULTS: Herein, we report Topomer CoMFA (Comparative Molecular Field Analysis) and HQSAR (Hologram Quantitative Structure Activity Relationship) models for third generation MDR modulators. The Topomer CoMFA model showed good correlation between the actual and predicted values for training set molecules. The developed model showed cross validated correlation coefficient (q2) = 0.536 and non-cross validated correlation coefficient (r2) = 0.975 with eight components. The best HQSAR model (q2 = 0.777, r2 = 0.956) with 5 8 atom counts was used to predict the activity of test set compounds. Both models were validated using test set compounds, and gave a good predictive values of 0.604 and 0.730. CONCLUSIONS: The contour map near R1 indicates that substitution of a bulkier and polar group to the ortho position of the benzene ring enhances the inhibitory effect. This explains why compounds with a nitro group have good inhibitory potency. Molecular fragment analyses shed light on some essential structural and topological features of third generation MDR modulators. Fragments analysis showed that the presence of tertiary nitrogen, a central phenyl ring and an aromatic dimethoxy group contributed to the inhibitory effect. Based on contour map information and fragment information, five new molecules with variable R1 substituents were designed. The activity of these designed molecules was predicted by the Topomer CoMFA and HQSAR models. The novel compounds showed higher potency than existing compounds. PMID- 21269450 TI - Transcriptome profile analysis of flowering molecular processes of early flowering trifoliate orange mutant and the wild-type [Poncirus trifoliata (L.) Raf.] by massively parallel signature sequencing. AB - BACKGROUND: After several years in the juvenile phase, trees undergo flowering transition to become mature (florally competent) trees. This transition depends on the balanced expression of a complex network of genes that is regulated by both endogenous and environmental factors. However, relatively little is known about the molecular processes regulating flowering transition in woody plants compared with herbaceous plants. RESULTS: Comparative transcript profiling of spring shoots after self-pruning was performed on a spontaneously early flowering trifoliate orange mutant (precocious trifoliate orange, Poncirus trifoliata) with a short juvenile phase and the wild-type (WT) tree by using massively parallel signature sequencing (MPSS). A total of 16,564,500 and 16,235,952 high quality reads were obtained for the WT and the mutant (MT), respectively. Interpretation of the MPSS signatures revealed that the total number of transcribed genes in the MT (31,468) was larger than in the WT (29,864), suggesting that newly initiated transcription occurs in the MT. Further comparison of the transcripts revealed that 2735 genes had more than twofold expression difference in the MT compared with the WT. In addition, we identified 110 citrus flowering-time genes homologous with known elements of flowering-time pathways through sequencing and bioinformatics analysis. These genes are highly conserved in citrus and other species, suggesting that the functions of the related proteins in controlling reproductive development may be conserved as well. CONCLUSION: Our results provide a foundation for comparative gene expression studies between WT and precocious trifoliate orange. Additionally, a number of candidate genes required for the early flowering process of precocious trifoliate orange were identified. These results provide new insight into the molecular processes regulating flowering time in citrus. PMID- 21269451 TI - Synopsis and meta-analysis of genetic association studies in osteoporosis for the focal adhesion family genes: the CUMAGAS-OSTEOporosis information system. AB - BACKGROUND: Focal adhesion (FA) family genes have been studied as candidate genes for osteoporosis, but the results of genetic association studies (GASs) are controversial. To clarify these data, a systematic assessment of GASs for FA genes in osteoporosis was conducted. METHODS: We developed Cumulative Meta Analysis of GAS-OSTEOporosis (CUMAGAS-OSTEOporosis), a web-based information system that allows the retrieval, analysis and meta-analysis (for allele contrast, recessive, dominant, additive and codominant models) of data from GASs on osteoporosis with the capability of update. GASs were identified by searching the PubMed and HuGE PubLit databases. RESULTS: Data from 72 studies involving 13 variants of 6 genes were analyzed and catalogued in CUMAGAS-OSTEOporosis. Twenty two studies produced significant associations with osteoporosis risk under any genetic model. All studies were underpowered (<50%). In four studies, the controls deviated from the Hardy-Weinberg equilibrium. Eight variants were chosen for meta-analysis, and significance was shown for the variants collagen, type I, alpha1 (COL1A1) G2046T (all genetic models), COL1A1 G-1997T (allele contrast and dominant model) and integrin beta-chain beta3 (ITGB3) T176C (recessive and additive models). In COL1A1 G2046T, subgroup analysis has shown significant associations for Caucasians, adults, females, males and postmenopausal women. A differential magnitude of effect in large versus small studies (that is, indication of publication bias) was detected for the variant COL1A1 G2046T. CONCLUSION: There is evidence of an implication of FA family genes in osteoporosis. CUMAGAS-OSTEOporosis could be a useful tool for current genomic epidemiology research in the field of osteoporosis. PMID- 21269452 TI - Pre-processing and differential expression analysis of Agilent microRNA arrays using the AgiMicroRna Bioconductor library. AB - BACKGROUND: The main research tool for identifying microRNAs involved in specific cellular processes is gene expression profiling using microarray technology. Agilent is one of the major producers of microRNA arrays, and microarray data are commonly analyzed by using R and the functions and packages collected in the Bioconductor project. However, an analytical package that integrates the specific characteristics of microRNA Agilent arrays has been lacking. RESULTS: This report presents the new bioinformatic tool AgiMicroRNA for the pre-processing and differential expression analysis of Agilent microRNA array data. The software is implemented in the open-source statistical scripting language R and is integrated in the Bioconductor project (http://www.bioconductor.org) under the GPL license. For the pre-processing of the microRNA signal, AgiMicroRNA incorporates the robust multiarray average algorithm, a method that produces a summary measure of the microRNA expression using a linear model that takes into account the probe affinity effect. To obtain a normalized microRNA signal useful for the statistical analysis, AgiMicroRna offers the possibility of employing either the processed signal estimated by the robust multiarray average algorithm or the processed signal produced by the Agilent image analysis software. The AgiMicroRNA package also incorporates different graphical utilities to assess the quality of the data. AgiMicroRna uses the linear model features implemented in the limma package to assess the differential expression between different experimental conditions and provides links to the miRBase for those microRNAs that have been declared as significant in the statistical analysis. CONCLUSIONS: AgiMicroRna is a rational collection of Bioconductor functions that have been wrapped into specific functions in order to ease and systematize the pre-processing and statistical analysis of Agilent microRNA data. The development of this package contributes to the Bioconductor project filling the gap in microRNA array data analysis. PMID- 21269453 TI - Human resources for health and burden of disease: an econometric approach. AB - BACKGROUND: The effect of health workers on health has been proven to be important for various health outcomes (e.g. mortality, coverage of immunisation or skilled birth attendants). The study aim of this paper is to assess the relationship between health workers and disability-adjusted life years (DALYs), which represents a much broader concept of health outcome, including not only mortality but also morbidity. METHODS: Cross-country multiple regression analyses were undertaken, with DALYs and DALYs disaggregated according to the three different groups of diseases as the dependent variable. Aggregate health workers and disaggregate physicians, nurses, and midwives were included as independent variables, as well as a variable accounting for the skill mix of professionals. The analysis also considers controlling for the effects of income, income distribution, percentage of rural population with access to improved water source, and health expenditure. RESULTS: This study presents evidence of a statistically negative relationship between the density of health workers (especially physicians) and the DALYs. An increase of one unit in the density of health workers per 1000 will decrease, on average, the total burden of disease between 1% and 3%. However, in line with previous findings in the literature, the density of nurses and midwives could not be said to be statistically associated to DALYs. CONCLUSIONS: If countries increase their health worker density, they will be able to reduce significantly their burden of disease, especially the burden associated to communicable diseases. This study represents supporting evidence of the importance of health workers for health. PMID- 21269454 TI - Detection of silent myocardial ischemia in asymptomatic patients with diabetes: results of a randomized trial and meta-analysis assessing the effectiveness of systematic screening. AB - BACKGROUND: Most guidelines recommend a systematic screening of asymptomatic high risk patients with diabetes for silent ischemia, but the clinical benefit of this strategy has not been demonstrated compared with the simple control of cardiovascular risk factors. We sought to determine whether referring asymptomatic diabetic patients for screening of silent ischemia decreases the risk of cardiovascular events compared with usual care. METHODS: DYNAMIT was a prospective, randomized, open, blinded end-point multicenter trial run between 2000 and 2005, with a 3.5 year mean follow-up in ambulatory care in 45 French hospitals. The study included 631 male and female with diabetes aged 63.9 +/- 5.1 years, with no evidence of coronary artery disease and at least 2 additional cardiovascular risk factors, receiving appropriate medical treatment. The patients were randomized centrally to either screening for silent ischemia using a bicycle exercise test or Dipyridamole Single Photon Emission Computed Tomography (N = 316), or follow-up without screening (N = 315). The main study end point was time to death from all causes, non-fatal myocardial infarction, non fatal stroke, or heart failure requiring hospitalization or emergency service intervention. The results of a meta-analysis of DYNAMIT and DIAD, a similar study, are also presented. RESULTS: The study was discontinued prematurely because of difficulties in recruitment and a lower-than expected event rate. Follow-up was complete for 98.9% patients regarding mortality and for 97.5% regarding the main study end point. Silent ischemia detection procedure was positive or uncertain in 68 (21.5%) patients of the screening group. There was no significant difference between the screening and the usual care group for the main outcome (hazard ratio = 1.00 95%CI 0.59 to 1.71). The meta-analysis of these and DIAD results gave similar results, with narrower confidence intervals for each endpoint. CONCLUSIONS: These results suggest that the systematic detection of silent ischemia in high-risk asymptomatic patients with diabetes is unlikely to provide any major benefit on hard outcomes in patients whose cardiovascular risk is controlled by an optimal medical treatment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00627783. PMID- 21269455 TI - Analysis on the clinical features of 22 basaloid squamous cell carcinoma of the lung. AB - BACKGROUND: Basaloid squamous cell carcinoma of the lung is a rare and highly malignant tumor mostly observed in the proximal bronchi. Basaloid squamous cell carcinoma of the lung cases typically show rapid clinical progression, very poor prognosis and special pathological morphology. This project aimed to examine the clinical features of basaloid squamous cell carcinoma of the lung and the factors related to its prognosis; and to compare survival outcomes between basaloid squamous cell carcinoma and poorly differentiated squamous cell carcinomas (PDSC). METHODS: Between January 2004 and December 2008, pathological sections from basaloid squamous cell carcinoma and PDSC of the lung were collected and retrospectively analyzed at Tianjin Medical University Cancer Institute and Hospital. Data analysis was performed using Statistical Package for the Social Sciences (SPSS11.0). The Kaplan-Meier method was used to calculate the survival rate. Log-rank test was used to compare the differences in survival rate between the two groups. The factors influencing prognosis were analyzed using the Cox proportional hazard model. RESULTS: A total of 120 pathological sections were used in the analysis of this study-22 from basaloid squamous cell carcinoma cases and 98 from PDSC cases. Compared to the PDSC group, the basaloid squamous cell carcinoma group had a larger proportion of female patients (p = 0.001); however it had higher proportion of male smokers (p = 0.003). There were no statistically significant differences in survival rate between the two groups (chi2 = 1.200, p = 0.273). Additionally, prognosis of basaloid squamous cell carcinoma is significantly influenced by treatment mode and clinical stages of the tumor. The post-operation mortality hazard of patients treated with a combination chemotherapy and radiotherapy was 1.296 times higher than other treatment modes (p = 0.025). Increases in post-operation mortality hazard ratio were also associated with more advanced clinical stage of tumors (chi2 trend = 11.907, p = 0.000). CONCLUSIONS: This study demonstrated that basaloid squamous cell carcinoma and PDSC have very similar clinical features, and there are no significant differences in survival rates between the two groups. Hence, we conclude that in the short term, the same clinical treatments and therapeutic modes can be administered to patients with basaloid squamous cell carcinoma and PDSC of the lung. PMID- 21269456 TI - Japanese encephalitis Virus wild strain infection suppresses dendritic cells maturation and function, and causes the expansion of regulatory T cells. AB - BACKGROUND: Japanese encephalitis (JE) caused by Japanese encephalitis virus (JEV) accounts for acute illness and death. However, few studies have been conducted to unveil the potential pathogenesis mechanism of JEV. Dendritic cells (DCs) are the most prominent antigen-presenting cells (APCs) which induce dual humoral and cellular responses. Thus, the investigation of the interaction between JEV and DCs may be helpful for resolving the mechanism of viral escape from immune surveillance and JE pathogenesis. RESULTS: We examined the alterations of phenotype and function of DCs including bone marrow-derived DCs (bmDCs) in vitro and spleen-derived DCs (spDCs) in vivo due to JEV P3 wild strain infection. Our results showed that JEV P3 infected DCs in vitro and in vivo. The viral infection inhibited the expression of cell maturation surface markers (CD40, CD80 and CD83) and MHCI, and impaired the ability of P3-infected DCs for activating allogeneic naive T cells. In addition, P3 infection suppressed the expression of interferon (IFN)-alpha and tumor necrosis factor (TNF)-alpha but enhanced the production of chemokine (C-C motif) ligand 2 (CCL2) and interleukin (IL)-10 of DCs. The infected DCs expanded the population of CD4+ Foxp3+ regulatory T cell (Treg). CONCLUSION: JEV P3 infection of DCs impaired cell maturation and T cell activation, modulated cytokine productions and expanded regulatory T cells, suggesting a possible mechanism of JE development. PMID- 21269457 TI - Tyrosine phosphorylation of tau by the SRC family kinases lck and fyn. AB - BACKGROUND: Tau protein is the principal component of the neurofibrillary tangles found in Alzheimer's disease, where it is hyperphosphorylated on serine and threonine residues, and recently phosphotyrosine has been demonstrated. The Src family kinase Fyn has been linked circumstantially to the pathology of Alzheimer's disease, and shown to phosphorylate Tyr18. Recently another Src family kinase, Lck, has been identified as a genetic risk factor for this disease. RESULTS: In this study we show that Lck is a tau kinase. In vitro, comparison of Lck and Fyn showed that while both kinases phosphorylated Tyr18 preferentially, Lck phosphorylated other tyrosines somewhat better than Fyn. In co-transfected COS-7 cells, mutating any one of the five tyrosines in tau to phenylalanine reduced the apparent level of tau tyrosine phosphorylation to 25 40% of that given by wild-type tau. Consistent with this, tau mutants with only one remaining tyrosine gave poor phosphorylation; however, Tyr18 was phosphorylated better than the others. CONCLUSIONS: Fyn and Lck have subtle differences in their properties as tau kinases, and the phosphorylation of tau is one mechanism by which the genetic risk associated with Lck might be expressed pathogenically. PMID- 21269458 TI - The Simple Triage Scoring System (STSS) successfully predicts mortality and critical care resource utilization in H1N1 pandemic flu: a retrospective analysis. AB - INTRODUCTION: Triage protocols are only initiated when it is apparent that resource deficits will occur across a broad geographical area despite efforts to expand or acquire additional capacity. Prior to the pandemic the UK Department of Health (DOH) recommended the use of a staged triage plan incorporating Sepsis related Organ Failure Assessment (SOFA) developed by the Ontario Ministry of Health to assist in the triage of critical care admissions and discharges during an influenza outbreak in the UK. There are data to suggest that had it been used in the recent H1N1 pandemic it may have led to inappropriate limitation of therapy if surge capacity had been overwhelmed. METHODS: We retrospectively reviewed the performance of the Simple Triage Scoring System (STSS) as an indicator of the utilization of hospital resources in adult patients with confirmed H1N1 admitted to a university teaching hospital. Our aim was to compare it against the staged initial SOFA score process with regards to mortality, need for intensive care admission and requirement for mechanical ventilation and assess its validity. RESULTS: Over an 8 month period, 62 patients with confirmed H1N1 were admitted. Forty (65%) had documented comorbidities and 27 (44%) had pneumonic changes on their admission CXR. Nineteen (31%) were admitted to the intensive care unit where 5 (26%) required mechanical ventilation (MV). There were 3 deaths. The STSS group categorization demonstrated a better discriminating accuracy in predicting critical care resource usage with a receiver operating characteristic area under the curve (95% confidence interval) for ICU admission of 0.88 (0.78-0.98) and need for MV of 0.91 (0.83-0.99). This compared to the staged SOFA score of 0.77 (0.65-0.89) and 0.87 (0.72-1.00) respectively. Low mortality rates limited analysis on survival predictions. CONCLUSIONS: The STSS accurately risk stratified patients in this cohort according to their risk of death and predicted the likelihood of admission to critical care and the requirement for MV. Its single point in time, accuracy and easily collected component variables commend it as an alternative reproducible system to facilitate the triage and treatment of patients in any future influenza pandemic. PMID- 21269459 TI - Proportionality between variances in gene expression induced by noise and mutation: consequence of evolutionary robustness. AB - BACKGROUND: Characterization of robustness and plasticity of phenotypes is a basic issue in evolutionary and developmental biology. The robustness and plasticity are concerned with changeability of a biological system against external perturbations. The perturbations are either genetic, i.e., due to mutations in genes in the population, or epigenetic, i.e., due to noise during development or environmental variations. Thus, the variances of phenotypes due to genetic and epigenetic perturbations provide quantitative measures for such changeability during evolution and development, respectively. RESULTS: Using numerical models simulating the evolutionary changes in the gene regulation network required to achieve a particular expression pattern, we first confirmed that gene expression dynamics robust to mutation evolved in the presence of a sufficient level of transcriptional noise. Under such conditions, the two types of variances in the gene expression levels, i.e. those due to mutations to the gene regulation network and those due to noise in gene expression dynamics were found to be proportional over a number of genes. The fraction of such genes with a common proportionality coefficient increased with an increase in the robustness of the evolved network. This proportionality was generally confirmed, also under the presence of environmental fluctuations and sexual recombination in diploids, and was explained from an evolutionary robustness hypothesis, in which an evolved robust system suppresses the so-called error catastrophe--the destabilization of the single-peaked distribution in gene expression levels. Experimental evidences for the proportionality of the variances over genes are also discussed. CONCLUSIONS: The proportionality between the genetic and epigenetic variances of phenotypes implies the correlation between the robustness (or plasticity) against genetic changes and against noise in development, and also suggests that phenotypic traits that are more variable epigenetically have a higher evolutionary potential. PMID- 21269460 TI - Initial characterization of the human central proteome. AB - BACKGROUND: On the basis of large proteomics datasets measured from seven human cell lines we consider their intersection as an approximation of the human central proteome, which is the set of proteins ubiquitously expressed in all human cells. Composition and properties of the central proteome are investigated through bioinformatics analyses. RESULTS: We experimentally identify a central proteome comprising 1,124 proteins that are ubiquitously and abundantly expressed in human cells using state of the art mass spectrometry and protein identification bioinformatics. The main represented functions are proteostasis, primary metabolism and proliferation. We further characterize the central proteome considering gene structures, conservation, interaction networks, pathways, drug targets, and coordination of biological processes. Among other new findings, we show that the central proteome is encoded by exon-rich genes, indicating an increased regulatory flexibility through alternative splicing to adapt to multiple environments, and that the protein interaction network linking the central proteome is very efficient for synchronizing translation with other biological processes. Surprisingly, at least 10% of the central proteome has no or very limited functional annotation. CONCLUSIONS: Our data and analysis provide a new and deeper description of the human central proteome compared to previous results thereby extending and complementing our knowledge of commonly expressed human proteins. All the data are made publicly available to help other researchers who, for instance, need to compare or link focused datasets to a common background. PMID- 21269461 TI - Identification of disease-causing genes using microarray data mining and Gene Ontology. AB - BACKGROUND: One of the best and most accurate methods for identifying disease causing genes is monitoring gene expression values in different samples using microarray technology. One of the shortcomings of microarray data is that they provide a small quantity of samples with respect to the number of genes. This problem reduces the classification accuracy of the methods, so gene selection is essential to improve the predictive accuracy and to identify potential marker genes for a disease. Among numerous existing methods for gene selection, support vector machine-based recursive feature elimination (SVMRFE) has become one of the leading methods, but its performance can be reduced because of the small sample size, noisy data and the fact that the method does not remove redundant genes. METHODS: We propose a novel framework for gene selection which uses the advantageous features of conventional methods and addresses their weaknesses. In fact, we have combined the Fisher method and SVMRFE to utilize the advantages of a filtering method as well as an embedded method. Furthermore, we have added a redundancy reduction stage to address the weakness of the Fisher method and SVMRFE. In addition to gene expression values, the proposed method uses Gene Ontology which is a reliable source of information on genes. The use of Gene Ontology can compensate, in part, for the limitations of microarrays, such as having a small number of samples and erroneous measurement results. RESULTS: The proposed method has been applied to colon, Diffuse Large B-Cell Lymphoma (DLBCL) and prostate cancer datasets. The empirical results show that our method has improved classification performance in terms of accuracy, sensitivity and specificity. In addition, the study of the molecular function of selected genes strengthened the hypothesis that these genes are involved in the process of cancer growth. CONCLUSIONS: The proposed method addresses the weakness of conventional methods by adding a redundancy reduction stage and utilizing Gene Ontology information. It predicts marker genes for colon, DLBCL and prostate cancer with a high accuracy. The predictions made in this study can serve as a list of candidates for subsequent wet-lab verification and might help in the search for a cure for cancers. PMID- 21269462 TI - Peritoneal mesothelioma in a woman who has survived for seven years: a case report. AB - INTRODUCTION: Malignant peritoneal mesothelioma is a rare cancer with poor patient survival. Female gender has been identified as a positive prognostic factor. Recently, it has been suggested that the expression of estrogen receptor beta in malignant mesothelioma leads to tumor suppression and a better prognosis. CASE PRESENTATION: We report the case of a 48-year-old Caucasian woman who is alive and disease-free seven years after the initial diagnosis and treatment of malignant peritoneal mesothelioma. CONCLUSION: This patient's long survival may be attributable to a combination of factors, including minimal disease, complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy plus the estrogen receptor beta positivity of the tumor. PMID- 21269463 TI - Selective frontal neurodegeneration of the inferior fronto-occipital fasciculus in progressive supranuclear palsy (PSP) demonstrated by diffusion tensor tractography. AB - BACKGROUND: The clinical presentation in progressive supranuclear palsy (PSP), an atypical parkinsonian disorder, includes varying degrees of frontal dysexecutive symptoms. Using diffusion tensor imaging (DTI) and tractography (DTT), we investigated whether diffusion changes and atrophy of the inferior fronto occipital fasciculus (IFO) occurs in PSP and if these changes correlate with disease stage and clinical phenotype. The corticospinal tract (CST), which is often involved in PSP, was investigated for comparison. METHODS: DTI of the whole brain was performed with a 3 T MR scanner using a single shot-EPI sequence with diffusion encoding in 48 directions. Scans were obtained in patients with PSP (n = 13) and healthy age-matched controls (n = 12). DTT of the IFO and CST was performed with the PRIDE fibre tracking tool (Philips Medical System). Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were calculated and correlated with disease stage and clinical phenotype. RESULTS: In patients with PSP, significantly decreased FA and increased ADC was found in the frontal part of IFO compared with the medial and occipital parts of IFO, as well as compared to controls. Four of the thirteen patients with PSP showed a marked decrease in the number of tracked voxels in the frontal part of IFO. These findings were most pronounced in patients with severe frontal cognitive symptoms, such as dysexecutive problems, apathy and personality change. There was a strong correlation (r2 = -0.84; p < 0,001) between disease stage and FA and ADC values in the CST. CONCLUSIONS: DTT for identification of neuronal tracts with subsequent measurement of FA and ADC is a useful diagnostic tool for demonstrating patterns of neuronal tract involvement in neurodegenerative disease. In selected tracts, FA and ADC values might act as surrogate markers for disease stage. PMID- 21269464 TI - Effect of childbirth on the course of Crohn's disease; results from a retrospective cohort study in the Netherlands. AB - BACKGROUND: Pregnant women with Crohn's disease needs proper counselling about the effect of pregnancy and childbirth on their disease. However, Literature about the effect of childbirth on Crohn's disease is limited. This study examined the effect of childbirth on the course of Crohn's disease and especially perianal Crohn's disease. METHODS: This is a retrospective cohort study which was performed in a tertiary level referral hospital in the Netherlands. From the IBD database, female patients aged 18-80 years in 2004 were selected. Data analysis took place in the years 2005 and 2006. Eventually, 114 women with at least one pregnancy after the diagnosis of Crohn's disease were eligible for the study. Differences between groups were analyzed using Wilcoxon Mann Whitney tests and Chi-square analysis with 2 * 2 or 2 * 3 contingency tables. Two-tailed values were used and p values < 0.05 were considered statistically significant. RESULTS: 21/114 women (18%) had active luminal disease prior to pregnancy, with significantly more pregnancy related complications compared to women with inactive luminal disease (Odds ratio 2.8; 95% CI 1.0 - 7.4). Caesarean section rate was relatively high (37/114, 32%), especially in patients with perianal disease prior to pregnancy compared to women without perianal disease (Odds ratio 4.6; 95% CI 1.8 - 11.4). Disease progression after childbirth was more frequent in patients with active luminal disease prior to pregnancy compared to inactive luminal disease (Odds ratio 9.7; 95% CI 2.1 - 44.3). Progression of perianal disease seems less frequent after vaginal delivery compared with caesarean section, in both women with prior perianal disease (18% vs. 31%, NS) and without prior perianal disease (5% vs 14%, NS). There were no more fistula-related complications after childbirth in women with an episiotomy or second degree tear. CONCLUSION: A relatively high rate of caesarean sections was observed in women with Crohn's disease, especially in women with perianal disease prior to pregnancy. A protective effect of caesarean section on progression of perianal disease was not observed. However, this must be interpreted carefully due to confounder effect by indication for caesarean section. PMID- 21269465 TI - The effect of hunger on the acoustic individuality in begging calls of a colonially breeding weaver bird. AB - BACKGROUND: In colonially breeding birds, the ability to discriminate between individuals is often essential. During post-fledging care, parents have to recognize their own offspring among many other unrelated chicks in the breeding colony. It is well known that fledglings and food-provisioning parents of many bird species use contact calls to convey their identity. These calls are also often used as hunger-related signals of need in young birds. Here, we investigate how such calls incorporate signals of need and at the same time act as reliable indicators of each chick's identity. RESULTS: In a field study, we experimentally manipulated the hunger level of colonially breeding Jackson's golden-backed weaver (Ploceus jacksoni) nestlings close to fledging and investigated its effects on acoustic call parameters. Some acoustic parameters that were related to the time-frequency pattern showed high individuality and were largely unaffected by a nestling's state of hunger. However, the majority of call parameters were significantly affected by hunger. Interestingly, most of these acoustic parameters showed both consistent changes with hunger and high between individual differences, i.e. potential for individual recognition. CONCLUSION: The results indicate that individual recognition processes can be based on static, hunger-independent call parameters, but also on dynamic hunger-related parameters that show high individuality. Furthermore, these signal properties suggest that the assessment of signals of need can be improved if the signal value is referenced to a chick's vocal spectrum. PMID- 21269466 TI - Insects in confined swine operations carry a large antibiotic resistant and potentially virulent enterococcal community. AB - BACKGROUND: Extensive use of antibiotics as growth promoters in the livestock industry constitutes strong selection pressure for evolution and selection of antibiotic resistant bacterial strains. Unfortunately, the microbial ecology and spread of these bacteria in the agricultural, urban, and suburban environments are poorly understood. Insects such as house flies (Musca domestica) and German cockroaches (Blattella germanica) can move freely between animal waste and food and may play a significant role in the dissemination of antibiotic resistant bacteria within and between animal production farms and from farms to residential settings. RESULTS: Enterococci from the digestive tract of house flies (n = 162), and feces of German cockroaches (n = 83) and pigs (n = 119), collected from two commercial swine farms were isolated, quantified, identified, and screened for antibiotic resistance and virulence. The majority of samples (93.7%) were positive for enterococci with concentrations 4.2 +/- 0.7 * 104 CFU/house fly, 5.5 +/- 1.1 * 106 CFU/g of cockroach feces, and 3.2 +/- 0.8 * 105 CFU/g of pig feces. Among all the identified isolates (n = 639) Enterococcus faecalis was the most common (55.5%), followed by E. hirae (24.9%), E. faecium (12.8%), and E. casseliflavus (6.7%). E. faecalis was most prevalent in house flies and cockroaches, and E. hirae was most common in pig feces. Our data showed that multi-drug (mainly tetracycline and erythromycin) resistant enterococci were common from all three sources and frequently carried antibiotic resistance genes including tet(M) and erm(B) and Tn916/1545 transposon family. E. faecalis frequently harbored virulence factors gelE, esp, and asa1. PFGE analysis of selected E. faecalis and E. faecium isolates demonstrated that cockroaches and house flies shared some of the same enterococcal clones that were detected in the swine manure indicating that insects acquired enterococci from swine manure. CONCLUSIONS: This study shows that house flies and German cockroaches in the confined swine production environment likely serve as vectors and/or reservoirs of antibiotic resistant and potentially virulent enterococci and consequently may play an important role in animal and public health. PMID- 21269467 TI - Helicobacter pylori infection and circulating ghrelin levels - a systematic review. AB - BACKGROUND: The nature of the association between ghrelin, an orexigenic hormone produced mainly in the stomach, and Helicobacter pylori (H pylori), a bacterium that colonises the stomach, is still controversial. We examined available evidence to determine whether an association exists between the two; and if one exists, in what direction. METHODS: We reviewed original English language studies on humans reporting circulating ghrelin levels in H pylori infected and un infected participants; and circulating ghrelin levels before and after H pylori eradication. Meta-analyses were conducted for eligible studies by combining study specific estimates using the inverse variance method with weighted average for continuous outcomes in a random effects model. RESULTS: Seventeen out of 27 papers that reported ghrelin levels in H pylori positive and negative subjects found lower circulating ghrelin levels in H pylori positive subjects; while 10 found no difference. A meta-analysis of 19 studies with a total of 1801 participants showed a significantly higher circulating ghrelin concentration in H pylori negative participants than in H pylori positive participants (Effect estimate (95%CI) = -0.48 (-0.60, -0.36)). However, eradicating H pylori did not have any significant effect on circulating ghrelin levels (Effect estimate (95% CI) = 0.08 (-0.33, 0.16); Test for overall effect: Z = 0.67 (P = 0.5)). CONCLUSIONS: We conclude that circulating ghrelin levels are lower in H pylori infected people compared to those not infected; but the relationship between circulating ghrelin and eradication of H pylori is more complex. PMID- 21269468 TI - Recombinant luciferase-expressing human cytomegalovirus (CMV) for evaluation of CMV inhibitors. AB - Recombinant Towne CMV expressing luciferase under the control of CMV-DNA polymerase (POL) or the late pp28 (UL99) promoters were evaluated for potential application in high-throughput screening of anti-viral compounds. POL-and pp28 luciferase displayed maximal expression 48 and 72 hours post infection, respectively. The pp28-luciferase virus achieved a wider dynamic range of luciferase expression (6-7 logs) and was selected for testing of inhibition by five anti-viral compounds. Luciferase expression highly correlated with plaque reduction and real-time PCR. The pp28-luciferase reporter system is rapid, reproducible, and highly sensitive. It may be applied to screening of novel anti CMV compounds. PMID- 21269469 TI - Information content in genome-wide scans: concordance between patterns of genetic differentiation and linkage mapping associations. AB - BACKGROUND: Scanning the genome with high density SNP markers has become a standard approach for identifying regions of the genome showing substantial between-population genetic differentiation, and thus evidence of diversifying selection. Such regions may contain genes of large phenotypic effect. However, few studies have attempted to address the power or efficacy of such an approach. RESULTS: In this study, the patterns of allele frequency differences between two cattle breeds based on the Bovine HapMap study were compared with statistical evidence for QTL based on a linkage mapping study of an experimental population formed by a cross between the same breeds. Concordance between the two datasets was seen for chromosomes carrying QTL with strong statistical support, such as BTA5 and BTA18, which carry genes associated with coat color. For these chromosomes, there was a correspondence between the strength of the QTL signal along the chromosome and the degree of genetic differentiation between breeds. However, such an association was not seen in a broader comparison that also included chromosomes carrying QTL with lower significance levels. In addition, other chromosomal regions with substantial QTL effects did not include markers showing extreme between-breed genetic differentiation. Furthermore, the overall consistency between the two studies was weak, with low genome-wide correlation between the statistical values obtained in the linkage mapping study and between breed genetic differentiation from the HapMap study. CONCLUSIONS: These results suggest that genomic diversity scans are capable of detecting regions associated with qualitative traits but may be limited in their power to detect regions associated with quantitative phenotypic differences between populations, which may depend on the marker resolution of the study and the level of LD in the populations under investigation. PMID- 21269470 TI - CMR assessment of endothelial damage and angiogenesis in porcine coronary arteries using gadofosveset. AB - BACKGROUND: Endothelial damage and angiogenesis are essential for atherosclerotic plaque development and destabilization. We sought to examine whether contrast enhanced cardiovascular magnetic resonance (CMR) using gadofosveset could show endothelial damage and neovessel formation in balloon injured porcine coronary arteries. METHODS AND RESULTS: Data were obtained from seven pigs that all underwent balloon injury of the left anterior descending coronary artery (LAD) to induce endothelial damage and angiogenesis. Between one - 12 days (average four) after balloon injury, in vivo and ex vivo T1-weighted coronary CMR was performed after intravenous injection of gadofosveset. Post contrast, CMR showed contrast enhancement of the coronary arteries with a selective and time-dependent average expansion of the injured LAD segment area of 45% (p = 0.04; CI95 = [15%-75%]), indicating local extravasation of gadofosveset. Vascular and perivascular extravasation of albumin (marker of endothelial leakiness) and gadofosveset was demonstrated with agreement between Evans blue staining and ex vivo CMR contrast enhancement (p = 0.026). Coronary MRI contrast enhancement and local microvessel density determined by microscopic examination correlated (rho = 0.82, p < 0.001). CONCLUSION: Contrast enhanced coronary CMR with gadofosveset can detect experimentally induced endothelial damage and angiogenesis in the porcine coronary artery wall. PMID- 21269471 TI - Gene set enrichment analysis of microarray data from Pimephales promelas (Rafinesque), a non-mammalian model organism. AB - BACKGROUND: Methods for gene-class testing, such as Gene Set Enrichment Analysis (GSEA), incorporate biological knowledge into the analysis and interpretation of microarray data by comparing gene expression patterns to pathways, systems and emergent phenotypes. However, to use GSEA to its full capability with non mammalian model organisms, a microarray platform must be annotated with human gene symbols. Doing so enables the ability to relate a model organism's gene expression, in response to a given treatment, to potential human health consequences of that treatment. We enhanced the annotation of a microarray platform from a non-mammalian model organism, and then used the GSEA approach in a reanalysis of a study examining the biological significance of acute and chronic methylmercury exposure on liver tissue of fathead minnow (Pimephales promelas). Using GSEA, we tested the hypothesis that fathead livers, in response to methylmercury exposure, would exhibit gene expression patterns similar to diseased human livers. RESULTS: We describe an enhanced annotation of the fathead minnow microarray platform with human gene symbols. This resource is now compatible with the GSEA approach for gene-class testing. We confirmed that GSEA, using this enhanced microarray platform, is able to recover results consistent with a previous analysis of fathead minnow exposure to methylmercury using standard analytical approaches. Using GSEA to compare fathead gene expression profiles to human phenotypes, we also found that fathead methylmercury-treated livers exhibited expression profiles that are homologous to human systems & pathways and results in damage that is similar to those of human liver damage associated with hepatocellular carcinoma and hepatitis B. CONCLUSIONS: This study describes a powerful resource for enabling the use of non-mammalian model organisms in the study of human health significance. Results of microarray gene expression studies involving fathead minnow, typically used for aquatic ecological toxicology studies, can now be used to generate hypotheses regarding consequences of contaminants and other stressors on humans. The same approach can be used with other model organisms with microarray platforms annotated in a similar manner. PMID- 21269472 TI - Genetic variation of ESR1 and its co-activator PPARGC1B is synergistic in augmenting the risk of estrogen receptor-positive breast cancer. AB - INTRODUCTION: Given the role of estrogen in breast carcinogenesis and the modification of estrogen receptor (ER) activity by its biochemical cofactors, we hypothesize that genetic variation within ER cofactor genes alters cellular response to estrogen exposure and consequently modifies the risk for ER-positive breast cancer. METHODS: We genotyped 790 tagging SNPs within 60 ER cofactor genes in 1,257 cases and 1,464 controls from Sweden and in 2,215 cases and 1,265 controls from Finland, and tested their associations with either ER-positive or ER-negative breast cancer. RESULTS: Seven SNPs showed consistent association with ER-positive breast cancer in the two independent samples, and six of them were located within PPARGC1B, encoding an ER co-activator, with the strongest association at rs741581 (odds ratio = 1.41, P = 4.84 * 10-5) that survived Bonferroni correction for multiple testing in the combined ER-positive breast cancer sample (Pcorrected = 0.03). Moreover, we also observed significant synergistic interaction (Pinteraction = 0.008) between the genetic polymorphisms within PPARGC1B and ESR1 in ER-positive breast cancer. By contrast, no consistent association was observed in ER-negative breast cancer. Furthermore, we found that administration of estrogen in the MCF-7 cell line induced PPARGC1B expression and enhanced occupancies of ER and RNA polymerase II within the region of SNP association, suggesting the upregulation of PPARGC1B expression by ESR1 activation. CONCLUSIONS: Our study revealed that DNA polymorphisms of PPARGC1B, coding a bona fide ER co-activator, are associated with ER-positive breast cancer risk. The feed-forward transcriptional regulatory loop between PPARGC1B and ESR1 further augments their protein interaction, which provides a plausible mechanistic explanation for the synergistic genetic interaction between PPARGC1B and ESR1 in ER-positive breast cancer. Our study also highlights that biochemically and genomically informed candidate gene studies can enhance the discovery of interactive disease susceptibility genes. PMID- 21269474 TI - Enhanced virtual microscopy for collaborative education. AB - BACKGROUND: Curricular reform efforts and a desire to use novel educational strategies that foster student collaboration are challenging the traditional microscope-based teaching of histology. Computer-based histology teaching tools and Virtual Microscopes (VM), computer-based digital slide viewers, have been shown to be effective and efficient educational strategies. We developed an open source VM system based on the Google Maps engine to transform our histology education and introduce new teaching methods. This VM allows students and faculty to collaboratively create content, annotate slides with markers, and it is enhanced with social networking features to give the community of learners more control over the system. RESULTS: We currently have 1,037 slides in our VM system comprised of 39,386,941 individual JPEG files that take up 349 gigabytes of server storage space. Of those slides 682 are for general teaching and available to our students and the public; the remaining 355 slides are used for practical exams and have restricted access. The system has seen extensive use with 289,352 unique slide views to date. Students viewed an average of 56.3 slides per month during the histology course and accessed the system at all hours of the day. Of the 621 annotations added to 126 slides 26.2% were added by faculty and 73.8% by students. The use of the VM system reduced the amount of time faculty spent administering the course by 210 hours, but did not reduce the number of laboratory sessions or the number of required faculty. Laboratory sessions were reduced from three hours to two hours each due to the efficiencies in the workflow of the VM system. CONCLUSIONS: Our virtual microscope system has been an effective solution to the challenges facing traditional histopathology laboratories and the novel needs of our revised curriculum. The web-based system allowed us to empower learners to have greater control over their content, as well as the ability to work together in collaborative groups. The VM system saved faculty time and there was no significant difference in student performance on an identical practical exam before and after its adoption. We have made the source code of our VM freely available and encourage use of the publically available slides on our website. PMID- 21269473 TI - The eMERGE Network: a consortium of biorepositories linked to electronic medical records data for conducting genomic studies. AB - INTRODUCTION: The eMERGE (electronic MEdical Records and GEnomics) Network is an NHGRI-supported consortium of five institutions to explore the utility of DNA repositories coupled to Electronic Medical Record (EMR) systems for advancing discovery in genome science. eMERGE also includes a special emphasis on the ethical, legal and social issues related to these endeavors. ORGANIZATION: The five sites are supported by an Administrative Coordinating Center. Setting of network goals is initiated by working groups: (1) Genomics, (2) Informatics, and (3) Consent & Community Consultation, which also includes active participation by investigators outside the eMERGE funded sites, and (4) Return of Results Oversight Committee. The Steering Committee, comprised of site PIs and representatives and NHGRI staff, meet three times per year, once per year with the External Scientific Panel. CURRENT PROGRESS: The primary site-specific phenotypes for which samples have undergone genome-wide association study (GWAS) genotyping are cataract and HDL, dementia, electrocardiographic QRS duration, peripheral arterial disease, and type 2 diabetes. A GWAS is also being undertaken for resistant hypertension in ~ 2,000 additional samples identified across the network sites, to be added to data available for samples already genotyped. Funded by ARRA supplements, secondary phenotypes have been added at all sites to leverage the genotyping data, and hypothyroidism is being analyzed as a cross network phenotype. Results are being posted in dbGaP. Other key eMERGE activities include evaluation of the issues associated with cross-site deployment of common algorithms to identify cases and controls in EMRs, data privacy of genomic and clinically-derived data, developing approaches for large-scale meta-analysis of GWAS data across five sites, and a community consultation and consent initiative at each site. FUTURE ACTIVITIES: Plans are underway to expand the network in diversity of populations and incorporation of GWAS findings into clinical care. SUMMARY: By combining advanced clinical informatics, genome science, and community consultation, eMERGE represents a first step in the development of data driven approaches to incorporate genomic information into routine healthcare delivery. PMID- 21269475 TI - High prevalence of childhood multi-drug resistant tuberculosis in Johannesburg, South Africa: a cross sectional study. AB - BACKGROUND: There are limited data on the prevalence of multi-drug resistant tuberculosis (MDR-TB), estimated at 0.6-6.7%, in African children with tuberculosis. We undertook a retrospective analysis of the prevalence of MDR-TB in children with Mycobacterium tuberculosis (MTB) at two hospitals in Johannesburg, South Africa. METHODS: Culture-confirmed cases of MTB in children under 14 years, attending two academic hospitals in Johannesburg, South Africa during 2008 were identified and hospital records of children diagnosed with drug resistant TB were reviewed, including clinical and radiological outcomes at 6 and 12 months post-diagnosis. Culture of Mycobacterium tuberculosis complex (MTB) was performed using the automated liquid broth MGITTM 960 method. Drug susceptibility testing (DST) was performed using the MGITTM 960 method for both first and second line anti-TB drugs. RESULTS: 1317 children were treated for tuberculosis in 2008 between the two hospitals where the study was conducted. Drug susceptibility testing was undertaken in 148 (72.5%) of the 204 children who had culture confirmed tuberculosis. The prevalence of isoniazid-resistance was 14.2% (n = 21) (95%CI, 9.0-20.9%) and the prevalence of MDR-TB 8.8% (n = 13) (95%CI, 4.8-14.6%). The prevalence of HIV co-infection was 52.1% in children with drug susceptible-TB and 53.9% in children with MDR-TB. Ten (76.9%) of the 13 children with MDR-TB received appropriate treatment and four (30.8%) died at a median of 2.8 months (range 0.1-4.0 months) after the date of tuberculosis investigation. CONCLUSIONS: There is a high prevalence of drug-resistant tuberculosis in children in Johannesburg in a setting with a high prevalence of HIV co-infection, although no association between HIV infection and MDR-TB was found in this study. Routine HIV and drug-susceptibility testing is warranted to optimize the management of childhood tuberculosis in settings such as ours. PMID- 21269476 TI - A major QTL controls susceptibility to spinal curvature in the curveback guppy. AB - BACKGROUND: Understanding the genetic basis of heritable spinal curvature would benefit medicine and aquaculture. Heritable spinal curvature among otherwise healthy children (i.e. Idiopathic Scoliosis and Scheuermann kyphosis) accounts for more than 80% of all spinal curvatures and imposes a substantial healthcare cost through bracing, hospitalizations, surgery, and chronic back pain. In aquaculture, the prevalence of heritable spinal curvature can reach as high as 80% of a stock, and thus imposes a substantial cost through production losses. The genetic basis of heritable spinal curvature is unknown and so the objective of this work is to identify quantitative trait loci (QTL) affecting heritable spinal curvature in the curveback guppy. Prior work with curveback has demonstrated phenotypic parallels to human idiopathic-type scoliosis, suggesting shared biological pathways for the deformity. RESULTS: A major effect QTL that acts in a recessive manner and accounts for curve susceptibility was detected in an initial mapping cross on LG 14. In a second cross, we confirmed this susceptibility locus and fine mapped it to a 5 cM region that explains 82.6% of the total phenotypic variance. CONCLUSIONS: We identify a major QTL that controls susceptibility to curvature. This locus contains over 100 genes, including MTNR1B, a candidate gene for human idiopathic scoliosis. The identification of genes associated with heritable spinal curvature in the curveback guppy has the potential to elucidate the biological basis of spinal curvature among humans and economically important teleosts. PMID- 21269477 TI - Kidney function and multiple hemostatic markers: cross sectional associations in the multi-ethnic study of atherosclerosis. AB - BACKGROUND: Defined as estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2, chronic kidney disease (CKD) is strongly and independently associated with cardiovascular and overall mortality. We hypothesized that reduced kidney function would be characterized by abnormalities of hemostasis. METHODS: We tested cross-sectional associations between (eGFR) and multiple hemostatic markers among 6751 participants representing a broad spectrum of kidney function in the Multi-Ethnic Study of Atherosclerosis (MESA). Kidney function was measured using cystatin C (eGFRcys) or creatinine, using CKD Epidemiology Collaboration (eGFRcr). Hemostatic markers included soluble thrombomodulin (sTM), soluble tissue factor (sTF), D-Dimer, von Willebrand factor (vWF), factor VIII, plasmin-antiplasmin complex (PAP), tissue factor pathway inhibitor (TFPI), plasminogen activator inhibitor-1 (PAI-1), and fibrinogen. Associations were tested using multivariable linear regression with adjustment for demographics and comorbidities. RESULTS: In comparison to persons with eGFRcys >90 ml/min/1.73 m2, subjects with eGFRcys < 60 ml/min/1.73 m2 had adjusted levels of sTM, sTF, D-Dimer, PAP, Factor VIII, TFPI, vWF and fibrinogen that were respectively 86%, 68%, 44%, 22%, 17%, 15%, 12% and 6% higher. Subjects with eGFRcys 60-90 ml/min/1.73 m2 had adjusted levels that were respectively 16%, 14%, 12%, 6%, 6%, 6%, 11% and 4% higher (p < 0.05 for all). Percent differences were not significantly different when groups were categorized by eGFRcr. CONCLUSIONS: Throughout a broad spectrum of kidney function, lower eGFR was associated with higher levels of hemostatic markers. Dysregulation of hemostasis may be a mechanism by which reduced kidney function promotes higher cardiovascular risk. PMID- 21269479 TI - Graphical analysis of pH-dependent properties of proteins predicted using PROPKA. AB - BACKGROUND: Charge states of ionizable residues in proteins determine their pH dependent properties through their pKa values. Thus, various theoretical methods to determine ionization constants of residues in biological systems have been developed. One of the more widely used approaches for predicting pKa values in proteins is the PROPKA program, which provides convenient structural rationalization of the predicted pKa values without any additional calculations. RESULTS: The PROPKA Graphical User Interface (GUI) is a new tool for studying the pH-dependent properties of proteins such as charge and stabilization energy. It facilitates a quantitative analysis of pKa values of ionizable residues together with their structural determinants by providing a direct link between the pKa data, predicted by the PROPKA calculations, and the structure via the Visual Molecular Dynamics (VMD) program. The GUI also calculates contributions to the pH dependent unfolding free energy at a given pH for each ionizable group in the protein. Moreover, the PROPKA-computed pKa values or energy contributions of the ionizable residues in question can be displayed interactively. The PROPKA GUI can also be used for comparing pH-dependent properties of more than one structure at the same time. CONCLUSIONS: The GUI considerably extends the analysis and validation possibilities of the PROPKA approach. The PROPKA GUI can conveniently be used to investigate ionizable groups, and their interactions, of residues with significantly perturbed pKa values or residues that contribute to the stabilization energy the most. Charge-dependent properties can be studied either for a single protein or simultaneously with other homologous structures, which makes it a helpful tool, for instance, in protein design studies or structure based function predictions. The GUI is implemented as a Tcl/Tk plug-in for VMD, and can be obtained online at http://propka.ki.ku.dk/~luca/wiki/index.php/GUI_Web. PMID- 21269478 TI - Vasculoprotective effects of rosiglitazone through modulating renin-angiotensin system in vivo and vitro. AB - BACKGROUND: The peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist rosiglitazone has been suggested to exert cardiovascular protection through the improvement of lipid metabolism, anti-inflammation, anti proliferation etc. However, whether renin-angiotensin system (RAS) is involved in the vascular protective effects of PPARgamma agonists is not fully understood. The present study aimed to investigate the effects of the renin-angiotensin system in vascular protection mediated by PPARgamma agonists. OBJECTIVE: To investigate the actions of the renin-angiotensin system in vascular protection mediated by activation of PPARgamma in vivo and in vitro. METHODS: Rats were fed a regular diet (n = 8), a cholesterol-rich diet plus methylthiouracil (80 mg/Kg/day, n = 10), a cholesterol-rich diet plus methylthiouracil and rosiglitazone (4 mg/kg/day, n = 10). The rosiglitazone treatment was started from one month after the start of cholesterol-rich diet plus methylthiouracil, and lasted five months. Cultured vascular smooth muscle cells (VSMCs) were pretreated with 1 MUmol/L angiotensin II (ANG II) for 6 h and randomly divided into the control group; the ANG II group (1 MUmol/L ANG II); the groups respectively treated with different concentration rosiglitazone (20, 30, 50) MUmol/L for 12 h; the groups treated with 30 MUmol/L rosiglitazone for (6, 12, 24) h. Morphology changes of the aortic tissues were observed by hematoxylin and eosin stain. The VSMC growth was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay. Angiotensin II and expression of angiotensin receptors were determined by radioimmunoassay, reverse transcription polymerase chain reaction (RT-PCR), western blot, and immunohistochemistry. RESULTS: After 6 months, lipid deposition, VSMC proliferation and migration toward intima were observed in aortic tissues in the rats on a cholesterol-rich diet plus methylthiouracil, while these pathological changes induced by the cholesterol rich diet were significantly suppressed by rosiglitazone. In addition, VSMC proliferation induced by ANG II was markedly inhibited by rosiglitazone. Rosiglitazone markedly down-regulated expression of angiotensin type 1 receptor (AT1R) and up-regulated expression of angiotensin type 2 receptor (AT2R) in the aortic tissues and ANG II-treated VSMCs. CONCLUSIONS: The present study demonstrated that PPARgamma agonist rosiglitazone suppressed ANG II-induced VSMC proliferation in vitro and early atherosclerotic formation evoked by cholesterol rich diet in vivo. These vasculoprotective effects of rosiglitazone were mediated at least partially by reduction in local tissue ANG II concentration, down regulation of AT1R expression and up-regulation of AT2R expression both at the mRNA and protein levels. PMID- 21269480 TI - Searching the protein structure database for ligand-binding site similarities using CPASS v.2. AB - BACKGROUND: A recent analysis of protein sequences deposited in the NCBI RefSeq database indicates that ~8.5 million protein sequences are encoded in prokaryotic and eukaryotic genomes, where ~30% are explicitly annotated as "hypothetical" or "uncharacterized" protein. Our Comparison of Protein Active-Site Structures (CPASS v.2) database and software compares the sequence and structural characteristics of experimentally determined ligand binding sites to infer a functional relationship in the absence of global sequence or structure similarity. CPASS is an important component of our Functional Annotation Screening Technology by NMR (FAST-NMR) protocol and has been successfully applied to aid the annotation of a number of proteins of unknown function. FINDINGS: We report a major upgrade to our CPASS software and database that significantly improves its broad utility. CPASS v.2 is designed with a layered architecture to increase flexibility and portability that also enables job distribution over the Open Science Grid (OSG) to increase speed. Similarly, the CPASS interface was enhanced to provide more user flexibility in submitting a CPASS query. CPASS v.2 now allows for both automatic and manual definition of ligand-binding sites and permits pair-wise, one versus all, one versus list, or list versus list comparisons. Solvent accessible surface area, ligand root-mean square difference, and Cbeta distances have been incorporated into the CPASS similarity function to improve the quality of the results. The CPASS database has also been updated. CONCLUSIONS: CPASS v.2 is more than an order of magnitude faster than the original implementation, and allows for multiple simultaneous job submissions. Similarly, the CPASS database of ligand-defined binding sites has increased in size by ~ 38%, dramatically increasing the likelihood of a positive search result. The modification to the CPASS similarity function is effective in reducing CPASS similarity scores for false positives by ~30%, while leaving true positives unaffected. Importantly, receiver operating characteristics (ROC) curves demonstrate the high correlation between CPASS similarity scores and an accurate functional assignment. As indicated by distribution curves, scores >= 30% infer a functional similarity. Software URL: http://cpass.unl.edu. PMID- 21269481 TI - Functional mapping of reaction norms to multiple environmental signals through nonparametric covariance estimation. AB - BACKGROUND: The identification of genes or quantitative trait loci that are expressed in response to different environmental factors such as temperature and light, through functional mapping, critically relies on precise modeling of the covariance structure. Previous work used separable parametric covariance structures, such as a Kronecker product of autoregressive one [AR(1)] matrices, that do not account for interaction effects of different environmental factors. RESULTS: We implement a more robust nonparametric covariance estimator to model these interactions within the framework of functional mapping of reaction norms to two signals. Our results from Monte Carlo simulations show that this estimator can be useful in modeling interactions that exist between two environmental signals. The interactions are simulated using nonseparable covariance models with spatio-temporal structural forms that mimic interaction effects. CONCLUSIONS: The nonparametric covariance estimator has an advantage over separable parametric covariance estimators in the detection of QTL location, thus extending the breadth of use of functional mapping in practical settings. PMID- 21269482 TI - Comparison of dietary control and atorvastatin on high fat diet induced hepatic steatosis and hyperlipidemia in rats. AB - BACKGROUND: Treatment with atorvastatin (ATO) or dietary control has been demonstrated to benefit patients with non-alcoholic fatty liver disease (NAFLD) and hyperlipidemia. However, little is known on whether combination of dietary control and ATO treatment could enhance the therapeutic effect. METHODS: We employed a rat model of NAFLD to examine the therapeutic efficacy of dietary control and/or ATO treatment. Sprague-Dawley rats were fed with normal chow diet as normal controls or with high fat diet (HFD) for 12 weeks to establish NAFLD. The NAFLD rats were randomized and continually fed with HFD, with normal chow diet, with HFD and treated with 30 mg/kg of ATO or with normal chow diet and treated with the same dose of ATO for 8 weeks. Subsequently, the rats were sacrificed and the serum lipids, aminotransferase, hepatic lipids, and liver pathology were characterized. The relative levels of fatty acid synthesis and beta-oxidation gene expression in hepatic tissues were measured by quantitative real-time polymerase chain reaction (qRT-PCR). Hepatic expression of hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase was determined by Western blot assay. RESULTS: While continual feeding with HFD deteriorated NAFLD and hyperlipidemia, treatment with dietary control, ATO or ATO with dietary control effectively improved serum and liver lipid metabolism and liver function. In comparison with ATO treatment, dietary control or combined with ATO treatment significantly reduced the liver weight and attenuated the HFD-induced hyperlipidemia and liver steatosis in rats. Compared to ATO treatment or dietary control, combination of ATO and dietary control significantly reduced the levels of serum total cholesterol and low density lipoprotein cholesterol (LDL-C). However, the combination therapy did not significantly improve triglyceride and free fatty acid metabolism, hepatic steatosis, and liver function, as compared with dietary control alone. CONCLUSIONS: ATO treatment effectively improved NAFLD related hyperlipidemia and inhibited liver steatosis, accompanied by modulating the expression of genes for regulating lipid metabolism. ATO enhanced the effect of dietary control on reducing the levels of serum total cholesterol and LDL-C, but not triglyceride, free fatty acid and hepatic steatosis in HFD-induced fatty liver and hyperlipidemia in rats. PMID- 21269483 TI - Study of 'Redhaven' peach and its white-fleshed mutant suggests a key role of CCD4 carotenoid dioxygenase in carotenoid and norisoprenoid volatile metabolism. AB - BACKGROUND: Carotenoids are plant metabolites which are not only essential in photosynthesis but also important quality factors in determining the pigmentation and aroma of flowers and fruits. To investigate the regulation of carotenoid metabolism, as related to norisoprenoids and other volatile compounds in peach (Prunus persica L. Batsch.), and the role of carotenoid dioxygenases in determining differences in flesh color phenotype and volatile composition, the expression patterns of relevant carotenoid genes and metabolites were studied during fruit development along with volatile compound content. Two contrasted cultivars, the yellow-fleshed 'Redhaven' (RH) and its white-fleshed mutant 'Redhaven Bianca' (RHB) were examined. RESULTS: The two genotypes displayed marked differences in the accumulation of carotenoid pigments in mesocarp tissues. Lower carotenoid levels and higher levels of norisoprenoid volatiles were observed in RHB, which might be explained by differential activity of carotenoid cleavage dioxygenase (CCD) enzymes. In fact, the ccd4 transcript levels were dramatically higher at late ripening stages in RHB with respect to RH. The two genotypes also showed differences in the expression patterns of several carotenoid and isoprenoid transcripts, compatible with a feed-back regulation of these transcripts. Abamine SG - an inhibitor of CCD enzymes - decreased the levels of both isoprenoid and non-isoprenoid volatiles in RHB fruits, indicating a complex regulation of volatile production. CONCLUSIONS: Differential expression of ccd4 is likely to be the major determinant in the accumulation of carotenoids and carotenoid-derived volatiles in peach fruit flesh. More in general, dioxygenases appear to be key factors controlling volatile composition in peach fruit, since abamine SG-treated 'Redhaven Bianca' fruits had strongly reduced levels of norisoprenoids and other volatile classes. Comparative functional studies of peach carotenoid cleavage enzymes are required to fully elucidate their role in peach fruit pigmentation and aroma. PMID- 21269484 TI - Effect of erythropoietin on level of circulating endothelial progenitor cells and outcome in patients after acute ischemic stroke. AB - INTRODUCTION: Erythropoietin (EPO) enhances the circulating level of endothelial progenitor cells (EPCs), which has been reported to be associated with prognostic outcome in ischemic stroke (IS) patients. The aim of this study was to evaluate the time course of circulating EPC level and the impact of EPO therapy on EPC level and clinical outcome in patients after acute IS. METHODS: In total, 167 patients were prospectively randomized to receive either EPO therapy (group 1) (5,000 IU each time, subcutaneously) at 48 h and 72 h after acute IS, or serve as placebo (group 2). The circulating level of EPCs (double-stained markers: CD31/CD34 (E1), CD62E/CD34 (E2) and KDR/CD34 (E3)) was determined using flow cytometry at 48 h and on days 7 and 21 after IS. EPC level was also evaluated once in 60 healthy volunteers. RESULTS: Circulating EPC (E1 to E3) level at 48 h after IS was remarkably higher in patients than in control subjects (P < 0.02). At 48 h and on Day 7 after IS, EPC (E1 to E3) level did not differ between groups 1 and 2 (all P > 0.1). However, by Day 21, EPC (E1 to E3) level was significantly higher in group 1 than in group 2 (all P < 0.03). Additionally, 90-day recurrent stroke rate was notably lower in group 1 compared with group 2 (P = 0.022). Multivariate analysis demonstrated that EPO therapy (95% confidence interval (CI), 0.153 to 0.730; P = 0.006) and EPC (E3) (95% CI, 0.341 to 0.997; P = 0.049) levels were significantly and independently predictive of a reduced 90-day major adverse neurological event (MANE) (defined as recurrent stroke, National Institutes of Health Stroke scale >=8, or death). CONCLUSIONS: EPO therapy significantly improved circulating EPC level and 90-day MANE. TRIAL REGISTRATION NUMBER: ISRCTN: ISRCTN96340690. PMID- 21269485 TI - Glycine-rich RNA binding protein of Oryza sativa inhibits growth of M15 E. coli cells. AB - BACKGROUND: Plant glycine-rich RNA binding proteins have been implicated to have roles in diverse abiotic stresses. FINDINGS: E. coli M15 cells transformed with full-length rice glycine-rich RNA binding protein4 (OsGR-RBP4), truncated rice glycine-rich RNA binding protein4 (OsGR-RBP4DeltaC) and rice FK506 binding protein (OsFKBP20) were analyzed for growth profiles using both broth and solid media. Expression of OsGR-RBP4 and OsGR-RBP4DeltaC proteins caused specific, inhibitory effect on growth of recombinant M15 E. coli cells. The bacterial inhibition was shown to be time and incubation temperature dependent. Removal of the inducer, IPTG, resulted in re-growth of the cells, indicating that effect of the foreign proteins was of reversible nature. Although noted at different levels of dilution factors, addition of purified Os-GR-RBP4 and OsGR-RBP4DeltaC showed a similar inhibitory effect as seen with expression inside the bacterial cells. CONCLUSIONS: Expression of eukaryotic, stress-associated OsGR-RBP4 protein in prokaryotic E. coli M15 cells proves injurious to the growth of the bacterial cells. E. coli genome does not appear to encode for any protein that has significant homology to OsGR-RBP4 protein. Therefore, the mechanism of inhibition appears to be due to some illegitimate interactions of the OsGR-RBP4 with possibly the RNA species of the trans-host bacterial cells. The detailed mechanism underlying this inhibition remains to be worked out. PMID- 21269486 TI - Chinese characters reveal impacts of prior experience on very early stages of perception. AB - BACKGROUND: Visual perception is strongly determined by accumulated experience with the world, which has been shown for shape, color, and position perception, in the field of visuomotor learning, and in neural computation. In addition, visual perception is tuned to statistics of natural scenes. Such prior experience is modulated by neuronal top-down control the temporal properties of which had been subject to recent studies. Here, we deal with these temporal properties and address the question how early in time accumulated past experience can modulate visual perception. RESULTS: We performed stimulus discrimination experiments and compared a group of Chinese participants with a German control group. The perception of our briefly presented visual objects (targets) was disturbed by masking stimuli which appeared in close spatiotemporal proximity. These masking stimuli were either intact or scrambled Chinese characters and did not overlap with the targets. In contrast to German controls, Chinese participants show substantial performance differences for real versus scrambled Chinese characters if these masking stimuli were presented as early as less than 100 milliseconds after the onset of the target. For Chinese observers, it even occured that meaningful masking stimuli enhanced target identification if they were shown at least 100 milliseconds after target onset while the same stimuli impaired recognition if presented in close temporal proximity to the target. The latter finding challenges interpretations of our data that solely rely on stimulus contours or geometric properties and emphasizes the impact of prior experience on the very early temporal dynamics of the visual system. CONCLUSIONS: Our findings demonstrate that prior experience which had been accummulated long before the experiments can modulate the time course of perception intriguingly early, namely already immediately after the perceptual onset of a visual event. This modulation cannot solely operate as a feedback in response to the visual event but is rather a permanent effect. PMID- 21269487 TI - Geospatial resources for supporting data standards, guidance and best practice in health informatics. AB - BACKGROUND: The 1980s marked the occasion when Geographical Information System (GIS) technology was broadly introduced into the geo-spatial community through the establishment of a strong GIS industry. This technology quickly disseminated across many countries, and has now become established as an important research, planning and commercial tool for a wider community that includes organisations in the public and private health sectors.The broad acceptance of GIS technology and the nature of its functionality have meant that numerous datasets have been created over the past three decades. Most of these datasets have been created independently, and without any structured documentation systems in place. However, search and retrieval systems can only work if there is a mechanism for datasets existence to be discovered and this is where proper metadata creation and management can greatly help.This situation must be addressed through support mechanisms such as Web-based portal technologies, metadata editor tools, automation, metadata standards and guidelines and collaborative efforts with relevant individuals and organisations. Engagement with data developers or administrators should also include a strategy of identifying the benefits associated with metadata creation and publication. FINDINGS: The establishment of numerous Spatial Data Infrastructures (SDIs), and other Internet resources, is a testament to the recognition of the importance of supporting good data management and sharing practices across the geographic information community. These resources extend to health informatics in support of research, public services and teaching and learning.This paper identifies many of these resources available to the UK academic health informatics community. It also reveals the reluctance of many spatial data creators across the wider UK academic community to use these resources to create and publish metadata, or deposit their data in repositories for sharing.The Go-Geo! service is introduced as an SDI developed to provide UK academia with the necessary resources to address the concerns surrounding metadata creation and data sharing. The Go-Geo! portal, Geodoc metadata editor tool, ShareGeo spatial data repository, and a range of other support resources, are described in detail. CONCLUSIONS: This paper describes a variety of resources available for the health research and public health sector to use for managing and sharing their data. The Go-Geo! service is one resource which offers an SDI for the eclectic range of disciplines using GIS in UK academia, including health informatics.The benefits of data management and sharing are immense, and in these times of cost restraints, these resources can be seen as solutions to find cost savings which can be reinvested in more research. PMID- 21269488 TI - Second harmonic generation analysis of early Achilles tendinosis in response to in vivo mechanical loading. AB - BACKGROUND: Tenocytes have been implicated in the development of tendinosis, a chronic condition commonly seen in musculoskeletal overuse syndromes. However, the relation between abnormal tenocyte morphology and early changes in the fibrillar collagen matrix has not been closely examined in vivo. Second harmonic generation (SHG) microscopy is a recently developed technique which allows examination of fibrillar collagen structures with a high degree of specificity and resolution. The goal of this study was to examine the potential utility of SHG and multiphoton excitation fluorescence (MPEF) microscopy in understanding the relation between tenocytes and their surrounding collagenous matrix in early tendon overuse lesions. METHODS: Histological preparations of tendon were prepared from adult male Sprague-Dawley rats subjected to an Achilles tendon loading protocol for 12 weeks (Rat-A-PED), or from sedentary age-matched cage controls. Second harmonic generation and multiphoton excitation fluorescence were performed simultaneously on these tissue sections in at least three different areas. RESULTS: SHG microscopy revealed an association between abnormal tenocyte morphology and morphological changes in the fibrillar collagen matrix of mechanically loaded Achilles tendons. Collagen density and organization was significantly reduced in focal micro-regions of mechanically loaded tendons. These pathological changes occurred specifically in association with altered tenocyte morphology. Normal tendons displayed a regular distribution of fibre bundles, and the average size of these bundles as determined by Gaussian analysis was 0.47 MUm +/- 0.02. In comparison, fibre bundle measures from tendon regions in the vicinity of abnormal tenocytes could not be quantified due to a reduction in their regularity of distribution and orientation. CONCLUSIONS: SHG microscopy allowed high resolution detection of focal tendon abnormalities affecting the fibrillar collagen matrix. With ongoing repetitive loading, these tenocyte associated focal collagen defects could predispose to the progression of overuse pathology. PMID- 21269489 TI - Consequences of cell-to-cell P-glycoprotein transfer on acquired multidrug resistance in breast cancer: a cell population dynamics model. AB - BACKGROUND: Cancer is a proliferation disease affecting a genetically unstable cell population, in which molecular alterations can be somatically inherited by genetic, epigenetic or extragenetic transmission processes, leading to a cooperation of neoplastic cells within tumoural tissue. The efflux protein P glycoprotein (P-gp) is overexpressed in many cancer cells and has known capacity to confer multidrug resistance to cytotoxic therapies. Recently, cell-to-cell P gp transfers have been shown. Herein, we combine experimental evidence and a mathematical model to examine the consequences of an intercellular P-gp trafficking in the extragenetic transfer of multidrug resistance from resistant to sensitive cell subpopulations. METHODOLOGY AND PRINCIPAL FINDINGS: We report cell-to-cell transfers of functional P-gp in co-cultures of a P-gp overexpressing human breast cancer MCF-7 cell variant, selected for its resistance towards doxorubicin, with the parental sensitive cell line. We found that P-gp as well as efflux activity distribution are progressively reorganized over time in co cultures analyzed by flow cytometry. A mathematical model based on a Boltzmann type integro-partial differential equation structured by a continuum variable corresponding to P-gp activity describes the cell populations in co-culture. The mathematical model elucidates the population elements in the experimental data, specifically, the initial proportions, the proliferative growth rates, and the transfer rates of P-gp in the sensitive and resistant subpopulations. CONCLUSIONS: We confirmed cell-to-cell transfer of functional P-gp. The transfer process depends on the gradient of P-gp expression in the donor-recipient cell interactions, as they evolve over time. Extragenetically acquired drug resistance is an additional aptitude of neoplastic cells which has implications in the diagnostic value of P-gp expression and in the design of chemotherapy regimens. PMID- 21269490 TI - Osteoblastic differentiation and stress response of human mesenchymal stem cells exposed to alternating current electric fields. AB - BACKGROUND: Electric fields are integral to many biological events, from maintaining cellular homeostasis to embryonic development to healing. The application of electric fields offers substantial therapeutic potential, while optimal dosing regimens and the underlying mechanisms responsible for the positive clinical impact are poorly understood. METHODS: The purpose of this study was to track the differentiation profile and stress response of human bone marrow derived mesenchymal stem cells (hMSCs) undergoing osteogenic differentiation during exposure to a 20 mV/cm, 60 kHz electric field. Morphological and biochemical changes were imaged using endogenous two-photon excited fluorescence (TPEF) and quantitatively assessed through eccentricity calculations and extraction of the redox ratio from NADH, FAD and lipofuscin contributions. Real time reverse transcriptase-polymerase chain reactions (RT PCR) were used to track osteogenic differentiation markers, namely alkaline phosphatase (ALP) and collagen type 1 (col1), and stress response markers, such as heat shock protein 27 (hsp27) and heat shock protein 70 (hsp70). Comparisons of collagen deposition between the stimulated hMSCs and controls were examined through second harmonic generation (SHG) imaging. RESULTS: Quantitative differences in cell morphology, as described through an eccentricity ratio, were found on days 2 and days 5 (p < 0.05) in samples exposed to the electric field. A delayed but two fold increase in ALP and col1 transcript was detected by week 2 (p < 0.05) in differentiating hMSCs exposed to an electric field in comparison to the nonstimulated controls. Upregulation in stress marker, hsp27, and type 1 collagen deposition were correlated with this response. Increases in NADH, FAD, and lipofuscin were traced in the stimulation group during the first week of field exposure with differences statistically significant on day 10 (p < 0.05). Changes in hsp27 expression correlate well with changes in lipofuscin detected in the stimulation group, suggesting a connection with oxidative stress. Both differentiation factors and electrical stimulation improved hMSC differentiation potential to bone based on calcium deposition on day 28. CONCLUSIONS: Electrical stimulation is a useful tool to improve hMSC osteogenic differentiation, while heat shock proteins may reveal underlying mechanisms, and optical non-invasive imaging may be used to monitor the induced morphological and biochemical changes. PMID- 21269491 TI - A novel SNP analysis method to detect copy number alterations with an unbiased reference signal directly from tumor samples. AB - BACKGROUND: Genomic instability in cancer leads to abnormal genome copy number alterations (CNA) as a mechanism underlying tumorigenesis. Using microarrays and other technologies, tumor CNA are detected by comparing tumor sample CN to normal reference sample CN. While advances in microarray technology have improved detection of copy number alterations, the increase in the number of measured signals, noise from array probes, variations in signal-to-noise ratio across batches and disparity across laboratories leads to significant limitations for the accurate identification of CNA regions when comparing tumor and normal samples. METHODS: To address these limitations, we designed a novel "Virtual Normal" algorithm (VN), which allowed for construction of an unbiased reference signal directly from test samples within an experiment using any publicly available normal reference set as a baseline thus eliminating the need for an in lab normal reference set. RESULTS: The algorithm was tested using an optimal, paired tumor/normal data set as well as previously uncharacterized pediatric malignant gliomas for which a normal reference set was not available. Using Affymetrix 250K Sty microarrays, we demonstrated improved signal-to-noise ratio and detected significant copy number alterations using the VN algorithm that were validated by independent PCR analysis of the target CNA regions. CONCLUSIONS: We developed and validated an algorithm to provide a virtual normal reference signal directly from tumor samples and minimize noise in the derivation of the raw CN signal. The algorithm reduces the variability of assays performed across different reagent and array batches, methods of sample preservation, multiple personnel, and among different laboratories. This approach may be valuable when matched normal samples are unavailable or the paired normal specimens have been subjected to variations in methods of preservation. PMID- 21269492 TI - A dated phylogeny and collection records reveal repeated biome shifts in the African genus Coccinia (Cucurbitaceae). AB - BACKGROUND: Conservatism in climatic tolerance may limit geographic range expansion and should enhance the effects of habitat fragmentation on population subdivision. Here we study the effects of historical climate change, and the associated habitat fragmentation, on diversification in the mostly sub-Saharan cucurbit genus Coccinia, which has 27 species in a broad range of biota from semi arid habitats to mist forests. Species limits were inferred from morphology, and nuclear and plastid DNA sequence data, using multiple individuals for the widespread species. Climatic tolerances were assessed from the occurrences of 1189 geo-referenced collections and WorldClim variables. RESULTS: Nuclear and plastid gene trees included 35 or 65 accessions, representing up to 25 species. The data revealed four species groups, one in southern Africa, one in Central and West African rain forest, one widespread but absent from Central and West African rain forest, and one that occurs from East Africa to southern Africa. A few individuals are differently placed in the plastid and nuclear (LFY) trees or contain two ITS sequence types, indicating hybridization. A molecular clock suggests that the diversification of Coccinia began about 6.9 Ma ago, with most of the extant species diversity dating to the Pliocene. Ancestral biome reconstruction reveals six switches between semi-arid habitats, woodland, and forest, and members of several species pairs differ significantly in their tolerance of different precipitation regimes. CONCLUSIONS: The most surprising findings of this study are the frequent biome shifts (in a relatively small clade) over just 6 - 7 million years and the limited diversification during and since the Pleistocene. Pleistocene climate oscillations may have been too rapid or too shallow for full reproductive barriers to develop among fragmented populations of Coccinia, which would explain the apparently still ongoing hybridization between certain species. Steeper ecological gradients in East Africa and South Africa appear to have resulted in more advanced allopatric speciation there. PMID- 21269493 TI - Genomic sequencing and analysis of a Chinese hamster ovary cell line using Illumina sequencing technology. AB - BACKGROUND: Chinese hamster ovary (CHO) cells are among the most widely used hosts for therapeutic protein production. Yet few genomic resources are available to aid in engineering high-producing cell lines. RESULTS: High-throughput Illumina sequencing was used to generate a 1x genomic coverage of an engineered CHO cell line expressing secreted alkaline phosphatase (SEAP). Reference-guided alignment and assembly produced 3.57 million contigs and CHO-specific sequence information for ~ 18,000 mouse and ~ 19,000 rat orthologous genes. The majority of these genes are involved in metabolic processes, cellular signaling, and transport and represent attractive targets for cell line engineering. CONCLUSIONS: This demonstrates the applicability of next-generation sequencing technology and comparative genomic analysis in the development of CHO genomic resources. PMID- 21269494 TI - An annotated genetic map of loblolly pine based on microsatellite and cDNA markers. AB - BACKGROUND: Previous loblolly pine (Pinus taeda L.) genetic linkage maps have been based on a variety of DNA polymorphisms, such as AFLPs, RAPDs, RFLPs, and ESTPs, but only a few SSRs (simple sequence repeats), also known as simple tandem repeats or microsatellites, have been mapped in P. taeda. The objective of this study was to integrate a large set of SSR markers from a variety of sources and published cDNA markers into a composite P. taeda genetic map constructed from two reference mapping pedigrees. A dense genetic map that incorporates SSR loci will benefit complete pine genome sequencing, pine population genetics studies, and pine breeding programs. Careful marker annotation using a variety of references further enhances the utility of the integrated SSR map. RESULTS: The updated P. taeda genetic map, with an estimated genome coverage of 1,515 cM(Kosambi) across 12 linkage groups, incorporated 170 new SSR markers and 290 previously reported SSR, RFLP, and ESTP markers. The average marker interval was 3.1 cM. Of 233 mapped SSR loci, 84 were from cDNA-derived sequences (EST-SSRs) and 149 were from non-transcribed genomic sequences (genomic-SSRs). Of all 311 mapped cDNA-derived markers, 77% were associated with NCBI Pta UniGene clusters, 67% with RefSeq proteins, and 62% with functional Gene Ontology (GO) terms. Duplicate (i.e., redundant accessory) and paralogous markers were tentatively identified by evaluating marker sequences by their UniGene cluster IDs, clone IDs, and relative map positions. The average gene diversity, He, among polymorphic SSR loci, including those that were not mapped, was 0.43 for 94 EST-SSRs and 0.72 for 83 genomic-SSRs. The genetic map can be viewed and queried at http://www.conifergdb.org/pinemap. CONCLUSIONS: Many polymorphic and genetically mapped SSR markers are now available for use in P. taeda population genetics, studies of adaptive traits, and various germplasm management applications. Annotating mapped genes with UniGene clusters and GO terms allowed assessment of redundant and paralogous EST markers and further improved the quality and utility of the genetic map for P. taeda. PMID- 21269495 TI - The spatial epidemiology and clinical features of reported cases of La Crosse virus infection in West Virginia from 2003 to 2007. AB - BACKGROUND: La Crosse virus (LACV) is a major cause of pediatric encephalitis in the United States. Since the mid-1980s, the number of reported cases of LACV infection in West Virginia has continued to rise and the state currently reports the most cases in the United States. The purpose of this study was to investigate and describe the spatial epidemiology and clinical presentation of LACV infection cases reported in West Virginia, as well as to provide a description of the environmental conditions present at the residences of the LACV infection cases. METHODS: Descriptive and spatial analyses were performed on LACV infection cases reported to the West Virginia Department of Health from 2003 to 2007. Clinical and environmental variables were available for 96 cases and residence data were available for 68 of these cases. Spatial analyses using the global Moran's I and Kulldorff's spatial scan statistic were performed using the population 15 years and younger at both the county and census tract levels to identify those geographic areas at the highest risk of infection. RESULTS: Two statistically significant (p < 0.05) high-risk clusters, involving six counties, were detected at the county level. At the census tract level, one statistically significant high-risk cluster involving 41 census tracts spanning over six counties was identified. The county level cumulative incidence for those counties in the primary high-risk cluster ranged from 100.0 to 189.0 cases per 100,000 persons (median 189.0) and the census tract level cumulative incidence for those counties in the high-risk cluster ranged from 61.7 to 505.9 cases per 100,000 persons (median 99.0). The counties and census tracts within high-risk clusters had a relative risk four to nine times higher when compared to those areas not contained within high-risk clusters. The majority of LACV infection cases were reported during the summer months in children 15 years and younger. Fever, vomiting, photophobia, and nausea were the most commonly reported signs and symptoms. A case fatality rate (CFR) of 3.1% was observed. Wooded areas and containers were present at the majority of case residences. CONCLUSIONS: The cumulative incidences of LACV infection from 2003 to 2007 were considerably higher than previously reported for West Virginia, and statistically significant high-risk clusters for LACV infection were detected at both the county and census tract levels. The finding of a high CFR and the identification of those areas at highest risk for infection will be useful for guiding future research and intervention efforts. PMID- 21269496 TI - Depletion of eIF4G from yeast cells narrows the range of translational efficiencies genome-wide. AB - BACKGROUND: Eukaryotic translation initiation factor 4G (eIF4G) is thought to influence the translational efficiencies of cellular mRNAs by its roles in forming an eIF4F-mRNA-PABP mRNP that is competent for attachment of the 43S preinitiation complex, and in scanning through structured 5' UTR sequences. We have tested this hypothesis by determining the effects of genetically depleting eIF4G from yeast cells on global translational efficiencies (TEs), using gene expression microarrays to measure the abundance of mRNA in polysomes relative to total mRNA for ~5900 genes. RESULTS: Although depletion of eIF4G is lethal and reduces protein synthesis by ~75%, it had small effects (less than a factor of 1.5) on the relative TE of most genes. Within these limits, however, depleting eIF4G narrowed the range of translational efficiencies genome-wide, with mRNAs of better than average TE being translated relatively worse, and mRNAs with lower than average TE being translated relatively better. Surprisingly, the fraction of mRNAs most dependent on eIF4G display an average 5' UTR length at or below the mean for all yeast genes. CONCLUSIONS: This finding suggests that eIF4G is more critical for ribosome attachment to mRNAs than for scanning long, structured 5' UTRs. Our results also indicate that eIF4G, and the closed-loop mRNP it assembles with the m7 G cap- and poly(A)-binding factors (eIF4E and PABP), is not essential for translation of most (if not all) mRNAs but enhances the differentiation of translational efficiencies genome-wide. PMID- 21269497 TI - Primary omental torsion (POT): a review of literature and case report. AB - Eitel first described omental torsion in 1899, since then, fewer than 250 cases have been reported. Although omental torsion is rarely diagnosed preoperatively, knowledge of this pathology is important to the surgeon because it mimics the common causes of acute surgical abdomen. For this reason, in the absence of diagnosed preexisting abdominal pathology, including cysts, tumors, foci of intra abdominal inflammation, postsurgical wounds or scarring, and hernial sacs, omental torsion still can represent a surprise. Explorative laparotomy represents the diagnostic and definitive therapeutic procedure. Presently laparoscopy is the first choice procedure. PMID- 21269498 TI - A role for p38 MAPK in the regulation of ciliary motion in a eukaryote. AB - BACKGROUND: Motile cilia are essential to the survival and reproduction of many eukaryotes; they are responsible for powering swimming of protists and small multicellular organisms and drive fluids across respiratory and reproductive surfaces in mammals. Although tremendous progress has been made to comprehend the biochemical basis of these complex evolutionarily-conserved organelles, few protein kinases have been reported to co-ordinate ciliary beat. Here we present evidence for p38 mitogen-activated protein kinase (p38 MAPK) playing a role in the ciliary beat of a multicellular eukaryote, the free-living miracidium stage of the platyhelminth parasite Schistosoma mansoni. RESULTS: Fluorescence confocal microscopy revealed that non-motile miracidia trapped within eggs prior to hatching displayed phosphorylated (activated) p38 MAPK associated with their ciliated surface. In contrast, freshly-hatched, rapidly swimming, miracidia lacked phosphorylated p38 MAPK. Western blotting and immunocytochemistry demonstrated that treatment of miracidia with the p38 MAPK activator anisomycin resulted in a rapid, sustained, activation of p38 MAPK, which was primarily localized to the cilia associated with the ciliated epidermal plates, and the tegument. Freshly-hatched miracidia possessed swim velocities between 2.17 - 2.38 mm/s. Strikingly, anisomycin-mediated p38 MAPK activation rapidly attenuated swimming, reducing swim velocities by 55% after 15 min and 99% after 60 min. In contrast, SB 203580, a p38 MAPK inhibitor, increased swim velocity by up to 15% over this duration. Finally, by inhibiting swimming, p38 MAPK activation resulted in early release of ciliated epidermal plates from the miracidium thus accelerating development to the post-miracidium larval stage. CONCLUSIONS: This study supports a role for p38 MAPK in the regulation of ciliary-beat. Given the evolutionary conservation of signalling processes and cilia structure, we hypothesize that p38 MAPK may regulate ciliary beat and beat-frequency in a variety of eukaryotes. PMID- 21269499 TI - Gene expression in the rat brain: high similarity but unique differences between frontomedial-, temporal- and occipital cortex. AB - BACKGROUND: The six-layered neocortex of the mammalian brain may appear largely homologous, but is in reality a modular structure of anatomically and functionally distinct areas. However, global gene expression seems to be almost identical across the cerebral cortex and only a few genes have so far been reported to show regional enrichment in specific cortical areas. RESULTS: In the present study on adult rat brain, we have corroborated the strikingly similar gene expression among cortical areas. However, differential expression analysis has allowed for the identification of 30, 24 and 11 genes enriched in frontomedial -, temporal- or occipital cortex, respectively. A large proportion of these 65 genes appear to be involved in signal transduction, including the ion channel Fxyd6, the neuropeptide Grp and the nuclear receptor Rorb. We also find that the majority of these genes display increased expression levels around birth and show distinct preferences for certain cortical layers and cell types in rodents. CONCLUSIONS: Since specific patterns of expression often are linked to equally specialised biological functions, we propose that these cortex sub-region enriched genes are important for proper functioning of the cortical regions in question. PMID- 21269500 TI - Three hydrophobic amino acids in Escherichia coli HscB make the greatest contribution to the stability of the HscB-IscU complex. AB - BACKGROUND: General iron-sulfur cluster biosynthesis proceeds through assembly of a transient cluster on IscU followed by its transfer to a recipient apo-protein. The efficiency of the second step is increased by the presence of HscA and HscB, but the reason behind this is poorly understood. To shed light on the function of HscB, we began a study on the nature of its interaction with IscU. Our work suggested that the binding site of IscU is in the C-terminal domain of HscB, and two different triple alanine substitutions ([L92A, M93A, F153A] and [E97A, E100A, E104A]) involving predicted binding site residues had detrimental effects on this interaction. However, the individual contribution of each substitution to the observed effect remains to be determined as well as the possible involvement of other residues in the proposed binding site. RESULTS: In the work reported here, we used isothermal titration calorimetry to characterize the affinity of single alanine HscB mutants for IscU, and subsequently confirmed our results with nuclear magnetic resonance spectroscopy. Alanine substitutions of L92, L96, and F153 severely impaired the ability of HscB to form a complex with IscU; substitutions of R87, R99, and E100 had more modest effects; and substitutions of T89, M93, E97, D103, E104, R152, K156, and S160 had only minor or no detectable effects. CONCLUSIONS: Our results show that the residues of HscB most important for strong interaction with IscU include three hydrophobic residues (L92, L96, and F153); in addition, we identified a number of other residues whose side chains contribute to a lesser extent to the interaction. Our results suggest that the triple alanine substitution at HscB positions 92, 96, and 153 will destabilize the HscB-IscU complex by DeltaDeltaGb? 5.7 kcal/mol, equivalent to a ? 15000-fold reduction in the affinity of HscB for IscU. We propose that this triple mutant could provide a more definitive test of the functional importance of the HscB-IscU interaction in vivo than those used previously that yielded inconclusive results. PMID- 21269502 TI - VennDiagram: a package for the generation of highly-customizable Venn and Euler diagrams in R. AB - BACKGROUND: Visualization of orthogonal (disjoint) or overlapping datasets is a common task in bioinformatics. Few tools exist to automate the generation of extensively-customizable, high-resolution Venn and Euler diagrams in the R statistical environment. To fill this gap we introduce VennDiagram, an R package that enables the automated generation of highly-customizable, high-resolution Venn diagrams with up to four sets and Euler diagrams with up to three sets. RESULTS: The VennDiagram package offers the user the ability to customize essentially all aspects of the generated diagrams, including font sizes, label styles and locations, and the overall rotation of the diagram. We have implemented scaled Venn and Euler diagrams, which increase graphical accuracy and visual appeal. Diagrams are generated as high-definition TIFF files, simplifying the process of creating publication-quality figures and easing integration with established analysis pipelines. CONCLUSIONS: The VennDiagram package allows the creation of high quality Venn and Euler diagrams in the R statistical environment. PMID- 21269501 TI - Insights into the innate immunity of the Mediterranean mussel Mytilus galloprovincialis. AB - BACKGROUND: Sessile bivalves of the genus Mytilus are suspension feeders relatively tolerant to a wide range of environmental changes, used as sentinels in ecotoxicological investigations and marketed worldwide as seafood. Mortality events caused by infective agents and parasites apparently occur less in mussels than in other bivalves but the molecular basis of such evidence is unknown. The arrangement of Mytibase, interactive catalogue of 7,112 transcripts of M. galloprovincialis, offered us the opportunity to look for gene sequences relevant to the host defences, in particular the innate immunity related genes. RESULTS: We have explored and described the Mytibase sequence clusters and singletons having a putative role in recognition, intracellular signalling, and neutralization of potential pathogens in M. galloprovincialis. Automatically assisted searches of protein signatures and manually cured sequence analysis confirmed the molecular diversity of recognition/effector molecules such as the antimicrobial peptides and many carbohydrate binding proteins. Molecular motifs identifying complement C1q, C-type lectins and fibrinogen-like transcripts emerged as the most abundant in the Mytibase collection whereas, conversely, sequence motifs denoting the regulatory cytokine MIF and cytokine-related transcripts represent singular and unexpected findings. Using a cross-search strategy, 1,820 putatively immune-related sequences were selected to design oligonucleotide probes and define a species-specific Immunochip (DNA microarray). The Immunochip performance was tested with hemolymph RNAs from mussels injected with Vibrio splendidus at 3 and 48 hours post-treatment. A total of 143 and 262 differentially expressed genes exemplify the early and late hemocyte response of the Vibrio-challenged mussels, respectively, with AMP trends confirmed by qPCR and clear modulation of interrelated signalling pathways. CONCLUSIONS: The Mytibase collection is rich in gene transcripts modulated in response to antigenic stimuli and represents an interesting window for looking at the mussel immunome (transcriptomes mediating the mussel response to non-self or abnormal antigens). On this basis, we have defined a new microarray platform, a mussel Immunochip, as a flexible tool for the experimental validation of immune candidate sequences, and tested its performance on Vibrio-activated mussel hemocytes. The microarray platform and related expression data can be regarded as a step forward in the study of the adaptive response of the Mytilus species to an evolving microbial world. PMID- 21269503 TI - Cost-effectiveness of novel vaccines for tuberculosis control: a decision analysis study. AB - BACKGROUND: The development of a successful new tuberculosis (TB) vaccine would circumvent many limitations of current diagnostic and treatment practices. However, vaccine development is complex and costly. We aimed to assess the potential cost effectiveness of novel vaccines for TB control in a sub-Saharan African country--Zambia--relative to the existing strategy of directly observed treatment, short course (DOTS) and current level of bacille Calmette-Guerin (BCG) vaccination coverage. METHODS: We conducted a decision analysis model-based simulation from the societal perspective, with a 3% discount rate and all costs expressed in 2007 US dollars. Health outcomes and costs were projected over a 30 year period, for persons born in Zambia (population 11,478,000 in 2005) in year 1. Initial development costs for single vaccination and prime-boost strategies were prorated to the Zambian share (0.398%) of global BCG vaccine coverage for newborns. Main outcome measures were TB-related morbidity, mortality, and costs over a range of potential scenarios for vaccine efficacy. RESULTS: Relative to the status quo strategy, a BCG replacement vaccine administered at birth, with 70% efficacy in preventing rapid progression to TB disease after initial infection, is estimated to avert 932 TB cases and 422 TB-related deaths (prevention of 199 cases/100,000 vaccinated, and 90 deaths/100,000 vaccinated). This would result in estimated net savings of $3.6 million over 30 years for 468,073 Zambians born in year 1 of the simulation. The addition of a booster at age 10 results in estimated savings of $5.6 million compared to the status quo, averting 1,863 TB cases and 1,011 TB-related deaths (prevention of 398 cases/100,000 vaccinated, and of 216 deaths/100,000 vaccinated). With vaccination at birth alone, net savings would be realized within 1 year, whereas the prime boost strategy would require an additional 5 years to realize savings, reflecting a greater initial development cost. CONCLUSIONS: Investment in an improved TB vaccine is predicted to result in considerable cost savings, as well as a reduction in TB morbidity and TB-related mortality, when added to existing control strategies. For a vaccine with waning efficacy, a prime-boost strategy is more cost-effective in the long term. PMID- 21269504 TI - Comparative analysis and supragenome modeling of twelve Moraxella catarrhalis clinical isolates. AB - BACKGROUND: M. catarrhalis is a gram-negative, gamma-proteobacterium and an opportunistic human pathogen associated with otitis media (OM) and exacerbations of chronic obstructive pulmonary disease (COPD). With direct and indirect costs for treating these conditions annually exceeding $33 billion in the United States alone, and nearly ubiquitous resistance to beta-lactam antibiotics among M. catarrhalis clinical isolates, a greater understanding of this pathogen's genome and its variability among isolates is needed. RESULTS: The genomic sequences of ten geographically and phenotypically diverse clinical isolates of M. catarrhalis were determined and analyzed together with two publicly available genomes. These twelve genomes were subjected to detailed comparative and predictive analyses aimed at characterizing the supragenome and understanding the metabolic and pathogenic potential of this species. A total of 2383 gene clusters were identified, of which 1755 are core with the remaining 628 clusters unevenly distributed among the twelve isolates. These findings are consistent with the distributed genome hypothesis (DGH), which posits that the species genome possesses a far greater number of genes than any single isolate. Multiple and pair-wise whole genome alignments highlight limited chromosomal re-arrangement. CONCLUSIONS: M. catarrhalis gene content and chromosomal organization data, although supportive of the DGH, show modest overall genic diversity. These findings are in stark contrast with the reported heterogeneity of the species as a whole, as wells as to other bacterial pathogens mediating OM and COPD, providing important insight into M. catarrhalis pathogenesis that will aid in the development of novel therapeutic regimens. PMID- 21269505 TI - TNFA deletion alters apoptosis as well as caspase 3 and 4 expression during otitis media. AB - BACKGROUND: Tumor necrosis factor (TNFA) is the canonical member of the TNF superfamily, which plays a major role in both inflammation and apoptosis. To evaluate the role of TNFs in otitis media (OM), the most common disease of childhood, we evaluated middle ear (ME) expression of genes encoding the TNF and TNF receptor superfamilies during bacterial OM in the mouse, characterized OM in TNFA-deficient mice, and assessed apoptosis during OM in normal versus TNF deficient MEs. RESULTS: TNFs and TNF receptors were broadly regulated during OM, with TNFA showing the highest level of up-regulation. TNF deficient mice exhibited mucosal hyperplasia even in the absence of infection and exuberant growth of the mucosa during OM, including the formation of mucosal polyps. Mucosal recovery during OM was also delayed, in parallel with a delay in mucosal apoptosis and reduced caspase gene expression. CONCLUSIONS: The TNF and TNF receptor superfamilies mediate both inflammation and apoptosis during OM. TNF appears to be critical for the maintenance of mucosal architecture in both the normal and infected ME, since excessive accumulation of mucosal tissue is seen in TNFA-/- MEs both before and after bacterial inoculation of the ME. TNFA is also required for appropriate regulation of caspase genes. PMID- 21269506 TI - Activation of the dopamine 1 and dopamine 5 receptors increase skeletal muscle mass and force production under non-atrophying and atrophying conditions. AB - BACKGROUND: Control of skeletal muscle mass and force production is a complex physiological process involving numerous regulatory systems. Agents that increase skeletal muscle cAMP levels have been shown to modulate skeletal muscle mass and force production. The dopamine 1 receptor and its closely related homolog, the dopamine 5 receptor, are G-protein coupled receptors that are expressed in skeletal muscle and increase cAMP levels when activated. Thus we hypothesize that activation of the dopamine 1 and/or 5 receptor will increase skeletal muscle cAMP levels thereby modulating skeletal muscle mass and force production. METHODS: We treated isolated mouse tibialis anterior (TA) and medial gastrocnemius (MG) muscles in tissue bath with the selective dopamine 1 receptor and dopamine 5 receptor agonist SKF 81297 to determine if activation of skeletal muscle dopamine 1 and dopamine 5 receptors will increase cAMP. We dosed wild-type mice, dopamine 1 receptor knockout mice and dopamine 5 receptor knockout mice undergoing casting induced disuse atrophy with SKF 81297 to determine if activation of the dopamine 1 and dopamine 5 receptors results in hypertrophy of non-atrophying skeletal muscle and preservation of atrophying skeletal muscle mass and force production. RESULTS: In tissue bath, isolated mouse TA and MG muscles responded to SKF 81297 treatment with increased cAMP levels. Treating wild-type mice with SKF 81297 reduced casting-induced TA and MG muscle mass loss in addition to increasing the mass of non-atrophying TA and MG muscles. In dopamine 1 receptor knockout mice, extensor digitorum longus (EDL) and soleus muscle mass and force was not preserved during casting with SKF 81297 treatment, in contrast to significant preservation of casted wild-type mouse EDL and soleus mass and EDL force with SKF 81297 treatment. Dosing dopamine 5 receptor knockout mice with SKF 81297 did not significantly preserve EDL and soleus muscle mass and force although wild-type mouse EDL mass and force was significantly preserved SKF 81297 treatment. CONCLUSIONS: These data demonstrate for the first time that treatment with a dopamine 1/5 receptor agonist results in (1) significant preservation of EDL, TA, MG and soleus muscle mass and EDL muscle force production during periods of atrophy and (2) hypertrophy of TA and MG muscle. These effects appear to be mainly mediated by both the dopamine 1 and dopamine 5 receptors. PMID- 21269508 TI - Signal processing of heart signals for the quantification of non-deterministic events. AB - BACKGROUND: Heart signals represent an important way to evaluate cardiovascular function and often what is desired is to quantify the level of some signal of interest against the louder backdrop of the beating of the heart itself. An example of this type of application is the quantification of cavitation in mechanical heart valve patients. METHODS: An algorithm is presented for the quantification of high-frequency, non-deterministic events such as cavitation from recorded signals. A closed-form mathematical analysis of the algorithm investigates its capabilities. The algorithm is implemented on real heart signals to investigate usability and implementation issues. Improvements are suggested to the base algorithm including aligning heart sounds, and the implementation of the Short-Time Fourier Transform to study the time evolution of the energy in the signal. RESULTS: The improvements result in better heart beat alignment and better detection and measurement of the random events in the heart signals, so that they may provide a method to quantify nondeterministic events in heart signals. The use of the Short-Time Fourier Transform allows the examination of the random events in both time and frequency allowing for further investigation and interpretation of the signal. CONCLUSIONS: The presented algorithm does allow for the quantification of nondeterministic events but proper care in signal acquisition and processing must be taken to obtain meaningful results. PMID- 21269507 TI - O6-Methylguanine-DNA methyltransferase protein expression by immunohistochemistry in brain and non-brain systemic tumours: systematic review and meta-analysis of correlation with methylation-specific polymerase chain reaction. AB - BACKGROUND: The DNA repair protein O6-Methylguanine-DNA methyltransferase (MGMT) confers resistance to alkylating agents. Several methods have been applied to its analysis, with methylation-specific polymerase chain reaction (MSP) the most commonly used for promoter methylation study, while immunohistochemistry (IHC) has become the most frequently used for the detection of MGMT protein expression. Agreement on the best and most reliable technique for evaluating MGMT status remains unsettled. The aim of this study was to perform a systematic review and meta-analysis of the correlation between IHC and MSP. METHODS: A computer-aided search of MEDLINE (1950-October 2009), EBSCO (1966-October 2009) and EMBASE (1974 October 2009) was performed for relevant publications. Studies meeting inclusion criteria were those comparing MGMT protein expression by IHC with MGMT promoter methylation by MSP in the same cohort of patients. Methodological quality was assessed by using the QUADAS and STARD instruments. Previously published guidelines were followed for meta-analysis performance. RESULTS: Of 254 studies identified as eligible for full-text review, 52 (20.5%) met the inclusion criteria. The review showed that results of MGMT protein expression by IHC are not in close agreement with those obtained with MSP. Moreover, type of tumour (primary brain tumour vs others) was an independent covariate of accuracy estimates in the meta-regression analysis beyond the cut-off value. CONCLUSIONS: Protein expression assessed by IHC alone fails to reflect the promoter methylation status of MGMT. Thus, in attempts at clinical diagnosis the two methods seem to select different groups of patients and should not be used interchangeably. PMID- 21269509 TI - Training family physicians and residents in family medicine in shared decision making to improve clinical decisions regarding the use of antibiotics for acute respiratory infections: protocol for a clustered randomized controlled trial. AB - BACKGROUND: To explore ways to reduce the overuse of antibiotics for acute respiratory infections (ARIs), we conducted a pilot clustered randomized controlled trial (RCT) to evaluate DECISION+, a training program in shared decision making (SDM) for family physicians (FPs). This pilot project demonstrated the feasibility of conducting a large clustered RCT and showed that DECISION+ reduced the proportion of patients who decided to use antibiotics immediately after consulting their physician. Consequently, the objective of this study is to evaluate, in patients consulting for ARIs, if exposure of physicians to a modified version of DECISION+, DECISION+2, would reduce the proportion of patients who decide to use antibiotics immediately after consulting their physician. METHODS/DESIGN: The study is a multi-center, two-arm, parallel clustered RCT. The 12 family practice teaching units (FPTUs) in the network of the Department of Family Medicine and Emergency Medicine of Universite Laval will be randomized to a DECISION+2 intervention group (experimental group) or to a no intervention control group. These FPTUs will recruit patients consulting family physicians and residents in family medicine enrolled in the study. There will be two data collection periods: pre-intervention (baseline) including 175 patients with ARIs in each study arm, and post-intervention including 175 patients with ARIs in each study arm (total n = 700). The primary outcome will be the proportion of patients reporting a decision to use antibiotics immediately after consulting their physician. Secondary outcome measures include: 1) physicians and patients' decisional conflict; 2) the agreement between the parties' decisional conflict scores; and 3) perception of patients and physicians that SDM occurred. Also in patients, at 2 weeks follow-up, adherence to the decision, consultation for the same reason, decisional regret, and quality of life will be assessed. Finally, in both patients and physicians, intention to engage in SDM in future clinical encounters will be assessed. Intention-to-treat analyses will be applied and account for the nested design of the trial will be taken into consideration. DISCUSSION: DECISION+2 has the potential to reduce antibiotics use for ARIs by priming physicians and patients to share decisional process and empowering patients to make informed, value-based decisions. PMID- 21269510 TI - AtRabD2b and AtRabD2c have overlapping functions in pollen development and pollen tube growth. AB - BACKGROUND: Rab GTPases are important regulators of endomembrane trafficking, regulating exocytosis, endocytosis and membrane recycling. Many Rab-like proteins exist in plants, but only a subset have been functionally characterized. RESULTS: Here we report that AtRabD2b and AtRabD2c play important roles in pollen development, germination and tube elongation. AtrabD2b and AtrabD2c single mutants have no obvious morphological changes compared with wild-type plants across a variety of growth conditions. An AtrabD2b/2c double mutant is also indistinguishable from wild-type plants during vegetative growth; however its siliques are shorter than those in wild-type plants. Compared with wild-type plants, AtrabD2b/2c mutants produce deformed pollen with swollen and branched pollen tube tips. The shorter siliques in the AtrabD2b/2c double mutant were found to be primarily due to the pollen defects. AtRabD2b and AtRabD2c have different but overlapping expression patterns, and they are both highly expressed in pollen. Both AtRabD2b and AtRabD2c protein localize to Golgi bodies. CONCLUSIONS: These findings support a partially redundant role for AtRabD2b and AtRabD2c in vesicle trafficking during pollen tube growth that cannot be fulfilled by the remaining AtRabD family members. PMID- 21269511 TI - Induction of B-cell lymphoma by UVB radiation in p53 haploinsufficient mice. AB - BACKGROUND: The incidence of non-Hodgkin's lymphoma has increased over recent years. The exact etiology of lymphoma remains unknown. Ultraviolet light exposure has been associated with the development of internal lymphoid malignancies and some reports suggest that it may play a role in the development of lymphoma in humans. Here we describe the characterization and progression of lymphoma in p53 heterozygous mice exposed to UVB irradiation. METHODS: UVB-irradiated p53+/- mice developed enlargement of the spleen. Isolated spleen cells were transplanted into Rag deficient hosts. The UV-induced tumor cells were analyzed by flow cytometry. The tumor cells were tagged with GFP to study their metastatic potential. SKY and karyotypic analysis were carried out for the detection of chromosomal abnormalities. Functional assays included in vitro class switch recombination assay, immunoglobulin rearrangement assay, as well as cytokine profiling. RESULTS: UVB-exposed mice showed enlargement of the spleen and lymph nodes. Cells transplanted into Rag deficient mice developed aggressive tumors that infiltrated the lymph nodes, the spleen and the bone marrow. The tumor cells did not grow in immune competent syngeneic C57Bl/6 mice yet showed a modest growth in UV irradiated B6 mice. Phenotypic analysis of these tumor cells revealed these cells are positive for B cell markers CD19+, CD5+, B220+, IgM+ and negative for T cell, NK or dendritic cell markers. The UV-induced tumor cells underwent robust in vitro immunoglobulin class switch recombination in response to lipopolysaccharide. Cytogenetic analysis revealed a t(14;19) translocation and trisomy of chromosome 6. These tumor cells secret IL-10, which can promote tumor growth and cause systemic immunosuppression. CONCLUSION: UV-irradiated p53+/- mice developed lymphoid tumors that corresponded to a mature B cell lymphoma. Our results suggest that an indirect mechanism is involved in the development of internal tumors after chronic exposure to UV light. The induction of B cell lymphoma in UV-irradiated p53 heterozygous mice may provide a useful model for lymphoma development in humans. PMID- 21269512 TI - Influence of lip closure on alveolar cleft width in patients with cleft lip and palate. AB - BACKGROUND: The influence of surgery on growth and stability after treatment in patients with cleft lip and palate are topics still under discussion. The aim of the present study was to investigate the influence of early lip closure on the width of the alveolar cleft using dental casts. METHODS: A total of 44 clefts were investigated using plaster casts, 30 unilateral and 7 bilateral clefts. All infants received a passive molding plate a few days after birth. The age at the time of closure of the lip was 2.1 month in average (range 1-6 months). Plaster casts were obtained at the following stages: shortly after birth, prior to lip closure, prior to soft palate closure. We determined the width of the alveolar cleft before lip closure and prior to soft palate closure measuring the alveolar cleft width from the most lateral point of the premaxilla/anterior segment to the most medial point of the smaller segment. RESULTS: After lip closure 15 clefts presented with a width of 0 mm, meaning that the mucosa of the segments was almost touching one another. 19 clefts showed a width of up to 2 mm and 10 clefts were still over 2 mm wide. This means a reduction of 0% in 5 clefts, of 1-50% in 6 clefts, of 51-99% in 19 clefts, and of 100% in 14 clefts. CONCLUSIONS: Early lip closure reduces alveolar cleft width. In most cases our aim of a remaining cleft width of 2 mm or less can be achieved. These are promising conditions for primary alveolar bone grafting to restore the dental bony arch. PMID- 21269513 TI - Characterization of the past and current duplication activities in the human 22q11.2 region. AB - BACKGROUND: Segmental duplications (SDs) on 22q11.2 (LCR22), serve as substrates for meiotic non-allelic homologous recombination (NAHR) events resulting in several clinically significant genomic disorders. RESULTS: To understand the duplication activity leading to the complicated SD structure of this region, we have applied the A-Bruijn graph algorithm to decompose the 22q11.2 SDs to 523 fundamental duplication sequences, termed subunits. Cross-species syntenic analysis of primate genomes demonstrates that many of these LCR22 subunits emerged very recently, especially those implicated in human genomic disorders. Some subunits have expanded more actively than others, and young Alu SINEs, are associated much more frequently with duplicated sequences that have undergone active expansion, confirming their role in mediating recombination events. Many copy number variations (CNVs) exist on 22q11.2, some flanked by SDs. Interestingly, two chromosome breakpoints for 13 CNVs (mean length 65 kb) are located in paralogous subunits, providing direct evidence that SD subunits could contribute to CNV formation. Sequence analysis of PACs or BACs identified extra CNVs, specifically, 10 insertions and 18 deletions within 22q11.2; four were more than 10 kb in size and most contained young AluYs at their breakpoints. CONCLUSIONS: Our study indicates that AluYs are implicated in the past and current duplication events, and moreover suggests that DNA rearrangements in 22q11.2 genomic disorders perhaps do not occur randomly but involve both actively expanded duplication subunits and Alu elements. PMID- 21269514 TI - The relationship between active travel to school and health-related fitness in children and adolescents: a systematic review. AB - BACKGROUND: Active travel to school (ATS) has been identified as an important source of physical activity for youth. However, the relationship between ATS and health-related fitness (HRF) among youth remains unclear. METHODS: A systematic search of seven electronic databases (EMBASE, OVID MEDLINE, PsycINFO, PubMed, Scopus, SPORTDiscus and TRIS on line) was conducted in December 2009 and studies published since 1980 were considered for inclusion. RESULTS: Twenty seven articles were identified that explored the relationship between ATS and the following aspects of HRF: weight status/body composition, cardiorespiratory fitness, muscular fitness and flexibility. Forty-eight percent of the studies that examined the relationship between ATS and weight status/body composition reported significant associations, this increased to 55% once poor quality studies were removed. Furthermore, the findings from five studies, including one longitudinal study, indicate that ATS is positively associated with cardiorespiratory fitness in youth. However, the evidence for the relationships between ATS and muscular fitness or flexibility is equivocal and limited by low study numbers. CONCLUSIONS: There is some evidence to suggest that ATS is associated with a healthier body composition and level of cardiorespiratory fitness among youth. Strategies to increase ATS are warranted and should be included in whole-of-school approaches to the promotion of physical activity. PMID- 21269515 TI - "Do I really want to do this?" Longitudinal cohort study participants' perspectives on postal survey design: a qualitative study. AB - BACKGROUND: Randomised controlled trials have investigated aspects of postal survey design yet cannot elaborate on reasons behind participants' decision making and survey behaviour. This paper reports participants' perspectives of the design of, and participation in, a longitudinal postal cohort survey. It describes strengths and weaknesses in study design from the perspectives of study participants and aims to contribute to the: 1) design of future cohort surveys and questionnaires generally and, 2) design of cohort surveys for people with musculoskeletal disorders (MSDs) specifically. METHODS: In-depth interviews explored the design of postal surveys previously completed by participants. Interviews used open ended questioning with a topic guide for prompts if areas of interest were not covered spontaneously. Thematic data analysis was undertaken based on the framework method. A second researcher verified all coding. RESULTS: Data from fourteen interviews were analysed within three main themes; participation, survey design and survey content. One of the main findings was the importance of clear communication aimed at the correct audience both when inviting potential participants to take part and within the survey itself. Providing enough information about the study, having a topic of interest and an explanation of likely benefits of the study were important when inviting people to participate. The neutrality of the survey and origination from a reputable source were both important; as was an explanation about why information was being collected within the survey itself. Study findings included participants' impressions when invited to take part, why they participated, the acceptability of follow-up of non-responders and why participants completed the follow-up postal survey. Also discussed were participants' first impression of the survey, its length, presentation and participants' views about specific questions within the survey. CONCLUSIONS: Ideas generated in this study provide an insight into participants' decision making and survey behaviour and may enhance the acceptability of future surveys to potential participants. As well as clear communication, participants valued incentives and survey questions that were relevant to them. However, opinions varied as to the preferred format for responses with some advising more opportunity for open-ended feedback. We also found that some standard format questions can raise quandaries for individual participants. PMID- 21269516 TI - Mortality from suicide and other external cause injuries in China: a prospective cohort study. AB - BACKGROUND: Premature death from suicide is a leading cause of death worldwide. However, the pattern and risk factors for suicide and other external cause injuries are not well understood. This study investigates mortality from suicide and other injuries and associated risk factors in China. METHODS: A prospective cohort study of 169,871 Chinese adults aged 40 years and older was conducted. Mortality due to suicide or other external cause injuries was recorded. RESULTS: Mortality from all external causes was 58.7/100,000 (72.3 in men and 44.4 in women): 14.1/100,000 (14.2 in men and 14.2 in women) for suicide and 44.6/100,000 (58.1 in men and 30.2 in women) for other external cause injuries. Transport accidents (17.2/100,000 overall, 23.4 in men and 10.8 in women), accidental poisoning (7.5/100,000 overall, 10.2 in men and 4.8 in women), and accidental falls (5.7/100,000 overall, 6.5 in men and 5.0 in women) were the three leading causes of death from other external cause injuries in China. In the multivariable analysis, male sex (relative risk [RR] 1.56, 95% confidence interval [CI] 1.03 2.38), age 70 years and older (2.27, 1.29-3.98), living in north China (1.68, 1.20-2.36) and rural residence (2.82, 1.76-4.51) were associated with increased mortality from suicide. Male sex (RR 2.50, 95% CI 1.95-3.20), age 60-69 years (1.93, 1.45-2.58) and 70 years and older (3.58, 2.58-4.97), rural residence (2.29, 1.77-2.96), and having no education (1.56, 1.00-2.43) were associated with increased mortality from other external cause injuries, while overweight (0.60, 0.43-0.83) was associated with decreased risk of mortality from other external cause injuries. CONCLUSIONS: External cause mortality has become a major public health problem in China. Developing an integrated national program for the prevention of mortality due to external cause injuries in China is warranted. PMID- 21269517 TI - ASPDock: protein-protein docking algorithm using atomic solvation parameters model. AB - BACKGROUND: Atomic Solvation Parameters (ASP) model has been proven to be a very successful method of calculating the binding free energy of protein complexes. This suggests that incorporating it into docking algorithms should improve the accuracy of prediction. In this paper we propose an FFT-based algorithm to calculate ASP scores of protein complexes and develop an ASP-based protein protein docking method (ASPDock). RESULTS: The ASPDock is first tested on the 21 complexes whose binding free energies have been determined experimentally. The results show that the calculated ASP scores have stronger correlation (r ~ 0.69) with the binding free energies than the pure shape complementarity scores (r ~ 0.48). The ASPDock is further tested on a large dataset, the benchmark 3.0, which contain 124 complexes and also shows better performance than pure shape complementarity method in docking prediction. Comparisons with other state-of-the art docking algorithms showed that ASP score indeed gives higher success rate than the pure shape complementarity score of FTDock but lower success rate than Zdock3.0. We also developed a softly restricting method to add the information of predicted binding sites into our docking algorithm. The ASP-based docking method performed well in CAPRI rounds 18 and 19. CONCLUSIONS: ASP may be more accurate and physical than the pure shape complementarity in describing the feature of protein docking. PMID- 21269518 TI - Image-guided intensity modulated radiotherapy with helical tomotherapy for postoperative treatment of high-risk oral cavity cancer. AB - BACKGROUND: The aim of this study was to assess the treatment results and toxicity profiles of helical tomotherapy (HT) for postoperative high-risk oral cavity cancer. METHODS: From December 6, 2006 through October 9, 2009, 19 postoperative high-risk oral cavity cancer patients were enrolled. All of the patients received HT with (84%) or without (16%) chemotherapy. RESULTS: The median follow-up time was 17 months. The 2-year overall survival, disease-free survival, locoregional control, and distant metastasis-free rates were 94%, 84%, 92%, and 94%, respectively. The package of overall treatment time > 13 wk, the interval between surgery and radiation <= 6 wk, and the overall treatment time of radiation <= 7 wk was 21%, 84%, and 79%, respectively. The percentage of grade 3 mucositis, dermatitis, and leucopenia was 42%, 5% and 5%, respectively. CONCLUSIONS: HT achieved encouraging clinical outcomes for postoperative high risk oral cavity cancer patients with high compliance. A long-term follow-up study is needed to confirm these preliminary findings. PMID- 21269519 TI - Virus-derived transgenes expressing hairpin RNA give immunity to Tobacco mosaic virus and Cucumber mosaic virus. AB - BACKGROUND: An effective method for obtaining resistant transgenic plants is to induce RNA silencing by expressing virus-derived dsRNA in plants and this method has been successfully implemented for the generation of different plant lines resistant to many plant viruses. RESULTS: Inverted repeats of the partial Tobacco mosaic virus (TMV) movement protein (MP) gene and the partial Cucumber mosaic virus (CMV) replication protein (Rep) gene were introduced into the plant expression vector and the recombinant plasmids were transformed into Agrobacterium tumefaciens. Agrobacterium-mediated transformation was carried out and three transgenic tobacco lines (MP16-17-3, MP16-17-29 and MP16-17-58) immune to TMV infection and three transgenic tobacco lines (Rep15-1-1, Rep15-1-7 and Rep15-1-32) immune to CMV infection were obtained. Virus inoculation assays showed that the resistance of these transgenic plants could inherit and keep stable in T4 progeny. The low temperature (15 degrees C did not influence the resistance of transgenic plants. There was no significant correlation between the resistance and the copy number of the transgene. CMV infection could not break the resistance to TMV in the transgenic tobacco plants expressing TMV hairpin MP RNA. CONCLUSIONS: We have demonstrated that transgenic tobacco plants expressed partial TMV movement gene and partial CMV replicase gene in the form of an intermolecular intron-hairpin RNA exhibited complete resistance to TMV or CMV infection. PMID- 21269520 TI - Analysis of nucleosome positioning determined by DNA helix curvature in the human genome. AB - BACKGROUND: Nucleosome positioning has an important role in gene regulation. However, dynamic positioning in vivo casts doubt on the reliability of predictions based on DNA sequence characteristics. What role does sequence dependent positioning play? In this paper, using a curvature profile model, nucleosomes are predicted in the human genome and patterns of nucleosomes near some key sites are investigated. RESULTS: Curvature profiling revealed that in the vicinity of a transcription start site, there is also a nucleosome-free region. Near transcription factor binding sites, curvature profiling showed a trough, indicating nucleosome depletion. The trough of the curvature profile corresponds well to the high binding scores of transcription factors. Moreover, our analysis suggests that nucleosome positioning has a selective protection role. Target sites of miRNAs are occupied by nucleosomes, while single nucleotide polymorphism sites are depleted of nucleosomes. CONCLUSIONS: The results indicate that DNA sequences play an important role in nucleosome positioning, and the positioning is important not only in gene regulation, but also in genetic variation and miRNA functions. PMID- 21269521 TI - Galectin-1 is expressed in early-type neural progenitor cells and down-regulates neurogenesis in the adult hippocampus. AB - BACKGROUND: In the adult mammalian brain, neural stem cells (NSCs) proliferate in the dentate gyrus (DG) of the hippocampus and generate new neurons throughout life. A multimodal protein, Galectin-1, is expressed in neural progenitor cells (NPCs) and implicated in the proliferation of the NPCs in the DG. However, little is known about its detailed expression profile in the NPCs and functions in adult neurogenesis in the DG. RESULTS: Our immunohistochemical and morphological analysis showed that Galectin-1 was expressed in the type 1 and 2a cells, which are putative NSCs, in the subgranular zone (SGZ) of the adult mouse DG. To study Galectin-1's function in adult hippocampal neurogenesis, we made galectin-1 knock out mice on the C57BL6 background and characterized the effects on neurogenesis. In the SGZ of the galectin-1 knock-out mice, increased numbers of type 1 cells, DCX-positive immature progenitors, and NeuN-positive newborn neurons were observed. Using triple-labeling immunohistochemistry and morphological analyses, we found that the proliferation of the type-1 cells was increased in the SGZ of the galectin-1 knock-out mice, and we propose that this proliferation is the mechanism for the net increase in the adult neurogenesis in these knock-out mice DG. CONCLUSIONS: Galectin-1 is expressed in the neural stem cells and down regulates neurogenesis in the adult hippocampus. PMID- 21269522 TI - Experimental infection of dogs with a feline endogenous retrovirus RD-114. AB - BACKGROUND: The feline endogenous retrovirus RD114 is contained in the genome of cats. The virus may contaminate live canine vaccines based on cultured feline cells. The in vivo infectivity, acute and subacute pathogenicity, and viral proliferation of the RD114 virus were evaluated by experimental infection of dogs. METHODS: Nine specific pathogen free dogs were divided into three groups, with each group consisting of one female and two male dogs. Dogs were subcutaneously inoculated in the neck with either 1 ml RD114 stock virus (group A), inactivated RD114 virus suspension (group B), or cell culture medium (group C) as a negative control. To assess blood cell counts and biochemical properties, blood samples from each group were collected 5 days before inoculation, just prior to inoculation, and 1, 3, 7 and 10 days post-inoculation. RESULT: During the experimental period of 51 days, none of the dogs inoculated with RD114 virus showed any clinical signs, significant increases in rectal temperature or abnormal blood biochemical characteristics including C-reactive protein when compared with the negative controls. We were not able to re-isolate the RD114 virus from buffy coat cells of group A dogs. Additionally, we could not detect RD114 provirus in the genomic DNA isolated from peripheral blood leukocytes, lymph node, spleen and sternal bone marrow cells. CONCLUSIONS: Signs of RD114 virus proliferation were not found after subcutaneous infection of dogs. Although the potential risk caused by infection with RD114 virus in dogs could not be assessed in this study, we suspect that RD114 virus has little or no virulence in dogs. PMID- 21269523 TI - Distinctive mitochondrial genome of Calanoid copepod Calanus sinicus with multiple large non-coding regions and reshuffled gene order: useful molecular markers for phylogenetic and population studies. AB - BACKGROUND: Copepods are highly diverse and abundant, resulting in extensive ecological radiation in marine ecosystems. Calanus sinicus dominates continental shelf waters in the northwest Pacific Ocean and plays an important role in the local ecosystem by linking primary production to higher trophic levels. A lack of effective molecular markers has hindered phylogenetic and population genetic studies concerning copepods. As they are genome-level informative, mitochondrial DNA sequences can be used as markers for population genetic studies and phylogenetic studies. RESULTS: The mitochondrial genome of C. sinicus is distinct from other arthropods owing to the concurrence of multiple non-coding regions and a reshuffled gene arrangement. Further particularities in the mitogenome of C. sinicus include low A + T-content, symmetrical nucleotide composition between strands, abbreviated stop codons for several PCGs and extended lengths of the genes atp6 and atp8 relative to other copepods. The monophyletic Copepoda should be placed within the Vericrustacea. The close affinity between Cyclopoida and Poecilostomatoida suggests reassigning the latter as subordinate to the former. Monophyly of Maxillopoda is rejected. Within the alignment of 11 C. sinicus mitogenomes, there are 397 variable sites harbouring three 'hotspot' variable sites and three microsatellite loci. CONCLUSION: The occurrence of the circular subgenomic fragment during laboratory assays suggests that special caution should be taken when sequencing mitogenomes using long PCR. Such a phenomenon may provide additional evidence of mitochondrial DNA recombination, which appears to have been a prerequisite for shaping the present mitochondrial profile of C. sinicus during its evolution. The lack of synapomorphic gene arrangements among copepods has cast doubt on the utility of gene order as a useful molecular marker for deep phylogenetic analysis. However, mitochondrial genomic sequences have been valuable markers for resolving phylogenetic issues concerning copepods. The variable site maps of C. sinicus mitogenomes provide a solid foundation for population genetic studies. PMID- 21269524 TI - "The metabolic syndrome... is dead": these reports are an exaggeration. AB - The debates continue over the validity of the metabolic syndrome concept. The continuous increment of the obesity pandemic is almost worldwide paralleled by rising rates of metabolic syndrome prevalence. Then, it seems obvious that these debates drove the need for further investigations as well as a deeper cooperation between relevant national and international organizations regarding the issue. Instead, part of the scientific community elected to totally "dismiss" the concept of the metabolic syndrome. Meanwhile, the best available evidence from three consecutive large meta-analyses has systematically shown that people with metabolic syndrome are at increased risk of cardiovascular events. The most recent and largest of them included near one million patients (total n = 951,083). The investigators concluded that the metabolic syndrome is associated with a 2-fold increase in cardiovascular outcomes and a 1.5-fold increase in all cause mortality rates. One of the ways to hit the metabolic syndrome is an utterly simplistic view on this concept as a predictive tool only. Of course, the presence of the metabolic syndrome possesses a definite predictive value, but first of all it is a widely accepted concept regarding a biological condition based on the complex and interrelated pathophysiological mechanisms starting from excess central adiposity and insulin resistance. Therefore, it is completely unfair to compare it with statistically constructed predictive tools, including stronger prognostic variables even unrelated to each other from the biological point of view. For example, in the criteria for metabolic syndrome (in contrast to Framingham score) age and cholesterol--presumably low density lipoprotein cholesterol (LDL-C)--levels are not included, as well as a variety of strong predictors used in other risk-stratification scores: previous myocardial infarction, heart failure, smoking, family history, etc. However, the metabolic syndrome identifies additional important residual vascular risk mainly associated with insulin resistance and atherogenic dyslipidemia (low high density lipoprotein-cholesterol (HDL-C), high triglycerides, small, dense LDL-C). Therefore, the metabolic syndrome could be a useful additional contributor in estimation of global cardiovascular risk beyond age, high LDL-C or other standard risk factors. The components of the metabolic syndrome have partially overlapping mechanisms of pathogenic actions mediated through common metabolic pathways. Therefore their total combined effect could be less than the summed of the individual effects. The concept that the metabolic syndrome is a consequence of obesity and insulin resistance, provides a useful "life-style changes" approach for prevention and treatment: caloric restriction, weight-loss and increased physical activity. The next step could theoretically be pharmacological interventions such as metformin, acarbose, fibrates, weight-loss drugs (currently only orlistat is practically available) and perhaps glucagon-like peptide-1 agonists. A third step should probably be kept for bariatric surgery. PMID- 21269525 TI - Analysis of the recurrence risk factors for the patients with hepatocellular carcinoma meeting University of California San Francisco criteria after curative hepatectomy. PMID- 21269526 TI - Comparing the effect of hydroxyethyl starch 130/0.4 with balanced crystalloid solution on mortality and kidney failure in patients with severe sepsis (6S- Scandinavian Starch for Severe Sepsis/Septic Shock trial): study protocol, design and rationale for a double-blinded, randomised clinical trial. AB - BACKGROUND: By tradition colloid solutions have been used to obtain fast circulatory stabilisation in shock, but high molecular weight hydroxyethyl starch (HES) may cause acute kidney failure in patients with severe sepsis. Now lower molecular weight HES 130/0.4 is the preferred colloid in Scandinavian intensive care units (ICUs) and 1st choice fluid for patients with severe sepsis. However, HES 130/0.4 is largely unstudied in patients with severe sepsis. METHODS/DESIGN: The 6S trial will randomize 800 patients with severe sepsis in 30 Scandinavian ICUs to masked fluid resuscitation using either 6% HES 130/0.4 in Ringer's acetate or Ringer's acetate alone. The composite endpoint of 90-day mortality or end-stage kidney failure is the primary outcome measure. The secondary outcome measures are severe bleeding or allergic reactions, organ failure, acute kidney failure, days alive without renal replacement therapy or ventilator support and 28-day and 1/2- and one-year mortality. The sample size will allow the detection of a 10% absolute difference between the two groups in the composite endpoint with a power of 80%. DISCUSSION: The 6S trial will provide important safety and efficacy data on the use of HES 130/0.4 in patients with severe sepsis. The effects on mortality, dialysis-dependency, time on ventilator, bleeding and markers of resuscitation, metabolism, kidney failure, and coagulation will be assessed. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00962156. PMID- 21269527 TI - Effects of purchaser competition in the Dutch health system: is the glass half full or half empty? AB - In 2006, the Dutch health insurance system was radically reformed to strengthen competition among health insurers as purchasers of health services. This article considers whether purchaser competition has improved efficiency in health-care provision. Although supply and price regulation still dominates the allocation of health services, purchaser competition has already significantly affected the provision of hospital care, pharmaceuticals and primary care, as well as efforts to gather and disseminate information about quality of care. From this perspective, the glass is half full. However, based on the crude performance indicators available, the reforms have not yet demonstrated significant effects on the performance of the Dutch health system. From this perspective the glass is half empty. The article concludes that the effectiveness of purchaser competition depends crucially on the success of ongoing efforts to improve performance indicators, product classification and the risk equalisation scheme. PMID- 21269528 TI - The politics of health-care reform in the Netherlands since 2006. AB - This article comments on Schut and van de Ven's overview of the results of purchaser competition in Dutch health care, which concludes that the glass can be seen as half full or half empty. Although it is true that results have been achieved, we believe that the evidence is incomplete and in some respects flimsy. More importantly, however, Schut and van de Ven neglect the political context of the market reform introduced in 2006. The reform is far from finished and there has been a constant need for political compromise. Optimism about the market's potential also seems to be on the wane. Several insurer and provider initiatives have provoked political resistance. As a result, there are good reasons to argue that the reform's future is uncertain. PMID- 21269529 TI - Managed competition in the Dutch health system: is there a realistic alternative? PMID- 21269530 TI - The practice of markets in Dutch health care: are we drinking from the same glass? PMID- 21269531 TI - Atheroprotective effects of dietary L-arginine increase with age in cholesterol fed rabbits. AB - NO has several putative atheroprotective properties but its precursor, L arginine, and inhibitors of its synthesis have had inconsistent effects on the extent of experimental atherosclerosis in rabbits. The location and character of experimental atherosclerosis differ between immature and mature rabbits; both phenomena have been attributed to changes with age in the NO pathway. We investigated whether the influence of dietary L-arginine on experimental atherosclerosis is also age-related. The frequency of lesions was mapped in the descending thoracic and upper abdominal aorta of immature and mature rabbits fed 1 % cholesterol, with or without supplementary L-arginine, for 8 weeks. Consistent with earlier data, the distribution of lesions around the branch points changed with age in control rabbits. The mean frequency of lesions was essentially the same at both ages. L-Arginine supplements had no effect on the distribution of lesions at either age. They significantly reduced the mean frequency of lesions in mature animals but not in immature animals. Thus, the atheroprotective effect of dietary L-arginine in cholesterol-fed rabbits increases with age. PMID- 21269532 TI - Green tea catechins suppress NF-kappaB-mediated inflammatory responses: relevance to nutritional management of inflammation. PMID- 21269533 TI - Transitions between food insecurity and food security predict children's social skill development during elementary school. AB - Recent findings indicate that household food insecurity affects children's social skill development in the early years of elementary school. It is important to assess the persistency of developmental consequences and investigate whether all categories of social skills are equally affected by food insecurity experiences. The present paper estimates population-averaged and subject-specific models for children's social skill scores reported by school teachers using longitudinal data on 2310 boys and 2400 girls in the USA enrolled in the 1st (aged 6-9 years), 3rd (aged 8-11 years) and 5th (aged 10-13 years) grades (1999-2003) from the Early Childhood Longitudinal Study-Kindergarten. The main findings are, first, significantly (P < 0.05) negative, contemporaneous and transitional relationships between food insecurity experiences and children's social skill scores are evident. Estimates based on sex-stratified samples indicate that the contemporaneous association is strongest among girls, while the association of an early transition from food insecurity in the 1st grade to food security in the 3rd grade is strongest among boys. Second, food insecurity experiences predict children's social skill scores emphasising self-control, attentiveness and task persistence, rather than interpersonal relationships or externalising behaviour. Overall, the findings underscore the multifaceted effect that household food insecurity has on children's social skills and provide the strongest empirical evidence to date that the experiences are linked with non-nutritional developmental consequences for children over a time horizon spanning several years. PMID- 21269534 TI - Chromium and iron content in duplicate meals at a university residence: daily intake and dialysability. AB - The objective of the present study was to determine total Cr and Fe content and the corresponding mineral dialysable fraction in a total of sixty-three duplicate meals. Samples of breakfast, lunch and dinner were taken over twenty-one consecutive days at a female university residence in Granada (Spain). Cr content in the duplicate daily meals ranged from 98.50 to 120.80 MUg, with a mean of 110.00 MUg, and Fe levels ranged from 9.50 to 40.00 mg, with a mean content of 18.50 mg. The mean Cr and Fe dialysable fractions ranged from 0.50 to 1.50 % and from 7.75 to 11.80 %, respectively. Possible correlations with energy and other nutrient intakes were also evaluated. Adherence of the meals to the Mediterranean dietary patterns was tested, and these findings reveal that a balanced and varied diet based on a Mediterranean-style diet plan provides adequate levels and bioaccessibility of Cr and Fe for young women, which is especially important to avoid mineral deficiencies. PMID- 21269535 TI - 1-Phenyl-6,7-dihydroxy-isochroman suppresses lipopolysaccharide-induced pro inflammatory mediator production in human monocytes. AB - Extra-virgin olive oil is an integral ingredient of the Mediterranean diet, and it has been suggested that its high consumption has beneficial effects on human health. Its protective effect, in particular against the development of CVD, has been related not only to the high content of oleic acid, but also to the antioxidant and anti-inflammatory properties of polyphenols. In order to verify the anti-inflammatory and anti-atherogenic properties of hydroxy-isochromans, a class of ortho-diphenols present in extra-virgin olive oil, we investigated the potential ability of 1-phenyl-6,7-dihydroxy-isochroman (L137) to modulate the production of key inflammatory mediators by human monocytes, by evaluating its in vitro effects on prostanoid (thromboxane A(2) and PGE(2)) and cytokine (TNF alpha) production. Its effect on the protein expression of the inducible form of cyclo-oxygenase-2 (COX-2), a pro-inflammatory enzyme responsible for elevated prostanoid levels, was also explored. The results showed that L137 significantly inhibited both prostanoid and TNF-alpha production in lipopolysaccharide-primed human monocytes in a dose-dependent manner, by inhibiting the COX activity of COX 2. We also demonstrated that the effects of the isochroman are mediated, at least partly, through the suppression of NF-kappaB activation leading to the down regulation of the synthesis of COX-2. PMID- 21269536 TI - Consumption of plant sterols in Belgium: consumption patterns of plant sterol enriched foods in Flanders, Belgium. AB - The present study describes the consumption of foods enriched with plant sterols (PS) and supplements containing PS, and evaluates PS intakes via the current consumption and for specific consumption scenarios. A market inventory was performed to collate different PS-enriched food items and supplements available in Belgium. An FFQ was developed to investigate the consumption of PS-enriched foods and supplements. A total of 139 pre-school children (2.5-7 years old) and 569 adults (308 women and 261 men) living in Flanders (the northern, Dutch speaking part of Belgium) participated in the study. Of these, 21 % (Flemish pre school children) and 28.5 % (Flemish adults) consume PS-enriched food products, leading to a mean PS intake in the consumer group of 0.70 (sd 0.61) g/d for pre school children and 1.51 (sd 1.42) g/d for adults. Of the adult PS consumers, 23.2 % did not suffer from elevated blood cholesterol levels; 50 % of them had a PS intake less than or equal to 1 g/d and 16.4 % had a PS intake above 3 g/d and 7.8 % even had an intake above 4 g/d. Scenario studies assessed the intake when all Belgian adults would consume PS-enriched margarines without (scenario 1) or with (scenario 2) a daily consumption of a PS-enriched yoghurt drink. This resulted in an intake above 3 g/d in 17 % (women) and 29 % (men) for scenario 1 and 40 % (women) and 53 % (men) for scenario 2. The results indicate that PS enriched food products are also consumed by the non-target group. Efficient communication tools are needed to inform consumers better about the target group of PS-enriched products, the advised dose per day and alternative dietary strategies to lower the blood cholesterol level. PMID- 21269537 TI - Effects of short-term infusion of lipid emulsions on pro-inflammatory cytokines and lymphocyte apoptosis in septic and non-septic rats. AB - Long-term administration of PUFA is known to modulate immune functions and apoptotic pathways depending on the respective amount of n-6 and n-3 fatty acids (FA). Data on short-term effects on apoptotic pathways are rare. Apoptosis of splenic lymphocytes is the hallmark of detrimental sepsis. Therefore, we aimed to compare the immediate effects of parenterally administered n-6-enriched soyabean oil (SO)- and n-3-enriched fish oil (FO)-based lipid emulsions after laparotomy (LAP; sham procedure) and after induction of acute, severe sepsis by caecal ligation and incision. After 390 min of observation time, plasma was analysed for IL-1beta, IL-6 and NEFA. Apoptosis in splenic lymphocytes was quantified by Annexin-V expression. After LAP, infusion of both FO and SO did not change cytokine concentrations. Sepsis increased both cytokines. FO but not SO further augmented the rise. After LAP, SO increased NEFA, and both lipid emulsions reduced free arachidonic acid (AA). Sepsis resulted in a dramatic decrease in NEFA and AA. The drop in NEFA and AA was prevented by both SO and FO. In addition, FO resulted in an increased concentration of n-3 FA under both conditions. Infusion of both lipid emulsions induced apoptosis in splenic lymphocytes after LAP. Sepsis-induced apoptosis was not further enhanced by FO or SO. The present study shows that short-term administration of FO as opposed to SO caused pro-inflammatory effects during sepsis. Moreover, short-term administration of both SO and FO suffices to induce apoptosis in splenic lymphocytes. Finally, SO and FO do not further enhance sepsis-induced splenic apoptosis. PMID- 21269538 TI - Cardiovascular effects of chronic and acute whey protein ingestion. PMID- 21269539 TI - Decline in arterial partial pressure of oxygen after exercise: a surrogate marker of pulmonary vascular obstructive disease in patients with atrial septal defect and severe pulmonary hypertension. AB - OBJECTIVES: To examine the utility of decline in arterial partial pressure of oxygen after exercise as a marker of pulmonary vascular obstructive disease in patients with atrial septal defect and pulmonary hypertension. METHODS: Treadmill exercise was performed in 18 patients with atrial septal defect and pulmonary hypertension. Arterial blood gas samples were obtained before and after peak exercise. A decline in the arterial pressure of oxygen of more than 10 millimetres of mercury after exercise was considered significant based on preliminary tests conducted on the controls. Cardiac catheterisation was performed in all patients and haemodynamic data sets were obtained on room air, oxygen, and a mixture of oxygen and nitric oxide (30-40 parts per million). RESULTS: There were 10 patients who had more than a 10 millimetres of mercury drop in arterial partial pressure of oxygen after exercise and who had a basal pulmonary vascular resistance index of more than 7 Wood units per square metre. Out of eight patients who had less than a 10 millimetres of mercury drop in arterial partial pressure of oxygen after exercise, seven had a basal pulmonary vascular resistance index of less than 7 Wood units per square metre, p equals 0.0001. A decline in arterial partial pressure of oxygen of more than 10 millimetres of mercury predicted a basal pulmonary vascular resistance index of more than 7 Wood units per square metre with a specificity of 100% and a sensitivity of 90%. CONCLUSIONS: A decline in arterial partial pressure of oxygen following exercise appears to predict a high pulmonary vascular resistance index in patients with atrial septal defect and pulmonary hypertension. This test is a useful non-invasive marker of pulmonary vascular obstructive disease in this subset. PMID- 21269540 TI - Exploration of serial structure procedural learning in children with language impairment. AB - Recent studies on specific language impairment (SLI) have suggested that language deficits are directly associated with poor procedural learning abilities. Findings from our previous work are contrary to this hypothesis; we found that children with SLI were able to learn eight-element-long sequences as fast and as accurately as children with normal language (NL) on a serial reaction time (SRT) task. A probabilistic rather than a deterministic SRT paradigm was used in the current study to explore procedural learning in children with SLI to mimic real conditions of language learning. Fifteen children with or without SLI were compared on an SRT task including a probabilistic eight-element-long sequence. Results show that children with SLI were able to learn this sequence as fast and as accurately as children with NL, and that similar sequence-specific learning was observed in both groups. These results are novel and suggest that children with SLI do not display global procedural system deficits. PMID- 21269541 TI - Do the GDS and the GDS-15 adequately capture the range of depressive symptoms among older residents in congregate housing? AB - BACKGROUND: In light of inconsistencies in cut points for identifying non-major depression, this study examined the classification efficiency of the Geriatric Depression Scale (GDS and GDS-15) total scores and individual items, and four additional depressive symptoms for identification of subthreshold, minor, or criterion depression among 166 vulnerable residents of congregate housing. METHODS: Depression (combined categories of major depressive episode, minor, or subthreshold depression) was determined by the Mini-International Neuropsychiatric Interview (MINI) diagnostic interview depression module administered by telephone to 166 older residents of congregate housing facilities who also completed the 30-item GDS and four other yes/no potential indicators of geriatric depression. Classification agreement and ROC curve analysis for the full and 15-item GDS scale scores were calculated. Individual item hit rates for MINI criterion were calculated for GDS items and four new items. RESULTS: GDS and GDS-15 at standard cut points had 70-75% agreement with MINI. Best sensitivity and specificity were obtained at lower than standard cut points. Some GDS Withdrawal, Apathy, lack of Vigor (WAV) and cognitive items obtained very low hit rates. New items "I just don't feel like myself" and "I feel I am a burden to others" better discriminated MINI depression than most GDS items and had good item-to-total correlations with the GDS. CONCLUSIONS: Diagnostic criteria and GDS screen had partial agreement. Some GDS items did not adequately represent depression among functionally impaired or oldest old older adults. Feeling one is a burden and the sense of feeling "different" from usual may be useful indicators of depression among vulnerable older adults. PMID- 21269542 TI - Prevalence, incidence and risk factors of paratonia in patients with dementia: a one-year follow-up study. AB - BACKGROUND: Paratonia is a progressive motor problem that is observed in individuals with dementia and is not a well-known phenomenon. This study explores the development and risk factors of paratonia in moderate stage dementia patients. METHODS: A multi-center, longitudinal, one-year follow-up cohort study was performed. Patients with an established diagnosis of dementia, with a score of 6 or lower on the Global Deterioration Scale (GDS) were included. The participants were assessed using the Paratonia Assessment Instrument (PAI), the Timed Up and GO test, the Qualidem, the Global Deterioration Scale (Reisberg et al., 1982) and the Mini-mental State Examination. Information about each patient's diagnosis of dementia, comorbidities and use of medication were obtained from the participant's medical file. The PAI was assessed every three months, the other variables at baseline and after 12 months. Cross-tabulation chi2 and logistic regression tests were used for the statistical analyses. RESULTS: Baseline measures were assessed in the 204 participants - 111 (54%) female and 93 (46%) male, with a mean age of 79.8 years (56-97). Seventy-one patients (34.8%) were diagnosed with paratonia at baseline, and 51 patients developed paratonia over one year. The highest hazard ratio (3.1) for developing paratonia within one year was observed in the vascular dementia group. The logistic regression analysis revealed that the presence of diabetes mellitus (OR = 10.7) was significantly related to the development of paratonia (Wald chi2 p value < 0.01). CONCLUSIONS: Diabetes mellitus and likely vascular damage are risk factors for the development of paratonia. PMID- 21269543 TI - Effect of trichostatin A on fertilization and embryo development during extended culture of mouse oocyte. AB - We performed this study to investigate the effect of histone deacetylase inhibition during extended culture of in vitro matured mouse oocytes. In vitro matured mouse (BDF1) oocytes were cultured in vitro for 6, 12, and 24 h, respectively, and then inseminated. During in vitro culture for 6 and 12 h, two doses of trichostatin A (TSA), a histone deacetylase inhibitor, were added (100 nM and 500 nM) to the culture medium and the oocytes were then inseminated. During the 24-h in vitro culture, two doses of TSA were added (100 nM and 500 nM) to the medium and the oocytes were activated with 10 mM SrCl2. After the 6-h culture, the fertilization rate was similar to that of the control group, but the blastocyst formation rate was significantly decreased. After the 12-h culture, both the fertilization and blastocyst formation rates were significantly decreased. After the 24-h culture, total fertilization failure occurred. In the oocytes cultured for 6 and 12 h, the fertilization and blastocyst formation rates did not differ between the TSA-supplemented and control groups. Although extended culture of the mouse oocytes significantly affected their fertilization and embryo development, TSA supplementation did not overcome their decreased developmental potential. PMID- 21269544 TI - Catalytic properties of the retinal rod outer segment disk ADP-ribosyl cyclase. AB - Cyclic ADP-ribose (cADPR) is a second messenger modulating intracellular calcium levels. We have previously described a cADPR-dependent calcium signaling pathway in bovine rod outer segments (ROS), where calcium ions play a pivotal role. ROS ADP-ribosyl cyclase (ADPR-cyclase) was localized in the membrane fraction. In the present work, we examined the properties of the disk ADPR-cyclase through the production of cyclic GDP-ribose from the NAD(+) analogue NGD(+). The enzyme displayed an estimated K(m) for NGD(+) of 12.5 +/- 0.3 MUM, a V(max) of 26.50 +/- 0.70 pmol cyclic GDP-ribose synthesized/min/mg, and optimal pH of 6.5. The effect of divalent cations (Zn(2+), Cu(2+), and Ca(2+)) was also tested. Micromolar Zn(2+) and Cu(2+) inhibited the disk ADPR-cyclase activity (half maximal inhibitory concentration, IC50=1.1 and 3.6 MUM, respectively). By contrast, Ca(2+) ions had no effect. Interestingly, the properties of the intracellular membrane-associated ROS disk ADPR-cyclase are more similar to those of the ADPR cyclase found in CD38-deficient mouse brain, than to those of CD38 or CD157. The novel intracellular mammalian ADPR-cyclase would elicit Ca(2+) release from the disks at various rates in response to change in free Ca(2+) concentrations, caused by light versus dark adaptation, in fact there was no difference in disk ADPR-cyclase activity in light or dark conditions. Data suggest that disk ADPR cyclase may be a potential target of retinal toxicity of Zn(2+) and may shed light to the role of Cu(2+) and Zn(2+) deficiency in retina. PMID- 21269545 TI - The effect of gestational undernutrition on maternal weight change and fetal weight in lines of mice selected for different growth characteristics. AB - The present study investigated whether the genetic growth characteristics (fast or slow growing, lean or fat) of a mother influences her ability to partition nutrients to developing offspring. A total of sixty-one pregnant mice of three selected lines were used: fast-growing, relatively fat (FF, n 19); fast-growing, relatively lean (FL, n 23); and normal growth, relatively lean (NL, n 19). On day 1 of pregnancy, mice were given either ad libitum access to food (control (C): n 32) or pair-fed at 80 % of C intake (restricted (R): n 29). Feed intake and dam weight were measured daily. The weight of the mouse, organs, mammary tissue and the weight of fetuses and placentas were determined at day 18 of gestation. Overall, R dams gained less than half the weight of C dams during gestation. NL dams gained the most weight, and FF dams gained the least weight (P < 0.001). R dams in the fast-growing lines mobilised significantly more body fat during gestation than the NL line (P < 0.001) and had a greater reduction in mammary tissue growth. The relative weight of the litter increased in R dams of the FF line but was reduced in both the lean lines. Undernutrition reduced fetal and placental weight, and reduced placental efficiency in all the lines. The reduction was least in the FF line and greatest in the FL line. The data suggest that selection of animals for different growth characteristics alters their response to undernutrition during pregnancy, the relatively fat line was better able to buffer its offspring from the effects of undernutrition than the lean lines, regardless of their underlying rate of growth. PMID- 21269546 TI - Maternal plasma fatty acid composition and pregnancy outcome in adolescents. AB - Adolescents are at a greater risk of adverse pregnancy outcome, including spontaneous preterm delivery and fetal growth restriction, and typically have a poorer-quality diet than adults have. In the present study, we addressed the hypothesis that low maternal dietary intake of n-3 long-chain PUFA (LCP) status adversely influences pregnancy outcome. A total of 500 adolescents (14-18 years) were recruited at <= 20 weeks' gestation. The frequency of consumption of oily fish was determined by questionnaire (at recruitment and during the third trimester). The fatty acid composition of plasma lipids during the third trimester was determined in 283 subjects. Principal components analysis (PCA) was used to derive components, which were divided into tertiles. The pregnancy outcomes were then compared by tertile, adjusting for potentially confounding variables. Of the participants, 69% reported never eating oily fish during pregnancy, although consumption was not associated with a shorter duration of gestation (P=0.33), lower customised birth weight (P=0.82) or higher incidence of small-for-gestational age (SGA) birth (P=0.55). PCA of the fatty acid composition of maternal plasma lipids identified a 'low PUFA:SFA (P:S) ratio' component and a 'high n-3 LCP' component. There were no differences between tertiles of the 'high n-3 LCP' component and gestational age at delivery (P=0.62), customised birth weight (P=0.38) or incidence of SGA birth (P=0.25), nor were there any associations between the 'low P:S' ratio component and pregnancy outcome. Lower proportions of n-3 LCP in plasma lipids are not associated with greater risk of adverse pregnancy outcomes in UK adolescents. PMID- 21269547 TI - Effect of hydrolysed egg protein on brain tryptophan availability. AB - Serotonin synthesis critically depends on plasma levels of tryptophan (TRP). Earlier studies have shown that for mood and cognitive benefits to occur, the ratio between TRP and other large neutral amino acids (LNAA) has to be increased by approximately 40 %. The present study investigated the dose-dependent effects of a TRP-rich hydrolysed protein (egg-protein hydrolysate, EPH) on the plasma TRP:LNAA. Moreover, it was investigated whether EPH could increase TRP:LNAA in the presence of 2 g of milk protein (MP). In a randomised double-blind crossover design, plasma amino acids were measured every 30 min for 3.5 h after ingestion of a drink containing either three different doses of 4, 8 and 12 g EPH containing 270, 560 or 800 mg of TRP, respectively, the combination of 4 g EPH and 2 g MP (74 mg TRP), or 4 g MP (148 mg TRP) in twenty healthy subjects with a mean age of 52 years. All three EPH doses caused significant increases of TRP:LNAA above 40 % at 30, 60 and 90 min after consumption in a dose-dependent manner. Compared with the 4 g EPH, the increase in TRP:LNAA in the 4 g EPH with 2 g MP condition was significantly lower at 60 min (63 v. 44 %, P < 0.001) and did not differ significantly at 90 min (58 v. 53 %, P>0.05). The present study showed that a low dose of 4 g EPH with even the addition of 2 g MP was sufficient to increase the ratio of TRP:LNAA above 40 %. Thus, EPH offers a viable ingredient to increase TRP availability. PMID- 21269548 TI - Relative validity of adolescent dietary patterns: a comparison of a FFQ and 3 d food record. AB - Interest in empirically derived dietary patterns has increased over the past decade. However, relatively few studies have evaluated dietary patterns using different dietary methods, or in young populations. We quantitatively compared dietary patterns from a FFQ with those from a 3 d food record (FR) in a cohort of adolescents. Subjects from the Western Australian Pregnancy Cohort (Raine) Study completed a semi-quantitative FFQ and a 3 d FR at 14 years of age (n 783). Major dietary patterns were identified using exploratory factor analysis on thirty eight food groups. Dietary pattern z-scores were compared using 95 % limits of agreement (LOA) and Spearman's r. Two major dietary patterns were identified in the FFQ and FR: a 'Healthy' pattern, which was high in fresh fruit, vegetables, whole grains and grilled or canned fish, and a 'Western' pattern, which was high in take-away foods, confectionery, soft drinks, crisps and fried potato. The nutrient profiles of these dietary patterns were similar when estimated by the FFQ and FR. The LOA between dietary pattern scores from the FFQ and FR were - 1.69 to 1.75 ('Healthy') and - 1.89 to 1.82 ('Western'). Minor differences in agreement were observed when boys and girls were analysed separately. Spearman's correlation coefficients between the FFQ and the FR were r 0.45 ('Healthy') and r 0.36 ('Western'). Comparable dietary patterns may be obtained from the FFQ and FR using exploratory factor analysis. This supports the use of major dietary patterns identified using the FFQ in this adolescent cohort. PMID- 21269549 TI - Involvement of host cell heparan sulfate proteoglycan in Trypanosoma cruzi amastigote attachment and invasion. AB - Cell surface glycosaminoglycans (GAGs) play an important role in the attachment and invasion process of a variety of intracellular pathogens. We have previously demonstrated that heparan sulfate proteoglycans (HSPG) mediate the invasion of trypomastigote forms of Trypanosoma cruzi in cardiomyocytes. Herein, we analysed whether GAGs are also implicated in amastigote invasion. Competition assays with soluble GAGs revealed that treatment of T. cruzi amastigotes with heparin and heparan sulfate leads to a reduction in the infection ratio, achieving 82% and 65% inhibition of invasion, respectively. Other sulfated GAGs, such as chondroitin sulfate, dermatan sulfate and keratan sulfate, had no effect on the invasion process. In addition, a significant decrease in infection occurred after interaction of amastigotes with GAG-deficient Chinese Hamster Ovary (CHO) cells, decreasing from 20% and 28% in wild-type CHO cells to 5% and 9% in the mutant cells after 2 h and 4 h of infection, respectively. These findings suggest that amastigote invasion also involves host cell surface heparan sulfate proteoglycans. The knowledge of the mechanism triggered by heparan sulfate binding T. cruzi proteins may provide new potential candidates for Chagas disease therapy. PMID- 21269550 TI - Intraosseous trigeminal schwannoma of mandible with intracranial extension. AB - OBJECTIVE: There have been few previous reports of intraosseous schwannomas within the mandible with extension into the cranium. We report two such cases and discuss the relevant clinical features, radiological manifestations and treatment protocols. METHOD: Two case reports of trigeminal schwannoma of the mandible with intracranial extension, including analysis of clinical, radiological and pathological aspects. RESULTS: Panoramic radiographs showed both tumours as multilocular radiolucencies. Solid and cystic components were seen on computed tomography and magnetic resonance imaging. The two tumours extended into the cranium through the pterygomandibular space and an obviously expanded foramen ovale. CONCLUSION: Trigeminal schwannoma of the mandible can develop to involve intracranial extension. Radiological identification of an expanded foramen ovale may facilitate pre-operative identification. PMID- 21269551 TI - Diagnosis of tuberculosis in the head and neck. AB - OBJECTIVES: To establish the features of Mycobacterium tuberculosis infection in the head and neck region, and to determine which investigations have the greatest diagnostic accuracy. STUDY DESIGN: Region-based, retrospective cohort study. METHOD: The study included 148 patients with tuberculosis of the head and neck treated in the Greater Glasgow and Clyde region between 2000 and 2007. RESULTS: The following diagnostic sensitivities were calculated: 53 per cent for fine needle aspiration, 95 per cent for core biopsy and 91 per cent for lymph node excision biopsy. There was a statistically significant difference between the sensitivity results for fine needle aspiration versus core biopsy (p = 0.0003) and fine needle aspiration versus excision biopsy (p < 0.0001). There was no statistically significant difference between the sensitivity results for core biopsy and excision biopsy. CONCLUSION: Core biopsy has equivalent diagnostic accuracy to excision biopsy in the investigation of head and neck tuberculosis. We suggest that core biopsy should be used in preference to lymph node excision, as it can be performed under local anaesthetic outside the operating theatre. A proposed algorithm for diagnostic management is included. PMID- 21269552 TI - Endoscopic resection of intracranial dermoid cysts. AB - INTRODUCTION: Nasal dermoid cysts are congenital lesions which are often diagnosed in infancy or childhood. However, a small number present in adulthood, and some extend intracranially. Traditional treatment for the intracranial portion of these cysts includes frontal craniotomy. CASE REPORTS: Two intracranial dermoid cysts were resected via a transnasal endoscopic approach, using 70 degrees nasal endoscopy for complete visualisation and intracranial tumour removal. We describe our technique for the procedure itself and for reconstruction of the skull base defect. DISCUSSION AND CONCLUSION: The endoscopic transnasal skull base approach is an excellent alternative to a traditional frontal craniotomy, to achieve complete resection of intracranial dermoid cysts. PMID- 21269553 TI - Epley's manoeuvre versus Epley's manoeuvre plus labyrinthine sedative as management of benign paroxysmal positional vertigo: prospective, randomised study. AB - INTRODUCTION: We report a prospective, randomised study of 51 patients with benign paroxysmal positional vertigo treated with Epley's manoeuvre alone or Epley's manoeuvre plus labyrinthine sedative, at Sundaram Medical Foundation, Chennai, India. AIM: To compare the efficacy of Epley's manoeuvre versus Epley's manoeuvre plus labyrinthine sedative in the treatment of benign paroxysmal positional vertigo. MATERIALS AND METHODS: Consecutive patients were selected based on history and positive Dix-Hallpike test. Patients were randomised to receive either Epley's manoeuvre alone or Epley's manoeuvre plus labyrinthine sedative for one week. Both groups were followed up for four weeks. RESULTS: Univariate analysis showed that one- and four-week outcomes were influenced by the number of episodes, symptom duration and treatment type. Multivariate logistic regression analysis showed that the one-week outcome was significantly influenced by symptom duration and treatment type, while the four-week outcome was significantly influenced by symptom duration alone. Patients receiving Epley's manoeuvre alone showed better recovery than those receiving both Epley's manoeuvre and labyrinthine sedative. CONCLUSION: Labyrinthine sedatives do not aid recovery from benign paroxysmal positional vertigo when used in addition to Epley's manoeuvre. PMID- 21269554 TI - Metastasis of follicular variant of papillary thyroid carcinoma masquerading as primary temporal bone tumour. AB - OBJECTIVE: We describe the first published case of papillary thyroid carcinoma metastatic to the temporal bone. CASE REPORT: A 64-year-old woman presented with a large left temporal bone mass centred in the jugular foramen, initially thought to be a paraganglioma or schwannoma. She was simultaneously being investigated for a left-sided thyroid nodule, which was found to be unremarkable on repeated fine needle aspiration cytology. A biopsy of the temporal bone mass indicated that it was of thyroid origin. The patient underwent total thyroidectomy, which enabled a final diagnosis of follicular-variant papillary thyroid carcinoma with metastasis to the temporal bone. CONCLUSION: Although biopsy is not the usual management for many types of temporal bone mass, pathological investigation is recommended if the tumour has an atypical growth rate, location, spread and/or radiological features. Metastasis of papillary thyroid carcinoma to the skull base is extremely rare, and correct diagnosis is essential in order to pursue an effective treatment plan. PMID- 21269555 TI - Computer-based analysis with three-dimensional imaging constructed from fine slice computed tomography scan of supracricoid laryngectomy with cricohyoidoepiglottopexy: report of two cases. AB - OBJECTIVE: Supracricoid laryngectomy with cricohyoidoepiglottopexy is an organ preserving surgical technique used to treat laryngeal cancer. This procedure resects the vocal folds; however, it is unclear how the sound source and airway morphology are involved in phonation through the post-operative neoglottis. METHOD: Multidetector helical computed tomography scanning was performed on two patients who had undergone supracricoid laryngectomy with cricohyoidoepiglottopexy. The cricoid and arytenoid cartilages and the airway were visualised using three-dimensional images. RESULTS: The mobility of the arytenoid cartilages was well preserved in the one patient with bilateral arytenoids, and in the other patient with only one arytenoid remaining. Two types of airway configuration were observed during phonation: one patient had a single stream airway, while the other had a combination of several streams. CONCLUSION: In the patient with only one arytenoid remaining, the preserved arytenoid tended to be rotated excessively inward. Therefore, phonation may have also occurred in various airways followed by mucosal vibration, which may be a sound source. PMID- 21269556 TI - Mucocele of a pneumatised uncinate process: first reported case. AB - OBJECTIVE: We report a unique case of a mucocele of a pneumatised uncinate process. METHOD: Clinical, radiological and intra-operative findings are presented. RESULTS: A 43-year-old woman was referred to our ENT department suffering from persistent symptoms of left-sided sinusitis. Although an initial computed tomography scan suggested a lacrimal duct mass, dacrocystography showed free flow through the nasolacrimal duct. The patient underwent surgery, revealing a mucocele within a pneumatised uncinate process. CONCLUSION: This patient's clinical, radiological and intra-operative findings illustrate how variations in sinus anatomy can pose a diagnostic challenge. PMID- 21269557 TI - Repair of nasal septal perforation using inferior turbinate graft. AB - OBJECTIVE: Nasal septal perforation can cause troublesome symptoms. Surgical repair is indicated in symptomatic patients. Many approaches and techniques have been described, each with its advantages and indications. METHOD: The study included six patients with symptomatic nasal septal perforations sized 1-2.5 cm horizontally by 0.5-1.5 vertically. Patient symptoms included nasal crusts (all patients), nasal obstruction (five), cacosmia (three) and recurrent epistaxis (three). Patients underwent endonasal endoscopic repair using an inferior turbinate free graft applied between the mucoperichondrium of both septum sides. Follow up ranged from six months to two years. RESULTS: Five patients (83 per cent) had complete perforation closure and one had partial closure. All patients were symptom-free post-operatively. CONCLUSION: This endoscopic endonasal approach, using an inferior turbinate free graft, is effective in closing small and medium-sized nasal septal perforations. PMID- 21269558 TI - Laryngeal carcinoma metastasis to the orbit: case report. AB - OBJECTIVE: We present the first report in the all English literature of a case of laryngeal squamous cell carcinoma metastasis to the orbit. METHOD: Case report of orbital metastasis from laryngeal carcinoma; clinical, radiological and pathological findings are discussed. RESULT: A 75-year-old man presented to the ENT department with a five-week history of left orbital pain, swelling and reduced vision. Past medical history included laryngectomy, bilateral neck dissection and post-operative radiotherapy for T4 N2c M0 squamous cell carcinoma of the supraglottis, 10 months earlier. Imaging showed an orbital mass extending along the roof and lateral aspect of the orbit into the optic canal and superior orbital fissure, and further posteriorly into the left cavernous sinus with meningeal enhancement in the left anterior cranial fossa. Histopathological analysis after biopsy showed the mass to be consistent with metastatic poorly differentiated squamous cell carcinoma. CONCLUSION: After searching the all English literature, we report what is, to our best knowledge, the first case of laryngeal carcinoma metastasis to the orbit. Despite its rarity and poor prognosis, such a metastasis should be considered as part of the differential diagnosis of an orbital mass, as timely recognition can improve the patient's quality of life. PMID- 21269559 TI - Detection of tympanic membrane movement using film patch with integrated strain gauge, assessed by optical coherence tomography: experimental study. AB - OBJECTIVE: We report an ex vivo and in vivo experimental study of a device designed to measure tympanic membrane movement under normal and pathological conditions, assessed using optical coherence tomography. MATERIALS AND METHODS: We designed two types of flexible, round film patch with integrated strain gauge, to be attached to the tympanic membrane in order to measure tympanic membrane movement. Tympanic membrane attachment was assessed using optical coherence tomography. The devices were tested experimentally using an ex vivo model with varying middle-ear pressure. RESULTS: Optical coherence tomography reliably assessed attachment of the film patch to the tympanic membrane, before and after middle-ear pressure changes. Strain gauge voltage changes were directly proportional to middle-ear pressure recordings, for low pressure changes. Tympanic membrane perforations smaller than 2 mm could be sealed off with the film patch. CONCLUSION: Attachment of the film patch with integrated strain gauge to the tympanic membrane was not ideal. Nevertheless, the strain gauge was able to precisely detect small pressure changes within the middle ear, in this experimental model. PMID- 21269560 TI - Editorial. Hematology as the official journal of the International Society of Hematology. PMID- 21269561 TI - Beyond diagnosis: subjective theories of illness in adult patients with acute myeloid leukemia. AB - Every acute myeloid leukemia (AML) patient asks: why me? But from the patients' perspective, there are no objective medical causes and no clear picture of AML. However, based on these missing medical answers, patients develop their own ideas about illness and treatment. These subjective theories of illness (STOI) are defined as the cognitive constructions ill people make regarding: (1) the nature of their disease; (2) its source; and (3) its treatment. STOI present a challenge for the physician-patient relationship. After the first interim staging, 12 patients with AML were interviewed. Case analyses were assigned to interindividual comparisons representing the predefined subject areas of STOI. Patients' vague subjective conceptions about the personalized etiology of AML resulted not only from health literacy deficits but also from their avoiding medical information to protect themselves from negative emotions. Through STOI, patients significantly co-determine the selection of (un-)conscious coping strategies with consequences for physician-patient communication. PMID- 21269562 TI - Impact of anti-oxidant status and apoptosis on the induction phase of chemotherapy in childhood acute lymphoblastic leukemia. AB - This study aimed to evaluate oxidative stress and apoptosis in childhood acute lymphoblastic leukemia (ALL) at diagnosis and their impact on outcome at the end of the induction phase. Our study included 50 newly diagnosed children with ALL. Evaluation of oxidative stresses (malondialdehyde and total anti-oxidant capacity) was made at diagnosis and at the end of the induction phase. Apoptosis level was determined by fluorometric terminal deoxynucleotidyl transferase dUTP nick end labeling system for patients at diagnosis and after 1 week of treatment. Our study showed that there was increased oxidative stress at diagnosis and after treatment with chemotherapy. Apoptosis index was higher after 1 week of treatment with chemotherapy when compared to its level at diagnosis. PMID- 21269563 TI - The association between the copy-number variations of ZMAT4 and hematological malignancy. AB - Copy-number variations (CNVs) have been found in association with various types of diseases, including hematological malignancies. A recent array-based study implicated the presence of CNVs of ZMAT4 in the genome of acute myelogenous leukemia. In our study, we collected 617 bone marrow samples from multitypes of hematological malignancies as well as healthy controls. We found significant association between the CNVs of ZMAT4 and these hematological malignancies, including acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, multiple myeloma, and myelodysplastic syndrome. We also examined the expression of ZMAT4 mRNA in the samples with 1 or 2 copies of DNA, and observed a weak yet positive correlation between the relative expression level and gene dosage. In conclusion, the CNVs of ZMAT4 have the potential to serve as a diagnostic indicator, alone or in combination with other markers, for hematological malignancies. PMID- 21269564 TI - Effect of D, L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol and tetrandrine on the reversion of multidrug resistance in K562/A02 cells. AB - In this study, we applied D, L-threo-1-phenyl-2-decanoylamino-3-morpholino-1 propanol (PDMP) hydrochloride as a chemical inhibitor for glucosylceramide synthase (GCS) and tetrandrine (Tet) for P-glycoprotein (P-gp) to reverse daunorubicin (DNR) resistance of human leukemia cell line K562/A02. Cytotoxicity assays showed that either PDMP or Tet enhanced cytotoxic effect of DNR on K562/A02 cells, while cotreatment of these two drugs had a more significant effect on chemosensitization. Using flow cytometric analysis, we confirmed that the enhancement effect was accompanied by elevated cellular DNR accumulation and DNR-induced apoptosis. According to reverse transcription-polymerase chain reaction and western blot, the reversal effect of that composite might owe to the significant downregulation of mdr1 and GCS gene expressions. Importantly, PDMP diminished mdr1 gene expression and Tet also downregulated GCS gene expression. Moreover, a positive correlation was observed between GCS and P-gp. Thus, our results suggest that a potential clinical application of PDMP in combination with Tet may enhance chemosensitivity in leukemia. PMID- 21269565 TI - Deficiency of CD3gamma, delta, epsilon, and zeta expression in T cells from AML patients. AB - In order to elucidate the feature of T-cell receptor (TCR) signal transduction in T-cells from acute myeloid leukemia (AML), the expression levels of CD3gamma, delta, epsilon and zeta chain genes in CD3+ T cells were analyzed using real-time PCR. CD3+ T cells sorted from peripheral blood of 10 AML patients and 10 healthy donors were used in the study. Significantly lower expression levels of all four CD3gamma, delta, epsilon, and zeta chain genes were found in the AML samples. The expression pattern of the four CD3 chains was epsilon>gamma>delta>zeta in CD3+ T cells from AML samples, which was different from the healthy control group. In conclusion, the results provide a global gene expression profile of CD3gamma, delta, epsilon, and zeta chains in AML patients. Deficiency of all four CD3 gene expression levels might represent the feature related to T-cell immunodeficiency. PMID- 21269566 TI - Wilms' tumor protein and FLT3-internal tandem duplication expression in patients with de novo acute myeloid leukemia. AB - Bone marrow samples of 30 patients with de novo adult acute myeloid leukemia (AML) were analyzed for Wt1 and FLT3-internal tandem duplication (FLT3-ITD) expression measured by western blot and reverse transcription-polymerase chain reaction analysis, respectively. Wt1 was detected in 53.3% of AML patients (16/30), while FLT3-ITD in 23.3% (7/30). The high Wt1 expression correlated with the presence of FLT3-ITD (P = 0.014) and lower rate of complete remission (P = 0.023). The cumulative survival in AML patients was affected significantly by the presence of FLT3-ITD, being lower in the FLT3-ITD (+) group (6.0+/-2.4 months) compared to the FLT3-ITD (-) patients (17.9+/-3.3; P = 0.04). The expression of FLT3-ITD could probably activate Wt1 expression in AML blast cells and thus might contribute to its oncogenic function to provide cells with survival advantages in vivo. The detection of both molecular markers (Wt1 and/or FLT3-ITD) may be helpful in defining high risk AML patients that need special therapeutic strategies. PMID- 21269567 TI - Restricted TRBV repertoire in CD4+ and CD8+ T-cell subsets from CML patients. AB - T-cell immunodeficiency is a common feature in cancer patients, which may relate to initiation and development of tumor. In expanding our previous observations in this area, we studied the repertoire of T-cell receptor beta variable region (TRBV) and T-cell proliferative history in CD4+ and CD8+ T cells from chronic myeloid leukemia (CML) patients. The expression and clonality analysis were performed by reverse transcription-polymerase chain reaction (RT-PCR) and GeneScan technique in peripheral blood mononuclear cells (PBMCs), CD4+ and CD8+ subsets of T cells. Nineteen CML cases in chronic phase were selected for this study and 17 healthy individuals served as controls. Marked restriction of TRBV repertoire was observed in both CD4+ and CD8+ T cells from CML. In most CML samples, clonally expanded T cells were identified in CD4+ and CD8+ T cells, predominantly in TRBV19 and TRBV21 (5/19) subfamilies. In conclusion, the restricted expression of TRBV subfamilies indicates the T-cell immunodeficiency in CML patients; however, clonally expanded T cells suggest a specific immune response to leukemia associated antigens. PMID- 21269568 TI - Incidence, etiology and bone marrow characteristics of non-chemotherapy-induced agranulocytosis. AB - OBJECTIVE: Agranulocytosis is a rare but fatal condition. The majority of cases are associated with drugs. However, in-patient incidences and the relationship between clinical outcomes and bone marrow characteristics have not been established. METHODS: We conducted a retrospective study in a university hospital. A total of 38 in-patients diagnosed with agranulocytosis were analyzed. RESULTS: The average incidence of agranulocytosis in Songklanagarind Hospital between 1993 and 2007 was 0.98 cases per 10 000 admissions per year. Antimicrobial agents were the most common etiology (63% of patients) and antithyroid agents were the second most common (13.6%). Two patterns of bone marrow were noted: type I was characterized by a left-shifted granulopoiesis and type II was recognized as having hypocellular bone marrow with markedly reduced granulocyte precursors. A significantly higher mortality was associated with type II. CONCLUSION: Antimicrobial agents are the most common cause and the rare granulocyte precursors in bone marrow are associated with higher mortality rates. PMID- 21269569 TI - Fok-I gene polymorphism of vitamin D receptor in patients with beta-thalassemia major and its effect on vitamin D status. AB - Most of the biological actions of vitamin D are mediated by an intracellular receptor (VDR) in which several single nucleotide gene polymorphisms have been identified. Vitamin D deficiency is increasingly identified among thalassemic patients and recent evidence links it with myocardial iron accumulation. The aim of this work was to assess the distribution of the Fok-I polymorphism of the VDR gene among Greek children and young adults with beta-thalassemia major and to investigate its association with 25(OH)D(3) and 1,25(OH)(2)D(3) serum levels. Sixty-nine thalassemic patients (35 females and 34 males), with a mean age of 23.05+/-6.07 years, participated in the study. Genotype frequencies of Fok-I were similar to those previously reported for other populations; 44.9% of the patients were homozygotes for F allele, 43.5% were heterozygotes and 11.6% were homozygotes for the f allele. Low levels of serum 25(OH)D(3) were recorded, as 41 patients (59.4%) were below the cut-off limit of 50 nmol/l that determines deficiency, whereas, levels of 1,25(OH)(2)D(3) showed wide variability ranging from deficiency (<=50 pmol/l) in 34 patients (49.3%) to excess (>=125 pmol/l) in 13 patients (18.8%). When stratifying patients according to serum 1,25(OH)(2) D(3) concentrations, a higher prevalence of the f allele was observed in the deficiency group (P = 0.03). A comparison of the serum concentrations of the two vitamin D metabolites produced a trend towards a negative correlation (r = 0.204, P = 0.09). Further studies are required to assess the genetic contribution to the regulation of vitamin D metabolites in the serum of patients with beta thalassemia major. PMID- 21269570 TI - Factor V Leiden and prothrombin gene mutations in Egyptian cases with unexplained recurrent pregnancy loss. AB - BACKGROUND: Thrombophilias have been suggested as a possible cause of recurrent pregnancy loss (RPL). OBJECTIVE: Testing for the association of factor V Leiden (FVL) and prothrombin (FII) mutations with RPL among cases from the Nile Delta region of Egypt. SUBJECTS AND METHODS: Participants included 72 cases having a history of two or more events of unexplained RPL and 70 controls with a good obstetric history. Detection of FVL (G1691A) and FII (G20210A) mutations was carried out using PCR with sequence specific primers. RESULTS: Cases showed a significantly higher frequency of FVL GA (OR = 21.38, P<0.0001) and FII GA (OR = 36.7, P<0.0001) genotypes. Cases with two or more risk factors had significant higher frequency of both mutant genotypes, while no significant difference could be elicited related to primary or secondary infertility, number of fetal losses, or phase of pregnancy loss. CONCLUSION: Screening for thrombophilic mutations may help in the prevention of unexplained RPL. PMID- 21269571 TI - Association of polymorphisms in the programmed cell death 1 (PD-1) and PD-1 ligand genes with ankylosing spondylitis in a Chinese population. AB - OBJECTIVES: To investigate the association of the polymorphisms and haplotypes in the PD-1 and PD-1 ligand genes with ankylosing spondylitis (AS) in a Chinese population. METHODS: A total of 196 Chinese patients with ankylosing spondylitis and 180 age- and sex-matched controls of the same ethnic origin were included in the study. The polymorphisms in PD-1 and PD-1 ligand genes were genotyped using polymerase chain reaction-restriction fragment length polymorphism, allele specific PCR and fluorescence melting curve methods. RESULTS: The T allele of the PD-1 rs2227982 polymorphism was more frequent in the patient group than in the controls (28.53% vs. 17.22%; p=0.000). The frequency of the CT haplotype (PD-1 rs2227981 C allele and PD-1 rs2227982 T allele) was higher in the AS patient group comparing with the controls (odds ratio (OR)=1.845, 95% confidence interval 1.220-2.789). The C allele of the PD-L1 rs822336 polymorphism was also more frequent in the patients than in the controls (34.69% vs. 27.22%; p=0.007). However, we did not find any evidence of genetic association between PD-L2 rs1009759/rs6476985 polymorphisms and AS (p=0.371 and 0.061, respectively). No significant difference in the distribution of the PD-1 rs2227981 alleles was found in our population when comparing AS patients with control groups (p=0.226). CONCLUSIONS: The results support a major role for PD-1/PD-L1 polymorphisms in disease susceptibility of AS. PMID- 21269572 TI - Diagnostic value of antibodies against mutated citrullinated vimentin for rheumatoid arthritis. AB - OBJECTIVES: To compare the diagnostic efficiency of anti-MCV, anti-CCP2 and RF detection for patients with RA. METHODS: Cross-sectional study of patients with established rheumatic disease: rheumatoid arthritis (RA; n=75), psoriatic arthritis (PsA; n=25), 27 patients with ankylosing spondylitis (AS; n=27) and connective tissue disease (CTD; n=17). Anti-CCP2, anti-MCV and RF were detected by enzyme-linked immunosorbent assays on stored serum according to the manufacturer's instructions. RESULTS: IgM-RF had the highest sensitivity, but the positive likelihood ratio is just 1.43. The detection of anti-MCV has a higher sensitivity for RA (76%), a specificity similar to anti-CCP2 (96%) resulting in the lowest negative likelihood ratio (0.25). Anti-MCV levels correlate well with anti-CCP2 levels (R=0.74; p<0.01). The mean level of anti-MCV is significantly higher in RA than in other subgroups (395 U/ml versus 14.4 U/ml, chi2=61.0; p<0.001) and in each other subgroup (Mann-Whitney-Wilcoxon: U=239, p<0.001 for RA and PsA; U=215, p<0.001 for RA and AS; U=192, p<0.001 for RA and CTD). Among RA patients, anti-CCP2 levels have a dichotomous distribution whereas anti-MCV levels have a homogeneous distribution. CONCLUSIONS: Anti-MCV could be a better test for diagnosing RA than anti-CCP2. PMID- 21269573 TI - Role of the rs6822844 gene polymorphism at the IL2-IL21 region in biopsy-proven giant cell arteritis. AB - OBJECTIVES: To assess the influence of the interleukin (IL)2-IL21 rs6822844 G/T polymorphism in the susceptibility to biopsy-proven giant cell arteritis (GCA) and in the clinical spectrum of manifestations of this vasculitis. METHODS: Two hundred and seventy-two biopsy-proven GCA patients were included in this study. DNA from patients and matched controls (n=791) was obtained from peripheral blood. Samples were genotyped for the rs6822844 polymorphism using a predesigned TaqMan allele discrimination assay and by polymerase chain reaction amplification. RESULTS: No significant differences in the allele and genotype frequencies between biopsy-proven GCA patients and controls were observed. However, the stratification of GCA patients disclosed some differences according to gender and ischemic manifestations of the disease. In this regard, the frequency of the minor allele T was increased in males (14.8%) compared to females (8.4%) (odds ratio-OR:1.89 (95% confidence interval-CI: 1.09-3.28); p=0.02; Bonferroni adjustment p=0.12). Also, minor allele T frequency was increased in GCA patients with severe ischemic complications (12.8%) compared to those without severe ischemic complications (7.7%) (OR:1.72 (95% CI: 0.97-3.05); p=0.05; Bonferroni adjustment p=0.30), and specifically in patients with jaw claudication (13.7% versus 8.2% in those without jaw claudication; OR:1.76 (95% CI: 1.02-3.04); p=0.04; Bonferroni adjustment p=0.24). CONCLUSIONS: IL2-IL21 rs6822844 polymorphism does not appear to be a genetic risk factor for susceptibility to biopsy-proven GCA. However, this gene polymorphism may contribute to the different phenotypic expression of this vasculitis, in particular in the development of ischemic complications of the disease. PMID- 21269574 TI - Vitamin D3 ameliorates herpes simplex virus-induced Behcet's disease-like inflammation in a mouse model through down-regulation of Toll-like receptors. AB - OBJECTIVES: This study was conducted to understand the role of vitamin D3 through the regulation of Toll like receptors (TLRs) and cytokines in herpes simplex virus-induced Behcet's disease (BD)-like mice. METHODS: Serum 25-hydroxyvitamin D (1,25(OH)2D3) levels were measured in BD-like mice, as well as virus injected and asymptomatic appearance BD normal mice (BDN). The frequencies of TLRs of peritoneal macrophages were compared by FACS. To determine the effect of vitamin D3 in vitro, peritoneal macrophages were isolated and then incubated with 1,25(OH)2D3. To identify the mechanism of improvement of BD-like symptoms induced by 1,25(OH)2D3, mice were orally administered 1,25(OH)2D3. RESULTS: The serum 25 hydroxyvitamin D levels in BD-like mice were 12.4 +/- 5.4ng/ml, while they were 17.5 +/- 7.2ng/ml in BDN mice. The frequency of TLR2 in BD-like mice was 32.91 +/ 20.88%, while it was 12.73 +/- 7.67% in BDN. The frequency of TLR4 was 26.09 +/- 10.20% in BD-like mice and 9.72 +/- 5.30% in BDN. In a 72 h culture of peritoneal macrophages in 10-8 M 1,25(OH)2D3, the frequency of TLR2 was 25.0 +/- 2.7%, while it was 37.3 +/- 5.8% in the control group. The frequency of TLR4 was 18.9 +/- 5.3% with 1,25(OH)2D3, while it was 30.3 +/- 0.1% in the control group. Treatment with 1,25(OH)2D3 improved the symptoms in six out of 11 BD-like mice and downregulated the frequency of TLR2 and TLR4. Moreover, 1,25(OH)2D3 influenced Interleukin-6 and TNF-alpha expression in the sera of BD-like mice. CONCLUSIONS: Vitamin D improved BD-like symptoms by down-regulating the expression of TLRs and pro-inflammatory cytokines in in vivo mouse models. PMID- 21269575 TI - Intentional etanercept use during pregnancy for maintenance of remission in rheumatoid arthritis. AB - OBJECTIVES: Rheumatoid arthritis is associated with an increased risk of adverse pregnancy outcomes. TNF inhibitors are effective in the treatment of signs and symptoms of the disease although their safety during pregnancy is debated. METHODS: Two cases of women with rheumatoid arthritis in complete remission of the disease with etanercept who decided to continue the therapy throughout their pregnancy are presented. A longitudinal evaluation of the disease activity showed a satisfactory control and good pregnancy outcomes were obtained. A flare of the disease after delivery was not observed. CONCLUSIONS: Etanercept seems to be safe during pregnancy and lactation. A good control of the activity of the disease was reported throughout the pregnancy and during puerperium, when a reactivation of rheumatoid arthritis is often observed. PMID- 21269577 TI - Growth in juvenile idiopathic arthritis: the role of inflammation. AB - Growth disorders are common among patients with juvenile idiopathic arthritis (JIA). These disorders range from general growth retardation to local acceleration of growth in the affected limb, and are associated with an increased production of pro-inflammatory cytokines, such as interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). Pro inflammatory cytokines may act individually or in combination to impair child growth through systemic mechanisms and/or a local action. Whereas IL-6 affects growth mainly via systemic mechanisms altering growth hormone secretion, IL-1beta and TNF-alpha can directly affect growth plate chondrocyte dynamics as well as longitudinal bone growth. There are emerging data suggesting that interleukin-15 and interleukin-5 may be new cytokines implicated in inflammatory diseases, but further well-designed longitudinal studies in larger groups of children are required to establish a causal relationship. Other factors, which might contribute to growth suppression associated with childhood arthritis, include the degree, extent, and duration of disease activity, age at onset, immobility, sub optimal nutrition and corticosteroid therapy. PMID- 21269578 TI - Clinical relevance of switching to a second tumour necrosis factor-alpha inhibitor after discontinuation of a first tumour necrosis factor-alpha inhibitor in rheumatoid arthritis: a systematic literature review and meta-analysis. AB - OBJECTIVES: To assess the clinical relevance of switching to a second tumour necrosis factor (TNF) alpha inhibitor after discontinuation of a first TNF-alpha inhibitor in patients with rheumatoid arthritis. METHODS: A systematic literature search of MEDLINE, EMBASE and Cochrane database and Congress abstracts up to March 2009 retrieved all studies assessing the efficacy of switching to a second TNF-alpha inhibitor. Key words were rheumatoid arthritis AND failure OR switching AND TNF-alpha inhibitors OR adalimumab OR etanercept OR infliximab. Efficacy was evaluated by American College of Rheumatology (ACR), European League Against Rheumatism (EULAR) response criteria and drug survival. A meta-analysis of the percentage of responders was carried out. Statistical heterogeneity was tested by the Q-test. RESULTS: In the 32 relevant studies (4,441 patients) selected, the pooled percentage of ACR 20 responders (12 studies; 1,570 patients) was 55.1% (95% confidence interval, CI 48.2-62) and that of EULAR responders (15 studies; 2,665 patients) was 74.9% (95% CI 72.3-77.5). In the 19 studies analysing the efficacy by the reason to switch, the pooled percentage of ACR20 responders was 54.3% (95% CI 45.8-62.5) for switch because of lack of efficacy and 62.5% (95% CI 57.3-67.6) because of adverse events. The percentage of EULAR response was similar in both groups. CONCLUSIONS: This meta-analysis suggests that switching to a second TNF-alpha inhibitor is clinically relevant in RA. Response to a second TNF-alpha inhibitor appears to be slightly better if the first TNF-alpha inhibitor was discontinued because of adverse events. PMID- 21269576 TI - Interactions of the innate and adaptive arms of the immune system in the pathogenesis of spondyloarthritis. AB - The immune system can be divided into the innate and adaptive arms. Historically, most of the research into the pathogenesis of spondyloarthritis (SpA) and other types of chronic arthritis focused on the adaptive immune system. Recently, the pendulum has shifted, and much current work in SpA focuses on innate immunity. Herein, I summarise evidence demonstrating that both the innate and the adaptive arms of the immune system are involved in the pathogenesis of SpA, propose a mechanism in which both arms interact to maintain chronic arthritis, and discuss potential research directions. PMID- 21269579 TI - Coccygodinia as a possible presenting symptom of psoriatic arthritis. PMID- 21269580 TI - MTHFR polymorphisms, C677T and A1298C, are not a genetic risk factor for liver stiffness index in methotrexate-treated rheumatoid arthritis patients. PMID- 21269581 TI - Analysis of the influence of the ghrelin receptor rs509035, rs512692 and rs2922126 polymorphisms in the risk of cardiovascular disease in patients with rheumatoid arthritis. PMID- 21269582 TI - The distribution of juvenile idiopathic arthritis in the eastern Mediterranean: results from the registry of the Turkish Paediatric Rheumatology Association. AB - OBJECTIVES: To analyse the demographics, main clinical and laboratory features and subtype distribution of juvenile idiopathic arthritis (JIA) in an eastern Mediterranean country, based on a multicentre registry. METHODS: Between March 2008 and February 2009 with this cross-sectional study, consecutive patients seen with JIA in selected centres were registered through a web-based registry. All patients were classified according to the International League of Associations for Rheumatology (ILAR) criteria. RESULTS: There were 634 patients with a mean age of 11.84 +/- 4.66 years and the female/male ratio was 1.2. The distributions of JIA patients according to onset of disease were as follows: systemic 92 (14.5%), oligoarticular extended 26 (4.1%), oligoarticular persistent 234 (36.9%), rheumatoid factor (RF) positive polyarthritis 20 (3.2%), RF negative polyarthritis 129 (20.3%), enthesitis-related 120 (18.9%), psoriatic 13(2.1%). The frequency of uveitis was 15.7% among all of the oligoarthritis patients. Anti nuclear antibody (ANA) was positive mainly among the oligoarticular onset patients. Twenty-one patients also had Familial Mediterranean fever (FMF). Among systemic JIA patients, the frequency of macrophage activation syndrome (MAS) was 15.2% (n=14). At the end of the mean follow-up of 7.6 +/- 4.4 years, 305 (48.1%) patients were defined to have inactive disease on medication, and 106 (16.7%) were completely free of any disease symptoms without medication. CONCLUSIONS: Enthesitis related arthritis had a high frequency whereas psoriatic arthritis was very rare compared to other series. We suggest that there are certain differences in the characteristics of JIA in our eastern Mediterranean population. Thus, genetic studies need to be assessed in these populations separately and findings of genome wide association studies need to be confirmed in different populations. PMID- 21269583 TI - The CD18 AvaII polymorphic site not associated with Henoch-Schonlein purpura. AB - Henoch-Schonlein purpura (HSP) is an immune complex-mediated systemic vasculitis. Its genetic etiology remains unknown. CD18, the subunit of integrin beta2 in leukocytes, has essential roles in the expression and function of ITGB2, mediating immune responses. CD18 has been proved to be associated with some systemic vasculitides, such as microscopic polyangiitis and Churg-Strauss syndrome. We aimed to assess the influence of CD18 AvaII polymorphism (rs235326, C->T) in the incidence of HSP and determine its possible implication in severe systemic complications by studying 73 patients with HSP and 156 controls in China. Our results showed that AvaII polymorphism was not associated with HSP susceptibility (odd ratio (OR)=0.48, 95% confidence interval (CI)=0.53-1.39, p=0.63) or with HSP nephritic syndrome (OR=0.88, 95%CI=0.35-2.06, p=0.90). Moreover, we did not observe any significant association between serum parameters, such as CRP, IgA, IgE, C3 and C4, and HSP severity. In conclusion, our results suggested that CD18 AvaII is not associated with HSP susceptibility and its clinical outcomes. PMID- 21269584 TI - Successful treatment of renal AA amyloidosis in familial Mediterranean fever with pegylated alpha-2a interferon. AB - Renal AA amyloidosis is a severe consequence of chronic inflammatory diseases such as familial Mediterranean fever (FMF). FMF is caused by mutations in the MEFV gene, resulting in defective control of granulocyte-mediated inflammation. Interferon-alpha is known to induce MEFV expression in monocytes and granulocytes in vitro. We present the first case of colchicine-resistant FMF in which a durable disease remission and regression of renal amyloidosis was induced by chronic treatment with pegylated interferon-alpha. PMID- 21269585 TI - Acute renal failure in dense deposit disease: complete recovery after combination therapy with immunosuppressant and plasma exchange. AB - We describe the clinical course of a female adolescent who was followed because of isolated microhematuria and hypocomplementemia before admission to hospital with a sudden onset of acute renal failure. At presentation, she exhibited complement consumption through the complement alternative pathway (AP) while other serologic tests were negative. Renal biopsy revealed dense deposit disease (DDD) with a crescentic pattern. Intravenous methylprednisolone, followed by plasma exchange (PE), and intravenous cyclophosphamide pulses were started shortly after admission. C3NeF and anti-factor H antibody tests were negative. Serum factor H and I levels were normal as well as factor H activity. Screening for mutation in the factor H gene revealed the H402 allele variant. Clinical remission, defined as normalization in renal function and in the activity levels of the complement AP, was noted at one month post-presentation and throughout the follow-up. A repeat renal biopsy showed the disappearance of crescent formation, whereas electron microscopy revealed no regression in dense transformation of the lamina densa. In summary, our patient was successfully treated with immunosuppressant and PE. The absence of known factors associated with DDD suggests that, in this particular case, other regulatory mechanisms of complement AP might have been involved in the disease process. PMID- 21269586 TI - Cocaine-associated acute severe hyponatremia. AB - Cocaine is an indirect sympathomimetic agent that acts in the nervous system to block the presynaptic reuptake of serotonin and catecholamines (dopamine, norepinephrine and epinephrine) and to increase their bioavailability at the post synaptic receptors. The association of cocaine and hyponatremia has not been reported in adults. We describe a case of acute severe hyponatremia that followed smoking cocaine. We propose that cocaine, via its effect on the neurotransmitters, stimulates antidiuretic hormone release and leads to a syndrome of inappropriate antidiuretic hormone secretion. PMID- 21269587 TI - Oxalate nephropathy in a diabetic patient after gastric by-pass. AB - We report a case of 48-year-old woman with history of diabetes and hypertension, who presented with acute to chronic kidney injury. Sixteen months before presentation, she had undergone Roux-en-Y gastric by-pass (RYGB) for morbid obesity. Kidney biopsy showed lesions consistent with oxalate nephropathy and deposition of calcium oxalate crystals. An extensive workshop excluded other causes of kidney injury. The patient subsequently required dialysis with no improvement of renal function on follow-up. The mechanism by which patients develop hyperoxaluria after RYGB remains obscure; it is suggested that RYGB provokes fat malabsorption, which results in increased load of free fatty acid in the intestine. Thus, calcium binds to free fatty acids provoking reduced synthesis of calcium oxalate. Consequently, increased quantity of oxalate remains free and is absorbed in the intestine causing hyperoxaluria. Similar to our case, oxalate nephropathy after RYGB is seen in patients with diabetes, hypertension and chronic kidney injury. Treatment includes low-fat, low-oxalate diet along with administration of calcium supplements. Unfortunately, prognosis is rather poor with the majority of patients eventually requiring permanent dialysis. Therefore, patients with history of chronic kidney disease undergoing RYGB should be closely monitored, particularly those with long standing history of diabetes and hypertension. PMID- 21269588 TI - Sequential rupture of triceps and quadriceps tendons in a dialysis patient using hormone supplements. AB - Spontaneous rupture of tendons is rare, and typically occurs in large weight bearing tendons such as the quadriceps, Achilles and patellar tendon, in the context of various chronic diseases including end-stage renal disease. In general, tendon rupture in dialysis patients is associated with hyperparathyroidism, long duration of dialysis, steroid and quinolone use. We present a case of a young man on chronic dialysis who presented with sequential rupture of triceps and quadriceps tendons requiring surgical repair, several months after initiating use of multiple hormone supplements including human growth hormone and androgens. The supplements were obtained over the internet with the aim of improving his kidney function. Although this patient did have hyperparathyroidism, it is likely his PTH elevation was exacerbated by use of human growth hormone, and tendon rupture risk increased by concurrent use of an androgen supplement. This case highlights the fact that dialysis patients do utilize alternative remedies and that there may be unexpected, dialysis-specific complications associated with their use. PMID- 21269589 TI - Efficacy of diffusion-weighted magnetic resonance imaging in detecting infected cysts in a case of polycystic kidney disease. AB - Hepatic and/or renal cyst infection is a major complication in patients with polycystic kidney disease. In many cases, drainage of infected cysts is necessary, although accurate detection of infected cysts from among the numerous hepatic or renal cysts present is often difficult, because the findings of infected cysts on computed tomography and T1- and T2-weighted magnetic resonance imaging resemble those of normal cysts. We describe here a case of polycystic kidney disease complicated by hepatic cyst infection. On diffusion-weighted magnetic resonance imaging (DWMRI), which is occasionally used in the diagnosis of cerebral abscesses, infected hepatic cysts showed higher signal intensity than other cysts, facilitating differentiation of the cysts requiring drainage from numerous other cysts. Infected cysts showed a marked decrease of the apparent diffusion coefficient (ADC) values compared with those of normal cysts. DWMRI was very effective in detecting infected cysts in our patient and may be of value in other such cases with polycystic kidney disease. PMID- 21269590 TI - Unusual acute promyelocytic leukemia following de novo renal transplant: case report and literature review. AB - Acute promyelocytic leukemia (APL) with transcripting three isoforms of mRNA from PML-RAR alpha fusion genes following renal transplantation has never been reported in the literature. A 39-year-old man received a cadaveric renal allograft for IgA chronic kidney disease in 2006 and was consecutively immunosuppressed by tacrolimus, mycophenolate mofetil, and prednisolone. In 2008, he presented with gum bleeding and weight loss. Following bone marrow biopsy, we diagnosed acute promyelocytic leukemia. Molecular analysis demonstrated atypical presence consisting of three isoforms of mRNA from PML-RAR alpha fusion genes. The patient was administered with three courses of consolidation chemotherapy plus atretinoin, resulting in complete remission and did not jeopardize his allograft function. This novel finding suggests that the leukemogenesis of APL may be polyclonal, sharing similar progenitor targeting on complicated karyotypes, responding well to current chemotherapy. PMID- 21269591 TI - Collapsing glomerulopathy in a patient with mixed connective tissue disease. AB - Collapsing glomerulopathy (CG) is a distinct clinicopathological entity characterized by glomerular capillary collapse, podocyte proliferation, diffuse mesangial sclerosis, and podocyte maturation arrest. Initially noted primarily in HIV infected patients, a number of other diseases have now been associated with CG. Mixed connective tissue disease (MCTD) is a disease with overlapping features of systemic lupus erythematosus, progressive systemic sclerosis, and polymyositis. It was originally thought that renal involvement was a rare complication of MCTD. However, over the years, it has become clearer that renal involvement, although not always clinically apparent, is frequent. In this report we present a patient with MCTD who developed CG. PMID- 21269592 TI - Superior mesenteric artery syndrome complicating dialysis patients with peritoneal failure--report of 3 cases. AB - We report 3 cases of superior mesenteric artery syndrome in patients previously on maintenance peritoneal dialysis converted to hemodialysis after peritoneal failure. All 3 patients presented with repeated vomiting and severe malnutrition. It is postulated that complications arising from peritoneal dialysis such as peritoneal sclerosis, adhesions and collections after CAPD peritonitis may be important contributing factors for the SMA syndrome in these 3 patients. All of them succumbed within six months of diagnosis. The first 2 patients received gastrointestinal bypass surgery and died post-operatively due to impaired wound healing and nosocomial sepsis. The 3rd patient was treated conservatively with nasoduodenal feeding but succumbed to aspiration pneumonia. It is postulated that complications arising from peritoneal dialysis including peritoneal sclerosis, adhesions and collections after CAPD peritonitis may contribute to the SMA syndrome in these patients. Our experience suggests that SMA syndrome in end stage renal disease patients is associated with high surgical morbidity and mortality possibly related to their poor pre-morbid condition and pre-existing malnutrition. Aggressive parenteral nutrition should be considered to build up the general status before proceeding to surgical intervention. PMID- 21269593 TI - Remission of membranous glomerulonephritis after pancreatectomy for pancreatic neuroendocrine neoplasm - a rare coincidence. AB - The concomitant existence of a non-malignant neuroendocrine tumor (NET) and membranous glomerulonephritis (MGN) is rare. We report a subject with kidney biopsy proven MGN and nephrotic syndrome in which a computerized scan tomography (CT) examination was performed revealing a pancreatic tumor. A pancreatectomy was performed and the tumor was shown to be a non-malignant NET with a malignant potential. Although treatment with corticosteroids was initiated remission of MGN was observed within the next month after pancreatectomy. The rapid remission observed shortly after pancreatectomy pointed to that tumor removal contributed to, and that neither spontaneous nor corticosteroid treatment alone did induce the rapid remission of the MGN. The coexistence of the two disorders NET and MGN is very rare, however. This is the first report on remission of MGN after pancreatectomy for a NET. PMID- 21269594 TI - Severe erosive lesions in the digestive tract of patients with Henoch-Schonlein Purpura (HSP) and its impact on prognosis - presentation of two cases and statistical review of adult-onset Japanese HSP. AB - INTRODUCTION: Although many pediatric patients with Henoch-Schonlein Purpura (HSP) recover spontaneously, disease activity in adult patients often cannot be controlled by treatment. PURPOSE: To assess the specific signs not formerly considered to be those of uncontrollable adult HSP patients. PATIENTS AND METHODS: Clinical records of 2 adult patients who died during HSP were reviewed and previous reports on HSP were consulted. RESULTS: Both patients had lesions in the digestive tract diagnosed as hemorrhagic erosion in the small intestine and colon. They were elderly and showed renal dysfunction. They died from severe infection after potent immunosuppressive treatment. A univariate analysis showed that age of over 60 years, severe renal symptoms (nephrotic syndrome and/or end stage renal failure), Birmingham Vasculitis Activity Score (BVAS) of more than 18 points, massive immunosuppression and melena had significantly higher prevalence among patients who died. Multivariate statistical analysis with theoretical quantification analysis II revealed that age of over 60 and severe renal symptoms (nephrotic syndrome and/or end-stage renal failure) contributed to poor prognosis. The presence of melena did not contribute to poor prognosis despite results of the univariate analysis and our clinical impressions. DISCUSSION: In multivariate statistical analysis, melena was selected as a sign of severe erosive lesions in the digestive tract because some of the patients were not examined by fiberscopy. Melena is caused by various lesions in the digestive tract and each of them has different effects on prognosis. CONCLUSION: Elderly HSP patients with severe renal impairment should be carefully treated. Examination of the digestive tract by fiberscopy is recommended when melena is observed in these patients. PMID- 21269595 TI - Unilateral breast swelling as a complication of innominate vein stenosis in a hemodialysis patient. AB - A 53-year-old African-American female with end-stage renal disease presented with 3 months history of right breast swelling. The patient had a right internal jugular tunneled catheter for dialysis access. Physical examination was significant for right breast swelling, peau d'orange appearance, and mild tenderness on palpation. Mammogram was normal. A CT scan of the chest with contrast demonstrated chest wall edema and prominent superficial collateral veins suggesting central vein obstruction. Right upper extremity venogram revealed right innominate vein occlusion up to its junction with the subclavian vein. Angioplasty of occluded segment was attempted and was unsuccessful, but right breast swelling significantly improved following the procedure. Pathogenesis, clinical manifestations and management of central vein stenosis is discussed. PMID- 21269596 TI - Ritonavir-induced acute kidney injury: kidney biopsy findings and review of literature. AB - Ritonavir therapy is not generally considered nephrotoxic. We report a case of acute kidney injury secondary to ritonavir, with kidney biopsy demonstrating extensive acute tubular injury. This is the first report of a kidney biopsy and pathology in acute kidney injury associated with ritonavir. A review of published medical literature on the topic is also presented. PMID- 21269597 TI - Aeromonas hydrophila as a causative organism in peritoneal dialysis-related peritonitis: case report and review of the literature. AB - Most episodes of peritoneal dialysis (PD)-related peritonitis could be attributed to a single organism, but in almost 10% of peritonitis episodes multiple organisms are identified. Polymicrobial peritonitis is often related to intra abdominal pathology, and the prognosis may be poor. Aeromonas spp. have rarely been identified as the causative pathogen in PD-related peritonitis, and a very small number of cases has been reported in the literature. These rod-shaped, gram negative microorganisms have been isolated from wastewater drainage systems, food, vegetables, and soil. Herein we report a case of polymicrobial peritonitis in a continuous ambulatory peritoneal dialysis (CAPD) patient with systemic lupus erythematosus (SLE), due to a combination of Streptococcus viridans and Aeromonas hydrophila infection. The patient was involved in gardening and was not compliant with her technique protocol. She did not wear a mask and omitted thorough hand washing. The patient was treated with i.p. vancomycin and ceftazidime and peritonitis was resolved. The patient's technique was reassessed, and she was retrained by our PD nurses. PMID- 21269598 TI - Renal dysfunction and barttin expression in Bartter syndrome Type IV associated with a G47R mutation in BSND in a family. AB - Bartter syndrome (BS) Type IV, associated with a G47R mutation in the BSND gene, is known to result in a mild renal phenotype. However, we report here on three brothers with varying degrees of renal dysfunction from mild to end-stage renal disease associated with renal barttin and ClC-K expression. The brothers had histories of polyhydramnios, prematurity, polyuria, deafness, and small body size. Laboratory findings showed hypokalemic metabolic alkalosis, normotensive hyperreninemic hyperaldosteronism, and an increased urinary excretion of sodium, potassium and chloride, consistent with BS Type IV. Microscopic examination of renal tissue showed hyperplasia of cells at the juxtaglomerular apparatus with dilated atrophic tubules and tubulointerstitial fibrosis. A weak barttin signal related to CIC-K expression in the cytoplasm of tubule cells, but not the basement membrane, was noted. A sequence analysis of the BSND gene showed that the affected males were homozygous for a missense G47R mutation in exon 1 of BSND. These findings suggest that the G47R mutation results in a dramatic decrease in barttin expression, which appears to be related to the location of CIC-K being changed from the basement membrane to the cytoplasm in the tubule and might have varying effects on renal function associated with factors other than this gene. PMID- 21269599 TI - Tubulointerstitial nephritis and uveitis syndrome (TINU) with Fanconi's syndrome. AB - We report a 57-year-old woman with concurrent tubulointerstitial nephritis and uveitis syndrome (TINU) and Fanconi's syndrome. She presented with sudden onset of bilateral ocular pain, blurred vision, acute renal failure, glucosuria and proteinuria. Slit lamp examination revealed acute bilateral anterior uveitis. Tubulointerstitial nephritis was confirmed by kidney biopsy. Laboratory examination revealed normoglycemic glucosuria, proteinuria, normal anion-gap metabolic acidosis, phosphaturia, urinary uric acid wasting and kaliuresis leading to hypokalemia. Her vision and renal function improved gradually after systemic steroid therapy. There have been rare reports of TINU syndrome which had features of Fanconi's syndrome. The prevalence of TINU syndrome may be underestimated, and its association with Fanconi's syndrome requires further investigation. PMID- 21269600 TI - Selective glucocorticoid receptor (type II) antagonists prevent weight gain caused by olanzapine in rats. AB - The use of antipsychotic medication has consistently been associated with serious side effects including weight gain and metabolic abnormalities. Strategies for mitigating these side effects have been tested, yet effective interventions have not been identified. The current study tested whether two recently identified selective glucocorticoid receptor antagonists would prevent weight gain induced by the antipsychotic olanzapine. Female Sprague-Dawley rats fed a normal chow diet were randomized (n=10 per group) to receive one of the following for 18days: vehicle, olanzapine plus vehicle (2.4mg/kg), olanzapine plus CORT 112716 (20mg/kg), olanzapine plus CORT 112716 (60mg/kg), olanzapine plus CORT 113083 (20mg/kg), or olanzapine plus CORT 113083 (60mg/kg). Rats receiving olanzapine plus CORT 112716 (60mg/kg) or olanzapine plus CORT 113083 (60mg/kg) gained significantly less weight than rats receiving only olanzapine. Both glucocorticoid receptor antagonists significantly attenuated the weight gain induced by olanzapine in a dose dependent manner. Differences in weight gain were not attributable to decreased food intake. PMID- 21269601 TI - Antipsychotic-induced catalepsy is attenuated in mice lacking the M4 muscarinic acetylcholine receptor. AB - A delicate balance exists between the central dopaminergic and cholinergic neurotransmitter systems with respect to motor function. An imbalance can result in motor dysfunction as observed in Parkinson's disease patients and in patients treated with antipsychotic compounds. Cholinergic receptor antagonists can alleviate extrapyramidal symptoms in Parkinson's disease and motor side effects induced by antipsychotics. The effects of anticholinergics are mediated by muscarinic receptors of which five subtypes (M(1)-M(5)) exist. Muscarinic M(4) receptors are found at high concentrations in motor parts of the striatum, suggesting a role for muscarinic M(4) receptors in the motor side effects of antipsychotics, and in the alleviation of these side effects by anticholinergics. Here we investigated the potential role of the muscarinic M(4) receptor in catalepsy induced by antipsychotics (haloperidol and risperidone) as well as the anti-cataleptic effects of the non-selective anticholinergic drug scopolamine in fully backcrossed muscarinic M(4) receptor knockout mice. The drug-induced catalepsy was strongly attenuated, but not abolished, in M(4) knockout mice as compared to wild-type controls. Scopolamine further attenuated the cataleptic response in M(4) knockout mice, suggesting that non-M(4) muscarinic receptors also participate in the anti-cataleptic effects. In conclusion, these data indicate an important role for M(4) receptors in antipsychotic-induced motor side effects and suggest that M(4) receptors could be a target for future pharmacological treatment of antipsychotic-induced as well as idiopathic parkinsonism. PMID- 21269603 TI - The impact of the Boston ocular surface prosthesis on wavefront higher-order aberrations. AB - PURPOSE: To evaluate the effect of the Boston Ocular Surface Prosthesis (Boston Foundation for Sight) on higher-order wavefront aberrations in eyes with keratoconus, eyes that have undergone penetrating keratoplasty, eyes that have undergone refractive surgery, and eyes with ocular surface diseases. DESIGN: Prospective, clinical study. METHODS: The study evaluated 56 eyes of 39 patients with irregular astigmatism who were treated with the Boston Ocular Surface Prosthesis when conventional treatments failed. Patients were sorted into 4 clinical groups based on the underlying cause of irregular astigmatism, including keratoconus (group 1), post-penetrating keratoplasty (group 2), post-refractive surgery (group 3), and ocular surface diseases (group 4). Another 6 eyes of 5 patients who were treated with rigid gas permeable lenses also were evaluated. Best-corrected visual acuity; topographic refractive indices, including spherical, cylindrical, spherical equivalent values; and higher-order and total wavefront aberration errors were noted at baseline and after fitting the lens. RESULTS: In all groups, higher-order wavefront aberration error was noted to decrease significantly in eyes wearing the Boston Ocular Surface Prosthesis (P<.001, P=.001, P=.002, and P=.001, respectively). By post hoc analysis, significant differences in the level of higher-order aberrations were observed only between groups 1 and 4 (P=.012) and groups 1 and 2 (P=.033). In the overall group, mean correction rate of higher-order aberration error with the Boston Ocular Surface Prosthesis was 72.3%. However, in eyes with rigid gas permeable lenses, 2 eyes demonstrated increased higher-order aberration error, whereas the mean correction rate in other 4 eyes was only 42.5%. CONCLUSIONS: With its unique structure, the Boston Ocular Surface Prosthesis was found to be very effective in reducing higher-order wavefront aberrations in patients with irregular astigmatism resulting from a number of corneal and ocular surface conditions who had not responded satisfactorily to conventional methods of optical correction. PMID- 21269602 TI - Structure and binding mechanism of vascular endothelial cadherin: a divergent classical cadherin. AB - Vascular endothelial cadherin (VE-cadherin), a divergent member of the type II classical cadherin family of cell adhesion proteins, mediates homophilic adhesion in the vascular endothelium. Previous investigations with a bacterially produced protein suggested that VE-cadherin forms cell surface trimers that bind between apposed cells to form hexamers. Here we report studies of mammalian-produced VE cadherin ectodomains suggesting that, like other classical cadherins, VE-cadherin forms adhesive trans dimers between monomers located on opposing cell surfaces. Trimerization of the bacterially produced protein appears to be an artifact that arises from a lack of glycosylation. We also present the 2.1-A-resolution crystal structure of the VE-cadherin EC1-2 adhesive region, which reveals homodimerization via the strand-swap mechanism common to classical cadherins. In common with type II cadherins, strand-swap binding involves two tryptophan anchor residues, but the adhesive interface resembles type I cadherins in that VE cadherin does not form a large nonswapped hydrophobic surface. Thus, VE-cadherin is an outlier among classical cadherins, with characteristics of both type I and type II subfamilies. PMID- 21269604 TI - Exposure to lead exacerbates dental fluorosis. AB - AIM: Our aim was to test the hypothesis that co-exposure to lead and fluoride alter the severity of enamel fluorosis. MATERIALS AND METHODS: Wistar rats were allocated in four groups: control, and 3 groups that received water containing 100 ppm of fluoride (F), 30 ppm of lead (Pb), or 100 ppm of F and 30 ppm of Pb (F+Pb) from the beginning of gestation. Enamel analysis and F and Pb determinations in enamel, dentine, and bone were performed in 81-day-old animals. Fluorosis was quantified using a new fluorosis index based on the identification of incisor enamel defects (white bands and white islets, representing hypomineralization, and cavities) weighted according to their severity and quantity. Hypomineralization was validated histopathologically by polarizing microscopy and microradiography. Scores were given by two blinded calibrated examiners (intra and interexaminer kappa values were 0.8 and 0.86, respectively). RESULTS: The control and the Pb groups presented normal enamel. The F+Pb group presented more severe enamel defects compared with the F group (P<0.0001). CONCLUSIONS: This study shows that lead exacerbates dental fluorosis in rodents, suggesting that co-exposure to lead may affect the degree of fluorosis. PMID- 21269605 TI - Evidence of benzilic rearrangement during the electrochemical oxidation of D glucose to D-glucaric acid. AB - During the course of the 2,2,6,6-tetramethyl-1-piperidinyloxy free radical catalyzed electrochemical oxidation of D-glucose to D-glucaric acid a new side product was observed. This compound was isolated and identified as a tricarboxylic acid of unique structure, which was named maribersonic acid. Its structure was proven by different experiments coupled with several analytical methods, and its appearance during the electrochemical oxidation of D-glucose was rationalized through a thorough study. PMID- 21269606 TI - [Preoperative biliary drainage in patients with hilar cholangiocarcinoma]. PMID- 21269607 TI - [Tertiary peritonitis: as difficult to define as it is to treat]. AB - Tertiary peritonitis is the most delayed and severe outcome of patients with complicated intra-abdominal infections. The major difficulty lies in giving a common, precise and consensus definition in order to know when to make its diagnosis and how it can be avoided and/or treated. This condition requires early and repeated surgery, wide spectrum antibiotic therapy against multi-resistant bacteria and intensive systemic support measures. Despite all this, the prognosis is extremely poor since it has a mortality which can reach up to 60%, with preventions being the most important measure to avoid it developing. In this article, we have made a specific review of tertiary peritonitis, of the accepted definitions, the risk factors, its pathophysiology, the microbiological flora involved, and its treatment. PMID- 21269608 TI - A tutorial introduction to Bayesian models of cognitive development. AB - We present an introduction to Bayesian inference as it is used in probabilistic models of cognitive development. Our goal is to provide an intuitive and accessible guide to the what, the how, and the why of the Bayesian approach: what sorts of problems and data the framework is most relevant for, and how and why it may be useful for developmentalists. We emphasize a qualitative understanding of Bayesian inference, but also include information about additional resources for those interested in the cognitive science applications, mathematical foundations, or machine learning details in more depth. In addition, we discuss some important interpretation issues that often arise when evaluating Bayesian models in cognitive science. PMID- 21269609 TI - Granulocyte colony-stimulating factor in conjunction with vascular endothelial growth factor maintains primordial follicle numbers in transplanted mouse ovaries. AB - OBJECTIVE: To determine whether granulocyte colony-stimulating factor (G-CSF), stem cell factor (SCF), or vascular endothelial growth factor (VEGF) improve the outcome of ovarian grafting. DESIGN: Experimental animal study. SETTING: Tertiary care hospital, animal facilities. ANIMAL(S): Young adult (6- to 8-week-old) C57BL/6 female mice. INTERVENTION(S): Orthotopic transplantation of the frozen thawed ovary. Group 1 (n = 6) received VEGF (8 g/kg/day); group 2 (n = 6) received VEGF and G-CSF (50 g/kg/day), group 3 (n = 6) received G-CSF and SCF (100 g/kg/day), and group 4 (n = 5) received saline (vehicle controls). All injections were given once daily for 5 days starting the day after surgery. Ovaries were collected 2 weeks after transplantation. MAIN OUTCOME MEASURE(S): Number of nonatretic immature (primordial, primary, and small preantral) follicles. RESULT(S): Transplanted ovaries in mice injected with VEGF concurrently with G-CSF maintained a statistically significantly larger pool of primordial follicles compared with transplanted ovaries in saline-injected controls. Follicle numbers (total immature and primordial) in transplanted ovaries showed no statistically significant difference in mice injected with VEGF alone or G-CSF plus SCF compared with saline-injected controls. CONCLUSION(S): After ovarian transplantation, mice treated with VEGF and G-CSF maintain a significantly greater number of primordial follicles compared with the transplanted ovaries in control animals, suggesting that the combination of G-CSF and VEGF minimizes ischemic damage and thus improves the viability and function of the ovarian graft. PMID- 21269610 TI - Experimental contamination assessment of a novel closed ultravitrification device. AB - OBJECTIVE: To evaluate the safety of a new ultravitrification closed device. DESIGN: Ultravitrification research. SETTING: Private assisted reproduction center. ANIMAL(S): Microorganisms (bacteria). INTERVENTION(S): A styrofoam container holding 1,000 mL of liquid nitrogen (LN2) was contaminated with Pseudomonas aeruginosa and Escherichia coli. Forty closed devices (Ultravit) and 20 open devices (Cryotop) loading approximately 0.5 MUL of antibiotic-free medium were plunged into this contaminated LN2 for 5-10 seconds and then inoculated into selective culture dishes. Colony-forming units were analyzed and counted after an overnight incubation at 37 degrees C. MAIN OUTCOME MEASURE(S): Detection of micro organisms in different devices after incubation. RESULT(S): There was no contamination in any of the closed devices, whereas in 45% of open devices these bacteria were present. CONCLUSION(S): With this study we demonstrated, in an experimental model using contaminated LN2, that this new closed device is a safe system that does not allow cell contact with LN2, avoiding cell contamination. PMID- 21269611 TI - Laparoscopic excision of malignant struma ovarii and 1 year follow-up without further treatment. AB - OBJECTIVE: To report the case of a patient with malignant struma ovarii, which was excised endoscopically. DESIGN: Case study and literature review. SETTING: Hospital outpatient clinic with subsequent hospitalization. PATIENT(S): A 40-year old gravida 5, para 3 with an incidental ultrasonographic finding of a solid right adnexal mass. INTERVENTION(S): Endoscopic resection and 1-year follow-up. MAIN OUTCOME MEASURE(S): Treatment options and differential diagnosis. RESULT(S): The tumor was excised endoscopically. CONCLUSION(S): Malignant struma ovarii is a very rare, highly specialized form of mature ovarian teratoma, in which thyroid tissue is the predominant element. Because of the nonspecific symptoms and a lack of specific features in imaging studies, preoperative diagnosis is very difficult, and there is no standard treatment. Struma ovarii, which is potentially malignant, should be included in the differential diagnosis of an ovarian mass with cystic, solid, or mixed cystic and solid structure. Standardized treatment of malignant struma ovarii still remains undefined; currently the laparoscopic removal of the tumor may be a treatment option, and thyroidectomy and radiotherapy with 131I should be offered. PMID- 21269612 TI - Weight of in vitro fertilization and intracytoplasmic sperm injection singletons in early childhood. AB - Birth weight and longitudinal growth in the first 4 years of life of term singletons conceived with the use of IVF and intracytoplasmic sperm injection (ICSI) were compared with those of naturally conceived singletons. Although IVF and ICSI singletons had a statistically significantly lower birth weight than naturally conceived singletons, the average individual weight curves showed that this difference was lost before the age of 4 years in all subgroups: IVF, ICSI, boys, and girls. PMID- 21269613 TI - Does advanced-stage endometriosis affect the gene expression of estrogen and progesterone receptors in granulosa cells? AB - OBJECTIVE: To evaluate how endometriosis affects the expression of estrogen and progesterone receptors mRNA in granulosa cells. DESIGN: Prospective study. SETTING: IVF-ET program at Osaka Medical College. PATIENT(S): Eighteen patients with revised American Fertility Society stage IV endometriosis and 23 patients with tubal infertility without endometriosis. INTERVENTION(S): Granulosa cells obtained from patients with endometriosis were examined for estrogen (ER-beta, ER alpha) and progesterone (PR-A, PR-B) receptor mRNA expression ratio against GAPDH. MAIN OUTCOME MEASURE(S): Hormonal environment and clinical outcome were investigated. Expression of ER and PR mRNA were evaluated by StepOne real-time polymerase chain reaction (PCR) analysis. RESULT(S): Total hMG/FSH levels were statistically higher in patients with endometriosis; however, high-quality embryo rates and pregnancy rates were lower in patients with endometriosis than in patients with tubal infertility. Expression of PR-A and ER-alpha in patients with endometriosis was statistically higher than in patients with tubal infertility. The expression of PRs and ERs in patients with tubal infertility showed a positive correlation; however, it was not identified in the endometriosis group. CONCLUSION(S): The higher PR-A and ER-alpha gene expression in granulosa cells in patients with endometriosis, compared with patients with tubal infertility, might be a leading cause of ovarian dysfunction due to endometriosis. PMID- 21269614 TI - Presence of hepatitis B virus in oocytes and embryos: a risk of hepatitis B virus transmission during in vitro fertilization. AB - OBJECTIVE: To define the risk of hepatitis B virus (HBV) transmission through oocytes and embryos from chronic HBV carriers. DESIGN: Laboratory-based study. SETTING: Research laboratory in a university hospital. PATIENT(S): Thirty-one couples with hepatitis B surface antigen (HBsAg)-negative women and HBsAg positive men, 41 couples with HBsAg-positive women and HBsAg-negative men, and 39 seronegative couples. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Hepatitis B virus DNA and RNA analyses in oocytes and embryos, and the location of virus particles containing HBsAgs. RESULT(S): Hepatitis B virus DNA was detected in 3 of 18 male HBsAg-positive/female HBsAg-negative couples (and in 13 of 84 embryos) and 3 of 14 male HBsAg-negative/female HBsAg-positive couples (and in 15 of 71 oocytes and embryos). Hepatitis B virus RNA was detected in 9 of 13 male HBsAg positive/female HBsAg-negative couples (and in 39 of 52 embryos) and 8 of 17 male HBsAg-negative/female HBsAg-positive couples (and in 30 of 63 oocytes and embryos). The HBsAg, which is present in the nuclei and cytoplasm of oocytes and embryos, was detected in 6 of 10 male HBsAg-negative/female HBsAg-positive couples (and in 13 of 20 oocytes and embryos). Hepatitis B virus DNA, HBV RNA, and HBsAg were not found in 135 oocytes and embryos from 39 seronegative couples. CONCLUSION(S): The presence of HBV in oocytes and embryos suggests the possibility of vertical transmission of HBV via the germ line. PMID- 21269615 TI - Effect of GnRH agonist and hCG treatment on VEGF, angiopoietin-2, and VE cadherin: trying to explain the link to ovarian hyperstimulation syndrome. AB - This study evaluated the differentially modulated expression of vascular mediators in oocyte donors after hCG vs. GnRHa triggering, trying to understand ovarian hyperstimulation syndrome pathophysiology. Donors who received GnRH agonist triggering showed a statistically significant decrease in vascular endothelial growth factor in follicular fluid and in mRNA expression in granulosa cells, with no differences in angiopoietin 2 and vascular endothelial cadherin levels in serum or follicular fluid. This differential regulation of vascular endothelial growth factor by hCG might explain the higher likelihood of ovarian hyperstimulation syndrome following hCG administration compared with GnRH agonists. PMID- 21269616 TI - Racial and ethnic disparities in assisted reproductive technology pregnancy and live birth rates within body mass index categories. AB - OBJECTIVE: To evaluate the effect of maternal race and ethnicity within body mass index (BMI) categories on assisted reproduction technology (ART) pregnancy and live birth rates. DESIGN: Historical cohort study. SETTING: Clinic-based data. PATIENT(S): 31,672 ART embryo transfers from the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System for 2007, limited to women with documented race, ethnicity, height, and weight, with women grouped as white, Asian, Hispanic, or black and by BMI. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Failure to achieve a clinical intrauterine gestation and failure to achieve a live birth as adjusted odds ratios within BMI categories overall with normal-weight women as the reference group, and by race and ethnicity with white women as the reference group. RESULT(S): Failure to achieve a clinical intrauterine gestation was significantly more likely among obese women overall (1.22), normal-weight and obese Asian women (1.36 and 1.73, respectively), normal weight Hispanic women (1.21), and overweight and obese black women (1.34 and 1.47, respectively). Among women who did conceive, failure to achieve a live birth was significantly more likely among overweight and obese women overall (1.16 and 1.27, respectively), overweight and obese Asian women (1.56 and 2.20, respectively) and Hispanic women (1.57 and 1.76, respectively), and normal-weight and obese black women (1.45 and 1.84, respectively). CONCLUSION(S): These findings indicate significant disparities in pregnancy and live birth rates by race and ethnicity, even within BMI categories. PMID- 21269618 TI - Media influence on awareness and utilization of assisted reproduction technology in Hispanic populations. PMID- 21269619 TI - Epistasis between FSHR and CYP19A1 polymorphisms is associated with premature ovarian failure. AB - Follicle-stimulating hormone secreted from the pituitary gland plays a key role in human reproduction and regulates estrogen production by acting on the regulatory region of CYP19A1. We observed a significant association between premature ovarian failure and the combined genetic effect of single nucleotide polymorphism (SNP) rs4646 (CA+AA) in the 3' untranslated region of CYP19A1 and the missense FSHR SNP rs6166 (AG+GG) genotype (odds ratio 5.42, 95% confidence interval 1.96-14.98), and we identified a significant association between premature ovarian failure and the combined genetic effect of the FSHR missense SNP rs6166 (AA) and the rs4646-rs10046 haplotype (C-T)+(C-C) (odds ratio 5.47, 95% confidence interval 2.03-14.75), suggesting that two biochemical pathways may be involved in the regulation of folliculogenesis. PMID- 21269620 TI - Endometrial polyps affect uterine receptivity. AB - This case-control study evaluated the effect of hysteroscopically identified endometrial polyps on endometrium by means of HOXA10 and HOXA11, known molecular markers of endometrial receptivity. Uteri with endometrial polyps demonstrated a marked decrease in HOXA10 and HOXA11 messenger RNA levels, which may impair implantation. These findings suggest a molecular mechanism to support the clinical findings of diminished pregnancy rates in women with endometrial polyps. PMID- 21269621 TI - Clear water filling and puncture: sufficient for endoscopic diagnosis of pneumatosis cystoides intestinalis? (with video). PMID- 21269622 TI - Non-operative management of renal trauma in very young children: experiences from a dedicated South African paediatric trauma unit. AB - Blunt abdominal trauma results in renal injury in 10% of paediatric cases. Over the last twenty years, the management of paediatric renal trauma has shifted towards a primarily non-operative approach that is now well-established for children up to 18 years old. This retrospective study reviews our experiences of non-operatively managing blunt renal trauma in a very young cohort of patients up to 11 years old. Between June 2006 and June 2010, 118 children presented to the Red Cross War Memorial Children's Hospital in Cape Town with blunt abdominal trauma. 16 patients shown to have sustained renal injury on abdominal computed tomography (CT) scanning were included in this study. Medical records were reviewed for the mechanism of injury, severity of renal injury, clinical presentation, associated injuries, management method and clinical outcomes. All renal injuries were graded (I-V) according to the American Association for the Surgery of Trauma Organ Injury Severity Scale. All renal trauma patients included in this study were aged between 1 and 11 years (mean of 6.5 years). 1 patient sustained grade V injuries; 2 grade IV, 6 grade III and 7 grade I injuries. The majority of injuries (9/16) were caused by motor vehicle crashes, whilst 5 children fell from height, 1 was struck by a falling tree and 1 hit by a moving train. 1 of 16 patients was haemodynamically unstable on presentation as a result of multiple splenic and hepatic lacerations. He was resuscitated and underwent immediate laparotomy. However, his renal injuries were not indications for surgical management. 15 haemodynamically stable patients were non-operatively managed for their renal injuries. Following lengths of admissions ranging from 4 to 132 days, all 16 patients were successfully discharged with no mortalities. No significant complications of renal trauma, such as new-onset hypertension, were detected during their first follow up outpatient appointments. Our findings successfully extend non-operative management of haemodynamically stable renal injuries to a very young cohort up to 11 years old. However, we still advocate immediate resuscitation and surgical intervention for any haemodynamically unstable child who had sustained any abdominal injury. We also argue for a limited role for abdominal CT imaging for diagnosing renal injury and routine follow up, instead recommending a greater emphasis on clinical observations for possible complications. PMID- 21269624 TI - FDA approved guidance conduits and wraps for peripheral nerve injury: a review of materials and efficacy. AB - Several nerve guidance conduits (NGCs) and nerve protectant wraps are approved by the US Food and Drug Administration (FDA) for clinical use in peripheral nerve repair. These devices cover a wide range of natural and synthetic materials, which may or may not be resorbable. This review consolidates the data pertaining to all FDA approved materials into a single reference, which emphasizes material composition alongside pre-clinical and clinical safety and efficacy (where possible). This article also summarizes the key advantages and limitations for each material as noted in the literature (with respect to the indication considered). In this context, this review provides a comprehensive reference for clinicians which may facilitate optimal material/device selection for peripheral nerve repair. For materials scientists, this review highlights predicate devices and evaluation methodologies, offering an insight into current deficiencies associated with state-of-the-art materials and may help direct new technology developments and evaluation methodologies thereof. PMID- 21269625 TI - Assessment of hepatic inflammation after spinal cord injury using intravital microscopy. AB - OBJECTIVES: The liver has been shown to play a particularly important role in the initiation and progression of the early systemic inflammatory response (SIR) to spinal cord injury (SCI). The purpose of this study was to determine the time course of leucocyte recruitment to the liver, and to determine the effect of injury severity on the magnitude of leucocyte recruitment and hepatic injury. METHODS: Rats were randomly assigned to one of the following groups: uninjured, sham-injured (laminectomy and no cord injury), cord compressed or cord transected. At 30 min and 90 min after SCI rats had the left lobe of their livers externalised and visualised using intravital video microscopy. RESULTS: Thirty minutes after injury the total number of leucocytes per post-sinusoidal venule was significantly increased after cord transection compared to that in uninjured and sham-injured rats (P<0.05). Of these leucocytes, significantly more were adherent to venule walls (P<0.05). At 90 min the total number of leucocytes per post-sinusoidal venule and the number of adherent and rolling leucocytes was significantly increased after cord transection and cord compression (P<0.05). DISCUSSION: This is the first study to use intravital microscopy to visualise systemic inflammation in the liver following SCI. We have demonstrated immediate leucocyte recruitment to the liver within 30 min after injury and have shown that systemic inflammation increases with time after injury and with severity of injury. PMID- 21269626 TI - Cost-effectiveness and quality of life associated with heavy menstrual bleeding among women using the levonorgestrel-releasing intrauterine system. AB - OBJECTIVE: To review the literature for economic and health-related quality of life outcomes data associated with the use of the levonorgestrel-releasing intrauterine system (LNG-IUS) in the management of heavy menstrual bleeding. METHODS: We searched the MEDLINE and EMBASE databases simultaneously using the Ovid interface to review the literature in a systematic manner for economic and health-related quality of life outcomes data associated with the use of the LNG IUS in women with heavy menstrual bleeding. Articles were then selected for further review based on the relevance of their titles and/or abstracts. We identified 17 articles for inclusion in this review. RESULTS: Treating heavy menstrual bleeding with the LNG-IUS was found to be cost-effective in various countries and settings. Moreover, irrespective of the measuring instrument used, health-related quality-of-life outcomes were found to be improved to a degree similar to that achieved with endometrial ablation or hysterectomy. In some cases, the LNG-IUS appeared to be more effective and less costly than the surgical options. CONCLUSION: The LNG-IUS is a cost-effective treatment option for heavy menstrual bleeding when pharmacologic treatment is indicated. PMID- 21269627 TI - Use of fetal colon thickness for auxiliary term dating of pregnancy. AB - OBJECTIVE: To verify whether fetal colon thickness can be used as a marker for estimating, independent of biometrics and fetal weight percentile, the gestational age (GA) of fetuses between 37 and 40 weeks. METHODS: The study group was 1296 fetuses aged between 33 and 40 weeks. The correlation between GA and colon thickness was assessed by the Pearson correlation test. For term fetuses (>= 37 weeks), comparisons among the mean colon thickness for different weight percentiles at each GA (in weeks) were made with an analysis of variance test. RESULTS: A significant relationship was observed between GA and colon thickness (P < 0.001, r(2) = 0.6). For term fetuses, significant differences were observed among the mean colon thickness values for different weight percentiles at 38 and 39 weeks. Of the 157 term fetuses for which biometrics would have underestimated GA by 2 weeks or more, 126 (80.3%) had a colon thickness equal to, or greater than, 14 mm. This colon thickness was also observed in 52 (70.3%) of term fetuses weighing less than the 10th percentile (n = 74). CONCLUSION: The present study suggested that colon thickness might be a good marker for 37 weeks of gestation, and might identify term fetuses for which biometrics has underestimated the GA. PMID- 21269628 TI - Two-dimensional counter-current chromatography: 1st traditional counter-current chromatography, 2nd acid-base elution counter-current chromatography. AB - An on-line column-switching counter-current chromatography (CCC) with solid-phase trapping interphase is presented in this paper. The large volume injection is avoided using solid-phase trapping interphase. Thereby, totally different chemical composition biphasic solvent system can be utilized to enhance system orthogonality. In the present work, a 140 mL-capacity CCC instrument was used in the first dimension, and a parallel three-coil CCC centrifuge (40 mL each coil) was used in the second dimensional separation allowing three injections at the same time. With biphasic solvent system composed of n-hexane: ethyl acetate: methanol: water (1:1:1:1, v/v), five well-separated fractions were obtained in the first dimension. Two fractions were online concentrated and further separated in the second dimension with solvent system composed of methyl tert-butyl ether: acetonitrile: water (2:2:3, v/v), where trifluoroacetic acid (10 mM) was added to the upper organic phase as a retainer and triethylamine (10mM) to the aqueous mobile phase as an eluter. Four hydroxyanthraquinones were successfully separated and purified from Chinese medicinal plant Rheum officinale in only one step. PMID- 21269629 TI - Fundamental challenges and opportunities for preparative supercritical fluid chromatography. AB - The use of supercritical fluids as mobile phases in chromatography was suggested nearly fifty years ago. In spite of some major potential advantages, this mode of chromatography, generally known as SFC, is only now beginning to be considered by the mainstream community but it still does not yet enjoy a popularity comparable to those of gas or liquid chromatography. This seems to be largely due to a combination of (1) the serious instrumental difficulties that took many years to solve; (2) the complexity of the behavior of supercritical fluids in chromatographic systems when their temperature, pressure, or composition changes; (3) the long-lasting absence of any substantial incentive to use more complex systems, when the simpler and more robust approaches provided by HPLC are available. This situation, however, has begun to significantly change during recent years. The incentive of employing green, sustainable technologies in industrial processes as well as in analyses is increasing. Because mobile phases generally used in SFC tend to be less environmentally harmful and less expensive than those used in HPLC, SFC presents strong economical and regulatory advantages over the latter technique. Added to that, steady advancements in LC techniques in the last three decades has solved many instrumental difficulties related to SFC, which is now taking full advantages of many of these advances. One factor, however, has remained mostly unresolved. A clearer understanding of the physico chemical behavior of supercritical fluids in preparative chromatographic columns under nonlinear conditions is still needed. This seems to be the main obstacle to the establishment of SFC as a sustainable separation tool. One aim of this review is to highlight these issues in more detail through a survey of the state-of-the art techniques available for the design and operation of SFC. Another aim is to outline a possible series of investigations, which are necessary to develop a better physical understanding of SFC. PMID- 21269630 TI - Hydrophobicity of ionisable compounds studied by countercurrent chromatography. AB - Countercurrent chromatography (CCC) is a liquid chromatography technique in which the stationary phase is also a liquid. The main chemical process involved in solute separation is partitioning between the two immiscible liquid phases: the mobile phase and the support-free liquid stationary phase. The octanol-water partition coefficients (P(o/w)) is the accepted parameter measuring the hydrophobicity of molecules. It is considered to estimate active principle partitioning over a biomembrane. It was related to the substance biological activity. CCC is able to work with an octanol stationary phase and an aqueous mobile phase. In this configuration, CCC is a useful and easy alternative to measure directly the P(o/w) of the molecules compared to other methods including the classical and tedious shake-flask method. Three ketones are used as model compounds to illustrate the CCC protocol of P(o/w) measurement. The focus of this work is put on ionisable molecules whose apparent P(o/w) is completely changed by ionization. beta-Blockers, diuretics and sulfonamides are compound classes that were studied. Some of the experimentally determined P(o/w) coefficients of the molecular forms disagreed with calculated and experimental values available in the literature. The P(o/w) coefficients of the ionic forms and the acidity constants were also calculated using a theoretical model. Relationships between biological properties and hydrophobicity are also discussed. PMID- 21269631 TI - Hollow fiber liquid phase microextraction as a preconcentration and clean-up step after pressurized hot water extraction for the determination of non-steroidal anti-inflammatory drugs in sewage sludge. AB - A method for the quantitative determination of non-steroidal anti-inflammatory drugs (NSAIDs) in sewage sludge was developed and validated. The target compounds were extracted using pressurized hot water extraction (PHWE) and then purified and preconcentrated by three-phase hollow fiber liquid phase microextraction (HF LPME) followed by LC-ESI-MS analysis. The PHWE was optimized with regard to the pH of solvent as well as other operational parameters. The optimum conditions were 0.01 M NaOH as the extraction solvent, temperature of 120 degrees C, pressure of 100 bar, static time 5 min, 5 cycles, flush volume 90% and purge time 60s. Spike recoveries for sludge samples spiked at 200 ng g-1 were in the range of 101-109% but for the native drugs in non-spiked sludge samples, recoveries were 38.9%, 59.8%, 90.3% and 47.8% for ketoprofen, naproxen, diclofenac and ibuprofen, respectively. Donor phase pH, ionic strength and extraction time were optimized for HF-LPME after PHWE. The optimum conditions were 2h extraction at pH 1.5 without salt addition. Enrichment factors in the range of 947-1213 times were achieved (extraction recoveries were 23.6-30.3%) for HF-LPME after PHWE. The matrix effect on the ionization of drugs in LC-ESI-MS was also investigated. The results show that there is a smaller matrix effect (-8.9% to +14.6%) in comparison with other published values obtained using solid phase extraction (SPE) for clean-up after pressurized liquid extraction (PLE). Method detection limits (MDLs) and method quantification limits (MQLs) for different drugs were in the range of 0.4-3.7 ng g-1 and 1.5-12.2 ng g-1 in dried sludge samples, respectively. The characteristics of the proposed method were compared with those of other published works. The considerably lower ion suppression/enhancement and minimum use of organic solvents (a few microliters of di-n-hexyl ether) in the sample preparation step are two highlighted advantages of the proposed method in comparison with previously published works. The method was applied to determine NSAIDs in sewage sludge from Kallby wastewater treatment plant (Lund, Sweden) in April, June, August and October 2010. The highest concentration level was recorded for ibuprofen in the April sewage sludge sample (588 ng g-1) and all of the selected NSAIDs were detected in all the samples analyzed. PMID- 21269632 TI - Recognition characteristics of molecularly imprinted microspheres for triazine herbicides using hydrogen-bond array strategy and their analytical applications for corn and soil samples. AB - The homogeneous molecularly imprinted microspheres (MIMs) based on a biologically inspired hydrogen-bond array were prepared using allobarbital as the novel functional monomer and divinylbenzene as the cross-linker. The host-guest binding characteristics were examined by molecular simulation and infrared spectroscopy. The resultant MIMs were evaluated using high performance liquid chromatography and solid-phase extraction. The results obtained demonstrate that the good imprinting effect and the excellent selectivity of MIMs are mainly due to the interaction involving the formation of three-point hydrogen bond between host and guest. The complete baseline separation was obtained for five triazine analogues and a metabolite on the MIM HPLC column. The MIMs were further successfully used as a specific sorbent for selective extraction of simetryne from corn and soil samples by molecularly imprinted solid phase extraction. Detection limits and recoveries were 5.8 MUg/kg and 0.14 MUg/kg and 87.4-105% and 94.6-101% for simetryne in corn and soil sample, respectively. PMID- 21269633 TI - On-line high-performance liquid chromatography-diode array detection-electrospray ionization-mass spectrometry-chemiluminescence assay of radical scavengers in Epimedium. AB - An on-line analysis method for the simultaneous detection and identification of radical scavenging compounds in plant extracts was developed by combining HPLC with hydrogen dioxide radical scavenging and HPLC-DAD-MS-CL system. The structural identification and activity characteristics of various constituents could be rapidly achieved by the on-line assay of UV, MS and CL in one run. In 4 species of Epimedium studied 32 compounds, including phenolic acids, 8 isopentenyl-flavonoid glycosides and flavonoid glycosides containing a ortho hydroxyl group, were identified by comparison with authentic standards and published mass data. Among these compounds, phenolic acids and flavonoid glycosides containing an ortho-hydroxyl group could obviously inhibit CL, which suggested their strong radical scavenging activity. These four species each exhibited different active properties, which might correlate to their respective quality. The results indicated that the on-line HPLC-DAD-MS-CL system would be a potential method to rapidly and sensitively screen radical scavengers in herbal medicines, and could display an integrated fingerprint based on different detectors. PMID- 21269634 TI - Enhanced adsorption of arsenate onto a natural polymer-based sorbent by surface atom transfer radical polymerization. AB - Arsenic contamination in water, especially in groundwater, has been recognized as an important issue of concern because of its high mobility and toxicity. In this study, N-methylglucamine was immobilized onto crosslinked chitosan beads via atom transfer radical polymerization for an efficient adsorption of arsenic. It was demonstrated that the immobilization significantly enhanced the adsorption capacity. The uptake onto the adsorbent was highly pH dependent, and a maximum adsorption capacity as high as 69.28 mg/g was obtained at the optimum pH of 5. Most of arsenate was rapidly adsorbed in the first 5h, and the adsorption equilibrium was established in 16 h, which was well described by an intraparticle diffusion model. The adsorbent exhibited a great uptake of the humic acid, which led to a decrease in the adsorption of arsenate. The effects of competitive anions on the adsorption exhibited the following descending sequence: sulfate ? phosphate>fluoride (negligible effect). Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy indicated that the arsenic adsorption resulted from the presence of tertiary amine and hydroxyl functional groups grafted on the crosslinked chitosan. PMID- 21269635 TI - Partition-induced vector chromatography in microfluidic devices. AB - We investigate by means of macrotransport theory the transport of Brownian particles in a slit geometry in the presence of an arbitrary two-dimensional periodic energy landscape and driven by an external force or convected by a flow field. We obtained analytical expressions for the probability distribution and the average migration angle of the particles under the Fick-Jacobs approximation. The migration angle is shown to differ from the angle of the driving field and to strongly depend on the physical properties of the suspended species, thus providing the basis for vector chromatography, in which different species move in different directions and can be continuously fractionated. The potential of microfluidic devices as a platform for partition-induced vector chromatography is demonstrated by considering the particular case of a piece-wise constant, periodic potential that, in equilibrium, induces the spontaneous partition of different species into high and low concentration stripes, and which can be easily fabricated by patterning physically or chemically one of the surfaces of a channel. We show the feasibility to fractionate a mixture of particles for systems in which partition is induced via 1-g gravity and Van der Waals interactions in physically or chemically patterned channels. PMID- 21269636 TI - Photocatalytic reduction of CO2 in methanol to methyl formate over CuO-TiO2 composite catalysts. AB - Photocatalytic reduction of CO(2) on CuO-TiO(2) composite catalysts in the presence of methanol to prepare methyl formate had been investigated. Methanol was used as sacrificial reagent to react with the photo-generated holes in the valence band, and CO(2) was reduced by the electrons in the conduction band. CuO TiO(2) was optimized for CuO loading, preparation method and calcination temperature. The catalyst of 1.0CuO-TiO(2), calcined at 450 degrees C and CTAB as a dispersant showed the highest overall activity. The heterojunction between CuO and TiO(2) demonstrated with HRTEM played an important role in enhancing the photocatalytic activity. PMID- 21269637 TI - Electrostatic effects on nanofiber formation of self-assembling peptide amphiphiles. AB - Self-assembling peptide amphiphile molecules have been of interest to various tissue engineering studies. These molecules self-assemble into nanofibers which organize into three-dimensional networks to form hydrocolloid systems mimicking the extracellular matrix. The formation of nanofibers is affected by the electrostatic interactions among the peptides. In this work, we studied the effect of charged groups on the peptides on nanofiber formation. The self assembly process was studied by pH and zeta potential measurements, FT-IR, circular dichroism, rheology, atomic force microscopy, scanning electron microscopy and transmission electron microscopy. The aggregation of the peptides was triggered upon neutralization of the charged residues by pH change or addition of electrolyte or biomacromolecules. Understanding the controlled formation of the hydrocolloid gels composed of peptide amphiphile nanofibers can lead us to develop in situ gel forming bioactive collagen mimetic nanofibers for various tissue engineering studies including bioactive surface coatings. PMID- 21269638 TI - Selective attachment of F-actin with controlled length for developing an intelligent nanodevice. AB - Development of the nanodevice that myosin-coated beads "walk" on actin filaments (F-actin) tracks for in vitro nanotransportation was hindered due to the difficulty of assembling large-area well-orientated F-actin tracks on the surface. In this work, we present a selective attachment of F-actin with controlled length on a patterned surface by employing biotinylated capped protein gelsolin as intermediate anchoring bridge. A patterned streptavidin layer was formed via coupling with a biotin layer that photo-actively attached to an amine functionalized glass surface. The patterned film was found stable and homogenous compared to that obtained by microcontact printing method, according to the profiling with fluorescence microscopy. By a secondary blocking process, non specific binding of F-actin to the patterned surface through electrostatic adsorption can be resisted. The length variation of F-actin as a function of gelsolin concentration was also investigated, implying that F-actin is appropriately of 2.5 MUm in average length once F-actin/gelsolin molar ratio is 4:1. Finally, the selective attachment of F-actin was well characterized with quantifying the number of attached F-actin per unit area in the patterned areas over that in blocked areas. The density of F-actin was estimated at c.a. 2 MUm(2) per actin filament molecule so that the distance between one another actin filament is estimated as c.a. 1.41-1.97 MUm. The unique properties of F-actin, e.g. well flexibility or electrical conductivity, make it feasible to lay them down and form unidirectional aligned tracks by fluidic flow or electrical field. This may open a possibility for the long-distant movement of myosin-coated beads, offering a novel discipline for the development of micro-biochip in vitro. PMID- 21269639 TI - Structure of nanofibrillated cellulose layers at the o/w interface. AB - The nature of layers formed by cellulose nanofibrils that had been surface modified (hydrophobized) at the oil/water (o/w) interface was investigated. The aim of the study was to clarify the mechanism underlying the excellent ability of these nanoparticles to stabilize emulsions. Layers of hydrophobized nanofibrillated cellulose spread at the o/w interface were deposited on glass slides by the Langmuir-Blodgett deposition technique. Overall evaluation of layer structures was performed by image analysis based on a Quadtree decomposition of images obtained from a flatbed scanner. A more detailed characterization of the layer structures was performed by Atomic Force Microscopy (AFM), and Field Emission Scanning Electron Microscopy (FE-SEM). The results show that nanofibrils that were able to stabilize emulsions occur as single, dispersed fibrils or form large, network-like aggregates at the o/w interface. Fibrils that were insufficiently hydrophobized and therefore did not stabilize emulsions were only partially deposited and formed small, compact aggregates. We conclude that it is likely that the network formation is the main mechanism by which the fibrils prevent coalescence of emulsion droplets. PMID- 21269640 TI - Photoluminescent Fe3O4/carbon nanocomposite with magnetic property. AB - Fe(3)O(4)/carbon nanocomposite has been prepared by a facile chemical method, and characterized by X-ray diffraction, X-ray photoelectron spectroscopy, transmission electron microscopy, fourier transform infrared spectroscopy and scanning electron microscopy. The fluorescent and magnetic properties of the sample were investigated by fluorescence spectroscopy and vibrating-sample magnetometer, respectively. The results indicate that the Fe(3)O(4)/carbon nanocomposite exhibit good photoluminescent (emission ranging from 425 to 550 nm) and strong magnetic (saturation magnetization of 44.2 emu/g) properties. PMID- 21269641 TI - A technique for implanting outflow cannulas for Berlin Heart EXCOR ventricular assist device in small pediatric patients. PMID- 21269642 TI - A simplified technique for caval occlusion in reoperative small thoracotomies. PMID- 21269643 TI - Transcatheter transapical mitral valve-in-valve implantations for a failed bioprosthesis: a case series. AB - OBJECTIVES: Mitral valve replacement with bioprosthetic valves is becoming more common. The incidence of structural valve deterioration and the need for reoperative mitral surgery are expected to increase. The operative mortality and morbidity associated with redo mitral surgery remains high. Transapical transcatheter mitral valve-in-valve implantation might offer an alternate and safer approach for high-risk patients. METHODS: From July 2007 to April 2010, 11 patients with symptomatic mitral prosthetic valve dysfunction underwent transapical transapical transcatheter mitral valve-in-valve implantation in our institution. Data were collected and entered into a database prospectively. The mean age was 81 +/- 5 years, with 64% being female. The mean Society of Thoracic Surgeons risk score was 16.1% +/- 5.8%. RESULTS: All patients had successful transapical transcatheter mitral valve-in-valve implantation with no 30-day mortality. One patient died 45 days after surgical intervention from respiratory failure, and 1 patient died on day 135. All other patients were alive and in New York Heart Association class I/II at a median follow-up of 357 days. The median postprocedural transvalvular gradient was 7 mm Hg, and minimal transvalvular or paravalvular regurgitation was seen. CONCLUSIONS: Transcatheter transapical valve in-valve implantations into a failed mitral bioprosthesis is technically feasible with acceptable results. It might be a viable approach for selected high-risk patients. PMID- 21269644 TI - Role of conservative management in traumatic aortic injury: comparison of long term results of conservative, surgical, and endovascular treatment. AB - OBJECTIVE: The purpose of this study is to compare early and long-term results in terms of survival and cardiovascular complications of patients with acute traumatic aortic injury who were conservatively managed with patients who underwent surgical or endovascular repair. METHODS: From January 1980 to December 2009, 66 patients with acute traumatic aortic injury were divided into 3 groups according to treatment intention at admission: 37 patients in a conservative group, 22 patients in a surgical group, and 7 patients in an endovascular group. Groups were similar with regard to gender, age, Injury Severity Score, Revised Trauma Score, and Trauma Injury Severity Score. RESULTS: In-hospital mortality was 21.6% in the conservative group, 22.7% in the surgical group, and 14.3% in the endovascular group (P = .57). In-hospital aortic-related complications occurred only in the conservative group. Median follow-up time was 75 months (range, 5-327 months). Conservative group survival was 75.6% at 1 year, 72.3% at 5 years, and 66.7% at 10 years. Surgical group survival remained at 77.2% at 1, 5, and 10 years, whereas survival in the endovascular group was 85.7% at 1 and 5 years (P = .18). No patient in the surgical or endovascular group required reintervention because of aortic-related complications, whereas 37.9% of the conservative group had an aortic-related complication that required surgery or caused the patient's death during the follow-up period. Cumulative survival free from aortic-related complications in the conservative group was 93% at 1 year, 88.5% at 5 years, and 51.2% at 10 years. Cox regression confirmed the initial type of aortic lesion (hazard ratio, 2.94; P = .002) and a Trauma Score-Injury Severity Score greater than 50% on admission (hazard ratio, 1.49; P = .042) as risk factors for the appearance of aortic-related complications. Two peaks in the complication rate of the conservative group were detected in the first week and between the first and third months after blunt thoracic trauma. CONCLUSIONS: The advent of thoracic aortic endografting has enabled a revolution in the management of acute traumatic aortic injury in patients with multisystem trauma with a low in-hospital morbimortality. Nonoperative management may be only a therapeutic option with acceptable survival in carefully selected patients. The natural history of these patients has revealed a marked trend of late aortic-related complications developing, which may justify an endovascular repair even in some low-risk patients. PMID- 21269645 TI - Elective cardiac retransplantation: a viable option that can be repeated. AB - OBJECTIVE: Our hypothesis is that cardiac retransplantation is a viable option for selected recipients. Furthermore, in some patients multiple retransplantations are reasonable. METHODS: We studied 23 patients who had all received an elective second, third, or fourth cardiac transplant over a 25-year period. Comparisons were made with 792 primary transplantations. Subsequent retransplantations (third and fourth time) were elective and included in the evaluation. RESULTS: Twenty-three patients electively received a second, 4 a third, and 1 a fourth transplant for coronary vasculopathy or chronic graft failure. Sixteen (70%) patients were men, and 7 (30%) were women. Median survival in years for primary cardiac recipients was 10.7 years; for a second transplantation, median survival from the date of retransplantation was 9.3 years. Average age at the time of first transplantation was 47.8 years, and it was 44.3 years at the time of second transplantation. No significant difference was noted in Kaplan-Meier survival curves between patients undergoing primary transplantation and elective retransplantation. Survival at 1 year for patients undergoing a first transplantation was 88.8%, and it was 81.8% for patients undergoing retransplantation. Patient survival at 10 years was nearly identical for patients undergoing first-time transplantation and those undergoing retransplantation (58%). All 5 third- and fourth-time transplant recipients survived. CONCLUSIONS: Cardiac retransplantation is a reasonable option for elective recipients with coronary vasculopathy or chronic graft failure. Survival for groups undergoing primary transplantation and retransplantation is similar. Careful selection of this small group of cardiac recipients (3% of the total) might be the key to success. PMID- 21269646 TI - Landiolol hydrochloride for prevention of atrial fibrillation after coronary artery bypass grafting: new evidence from the PASCAL trial. AB - OBJECTIVE: Atrial fibrillation occurs frequently after cardiac surgery and not only prolongs hospitalization but also influences the prognosis. We investigated whether landiolol hydrochloride, an ultrashort-acting beta-blocker, could reduce postoperative atrial fibrillation in a randomized controlled trial. METHODS: The subjects were 140 patients undergoing coronary artery bypass grafting at the Nihon University School of Medicine. The primary end point was occurrence/non occurrence of atrial fibrillation up to 1 week postoperatively. Logistic regression analysis was performed to investigate risk factors for atrial fibrillation among preoperative, perioperative, and postoperative variables. RESULTS: Atrial fibrillation occurred in 7 patients (10%) in the landiolol group versus 24 patients (34.3%) in the placebo group; the landiolol group had a significantly lower incidence (P = .0006). Postoperative heart rate was significantly lower in the landiolol group than in the placebo group. On returning to the intensive care unit, the landiolol group had significantly lower inflammatory and ischemic parameters. Medical costs were also significantly lower in the landiolol group. Multivariate analysis revealed that significant risk factors for atrial fibrillation were a European System for Cardiac Operative Risk Evaluation of 10 or more, preoperative non-use of angiotensin receptor blockers, and non-use of landiolol. CONCLUSIONS: Postoperative atrial fibrillation was reduced by treatment with landiolol hydrochloride. Amelioration of ischemia, an anti-inflammatory effect, and inhibition of sympathetic hypertonia by landiolol presumably reduced the occurrence of atrial fibrillation. Hypotension or bradycardia did not develop in any of the patients, indicating the safety of this beta-blocker. These findings suggest that landiolol hydrochloride could be useful in the perioperative management of patients undergoing cardiac surgery. PMID- 21269647 TI - Axillary cannulation for endo-occlusion and antegrade flow during complex reoperative mitral valve surgery. PMID- 21269648 TI - SYNTAX Score is associated with worse outcomes after off-pump coronary artery bypass grafting surgery for three-vessel or left main complex coronary disease. AB - OBJECTIVE: The SYNergy between percutaneous intervention with TAXus drug eluting stents and cardiac surgery (SYNTAX) Score is a tool for risk stratification of patients according to the complexity of coronary lesions developed during the SYNTAX trial. We examined the influence of the SYNTAX Score on the incidence of major adverse cardiac and cerebrovascular events. METHODS: All patients with de novo left main or 3-vessel disease undergoing coronary artery bypass grafting from January 2005 to December 2008 at our institution (Hospital Clinico San Carlos, Madrid, Spain) were retrospectively assessed, and their SYNTAX Score was calculated. The influence of the SYNTAX Score on postprocedural and follow-up mortality and combined major adverse cardiac and cerebrovascular events (including death, myocardial infarction, cerebrovascular accident, and repeat revascularization) was identified by multivariate analysis. Balancing score analysis was performed to eliminate the effect of potential confounders. RESULTS: A total of 716 patients were enrolled. Mean SYNTAX Score was 34.5 (standard deviation, 6.7; range, 11.5-76). Three groups of patients were identified according to the score terciles: low (<=33), intermediate (33-37), and high (>37). These terciles scores differed greatly from those reported by the SYNTAX trial investigators. The multivariate analysis identified that the SYNTAX Score was associated with follow-up mortality (hazard ratio = 1.046, P = .015) and combined early and follow-up major adverse cardiac and cerebrovascular events (odds ratio = 1.079, P < .001; and hazard ratio = 1.034, P = .026, respectively). Balancing score-adjusted analyses demonstrated that the SYNTAX Score was independently associated with early and late major adverse cardiac and cerebrovascular events (odds ratio = 1.65, P < .001; and hazard ratio = 1.034, P = .027, respectively). CONCLUSIONS: SYNTAX Score was remarkably high among patients undergoing surgical off-pump myocardial revascularization at our institution. In this subset of patients, a higher SYNTAX Score was associated with a higher incidence of in-hospital and follow-up major adverse cardiac and cerebrovascular events after coronary artery bypass grafting, but not with early or late mortality. PMID- 21269649 TI - Mitral valve repair in heart failure: five-year follow-up from the mitral valve replacement stratum of the Acorn randomized trial. AB - OBJECTIVE: The study objective was to evaluate the long-term (5-year) safety and efficacy of mitral valve surgery with and without the CorCap cardiac support device (Acorn Cardiovascular, St Paul, Minn) in patients with dilated cardiomyopathy and New York Heart Association class II-IV heart failure. BACKGROUND: The Acorn trial provided a unique opportunity to assess the long-term safety and efficacy of mitral valve surgery because clinical visits and echocardiograms (read by a core laboratory) were completed for 5 years of follow up. Further, this study provided follow-up data on the long-term effect of the CorCap cardiac support device as an adjunct to mitral valve surgery. METHODS: From the original Acorn trial (n = 300 patients), 193 patients were enrolled in the mitral valve repair/replacement stratum. A total of 102 were randomized to mitral valve surgery alone (control group) and 91 were randomized to mitral valve surgery with implantation of the CorCap cardiac support device (treatment group). Patients were followed up for 5 years. RESULTS: As previously reported, 30-day operative mortality was only 1.6%. At 5 years, the total mortality was 30% with an average annual mortality rate of approximately 6% per year. The effects of mitral valve surgery led to a progressive decrease in left ventricular end diastolic and end-systolic volumes, which were highly significant at all time points. At the end of 5 years, there was an average reduction in left ventricular end-diastolic volume of 75 mL, which represents a 28% reduction from baseline. During 5 years of follow-up, 29 patients had recurrent mitral regurgitation and 5 patients underwent repeat mitral valve surgery. The addition of the CorCap device led to greater decreases in left ventricular end-diastolic volume (average difference of 16.5 mL; P = .05), indicating that the CorCap device had an additive effect to the mitral valve operation. CONCLUSIONS: This study demonstrates long-term improvement in left ventricular structure and function after mitral valve surgery for up to 5 years. These data provide evidence supporting mitral valve repair in combination with the Acorn CorCap device for patients with nonischemic heart failure with severe left ventricular dysfunction who have been medically optimized yet remain symptomatic with significant mitral regurgitation. PMID- 21269650 TI - Repair of ascending and transverse aortic arch. AB - OBJECTIVES: This is a report to update our experience with repairs of the ascending and transverse arch, with an emphasis on the protective measures, including retrograde cerebral perfusion and blood flow and neurologic monitoring. METHODS: Retrospective data were collected from January 1991 to February 2010, and analysis was conducted on 1193 patients who had aneurysms involving the ascending aorta and arch. RESULTS: The 30-day mortality rate was 9.3%, but with a normal glomerular filtration rate, the mortality rate was 3%. In univariate analysis of the risk factors for death, the factors were advancing age of greater than 72 years (mortality, 14.8%; P = .002), the presence of coronary artery disease (mortality, 13.5%; P = .02), aortic pathology of acute dissection (mortality, 13.9%; P = .004), the emergency nature of the operation (mortality, 16.1%; P = .0001), and renal function in the lowest 3 quartiles of glomerular filtration rate (mortality, 6.9%, 10%, and 18.3%; P = .03, .0005, and .0001, respectively, with decreasing glomerular filtration rate). The highest quartile for pump time (>179 minutes) had a mortality rate of 18.1% (P = .0001). The overall stroke rate was 3%. In univariate analysis of risk factors for stroke, the stroke rate was 2.8% with and 4.2% without retrograde cerebral perfusion (P = .30), but when circulatory arrest time exceeded 40 minutes, the stroke rate was 1.7% with and 30% without retrograde cerebral perfusion (P = .002). Risk factors included age greater than 62 years (stroke rate, 4%; P = .04), hypertension (stroke rate, 3.7%; P = .03), emergency operations (stroke rate, 4.9%; P = .04), and glomerular filtration rate of less than 56 (stroke rate, 4.3%; P = .05). In multiple logistic regression for risk factors for stroke, age was associated with an odds ratio of 1.04 (P = .008), and emergency conditions had an odds ratio of 2.17 (P = .03). CONCLUSIONS: Retrograde cerebral perfusion was associated with a trend toward a reduced incidence of hospital mortality and, in patients receiving prolonged hypothermic circulatory arrest, a reduced incidence of stroke. PMID- 21269651 TI - Effective closure of a tracheal incision by BioGlue in natural orifice transluminal endoscopic surgery performed for thoracic exploration. PMID- 21269652 TI - Polybrominated diphenyl ethers and polychlorinated biphenyls in sediments of southwest Taiwan: regional characteristics and potential sources. AB - Very little information is available on the contamination of coastal sediments of Taiwan by PBDEs and PCBs. In this study, we determined the concentrations of 19 PBDE and 209 PCB congeners in 57 surface sediment samples to identify the possible sources of PBDEs and PCBs. The total PBDE and PCB concentrations ranged from below detection limit to 7.73 ng/g and 0.88-7.13 ng/g, respectively; these values are within the ranges observed for most coastal sediments worldwide. The PBDE congeners were dominated by BDE-209 (50.7-99.7%), with minor contributions from penta- and octa-BDEs. The signatures of PCB congeners suggested that PCB residues in Kaohsiung coast may be the legacy of past use or the result of ongoing inputs from the maintenance, repair and salvage of old ships. Principal component analysis of the congener-specific composition of PBDEs and PCBs revealed distinct regional patterns that are related to the use of commercial products. PMID- 21269653 TI - [Sentinel node procedure in head and neck cutaneous melanoma]. AB - INTRODUCTION: Sentinel lymph node (SLN) biopsy is frequently discussed in the management of cutaneous melanoma, especially in head and neck localizations where SLN biopsy is much more demanding. The benefits of SLN protocol are not proved yet. The aim of our study was to present our experience of SLN biopsy in head and neck cutaneous melanoma. PATIENTS AND METHODS: This retrospective study included all patients managed for head and neck malignant melanoma from 2002 to 2006. We reviewed the technique, implementation and difficulties of the procedure, postoperative outcome, and complications. RESULTS: Nineteen patients were included. An average of 2.2 lymph nodes were localized per patient using lymphoscintigraphy. Biopsy was impossible for one patient because the deep spinal node was not found. An average of 1.2 nodes was biopsied per patient. One patient presented with micrometastases. Another presented with lymphorrhea. DISCUSSION: Sentinel node biopsy is widely performed in the management of cutaneous melanoma but remains an option for these indications in the last update of the French Society of Dermatology. SLN biopsy is difficult to implement because of the complexity of head and neck lymphatic system. PMID- 21269654 TI - Extension of the distributed point source method for ultrasonic field modeling. AB - The distributed point source method (DPSM) was recently proposed for ultrasonic field modeling and other applications. This method uses distributed point sources, placed slightly behind transducer surface, to model the ultrasound field. The acoustic strength of each point source is obtained through matrix inversion that requires the number of target points on the transducer surface to be equal to the number of point sources. In this work, DPSM was extended and further developed to overcome the limitations of the original method and provide a solid mathematical explanation of the physical principle behind the method. With the extension, the acoustic strength of the point sources was calculated as the solution to the least squares minimization problem instead of using direct matrix inversion. As numerical examples, the ultrasound fields of circular and rectangular transducers were calculated using the extended and original DPSMs which were then systematically compared with the results calculated using the theoretical solution and the exact spatial impulse response method. The numerical results showed the extended method can model ultrasonic fields accurately without the scaling step required by the original method. The extended method has potential applications in ultrasonic field modeling, tissue characterization, nondestructive testing, and ultrasound system optimization. PMID- 21269655 TI - Pol as a target for antibody dependent cellular cytotoxicity responses in HIV-1 infection. AB - Antibody-dependent cellular cytotoxicity (ADCC) may assist in preventing HIV or delaying disease progression. Most prior studies have analysed Env-specific ADCC responses. We hypothesized that effective ADCC-based immunity may target conserved internal viral proteins such as Pol. We analysed the ability overlapping Pol peptides to induce activation of NK cells via ADCC. We prospectively studied ADCC responses in 83 HIV+ subjects followed for 3 years. Pol peptides were commonly targeted by ADCC responses in these chronically infected subjects (in 32 of the 83 subjects). However, Pol-specific ADCC responses declined over time and did not correlate with delayed HIV progression, measured by either baseline CD4 T cells, CD4 T cell loss over time, baseline viral load or the need to start antiretroviral therapy. Although Pol is frequently targeted by ADCC in HIV+ subjects, the strength or specificity of Pol specific ADCC responses needs to be modulated to be effective in delaying HIV progression. PMID- 21269656 TI - The lectin pathway of complement activation contributes to protection from West Nile virus infection. AB - The function of the lectin pathway of complement activation in vivo against West Nile virus (WNV) or many other pathogenic viruses has not been defined. Mice deficient in lectin pathway recognition molecules (mannose binding lectin-A (MBL A) and mannose binding lectin-C (MBL-C)) or the effector enzyme mannan-binding lectin-associated serine protease-2 (MASP-2), were more vulnerable to WNV infection than wild type mice. Compared with studies of mice deficient in factors of the classical or alternative pathway, MBL-A(-/-) * MBL-C(-/-) or MASP-2(-/-) mice showed a less severe course of WNV infection. Indeed, a deficiency in lectin pathway activation did not significantly affect the kinetics of viral spread to the central nervous system (CNS) nor did it profoundly alter generation of adaptive B and T cell immune responses. We conclude that MBL-mediated recognition and lectin pathway activation have important yet subordinate functions in protecting against WNV infection and disease. PMID- 21269657 TI - Characterization of organic membrane foulants in a submerged membrane bioreactor with pre-ozonation using three-dimensional excitation-emission matrix fluorescence spectroscopy. AB - This study focuses on organic membrane foulants in a submerged membrane bioreactor (MBR) process with pre-ozonation compared to an individual MBR using three-dimensional excitation-emission matrix (EEM) fluorescence spectroscopy. While the influent was continuously ozonated at a normal dosage, preferable organic matter removal was achieved in subsequent MBR, and trans-membrane pressure increased at a much lower rate than that of the individual MBR. EEM fluorescence spectroscopy was employed to characterize the dissolved organic matter (DOM) samples, extracellular polymeric substance (EPS) samples and membrane foulants. Four main peaks could be identified from the EEM fluorescence spectra of the DOM samples in both MBRs. Two peaks were associated with the protein-like fluorophores, and the other ones were related to the humic-like fluorophores. The results indicated that pre-ozonation decreased fluorescence intensities of all peaks in the EEM spectra of influent DOM especially for protein-like substances and caused red shifts of all fluorescence peaks to different extents. The peak intensities of the protein-like substances represented by Peak T(1) and T(2) in EPS spectra were obviously decreased as a result of pre-ozonation. Both external and internal fouling could be effectively mitigated by the pre-ozonation. The most primary component of external foulants was humic acid-like substance (Peak C) in the MBR with pre-ozonation and protein like substance (Peak T(1)) in the individual MBR, respectively. The content decrease of protein-like substances and structural change of humic-like substances were observed in external foulants from EEM fluorescence spectra due to pre-ozonation. However, it could be seen that ozonation resulted in significant reduction of intensities but little location shift of all peaks in EEM fluorescence spectra of internal foulants. PMID- 21269659 TI - Removal capacity and pathways of phenolic endocrine disruptors in an estuarine wetland of natural reed bed. AB - Phenolic compounds are partly known as endocrine disruptors with various harmful effects including feminization and carcinogenesis at very low concentrations. Consequently, the pathways and removal of these compounds in natural and artificial sewage treatment systems such as wetlands have received wide concern. In this paper, a natural reed bed wetland with an area of 695ha located in the Liaohe River estuary in Northeast China was employed as a demonstration site to study the retention and removal efficiency of phenolic compounds including 4 nonylphenol (4-NP), bisphenol A (BPA), 4-t-octylphenol (4-t-OP), and 2,4 dichlorophenol (DCP), and to evaluate their purification capacity via water and mass balance analyses during an irrigation period from May 9 to September 8, 2009. The results showed that the phenolic compounds could be retained in the wetland system and removed through various processes. On average, 27.5% of phenolic compounds could be retained by the wetland substrate during the initial three-day irrigation period with a retention capacity order of 4-t-OP>4 NP>BPA>DCP. During the following 120d irrigation period, the phenolic compounds could be efficiently removed with an average percentage of 91.6%. It is estimated that 1.76kgd(-1) of phenolic compounds could be removed by the Liaohe River estuarine wetland (~8*10(4)ha). The reed bed wetland system therefore provides a feasible mitigation option for phenolic pollutants in sewage and wastewater. PMID- 21269658 TI - PCDD/F, PCB, PBDE, HBCD and chlorinated pesticides in a Swedish market basket from 2005--levels and dietary intake estimations. AB - Based on consumption data statistics, food items from four regions in Sweden were sampled in a so-called market basket study. Food items from five food groups, i.e. fish, meat, dairy products, eggs and fat/oils, were analyzed for persistent organic pollutants (POPs) followed by per capita intake calculations. The highest levels of PCDD/F, PCB, PBDE, HBCD and chlorinated pesticides were found in the fish/fish products. The estimated market basket per capita intake of PCDD/F and dl-PCB was 0.7pg WHO-TEQ kg bw(-1) d(-1) (TEFs from 1998). The intake of ?PCB was estimated to 4.9 ng kg bw(-1) d(-1) and fish was found to be the major contributor with 64%. The intake of ?PBDE was found to be 0.7 ng kg bw(-1) d(-1). Fish (38%) and dairy products (31%) were the largest contributors to the total PBDE intake. The intake of HBCD was estimated to 0.14 ng kg bw(-1) d(-1). HBCD mainly came from fish (65%), but also dairy products (24%) and meat (10%) contributed. Also regarding the chlorinated pesticides, fish was found to be the major contributor, with 51% of the ?DDT coming from fish. The intake of ?DDT, ?HCH and HCB was 4.0, 1.0 and 1.1 ng kg bw(-1) d(-1), respectively. Most of the ?HCH and HCB originate from dairy products (43% and 55%, respectively). This study shows that the levels, and intake, of different POPs from food of animal origin in the market basket of 2005 seem to have decreased since the market basket study in 1999. PMID- 21269660 TI - Calcaneus length determines running economy: implications for endurance running performance in modern humans and Neandertals. AB - The endurance running (ER) hypothesis suggests that distance running played an important role in the evolution of the genus Homo. Most researchers have focused on ER performance in modern humans, or on reconstructing ER performance in Homo erectus, however, few studies have examined ER capabilities in other members of the genus Homo. Here, we examine skeletal correlates of ER performance in modern humans in order to evaluate the energetics of running in Neandertals and early Homo sapiens. Recent research suggests that running economy (the energy cost of running at a given speed) is strongly related to the length of the Achilles tendon moment arm. Shorter moment arms allow for greater storage and release of elastic strain energy, reducing energy costs. Here, we show that a skeletal correlate of Achilles tendon moment arm length, the length of the calcaneal tuber, does not correlate with walking economy, but correlates significantly with running economy and explains a high proportion of the variance (80%) in cost between individuals. Neandertals had relatively longer calcaneal tubers than modern humans, which would have increased their energy costs of running. Calcaneal tuber lengths in early H. sapiens do not significantly differ from those of extant modern humans, suggesting Neandertal ER economy was reduced relative to contemporaneous anatomically modern humans. Endurance running is generally thought to be beneficial for gaining access to meat in hot environments, where hominins could have used pursuit hunting to run prey taxa into hyperthermia. We hypothesize that ER performance may have been reduced in Neandertals because they lived in cold climates. PMID- 21269661 TI - The effects of angiotensin-II receptor blockers on podocyte damage and glomerular apoptosis in a rat model of experimental streptozotocin-induced diabetic nephropathy. AB - The aim of the study was to determine in a rat model of streptozotocin-induced diabetic nephropathy the expression of: WT-1 (for podocyte loss in the glomerulus), TGF-beta 1 (for tissue damage), caspase-3 and bax (for glomerular apoptosis) and the possible protective effects of an angiotensin II type 1 receptor blocker. Three groups of male Wistar albino rats were used. The first group consisted of non-diabetic control rats. The second group was the untreated diabetic rats. The third group consisted of diabetic rats treated with Irbesartan, which is an angiotensin II receptor antagonist, widely used in treatment for hypertension. Immunohistochemical stainings for TGF-beta 1, bax, caspase-3 and WT-1 were performed. The microalbuminuria levels of the Irbesartan treated diabetic group were lower than those of the untreated diabetic group (P<0.01). The immunostaining of TGF-beta 1, bax and caspase-3 was decreased in glomeruli of the Irbesartan-treated diabetic group compared to the untreated diabetic group. WT-1 immunopositive podocyte numbers were found to be significantly lower in the untreated diabetic group than in the other groups (P<0.01). In the Irbesartan-treated diabetic group, the WT-1 immunopositive cell numbers were higher compared to the untreated diabetic group (P<0.01). We conclude that the decrease in the number of podocytes is an early marker of diabetic nephropathy, AT1 receptor blocker has renoprotective effects on the regulation of renal hemodynamics and on the control of tissue damage by preventing podocyte loss, which leads to decrease of bax and caspase-3 expressions of apoptosis related proteins, and may prevent glomerular cell apoptosis via angiotensin II. PMID- 21269662 TI - Expression of coxsackievirus and adenovirus receptor isoforms in developing mouse bladder uroepithelium. AB - OBJECTIVES: Tight junctions are important for uroepithelial paracellular permeability barriers. In the present study, we examined the developmental changes in the expression of coxsackievirus and adenovirus receptor (CAR) isoforms in mouse bladder uroepithelium. METHODS: Multiplex reverse transcriptase polymerase chain reaction using CAR isoform-specific primer sets and Western blotting were conducted on gestational day 19 and postnatal days 1, 7, and 55. Subcellular localization of CAR was examined, together with occludin and zonula occludens-1, in neonatal and adult bladder using light microscopy and immunofluorescence microscopy. RESULTS: The total CAR and short CAR isoform mRNA were significantly increased from gestational day 19 to birth. Long CAR isoform mRNA was transiently decreased on postnatal day 7 and had recovered during adulthood. On Western blotting, molecular weight 46-kDa CAR was abundant in the mucosa and increased postnatally. In the neonatal, as well as the adult, bladder uroepithelium, CAR immunoreactivity was observed, together with occludin and zonula occludens-1 at the apical tight junctions and basolateral contacts between the adjacent uroepithelial cells. In adult bladder uroepithelium, CAR was increased at the interface between the basal cells and basal lamina. CONCLUSIONS: The expression patterns of CAR isoforms changed during the late fetal to adult development of the mouse bladder. CAR at the apical tight junctions and cellular adhesions between the uroepithelial cells and the interfaces between the basal cells and basal lamina might support the paracellular permeability barrier and structural integrity of the uroepithelium in the mouse bladder. The expression of CAR in the uroepithelial cells can be integrated as a part of the strategy for virus-mediated gene therapy in the bladder uroepithelium. PMID- 21269663 TI - Multicenter analysis of postoperative CT findings after percutaneous nephrolithotomy: defining complication rates. AB - OBJECTIVES: To perform a multi-institutional study to characterize CT-detected complications after PNL. Computed tomography (CT) is commonly performed after percutaneous nephrolithotomy (PNL). One benefit of this imaging modality is the detection of procedure-related complications. Presently, the incidence of such complications is not well-defined. PATIENTS AND METHODS: PNL procedures performed at 5 stone referral centers between July 2007 and June 2008 were reviewed. All patients undergoing CT within 24 hours after surgery were selected for further analysis. All CT studies were reviewed by a staff radiologist. RESULTS: One hundred ninety-seven patients satisfied the study inclusion criteria. A body mass index >30 was present in 27.5% of patients. Treated stone burden was staghorn in 70 (35.5%), >2 cm in 72 (36.5%), and <2 cm in 55 (28%). Six treated renal units (3%) were ectopic; 45.4% of calculi were predominantly lower pole. Thoracic complications encountered were atelectasis in 88 (44.7%), pleural effusion in 17 (8.6%), pneumothorax in 3 (1.5%), hemothorax in 2 (1%), and hydrothorax in 1 (0.5%). Renal complications were perinephric hematoma in 15 (7.6%), collecting system perforation in 4 (2%), subcapsular hematoma in 3 (1.5%), urinoma in 2 (1%), and pseudoaneurysm in 1 (0.5%). There was 1 trans-splenic nephrostomy without splenic hematoma. No injuries to hollow viscera were detected. Two patients (1%) were found to have ascites. CONCLUSIONS: Major post-PNL complications detected by CT are uncommon, and when encountered, they are generally amenable to conservative management. PMID- 21269664 TI - Antegrade percutaneous balloon dilation of ureteral strictures after failed pelviureteric or ureterovesical reimplantation in children. AB - OBJECTIVES: To assess the morbidity and success rate of percutaneous treatment of the postoperative ureteric strictures in children. MATERIALS AND METHODS: Between January 1994 and December 2003, 12 children were treated by antegrade percutaneous balloon dilation for postoperative ureteric strictures. Stenosis occurred at the pelviureteric junction in 5 cases and ureterovesical junction in 7 cases. The 10 boys and 2 girls were between 3 months and 14 years old (mean, 5 years +/- 4.7 years). General anesthesia was used in 10 cases for nephrostomy catheter placement. Five ureteral stents were used additionally for nephrostomy drainage with a 6-F catheter. Both nephrostomy and ureteric stents were in place for 28.5 +/- 12 days, then removed after control antegrade pyelography. RESULTS: Dilation was technically successful in 9 of our patients. Two peroperative complications occurred. Postoperative results were evaluated by ultrasonography, intravenous urography, antegrade pyelography, and diethylene triamine pentaacetic acid renography that confirmed no obstacle in all 5 cases of pelviureteric stricture with a follow-up of 4 +/- 2.9 years and in 4 cases of ureterovesical junction with a follow-up of 4.7 +/- 2.8 years. Three unsuccessful results were reported: in 2 cases, the guide wire could not be advanced over the stenotic ureterovesical junction and in 1 case an early restenosis occurred that eventually required surgery. CONCLUSIONS: Although the main treatment of the postoperative ureteral strictures is surgical, the percutaneous antegrade balloon dilation seems to be an alternative to surgery with a low morbidity rate and short hospitalization period. PMID- 21269666 TI - Effects of artery-ligating and artery-preserving varicocelectomy on ipsilateral epididymis of varicocele-induced rats. AB - OBJECTIVES: To investigate the effects of artery-ligating varicocelectomy (ALV) and artery-preserving varicocelectomy (APV) on the ipsilateral epididymis of varicocele-induced rats. METHODS: A total of 50 adolescent male rats were randomly divided into the 4 groups: control group (n = 8), experimental varicocele (EV) without treatment (EV group, n = 14), EV with ALV (ALV group, n = 14), and EV with APV (APV group, n = 14). The EV was induced by partial ligation of the left renal vein. ALV was performed by total ligation of the left internal spermatic artery and vein. APV was performed by ligation of the left internal spermatic vein only. The microstructure, epithelial ultrastructure, sialic acid and carnitine concentration, and epithelial apoptotic index of the left epididymis were measured. RESULTS: Microstructural and ultrastructural abnormalities of the left epididymis were observed in the EV group and especially in the ALV group. Both the mean epididymal tubular diameter and the concentration of sialic acid, carnitine gradually decreased or increased from the control group to the EV group then to the ALV group (P < .05). However, the epithelial apoptotic index orderly increased for the control group, EV group, and ALV group (P < .05). Furthermore, no significant difference was found between the control and APV groups for these parameters (P > .05). CONCLUSIONS: Varicocele was demonstrated to cause lesions of the ipsilateral epididymis. APV was able to repair the lesions; however, ALV led to additional lesions. PMID- 21269665 TI - Obese frailty, physical performance deficits, and falls in older men with biochemical recurrence of prostate cancer on androgen deprivation therapy: a case control study. AB - OBJECTIVES: To test the hypothesis that early androgen deprivation therapy (ADT) has no proven survival advantage in older men with biochemical recurrence (BCR) of prostate cancer (PCa), and it may contribute to geriatric frailty. METHODS: We conducted a case-control study of men aged 60+ years with BCR on ADT (n = 63) vs PCa survivors without recurrence (n = 71). Frailty prevalence, "obese" frailty, Short Physical Performance Battery (SPPB) scores, and falls were compared. An exploratory analysis of frailty biomarkers (C-reactive protein, erythrocyte sedimentation rate, hemoglobin, albumin, and total cholesterol) was performed. Summary statistics and univariate and multivariate regression analyses were conducted. RESULTS: More patients on ADT were obese (body mass index >30; 46.2% vs 20.6%; P = .03). There were no statistical differences in SPPB (P = .41) or frailty (P = .20). Using a proposed "obese" frailty criteria, 8.7% in ADT group were frail and 56.5% were "prefrail," compared with 2.9% and 48.8% of controls (P = .02). Falls in the last year were higher in the ADT group (14.3% vs 2.8%; P = .02). In analyses controlling for age, clinical characteristics, and comorbidities, the ADT group trended toward significance for "obese" frailty (P = .14) and falls (OR = 4.74, P = .11). Comorbidity significantly increased the likelihood of "obese" frailty (P = .01) and falls (OR 2.02, P = .01). CONCLUSIONS: Men with BCR on ADT are frailer using proposed modified "obese" frailty criteria. They may have lower performance status and more falls. A larger, prospective trial is necessary to establish a causal link between ADT use and progression of frailty and disability. PMID- 21269667 TI - A nomogram for estimating the probability of ovarian cancer. AB - OBJECTIVE: Accurate preoperative estimates of the probability of malignancy in women with adnexal masses are essential for ensuring optimal care. This study presents a new statistical model for combining predictive information and a graphic decision support tool for calculating risk of malignancy. METHODS: The study included 153 women treated with definitive surgery for adnexal mass between 2001 and 2007 with preoperative ultrasound testing and a serum CA125. Multivariable logistic regression was used to develop a statistical model for estimating the probability of ovarian cancer as a function of age, ultrasound score, and CA125 value, with adjustments for nonlinear and interactive relationships. RESULTS: A total of 20 cases of pathologically confirmed cancer (13 invasive malignancies, and 7 tumors of low malignant potential) were identified (20/153=13%). The model obtained excellent discrimination (ROC area=0.87), explained nearly half of the observed variation in the risk of malignancy (R2=0.43), and was well calibrated across the full range of malignancy probabilities. The model equation is represented in the form of a nomogram, which can be used to calculate preoperative probability of malignancy. At a 5% risk of malignancy threshold, the model has a sensitivity of 90% and a specificity of 73%. CONCLUSIONS: Statistical models for estimating the probability of adnexal mass malignancy are substantially improved by including adjustments for non linear relationships among key variables. A clinically relevant nomogram provides an objective tool to further aid clinicians in counseling patients and ensuring proper referral to surgical sub-specialists when indicated. PMID- 21269668 TI - Intra-operative detection of nodal metastasis in early stage cervical cancer: a survey of the practice patterns of SGO members. AB - OBJECTIVES: To determine the practice patterns of members of Society of Gynecologic Oncologists (SGO) in different clinical situations involving the intra-operative detection of nodal metastasis in early stage cervical cancer. METHODS: A study questionnaire was mailed to the current members of SGO (n=874). Data were collected using an internet survey database. Frequency distributions were determined, and non parametric tests were performed. RESULTS: Thirty percent SGO members responded (n=274). Only 38.6% routinely performed an intra-operative frozen section evaluation of the lymph nodes. Of these; most (79%) did not abort the radical hysterectomy (RH) for an isolated microscopically positive pelvic lymph node. The likelihood of aborting RH for microscopic nodal involvement increased however with number of positive pelvic lymph nodes (21% with 1, 40% with 2-3, and 61% with >3 positive pelvic lymph nodes), involvement of para aortic lymph nodes (61%), or bilaterally positive lymph nodes (54%). Similarly, a large number did not complete the RH due to gross involvement of pelvic (45%) or para-aortic lymph node/s (69%). Most (90%) completed the lymphadenectomy before aborting RH. When completing RH, the majority tailored its extent to perform a less radical resection. Variables significantly associated with the likelihood of completing RH in different clinical situations included: location of current practice (West), practice type (private), years in practice (>15 years), and number of cases seen per year (>10/month). CONCLUSION: Practice patterns of SGO members are considerably diverse, which is reflective of the conflicting evidence available in the literature. Well designed studies are required to determine the best overall approach. PMID- 21269669 TI - Host and viral factors associated with severity of human rhinovirus-associated infant respiratory tract illness. AB - BACKGROUND: Risk factors for severe human rhinovirus (HRV)-associated infant illness are unknown. OBJECTIVES: We sought to examine the role of HRV infection in infant respiratory tract illness and assess viral and host risk factors for HRV-associated disease severity. METHODS: We used a prospective cohort of term, previously healthy infants enrolled during an inpatient or outpatient visit for acute upper or lower respiratory tract illness during the fall-spring months of 2004-2008. Illness severity was determined by using an ordinal bronchiolitis severity score, with higher scores indicating more severe disease. HRV was identified by means of real-time RT-PCR. The VP4/VP2 region from HRV-positive specimens was sequenced to determine species. RESULTS: Of 630 infants with bronchiolitis or upper respiratory tract illnesses (URIs), 162 (26%) had HRV infection; HRV infection was associated with 18% of cases of bronchiolitis and 47% of cases of URI. Among infants with HRV infection, 104 (64%) had HRV infection alone. Host factors associated with more severe HRV-associated illness included a maternal and family history of atopy (median score of 3.5 [interquartile range [IQR], 1.0-7.8] vs 2.0 [IQR, 1.0-5.2] and 3.5 [IQR, 1.0-7.5] vs 2.0 [IQR, 0-4.0]). In adjusted analyses maternal history of atopy conferred an increase in the risk for more severe HRV-associated bronchiolitis (odds ratio, 2.39; 95% CI, 1.14-4.99; P = .02). In a similar model maternal asthma was also associated with greater HRV-associated bronchiolitis severity (odds ratio, 2.49, 95% CI, 1.10-5.67; P = .03). Among patients with HRV infection, 35% had HRVA, 6% had HRVB, and 30% had HRVC. CONCLUSION: HRV infection was a frequent cause of bronchiolitis and URIs among previously healthy term infants requiring hospitalization or unscheduled outpatient visits. Substantial viral genetic diversity was seen among the patients with HRV infection, and predominant groups varied by season and year. Host factors, including maternal atopy, were associated with more severe infant HRV-associated illness. PMID- 21269670 TI - How representative are clinical study patients with allergic rhinitis in primary care? AB - BACKGROUND: Guidelines are the cornerstone of health care decision making and are based on the best available evidence, ideally large randomized controlled trials (RCTs). Although guidelines target typical patients, RCTs are often based on narrow inclusion and exclusion criteria. OBJECTIVES: We explored to what extent typical patients, such as those consulting general practitioners for allergic rhinitis, differ from patients enrolled in RCTs. METHODS: We conducted a prospective cohort study including all the consecutive patients with allergic rhinitis cared for by general practitioners in the Languedoc-Roussillon region of France within 2 weeks during the grass pollen season. We evaluated how the characteristics of these patients differed from those of patients included in the 4 largest placebo-controlled RCTs of persistent and intermittent allergic rhinitis. RESULTS: Three hundred eleven patients seen by 48 general practitioners were enrolled in this study. Only 7.4% (95% CI, 4.5% to 10.3%) of the patients would have been enrolled in the RCTs. The primary reasons for this difference were as follows: diagnosis of allergy based on skin test results, serum specific IgE levels, or both (20.4%); severity of allergic rhinitis (11.5%); other chronic diseases (11.4%); history of sinusitis (10.4%); and asthma comorbidity (10.1%). A sensitivity analysis excluding contraception and the diagnosis of allergy showed that the percentage of representative patients increased to 20.2% (95% CI, 15.8% to 24.7%). CONCLUSION: Only a small proportion of patients with allergic rhinitis seen in the primary care setting for allergic rhinitis would be eligible for RCTs. Thus guideline developers and health decision makers need to make careful judgments about the directness of the evidence from RCTs conducted in highly controlled settings. PMID- 21269671 TI - Role of p63/p73 in epithelial remodeling and their response to steroid treatment in nasal polyposis. AB - BACKGROUND: Nasal polyposis (NP) is recognized as aberrant epithelial remodeling, but the molecular mechanism underlying this process is poorly understood. Two important p53 homologues (p63 and p73) play a key role in orchestrating the epithelial development. OBJECTIVE: We intended to study whether p63 and p73 are involved in the epithelial remodeling seen in patients with NP and their response to oral glucocorticosteroid (GC) treatment. METHODS: Nasal polyp tissues were obtained from 65 patients, and inferior turbinates were obtained from 19 control subjects without NP. Among patients with NP, 20 were treated with oral prednisone, so that 2 sets of polyp biopsy specimens were taken before (GC naive) and after (GC treated) treatment. Immunohistochemistry and quantitative PCR were performed to determine the expression levels of p63 and p73. RESULTS: The increase in p63-positive cell numbers was significant in GC-naive NP epithelium (46%) compared with that seen in control epithelium (5%), and it was positively related to the epithelial hyperplasia in patients with NP. The increase in N terminal transactivation domain p73-positive cell numbers was found in 27% of GC naive patients with NP and 16% of control subjects, with no statistical difference. The mRNA expression of both p63 and p73 was significantly upregulated in GC-naive patients with NP versus control subjects, and a positive correlation between the p63 and p73 mRNAs was found in all nasal tissues. Furthermore, the improvement of epithelial structure and reduction of p63 mRNA/protein levels were found in patients with NP after GC treatment. CONCLUSIONS: Our results suggest that the ectopic expression of p63 in multiple cell layers is an important pathologic phenomenon in the epithelial remodeling seen in chronically inflamed airway epithelium (eg, in patients with NP), and its aberrant expression can be suppressed with GC treatment. PMID- 21269672 TI - Assessing the reproducibility of asthma genome-wide association studies in a general clinical population. PMID- 21269673 TI - Histamine receptor H1 signaling on dendritic cells plays a key role in the IFN gamma/IL-17 balance in T cell-mediated skin inflammation. AB - BACKGROUND: The diverse effects of histamine on immune regulation are a result of the differential expression and regulation of 4 histamine receptors. Many of the immediate allergic and inflammatory actions of histamine are mediated via the type 1 receptor (H1R). OBJECTIVES: We hypothesized that H1R was involved in the fine-tuning of the initiation of T cell-mediated skin pathology-that is, dermatitis. METHODS: The impact of the H1R invalidation on the development of skin inflammation was analyzed in a mouse model of atopic dermatitis. RESULTS: We show that H1r(-)/(-) mice developed reduced allergen-specific skin lesions. Lack of H1R expression on dendritic cells (DCs) led to diminished IL-12, upregulated IL-23, and IL-6 production upon allergen stimulation. H1R engagement on dendritic cells was necessary for DC activation and subsequent priming of effector IFN gamma(+)CD8(+) T cells. We demonstrate here that H1R blockade on DCs promotes generation of noneffector IL-17(+)CD8(+) T cells that are unable to initiate the skin inflammation. CONCLUSION: Our data identify that histamine signaling through the H1R on DCs is an important early event conditioning the quality of the skin effector immune response. PMID- 21269674 TI - Human resources for health in southeast Asia: shortages, distributional challenges, and international trade in health services. AB - In this paper, we address the issues of shortage and maldistribution of health personnel in southeast Asia in the context of the international trade in health services. Although there is no shortage of health workers in the region overall, when analysed separately, five low-income countries have some deficit. All countries in southeast Asia face problems of maldistribution of health workers, and rural areas are often understaffed. Despite a high capacity for medical and nursing training in both public and private facilities, there is weak coordination between production of health workers and capacity for employment. Regional experiences and policy responses to address these challenges can be used to inform future policy in the region and elsewhere. A distinctive feature of southeast Asia is its engagement in international trade in health services. Singapore and Malaysia import health workers to meet domestic demand and to provide services to international patients. Thailand attracts many foreign patients for health services. This situation has resulted in the so-called brain drain of highly specialised staff from public medical schools to the private hospitals. The Philippines and Indonesia are the main exporters of doctors and nurses in the region. Agreements about mutual recognition of professional qualifications for three groups of health workers under the Association of Southeast Asian Nations Framework Agreement on Services could result in increased movement within the region in the future. To ensure that vital human resources for health are available to meet the needs of the populations that they serve, migration management and retention strategies need to be integrated into ongoing efforts to strengthen health systems in southeast Asia. There is also a need for improved dialogue between the health and trade sectors on how to balance economic opportunities associated with trade in health services with domestic health needs and equity issues. PMID- 21269675 TI - Maternal, neonatal, and child health in southeast Asia: towards greater regional collaboration. AB - Although maternal and child mortality are on the decline in southeast Asia, there are still major disparities, and greater equity is key to achieve the Millennium Development Goals. We used comparable cross-national data sources to document mortality trends from 1990 to 2008 and to assess major causes of maternal and child deaths. We present inequalities in intervention coverage by two common measures of wealth quintiles and rural or urban status. Case studies of reduction in mortality in Thailand and Indonesia indicate the varying extents of success and point to some factors that accelerate progress. We developed a Lives Saved Tool analysis for the region and for country subgroups to estimate deaths averted by cause and intervention. We identified three major patterns of maternal and child mortality reduction: early, rapid downward trends (Brunei, Singapore, Malaysia, and Thailand); initially high declines (sustained by Vietnam but faltering in the Philippines and Indonesia); and high initial rates with a downward trend (Laos, Cambodia, and Myanmar). Economic development seems to provide an important context that should be coupled with broader health-system interventions. Increasing coverage and consideration of the health-system context is needed, and regional support from the Association of Southeast Asian Nations can provide increased policy support to achieve maternal, neonatal, and child health goals. PMID- 21269676 TI - Commitment and action to boost health workforce. PMID- 21269677 TI - The rise of chronic non-communicable diseases in southeast Asia: time for action. AB - Southeast Asia faces an epidemic of chronic non-communicable diseases, now responsible for 60% of deaths in the region. The problem stems from environmental factors that promote tobacco use, unhealthy diet, and inadequate physical activity. Disadvantaged populations are the hardest hit, with death rates inversely proportional to a country's gross national income. Families shoulder the financial burden, but entire economies suffer as well. Although attempts to control non-communicable diseases are increasing, more needs to be done. Health care systems need to be redesigned to deliver chronic care that is founded on existing primary health-care facilities, but supported by good referral systems. Surveillance of key modifiable risk factors is needed to monitor the magnitude of the problem and to study the effects of interventions. All branches of government and all sectors of society have to get involved in establishing environments that are conducive to healthy living. The Association of Southeast Asian Nations is in a unique position to make a united stand against chronic non-communicable diseases in the region. Inaction will affect millions of lives-often, the lives of those who have the least. PMID- 21269678 TI - Emerging infectious diseases in southeast Asia: regional challenges to control. AB - Southeast Asia is a hotspot for emerging infectious diseases, including those with pandemic potential. Emerging infectious diseases have exacted heavy public health and economic tolls. Severe acute respiratory syndrome rapidly decimated the region's tourist industry. Influenza A H5N1 has had a profound effect on the poultry industry. The reasons why southeast Asia is at risk from emerging infectious diseases are complex. The region is home to dynamic systems in which biological, social, ecological, and technological processes interconnect in ways that enable microbes to exploit new ecological niches. These processes include population growth and movement, urbanisation, changes in food production, agriculture and land use, water and sanitation, and the effect of health systems through generation of drug resistance. Southeast Asia is home to about 600 million people residing in countries as diverse as Singapore, a city state with a gross domestic product (GDP) of US$37,500 per head, and Laos, until recently an overwhelmingly rural economy, with a GDP of US$890 per head. The regional challenges in control of emerging infectious diseases are formidable and range from influencing the factors that drive disease emergence, to making surveillance systems fit for purpose, and ensuring that regional governance mechanisms work effectively to improve control interventions. PMID- 21269679 TI - A stormy future for population health in southeast Asia? PMID- 21269680 TI - Mental health in southeast Asia. PMID- 21269681 TI - Civil society in ASEAN: a healthy development? PMID- 21269682 TI - Health-financing reforms in southeast Asia: challenges in achieving universal coverage. AB - In this sixth paper of the Series, we review health-financing reforms in seven countries in southeast Asia that have sought to reduce dependence on out-of pocket payments, increase pooled health finance, and expand service use as steps towards universal coverage. Laos and Cambodia, both resource-poor countries, have mostly relied on donor-supported health equity funds to reach the poor, and reliable funding and appropriate identification of the eligible poor are two major challenges for nationwide expansion. For Thailand, the Philippines, Indonesia, and Vietnam, social health insurance financed by payroll tax is commonly used for formal sector employees (excluding Malaysia), with varying outcomes in terms of financial protection. Alternative payment methods have different implications for provider behaviour and financial protection. Two alternative approaches for financial protection of the non-poor outside the formal sector have emerged-contributory arrangements and tax-financed schemes with different abilities to achieve high population coverage rapidly. Fiscal space and mobilisation of payroll contributions are both important in accelerating financial protection. Expanding coverage of good-quality services and ensuring adequate human resources are also important to achieve universal coverage. As health-financing reform is complex, institutional capacity to generate evidence and inform policy is essential and should be strengthened. PMID- 21269683 TI - Challenges in infection in ASEAN. PMID- 21269684 TI - Southeast Asia: an emerging focus for global health. PMID- 21269685 TI - Health and health-care systems in southeast Asia: diversity and transitions. AB - Southeast Asia is a region of enormous social, economic, and political diversity, both across and within countries, shaped by its history, geography, and position as a major crossroad of trade and the movement of goods and services. These factors have not only contributed to the disparate health status of the region's diverse populations, but also to the diverse nature of its health systems, which are at varying stages of evolution. Rapid but inequitable socioeconomic development, coupled with differing rates of demographic and epidemiological transitions, have accentuated health disparities and posed great public health challenges for national health systems, particularly the control of emerging infectious diseases and the rise of non-communicable diseases within ageing populations. While novel forms of health care are evolving in the region, such as corporatised public health-care systems (government owned, but operating according to corporate principles and with private-sector participation) and financing mechanisms to achieve universal coverage, there are key lessons for health reforms and decentralisation. New challenges have emerged with rising trade in health services, migration of the health workforce, and medical tourism. Juxtaposed between the emerging giant economies of China and India, countries of the region are attempting to forge a common regional identity, despite their diversity, to seek mutually acceptable and effective solutions to key regional health challenges. In this first paper in the Lancet Series on health in southeast Asia, we present an overview of key demographic and epidemiological changes in the region, explore challenges facing health systems, and draw attention to the potential for regional collaboration in health. PMID- 21269686 TI - Health in southeast Asia. PMID- 21269688 TI - Combined cytotoxic and anti-invasive properties of redox-active nanoparticles in tumor-stroma interactions. AB - Tumor-stroma interaction plays an important role in tumor progression. Myofibroblasts, pivotal for tumor progression, populate the microecosystem of reactive stroma. The formation of myofibroblasts is mediated by tumor derived transforming growth factor beta1 (TGFbeta1) which initiates a reactive oxygen species cell type dependent expression of alpha-smooth muscle actin, a biomarker for myofibroblastic cells. Myofibroblasts express and secrete proinvasive factors significantly increasing the invasive capacity of tumor cells via paracrine mechanisms. Although antioxidants prevent myofibroblast formation, the same antioxidants increase the aggressive behavior of the tumor cells. In this study, the question was addressed of whether redox-active polymer-coated cerium oxide nanoparticles (CNP, nanoceria) affect myofibroblast formation, cell toxicity, and tumor invasion. Herein, nanoceria downregulate both the expression of alpha smooth muscle actin positive myofibroblastic cells and the invasion of tumor cells. Furthermore, concentrations of nanoceria being non-toxic for normal (stromal) cells show a cytotoxic effect on squamous tumor cells. The treatment with redox-active CNP may form the basis for protection of stromal cells from the dominating influence of tumor cells in tumor-stroma interaction, thus being a promising strategy for chemoprevention of tumor invasion. PMID- 21269687 TI - Spatial control of gene expression within a scaffold by localized inducer release. AB - Gene expression can be controlled in genetically modified cells by employing an inducer/promoter system where presence of the inducer molecule regulates the timing and level of gene expression. By applying the principles of controlled release, it should be possible to control gene expression on a biomaterial surface by the presence or absence of inducer release from the underlying material matrix, thus avoiding alternative techniques that rely upon uptake of relatively labile DNA from material surfaces. To evaluate this concept, a modified ecdysone-responsive gene expression system was transfected into B16 murine cells and the ability of an inducer ligand, which was released from elastomeric poly(ester urethane) urea (PEUU), to initiate gene expression was studied. The synthetic inducer ligand was first loaded into PEUU to demonstrate extended release of the bioactive molecule at various loading densities over a one year period in vitro. Patterning films of PEUU variably-loaded with inducer resulted in spatially controlled cell expression of the gene product (green fluorescent protein, GFP). In porous scaffolds made from PEUU by salt leaching, where the central region was exclusively loaded with inducer, cells expressed GFP predominately in the loaded central regions whereas expression was minimal in outer regions where ligand was omitted. This scaffold system may ultimately provide a means to precisely control progenitor cell commitment in a spatially defined manner in vivo for soft tissue repair and regeneration. PMID- 21269689 TI - Intracellular trafficking and gene expression of pH-sensitive, artificially enveloped adenoviruses in vitro and in vivo. AB - Recombinant adenovirus (Ad) has shown great promise in gene therapy. Artificial envelopment of adenovirus within lipid bilayers has previously been shown to decrease the immunogenicity and hepatic affinity of naked Ad in vivo. Unfortunately, this also resulted in a significant reduction of gene expression, which we attributed to poor endosomal release of the Ad from its artificial lipid envelope. In this work, we explored the artificial envelopment of Ad within pH sensitive DOPE:CHEMS bilayers and characterized this vector by TEM, AFM, dot blot, dynamic light scattering and zeta potential measurements. The artificially enveloped viral vectors exhibited good stability at physiological pH but immediately collapsed and released naked Ad virions at pH 5.5. Intracellular trafficking using confocal laser scanning microscopy (CLSM) revealed that Cy3 labelled Ad enveloped in DOPE:CHEMS bilayers exhibited the characteristic Ad distribution within the cytoplasm that led to virion accumulation around the nuclear membrane, indicating endosomal release of Ad. We obtained equivalent levels of gene expression as those of naked Ad in a series of CAR-positive (CAR+) and CAR-negative (CAR-) cell lines. This suggested that the mechanism of infection for the artificially enveloped Ad remained dependent on the presence of CAR receptors. Finally, the pH-sensitive enveloped Ad were injected intratumorally in human cervical carcinoma xenograft-bearing nude mice, also illustrating their capacity for efficient in vivo marker gene expression. This study is a step forward toward the engineering of functional, artificially enveloped adenovirus vectors for gene transfer applications. PMID- 21269690 TI - Calcitonin gene-related peptide (CGRP) and its role in hypertension. AB - Hypertension is still presently the number one "silent killer" in the Western World, and a major risk factor for the development of secondary diseases contributing to cardiovascular disease (CVD). However, despite a broad range of therapies, the mechanisms involved in the onset of hypertension remains unclear, therefore there is a real need to investigate the mechanisms involved. Calcitonin gene-related peptide (CGRP) is the most potent microvascular vasodilator known to date. Widely expressed in the nervous system, this peptide is considered to play a positive role in wound healing and protects against ischaemic and other traumas. However, whilst the protective mechanisms are not well understood, evidence indicates that these mechanisms become important in vascular-related stress. This review provides evidence that CGRP is both a potent vasodilator and hypotensive agent. However studies to date suggest that CGRP does not contribute to the physiological regulation of blood pressure. By comparing results from a range of human and animal studies, findings broadly suggest an association between CGRP and the pathophysiology of hypertension in terms of protective mechanisms, with possibly the RAMP1 component of the CGRP receptor playing a key role in the brain stem, in addition to peripheral receptors. The studies of agents that release CGRP agonists are at an early stage, with analogues for human use currently under development. However, at this stage, further research is required to establish the mechanisms by which CGRP is protective in the onset of hypertension, if novel and therapeutic modes of treatment are to be developed. PMID- 21269691 TI - Cellular elements of the subarachnoid space promote ALL survival during chemotherapy. AB - CNS infiltration by leukemic cells remains a problematic disease manifestation of acute lymphoblastic leukemia (ALL). Prophylactic regimens for CNS leukemia including intrathecal chemotherapeutics have decreased CNS involvement in ALL, but are not without toxicities. Using co-culture models, we show that astrocytes, choroid plexus epithelial cells, and meningeal cells protect ALL cells from chemotherapy-induced cell death using drugs included in prophylactic regimens cytarabine, dexamethasone, and methotrexate. Understanding how ALL cells survive in the CNS remains invaluable for designing strategies to prevent CNS leukemia and minimizing the need for treatment in this sensitive anatomical site where treatment-induced toxicity is of significant concern. PMID- 21269692 TI - Clinical impact of the clone size in MDS cases with monosomy 7 or 7q deletion, trisomy 8, 20q deletion and loss of Y chromosome. AB - The clone size has been postulated as a prognostic factor in myelodysplastic syndromes (MDS), though it has not been studied systematically. We tested its impact (<100% vs. 100%) in a population of 216 MDS with chromosome 7 abnormalities (-7/7q-) (n=84), trisomy 8 (n=99), 20q deletion (n=28) and loss of Y chromosome (n=26). Focusing on the survival the bad prognosis of -7/7q- was independent of the clone size (9.3 vs. 5.0 months, P=0.188, not significant) but trisomy 8 cases with 100% aberrant metaphases did reveal a worse prognosis (13.9 vs. 5.9 months, P=0.003). PMID- 21269693 TI - Dimethyl sulfoxide activates tumor necrosis factoralpha-p53 mediated apoptosis and down regulates D-fructose-6-phosphate-2-kinase and lactate dehydrogenase-5 in Dalton's lymphoma in vivo. AB - Dimethyl sulfoxide (DMSO) is evident to induce apoptosis in certain tumor cells in vitro. However, its apoptotic mechanism remains unexplored in in vivo tumors. This article describes that DMSO, being non-toxic to the normal lymphocytes, up regulated TNFalpha and p53, declined Bcl-2/Bax ratio, activated caspase 9 and PARP-1 cleavage and produced apoptotic pattern of DNA ladder in Dalton's lymphoma (DL) in vivo. This was consistent with the declined expressions of tumor growth supportive glycolytic enzymes; inducible D-fructose-6-phosphate-2-kinase and lactate dehydrogenase-5 in the DL cells. The findings suggest induction of TNFalpha-p53-mitochondrial pathway of apoptosis by DMSO in a non-Hodgkin's lymphoma and support evolving concept of glycolytic inhibition led apoptosis in a tumor cell in vivo. PMID- 21269694 TI - Characterization of the porcine p65 subunit of NF-kappaB and its association with virus antibody levels. AB - NF-kappaB p65 subunit plays important roles in controlling both innate and adaptive immunity. Here we report the characterization of porcine NF-kappaB p65 subunit (pp65). pp65 shows high similarity to other mammalian counterparts. pp65 mRNA expression was mainly observed in lung, spleen, liver and small intestine. Furthermore, overexpression of pp65 activates NF-kappaB in porcine endothelial cell line PIEC, porcine alveolar macrophages cell line 3D4/21 and porcine primary fetal fibroblasts. A COOH-terminal truncation derivative of pp65 (pp65RHD) has been identified as a specific transdominant inhibitor of NFkappaB. Association study was performed on the selected SNP and indel. The results revealed that the SNP BglI was significantly associated (P<0.05) with pig reproduction and respiratory syndrome virus antibody level (PRRSV-AB) (0 day and 17 days), the classical swine fever virus (CSFV) antibody blocking rates (CSFV-AB) (0 day and 17 days) and pseudorabies virus antibody level (PRV-AB) (0 day and 32 days). PMID- 21269695 TI - Alloimmunization against RBC or PLT antigens is independent of TRIM21 expression in a murine model. AB - Generation of alloantibodies to transfused RBCs can be a serious medical problem for patients who require chronic RBC transfusion therapy. Patients with sickle cell disease have a substantially increased rate of alloimmunization compared to other chronically transfused populations. A recent study has forwarded the hypothesis that a polymorphism in an immunoregulatory gene in close proximity to beta-globin (TRIM21 rs660) plays a role in the increased rates of RBC alloimmunization in sickle cell patients. In particular, it was hypothesized that rs660C/T decreases expression of TRIM21, resulting in loss of a negative feedback pathway in immune responses and increased RBC alloimmunization. To test the effects of TRIM21 expression on alloimmunization, we analyzed antibody responses to alloantigens on RBCs and platelets transfused into wild-type and TRIM21 KO mice. No significant increases were seen in the frequency or magnitude of humoral immunization to alloantigens on transfused RBCs or platelets in adult or juvenile TRIM21 KO recipients compared to wild-type controls. Moreover, recipient inflammation with poly (I:C) enhanced RBC alloimmunization to similar degrees in both TRIM21 KO and wild-type control recipients. Together, these data rule out the hypothesis that decreased TRIM21 expression enhances transfusion induced humoral alloimmunization, in the context of a reductionist murine model. PMID- 21269696 TI - The dominant 55 kDa allergen of the subtropical Bahia grass (Paspalum notatum) pollen is a group 13 pollen allergen, Pas n 13. AB - Bahia grass, Paspalum notatum, is an important pollen allergen source with a long season of pollination and wide distribution in subtropical and temperate regions. We aimed to characterize the 55 kDa allergen of Bahia grass pollen (BaGP) and ascertain its clinical importance. BaGP extract was separated by 2D-PAGE and immunoblotted with serum IgE of a grass pollen-allergic patient. The amino terminal protein sequence of the predominant allergen isoform at 55 kDa had similarity with the group 13 allergens of Timothy grass and maize pollen, Phl p 13 and Zea m 13. Four sequences obtained by rapid amplification of the allergen cDNA ends represented multiple isoforms of Pas n 13. The predicted full length cDNA for Pas n 13 encoded a 423 amino acid glycoprotein including a signal peptide of 28 residues and with a predicted pI of 7.0. Tandem mass spectrometry of tryptic peptides of 2D gel spots identified peptides specific to the deduced amino acid sequence for each of the four Pas n 13 cDNA, representing 47% of the predicted mature protein sequence of Pas n 13. There was 80.6% and 72.6% amino acid identity with Zea m 13 and Phl p 13, respectively. Reactivity with a Phl p 13-specific monoclonal antibody AF6 supported designation of this allergen as Pas n 13. The allergen was purified from BaGP extract by ammonium sulphate precipitation, hydrophobic interaction and size exclusion chromatography. Purified Pas n 13 reacted with serum IgE of 34 of 71 (48%) grass pollen-allergic patients and specifically inhibited IgE reactivity with the 55 kDa band of BaGP for two grass pollen-allergic donors. Four isoforms of Pas n 13 from pI 6.3-7.8 had IgE-reactivity with grass pollen allergic sera. The allergenic activity of purified Pas n 13 was demonstrated by activation of basophils from whole blood of three grass pollen-allergic donors tested but not control donors. Pas n 13 is thus a clinically relevant pollen allergen of the subtropical Bahia grass likely to be important in eliciting seasonal allergic rhinitis and asthma in grass pollen-allergic patients. PMID- 21269697 TI - Benznidazole treatment attenuates liver NF-kappaB activity and MAPK in a cecal ligation and puncture model of sepsis. AB - Recent studies have shown that Benznidazole (BZL), known for its antiparasitic action on Trypanosoma cruzi, modulates pro-inflammatory cytokines and nitric oxide (NO) release in activated macrophages by blocking NF-kappaB through inhibition of IKK in vitro. As so far, little is known about the mechanism by which BZL provokes the inhibition of inflammatory response in sepsis in vivo, we aimed to delineate the possible role of BZL as a modulator in liver inflammation in mice with sepsis induced by cecal ligation and puncture (CLP). Specifically, we analyzed leukocytes, liver production of TNF-alpha and NO and the intracellular pathways modulated by these mediators, including NF-kappaB and MAPKs, in the liver of mice 24 h post-CLP. Our results show that BZL reduces leukocytes in peripheral blood accompanied by an increase in peritoneal macrophages 24h after CLP. In the liver of these septic mice, BZL decreased expression of mRNA and protein for TNF-alpha and NOS-2 by inhibition of NF-kappaB and MAPK (p-38 and ERK). The body of evidence suggests that the immunomodulatory effects of BZL could act selectively, as it is able to decrease the systemic inflammatory reaction and the hepatic response but it can increase the number of cells in the site of infection. PMID- 21269698 TI - Human complement receptor type 2 (CR2/CD21) transgenic mice provide an in vivo model to study immunoregulatory effects of receptor antagonists. AB - We found that transgenic (tg) mice stably expressing a bacterial artificial chromosome (BAC)-derived human complement receptor type 2 (CR2/CD21) gene demonstrate B cell specific hCR2 protein expression, normal B cell development and no changes in B cell subpopulations. To determine whether this BAC-encoded human CR2 (hCR2) can replace mouse CR2/CR1 in Cr2(-/-) mice and restore humoral immune responses to model foreign antigens (Ags), we generated hCR2(+/-)Cr2(-/-) tg mice and immunized them with sheep red blood cells (SRBC). We found that hCR2(+/-)Cr2(-/-) mice demonstrated anti-SRBC antibody (Ab) levels that were initially comparable to Cr2(-/-) mice after a single injection of the Ag, but then showed marked increases in anti-SRBC IgM and IgG1 levels after a second immunization. Identical results were found with a second model Ag, NP-Ficoll. To further confirm that this improvement in Ag-specific Ab production over Cr2(-/-) mice was indeed due to hCR2 expression, as well as to examine the effects of treating hCR2(+/-)Cr2(-/-) mice with an inhibitory anti-hCR2 monoclonal Ab (mAb) in vivo, we used mAb 171, an anti-hCR2 mAb that we have shown directly recognizes the C3d ligand binding site on hCR2. We first found that mAb 171 completely blocked hCR2-dependent co-activation of hCR2-tg B cells by anti-BCR/C3d complexes as measured in vitro by intracellular calcium influx. The i.p. injection of 1mg of mAb 171 was then found to induce for at least three weeks only partial loss of hCR2 surface expression, without modifying B and T cell numbers or the apparent activation status of the cells. Treatment of hCR2(+/-)Cr2(-/-) mice with mAb 171 also substantially suppressed the development of anti-SRBC and anti-NP Abs following immunization with Ags. The development of this model system should allow the study of the effects of manipulating hCR2 function in vivo with potential therapeutic compounds. PMID- 21269699 TI - Systematic screening of BEST1 and PRPH2 in juvenile and adult vitelliform macular dystrophies: a rationale for molecular analysis. AB - PURPOSE: To evaluate a genetic approach of BEST1 and PRPH2 screening according to age of onset, family history, and Arden ratio in patients with juvenile vitelliform macular dystrophy (VMD2) or adult-onset vitelliform macular dystrophy (AVMD), which are characterized by autofluorescent deposits. DESIGN: Clinical, electrophysiologic, and molecular retrospective study. PARTICIPANTS: The database of a clinic specialized in genetic sensory diseases was screened for patients with macular vitelliform dystrophy. Patients with an age of onset less than 40 years were included in the VMD2 group (25 unrelated patients), and patients with an age of onset more than 40 years were included in the AVMD group (19 unrelated patients). METHODS: Clinical, fundus photography, and electro-oculogram (EOG) findings were reviewed. Mutation screening of BEST1 and PRPH2 genes was systematically performed. MAIN OUTCOME MEASURES: Relevance of age of onset, family history, and Arden ratio were reviewed. RESULTS: Patients with VMD2 carried a BEST1 mutation in 60% of the cases. Seven novel mutations in BEST1 (p.V9L, p.F80V, p.I73V, p.R130S, pF298C, pD302A, and p.179delN) were found. Patients with VMD2 with a positive family history or a reduced Arden ratio carried a BEST1 mutation in 70.5% of cases and in 83% if both criteria were fulfilled. Patients with AVMD carried a PRPH2 mutation in 10.5% of cases and did not carry a BEST1 mutation. The probability of finding a PRPH2 mutation increased in the case of a family history (2/5 patients). Electro-oculogram was normal in 3 of 15 patients with BEST1 mutations and reduced in the 3 patients with PRPH2 mutations. CONCLUSIONS: Age of onset is a major criterion to distinguish VMD2 from AVMD. Electro-oculogram is not as relevant because decreased or normal Arden ratios have been associated with mutations in both genes and diseases. A positive family history increased the probability of finding a mutation. BEST1 screening should be recommended to patients with an age of onset less than 40 years, and PRPH2 screening should be recommended to patients with an age of onset more than 40 years. For an onset between 30 and 40 years, PRPH2 can be screened if no mutation has been detected in BEST1. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 21269700 TI - Role of inflammation-related gene polymorphisms in patients with central retinal vein occlusion. AB - OBJECTIVE: Central retinal vein occlusion (CRVO) is a vision-threatening disease, primarily occurring among patients aged more than 60 years. Several risk factors, including arterial hypertension and diabetes mellitus, have been identified. Compression of the central retinal vein by an atherosclerotic retinal artery at the lamina cribrosa also has been implicated in the pathogenesis of the disease. Functional gene polymorphisms of cytokines or chemokines previously shown to affect atherogenesis or hemostasis are potential risk factors for CRVO. The present study investigates a hypothesized association between inflammation related gene polymorphisms and the presence of CRVO in a relatively large cohort of patients. DESIGN: Case-control study. PARTICIPANTS: The study group consisted of 315 patients with CRVO and 335 control subjects. METHODS: Determination of genotypes was done by 5' exonuclease assay (TaqMan). MAIN OUTCOME MEASURES: Genotypes of interleukin (IL)1beta -511C>T, IL1 receptor antagonist (IL1RN) 1018T>C, IL4 -584C>T, IL6 -174G>C, IL10 -592C>A, IL18 183A>G, tumor necrosis factor (TNF)-alpha -308G>A, monocyte chemoattractant protein (MCP)-1/CCL2 2518A>G, IL8 -251A>T, and RANTES (CCL5) -403G>A polymorphisms. RESULTS: Genotype distributions and allele frequencies of the investigated gene polymorphisms did not significantly differ between both groups (P>0.05). Arterial hypertension, diabetes mellitus, and cigarette smoking were significantly more frequent in patients with CRVO than among control subjects (arterial hypertension: 67.0% vs. 52.2%, P<0.001; diabetes mellitus: 16.8% vs. 6.3%, P<0.001, cigarette smoking: 32.1% vs. 23.6%, P = 0.02). In a logistic regression analysis, the presence of arterial hypertension was associated with an odds ratio (OR) of 1.75 (95% confidence interval [CI], 1.26-2.44) in those with CRVO, whereas an OR of 2.52 (95% CI, 1.46-4.35) was found in those with diabetes mellitus. A history of cigarette smoking was associated with an OR of 1.57 (95% CI, 1.09 - 2.25) for CRVO. CONCLUSIONS: Our data suggest that the investigated inflammation-related gene polymorphisms are unlikely major risk factors for CRVO. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 21269701 TI - Clinical evaluation and treatment accuracy in diabetic macular edema using navigated laser photocoagulator NAVILAS. AB - PURPOSE: To evaluate the clinical use and accuracy of a new retinal navigating laser technology that integrates a scanning slit fundus camera system with fluorescein angiography (FA), color, red-free, and infrared imaging capabilities with a computer steerable therapeutic 532-nm laser. DESIGN: Interventional case series. PARTICIPANTS: Eighty-six eyes of 61 patients with diabetic retinopathy and macular edema treated by NAVILAS. METHODS: The imaging included digital color fundus photographs and FA. The planning included graphically marking future treatment sites (microaneurysms for single-spot focal treatment and areas of diffuse leakage for grid pattern photocoagulation) on the acquired images. The preplanned treatment was visible and overlaid on the live fundus image during the actual photocoagulation. The NAVILAS automatically advances the aiming beam location from one planned treatment site to the next after each photocoagulation spot until all sites are treated. Aiming beam stabilization compensated for patient's eye movements. The pretreatment FA with the treatment plan was overlaid on top of the posttreatment color fundus images with the actual laser burns. This allowed treatment accuracy to be calculated. Independent observers evaluated the images to determine if the retinal opacification after treatment overlapped the targeted microaneurysm. MAIN OUTCOME MEASURES: Safety and accuracy of laser photocoagulation. RESULTS: The images were of very good quality compared with standard fundus cameras, allowing careful delineation of target areas on FA. Toggling from infrared, to monochromatic, to color view allowed evaluation and adjustment of burn intensity during treatment. There were no complications during or after photocoagulation treatment. An analysis of accuracy of 400 random focal targeted spots found that the NAVILAS achieved a microaneurysm hit rate of 92% when the placement of the treatment circle was centered by the operating surgeon on the microaneurysm. The accuracy for the control group analyzing 100 focal spots was significantly lower at 72% (P<0.01). CONCLUSIONS: Laser photocoagulation using the NAVILAS system is safe and achieves a higher rate of accuracy in photocoagulation treatments of diabetic retinopathy lesions than standard manual-technique laser treatment. Precise manual preplanning and positioning of the treatment sites by the surgeon is possible, allowing accurate and predictable photocoagulation of these lesions. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 21269703 TI - Prevalence of primary open-angle glaucoma in central South Korea the Namil study. AB - PURPOSE: To assess the prevalence of primary open-angle glaucoma (POAG) in the Namil-myon area in central South Korea. DESIGN: A cross-sectional, epidemiologic study in a defined population. PARTICIPANTS: Residents aged >= 40 years in Namil myon, a rural agricultural area in central South Korea. METHODS: Each subject underwent a screening that consisted of an interview and ophthalmic examinations, including visual acuity measurement, autorefraction, anterior segment evaluation by optical biometry, slit-lamp examination, Goldmann applanation tonometry, binocular optic disc evaluation, fundus photography, pachymetry, gonioscopy, and screening visual field test using frequency doubling technology. Subjects with suspected glaucoma were referred for definitive examinations. Standard automated field tests and retinal nerve fiber layer analysis using optical coherence tomography (Stratus OCT) or scanning laser polarimetry (GDx VCC) were performed. A diagnosis of glaucoma was made based on the optic disc shape, retinal nerve fiber layer appearance, perimetric results, and other ocular findings. MAIN OUTCOME MEASURES: Prevalence of POAG, mean intraocular pressure (IOP), and mean central corneal thickness (CCT). RESULTS: Of 1928 eligible residents in the area, 1532 (79.5%) participated in this study. The estimated prevalence of POAG in the population aged >= 40 years was 3.5% (95% confidence interval [CI], 2.7%-4.3%). The prevalence of POAG with an IOP of <= 21 mmHg was 2.7% (95% CI, 2.1%-3.3%), and the prevalence of POAG with an IOP of >= 22 mmHg was 0.8% (95% CI, 0.4% 1.2%). The mean IOP for POAG eyes (16.3 +/- 4.6 mmHg) was significantly higher than nonglaucomatous eyes (13.3 +/- 2.7 mmHg; P = .001). The mean CCT of POAG eyes with an IOP of <= 21 mmHg was 528 +/- 26 MUm, and that of POAG eyes with an IOP >= 22 mmHg was 531 +/- 37 MUm; these values were not significantly different from that of nonglaucomatous eyes (530 +/- 31 MUm; P = .943 and .996, respectively). CONCLUSIONS: The prevalences of POAG and POAG with an IOP <= 21 mmHg in the Namil-myon region of central South Korea were higher than that in most previous reports worldwide, but were similar to the reported rates in black and Japanese populations. The mean IOP of POAG eyes was higher than nonglaucomatous eyes, but the mean CCTs were not different. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any of the materials discussed in this article. PMID- 21269704 TI - Subspecialization of the ophthalmic literature: a review of the publishing trends of the top general, clinical ophthalmic journals. AB - PURPOSE: To investigate the publishing trends of the top general clinical ophthalmic journals and to report: (1) the proportions of articles published in terms of ophthalmic subspecialty, (2) the study design used, (3) any changes in publishing trends, and (4) any differences in the quality of study design between the subspecialties. DESIGN: Retrospective, database review. PARTICIPANTS: All original articles published in the top general, clinical ophthalmology journals from 2005 through 2009. METHODS: All general, clinical ophthalmic journals were selected from the top 20 journals based on 2008 impact factor. All abstracts from original articles were reviewed, and the subject matter was recorded as belonging to 1 of the 11 ophthalmic subspecialties. After the content of the article was assigned, then the study design was recorded as one of the following: nonanalytic study, case-control or cohort study, randomized control trial, meta-analysis, laboratory science article, or systemic review. MAIN OUTCOME MEASURES: Subspecialty of the article and the study design used. RESULTS: Seven journals were included, and 12 426 abstracts were reviewed. Articles relating to medical retina were the most prevalent (29.1%), and those relating to strabismus were the least prevalent (2.3%). Case-control or cohort studies comprised most study designs (40.1%), with meta-analyses comprising the least (0.3%). The mean number of articles per year was 2485 (standard deviation, 125.1), remaining stable over the study period. Medical retina articles were significantly more common in 2009 than in 2005 (chi-square, 11.2; P = 0.0008), whereas the proportion of oculoplastic articles was significantly reduced (chi-square, 16.9; P<0.0001). Cataract and refractive surgery had the highest proportions of articles using the higher forms of study design (7.8%), and oculoplastics had the highest proportion of nonanalytic studies (64.5%). CONCLUSIONS: There are great differences across the specialty of ophthalmology in the subject matter of published literature, probably driven by recent advances in treatments. Medical retina is the subspecialty that is most represented in the literature, with strabismus being the least represented. Cataract and refractive surgery articles have the greatest proportion of higher-quality research strategies. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 21269705 TI - Information processing efficiency and regulation at five months. AB - Infants with short look durations are generally thought to have better attentional capabilities due to their efficient information processing. Although effortful attention is considered a key component of developing regulatory abilities, little is known about the relation between speed and efficiency of processing and self-regulation. In this study, 5-month-old infants with shorter look duration had greater EEG power values than infants with longer look duration during baseline, as well as during a distressing task and a post-distress attentional processing task. These short looking infants also demonstrated higher heart rate, relative to long looking infants, during post-distress information processing. Behaviorally the two groups differed in the amount of distraction during distress. These data provide evidence for an association between the efficiency of information processing and beginning regulatory abilities in early infancy. PMID- 21269706 TI - Family history of psychiatric disorders and the outcome of psychiatric patients with DSM-IV major depressive disorder. AB - BACKGROUND: Major Depressive Disorder (MDD) is often comorbid with other heritable disorders. The correlates of a family history (FH) of mood disorders but not of comorbid disorders among MDD patients have been investigated. Since bipolar disorder (BD) is highly heritable, latent BD may bias findings. METHODS: The Vantaa Depression Study included 269 psychiatric out- and in-patients with DSM-IV MDD, diagnosed with semistructured interviews and followed-up for 5 years with a life-chart. The FH of mood, psychotic disorders, and alcoholism among first-degree relatives of 183 patients was investigated. RESULTS: Three fourths (74.9%) of patients reported a FH of some major mental disorder; 60.7% of mood disorder, 36.6% alcoholism, and 10.9% psychotic disorder. In multivariate regression models, a FH of mood disorder was associated with high neuroticism (OR 1.08 [1.02-1.15], p=0.014); a FH of alcoholism with alcohol dependence, number of cluster B personality disorder symptoms, and dysthymia (OR 2.27 [1.01-5.08], p=0.047; OR=1.11 [1.01-1.23], p=0.030; and OR 4.35 [1.51-12.5], p=0.007), and a FH of psychotic disorder with more time spent with depressive symptoms (OR 1.03 [1.00-1.05], p=0.043). However, after excluding those who later switched to BD, several of the associations abated or lost significance. LIMITATIONS: Family history was ascertained only by an interview of the proband. CONCLUSIONS: The majority of MDD patients have a positive FH besides mood also of other disorders. A mood disorder FH may correlate with higher neuroticism, alcoholism FH with alcoholism or personality disorders. FH studies of MDD should take into account the impact of patients switching to BD. PMID- 21269707 TI - Depression and midlife: are we overpathologising the menopause? AB - OBJECTIVE: Cross sectional and longitudinal studies have suggested that the menopausal transition is a period of vulnerability for the development of depressive symptoms in women. It has been proposed that depression at the time of transition to menopause is part of a distinct diagnostic group of 'reproductive related depressive disorders'. Furthermore it is proposed that these disorders are so prevalent that that middle aged women should be routinely screened to improve detection. The aims of this paper were to explore key studies undertaken over the past three decades to examine what evidence exists to support the proposals that depression in midlife women occurs as a biological response to hormonal change and that it is so common that all middle aged women should be routinely screened for depression. METHOD: A systematic search was carried out of electronic databases for original research using population-based studies examining the relationship between menopause and depression. RESULTS: Longitudinal change in menopausal status over time is associated with an increased risk of elevated depressive symptoms, independent of relevant demographic, psychosocial, behavioural and health factors. However, depressive symptoms have non-specific diagnostic significance, and even when severe do not always reflect a depressive syndrome. There is no clear evidence that depressive disorders occur more commonly in association with the menopause. Rather, it appears that the true rate of disorder is similar to that at other times in a woman's reproductive life. CONCLUSIONS: The studies identified here do not provide evidence for the delineation of depression at the menopausal transition as part of a distinctive diagnostic group of 'reproductive-related depressive disorders' which occur as a biological response to hormonal change. The most plausible explanation is a bio-psycho-socio-cultural model of the processes which might lead to a depressive disorder in midlife. Although depressive symptoms are common at this time, data do not support the call for screening of all women for depression at the time of the MT. Rather, given the frequency of depression in the general population, clinicians should be alert to the possibility of depression in every clinical encounter. PMID- 21269709 TI - Regulatory T cells and other leukocytes in the pathogenesis of endometriosis. AB - Endometriosis is a common and puzzling gynaecological condition which shows a great deal of variability between women. It affects up to 15% of all women of reproductive age. There is a strong familial component, but the aetiology and pathogenesis are still uncertain. Endometriosis is an 'inflammatory' condition with substantial numbers of leukocytes recruited into the lesion sites. There is increasing evidence to demonstrate marked changes in numbers and functions of these leukocytes in the eutopic endometrium and peritoneal fluid as well as in the lesions. We hypothesise that endometriosis is primarily an endometrial disease with underlying genetic disturbances which lead to a number of major molecular changes in function, enhancing the likelihood that viable fragments of endometrial tissue will pass through the fallopian tubes and attach and grow on the peritoneum. We have demonstrated disturbances in the populations of T cells, B cells, mast cells, dendritic cells and macrophages within the endometrium and ectopic lesions, and are intrigued by the potential for changes in regulatory T cells to influence disease establishment and progression. Interestingly, we have shown that in endometriosis, naturally occurring FOXP3+ regulatory T cells fail to undergo the expected decline in number during the secretory phase, which may account for a decreased ability of newly recruited leukocytes to initiate effective immune responses against viable endometrial fragments, permitting their survival and subsequent establishment. To better understand the pathogenesis of endometriosis, we must learn about how the immune system recognises this disease and how the endometrial immune response is regulated. PMID- 21269708 TI - Generalized anxiety disorder: course and risk factors in pregnancy. AB - BACKGROUND: There are limited studies of generalized anxiety disorder (GAD) across pregnancy. METHODS: Women (n = 2793) were enrolled in the Yale Pink and Blue study, a cohort enriched with subjects who suffered from major depressive disorder (MDD) within the past five years or used antidepressants in the past year. Subjects were evaluated with the Composite International Diagnostic Interview at three time points: twice in pregnancy and once after delivery. We defined a generalized anxiety disorder (GAD) episode as per DSM IV but with required duration reduced to one month or longer. Course and correlates of GAD were examined in women who had: 1) no GAD during the 6 months prior or in pregnancy (Group A), 2) GAD in the 6 months prior to but not in pregnancy (Group B), 3) GAD in pregnancy only (Group C) and 4) GAD both in the 6 months prior to and during pregnancy (Group D). RESULTS: 9.5% of the cohort suffered from GAD at some point in pregnancy. Anxiety symptoms were highest in the first trimester and decreased across pregnancy. Regression analysis revealed that previous GAD episodes, education, social support and a history of child abuse distinguished between membership in the four groups. LIMITATIONS: The sample may not be representational, as it was enhanced with those at risk, and had relatively low representation of socio-economically disadvantaged women. CONCLUSIONS: Identification of anxious patients during pregnancy may provide an opportunity to engage those in need of psychiatric treatment. PMID- 21269710 TI - Emotional sensitivity in youth with borderline personality pathology. AB - If Borderline Personality Disorder (BPD) is characterized by an underlying emotional sensitivity, individuals with this disorder would be expected to demonstrate accurate identification of emotional expressions at earlier stages of expression (i.e., lower thresholds of facial expressivity across all emotional valences). Twenty-one outpatient youth (aged 15-24 years) meeting 3 or more DSM IV BPD criteria and 20 community-derived participants (aged 15-24 years) with no history of psychiatric problems were tested on a measure of emotional sensitivity, the Face Morph Task. In this test faces morph from neutral to each of the six basic emotional expressions. The BPD group showed no evidence of heightened sensitivity to emotional facial expressions compared to the community control group (all P>0.05 and effect sizes ranging from 0 to 0.6). They require comparable levels of emotional expressivity in order to correctly identify emotions. Therefore, emotional sensitivity might not be apparent early in the course of BPD. Rather, it might develop later in the course of the disorder or be present only in severe BPD. PMID- 21269711 TI - Memantine reduces mania-like symptoms in animal models. AB - Memantine, a selective antagonist of the N-methyl-D-aspartate receptor, is approved for the treatment of moderate to severe Alzheimer's disease. Ion dysregulation is thought to be involved in the pathophysiology of bipolar illness, suggesting that memantine may be effective in treating bipolar manic and/or depressive episodes. We utilized two preclinical models of mania that mimic pathophysiologic changes seen in bipolar illness to examine the potential efficacy of memantine in the treatment of this disorder. Locomotor hyperactivity of male Sprague-Dawley rats in an open field was induced with intracerebroventricular (ICV) administration of 10(-3) M ouabain. Memantine (2.5, 5 or 7.5mg/kg), lithium (6.75 mEq/kg), or vehicle were administered acutely via intraperitoneal injection immediately prior to ouabain, then chronically for 7 days (oral memantine 20, 30, and 40 mg/kg/day in water; lithium 2.4 g/kg food). In a second model of bipolar disorder, cycling between population spikes and epileptiform bursts was investigated in rat hippocampal slices treated with ouabain (3.3 MUM) alone or in combination with memantine (0.5, 1.0, and 5.0 MUM). Ouabain-induced hyperlocomotion was normalized with acute and chronic lithium and chronic use of memantine. Memantine delayed the onset of ouabain-induced-cycling in hippocampal slices. Memantine may have antimanic properties. PMID- 21269712 TI - The association between socioeconomic status, oral hygiene practice, denture stomatitis and oral status in elderly people living different residential homes. AB - Oral hygiene practices and denture status of elderly people living in residential homes are different depending on the type of residential homes. In this study the elderly people living in three different residential homes were investigated for this purpose. A total of 269 subjects, 119 males (mean age 73.9+/-8.8) and 150 females (mean age 78.5+/-7.2) were involved in this study. All subjects were interviewed and clinically examined. Age, sex, educational status, financial status, general health, dental visiting, overnight denture wearing, brushing habits and frequency were recorded using a structured questionnaire. The prevalence of edentulism, the presence and type of dental prostheses, denture cleanliness and the presence of denture stomatitis were evaluated. Forty-one percent of subjects were non-educated. Fifty-one percent of subjects had low income. The majority of people (66.6%) were edentulous. Among the edentulous subjects 32% had full denture and 16% had no denture. Forty three percent of the subjects reported cleaning their dentures with water and 40% with a toothbrush only. Denture hygiene was good for 14% of the subjects. Denture stomatitis was observed in 44% of the subjects wearing dentures. There was statistically significant difference between residential homes and educational status, level of income, dental visiting, denture status, brushing methods and brushing frequency (p<0.001). A positive relationship was observed between poor denture hygiene habits and the presence of denture-related stomatitis. The most important need within the residents of the residential home was the enhancement of oral care social insurance. PMID- 21269714 TI - Does atlas-based autosegmentation of neck levels require subsequent manual contour editing to avoid risk of severe target underdosage? A dosimetric analysis. AB - BACKGROUND AND PURPOSE: To investigate the dosimetric impact of not editing auto contours of the elective neck and organs at risk (OAR), generated with atlas based autosegmentation (ABAS) (Elekta software) for head and neck cancer patients. MATERIALS AND METHODS: For nine patients ABAS auto-contours and auto contours edited by two observers were available. Based on the non-edited auto contours clinically acceptable IMRT plans were constructed (designated 'ABAS plans'). These plans were then evaluated for the two edited structure sets, by quantifying the percentage of the neck-PTV receiving more than 95% of the prescribed dose (V(95)) and the near-minimum dose (D(99)) in the neck PTV. Dice coefficients and mean contour distances were calculated to quantify the similarity of ABAS auto-contours with the structure sets edited by observer 1 and observer 2. To study the dosimetric importance of editing OAR auto-contours a new IMRT plan was generated for each patient-observer combination, based on the observer's edited CTV and the non-edited salivary gland auto-contours. For each plan mean doses for the non-edited glands were compared with doses for the same glands edited by the observer. RESULTS: For both observers, edited neck CTVs were larger than ABAS auto-contours (p<= 0.04), by a mean of 8.7%. When evaluating ABAS plans on the PTVs of the edited structure sets, V(95) reduced by 7.2%+/-5.4% (1 SD) (p<0.03). The mean reduction in D(99) was 14.2 Gy (range 1-54 Gy). Even for Dice coefficients >0.8 and mean contour distances <1mm, reductions in D(99) up to 11Gy were observed. For treatment plans based on observer PTVs and non edited auto-contoured salivary glands, the mean doses in the edited glands differed by only -0.6 Gy+/-1.0 Gy (p=0.06). CONCLUSIONS: Editing of auto contoured neck CTVs generated by ABAS is required to avoid large underdosages in target volumes. Often used similarity measures for evaluation of auto-contouring algorithms, such as dice coefficients, do not predict well for expected PTV underdose. Editing of salivary glands is less important as mean doses achieved for non-edited glands predict well for edited structures. PMID- 21269713 TI - Phosphorus-32 therapy for cystic craniopharyngiomas. AB - BACKGROUND AND PURPOSE: To examine control rates for predominantly cystic craniopharyngiomas treated with intracavitary phosphorus-32 (P-32). MATERIAL AND METHODS: 22 patients with predominantly cystic craniopharyngiomas were treated at Indiana University between October 1997 and December 2006. Nineteen patients with follow-up of at least 6 months were evaluated. The median patient age was 11 years, median cyst volume was 9 ml, a median dose of 300 Gy was prescribed to the cyst wall, and median follow-up was 62 months. RESULTS: Overall cyst control rate after the initial P-32 treatment was 67%. Complete tumor control after P-32 was 42%. Kaplan-Meier 1-, 3-, and 5-year initial freedom-from-progression rates were 68%, 49%, and 31%, respectively. Following salvage therapy, the Kaplan-Meier 1-, 3-, and 5-year ultimate freedom-from-progression rates were 95%, 95%, and 86%, respectively. All patients were alive at the last follow-up. Visual function was stable or improved in 81% when compared prior to P-32 therapy. Pituitary function remained stable in 74% of patients following P-32 therapy. CONCLUSIONS: Intracystic P-32 can be an effective and tolerable treatment for controlling cystic components of craniopharyngiomas as a primary treatment or after prior therapies, but frequently allows for progression of solid tumor components. Disease progression in the form of solid tumor progression, re-accumulation of cystic fluid, or development of new cysts may require further radiotherapy or surgical intervention for optimal long-term disease control. PMID- 21269715 TI - A significant decrease in rectal volume and diameter during prostate IMRT. AB - PURPOSE: To record changes in rectal volume (RV) and diameter (RD) of patients with prostate adenocarcinoma prior to and at an interim period during radiotherapy, which could potentially affect treatment toxicity and tumor control. METHODS: Three hundred and fifteen patients treated with intensity modulated radiotherapy (IMRT) underwent planning CT scans before radiation and after 45 Gy. For each scan, RV and RD were recorded and compared using a two tailed paired t-test. Robust linear regression analysis assessed correlation between initial RV and percent RV change. RESULTS: The mean change in RV was 8.62 cm(3) and in RD was -0.19 cm(3), (p<0.05). A decrease >=10% in RV and RD was seen in 159 patients (50.5%) and 117 patients (37.1%), respectively. Patients with >=10% volume change had larger initial RVs than those with <10% decrease, (78.1 vs. 50.8 cm(3), p<0.0001). CONCLUSIONS: A significant decrease in RV and RD occurs during prostate IMRT delivery. More than half of patients had decreased RV and over a third had decreased RD. This observation is pertinent to prostate localization, planning margins, and implies that dose-volume histogram (DVH) analysis of rectal irradiation based on pre-treatment CT scanning may inaccurately estimate the risk of rectal toxicity when the initial RV is larger than 70 cm(3). PMID- 21269716 TI - Age and gender moderate the effects of localized muscle fatigue on lower extremity joint torques used during quiet stance. AB - This study examined the effects of localized muscle fatigue, age, and gender on lower extremity joint torques used during quiet stance. Thirty-two participants performed exercises designed to fatigue the ankle plantarflexors, knee extensors, torso extensors, or shoulder flexors. Body kinematics and ground reaction forces were obtained both before and after the exercises, and joint torques were derived via inverse dynamics. Single joint fatigue affected torque variability at all lower extremity joints, with similar changes for both age groups. Males and females exhibited increased ankle torque variability after different tasks, with males showing more variability after ankle fatigue and females after shoulder and lumbar fatigue. Correlations between peak torques and torque variability differed between males and females and between age groups in certain cases. The results of this study suggested that both age and gender moderate the effects of fatigue on postural control and should be considered when developing strategies to prevent occupational falls. PMID- 21269717 TI - Change in attachment of Salmonella Typhimurium, Yersinia enterocolitica, and Listeria monocytogenes to pork skin and muscle after hot water and lactic acid decontamination. AB - The attachment of Salmonella enterica subsp. enterica serovar Typhimurium, Yersinia enterocolitica, and Listeria monocytogenes to pig skin and muscle tissue decontaminated with 80 degrees C water or 55 degrees C, 1% lactic acid for 5 and 15s was investigated. Attachment properties differed between skin and muscle surfaces. A significantly higher number of firmly attached bacteria was found on the decontaminated skin surface compared to the non-treated skin surface, both on hot water (P<0.0001) and on lactic acid treated skin (P<0.001). At the muscle surfaces, no such difference in attachment were shown between hot water treated surfaces and non-treated surfaces. In contrast, for lactic acid decontamination, significantly fewer bacteria attached to the treated muscle surfaces (P<0.0001). The study did not show significant differences in surface attachment, between Salmonella, Yersinia and Listeria, which indicate that surface and environmental factors may influence attachment more than bacterial properties. A more profound location of attached bacteria at muscle compared to skin was indicated. Confocal laser scanning microscopy studies showed that bacteria located in deep tissue structures of non-decontaminated and decontaminated skin and muscle surfaces. In the latter, bacteria tended to "hide" between the muscle fibres and may be entrapped at those sites. The finding of changed attachment properties at skin after decontamination may play a role in cross- and recontamination, during subsequent meat processing. PMID- 21269718 TI - Development of oscillation method for reducing foodborne pathogens on lettuce and spinach. AB - In this study, the efficacy of an oscillator for reducing the numbers of foodborne pathogens on lettuce and spinach was tested. A cocktail of three strains each of Salmonella typhimurium, Escherichia coli O157:H7 and Listeria monocytogenes cells and of Bacillus cereus spores was inoculated onto lettuce and spinach leaves and followed by oscillation at 10 Hz and 20 Hz for up to 30s. After treatment of inoculated lettuce leaf with an oscillator at 20 Hz for 30s, 2.58, 2.82, 2.21 and 2.22 Log(10)CFU/g reductions were obtained with the cells of S. typhimurium, E. coli O157:H7 and L. monocytogenes and the spores of B. cereus, respectively. In the case of the oscillation treatment of spinach leaf, 2.89, 3.73, 2.46 and 2.25 Log(10)CFU/g reductions of those pathogens were achieved under the same condition. Statistically significant reductions were observed after oscillation treatment at 20 Hz for 5-10s. The oscillation treatment at 10 Hz led to slightly less reductions of the pathogens tested as compared to the treatment at 20 Hz. In conclusion, the oscillation method developed shows to be highly efficacious in reducing foodborne pathogens on lettuce and spinach leaves. PMID- 21269719 TI - The use of a CYP51C gene based PCR-RFLP assay for simultaneous detection and identification of Fusarium avenaceum and F. tricinctum in wheat. AB - Contamination of cereals with mycotoxins such as beauvericin (BEA), enniatins (Ens) and moniliformin (MON) is mainly caused by Fusarium avenaceum and F. tricinctum. This is a world-wide problem which requires rapid and sensitive detection methods. To allow for high throughput screening of large numbers of samples, a diagnostic PCR method was developed for the simultaneous detection of F. avenaceum and F. tricinctum. The interspecific divergence found in the Fusarium-specific CYP51C gene was used to design species-specific PCR primers. The specificity of the assay was demonstrated for DNA samples extracted from a wide range of Fusarium species belonging to the Fusarium head blight (FHB) complex, as well as for naturally-infected grain samples. The PCR-amplified products were digested with the restriction enzyme XbaI to enable differentiation between F. avenaceum and F. tricinctum. This PCR- restriction fragment length polymorphism (RFLP) assay proved to be a simple and relatively inexpensive method highly suited for routine detection and identification of F. avenaceum and F. tricinctum in wheat samples. PMID- 21269720 TI - Transfer and internalisation of Escherichia coli O157:H7 and Salmonella enterica serovar Typhimurium in cabbage cultivated on contaminated manure-amended soil under tropical field conditions in Sub-Saharan Africa. AB - Surface contamination and internalisation of Escherichia coli O157:H7 and Salmonella Typhimurium in cabbage leaf tissues at harvest (120 days post transplantation) following amendment of contaminated bovine manure to soil at different times during crop cultivation were investigated under tropical field conditions in the Central Agro-Ecological Zone of Uganda. Fresh bovine manure inoculated with rifampicin-resistant derivatives of non-virulent strains of E. coli O157:H7 and S. Typhimurium was incorporated into the soil to achieve inoculum concentrations of 4 and 7 log CFU/g at the point of transplantation, 56 or 105 days post-transplantation of cabbage seedlings. Frequent sampling of the soil enabled the accurate identification of the survival kinetics in soil, which could be described by the Double Weibull model in all but one of the cases. The persistence of 4 log CFU/g E. coli O157:H7 and S. Typhimurium in the soil was limited, i.e. only inocula applied 105 days post-transplantation were still present at harvest. Moreover, no internalisation in cabbage leaf tissues was observed. In contrast, at the 7 log CFU/g inoculum level, E. coli O157:H7 and S. Typhimurium survived in the soil throughout the cultivation period. All plants (18/18) examined for leaf contamination were positive for E. coli O157:H7 at harvest irrespective of the time of manure application. A similar incidence of leaf contamination was found for S. Typhimurium. On the other hand, only plants (18/18) cultivated on soil amended with contaminated manure at the point of transplantation showed internalised E. coli O157:H7 and S. Typhimurium at harvest. These results demonstrate that under tropical field conditions, the risk of surface contamination and internalisation of E. coli O157:H7 and S. Typhimurium in cabbage leaf tissues at harvest depend on the inoculum concentration and the time of manure application. Moreover, the internalisation of E. coli O157:H7 and S. Typhimurium in cabbage leaf tissues at harvest seems to be limited to the worst case situation, i.e., when highly contaminated manure is introduced into the soil at the time of transplantation of cabbage seedlings. PMID- 21269721 TI - Reduced insulin requirements during participation in the DAFNE (dose adjustment for normal eating) structured education programme. AB - Dose adjustment for normal eating (DAFNE) is a well-established structured education programme for patients with type 1 diabetes. We conducted a retrospective analysis of insulin dose changes associated with DAFNE training. Our results show significant reductions in total, quick acting and basal insulin doses in patients undergoing DAFNE training. PMID- 21269722 TI - Vaccination against hepatitis B among prisoners in Iran: accelerated vs. classic vaccination. AB - BACKGROUND: Prisoners and injecting drug users are at constant risk of hepatitis B virus (HBV) infection and the classic 6-months HBV vaccination might not provide immunization rapidly enough. In this randomized clinical trial we investigated the efficacy of an accelerated vaccination protocol vs. classic schedule among prisoners in Iran. METHODS: 180 prisoners were randomized into 2 vaccination groups; group A underwent accelerated vaccination at 0, 1, 4 and 8 weeks and group C were vaccinated at 0, 1 and 6 months. Antibody against Hepatitis-B surface-antigen (anti-HBs) was assessed at baseline, one, two, six and eight months after the first vaccine dose using immunoenzymatic assays. Seroprotection was defined as anti-HBs titer of 10 IU/L or more. Anti-HBc and HBsAg were measured at baseline and 8th month to evaluate new HBV infection and failure of vaccination. RESULTS: Overall compliance was 100% and 90.4% in groups A and C respectively. While seroprotection rate at one month was significantly higher in group A (22.4%) compared to group C (4.7%), in the 8th month 78.8% and 93.4% seroprotection was achieved in groups A and C respectively (P < 0.002). CONCLUSION: Compared to classic HBV vaccination regimen, an accelerated 0, 1, 4 and 8 weeks vaccination schedule can achieve early seroprotection more rapidly, provides clinically sufficient seroprotection with higher compliance in prisoners and can be suggested in situations that rapid immunization against HBV infection is warranted. PMID- 21269723 TI - Newspapers' coverage of contaminated intravenous fluids from an Indian manufacturer distributed by Public Central Medical Supplies in Sudan: lessons to be learned. AB - OBJECTIVES: This study aims to answer the question whether or not newspapers have a role in decision-making process in non-democratic settings. METHOD: This cross sectional study has reviewed newspapers' articles published in Sudan about the questioned quality of intravenous fluid imported by Sudan Central Medical Supplies Public Corporation. It covered the period from 17 January 1999 to 8 October 2007. A total number of 310 articles published in 18 newspapers about the topic was retrieved. RESULTS: Of the total number, 165 (53.2%) articles were against the selling of the suspiciously contaminated intravenous fluids from Core Parentral (the Indian manufacturer of the products). The remaining 143 (46.1%) articles are in favor of selling such fluids. CONCLUSION: Health authorities need to have good communication with media. The incident has proven that the lack of this communication is harmful both for the health authorities and for the population. PMID- 21269724 TI - Social capital, community size and utilization of health services: a lagged analysis. AB - OBJECTIVES: We examine the relationship between social capital, community size and GP visits, and conceptualize social capital as a stock variable measured at a prior point in time. METHODS: Data from the 2002 Canadian Community Health Survey and the 2001 Canadian Census are merged with GP visit data from the Ontario Health Ministry. Negative binomial regression is used to measure the impact of community-level (CSC) and individual-level social capital (ISC) on GP visits. CSC is measured with the Petris Index using employment levels in religious and community-based organizations, and ISC is measured along multiple dimensions. RESULTS: The effect of social capital varies by community size. A one standard deviation increase in the Petris Index in larger communities (population>100,000) leads to a 2.6% decrease in GP visits with an annual offset in public spending of $66.4M. Tangible social support-a measure of ISC-also exhibited large effects on GP visits. In smaller communities (population 10,000-100,000), only increased ISC exhibited an impact on GP visits. Age had no effect on the association between social capital and GP visits. CONCLUSIONS: Each form of social capital likely operates through different mechanisms and impact differs by community size. Stronger CSC likely obviates some physician visits in larger communities that involve counseling/caring services while some forms of ISC may act similarly in smaller communities. PMID- 21269725 TI - Extracting 3D information on bone remodeling in the proximity of titanium implants in SRMUCT image volumes. AB - Bone-implant integration is measured in several ways. Traditionally and routinely, 2D histological sections of samples, containing bone and the biomaterial, are stained and analyzed using a light microscope. Such histological section provides detailed cellular information about the bone regeneration in the proximity of the implant. However, this information reflects the integration in only a very small fraction, a 10 MUm thick slice, of the sample. In this study, we show that feature values quantified on 2D sections are highly dependent on the orientation and the placement of the section, suggesting that a 3D analysis of the whole sample is of importance for a more complete judgment of the bone structure in the proximity of the implant. We propose features describing the 3D data by extending the features traditionally used for 2D-analysis. We present a method for extracting these features from 3D image data and we measure them on five 3D SRMUCT image volumes. We also simulate cuts through the image volume positioned at all possible section positions. These simulations show that the measurement variations due to the orientation of the section around the center line of the implant are about 30%. PMID- 21269726 TI - Symposium on Modelling and Control in Biomedical Systems, Aalborg, Denmark, 2009. Introduction. PMID- 21269727 TI - Algorithm for registration of full Scanning Laser Ophthalmoscope video sequences. AB - Fluorescein angiography is an established technique for examining the functional integrity of the retinal microcirculation for early detection of changes due to retinopathy. This paper describes a new method for the registration of large Scanning Laser Ophthalmoscope sequences (SLO), where the patient has been injected with a fluorescent dye. This allows the measurement of parameters such as the arteriovenous passage time. Due to the long time needed to acquire these sequences, there will inevitably be eye movement, which must be corrected prior to the application of quantitative analysis. The algorithm described here combines mutual information-based registration and landmark-based registration. The former will allow the alignment of the darkest frames of the sequence, where the dye has not still arrived to the retina, because of its ability to work with images without a preprocessing or segmentation, while the latter uses relevant features (the vessels) extracted by means of a robust creaseness operator, to get a very fast and accurate registration. The algorithm only detects rigid transformations but proves to be robust against the slight alterations derived from the eye location perspective during acquisition. Results were validated by expert clinicians. PMID- 21269728 TI - Macrodispersion by diverging radial flows in randomly heterogeneous porous media. AB - Radial flow takes place in a heterogeneous porous formation where the transmissivity T is modelled as a stationary random space function (RSF). The steady flow is driven by a given rate, and the mean velocity is radial. A pulse like of a tracer is injected in the porous formation, and the thin plume spreads due to the fluctuations of the velocity which results a RSF as well. Transport is characterized by the mean front, and by the second spatial moment of the plume. We are primarily interested in tracer macrodispersion modelling. With the neglect of pore-scale dispersion, macrodispersion coefficients are computed at the second order of approximation, without neglecting the head-gradient fluctuations. Although transport is non-ergodic at the source, it is shown that ergodicity is achieved at small distances from the source. This is due to the fact that close to the source local velocities are quite large, and therefore solute particles become uncorrelated very soon. Under ergodic conditions, we compare macrodispersion mechanism in radial flows with that occurring in mean uniform flows. At short distances the spreading effect is highly enhanced by the large variability of the flow field, whereas at large distances transport exhibits a lesser dispersion due to the reduction of velocities. This supports the explanation provided by Indelman and Dagan (1999) to justify why the macrodispersivity is found smaller than that pertaining to mean uniform flows. The model is tested against a tracer transport experiment (Fernandez-Garcia et al., 2004) by comparing the theoretical and experimental breakthrough curves. The accordance with real data, that is achieved without any fitting to concentration values, strengthens the capability of the proposed model to grasp the main features of such an experiment, the approximations as well as experimental uncertainties notwithstanding. PMID- 21269729 TI - Induction of a Th17 cell response by Helicobacter pylori Urease subunit B. AB - Th17 cells represent a novel subset of CD4(+) T cells, which is associated with Helicobacter pylori infection. In the present study, we investigated the potential role of Urease subunit B (UreB) in the induction of Th17 cell response. Co-cultured splenic lymphocytes from H. pylori-infected mice with the recombinant UreB (rUreB) elevated IL-17 secretion and caused an increase in the number of Th17 cells. The expression of IL-6 and IL-23 p19 was significantly increased in rUreB-stimulated macrophages. Whole cell protein (WCP) of UreB-deficient strain (UreB(-) strain) induced less Th17 cell responses than that of wild-type strain. In addition, subcutaneous and intranasal immunization of rUreB elicited antigen specific Th17 cell responses. Intranasal immunization of rUreB reduced H. pylori colonization in the stomach, which was closely related with the increased rUreB specific Th17 cell responses. These results suggest that UreB is an important protein which is able to elicit Th17 cell responses against H. pylori both in vivo and in vitro. PMID- 21269730 TI - Macrophages from IBD patients exhibit defective tumour necrosis factor-alpha secretion but otherwise normal or augmented pro-inflammatory responses to infection. AB - Defects in macrophage function have been implicated in the establishment of Crohn's disease (CD). However, the response of macrophages from CD patients to live bacteria, particularly Mycobacterium avium subsp. paratuberculosis (MAP), has not been addressed. Considering MAP has long been associated to CD, our objective was to assess whether macrophages from CD patients showed impaired inflammatory response to infection by MAP comparing to M. avium subsp. avium (MA) and other live intestinal commensal bacteria. Human peripheral blood monocyte derived macrophages were obtained from CD patients, ulcerative colitis (UC) patients and controls. Following in vitro infection with MAP, MA, Escherichia coli or Enterococcus faecalis, cytokine levels and cell surface receptor expression were evaluated at different time points. Macrophages from CD patients showed impaired TNF-alpha secretion in response to bacterial challenge, but augmented IL-23 secretion and preserved IL-12 secretion and CD-40 expression. In addition, CD macrophages showed low IL-10 secretion. Macrophages from IBD patients showed increased expression of TLR-2 and -4, unaffected by infection. Differences in cytokine secretion observed after bacterial challenge were not MAP specific, as other bacteria (E. coli and MA) showed similar effects. Macrophages from UC patients showed a less compromised TNF-alpha synthesis in response to mycobacterial infection than CD macrophages, with increased constitutive IL-12 secretion, and preserved IL-10 secretion. The increased IL-23 levels in response to infection and decreased IL-10 production observed in macrophages from CD patients may contribute to the inflammatory exacerbation observed in those patients. PMID- 21269731 TI - Starch-related cytosolic heteroglycans in roots from Arabidopsis thaliana. AB - Both photoautotrophic and heterotrophic plant cells are capable of accumulating starch inside the plastid. However, depending on the metabolic state of the respective cell the starch-related carbon fluxes are different. The vast majority of the transitory starch biosynthesis relies on the hexose phosphate pools derived from the reductive pentose phosphate cycle and, therefore, is restricted to ongoing photosynthesis. Transitory starch is usually degraded in the subsequent dark period and mainly results in the formation of neutral sugars, such as glucose and maltose, that both are exported into the cytosol. The cytosolic metabolism of the two carbohydrates includes reversible glucosyl transfer reactions to a heteroglycan that are mediated by two glucosyl transferases, DPE2 and PHS2 (or, in all other species, Pho2). In heterotrophic cells, accumulation of starch mostly depends on the long distance transport of reduced carbon compounds from source to sink organs and, therefore, includes as an essential step the import of carbohydrates from the cytosol into the starch forming plastids. In this communication, we focus on starch metabolism in heterotrophic tissues from Arabidopsis thaliana wild type plants (and in various starch-related mutants as well). By using hydroponically grown A. thaliana plants, we were able to analyse starch-related biochemical processes in leaves and roots from the same plants. Within the roots we determined starch levels and the morphology of native starch granules. Cytosolic and apoplastic heteroglycans were analysed in roots and compared with those from leaves of the same plants. A. thaliana mutants lacking functional enzymes either inside the plastid (such as phosphoglucomutase) or in the cytosol (disproportionating isoenzyme 2 or the phosphorylase isozyme, PHS2) were included in this study. In roots and leaves from the three mutants (and from the respective wild type organ as well), starch and heteroglycans as well as enzyme patterns were analysed. PMID- 21269732 TI - A survey on basal resistance and riboflavin-induced defense responses of sugar beet against Rhizoctonia solani. AB - We examined basal defense responses and cytomolecular aspects of riboflavin induced resistance (IR) in sugar beet-Rhizoctonia solani pathsystem by investigating H(2)O(2) burst, phenolics accumulation and analyzing the expression of phenylalanine ammonia-lyase (PAL) and peroxidase (cprx1) genes. Riboflavin was capable of priming plant defense responses via timely induction of H(2)O(2) production and phenolics accumulation. A correlation was found between induction of resistance by riboflavin and upregulation of PAL and cprx1 which are involved in phenylpropanoid signaling and phenolics metabolism. Application of peroxidase and PAL inhibitors suppressed not only basal resistance, but also riboflavin-IR of sugar beet to the pathogen. Treatment of the leaves with each inhibitor alone or together with riboflavin reduced phenolics accumulation which was correlated with higher level of disease progress. Together, these results demonstrate the indispensability of rapid H(2)O(2) accumulation, phenylpropanoid pathway and phenolics metabolism in basal defense and riboflavin-IR of sugar beet against R. solani. PMID- 21269733 TI - Economic and clinical impact of nosocomial meticillin-resistant Staphylococcus aureus infections in Singapore: a matched case-control study. AB - We performed a prospective matched case-control study, with six-month follow-up for discharged subjects, to evaluate the direct clinical and financial impact of nosocomial meticillin-resistant Staphylococcus aureus (MRSA) infections in Singaporean hospitals. Consecutive nosocomial MRSA-infected cases at both tertiary public sector hospitals in Singapore were matched for age, specialty service, major surgical procedure (if applicable) and Charlson comorbidity index with up to two non-infected controls each. Chart reviews and subject interviews were performed during hospitalisation and also upon six months post-discharge for survivors. The outcomes analysed were: mortality, length of hospitalisation (LOS), healthcare-associated financial costs, and health-related quality of life. The last was evaluated via an interviewer-administered EuroQol-5D questionnaire on discharge, with conversion to a single health state summary index. Attributable outcomes were ascertained by conditional logistic and linear regression. There were 181 cases and 351 controls. MRSA infection was independently associated with in-hospital death [14.4% vs 1.4%; odds ratio (OR): 5.54; 95% confidence interval (CI): 1.63-18.79, P=0.006], longer LOS (median of 32 days vs 7 days; coefficient: 1.21; 95% CI: 1.02-1.40, P<0.001), higher hospitalisation costs (median of US$18,129.89 vs US$4,490.47; coefficient: 1.14; 95% CI: 0.93-1.35; P<0.001), higher post-discharge healthcare-associated financial costs (median of US$337.24 vs US$259.29; coefficient: 0.39; 95% CI: 0.06-0.72; P=0.021), and poorer health-related quality of life (coefficient: 0.14; 95% CI: -0.21 to -0.08; P<0.001). Outcomes were not significantly different between both hospitals. The attributable individual, institutional and societal impact of MRSA infections is considerable in Singapore. Preventing such infections will result in substantial improvements in patient outcomes and healthcare delivery. PMID- 21269734 TI - Healthcare-associated bacteraemia caused by Leuconostoc species at a university hospital in Taiwan between 1995 and 2008. AB - We studied twenty patients with Leuconostoc spp. bacteraemia at a tertiary hospital in northern Taiwan between 1995 and 2008. All isolates were identified to species level using conventional and commercial automated methods in conjunction with 16S rRNA sequencing analysis. Leuconostoc lactis (15/20, 75%) constituted the most common species but required molecular methods for accurate identification. Minimum inhibitory concentrations (MICs) of 10 antimicrobial agents were determined using the broth microdilution method. Among these 20 patients, 19 had healthcare-associated Leuconostoc spp. bacteraemia and 11 patients (55%) had underlying malignancies. Eleven had been hospitalised for more than 30 days (median: 32.5 days; range: 0-252 days) before the bacteraemic episode. At the time of bacteraemia, 11 had a Pitt bacteraemia score of >= 4 (median: 4; range: 0-7) and 12 had a modified Acute Physiological Assessment and Chronic Health Evaluation (APACHE II) score of >= 20 (median: 22; range: 5-37). Azithromycin (MIC: 0.12 MUg/mL), moxifloxacin (MIC: 0.25-0.5 MUg/mL), daptomycin (MIC: 0.03-0.25 MUg/mL) and tigecycline (MIC: 0.06-0.12 MUg/mL) exhibited good in vitro activity against Leuconostoc spp. although bacteraemia due to L. lactis was associated with high mortality in immunocompromised patients. PMID- 21269735 TI - Vaccine-related varicella-zoster rash in a hospitalized immunocompetent patient. AB - An immunocompetent health care worker with no known history of varicella-zoster virus (VZV) disease was exposed to a patient with herpes zoster and was immunized 2 days later. Twenty-seven days after receiving the varicella vaccine, while hospitalized, she developed a disseminated rash. This exposure and subsequent development of symptoms posed infection control challenges. A polymerase chain reaction analysis of her vesicular fluid was positive for vaccine-type VZV, and a blood specimen collected before vaccination demonstrated a positive VZV titer by the fluorescent antibody to membrane antigen test. To the best of our knowledge, there have been no previous reports of an immunocompetent seropositive person developing vaccine-type VZV after receiving the vaccine. PMID- 21269736 TI - [Cost-effectiveness of the combination therapy of dutasteride and tamsulosin in the treatment of benign prostatic hyperlasia in Spain]. AB - OBJECTIVES: to evaluate the incremental cost-effectiveness ratio (ICER) of the combination therapy with dutasteride and tamsulosin (DUT+TAM) as initiation treatment versus the most used drug in Spain, tamsulosin (TAM), in the treatment of moderate to severe benign prostatic hyperplasia (BPH) with risk of progression. METHODS: a semi-Markov model was developed using 4-year and 35-year time horizons and from the Spanish National Healthcare Service perspective. Data were obtained from the CombAT trial. Effectiveness was measured in terms of quality adjusted life years (QALYs). Health care resources were defined by an experts' panel, and unitary costs were obtained from published Spanish sources. Pharmacologic cost is expressed in PTP(WAT); in the case of TAM, the generic price is used, in the case of DUT+TAM the price of a fixed dose combination is used. Costs are expressed in 2010 Euros. RESULTS: combination therapy with DUT+TAM produces an incremental effectiveness of 0.06QALY at year 4 and 0.4QALY at year 35. DUT+TAM represents an incremental cost of ? 810.53 at 4 years and ? 3,443.62 at 35 years. Therefore, the ICER for DUT+TAM versus TAM is ? 14,023.32/QALY at year 4 and ? 8,750.15/QALY at year 35. CONCLUSIONS: initiation treatment with DUT+TAM represents a cost-effective treatment versus TAM, the most used treatment in Spain, due to the fact the ICER is below the threshold that usually allows a technology to be considered as cost-effective. PMID- 21269737 TI - Protein-based alignment in 3D-QSAR of FBPase inhibitors. AB - Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were performed on Frusectose-1, 6-bisphosphatase (FBPase) inhibitors, based on molecular docking obtained by using GOLD and comparative molecular field analysis (CoMFA). Three random splits into training and test sets had been performed and the high leave-one-out (LOO) cross-validated correlation coefficients q(2) of 0.781, 0.725 and 0.801, respectively, revealed that the models are useful tools for the prediction of test sets as well as newly designed structures against FBPase activity. The superimposed CoMFA models on the receptor site of FBPase are guiding the design of potential inhibitory structures directed against FBPase activity. PMID- 21269738 TI - [Visual hallucinations and giant cell arteritis: the Charles Bonnet syndrome]. AB - In patients with visual hallucinations, diagnostic strategy is unclearly codified. In patients known to have giant cell arteritis, the main diagnostic assumption is disease relapse. Indeed, this should lead to rapid corticosteroid therapy. However, the Charles Bonnet syndrome, that is a poorly known etiology of visual hallucinations usually observed in elderly people, should be part of the differential diagnosis. We report a 87-year-old woman, with a 2-year history of giant cell arteritis who was admitted with an acute onset of visual hallucinations and who met all the criteria for Charles Bonnet syndrome. PMID- 21269739 TI - [An unusual cause of occlusion]. PMID- 21269740 TI - [Wilson's disease in an adult]. AB - PURPOSE: Wilson's disease (WD) is an inherited disorder of copper metabolism, characterized by the accumulation of copper in the body due to defective biliary copper excretion by hepatocytes. We report a series of 19 patients with WD. PATIENTS AND METHODS: This is a retrospective and descriptive case series of patients with WD followed in two hospitals of North East of France. RESULTS: Eight men and 11 women were studied. Median follow-up time was 16 years, median age at diagnosis was 18 years (range: 5-71 years). Median age at first symptom was 16 years. In addition to four cases diagnosed by familial screening, clinical manifestations at diagnosis were fatigue (n=5), jaundice (n=5), bleeding (n=1), abnormal movement disorders (n=2) and fortuitous (n=2). Cirrhosis was identified in 14 patients, neurological involvement occurred in seven patients and four patients presented with psychiatric disorders. d-penicillamine was the first treatment in 18 patients, discontinued for severe adverse events in seven patients. Trientine or zinc salts were then prescribed. Medical treatment was successful in 13 patients, but five patients underwent liver transplantation. Haemochromatosis was associated in one case, and one patient developed cholangiocarcinoma. CONCLUSION: WD is severe. Medical treatment allows disease control if it is correctly observed. Conversely, worsening with irreversible damage can occur if the treatment is discontinued. PMID- 21269741 TI - [Upper limb deep venous thrombosis]. AB - Deep venous thrombosis of the upper limb has become recently more common because of the increasing use of central venous catheters. Diagnosis is sometimes difficult. Main causes are pacemaker and central venous catheter related thrombosis. The thoracic outlet syndrome is a rare cause and requires a multidisciplinary diagnostic and therapeutic approach. A systematic research of a thrombophilic disorder is not recommended because of the weak therapeutic impact. Duration of anticoagulation is similar to lower limb deep venous thrombosis despite a lower rate of recurrence. Therapeutic alternatives recently developed include thrombolysis, angioplasty and vein stenting. To date, no randomized controlled studies have evaluated the efficacy and safety of the various treatments that have been proposed for upper limb deep venous thrombosis. PMID- 21269742 TI - "Coming ready or not" high fidelity human patient simulation in child and adolescent psychiatric nursing education: diffusion of Innovation. AB - This paper is the first to address high fidelity human patient simulation (HFHPS) as a technique to prepare pre-registration nursing students for practice in child and adolescent psychiatric nursing (CAPN). By examining the published literature in a systematic review, no evidence was located that discussed the application of this innovative mannequin-based educational technique for this population. Indeed, mental health nursing preparation generally had minimal literature addressing the adoption of HFHPS. Rogers' (2003) model of the "Diffusion of Innovation" was applied as a lens to explain this observation. His model fitted this observed pattern well and provided a range of explanatory paradigms. It was limited, however, in its predictive ability to suggest when and under what conditions HFHPS might be expected to be adopted by nursing preparation programmes for CAPN. At the conclusion to this examination, the absence of a conversation evident in the mental health or CAPN literature on the preparation of pre-registration nursing students using this educational technique is striking. The potential of this approach to be combined in new ways to better prepare nursing students for the challenges of practice in mental health or CAPN needs extensive examination. PMID- 21269743 TI - Should all skin grafts be low fat? Composite skin and fat grafts in facial reconstruction. AB - Reconstruction of the nose and scalp after resection of cutaneous malignancy can be challenging, and can involve multiple stage surgery and cause secondary scarring in adjacent facial areas. The author describes his experience of a series of 100 composite full thickness skin and fat grafts in the head and neck region using the neck as the donor site. The technique was used to reconstruct the nose (n=48) and scalp including temple and forehead (n=46), and at 6 other sites, mainly the cheek or lower eyelid. Defects ranged in size from 11 to 36mm and the thickness of fat varied from 1 to 5mm. One flap failed, one patient had necrosis of roughly 30% of the graft, which did not require surgical intervention, and one patient had early defatting of a prominent graft. The author outlines the technique used and the complications, and discusses the benefits and limitations of the technique, which, he believes, has a role in carefully selected patients. PMID- 21269744 TI - Allogeneic stem cell transplantation for chronic lymphocytic leukemia: lessons to be learned from minimal residual disease studies. AB - Allogeneic stem cell transplantation (alloSCT) is a potentially curative treatment strategy for poor-risk chronic lymphocytic leukemia (CLL). The crucial anti-leukemic principle of alloSCT in CLL appears to be the graft-versus-leukemia effect (GVL). Evidence for GVL in CLL is particularly provided by studies analysing the kinetics of minimal residual disease (MRD). The purpose of this review is to summarize the methodologies of MRD assessment, its proven benefits and its further perspectives for optimizing the outcome of transplantation. Proven value of quantitative MRD monitoring by RQ-PCR or MRD-flow consists in using it as an indicator of long-term disease control and potential cure. As MRD kinetics correlates with GVL activity, its suitability for guiding GVL-inducing immunomodulation is currently under investigation. In conclusion, quantitative MRD monitoring seems to be mandatory to assure safe and effective immunotherapy in the context of alloSCT for CLL, which should, however, be best performed within clinical studies. PMID- 21269745 TI - Modelling the influence of peri-urban trees in the air quality of Madrid region (Spain). AB - Tropospheric ozone (O(3)) is considered one of the most important air pollutants affecting human health. The role of peri-urban vegetation in modifying O(3) concentrations has been analyzed in the Madrid region (Spain) using the V200603par-rc1 version of the CHIMERE air quality model. The 3.7 version of the MM5 meteorological model was used to provide meteorological input data to the CHIMERE. The emissions were derived from the EMEP database for 2003. Land use data and the stomatal conductance model included in CHIMERE were modified according to the latest information available for the study area. Two cases were considered for the period April-September 2003: (1) actual land use and (2) a fictitious scenario where El Pardo peri-urban forest was converted to bare-soil. The results show that El Pardo forest constitutes a sink of O(3) since removing this green area increased O(3) levels over the modified area and over down-wind surrounding areas. PMID- 21269746 TI - Mapping urban climate zones and quantifying climate behaviors--an application on Toulouse urban area (France). AB - Facing the concern of the population to its environment and to climatic change, city planners are now considering the urban climate in their choices of planning. The use of climatic maps, such Urban Climate Zone-UCZ, is adapted for this kind of application. The objective of this paper is to demonstrate that the UCZ classification, integrated in the World Meteorological Organization guidelines, first can be automatically determined for sample areas and second is meaningful according to climatic variables. The analysis presented is applied on Toulouse urban area (France). Results show first that UCZ differentiate according to air and surface temperature. It has been possible to determine the membership of sample areas to an UCZ using landscape descriptors automatically computed with GIS and remote sensed data. It also emphasizes that climate behavior and magnitude of UCZ may vary from winter to summer. Finally we discuss the influence of climate data and scale of observation on UCZ mapping and climate characterization. PMID- 21269747 TI - Application of air pollution dispersion modeling for source-contribution assessment and model performance evaluation at integrated industrial estate Pantnagar. AB - Source-contribution assessment of ambient NO2 concentration was performed at Pantnagar, India through simulation of two urban mathematical dispersive models namely Gaussian Finite Line Source Model (GFLSM) and Industrial Source Complex Model (ISCST-3) and model performances were evaluated. Principal approaches were development of comprehensive emission inventory, monitoring of traffic density and regional air quality and conclusively simulation of urban dispersive models. Initially, 18 industries were found responsible for emission of 39.11 kg/h of NO2 through 43 elevated stacks. Further, vehicular emission potential in terms of NO2 was computed as 7.1 kg/h. Air quality monitoring delineates an annual average NO2 concentration of 32.6 MUg/m3. Finally, GFLSM and ISCST-3 were simulated in conjunction with developed emission inventories and existing meteorological conditions. Models simulation indicated that contribution of NO2 from industrial and vehicular source was in a range of 45-70% and 9-39%, respectively. Further, statistical analysis revealed satisfactory model performance with an aggregate accuracy of 61.9%. PMID- 21269748 TI - Intra-Hisian block during transcatheter aortic valve implantation with the CoreValve prosthesis. PMID- 21269749 TI - Non-invasive imaging tests for the evaluation of low risk patients in chest pain units: availability, contributions and drawbacks in real practice. PMID- 21269750 TI - Suspicion of macrolide allergy after treatment of infectious diseases including Helicobacter pylori: results of allergological testing. AB - BACKGROUND: Macrolides are useful in a wide range of bacterial infections including upper and lower respiratory tract, skin, and sexually transmitted diseases and are used in Helicobacter pylori eradication regimen. Skin symptoms occurring during drug therapy are mostly attributed to the antibiotic, causing considerable limitations of future therapeutic options. The aim of this retrospective analysis was to demonstrate results of diagnostic testing in cases of clinically suspected immediate and delayed macrolide hypersensitivity. METHODS: A total of 125 patients with a history of immediate or delayed hypersensitivity symptoms in temporal relation to treatment with a macrolide antibiotic were studied using standardised skin tests followed by oral challenges. Selected patients with severe symptoms were further evaluated with in vitro tests. RESULTS: Macrolide hypersensitivity was excluded in 109 patients (87.2%) by tolerated oral challenge tests. During 113 challenges in four patients an exanthema was provoked by the suspected macrolide. Only one patient developed a positive late skin test reaction. Out of the 28 Helicobacter pylori-treated patients, one patient with clarithromycin allergy was identified, whereas in eight cases amoxicillin allergy caused the exanthema. Laboratory tests using the suspected macrolides were constantly negative. CONCLUSIONS: History alone leads to an over-estimation of macrolide hypersensitivity. Moreover, skin and in vitro tests seem to be not very useful in identifying hypersensitive patients. Challenge tests appear to be necessary for definitely confirming or ruling out macrolide allergy. PMID- 21269751 TI - Food allergy to spinach in an infant. PMID- 21269752 TI - The management of pregnancy in Gaucher disease. AB - Gaucher disease (GD), characterized by deficient acid beta-glucosidase activity, is the most common lysosomal storage disorder. The disease is progressive with manifestations that include anemia, thrombocytopenia, organomegaly and bone disease. Pregnancy has the potential to exacerbate these manifestations, compounding the risk of complications during pregnancy, delivery and postpartum. Enzyme replacement therapy with imiglucerase, before and during pregnancy, has demonstrated benefits in reducing the risk of spontaneous abortion and GD-related complications, especially bleeding during delivery and postpartum. European Medicines Agency guidelines now indicate that treatment-naive women should be advised to consider imiglucerase therapy before conception to obtain optimal health, and that imiglucerase treatment should be considered throughout pregnancy for women already receiving therapy. Many questions remain, however, on the indications for treatment and optimal management of women with GD. Based on a comprehensive review of outcomes in the management of pregnancy in GD, we present recommendations that aim to optimize patient care around pregnancy, delivery and the postpartum period, and alert attending physicians to the possible complications of pregnancy and delivery in GD. PMID- 21269753 TI - Relationships between transvaginal colour Doppler findings, infectious parameters and visual analogue scale scores in patients with mild acute pelvic inflammatory disease. AB - OBJECTIVE: To investigate the relationships between colour Doppler findings, infectious parameters and visual analogue scale (VAS) scores in patients with mild acute pelvic inflammatory disease (PID). STUDY DESIGN: Twenty-seven patients diagnosed with PID were enrolled in the study. Resistance index (RI) and pulsatility index (PI) of uterine, arcuate and utero-ovarian arteries were measured, as well as VAS score, erythrocyte sedimentation rate, C-reactive protein, white blood cell count and body temperature at hospital admission. After the initial visit, all measurements were repeated and recorded on days 7, 15 and 30. RESULTS: PI and RI values of uterine arteries showed significant increases between days 1 and 7. However, PI and RI values of uterine arteries, RI values of arcuate arteries and RI values of utero-ovarian arteries showed significant increases between days 1 and 30. Statistically significant decreases in infectious parameters and VAS scores were observed between days 1 and 7, days 1 and 15 and days 1 and 30. CONCLUSION: Infectious parameters and VAS scores showed concordant changes with clinical recovery in mild PID. Significant changes were also observed in PI and RI values of uterine arteries, but Doppler measurements of arcuate and utero-ovarian arteries showed a slower and later response to treatment. PMID- 21269754 TI - A comparative study of laparoscopic radical hysterectomy with radical abdominal hysterectomy for early-stage cervical cancer: a long-term follow-up study. AB - OBJECTIVE: To determine whether laparoscopic radical hysterectomy (LRH) is a feasible alternative to radical abdominal hysterectomy (RAH) for early-stage cervical cancer. STUDY DESIGN: A retrospective, matched case-control study of 24 consecutive cases with International Federation of Gynecology and Obstetrics stage I-II cervical cancer who underwent LRH by a single surgeon between January 1994 and December 2001. Cases were matched with controls (ratio 1:2) who underwent RAH by surgeon, age, stage and histology. Patient characteristics, clinical course, intra-operative complications and disease-free survival were compared between the two groups. Median counts were analyzed using the Mann Whitney U-test. Differences between means were compared using Student's t-test. Dichotomous groupings were analyzed using Chi-squared test and Fisher's exact test as appropriate. Survival data were estimated using Kaplan-Meier estimates and compared with the log-rank test. RESULTS: The mean estimated blood loss in the RAH group was significantly greater than that in the LRH group (836.0 ml and 414.3 ml, respectively; p<0.001). Five patients (20.8%) from the LRH group and 23 patients (47.9%) from the RAH group received blood transfusion (p<0.03). The mean length of hospital stay was significantly shorter in the LRH group compared with the RAH group (10.7 days and 18.8 days, respectively; p<0.01). No statistically significant difference existed between the two groups with respect to operative time, pelvic lymph node count, frequency of lymph node involvement, extent of parametrial or vaginal resection margins, adjuvant treatment and intra-operative complications. Median follow-up was 78 months for the LRH group and 75 months for the RAH group. There was no significant difference in the 5-year disease-free survival rate between the groups (90.5% and 93.3% for LRH and RAH, respectively; p=0.918). CONCLUSIONS: LRH is a useful alternative to RAH for the management of early-stage cervical cancer. The benefits of LRH include reduced blood loss, fewer transfusions and shorter hospital stay, with comparable oncologic outcome. PMID- 21269755 TI - Adenosine deaminase activity during menses, follicular and luteal phases of the menstrual cycle. PMID- 21269756 TI - European guidelines for the diagnosis and management of upper urinary tract urothelial cell carcinomas: 2011 update. AB - CONTEXT: The European Association of Urology (EAU) Guideline Group for urothelial cell carcinoma of the upper urinary tract (UUT-UCC) has prepared new guidelines to aid clinicians in assessing the current evidence-based management of UUT-UCC and to incorporate present recommendations into daily clinical practice. OBJECTIVE: This paper provides a brief overview of the EAU guidelines on UUT-UCC as an aid to clinicians in their daily practice. EVIDENCE ACQUISITION: The recommendations provided in the current guidelines are based on a thorough review of available UUT-UCC guidelines and papers identified using a systematic search of Medline. Data on urothelial malignancies and UUT-UCCs in the literature were searched using Medline with the following keywords: urinary tract cancer, urothelial carcinomas, upper urinary tract, carcinoma, transitional cell, renal pelvis, ureter, bladder cancer, chemotherapy, nephroureterectomy, adjuvant treatment, neoadjuvant treatment, recurrence, risk factors, and survival. A panel of experts weighted the references. EVIDENCE SYNTHESIS: There is a lack of data in the current literature to provide strong recommendations due to the rarity of the disease. A number of recent multicentre studies are now available, whereas earlier publications were based only on limited populations. However, most of these studies have been retrospective analyses. The TNM classification 2009 is recommended. Recommendations are given for diagnosis as well as for radical and conservative treatment; prognostic factors are also discussed. Recommendations are provided for patient follow-up after different therapeutic options. CONCLUSIONS: These guidelines contain information for the diagnosis and treatment of individual patients according to a current standardised approach. When determining the optimal treatment regimen, physicians must take into account each individual patient's specific clinical characteristics with regard to renal function including medical comorbidities; tumour location, grade and stage; and molecular marker status. PMID- 21269757 TI - Treatment options for patients with stage I nonseminomatous testis cancer: it's all good. PMID- 21269759 TI - Anterior communicating artery aneurysm associated with an infraoptic course of anterior cerebral artery and rare variant of the persistent trigeminal artery: a case report and literature review. AB - Infraoptic course of the precommunicating segment of the anterior cerebral artery (A1) is a rare anomaly. Furthermore, the presence of this anomaly associated with persistent trigeminal artery variant has been reported in the literature only once. We present a patient who had infraoptic course of A1 associated with an ipsilateral persistent trigeminal artery variant arising from the right internal carotid artery with no apparent connection to the basilar artery. The persistent trigeminal artery variant supplied to the right posteroinferior cerebellar artery territory. The patient also had hypoplastic left vertebral artery, superior cerebellar arteries originating from posterior cerebellar arteries bilaterally, and a bilobed aneurysm of the anterior communicating artery. The aneurysm was clipped and the infraoptic course was verified during the surgery. The post operative course was uneventful and a follow-up arteriogram on the 7th postoperative day revealed successful obliteration of the aneurysm. We reviewed the literature with respect to presentation, associated vascular anomalies, imaging, associated cerebral aneurysms and other cerebral abnormalities, and treatment of the associated aneurysms. A discussion of the embryogenesis of this rare anomaly is also provided. PMID- 21269758 TI - Anoikis disruption of focal adhesion-Akt signaling impairs renal cell carcinoma. AB - BACKGROUND: Quinazoline-based alpha1-adrenoceptor antagonists suppress tumor growth by inducing apoptosis via an alpha1-adrenoceptor-independent action. Anoikis is a unique mode of apoptosis consequential to insufficient cell-matrix interactions. OBJECTIVE: This study investigated the apoptotic effect of novel quinazoline-based compounds on human renal cancer cells. DESIGN, SETTING, AND PARTICIPANTS: Two cell lines were used: renal cell carcinoma (RCC) 786-0, harboring a von Hippel-Lindau (VHL) tumor-suppressor gene mutation with a highly angiogenic phenotype, and Caki cells (no VHL mutation). MEASUREMENTS: The lead compound DZ-50 (10 MUM) led to significant inhibition of tumor-cell adhesion, migration, and invasion at a lower dose than doxazosin (25 MUM) in both RCC lines. RESULTS AND LIMITATIONS: Doxazosin induced death-receptor-mediated apoptosis, while DZ-50 led to anoikis via targeting of the focal adhesion complex and AKT signaling that subsequently increased RCC susceptibility to caspase-8 mediated apoptosis. Both quinazoline compounds, doxazosin and DZ-50, significantly reduced RCC metastatic potential in vivo. CONCLUSIONS: Quinazoline based drugs trigger anoikis in RCC by targeting the focal adhesion survival signaling. This potent antitumor action against human RCC suggests a novel quinazoline-based therapy targeting renal cancer. PMID- 21269760 TI - Paroxysmal radiculopathy associated to raised CSF pressure in a patient with spinal meningeal cysts. PMID- 21269761 TI - Injection of interferon-beta in the morning decreases flu-like syndrome in many patients with multiple sclerosis. AB - BACKGROUND: Although it is recommended that interferon-beta (IFNbeta) injections be administered in the evening, it is possible that morning injections could more effectively decrease interleukin 6 secretion. METHODS: This study evaluated the effects of switching from an evening injection of IFNbeta to a morning injection on the intensity of flu-like syndrome in patients with multiple sclerosis (MS). We performed an intervention study that consisted of a quantitative evaluation of IFNbeta-related flu-like syndrome in a cohort of 105 MS patients. Patients with persistent flu-like reactions who injected IFNbeta in the evening were encouraged to switch to morning injections. After one month, we evaluated various quantitative and qualitative changes (e.g., severity of flu-like syndrome, sleep quality, antipyretic drug use). RESULTS: Of the 98 patients (93%) who injected IFNbeta in the evening, 88 (85%) had a persistent flu-like syndrome (the severity score was 3.92+/-0.26). A total of 50 (57%) patients switched to morning injections. One month after changing the injection time, 29 patients (58%) reported that their flu-like syndrome was decreased, 11 (24%) thought that it was unchanged and 9 (18%) thought that it was increased (p=0.014). In addition, 23 patients (48%) reported improved sleep (p=0.001), and 33 (68%) patients chose to continue morning injections, whereas 17 (32%) patients switched back to evening injections (p=0.024). Quantitative measures, however, indicated that there was no change in the severity of flu-like syndrome or the number of antipyretic doses taken for its management. CONCLUSION: Morning injections qualitatively improved IFNbeta-related flu-like syndrome and sleep. A change in IFNbeta injection time from evening to morning could benefit a significant proportion of patients with MS. PMID- 21269762 TI - Targeting apoptosis pathways in glioblastoma. AB - The treatment of glioblastoma remains a major challenge for clinicians since these highly aggressive brain tumors are relatively resistant towards radio- and chemotherapy. The pathways that control apoptosis are altered in glioblastoma cells leading to resistance towards apoptotic stimuli in general. In this review we describe the alterations affecting the p53 pathway, the BCL-2 protein family, the inhibitor of apoptosis proteins and several growth factor pathways involved in the regulation of programmed cell death and define possible targets for new therapies within these apoptotic pathways in glioblastomas. Moreover, we review strategies to target death receptor pathways, most notably to render the glioblastoma cells more susceptible towards this approach without enhancing toxicity in general. Most of the strategies targeting apoptosis in glioblastomas presented here are in a pre-clinical stage of development, however, they all share the ultimative goal to improve the outcome for glioblastoma patients. PMID- 21269763 TI - Phytoremediation for co-contaminated soils of benzo[a]pyrene (B[a]P) and heavy metals using ornamental plant Tagetes patula. AB - Pot-culture experiments were conducted to investigate the single effect of benzo[a]pyrene (B[a]P) and the joint effect of metal-B[a]P on the growth of Tagetes patula and its uptake, accumulation and dissipation of heavy metals and B[a]P. Results showed that the low concentration of B[a]P (<=10 mg kg(-1)) could facilitate plant growth and resulted in an increase in biomass at the rate of 10.0-49.7% relative to the control. There were significantly positive correlations between the concentrations of B[a]P accumulated in tissues of the plants and soil B[a]P (P<0.001). However, the occurrence of Cd, Cu and Pb had inhibitive effects on plant growth and B[a]P uptake and accumulation on the whole. T. patula still exhibited a steady feature of Cd-hyperaccumulator under combined contaminated soils. By contrast, the effectiveness of Cu and Pb absorption in the plants was very weak. Plant-promoted biodegradation of B[a]P was the dominant contribution, 79.2-92.4% and 78.2-92.9% of dissipation of B[a]P came from plant-biodegradation under single B[a]P and metal-B[a]P contaminated soils, respectively. Therefore, T. patula might be useful for phytoremediation of B[a]P and B[a]P-Cd contaminated sites. PMID- 21269764 TI - A new nano-TiO2 immobilized biodegradable polymer with self-cleaning properties. AB - This study concentrated on the direct immobilization of anatase nano titanium dioxide particles (TiO(2), 10nm particle size) into or onto a biodegradable polymer, polycaprolactone, by solvent-cast processes. The self-cleaning, namely photocatalytic properties of the produced materials were tested by photocatalytic removal of methylene blue as model compound and antimicrobial properties were investigated using Candida albicans as model microorganism. Produced TiO(2) immobilized polymer successfully removed methylene blue (MB, 1 * 10(-5)M) from aqueous solution without additional pH arrangement employing a UV-A light (365 nm) source. Almost 83.2% of dye was removed or decomposed by 5 wt% TiO(2) immobilized into PCL (0.08 g) and removal percentage reached to 94.2% with 5 wt% TiO(2) immobilized onto PCL after a 150 min exposure period. Although removal percentage decrease with increased ionic strength and usage of a visible light source, produced materials were still effective. TiO(2) immobilized onto PCL (5 wt%) was quite effective killing almost 54% of C. albicans (2 * 10(6)CFU/mL) after only 60 min exposure with a near visible light source. Control experiments employing PCL alone in the presence and absence of light were ineffective under the same condition. PMID- 21269765 TI - Long-term field and laboratory leaching tests of cemented radioactive wastes. AB - Experiments with real and simulated radioactive cementitious wasteforms were set up to compare the leaching behaviour of cementitious wasteforms containing nuclear power plant operational waste in field and laboratory test conditions. Experiments revealed that the average annual (137)Cs leach rate in deionised water was about thirty-five times greater compared with the measured average value for the 1st year of the field test. Cumulative leached fraction of (137)Cs for 1st year (3.74%) was close to values reported in literature for similar laboratory experiments in deionised water, however more than two orders of magnitude higher than the 1st year leached fraction of (137)Cs in the repository test (0.01%). Therefore, to compare field and laboratory test results, a scaling factor is required in order to account for surface to volume factor difference, multiplied by a temperature factor and a leach rate decrease coefficient related to the ground water composition. PMID- 21269766 TI - Laser-induced efficient reduction of Cr(VI) catalyzed by ZnO nanoparticles. AB - The present study demonstrates the complete removal of Cr(VI) in aqueous suspensions of zinc oxide nanoparticles using a novel laser-induced photocatalytic process without the use of any additive. The study showed that ~95% Cr(VI) was removed within short time (60 min) of laser exposure in the presence of ZnO. However, the removal of chromium using conventional setup under identical conditions was found to be negligible. Effect of critical parameters, such as laser energy, catalyst concentration, chromium concentration, and added electron donor and acceptor on the photocatalytic reduction process was also investigated. The data regarding temporal behavior of metal removal was fitted to first-order kinetic and reaction rate was computed. PMID- 21269767 TI - Removal of water-soluble acid dyes from water environment using a novel magnetic molecularly imprinted polymer. AB - Novel magnetic and hydrophilic molecularly imprinted polymers (mag-MIPs) were prepared by an inverse emulsion-suspension polymerization to remove water-soluble acid dyes from contaminated water with 1-(alpha-methyl acrylate)-3 methylimidazolium bromide (1-MA-3MI-Br) being utilized as a new functional monomer. The thermal stability, chemical structure and magnetic property of the 1 MA-3MI-Br-mag-MIPs were characterized by the thermal-gravimetric analyzer (TGA), Fourier transform infrared spectrometer (FT-IR) and vibrating sample magnetometer (VSM), respectively. Moreover, effect of concentration and pH value of water soluble acid dye solutions was optimized. Compared with the methyl acrylic acid and 4-vinylpyridine modified mag-MIPs, the 1-MA-3MI-Br-mag-MIPs showed enhanced removal efficiency. Kinetic studies depicted that the adsorption process on 1-MA 3MI-Br-mag-MIPs followed pseudo-second-order rate mechanism. Investigation results of 5 times removal-regeneration cycles by employing the 1-MA-3MI-Br-mag MIPs showed that the resulting material was with high stability. PMID- 21269768 TI - Removal of patulin from aqueous solutions by propylthiol functionalized SBA-15. AB - Propylthiol functionalized SBA-15 silica was investigated to detoxify aqueous solutions contaminated with the regulated mycotoxin patulin. Micelle templated silicas with a specific pore size were synthetically modified to possess propylthiol groups, a functional group known to form Michael reaction products with the conjugated double bond system of patulin. BET surface area analysis indicated the propylthiol functionalized SBA-15 possesses channels with the pore size of 5.4 nm and a surface area of 345 m(2)g(-1). Elemental analysis indicates the silicon/sulfur ratio to be 10:1, inferring one propylthiol substituent for every ten silica residues. The propylthiol modified SBA-15 was effective at significantly reducing high levels of patulin from aqueous solutions (pH 7.0) in batch sorption assays at room temperature. The material was less effective at lower pH; however heating low pH solutions and apple juice to 60 degrees C in the presence of propylthiol functionalized SBA-15 significantly reduced the levels of patulin in contaminated samples. Composite molecular models developed by semi-empirical PM3 and empirical force field methods support patulin permeation through the mesoporous channels of propylthiol functionalized SBA-15. Density functional study at the B3LYP/6-31G(d,p) level predicts the proposed patulin adducts formed by reaction with the thiol residues exhibit less electrophilic properties than patulin. It is demonstrated the use of propylthiol functionalized SBA-15 is a viable approach to reduce patulin levels in aqueous solutions, including contaminated apple juice. PMID- 21269769 TI - Catalytic wet peroxide oxidation of azo dye (Direct Blue 15) using solvothermally synthesized copper hydroxide nitrate as catalyst. AB - Copper hydroxide nitrate (Cu(2)(OH)(3)NO(3)) was synthesized solvothermally in anhydrous ethanol and characterized by XRD, FTIR, TG-DTA and SEM. The peroxide degradation of an azo dye (Direct Blue 15) on this material was evaluated by examining catalyst loading, initial pH, hydrogen peroxide dosage, initial dye concentration and temperature. The leaching of Cu from the copper hydroxide nitrate during the reaction was also measured. The copper hydroxide nitrate synthesized solvothermally, which was of a novel spherical morphology with complex secondary structures and contained high-dispersed Cu(2)O impurity, showed good performance for oxidation degradation of the azo dye, especially high catalytic activity, high utilization of hydrogen peroxide and a wide pH range, whereas the copper hydroxide nitrate synthesized by the direct reaction of copper nitrate and sodium hydroxide showed low catalytic activity. PMID- 21269770 TI - Silver nanoparticles embedded polymer sorbent for preconcentration of uranium from bio-aggressive aqueous media. AB - Adsorptive sorbent for bio-aggressive natural aqueous media like seawater was developed by one pot simultaneous synthesis of silver nanoparticles (Ag nps) and poly(ethylene glycol methacrylate phosphate) (PEGMP) by UV-initiator induced photo-polymerization. The photo-polymerization was carried out by irradiating N,N'-dimethylformamide (DMF) solution containing appropriate amounts of the functional monomer (ethylene glycol methacrylate phosphate), UV initiator (alpha,alpha'-dimethoxy-alpha-phenyl acetophenone), and Ag(+) ions with 365 nm UV light in a multilamps photoreactor. To increase mechanical strength, nano composite sorbent (Ag@PEGMP) was also reinforced with thermally bonded non-woven poly(propylene) fibrous sheet. Transmission electron microscopy (TEM) of the nano composite sorbent showed uniform distribution of spherical Ag nanoparticles with particles size ranging from 3 to 6 nm. The maximum amount of Ag(0) that could be anchored in the form of nanoparticles were 5+/-1 and 10+/-1 wt.% in self supported PEGMP and poly(propylene) reinforced PEGMP matrices, respectively. Ag@PEGMP sorbent was found to be stable under ambient conditions for a period of six months. Ag@PEGMP composite sorbent did not exhibit growth at all after incubation with pre-grown Escherichia coli cells, and showed non-adherence of this bacteria to the composite. This indicated that composite sorbent has the bio resistivity due to bacterial repulsion and bactericidal properties of Ag nanoparticles embedded in the PEGMP. Sorption of U(VI) in PEGMP and Ag@PEGMP nano composite sorbents from well-stirred seawater was studied to explore the possibility of using it for uranium preconcentration from bio-aggressive aqueous streams. The nano-composite sorbent was used to preconcentrate U(VI) from a process aqueous waste stream. PMID- 21269771 TI - Effect of laser power and specimen temperature on atom probe analyses of magnesium alloys. AB - The influence of laser power, wave length, and specimen temperature on laser assisted atom probe analyses for Mg alloys was investigated. Higher laser power and lower specimen temperature led to improved mass and spatial resolutions. Background noise and mass resolutions were degraded with lower laser power and higher specimen temperature. By adjusting the conditions for laser assisted atom probe analyses, atom probe results with atomic layer resolutions were obtained from all the Mg alloys so far investigated. Laser assisted atom probe investigations revealed detailed chemical information on Guinier-Preston zones in Mg alloys. PMID- 21269772 TI - Protostrongylid infection in meat sheep from Northwestern Spain: prevalence and risk factors. AB - 2093 Faecal samples from 74 commercial meat ovine flocks were collected and examined by the Baermann-Wetzel method for protostrongylid infection. The risk of being infected by lungworms was evaluated with a data mining classification tree (CHAID), and the intensity of infection with a general linear model (GLM). 242 out of 2093 faecal samples examined were positive for protostrongylid infection (11.6%; 95% CI 10.2-12.9). Only two species were found, Muellerius capillaris (97.9%) and Neostrongylus linearis (5.4%). 50 out of 74 farms presented at least one animal shedding protostrongylid larvae in faeces. All of them held animals infected by M. capillaris and seven presented mixed infections with N. linearis. Average larval output in infected sheep was 11.9 (SD 30.91). This study showed that protostrongylid prevalence in sheep for meat production was determined mainly by a positive interaction with Dictyocaulus filaria infection; other factors that have influenced over protostrongylid infection were age, introducing external animals in the flocks, mixed management with goats and animal density in pastures. Treatment effects on prevalence were only observed in flocks that did not introduce ewes. The lowest protostrongylid prevalence has been reported in flocks without D. filaria infection and without contact with goats. PMID- 21269773 TI - Validation of ethnoveterinary medicinal treatments. PMID- 21269774 TI - Gastrointestinal parasites presence during the peripartum decreases total milk production in grazing dairy Holstein cows. AB - Parasitism in cattle is known to impair growth and development. Recent findings suggest that productivity of adult animals is also affected, but little is known about the physiological mechanisms involved. Furthermore, development of nematode resistance to drugs makes imperative the search of management practices that avoid whole herd treatment. We undertook an epidemiological and endocrine study in a grass based dairy farm in Argentina to study the effect of parasites on milk production and the underlying mechanisms involved, and identify individual animals that would benefit from antiparasitic treatment. All the cows in the dairy were followed monthly for egg parasite output in feces. Samples were cultured for genera determination. Milk production and reproductive results were recorded and periodical bleedings for hormone determination were performed. Nematode egg output (EPG) was maximal in late Summer and Autumn and minimal in Spring in coincidence with the Ostertagia inhibition-disinhibition cycle as this genus had the highest prevalence in all the study. The highest proportion of positive samples was found in the high producing herd and maximal counts were found in the peripartal period. Milk production did not correlate with EPG mean values but, when cows were grouped by EPG positivity around parturition, a significant difference in total milk production between EPG null and positive cows was observed. Positive cows produced 7%, 12% or 15% less milk than null EPG cows, depending on the sampling month/s chosen for classification. The highest difference was seen when both prepartum and postpartum samples were taken into account. No difference in lactation length and a marginal effect on partum to first service interval were encountered. Endocrine studies revealed a decrease in serum growth hormone (GH), type I insulin-like growth factor (IGF-I) and prolactin during lactation in cows with positive EPG in the first postpartum sample with respect to null EPG cows at that time. GH levels decreased and prolactin and IGF-I levels increased in both groups of cows from month 0 to 6 in milk. Serum insulin levels remained stable throughout lactation and were similar in both groups of cows. In conclusion, EPG around parturition may be a useful tool for identifying cows that will have a decrease in productivity due to parasite effects and would possibly benefit from an antiparasitic treatment. Besides, our results suggest that detrimental effect of parasites on milk production may be mediated by GH, IGF-I and prolactin serum levels. PMID- 21269775 TI - The first report on natural Enterocytozoon bieneusi and Encephalitozoon spp. infections in wild East-European House Mice (Mus musculus musculus) and West European House Mice (M. m. domesticus) in a hybrid zone across the Czech Republic Germany border. AB - To determine the occurrence of potentially human pathogenic microsporidia (Enterocytozoon bieneusi and Encephalitozoon spp.) in wild mice, we examined 289 East-European House Mice (Mus musculus musculus) and West-European House Mice (M. m. domesticus) trapped at 74 localities in an area across the Czech-German border. Microsporidia were detected at 33 localities, in 34% of M. m. musculus and 33% of M. m. domesticus examined specimens. Single-species infection was detected in 23 mice for E. hellem, 42 mice for E. cuniculi and 25 mice for E. bieneusi. No Encephalitozoon intestinalis positive animals were identified. Moreover, co-infections were detected in 6 animals; E. bieneusi co-existed with E. cuniculi or E. hellem in 3 mice. The natural infection of E. hellem has never been recorded in mice before. No differences were found by a statistical analysis of microsporidia occurrence between the House Mouse subspecies. Although the gender-dependent infestation of microsporidia was statistically supported in M. m. musculus, no significant differences were observed when the occurrence of microsporidia was estimated for all males and females irrespective of the House Mouse subspecies. The results of this report document the low host specificity of detected microsporidia species and imply the importance of synanthropic rodents as a potential source of human microsporidial infection. PMID- 21269776 TI - Lichtenberg figures associated with a high-voltage industrial burn. PMID- 21269778 TI - Evaluation of amniotic fluid as a skin graft storage media compared with RPMI and saline. AB - We aimed to assess and compare the histological changes of grafts stored in Roswell Park Memorial Institute-1640 solution (RPMI), amniotic fluid (AF), and saline. Amniotic fluid which has abundant nutrients, proteins, and growth factors, and antimicrobial features may be an easily achievable and cheap alternative for the short term preservation of skin grafts. Discarded surgical skin pieces obtained from 15 trauma patients were divided into three groups as RPMI, AF, and saline. The specimens were evaluated at days 7, 14, 21, and 28 for histological alterations by a 3-point scoring scale. Histological scores in the grafts stored in amniotic fluid and RPMI were found significantly lower than those stored in saline (p<0.01). No significant difference was detected between AF and RPMI stored grafts. AF may be a good alternative for skin graft preservation as demonstrated by histological changes. New studies with multiple AF donators and repeated experiments will be worthwhile. Besides, restrictions of some ethical and legal issues for AF use should be solved. PMID- 21269780 TI - In search of the biological basis of mood disorders: exploring out of the mainstream. PMID- 21269779 TI - Hydrocortisone suppression of the fear-potentiated startle response and posttraumatic stress disorder. AB - This study examined the effects of oral administration of 20mg hydrocortisone on baseline and fear-potentiated startle in 63 male veterans with or without PTSD. The procedure was based on a two-session, within-subject design in which acoustic startle eyeblink responses were recorded during intervals of threat or no threat of electric shock. Results showed that the magnitude of the difference between startle responses recorded during anticipation of imminent shock compared to "safe" periods was reduced after hydrocortisone administration relative to placebo. This effect did not vary as a function of PTSD group nor were there were any significant group differences in other indices startle amplitude. Findings suggest that the acute elevations in systemic cortisol produced by hydrocortisone administration may have fear-inhibiting effects. This finding may have implications for understanding the role of hypothalamic-pituitary-adrenal (HPA) axis function in vulnerability and resilience to traumatic stress. PMID- 21269781 TI - The effects of modified atmosphere gas composition on microbiological criteria, color and oxidation values of minced beef meat. AB - This paper reports the effects of modified atmosphere gas compositions with different concentrations of CO(2)/O(2)/N(2) on color properties (L*, a* and b* values), oxidation stability (TBARS value) and microbiological properties of minced beef meat stored at +4 degrees C. Sampling was carried out on the 1st, 3rd, 5th, 7th, 9th, 11th and 14th day of storage. The gas mixtures used were as follows: (i) %30O(2) + %70CO(2) (MAP1), (ii) %50O(2) + %50CO(2) (MAP2), (iii) %70O(2) + %30CO(2) (MAP3), (iv) %50O(2) + %30CO(2) + %20N(2) (MAP4), and (v) %30O(2) + %30CO(2) + %40N(2) (MAP5). Control samples (AP) were packaged under atmospheric air. Pseudomonas, lactic acid bacteria, Brochothrix thermosphacta, and Enterobacteriaceae members were monitored. Among these five modified atmosphere gas compositions, the best preservation for minced beef meat was in MAP4 gas combination maintaining acceptable color together with oxidation stability and acceptable microbial loads until the end of storage period of fourteen days. PMID- 21269782 TI - [Sperm immobilizing effect of leaves extracts of Cestrum parqui]. AB - OBJECTIVE: The leaves extracts of Cestrum parqui were reported to have spermicidal activity. The current investigation identified the spermicidal component of the extracts and evaluated its spermicidal potential in vitro, particularly the effects on sperm motility and vitality. METHODS: Sperms were prepared by discontinuous buoyant density gradient centrifugation and incubated with varying concentrations of extract from C. parqui (40-250 MUg/ml) at 37 degrees C and 5% CO(2). The mode of spermicidal action was evaluated by sperm motility and vitality at different intervals ranging from 5 to 240 minutes. Morphological changes in human spermatozoa after exposure to the extract were evaluated under transmission electron microscope. RESULTS: A dose- and time dependent effect of this extract on sperm motility and viability was observed. The mean effective concentration of extracts that induced irreversible immobilization was 250 MUg/ml. Transmission electron microscope revealed a significant damage to sperm membrane in head and acrosomal membranes, notable swelling and disruption. CONCLUSION: Our study indicates that this natural extract has potential spermicidal effect in vitro. It can adequately replace nonoxynol-9 in vaginal contraceptives to make them more vaginally safe and ecofriendly. PMID- 21269783 TI - 3,4-Methylenedioxymethamphetamine (MDMA) alters acute gammaherpesvirus burden and limits interleukin 27 responses in a mouse model of viral infection. AB - AIMS: To test whether 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") abuse might increase the susceptibility, or alter the immune response, to murine gammaherpesvirus 68 (HV-68) and/or bacterial lipopolysaccharide. METHODS: Groups of experimental and control mice were subjected to three day binges of MDMA, and the effect of this drug abuse on acute and latent HV-68 viral burden were assessed. In vitro and in vivo studies were also performed to assess the MDMA effect on IL-27 expression in virally infected or LPS-exposed macrophages and dendritic cells, and latently infected animals, exposed to this drug of abuse. RESULTS: Acute viral burden was significantly increased in MDMA-treated mice when compared to controls. However the latent viral burden, and physiological and behavioral responses were not altered in infected mice despite repeated bingeing with MDMA. MDMA could limit the IL-27 response of HV-68 infected or LPS-exposed macrophages and dendritic cells in vitro and in vivo, demonstrating the ability of this drug to alter normal cytokine responses in the context of a viral infection and/or a TLR4 agonist. CONCLUSION: MDMA bingeing could alter the host's immune response resulting in greater acute viral replication and reductions in the production of the cytokine, IL-27 during immune responses. PMID- 21269784 TI - Molecular characterization of Mycobacterium avium subsp. paratuberculosis using multi-locus short sequence repeat (MLSSR) and mycobacterial interspersed repetitive units-variable number tandem repeat (MIRU-VNTR) typing methods. AB - The aim of this study was to characterize 38 bovine strains of Mycobacterium avium subsp. paratuberculosis isolated in Ireland using 11 multi locus short sequence repeat (MLSSR) loci and 8 mycobacterial interspersed repetitive units variable number of tandem repeat (MIRU-VNTR) loci. The discriminatory power of these two typing methods alone and combined was evaluated, as was the epidemiology of the isolates and the genotypes obtained. Using the MIRU-VNTR typing method (8 loci analysed), only 3 subtypes were detected with a discrimination index (DI) of 0.54, but one MIRU-VNTR type has not been identified in other studies. In contrast the MLSSR method (using 11 loci) differentiated the 38 MAP isolates into 18 types with DI of 0.92. Among these 18 types 6 have not been recorded previously. The combination of the 2 methods (MIRU-VNTR and MLSSR) produced 22 distinct genotypes giving a maximal DI of 0.94. According to the allelic diversity, some markers are more polymorphic than others and must be applied in priority for the differentiation of MAP bovine isolates. This is the first report of genotyping data for MAP on the island of Ireland and will be very useful for analysing its epidemiology, transmission and virulence. PMID- 21269785 TI - Drug policy in Europe Research and funding in neonates: current challenges, future perspectives, new opportunities. AB - The availability of drugs for neonates is limited as evaluation is said more difficult in neonates than in older patients and adults, resulting in off-label drug use. Indeed, diseases may be specific to the neonatal period, the impact of immaturity and rapid developmental changes in the first days/weeks of life is important, and drugs may have short and long-term effects including developmental toxicity. To improve such situation, both the US and the EU have introduce paediatric legislation and the EMA has issued guidelines to optimize drug evaluation in paediatric populations including neonates. In addition, the following collaborative projects were funded by the EU in the co-operative programme of FP7. As preterm and term neonates are prone to infections which result in increase morbidity and mortality, the TINN (Treat Infections in Neonates) and TINN2 projects aim to evaluate off-patent anti-infectious drugs included in the EMEA priority list, ciprofloxacin/fluconazole and azithromycin respectively in the two projects. The final aim is to obtain a Paediatric Use Marketing Authorization for these drugs in neonates. In addition, TINN will build up a network of units with experience in evaluating anti-infective agents in neonates. An additional important initiative called GRIP (Global Research in Paediatrics) will focus on paediatric clinical pharmacology training and will facilitate the development and safe use of medicine in children. PMID- 21269786 TI - Formula milk and neurodevelopmental and cognitive outcomes: where are we now? AB - The hypothesis that nutrition during critical windows in fetal and early life can program long-term health is intriguing and has a potentially strong implication for public health and pediatric nutritional practice. Specifically, it has been hypothesized that there are critical periods in the differentiation and maturation of the central nervous system during which environmental and nutritional factors can produce long-term structural and/or functional changes. Many studies have focused on the relationship between nutrition during early life and long-term neurodevelopmental outcome, leading to contrasting results: in fact, although experimental data in animals and short-term follow-up studies indicate a possible relationship between nutrition during early life and neurodevelopment, the results of long-term follow-up studies are more controversial and less convincing. PMID- 21269787 TI - Death by complete decapitation of motorcyclist wearing full face helmet: case report. AB - We describe a case of complete decapitation following a motorcycle accident in which the victim was wearing a full face helmet. A young man lost control of his motorcycle and was thrown about 20 m, hitting his head against the barrier separating a tramline from the road. The resulting trauma caused his decapitation, the only fatal wound ascertained by the various forensic investigations. The authors present this rare case and compare it against the other two cases reported in the literature, providing some observations on the ways in which this injury can come about. The absence of abrasions or signs that the wound edges came into contact with a metal structure, the presence of signs of impact on the side of the helmet and the finding of a transversal fracture at the base of the skull point to the violent action of a side-to-side opposite force, due to the resistance provided by the lower edge of the protective helmet. PMID- 21269788 TI - Role of ultrasonography in patients with cytologically follicular thyroid tumor. AB - OBJECTIVE: The purpose of this study is to evaluate the role of ultrasonography (US) in the management of thyroid nodules when the cytology is indeterminate as follicular tumor on fine needle aspiration biopsy (FNAB). METHODS: In 2006, 6586 patients with thyroid nodules, which were detected on US underwent FNAB in our department. Of these patients, we extracted 438 patients (6.7%) whose nodules were cytologically diagnosed as indeterminate. Of them, 227 patients were diagnosed as follicular tumor were enrolled in this study. Surgery was performed according to our criteria for surgical indication. We compared the results of clinical findings including US classification and final histopathological diagnosis. RESULTS: One hundred thirty-seven of 227 underwent surgical treatment. Thirty-three (24%) were diagnosed as malignancy pathologically. Large nodule or high serum thyroglobulin level were not associated with an increased risk of malignancy. Ultrasonographic evaluation as malignancy was directly linked to pathological diagnosis as thyroid carcinoma (p<0.0001). CONCLUSION: US plays a crucial role in deciding whether surgical treatment is necessary for cytologically indeterminate thyroid nodules as follicular tumor. PMID- 21269789 TI - Effective electrophoretic mobilities and charges of anti-VEGF proteins determined by capillary zone electrophoresis. AB - Macromolecules such as therapeutic proteins currently serve an important role in the treatment of eye diseases such as wet age-related macular degeneration and diabetic retinopathy. Particularly, bevacizumab and ranibizumab have been shown to be effective in the treatment of these diseases. Iontophoresis can be employed to enhance ocular delivery of these macromolecules, but the lack of information on the properties of these macromolecules has hindered its development. The objectives of the present study were to determine the effective electrophoretic mobilities and charges of bevacizumab, ranibizumab, and model compound polystyrene sulfonate (PSS) using capillary zone electrophoresis. Salicylate, lidocaine, and bovine serum albumin (BSA), which have known electrophoretic mobilities in the literature, were also studied to validate the present technique. The hydrodynamic radii and diffusion coefficients of BSA, bevacizumab, ranibizumab, and PSS were measured by dynamic light scattering. The effective charges were calculated using the Einstein relation between diffusion coefficient and electrophoretic mobility and the Henry equation. The results show that bevacizumab and ranibizumab have low electrophoretic mobilities and are net negatively charged in phosphate buffered saline (PBS) of pH 7.4 and 0.16M ionic strength. PSS has high negative charge but the electrophoretic mobility in PBS is lower than that expected from the polymer structure. The present study demonstrated that capillary electrophoresis could be used to characterize the mobility and charge properties of drug candidates in the development of iontophoretic drug delivery. PMID- 21269790 TI - Operation care: a pilot case management intervention for frequent emergency medical system users. AB - OBJECTIVES: This study aims to determine if a prehospital case management intervention reduces transport and nontransport emergency medical system (EMS) responses to frequent EMS users. METHODS: The 25 most frequent EMS users in a major metropolitan area were identified, and 10 were enrolled in the intervention. These patients received linkage to psychosocial and medical resources through weekly case management visits for 5 to 12 weeks between May and August 2008. Main outcome measures were the number of transport and nontransport EMS responses to patients during the intervention as compared with predicted EMS responses based on each patient's previous year's EMS use. Transport data were available for all patients, but nontransport data were unavailable for 1 patient who was homeless and 6 patients living in apartment buildings. Secondary outcome measures included cost savings to the entire health care system and the Baltimore City Fire Department. RESULTS: Transport responses decreased 32% over the 76 predicted transport responses during the intervention, and nontransport responses decreased 79% over the 24 predicted nontransport responses during the intervention. Including the dedicated case manager's salary, this represented a cost savings to the entire health care system and to the Baltimore City Fire Department of $14 461 and $6311, respectively, over 12 weeks. CONCLUSIONS: Prehospital case management may reduce EMS use in high-frequency EMS users and create significant cost savings to municipalities and the health care system. Additional large-scale studies are needed to validate these findings. PMID- 21269791 TI - Diagnosing cervical spine instability: role of the post-computed tomography scan out-of-collar lateral radiograph. AB - BACKGROUND: Cervical spine injuries may have devastating neurological consequences, which makes accurate diagnosis of injury a key part of the trauma evaluation. Imaging plays a significant role in making the diagnosis and guiding management. Current American College of Radiology Appropriateness Criteria guidelines recommend computed tomography (CT) of the cervical spine with multi planar reformats as the highest-rated imaging examination for patients meeting clinical criteria, without subsequent need for further imaging with a negative scan in a neurologically intact and non-obtunded patient. Although CT is fast and accurate for evaluation of bony injury, it may overlook ligamentous injury. OBJECTIVE AND CASE REPORT: We report a case in which ligamentous instability was demonstrated as subluxation with an out-of-collar lateral radiograph after a CT scan showed no subluxation or fracture in a patient without neurological deficits. Our Radiology Department routinely performs an out-of-collar lateral radiograph after a negative CT scan, and this case suggests that there may be an important role for this practice. CONCLUSION: Magnetic resonance is the optimal study for soft tissue and ligamentous evaluation; however, a simple lateral out of-collar radiograph after CT clearance, in an otherwise neurologically intact and non-obtunded patient, may be a quick and cost-effective means to assess for instability of the cervical spine. PMID- 21269792 TI - Initiating palliative care in the emergency department. AB - BACKGROUND: In 2006, nearly a quarter of a million patients either arrived dead or died in the Emergency Department (ED). The role of palliative care (PC) in the ED is not well defined, and education of medical students and residents in the area is sparse. OBJECTIVES: We use an illustrative case to discuss important concepts in PC for the emergency physician (EP). The reader should be able to define hospice and PC, recognize its importance in the practice of Emergency Medicine, and understand the benefits PC has for the patient, the patient's family and caregivers, and the health care system as a whole. DISCUSSION: PC excels at treating pain and addressing end-of-life issues. Families and caregivers of patients benefit from PC in terms of improved personal quality of life after the patient's death. PC is more cost-effective than traditional medical care. CONCLUSION: Research on PC in the ED is sparse but it is a growing need, and the EP will need to become proficient in the delivery of PC in the ED. PMID- 21269793 TI - Informed choice on Pap smear still limited by lack of knowledge on the meaning of false-positive or false-negative test results. AB - OBJECTIVE: Screening for cervical cancer may have favourable or unfavourable effects at the individual level. This study assesses whether invitees in The Netherlands made an informed choice about screen uptake. METHODS: Attached to the invitation letter and the information leaflet, screen invitees were sent a questionnaire. An informed decision was defined as based on decision-relevant knowledge, while the woman's attitude was consistent with her actual screening behaviour. RESULTS: Of all cervical screen participants, 60% (924/1551) responded to the questionnaire. Decision-relevant knowledge was sufficient in 595 women. Especially knowledge about false-positive and false-negative test results was limited. The attitude towards cervical screening was mainly positive (99%). Requirements for informed decision making were met in 571 (68%) women and in 91% when an alternative cut-off point of sufficient decision-relevant knowledge was applied. Most frequently reported main reasons to attend were early detection of abnormalities (67%) and reassurance in case of a normal smear (22%). CONCLUSION: Insufficient decision-relevant knowledge was the main cause of uninformed attendance. PRACTICE IMPLICATION: Adequate strategies to provide invitees with sufficient decision-relevant information are still needed, especially regarding false-positive and false-negative test results. PMID- 21269794 TI - How much does trust really matter? A study of the longitudinal effects of trust and decision-making preferences on diabetic patient outcomes. AB - OBJECTIVE: To examine the impact of trust on patient outcomes (satisfaction, HbA(1C), physical and mental health-related quality of life (HRQoL)) and to investigate the role of decision-making preferences in the trust-outcome relationship. METHODS: We conducted a one-year longitudinal analysis of 614 type 2 diabetic patients (mean age: 59.3 years; mean disease duration: 6.7 years). Patients' self-administered questionnaires and medical record were used for the research. Multiple regression analyses were conducted to investigate the relationship among variables during a 12-month follow-up. Further, we used latent growth modeling (LGM) to assess changes in health outcomes and to examine how these changes were related to trust. RESULTS: Regression analyses revealed that trust was positively related to glycemic control, physical HRQoL, and satisfaction at 12 months. Patients with higher decision-making preferences experienced a greater increase in subsequent satisfaction. The results of LGM showed that higher levels of trust were associated with greater increases in physical HRQoL. CONCLUSION: Trust contributes to improvements in health outcomes. The relationship between trust and satisfaction may be stronger among patients with higher decision-making preferences. PRACTICE IMPLICATIONS: For healthcare providers, efforts should be made to cultivate patients' trust and enhance their decision-making preferences to maximize satisfaction and improve outcomes. PMID- 21269795 TI - Positron emission tomography (PET) for assessment of axillary lymph node status in early breast cancer: A systematic review and meta-analysis. AB - PURPOSE: Sentinel lymph node biopsy (SLNB) and axillary lymph node dissection (ALND) are used to assess axillary nodal status in breast cancer, but are invasive procedures associated with morbidity, including lymphoedema. This systematic review evaluates the diagnostic accuracy of positron emission tomography (PET), with or without computed tomography (CT), for assessment of axillary nodes in early breast cancer. METHODS: Eleven databases including MEDLINE, EMBASE and the Cochrane Library, plus research registers and conference proceedings, were searched in April 2009. Study quality was assessed using the QUality Assessment of Diagnostic Accuracy Studies (QUADAS) checklist. Sensitivity and specificity were meta-analysed using a bivariate random effects approach. RESULTS: Across 26 studies evaluating PET or PET/CT (n = 2591 patients), mean sensitivity was 63% (95% CI: 52-74%; range 20-100%) and mean specificity 94% (95% CI: 91-96%; range 75-100%). Across 7 studies of PET/CT (n = 862), mean sensitivity was 56% (95% CI: 44-67%) and mean specificity 96% (90-99%). Across 19 studies of PET-only (n = 1729), mean sensitivity was 66% (50-79%) and mean specificity 93% (89-96%). Mean sensitivity was 11% (5-22%) for micrometastases (<=2 mm; five studies; n = 63), and 57% (47-66%) for macrometastases (>2 mm; four studies; n = 111). CONCLUSIONS: PET had lower sensitivity and specificity than SLNB. Therefore, replacing SLNB with PET would avoid the adverse effects of SLNB, but lead to more false negative patients at risk of recurrence and more false positive patients undergoing unnecessary ALND. The present evidence does not support the routine use of PET or PET-CT for the assessment of the clinically negative axilla. PMID- 21269796 TI - [Acute surgical abdomen revealing a Churg-Strauss syndrome]. PMID- 21269797 TI - [French version of screening questionnaire for high-functioning autism or Asperger syndrome in adolescent: Autism Spectrum Quotient, Empathy Quotient and Systemizing Quotient. Protocol and questionnaire translation]. AB - AIM: No tools are currently available in France, for the detection of autism without mental retardation (high functioning autism and Asperger syndrome here referred as TED SDI). Use of screening tests by first-line clinicians would allow better detection of children who are likely to display such difficulties and to improve patients' care. In England, 3 questionnaires have been evaluated: Autism Spectrum Quotient (AQ), Empathy Quotient (EQ), and Systemizing Quotient (SQ). This is the translation and evaluation of 3 questionnaires in France for TED SDI and control adolescents. METHODS: The translation of the questionnaires into French required two simultaneous translations, two back-translations and two consensus meetings. This is a cross-sectional study comparing scores obtained with the three AQ, EQ and SQ questionnaires. These questionnaires were completed by the parents of four groups of adolescents 11-18 years: 100 TED SDI adolescents (50 with IQ >= 85 and 50 with 70<=IQ<85), 50 adolescents with another psychiatric disorder (TP) and 200 control adolescents (T). RESULTS: 580 questionnaires have been sent to 40 recruiting centres. By the 28th of February, 2010, 277 completed questionnaires were received completed (TED SDI: 70 (70%); TP: 25 (50%) et T: 182 (91%)). In the control group, 92 girls (mean 14.4+/-1.7 years) and 66 boys (14.5+/-1.7 years) were recruited. In the TED SDI group, 4 girls (14.3+/-2.4 years) and 42 boys (14.5+/-1.7 years) were recruited. One girl (81) and 6 boys (72.2+/-7.7) have an IQ between 70 and 85, and 3 girls (95.3+/-4.2) and 36 boys (102.9+/-12) have an IQ higher than 85. In the TP group, 9 girls (15.9+/-1.7 years) and 4 boys (15.8+/-1.9 years) were recruited. CONCLUSION: The aim of this study is to make the AQ, EQ and SQ questionnaires available in French for French speaking clinicians. This study will allow a rigorous evaluation of the usefulness of the AQ questionnaire in the screening of TED SDI in adolescents. PMID- 21269798 TI - Is there a legitimate role for the therapeutic use of cannabinoids for symptom management in chronic kidney disease? AB - Chronic pain is a common and debilitating symptom experienced in the context of numerous other physical and emotional symptoms by many patients with chronic kidney disease (CKD). Management of pain with opioids in CKD can be problematic given the prominence of adverse effects of opioids in CKD, which may exacerbate symptoms, such as nausea, anorexia, pruritus, and insomnia, all of which impact negatively on patients' health-related quality of life. Novel therapeutic approaches for pain and symptom management in CKD are required. Recent research in the area of cannabinoids (CBs) is legitimizing the use of cannabis-based medicine. In this review, we describe the symptom burden borne by patients with CKD and review some of the key basic science and clinical literature to evaluate the potential use of CBs for the management of overall symptom burden in CKD. PMID- 21269799 TI - Recurrent aortoduodenal fistula. AB - Aortoenteric fistula is defined as a communication between the aorta and an adjacent loop of the bowel and is often the cause of devastating upper gastrointestinal tract bleeding with only few survivors. According to the etiology, the aortoenteric fistulas are classified as primary aortoenteric fistula or secondary aortoenteric fistula (SAEF) after previous aortic surgery. The recurrence of a fistula on a previous SAEF is defined as recurrent aortoenteric fistula and is reported only in a few rare cases occurring within an unpredictable period from the previous surgical treatment. We describe a unique case of recurrent aortoenteric fistula, in which the relationship with recurrence consisted of the presence of the metallic clips of a stapled suture to close the duodenal wall during the previous SAEF repair. A review of the published data on this subject was performed to analyze the clinical features, the overall results, the risk factors of recurrence, and the main technical points of surgical treatment to prevent it. PMID- 21269800 TI - Hybrid aortoiliac revascularization to avoid nonautogenous groin reconstruction in an intravenous drug abuser. AB - Traditional methods for revascularization of an occluded aortoiliac system have necessitated either in-line aortic reconstruction through an aortobifemoral bypass or extra-anatomic bypass. However, both these approaches require artificial material to be placed in the groin. The consequence of groin infection can be devastating leading to high rates of both limb loss and mortality. One of the most feared patient populations presenting with groin complications is that of the intravenous drug abuser. We present the case of a patient with a long history of intravenous drug abuse with severe aortoiliac disease. Instead of resorting to a more traditional open surgical approach necessitating artificial reconstruction in the groin, we chose to proceed with a hybrid open and endovascular procedure through a direct open surgical access to the aortic bifurcation. This allowed for revascularization without the placement of artificial material in the groin. PMID- 21269801 TI - Primary aortoenteric fistulae: the challenges in diagnosis and review of treatment. AB - Primary aortoenteric fistula (PAEF) is a potentially fatal condition which poses a considerable diagnostic challenge because of its infrequency and the nonspecific presentation. We report the case of a 61-year old woman who presented to her general practitioner with nonspecific and intermittent rectal bleeding, hematemesis, and weight loss. Four days later, she presented to the emergency department with worsening symptoms. The investigations revealed a new small 3.8 cm abdominal aortic aneurysm on computed axial tomography (CT), however, no evidence of a fistula was observed either on CT scan or endoscopy. Two days later, she became unstable requiring an emergency laparotomy and was taken to the operation theater for an en bloc resection of a segment of the aorta and duodenum with exclusion of the duodenum with an inline reconstruction of the aorta using a Dacron graft for a PAEF. The published data were reviewed to address the issues of optimal diagnostic methods and management of PAEF. PMID- 21269802 TI - Retrospective analysis of bovine pericardium (Vascu-Guard) for patch closure in carotid endarterectomies. AB - BACKGROUND: It has been shown that patch closure after carotid endarterectomy (CEA) decreases the rate of recurrent stenosis. This study was designed to evaluate the utility of bovine pericardium patch as an option for patch closure after CEA. METHODS: This retrospective study examined 845 CEAs with bovine patch closure that were performed by the surgeons of Indiana-Ohio Heart, Fort Wayne, IN, between May 2003 and March 2009. The average age of the patients was 72.7 +/- 10.6 years and postoperative follow-up was performed using duplex ultrasound at (ideally) 1 month, 6 months, 12 months, and annually thereafter. The average duration of follow-up for this study was 19.2 +/- 16.8 months (ranging from 1 day to 72 months). All patients were evaluated for demographics and postoperative medications. Restenosis was categorized in three ways: nonsignificant (0-59% narrowing of the artery), significant (60-79%), or critical (80-99%). A total of 796 arteries were studied at least once during the postoperative period. RESULTS: None of the postoperative duplex studies revealed occlusion of the endarterectomized artery. At the mean follow-up duration, 323 endarterectomized arteries were studied. In all, 24 arteries (7.43%) had significant stenosis and only two (0.62%) had critical stenosis. These numbers compare favorably with the recurrent restenosis rates of other materials. Additionally, the effect of statins on restenosis rates was studied. We were unable to demonstrate a beneficial effect of postoperative statin therapy on restenosis rates. CONCLUSION: The use of bovine pericardium for patch closure in CEA yields excellent freedom from residual or recurrent postoperative stenosis and the use of statins postoperatively failed to reduce the likelihood of residual or recurrent stenosis. PMID- 21269803 TI - Impairments in speech and nonspeech sound categorization in children with dyslexia are driven by temporal processing difficulties. AB - Auditory processing problems in persons with dyslexia are still subject to debate, and one central issue concerns the specific nature of the deficit. In particular, it is questioned whether the deficit is specific to speech and/or specific to temporal processing. To resolve this issue, a categorical perception identification task was administered in thirteen 11-year old dyslexic readers and 25 matched normal readers using 4 sound continua: (1) a speech contrast exploiting temporal cues (/bA/-/dA/), (2) a speech contrast defined by nontemporal spectral cues (/u/-/y/), (3) a nonspeech temporal contrast (spectrally rotated/bA/-/da/), and (4) a nonspeech nontemporal contrast (spectrally rotated/u/-/y/). Results indicate that children with dyslexia are less consistent in classifying speech and nonspeech sounds on the basis of rapidly changing (i.e., temporal) information whereas they are unimpaired in steady-state speech and nonspeech sounds. The deficit is thus restricted to categorizing sounds on the basis of temporal cues and is independent of the speech status of the stimuli. The finding of a temporal-specific but not speech specific deficit in children with dyslexia is in line with findings obtained in adults using the same paradigm (Vandermosten et al., 2010, Proceedings of the National Academy of Sciences of the United States of America, 107: 10389-10394). Comparison of the child and adult data indicates that the consistency of categorization considerably improves between late childhood and adulthood, particularly for the continua with temporal cues. Dyslexic and normal readers show a similar developmental progress with the dyslexic readers lagging behind both in late childhood and in adulthood. PMID- 21269804 TI - The more you remember the more you decide: collaborative memory in adolescents with intellectual disability and their assistants. AB - The aim of the present study was to investigate collaborative memory in adolescents with intellectual disabilities when collaborating with an assistant, and also the extent to which decisiveness is related to individual memory performance. Nineteen students with intellectual disabilities (mean age=18.5, SD=0.9) each collaborated with a teaching assistant (mean age 40.3, SD=12.1) familiar from everyday work in school. Pictures were presented individually. Recognition was performed in two parts, first individually and thereafter collaboratively. The design involved 2 settings, one natural (with equal encoding time) and another with equal individual memory performance (assistants had shorter encoding time than the students). Results showed collaborative inhibition in this previously uninvestigated collaboration setting with adolescents with intellectual disabilities and their assistants. The assistants both performed higher and decided more than the students with intellectual disabilities in the natural setting, but not in the equated performance setting. Inhibition was larger in the equated setting. The assistants' decisiveness was moderately correlated with individual memory performance. Implications for everyday life are discussed. PMID- 21269805 TI - Handwriting development in grade 2 and grade 3 primary school children with normal, at risk, or dysgraphic characteristics. AB - The wide variation in prevalence of dysgraphic handwriting (5-33%) is of clinical importance, because poor handwriting has been identified as one of the most common reasons for referring school-age children to occupational therapy or physiotherapy, and is included as an criterion for the diagnosis of Developmental Coordination Disorder. This study aimed to map the development and improvement in handwriting during the early grades to differentiate between temporary and consistent dysgraphic handwriting. In this longitudinal and cross-sectional study, children in grade 2 (age 7-8 years, n=169) and grade 3 (8-9 years, n=70) took handwriting (Concise Assessment Method for Children's Handwriting; acronym BHK) and visuomotor integration (BeeryVMI) screening tests twice within one school year. Dysgraphia decreased strongly from 37% to 17% in grade 2 and diminished further to a low and stable rate of 6% in grade 3. Stability in handwriting quality only occurred in the children whose scores were within the normal range. The at risk and dysgraphic children continued to show significant and substantial improvement during grades 2 and 3. BeeryVMI was inappropriate as a screening instrument for handwriting problems. It was concluded that handwriting must be consistently dysgraphic before making any decisions about a diagnosis of dysgraphia or referral for therapy. PMID- 21269806 TI - Cooperation and competition between lateral and medial perforant path synapses in the dentate gyrus. AB - It has been suggested that non-spatial and spatial pieces of information are transmitted to the dentate gyrus from entorhinal cortex layer II through the lateral and medial perforant paths (LPP and MPP), which establish synapses on granule cell dendrites in the outer and middle one-thirds of the dentate molecular layer, respectively. In the present paper, we first investigated cooperation and competition between MPP and LPP synapses being subject to STDP rules, using a four-compartmental granule cell model. MPP and LPP were stimulated simultaneously by periodic and random pulse trains, respectively. Both synapses were gradually enhanced by cooperation between those synapses in the early stage, and then either the MPP or the LPP synapse was rapidly enhanced through synaptic competition in the following stage, depending on their initial synaptic conductances. The dominant cause of synaptic competition is that the distance between the MPP synapse and the soma is shorter than that between the LPP synapse and the soma. These results suggest that the LPP and MPP synapses tend to be enhanced in the dentate supra- and infrapyramidal blades, respectively, taking account of the thickness of each of the LPP and MPP fiber laminae in the blades. The dentate gyrus may select spatial and non-spatial pieces of information through synaptic cooperation, and may open a gate for each piece of information through synaptic competition. Then we investigated the role of inhibitory local circuits in synaptic competition in the dentate gyrus. The feed-forward GABA(B) inhibition suppressed unusual high-frequency firing of the granule cell, and consequently prevented excessive synaptic depression due to synaptic competition through STDP. The feed-forward and feedback GABA(A) inhibitions tend to reduce synaptic conductance fluctuations resulting from large increments and decrements due to very small spike-timings happening occasionally. PMID- 21269807 TI - Ensemble based system for whole-slide prostate cancer probability mapping using color texture features. AB - We present a tile-based approach for producing clinically relevant probability maps of prostatic carcinoma in histological sections from radical prostatectomy. Our methodology incorporates ensemble learning for feature selection and classification on expert-annotated images. Random forest feature selection performed over varying training sets provides a subset of generalized CIEL*a*b* co-occurrence texture features, while sample selection strategies with minimal constraints reduce training data requirements to achieve reliable results. Ensembles of classifiers are built using expert-annotated tiles from training images, and scores for the probability of cancer presence are calculated from the responses of each classifier in the ensemble. Spatial filtering of tile-based texture features prior to classification results in increased heat-map coherence as well as AUC values of 95% using ensembles of either random forests or support vector machines. Our approach is designed for adaptation to different imaging modalities, image features, and histological decision domains. PMID- 21269808 TI - Prognostic significance of immunohistochemical biomarkers in oral squamous cell carcinoma. AB - Advances in understanding of the molecular mechanisms underlying oral squamous cell carcinoma (OSCC) have resulted in an increasing number of biomarkers that can be used to predict the behaviour of this disease. The authors conducted a literature review of studies examining the role of immunohistochemistry-based protein biomarkers in predicting OSCC outcome. Only articles published in PubMed indexed journals over the past 5 years were considered. 22 molecular biomarkers were identified and classified into five groups based on their biological functions: cell cycle acceleration and proliferation; tumour suppression and apoptosis; hypoxia; angiogenesis; and cell adhesion and matrix degradation. The cell cycle acceleration and proliferation biomarkers showed the most divergent prognostic findings. Studies on tumour suppression and apoptosis biomarkers were the most prevalent. There were only a few studies examining molecular biomarkers of hypoxia and angiogenesis, and studies examining cell adhesion and matrix degradation biomarkers have shown that this group has the greatest potential for assessing prognostic parameters. Amongst the several proteins analysed, the immunohistochemical expression levels of epithelial growth factor receptor (EGFR), p53, and matrix metalloproteinases (MMPs) have demonstrated the greatest potential for survival prediction in OSCC, but this review demonstrates that their prognostic relevance is debatable and requires further standardisation. PMID- 21269809 TI - Differences in vancomycin minimum inhibitory concentrations for Staphylococcus aureus obtained with the automated PhoenixTM system, the Clinical and Laboratory Standards Institute broth microdilution method and the standard Etest. PMID- 21269810 TI - Cockroaches and locusts: physicians' answer to infectious diseases. PMID- 21269811 TI - In vitro susceptibilities of clinical isolates of ertapenem-non-susceptible Enterobacteriaceae to nemonoxacin, tigecycline, fosfomycin and other antimicrobial agents. PMID- 21269812 TI - (Don't) panic in the scanner! How panic patients with agoraphobia experience a functional magnetic resonance imaging session. AB - Although functional magnetic resonance imaging (fMRI) has gained increasing importance in investigating neural substrates of anxiety disorders, less is known about the stress eliciting properties of the scanner environment itself. The aim of the study was to investigate feasibility, self-reported distress and anxiety management strategies during an fMRI experiment in a comprehensive sample of patients with panic disorder and agoraphobia (PD/AG). Within the national research network PANIC-NET, n=89 patients and n=90 controls participated in a multicenter fMRI study. Subjects completed a retrospective questionnaire on self reported distress, including a habituation profile and exploratory questions about helpful strategies. Drop-out rates and fMRI quality parameters were employed as markers of study feasibility. Different anxiety measures were used to identify patients particularly vulnerable to increased scanner anxiety and impaired data quality. Three (3.5%) patients terminated the session prematurely. While drop-out rates were comparable for patients and controls, data quality was moderately impaired in patients. Distress was significantly elevated in patients compared to controls; claustrophobic anxiety was furthermore associated with pronounced distress and lower fMRI data quality in patients. Patients reported helpful strategies, including motivational factors and cognitive coping strategies. The feasibility of large-scale fMRI studies on PD/AG patients could be proved. Study designs should nevertheless acknowledge that the MRI setting may enhance stress reactions. Future studies are needed to investigate the relationship between self-reported distress and fMRI data in patient groups that are subject to neuroimaging research. PMID- 21269813 TI - [Neonatal seizures, buprenorphine abstinence syndrome, and substitutive treatment with morphine]. AB - We report the case of a hypotrophic twin who presented neonatal abstinence syndrome to buprenorphine and developed neonatal seizures when the substitutive treatment by morphine was stopped. The other eutrophic twin did not develop withdrawal symptoms. This case demonstrates the unpredictable nature of transplacental transfer of buprenorphine. It also shows that neonatal abstinence syndrome can be potentially severe and that morphine treatment is not without risk. PMID- 21269814 TI - [Hemolytic and uremic syndrome and maternal-fetal Escherichia coli K1 infection]. AB - Hemolytic uremic syndrome (HUS) is primarily a disease of infancy and early childhood. In its classic form, it is preceded by a prodrome of Escherichia coli mediated bloody mucoid diarrhea. Typical HUS is commonly related to an infection by shiga-toxin producing E. coli. Stool cultures may detect this bacteria or its toxin, and PCRs can detect the shiga-toxin virulence genes. Atypical cases of HUS are mainly related to abnormalities of the alternative complement pathway and mutations of H, I, or B factors. Some atypical cases of HUS may also be related to von Willebrand factor or vitamin B12 metabolism abnormalities. A number of HUS cases related to invasive pneumococcal infections (pneumonia or meningitis) have been reported. We report a case of HUS associated with a bacterial E. coli K1 infection in a newborn baby, with a good clinical outcome: there was no need for dialysis and normal renal function was quickly regained. The workup did not favor a toxinic origin or an abnormality on the alternative complement pathway. PMID- 21269815 TI - [Traumatic lacerations: wound closure]. AB - The suture, when possible, is the best method to close a simple wound. It must be preceded by debridement and performed with great care. A rigorous technique applied in the best possible environment is necessary but not always sufficient to achieve a good cosmetic result. PMID- 21269816 TI - [Maternal-fetal chikungunya infection associated with Bernard-Soulier syndrome]. AB - Neonatal thrombocytopenia may stem from several origins. A newborn was hospitalized on the 3rd day of life with thrombocytopenia likely due to maternofetal autoimmune thrombocytopenia. Two days later, he displayed a chikungunya virus infection, during a severe epidemic on Reunion Island. The characterization of human platelet antigen (HPA) in the parents showed incompatibility in the HPA-3 system; however, no detectable antiHPA-3a antibody was found in the mother's serum. The persistence of moderate thrombocytopenia led to the diagnosis, using flow cytometry, of Bernard-Soulier syndrome (BSS), with no detectable GPIbIX. This case shows that neonatal inherited thrombocytopenia may be difficult to characterize, especially when it is associated with an acquired cause. PMID- 21269817 TI - [Are mydriatic eyedrops dangerous for pre-term infants?]. AB - The funduscopic examination is essential in neonatology to screen for retinopathy in the pre-term infant. Mydriatic eyedrops, which are used for this examination, are known to induce digestive side effects. We present a case of necrotizing enterocolitis developing in a pre-term infant as a complication of mydriatics. This infant was a girl born at 28 weeks gestation and 5 days, with Down's syndrome, who died on the 44th day of life, due to necrotizing enterocolitis, after instillation of 1 drop of atropine 0.3% in each eye. The chronology of events, the application method, and the clinical symptoms of atropine impregnation argue in favor of a causal relationship between atropine and necrotizing enterocolitis. The review of the literature made on the basis of this observation shows that side effects of mydriatic eyedrops are frequent in pre term infants and raise the question of atropine hypersensitivity in pre-term infants with Down's syndrome. PMID- 21269818 TI - Development, repeatability and validity regarding energy and macronutrient intake of a semi-quantitative food frequency questionnaire: methodological considerations. AB - BACKGROUND AND AIM: The aim of this work was to evaluate the repeatability and the validity of a food frequency questionnaire (FFQ), and to discuss the methodological framework of such procedures. METHODS AND RESULTS: The semi quantitative FFQ included 69 questions regarding the frequency of consumption of all main food groups and beverages usually consumed and 7 questions regarding eating behaviors. Five hundred individuals (37 +/- 15 yrs, 38% males) were recruited for the repeatability process, while another 432 (46 +/- 16 yrs, 40% males) also completed 3-Day Diaries (3DD) for the validation process. The repeatability of the FFQ was adequate for all food items tested (Kendall's tau-b: 0.26-0.67, p < 0.05), energy and macronutrients intake (energy adjusted correlation coefficients ranged between 0.56-0.69, p < 0.05). Moderate validity of the FFQ was observed for "dairy products", "fruit", "alcohol" and "stimulants" (tau-b: 0.31-0.60, p < 0.05), whereas low agreement was shown for "starchy products", "legumes", "vegetables", "meat", "fish", "sweets", "eggs", "fats and oils" (tau-b < 0.30, p < 0.05). The FFQ was also valid regarding energy and macronutrients intake. Sensitivity analyses by sex and BMI category (< or >=25 kg/m(2)) showed similar validity of the FFQ for all food groups (apart from "fats and oils" intake), as well as energy and nutrient intake. CONCLUSION: The proposed FFQ has proven repeatable and relatively valid for foods' intake, and could therefore be used for nutritional assessment purposes. PMID- 21269819 TI - Immune defence against EBV and EBV-associated disease. AB - Epstein-Barr virus (EBV), a B-lymphotropic herpesvirus widespread in the human population and normally contained as an asymptomatic infection by T cell surveillance, nevertheless causes infectious mononucleosis and is strongly linked to several types of human cancer. Here we describe new findings on the range of cellular immune responses induced by EBV infection, on viral strategies to evade those responses and on the links between HLA gene loci and EBV-induced disease. The success of adoptive T cell therapy for EBV-driven post-transplant lymphoproliferative disease is stimulating efforts to target other EBV-associated tumours by immunotherapeutic means, and has reawakened interest in the ultimate intervention strategy, a prophylactic EBV vaccine. PMID- 21269820 TI - Highly sensitive single polyaniline nanowire biosensor for the detection of immunoglobulin G and myoglobin. AB - A single polyaniline (PANI) nanowire-based biosensor was established to detect immunoglobulin G (IgG) and myoglobin (Myo), which is one of the cardiac biomarkers. The single PANI nanowires were fabricated via an electrochemical growth method, in which single nanowires were formed between a pair of patterned electrodes. The single PANI nanowires were functionalized with monoclonal antibodies (mAbs) of IgG or Myo via a surface immobilization method, using 1 ethyl-3-(3-dimethyaminopropyl) carbodiimide (EDC), and N-hydroxysuccinimde (NHS). The functionalization was then verified by Raman spectroscopy and fluorescence microscopy. The target proteins of IgG and Myo were detected by measuring the conductance change of functionalized single PANI nanowires owing to the capturing of target proteins by mAbs. The detection limit was found to be 3 ng/mL for IgG and 1.4 ng/mL for Myo. No response was observed when single nanowires were exposed to a non-specific protein, demonstrating excellent specificity to expected target detection. Together with the fast response time (a few seconds), high sensitivity, and good specificity, this single PANI nanowire-based biosensor shows great promise in the detection of cardiac markers and other proteins. PMID- 21269821 TI - The glutathione transferase inhibitor 6-(7-nitro-2,1,3-benzoxadiazol-4 ylthio)hexanol (NBDHEX) increases temozolomide efficacy against malignant melanoma. AB - First line treatment of metastatic melanoma includes the methylating agent dacarbazine or its analogue temozolomide (TMZ) with improved pharmacokinetics and tolerability. However, the prognosis of the metastatic disease is poor and several trials are evaluating TMZ in polychemotherapy protocols. The novel glutathione transferase P1-1 (GSTP1-1) inhibitor 6-(7-nitro-2,1,3-benzoxadiazol-4 ylthio)hexanol (NBDHEX) has recently shown activity against melanoma through c Jun N-terminal kinase activation. In this study we have investigated the in vitro and in vivo efficacy of NBDHEX and TMZ combination against melanoma. The results indicated that NBDHEX and TMZ exerted in vitro synergistic anti-proliferative effects in murine B16 and human A375 melanoma cells. In B16 cells TMZ as single agent caused cell accumulation at the G(2)/M phase of cell cycle, whereas NBDHEX induced mainly apoptotic effects. NBDHEX provoked a higher level of p53 phosphorylation with respect to TMZ and the drug combination caused a more than additive increase of p53 activation. The in vivo efficacy of NBDHEX and TMZ has been investigated in an orthotopic B16 model. Treatment with NBDHEX provoked a reduction of tumour growth comparable to that obtained with TMZ, whereas the drug combination significantly increased tumour growth inhibition with respect to the single agents, without worsening TMZ myelotoxicity. Immunohistochemical analysis of tumour grafts revealed a profound reduction of Cyclin D1 and CD31 in all treatment groups; VEGF expression was, instead, markedly decreased only in NBDHEX or NBDHEX and TMZ treated samples. These findings indicate that NBDHEX represents a good candidate for combination therapies including TMZ, offering new perspectives for the treatment of melanoma. PMID- 21269822 TI - Docetaxel and irinotecan as second-line therapy for advanced oesophagogastric cancer. AB - INTRODUCTION: Systemic chemotherapy improves survival in oesophagogastric cancer however no standard second-line regimen exists due to a paucity of randomised data. Docetaxel combined with irinotecan (DI) provides a suitable option due to the lack of cross-reactivity with first-line therapeutics and a tolerable toxicity profile. METHODS: We retrospectively reviewed a cohort of patients with advanced oesophagogastric cancer in two institutions treated with the combination of docetaxel 35 mg/m(2) plus irinotecan 60 mg/m(2) day 1 and day 8 every 21 days, following progression with first-line platinum-based therapy. RESULTS: Between January 2000 and September 2009, 41 eligible patients were identified. Median age was 58 years, male:female 25:16, adenocarcinoma:squamous cell carcinoma 37:4, oesophageal:oesophagogastric junction:gastric 7:10:24. Locally advanced:metastatic disease 6:35. Previous radical surgery:radiotherapy:both 6:4:7. 27/41 had progressed within 90 days of receiving platinum-based therapy. Median number of chemotherapy cycles: 3 (range 1-12). Eight patients required dose reductions due to DI toxicity. 10/28 evaluable patients had a response, median progression-free survival (PFS) was 11 weeks (95% confidence intervals (CI): 9-13 weeks) with median overall survival 24 weeks (95%CI: 12-35 weeks). No significant prognostic factors were identified. CONCLUSION: Weekly docetaxel combined with irinotecan has acceptable safety and modest efficacy in the second line treatment of advanced oesophagogastric cancer. Further prospective evaluation of this regimen is warranted. PMID- 21269823 TI - Performance of a membrane bioreactor used for the treatment of wastewater contaminated with heavy metals. AB - In this work the performance of a Membrane bioreactor (MBR) was assessed for the removal of 3-15 mg/l of copper, lead, nickel and zinc from wastewater. The average removal efficiencies accomplished by the MBR system were 80% for Cu(II), 98% for Pb(II), 50% for Ni(II) and 77% for Zn(II). The addition of 5 g/l vermiculite into the biological reactor enhanced metal removal to 88% for copper, 85% for zinc and 60% for nickel due to adsorption of metal ions on the mineral, while it reduced biomass inhibition and increased biomass growth. The metal ions remaining in soluble form penetrated into the permeate, while those attached to sludge flocs were effectively retained by the ultrafiltration membranes. The average heterotrophic biomass inhibition was 50%, while it reduced to 29% when lower metal concentrations were fed into the reactor in the presence of vermiculite. The respective autotrophic biomass inhibition was 70% and 36%. The presence of heavy metals and vermiculite in the mixed liquor adversely impacted on membrane fouling. PMID- 21269824 TI - Optimization of a novel class of benzimidazole-based farnesoid X receptor (FXR) agonists to improve physicochemical and ADME properties. AB - Structure-guided lead optimization of recently described benzimidazolyl acetamides addressed the key liabilities of the previous lead compound 1. These efforts culminated in the discovery of 4-{(S)-2-[2-(4-chloro-phenyl)-5,6-difluoro benzoimidazol-1-yl]-2-cyclohexyl-acetylamino}-3-fluoro-benzoic acid 7g, a highly potent and selective FXR agonist with excellent physicochemical and ADME properties and potent lipid lowering activity after oral administration to LDL receptor deficient mice. PMID- 21269825 TI - Diamide amino-imidazoles: a novel series of gamma-secretase inhibitors for the treatment of Alzheimer's disease. AB - The synthesis and structure-activity relationship (SAR) of a novel series of di substituted imidazoles, derived from modification of DAPT, are described. Subsequent optimization led to identification of a highly potent series of inhibitors that contain a beta-amine in the imidazole side-chain resulting in a robust in vivo reduction of plasma and brain Abeta in guinea pigs. The therapeutic index between Abeta reductions and changes in B-cell populations were studied for compound 10 h. PMID- 21269826 TI - Quinazolines with intra-molecular hydrogen bonding scaffold (iMHBS) as PI3K/mTOR dual inhibitors. AB - Intra-molecular hydrogen bonding was introduced to the quinazoline motif to form a pseudo ring (intra-molecular H-bond scaffold, iMHBS) to mimic our previous published core structures, pyrido[2.3-D]pyrimidin-7-one and pteridinone, as PI3K/mTOR dual inhibitors. This design results in potent PI3K/mTOR dual inhibitors and the purposed intra-molecular hydrogen bonding structure is well supported by co-crystal structure in PI3Kgamma enzyme. In addition, a novel synthetic route was developed for these analogs. PMID- 21269827 TI - Design, synthesis, and in vivo characterization of a novel series of tetralin amino imidazoles as gamma-secretase inhibitors: discovery of PF-3084014. AB - A novel series of tetralin containing amino imidazoles, derived from modification of the corresponding phenyl acetic acid derivatives is described. Replacement of the amide led to identification of a potent series of tetralin-amino imidazoles with robust central efficacy. The reduction of brain Abeta in guinea pigs in the absence of changes in B-cells suggested a potential therapeutic index with respect to APP processing compared with biomarkers of notch related toxicity. Optimization of the FTOC to plasma concentrations at the brain Abeta EC(50) lead to the identification of compound 14f (PF-3084014) which was selected for clinical development. PMID- 21269828 TI - Synthesis and evaluation of trehalose-based compounds as anti-invasive agents. AB - Brartemicin is a trehalose-based inhibitor of tumor cell invasion produced by the actinomycete of the genus Nonomuraea. In order to explore the preliminary structure-activity relationship and obtain more potent inhibitors, a series of brartemicin analogs were synthesized through the Mitsunobu coupling of the secondary hydroxyls benzyl protected alpha,alpha-D-trehalose with benzoic acid derivatives, followed by modification of functional groups and deprotection. These compounds were evaluated for their inhibitory activity against invasion of murine colon 26-L5 carcinoma cells in vitro. Among the synthetic analogs tested, 6,6'-bis(2,3-dimethoxybenzoyl)-alpha,alpha-D-trehalose (5e) was found to be the most potent anti-invasive agent, exhibited a 2.6-fold improvement with regard to the parent natural product brartemicin, and it is considered to be a promising lead molecule for the anti-metastasis. PMID- 21269829 TI - Identification of small molecular inhibitors for Ero1p by structure-based virtual screening. AB - Ero1p, using molecular oxygen as its preferred terminal electron acceptor, promotes disulfide bond formation by interaction with protein disulfide isomerase. Dysfunction of Ero1p leads to strong activation of the unfolded protein response and marked loss of cell viability. However, modest attenuation of Ero1p improves the fitness of yeast challenged with high levels of protein misfolding in their endoplasmic reticulum stress. Partial inhibition of Ero1p is hence of great significance. In the present paper, a docking-based virtual screening method was performed to identify inhibitors of Ero1p and 12 hits were successfully obtained from 81 purchased compounds with micromolar inhibition against Ero1p. Particularly, six of the hits demonstrated remarkable potency with IC(50)<30MUM and held the prospect of becoming lead compounds. Then the interaction modes were analyzed for further lead optimization. PMID- 21269830 TI - Gait patterns of patients with inclusion body myositis. AB - Inclusion body myositis (IBM) is a progressive, inflammatory muscle disease that is known to cause quadriceps weakness and knee buckling during gait. This is the first known report of gait characteristics in patients with IBM. Nine subjects with IBM and quadriceps weakness underwent gait analysis and quantitative strength testing. A wide range of strength and gait abilities were present in the subject group. Subjects with stronger knee extensors exhibited nearly normal sagittal knee kinematics and kinetics. As quadriceps strength decreased, kinematic and kinetic patterns were increasingly abnormal. Exceptions to this pattern could be explained by examining strength at adjacent joints. Gait analysis and strength testing is a helpful tool in evaluating the functional status of this population and aiding in determination of the needs for interventions such as assistive devices. PMID- 21269831 TI - Activation of transversus abdominis varies with postural demand in standing. AB - Transversus abdominis (TrA) is a multifunctional muscle, being involved in pressure regulation within the abdominal cavity and thereby in direction independent stabilization of the spine and resistance to imposed trunk flexion moments. Indirect evidence suggests a role of TrA also in postural control of the erect human trunk. The main purpose here was to investigate if the magnitude of TrA activation is related to postural demand. Eleven healthy males performed seven different symmetrical static bilateral arm positions holding 3 kg in each hand. The arm positions were selected to systematically vary the height of the centre of mass (COM) keeping imposed moments constant and vice versa. EMG was recorded bilaterally with fine-wire intramuscular electrodes from TrA and obliquus internus (OI) and with surface electrodes from rectus abdominis (RA) and erector spinae (ES). Intra-abdominal pressure (IAP) was measured via a pressure transducer in the gastric ventricle. TrA was the only muscle that displayed activation co-varying with the vertical position of the COM. Further, TrA activation increased, together with IAP and ES activation, with imposed flexion moment, i.e. with arms extended horizontally forward. In contrast to OI, RA and ES, TrA activation was independent of the direction of the imposed moment (arms held inclined forward or backward). In conclusion, TrA activation level is uniquely associated with increased postural demand caused by elevated COM. Also, TrA appears to assist in counteracting trunk flexion via increased IAP, and contribute to general spine stabilization when the trunk is exposed to moderate flexion and extension moments. PMID- 21269832 TI - Dynamic loading of the knee and hip joint and compensatory strategies in children and adolescents with varus malalignment. AB - Three-dimensional gait analysis is a diagnostic tool that can be used to gain a better understanding of the relationship between joint loading and the onset or progression of articular cartilage degeneration in subjects with varus malalignment. The purpose of the present study was to investigate knee and hip joint angles and moments in children and adolescents with pathological varus alignment of the knee without signs of knee osteoarthritis (OA). Moreover, we wanted to know if compensatory mechanisms are present in this young patient group. Fourteen, otherwise healthy patients with varus malalignment of the knee and 15 healthy control subjects were analysed. Patients showed a reduced knee extension and a significantly lower maximum knee extension moment in terminal stance compared to controls. The maximum knee adduction moment in mid and terminal stance and the maximum hip abduction moment in loading response were significantly higher in the patient group. In the transverse plane, abnormally increased knee internal rotation and hip external rotation moments were present in patients with varus malalignment. These findings imply that varus malalignment is not an isolated problem in the frontal plane. In contrast to adult patients with established medial knee OA, the young patients assessed in the present study did not show typical compensatory mechanisms such as increased foot progression angle or reduced walking speed. This suggests that children and adolescents with varus malalignment of the knee probably do not need to alter their spatio temporal gait parameters in order to decrease knee joint loading. PMID- 21269833 TI - Clarithromycin-induced neurotoxicity in adults. AB - Clarithromycin is a relatively new antibiotic of the macrolide family heralded for an improved side effect profile, dosing schedule, and microbiological activity relative to its parent compound, erythromycin. We review the literature on clarithromycin-induced neurotoxicity in adults and present an illustrative case. A total of 38 patients with clarithromycin-induced neurotoxicity have been reported. The average age of patients was 51.3 years (range: 19-87 years) with females comprising 52.6% of patients. Psychiatric illness was the most common comorbidity, while only two patients had renal failure. Clarithromycin had been prescribed for respiratory infections in most patients, and only two patients were receiving more than 1000 mg/day of antibiotic. The symptoms started 1 day to 10 days after starting clarithromycin (mean: 5 days). A total of 71% of patients were under treatment with concomitant medication, and eight patients were undergoing treatment with psychoactive drugs. Patients had a very good outcome after clarithromycin was discontinued, but medication with neuroleptics or benzodiazepine was required for 58% of patients in the acute phase. Only four patients underwent an electroencephalogram (EEG). Our illustrative patient was a 74-year-old woman with clarithromycin-induced delirium due to non-convulsive status epilepticus (NCSE). Her clinical symptoms and electroencephalogram (EEG) readings dramatically improved after discontinuation of clarithromycin. The mechanism underlying the central nervous system side effects remains unclear. We suggest including an EEG in the diagnostic procedures of patients under treatment with clarithromycin who develop features of neurotoxicity because an EEG can help to differentiate patients with psychiatric illness from those with encephalopathy or epilepsy. Because of the widespread use of clarithromycin, clinicians should be aware of its neurotoxicity. Early detection of clarithromycin-induced neurotoxicity and discontinuation of the drug may result in full recovery. PMID- 21269834 TI - Attributing functions to genes and gene products. AB - A major focus of modern biochemical, biophysical and cell biological research is the attribution of function to elements of structure: gene products, genes and higher-order cellular structures. Misunderstandings and controversies can arise in connection with such assignments, in part because of the logical complexity inherent in the relating of structure to function and the failure to distinguish clearly among the different senses in which function can be imputed to elements of structure. I explore distinct ways in which functions are connected to structures and factors that contribute to the context-dependence of such associations so that the multiple senses of function can be made explicit. PMID- 21269835 TI - Can single limb support objectively assess the functional severity of knee osteoarthritis? AB - There is a lack in objective measurements that can assess the symptoms of knee osteoarthritis (KOA). In a previous study it was shown that pain and function are in higher correlation with the single-limb support gait parameter than with radiographic KOA stage. Single limb support represents a phase in the gait cycle when the body weight is entirely supported by one limb, while the contra-lateral limb swings forward. The purpose of this study was to further examine the relationship between single-limb support and the level of pain and function in patients with KOA. 125 adults with bilateral KOA underwent a physical and radiographic evaluation, and completed the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the SF-36 health survey. Patients walked barefoot at a self-selected speed on a computerized mat. Statistical analysis was used to divide the patients into quintiles based on single-limb support phase value and determine the differences in WOMAC and SF-36 scores between quintiles. Significant differences were found in WOMAC and SF-36 sub category scores between the single-limb support quintiles. The means of the WOMAC pain and WOMAC-function sub-categories decreased gradually over single-limb support quintiles (P<0.001), and the means of the SF-36 sub-categories increased gradually over the quintiles (P<0.001). Results show that single-limb support quintiles can help determine the level of pain, function and quality of life in patients with KOA. These results suggest that single-limb support quintiles may be added as an additional scale for generally assessing the symptomatic stage of KOA. PMID- 21269836 TI - Indol-2-yl ethanones as novel indoleamine 2,3-dioxygenase (IDO) inhibitors. AB - Indoleamine 2,3-dioxygenase (IDO) is a heme dioxygenase which has been shown to be involved in the pathological immune escape of diseases such as cancer. The synthesis and structure-activity relationships (SAR) of a novel series of IDO inhibitors based on the indol-2-yl ethanone scaffold is described. In vitro and in vivo biological activities have been evaluated, leading to compounds with IC(50) values in the micromolar range in both tests. Introduction of small substituents in the 5- and 6-positions of the indole ring, indole N-methylation and variations of the aromatic side chain are all well tolerated. An iron coordinating group on the linker is a prerequisite for biological activity, thus corroborating the virtual screening results. PMID- 21269837 TI - Live broadcasting in cardiac surgery does not increase the operative risk. AB - OBJECTIVE: Live broadcasting of cardiac surgical procedures has an educational intention. There is an ongoing debate whether live surgery increases risk. Aim of this study was to evaluate the outcomes of patients who underwent a cardiac surgical procedure during live broadcasting. METHODS: A total of 250 cardiac operations were performed during 32 live broadcastings at four different clinical sites between 1999 and 2009. Data on patient characteristics, intra-operative procedures and patient short- and long-term outcome were collected and analyzed. All participating centers complied with the rules for the conduct of live surgery developed by the European Association of Cardiovascular and Thoracic Surgery (EACTS) Techno College Committee. RESULTS: Primary educational focus was the mitral valve in 126 cases, aortic valve including transcatheter valve implantations in 34, coronary artery bypass grafting (CABG) in 29, congenital in 26, aortic (ascending, arch, and descending) in 15, atrial fibrillation in 13, and heart failure in seven. Mean EuroSCORE (European System for Cardiac Operative Risk Evaluation) was 8.7 +/- 11.5 (range: 0.8-72). Thirty-day mortality was 1.2% (3/250): reasons for death were multi-organ failure in two and respiratory failure in one patient, respectively. Stroke rate was 2.4% (6/250). Five patients (2%) required cardiac re-operations within 30 days. The rate of mitral valve repair was 96% (121) and compares favourably with repair rates presented in national registries. Mean follow-up of all patients was 3.7 +/- 2.8 years with an estimated survival of 92% (95% confidence interval (CI): 87-95%) at 5 years. CONCLUSIONS: Based on this large experience there is no evidence for an excess perioperative risk for patients operated under the conditions of live broadcasting. PMID- 21269839 TI - Targeted antigen delivery and activation of dendritic cells in vivo: steps towards cost effective vaccines. AB - During the past decade, the immunotherapeutic potential of ex vivo generated professional antigen presenting dendritic cells (DCs) has been explored in the clinic. Albeit safe, clinical results have thus far been limited. A major disadvantage of current cell-based dendritic cell (DC) therapies, preventing universal implementation of this form of immunotherapy, is the requirement that vaccines need to be tailor made for each individual. Targeted delivery of antigens to DC surface receptors in vivo would circumvent this laborious and expensive ex vivo culturing steps involved with these cell-based therapies. In addition, the opportunity to target natural and often rare DC subsets in vivo might have advantages over loading more artificial ex vivo cultured DCs. Preclinical studies show targeting antigens to DCs effectively induces humoral responses, while cellular responses are induced provided a DC maturation or activation stimulus is co-administered. Here, we discuss strategies to target antigens to distinct DC subsets and to simultaneously employ adjuvants to activate these cells to induce immunity. PMID- 21269838 TI - mTOR couples cellular nutrient sensing to organismal metabolic homeostasis. AB - The mammalian target of rapamycin complex 1 (mTORC1) has the ability to sense a variety of essential nutrients and respond by altering cellular metabolic processes. Hence, this protein kinase complex is poised to influence adaptive changes to nutrient fluctuations toward the maintenance of whole-body metabolic homeostasis. Defects in mTORC1 regulation, arising from either physiological or genetic conditions, are believed to contribute to the metabolic dysfunction underlying a variety of human diseases, including type 2 diabetes. We are just now beginning to gain insights into the complex tissue-specific functions of mTORC1. In this review, we detail the current knowledge of the physiological functions of mTORC1 in controlling systemic metabolism, with a focus on advances obtained through genetic mouse models. PMID- 21269841 TI - Deficits in the ability to recognize one's own affects and those of others: associations with neurocognition, symptoms and sexual trauma among persons with schizophrenia spectrum disorders. AB - While many with schizophrenia experience deficits in metacognition it is unclear whether those deficits are related to other features of illness. To explore this issue, the current study classified participants with schizophrenia as possessing a deficit in both awareness of their own emotions and those of others (n=30), aware of their own emotions but unaware of the emotions of others (n=50) and aware of their own emotions and of other's emotions (n=17). Groups were compared on assessments of neurocognitive function, symptoms, and history of sexual trauma. ANCOVA controlling for education found that the group unaware of their own emotions and those of others demonstrated poorer verbal memory, processing speed, executive function, less emotional discomfort and higher levels of disorganization symptoms relative to the other groups. The group aware of their own emotions but not those of others had a significantly higher report of childhood sexual abuse. PMID- 21269840 TI - A case-control investigation of adenomyosis: impact of control group selection on risk factor strength. AB - OBJECTIVE: Using a medical record abstraction-based case-control study with two control groups, we evaluated adenomyosis risk factors and investigated differences related to comparison group selection. MATERIALS AND METHODS: Medical records of all female 18- to 49-year-old Group Health (GH) enrollees with ICD-9 code 617.0 were abstracted using a standard data collection form. Cases were enrollees diagnosed with adenomyosis (n = 174) between April 1996 and September 2001. For comparison, medical records of two control groups were selected from the GH population: An age-matched sample of female enrollees (population-based controls; n = 149) and all female 18- to 49-year-old enrollees undergoing a hysterectomy (hysterectomy controls; n = 106) during the same time without adenomyosis. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression, adjusted for identified covariates. RESULTS: Compared with normal and underweight women, overweight and obese women had increased adenomyosis risk using hysterectomy controls (OR, 2.2, 95% CI, 1.0-4.5; obese: OR, 2.2; 95% CI, 1.1-4.3) and population controls (overweight: OR, 2.1; 95% CI, 1.2-4.0; obese: OR, 3.8; 95% CI, 2.0-7.0). Using population controls, women with at least one live birth were more likely to have adenomyosis than nulliparous women (OR, 3.4; 95% CI, 1.9-6.2). CONCLUSION: Although some risk factors persisted in analyses using either control group, divergent results in relation to other risk factors for adenomyosis suggest that results of investigations of this disease may be affected by the choice of the comparison population. PMID- 21269842 TI - Anticipatory attention during the sleep onset period. AB - To examine whether anticipatory attention or expectancy is a cognitive process that is automatic or requires conscious control, we employed a paired-stimulus event-related potential (ERP) paradigm during the transition to sleep. The slow negative ERP wave observed between two successive stimuli, the Contingent Negative Variation (CNV), reflects attention and expectancy to the second stimulus. Thirteen good sleepers were instructed to respond to the second stimulus in a pair during waking sessions. In a non-response paradigm modified for sleep, participants then fell asleep while tones played. As expected, N1 decreased and P2 increased in amplitude systematically with the loss of consciousness at sleep onset; the CNV was increasingly more positive. Sleep onset latency was correlated with the amplitude of the CNV. The systematic attenuation of the CNV waveform at sleep onset and its absence in sleep indicates that anticipatory attention requires endogenous conscious control. PMID- 21269843 TI - Epileptiform response of CA1 neurones to convulsant stimulation by cyclothiazide, kainic acid and pentylenetetrazol in anaesthetized rats. AB - We have previously reported that cyclothiazide (CTZ) evokes epileptiform activities in hippocampal neurons and induces seizure behavior. Here we further studied in vivo the sensitivity of the hippocampal CA1 neurons in response to CTZ in epileptogenesis in comparison with two other classic convulsants of kainic acid (KA) and pentylenetetrazol (PTZ). CTZ administered intracerebral ventricle (i.c.v.) induced epileptiform activities from an initial of multiple evoked population spikes, progressed to spontaneous spikes and finally to highly synchronized burst activities in hippocampal CA1 neurons. PTZ, when given by subcutaneously, but not by intracerebral ventricle injection, evoked similar progressive epileptiform activities. In contrast, KA given by i.c.v. induced a quick development of epileptiform burst activities and then shortly switched to continuous high frequency firing as acute status epilepticus (ASE). Pharmacologically, alprazolam, a high-potency benzodiazepine ligand, inhibited CTZ and PTZ, but not KA, induced epileptiform burst activities while GYKI 53784, an AMPA receptor antagonist, suppressed CTZ and KA but not PTZ evoked epileptiform activities. In conclusion, CTZ and PTZ induced epileptiform activities are most likely to share a similar progressive pattern in hippocampus with GABAergic mechanism dominant in epileptogenesis, while CTZ model involves additional glutamate receptor activation. KA induced seizure in hippocampus is different to that of both CTA and PTZ. The results from this study indicate that hippocampal neurons respond to various convulsant stimulation differently which may reflect the complicated causes of the seizure in clinics. PMID- 21269844 TI - Suicidal risk and suicide attempts in people treated with antiepileptic drugs for epilepsy. AB - OBJECTIVE: To determine whether antiepileptic drugs constitute in themselves an independent risk factor for suicidality in patients with epilepsy. METHODS: One hundred and thirty one patients with epilepsy were recruited and followed-up during 5 years. A detailed medical history, neurological examination, EEGs, Mini International Neuropsychiatric Interview, executive function, and MRI were assessed. Systematically collected data were used to assess suicidality. Multiple regression analysis was carried out to examine predictive associations between clinical variables, psychiatric disorders, antiepileptic drugs and suicidality. RESULTS: We identified two AEDs related with suicide attempts (PHB and LTG) and four with suicidal risk: PHB, PRM, PHT and LTG, but the increased of risk diminished or disappeared when psychiatric comorbidity and other well established risk factors for suicidality were analyzed. We found a significant proportion of patients with depressive episodes associated with Topiramate, Phenitoin, Phenobarbital and Lamotrigine. CONCLUSION: Antiepileptic drugs probably do not have an impact on suicidality. PMID- 21269845 TI - Academic and social success in adolescents with previous febrile seizures. AB - OBJECTIVE: To study academic achievement and social success in adolescents with febrile seizures (FS) before their 5th birthday. SUBJECTS AND METHODS: A random birth cohort (n=900) was prospectively followed from early pregnancy and examined at ages 12 and 18 years to study the relationships between FS and school achievement (three most important school marks), behavior and social competence (Achenbach Childhood Behavior Checklist, Youth Self-Report), life management (Antonovsky Sense of Coherence Scale) and social participation. RESULTS: No significant differences could be detected between children with vs. without FS or between boys vs. girls in academic achievement, behavior, social competence, life management, or social participation, either at age 12 or 18 years, except for more somatic complaints of girls at age 18. Of adolescents with previous FS, 29% had not participated in the maturity examination, 20% had participated but failed and 51% had passed, comparing 35%, 18% and 47%, respectively, of those without FS (p=0.6676). CONCLUSIONS: Our study confirms the findings of the previous population studies reporting similar academic and social success between children with and without febrile seizures before the 5th birthday. Reassurance of the parents about a favorable future may ameliorate their worries at this frightening event in their child's life. PMID- 21269846 TI - The impact of intraluminal thrombus failure on the mechanical stress in the wall of abdominal aortic aneurysms. AB - OBJECTIVES: The role of the intraluminal thrombus (ILT) in abdominal aortic aneurysm (AAA) rupture is controversial, and it is still not clear if an ILT increases or decreases AAA rupture risk. Specifically, signs of bleeding in the ILT are considered to increase AAA rupture risk. To further explore this hypothesis, intact AAAs (n = 4) with clear signs of fissures in the ILT, identified by computed tomography angiography (CTA) were investigated. METHODS: Two different cases of ILT fissuring were investigated, where (1) ILT fissures were extracted directly from the CTA data and (2) a hypothetical fissure was introduced in the otherwise-intact ILT tissue. Wall stress distributions were predicted based on detailed Finite Element (FE) models. RESULTS: ILT fissures extracted from CTA data locally increase the mechanical stress in the underlying wall by up to 30%. The largest impact on wall stress was observed if the ILT crack reaches the aneurysm wall, or if it involves large parts of the ILT. By contrast, a concentric failure in the medial ILT, which does not reach the aneurysm wall, has almost no impact on wall stress distribution. Hypothetical ILT fissures that connect the lumen with the wall cause a twofold increase of the stress in the underlying wall. CONCLUSIONS: ILT fissures increase the stress in the underlying wall, whereas regions other than that remain unaffected. If ILT fissures reach the wall or involve large parts of the ILT, the resulting increase in wall stress could possibly cause AAA rupture. PMID- 21269847 TI - Age modifies the relative risk of stenting versus endarterectomy for symptomatic carotid stenosis--a pooled analysis of EVA-3S, SPACE and ICSS. AB - BACKGROUND: Recent randomised controlled trials comparing carotid artery stenting (CAS) with endarterectomy (CEA) for the treatment of symptomatic carotid stenosis were not powered to investigate differences in risks in specific patient subgroups. We therefore performed a pooled analysis of individual patient data from the Symptomatic Severe Carotid Stenosis trial (EVA-3S), the Stent-Protected Angioplasty versus Carotid Endarterectomy trial (SPACE), and the International Carotid Stenting Study (ICSS). METHODS: Individual data from all 3433 patients randomised and analysed in these trials were pooled and analysed with fixed effect binomial regression models adjusted for source trial. The primary outcome event was any stroke or death. RESULTS: In the first 120 days after randomisation (ITT analysis), the primary outcome event occurred in 153/1725 patients in the CAS group (8.9%) compared with 99/1708 patients in the CEA group (5.8%, risk ratio [RR] 1.53, 95% confidence interval [CI] 1.20-1.95, p = 0.0006; absolute risk difference 3.2, 95% CI 1.4-4.9). Age was the only subgroup variable which significantly modified the treatment effect: in patients <70 years old (the median age), the 120-day stroke or death risk was 5.8% in CAS and 5.7% in CEA (RR 1.00, 0.68-1.47); in patients 70 years or older, there was an estimated two-fold increase in risk with CAS over CEA (12.0% vs. 5.9%, RR 2.04, 1.48-2.82, interaction p = 0.0053). INTERPRETATION: Endarterectomy was safer in the short term than stenting, because of an increased risk of stroke associated with stenting in patients over the age of 70 years. Stenting should be avoided in older patients, but may be as safe as endarterectomy in younger patients. Determination of the efficacy and ultimate balance between the two procedures requires further data on long-term stroke recurrence. PMID- 21269848 TI - Enzymatic and metabolic characterization of the phosphoglycerate kinase deficiency associated with chronic hemolytic anemia caused by the PGK-Barcelona mutation. AB - Recently, we reported a new mutation of phosphoglycerate kinase (PGK), called PGK Barcelona, which causes chronic hemolytic anemia associated with progressive neurological impairment. We found a 140T->A substitution that produces an Ile46Asn change located at the N-domain of the enzyme and we suggested that the decrease of the PGK activity is probably related to a loss of enzyme stability. In this paper, by analyzing whole hemolysates and cloned enzymes, we show that both enzymes possess similar kinetic properties (although some differences are observed in the Km values) and the same electrophoretic mobility. However, PGK Barcelona has higher thermal instability. Therefore, we confirm that the decrease of the red blood cell (RBC) PGK activity caused by the PGK-Barcelona mutation is more closely related to a loss of enzyme stability than to a decrease of enzyme catalytic function. Furthermore, we have measured the levels of glycolytic metabolites and adenine nucleotides in the RBC from controls and from the patient. The increase of 2,3-bisphosphoglycerate and the decrease of ATP RBC levels are the only detected metabolic changes that could cause hemolytic anemia. PMID- 21269849 TI - Factors affecting sex education in the school system. AB - STUDY OBJECTIVE: To describe the current status of school based sex education and to determine predictors of providing a comprehensive sex education curriculum. DESIGN: Cross-sectional mailed survey SETTING: Hawaii PARTICIPANTS: Seventh and eighth grade health teachers INTERVENTIONS: Participants were surveyed regarding the content, quality, and influences on sex education for the 2007 to 2008 academic year. MAIN OUTCOME MEASURES: Measures of association (chi-square, ANOVA) and multiple logistic regression were used to determine predictors for teaching comprehensive sex education topics including sexually transmitted infections and pregnancy prevention. RESULTS: Approximately 80% of teachers incorporated some form of sex education into their curriculum and 54.4% of teachers incorporated a comprehensive education. Teachers indicated that personal values and the availability of curriculum had the greatest influence on the content of the curriculum. Specific factors which were associated with an increased likelihood of providing a comprehensive curriculum included teaching in a public school (public 66.7% versus private 34.6%, P = 0.01), receiving formal training in sex education (received training 77.8% versus did not receive training 50.0%, P = 0.03) and having contact with a student who became pregnant (contact 72.7% versus no contact 46.7%, P = 0.04). CONCLUSION: Although most teachers incorporate some form of sex education, only half incorporate a comprehensive curriculum. Personal values as well as teacher resources play an important role in the content of the curriculum. PMID- 21269850 TI - A family systems approach to primary ovarian insufficiency. AB - Receiving the diagnosis of Primary Ovarian Insufficiency (POI) can be emotionally difficult and confusing for young girls and their families. Parents need assistance in knowing how to help their daughters understand and live with the diagnosis in a way that allows for healthy growth and development. This paper provides a starting point for parents and clinicians with "Tips and Tools for Talking: Helping Your Daughter Understand Primary Ovarian Insufficiency". PMID- 21269851 TI - Orexin/hypocretin plays a role in the response to physiological disequilibrium. AB - In the decade since the discovery that pathology of the orexin/hypocretin system is causative for the sleep disorder narcolepsy, considerable progress has been made in understanding the functional role of the neuropeptide. Two, apparently separate functions of orexin have emerged as a consensus from studies to date. The first is the effect on vigilance state boundaries, as exemplified by narcolepsy. Thus the absence of orexin severely limits the ability to maintain prolonged periods of wakefulness or sleep and also allows the unregulated appearance of cataplexy as sudden muscle weakness during wakefulness. The second function is that orexin acts as a signaling molecule in transferring information about physiological disequilibrium to the central nervous system. Orexin activates the central arousal and motor systems during such disequilibrium and so may facilitate the necessary response and adaptation to restore equilibrium. A feasible relationship between these two functions is therefore that the maintenance of prolonged and active wakefulness is an integral part of this adaptive process. Furthermore, the limit placed on the onset of sleep by orexin suggests that these adaptive processes then continue during sleep to become integrated into the development of a coping strategy for the longer term. PMID- 21269852 TI - Immunohistochemical evaluation of MMP-2 and TIMP-2 in canine mammary tumours: a survival study. AB - Canine mammary tumours (CMTs) are a very heterogeneous group of neoplasms with variable prognosis. Their aggressiveness is mainly due to their ability to invade locally and to metastasize. The degradation of extracellular matrix components is an important determinant of the invasive phenotype. The aims of this study were to analyse by immunohistochemistry and double immunofluorescence the expression of metalloproteinase 2 (MMP-2) and tissue inhibitor of metalloproteinase 2 (TIMP 2) in eight normal canine mammary glands and 118 CMTs (24 benign, 94 malignant) and to investigate relationships with metastatic disease and survival. MMP-2 and TIMP-2 expression was higher in malignant tumours than in normal canine mammary tissue and benign tumours. The main difference between benign and malignant CMTs was the pattern of expression of both molecules: benign tumours presented TIMP-2 and MMP-2 immunoreactivity in the myoepithelial cells lining the basement membrane of tubuloalveolar structures, while malignant tumours showed mainly diffuse expression in neoplastic cells. In malignant tumours, increased TIMP-2 expression was significantly associated with the development of distant metastases, lower overall survival and lower disease-free survival. MMP-2 expression was not significantly associated to any of these parameters. These results suggest that the immunohistochemical expression of TIMP-2 is a useful prognostic factor in CMTs. PMID- 21269853 TI - A Bayesian approach to characterising multi-phase flows using magnetic resonance: application to bubble flows. AB - Magnetic Resonance (MR) imaging is difficult to apply to multi-phase flows due to both the inherently short T2* characterising such systems and the relatively long time taken to acquire the data. We develop a Bayesian MR approach for analysing data in k-space that eliminates the need for image acquisition, thereby significantly extending the range of systems that can be studied. We demonstrate the technique by measuring bubble size distributions in gas-liquid flows. The MR approach is compared with an optical technique at a low gas fraction (~2%), before being applied to a system where the gas fraction is too high for optical measurements (~15%). PMID- 21269854 TI - Selective detection of 13CHD2 signals from a mixture of 13CH3/13CH2D/13CHD2 methyl isotopomers in proteins. AB - In NMR spectra of partially deuterated proteins methyl correlations are commonly observed as a combination of signals from 13CH3, 13CH2D and 13CHD2 isotopomers. In a number of NMR applications, methyl groups of the 13CHD2 variety are targeted because of their AX-like character and concomitant simplification of the involved relaxation mechanisms. Although complete elimination of signals from 13CH2D methyl groups can be easily achieved in such applications, if the magnetization is not transferred through deuterium nuclei, efficient suppression of usually stronger 13CH3 peaks is more problematic. A pair of simple pulse-scheme elements are presented that achieve almost complete suppression of 13CH3 signals in the mixtures of 13CH3/13CH2D/13CHD2 methyl isotopomers of small proteins at the expense of a moderate (~20-to-40%) reduction in intensities of the targeted 13CHD2 groups. The approaches described are based purely on scalar coupling (1J(CH)) evolution properties of different 13C and 1H transitions within 13CH3 spin-systems and are superior to magnetization transfer through deuterons with respect to sensitivity of the detected 13CHD2 methyl signals. PMID- 21269855 TI - Thymidylate synthase gene polymorphisms and markers of DNA methylation capacity. AB - BACKGROUND: DNA methylation plays a critical role in gene regulation and has been implicated in the etiology of chronic disease including atherosclerosis, neural degeneration and cancer. One-carbon metabolism serves two critically important functions: one concerning the production of purines and thymidine for DNA synthesis and the other related to the provision of methyl groups through the metabolism of methionine. Critical intermediates of methionine metabolism relevant to DNA methylation include S-adenosylmethionine (SAM), a universal methyl donor, and S-adenosylhomocysteine (SAH), a potent inhibitor of most methylation reactions. Thymidine synthesis, catalyzed by the crucial enzyme thymidylate synthase (TS), competes with methionine metabolism for a common substrate. Three functional polymorphisms in the TS gene have been identified including: (i) the thymidylate synthase enhancer region (TSER) tandem repeat polymorphism and (ii) the G to C single nucleotide polymorphism (G/C SNP) both of which occur in the 5'untranslated region (UTR) of the TS gene; and (iii) the 6-bp deletion at base pair 1494 (TS1494del6) located in the 3'UTR. PURPOSE: The purpose of this research was to investigate the relationship between TS polymorphisms and concentrations of SAM and SAH, markers of DNA methylation capacity. METHODS: The study population consisted of 395 healthy male and female volunteers from Kingston, Ontario and Halifax, Nova Scotia, Canada between 2006 and 2008. The effect of each TS polymorphism on SAM and SAH concentrations was investigated, and further analyses were conducted on categorization of polymorphisms based on 5' or 3'UTR. The combined effect of TS polymorphisms on SAM and SAH concentrations was also investigated, in addition to interactions between polymorphisms in TS and MTHFR 677C>T and interactions between TS polymorphisms and serum folate and vitamin B(12) status. RESULTS: No associations were observed between TS polymorphisms and concentrations of SAM and SAH. Analysis of interaction between TS and MTHFR polymorphisms on SAH levels revealed a significant interaction with TS 3'polymorphism and MTHFR C677T (p=0.03). As well, interactions between TS 3'polymorphism and serum folate (p=0.03) and the combined effect of TS polymorphisms and serum folate on SAH levels (p=0.04) were found. CONCLUSIONS: The findings of this research provide evidence that SAH, a marker of methylation capacity, is influenced by genetic and environmental factors and their interactions. PMID- 21269856 TI - [Evaluation of the compliance of semirecumbent position between 30-45 degrees in intubated patients]. AB - AIMS: To determine compliance of the standard "semirecumbent position between 30 45 degrees in patients with artificial airway (AA)". To know the opinion of the professionals on this issue. MATERIAL AND METHODS: An observational, prospective study was carried out in December 2009 in the ICU department of a tertiary hospital that excluded the limitation of therapeutic effort, prone position and antitrendelemburg. DATA COLLECTED: headrest angle, professional experience of the nurse, shift, perception of the auditor, diagnostic, type of AA (tracheostomy or endotracheal tube), mechanical ventilation (MV) (yes/no) and enteral nutrition (EN). Nurses were surveyed to verify if they knew the standard, if they complied with it, the method used and their suggestions. We used the Student's t test and ANOVA for multivariable analysis, and Fisher's chi2; p<0.05=significant. RESULTS: A total of 546 valid measurements were obtained from 53 patients, of which 40.9% had the correct semirecumbent position (30-45 degrees ). Professionals with <1 year of experience were those who raised the headrest the least, with only 26.4% of these measurements over 30 degrees . The standard was met in only 34.8% of the neurocritical patients (NC) vs non NC (46.7%) (p<0.05). It was <30 degrees in 29.2% of patients with tracheostomy vs 44% measurements performed on patients with TOT (p<0.05). There were no differences between shifts, the use of MV or EN. Diagnostic accuracy of the auditor: sensitivity: 91.6%; specificity: 72.5%; positive predictive value: 70.2%; negative predictive value (NPV): 92.4%. 97.9% of responders know the standard. Visual judgment was used in 97.2% of the cases. CONCLUSIONS: Measured compliance was less than 50% although the standard is well known by the nursing team. Even though the subjective perception has a high NPV, it does not achieve the standard. PMID- 21269857 TI - [The impact factor, the perspective of nursing care professionals]. PMID- 21269858 TI - Single-dose extended-release azithromycin versus a 10-day regimen of amoxicillin/clavulanate for the treatment of children with acute otitis media. AB - OBJECTIVES: A randomized, double-blind, double-dummy, multicenter international study was conducted to assess the clinical and bacteriologic response, safety, and compliance of a single 60-mg/kg dose of azithromycin extended-release (ER) versus a 10-day regimen of amoxicillin/clavulanate 90/6.4 mg/kg per day in children with acute otitis media at high risk of persistent or recurrent middle ear infection. METHODS: Children aged 3 to 48 months were enrolled and stratified into two age groups (<= 24 months and >24 months). Pretreatment tympanocentesis was performed at all sites and was repeated during treatment at selected sites. RESULTS: The primary endpoint, clinical response at the test-of-cure visit in the bacteriologic eligible population, was achieved in 80.5% of children in the azithromycin ER group and 84.5% of children in the amoxicillin/clavulanate group (difference-3.9%; 95% confidence interval-10.4, 2.6). Bacteriologic eradication was 82.6% in the azithromycin ER group and 92% in the amoxicillin/clavulanate group (p=0.050). Children who received amoxicillin/clavulanate had significantly higher rates of dermatitis and diarrhea, a greater burden of adverse events, and a lower rate of compliance to study drug compared to those who received azithromycin ER. CONCLUSIONS: A single 60-mg/kg dose of azithromycin ER provides near equivalent effectiveness to a 10-day regimen of amoxicillin/clavulanate 90/6.4 mg/kg per day in the treatment of children with acute otitis media. PMID- 21269859 TI - Cervical flexion myelopathy in a patient showing apparent long tract signs: a severe form of Hirayama disease. AB - We describe an 18-year-old male with cervical flexion myelopathy with Hirayama disease-like features who showed apparent long tract signs. He first experienced insidious-onset hand muscle weakness and atrophy at the age of 15. Subsequently, he developed sensory disturbance in his lower limb. Neurological examination revealed atrophy and weakness in the right hand and forearm, pyramidal signs in the right lower extremity, and disturbance of superficial sensation in the lower left half of the body. Cervical magnetic resonance images and computed tomographic myelography revealed anterior displacement with compression of the cervical cord in flexion that was more apparent in the right side. The right side of the cervical cord showed severe atrophy. The mechanisms of myelopathy in our patient appeared to be same as that of "tight dural canal in flexion," which has been reported to be the mechanism of juvenile muscular atrophy of the unilateral upper extremity (Hirayama disease). Patients with Hirayama disease generally show minimal sensory signs and no pyramidal signs. An autopsy case of Hirayama disease revealed confined necrosis of the cervical anterior horn without obvious changes in the white matter. Our patient's disease progression suggests that cervical flexion myelopathy patients with severe cervical cord compression in flexion may develop extensive cervical cord injury beyond the anterior horn. PMID- 21269860 TI - Death by biscuit--exhumation, post-mortem CT, and revision of the cause of death one year after interment. AB - We describe a case of exhumation, performed to investigate the circumstances and cause of death, one year after burial. Post mortem computed tomography (PMCT) revealed a mass in the pharynx. Imaging directed the subsequent forensic autopsy to careful retrieval of a foreign body. Histological analysis revealed a non cellular composition. The detection of foreign material in the pharynx and its composition indicated accidental, rather than natural death, secondary to choking on food. This unusual case illustrates how post mortem imaging can significantly contribute to forensic investigation and stresses the importance of interdisciplinary collaboration between forensic pathologists and radiologists. PMID- 21269861 TI - STRs, mini STRs and SNPs--a comparative study for typing degraded DNA. AB - Short tandem repeat (STR) systems are the most powerful and widely used genetic marker systems in forensic DNA typing. Optimized amplification conditions and PCR reagents in combination with laser fluorescence based detection methods have increased the sensitivity and decreased the detection threshold down to approximately 100 pg. The quality of human DNA from forensic samples can be influenced by environmental factors. These may cause different degrees of degradation which have a negative impact on the amplification process especially of STR systems with large amplicons. Therefore, methods which need only small amplicon sizes to detect DNA markers are a better choice for typing degraded DNA. Here we report investigations on different types of DNA markers and typing methods which should all be applicable for analysing degraded DNA. These are two commercially available mini STR kits and five SNP markers which were analysed with two self established assays, a 5' nuclease assay and a minisequencing (SNaPshot) assay. The investigations comprised sensitivity studies, different types of stain material, as well as intact and degraded DNA. Results indicate that mini STRs are superior to standard STR typing methods, especially for typing old stain material with small amounts of degraded DNA. SNP typing based on the minisequencing (SNaPshot) assay achieved a better success rate in typing aged blood and saliva stains compared to standard STRs and SNP typing using the 5' nuclease assay. PMID- 21269862 TI - Sudden death associated to vascular Ehlers-Danlos syndrome. A case report. AB - This article describes the case of a sudden death in a 45-year-old female consecutive to acute and extensive arterial dissection in a context of Ehlers Danlos syndrome type IV. The interest of this case report is that autopsy findings led to the suspicion of a clinical diagnosis prompting as carrying out a genetic testing which definitively confirms the diagnosis, opening the way to genetic council for family members. Criteria for this disease diagnosis and full methodology are described, that may help forensic practitioners. PMID- 21269863 TI - Forensic biochemistry for functional investigation of death: concept and practical application. AB - The essential tasks of forensic pathology involve investigation of the cause and process of death, especially in traumatic and unexpected sudden deaths, largely including unwitnessed deaths. Thus, agonal and postmortem interference is inevitable and unpredictable in all forensic procedures; this is not particular to forensic biochemistry, but also occurs in morphology and toxicology. Therefore, findings should be assessed based on the postmortem data established through serial investigations of autopsy materials using easily accessible standardized procedures. With respect to this, biochemical procedures have advantages of standardization, quality assurance, quantitative analyses, statistic assessment and availability of multiple markers, despite several problems involved in the selection and collection of materials and applicability of analytical procedures. The main purpose of using postmortem biochemistry as well as molecular biology is to investigate the systemic pathophysiological changes involved in the death process that cannot usually be detected by morphological methods; these may be called 'pathophysiological vital reactions'. These procedures can provide useful support for pathological evidence by 'visualization' of functional alterations, and are also essential for the pathognomonic assessment of both the cause and process of death as part of routine laboratory investigations involved in 'full autopsy' in the context of social risk management. PMID- 21269864 TI - China's criminal penalty for medical malpractice: too lenient or not? AB - Although China had greatly improved its health and medical system, the contradiction between arduous medical tasks and insufficient health resources has not been fundamentally resolved. This contradiction raised a large number of legal issues in medical industry. Literatures about these issues are usually published in legal journal, and are not easy accessible to clinicians. We thus provide clinicians a brief introduction to the legal liability of medical malpractice, and describe the debate about the punishment setting of China's medical malpractice crime in detail. Considering the complexity and humanitarian nature of medical practice, legislators set a relative lenient punishment system for medical malpractice crime. But the "aggravating" supporter argued that, judging from criminal jurisprudence, only serious irresponsible medical personnel might face criminal penalty, so severe penalty was not conflict with the humanitarian nature of medical work. They also deemed that, too lenient penalties of this crime had broken the internal harmony of Criminal Law, and violated the basic principles of law. The opponents believed that: although the statutory penalty for medical malpractice crime seemed lenient, the declared sentence was more severe than surrounding areas. And, too severe penalties would not only aggravate the shortage of Chinese medical personnel, but also deteriorate the unbalanced physician-patient relationship. So, they did not agree enhancing the penalty of medical malpractice crime. We propose to add disqualification to the punishment setting of medical malpractice crime, reform the health system more thoroughly. We also hope Chinese governments could encourage medicolegal research. And, from the viewpoint of risk management in health care, we emphasize the role of Medical Professional Liability Insurance system as a powerful tool to prevent medical malpractice. PMID- 21269865 TI - Y chromosome comparative analysis of Rondonia with other Brazilian populations. AB - In the present study, a Brazilian population, located in the Rondonia state, was genetically characterized for a set of Y chromosome specific STRs included in the Applied Biosystems kit (AmpFlSTR(r)YfilerTM), which allows the simultaneous amplification of 16 markers: DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS385a/b, DYS438, DYS439, DYS437, DYS448, DYS456, DYS458, DYS635 and GATA H4. The studied population from Rondonia state, in the North of Brazil, included individuals with admixed Native American, African and European ancestry. When comparing Rondonia with other Brazilian populations no significant genetic distances were found. In the comparison with other worldwide populations, although a predominant male European influence could be detected, there were significant differences with some populations from Central and South America and Africa. PMID- 21269866 TI - Sonochemical syntheses of a new nano-plate cadmium(II) coordination polymer as a precursor for the synthesis of cadmium(II) oxide nanoparticles. AB - Nanoplates of the three-dimensional coordination polymer, {[Cd(3)(3 pyc)(4)(N(3))(2)(H(2)O)](n) (1), 3-pyc(-)=pyridine-3-carboxylate), have been synthesized by a sonochemical process and characterized by scanning electron microscopy, X-ray powder diffraction, IR spectroscopy and elemental analyses. Cadmium(II) oxide nanoparticles were prepared from thermal decomposition in oleic acid and direct calcination of compound 1 at different temperatures. The thermal stability of nano-sized compound 1 was studied by thermal gravimetric (TG) and differential thermal analyses (DTA). Results show that the size and morphology of the CdO nanoparticles are dependent upon the particles size of compound 1 and the thermolysis temperature. A decrease in the particle size of compound 1 leads to a decrease in the particle size of the CdO, while an increase in the processing temperature leads to an increase in the particle size of the produced cadmium(II) oxide nano-particles. PMID- 21269867 TI - Adaptive motor unit potential train validation using MUP shape information. AB - A decomposed electromyographic (EMG) signal provides information that can be used clinically or for physiological investigation. However, in all instances the validity of the extracted motor unit potential trains (MUPTs) must first be determined because, as with all pattern recognition applications, errors will occur during decomposition. Moreover, detecting invalid MUPTs during EMG signal decomposition can enhance decompositions results. Eight methods to validate an extracted MUPT using its motor unit potential (MUP) shape information were studied. These MUPT validation methods are based on existing cluster analysis algorithms, four were newly developed adaptive methods and four were classical cluster validation methods. The methods evaluate the shapes of the MUPs of a MUPT to determine whether the MUPT represents the activity of a single motor unit (i.e. it is a valid MUPT) or not. Evaluation results using both simulated and real data show that the newly developed adaptive methods are sufficiently fast and accurate to be used during or after the decomposition of EMG signals. The adaptive gap-based Duda and Hart (AGDH) method had significantly better accuracies in correctly categorizing the MUPTs extracted during decomposition (91.3% and 94.7% for simulated and real data, respectively; assuming 12.7% of the extracted MUPTs are on average invalid). The accuracy with which invalid MUPTs can be detected is dependent on the similarity of the MUP templates of the MUPTs merged to create the invalid train and suggests the need, in some cases, for the combined use of motor unit firing pattern and MUP shape information. PMID- 21269868 TI - Quantitative study of cardiac motion estimation and abnormality classification in emission computed tomography. AB - Quantitative description of cardiac motion is desirable to assist in detecting myocardial abnormalities from gated myocardial perfusion (GMP) emission computed tomography (ECT) images. While "optical flow" type of cardiac motion estimation (ME) techniques have been developed in the past, there has been no quantitative evaluation of their performance. Moreover, no investigation has been performed in terms of applying an ME technique to quantify cardiac motion abnormalities. Using the four-dimensional NCAT beating heart phantom with known built-in motion, the current work aimed at addressing the aforementioned two issues. A three dimensional cardiac ME technique was developed to search for a motion vector field (MVF) that establishes voxel-by-voxel correspondence between two GMP ECT images. The weighted myocardial strain energy served as the constraint in the process to minimize the difference between one intensity image and the MVF warped other. We studied the convergence of the ME technique using different initial estimates and cost functions. The dependence of estimated MVF on the initialization was attributed to the tangential motion that is undetectable while not suppressed by the strain energy constraint. We optimized the strain energy constraint weighting using noise-free phantom images and noisy reconstructed images, the former against the known MVF and the later in the task of regional motion classification. While the results from the above two studies well coincide with each other, we also demonstrated that upon appropriate optimization the ME method has the capability of serving as a computer motion observer in separating simulated noisy reconstructed GMP SPECT images corresponding to hearts with and without regional motion abnormalities. PMID- 21269869 TI - Extrinsic feedback and management of low back pain: A critical review of the literature. AB - Effective intervention for low back pain (LBP) can include feedback in one form or other. Although extrinsic feedback (EF) can be provided in a number of ways, most research has not considered how different EF characteristics (e.g. timing and content) influence treatment outcomes. A systematic search related to feedback and LBP was performed on relevant electronic databases. This narrative review aims to describe the forms of feedback provision in the literature regarding management of LBP, and to discuss these in light of previously recommended principles for the use of extrinsic feedback. The present review found support for the provision of EF that focuses on content characteristics including program feedback, summary results feedback, and external focus of attention. Temporal characteristics should enhance the use of intermittent or self-selected feedback. The literature does not support the provision of concurrent or constant EF. As much of the literature related to EF in the management of LBP has not considered content and timing characteristics we have identified future research directions that will clarify the use of content and timing characteristics of EF relative to the management of LBP. PMID- 21269870 TI - Validation of the comprehensive ICF core set for low back pain: the perspective of physical therapists. AB - The "Comprehensive ICF Core Set for Low Back Pain (LBP)" is an application of the International Classification of Functioning, Disability and Health (ICF) and represents the typical spectrum of problems in functioning for patients with LBP. The aim of this study was to validate the Comprehensive ICF Core Set for low back pain from the perspective of physical therapists. Physical therapists experienced in LBP treatment were asked about the patients' problems, patients' resources and aspects of environment treated by physical therapists in a three-round survey using the Delphi technique. Responses were linked to the ICF. Eighty-four physical therapists in 32 countries named 1955 concepts that covered all ICF components. Fourteen ICF categories were not represented in the Comprehensive ICF Core Set for LBP although at least 75% of the participants have rated them as important. Most of them belonged to the ICF component "Body Functions". Twenty eight concepts were linked to the not-yet-developed ICF component personal factors. Further, 21 issues were not covered by the ICF. The validity of the ICF components "Body Structures", "Activities and Participation" and "Environmental Factors" was largely supported by the physical therapists. However, several body functions were identified which are not covered and need further investigation. PMID- 21269871 TI - Prevalence and impact of ocular allergy in the population attending UK optometric practice. AB - PURPOSE: To determine the prevalence of ocular allergy in patients attending optometric practices in the UK West Midlands and the impact this has on patients' daily lives. METHOD: Patients attending 9 optometric practices in the West Midlands, UK, were surveyed about the occurrence of ocular allergy, the severity of the symptoms and their treatment. Patients self-reporting ocular allergy were invited to complete a more detailed questionnaire. RESULTS: Of the 1904 consecutive patients assessed (mean age 47.7+/-23.2 years, 55% female), 13% reported an allergy, 8% an ocular allergy, rated as at least mild in 85% of cases. Medication was used by 77% of patients reporting ocular symptomology. Patients with ocular allergy (n=126) completed the detailed questionnaire. Seasonal symptoms occurred for 3.4+/-1.9 months of the year with a peak in June to July. The most common 'hayfever' type symptoms were itchy eyes and a runny nose, and ocular symptoms were itchiness and a desire to rub the eyes. Most had gained medication over the counter (73%) with advice from GPs (53%), pharmacists (41%) or a friend or relative (18%). Only 11% consulted an optometrist. Medication was mainly in the form of antihistamine tablets (71%), eye drops (40%) and nasal spray (40%). Those interested in a specialist ocular allergy service (83%) were willing to pay L15.50 on average. CONCLUSION: Ocular allergy is relatively common, but treatment is often self-managed, does not appear to totally overcome the discomfort and rarely involves a detailed eye examination. PMID- 21269872 TI - Electron paramagnetic resonance, NIR studies on zoisite, clinozoisite and chrom zoisite minerals. AB - A zoisite group of mineral samples from different localities are used in the present study. An EPR study on powdered samples confirms the presence of Mn(II), Fe(III) and Cr(III) in the minerals. NIR studies confirm the presence of these ions in the minerals. PMID- 21269873 TI - Infrared and infrared emission spectroscopy of nesquehonite Mg(OH)(HCO3).2H2O implications for the formula of nesquehonite. AB - The mineral nesquehonite Mg(OH)(HCO(3)).2H(2)O has been analysed by a combination of infrared (IR) and infrared emission spectroscopy (IES). Both techniques show OH vibrations, both stretching and deformation modes. IES proves the OH units are stable up to 450 degrees C. The strong IR band at 934 cm(-1) is evidence for MgOH deformation modes supporting the concept of HCO(3)(-) units in the molecular structure. Infrared bands at 1027, 1052 and 1098 cm(-1) are attributed to the symmetric stretching modes of HCO(3)(-) and CO(3)(2-) units. Infrared bands at 1419, 1439, 1511, and 1528 cm(-1) are assigned to the antisymmetric stretching modes of CO(3)(2-) and HCO(3)(-) units. IES supported by thermoanalytical results defines the thermal stability of nesquehonite. IES defines the changes in the molecular structure of nesquehonite with temperature. The results of IR and IES supports the concept that the formula of nesquehonite is better defined as Mg(OH)(HCO(3)).2H(2)O. PMID- 21269874 TI - Temperature dependence of resonance Raman spectra of carotenoids. AB - To understand the mechanism of the photoprotective and antioxidative functions of carotenoids, it is essential to have a profound knowledge of their excited electronic and vibronic states. In the present study we investigate the most powerful antioxidants: beta-carotene and lutein by means of resonance Raman spectroscopy. The aim was to study in detail their Raman spectra in solution at room temperature and their changes as a function of temperature. To measure the spectra in their natural environment pyridine has been used as a solvent. It has been chosen because of its polarizability (n=1.5092) which is close to that of membrane lipids and proteins. The temperature dependence of the most intensive nu(1) band in the range from 77 K to 295 K at 514.5 nm excitation has been obtained. It was found that in pyridine the CC stretching frequency, its intensity, line shape, and line width are very sensitive to the temperature (the sensitivity being different for the two studied carotenoids). The observed linear temperature dependence of the CC stretching frequency is explained by a mechanism involving changes of the vibronic coupling and the extent of pi-electron delocalization. The different behavior of the temperature-induced broadening of the nu(1) band and its intensity for the two studied carotenoids can be associated with the different nature of their solid matrices: glassy for beta carotene and crystalline-like for lutein, owing to their different chemical structures. PMID- 21269875 TI - A near-infrared and Raman spectroscopic study of the mineral richelsdorfite Ca2Cu5Sb[Cl|(OH)6|(AsO4)4].6H2O. AB - Raman spectroscopy has enabled insights into the molecular structure of the richelsdorfite Ca(2)Cu(5)Sb[Cl|(OH)(6)|(AsO(4))(4)].6H(2)O. This mineral is based upon the incorporation of arsenate or phosphate with chloride anion into the structure and as a consequence the spectra reflect the bands attributable to these anions, namely arsenate or phosphate and chloride. The richelsdorfite Raman spectrum reflects the spectrum of the arsenate anion and consists of nu(1) at 849, nu(2) at 344 cm(-1), nu(3) at 835 and nu(4) at 546 and 498 cm(-1). A band at 268 cm(-1) is attributed to CuO stretching vibration. Low wavenumber bands at 185 and 144 cm(-1) may be assigned to CuCl TO/LO optic vibrations. PMID- 21269876 TI - Cloning of a thermostable xylanase from Actinomadura sp. S14 and its expression in Escherichia coli and Pichia pastoris. AB - A thermophilic xylan-degrading Actinomadura sp. S14 was isolated from compost in Thailand. Hemicellulase activities such as endo-1,4-beta-xylanase, beta xylosidase and alpha-arabinofuranosidase were induced with xylan-containing agriculture wastes and oat spelt xylan. The gene encoding xylanase consisting of 687bp was cloned from Actinomadura sp. S14. The deduced amino acid sequence contained a signal peptide of 41 amino acids and a probable mature xylanase of 188 amino acids. An open reading frame (xynS14) corresponding to a mature xylanase was expressed in Escherichia coli and Pichia pastoris. The specific activity of purified XynS14 (P. pastoris) was 2.4-fold higher than XynS14 (E. coli). Both XynS14s showed the same basic properties such as optimal pH and temperature (pH 6.0 and 80 degrees C) and stability in a broad pH range (pH 5.0 11.0) and at high temperatures up to 80 degrees C. Both XynS14s showed approximately the same substrate specificity and K(m) values toward various xylans, but XynS14 (P. pastoris) showed higher V(max) and K(cat) than XynS14 (E. coli). Higher specific activities of XynS14 (P. pastoris) may be due to protein folding in the host. Purified XynS14 showed more endo-1,4-beta-xylanase activity on xylan and xylooligosaccharides than on xylotriose. PMID- 21269877 TI - Role of angiotensin in the rostral ventrolateral medulla in the development and maintenance of hypertension. AB - Whilst crucial for behavioural and homeostatic responses to environmental challenges, chronic elevation of sympathetic nervous system activity to specific vascular beds is associated with hypertension. Indeed such elevated activity may drive the increase in blood pressure seen in some people and in some experimental models of hypertension. This review discusses the neural circuitry involved in generating and modulating sympathetic efferent nerve activity, focusing on the premotor neurons of the rostral ventrolateral medulla. Neurons in the rostral ventrolateral medulla show altered responses to angiotensin II in experimental models of hypertension, suggesting that this might be an important node for interaction between these two systems that are crucial for regulation of blood pressure. PMID- 21269878 TI - What the Myddosome structure tells us about the initiation of innate immunity. AB - Signaling by the toll-like receptor (TLR) and interleukin-1 receptor superfamily requires the adapter protein myeloid differentiation primary response protein 88 (MyD88). The recent determination of the structure of the so-called Myddosome provides us with new insights into the structural basis for innate immune signaling. Other information on the biochemistry and genetics of MyD88 and other adapters, such as MyDD adapter-like and TRIF-related adapter molecule, allows us to describe in some detail the signaling process activated by TLRs and provides new insights into the role these important proteins play in innate immunity. PMID- 21269879 TI - Quality assessment of induced spermatogenesis in hypogonadotrophic hypogonadic men treated with gonadotrophins. AB - Hypogonadotrophic hypogonadism (HH) is characterized by deficient gonadotrophin secretion, resulting from pituitary or hypothalamic defects. In order to induce spermatogenesis, HH patients are treated with commercially available gonadotrophins. As far as is known, quality and genetic integrity of induced sperm cells have never been investigated, although they represent an important issue, since the ultimate goal of this treatment is to have competent spermatozoa in order to achieve paternity. In order to evaluate the nuclear integrity of induced sperm cells, sperm samples from treated HH patients were compared with sperm samples from normospermic control donors. Sperm cells were analysed by fluorescence in-situ hybridization, using probes specific for chromosomes 13, 21, 18, X and Y, and by TdT (terminal deoxynucleotidyl transferase)-mediated dUDP nick-end labelling assay. Results showed that the rate of aneuploid and diploid sperm cells in patients was not statistically different from controls and that the rate of sperm cells with fragmented DNA was within the normal values. Spermatozoa obtained by gonadotrophin treatment in HH patients are likely to have a balanced chromosomal content and a normal DNA integrity but this conclusion needs to be confirmed by further studies dealing with a greater number of patients. PMID- 21269880 TI - Utility of age-specific serum anti-Mullerian hormone concentrations. AB - This study assessed whether age-specific (as-) cutoffs for anti-Mullerian hormone (AMH) have higher specificity in reflecting ovarian reserve than non-age-specific (nas-) AMH values. as-AMH values were defined in 792 consecutive infertility patients by establishing as-quartiles of AMH within five age groups. Oocyte yields were then compared among women with AMH below or above the 25th centile at each age group. AMH continually decreased with advancing female age (P<0.0001) and differed significantly in each of five selected age categories (P<0.001). In 442 women who reached IVF, as-AMH was predictive of lower oocyte yield if below as-25th centile and of higher oocyte yield if above as-75th centile. Combined normal and elevated as-AMH demonstrated 6.4 times (95% CI 3.9-20.6) odds of retrieving more than four oocytes than low as-AMH. Like as-FSH, as-AMH better reflects ovarian reserve than nas-ovarian reserve testing. However, in contrast to as-FSH, as-AMH defines risk for diminished ovarian reserve or high oocyte yields (i.e. ovarian hyperstimulation syndrome) and, therefore, may be a particularly useful ovarian reserve test in younger women in whom diminished ovarian reserved is most frequently overlooked, and who are at highest risk for ovarian hyperstimulation syndrome. PMID- 21269881 TI - A unique biological in-vivo model to evaluate follicular development during in vitro maturation treatment. AB - The aim of this study was to identify the size in which the dominant follicle acquires the ability to produce a functional corpus luteum. This observational study includes 15 women with ovulatory cycles who underwent human chorionic gonadotrophin (HCG)-primed in-vitro maturation (IVM) treatments without embryo transfer. All patients received subcutaneous injection of HCG 10,000 IU 38 h prior to oocyte retrieval. Five to seven days following retrieval, serum concentrations of progesterone and oestradiol were measured along with ultrasound scan measuring the antral follicle count. Using receiver operating characteristic curves and the Youden index (J), this study clearly shows that the diameter of the dominant follicle at the time of the LH surge is a good predictor for its ability to form a progesterone-producing corpus luteum (area under the curve 0.94). These findings revealed that the dominant follicle develops the competence to form a corpus luteum, signified by the production of more than 10 nmol/l serum progesterone at 5-7 days from oocyte retrieval, as soon as it acquires a diameter of 10.5-12.0mm. In addition, a new cohort of viable antral follicles can be identified as early as 5-7 days following IVM oocyte retrieval. PMID- 21269882 TI - Donor information considered important to donors, recipients and offspring: an Australian perspective. AB - Donor conception research supports open-identity donor programmes and disclosure to donor-conceived offspring. This study examines Australian donors', recipients' and donor-conceived offspring's views on the importance of different types of biographical information about the donor. Participants (125 recipients, 39 donors (known, identity-release and anonymous), 23 donor-conceived offspring) completed an online or paper self-administered anonymous questionnaire. Individuals rated the importance of 15 types of biographical information and subsequently chose the three they deemed most important. All groups included donor's health history and name as key variables to be available to donor-conceived offspring. Recipients viewed the donor's decision to donate as important, donors thought their feelings about being contacted were important and donor-conceived offspring expressed an interest in the donor's own family. Sperm donors were less inclined to view the provision of information as important compared with offspring. For recipients, the importance of information became apparent once they had disclosed to their children. This is the first study to gauge Australian stakeholders' attitudes to release of information in the donor conception process. The findings support the move to open-identity donation systems and emphasize the importance of considering the varying perspectives of all stakeholders by policy developers. PMID- 21269883 TI - Sperm chromatin structure correlates with spontaneous abortion and multiple pregnancy rates in assisted reproduction. AB - The objective of this study was to determine if a relationship exists between sperm parameters, measured by sperm chromatin structure assay (SCSA), and spontaneous abortion and multiple births in couples undergoing assisted reproduction treatment. Retrospective analysis of infertility treatment outcomes and occurrence of spontaneous abortion and multiple births was conducted in 233 couples who underwent treatment by intracytoplasmic sperm injection or intrauterine insemination at the Sher Institute for Reproductive Medicine, between 2001 and 2004. Sperm samples used for treatments were analysed for sperm concentration, sperm motility and two different parameters of SCSA (DNA fragmentation index, DFI, and high DNA stainability, HDS). Pregnancy, spontaneous abortion and multiple birth rates were recorded for all couples. A statistically significant relationship (P<0.001) was observed between DFI and spontaneous abortion. However, the correlation between HDS and spontaneous abortion was not statistically significant. Significantly lower levels of DFI were observed in men from couples having triplet pregnancies compared with those in the spontaneous abortion group (P <= 0.05). It is concluded that the parameters of SCSA correlate significantly with spontaneous abortion and multiple birth and may provide guidance for clinical decision making (number of embryos per transfer) and management of spontaneous abortion-prone cases. PMID- 21269884 TI - Cancer and fertility: strategies to preserve fertility. AB - Fertility preservation is a key component of cancer management in young people. The Fourth Evian Annual Reproduction Workshop Meeting was held in April 2009 to discuss cancer and fertility in young adults. Specialists in oncology, assisted reproduction, embryology and clinical genetics presented published data and ongoing research on cancer and fertility, with particular focus on strategies to preserve fertility. This report is based on the expert presentations and group discussions, supplemented with publications from literature searches and the authors' knowledge. Fertility preservation should be considered for all young people undergoing potentially gonadotoxic cancer treatment. A variety of options are required to facilitate safe and effective fertility preservation for individual patients. Sperm banking is a simple and low-cost intervention. Embryo cryopreservation is the only established method of female fertility preservation. Oocyte cryopreservation offers a useful option for women without a male partner. Emergency ovarian stimulation and cryopreservation of ovarian tissue (followed by tissue transplantation or in-vitro maturation of oocytes) are experimental techniques for women who require urgent cancer treatment. Further prospective studies are required to validate cryopreservation of oocytes and ovarian tissue, in-vitro maturation of oocytes and new vitrification techniques and to identify any long-term sequelae of slow freezing of embryos. PMID- 21269885 TI - Effects of two vitrification protocols on the developmental potential of human mature oocytes. AB - The aim of the present study was to compare an 'open' vitrification protocol to a 'closed' vitrification protocol for mature human oocytes. A prospective comparison between fresh and sibling vitrified oocytes and a retrospective comparison between the two vitrification protocols were performed. For recruited patients undergoing an IVF cycle, two or three fresh oocytes were inseminated with intracytoplasmic sperm injection (ICSI) and the remaining three or more oocytes were vitrified according to manufacturer's instructions with a 'closed' or an 'open' vitrification system. After an unsuccessful fresh cycle, oocytes were warmed and inseminated with ICSI. Embryological parameters were recorded and compared between fresh and sibling vitrified oocytes (intrapatient) as well as between the two vitrification techniques (interpatient). Oocytes vitrified with the 'closed' system showed significantly lower fertilization and cleavage rates and a reduction in the quantity and quality of obtained embryos compared with fresh sibling oocytes (P<0.001). On the contrary, the same parameters were similar between fresh and sibling oocytes vitrified using the 'open' system. The retrospective comparison between the two vitrification protocols also showed a significant increase in clinical pregnancy rate and a reduced proportion of cancelled cycles using the 'open' system (P<0.01). PMID- 21269886 TI - International travel with acquisition of multi-drug resistant Gram negative bacteria containing the New Delhi metallo-beta-lactamase gene, bla NDM-1. PMID- 21269887 TI - May lovastatin target both autism and epilepsy? A novel hypothesized treatment. PMID- 21269888 TI - Magnetic resonance imaging of subjects with acute unilateral neck pain and restricted motion: a prospective case series. AB - BACKGROUND CONTEXT: Zygapophyseal joint injury and inflammation have been proposed as causes of acute benign spinal pain, but this etiology has not been investigated. PURPOSE: To investigate the presence of periarticular tissue inflammation and zygapophysial joint synovitis in the cervical region using magnetic resonance imaging (MRI) in subjects with acute unilateral cervical pain and limited motion (acute "crick in the neck" <48 hours from onset), as well as the feasibility of recruiting these subjects. STUDY DESIGN/SETTING: Three-month case series in a university setting and private radiology clinic. PATIENT SAMPLE: Five subjects (three women and two men; mean age, 31.6 years; standard deviation [SD], 12.4). METHODS: Each subject was examined by a researcher experienced in manual medicine to assess active range of neck movement and the side and symptomatic segmental level of pain. Subjects then underwent a blinded MRI investigation, which included sagittal images through the entire neck and cervical spine and axial images from C2 to T1. Evidence of capsule or periarticular edema and joint space T2 increase was recorded and scored. Additionally, signs of muscle edema, alignment, disc disease, facet arthritic change, and spinal stenosis were recorded. RESULTS: Subjects presented with mean current pain of 4.8 (SD, 1.6; visual analog scale, 0-10), worst pain since onset of 7.0 (SD, 0.7), and duration of symptoms of 12.4 hours (SD, 14.1). The plane of active motion most commonly limited was rotation to the painful side, followed by side bending to the painful side and extension. No MRI findings demonstrated clear evidence of synovial effusion or inflammation around the joints of the cervical spine. In some individuals, signs of muscle edema, altered alignment, disc and facet arthrosis, and spinal stenosis were noted, but these did not appear to be related to the side of pain or symptomatic level. CONCLUSIONS: No evidence of cervical joint inflammation was detected, and more sensitive imaging methods may be required to detect inflammatory changes in or around the cervical joints of subjects with acute benign neck pain. Recruitment of subjects with acute "crick in the neck" pain (<48 hours duration) is difficult but feasible over a long data collection period. PMID- 21269889 TI - The Professional Athlete Spine Initiative: outcomes after lumbar disc herniation in 342 elite professional athletes. AB - BACKGROUND CONTEXT: Although clinical outcomes after lumbar disc herniations (LDHs) in the general population have been well studied, those in elite professional athletes have not. Because these athletes have different measures of success, studies on long-term outcomes in this patient population are necessary. PURPOSE: This study seeks to define the outcomes after an LDH in a large cohort of professional athletes of American football, baseball, hockey, and basketball. STUDY DESIGN/SETTING: Retrospective cohort study. PATIENT SAMPLE: A total of 342 professional athletes from four major North American sports from 1972 to 2008 diagnosed with an LDH were identified via a previously published protocol. Two hundred twenty-six players underwent lumbar discectomy, and 116 athletes were treated nonoperatively. Only those players who had at least 2 years of follow-up were included. OUTCOME MEASURES: Functional outcome measures as defined by successful return-to-play (RTP), career games, and years played for each player cohort were recorded both before and after treatment. Conversion factors based on games/regular season and expected career length (based on individual sport) were used to standardize the outcomes across each sport. METHODS: Using Statistical Analysis Software v. 9.1, outcome measures were compared in each cohort both before and after treatment using linear and mixed regression analyses and Cox proportional hazards models. A Kaplan-Meier survivorship curve was calculated for career length after injury. Statistical significance was defined as p<.05. RESULTS: After the diagnosis of an LDH, professional athletes successfully returned to sport 82% of the time, with an average career length of 3.4 years. Of the 226 patients who underwent surgical treatment, 184 successfully returned to play (81%), on average, for 3.3 years after surgery. Survivorship analysis demonstrated that 62.3% of players were expected to remain active 2 years after diagnosis. There were no statistically significant differences in outcome in the surgical and nonoperative cohorts. Age at diagnosis was a negative predictor of career length after injury, whereas games played before injury had a positive effect on outcome after injury. Major League Baseball (MLB) players demonstrated a significantly higher RTP rate than those of other sports, and conversely, National Football League (NFL) athletes had a lower RTP rate than players of other sports (p<.05). However, the greatest positive treatment effect from surgery for LDH was seen in NFL players, whereas for MLB athletes, a lumbar discectomy led to a shorter career compared with the nonoperative cohort (p<.05). CONCLUSIONS: Professional athletes diagnosed with an LDH successfully returned to play at a high rate with productive careers after injury. Whereas older athletes have a shorter career length after diagnosis of LDH, experienced players (high number of games played) demonstrate more games played after treatment than inexperienced athletes. Notably, surgical treatment in baseball players led to significantly shorter careers, whereas for NFL athletes, posttreatment careers were longer than those of the corresponding nonoperative cohort. The explanation for this is likely multifactorial, including the age at diagnosis, respective contractual obligations, and different physical demands imposed by each individual professional sport. PMID- 21269890 TI - Total laparoscopic hysterectomy in early-stage endometrial cancer using an intrauterine manipulator: is it a bias for frozen section analysis? Case-control study. AB - STUDY OBJECTIVE: To evaluate whether the systematic use of an intrauterine manipulator influences the accuracy of frozen section analysis in early-stage endometrial cancer. DESIGN: Case-control study (Canadian Task Force classification II-1). PATIENTS: Three hundred fourteen consecutive women with early-stage endometrial cancer. INTERVENTIONS: Between January 2004 and December 2009, 314 women with early-stage endometrial cancer underwent staging at laparoscopy (case group) or laparotomy (control group). All women in the case group underwent total laparoscopic hysterectomy using an intrauterine manipulator. MEASUREMENTS AND MAIN RESULTS: The positive predictive value of frozen section analysis for myometrial infiltration, histotype, and grade of differentiation was 97.2%, 100%, and 97.2%, respectively. The correct diagnosis rate was of 85.7%. The accuracy of frozen section analysis, rate of correct diagnosis, and rate of tumor vascular invasion did not seem to be significantly modified by systematic use of an intrauterine manipulator for total laparoscopic hysterectomy compared with total abdominal hysterectomy in early-stage endometrial cancer staging. CONCLUSIONS: Frozen section analysis of early-stage endometrial cancer is highly accurate, and systematic use of an intrauterine manipulator does not represent a bias for correct evaluation of the specimen. PMID- 21269891 TI - HLTF and SHPRH are not essential for PCNA polyubiquitination, survival and somatic hypermutation: existence of an alternative E3 ligase. AB - DNA damage tolerance is regulated at least in part at the level of proliferating cell nuclear antigen (PCNA) ubiquitination. Monoubiquitination (PCNA-Ub) at lysine residue 164 (K164) stimulates error-prone translesion synthesis (TLS), Rad5-dependent polyubiquitination (PCNA-Ub(n)) stimulates error-free template switching (TS). To generate high affinity antibodies by somatic hypermutation (SHM), B cells profit from error-prone TLS polymerases. Consistent with the role of PCNA-Ub in stimulating TLS, hypermutated B cells of PCNA(K164R) mutant mice display a defect in generating selective point mutations. Two Rad5 orthologs, HLTF and SHPRH have been identified as alternative E3 ligases generating PCNA Ub(n) in mammals. As PCNA-Ub and PCNA-Ub(n) both make use of K164, error-free PCNA-Ub(n)-dependent TS may suppress error-prone PCNA-Ub-dependent TLS. To determine a regulatory role of Shprh and Hltf in SHM, we generated Shprh/Hltf double mutant mice. Interestingly, while the formation of PCNA-Ub and PCNA-Ub(n) is prohibited in PCNA(K164R) MEFs, the formation of PCNA-Ub(n) is not abolished in Shprh/Hltf mutant MEFs. In line with these observations Shprh/Hltf double mutant B cells were not hypersensitive to DNA damage. Furthermore, SHM was normal in Shprh/Hltf mutant B cells. These data suggest the existence of an alternative E3 ligase in the generation of PCNA-Ub(n). PMID- 21269892 TI - Plasma pharmacokinetics and tissue distribution study of physalin D in rats by ultra-pressure liquid chromatography with tandem mass spectrometry. AB - Physalin D is an important constituent of some traditional Chinese medicines, and has several known bioactivities. An UPLC-MS/MS method for the determination of physalin D in rat plasma and tissues was developed and the pharmacokinetic and tissue distribution characteristics of physalin D after intravenous administrations were investigated. The bio-samples were prepared by a simple protein precipitation, and the separation of physalin D was achieved on a UPLC HSS T3 column with a mobile phase consisting of methanol/acetonitrile (70:30, v/v) and water (containing 0.1% formic acid and 10 mM ammonium acetate) at a flow rate of 0.3 mL/min. The MS/MS detection was carried out by monitoring the fragmentation of m/z 544.9->508.8 for physalin D and m/z 286.7->152.8 for luteolin (internal standard; IS) on a triple-quadrupole mass spectrometer. The total run time was only 3.6 min. The analyte showed good linearity over a wide concentration range (R(2)>0.995) and its lower limit of quantification was 2 ng/mL. The pharmacokinetic study found that physalin D was distributed and eliminated rapidly in rats (t(1/2)<10 min). Tissue distribution showed the highest level was observed in kidney, then in liver, but no physalin D was detected in brain, which indicated that kidney was the major distribution tissue for physalin D in rats and that physalin D does not cross the blood-brain barrier. PMID- 21269893 TI - Determination of Ganciclovir and its prodrug Valganciclovir by hydrophilic interaction liquid chromatography-tandem mass spectrometry. AB - This manuscript describes the determination of Ganciclovir (GCV), active component of the antiviral drug Valcyte(r), and its ester prodrug Valganciclovir (VGC) in human and rat plasma, using liquid chromatography coupled to tandem mass spectrometry. Protein precipitation with acetonitrile was followed by hydrophilic interaction liquid chromatography on a silica column with 4 min run time. After electrospray ionization, the compounds were detected in positive ion selected reaction monitoring (SRM) mode. The lower limits of quantification (LLOQ) were 16 ng/mL for GCV and 4 ng/mL for VGC in human and rat plasma. Inter-day and intra day precisions and inaccuracies were below 15% and between 85 and 115%, respectively. Five-fold deuterated GCV and VGC were used as internal standards and compensated for any matrix effect. The method was successfully applied to samples from a rat pharmacokinetic study. The feasibility of blood analysis as dried blood spots (DBS) was investigated. PMID- 21269894 TI - Current status of cleaning and disinfection for gastrointestinal endoscopy in China: a survey of 122 endoscopy units. AB - BACKGROUND: Adequate compliance with the existing guidelines for cleaning and disinfection of gastrointestinal endoscopes and accessories is necessary to obtain high-level disinfection and prevent pathogen transmission. AIM: To investigate cleaning and disinfection practice in China. METHODS: A questionnaire with 21 questions concerning gastrointestinal endoscopy reprocessing was sent by e-mail to 189 endoscopy units in China. RESULTS: One hundred and twenty-two (80.39%) of the 189 units responded. Compared with the low-workload units (<5000 procedures/year), the high-workload units (>=5000 procedures/year) had a significantly higher number of gastrointestinal endoscopes (25.8 +/- 3.6 vs. 4.7 +/- 1.8, p < 0.01) and the higher possessing rate of automated endoscope reprocessors (43.9% vs. 3.1%, p<0.01). Glutaraldehyde was the most commonly employed disinfectant (88.5%) in all the units. In 23/122 (18.8%) units, the exposure time to glutaraldehyde was <45 min in the case of infectious disease patients. Eighty-six of 122 (70.5%) units reused disposable materials, of which 21/86 (24.4%) reused disposable forceps and disposable polypectomy hooks, and 2/86 (1.6%) reused disposable injection needles intermittently. CONCLUSION: Although gastrointestinal endoscopy has developed rapidly in China in the past decade, there is still room for improvement in the practice of endoscopy reprocessing, especially in middle-sized and small cities. PMID- 21269895 TI - Prospective analysis of waiting times for emergency plastic surgery in four units. AB - INTRODUCTION: Trauma is a significant part of the workload in plastic surgery. There are currently wide variations in the available resource for dealing with these patients. Delays to treatment currently exist and may result in poorer clinical outcomes. METHOD: Data was collected prospectively in 4 centres (Cork University Hospital, John Radcliffe Hospital, Stoke Mandeville Hospital and Salisbury District Hospital) assessing delays to theatre. We assessed time to theatre, both from injury and from review, cancellation rate, starvation time and patient satisfaction. RESULTS: 424 patients were audited over an 8-week period. The average time from review to theatre was 15.7 h and the average injury-to theatre time was 58.6 h. The average starvation time was 10 h; the mean cancellation rate was 25%. Patients are satisfied overall with the service provided with 83% rating the service as excellent or good, and 63% feeling that there wait was not too long. CONCLUSIONS: Despite an increase in provision of emergency plastic surgery trauma lists, the average wait for emergency plastic surgery is increasing. Despite this patients remain, on the whole, satisfied with the service that they are receiving. PMID- 21269896 TI - Body dysmorphic disorder and other psychiatric morbidity in aesthetic rhinoplasty candidates. AB - BACKGROUND: Body dysmorphic disorder (BDD) is a psychiatric disorder characterised by the patient's preoccupation with an imagined defect in his or her physical appearance. Subjects with BDD often seek cosmetic surgery; however, the outcome of surgery is usually not satisfactory. The aim of current study was to investigate the prevalence of BDD among the patients seeking cosmetic surgery. METHOD: In a cross-sectional study, 306 patients referred to cosmetic surgery clinics were recruited. Two psychiatrists detected BDD by interviewing the patients using Diagnostic and Statistical Manual of Mental Disorders fourth edition Text Revision (DSM IV-TR) criteria. Data analysis was done in Statistical Package for Social Sciences (SPSS) using the t-test and the Mann-Whitney test for numeral variables and the chi-square and Fisher's exact tests for nominal variables. RESULTS: Data analysis of demographics showed that 80% of patients were female. Analysis on disease-related variables showed that 126 (41%) of patients had an associated psychiatric disorder. Moreover, 75 patients (24.5%) fulfilled the DSM IV criteria for BDD. CONCLUSION: Findings from this study support earlier studies, which found that BDD is a relatively common disorder among individuals seeking aesthetic surgery, in particular in rhinoplasty patients. Preoperative psychiatry assessment recommends avoiding subsequent risk for both patients and surgeons. PMID- 21269897 TI - Functional and fixed orthodontics-induced growth of an aplastic condyle in a young patient: a case report. AB - Condylar aplasia is a condition characterized by the complete lack of a condyle. It is a rare disease, most often associated with more complex syndromes such as Hemifacial Microsomia, Treacher-Collins and Goldenhar. In this article, we present the case of a young female patient (4.3 years) with an aplastic left condyle. She received early two-phase treatment: first, a functional appliance to stimulate condylar growth and, second, fixed multibracket therapy and Class II elastics to improve the occlusal relationship. Functional therapy lasted many years due to non-compliance. Intermediate radiographic controls (at 8.6 years and at 10.4 years) showed no improvement in the growth of the aplastic condyle. The growing process started during fixed orthodontic therapy (beginning at 10.6 years). At the end of treatment, when the patient was 14, the size of the left condyle was similar to that of the controlateral. Below, we describe and discuss the treatment. PMID- 21269899 TI - Behavior of NiTi in the presence of oral bacteria: corrosion by Streptococcus mutans. AB - The aim of this study was to investigate the electrochemical behavior of nickel titanium (NiTi) orthodontic wires in a solution containing Streptococcus mutans oral bacteria. In this article, we explain our choice of bacterial species before describing the culture process in artificial saliva and the precautions needed to prevent contamination by other bacteria. The electrochemical behavior of the alloy (NiTi) was analyzed electrochemically in Ringer sterile artificial saliva and in artificial saliva enriched with a sterile broth and modified by addition of bacteria. The electrochemical procedures chosen for this study were: free corrosion potential, potentiodynamic curves and impedance spectroscopy. In this way, we were able to show that the free corrosion potential of the NiTi in the Ringer solution increases with time and then stabilizes, thus passivating the alloy. We also demonstrated that colonization of the metal surface by bacteria triggered a drop in the free corrosion potential. The electrochemical impedance findings revealed no significant difference in NiTi behavior between the two media. Finally, we observed a slight difference between the two corrosion currents in favor of the bacteria-enriched solution, in which the NiTi underwent greater corrosion. These findings demonstrate the impact of acidogenic bacteria on corrosion behavior of the NiTi wires investigated. However, further research is required, notably incorporating longer immersion times in the two media. PMID- 21269900 TI - Evidence-based orthodontics or the paradigm shift. AB - Practicing evidence-based orthodontics means offering patients treatment, which complies with scientifically-established data. However, how can we assess what science has determined to be certain given the confusing welter of information made available to us? The search for proof is a process, which requires knowledge of clinical methodology. It aims to set up a hierarchical classification of scientific and clinical studies and to assess their validity. By taking into account these different levels of proof, clinicians are in a position to make informed decisions regarding their clinical procedures and are thus empowered to take control of their learning process and the development of their skills. PMID- 21269903 TI - Population data on 5 non-CODIS STR loci (D10S1248, D22S1045, D2S441, D1S1656, D12S391) in a population sample from Brescia county (Northern Italy). PMID- 21269904 TI - Y-chromosome STR haplotype diversity in three ethnically isolated population from North-Western Romania. PMID- 21269905 TI - Genetic polymorphism of 15 STR loci in a Manchu population in Northeast China. PMID- 21269906 TI - Low-intensity pulsed ultrasound for non-union treatment: a 14-case series evaluation. AB - INTRODUCTION: Non-union is presently managed exclusively by surgery, but alternative treatments are under evaluation. OBJECTIVE: To assess the benefit of external ultrasound stimulation in surgically treated lowerlimb long-bone non union. PATIENTS AND METHODS: A retrospective series of 14 patients were treated using the Exogen((r)) ultrasound stimulator (Smith & Nephew Inc., Memphis, TN, USA) as part of management of surgically treated long-bone non-union. They received 20min stimulation daily over a period of 3 months. Regular clinical and radiological follow-up checked treatment efficacy. RESULTS: The mean interval to initiation of Exogen((r)) treatment after initial surgery was 361 days (range, 6, 38 months). Bone consolidation was obtained in 11 of the 14 cases (79%), and within 3 months of initiation of Exogen((r)) treatment in 27% (3/11), within 6 months in 27% (3/11) and within 9 months in 46% (5/11). There were no treatment linked complications. There was no significant correlation between interval to initiation of ultrasound treatment and bone consolidation. Associated sepsis or atrophy did not significantly impact treatment efficacy. DISCUSSION: The reference treatment strategy in non-union is surgical revision, with consolidation rates ranging from 85 to 100% according to the series. This attitude entails risk of complications, notably infection and postoperative pain. The present results were comparable to those of the literature, with 79% bone consolidation and no complications. Ultrasound stimulation proved an effective and non-invasive treatment for non-union. LEVEL OF EVIDENCE: Retrospective study, level IV. PMID- 21269907 TI - Korotkoff sound versus oscillometric cuff sphygmomanometers: comparison between auscultatory and DynaPulse blood pressure measurements. AB - Listening to Korotkoff sounds (K-sounds) to determine systolic and diastolic blood pressure (BP) has been the standard for noninvasive BP measurement in medical practices for nearly 100 years. It is the essential tool used for evaluation and assessment of patients with hypertension and risks of cardiovascular diseases (CVD) by physicians and nurses despite limited understanding of the nature of K-sounds. Analyzing cuff oscillometric signals to obtain BP has been the foundation of most digital BP monitors available today. DynaPulse is an oscillometric digital BP monitor that records and analyzes subtle changes of pulse waveforms during the course of a BP measurement while cuff pressure slowly decreases from above systolic to below diastolic. This study compares systolic and diastolic readings obtained by K-sound method following the Bogalusa Heart Study protocol and BP measured by DynaPulse (DP2000A) monitor, in order to better understand the nature and difference between K-sound and oscillometric methods. Analysis of means and differences is applied to BP data collected from 803 subjects examined in the Bogalusa Heart Study. The results indicated: 1) DynaPulse systolic was 9 mm Hg higher (P < .0001) than Phase 1 (K1) systolic, 2) DynaPulse diastolic was 5 mm Hg lower (P < .0001) than Phase 4 (K4), and 3) is less than 1 mm Hg higher than Phase 5 (K5) diastolic (P < .0001), when compared with K-sound auscultatory measurement. Understanding the methods and differences of DynaPulse oscillometric and K-sound BP measurements is important for clinic BP screening and self-BP monitoring, as well as future research to improve hypertension and CVD managements. PMID- 21269908 TI - Abnormal circadian blood pressure pattern 1-year after kidney transplantation is associated with subsequent lower glomerular filtration rate in recipients without rejection. AB - Abnormal circadian blood pressure (BP) pattern is common after kidney transplantation but its relationship to long term allograft function is unclear. Of 119 kidney recipients who had ambulatory BP monitoring 1 year from transplantation, 36 patients without history of rejection were selected. Twenty nine recipients were followed for 4 years and seven for 3 years. Iothalamate glomerular filtration rate (GFR) was obtained at 3 weeks then annually. Dippers (n = 10) had day-night systolic BP (SBP) drop (DeltaSBP) of >=10%, nondippers (n = 15) had DeltaSBP 0%-9%, whereas reverse dippers (n = 11) had nocturnal rise in SBP. Compared with dippers, reverse and nondippers had a higher Banff cv score at 1 year (P = .03), lower GFR at last follow-up (73.7 +/- 18.1, 55.7 +/- 16.3, and 56.6 +/- 21 mL/min/1.73 m(2) for dippers, non-, and reverse dippers, respectively, P = .05) and higher kidney function loss (8.0 +/- 20, -9 +/- 17, and 1 +/- 14 mL/min/1.73 m(2) for dippers, non-, and reverse dippers, respectively, P = .02). GFR at 4 years and at last follow-up independently correlated with DeltaSBP at 1 year (r = 0.46, P = .01; r = 0.34, P = .03). The current study indicates that abnormal circadian BP pattern at 1 year identifies a group of kidney recipients at risk for increased kidney function loss and lower GFR 3-4 years from transplantation. PMID- 21269909 TI - Diurnal blood pressure pattern and development of prehypertension or hypertension in young adults: the CARDIA study. AB - Nondippers (people whose sleep systolic blood pressure [SBP] fails to decrease >10% from daytime SBP) have increased risk of cardiovascular disease. The prevalence of nondipping in younger adults has not been well studied, nor has its value for predicting hypertension. We examined the prevalence of nondipping in a substudy of the Coronary Artery Risk Development in Young Adults (CARDIA) Study. We used Cox regression to estimate the hazard ratio (HR) conferred by nondipping for incident prehypertension or hypertension (preHTN/HTN) over 15 years. Of the 264 nonhypertensive participants at baseline, 118 (45%) were nondippers. Blacks were more likely than whites to be nondippers (52% versus 33%, P = .004). The incidence rate of preHTN/HTN was 29.2/1000 person-years among dippers and 36.2/1000 person-years among nondippers. Compared with those in the lowest quartile of nighttime to daytime SBP, those in the highest quartile were more likely to develop preHTN/HTN (HR 1.61; P = .06), but this relationship was attenuated after adjustment (HR 1.34; P = .27). Our results demonstrate that nondipping is common in young, nonhypertensive adults, and is more common in blacks than whites. Nondipping might predate a meaningful clinically detected increase in BP in some people, but more research in larger study samples is needed. PMID- 21269910 TI - Female type 2 diabetes mellitus mice exhibit severe ischemic brain damage. AB - Type 2 diabetes can impair the outcome of stroke as well as increase stroke risk; however, the sex difference in ischemic brain damage is not well known, and even less is known about the difference in diabetes. We therefore investigated the possible gender difference in brain damage after stroke associated with type 2 diabetes using a mouse model, KKAy. Female KKAy showed a much larger ischemic area compared with male KKAy. NADPH oxidase activity in the brain was also increased more in female than in male mice. Ovariectomy enhanced the ischemic area, and treatment with estradiol markedly attenuated the ischemic area to that in female KKAy, with a reduction of NADPH oxidase activity. Female and OVX mice showed improvement of cerebral blood flow (CBF) at 1 hour after middle cerebral artery (MCA) occlusion, but no significant difference in CBF of the ipsilateral penumbra and ipsilateral core 24 hours after MCA occlusion was observed among each group. Severe ischemic brain damage was observed in female KKAy compared with male KKAy. Estrogen showed a protective effect on the brain, at least partly from attenuation of oxidative stress in the female brain. These findings suggest that brain damage in diabetes mellitus might be more marked in women than in men. PMID- 21269911 TI - From the editor. PMID- 21269926 TI - Does air pollution trigger infant mortality in Western Europe? A case-crossover study. AB - BACKGROUND: Numerous studies show associations between fine particulate air pollutants [particulate matter with an aerodynamic diameter <= 10 MUm (PM10)] and mortality in adults. OBJECTIVES: We investigated short-term effects of elevated PM10 levels on infant mortality in Flanders, Belgium, and studied whether the European Union (EU) limit value protects infants from the air pollution trigger. METHODS: In a case-crossover analysis, we estimated the risk of dying from nontraumatic causes before 1 year of age in relation to outdoor PM10 concentrations on the day of death. We matched control days on temperature to exclude confounding by variations in daily temperature. RESULTS: During the study period (1998-2006), PM10 concentration averaged 31.9 +/- 13.8 MUg/m3. In the entire study population (n = 2,382), the risk of death increased by 4% [95% confidence interval (CI), 0-8%; p = 0.045] for a 10-MUg/m3 increase in daily mean PM10. However, this association was significant only for late neonates (2-4 weeks of age; n = 372), in whom the risk of death increased by 11% (95% CI, 1-22%; p = 0.028) per 10-MUg/m3 increase in PM10. In this age class, infants were 1.74 (95% CI, 1.18-2.58; p = 0.006) times more likely to die on days with a mean PM10 above the EU limit value of 50 MUg/m3 than on days below this cutoff. CONCLUSIONS: Even in an affluent region in Western Europe, where infant mortality is low, days with higher PM air pollution are associated with an increased risk of infant mortality. Assuming causality, the current EU limit value for PM10, which may be exceeded on 35 days/year, does not prevent PM10 from triggering mortality in late neonates. PMID- 21269928 TI - Respiratory and allergic health effects of dampness, mold, and dampness-related agents: a review of the epidemiologic evidence. AB - OBJECTIVES: Many studies have shown consistent associations between evident indoor dampness or mold and respiratory or allergic health effects, but causal links remain unclear. Findings on measured microbiologic factors have received little review. We conducted an updated, comprehensive review on these topics. DATA SOURCES: We reviewed eligible peer-reviewed epidemiologic studies or quantitative meta-analyses, up to late 2009, on dampness, mold, or other microbiologic agents and respiratory or allergic effects. DATA EXTRACTION: We evaluated evidence for causation or association between qualitative/subjective assessments of dampness or mold (considered together) and specific health outcomes. We separately considered evidence for associations between specific quantitative measurements of microbiologic factors and each health outcome. DATA SYNTHESIS: Evidence from epidemiologic studies and meta-analyses showed indoor dampness or mold to be associated consistently with increased asthma development and exacerbation, current and ever diagnosis of asthma, dyspnea, wheeze, cough, respiratory infections, bronchitis, allergic rhinitis, eczema, and upper respiratory tract symptoms. Associations were found in allergic and nonallergic individuals. Evidence strongly suggested causation of asthma exacerbation in children. Suggestive evidence was available for only a few specific measured microbiologic factors and was in part equivocal, suggesting both adverse and protective associations with health. CONCLUSIONS: Evident dampness or mold had consistent positive associations with multiple allergic and respiratory effects. Measured microbiologic agents in dust had limited suggestive associations, including both positive and negative associations for some agents. Thus, prevention and remediation of indoor dampness and mold are likely to reduce health risks, but current evidence does not support measuring specific indoor microbiologic factors to guide health-protective actions. PMID- 21269927 TI - Rotenone, paraquat, and Parkinson's disease. AB - BACKGROUND: Mitochondrial dysfunction and oxidative stress are pathophysiologic mechanisms implicated in experimental models and genetic forms of Parkinson's disease (PD). Certain pesticides may affect these mechanisms, but no pesticide has been definitively associated with PD in humans. OBJECTIVES: Our goal was to determine whether pesticides that cause mitochondrial dysfunction or oxidative stress are associated with PD or clinical features of parkinsonism in humans. METHODS: We assessed lifetime use of pesticides selected by mechanism in a case control study nested in the Agricultural Health Study (AHS). PD was diagnosed by movement disorders specialists. Controls were a stratified random sample of all AHS participants frequency-matched to cases by age, sex, and state at approximately three controls:one case. RESULTS: In 110 PD cases and 358 controls, PD was associated with use of a group of pesticides that inhibit mitochondrial complex I [odds ratio (OR)=1.7; 95% confidence interval (CI), 1.0-2.8] including rotenone (OR=2.5; 95% CI, 1.3-4.7) and with use of a group of pesticides that cause oxidative stress (OR = 2.0; 95% CI, 1.2-3.6), including paraquat (OR=2.5; 95% CI, 1.4-4.7). CONCLUSIONS: PD was positively associated with two groups of pesticides defined by mechanisms implicated experimentally-those that impair mitochondrial function and those that increase oxidative stress-supporting a role for these mechanisms in PD pathophysiology. PMID- 21269929 TI - Cholangiocarcinoma: principles and current trends. AB - BACKGROUND: Cholangiocarcinoma (CCA) is a lethal cancer of the biliary epithelium, originating from the liver (intrahepatic), at the confluence of the right and left hepatic ducts (hilar) or in the extrahepatic bile ducts. It is a rare malignancy associated with poor prognosis. DATA SOURCES: We searched the PubMed/MEDLINE database for relevant articles published from 1989 to 2008. The search terms used were related to "cholangiocarcinoma" and its "treatment". Although no language restrictions were imposed initially, for the full-text review and final analysis, our resources only permitted the review of articles published in English. This review deals with the treatment of cholangiocarcinoma, the principles and the current trends. RESULTS: The risks and prognostic factors, symptoms and differential diagnosis are thoroughly discussed. In addition, the tools of preoperative diagnosis such as endoscopic retrograde cholangiopancreatography, digital image analysis, fluorescence in situ hybridization and magnetic resonance cholangiopancreatography are reviewed. Moreover, the treatment of CCA is discussed. CONCLUSIONS: The only curative treatment available is surgical management. Unfortunately, many patients present with unresectable tumors, the majority of whom die within a year of diagnosis. Surgical treatment involves major resections of the liver, pancreas and bile duct, with considerable mortality and morbidity. However, in selected cases and where indicated, appropriate management with aggressive surgery may achieve a good outcome with a prolonged survival expectancy. PMID- 21269930 TI - Current opinion on lymphadenectomy in pancreatic cancer surgery. AB - BACKGROUND: Adenocarcinoma of the pancreas exhibits aggressive behavior in growth, inducing an extremely poor prognosis with an overall median 5-year survival rate of only 1%-4%. Curative resection is the only potential therapeutic opportunity. DATA SOURCES: A PubMed search of relevant articles published up to 2009 was performed to identify information about the value of lymphadenectomy and its extent in curative resection of pancreatic adenocarcinoma. RESULTS: Despite recent advances in chemotherapy, radiotherapy or even immunotherapy, surgery still remains the major factor that affects the outcome. The initial promising performance in Japan gave conflicting results in Western countries for the extended and more radical pancreatectomy; it has failed to prove beneficial. Four prospective, randomized trials on extended versus standard lymphadenectomy during pancreatic cancer surgery have shown no improvement in long-term survival by the extended resection. The exact lymph node status, including malignant spread and the total number retrieved as well as the lymph node ratio, is the most important prognostic factor. Positive lymph nodes after pancreatectomy are present in 70%. Paraaortic lymph node spread indicates poor prognosis. CONCLUSIONS: Undoubtedly, a standard lymphadenectomy including >15 lymph nodes must be no longer preferred in patients with the usual head location. The extended lymphadenectomy does not have any place, unless in randomized trials. In cases with body or tail location, the radical antegrade modular pancreatosplenectomy gives promising results. Nevertheless, accurate localization and detailed examination of the resected specimen are required for better staging. PMID- 21269931 TI - Monday blues of deceased-donor liver transplantation. AB - BACKGROUND: There is a constant and global shortage of deceased-donor organs for transplantation. Ways to identify areas for securing potential deceased-donor organs may improve the supply and hence benefit more patients in need of transplantation. METHODS: We looked into the disparity of the number of deceased donor liver transplantation (DDLT) performed at our hospital on different days of the weeks from January 2000 to the end of December 2009 (237 DDLTs). The number of DDLT performed on each day was compared with the other days of the week. RESULTS: It was apparent that there were fewer DDLTs on Mondays, as shown by the numbers of DDLT performed on different days of the week in an ascending order: Monday 18 (7.6%), Sunday 30 (12.7%), Thursday 34 (14.3%), Friday 36 (15.2%), Wednesday 38 (16.0%), Tuesday 40 (16.9%), and Saturday 41 (17.3%). The difference reached statistical significance when Monday was compared with Tuesday (P=0.019), Wednesday (P=0.010), Friday (P=0.021), and Saturday (P=0.007). It was twice as unlikely a DDLT would be performed on Monday as compared with other days. Such a trend did not change even with an increase in the number of deceased-donor liver grafts in the last year. As consent to donation was obtained from the donor family the day before DDLT, fewer consents were thus obtained on Sundays. CONCLUSION: These findings suggested that deceased-donor organ donation activities were less active on Sundays and could be improved. This further raises the concern of possible wastage of potential cases of organ donation. PMID- 21269932 TI - Expression of L amino acid transport system 1 and analysis of iodine-123 methyltyrosine tumor uptake in a pancreatic xenotransplantation model using fused high-resolution-micro-SPECT-MRI. AB - BACKGROUND: The specificity in discriminating pancreatitis is limited in the positron emission tomography (PET) using Fluorine-18-fluorodeoxyglucose. Furthermore, PET is not widely available compared to the single photon emission computed tomography (SPECT). Since amino acids play a minor role in metabolism of inflammatory cells, the potential of the SPECT tracer, 3-[123I]iodo-L-alpha methyltyrosine (123I-IMT), for detecting pancreatic cancer was examined in xenotransplantation models of human pancreatic carcinoma in mice. METHODS: 123I IMT was injected to eight mice inoculated with subcutaneous or orthotopic pancreatic tumors. Fused high-resolution-micro-SPECT (Hi-SPECT) and magnetic resonance imaging were performed. The gene expression level of L amino acid transport-system 1 (LAT1) was analyzed and correlated with tumor uptake of 123I IMT. RESULTS: A high uptake of 123I-IMT was detected in all tumor-bearing mice. The median tumor-to-background ratio (T/B) was 12.1 (2.0-13.2) for orthotopic and 8.4 (1.8-11.1) for subcutaneous xenotransplantation, respectively. Accordingly, the LAT1 expression in transplanted Colo357 cells was increased compared to non malignant controls. CONCLUSIONS: Our mouse model could show a high 123I-IMT uptake in pancreatic cancer. Fused MRI scans facilitate precise evaluation of uptake in the specific regions of interest. Further studies are required to confirm these findings in tumors derived from other human pancreatic cancer cells. Since amino acids play a minor role in the metabolism of inflammatory cells, the potential for application of 123I-IMT to distinguish pancreatic tumor from inflammatory pancreatitis warrants further investigation. PMID- 21269933 TI - Laparoscopic liver resection for benign and malignant liver tumors. AB - BACKGROUND: Laparoscopic liver resection is one of the most complex procedures in hepatobiliary surgery. In the last two decades, laparoscopic liver surgery has emerged as an option at major academic institutions. The purpose of this study is to describe the initial experience of minimally invasive liver resections at a non-academic institution. METHODS: We retrospectively reviewed medical records of patients undergoing laparoscopic liver resections between June 2006 and December 2009 at our center. Indications, technical aspects, and outcomes of these patients are described. RESULTS: Laparoscopic liver resection was attempted in 28 patients. Of these, 27 patients underwent laparoscopic liver resection (22 total laparoscopic and 5 hand assisted) and one needed conversion to open surgery. Twenty patients had a benign lesion and 8 had malignant lesions. Three patients had multiple lesions in different segments requiring separate resections. The lesions were located in segments II-III (n=18), IV (n=3), V-VI (n=9), and VII (n=1). Tumor size ranged from 1.5 cm to 8.5 cm. The surgical procedures included left lateral sectionectomy (n=17), left hepatectomy (n=2), sectionectomy (n=8), and local resections (n=4). Median operative time was 110 minutes (range 55-210 minutes), and the median length of hospital stay was 2.5 days (range 1-7 days). There was no perioperative mortality. One patient developed hernia at the site of tumor extraction requiring repair at 3 months. CONCLUSIONS: Laparoscopic liver resections can be safely performed in selected patients with benign and malignant liver tumors. With increasing experience, laparoscopic liver resections are likely to become a favorable alternative to open resection. PMID- 21269934 TI - Assessment of tumor vascularization with functional computed tomography perfusion imaging in patients with cirrhotic liver disease. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is a common malignant tumor in China, and early diagnosis is critical for patient outcome. In patients with HCC, it is mostly based on liver cirrhosis, developing from benign regenerative nodules and dysplastic nodules to HCC lesions, and a better understanding of its vascular supply and the hemodynamic changes may lead to early tumor detection. Angiogenesis is essential for the growth of primary and metastatic tumors due to changes in vascular perfusion, blood volume and permeability. These hemodynamic and physiological properties can be measured serially using functional computed tomography perfusion (CTP) imaging and can be used to assess the growth of HCC. This study aimed to clarify the physiological characteristics of tumor angiogenesis in cirrhotic liver disease by this fast imaging method. METHODS: CTP was performed in 30 volunteers without liver disease (control subjects) and 49 patients with liver disease (experimental subjects: 27 with HCC and 22 with cirrhosis). All subjects were also evaluated by physical examination, laboratory screening and Doppler ultrasonography of the liver. The diagnosis of HCC was made according to the EASL criteria. All patients underwent contrast-enhanced ultrasonography, pre- and post-contrast triple-phase CT and CTP study. A mathematical deconvolution model was applied to provide hepatic blood flow (HBF), hepatic blood volume (HBV), mean transit time (MTT), permeability of capillary vessel surface (PS), hepatic arterial index (HAI), hepatic arterial perfusion (HAP) and hepatic portal perfusion (HPP) data. The Mann-Whitney U test was used to determine differences in perfusion parameters between the background cirrhotic liver parenchyma and HCC and between the cirrhotic liver parenchyma with HCC and that without HCC. RESULTS: In normal liver, the HAP/HVP ratio was about 1/4. HCC had significantly higher HAP and HAI and lower HPP than background liver parenchyma adjacent to the HCC. The value of HBF at the tumor rim was significantly higher than that in the controls. HBF, HBV, HAI, HAP and HPP, but not MTT and PS, were significantly higher in the cirrhotic liver parenchyma involved with HCC than those of the controls. Perfusion parameters were not significantly different between the controls and the cirrhotic liver parenchyma not involved with HCC. CONCLUSIONS: CTP can clearly distinguish tumor from cirrhotic liver parenchyma and controls and can provide quantitative information about tumor-related angiogenesis, which can be used to assess tumor vascularization in cirrhotic liver disease. PMID- 21269935 TI - Relationship between model for end-stage liver disease score and left ventricular function in patients with end-stage liver disease. AB - BACKGROUND: Decreased cardiac contractility has been observed in cirrhosis, suggesting a latent cardiomyopathy in these patients. This study was designed to evaluate left ventricular structure and function in patients with end-stage liver disease by the model for end-stage liver disease (MELD) scoring system. METHODS: We recruited 82 patients (72 male, 10 female; mean age 50.3+/-8.9 years) with end stage liver disease who underwent orthotopic liver transplantation between January 2002 and May 2008. Seventy-eight patients had cirrhosis and 4 had primary liver cancer. Patients were categorized into three groups on the basis of MELD score: <= 9 (27 patients, 33%); 10-19 (40, 49%); and >= 20 (15, 18%). The relationship between MELD score and cardiac structure and function was determined. Preoperative assessments of blood biochemistry, blood coagulation, serum virology, echocardiography and electrocardiography were performed. RESULTS: MELD score was positively correlated with enlarged left atrial diameter, increased interventricular septum thickness (IVST), increased aortic flow, corrected QT interval (QTc) extension and cardiac output (P=0.033, 0.002, 0.000, 0.000 and 0.009, respectively). International normalized ratio also had a correlation with the above parameters and enlarged left ventricular end-diastolic diameter (P=0.043, 0.010, 0.000, 0.001, 0.016 and 0.008, respectively). Serum creatinine was positively correlated with IVST (r=0.257, P=0.020), but negatively correlated with early maximal ventricular filling velocity/late diastolic or atrial velocity ratio (r=-0.300, P=0.006). A difference of QTc >440 ms among the three groups was statistically significant (X2=9.791, P=0.007). CONCLUSIONS: Abnormalities in cardiac structure and function are common in patients with end stage liver disease. MELD score is a practically useful approach for the assessment of cardiac function in such patients. PMID- 21269936 TI - Hepatocyte differentiation of human fibroblasts from cirrhotic liver in vitro and in vivo. AB - BACKGROUND: Mesenchymal stem cells (MSCs) and fibroblasts have intimate relationships, and the phenotypic homology between fibroblasts and MSCs has been recently described. The aim of this study was to investigate the hepatic differentiating potential of human fibroblasts in cirrhotic liver. METHODS: The phenotypes of fibroblasts in cirrhotic liver were labeled by biological methods. After that, the differentiation potential of these fibroblasts in vitro was characterized in terms of liver-specific gene and protein expression. Finally, an animal model of hepatocyte regeneration in severe combined immunodeficient (SCID) mice was created by retrorsine injection and partial hepatectomy, and the expression of human hepatocyte proteins in SCID mouse livers was checked by immunohistochemical analysis after fibroblast administration. RESULTS: Surface immunophenotyping revealed that a minority of fibroblasts expressed markers of MSCs and hepatic epithelial cytokeratins as well as alpha-smooth muscle actin, but homogeneously expressed vimentin, desmin, prolyl 4-hydroxylase and fibronectin. These fibroblasts presented the characteristics of hepatocytes in vitro and differentiated directly into functional hepatocytes in the liver of hepatectomized SCID mice. CONCLUSIONS: This study demonstrated that fibroblasts in cirrhotic liver have the potential to differentiate into hepatocyte-like cells in vitro and in vivo. Our findings infer that hepatic differentiation of fibroblasts may serve as a new target for reversion of liver fibrosis and a cell source for tissue engineering. PMID- 21269937 TI - Peroxisome proliferator-activated receptor gamma inhibits hepatic fibrosis in rats. AB - BACKGROUND: Hepatic fibrosis is a necessary step in the development of hepatic cirrhosis. In this study we used lentiviral vector-mediated transfection technology to evaluate the effect of peroxisome proliferator-activated receptor gamma (PPAR-gamma) on rat hepatic fibrosis. METHODS: Hepatic fibrosis in rats was induced by CCl4 for 2 weeks (early fibrosis) and 8 weeks (sustained fibrosis). The rats were randomly divided into four groups: normal control, fibrosis, blank vector, and PPAR-gamma. They were infected with the recombinant lentiviral expression vector carrying the rat PPAR-gamma gene by portal vein injection. The liver of the rats was examined histologically and hydroxyproline was assessed. In vitro primary hepatic stellate cells (HSCs) were infected with the recombinant lentiviral expression vector carrying the rat PPAR-gamma gene. The status of HSC proliferation was measured by the MTT assay. The protein levels of PPAR-gamma, alpha-smooth muscle actin (alpha-SMA) and type I collagen expression were evaluated by the Western blotting method. RESULTS: In vitro studies revealed that expression of PPAR-gamma inhibited expression of alpha-SMA and type I collagen in activated HSCs (P<0.01) as well as HSC proliferation (P<0.01). In vivo experiments indicated that in the early hepatic fibrosis group, the hydroxyproline content and the level of collagen I protein in the liver in the PPAR-gamma transfected group were not significantly different compared to the hepatic fibrosis group and the blank vector group; whereas the expressions of PPAR-gamma and alpha-SMA were different compared to the hepatic fibrosis group (P<0.01). In the sustained hepatic fibrosis group, there were significant differences in the hydroxyproline content and the expression of PPAR-gamma, alpha SMA, and type I collagen between each group. CONCLUSION: PPAR-gamma can inhibit HSC proliferation and hepatic fibrosis, and suppress alpha-SMA and type I collagen expression. PMID- 21269938 TI - Effects of suppressing glucose transporter-1 by an antisense oligodeoxynucleotide on the growth of human hepatocellular carcinoma cells. AB - BACKGROUND: The glucose transporter-1 (Glut-1), a key rate-limiting factor in the transport and metabolism of glucose in cancer cells, is over-expressed in many human cancer cells and this over-expression is correlated with poor biological behavior. The increased levels of Glut-1 expression in hepatocellular carcinoma (HCC) cells functionally affect tumorigenicity. This study was undertaken to investigate effects of suppressing Glut-1 by an antisense oligodeoxynucleotide (AS-ODN) on the growth of human hepatocellular carcinoma (HepG-2) cells. METHODS: We used AS-ODN targeting against the Glut-1 gene in a HepG-2 cell line. There were four experimental groups: empty pcDNA3.1 vector (mock transfection), pcDNA3.1-anti-Glut (+), pcDNA3.1-Glut (+), and non-transfected HepG-2 cells. The Glut-1 mRNA expression was detected by RT-PCR and the Glut-1 protein expression by Western blotting after cell culture, and the glucose uptake was detected after glucose stimulation in each group. RESULTS: Compared with non-transfected HepG-2 or Glut-1 pcDNA3.1, a down-regulation of Glut-1 mRNA in HepG-2 cells transfected with anti-Glut-1 pcDNA3.1 was noted (P<0.05). Glut-1 protein in HepG-2 cells transfected with Glut-1 AS-ODN was decreased compared with non-transfected HepG 2, Glut-1 pcDNA3.1, or empty vectors. Glucose uptake by the HepG-2 cells transfected with AS-ODN was decreased at 1 hour after glucose stimulation. CONCLUSIONS: The application of Glut-1 AS-ODN can down-regulate the expression of Glut-1 at mRNA and protein, and inhibit glucose uptake partially in HepG-2 cells. The Glut-1 gene maybe a potential therapeutic target for HCC. PMID- 21269939 TI - Protective effects of glutamine preconditioning on ischemia-reperfusion injury in rats. AB - BACKGROUND: Hepatic ischemia-reperfusion injury is a common phenomenon in hepatic surgical procedures and can result in further severe damage. This study aimed to investigate the protective effects of glutamine preconditioning on hepatic ischemia-reperfusion injury in rats and its dose-dependency. METHODS: Thirty-two healthy male Wistar rats were randomly divided into four groups (n=8 per group). One group received 0.9% NaCl (control) and the other three received glutamine (Gln groups) 4 hours before ischemia. The Gln groups were named GL, GM, and GH according to the glutamine dose. The liver was subjected to 1 hour of ischemia and 2 hours of reperfusion. Two hours later, the levels of alanine aminotransferase (ALT), intracellular free calcium (Ca2+), and activity of Na+/K+ adenosine triphosphatase (ATPase) and superoxide dismutase (SOD) were assessed, and liver tissue sections were examined under a microscope. RESULTS: The Gln and control groups differed in the concentration of intracellular free calcium (P<0.05), and the activity of Na+/K+ ATPase and SOD in the Gln groups was higher than in the control group (P<0.05). The ALT level was lower in the GM and GH groups than in the control group (P<0.05). The levels of Na+/K+ ATPase and SOD rose gradually with increasing glutamine dose (P<0.05), and the concentration of Ca2+ declined gradually with increasing glutamine dose (P<0.05). The degree of hepatocyte injury was milder in the Gln groups than in the control group. CONCLUSIONS: Glutamine preconditioning protected effectively against hepatic ischemia-reperfusion injury. These protective effects were related to the dose of glutamine and due to the reduction of intracellular calcium overload and the improvements in the activity of Na+/K+ ATPase and SOD. PMID- 21269940 TI - Microvessel density at different levels of normal or injured bile duct in dogs and its surgical implications. AB - BACKGROUND: Ischemic recurrent stricture after surgical repair for iatrogenic bile duct injury (BDI) remains a challenge in clinical practice. The present study was designed to investigate whether ischemia is universal and of varied severity at different levels of the proximal bile duct after BDI. METHODS: A total of 30 beagle dogs were randomly divided into control, BDI, and BDI-repaired groups. The BDI animal model was established based on the classic pattern of laparoscopic cholecystectomy-related BDI. The animals were sacrificed on postoperative day 15, and bile duct tissue was harvested to assess microvessel density (MVD) at selected levels of the normal, post-BDI and BDI-repaired bile duct with the CD34 immunohistochemistry technique. RESULTS: In the control group, MVD at level H (high level) was remarkably higher than that at level L (low level). No significant difference was found between MVDs at levels H and M (middle level), as well as at levels M and L. However, the tendency was noted that the closer the level to the hilus, the greater the MVD at that level. In both the BDI and BDI-repaired groups, MVDs at level H were generally greater than those at level L, despite the unremarkable differences between MVDs at neighboring levels. In these two groups, a similar tendency of MVD distribution to that in the control group was found; the closer the level to the injury site, the lower was the MVD at that level. Moreover, compared with the MDVs at the levels M and L in the control group, MVDs at the corresponding levels in the BDI and BDI-repaired groups were all remarkably reduced (P<0.05). In addition, MVDs at all three levels in the BDI group significantly declined further after BDI repair. CONCLUSIONS: After BDI, universal ischemic damage in the injured proximal bile duct develops close to the injury site, while close to the hilus, ischemia is relatively slight. High hepaticojejunostomy, rather than low biloenterostomy or end-to-end duct anastomosis, should be recommended for BDI repair. Great care should be taken to protect the peribiliary plexus during repair. PMID- 21269941 TI - Roles of sulfonylurea receptor 1 and multidrug resistance protein 1 in modulating insulin secretion in human insulinoma. AB - BACKGROUND: Sulfonylurea receptor 1 (SUR1) and multidrug resistance protein 1 (MRP1) are two prominent members of multidrug resistance proteins associated with insulin secretion. The aims of this study were to investigate their expression in insulinomas and their sole and synergistic effects in modulating abnormal insulin secretion. METHODS: Fasting glucose, insulin and C-peptide were measured in 11 insulinoma patients and 11 healthy controls. Prolonged oral glucose tolerance tests were performed in 6 insulinoma patients. Insulin content, SUR1 and MRP1 were detected in 11 insulinoma patients by immunohistochemistry. SUR1 and MRP1 were also detected in 6 insulinoma patients by immunofluorescence. RESULTS: Insulinoma patients presented the typical demonstrations of Whipple's triad. Fasting glucose of each insulinoma patient was lower than 2.8 mmol/L, and simultaneous insulin and C-peptide were increased in insulinoma patients. Prolonged oral glucose tolerance tests showed that insulin secretion in insulinoma patients were also stimulated by high glucose. Immunohistochemistry and immunofluorescence staining showed that SUR1 increased, but MRP1 decreased in insulinoma compared with the adjacent islets. CONCLUSIONS: The hypersecretion of insulin in insulinomas might be, at least partially, due to the enrichment of SUR1. In contrast, MRP1, which is down-regulated in insulinomas, might reflect a negative feedback in insulin secretion. PMID- 21269942 TI - Aberrant methylation frequency of TNFRSF10C promoter in pancreatic cancer cell lines. AB - BACKGROUND: A growing body of evidence suggests that many tumors are initiated by both epigenetic abnormalities and gene mutations, which promote tumor progression. Epigenetic abnormalities include changes in DNA methylation and in the modification of histones. This study aimed to assess the status of methylation in the CpG island (CGI) of the tumor necrosis factor receptor superfamily member 10c (TNFRSF10C) with combined bisulfite restriction analysis (COBRA) and to evaluate its role in the progression of pancreatic cancer (PC). METHODS: The methylation status of four PC cell lines was assessed using COBRA and/or bisulfite genomic sequencing (BGS). Changes in methylation and TNFRSF10C expression in PC cell lines before and after treatment with 5-aza-2' deoxycytidine (5-aza-dC) and/or trichostatin A (TSA) were assessed by BGS and real-time RT-PCR. Apoptosis in the four cell lines was tested by flow cytometry (FCM) and TUNEL assay. RESULTS: The methylation status of the TNFRSF10C promoter was assessed in PC cells (BxPC-3: 68.84+/-8.71%; CFPAC-1: 0; PANC-1: 96.77+/ 4.57%; SW1990: 54.97+/-7.33%) with the COBRA assay, which was confirmed by the results of BGS. After treatment with 5-aza-dC and/or TSA, apoptosis was induced in PC cells to different degrees, and the levels of TNFRSF10C transcriptional expression in the PC cell lines (except CFPAC-1) increased markedly after 5-aza dC treatment. CONCLUSIONS: A high frequency of CGI methylation in the TNFRSF10C promoter results in inactivation of the gene and enhancement of tumor growth in most PC cell lines (except CFPAC-1). Inactivation of TNFRSF10C by CGI hypermethylation can play an important role in PC progression and be potentially useful as a diagnostic marker and a new therapeutic approach for PC. PMID- 21269943 TI - Primary hepatic carcinosarcoma. AB - BACKGROUND: Primary hepatic carcinosarcoma is a rare malignant tumor containing an intimate mixture of carcinomatous and sarcomatous elements. Reports on risk factors, epidemiology, and pathogenesis of the tumor as well as the experience in its treatment are limited. METHOD: We present a case of primary carcinosarcoma of the liver in a 69-year-old man who complained of right hypochondrial pain and weight loss for two months. RESULTS: Magnetic resonance imaging revealed a 14 x 12 cm mass in segments 7-8 and 4 of the liver with vena hepatica invasion. An ultrasonography-guided biopsy showed osteoid tissue without osteoblastic rimming. Vascular structures accompanied the osteoid tissue. The patient underwent surgery after a diagnosis of hemangioma. Intraoperative frozen sections revealed a carcinosarcoma associated with an osteosarcoma and cholangiocellular carcinoma components. CONCLUSIONS: Preoperative diagnosis of this rare primary hepatic malignant tumor may be difficult by biopsy owing to intratumoral heterogeneity. Highly mature areas of the osteosarcomatous component may lead to misdiagnosis of metaplastic bone tissue. Clinicopathologic features of this rare entity are discussed. PMID- 21269944 TI - Atypical focal nodular hyperplasia of the liver. AB - BACKGROUND: Focal nodular hyperplasia, a benign hepatic tumor, is usually asymptomatic. However, rarely the entity can cause symptoms, mandating intervention. METHOD: We present a case of focal nodular hyperplasia of the liver, which caused a considerable diagnostic dilemma due to its atypical presentation. RESULTS: A 29-year-old woman presented with a 15-year history of a progressively increasing mass in the right upper quadrant which was associated with pain and emesis. Examination showed a firm, mobile mass palpable below the right subcostal margin. A computed tomography scan of the abdomen showed an exophytic mass arising from hepatic segments III and IVb. Trucut biopsy of the hepatic mass was equivocal. Angiography showed a vascular tumor that was supplied by a tortuous branch of the proper hepatic artery. Surgical intervention for removal of the mass was undertaken. Intra-operatively, two large discrete tumors were found and completely resected. Histopathological examination showed features consistent with focal nodular hyperplasia. CONCLUSION: This description of an unusual case of focal nodular hyperplasia of the liver highlights the point that the diagnosis of otherwise benign hepatic tumors may be difficult despite extensive work-up in some cases. PMID- 21269945 TI - SpyGlass cholangioscopy for management of choledocholithiasis during pregnancy. PMID- 21269946 TI - Effect of asymmetric dimethylarginine on MIF expression and TNF-alpha and IL-8 secretion in THP-1 monocytes-derived macrophages. AB - OBJECTIVE: To investigate the effect of ADMA on macrophage migration inhibitory factor (MIF) expression and tumor necrosis factor-alpha (TNF-alpha) and IL-8 secretion in THP-1 monocyte-derived macrophages. METHIDS: THP-1 monocytes were induced to differentiate into macrophages by a 24-h incubation with 160 nmol/L PMA. The THP-1 monocyte-derived macrophages were exposed to different concentrations of ADMA for 24 h, and the changes in MIF mRNA and protein expressions were analyzed with RT-PCR and Western blotting, respectively. Enzyme linked immunosorbent assay was used to detect the levels of TNF-alpha and IL-8 in the supernatant of THP-1-derived macrophages following ADMA treatments. RESULTS: ADMA obviously up-regulated MIF mRNA and protein expressions in THP-1-derived macrophages in a concentration- dependent manner. Exposure of the cells to 15 umol/L ADMA for 24 h showed the most potent effect in up-regulating MIF mRNA and protein expressions. ADMA treatment also resulted in a dose-dependent increase of the levels of TNF-alpha and IL-8 in the culture supernatant of the macrophages, and the peak levels occurred following the treatment with 15 umol/L ADMA. CONCLUSION: ADMA can up-regulate MIF expression and induce TNF-alpha and IL-8 secretion in THP-1 monocyte-derived macrophages. PMID- 21269947 TI - [Isolation of human amniotic mesenchymal cells and their differentiation potential into islet-like cells in vitro]. AB - OBJECTIVE: To isolate human amniotic mesenchymal cells (hAMCs) and investigate their transdifferentiation ability into islet-like cells in vitro. METHODS: Human amnion was treated with the trypsin/EDTA to remove the amniotic epithelial cells and then incubated with collagenase I and dispase at 37 degrees celsius; overnight. The cells were collected by centrifugation and identified for the expressions of vimentin and SSEA-4 using immunofluorescence assay and for CD29, CD90, CD34, and CD45 using flow cytometry. RT-PCR was performed to detect the expressions of ACTG2, ACTA2, MMP2, Cripto, Sox2, LEFTYA, nanog, and Oct-4 in the cells. The differentiation potential of the isolated cells into inslet-like cells was assessed after a 14-day induction with the inducing factors by RT-PCR and immunofluorescence assay. RESULTS: The hAMCs were capable of in vitro proliferation and passaging for 10 passages while retaining the normal karyotype. The isolated cells were positive for staining of vimentin and SSEA-4 and negative for CD34 and CD45; the CD29 and CD90 cells accounted for (91.5?9.93)% and (48.7?9.47)% of the cells, respectively. The hAMCs expressed several pluripotency related genes, including Cripto, Sox2, LEFTYA, nanog, and Oct-4. After induction, endocrine-related genes were expressed in the islet-like cells, including PDX1, ngn3, insulin and glucagon. CONCLUSION: We have successfully established the method for isolating hAMCs, which possess the potential of differentiation into islet-like cells in vitro. PMID- 21269948 TI - [Effects of Qufengtongluo recipe on proteinuria and glomerular filtration membrane in rats with adriamycin-induced nephropathy]. AB - OBJECTIVE: To assess the therapeutic effect of Qufengtongluo (QFTL) recipe against proteinuria and glomerular filtration membrane damage in rats with adriamycin-induced nephropathy (AN). METHODS: Fifty-six SD rats were randomized into normal control (A) and AN model groups. In the AN model group, the rat AN models established by a single intravenous injection of adriamycin via the tail vein were subdivided into model (B), QFTL recipe (C), prednisone (D), and benazepril (E) groups 3 weeks after adriamycin injection. The 24-h urinary protein level was measured and the expression of anionic sites on the filtration membrane was evaluated using electron microscope with PEI staining. Nephrin expression on the glomerular filtration membrane was detected with indirect immunofluorescence assay. RESULTS: Compared with group A, the model group showed significantly increased level of 24-h urinary protein (P<0.01), suggesting successful establishment of the AN model. Treatment with QFTL recipe obviously lowered the 24-h urinary protein (P<0.01), and increased the expression of anionic sites and nephrin on the glomerular filtration membrane in the AN rats (P<0.01). CONCLUSION: QFTL recipe can effectively decrease 24-h urinary protein, improve the symptoms, and up-regulate the expressions of anionic sites and nephrin on the glomerular filtration membrane in rats with AN. PMID- 21269949 TI - [Effect of erythropoietin combined with granulocyte-colony stimulating factor in the treatment of acute myocardial infarction in rats]. AB - OBJECTIVE: To evaluate the effects of erythropoietin (EPO) combined with granulocyte-colony stimulating factor (G-CSF) on left ventricular function and ventricular remodeling after acute myocardial infarction (AMI) and investigate the possible mechanism. METHODS: The experimental design consisted of 5 groups of rats, namely the sham, myocardial infarction (MI) model, MI with EPO treatment, MI with G-CSF treatment, and MI with EPO plus G-CSF treatment groups. Apoptosis of the cardiomyocytes was detected by TUNEL staining, and HE staining, Masson trichrome staining, scarlatinum staining, and VIII agent staining were used to evaluate the survival, scar collagen deposition, and angiogenic effects. The cardiac structure and function of the rats after the treatments were assessed by echocardiography and hemodynamic examination. RESULTS: Echocardiography indicated that LVEF and FS were improved in all the intervention groups 7 days after MI, and the rats in EPO plus G-CSF treatment group showed the most obvious reduction of LVESD and LVESV (P<0.01). On day 28 after MI, all the intervention groups showed improvements in LVEF, FS, LVESD, LVEDD, LVESV and LVEDV, which were especially obvious in the combined treatment group; the interventions, especially the combined treatment, also resulted in decreased LVEDP and increased LVSP and +dP/dtmax. On day 1 after MI, the number of apoptotic cells was significantly greater in the MI model group than in EPO and G-CSF groups, and was the fewest in the combined treatment group (P<0.01). On day 28, the number of new vessels increased and the scar and collagen deposition reduced in the EPO and G-CSF groups, and these changes were more obvious in the combined treatment group. CONCLUSIONS: EPO combined with G-CSF can prevent left ventricular remodeling and improve cardiac systolic and diastolic functions by inhibiting cardiomyocyte apoptosis, reducing tissue collagen deposition and inducing neovascularisation. PMID- 21269950 TI - [Differential expression of hsa-miR-126 and hsa-miR-518b in esophageal squamous carcinoma]. AB - OBJECTIVE: To identify the differentially expressed microRNAs (miRNAs) between esophageal squamous carcinoma (ESC) and adjacent non-tumorous tissue (NT). METHODS: The expression levels of the miRNAs were detected in 3 fresh ESC and NT samples by hybridization with miRNAs microarray chip. Real-time quantitative RT PCR was performed to confirm the results of the microarray analysis. The expressions of hsa-miR-126 and hsa-miR-518b in ESC were validated by real-time quantitative RT-PCR in another independent 15 matched samples. RESULTS: A total of 11 miRNAs exhibited differential expressions in ESC samples as compared to their expressions in the NT samples, including a 1 up-regulated miRNA and 10 down regulated miRNAs. Compared with normal esophageal samples, the ESC tissues showed up-regulated hsa-miR-126 and down-regulated hsa-miR-518b expression. CONCLUSION: hsa-miR-126 and hsa-miR-518b are differentially expressed in ESC, and they might play important roles in the carcinogenesis and progression of ESC. PMID- 21269951 TI - [Iodoacetamide-induced aquaporin 1 expression in fibroblasts is energy dependent]. AB - OBJECTIVE: To investigate the impact of energy metabolism at the cellular level on the expression of the water channel protein aquaporin 1 (AQP1). METHODS: Balb/c mouse fibroblasts were incubated with iodoacetamide (IA) in vitro, and the changes in AQP1 expression were detected by immunoblotting and immunohistochemistry at 0, 4, and 6 h. RESULTS: IA induced the expression of AQP1 at 4 and 6 h accompanied with cell death. Reverse transcription PCR showed an increased expression of AQP1 mRNA in the cells. AQP1 expression was also upregulated by the inhibitor of microtubule and cytochrome C oxidase. CONCLUSION: A pretranslational regulation occurs in IA-induced AQP1 expression in mouse fibroblasts, and the up-regulated AQP1 accumulation is characterized by mitochondria-related energy dependence. PMID- 21269952 TI - [Assessment of the reliability and validity of the Sub-health Measurement Scale Version1.0]. AB - OBJECTIVE: To assess the reliability and validity of the Sub-health Measurement Scale Version 1.0 (SHMS V1.0). METHODS: A spot trial sampling of 2000 individuals was conducted to study the test-retest reliability, Cronbach alpha coefficient, split-half reliability, contract validity, content validity and criterion-related validity of SHMS V1.0. RESULTS: The spot trial results indicated a test-retest reliability of SHMS V1.0 of 0.644 (P<0.001) with a Cronbach alpha coefficient of 0.917 and a split-half reliability of 0.831. The results showed a close correlation between each item of SHMS V1.0 and its dimension, but a low correlation between a particular item and other dimensions. The dimension score was significantly correlated to its subscale scores, but not to other subscale scores. The results of factor analysis matched the theoretical conception of SHMS V1.0. The correlation coefficient between SHMS V1.0 and SF-36 was 0.664 (P<0.001). CONCLUSION: SHMS V1.0 has a good reliability and validity, and is a reliable and valid measurement scale for sub-health evaluation. PMID- 21269953 TI - [Primary investigation of methamphetamine-induced toxicity in PC12 cells]. AB - OBJECTIVE: To investigate the mechanism of methamphetamine (METH)-induced toxicity in PC12 cells. METHODS: PC12 cells were treated with METH for 24 h at the doses of 0, 0.5, 1.0, 1.5, 2.0, or 2.5 mmol/L. The morphological changes of the cells were observed under inverted microscope after the treatment. MTT assay and flow cytometry were used to assess the cell viability and apoptotic rates, respectively, and the level of nitric oxide (NO) was measured by enzyme reduction method. RESULTS: The PC12 cells exposed to METH were morphologically featured by cell shrinkage, dendrite disruption and disappearance of cell reticular formation. METH exposure caused a dose-dependent reduction in the cell viability (P<0.01), resulting in also increased cell apoptotic rate and significant elevation of NO in the cell culture supernatant (P<0.05). CONCLUSION: METH exposure induces cytotoxicity and injury of differentiated PC12 cells, leading to decreased cell viability and increased cell apoptosis and NO level. Cell apoptosis and excessive NO production are involved in METH-induced cytotoxicity. PMID- 21269954 TI - [Enhancement of target gene expression by recombinant adeno-associated virus combined with recombinant adenovirus in vivo]. AB - OBJECTIVE: To study the changes in the intensity and temporal pattern of target gene expression in the tumor tissue of nude mice bearing human nasopharyngeal carcinoma (NPC) following injection of recombinant adeno-associated virus (rAAV) and recombinant adenovirus (AdV) in vivo. METHODS: EBV-positive human NPC cell line C666-1 was inoculated subcutaneouly in nude mice. After the tumor mass reached 3 mm in diameter, 1.5 * 10(11) v.g (virus genome) rAAV-EGFP, 2.5 * 10(8) pfu rAdV-EGFP or their balanced mixture was injected intratumorally. At 5 and 10 days after the injection, the tumor tissues were harvested for immunohistochemical staining of GFP, and the ratio of the GFP-positive cells and the intensity of GFP expression was determined. RESULTS: Immunohistochemistry for GFP showed that 5 days after the injection, GFP expression was detected (1.70 ? 0.48) in the tumor tissue in rAAV group, and the peak expression levels was seen in rAdV group (6.00?1.94); the expression level was comparable between the combination group (6.90 ? 1.92) and rAdV group. At 10 days, GFP expression was considerably lowered to 2.00 ? 0.67 in rAdV group but increased to 8.00?1.15 in rAAV group. The expression in the combination group maintained a high level at 10 days (10.10?1.63), which was significantly higher than that in rAAV group (P%0.001). CONCLUSION: Transfection with rAAV combined with rAdV allows instant, sustained and significantly enhanced expression of the target gene in the tumor tissue. This approach takes advantages of the two viruses and can be ideal for exogenous gene delivery into the tumor tissues. PMID- 21269955 TI - [hTERT single nucleotide polymorphism is associated with increased risks of hepatocellular carcinoma and tumor metastasis]. AB - OBJECTIVE: To investigate the effect of hTERT single nucleotide polymorphisms on the development and metastasis of hepatocellular carcinoma. METHODS: A total of 290 male patients were divided into hepatitis-induced primary hepatocellular carcinoma (HCC) group (n%162), metastatic HCC group (n%22), and control group (n%106). hTERT gene was amplified and hTERT single nucleotide polymorphisms (SNPs) were tested in these subjects. RESULTS: Significant differences were found in rs2853690 and rs10069690 distribution, but the difference in rs6554743 remained uncertain. The C and T alleles of rs10069690 and rs6554743 showed significant differences between the 3 groups; the carriers of non-T allele of rs10069690 had higher frequencies in both primary and metastatic HCC groups. CONCLUSION: Some of the polymorphisms of hTERT may increase the risks of development and metastasis of hepatocellular carcinoma. PMID- 21269956 TI - [Radiation-induced G2 phase arrest may contribute to the radioresistance of breast cancer stem cells]. AB - OBJECTIVE: To investigate radiation-induced cell cycle changes of human breast cancer stem cells enriched by suspension culture. METHODS: The tumorigenicity of human breast cancer stem cell line MCF-7 cultured in serum-free media was confirmed in NOD/SCID mice, and the radiosensitivity of the cells was tested by clone formation assay following radiation exposure. Flow cytometry was performed to evaluate radiation-induced cell cycle changes, and the protein expression of pCDC25C (ser216) was measured by Western blotting. RESULTS: After the exposure to 2 Gy radiation, the survived fraction of the cells in suspension culture and those in adherent culture was 0.856 ? 0.061 and 0.783 ? 0.097, respectively, and the cells in suspension culture showed an obviously greater capacity of tumorigenicity in NOD/SCID mice. The radiation exposure resulted in an obvious increase in the proportion of G2 phase cells from (22.03 ? 2.12)% to (45.83 ? 2.25)% and significantly increased the expression of pCDC25C (ser216). CONCLUSION: Radiation- induced G2 phase arrest may contribute to the resistance of the breast cancer stem cells to radiotherapy. PMID- 21269957 TI - [Mechanisms of ultraviolet B irradiation-induced injuries in 16HBE cells]. AB - OBJECTIVE: To investigate the biological effects of ultraviolet B (UVB) irradiation on human bronchial epithelial cells (16HBE cells) and explore the possible mechanism. METHODS: The survival rates of 16HBE cells were detected by MTT assay at 12 h after UVB irradiation at different doses (0, 10, 30, 50, 70, and 100 J/m(2)) or at 50 J/m(2) for different durations (2, 4, 8, 12, and 24 h). The DNA ladder was detected by agarose gel electrophoresis, the cell cycle changes were analyzed by flow cytometry, and the expression of nuclear factor kappaB (NF-kappaB)/p65 protein was assayed by Western blotting following the exposures. RESULTS: UVB irradiation of the cells resulted in lowered cell survival rates, DNA fragmentation, S phase arrest and up-regulation of NF kappaB/p65 protein expression. CONCLUSIONS: UVB irradiation can induce growth inhibition and apoptosis of 16HBE cells, in which process NF-kappaB protein may play a key role. PMID- 21269958 TI - [Correlation analysis of sub-health status and health-related risk behaviors in college students]. AB - OBJECTIVE: To study the sub-health status in college students in relation to health-related risk behaviors. METHODS: Using convenient sampling method, 6176 college students (3285 male and 2891 female students) were surveyed with questionnaires for general demographical data, sub-health state and health-risk behaviors. RESULTS: The reported rate of sub-health state was 10.2%. The reported rate of physical sub-health was 11.7%, and the rate was 21.7%, 13.9% and 15.0% for inadequate physical activities, poor physical function and poor immunity, respectively. The reported rate of psychological sub-health was 10.5%, with a rate of 14.7%, 22.6% and 7.3% for emotional problems, behavioral problems and social adaptation difficulties, respectively. The risk factors for college students included insufficient sleeping, inadequate sport activities, missing breakfast, partial dietary, smoking and drinking (P<0.05). CONCLUSION: The reported rate of sub-health is rather high. Early intervention for health-related risk behaviors should be conducted to prevent the incidence of sub-health among college students. PMID- 21269959 TI - [Construction of a lentiviral vector containing human NESG1 gene and its expression in 293FT cells]. AB - OBJECTIVE: To construct a lentiviral vector carrying human NESG1-EGFP gene and observe its expression in 293FT cells. METHODS: The CDS region of NESG1 gene was amplified from a plasmid containing the full-length NESG1 sequence and cloned into the lentiviral vector pGC-FU-EGFP by restriction endonuclease AgeI digestion and T(4) DNA ligase ligation. After transformation into competent E. coli cells, the candidate clones were identified by PCR and sequencing. The recombinant plasmid and the two packaging plasmids were co-transfected into human embryonic kidney cell line 293FT cells by lipofectamine 2000 to produce the lentiviral particles, and the viral titer was determined. The 293FT cells were infected by the lentiviral particles obtained and the transfection efficiency was assessed under fluorescent microscope. Western blotting was used to detect the expression of NESG1 protein in the transfected cells. RESULTS: The lentiviral vector pGC-FU NESG1-EGFP for NESG1 gene was constructed successfully. Strong green fluorescence was observed in 293FT cells under fluorescent microscope after co-transfection of the cells with the 3 plasmids of lentiviral vector. The virus in the supernatant reached a titer of 2*10(7) TU/ml. The transfection efficiency of the collected virus exceeded 90% in 293FT cells with a multiplicity of infection of 1. Western blotting identified the presence of NESG1 expression in the transfected 293FT cells. CONCLUSION: The lentiviral vector for NESG1 has been successfully constructed with a high yield of lentivirus, which facilitate further investigation of the roles of NESG1 gene in the development and progression of nasopharyngeal carcinoma. PMID- 21269960 TI - [Preparation of a decellularized rat liver scaffold and its biocompatibility]. AB - OBJECTIVE: To develop a novel method for preparing decellularized liver biological scaffold (DLBS) for liver tissue engineering. METHODS: DLBS was prepared by treatment of rat livers with detergent and enzymatic cell extraction and observed under optical and scanning electron microscopes. To assess the biocompatibility of the product, C3A cells and bone marrow-derived mesenchymal cells (BM-MSCs) were cocultured with DLBS as the scaffold, and the effect of DLBS on the proliferation of C3A cells was evaluated by MTT assay. DLBS was also implanted under the dorsal skin of SD rats to evaluate the tissue biocompatibility of this material. RESULTS: Application of the detergent and enzymatic extraction allowed full extraction of the cells in the liver, leaving an extracellular matrix scaffold composed mainly of collagen and elastic fibrin. The coculture experiment showed that C3A cells and BM-MSCs could grow on and adhere to DLBS. The result of MTT assay showed that DLBS could promote the proliferation of C3A cells. CONCLUSION: This cell-free DLBS, which retains intact extracellular matrix and promotes cell attachment, proliferation, growth and differentiation, can be an ideal biological matrix scaffold material. PMID- 21269961 TI - [Molecular mechanism of interleukin-13-induced mucus hypersecretion in rat airway]. AB - OBJECTIVE: To investigate the effect of interleukin-13 (IL-13) on mucus secretion in vivo and the possible mechanism. METHODS: The SD rats were randomly divided into control group, IL-13 group and IL-13 plus SP600125 group. The phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N terminal kinase 1/2 (JNK1/2) and the level of MUC5AC in the lung tissues were examined using Western blotting. RT-PCR was performed to examine the mRNA level of STAT4 and STAT6, and electrophoretic mobility shift assays (EMSA) was used to detect the DNA-binding activities of Forkhead box a2 (FOXA2) and activator protein-1 (AP-1). RESULTS: IL-13 caused a significant increase in MUC5AC and p JNK1/2 expression, but did not affect the phosphorylation of ERK1/2. The expression of MUC5AC was attenuated after treatment with SP600125. A significant increase in STAT6 was observed in IL-13 group compared with that in the control group, whereas the expression of STAT4 mRNA was not significantly affected. The DNA-binding activity of FOXA2 was down-regulated after IL-13 exposure, which did not affect the DNA-binding activity of AP-1. CONCLUSION: IL-13 down-regulates mucus secretion via STAT6-FOXA2 pathway in vitro. PMID- 21269962 TI - [Response properties of cochlear nucleus neurons: a digital model-based study]. AB - OBJECTIVE: To investigate the mechanisms of different response patterns of the cochlear nucleus neurons based on a digital model. METHODS: Based on the platform of Matlab7.0 and the integrate-and-fire model, we constructed the temporal coding model. RESULTS: The model well simulated the response types of the primary-like, chopper, onset and buildup neurons by changing the settings of some parameters related to the properties of the neurons. CONCLUSIONS: The properties of the neurons dictate the response patterns of the cochlear nucleus neurons. The simulation results are consistent with the literature. Understanding of the response properties of the cochlear nucleus neurons can provide assistance in the study of the auditory system. PMID- 21269963 TI - [Effect of physiological doses of testosterone on mitochondrial DNA deletion in castrated mice]. AB - OBJECTIVE: To evaluate the effect of physiological doses of testosterone on mitochondrial DNA (mtDNA) deletion in the aortic vascular wall of castrated C57BL/6J mice. METHOD: Twenty-four male C57BL/6J mice were randomized into normal control group (n=8), castrated+placebo group (castrated group, n=8), and castrated+physiological doses (1 mg/kg every 3 days) of testosterone group (n=8). The mice were fed normally for 3 months along with 8 mice with natural aging (18 months old), after which blood samples were obtained from all the groups for measurement of testosterone concentrations. The aortic mtDNA was extracted to analyze the deleted fragments using nested PCR, and fragments with deletions were purified and identified by sequence analysis. RESULTS: Compared with the normal control group, the castrated group showed a significantly higher optical density ratio of the deletions [(18.1713 ? 2.4317)% vs (36.8475 ? 3.3365)%], but no significant difference was found between the castrated and natural ageing group [(42.3075 ? 3.6556)%]. The castrated+testosterone showed a lowered optical density ratio of (23.6488 ? 2.7634)% as compared with the castrated and natural ageing group, but a similar one with the normal control group. Sequence analysis identified 4 different types of deletions in the aging aorta at 3713, 3864, 4236, and 4415 bp, and the presence of direct repeats was confirmed to flank the deletions. CONCLUSIONS: Multiple mtDNA deletions occur in ageing mice at a higher rate than in young mice. Testosterone deficiency is associated with increased aortic mtDNA deletions, which can be decreased by physiological doses of testosterone. PMID- 21269964 TI - [Identification and expression of shRNA vectors targeting human AMPKalpha2]. AB - OBJECTIVE: To construct pGPU6/GFP/Neo-shRNA expression vector targeting human AMPKalpha2 gene and evaluate its silencing effect in SH-SY5Y cell line. METHODS: The oligonucleotides designed by Ambion online CAD software targeting AMPKalpha2 were cloned into the pGPU6/GFP/Neo vector. After confirmation by DNA sequencing and enzyme digestion analysis, the recombinant vectors were transfected into the SH-SY5Y cell line via lipofectamine and the positive clones were selected using G418. The expression levels of AMPKalpha2 mRNA and protein in the transfected cells were detected by RT-PCR and Western blotting, respectively. RESULTS: Four shRNA vectors were successfully constructed as confirmed by DNA sequencing and the enzyme digestion analysis. Among the 4 recombinant vectors, pGPU6/GFP/Neo shRNA AMPKalpha2(3) showed the strongest gene silencing effect and down-regulated the protein expression of AMPKalpha2 by 63% in the transfected cells. CONCLUSION: Transfection with pGPU6/GFP/Neo-shRNA AMPKalpha2(3) results in effective inhibition of AMPKalpha2 gene expression in SH-SY5Y cells, which provide a means for studying AMPK-mediated cell injury. PMID- 21269965 TI - [Effect of Bushenhuoxue Yin on cerebral levels of nitric oxide, tumor necrosis factor-alpha and interferon-gamma in a mouse model of Parkinson disease]. AB - OBJECTIVE: To observe the effects of Bushenhuoxue Yin (BSHXY), a compound traditional Chinese herbal medicine, on nitric oxide (NO), tumor necrosis factor alpha (TNF-alpha) and interferon-gamma (IFN-gamma) levels in the brain of a mouse model of Parkinson disease (PD). METHODS: Forty-five C57BL/6 mice were randomized into MPTP-induced PD model group, BSHXY treatment group and normal control group. The contents of NO and the two cytokines in the brain tissue of the mice were determined by spectroscopy and enzyme-linked immunosorbent assay, respectively. RESULTS: The concentration of NO in the brain tissue of the PD model group was 5.93 ? 0.79 umol/g.protein, significantly higher than that in BSHXY group (P<0.01) and normal control group (P<0.01). The levels of TNF-alpha and IFN-gamma in the PD model group were 0.36 ? 0.11 ng/L and 0.83 ? 0.25 ng/L, respectively, also higher than those in the other two groups (P<0.01 or 0.001). But BSHXY group and the normal control group showed no significant differences in the levels of NO, TNF-alpha and IFN-gamma (P>0.05). CONCLUSION: The therapeutic effect of BSHXY on PD is partially attributed to decreased content of NO, TNF-alpha and IFN-gamma in the brain. PMID- 21269966 TI - [Scavenging effect of Sarcandra glabra powder on radiation-induced reactive oxygen species in the parotid gland of miniature pigs]. AB - OBJECTIVE: To investigate the effect of Sarcandra glabra in scavenging reactive oxygen species (ROS) produced by gamma-ray irradiation in the parotid gland of miniature pigs. METHODS: Forty-five male miniature pigs were randomly divided into control group, radiation group and radiation plus medication group, and each group contained 3 parallel groups (subgroups a, b and c). From 1 week before exposure of the parotid gland region to 15 Gy gamma-ray irradiation (which was not administered in the control group), the miniature pigs in radiation plus medication group were given Sarcandra glabra powder, while those in the other groups received an equal amount of saline. Bilateral parotid glands were taken and weighed on the days 10, 40 and 90 following the exposure in subgroups a, b, and c, respectively, and ROS content in the parotid glands were determined by enzyme-linked immunosorbent assay. RESULTS: The content of ROS was significantly lower in radiation plus medication group than in the radiation group (P<0.01). In the radiation plus medication group, the ROS content showed no significant difference between subgroups a and b or between subgroups a and c (P>0.01), but differed significantly between subgroups b and c (P<0.01). Sarcandra glabra showed a strong ROS-scavenging effect 10 days after the irradiation, and the ROS content was similar with that in the control group (P>0.01); at 40 and 90 days, the ROS-scavenging effect of Sarcandra glabra was still observable, but the ROS content was significantly higher in the irradiation plus medication group than in the control group (P<0.01). CONCLUSION: Sarcandra glabra displays a ROS scavenging effect in the parotid gland of miniature pigs against irradiation, especially at 10 days following the exposure, which may serve as the main mechanism for the protective effect of Sarcandra glabra against radiation injury in the parotid gland. PMID- 21269967 TI - [Expression of ghrelin and its receptor GHS-R in the hypothalamus and gastrointestinal tract in rats with chronic renal failure]. AB - OBJECTIVE: To investigate the expression of ghrelin and its receptor, growth hormone secretagogue receptor (GHS-R), in the hypothalamus and gastrointestinal tract in rats with chronic renal failure (CRF) and explore their relationship with the disorder of gastrointestinal tract motility. METHODS: SD rats were randomly divided into sham-operated group (n=8) and CRF group (n=16), and in the latter group, the rats were subjected to 5/6 nephrectomy to induce CRF. Real-time PCR and immunohistochemical staining were used to detect the distribution of mRNA and protein of ghrelin and GHS-R in the gastric fundus, duodenum, and hypothalamus. RESULTS: The rats in the CRF group showed a significantly higher expression of ghrelin mRNA and protein in the gastric fundus but a lower expression in the hypothalamus than those in the sham-operated group (P<0.01), but the expression in the duodenum was similar between the two groups (P>0.05). The expression of GHS-R mRNA and protein in the gastric fundus was significantly higher in the CRF group than in the sham-operated group (P<0.01), while in the hypothalamus and duodenum, the expression was significantly lower in the CRF group (P<0.01). CONCLUSION: The different distribution patterns of ghrelin and GHS-R in the tissues may be an important pathological basis of gastrointestinal motility disorder in CRF. PMID- 21269968 TI - [Impact of body mass index on blood pressures in a college student population]. AB - OBJECTIVE: To explore the morbidity of hypertension and prehypertension and analyze the association between body mass index (BMI) and blood pressure in Chinese college students. METHODS: This epidemiological study involved 490 Chinese college students (aged 15-25 years, mean 18.9?1.2 years), and their body height, body weight, blood pressure and heart rate were recorded. The BMI was divided into four groups according to Chinese population standard classification. RESULTS: Most students were southern Han Chinese. The incidences of overweight plus obesity and obesity were 12.9% and 4.1%, respectively. The morbidity of hypertension was 0.8% in this student population. The incidences of hypertension and pre-hypertension were higher in high BMI groups than those in low BMI groups. The systolic blood pressures were significantly higher in over-weight and obese groups than in the normal BMI and lean groups. BMI was positively correlated to systolic and diastolic blood pressures in this population. CONCLUSION: High BMI is a predictor of elevated blood pressure in adolescent students. PMID- 21269969 TI - [Pharmacokinetic study of a new chewing gum dextromethorphan delivery system]. AB - OBJECTIVE: To establish an high-performance liquid chromatography (HPLC)-based method for analysis of the pharmacokinetics and relative bioavailability of dextromethorphan chewing gum tablets in rabbits. METHODS: The pharmacokinetic parameters and the relative bioavailability of dextromethorphan chewing gum preparation in rabbits were compared with those of the commercially available chewing dextromethorphan tablets using 3P97 software. RESULTS: Pharmacokinetic analysis of the new dextromethorphan chewing gum tablets showed a AUC of 488.76 ? 175.00 ng.ml(-1).h, C(max) of 95.45 ? 17.53 ng/ml, and t(max) of 1.83 ? 0.57 h as compared with the corresponding parameters of 370.13 ? 90.56 ng.ml(-1).h, 174.00 ? 47.88 ng.ml, and 1.04 ? 0.14 h for the commercially available chewing tablets. The relative bioavailability of the new chewing gum medicine system was (140.73 ? 65.91)%. CONCLUSION: The new dextromethorphan chewing gum preparation shows an increased AUC((0->)), decreased C(max), and prolonged t(max) in comparison with the commercially available chewing tablets, with also a greatly enhanced relative bioavailability. PMID- 21269970 TI - [Mouse sperm DNA damage induced by exogenous BDE-209]. AB - OBJECTIVE: To assess the DNA damage in mouse sperms induced by exogenous BDE-209 and explore the possible mechanism of BDE-209 in affecting normal zygote development. METHODS: Mouse sperms were harvested from the epididymal tail and suspended in HTF medium for a 90-min exposure to BDE-209 at varied concentrations of 0, 2.5, 5.0, 10, and 20 ug/ml (groups A-E, respectively). After the exposure, the sperms were subjected to single-cell gel electrophoresis (SCGE) to assess the DNA damage. RESULTS: The tail length of the sperms averaged 1.15 ? 1.27 um in group A. Exposure to 10 and 20 ug/ml BDE-209 resulted in a significant lengthening of the sperm tails (2.13 ? 1.29 um and 2.83 ? 2.46 um, respectively, P<0.01) as well as increased DNA content in the tail of the cells (P<0.01). The Olive tail moment in group A was 0.270 ? 0.322, and increased after BDE-209 exposure to 0.453 ? 0.375 and 808 ? 0.822 in groups D and E, respectively. The tail/head length ratio in groups C, D, and E (0.077 ? 0.093, 0.112 ? 0.068, and 0.191 ? 0.207) were significantly greater than that in group A (0.045 ? 0.049). The DNA damage of the mouse sperms was directly correlated to the concentrations of BDE-209, with correlation coefficients all above 0.9. CONCLUSIONS: Exogenous BDE-209 can cause mouse sperm DNA damage and lead to sperm DNA chain breakage, and this effect shows an obvious dose dependence. PMID- 21269971 TI - [Effect of Shuyusan on neuropeptide Y and serotonin expression in the hippocampal neurons of rats with chronic mild unpredictable stress-induced depression]. AB - OBJECTIVE: To investigate the effect of Shuyusan decoction on neuropeptide Y (NPY) and serotonin (5-HT) expression in the hippocampus and plasma of rats with chronic mild unpredictable stressors depression. METHODS: Fifty Wistar rats were randomly divided into 5 groups, namely the normal control group, model group, fluoxetine group, and high- and low-dose Shuyusan groups. Except for those in the normal control group, all the rats were subjected to chronic mild unpredicted stress for 21 consecutive days with corresponding treatments. Open-field test was used to assess the behavioral changes of the rats. The content of NPY in the hippocampus and plasma was detected by competitive enzyme-linked immunosorbent assay, and immunocytochemistry was used to determine the expression of 5-HT in the hippocampus. RESULTS: NPY levels in the hippocampus and plasma was significantly decreased in the model group as compared with that in the normal control group (P<0.05). Treatments with fluoxetine and high-dose Shuyusan both significantly increased NPY levels in the hippocampus and plasma in the depressive rats (P<0.05), resulting also in significantly increased 5-HT immunoreactive neurons in the cerebral cortex and hippocampus and the average optical density (P<0.05). CONCLUSION: Shuyusan decoction can effectively increase plasma and hippocampus NPY levels and the number of 5-HT-positive neurons in the cerebral cortex and happocampus of rats with chronic mild unpredictable stress induced depression. PMID- 21269972 TI - [Expression of hypoxia-inducible factor-1alpha and vascular endothelial growth factor in the synovium of patients with osteoarthritis]. AB - OBJECTIVE: To detect the expression of hypoxia-inducible factor-1alpha (HIF 1alpha) and vascular endothelial growth factor (VEGF) in patients with osteoarthritis and investigate their roles in the synovial lesions of osteoarthritis. METHODS: The expressions of HIF-1alpha and VEGF in the synovium were detected by immunohistochemical staining in 30 osteoarthritis cases, 20 acute traumatic arthritis cases and 10 normal synovial biopsy samples. The correlation between HIF-1alpha and VEGF, and their relationships with osteoarthritis were analyzed. RESULTS: The rates of positive expression of HIF 1alpha and VEGF in osteoarthritis cases were significantly higher than those in acute traumatic arthritis (86.7% vs 60% and 80% vs 48%, P<0.05). Normal human synovium showed no positive expressions of HIF-1alpha and VEGF. HIF-1alpha expression was positively correlated to VEGF expression in acute traumatic synovitis and osteoarthritis cases, with correlation coefficients of 0.666 and 0.678, respectively. CONCLUSION: The expressions of HIF-1alpha and VEGF in the synovial tissue are significantly higher in osteoarthritis cases than in cases of acute traumatic arthritis. They have close relationship in the synovial lesions of osteoarthritis and both contribute to the development of osteoarthritis. PMID- 21269973 TI - [Three-dimensional reconstruction and anatomic variation of the portal vein based on 64-slice spiral CT data]. AB - OBJECTIVE: To investigate the three-dimensional reconstruction methods of the portal vein using 64-slice spiral CT data and the anatomical variation of the portal vein. METHODS: Three-dimensional reconstruction of the portal vein was performed using Mimics software based on the 64-slice spiral CT data of 64 cases. Each model of the portal vein and its branches was evaluated according to the presentation rate, depiction quality and anatomic variation. RESULTS: The reconstructed model showed a depiction rates of 100% for the 4-grade branches of the portal vein. The stem of the portal vein and the left and right branches of the level III or above were all displayed, but in 2 cases the superior mesenteric vein and in 1 case the spleen vein was displayed only to the level IV. Of the 64 cases, 50 (78.1%) had normal portal vein and 14 (21.9%) showed anatomical variations. CONCLUSION: The 3D model vividly mimics the anatomic variations of the portal vein to provide valuable information for surgical plans. PMID- 21269975 TI - [CT and MRI features of Castleman's disease of the abdomen and pelvis]. AB - OBJECTIVE: To analyze the CT/MRI features of Castleman's disease of the abdomen and pelvis. METHODS: CT/MRI images of 6 cases of pathologically confirmed Castleman's disease of the abdomen and pelvis were retrospectively reviewed. All the patients received plain CT scan and dynamic enhanced scan, and one had an additional MR scan. RESULTS: One case was identified as the disseminated type with multicentric enlarged lymph nodes and hepatosplenomegaly, and 5 cases were found to have localized type, of which 3 had retroperitoneal, 1 had mesentery and 1 had pelvic lesions. On CT scan, all the 5 cases with localized lesions showed single, round or ellipse soft tissue masses, with intra-tumoral calcification in 2 cases, fascial thickening around the mass in 3 cases, and satellite nodules in 4 cases. Enhanced scanning revealed obvious enhancement in the arterial phase and continuous enhancement in the portal vein and delayed phase in all the lesions, with an attenuation pattern similar to that of large vessels; enlarged blood vessels within or around the mass were displayed in each case. In 4 cases, the intra-tumoral radial or fissured non-enhanced areas in early stage of enhancement were gradually filled up as the scan time was delayed. The patient receiving MRI showed hypo-intensity on T(1)WI and hyper-intensity on T(2)WI, presenting with an enhancement feature similar to that of CT. CONCLUSION: Castleman's disease in the abdomen and pelvis is rare and liable to misdiagnosis, but its characteristic imaging features can help in the diagnosis and differential diagnosis. PMID- 21269974 TI - [A rat model of focal lymph encephalopathy established by partial ligation of the cerebral superficial artery]. AB - OBJECTIVE: To establish a rat model of focal lymphatic encephalopathy by partial ligation of the cerebral superficial artery for observation of the changes of Virchow-Robin spaces (VRS). METHODS: Thirty male SD rats were randomized into 3 groups (n=10), including two model groups and a sham-operated group. The rats in the model groups were subjected to partial ligation of the cerebral superficial arteries under EEG monitoring to induce focal lymphatic encephalopathy, and those in the sham-operated group underwent only dissociation of the cerebral superficial artery without ligation. The rats in the two model groups were executed at 24 and 48 h, and those in the sham-operated group at 48 h following the operation, respectively. Frozen sections of the brain tissues were prepared for microscopic morphological observation and quantitative analysis of the VRS using HE staining and an image analysis system, respectively. RESULTS: EEG remained normal during the operations suggesting intact brain function. Partial ligation of the cerebral superficial arteries resulted in obvious dilation of the VRS in the cerebral cortex and subcortical medulla, and the tissues around the dilated VRSs appeared pale and structurally loosened. The two model groups showed significantly enlarged VRS areas as compared to the sham-operated group (P<0.01), but no significant differences were found in the mean VRS areas between the two model groups. CONCLUSION: Partial dilation of the cerebral superficial artery is effective and convenient to induce focal lymphatic encephalopathy in rats, and this model can be ideal for studying focal cerebral lymph circulation. PMID- 21269976 TI - [Changes in the biological behaviors of colon cancer cells under simulated hypoxia in vitro]. AB - OBJECTIVE: To investigate the reactivity of colon cancer cell line SW480 and CD133(+) SW480 subsets to hypoxia in vitro and the changes in the expressions of anti-apoptosis and angiogenesis genes. METHODS: SW480 cells was subjected to CoCl(2) exposure at varying concentrations and for different time lengths to induce hypoxia, and the protein expression of hypoxia induced factor 1alpha (HIF 1alpha) was detected by Western blotting. The CD133(+) SW480 cells were sorted by magnetic activated cell sorting (MACS) and their proportion was assayed by flow cytometry (FCM). The CD133(+) SW480 subsets were exposed to CoCl(2) at the optimal concentration with exposure time selected in terms of HIF-1alpha level, and their tumor stem cell sphere formation ability was evaluated. Real-time PCR was used to compare the mRNA expression levels of the surface markers of colon cancer stem cells (CD133 and PROM1), survivin, and vascular endothelial growth factor (VEGF). RESULTS: Exposure to 200 umol/L CoCl(2) for 8 h resulted in the highest HIF-1alpha expression in SW480 cells, but the same exposure failed to induce HIF-1alpha expression in CD133(+) SW480 subsets. The CD133(+) SW480 subsets, after CoCl(2)-induced hypoxia, showed significantly enhanced ability of cell sphere formation. Hypoxia of SW480 cells caused significant increases in CD133, survivin and VEGF mRNA levels by 1.607?0.103, 2.745?0.370 and 3.798?0.091 folds, respectively (P<0.05). CONCLUSION: CoCl(2) can simulate hypoxia in colon cancer cells in vitro to induce stable HIF-1alpha expression, which is concentration- and time-dependent. The hypoxia-stimulated tumor stem sells show an enhanced sphere formation and anti-apoptotic and anti-angiogenic abilities. PMID- 21269977 TI - [Oxidation status and gamma-glutamylcysteine synthetase expression in the kidney of MRL/lpr lupus mice]. AB - OBJECTIVE: [corrected] To investigate the role of glutathione (GSH) and gamma glutamylcysteine synthetase (gamma-GCS) in lupus nephritis. METHODS: Spectrophotometry was used to measure the oxidative/anti-oxidative indices including malonyldialdehyed (MDA) and GSH in the kidney of MRL/lpr lupus mice. Quantitative PCR and Western blotting were used to detected the expression of gamma-GCS. RESULTS: The level of GSH was lowered whereas the level of MDA increased significantly in the kidney tissue of MRL/lpr lupus mice as compared with that in normal control mice. The expression of gamma-GCS mRNA and protein was significantly decreased in MRL/lpr lupus mice (P<0.05). CONCLUSION: MRL/lpr lupus mice have abnormal oxidative stress in the kidney tissue, where the expression of gamma-GCS decreased to lead to reduced GSH production, damaged antioxidative capacity, and eventually exacerbation of oxidative damage in the kidney. PMID- 21269978 TI - [Effect of bone-marrow mesenchymal stem cells on the immune function of aging rats]. AB - OBJECTIVE: To investigate the effect of transplantation of bone-marrow mesenchymal stem cells (MSCs) on the immune functions of aging rats. METHODS: Healthy SD rats were randomized into normal control, aging model group and MSCs group. The aging model was established by daily subcutaneous injection of D galactose for 4 consecutive months. MSCs were isolated from the bone marrow of adult SD rats and injected (3*10(6) MSCs) in rats in the MSCs group via the tail vein once a week for 4 weeks. The spleen index, activity of T lymphocytes and the levels of IL-2 and IL-10 in spleen were measured, and the pathological changes of the spleen were observed after the treatments. RESULTS: MSCs transplantation enhanced the cellular immune function of aging rats manifested by obviously increased spleen index, activity of T lymphocyte and the level of IL-2, and lowered level of IL-10 in the spleen. The rats in the aging model group showed serious spleen injury, which was obviously lessened by MSCs injection. CONCLUSION: MSCs transplantation can improve the cellular immune function of aging rats and ameliorate spleen injury induced by D-galactose. PMID- 21269979 TI - [Effect of carbamide peroxide bleaching agents on micro-leakage of composite resin interface in vitro]. AB - OBJECTIVE: To evaluate the effect of carbamide peroxide (CP) bleaching agents at different concentrations and with different carriers on the micro-leakage of composite resin interface. METHODS: Class V cavity (2 mm in diameter and 2 mm in depth) preparations were made at the enamelo-cemental junction on the buccal and lingual surfaces of 35 extracted human premolars. The cavities were filled with hybrid composite resin. The teeth were stored for 24 h in distilled water at 37 degrees celsius; before thermocyling for 500 times between 5 and 55 degrees celsius;. The teeth were then randomly assigned into 7 groups, and in groups 1-6, the bleaching gels containing 10% or 20% of CP were applied on the buccal and lingual surface of the teeth for two weeks (6-8 h/day, 37 degrees celsius;, 100% relative humidity) using Carbopol, PVP or Poloxamer as the thickening carriers, respectively. The seventh group served as the control without bleaching treatment. Nail polish was applied to the surface of the tooth, and all the teeth were immersed in ammoniacal silver nitrate solution followed by developing solution. The teeth were finally sectioned through the midline of the restoration and observed under stereomicroscope. SEM micrographs were also made to observe the interface. RESULTS: With the same bleaching agent, the micro-leakage in the gingival wall was slightly greater than in the occlusive wall, but the difference was not significant. Only 20% CP with Poloxamer as the thickening agent significantly increased the leakage of dentine-resin composite interface, and 10% and 20% CP with Carbopol or PVP as the thickening agents and 10% CP with Poloxamer produced minimal effects on filling the micro-leakage. CONCLUSION: Thickening carriers and the concentration of CP (20% or below) have no significant effect on micro-leakage of composite resin. PMID- 21269980 TI - [Efficacy and safety evaluation of two insulin treatment protocols using a continuous glucose monitoring system]. AB - OBJECTIVE: To evaluate the efficacy and safety of two insulin treatment protocols using a continuous glucose monitoring system. METHODS: Type 2 diabetic patients mellitus with unsatisfactory control of fasting blood glucose by oral antidiabetic drugs were included in the study. The patients were randomized into two groups to receive bedtime injection of glargine and oral antidiabetic drugs (group A) or injection of Novolin 30 R twice a day (group B) for 12 weeks. The insuline dose was adjusted according to fasting blood glucose till discharge. Continuous glucose monitoring system was used to record the average blood glucose, fasting blood glucose, 2 h postprandial blood glucose, AUCPG >= 10.0 mmol/L%, HbA1c and C peptide, bedtime blood glucose, 3:00 AM blood glucose, the incidence of hypoglycemia and body mass index. RESULTS: The average blood glucose, fasting blood glucose, 2 h postprandial blood glucose, AUCPG >= 10.0 mmol/L% and HbA1c was significantly decreased and C peptide significantly increased in the two groups after the treatments. The patients in glargine group showed better improvement with a significantly lower incidence of hypoglycemia than those in Novolin 30 R group. BMI underwent no significant changes in the two groups after the treatments. CONCLUSION: Glargine therapy better mimics the physiological insulin secretion patterns, and when combined with oral antidiabetic drugs, can be more effective and safer than premixed insulin. PMID- 21269981 TI - [Diagnostic value of serum CEACAM1 in patients with pancreatic cancer]. AB - OBJECTIVE: To investigate the diagnostic value of serum CEACAM1 in patients with pancreatic cancer. METHODS: Fifty patients with pancreatic cancer and 50 with chronic pancreatitis were examine for serum levels of CEACAM1 by enzyme-linked immunosorbent assay (ELISA). The cut-off values and area under curve (AUC) of CEACAM1 was obtained by receiver operating characteristic (ROC) curve. The diagnostic efficiency of the tumor markers for pancreatic cancer was assessed by the fourfold table. RESULTS: The serum level and positivity rate of CEACAM1 in pancreatic cancer patients were higher than those in chronic pancreatitis patients (P<0.05). Based on the ROC curve, the cut-off values and AUC of CEACAM1 were 13.835 ng/ml and 0.780, respectively (P<0.05). In pancreatic cancer patients, the diagnostic sensitivities of the tumor markers decreased in the order of CEACAM1 < CA242 < CA19-9 (P<0.05), and the specificity in the order of CA242 < CA19-9 < CEACAM1 (P<0.05). CONCLUSION: CEACAM1 shows a higher diagnostic sensitivity than CA19-9 and CA242 for pancreatic cancer, but due to its low specificity this marker alone is not sufficient for diagnostic purposes. PMID- 21269982 TI - [Correlation of the expressions of VEGF-C and VEGFR-3 to the pathological grade of prostate cancer]. AB - OBJECTIVE: To investigate the correlation of the expression of VEGF-C and VEGFR-3 to the pathological grade of human prostate cancer. METHODS: Immunohistochemistry was used to detect the expression of VEGF-C and VEGFR-3 in 25 cases of prostate cancer tissues. RESULTS: The total positivity rates of VEGF-C and VEGFR-3 were 80% and 76% in these cancer tissues, respectively. The positivity rates of VEGF-C was 94.7% in the 19 cases with Gleason scores no less than 6 (group I), significantly higher than the rate (33%) in the 6 cases with Gleason scores between 4 and 6 (group II) (P<0.01). The positivity rates for VEGFR-3 also showed a significant difference between groups I and II (89.5% vs 33.3%, P<0.05). The expression level of VEGF-C was correlated to the Gleason score of prostate cancer (R=0.436, P<0.05), and the correlation between VEGFR-3 and the Gleason score was even more obvious (R=0.608, P<0.01). Their expressions, however, did not show any correlations to the patients age, PSA or the volume of the prostate. CONCLUSION: VEGF-C and VEGFR-3 may serve as new markers for evaluating the malignancy of prostate cancer with Gleason score not less than 4. PMID- 21269983 TI - [Anesthetic management for neurosurgery using intraoperative magnetic resonance imaging]. AB - OBJECTIVE: To analyze the anesthetic management for neurosurgery using intraoperative magnetic resonance imaging (iMRI). METHODS: Thirty patients with intracranial tumor received MRI for preoperative safety screening and the operation was performed with general anesthesia and support by MRI-compatible machines. The operative time, frequency and duration of MRI, MRI-related time (from the preparation for MRI to the beginning of the surgery), time delay by MRI, body temperature at the initial iMRI and special issues related to the scanning and perioperative anesthesia were recorded. RESULTS: Thirty patients successfully completed the operations without any incidents related to anesthesia or scanning. The mean frequency of MRI was 1.8, the mean duration of MRI was 29.24 ? 10.10 min, and the MRI-related time was 43.83 ? 10.23 min; the time delay MRI was 92.63 ? 28.31 min, and the body temperature was significantly higher at 2 h after MRI than that after induction. CONCLUSION: In the anesthetic management for neurosurgery with iMRI, the anesthesiologists should focus on the safety precaution and anesthetic modulation according to the special environment and procedure of iMRI. PMID- 21269984 TI - [Expression of Rho-GDP dissociation inhibitor in the decidual tissues of preeclampsia patients and its clinical implication]. AB - OBJECTIVE: To investigate the expression of Rho-GDI in the decidual tissues of patients preeclampsia and explore its clinical implication. METHODS: Real-time PCR, Western blotting and immunohistochemistry were used to detect the mRNA and protein expressions of Rho-GDI in the decidual tissues from 30 normal women with full-term pregnancy, 30 patients with early-onset severe preeclampsia and 30 with late-onset severe preeclampsia. RESULTS: Rho-GDI expression was found mainly on the cell membrane and in the cytoplasm and nuclei of the decidual cells, occasionally occurring in the stroma. Both the mRNA and protein expressions of Rho-GDI in the decidual tissues were significantly higher in the normal pregnancy group than in the two severe preeclampsia groups (P<0.05), and the patients with late-onset severe preeclampsia had the lowest expressions of Rho-GDI. CONCLUSION: The lowered expression of Rho-GDI in the deciduas might be involved in the pathogenesis and progression of preeclampsia. PMID- 21269985 TI - [Effect of propofol on proliferation and differentiation of rat embryonic neural stem cells in vitro]. AB - OBJECTIVE: To investigate the effect of propofol on the proliferation and differentiation of rat embryonic neural stem cells in vitro. METHODS: Embryonic neural stem cells of fetal Wistar rats (gestational age of 14-16 days) in primary culture, after identification for nestin expression, were divided into control group, introlipid group, and propofol groups (treated with propofol at the doses of 5, 25, 50, and 100 umol/L). The changes in the proliferation of the embryonic neural stem cells after the treatments were observed using Brdu incorporation assay. In the course of induced differentiation of the embryonic neural stem cells, 50 umol/L propofol was added in the cells to assess its impact on the differentiation of the cells by immunohistochemical detection of NeuN and GFAP expressions. RESULTS: More than 95% of the embryonic neural stem cells in primary culture were Nestin-positive. The percentages of Brdu-positive cells showed no significant changes after treatment with different concentrations of propofol, whereas the addition of 50 umol/L propofol resulted in a significant increase of NeuN-positive cell percentage to (23.1?0.9)% as compared with that of (13.4?0.8)% in the control group (P<0.05) without affecting the GFAP-positive cells. CONCLUSION: Clinically relevant doses of propofol have no obvious effect on the proliferation of rat neural stem cells cultured in vitro, but can induce their differentiation into neuron-like cells. PMID- 21269986 TI - [Clinical analysis of 47 misdiagnosed cases of atypical tuberculous meningitis]. AB - OBJECTIVE: To improve the differential diagnosis of tuberculous meningitis (TBM) and reduced potential misdiagnosis of TBM. METHODS: The clinical data of 47 misdiagnosed cases of TBM between January, 1994 and June, 2009 were investigated retrospectively. The clinical presentations and causes for the misdiagnoses were analyzed. RESULTS: The 47 patients with misdiagnosed TBM included 28 male and 19 female patients with a mean age of 36.84?16.41 years. Eight patients had an acute onset, 10 had a subacute onset, and 29 had chronic disease. The initial symptoms, in the descending order of their frequencies, included fever and headache (87.2%), anergia and dyskinesia (27.7%), cerebral nerve damage (23.4%), decreased level of consciousness (14.9%), and urinary and fecal incontinence (2%). Meningeal irritation was present in 25 cases and positive Babinksi sign was found in 19 cases. Elevated intracranial pressure occurred in 51.1% of the cases, and 16 cases showed papilloedema. Non-purulent CSF with elevated protein was found in 86.7%, decreased glucose in 50%, and decreased chlorinate in 53.3% of the cases. Eight out of 23 cases showed a positive result of PPD test. MRI identified abnormitis with meningeal enhancement in 15 cases, hydrocephalus in 7 cases and infarction in 14 cases. Tuberculoma was found in 2 cases, and spinal cord lesions were found 4 cases. All the patients received anti-tuberculosis therapy, which resulted in symptomatic improvement in 39 cases, fluctuated condition in 2 cases; 5 patients discontinued the treatment and 1 died. CONCLUSION: Early TBM often presents with atypical features and its differential diagnosis can be difficult. CSF monitoring and careful inspection of the radiographic data can be helpful in the diagnosis of suspected cases, for which early anti-TB treatment is an important means to reduce misdiagnosis. PMID- 21269987 TI - [Bioinformatic analysis of genes related to temporal epilepsy]. AB - OBJECTIVE: To investigate the genes associated with temporal epilepsy and explore the molecular mechanism of epilepsy. METHODS: The microarray data of temporal epilepsy were downloaded from the Gene Expression Omnibus (GEO) database and analyzed by bioinformatics methods using String, KEGG and Panther databases. RESULTS: Of all the 71 differentially expressed genes, 51 were found to encode proteins with interactions; the main biological pathways involved included neuroactive ligand-receptor interactions, MAPK signaling pathway, and calcium signaling pathway etc. CONCLUSION: The pathogenesis of epilepsy involves multiple genes, and investigations of these genes may provide valuable insights into the mechanism of epilepsy. PMID- 21269988 TI - [Assessment of intraventricular mechanical synchrony in systole by tissue synchronization imaging in normal subjects]. AB - OBJECTIVE: To evaluate intraventricular mechanical synchrony in systole by real time tri-plane tissue synchronization imaging (TSI). METHODS: Real-time tri-plane TSI was performed in 20 normal subjects, and the apical 4-chamber, 2-chamber and long-axis views of the left ventricular (LV) were obtained simultaneously. The data were post-processed offline, and a TSI surface map of LV colorized according to the time-to-positive peak systolic velocity (TTP) was generated to reflect the segment TTP semi-quantitatively. The segmental TTP of the six-basal and six-mid segments of LV was measured and compared. RESULTS: The myocardium was color-coded mainly by well-distributed green, and only a small portion displayed yellow or red color in the apical area; the TTP showed no significant differences between the segments measured (P>0.05). CONCLUSIONS: In normal subjects, the long-axis systolic motions of the LV are highly synchronized. TSI allows immediate visual identification of intraventricular mechanical synchrony and quantitative measurement of regional TTP. PMID- 21269989 TI - [Role of vascular endothelial growth factor in rats with severe acute pancreatitis]. AB - OBJECTIVE: To investigate the role of vascular endothelial growth factor (VEGF) in the pathogenesis of severe acute pancreatitis (SAP) in rats. METHODS: Sixty four male SD rats were randomly divided into control group and SAP group, and in the latter group, SAP was induced by retrograde injection of 5% sodium taurocholate in the pancreaticobiliary duct. The rats were sacrificed at 1, 3, 6 and 12 h after the operation, and the severity of pancreatitis was assessed according to histological scoring. The serum levels of VEGF were examined with enzyme-linked immunosorbent assay, and the expression of VEGF in the pancreatic tissues was measured by SP immunohistochemistry. Another 30 SD rats were randomized into the control group, SAP group and SAP+recombinant rat VEGF injection group, and the vascular permeability of the pancreatic microcirculation was determined by Evans Blue leakage test. RESULTS: At each of the time points for measurement, both the serum VEGF level and scores of pancreatic tissue injury were significantly higher in SAP group than in the control group (P<0.05). Compared with the control group, the expressions of VEGF in the pancreatic tissues of SAP group were significantly up-regulated following the operation (P<0.05). The vascular permeability of the pancreatic microcirculation significantly increased after the onset of SAP, and injection of recombinant rat VEGF significantly increased the leakage rate of Evans Blue. CONCLUSION: VEGF may play an important role in the pathogenesis of pancreatitis and in causing edema and hemorrhage in SAP, and the level of serum VEGF may reflect the severity of pancreatic injury. PMID- 21269991 TI - Prevalence of Salmonella in Australian reptiles. AB - From January 2007 until June 2008, 504 reptiles of four families and 57 species were examined for Salmonella by using cloacal or intestinal swabs. Salmonella was identified in 139 (28%) of the 504 animals tested. Of the 504 reptiles examined, 210 were captive and 294 were wild. Ninety-eight (47%) of the captive reptiles were shedding Salmonella at the time of sampling. In contrast, only 41 (14%) of the wild reptiles were shedding Salmonella. The higher prevalence of Salmonella in captive reptiles was statistically significant (P<0.0001). No Salmonella was found in 60 wild, freshwater chelonians or 48 wild southern water skinks (Eulamprus heatwolei). Our results suggest that some species of wild reptiles in Australia are not natural carriers of Salmonella and that diet and captivity may influence Salmonella excretion in other species. PMID- 21269990 TI - Health literacy and task environment influence parents' burden for data entry on child-specific health information: randomized controlled trial. AB - BACKGROUND: Health care systems increasingly rely on patients' data entry efforts to organize and assist in care delivery through health information exchange. OBJECTIVES: We sought to determine (1) the variation in burden imposed on parents by data entry efforts across paper-based and computer-based environments, and (2) the impact, if any, of parents' health literacy on the task burden. METHODS: We completed a randomized controlled trial of parent-completed data entry tasks. Parents of children with attention deficit hyperactivity disorder (ADHD) were randomized based on the Test of Functional Health Literacy in Adults (TOFHLA) to either a paper-based or computer-based environment for entry of health information on their children. The primary outcome was the National Aeronautics and Space Administration Task Load Index (TLX) total weighted score. RESULTS: We screened 271 parents: 194 (71.6%) were eligible, and 180 of these (92.8%) constituted the study cohort. We analyzed 90 participants from each arm. Parents who completed information tasks on paper reported a higher task burden than those who worked in the computer environment: mean (SD) TLX scores were 22.8 (20.6) for paper and 16.3 (16.1) for computer. Assignment to the paper environment conferred a significant risk of higher task burden (F(1,178) = 4.05, P = .046). Adequate literacy was associated with lower task burden (decrease in burden score of 1.15 SD, P = .003). After adjusting for relevant child and parent factors, parents' TOFHLA score (beta = -.02, P = .02) and task environment (beta = .31, P = .03) remained significantly associated with task burden. CONCLUSIONS: A tailored computer-based environment provided an improved task experience for data entry compared to the same tasks completed on paper. Health literacy was inversely related to task burden. PMID- 21269992 TI - Filter-paper blood samples for ELISA detection of Brucella antibodies in caribou. AB - We evaluated blood collected on Nobuto filter-paper (FP) strips for use in detecting Brucella spp. antibodies in caribou. Whole blood (for serum) and blood saturated FP strips were obtained from 185 killed arctic caribou (Rangifer tarandus groenlandicus). Sample pairs (serum and FP eluates) were simultaneously tested in duplicate using competitive enzyme-linked immunosorbent assay (c-ELISA) and indirect ELISA (i-ELISA) for Brucella spp. Prior work based on isolation of Brucella spp. revealed sensitivity (SE) and specificity (SP) of 100% and 99%, respectively, for both these serum assays in caribou. Infection status of the animals in the current study was unknown but recent sampling had revealed clinical brucellosis and >40% Brucella antibody prevalence in the herd. To assess the performance of FP relative to serum in these assays, serum was used as the putative gold standard. On both assays, the findings for duplicate runs (A and B) were similar. For c-ELISA run A, the FP Brucella prevalence (47%) was lower than serum prevalence (52%), with SE 89% (95% confidence interval [CI]: 82-95%) and SP 99% (97-100%). For i-ELISA run A, serum and FP Brucella prevalence rates were identical (43%), and the SE and SP of FP testing were 100% and 99% (97-100%), respectively. The findings suggest better FP test performance with i-ELISA than with c-ELISA; however, i-ELISA does not distinguish cross-reacting antibodies induced by Brucella vaccination or exposure to certain other Gram-negative pathogens. Results for duplicate FP eluates (prepared using separate FP strips from each animal) were strongly correlated for both protocols (r=0.996 and 0.999 for c-ELISA and i-ELISA, respectively), indicating minimal variability among FPs from any individual caribou. Dried caribou FP blood samples stored for 2 mo at room temperature are comparable with serum for use in Brucella spp. c-ELISA and i ELISA. Hunter-based FP sampling can facilitate detection of disease exposure in remote regions and under adverse conditions, and can expand wildlife disease surveillance across temporospatial scales. PMID- 21269993 TI - Antigenic profiling of yersinia pestis infection in the Wyoming coyote (Canis latrans). AB - Although Yersinia pestis is classified as a "high-virulence" pathogen, some host species are variably susceptible to disease. Coyotes (Canis latrans) exhibit mild, if any, symptoms during infection, but antibody production occurs postinfection. This immune response has been reported to be against the F1 capsule, although little subsequent characterization has been conducted. To further define the nature of coyote humoral immunity to plague, qualitative serology was conducted to assess the antiplague antibody repertoire. Humoral responses to six plasmid-encoded Y. pestis virulence factors were first examined. Of 20 individual immune coyotes, 90% were reactive to at least one other antigen in the panel other than F1. The frequency of reactivity to low calcium response plasmid (pLcr)-encoded Yersinia protein kinase A (YpkA) and Yersinia outer protein D (YopD) was significantly greater than that previously observed in a murine model for plague. Additionally, both V antigen and plasminogen activator were reactive with over half of the serum samples tested. Reactivity to F1 was markedly less frequent in coyotes (35%). Twenty previously tested antibody negative samples were also examined. While the majority were negative across the panel, 15% were positive for 1-3 non-F1 antigens. In vivo-induced antigen technology employed to identify novel chromosomal genes of Y. pestis that are up regulated during infection resulted in the identification of five proteins, including a flagellar component (FliP) that was uniquely reactive with the coyote serum compared with immune serum from two other host species. Collectively, these data suggest that humoral immunity to pLcr-encoded antigens and the pesticin plasmid (pPst)-encoded Pla antigen may be relevant to plague resistance in coyotes. The serologic profile of Y. pestis chromosomal antigens up-regulated in vivo specific to C. latrans may provide insight into the differences in the pathogen-host responses during Y. pestis infection. PMID- 21269994 TI - Winter body condition of moose (Alces alces) in a declining population in northeastern Minnesota. AB - Assessments of the condition of moose (Alces alces) may be particularly informative to understanding the dynamics of populations and other influential factors. During February-March 2003 to 2005, we assessed the nutritional condition of 79 moose (39 females, 40 males) in northeastern Minnesota by body condition scoring (BCS(F), scale of 0-10); 67 of these by were assessed by ultrasonographic measurements of rump fat (Maxfat), which was used to estimate ingesta-free body fat (IFBF) in all but two of the females. Scores of the BCS(F) were related (r(2)=0.34, P<0.0001) to Maxfat. Body condition scores were not affected by sex * capture-year, capture-year, or age-at-capture, but the mean body condition score of males (6.5 +/- 0.2 [SE], n=40) was less (P <= 0.009) than that of females (7.4 +/- 0.2, n=39). Overall, Maxfat ranged from 0.0 to 4.6 and 0.3 to 2.8 cm in females and males, respectively, and was unaffected by age-at capture. There was a sex*capture-year effect (P=0.021) on Maxfat; mean values were stable for males during the winters of 2003 to 2005 but in females were lowest during 2003, consistent with the lowest pregnancy rates and lowest winter and spring survival compared to 2004 and 2005. Based on estimates of percent IFBF, late winter-early spring survival in 2003 of at least 11% of the collared animals assessed by Maxfat, 21% of the adult females, specifically, may have been seriously challenged directly by poor condition. Data from this study provide reference values and assessments of body condition of moose that will be an essential component of the additional, comprehensive research needed to better understand the influence of extrinsic and intrinsic factors on the performance of this viable, but declining, population. For future research, we will concentrate on developing a more-reliable BCS which would allow IFBF estimation once rump fat is depleted. PMID- 21269995 TI - White-nose syndrome and wing damage index scores among summer bats in the northeastern United States. AB - White-nose syndrome (WNS) adversely affects millions of bats hibernating in caves of the eastern United States. Beginning in 2009, the US Fish and Wildlife Service supported use of a wing damage index (WDI) scoring system (scale of 0 to 3, or no damage to severe) to assess wing damage of bats captured during summer. Based on bat captures at 459 mist net sites in Pennsylvania, New York, Maryland, Virginia, and New Jersey, USA, we questioned whether WDI scores varied by species group, date, and distance to the closest known affected hibernaculum. We also compared relative health (body mass index [BMI] scores) to WDI scores. Of 3,419 bats (nine species), only four individuals (0.1%; little brown [Myotis lucifugus] and northern bats [Myotis septentrionalis]) were scored as a 3 and 47 (1.4%; big brown [Eptesicus fuscus], little brown, and northern bats) as a 2. All tree bats (eastern red [Lasiurus borealis], hoary [Lasiurus cinereus], and silver-haired bats [Lasionycteris noctivagans]) scored a 0 or 1, suggesting that these species were not affected by WNS. The average WDI score decreased as summer progressed, although trends were weak. Average WDI score and number of bats with class 2 and 3 damage increased with proximity to a known WNS-positive hibernaculum. Similarly, the number of bats with severe wing damage (scoring 2 or 3) was greater at sites closer to infected hibernacula, but little variance was explained by the trend. When species-specific BMI was examined, trends were consistent by sex (female BMI scores were higher than those of males), but no relationship was discovered between BMI and WDI scores. We conclude that, at this larger geographic scale, WDI is not a clear indicator of bat health. PMID- 21269996 TI - Steatitis in egrets and herons from Japan. AB - More than 70 egrets and herons were found sick or dead at an agricultural water reservoir in Kanagawa Prefecture, Japan between September and October 2008. The birds showed weakness, lethargy, and inability to fly before death. Postmortem findings included large amounts of firm subcutaneous and cavitary fat comprised of necrotic adipose tissues with infiltrates of heterophils and macrophages. The birds were diagnosed with steatitis on the basis of the gross lesions and histopathology. Egrets with steatitis had low blood levels of vitamin E. High counts of cyanobacteria (Microcystis aeruginosa) were found in the reservoir concurrent with the outbreak of steatitis. No microcystin was detected in the reservoir water or the livers from the egrets. This is the first report of steatitis in wild birds in Japan. PMID- 21269997 TI - Delayed density-dependent prevalence of Sin Nombre virus infection in deer mice (Peromyscus maniculatus) in central and western Montana. AB - Understanding how transmission of zoonoses takes place within reservoir populations, such as Sin Nombre virus (SNV) among deer mice (Peromyscus maniculatus), is important in determining the risk of exposure to other hosts, including humans. In this study, we examined the relationship between deer mouse populations and the prevalence of antibodies to SNV, a system where the effect of host population abundance on transmission is debated. We examined the relationship between abundance of deer mice in late summer-early autumn and SNV antibody prevalence the following spring-early summer (termed delayed density dependent [DDD] prevalence of infection) at both regional and local scales, using 12 live-trapping grids for 11-14 yr, across central and western Montana. When all trapping grids were combined (regional scale), there was a significant DDD relationship for individual months and when months within seasons were averaged. However, within individual grids (local scale), evidence of DDD prevalence of infection was observed consistently at only one location. These findings suggest that, although there is evidence of DDD prevalence of infection at regional scales, it is not always apparent at local scales, possibly because the regional pattern of DDD infection prevalence is driven by differences in abundance and prevalence among sites, rather than in autumn-spring delays. Transmission of SNV may be more complex than the original hypothesis of autumn-spring delayed density dependence suggests. This complexity is also supported by recent modeling studies. Empirical investigations are needed to determine the duration and determinants of time-lagged abundance and antibody prevalence. Our study suggests predicting local, human exposure risk to SNV in spring, based on deer mouse abundance in autumn, is unlikely to be a reliable public health tool, particularly at local scales. PMID- 21269998 TI - Rabies prevalence in migratory tree-bats in Alberta and the influence of roosting ecology and sampling method on reported prevalence of rabies in bats. AB - The migratory tree-roosting hoary bat (Lasiurus cinereus) and silver-haired bat (Lasionycteris noctivagans) are among the bat species with the highest reported prevalence of rabies in North America. However, bats submitted for rabies testing typically have been those that have come in contact with humans or pets. Given the roosting ecology of L. cinereus and L. noctivagans, contact with healthy individuals of these species is expected to be rare, with a bias in contact and submission of infected individuals and thus an overestimation of rabies prevalence. We tested 121 L. cinereus and 96 L. noctivagans specimens, collected during mortality surveys at wind energy facilities in Southern Alberta, Canada in 2007 and 2008, for rabies. None of the L. cinereus (0%) and one L. noctivagans (1%) tested positive for rabies. Prevalence of rabies was significantly lower than previously reported estimates, passive and active, for L. cinereus and L. noctivagans. In a review of the literature including multiple bat species, we found a significant difference in estimates of rabies prevalence based on passive versus active surveillance testing. Furthermore, roosting ecology influenced estimates of rabies prevalence, with significantly higher prevalence among passive surveillance submissions of nonsynanthropic species compared to synanthropic species, a trend not evident in active surveillance reports. We conclude that rabies prevalence in randomly collected L. cinereus and L. noctivagans is low and comparable to active surveillance estimates from other species (<= 1%), and that roosting ecology influences estimates of rabies prevalence among bats submitted to public health laboratories in North America. PMID- 21269999 TI - The role of predation in disease control: a comparison of selective and nonselective removal on prion disease dynamics in deer. AB - Effective measures for controlling chronic wasting disease (CWD), a contagious prion disease of cervids, remain elusive. We review theoretic relationships between predation and host-parasite dynamics and describe a mathematical model to evaluate the potential influence of random removal through harvest or culling and selective predation by wolves (Canis lupus) upon CWD dynamics in deer (Odocoileus spp.) populations. Imposing nonselective mortality representing a 15% annual harvest or cull 51 yr after CWD introduction lowered both deer population size and steady state CWD. Selective (4*) mortality at the same 15% predation rate caused a more modest reduction in deer population size accompanied by a relatively rapid decline in CWD prevalence and elimination of the disease from a closed population. The impacts of selective predation on epidemic dynamics were sensitive to assumptions on parameter estimates; however, within expected ranges, the results of selective predation were consistent and robust. We suggest that as CWD distribution and wolf range overlap in the future, wolf predation may suppress disease emergence or limit prevalence. PMID- 21270000 TI - Comparison of blood values and health status of Floreana Mockingbirds (Mimus trifasciatus) on the islands of Champion and Gardner-by-Floreana, Galapagos Islands. AB - The Floreana Mockingbird (Mimus trifasciatus) is one of the rarest bird species in the world, with an estimated 550 individuals remaining on two rocky islets off the coast of Floreana, Galapagos, Ecuador, from which the main population was extirpated more than 100 yr ago. Because they have been listed in critical danger of extinction, a plan to reintroduce this species to Floreana has been initiated. Determining the health status of the source mockingbird populations is a top priority within the reintroduction plan. We report the health status, over the course of 4 yr, of 75 Floreana Mockingbirds on Champion Island and 160 Floreana Mockingbirds on Gardner-by-Floreana, based on physical examinations, hematology, hemolysis-hemagglutination assay, exposure to selected infectious disease agents, and ecto- and endoparasite counts. Birds on Gardner-by-Floreana had higher body condition index scores, packed cell volumes, total solids, and lymphocyte counts. Additionally, Gardner-by-Floreana birds had lower heterophil counts, eosinophil counts, and heterophil:lymphocyte ratios. No Chlamydophila psittaci DNA or antibodies to paramyxovirus-I, adenovirus-II, or Mycoplasma gallisepticum were found in any of the mockingbirds tested. Ectoparasites were present on birds from both islands, although species varied between islands. A coccidian species was found in eight of the 45 fecal samples from birds on Gardner-by-Floreana, but none of 33 birds examined from Champion. Birds on Gardner-by-Floreana were classified as healthier than those on Champion based on clinical and laboratory findings. These health data will be analyzed in conjunction with genetics, population structure, and disease presence on Floreana for developing recommendations for the Floreana Mockingbird reintroduction plan. PMID- 21270001 TI - Pathologic and hematologic responses to surgically implanted transmitters in eastern massasauga rattlesnakes (Sistrurus catenatus catenatus). AB - The study of secretive snakes, such as rattlesnakes, has benefited from the use of radiotelemetry. However, the principal assumption in telemetry studies is that the transmitter has no significant effect on the study animal. To test the validity of this assumption, the physiologic and pathologic effects of intracoelomic implants were examined in a group of 24 eastern massasauga rattlesnakes (Sistrurus catenatus catenatus) in a laboratory setting over a period of 58 wk between March 2005 and April 2006. Inflammation and infection were evaluated using gross examination, histopathology, bacteriology, hematology, and plasma protein electrophoresis. Inflammation and infection occurred despite careful surgical procedures and advanced veterinary care. Four of 12 (33%) snakes developed extensive inflammatory response to the transmitter and associated anaerobic and gram-negative bacterial infections. Another four (33%) snakes showed mild inflammatory responses without infection. Reaction to the transmitters was reflected in changes in values for heterophils, monocytes, alpha 1, and beta globulin levels. Some conclusions reached in field studies using implanted radiotransmitters in snakes may be invalid if the implant influences the behavior or survival of the subject. Advances in attachment methods and transmitter coating technology may prevent some of the adverse effects associated with surgically implanted transmitters. PMID- 21270002 TI - Ecology and dynamics of the blood parasite, Hepatozoon tuatarae (Apicomplexa), in tuatara (Sphenodon punctatus) on Stephens Island, New Zealand. AB - We explored infection patterns and temporal dynamics of the protozoan blood parasite Hepatozoon tuatarae (Apicomplexa) infecting the tuatara (Sphenodon punctatus), a protected reptile living on Stephens Island, New Zealand. In March 2006, we surveyed tuatara in five study sites to examine spatial variation in infection prevalence, and four times, from May 2005 to November 2006, we recaptured marked individuals within three study sites to examine the temporal dynamics of infection. We also examined how blood-parasite infection patterns were influenced by host sex, body size, and host infestation with ticks (Amblyomma sphenodonti) and mites (Neotrombicula spp.), which are potential vectors of the blood parasite. Infection prevalence (16.9-24% infected) and intensity (<0.01-0.1% blood cells infected) were low in all samples. Infection intensity varied among the five sampled sites in March 2006, but prevalence did not. Neither infection prevalence nor intensity varied with time, and infections were detected in consecutive samples from recaptured individuals for up to 18 mo. Neither survey showed an influence of host sex on infection, but both surveys showed infection intensity declined with increasing host body size, as did infection prevalence in the spatial survey. In the temporal survey, we found a positive relationship between the tick numbers on hosts and blood-parasite infection intensity, which were stronger in two of the sampling periods and among larger hosts. These data suggest that exposure and susceptibility to infection decreases with host size and that ticks, but not mites, are probably the vectors in this ancient host-parasite association of a long-lived (>50 yr) host. PMID- 21270003 TI - Cylicospirura species (Nematoda: Spirocercidae) and stomach nodules in cougars (Puma concolor) and bobcats (Lynx rufus) in Oregon. AB - The stomachs and proximal duodena of 160 cougars (Puma concolor) and 17 bobcats (Lynx rufus), obtained throughout Oregon during 7 yr, were examined for Cylicospirura spp. and associated lesions. Prevalence in cougars was 73%, with a range in intensity of 1-562 worms. The mean diameter of nodules was 1.2 cm (SD=0.5), and many extended through the submucosa to the muscularis. About 83% of cougars had nodules; most nodules contained worms, but 14% of the smaller nodules (<0.2 cm) contained porcupine (Erethizon dorsatum) quills. A mean of 12.4 worms/nodule (SD=34.1) was observed, with a maximum of 340 worms/nodule. Prevalence in bobcats was 53%, with an intensity of 1-25 worms. About 65% of bobcats had nodules, which were slightly smaller than those in cougars but appeared to involve similar layers of gastrointestinal tissue. One to 25 Cylicospirura sp. were found in all but two small nodules in bobcats. Cougars killed for livestock damage or safety concerns had a significantly higher median worm intensity than did those that died of other causes. Also, the median worm intensity of older cougars was higher than that of younger lions. There were more males than females killed for livestock damage or safety concerns. The cylicospirurid from cougars was Cylicospirura subaequalis, and that of bobcats was Cylicospirura felineus. These two similar species were separated morphologically by differences in tooth and sex organ morphology. They were also differentiated by DNA sequence analysis of the mitochondrial cytochrome c oxidase subunit 1 gene (cox1). Worm sequences from cougars differed from those from bobcats by 11%, whereas essentially no difference was found among worms from the same host. Phylogenetic analysis showed that within the order Spirurida, both cylicospirurids were most closely related to Spirocerca lupi, based on this gene sequence. PMID- 21270004 TI - Natural toxoplasma gondii infections in European brown hares and mountain hares in Finland: proportional mortality rate, antibody prevalence, and genetic characterization. AB - In material examined postmortem in Finland from May 2006 to April 2009, acute generalized toxoplasmosis was the immunohistochemically confirmed cause of death in 14 (8.1%) of 173 European brown hares (Lepus europaeus) and four (2.7%) of 148 mountain hares (Lepus timidus). Sera from 116 of the European brown hares and 99 of the mountain hares were screened with a commercial direct agglutination test for Toxoplasma gondii-specific IgG antibodies at a dilution of 1:40. All sera from cases of fatal toxoplasmosis had high titers of antibodies reactive to T. gondii. In contrast, none of 107 European brown hares and four (4%) of 96 mountain hares that died of other causes were antibody-positive. The proportional mortality rates and the T. gondii antibody prevalences among noncases differed significantly between the two host species (P<0.05). Direct genetic characterization of the causative agent was performed on DNA extracted from formalin-fixed, paraffin-embedded tissue of the hares with fatal toxoplasmosis. Based on the results with six microsatellite markers (B18, TUB2, TgM-A, W35, B17, and M33; all six in 15 cases and four in three cases), all the cases were caused by T. gondii genotype II; the size of the PCR product at the seventh marker (M48) varied (213-229 base pairs). The presence of T. gondii genotype II, which is endemic in Europe, is now confirmed in Finnish wildlife: Natural infections with T. gondii parasites belonging to this widespread genotype caused fatal generalized toxoplasmosis in the two species of wild hares. PMID- 21270005 TI - The parasites of giant pandas: individual-based measurement in wild animals. AB - There is a growing recognition of parasites as a significant factor in the successful conservation of endangered species. Determining parasite infection and load in free-ranging populations traditionally is done via necropsy or coproscopy. For studies of wild animals, fecal sample collection can result in bias because the individual identity of animals is unknown and multiple samples may be collected from the same individual, yet treated as unrelated samples. We studied parasite load in wild giant pandas (Ailuropoda melanoleuca) across six mountain ranges in China. Genetic identification was used to determine the exact number of individuals sampled. The parasite fauna consisted of five species, dominated by Baylisascaris shroederi. The pattern of statistical difference between mountains was artificially inflated when animal identity was not included in the model. Our results suggest that caution should be exercised in inferring patterns from comparative parasitologic studies when samples cannot be attributed to specific individuals. Using noninvasive genetic sampling to avoid such bias should form a standard tool in the management of endangered species and their parasites. PMID- 21270006 TI - Effects of rainfall, host demography, and musth on strongyle fecal egg counts in African elephants (Loxodonta africana) in Namibia. AB - Wild African elephants (Loxodonta africana) are commonly infected with intestinal strongyle parasites. Our objective was to determine baseline fecal strongyle egg counts for elephants in the northeast region of Etosha National Park, Namibia and determine if these numbers were affected by annual rainfall, elephant demography (age of individuals and composition of groups), and hormonal state of males. We found that matriarchal family group members have significantly higher fecal egg counts than male elephants (bulls). Among family group members, strongyle egg counts increased with age, whereas among bulls, strongyle egg counts decreased with age. Years of higher rainfall were correlated with decreased numbers of strongyle eggs among bulls. Finally, bulls were not affected by their physiologic (hormonal) status (musth vs. nonmusth). These results suggest that infection by strongyle parasites in Namibian African elephants is a dynamic process affected by intrinsic and extrinsic factors including host demography and rainfall. PMID- 21270007 TI - Immunogenicity and efficacy of two rabies vaccines in wild-caught, captive raccoons. AB - The immunogenicity and efficacy of two rabies vaccines in wild-caught, captive raccoons (Procyon lotor) were investigated. Raccoons were fed Ontario Slim (OS) baits containing a recombinant vaccinia virus-rabies glycoprotein (VRG) oral rabies vaccine, or they were given an intramuscular (IM) injection of IMRAB((r)) 3 rabies vaccine. Blood samples collected before treatment and from weeks 1 to 16 posttreatment were assessed for the presence of rabies virus antibody (RVA). There were significantly more positive responders in the group that received an IM injection of IMRAB 3 (18/27) than in the group that consumed VRG in OS baits (VRG-OS; 4/ 26). There were no significant associations among age, sex, and seroconversion. Of those animals that mounted a humoral immune response to vaccination, RVA was first detected between weeks 1 and 5, with the majority of initial seroconversions detectable at week 2. A subsample of 50 raccoons (19 VRG OS, 18 IMRAB 3, and 13 controls) from the longitudinal serology study was challenged with live raccoon variant rabies virus 442 days after initial treatment. There were significantly more survivors in the group that received IMRAB 3 (13/18) than in the VRG-OS (5/19) or control (2/13) groups. All 15 raccoons that demonstrated a serologic response survived challenge regardless of treatment. Of the 35 raccoons with no detectable serologic response, 30 (86%) succumbed to rabies virus infection (14/15 VRG-OS, 5/7 IMRAB 3, and 11/13 controls). PMID- 21270008 TI - Mycoplasma and herpesvirus PCR detection in tortoises with rhinitis-stomatitis complex in Spain. AB - Chelonid herpesvirus (ChHV) and mycoplasmal infections cause similar clinical signs in terrestrial tortoises and may be the most important causative agents of rhinitis-stomatitis complex, a common disease in captive tortoises worldwide. Currently, diagnosis of ChHV and Mycoplasma spp. infections is most often based on serologic testing. However, serologic results only detect past exposure, and the specificity of these tests can be reduced due to antigenic cross-reactions with other pathogens. Molecular-based techniques could help to define the causative agent and to better manage infected tortoises. Using polymerase chain reaction, we analyzed 63 tortoises (59 spur-thighed tortoise, Testudo graeca; three Greek tortoise, Testudo ibera; and one Russian tortoise, Agryonemys horsfieldii) with clinical signs of rhinitis-stomatitis complex to identify the causative agent. Molecular evidence of ChHV type I (24%), type II (3%), and Mycoplasma agassizii (6%) infections, as well as coinfection of Mycoplasma-ChHV and both types of ChHV, were detected. Both ChHV and M. agassizii are considered pathogenic in captive tortoises and both are a threat to wild populations. However, neither agent was detected from most of the symptomatic tortoises we evaluated, indicating that other agents could be involved in the rhinitis stomatitis complex. PMID- 21270009 TI - Pancreatitis associated with the helminth Serpinema microcephalus (Nematoda: Camallanidae) in exotic red-eared slider turtles (Trachemys scripta elegans). AB - Pancreatitis associated with the helminth Serpinema microcephalus was found in three of 19 free-ranging red-eared slider turtles (Trachemys scripta elegans) captured between March 2003 and September 2004 in southern Spain. Microscopic changes were associated with parasite migrations and were characterized by central areas of necrosis surrounded by leukocytes and resulted in destruction of exocrine tissue. The blood profile of one of the three female turtles revealed eosinophilia and hyperglycemia, common in helminth infections and pancreatic disorders respectively. These are the first reported cases of pancreatitis caused by the nematode S. microcephalus in the exotic and newly colonized host T. s. elegans. PMID- 21270010 TI - Mycoplasma species isolated from harbor porpoises (Phocoena phocoena) and a Sowerby's beaked whale (Mesoplodon bidens) stranded in Scottish waters. AB - Mycoplasma species were recovered from 10 cetacean carcasses that stranded around Scotland. Mycoplasma phocicerebrale was isolated from the lungs of three harbor porpoises (Phocoena phocoena) as well as from the liver of one of these animals. Novel Mycoplasma spp. were isolated from the lungs of five additional harbor porpoises and the kidney of another. In addition an isolate closely related to Mycoplasma species 13CL was obtained from the kidney of a Sowerby's beaked whale (Mesoplodon bidens). The role of these Mycoplasma species in the disease of cetaceans, their host specificity, diversity, and any relation to cetacean strandings are unknown. PMID- 21270011 TI - Intoxication of nontarget wildlife with rodenticides in northwestern Kansas. AB - The perception of prairie dogs (Cynomys spp.) both as a nuisance species and a keystone species presents a significant challenge to land, livestock, and wildlife managers. Anticoagulant and nonanticoagulant rodenticides are commonly employed to control prairie dog populations throughout their range. Chlorophacinone, and to a lesser extent zinc phosphide, are widely used in northwestern Kansas for controlling black-tailed prairie dog (Cynomys ludovicianus) populations. Although zinc phosphide poisoning of gallinaceous birds is not uncommon, there are few published accounts of nontarget chlorophacinone poisoning of wildlife. We report three mortality events involving nontarget rodenticide poisoning in several species, including wild turkeys (Meleagris gallopavo), a raccoon (Procyon lotor), and an American badger (Taxidea taxus). This includes the first documentation of chlorophacinone intoxication in wild turkeys and an American badger in the literature. The extent of nontarget poisoning in this area is currently unknown and warrants further investigation. PMID- 21270012 TI - Hematology of free-ranging, lactating northern fur seals, Callorhinus ursinus. AB - Thirteen standard hematology values were determined for a healthy and growing population of free-ranging, lactating northern fur seals (Callorhinus ursinus) from Lovushki Island in the Kuril Islands of far-east Russia. Results are presented from 24 females sampled between June and August during the 3-yr period of 2006-08. Hematologic values have been made available for future comparisons with the declining population of northern fur seals on the Pribilof Islands, Alaska, and are compared with published values for other otariid species. PMID- 21270013 TI - Diseases and parasites in wolves of the Riding Mountain National Park region, Manitoba, Canada. AB - We examined wolf (Canis lupus) blood and fecal samples from the Riding Mountain National Park (RMNP) region of Manitoba, Canada. In 601 fecal samples collected during two study periods in RMNP and the Duck Mountain Provincial Park and Forest (DMPPF) we found gastrointestinal helminth eggs from Alaria sp. (15.5%), Capillaria sp. (1.0%), taeniid tapeworms (30.8%), Toxascaris sp. (1.7%), Toxocara sp. (0.2%), Trichuris sp. (2.2%), and Moniezia sp. (0.5%). In addition, we found Demodex sp. (0.2%) and the protozoal cysts/oocysts of Sarcocystis sp. (37.3%), Cryptosporidium sp. (1.2%), coccidia (Isospora sp. or Eimeria sp.) (1.7%), and Giardia sp. (29.5%). No fecal shedding of canine parvovirus (CPV, n=387) was detected. All 18 blood samples collected in RMNP showed CPV exposure and eight of 18 blood samples indicated canine distemper virus (CDV) exposure. One wolf died from CDV. Our results are consistent with previous findings on pathogens affecting wolves and with high Giardia sp. prevalence in wolves inhabiting agricultural regions. PMID- 21270014 TI - Rabid foxes, rabid raccoons, and the odds of a human bite exposure, New York State, 1999-2007. AB - Anecdotal evidence suggests that rabid foxes are more likely to attack humans than are other rabid terrestrial animals. To examine this issue, we analyzed rabies surveillance data (1999-2007) maintained by the New York State Department of Health. Compared to rabid raccoons (Procyon lotor), foxes infected with raccoon variant rabies were more likely to bite during a human exposure incident (P<0.01). Additionally, rabid gray foxes (Urocyon cinereoargenteus) were significantly more likely to bite a human than were rabid red foxes (Vulpes vulpes; P<0.01). Animal control personnel and others who handle wildlife should be educated about the increased risk of bite exposure when dealing with potentially rabid foxes. PMID- 21270015 TI - Detection and phylogenetic characterization of a novel herpesvirus from the trachea of two stranded Common Loons (Gavia immer). AB - Two wild adult Common Loons (Gavia immer) were evaluated after being found stranded in mainland north-central Florida on separate occasions. On the basis of upper airway endoscopic and cytologic findings, we diagnosed severe ulcerative tracheitis antemortem in one of the birds while more subtle lesions were observed in the other. A novel herpesvirus was detected in antemortem tracheal samples using nested consensus PCR amplification of the polymerase gene and sequencing. Despite prolonged intensive medical care, the bird with severe lesions failed to improve and was euthanized 9 days after endoscopy. No viral inclusions were evident histologically in the lesions. However, an undulating tracheal mucosa in a "mountain ridge" pattern, resulting from epithelial regeneration and hyperplasia, was present, as is seen in the late stages of infectious laryngotracheitis in chickens. The second bird recovered and was released. The genetic distance between this and other characterized herpesviruses supports placement of this virus as a novel species, referred to as Gaviid herpesvirus 1 (GavHV1). Phylogenetically, GavHV1 clusters within the genus Iltovirus. The relationship between the observed lesions and the virus remains to be demonstrated. PMID- 21270016 TI - Avian influenza viruses and avian paramyxoviruses in wintering and breeding waterfowl populations in North Carolina, USA. AB - Although wild ducks are recognized reservoirs for avian influenza viruses (AIVs) and avian paramyxoviruses (APMVs), information related to the prevalence of these viruses in breeding and migratory duck populations on North American wintering grounds is limited. Wintering (n=2,889) and resident breeding (n=524) ducks were sampled in North Carolina during winter 2004-2006 and summer 2005-2006, respectively. Overall prevalence of AIV was 0.8% and restricted to the winter sample; however, prevalence in species within the genus Anas was 1.3% and was highest in Black Ducks (7%; Anas rubripes) and Northern Shovelers (8%; Anas clypeata). Of the 24 AIVs, 16 subtypes were detected, representing nine hemagglutinin and seven neuraminidase subtypes. Avian paramyxoviruses detected in wintering birds included 18 APMV-1s, 15 APMV-4s, and one APMV-6. During summers 2005 and 2006, a high prevalence of APMV-1 infection was observed in resident breeding Wood Ducks (Aix sponsa) and Mallards (Anas platyrhynchos). PMID- 21270017 TI - Congenital neuroglial heterotopia in a neonatal harbor seal (Phoca vitulina richardsi ) with evidence of recent exposure to polycyclic aromatic hydrocarbons. AB - A male neonatal Pacific harbor seal (Phoca vitulina richardsi) stranded off the coast of California, USA, was presented for rehabilitation with numerous partially haired, soft tissue masses around the mouth and in the oropharynx. Because of the extent of the lesions, the seal was humanely euthanized. Histologically, the masses consisted of subepithelial connective tissue and subcutis expanded by a proliferation of streams and bundles of spindle to stellate cells. Morphology of these cells suggested a neural origin, which was confirmed by positive immunohistochemistry for two neural markers, S-100 protein and glial fibrillary acidic protein, so the masses were diagnosed as neuroglial heterotopia. Heterotopic neuroglial tissue is a rare lesion comprised of benign mature neural tissue in an ectopic location with no connection to the central nervous system. Results of polycyclic aromatic hydrocarbon (PAH) metabolite analysis of bile indicated recent exposure to a petroleum source. Although fetal exposure to PAHs in utero can cause neurotoxicity and affect normal embryonic development, it is unknown whether gestational exposure occurred in this case. PMID- 21270018 TI - Presence of hyperplastic pectoral mammary glands in a white-footed mouse (Peromyscus leucopus) from a Superfund Site in Oklahoma, USA. AB - Laboratory experiments have documented the effects of hormones and endocrine disrupting compounds on mammary development in mammals. However, few observations of mammary hyperplasia have been presented for wild rodents. We describe hyperplastic mammary glands in a wild-caught white-footed mouse (Peromyscus leucopus) from an area contaminated with heavy metals. PMID- 21270020 TI - Does reduced heterozygosity influence dispersal? A test using spatially structured populations in an alpine ungulate. AB - Despite having a profound effect on population dynamics, the reasons that animals disperse are poorly understood. Evolutionary explanations have focused on inbreeding and competition, where the potential cost of philopatry is negated through dispersal. Such scenarios lead to the prediction that less successful individuals preferentially disperse, termed 'fitness-associated dispersal'. Since heterozygosity is associated with fitness, we assessed whether dispersed animals had less observed heterozygosity (H(O)) than residents. We tested this prediction using both genetic and population-monitoring data of mountain goats (Oreamnos americanus). Individuals classified as dispersers through cross-assignment had the lowest mean H(O), followed by residents, and then admixed individuals. Dispersed individuals had 6.3 per cent less H(O) than their subpopulation of origin. In the long-term study of the mountain goat herd at Caw Ridge, Alberta, immigrants had the lowest H(O); however, the opposite pattern was seen in emigrants, which may be related to density dependence. This study is the first to provide empirical evidence that heterozygosity is associated with dispersal. PMID- 21270021 TI - Chronic exposure to dim light at night suppresses immune responses in Siberian hamsters. AB - Species have been adapted to specific niches optimizing survival and reproduction; however, urbanization by humans has dramatically altered natural habitats. Artificial light at night (LAN), termed 'light pollution', is an often overlooked, yet increasing disruptor of habitats, which perturbs physiological processes that rely on precise light information. For example, LAN alters the timing of reproduction and activity in some species, which decreases the odds of successful breeding and increases the threat of predation for these individuals, leading to reduced fitness. LAN also suppresses immune function, an important proxy for survival. To investigate the impact of LAN in a species naive to light pollution in its native habitat, immune function was examined in Siberian hamsters derived from wild-caught stock. After four weeks exposure to dim LAN, immune responses to three different challenges were assessed: (i) delayed-type hypersensitivity (DTH), (ii) lipopolysaccharide-induced fever, and (iii) bactericide activity of blood. LAN suppressed DTH response and reduced bactericide activity of blood after lipopolysaccharide treatment, in addition to altering daily patterns of locomotor activity, suggesting that human encroachment on habitats via night-time lighting may inadvertently compromise immune function and ultimately fitness. PMID- 21270022 TI - The evolution of island gigantism and body size variation in tortoises and turtles. AB - Extant chelonians (turtles and tortoises) span almost four orders of magnitude of body size, including the startling examples of gigantism seen in the tortoises of the Galapagos and Seychelles islands. However, the evolutionary determinants of size diversity in chelonians are poorly understood. We present a comparative analysis of body size evolution in turtles and tortoises within a phylogenetic framework. Our results reveal a pronounced relationship between habitat and optimal body size in chelonians. We found strong evidence for separate, larger optimal body sizes for sea turtles and island tortoises, the latter showing support for the rule of island gigantism in non-mammalian amniotes. Optimal sizes for freshwater and mainland terrestrial turtles are similar and smaller, although the range of body size variation in these forms is qualitatively greater. The greater number of potential niches in freshwater and terrestrial environments may mean that body size relationships are more complicated in these habitats. PMID- 21270023 TI - A novel resource-service mutualism between bats and pitcher plants. AB - Mutualistic relationships between vertebrates and plants apart from the pollen and seed-dispersal syndromes are rare. At first view, carnivorous pitcher plants of the genus Nepenthes seem to be highly unlikely candidates for mutualistic interactions with animals, as they form dimorphic terrestrial and aerial pitchers that trap arthropods and small vertebrates. Surprisingly, however, the aerial pitchers of Nepenthes rafflesiana variety elongata are poor insect traps, with low amounts of insect-attractive volatile compounds and low amounts of digestive fluid. Here, we show that N. rafflesiana elongata gains an estimated 33.8 per cent of the total foliar nitrogen from the faeces of Hardwicke's woolly bats (Kerivoula hardwickii hardwickii) that exclusively roost in its aerial pitchers. This is the first case in which the faeces-trapping syndrome has been documented in a pitcher plant that attracts bats and only the second case of a mutualistic association between a carnivorous plant and a mammal to date. PMID- 21270024 TI - Origin of invasive Florida frogs traced to Cuba. AB - Two of the earliest examples of successful invasive amphibians are the greenhouse frog (Eleutherodactylus planirostris) and the Cuban treefrog (Osteopilus septentrionalis) in Florida. Although both are generally assumed to be recent introductions, they are widespread on Caribbean islands and also have been proposed as natural colonizers. We obtained nucleotide sequence data for both species and their closest relatives in their native and introduced ranges. Phylogenetic analyses trace the origin of E. planirostris to a small area in western Cuba, while O. septentrionalis is derived from at least two Cuban sources, one probably a remote peninsula in western Cuba. The tropical-to temperate invasion began with colonization of the Florida Keys followed by human mediated dispersal within peninsular Florida. The subtropical Keys may have served as an adaptive stepping stone for the successful invasion of the North American continent. PMID- 21270025 TI - Comparative analysis of European wide marine ecosystem shifts: a large-scale approach for developing the basis for ecosystem-based management. AB - Abrupt and rapid ecosystem shifts (where major reorganizations of food-web and community structures occur), commonly termed regime shifts, are changes between contrasting and persisting states of ecosystem structure and function. These shifts have been increasingly reported for exploited marine ecosystems around the world from the North Pacific to the North Atlantic. Understanding the drivers and mechanisms leading to marine ecosystem shifts is crucial in developing adaptive management strategies to achieve sustainable exploitation of marine ecosystems. An international workshop on a comparative approach to analysing these marine ecosystem shifts was held at Hamburg University, Institute for Hydrobiology and Fisheries Science, Germany on 1-3 November 2010. Twenty-seven scientists from 14 countries attended the meeting, representing specialists from seven marine regions, including the Baltic Sea, the North Sea, the Barents Sea, the Black Sea, the Mediterranean Sea, the Bay of Biscay and the Scotian Shelf off the Canadian East coast. The goal of the workshop was to conduct the first large-scale comparison of marine ecosystem regime shifts across multiple regional areas, in order to support the development of ecosystem-based management strategies. PMID- 21270026 TI - Spatial facilitation by a high-performance dragonfly target-detecting neuron. AB - Many animals visualize and track small moving targets at long distances-be they prey, approaching predators or conspecifics. Insects are an excellent model system for investigating the neural mechanisms that have evolved for this challenging task. Specialized small target motion detector (STMD) neurons in the optic lobes of the insect brain respond strongly even when the target size is below the resolution limit of the eye. Many STMDs also respond robustly to small targets against complex stationary or moving backgrounds. We hypothesized that this requires a complex mechanism to avoid breakthrough responses by background features, and yet to adequately amplify the weak signal of tiny targets. We compared responses of dragonfly STMD neurons to small targets that begin moving within the receptive field with responses to targets that approach the same location along longer trajectories. We find that responses along longer trajectories are strongly facilitated by a mechanism that builds up slowly over several hundred milliseconds. This allows the neurons to give sustained responses to continuous target motion, thus providing a possible explanation for their extraordinary sensitivity. PMID- 21270027 TI - Confirmation of right whales near a nineteenth-century whaling ground east of southern Greenland. AB - North Atlantic right whales (Eubalaena glacialis) were found in an important nineteenth century whaling area east of southern Greenland, from which they were once thought to have been extirpated. In 2007-2008, a 1-year passive acoustic survey was conducted at five sites in and near the 'Cape Farewell Ground', the former whaling ground. Over 2000 right whale calls were recorded at these sites, primarily during July-November. Most calls were northwest of the historic ground, suggesting a broader range in this region than previously known. Geographical and temporal separation of calls confirms use of this area by multiple animals. PMID- 21270028 TI - Sex differences in spatial ability: a test of the range size hypothesis in the order Carnivora. AB - Sex differences in spatial cognition have been reported for many species ranging from voles to humans. The range size hypothesis predicts that sex differences in spatial ability will only occur in species in which the mating system selects for differential range size. Consistent with this prediction, we observed sex differences in spatial ability in giant pandas, a promiscuous species in which males inhabit larger ranges than females, but did not observe sex differences in Asian small-clawed otters, a related monogamous species in which males and females share home ranges. These results provide the first evidence of sex differences in spatial ability in the order Carnivora, and are consistent with the range size hypothesis. PMID- 21270029 TI - Intercontinental dispersal by a microendemic burrowing reptile (Dibamidae). AB - Intercontinental dispersal via land bridge connections has been important in the biogeographic history of many Holarctic plant and animal groups. Likewise, some groups appear to have accomplished trans-oceanic dispersal via rafting. Dibamid lizards are a clade of poorly known fossorial, essentially limbless species traditionally split into two geographically disjunct genera: Dibamus comprises approximately 20 Southeast Asian species, many of which have very limited geographical distributions, and the monotypic genus Anelytropsis occupies a small area of northeastern Mexico. Although no formal phylogeny of the group exists, a sister-taxon relationship between the two genera has been assumed based on biogeographic considerations. We used DNA sequence data from one mitochondrial and six nuclear protein-coding genes to construct a phylogeny of Dibamidae and to estimate divergence times within the group. Surprisingly, sampled Dibamus species form two deeply divergent, morphologically conserved and geographically concordant clades, one of which is the sister taxon of Anelytropsis papillosus. Our analyses indicate Palaearctic to Nearctic Beringian dispersal in the Late Palaeocene to Eocene. Alternatively, a trans-Pacific rafting scenario would extend the upper limit on dispersal to the Late Cretaceous. Either scenario constitutes a remarkable long-distance dispersal in what would seem an unlikely candidate. PMID- 21270030 TI - An island paradigm on the mainland: host population fragmentation impairs the community of avian pathogens. AB - Emergent infectious diseases represent a major threat for biodiversity in fragmented habitat networks, but their dynamics in host metapopulations remain largely unexplored. We studied a large community of pathogens (including 26 haematozoans, bacteria and viruses as determined through polymerase chain reaction assays) in a highly fragmented mainland bird metapopulation. Contrary to recent studies, which have established that the prevalence of pathogens increase with habitat fragmentation owing to crowding and habitat-edge effects, the analysed pathogen parameters were neither dependent on host densities nor related to the spatial structure of the metapopulation. We provide, to our knowledge, the first empirical evidence for a positive effect of host population size on pathogen prevalence, richness and diversity. These new insights into the interplay between habitat fragmentation and pathogens reveal properties of a host pathogen system resembling island environments, suggesting that severe habitat loss and fragmentation could lower pathogen pressure in small populations. PMID- 21270031 TI - Parasitoids select plants more heavily infested with their caterpillar hosts: a new approach to aid interpretation of plant headspace volatiles. AB - Plants produce volatile organic compounds (VOCs) in response to herbivore attack, and these VOCs can be used by parasitoids of the herbivore as host location cues. We investigated the behavioural responses of the parasitoid Cotesia vestalis to VOCs from a plant-herbivore complex consisting of cabbage plants (Brassica oleracea) and the parasitoids host caterpillar, Plutella xylostella. A Y-tube olfactometer was used to compare the parasitoids' responses to VOCs produced as a result of different levels of attack by the caterpillar and equivalent levels of mechanical damage. Headspace VOC production by these plant treatments was examined using gas chromatography-mass spectrometry. Cotesia vestalis were able to exploit quantitative and qualitative differences in volatile emissions, from the plant-herbivore complex, produced as a result of different numbers of herbivores feeding. Cotesia vestalis showed a preference for plants with more herbivores and herbivore damage, but did not distinguish between different levels of mechanical damage. Volatile profiles of plants with different levels of herbivores/herbivore damage could also be separated by canonical discriminant analyses. Analyses revealed a number of compounds whose emission increased significantly with herbivore load, and these VOCs may be particularly good indicators of herbivore number, as the parasitoid processes cues from its external environment. PMID- 21270032 TI - Paradoxical persistence through mixed-system dynamics: towards a unified perspective of reversal behaviours in evolutionary ecology. AB - Counterintuitive dynamics of various biological phenomena occur when composite system dynamics differ qualitatively from that of their component systems. Such composite systems typically arise when modelling situations with time-varying biotic or abiotic conditions, and examples range from metapopulation dynamics to population genetic models. These biological, and related physical, phenomena can often be modelled as simple financial games, wherein capital is gained and lost through gambling. Such games have been developed and used as heuristic devices to elucidate the processes at work in generating seemingly paradoxical outcomes across a spectrum of disciplines, albeit in a field-specific, ad hoc fashion. Here, we propose that studying these simple games can provide a much deeper understanding of the fundamental principles governing paradoxical behaviours in models from a diversity of topics in evolution and ecology in which fluctuating environmental effects, whether deterministic or stochastic, are an essential aspect of the phenomenon of interest. Of particular note, we find that, for a broad class of models, the ecological concept of equilibrium reactivity provides an intuitive necessary condition that must be satisfied in order for environmental variability to promote population persistence. We contend that further investigations along these lines promise to unify aspects of the study of a range of topics, bringing questions from genetics, species persistence and coexistence and the evolution of bet-hedging strategies, under a common theoretical purview. PMID- 21270034 TI - Fluorescence of coral larvae predicts their settlement response to crustose coralline algae and reflects stress. AB - Multi-coloured homologues of the green fluorescent protein generate some of the most striking visual phenomena in the ocean. Despite their natural prominence in reef-building corals and widespread use in biotechnology, their biological role remains obscure. Here, we experimented with larvae of Acropora millepora to determine what can be learned about a coral larva or recruit from its fluorescent colour. We performed 12 crosses between seven A. millepora colonies representing differing fluorescence phenotypes, the larvae of which were exposed to a natural settlement cue (crustose coralline algae) and heat-light stress. Parental effects explained 18 per cent of variation in colour and 47 per cent of variation in settlement. The colour of the larval family emerged as a predictor of the settlement success: redder families were significantly less responsive to the provided settlement cue (p = 0.006). This relationship was owing to a correlation between parental effects on settlement and colour (r(2) = 0.587, p = 0.045). We also observed pronounced (16%) decline in settlement rate, as well as subtle (2%), but a statistically significant decrease in red fluorescence, as a consequence of heat-light stress exposure. Variation in settlement propensity in A. millepora is largely owing to additive genetic effects, and is thought to reflect variation in dispersal potential. Our results suggest an optical signature to discriminate between long- and short-range dispersing genotypes, as well as to evaluate stress. Further research in this direction may lead to the development of field applications to trace changes in coral life history and physiology caused by global warming. PMID- 21270035 TI - Sense and sensitivity: responsiveness to offspring signals varies with the parents' potential to breed again. AB - How sensitive should parents be to the demands of their young? Offspring are under selection to seek more investment than is optimal for parents to supply, which makes parents vulnerable to losing future fitness by responding to manipulative displays. Yet, parents cannot afford to ignore begging and risk allocating resources inefficiently. Here, we show that parents may solve this problem by adjusting their sensitivity to begging behaviour in relation to their own likelihood of breeding again, a factor largely neglected in previous analyses of parent-offspring interactions. In two carotenoid-supplementation experiments on a New Zealand passerine, the hihi Notiomystis cincta, we supplemented adults to enhance their propensity to breed again, and supplemented entire broods to increase their mouth colour, thus enhancing their solicitation display. We found that adults that attempted two breeding attempts a season were largely insensitive to the experimentally carotenoid-rich gapes of their brood, whereas those that bred just once responded by increasing their rate of provisioning at the nest. Our results show that parents can strategically vary their sensitivity to begging in relation to their future reproductive potential. By restricting opportunities for offspring to influence provisioning decisions, parents greatly limit the potential for offspring to win parent-offspring conflict. PMID- 21270033 TI - Phylogeny and palaeoecology of Polyommatus blue butterflies show Beringia was a climate-regulated gateway to the New World. AB - Transcontinental dispersals by organisms usually represent improbable events that constitute a major challenge for biogeographers. By integrating molecular phylogeny, historical biogeography and palaeoecology, we test a bold hypothesis proposed by Vladimir Nabokov regarding the origin of Neotropical Polyommatus blue butterflies, and show that Beringia has served as a biological corridor for the dispersal of these insects from Asia into the New World. We present a novel method to estimate ancestral temperature tolerances using distribution range limits of extant organisms, and find that climatic conditions in Beringia acted as a decisive filter in determining which taxa crossed into the New World during five separate invasions over the past 11 Myr. Our results reveal a marked effect of the Miocene-Pleistocene global cooling, and demonstrate that palaeoclimatic conditions left a strong signal on the ecology of present-day taxa in the New World. The phylogenetic conservatism in thermal tolerances that we have identified may permit the reconstruction of the palaeoecology of ancestral organisms, especially mobile taxa that can easily escape from hostile environments rather than adapt to them. PMID- 21270036 TI - Intuitive physical reasoning about occluded objects by inexperienced chicks. AB - Questions concerning the role of nature and nurture in higher cognition appear to be intractable if one restricts one's attention to development in humans. However, in other domains, such as sensory development, much information has been gained from controlled rearing studies with animals. Here, we used a similar experimental strategy to investigate intuitive reasoning about occluded objects. Newborn domestic chicks (Gallus gallus) were reared singly with a small object that became their social partner. They were then accustomed to rejoin such an imprinting object when it was made to move and disappear behind either one of two identical opaque screens. After disappearance of the imprinting object, chicks were faced with two screens of different slants, or of different height or different width, which may or may not have been compatible with the presence of the imprinting object hidden beneath/behind them. Chicks consistently chose the screen of slant/height/width compatible with the presence of the object beneath/behind it. Preventing chicks from touching and pecking at the imprinting object before testing did not affect the results, suggesting that intuitive reasoning about physical objects is largely independent of specific experience of interaction with objects and of objects' occluding events. PMID- 21270037 TI - Intra-guild competition and its implications for one of the biggest terrestrial predators, Tyrannosaurus rex. AB - Identifying tradeoffs between hunting and scavenging in an ecological context is important for understanding predatory guilds. In the past century, the feeding strategy of one of the largest and best-known terrestrial carnivores, Tyrannosaurus rex, has been the subject of much debate: was it an active predator or an obligate scavenger? Here we look at the feasibility of an adult T. rex being an obligate scavenger in the environmental conditions of Late Cretaceous North America, given the size distributions of sympatric herbivorous dinosaurs and likely competition with more abundant small-bodied theropods. We predict that nearly 50 per cent of herbivores would have been within a 55-85 kg range, and calculate based on expected encounter rates that carcasses from these individuals would have been quickly consumed by smaller theropods. Larger carcasses would have been very rare and heavily competed for, making them an unreliable food source. The potential carcass search rates of smaller theropods are predicted to be 14-60 times that of an adult T. rex. Our results suggest that T. rex and other extremely large carnivorous dinosaurs would have been unable to compete as obligate scavengers and would have primarily hunted large vertebrate prey, similar to many large mammalian carnivores in modern-day ecosystems. PMID- 21270038 TI - Failure to fix nitrogen by non-reproductive symbiotic rhizobia triggers host sanctions that reduce fitness of their reproductive clonemates. AB - The legume-rhizobia symbiosis is a classical mutualism where fixed carbon and nitrogen are exchanged between the species. Nonetheless, the plant carbon that fuels nitrogen (N(2)) fixation could be diverted to rhizobial reproduction by 'cheaters'--rhizobial strains that fix less N(2) but potentially gain the benefit of fixation by other rhizobia. Host sanctions can decrease the relative fitness of less-beneficial reproductive bacteroids and prevent cheaters from breaking down the mutualism. However, in certain legume species, only undifferentiated rhizobia reproduce, while only terminally differentiated rhizobial bacteroids fix nitrogen. Sanctions were, therefore, tested in two legume species that host non reproductive bacteroids. We demonstrate that even legume species that host non reproductive bacteroids, specifically pea and alfalfa, can severely sanction undifferentiated rhizobia when bacteroids within the same nodule fail to fix N(2). Hence, host sanctions by a diverse set of legumes play a role in maintaining N(2) fixation. PMID- 21270039 TI - A small increase in UV-B increases the susceptibility of tadpoles to predation. AB - Increased ultraviolet-B (UV-B) radiation as a consequence of ozone depletion is one of the many potential drivers of ongoing global amphibian declines. Both alone and in combination with other environmental stressors, UV-B is known to have detrimental effects on the early life stages of amphibians, but our understanding of the fitness consequences of these effects remains superficial. We examined the independent and interactive effects of UV-B and predatory chemical cues (PCC) on a suite of traits of Limnodynastes peronii embryos and tadpoles, and assessed tadpole survival time in a predator environment to evaluate the potential fitness consequences. Exposure to a 3 to 6 per cent increase in UV-B, which is comparable to changes in terrestrial UV-B associated with ozone depletion, had no effect on any of the traits measured, except survival time in a predator environment, which was reduced by 22 to 28 per cent. Exposure to PCC caused tadpoles to hatch earlier, have reduced hatching success, have improved locomotor performance and survive for longer in a predator environment, but had no effect on tadpole survival, behaviour or morphology. Simultaneous exposure to UV-B and PCC resulted in no interactive effects. These findings demonstrate that increased UV-B has the potential to reduce tadpole fitness, while exposure to PCCs improves their fitness. PMID- 21270040 TI - Intraspecific evidence from guppies for correlated patterns of male and female genital trait diversification. AB - The role of sexual selection in fuelling genital evolution is becoming increasingly apparent from comparative studies revealing interspecific divergence in male genitalia and evolutionary associations between male and female genital traits. Despite this, we know little about intraspecific variance in male genital morphology, or how male and female reproductive traits covary among divergent populations. Here we address both topics using natural populations of the guppy, Poecilia reticulata, a livebearing fish that exhibits divergent patterns of male sexual behaviour among populations. Initially, we performed a series of mating trials on a single population to examine the relationship between the morphology of the male's copulatory organ (the gonopodium) and the success of forced matings. Using a combination of linear measurements and geometric morphometrics, we found that variation in the length and shape of the gonopodium predicted the success of forced matings in terms of the rate of genital contacts and insemination success, respectively. We then looked for geographical divergence in these traits, since the relative frequency of forced matings tends to be greater in high-predation populations. We found consistent patterns of variation in male genital size and shape in relation to the level of predation, and corresponding patterns of (co)variation in female genital morphology. Together, these data enable us to draw tentative conclusions about the underlying selective pressures causing correlated patterns of divergence in male and female genital traits, which point to a role for sexually antagonistic selection. PMID- 21270041 TI - Using knockout mutants to reveal the growth costs of defensive traits. AB - We used a selection of Arabidopsis thaliana mutants with knockouts in defence genes to demonstrate growth costs of trichome development and glucosinolate production. Four of the seven defence mutants had significantly higher size standardized growth rates (SGRs) than the wild-type in early life, although this benefit declined as plants grew larger. SGR is known to be a good predictor of success under high-density conditions, and we confirmed that mutants with higher growth rates had a large advantage when grown in competition. Despite the lack of differences in flowering-time genes, the mutants differed in flowering time, a trait that strongly correlated with early growth rate. Aphid herbivory decreased plant growth rate and increased flowering time, and aphid population growth rate was closely coupled to the growth rate of the host plant. Small differences in early SGR thus had cascading effects on both flowering time and herbivore populations. PMID- 21270042 TI - Adaptation improves discrimination of face identity. AB - Whether face adaptation confers any advantages to perceptual processing remains an open question. We investigated whether face adaptation can enhance the ability to make fine discriminations in the vicinity of the adapted face. We compared face discrimination thresholds in three adapting conditions: (i) same-face: where adapting and test faces were the same, (ii) different-face: where adapting and test faces differed, and (iii) baseline: where the adapting stimulus was a blank. Discrimination thresholds for morphed identity changes involving the adapted face (same-face) improved compared with those from both the baseline (no-adaptation) and different-face conditions. Since adapting to a face did not alter discrimination performance for other faces, this effect is selective for the facial identity that is adapted. These results indicate a form of gain control to heighten perceptual sensitivity in the vicinity of a currently viewed face, analogous to forms of adaptive gain control at lower levels of the visual system. PMID- 21270043 TI - The relationship between pink salmon biomass and the body condition of short tailed shearwaters in the Bering Sea: can fish compete with seabirds? AB - Seabirds and large fishes are important top predators in marine ecosystems, but few studies have explored the potential for competition between these groups. This study investigates the relationship between an observed biennial change of pink salmon (Oncorhynchus gorbuscha) biomass in the central Bering Sea (23 times greater in odd-numbered than in even-numbered years) and the body condition and diet of the short-tailed shearwater (Puffinus tenuirostris) that spends the post breeding season there. Samples were collected with research gill nets over seven summers. Both species feed on krill, small fishes and squid. Although the mean pink salmon catch per unit effort (in mass) over the study region was not related significantly with shearwater's stomach content mass or prey composition, the pink salmon biomass showed a negative and significant relationship with the shearwater's body mass and liver mass (proxies of energy reserve). We interpret these results as evidence that fishes can negatively affect mean prey intake of seabirds if they feed on a shared prey in the pelagic ecosystem. PMID- 21270044 TI - Sexual imprinting on ecologically divergent traits leads to sexual isolation in sticklebacks. AB - During sexual imprinting, offspring learn parental phenotypes and then select mates who are similar to their parents. Imprinting has been thought to contribute to the process of speciation in only a few rare cases; this is despite imprinting's potential to generate assortative mating and solve the problem of recombination in ecological speciation. If offspring imprint on parental traits under divergent selection, these traits will then be involved in both adaptation and mate preference. Such 'magic traits' easily generate sexual isolation and facilitate speciation. In this study, we show that imprinting occurs in two ecologically divergent stickleback species (benthics and limnetics: Gasterosteus spp.). Cross-fostered females preferred mates of their foster father's species. Furthermore, imprinting is essential for sexual isolation between species; isolation was reduced when females were raised without fathers. Daughters imprinted on father odour and colour during a critical period early in development. These traits have diverged between the species owing to differences in ecology. Therefore, we provide the first evidence that imprinting links ecological adaptation to sexual isolation between species. Our results suggest that imprinting may facilitate the evolution of sexual isolation during ecological speciation, may be especially important in cases of rapid diversification, and thus play an integral role in the generation of biodiversity. PMID- 21270045 TI - Interpopulation variation in a fish predator drives evolutionary divergence in prey in lakes. AB - Ecological factors are known to cause evolutionary diversification. Recent work has shown that evolution in strongly interacting predator species has reciprocal impacts on ecosystems. These divergent impacts of predators may alter the selective landscape and cause the evolution of prey. Yet, this link between intraspecific variation and evolution is unexplored. We compared the life history of a species of zooplankton (Daphnia ambigua) from lakes in New England in which the dominant planktivorous predator, the alewife (Alosa pseudoharengus), differs in feeding traits and migratory behaviour. Anadromous alewife (seasonal migrants) exhibit larger gapes, gill-raker spacing and target larger prey than landlocked alewife (year-round freshwater resident). In 'anadromous' lakes, Daphnia are abundant in the spring but extirpated by alewife predation in summer. Daphnia are rare year-round in 'landlocked' lakes. We show that Daphnia from lakes with anadromous alewife grew faster, matured earlier but at the same size and produced more offspring than Daphnia from lakes with landlocked or no alewife across multiple temperature and resource treatments. Our results are inconsistent with a response to size-selective predation but are better explained as an adaptation to colder temperatures and shorter periods of development (countergradient variation) mediated by seasonal alewife predation. PMID- 21270046 TI - The effect of PACS on the practice of orthopaedic surgeons. AB - When new information and communication technologies are implemented there are organizational effects. Picture Archiving and Communication Systems (PACS) have been implemented not only within radiology but also within the orthopaedic context. We studied the impact of PACS on the work practice and professional role of orthopaedic surgeons in relation to radiologists. Qualitative interviews were performed with 15 surgeons at two hospitals. The interviews were transcribed, analysed and then coded using grounded theory. Three main categories were defined: professional role, diagnostic practice and technology used. There was a shift in orthopaedics from a single to a mixed profession, and from a relatively static practice in interpreting images to a more flexible practice, where every orthopaedic surgeon could view and access images from anywhere at any time, including three-dimensional imaging. It was easier for surgeons to see and interpret the images, and their diagnostic skills became accessible to everyone. The use of PACS also improved the dialogue with patients, according to the respondents. This was necessary in order to explain the treatment options for the patient or the details of the disease. PACS therefore acts as an information and communications technology and users required new knowledge and skills. PMID- 21270047 TI - The benefit of smart phone usage in liver organ procurement. AB - A 56-year-old man was on the transplant list with end-stage liver disease secondary to hepatitis C when a donor liver became available at a location 545 km away. The procurement team, consisting of a senior and junior fellow, went on the retrieval, while the staff surgeon remained in the hospital with the recipient. At the time of organ procurement, a suspicious lesion was identified in the left lateral lobe. The transplant fellows took intraoperative pictures of the lesion with a smart phone and sent them to the staff surgeon for advice. A teleconsultation, facilitated by images sent from the smart phone, took place over the next 22 min. The decision was made to proceed with the transplant, as it was felt that the lesion could be resected from the liver allograft. Had the fellows not been able to interact with the staff surgeon in real-time during the surgery, there is a high likelihood that the organ would have been rejected by the staff surgeon due to the unexpected finding. The patient's postoperative course was relatively uneventful with no evidence of infection. The patient was discharged from hospital and continues to do well. We expect that the role of smart phones in remote consultation will continue to expand in future. PMID- 21270048 TI - Electronic follow-up of facial lacerations in the emergency department. AB - It is often difficult for emergency department staff to follow up the primary closure of simple facial lacerations. This is important to allow closure of the feedback loop. Consecutive patients who were sutured by a single operator using the same technique were asked to send a photograph of the laceration six months and 12 months afterwards. The patients had Internet access and a digital camera, or a mobile phone with a camera. They were given a leaflet with the details of the email address or mobile number to send the picture to. A reminder telephone call was made to each patient at six months and 12 months, and the email address or mobile number to send the picture to was given again. In each telephone call patients were asked to grade the healing on a 5-point scale from 1 = very happy to 5 = very unhappy. At 13 months all patients were re-contacted and reminded again. Fifty patients were included in the study (33 males). The cause of injury was sport in 17 patients, assault in 18 and accidents in 15. At six months, 23 patients stated that they were happy and 27 were very happy with the scar. The mean score was 1.5. At 12 and 13 months, four patients were happy and 46 very happy. The mean score was 1.1. Twenty-four patients said they would use a computer/camera to send in the follow-up image, and 26 patients had a mobile phone with a camera and said they would use that. Despite the reminders, no patients sent a photograph. The results provide no evidence to support the use of photographs sent by email or text message for the follow-up of facial lacerations sutured in the emergency department. PMID- 21270049 TI - A pilot programme using mobile phones for HIV prevention. AB - We explored the feasibility of engaging young black men in a 12-week text messaging programme about HIV prevention. There were two non-randomized groups of 30 young men each. The participants were aged 16-20 years, self-identifying as black or African-American, sexually active, who owned a mobile phone and lived in Philadelphia. They received three text messages per week for 12 weeks. People in the intervention group received text messages about HIV prevention, while those in the control group received text messages about nutrition. The intervention participants showed trends in increased monogamy at follow-up compared to controls. Awareness of sexual health was significantly higher in the intervention group. Condom norms were significantly higher for the control group. There were no differences in the proportion of protected sex acts. The participants embraced the project, and were enrolled and retained in numbers that suggest such an intervention is worth examining for efficacy. PMID- 21270050 TI - Dlx5 and Dlx6 expression in the anterior neural fold is essential for patterning the dorsal nasal capsule. AB - Morphogenesis of the vertebrate facial skeleton depends upon inductive interactions between cephalic neural crest cells (CNCCs) and cephalic epithelia. The nasal capsule is a CNCC-derived cartilaginous structure comprising a ventral midline bar (mesethmoid) overlaid by a dorsal capsule (ectethmoid). Although Shh signalling from the anterior-most region of the endoderm (EZ-I) patterns the mesethmoid, the cues involved in ectethmoid induction are still undefined. Here, we show that ectethmoid formation depends upon Dlx5 and Dlx6 expression in a restricted ectodermal territory of the anterior neural folds, which we name NF ZA. In both chick and mouse neurulas, Dlx5 and Dlx6 expression is mostly restricted to NF-ZA. Simultaneous Dlx5 and Dlx6 inactivation in the mouse precludes ectethmoid formation, while the mesethmoid is still present. Consistently, siRNA-mediated downregulation of Dlx5 and Dlx6 in the cephalic region of the early avian neurula specifically prevents ectethmoid formation, whereas other CNCC-derived structures, including the mesethmoid, are not affected. Similarly, NF-ZA surgical removal in chick neurulas averts ectethmoid development, whereas grafting a supernumerary NF-ZA results in an ectopic ectethmoid. Simultaneous ablation or grafting of both NF-ZA and EZ-I result, respectively, in the absence or duplication of both dorsal and ventral nasal capsule components. The present work shows that early ectodermal and endodermal signals instruct different contingents of CNCCs to form the ectethmoid and the mesethmoid, which then assemble to form a complete nasal capsule. PMID- 21270051 TI - Origin of muscle satellite cells in the Xenopus embryo. AB - We have studied the origin of muscle satellite cells in embryos of Xenopus laevis. Fate mapping at the open neural plate stage was carried out using orthotopic grafts from transgenic embryos expressing GFP. This shows that most satellite cells originate from the dorsolateral plate rather than from the paraxial mesoderm. Specification studies were made by isolation of explants from the paraxial and dorsolateral regions of neurulae and these also indicated that the satellite cell progenitors arise from the dorsolateral plate. Muscle satellite cells express Pax7, but overexpression of Pax7 in blastomeres of whole embryos that populate the myogenic areas does not induce the formation of additional satellite cells. Moreover, a dominant-negative construct, Pax7EnR, does not reduce satellite cell formation. Neither Pax7 nor other myogenic transcription factor genes will induce satellite cell formation in animal caps treated with FGF. However, BMP RNA or protein will do so, both for FGF-treated animal caps and for paraxial neurula explants. Conversely, the induction of Noggin in dorsolateral explants from HGEM-Noggin transgenic neurulae will block formation of satellite cells, showing that BMP signaling is required in vivo for satellite cell formation. We conclude that satellite cell progenitors are initially specified in the dorsal part of the lateral plate mesoderm and later become incorporated into the myotomes. The initial specification occurs at the neurula stage and depends on the ventral-to-dorsal BMP gradient in the early embryo. PMID- 21270053 TI - Brassinosteroid perception in the epidermis controls root meristem size. AB - Multiple small molecule hormones contribute to growth promotion or restriction in plants. Brassinosteroids (BRs), acting specifically in the epidermis, can both drive and restrict shoot growth. However, our knowledge of how BRs affect meristem size is scant. Here, we study the root meristem and show that BRs are required to maintain normal cell cycle activity and cell expansion. These two processes ensure the coherent gradient of cell progression, from the apical to the basal meristem. In addition, BR activity in the meristem is not accompanied by changes in the expression level of the auxin efflux carriers PIN1, PIN3 and PIN7, which are known to control the extent of mitotic activity and differentiation. We further demonstrate that BR signaling in the root epidermis and not in the inner endodermis, quiescent center (QC) cells or stele cell files is sufficient to control root meristem size. Interestingly, expression of the QC and the stele-enriched MADS-BOX gene AGL42 can be modulated by BRI1 activity solely in the epidermis. The signal from the epidermis is probably transmitted by a different component than BES1 and BZR1 transcription factors, as their direct targets, such as DWF4 and BRox2, are regulated in the same cells that express BRI1. Taken together, our study provides novel insights into the role of BRs in controlling meristem size. PMID- 21270052 TI - Stage-specific signaling through TGFbeta family members and WNT regulates patterning and pancreatic specification of human pluripotent stem cells. AB - The generation of insulin-producing beta-cells from human pluripotent stem cells is dependent on efficient endoderm induction and appropriate patterning and specification of this germ layer to a pancreatic fate. In this study, we elucidated the temporal requirements for TGFbeta family members and canonical WNT signaling at these developmental stages and show that the duration of nodal/activin A signaling plays a pivotal role in establishing an appropriate definitive endoderm population for specification to the pancreatic lineage. WNT signaling was found to induce a posterior endoderm fate and at optimal concentrations enhanced the development of pancreatic lineage cells. Inhibition of the BMP signaling pathway at specific stages was essential for the generation of insulin-expressing cells and the extent of BMP inhibition required varied widely among the cell lines tested. Optimal stage-specific manipulation of these pathways resulted in a striking 250-fold increase in the levels of insulin expression and yielded populations containing up to 25% C-peptide+ cells. PMID- 21270054 TI - The APC/C activator FZR1 coordinates the timing of meiotic resumption during prophase I arrest in mammalian oocytes. AB - FZR1, an activator of the anaphase-promoting complex/cyclosome (APC/C), is recognized for its roles in the mitotic cell cycle. To examine its meiotic function in females we generated an oocyte-specific knockout of the Fzr1 gene (Fzr1(Delta/Delta)). The total number of fully grown oocytes enclosed in cumulus complexes was 35-40% lower in oocytes from Fzr1(Delta/Delta) mice and there was a commensurate rise in denuded, meiotically advanced and/or fragmented oocytes. The ability of Fzr1(Delta/Delta) oocytes to remain prophase I/germinal vesicle (GV) arrested in vitro was also compromised, despite the addition of the phosphodiesterase milrinone. Meiotic competency of smaller diameter oocytes was also accelerated by Fzr1 loss. Cyclin B1 levels were elevated ~5-fold in Fzr1(Delta/Delta) oocytes, whereas securin and CDC25B, two other APC/C(FZR1) substrates, were unchanged. Cyclin B1 overexpression can mimic the effects of Fzr1 loss on GV arrest and here we show that cyclin B1 knockdown in Fzr1(Delta/Delta) oocytes affects the timing of meiotic resumption. Therefore, the effects of Fzr1 loss are mediated, at least in part, by raised cyclin B1. Thus, APC/C(FZR1) activity is required to repress cyclin B1 levels in oocytes during prophase I arrest in the ovary, thereby maintaining meiotic quiescence until hormonal cues trigger resumption. PMID- 21270055 TI - Smad1 and its target gene Wif1 coordinate BMP and Wnt signaling activities to regulate fetal lung development. AB - Bone morphogenetic protein 4 (Bmp4) is essential for lung development. To define the intracellular signaling mechanisms by which Bmp4 regulates lung development, BMP-specific Smad1 or Smad5 was selectively knocked out in fetal mouse lung epithelial cells. Abrogation of lung epithelial-specific Smad1, but not Smad5, resulted in retardation of lung branching morphogenesis and reduced sacculation, accompanied by altered distal lung epithelial cell proliferation and differentiation and, consequently, severe neonatal respiratory failure. By combining cDNA microarray with ChIP-chip analyses, Wnt inhibitory factor 1 (Wif1) was identified as a novel target gene of Smad1 in the developing mouse lung epithelial cells. Loss of Smad1 transcriptional activation of Wif1 was associated with reduced Wif1 expression and increased Wnt/beta-catenin signaling activity in lung epithelia, resulting in specific fetal lung abnormalities. This suggests a novel regulatory loop of Bmp4-Smad1-Wif1-Wnt/beta-catenin in coordinating BMP and Wnt pathways to control fetal lung development. PMID- 21270057 TI - Brassinosteroids control meristem size by promoting cell cycle progression in Arabidopsis roots. AB - Brassinosteroids (BRs) play crucial roles in plant growth and development. Previous studies have shown that BRs promote cell elongation in vegetative organs in several plant species, but their contribution to meristem homeostasis remains unexplored. Our analyses report that both loss- and gain-of-function BR-related mutants in Arabidopsis thaliana have reduced meristem size, indicating that balanced BR signalling is needed for the optimal root growth. In the BR insensitive bri1-116 mutant, the expression pattern of the cell division markers CYCB1;1, ICK2/KRP2 and KNOLLE revealed that a decreased mitotic activity accounts for the reduced meristem size; accordingly, this defect could be overcome by the overexpression of CYCD3;1. The activity of the quiescent centre (QC) was low in the short roots of bri1-116, as reported by cell type-specific markers and differentiation phenotypes of distal stem cells. Conversely, plants treated with the most active BR, brassinolide, or mutants with enhanced BR signalling, such as bes1-D, show a premature cell cycle exit that results in early differentiation of meristematic cells, which also negatively influence meristem size and overall root growth. In the stem cell niche, BRs promote the QC renewal and differentiation of distal stem cells. Together, our results provide evidence that BRs play a regulatory role in the control of cell-cycle progression and differentiation in the Arabidopsis root meristem. PMID- 21270056 TI - Capicua DNA-binding sites are general response elements for RTK signaling in Drosophila. AB - RTK/Ras/MAPK signaling pathways play key functions in metazoan development, but how they control expression of downstream genes is not well understood. In Drosophila, it is generally assumed that most transcriptional responses to RTK signal activation depend on binding of Ets-family proteins to specific cis-acting sites in target enhancers. Here, we show that several Drosophila RTK pathways control expression of downstream genes through common octameric elements that are binding sites for the HMG-box factor Capicua, a transcriptional repressor that is downregulated by RTK signaling in different contexts. We show that Torso RTK dependent regulation of terminal gap gene expression in the early embryo critically depends on Capicua octameric sites, and that binding of Capicua to these sites is essential for recruitment of the Groucho co-repressor to the huckebein enhancer in vivo. We then show that subsequent activation of the EGFR RTK pathway in the neuroectodermal region of the embryo controls dorsal-ventral gene expression by downregulating the Capicua protein, and that this control also depends on Capicua octameric motifs. Thus, a similar mechanism of RTK regulation operates during subdivision of the anterior-posterior and dorsal-ventral embryonic axes. We also find that identical DNA octamers mediate Capicua dependent regulation of another EGFR target in the developing wing. Remarkably, a simple combination of activator-binding sites and Capicua motifs is sufficient to establish complex patterns of gene expression in response to both Torso and EGFR activation in different tissues. We conclude that Capicua octamers are general response elements for RTK signaling in Drosophila. PMID- 21270058 TI - Texture analysis differentiates persistent and transient T1 black holes at acute onset in multiple sclerosis: a preliminary study. AB - BACKGROUND AND OBJECTIVE: The persistence of new enhancing T1 hypointense lesions (acute black holes, ABHs) in multiple sclerosis (MS) cannot be predicted visually at lesion onset. Texture analysis using the polar Stockwell transform (PST) applied to conventional MR images however shows promise in quantifying tissue injury early. The objective of this study was to explore whether ABHs that persist (pABHs) differ from those that are transient (tABHs) using PST texture analysis. METHODS: Fifteen ABHs (8 pABHs; 7 tABHs) from 9 patients were analyzed on 3T images obtained during a clinical trial. Persistence was defined as remaining T1 hypointense 5-8 months later. NAWM regions were examined to control for changes unrelated to ABHs. RESULTS: At first appearance, there was higher coarse texture indicating greater tissue damage in the pABHs than in the tABHs (p<0.01). Both had greater coarse texture than the contralateral and general NAWM (p<=0.01). No difference was identified in normalized signal intensity between pABHs and tABHs and neither demonstrated location preference. While tABHs tended to be smaller than pABHs there was no correlation between lesion size and texture (r=0.44, p>0.05). Furthermore, coarse texture content appeared to predict persistence of individual lesions. CONCLUSIONS: This preliminary study suggests that PST texture could predict persistence of tissue injury based on the severity of structural disorganization within acute lesions. While confirmation of this data is required texture analysis may prove to be a valuable tool to quantify tissue damage and predict recovery in proof-of-concept neuroprotection and repair trials. PMID- 21270059 TI - Trend for decreasing Multiple Sclerosis Severity Scores (MSSS) with increasing calendar year of enrollment into the New York State Multiple Sclerosis Consortium. AB - BACKGROUND: Although the natural history of multiple sclerosis has been charted extensively, it is still not known whether the trajectory of disability accumulation has changed in the era of disease-modifying therapies (DMTs). OBJECTIVE: The objective of this study was to examine trends in Multiple Sclerosis Severity Score (MSSS) with regard to calendar year of enrollment into the New York State MS Consortium (NYSMSC). METHODS: Distributions of MSSS were calculated for each year of enrollment, from 1996 to 2007. Quantile regression was used in a multivariable analysis to model for conditional distribution of MSSS quantiles as functions of potential confounders. RESULTS: The cohort consisted of 6238 patients. Mean age at enrollment was 38 years (SD=10) and mean disease duration was 10.1 years (SD=7.3); 57% were on DMTs. The quantile regression model of trends in MSSS between 1996 and 2007 controlled for age, sex, ethnicity, diagnostic delay, and disease duration and demonstrated a robust trend toward lower MSSS with increasing year of enrollment. The model-predicted median MSSS at enrollment in 1996 was 5.04 (95% CI, 4.86-5.21), and in 2007 was 3.78 (95%CI, 3.36-4.20; p<0.001). The downward trend in MSSS during the enrollment period was confirmed by analysis of Expanded Disability Status Scale (EDSS) distributions, adjusted for disease duration, in successive years of enrollment. CONCLUSIONS: The recent enrollees into the NYSMSC had lower MSSSs compared to the earlier enrollees. The apparent slowing in disability accumulation is likely due to a complex combination of factors: advent of DMTs and improvements in MS care, as well as selection, migration, and recall biases. PMID- 21270060 TI - Fatalities in swimming pools with lifeguards: USA, 2000-2008. AB - BACKGROUND: Pools with lifeguards are often perceived to represent a safe environment for swimming. OBJECTIVES: To examine how often fatalities occurred in pools with lifeguards and what factors were common in these incidents. DESIGN: Case series. SETTING: USA. SUBJECTS: A case was defined as a death in a swimming pool with at least one lifeguard that occurred in the USA from 2000 to 2008. Potential cases were identified from media accounts using Lexis-Nexis and ProQuest databases. Supplemental information was obtained through internet based searches and review of death certificates. RESULTS: A total of 140 deaths from 37 states were identified. Of decedents, 109 (78%) were children and 93 (66%) were males. African Americans accounted for 44% of deaths among those of known race. 104 (74%) fatalities occurred during May through August; 85 (61%) deaths occurred in outdoor pools. Sites for fatal incidents included 53 (38%) municipal pools, 21 (15%) community organisations, and 20 (14%) schools. The median swimmer to lifeguard ratio was 13:1. Decedents were initially identified in the pool twice as often by non-lifeguards (eg, other swimmers or bystanders) as by lifeguards. CONCLUSIONS: Deaths in pools with lifeguards are uncommon, but do occur. Groups most affected include children, males, and African Americans. While lifeguards provide an important layer of protection at swimming pools, they alone cannot prevent all drownings. Additional safety measures are needed. PMID- 21270062 TI - Tumour marker requesting in primary care and the role of the laboratory. AB - AIMS: To review the incidence of multiple tumour marker (TM) requesting in the primary care setting and determine whether the rationale for requesting a TM panel is in agreement with evidence-based guidelines. METHODS: Data-mining software was used to retrospectively identify multiple TM requests and requesting practices of GP surgeries over a 34-month period for alpha-fetoprotein, CA125, CA15-3, CA19-9, carcinoembryonic antigen and prostate-specific antigen. The appropriateness of each test was reviewed by a clinical biochemist in accordance with National Association of Clinical Biochemistry best-practice guidelines. RESULTS: 505 multiple TM requests were identified which corresponded to 1304 TM tests. Comparison with best-practice guidelines suggested that 68% of request cards contained no appropriate TM request, and 84% of the tests requested were inappropriate. CONCLUSION: A review of requesting practices in primary care for TMs highlights the need for laboratories to be more proactive in educating their users on their clinical utility and limitations. PMID- 21270061 TI - Prognostic significance and potential therapeutic target of VEGFR2 in hepatocellular carcinoma. AB - BACKGROUND: Vascular endothelial growth factor receptor 2 (VEGFR2) has been suggested to play an important role in solid tumours. Although several reports have shown the relationship between VEGFR2 expression and hepatocellular carcinoma (HCC), the expression pattern of VEGFR2 in HCC parenchyma or stroma, as well as the relationship between VEGFR2 expression and clinicopathological characteristics in HCC, are yet to be satisfactorily defined. METHODS: One-step real-time PCR, western blotting and immunohistochemistry were used to characterise the expression of VEGFR2 in HCC using a self-made anti-VEGFR2 monoclonal antibody (A8H1). RESULTS: Expression of VEGFR2 in HCC cells was higher than in hepatic cells (p<0.001). Comparison of clinicopathological characteristics and immunohistochemistry by chi(2) test analysis showed that the high expression of VEGFR2 in HCC was related to large tumour diameter (p=0.012), poor differentiation (p=0.007), high serum alpha-fetoprotein (p=0.029), multifocal gross classification (p=0.007), and less than 5 years' survival (p=0.029). Kaplan-Meier survival and Cox regression analyses showed that high VEGFR2 expression (p=0.009) and stage grouping with TNM classification (p=0.004) were independent prognotic factors. CONCLUSIONS: The efficacy of A8H1 in immunohistochemistry using HCC tissues was confirmed. There was a correlation of high VEGFR2 expression with prognostic significance in HCC. Additionally, the self-made anti-VEGFR2 monoclonal antibody could be used for future anti-HCC targeted therapy research. PMID- 21270063 TI - Guillain-Barre syndrome subtypes related to Campylobacter infection. AB - BACKGROUND: In Guillain-Barre syndrome (GBS), the diversity in electrophysiological subtypes is unexplained but may be determined by geographical factors and preceding infections. Acute motor axonal neuropathy (AMAN) is a frequent GBS variant in Japan and one study proposed that in Japan, Campylobacter jejuni infections exclusively elicit AMAN. In The Netherlands C jejuni is the predominant type of preceding infection yet AMAN is rare. This may indicate that not all Dutch GBS patients with C jejuni infections have AMAN. OBJECTIVE: To determine if GBS patients with a preceding C jejuni infection in The Netherlands exclusively have AMAN. METHODS: Retrospective analysis of preceding infections in relation to serial electrophysiology and clinical data from 123 GBS patients. C jejuni related cases were defined as having preceding diarrhoea and positive C jejuni serology. Electrophysiological characteristics in C jejuni related cases were compared with those in viral related GBS patients. In addition, eight GBS patients from another cohort with positive stool cultures for C jejuni were analysed. RESULTS: 17 (14%) of 123 patients had C jejuni related GBS. C jejuni patients had lower motor and higher sensory action potentials compared with viral related cases. Nine (53%) C jejuni patients had either AMAN or inexcitable nerves. However, three (18%) patients fulfilled the criteria for acute inflammatory demyelinating polyneuropathy (AIDP). Also, two (25%) of eight additional patients with a C jejuni positive stool sample had AIDP. CONCLUSION: In The Netherlands, C jejuni infections are strongly, but not exclusively, associated with axonal GBS. Some patients with these infections fulfil current criteria for demyelination. PMID- 21270065 TI - The problems with utilitarian conceptions of personhood in the abortion debate. AB - This article seeks to explore utilitarian conceptions of personhood which for a long time have been employed as part of a rational moral justification for the termination of pregnancy. Michael Tooley's desires-based rights approach to personhood presented in his work Abortion and Infanticide is considered and, it is argued, is found wanting when one considers unconscious adults and their ability to desire life. This article will offer that unconscious sleeping individuals only have the potential to regain the capacity to value their own life and, as such, under Tooley's formula for personhood, temporarily lose their status as a person. Following this, John Harris's utilitarian views on the status of the sleeping adult will be considered and deconstructed to show that, like Tooley, his ascription for personhood falls down at the sleeping adult. This article illustrates that utilitarian conceptions of personhood leave the sleeping adult human devoid of the rights of a person and hence render the value of this consquentialist theory, with regard to the idea of personhood, in severe doubt. The paper argues that utilitarian conceptions of personhood do little more than obstruct the worthy debate over the morality of abortion. PMID- 21270064 TI - Mutations in TGFBR2 gene cause spontaneous cervical artery dissection. AB - Mutations in the genes encoding transforming growth factor beta receptors 1 and 2 (TGFBR1 and TGFBR2) have recently been associated with hereditary connective tissue disorders with widespread vascular involvement, including arterial dissection. To determine whether mutations in these genes cause spontaneous cervical artery dissection (sCAD), all coding exons of TGFBR1 and TGFBR2 were sequenced in 56 consecutive patients with sCAD. Novel TGFBR2 disease causing mutations were found in two patients. The two mutations were the pK327R substitution affecting the kinase domain of TGFBR2 and the pC138R substitution falling in the extracellular domain of the protein, involved in TGFbeta binding and signalling. No TGFBR1 mutation was found. The findings indicate that TGFBR2 gene mutations are responsible for sCAD in 3.6% (95% CI 0.0 to 8.4) of cases, have implications in understanding the role of TGFbeta signalling in the pathogenesis of sCAD and emphasise the importance of considering molecular characterisation of the TGFBR2 gene in these patients, regardless of the presence of clinical features suggestive of hereditary connective tissue disorders. PMID- 21270066 TI - Lymphogranuloma venereum presenting as perianal ulceration: an emerging clinical presentation? AB - An outbreak of lymphogranuloma venereum (LGV) infection has been recognised in the UK since 2004, predominantly affecting HIV-positive men who have sex with men (MSM). Patients typically present with proctitis symptoms. The prevalence of rectal LGV in MSM attending sexually transmitted infection clinics in London is estimated at 1%. Health Protection Agency surveillance has shown a decrease in anorectal manifestations despite little demographic change. Two cases of HIV infected patients presenting with isolated perianal ulcer disease are reported here. Both cases were confirmed to have rectal Chlamydia trachomatis-specific DNA of an LGV associated serovar. As presentations of LGV diversify, further education and surveillance are needed in order to reduce transmission and prevent long-term complications. A strong argument already exists for the incorporation of chlamydia nucleic acid amplification tests in the management of MSM with proctitis; this paper provides evidence that this should be extended to MSM with perianal ulcer disease. PMID- 21270067 TI - Condom use by female sex workers and their clients in Mexico: who decides and does it matter? AB - OBJECTIVES: To explore the effect of different patterns of condom use by clients and female sex workers (FSW) on HIV transmission in Mexico. METHODS: Data from 2401 face-to-face interviews among FSW from Morelos and Michoacan in Mexico were used to build and parameterise a deterministic model of HIV transmission between FSW, their stable partners and clients. RESULTS: For the observed patterns of condom use among FSW, a range of patterns of use among clients would be consistent. Two extreme patterns were explored: either clients conformed to FSW decision, or they had a strict preference for bought sex with or without condoms. HIV prevalence in the model is greater in the first of these scenarios. CONCLUSIONS: Patterns of condom use between sex workers and clients are an important, but hidden, determinant of epidemic spread. More detailed information on condom use negotiation and behavioural patterns of clients is needed to understand the potential for transmission in these populations and in order to direct intervention efforts more effectively. PMID- 21270068 TI - Which Chinese men who have sex with men miss out on HIV testing? AB - OBJECTIVES: To describe socio-demographic, behavioural and other characteristics associated with HIV testing behaviour among men who have sex with men (MSM) in Jinan, China. METHODS: A cross-sectional survey was conducted among MSM (N=500) in Jinan in 2008 using respondent-driven sampling--a method used worldwide to reach hidden high-risk populations. Bivariate and multivariate analyses, adjusted for the sampling method, were conducted to identify correlates of not having an HIV test. RESULTS: Overall, 80.7% (95% CI 75.0% to 85.0%) of MSM in Jinan have not had an HIV test in the past 12 months. In the multivariate analyses, having not visited the local Centers for Disease Control and Prevention's website (AOR 5.59, 95% CI 2.62 to 11.95), being over the age of 35 years (AOR 3.77, 95% CI 1.19 to 11.93) and self-identified as bisexual or unsure (AOR 3.85, 95% CI 2.16 to 6.85) are significantly associated with having not had an HIV test. In addition, married men are slightly less likely to have not been tested compared to single men (AOR 0.38, 95% CI 0.17 to 0.85). Those who report meeting their sex partners at high-risk venues are two times more likely to have not had an HIV test (AOR 2.02, 95% CI 0.97 to 4.21). CONCLUSIONS: Targeted, culturally appropriate and innovative interventions to increase HIV testing uptake should be a top priority for HIV prevention among MSM in China. PMID- 21270069 TI - Use of culture and molecular analysis to determine the effect of antibiotic treatment on microbial community diversity and abundance during exacerbation in patients with cystic fibrosis. AB - BACKGROUND: Anaerobic bacteria are increasingly regarded as important in cystic fibrosis (CF) pulmonary infection. The aim of this study was to determine the effect of antibiotic treatment on aerobic and anaerobic microbial community diversity and abundance during exacerbations in patients with CF. METHODS: Sputum was collected at the start and completion of antibiotic treatment of exacerbations and when clinically stable. Bacteria were quantified and identified following culture, and community composition was also examined using culture independent methods. RESULTS: Pseudomonas aeruginosa or Burkholderia cepacia complex were detected by culture in 24/26 samples at the start of treatment, 22/26 samples at completion of treatment and 11/13 stable samples. Anaerobic bacteria were detected in all start of treatment and stable samples and in 23/26 completion of treatment samples. Molecular analysis showed greater bacterial diversity within sputum samples than was detected by culture; there was reasonably good agreement between the methods for the presence or absence of aerobic bacteria such as P aeruginosa (kappa=0.74) and B cepacia complex (kappa=0.92), but agreement was poorer for anaerobes. Both methods showed that the composition of the bacterial community varied between patients but remained relatively stable in most individuals despite treatment. Bacterial abundance decreased transiently following treatment, with this effect more evident for aerobes (median decrease in total viable count 2.3*10(7) cfu/g, p=0.005) than for anaerobes (median decrease in total viable count 3*10(6) cfu/g, p=0.046). CONCLUSION: Antibiotic treatment targeted against aerobes had a minimal effect on abundance of anaerobes and community composition, with both culture and molecular detection methods required for comprehensive characterisation of the microbial community in the CF lung. Further studies are required to determine the clinical significance of and optimal treatment for these newly identified bacteria. PMID- 21270070 TI - Creating effective quality-improvement collaboratives: a multiple case study. AB - OBJECTIVE: To explore whether differences between collaboratives with respect to type of topic, type of targets, measures (systems) are also reflected in the degree of effectiveness. STUDY SETTING: 182 teams from long-term healthcare organisation developed improvement initiatives in seven quality-improvement collaboratives (QICs) focusing on patient safety and autonomy. STUDY DESIGN: Multiple case before-after study. DATA COLLECTION: 75 team leaders completed a written questionnaire at the end of each QIC on achievability and degree of challenge of targets and measurability of progress. Main outcome indicators were collaborative-specific measures (such as prevalence of pressure ulcers). PRINCIPAL FINDINGS: The degree of effectiveness and percentage of teams realising targets varied between collaboratives. Collaboratives also varied widely in perceived measurability (F=6.798 and p=0.000) and with respect to formulating achievable targets (F=6.566 and p=0.000). The Problem Behaviour collaborative scored significantly lower than all other collaboratives on both dimensions. The collaborative on Autonomy and control scored significantly lower on measurability than the other collaboratives. Topics for which there are best practices and evidence of effective interventions do not necessarily score higher on effectiveness, measurability, achievable and challenging targets. CONCLUSIONS: The effectiveness of a QIC is associated with the efforts of programme managers to create conditions that provide insight into which changes in processes of care and in client outcomes have been made. Measurability is not an inherent property of the improvement topic. Rather, creating measurability and formulating challenging and achievable targets is one of the crucial tasks for programme managers of QICs. PMID- 21270071 TI - Smoke-free households with children and decreasing rates of paediatric clinical encounters for otitis media in the United States. AB - OBJECTIVE: Temporal trends in paediatric encounters for otitis media (OM) were last characterised and observed to be steadily increasing from 1975 to the mid 1990 s. The present study uses an ecological design to quantify trends in paediatric encounters for OM concurrent with a period of decline of an important risk factor, secondhand smoke (SHS) exposure among children. PATIENTS AND METHODS: Annual paediatric ambulatory visit and hospital discharge rates for children <= 6 years with OM as primary diagnosis were computed with nationally representative data for 1993-2006. Percentages of households with children <= 6 years and no-smoking rules were computed using Tobacco Use Supplement to the Current Population Survey data. Average annual percentage changes were determined for covariate-adjusted rates of paediatric encounters for OM using joinpoint analysis. RESULTS: While percentages of homes with children and no-smoking rules increased by 89% from 45.5% in 1993 to 86.1% in 2006, average annual covariate adjusted paediatric encounters for OM decreased by 4.6% (95% CI 4.5% to 4.8%) for ambulatory visits and by 9.8% (95% CI 9.1% to 10.6%) for hospital discharges. Coverage by 7-valent pneumococcal conjugate vaccination (PCV7) increased since 2002, while little variation occurred in other potentially associated risk factors. CONCLUSIONS: Paediatric encounter rates for OM decreased steadily over a 13-year period reversing a previously reported long-term increasing trend reported. Reduced SHS exposure, PCV7 coverage since 2002 and other factors may have contributed to the decline. Further research is needed to provide direct estimates of paediatric encounter rates in exposed and unexposed populations for causal inference. PMID- 21270072 TI - Understanding worldwide youth attitudes towards smoke-free policies: an analysis of the Global Youth Tobacco Survey. AB - BACKGROUND: Smoke-free policies (SFPs) in public places are increasing globally, but developing countries are lagging behind. Understanding youth attitudes towards SFPs can inform SFP initiatives. METHODS: A multilevel logistic regression analysis of data collected from youth aged 13-15 years (2000-2006) who completed the Global Youth Tobacco Survey (GYTS) in 115 countries, primarily in the developing world, was conducted. The analysis examined relationships between support for SFPs and individual-level measures related to smoking status, and exposure to secondhand smoke (SHS), controlling for demographic and environmental factors of interest and country-level policy factors. RESULTS: In all, 77.3% of 356,395 youth in 115 countries favoured SFPs, including majorities of non-smokers (78.7%) and smokers (63.6%). In the multivariable analysis knowledge of smoke harm was the strongest predictor of favouring SFPs (OR 2.42, 95% CI 2.27 to 2.67). Exposure to countermarketing (OR 1.40, 95% CI 1.25 to 1.57) and school anti-smoking education (OR 1.22, 95% CI 1.13 to 1.31) were also positively associated. Current smoking (OR 0.48, 95% CI 0.41 to 0.53), susceptibility to smoking (OR 0.46, 95% CI 0.40 to 0.52) and exposure to tobacco promotion were negatively associated. Significant country-level variation was observed. The presence of any national smoke-free legislation in a country was positively associated with youth favouring such policies. CONCLUSIONS: The majority of youth worldwide support, yet lack, smoke-free policies in public places, while being regularly exposed to SHS. Youth support of SFPs is most positively associated with knowledge of the harmful effects of tobacco smoke. Redoubling education efforts represents an opportunity to establish smoke-free environments and improve health of children in developing countries. PMID- 21270073 TI - Elevated serum osteoprotegerin levels measured early after acute ST-elevation myocardial infarction predict final infarct size. AB - BACKGROUND: Increased serum osteoprotegerin has been shown to be associated with increased mortality and heart failure development in patients with acute coronary syndromes. The aim of the present study was to elucidate a possible association between serum osteoprotegerin measured acutely in patients with ST-elevation myocardial infarction (STEMI) and final infarct size. METHODS Serum osteoprotegerin was measured in fasting blood samples from 199 patients with acute STEMI, sampled at a median time of 16 h after primary percutaneous coronary intervention (PCI). After 3 months, final infarct size (in percentage of left ventricular mass; LVM) was assessed by single-photon emission CT. The outcome variable final infarct size was dichotomised using the 75th percentile as the cutoff value (large infarct size >= 29.0%). A multivariable analysis was performed adjusting for multiple clinical and biochemical covariates. RESULTS: Median (IQR) osteoprotegerin concentration was 1.4 (1.0, 2.1) ng ml-1 and patients with high osteoprotegerin level (> median) at baseline had larger infarct size at 3 months compared with patients with low osteoprotegerin levels (< median) (25 (8, 40) vs 6 (0, 19)% of LVM, respectively, p < 0.0001). A high osteoprotegerin level was also associated with an approximately sevenfold increase in the odds of developing a large myocardial infarct (OR 7.0; 3.2, 15.5, p < 0.001). After adjustment for potential confounders including peak troponin T, the adjusted OR was 5.2 (2.0, 13.1) p < 0.001. CONCLUSION: High levels of circulating osteoprotegerin measured the first morning after a PCI-treated acute STEMI were strongly associated with final infarct size. PMID- 21270074 TI - Defective recovery of QT dispersion predicts late cardiac mortality after percutaneous coronary intervention. AB - BACKGROUND: It has been suggested that corrected QT dispersion (cQTD) provides a measure of repolarisation inhomogeneity; however, the existence of a relationship between cQTD and cardiac outcomes is controversial. OBJECTIVE: To assess whether changes in cQTD following percutaneous coronary intervention (PCI) predict long term survival. DESIGN: Prospective observational study. SETTING: Single tertiary care centre. Main outcome measures Cardiac mortality. PATIENTS: 612 patients had a 12-lead ECG recorded before and 6 h after PCI, and were followed-up for 49 +/- 10 months. RESULTS: PCI was associated with a significant overall reduction of cQTD at 6 h versus baseline (p < 0.001); a reduction in cQTD occurred in 343 patients (56%). During the follow-up, 46 deaths (7.5%) were recorded, 21 of which for non-cardiac and 25 for cardiac causes. At Cox regression analysis, a reduced DeltacQTD (cQTD baseline - 6 h) was an independent predictor of cardiac mortality (HR = 1.497; 95% CI 1.081 to 2.075 for each 20 ms decrease; p = 0.015), together with age (HR = 1.672; 95% CI 1.039 to 2.691 per 10 years increase; p = 0.034), diabetes (HR = 2.622; 95% CI 1.112 to 6.184; p=0.028), peak CK-MB (HR = 1.798; 95% CI 1.063 to 3.039 per each unit increase over normal level; p = 0.029), three vessel coronary artery disease (HR=3.626; 95% CI 1.079 to 12.187; p = 0.037) and the number of treated lesions (HR=2.066; 95% CI 1.208 to 3.532; p = 0.008). Patients in the lowest tertile of DeltacQTD and having a post-procedural increase of CK-MB had a considerably higher cardiac mortality than the remaining population (14.6 vs 2.4%, p < 0.001). CONCLUSIONS: cQTD decreases after PCI. A defective cQTD recovery, suggesting the persistence of repolarisation inhomogeneities, predicts long-term cardiac mortality. PMID- 21270075 TI - Electrocardiographic changes in early recognition of Fabry disease. AB - BACKGROUND: Fabry disease (FD) is an inherited X-chromosomal lysosomal storage disease resulting in intracellular storage of globotriaosylceramide. Cardiac involvement is most frequently manifested as left ventricular hypertrophy (LVH). However, patients with FD may also have various conduction abnormalities before LVH develops. The present study was designed to analyse early conduction abnormalities on baseline ECG of patients with FD and to investigate their diagnostic value. METHODS AND RESULTS: Baseline electrocardiographic (ECG) and echocardiographic measurements of patients with FD (n = 30) were compared with those of heart rate and age-matched healthy individuals (n = 50). The PQ-interval (131 +/- 18 vs 155 +/- 20 ms, p < 0.000001) and the QRS width (83 +/- 11 vs 90 +/ 9 ms, p < 0.05) were significantly shorter and repolarisation dispersion was more pronounced in patients with FD (QTc dispersion: 66 +/- 32 vs 40 +/- 24 ms, p < 0.001, T(peak)-T(end) dispersion: 56 +/- 20 vs 37 +/- 16 ms, p < 0.0005). Moreover, P-wave duration was significantly shorter (74 +/- 16 vs 105 +/- 14 ms, p < 0.000001) in FD and accounted predominantly for the shortening of the PQ interval. P-wave duration showed a 92% sensitivity and 80% specificity for the diagnosis of FD. CONCLUSIONS: P-wave duration, PQ-interval and QRS width are shorter and repolarisation dispersion more pronounced in patients with FD compared with heart rate and age-matched controls. The significant shortening of the PQ-interval in FD occurs because of a marked shortening of the P-wave duration, which in itself demonstrated a high sensitivity and specificity for early detection and treatment of this disease. PMID- 21270076 TI - Coronary collateral function in the transplanted heart: propensity score matching with coronary artery disease. AB - BACKGROUND: The function of the coronary collateral circulation in heart transplant patients has not been investigated in a controlled fashion. Since it partly belongs to the microcirculation, which is affected by transplant vasculopathy, the hypothesis was tested that the coronary collateral circulation in heart transplant recipients is less developed than in coronary artery disease (CAD) patients. METHODS: 40 heart transplant patients underwent a total of 51 quantitative, coronary pressure-derived collateral measurements and intravascular ultrasound (IVUS). The collateral flow index (CFI) was calculated as mean coronary occlusive pressure divided by mean aortic pressure, both subtracted by central venous pressure. A propensity score matching for angiographic coronary stenosis severity, heart rate, the presence of arterial hypertension and dyslipidaemia was performed using CAD patients of the institutional CFI database (n = 1076) as the control group. RESULTS: Eighty per cent (32/40) of the heart transplant patients showed transplant vasculopathy as assessed by IVUS (intima thickness >= 0.5 mm). Without propensity score matching, CFI was equal to 0.152 +/- 0.102 in the heart transplant group (age 55 +/- 14 years) and 0.189 +/- 0.134 in the entire CAD group (p = 0.054). After matching, CFI was 0.152 +/- 0.102 in the heart transplant group and 0.176 +/- 0.096 (p = 0.37) in the matched CAD group (age 63 +/- 10 years). IVUS data were unrelated to CFI in the heart transplant group. CONCLUSIONS: Heart transplant patients present with the same degree of functional collateral flow compared with a matched group of CAD patients. PMID- 21270077 TI - Do statins improve outcomes and delay the progression of non-rheumatic calcific aortic stenosis? AB - CONTEXT: It is not known whether statin treatment improves clinical outcomes and reduces aortic stenosis progression in non-rheumatic calcific aortic stenosis. OBJECTIVE: A meta-analysis of studies was performed comparing statin therapy with placebo or no treatment on outcomes and on aortic stenosis progression echocardiographic parameters. DATA SOURCES: The authors searched Medline and Pubmed up to January 2010. DATA EXTRACTION: Two independent reviewers independently abstracted information on study design (prospective vs retrospective or randomised vs non-randomised), study and participant characteristics. Fixed and random effects models were used. A-priori subanalyses assessed the effect of statins on low-quality (retrospective or non-randomised) and on high-quality (prospective or randomised) studies separately. RESULTS: Meta analysis identified 10 studies with a total of 3822 participants (2214 non-statin treated and 1608 statin-treated); five studies were classified as prospective and five as retrospective; concerning randomisation, three trials were randomised whereas seven were not. No significant differences were found in all-cause mortality, cardiovascular mortality or in the need for aortic valve surgery. Lower-quality (retrospective or non-randomised) studies showed that, in statin treated patients, the annual increase in peak aortic jet velocity and the annual decrease in aortic valve area were lower, but this was not confirmed by the analysis in high-quality (prospective or randomised) studies. Statins did not significantly affect the progression over time of peak and mean aortic gradient. CONCLUSIONS: Currently available data do not support the use of statins to improve outcomes and to reduce disease progression in non-rheumatic calcific aortic valve stenosis. PMID- 21270078 TI - Elevated troponin in stable coronary artery disease: the sound of silence. PMID- 21270079 TI - How should we balance individual and population benefits of statins for preventing cardiovascular disease? PMID- 21270080 TI - Unanswered questions over NHS health checks. PMID- 21270081 TI - Management of generalised anxiety disorder in adults: summary of NICE guidance. PMID- 21270082 TI - Personal view. Should the spectacle of surgery be sold to the highest bidder? PMID- 21270087 TI - Governments call on WHO to improve cholera control. PMID- 21270085 TI - Health and social care bill. PMID- 21270088 TI - Families at risk of genetically high cholesterol are not being spotted, says royal college. PMID- 21270089 TI - Greed isn't good. PMID- 21270091 TI - An odd eruption. PMID- 21270092 TI - Recent advances in distal tubular potassium handling. AB - It is well known that sodium reabsorption and aldosterone play important roles in potassium secretion by the aldosterone-sensitive distal nephron. Sodium- and aldosterone-independent mechanisms also exist. This review focuses on some recent studies that provide novel insights into the sodium- and aldosterone-independent potassium secretion by the aldosterone-sensitive distal nephron. In addition, we discuss a study reporting on the regulation of the mammalian potassium kidney channel ROMK by intracellular and extracellular magnesium, which may be important in the pathogenesis of persistent hypokalemia in patients with concomitant potassium and magnesium deficiency. We also discuss outstanding questions and propose working models for future investigation. PMID- 21270093 TI - Renal injury in angiotensin II+L-NAME-induced hypertensive rats is independent of elevated blood pressure. AB - The balance between angiotensin II (ANG II) and nitric oxide plays an important role in renal function and is thought to contribute to the progression of renal injury in experimental hypertension. In the present study, we investigated the extent of blood pressure (BP)-dependent and BP-independent pathways of renal injury following 2 wk of hypertension produced by intravenous infusion of ANG II (5 ng.kg-1.min-1)+N(omega)-nitro-l-arginine methyl ester (l-NAME; 1.4 MUg.kg 1.min-1) in male Sprague-Dawley rats. An aortic balloon occluder was positioned between the renal arteries to maintain (24 h/day) BP to the left kidney (servo controlled) at baseline levels, whereas the right kidney (uncontrolled) was chronically exposed to elevated BP. Over the 14-day experimental protocol, the average BP to uncontrolled kidneys (152.7 +/- 1.8 mmHg) was significantly elevated compared with servo-controlled (113.0 +/- 0.2 mmHg) kidneys and kidneys from sham rats (108.3 +/- 0.1 mmHg). ANG II+l-NAME infusion led to renal injury that was focal in nature and mainly confined to the outer medulla. Despite the differences in BP between servo-controlled and uncontrolled kidneys, there was a similar ~3.5-fold increase in renal outer medullary tubular injury, ~2-fold increase in outer medullary interstitial fibrosis, ~2-fold increase in outer medullary macrophage infiltration, and a significant increase in renal oxidative stress, all of which are indicative of BP-independent mediated pathways. The results of this study have important implications regarding the pathogenesis of renal injury in various experimental models of hypertension and provide novel insights regarding the variable association observed between hypertension and renal injury in some human populations. PMID- 21270094 TI - Vitronectin accumulates in the interstitium but minimally impacts fibrogenesis in experimental chronic kidney disease. AB - Vitronectin (Vtn) is a glycoprotein found in normal serum and pathological extracellular matrix. Given its known interactions with plasminogen activator inhibitor-1 (PAI-1) and Vtn cellular receptors, especially alphavbeta3 integrin and the urokinase receptor (uPAR), this study was designed to investigate its role in renal fibrogenesis in the mouse model of unilateral ureteral obstruction (UUO). Kidney Vtn mRNA levels were increased *1.8-5.1 and Vtn protein levels *1.9 3 on days 7, 14, and 21 after UUO compared with sham kidney levels. Groups of age matched C57BL/6 wild-type (Vtn+/+) and Vtn-/- mice (n = 10-11/group) were killed 7, 14, or 21 days after UUO. Absence of Vtn resulted in the following significant differences, but only on day 14: fewer alphaSMA+ interstitial myofibroblasts (*0.53), lower procollagen III mRNA levels (*0.41), lower PAI-1 protein (*0.23), higher uPA activity (*1.1), and lower alphav protein (*0.32). The number of CD68+ macrophages did not differ between the genotypes. Despite these transient differences on day 14, the absence of Vtn had no effect on fibrosis severity based on both picrosirius red-positive interstitial area and total kidney collagen measured by the hydroxyproline assay. These findings suggest that despite significant interstitial Vtn deposition in the UUO model of chronic kidney disease, its fibrogenic role is either nonessential or redundant. These data are remarkable given Vtn's strong affinity for the potent fibrogenic molecule PAI-1. PMID- 21270096 TI - Acid retention accompanies reduced GFR in humans and increases plasma levels of endothelin and aldosterone. AB - Dietary alkali slows GFR decline in humans with a moderately reduced glomerular filtration rate (GFR) despite the absence of metabolic acidosis. Similarly, dietary alkali slows GFR decline in animals with 2/3 nephrectomy (Nx), a chronic kidney disease (CKD) model without metabolic acidosis in which GFR decline is mediated by acid (H(+)) retention through endothelin (ET) and mineralocorticoid receptors. To gain insight as to whether this mechanism might mediate GFR decline in humans, we explored whether macroalbuminuric subjects with moderately reduced (CKD stage 2 = 60-90 ml/min; CKD 2) compared with normal estimated GFR (> 90 ml/min; CKD 1), each without metabolic acidosis, have H(+) retention that increases plasma levels of ET-1 and aldosterone. Baseline plasma ET and aldosterone concentrations were each higher in CKD 2 than CKD 1. Baseline dietary H(+) and urine net acid excretion (NAE) were not different between groups, but an acute oral NaHCO3 bolus reduced urine NAE less (i.e., postbolus urine NAE was higher) in CKD 2 than CKD 1, consistent with greater H(+) retention in CKD 2 subjects. Thirty days of oral NaHCO3 reduced H(+) retention in CKD 2 but not CKD 1 subjects and reduced plasma ET and aldosterone in both groups but to levels that remained higher in CKD 2 for each. Subjects with CKD stage 2 eGFR and no metabolic acidosis nevertheless have H(+) retention that increases plasma ET and aldosterone levels, factors that might mediate subsequent GFR decline and other untoward vascular effects. PMID- 21270095 TI - Hypoxia-inducible factor-1alpha (HIF-1alpha) and autophagy in polycystic kidney disease (PKD). AB - Cyst expansion in polycystic kidney disease (PKD) results in localized hypoxia in the kidney that may activate hypoxia-inducible factor-1alpha (HIF-1alpha). HIF 1alpha and autophagy, a form of programmed cell repair, are induced by hypoxia. The purposes were to determine HIF-1alpha expression and autophagy in rat and mouse models of PKD. HIF-1alpha was detected by electrochemiluminescence. Autophagy was visualized by electron microscopy (EM). LC3 and beclin-1, markers of autophagy, were detected by immunoblotting. Eight-week-old male heterozygous (Cy/+) and 4-wk-old homozygous (Cy/Cy) Han:SPRD rats, 4-wk-old cpk mice, and 112 day-old Pkd2WS25/- mice with a mutation in the Pkd2 gene were studied. HIF-1alpha was significantly increased in massive Cy/Cy and cpk kidneys and not smaller Cy/+ and Pkd2WS25/- kidneys. On EM, features of autophagy were seen in wild-type (+/+), Cy/+, and cpk kidneys: autophagosomes, mitophagy, and autolysosomes. Specifically, autophagosomes were found on EM in the tubular cells lining the cysts in cpk mice. The increase in LC3-II, a marker of autophagosome production and beclin, a regulator of autophagy, in Cy/Cy and cpk kidneys, followed the same pattern of increase as HIF-1alpha. To determine the role of HIF-1alpha in cyst formation and/or growth, Cy/+ rats, Cy/Cy rats, and cpk mice were treated with the HIF-1alpha inhibitor 2-methoxyestradiol (2ME2). 2ME2 had no significant effect on kidney volume or cyst volume density. In summary, HIF-1alpha is highly expressed in the late stages of PKD and is associated with an increase in LC3-II and beclin-1. The first demonstration of autophagosomes in PKD kidneys is reported. Inhibition of HIF-1alpha did not have a therapeutic effect. PMID- 21270097 TI - Aldosterone stimulates superoxide production in macula densa cells. AB - Two major factors which regulate tubuloglomerular feedback (TGF)-mediated constriction of the afferent arteriole are release of superoxide (O(2)(-)) and nitric oxide (NO) by macula densa (MD) cells. MD O(2)(-) inactivates NO; however, among the factors that increase MD O(2)(-) release, the role of aldosterone is unclear. We hypothesize that aldosterone activates the mineralocorticoid receptor (MR) on MD cells, resulting in increased O(2)(-) production due to upregulation of cyclooxygenase-1 (COX-2) and NOX-2, and NOX-4, isoforms of NAD(P)H oxidase. Studies were performed on MMDD1 cells, a renal epithelial cell line with properties of MD cells. RT-PCR and Western blotting confirmed the expression of MR. Aldosterone (10(-8) mol/l for 30 min) doubled MMDD1 cell O(2)(-) production, and this was completely blocked by MR inhibition with 10(-5) mol/l eplerenone. RT PCR, real-time PCR, and Western blotting demonstrated aldosterone-induced increases in COX-2, NOX-2, and NOX-4 expression. Inhibition of COX-2 (NS398), NADPH oxidase (apocynin), or a combination blocked aldosterone-induced O(2)(-) production to the same degree. These data suggest that aldosterone-stimulated MD O(2)(-) production is mediated by COX-2 and NADPH oxidase. Next, COX-2 small interfering RNA (siRNA) specifically decreased COX-2 mRNA without affecting NOX-2 or NOX-4 mRNAs. In the presence of the COX-2 siRNA, the aldosterone-induced increases in COX-2, NOX-2, and NOX-4 mRNAs and O(2)(-) production were completely blocked, suggesting that COX-2 causes increased expression of NOX-2 and NOX-4. In conclusion 1) MD cells express MR; 2) aldosterone increases O(2)(-) production by activating MR; and 3) aldosterone stimulates COX-2, which further activates NOX-2 and NOX-4 and generates O(2)(-). The resulting balance between O(2)(-) and NO in the MD is important in modulating TGF. PMID- 21270098 TI - Determination of lipoprotein lipase activity using a novel fluorescent lipase assay. AB - A novel, real-time, homogeneous fluorogenic lipoprotein lipase (LPL) assay was developed using a commercially available substrate, the EnzChek lipase substrate, which is solubilized in Zwittergent. The triglyceride analog substrate does not fluoresce, owing to apposition of fluorescent and fluorescent quenching groups at the sn-1 and sn-2 positions, respectively, fluorescence becoming unquenched upon release of the sn-1 BODIPY FA derivative following hydrolysis. Increase in fluorescence intensity at 37 degrees C was proportional to LPL concentration. The assay was more sensitive than a similar assay using 1,2-O-dilauryl-rac-glycero-3 glutaric acid-(6-methylresorufin ester) and was validated in biological samples, including determination of LPL-specific activity in postheparin mouse plasma. The simplicity and reproducibility of the assay make it ideal for in vitro, high throughput screening for inhibitors and activators of LPL, thus expediting discovery of drugs of potential clinical value. PMID- 21270099 TI - In vivo NMR detection of diet-induced changes in adipose tissue composition. AB - We introduce an in vivo spectroscopic method to assess the effects of diet on fatty acid composition of the predominant chemical constituent of adipocytes in mice. To do this, we make use of a nonlinear NMR signal that, unlike a standard NMR signal, is intrinsically insensitive to local magnetic field inhomogeneities and which naturally suppresses the large water signal from nonfatty tissues. Our method yields fat composition information from fat depots distributed over large sample volumes in a single experiment, without requiring the use of tedious shimming procedures, voxel selection, or water suppression. Our results suggest that this method can reveal clear differences in adipose tissue composition of mice fed a standard chow diet compared with mice fed a diet rich in polyunsaturated fatty acids. With further developments this method could be used to obtain information on human lipid composition noninvasively and to track changes in lipid composition induced by diet intervention, pharmaceutical drugs, and exercise. PMID- 21270100 TI - The role of the renin--angiotensin system in the pathogenesis of intracranial aneurysms. AB - INTRODUCTION: Recent work has begun to elucidate the pathogenesis of intracranial aneurysms (IA) and has shown that many genes are involved in the risk for this condition. There has also been increasing research interest in the renin angiotensin system (RAS) in the brain and it involvement in a range of cardiovascular and neurological disorders. The possibility that the RAS is implicated in the pathogenesis of IA merits further investigation. The aim of this article is to review the literature on the pathogenesis of IA and the pathophysiological significance of the brain RAS, and to identify directions for research into their association. METHODS AND RESULTS: A survey of the literature in these fields shows that although factors contributing to systemic hypertension predispose to IA, a large number of genes involved in endothelial cell adhesion, smooth muscle activity, extracellular matrix dynamics and the inflammatory and immune responses are also implicated. The brain RAS has a significant role in regulating blood pressure and in maintaining cerebrovascular autoregulation, but angiotensin II receptors are also involved in the maintenance of endothelial cell and vascular smooth muscle function and in the inflammatory response in the brain. CONCLUSIONS: There is strong, albeit largely circumstantial, evidence in the literature for a relationship between the brain RAS and the formation of IA. Research on the association between polymorphisms in RAS-related genes and the incidence of unruptured and ruptured IA is indicated. PMID- 21270102 TI - Percutaneous transhepatic venous access for catheter ablation procedures in patients with interruption of the inferior vena cava. AB - BACKGROUND: Catheter ablation of left-sided atrial arrhythmias generally is performed using a transfemoral venous approach through the inferior vena cava (IVC). In this report, we assessed the feasibility of a percutaneous transhepatic approach to ablation of left-sided atrial arrhythmias in 2 patients with interruption of the IVC. METHODS AND RESULTS: Patient 1 had atrial flutter in the setting of complex congenital heart disease and prior Fontan for univentricular physiology and a single atrium. Patient 2 had atrial fibrillation. Percutaneous hepatic vein access was obtained with ultrasound and fluoroscopic guidance. Transseptal catheterization was performed in patient 2. After the procedure, the hepatic tract in patient 1 was cauterized using a bipolar radiofrequency catheter, and an Amplatzer vascular plug was used in patient 2 to obtain hemostasis. Percutaneous hepatic vein access was achieved without complications. After electroanatomical mapping, a linear lesion was placed between the single atrioventricular valve and the confluence of the hepatic veins in patient 1; this terminated the flutter, and bidirectional block was achieved. In patient 2, the pulmonary veins were electrically isolated using an extraostial approach, isolating the ipsilateral veins in pairs. Additionally, ablation of right-side atrial flutter was achieved by obtaining bidirectional block across a linear lesion between the tricuspid valve and confluence of the hepatic veins. Hemostasis of the transhepatic tract was attained in both patients. CONCLUSIONS: In patients with interrupted IVCs, a percutaneous transhepatic approach is a feasible alternative for performing catheter ablation of complex left-sided arrhythmias. PMID- 21270101 TI - Inhibition of cardiac Ca2+ release channels (RyR2) determines efficacy of class I antiarrhythmic drugs in catecholaminergic polymorphic ventricular tachycardia. AB - BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by mutations in the cardiac ryanodine receptor (RyR2) or calsequestrin (Casq2) and can be difficult to treat. The class Ic antiarrhythmic drug flecainide blocks RyR2 channels and prevents CPVT in mice and humans. It is not known whether other class I antiarrhythmic drugs also block RyR2 channels and to what extent RyR2 channel inhibition contributes to antiarrhythmic efficacy in CPVT. METHODS AND RESULTS: We first measured the effect of all class I antiarrhythmic drugs marketed in the United States (quinidine, procainamide, disopyramide, lidocaine, mexiletine, flecainide, and propafenone) on single RyR2 channels incorporated into lipid bilayers. Only flecainide and propafenone inhibited RyR2 channels, with the S-enantiomer of propafenone having a significantly lower potency than R-propafenone or flecainide. In Casq2(-/-) myocytes, the propafenone enantiomers and flecainide significantly reduced arrhythmogenic Ca(2+) waves at clinically relevant concentrations, whereas Na(+) channel inhibitors without RyR2 blocking properties did not. In Casq2(-/-) mice, 5 mg/kg R-propafenone or 20 mg/kg S-propafenone prevented exercise-induced CPVT, whereas procainamide (20 mg/kg) or lidocaine (20 mg/kg) were ineffective (n=5 to 9 mice, P<0.05). QRS duration was not significantly different, indicating a similar degree of Na(+) channel inhibition. Clinically, propafenone (900 mg/d) prevented ICD shocks in a 22-year-old CPVT patient who had been refractory to maximal standard drug therapy and bilateral stellate ganglionectomy. CONCLUSIONS: RyR2 cardiac Ca(2+) release channel inhibition appears to determine efficacy of class I drugs for the prevention of CPVT in Casq2(-/-) mice. Propafenone may be an alternative to flecainide for CPVT patients symptomatic on beta-blockers. PMID- 21270103 TI - MRI-Guided ventricular tachycardia ablation: integration of late gadolinium enhanced 3D scar in patients with implantable cardioverter-defibrillators. AB - BACKGROUND: Substrate-guided ablation of ventricular tachycardia (VT) in patients with implanted cardioverter-defibrillators (ICDs) relies on voltage mapping to define the scar and border zone. An integrated 3D scar reconstruction from late gadolinium enhancement (LGE) MRI could facilitate VT ablations. METHODS AND RESULTS: Twenty-two patients with ICD underwent contrast-enhanced cardiac MRI with a specific absorption rate of <2.0 W/kg before VT ablation. Device interrogation demonstrated unchanged ICD parameters immediately before, after, or at 68+/-21 days follow-up (P>0.05). ICD imaging artifacts were most prominent in the anterior wall and allowed full and partial assessment of LGE in 9+/-4 and 12+/-3 of 17 segments, respectively. In 14 patients with LGE, a 3D scar model was reconstructed and successfully registered with the clinical mapping system (accuracy, 3.9+/-1.8 mm). Using receiver operating characteristic curves, bipolar and unipolar voltages of 1.49 and 4.46 mV correlated best with endocardial MRI scar. Scar visualization allowed the elimination of falsely low voltage recordings (suboptimal catheter contact) in 4.1+/-1.9% of <1.5-mV mapping points. Display of scar border zone allowed identification of excellent pace mapping sites, with only limited voltage mapping in 64% of patients. Viable endocardium of >2 mm resulted in >1.5-mV voltage recordings despite up to 63% transmural midmyocardial scar successfully ablated with MRI guidance. All successful ablation sites demonstrated LGE (transmurality, 68+/-26%) and were located within 10 mm of transition zones to 0% to 25% scar in 71%. CONCLUSIONS: Contrast enhanced cardiac MRI can be safely performed in selected patients with ICDs and allows the integration of detailed 3D scar maps into clinical mapping systems, providing supplementary anatomic guidance to facilitate substrate-guided VT ablations. PMID- 21270104 TI - Long-term outcomes of combined epicardial and endocardial ablation of monomorphic ventricular tachycardia related to hypertrophic cardiomyopathy. AB - BACKGROUND: Monomorphic ventricular tachycardia (MMVT) is rare in patients with hypertrophic cardiomyopathy (HCM). There are limited data on the utility of catheter ablation for the treatment of MMVT in this population. This study details a series of case reports from multiple centers where combined epicardial endocardial ablation was performed in a highly selected group of patients with HCM-related MMVT. METHODS AND RESULTS: The cohort consisted of 10 patients with HCM-related MMVT. Pericardial access was achieved using the percutaneous subxyphoid approach. Epicardial and endocardial ventricular 3D bipolar voltage maps were generated. Ablation sites were identified using a combination of entrainment, activation, late/fractionated potential, and pace mapping. Electrophysiological-identified epicardial scar was present in 8 (80%) patients, endocardial scar in 6 (60%), and no scar in 1 (10%). In the 5 patients with inducible, stable MMVT, 3 cases were successfully terminated with ablation from the epicardium and 1 from the endocardium. The case that failed catheter ablation required surgical cryoablation to abolish the incessant VT. In the remaining 5 patients, 4 underwent epicardial and endocardial ablation of sites with good pace maps and late/fractionated potentials. No ablation was performed in the remaining patient because of noninducibility and lack of identifiable scar. After 37+/-17 months (limits, 2 to 62 months; median, 37 months), the freedom from recurrent implantable cardioverter-defibrillator shocks was 78% (7/9 patients) in those who underwent ablation. CONCLUSIONS: In highly selected patients with HCM, combined epicardial and endocardial mapping and ablation is a feasible and reasonably efficacious option for MMVT if refractory to aggressive trials of antiarrhythmic drugs and antitachycardia pacing. PMID- 21270105 TI - In vivo magnetic resonance imaging to detect biliary excretion of 19F-labeled drug in mice. AB - Isoflurane is an inhaled halogenated hydrocarbon anesthetic commonly used for animal research. In our quest to develop a method for measuring bile acid transport in live animals using (19)F magnetic resonance (MR) imaging, it occurred to us that isoflurane, which contains five fluorines per molecule and is probably widely distributed, would provide an excellent test drug to evaluate the merits of this approach. Experiments in 20- to 28-g male C57BL/6 mice were performed using a horizontal bore scanner with a 30-mm (19)F/(1)H dual-tuned surface coil used to transmit and receive radiofrequency signals at 300.28 MHz for (1)H and 282.55 MHz for (19)F nuclei. Proton MR imaging was used to identify the mouse gallbladder in vivo, which was verified by anatomical dissection. Subsequent experiments in mice inhaling 1.5% isoflurane for 1 to 2 h revealed robust (19)F signals from the gallbladder, verified by overlying (1)H and (19)F signals. No (19)F signal was detected in mice anesthetized with nonhalogenated anesthetics. The presence of isoflurane in gallbladder bile of isoflurane-treated mice was verified using liquid chromatography-mass spectrometry. Gallbladder bile isoflurane content ranged from 3.2 to 4.7 MUg. The data presented here provide proof of concept that this novel approach can be used for in vivo measurement of biliary excretion of both existing and novel (19)F-labeled drugs. PMID- 21270106 TI - Effect of the CYP2C8 genotype on the pharmacokinetics and pharmacodynamics of repaglinide. AB - The pharmacokinetics of repaglinide shows pronounced interindividual variability, for which several reasons have been considered, including interactions with drugs inhibiting CYP2C8 and CYP2C8 genetic polymorphism. However, existing data on the role of genetic polymorphisms in repaglinide disposition are not fully consistent. We studied the effect of CYP2C8*3 on the pharmacokinetics and pharmacodynamics of repaglinide in 29 healthy whites carrying CYP2C8*3/*3 (n = 4), CYP2C8*1/*3 (n = 13), or CYP2C8*1/*1 (n = 12). After administration of a single dose of 2 mg of repaglinide, blood was drawn for assessment of repaglinide pharmacokinetics and pharmacodynamics, and urine was collected to quantify the main repaglinide metabolites M1 and M4 up to 24 h postdose. Repaglinide and the metabolites were quantified by liquid chromatography-tandem mass spectrometry. Considering only the effect of CYP2C8*3, the mean (95% confidence interval) area under the time-concentration curve (AUC) from zero to infinity of repaglinide was 72.4 (6.7-138.0), 97.2 (59.2-135.2), and 105.9 (52.4-159.3) ng . ml(-1) . h and the maximal concentration (C(max)) was 38.5 (3.8-73.2), 50.3 (37.5-63.0), and 60.3 (31.5-89.1) ng . ml(-1), respectively, in carriers of CYP2C8*3/*3, CYP2C8*1/*3, and CYP2C8*1/*1 [p > 0.05, one-way analysis of variance (ANOVA)]. In addition, for urinary metabolite excretion and pharmacodynamic parameters, i.e., mean and maximal changes in insulin and glucose concentration, no significant differences between CYP2C8 genotypes were observed. Likewise, no significant effects on the pharmacokinetics or pharmacodynamics were observed when AUC and C(max) of repaglinide were corrected for reported effects of the SLCO1B1 521T>C polymorphism or when both polymorphisms were tested in a two-way ANOVA. In conclusion, CYP2C8*3 does not seem to play an important role in the pharmacokinetics and pharmacodynamics of repaglinide given in a therapeutic dose. PMID- 21270107 TI - The atr protein kinase controls UV-dependent upregulation of p16INK4A through inhibition of Skp2-related polyubiquitination/degradation. AB - The tumor suppressor p16(INK4A), a phosphoprotein that exists in human cells under both phosphorylated and nonphosphorylated forms, plays crucial roles during the cellular response to UV light. However, it is still unclear how this protein is activated in response to this carcinogenic agent. We have shown here that UVC upregulates p16(INK4A) and the phosphorylated form of the protein at the 4 serine sites; Ser-7, Ser-8, Ser-140, and Ser-152. This accumulation of p16(INK4A) occurred through increasing the stability of both forms of the protein. Importantly, phospho-p16(INK4A) showed much higher stability, and UV treatment strongly increased its level in absence of de novo protein synthesis. Furthermore, we have shown that the UV-dependent upregulation of both forms of p16(INK4A) is under the control of the protein kinase Atr, which suppresses their UVC-dependent proteasomal degradation. Interestingly, although this degradation is ubiquitin-related for p16(INK4A) through the Skp2 ubiquitin ligase protein, it is ubiquitin-independent for the phosphorylated form. In addition, we present clear evidence that Skp2 is upregulated in ATR-deficient cells, leading to the downregulation of the p27(Kip1) protein in response to UVC light. Moreover, we have shown a preferential association of endogeneous phospho-p16(INK4A) with Cdk4. This association increased following UV-treatment mainly for p16(INK4A) phosphorylated at Ser-140 and Ser-152. Besides, we have shown that Atr regulates UV-related p16/Cdk4-dependent and -independent phosphorylation of pRB and G1 cell cycle delay. Together, these results indicate that p16(INK4A) and p27(Kip1) are key targets in the Atr-dependent signaling pathway in response to UV damage. PMID- 21270108 TI - Paradoxical relationship between chromosomal instability and survival outcome in cancer. AB - Chromosomal instability (CIN) is associated with poor prognosis in human cancer. However, in certain animal tumor models elevated CIN negatively impacts upon organism fitness, and is poorly tolerated by cancer cells. To better understand this seemingly contradictory relationship between CIN and cancer cell biological fitness and its relationship with clinical outcome, we applied the CIN70 expression signature, which correlates with DNA-based measures of structural chromosomal complexity and numerical CIN in vivo, to gene expression profiles of 2,125 breast tumors from 13 published cohorts. Tumors with extreme CIN, defined as the highest quartile CIN70 score, were predominantly of the estrogen receptor negative (ER(-)), basal-like phenotype and displayed the highest chromosomal structural complexity and chromosomal numerical instability. We found that the extreme CIN/ER(-) tumors were associated with improved prognosis relative to tumors with intermediate CIN70 scores in the third quartile. We also observed this paradoxical relationship between CIN and prognosis in ovarian, gastric, and non-small cell lung cancer, with poorest outcome in tumors with intermediate, rather than extreme, CIN70 scores. These results suggest a nonmonotonic relationship between gene signature expression and HR for survival outcome, which may explain the difficulties encountered in the identification of prognostic expression signatures in ER(-) breast cancer. Furthermore, the data are consistent with the intolerance of excessive CIN in carcinomas and provide a plausible strategy to define distinct prognostic patient cohorts with ER(-) breast cancer. Inclusion of a surrogate measurement of CIN may improve cancer risk stratification and future therapeutic approaches. PMID- 21270109 TI - A germline variant in the interferon regulatory factor 4 gene as a novel skin cancer risk locus. AB - Genome-wide association studies on pigmentary phenotypes provide a pool of candidate genetic markers for skin cancer risk. The SNPs identified from a genome wide association study of natural hair color were assessed for associations with the risk of three types of skin cancer simultaneously in a nested case-control study within the Nurses' Health Study [218 melanoma, 285 squamous cell carcinoma (SCC), and 300 basal cell carcinoma (BCC) cases, and 870 common controls]. Along with two known pigmentation loci, MC1R and OCA2, the IRF4 rs12203592 T allele was associated with an increased risk of each type of skin cancer (P value, 6.6 * 10( 4) for melanoma, 7.0 * 10(-7) for SCC, and 0.04 for BCC). This association was further replicated in additional samples (190 melanoma, 252 SCC, and 634 common controls). The P value in the replication set was 0.03 for melanoma and 4.2 * 10( 3) for SCC. The risk of BCC was replicated in an independent set of 213 cases and 718 controls (P value, 0.02). The combined results showed that the association with SCC reached the genome-wide significance level [odds ratio (OR) for additive model = 1.61, 95%CI, 1.36-1.91, P = 3.2 * 10(-8)]. The OR was 1.49 for melanoma (95%CI, 1.23-1.80; P = 4.5 * 10(-5)), and 1.32 for BCC (95%CI, 1.11-1.57; P = 1.6 * 10(-3)). Given that the T allele was shown previously to be associated with increased expression of IRF4 locus, further studies are warranted to elucidate the role of the IRF4 gene in human pigmentation and skin cancer development. PMID- 21270110 TI - Clinical significance of osteoprotegerin expression in human colorectal cancer. AB - PURPOSE: This study aimed to identify a novel biomarker or a target of treatment for colorectal cancer (CRC). EXPERIMENTAL DESIGN: The expression profiles of cancer cells in 104 patients with CRC were examined using laser microdissection and oligonucleotide microarray analysis. Overexpression in CRC cells, especially in patients with distant metastases, was a prerequisite to select candidate genes. The mRNA expression of candidate genes was investigated by quantitative reverse transcriptase PCR (RT-PCR) in 77 patients as a validation study. We analyzed the protein expression and localization of the candidate gene by immunohistochemical study and investigated the relationship between protein expression and clinicopathologic features in 274 CRC patients. RESULTS: Using microarray analysis, we identified 6 candidate genes related to distant metastases in CRC patients. Among these genes, osteoprotegerin (OPG) is known to be associated with aggressiveness in several cancers through inhibition of apoptosis via neutralization of the function of TNF-related apoptosis-inducing ligand. The mRNA expression of OPG in cancer tissues was significantly higher in patients with distant metastases than those without metastases. Overexpression of OPG protein was associated with significantly worse overall survival and relapse free survival. Moreover, overexpression of the OPG protein was an independent risk factor for CRC recurrence. CONCLUSION: Overexpression of OPG may be a predictive biomarker of CRC recurrence and a target for treatment of this disease. PMID- 21270111 TI - Oncogenic B-RAF signaling in melanoma impairs the therapeutic advantage of autophagy inhibition. AB - PURPOSE: Metastatic melanoma is characterized by extremely poor survival rates and hence novel therapies are urgently required. The ability of many anticancer drugs to activate autophagy, a lysosomal-mediated catabolic process which usually promotes cell survival, suggests targeting the autophagy pathway may be a novel means to augment therapy. EXPERIMENTAL DESIGN: Autophagy and apoptosis were assessed in vitro in human melanoma cell lines in response to clinically achievable concentrations of the endoplasmic reticulum (ER) stress-inducing drugs fenretinide or bortezomib, and in vivo using a s.c. xenograft model. RESULTS: Autophagy was activated in response to fenretinide or bortezomib in B-RAF wild type cells, shown by increased conversion of LC3 to the autophagic vesicle associated form (LC3-II) and redistribution to autophagosomes and autolysosomes, increased acidic vesicular organelle formation and autophagic vacuolization. In contrast, autophagy was significantly reduced in B-RAF-mutated melanoma cells, an effect attributed partly to oncogenic B-RAF. Rapamycin treatment was unable to stimulate LC3-II accumulation or redistribution in the presence of mutated B-RAF, indicative of de-regulated mTORC1-dependent autophagy. Knockdown of Beclin-1 or ATG7 sensitized B-RAF wild-type cells to fenretinide- or bortezomib-induced cell death, demonstrating a pro-survival function of autophagy. In addition, autophagy was partially reactivated in B-RAF-mutated cells treated with the BH3 mimetic ABT737 in combination with fenretinide or bortezomib, suggesting autophagy resistance is partly mediated by abrogated Beclin-1 function. CONCLUSIONS: Our findings suggest inhibition of autophagy in combination with ER stress-inducing agents may represent a means by which to harness autophagy for the therapeutic benefit of B-RAF wild-type melanoma. PMID- 21270112 TI - Pituitary stalk interruption syndrome in 83 patients: novel HESX1 mutation and severe hormonal prognosis in malformative forms. AB - BACKGROUND: Pituitary stalk interruption syndrome (PSIS) is a particular entity in the population of patients with hypopituitarism. Only rare cases have a known genetic cause. OBJECTIVES: i) To compare subgroups with or without extra pituitary malformations (EPM) in a cohort of PSIS patients to identify predictive factors of evolution, ii) to determine the incidence of mutations of the known pituitary transcription factor genes in PSIS. Study design We analyzed features of 83 PSIS patients from 80 pedigrees and screened HESX1, LHX4, OTX2, and SOX3 genes. RESULTS: PSIS had a male predominance and was rarely familial (5%). Pituitary hypoplasia was observed only in the group with EPM. Multiple hormone deficits were observed significantly more often with versus without EPM (87.5 vs 69.5% respectively). Posterior pituitary location along the stalk was a significant protective factor regarding severity of hormonal phenotype. A novel HESX1 causative mutation was found in a consanguineous family, and two LHX4 mutations were present in familial PSIS. CONCLUSION: PSIS patients with EPM had a more severe hormonal disorder and pituitary imaging status, suggesting an antenatal origin. HESX1 or LHX4 mutations accounted for <5% of cases and were found in consanguineous or familial cases. PMID- 21270113 TI - Aldosterone- and cortisol-co-secreting adrenal tumors: the lost subtype of primary aldosteronism. AB - Current guidelines suggest proving angiotensin-independent aldosterone secretion in patients with primary aldosteronism (PA). It is further recommended to demonstrate unilateral disease because of its consequence for therapy. A general screening for excess secretion of other hormones is not recommended. However, clinically relevant autonomous aldosterone production rarely originates in adrenal tumors, compromised of zona glomerulosa cells only. This article reviews published data on aldosterone- and cortisol-co-secreting tumors and shows that pre-operative diagnosis of such a lesion is beneficial for patients. Overt or subclinical glucocorticoid hypersecretion may interfere with diagnostic studies, e.g. adrenal venous sampling, screening of familial forms of PA on the basis of serum 18-hydroxy-cortisol (18-OH-F) determination, and provoke glucocorticoid deficiency after surgical removal of the tumor. In addition, knowledge from histological and molecular studies in patients with aldosterone- and cortisol-co secreting tumors challenges some concepts of the development of adrenal autonomy. The presence of an aldosterone- and cortisol-co-secreting adrenocortical tumor should be considered if a patient has i) PA and an adenoma that is larger than 2.5 cm, ii) cortisol that is non-suppressible with overnight low-dose dexamethasone, or iii) grossly elevated serum levels of hybrid steroids, such as 18-OH-F. PMID- 21270114 TI - Perceiving path from optic flow. AB - We examined how people perceive their path of traveling from optic flow. Observers viewed displays simulating their traveling on a circular path over a textured ground, a random-dot ground, or a dynamic random-dot ground display in which dots were periodically redrawn to remove extended dot motion trajectories (flow lines) in the flow field. Five viewing conditions were tested in which the simulated observer gaze direction was pointed to (1) a target on the path at 30 degrees away from the initial heading, (2) a target at 15 degrees outside of the path, (3) a target at 15 degrees inside of the path, (4) along the instantaneous heading, or (5) along the Z-axis of the simulated environment. Path performance was similar for all three display conditions, indicating that observers did not rely on flow lines to perceive path from optic flow. Furthermore, contrary to the idea that looking where you want to go provides accurate path perception, path perception was accurate only when the simulated observer gaze direction pointed in the instantaneous heading direction. In contrast, heading perception was accurate and not affected by path curvature regardless of the simulated gaze direction. The results suggest that heading perception is more robust than path perception. PMID- 21270115 TI - The absolute threshold of cone vision. AB - We report measurements of the absolute threshold of cone vision, which has been previously underestimated due to suboptimal conditions or overly strict subjective response criteria. We avoided these limitations by using optimized stimuli and experimental conditions while having subjects respond within a rating scale framework. Small (1' fwhm), brief (34 ms), monochromatic (550 nm) stimuli were foveally presented at multiple intensities in dark-adapted retina for 5 subjects. For comparison, 4 subjects underwent similar testing with rod-optimized stimuli. Cone absolute threshold, that is, the minimum light energy for which subjects were just able to detect a visual stimulus with any response criterion, was 203 +/- 38 photons at the cornea, ~0.47 log unit lower than previously reported. Two-alternative forced-choice measurements in a subset of subjects yielded consistent results. Cone thresholds were less responsive to criterion changes than rod thresholds, suggesting a limit to the stimulus information recoverable from the cone mosaic in addition to the limit imposed by Poisson noise. Results were consistent with expectations for detection in the face of stimulus uncertainty. We discuss implications of these findings for modeling the first stages of human cone vision and interpreting psychophysical data acquired with adaptive optics at the spatial scale of the receptor mosaic. PMID- 21270116 TI - FXR activation inhibits inflammation and preserves the intestinal barrier in IBD. PMID- 21270117 TI - Hepatic fatty acid translocase CD36 upregulation is associated with insulin resistance, hyperinsulinaemia and increased steatosis in non-alcoholic steatohepatitis and chronic hepatitis C. AB - BACKGROUND: Fatty acid translocase CD36 (FAT/CD36) mediates uptake and intracellular transport of long-chain fatty acids in diverse cell types. While the pathogenic role of FAT/CD36 in hepatic steatosis in rodents is well-defined, little is known about its significance in human liver diseases. OBJECTIVE: To examine the expression of FAT/CD36 and its cellular and subcellular distribution within the liver of patients with non-alcoholic fatty liver disease (NAFLD) and chronic hepatitis C virus (HCV) infection. PATIENTS: 34 patients with non alcoholic steatosis (NAS), 30 with non-alcoholic steatohepatitis (NASH), 66 with HCV genotype 1 (HCV G1) and 32 with non-diseased liver (NL). METHODS: Real-time PCR and western blot analysis were used to assess hepatic FAT/CD36 expression. Computational image analysis of immunostained liver biopsy sections was performed to determine subcellular distribution and FAT/CD36 expression index. RESULTS: Compared with NL, hepatic mRNA and protein levels of FAT/CD36 were significantly higher in patients with NAS (median fold increase 0.84 (range 0.15-1.61) and 0.66 (range 0.33-1.06), respectively); NASH (0.91 (0.22-1.81) and 0.81 (0.38-0.92), respectively); HCV G1 without steatosis (0.30 (0.17-1.59) and 0.33 (0.29-0.52), respectively); and HCV G1 with steatosis (0.85 (0.15-1.98) and 0.87 (0.52-1.26), respectively). In contrast to NL, FAT/CD36 was predominantly located at the plasma membrane of hepatocytes in patients with NAFLD and HCV G1 with steatosis. A significant correlation was observed between hepatic FAT/CD36 expression index and plasma insulin levels, insulin resistance (HOMA-IR) and histological grade of steatosis in patients with NASH (r=0.663, r=0.735 and r=0.711, respectively) and those with HCV G1 with steatosis (r=0.723, r=0.769 and r=0.648, respectively). CONCLUSIONS: Hepatic FAT/CD36 upregulation is significantly associated with insulin resistance, hyperinsulinaemia and increased steatosis in patients with NASH and HCV G1 with fatty liver. Translocation of this fatty acid transporter to the plasma membrane of hepatocytes may contribute to liver fat accumulation in patients with NAFLD and HCV. PMID- 21270118 TI - Virological suppression does not prevent the development of hepatocellular carcinoma in HBeAg-negative chronic hepatitis B patients with cirrhosis receiving oral antiviral(s) starting with lamivudine monotherapy: results of the nationwide HEPNET. Greece cohort study. AB - OBJECTIVE: To evaluate the risk and predictors of hepatocellular carcinoma (HCC) in HBeAg-negative chronic hepatitis B patients of the large HEPNET.Greece cohort study who received long-term oral antivirals starting with lamivudine monotherapy. DESIGN: Retrospective analysis of HCC incidence in HBeAg-negative chronic hepatitis B patients from a retrospective-prospective cohort who were treated with nucleos(t)ide analogue(s) starting with lamivudine monotherapy for >=12 months. SETTING: A nationwide network of liver centres. PATIENTS: 818 patients were included: 517 with chronic hepatitis B only; 160 with compensated cirrhosis; 56 with decompensated cirrhosis; 85 with unclassified disease severity. INTERVENTIONS: All patients were treated with nucleos(t)ide analogue(s) starting with lamivudine monotherapy. MAIN OUTCOME MEASURES: Development of HCC. RESULTS: During a median follow-up of 4.7 years, HCC developed in 49 (6.0%) patients. The 5-year cumulative incidence of HCC was higher in patients with cirrhosis than in those with chronic hepatitis B only (11.5% vs 3.2%, respectively; p<0.001). HCC developed in 0.7%, 6.7% and 11.7% of patients <50, 50 60 and >60 years old, respectively (p<0.001). Virological on-therapy remission did not significantly affect the incidence of HCC in all patients or those with cirrhosis, but it showed a trend for lower HCC incidence in patients with chronic hepatitis B only (p=0.076). In multivariate analysis, age, gender and cirrhosis were independently associated with HCC risk regardless of virological remission. CONCLUSIONS: Long-term therapy with nucleos(t)ide analogue(s) starting with lamivudine monotherapy does not eliminate HCC risk in HBeAg-negative chronic hepatitis B. The risk of HCC is particularly high in patients with cirrhosis, who should remain under HCC surveillance even during effective therapy. Older age and male gender remain independent risk factors for HCC, while virological on-therapy remission does not seem to significantly reduce the overall incidence of HCC. PMID- 21270119 TI - Portal cholangiopathy: radiological classification and natural history. AB - BACKGROUND/AIM: Portal cholangiopathy (PC) is identified in over 80% of patients with portal vein thrombosis (PVT), but the true impact of this condition is not well known. This study investigated the relationship between cholangiographic abnormalities and clinical symptoms and their evolution over time. PATIENTS/METHODS: 67 consecutive patients with non-tumoral non-cirrhotic PVT following a standardised diagnostic protocol were studied. Findings at magnetic resonance angiography and cholangiography (MRA/MRC) were classified as no PC, grade I PC (minimal irregularities), grade II PC (stenosis without dilation) and grade III PC (stenosis with dilation). These changes were related to the presence of symptoms. RESULTS: 22 patients were diagnosed with acute PVT and 45 presented with chronic PVT. Overall, 52 patients had PC (6 grade I, 12 grade II and 34 grade III). 14 patients developed symptoms, all of whom had grade III PC. 30% of patients with acute PVT developed grade III PC within 1 year. In those without grade III PC, follow-up MRC showed no progression of the biliary lesions to grade III. The 5-year probability of developing symptoms of PC after acute PVT was 19%. In 45 patients with chronic PVT, MRA/MRC showed grade III PC in 26. In those without grade III PC, no progression of PC was observed at further follow-up MRC. The prevalence of symptoms of PC in these patients was 22%. CONCLUSIONS: PC is a frequent complication that develops and stabilises early after PVT and becomes symptomatic in its more severe form (grade III). These data suggest that follow up MRA/MRC is not mandatory and strategies to prevent the development of symptoms of PC should be tested in patients with grade III PC. PMID- 21270120 TI - Influenza vaccines in patients with IBD: ready for primetime? PMID- 21270121 TI - H1N1 vaccines in a large observational cohort of patients with inflammatory bowel disease treated with immunomodulators and biological therapy. AB - BACKGROUND: Safety data are lacking on influenza vaccination in general and on A (H1N1)v vaccination in particular in patients with inflammatory bowel disease (IBD) receiving immmunomodulators and/or biological therapy. AIMS AND METHODS: The authors conducted a multicentre observational cohort study to evaluate symptoms associated with influenza H1N1 adjuvanted (Pandemrix, Focetria, FluvalP) and non-adjuvanted (Celvapan) vaccines and to assess the risk of flare of IBD after vaccination. Patients with stable IBD treated with immunomodulators and/or biological therapy were recruited from November 2009 until March 2010 in 12 European countries. Harvey-Bradshaw Index and Partial Mayo Score were used to assess disease activity before and 4 weeks after vaccination in Crohn's disease (CD) and ulcerative colitis (UC). Vaccination-related events up to 7 days after vaccination were recorded. RESULTS: Of 575 patients enrolled (407 CD, 159 UC and nine indeterminate colitis; 53.9% female; mean age 40.3 years, SD 13.9), local and systemic symptoms were reported by 34.6% and 15.5% of patients, respectively. The most common local and systemic reactions were pain in 32.8% and fatigue in 6.1% of subjects. Local symptoms were more common with adjuvanted (39.3%) than non-adjuvanted (3.9%) vaccines (p < 0.0001), whereas rates of systemic symptoms were similar with both types (15.0% vs 18.4%, p = 0.44). Among the adjuvanted group, Pandemrix more often induced local reactions than FluvalP and Focetria (51.2% vs 27.6% and 15.4%, p < 0.0001). Solicited adverse events were not associated with any patient characteristics, specific immunomodulatory treatment, or biological therapy. Four weeks after vaccination, absence of flare was observed in 377 patients with CD (96.7%) and 151 with UC (95.6%). CONCLUSION: Influenza A (H1N1)v vaccines are well tolerated in patients with IBD. Non adjuvanted vaccines are associated with fewer local reactions. The risk of IBD flare is probably not increased after H1N1 vaccination. PMID- 21270122 TI - Deconstructing tick saliva: non-protein molecules with potent immunomodulatory properties. AB - Dendritic cells (DCs) are powerful initiators of innate and adaptive immune responses. Ticks are blood-sucking ectoparasite arthropods that suppress host immunity by secreting immunomodulatory molecules in their saliva. Here, compounds present in Rhipicephalus sanguineus tick saliva with immunomodulatory effects on DC differentiation, cytokine production, and costimulatory molecule expression were identified. R. sanguineus tick saliva inhibited IL-12p40 and TNF-alpha while potentiating IL-10 cytokine production by bone marrow-derived DCs stimulated by Toll-like receptor-2, -4, and -9 agonists. To identify the molecules responsible for these effects, we fractionated the saliva through microcon filtration and reversed-phase HPLC and tested each fraction for DC maturation. Fractions with proven effects were analyzed by micro-HPLC tandem mass spectrometry or competition ELISA. Thus, we identified for the first time in tick saliva the purine nucleoside adenosine (concentration of ~110 pmol/MUl) as a potent anti inflammatory salivary inhibitor of DC cytokine production. We also found prostaglandin E(2) (PGE(2) ~100 nM) with comparable effects in modulating cytokine production by DCs. Both Ado and PGE(2) inhibited cytokine production by inducing cAMP-PKA signaling in DCs. Additionally, both Ado and PGE(2) were able to inhibit expression of CD40 in mature DCs. Finally, flow cytometry analysis revealed that PGE(2), but not Ado, is the differentiation inhibitor of bone marrow-derived DCs. The presence of non-protein molecules adenosine and PGE(2) in tick saliva indicates an important evolutionary mechanism used by ticks to subvert host immune cells and allow them to successfully complete their blood meal and life cycle. PMID- 21270123 TI - The IL1alpha-S100A13 heterotetrameric complex structure: a component in the non classical pathway for interleukin 1alpha secretion. AB - Interleukin 1alpha (IL1alpha) plays an important role in several key biological functions, such as angiogenesis, cell proliferation, and tumor growth in several types of cancer. IL1alpha is a potent cytokine that induces a wide spectrum of immunological and inflammatory activities. The biological effects of IL1alpha are mediated through the activation of transmembrane receptors (IL1Rs) and therefore require the release of the protein into the extracellular space. IL1alpha is exported through a non-classical release pathway involving the formation of a specific multiprotein complex, which includes IL1alpha and S100A13. Because IL1alpha plays an important role in cell proliferation and angiogenesis, inhibiting the formation of the IL1alpha-S100A13 complex would be an effective strategy to inhibit a wide range of cancers. To understand the molecular events in the IL1alpha release pathway, we studied the structure of the IL1alpha-S100A13 tetrameric complex, which is the key complex formed during the non-classical pathway of IL1alpha release. PMID- 21270124 TI - Synergistic interaction between leptin and cholecystokinin in the rat nodose ganglia is mediated by PI3K and STAT3 signaling pathways: implications for leptin as a regulator of short term satiety. AB - Research has shown that the synergistic interaction between vagal cholecystokinin A receptors (CCKARs) and leptin receptors (LRbs) mediates short term satiety. We hypothesize that this synergistic interaction is mediated by cross-talk between signaling cascades used by CCKARs and LRbs, which, in turn, activates closure of K(+) channels, leading to membrane depolarization and neuronal firing. Whole cell patch clamp recordings were performed on isolated rat nodose ganglia neurons. Western immunoblots elucidated the intracellular signaling pathways that modulate leptin/CCK synergism. In addition, STAT3, PI3K, Src, and MAPK genes were silenced by lentiviral infection and transient Lipofectamine transfection of cultured rat nodose ganglia to determine the effect of these molecules on leptin/CCK synergism. Patch clamp studies showed that a combination of leptin and CCK-8 caused a significant increase in membrane input resistance compared with leptin or CCK-8 alone. Silencing the STAT3 gene abolished the synergistic action of leptin/CCK-8 on neuronal firing. Leptin/CCK-8 synergistically stimulated a 7.7 fold increase in phosphorylated STAT3 (pSTAT3), which was inhibited by AG490, C3 transferase, PP2, LY294002, and wortmannin, but not PD98059. Silencing the Src and PI3K genes resulted in a loss of leptin/CCK-stimulated pSTAT3. We conclude that the synergistic interaction between vagal CCKARs and LRbs is mediated by the phosphorylation of STAT3, which, in turn, activates closure of K(+) channels, leading to membrane depolarization and neuronal firing. This involves the interaction between CCK/Src/PI3K cascades and leptin/JAK2/PI3K/STAT3 signaling pathways. Malfunctioning of these signaling molecules may result in eating disorders. PMID- 21270125 TI - Modulation of substrate specificities of D-sialic acid aldolase through single mutations of Val-251. AB - In a recent directed-evolution study, Escherichia coli D-sialic acid aldolase was converted by introducing eight point mutations into a new enzyme with relaxed specificity, denoted RS-aldolase (also known formerly as L-3-deoxy-manno-2 octulosonic acid (L-KDO) aldolase), which showed a preferred selectivity toward L KDO. To investigate the underlying molecular basis, we determined the crystal structures of D-sialic acid aldolase and RS-aldolase. All mutations are away from the catalytic center, except for V251I, which is near the opening of the (alpha/beta)(8)-barrel and proximal to the Schiff base-forming Lys-165. The change of specificity from D-sialic acid to RS-aldolase can be attributed mainly to the V251I substitution, which creates a narrower sugar-binding pocket, but without altering the chirality in the reaction center. The crystal structures of D-sialic acid aldolase.l-arabinose and RS-aldolase.hydroxypyruvate complexes and five mutants (V251I, V251L, V251R, V251W, and V251I/V265I) of the D-sialic acid aldolase were also determined, revealing the location of substrate molecules and how the contour of the active site pocket was shaped. Interestingly, by mutating Val251 alone, the enzyme can accept substrates of varying size in the aldolase reactions and still retain stereoselectivity. The engineered D-sialic acid aldolase may find applications in synthesizing unnatural sugars of C(6) to C(10) for the design of antagonists and inhibitors of glycoenzymes. PMID- 21270126 TI - Combined X-ray, NMR, and kinetic analyses reveal uncommon binding characteristics of the hepatitis C virus NS3-NS4A protease inhibitor BI 201335. AB - Hepatitis C virus infection, a major cause of liver disease worldwide, is curable, but currently approved therapies have suboptimal efficacy. Supplementing these therapies with direct-acting antiviral agents has the potential to considerably improve treatment prospects for hepatitis C virus-infected patients. The critical role played by the viral NS3 protease makes it an attractive target, and despite its shallow, solvent-exposed active site, several potent NS3 protease inhibitors are currently in the clinic. BI 201335, which is progressing through Phase IIb trials, contains a unique C-terminal carboxylic acid that binds noncovalently to the active site and a bromo-quinoline substitution on its proline residue that provides significant potency. In this work we have used stopped flow kinetics, x-ray crystallography, and NMR to characterize these distinctive features. Key findings include: slow association and dissociation rates within a single-step binding mechanism; the critical involvement of water molecules in acid binding; and protein side chain rearrangements, a bromine oxygen halogen bond, and profound pK(a) changes within the catalytic triad associated with binding of the bromo-quinoline moiety. PMID- 21270127 TI - A germ cell-specific gene, Prmt5, works in somatic cell reprogramming. AB - Germ cells possess the unique ability to acquire totipotency during development in vivo as well as give rise to pluripotent stem cells under the appropriate conditions in vitro. Recent studies in which somatic cells were experimentally converted into pluripotent stem cells revealed that genes expressed in primordial germ cells (PGCs), such as Oct3/4, Sox2, and Lin28, are involved in this reprogramming. These findings suggest that PGCs may be useful for identifying factors that successfully and efficiently reprogram somatic cells into toti- and/or pluripotent stem cells. Here, we show that Blimp-1, Prdm14, and Prmt5, each of which is crucial for PGC development, have the potential to reprogram somatic cells into pluripotent stem cells. Among them, Prmt5 exhibited remarkable reprogramming of mouse embryonic fibroblasts into which Prmt5, Klf4, and Oct3/4 were introduced. The resulting cells exhibited pluripotent gene expression, teratoma formation, and germline transmission in chimeric mice, all of which were indistinguishable from those induced with embryonic stem cells. These data indicate that some of the factors that play essential roles in germ cell development are also active in somatic cell reprogramming. PMID- 21270128 TI - Calpain-mediated proteolysis of paxillin negatively regulates focal adhesion dynamics and cell migration. AB - The dynamic turnover of integrin-mediated adhesions is important for cell migration. Paxillin is an adaptor protein that localizes to focal adhesions and has been implicated in cell motility. We previously reported that calpain mediated proteolysis of talin1 and focal adhesion kinase mediates adhesion disassembly in motile cells. To determine whether calpain-mediated paxillin proteolysis regulates focal adhesion dynamics and cell motility, we mapped the preferred calpain proteolytic site in paxillin. The cleavage site is between the paxillin LD1 and LD2 motifs and generates a C-terminal fragment that is similar in size to the alternative product paxillin delta. The calpain-generated proteolytic fragment, like paxillin delta, functions as a paxillin antagonist and impairs focal adhesion disassembly and migration. We generated mutant paxillin with a point mutation (S95G) that renders it partially resistant to calpain proteolysis. Paxillin-deficient cells that express paxillin S95G display increased turnover of zyxin-containing adhesions using time-lapse microscopy and also show increased migration. Moreover, cancer-associated somatic mutations in paxillin are common in the N-terminal region between the LD1 and LD2 motifs and confer partial calpain resistance. Taken together, these findings suggest a novel role for calpain-mediated proteolysis of paxillin as a negative regulator of focal adhesion dynamics and migration that may function to limit cancer cell invasion. PMID- 21270129 TI - Cardiomyocyte-specific prolyl-4-hydroxylase domain 2 knock out protects from acute myocardial ischemic injury. AB - Prolylhydroxylase domain proteins (PHD) are cellular oxygen-sensing molecules that regulate the stability of the alpha-subunit of the transcription factor hypoxia inducible factor (HIF)-1. HIF-1 affects cardiac development as well as adaptation of the heart toward increased pressure overload or myocardial infarction. We have disrupted PHD2 in cardiomyocytes (cPhd (-/-)) using Phd2(flox/flox) mice in combination with MLCvCre mice, which resulted in HIF 1alpha stabilization and activation of HIF target genes in the heart. Although cPhd2(-/-) mice showed no gross abnormalities in cardiac filament structure or function, we observed a significant increased cardiac capillary area in those mice. cPhd2 (-/-) mice did not respond differently to increased mechanical load by transverse aortic constriction compared with their wild-type (wt) littermates. After ligation of the left anterior descending artery, however, the area at risk and area of necrosis were significantly smaller in the cPhd2(-/-) mice compared with Phd2 wt mice in line with the described pivotal role of HIF-1alpha for tissue protection in case of myocardial infarction. This correlated with a decreased number of apoptotic cells in the infarcted myocardium in the cPhd2(-/-) mice and significantly improved cardiac function 3 weeks after myocardial infarction. PMID- 21270130 TI - Lef1DeltaN binds beta-catenin and increases osteoblast activity and trabecular bone mass. AB - Lymphoid enhancer-binding factor (Lef) 1 is a high mobility group protein best known as a Wnt-responsive transcription factor that associates with beta-catenin. Lef1DeltaN is a short isoform of Lef1 that lacks the first 113 amino acids and a well characterized high affinity beta-catenin binding domain present in the full length protein. Both Lef1 isoforms bind DNA and regulate gene expression. We previously reported that Lef1 is expressed in proliferating osteoblasts and blocks osteocalcin expression. In contrast, Lef1DeltaN is only detectable in the later stages of osteoblast differentiation and promotes osteogenesis in vitro. Here, we show that Lef1DeltaN retains the ability to interact physically and functionally with beta-catenin. Unlike what has been reported in T cells and colon cancer cell lines, Lef1DeltaN activated gene transcription in the absence of exogenous beta-catenin and cooperated with constitutively active beta-catenin to stimulate gene transcription in mesenchymal and osteoblastic cells. Residues at the N terminus of Lef1DeltaN were required for beta-catenin binding and the expression of osteoblast differentiation genes. To determine the role of Lef1DeltaN on bone formation in vivo, a Lef1DeltaN transgene was expressed in committed osteoblasts using the 2.3-kb fragment of the type 1 collagen promoter. The Lef1DeltaN transgenic mice had higher trabecular bone volume in the proximal tibias and L5 vertebrae. Histological analyses of tibial sections revealed no differences in osteoblast, osteoid, or osteoclast surface areas. However, bone formation and mineral apposition rates as well as osteocalcin levels were increased in Lef1DeltaN transgenic mice. Together, our data indicate that Lef1DeltaN binds beta-catenin, stimulates Lef/Tcf reporter activity, and promotes terminal osteoblast differentiation. PMID- 21270131 TI - Information needs of case managers caring for persons living with HIV. AB - OBJECTIVE: The goals of this study were to explore the information needs of case managers who provide services to persons living with HIV (PLWH) and to assess the applicability of the Information Needs Event Taxonomy in a new population. DESIGN: The study design was observational with data collection via an online survey. MEASUREMENTS: Responses to open-ended survey questions about the information needs of case managers (n=94) related to PLWH of three levels of care complexity were categorized using the Information Needs Event Taxonomy. RESULTS: The most frequently identified needs were related to patient education resources (33%), patient data (23%), and referral resources (22%) accounting for 79% of all (N=282) information needs. LIMITATIONS: Study limitations include selection bias, recall bias, and a relatively narrow focus of the study on case-manager information needs in the context of caring for PLWH. CONCLUSION: The study findings contribute to the evidence base regarding information needs in the context of patient interactions by: (1) supporting the applicability of the Information Needs Event Taxonomy and extending it through addition of a new generic question; (2) providing a foundation for the addition of context-specific links to external information resources within information systems; (3) applying a new approach for elicitation of information needs; and (4) expanding the literature regarding addressing information needs in community-based settings for HIV services. PMID- 21270132 TI - The case for randomized controlled trials to assess the impact of clinical information systems. AB - There is a persistent view of a significant minority in the medical informatics community that the randomized controlled trial (RCT) has a limited role to play in evaluating clinical information systems. A common reason voiced by skeptics is that these systems are fundamentally different from drug interventions, so the RCT is irrelevant. There is an urgent need to promote the use of RCTs, given the shift to evidence-based policy and the need to demonstrate cost-effectiveness of these systems. The authors suggest returning to first principles and argue that what is required is clarity about how to match methods to evaluation questions. The authors address common concerns about RCTs, and the extent to which they are fallacious, and also discuss the challenges of conducting RCTs in informatics and alternative study designs when randomized trials are infeasible. While neither a perfect nor universal evaluation method, RCTs form an important part of an evaluator's toolkit. PMID- 21270133 TI - Age dependency of inhibition of alpha7 nicotinic receptors and tonically active N methyl-D-aspartate receptors by endogenously produced kynurenic acid in the brain. AB - In the mouse hippocampus normal levels of kynurenic acid (KYNA), a neuroactive metabolite synthesized in astrocytes primarily by kynurenine aminotransferase II (KAT II)-catalyzed transamination of L-kynurenine, maintain a degree of tonic inhibition of alpha7 nicotinic acetylcholine receptors (nAChRs). The present in vitro study was designed to test the hypothesis that alpha7 nAChR activity decreases when endogenous production of KYNA increases. Incubation (2-7 h) of rat hippocampal slices with kynurenine (200 MUM) resulted in continuous de novo synthesis of KYNA. Kynurenine conversion to KYNA was significantly decreased by the KAT II inhibitor (S)-(-)-9-(4-aminopiperazine-1-yl)-8-fluoro-3-methyl-6-oxo 2,3,5,6-tetrahydro-4H-1-oxa-3a-azaphenalene-5carboxylic acid (BFF122) (100 MUM) and was more effective in slices from postweaned than preweaned rats. Incubation of slices from postweaned rats with kynurenine inhibited alpha7 nAChRs and extrasynaptic N-methyl-D-aspartate receptors (NMDARs) on CA1 stratum radiatum interneurons. These effects were attenuated by BFF122 and mimicked by exogenously applied KYNA (200 MUM). Exposure of human cerebral cortical slices to kynurenine also inhibited alpha7 nAChRs. The alpha7 nAChR sensitivity to KYNA is age dependent, because neither endogenously produced nor exogenously applied KYNA inhibited alpha7 nAChRs in slices from preweaned rats. In these slices, kynurenine-derived KYNA also failed to inhibit extrasynaptic NMDARs, which could, however, be inhibited by exogenously applied KYNA. In slices from preweaned and postweaned rats, glutamatergic synaptic currents were not affected by endogenously produced KYNA, but were inhibited by exogenously applied KYNA. These results suggest that in the mature brain alpha7 nAChRs and extrasynaptic NMDARs are in close apposition to KYNA release sites and, thereby, readily accessible to inhibition by endogenously produced KYNA. PMID- 21270134 TI - Improved cerebrovascular function and reduced histological damage with darbepoietin alfa administration after cortical impact injury in rats. AB - Darbepoetin alfa (darbEpo) is an erythropoietic glycoprotein that activates the erythropoietin receptor. The aim of our study was to determine whether darbEpo is neuroprotective in a cortical impact injury (CII) model and to determine the characteristics of dose response and time window. To better understand the vascular mechanism of darbEpo neuroprotection, the reactivity of cerebral blood flow (CBF) to l-arginine administration was also studied. Rats were given saline or darbEpo from 2.5 to 50 MUg/kg at 5 min after CII or a dose of 25 MUg/kg darbEpo at times ranging from 5 min to 24 h after CII. Histological assessment was determined 2 weeks after a severe CII. Other rats were given either darbEpo (25 MUg/kg) or saline daily for 3 days before injury. Five minutes after severe CII, they were given either l-arginine or d-arginine. Hemodynamic variables were monitored for 2 h after injury. In the dose-response study, darbEpo in doses of 25 and 50 MUg/kg significantly reduced contusion volume from 39.1 +/- 6.7 to 8.1 +/- 3.1 and 11.2 +/- 6.0 mm(3), respectively. In the time window study, darbEpo reduced contusion volume when given in a dose of 25 MUg/kg at 5 min to 6 h after the impact injury. In animals pretreated with darbEpo, the CBF response to l arginine was significantly greater than in the animals pretreated with saline. These data demonstrate that darbEpo has neuroprotective effects in traumatic brain injury in a dose- and time-dependent manner and that vascular effects of darbEpo may have a role in neuroprotection. PMID- 21270135 TI - 2'-AMP and 3'-AMP inhibit proliferation of preglomerular vascular smooth muscle cells and glomerular mesangial cells via A2B receptors. AB - Studies show that kidneys produce 2',3'-cAMP, 2',3'-cAMP is exported and metabolized to 2'-AMP and 3'-AMP, 2'-AMP and 3'-AMP are metabolized to adenosine, 2',3'-cAMP inhibits proliferation of preglomerular vascular smooth muscle cells (PGVSMCs) and glomerular mesangial cells (GMCs), and A(2B) (not A(1), A(2A), or A(3)) adenosine receptors mediate part of the antiproliferative effects of 2',3' cAMP. These findings suggest that extracellular 2',3'-cAMP attenuates proliferation of PGVSMCs and GMCs partly via conversion to corresponding AMPs, which are metabolized to adenosine that activates A(2B) receptors. This hypothesis predicts that extracellular 2'-AMP and 3'-AMP should exert A(2B) receptor-mediated antiproliferative effects. Therefore, we examined the antiproliferative effects (cell counts) of 2'-AMP and 3'-AMP. In PGVSMCs and GMCs, 2'-AMP and 3'-AMP exerted concentration-dependent antiproliferative effects. 3'-AMP was equipotent with and 2'-AMP was 3-fold less potent than 5'-AMP (prototypical adenosine precursor). In PGVSMCs, the effects of 2'-AMP and 3'-AMP were mimicked by adenosine, and 8-[4-[((4-cyanophenyl)carbamoylmethyl)oxy]phenyl] 1,3-di(n-propyl)xanthine (MRS-1754) (A(2B) receptor antagonist) equally blocked the antiproliferative effects of 2'-AMP, 3'-AMP, and adenosine but less effectively blocked the effects of 2',3'-cAMP. Similar results were obtained in GMCs except that MRS-1754 also incompletely blocked the effects of 3'-AMP. We conclude that in PGVSMCs, 2'-AMP and 3'-AMP are antiproliferative, the antiproliferative effects of 2'-AMP and 3'-AMP are mediated nearly entirely by adenosine/A(2B) receptors, and some of the antiproliferative effects of 2',3' cAMP are independent of adenosine/A(2B) receptors. Similar conclusions apply to GMCs except that 3'-AMP also has actions independent of adenosine/A(2B) receptors. Because A(2B) receptors are renoprotective, 2'-AMP and 3'-AMP may provide renoprotection by generating adenosine that activates A(2B) receptors. PMID- 21270136 TI - Specific requirement of DRB4, a dsRNA-binding protein, for the in vitro dsRNA cleaving activity of Arabidopsis Dicer-like 4. AB - Arabidopsis thaliana Dicer-like 4 (DCL4) produces 21-nt small interfering RNAs from both endogenous and exogenous double-stranded RNAs (dsRNAs), and it interacts with DRB4, a dsRNA-binding protein, in vivo and in vitro. However, the role of DRB4 in DCL4 activity remains unclear because the dsRNA-cleaving activity of DCL4 has not been characterized biochemically. In this study, we biochemically characterize DCL4's Dicer activity and establish that DRB4 is required for this activity in vitro. Crude extracts from Arabidopsis seedlings cleave long dsRNAs into 21-nt small RNAs in a DCL4/DRB4-dependent manner. Immunoaffinity-purified DCL4 complexes produce 21-nt small RNAs from long dsRNA, and these complexes have biochemical properties similar to those of known Dicer family proteins. The DCL4 complexes purified from drb4-1 do not cleave dsRNA, and the addition of recombinant DRB4 to drb4-1 complexes specifically recovers the 21-nt small RNA generation. These results reveal that DCL4 requires DRB4 to cleave long dsRNA into 21-nt small RNAs in vitro. Amino acid substitutions in conserved dsRNA binding domains (dsRBDs) of DRB4 impair three activities: binding to dsRNA, interacting with DCL4, and facilitating DCL4 activity. These observations indicate that the dsRBDs are critical for DRB4 function. Our biochemical approach and observations clearly show that DRB4 is specifically required for DCL4 activity in vitro. PMID- 21270137 TI - Useful tests of usefulness of new risk factors: tools for assessing reclassification and discrimination. AB - New risk factors for various diseases are suggested at an increasing pace, with promise of clinical usefulness for risk prediction, but almost unvaryingly without formal testing of that property. We propose that a risk factor clinically relevant for risk prediction can be defined as one that correctly alters predicted risk to a clinically relevant extent in persons with a relevant absolute risk, such that it affects clinical decision making. We recommend that investigators who suggest a new risk factor for clinical use investigate if the new risk factor adds capacity to discriminate between persons who will subsequently experience the outcome from those who will not. For that purpose, we provide tools for calculating the net reclassification improvement, NRI, and the integrated discrimination improvement, IDI, using major statistical packages. PMID- 21270138 TI - Immigrant general practitioners in Norway: a special resource? A qualitative study. AB - AIMS: To explore whether and how immigrant general practitioners (GPs) in two major cities in Norway think that their own ethnic background affects their practices and their work. METHODS: Qualitative focus group and individual interviews with seven immigrant GPs, five men and two women, age 36-65 years. Their clinical experience in Norwegian primary health care ranged from four to 30 years. Analysis was conducted by systematic text condensation. RESULTS: First, immigrant GPs described a gradual process of becoming bicultural: the GPs communicate with immigrant patients on their own terms and draw upon their special knowledge from abroad to help selected patients, while also adapting to Norwegian cultural expectations of the GP's role. Second, the GPs described being aware of cultural issues in consultations with immigrant and Norwegian patients, but rarely making these issues explicit. The GPs ventured that cultural awareness, together with their personal experience in their own countries and as immigrants in Norway, made them able to sometimes help immigrant patients better than Norwegian GPs. Third, immigrant GPs experienced a big workload related to immigrant patients, but they accepted this as a natural part of their work. Fourth, immigrant GPs felt that they had to work harder and be more careful than their Norwegian colleagues in order to avoid complaints from patients, and to be accepted by colleagues. CONCLUSIONS: Immigrant GPs express broad cultural competence and keen cultural awareness in their consultations. The immigrant background of these GPs could be considered as a special resource for clinical practice. PMID- 21270139 TI - Obesity in a life-course perspective: an exploration of lay explanations of weight gain. AB - AIM: The present study investigated the way in which people who had experienced medically defined obesity understood and explained the causes of the weight gains they had experienced during their life course and related such explanations to gender and social background. METHOD: The study was a qualitative in-depth interview study of 20 Danish middle-aged women and men with high and low levels of education who had experienced obesity. RESULTS: Women mainly related weight gain to life-course transitions associated with the female biological lifecycle; to changes in social relations; or to personal problems connected with close social relationships and to side-effects of psycho-pharmaceuticals. Women with high levels of education tended more often to explain weight gain within a depth psychological framework. Men related weight gain mainly to life-course transitions involving changing obligations connected with education, work, and family life; to periods of injury (sports or other) involving reduced levels of physical activity; and to personal problems connected with their work situation or financial troubles. Men with low levels of education tended to link weight gain directly to work environments, which were considered especially likely to lead to weight gain. CONCLUSIONS: The study highlights marked differences in the way individuals explain their own weight gain. These differences relate to gender and, to some degree, social background. The findings may both inform and challenge public health promotion. PMID- 21270140 TI - Municipal variation in health and social service use in the last 2 years of life among old people. AB - AIMS: To describe and analyse municipal differences in health and social service use among old people in the last 2 years of life. METHODS: The data were derived from national registers. All those who died in 2002 or 2003 at the age of >= 70 years were included except those who lived in very small municipalities. The services included were different types of hospitals, long-term care, and home care. The variation in service use was described by coefficients of variation (CV). To analyse local differences, three-level (individual, municipal, and regional) binary logistic and Poisson regression analyses were performed. RESULTS: A total of 67,027 decedents from 315 municipalities in 20 hospital districts were included. There was considerable variation in service use between residents of different municipalities, especially in the types of hospital used. Of the individual-level variables age and use of other services were associated (p < 0.05) with use of all services. Of the municipal-level variables, indicators describing the service pattern in the municipality were associated with use of all services and average age of decedents with most of the services. The presence of a university hospital in the hospital district increased the probability of using university and general hospitals, but among the users increased days in university hospital and decreased days in general hospital. CONCLUSIONS: Considerable differences between municipalities exist, but these cannot be exhaustively explained. Behind the differences are probably factors which are difficult to describe and quantify, such as historical developments and political realities. PMID- 21270141 TI - Randomized trials of alcohol-use interventions with college students and their parents: lessons from the Transitions Project. AB - BACKGROUND: Matriculation from high school to college is typified by an increase in alcohol use and related harm for many students. Therefore, this transition period is an ideal time for preventive interventions to target alcohol use and related problems. PURPOSE: The purpose of this report is to describe the design and methods used in the Transitions Project, a randomized controlled trial of two interventions designed to prevent and reduce heavy episodic drinking and alcohol related negative consequences among incoming college students. METHODS: This study used a 2 * 2 factorial design to investigate the effects of a two-session brief motivational intervention delivered to students and a handbook-based parent intervention. Interventions were administered to students and parents. Follow-up assessment took place at 10- and 22-months post-baseline. RESULTS: The Transitions Project successfully recruited and retained participants across a major transition period (i.e., entering college), administered and compared two distinct but complementary interventions, and collected and analyzed highly skewed data. The application of a factorial design and two-part latent growth curve modeling allowed us to examine main and interactive intervention effects in terms of both initiation and growth in heavy drinking and alcohol-related problems. LIMITATIONS: While we conducted successful tests of our primary and secondary study hypotheses over a lengthy follow-up period, our study design did not permit full interpretation of null findings. We suggest that researchers carefully consider assessment timing, tests of assessment reactivity, and ensure objective tests of intervention efficacy when conducting clinical trials of motivational interventions. CONCLUSIONS: The lessons we learned while conducting this trial have the potential to assist other researchers designing and conducting future preventive interventions targeting parents and college students. The data analytic procedures presented can also help guide trials that plan to analyze zero-inflated non-normal outcome data. PMID- 21270142 TI - Planning and core analyses for periodic aggregate safety data reviews. AB - BACKGROUND: In 2009, the Safety Planning, Evaluation and Reporting Team gave detailed recommendations for a well-planned and systematic approach for safety data collection and analysis. Important aspects of this approach included regular reviews of aggregate data by a multidisciplinary team focusing on safety. PURPOSE: This article provides information to facilitate the planning and implementation of aggregate data reviews. METHODS: Our recommendations are based on experience of the authors and review of relevant literature. RESULTS: We present information regarding the planning of aggregate data reviews as well as examples of data displays that are useful for many different compounds. A subset of these data displays could form a set of 'core' analyses to be generated for aggregate data reviews. PMID- 21270143 TI - Challenges in the design and conduct of controlled clinical effectiveness trials in schizophrenia. AB - BACKGROUND: The introduction of antipsychotic medication has been a major advance in the treatment of schizophrenia and allows millions of people to live outside of institutions. It is generally believed that long-acting intramuscular antipsychotic medication is the most effective approach to increasing medication adherence and thereby reduce relapse in high-risk patients with schizophrenia, but the data are scant. PURPOSE: To report the design of a study to assess the effect of long-acting injectable risperidone in unstable patients and under more realistic conditions than previously studied and to evaluate the effect of this medication on psychiatric inpatient hospitalization, schizophrenia symptoms, quality of life, medication adherence, side effects, and health care costs. METHODS: The trial was an open randomized clinical comparative effectiveness trial in patients with schizophrenia or schizo-affective disorders in which parenteral risperidone was compared to an oral antipsychotic regimen selected by each control patient's psychiatrist. Participants had unstable psychiatric disease defined by recent hospitalization or exhibition of unusual need for psychiatric services. The primary endpoint was hospitalization for psychiatric indications; the secondary endpoint was psychiatric symptoms. RESULTS: Overall, 382 patients were randomized. Determination of a persons' competency to understand the elements of informed consent was addressed. The use of a closed circuit TV interview for psychosocial measures provided an economical, high quality, reliable means of collecting data. A unique method for insuring that usual care was optimal was incorporated in the follow-up of all subjects. LIMITATIONS: Patients with schizophrenia or schizo-affective disorders and with the common co-morbid illnesses seen in the VA are a challenging group of subjects to study in long-term trials. Some techniques unique in the VA and found useful may not be generalizable or applicable in other research or treatment settings. CONCLUSIONS: The trial tested a new antipsychotic medication early in its adoption in the Veterans Health Administration. The VA has a unique electronic medical record and database which can be used to identify the endpoint, that is, first hospitalization due to a psychiatric problem, with complete ascertainment. Several methodologic solutions addressed competency to understand elements of consent, the costs and reliability of collecting interview data gathering, and insuring usual care. PMID- 21270144 TI - NF-kappaB activation stimulates transcription and replication of retrovirus XMRV in human B-lineage and prostate carcinoma cells. AB - Xenotropic murine leukemia virus-related virus (XMRV) is a gammaretrovirus linked to prostate carcinoma and chronic fatigue syndrome. Here we report that NF-kappaB activation can markedly increase XMRV production. The inflammatory cytokine tumor necrosis factor alpha (TNF-alpha), which activates NF-kappaB, significantly augmented viral Gag protein production in XMRV-infected cells. Reporter assays showed that TNF-alpha and Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1), an intrinsic NF-kappaB activator, increased long terminal repeat (LTR) dependent XMRV transcription. We identified two NF-kappaB binding sites (designated kappaB-1 and kappaB-2) in the LTR U3 region of XMRV and demonstrated that both sites bind to the NF-kappaB component p65/RelA. Mutation of the kappaB 1 site, but not the kappaB-2 site, impaired responsiveness to TNF-alpha and LMP1 in reporter assays. A mutant XMRV with a mutation at the kappaB-1 site replicated significantly less efficiently than the wild-type XMRV in the prostate carcinoma LNCaP, DU145, and PC-3 cell lines, HEK293 cells, the EBV-immortalized cell line IB4, and the Burkitt's lymphoma cell line BJAB. These results demonstrate that TNF-alpha and EBV LMP1 enhance XMRV replication in prostate carcinoma and B lineage cells through the kappaB-1 site in the XMRV LTR, suggesting that inflammation, EBV infection, and other conditions leading to NF-kappaB activation may promote XMRV spread in humans. PMID- 21270145 TI - Analysis of human APOBEC3H haplotypes and anti-human immunodeficiency virus type 1 activity. AB - Human APOBEC3H (A3H) has one cytidine deaminase domain (CDD) and inhibits the replication of retrotransposons and human immunodeficiency virus type 1 (HIV-1) in a Vif-resistant manner. Human A3H has five single amino acid polymorphisms (N15Delta, R18L, G105R, K121D, and E178D), and four haplotypes (I to IV) have previously been identified in various human populations. Haplotype II was primarily found in African-derived populations, and it was the only one that could be stably expressed. Here, we identified three new haplotypes from six human population samples, which we have named V, VI, and VII. Haplotypes V and VII are stably expressed and inhibit HIV-1 replication. Notably, haplotype V was identified in samples from all African-, Asian-, and Caucasian-derived populations studied. Using haplotype VII, we investigated the A3H anti-HIV-1 mechanism. We found that A3H virion packaging is independent of its CDD but dependent on a (112)YYXW(115) motif. This motif binds HIV-1 nucleocapsid in an RNA-dependent manner, and a single Y112A mutation completely disrupts A3H virion incorporation. We further studied the mechanism of A3H resistance to Vif. Although the previously identified APOBEC3G Vif-responsive motif (128)DPDY(131) is not conserved in A3H, placement of this motif into A3H does not make it become less resistant to HIV-1 Vif. We conclude that stably expressed A3H haplotypes may be more broadly distributed in humans than previously realized, and A3H protein is resistant to Vif. These results have important implications for the role of A3H in retrotransposon and HIV-1 inhibition. PMID- 21270146 TI - Global analysis of the transcriptional response of whitefly to tomato yellow leaf curl China virus reveals the relationship of coevolved adaptations. AB - The begomoviruses are the largest and most economically important group of plant viruses transmitted exclusively by the whitefly Bemisia tabaci in a circulative, persistent manner. The circulation of the viruses within the insect vectors involves complex interactions between virus and vector components; however, the molecular mechanisms of these interactions remain largely unknown. Here we investigated the transcriptional response of the invasive B. tabaci Middle East Asia Minor 1 species to Tomato yellow leaf curl China virus (TYLCCNV) using Illumina sequencing technology. Results showed that 1,606 genes involved in 157 biochemical pathways were differentially expressed in the viruliferous whiteflies. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that TYLCCNV can perturb the cell cycle and primary metabolism in the whitefly, which explains the negative effect of this virus on the longevity and fecundity of B. tabaci. Our data also demonstrated that TYLCCNV can activate whitefly immune responses, such as autophagy and antimicrobial peptide production, which might lead to a gradual decrease of viral particles within the body of the viruliferous whitefly. Furthermore, PCR results showed that TYLCCNV can invade the ovary and fat body tissues of the whitefly, and Lysotracker and Western blot analyses revealed that the invasion of TYLCCNV induced autophagy in both the ovary and fat body tissues. Surprisingly, TYLCCNV also suppressed the whitefly immune responses by downregulating the expression of genes involved in Toll-like signaling and mitogen-activated protein kinase (MAPK) pathways. Taken together, these results reveal the relationship of coevolved adaptations between begomoviruses and whiteflies and will provide a road map for future investigations into the complex interactions between plant viruses and their insect vectors. PMID- 21270147 TI - Cytomegalovirus capsid protease: biological substrates are cleaved more efficiently by full-length enzyme (pUL80a) than by the catalytic domain (assemblin). AB - We compared the full-length capsid maturational protease (pPR, pUL80a) of human cytomegalovirus with its proteolytic domain (assemblin) for the ability to cleave two biological substrates, and we found that pPR is more efficient with both. Affinity-purified, refolded enzymes and substrates were combined under defined reaction conditions, and cleavage was monitored and quantified following staining of the resulting electrophoretically separated fragments. The enzymes were stabilized against self-cleavage by a single point mutation in each cleavage site (ICRMT-pPR and IC-assemblin). The substrates were pPR itself, inactivated by replacing its catalytic nucleophile (S132A-pPR), and the sequence-related assembly protein precursor (pAP, pUL80.5). Our results showed that (i) ICRMT-pPR is 5- to 10-fold more efficient than assemblin for all cleavages measured (i.e., the M site of pAP and the M, R, and I sites of S132A-pPR). (ii) Cleavage of substrate S132A-pPR proceeded M>R>I for both enzymes. (iii) Na(2)SO(4) reduced M- and R-site cleavage efficiency by ICRMT-pPR, in contrast to its enhancing effect for both enzymes on I site and small peptide cleavage. (iv) Disrupting oligomerization of either the pPR enzyme or substrate by mutating Leu382 in the amino-conserved domain reduced cleavage efficiency two- to fourfold. (v) Finally, ICRMT-pPR mutants that include the amino-conserved domain, but terminate with Pro481 or Tyr469, retain the enzymatic characteristics that distinguish pPR from assemblin. These findings show that the scaffolding portion of pPR increases its enzymatic activity on biologically relevant protein substrates and provide an additional link between the structure of this essential viral enzyme and its biological mechanism. PMID- 21270148 TI - Identification of domains on the fusion (F) protein trimer that influence the hemagglutinin-neuraminidase specificity of the f protein in mediating cell-cell fusion. AB - For most paramyxoviruses, virus type-specific interaction between fusion (F) protein and attachment protein (hemagglutinin-neuraminidase [HN], hemagglutinin [H], or glycoprotein [G]) is a prerequisite for mediating virus-cell fusion and cell-cell fusion. Our previous cell-cell fusion assay using the chimeric F proteins of human parainfluenza virus 2 (HPIV2) and simian virus 41 (SV41) suggested that the middle region of the HPIV2 F protein contains the site(s) that determines its specificity for the HPIV2 HN protein. In the present study, we further investigated the sites of the F protein that could be critical for determining the HN protein specificity. By analyzing the reported structure of the F protein of parainfluenza virus 5 (PIV5), we found that four major domains (M1, M2, M3, and M4) and five minor domains (A to E) in the middle region of the PIV5 F protein were exposed on the trimer surface. We then replaced these domains with the SV41 F counterparts individually or in combination and examined whether the resulting chimeras could mediate cell-cell fusion when coexpressed with the SV41 HN protein. The results showed that a chimera designated M(1+2), which harbored SV41 F-derived domains M1 and M2, mediated cell-cell fusion with the coexpressed SV41 HN protein, suggesting that these domains are involved in determining the HN protein specificity. Intriguingly, another chimera which harbored the SV41 F-derived domain B in addition to domains M1 and M2 showed increased specificity for the SV41 HN protein compared to that of M(1+2), although it was capable of mediating cell-cell fusion by itself. PMID- 21270149 TI - N1L is an ectromelia virus virulence factor and essential for in vivo spread upon respiratory infection. AB - The emergence of zoonotic orthopoxvirus infections and the threat of possible intentional release of pathogenic orthopoxviruses have stimulated renewed interest in understanding orthopoxvirus infections and the resulting diseases. Ectromelia virus (ECTV), the causative agent of mousepox, offers an excellent model system to study an orthopoxvirus infection in its natural host. Here, we investigated the role of the vaccinia virus ortholog N1L in ECTV infection. Respiratory infection of mice with an N1L deletion mutant virus (ECTVDeltaN1L) demonstrated profound attenuation of the mutant virus, confirming N1 as an orthopoxvirus virulence factor. Upon analysis of virus dissemination in vivo, we observed a striking deficiency of ECTVDeltaN1L spreading from the lungs to the livers or spleens of infected mice. Investigating the immunological mechanism controlling ECTVDeltaN1L infection, we found the attenuated phenotype to be unaltered in mice deficient in Toll-like receptor (TLR) or RIG-I-like RNA helicase (RLH) signaling as well as in those missing the type I interferon receptor or lacking B cells. However, in RAG-1(-/-) mice lacking mature B and T cells, ECTVDeltaN1L regained virulence, as shown by increasing morbidity and virus spread to the liver and spleen. Moreover, T cell depletion experiments revealed that ECTVDeltaN1L attenuation was reversed only by removing both CD4(+) and CD8(+) T cells, so the presence of either cell subset was still sufficient to control the infection. Thus, the orthopoxvirus virulence factor N1 may allow efficient ECTV infection in mice by interfering with host T cell function. PMID- 21270150 TI - T cell-, interleukin-12-, and gamma interferon-driven viral clearance in measles virus-infected brain tissue. AB - Genetic studies with immunocompetent mice show the importance of both T cells and gamma interferon (IFN-gamma) for survival of a measles virus (MV) challenge; however, the direct role of T cells and IFN-gamma within the MV-infected brain has not been addressed. Organotypic brain explants represent a successful ex vivo system to define central nervous system (CNS)-specific mechanisms of leukocyte migration, activation, and MV clearance. Within the heterogeneous, brain-derived, primed leukocyte population which reduced MV RNA levels in brain explants by 60%, CD3 T cells are the active antiviral cells, as purified CD3-positive cells are highly antiviral and CD3-negative leukocytes are unable to reduce the viral load. Neutralization of CCL5 and CXCL10 decreases leukocyte migration to areas of infection by 70%. However, despite chemokines directing the migration of T cells to infected neurons, chemokine neutralization revealed that migration is not required for viral clearance, suggesting a cytokine-mediated antiviral mechanism. In accordance with our hypothesis, the ability of leukocytes to clear the virus is abrogated when explants are treated with anti-IFN-gamma neutralizing antibodies. IFN-gamma applied to infected slices in the absence of primed leukocytes reduces the viral load by more than 80%; therefore, in brain tissue, IFN-gamma is both necessary and sufficient to clear MV. Secretion of IFN-gamma is stimulated by interleukin-12 (IL-12) in the brain, as neutralization of IL-12 results in loss of antiviral activity and stimulation of leukocytes with IL-12/IL 18 enhances their immune effector function of viral clearance. MV-primed leukocytes can reduce both West Nile and mouse hepatitis viral RNAs, indicating that cytokine-mediated viral clearance occurs in an antigen-independent manner. The IFN-gamma signal is transduced within the brain explant by the Jak/STAT signaling pathway, as inhibition of Jak kinases results in a loss of antiviral activity driven by either brain-derived leukocytes or recombinant IFN-gamma. These results reveal that primed T cells directly act to clear MV infection of the brain by using a noncytolytic IL-12- and IFN-gamma-dependent mechanism in the CNS and that this mechanism relies upon Jak/STAT signaling. PMID- 21270151 TI - The transmembrane domain sequence affects the structure and function of the Newcastle disease virus fusion protein. AB - The role of specific sequences in the transmembrane (TM) domain of Newcastle disease virus (NDV) fusion (F) protein in the structure and function of this protein was assessed by replacing this domain with the F protein TM domains from two other paramyxoviruses, Sendai virus (SV) and measles virus (MV), or the TM domain of the unrelated glycoprotein (G) of vesicular stomatitis virus (VSV). Mutant proteins with the SV or MV F protein TM domains were expressed, transported to cell surfaces, and proteolytically cleaved at levels comparable to that of the wild-type protein, while mutant proteins with the VSV G protein TM domain were less efficiently expressed on cell surfaces and proteolytically cleaved. All mutant proteins were defective in all steps of membrane fusion, including hemifusion. In contrast to the wild-type protein, the mutant proteins did not form detectable complexes with the NDV hemagglutinin-neuraminidase (HN) protein. As determined by binding of conformation-sensitive antibodies, the conformations of the ectodomains of the mutant proteins were altered. These results show that the specific sequence of the TM domain of the NDV F protein is important for the conformation of the preactivation form of the ectodomain, the interactions of the protein with HN protein, and fusion activity. PMID- 21270152 TI - Assembly and replication of HIV-1 in T cells with low levels of phosphatidylinositol-(4,5)-bisphosphate. AB - HIV-1 Gag assembles into virus particles predominantly at the plasma membrane (PM). Previously, we observed that phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P(2)] is essential for Gag binding to the plasma membrane and virus release in HeLa cells. In the current study, we found that PI(4,5)P(2) also facilitates Gag binding to the PM and efficient virus release in T cells. Notably, serial passage of HIV-1 in an A3.01 clone that expresses polyphosphoinositide 5-phosphatase IV (5ptaseIV), which depletes cellular PI(4,5)P(2), yielded an adapted mutant with a Leu-to-Arg change at matrix residue 74 (74LR). Virus replication in T cells expressing 5ptaseIV was accelerated by the 74LR mutation relative to replication of wild type HIV-1 (WT). This accelerated replication of the 74LR mutant was not due to improved virus release. In control T cells, the 74LR mutant releases virus less efficiently than does the WT, whereas in cells expressing 5ptaseIV, the WT and the 74LR mutant are similarly inefficient in virus release. Unexpectedly, we found that the 74LR mutation increased virus infectivity and compensated for the inefficient virus release. Altogether, these results indicate that PI(4,5)P(2) is essential for Gag membrane binding, targeting of Gag to the PM, and efficient virus release in T cells, which in turn likely promotes efficient virus spread in T cell cultures. In T cells with low PI(4,5)P(2) levels, however, the reduced virus particle production can be compensated for by a mutation that enhances virus infectivity. PMID- 21270153 TI - Primate gammaretroviruses require an ancillary factor not required for murine gammaretroviruses to infect BHK cells. AB - BHK cells remain resistant to xenotropic murine retrovirus-related virus (XMRV) or gibbon ape leukemia virus (GALV) infection, even when their respective receptors, Xpr1 or PiT1, are expressed. We set out to determine the stage at which viral infection is blocked and whether this block is mediated by a dominant negative factor or the absence of a requisite ancillary factor. BHK cells bind neither XMRV nor GALV envelope proteins. BHK cells expressing the appropriate receptors bind XMRV or GALV envelope proteins. BHK cells can be infected by NZB XMV(New Zealand Black mouse xenotropic murine virus)-enveloped vectors, expressing an envelope derived from a xenotropic retrovirus that, like XMRV, employs Xpr1 as a receptor, and also by vectors bearing the envelope of 10A1 murine leukemia virus (MLV), a murine retrovirus that can use PiT1 as a receptor. The retroviral vectors used in these analyses differ solely in their viral envelope proteins, suggesting that the block to XMRV and GALV infection is mediated at the level of envelope-receptor interactions. N-linked glycosylation of the receptors was not found to mediate resistance of receptor-expressing BHK cells to GALV or XMRV, as shown by tunicamycin treatment and mutation of the specific glycosylation site of the PiT1 receptor. Hybrid cells produced by fusing BHKXpr1 or BHKPiT1 to XMRV- or GALV-resistant cells, respectively, can mediate efficient XMRV or GALV infection. These findings indicate that BHK cells lack a factor that is required for infection by primate xenotropic viruses. This factor is not required for viruses that use the same receptors but were directly isolated from mice. PMID- 21270154 TI - Biosynthesis of classical swine fever virus nonstructural proteins. AB - Proteolytic processing of polyproteins is considered a crucial step in the life cycle of most positive-strand RNA viruses. An enhancement of NS2-3 processing has been described as a major difference between the noncytopathogenic (non-CP) and the cytopathogenic (CP) biotypes of pestiviruses. The effects of accelerated versus delayed NS2-3 processing on the maturation of the other nonstructural proteins (NSP) have never been compared. In this study, we analyzed the proteolytic processing of NSP in Classical swine fever virus (CSFV). Key to the investigation was a panel of newly developed monoclonal antibodies (MAbs) that facilitated monitoring of all nonstructural proteins involved in virus replication (NS2, NS3, NS4A, NS5A, and NS5B). Applying these MAbs in Western blotting and radioimmunoprecipitation allowed an unambiguous identification of the mature proteins and precursors in non-CP CSFV-infected cells. Furthermore, the kinetics of processing were determined by pulse-chase analyses for non-CP CSFV, CP CSFV, and a CP CSFV replicon. A slow but constant processing of NS4A/B 5A/B occurred in non-CP CSFV-infected cells, leading to balanced low-level concentrations of mature NSP. In contrast, the turnover of the polyprotein precursors was three times faster in CP CSFV-infected cells and in cells transfected with a CP CSFV replicon, causing a substantial increase of mature NSP concentrations. We conclude that a delayed processing not only of NS3 but further of all NSP represents a hallmark of regulation in non-CP pestiviruses. PMID- 21270155 TI - Jaagsiekte sheep retrovirus infects multiple cell types in the ovine lung. AB - Ovine pulmonary adenocarcinoma (OPA) is a transmissible lung cancer of sheep caused by Jaagsiekte sheep retrovirus (JSRV). The details of early events in the pathogenesis of OPA are not fully understood. For example, the identity of the JSRV target cell in the lung has not yet been determined. Mature OPA tumors express surfactant protein-C (SP-C) or Clara cell-specific protein (CCSP), which are specific markers of type II pneumocytes or Clara cells, respectively. However, it is unclear whether these are the cell types initially infected and transformed by JSRV or whether the virus targets stem cells in the lung that subsequently acquire a differentiated phenotype during tumor growth. To examine this question, JSRV-infected lung tissue from experimentally infected lambs was studied at early time points after infection. Single JSRV-infected cells were detectable 10 days postinfection in bronchiolar and alveolar regions. These infected cells were labeled with anti-SP-C or anti-CCSP antibodies, indicating that differentiated epithelial cells are early targets for JSRV infection in the ovine lung. In addition, undifferentiated cells that expressed neither SP-C nor CCSP were also found to express the JSRV Env protein. These results enhance the understanding of OPA pathogenesis and may have comparative relevance to human lung cancer, for which samples representing early stages of tumor growth are difficult to obtain. PMID- 21270156 TI - Potent and broad neutralization of HIV-1 subtype C by plasma antibodies targeting a quaternary epitope including residues in the V2 loop. AB - The targets of broadly cross-neutralizing (BCN) antibodies are of great interest in the HIV vaccine field. We have identified a subtype C HIV-1-superinfected individual, CAP256, with high-level BCN activity, and characterized the antibody specificity mediating breadth. CAP256 developed potent BCN activity peaking at 3 years postinfection, neutralizing 32 (76%) of 42 heterologous viruses, with titers of antibodies against some viruses exceeding 1:10,000. CAP256 showed a subtype bias, preferentially neutralizing subtype C and A viruses over subtype B viruses. CAP256 BCN serum targeted a quaternary epitope which included the V1V2 region. Further mapping identified residues F159, N160, L165, R166, D167, K169, and K171 (forming the FN/LRD-K-K motif) in the V2 region as crucial to the CAP256 epitope. However, the fine specificity of the BCN response varied over time and, while consistently dependent on R166 and K169, became gradually less dependent on D167 and K171, possibly contributing to the incremental increase in breadth over 4 years. The presence of an intact FN/LRD-K-K motif in heterologous viruses was associated with sensitivity, although the length of the adjacent V1 loop modulated the degree of sensitivity, with a shorter V1 region significantly associated with higher titers. Repair of the FN/LRD-K-K motif in resistant heterologous viruses conferred sensitivity, with titers sometimes exceeding 1:10,000. Comparison of the CAP256 epitope with that of the PG9/PG16 monoclonal antibodies suggested that these epitopes overlapped, adding to the mounting evidence that this may represent a common neutralization target that should be further investigated as a potential vaccine candidate. PMID- 21270157 TI - Reproduction in vitro of a quasispecies from a hepatitis C virus-infected patient and determination of factors that influence selection of a dominant species. AB - Hepatitis C virus infections proceed to chronicity in the majority of cases. In patients, hepatitis C viruses exist as a dynamic and complex quasispecies. The dominant species at any one time arises in response to host immune pressure and other, incompletely understood factors. It is critical to understand all the mechanisms by which dominance is achieved, but this is difficult to study in vivo. Therefore, it would be useful to develop a cell culture system in which naturally occurring quasispecies could be studied. Hepatitis C virus glycoprotein genes E1 and E2 were PCR amplified as a cassette from the plasma of a chronically infected patient and shotgun cloned into a modified 1a/JFH1 infectious cDNA clone. Following transformation of bacteria, plasmids were batch harvested, transcribed, and transfected into Huh7.5 cells to produce a quasispecies of hypervariable region 1 (HVR1) that mimicked that circulating in vivo. Serial passage of the quasispecies in vitro resulted in replacement of the initially dominant species with a new HVR1 species coexisting with selected growth enhancing mutations located outside HVR1. Antibody raised against one HVR1 sequence neutralized virus with the homologous HVR1 and cross-neutralized virus with a different sequence. Reciprocal swapping of the HVR1 regions between the two dominating species demonstrated that the HVR1 sequence affects the efficiency of replication and of neutralization by anti-HVR1 but that both processes are strongly influenced by regions outside HVR1. PMID- 21270158 TI - Regulation of Nm23-H1 and cell invasiveness by Kaposi's sarcoma-associated herpesvirus. AB - The Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS), and the induction of an invasive cellular phenotype by KSHV following de novo infection is an important pathogenic component mediating tumor progression. The metastasis suppressor gene known as Nm23-H1 regulates tumor cell invasiveness, but whether KSHV itself regulates Nm23-H1 expression or subcellular localization, and whether this impacts cell invasiveness, has not been established. We found that KSHV increases expression and nuclear translocation of Nm23-H1 and that nuclear translocation of Nm23-H1 is regulated by the KSHV-encoded latency-associated nuclear antigen (LANA). Moreover, activation of the Ras-BRaf-MAPK (mitogen-activated protein kinase) signal transduction pathway, secretion of promigratory factors associated with this pathway, and cell invasiveness are dependent on KSHV regulation of Nm23-H1. Finally, induction of cytoplasmic overexpression of Nm23-H1 using a pharmacologic inhibitor of DNA methylation reduced KSHV-associated Ras-BRaf-MAPK pathway activation and suppressed KSHV-induced invasiveness. These data provide the first evidence for KSHV regulation of Nm23-H1 as a mechanism for KSHV induction of an invasive cellular phenotype and support the potential utility of targeting Nm23 H1 as a therapeutic approach for the treatment of KS. PMID- 21270159 TI - Simian immunodeficiency virus SIVmac239Deltanef vaccination elicits different Tat28-35SL8-specific CD8+ T-cell clonotypes compared to a DNA prime/adenovirus type 5 boost regimen in rhesus macaques. AB - Different human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) vaccine vectors expressing the same viral antigens can elicit disparate T-cell responses. Within this spectrum, replicating variable vaccines, like SIVmac239Deltanef, appear to generate particularly efficacious CD8(+) T-cell responses. Here, we sequenced T-cell receptor beta-chain (TRB) gene rearrangements from immunodominant Mamu-A 01-restricted Tat(28-35)SL8-specific CD8(+) T-cell populations together with the corresponding viral epitope in four rhesus macaques during acute SIVmac239Deltanef infection. Ultradeep pyrosequencing showed that viral variants arose with identical kinetics in SIVmac239Deltanef and pathogenic SIVmac239 infection. Furthermore, distinct Tat(28-35)SL8-specific T-cell receptor (TCR) repertoires were elicited by SIVmac239Deltanef compared to those observed following a DNA/Ad5 prime-boost regimen, likely reflecting differences in antigen sequence stability. PMID- 21270160 TI - Immunization with herpes simplex virus 2 (HSV-2) genes plus inactivated HSV-2 is highly protective against acute and recurrent HSV-2 disease. AB - To date, no vaccine that is safe and effective against herpes simplex virus 2 (HSV-2) disease has been licensed. In this study, we evaluated a DNA prime formalin-inactivated-HSV-2 (FI-HSV2) boost vaccine approach in the guinea pig model of acute and recurrent HSV-2 genital disease. Five groups of guinea pigs were immunized and intravaginally challenged with HSV-2. Two groups were primed with plasmid DNAs encoding the secreted form of glycoprotein D2 (gD2t) together with two genes required for viral replication, either the helicase (UL5) and DNA polymerase (UL30) genes or the single-stranded DNA binding protein (UL29) and primase (UL52) genes. Both DNA-primed groups were boosted with FI-HSV2 formulated with monophosphoryl lipid A (MPL) and alum adjuvants. Two additional groups were primed with the empty backbone plasmid DNA (pVAX). These two groups were boosted with MPL and alum (MPL-alum) together with either formalin-inactivated mock HSV-2 (FI-Mock) or with FI-HSV2. The final group was immunized with gD2t protein in MPL alum. After challenge, 0/9 animals in the group primed with UL5, UL30, and gD2t DNAs and all 10 animals in the mock-immunized control group (pVAX-FI-Mock) developed primary lesions. All mock controls developed recurrent lesions through day 100 postchallenge. Only 1 guinea pig in the group primed with pVAX DNA and boosted with FI-HSV2 (pVAX-FI-HSV2 group) and 2 guinea pigs in the group primed with UL5, UL30, and gD2t DNAs and boosted with FI-HSV2 (UL5, UL30, gD2t DNA-FI HSV2 group) developed recurrent lesions. Strikingly, the UL5, UL30, gD2t DNA-FI HSV2 group showed a 97% reduction in recurrent lesion days compared with the mock controls, had the highest reduction in days with recurrent disease, and contained the lowest mean HSV-2 DNA load in the dorsal root ganglia. PMID- 21270161 TI - Bovine viral diarrhea virus strain- and cell type-specific inhibition of type I interferon pathways. PMID- 21270162 TI - The measles virus V protein binds to p65 (RelA) to suppress NF-kappaB activity. AB - Nuclear factor kappaB (NF-kappaB) transcription factors are involved in controlling numerous cellular processes, including inflammation, innate and adaptive immunity, and cell survival. Here we show that the immunosuppressive measles virus (MV; Morbillivirus genus, Paramyxoviridae) has evolved multiple functions to interfere with canonical NF-kappaB signaling in epithelial cells. The MV P, V, and C proteins, also involved in preventing host cell interferon responses, were found to individually suppress NF-kappaB-dependent reporter gene expression in response to activation of the tumor necrosis factor (TNF) receptor, RIG-I-like receptors, or Toll-like receptors. NF-kappaB activity was most efficiently suppressed in the presence of V, while expression of P or C resulted in moderate inhibition. As indicated by reporter gene assays involving overexpression of the IkappaB kinase (IKK) complex, which phosphorylates the inhibitor of kappaB to liberate NF-kappaB, V protein targets a downstream step in the signaling cascade. Coimmunoprecipitation experiments revealed that V specifically binds to the Rel homology domain of the NF-kappaB subunit p65 but not of p50. Notably, the short C-terminal domain of the V protein, which is also involved in binding STAT2, IRF7, and MDA5, was sufficient for the interaction and for preventing reporter gene activity. As observed by confocal microscopy, the presence of V abolished nuclear translocation of p65 upon TNF-alpha stimulation. Thus, MV V appears to prevent NF-kappaB-dependent gene expression by retaining p65 in the cytoplasm. These findings reveal NF-kappaB as a key target of MV and stress the importance of the V protein as the major viral immune-modulatory factor. PMID- 21270163 TI - Variations of coxsackievirus B3 capsid primary structure, ligands, and stability are selected for in a coxsackievirus and adenovirus receptor-limited environment. AB - While group B coxsackieviruses (CVB) use the coxsackievirus and adenovirus receptor (CAR) as the receptor through which they infect susceptible cells, some CVB strains are known for their acquired capacity to bind other molecules. The CVB3/RD strain that emerged from a CVB3/Nancy population sequentially passaged in the CAR-poor RD cell line binds decay-accelerating factor (DAF) (CD55) and CAR. A new strain, CVB3/RDVa, has been isolated from RD cells chronically infected with CVB3/RD and binds multiple molecules in addition to DAF and CAR. The capsid proteins of CVB3/RD differ from those of CVB3/28, a cloned strain that binds only CAR, by only four amino acids, including a glutamate/glutamine dimorphism in the DAF-binding region of the capsid. The capsid proteins of CVB3/RD and CVB3/RDVa differ by seven amino acids. The ability of CVB3/RDVa to bind ligands in addition to CAR and DAF may be attributed to lysine residues near the icosahedral 5-fold axes of symmetry. Considered with differences in the stability of the CVB3 strains, these traits suggest that in vitro selection in a CAR-limited environment selects for virus populations that can associate with molecules on the cell surface and survive until CAR becomes available to support infection. PMID- 21270164 TI - Chromatin reassembly factors are involved in transcriptional interference promoting HIV latency. AB - The establishment of a stable reservoir of latently infected cells allows HIV to persist in the host. Usually, HIV infection of T cells results in integration of the viral genome, with a preference for regions in the human genome containing active genes, viral expression, and production of new viruses. However, in rare cases T cells become latently infected, and this is presumed to be due to a combination of two factors: integrated viruses are not efficiently transcribed and infected T cells revert to a resting memory state. HIV latency has been associated with provirus integration in regions of constitutive heterochromatin, gene deserts, or very highly expressed genes. We have investigated the transcriptional consequences of latent HIV integration into cellular genes and the involvement of chromatin reassembly factors (CRFs) in the transcriptional interference that a host gene exerts on the integrated cryptic HIV promoter. Chimeric transcripts containing sequences from the host gene and HIV can be detected, having been initiated at promoters of either the cell or the virus. Reactivation of HIV downregulates host gene expression. Cryptic promoters might remain inactive due to the repressive chromatin configuration established by CRFs during transcription elongation. Depletion of CRFs such as Spt6, Chd1, and FACT, or the histone chaperones ASF1a and HIRA, promoted HIV reactivation, concomitantly with chromatin relaxation and a decrease in general RNA polymerase activity. Overall, our results indicate that CRFs play a role in maintaining HIV latency by transcriptional interference when the provirus is integrated into an intron of a highly active gene. PMID- 21270165 TI - Replication of avocado sunblotch viroid in the yeast Saccharomyces cerevisiae. AB - Viroids are the smallest known pathogenic agents. They are noncoding, single stranded, closed-circular, "naked" RNAs, which replicate through RNA-RNA transcription. Viroids of the Avsunviroidae family possess a hammerhead ribozyme in their sequence, allowing self-cleavage during their replication. To date, viroids have only been detected in plant cells. Here, we investigate the replication of Avocado sunblotch viroid (ASBVd) of the Avsunviroidae family in a nonconventional host, the yeast Saccharomyces cerevisiae. We demonstrate that ASBVd RNA strands of both polarities are able to self-cleave and to replicate in a unicellular eukaryote cell. We show that the viroid monomeric RNA is destabilized by the nuclear 3' and the cytoplasmic 5' RNA degradation pathways. For the first time, our results provide evidence that viroids can replicate in other organisms than plants and that yeast contains all of the essential cellular elements for the replication of ASBVd. PMID- 21270166 TI - Differences in HIV-specific T cell responses between HIV-exposed and -unexposed HIV-seronegative individuals. AB - HIV-1-specific T lymphocyte responses in individuals exposed to HIV-1 but who remain persistently seronegative (HESNs) have been reported in some but not all previous studies. This study was designed to resolve unequivocally the question of whether HESNs make HIV-1-specific T cell responses. We performed a blind investigation to measure HIV-1-specific T cell responses in both HIV-1 serodiscordant couples and HIV-1-unexposed seronegative controls (HUSNs). We found low-frequency HIV-1-specific T cells in both HESNs and HUSNs but show that the response rates were higher over time in the former (P = 0.01). Furthermore, the magnitudes of the HIV-1-specific T cell responses were significantly higher among responding HESNs than among HUSNs over time (P = 0.002). In both groups, responses were mediated by CD4 T cells. The responses were mapped to single peptides, which often corresponded to epitopes restricted by multiple HLA-DR types that have previously been detected in HIV-1-infected patients. HIV-1 specific T cell responses in HUSNs and some HESNs likely represent cross reactivity to self or foreign non-HIV-1 antigens. The significantly greater T cell responses in HESNs, including in two who were homozygous for CCR5Delta32, demonstrates that HIV-1-specific T cell responses can be induced or augmented by exposure to HIV-1 without infection. PMID- 21270167 TI - The TY3 Gag3 spacer controls intracellular condensation and uncoating. AB - Cells expressing the yeast retrotransposon Ty3 form concentrated foci of Ty3 proteins and RNA within which virus-like particle (VLP) assembly occurs. Gag3, the major structural protein of the Ty3 retrotransposon, is composed of capsid (CA), spacer (SP), and nucleocapsid (NC) domains analogous to retroviral domains. Unlike the known SP domains of retroviruses, Ty3 SP is highly acidic. The current studies investigated the role of this domain. Although deletion of Ty3 SP dramatically reduced retrotransposition, significant Gag3 processing and cDNA synthesis occurred. Mutations that interfered with cleavage at the SP-NC junction disrupted CA-SP processing, cDNA synthesis, and electron-dense core formation. Mutations that interfered with cleavage of CA-SP allowed cleavage of the SP-NC junction, production of electron-dense cores, and cDNA synthesis but blocked retrotransposition. A mutant in which acidic residues of SP were replaced with alanine failed to form both Gag3 foci and VLPs. We propose a speculative "spring" model for Gag3 during assembly. In the first phase during concentration of Gag3 into foci, intramolecular interactions between negatively charged SP and positively charged NC domains of Gag3 limit multimerization. In the second phase, the NC domain binds RNA, and the bound form is stabilized by intermolecular interactions with the SP domain. These interactions promote CA domain multimerization. In the third phase, a negatively charged SP domain destabilizes the remaining CA-SP shell for cDNA release. PMID- 21270168 TI - Differential sensitivities of retroviruses to integrase strand transfer inhibitors. AB - Integrase inhibitors are emerging anti-human immunodeficiency virus (HIV) drugs, and multiple retroviruses and transposable elements were evaluated here for susceptibilities to raltegravir (RAL) and elvitegravir (EVG). All viruses, including primate and nonprimate lentiviruses, a Betaretrovirus, a Gammaretrovirus, and the Alpharetrovirus Rous sarcoma virus (RSV), were susceptible to inhibition by RAL. EVG potently inhibited all lentiviruses and intermediately inhibited Betaretrovirus and Gammaretrovirus infections yet was basically ineffective against RSV. Substitutions based on HIV type 1 (HIV-1) resistance changes revealed that integrase residue Ser150 contributed significantly to the resistance of RSV. The drugs intermediately inhibited intracisternal A-particle retrotransposition but were inactive against Sleeping Beauty transposition and long interspersed nucleotide element 1 (LINE-1) retrotransposition. PMID- 21270169 TI - Transcriptionally abundant major histocompatibility complex class I alleles are fundamental to nonhuman primate simian immunodeficiency virus-specific CD8+ T cell responses. AB - Simian immunodeficiency virus (SIV)-infected macaques are the preferred animal model for human immunodeficiency virus (HIV) vaccines that elicit CD8(+) T cell responses. Unlike humans, whose CD8(+) T cell responses are restricted by a maximum of six HLA class I alleles, macaques express up to 20 distinct major histocompatibility complex class I (MHC-I) sequences. Interestingly, only a subset of macaque MHC-I sequences are transcriptionally abundant in peripheral blood lymphocytes. We hypothesized that highly transcribed MHC-I sequences are principally responsible for restricting SIV-specific CD8(+) T cell responses. To examine this hypothesis, we measured SIV-specific CD8(+) T cell responses in MHC I homozygous Mauritian cynomolgus macaques. Each of eight CD8(+) T cell responses defined by full-proteome gamma interferon (IFN-gamma) enzyme-linked immunospot (ELISPOT) assay were restricted by four of the five transcripts that are transcriptionally abundant (>1% of total MHC-I transcripts in peripheral blood lymphocytes). The five transcriptionally rare transcripts shared by these animals did not restrict any detectable CD8(+) T cell responses. Further, seven CD8(+) T cell responses were defined by identifying peptide binding motifs of the three most frequent MHC-I transcripts on the M3 haplotype. Combined, these results suggest that transcriptionally abundant MHC-I transcripts are principally responsible for restricting SIV-specific CD8(+) T cell responses. Thus, only a subset of the thousands of known MHC-I alleles in macaques should be prioritized for CD8(+) T cell epitope characterization. PMID- 21270170 TI - Identification of a small-molecule entry inhibitor for filoviruses. AB - Ebola virus (EBOV) causes severe hemorrhagic fever, for which therapeutic options are not available. Preventing the entry of EBOV into host cells is an attractive antiviral strategy, which has been validated for HIV by the FDA approval of the anti-HIV drug enfuvirtide. To identify inhibitors of EBOV entry, the EBOV envelope glycoprotein (EBOV-GP) gene was used to generate pseudotype viruses for screening of chemical libraries. A benzodiazepine derivative (compound 7) was identified from a high-throughput screen (HTS) of small-molecule compound libraries utilizing the pseudotype virus. Compound 7 was validated as an inhibitor of infectious EBOV and Marburg virus (MARV) in cell-based assays, with 50% inhibitory concentrations (IC(50)s) of 10 MUM and 12 MUM, respectively. Time of-addition and binding studies suggested that compound 7 binds to EBOV-GP at an early stage during EBOV infection. Preliminary Schrodinger SiteMap calculations, using a published EBOV-GP crystal structure in its prefusion conformation, suggested a hydrophobic pocket at or near the GP1 and GP2 interface as a suitable site for compound 7 binding. This prediction was supported by mutational analysis implying that residues Asn69, Leu70, Leu184, Ile185, Leu186, Lys190, and Lys191 are critical for the binding of compound 7 and its analogs with EBOV-GP. We hypothesize that compound 7 binds to this hydrophobic pocket and as a consequence inhibits EBOV infection of cells, but the details of the mechanism remain to be determined. In summary, we have identified a novel series of benzodiazepine compounds that are suitable for optimization as potential inhibitors of filoviral infection. PMID- 21270171 TI - LEDGF dominant interference proteins demonstrate prenuclear exposure of HIV-1 integrase and synergize with LEDGF depletion to destroy viral infectivity. AB - Target cell overexpression of the integrase binding domain (IBD) of LEDGF/p75 (LEDGF) inhibits HIV-1 replication. The mechanism and protein structure requirements for this dominant interference are unclear. More generally, how and when HIV-1 uncoating occurs postentry is poorly defined, and it is unknown whether integrase within the evolving viral core becomes accessible to cellular proteins prior to nuclear entry. We used LEDGF dominant interference to address the latter question while characterizing determinants of IBD antiviral activity. Fusions of green fluorescent protein (GFP) with multiple C-terminal segments of LEDGF inhibited HIV-1 replication substantially, but minimal chimeras of either polarity (GFP-IBD or IBD-GFP) were most effective. Combining GFP-IBD expression with LEDGF depletion was profoundly antiviral. CD4(+) T cell lines were rendered virtually uninfectable, with single-cycle HIV-1 infectivity reduced 4 logs and high-input (multiplicity of infection = 5.0) replication completely blocked. We restricted GFP-IBD to specific intracellular locations and found that antiviral activity was preserved when the protein was confined to the cytoplasm or directed to the nuclear envelope. The life cycle block triggered by the cytoplasm restricted protein manifested after nuclear entry, at the level of integration. We conclude that integrase within the viral core becomes accessible to host cell protein interaction in the cytoplasm. LEDGF dominant interference and depletion impair HIV-1 integration at distinct postentry stages. GFP-IBD may trigger premature or improper integrase oligomerization. PMID- 21270173 TI - Incomplete lineage sorting patterns among human, chimpanzee, and orangutan suggest recent orangutan speciation and widespread selection. AB - We search the complete orangutan genome for regions where humans are more closely related to orangutans than to chimpanzees due to incomplete lineage sorting (ILS) in the ancestor of human and chimpanzees. The search uses our recently developed coalescent hidden Markov model (HMM) framework. We find ILS present in ~1% of the genome, and that the ancestral species of human and chimpanzees never experienced a severe population bottleneck. The existence of ILS is validated with simulations, site pattern analysis, and analysis of rare genomic events. The existence of ILS allows us to disentangle the time of isolation of humans and orangutans (the speciation time) from the genetic divergence time, and we find speciation to be as recent as 9-13 million years ago (Mya; contingent on the calibration point). The analyses provide further support for a recent speciation of human and chimpanzee at ~4 Mya and a diverse ancestor of human and chimpanzee with an effective population size of about 50,000 individuals. Posterior decoding infers ILS for each nucleotide in the genome, and we use this to deduce patterns of selection in the ancestral species. We demonstrate the effect of background selection in the common ancestor of humans and chimpanzees. In agreement with predictions from population genetics, ILS was found to be reduced in exons and gene-dense regions when we control for confounding factors such as GC content and recombination rate. Finally, we find the broad-scale recombination rate to be conserved through the complete ape phylogeny. PMID- 21270172 TI - Directed networks reveal genomic barriers and DNA repair bypasses to lateral gene transfer among prokaryotes. AB - Lateral gene transfer (LGT) plays a major role in prokaryote evolution with only a few genes that are resistant to it; yet the nature and magnitude of barriers to lateral transfer are still debated. Here, we implement directed networks to investigate donor-recipient events of recent lateral gene transfer among 657 sequenced prokaryote genomes. For 2,129,548 genes investigated, we detected 446,854 recent lateral gene transfer events through nucleotide pattern analysis. Among these, donor-recipient relationships could be specified through phylogenetic reconstruction for 7% of the pairs, yielding 32,028 polarized recent gene acquisition events, which constitute the edges of our directed networks. We find that the frequency of recent LGT is linearly correlated both with genome sequence similarity and with proteome similarity of donor-recipient pairs. Genome sequence similarity accounts for 25% of the variation in gene-transfer frequency, with proteome similarity adding only 1% to the variability explained. The range of donor-recipient GC content similarity within the network is extremely narrow, with 86% of the LGTs occurring between donor-recipient pairs having <=5% difference in GC content. Hence, genome sequence similarity and GC content similarity are strong barriers to LGT in prokaryotes. But they are not insurmountable, as we detected 1530 recent transfers between distantly related genomes. The directed network revealed that recipient genomes of distant transfers encode proteins of nonhomologous end-joining (NHEJ; a DNA repair mechanism) far more frequently than the recipient lacking that mechanism. This implicates NHEJ in genes spread across distantly related prokaryotes through bypassing the donor-recipient sequence similarity barrier. PMID- 21270174 TI - Insulin degludec in type 1 diabetes: a randomized controlled trial of a new generation ultra-long-acting insulin compared with insulin glargine. AB - OBJECTIVE: Insulin degludec (IDeg) is a basal insulin that forms soluble multihexamers after subcutaneous injection, resulting in an ultra-long action profile. We assessed the efficacy and safety of IDeg formulations administered once daily in combination with mealtime insulin aspart in people with type 1 diabetes. RESEARCH DESIGN AND METHODS: In this 16-week, randomized, open-label trial, participants (mean: 45.8 years old, A1C 8.4%, fasting plasma glucose [FPG] 9.9 mmol/L, BMI 26.9 kg/m(2)) received subcutaneous injections of IDeg(A) (600 MUmol/L; n = 59), IDeg(B) (900 MUmol/L; n = 60), or insulin glargine (IGlar; n = 59), all given once daily in the evening. Insulin aspart was administered at mealtimes. RESULTS At 16 weeks, mean A1C was comparable for IDeg(A) (7.8 +/- 0.8%), IDeg(B) (8.0 +/- 1.0%), and IGlar (7.6 +/- 0.8%), as was FPG (8.3 +/- 4.0, 8.3 +/- 2.8, and 8.9 +/- 3.5 mmol/L, respectively). Estimated mean rates of confirmed hypoglycemia were 28% lower for IDeg(A) compared with IGlar (rate ratio [RR]: 0.72 [95% CI 0.52-1.00]) and 10% lower for IDeg(B) compared with IGlar (RR: 0.90 [0.65-1.24]); rates of nocturnal hypoglycemia were 58% lower for IDeg(A) (RR: 0.42 [0.25-0.69]) and 29% lower for IDeg(B) (RR: 0.71 [0.44-1.16]). Mean total daily insulin dose was similar to baseline. The frequency and pattern of adverse events was similar between insulin treatments. CONCLUSIONS: In this clinical exploratory phase 2 trial in people with type 1 diabetes, IDeg is safe and well tolerated and provides comparable glycemic control to IGlar at similar doses, with reduced rates of hypoglycemia. PMID- 21270175 TI - Type 2 diabetes: uses of thiazolidinediones and insulin. PMID- 21270176 TI - Glycemic response to ingested dreamfields pasta compared with traditional pasta. PMID- 21270177 TI - HDL dysfunctionality (Paraoxonase) is worse in nondiabetic, postmenopausal African American than in white women. PMID- 21270178 TI - Comment on: Zhang et al. A1C level and future risk of diabetes: a systematic review. Diabetes Care 2010;33:1665-1673. PMID- 21270180 TI - Comment on: Luijf et al. Premeal Injection of rapid-acting insulin reduces postprandial glycemic excursions in type 1 diabetes. Diabetes Care 2010;33:2152 2155. PMID- 21270182 TI - The DURAbility of Basal versus Lispro mix 75/25 insulin Efficacy (DURABLE) trial: comparing the durability of lispro mix 75/25 and glargine. AB - OBJECTIVE: This study compared the durability of glycemic control of twice-daily insulin lispro mix 75/25 (LM75/25: 75% insulin lispro protamine suspension/25% lispro) and once-daily insulin glargine, added to oral antihyperglycemic drugs in type 2 diabetes patients. RESEARCH DESIGN AND METHODS: During the initiation phase, patients were randomized to LM75/25 or glargine. After 6 months, patients with A1C <= 7.0% advanced to the maintenance phase for <= 24 months. The primary objective was the between-group comparison of duration of maintaining the A1C goal. RESULTS: Of 900 patients receiving LM75/25 and 918 patients receiving glargine who completed initiation, 473 and 419, respectively, had A1C <= 7.0% and continued into maintenance. Baseline characteristics except age were similar in this group. Median time of maintaining the A1C goal was 16.8 months for LM75/25 (95% CI 14.0-19.7) and 14.4 months for glargine (95% CI 13.4-16.8; P = 0.040). A1C goal was maintained in 202 LM75/25-treated patients (43%) and in 147 glargine treated patients (35%; P = 0.006). No differences were observed in overall, nocturnal, or severe hypoglycemia. LM75/25 patients had higher total daily insulin dose (0.45 +/- 0.21 vs. 0.37 +/- 0.21 units/kg/day) and more weight gain (5.4 +/- 5.8 vs. 3.7 +/- 5.6 kg) from baseline. Patients taking LM75/25 and glargine with lower baseline A1C levels were more likely to maintain the A1C goal (P = 0.043 and P < 0.001, respectively). CONCLUSIONS: A modestly longer durability of glycemic control was achieved with LM75/25 compared with glargine. Patients with lower baseline A1C levels were more likely to maintain the goal, supporting the concept of earlier insulin initiation. PMID- 21270183 TI - Structured self-monitoring of blood glucose significantly reduces A1C levels in poorly controlled, noninsulin-treated type 2 diabetes: results from the Structured Testing Program study. AB - OBJECTIVE: To assess the effectiveness of structured blood glucose testing in poorly controlled, noninsulin-treated type 2 diabetes. RESEARCH DESIGN AND METHODS: This 12-month, prospective, cluster-randomized, multicenter study recruited 483 poorly controlled (A1C >= 7.5%), insulin-naive type 2 diabetic subjects from 34 primary care practices in the U.S. Practices were randomized to an active control group (ACG) with enhanced usual care or a structured testing group (STG) with enhanced usual care and at least quarterly use of structured self-monitoring of blood glucose (SMBG). STG patients and physicians were trained to use a paper tool to collect/interpret 7-point glucose profiles over 3 consecutive days. The primary end point was A1C level measured at 12 months. RESULTS: The 12-month intent-to-treat analysis (ACG, n = 227; STG, n = 256) showed significantly greater reductions in mean (SE) A1C in the STG compared with the ACG: -1.2% (0.09) vs. -0.9% (0.10); Delta = -0.3%; P = 0.04. Per protocol analysis (ACG, n = 161; STG, n = 130) showed even greater mean (SE) A1C reductions in the STG compared with the ACG: -1.3% (0.11) vs. -0.8% (0.11); Delta = -0.5%; P < 0.003. Significantly more STG patients received a treatment change recommendation at the month 1 visit compared with ACG patients, regardless of the patient's initial baseline A1C level: 179 (75.5%) vs. 61 (28.0%); <0.0001. Both STG and ACG patients displayed significant (P < 0.0001) improvements in general well-being (GWB). CONCLUSIONS: Appropriate use of structured SMBG significantly improves glycemic control and facilitates more timely/aggressive treatment changes in noninsulin-treated type 2 diabetes without decreasing GWB. PMID- 21270184 TI - Glycemic control and health disparities in older ethnically diverse underserved adults with diabetes: five-year results from the Informatics for Diabetes Education and Telemedicine (IDEATel) study. AB - OBJECTIVE: The Informatics for Diabetes Education and Telemedicine (IDEATel) project randomized ethnically diverse underserved older adults with diabetes to a telemedicine intervention or usual care. Intervention participants had lower A1C levels over 5 years. New analyses were performed to help better understand this difference. RESEARCH DESIGN AND METHODS: IDEATel randomized Medicare beneficiaries with diabetes (n = 1,665) to receive home video visits with a diabetes educator and upload glucose levels every 4-6 weeks or usual care (2000 2007). Annual measurements included BMI, A1C (primary outcome), and completion of questionnaires. Mixed-model analyses were performed using random effects to adjust for clustering within primary care physicians. RESULTS: At baseline, A1C levels (mean +/- SD) were 7.02 +/- 1.25% in non-Hispanic whites (n = 821), 7.58 +/- 1.78% in non-Hispanic blacks (n = 248), and 7.79 +/- 1.68% in Hispanics (n = 585). Over time, lower A1C levels were associated with more glucose uploads (P = 0.02) and female sex (P = 0.002). Blacks, Hispanics, and insulin-users had higher A1C levels than non-Hispanic whites (P < 0.0001). BMI was not associated with A1C levels. Blacks and Hispanics had significantly fewer uploads than non-Hispanic whites over time. Hispanics had the highest baseline A1C levels and showed the greatest improvement in the intervention, but, unlike non-Hispanic whites, Hispanics did not achieve A1C levels <7.0% at 5 years. CONCLUSIONS: Racial/ethnic disparities were observed in this cohort of underserved older adults with diabetes. The IDEATel telemedicine intervention was associated with improvement in glycemic control, particularly in Hispanics, who had the highest baseline A1C levels, suggesting that telemedicine has the potential to help reduce disparities in diabetes management. PMID- 21270186 TI - Urinary C-peptide creatinine ratio is a practical outpatient tool for identifying hepatocyte nuclear factor 1-{alpha}/hepatocyte nuclear factor 4-{alpha} maturity onset diabetes of the young from long-duration type 1 diabetes. AB - OBJECTIVE: Hepatocyte nuclear factor 1-alpha (HNF1A)/hepatocyte nuclear factor 4 alpha (HNF4A) maturity-onset diabetes of the young (MODY) is frequently misdiagnosed as type 1 diabetes, and patients are inappropriately treated with insulin. Blood C-peptide can aid in the diagnosis of MODY, but practical reasons limit its widespread use. Urinary C-peptide creatinine ratio (UCPCR), a stable measure of endogenous insulin secretion, is a noninvasive alternative. We aimed to compare stimulated UCPCR in adults with HNF1A/4A MODY, type 1 diabetes, and type 2 diabetes. RESEARCH DESIGN AND METHODS: Adults with diabetes for >= 5 years, without renal impairment, were studied (HNF1A MODY [n = 54], HNF4A MODY [n = 23], glucokinase MODY [n = 20], type 1 diabetes [n = 69], and type 2 diabetes [n = 54]). The UCPCR was collected in boric acid 120 min after the largest meal of the day and mailed for analysis. Receiver operating characteristic (ROC) curves were used to identify optimal UCPCR cutoffs to differentiate HNF1A/4A MODY from type 1 and type 2 diabetes. RESULTS: UCPCR was lower in type 1 diabetes than HNF1A/4A MODY (median [interquartile range]) (<0.02 nmol/mmol [<0.02 to <0.02] vs. 1.72 nmol/mmol [0.98-2.90]; P < 0.0001). ROC curves showed excellent discrimination (area under curve [AUC] 0.98) and identified a cutoff UCPCR of >= 0.2 nmol/mmol for differentiating HNF1A/4A MODY from type 1 diabetes (97% sensitivity, 96% specificity). UCPCR was lower in HNF1A/4A MODY than in type 2 diabetes (1.72 nmol/mmol [0.98-2.90] vs. 2.47 nmol/mmol [1.4-4.13]); P = 0.007). ROC curves showed a weak distinction between HNF1A/4A MODY and type 2 diabetes (AUC 0.64). CONCLUSIONS: UCPCR is a noninvasive outpatient tool that can be used to discriminate HNF1A and HNF4A MODY from long-duration type 1 diabetes. To differentiate MODY from type 1 diabetes of >5 years' duration, UCPCR could be used to determine whether genetic testing is indicated. PMID- 21270187 TI - Breastfeeding in women with type 1 diabetes: exploration of predictive factors. AB - OBJECTIVE: To identify predictive factors for initiation and maintenance of breastfeeding with a focus on mothers with type 1 diabetes. RESEARCH DESIGN AND METHODS: This is a prospective observation survey, using a case-control design, comparing the outcomes of 108 mothers with type 1 diabetes with 104 mothers without diabetes that were matched for parity and gestational age. Mother and infant outcomes were collected from medical records and through telephone interviews 2 and 6 months after delivery. Predictive factors were calculated by logistic regression analyses. RESULTS: Mothers with diabetes were less likely to partly or exclusively breastfeed their children at 2 months (OR 0.42 [95% CI 0.18 0.96], P = 0.041) and 6 months (0.50 [0.27-0.90], P = 0.022) than mothers without diabetes. On multivariable analysis, type 1 diabetes did not remain an independent predictive factor. Instead, higher education level and breastfeeding at discharge from hospital were predictive factors for breastfeeding at 2 months postpartum. These variables as well as delivery >37 weeks and early breastfeeding predicted breastfeeding 6 months postpartum. CONCLUSIONS: Factors associated with maternal diabetes, such as problems with establishing breastfeeding in the early postpartum period, affects the likelihood of long-term breastfeeding. PMID- 21270185 TI - Low-dose aspirin therapy in patients with type 2 diabetes and reduced glomerular filtration rate: subanalysis from the JPAD trial. AB - OBJECTIVE: Type 2 diabetes accompanied by renal damage is a strong risk factor for atherosclerotic events. The purpose of this study was to investigate the efficacy of low-dose aspirin therapy on primary prevention of atherosclerotic events in patients with type 2 diabetes and coexisting renal dysfunction. RESEARCH DESIGN AND METHODS: The Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) trial was a prospective, randomized, open-label trial conducted throughout Japan that enrolled 2,539 type 2 diabetic patients without a history of atherosclerotic diseases. Patients were assigned to the aspirin group (81 mg/day or 100 mg/day) or the nonaspirin group and followed for a median of 4.37 years. The primary end points were atherosclerotic events of fatal and nonfatal ischemic heart disease, stroke, and peripheral arterial disease. RESULTS: The analysis included 2,523 patients who had serum creatinine measured. In 1,373 patients with baseline estimated glomerular filtration rate (eGFR) 60-89 mL/min/1.73 m(2), the incidence of primary end points was significantly lower in the aspirin group than in the nonaspirin group (aspirin, 30/661; nonaspirin, 55/712; hazard ratio 0.57 [95% CI 0.36-0.88]; P = 0.011). Low dose aspirin therapy did not reduce primary end points in patients with eGFR >= 90 mL/min/1.73 m(2) (aspirin, 9/248; nonaspirin, 11/270; 0.94 [0.38-2.3]) or those with eGFR <60 mL/min/1.73 m(2) (aspirin, 29/342; nonaspirin, 19/290; 1.3 [0.76-2.4]). The Cox proportional hazard model demonstrated a significant interaction between mild renal dysfunction (eGFR 60-89 mL/min/1.73 m(2)) and aspirin (P = 0.02). CONCLUSIONS: These results suggest a differential effect of low-dose aspirin therapy in diabetic patients with eGFR 60-89 mL/min/1.73 m(2). PMID- 21270188 TI - Improved glycemic control without hypoglycemia in elderly diabetic patients using the ubiquitous healthcare service, a new medical information system. AB - OBJECTIVE: To improve quality and efficiency of care for elderly patients with type 2 diabetes, we introduced elderly-friendly strategies to the clinical decision support system (CDSS)-based ubiquitous healthcare (u-healthcare) service, which is an individualized health management system using advanced medical information technology. RESEARCH DESIGN AND METHODS: We conducted a 6 month randomized, controlled clinical trial involving 144 patients aged >60 years. Participants were randomly assigned to receive routine care (control, n = 48), to the self-monitored blood glucose (SMBG, n = 47) group, or to the u healthcare group (n = 49). The primary end point was the proportion of patients achieving A1C <7% without hypoglycemia at 6 months. U-healthcare system refers to an individualized medical service in which medical instructions are given through the patient's mobile phone. Patients receive a glucometer with a public switched telephone network-connected cradle that automatically transfers test results to a hospital-based server. Once the data are transferred to the server, an automated system, the CDSS rule engine, generates and sends patient-specific messages by mobile phone. RESULTS: After 6 months of follow-up, the mean A1C level was significantly decreased from 7.8 +/- 1.3% to 7.4 +/- 1.0% (P < 0.001) in the u healthcare group and from 7.9 +/- 1.0% to 7.7 +/- 1.0% (P = 0.020) in the SMBG group, compared with 7.9 +/- 0.8% to 7.8 +/- 1.0% (P = 0.274) in the control group. The proportion of patients with A1C <7% without hypoglycemia was 30.6% in the u-healthcare group, 23.4% in the SMBG group (23.4%), and 14.0% in the control group (P < 0.05). CONCLUSIONS: The CDSS-based u-healthcare service achieved better glycemic control with less hypoglycemia than SMBG and routine care and may provide effective and safe diabetes management in the elderly diabetic patients. PMID- 21270189 TI - Weight-related quality of life, health utility, psychological well-being, and satisfaction with exenatide once weekly compared with sitagliptin or pioglitazone after 26 weeks of treatment. AB - OBJECTIVE: To assess change in patient-reported outcomes in subjects with type 2 diabetes treated with exenatide once weekly compared with those treated with sitagliptin or pioglitazone. RESEARCH DESIGN AND METHODS: In this 26-week randomized, multicenter, double-dummy study, 491 subjects received 2 mg of exenatide once weekly or maximum daily doses of sitagliptin (100 mg) or pioglitazone (45 mg) on a background of metformin. Weight-related quality of life, health utility, psychological well-being, and diabetes treatment satisfaction were assessed at baseline and week 26. Mean group changes from baseline to week 26 were estimated by ANCOVA. RESULTS: Weight-related quality of life total scores improved significantly in the exenatide once weekly and sitagliptin arms only; the exenatide once weekly group experienced significantly greater improvement than the pioglitazone group in weight-related quality of life total scores and in several domain scores. Health utility scores improved significantly for exenatide once weekly and sitagliptin groups (P < 0.05) with no significant difference between the exenatide once weekly group and either comparison group. All groups experienced significant improvements on the psychological well-being global scale and all six domain scores, with no significant difference between the exenatide once weekly group and either comparator. All groups experienced significant improvements in total diabetes treatment satisfaction scores. The exenatide once weekly group experienced greater improvement than the sitagliptin group in treatment satisfaction total scores. CONCLUSIONS: In combination with clinical outcomes from this study, these results indicate it is possible for patients treated with metformin to initiate exenatide therapy with potential benefits in both clinical and patient-reported outcomes. PMID- 21270190 TI - Improvement in sexual functioning in patients with type 2 diabetes and depression treated with bupropion. AB - OBJECTIVE: Major depressive disorder (MDD) and type 2 diabetes have independent adverse effects on sexual functioning (SF). Bupropion (BU) reportedly has few sexual side effects, but its use in diabetes has not been studied. RESEARCH DESIGN AND METHODS: This article reports a planned secondary analysis of SF in 90 patients with type 2 diabetes treated with BU for MDD. RESULTS: At baseline, 71.1% of patients had insufficient SF. Mean Sexual Energy Scale (SES) scores improved during treatment (P < 0.0001), as did the percentage with sufficient SF (30.6 vs. 68.1%, P = 0.001). Patients with persistent hyperglycemia had higher rates of sexual dysfunction; however, SES improvement was evident in some with persistent depression or hyperglycemia (18.2% and 25.9%, respectively). CONCLUSIONS: Insufficient SF is prevalent and may be suspected in patients with MDD and type 2 diabetes. BU treatment of MDD had few sexual side effects and was associated with significant improvements in SF. PMID- 21270191 TI - Illness and treatment perceptions are associated with adherence to medications, diet, and exercise in diabetic patients. AB - OBJECTIVE: To investigate diabetic patients' perceptions of illness and treatments, and explore relationships to adherence and blood glucose control. RESEARCH DESIGN AND METHODS: Forty-nine type 1 and one hundred and eight type 2 diabetic patients completed questionnaires assessing illness perceptions, treatment beliefs, and adherence to medications, diet, and exercise. Blood glucose control was assessed from blood tests. RESULTS: Patients rated medication more important than diet and exercise, and reported higher adherence to medications. Insulin was perceived as more helpful for diabetes, while antihypertensives and cholesterol medication were perceived more helpful for preventing heart problems. Perceptions were associated with adherence to insulin, cholesterol and antihypertensive medications, exercise, and diet. Blood glucose control in type 1 diabetic patients was associated with insulin adherence and perceived personal control, and in type 2 diabetic patients to being prescribed insulin or antihypertensives, and perceived personal control. CONCLUSIONS: Patients hold specific mental models about diabetes treatments, which are associated with adherence. PMID- 21270193 TI - Islet autoantibody seroconversion in the DPT-1 study: justification for repeat screening throughout childhood. AB - OBJECTIVE: Although type 1 diabetes autoimmunity frequently begins in childhood, little is known about the relationship between age and autoimmunity development. Our aim was to determine the timing of seroconversion to diabetes-associated autoantibody (DAA) positivity and risk in first- and second-degree relatives of patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: Study subjects were identified through the Diabetes Prevention Trial-Type 1 (DPT-1). Children 3-18 years of age (n = 42,447) were screened for DAAs; 1,454 were ICA positive (>= 10 JDF units), 1,758 were GAD65 positive, and 899 were ICA512 positive at the time of initial screening. Subjects who were initially antibody negative (n = 39,212) were recalled for rescreening, and 11,813 returned for rescreening. RESULTS: DAA seroconversion occurred in 469 (4%) children; 258 seroconverted to ICA, 234 to GAD65, and 99 to ICA512. The median time to seroconversion was 2 years. The 2 year risk for DAAs was highest in early childhood. For each 1-year increase in age in this cohort, the risk of any autoantibody seroconversion (HR 0.95, 95% CI 0.92-0.97) decreased by 5%, and for any two autoantibodies risk decreased by 13% (0.87, 0.82-0.93). CONCLUSIONS: Risk of autoantibody seroconversion among children followed in DPT-1 is age dependent. Younger children have the highest risk for DAAs, with the majority of children seroconverting by 13 years of age (75%). This suggests that annual screenings should be started in early childhood and continued through early adolescence to identify the majority of subjects at risk for type 1 diabetes and eligible for prevention trials. PMID- 21270192 TI - Quality of diabetes care predicts the development of cardiovascular events: results of the AMD-QUASAR study. AB - OBJECTIVE: The QUASAR (Quality Assessment Score and Cardiovascular Outcomes in Italian Diabetes Patients) study aimed to assess whether a quality-of-care summary score predicted the development of cardiovascular (CV) events in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: In 67 diabetes clinics, data on randomly selected patients were extracted from electronic medical records. The score was calculated using process and outcome indicators based on monitoring, targets, and treatment of A1C, blood pressure, LDL cholesterol, and microalbuminuria. The score ranged from 0 to 40. RESULTS: Overall, 5,181 patients were analyzed; 477 (9.2%) patients developed a CV event after a median follow-up of 28 months. The incidence rate (per 1,000 person-years) of CV events was 62.4 in patients with a score of <15, 41.0 in those with a score between 20 and 25 and 36.7 in those with a score of >25. Multilevel analysis, adjusted for clustering and case-mix, showed that the risk to develop a new CV event was 84% higher in patients with a score of <15 (incidence rate ratio [IRR] = 1.84; 95% confidence interval [CI] 1.29-2.62) and 17% higher in those with a score between 15 and 25 (IRR = 1.17; 95% CI 0.93-1.49) compared with those with a score of >25. Mean quality score varied across centers from 16.5 +/- 7.5 to 29.1 +/- 6.3. When the score was tested as the dependent variable, it emerged that 18% of the variance in the score could be attributed to setting characteristics. CONCLUSIONS: Our study documented a close relationship between quality of diabetes care and long term outcomes. A simple score can be used to monitor quality of care and compare the performance of different centers/physicians. PMID- 21270194 TI - Fasting plasma glucose and hemoglobin A1c in identifying and predicting diabetes: the strong heart study. AB - OBJECTIVE: To compare fasting plasma glucose (FPG) and HbA(1c) in identifying and predicting type 2 diabetes in a population with high rates of diabetes. RESEARCH DESIGN AND METHODS: Diabetes was defined as an FPG level >= 126 mg/dL or an HbA(1c) level >= 6.5%. Data collected from the baseline and second exams (1989 1995) of the Strong Heart Study were used. RESULTS For cases of diabetes identified by FPG >= 126 mg/dL, using HbA(1c) >= 6.5% at the initial and 4-year follow-up diabetes screenings (or in identifying incident cases in 4 years) among undiagnosed participants left 46% and 59% of cases of diabetes undetected, respectively, whereas for cases identified by HbA(1c) >= 6.5%, using FPG >= 126 mg/dL left 11% and 59% unidentified, respectively. Age, waist circumference, urinary albumin-to-creatinine ratio, and baseline FPG and HbA(1c) levels were common significant risk factors for incident diabetes defined by either FPG or HbA(1c); triglyceride levels were significant for diabetes defined by HbA(1c) alone, and blood pressure and sibling history of diabetes were significant for diabetes defined by FPG alone. Using both the baseline FPG and HbA(1c) in diabetes prediction identified more people at risk than using either measure alone. CONCLUSIONS Among undiagnosed participants, using HbA(1c) alone in initial diabetes screening identifies fewer cases of diabetes than FPG, and using either FPG or HbA(1c) alone cannot effectively identify diabetes in a 4-year periodic successive diabetes screening or incident cases of diabetes in 4 years. Using both criteria may identify more people at risk. The proposed models using the commonly available clinical measures can be applied to assessing the risk of incident diabetes using either criterion. PMID- 21270195 TI - Use of dipeptidyl peptidase-4 inhibitors and the reporting of infections: a disproportionality analysis in the World Health Organization VigiBase. AB - OBJECTIVE: Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of antidiabetic drugs. They inactivate incretin hormones but also have many other effects throughout the body, among which are effects on the immune system. This might result in an increased infection risk. This study assessed the association between use of DPP-4 inhibitors and the reporting of infections. RESEARCH DESIGN AND METHODS: A nested case-control was conducted using VigiBase, the World Health Organization-Adverse Drug Reactions (WHO-ADR) database. The base cohort consisted of ADRs for antidiabetic drugs (Anatomical Therapeutic Chemical code A10). Cases were defined as ADRs of infection according to the Medical Dictionary for Regulatory Activities (MedDRA) classification system. All other ADRs were considered controls. Reporting odds ratios (RORs) were calculated to estimate the strength of the association between different classes of antidiabetic drugs and the reporting of infections. RESULTS: We identified 305,415 suspected ADRs involving antidiabetic drugs in 106,469 case reports, of which 8,083 involved DPP 4 inhibitors monotherapy. Overall, the reporting of infections was higher for patients using DPP-4 inhibitors compared with users of biguanides (ROR 2.3 [95% CI 1.9-2.7]). Reporting of upper respiratory tract infections (ROR 12.3 [95% CI 8.6-17.5]) was significantly associated with use of DPP-4 inhibitors. CONCLUSIONS: This study indicates an increased reporting of infections, in particular upper respiratory tract infections, for users of DPP-4 inhibitors compared with users of other antidiabetic drugs. However, the limitations of spontaneous reporting systems (e.g., underreporting, the Weber-effect, reporting bias) should be taken into account. Therefore, further research is needed to evaluate this suspicion and the underlying mechanism. PMID- 21270196 TI - Implications of alternative definitions of prediabetes for prevalence in U.S. adults. AB - OBJECTIVE: To compare the prevalence of prediabetes using A1C, fasting plasma glucose (FPG), and oral glucose tolerance test (OGTT) criteria, and to examine the degree of agreement between the measures. RESEARCH DESIGN AND METHODS: We used the 2005-2008 National Health and Nutrition Examination Surveys to classify 3,627 adults aged >= 18 years without diabetes according to their prediabetes status using A1C, FPG, and OGTT. We compared the prevalence of prediabetes according to different measures and used conditional probabilities to examine agreement between measures. RESULTS: In 2005-2008, the crude prevalence of prediabetes in adults aged >= 18 years was 14.2% for A1C 5.7-6.4% (A1C5.7), 26.2% for FPG 100-125 mg/dL (IFG100), 7.0% for FPG 110-125 mg/dL (IFG110), and 13.7% for OGTT 140-199 mg/dL (IGT). Prediabetes prevalence varied by age, sex, and race/ethnicity, and there was considerable discordance between measures of prediabetes. Among those with IGT, 58.2, 23.4, and 32.3% had IFG100, IFG110, and A1C5.7, respectively, and 67.1% had the combination of either A1C5.7 or IFG100. CONCLUSIONS: The prevalence of prediabetes varied by the indicator used to measure risk; there was considerable discordance between indicators and the characteristics of individuals with prediabetes. Programs to prevent diabetes may need to consider issues of equity, resources, need, and efficiency in targeting their efforts. PMID- 21270197 TI - Endotoxemia is associated with an increased risk of incident diabetes. AB - OBJECTIVE: Diabetes is accompanied with a chronic low-grade inflammation, which may in part be mediated by endotoxins derived from Gram-negative bacteria. RESEARCH DESIGN AND METHODS: We investigated in a population-based cohort whether endotoxemia is associated with clinically incident diabetes. The serum endotoxin activity was measured by limulus assay from the FINRISK97 cohort comprising 7,169 subjects aged 25-74 years and followed up for 10 years. RESULTS: Both the subjects with prevalent diabetes (n = 537) and those with incident diabetes (n = 462) had higher endotoxin activity than the nondiabetic individuals (P < 0.001). The endotoxin activity was significantly associated with increased risk for incident diabetes with a hazard ratio 1.004 (95% CI 1.001-1.007; P = 0.019) per unit increase resulting in a 52% increased risk (P = 0.013) in the highest quartile compared with the lowest one. The association was independent of diabetes risk factors: serum lipids, gamma-glutamyl transferase, C-reactive protein, BMI, and blood glucose. Furthermore, the association of endotoxemia with an increased risk of incident diabetes was independent of the metabolic syndrome as defined either by the National Cholesterol Educational Program-Adult Treatment Panel III or the International Diabetes Federation. Endotoxin activity was linearly related (P < 0.001) to the number of components of the metabolic syndrome. CONCLUSIONS: Both prevalent and incident diabetes were associated with endotoxemia, which may link metabolic disorders to inflammation. The results suggest that microbes play a role in the pathogenesis of diabetes. PMID- 21270198 TI - HbA1c in nondiabetic Dutch infants aged 8-12 months: the GECKO-Drenthe birth cohort study. AB - OBJECTIVE: An international committee of experts recommended using HbA(1c) for diagnostic testing for diabetes. Little is known about normal values of HbA(1c) in infants. The aim of this study is to describe the distribution of HbA(1c) in 8 to 12-month-old nondiabetic infants. RESEARCH DESIGN AND METHODS: HbA(1c) was measured in 86 infants participating in the Groningen Expert Center for Kids with Obesity (GECKO)-Drenthe birth cohort study. Anthropometric measurements were performed at Well Baby Clinics. Data on parents and children were collected prospectively using questionnaires. RESULTS: HbA(1c) was normally distributed with a mean (SD) HbA(1c) level of 5.38% (0.24), range 4.8-6.0% or 35.29 mmol/mol (2.65), range 29.1-42.1 mmol/mol. Age, sex, birth weight, duration of breastfeeding, anthropometric measurements, and maternal BMI were not associated with HbA(1c). CONCLUSIONS: We found a normal distribution of HbA(1c) with a relatively high mean HbA(1c) of 5.38%. No significant association between risk factors for type 2 diabetes and HbA(1c) levels was found. PMID- 21270199 TI - Higher plasma levels of advanced glycation end products are associated with incident cardiovascular disease and all-cause mortality in type 1 diabetes: a 12 year follow-up study. AB - OBJECTIVE: To investigate the associations of plasma levels of advanced glycation end products (AGEs) with incident cardiovascular disease (CVD) and all-cause mortality in type 1 diabetes and the extent to which any such associations could be explained by endothelial and renal dysfunction, low-grade inflammation, and arterial stiffness. RESEARCH DESIGN AND METHODS: We prospectively followed 169 individuals with diabetic nephropathy and 170 individuals with persistent normoalbuminuria who were free of CVD at study entry and in whom levels of N(epsilon)-(carboxymethyl)lysine, N(epsilon)-(carboxyethyl)lysine, pentosidine and other biomarkers were measured at baseline. The median follow-up duration was 12.3 (interquartile range 7.6-12.5) years. RESULTS: During the course of follow up, 82 individuals (24.2%) died; 85 (25.1%) suffered a fatal (n = 48) and/or nonfatal (n = 53) CVD event. The incidence of fatal and nonfatal CVD and of all cause mortality increased with higher baseline levels of AGEs independently of traditional CVD risk factors: hazard ratio (HR) = 1.30 (95% CI = 1.03-1.66) and HR = 1.27 (1.00-1.62), respectively. These associations were not attenuated after further adjustments for markers of renal or endothelial dysfunction, low-grade inflammation, or arterial stiffness. CONCLUSIONS: Higher levels of AGEs are associated with incident fatal and nonfatal CVD as well as all-cause mortality in individuals with type 1 diabetes, independently of other risk factors and of several potential AGEs-related pathophysiological mechanisms. Thus, AGEs may explain, in part, the increased cardiovascular disease and mortality attributable to type 1 diabetes and constitute a specific target for treatment in these patients. PMID- 21270201 TI - Relationship between carotid intima-media thickness and the presence and extent of coronary stenosis in type 2 diabetic patients with carotid atherosclerosis but without history of coronary artery disease. AB - OBJECTIVE: We examined the relationship between the presence and extent of coronary stenosis and carotid intima-media thickness (CIMT) in type 2 diabetic patients without history of coronary artery disease (CAD) but with carotid atherosclerosis. RESEARCH DESIGN AND METHODS: A total of 91 type 2 diabetic patients underwent multi-slice computed tomography coronary angiography. RESULTS: Max-IMT in the >= 50% stenosis group by multi-slice computed tomography coronary angiography estimation was significantly greater than the 0-25 and 25-50% stenosis group (2.68 +/- 0.77 vs. 1.61 +/- 0.49 mm, P < 0.0005, and 2.14 +/- 0.81 mm, P < 0.05, respectively), and max-IMT in the 25-50% stenosis group was significantly greater than the 0-25% stenosis group (P < 0.05) after adjustment for age, sex, duration of type 2 diabetes, hypertension, and dyslipidemia. In the analysis for trend through the categories of max-IMT, as max-IMT increased, the percentage of >= 50% stenosis increased and the percentage of 0-25% stenosis decreased. CONCLUSIONS: Our data suggest that max-IMT might be closely associated with the extent of coronary stenosis in type 2 diabetic patients without history of CAD but with carotid atherosclerosis. PMID- 21270202 TI - Clinical and genetic characteristics of patients with type 1 diabetes associated with interferon therapy. AB - OBJECTIVE: This study clarified characteristics of interferon-associated type 1 diabetes. RESEARCH DESIGN AND METHODS: The study compared 12 patients with interferon-associated type 1 diabetes with 128 patients with type 1A diabetes with respect to clinical characteristics, and with 10 patients without diabetes despite interferon therapy and 136 normal controls with respect to HLA allele distributions. RESULTS: Patients with interferon-associated type 1 diabetes retained higher levels of fasting serum C peptide as well as GAD65 antibodies than those with type 1A diabetes until 2 to 4 years after onset. HLA-A*2402 was increased among patients with interferon-associated type 1 diabetes compared with those without diabetes, despite interferon therapy (odds ratio [OR] 4.00 [95% CI 1.09-17.26]). The haplotype of DRB1*1302-DQA1*0102-DQB1*0604 was increased in these two groups combined compared with normal controls (OR 5.64 [95% CI 2.67 11.81]). CONCLUSIONS: Interferon-associated type 1 diabetes is characterized clinically by high titers of GAD65 antibodies and preserved beta-cell function, and genetically by addition of HLA-A*2402to DRB1*1302-DQA1*0102-DQB1*0604. PMID- 21270203 TI - Serum apolipoprotein AI and B are stronger biomarkers of diabetic retinopathy than traditional lipids. AB - OBJECTIVE: To describe and compare the associations of serum lipoproteins and apolipoproteins with diabetic retinopathy. RESEARCH DESIGN AND METHODS: This was a cross-sectional study of 224 diabetic patients (85 type 1 and 139 type 2) from a diabetes clinic. Diabetic retinopathy was graded from fundus photographs according to the Airlie House Classification system and categorized into mild, moderate, and vision-threatening diabetic retinopathy (VTDR). Serum traditional lipids (total, LDL, non-HDL, and HDL cholesterol and triglycerides) and apolipoprotein AI (apoAI), apolipoprotein B (apoB), and the apoB-to-apoAI ratio were assessed. RESULTS: Diabetic retinopathy was present in 133 (59.4%) individuals. After adjustment for age, sex, diabetes duration, A1C, systolic blood pressure, and diabetes medications, the HDL cholesterol level was inversely associated with diabetic retinopathy (odds ratio 0.39 [95% CI 0.16-0.94], highest versus lowest quartile; P(trend) = 0.017). The ApoAI level was inversely associated with diabetic retinopathy (per SD increase, 0.76 [95% CI 0.59-0.98]), whereas apoB (per SD increase, 1.31 [1.02-1.68]) and the apoB-to-apoAI ratio (per SD increase, 1.48 [1.13-1.95]) were positively associated with diabetic retinopathy. Results were similar for mild to moderate diabetic retinopathy and VTDR. Traditional lipid levels improved the area under the receiver operating curve by 1.8%, whereas apolipoproteins improved the area by 8.2%. CONCLUSIONS: ApoAI and apoB and the apoB-to-apoAI ratio were significantly and independently associated with diabetic retinopathy and diabetic retinopathy severity and improved the ability to discriminate diabetic retinopathy by 8%. Serum apolipoprotein levels may therefore be stronger biomarkers of diabetic retinopathy than traditional lipid measures. PMID- 21270204 TI - Ethnic differences in pancreatic fat accumulation and its relationship with other fat depots and inflammatory markers. AB - OBJECTIVE: Visceral adipose tissue (VAT) and hepatic fat are associated with insulin resistance and vary by sex and ethnicity. Recently, pancreatic fat fraction (PFF) has also been linked with increasing obesity. Our aim was to assess ethnic and sex differences in PFF and its relationship to other fat depots, circulating free fatty acids (FFA), insulin secretion and sensitivity, and inflammation in obese adolescents and young adults. RESEARCH DESIGN AND METHODS: We examined 138 (40 males, 98 females) obese Hispanics and African Americans (13-25 years). Subcutaneous adipose tissue and VAT volumes, hepatic fat fraction (HFF), and PFF were determined by magnetic resonance imaging. Insulin sensitivity and beta-cell function were assessed during an intravenous glucose tolerance test. RESULTS: Hispanics had higher PFF than African Americans (7.3 +/- 3.8 vs. 6.2 +/- 2.6%, P = 0.03); this ethnic difference was higher in young adults compared with children and adolescents (ethnicity * age: P = 0.01). Males had higher PFF than females (P < 0.0001). PFF was positively correlated with VAT (r = 0.45, P < 0.0001), HFF (r = 0.29, P < 0.0001), and FFA (r = 0.32, P = 0.001). PFF positively correlated with inflammatory markers but lost significance when adjusted for VAT. In multiple stepwise regression analysis, VAT and FFA were the best predictors of PFF (adjusted R(2) = 0.40). There were no significant correlations between PFF and markers of insulin sensitivity or beta-cell function. CONCLUSIONS: PFF is higher in Hispanics than African Americans, and this difference increases with age. In young obese individuals, PFF is related to VAT, HFF, and circulating FFA, thus possibly contributing to their increased risk for type 2 diabetes and related metabolic disorders. PMID- 21270205 TI - Urbanization, physical activity, and metabolic health in sub-Saharan Africa. AB - OBJECTIVE: We examined the independent associations between objectively measured free-living physical activity energy expenditure (PAEE) and the metabolic syndrome in adults in rural and urban Cameroon. RESEARCH DESIGN AND METHODS: PAEE was measured in 552 rural and urban dwellers using combined heart rate and movement sensing over 7 continuous days. The metabolic syndrome was defined using the National Cholesterol Education Program-Adult Treatment Panel III criteria. RESULTS: Urban dwellers had a significantly lower PAEE than rural dwellers (44.2 +/- 21.0 vs. 59.6 +/- 23.7 kJ/kg/day, P < 0.001) and a higher prevalence of the metabolic syndrome (17.7 vs. 3.5%, P < 0.001). In multivariate regression models adjusted for possible confounders, each kJ/kg/day of PAEE was associated with a 2.1% lower risk of prevalent metabolic syndrome (odds ratio 0.98, P = 0.03). This implies a 6.5 kJ/kg/day difference in PAEE, equivalent to 30 min/day of brisk walking, corresponds to a 13.7% lower risk of prevalent metabolic syndrome. The population attributable fraction of prevalent metabolic syndrome due to being in the lowest quartile of PAEE was 26.3% (25.3% in women and 35.7% in men). CONCLUSIONS: Urban compared with rural residence is associated with lower PAEE and higher prevalence of metabolic syndrome. PAEE is strongly independently associated with prevalent metabolic syndrome in adult Cameroonians. Modest population-wide changes in PAEE may have significant benefits in terms of reducing the emerging burden of metabolic diseases in sub-Saharan Africa. PMID- 21270200 TI - The prevalence and predictors of an abnormal ankle-brachial index in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. AB - OBJECTIVE: To examine ankle-brachial index (ABI) abnormalities in patients with type 2 diabetes and coronary artery disease (CAD). RESEARCH DESIGN AND METHODS: An ABI was obtained in 2,240 patients in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial. ABIs were classified as: normal, 0.91 1.3; low, <= 0.9; high, >1.3; or noncompressible artery (NC). Baseline characteristics were examined according to ABI and by multivariate analysis. RESULTS ABI was normal in 66%, low in 19%, and high in 8% of patients, and 6% of patients had NC. Of the low ABI patients, 68% were asymptomatic. Using normal ABI as referent, low ABI was independently associated with smoking, female sex, black race, hypertension, age, C-reactive protein, diabetes duration, and lower BMI. High ABI was associated with male sex, nonblack race, and higher BMI; and NC artery was associated with diabetes duration, higher BMI, and hypertension. CONCLUSIONS: ABI abnormalities are common and often asymptomatic in patients with type 2 diabetes and CAD. PMID- 21270206 TI - Sedentary activity associated with metabolic syndrome independent of physical activity. AB - OBJECTIVE: This study examined the association between objectively measured sedentary activity and metabolic syndrome among older adults. RESEARCH DESIGN AND METHODS: Data were from 1,367 men and women, aged >= 60 years who participated in the 2003-2006 National Health and Nutrition Examination Survey (NHANES). Sedentary time during waking hours was measured by an accelerometer (<100 counts per minute). A sedentary bout was defined as a period of time >5 min. A sedentary break was defined as an interruption in sedentary time (>= 100 counts per minute). Metabolic syndrome was defined according to the Adult Treatment Panel (ATP) III criteria. RESULTS: On average, people spent 9.5 h (65% of wear time) as sedentary. Compared with people without metabolic syndrome, people with metabolic syndrome spent a greater percentage of time as sedentary (67.3 vs. 62.2%), had longer average sedentary bouts (17.7 vs. 16.7 min), had lower intensity during sedentary time (14.8 vs. 15.8 average counts per minute), and had fewer sedentary breaks (82.3 vs. 86.7), adjusted for age and sex (all P < 0.01). A higher percentage of time sedentary and fewer sedentary breaks were associated with a significantly greater likelihood of metabolic syndrome after adjustment for age, sex, ethnicity, education, alcohol consumption, smoking, BMI, diabetes, heart disease, and physical activity. The association between intensity during sedentary time and metabolic syndrome was borderline significant. CONCLUSIONS: The proportion of sedentary time was strongly related to metabolic risk, independent of physical activity. Current results suggest older people may benefit from reducing total sedentary time and avoiding prolonged periods of sedentary time by increasing the number of breaks during sedentary time. PMID- 21270207 TI - A1C versus glucose testing: a comparison. PMID- 21270209 TI - Home blood glucose monitoring in type 2 diabetes: broken health care system undermines study's impact. PMID- 21270208 TI - Diagnosing diabetes with glucose criteria: worshiping a false God. PMID- 21270210 TI - Apolipoproteins and diabetic retinopathy. PMID- 21270212 TI - Three cases of severe invasive infections caused by Campylobacter rectus and first report of fatal C. rectus infection. AB - We report the first fatal case of Campylobacter rectus infection due to a subdural empyema and ruptured mycotic intracranial aneurysm and two cases of limb threatening C. rectus necrotizing soft tissue and bone infection and empyema thoracis that responded to amoxicillin-clavulanate and surgical debridement and drainage. All three strains were identified by 16S rRNA sequencing. PMID- 21270213 TI - Assessment of impact of peptide nucleic acid fluorescence in situ hybridization for rapid identification of coagulase-negative staphylococci in the absence of antimicrobial stewardship intervention. AB - Peptide nucleic acid fluorescence in situ hybridization (PNA FISH) was instituted at Boston Medical Center for the rapid identification of coagulase-negative staphylococci (CoNS). Without active notification or antimicrobial stewardship intervention, a pre- and postimpact analysis showed no benefit of this assay with respect to the length of hospital stay or vancomycin use. PMID- 21270214 TI - Emergence of disseminated infections due to Geosmithia argillacea in patients with chronic granulomatous disease receiving long-term azole antifungal prophylaxis. AB - We report two cases of invasive infections due to Geosmithia argillacea, an emerging mold, in patients with chronic granulomatous disease receiving prolonged azole antifungal prophylaxis. One patient died despite receiving a combination of four antifungals, and the other developed cerebral and medullary lesions under a combination of caspofungin, posaconazole, terbinafine, and gamma interferon. PMID- 21270215 TI - Diagnostic accuracy assessment of Sensititre and agar disk diffusion for determining antimicrobial resistance profiles of bovine clinical mastitis pathogens. AB - Determining the accuracy and precision of a measuring instrument is pertinent in antimicrobial susceptibility testing. This study was conducted to predict the diagnostic accuracy of the Sensititre MIC mastitis panel (Sensititre) and agar disk diffusion (ADD) method with reference to the manual broth microdilution test method for antimicrobial resistance profiling of Escherichia coli (n = 156), Staphylococcus aureus (n = 154), streptococcal (n = 116), and enterococcal (n = 31) bovine clinical mastitis isolates. The activities of ampicillin, ceftiofur, cephalothin, erythromycin, oxacillin, penicillin, the penicillin-novobiocin combination, pirlimycin, and tetracycline were tested against the isolates. Diagnostic accuracy was determined by estimating the area under the receiver operating characteristic curve; intertest essential and categorical agreements were determined as well. Sensititre and the ADD method demonstrated moderate to highly accurate (71 to 99%) and moderate to perfect (71 to 100%) predictive accuracies for 74 and 76% of the isolate-antimicrobial MIC combinations, respectively. However, the diagnostic accuracy was low for S. aureus ceftiofur/oxacillin combinations and other streptococcus-ampicillin combinations by either testing method. Essential agreement between Sensititre automatic MIC readings and MIC readings obtained by the broth microdilution test method was 87%. Essential agreement between Sensititre automatic and manual MIC reading methods was 97%. Furthermore, the ADD test method and Sensititre MIC method exhibited 92 and 91% categorical agreement (sensitive, intermediate, resistant) of results, respectively, compared with the reference method. However, both methods demonstrated lower agreement for E. coli-ampicillin/cephalothin combinations than for Gram-positive isolates. In conclusion, the Sensititre and ADD methods had moderate to high diagnostic accuracy and very good essential and categorical agreement for most udder pathogen-antimicrobial combinations and can be readily employed in veterinary diagnostic laboratories. PMID- 21270216 TI - Development of a selective culture medium for primary isolation of the main Brucella species. AB - Bacteriological diagnosis of brucellosis is performed by culturing animal samples directly on both Farrell medium (FM) and modified Thayer-Martin medium (mTM). However, despite inhibiting most contaminating microorganisms, FM also inhibits the growth of Brucella ovis and some B. melitensis and B. abortus strains. In contrast, mTM is adequate for growth of all Brucella species but only partially inhibitory for contaminants. Moreover, the performance of both culture media for isolating B. suis has never been established properly. We first determined the performance of both media for B. suis isolation, proving that FM significantly inhibits B. suis growth. We also determined the susceptibility of B. suis to the antibiotics contained in both selective media, proving that nalidixic acid and bacitracin are highly inhibitory, thus explaining the reduced performance of FM for B. suis isolation. Based on these results, a new selective medium (CITA) containing vancomycin, colistin, nystatin, nitrofurantoin, and amphotericin B was tested for isolation of the main Brucella species, including B. suis. CITA's performance was evaluated using reference contaminant strains but also field samples taken from brucella-infected animals or animals suspected of infection. CITA inhibited most contaminant microorganisms but allowed the growth of all Brucella species, to levels similar to those for both the control medium without antibiotics and mTM. Moreover, CITA medium was more sensitive than both mTM and FM for isolating all Brucella species from field samples. Altogether, these results demonstrate the adequate performance of CITA medium for the primary isolation of the main Brucella species, including B. suis. PMID- 21270217 TI - Gordonia bronchialis bacteremia and pleural infection: case report and review of the literature. AB - Gordonia species are aerobic actinomycetes recently recognized as causing human disease, often in the setting of intravascular catheter-related infections. We describe a case of Gordonia bronchialis bacteremia and pleural space infection in the absence of an indwelling intravascular catheter and review the breadth of reported infections with this emerging pathogen. PMID- 21270218 TI - Disseminated fusariosis occurring in two patients despite posaconazole prophylaxis. AB - Posaconazole is widely used for prophylaxis against invasive fungal infections in patients undergoing myeloablative therapy. Disseminated fusariosis is a serious invasive mold infection in such patients. Preclinical and clinical studies indicate activity of posaconazole against Fusarium. We describe two cases of disseminated fusariosis that occurred despite posaconazole prophylaxis. PMID- 21270219 TI - Analysis of invasiveness of pneumococcal serotypes and clones circulating in Portugal before widespread use of conjugate vaccines reveals heterogeneous behavior of clones expressing the same serotype. AB - To estimate the invasive disease potential of serotypes and clones circulating in Portugal before extensive use of the seven-valent pneumococcal conjugate vaccine, we analyzed 475 invasive isolates recovered from children and adults and 769 carriage isolates recovered from children between 2001 and 2003. Isolates were serotyped and genotyped by pulsed-field gel electrophoresis, and a selection of isolates were also characterized by multilocus sequence typing. We found that the diversities of serotypes and genotypes of pneumococci responsible for invasive infections and carriage were identical and that most carried clones could also be detected as causes of invasive disease. Their ability to do so, however, varied substantially. Serotypes 1, 3, 4, 5, 7F, 8, 9N, 9L, 12B, 14, 18C, and 20 were found to have an enhanced propensity to cause invasive disease, while serotypes 6A, 6B, 11A, 15B/C, 16F, 19F, 23F, 34, 35F, and 37 were associated with carriage. In addition, significant differences in invasive disease potential between clones sharing the same serotype were found among several serotypes, namely, 3, 6A, 6B, 11A, 14, 19A, 19F, 22F, 23F, 34, and NT. This heterogeneous behavior of the clones was found irrespective of the serotype's overall invasive disease potential. Our results highlight the importance of the genetic background when analyzing the invasive disease potential of certain serotypes and provide an important baseline for its monitoring following conjugate vaccine use. Continuous surveillance should be maintained, and current research should focus on uncovering the genetic determinants that contribute to the heterogeneity of invasive disease potential of clones sharing the same serotype. PMID- 21270220 TI - Isothermal microcalorimetry to study drugs against Schistosoma mansoni. AB - Alternative antischistosomal drugs are required since praziquantel is virtually the only drug available for treatment and morbidity control of schistosomiasis. Manual microscopic reading is the current "gold standard" to assess the in vitro antischistosomal properties of test drugs; however, it is labor-intensive, subjective, and difficult to standardize. Hence, there is a need to develop novel tools for antischistosomal drug discovery. The in vitro effects of praziquantel, oxamniquine, artesunate, and mefloquine on metabolic activity and parasite motility of Schistosoma mansoni (newly transformed schistosomula [NTS] and 49-day old adult worms) were studied using isothermal microcalorimetry (IMC). Results were compared to morphological readouts of viability. Results obtained for the four drugs tested with phenotypic evaluation by microscopy and IMC showed a good correlation, but IMC also identified drug effects that were not visible by microscopic evaluation, and IMC precisely determined the onset of action of the test drugs. Similar sensitivities on NTS and adult schistosomes were observed for praziquantel and mefloquine, while slight differences in the drug susceptibilities of the two developmental stages were noted with oxamniquine and artesunate. IMC is a useful tool for antischistosomal drug discovery that should be further validated. In addition, our data support the use of NTS in in vitro antischistosomal drug assays. PMID- 21270222 TI - Clinical significance of a single Staphylococcus lugdunensis-positive blood culture. PMID- 21270224 TI - Novel nested direct PCR technique for malaria diagnosis using filter paper samples. AB - The use of direct nested PCR enables the detection of Plasmodium spp. from blood samples collected on filter papers without requiring the time-consuming procedures associated with DNA extraction. Direct PCR provides a rapid, highly sensitive, and cost-effective alternative to diagnosing malaria using filter paper samples and standard nested PCR. PMID- 21270223 TI - High failure rate of the ViroSeq HIV-1 genotyping system for drug resistance testing in Cameroon, a country with broad HIV-1 genetic diversity. AB - The ViroSeq HIV-1 genotyping system is used in many African countries for drug resistance testing. In this study, we used a panel of diverse HIV-1 group M isolates circulating in Cameroon to show that the performance of this assay can be altered by the sequence variation of non-B HIV-1 strains that predominate in African settings. PMID- 21270225 TI - Haemophilus influenzae type b carriage and novel bacterial population structure among children in urban Kathmandu, Nepal. AB - Haemophilus influenzae type b (Hib) is a major cause of invasive bacterial infection in children that can be prevented by a vaccine, but there is still uncertainty about its relative importance in Asia. This study investigated the age-specific prevalence of Hib carriage and its molecular epidemiology in carriage and disease in Nepal. Oropharyngeal swabs were collected from children in Kathmandu, Nepal, from 3 different settings: a hospital outpatient department (OPD), schools, and children's homes. Hib was isolated using Hib antiserum agar plates, and serotyping was performed with latex agglutination. Hib isolates from children with invasive disease were obtained during active microbiological surveillance at Patan Hospital, Kathmandu, Nepal. Genotyping of disease and carriage isolates was undertaken using multilocus sequence typing (MLST). Swabs were taken from 2,195 children, including 1,311 children at an OPD, 647 children attending schools, and 237 children in homes. Overall, Hib was identified in 5.0% (110/2,195; 95% confidence interval [95% CI], 3.9% to 6.4%). MLST was performed on 108 Hib isolates from children carrying Hib isolates and 15 isolates from children with invasive disease. Thirty-one sequence types (STs) were identified, and 20 of these were novel STs. The most common ST isolates were sequence type 6 (ST6) and the novel ST722. There was marked heterogeneity among the STs from children with disease and children carrying Hib. STs identified from invasive infections were those commonly identified in carriage. This study provides evidence of Hib carriage among children in urban Nepal with genetically diverse strains prior to introduction of universal vaccination. The Hib carriage rate in Nepal was similar to the rates observed in other populations with documented high disease rates prior to vaccination, supporting implementation of Hib vaccine in Nepal in 2009. PMID- 21270226 TI - Detection of bacillus Galmette-Guerin (Mycobacterium bovis BCG) DNA in urine and blood specimens after intravesical immunotherapy for bladder carcinoma. AB - A real-time PCR targeting IS6110 was employed for the detection of Mycobacterium tuberculosis DNA in specimens collected from 10 patients treated with intravesical M. bovis bacillus Galmette-Guerin (BCG) immunotherapy for bladder malignancy. BCG DNA was detected in all urine specimens taken 24 h after the instillations, as well as in 24% of the specimens collected 7 days after the instillations; it was also detected in a single specimen taken 6 weeks after the last instillation. BCG DNA was detected in 8.3% of the blood specimens taken 1 day after instillation, and its amplification was associated with cases of self limiting fever. These findings give indications that this real-time PCR is helpful to recognize BCG bacteremic cases, which may lead to mycobacterial infection. PMID- 21270227 TI - Salmonella enterica serotype Gambia with CTX-M-3 and armA resistance markers: nosocomial infections with a fatal outcome. AB - We report two cases of bacteremia caused by the Salmonella enterica serotype Gambia in our children's hospital, with one fatal outcome. The isolates showed indistinguishable genotypes and infrequent resistance markers: CTX-M-3 extended spectrum beta-lactamase and armA methyltransferase. This is the first report of S. Gambia exhibiting CTX-M-3 and armA markers involved in serious infections. PMID- 21270221 TI - Multilocus sequence typing subtypes of poultry Clostridium perfringens isolates demonstrate disease niche partitioning. AB - Clostridium perfringens is a ubiquitous and versatile pathogenic bacterium and is implicated in the etiology of the poultry diseases necrotic enteritis (NE) and poultry gangrene (PG). In this study, multilocus sequence typing was used to investigate genotypic relationships among 139 C. perfringens isolates from 74 flocks. These isolates had multiple disease, host, and environmental origins. The results indicated a polymorphic yet highly clonal population, with 79.6% of all isolates partitioning into one of six clonal complexes or two dominant sequence types, ST-9 and ST-31. The most prolific clonal complex, CC-1, contained 27.3% of all isolates and was not clearly associated with one particular disease. The subtypes CC-4 and ST-31 were highly associated with NE and represented 9.4% and 7.2% of the total isolates, respectively. No PG-associated and NE-associated C. perfringens isolates shared the same sequence type or clonal complex. NE associated subtypes were more clonal and appeared more evolutionarily divergent than PG-associated subtypes, which tended to cluster in the more ancestral lineages alongside isolates from asymptomatic chickens and turkeys. Toxin gene screening identified cpb2 throughout these isolates and correlated the presence of netB with NE pathology. Previous investigations into the genetic basis of C. perfringens pathogenicity have focused on toxins and other variable genetic elements. This study presents the first sequence-based comparison of C. perfringens isolates recovered in clinical cases of PG and NE and demonstrates that niche specialization is observable in the core genomes of poultry-associated C. perfringens isolates, a concept with both epidemiological and evolutionary significance. PMID- 21270228 TI - Comparison of BD Bactec Plus Aerobic/F medium to VersaTREK Redox 1 blood culture medium for detection of Candida spp. in seeded blood culture specimens containing therapeutic levels of antifungal agents. AB - Recovery of Candida spp. using the BD Bactec FX blood culture (BC) system (Bactec Plus Aerobic/F medium) and the VersaTREK system (aerobic Redox medium) was evaluated using seeded BC bottles with and without the addition of commonly used antifungal agents. BC bottles (n = 1,442) were each inoculated with 10 ml human whole blood and 0.1 ml of suspensions of Candida spp., with or without antifungal agents. BC bottles were incubated in the corresponding system for a maximum of 5 days. In the absence of antifungal agents, Bactec FX recovered 97.4% of Candida spp., and VersaTREK recovered 99.1% (P = 0.154). With regard to length of time to detection (LTD) and overall recovery, both systems had various levels of effectiveness in recovering C. glabrata. In bottles containing antifungal agents, Bactec FX recovered 83.1% of isolates, whereas VersaTREK recovered 50.7% of Candida spp. (P < 0.001). For BC bottles without the addition of antifungal agents, the median LTD for VersaTREK was 2.2 h faster than that of Bactec FX (P < 0.001). In the presence of antifungal agents, the Bactec FX recovery time was significantly faster than that of VersaTREK (median difference of 10.8 h, P < 0.001). We conclude that both systems have comparable abilities to recover Candida spp. from seeded blood cultures in the absence of antifungal agents. In the presence of therapeutic levels of commonly used antifungal agents, the Bactec FX system demonstrated a significantly greater recovery of various Candida spp., as well as a shorter LTD. PMID- 21270229 TI - Isolation and characterization of "Pseudomonas andersonii" from four cases of pulmonary granulomas and emended species description. AB - "Pseudomonas andersonii" is a Gram-negative bacillus initially isolated from a granulomatous lung lesion. Novel species status has not been validated for this single strain. We report four additional cases of pulmonary granuloma involving P. andersonii and further characterize the organism. These patients had pulmonary nodules that were surgically resected and which grew P. andersonii on routine culture. Mycobacterium avium complex was concomitantly isolated in two cases, and fungal structures were identified histopathologically in two other cases. The five P. andersonii strains described to date were similar in growth characteristics, biochemical reactions, matrix-assisted laser desorption ionization-time of flight mass spectrometry protein profiles, and susceptibility to antimicrobial agents. Their 16S rRNA genes were 99.9 to 100% identical but less than 95.0% similar to those of all other known bacteria. The gyrA genes of these strains were 99.5 to 100% identical. These shared features illustrate P. andersonii as a unique and distinct bacterium and support the novel species status of the organism. PMID- 21270230 TI - Rapid molecular detection of extrapulmonary tuberculosis by the automated GeneXpert MTB/RIF system. AB - In total, 521 nonrespiratory specimens (91 urine, 30 gastric aspirate, 245 tissue, 113 pleural fluid, 19 cerebrospinal fluid [CSF], and 23 stool specimens) submitted to the German National Reference Laboratory for Mycobacteria (NRL) from May 2009 to August 2010 were comparatively investigated with the new molecular based GeneXpert MTB/RIF (Xpert) assay system and conventional liquid and solid culture methods. Twenty (3.8%) of the 521 specimens gave no interpretable result. Whereas the sensitivity of the Xpert assay with tissue specimens was 69.0% (20 out of 29 culture-positive cases detected), 100% sensitivity was found with the urine and stool specimens. The combined sensitivity and specificity of the Xpert assay were calculated to be 77.3% and 98.2%, respectively. PMID- 21270231 TI - Utility of a panviral microarray for detection of swine respiratory viruses in clinical samples. AB - Several factors have recently converged, elevating the need for highly parallel diagnostic platforms that have the ability to detect many known, novel, and emerging pathogenic agents simultaneously. Panviral DNA microarrays represent the most robust approach for massively parallel viral surveillance and detection. The Virochip is a panviral DNA microarray that is capable of detecting all known viruses, as well as novel viruses related to known viral families, in a single assay and has been used to successfully identify known and novel viral agents in clinical human specimens. However, the usefulness and the sensitivity of the Virochip platform have not been tested on a set of clinical veterinary specimens with the high degree of genetic variance that is frequently observed with swine virus field isolates. In this report, we investigate the utility and sensitivity of the Virochip to positively detect swine viruses in both cell culture-derived samples and clinical swine samples. The Virochip successfully detected porcine reproductive and respiratory syndrome virus (PRRSV) in serum containing 6.10 * 10(2) viral copies per microliter and influenza A virus in lung lavage fluid containing 2.08 * 10(6) viral copies per microliter. The Virochip also successfully detected porcine circovirus type 2 (PCV2) in serum containing 2.50 * 10(8) viral copies per microliter and porcine respiratory coronavirus (PRCV) in turbinate tissue homogenate. Collectively, the data in this report demonstrate that the Virochip can successfully detect pathogenic viruses frequently found in swine in a variety of solid and liquid specimens, such as turbinate tissue homogenate and lung lavage fluid, as well as antemortem samples, such as serum. PMID- 21270232 TI - Performance of various testing methodologies for detection of heteroresistant vancomycin-intermediate Staphylococcus aureus in bloodstream isolates. AB - The best screening method for detecting heteroresistant vancomycin-intermediate Staphylococcus aureus (hVISA) remains unclear. Using population analysis profiling utilizing the area under the concentration-time curve (PAP-AUC) as the gold standard, we screened 458 consecutive methicillin-resistant S. aureus (MRSA) bloodstream isolates to determine the most accurate and cost-effective testing strategy to detect the presence of heteroresistance. All isolates were also tested using the macromethod Etest (MET) and glycopeptide resistance detection (GRD) Etest. The MIC was determined by several methods, including standard vancomycin Etest, vancomycin broth microdilution (BMD), and Vitek2 testing. Fifty five (12%) hVISA and 4 (1%) VISA isolates were detected by PAP-AUC. Compared to PAP-AUC, the sensitivities and specificities of MET, GRD Etest, BMD (using a MIC cutoff of >= 2 mg/liter), and standard vancomycin Etest (using a MIC cutoff of >= 2 mg/liter) were 89 and 55%, 71 and 94%, 82 and 97%, and 71 and 94%, respectively. Combination testing increased the overall testing accuracy by reducing the number of false-positive results. Cost was determined predominately by the number of PAP-AUC runs required following a screening assay. The most cost effective strategy was BMD (using a MIC cutoff of >= 2 MUg/ml) as a standalone assay or in combination with PAP-AUC, provided that BMD testing was batched. GRD Etest remained an alternative, with 71% of hVISA isolates detected. Prevalence influenced both cost and test accuracy, with results remaining unchanged for hVISA prevalences of up to 25%. Implementation of any testing strategy would therefore be dependent on balancing cost with accuracy in a given population and clinical context. PMID- 21270233 TI - Simultaneous detection of influenza A, influenza B, and respiratory syncytial viruses and subtyping of influenza A H3N2 virus and H1N1 (2009) virus by multiplex real-time PCR. AB - A multiplex real-time PCR assay was developed to simultaneously detect and discriminate influenza A virus subtypes, including novel H1N1 (2009) and seasonal H3N2 virus, influenza B virus, and respiratory syncytial virus (RSV) in a single test tube, with detection sensitivity and specificity of 99% and 100%, respectively, for the four pathogens. PMID- 21270234 TI - Performance and cost analysis of matrix-assisted laser desorption ionization-time of flight mass spectrometry for routine identification of yeast. AB - Matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry was compared to phenotypic testing for yeast identification. MALDI TOF mass spectrometry yielded 96.3% and 84.5% accurate species level identifications (spectral scores, >= 1.8) for 138 common and 103 archived strains of yeast. MALDI-TOF mass spectrometry is accurate, rapid (5.1 min of hands-on time/identification), and cost-effective ($0.50/sample) for yeast identification in the clinical laboratory. PMID- 21270235 TI - Molecular and phenotypic characterization of Phialemonium and Lecythophora isolates from clinical samples. AB - Several members of the fungal genera Phialemonium and Lecythophora are occasional agents of severe human and animal infections. These species are difficult to identify, and relatively little is known about their frequency in the clinical setting. The objective of this study was to characterize morphologically and molecularly, on the basis of the analysis of large-subunit ribosomal DNA sequences, a set of 68 clinical isolates presumed to belong to these genera. A total of 59 isolates were determined to be Phialemonium species (n = 32) or a related Cephalotheca species (n = 6) or Lecythophora species (n = 20) or a related Coniochaeta species (n = 1). Nine isolates identified to be Acremonium spp. or Phaeoacremonium spp. were excluded from further study. The most common species were Phialemonium obovatum and Phialemonium curvatum, followed by Lecythophora hoffmannii, Cephalotheca foveolata, and Lecythophora mutabilis. PMID- 21270236 TI - Natural killer cells from children with type 1 diabetes have defects in NKG2D dependent function and signaling. AB - OBJECTIVE: Natural killer (NK) cells from NOD mice have numeric and functional abnormalities, and restoration of NK cell function prevents autoimmune diabetes in NOD mice. However, little is known about the number and function of NK cells in humans affected by type 1 diabetes. Therefore, we evaluated the phenotype and function of NK cells in a large cohort of type 1 diabetic children. RESEARCH DESIGN AND METHODS: Peripheral blood mononuclear blood cells were obtained from subjects whose duration of disease was between 6 months and 2 years. NK cells were characterized by flow cytometry, enzyme-linked immunosorbent spot assays, and cytotoxicity assays. Signaling through the activating NK cell receptor, NKG2D, was assessed by immunoblotting and reverse-phase phosphoprotein lysate microarray. RESULTS: NK cells from type 1 diabetic subjects were present at reduced cell numbers compared with age-matched, nondiabetic control subjects and had diminished responses to the cytokines interleukin (IL)-2 and IL-15. Analysis before and after IL-2 stimulation revealed that unlike NK cells from nondiabetic control subjects, NK cells from type 1 diabetic subjects failed to downregulate the NKG2D ligands, major histocompatibility complex class I-related chains A and B, upon activation. Moreover, type 1 diabetic NK cells also exhibited decreased NKG2D-dependent cytotoxicity and interferon-gamma secretion. Finally, type 1 diabetic NK cells showed clear defects in NKG2D-mediated activation of the phosphoinositide 3-kinase-AKT pathway. CONCLUSIONS: These results are the first to demonstrate that type 1 diabetic subjects have aberrant signaling through the NKG2D receptor and suggest that NK cell dysfunction contributes to the autoimmune pathogenesis of type 1 diabetes. PMID- 21270237 TI - Sodium phenylbutyrate, a drug with known capacity to reduce endoplasmic reticulum stress, partially alleviates lipid-induced insulin resistance and beta-cell dysfunction in humans. AB - OBJECTIVE: Chronically elevated free fatty acids contribute to insulin resistance and pancreatic beta-cell failure. Among numerous potential factors, the involvement of endoplasmic reticulum (ER) stress has been postulated to play a mechanistic role. Here we examined the efficacy of the chemical chaperone, sodium phenylbutyrate (PBA), a drug with known capacity to reduce ER stress in animal models and in vitro, on lipid-induced insulin resistance and beta-cell dysfunction in humans. RESEARCH DESIGN AND METHODS: Eight overweight or obese nondiabetic men underwent four studies each, in random order, 4 to 6 weeks apart. Two studies were preceded by 2 weeks of oral PBA (7.5 g/day), followed by a 48-h i.v. infusion of intralipid/heparin or saline, and two studies were preceded by placebo treatment, followed by similar infusions. Insulin secretion rates (ISRs) and sensitivity (S(I)) were assessed after the 48-h infusions by hyperglycemic and hyperinsulinemic-euglycemic clamps, respectively. RESULTS: Lipid infusion reduced S(I), which was significantly ameliorated by pretreatment with PBA. Absolute ISR was not affected by any treatment; however, PBA partially ameliorated the lipid-induced reduction in the disposition index (DI = ISR * S(I)), indicating that PBA prevented lipid-induced beta-cell dysfunction. CONCLUSIONS: These results suggest that PBA may provide benefits in humans by ameliorating the insulin resistance and beta-cell dysfunction induced by prolonged elevation of free fatty acids. PMID- 21270238 TI - Ongoing beta-cell turnover in adult nonhuman primates is not adaptively increased in streptozotocin-induced diabetes. AB - OBJECTIVE: beta-Cell turnover and its potential to permit beta-cell regeneration in adult primates are unknown. Our aims were 1) to measure beta-cell turnover in adult nonhuman primates; 2) to establish the relative contribution of beta-cell replication and formation of new beta-cells from other precursors (defined thus as beta-cell neogenesis); and 3) to establish whether there is an adaptive increase in beta-cell formation (attempted regeneration) in streptozotocin (STZ) induced diabetes in adult nonhuman primates. RESEARCH DESIGN AND METHODS: Adult (aged 7 years) vervet monkeys were administered STZ (45-55 mg/kg, n = 7) or saline (n = 9). Pancreas was obtained from each animal twice, first by open surgical biopsy and then by euthanasia. beta-Cell turnover was evaluated by applying a mathematic model to measured replication and apoptosis rates. RESULTS: beta-Cell turnover is present in adult nonhuman primates (3.3 +/- 0.9 mg/month), mostly (~80%) derived from beta-cell neogenesis. beta-Cell formation was minimal in STZ-induced diabetes. Despite marked hyperglycemia, beta-cell apoptosis was not increased in monkeys administered STZ. CONCLUSIONS: There is ongoing beta cell turnover in adult nonhuman primates that cannot be accounted for by beta cell replication. There is no evidence of beta-cell regeneration in monkeys administered STZ. Hyperglycemia does not induce beta-cell apoptosis in nonhuman primates in vivo. PMID- 21270239 TI - Genetic defects in human pericentrin are associated with severe insulin resistance and diabetes. AB - OBJECTIVE: Genetic defects in human pericentrin (PCNT), encoding the centrosomal protein pericentrin, cause a form of osteodysplastic primordial dwarfism that is sometimes reported to be associated with diabetes. We thus set out to determine the prevalence of diabetes and insulin resistance among patients with PCNT defects and examined the effects of pericentrin depletion on insulin action using 3T3-L1 adipocytes as a model system. RESEARCH DESIGN AND METHODS: A cross sectional metabolic assessment of 21 patients with PCNT mutations was undertaken. Pericentrin expression in human tissues was profiled using quantitative real-time PCR. The effect of pericentrin knockdown on insulin action and adipogenesis in 3T3-L1 adipocytes was determined using Oil red O staining, gene-expression analysis, immunoblotting, and glucose uptake assays. Pericentrin expression and localization also was determined in skeletal muscle. RESULTS: Of 21 patients with genetic defects in PCNT, 18 had insulin resistance, which was severe in the majority of subjects. Ten subjects had confirmed diabetes (mean age of onset 15 years [range 5-28]), and 13 had metabolic dyslipidemia. All patients without insulin resistance were younger than 4 years old. Knockdown of pericentrin in adipocytes had no effect on proximal insulin signaling but produced a twofold impairment in insulin-stimulated glucose uptake, approximately commensurate with an associated defect in cell proliferation and adipogenesis. Pericentrin was highly expressed in human skeletal muscle, where it showed a perinuclear distribution. CONCLUSIONS: Severe insulin resistance and premature diabetes are common features of PCNT deficiency but are not congenital. Partial failure of adipocyte differentiation may contribute to this, but pericentrin deficiency does not impair proximal insulin action in adipocytes. PMID- 21270240 TI - An allele of IKZF1 (Ikaros) conferring susceptibility to childhood acute lymphoblastic leukemia protects against type 1 diabetes. AB - OBJECTIVE: IKZF1 encoding Ikaros, an essential regulator of lymphopoiesis and immune homeostasis, has been implicated in the development of childhood acute lymphoblastic leukemia (C-ALL). Because recent genome-wide association (GWA) studies have linked a region of the 3'-UTR of IKZF1 with C-ALL susceptibility, we tested whether IKZF1 is associated with the autoimmune disease type 1 diabetes. RESEARCH DESIGN AND METHODS: rs10272724 (T>C) near IKZF1 at 7p12 was genotyped in 8,333 individuals with type 1 diabetes, 9,947 control subjects, and 3,997 families of European ancestry. Association was tested using logistic regression in the case-control data and by the transmission disequilibrium test in the families. Expression data for IKZF1 by rs10272724 genotype were obtained using quantitative PCR of mRNA/cDNA generated from peripheral blood mononuclear cells from 88 individuals, whereas expression data for five other neighboring genes were obtained from the online Genevar dataset. RESULTS: The minor allele of rs10272724 (C) was found to be protective from type 1 diabetes (odds ratio 0.87 [95% CI 0.83-0.91]; P = 1.1 * 10(-11)). rs10272724 was not correlated with levels of two transcripts of IKZF1 in peripheral blood mononuclear cells. CONCLUSIONS: The major susceptibility genotype for C-ALL confers protection from type 1 diabetes. Our finding strengthens the link between autoimmunity and lymphoid cancers. Further investigation is warranted for the genetic effect marked by rs10272724, its impact on IKZF1, and the role of Ikaros and other family members, Ailios (IKZF3) and Eos (IKZF4), in autoimmunity. PMID- 21270241 TI - Intracavernous delivery of a designed angiopoietin-1 variant rescues erectile function by enhancing endothelial regeneration in the streptozotocin-induced diabetic mouse. AB - OBJECTIVE: Patients with diabetic erectile dysfunction often have severe endothelial dysfunction and respond poorly to oral phosphodiesterase-5 inhibitors. We examined the effectiveness of the potent angiopoietin-1 (Ang1) variant, cartilage oligomeric matrix protein (COMP)-Ang1, in promoting cavernous endothelial regeneration and restoring erectile function in diabetic animals. RESEARCH DESIGN AND METHODS: Four groups of mice were used: controls; streptozotocin (STZ)-induced diabetic mice; STZ-induced diabetic mice treated with repeated intracavernous injections of PBS; and STZ-induced diabetic mice treated with COMP-Ang1 protein (days -3 and 0). Two and 4 weeks after treatment, we measured erectile function by electrical stimulation of the cavernous nerve. The penis was harvested for histologic examinations, Western blot analysis, and cGMP quantification. We also performed a vascular permeability test. RESULTS: Local delivery of the COMP-Ang1 protein significantly increased cavernous endothelial proliferation, endothelial nitric oxide (NO) synthase (NOS) phosphorylation, and cGMP expression compared with that in the untreated or PBS treated STZ-induced diabetic group. The changes in the group that received COMP Ang1 restored erectile function up to 4 weeks after treatment. Endothelial protective effects, such as marked decreases in the expression of p47(phox) and inducible NOS, in the generation of superoxide anion and nitrotyrosine, and in the number of apoptotic cells in the corpus cavernosum tissue, were noted in COMP Ang1-treated STZ-induced diabetic mice. An intracavernous injection of COMP-Ang1 completely restored endothelial cell-cell junction proteins and decreased cavernous endothelial permeability. COMP-Ang1-induced promotion of cavernous angiogenesis and erectile function was abolished by the NOS inhibitor, N-nitro-L arginine methyl ester, but not by the NADPH oxidase inhibitor, apocynin. CONCLUSIONS: These findings support the concept of cavernous endothelial regeneration by use of the recombinant Ang1 protein as a curative therapy for diabetic erectile dysfunction. PMID- 21270242 TI - Activation of peroxisome proliferator-activated receptor delta inhibits streptozotocin-induced diabetic nephropathy through anti-inflammatory mechanisms in mice. AB - OBJECTIVE: Activation of the nuclear hormone receptor peroxisome proliferator activated receptor (PPAR)-delta has been shown to improve insulin resistance, adiposity, and plasma HDL levels. Several studies have reported that activation of PPARdelta is atheroprotective; however, the role of PPARdelta in renal function remains unclear. Here, we report the renoprotective effects of PPARdelta activation in a model of streptozotocin-induced diabetic nephropathy. RESEARCH DESIGN AND METHODS: Eight-week-old male C57BL/6 mice were divided into three groups: 1) nondiabetic control mice, 2) diabetic mice, and 3) diabetic mice treated with the PPARdelta agonist GW0742 (1 mg/kg/day). GW0742 was administered by gavage for 8 weeks after inducing diabetes. RESULTS: GW0742 decreased urinary albumin excretion without altering blood glucose levels. Macrophage infiltration, mesangial matrix accumulation, and type IV collagen deposition were substantially attenuated by GW0742. The gene expression of inflammatory mediators in the kidney cortex, such as monocyte chemoattractant protein-1 (MCP-1) and osteopontin (OPN), was also suppressed. In vitro studies demonstrated that PPARdelta activation increased the expression of anti-inflammatory corepressor B-cell lymphoma-6, which subsequently suppressed MCP-1 and OPN expression. CONCLUSIONS: These findings uncover a previously unrecognized mechanism for the renoprotective effects of PPARdelta agonists and support the concept that PPARdelta agonists may offer a novel therapeutic approach for the treatment of diabetic nephropathy. PMID- 21270243 TI - Comment on: Soranzo et al. Common variants at 10 genomic loci influence hemoglobin A1C levels via glycemic and nonglycemic pathways. Diabetes 2010;59:3229-3239. PMID- 21270245 TI - Comment on: Meagher et al. Neutralization of interleukin-16 protects nonobese diabetic mice from autoimmune type 1 diabetes by a CCL4-dependent mechanism. Diabetes 2010;59:2862-2871. PMID- 21270247 TI - It's time to consider changing the rules: the rationale for rethinking control groups in clinical trials aimed at reversing type 1 diabetes. PMID- 21270248 TI - Historical perspective: beginnings of the beta-cell: current perspectives in beta cell development. PMID- 21270249 TI - Glucagon as a critical factor in the pathology of diabetes. PMID- 21270250 TI - A therapeutic insight in beta-cell imaging? PMID- 21270251 TI - Glucagon receptor knockout prevents insulin-deficient type 1 diabetes in mice. AB - OBJECTIVE: To determine the role of glucagon action in the metabolic phenotype of untreated insulin deficiency. RESEARCH DESIGN AND METHODS: We compared pertinent clinical and metabolic parameters in glucagon receptor-null (Gcgr(-/-)) mice and wild-type (Gcgr(+/+)) controls after equivalent destruction of beta-cells. We used a double dose of streptozotocin to maximize beta-cell destruction. RESULTS: Gcgr(+/+) mice became hyperglycemic (>500 mg/dL), hyperketonemic, polyuric, and cachectic and had to be killed after 6 weeks. Despite comparable beta-cell destruction in Gcgr(-/-) mice, none of the foregoing clinical or laboratory manifestations of diabetes appeared. There was marked alpha-cell hyperplasia and hyperglucagonemia (~1,200 pg/mL), but hepatic phosphorylated cAMP response element binding protein and phosphoenolpyruvate carboxykinase mRNA were profoundly reduced compared with Gcgr(+/+) mice with diabetes--evidence that glucagon action had been effectively blocked. Fasting glucose levels and oral and intraperitoneal glucose tolerance tests were normal. Both fasting and nonfasting free fatty acid levels and nonfasting beta-hydroxy butyrate levels were lower. CONCLUSIONS: We conclude that blocking glucagon action prevents the deadly metabolic and clinical derangements of type 1 diabetic mice. PMID- 21270252 TI - Hepatic glycogen supercompensation activates AMP-activated protein kinase, impairs insulin signaling, and reduces glycogen deposition in the liver. AB - OBJECTIVE: The objective of this study was to determine how increasing the hepatic glycogen content would affect the liver's ability to take up and metabolize glucose. RESEARCH DESIGN AND METHODS: During the first 4 h of the study, liver glycogen deposition was stimulated by intraportal fructose infusion in the presence of hyperglycemic-normoinsulinemia. This was followed by a 2-h hyperglycemic-normoinsulinemic control period, during which the fructose infusion was stopped, and a 2-h experimental period in which net hepatic glucose uptake (NHGU) and disposition (glycogen, lactate, and CO(2)) were measured in the absence of fructose but in the presence of a hyperglycemic-hyperinsulinemic challenge including portal vein glucose infusion. RESULTS: Fructose infusion increased net hepatic glycogen synthesis (0.7 +/- 0.5 vs. 6.4 +/- 0.4 mg/kg/min; P < 0.001), causing a large difference in hepatic glycogen content (62 +/- 9 vs. 100 +/- 3 mg/g; P < 0.001). Hepatic glycogen supercompensation (fructose infusion group) did not alter NHGU, but it reduced the percent of NHGU directed to glycogen (79 +/- 4 vs. 55 +/- 6; P < 0.01) and increased the percent directed to lactate (12 +/- 3 vs. 29 +/- 5; P = 0.01) and oxidation (9 +/- 3 vs. 16 +/- 3; P = NS). This change was associated with increased AMP-activated protein kinase phosphorylation, diminished insulin signaling, and a shift in glycogenic enzyme activity toward a state discouraging glycogen accumulation. CONCLUSIONS: These data indicate that increases in hepatic glycogen can generate a state of hepatic insulin resistance, which is characterized by impaired glycogen synthesis despite preserved NHGU. PMID- 21270253 TI - Diet-induced muscle insulin resistance is associated with extracellular matrix remodeling and interaction with integrin alpha2beta1 in mice. AB - OBJECTIVE: The hypothesis that high-fat (HF) feeding causes skeletal muscle extracellular matrix (ECM) remodeling in C57BL/6J mice and that this remodeling contributes to diet-induced muscle insulin resistance (IR) through the collagen receptor integrin alpha(2)beta(1) was tested. RESEARCH DESIGN AND METHODS: The association between IR and ECM remodeling was studied in mice fed chow or HF diet. Specific genetic and pharmacological murine models were used to study effects of HF feeding on ECM in the absence of IR. The role of ECM-integrin interaction in IR was studied using hyperinsulinemic-euglycemic clamps on integrin alpha(2)beta(1)-null (itga2(-/-)), integrin alpha(1)beta(1)-null (itga1( /-)), and wild-type littermate mice fed chow or HF. Integrin alpha(2)beta(1) and integrin alpha(1)beta(1) signaling pathways have opposing actions. RESULTS: HF fed mice had IR and increased muscle collagen (Col) III and ColIV protein; the former was associated with increased transcript, whereas the latter was associated with reduced matrix metalloproteinase 9 activity. Rescue of muscle IR by genetic muscle-specific mitochondria-targeted catalase overexpression or by the phosphodiesterase 5a inhibitor, sildenafil, reversed HF feeding effects on ECM remodeling and increased muscle vascularity. Collagen remained elevated in HF fed itga2(-/-) mice. Nevertheless, muscle insulin action and vascularity were increased. Muscle IR in HF-fed itga1(-/-) mice was unchanged. Insulin sensitivity in chow-fed itga1(-/-) and itga2(-/-) mice was not different from wild-type littermates. CONCLUSIONS: ECM collagen expansion is tightly associated with muscle IR. Studies with itga2(-/-) mice provide mechanistic insight for this association by showing that the link between muscle IR and increased collagen can be uncoupled by the absence of collagen-integrin alpha(2)beta(1) interaction. PMID- 21270254 TI - The adipocyte-expressed forkhead transcription factor Foxc2 regulates metabolism through altered mitochondrial function. AB - OBJECTIVE: Previous findings demonstrate that enhanced expression of the forkhead transcription factor Foxc2 in adipose tissue leads to a lean and insulin sensitive phenotype. These findings prompted us to further investigate the role of Foxc2 in the regulation of genes of fundamental importance for metabolism and mitochondrial function. RESEARCH DESIGN AND METHODS: The effects of Foxc2 on expression of genes involved in mitochondriogenesis and mitochondrial function were assessed by quantitative real-time PCR. The potential of a direct transcriptional regulation of regulated genes was tested in promoter assays, and mitochondrial morphology was investigated by electron microscopy. Mitochondrial function was tested by measuring oxygen consumption and extracellular acidification rates as well as palmitate oxidation. RESULTS: Enhanced expression of FOXC2 in adipocytes or in cells with no endogenous Foxc2 expression induces mitochondriogenesis and an elongated mitochondrial morphology. Together with increased aerobic metabolic capacity, increased palmitate oxidation, and upregulation of genes encoding respiratory complexes and of brown fat-related genes, Foxc2 also specifically induces mitochondrial fusion genes in adipocytes. Among tested forkhead genes, Foxc2 is unique in its ability to trans-activate the nuclear-encoded mitochondrial transcription factor A (mtTFA/Tfam) gene--a master regulator of mitochondrial biogenesis. In human adipose tissue the expression levels of mtTFA/Tfam and of fusion genes also correlate with that of Foxc2. CONCLUSIONS: We previously showed that a high-calorie diet and insulin induce Foxc2 in adipocytes; the current findings identify a previously unknown role for Foxc2 as an important metabo-regulator of mitochondrial morphology and metabolism. PMID- 21270255 TI - Participation of hindbrain AMP-activated protein kinase in glucoprivic feeding. AB - OBJECTIVE: To examine the role of AMP-activated protein kinase (AMPK) in the control of glucoprivic feeding by hindbrain catecholamine neurons. RESEARCH DESIGN AND METHODS: Micropunched hindbrain samples were collected from control and 2-deoxy-d-glucose (2DG)-injected rats for Western blot analysis of phosphorylated (activated) AMPK (pAMPK). Samples also were collected from 2DG injected rats pretreated with anti-dopamine-beta-hydroxylase conjugated to saporin to lesion hindbrain catecholamine neurons. In a second experiment, rats were given a fourth-ventricle injection of compound C (CC) or 5-aminoimidazole-4 carboxyamide ribonucleoside (AICAR), an inhibitor and activator of AMPK, to identify a role for AMPK in hindbrain neurons required for elicitation of 2DG induced feeding. RESULTS: Systemic 2DG stimulated food intake in controls but not in catecholamine-lesioned rats. In controls, but not catecholamine-lesioned rats, 2DG also increased phosphorylated Thr172 at AMPKalpha subunits (pAMPKalpha) in hindbrain micropunches containing catecholaminergic cell groups A1 through the middle region of C1 (A1-C1m). Increased pAMPKalpha was not observed in the adjacent noncatecholaminergic ventromedial medulla or in the A2-C2 catecholamine cell groups in the dorsal hindbrain. Fourth-ventricle injection of CC attenuated 2DG-induced feeding during the first 2 h of the test, and AICAR alone increased food intake only during the first 60 min of the 4-h test. CONCLUSIONS: Results indicate that AMPK in catecholaminergic A1-C1m neurons is activated by glucoprivation. Therefore, AMPK may contribute to the glucose-sensing mechanism by which these neurons detect and signal a glucose deficit in the service of systemic glucoregulation. PMID- 21270256 TI - Effects of insulin on brain glucose metabolism in impaired glucose tolerance. AB - OBJECTIVE: Insulin stimulates brain glucose metabolism, but this effect of insulin is already maximal at fasting concentrations in healthy subjects. It is not known whether insulin is able to stimulate glucose metabolism above fasting concentrations in patients with impaired glucose tolerance. RESEARCH DESIGN AND METHODS: We studied the effects of insulin on brain glucose metabolism and cerebral blood flow in 13 patients with impaired glucose tolerance and nine healthy subjects using positron emission tomography (PET). All subjects underwent PET with both [(18)F]fluorodeoxyglucose (for brain glucose metabolism) and [(15)O]H(2)O (for cerebral blood flow) in two separate conditions (in the fasting state and during a euglycemic-hyperinsulinemic clamp). Arterial blood samples were acquired during the PET scans to allow fully quantitative modeling. RESULTS: The hyperinsulinemic clamp increased brain glucose metabolism only in patients with impaired glucose tolerance (whole brain: +18%, P = 0.001) but not in healthy subjects (whole brain: +3.9%, P = 0.373). The hyperinsulinemic clamp did not alter cerebral blood flow in either group. CONCLUSIONS: We found that insulin stimulates brain glucose metabolism at physiological postprandial levels in patients with impaired glucose tolerance but not in healthy subjects. These results suggest that insulin stimulation of brain glucose metabolism is maximal at fasting concentrations in healthy subjects but not in patients with impaired glucose tolerance. PMID- 21270257 TI - Distinct roles of endothelial and adipocyte caveolin-1 in macrophage infiltration and adipose tissue metabolic activity. AB - OBJECTIVE: Defective caveolin-1 expression is now recognized as a cause of lipoatrophic diabetes in patients, due to primary caveolin gene mutations or secondary caveolin deficiency caused by PTRF/cavin gene defects. The goal of this study was to establish the relative contribution of endothelial cells and adipocytes, both highly expressing caveolin-1 to the lipoatrophic phenotype of mice with global caveolin-1 gene invalidation (Cav1-KO). RESEARCH DESIGN AND METHODS: We compared adipose tissue development and metabolic phenotype of wild type (WT), lipoatrophic Cav1-KO, and a murine model with specific rescue of caveolin-1 expression in endothelial cells (caveolin-1-reconstituted [Cav1-RC]). RESULTS: Defective adipose tissue development, reduced adipocyte size, and global alteration in adipose tissue gene expression that characterize lipoatrophic caveolin-1 null mice were still observed in Cav1-RC, indicating a prominent role of adipocyte-derived caveolin in lipoatrophy. We also observed that Cav1-KO adipose tissue contained an increased proportion of infiltrated macrophages compared with control mice, mostly with an alternate activation M2 phenotype. In contrast with defective lipid storage and lipoatrophy, macrophage infiltration was normalized in Cav1-RC mice, pointing to caveolin-1-dependent endothelium permeability as the causing factor for adipose tissue macrophage infiltration in this model. CONCLUSIONS: This is the first report of a specific role for adipocyte caveolin expression in lipid storage. Our study also shows that endothelium caveolin critically participates in the control of macrophage extravasation from the blood into adipose tissue, therefore establishing distinct roles depending on topology of caveolin expression in different cell types of adipose tissue. PMID- 21270258 TI - Phosphatidylinositol-4-phosphate-5-kinase alpha deficiency alters dynamics of glucose-stimulated insulin release to improve glucohomeostasis and decrease obesity in mice. AB - OBJECTIVE: Phosphatidylinositol-4-phosphate-5-kinase (PI4P5K) has been proposed to facilitate regulated exocytosis and specifically insulin secretion by generating phosphatidylinositol-4,5-bisphosphate (PIP(2)). We sought to examine the role of the alpha isoform of PI4P5K in glucohomeostasis and insulin secretion. RESEARCH DESIGN AND METHODS: The response of PI4P5Kalpha(-/-) mice to glucose challenge and a type 2-like diabetes-inducing high-fat diet was examined in vivo. Glucose-stimulated responses and PI4P5Kalpha(-/-) pancreatic islets and beta-cells were characterized in culture. RESULTS: We show that PI4P5Kalpha(-/-) mice exhibit increased first-phase insulin release and improved glucose clearance, and resist high-fat diet-induced development of type 2-like diabetes and obesity. PI4P5Kalpha(-/-) pancreatic islets cultured in vitro exhibited decreased numbers of insulin granules docked at the plasma membrane and released less insulin under quiescent conditions, but then secreted similar amounts of insulin on glucose stimulation. Stimulation-dependent PIP(2) depletion occurred on the plasma membrane of the PI4P5Kalpha(-/-) pancreatic beta-cells, accompanied by a near-total loss of cortical F-actin, which was already decreased in the PI4P5Kalpha(-/-) beta-cells under resting conditions. CONCLUSIONS: Our findings suggest that PI4P5Kalpha plays a complex role in restricting insulin release from pancreatic beta-cells through helping to maintain plasma membrane PIP(2) levels and integrity of the actin cytoskeleton under both basal and stimulatory conditions. The increased first-phase glucose-stimulated release of insulin observed on the normal diet may underlie the partial protection against the elevated serum glucose and obesity seen in type 2 diabetes-like model systems. PMID- 21270259 TI - Smad3 deficiency in mice protects against insulin resistance and obesity induced by a high-fat diet. AB - OBJECTIVE: Obesity and associated pathologies are major global health problems. Transforming growth factor-beta/Smad3 signaling has been implicated in various metabolic processes, including adipogenesis, insulin expression, and pancreatic beta-cell function. However, the systemic effects of Smad3 deficiency on adiposity and insulin resistance in vivo remain elusive. This study investigated the effects of Smad3 deficiency on whole-body glucose and lipid homeostasis and its contribution to the development of obesity and type 2 diabetes. RESEARCH DESIGN AND METHODS: We compared various metabolic profiles of Smad3-knockout and wild-type mice. We also determined the mechanism by which Smad3 deficiency affects the expression of genes involved in adipogenesis and metabolism. Mice were then challenged with a high-fat diet to study the impact of Smad3 deficiency on the development of obesity and insulin resistance. RESULTS: Smad3-knockout mice exhibited diminished adiposity with improved glucose tolerance and insulin sensitivity. Chromatin immunoprecipitation assay revealed that Smad3 deficiency increased CCAAT/enhancer-binding protein beta-C/EBP homologous protein 10 interaction and exerted a differential regulation on proliferator-activated receptor beta/delta and proliferator-activated receptor gamma expression in adipocytes. Focused gene expression profiling revealed an altered expression of genes involved in adipogenesis, lipid accumulation, and fatty acid beta oxidation, indicative of altered adipose physiology. Despite reduced physical activity with no modification in food intake, these mutant mice were resistant to obesity and insulin resistance induced by a high-fat diet. CONCLUSIONS: Smad3 is a multifaceted regulator in adipose physiology and the pathogenesis of obesity and type 2 diabetes, suggesting that Smad3 may be a potential target for the treatment of obesity and its associated disorders. PMID- 21270260 TI - Selective inactivation of c-Jun NH2-terminal kinase in adipose tissue protects against diet-induced obesity and improves insulin sensitivity in both liver and skeletal muscle in mice. AB - OBJECTIVE: Obesity is associated with increased activation of the c-Jun NH(2) terminal kinase (JNK) in several metabolic organs, including adipose tissue, liver, and skeletal muscle. In this study, we aimed to define the role of JNK activation in adipose tissue in the development of obesity-related insulin resistance. RESEARCH DESIGN AND METHODS: Transgenic mice with adipose tissue specific overexpression of dominant-negative JNK (ap2-dn-JNK) under the transcriptional control of the aP2 gene promoter were generated and subjected to metabolic characterization together with the wild-type littermates. RESULTS: On a high-fat diet (HFD), the ap2-dn-JNK mice displayed a marked suppression of both JNK1 and JNK2 activation in their adipose tissue, accompanied by a marked reduction in weight gain, fat mass, and size of the adipocytes. The transgenic mice were resistant to the deleterious impact of an HFD on systemic insulin sensitivity, glucose tolerance, and hepatic steatosis. Reduced hepatic gluconeogenesis was evident in in vivo and ex vivo studies and showed greater insulin-induced glucose uptake in skeletal muscles. These changes were accompanied by reduced macrophage infiltration in adipose tissue, decreased production of proinflammatory adipokines, and increased expression of adiponectin. Indirect calorimetry analysis showed that the transgenic mice had significant increases in oxygen consumption and reductions in respiration exchange rates compared with their wild-type littermates. CONCLUSIONS: Selective suppression of JNK activation in adipose tissue alone is sufficient to counteract HFD-induced obesity and its associated metabolic dysregulations, in part through an increase in energy expenditure and a decrease in systemic inflammation. PMID- 21270261 TI - A newly identified CG301269 improves lipid and glucose metabolism without body weight gain through activation of peroxisome proliferator-activated receptor alpha and gamma. AB - OBJECTIVE: Peroxisome proliferator-activated receptor (PPAR)-alpha/gamma dual agonists have been developed to alleviate metabolic disorders. However, several PPARalpha/gamma dual agonists are accompanied with unwanted side effects, including body weight gain, edema, and tissue failure. This study investigated the effects of a novel PPARalpha/gamma dual agonist, CG301269, on metabolic disorders both in vitro and in vivo. RESEARCH DESIGN AND METHODS: Function of CG301269 as a PPARalpha/gamma dual agonist was assessed in vitro by luciferase reporter assay, mammalian one-hybrid assay, and analyses of PPAR target genes. In vitro profiles on fatty acid oxidation and inflammatory responses were acquired by fatty acid oxidation assay and quantitative (q)RT-PCR of proinflammatory genes. In vivo effect of CG301269 was examined in db/db mice. Total body weight and various tissue weights were measured, and hepatic lipid profiles were analyzed. Systemic glucose and insulin tolerance were measured, and the in vivo effect of CG301269 on metabolic genes and proinflammatory genes was examined by qRT-PCR. RESULTS: CG301269 selectively stimulated the transcriptional activities of PPARalpha and PPARgamma. CG301269 enhanced fatty acid oxidation in vitro and ameliorated insulin resistance and hyperlipidemia in vivo. In db/db mice, CG301269 reduced inflammatory responses and fatty liver, without body weight gain. CONCLUSIONS: We demonstrate that CG301269 exhibits beneficial effects on glucose and lipid metabolism by simultaneous activation of both PPARalpha and PPARgamma. Our data suggest that CG301269 would be a potential lead compound against obesity and related metabolic disorders. PMID- 21270262 TI - Hypoxia-induced intrauterine growth restriction increases the susceptibility of rats to high-fat diet-induced metabolic syndrome. AB - OBJECTIVE: It is recognized that there is a remarkable variability in the systemic response to high-fat (HF) diets that cannot be completely explained by genetic factors. In addition, pregnancy complications leading to intrauterine growth restriction (IUGR) have been associated with an increased risk of developing metabolic syndrome (MetS) later in life. Thus, we hypothesized that offspring born with IUGR exhibit permanent metabolic changes that make them more susceptible to HF diet-induced MetS. RESEARCH DESIGN AND METHODS: SD rats born normal (control) or with hypoxia-induced IUGR were randomized to low-fat (10% fat) or HF (45% fat) diets. After 9 weeks of feeding, physiological and molecular pathways involved in the MetS were evaluated. RESULTS: IUGR offspring exhibited decreased energy intake and physical activity relative to controls. In offspring fed a HF diet, IUGR was associated with decreased total body fat content, a relative increase in intra-abdominal fat deposition and adipocyte size, an increase in fasting plasma concentrations of leptin, triglyceride and free fatty acids, and an increased concentration of triglycerides and ceramides in both liver and skeletal muscle. These changes in lipid homeostasis were accompanied by in vivo insulin resistance and impaired glucose tolerance and associated with increased phosphorylation of protein kinase C , inhibition of insulin receptor substrate 1, and a decreased activation of protein kinase B (PKB; also known as Akt) in liver and skeletal muscle in response to insulin. CONCLUSIONS: IUGR enhances specific deleterious metabolic responses to a HF diet. Our results suggest that offspring born with IUGR may require special attention and follow-up to prevent the early onset of MetS. PMID- 21270263 TI - Hyperglycemia activates caspase-1 and TXNIP-mediated IL-1beta transcription in human adipose tissue. AB - OBJECTIVE: Obesity is characterized by elevated levels of proinflammatory cytokines, including interleukin (IL)-1beta, that contribute to the development of insulin resistance. In this study, we set out to investigate whether hyperglycemia drives IL-1beta production and caspase-1 activation in murine and human adipose tissue, thus inducing insulin resistance. RESEARCH DESIGN AND METHODS: ob/ob animals were used as a model to study obesity and hyperglycemia. Human adipose tissue fragments or adipocytes were cultured in medium containing normal or high glucose levels. Additionally, the role of thioredoxin interacting protein (TXNIP) in glucose-induced IL-1beta production was assessed. RESULTS: TXNIP and caspase-1 protein levels were more abundantly expressed in adipose tissue of hyperglycemic ob/ob animals as compared with wild-type mice. In human adipose tissue, high glucose resulted in a 10-fold upregulation of TXNIP gene expression levels (P < 0.01) and a 10% elevation of caspase-1 activity (P < 0.05), together with induction of IL-1beta transcription (twofold, P < 0.01) and a significant increase in IL-1beta secretion. TXNIP suppression in human adipocytes, either by a small interfering RNA approach or a peroxisome proliferator-activated receptor-gamma agonist, counteracted the effects of high glucose on bioactive IL-1 production (P < 0.01) mainly through a decrease in transcription levels paralleled by reduced intracellular pro-IL-1beta levels. CONCLUSIONS: High glucose activates caspase-1 in human and murine adipose tissue. Glucose-induced activation of TXNIP mediates IL-1beta mRNA expression levels and intracellular pro-IL-1beta accumulation in adipose tissue. The concerted actions lead to enhanced secretion of IL-1beta in adipose tissue that may contribute to the development of insulin resistance. PMID- 21270264 TI - Interleukin-6 enhances glucose-stimulated insulin secretion from pancreatic beta cells: potential involvement of the PLC-IP3-dependent pathway. AB - OBJECTIVE: Interleukin-6 (IL-6) has a significant impact on glucose metabolism. However, the effects of IL-6 on insulin secretion from pancreatic beta-cells are controversial. Therefore, we analyzed IL-6 effects on pancreatic beta-cell functions both in vivo and in vitro. RESEARCH DESIGN AND METHODS: First, to examine the effects of IL-6 on in vivo insulin secretion, we expressed IL-6 in the livers of mice using the adenoviral gene transfer system. In addition, using both MIN-6 cells, a murine beta-cell line, and pancreatic islets isolated from mice, we analyzed the in vitro effects of IL-6 pretreatment on insulin secretion. Furthermore, using pharmacological inhibitors and small interfering RNAs, we studied the intracellular signaling pathway through which IL-6 may affect insulin secretion from MIN-6 cells. RESULTS: Hepatic IL-6 expression raised circulating IL-6 and improved glucose tolerance due to enhancement of glucose stimulated insulin secretion (GSIS). In addition, in both isolated pancreatic islets and MIN 6 cells, 24-h pretreatment with IL-6 significantly enhanced GSIS. Furthermore, pretreatment of MIN-6 cells with phospholipase C (PLC) inhibitors with different mechanisms of action, U-73122 and neomycin, and knockdowns of the IL-6 receptor and PLC-beta(1), but not with a protein kinase A inhibitor, H-89, inhibited IL-6 induced enhancement of GSIS. An inositol triphosphate (IP(3)) receptor antagonist, Xestospondin C, also abrogated the GSIS enhancement induced by IL-6. CONCLUSIONS: The results obtained from both in vivo and in vitro experiments strongly suggest that IL-6 acts directly on pancreatic beta-cells and enhances GSIS. The PLC-IP(3)-dependent pathway is likely to be involved in IL-6-mediated enhancements of GSIS. PMID- 21270265 TI - The expression and function of glucose-dependent insulinotropic polypeptide in the embryonic mouse pancreas. AB - OBJECTIVE: Glucose-dependent insulinotropic polypeptide (GIP) is a member of a structurally related group of hormones that also includes glucagon, glucagon-like peptides, and secretin. GIP is an incretin, known to modulate glucose-induced insulin secretion. Recent studies have shown that glucagon is necessary for early insulin-positive differentiation, and a similar role for incretins in regulating embryonic insulin-positive differentiation seems probable. Here we studied the role of GIP signaling in insulin-positive differentiation in the embryonic mouse pancreas. RESEARCH DESIGN AND METHODS: The ontogeny of the GIP ligand and GIP receptor in the embryonic pancreas was investigated by immunohistochemistry and RT-PCR. GIP signaling was inhibited in cultured embryonic pancreata using morpholine-ring antisense against GIP ligand and receptor, or small interfering RNA (siRNA) for GIP ligand and receptor. Markers of endocrine cells and their progenitors were studied by immunohistochemistry and RT-PCR. RESULTS: GIP and GIP receptor mRNA were both detected in the embryonic pancreas by embryonic day 9.5 and then persisted throughout gestation. GIP was generally coexpressed with glucagon by immunostaining. The GIP receptor was typically coexpressed with insulin. Morpholine-ring antisense or siRNA against either GIP ligand or GIP receptor both inhibited the differentiation of insulin-positive cells. Inhibition of GIP or its receptor also led to a decrease in the number of Pdx-1-positive and sox9-positive cells in the cultured embryonic pancreas. The number of Pax6- and Nkx2.2-positive cells, representative of developing pancreatic endocrine cells and beta-cells, respectively, was also decreased. CONCLUSIONS: GIP signaling may play a role in early embryonic pancreas differentiation to form insulin-positive cells or beta-cells. PMID- 21270266 TI - Induction of mixed chimerism with MHC-mismatched but not matched bone marrow transplants results in thymic deletion of host-type autoreactive T-cells in NOD mice. AB - OBJECTIVE: Induction of mixed or complete chimerism via hematopoietic cell transplantation (HCT) from nonautoimmune donors could prevent or reverse type 1 diabetes (T1D). In clinical settings, HLA-matched HCT is preferred to facilitate engraftment and reduce the risk for graft versus host disease (GVHD). Yet autoimmune T1D susceptibility is associated with certain HLA types. Therefore, we tested whether induction of mixed chimerism with major histocompatibility complex (MHC)-matched donors could reverse autoimmunity in the NOD mouse model of T1D. RESEARCH DESIGN AND METHODS: Prediabetic wild-type or transgenic BDC2.5 NOD mice were conditioned with a radiation-free GVHD preventative anti-CD3/CD8 conditioning regimen and transplanted with bone marrow (BM) from MHC-matched or mismatched donors to induce mixed or complete chimerism. T1D development and thymic deletion of host-type autoreactive T-cells in the chimeric recipients were evaluated. RESULTS: Induction of mixed chimerism with MHC-matched nonautoimmune donor BM transplants did not prevent T1D in wild-type NOD mice, although induction of complete chimerism did prevent the disease. However, induction of either mixed or complete chimerism with MHC-mismatched BM transplants prevented T1D in such mice. Furthermore, induction of mixed chimerism in transgenic BDC2.5 NOD mice with MHC-matched or -mismatched MHC II(-/-) BM transplants failed to induce thymic deletion of de novo developed host-type autoreactive T-cells, whereas induction of mixed chimerism with mismatched BM transplants did. CONCLUSIONS: Induction of mixed chimerism with MHC-mismatched, but not matched, donor BM transplants re-establishes thymic deletion of host-type autoreactive T cells and prevents T1D, with donor antigen-presenting cell expression of mismatched MHC II molecules being required. PMID- 21270267 TI - Combined small interfering RNA therapy and in vivo magnetic resonance imaging in islet transplantation. AB - OBJECTIVE: Recent advances in human islet transplantation are hampered by significant graft loss shortly after transplantation and inability to follow islet fate directly. Both issues were addressed by utilizing a dual-purpose therapy/imaging small interfering RNA (siRNA)-nanoparticle probe targeting apoptotic-related gene caspase-3. We expect that treatment with the probe would result in significantly better survival of transplanted islets, which could be monitored by in vivo magnetic resonance imaging (MRI). RESEARCH DESIGN AND METHODS: We synthesized a probe consisting of therapeutic (siRNA to human caspase 3) and imaging (magnetic iron oxide nanoparticles, MN) moieties. In vitro testing of the probe included serum starvation of the islets followed by treatment with the probe. Caspase-3 gene silencing and protein expression were determined by RT PCR and Western blot, respectively. In vivo studies included serial MRI of NOD SCID mice transplanted with MN-small interfering (si)Caspase-3-labeled human islets under the left kidney capsule and MN-treated islets under the right kidney capsule. RESULTS: Treatment with MN-siCaspase-3 probe resulted in decrease of mRNA and protein expression in serum-starved islets compared with controls. In vivo MRI showed that there were significant differences in the relative volume change between MN-siCaspase-3-treated grafts and MN-labeled grafts. Histology revealed decreased caspase-3 expression and cell apoptosis in MN-siCaspase-3 treated grafts compared with the control side. CONCLUSIONS: Our data show the feasibility of combining siRNA therapy and in vivo monitoring of transplanted islets in mice. We observed a protective effect of MN-siCaspase-3 in treated islets both in vitro and in vivo. This study could potentially aid in increasing the success of clinical islet transplantation. PMID- 21270268 TI - Reduction in basal nitric oxide activity causes albuminuria. AB - OBJECTIVE: The barrier function of the glomerular filter has been studied for decades. Albuminuria reflects a malfunction of this barrier, and in animals dysfunctional endothelial nitric-oxide (NO) synthase results in albuminuria. We aimed to analyze the importance of NO for the glomerular barrier function in humans. RESEARCH DESIGN AND METHODS: To assess the effect of endothelial dysfunction on albuminuria, we measured the urine albumin-to-creatinine ratio (UACR) both before and after the blockade of NO synthases (NOSs) with systemic infusion of N(G)-monomethyl-L-arginine (L-NMMA) in two distinct study populations. In population A, 62 hypertensive patients with type 2 diabetes and, in population B, 22 patients with hypercholesterolemia but without hypertension or type 2 diabetes were examined. All subjects had normal renal function. RESULTS: There was a significant increase in the UACR in response to NOS inhibition with L-NMMA in hypertensive patients with type 2 diabetes (study population A) and in patients with hypercholesterolemia (study population B). Linear regression analyses revealed that the change in mean arterial presssure in response to L-NMMA was not related to the increase in the UACR in response to L NMMA in either population, even after adjusting for filtration fraction. CONCLUSIONS: NOS inhibition provokes albuminuria that is unrelated to changes in blood pressure. It is noteworthy that this finding was evident in patient groups prone to endothelial dysfunction and albuminuria. Thus, acute deterioration of endothelial function by reducing NO activity causes an increase in albuminuria. PMID- 21270269 TI - Thirty years of prospective nationwide incidence of childhood type 1 diabetes: the accelerating increase by time tends to level off in Sweden. AB - OBJECTIVE: During the past few decades, a rapidly increasing incidence of childhood type 1 diabetes (T1D) has been reported from many parts of the world. The change over time has been partly explained by changes in lifestyle causing rapid early growth and weight development. The current study models and analyzes the time trend by age, sex, and birth cohort in an exceptionally large study group. RESEARCH DESIGN AND METHODS: The present analysis involved 14,721 incident cases of T1D with an onset of 0-14.9 years that were recorded in the nationwide Swedish Childhood Diabetes Registry from 1978 to 2007. Data were analyzed using generalized additive models. RESULTS: Age- and sex-specific incidence rates varied from 21.6 (95% CI 19.4-23.9) during 1978-1980 to 43.9 (95% CI 40.7-47.3) during 2005-2007. Cumulative incidence by birth cohort shifted to a younger age at onset during the first 22 years, but from the birth year 2000 a statistically significant reversed trend (P < 0.01) was seen. CONCLUSIONS: Childhood T1D increased dramatically and shifted to a younger age at onset the first 22 years of the study period. We report a reversed trend, starting in 2000, indicating a change in nongenetic risk factors affecting specifically young children. PMID- 21270270 TI - Adrenergic mediation of hypoglycemia-associated autonomic failure. AB - OBJECTIVE: We tested the hypothesis that adrenergic activation, cholinergic activation, or both, mediate the effect of recent antecedent hypoglycemia to reduce the sympathoadrenal response to subsequent hypoglycemia, the key feature of hypoglycemia-associated autonomic failure in diabetes, in humans. RESEARCH DESIGN AND METHODS: Seventeen healthy adults were studied on 2 consecutive days on three occasions. Day 1 involved hyperinsulinemic euglycemic (90 mg/dL * 1 h), then hypoglycemic (54 mg/dL * 2 h) clamps, in the morning and afternoon on all three occasions with 1) saline infusion, 2) adrenergic blockade with the nonselective alpha-adrenergic and beta-adrenergic antagonists phentolamine and propranolol, or 3) adrenergic blockade plus cholinergic blockade with the muscarinic cholinergic antagonist atropine in random sequence. Day 2 involved similar morning euglycemic and hypoglycemic clamps, with saline infusion, on all three occasions. RESULTS: Compared with the responses to hypoglycemia during saline infusion on day 1, the plasma epinephrine and norepinephrine responses to hypoglycemia were reduced on day 2 (351 +/- 13 vs. 214 +/- 22 pg/mL for epinephrine and 252 +/- 4 vs. 226 +/- 7 pg/mL for norepinephrine during the last hour; both P < 0.0001). However, the plasma epinephrine and norepinephrine responses to hypoglycemia were not reduced on day 2 when adrenergic or adrenergic plus cholinergic blockade was produced during hypoglycemia on day 1. CONCLUSIONS: Adrenergic blockade prevents the effect of hypoglycemia to reduce the plasma catecholamine responses to subsequent hypoglycemia. Thus, adrenergic activation mediates the effect of recent antecedent hypoglycemia to reduce the sympathoadrenal response to subsequent hypoglycemia, the key feature of hypoglycemia-associated autonomic failure in diabetes, in humans. PMID- 21270271 TI - Progression of carotid artery intima-media thickness during 12 years in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. AB - OBJECTIVE: This study investigated the long-term effects of intensive diabetic treatment on the progression of atherosclerosis, measured as common carotid artery intima-media thickness (IMT). RESEARCH DESIGN AND METHODS: A total of 1,116 participants (52% men) in the Epidemiology of Diabetes Interventions and Complications (EDIC) trial, a long-term follow-up of the Diabetes Control and Complications Trial (DCCT), had carotid IMT measurements at EDIC years 1, 6, and 12. Mean age was 46 years, with diabetes duration of 24.5 years at EDIC year 12. Differences in IMT progression between DCCT intensive and conventional treatment groups were examined, controlling for clinical characteristics, IMT reader, and imaging device. RESULTS: Common carotid IMT progression from EDIC years 1 to 6 was 0.019 mm less in intensive than in conventional (P < 0.0001), and from years 1 to 12 was 0.014 mm less (P = 0.048); but change from years 6 to 12 was similar (intensive - conventional = 0.005 mm, P = 0.379). Mean A1C levels during DCCT and DCCT/EDIC were strongly associated with progression of IMT, explaining most of the differences in IMT progression between DCCT treatment groups. Albuminuria, older age, male sex, smoking, and higher systolic blood pressure were significant predictors of IMT progression. CONCLUSIONS: Intensive treatment slowed IMT progression for 6 years after the end of DCCT but did not affect IMT progression thereafter (6-12 years). A beneficial effect of prior intensive treatment was still evident 13 years after DCCT ended. These differences were attenuated but not negated after adjusting for blood pressure. These results support the early initiation and continued maintenance of intensive diabetes management in type 1 diabetes to retard atherosclerosis. PMID- 21270272 TI - Diabetic downregulation of Nrf2 activity via ERK contributes to oxidative stress induced insulin resistance in cardiac cells in vitro and in vivo. AB - OBJECTIVE: Oxidative stress is implicated in cardiac insulin resistance, a critical risk factor for cardiac failure, but the direct evidence remains missing. This study explored a causal link between oxidative stress and insulin resistance with a focus on a regulatory role of redox sensitive transcription factor NF-E2-related factor 2 (Nrf2) in the cardiac cells in vitro and in vivo. RESEARCH DESIGN AND METHODS: Chronic treatment of HL-1 adult cardiomyocyte with hydrogen peroxide led to insulin resistance, reflected by a significant suppression of the insulin-induced glucose uptake. This was associated with an exaggerated phosphorylation of extracellular signal-related kinase (ERK). Although U0126, an ERK inhibitor, enhanced insulin sensitivity and attenuated oxidative stress-induced insulin resistance, LY294002, an inhibitor of phosphoinositide 3-kinase (PI3K), worsened the insulin resistance. Moreover, insulin increased Nrf2 transcriptional activity, which was blocked by LY294002 but enhanced by U0126. Forced activation of Nrf2 by adenoviral over-expression of Nrf2 inhibited the increased ERK activity and recovered the blunted insulin sensitivity on glucose uptake in cardiomyocytes that were chronically treated with H(2)O(2). In the hearts of streptozotocin-induced diabetic mice and diabetic patients Nrf2 expression significantly decreased along with significant increases in 3-nitrotyrosine accumulation and ERK phosphorylation, whereas these pathogenic changes were not observed in the heart of diabetic mice with cardiac-specific overexpression of a potent antioxidant metallothionein. Upregulation of Nrf2 by its activator, Dh404, in cardiomyocytes in vitro and in vivo prevented hydrogen peroxide- and diabetes-induced ERK activation and insulin-signaling downregulation. CONCLUSIONS: ERK-mediated suppression of Nrf2 activity leads to the oxidative stress-induced insulin resistance in adult cardiomyocytes and downregulated glucose utilization in the diabetic heart. PMID- 21270273 TI - Resveratrol improves oxidative stress and protects against diabetic nephropathy through normalization of Mn-SOD dysfunction in AMPK/SIRT1-independent pathway. AB - OBJECTIVE: Despite the beneficial effects of resveratrol (RSV) on cardiovascular disease and life span, its effects on type 2 diabetic nephropathy remain unknown. This study examined the renoprotective effects of RSV in db/db mice, a model of type 2 diabetes. RESEARCH DESIGN AND METHODS: db/db mice were treated with RSV (0.3% mixed in chow) for 8 weeks. We measured urinary albumin excretion (UAE), histological changes (including mesangial expansion, fibronectin accumulation, and macrophage infiltration), oxidative stress markers (urinary excretion and mitochondrial content of 8-hydroxy-2'-deoxyguanosine [8-OHdG], nitrotyrosine expression), and manganese-superoxide dismutase (Mn-SOD) activity together with its tyrosine-nitrated modification and mitochondrial biogenesis in the kidney. Blood glucose, glycated hemoglobin, and plasma lipid profiles were also measured. The phosphorylation of 5'-AMP-activated kinase (AMPK) and expression of silent information regulator 1 (SIRT1) in the kidney were assessed by immunoblotting. RESULTS: RSV significantly reduced UAE and attenuated renal pathological changes in db/db mice. Mitochondrial oxidative stress and biogenesis were enhanced in db/db mice; however, Mn-SOD activity was reduced through increased tyrosine nitrated modification. RSV ameliorated such alterations and partially improved blood glucose, glycated hemoglobin, and abnormal lipid profile in db/db mice. Activation of AMPK was decreased in the kidney of db/db mice compared with db/m mice. RSV neither modified AMPK activation nor SIRT1 expression in the kidney. CONCLUSIONS: RSV ameliorates renal injury and enhanced mitochondrial biogenesis with Mn-SOD dysfunction in the kidney of db/db mice, through improvement of oxidative stress via normalization of Mn-SOD function and glucose-lipid metabolism. RSV has antioxidative activities via AMPK/SIRT1-independent pathway. PMID- 21270274 TI - Selective reversible inhibition of liver carnitine palmitoyl-transferase 1 by teglicar reduces gluconeogenesis and improves glucose homeostasis. AB - OBJECTIVE: We have developed a new antihyperglycemic agent (teglicar) through the selective and reversible inhibition of the liver isoform of carnitine palmitoyl transferase 1 (L-CPT1). RESEARCH DESIGN AND METHODS: Glucose production was investigated in isolated hepatocytes and during pancreatic clamps in healthy rats. Chronic treatments on C57BL/6J, db/db, high-fat fed mice, and rats were performed to understand glucose metabolism and insulin sensitivity. RESULTS: In isolated hepatocytes, teglicar concentration dependently reduced ketone bodies and glucose production up to 72 and 50%, respectively. In rats, teglicar reduced the endogenous glucose production (-62%) without affecting peripheral glucose utilization. Heart 2-[(3)H]deoxyglucose uptake in mice was also not affected, confirming in vivo the drug selectivity toward L-CPT1. Chronic treatment in db/db mice (50 mg/kg/bid; 45 days) reduced postabsorptive glycemia (-38%), water consumption (-31%), and fructosamine (-30%). Such antidiabetic activity was associated with an improved insulin sensitivity assessed by the insulin tolerance test. A significant 50% increase in hepatic triglyceride content (HTGC) was found, although plasma alanineaminotransferase was not altered. In addition, long term teglicar administration to high-fat fed C57BL/6J mice normalized glycemia ( 19%) and insulinemia (-53%). Long-term teglicar administration (30 days, 80 mg/kg) in healthy overnight-fasted rats slightly reduced basal glycemia (-20%, ns), reduced basal insulin levels by 60%, doubled triglycerides, and increased free-fatty acids (+53%). HTGC was markedly increased, but liver and peripheral insulin sensitivity assessed by hyperinsulinemiceuglycemic clamp were not affected. CONCLUSIONS: Teglicar, in vitro and in animal models, reduces gluconeogenesis and improves glucose homeostasis, refreshing the interest in selective and reversible L-CPT1 inhibition as a potential antihyperglycemic approach. PMID- 21270275 TI - Adiponectin pretreatment counteracts the detrimental effect of a diabetic environment on endothelial progenitors. AB - OBJECTIVE: It has been shown that vascular progenitors from patients with diabetes are dysfunctional. However, therapeutic strategies to counteract their reduced functional capacity are still lacking. Because adiponectin has reported salutary effects on endothelial function, we investigated the functional effects of globular adiponectin (gAcrp), the active domain of adiponectin, on isolated endothelial colony-forming cells (ECFC). RESEARCH DESIGN AND METHODS: ECFC were isolated from peripheral blood of type 2 diabetic patients (dmECFC) and compared with ECFC of healthy young volunteers (yECFC) and nondiabetic age-matched control subjects (hECFC). Cells were treated with gAcrp for 48 h followed by assessment of cell counts, cell cycle analysis, and migration capacity. For in vivo evaluation, human ECFC were injected into normoglycemic or streptozotocin-induced hyperglycemic nu/nu mice after hind limb ischemia. RESULTS: Whereas dmECFC were functionally impaired compared with yECFC and hECFC, gAcrp significantly enhanced their in vitro proliferation and migratory activity. In vitro effects were significantly stronger in hECFC compared with dmECFC and were mediated through the cyclooxygenase-2 pathway. Most important, however, we observed a profound and sustained increase of the in vivo neovascularization in mice receiving gAcrp pretreated dmECFC compared with untreated dmECFC under both normoglycemic and hyperglycemic conditions. CONCLUSIONS: Pretreatment of ECFC with gAcrp enhanced the functional capacity of ECFC in vitro and in vivo in normoglycemic and hyperglycemic environments. Therefore, preconditioning of dmECFC with gAcrp may be a novel approach to counteract their functional impairment in diabetes. PMID- 21270276 TI - Links between insulin resistance, adenosine A2B receptors, and inflammatory markers in mice and humans. AB - OBJECTIVE: To determine the mechanisms by which blockade of adenosine A(2B) receptors (A(2B)Rs) reduces insulin resistance. RESEARCH DESIGN AND METHODS: We investigated the effects of deleting or blocking the A(2B)R on insulin sensitivity using glucose tolerance tests (GTTs) and hyperinsulinemic-euglycemic clamps in mouse models of type 2 diabetes. The effects of diabetes on A(2B)R transcription and signaling were measured in human and mouse macrophages and mouse endothelial cells. In addition, tag single nucleotide polymorphisms (SNPs) in ~42 kb encompassing the A(2B)R gene, ADORA2B, were evaluated for associations with markers of diabetes and inflammation. RESULTS: Treatment of mice with the nonselective adenosine receptor agonist 5'-N-ethylcarboxamidoadensoine (NECA) increased fasting blood glucose and slowed glucose disposal during GTTs. These responses were inhibited by A(2B)R deletion or blockade and minimally affected by deletion of A(1)Rs or A(2A)Rs. During hyperinsulinemic-euglycemic clamp of diabetic KKA(Y) mice, A(2B)R antagonism increased glucose infusion rate, reduced hepatic glucose production, and increased glucose uptake into skeletal muscle and brown adipose tissue. Diabetes caused a four- to sixfold increase in A(2B)R mRNA in endothelial cells and macrophages and resulted in enhanced interleukin (IL)-6 production in response to NECA due to activation of protein kinases A and C. Five consecutive tag SNPs in ADORA2B were highly correlated with IL-6 and C-reactive protein (CRP). Diabetes had a highly significant independent effect on variation in inflammatory markers. The strength of associations between several ADORA2B SNPs and inflammatory markers was increased when accounting for diabetes status. CONCLUSIONS: Diabetes affects the production of adenosine and the expression of A(2B)Rs that stimulate IL-6 and CRP production, insulin resistance, and the association between ADORA2B SNPs and inflammatory markers. We hypothesize that increased A(2B)R signaling in diabetes increases insulin resistance in part by elevating proinflammatory mediators. Selective A(2B)R blockers may be useful to treat insulin resistance. PMID- 21270277 TI - The same chromosome 9p21.3 locus is associated with type 2 diabetes and coronary artery disease in a Chinese Han population. AB - OBJECTIVE: Recent genome-wide association studies (GWAS) revealed that a 9p21.3 locus was associated with type 2 diabetes. In this study, we carried out a large scale case-control study in the GeneID Chinese Han population to 1) further replicate the association of 9p21.3 type 2 diabetes GWAS single nucleotide polymorphisms (SNPs) and 2) assess the association of these SNPs with coronary artery disease. RESEARCH DESIGN AND METHODS: Three SNPs (rs2383208, rs10811661, and rs10757283) were genotyped in two GeneID cohorts of 3,167 Chinese Han individuals. Case-control association design was used to determine the association of the SNPs with type 2 diabetes and coronary artery disease. Gensini scores were calculated in the coronary artery disease subjects and were tested for association with the variants. Multivariate logistic regressions were performed on association studies. RESULTS: The association between two of the three SNPs and type 2 diabetes was replicated in the GeneID population (rs2383208, P = 0.936; rs10811661-T, P = 0.02, odds ratio [OR] = 1.23; rs10757283 C, P = 0.003, OR = 1.30). The same two SNPs also contributed to the risk of coronary artery disease (CAD) (rs10811661-T, P = 0.002, OR = 1.19; rs10757283-C, P = 0.003, OR = 1.18). In addition, rs10757283 was associated with severity of coronary atherosclerosis estimated by the Gensini scoring system (risk allele C, quantitative-trait regression adjusted P = 0.002). CONCLUSIONS: For the first time to our knowledge, our results indicated that the same 9p21.3 locus, represented by SNPs rs10811661 and rs10757283, contributed to the risk of type 2 diabetes and coronary artery disease in our GeneID Chinese Han population. PMID- 21270278 TI - An interferon-induced helicase (IFIH1) gene polymorphism associates with different rates of progression from autoimmunity to type 1 diabetes. AB - OBJECTIVE: Genome-wide association studies have identified gene regions associated with the development of type 1 diabetes. The aim of this study was to determine whether these associations are with the development of autoimmunity and/or progression to diabetes. RESEARCH DESIGN AND METHODS: Children (n = 1,650) of parents with type 1 diabetes were prospectively followed from birth (median follow-up 10.20 years) for the development of islet autoantibodies, thyroid peroxidase antibodies, tissue transglutaminase antibodies, and diabetes. Genotyping for single-nucleotide polymorphisms of the PTPN22, ERBB3, PTPN2, KIAA0350, CD25, and IFIH1 genes was performed using the MassARRAY system with iPLEX chemistry. RESULTS: Islet autoantibodies developed in 137 children and diabetes developed in 47 children. Type 1 diabetes risk was associated with the IFIH1 rs2111485 single-nucleotide polymorphism (hazard ratio 2.08; 95% CI 1.16 3.74; P = 0.014). None of the other genes were significantly associated with diabetes development in this cohort. IFIH1 genotypes did not associate with the development of islet autoantibodies (P = 0.80) or autoantibodies against thyroid peroxidase (P = 0.55) and tissue transglutaminase (P = 0.66). Islet autoantibody positive children with the IFIH1 rs2111485 GG genotype had a faster progression to diabetes (31% within 5 years) than children with the type 1 diabetes protective GA or AA genotypes (11% within 5 years; P = 0.006). CONCLUSIONS: The findings indicate that IFIH1 genotypes influence progression from autoimmunity to diabetes development, consistent with the notion that protective genotypes downregulate responses to environmental insults after initiation of autoimmunity. PMID- 21270280 TI - Antibody recognition of the dengue virus proteome and implications for development of vaccines. AB - Dengue is a mosquito-borne infection caused by four distinct serotypes of dengue virus, each appearing cyclically in the tropics and subtropics along the equator. Although vaccines are currently under development, none are available to the general population. One of the main impediments to the successful advancement of these vaccines is the lack of well-defined immune correlates of protection. Here, we describe a protein microarray approach for measuring antibody responses to the complete viral proteome comprised of the structural (capsid, membrane, and envelope) and nonstructural (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) components of all four dengue virus serotypes (1 to 4). We examined rhesus macaques vaccinated with tetravalent vaccines consisting of live-attenuated virus (LAV) or purified inactivated virus (PIV), followed by boosting with LAV and challenging with wild-type dengue virus. We detected temporal increases in antibodies against envelope proteins in response to either vaccine, while only the PIV/LAV vaccination strategy resulted in anticapsid antibodies. In contrast to results from vaccination, naive macaques challenged with wild-type viruses of each serotype demonstrated a balanced response to nonstructural and structural components, including responses against the membrane protein. Our results demonstrate discriminating details concerning the nature of antibody responses to dengue virus at the proteomic level and suggest the usefulness of this information for vaccine development. PMID- 21270281 TI - Elevated serum levels of CCL17 correlate with increased peripheral blood platelet count in patients with active tuberculosis in China. AB - The serum levels of Th2 markers, including CCL17 (thymus and activation-regulated chemokine [TARC]), CCL22 (macrophage-derived chemokine [MDC]), and soluble CD30, were measured in 101 HIV-negative tuberculosis patients, 103 healthy community controls, and 18 tuberculosis patients in recovery. The levels of CCL17/TARC (249.8 +/- 19.91 versus 143.9 +/- 10.54, P < 0.0001) and sCD30 (7.78 +/- 0.44 versus 4.93 +/- 0.23, P < 0.0001) were significantly higher in patients with active tuberculosis than in controls; however, the CCL22/MDC serum level had no statistical difference between the groups (579.9 +/- 16.42 versus 556.5 +/- 15.29, P = 0.298). The counts of platelet and eosinophil in the peripheral blood of patients with active tuberculosis are significantly increased as well (289.4 +/- 8.14 versus 248.3 +/- 5.34 [P < 0.0001] and 165.1 +/- 14.33 versus 102.5 +/- 10.72 [P = 0.0005], respectively), and the platelet counts were positively correlated with serum TARC levels (Pearson r = 0.456, P < 0.0001), which indicates a new source of Th2 bias showing in active TB patients. PMID- 21270282 TI - Intranasal vaccination with the recombinant Listeria monocytogenes DeltaactA prfA* mutant elicits robust systemic and pulmonary cellular responses and secretory mucosal IgA. AB - We previously showed that recombinant (r) Listeria monocytogenes carrying DeltaactA and a selected prfA* mutation (r-Listeria DeltaactA prfA*) secreted >100-fold more immunogen in broth culture than wild-type r-Listeria or r-Listeria DeltaactA and elicited much greater cellular and humoral immune responses than r Listeria DeltaactA after intravenous vaccination of mice. Here, we conducted comparative studies evaluating vaccine-elicited immune responses in systemic and mucosal sites after intranasal, intravenous, intraperitoneal, or subcutaneous immunization of mice with r-Listeria DeltaactA prfA* vaccine candidates. Intranasal vaccination of mice with r-Listeria DeltaactA prfA* vaccine candidates elicited a robust gamma interferon-positive (IFN-gamma(+)) cellular response in systemic sites, although intravenous or intraperitoneal immunization was more efficient. Surprisingly, intranasal vaccination elicited an appreciable pulmonary IFN-gamma(+) cellular response that was nonstatistically higher than the magnitude induced by the intravenous route but was significantly greater than that elicited by subcutaneous immunization. Furthermore, although intranasal r Listeria DeltaactA prfA* delivery induced poor systemic IgG responses, intranasal vaccination elicited appreciable secretory immunogen-specific IgA titers that were similar to or higher in mucosal fluid than those induced by subcutaneous and intravenous immunizations. Thus, intranasal vaccination with r-Listeria DeltaactA prfA* appears to be a useful approach for eliciting robust systemic and pulmonary cellular responses and measurable secretory mucosal IgA titers. PMID- 21270283 TI - Serum neopterin levels as a diagnostic marker of hemophagocytic lymphohistiocytosis syndrome. AB - The objective of this study was to retrospectively evaluate the utility of serum neopterin as a diagnostic marker of hemophagocytic lymphohistiocytosis (HLH). The medical records of patients diagnosed with HLH (familial and secondary) between January 2000 and May 2009 were reviewed retrospectively, and clinical and laboratory information related to HLH criteria, in addition to neopterin levels, was recorded. A group of 50 patients with active juvenile dermatomyositis (JDM) (who routinely have neopterin levels assessed) served as controls for the assessment of the accuracy, sensitivity, and specificity of neopterin as a diagnostic test for HLH. The Pearson correlation was used to measure the association between serum neopterin levels and established HLH-related laboratory data. Serum neopterin levels were measured using a competitive enzyme immunoassay. During the time frame of the study, 3 patients with familial HLH and 18 patients with secondary HLH were identified as having had serum neopterin measured (all HLH patients were grouped together). The mean neopterin levels were 84.9 nmol/liter (standard deviation [SD], 83.4 nmol/liter) for patients with HLH and 21.5 nmol/liter (SD, 10.13 nmol/liter) for patients with JDM. A cutoff value of 38.9 nmol/liter was 70% sensitive and 95% specific for HLH. For HLH patients, neopterin levels correlated significantly with ferritin levels (r = 0.76, P = 0.0007). In comparison to the level in a control group of JDM patients, elevated serum neopterin was a sensitive and specific marker for HLH. Serum neopterin has value as a diagnostic marker of HLH, and prospective studies are under way to further evaluate its role as a marker for early diagnosis and management of patients. PMID- 21270284 TI - Capsid proteins from field strains of foot-and-mouth disease virus confer a pathogenic phenotype in cattle on an attenuated, cell-culture-adapted virus. AB - Chimeric foot-and-mouth disease viruses (FMDVs) have been generated from plasmids containing full-length FMDV cDNAs and characterized. The parental virus cDNA was derived from the cell-culture-adapted O1Kaufbeuren B64 (O1K B64) strain. Chimeric viruses, containing capsid coding sequences derived from the O/UKG/34/2001 or A/Turkey 2/2006 field viruses, were constructed using the backbone from the O1K B64 cDNA, and viable viruses (O1K/O-UKG and O1K/A-Tur, respectively) were successfully rescued in each case. These viruses grew well in primary bovine thyroid cells but grew less efficiently in BHK cells than the rescued parental O1K B64 virus. The two chimeric viruses displayed the expected antigenicity in serotype-specific antigen ELISAs. Following inoculation of each virus into cattle, the rescued O1K B64 strain proved to be attenuated whereas, with each chimeric virus, typical clinical signs of foot-and-mouth disease were observed, which then spread to in-contact animals. Thus, the surface-exposed capsid proteins of the O1K B64 strain are responsible for its attenuation in cattle. Consequently, there is no evidence for any adaptation, acquired during cell culture, outside the capsid coding region within the O1K B64 strain that inhibits replication in cattle. These chimeric infectious cDNA plasmids provide a basis for the analysis of FMDV pathogenicity and characterization of receptor utilization in vivo. PMID- 21270285 TI - Full genomic analyses of two human G2P[4] rotavirus strains detected in 2005: identification of a caprine-like VP3 gene. AB - Although G2P[4] rotaviruses are common causes of infantile diarrhoea, to date only the full genomes of the prototype (strain DS-1) and another old strain, TB Chen, have been analysed. We report here the full genomic analyses of two Bangladeshi G2P[4] strains, MMC6 and MMC88, detected in 2005. Both the strains exhibited a DS-1-like genotype constellation. Excluding the VP4 and VP7 genes, and except for VP3 of MMC88, the MMC strains were genetically more closely related to the contemporary G2P[4] and several non-G2P[4] human strains than the prototype G2P[4] strain. However, by phylogenetic analyses, the VP2, VP3 (except MMC88), NSP1 and NSP3-5 genes of these strains appeared to share a common origin with those of the prototype strain, whilst their VP1, VP6 and NSP2 genes clustered near a caprine strain. The VP3 gene of MMC88 exhibited maximum relatedness to a local caprine strain, representing the first reported human G2P[4] strain with a gene of animal origin. PMID- 21270286 TI - Nucleotide requirements at positions +1 to +4 for the initiation of hepatitis C virus positive-strand RNA synthesis. AB - RNA virus genome replication requires initiation at the precise terminus of the template RNA. To investigate the nucleotide requirements for initiation of hepatitis C virus (HCV) positive-strand RNA replication, a hammerhead ribozyme was inserted at the 5' end of an HCV subgenomic replicon, allowing the generation of replicons with all four possible nucleotides at position 1. This analysis revealed a preference for a purine nucleotide at this position for initiation of RNA replication. The sequence requirements at positions 2-4 in the context of the J6/JFH-1 virus were also examined by selecting replication-competent virus from a pool containing randomized residues at these positions. There was strong selection for both the wild-type cytosine at position 2, and the wild-type sequence at positions 2-4 (CCU). An adenine residue was well tolerated at positions 3 and 4, which suggests that efficient RNA replication is less dependent on these residues. PMID- 21270287 TI - Emergence of multiple prion strains from single isolates of ovine scrapie. AB - The infectious agent associated with prion diseases such as ovine scrapie shows strain diversity. Ovine prion strains have typically been identified by their transmission properties in wild-type mice. However, strain typing of ovine scrapie isolates in wild-type mice may not reveal properties of the infectious prion agent as they exist in the original host. This could be circumvented if ovine scrapie isolates are passaged in ovine prion protein (PrP)-transgenic mice. This study used incubation time, lesion profile, immunohistochemistry of the disease-associated PrP (PrP(Sc)) and molecular profile to compare the range of ovine prion strains that emerged from sheep scrapie isolates following serial passage in wild-type and ovine PrP transgenic mice. It was found that a diverse range of ovine prion strains emerged from homozygous ARQ and VRQ scrapie isolates passaged in wild-type and ovine PrP transgenic mice. However, strain-specific PrP(Sc) deposition and PrP27-30 molecular profile patterns were identified in ovine PrP transgenic mice that were not detected in wild-type mice. Significantly, it was established that the individual mouse brain selected for transmission during prion strain typing had a significant influence on strain definition. Serial passage of short- and long-incubation-time animals from the same group of scrapie-inoculated mice revealed different prion strain phenotypes. These observations are consistent with the possibility that some scrapie isolates contain more than one prion strain. PMID- 21270288 TI - Re-evaluation of the genome sequence of guinea pig cytomegalovirus. AB - Congenital infection by human cytomegalovirus (HCMV) is a major cause of birth defects and developmental abnormalities. Since guinea pig cytomegalovirus (GPCMV) crosses the placenta and causes infection in utero, GPCMV models are useful for studies of the mechanisms of transplacental transmission. During our characterization of a genomic locus required for GPCMV dissemination in animals, we found that the nucleotide sequence in and around the nearby immediate-early genes in our lineage of GPCMV strain 22122 [designated GPCMV (ATCC-P5)] showed clear differences from that reported previously for the same strain [designated GPCMV (UMN)] passaged extensively in vitro. Since in vitro passaging of HCMV is known to result in genetic alterations, especially in the UL128-UL131A locus, and loss of growth ability in particular cell types, in this study we determined the complete genome sequence of GPCMV (ATCC-P5), which grows efficiently in animals. A total of 359 differences were identified between the genome sequences of GPCMV (UMN) and GPCMV (ATCC-P5), and these resulted in structural differences in 29 protein-encoding regions. In addition, some genes predicted from our analysis but not from GPCMV (UMN) are well conserved among cytomegaloviruses. An additional 18 passages of GPCMV (ATCC-P5) in vitro generated no further marked alterations in these genes or in the locus corresponding to the HCMV UL128-UL131A. Our analyses indicate that the published sequence of GPCMV (UMN) contains a substantial number of sequencing errors and, possibly, some mutations resulting from a long history of passaging in vitro. Our re-evaluation of the genetic content of GPCMV will provide a solid foundation for future studies. PMID- 21270289 TI - Severe acute respiratory syndrome coronavirus papain-like protease suppressed alpha interferon-induced responses through downregulation of extracellular signal regulated kinase 1-mediated signalling pathways. AB - Severe acute respiratory syndrome coronavirus (SARS-CoV) papain-like protease (PLpro), a deubiquitinating enzyme, reportedly blocks poly I : C-induced activation of interferon regulatory factor 3 and nuclear factor kappa B, reducing interferon (IFN) induction. This study investigated type I IFN antagonist mechanism of PLpro in human promonocytes. PLpro antagonized IFN-alpha-induced responses such as interferon-stimulated response element- and AP-1-driven promoter activation, protein kinase R, 2'-5'-oligoadenylate synthetase (OAS), interleukin (IL)-6 and IL-8 expression, and signal transducers and activators of transcription (STAT) 1 (Tyr701), STAT1 (Ser727) and c-Jun phosphorylation. A proteomics approach demonstrated downregulation of extracellular signal-regulated kinase (ERK) 1 and upregulation of ubiquitin-conjugating enzyme (UBC) E2-25k as inhibitory mechanism of PLpro on IFN-alpha-induced responses. IFN-alpha treatment significantly induced mRNA expression of UBC E2-25k, but not ERK1, causing time dependent decrease of ERK1, but not ERK2, in PLpro-expressing cells. Poly ubiquitination of ERK1 showed a relationship between ERK1 and ubiquitin proteasome signalling pathways associated with IFN antagonism by PLpro. Combination treatment of IFN-alpha and the proteasome inhibitor MG-132 showed a time-dependent restoration of ERK1 protein levels and significant increase of ERK1, STAT1 and c-Jun phosphorylation in PLpro-expressing cells. Importantly, PD098059 (an ERK1/2 inhibitor) treatment significantly reduced IFN-alpha-induced ERK1 and STAT1 phosphorylation, inhibiting IFN-alpha-induced expression of 2'-5' OAS in vector control cells and PLpro-expressing cells. Overall results proved downregulation of ERK1 by ubiquitin proteasomes and suppression of interaction between ERK1 and STAT1 as type I IFN antagonist function of SARS-CoV PLpro. PMID- 21270290 TI - Strategies for optimizing glycemic control and cardiovascular prognosis in patients with type 2 diabetes mellitus. AB - Type 2 diabetes mellitus (DM) is a major cardiovascular (CV) risk factor and, as such, is considered a coronary artery disease risk equivalent. Although glycemic control is associated with decreased CV events epidemiologically, many prospective clinical trials have failed to conclusively demonstrate that aggressive glycemic control improves the CV prognosis of patients with type 2 DM, especially those with long-standing DM. Many therapies for type 2 DM with widely divergent mechanisms of action are available. Some of these drugs, in addition to their glucose-lowering actions, have properties that may reduce or increase CV events. Agents that lower both insulin resistance and postprandial hyperglycemia while at the same time avoiding hypoglycemia may be beneficial for CV health. This article reviews the evidence regarding the use of these agents and appropriate glycemic control targets for improving the adverse CV prognosis associated with type 2 DM. We conducted a systematic review of English articles using MEDLINE and the Cochrane Controlled Trials Register (1970-2010) using the following search terms: cardiovascular disease, randomized trials, hypoglycemia, and insulin resistance. PMID- 21270291 TI - Abnormal cervical appearance: what to do, when to worry? AB - Many clinicians encounter cervical lesions that may or may not be associated with cytologic abnormalities. Such abnormalities as ectropion, Nabothian cysts, and small cervical polyps are quite benign and need not generate concern for patient or clinician, whereas others, including those associated with a history of exposure to diethylstilbestrol, cervical inflammation, abnormal cervical cytology, and postcoital bleeding, should prompt additional evaluation. Further, in some patients, the cervix may be difficult to visualize. Several useful clinical suggestions for the optimal examination of the cervix are presented. PMID- 21270292 TI - Neuropeptide Y inhibits cholangiocarcinoma cell growth and invasion. AB - No information exists on the role of neuropeptide Y (NPY) in cholangiocarcinoma growth. Therefore, we evaluated the expression and secretion of NPY and its subsequent effects on cholangiocarcinoma growth and invasion. Cholangiocarcinoma cell lines and nonmalignant cholangiocytes were used to assess NPY mRNA expression and protein secretion. NPY expression was assessed by immunohistochemistry in human liver biopsies. Cell proliferation and migration were evaluated in vitro by MTS assays and matrigel invasion chambers, respectively, after treatment with NPY or a neutralizing NPY antibody. The effect of NPY or NPY depletion on tumor growth was assessed in vivo after treatment with NPY or the neutralizing NPY antibody in a xenograft model of cholangiocarcinoma. NPY secretion was upregulated in cholangiocarcinoma compared with normal cholangiocytes. Administration of exogenous NPY decreased proliferation and cell invasion in all cholangiocarcinoma cell lines studied and reduced tumor cell growth in vivo. In vitro, the effects of NPY on proliferation were blocked by specific inhibitors for NPY receptor Y2, but not Y1 or Y5, and were associated with an increase in intracellular d-myo-inositol 1,4,5-trisphosphate and PKCalpha activation. Blocking of NPY activity using a neutralizing antibody promoted cholangiocarcinoma growth in vitro and in vivo and increased the invasiveness of cholangiocarcinoma in vitro. Increased NPY immunoreactivity in human tumor tissue occurred predominantly in the center of the tumor, with less expression toward the invasion front of the tumor. We demonstrated that NPY expression is upregulated in cholangiocarcinoma, which exerts local control on tumor cell proliferation and invasion. Modulation of NPY secretion may be important for the management of cholangiocarcinoma. PMID- 21270293 TI - 4F2hc stabilizes GLUT1 protein and increases glucose transport activity. AB - Glucose transporter 1 (GLUT1) is widely distributed throughout various tissues and contributes to insulin-independent basal glucose uptake. Using a split ubiquitin membrane yeast two-hybrid system, we newly identified 4F2 heavy chain (4F2hc) as a membrane protein interacting with GLUT1. Though 4F2hc reportedly forms heterodimeric complexes between amino acid transporters, such as LAT1 and LAT2, and regulates amino acid uptake, we investigated the effects of 4F2hc on GLUT1 expression and the associated glucose uptake. First, FLAG-tagged 4F2hc and hemagglutinin-tagged GLUT1 were overexpressed in human embryonic kidney 293 cells and their association was confirmed by coimmunoprecipitation. The green fluorescent protein-tagged 4F2hc and DsRed-tagged GLUT1 showed significant, but incomplete, colocalization at the plasma membrane. In addition, an endogenous association between GLUT1 and 4F2hc was demonstrated using mouse brain tissue and HeLa cells. Interestingly, overexpression of 4F2hc increased the amount of GLUT1 protein in HeLa and HepG2 cells with increased glucose uptake. In contrast, small interfering RNA (siRNA)-mediated 4F2hc gene suppression markedly reduced GLUT1 protein in both cell types, with reduced glucose uptake. While GLUT1 mRNA levels were not affected by overexpression or gene silencing of 4F2hc, GLUT1 degradation after the addition of cycloheximide was significantly suppressed by 4F2hc overexpression and increased by 4F2hc siRNA treatment. Taken together, these observations indicate that 4F2hc is likely to be involved in GLUT1 stabilization and to contribute to the regulation of not only amino acid but also glucose metabolism. PMID- 21270294 TI - Interfacial sensing by alveolar type II cells: a new concept in lung physiology? AB - Alveolar type II (AT II) cells are in close contact with an air-liquid interface (I(AL)). This contact may be of considerable physiological relevance; however, no data exist to provide a satisfying description of this specific microenvironment. This is mainly due to the experimental difficulty to manipulate and analyze cell air contacts in a specific way. Therefore, we designed assays to quantify cell viability, Ca(2+) changes, and exocytosis in the course of interface contact and miniaturized I(AL) devices for direct, subcellular, and real-time analyses of cell-interface interactions by fluorescence microscopy or interferometry. The studies demonstrated that the sole presence of an I(AL) is not sensed by the cells. However, when AT II cells are forced into closer contact with it, they respond promptly with sustained Ca(2+) signals and surfactant exocytosis before the occurrence of irreversible cell damage. This points to a paradoxical situation: a potential threat and potent stimulus for the cells. Furthermore, we found that the signalling mechanism underlying sensation of an I(AL) can be sufficiently explained by mechanical forces. These results demonstrate that the I(AL) itself can play a major, although so-far neglected, role in lung physiology, particularly in the regulatory mechanisms related with surfactant homeostasis. Moreover, they also support a general new concept of mechanosensation in the lung. PMID- 21270295 TI - Nitric oxide donors improve prednisone effects on muscular dystrophy in the mdx mouse diaphragm. AB - In Duchenne muscular dystrophy (DMD), palliative glucocorticoid therapy can produce myopathy or calcification. Since increased nitric oxide synthase activity in dystrophic mice promotes regeneration, the outcome of two nitric oxide (NO) donor drugs, MyoNovin (M) and isosorbide dinitrate (I), on the effectiveness of the anti-inflammatory drug prednisone (P) in alleviating progression of dystrophy was tested. Dystrophic mdx mice were treated (18 days) as controls or with an NO donor +/- P. Fiber permeability and DNA synthesis were labeled by Evans blue dye (EBD) and bromodeoxyuridine uptake, respectively. P decreased body weight gain, M increased quadriceps mass, and I increased heart mass. P increased fiber permeability (%EBD+ fibers) and calcification in diaphragm. Treatment with NO donors + P (M+P, I+P) reduced %EBD+ fibers and calcification vs. P alone. %EBD+ fibers in M+P diaphragm did not differ from control. NO donor treatment reduced proliferation and the population of c-met+ cells and accelerated fiber regeneration. Concurrent with P, NO donor treatment suppressed two important detrimental effects of P in mice, possibly by accelerating regeneration, rebalancing satellite cell quiescence and activation in dystrophy, and/or increasing perfusion. Results suggest that NO donors could improve current therapy for DMD. PMID- 21270296 TI - S1P activates store-operated calcium entry via receptor- and non-receptor mediated pathways in vascular smooth muscle cells. AB - Sphingosine-1-phosphate (S1P) has been shown to modulate intracellular Ca(2+) through both G protein-coupled receptors and intracellular second messenger pathways. The precise mechanism by which S1P activates store-operated calcium entry (SOCE) in vascular smooth muscle cells (VSMCs) has not been fully characterized. Because sphingolipids and Ca(2+) modulate proliferation and constriction in VSMCs, characterizing the connection between S1P and SOCE may provide novel therapeutic targets for vascular diseases. We found that S1P triggered STIM1 puncta formation and SOCE in VSMCs. S1P-activated SOCE was inhibited by 2-aminoethoxydiphenyl borate (2-APB), diethylstilbestrol (DES), and gadolinium (Gd(3+)). SOCE was observed in VSMCs lacking either S1P(2) or S1P(3) receptors, suggesting that S1P acts via multiple signaling pathways. Indeed, both extracellular and intracellular S1P application increased the total internal reflection fluorescence signal in VSMCs cells transfected with STIM1-yellow fluorescent protein in a 2-APB-sensitive manner. These data, and the fact that 2 APB, DES, and Gd(3+) all inhibited S1P-induced cerebral artery constriction, suggest that SOCE modulates S1P-induced vasoconstriction in vivo. Finally, S1P induced SOCE was larger in proliferative than in contractile VSMCs, correlating with increases in STIM1, Orai1, S1P(1), and S1P(3) receptor mRNA. These data demonstrate that S1P can act through both receptors and a novel intracellular pathway to activate SOCE. Because S1P-induced SOCE contributes to vessel constriction and is increased in proliferative VSMCs, it is likely that S1P/SOCE signaling in proliferative VSMCs may play a role in vascular dysfunction such as atherosclerosis and diabetes. PMID- 21270297 TI - Using changes in hydrostatic and osmotic pressure to manipulate metabolic function in chondrocytes. AB - Articular cartilage has distinct histological depth zones. In each zone, chondrocytes are subject to different hydrostatic (HP) and osmotic pressure (OP) due to weight-bearing and joint-loading. Previous in vitro studies of regeneration and pathophysiology in cartilage have failed to consider the characteristics of histological heterogeneity and the effects of combinations of changes in HP and OP. Thus, we have constructed molecular, biochemical, and histological profiles of anabolic and catabolic molecules produced by chondrocytes from each depth zone isolated from bovine articular cartilage in response to changes in HP and OP. We cultured the chondrocytes with combinations of loading or off-loading of HP at 0-0.5 MPa, 0.5 Hz, and changes in OP of 300 450 mosM over 1 wk, and evaluated mRNA expression and immunohistology of both anabolic and catabolic molecules and amounts of accumulated sulfated glycosaminoglycan. Any changes in HP and OP upregulated mRNA of anabolic and catabolic molecules in surface-, middle-, and deep-zone cells, in descending order of magnitude. Off-loading HP maintained the anabolic and reduced the catabolic mRNA; high OP retained upregulation of catabolic mRNA. These molecular profiles were consistent with immunohistological and biochemical findings. Changes in HP and OP are essential for simulating chondrocyte physiology and useful for manipulating phenotypes. PMID- 21270299 TI - The mechanics of explosive dispersal and self-burial in the seeds of the filaree, Erodium cicutarium (Geraniaceae). AB - The filaree (Erodium cicutarium), a small, flowering plant related to geraniums, possesses a unique seed dispersal mechanism: the plant can fling its seeds up to half a meter away; and the seeds can bury themselves by drilling into the ground, twisting and untwisting in response to changes in humidity. These feats are accomplished using awns, helical bristles of dead but hygroscopically active tissue attached to the seeds. Here, we describe the kinematics of explosive dispersal and self-burial based on detailed high-speed and time-lapse videos. We use these observations to develop a simple mechanical model that accounts for the coiling behavior of the awn and allows comparison of the strain energy stored in the awn with the kinetic energy at launch. The model is used to examine tradeoffs between dispersal distance and reliability of the dispersal mechanism. The mechanical model may help in understanding the invasive potential of this species and provides a framework for examining other evolutionary tradeoffs in seed dispersal mechanisms among the Geraniaceae. PMID- 21270298 TI - Hypoxia. 3. Hypoxia and neurotransmitter synthesis. AB - Central and peripheral neurons as well as neuroendocrine cells express a variety of neurotransmitters/modulators that play critical roles in regulation of physiological systems. The synthesis of several neurotransmitters/modulators is regulated by O(2)-requiring rate-limiting enzymes. Consequently, hypoxia resulting from perturbations in O(2) homeostasis can affect neuronal functions by altering neurotransmitter synthesis. Two broad categories of hypoxia are frequently encountered: continuous hypoxia (CH) and intermittent hypoxia (IH). CH is often seen during high altitude sojourns, whereas IH is experienced in sleep disordered breathing with recurrent apneas (i.e., brief, repetitive cessations of breathing). This article presents what is currently known on the effects of both forms of hypoxia on neurotransmitter levels and neurotransmitter synthesizing enzymes in the central and peripheral nervous systems. PMID- 21270300 TI - Locomotor behavior across an environmental transition in the ropefish, Erpetoichthys calabaricus. AB - Many amphibious organisms undergo repeated aquatic to terrestrial transitions during their lifetime; limbless, elongate organisms that make such transitions must rely on axial-based locomotion in both habitats. How is the same anatomical structure employed to produce an effective behavior across such disparate habitats? Here, we examine an elongate amphibious fish, the ropefish (Erpetoichthys calabaricus), and ask: (1) how do locomotor movements change during the transition between aquatic and terrestrial environments and (2) do distantly related amphibious fishes demonstrate similar modes of terrestrial locomotion? Ropefish were examined moving in four experimental treatments (in which the water level was to lowered mimic the transition between environments) that varied from fully aquatic to fully terrestrial. Kinematic parameters (lateral excursion, wavelength, amplitude and frequency) were calculated for points along the midline of the body and compared across treatments. Terrestrial locomotion in the ropefish is characterized by long, slow, large-amplitude undulations down the length of the body; in contrast, aquatic locomotion is characterized by short-wavelength, small-amplitude, high-frequency undulations that gradually increase in an anterior to posterior direction. Experimental treatments with intermediate water levels were more similar to aquatic locomotion in that they demonstrated an anterior to posterior pattern of increasing lateral excursion and wave amplitude, but were more similar to terrestrial locomotion with regard to wavelength, which did not change in an anterior to posterior direction. Finally, the ropefish and another elongate amphibious fish, the eel, consistently exhibit movements characterized by 'path following' when moving on land, which suggests that elongate fishes exhibit functional convergence during terrestrial locomotion. PMID- 21270301 TI - Stable isotopes of captive cetaceans (killer whales and bottlenose dolphins). AB - There is currently a great deal of interest in using stable isotope methods to investigate diet, trophic level and migration in wild cetaceans. In order to correctly interpret the results stemming from these methods, it is crucial to understand how diet isotopic values are reflected in consumer tissues. In this study, we investigated patterns of isotopic discrimination between diet and blood constituents of two species of cetaceans (killer whale, Orcinus orca, and bottlenose dolphin, Tursiops truncatus) fed controlled diets over 308 and 312 days, respectively. Diet discrimination factors (Delta; mean +/- s.d.) for plasma were estimated to Delta(13)C=2.3+/-0.60/00 and Delta(15)N=1.8+/-0.30/00, respectively, for both species and to Delta(13)C=2.7+/-0.30/00 and Delta(15)N=0.5+/-0.10/00 for red blood cells. Delipidation did not have a significant effect on carbon and nitrogen isotopic values of blood constituents, confirming that cetacean blood does not serve as a reservoir of lipids. In contrast, carbon isotopic values were higher in delipidated samples of blubber, liver and muscle from killer whales. The potential for conflict between fisheries and cetaceans has heightened the need for trophic information about these taxa. These results provide the first published stable isotope incorporation data for cetaceans, which are essential if conclusions are to be drawn on issues concerning trophic structures, carbon sources and diet reconstruction. PMID- 21270302 TI - Colour blindness of the movement-detecting system of the spider Cupiennius salei. AB - The nocturnal wandering spider Cupiennius salei has one pair of principal eyes and three pairs of secondary eyes located on the prosoma, which differ in both morphology and function. Their spectral sensitivity, measured with intracellular recordings, is due to three different types of photoreceptors with absorbance maxima in the mid-range of the spectrum, at 480 nm and 520 nm and in the UV at 360 nm. Based on these physiological data colour vision might be possible. In the present study, the ability to discriminate coloured moving stimuli from grey backgrounds was tested. The perception of moving coloured stripes in front of backgrounds with 29 different grey levels was measured by using extracellular recordings from the anterior median eye muscles as a monitoring system. Each of these eyes has two muscles, which increase their activity when moving stimuli are presented in front of a secondary eye. This variation in eye muscle activity can be recorded extracellulary in a living spider using a single channel telemetry device. If colour perception exists, the animal should be able to detect a moving coloured stripe in front of any grey level. Blue, green and red stripes were used as moving stimuli, in front of all 29 grey backgrounds. The results indicate that C. salei is not able to discriminate the coloured stimuli from distinct shades of grey. It is therefore evident that the movement-detecting system in this spider appears to be colour blind. PMID- 21270303 TI - Physiological flexibility and acclimation to food shortage in a heterothermic primate. AB - As ecosystems undergo changes worldwide, physiological flexibility is likely to be an important adaptive response to increased climate instability. Extreme weather fluctuations impose energetical constraints such as unpredictable food shortage. We tested how grey mouse lemurs (Microcebus murinus) could adjust their daily heterothermy and locomotor activity to these 'energetic accidents' with a food restriction experiment. The experimental design consisted of acute calorie restriction (2 weeks, 80% restriction) in the middle of winter, after a fattening season with low (11 weeks, 40% restriction) versus high (ad libitum) food availability. This design aimed at simulating the combined effects of the quality of the fattening season (acclimation effect) and a sudden, severe food shortage during the lean season. Hour of start and duration of torpor were the most flexible components of energy savings, increasing in response to the acute food shortage with facilitation by chronic restriction (acclimation effect). Modulations of locomotor activity did not support the hypothesis of energy savings, as total locomotor activity was not reduced. Nonetheless, acutely restricted individuals modified their temporal pattern of locomotor activity according to former food availability. We provide the first experimental evidence of different temporal levels of flexibility of energy-saving mechanisms in a heterotherm exposed to food shortage. The acclimation effect of past food scarcity suggests that heterothermic organisms are better able to respond to unpredicted food scarcity during the lean season. The flexible control of energy expenditure conferred by heterothermy may facilitate the plastic response of heterothermic species to more frequent climatic hazards. PMID- 21270304 TI - Mechanisms underlying rhythmic locomotion: body-fluid interaction in undulatory swimming. AB - Swimming of fish and other animals results from interactions of rhythmic body movements with the surrounding fluid. This paper develops a model for the body fluid interaction in undulatory swimming of leeches, where the body is represented by a chain of rigid links and the hydrodynamic force model is based on resistive and reactive force theories. The drag and added-mass coefficients for the fluid force model were determined from experimental data of kinematic variables during intact swimming, measured through video recording and image processing. Parameter optimizations to minimize errors in simulated model behaviors revealed that the resistive force is dominant, and a simple static function of relative velocity captures the essence of hydrodynamic forces acting on the body. The model thus developed, together with the experimental kinematic data, allows us to investigate temporal and spatial (along the body) distributions of muscle actuation, body curvature, hydrodynamic thrust and drag, muscle power supply and energy dissipation into the fluid. We have found that: (1) thrust is generated continuously along the body with increasing magnitude toward the tail, (2) drag is nearly constant along the body, (3) muscle actuation waves travel two or three times faster than the body curvature waves and (4) energy for swimming is supplied primarily by the mid-body muscles, transmitted through the body in the form of elastic energy, and dissipated into the water near the tail. PMID- 21270305 TI - Developmental regulation of hemoglobin synthesis in the green anole lizard Anolis carolinensis. AB - Tetrapod vertebrates possess multiple alpha- and beta-like globin genes that are ontogenetically regulated, such that functionally distinct hemoglobin (Hb) isoforms are synthesized during different stages of development. The alpha- and beta-like globin genes of amphibians, birds and mammals are differentially expressed during embryonic development and postnatal life, but little is known about the developmental regulation of globin gene expression in non-avian reptiles. Here we report an investigation into the developmental regulation of Hb synthesis in the green anole lizard Anolis carolinensis. We tested two hypotheses derived from comparative genomic studies of the globin gene clusters in tetrapod vertebrates. First, we tested whether the product of the Anolis alpha(D)-globin gene is incorporated into embryonic Hb, thereby performing the role that would normally be performed by the embyronic alpha(E)-globin gene (which has been deleted from the green anole genome). Second, we tested whether two 'lizard specific' beta-globin paralogs have independently evolved a division of labor between an early-expressed embryonic gene and a later-expressed adult gene. Results of a proteomic analysis revealed that alpha- and beta-like globin genes of the anole are differentially expressed during embryonic development. However, the same repertoire of alpha- and beta-chain Hb isoforms was expressed during all stages of development and postnatal life, and the ontogenetic shifts in isoform composition were relatively subtle. In contrast to the pattern that has been documented in other tetrapod vertebrates, it appears that the developmental regulation of Hb synthesis in the green anole lizard does not involve discrete, stage-specific switches in gene activation and gene silencing. PMID- 21270307 TI - Olfactory lateralization in homing pigeons: a GPS study on birds released with unilateral olfactory inputs. AB - A large body of evidence has shown that pigeons rely on an olfactory-based navigational map when homing from unfamiliar locations. Previous studies on pigeons released with one nostril occluded highlighted an asymmetry in favour of the right nostril, particularly concerning the initial orientation performance of naive birds. Nevertheless, all pigeons experiencing only unilateral olfactory input showed impaired homing, regardless of the side of the occluded nostril. So far this phenomenon has been documented only by observing the birds' vanishing bearings. In the present work we recorded the flight tracks of pigeons with previous homing experience equipped with a GPS data logger and released from an unfamiliar location with the right or the left nostril occluded. The analysis of the tracks revealed that the flight path of the birds with the right nostril occluded was more tortuous than that of unmanipulated controls. Moreover, the pigeons smelling with the left nostril interrupted their journey significantly more frequently and displayed more exploratory activity than the control birds, e.g. during flights around a stopover site. These data suggest a more important involvement of the right olfactory system in processing the olfactory information needed for the operation of the navigational map. PMID- 21270306 TI - Deconstructing honeybee vitellogenin: novel 40 kDa fragment assigned to its N terminus. AB - Vitellogenin, an egg-yolk protein precursor common to oviparous animals, is found abundantly in honeybee workers - a caste of helpers that do not usually lay eggs. Instead, honeybee vitellogenin (180 kDa) participates in processes other than reproduction: it influences hormone signaling, food-related behavior, immunity, stress resistance and longevity. The molecular basis of these functions is largely unknown. Here, we establish and compare the molecular properties of vitellogenin from honeybee hemolymph (blood) and abdominal fat body, two compartments that are linked to vitellogenin functions. Our results reveal a novel 40 kDa vitellogenin fragment in abdominal fat body tissue, the main site for vitellogenin synthesis and storage. Using MALDI-TOF combined with MS/MS mass spectroscopy, we assign the 40 kDa fragment to the N terminus of vitellogenin, whereas a previously observed 150 kDa fragment corresponded to the remainder of the protein. We show that both protein units are N glycosylated and phosphorylated. Focusing on the novel 40 kDa fragment, we present a homology model based on the structure of lamprey lipovitellin that includes a conserved beta-barrel-like shape, with a lipophilic cavity in the interior and two insect specific loops that have not been described before. Our data indicate that the honeybee fat body vitellogenin experiences cleavage unlike hemolymph vitellogenin, a pattern that can suggest a tissue-specific role. Our experiments advance the molecular understanding of vitellogenin, of which the multiple physiological and behavioral effects in honeybees are well established. PMID- 21270308 TI - Ott's protein osmotic pressure of serum and interstitial fluid in chickens (Gallus gallus): effect of age and gender. AB - Protein, or colloid, osmotic pressure (COP) is of sufficient magnitude to exert a powerful effect on Starling forces across the capillary wall. Although avian skin lacks active mechanisms for fluid transmission, such as sweating, it is now hypothesized that passive oncotic forces may regulate fluid flow and distribution in the skin and related phenomena. In this study, serum protein profiles, as well as COP in serum (COP(s)) and in suction blister fluid (COP(sbf)), were determined in juvenile, young and adult female and male chickens. For assessing COP, the Ott Ahlqvist equation was applied. This equation can formulate the effects of multiple serum proteins on COP, according to their molecular mass. The COP values determined in chickens were lower than those previously found in mammals. COP(s) increased with age in males, and was higher in adult males than in adult females. In contrast, COP(sbf) decreased with age in females, although it was better preserved in adult males. The age-dependent decrease in COP was associated with a parallel decrease in the concentration of alpha(1)-globulin and albumin, and a positive correlation between packed cell volume (PCV) and COP was found. It is concluded that ageing affects Ott's COP around the vessel wall, and that an oncotic mechanism preserves plasma volume. The preservation of COP(sbf) in males suggests better maintenance of the interstitial ground substance. Females seem to lose more of a tissue's COP(s) counteracting force than males, probably as a result of gender-specific changes in the composition of the interstitial matrix. Further studies are required to elucidate the structure and function of avian lymphatics and their role in skin rheology. PMID- 21270309 TI - Digestive efficiency of Knysna and purple-crested turacos fed varying concentrations of equicaloric and equimolar artificial fruit. AB - Avian frugivores have been somewhat poorly studied with regards to the effects that different fruit sugar types and concentrations have on their digestive efficiencies. Therefore, two relatively large South African frugivores, the Knysna turaco (Tauraco corythaix) and the purple-crested turaco (Gallirex porphyreolophus), were fed artificial fruit that contained equicaloric and equimolar concentrations of different sugars, to determine their daily food and energy intake, digestive efficiencies and digestive transit times. The artificial fruit contained 6.6, 12.4 or 22%, or 0.42, 0.83 or 1.66 mol l(-1) sucrose or glucose. Food intake of both turaco species increased with decreasing sugar concentration and molarity, irrespective of sugar type, suggesting compensatory mechanisms for energy requirements. Apparent assimilation efficiencies of both turaco species ranged from 61.4-90.0% and 60.2-92.4% for equicaloric and equimolar artificial fruit diets, respectively. Digestive transit times for both turaco species were slowed with an increase in sugar concentration and molarity, irrespective of sugar type. Consequently these two frugivores appear to be tolerant of sugar type and would be expected to select fruits based on energy yields. Future studies of the composition of indigenous forest fruit sugars may give insight into food preferences of the turaco species and their role as potential seed dispersers of fruiting tree species. PMID- 21270310 TI - Food preferences of Knysna and purple-crested turacos fed varying concentrations of equicaloric and equimolar artificial fruit. AB - The effects that different fruit sugar types and concentrations have on food preferences of avian frugivores have been relatively poorly studied. Although it has been recently advocated that preference is based on equicaloric energy it is also important to note whether preferences change as energy content changes. Therefore, sugar preferences of equicaloric and equimolar artificial fruit of different sugar types at varying concentrations and molarities were investigated in two relatively large South African frugivores, Knysna (Tauraco corythaix) and purple-crested (Gallirex porphyreolophus) turacos. Artificial fruits containing 6.6, 12.4 or 22% sucrose or glucose, and artificial fruits containing 0.42, 0.83 or 1.66 mol l(-1) sucrose or glucose, were used to determine sugar preferences. Knysna turacos preferred the sucrose to the glucose equicaloric artificial fruit diet at low concentrations whereas purple-crested turacos showed no preference for either diet. Both turacos species preferred the sucrose equimolar artificial fruit diet to the glucose at low concentrations. At high concentrations neither species showed a preference for either equicaloric or equimolar artificial fruit diets. This suggests that energy requirements influence food preferences more than sugar type and that birds will select fruit that is higher in energy irrespective of sugar type. This complements an earlier study on digestion of differing equicaloric and equimolar artificial fruit sugar types. It again emphasizes the need for future studies looking at the composition of indigenous forest fruit sugars in order to obtain insight into the role of these avian frugivores as potential seed dispersers of fruiting tree species. PMID- 21270311 TI - Egg yolk environment differentially influences physiological and morphological development of broiler and layer chicken embryos. AB - Maternal effects are important in epigenetic determination of offspring phenotypes during all life stages. In the chicken (Gallus gallus domesticus), transgenerational transfer of egg yolk factors may set the stage for morphological and physiological phenotypic differences observed among breeds. To investigate the effect of breed-specific yolk composition on embryonic broiler and layer chicken phenotypes, we employed an ex ovo, xenobiotic technique that allowed the transfer of broiler and layer chicken embryos from their natural yolks to novel yolk environments. Embryonic day two broiler embryos developing on broiler yolk culture medium (YCM) had significantly higher heart rates than layer embryos developing on layer YCM (176+/-7 beats min(-1) and 147+/-7 beats min(-1), respectively). Broiler embryos developing on layer YCM exhibited heart rates typical of layer embryos developing normally on layer YCM. However, layer embryo heart rates were not affected by development on broiler YCM. Unlike O(2) consumption, development rate and body mass of embryos were significantly affected by exposure to different yolk types, with both broiler and layer embryos displaying traits that reflected yolk source rather than embryo genotype. Analysis of hormone concentrations of broiler and layer egg yolks revealed that testosterone concentrations were higher in broiler yolk (4.63+/-2.02 pg mg(-1) vs 3.32+/-1.92 pg mg(-1)), whereas triiodothyronine concentrations were higher in layer yolk (1.05+/-0.18 pg mg(-1) vs 0.46+/-0.22 pg mg(-1)). Thus, a complex synergistic effect of breed-specific genotype and yolk environment exists early in chicken development, with yolk thyroid hormone and yolk testosterone as potential mediators of the physiological and morphological effects. PMID- 21270312 TI - Underwater and surface behavior of homing juvenile northern elephant seals. AB - Northern elephant seals, Mirounga angustirostris, travel between colonies along the west coast of North America and foraging areas in the North Pacific. They also have the ability to return to their home colony after being experimentally translocated. However, the mechanisms of this navigation are not known. Visual information could serve an important role in navigation, either primary or supplementary. We examined the role of visual cues in elephant seal navigation by translocating three seals and recording their heading direction continuously using GPS, and acceleration and geomagnetic data loggers while they returned to the colony. The seals first reached the coast and then proceeded to the colony by swimming along the coast. While underwater the animals exhibited a horizontally straight course (mean net-to-gross displacement ratio=0.94+/-0.02). In contrast, while at the surface they changed their headings up to 360 deg. These results are consistent with the use of visual cues for navigation to the colony. The seals may visually orient by using landmarks as they swim along the coast. We further assessed whether the seals could maintain a consistent heading while underwater during drift dives where one might expect that passive spiraling during drift dives could cause disorientation. However, seals were able to maintain the initial course heading even while underwater during drift dives where there was spiral motion (to within 20 deg). This behavior may imply the use of non-visual cues such as acoustic signals or magnetic fields for underwater orientation. PMID- 21270313 TI - Ordinary glomeruli in the antennal lobe of male and female tortricid moth Grapholita molesta (Busck) (Lepidoptera: Tortricidae) process sex pheromone and host-plant volatiles. AB - Both sexes of Grapholita molesta, a key pest of stone fruits, are able to detect host-plant volatiles and the sex pheromone emitted by females, and to modify their behaviour accordingly. How olfactory information is processed in the central nervous system is unknown. Intracellular recordings and stainings were used to characterize antennal lobe (AL) neuron responses to single pheromone components, a behaviourally active blend of five peach volatiles and a pear-fruit ester. AL neurons with different response patterns responded to pheromone components and plant volatiles. In males more neurons responded specifically to the main pheromone component than in females, whereas neurons responding to all three pheromone components were more abundant in females. Neurons responding to all three pheromone components often responded also to the tested plant volatiles in both sexes. Responses to all pheromone components were dose dependent in males and females, but dose-response relationships differed between neurons and tested pheromone components. Among the five AL projection neurons identified neuroanatomically in males, no arborizations were observed in the enlarged cumulus (Cu), although all of them responded to pheromone compounds. In one of two stained projection neurons in females, however, the glomerulus, which is thought to be homologous to the Cu, was targeted. The processing of pheromone information by ordinary glomeruli rather than by the macroglomerular complex is thus a striking feature of this species, indicating that pheromone and plant volatile processing are not entirely separate in this tortricid moth AL. However, the absence of recorded pheromone responses in the Cu needs to be confirmed. PMID- 21270314 TI - N-dimensional animal energetic niches clarify behavioural options in a variable marine environment. AB - Animals respond to environmental variation by exhibiting a number of different behaviours and/or rates of activity, which result in corresponding variation in energy expenditure. Successful animals generally maximize efficiency or rate of energy gain through foraging. Quantification of all features that modulate energy expenditure can theoretically be modelled as an animal energetic niche or power envelope; with total power being represented by the vertical axis and n dimensional horizontal axes representing extents of processes that affect energy expenditure. Such an energetic niche could be used to assess the energetic consequences of animals adopting particular behaviours under various environmental conditions. This value of this approach was tested by constructing a simple mechanistic energetics model based on data collected from recording devices deployed on 41 free-living Magellanic penguins (Spheniscus magellanicus), foraging from four different colonies in Argentina and consequently catching four different types of prey. Energy expenditure was calculated as a function of total distance swum underwater (horizontal axis 1) and maximum depth reached (horizontal axis 2). The resultant power envelope was invariant, irrespective of colony location, but penguins from the different colonies tended to use different areas of the envelope. The different colony solutions appeared to represent particular behavioural options for exploiting the available prey and demonstrate how penguins respond to environmental circumstance (prey distribution), the energetic consequences that this has for them, and how this affects the balance of energy acquisition through foraging and expenditure strategy. PMID- 21270315 TI - Locomotory transition from water to sand and its effects on undulatory kinematics in sand lances (Ammodytidae). AB - Sand lances, fishes in the genus Ammodytes, exhibit a peculiar burrowing behavior in which they appear to swim rapidly into the substrate. They use posteriorly propagated undulations of the body to move in both water, a Newtonian fluid, and in sand, a non-Newtonian, granular substrate. In typical aquatic limbless locomotion, undulations of the body push against water, which flows because it is incapable of supporting the static stresses exerted by the animal, thus the undulations move in world space (slipping wave locomotion). In typical terrestrial limbless locomotion, these undulations push against substrate irregularities and move relatively little in world space (non-slipping wave locomotion). We used standard and X-ray video to determine the roles of slipping wave and non-slipping wave locomotion during burrowing in sand lances. We find that sand lances in water use slipping wave locomotion, similar to most aquatic undulators, but switch to non-slipping waves once they burrow. We identify a progression of three stages in the burrowing process: first, aquatic undulations similar to typical anguilliform locomotion (but without head yaw) push the head into the sand; second, more pronounced undulations of the aquatic portion of the body push most of the animal below ground; third, the remaining above-ground portion of the body ceases undulation and the subterranean portion takes over, transitioning to non-slipping wave locomotion. We find no evidence that sand lances use their body motions to fluidize the sand. Instead, as soon as enough of the body is underground, they undergo a kinematic shift and locomote like terrestrial limbless vertebrates. PMID- 21270316 TI - Amblyomma americanum (L.) (Acari: Ixodidae) tick salivary gland serine protease inhibitor (serpin) 6 is secreted into tick saliva during tick feeding. AB - In order to successfully feed and transmit disease agents, ticks are thought to inject serine protease inhibitors (serpins) into the host to modulate host defense responses to tick feeding, such as inflammation, the complement activation pathway and blood coagulation. In this study, we show that Amblyomma americanum (Aam) serpin (S) 6 is putatively injected into the host during tick feeding, in that the antibody to recombinant (r) AamS6 specifically reacted with the expected ~43/45 kDa AamS6 protein band on western blots of pilocarpine induced tick saliva. Additionally, antibodies to tick saliva proteins that were generated by repeated 48 h infestations of rabbits with adult A. americanum specifically reacted with rAamS6. We speculate that AamS6 is associated with regulating events at the start of the tick feeding process, as temporal and spatial RT-PCR and western blot analyses revealed that both AamS6 mRNA and protein are strongly expressed during the first 24-72 h of feeding time before starting to fade from 96 h. The AamS6 protein has an apparently slow turnover rate in that, although the injection of AamS6 dsRNA into unfed ticks triggered complete disruption of the AamS6 mRNA by the 48 h feeding time point, western blot analysis of protein extracts of the same animals showed that the AamS6 protein that may have been expressed prior to disruption of the AamS6 mRNA was not depleted. We speculate that the presence of the AamS6 protein in ticks despite the complete disruption of the AamS6 mRNA explains the observation that RNAi-mediated silencing of the AamS6 mRNA did not affect the ability of A. americanum ticks to attach onto host skin, successfully feed and lay eggs. These findings are discussed in regards to advances in the molecular biology of ticks. PMID- 21270317 TI - Muscle damage and muscle remodeling: no pain, no gain? AB - Skeletal muscle is a dynamic tissue that responds adaptively to both the nature and intensity of muscle use. This phenotypic plasticity ensures that muscle structure is linked to patterns of muscle use throughout the lifetime of an animal. The cascade of events that result in muscle restructuring - for example, in response to resistance exercise training - is often thought to be initiated by muscle damage. We designed this study to test the hypothesis that symptomatic (i.e. detectable) damage is a necessary precursor for muscle remodeling. Subjects were divided into two experimental populations: pre-trained (PT) and naive (NA). Demonstrable muscle damage was avoided in the PT group by a three-week gradual 'ramp-up' protocol. By contrast, the NA group was subjected to an initial damaging bout of exercise. Both groups participated in an eight-week high-force eccentric-cycle ergometry program (20 min, three times per week) designed to equate the total work done during training between the groups. The NA group experienced signs of damage, absent in the PT group, as indicated by greater than five times higher levels of plasma creatine kinase (CK) and self-reporting of initial perceived soreness and exertion, yet muscle size and strength gains were not different for the two groups. RT-PCR analysis revealed similar increases in levels of the growth factor IGF-1Ea mRNA in both groups. Likewise, the significant (P<0.01) increases in mean cross-sectional area (and total muscle volume) were equal in both groups. Finally, strength increases were identical for both groups (PT=25% and NA=26% improvement). The results of this study suggest that muscle rebuilding - for example, hypertrophy - can be initiated independent of any discernible damage to the muscle. PMID- 21270318 TI - Loss of Angiotensin-converting enzyme-related (ACER) peptidase disrupts night time sleep in adult Drosophila melanogaster. AB - Drosophila Acer (Angiotensin-converting enzyme-related) encodes a member of the angiotensin-converting enzyme family of metallopeptidases that have important roles in the endocrine regulation of blood homeostasis in mammals. Acer is expressed in the embryonic heart of Drosophila and expression in the adult head appears to be regulated by two clock genes. To study the role of Acer in development and in circadian activity, we have generated Acer null mutants by imprecise excision of a P-element and have compared their development and circadian behaviour with that of wild-type flies with the same genetic background. We show that Acer is not required for normal development, but that night sleep, which is clock regulated, is disrupted in adult flies lacking ACER. Acer null adults have reduced night-time sleep and greater sleep fragmentation, but normal levels of daytime sleep. The quality of night sleep in flies fed inhibitors of ACER is affected in a very similar manner. We have shown, using specific antibodies, that ACER is present in the adult fat body of the head and abdomen, and is secreted into the haemolymph. ACER might therefore have a role in cleaving regulatory peptides involved in metabolism and activity behaviour. There are similarities with mammals, where ACE peptidases are also expressed in adipose tissue and are thought to be part of a signalling system linking metabolism with sleep. PMID- 21270319 TI - The effect of substrate compliance on the biomechanics of gibbon leaps. AB - The storage and recovery of elastic strain energy in the musculoskeletal systems of locomoting animals has been extensively studied, yet the external environment represents a second potentially useful energy store that has often been neglected. Recent studies have highlighted the ability of orangutans to usefully recover energy from swaying trees to minimise the cost of gap crossing. Although mechanically similar mechanisms have been hypothesised for wild leaping primates, to date no such energy recovery mechanisms have been demonstrated biomechanically in leapers. We used a setup consisting of a forceplate and two high-speed video cameras to conduct a biomechanical analysis of captive gibbons leaping from stiff and compliant poles. We found that the gibbons minimised pole deflection by using different leaping strategies. Two leap types were used: slower orthograde leaps and more rapid pronograde leaps. The slower leaps used a wider hip joint excursion to negate the downward movement of the pole, using more impulse to power the leap, but with no increase in work done on the centre of mass. Greater hip excursion also minimised the effective leap distance during orthograde leaps. The more rapid leaps conversely applied peak force earlier in stance where the pole was effectively stiffer, minimising deflection and potential energy loss. Neither leap type appeared to usefully recover energy from the pole to increase leap performance, but the gibbons demonstrated an ability to best adapt their leap biomechanics to counter the negative effects of the compliant pole. PMID- 21270320 TI - Mass arsenic poisoning and the public health response in Maine. AB - Created in the wake of the September 11, 2001 terrorist attacks, Maine's Office of Public Health Emergency Preparedness within the Maine Center for Disease Control and Prevention undertook a major reorganization of epidemiology and laboratory services and began developing relationships with key partners and stakeholders, and a knowledgeable and skilled public health emergency preparedness workforce. In 2003, these newly implemented initiatives were tested extensively during a mass arsenic poisoning at the Gustav Adolph Lutheran Church in the rural northern community of New Sweden, Maine. This episode serves as a prominent marker of how increased preparedness capabilities, as demonstrated by the rapid identification and administration of antidotes and effective collaborations between key partners, can contribute to the management of broader public health emergencies in rural areas. PMID- 21270321 TI - Comparison of two cone beam computed tomographic systems versus panoramic imaging for localization of impacted maxillary canines and detection of root resorption. AB - The diagnostic accuracy for the localization of impacted canines and the detection of canine-induced root resorption of maxillary incisors were compared between conventional radiographic procedures using one two-dimensional (2D) panoramic radiograph with that of two three-dimensional (3D) cone beam computed tomography (CBCT) scans. The clinical records of 60 consecutive patients who had impacted or ectopically erupting maxillary canines were identified from those seeking orthodontic treatment. For each case, two sets of radiographic information were obtained. The study sample was divided into two groups: group A (n = 30) included those for whom a dental pantomograph (DPT) and CBCT obtained with a 3D Accuitomo-XYZ Slice View Tomograph were available and group B (n = 30) who had a DPT and CBCT obtained with a Scanora. The DPT and CBCT images were subsequently analysed by 11 examiners. Statistical analysis included an evaluation of the agreement between observers based on the standard error of the measurement, kappa statistics and coefficient of concordance, as well as an assessment of the differences between 2D and 3D imaging employing Wilcoxon signed rank and McNemar tests. There was a highly significant difference between the 2D and 3D images in the width of the canine crown (P < 0.001) and in canine angulation to the occlusal plane. Moreover, there was a highly significant difference between the DPT and Scanora CBCT images in canine angulation to the midline (P < 0.001). There was also a significant difference between 2D and 3D images with respect to canine location (P = 0.0074 for group A and P = 0.0008 for group B). The presence or absence of root resorption of the lateral incisor was also significantly different in both groups (P = 0.0201 and P < 0.001 for groups A and B, respectively). Detection of central incisor root resorption was significantly different between the Accuitomo and DPT images (P = 0.045). There was also a significant difference in the severity of lateral incisor root resorption between the DPT and CBCT in both groups (P = 0.02). The results of this study suggest that CBCT is more sensitive than conventional radiography for both canine localization and identification of root resorption of adjacent teeth. PMID- 21270322 TI - Retraction. Caveolin 1 is required for the activation of endothelial nitric oxide synthase in response to 17beta-estradiol. PMID- 21270323 TI - Surfactant protein-A (SP-A) selectively inhibits prostaglandin F2alpha (PGF2alpha) production in term decidua: implications for the onset of labor. AB - CONTEXT: Labor is characterized by "decidual activation" with production of inflammatory mediators. Recent data suggest that surfactant protein-A (SP-A) may be critical to the onset of labor in mice. Whether this is also true in humans is unclear. OBJECTIVES: The aim was to investigate: 1) the expression of SP-A at the maternal-fetal interface; 2) the effect of SP-A on the production of inflammatory mediators by human decidua; and 3) the association between single nucleotide polymorphisms in maternal SP-A genes and spontaneous preterm birth. RESEARCH DESIGN AND METHODS: In situ expression of SP-A was investigated by immunohistochemistry and quantitative RT-PCR. Term decidual stromal cells were isolated, purified, and treated with/without SP-A (1-100 MUg/ml), IL-1beta, and/or thrombin. Levels of inflammatory mediators [IL-6, IL-8, TNFalpha, matrix metalloproteinase-3, monocyte chemotactic protein-1, IL-1beta, PGE(2), prostaglandin F(2alpha) (PGF(2alpha))] and angiogenic factors (soluble fms-like tyrosine kinase-1, vascular endothelial growth factor) were measured in conditioned supernatant by ELISA and corrected for protein content. The effect of SP-A on eicosanoid gene expression was measured by quantitative RT-PCR. RESULTS: SP-A localized to endometrium/decidua. High-dose SP-A (100 MUg/ml) inhibited PGF(2alpha) by term decidual stromal cells without affecting the production of other inflammatory mediators, and this effect occurred at a posttranscriptional level. Decidual SP-A expression decreased significantly with labor. Single nucleotide polymorphisms in the SP-A genes do not appear to be associated with preterm birth. CONCLUSIONS: SP-A is produced by human endometrium/decidua, where it significantly and selectively inhibits PGF(2alpha) production. Its expression decreases with labor. These novel observations suggest that decidual SP-A likely plays a critical role in regulating prostaglandin production within the uterus, culminating at term in decidual activation and the onset of labor. PMID- 21270324 TI - Bone mass in subjects with Klinefelter syndrome: role of testosterone levels and androgen receptor gene CAG polymorphism. AB - CONTEXT: Klinefelter syndrome (KS) is a chromosomal alteration characterized by supernumerary X-chromosome(s), primary hypogonadism, decreased pubertal peak bone mineral density (BMD), and accelerated bone loss during adulthood. Decreased bone mass has been traditionally related to low testosterone levels. However, testosterone replacement therapy does not necessarily increase bone mass in these patients, and low BMD can be observed also in patients with normal testosterone levels. The androgen receptor (AR) gene CAG polymorphism seems to modulate the sensitivity to testosterone and previous studies have related it to some clinical aspects of KS, to include BMD, gynecomastia, testes and prostate volume, and hemoglobin concentration. OBJECTIVE: To analyze the relation between bone mass, testosterone, and AR CAG polymorphism in men with KS. DESIGN: Cross-sectional cohort study. SETTING: University department. PATIENTS: One hundred twelve consecutive treatment-naive 47,XXY Klinefelter patients (mean age 33.5 +/- 4.7 yr) and 51 age-matched normal male controls. MAIN OUTCOME MEASURES: Dual-energy x ray absorptiometry, CAG repeat length polymorphism, X-chromosome inactivation, and testosterone levels. RESULTS: Forty-nine of 112 KS subjects (42.5%) had low bone mass (osteopenia or osteoporosis). Lumbar and/or femoral T-scores were lower in KS patients compared with controls. No significant relationship was observed between testosterone levels and bone parameters, and the prevalence of osteopenia/osteoporosis was similar in subjects with normal and low testosterone levels (43.7% and 40.5%, respectively). The mean CAG repeat length calculated after X-chromosome inactivation analysis showed no differences between patients with normal and low bone mass. CONCLUSIONS: Testosterone levels and AR CAG polymorphism are not associated with bone mass phenotype in KS. PMID- 21270325 TI - Effects of insulin sensitivity, body composition, and fitness on lipoprotein particle sizes and concentrations determined by nuclear magnetic resonance. AB - CONTEXT: Insulin resistance has been reported to be associated with development of atherogenic dyslipidemia. However, the confounding effects that obesity and low levels of cardiorespiratory fitness have on the relationship between insulin resistance and the development of atherogenic dyslipidemia remain to be adequately addressed. OBJECTIVE: This study sought to examine the independent and combined effects of insulin sensitivity, body composition, and cardiorespiratory fitness on lipoprotein particle sizes and concentrations. METHODS: Eight-four healthy, nondiabetic men (n = 43) and women (n = 41) were studied. The participants had a wide range of ages (18-30 and 65-80 yr), body composition (7.2 52.8% fat), and cardiorespiratory fitness (VO(2) peak, 13.5-66.2 ml/kg . min). Body composition, cardiorespiratory fitness, insulin sensitivity, and lipoprotein particle profiles were assessed using dual-energy x-ray absorptiometry, cardiopulmonary exercise testing, a hyperinsulinemic-euglycemic clamp, and nuclear magnetic resonance spectroscopy, respectively. RESULTS: Low levels of insulin sensitivity and cardiorespiratory fitness and higher levels of adiposity were associated with the accumulation of small, dense, low-density lipoprotein particles; small high-density lipoprotein particles; triglycerides; and very low density lipoprotein particles. Multivariate forward-stepwise regression revealed that higher levels of adiposity, in particular truncal fat, were the strongest predictor of the lipoprotein particle size and concentration data, followed by insulin sensitivity. CONCLUSIONS: As expected, the accumulation of atherogenic lipoprotein particles (e.g. small, dense, low-density lipoprotein particles and small, high-density lipoprotein particles) was associated with low levels of insulin sensitivity, cardiorespiratory fitness, and higher levels of adiposity. However, multivariate forward-stepwise regression revealed that triglycerides, followed by truncal fat mass, were the strongest predictors of the lipoprotein particle size and concentration data. PMID- 21270326 TI - Clinical evidence for predominance of delta-5 steroid production in women with polycystic ovary syndrome. AB - CONTEXT: In women with polycystic ovary syndrome (PCOS), the basis for ovarian androgen overproduction involves an overall increase of steroidogenesis, notably in the delta-4 pathway. However, in vitro studies have suggested that excessive androgen production occurs predominantly through the delta-5 pathway. OBJECTIVE: This study was performed to assess androgen dose-responses after human chorionic gonadotropin (hCG) stimulation in PCOS and normal women. DESIGN: We conducted a prospective study to compare androgen production after iv hCG in PCOS and normal women. SETTING: The study was conducted in a General Clinical Research Center in an academic medical center. PARTICIPANTS: Women with PCOS (age, 18-37 yr; n = 10) and normal ovulatory controls (age, 18-37 yr; n = 11) were recruited. INTERVENTIONS: For dose-response studies, blood samples were obtained before and at 0.5, 24, and 48 h after iv recombinant hCG (1, 10, 25, 100, and 250 MUg). A subset of subjects underwent frequent blood sampling over 24 h after iv injection of 25 MUg of recombinant hCG. MAIN OUTCOME MEASURE(S): We measured basal and stimulated serum 17-hydroxyprogesterone (17-OHP), androstenedione (A), testosterone (T), dehydroepiandrosterone, estradiol, and progesterone responses after hCG administration. RESULTS: In PCOS women, maximal A and T production was observed at the lowest doses of hCG, whereas responses were minimal in normal women. Incremental responses of 17-OHP, estradiol, and progesterone were greater in PCOS compared to normal women. CONCLUSION: In PCOS women, maximal A and T responses to hCG relative to those of 17-OHP are consistent with ovarian androgen overproduction via the delta-5 pathway. PMID- 21270327 TI - Bone mineral density and testicular failure: evidence for a role of vitamin D 25 hydroxylase in human testis. AB - WORKING HYPOTHESIS: Mutations in the CYP2R1 gene, highly expressed in the testis and encoding vitamin D 25-hydroxylase, result in a vitamin D deficiency and a defective calcium homeostasis leading to rickets. OBJECTIVE: Our aim was to investigate CYP2R1 expression in pathological testis samples and relate this to vitamin D metabolism in testiculopathic patients. DESIGN, PATIENTS, SETTING: Testis samples for in vitro study and 98 young men were transversally evaluated at Padova's Center for Male Gamete Cryopreservation. METHODS: CYP2R1 mRNA expression and protein production were evaluated by quantitative RT-PCR, Western blot analysis, and immunofluorescence. Hormonal and bone-marker levels, and bone densitometry by dual-energy x-ray absorptiometry, were determined in patients with Sertoli-cell-only syndrome and severe hypospermatogenesis. RESULTS: We found a lower gene and protein expression of CYP2R1 in samples with hypospermatogenesis and Sertoli-cell-only syndrome (P < 0.05) and a colocalization with INSL-3, a Leydig cell marker, at immunofluorescence. In all testiculopathic patients 25 hydroxyvitamin D levels were significantly lower and PTH levels higher compared to controls (P < 0.05). Furthermore, testiculopathic patients showed osteopenia and osteoporosis despite normal testosterone levels compared with controls both with increased bone-marker levels and altered dual-energy x-ray absorptiometry in the femoral neck and lumbar spine (for all parameters, P < 0.05). CONCLUSIONS: Our data show an association between testiculopathy and alteration of the bone status, despite unvaried androgen and estrogen levels and no other evident cause of vitamin D reduction. Further studies in larger cohorts are needed to confirm our results. PMID- 21270328 TI - Type B insulin resistance syndrome associated with an immune reconstitution inflammatory syndrome in an HIV-infected woman. AB - CONTEXT: Type B insulin resistance syndrome is a rare condition characterized by the presence of autoantibodies directed against the insulin receptor. It has been reported in association with autoimmune diseases such as systemic lupus erythematosus. OBJECTIVE: We report a case of type B insulin resistance syndrome in a patient with HIV infection on highly active antiretroviral therapy (HAART). PATIENT AND METHODS: A 27-yr-old African woman with ketosis-prone diabetes and HIV infection developed severe insulin resistance after the initiation of HAART. Standard oral glucose tolerance tests using 75 g of glucose performed 1, 2, and 3 months after the initiation of HAART showed severe hyperinsulinemia and hypoglycemia. Six months later, she developed symptomatic hyperglycemia resistant to high-dose insulin therapy. To determine the cause of insulin resistance, we assayed the titer of insulin receptor autoantibodies in the serum of the patient. RESULTS: Plasma insulin receptor autoantibodies were present at the time of marked hyperglycemia and insulin resistance, confirming the diagnosis of type B insulin resistance syndrome. Simultaneously the diagnosis of immune reconstitution inflammatory syndrome was established according to increased CD4 T cell count, decreased plasma HIV1-RNA level, and tuberculosis reactivation, shortly after institution of HAART. Corticosteroid therapy improved insulin resistance and hyperglycemia. CONCLUSION: We report the first case of type B insulin resistance syndrome associated with immune reconstitution inflammatory syndrome in an HIV-infected patient. PMID- 21270329 TI - Beta-adrenergic receptor blockade does not inhibit cold-induced thermogenesis in humans: possible involvement of brown adipose tissue. AB - CONTEXT: Recently, brown adipose tissue (BAT) gained interest as a possible target for cold-induced thermogenesis, and therefore a target for treatment of obesity in adult humans. However, mitochondrial uncoupling takes place not only in BAT but also in skeletal muscle tissue. Both tissues may be involved in cold induced thermogenesis, which is presumably regulated by the sympathetic nervous system. OBJECTIVE: Here we studied whether blockade of beta-adrenergic receptors using propranolol diminishes cold-induced thermogenesis and mitochondrial uncoupling in skeletal muscle tissue. DESIGN: Ten lean subjects participated in this study and stayed twice (control and beta-blockade using propranolol) for 84 h in a respiration chamber-the first 36 h for baseline measurements, followed by 48 h of mild cold exposure (16 C). Energy expenditure was measured continuously. After 36 and 84 h, muscle biopsies were taken in which mitochondrial uncoupling was studied. RESULTS: Energy expenditure increased upon mild cold exposure (+5.0 +/- 1.2 W; P < 0.005), i.e. cold-induced thermogenesis. However, contrary to our hypothesis, this cold-induced thermogenesis was not diminished after beta blockade (+4.7 +/- 2.1 W for blockade vs. +5.1 +/- 1.4 W for control; P = 0.59 for interaction cold blockade). Skeletal muscle mitochondrial uncoupling was significantly related to cold-induced thermogenesis in the control situation (R(2) = 0.650; P < 0.01). There was no such relation during beta-blockade. CONCLUSIONS: Our results suggest that skeletal muscle mitochondrial uncoupling may be involved in cold-induced thermogenesis and that this may be regulated by beta(2)-receptors. When the beta(1)- and beta(2)-receptors are blocked, a beta(3) regulated process like mitochondrial uncoupling in BAT might take over the role of skeletal muscle mitochondrial uncoupling. PMID- 21270330 TI - Insufficient activation of autophagy allows cellular damage to accumulate in critically ill patients. AB - CONTEXT: Responses to critical illness, such as excessive inflammation and hyperglycemia, may trigger detrimental chain reactions that damage cellular proteins and organelles. Such responses to illness contribute to the risk of (nonresolving) multiple organ dysfunction and adverse outcome. OBJECTIVE: We studied autophagy as a bulk degradation pathway able to remove toxic protein aggregates and damaged organelles and how these are affected by preventing hyperglycemia with insulin during critical illness. DESIGN AND SETTING: Patients participated in a randomized study, conducted at a university hospital surgical/medical intensive care unit. PATIENTS: We studied adult prolonged critically ill patients vs. controls. INTERVENTIONS: Tolerating excessive hyperglycemia was compared with intensive insulin therapy targeting normoglycemia. MAIN OUTCOME MEASURES: We quantified (ultra)structural abnormalities and hepatic and skeletal muscle protein levels of key players in autophagy. RESULTS: Morphologically, both liver and muscle revealed an autophagy deficiency phenotype. Proteins involved in initiation and elongation steps of autophagy were induced 1.3- to 6.5-fold by critical illness (P <= 0.01), but mature autophagic vacuole formation was 62% impaired (P = 0.05) and proteins normally degraded by autophagy accumulated up to 97-fold (P <= 0.03). Mitophagy markers were unaltered or down-regulated (P = 0.05). Although insulin preserved hepatocytic mitochondrial integrity (P = 0.05), it further reduced the number of autophagic vacuoles by 80% (P = 0.05). CONCLUSIONS: Insufficient autophagy in prolonged critical illness may cause inadequate removal of damaged proteins and mitochondria. Such incomplete clearance of cellular damage, inflicted by illness and aggravated by hyperglycemia, could explain lack of recovery from organ failure in prolonged critically ill patients. These data open perspectives for therapies that activate autophagy during critical illness. PMID- 21270331 TI - Differential acylated ghrelin, peptide YY3-36, appetite, and food intake responses to equivalent energy deficits created by exercise and food restriction. AB - CONTEXT: Acute energy deficits imposed by food restriction increase appetite and energy intake; however, these outcomes remain unchanged when energy deficits are imposed by exercise. OBJECTIVE: Our objective was to determine the potential role of acylated ghrelin and peptide YY(3-36) (PYY(3-36)) in mediating appetite and energy intake responses to identical energy deficits imposed by food restriction and exercise. DESIGN: Twelve healthy males completed three 9-h trials (exercise deficit, food deficit, and control) in a randomized counterbalanced design. Participants ran for 90 min (70% of VO(2) max) at the beginning of the exercise deficit trial and then rested for 7.5 h. Participants remained sedentary throughout the food deficit and control trials. Test meals were consumed by participants at 2 and 4.75 h in all trials. The amount provided in the food deficit trial was restricted so that an energy deficit (equivalent to that imposed by exercise) was induced relative to control. Participants were permitted access to a buffet meal at 8 h. RESULTS: The energy deficits imposed by food restriction (4820 +/- 151 kJ) and exercise (4715 +/- 113 kJ) were similar. Appetite and ad libitum energy intake responded in a compensatory fashion to food restriction yet were not influenced by exercise. Plasma acylated ghrelin concentrations increased, whereas PYY(3-36) decreased, in response to food restriction (two-way ANOVA, trial * time interaction, P < 0.001 for each). Exercise did not induce such compensatory responses. CONCLUSIONS: These findings suggest a mediating role of acylated ghrelin and PYY(3-36) in determining divergent feeding responses to energy deficits imposed by food restriction and exercise. PMID- 21270332 TI - Crystal structures of two active proliferating cell nuclear antigens (PCNAs) encoded by Thermococcus kodakaraensis. AB - Proliferating cell nuclear antigen (PCNA) is a ring-shaped protein that encircles duplex DNA and plays an essential role in many DNA metabolic processes in archaea and eukarya. The eukaryotic and euryarchaea genomes contain a single gene encoding for PCNA. Interestingly, the genome of the euryarchaeon Thermococcus kodakaraensis contains two PCNA-encoding genes (TK0535 and TK0582), making it unique among the euryarchaea kingdom. It is shown here that the two T. kodakaraensis PCNA proteins support processive DNA synthesis by the polymerase. Both proteins form trimeric structures with characteristics similar to those of other archaeal and eukaryal PCNA proteins. One of the notable differences between the TK0535 and TK0582 rings is that the interfaces are different, resulting in different stabilities for the two trimers. The possible implications of these observations for PCNA functions are discussed. PMID- 21270333 TI - Protein-only mechanism induces self-perpetuating changes in the activity of neuronal Aplysia cytoplasmic polyadenylation element binding protein (CPEB). AB - Neuronal cytoplasmic polyadenylation element binding protein (CPEB) plays a critical role in maintaining the functional and morphological long-lasting synaptic changes that underlie learning and memory. It can undergo a prion switch, but it remains unclear if this self-templating change in protein conformation is alone sufficient to create a stable change in CPEB activity: a robust "protein-only" biochemical memory. To investigate, we take advantage of yeast cells wherein the neuronal CPEB of Aplysia is expressed in the absence of any neuronal factors and can stably adopt either an active or an inactive state. Reminiscent of well-characterized yeast prions, we find that CPEB can adopt several distinct activity states or "strains." These states are acquired at a much higher spontaneous rate than is typical of yeast prions, but they are extremely stable--perpetuating for years--and have all of the non-Mendelian genetic characteristics of bona fide yeast prions. CPEB levels are too low to allow direct physical characterization, but CPEB strains convert a fusion protein, which shares only the prion-like domain of CPEB, into amyloid in a strain-specific manner. Lysates of CPEB strains seed the purified prion domain to adopt the amyloid conformation with strain-specific efficiencies. Amyloid conformers generated by spontaneous assembly of the purified prion domain (and a more biochemically tractable derivative) transformed cells with inactive CPEB into the full range of distinct CPEB strains. Thus, CPEB employs a prion mechanism to create stable, finely tuned self-perpetuating biochemical memories. These biochemical memories might be used in the local homeostatic maintenance of long-term learning-related changes in synaptic morphology and function. PMID- 21270334 TI - Poly(ADP-ribose) polymerase 3 (PARP3), a newcomer in cellular response to DNA damage and mitotic progression. AB - The ADP ribosyl transferase [poly(ADP-ribose) polymerase] ARTD3(PARP3) is a newly characterized member of the ARTD(PARP) family that catalyzes the reaction of ADP ribosylation, a key posttranslational modification of proteins involved in different signaling pathways from DNA damage to energy metabolism and organismal memory. This enzyme shares high structural similarities with the DNA repair enzymes PARP1 and PARP2 and accordingly has been found to catalyse poly(ADP ribose) synthesis. However, relatively little is known about its in vivo cellular properties. By combining biochemical studies with the generation and characterization of loss-of-function human and mouse models, we describe PARP3 as a newcomer in genome integrity and mitotic progression. We report a particular role of PARP3 in cellular response to double-strand breaks, most likely in concert with PARP1. We identify PARP3 as a critical player in the stabilization of the mitotic spindle and in telomere integrity notably by associating and regulating the mitotic components NuMA and tankyrase 1. Both functions open stimulating prospects for specifically targeting PARP3 in cancer therapy. PMID- 21270335 TI - Point mutation in the glycoprotein of lymphocytic choriomeningitis virus is necessary for receptor binding, dendritic cell infection, and long-term persistence. AB - Arenaviruses are a major cause of hemorrhagic fevers endemic to Sub-Saharan Africa and South America, and thus a major public health and medical concern. The prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) is widely used as a model system for studying persistent and acute infections, as well as for gaining an understanding of mammalian immune function. When originally characterized three decades ago, the LCMV isolate, Armstrong, which causes an acute infection in adult mice, was found to differ from the LCMV Clone 13 strain that causes a persistent infection by two amino acid changes, one within the virus surface glycoprotein (GP1: F260L) and the other within the virus L polymerase (K1076Q). Mutation F260L was considered solely responsible for the exceptionally strong binding affinity of Clone 13 (L at GP1 260) to its cellular receptor, alpha-dystroglycan, which among cells of the immune system is preferentially expressed on dendritic cells, and consequently, alters dendritic cell function leading to viral persistence. Recently, we noted a previously overlooked nucleotide difference between these two strains that results in an additional amino acid change in GP1, N176D. To investigate the potential contribution of this newly identified mutation to the Clone 13 phenotype, we used reverse-genetics approaches to generate recombinant LCM viruses with each of these individual mutations. Phenotypic characterization of these rLCMV showed that mutation F260L, but not N176D, in the GP1 of LCMV is essential for mediating the long-term persistence of Clone 13 infections. This work emphasizes the importance of subtle differences in viral strains that determine disease outcomes. PMID- 21270336 TI - Inflammasome-independent role of the apoptosis-associated speck-like protein containing CARD (ASC) in the adjuvant effect of MF59. AB - Clinical studies have indicated that subvirion inactivated vaccines against avian influenza viruses, particularly H5N1, are poorly immunogenic in humans. As a consequence, the use of adjuvants has been championed for the efficient vaccination of a naive population against avian influenza. Aluminum salts (alum) and the oil-in-water emulsion MF59 are safe and effective adjuvants that are being used with influenza vaccines, but the mechanism underlying their stimulation of the immune system remains poorly understood. It was shown recently that activation of a cytosolic innate immune-sensing complex known as "NLR-Pyrin domain containing 3" (NLRP3) inflammasome, also known as "cryopyrin," "cold induced autoinflammatory syndrome 1" (CIAS1), or nacht domain-, leucine-rich repeat-, and PYD-containing protein 3 (Nalp3), is essential for the adjuvant effect of alum. Here we show that the inflammasome component apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), an adapter protein within the NLRP3 inflammasome, is a crucial element in the adjuvant effect of MF59 when combined with H5N1 subunit vaccines. In the absence of ASC, H5-specific IgG antibody responses are significantly reduced, whereas the responses are intact in NLRP3(-/-) and caspase-1(-/-) mice. This defect is caused mainly by the failure of antigen-specific B cells to switch from IgM to IgG production. We conclude that ASC plays an inflammasome-independent role in the induction of antigen-specific humoral immunity after vaccination with MF59 adjuvanted influenza vaccines. These findings have important implications for the rational design of next-generation adjuvants. PMID- 21270337 TI - Between confidentiality and scientific exchange: the place of publication in drug discovery and pharmaceutical research. AB - To continue to improve life expectancy and quality of life, the discovery of innovative therapies should be among the prime goals of the life sciences. The large majority of the drugs that are discovered and successfully developed to the point of being used by patients come from the drug industry, but publications from this sector are rare among life sciences research publications. Publications in the field of pharmaceutical drug discovery should take into account the confidentiality inherent to the protection of the intellectual property rights of a discovery, but they are fundamentally important because they can enhance scientific knowledge, improve the care and safety of patients, provide information for prescribers, and educate the public about the pharmaceutical industry. PMID- 21270338 TI - Uroporphyrinogen decarboxylase is a radiosensitizing target for head and neck cancer. AB - Head and neck cancer (HNC) is the eighth most common malignancy worldwide, comprising a diverse group of cancers affecting the head and neck region. Despite advances in therapeutic options over the last few decades, treatment toxicities and overall clinical outcomes have remained disappointing, thereby underscoring a need to develop novel therapeutic approaches in HNC treatment. Uroporphyrinogen decarboxylase (UROD), a key regulator of heme biosynthesis, was identified from an RNA interference-based high-throughput screen as a tumor-selective radiosensitizing target for HNC. UROD knockdown plus radiation induced caspase mediated apoptosis and cell cycle arrest in HNC cells in vitro and suppressed the in vivo tumor-forming capacity of HNC cells, as well as delayed the growth of established tumor xenografts in mice. This radiosensitization appeared to be mediated by alterations in iron homeostasis and increased production of reactive oxygen species, resulting in enhanced tumor oxidative stress. Moreover, UROD was significantly overexpressed in HNC patient biopsies. Lower preradiation UROD mRNA expression correlated with improved disease-free survival, suggesting that UROD could potentially be used to predict radiation response. UROD down-regulation also radiosensitized several different models of human cancer, as well as sensitized tumors to chemotherapeutic agents, including 5-fluorouracil, cisplatin, and paclitaxel. Thus, our study has revealed UROD as a potent tumor selective sensitizer for both radiation and chemotherapy, with potential relevance to many human malignancies. PMID- 21270339 TI - Manipulating the bioenergetics of alloreactive T cells causes their selective apoptosis and arrests graft-versus-host disease. AB - Cells generate adenosine triphosphate (ATP) by glycolysis and by oxidative phosphorylation (OXPHOS). Despite the importance of having sufficient ATP available for the energy-dependent processes involved in immune activation, little is known about the metabolic adaptations that occur in vivo to meet the increased demand for ATP in activated and proliferating lymphocytes. We found that bone marrow (BM) cells proliferating after BM transplantation (BMT) increased aerobic glycolysis but not OXPHOS, whereas T cells proliferating in response to alloantigens during graft-versus-host disease (GVHD) increased both aerobic glycolysis and OXPHOS. Metabolomic analysis of alloreactive T cells showed an accumulation of acylcarnitines consistent with changes in fatty acid oxidation. Alloreactive T cells also exhibited a hyperpolarized mitochondrial membrane potential (DeltaPsim), increased superoxide production, and decreased amounts of antioxidants, whereas proliferating BM cells did not. Bz-423, a small molecule inhibitor of the mitochondrial F(1)F(0) adenosine triphosphate synthase (F(1)F(0)-ATPase), selectively increased superoxide and induced the apoptosis of alloreactive T cells, which arrested established GVHD in several BMT models without affecting hematopoietic engraftment or lymphocyte reconstitution. These findings challenge the current paradigm that activated T cells meet their increased demands for ATP through aerobic glycolysis, and identify the possibility that bioenergetic and redox characteristics can be selectively exploited as a therapeutic strategy for immune disorders. PMID- 21270341 TI - NAD(P)H oxidase and renal epithelial ion transport. AB - A fundamental requirement for cellular vitality is the maintenance of plasma ion concentration within strict ranges. It is the function of the kidney to match urinary excretion of ions with daily ion intake and nonrenal losses to maintain a stable ionic milieu. NADPH oxidase is a source of reactive oxygen species (ROS) within many cell types, including the transporting renal epithelia. The focus of this review is to describe the role of NADPH oxidase-derived ROS toward local renal tubular ion transport in each nephron segment and to discuss how NADPH oxidase-derived ROS signaling within the nephron may mediate ion homeostasis. In each case, we will attempt to identify the various subunits of NADPH oxidase and reactive oxygen species involved and the ion transporters, which these affect. We will first review the role of NADPH oxidase on renal Na(+) and K(+) transport. Finally, we will review the relationship between tubular H(+) efflux and NADPH oxidase activity. PMID- 21270342 TI - Exercise training augments the dynamic heart rate response to vagal but not sympathetic stimulation in rats. AB - We examined the transfer function of autonomic heart rate (HR) control in anesthetized sedentary and exercise-trained (16 wk, treadmill for 1 h, 5 times/wk at 15 m/min and 15-degree grade) rats for comparison to HR variability assessed in the conscious resting state. The transfer function from sympathetic stimulation to HR response was similar between groups (gain, 4.2 +/- 1.5 vs. 4.5 +/- 1.5 beats.min(-1).Hz(-1); natural frequency, 0.07 +/- 0.01 vs. 0.08 +/- 0.01 Hz; damping coefficient, 1.96 +/- 0.55 vs. 1.69 +/- 0.15; and lag time, 0.7 +/- 0.1 vs. 0.6 +/- 0.1 s; sedentary vs. exercise trained, respectively, means +/- SD). The transfer gain from vagal stimulation to HR response was 6.1 +/- 3.0 in the sedentary and 9.7 +/- 5.1 beats.min(-1).Hz(-1) in the exercise-trained group (P = 0.06). The corner frequency (0.11 +/- 0.05 vs. 0.17 +/- 0.09 Hz) and lag time (0.1 +/- 0.1 vs. 0.2 +/- 0.1 s) did not differ between groups. When the sympathetic transfer gain was averaged for very-low-frequency and low-frequency bands, no significant group effect was observed. In contrast, when the vagal transfer gain was averaged for very-low-frequency, low-frequency, and high frequency bands, exercise training produced a significant group effect (P < 0.05 by two-way, repeated-measures ANOVA). These findings suggest that, in the frequency domain, exercise training augments the dynamic HR response to vagal stimulation but not sympathetic stimulation, regardless of the frequency bands. PMID- 21270343 TI - Exercise-rest cycles do not alter local and whole body heat loss responses. AB - Previous studies have suggested that greater core temperatures during intermittent exercise (Ex) are due to attenuated sweating [upper back sweat rate (SR)] and skin blood flow (SkBF) responses. We evaluated the hypothesis that heat loss is not altered during exercise-rest cycles (ER). Ten male participants randomly performed four 120-min trials: 1) 60-min Ex and 60-min recovery (60ER); 2) 3 * 20-min Ex separated by 20-min recoveries (20ER); 3) 6 * 10-min Ex separated by 10-min recoveries (10ER), or 4) 12 * 5-min Ex separated by 5-min recoveries (5ER). Exercise was performed at a workload of 130 W at 35 degrees C. Whole body heat exchange was determined by direct calorimetry. Core temperature, SR (by ventilated capsule), and SkBF (by laser-doppler) were measured continuously. Evaporative heat loss (EHL) progressively increased with each ER, such that it was significantly greater (P <= 0.05) at the end of the last compared with the first Ex for 5ER (299 +/- 39 vs. 440 +/- 41 W), 10ER (425 +/- 51 vs. 519 +/- 45 W), and 20ER (515 +/- 63 vs. 575 +/- 74 W). The slope of the EHL response against esophageal temperature significantly increased from the first to the last Ex within the 10ER (376 +/- 56 vs. 445 +/- 89 W/ degrees C, P <= 0.05) and 20ER (535 +/- 85 vs. 588 +/- 28 W/ degrees C, P <= 0.05) conditions, but not during 5ER (296 +/- 96 W/ degrees C vs. 278 +/- 95 W/ degrees C, P = 0.237). In contrast, the slope of the SkBF response against esophageal temperature did not significantly change from the first to the last Ex (5ER: 51 +/- 23 vs. 54 +/- 19%/ degrees C, P = 0.848; 10ER: 53 +/- 8 vs. 56 +/- 21%/ degrees C, P = 0.786; 20ER: 44 +/- 20 vs. 50 +/- 27%/ degrees C, P = 0.432). Overall, no differences in body heat content and core temperature were observed. These results suggest that altered local and whole body heat loss responses do not explain the previously observed greater core temperatures during intermittent exercise. PMID- 21270344 TI - Combined diffusion and strain tensor MRI reveals a heterogeneous, planar pattern of strain development during isometric muscle contraction. AB - The purposes of this study were to create a three-dimensional representation of strain during isometric contraction in vivo and to interpret it with respect to the muscle fiber direction. Diffusion tensor MRI was used to measure the muscle fiber direction of the tibialis anterior (TA) muscle of seven healthy volunteers. Spatial-tagging MRI was used to measure linear strains in six directions during separate 50% maximal isometric contractions of the TA. The strain tensor (E) was computed in the TA's deep and superficial compartments and compared with the respective diffusion tensors. Diagonalization of E revealed a planar strain pattern, with one nonzero negative strain (epsilon(N)) and one nonzero positive strain (epsilon(P)); both strains were larger in magnitude (P < 0.05) in the deep compartment [epsilon(N) = -40.4 +/- 4.3%, epsilon(P) = 35.1 +/- 3.5% (means +/- SE)] than in the superficial compartment (epsilon(N) = -24.3 +/- 3.9%, epsilon(P) = 6.3 +/- 4.9%). The principal shortening direction deviated from the fiber direction by 24.0 +/- 1.3 degrees and 39.8 +/- 6.1 degrees in the deep and superficial compartments, respectively (P < 0.05, deep vs. superficial). The deviation of the shortening direction from the fiber direction was due primarily to the lower angle of elevation of the shortening direction over the axial plane than that of the fiber direction. It is concluded that three-dimensional analyses of strain interpreted with respect to the fiber architecture are necessary to characterize skeletal muscle contraction in vivo. The deviation of the principal shortening direction from the fiber direction may relate to intramuscle variations in fiber length and pennation angle. PMID- 21270345 TI - Effect of clonidine on cardiac baroreflex delay in humans and rats. AB - The delay tau between rising systolic blood pressure (SBP) and baroreflex bradycardia has been found to increase when vagal tone is low. The alpha(2) agonist clonidine increases cardiac vagal tone, and this study tested how it affects tau. In eight conscious supine human volunteers clonidine (6 MUg/kg po) reduced tau, assessed both by cross correlation baroreflex sensitivity and sequence methods (both P < 0.05). Experiments on urethane-anaesthetized rats reproduced the phenomenon and investigated the underlying mechanism. Heart rate (HR) responses to increasing SBP produced with an arterial balloon catheter showed reduced tau (P < 0.05) after clonidine (100 MUg/kg iv). The central latency of the reflex was unaltered, however, as shown by the unchanged timing with which antidromically identified cardiac vagal motoneurons (CVM) responded to the arterial pulse. Testing the latency of the HR response to brief electrical stimuli to the right vagus showed that this was also unchanged by clonidine. Nevertheless, vagal stimuli delivered at a fixed time in the cardiac cycle (triggered from the ECG R-wave) slowed HR with a 1-beat delay in the baseline state but a 0-beat delay after clonidine (n = 5, P < 0.05). This was because clonidine lengthened the diastolic period, allowing the vagal volleys to arrive at the heart just in time to postpone the next beat. Calculations indicate that naturally generated CVM volleys in both humans and rats arrive around this critical time. Clonidine thus reduces tau not by changing central or efferent latencies but simply by slowing the heart. PMID- 21270346 TI - Low intrinsic running capacity is associated with reduced skeletal muscle substrate oxidation and lower mitochondrial content in white skeletal muscle. AB - Chronic metabolic diseases develop from the complex interaction of environmental and genetic factors, although the extent to which each contributes to these disorders is unknown. Here, we test the hypothesis that artificial selection for low intrinsic aerobic running capacity is associated with reduced skeletal muscle metabolism and impaired metabolic health. Rat models for low- (LCR) and high- (HCR) intrinsic running capacity were derived from genetically heterogeneous N:NIH stock for 20 generations. Artificial selection produced a 530% difference in running capacity between LCR/HCR, which was associated with significant functional differences in glucose and lipid handling by skeletal muscle, as assessed by hindlimb perfusion. LCR had reduced rates of skeletal muscle glucose uptake (~30%; P = 0.04), glucose oxidation (~50%; P = 0.04), and lipid oxidation (~40%; P = 0.02). Artificial selection for low aerobic capacity was also linked with reduced molecular signaling, decreased muscle glycogen, and triglyceride storage, and a lower mitochondrial content in skeletal muscle, with the most profound changes to these parameters evident in white rather than red muscle. We show that a low intrinsic aerobic running capacity confers reduced insulin sensitivity in skeletal muscle and is associated with impaired markers of metabolic health compared with high intrinsic running capacity. Furthermore, selection for high running capacity, in the absence of exercise training, endows increased skeletal muscle insulin sensitivity and oxidative capacity in specifically white muscle rather than red muscle. These data provide evidence that differences in white muscle may have a role in the divergent aerobic capacity observed in this generation of LCR/HCR. PMID- 21270347 TI - Parabrachial and hypothalamic interaction in sodium appetite. AB - Rats with bilateral lesions of the lateral hypothalamus (LH) fail to exhibit sodium appetite. Lesions of the parabrachial nuclei (PBN) also block salt appetite. The PBN projection to the LH is largely ipsilateral. If these deficits are functionally dependent, damaging the PBN on one side and the LH on the other should also block Na appetite. First, bilateral ibotenic acid lesions of the LH were needed because the electrolytic damage used previously destroyed both cells and axons. The ibotenic LH lesions produced substantial weight loss and eliminated Na appetite. Controls with ipsilateral PBN and LH lesions gained weight and displayed robust sodium appetite. The rats with asymmetric PBN-LH lesions also gained weight, but after sodium depletion consistently failed to increase intake of 0.5 M NaCl. These results dissociate loss of sodium appetite from the classic weight loss after LH damage and prove that Na appetite requires communication between neurons in the LH and the PBN. PMID- 21270348 TI - Distribution of regional lung aeration and perfusion during conventional and noisy pressure support ventilation in experimental lung injury. AB - In acute lung injury (ALI), pressure support ventilation (PSV) may improve oxygenation compared with pressure-controlled ventilation (PCV), and benefit from random variation of pressure support (noisy PSV). We investigated the effects of PCV, PSV, and noisy PSV on gas exchange as well as the distribution of lung aeration and perfusion in 12 pigs with ALI induced by saline lung lavage in supine position. After injury, animals were mechanically ventilated with PCV, PSV, and noisy PSV for 1 h/mode in random sequence. The driving pressure was set to a mean tidal volume of 6 ml/kg and positive end-expiratory pressure to 8 cmH2O in all modes. Functional variables were measured, and the distribution of lung aeration was determined by static and dynamic computed tomography (CT), whereas the distribution of pulmonary blood flow (PBF) was determined by intravenously administered fluorescent microspheres. PSV and noisy PSV improved oxygenation and reduced venous admixture compared with PCV. Mechanical ventilation with PSV and noisy PSV did not decrease nonaerated areas but led to a redistribution of PBF from dorsal to ventral lung regions and reduced tidal reaeration and hyperinflation compared with PCV. Noisy PSV further improved oxygenation and redistributed PBF from caudal to cranial lung regions compared with conventional PSV. We conclude that assisted ventilation with PSV and noisy PSV improves oxygenation compared with PCV through redistribution of PBF from dependent to nondependent zones without lung recruitment. Random variation of pressure support further redistributes PBF and improves oxygenation compared with conventional PSV. PMID- 21270349 TI - Does a reduction in anabolic signaling contribute to muscle wasting in chronic heart failure? PMID- 21270350 TI - Acute antibody-directed myostatin inhibition attenuates disuse muscle atrophy and weakness in mice. AB - Counteracting the atrophy of skeletal muscle associated with disuse has significant implications for minimizing the wasting and weakness in plaster casting, joint immobilization, and other forms of limb unloading, with relevance to orthopedics, sports medicine, and plastic and reconstructive surgery. We tested the hypothesis that antibody-directed myostatin inhibition would attenuate the loss of muscle mass and functional capacity in mice during 14 or 21 days of unilateral hindlimb casting. Twelve-week-old C57BL/10 mice were subjected to unilateral hindlimb plaster casting or served as controls. Mice received subcutaneous injections of saline or a mouse chimera of anti-human myostatin antibody (PF-354, 10 mg/kg; n = 6-9) on days 0 and 7 and were tested for muscle function on day 14, or were treated on days 0, 7, and 14 and tested for muscle function on day 21. Hindlimb casting reduced muscle mass, fiber size, and function of isolated soleus and extensor digitorum longus (EDL) muscles (P < 0.05). PF-354 attenuated the loss of muscle mass, fiber size, and function with greater effects after 14 days than after 21 days of casting, when wasting and weakness had plateaued (P < 0.05). Antibody-directed myostatin inhibition therefore attenuated the atrophy and loss of functional capacity in muscles from mice subjected to unilateral hindlimb casting with reductions in muscle size and strength being most apparent during the first 14 days of disuse. These findings highlight the therapeutic potential of antibody-directed myostatin inhibition for disuse atrophy especially within the first 2 wk of disuse. PMID- 21270351 TI - Metabolomic response to exercise training in lean and diet-induced obese mice. AB - Exercise training is a common therapeutic approach known to antagonize the metabolic consequences of obesity. The aims of the present study were to examine 1) whether short-term, moderate-intensity exercise training alters the basal metabolite profile and 2) if 10 days of mild exercise training can correct obesity-induced shifts in metabolic spectra. After being weaned, male C57BL/6J littermates were randomly divided into two diet groups: low fat (LF) or high fat (HF). After 12 wk of dietary manipulation, HF animals were obese and hyperglycemic compared with LF animals. Mice from each group were further divided into sedentary or exercise treatments. Exercise training consisted of wheel running exercise (2 h/day, 10 days, 5.64 m/min). After exercise training, animals were rested (36 h) and fasted (6 h) before serum collection. Samples were analyzed by high-resolution one-dimensional proton NMR. Fifty high- and medium concentration metabolites were identified. Pattern recognition algorithms and multivariate modeling were used to identify and isolate significant metabolites changing in response to HF and exercise training. The results showed that while exercise can mitigate some of the abnormal patterns in metabolic spectra induced by HF diet feeding, they cannot negate it. In fact, when the effects of diet and exercise were compared, diet was a stronger predictor and had the larger influence on the metabolic profile. External validation of models showed that diet could be correctly classified with an accuracy of 89%, whereas exercise training could be classified 73% of the time. The results demonstrate metabolomics to effectively characterize obesity-induced perturbations in metabolism and support the concept that exercise is beneficial for this condition. PMID- 21270352 TI - 2010 Carl Ludwig Distinguished Lectureship of the APS Neural Control and Autonomic Regulation Section: Central neural pathways for thermoregulatory cold defense. AB - Central neural circuits orchestrate the homeostatic repertoire to maintain body temperature during environmental temperature challenges and to alter body temperature during the inflammatory response. This review summarizes the research leading to a model representing our current understanding of the neural pathways through which cutaneous thermal receptors alter thermoregulatory effectors: the cutaneous circulation for control of heat loss, and brown adipose tissue, skeletal muscle, and the heart for thermogenesis. The activation of these effectors is regulated by parallel but distinct, effector-specific core efferent pathways within the central nervous system (CNS) that share a common peripheral thermal sensory input. The thermal afferent circuit from cutaneous thermal receptors includes neurons in the spinal dorsal horn projecting to lateral parabrachial nucleus neurons that project to the medial aspect of the preoptic area. Within the preoptic area, warm-sensitive, inhibitory output neurons control heat production by reducing the discharge of thermogenesis-promoting neurons in the dorsomedial hypothalamus. The rostral ventromedial medulla, including the raphe pallidus, receives projections form the dorsomedial hypothalamus and contains spinally projecting premotor neurons that provide the excitatory drive to spinal circuits controlling the activity of thermogenic effectors. A distinct population of warm-sensitive preoptic neurons controls heat loss through an inhibitory input to raphe pallidus sympathetic premotor neurons controlling cutaneous vasoconstriction. The model proposed for central thermoregulatory control provides a platform for further understanding of the functional organization of central thermoregulation. PMID- 21270353 TI - Non-hardware posterior cruciate ligament reconstruction using knot/press-fit technique with periosteum-enveloped hamstrings tendon autograft. AB - BACKGROUND: Several posterior cruciate ligament reconstruction procedures have been proposed to manage ruptures. PURPOSE: This study was intended to present the clinical results of non-hardware reconstruction of posterior cruciate ligament using a knot/press-fit technique with periosteum-enveloped autogenous hamstring tendons. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: This arthroscopically assisted technique was used in 33 patients with posterior cruciate ligament ruptures. In this non-hardware technique, semitendinosus and gracilis tendons were prepared as 2 loops with knots. Each loop was enveloped in periosteum. After passing a bottleneck femoral tunnel, the grafts were fixed with a press-fit method (knotted grafts lodging in the bottleneck of the femoral tunnel). Simultaneously, the intra-articular opening of the tibial tunnel was filled with the periosteum-enveloped portion of the graft. A tie with Mersilene tape over a bone bridge for each tendon loop was used for tibial fixation. RESULTS: The average follow-up was 35 months (range, 24-60 months). Clinical assessments included Tegner score, Lysholm knee score, International Knee Documentation Committee scores, thigh muscle assessment, and radiographic evaluation. The stress radiography results for posterior displacement changed from 13.7 +/- 2.1 mm preoperatively to 4.8 +/- 1.1 mm postoperatively. Average preinjury Tegner score was 5.9 (range, 3-9), decreasing to 2.9 (range, 2-5) preoperatively and increasing to 5.2 (range, 2-9) postoperatively. The Lysholm score increased from 58.5 +/- 5.2 to 94.2 +/- 4.1 (P < .01). Finally, 26 patients (89.7%) were assessed as nearly normal by International Knee Documentation Committee guidelines. CONCLUSION: The study revealed satisfactory clinical subjective and objective results at a minimum of 2 years' follow-up. Without using hardware, this alternative technique has the advantage of no need for removal of hardware and potentially easier magnetic resonance imaging interpretation and revision surgery. PMID- 21270354 TI - Responsive feeding and child undernutrition in low- and middle-income countries. AB - Growth faltering and nutritional deficiencies continue to be highly prevalent in infants and young children (IYC) living in low- and middle-income (LAMI) countries. There is increasing recognition that feeding behaviors and styles, particularly responsive feeding (RF), could influence acceptance of food and dietary intake and thus the growth of IYC. This paper presents the evolution of RF research and the strength of the evidence for RF on child undernutrition in LAMI countries. Multiple approaches were used to identify studies, including keyword searches in many databases, hand searches of retrieved articles, and consultation with experts in the field. Articles were included if they contained a RF exposure and child undernutrition outcome. In total, we identified 21 studies: 15 on child growth, 4 on dietary intake, 3 on disease, and 8 on eating behaviors. Most studies were conducted among children <36 mo of age and were published in the last 10 y. Cross-study comparisons were difficult due to multiple definitions of RF. One-half of the studies were observational with cross sectional designs and few interventions were designed to isolate the effect of RF on child undernutrition. Overall, few studies have demonstrated a positive association between RF and child undernutrition, although there is promising evidence that positive caregiver verbalizations during feeding increase child acceptance of food. Recommendations for future research include consensus on the definition and measurement of RF, longitudinal studies that begin early in infancy, and randomized controlled trials that isolate the effect of RF on child undernutrition. PMID- 21270355 TI - Maternal DHA equilibrium during pregnancy and lactation is reached at an erythrocyte DHA content of 8 g/100 g fatty acids. AB - Low long-chain PUFA (LC-PUFA, or LCP) consumption relates to suboptimal neurodevelopment, coronary artery disease, and [postpartum (PP)] depression. Maternal-to-infant LCP transport during pregnancy and lactation is at the expense of maternal status, a process known as biomagnification. Despite biomagnification, maternal and infant LCP status generally declines during lactation. To assess the 1) turning point of biomagnification [level from which maternal (m)LCP status exceeds infant (i)LCP status]; 2) LCP equilibrium (steady state-level from which mRBC-LCP stop declining during lactation); 3) corresponding iLCP-status; and 4) the relationship between RBC-DHA and RBC arachidonic acid (AA), we measured RBC-fatty acids in 193 Tanzanian mother-infant pairs with no, intermediate (2-3 times/wk), and high (4-5 times/wk) freshwater fish consumption at delivery and after 3 mo of exclusive breast-feeding. At 3 mo, mRBC-DHA was lower than the corresponding iRBC-DHA up to a mRBC-DHA of 7.9 g%. mRBC-DHA equilibrium, with equivalent mRBC-DHA at both delivery and at 3 mo PP, occurred at 8.1 g%. This mRBC-DHA equilibrium of 8.1 g% corresponded with an iRBC DHA of 7.1-7.2 g% at delivery that increased to 8.0 g% at 3 mo. We found between group differences in mRBC-AA; however, no differences in iRBC-AA were observed at delivery or 3 mo. Relations between RBC-DHA and RBC-AA were bell-shaped. We conclude that, at steady-state LCP intakes during lactation: 1) biomagnification occurs up to 8 g% mRBC-DHA; 2) mRBC-DHA equilibrium is reached at 8 g%; 3) mRBC DHA equilibrium corresponds with an iRBC-DHA of 7 g% at delivery and 8 g% after 3 mo; 4) unlike RBC-DHA, mRBC-AA and iRBC-AA are independently regulated in these populations; and 5) bell-shaped RBC-DHA vs. RBC-AA-relations might support uniform iRBC-AA. A (maternal) RBC-DHA of 8 g% might be optimal for infant neurodevelopment and adult cardiovascular disease incidence. PMID- 21270356 TI - Diet quality is independently associated with weight status in children aged 9-10 years. AB - Although energy imbalance is key to the development of childhood obesity, the association between different dietary components, reflected in diet quality scores, and children's weight status has not been extensively studied. The current study determined if diet quality, characterized according to 3 predefined scores, was associated with weight status in a population-based sample of 9- to 10-y-old British children, independently of factors previously associated with weight status. In a cross-sectional study of 1700 children (56% girls), data from 4-d food diaries were used to calculate 3 diet quality scores modified to be reflective of children's diets: the Diet Quality Index (DQI), Healthy Diet Indicator (HDI), and Mediterranean Diet Score (MDS). Physical activity was measured with 7-d accelerometery, and height, weight, waist, and bio-impedance were objectively measured and used to calculate weight status variables. After multiple adjustments, including physical activity and overall energy density, higher DQI and HDI scores were significantly associated with improved weight status. Comparing extreme quintiles of the scores revealed the DQI and HDI were associated with lower waist circumference (-3.0%, P = 0.005 and -2.5%, P = 0.033, respectively), and lower body fat (-5.1%, P = 0.023 and -4.9%, P = 0.026, respectively). The DQI was also associated with lower weight (-5.9%; P = 0.002) and BMI (-4.2%; P = 0.004). No significant associations were observed with the MDS. These findings suggest that diet quality is independently associated with children's weight status. Future work should consider if diet quality scores could be key components of interventions designed to reduce obesity in children. PMID- 21270357 TI - Current understanding of the genetic basis for physical activity. AB - Although it is well known that physical activity prevents and ameliorates a large number of conditions and chronic diseases, it is also incontrovertible that physical inactivity is becoming more prevalent. This paradox has led some to suggest that genetic/biological factors influence activity levels as opposed to the classical notion that voluntary activity is solely regulated by environmental factors. There is a plethora of recent data showing that there is considerable genetic influence on activity levels in both humans and animals and emerging evidence suggesting potential genomic locations for those genetic factors. Several independent lines of evidence suggest that dopamine receptor 1 (Drd1) and nescient helix loop helix (Nhlh2) are excellent candidate genes for the regulation of physical activity, with several other potential candidate genes only partially supported. This foundation provides the basis for continuing work to identify additional candidate genes, to identify other genetic factors that are involved in the regulation of physical activity, and to investigate the mechanisms by which these genes and genetic factors regulate activity. PMID- 21270358 TI - Introduction to a supplement on responsive feeding: promoting healthy growth and development for infants and toddlers. PMID- 21270359 TI - Maintenance of wintertime vitamin D status with cholecalciferol supplementation is not associated with alterations in serum cytokine concentrations among apparently healthy younger or older adults. AB - Epidemiological studies have shown that low vitamin D status results in impaired immune function and is associated with the prevalence of autoimmune and inflammatory conditions. Vitamin D supplementation has been shown to reduce circulating concentrations of inflammatory markers in such conditions. However, the possible beneficial effect of vitamin D supplementation in the general population, particularly for those individuals living at high latitudes where hypovitaminosis D is common during wintertime, remains unclear. The aim of this study was to assess the effect of vitamin D supplementation using doses of 5, 10, and 15 MUg/d cholecalciferol (D3) compared with placebo on cytokine concentrations throughout winter in apparently healthy younger (aged 20-40 y) and older (aged >=64 y) adults. A total of 211 younger and 202 older adults completed the 22-wk intervention (from October to March) with >85% compliance. Serum concentrations of 25-hydroxycholecalciferol [25(OH)D3], high sensitivity C reactive protein, IL-6, IL-10, soluble CD40 ligand, TGFbeta, TNFalpha, and fibrinogen were measured using ELISA. 25(OH)D3 concentrations significantly decreased in the placebo and 5 and 10/d MUg D3 groups in the younger cohort and in the placebo group in the older cohort. Whereas 15 MUg/d D3 supplementation maintained 25(OH)D3 concentrations in the younger cohort (baseline, 75.9 nmol/L; postintervention, 69.0 nmol/L) and significantly increased concentrations in the older cohort (baseline, 55.1 nmol/L; postintervention, 73.9 nmol/L), it had no significant effect on cytokine concentrations (ANCOVA, P > 0.05). The long-term effects of low vitamin D status remain to be elucidated and optimization of vitamin D status in otherwise healthy individuals may potentially have lasting beneficial effects on the immune system. PMID- 21270360 TI - A systematic review of responsive feeding and child obesity in high-income countries. AB - Child overweight/obesity continues to be a serious public health problem in high income countries. The current review had 3 goals: 1) to summarize the associations between responsive feeding and child weight status in high-income countries; 2) to describe existing responsive feeding measures; and 3) to generate suggestions for future research. Articles were obtained from PubMed and PsycInfo using specified search criteria. The majority (24/31) of articles reported significant associations between nonresponsive feeding and child weight for-height Z-score, BMI Z-score, overweight/obesity, or adiposity. Most studies identified were conducted exclusively in the United States (n = 22), were cross sectional (n = 25), and used self-report feeding questionnaires (n = 28). A recent trend exists toward conducting research among younger children (i.e. infants and toddlers) and low-income and/or minority populations. Although current evidence suggests that nonresponsive feeding is associated with child BMI or overweight/obesity, more research is needed to understand causality, the reliability and validity between and within existing feeding measures, and to test the efficacy of responsive feeding interventions in the prevention and treatment of child overweight/obesity in high-income countries. PMID- 21270361 TI - Responsive feeding: implications for policy and program implementation. AB - In this article, we examine responsive feeding as a nutrition intervention, with an emphasis on the development and incorporation of responsive feeding into policies and programs over the last 2 decades and recommendations for increasing the effectiveness of responsive feeding interventions. A review of policy documents from international agencies and high-income countries reveals that responsive feeding has been incorporated into nutrition policies. Official guidelines from international agencies, nongovernmental organizations, and professional organizations often include best practice recommendations for responsive feeding. Four potential explanations are offered for the rapid development of policies related to responsive feeding that have occurred despite the relatively recent recognition that responsive feeding plays a critical role in child nutrition and growth and the paucity of effectiveness trials to determine strategies to promote responsive feeding. Looking to the future, 3 issues related to program implementation are highlighted: 1) improving intervention specificity relative to responsive feeding; 2) developing protocols that facilitate efficient adaptation of generic guidelines to national contexts and local conditions; and 3) development of program support materials, including training, monitoring, and operational evaluation. PMID- 21270362 TI - Systems genetics: a powerful approach for gene-environment interactions. AB - Genetic variation in a population creates an impressive spectrum of phenotypic diversity, particularly when changes in diet or the environment are imposed on the population. Genome-wide association studies have become a powerful tool for linking sequence variants with overlying systems level phenotypes, but they do not provide insight into the mechanisms through which genetic variation drives phenotypic variation. Systems genetics is an emerging discipline that provides a means to fill this knowledge gap by assembling the hierarchy of interactions among genes, proteins, and other intermediate phenotypes that manifest as phenotypic variation. When applied to nutrition, systems genetics enables the identification of pathways through which nutrients influence health and the determination of the mechanisms that cause individuals to differ in their response to diet. PMID- 21270363 TI - Nutritional genomics: defining the dietary requirement and effects of choline. AB - As it becomes evident that single nucleotide polymorphisms (SNPs) in humans can create metabolic inefficiencies, it is reasonable to ask if such SNPs influence dietary requirements. Epidemiologic studies that examine SNPs relative to risks for diseases are common, but there are few examples of clinically sized nutrition studies that examine how SNPs influence metabolism. Studies on how SNPs influence the dietary requirement for choline provide a model for how we might begin examining the effects of SNPs on nutritional phenotypes using clinically sized studies (clinical nutrigenomics). Most men and postmenopausal women develop liver or muscle dysfunction when deprived of dietary choline. More than one-half of premenopausal women may be resistant to choline deficiency-induced organ dysfunction, because estrogen induces the gene [phosphatidylethanolamine-N methyltransferase (PEMT)] that catalyzes endogenous synthesis of phosphatidylcholine, which can subsequently yield choline. Those premenopausal women that do require a dietary source of choline have a SNP in PEMT, making them unresponsive to estrogen induction of PEMT. It is important to recognize differences in dietary requirements for choline in women, because during pregnancy, maternal dietary choline modulates fetal brain development in rodent models. Because choline metabolism and folate metabolism intersect at the methylation of homocysteine, manipulations that limit folate availability also increase the use of choline as a methyl donor. People with a SNPs in MTHFD1 (a gene of folate metabolism that controls the use of folate as a methyl donor) are more likely to develop organ dysfunction when deprived of choline; their dietary requirement is increased because of increased need for choline as a methyl donor. PMID- 21270364 TI - Methylenetetrahydrofolate reductase variants associated with hypertension and cardiovascular disease interact with dietary polyunsaturated fatty acids to modulate plasma homocysteine in puerto rican adults. AB - Although methylenetetrahydrofolate reductase (MTHFR) genetic variants are associated with plasma homocysteine (Hcy) and cardiovascular disease (CVD), little is known whether dietary fatty acid intake modulates these associations. The goal was to examine the interaction of MTHFR variants with dietary fatty acids influencing plasma Hcy in 995 Boston Puerto Rican adults. We found that plasma Hcy concentration was negatively correlated with (n-3) PUFA intake (r = 0.117; P = 0.022), and the ratio of (n-3):(n-6) PUFA in the diet (r = -0.122; P = 0.009). Further, 2 functional MTHFR variants, 1298A>C and 677C>T, which are not in linkage disequilibrium in this population, were significantly associated with hypertension (OR = 1.72, P = 0.024, and OR = 1.60, P = 0.002, respectively). In addition, the 1298A>C variant was significantly associated with CVD (OR = 3.32; P = 0.030). Importantly, this variant exhibited significant interactions with intakes of total and (n-6) PUFA and the (n-3):(n-6) PUFA ratio of the diet. The plasma Hcy concentration of carriers of risk allele 1298C was greater than that of noncarriers only when participants had consumed a high-PUFA diet (>7.8% energy) but was not greater when they had low intake of PUFA (<=7.8% energy). In addition, participants with combined genotypes of both SNP (677 TT with 1298 AC or CC) who consumed high levels of (n-3) PUFA (>0.66% energy) had lower plasma Hcy compared with those who had the same genotype and consumed low levels of (n 3) PUFA (<=0.66% energy). Our study suggests that dietary PUFA intake modulates the effect of 2 MTHFR variants on plasma Hcy in Boston Puerto Rican adults. PMID- 21270365 TI - Overview of symposium "Systems Genetics in Nutrition and Obesity Research". AB - Systems genetics is a novel approach for identifying the complex genetic architecture of quantitative traits and gene-environment interactions via detection of connections from genetic variation through intermediate phenotypes to overlying systems level phenotypes. This symposium, conducted at the Experimental Biology 2010 conference, aimed at educating nutrition researchers about the use of systems genetics as a tool for linking genetic variation to nutrient metabolism and energy balance and their overlying effects on health and disease. Basic concepts of systems genetics and the analytical framework used in these studies were presented. Further, the utility of genetic reference populations for gene-environment interaction studies along with specific studies addressing genetic variation in responsiveness to nutrients were discussed. PMID- 21270366 TI - Responsive feeding is embedded in a theoretical framework of responsive parenting. AB - Children throughout the world are confronted with growth problems ranging from underweight and stunting to overweight and obesity. The development of healthy eating behaviors depends on both healthy food and responsive parenting behaviors. With origins from anthropology, psychology, and nutrition, responsive parenting reflects reciprocity between child and caregiver, conceptualized as a 4-step mutually responsive process: 1) the caregiver creates a routine, structure, expectations, and emotional context that promote interaction; 2) the child responds and signals to the caregiver; 3) the caregiver responds promptly in a manner that is emotionally supportive, contingent, and developmentally appropriate; and 4) the child experiences predictable responses. This paper examines evidence for the practice and developmental benefits of responsive parenting with a view to providing a theoretical basis for responsive feeding. Recommendations are made that future efforts to promote healthy growth and to prevent underweight and overweight among young children incorporate and evaluate responsive feeding. PMID- 21270367 TI - Estimation of daily proanthocyanidin intake and major food sources in the U.S. diet. AB - Proanthocyanidins (PA), the polymers of flavan-3-ols, have cardioprotective and cancer preventive properties as shown in clinical studies. The PA intake in a free-living population has not yet been reported, however. We aimed to estimate the dietary intake of PA and identify its major sources by combining the recently released and expanded USDA PA database with food consumption data of 8809 U.S. adults in the NHANES 1999-2002. U.S. adults over 19 y had a total PA intake of 95 mg/d, in the order of polymers (30%), monomers (22%), dimers (16%), 4-6 mers (15%), 7-10 mers (11%), and trimers (5%). When adjusted for energy intake, the total PA intake increased with age (P < 0.001), was higher in women than men (P < 0.01) and in alcohol consumers compared with nonconsumers (P < 0.05), and was lower in non-Hispanic blacks compared with other ethnicities (P < 0.001). Three major food sources, tea, legumes, and wines, contributed 45 mg (48%) of daily PA intake. The marked differences in PA intake among various sociodemographic subgroups need further investigation in relation to health disparities and chronic disease prevalence in the US. PMID- 21270368 TI - Dietary oligosaccharides increase colonic weight and the amount but not concentration of bacterially synthesized folate in the colon of piglets. AB - Recently, we demonstrated that the large pool of folate present in the colon of humans can be absorbed. Here, we investigated whether the net amount of folate synthesized by bacteria in the colon of piglets can be modified by feeding prebiotics to alter their microbial milieu. Male piglets (age 5 d, n = 12) were randomized to a milk-based formula containing either 5 g/L inulin + 5 g/L galactooligosaccharides (IN-GOS) or 5 g/L maltodextrin (control). Body weight did not differ between groups during the 28-d feeding intervention. However, the mean weight of colonic tissue (38%) and their contents (238%) was higher in the IN-GOS than in the control group (P = 0.004, P = 0.0001, respectively). Total bacterial load in the colon of piglets fed IN-GOS was 531% greater and the total amount of folate found in the colon contents was 53% greater than that of controls (P = 0.002, P = 0.02, respectively). Indices of blood folate status (plasma and RBC folate and plasma homocysteine) and folate concentrations in liver and kidneys were unaffected. Both groups exhibited low RBC folate (56 +/- 23 nmol/L) and elevated homocysteine (24 +/- 7 MUmol/L) concentrations, evidence of deficiency if present in humans. In conclusion, dietary supplementation with 5 g of inulin + 5 g of galactooligosaccharides increased the weight, bacterial load, and total folate content in the piglet colon; however, these changes were insufficient to modify indices of whole body folate status. Future studies investigating the impact of feeding prebiotics on localized folate status at the level of the colonocyte are warranted. PMID- 21270369 TI - Adherence index based on the AHA 2006 diet and lifestyle recommendations is associated with select cardiovascular disease risk factors in older Puerto Ricans. AB - In 2006, the AHA released diet and lifestyle recommendations (AHA-DLR) for cardiovascular disease (CVD) risk reduction. The effect of adherence to these recommendations on CVD risk is unknown. Our objective was to develop a unique diet and lifestyle score based on the AHA-DLR and to evaluate this score in relation to available CVD risk factors. In a cross-sectional study of Puerto Rican adults aged 45-75 y living in the greater Boston area, information was available for the following variables: diet (semiquantitative FFQ), blood pressure, waist circumference (WC), 10-y risk of coronary heart disease (CHD) (Framingham risk score), and fasting plasma lipids, serum glucose, insulin, and C reactive protein (CRP) concentrations. We developed a diet and lifestyle score (AHA-DLS) based on the AHA-DLR. The AHA-DLS had both internal consistency and content validity. It was associated with plasma HDL cholesterol (P = 0.001), serum insulin (P = 0.0003), and CRP concentrations (P = 0.02), WC (P < 0.0001), and 10-y risk of CHD score (P = 0.01 in women). The AHA-DLS was inversely associated with serum glucose among those with a BMI < 25 (P = 0.01). Women and men in the highest quartile of the AHA-DLS had lower serum insulin (P-trend = 0.0003) and CRP concentrations (P-trend = 0.002), WC (P-trend = 0.0003), and higher HDL cholesterol (P-trend = 0.008). The AHA-DLS is a useful tool to measure adherence to the AHA-DLR and may be used to examine associations between diet and lifestyle behaviors and CVD risk. PMID- 21270370 TI - Staggered meal consumption facilitates appetite control without affecting postprandial energy intake. AB - Meal pattern may influence hormone and appetite dynamics and food intake. The objective of the study was to determine the effects of staggered compared with nonstaggered meal consumption on hormone and appetite dynamics, food reward (i.e. "liking," "wanting"), and subsequent energy intake. The study was conducted in a randomized cross-over design. Participants (n = 38, age = 24 +/- 6 y, BMI = 25.0 +/- 3.1 kg/m(2)) came to the university twice for consumption of a 4-course lunch (40% of the daily energy requirements) in 0.5 h (nonstaggered) or in 2 h with 3 within-meal pauses (staggered) followed by ad libitum food intake. Throughout the test sessions, glucagon-like peptide (GLP)-1, peptide tyrosine-tyrosine (PYY(3 36)), ghrelin, appetite, and food reward were measured. In the staggered compared with nonstaggered meal condition, peak values of GLP-1, PYY(3-36), and satiety were lower and time to peak values were higher (P < 0.02); the nadir value of hunger was higher, and time to nadir values of ghrelin and hunger were higher (P < 0.0001). Prior to ad libitum food intake, GLP-1 concentrations and satiety ratings were greater, ghrelin concentrations and hunger ratings were smaller, and food "wanting" was less in the staggered compared with nonstaggered meal condition (P < 0.05). However, this did not affect ad libitum energy intake (1.7 +/- 0.3 vs. 1.9 +/- 0.2 MJ). In conclusion, staggered compared with nonstaggered meal consumption induces less pronounced hormone and appetite dynamics. Moreover, it results in higher final GLP-1 concentrations and satiety ratings, lower ghrelin concentrations and hunger ratings, and lower food "wanting" prior to ad libitum food intake. However, this was not translated into lower energy intake. PMID- 21270371 TI - Systems genetics of mineral metabolism. AB - Minerals are essential and toxic elements that have an impact on human health. Although we have learned a tremendous amount about the metabolism, biological roles, and health effects of minerals with the tools of biochemistry, cell biology, and molecular genetics, there are gaps in our knowledge of mineral biology that will benefit from new approaches. Forward genetics, whereby variations in phenotypes are mapped to natural genetic variation in the genome, has been successfully used to increase our understanding of many biologically important traits but has not yet been used extensively for mineral metabolism. In addition, the well-appreciated existence of interactions between minerals justifies a broader, systems approach to the study of mineral metabolism, i.e., ionomics. This short review will explain the value of forward genetics and ionomics as tools for exploring mammalian mineral metabolism. PMID- 21270372 TI - Challenges and new opportunities for clinical nutrition interventions in the aged. AB - Nutritional status plays a critical role in the prevention and management of many chronic health conditions that are common in the elderly and are likely to become more prevalent as the population ages. This paper highlights several aspects of nutrition that require additional basic science and clinical application research to improve the health and well-being of older adults. Topics addressed are selected demographic and health indices, the uncertain benefits of energy restriction in aged humans compared with other species, the impact of food insecurity on health, the relationship between dietary protein and sarcopenia, the prevention and management of obesity while maintaining muscle mass and functional status, and controversy regarding high intakes of folic acid. Research needs regarding the safety, efficacy, and application of clinical interventions related to these topics also are discussed. PMID- 21270373 TI - Is dietary fat important? PMID- 21270374 TI - Folate intake and risk of colorectal cancer and adenoma: modification by time. AB - BACKGROUND: Experimental and observational studies have suggested that folate may play dual roles in colorectal cancer risk depending on the timing and dose. OBJECTIVE: We examined the latency between folate intake and the incidence of colorectal cancer. DESIGN: We prospectively examined associations between folate intake assessed every 2 to 4 y by using validated food-frequency questionnaires and risk of colorectal cancer and adenoma in the Nurses' Health Study and Health Professionals Follow-Up Study, which included 2299 incident colorectal cancers and 5655 colorectal adenomas from 1980 to 2004. RESULTS: There was an association between total folate intake 12-16 y before diagnosis and lower risk of colorectal cancer (relative risk: 0.69; 95% CI: 0.51, 0.94; >=800 compared with <250 MUg folate/d), but there was no association between intake in the recent past and colorectal cancer risk. Long- and short-term intakes of total folate were associated with a lower risk of colorectal adenoma, with a strong association with intake 4-8 y before diagnosis (odds ratio: 0.68; 95% CI: 0.60, 0.78; >=800 compared with <250 MUg folate/d). The current use of multivitamins for >15 y, but not a shorter duration of use, was associated with lower risk of colorectal cancer; and a shorter duration of use was related to lower risk of adenoma. We did not observe an adverse effect of total folate or synthetic folic acid on risk of colorectal cancer or adenoma even during the folic acid fortification era. CONCLUSION: Folate intake is inversely associated with risk of colorectal cancer only during early preadenoma stages. PMID- 21270375 TI - Energy-adjusted food costs make little economic sense. PMID- 21270376 TI - Exploring how calorie information and taxes on high-calorie foods influence lunch decisions. AB - BACKGROUND: The potential combined effects of public policy tools-such as calorie information and taxes on highly caloric foods-on purchasing behavior are rarely studied. Furthermore, these tools are rarely studied in the context of individual differences (eg, dietary restraint), which may play a key role in their effectiveness. OBJECTIVE: The current study tests the combined effects of providing calorie information and increased taxes on the total number of calories purchased for lunch. Furthermore, these public policy tools were investigated in the context of high- and low-restrained eaters. DESIGN: University students (n = 178) had to choose lunch from a menu 3 different times. The prices for the high calorie foods on the menu increased each time (125% and 150% of base price). In addition, there were 3 between-subject factors: budget (high compared with low), calorie-information (calorie information compared with no calorie information), and dietary restraint. RESULTS: Elasticity analyses show a tax * calorie information interaction. A price increase for the high-calorie foods reduced the percentage of calories chosen for lunch but only in the absence of calorie information. CONCLUSIONS: A tax of >=25% on high-calorie foods may decrease the demand for calories and could be a good policy measure to decrease the prevalence of obesity. However, calorie information seems to interfere with the effect of a tax on high-calorie foods. PMID- 21270377 TI - Dairy consumption and 10-y total and cardiovascular mortality: a prospective cohort study in the Netherlands. AB - BACKGROUND: The consumption of dairy products (milk, cheese, and butter) has been positively associated with the risk of ischemic heart disease (IHD), stroke, and total mortality because of the saturated fat content of these products; and protective effects against these outcomes have been attributed to the calcium content and low-fat choices of dairy products. However, robust evidence on the net effect of dairy product consumption on mortality is limited. OBJECTIVE: The objective was to investigate the association between dairy product consumption and the risk of death (from all causes, IHD, and stroke) in the Netherlands Cohort Study (NLCS). DESIGN: The NLCS was initiated in 120,852 men and women aged 55-69 y at baseline in 1986. After 10 y of follow-up, 16,136 subjects with complete dietary information had died. Twenty-nine percent (men) and 22% (women) of these deaths were due to IHD or stroke. The validated 150-item food-frequency questionnaire provided detailed information on dairy products. RESULTS: Multivariate survival analyses following a case-cohort approach showed only a few statistically significant, but mostly weak, associations. A slightly increased risk of all-cause and IHD mortality was found for both butter and dairy fat intake (per 10 g/d; rate ratio(mortality): 1.04; 95% CI: 1.01, 1.06) only in women. Fermented full-fat milk was inversely associated with all-cause and nonsignificantly with stroke mortality in both sexes. CONCLUSIONS: The role of dairy product consumption in mortality generally appeared to be neutral in men. In women, dairy fat intake was associated with slightly increased all-cause and IHD mortality. More research is warranted on a possible protective effect of fermented milk on stroke mortality. PMID- 21270378 TI - Folate and cobalamin status in relation to diet in healthy 2-y-old children. AB - BACKGROUND: Limited data exist on sources of folate and cobalamin in the toddler diet. OBJECTIVE: We examined the influence of diet on folate and cobalamin status in healthy toddlers in an unfortified population. DESIGN: Dietary intake was assessed in 178 children, aged 24 mo, by using 7-d food records and related to serum folate and cobalamin status in 155 children. RESULTS: Median (25th-75th percentile) daily intakes of folate and cobalamin were 87 MUg (74-104 MUg) and 3.1 MUg (2.4-3.8 MUg), respectively. Thirty-five percent of subjects had a folate intake below the Norwegian recommendations (80 MUg folate/d), but only 5.8% of subjects had low serum folate concentrations (<10 nmol/L). All children reached the recommended cobalamin intake (0.8 MUg cobalamin/d). Median (25th-75th percentile) serum concentrations were as follows: folate, 19 nmol/L (14-24 nmol/L); cobalamin, 410 pmol/L (334-521 pmol/L); holotranscobalamin, 94 pmol/L (67-121 pmol/L); holohaptocorrin, 315 pmol/L (241-409 pmol/L); methylmalonic acid, 0.16 MUmol/L (0.13-0.20 MUmol/L); and total homocysteine, 5.0 MUmol/L (4.2 5.7 MUmol/L). Folate intake correlated with serum folate concentrations (rho = 0.25, P < 0.01), and cobalamin intake correlated with serum holotranscobalamin concentrations (rho = 0.21, P < 0.05). In multivariate models, serum folate concentrations were significantly positively associated with the consumption of fruit and berries and grain products; however, this was not the case with dairy products, which was the food group that contributed most to folate intake. Cobalamin status was associated with dairy products (cobalamin and holotranscobalamin), cobalamin supplements (cobalamin and holohaptocorrin), and liver pate (holotranscobalamin). CONCLUSIONS: In this unfortified toddler population, folate status was associated with intakes of fruit and berries and grain products. Cobalamin status was associated with intakes of dairy, liver pate, and supplements. In the assessment of vitamin sources, vitamin availability must be considered. PMID- 21270379 TI - The role of reducing intakes of saturated fat in the prevention of cardiovascular disease: where does the evidence stand in 2010? AB - Current dietary recommendations advise reducing the intake of saturated fatty acids (SFAs) to reduce coronary heart disease (CHD) risk, but recent findings question the role of SFAs. This expert panel reviewed the evidence and reached the following conclusions: the evidence from epidemiologic, clinical, and mechanistic studies is consistent in finding that the risk of CHD is reduced when SFAs are replaced with polyunsaturated fatty acids (PUFAs). In populations who consume a Western diet, the replacement of 1% of energy from SFAs with PUFAs lowers LDL cholesterol and is likely to produce a reduction in CHD incidence of >=2-3%. No clear benefit of substituting carbohydrates for SFAs has been shown, although there might be a benefit if the carbohydrate is unrefined and has a low glycemic index. Insufficient evidence exists to judge the effect on CHD risk of replacing SFAs with MUFAs. No clear association between SFA intake relative to refined carbohydrates and the risk of insulin resistance and diabetes has been shown. The effect of diet on a single biomarker is insufficient evidence to assess CHD risk. The combination of multiple biomarkers and the use of clinical endpoints could help substantiate the effects on CHD. Furthermore, the effect of particular foods on CHD cannot be predicted solely by their content of total SFAs because individual SFAs may have different cardiovascular effects and major SFA food sources contain other constituents that could influence CHD risk. Research is needed to clarify the role of SFAs compared with specific forms of carbohydrates in CHD risk and to compare specific foods with appropriate alternatives. PMID- 21270380 TI - Estimation of the dietary requirement for vitamin D in healthy adolescent white girls. AB - BACKGROUND: Knowledge gaps have contributed to considerable variation (between 0 and 15 MUg/d) in international dietary recommendations for vitamin D in adolescents. OBJECTIVE: We aimed to establish the distribution of dietary vitamin D required to maintain serum 25-hydroxyvitamin D [25(OH)D] concentrations above several proposed cutoffs (25, 37.5, 40, and 50 nmol/L) during wintertime in adolescent white girls. DESIGN: Data (baseline and 6 mo) from 2 randomized, placebo-controlled, double-blind, 12-mo intervention studies in Danish (55 degrees N) and Finnish (60 degrees N) girls (n = 144; mean age: 11.3 y; mean vitamin D intake: 3.7 MUg/d) at vitamin D(3) supplementation amounts of 0, 5, and 10 MUg/d were used. Serum 25(OH)D was measured with an HPLC assay in a centralized laboratory. RESULTS: Clear dose-related increments (P < 0.0001) in serum 25(OH)D with increasing supplemental vitamin D(3) were observed. The slope of the relation between vitamin D intake and serum 25(OH)D at the end of winter was 2.43 nmol ? L(-1) ? MUg intake(-1), and no difference in the slopes between Finnish and Danish girls was observed. The vitamin D intakes that maintained serum 25(OH)D concentrations at >25, >37.5, and >50 nmol/L in 97.5% of the sample were 8.3, 13.5, and 18.6 MUg/d, respectively, whereas an intake of 6.3 MUg/d maintained a serum 25(OH)D concentration >40 nmol/L in 50% of the sample. CONCLUSION: The vitamin D intakes required to ensure that adequate vitamin D status [defined variably as serum 25(OH)D >25 and >50 nmol/L] is maintained during winter in the vast majority (>97.5%) of adolescent girls (mean age: 11.3 y) at northern latitudes (>55 degrees N) are 8.3 and 18.6 MUg/d, respectively. This trial was registered at clinicaltrials.gov as NCT00267540. PMID- 21270381 TI - Size matters. PMID- 21270382 TI - Genome-wide association studies identify genetic loci related to alcohol consumption in Korean men. AB - BACKGROUND: Genome-wide association (GWA) studies regarding the quantitative trait of alcohol consumption are limited. OBJECTIVE: The objective of the study was to explore genetic loci associated with the amount of alcohol consumed. DESIGN: We conducted a GWA study with discovery data on single nucleotide polymorphisms (SNPs) for 1721 Korean male drinkers aged 40-69 y who were included in an urban population-based cohort. Another sample that comprised 1113 male drinkers who were from an independent cohort enrolled in a rural area served as a resource for replication. At baseline (18 June 2001 through 29 January 2003), members of both cohorts provided information on average daily alcohol consumptions, and their DNA samples were collected for genotyping. RESULTS: We tested 315,914 SNPs of discovery data by using multivariate linear regression analysis adjusted for age and smoking, and 12 SNPs on chromosome 12q24 had genome wide significant associations with alcohol consumption; adjusted P values by using Bonferroni correction were 1.6 * 10(-5) through 5.8 * 10(-46). We observed most SNPs in intronic regions and showed that the genes that harbor SNPs were C12orf51, CCDC63, MYL2, OAS3, CUX2, and RPH3A. In particular, signals in or near C12orf51, CCDC63, and MYL2 were successfully replicated in the test for 317,951 SNPs; rs2074356 in C12orf51 was in high linkage disequilibrium with SNPs in ALDH2, but other SNPs were not. CONCLUSIONS: In a GWA study, we identified loci and alleles highly associated with alcohol consumption. The findings suggest the need for further investigations on the genetic propensity for drinking excessive amounts of alcohol. PMID- 21270383 TI - Long-term effects of iron and zinc supplementation during infancy on cognitive function at 9 y of age in northeast Thai children: a follow-up study. AB - BACKGROUND: Iron and zinc are important micronutrients for child growth and development. One would expect that iron and zinc supplementation in infancy would affect long-term cognitive development and school achievement, but this has not been evaluated. OBJECTIVE: We investigated the effect of iron or zinc supplementation or both during infancy on cognitive performance 8 y later. DESIGN: A follow-up study was performed in 560 children aged 9 y or 92% of those who had participated in a randomized controlled trial involving 4 groups who received daily iron, zinc, iron plus zinc, or a placebo at 4-6 mo of age for 6 mo. Cognitive performance was assessed by using the Wechsler Intelligence Scale for Children-Third Edition (Thai version), the Raven's Colored Progressive Matrices (CPM), and school performance tests. General linear mixed models were used to assess long-term effects. RESULTS: No significant differences in any of the outcomes at 9 y of age were observed at follow-up between the 4 groups. Mean intelligence quotients ranged across groups from 92.9 to 93.7 for full scale, 93.9-95.4 for verbal, and 93.1-94.0 for performance. The Raven's CPM score ranged from 21.4 to 22.4. CONCLUSION: Supplementation with iron or zinc or both during infancy does not lead to long-term cognitive improvement in 9-y-old children. This trial was registered at clinicaltrials.gov as NCT00824304. PMID- 21270384 TI - Hormonal and metabolic effects of polyunsaturated fatty acids in young women with polycystic ovary syndrome: results from a cross-sectional analysis and a randomized, placebo-controlled, crossover trial. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is characterized by an adverse metabolic profile. Although dietary changes are advocated, optimal nutritional management remains uncertain. Polyunsaturated fatty acids (PUFAs), particularly long-chain (LC) n-3 (omega-3) PUFAs, improve metabolic health, but their therapeutic potential in PCOS is unknown. OBJECTIVES: We aimed to determine the associations between plasma PUFAs and metabolic and hormonal aspects of PCOS to investigate the efficacy of LC n-3 PUFA supplementation and to support the findings with mechanistic cellular studies. DESIGN: We selected a cross-sectional PCOS cohort (n = 104) and conducted a principal component analysis on plasma fatty acid profiles. Effects of LC n-3 PUFA supplementation on fasting and postprandial metabolic and hormonal markers were determined in PCOS subjects (n = 22) by a randomized, crossover, placebo-controlled intervention. Direct effects of n-6 (omega-6) compared with n-3 PUFAs on steroidogenesis were investigated in primary bovine theca cells. RESULTS: Cross-sectional data showed that a greater plasma n-6 PUFA concentration and n-6:n-3 PUFA ratio were associated with higher circulating androgens and that plasma LC n-3 PUFA status was associated with a less atherogenic lipid profile. LC n-3 PUFA supplementation reduced plasma bioavailable testosterone concentrations (P < 0.05), with the greatest reductions in subjects who exhibited greater reductions in plasma n-6:n-3 PUFA ratios. The treatment of bovine theca cells with n-6 rather than with n-3 PUFAs up-regulated androstenedione secretion (P < 0.05). CONCLUSIONS: Cross-sectional data suggest that PUFAs modulated hormonal and lipid profiles and that supplementation with LC n-3 PUFAs improves androgenic profiles in PCOS. In bovine theca cells, arachidonic acid modulated androstenedione secretion, which suggests an indirect effect of n-3 PUFAs through the displacement of or increased competition with n-6 PUFAs. This trial was registered at clinicaltrials.gov as NCT01189669. PMID- 21270385 TI - Permissive underfeeding and intensive insulin therapy in critically ill patients: a randomized controlled trial. AB - BACKGROUND: Nutritional support has been recognized as an essential part of intensive care unit management. However, the appropriate caloric intake for critically ill patients remains ill defined. OBJECTIVE: We examined the effect of permissive underfeeding compared with that of target feeding and of intensive insulin therapy (IIT) compared with that of conventional insulin therapy (CIT) on the outcomes of critically ill patients. DESIGN: This study had a 2 * 2 factorial, randomized, controlled design. Eligible patients were randomly assigned to permissive underfeeding or target feeding groups (caloric goal: 60 70% compared with 90-100% of calculated requirement, respectively) with either IIT or CIT (target blood glucose: 4.4-6.1 compared with 10-11.1 mmol/L, respectively). RESULTS: Twenty-eight-day all-cause mortality was 18.3% in the permissive underfeeding group compared with 23.3% in the target feeding group (relative risk: 0.79; 95% CI: 0.48, 1.29; P = 0.34). Hospital mortality was lower in the permissive underfeeding group than in the target group (30.0% compared with 42.5%; relative risk: 0.71; 95% CI: 0.50, 0.99; P = 0.04). No significant differences in outcomes were observed between the IIT and CIT groups. CONCLUSION: In critically ill patients, permissive underfeeding may be associated with lower mortality rates than target feeding. This trial was registered at controlled trials.com as ISRCTN96294863. PMID- 21270386 TI - A high-fat diet impairs cardiac high-energy phosphate metabolism and cognitive function in healthy human subjects. AB - BACKGROUND: High-fat, low-carbohydrate diets are widely used for weight reduction, but they may also have detrimental effects via increased circulating free fatty acid concentrations. OBJECTIVE: We tested whether raising plasma free fatty acids by using a high-fat, low-carbohydrate diet results in alterations in heart and brain in healthy subjects. DESIGN: Men (n = 16) aged 22 +/- 1 y (mean +/- SE) were randomly assigned to 5 d of a high-fat, low-carbohydrate diet containing 75 +/- 1% of calorie intake through fat consumption or to an isocaloric standard diet providing 23 +/- 1% of calorie intake as fat. In a crossover design, subjects undertook the alternate diet after a 2-wk washout period, with results compared after the diet periods. Cardiac (31)P magnetic resonance (MR) spectroscopy and MR imaging, echocardiography, and computerized cognitive tests were used to assess cardiac phosphocreatine (PCr)/ATP, cardiac function, and cognitive function, respectively. RESULTS: Compared with the standard diet, subjects who consumed the high-fat, low-carbohydrate diet had 44% higher plasma free fatty acids (P < 0.05), 9% lower cardiac PCr/ATP (P < 0.01), and no change in cardiac function. Cognitive tests showed impaired attention (P < 0.01), speed (P < 0.001), and mood (P < 0.01) after the high-fat, low carbohydrate diet. CONCLUSION: Raising plasma free fatty acids decreased myocardial PCr/ATP and reduced cognition, which suggests that a high-fat diet is detrimental to heart and brain in healthy subjects. PMID- 21270387 TI - Vitamin D requirements in adolescents: what is the target? PMID- 21270388 TI - Augmented annotation of the Schizosaccharomyces pombe genome reveals additional genes required for growth and viability. AB - Genome annotation is a synthesis of computational prediction and experimental evidence. Small genes are notoriously difficult to detect because the patterns used to identify them are often indistinguishable from chance occurrences, leading to an arbitrary cutoff threshold for the length of a protein-coding gene identified solely by in silico analysis. We report a systematic reappraisal of the Schizosaccharomyces pombe genome that ignores thresholds. A complete six frame translation was compared to a proteome data set, the Pfam domain database, and the genomes of six other fungi. Thirty-nine novel loci were identified. RT PCR and RNA-Seq confirmed transcription at 38 loci; 33 novel gene structures were delineated by 5' and 3' RACE. Expression levels of 14 transcripts fluctuated during meiosis. Translational evidence for 10 genes, evolutionary conservation data supporting 35 predictions, and distinct phenotypes upon ORF deletion (one essential, four slow-growth, two delayed-division phenotypes) suggest that all 39 predictions encode functional proteins. The popularity of S. pombe as a model organism suggests that this augmented annotation will be of interest in diverse areas of molecular and cellular biology, while the generality of the approach suggests widespread applicability to other genomes. PMID- 21270389 TI - Transcriptional networks for alcohol sensitivity in Drosophila melanogaster. AB - Understanding the genetic architecture of polygenic traits requires investigating how complex networks of interacting molecules mediate the effect of genetic variation on organismal phenotypes. We used a combination of P-element mutagenesis and analysis of natural variation in gene expression to predict transcriptional networks that underlie alcohol sensitivity in Drosophila melanogaster. We identified 139 unique P-element mutations (124 in genes) that affect sensitivity or resistance to alcohol exposure. Further analyses of nine of the lines showed that the P-elements affected expression levels of the tagged genes, and P-element excision resulted in phenotypic reversion. The majority of the mutations were in computationally predicted genes or genes with unexpected effects on alcohol phenotypes. Therefore we sought to understand the biological relationships among 21 of these genes by leveraging genetic correlations among genetically variable transcripts in wild-derived inbred lines to predict coregulated transcriptional networks. A total of 32 "hub" genes were common to two or more networks associated with the focal genes. We used RNAi-mediated inhibition of expression of focal genes and of hub genes connected to them in the network to confirm their effects on alcohol-related phenotypes. We then expanded the computational networks using the hub genes as foci and again validated network predictions. Iteration of this approach allows a stepwise expansion of the network with simultaneous functional validation. Although coregulated transcriptional networks do not provide information about causal relationships among their constituent transcripts, they provide a framework for subsequent functional studies on the genetic basis of alcohol sensitivity. PMID- 21270390 TI - An accurate sequentially Markov conditional sampling distribution for the coalescent with recombination. AB - The sequentially Markov coalescent is a simplified genealogical process that aims to capture the essential features of the full coalescent model with recombination, while being scalable in the number of loci. In this article, the sequentially Markov framework is applied to the conditional sampling distribution (CSD), which is at the core of many statistical tools for population genetic analyses. Briefly, the CSD describes the probability that an additionally sampled DNA sequence is of a certain type, given that a collection of sequences has already been observed. A hidden Markov model (HMM) formulation of the sequentially Markov CSD is developed here, yielding an algorithm with time complexity linear in both the number of loci and the number of haplotypes. This work provides a highly accurate, practical approximation to a recently introduced CSD derived from the diffusion process associated with the coalescent with recombination. It is empirically demonstrated that the improvement in accuracy of the new CSD over previously proposed HMM-based CSDs increases substantially with the number of loci. The framework presented here can be adopted in a wide range of applications in population genetics, including imputing missing sequence data, estimating recombination rates, and inferring human colonization history. PMID- 21270391 TI - Cohesin plays a dual role in gene regulation and sister-chromatid cohesion during meiosis in Saccharomyces cerevisiae. AB - Sister-chromatid cohesion mediated by cohesin ensures proper chromosome segregation during cell division. Cohesin is also required for postreplicative DNA double-strand break repair and gene expression. The molecular mechanisms of these diverse cohesin functions remain to be elucidated. Here we report that the cohesin subunits Scc3 and Smc1 are both required for the production of the meiosis-specific subunit Rec8 in the budding yeast Saccharomyces cerevisiae. Using a genetic approach, we depleted Scc3 and Smc1 independently in cells that were undergoing meiosis. Both Scc3- and Smc1-depleted cells were inducible for meiosis, but the REC8 promoter was only marginally activated, leading to reduced levels of REC8 transcription and protein production. In contrast, the expression of MCD1, the mitotic counterpart of REC8, was not subject to Scc3 regulation in vegetative cells. We provide genetic evidence to show that sister-chromatid cohesion is not necessary for activation of REC8 gene expression. Cohesin appears to positively regulate the expression of a variety of genes during yeast meiosis. Our results suggest that the cohesin complex plays a dual role in gene regulation and sister-chromatid cohesion during meiotic differentiation in yeast. PMID- 21270392 TI - Analysis of stunter1, a maize mutant with reduced gametophyte size and maternal effects on seed development. AB - Many higher eukaryotes have evolved strategies for the maternal control of growth and development of their offspring. In higher plants this is achieved in part by postmeiotic gene activity controlling the development of the haploid female gametophyte. stunter1 (stt1) is a novel, recessive, maternal effect mutant in maize that displays viable, miniature kernels. Maternal inheritance of stt1 results in seeds with reduced but otherwise normal endosperms and embryos. The stt1 mutation displays reduced transmission through the male and female parents and causes significant changes in the sizes of both male and female gametophytes. stt1 pollen grains are smaller than wild type, have reduced germination efficiency, and reduced pollen tube growth. stt1 embryo sacs have smaller central cells and abnormal antipodal cells that are larger, more vacuolated, and fewer in number than wild type. Embryos and endosperms produced by fertilization of stt1 embryo sacs develop and grow more slowly than wild type. The data suggest that the morphology of mutant embryo sacs influences endosperm development, leading to the production of miniature kernels in stt1. Analysis of seeds carrying a mutant maternal allele of stt1 over a deletion of the paternal allele demonstrates that both parental alleles are active after fertilization in both the endosperm and embryo. This analysis also indicates that embryo development until the globular stage in maize can proceed without endosperm development and is likely supported directly by the diploid mother plant. PMID- 21270393 TI - The dual functions of IL-1 receptor-associated kinase 2 in TLR9-mediated IFN and proinflammatory cytokine production. AB - Bone marrow-derived plasmacytoid dendritic cells (pDCs) from IL-1R-associated kinase (IRAK)2-deficient mice produced more IFNs than did wild-type pDCs upon stimulation with the TLR9 ligand CpG. Furthermore, in CpG-stimulated IRAK2 deficient pDCs there was increased nuclear translocation of IFN regulatory factor 7, the key transcription factor for IFN gene transcription in these cells. In IRAK2-deficient macrophages, enhanced NF-kappaB activation and increased expression of CpG-induced genes were detected within 2 h after treatment. However, at later times, NF-kappaB activation was decreased and, in contrast to the results with IFN, there was less secretion of other proinflammatory cytokines (such as TNF-alpha) and chemokines in CpG-stimulated IRAK2-deficient pDCs and macrophages. Therefore, although IRAK2 is a negative regulator of TLR9-mediated IFN production through its modulation of the transcriptional activity of IFN regulatory factor 7, it is also a positive regulator of TLR9-mediated proinflammatory cytokine and chemokine production at some level subsequent to transcription. PMID- 21270394 TI - Deletion of tristetraprolin caused spontaneous reactive granulopoiesis by a non cell-autonomous mechanism without disturbing long-term hematopoietic stem cell quiescence. AB - Tristetraprolin (TTP, Zfp36, Nup475, Tis11) dramatically reduces the stability of target mRNAs by binding to AU-rich elements in their 3' untranslated regions. Through this mechanism, TTP functions as a rheostatic, temporal regulator of gene expression. TTP knockout (KO) mice exhibit completely penetrant granulocytic hyperplasia. We have shown that the hematopoietic stem-progenitor cell compartment in TTP KO mice is also altered. Although no change was detected in long-term hematopoietic stem cell (HSC) frequency or function, as assayed by immunophenotypic markers or limiting dilution transplants, we observed increases in the frequencies and numbers of short-term HSCs, multipotent progenitors, and granulocyte-monocyte progenitors. This pattern is consistent with "reactive granulopoiesis," in which committed myeloid progenitors and more primitive progenitors cycle more actively to increase production of mature granulocytes in response to infection or adjuvant. We created reverse chimeras by transplanting wild-type bone marrow into TTP KO mice and found the "reactive granulopoiesis" phenocopied, indicating a non-hematopoietic stem-progenitor cell-autonomous mechanism. Correspondingly, we found elevated levels of the granulopoietic TTP targets IL-1beta, TNF-alpha, and IL-6 in the plasma of TTP KO mice. Consistent with the non-cell-autonomous nature of the phenotype, we found elevated levels of IL-1beta, TNF-alpha, and IL-6 transcripts in the livers of TTP KO mice and no detectable difference in the bone marrows. These findings demonstrate the importance of TTP in inflammatory homeostasis and highlight the ability of the hematopoietic system to respond to stress without significant numbers of quiescent HSCs entering the cell cycle. PMID- 21270395 TI - 2B4 engagement mediates rapid LFA-1 and actin-dependent NK cell adhesion to tumor cells as measured by single cell force spectroscopy. AB - Adhesion to tumor target cells is essential for initiation and execution of cellular cytotoxicity. In this study, we use single cell force spectroscopy to determine the exact biophysical values of the interaction forces between NK cells and tumor cells. We show that engagement of the activating NK cell receptor 2B4 can rapidly mediate an increase in the force necessary to separate NK cells from tumor cells, starting from 1 nN and increasing to 3 nN after only 120 s tumor cell contact. This early adhesion was mediated by the integrin LFA-1 and dependent on the actin cytoskeleton. The ability of NK cells to rapidly adhere to tumor target cells is consistent with their function in innate immune responses. Our data further suggest that a killing decision is already made within 120- 300 s of tumor cell contact, supporting the essential function of cell adhesion during the early phase of cellular cytotoxicity. PMID- 21270396 TI - Intrinsic requirement for the vitamin D receptor in the development of CD8alphaalpha-expressing T cells. AB - Vitamin D and vitamin D receptor (VDR) deficiency results in severe symptoms of experimental inflammatory bowel disease in several different models. The intraepithelial lymphocytes of the small intestine contain large numbers of CD8alphaalpha(+) T cells that have been shown to suppress the immune response to Ags found there. In this study, we determined the role of the VDR in the development of CD8alphaalpha(+) T cells. There are fewer total numbers of TCRalphabeta(+) T cells in the gut of VDR knockout (KO) mice, and that reduction was largely in the CD8alphaalpha(+) TCRalphabeta(+) cells. Conversely TCRgammadelta(+) T cells were normal in the VDR KO mice. The thymic precursors of CD8alphaalpha(+) TCRalphabeta(+) cells (triple-positive for CD4, CD8alphaalpha, and CD8alphabeta) were reduced and less mature in VDR KO mice. In addition, VDR KO mice had a higher frequency of the CD8alphaalpha(+) TCRalphabeta(+) precursors (double-negative [DN] TCRalphabeta(+) T cells) in the gut. The proliferation rates of the DN TCRalphabeta(+) gut T cells were less in the VDR KO compared with those in wild type. Low proliferation of DN TCRalphabeta(+) T cells was a result of the very low expression of the IL-15R in this population of cells in the absence of the VDR. Bone marrow transplantation showed that the defect in VDR KO CD8alphaalpha(+) TCRalphabeta(+) cells was cell intrinsic. Decreased maturation and proliferation of CD8alphaalpha(+) TCRalphabeta(+) cells in VDR KO mice results in fewer functional CD8alphaalpha(+) TCRalphabeta(+) T cells, which likely explains the increased inflammation in the gastrointestinal tract of VDR KO and vitamin D-deficient mice. PMID- 21270397 TI - Ubiquitylation of an internalized killer cell Ig-like receptor by Triad3A disrupts sustained NF-kappaB signaling. AB - Killer cell Ig-like receptor (KIR) with two Ig-like domains and a long cytoplasmic domain 4 (2DL4; CD158d) is a unique KIR expressed on human NK cells, which stimulates cytokine production, but mechanisms regulating its expression and function are poorly understood. By yeast two-hybrid screening, we identified the E3 ubiquitin ligase, Triad3A, as an interaction partner for the 2DL4 cytoplasmic domain. The protein interaction was confirmed in vivo, and Triad3A expression induced polyubiquitylation and degradation of 2DL4. Overexpression of Triad3A selectively abrogated the cytokine-producing function of 2DL4, whereas Triad3A short hairpin RNA reversed ubiquitylation and restored cytokine production. Expression of Triad3A in an NK cell line did not affect receptor surface expression, internalization, or early signaling, but significantly reduced receptor turnover and suppressed sustained NF-kappaB activation. 2DL4 endocytosis was found to be vital to stimulate cytokine production, and Triad3A expression diminished localization of internalized receptor in early endosomes. Our results reveal a critical role for endocytosed 2DL4 receptor to generate sustained NF-kappaB signaling and drive cytokine production. We conclude that Triad3A is a key negative regulator of sustained 2DL4-mediated NF-kappaB signaling from internalized 2DL4, which functions by promoting ubiquitylation and degradation of endocytosed receptor from early endosomes. PMID- 21270398 TI - beta2 integrin induces TCRzeta-Syk-phospholipase C-gamma phosphorylation and paxillin-dependent granule polarization in human NK cells. AB - Cytotoxic lymphocytes kill target cells through polarized release of the content of lytic granules at the immunological synapse. In human NK cells, signals for granule polarization and for degranulation can be uncoupled: Binding of beta(2) integrin LFA-1 to ICAM is sufficient to induce polarization but not degranulation, whereas CD16 binding to IgG triggers unpolarized degranulation. In this study, we investigated the basis for this difference. IL-2-expanded human NK cells were stimulated by incubation with plate-bound ligands of LFA-1 (ICAM-1) and CD16 (human IgG). Surprisingly, LFA-1 elicited signals similar to those induced by CD16, including tyrosine phosphorylation of the TCR zeta-chain, tyrosine kinase Syk, and phospholipase C-gamma. Whereas CD16 activated Ca(2+) mobilization and LAT phosphorylation, LFA-1 did not, but induced strong Pyk2 and paxillin phosphorylation. LFA-1-dependent granule polarization was blocked by inhibition of Syk, phospholipase C-gamma, and protein kinase C, as well as by paxillin knockdown. Therefore, common signals triggered by CD16 and LFA-1 bifurcate to provide independent control of Ca(2+)-dependent degranulation and paxillin-dependent granule polarization. PMID- 21270399 TI - Nonhematopoietic cells are key players in innate control of bacterial airway infection. AB - Airborne pathogens encounter several hurdles during host invasion, including alveolar macrophages (AMs) and airway epithelial cells (AECs) and their products. Although growing evidence indicates pathogen-sensing capacities of epithelial cells, the relative contribution of hematopoietic versus nonhematopoietic cells in the induction of an inflammatory response and their possible interplay is still poorly defined in vivo in the context of infections with pathogenic microorganisms. In this study, we show that nonhematopoietic cells, including AECs, are critical players in the inflammatory process induced upon airway infection with Legionella pneumophila, and that they are essential for control of bacterial infections. Lung parenchymal cells, including AECs, are not infected themselves by L. pneumophila in vivo but rather act as sensors and amplifiers of inflammatory cues delivered by L. pneumophila-infected AM. We identified AM derived IL-1beta as the critical mediator to induce chemokine production in nonhematopoietic cells in the lung, resulting in swift and robust recruitment of infection-controlling neutrophils into the airways. These data add a new level of complexity to the coordination of the innate immune response to L. pneumophila and illustrate how the cross talk between leukocytes and nonhematopoietic cells contributes to efficient host protection. PMID- 21270400 TI - Mucosal allergic sensitization to cockroach allergens is dependent on proteinase activity and proteinase-activated receptor-2 activation. AB - We have shown that proteinase-activated receptor-2 (PAR(2)) activation in the airways leads to allergic sensitization to concomitantly inhaled Ags, thus implicating PAR(2) in the pathogenesis of asthma. Many aeroallergens with proteinase activity activate PAR(2). To study the role of PAR(2) in allergic sensitization to aeroallergens, we developed a murine model of mucosal sensitization to cockroach proteins. We hypothesized that PAR(2) activation in the airways by natural allergens with serine proteinase activity plays an important role in allergic sensitization. Cockroach extract (CE) was administered to BALB/c mice intranasally on five consecutive days (sensitization phase) and a week later for four more days (challenge phase). Airway hyperresponsiveness (AHR) and allergic airway inflammation were assessed after the last challenge. To study the role of PAR(2), mice were exposed intranasally to a receptor-blocking anti PAR(2) Ab before each administration of CE during the sensitization phase. Mucosal exposure to CE induced eosinophilic airway inflammation, AHR, and cockroach-specific IgG1. Heat-inactivated or soybean trypsin inhibitor-treated CE failed to induce these effects, indicating that proteinase activity plays an important role. The use of an anti-PAR(2) blocking Ab during the sensitization phase completely inhibited airway inflammation and also decreased AHR and the production of cockroach-specific IgG1. PAR(2) activation by CE acts as an adjuvant for allergic sensitization even in the absence of functional TLR4. We conclude that CE induces PAR(2)-dependent allergic airway sensitization in a mouse model of allergic airway inflammation. PAR(2) activation may be a general mechanism used by aeroallergens to induce allergic sensitization. PMID- 21270401 TI - Immune evasion of Moraxella catarrhalis involves ubiquitous surface protein A dependent C3d binding. AB - The complement system plays an important role in eliminating invading pathogens. Activation of complement results in C3b deposition (opsonization), phagocytosis, anaphylatoxin (C3a, C5a) release, and consequently cell lysis. Moraxella catarrhalis is a human respiratory pathogen commonly found in children with otitis media and in adults with chronic obstructive pulmonary disease. The species has evolved multiple complement evasion strategies, which among others involves the ubiquitous surface protein (Usp) family consisting of UspA1, A2, and A2 hybrid. In the present study, we found that the ability of M. catarrhalis to bind C3 correlated with UspA expression and that C3 binding contributed to serum resistance in a large number of clinical isolates. Recombinantly expressed UspA1 and A2 inhibit both the alternative and classical pathways, C3b deposition, and C3a generation when bound to the C3 molecule. We also revealed that the M. catarrhalis UspA-binding domain on C3b was located to C3d and that the major bacterial C3d-binding domains were within UspA1(299-452) and UspA2(165-318). The interaction with C3 was not species specific since UspA-expressing M. catarrhalis also bound mouse C3 that resulted in inhibition of the alternative pathway of mouse complement. Taken together, the binding of C3 to UspAs is an efficient strategy of Moraxella to block the activation of complement and to inhibit C3a mediated inflammation. PMID- 21270402 TI - TANK-binding kinase 1 attenuates PTAP-dependent retroviral budding through targeting endosomal sorting complex required for transport-I. AB - Retroviruses need to bud from producer cells to spread infection. To facilitate its budding, some virus hijacks the multivesicular body (MVB) pathway that is normally used to cargo and degrade ubiquitylated cellular proteins, through interaction between the late domain of Gag polyproteins and the components of MVB machinery. In this study, we demonstrated that TANK-binding kinase 1 (TBK1) directly interacted with VPS37C, a subunit of endosomal sorting complex required for transport-I (ESCRT-I) in the MVB pathway, without affecting the ultrastructure or general function of MVB. Interestingly, overexpression of TBK1 attenuated, whereas short hairpin RNA interference of TBK1 enhanced HIV-1 pseudovirus release from Vero cells in type I IFN (IFN-I)-independent manner. Down-regulation of TBK1 by short hairpin RNA in TZM-bl cells also enhanced live HIV-1 NL4-3 or JR-CSF virus budding without involvement of IFN-I induction. Furthermore, infection of TBK1-deficient mouse embryonic fibroblast cells with a chimeric murine leukemia virus/p6, whose PPPY motif was replaced by PTAP motif of HIV-1, showed that lack of TBK1 significantly enhanced PTAP-dependent, but not PPPY-dependent retrovirus budding. Finally, phosphorylation of VPS37C by TBK1 might regulate the viral budding efficiency, because overexpression of the kinase inactive mutant of TBK1 (TBK1-K38A) in Vero cells accelerated HIV-1 pseudovirus budding. Therefore, through tethering to VPS37C of the ESCRT-I complex, TBK1 controlled the speed of PTAP-dependent retroviral budding through phosphorylation of VPS37C, which would serve as a novel mechanism of host cell defense independent of IFN-I signaling. PMID- 21270403 TI - Septic shock is associated with receptor for advanced glycation end products ligation of LPS. AB - Septic shock is a severe systemic response to bacterial infection. Receptor for advanced glycation end products (RAGE) plays a role in immune reactions to recognize specific molecular patterns as pathogen recognition receptors. However, the interaction between LPS, the bioactive component of bacterial cell walls, and RAGE is unclear. In this study, we found direct LPS binding to RAGE by a surface plasmon resonance assay, a plate competition assay, and flow cytometry. LPS increased TNF-alpha secretion from peritoneal macrophages and an NF-kappaB promoter-driven luciferase activity through RAGE. Blood neutrophils and monocytes expressed RAGE, and TLR2 was counterregulated in RAGE(-/-) mice. After LPS injection, RAGE(+/+) mice showed a higher mortality, higher serum levels of IL-6, TNF-alpha, high mobility group box 1, and endothelin-1, and severe lung and liver pathologies compared with RAGE(-/-) mice without significant differences in plasma LPS level. Administration of soluble RAGE significantly reduced the LPS induced cytokine release and tissue damage and improved the LPS-induced lethality even in RAGE(-/-) as well as RAGE(+/+) mice. The results thus suggest that RAGE can associate with LPS and that RAGE system can regulate inflammatory responses. Soluble RAGE would be a therapeutic tool for LPS-induced septic shock. PMID- 21270404 TI - 5-Lipoxygenase-deficient mice infected with Borrelia burgdorferi develop persistent arthritis. AB - The enzyme 5-lipoxygenase (5-LO) catalyzes the conversion of arachidonic acid into the leukotrienes, which are critical regulators of inflammation and inflammatory diseases, such as asthma and arthritis. Although leukotrienes are present in the synovial fluid of Lyme disease patients, their role in the development of Lyme arthritis has not been determined. In the current study, we used a murine model of Lyme arthritis to investigate the role 5-LO products might have in the development of this inflammatory disease. After infection of Lyme arthritis-susceptible C3H/HeJ mice with Borrelia burgdorferi, mRNA expression of 5-LO and 5-LO-activating protein was induced in the joints, and the 5-LO product leukotriene B(4) was produced. Using C3H 5-LO-deficient mice, we demonstrated that 5-LO activity was not necessary for the induction of Lyme arthritis, but that its deficiency resulted in earlier joint swelling and an inability to resolve arthritis as demonstrated by sustained arthritis pathology through day 60 postinfection. Although production of anti-Borrelia IgG was decreased in 5-LO deficient mice, bacterial clearance from the joints was unaffected. Phagocytosis of B. burgdorferi and efferocytosis of apoptotic neutrophils was defective in macrophages from 5-LO-deficient mice, and uptake of opsonized spirochetes by neutrophils was reduced. These results demonstrate that products of the 5-LO metabolic pathway are not required for the development of disease in all models of arthritis and that caution should be used when targeting 5-LO as therapy for inflammatory diseases. PMID- 21270405 TI - CXCR4 expression on activated B cells is downregulated by CD63 and IL-21. AB - CXCR4 expression is critical for localization of centroblasts in the dark zone of germinal centers (GCs), and centrocytes downregulate CXCR4 and thus leave the dark zone to reside in the light zone. However, mechanisms governing CXCR4 downregulation on centrocytes are not known. In this study, we show that the amount of intracellular CXCR4 in centroblasts was similar to that in centrocytes, suggesting differential control of CXCR4 protein expression in these GC B cells. Restimulation of activated B cells with IL-21, which is a major cytokine produced by T follicular helper cells, accelerated CXCR4 internalization by inducing endocytosis-related GRK6 expression. Although CXCR4 expression was downregulated on GC B cells by IL-21 stimulation, CXCR4(low) centrocytes developed in the spleens of IL-21R-deficient mice, suggesting other mechanisms for downregulation. The level of CD63 (which recruits CXCR4 to late endosome in CD4 T cells) in centrocytes was more than that in centroblasts and was strikingly elevated in activated Bcl6-deficient B cells. Bcl6, a transcriptional repressor, was detected on the chromatin of the CD63 gene in resting B cells, therefore CD63 is a molecular target of Bcl6. Downregulation of CD63 mRNA in activated Bcl6-deficient B cells by small interfering RNA upregulated CXCR4 expression on the B cells. Furthermore, addition of Bcl6 inhibitor to activated B cell cultures increased CD63 mRNA expression in (and downregulated CXCR4 expression on) those activated B cells. Thus, CXCR4 can be downregulated on activated B cells by IL-21-induced endocytosis and CD63-mediated endosomal recruitment, and these mechanisms may contribute to downregulation of CXCR4 on centrocytes. PMID- 21270406 TI - Genetic labeling reveals altered turnover and stability of innate lymphocytes in latent mouse cytomegalovirus infection. AB - Mouse CMV (MCMV) infection rapidly induces the proliferation of NK cells, which correlates with immunological protection. Whether NK cells primed during acute response against MCMV are maintained for the long term is not known. In this study, we used TcrdH2BeGFP mice in which maturing NK cells are genetically labeled with a pulse of very stable histone-2B-eGFP. In this system, we found that the reporter protein was diluted out upon NK cell division during acute MCMV infection. At the same time, mature NK cells in uninfected mice showed only very limited turnover in vivo. Three months after primary infection when MCMV latency was established, the majority of peripheral NK cells still displayed a higher record of proliferation than NK cells in mock-infected controls. This observation included both Ly49H(+) and Ly49H(-) NK cells. Conversely, naive NK cells did not show more proliferation after transfer into latently MCMV-infected mice than that after transfer into mock-infected control mice. This indicated that the observed alterations of the NK cell compartment in MCMV latency were "legacy" (i.e., resulting from prior events during the initial immune response). Together, these results suggest that antiviral immune responses induce sustained alterations of innate lymphocyte populations that extend far beyond the first days of acute infection. PMID- 21270407 TI - Memory CD4 T cells that express CXCR5 provide accelerated help to B cells. AB - CD4 T cell help for B cells is critical for effective Ab responses. Although many of the molecules involved in helper functions of naive CD4 T cells have been characterized, much less is known about the helper capabilities of memory CD4 T cells, an important consideration for the design of vaccines that aim to prime protective memory CD4 T cells. In this study, we demonstrate that memory CD4 T cells enable B cells to expand more rapidly and class switch earlier than do primary responding CD4 T cells. This accelerated response does not require large numbers of memory cells, and similar numbers of primary responding cells provide less effective help than do memory cells. However, only memory CD4 T cells that express the B cell follicle homing molecule, CXCR5, are able to accelerate the response, suggesting that the rapidity of the Ab response depends on the ability of CD4 memory T cells to migrate quickly toward B cells. PMID- 21270408 TI - HLA class I allelic sequence and conformation regulate leukocyte Ig-like receptor binding. AB - Leukocyte Ig-like receptors (LILRs) are a family of innate immune receptors predominantly expressed by myeloid cells that can alter the Ag presentation properties of macrophages and dendritic cells. Several LILRs bind HLA class I. Altered LILR recognition due to HLA allelic variation could be a contributing factor in disease. We comprehensively assessed LILR binding to >90 HLA class I alleles. The inhibitory receptors LILRB1 and LILRB2 varied in their level of binding to different HLA alleles, correlating in some cases with specific amino acid motifs. LILRB2 displayed the weakest binding to HLA-B*2705, an allele genetically associated with several autoimmune conditions and delayed progression of HIV infection. We also assessed the effect of HLA class I conformation on LILR binding. LILRB1 exclusively bound folded beta(2)-microglobulin-associated class I, whereas LILRB2 bound both folded and free H chain forms. In contrast, the activating receptor LILRA1 and the soluble LILRA3 protein displayed a preference for binding to HLA-C free H chain. To our knowledge, this is the first study to identify the ligand of LILRA3. These findings support the hypothesis that LILR mediated detection of unfolded versus folded MHC modulates immune responses during infection or inflammation. PMID- 21270409 TI - Anaphylaxis and mortality induced by treatment of mice with anti-VLA-4 antibody and pertussis toxin. AB - Ab-mediated blockade of the adhesion molecule VLA-4 has been shown to ameliorate disease in human multiple sclerosis patients and experimental autoimmune encephalomyelitis (EAE) animal models. We wanted to determine whether anti-VLA-4 Ab treatment affected the function and persistence of autoreactive T cells in mice with EAE. Unexpectedly, we observed a high level of mortality in anti-VLA-4 mAb (PS/2)-treated mice with actively induced EAE despite decreased disease severity. Investigation of the underlying mechanism showed that injection of PS/2 mAb in combination with pertussis toxin resulted in anaphylaxis and mortality. Furthermore, the data showed that CD4(+) T cells were required for this effect and suggested a role for IL-1beta and TNF-alpha in the underlying pathology. The results reveal a previously not appreciated deleterious effect of anti-VLA-4 Ab treatment in combination with exposure to pertussis toxin. PMID- 21270410 TI - Basophils are the major producers of IL-4 during primary helminth infection. AB - IL-4 production by leukocytes is a key regulatory event that occurs early in the type 2 immune response, which induces allergic reactions and mediates expulsion of parasites. CD4(+) T cells and basophils are thought to be the key cell types that produce IL-4 during a type 2 response. In this study, we assessed the relative contribution of both CD4(+) T cell- and basophil-IL-4 production during primary and secondary responses to Nippostrongylus brasiliensis using a murine IL 4-enhanced GFP reporter system. During infection, IL-4-producing basophils were detected systemically, and tissue recruitment occurred independent of IL-4/STAT6 signaling. We observed that basophil recruitment to a tissue environment was required for their full activation. Basophil induction in response to secondary infection exhibited accelerated kinetics in comparison with primary infection. However, total basophil numbers were not enhanced, as predicted by previous models of protective immunity. Overall, the induction and migration of IL-4 producing basophils into peripheral tissues was found to be a prominent characteristic of the primary but not memory responses to N. brasiliensis infection, in which CD4(+) T cells were identified as the major source of IL-4. Whereas basophils were the major initial producers of IL-4, we determined that normal Th2 differentiation occurs independently of basophils, and depletion of basophils led to an enhancement of inflammatory cell recruitment to the site of infection. PMID- 21270411 TI - Identification of semaphorin 4B as a negative regulator of basophil-mediated immune responses. AB - Basophils are strong mediators of Th2 responses during helminthic infections. Recently, basophils were shown to function as APCs and promote both Th2 skewing and humoral memory responses. However, the mechanisms that regulate basophils are still unclear. In this article, we show that a class IV semaphorin, Sema4B, negatively regulates basophil functions through T cell-basophil contacts. In a screen to identify semaphorins that function in the immune system, we determined that Sema4B is expressed in T and B cells. Interestingly, Sema4B(-/-) mice had considerably increased serum IgE levels despite normal lymphocyte and dendritic cell functions. Recombinant Sema4B significantly inhibited IL-4 and IL-6 production from basophils in response to various stimuli, including IL-3, papain, and FcepsilonRI cross-linking. In addition, T cell-derived Sema4B, which accumulated at contact sites between basophils and CD4(+) T cells, suppressed basophil-mediated Th2 skewing, suggesting that Sema4B regulates basophil responses through cognate cell-cell contacts. Furthermore, Sema4B(-/-) mice had enhanced basophil-mediated memory IgE production, which was abolished by treating with an anti-FcepsilonRIalpha Ab. Collectively, these results indicate that Sema4B negatively regulates basophil-mediated Th2 and humoral memory responses. PMID- 21270412 TI - Regulatory T cells require mammalian target of rapamycin signaling to maintain both homeostasis and alloantigen-driven proliferation in lymphocyte-replete mice. AB - Rapamycin (Rapa), an immunosuppressive drug that acts through mammalian target of Rapa inhibition, broadly synergizes with tolerogenic agents in animal models of transplantation and autoimmunity. Rapa preferentially inhibits conventional CD4(+) Foxp3(-) T cells (Tconv) and promotes outgrowth of CD4(+)Foxp3(+) regulatory T cells (Treg) during in vitro expansion. Moreover, Rapa is widely perceived as augmenting both expansion and conversion of Treg in vivo. However, most quantitative studies were performed in lymphopenic hosts or in graft-versus host disease models. We show in this study that in replete wild-type mice, Rapa significantly inhibits both homeostatic and alloantigen-induced proliferation of Treg, and promotes their apoptosis. Together, these lead to significant Treg depletion. Tconv undergo depletion to a similar degree, resulting in no change in the percent of Treg among CD4 cells. Moreover, in this setting, there was no evidence of conversion of Tconv into Treg. However, after withdrawal of Rapa, Treg recover Ag-induced proliferation more quickly than Tconv, leading to recovery to baseline numbers and an increase in the percent of Treg compared with Tconv. These findings suggest that the effects of Rapa on Treg survival, homeostasis, and induction, depend heavily on the cellular milieu and degree of activation. In vivo, the resistance of Treg to mammalian target of Rapa inhibition is relative and results from lymphopenic and graft-versus-host disease models cannot be directly extrapolated to settings more typical of solid organ transplantation or autoimmunity. Moreover, these results have important implications for the timing of Rapa therapy with tolerogenic agents designed to increase the number of Treg in vivo. PMID- 21270413 TI - Rates, predictors, and consequences of remission from chronic migraine to episodic migraine. AB - OBJECTIVES: This study has 3 objectives: 1) to estimate remission rates in a population-based sample of subjects with chronic migraine (CM); 2) to identify potential predictors of CM remission; and 3) to assess the influence of CM remission on headache-related disability. METHODS: The American Migraine Prevalence and Prevention study is a prospective, population-based, mailed questionnaire survey, which included questions regarding headache frequency, symptomatology, demographics, comorbidities, health care utilization, and headache-related disability. Three years of longitudinal data were analyzed to determine rates of CM remission and assess predictors of remission using logistical regression models. The consequence of remission was measured by changes in disability, as measured by the Migraine Disability Assessment, over time. RESULTS: A total of 383 respondents had CM in 2005 and follow-up data in 2006 and 2007. Over 2 years, among those with CM at baseline, approximately 34% (n = 130) had persistent CM while 26% (n = 100) had remitted CM. In our final multivariate model, predictors of remission included baseline headache frequency (15-19 vs 25-31 headache days/month; odds ratio [OR] 0.29; 95% confidence interval [CI] 0.11 to 0.75) and absence of allodynia (OR 0.45; 95% CI 0.23 to 0.89). Preventive medication use was associated with lower remission rate (OR 0.41; 95% CI 0.23 to 0.75), but this effect lost significance when headache frequency was included. Over 2 years, those with persistent CM demonstrated increased disability while those with remitted CM demonstrated decreased disability. CONCLUSIONS: These findings have clinical practice implications, as it is important to consider that remission rates are variable. However, the benefit of remission goes beyond symptom reduction and may translate to marked decreases in headache-related disability. PMID- 21270414 TI - The radiologically isolated syndrome revisited: when is it presymptomatic multiple sclerosis? PMID- 21270415 TI - Increased risk of stroke after discontinuation of acetylsalicylic acid: a UK primary care study. AB - OBJECTIVES: Discontinuation of low-dose acetylsalicylic acid (ASA) therapy may increase the risk of ischemic events. This study evaluated the risk of ischemic stroke (IS) and TIA after low-dose ASA discontinuation in patients with cardiovascular disease or cerebrovascular disease. METHODS: The Health Improvement Network UK primary care database was used to identify a cohort of individuals aged 50-84 years with a first prescription for low-dose ASA (75-300 mg/day) for the secondary prevention of cardiovascular or cerebrovascular events in 2000-2007 (n = 39,512). Individuals were followed up for a mean of 3.4 years to identify cases of IS/TIA. Nested case-control analyses were used to assess risk factors for IS/TIA, including low-dose ASA discontinuation. RESULTS: The overall incidence of IS/TIA was 5.0 per 1,000 person-years (95% confidence interval [CI] 4.6-5.4). IS/TIA was significantly more common in patients with a previous diagnosis of cerebrovascular disease (relative risk [RR] 2.79; 95% CI 2.05-3.80) or atrial fibrillation (RR 1.71; 95% CI 1.28-2.29) than in those without these conditions. Compared with current users of low-dose ASA, those who discontinued treatment 31-180 days before the index date had a significantly increased overall risk of IS/TIA (RR 1.40; 95% CI 1.03-1.92). The most common reason for discontinuation was patient nonadherence. CONCLUSION: In patients prescribed low-dose ASA for the secondary prevention of cardiovascular or cerebrovascular events, discontinuation of low-dose ASA was associated with a 40% increase in the risk of IS/TIA compared with continuation of therapy. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that discontinuation of low-dose ASA is associated with a 40% increased risk of stroke within 31-180 days of discontinuation. PMID- 21270416 TI - Can we help patients with chronic migraine? PMID- 21270417 TI - Asymptomatic spinal cord lesions predict disease progression in radiologically isolated syndrome. AB - BACKGROUND: Technological advancements in neuroimaging and the increased use of these diagnostic modalities are responsible for the discovery of incidentally identified anomalies within the CNS. In addition to the identification of unanticipated brain MRI abnormalities suggestive of demyelinating disease in patients undergoing neuroimaging for a medical reason other than evaluation for multiple sclerosis (MS), asymptomatic spinal cord lesions are periodically identified. OBJECTIVE: To determine if asymptomatic spinal cord lesions are associated with clinical progression in subjects with radiologically isolated syndrome (RIS). METHODS: A retrospective review of RIS cases at the University of California, San Francisco Multiple Sclerosis Center was performed. The presence of asymptomatic cervical spinal cord MRI lesions was analyzed as a potential predictor for clinical progression. RESULTS: Twenty-five of 71 subjects with RIS possessed findings within the cervical spine that were highly suggestive of demyelinating disease. Of these subjects, 21 (84%) progressed clinically to clinically isolated syndrome (n = 19) or primary progressive multiple sclerosis (n = 2) over a median time of 1.6 years from the date of RIS identification (interquartile range 0.8-3.8). The sensitivity, specificity, and positive predictive value of an asymptomatic spinal cord lesion for subsequent development of either a first demyelinating attack or primary progressive MS were 87.5%, 91.5%, and 84%, respectively. The odds ratio of clinical progression was 75.3 (95% confidence interval 16.1-350.0, p < 0.0001). This association remained significant after adjusting for potential confounders. CONCLUSION: These findings suggest that the presence of asymptomatic spinal cord lesions place subjects with RIS at substantial risk for clinical conversion to either an acute or progressive event, a risk that is independent of brain lesions on MRI. PMID- 21270418 TI - Cup feeding--a valuable tool. PMID- 21270419 TI - International board certified lactation consultants are needed from every background. PMID- 21270420 TI - ILCA's inside track: a resource for breastfeeding mothers. Kangaroo care for your premature or sick baby. PMID- 21270421 TI - Evaluating the evidence: is there an effective treatment for breast engorgement? PMID- 21270422 TI - A spontaneous teratocarcinoma in the testis of a swiss albino mouse. AB - A unilateral non-metastatic embryonal carcinoma and teratoma of the testis was observed in a 12-week-old Swiss Albino mouse at the end of a 28-day repeated dose toxicity study. The teratocarcinoma almost completely replaced the parenchyma of the left testis. The tumor was composed of sheets and rosettes of primitive embryonal cells, anaplastic cells, skeletal muscle tissue, sebaceous gland tissue, keratinized stratified squamous epithelium, and ciliated cuboidal epithelium. The histomorphological characteristics of the tumor were reviewed and presented in this report. To the best of the authors' knowledge, this is the first report of spontaneous teratocarcinoma of testis in the Swiss Albino strain of mice. PMID- 21270423 TI - Industry-contract research organization pathology interactions: a perspective of contract research organizations in producing the best quality pathology report. AB - This article provides observations on the features of sponsor-contract research organization communication that will achieve the best quality pathology report based on our collective experience. Information on the test article and any anticipated findings should be provided, and initial slide examination should be done with knowledge of treatment group (but may be followed by blinded review of target tissues to determine no-effect levels). Only a pathologist should write or revise the pathology report or the pathology section of the overall study report. To address concerns related to undue sponsor influence, comments by sponsors should be presented as suggestions rather than directives. Adversity should be defined for each finding by the study pathologist, but the no-observed adverse effect level should not be discussed in the pathology report. Board-certified pathologists are recommended, but are not essential. Sponsors that have a particular format or report preferences should make them known well in advance. Histologic processing "to glass" of protocol-specified tissues from all dosage groups is recommended for rapid evaluation of target tissues. Telepathology is beneficial in certain situations, but it is usually more efficient for the study pathologist and reviewing pathologist to be in the same physical location to review differences of opinion and reach a consensus. PMID- 21270424 TI - Proliferative and molecular effects of the dual PPARalpha/gamma agonist tesaglitazar in rat adipose tissues: relevance for induction of fibrosarcoma. AB - The dual peroxisome-proliferator-activated receptor (PPAR) alpha/gamma agonist tesaglitazar has been shown to produce fibrosarcomas in rats. Here, the authors studied morphology, proliferation, differentiation, and inflammation markers in adipose tissue from rats exposed to 1, 3, or 10 umol/kg tesaglitazar for 2 or 12 weeks, including recovery groups (12 weeks treatment followed by 12 weeks recovery), and 3 or 10 umol/kg tesaglitazar for 24 weeks. Subcutaneous white and brown fat revealed reversible dose-related histopathological alterations and after 12 and 24 weeks developed areas of thickened skin (fatty lumps). There was a dose-dependent increase in proliferation of interstitial cells in white and brown fat as shown by increased mitotic index in all dose groups after 2 weeks. This was limited to the high dose after 12 and 24 weeks in white fat. Gene expression analyses showed that while tesaglitazar induced differentiation of adipose tissue characterized with a switch in cyclin D1 and D3 mRNA by 12 weeks, longer exposure at high doses reversed this differentiation concurrent with a reappearance of early adipocyte and inflammatory markers. These data suggest that sustained increased turnover of mesenchymal cells in adipose tissues, concomitant with onset of inflammation and fibrosis, drives development of fibrosarcomas in rats treated with tesaglitazar. PMID- 21270425 TI - Decreased degradation of internalized follicle-stimulating hormone caused by mutation of aspartic acid 6.30(550) in a protein kinase-CK2 consensus sequence in the third intracellular loop of human follicle-stimulating hormone receptor. AB - A naturally occurring mutation in follicle-stimulating hormone receptor (FSHR) gene has been reported: an amino acid change to glycine occurs at a conserved aspartic acid 550 (D550, D567, D6.30(567)). This residue is contained in a protein kinase-CK2 consensus site present in human FSHR (hFSHR) intracellular loop 3 (iL3). Because CK2 has been reported to play a role in trafficking of some receptors, the potential roles for CK2 and D550 in FSHR function were evaluated by generating a D550A mutation in the hFSHR. The hFSHR-D550A binds hormone similarly to WT-hFSHR when expressed in HEK293T cells. Western blot analyses showed lower levels of mature hFSHR-D550A. Maximal cAMP production of both hFSHR D550A as well as the naturally occurring mutation hFSHR-D550G was diminished, but constitutive activity was not observed. Unexpectedly, when (125)I-hFSH bound to hFSHR-D550A or hFSHR-D550G, intracellular accumulation of radiolabeled FSH was observed. Both sucrose and dominant-negative dynamin blocked internalization of radiolabeled FSH and its commensurate intracellular accumulation. Accumulation of radiolabeled FSH in cells transfected with hFSHR-D550A is due to a defect in degradation of hFSH as measured in pulse chase studies, and confocal microscopy imaging revealed that FSH accumulated in large intracellular structures. CK2 kinase activity is not required for proper degradation of internalized FSH because inhibition of CK2 kinase activity in cells expressing hFSHR did not uncouple degradation of internalized radiolabeled FSH. Additionally, the CK2 consensus site in FSHR iL3 is not required for binding because CK2alpha coimmunoprecipitated with hFSHR-D550A. Thus, mutation of D550 uncouples the link between internalization and degradation of hFSH. PMID- 21270427 TI - Glucose metabolism in mouse cumulus cells prevents oocyte aging by maintaining both energy supply and the intracellular redox potential. AB - Inhibiting oocyte postovulatory aging is important both for healthy reproduction and for assisted reproduction techniques. Some studies suggest that glucose promotes oocyte meiotic resumption through glycolysis, but others indicate that it does so by means of the pentose phosphate pathway (PPP). Furthermore, although pyruvate was found to prevent oocyte aging, the mechanism is unclear. The present study addressed these issues by using the postovulatory aging oocyte model. The results showed that whereas the oocyte itself could utilize pyruvate or lactate to prevent aging, it could not use glucose unless in the presence of cumulus cells. Glucose metabolism in cumulus cells prevented oocyte aging by producing pyruvate and NADPH through glycolysis and PPP. Whereas PPP was still functioning after inhibition of glycolysis, the glycolysis was completely inactivated after inhibition of PPP. Addition of fructose-6-phosphate, an intermediate product from PPP, alleviated oocyte aging significantly when the PPP was totally inhibited. Lactate prevented oocyte aging through its lactate dehydrogenase-catalyzed oxidation to pyruvate, but pyruvate inhibited oocyte aging by its intramitochondrial metabolism. However, both lactate and pyruvate required mitochondrial electron transport to prevent oocyte aging. The inhibition of oocyte aging by both PPP and pyruvate involved regulation of the intracellular redox status. Together, the results suggest that glucose metabolism in cumulus cells prevented oocyte postovulatory aging by maintaining both energy supply and the intracellular redox potential and that) glycolysis in cumulus cells might be defective, with pyruvate production depending upon the PPP for intermediate products. PMID- 21270426 TI - Activation of the aryl hydrocarbon receptor during pregnancy in the mouse alters mammary development through direct effects on stromal and epithelial tissues. AB - Activation of the aryl hydrocarbon receptor (AHR), an environment-sensing transcription factor, causes profound impairment of mammary gland differentiation during pregnancy. Defects include decreased ductal branching, poorly formed alveolar structures, suppressed expression of milk proteins, and failure to nutritionally support offspring. AHR is activated by numerous environmental toxins, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and plays an as yet poorly understood role in development and reproduction. To better understand how AHR activation affects pregnancy-associated mammary gland differentiation, we used a combination of ex vivo differentiation, mammary epithelial transplantation, and AHR-deficient mice to determine whether AHR modulates mammary development through a direct effect on mammary epithelial cells (MECs) or by altering paracrine or systemic factors that drive pregnancy-associated differentiation. Studies using mutant mice that express an AHR protein lacking the DNA-binding domain show that defects in pregnancy-associated differentiation require AHR:DNA interactions. We then used fluorescence-based cell sorting to compare changes in gene expression in MECs and whole mammary tissue to gain insight into affected signaling pathways. Our data indicate that activation of the AHR during pregnancy directly affects mammary tissue development via both a direct effect on MECs and through changes in cells of the fat pad, and point to gene targets in MECs and stromal tissues as putative AHR targets. PMID- 21270428 TI - Prostaglandins regulate conceptus elongation and mediate effects of interferon tau on the ovine uterine endometrium. AB - In ruminants, both the endometrium and the conceptus (embryo and associated extraembryonic membranes) trophectoderm synthesizes and secretes prostaglandins (PG) during early pregnancy. In mice and humans, PGs regulate endometrial function and conceptus implantation. In Study One, bred ewes received intrauterine infusions of vehicle as a control (CX) or meloxicam (MEL), a PG synthase (PTGS) inhibitor from Days 8-14 postmating, and the uterine lumen was flushed on Day 14 to recover conceptuses and assess their morphology. Elongating and filamentous conceptuses (12 cm to >14 cm in length) were recovered from all CX-treated ewes. In contrast, MEL-treated ewes contained mostly ovoid or tubular conceptuses. PTGS activity in the uterine endometrium and amounts of PGs were substantially lower in uterine flushings from MEL-treated ewes. Receptors for PGE2 and PGF2 alpha were present in both the conceptus and the endometrium, particularly the epithelia. In Study Two, cyclic ewes received intrauterine infusions of CX, MEL, recombinant ovine interferon tau (IFNT), or IFNT and MEL from Days 10-14 postestrus. Infusion of MEL decreased PGs in the uterine lumen and expression of a number of progesterone-induced endometrial genes, particularly IGFBP1 and HSD11B1. IFNT increased endometrial PTGS activity and the amount of PGs in the uterine lumen. Interestingly, IFNT stimulation of many genes (FGF2, ISG15, RSAD2, CST3, CTSL, GRP, LGALS15, IGFBP1, SLC2A1, SLC5A1, SLC7A2) was reduced by co-infusion with MEL. Thus, PGs are important regulators of conceptus elongation and mediators of endometrial responses to progesterone and IFNT in the ovine uterus. PMID- 21270429 TI - Decreased oocyte DAZL expression in mice results in increased litter size by modulating follicle-stimulating hormone-induced follicular growth. AB - While the germ cell-specific RNA binding protein, DAZL, is essential for oocytes to survive meiotic arrest, DAZL heterozygous (het) mice have an increased ovulation rate that is associated with elevated inhibin B and decreased plasma follicle-stimulating hormone (FSH). The relationship between decreased oocyte DAZL expression and enhanced follicular development in het mice was investigated using in vitro follicle cultures and in vivo modulation of endogenous FSH, by treating mice with inhibin and exogenous FSH. In vitro, follicles from het mice are more sensitive to FSH than those of wild-type (wt) mice and can grow in FSH concentrations that are deleterious to wild-type follicles. In vivo, despite no differences between genotypes in follicle population profiles, analysis of granulosa cell areas in antral follicles identified a significantly greater number of antral follicles with increased granulosa cell area in het ovaries. Modulation of FSH in vivo, using decreasing doses of FSH or ovine follicular fluid as a source of inhibin, confirmed the increased responsiveness of het antral follicles to FSH. Significantly more follicles expressing aromatase protein confirmed the earlier maturation of granulosa cells in het mice. In conclusion, it is suggested that DAZL expression represses specific unknown genes that regulate the response of granulosa cells to FSH. If this repression is reduced, as in DAZL het mice, then follicles can grow to the late follicular stage despite declining levels of circulating FSH, thus leading to more follicles ovulating and increased litter size. PMID- 21270430 TI - Nodal expression in the uterus of the mouse is regulated by the embryo and correlates with implantation. AB - Nodal, a transforming growth factor beta (TGFB) superfamily member, plays a critical role during early embryonic development. Recently, components of the Nodal signaling pathway were characterized in the human uterus and implicated in the tissue remodeling events during menstruation. Furthermore, the Nodal inhibitor, Lefty, was identified in the mouse endometrium during pregnancy, and its overexpression led to implantation failure. Nonetheless, the precise function and mechanism of Nodal signaling during pregnancy remains unclear. In order to elucidate the potential roles Nodal plays in these processes, we have generated a detailed profile of maternal Nodal expression in the mouse uterus throughout pregnancy. NODAL, although undetectable during the nonpregnant estrus cycle, was localized throughout the glandular epithelium of the endometrium during the peri implantation period. Interestingly, Nodal expression generated a banding pattern along the proximal-distal axis of the uterine horn on Day 4.5 that directly correlated with blastocyst implantation. Embryo transfer experiments indicate the embryo regulates Nodal expression in the uterus and directs its expression at the time of implantation, restricting NODAL to the sites between implantation crypts. During the later stages of pregnancy, Nodal exhibits a dynamic expression profile that suggests a role in regulating the endometrial response to decidualization and associated trophoblast invasion. PMID- 21270431 TI - Placental regulation of peptide hormone and growth factor activity by proMBP. AB - The gene PRG2, encoding the proform of eosinophil major basic protein (proMBP), is one of the most highly expressed genes during human pregnancy, and low proMBP levels predict Down syndrome and poor pregnancy outcome. Reminiscent of a magnet, the primary structure of proMBP is extremely charge polarized, consisting of an N terminal acidic propiece followed by a highly basic MBP domain in the C-terminal. Many tissues synthesize and secrete full-length proMBP, but only distinct cell types of the immune system process and store mature MBP in intracellular granules. MBP is released upon degranulation of eosinophil leukocytes and is toxic to bacteria, parasites, and mammalian cells. In contrast, proMBP is apparently nontoxic and functions in the inhibition of proteolysis and prohormone conversion. Recent research has revealed the complexity of proMBP biology and shed light on the process of MBP generation. ProMBP specifically forms disulfide mediated, covalent complexes with the metzincin metalloproteinase pregnancy associated plasma protein A (PAPPA) and the prohormone angiotensinogen (AGT). In both processes, PAPPA and AGT have reduced biological activity in the resulting complexes. In addition, proMBP is a component of high-molecular-weight AGT and, therefore, is potentially involved in the development of preeclampsia and in pregnancy-induced hypertension. PMID- 21270432 TI - Comparison of expert graders to computer-assisted image analysis of the retina in retinopathy of prematurity. AB - AIMS: To determine correlation of width and tortuosity between expert graders and computer-assisted image analysis of the retina in narrow-field images of eyes with retinopathy of prematurity. METHODS: 11 digital images were selected based on severity of retinopathy of prematurity (ROP). Narrow field images were analysed for width and tortuosity of vessels using computer-aided image analysis of the retina (CAIAR), an image analysis software, and by four ROP experts. Spearman correlation coefficients (rho) assessed the correlation of CAIAR grading with expert grading. Intra-class correlations assessed agreement among graders. Width and tortuosity were compared among severity of ROP and treatment status using analysis of variance and generalised estimating equations. RESULTS: Expert measurements correlated well with measures from CAIAR for venule width (rho=0.57 0.66) and arteriole tortuosity (rho=0.71-0.81). Measurements from four graders agreed moderately well (intra-class correlations were 0.49 and 0.69 for venule width and arteriole tortuosity, respectively). Increased severity of ROP (no pre plus/plus, pre-plus, plus) was associated with larger width (linear trend p=0.02 in two graders) and tortuosity (linear trend p<0.03 in all graders). Tortuosity measurements by CAIAR and graders were statistically different between treated and untreated eyes (p<0.002). CONCLUSIONS: We found moderate correlation between expert graders' assessment of vessel tortuosity and width and CAIAR using narrow field images. PMID- 21270433 TI - Spectral domain optical coherence tomography for higher precision in the evaluation of vitreoretinal adhesions in exudative age-related macular degeneration. AB - AIM: The role of changes at the vitreoretinal interface and vitreomacular traction forces in pathogenesis, and the course of exudative age-related macular degeneration (AMD) need further exploration. This study examines the localisation of adhesion and the direction of traction lines in eyes with exudative AMD. METHODS: The cubes 512*128 of Cirrus optical coherence tomography (OCT) and volume scans of Spectralis OCT were reviewed in a consecutive series of patients presenting between December 2008 and March 2009 with vitreomacular adhesion in exudative AMD. RESULTS: 30 eyes of 25 patients with exudative AMD and vitreomacular adhesion were studied. 50% had type III lesions, 46.7% occult and 3.3% predominantly classic lesions. The localisation of the adhesion corresponded in 100% with the area of the neovascularisation (CNV), in 73.3% traction directed towards the CNV and in 83.3% towards the optic disc could be noted. Spectral domain OCT and 3D visualisation enabled clearer localisation of vitreomacular adhesion and definition of resulting traction lines. CONCLUSION: There is a high prevalence of type III lesions within eyes with vitreomacular adhesions, and complete correspondence between the location of the adhesion and the CNV. There is also a high incidence of vitreopapillary adhesion in these cases, suggesting a possible role in pathogenesis. PMID- 21270434 TI - Distinguishing wet from dry age-related macular degeneration using three dimensional computer-automated threshold Amsler grid testing. AB - BACKGROUND/AIMS: With the increased efficacy of current therapy for wet age related macular degeneration (AMD), better ways to detect wet AMD are needed. This study was designed to test the ability of three-dimensional contrast threshold Amsler grid (3D-CTAG) testing to distinguish wet AMD from dry AMD. METHODS: Conventional paper Amsler grid and 3D-CTAG tests were performed in 90 eyes: 63 with AMD (34 dry, 29 wet) and 27 controls. Qualitative comparisons were based upon the three-dimensional shapes of central visual field (VF) defects. Quantitative analyses considered the number and volume of the three-dimensional defects. RESULTS: 25/34 (74%) dry AMD and 6/29 (21%) wet AMD eyes had no distortions on paper Amsler grid. Of these, 5/25 (20%) dry and 6/6 (100%) wet (p=0.03) AMD eyes exhibited central VF defects with 3D-CTAG. Wet AMD displayed stepped defects in 16/28 (57%) eyes, compared with only 2/34 (6%) of dry AMD eyes (p=0.002). All three volumetric indices of VF defects were two- to four-fold greater in wet than dry AMD (p<0.006). 3D-CTAG had 83.9% positive and 90.6% negative predictive values for wet AMD. CONCLUSIONS: 3D-CTAG has a higher likelihood of detecting central VF defects than conventional Amsler grid, especially in wet AMD. Wet AMD can be distinguished from dry AMD by qualitative and quantitative 3D-CTAG criteria. Thus, 3D-CTAG may be useful in screening for wet AMD, quantitating disease severity, and providing a quantitative outcome measure of therapy. PMID- 21270435 TI - Prospective evaluation of cataract surgery in female patients taking tamsulosin. PMID- 21270436 TI - Letter to the editor: 24-hour versus daytime intraocular pressure phasing in the management of patients with treated glaucoma. PMID- 21270437 TI - Temporal control of a dendritogenesis-linked gene via REST-dependent regulation of nuclear factor I occupancy. AB - Developing neurons undergo a series of maturational stages, and the timing of these events is critical for formation of synaptic circuitry. Here we addressed temporal regulation of the Gabra6 gene, which is expressed in a delayed manner during dendritogenesis in maturing cerebellar granule neurons (CGNs). Developmental up-regulation of Gabra6 transcription required a binding site for nuclear factor I (NFI) proteins. The amounts and DNA binding activities of NFI proteins were similar in immature and mature CGNs; however, NFI occupancy of the Gabra6 promoter in native chromatin was temporally delayed in parallel with Gabra6 gene expression, both in vivo and in culture. The trans-repressor RE1 silencing transcription factor (REST) occupied the Gabra6 proximal promoter in CGN progenitors and early postmitotic CGNs, and its departure mirrored the initial onset of NFI binding as CGNs differentiated. Furthermore constitutive REST expression blocked both Gabra6 expression and NFI occupancy in mature CGNs, whereas REST knockdown in immature CGNs accelerated the initiation of both events. These studies identify a novel mechanism for controlling the timing of dendritogenesis-associated gene expression in maturing neurons through delayed binding of NFI proteins to chromatin. They also establish a temporal function for REST in preventing premature promoter occupancy by NFI proteins in early-stage postmitotic neurons. PMID- 21270438 TI - Soluble levels of cytosolic tubulin regulate ciliary length control. AB - The primary cilium is an evolutionarily conserved dynamic organelle important for regulating numerous signaling pathways, and, as such, mutations disrupting ciliogenesis result in a variety of developmental abnormalities and postnatal disorders. The length of the cilium is regulated by the cell through largely unknown mechanisms. Normal cilia length is important, as either shortened or elongated cilia have been associated with disease and developmental defects. Here we explore the importance of cytoskeletal dynamics in regulating cilia length. Using pharmacological approaches in different cell types, we demonstrate that actin depolymerization or stabilization and protein kinase A activation result in a rapid elongation of the primary cilium. The effects of pharmacological agents on cilia length are associated with a subsequent increase in soluble tubulin levels and can be impaired by depletion of soluble tubulin with taxol. In addition, subtle nocodazole treatment was able to induce ciliogenesis under conditions in which cilia are not normally formed and also increases cilia length on cells that have already established cilia. Together these data indicate that cilia length can be regulated through changes in either the actin or microtubule network and implicate a possible role for soluble tubulin levels in cilia length control. PMID- 21270439 TI - The NDC80 complex proteins Nuf2 and Hec1 make distinct contributions to kinetochore-microtubule attachment in mitosis. AB - Successful mitosis requires that kinetochores stably attach to the plus ends of spindle microtubules. Central to generating these attachments is the NDC80 complex, made of the four proteins Spc24, Spc25, Nuf2, and Hec1/Ndc80. Structural studies have revealed that portions of both Hec1 and Nuf2 N termini fold into calponin homology (CH) domains, which are known to mediate microtubule binding in certain proteins. Hec1 also contains a basic, positively charged stretch of amino acids that precedes its CH domain, referred to as the "tail." Here, using a gene silence and rescue approach in HeLa cells, we show that the CH domain of Hec1, the CH domain of Nuf2, and the Hec1 tail each contributes to kinetochore microtubule attachment in distinct ways. The most severe defects in kinetochore microtubule attachment were observed in cells rescued with a Hec1 CH domain mutant, followed by those rescued with a Hec1 tail domain mutant. Cells rescued with Nuf2 CH domain mutants, however, generated stable kinetochore-microtubule attachments but failed to generate wild-type interkinetochore tension and failed to enter anaphase in a timely manner. These data suggest that the CH and tail domains of Hec1 generate essential contacts between kinetochores and microtubules in cells, whereas the Nuf2 CH domain does not. PMID- 21270440 TI - Global gene expression analysis of human erythroid progenitors. AB - Understanding the pattern of gene expression during erythropoiesis is crucial for a synthesis of erythroid developmental biology. Here, we isolated 4 distinct populations at successive erythropoietin-dependent stages of erythropoiesis, including the terminal, pyknotic stage. The transcriptome was determined using Affymetrix arrays. First, we demonstrated the importance of using defined cell populations to identify lineage and temporally specific patterns of gene expression. Cells sorted by surface expression profile not only express significantly fewer genes than unsorted cells but also demonstrate significantly greater differences in the expression levels of particular genes between stages than unsorted cells. Second, using standard software, we identified more than 1000 transcripts not previously observed to be differentially expressed during erythroid maturation, 13 of which are highly significantly terminally regulated, including RFXAP and SMARCA4. Third, using matched filtering, we identified 12 transcripts not previously reported to be continuously up-regulated in maturing human primary erythroblasts. Finally, using transcription factor binding site analysis, we identified potential transcription factors that may regulate gene expression during terminal erythropoiesis. Our stringent lists of differentially regulated and continuously expressed transcripts containing many genes with undiscovered functions in erythroblasts are a resource for future functional studies of erythropoiesis. Our Human Erythroid Maturation database is available at https://cellline.molbiol.ox.ac.uk/eryth/index.html. [corrected]. PMID- 21270441 TI - Peripheral T-cell lymphoma, not otherwise specified: a report of 340 cases from the International Peripheral T-cell Lymphoma Project. AB - The International Peripheral T-cell Lymphoma Project is a collaborative effort to better understand peripheral T-cell lymphoma (PTCL). A total of 22 institutions submitted clinical and pathologic material on 1314 cases. One objective was to analyze the clinical and pathologic features of 340 cases of PTCL, not otherwise specified. The median age of the patients was 60 years, and the majority (69%) presented with advanced stage disease. Most patients (87%) presented with nodal disease, but extranodal disease was present in 62%. The 5-year overall survival was 32%, and the 5-year failure-free survival was only 20%. The majority of patients (80%) were treated with combination chemotherapy that included an anthracycline, but there was no survival advantage. The International Prognostic Index (IPI) was predictive of both overall survival and failure-free survival (P < .001). Multivariate analysis of clinical and pathologic prognostic factors, respectively, when controlling for the IPI, identified bulky disease (>= 10 cm), thrombocytopenia (< 150 * 10(9)/L), and a high number of transformed tumor cells (> 70%) as adverse predictors of survival, but only the latter was significant in final analysis. Thus, the IPI and a single pathologic feature could be used to stratify patients with PTCL-not otherwise specified for novel and risk-adapted therapies. PMID- 21270442 TI - Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse. AB - In a randomized trial of therapy for FMS-like tyrosine kinase-3 (FLT3) mutant acute myeloid leukemia in first relapse, 224 patients received chemotherapy alone or followed by 80 mg of the FLT3 inhibitor lestaurtinib twice daily. Endpoints included complete remission or complete remission with incomplete platelet recovery (CR/CRp), overall survival, safety, and tolerability. Correlative studies included pharmacokinetics and analysis of in vivo FLT3 inhibition. There were 29 patients with CR/CRp in the lestaurtinib arm and 23 in the control arm (26% vs 21%; P = .35), and no difference in overall survival between the 2 arms. There was evidence of toxicity in the lestaurtinib-treated patients, particularly those with plasma levels in excess of 20 MUM. In the lestaurtinib arm, FLT3 inhibition was highly correlated with remission rate, but target inhibition on day 15 was achieved in only 58% of patients receiving lestaurtinib. Given that such a small proportion of patients on this trial achieved sustained FLT3 inhibition in vivo, any conclusions regarding the efficacy of combining FLT3 inhibition with chemotherapy are limited. Overall, lestaurtinib treatment after chemotherapy did not increase response rates or prolong survival of patients with FLT3 mutant acute myeloid leukemia in first relapse. This study is registered at www.clinicaltrials.gov as #NCT00079482. PMID- 21270443 TI - KNG1 Ile581Thr and susceptibility to venous thrombosis. AB - Three single nucleotide polymorphisms (SNPs) were recently found to be associated with activated partial thromboplastin time (aPTT). Because shortened aPTT levels have been observed in patients experiencing venous thrombosis (VT), we investigated the effects of these 3 aPTT-associated SNPs, rs2731672, rs9898, and rs710446, on the risk of VT in a sample of 1110 healthy patients and 1542 patients with VT. Among the 3 tested SNPs, only rs710446 was associated with VT risk; the rs710446-C allele was associated with an increased risk of VT (odds ratio 1.196, 95% confidence interval 1.071-1.336, P = .0012). This association also was observed in an independent sample of 590 controls and 596 patients (odds ratio 1.171, 95% confidence interval 0.889-1.541, P = .059). We also confirmed that the rs710446-C allele was associated with decreased aPTT levels, making this nonsynonymous Ile581Thr variant a new genetic risk factor for VT. PMID- 21270444 TI - Definition and characterization of the systemic T-cell dysregulation in untreated indolent B-cell lymphoma and very early CLL. AB - Epidemiologic data show that the immune system may control or promote the emergence and growth of neoplastic lymphomatous clones. Conversely, systemic lymphomas, especially myeloma and chronic lymphocytic leukemia (CLL), are associated with clinical immunodeficiency. This prospective controlled study demonstrates substantially reduced circulating T helper cells, predominantly naive CD4(+) cells, in patients with nonleukemic follicular lymphoma and extranodal marginal zone lymphoma, but not in monoclonal gammopathy and early CLL. These changes were correlated with a preactivated phenotype, hyperreactivity in vitro, pre-senescence, and a T helper 2 shift of peripheral T helper cells. No prominent alterations existed in the regulatory T-cell compartment. Gene expression profiling of in vitro-stimulated CD4(+) cells revealed an independent second alteration of T helper cell physiology, which was most pronounced in early CLL but also detectable in follicular lymphoma/extranodal marginal zone lymphoma. This pattern consisted of down-regulation of T-cell receptor signaling cascades and globally reduced cytokine secretion. Both types of T-cell dysfunction may contribute to significant immunodeficiency in nonleukemic indolent B-cell lymphomas as demonstrated by unresponsiveness to hepatitis B vaccination. The precise definition of systemic T-cell dysfunction serves as the basis to study its prognostic impact, its relationship to the established influence of the lymphoma microenvironment, and its therapeutic manipulation. PMID- 21270445 TI - Deficiency of SATB1 expression in Sezary cells causes apoptosis resistance by regulating FasL/CD95L transcription. AB - Sezary syndrome (SS) is an aggressive subtype of cutaneous T-cell lymphoma that is characterized by circulating leukemic Sezary cells. The accumulation of these malignant cells has been shown to be the result of the resistance to apoptosis, in particular, activation-induced cell death. However, the mechanism of apoptosis resistance remains unknown. By characterizing the gene transcription profiles of purified CD4(+)CD7(-) Sezary cells from patients with SS and cultured Sezary cells, it was found that Sezary cells are deficient in the expression of special AT-rich region binding protein 1 (SATB1), a key regulator of T-cell development and maturation. Retrovirus-mediated gene transduction revealed that SATB1 restoration in cultured Sezary cells (Hut78) triggered spontaneous cell death and sensitized Hut78 cells to activation-induced cell death, with associated activation of caspase 8 and caspase 3. Furthermore, endogenous expression of FasL in Sezary cells was increased in transcriptional and translational levels on restoration of SATB1 expression in cultured Sezary cells. These results suggest that deficiency in SATB1 expression in Sezary cells plays an important role in SS pathogenesis by causing apoptosis resistance. Thus, restoration of SATB1 expression may represent a potential molecular targeted therapy for SS, which does not have a cure at present. PMID- 21270446 TI - Dissociating spatial attention and awareness in emotion-induced blindness. AB - Emotional stimuli attract spatial attention, sometimes improving perception at their location. But they also can disrupt awareness of targets at their location, a phenomenon known as emotion-induced blindness. Such discrepant findings might reflect the impact of emotional stimuli on different perception mechanisms. We dissociated spatial attention and awareness by investigating the spatial distribution of emotion-induced blindness. Participants searched for a target within two simultaneous rapid streams of pictures, one of which could also contain a preceding emotional distractor. When targets were followed by additional stream items, emotion-induced blindness occurred only at the location of the distractor. However, when no items appeared after the target, so that it could persist in iconic memory and its temporal position was easily discernible, emotional disruption of target perception was more robust away from the distractor's location than at the distractor's location. The results suggest that although emotional distractors attract spatial attention, they inhibit identification of competing items potentially linked to the same spatiotemporal position. PMID- 21270447 TI - Us versus them: social identity shapes neural responses to intergroup competition and harm. AB - Intergroup competition makes social identity salient, which in turn affects how people respond to competitors' hardships. The failures of an in-group member are painful, whereas those of a rival out-group member may give pleasure-a feeling that may motivate harming rivals. The present study examined whether valuation related neural responses to rival groups' failures correlate with likelihood of harming individuals associated with those rivals. Avid fans of the Red Sox and Yankees teams viewed baseball plays while undergoing functional magnetic resonance imaging. Subjectively negative outcomes (failure of the favored team or success of the rival team) activated anterior cingulate cortex and insula, whereas positive outcomes (success of the favored team or failure of the rival team, even against a third team) activated ventral striatum. The ventral striatum effect, associated with subjective pleasure, also correlated with self-reported likelihood of aggressing against a fan of the rival team (controlling for general aggression). Outcomes of social group competition can directly affect primary reward-processing neural systems, which has implications for intergroup harm. PMID- 21270448 TI - Predicting sensation seeking from dopamine genes: use and misuse of genetic prediction. PMID- 21270449 TI - I 5683 you: dialing phone numbers on cell phones activates key-concordant concepts. AB - When people perform actions, effects associated with the actions are activated mentally, even if those effects are not apparent. This study tested whether sequences of simulations of virtual action effects can be integrated into a meaning of their own. Cell phones were used to test this hypothesis because pressing a key on a phone is habitually associated with both digits (dialing numbers) and letters (typing text messages). In Experiment 1, dialing digit sequences induced the meaning of words that share the same key sequence (e.g., 5683, LOVE). This occurred even though the letters were not labeled on the keypad, and participants were not aware of the digit-letter correspondences. In Experiment 2, subjects preferred dialing numbers implying positive words (e.g., 37326, DREAM) over dialing numbers implying negative words (e.g., 75463, SLIME). In Experiment 3, subjects preferred companies with phone numbers implying a company-related word (e.g., LOVE for a dating agency, CORPSE for a mortician) compared with companies with phone numbers implying a company-unrelated word. PMID- 21270450 TI - Independent allocation of attention to eye and hand targets in coordinated eye hand movements. AB - When reaching for objects, people frequently look where they reach. This raises the question of whether the targets for the eye and hand in concurrent eye and hand movements are selected by a unitary attentional system or by independent mechanisms. We used the deployment of visual attention as an index of the selection of movement targets and asked observers to reach and look to either the same location or separate locations. Results show that during the preparation of coordinated movements, attention is allocated in parallel to the targets of a saccade and a reaching movement. Attentional allocations for the two movements interact synergistically when both are directed to a common goal. Delaying the eye movement delays the attentional shift to the saccade target while leaving attentional deployment to the reach target unaffected. Our findings demonstrate that attentional resources are allocated independently to the targets of eye and hand movements and suggest that the goals for these effectors are selected by separate attentional mechanisms. PMID- 21270451 TI - 2010: the year in review. PMID- 21270452 TI - Overcoming the 99mTc shortage: are options being overlooked? PMID- 21270454 TI - PET and PET/CT of the neck lymph nodes improves risk prediction in patients with squamous cell carcinoma of the oral cavity. AB - We prospectively evaluated the sensitivity and specificity of (18)F-FDG PET in the detection of neck lymph node metastases in patients with oral cavity squamous cell carcinoma (OSCC). We also sought to evaluate whether pretreatment PET visual scores in the neck lymph nodes may improve risk stratification. METHODS: We enrolled 473 OSCC patients (445 men and 28 women; mean age +/- SD, 50.9 +/- 11.7 y) without distant metastases. All participants underwent (18)F-FDG PET within 2 wk before surgery and neck dissection. Histopathology was taken as the reference standard for neck lymph node status. The duration of follow-up was at least 24 mo in all surviving patients. RESULTS: (18)F-FDG PET correctly diagnosed 164 of 211 patients with neck metastases and 152 of 262 subjects without pathologic neck metastases, resulting in a patient-based sensitivity and specificity of 77.7% and 58.0%, respectively. In Cox models adjusting for age, sex, traditional risk factors, and treatment modality, PET results at the neck lymph nodes were significantly and independently associated with rates of neck control, distant metastasis, disease-free survival, disease-specific survival, and overall survival. Notably, the results of the c-statistics demonstrated that PET score improved the accuracy of risk prediction in terms of overall and disease-free survival rates. CONCLUSION: PET findings at the neck lymph nodes have limited sensitivity and specificity for primary staging of OSCC but improve risk stratification beyond that of traditional risk factors. PMID- 21270455 TI - Improved outcome prediction by SPECT myocardial perfusion imaging after CT attenuation correction. AB - The aim of this study was to determine the impact of attenuation correction with CT (CT-AC) on the prognostic value of SPECT myocardial perfusion imaging (SPECT MPI). METHODS: The summed stress score (SSS; 20-segment model) was obtained from filtered backprojection (FBP) and iterative reconstruction with CT-AC in 876 consecutive patients undergoing a 1-d stress-rest (99m)Tc-tetrofosmin SPECT MPI study for the evaluation of known or suspected coronary artery disease. Survival free of major adverse cardiac events (MACEs; cardiac death or nonfatal myocardial infarction) and survival free of any adverse cardiac events (including cardiac hospitalization, unstable angina, and late coronary revascularization) were analyzed by Kaplan-Meier analysis. RESULTS: At a mean follow-up of 2.3 +/- 0.6 y, a total of 184 adverse events occurred in 145 patients, including 35 MACEs (16 cardiac deaths [rate, 1.8%] and 19 nonfatal myocardial infarctions [rate, 2.2%]). With FBP, an SSS of 0-3 best distinguished patients with a low MACE rate (0.6%), followed by an SSS of 4-8 (4.3%), with increased MACE rate, and an SSS of 9-13 (3.8%), which was comparable. By contrast, with CT-AC the discrimination of low from intermediate MACE rate was best observed between an SSS of 0 (0%) and an SSS of 1-3 (3.7%), with a plateau at an SSS of 4-8 (3.2%). CONCLUSION: CT-AC for SPECT MPI allows improved risk stratification. The prognostically relevant SSS cutoff is shifted toward lower values. PMID- 21270456 TI - Examination of 11C-methionine metabolism by the standardized uptake value in the normal brain of children. AB - The aim of this study was to determine the uptake of L-[methyl-(11)C]-methionine ((11)C-MET) in the normal brain of patients younger than 20 y, to facilitate more accurate diagnoses in young patients. METHODS: Eighty-two patients were categorized into 4 groups according to their age. They underwent (11)C-MET PET, and a standardized uptake value (SUV) was determined for different brain regions including the frontal lobe, parietal lobe, cerebellum, and brain stem. RESULTS: Compared with all other parts of the brain, the cerebellum had the highest SUV. A tendency for a positive relationship between SUV and age was found in all regions, and a significant relationship with SUV was found in the frontal lobe and cerebellum. CONCLUSION: The character of SUV in the normal brains of children is different from that of adults, and these normal SUV data will play an important role as a critical reference value. PMID- 21270457 TI - PET of (R)-11C-rolipram binding to phosphodiesterase-4 is reproducible and sensitive to increased norepinephrine in the rat heart. AB - Phosphodiesterase-4 (PDE4) plays a critical role in the regulation of beta adrenergic receptor-stimulated cyclic adenosine monophosphate cell signaling in the heart. (R)-rolipram, a PDE4-selective inhibitor, has been studied previously as a radiotracer for the quantification of PDE4 levels. The aim of this study was to characterize (R)-(11)C-rolipram binding in the rat myocardium in vivo, using small-animal PET. METHODS: Male Sprague-Dawley rats (n = 30) were administered (R)-(11)C-rolipram and imaged for 60 min to evaluate tracer binding and reproducibility, quantified using Logan slope analysis of the distribution volume. Dynamic (13)N-ammonia imaging was performed to quantify myocardial blood flow and assist in cardiac regional analysis. Saturation studies evaluated the sensitivity of (R)-(11)C-rolipram to PDE4 blocking by unlabeled cold (R)-rolipram (0.0001-1.0 mg/kg), for estimation of the median effective dose (ED(50)) in the heart. (R)-(11)C-rolipram response to enhanced norepinephrine stimulation of the beta-adrenergic receptor with desipramine (20 mg/kg, intravenous) was also studied. Intrarat variability studies (n = 5) were conducted with test-retest imaging at 16 +/- 7 d. RESULTS: A reduction of Logan slope was observed with increasing cold mass coadministered with the tracer, with an ED(50) of 0.0019 mg/kg (95% confidence interval, 0.0014-0.0052) estimated from the saturation studies. This ED(50) predicted less than 10% enzyme occupancy at 0.0002 mg of cold (R)-rolipram per kilogram (mass/body weight). Low-occupancy imaging at 0.00018 +/- 0.00002 mg/kg produced a mean Logan slope of 5.5 +/- 0.85 mL/cm(3). Enzyme saturation of more than 90%, compared with low-occupancy conditions, occurred at more than 0.02 mg/kg, with a complete blocking dose (>1 mg of (R) rolipram per kilogram) resulting in a Logan slope of 3.3 +/- 0.1 mL/cm(3), representing a 40% reduction. Compared with baseline, a Logan slope of 6.8 +/- 0.7 mL/cm(3) in desipramine-challenged animals was observed, representing a 30% increase due to acute norepinephrine stimulation, despite a reduction in myocardial blood flow. Intrarat and intraoperator variability was less than 5% between repeated measures. CONCLUSION: (R)-(11)C-rolipram shows the ability to monitor increases and decreases in PDE4 availability in the rat myocardium, with good reproducibility. PMID- 21270458 TI - Conjoint Statement of the SNM, ACNM, and ABNM on credentialing and delineation of privileges for therapeutic procedures using radiopharmaceuticals. PMID- 21270459 TI - The odontogenic keratocyst: a cyst, or a cystic neoplasm? AB - The odontogenic keratocyst (OKC, currently designated by the World Health Organization as a keratocystic odontogenic tumor) is a locally aggressive, cystic jaw lesion with a putative high growth potential and a propensity for recurrence. Although it is generally agreed that some features of OKCs are those of a neoplasia, notably the relatively high proliferative rate of epithelial cells, controversies over the behavior and management of OKCs still exist. This article is intended to review this intriguing entity and to summarize the findings of recent studies related to the nature of OKCs and their clinical and therapeutic implications. Recent advances in genetic and molecular research, i.e., PTCH1 mutations and involvement of the Hedgehog signaling pathway, have led to increased knowledge of OKC pathogenesis which hints at potential new treatment options, although the question of whether the OKC is a cyst or a cystic neoplasm is yet to be answered with certainty. Since some advocate a more conservative treatment for OKCs, notably marsupialization and decompression, future treatment strategies may focus on molecular approaches and eventually reduce or eliminate the need for aggressive surgeries. PMID- 21270460 TI - LPS promotes pre-osteoclast activity by up-regulating CXCR4 via TLR-4. AB - Lipopolysaccharide (LPS) has been shown to be a prominent pathogenic factor in inflammatory bone loss. However, knowledge of the mechanisms involved is limited. The role of the SDF-1/CXCR4 (Stromal-derived factor-1 and its unique chemokine receptor) axis in LPS-induced bone loss has not been studied. The aim of this study was to investigate the role of the SDF-1/CXCR4 axis in LPS-stimulated inflammatory bone loss. The results show that LPS does not influence the expression of SDF-1/CXCR4 in osteoblasts, but up-regulates the expression of CXCR4 in pre-osteoclasts via Toll-like receptor 4, which subsequently enhances pre-osteoclast migration. Moreover, LPS promoted RANKL-induced osteoclast differentiation partially through CXCR4 up-regulation. In conclusion, the present study demonstrated, for the first time, that the up-regulated expression of CXCR4 in pre-osteoclasts by LPS stimulation is involved in LPS-induced bone resorption. PMID- 21270461 TI - The roles of angiotensin II in stretched periodontal ligament cells. AB - The loading caused by occlusion and mastication plays an important role in maintaining periodontal ligament (PDL) tissues. We hypothesized that a loading magnitude would be involved in the production of biological factors that function in the maintenance of PDL tissues. Here, we identified up-regulated gene expressions of transforming growth factor-beta1 (TGF-beta1), alkaline phosphatase (ALP), and angiotensinogen in human PDL fibroblastic cells (HPLFs) that were exposed to 8% stretch loading. Immunolocalization of angiotensin I/II (Ang I/II), which was converted from angiotensinogen, was detected in rat PDL tissues. HPLFs that were stimulated by Ang II also increased their gene expressions of TGF-beta1 and ALP. Furthermore, the antagonist for Ang II type 2 receptor, rather than for type 1, significantly inhibited gene expressions induced by the stretch loading. Analysis of these data suggests that Ang II mediates the loading signal in stretched HPLFs to induce expressions of TGF-beta1 and ALP. PMID- 21270462 TI - Five-year incidence of periodontal disease is related to body mass index. AB - Numerous cross-sectional epidemiological studies suggest that obesity is associated with periodontal disease. This longitudinal study tested whether body mass index (BMI) was related to the development of periodontal disease in a sample of employed Japanese participants. Data are from the statutory medical checkups routinely collected for employees in and around Nagoya, Japan. The authors tested the relationship between BMI at baseline and the 5-year incidence of periodontal disease in a sample of 2787 males and 803 females. The hazard ratios for developing periodontal disease after 5 years were 1.30 (P < .001) and 1.44 (P = .072) in men and 1.70 (P < .01) and 3.24 (P < .05) in women for those with BMIs of 25-30 and >= 30, respectively, compared to those with BMI < 22, after adjusting for age, smoking status, and clinical history of diabetes mellitus. These findings demonstrate a dose-response relationship between BMI and the development of periodontal disease in a population of Japanese individuals. PMID- 21270463 TI - Biomarkers of fluoride in children exposed to different sources of systemic fluoride. AB - There has been no comparison between fluoride concentrations in urine and nails of children exposed to different sources of systemic fluoride. The aim of this study was to compare the relationship between fluoride intake with urinary fluoride excretion and fluoride concentrations in fingernails and toenails of children receiving fluoride from artificially fluoridated water (0.6-0.8 mg F/L, n = 25), naturally fluoridated water (0.6-0.9 mg F/L, n = 21), fluoridated salt (180-200 mg F/Kg, n = 26), and fluoridated milk (0.25 mg F, n = 25). A control population was included (no systemic fluoride, n = 24). Fluoride intake from diet and dentifrice, urinary fluoride excretion, and fluoride concentrations in fingernails/toenails were evaluated. Fluoride was analyzed with an ion-selective electrode. Urinary fluoride excretion in the control community was significantly lower when compared with that in the fluoridated cities, except for the naturally fluoridated community. However, the same pattern was not as evident for nails. Both urinary fluoride output and fluoride concentrations in fingernails/toenails were significantly correlated to total fluoride intake. However, the correlation coefficients for fluoride intake and urinary fluoride output were lower (r = 0.28, p < 0.01) than those observed for fingernails/toenails (r = 0.36, p < 0.001), suggesting that nails might be slightly better indicators of fluoride intake at the individual level. PMID- 21270465 TI - Disease-associated N-terminal complement factor H mutations perturb cofactor and decay-accelerating activities. AB - Many mutations associated with atypical hemolytic uremic syndrome (aHUS) lie within complement control protein modules 19-20 at the C terminus of the complement regulator factor H (FH). This region mediates preferential action of FH on self, as opposed to foreign, membranes and surfaces. Hence, speculation on disease mechanisms has focused on deficiencies in regulation of complement activation on glomerular capillary beds. Here, we investigate the consequences of aHUS-linked mutations (R53H and R78G) within the FH N-terminal complement control protein module that also carries the I62V variation linked to dense-deposit disease and age-related macular degeneration. This module contributes to a four module C3b-binding site (FH1-4) needed for complement regulation and sufficient for fluid-phase regulatory activity. Recombinant FH1-4(V62) and FH1-4(I62) bind immobilized C3b with similar affinities (K(D) = 10-14 MUM), whereas FH1-4(I62) is slightly more effective than FH1-4(V62) as cofactor for factor I-mediated cleavage of C3b. The mutant (R53H)FH1-4(V62) binds to C3b with comparable affinity (K(D) ~12 MUM) yet has decreased cofactor activities both in fluid phase and on surface-bound C3b, and exhibits only weak decay-accelerating activity for C3 convertase (C3bBb). The other mutant, (R78G)FH1-4(V62), binds poorly to immobilized C3b (K(D) >35 MUM) and is severely functionally compromised, having decreased cofactor and decay-accelerating activities. Our data support causal links between these mutations and disease; they demonstrate that mutations affecting the N-terminal activities of FH, not just those in the C terminus, can predispose to aHUS. These observations reinforce the notion that deficiency in any one of several FH functional properties can contribute to the pathogenesis of this disease. PMID- 21270466 TI - Influenza-associated encephalopathy with elevated antibody titers to pandemic (H1N1) 2009 influenza. AB - Pandemic H1N1 influenza (pH1N1) has been associated with encephalopathy, but the role of adaptive immunity in disease pathogenesis remains unclear. A child presented with seizures 5 days after onset of respiratory symptoms with pH1N1, with no detectable virus in cerebrospinal fluid. The authors compared her serum cytokines and pH1N1 antibody titers to those of 22 children with pH1N1, seasonal influenza, or other respiratory viral infections. They also compared her cerebrospinal fluid biomarkers to those of 20 children with confirmed or probable central nervous system infection or viral infection without central nervous system involvement. Her serum antibody titers were several-fold higher, and levels of proinflammatory cytokines in cerebrospinal fluid and serum were lower than those of controls. Antibody titers in cerebrospinal fluid were undetectable. The delayed onset of neurologic manifestations, normal cytokine levels in serum and cerebrospinal fluid, markedly elevated hemagglutinating and neutralizing antibody titers, and absence of virus and antibodies in cerebrospinal fluid raise the possibility of a post-infectious autoimmune-mediated process. PMID- 21270467 TI - Idiopathic hypersomnia: a report of three adolescent-onset cases in a two generation family. AB - Idiopathic hypersomnia is an uncommon sleep disorder characterized by prolonged sleep time and excessive daytime sleepiness without cataplexy. This study concerned a case of familial occurrence. The proband expressed an idiopathic hypersomnia with long sleep time at the age of 12 years. Clinical interview and ad libitum polysomnographic study did not reveal any symptoms of narcolepsy or other sleep disorders. Family history revealed that a 20-year-old sister had experienced symptoms of hypersomnia from the age of 16 and their mother had been diagnosed with idiopathic hypersomnia previously. The diagnosis of idiopathic hypersomnia with long sleep time was confirmed in the sister by clinical interview and ad libitum polysomnography. Human leukocyte antigen (HLA) did not reveal the DQB1-0602 phenotype in the proband and relatives. This report confirms the hypothesis of a genetic predisposition in idiopathic hypersomnia. PMID- 21270468 TI - Functional outcomes of multilevel botulinum toxin and comprehensive rehabilitation in cerebral palsy. AB - The objective of this study was to measure the effect of lower extremity multilevel botulinum toxin A injections and comprehensive rehabilitation on spasticity and to determine the functional gains in ambulatory children with cerebral palsy. Sixteen ambulatory children with spastic cerebral palsy (9 hemiplegic, 7 diplegic), aged between 3 and 8 years, who were able to walk with or without assistance (Gross Motor Functional Classification System I-III) were recruited to the study. Botulinum toxin A injections were applied to a total of 23 extremities, followed by a comprehensive rehabilitation program. Walking distance and walking speed (evaluated by the Six-Minute Walk Test) were significantly improved after treatment. Similarly, scores on the Observational Gait Scale (assessed by video gait analysis) increased significantly. Improvements in muscle length, spasticity, and selectivity were recorded. Reduced muscle spasticity after botulinum toxin A injections in children with cerebral palsy, with a comprehensive rehabilitation program, enabled clinically relevant improvements in functional ability. PMID- 21270469 TI - Predictors of outcome in term infants with neonatal seizures subsequent to intrapartum asphyxia. AB - The objective of this study was to define potential clinical prognostic factors for term infants with neonatal seizures subsequent to intrapartum asphyxia. The authors completed a retrospective analysis of 62 term infants with clinical neonatal seizures subsequent to intrapartum asphyxia. Logistic regression analysis was applied to determine the independent prognostic indicators of an adverse outcome. A total of 23 (37%) infants had a normal outcome, 34 (55%) survived with 1 or more neurodevelopmental impairments (23 cerebral palsy, 28 global developmental delay, 15 epilepsy, with 18 combination of two, and 9 all three), and 5 (8%) died. Six variables were associated with an adverse outcome, but only the presence of meconium aspiration, a low (<= 3) 1-minute Apgar score, seizure type other than focal clonic, and moderately severely abnormal electroencephalography (EEG) background findings were independently associated with an adverse outcome. Signs of acute distress are predictors of adverse outcome, alongside seizure semiology and moderate to severe EEG background abnormalities. PMID- 21270470 TI - Role of methylenetetrahydrofolate reductase gene (MTHFR) 677C>T polymorphism in pediatric cerebrovascular disorders. AB - Homozygosity for the methylenetetrahydrofolate reductase (MTHFR) 677C>T mutation (MTHFR TT) has been linked to an increased risk for stroke, coronary artery disease, and migraine headaches. The authors analyzed the potential link between MTHFR 677C>T homozygosity and childhood stroke. A true association might facilitate screening, recurrence risk stratification, and treatment in patients with cerebrovascular disease. They performed a retrospective chart review of children tested for the MTHFR 677C>/T mutation; 533 patients underwent MTHFR testing, and 8% were homozygous for the MTHFR 677C>T mutation. There was no difference in the cohort compared with the prevalence in the general population. This suggests that the MTHFR 677 C>T polymorphism played a minimal role or no role in stroke risk. However, the data suggest that the MTHFR TT genotype may influence migraine susceptibility in children because there was a higher proportion of migraine patients (28.6%) with the MTHFR TT homozygous genotype. PMID- 21270471 TI - Magnetic resonance spectroscopy in the diagnostic evaluation of brainstem lesions in Alexander disease. AB - Alexander disease is a progressive neurodegenerative disease, which can present with brainstem lesions with imaging characteristics similar to multifocal low grade glioma, thus presenting a diagnostic dilemma. The authors report a 6-year old child presenting with multifocal brainstem lesions subsequently diagnosed to have Alexander disease. In vivo magnetic resonance spectroscopy generated a metabolite profile of the lesion allowing differentiation from low-grade glioma. Magnetic resonance spectroscopy is a powerful tool in the assessment of brainstem lesions and is a useful adjunct to conventional magnetic resonance imaging in the assessment and diagnosis of atypical brain lesions. PMID- 21270472 TI - Histidyl-tRNA synthetase urzymes: Class I and II aminoacyl tRNA synthetase urzymes have comparable catalytic activities for cognate amino acid activation. AB - Four minimal (119-145 residue) active site fragments of Escherichia coli Class II histidyl-tRNA synthetase were constructed, expressed as maltose-binding protein fusions, and assayed for histidine activation as fusion proteins and after TEV cleavage, using the (32)PP(i) exchange assay. All contain conserved Motifs 1 and 2. Two contain an N-terminal extension of Motif 1 and two contain Motif 3. Five experimental results argue strongly for the authenticity of the observed catalytic activities: (i) active site titration experiments showing high (~0.1 0.55) fractions of active molecules, (ii) release of cryptic activity by TEV cleavage of the fusion proteins, (iii) reduced activity associated with an active site mutation, (iv) quantitative attribution of increased catalytic activity to the intrinsic effects of Motif 3, the N-terminal extension and their synergistic effect, and (v) significantly altered K(m) values for both ATP and histidine substrates. It is therefore plausible that neither the insertion domain nor Motif 3 were essential for catalytic activity in the earliest Class II aminoacyl-tRNA synthetases. The mean rate enhancement of all four cleaved constructs is ~10(9) times that of the estimated uncatalyzed rate. As observed for the tryptophanyl tRNA synthetase (TrpRS) Urzyme, these fragments bind ATP tightly but have reduced affinity for cognate amino acids. These fragments thus likely represent Urzymes (Ur = primitive, original, earliest + enzyme) comparable in size and catalytic activity and coded by sequences proposed to be antisense to that coding the previously described Class I TrpRS Urzyme. Their catalytic activities provide metrics for experimental recapitulation of very early evolutionary events. PMID- 21270473 TI - Methodological issues in negative symptom trials. AB - Individuals from academia, the pharmaceutical industry, and the US Food and Drug Administration used a workshop format to discuss important methodological issues in the design of trials of pharmacological agents for improving negative symptoms in schizophrenia. The issues addressed included the need for a coprimary functional measure for registration trials; the characteristics of individuals who should enter negative symptom trials; the optimal duration for a proof-of concept or registration trial; the optimal design of a study of a broad-spectrum agent that treats both positive and negative symptoms or a co-medication that is added to an antipsychotic; the relative strengths and weaknesses of available instruments for measuring negative symptoms; the definition of clinically meaningful improvement for these trials; and whether drugs can be approved for a subdomain of negative symptoms. PMID- 21270474 TI - From the ideal market to the ideal clinic: constructing a normative standard of fairness for human subjects research. AB - Preventing exploitation in human subjects research requires a benchmark of fairness against which to judge the distribution of the benefits and burdens of a trial. This paper proposes the ideal market and its fair market price as a criterion of fairness. The ideal market approach is not new to discussions about exploitation, so this paper reviews Wertheimer's inchoate presentation of the ideal market as a principle of fairness, attempt of Emanuel and colleagues to apply the ideal market to human subjects research, and Ballantyne's criticisms of both the ideal market and the resulting benchmark of fairness. It argues that the criticism of this particular benchmark is on point, but the rejection of the ideal market is mistaken. After presenting a complete account of the ideal market, this paper proposes a new method for applying the ideal market to human subjects research and illustrates the proposal by considering a sample case. PMID- 21270475 TI - [Cell therapy for central nervous system disorders]. PMID- 21270476 TI - [Targeting methods in deep brain stimulation for Parkinson's disease]. PMID- 21270477 TI - [The study of spinal abnormalities associated with cloacal exstrophy]. AB - The treatment of spinal abnormalities with cloacal exstrophy is controversial. Ten cases of this complex treated at Hyogo Prefectural Kobe Children's Hospital between 1991 and 2010 are presented. In our series, all 10 patients had tethered spinal cords. In addition, there were 3 terminal myelocystoceles, 2 meningoceles, 7 lipomas, 5 thickened filums and 3 syrinxes. Eight of 10 patients underwent surgery, and no patient deteriorated. All 3 patients with terminal myelocystocele had lower extremity weakness, but motor functions in two patients improved after surgery. All 4 patients with lipoma and/or thickened filum were asymptomatic. Two of them were conservatively treated, and they remain asymptomatic. Terminal myelocystocele and symptomatic syrinx should be surgically treated. PMID- 21270478 TI - [Exacerbation of radiation induced meningioma due to hemorrhage after cerebral angiography: a case report]. AB - We report the case of a 34-year-old woman who exhibited acute deterioration in her condition after cerebral angiography for evaluation of a large meningioma. She had undergone surgery and irradiation for a glioma in the right occipital lobe 23 years before this episode. She experienced incapacity at work. On CT and MRI, a large meningioma was detected on the left frontal convexity; this tumor was thought to be radiation-induced. Cerebral angiography was performed to assess the vascularization of the tumor. Her condition began to deteriorate 2.5 h after the cerebral angiography. CT revealed an increase in the mass of the tumor, and a high density area in the tumor. We immediately removed the tumor. Histopathological examination revealed the tumor to be a meningothelial meningioma. New hemorrhagic foci were identified in the tumor. In addition, macrophages containing hemosiderin were detected, and some of the tumor vessels exhibited hyaline degeneration. We suspected that angiography triggered bleeding in the meningioma, which was already predisposed to hemorrhage. PMID- 21270479 TI - [Schwannoma developing in the psoas major muscle: a case report]. AB - Schwannoma can occur wherever peripheral nerve Schwann cells are found. However, retroperitoneal schwannoma is extremely rare in that only 16 cases have been reported, including that of the present patient. A 51-year-old male complained of chronic lower back pain and paresthesia in the lower left region. Lower back pain increased with leftward bending. Magnetic resonance imaging (MRI) revealed a neoplastic lesion about 6 cm in diameter in the left psoas major muscle, and the lesion was in contact with the L4 and L5 vertebral bodies. The tumor did not continue to the lumbar foramen. The symptom had become disabling, therefore tumor removal was performed using Wiltse's approach. From intraoperative findings, the origin of the tumor was suspected to be the L4 nerve root. The ventral surface of the tumor could not be observed with this posterior approach. Lumbar plexus might adhere closely to the ventral surface of the tumor, therefore the capsule of the tumor was left to avoid neurological deterioration. Schwannoma was diagnosed by pathological analysis, and no malignancy was evident. After the operation, symptoms were completely relieved, and the residual capsule of the tumor diminished in size on MRI after 12 months. The posterior Wiltse's approach can be useful to treat mass lesions in the psoas major muscle. The 16 reported cases of retroperitoneal schwannoma, including that of the present patient, are reviewed. PMID- 21270480 TI - [Flow diversion by double-overlapping-stent for fusiform vertebral artery aneurysm: a case report]. AB - The authors present the case of a 61-year-old male with a de novo fusiform vertebral artery aneurysm, probably due to non-traumatic dissection. He underwent flow diversion therapy, using a double overlapping technique, because the origin of the contralateral vertebral artery was stenotic. Placement of two stents resulted in marked reduction of blood flow in the aneurysm. Postoperative course was uneventful. Follow-up 3D-CT angiography revealed a patent blood flow in the stent and a gradual progression of intra-aneurysmal thrombosis. Flow diversion therapy can potentially obliterate the complicated cerebral aneurysm with the preservation of blood flow in the parent artery, and would be one of the important therapeutic options in patients with complicated aneurysms in which conventional strategies such as neck clipping, endovascular coiling and parent artery occlusion are not feasible or contraindicated. PMID- 21270481 TI - [Congenital anomalies in the central nervous system (2) molecular biology in pediatric neurosurgery]. PMID- 21270482 TI - Multiwall carbon nanotubes as MRI contrast agents for tracking stem cells. AB - In this study we investigate the potential of multiwall carbon nanotubes (MWCNTs) with low metal impurities (2.57% iron) as magnetic resonance imaging (MRI) contrast agents. Taking into account probable aggregation at high MWCNTs concentration analysis shows that the r(2) relaxivity of MWCNTs in 1% agarose gels at 19 degrees C is 564 +/- 41 s(-1) mM(-1); this is attributed to both the presence of iron oxide impurities and also to the carbon MWCNT structure itself. Stem cells were labelled with MWCNTs to demonstrate the effectiveness of MWCNTs as MRI contrast agents for cellular MRI. The MWCNTs did not impair cell viability or proliferation. These results suggest that the MRI contrast agent properties of the MWCNTs could be used in vivo for stem cell tracking/imaging and during MWCNT mediated targeted electro-chemotherapy of tumours. PMID- 21270483 TI - The fabrication of highly ordered silver nanodot patterns by platinum assisted nanoimprint lithography. AB - Silver has been widely used for optical sensing and imaging applications which benefit from localized surface plasmon resonance (LSPR) in a nanoscale configuration. Many attempts have been made to fabricate and control silver nanostructures in order to improve the high performance in sensing and other applications. However, a fatal mechanical weakness of silver and a lack of durability in oxygen-rich conditions have disrupted the manufacturing of reproducible nanostructures by the top-down lithography approach. In this study, we suggest a steady fabrication strategy to obtain highly ordered silver nanopatterns that are able to provide tunable LSPR characteristics. By using a protecting layer of platinum on a silver surface in the lithography process, we successfully obtained large-area (2.7 * 2.7 mm(2)) silver nanopatterns with high reproducibility. This large-area silver nanopattern was capable of enhancing the low concentration of a Cy3 fluorescence signal (~10(-10) M) which was labeled with DNA oligomers. PMID- 21270484 TI - Electrical transport properties of peptide nanotubes coated with gold nanoparticles via peptide-induced biomineralization. AB - We present temperature dependent electrical transport measurements of peptide nanotube devices coated with monodisperse arrays of gold nanoparticles (AuNP). As the temperature is lowered, the current-voltage (I-V) characteristics become increasingly nonlinear and below 20 K conduction only occurs above a threshold voltage V(T). The current follows the scaling behavior I ? [(V - V(T))/V(T)]alpha for V > V(T) with alpha ~ 2.5 signifying two-dimensional (2D) charge transport. The temperature dependence of the resistance shows thermally activated behavior with an activation energy of 18.2 meV corresponding to the sequential tunneling of charges through 6 nm monodispersed AuNP arrays grown on a peptide surface. PMID- 21270485 TI - Temperature effects on the occurrence of long interatomic distances in atomic chains formed from stretched gold nanowires. AB - The origin of long interatomic distances in suspended gold atomic chains formed from stretched nanowires remains the object of debate despite the large amount of theoretical and experimental work. Here, we report new atomic resolution electron microscopy observations acquired at room and liquid-nitrogen temperatures and theoretical results from ab initio quantum molecular dynamics on chain formation and stability. These new data are suggestive that the long distances are due to contamination by carbon atoms originating from the decomposition of adsorbed hydrocarbon molecules. PMID- 21270486 TI - Flow-dependent directional growth of carbon nanotube forests by chemical vapor deposition. AB - We demonstrated that the structural formation of vertically aligned carbon nanotube (CNT) forests is primarily affected by the geometry-related gas flow, leading to the change of growth directions during the chemical vapor deposition (CVD) process. By varying the growing time, flow rate, and direction of the carrier gas, the structures and the formation mechanisms of the vertically aligned CNT forests were carefully investigated. The growth directions of CNTs are found to be highly dependent on the nonlinear local gas flows induced by microchannels. The angle of growth significantly changes with increasing gas flows perpendicular to the microchannel, while the parallel gas flow shows almost no effect. A computational fluid dynamics (CFD) model was employed to explain the flow-dependent growth of CNT forests, revealing that the variation of the local pressure induced by microchannels is an important parameter determining the directionality of the CNT growth. We expect that the present method and analyses would provide useful information to control the micro- and macrostructures of vertically aligned CNTs for various structural/electrical applications. PMID- 21270487 TI - Structure and nano-mechanical characteristics of surface oxide layers on a metallic glass. AB - Owing to their low elastic moduli, high specific strength and excellent processing characteristics in the undercooled liquid state, metallic glasses are promising materials for applications in micromechanical systems. With miniaturization of metallic mechanical components down to the micrometer scale, the importance of a native oxide layer on a glass surface is increasing. In this work we use TEM and XPS to characterize the structure and properties of the native oxide layer grown on Ni(62)Nb(38) metallic glass and their evolution after annealing in air. The thickness of the oxide layer almost doubled after annealing. In both cases the oxide layer is amorphous and consists predominantly of Nb oxide. We investigate the friction behavior at low loads and in ambient conditions (i.e. at T = 295 K and 60% air humidity) of both as-cast and annealed samples by friction force microscopy. After annealing the friction coefficient is found to have significantly increased. We attribute this effect to the increase of the mechanical stability of the oxide layer upon annealing. PMID- 21270488 TI - Controlling spatial density and size of nanocrystals by two-step atomic layer deposition. AB - Two-step atomic layer deposition (ALD) is proposed in order to control both the spatial density and size of nanocrystals (NCs) via modulation of the nucleation rate during deposition. In this process, two different deposition conditions are sequentially used: a high nucleation rate condition for the formation of high density NCs and a low nucleation rate condition with a slow growth rate for the subsequent growth of pre-formed NCs. To control the nucleation rate of Ru during ALD, pulsing time and carrier flow rate of the Ru precursor are varied. By controlling those factors, both the film growth rate and a nucleation rate of Ru are decreased considerably. Two-step ALD of Ru NCs using the surface-saturated condition followed by the reduced condition allows for variation of the spatial density from 7.9 * 10(11) to 3.2 * 10(12) cm(-2) and variation of the average diameter from 1.9 to 3.3 nm. PMID- 21270489 TI - Nanodevices come to life. PMID- 21270490 TI - Selective-area catalyst-free MBE growth of GaN nanowires using a patterned oxide layer. AB - GaN nanowires (NWs) were grown selectively in holes of a patterned silicon oxide mask, by rf-plasma-assisted molecular beam epitaxy (PAMBE), without any metal catalyst. The oxide was deposited on a thin AlN buffer layer previously grown on a Si(111) substrate. Regular arrays of holes in the oxide layer were obtained using standard e-beam lithography. The selectivity of growth has been studied varying the substrate temperature, gallium beam equivalent pressure and patterning layout. Adjusting the growth parameters, GaN NWs can be selectively grown in the holes of the patterned oxide with complete suppression of the parasitic growth in between the holes. The occupation probability of a hole with a single or multiple NWs depends strongly on its diameter. The selectively grown GaN NWs have one common crystallographic orientation with respect to the Si(111) substrate via the AlN buffer layer, as proven by x-ray diffraction (XRD) measurements. Based on the experimental data, we present a schematic model of the GaN NW formation in which a GaN pedestal is initially grown in the hole. PMID- 21270491 TI - Processive behaviour of kinesin observed using micro-fabricated cantilevers. AB - The mechanical characterization of biomolecular motors requires force sensors with sub-piconewton resolution. The coupling of a nanoscale motor to this type of microscale sensors introduces structural deformations in the motor according to the thermally activated degrees of freedom of the sensor. At present, no simple solution is available to reduce these effects. Here, we exploit the advantages of micro-fabricated cantilevers to produce a force sensor with essentially one degree of freedom and a spring constant of 0.03 pN nm(-1) for the study of the molecular motor protein kinesin-1. During processive runs, the cantilever constrains the movement of the cargo binding domain of kinesin in a straight line, parallel to the microtubule track, and excludes specific reaction coordinates such as cargo rotation. In these conditions, we measured a step size of 8.0 +/- 0.4 nm and a maximal unloaded velocity of 820 +/- 80 nm s(-1) at saturated adenosine triphosphate (ATP) concentration. We concluded that the motor does not need to rotate its tail as it moves through consecutive stepping cycles. PMID- 21270492 TI - Growth of carbon nanotube field emitters on single strand carbon fiber: a linear electron source. AB - The multi-stage effect has been revisited through growing carbon nanotube field emitters on single strand carbon fiber with a thickness of 11 um. A prepared linear electron source exhibits a turn-on field as low as 0.4 V um(-1) and an extremely high field enhancement factor of 19,300, when compared with those results from reference nanotube emitters grown on flat silicone wafer; 3.0 V um( 1) and 2500, respectively. In addition, we introduce a novel method to grow nanotubes uniformly around the circumference of carbon fibers by using direct resistive heating on the continuously feeding carbon threads. These results open up not only a new path for synthesizing nanocomposites, but also offer an excellent linear electron source for special applications such as backlight units for liquid crystal displays and multi-array x-ray sources. PMID- 21270493 TI - Bias-dependent conductive characteristics of individual GeSi quantum dots studied by conductive atomic force microscopy. AB - The bias-dependent electrical characteristics of individual self-assembled GeSi quantum dots (QDs) are investigated by conductive atomic force microscopy. The results reveal that the conductive characteristics of QDs are strongly influenced by the applied bias. At low (-0.5 to - 2.0 V) and high (-2.5 to - 4.0 V) biases, the current distributions of individual GeSi QDs exhibit ring-like and disc-like characteristics respectively. The current of the QD's central part increases more quickly than that of the other parts as the bias magnitude increases. Histograms of the magnitude of the current on a number of QDs exhibit the same single-peak feature at low biases, and double- or three-peak features at high biases, where additional peaks appear at large-current locations. On the other hand, histograms of the magnitude of the current on the wetting layers exhibit the same single peak feature for all biases. This indicates the conductive mechanism is significantly different for QDs and wetting layers. While the small-current peak of QDs can be attributed to the Fowler-Nordheim tunneling model at low biases and the Schottky emission model at high biases respectively, the large-current peak(s) may be attributed to the discrete energy levels of QDs. The results suggest the conductive mechanisms of GeSi QDs can be regulated by the applied bias. PMID- 21270494 TI - Improving anticancer activity and reducing systemic toxicity of doxorubicin by self-assembled polymeric micelles. AB - In an attempt to improve anticancer activity and reduce systemic toxicity of doxorubicin (Dox), we encapsulated Dox in monomethoxy poly(ethylene glycol) poly(epsilon-caprolactone) (MPEG-PCL) micelles by a novel self-assembly procedure without using surfactants, organic solvents or vigorous stirring. These Dox encapsulated MPEG-PCL (Dox/MPEG-PCL) micelles with drug loading of 4.2% were monodisperse and ~ 20 nm in diameter. The Dox can be released from the Dox/MPEG PCL micelles; the Dox-release at pH 5.5 was faster than that at pH 7.0. Encapsulation of Dox in MPEG-PCL micelles enhanced the cellular uptake and cytotoxicity of Dox on the C-26 colon carcinoma cell in vitro, and slowed the extravasation of Dox in the transgenic zebrafish model. Compared to free Dox, Dox/MPEG-PCL micelles were more effective in inhibiting tumor growth in the subcutaneous C-26 colon carcinoma and Lewis lung carcinoma models, and prolonging survival of mice bearing these tumors. Dox/MPEG-PCL micelles also induced lower systemic toxicity than free Dox. In conclusion, incorporation of Dox in MPEG-PCL micelles enhanced the anticancer activity and decreased the systemic toxicity of Dox; these Dox/MPEG-PCL micelles are an interesting formulation of Dox and may have potential clinical applications in cancer therapy. PMID- 21270495 TI - Editorial: The alliance of mental health and education regarding the needs for services for the young. PMID- 21270496 TI - The Israel Survey of Mental Health Among Adolescents: aims and methods? AB - OBJECTIVE: The Israel Survey of Mental Health among Adolescents (ISMEHA) aimed to ascertain the prevalence of selected mental disorders and patterns of comorbidity, service utilization and unmet needs, health and sociodemographic covariates, and risk and protective factors. This paper reviews the methods used and discusses the strengths and limitations of the survey. METHOD: The ISMEHA was a cross-sectional survey that included 957 Israeli adolescents, representative of the adolescent population aged 14-17 years. The Strengths and Difficulties Questionnaire, Hebrew version (SDQ-H), the Development and Well-Being Assessment (DAWBA) inventory, services utilization, health status and sociodemographic questions were administered to adolescents and their mothers at the respondents homes between January 2004 and March 2005. RESULTS: The overall response rate was 68.2%, and it varied by gender and type of locality. Among boys, 71.3% responded, as compared to 65.2% among girls. The response rate among adolescents living in a Jewish or mixed city was 62.5% as compared to 89.6% among adolescents living in an exclusively Arab-populated city. CONCLUSIONS: The ISMEHA allows the creation of a unique and comprehensive database informing on the prevalence, burden, services utilization and unmet needs of adolescents with psychiatric disorders. These data will enable policymakers to more rationally plan services and prevention programs for the target population. PMID- 21270497 TI - Postpartum depression: a chronicle of health policy development. AB - The current report presents an example of the path taken from identification of a public health problem at the primary health service level, to conducting research documenting the scope of the problem and nature of the risk factors, disseminating the findings, and fostering development and application of relevant policy. The example presented is the case of postpartum depression, an issue with bio-psycho-social implications. Public health nurses identified the problem, prompting epidemiological research. The findings encouraged the Ministry of Health (MOH) to conduct a pilot program for screening and early intervention among pregnant and postpartum women reporting depressive symptoms. Based on the results of the pilot program, the MOH is expanding the program to all Mother Child Health (MCH) clinics. Israel?s largest Health Maintenance Organization has followed suit and is including this program in its own clinics. This Israeli experience may serve as an instructive example of a locally identified problem evolving into a national policy. PMID- 21270498 TI - Guardianship appointment: current status in Israel. AB - The appointment of a guardian is an important complex process that significantly infringes upon the individuals liberty and autonomy; however it is a necessary paternalistic intervention when called for. The law does not provide precise criteria for the appointment of a guardian, though physicians have tried to determine criteria for the initiation of the process. The authors present a review of the various aspects of the assessment of the need for guardianship and the appointment process for guardians for adults in Israel. The medical document that will ultimately determine the need for the appointment of a guardian for an elderly person should be the product of a comprehensive medical, psychiatric and cognitive evaluation and an accurate evaluation of competence. PMID- 21270499 TI - Health-related quality of life two years after injury due to terrorism. AB - BACKGROUND: During the past few decades, terrorist acts have been an unfortunate reality worldwide. There is a striking paucity of research investigating the multitude of long-term outcomes after severe physical injury due to terrorist attacks, a unique subgroup of trauma patients. The purpose of this study was to provide a profile of the long-term health-related quality of life (HR-QOL) after injury due to terrorist attacks and to explore the relationships between Post Traumatic Stress Disorder (PTSD), occupational status and injury severity with HR QOL. METHODS: We included 35 survivors of terrorist attacks living in the community, two years on average after the injury, mean age at follow-up = 32.1 (+/-13.8), mean Injury Severity Score (ISS) = 27 (+/-14.2). The subjects were recruited from consecutive admissions to a rehabilitation department in a tertiary care center between September 2000 - June 2004. Most of the subjects suffered multiple trauma. The main outcome measures were the Short-Form Health Survey (SF-36), Post Traumatic Diagnostic Scale and return to work rates. RESULTS: The mean scores on 6/8 of the SF-36 subscales were significantly lower among the survivors compared to normative population norms. Post Traumatic Stress Disorder (PTSD) was found in 39% of the sample and 43% did not resume their main occupation two years after the injury. Multivariate analysis of variance of PTSD and occupational status (returned vs. did not return to work) on quality of life scores revealed significant main effects for both PTSD (p=. 000) and occupational status (p=. 005) with no interaction effect (p=. 476). No significant correlations were found between injury severity and the SF-36 scores. CONCLUSIONS: This study demonstrated the long-term impact of injury due to terrorism. Results showed independent effects of PTSD and occupational status on health related quality of life, two years after injury. These findings suggest that this group may benefit from intervention focusing on their emotional and occupational status in order to improve their quality of life. PMID- 21270500 TI - Combat exposure, posttraumatic stress symptoms and risk-taking behavior in veterans of the Second Lebanon War. AB - Prior research has revealed heightened risk-taking behavior among veterans with posttraumatic stress disorder (PTSD). This study examined whether the risktaking behavior is a direct outcome of the traumatic exposure or whether this relationship is mediated by posttraumatic stress symptoms. The sample was comprised of 180 traumatized Israeli reserve soldiers, who sought treatment in the wake of the Second Lebanon War. Combat exposure was indirectly associated with risk-taking behavior primarily through its relationship with posttraumatic stress symptoms. Results of the multivariate analyses depict the implication of posttraumatic stress symptoms in risk taking behavior, and the role of self medication and of aggression in traumatized veterans. PMID- 21270501 TI - The relationship between type of insurance, time period and length of stay in psychiatric hospitals: the Israeli case. AB - BACKGROUND: According to the current standard of practice in modern medicine, medical decision-making is often forced to comply with stipulations of the insurance provider. In the field of psychiatry, there has been a trend of shortened psychiatric hospitalizations which some have suggested may be due to pressures related to insurance coverage. In Israel, soldiers have comprehensive medical coverage provided by the military, and this coverage includes full payment for psychiatric hospitalizations. In contrast, Israeli civilians are insured by the government according to a global payment system. In this study, we aimed to examine differences between these two groups in terms of length of stay (LOS) in psychiatric hospitals. METHODS: Data on psychiatric admissions of soldiers (aged 18-21) spanning the past 30 years was obtained from the military database (N=2,106). Corresponding data was collected on first psychiatric hospitalizations of a cohort of matched civilians (N=6556). The mean LOS of the two groups was compared. RESULTS: Civilians had a significantly longer LOS than soldiers. Moreover, LOS decreased between the seventies and the nineties for both groups, and the decrease was observed for all diagnoses regardless of disease severity. DISCUSSION: We conclude that in the managed care era, economic considerations may at times take precedence over psychiatric ones, irrespective of the degree of severity of illness. The parallel process is manifested in a general trend towards deinstitutionalization in the United States, Canada and Europe. PMID- 21270502 TI - Self-estimation of performance time versus actual performance time in older adults with suspected mild cognitive impairment: a clinical perspective. AB - BACKGROUND: Estimation of the passage of time has received marginal attention in contemporaneous psychiatric assessment and diagnosis. There is disagreement regarding the ability of older adults with dementia, particularly of the Alzheimers type, to estimate time passage, and there is lack of data concerning the ability of older adults in the early stages of cognitive impairment to estimate the passage of time. OBJECTIVE: We investigated the hypothesis that individuals with mild dementia perform worse compared to those with no cognitive impairment, and that those with mild cognitive impairment (MCI) assume an intermediate position in terms of their ability to accurately estimate time passage. Another objective was to study demographic and clinical (cognitive, functional, psychiatric) predictors of self-estimation of performance time versus actual performance time. METHOD: In the context of a comprehensive psychogeriatric evaluation, three performance time measures were established: actual performance time, subjective estimation of performance time, and accuracy of estimation of performance time. RESULTS: 102 consecutive persons with suspected MCI were assessed. Final cognitive diagnoses were: dementia 49 (48%), MCI 36 (35%), no cognitive impairment (NCI) 17 (17%). Whereas there were significant group differences (dementia, MCI, NCI) on all cognitive measures and on functional impairment, there were no significant group differences on the three time measures. With the exception of age, estimation of performance time was not associated with any of the other demographic and clinical variables. CONCLUSION: Self-estimation of performance time versus actual performance time was not found impaired either in the dementia group or in the MCI group when compared to participants without cognitive impairment. PMID- 21270503 TI - Male genital self-mutilation as a psychotic solution. AB - BACKGROUND: Male genital self-mutilation (GSM) is a rare, but serious phenomenon. Some of the risk factors for this act are: presence of religious delusions, command hallucinations, low self-esteem and feelings of guilt associated with sexual offences. Other risk factors include failures in the male role, problems in the early developmental period, such as experiencing difficulties in male identification and persistence of incestuous desires, depression and having a history of GSM. The eponym Klingsor Syndrome, which involves the presence of religious delusions, is proposed for GSM. DATA SECTION: Four male GSM cases are presented: Case 1 and Case 2 were diagnosed with schizophrenia, Case 3 with schizophrenia and depressive disorder, not otherwise specified, and Case 4 with bipolar depression with psychotic features. DISCUSSION: All definite and probable motives and cultural aspects for their GSM are discussed. Atonement is proposed as a new concept in formulating religiously themed psychotic male GSM. PMID- 21270504 TI - Predictors of cumulative length of psychiatric inpatient stay over one year: a national case register study. AB - BACKGROUND: Prior studies have shown inconsistent results regarding predictors of length of stay (LOS) and of readmission in psychiatric hospitals. "Cumulative LOS" over a given period, which reflects both LOS and readmission, has not been examined so far in a systematic way. The Israel Psychiatric Case Register in Israel made it possible to examine predictors of Cumulative LOS in a nationwide, representative sample. METHOD: All hospitalization admissions during a six-month period in Israel were recorded and followed-up for one year. The variables predicting Cumulative LOS over one year were identified through a Cox regression. RESULTS: The median Cumulative LOS during one year was 43.0 days, and only 1.7% of the patients remained hospitalized for more than one year after admission. The variables significantly predicting longer Cumulative LOS were: Jewish ethnicity, a diagnosis of schizophrenia or other functional psychosis, prior hospitalization, compulsory admission and Northern and Jerusalem districts of hospitalization (which have a lower admission rate). LIMITATIONS: Lack of information on severity of pathology and type of treatment. CONCLUSION: Cumulative LOS, which reflects both the length of each inpatient episode and the rate of readmission, is affected not only by clinical factors,but also by the cultural background of the patient population and by administrative factors such as bed pressure. PMID- 21270505 TI - Diagnosing ADHD in Israeli adults: the psychometric properties of the adult ADHD Self Report Scale (ASRS) in Hebrew. AB - This paper argues for the importance of diagnosing ADHD in adults, while acknowledging the many attendant difficulties. The paper presents results from two studies implementing the Adult ADHD Self Report Screen (ASRS) in Hebrew. The Hebrew version of the ASRS as approved by the World Health Organization is appended to this paper. The first of the two studies used a paper and pencil version of the ASRS (ASRS_PP) and the second used a computer administered version (ASRS_C). A subset of the participants in the two studies was given both versions. The Hebrew ASRS had excellent test-retest reliability. It had good internal consistency in both forms. Support for the validity of the Hebrew ASRS is given by the significantly higher scores of adults with ADHD versus those without, on both versions of the ASRS and on all of its subscales. The sensitivity of the raw sum of all 18 items was significantly higher than that of the 6-item screen suggested by the authors of the ASRS. The sensitivity and specificity of the ASRS in Hebrew should be further examined in future studies including clinically referred participants. The benefit of using the ASRS as part of the diagnostic process for adult ADHD is discussed. PMID- 21270506 TI - Genetic controls of Th17 cell differentiation and plasticity. AB - CD4+ T lymphocytes play a major role in regulation of adaptive immunity. Upon activation, naive T cells differentiate into different functional subsets. In addition to the classical Th1 and Th2 cells, several novel effector T cell subsets have been recently identified, including Th17 cells. There has been rapid progress in characterizing the development and function of Th17 cells. Here I summarize and discuss on the genetic controls of their differentiation and emerging evidence on their plasticity. This information may benefit understanding and treating immune diseases. PMID- 21270507 TI - Clusterin protects H9c2 cardiomyocytes from oxidative stress-induced apoptosis via Akt/GSK-3beta signaling pathway. AB - Clusterin is a secretory glycoprotein, which is highly up-regulated in a variety of normal and injury tissues undergoing apoptosis including infarct region of the myocardium. Here, we report that clusterin protects H9c2 cardiomyocytes from H2O2 induced apoptosis by triggering the activation of Akt and GSK-3beta. Treatment with H2O2 induces apoptosis of H9c2 cells by promoting caspase cleavage and cytochrome c release from mitochondria. However, co-treatment with clusterin reverses the induction of apoptotic signaling by H2O2, thereby recovers cell viability. The protective effect of clusterin on H2O2-induced apoptosis is impaired by PI3K inhibitor LY294002, which effectively suppresses clusterin induced activation of Akt and GSK-3beta. In addition, the protective effect of clusterin is independent on its receptor megalin, because inhibition of megalin has no effect on clusterin-mediated Akt/GSK-3beta phosphoylation and H9c2 cell viability. Collectively, these results suggest that clusterin has a role protecting cardiomyocytes from oxidative stress and the Akt/GSK-3beta signaling mediates anti-apoptotic effect of clusterin. PMID- 21270508 TI - Targeted thyroid testing in acute illness: achieving success through audit. AB - Thyroid tests are done in acutely ill patients who often have confusing transient thyroid abnormalities, despite a lack of clarity about intervention and cost benefit. A retrospective analysis of patients admitted to the Medical Assessment Unit (MAU) was undertaken in 2004 to assess the frequency and utility, pattern of abnormalities and cost of thyroid testing. Guidelines were issued and the audit was repeated in 2008. 53.8% of 1593 subjects were offered thyroid tests in 2004 with a significant reduction to 21.7% of 1176 in 2008 (p<0.001). Free T4 or TSH was outside the reference range in 11.2% (2004) and 7.5% (2008) (p=0.10) and low TSH (52.7% in 2004 and 64.3% in 2008) was commonly combined with normal free T4. Appropriate indications for testing were documented in 43.9 vs 73.7% of patients with abnormal thyroid results (p=0.004) and in 14.3 vs 16% (2004 vs 2008) of a random sample of subjects with normal thyroid results, respectively (p=0.77). Documentation of intervention (25.5. vs 92.9%; p=0.001) and follow-up (45.5 vs 85.7%; p=0.001) had also improved significantly in 2008. We have demonstrated a significant reduction in thyroid testing in acutely ill patients after audit and the issue of guidelines. We currently recommend thyroid tests only in those with previous thyroid disease, the presence of clinical features and risk factors for thyroid disease, the use of relevant drugs, and unexplained tachydysrhythmias. The difficulties in interpreting results, the lack of clarity about intervention and follow up and possible cost savings would argue against an unrestricted policy. PMID- 21270509 TI - Expression of CRABP1, GRP, and RERG mRNA in clinically non-functioning and functioning pituitary adenomas. AB - BACKGROUND: Pituitary tumors account for approximately 10-15% of intracranial neoplasms. AIM: Using the cDNA microarray method, we have previously compared expression under two distinct conditions: a pool of 4 clinically non-functioning pituitary adenomas (NFPA) and a spinal cord metastasis of a non-functioning pituitary carcinoma, in order to gain biological insights into genomic changes of pituitary neoplasias. In the present study, we further investigated the mRNA expression of 3 selected genes previously described as being involved in other neoplasias based on a series of 60 pituitary adenomas: CRABP1 (cellular retinoic acid binding protein 1), GRP (gastrin-releasing peptide), and RERG (Ras-related, estrogen- regulated, growth inhibitor). MATERIAL AND METHODS: The expression of CRABP1, GRP, and RERG was determined by quantitative RT-PCR. RESULTS: A significantly higher content of CRABP1 mRNA was observed in NFPA compared to functioning adenomas, and PRL-secreting adenomas showed a lower expression of this gene compared to normal pituitary. A lower expression of GRP mRNA was detected in NFPA compared to normal pituitary and also to functioning adenomas. RERG mRNA was overexpressed in NFPA in comparison to functioning adenomas and to normal pituitary. Among the functioning adenomas, only the ACTH-secreting adenomas presented a higher expression of RERG mRNA compared to normal pituitary. CONCLUSIONS: The findings of differential expression of CRABP1 in prolactinomas and of RERG in NFPA compared to normal pituitary suggests that retinoic acid and estrogen receptor, respectively, could be involved in the tumorigenesis of these adenomas subtypes. Additional studies are required to further confirm this hypothesis. PMID- 21270510 TI - Prevalence of metabolic syndrome in rural and urban Chinese population in Qingdao. AB - AIMS: To investigate the prevalence of metabolic syndrome and its components in both rural and urban Chinese population. SUBJECTS AND METHODS: A population-based crosssectional survey was conducted in Qingdao, China in 2006 with 6100 Chinese aged 35-74 yr invited and 5355 who attended; 3357 subjects, 1562 urban (46.5%) and 1795 rural residents (53.5%) met the inclusion criteria for the current data analysis. The metabolic syndrome definitions of National Cholesterol Education Program Adult Treatment Expert Panel III (NCEPATPIII) 2004, NCEP 2005 and International Diabetes Federation (IDF) were used. RESULTS: The age-standardized prevalences of metabolic syndrome were 16.2%, 32.2%, and 28.3% in men and 26.8%, 37.2%, and 34.6%in women, according to the definitions of the NCEP 2004, NCEP 2005, and IDF, respectively. Urban men have more risk factors and higher prevalence of the metabolic syndrome than rural men, but the differences in women were not that striking. Elevated blood pressure (62.6%) was, among risk factors, most common in the study population, followed by central obesity (53.4%), and hyperglycemia (52.2%) defined using the NCEP 2005 criteria. CONCLUSIONS: Metabolic disorders were common among adult Chinese in both rural and urban areas in Qingdao. PMID- 21270511 TI - Growth hormone treatment in adults with growth hormone deficiency: the transition. AB - The approval of GH treatment of adults with GH deficiency (GHD) raises issues regarding continuation of GH treatment in the GH-deficient child following achievement of near adult height. The transition period begins in late puberty and ends with full adult maturation and includes hormonal and many lifestyle changes. Children treated with GH should be retested near the time of reaching adult height to determine if they have persistence of GHD. Although most children with organic causes of GHD will again be found to have GHD on retesting, most of those with idiopathic GHD will not. Retesting usually involves measurement of IGF I and stimulation with insulin-induced hypoglycemia or arginine-GHRH, but important questions remain about adjustment of established cut-offs for age and body mass index. Most studies have shown the benefit of GH treatment in young adults with GHD in body composition, especially the achievement of peak bone mass. It is important for pediatric endocrinologists to discuss the potential need for continued treatment beyond achievement of adult height at the time of initiation of GH treatment, especially in those children with organic causes of GHD. PMID- 21270512 TI - Two novel DAX1 gene mutations in Chinese patients with X-linked adrenal hypoplasia congenita: clinical, hormonal and genetic analysis. AB - Mutations in the DAX1 gene result in X-linked congenital adrenal hypoplasia (AHC). Affected boys usually present with primary adrenal failure in early infancy or childhood and hypogonadotropic hypogonadism (HH) at puberty. This paper describes the clinical, hormonal, radiological, and genetic characteristics of 2 Chinese patients with X-linked AHC. Primary adrenal insufficiency occurred in the 2 patients during their childhood and HH was recognized at puberty. Genomic DNA was extracted from their peripheral blood leukocytes and coding sequence abnormalities of the DAX1 gene were assessed by PCR and direct sequencing analysis. Genetic analysis of the DAX1 gene revealed 2 novel mutations c.572-575 dupGGGC, p.Thr193Gly,fs,205X and c.773- 774 dupCC, p.Ser259Pro,fs,264X in exon 1, causing frameshifts and yeilding premature stop codons at 205 and 264, respectively. This study identifies 2 novel mutations in the DAX1 gene which can further expand the mutation database and benefit patients in the diagnosis and treatment of AHC. PMID- 21270513 TI - Therapy mediated by mitophagy abrogates tumor progression. AB - Autophagy is mainly a cellular recycling process that promotes survival, but it can also cause cell death if cell injury persists. The role of mitophagy in tumorigenesis remains uncertain. Other cell death types, such as apoptosis or necrosis, are often altered during tumor development and therefore are not ideal targets to generate efficient antitumor therapies. We have used the system linamarase/linamarin/glucose oxidase (lis/lin/GO) to eliminate tumor cells. This therapeutic strategy is based on the combination of cyanide and oxidative stress to abrogate tumor growth. After severe mitochondrial insult by lis/lin/GO, the electron transport chain is blocked and hydrogen peroxide production increased. This triggers a degradative phase of these damaged organelles inducing mitophagy that finally leads to cell death. This death process depends on the vacuole generation, BNIp3 and the formation of autolysosomes. Importantly, evasion of apoptosis is known to result in resistance to anti-cancer therapies but this inhibition also augments sensitivity to autophagy, which could be used to promote tumor regression. We explored the potential of this powerful mitophagy-inducing system in vitro and in vivo to eradicate human malignant tumors. PMID- 21270514 TI - I think autophagy controls the death of my cells: what do I do to get my paper published? PMID- 21270515 TI - More than MAX: Discovering the Myc interactome. PMID- 21270516 TI - Loss of CC3/TIP30 allows tumor cells to cope with low glucose. PMID- 21270517 TI - Selective targeting of histone methylation. AB - Histones are post-translationally modified by multiple histone-modifying enzymes, which in turn influences gene expression. Much of the work in the field to date has focused on genetic, biochemical and structural characterization of these enzymes. The most recent genome-wide methods provide insights into specific recruitment of histone-modifying enzymes in vivo and, therefore, onto mechanisms of establishing a differential expression pattern. Here we focus on the recruitment mechanisms of the enzymes involved in the placement of two contrasting histone marks, histone H3 lysine 4 (H3K4) methylation and histone H3 lysine 27 (H3K27) methylation. We describe distribution of their binding sites and show that recruitment of different histone-modifying proteins can be coordinated, opposed, or alternating. Specifically, genomic sites of the H3K4 histone demethylase KDM5A become accessible to its homolog KDM5B in cells with a lowered KDM5A level. The currently available data on recruitment of H3K4/H3K27 modifying enzymes suggests that the formed protein complexes are targeted in a sequential and temporal manner, but that additional, still unknown, interactions contribute to targeting specificity. PMID- 21270518 TI - Multiple faces of FoxM1 transcription factor: lessons from transgenic mouse models. AB - FoxM1 transcription factor (previously called HFH-11B, Trident, FoxM1b, Win, and MPP2) is expressed in actively dividing cells and critical for cell cycle progression. FoxM1 expression is induced in a variety of tissues during embryogenesis, and Foxm1 (-/-) mice exhibit embryonic lethal phenotype due to multiple abnormalities in the liver, heart, lung and blood vessels. FoxM1 levels are dramatically decreased in adult tissues, but FoxM1 expression is re-activated during organ injury and numerous cancers. In this review, we discussed the role of FoxM1 in different cell lineages using recent data from transgenic mouse models with conditional "gain-of-function" and "loss-of-function" of FoxM1, as well as tissue samples from human patients. In addition, we provided experimental data showing additional sites of FoxM1 expression in the mouse embryo. Novel cell autonomous roles of FoxM1 in embryonic development, organ injury and cancer formation in vivo were analyzed. Potential application of these findings for the diagnosis and treatment of human diseases were discussed. PMID- 21270519 TI - MicroRNAs in skeletal myogenesis. AB - MicroRNAs (miRNAs) have emerged as critical regulators of numerous biological processes by modulating gene expression at the post-transcriptional level. It has become increasingly clear that almost all aspects of skeletal muscle development involve regulation by miRNAs. Many of these miRNAs have distinct expression profiles in skeletal muscles, under the regulation by the myogenic program. In the last few years the field has seen a rapid expansion of our knowledge of myogenic miRNAs that target a wide range of muscle genes to coordinately control the myogenic process. In this review we provide an up-to-date list of reported myogenic miRNAs and survey their expression patterns, regulation of biogenesis, and gene targets in skeletal muscles. Emerging themes of miRNA regulation in the context of skeletal myogenesis will also be discussed. PMID- 21270520 TI - Distinct and redundant functions of histone deacetylases HDAC1 and HDAC2 in proliferation and tumorigenesis. AB - Histone deacetylases (HDACs) are negative regulators of gene expression and have been implicated in tumorigenesis and tumor progression. Therefore, HDACs are promising targets for anti-tumor drugs. However, the relevant isoforms of the 18 members encompassing HDAC family have not been identified. Studies utilizing either gene targeting or knockdown approaches reveal both specific and redundant functions of the closely related class I deacetylases HDAC1 and HDAC2 in the control of proliferation and differentiation. Combined ablation of HDAC1 and HDAC2 in different cell types led to a severe proliferation defects or enhanced apoptosis supporting the idea that both enzymes are relevant targets for tumor therapy. In a recent study on the role of HDAC1 in teratoma formation we have reported a novel and surprising function of HDAC1 in tumorigenesis. In this tumor model HDAC1 attenuates proliferation during teratoma formation. In the present work we discuss new findings on redundant and unique functions of HDAC1 and HDAC2 as regulators of proliferation and tumorigenesis and potential implications for applications of HDAC inhibitors as therapeutic drugs. PMID- 21270521 TI - Unexpected role of nucleoporins in coordination of cell cycle progression. AB - Many human cancers have irregular chromosome content, a condition known as aneuploidy. Several nuclear pore proteins (nucleoporins/Nups) that mediate transport of RNA or macromolecules into and out of the nucleus have been implicated in mitosis. These nucleoporins are involved in molecular networks that function in a variety of mitotic processes, including chromosome condensation, sister chromatid cohesion, kinetochore assembly and spindle formation. An alteration in the concentration of Nups inside cells often causes aneuploidy. In this review, we discuss this sprouting area and the possible functions of Nups during mitosis. PMID- 21270522 TI - In vitro and in vivo anticancer action of Saquinavir-NO, a novel nitric oxide derivative of the protease inhibitor saquinavir, on hormone resistant prostate cancer cells. AB - The NO-derivative of the HIV protease inhibitor saquinavir (Saq-NO) is a nontoxic variant of the parental drug with enhanced anticancer activity on several cell lines. However, it is still unclear whether the p53 status of the target cell might influence the sensitivity to Saq-NO. In this study we evaluated the in vitro and in vivo activity of Saq-NO on the p53-deficient hormone resistant prostate cancer PC-3 cells. We demonstrate that the absence of functional p53 is not essential for the capacity of Saq-NO to reduce prostate cancer cell growth. In contrast to its previously described cytostatic action in B16 and C6 cell lines, Saq-NO exerted cytotoxic effects in PC-3 cells leading to dominant induction of apoptosis and enhanced production of proapoptotic Bim. In addition, differently from saquinavir, Saq-NO restored TRAIL sensitivity that was correlated with increased expression of DR5 independent from ROS/RNS production and YY1 repression. NF-kappaB activation may be responsible of the Saq-NO induced DR5 expression. Moreover, Saq-NO but not saquinavir, exerted synergistic activity with conventional cytostatic therapy. In agreement with these in vitro studies, Saq-NO inhibited the in vivo growth of PC-3 cells xenotransplants to a greater extent than the parental compound. Taken together, these data indicate that Saq NO possesses powerful and suitable in vitro and in vivo chemotherapeutic potential to be further studied as a novel drug for the treatment of prostate cancer in the clinical setting. PMID- 21270523 TI - Role of nucleosomes in mitotic bookmarking. PMID- 21270524 TI - BRCA1, microRNAs and cancer predisposition: challenging the dogma. PMID- 21270525 TI - PKCepsilon paves the way for prostate cancer. PMID- 21270526 TI - A tale of three PKCs: epsilon emerges as a driver of pre-neoplastic phenotypes. PMID- 21270527 TI - MicroRNA expression analysis in triple-negative (ER, PR and Her2/neu) breast cancer. AB - miRNAs are small, regulatory molecules approximately 21-24 nucleotides in length. They function at the post-transcriptional level by controlling the expression of more than 50% of human protein-coding genes and play an essential role in cell signaling pathways. The objective of the present study was to explore the expression profile of oncomiRs and tumor-suppressor miRs, and to define their possible correlations in triple-negative (ER, PR and Her2/neu) primary breast cancers. Forty-nine primary triple-negative breast cancer cases, along with 34 matched tumor-associated normal samples were investigated for the expression of 9 miRNAs using qPCR. Relationships between the expression of miR-10b, miR-21, miR 122a, miR-145, miR-205, miR-210, miR-221, miR-222 and miR-296 and the pathologic features of the tumors were examined, as were the influences of miR expression on patient overall and cancer-specific survival. miR-21, miR-210 and miR-221 were significantly overexpressed, whereas miR-10b, miR-145, miR-205, miR-122a were significantly underexpressed in the triple-negative primary breast cancers. Significant correlations among all of the studied miRs were scored both in the breast cancer and control tissue. Expression of miR-222 and miR-296 did not exhibit any significant difference between the breast cancer and normal tissue. There was a non-significant trend for high expression levels of the microRNAs, miR-21, miR-210, miR-221 and miR-222, to be associated with worse patient disease free and overall survival. miR-21, miR-210 and miR-221 expression plays a significant role in triple- negative primary breast cancers. PMID- 21270528 TI - An example of functional interaction between NFAT5/TonEBP and nuclear factor kappaB by hypertonic stress: aquaporin-2 transcription. PMID- 21270529 TI - You'd better catch that Wnt: primitive hematopoiesis requires canonical Wnt signaling. PMID- 21270530 TI - It never rains but it pours: potential role of butyrophilins in inhibiting anti tumor immune responses. PMID- 21270531 TI - A non-glycosylated, plant-produced human monoclonal antibody against anthrax protective antigen protects mice and non-human primates from B. anthracis spore challenge. AB - The health and economic burden of infectious diseases in general and bioterrorism in particular necessitate the development of medical countermeasures. One proven approach to reduce the disease burden and spread of pathogen is treatment with monoclonal antibodies (mAb). mAbs can prevent or reduce severity of the disease by variety of mechanisms, including neutralizing pathogen growth, limiting its spread from infected to adjacent cells, or by inhibiting biological activity of toxins, such as anthrax lethal toxin. Here, we report the production of glycosylated (pp-mAb (PA) ) and non-glycosylated (pp-mAb (PANG) ) versions of a plant-derived mAb directed against protective antigen (PA) of Bacillus anthracis in Nicotiana benthamiana plants using agroinfiltration. Both forms of the antibody were able to neutralize anthrax lethal toxin activity in vitro and protect mice against an intraperitoneal challenge with spores of B. anthracis Sterne strain. A single 180 ug intraperitoneal dose of pp-mAb (PA) or pp-mAb (PANG) provided 90% and 100% survival, respectively. When tested in non-human primates, pp-mAb (PANG) was demonstrated to be superior to pp-mAb (PA) in that it had a significantly longer terminal half-life and conferred 100% protection against a lethal dose of aerosolized anthrax spore challenge after a single 5 mg/kg intravenous dose compared to a 40% survival rate conferred by pp-mAb (PA) . This study demonstrates the potential of a plant-produced non-glycosylated antibody as a useful tool for the treatment of inhalation anthrax. PMID- 21270532 TI - CHIP and gp78-mediated ubiquitination of CYP3A4: Implications for the pharmacology of anticancer agents. AB - The autocrine motility factor receptor or glycoprotein-78 (gp78) and C-terminus of Hsp70-interacting protein (CHIP) are E3-ligases required for ubiquitination of cytochrome P450s of the 3A subfamily (CYP3A) in endoplasmic reticulum-associated degradation (ERAD). The CYP isozyme 3A4 (CYP3A4) is responsible for the metabolism of the majority of xenobiotics including anticancer agents. Much variability in clinical response to chemotherapy is observed and it has been suggested that variability in CYP3A4 expression could be a factor. The study reviewed in this journal club comments on the importance of further characterizing gp78 and CHIP as relevant proteins in ERAD of CYP3A4. This study demonstrated how both gp78 and CHIP play direct roles in reducing CYP3A4 protein content as well as CYP3A4 ubiquitination. Interestingly, when gp78 and CHIP were knocked down by siRNAs directed towards each protein, the stabilized CYP3A4 remained functional. This has implications for drug-drug interactions for agents metabolized by CYP3A4, which can influence drug exposure levels. This is relevant because most anticancer agents have very narrow therapeutic windows, thus even slight changes in CYP3A4 levels could alter the exposure of that drug and result in either insufficient efficacy or toxicity. Future studies must explore genetic variability in the ERAD pathway and identify new factors that influence CYP3A ERAD in order to better characterize how CYP3A variability affects anticancer drug pharmacology. PMID- 21270533 TI - Melanoma B16-F1 cells coated with fusion protein of mouse calreticulin and virus G-protein coupled receptor induced the antitumor immune response in Balb/C mice. AB - In apoptotic progress of tumor cells stimulated by special agents, the calreticulin (CRT) was relocated from endoplasmic reticulum onto the cell surface. When used as cellular antigen to immunize experimental animals, these CRT-coated apoptotic tumor cells could initiate effective anti-tumor immunoresponse against homologous tumor cells, indicating the value of CRT in anti-tumor immunotherapy. In order to develop an universal technique that could make CRT-coating more efficiently in the tumor cells, in this study, a mouse CRT recombinant gene with virus G-protein coupled receptor (vGPCR) was constructed and cloned into vector pcDNA3.1(+). When resulted plasmid pcDNA3.1(+)-mCRT/ vGPCR was stably transfected into the mouse melanoma B16-F1 cells, the mCRT-vGPCR recombinant protein was synthesized. With the membrane-locating ability of vGPCR in the recombinant protein, mCRT-vGPCR was carried onto the surface of B16-F1 cells efficiently. Overexpression of mCRT-vGPCR on the cell surface could enhance the phagocytosis of B16-F1 by macrophages in vitro. When mCRT-vGPCR coated B16-F1 cells were used as a cell-antigen to immunize mice, the specific anti-tumor immune response against the homologous tumor cells was initiated efficiently. Our data in this study may provide a new possibility for CRT-mediated tumor immune prevention and treatment. PMID- 21270534 TI - Understanding DNA repair and recombination in higher plant genome: information from genome-wide screens in Arabidopsis and rice. AB - Recently we have reported the in silico identification and in depth analysis of genes potentially involve in DNA repair and recombination (DRR) in two fully sequenced higher plant genomes, Arabidopsis and rice. In spite of strong conservation of DRR gene along with all three domain of life, we found some peculiar difference in presence and function of DRR genes in plants. Beside the eukaryotic homologs, several prokaryotes specific genes were also found to be well conserved in both plant genomes. Several functionally important DRR gene duplications were found in Arabidopsis, which do not occur in rice. In spite of the fact that same DRR protein functions in different DNA repair pathways, we found that proteins belonging to the nucleotide excision repair (NER) pathway were relatively more conserved than proteins needed for the other DRR pathways. Identified DRR gene were found to reside in nucleus mainly while gene drain in between nucleus and cell organelles were also found in some cases. Here, we have discussed the peculiar features of DRR genes in higher plant genomes. PMID- 21270535 TI - Aboveground to belowground herbivore defense signaling in maize: a two-way street? AB - Insect pests that attempt to feed on the caterpillar-resistant maize genotype Mp708 encounter a potent, multipronged defense system that thwarts their invasion. First, these plants are on "constant alert" due to constitutively elevated levels of the phytohormone jasmonic acid that signals the plant to activate its defenses. The higher jasmonic acid levels trigger the expression of defense genes prior to herbivore attack so the plants are "primed" and respond with a faster and stronger defense. The second defense is the rapid accumulation of a toxic cysteine protease called Mir1-CP in the maize whorl in response to caterpillar feeding. When caterpillars ingest Mir1-CP, it damages the insect's midgut and retards their growth. In this article, we discuss a third possible defense strategy employed by Mp708. We have shown that foliar caterpillar feeding causes Mir1-CP and defense gene transcripts to accumulate in its roots. We propose that caterpillar feeding aboveground sends a signal belowground via the phloem that results in Mir1-CP accumulation in the roots. We also postulate that the roots serve as a reservoir of Mir1-CP that can be mobilized to the whorl in response to caterpillar assault. PMID- 21270536 TI - Mass spectrometric identification of SUMO substrates provides insights into heat stress-induced SUMOylation in plants. AB - The covalent addition of Small Ubiquitin-Related Modifier (SUMO) to various intracellular proteins is an essential regulatory step in most eukaryotes. Due to its necessity and the large number of putative targets, SUMO is thought to be second only to ubiquitin (Ub) among Ub-fold proteins in terms of regulatory influence. Whereas, ubiquitylation (i.e., the attachment of Ub) is generally associated with protein degradation, SUMOylation appears to have more diverse consequences, including the regulation of transcription, chromatin structure/accessibility, nuclear import, and various protein-protein interactions, and even appears to block the action of Ub by competing for the same binding sites on targets. Paramount to understanding SUMO function(s) is knowing the complete catalog of SUMO targets. In the following addendum we review our recent publication describing the proteomic identification of SUMO substrates in the model plant, Arabidopsis thaliana, and expand our analyses with regard to the changes in SUMOylation patterns that are induced by heat stress. Collectively, our data indicate that SUMOylation is highly dynamic with evidence that SUMO addition globally modifies transcription and chromatin accessibility, especially during stress. PMID- 21270537 TI - The conserved mobility of mitochondria during leaf senescence reflects differential regulation of the cytoskeletal components in Arabidopsis thaliana. AB - Leaf senescence is an organized process, which requires fine tuning between nuclear gene expression, activity of proteases and the maintenance of primary metabolism. Recently, we reported that leaf senescence was accompanied by an early degradation of the microtubule cytoskeleton in Arabidopsis thaliana. As the cytoskeleton is essential for cell stability, vesicle shuttling and organelle mobility, it might be asked how the regulation of these cell functions occurs with such drastic modifications of the cytoskeleton. Based on confocal laser microscopy observations and a micro-array analysis, the following addendum shows that mitochondrial mobility is conserved until the late stages of leaf senescence and provides evidences that the actin-cytoskeleton is maintained longer than the microtubule network. This conservation of actin-filaments is discussed with regards to energy metabolism as well as calcium signaling during programmed cell death. PMID- 21270538 TI - CLE genes may act in a variety of tissues/cells and involve other signaling cascades in addition to CLV3-WUS-like pathways. AB - CLE, which is the term for the CLV3/ESR-related gene family, is thought to participate in CLAVATA3-WUSCHEL (CLV3-WUS) and CLV3-WUS-like signaling pathways to regulate meristem activity in plant. Although some CLE genes are expressed in meristems, many CLE genes appear to express in a variety of tissues/cells. Here we report that CLE14 and CLE20 express in various specific tissues/cells outside the shoot/root apical meristem (SAM/RAM), including in highly differentiated cells, and at different developmental stages. Over-expressing CLE14 or CLE20 also causes multiple phenotypes, which is consistent with its expression pattern in Arabidopsis. These results suggest that CLE genes may play multiple roles and involve other signaling cascades in addition to the CLV3-WUS and CLV3-WUS-like pathways. PMID- 21270539 TI - To transform or not to transform: that is the dilemma in the statistical analysis of plant volatiles. AB - Chemical ecology, be it the study of plant volatiles or insect cuticular hydrocarbons, largely involves the analysis of compositions or "blends" of a mixture of compounds. Compositional data have intrinsic properties such as a "constant-sum constraint" which should be taken into account when statistically analysing these data. The field of compositional data analysis has greatly improved our understanding of the nature of such compositions and has provided us with insights on statistically rigorous ways of analysing such constrained data. Employment of standard multivariate statistical procedures on compositional data necessitates the use of appropriate transformation procedures, which removes the non-independence of data points, thus rendering the data suitable for such analysis. Here we present the current situation of the analysis of compositional data in chemical ecology; the awareness of this constraint of compositional data; and alternative ways of analysing such constrained data using Random Forests, a data-mining algorithm which has many features that facilitate the analysis of such data. Two such features of particular relevance to compositional data are that Random Forests does not incorporate implicit assumptions about the distribution of the data and can deal with auto-correlations between data points. PMID- 21270540 TI - Response of mitochondrial alternative oxidase (AOX) to light signals. AB - Mitochondrial alternative oxidase (AOX), the unique respiratory terminal oxidase in plants, catalyzes the energy wasteful cyanide (CN)-resistant respiration and plays a role in optimizing photosynthesis. Recent studies from our group indicated that AOX plays a crucial role in chloroplast protection under extreme environments, such as high light (HL). Genetic data suggest that AOX is upregulated by light that was mediated by photoreceptors (phytochromes, phototropins and cryptochromes), and it also might have a particular role in relieving the overreduction of chloroplasts. Physiological analyses further suggest that AOX is essential for the dark-to-light transition, especially in de etiolation course. In this mini-review, we highlight recent progresses in understanding the beneficial interaction between photosynthesis and mitochondria metabolism and discuss the possible role and mechanism of AOX in dissipation of excess reduced equivalents for chloroplasts under high light condition. PMID- 21270541 TI - A rodent model of schizophrenia reveals increase in creatine kinase activity with associated behavior changes. AB - Schizophrenia is a debilitating mental disorder characterized by positive (delusions, hallucinations, disorganized speech) and negative (affective flattering, avolition, and social withdrawal) symptoms as well as cognitive deficits. The frequency, severity, and topography characterize the disorder as heterogeneous, the pathophysiology of schizophrenia is poorly understood. Sub anesthetic doses of ketamine produce hyperactivity, stereotypy, and abnormal social interaction and it is used as a model of schizophrenia. In this study, we induced an animal model by acute sub-anesthetic doses of ketamine and tested different behavioral parameters. We also evaluated the activity of creatine kinase (CK) in brain of rats treated with ketamine. Our results demonstrated that administration of 10, 25 and 50 mg/kg of ketamine induced an increase of covered distance in habituated and non-habituated rats to the behavioral apparatus. Ketamine administration induced significant social deficits and stereotypic behavioral in all doses tested. Finally we evaluated the effect of different doses of ketamine on creatinine kinase (CK) activity and we observed that CK activity is increased inspecific regions of the brain. Our study suggests that our animal model may be used as a model of schizophrenia and that cerebral energy metabolism might be altered in the brain of schizophrenic patients, probably leading to alterations that might be involved in the pathogenesis of schizophrenia. PMID- 21270542 TI - Just in the nick of time: targeting acute versus chronic disease. PMID- 21270543 TI - Career guidance and the quality of the dialogue. PMID- 21270545 TI - Virtual patients: are we in a new era? PMID- 21270546 TI - How we can improve physicians' teaching skills. PMID- 21270547 TI - Motivating students to attend basic science lectures. PMID- 21270548 TI - Risks of online forums for premedical and medical students. PMID- 21270549 TI - Why the anatomy demonstratorship should be included in surgical training. PMID- 21270550 TI - Commentary: Adopting postbaccalaureate premedical programs to enhance physician workforce diversity. AB - Postbaccalaureate premedical programs increase the likelihood that students from groups underrepresented in medicine will succeed in matriculating into medical school. Although about 20 U.S. medical schools administer academic enhancer postbaccalaureate programs, they often do so with some ambivalence about whether these premedical programs are truly part of the school's mission as a professional-degree-awarding institution. As a result, these programs often are orphans in the world of medical education and lack adequate institutional support. This commentary discusses findings from recent research demonstrating low attrition rates for postbaccalaureate program completers who attend medical school, and the relatively high interest these students have in practicing in underserved communities after completing their training. The author proposes that a comprehensive strategy for health career pipeline programs should emphasize high-yield strategies at the distal stages, such as postbaccalaureate programs, and then work backward up the educational pipeline toward interventions at earlier educational stages. The Association of American Medical Colleges (AAMC) could play a key role in this effort by creating a standing committee on postbaccalaureate programs within its Group on Diversity and Inclusion. Creating such a committee could send a statement to AAMC member schools about postbaccalaureate programs being integral to the medical school mission and schools' ability to meet Liaison Committee on Medical Education standards on diversity, and could provide an organizational nidus for a national consortium of academic enhancer postbaccalaureate programs. Postbaccalaureate premedical programs deserve to be fully adopted as essential components of a comprehensive physician workforce development strategy. PMID- 21270551 TI - The soul-less note. PMID- 21270552 TI - Commentary: Health care reform and primary care: training physicians for tomorrow's challenges. AB - Although Congress recently passed health insurance reform legislation, the real catalyst for change in the health care delivery system, the author's argue, will be changes to the reimbursement model. To rein in increasing costs, the Centers for Medicare and Medicaid aims to move Medicare from the current fee-for-service model to a reimbursement approach that shifts the risk to providers and encourages greater accountability both for the cost and the quality of care. This level of increased accountability can only be achieved by clinical integration among health care providers. Central to this reorganized delivery model are primary care providers who coordinate and organize the care of their patients, using best practices and evidence-based medicine while respecting the patient's values, wishes, and dictates. Thus, the authors ask whether primary care physicians will be available in sufficient numbers and if they will be adequately and appropriately trained to take on this role. Most workforce researchers report inadequate numbers of primary care doctors today, a shortage that will only be exacerbated in the future. Even more ominously, the authors argue that primary care physicians being trained today will not have the requisite skills to fulfill their contemplated responsibilities because of a variety of factors that encourage fragmentation of care. If this training issue is not debated vigorously to determine new and appropriate training approaches, the future workforce may eventually have the appropriate number of physicians but inadequately trained individuals, a situation that would doom any effort at system reform. PMID- 21270553 TI - Artist statement. "The Disaster Series". PMID- 21270554 TI - Medicine and the arts. Death by John Stone. Commentary. PMID- 21270556 TI - AM last page. Truths about the rural physician supply. PMID- 21270557 TI - Few happy endings for victims of trafficking. PMID- 21270558 TI - The patient's responsibility. PMID- 21270566 TI - Giving blood. PMID- 21270567 TI - The BSN requirement. PMID- 21270568 TI - The future of nursing--making waves. PMID- 21270581 TI - The role of the nurse in combating human trafficking. AB - Human trafficking, also called modern slavery, happens worldwide--and the United States is no exception. Within our borders, thousands of foreign nationals and U.S. citizens, many of them children, are forced or coerced into sex work or various forms of labor every year. Nurses and other health care providers who encounter victims of trafficking often don't realize it, and opportunities to intervene are lost. Although no one sign can demonstrate with certainty when someone is being trafficked, there are several indicators that clinicians should know. This article provides an overview of human trafficking, describes how to recognize signs that a person is being trafficked and how to safely intervene, and offers an extensive resource list. PMID- 21270583 TI - Local anesthesia before IV catheterization. AB - BACKGROUND: Intradermal buffered lidocaine is known to be effective in producing local anesthesia prior to IV catheterization. Recently, intradermal bacteriostatic normal saline has been suggested as a possible alternative. OBJECTIVE: To compare the efficacy of intradermal bacteriostatic normal saline with that of intradermal buffered lidocaine in providing local anesthesia to adult patients prior to IV catheterization. METHODS: In a randomized, double blind, parallel-design, quasiexperimental study, we compared pain ratings of adult patients receiving either intradermal buffered lidocaine or intradermal bacteriostatic normal saline before IV catheterization. We measured pain at venipuncture through the use of a verbal numeric rating scale, used the test to compare group differences, and performed an analysis of covariance to test for outcome differences related to age, sex, and race or ethnicity. RESULTS: The final sample (N = 148) was 65% women and 82% white, with a mean age of 52 years (range, 19 to 80 years). Demographic characteristics between the two treatment groups were similar. Intradermal buffered lidocaine was demonstrated to be significantly superior to intradermal bacteriostatic normal saline in reducing the pain of IV catheterization (P = 0.007). Differences in pain ratings between the two groups were not associated with age, sex, race or ethnicity, catheter size, or location of the IV site. CONCLUSIONS: Intradermal buffered lidocaine was superior to intradermal bacteriostatic normal saline in providing local anesthesia prior to IV catheterization in this group of predominately white adults and should be the solution of choice for venipuncture pretreatment. PMID- 21270585 TI - Managing pediatric asthma exacerbations in the ED. PMID- 21270587 TI - Letters from Afghanistan: Daily life and 'dirty' work. PMID- 21270588 TI - Atrial fibrillation ablation. PMID- 21270589 TI - The last of its kind. PMID- 21270590 TI - Rising Hope: helping parents with life after loss. Interview by Patrice O'Shaughnessy. PMID- 21270597 TI - The wisdom of nursery rhymes. PMID- 21270598 TI - American college of radiology appropriateness criteria. PMID- 21270599 TI - ACR appropriateness criteria postradical prostatectomy irradiation in prostate cancer. AB - The role of postradical prostatectomy radiation therapy continues to evolve under the influence of new clinical data. In particular, 2 recently published or updated randomized trials have prompted a reevaluation of its utility in the adjuvant and salvage setting. The Southwest Oncology Group 8794 trial randomized 473 patients with stage T3a-T3b disease to adjuvant radiotherapy versus observation. With a median follow-up of 12.7 years, this trial demonstrates an improvement in metastasis-free (93/214 vs. 114/211, P = 0.016) and overall survival (88 vs. 110 deaths, P = 0.023) favoring adjuvant radiotherapy. The European Organization for Research and Treatment of Cancer 22911 study of 972 patients with at least 1 "high risk" feature at surgery (extracapsular extension, positive surgical margins, seminal vesicle involvement) randomized to immediate adjuvant radiotherapy (60 Gy) versus observation. The freedom from biochemical failure at 5 years was 53% in the observation alone group versus 74% in the adjuvant radiotherapy group (P < 0.0001). This review summarizes the current evidence-based literature supporting the use of postradical prostatectomy radiation therapy in various common clinical settings and will serve to illustrate the appropriateness of postoperative radiotherapy by reviewing its implementation in a variety of commonly occurring clinical scenarios. It is intended to serve both as a guideline for the practicing radiation oncologist and a resource for further learning. PMID- 21270601 TI - Significance of nuclear p-Akt in endometrial carcinogenesis: rapid translocation of p-Akt into the nucleus by estrogen, possibly resulting in inhibition of apoptosis. AB - INTRODUCTION: Endometrial endometrioid adenocarcinoma (endometrial cancer) develops through endometrial hyperplasia caused by estrogenic hyperstimulation. Estrogen is known to activate growth factor signaling pathways, resulting in cellular proliferation, but precisely how has not been clarified. The aim of this study was to investigate the significance of estrogen and downstream factors such as the MAPK (MEK, ERK) and Akt pathways in endometrial carcinogenesis. METHODS: The expression of p-MEK, p-ERK, and p-Akt was analyzed immunohistochemically in normal, hyperplastic, and neoplastic endometria. The estrogenic effect on p-Akt was examined using an endometrial cancer cell line (Ishikawa cells). The estrogenic effect on the apoptosis of Ishikawa cells was assessed by the TUNEL method. RESULTS: Phospho-MEK (p-MEK) and p-ERK expression levels were similar among histological types but correlated with each other. The nuclear p-Akt labeling index (LI) was higher in cancer than in normal endometrium and hyperplasia. The nuclear p-Akt LI of well-differentiated cancer (G1) was higher than that of moderately (G2) or poorly (G3) differentiated cancers. The nuclear expression of p-Akt was correlated with that of estrogen receptor alpha (ER alpha). The nuclear p-Akt level was significantly correlated with prognosis in cases of G1. In Ishikawa cells transfected with ERalpha, p-Akt was translocated into the nucleus from the cytoplasm in 1 to 3 hours after estrogenic stimulation. Further, apoptosis induced by H2O2 was inhibited by estrogen in the ER-alpha positive cells. CONCLUSIONS: The translocation of p-Akt into the nucleus by estrogen may be related to the suppression of apoptosis by estrogen and consequently to endometrial carcinogenesis and prognosis in G1 endometrial cancer. PMID- 21270602 TI - Kit gene in endometrial carcinoma: an immunohistochemical and mutational analysis. AB - OBJECTIVE: : Because the outcome of recurrent disease of endometrial carcinoma is cumbersome, the development of target treatment strategies is critical. We evaluated KIT, a receptor tyrosine kinase, to determine a potential role for imatinib mesylate in the treatment of endometrial carcinoma. MATERIALS AND METHODS: : Immunohistochemical analysis for KIT expression was performed on paraffin sections from 45 patients: 30 primary and 15 recurrent tumors. Fifteen primary cases were available for mutation analysis. RESULTS: : Histopathological distribution of paraffin-embedded tissue was as follows: 30 type I and 15 type II endometrial carcinoma. Histopathological distribution of fresh-frozen tissue was as follows: 8 type I and 7 type II. Cases did not show KIT expression or mutations in mutational hotspot exons of KIT gene. CONCLUSIONS: : On the basis of the absence of KIT expression or mutations, endometrial carcinoma is unlikely to respond to imatinib mesylate. PMID- 21270603 TI - MYBL2 (B-MYB) in cervical cancer: putative biomarker. AB - INTRODUCTION: Cervical cancer is the second most common cancer affecting women worldwide. It is characterized by chromosomal aberrations and alteration in the expression levels of many cell cycle regulatory proteins. MYBL2 is a member of the MYB proto-oncogene family that encodes DNA binding proteins. These proteins are involved in cell proliferation and control of cellular differentiation. MATERIALS AND METHODS: Four established cervical cancer cell lines were examined and compared with normal cervix using gene expression profiling and comparative genomic hybridization, and results were correlated to identify potential novel cervical cancer biomarkers. Results were validated using TaqMan polymerase chain reaction, and the potential role of MYBL2 as a clinical biomarker was then evaluated by immunohistochemistry on 30 tissue samples. RESULTS: MYBL2 was found to be overexpressed in the cervical cancer cell lines by gene expression profiling, and this result was confirmed using TaqMan polymerase chain reaction. Analysis of comparative genomic hybridization data indicated that chromosome 20q13.1, which encodes the MYBL2 gene, was amplified in the human papillomavirus (HPV) type 16-positive CaSki and SiHa cell lines but not in the HPV-18-positive HeLa or HPV-negative C33A cell lines. DISCUSSION: Although MYBL2 staining was predominantly absent in normal cervical epithelium, strong staining (score of 2 or 3) was identified in all cases of cervical intraepithelial neoplasia, cervical glandular intraepithelial neoplasia, and invasive cancer on immunohistochemistry. In addition, strong staining of a population of diffusely scattered single cells is identified. We postulate that these may represent so-called cancer stem-like cells. PMID- 21270604 TI - Metformin reverses progestin resistance in endometrial cancer cells by downregulating GloI expression. AB - INTRODUCTION: A long-term treatment with progestin commonly results in progestin resistance in endometrial cancer. So, the aim of this study was to investigate the role of glyoxalase I (GloI), a mediator of chemotherapy resistance, in metformin reversal of progestin resistance in endometrial carcinoma. METHODS: The proliferation variety of endometrial cancer cells was determined by 3-(4, 5 dimethylthiazol-2-yl)-2, 5-Diphenyltetrazolium (MTT) assay after exposure to medroxyprogesterone acetate, metformin, or both reagents; apoptosis rates were assessed by flow cytometry. Real-time polymerase chain reaction was used to evaluate the effect of small interfering RNA sequence on target gene expression. Western immunoblotting was performed to determine the expression of GloI and the molecules of the mammalian target of rapamycin (mTOR) pathway. RESULT: Knocking down GloI sensitized progestin-resistant Ishikawa cells to progestin. Metformin downregulated GloI expression, reversed progestin resistance, enhanced progestin induced cell proliferation inhibition, and induced apoptosis in progestin resistant Ishikawa cells. In addition, medroxyprogesterone acetate-induced mTOR phosphorylation was blocked by metformin. Metformin abolishes mTOR phosphorylation and inhibits GloI expression, attenuating proliferation and inducing apoptosis in progestin-resistant Ishikawa cells. CONCLUSIONS: Dysregulation of GloI expression in endometrial cancer may be part of the molecular mechanisms for progestin resistance. PMID- 21270605 TI - Phylogeny and polymorphism in the long control region, E6, and L1 of human papillomavirus types 53, 56, and 66 in central Brazil. AB - INTRODUCTION: Several studies related that different human papillomavirus (HPV) types and intratype variants can present different oncogenic potential. In opposite to HPVs 16 and 18 variants, information about variants of other carcinogenic HPV types is still scarce. The aim of this study was to investigate the genetic variability of HPVs 53, 56, and 66 from Central Brazil isolates. METHODS: The long control region (LCR), E6, and L1 genomic regions were amplified and sequenced. We evaluate for nucleotide variations in relation to the reference sequence of each HPV type and also the conservation of physicochemical properties of the deduced amino acid substitutions. In silico analysis was performed to locate binding sites for transcriptional factors within the LCR. Moreover, we performed a phylogenetic analysis with the Central Brazilian and worldwide sequences available at genomic databases. RESULTS: Gathering LCR, E6, and L1 genomic regions, the highest genetic variability was found among HPV-53 isolates with 52 nucleotide variations, followed by HPVs 56 and 66 with 24 and 16 nucleotide substitutions, respectively. The genetic analysis revealed 11 new molecular variants of all HPV types analyzed, totalizing 31 new nucleotide and 3 new amino acid variations. Eight nonconservative amino acid substitutions were detected, which may indicate a biological and pathogenic diversity among HPV types. Furthermore, 8 nucleotide substitutions were localized at putative binding sites for transcription factors in the LCR with a potential implication on viral oncogene expression. The HPVs 53, 56, and 66 phylogenetic analysis confirmed a dichotomic division only described to HPV subtypes and different from the patterns described for HPVs 16 and 18 variants. CONCLUSIONS: The high genetic variability observed emphasizes the importance of investigating polymorphisms in types other than HPVs 16 or 18 to better understand the molecular genomic profile of viral infection by different HPV types. PMID- 21270606 TI - Ovarian cancer debulking surgery: a survey of practice in Australia and New Zealand. AB - INTRODUCTION: The purpose of our study was to survey all practicing gynecological oncologists in Australia and New Zealand to determine their definition of optimal debulking, their current surgical techniques used to achieve optimal debulking, and their reasons for using or not using such techniques. METHODS: In October 2007, an email survey was distributed to all 42 practicing gynecological oncologists in Australia and New Zealand. Information obtained included practice patterns, as well as surgical expertise, techniques, and rationale with respect to primary debulking surgery for advanced epithelial ovarian cancer. RESULTS: There was an 81% response rate. Fifty-eight percent of respondents considered optimal debulking to be residual disease less than 10 mm, 21% considered it to be less than 5 mm, and 18% considered it to be no visible disease. Sixty-five percent were able to achieve optimal debulking in their patients, as measured by their own criteria. Patient factors considered to be most frequent barriers to optimal debulking were medical comorbidities (91%) and older patient population (59%). Disease findings which most often precluded optimal debulking were disease involving the base of the mesentery (94%), confluent diaphragmatic disease (74%), and large volume, confluent peritoneal disease (50%). A variety of procedures were used by either gynecological oncologists or their colleagues, but more than 50% would never perform resection of diaphragmatic disease, resection of parenchymal liver metastases, or ablation with cavitron ultrasonic surgical aspirator or argon beam. The most common reasons for not performing ultraradical procedures were concerns regarding benefit (39%), concerns regarding morbidity (24%), and lack of personal expertise (24%). CONCLUSIONS: Most gynecological oncologists use a variety of surgical techniques to achieve optimal debulking. However, patient factors as well as concerns regarding benefit and lack of expertise were reasons cited for not performing ultraradical surgery. PMID- 21270607 TI - Prognostic impact of p53, p27, and C-MYC on clinicopathological features and outcome in early-stage (FIGO I-II) epithelial ovarian cancer. AB - INTRODUCTION: The objective of the study was to evaluate the prognostic effect of p53, p27, and C-MYC on clinicopathological features, recurrent disease, and disease-free survival (DFS) of 131 patients with ovarian cancer in International Federation of Gynecology and Obstetrics (FIGO) stages I-II. METHODS: The technique of tissue microarray and immunohistochemistry was used for detection of positivity/overexpression of the biological markers p53, p27, and C-MYC. RESULTS: In the complete series, the 5-year and overall survival rates were 68% and 71%, respectively. Positive staining for p53, p27, and C-MYC was detected in 25%, 57%, and 76% of cases, respectively. Positivity of p53, p27, concomitant p53-p27, C MYC, and C-MYC-p27 status were associated with tumor grade. Positivity of p27 and concomitant p53-p27 were related to serous tumors. In survival analysis, DFS was related to p53, combined p53-p27, and combined p53-C-MYC status. Significant predictive factors for tumor recurrences were the FIGO stage (odds ratio [OR] = 9.8), status of node sampling (OR = 0.2), and p53 status (OR = 3.7) in a logistic regression analysis. In a multivariate Cox regression analysis, FIGO stage (hazard ratio [HR] = 4.3) and p53 status (HR = 3.0) were significant prognostic factors for DFS. In a separate Cox regression analysis, FIGO stage (HR = 2.0) and concomitant p53-p27-C-MYC status (HR = 0.3) were independent prognostic factors for DFS. It was possible to identify a subgroup, constituting 30% of the patients, who had excellent survival with tumors of concomitant p53 negativity, p27 positivity, and C-MYC positivity apart from the clinicopathological factors. Patients in this subgroup were longtime survivors with DFS of 92% at 5 and 9 years. CONCLUSIONS: The results of this study strongly suggest that patients with p53-positive tumors (alone/or combined with p27 and/or C-MYC) had significantly worse survival (DFS) compared with patients with p53-negative tumors. Patients with p53-positive tumors continued to have recurrences after the 5-year follow-up and die in disease. PMID- 21270608 TI - Comparisons of surgical outcomes, complications, and costs between laparotomy and laparoscopy in early-stage ovarian cancer. AB - OBJECTIVES: The purpose of this study was to compare the surgical outcomes, complications, and costs between laparoscopic staging and laparotomic staging for early-stage ovarian cancer. METHODS: We evaluated 113 patients who underwent laparoscopy (n = 26) or laparotomy (n = 87) for staging. We retrospectively analyzed patients' demographics and operative variables, including operative time, estimated blood loss, lymph node count, hospital stay, complications, postoperative pain, and return to normal activity. In addition, costs for laparoscopy and laparotomy groups were also compared. RESULTS: The mean operation time was longer in laparoscopy group compared to laparotomy group (227.6 minutes vs 184.6 minutes, P = 0.016). The laparoscopy group had less intraoperative blood loss, less transfusion requirement, shorter postoperative hospital stay, earlier general diet intake, shorter time to adjuvant chemotherapy, and lower postoperative pain score after 6, 24, and 48 hours compared with the laparotomy group. The mean number of lymph node retrievals was comparable between the groups. The incidence of operative complications was lower in the laparoscopy group (7.7%) relative to the laparotomy group (23.0%). The total average cost for staging completed via laparotomy was $1237 and that via laparoscopy was $1998, with significant difference. CONCLUSIONS: Complete surgical staging by laparoscopy was achieved in all cases with comparable operative time and less operative complications compared with laparotomy for selected patients with early stage ovarian cancer. However, the operation costs for laparoscopy were significantly higher than the operation costs for laparotomic staging surgery. PMID- 21270609 TI - Potential survival benefit of secondary cytoreductive surgery for recurrent epithelial ovarian, tubal, and peritoneal cancers. AB - OBJECTIVE: Although treatment for recurrent epithelial ovarian, tubal, and peritoneal cancers is usually not curative and intends to be palliative, a certain significance of secondary cytoreductive surgery (SCS) for recurrent tumor has been reported; still, there are limitations in this strategy including difficulty in predicting successful complete resection and selecting good candidates. The purpose of this study was to explore the potential survival benefit of SCS in patients with recurrent epithelial ovarian, tubal, and peritoneal cancers. METHODS: Among all patients who underwent primary therapy for epithelial ovarian, tubal, and peritoneal cancers between 1994 and 2006 at our institute, medical records of patients who were submitted to SCS for recurrence following complete remission after primary therapy were retrospectively investigated. Kaplan-Meier method and log-rank test were used for survival analysis, and Cox proportional hazard regression model was used for quantifying the relations between survival and covariates. RESULTS: Thirty-four patients met the inclusion criteria. Complete resection of all visible tumors at SCS was achieved in 24 of patients (75%). Median postrecurrence survival was 60 months. On univariate analysis, solitary recurrence, disease-free interval, CA125 value at recurrence, and complete resection were significant prognostic factors on postrecurrence survival; whereas on multivariate analysis, CA125 value at recurrence and complete resection were independent prognostic factors. In addition, a comparison according to the initial method that detected recurrence revealed that patients whose recurrence was detected with CA125 elevations had significantly worse postrecurrence survival than those detected with routine examinations including image scans (P = 0.021). CONCLUSIONS: In the present study, the impact of SCS on the significant survival benefit was identified for patients with low CA125 value at recurrence as well as with complete resection. Although further analyses are needed, patients whose recurrence was diagnosed by routine examinations without CA125 elevation might be better candidates for SCS. PMID- 21270610 TI - Genome-wide de novo methylation in epithelial ovarian cancer. AB - BACKGROUND: DNA methylation regulates gene expression during development. The methylation pattern is established at the time of implantation. CpG islands are genome regions usually protected from methylation; however, selected islands are methylated later. Many undergo methylation in cancer, causing epigenetic gene silencing. Aberrant methylation occurs early in tumorigenesis, in a specific pattern, inhibiting differentiation.Although methylation of specific genes in ovarian tumors has been demonstrated in numerous studies, they represent only a fraction of all methylated genes in tumorigenesis. OBJECTIVES: To explore the hypermethylation design in ovarian cancer compared with the methylation profile of normal ovaries, on a genome-wide scale, thus shedding light on the role of gene silencing in ovarian carcinogenesis.Identifying genes that undergo de novo methylation in ovarian cancer may assist in creating biomarkers for disease diagnosis, prognosis, and treatment responsiveness. METHODS: DNA was collected from human epithelial ovarian cancers and normal ovaries. Methylation was detected by immunoprecipitation using 5-methyl-cytosine-antibodies. DNA was hybridized to a CpG island microarray containing 237,220 gene promoter probes. Results were analyzed by hybridization intensity, validated by bisulfite analysis. RESULTS: : A total of 367 CpG islands were specifically methylated in cancer cells. There was enrichment of methylated genes in functional categories related to cell differentiation and proliferation inhibition. It seems that their silencing enables tumor proliferation. CONCLUSIONS: This study provides new perspectives on methylation in ovarian carcinoma, genome-wide. It illustrates how methylation of CpG islands causes silencing of genes that have a role in cell differentiation and functioning. It creates potential biomarkers for diagnosis, prognosis, and treatment responsiveness. PMID- 21270611 TI - Wnt5a as a predictor in poor clinical outcome of patients and a mediator in chemoresistance of ovarian cancer. AB - INTRODUCTION: Wnt5a regulates numerous signaling pathways controlling a wide range of cellular processes, including cell proliferation, differentiation, and apoptosis. However, it is still unclear whether Wnt5a is involved in mediating chemoresistance in cancer. We studied the correlation of Wnt5a expression with clinicopathologic parameters and survival in epithelial ovarian cancer and the effect of Wnt5a expression on chemoresistance of ovarian cancer cells. METHODS: Wnt5a expression was immunohistochemically examined in ovarian cancer, benign tumor, and normal ovarian tissues. Two stable cell lines were established, namely, SKOV3/Wnt5a, which overexpressed Wnt5a, and SKOV3/miRNA, which downregulated Wnt5a expression using microRNA (miRNA). Wnt5a expression level was evaluated by semiquantitative reverse transcription-polymerase chain reaction, Western blot analysis, and immunofluorescence assay. The sensitivity of all transfected and untransfected cell lines to chemotherapeutic drugs (paclitaxel, oxaliplatin, 5-fluorouracil, epirubicin, and etoposide) was detected by 3-(4,5 dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay. RESULTS: Wnt5a was found to be significantly higher in ovarian cancer compared with benign tumors and normal ovaries. High levels of Wnt5a expression were associated with the International Federation of Gynecology and Obstetrics stage and significantly predicted a poorer overall survival and progression-free survival compared with low Wnt5a expression. In addition, Wnt5a overexpression in SKOV3/Wnt5a cells decreased chemosensitivity compared with normal and empty vector controls (P < 0.05). Alternatively, Wnt5a down-regulation in SKOV3/miRNA cells led to a significant increase in chemosensitivity (P < 0.05). CONCLUSIONS: Wnt5a immunoreactivity may be a useful prognostic indicator in patients with ovarian cancer. These results clarified for the first time the possibility that Wnt5a plays an important role in regulating chemosensitivity to anticancer drugs in ovarian cancer cells. PMID- 21270612 TI - Prospective validation study of a predictive score for operability of recurrent ovarian cancer: the Multicenter Intergroup Study DESKTOP II. A project of the AGO Kommission OVAR, AGO Study Group, NOGGO, AGO-Austria, and MITO. AB - PURPOSE: The DESKTOP I trial proposed a score for the prediction of complete cytoreduction in recurrent ovarian cancer. Resectability was assumed if 3 factors were present: (1) complete resection at first surgery, (2) good performance status, and (3) absence of ascites. The DESKTOP II trial was planned to verify this hypothesis prospectively in a multicenter setting. METHODS: Participating centers prospectively enrolled all consecutive patients with platinum-sensitive first or second relapse. The score was applied to all patients, but centers were free to decide on therapy. All further therapies were documented, and the outcome of patients was analyzed. A 75% complete resection rate in 110 prospectively classified patients had to be achieved to confirm a positive predictive value of 2 or higher of 3 with 95% probability. RESULTS: A total of 516 patients were screened within 19 months; of these, 261 patients (51%) were classified as score positive, and 129 patients with a positive score and first relapse were operated on. The rate of complete resection was 76%, thus confirming the validity of this score regarding positive prediction of complete resectability in 2 or more of 3 patients. Complication rates were moderate including second operations in 11% and perioperative mortality in 0.8%. CONCLUSIONS: This score is the first prospectively validated instrument to positively predict surgical outcome in recurrent ovarian cancer. It can aid in the selection of patients who might benefit from secondary cytoreductive surgery and will be enrolled in the recently started randomized prospective DESKTOP III trial investigating the role of surgery in recurrent platinum-sensitive ovarian cancer. PMID- 21270613 TI - Cytochrome P450 1A1 gene polymorphisms and endometrial cancer risk: a meta analysis. AB - INTRODUCTION: This meta-analysis aims to examine whether the genotype status of Msp1, Ile462Val, and Thr461Asn polymorphisms in cytochrome P450 1A1 (CYP1A1) is associated with endometrial cancer risk. METHODS: Eligible case-control studies were identified through search in MEDLINE (end of search: August 2010). Pooled odds ratios (ORs) were appropriately derived from fixed-effects or random-effects models. RESULTS: Concerning MspI polymorphism, 8 studies were eligible (1456 cases and 2371 controls); 9 studies were eligible (1889 cases and 3662 controls) for Ile462Val and 6 studies were eligible (1272 cases and 2122 controls) for Thr461Asn. MspI polymorphism was not associated with endometrial cancer risk (for heterozygous TC vs TT carriers: OR = 0.83, 95% confidence interval [CI], 0.59 1.15, random effects; for homozygous CC vs TT carriers: OR = 1.00, 95% CI, 0.55 1.82, fixed effects). Similarly, Ile462Val polymorphism was not associated with endometrial cancer risk (for heterozygous Ile/Val vs Ile/Ile carriers: OR = 1.27, 95% CI, 0.78-2.06, random effects; for homozygous Val/Val vs Ile/Ile carriers: OR = 1.16, 95% CI, 0.48-2.81, fixed effects). Accordingly, Thr461Asn status was not significantly associated with endometrial cancer risk. The same results were reproduced in Caucasians. CONCLUSIONS: The 3 examined CYP1A1 genotype polymorphisms do not seem to confer any additional risk for endometrial cancer in Caucasians. Accumulation of further data seems mandatory for future race-specific analyses. PMID- 21270614 TI - The role of adjuvant chemotherapy in surgical stages I-II serous and clear cell carcinomas and carcinosarcoma of the endometrium: a collaborative study. AB - OBJECTIVE: To assess the impact of adjuvant chemotherapy in early surgically staged type II endometrial cancer (serous [S], clear cell carcinoma [CC]) and carcinosarcomas (CS) on recurrence and survival. MATERIALS AND METHODS: Patients diagnosed with stages I-II S-CC and CS after comprehensive surgical staging were retrospectively collected. Surgical staging was defined as pelvic lymphadenectomy of more than 11 nodes harvested and exploration of the upper abdomen, with our without omentectomy. Groups with (group A) and without (group B) platinum-based chemotherapy were compared. RESULTS: We identified 69 patients with a mean age of 66 years (range, 48-88 years). Both groups showed similar baseline characteristics. Group A consisted of 34 patients (23 S-CC, 11 CS) with 10 (29%) recurrences outside the pelvis (7 S-CC, 3 CS). Group B included 35 patients (28 S CC, 7 CS) of which 10 (29%) developed recurrence outside the pelvis (7 S-CC, 3 CS). The median recurrence-free survival was 22 months (range, 13-51 months) for group A versus 10 months (range, 1-59 months) for group B (P = 0.437). Five patients (15%) of group A and 9 (26%) of group B died of disease after a median follow-up of 29 months (range, 20-59 months) and 17 months (range, 4-64 months), respectively (P = 0.168). CONCLUSION: Recurrences in early-stage type II endometrial cancer and carcinosarcomas occur irrespective of adjuvant chemotherapy, but recurrence-free survival is prolonged when adjuvant chemotherapy is administered. Only prospective randomized intergroup trials can address the benefit of adjuvant chemotherapy in early-stage high-risk endometrial cancer. PMID- 21270615 TI - Clinicopathologic implications of the epidermal growth factor receptor, cyclooxygenase 2 expression, and human papillomavirus status in squamous cell carcinoma of the uterine cervix in the elderly. AB - OBJECTIVES: To find information on invasive squamous cervical carcinoma in the elderly, 110 invasive squamous cervical carcinomas obtained from 2 groups of patients (aged <60 and >60 years) were analyzed for human papillomavirus (HPV) status by polymerase chain reaction study, for immunohistochemical epidermal growth factor receptor (EGFR), cyclooxygenase 2 (Cox-2) expression, and clinicopathologic features. METHODS: The HPV status and the expression of Cox-2 and EGFR in the younger and older women were compared and correlated with the grading, staging neoplasm, and lymph nodal status, using Fisher test and Spearman nonparametric correlation test. Overall survival curves were drawn using Kaplan Meier estimates and were compared using log-rank tests in the whole series of 110 patients. Multinomial logistic regression was also used. RESULTS AND CONCLUSIONS: The number of neoplasms with higher staging was significantly greater than those in the younger women (P = 0.04). The mortality was higher in the older group than in the younger patients (P = 0.006).In the elderly, the presence of HPV DNA in 65% of cases, and in the absence of sexual activity, could be due to reactivation of latent HPV infection, which might be due to an impairment of host immunologic response.The overexpression of Cox-2 in a number of cases was significantly higher in the older group than in the younger group (P = 0.032, Fisher exact test), but this immunoreactivity is not related to the staging, grading, EGFR expression, or to the presence of HPV.The simultaneous expression of Cox-2 and EGFR had a poor prognostic significance, showing lower survival rates than cases without this immunoreactivity (P = 0.002), on univariate analysis.On multivariate analysis, Cox-2 and EGFR immunopositivity did not reveal any correlation between these markers and prognosis probably because the number of cases considered was not particularly high. PMID- 21270616 TI - Oncologic results and surgical morbidity of laparoscopic nerve-sparing radical hysterectomy in the treatment of FIGO stage IB cervical cancer: long-term follow up. AB - OBJECTIVES: The aim of this study was to evaluate a long-term follow-up data for oncologic results and surgical morbidity of a laparoscopic nerve-sparing radical hysterectomy (NSRH) in the treatment of FIGO stage IB cervical cancer. METHODS: This was a retrospective study that comprised consecutive 125 patients with cervical cancer stage IB1 (n = 105) and IB2 (n = 20) who underwent a laparoscopic NSRH (Piver type III) by a gynecologic oncologist without selecting patients from January 1999 to December 2007. RESULTS: In regression analysis, the operating time (R linear = 0.311, P < 0.001) and estimated blood loss (R linear = 0.261, P < 0.001) were decreased, whereas the number of harvested pelvic lymph nodes (R linear = 0.250, P < 0.001) was increased. Seventeen patients (13.6%, 17/125) were found to have pelvic node metastasis. Para-aortic node metastasis had occurred in 2 patients (5.1%, 2/39). There were high urological complications (13/125, 10.4%) related to radical surgery. Forty-one patients (33%) needed transfusions. Positive surgical margins did not exist. Patients were able to self-void at a mean of 10.3 days postoperatively. The return rates to normal voiding function at postoperative 14 and 21 days were 92.0% and 95.2%, respectively. Thirteen patients (IB1 n = 9, IB2 n = 4) experienced a recurrence postoperatively. Six patients (IB1 n = 3, IB2 n = 3) died of recurrent disease. Five-year disease-free survival rates of cervical cancer IB1 and IB2 were 92% and 78%, respectively (P = 0.1772). Five-year overall survival rates of cervical cancer IB1 and IB2 were 96% and 83%, respectively (P = 0.0437). CONCLUSIONS: A laparoscopic NSRH for FIGO stage IB cervical cancer was comparable to open NSRH in terms of early recovery of bladder function. It did not compromise surgical radicality, but revealed high urological complications, long operating time, and much blood loss, compared with conventional radical hysterectomy. However, these surgical morbidities were corrected with increase in experiences. PMID- 21270617 TI - Age at diagnosis of preinvasive and invasive cervical neoplasia in South Africa: HIV-positive versus HIV-negative women. AB - HYPOTHESIS: Human immunodeficiency virus-positive women develop invasive cervical cancer at a significantly earlier age than seronegative women. It is hypothesized that this might result from shorter preinvasive stages. METHODS: Prospective observational study of histologically diagnosed 398 low-grade (LGSIL), 738 high grade intraepithelial lesions (HGSIL), and 1048 invasive cancers (IC) in a black South African population. The study comprised of 493 (22.6%) seropositive women and 1691 (77.4%) seronegative women who served as the controls. All were subdivided into 5-years age bands. RESULTS: The mean age at diagnosis of LGSIL and HGSIL was similar in the cases (t = 0.7; P = 0.49) and the controls (t = 1.2; P = 0.22). The mean age at diagnosis of IC was significantly younger in the HIV seropositive women than in the HIV-seronegative women (t = 14.0; P < 0.0001). The relative age distribution curves of LGSIL, HGSIL, and IC evolved close to each other in the cases. In the seronegative women, there was an 18-year lag between the peak age distribution of HGSIL and IC. CONCLUSION: Our data support the hypothesis of a shorter preinvasive stage in HIV-positive women. PMID- 21270618 TI - Olfactomedin 4 is a marker for progression of cervical neoplasia. AB - INTRODUCTION: Olfactomedin 4 (OLFM4) is expressed in gastrointestinal cancers and related to progression and differentiation of these malignancies. However, whether OLFM4 contributes to tumorigenesis of other tissues has not been thoroughly investigated. The purpose of the study was to investigate OLFM4 expression in cervical epithelium and its association with progression of cervical neoplasia and differentiation of cervical carcinomas. METHODS: Immunohistochemistry and real-time reverse transcription-polymerase chain reaction were used to evaluate the expression and distribution of OLFM4 in cervical intraepithelial neoplasia (CIN) and invasive squamous cell carcinomas (ISCCs). RESULTS: The overall positive OLFM4 staining levels in normal cervical epithelia, CIN I, CIN II, CIN III, and ISCCs are 22.0%, 94.2%, 93.7%, 94.6%, and 96.7%, respectively. The intensity of OLFM4 staining was enhanced according to increased pathologic grade of cervical squamous intraepithelial lesion. The immunoreactivity to OLFM4 was stronger in well-differentiated ISCCs than in poorly differentiated ISCCs. CONCLUSIONS: Olfactomedin 4 expression has been associated with progression of CIN and differentiation of cervical cancer. The results provide new evidence that OLFM4 plays an important role in tumorigenesis in the female reproductive tract. PMID- 21270619 TI - Phase II trial of capecitabine and cisplatin in advanced, persistent, or recurrent carcinoma of the cervix. AB - PURPOSE: Platinum-based drugs are the most active agents in cervical carcinoma. The aim of this study was to assess the activity and toxicity of the association of cisplatin and capecitabine as first-line treatment in patients with advanced, persistent, or recurrent carcinoma of the cervix. PATIENTS AND METHODS: Patients with histological proven primary carcinoma, presence of measurable tumors, age 18 years or older, performance status of 2 or less, and adequate bone marrow, renal, and hepatic functions were potentially eligible for this trial. Prior chemotherapy was allowed only in the context of radiosensitization. Treatment consisted of 50 mg/m of intravenous cisplatin on day 1 with 2500 mg/m oral capecitabine daily in 2 divided doses for 14 consecutive days in 21-day cycles. Responses were assessed using response evaluation criteria in solid tumors. RESULTS: Between November 2004 and October 2007, 22 women were entered into the trial. Median age was 51 years (range, 37-70 years). Seventeen patients had prior radiotherapy, and 13 received a radiation sensitizer, whereas 2 patients underwent surgery exclusively and 3 patients had no prior treatment. A median of 5 cycles was administered (range, 2-8 cycles). There were one septic death, one grade 4 neutropenia, and one grade 4 anemia. Grade 3 fatigue, gastrointestinal toxicity, renal toxicity, and hand-foot syndrome were seen in 31.8%, 22.7%, 9%, and 9% of the patients, respectively. There were 1 complete response and 6 partial responses for an overall response rate of 31.8%. Seven patients (31.8%) each had stable disease, and 8 patients showed progression. The median time to progression was 7.6 months, with a median overall survival of 20 months. CONCLUSION: These results seem to suggest that the capecitabine-cisplatin combination is a moderately tolerated and active regimen in advanced, persistent, or recurrent cervical carcinoma patients. Further evaluation of this drug combination may be warranted. PMID- 21270620 TI - Primary vaginal cancer and chemoradiotherapy: a patterns-of-care analysis. AB - INTRODUCTION: No prospective randomized trials exist to delineate the role of combined chemoradiotherapy (CRT) in the treatment of vaginal cancer (VC). We sought to describe the utilization rate of CRT and evaluate the potential survival benefit of CRT over radiotherapy alone in VC. METHODS: A retrospective analysis of the SEER-Medicare-linked database was performed analyzing women with VC treated with external beam radiation and/or brachytherapy and diagnosed between 1991 and 2005. RESULTS: Of the 1709 primary VC patients in the SEER Medicare database, 326 met inclusion criteria. Most were white (80.1%) and in the 70- to 74-year age group (42.1%). Squamous cell carcinoma was the most predominant histologic diagnosis (80.4%). Brachytherapy was used in 34% of patients, whereas cisplatin was the chemotherapy of choice in 59% of CRT patients. Median follow-up was 21.5 months. Kaplan-Meier estimated that 5-year cause-specific survival (CSS) and overall survival (OS) was 67.6% and 27.1%, respectively. Before 1999, CRT was used in 7.5% of patients compared with 36.1% of patients thereafter (P < 0.001). Chemoradiotherapy was less likely to be used in patients older than 80 years (P < 0.001) but was otherwise balanced in race, stage, grade, histologic diagnosis, comorbidities, and brachytherapy use. Chemoradiotherapy did not correlate with CSS (hazard ratio [HR], 0.91; P = 0.84) or OS (HR, 1.34; P = 0.21) by multivariate analysis. Factors associated with worse CSS include stage IVA disease (HR, 4.2; P = 0.003) and 2 or more comorbidities (HR, 2.89; P = 0.03). Factors associated with worse OS include age older than 80 years (HR, 1.78; P = 0.04), stage IVA disease (HR, 3.35; P < 0.0001), and 2 or more comorbidities (HR, 2.58; P = 0.001). CONCLUSIONS: Chemoradiotherapy utilization for VC has increased since 1999. We failed to delineate a CSS or OS benefit for CRT in this cohort. PMID- 21270621 TI - A retrospective analysis of postoperative complications with or without para aortic lymphadenectomy in endometrial cancer. AB - INTRODUCTION: Although para-aortic lymphadenectomy (PALX) has not been accepted as a standard treatment for patients with endometrial cancer, it is possible that systematic lymphadenectomy including PALX has therapeutic significance for patients with intermediate-/high-risk endometrial cancer. On the other hand, a consensus regarding the safety of PALX has not been reached. The aim of this study was to compare the incidence rates of postoperative complications after pelvic lymphadenectomy (PLX) with or without PALX in patients with uterine corpus cancer. METHODS: A retrospective chart review was carried out for all patients with endometrial cancer treated at 2 tertiary centers between 1998 and 2004. Surgery at one institute included both PLX and PALX, whereas PLX alone was routinely performed at the other institute. A total of 142 patients underwent PLX + PALX and 138 patients underwent PLX alone. We evaluated postoperative complications including intraoperative injury, ileus, lymphedema, lymphocyst, and thrombosis. RESULTS: There was no fatal accident associated with surgery. Lymphedema was the most frequent complication. Comparing the PLX + PALX group and the PLX group, there were no significant differences in the rate of cases of lymphedema (23.2% vs 28.3%), lymphocyst (9.2% vs 9.4%), and thrombosis (4.9% vs 2.2%). The rate of cases of mild/moderate ileus in the PLX + PALX group was significantly higher than that in the PLX group (10.5% vs 2.9%; P = 0.011). However, no significant difference in the rates of cases of severe ileus was found between the 2 groups (1.4% vs 0.7%). There were also no significant differences between the 2 groups in the rates of intraoperative organ injury (2.8% vs 2.2%) and secondary operation for postoperative complications (4.9% vs 4.3%). CONCLUSIONS: Para-aortic lymphadenectomy can be performed with an acceptable morbidity under the conditions in which it is performed by experienced surgeons, and measures to prevent complications are properly taken. PMID- 21270622 TI - Robotic uterine artery preservation and nerve-sparing radical trachelectomy with bilateral pelvic lymphadenectomy in early-stage cervical cancer. AB - OBJECTIVE: The aim of the study was to evaluate the safety and feasibility of robotic uterine artery preservation and nerve-sparing radical trachelectomy with pelvic lymphadenectomy using the da Vinci surgical system. METHODS: Three patients who were diagnosed with early-stage cervical cancer underwent robotic uterine artery preservation and nerve-sparing radical trachelectomy with bilateral lymphadenectomy from January 2010 to March 2010. The data were compared with those of 4 cases of total laparoscopic nerve-sparing radical trachelectomy that were performed from July 2004 to May 2005 and were previously reported. RESULTS: In the robotic group, the mean console time was 275 minutes (range, 240 305 minutes). The mean postoperative hemoglobin change was 0.4 g/dL (range, 0.2 0.6 g/dL). The mean estimated blood loss was 23 mL (range, 15-40 mL), which is less than that of the laparoscopic group. There were no metastases detected in any of the cases, and the resection margins were negative in both groups. CONCLUSIONS: The robotic uterine artery preservation and nerve-sparing radical trachelectomy with pelvic lymphadenectomy were efficient in reducing blood loss and feasible methods such as other approaches. PMID- 21270623 TI - Assessment of bilateral limb lymphedema by bioelectrical impedance spectroscopy. AB - OBJECTIVE: The aim of the present study was to determine if the ratio of extracellular fluid (ECF), including the lymph, to that of intracellular fluid (ICF), as measured by bioimpedance spectroscopy (BIS), could be used to assess bilateral lymphedema (LE). BACKGROUND: The presence of LE is commonly determined as an increase in tissue volume due to the presence of excess lymph relative to the volume of a comparable unaffected body region or to comparative normative data. However, in bilateral LE of the limbs, a comparable body region, the contralateral limb, is also affected, precluding normalization. An alternative is to normalize the increase in lymph volume, as ECF, to that of ICF volume. METHODS: Extracellular/intracellular fluid ratios, expressed as the ratio of intracellular impedance (Ri) to extracellular impedance (R0), for the limbs of 277 female and 224 male controls were determined from an accumulated database of impedance data. Equivalent data were obtained for an opportunistic cross sectional sample of 37 female and 5 male participants with bilateral LE of the legs. The ratios of Ri/R0 in the lymphedematous legs of the affected participants were compared with the equivalent ratios in the unaffected arms of the same participants and with those of the controls using box plots and visualized as bivariate data using tolerance ellipses. RESULTS: Despite Ri/R0 ratios varying with age, sex, and limb dominance, comparison of the ratio for affected legs (normalized to the ratio in the unaffected arms) with equivalent ratios observed in a control population (as bivariate tolerance plots) was capable of discriminating between 70% and 89% of the participants with LE. CONCLUSIONS: Bioelectrical impedance spectroscopy and determination of Ri/R0 ratios as indices of ECF/ICF ratios holds promise for the semiquantitative assessment of bilateral LE. PMID- 21270624 TI - Definitions for response and progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer Intergroup (GCIG). AB - The Gynecological Cancer Intergroup (GCIG) has previously reached consensus regarding the criteria that should be used in clinical trial protocols to define progression-free survival after first-line therapy as well as the criteria to define response to treatment in recurrent disease using the serum marker CA 125 and has specified the situations where these criteria should be used. However, the publications did not include detailed definitions, nor were they written to accommodate the new version of Response Evaluation Criteria In Solid Tumors (RECIST) criteria (version 1.1) now available. Thus, we recommend that the definitions described later in detail are incorporated into clinical trial protocols to maintain consistency. The criteria for defining progression are now acceptable in clinical trials of recurrent disease as they have since been validated (Pujade-Lauraine, personal communication, 2010). The GCIG requests that data from all clinical trials using these definitions are made available to GCIG trial centers so that continual validation and improvement can be accomplished. These definitions were developed from analyzing patients receiving cytotoxic chemotherapy and have not yet been validated in patients receiving molecular targeting agents. PMID- 21270625 TI - Rigid versus nonrigid occipitocervical fusion: a clinical comparison of short term outcomes. AB - STUDY DESIGN: Retrospective data review. OBJECTIVE: To report clinical outcomes of both rigid and nonrigid occipitocervical (OC) fusion constructs of a multicenter cervical spine study group. BACKGROUND: The OC junction is susceptible to a wide variety of pathologic conditions that predispose it to instability. The need for arthodesis in symptomatic or neurologically unstable cases has led to the development of a variety of fusion techniques that can be classified as either nonrigid fixation techniques, such as sublaminar wiring or onlay bone grafting, or rigid internal fixation constructs, such as screws with plate or rods. Rigid fixation provides immediate stability and eliminates the need for external fixators, that is, halo-vest. Although a rigid construct would seem to confer several advantages over a nonrigid construct with external inmobilization supplementation, comparative clinical data are is lacking. METHODS: A clinical comparison of the rigid and the nonrigid forms of OC fusion was done retrospectively from the data of a multicenter cervical spine study group. A total of 71 occipitocervical fusion patients were identified: 25 with a nonrigid technique and 46 with a rigid construct. Average follow-up time was 6.3 months with a range of 1.5 to 36 for the rigid construct cohort and 15.7 months with a range of 1 to 36 months for the nonrigid cohort. Complications were recorded and correlated to the type of fixation and the type of external immobilization used. A chi analysis was done to evaluate the significant differences between complication rates of both the groups, that is, rigid and nonrigid constructs. RESULTS: Twenty-five nonrigidly fused patients had a complication rate of 48%, whereas 46 rigidly fused patients had a complication rate of 10% (P<0.01). Rigid forms of internal fixation for OC fusion has a significantly lower complication rate in short term. CONCLUSION: In addition to the many advantages of a rigid occipitocervical construct, the clinical complication rates are statistically significantly lower versus a nonrigidly fixed construct. PMID- 21270626 TI - Restoration and preservation of disc height and segmental lordosis with circumferential lumbar fusion: a retrospective analysis of cage versus bone graft. AB - STUDY DESIGN: Retrospective radiographic analysis. OBJECTIVE: To determine whether restoration and preservation of (a) disc height and (b) segmental lordosis differ between patients treated with circumferential lumbar fusion using a bone graft or a cage for anterior support. SUMMARY OF BACKGROUND DATA: Restoration of disc height and lordosis is considered to be of crucial importance in circumferential fusion (CF). To determine whether restoration and preservation of disc height and segmental lordosis are dependent on the type of anterior support used, we compared the use of a cage with that of a bone graft in CF. METHODS: We retrospectively analyzed disc height and segmental lordosis in patients treated with primary lumbar monosegmental CF. The minimum period of follow-up was 9 months. A cage was used for anterior support in 23 patients and a bone graft in a further 23 patients. Disc height was determined on radiographs using an earlier introduced and validated distortion-compensated roentgen analysis, which was developed to compensate for distortion in central projection, off-center position, variation of stature, axial rotation, and lateral tilt of the spine. RESULTS: Disc height was restored in both groups but differences between preoperative and postoperative disc heights were significantly greater in the cage group (P=0.006). The cage also proved to be superior with regard to disc height preservation after follow-up (P=0.001). In addition, there was significantly less postoperative loss of segmental lordosis in the cage group (P=0.026). CONCLUSIONS: The cage proved superior to the bone graft as anterior support in CF with respect to restoration/preservation of lordosis and disc height. However, no conclusions concerning clinical outcome or cost effectiveness can be drawn on the basis of this study. PMID- 21270627 TI - Comparisons of outcomes after single or multilevel dynamic stabilization: effects on adjacent segment. AB - STUDY DESIGN: A retrospective study. OBJECTIVES: To compare the clinical/radiologic outcomes and effects on adjacent segments by Dynesys stabilization. SUMMARY OF BACKGROUND DATA: Dynamic stabilization is known to preserve some range of motion (ROM) and to lessen the load on adjacent levels compared with rigid fixation. However, there is concern about the stiffness of Dynesys. In a long-term follow-up study (>4 y), motion of Dynesys was preserved in only 8% of patients and adjacent segment degeneration occurred up to 47% of patients. Little information is available about the risk factor regarding adjacent segment motion. METHODS: Twenty-one patients underwent lumbar spine stabilization with Dynesys owing to degenerative spinal disease (single, 7; multiple-level, 14). Clinical outcomes were evaluated using K-ODI, VAS, and MacNab criteria. Radiologic evaluations included whole spine AP/lateral, lumbar neutral, flexion, and extension x-ray. Follow-up period was 31+/-14 months. Single (group A) and multiple-level stabilization (group B, average 2.3 levels) were compared. RESULTS: Clinical improvement was not different between the 2 groups (P>0.05). Sagittal balance, lumbar lordosis, ROM of the lumbar spine, pelvic tilt, and sacral slope were not changed postoperatively (P>0.05) in either group. Postoperatively, ROM of stabilized segments were significantly decreased from 12.8+/-4.8 degrees to 3.9+/-5 degrees, while ROM of segments above was increased in both groups (P<0.01). Disc height was not decreased in either group (P>0.05). However, retrolisthesis was observed on adjacent segments above in 6 patients only in group B, which may suggests adjacent segment problem. CONCLUSIONS: Clinically, dynamic stabilization is a good alternative treatment option for degenerative spinal disease. However, dynamic stabilization preserves only limited motion and may cause stress on the adjacent level above. Adjacent segment disease may be closely monitored, especially in cases of multiple-levels dynamic stabilization. PMID- 21270629 TI - Toll-like receptor 4 signaling confers cardiac protection against ischemic injury via inducible nitric oxide synthase- and soluble guanylate cyclase-dependent mechanisms. AB - BACKGROUND: Prior administration of a small dose of lipopolysaccharide confers a cardiac protection against ischemia-reperfusion injury. However, the signaling mechanisms that control the protection are incompletely understood. We tested the hypothesis that Toll-like receptor 4 (TLR4) mediates the ability of lipopolysaccharide to protect against cardiac ischemia-reperfusion injury through distinct intracellular pathways involving myeloid differentiation factor 88 (MyD88), TIR-domain-containing adaptor protein-inducing interferon-beta-mediated transcription factor (Trif), inducible nitric oxide synthase (iNOS), and soluble guanylate cyclase (sGC). METHODS: Wild-type mice and genetically modified mice, that is TLR4-deficient (TLR4(-def)), TLR2 knockout (TLR2(-/-)), MyD88(-/-), Trif( /-), iNOS(-/-), and sGCalpha1(-/-), were treated with normal saline or 0.1 mg/kg lipopolysaccharide intraperitoneally. Twenty-four hours later, isolated hearts were perfused in a Langendorff apparatus and subsequently subjected to 30 min global ischemia and reperfusion for as long as 60 min. Left ventricular function and myocardial infarction sizes were examined. RESULTS: Compared with saline treated mice, lipopolysaccharide-treated mice had markedly improved left ventricular developed pressure and dP/dt(max) (P < 0.01) and reduced myocardial infarction sizes (37.2 +/- 3.4% vs. 19.8 +/- 4.9%, P < 0.01) after ischemia reperfusion. The cardiac protective effect of lipopolysaccharide was abolished in the TLR4(-def) and MyD88(-/-) mice but remained intact in TLR2(-/-) or Trif(-/-) mice. iNOS(-/-) mice or wild-type mice treated with the iNOS inhibitor 1400W failed to respond to the TLR4-induced nitric oxide production and were not protected by the lipopolysaccharide preconditioning. Although sGCalpha(1)(-/-) mice had robust nitric oxide production in response to lipopolysaccharide, they were not protected by the TLR4-elicited cardiac protection. CONCLUSIONS: TLR4 activation confers a potent cardiac protection against ischemia-reperfusion injury via a MyD88-dependent, but Trif-independent, mechanism. iNOS/sGC are essential for the TLR4-induced cardiac protection. PMID- 21270630 TI - Nitrous oxide diffusion and the second gas effect on emergence from anesthesia. AB - BACKGROUND: Rapid elimination of nitrous oxide from the lungs at the end of inhalational anesthesia dilutes alveolar oxygen, producing "diffusion hypoxia." A similar dilutional effect on accompanying volatile anesthetic agent has not been evaluated and may impact the speed of emergence. METHODS: Twenty patients undergoing surgery were randomly assigned to receive an anesthetic maintenance gas mixture of sevoflurane adjusted to bispectral index, in air-oxygen (control group) versus a 2:1 mixture of nitrous oxide-oxygen (nitrous oxide group). After surgery, baseline arterial and tidal gas samples were taken. Patients were ventilated with oxygen, and arterial and tidal gas sampling was repeated at 2 and 5 min. Arterial sampling was repeated 30 min after surgery. Sevoflurane partial pressure was measured in blood by the double headspace equilibration technique and in tidal gas using a calibrated infrared gas analyzer. Time to eye opening and time extubation were recorded. The primary endpoint was the reduction in sevoflurane partial pressures in blood at 2 and 5 min. RESULTS: Relative to baseline, arterial sevoflurane partial pressure was 39% higher at 5 min in the control group (P < 0.04) versus the nitrous oxide group. At 30 min the difference was not statistically significant. Time to eye opening (8.7 vs. 10.1 min) and time to extubation (11.0 vs.13.2 min) were shorter in the nitrous oxide group versus the control group (P < 0.04). CONCLUSIONS: Elimination of nitrous oxide at the end of anesthesia produces a clinically significant acceleration in the reduction of concentrations of the accompanying volatile agents, contributing to the speed of emergence observed after inhalational nitrous oxide anesthetic. PMID- 21270631 TI - Tracheobronchomegaly: a rare cause of endotracheal tube cuff leak. PMID- 21270632 TI - Scrub the hub! Catheter needleless port decontamination. PMID- 21270633 TI - The value of lesser-impact-factor surgical journals as a source of negative and inconclusive outcomes reporting. AB - OBJECTIVES: (1) Examine the tendency of peer-reviewed surgical journals to publish positive reports or negative and inconclusive outcome articles as a function of the journals' impact factor (IF). (2) Examine the frequency with which surgical journal editors/publishers adhere to the International Committee of Medical Journal Editors statement on sources of funding and/or conflicts of interest (COI). BACKGROUND: Evidence-based medicine is often used as a template for measuring quality of medical care. Clinicians put their faith in peer reviewed articles as quality-assured and reliable information. However, peer reviewed literature does not provide balanced access to positive, negative, and inconclusive reports. Funding may also influence the decision to publish certain articles and can thus add to the reported bias in the literature. METHODS: Articles from 15 surgical journals comprising 3 separate journal groups based upon 2006 impact factor (IF) rankings were reviewed. All were published in 2007. Manuscripts were classified by 5 independent reviewers as having positive, negative, or inconclusive primary and secondary outcomes and for statements on funding/COI. Positive reports were defined as P < 0.05, null hypothesis rejected; negative reports defined as P < 0.05, null hypothesis accepted; and inconclusive reports defined as P > 0.05. Inter-observer consistency was affirmed. Separate analysis of randomized controlled trials (RCT) was performed to assess for the quality of published positive and negative trials. RESULTS: We evaluated 2457 published articles. Positive primary outcomes were reported in 67% to 100% of studied articles in selected journals. Negative and inconclusive primary outcomes were less likely to be reported, except for one journal that reported a high of 33% negative articles. Higher-ranked journals published fewer negative and inconclusive studies (5%-7%) than both medium- and lowly-ranked journals (P < 0.0001). The proportion of RCTs published varied, constituting 18% to 21% of articles in the 5 high-ranked journals compared to 6% to 14% in the 5 more lowly ranked journals (P < 0.0001). Reporting of COIs and funding were more frequent in high-IF compared to low-IF journals (P < 0.0001). CONCLUSIONS: Quality rather than outcome should be the measure on which a publication decision is made; commercial bias may further complicate this balance. Lower IF-rated journals may serve a decidedly useful purpose by publishing more negative and inconclusive outcome studies. The practice of focusing disproportionately on the positive outcomes of most studies may result in unbalanced evidence. PMID- 21270634 TI - Impact of bar-code medication administration on nursing activity patterns and usage experience in Taiwan. AB - As medication safety is a foremost goal of patient safety, the adoption of bar code medication administration can help nurses ensure safe medication administration. The aims of the study were to explore the impact on nursing activity patterns of using this device and to understand the nurses' usage of this technology. The data collection was conducted in a medical center in northern Taiwan using work sampling observation and qualitative interviews. A total of 4940 observations were conducted on two groups of nurses who did or did not use the device, and six nurses were interviewed using a semistructured interview guide. The results showed that the nurses who used this device spent less time on medication-related activities and more on indirect care and unit related activities, especially on the day and night shifts. Three themes were identified from the follow-up interviews: facilitating nursing workflow, improving medication safety, and encountering operational difficulties. Although the technology use could divert the nurses' practice patterns from medication related activities to indirect care and unit-related activities, their direct care was not compromised. In addition, although the bar-code medication administration use could improve workflow and patient safety, hardware sufficiency and system functionality deserve more attention in the technology adoption process. PMID- 21270635 TI - Data collection variation in preoperative assessment: a literature review. AB - This study is a systematic literature review to identify data collected in the preoperative assessment. The PubMed and CINAHL databases were searched for articles published from 1997 to 2007. From the included articles, data items that were described as part of the preoperative assessment were extracted. Identified data items were categorized into 13 categories originating from SNOMED CT. Forty one relevant articles were found. Preoperative assessment was equally performed in outpatient clinics and in-hospitals. The assessment was performed between the day of surgery and 30 days before surgery by anesthesiologists (51%) and/or nurses (39%) and/or other professionals (34%). The included articles described 541 data items. The two largest categories of data were "past history of clinical finding" and "physical examination procedure," with 212 and 75 data items. Only 6 data items "age," "diabetes," "ECG," "cardiovascular diseases," "hypertension," and "cigarette smoking and other use of tobacco" were stated in 50% or more of the articles. This study revealed a high diversity of data being collected during the preoperative assessment. Because of the diversity of patients, one undisputed preoperative assessment data set is hard to define. However, to solve the problem of data exchangeability, professionals should at least use a common core data set. PMID- 21270636 TI - Changes to perceptions of the pros and cons of genetic susceptibility testing after APOE genotyping for Alzheimer disease risk. AB - PURPOSE: Perceptions about the pros and cons of genetic susceptibility testing are among the best predictors of test utilization. How actual testing changes such perceptions has yet to be examined. METHODS: In a clinical trial, first degree relatives of patients with Alzheimer disease received genetic risk assessments for Alzheimer disease including APOE disclosure. Participants rated 11 possible benefits associated with genetic testing (pros) and 10 risks or limitations (cons) before genetic risk disclosure and again 12 months afterward. RESULTS: Pros were rated higher than cons at baseline (3.53 vs. 1.83, P < 0.001) and at 12 months after risk disclosure (3.33 vs. 1.88, P < 0.001). Ratings of pros decreased during the 12-month period (3.33 vs. 3.53, P < 0.001). Ratings of cons did not change (1.88 vs. 1.83, P = 0.199) except for a three-item discrimination subscale which increased (2.07 vs. 1.92, P = 0.012). Among specific pros and cons, three items related to prevention and treatment changed the most. CONCLUSION: The process of APOE genetic risk assessment for Alzheimer disease sensitizes some to its limitations and the risks of discrimination; however, 1-year after disclosure, test recipients still consider the pros to strongly outweigh the cons. PMID- 21270637 TI - Evidence for the toxicity of bidirectional transcripts and mitochondrial dysfunction in blood associated with small CGG expansions in the FMR1 gene in patients with parkinsonism. AB - PURPOSE: Our previous results showed that both gray zone and lower end premutation range (40-85 repeats) fragile X mental retardation 1 (FMR1) alleles were more common among males with parkinsonism than in the general population. This study aimed to determine whether these alleles have a significant role in the manifestations and pathogenesis of parkinsonian disorders. METHODS: Detailed clinical assessment and genetic testing were performed in 14 male carriers of premutation and gray zone FMR1 alleles and in 24 noncarriers identified in a sample of males with parkinsonism. RESULTS: The premutation + gray zone carriers presented with more severe symptoms than disease controls matched for age, diagnosis, disease duration, and treatment. The Parkinson disease (Unified Parkinson's Disease Rating Scale) motor score and the measures of cognitive decline (Mini-Mental State Examination and/or Addenbrooke's Cognitive Examination Final Revised Version A scores) were significantly correlated with the size of the CGG repeat and the (elevated) levels of antisense FMR1 and Cytochrome C1 mRNAs in blood leukocytes. In addition, the carriers showed a significant depletion of the nicotinamide adenine dinucleotide, reduced dehydrogenase subunit 1 mitochondrial gene in whole blood. CONCLUSION: Small CGG expansion FMR1 alleles (gray zone and lower end premutation) play a significant role in the development of the parkinsonian phenotype, possibly through the cytotoxic effect of elevated sense and/or antisense FMR1 transcripts involving mitochondrial dysfunction and leading to progressive neurodegeneration. PMID- 21270638 TI - How well does family history predict who will get colorectal cancer? Implications for cancer screening and counseling. AB - PURPOSE: Using a large, retrospective cohort from the Utah Population Database, we assess how well family history predicts who will acquire colorectal cancer during a 20-year period. METHODS: Individuals were selected between ages 35 and 80 with no prior record of colorectal cancer diagnosis, as of the year 1985. Numbers of colorectal cancer-affected relatives and diagnosis ages were collected. Familial relative risk and absolute risk estimates were calculated. Colorectal cancer diagnoses in the cohort were counted between years 1986 and 2005. Cox regression and Harrell's C were used to measure the discriminatory power of resulting models. RESULTS: A total of 431,153 individuals were included with 5,334 colorectal cancer diagnoses. Familial relative risk ranged from 0.83 to 12.39 and 20-year absolute risk from 0.002 to 0.21. With familial relative risk as the only predictor, Harrell's C = 0.53 and with age only, Harrell's C = 0.66. Familial relative risk combined with age produced a Harrell's C = 0.67. CONCLUSION: Family history by itself is not a strong predictor of exactly who will acquire colorectal cancer within 20 years. However, stratification of risk using absolute risk probabilities may be more helpful in focusing screening on individuals who are more likely to develop the disease. PMID- 21270639 TI - Patient reactions to personalized medicine vignettes: an experimental design. AB - PURPOSE: Translational investigation on personalized medicine is in its infancy. Exploratory studies reveal attitudinal barriers to "race-based medicine" and cautious optimism regarding genetically personalized medicine. This study describes patient responses to hypothetical conventional, race-based, or genetically personalized medicine prescriptions. METHODS: Three hundred eighty seven participants (mean age = 47 years; 46% white) recruited from a Baltimore outpatient center were randomized to this vignette-based experimental study. They were asked to imagine a doctor diagnosing a condition and prescribing them one of three medications. The outcomes are emotional response to vignette, belief in vignette medication efficacy, experience of respect, trust in the vignette physician, and adherence intention. RESULTS: Race-based medicine vignettes were appraised more negatively than conventional vignettes across the board (Cohen's d = -0.51-0.57-0.64, P < 0.001). Participants rated genetically personalized comparably with conventional medicine (-0.14-0.15-0.17, P = 0.47), with the exception of reduced adherence intention to genetically personalized medicine (Cohen's d = -0.38-0.41-0.44, P = 0.009). This relative reluctance to take genetically personalized medicine was pronounced for racial minorities (Cohen's d = -0.38-0.31-0.25, P = 0.02) and was related to trust in the vignette physician (change in R = 0.23, P < 0.001). CONCLUSIONS: This study demonstrates a relative reluctance to embrace personalized medicine technology, especially among racial minorities, and highlights enhancement of adherence through improved doctor- patient relationships. PMID- 21270640 TI - Medical and graduate students' attitudes toward personal genomics. AB - PURPOSE: Medical schools are being approached by direct-to-consumer genotyping companies about genotyping faculty or trainees as a method to "teach" them about the potential implications of genotyping. In thinking about the future incorporation of genotyping into a graduate level genetics course, the purpose of this study was 2-fold: first, to assess knowledge, attitudes, and beliefs of students toward personal genomics as it related to themselves as both as customers and future physicians and as it related to consumers at large, and second, to determine the impact of the course (as taught without genotyping) on knowledge, attitudes, and beliefs. METHODS: We surveyed first-year medical students and graduate students before and after a core genetics course. RESULTS: After the course, students were less likely to believe that genotyping information would be useful to physicians, patients, or consumers; genotyping would provide information to improve their own personal health; or personal genomic testing services are diagnostic of medical conditions. They were more likely to answer knowledge questions accurately after the course but still had difficulty with clinical interpretation. Despite these changes, a slight majority of students were, and remained, interested in undergoing genotyping themselves. Of note, the number who believed genotyping "would help them understand genetic concepts better than someone else's data" decreased. General curiosity was the most commonly chosen reason for interest in undergoing genotyping, and approximately 50% of respondents expressed concern about confidentiality of results. CONCLUSIONS: In conclusion, even without the genotyping process, an educational program about genotyping increased knowledge, particularly about the clinical limitations of genotyping, but student interest in genotyping did not significantly change. Institutions thinking about offering genotyping to their students as part of a learning experience should consider the pros and cons of doing so. PMID- 21270641 TI - Next generation massively parallel sequencing of targeted exomes to identify genetic mutations in primary ciliary dyskinesia: implications for application to clinical testing. AB - PURPOSE: Advances in genetic sequencing technology have the potential to enhance testing for genes associated with genetically heterogeneous clinical syndromes, such as primary ciliary dyskinesia. The objective of this study was to investigate the performance characteristics of exon-capture technology coupled with massively parallel sequencing for clinical diagnostic evaluation. METHODS: We performed a pilot study of four individuals with a variety of previously identified primary ciliary dyskinesia mutations. We designed a custom array (NimbleGen) to capture 2089 exons from 79 genes associated with primary ciliary dyskinesia or ciliary function and sequenced the enriched material using the GS FLX Titanium (Roche 454) platform. Bioinformatics analysis was performed in a blinded fashion in an attempt to detect the previously identified mutations and validate the process. RESULTS: Three of three substitution mutations and one of three small insertion/deletion mutations were readily identified using this methodology. One small insertion mutation was clearly observed after adjusting the bioinformatics handling of previously described SNPs. This process failed to detect two known mutations: one single-nucleotide insertion and a whole-exon deletion. Additional retrospective bioinformatics analysis revealed strong sequence-based evidence for the insertion but failed to detect the whole-exon deletion. Numerous other variants were also detected, which may represent potential genetic modifiers of the primary ciliary dyskinesia phenotype. CONCLUSIONS: We conclude that massively parallel sequencing has considerable potential for both research and clinical diagnostics, but further development is required before widespread adoption in a clinical setting. PMID- 21270642 TI - Pulmonary hypertension in a patient with subarachnoid hemorrhage. PMID- 21270643 TI - Anesthetic management of patient with Kugelberg-Welander syndrome undergoing removal of scalp dermoid. PMID- 21270644 TI - Do patients still require admission to an intensive care unit after elective craniotomy for brain surgery? AB - BACKGROUND: After elective craniotomy for brain surgery, patients are usually admitted to an intensive care unit (ICU). We sought to identify predictors of postoperative complications to define perioperative conditions that would safely allow ICU bypass. METHODS: This observational cohort study enrolled 358 patients admitted to neuro-ICU after elective intracranial procedures. Postoperative complications were defined as unexpected events occurring within 24 hours of surgery that required imaging or treatment for neurologic deterioration. RESULTS: Fifty-two patients were transferred postoperatively to neuro-ICU with sedation and mechanical ventilation. Of the remaining 306 patients subjected to an attempt to awake and extubate in the operating room, 26 (8%) developed 1 postoperative complication, primarily a new motor deficit, unexpected awakening delay, or subsequent deterioration in consciousness. Four intracerebral hematomas required surgical evacuation and each of these was detected within 2 hours after surgery. Predictors of postoperative complications included failure to extubate the trachea in operating room [odds ratio 61.8; 95% confidence interval (CI) 12.2 312.5], and, to a lesser extent, a duration of surgery of more than 4 hours (odds ratio 3.3; 95% CI 1.4-7.8), and lateral positioning of the patient during the procedure (odds ratio 2.8, 95% CI 1.2-6.4). CONCLUSIONS: Our results encourage prospectively testing the hypothesis that patients with immediate, successful tracheal extubation after elective craniotomy for brain surgery, with a surgical duration of less than 4 hours in a nonlateral position could be monitored safely in the postanesthesia care unit before being discharged to a neurosurgical ward. PMID- 21270645 TI - Posthypoxic moderate hypothermia improves electrophysiological recovery in the rat hippocampal slice. AB - BACKGROUND: Animal studies have shown that prehypoxic or intrahypoxic hypothermia is protective against hypoxic neuronal injury, whereas posthypoxic hypothermia produced divergent findings. This study examined the protective effects of posthypoxic hypothermia on the electrophysiological recovery in the rat hippocampal slice. METHODS: Eighty-three male Sprague-Dawley rats were used after approval of the Institutional Animal Care and Use Committee. Hippocampal slices were obtained and electrophysiological recordings from the CA1 pyramidal cell layer were used as an indicator of cell function. Moderate hypothermia (30 degrees C) was used for only 30 minutes after hypoxia in the study group, whereas normothermia was maintained throughout the experiment in the control group. Three different periods of hypoxia were used (3, 3.5, and 4 min). Recovery was measured as the ratio of the amplitude of the population spike at the end of 2 hours of recovery to that of the baseline that was obtained immediately before hypoxia. RESULTS: Posthypoxic hypothermia improved electrophysiological recovery in slices exposed to 3 minutes of hypoxia but not in those exposed to 3.5 or 4 minutes of hypoxia. CONCLUSIONS: Moderate hypothermia (30 degrees C) applied after hypoxia is protective against short periods (3 min) of hypoxia but not after slightly longer periods (3.5 or 4 min) of hypoxia. PMID- 21270646 TI - Spatial memory using active allothetic place avoidance in adult rats after isoflurane anesthesia: a potential model for postoperative cognitive dysfunction. AB - BACKGROUND: We described a paradigm of active allothetic place avoidance (AAPA) as a measure of spatial memory in adult rats. We hypothesized that, pending successful AAPA training, treatment with isoflurane would trigger spatial memory deficits. METHODS: Fifteen of 20 adult rats were successfully trained and randomly allocated to control and isoflurane treatment groups. An additional 7 animals were used to demonstrate hemodynamic stability during general anesthesia. After training, experimental animals received a 2-hour isoflurane anesthetic. General endotracheal anesthesia was maintained at an isoflurane concentration of 1.8% to 2%. After intervention, retention of training was tested on postanesthesia days 1, 3, and 7. RESULTS: Animals treated with isoflurane displayed selected spatial memory changes up to postanesthesia day 7. There were 2 findings of decreased active avoidance behavior in rats receiving isoflurane: a significant (P=0.029) reduction in maximum path of avoidance in the isoflurane treated rats compared with controls, and a significant (P=0.038) increase in total path length in the controls. No other measured AAPA parameters achieved statistical significance. CONCLUSIONS: Control animals demonstrated increased active avoidance behavior in the AAPA task compared with isoflurane-treated animals. Animals exposed to 2-hour isoflurane general anesthetic had a reduction in the maximum path of avoidance measure up to 7 days postanesthesia, whereas gross spatial parameters such as number of entrances into the shock zone were not significantly different between groups. The AAPA model may prove useful in ascertaining the learning and memory deficits of postoperative cognitive dysfunction. PMID- 21270647 TI - Posterior optic nerve ischemic neuropathy in the setting of phenoxybenzamine therapy after uneventful spinal fusion. PMID- 21270648 TI - Renal cancer risk and occupational exposure to polycyclic aromatic hydrocarbons and plastics. AB - OBJECTIVE: To investigate whether occupational exposure to polycyclic aromatic hydrocarbons and certain plastic monomers increased renal cell carcinoma (RCC) risk. METHODS: Unconditional logistic regression was used to calculate RCC risk in relation to exposure. RESULTS: No association between RCC risk and having ever been occupationally exposed to any polycyclic aromatic hydrocarbons or plastics was observed. Duration of exposure and average exposure also showed no association with risk. Suggestive positive associations between RCC risk and cumulative exposure to styrene (P-trend = 0.02) and acrylonitrile (P-trend = 0.06) were found. Cumulative exposure to petroleum/gasoline engine emissions was inversely associated with risk (P-trend = 0.02). CONCLUSIONS: Results indicate a possible association between occupational styrene and acrylonitrile exposure and RCC risk. Additional studies are needed to replicate findings, as this is the first time these associations have been reported and they may be due to chance. PMID- 21270649 TI - Trends in the health care use and expenditures associated with no-lost-time claims in Ontario: 1991 to 2006. AB - OBJECTIVE: To examine trends in health care usage and expenditures associated with no-lost-time claims in Ontario over a 15-year period. METHODS: A secondary analysis of administrative workers' compensation claims occurring between 1991 and 2006 (N = 2,290,101). We used regression analysis to model health care expenditures using a zero-inflated linear model, adjusting for age, gender, industry group and size of payroll. RESULTS: The probability of using health care increased over the time period. Health care expenditures per claim declined between 1991 and 1997, but then increased between 1998 and 2006, coinciding with the introduction of occupational health and safety legislation promoting early return to work in Ontario. CONCLUSIONS: Our results provide support to the hypothesis that the increasing use of workplace accommodation since 1998 is a driver of the relatively stable rate of no-lost-time claims in Ontario. PMID- 21270650 TI - The impact of worksite wellness in a small business setting. AB - OBJECTIVE: This study evaluates the level of participation and effectiveness of a worksite wellness program in a small business setting. METHODS: Three years of wellness participation and risk data from Lincoln Industries was analyzed. RESULTS: All Lincoln Industry employees participated in at least some level of wellness programming. Significant improvements in body fat, blood pressure, and flexibility were observed across time. The largest improvements in risk were seen among older employees and those with the highest baseline values. CONCLUSIONS: This small business was able to improve the health of the entire workforce population by integrating wellness deeply into their culture and operations. Replication of this program in other small business settings could have a large impact on public health since 60 million adults in the United States work in small businesses. PMID- 21270651 TI - The relationship between patient-reported tolerability issues with oral antidiabetic agents and work productivity among patients having type 2 diabetes. AB - OBJECTIVE: To investigate the association between reported oral antidiabetic tolerability issues and work productivity, activity impairment, and indirect costs. METHODS: Data were collected from the 2006 to 2008 US National Health and Wellness Survey and the Lightspeed Research, using an Internet-based questionnaire (N = 2074). RESULTS: Absenteeism, presenteeism, overall work impairment, and activity impairment increased as the number of tolerability issues increased. Similar results were observed using a diabetes-specific productively measure. Total annual adjusted indirect costs (absenteeism and presenteeism costs summed) were $2759, $5533, $7537, and $8405 for patients with 1, 2, 3, and 4 or more tolerability issues, respectively. CONCLUSIONS: The consideration of tolerability profiles of oral antidiabetic agents may lead to improved productivity among treated patients. Furthermore, targeted educational programs regarding risks and management of these issues to employees with type 2 diabetes mellitus may benefit both employers and patients. PMID- 21270652 TI - Associations of outdoor air pollution with hemorrhagic stroke mortality. AB - OBJECTIVE: Evidence linking short-term exposure to outdoor air pollution with hemorrhagic stroke is inconsistent. METHODS: We evaluated the associations between outdoor air pollution and specific types of stroke in Tokyo, Japan, from April 2003 to December 2008. We obtained daily counts of stroke mortality (n = 41,440) and concentrations of nitrogen dioxide as well as particles less than 2.5 MUm in diameter. Time-series analysis was employed. RESULTS: Although same-day air pollutants were positively associated with ischemic stroke and intracerebral hemorrhage mortality, both air pollutants were more strongly associated with subarachnoid hemorrhage mortality: rate ratio was 1.041 (95% confidence interval: 1.011-1.072) for each 10 MUg/m3 increase in the previous-day particles less than 2.5 MUm. CONCLUSIONS: This study suggests that short-term exposure to outdoor air pollution increases the risks of hemorrhagic stroke mortality as well as ischemic stroke mortality. PMID- 21270653 TI - Health indicators among unemployed and employed young adults. AB - OBJECTIVE: Research on the prevalence of health indicators by employment status among young US adults is limited. METHODS: We analyzed data from a nationally representative sample of young adults aged 18 to 24 years to document the prevalence of five health behaviors (cigarette smoking, risky drinking, leisure time physical activity, and fruit and French fries consumption) by employment status. RESULTS: Unemployed young adults reported higher levels of risky drinking and nonengagement in leisure-time physical activity, while employed young adults had higher levels of smoking, French fries consumption, and low fruit/vegetable consumption. Transportation/material-moving young adult workers reported the highest level of risky drinking (13.5%), and precision production/craft/repair workers reported the highest smoking rates (39.7%). CONCLUSIONS: We found an elevated prevalence of risk factors, which places young workers at increased risk for the development of chronic conditions later in life. PMID- 21270654 TI - Neurologic symptoms associated with raising poultry and swine among participants in the Agricultural Health Study. AB - OBJECTIVE: Guillain-Barre Syndrome (GBS) is the leading cause of acute peripheral neuropathy worldwide, often associated with recent foodborne infection with Campylobacter jejuni. In this cross-sectional analysis of data from the Agricultural Health Study, we tested whether swine and poultry exposure were associated with increased prevalence of GBS-like neurologic symptoms. METHODS: Using multivariate analysis, we tested the symptoms such as numbness and weakness, relevant to inflammatory peripheral neuropathies, among farmers with self-reported occupational poultry or swine exposure compared with farmers who reported no occupational animal exposure. RESULTS: Among swine farmers/workers, prevalence of weakness and numbness were increased (P < 0.05). Among poultry farmers/workers, prevalence of weakness and numbness were increased, but increased prevalence of weakness was not statistically significant. CONCLUSIONS: Occupational contact with live poultry or swine, potentially related to C. jejuni exposure, was associated with increased reporting of GBS-like symptoms. PMID- 21270655 TI - Influence of psychosocial work environment on adherence to workplace exercise. AB - OBJECTIVE: Physical exercise can reduce the prevalence of musculoskeletal disorders, but adherence to exercise is challenging for many employees. This study determines prognostic factors for adherence to workplace exercise. METHODS: In Copenhagen, 132 office workers with neck/shoulder pain were randomized to 2 or 12 minutes of exercise five days a week. Low, medium, and high adherence was defined as performing less than 10, 10-30, or more than 30 exercise sessions during the subsequent 10 weeks. Odds ratios (OR) for adherence were modeled by logistic regression. RESULTS: Lower adherence to the 10-week exercise program was predicted by poorer psychosocial work environment and lower exercise self efficacy. A longer exercise program was not associated with lower adherence. CONCLUSIONS: Concurrent strategies to improve psychosocial work environment and individual exercise beliefs should be considered when implementing exercise at the workplace. PMID- 21270656 TI - Psychological distress, depression, and burnout: similar contribution of the job demand-control and job demand-control-support models? AB - OBJECTIVE: This study examines the contribution of the Job Demand-Control (JDC) and the Job Demand-Control-Support (JDCS) models to three mental health outcomes. METHODS: Data were collected from 410 Canadian municipal police employees. Mental health was evaluated with the General Health Questionnaire 12 items (GHQ-12), the Beck Depression Inventory (BDI-21) 21 items, and the Maslach Burnout Inventory 16 items general survey (MBI-16). Karasek's Job Content Questionnaire was used to measure JDC and JDCS. RESULTS: The results revealed a differential impact of JDC and JDCS models according to the type of mental health outcome. The MBI-16 was the best-predicted outcome. Interactions at the core of the JDC and JDCS models were weakly supported. CONCLUSIONS: The JDC and JDCS models contribute differently to workers mental health, depending on the instrument used to measure mental health. Implications for workplace health interventions are discussed. PMID- 21270657 TI - Organizational change and employees' mental health: the protective role of sense of coherence. AB - OBJECTIVE: To examine the impact of sense of coherence (SOC) on psychiatric events in the context of organizational merger. METHODS: Data were derived from a prospective "Still Working" study using questionnaire and health register data. The study population (n = 4279) consisted of employees with no psychiatric events prior to the 5-year mental health follow-up. RESULTS: Employees with a weaker premerger SOC were at a higher risk of perceiving the organizational change negatively (odds ratio = 1.83, 95% CI: 1.57 to 2.14) and had an elevated risk of postmerger psychiatric events (hazard ratio = 1.42, 95% CI: 1.04 to 1.94). A stronger SOC decreased the adverse effect of negative appraisal of change on psychiatric events. CONCLUSIONS: A strong premerger SOC seems to be a protective factor for mental health when the employee experiences negative changes during an organizational merger. PMID- 21270658 TI - The genetics of altitude tolerance: the evidence for inherited susceptibility to acute mountain sickness. AB - OBJECTIVE: Acute mountain sickness (AMS) has become a significant environmental health issue as improvements in transportation, "environmental tourism," and resource development lure more people to the highlands. Whether there is a genetic contribution to AMS susceptibility is a central question in high-altitude medicine. This article provides a systematic review of the evidence supporting such an innate predisposition. METHODS: Scientific literature databases were screened using the terms "acute mountain sickness/AMS" and "altitude illness" combined with the terms "DNA," "gene," "genetic," or "polymorphism." RESULTS: Sixteen genes from a variety of pathways have been tested for association with AMS and variants in eight showed positive associations suggesting that AMS is an environmentally mediated polygenic disorder. CONCLUSIONS: The data suggest that genotype contributes to capacity to rapidly and efficiently acclimatize to altitude; nevertheless, the mechanisms by which this occurs have yet to be elucidated. PMID- 21270659 TI - Factors associated with obstructive sleep apnea among commercial motor vehicle drivers. AB - OBJECTIVE: Identify factors associated with obstructive sleep apnea (OSA) risk during commercial driver medical examinations. METHODS: A case-control study was conducted at an occupational health clinic by reviewing the commercial driver medical examinations medical records performed from January 2007 to December 2008. The magnitude of association with OSA was estimated with logistic regression. RESULTS: Among 1890 commercial motor vehicle drivers, 51 were confirmed positive for OSA by polysomnography after initial screening by Joint Task Force guidelines, yielding estimated positive predictive values of 78.5% for the screening criteria. Multivariable logistic regression showed that body mass index >= 30 (odds ratio: 26.86), hypertension (odds ratio: 2.57), and diabetes (odds ratio: 2.03) were independently associated with OSA. CONCLUSION: Medical examiners' use of objectively measurable risk factors, such as obesity, history of hypertension, and/or diabetes, rather than symptoms, may be more effective in identifying undiagnosed OSA in commercial drivers during the commercial driver medical examinations. PMID- 21270660 TI - Organizational justice, willingness to work, and psychological distress: results from a private Japanese company. AB - OBJECTIVES: This study assessed the risk of low organizational justice (OJ) on psychological distress as well as on low willingness to work, and also investigated the underlying factors between OJ and these outcomes. METHODS: Cross sectional questionnaire data of 1804 employees (93.6% of subjects) of a Japanese company were collected. Logistic regression analysis was conducted to explore the objectives. RESULTS: Subjects with low overall OJ had a higher risk of psychological distress compared with their counterparts (odds ratio: 4.93; 95% confidence interval: 3.17 to 7.68). The corresponding odds ratio for low willingness to work was 2.87 (95% confidence interval: 2.06 to 4.00). Job satisfaction and organizational citizenship behavior play a role of mediation between OJ and these outcomes. CONCLUSION: Low OJ was a notable risk factor for psychological distress as well as for low willingness to work. High OJ might prevent psychological distress and promote willingness to work. PMID- 21270661 TI - The association between shift work and unhealthy weight: a cross-sectional analysis from the Nurses and Midwives' e-cohort Study. AB - OBJECTIVE: To examine the association between shift work and unhealthy weight among female nurses and midwives. METHODS: A cross-sectional study. Measurement outcomes included shift work, unhealthy weight (underweight: body mass index [BMI] < 18.5; overweight: BMI 25.0 to 29.9; obesity: BMI > 30.0), diet quality, physical-activity level, alcohol consumption, and smoking status. RESULTS: Among the 2494 participants (1259 day and 1235 shift workers), only 1% of the participants were underweight, 31.8% were overweight, and 26.9% were obese. After adjusting the selected confounders, shift workers were 1.15 times more likely to be overweight/obese than day workers (P = 0.013, 95% confidence interval, 1.03 to 1.28; P = 0.02, 95% confidence interval, 1.02 to 1.30, respectively). CONCLUSIONS: Shift work is associated with higher risk of being overweight/obese. Longitudinal studies are being undertaken to better understand the causal relationship between shift work and unhealthy weight. PMID- 21270662 TI - An observed relationship between vestibular function and auditory thresholds in aircraft-maintenance workers. AB - OBJECTIVE: We sought to examine the vestibular function and whether an association exists between vestibular function and hearing thresholds in a group of military aircraft-maintenance workers with exposures to high levels of noise and organic solvents, relative to two different comparison groups. METHODS: Vestibular function (using functional reach) and hearing (with pure-tone audiometry) were assessed in 601 exposed personnel, compared with two unexposed groups (500 technical trade and 391 nontrade). RESULTS: Linear regression model showed that functional reach was slightly better for the comparison groups than the exposed group, with only one group being statistically significant, and there was a significant association between vestibular function and auditory thresholds at 500 and 1000 Hz. CONCLUSION: This study has demonstrated a relationship between low-frequency hearing loss, vestibular dysfunction, anxiety, and depression in an occupational population. PMID- 21270663 TI - Low-socioeconomic status workers: their health risks and how to reach them. AB - OBJECTIVE: To help workplace health promotion practitioners reach low socioeconomic status workers at high risk for chronic diseases. METHODS: We describe low-socioeconomic status workers' diseases, health status, demographics, risk behaviors, and workplaces, using data from the Behavioral Risk Factor Surveillance System, Medical Expenditure Panel Survey, and Bureau of Labor Statistics. RESULTS: Workers with household annual incomes less than $35,000, or a high school education or less, report more chronic diseases and lower health status. They tend to be younger, nonwhite, and have much higher levels of smoking and missed cholesterol screening. They are concentrated in the smallest and largest workplaces and in three low-wage industries that employ one-quarter of the population. CONCLUSIONS: To decrease chronic diseases among low-socioeconomic status workers, we need to focus workplace health promotion programs on workers in low-wage industries and small workplaces. PMID- 21270664 TI - Association of self-rated physical health and incident hypertension with O*NET factors: validation using a representative national survey. AB - OBJECTIVE: To examine the predictive validity of Occupational Information Network (O*NET)-based constructs with health outcomes. METHODS: Data from the National Survey of Midlife in the United States (MIDUS) surveys were used to examine associations of self-rated health and incident hypertension with work characteristics. Job control and substantive complexity (SC) scores derived from the O*NET were imputed to occupation in the MIDUS surveys. Validity was assessed through variance partitioning and regression models contrasting O*NET and survey based constructs. RESULTS: Congruence between control scores derived from O*NET and from self-rated scores from MIDUS was good. Shared variance between SC scores and survey-based control was less. All constructs were modest predictors of self rated health. Substantive complexity was a stronger predictor of incident hypertension (Adjusted Odds Ratio = 1.87). CONCLUSIONS: Occupational characteristics derived from O*NET variables performed as well as or better than survey-based job control in describing associations with self-rated health and incident hypertension. PMID- 21270665 TI - Summary of presentations from the 46th annual meeting of the American Society of Clinical Oncology (2010): focus on supportive care issues related to lung cancer. AB - BACKGROUND: Patients with advanced cancer, particularly of the lung, frequently experience deteriorating physical health. Supportive care measures help ensure optimal quality of life during difficult psychologic and social situations. Research in the area of supportive care in patients with cancer should be made a priority. METHODS: This review summarizes the findings from selected supportive care studies presented at the recently concluded 46 annual meeting of the American Society of Clinical Oncology. DISCUSSION: Topics discussed include the use of a single dose of fosaprepitant for prevention of chemotherapy-induced nausea and vomiting, statins to lower the incidence of venous thromboembolic events, fentanyl pectin nasal spray for cancer-related pain, and a closer look at the utilization of complementary and alternative medicine in patients with cancer. PMID- 21270666 TI - The human immunodeficiency virus protease inhibitor ritonavir inhibits lung cancer cells, in part, by inhibition of survivin. AB - INTRODUCTION: Ritonavir is a potential therapeutic agent in lung cancer, but its targets in lung adenocarcinoma are unknown, as are candidate biomarkers for its activity. METHODS: RNAi was used to identify genes whose expression affects ritonavir sensitivity. Synergy between ritonavir, gemcitabine, and cisplatin was tested by isobologram analysis. RESULTS: Ritonavir inhibits growth of K-ras mutant lung adenocarcinoma lines A549, H522, H23, and K-ras wild-type line H838. Ritonavir causes G0/G1 arrest and apoptosis. Associated with G0/G1 arrest, ritonavir down-regulates cyclin-dependent kinases, cyclin D1, and retinoblastoma protein phosphorylation. Associated with induction of apoptosis, ritonavir reduces survivin messenger RNA and protein levels more than twofold. Ritonavir inhibits phosphorylation of c-Src and signal transducer and activator of transcription protein 3, which are important events for survivin gene expression and cell growth, and induces cleavage of PARP1. Although knock down of survivin, c-Src, or signal transducer and activator of transcription protein 3 inhibits cell growth, only survivin knock down enhances ritonavir inhibition of growth and survivin overexpression promotes ritonavir resistance. Ritonavir was tested in combination with gemcitabine or cisplatin, exhibiting synergistic and additive effects, respectively. The combination of ritonavir/gemcitabine/cisplatin is synergistic in the A549 line and additive in the H522 line, at clinically feasible ritonavir concentrations (<10 MUM). CONCLUSIONS: Ritonavir is of interest for lung adenocarcinoma therapeutics, and survivin is an important target and potential biomarker for its sensitivity. Ritonavir cooperation with gemcitabine/cisplatin might be explained by involvement of PARP1 in repair of cisplatin-mediated DNA damage and survivin in repair of gemcitabine-mediated double-stranded DNA breaks. PMID- 21270667 TI - MicroRNA-101 exerts tumor-suppressive functions in non-small cell lung cancer through directly targeting enhancer of zeste homolog 2. AB - INTRODUCTION: Overexpression of the enhancer of zeste homolog 2 (EZH2) protein has been found in broad range of cancer types, including non-small cell lung cancer (NSCLC). Nevertheless, the mechanisms by which EZH2 becomes overexpressed in NSCLC remain unclear. MicroRNAs (miRNAs) can regulate target gene expression through translational control. In this study, we investigate whether miRNA (miR 101) regulates EZH2 expression in NSCLC. METHODS: We evaluated the expression of miR-101 and EZH2 in 20 matched NSCLC and adjacent nontumor lung tissues by reverse-transcriptase polymerase chain reaction and immunohistochemistry, respectively. Luciferase reporter assay was used to determine whether miR-101 directly targets EZH2. To assess the effect of miR-101 on NSCLC biological behavior, cell proliferation, invasion, and response to chemotherapy were analyzed using NSCLC cells transfected with miR-101 mimics or transfected with specific small interfering RNA to deplete EZH2 (small interfering RNA-EZH2). RESULTS: Reduced expression of miR-101 was associated with overexpression of EZH2 in NSCLC tumor tissues. Transfection of miR-101 mimics significantly suppressed the activity of the luciferase reporter containing wild type but not mutant EZH2 3'-UTR and decreased EZH2 expression in NSCLC cell lines. Furthermore, enforced expression of miR-101 or knockdown of EZH2 led to reduced NSCLC cell proliferation and invasion and sensitized cancer cells to paclitaxel-mediated apoptosis through inducing expression of the proapoptotic protein Bim. CONCLUSIONS: miR-101 inhibits cell proliferation and invasion and enhances paclitaxel-induced apoptosis in NSCLC cells, at least in part, by directly repressing EZH2 expression. Therapeutic strategies to rescue miR-101 expression or silence EZH2 may be beneficial to patients with NSCLC in the future. PMID- 21270668 TI - A practical guide of the Southwest Oncology Group to measure malignant pleural mesothelioma tumors by RECIST and modified RECIST criteria. AB - Malignant pleural mesothelioma (MPM) is difficult to measure radiographically due to the nonradial and variable pattern of growth and response to therapy. Inaccurate and inconsistent tumor measurements often compromise results from clinical trials that are dependent on identifying response rate and progression free survival. In this article, we sought to provide a practical guide through the Southwest Oncology Group on how to measure MPM by the updated RECIST version 1.1 and by modified RECIST. We hope that these steps will provide a simple means by which computed tomography measurements can be consistently performed, minimizing intra- and interobserver variability. With this consistency, we may be able to better estimate the prognosis and response to therapy. With greater utilization, we will be able to better understand the biology of MPM. PMID- 21270670 TI - The impact of menopause on voice: past, present, and future. PMID- 21270669 TI - Epidemiology and treatment costs of bone metastases from lung cancer: a French prospective, observational, multicenter study (GFPC 0601). AB - INTRODUCTION: The aim of this prospective, observational, multicenter study was to examine the epidemiology and management costs of bone metastatic disease (BMD) in patients with lung cancer. METHODS: The analysis included all patients with BMD from lung cancer diagnosed between May 2006 and May 2007 in 40 centers. We analyzed their management and the direct costs of BMD from the health care provider's perspective, using a Markov model. Skeletal-related event (SRE) was defined as pathological fractures, spinal cord compression, or hypercalcemia (clinical SRE [cSRE]) for an initial analysis; a second analysis included palliative radiotherapy and surgery (therapeutic SRE [tSRE]). RESULTS: Among the 554 patients enrolled (62 +/- 11 years, 76.5% males, 69.3% performance status 0/1, 91% non-small cell lung cancer), 24.7% had a cSRE and 26.7% a tSRE at baseline and 9% and 39% during follow-up, respectively; 81.8% received at least one chemotherapy cycle. The median survival time was 5.8 months, and the 1- and 2 year survival rates were 22% and 7%, respectively; there was no significant difference in overall survival between the patients with and without SRE at enrollment. The main BMD treatments were opiate therapy (77.7%), biphosphonates (52.3%), radiotherapy (42.1%), and surgery (9.2%). The mean monthly BMD treatment costs in euros were ?190, ?374, and ?4672 for asymptomatic patients, symptomatic patients, and patients with SRE, respectively. The average first-year BMD management cost in euros was ?3999 +/- 4135 (95% confidence interval: 374 15,886), and 49.5% of this cost was attributable to patients with SRE. CONCLUSIONS: This analysis confirms the poor prognosis of BMD from lung cancer and underlines the burden of SRE in overall treatment costs. PMID- 21270671 TI - Corneal crystals: a precursor to cancer. AB - PURPOSE: Corneal crystalline deposits are a sign of a limited number of conditions that can often be differentiated based on the appearance and pattern of the deposits. Although, there are limited treatment options available to reduce the appearance or effects of corneal crystals, it is important to identify the correct etiology of these deposits. There are several associated systemic conditions, some of which are life threatening, for which treatments are available. METHODS: A 51-year-old black male presented to the clinic with the complaint of "glare at night due to crystals on [the] cornea." Slitlamp findings revealed diffuse subepithelial and anterior stromal crystals across both corneas. RESULTS: The patient had a medical history of renal insufficiency and arthralgia. Through systemic testing, the patient was found to have monoclonal gammopathy of undetermined significance (MGUS), and subsequent follow-up of this patient revealed a conversion of MGUS to multiple myeloma. CONCLUSIONS: Corneal crystals can appear diffusely through the cornea secondary to corneal dystrophies, gammopathies, cystinosis, or other rare systemic conditions. In this case report, these crystals are secondary to MGUS, which progressed to multiple myeloma. These crystals consist of immunoglobulin, primarily IgG, and excessive kappa light chains. It is important to obtain laboratory tests and make appropriate referrals to determine whether corneal crystal deposits are associated with a serious systemic disease or merely a corneal dystrophy. PMID- 21270672 TI - Lens Dk/t influences the clinical response in overnight orthokeratology. AB - PURPOSE: To investigate the influence of lens oxygen transmissibility (Dk/t) on the clinical response to overnight (ON) orthokeratology (OK) lens wear over 2 weeks. METHODS: Eleven subjects (age, 20 to 39 years) were fitted with OK lenses (BE; Capricornia Contact Lens) in both eyes. Lenses in matched design/fitting but different materials (Boston EO and XO; nominal Dk/t: 26 and 46 ISO Fatt, respectively) were worn ON only in the two eyes over a 2-week period. Changes in logarithm of the minimum angle of resolution visual acuity, subjective refraction (spherical equivalent), corneal apical radius ro and asphericity Q (Medmont E300), and central stromal thickness (Holden-Payor optical pachometer) were measured. RESULTS: There were statistically significant differences in outcomes between the two lens materials (analysis of variance, p < 0.001) throughout the study. After 2 weeks of ON OK lens wear, changes from baseline (mean +/- standard deviation) with the EO lenses were significantly less than XO for visual acuity ( 0.72 +/- 0.37 vs. -0.83 +/- 0.41; p = 0.012), refraction [+2.19 +/- 0.73 diopter (D) vs. +2.74 +/- 0.70 D; p = 0.004], ro (0.34 +/- 0.08 mm vs. 0.46 +/- 0.11 mm; p < 0.001), and Q (0.26 +/- 0.08 vs. 0.36 +/- 0.08; p < 0.001). After the first ON OK lens wear, change in central stromal thickness was greater for EO compared with XO (27 +/- 36 MUm vs. 10 +/- 31 MUm; p = 0.05), but ON edema was reduced after 2 weeks for both lens materials (8 +/- 25 MUm vs. -1 +/- 33 MUm; p > 0.05). CONCLUSIONS: An increase in lens Dk/t appears to increase the clinical effects of ON reverse-geometry lens wear over the medium term. This adds further support to the recommendation that high Dk materials should be used for ON OK not only to provide physiological advantages but also to optimize clinical outcomes. PMID- 21270673 TI - Correlation of both corneal surfaces in corneal ectasia after myopic LASIK. AB - We report a case of corneal ectasia in a 25-year-old man after myopic laser in situ keratomileusis in which a complete characterization of the corneal structure was performed by means of a Scheimpflug photography-based system. The patient presented in the ectatic eye with a subjective refraction of +0.50 to 6.00 * 100 degrees , which with correction gave a visual acuity of 20/25. With the topographic analysis, corneal shapes from both corneal surfaces at the four different quadrants were found to be complementary, maintaining the meniscus shaped profile of the cornea. This correlation between the anterior and posterior corneal surfaces was also confirmed with an optical tomography evaluation. Corneal biomechanics was also evaluated by means of the Ocular Response Analyzer (Reichert), which confirmed the biomechanical alteration. In summary, biomechanical changes leading to corneal ectasia in this case affected the global corneal structure, inducing alterations in the shape of both anterior and posterior corneal surfaces. PMID- 21270674 TI - Keeping the world in focus: how might this be achieved? AB - To see clearly, the eye needs to have a sharply focused image on its retina. For distance vision, the eye should ideally develop toward emmetropia, and for near vision, the accommodation system should produce an appropriate increase in ocular power. The characteristics of the emmetropization and accommodation mechanisms are compared. Following Howland (paper presented at the 13th International Myopia Conference, July 26-29, 2010, Tubingen, Germany), it is suggested that emmetropization may be guided by imagery in the peripheral retina, perhaps making use of oblique astigmatism; however, such a mechanism can only be effective if dioptric stimuli approximate to 0 across the visual field, as is the case in many outdoor environments. In contrast, the accommodation system must be driven mainly by the axial image, because during most close work, dioptric stimuli vary widely across the peripheral field. Thus, the differences between the emmetropization and accommodation mechanisms may reflect the nature of the spatial distribution of object vergence in the outdoor and near environments. PMID- 21270675 TI - Fetal hippocampal development: analysis by magnetic resonance imaging volumetry. AB - The hippocampal formation plays an important role in learning and memory; however, data on its development in utero in humans are limited. This study was performed to evaluate hippocampal development in healthy fetuses using 3D reconstructed MRI. A cohort of 20 healthy pregnant women underwent prenatal MRI at a median GA of 24.9 wk (range, 21.3-31.9 wk); six of the women also had a second fetal MRI performed at a 6-wk interval. Routine 2D ultrafast T2-weighted images were used to reconstruct a 3D volume image, which was then used to manually segment the right and left hippocampi. Total hippocampal volume was calculated for each subject and compared against GA. There was a linear increase in total hippocampal volume with increasing GA (p < 0.001). For subjects scanned twice, there was an increase in hippocampal size on the second fetal MRI (p = 0.0004). This represents the first volumetric study of fetal hippocampal development in vivo. This normative volumetric data will be helpful for future comparison studies of suspected developmental abnormalities of hippocampal structure and function. PMID- 21270676 TI - A glucosylceramide synthase inhibitor protects rats against the cytotoxic effects of shiga toxin 2. AB - Postdiarrhea hemolytic uremic syndrome is the most common cause of acute renal failure in children in Argentina. Renal damage has been strongly associated with Shiga toxin (Stx), which binds to the globotriaosylceramide (Gb3) receptor on the plasma membrane of target cells. The purpose of the study was to evaluate the in vivo effects of C-9, a potent inhibitor of glucosylceramide synthase and Gb3 synthesis, on kidney and colon in an experimental model of hemolytic uremic syndrome in rats. Rats were i.p. injected with supernatant from recombinant Escherichia coli expressing Stx2 (sStx2). A group of these rats were orally treated with C-9 during 6 d, from 2 d prior until 4 d after sStx2 injection. The injection of sStx2 caused renal damage as well as a loss of goblet cells in colonic mucosa. Oral treatment with C-9 significantly decreased rat mortality to 50% and reduced the extension of renal and intestinal injuries in the surviving rats. The C-9 also decreased Gb3 and glucosylceramide expression levels in rat kidneys. It is particularly interesting that an improvement was seen when C-9 was administered 2 d before challenge, which makes it potentially useful for prophylaxis. PMID- 21270677 TI - Hyperoxia impairs alveolar formation and induces senescence through decreased histone deacetylase activity and up-regulation of p21 in neonatal mouse lung. AB - Alveolar development comprises the transition of lung architecture from saccules to gas-exchange units during late gestation and early postnatal development. Exposure to hyperoxia disrupts developmental signaling pathways and causes alveolar hypoplasia as seen in bronchopulmonary dysplasia affecting preterm human newborns. Expanding literature suggests that epigenetic changes caused by environmental triggers during development may lead to heritable changes in gene expression. Given recent data on altered histone deacetylase (HDAC) activity in lungs of humans and animal models with airspace enlargement/emphysema, we hypothesized that alveolar hypoplasia from hyperoxia exposure in neonatal mice is a consequence of cell cycle arrest and reduced HDAC activity and up-regulation of the cyclin-dependent kinase inhibitor, p21. We exposed newborn mice to hyperoxia and compared lung morphologic and epigenetic changes to room air controls. Furthermore, we pretreated a subgroup of animals with the macrolide antibiotic azithromycin (AZM), known to possess antiinflammatory properties. Our results showed that hyperoxia exposure resulted in alveolar hypoplasia and was associated with decreased HDAC1 and HDAC2 and increased p53 and p21 expression. Furthermore, AZM did not confer protection against hyperoxia-induced alveolar changes. These findings suggest that alveolar hypoplasia caused by hyperoxia is mediated by epigenetic changes affecting cell cycle regulation/senescence during lung development. PMID- 21270679 TI - The functional rating index: reliability and validity of the Persian language version in patients with low back pain. AB - STUDY DESIGN: Crosscultural adaptation and psychometric measurements of the Functional Rating Index (FRI). OBJECTIVE: To develop and investigate the reliability and validity of the Persian version of the FRI when applied to patients with low back pain (LBP). SUMMARY OF BACKGROUND DATA: The FRI is a self report questionnaire designed to assess patient's perception of function and pain. Despite the use of this outcome measure in clinical trials in Iran, it was not translated and culturally adapted. METHODS: The FRI was translated into Persian language and crossculturally adapted. The Persian FRI was administered to 100 patients with LBP (male patients/female patients = 22/78). A numerical rating scale, the Roland-Morris Disability Questionnaire, the Oswestry Disability Questionnaire, and the Quebec Back Pain Disability Scale were also recorded. The test-retest reliability (time interval = 7 days) was assessed in 50 patients. RESULTS: There were no missing responses and floor or ceiling effects. The examination of discriminative validity showed that the questionnaire discriminated clearly between patients and healthy participants (P < 0.001). The concurrent criterion validity was confirmed by the Spearman rank correlation between the Persian FRI and the numerical rating scale (0.73, P < 0.0001 for test; and 0.77 for retest, P < 0.0001). Evidence for construct validity was found with a significant Pearson correlation between the FRI and the Roland-Morris Disability Questionnaire (r = 0.61; P < 0.0001), the Oswestry Disability Questionnaire (r = 0.75; P < 0.0001), or Quebec Back Pain Disability Scale (r = 0.76; P < 0.0001). Internal consistency reliability estimates (Cronbach alpha) for the Persian FRI were high, with 0.89 for test and 0.92 for retest. The test retest reliability for the total score was excellent with an intraclass correlation coefficient (agreement) (ICCagreement) of 0.81 (P < 0.0001). CONCLUSION: The Persian version of the FRI seems to have an excellent reliability and validity when applied to patients with LBP. PMID- 21270680 TI - Thoracic pedicle morphometry in different body height population: a three dimensional study using reformatted computed tomography. AB - STUDY DESIGN: A three-dimensional study of the thoracic pedicle (T1-T12) morphometry in Chinese patients with different body height, using reformatted computed tomography (CT). OBJECTIVE: To quantify the dimensions of the thoracic pedicles and to analyze the relationship between body height and thoracic pedicle parameters. SUMMARY OF BACKGROUND DATA: The thoracic pedicle morphometry has been studied extensively in different populations using various techniques. Previous studies have shown a significantly smaller size of the thoracic pedicles in women than in men and in Asians than in Caucasians. Some authors postulated that it is the body height that contributes to the variation in the pedicle size. To our knowledge, however, no study has specifically analyzed the relationship between body height and thoracic pedicle parameters in detail. METHODS: In this study, T1 to T12 vertebrae were imaged in 126 Chinese patients by a Lightspeed Vct CT (General Electric, Bridgeport, Connecticut, USA). After reformatting the original images, the following parameters were calculated: outer pedicle width, outer pedicle height and pedicle cortical thickness of the pedicle isthmus, pedicle length, and transverse pedicle angle. All measured data were statistically analyzed by the independent t test and Pearson correlation test using SPSS software (SPSS Inc, Chicago, IL). RESULTS: The thoracic pedicle parameters were significantly smaller in women than in men except for the transverse pedicle angles and the pedicle cortical thickness. The percentage of outer pedicle widths less than 4.5 mm was extremely high at T3 to T9 in females and T4 to T7 in males. There was a much higher percentage of pedicle width of 4.5 mm or lesser, 4.0 mm or lesser, and 3.5 mm or lesser when body height was less than 160 cm. Body height is probably one of the main factors that contribute to the variation in pedicle size since a significant positive correlation was observed between pedicle size and body height. CONCLUSION: Body height is probably one of the main factors that contribute to the variation in pedicle size among different ethnic and sex groups. Transpedicular procedures using a 4.5-mm screw may not be applicable to much of the Chinese population at the upper and middle thoracic segments, especially for patients less than 160 cm in height. A reformatted CT evaluation is routinely recommended not only for choosing the proper screw but also for determining the feasibility of a true transpedicular procedure. PMID- 21270681 TI - The chemokines CXCL10 and XCL1 recruit human annulus fibrosus cells. AB - STUDY DESIGN: Human annulus fibrosus tissue and cells were analyzed for the presence of chemokine receptors and the migratory effect of selected chemokines. OBJECTIVE: To investigate spontaneous repair mechanisms and underlying cell recruitment in response to annular tears and degenerative defects. SUMMARY OF BACKGROUND DATA: Resorption of herniated disc tissue and the attempt to close annulus tears with repair tissue occur spontaneously. Although chemokines are suggested to play a role in resorption of herniated disc tissue, the role of chemokines in annulus fibrosus homeostasis and repair remains unclear. METHODS: Cells were isolated from annulus fibrosus tissue and expanded in the presence of human serum. Multiwell chemotaxis assays were used to analyze the migratory effect of human serum and 0 to 1000 nM concentrations of the chemokines CXCL7, CXCL10, CXCL12, CCL25, and XCL1 on annulus fibrosus cells (AFCs) (n = 9 per chemokine and dose). Presence of corresponding chemokine receptors in AFCs was determined by real-time polymerase chain reaction analysis and immunohistochemistry. RESULTS: Serum (0.1%-10%) significantly (P < 0.01) stimulates the migration of AFCs. Compared with untreated cells, the migration of cells was significantly (P < 0.01) enhanced upon stimulation with 100 to 1000 nM CXCL10 and 1000 nM XCL1. Chemokine receptors showed low expression levels in expanded AFCs as assessed by polymerase chain reaction. Immunohistochemical staining of the CXCL10 receptor CXCR3 and the XCL1 receptor XCR1 showed that the presence of the particular receptors in AFCs expanded under conventional cell culture conditions. In native annulus fibrosus tissue, CXCR3 was evident, whereas XCR1 could not be detected. CONCLUSION: The findings suggest that chemokines, in particular CXCL10, effectively recruit isolated AFCs. This suggests that chemokines are involved in annulus fibrosus homeostasis and potentially in spontaneous annulus repair attempts. This might have important implications for biological annulus-sealing strategies. PMID- 21270682 TI - Lumbar disc degeneration induces persistent groin pain. AB - STUDY DESIGN: Prospective study of 212 patients with groin pain but without low back pain. OBJECTIVE: To evaluate discogenic groin pain without low back pain or radicular pain. SUMMARY OF BACKGROUND DATA: Patients feel low back pain originating from discogenic disease. It has been reported that the rat lower lumbar discs are innervated mainly by L2 dorsal root ganglion neurons. Thus, it is possible that patients feel referred groin pain corresponding to the L2 dermatome originating from intervertebral discs; however, the referred pain has not been fully clarified in humans. METHODS: We selected 5 patients with groin pain alone for investigation. The patients suffered from groin pain and showed disc degeneration only at 1 level (L4-L5 or L5-S1) on magnetic resonance imaging. Patients did not show any hip joint abnormality on radiography or magnetic resonance imaging. To prove that their groin pain originated in degenerated intervertebral discs, we evaluated changes in groin pain after infiltration of lidocaine into hip joints and examined pain provocation on discography, pain relief by anesthetic discoblock, and finally anterior lumbar interbody fusion surgery. RESULTS: All patients were negative for hip joint block, positive for pain provocation on discography, and positive for pain relief by anesthetic discoblock. Furthermore, bony union was achieved 1 year after anterior interbody fusion surgery in all patients, and visual analogue scale score of groin pain was significantly improved at 1 year after surgery in all patients (P < 0.05). CONCLUSION: In the current study, we diagnosed discogenic groin pain, using magnetic resonance imaging, infiltration of lidocaine into the hip joint, pain provocation on discography, pain relief by anesthetic discoblock, and lumbar surgery. It is important to consider the existence of discogenic groin pain if patients do not show low back pain. PMID- 21270683 TI - Evaluation of bioabsorbable multiamino acid copolymer/alpha-tri-calcium phosphate interbody fusion cages in a goat model. AB - STUDY DESIGN: A study of cervical interbody fusion using polyamino acid-based bioabsorbable fusion cages in a goat model. OBJECTIVE: To compare interbody fusion of a bioabsorbable multiamino acid copolymer/alpha-tri-calcium phosphate (MAACP/alpha-TCP) fusion cage with an autologous tricortical iliac-crest bone graft and a titanium cage. SUMMARY OF BACKGROUND DATA: Polyamino acid is widely used as a carrier for drug delivery. To our knowledge, no study investigates interbody fusion cage made of polyamino acid. METHODS: A total of 15 sheep underwent C3/C4 discectomy and fusion. The following stabilization techniques were used: group A, autologous tricortical iliac crest bone graft (n = 5); group B, MAACP/alpha-TCP cage filled with autologous cancellous bone graft (n = 5); group C, titanium cage filled with autologous cancellous bone graft (n = 5). Radiographic scans to determine disc space height were performed before and after surgery and after 4, 8, and 12 weeks, respectively. After 12 weeks, the C3/C4 motion segment was isolated and sectioned to create a 5-mm thick parasagittal section from which lateral radiographs were obtained. All the radiographs were encoded and reviewed in a blinded fashion to evaluate interbody fusion within the cage devices according to a three-point radiographic score. Biomechanical testing was performed in flexion, extension, axial rotation, and lateral bending to determine range of motion (ROM). Histomorphological and histomorphometrical analyses were performed to evaluate fusion and foreign-body reactions associated with the bioabsorbable cages. RESULTS: Radiographic results showed that the disc space height (DSH) in MAACP/alpha-TCP cage group was better than that of bone graft group and the best radiographic score was found in MAACP/alpha-TCP cage group. Biomechanical test showed that no significant difference was found in ROM between MAACP/alpha-TCP cage group and titanium cage group whereas the value of ROM in bone graft group was the largest. Histologic evaluation showed a higher intervertebral bone volume/total volume ratio and a better interbody fusion in the MAACP/alpha-TCP cage group than in the other two groups. Two MAACP/alpha-TCP cages showed microcracks and the other three cages had maintained their original geometry. All MAACP/alpha-TCP cages showed excellent biocompatibility. CONCLUSION: After 12 weeks, there was no significant difference between the MAACP/alpha-TCP cage and the titanium cage in distractive properties and biomechanical properties. Compared with titanium cages, MAACP/alpha-TCP cages showed an advanced interbody fusion. Although MAACP/alpha-TCP cages developed cracks after only 12 weeks, they showed significantly better distractive properties, biomechanical properties, and an advanced interbody fusion than the tricortical iliac crest bone graft. Improvement should be made to insure the strength of MAACP/alpha-TCP cage last at least 6 month after implantion. PMID- 21270684 TI - Facet joints arthrosis in normal and stenotic lumbar spines. AB - STUDY DESIGN: A descriptive CT study of lumbar facet joint (FJ) arthrosis in general and spinal stenosis populations. OBJECTIVE: To reveal the prevalence of FJ arthrosis in general and stenosis populations and to establish its relationship to age and sex. SUMMARY OF BACKGROUND DATA: FJ arthrosis is a common radiographic finding and has been suggested as a cause of low back and lower extremity pain. It is also considered a dominant player in the genesis of lumbar spinal stenosis. Although it is well accepted that FJ arthrosis is an age dependent phenomenon, controversies still exist as to its association with sex and its prevalence at different spine levels. In addition, data on FJ arthrosis frequency in spinal stenosis population are missing. METHODS: Two groups were studied. The first included 65 individuals with LSS (mean age = 66 +/- 10 yr) and the second, 150 individuals (mean age = 52 +/- 19 yr) without LSS related symptoms. Both left and right FJ arthrosis for each vertebral level (L3-S1) were evaluated on CT images (Brilliance 64, Philips Medical System, Cleveland, OH). Chi-square, Linear-by-Linear Association and McNemar test were carried out to reveal the correlation between FJ arthrosis and demographic factors (age, sex) and prevalence at different lumbar levels in both stenosis and nonstenosis groups. In addition, a two-way analysis of variance (ANOVA) was used to determine the association between body mass index (BMI) and FJ arthrosis. RESULTS: The rate of FJ arthrosis at L3-L4 and L4-L5 were significantly higher (P < 0.001) in the stenotic group compared to the control. In the control group the prevalence of FJ arthrosis increases cephalocaudally (L3-L4 = 16%, L4-L5 = 28%, L5-S1 = 55%), whereas in the stenotic group there is a sharp increase from L3-L4 (27%) to L4-L5 (58%), but not from L4-L5 to L5-S1 (55%). No association between FJ arthrosis and sex was noted. Although, mean BMI was significantly smaller in the control group compared to the stenotic group, no association between BMI and facet arthrosis was found. In the general population the prevalence of FJ arthrosis at all three levels was greater for the right side; however, significant difference (P = 0.004) was obtained only for L3-L4. In all joints studied, the prevalence of FJ arthrosis increases considerably from the young age cohort (18-39) to the old age cohort (>60). Nevertheless, 10% of the young individuals (18-39) have already manifested FJ arthrosis at L5-S1. No arthrosis at that age was observed at L3-L4. CONCLUSION: FJ arthrosis is an age-dependent and BMI and sex independent phenomenon. In the general population, the prevalence of FJ arthrosis increases cephalocaudally with the highest frequency at L5-S1. In the stenotic group, the highest frequency was observed at the two caudal levels; L4-L5 and L5-S1. The prevalence of FJ arthrosis was greater for the right side. PMID- 21270685 TI - Early versus late stabilization of spine injuries: a systematic review. AB - STUDY DESIGN: Systematic review. OBJECTIVE: The objective of this study is to determine safety, benefits, outcomes, and costs of early versus late stabilization of spine injuries using data available in the current literature. SUMMARY OF BACKGROUND DATA: There is currently a lack of consensus regarding the timing of surgical stabilization of the injured spine. This is limited by the reality that a randomized clinical trial to evaluate early versus late surgery is difficult to design and perform. METHODS: A computer-aided search using the keywords Spine or Spinal, Trauma, Spinal Cord Injury, and Surgery that included MEDLINE, EMBASE, HealthSTAR, Cumulative Index to Nursing and Allied Health Literature, Cochrane Database of Systematic Reviews, ACP Journal Club, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, from January 1990 to July 2009 was done. RESULTS: Eleven articles directly comparing two cohorts that had early or late surgery were identified. All of the studies consistently demonstrated shorter hospital and intensive care unit length of stays, fewer days on mechanical ventilation and lower pulmonary complications in patients who are treated with early surgical spine decompression and stabilization. These advantages are more marked in patients with polytrauma. Consequently, costs associated with late surgery were higher compared with early surgery. CONCLUSION: There is evidence in the current literature to show that early surgical stabilization leads to shorter hospital stays, shorter intensive care unit stays, less days on mechanical ventilation and lower pulmonary complications. This effect is more evident in patients who have more severe associated injuries as measured by ISS. This benefit is seen in patients who have cord injury as well as those who do not. There is some evidence that early stabilization does not increase the complication rates compared with late surgery. PMID- 21270686 TI - Lumbar facet joint motion in patients with degenerative disc disease at affected and adjacent levels: an in vivo biomechanical study. AB - STUDY DESIGN: Controlled laboratory study. OBJECTIVE: To evaluate the effect of lumbar degenerative disc diseases (DDDs) on motion of the facet joints during functional weight-bearing activities. SUMMARY OF BACKGROUND DATA: It has been suggested that DDD adversely affects the biomechanical behavior of the facet joints. Altered facet joint motion, in turn, has been thought to associate with various types of lumbar spine pathology including facet degeneration, neural impingement, and DDD progression. However, to date, no data have been reported on the motion patterns of the lumbar facet joint in DDD patients. METHODS: Ten symptomatic patients of DDD at L4-S1 were studied. Each participant underwent magnetic resonance images to obtain three-dimensional models of the lumbar vertebrae (L2-S1) and dual fluoroscopic imaging during three characteristic trunk motions: left-right torsion, left-right bending, and flexion-extension. In vivo positions of the vertebrae were reproduced by matching the three-dimensional models of the vertebrae to their outlines on the fluoroscopic images. The kinematics of the facet joints and the ranges of motion (ROMs) were compared with a group of healthy participants reported in a previous study. RESULTS: In facet joints of the DDD patients, there was no predominant axis of rotation and no difference in ROMs was found between the different levels. During left-right torsion, the ROMs were similar between the DDD patients and the healthy participants. During left-right bending, the rotation around mediolateral axis at L4-L5, in the DDD patients, was significantly larger than that of the healthy participants. During flexion-extension, the rotations around anterioposterior axis at L4-L5 and around craniocaudal axis at the adjacent level (L3-L4), in the DDD patients, were also significantly larger, whereas the rotation around mediolateral axis at both L2-L3 and L3-L4 levels in the DDD patients were significantly smaller than those of the healthy participants. CONCLUSION: DDD alters the ROMs of the facet joints. The rotations can increase significantly not only at the DDD levels but also at their adjacent levels when compared to those of the healthy participants. The increase in rotations did not occur around the primary rotation axis of the torso motion but around the coupled axes. This hypermobility in coupled rotations might imply a biomechanical mechanism related to DDD. PMID- 21270687 TI - A cross-sectional survey of nonspecific low back pain among 2083 schoolchildren in China. AB - STUDY DESIGN: A cross-sectional survey of 2083 schoolchildren. OBJECTIVE: To investigate the prevalence of nonspecific low back pain (LBP) among schoolchildren aged between 10 and 18 years in China. SUMMARY OF BACKGROUND DATA: LBP have been a serious health problem in schoolchildren. On the basis of literature, the lifetime occurrence of nonspecific LBP in children and adolescents varies between 7% and 72%, but little is known about LBP among this demographic group in China. METHODS: Schoolchildren aged 10 to 18 years were sampled from two grades in an elementary school and four grades in a secondary school. Participants were asked to fill in a questionnaire on LBP. The questionnaire addressed demographic items, anthropometric factors and characteristics of nonspecific LBP, such as frequency, duration, nature, pain scale. Nonspecific LBP is defined as the pain in the back from the 12th ribs to the buttock area without organic factors. A total of 2235 questionnaires were distributed, of which 2100 were answered, a response rate of 93.7%. Among those answers, 2083 (977 from male students and 1106 from female students) provided measurable data. RESULTS: The occurrence of nonspecific LBP was high, with 29.1% students suffering from this condition in the past 3 months (24.7% in boys, 33.1% in girls). In addition, an increased occurrence was observed with age. The occurrences of LBP in 10 to 14 years and 15 to 18 years were 21.5% and 38.2%, respectively. In several aspects of LBP, statistically significant differences were observed between boys and girls, including the frequency of the pain (P = 0.003), the nature of the pain (P = 0.000), the likelihood of seeking for medical assistance (P = 0.007), the impact on normal daily life (P = 0.016), and the occurrence of LBP after bending over the desk for a period of time (P = 0.024). Female students had more frequent LBP and were less willing to see a physician. In addition, more female students (45/366) had LBP accompanied with radiating pain than male students (20/241). CONCLUSION: There is a high prevalence of LBP in Chinese schoolchildren. The occurrence of LBP increases with age in both sexes. LBP is significantly more prevalent in girls. PMID- 21270688 TI - Intervertebral thoracic disc calcification associated with ossification of posterior longitudinal ligament in an eleven-year-old child. AB - STUDY DESIGN: Intervertebral disc calcification of T6-T7, T7-T8 discs associated with ossification of posterior longitudinal ligament (OPLL) in a child is reported. OBJECTIVE: To discuss the natural history and management of calcification of T6-T7, T7-T8 discs with OPLL. SUMMARY OF BACKGROUND DATA: Calcified intervertebral discs are rare in children. Cervical disc calcification has already been described. However, thoracic disc calcification associated with OPLL has not been reported. METHODS: An 11-year-old boy presented with progressive back pain for 6 months. Neurologic examination showed numbness in both lower extremities. The knee jerk reflex of the patient was hypertonic. The muscle strength of both lower extremities were Grade 4, with reduction. He was treated with a lumbar belt for 2 weeks. RESULTS: Initial thoracic spine radiograph and CT scan showed two adjacent calcified discs of T6-T7, T7-T8 associated with T6-T7 OPLL, resulting in marked spinal canal stenosis. His neurologic symptoms subsided and his back pain disappeared after a 2-week conservative treatment. Three months later CT scan showed that the calcification of T6-T7, T7-T8 discs was aggravated, but the T6-T7 OPLL was relieved. CONCLUSION: The natural history of intervertebral disc calcification is usually benign. In this case, the improvement of OPLL is associated with the stabilization of the maturely fused calcified disc. Spontaneous resolution of the OPLL and recovery of normal neurologic function can be expected with conservative treatment. PMID- 21270689 TI - Symptomatic vertebral artery compression by the rod of a C1-C2 posterior fusion construct: case report and review of the literature. AB - STUDY DESIGN: Case report. OBJECTIVE: To report a rare complication of atlantoaxial fusion. SUMMARY OF BACKGROUND DATA: Vertebral artery injury is a serious complication of screw-based atlantoaxial fusion. To our knowledge, injury to the vertebral artery has only been described as a result of screw placement. We describe the first case of atlantoaxial fixation complicated by symptomatic and reversible external compression of the vertebral artery by the rod in a Harms construct. METHODS: Medical records and imaging reports were reviewed. RESULTS: A neurologically intact 84-year-old woman presented after a ground-level fall. Imaging revealed a nondisplaced type II odontoid fracture associated with a C1 ring fracture. She underwent a minimally invasive Harms atlantoaxial fusion. After surgery, she developed fluctuating level of consciousness in the setting of an otherwise normal neurologic and metabolic workup. A computed tomographic angiogram was obtained and showed good screw placement except for compression of the right vertebral artery from the right transfixing rod causing 75% luminal narrowing. She underwent a revision with rod shortening, and after surgery, improved neurologically, without any further episodes of altered mental status. CONCLUSION: In atlantoaxial fusion, the incidence of vertebral artery compression by the rod component of fusion construct may be underreported because it is difficult to detect with noncontrast computed tomography without computed tomographic angiography, which is not routinely obtained unless there is a high suspicion for vascular injury. We recommend inserting the rods with the cut (sharp) end pointing inferiorly, to avoid lacerating the vertebral artery. A vertebral artery compression from the rod in the absence of screw violation of the foramen transversarium should be considered in a patient with altered mental status after atlantoaxial fusion. PMID- 21270690 TI - Analgesic effects of prostaglandin E2 receptor subtype EP1 receptor antagonist: experimental study of application of nucleus pulposus. AB - STUDY DESIGN: The effect of an EP1 receptor antagonist on pain-related behavior induced by nucleus pulposus (NP) applied to the dorsal root ganglion (DRG) in rats was investigated. OBJECTIVE: We investigated pain-related behavior, the amount of prostaglandin E2 (PGE2), and neural damage to the DRG after application of NP to the DRG after administration of an EP1 receptor antagonist. SUMMARY OF BACKGROUND DATA: PGE2 induces mechanical allodynia and hyperalgesia, which are mediated by PGE2 receptors. EP1 is one of the PGE2 receptor subtypes. An EP1 antagonist reduces hyperalgesia, allodynia, and c-fos expression in the rat chronic nerve constriction model. METHODS: Sprague-Dawley rats (n = 103) were used. Animals receiving NP were divided into three experimental groups (n = 12 in each group): saline, high-dose (5 mg/kg) EP1 receptor antagonist (RA), and low dose (2.5 mg/kg) EP1-RA (orally once daily for 5 days). Animals in the sham group did not receive NP. Von Frey tests were used for pain-behavior testing. The amount of PGE2 in DRG and the number of activating transcription factor-3 (ATF3) immunoreactive positive cells were compared among groups. RESULTS: The mechanical thresholds in the three groups decreased 7 days after surgery (just before treatment). The threshold in both the high- and low-dose EP1-RA groups increased at 11 days (5 days after treatment) and continued for 14 days. The thresholds in both the low- and high-dose EP1-RA groups increased significantly compared with the saline group (P < 0.05). The amount of PGE2 was significantly increased in the NP group compared with the sham and naive animals after application of NP. ATF3 expression was increased by NP but was not increased after administration of the EP1-RA. CONCLUSION: An EP1 receptor antagonist improves pain-related behavior in the rat model and might be a potential agent to improve pain-related behavior in patients with lumbar disc herniation. PMID- 21270691 TI - Low back pain in Iran: a growing need to adapt and implement evidence-based practice in developing countries. AB - STUDY DESIGN: A descriptive overview of the literature. OBJECTIVE: To present a comprehensive descriptive overview of the published papers about epidemiologic features, burden, and current management of low back pain (LBP) in Iran. SUMMARY OF BACKGROUND DATA: Little is known about the epidemiology, burden, and management of LBP in developing and low- to middle-income countries, such as Iran. METHODS: A literature search was carried out using MEDLINE database to assess existing literature about prevalence, disease burden, impact, and current management of nonspecific LBP in Iran. RESULTS: Twenty-six articles matched inclusion criteria and included in the study. The findings related to point, period, and lifetime prevalence of LBP in general population, working population, school children, and pregnant women ranged from 14.4% to 84.1%. The 1-year incidence of disabling LBP was found to be 2.1%. LBP is the third leading cause of disease burden (measured by Disability Adjusted Life Years) in Iranian population aged 15 to 69 years, without considering causes of intentional and unintentional injuries. High levels of anxiety and depression among patients with LBP and the etiological role of job strain in causing LBP in workers have been reported in Iran. Our search failed to find any articles about referral system, direct and indirect costs, social determinants, and current management of LBP in Iran. CONCLUSION: This overview of the literature illustrates that LBP is a common symptom and an important cause of disease burden in Iran, in particular, in the most productive age for both males and females. The 1-year incidence of disabling LBP in Iran was found to be low. Future research will be necessary to investigate economic cost, social determinants, health technology assessment, and management of LBP in Iran. PMID- 21270692 TI - 2011 Young Investigator Award winner: Increased fat mass is associated with high levels of low back pain intensity and disability. AB - STUDY DESIGN: A cross-sectional study. OBJECTIVE: To determine whether body composition is associated with low back pain intensity and/or disability. SUMMARY OF BACKGROUND DATA: The relationship between obesity and low back pain and disability is unclear. No study has examined the role of body composition in low back pain and disability. METHODS: A total of 135 participants (25-62 years), with a range of body mass indices (18-55 kg/m), were recruited for a study examining the relationship between obesity and musculoskeletal disease. Participants completed the Chronic Back Pain Grade Questionnaire, which examines individuals' levels of low back pain intensity and disability. Body composition was assessed using dual radiograph absorptiometry. RESULTS: Body mass index was associated with higher levels of back pain intensity (Odds ratio [OR] = 1.35; 95% confidence interval [CI] = 1.09, 1.67) and disability (OR = 1.66; 95% CI = 1.31, 2.09). Higher levels of pain intensity were positively associated with total body (OR = 1.19; 95% CI = 1.04, 1.38) and lower limb fat mass (OR = 1.51; 95% CI = 1.04, 2.20), independent of lean tissue mass. There were also positive associations between higher levels of low back disability and total body (OR = 1.41; 95% CI = 1.20, 1.67) and upper (OR = 1.67; 95% CI = 1.27, 2.19) and lower (OR = 2.29; 95% CI = 1.51, 3.49) limbs fat mass. Similar relationships were observed with trunk, android, and gynoid fat mass. After adjusting for confounders, no measures of lean tissue mass were associated with higher pain intensity or disability (P > 0.10). CONCLUSION: Greater fat, but not lean tissue mass, was associated with high levels of low back pain intensity and disability. Longitudinal investigation is needed to determine whether fat mass is predictive of low back pain and disability, as this may have important implications for further prevention strategies. Understanding the mechanism for these relationships may provide novel approaches to managing low back pain. PMID- 21270693 TI - Impact of the O-C2 angle on the oropharyngeal space in normal patients. AB - STUDY DESIGN: Radiographic analysis using normal patients. OBJECTIVE: To analyze the relationship between the cervical alignment and the oropharyngeal space. SUMMARY OF BACKGROUND DATA: Few clinical studies stress the effect of the occipito-C2 (O-C2) alignment on the oropharyngeal space. A previous study showed dysphagia and/or dyspnea after occipitocervical fusion was caused by oropharyngeal stenosis resulting from O-C2 fixation in a flexed position. Other independent researchers showed that development or improvement of obstructive sleep apnea in rheumatoid arthritis patients was related to the O-C2 alignment. However, there are limited basic data demonstrating the relationship between the O-C2 alignment and the oropharyngeal space. METHODS: Plain lateral cervical radiographs in five tested positions--neutral, flexion, extension, protrusion, and retraction--of 40 asymptomatic volunteers were collected. The O-C2 angle, the C2-C6 angle, and the anterior-posterior distance of the narrowest oropharyngeal airway space (nPAS) were measured, and the changes in value from the neutral to the other four positions were calculated for each patient. RESULTS: According to the multiple regression analysis, there was an extremely strong linear correlation of the change in the O-C2 angle with the percentage change in the nPAS. Referring to the multiple regression analysis, a decrease of 10 degrees in the O-C2 angle caused a 37% reduction in the nPAS in the neutral position. In contrast, no significant correlation was found between the change in the C2-C6 angle and the percentage change in the nPAS. CONCLUSION: Our results show the impact of the O-C2 angle on the oropharyngeal space. This knowledge will be useful for the diagnosis and treatment of the upper cervical lesion combined with the upper airway stenosis, and for the determination of the optimal fixation angle in occipitocervical fusion. PMID- 21270694 TI - Spondylolisthesis in twins: multifactorial etiology: a case report and review of the literature. AB - STUDY DESIGN: Report of a high dysplastic developmental spondylolisthesis in two identical twins of two unrelated families. OBJECTIVE: To investigate the multifactorial etiology of developmental spondylolisthesis. SUMMARY OF BACKGROUND DATA: Multiple studies have suggested an association between a high pelvic incidence and the presence of isthmic spondylolisthesis. Other studies suggest a genetic background for spondylolysis and a pattern of inheritance of susceptibility to spondylolysis and spondylolisthesis. Heterozygous cartilage derived morphogenetic protein-1 (CDMP-1) mutation has previously been associated with spondylolysis and severe spondylolisthesis. METHODS: Two identical female twins presented with a developmental spondylolisthesis. Pelvic parameters, lumbar lordosis and grade of spondylolisthesis were calculated on a lateral standing spine radiograph. MRI is performed to confirm a high dysplastic developmental spondylolisthesis. Blood sample of these four individuals were analyzed for the presence of a CDMP-1 mutation, a cartilage-specific member of the TGF-b superfamily of secreted signaling molecules that plays a key role in chondrogenesis, growth, and patterning of the developing vertebrate skeleton. RESULTS: PI, SS, PT, LL, and SI are significantly greater in all of these patients in comparison with the general population. Spinal MRI confirms a high dysplastic developmental spondylolisthesis in both twins. Mutation analysis of the two coding exons of CDMP-1 did not reveal any mutation in all four individuals. CONCLUSION: To our knowledge, this is the first report of a high dysplastic developmental spondylolisthesis in identical twins. The presence of a high dysplastic developmental spondylolisthesis in two identical twins shows the convergence in etiology of different factors such as genetics, maturation, critical age, female sex, high pelvic incidence. Although we cannot confirm that CDMP-1 mutation plays a key role in the etiology of spondylolysis/spondylolisthesis, neither can we rule out that CDMP-1 problems may be an etiology for at least a subpopulation of patients. However, the presence of a developmental spondylolisthesis in two sets of identical twins still suggests a genetic susceptibility to spondylolysis and spondylolisthesis. PMID- 21270695 TI - Occupational and other predictors of herniated lumbar disc disease-a 33-year follow-up in the Copenhagen male study. AB - STUDY DESIGN: Cohort study. OBJECTIVE: To examine the association between self reported physical workload and risk of herniated lumbar disc disease (HLDD) in a long-term follow-up of men without a history of back disorders at baseline. SUMMARY OF BACKGROUND DATA: Heavy physical workload is considered a risk factor for HLDD, but the issue is not definitively settled. METHODS: The Copenhagen Male Study is a prospective cohort study established in 1970 to 1971. At baseline, 5245 men answered a questionnaire about history of back disease and physical workload. Psychosocial working conditions, lifestyle, social class, and measured height and weight were included as potential confounders. Information about hospitalization due to HLDD was obtained from the National Hospital Register covering the period from 1977 to 2003. Hazard ratios were calculated by Cox proportional hazard regression model. RESULTS: Among 3833 men without back disease history at baseline, the strongest predictor of hospitalization for HLDD was frequent strenuous physical activity at work; compared with unexposed, the hazard ratio with 95% confidence interval was 3.90 (1.82-8.38). Also, body height was a significant predictor, whereas body weight was only insignificantly associated with HLDD. CONCLUSION: Among men without history of back disease reporting of frequent exposure to strenuous physical activity at work was a strong risk factor for later hospitalization due to HLDD. PMID- 21270696 TI - Multiple supra- and infratentorial intraparenchymal hemorrhages presenting with seizure after massive sacral cerebrospinal fluid drainage. AB - STUDY DESIGN: Case report and review of the literature. OBJECTIVE: To describe a case of multiple supra- and infratentorial hemorrhages after spinal surgery presenting with seizure. SUMMARY OF BACKGROUND DATA: Cerebrospinal fluid overdrainage is a well-documented factor associated with remote cerebellar hemorrhage, but supratentorial hemorrhages after spinal surgery have been reported rarely. METHODS: A 64-year-old woman underwent a sacral laminectomy for recurrent chordoma. A negative pressure wound drain was left in after surgery and drained 1300 mL in the first 48 hours. On the fourth postoperative day, the patient presented with tonic-clonic seizures. RESULTS: Diagnostic imaging showed multiple supra- and infratentorial intraparenchymal hemorrhages and a massive sacral cerebrospinal fluid leak. The patient underwent emergent surgery for a primary repair of the presumed dural defect. CONCLUSION: Patients who present with severe positional headache, altered mental status, or tonic-clonic seizures after undergoing intradural spinal procedures involving massive cerebrospinal fluid loss may be suffering from multiple supra- and infratentorial intracranial hemorrhages. PMID- 21270697 TI - A comparison of a commercially made pedicle stimulating probe with a custom-made device: does the commercial device detect pedicle wall breaches more reliably? AB - STUDY DESIGN: Clinical trial. OBJECTIVE: To compare the efficacy of a commercially available stimulating pedicle probe with a custom-made probe for the detection of pedicle wall breaches during screw insertion for the surgical correction of scoliosis. SUMMARY OF BACKGROUND DATA: Stimulus triggered electromyography has been used to detect small breaches in the walls of the spinal pedicles during pedicle screw insertion. We routinely use a reusable, custom-made clip that can be attached to the screw, pedicle probe, or other instruments. Commercial systems are available in which the instrument is electrically instrumented to deliver current. METHODS: In five patients (173 pairs of tests), we compared the threshold current required to trigger an electromyographic response during testing of the pedicle. Each track or screw was tested with both the custom-made and the commercial probe and the threshold current recorded. RESULTS: Both systems were able to detect pedicle wall breaches using triggered electromyography. The threshold current recorded was not significantly different between the two systems (P > 0.1, paired t test) nor was the difference (0.16 mA) clinically significant. CONCLUSION: No difference was found between the thresholds detected with either system. There is however, a significant difference in the costs of the two probe systems. PMID- 21270698 TI - Short segment bone-on-bone instrumentation for adolescent idiopathic scoliosis: a mean follow-up of six years. AB - STUDY DESIGN: Prospective case series. OBJECTIVE: To evaluate the clinical and radiologic outcomes of short segment anterior scoliosis surgery with bone-on-bone apposition using a dual screw, dual rod system. SUMMARY OF BACKGROUND DATA: Posterior segmental fixation for correction of AIS involves instrumentation of all the vertebrae included in the major curve. Our short segment anterior technique produces similar results by fusion of fewer levels. METHODS: Forty-five patients operated between 1996 and 2004. Twenty-eight thoracic (Lenke 1) and 17 thoracolumbar (Lenke 5). The mean age was 19 years, 87% were females, and the mean follow-up was 72 months (range 28-121 months). We operated on curves less than 85 degrees with "total discectomy," bone-on-bone apposition, and dual screw, dual-rod fixation. RESULTS: A mean of five vertebrae (four discs) were instrumented, with a mean operative time of 360 minutes, blood loss of 877 mL and a hospital stay of 9.1 day. Lenke 1. The main preop thoracic curve was 52.5 degrees , final postop curve 27.9 degrees , by fusing five vertebrae, four discs. A spontaneous improvement of 47.5% of the lumbar compensatory curve was seen. The lower tilt angle corrected from 20.9 degrees to 11 degrees . Lenke 5. The preoperative thoracolumbar major curve corrected from 50.5 degrees to 18.3 degrees (final) with fusion of four vertebrae, three discs. A spontaneous improvement of 37.4% occurred in the thoracic compensatory curve. The preop tilt angle improved from 27.7 degrees to 8.3 degrees .The sagittal and coronal balance was restored in all the patients. There were no neurologic, vascular, pulmonary, or implant-related complications. Union occurred within 3 months. All the patients returned to an unrestricted lifestyle within 4 months. CONCLUSION: We report good results after surgical correction using our short segment bone-on bone technique. Improvements were noted and maintained, over a 6-year period. PMID- 21270699 TI - Correlation of preoperative deformity magnitude and pulmonary function tests in adolescent idiopathic scoliosis. AB - STUDY DESIGN: Clinical study correlating preoperative pulmonary function tests (PFTs) to radiographic measures of thoracic deformity severity in adolescent idiopathic scoliosis (AIS) patients. OBJECTIVE: To determine (1) the incidence of clinically relevant (<65% predicted value) pulmonary impairment in AIS patients; (2) if patients with more severe deformity have greater impairment of PFTs than those with lesser deformity; (3) the effect, if any, of juvenile onset deformity (onset65%. Patients with MT curves>70 degrees , and especially >80 degrees ; proximal thoracic (PT) curves which were >30 degrees or structural; or T5-T12 kyphosis<10 degrees had significantly (P<=0.001) lower FEV1 or FVC compared to those with less deformity. Axial plane deformity did not correlate with PFT impairment. Juvenile-onset patients had greater PFT impairment than AIS patients, along with slightly larger MT curves. Patients who were braced before surgery had worse PFTs than those had no treatment before surgery. CONCLUSION: Preoperative PFTs are clinically impaired in 19% of AIS patients, and correlate significantly with the MT and sagittal plane deformity severity, and with PT curve severity to a lesser degree. PFTs do not correlate with degree of axial deformity. From a purely pulmonary standpoint, attention directed to coronal and sagittal plane deformity correction appears warranted, to address the specific deformities which are associated with PFT impairment. PMID- 21270700 TI - The effect of fear of movement beliefs on pain and disability after surgery for lumbar and cervical degenerative conditions. AB - STUDY DESIGN: Prospective cohort study. OBJECTIVE: To examine differences between preoperative and postoperative fear of movement and investigate the relationship between fear of movement and pain, disability and physical health after spinal surgery for degenerative conditions. SUMMARY OF BACKGROUND DATA: Consistent evidence supports the relationship between fear of movement and higher levels of pain and disability in various chronic pain populations. Fear of movement among patients undergoing spinal surgery for chronic pain has received little attention in the literature. METHODS: Participants were 141 patients treated with surgery for lumbar and cervical degenerative conditions. Assessments were conducted before surgery and 6 weeks and 3 months after hospitalization. Fear of movement was measured with the Tampa Scale for Kinesiophobia and outcomes were measured with the Brief Pain Inventory, Oswestry or Neck Disability Index, and 12-Item Short Form Health Survey (SF-12). RESULTS: Follow-up rates were 91% and 87% for 6 weeks and 3 months, respectively. Fear of movement beliefs improved after surgery, but 49% of patients continued to have high fear of movement at 6-week follow-up and 39% at 3-month follow-up. Patients with higher levels of fear of movement had poorer postoperative outcomes. Multilevel linear regression analyses found that postoperative fear of movement was independently associated with postoperative pain intensity, pain interference, disability, and physical health (P < 0.001), after controlling for depression, age, sex, education, race, comorbidities, type and area of surgery, prior surgeries, and baseline outcome score. Preoperative fear of movement was not predictive of poorer surgical outcomes. CONCLUSION: Results demonstrate that postoperative but not preoperative fear of movement beliefs explain unique and significant variance in postoperative pain, disability, and physical health. Clinicians interested in improving surgical outcomes should address postoperative fear of movement along with other traditional clinical and medical risk factors. Recommendations include postoperative screening for high fear of movement beliefs and incorporating cognitive-behavioral techniques into postoperative rehabilitation for at-risk surgical spine patients. PMID- 21270701 TI - A rare case of spinal dumbbell tanycytic ependymoma. AB - STUDY DESIGN: Case report. OBJECTIVE: To report an extremely rare case of spinal dumbbell-type tanycyticependymoma. SUMMARY OF BACKGROUND DATA: Only two previous cases of a dumbbell-type tanycyticependymoma in the spinal cordhave been reported. METHODS: A 40-year-old female presented with low back pain and numbness of the left leg. Magnetic resonance imaging revealed a dumbbell tumor at the Th10 11 level that compressed the spinal cord extensively. The diagnosis of extradural dumbell spinal tumor was made, and a total tumor excision was performed with a thoracic 10-11 laminectomy. RESULTS: After surgery, the patient's low back pain and numbness disappeared. Detailed immunohistological examinations confirmed the diagnosis of tanycyticependymoma. At 16 months, there was no evidence of tumor recurrence and no further treatment was needed. CONCLUSION: A rare case of spinal dumbbell-type tanycyticependy-moma was presented. Detailed histologic examinations are essential to differentiate tanycyticependymoma from other tumors such as schwannoma and pilocyticastrocytoma. PMID- 21270702 TI - Mechanical deformation and glycosaminoglycan content changes in a rabbit annular puncture disc degeneration model. AB - STUDY DESIGN: Evaluation of degenerated intervertebral discs from a rabbit annular puncture model by using specialized magnetic resonance imaging (MRI) techniques, including displacement encoding with stimulated echoes and a fast spin echo (DENSE-FSE) acquisition and delayed gadolinium-enhanced MRI of cartilage (dGEMRIC). OBJECTIVE: To evaluate a rabbit disc degeneration model by using various MRI techniques. To determine the displacements and strains, spin lattice relaxation time (T1), and glycosaminoglycan (GAG) distribution of degenerated discs as compared to normal and adjacent level discs. SUMMARY OF BACKGROUND DATA: Annular puncture of the intervertebral disc produces disc degeneration in rabbits. DENSE-FSE has been previously demonstrated in articular cartilage for the measurement of soft tissue displacements and strains. MRI also can measure the T1 of tissue, and dGEMRIC can quantify GAG concentration in cartilage. METHODS.: In eight New Zealand white rabbits, the annulus fibrosis of a lumbar disc was punctured. After 4 weeks, the punctured and cranially adjacent motion segments were isolated for MRI and histology. MRI was used to estimate the disc volume and map T1. DENSE-FSE was used to determine displacements for the estimation of strains. dGEMRIC was then used to determine GAG distributions. RESULTS: Histology and standard MRI indicated degeneration in punctured discs. Disc volume increased significantly at 4 weeks after the puncture. Displacement of the nucleus pulposus was distinct from that of the annulus fibrosis in most untreated discs but not in punctured discs. T1 was significantly higher and GAG concentration significantly lower in punctured discs compared with untreated adjacent level discs. CONCLUSION: Noninvasive and quantitative MRI techniques can be used to evaluate the mechanical and biochemical changes that occur with animal models of disc degeneration. DENSE-FSE, dGEMRIC, and similar techniques have potential for evaluating the progression of disc degeneration and the efficacy of treatments. PMID- 21270704 TI - The ATA and its surgical importance: a newly described ligament lying between the dural sac and the ligamentum flavum at the L5 level. AB - STUDY DESIGN: The anatomy of a new ligament in the human spine the ATA is described. OBJECTIVE: To describe a new ligament; the ATA, which lies between the dural sac and the ligamentum flavum at the L5 level and to discuss it's surgical importance. SUMMARY OF BACKGROUND DATA: Postoperative cerebrospinal fluid (CSF) leakage translates into longer hospital stays with significant implications for the patient, the health care system, and society as a whole. To avoid injury to the dural sac during lumbar surgery, it is crucial to know the surgical anatomy and its variations. METHODS: The length and the number of ATAs were examined in 14 consecutive patients, which underwent an L5 laminoflavectomy in our department. The ATA and its anatomic landmarks are described here for the first time in the literature. We named this ligament the ATA; reminding us to pay attention to the Terminal Attachment. RESULTS: The presence of the ATA is demonstrated in 10 patients (71%). There was a double ATA in four patients (40%). The mean length of the ATA was 7.7 +/- 1.8 mm. The ATA originates from the dorsal surface of the dura mater at the level of the superior border of the superior facet of the S1 vertebra and projects toward the ligamentum flavum. Histologic examination of the ATA revealed fibrous connective tissue. CONCLUSION: In this preliminary study, we have described a new ligament, the ATA, between the dural sac and the ligamentum flavum at the L5 level. The ATA is an important structure that creates a potential risk for inadvertent dural lacerations during flavectomy. Dissecting the ATA before the flavectomy may be an important step in reducing postoperative cerebrospinal fluid leaks, which may result in significant benefits for patients and health care organizations. PMID- 21270705 TI - Development of an organ culture system for long-term survival of the intact human intervertebral disc. AB - STUDY DESIGN: Human intervertebral discs were used to develop an intact whole disc organ culture system with long-term cell viability. OBJECTIVE: To develop and validate a long-term organ culture system for intact human intervertebral discs, in which the potential for biologic repair of disc degeneration can be studied. SUMMARY OF BACKGROUND DATA: Intervertebral disc degeneration is a common cause of back pain, which can be costly to the health care system and have a negative impact on the quality of life of the patient. Once injured the adult human intervertebral disc seems incapable of intrinsic repair, but the early stages of disc degeneration can potentially be retarded or even reversed by the administration of growth factors to promote new extracellular matrix synthesis. METHODS: Intervertebral discs were prepared by three isolation techniques and placed in free swelling organ culture. Cell viability, disc swelling, glycosaminoglycan content, and extracellular matrix degradation were assessed under a variety of culture conditions. RESULTS: Human intervertebral discs isolated with intact cartilage end plates retained cell viability and did not undergo matrix degradation when cultured for 4 weeks with both a high and low nutrient level. This contrasted with the excessive cell death that was observed if the cartilage end plates were removed before culture or if vertebral bone was retained. CONCLUSION: Retention of the cartilage end plates limits tissue swelling and permits efficient nutrient supply, thus allowing viable long-term organ culture. The availability of such a system will permit the repair potential of therapeutic candidates to be studied in human discs with naturally occurring degeneration. Furthermore, the system is simple and economical, as no apparatus is needed to limit the detrimental effects of excessive tissue swelling. PMID- 21270706 TI - Intraoperative monitoring in pediatric orthopedic spinal surgery: three hundred consecutive monitoring cases of which 10% of patients were younger than 4 years of age. AB - STUDY DESIGN: Analysis of a prospective series of 300 consecutive cases undergoing intraoperative monitoring in pediatric orthopedic spinal surgery, of which 10% were children younger than 4 years. OBJECTIVE: Determine feasibility and performance of intraoperative monitoring in children younger than 4 years. Analyze distinct physiopathologic mechanisms of relevant alerts. SUMMARY OF BACKGROUND DATA: There are few studies in the literature concerning the intraoperative monitoring of children younger than 4 years. During childhood, the development of sensori-motor pathways is dominated by two coexisting phenomena, which have opposite effects: maturation decreasing latencies and height increasing them. METHODS: We used intraoperative somatosensory-evoked potentials and neurogenic mixed evoked potentials with a flexible bipolar epidural electrode. Uniform total intravenous anesthesia was used. RESULTS: Values of sensitivity and specificity of the monitoring showed slight differences between patients younger than 4 years versus older patients. There was no false-negative outcome. Various tendencies were highlighted. There were more true positive alerts for secondary etiologies than for idiopathic ones, for revision spinal surgeries than for index ones, and for boys than for girls. There were no more true positive alerts for children younger than 4 years than for older patients whereas the proportion of hemivertebrae was obviously greater for the younger group. Relevant monitoring alerts were more frequent in case of kyphoscoliosis. This is highlighted in case reports. CONCLUSION: In some cases of kyphoscoliosis, during a posterior-based vertebral column resection, monitoring changes were corrected by positioning a rod that allowed correction of the position of the spine in the sagittal plane. Intraoperative spinal cord monitoring can be performed in children younger than 4 years and allows real-time assessment of spinal functional integrity. PMID- 21270707 TI - Treatment of primary basilar invagination by cervical traction and posterior instrumented reduction together with occipitocervical fusion. AB - STUDY DESIGN: This retrospective study was conducted to analyze the radiographic and clinical results in seven patients with primary basilar invagination who accepted a combination of continuous cervical traction before operation and posterior screw/rod system reduction together with occipitocervical fusion. OBJECTIVE: To evaluate the radiographic and clinical outcomes of this treatment regimen in combination of continuous cervical traction and posterior instrumented reduction with pedicle screw/rod system. SUMMARY OF BACKGROUND DATA: Primary basilar invagination poses considerable difficulties in the surgical management regarding surgical approach, reduction, and decompression. A variety of methods have been described to treat primary basilar invagination and all methods existed limits. METHODS: There were four male and three female patients, and the ages ranged from 12 to 40 years (average age, 22.3 yr). Six patients presented neurologic deficits. The Nurick scale was from 1 grade to 4 grades (average, 2.7 grades). The distance of the odontoid tip in relation to Wackenheim line, atlantodental interval, Klaus height index, craniospinal angle, modified Omega angle, and cervicomedullary angle were measured pretreated and after surgery. When the tip of odontoid process was inferior or approximate to Wackenheim line and McRae line after cervical traction, the operation of reduction and fixation should be accepted. RESULTS: After surgery, the mean Wackenheim value and atlantodental distance were reduced 9.3 mm and 2.0 mm, respectively. The mean Klaus height index, craniospinal angle, Omega angle, and cervicomedullary angle improved 6.5 mm, 17.0 degrees , 11.6 degrees , and 27.4 degrees , respectively. All postoperative data had a significance compared with pretreatment data (P < 0.05). There was a tendency that younger patients were able to obtain more ideal reduction than adults. Of six patients with neurologic symptoms, five patients were normal or nearly normal. All patients achieved solid fusion. CONCLUSION: This case series demonstrates a safe, easy, and effective treatment regimen for the patients with primary basilar invagination. PMID- 21270708 TI - Delayed pleural effusion after anterior thoracic spinal fusion using bone morphogenetic protein-2. PMID- 21270709 TI - The effect of sacral decortication on lumbosacral fixation in a calf spine model. AB - STUDY DESIGN: Animal cadaveric biomechanical study. OBJECTIVE: We hypothesized that increasing bony destabilization of a bovine cadaveric sacrum by anterior pedicle screw penetration and bilateral alar decortication would decrease the amount of load necessary for failure of the construct and result in failure through the decortication sites. SUMMARY OF BACKGROUND DATA: Fusion to the sacrum has become commonly used for treatment of neuromuscular scoliosis and fusions in osteoporotic patients. Fixation failure after attempted fusion to the sacrum may be attributed to iatrogenic causes such as S1 screw penetration and sacral ala decortication. METHODS: Sixteen fresh-frozen 6- to 8-week-old calf spines were tested after instrumentation with pedicle screws and bilateral rods from L2 to S1 using four constructs: (1) S1 screws with posterior-only purchase; (2) S1 screws with bicortical purchase; (3) S1 screws with bicortical purchase and sacral alar decortication; and (4) S1 screws with bicortical purchase, decortication, and iliac fixation. A destructive flexural bending load was applied at L2 to each construct. Ultimate failure moment (Nm) was compared among the four groups, using a one-way analysis of variance combined with Holm-Sidak post hoc test. RESULTS: No significant difference in failure moment was found among groups 1, 2, and 3. The addition of iliac fixation (group 4) significantly increased bending load to failure (P < 0.01), and iliac screw dislodgement was the dominant mechanism of failure. All specimens in group 3 failed with fractures extending through the decortication site. Groups 1 and 2 specimens failed by fracturing through the S1 body. CONCLUSION: Sacral alar decortication and anterior pedicle screw purchase did not decrease the failure moment in long instrumentation to the sacrum. Pattern of failure was affected, with alar decortication being the site of fracture in each construct in which it was performed. Iliac fixation increased the failure moment under catastrophic loading conditions even when combined with sacral alar decortication and bicortical pedicle screw purchase. PMID- 21270710 TI - Intervertebral disc development is regulated by Wnt/beta-catenin signaling. AB - STUDY DESIGN: Histologic analysis of intervertebral disc (IVD) in three types of transgenic mice. OBJECTIVE: To investigate the role of Wnt/beta-catenin signaling in regulation of IVD development and organization. SUMMARY OF BACKGROUND DATA: beta-catenin dependent Wnt signaling is one of the central regulators in cartilage development during limb skeletal formation. Little is known, however, about the physiologic relevance of this signaling pathway to IVD development and organization. METHODS: Temporal-spatial distribution of Wnt/beta-catenin signaling activity was examined in IVD using Wnt/beta-catenin reporter (TOPGAL) mice. The structural changes in the mouse IVD components such as the nucleus pulposus (NP), endplate (EP), annulus fibrosus (AF), and the growth plate (GP) of the vertebral body were analyzed after transient activation of Wnt/beta-catenin signaling or deletion of beta-catenin in the mice. RESULTS: Activity of Wnt/beta catenin signaling was high in EP, AF, and GP in the embryonic stages and decreased at the postnatal stage; it was undetectable in the embryonic NP but upregulated after birth. The transient activation of Wnt/beta-catenin signaling caused severe deterioration of the GP and the AF, whereas deficiency of beta catenin accelerated bone formation in between EP and GP. CONCLUSION: The findings in this study suggest that proper regulation of Wnt/beta-catenin signaling is required for development and organization of IVD. PMID- 21270711 TI - Piriformis syndrome versus radiculopathy following lumbar artificial disc replacement. AB - STUDY DESIGN: Case series. OBJECTIVE: To describe the presentation, diagnostic challenges, and treatment of five patients with piriformis syndrome after lumbar artificial disc replacement. SUMMARY OF BACKGROUND DATA: Until recently, spinal fusion was considered the standard for surgical treatment of severe lumbar degenerative disc disease. However, artificial disc replacement now offers an alternative solution. Piriformis syndrome results from entrapment of the sciatic nerve at the greater sciatic notch, with symptoms of pain and numbness radiating from the buttock to the foot, mimicking radiculopathy. METHODS: In this case series, we report five patients who developed piriformis at our institution after artificial disc replacement. RESULTS: Five patients, aged 35 to 46 years, developed some or all of the following symptoms in the affected leg after artificial disc replacement: posterior leg and buttock pain, calf weakness, and toe and ball of foot numbness and tingling. The onset of symptoms ranged from 6 days to 8 months postoperative, and became debilitating over time. Each patient was diagnosed with piriformis syndrome through physical examination. Three of the patients received a piriformis injection and reported 50% to 100% pain relief lasting 1 to 3 weeks. The patients subsequently underwent physical therapy that provided relief of their piriformis syndrome-related pain and enabled them to resume their normal activities. CONCLUSION: Piriformis syndrome has not previously been described in the literature as a sequela of lumbar artificial disc replacement. Our case series indicates that this complication may be underdiagnosed. Careful consideration after artificial disc replacement is required if the patient presents with buttock, leg or foot pain, and/or numbness. It is important for physicians to recognize the symptoms of piriformis syndrome and to differentiate piriformis syndrome from nerve root compression and irritation or referred pain from spinal structures. Although controversial, the proper diagnosis of piriformis syndrome may have prevented some of these patients from undergoing unnecessary surgical procedures. PMID- 21270712 TI - Course of back pain across 5 years: a retrospective cohort study in the general population of Switzerland. AB - STUDY DESIGN: A retrospective cohort study in the general population of Switzerland. OBJECTIVE: To investigate the course of back pain (BP) across 5 years and the impact of BP history on its incidence and recurrence. SUMMARY OF BACKGROUND DATA: Longitudinal studies on BP performed in the general population have reported varying prevalence and incidence rates. Most studies compared two points in time with varying time periods. This study adds information about the course of BP exploring five points in time with annual intervals. METHODS: The Swiss Household Panel is a representative population-based cohort study (N = 7799). The question analyzed in the present study asked about "bad back or lower back problems at least once a month in the last 12 months (BP)." Among 7791 persons who answered this question during the baseline survey in 1999, 3881 persons (49.8%) completed all annual follow-up surveys through 2003 and represent the study sample. In each year, the 1-year prevalence, incidence, and recurrence of BP were calculated. The course of BP was analyzed according to the number of years with BP, the constancy of BP status, and the trend of BP. For each analysis, the observed frequency was compared with expected frequencies on the basis of two theoretical models. RESULTS: In the study sample (age 44.0 +/- 15.6 years, 57.7% women), BP prevalence was 33.2% at baseline. In the follow-up surveys, mean prevalence was 37.7%, mean incidence 19.6%, and mean recurrence 69.0%. The most frequently observed courses across 5 years were those with a constant status: BP always absent (n = 1346, 34.7%) or BP always present (n = 538, 13.9%). BP recurrences increased with increasing numbers of previous consecutive years with BP from 46.9% (1 year of previous BP) to 88.1% (at least 4 years of previous BP). CONCLUSION: BP history is highly predictive for future BP episodes. PMID- 21270713 TI - Cost-effectiveness of the X-STOP(r) interspinous spacer for lumbar spinal stenosis. PMID- 21270714 TI - Simulation of inhomogeneous rather than homogeneous poroelastic tissue material properties within disc annulus and nucleus better predicts cervical spine response: a C3-T1 finite element model analysis under compression and moment loadings. AB - STUDY DESIGN: A finite element (FE) modeling of homogeneous and inhomogeneous poroelastic tissue material properties within disc anulus fibrosus (AF) and nucleus pulposus (NP). OBJECTIVE: To test the hypothesis that simulation of inhomogeneous poroelastic tissue material properties within AF and NP quadrants, rather than homogeneous properties within regions of AF and NP without quadrants, would better predict the cervical spine biomechanics. SUMMARY OF BACKGROUND DATA: In order to represent tissue swelling and creep deformation behavior more physiologically in FE models, disc poroelastic tissue material properties should be modeled appropriately. Past studies show an existence of inhomogeneous rather than homogeneous nature of the tissue properties in various quadrants of AF and NP, and this has been simulated in a single-segment FE lumbar model with only compression analysis. This article simulated these tissue properties in a multisegmental cervical spine and reported the results of both compression and moment loads. METHODS: Two three-dimensional FE models of a C3-T1 segment were developed. Model I included homogeneous poroelastic tissue properties in AF and NP, whereas Model II included inhomogeneous poroelastic tissue properties in AF and NP quadrants. Biomechanical responses of the FE models under diurnal compression and moment loads were compared with corresponding in vivo published studies. RESULTS: Model II with disc quadrant-based inhomogeneous poroelastic tissue properties predicted better, mainly in flexion and extension, than the Model I with homogeneous tissue properties when compared with the corresponding in vivo results, thereby confirming the current study hypothesis. Inhomogeneous tissue properties govern segmental behavior mainly during sagittal plane motions, with a root-mean-square difference of nearly 50% across the motion segments. CONCLUSION: The current data justify the need to simulate inhomogeneous tissue properties within disc quadrants for any FE model analysis. Model II can be further used to understand the biomechanical effects of quadrant-based degenerative poroelastic tissue properties on cervical spine behavior. Future experiments are necessary to support the current study results. PMID- 21270715 TI - The impact of diabetes on the outcomes of surgical and nonsurgical treatment of patients in the spine patient outcomes research trial. AB - STUDY DESIGN: A secondary analysis comparing diabetic patients with nondiabetic patients enrolled in the Spine Patient Outcomes Research Trial (SPORT). OBJECTIVE: To compare surgical outcomes and complications between diabetic and nondiabetic spine patients. SUMMARY OF BACKGROUND DATA: Patients with diabetes are predisposed to comorbidities that may confound the diagnosis and treatment of patients with spinal disorders. METHODS: Baseline characteristics and outcomes of 199 patients with diabetes were compared with those of the nondiabetic population in a total of 2405 patients enrolled in the Spine Patient Outcomes Research Trial for the diagnoses of intervertebral disc herniation (IDH), spinal stenosis (SpS), and degenerative spondylolisthesis (DS). Primary outcome measures include the 36 Item Short Form Health Survey (SF-36) Health Status questionnaire and the Oswestry Disability Index. RESULTS: Patients with diabetes were significantly older and had a higher body mass index than nondiabetic patients. Comorbidities, including hypertension, stroke, cardiovascular disease, and joint disease, were significantly more frequent in diabetic patients than in nondiabetic patients. Patients with diabetes and IDH did not make significant gains in pain and function with surgical intervention relative to diabetic patients who underwent nonoperative treatment. Diabetic patients with SpS and DS experienced significantly greater improvements in pain and function with surgical intervention when compared with nonoperative treatment. Among those who had surgery, nondiabetic patients with SpS achieved marginally significantly greater gains in function than their diabetic counterparts (SF-36 physical function, P = 0.062). Among patients who had surgery for DS, diabetic patients did not have as much improvement in pain or function as did the nondiabetic population (SF-36 bodily pain, P = 0.003; physical function, P = 0.002). Postoperative complications were more prevalent in patients with diabetes than in nondiabetic patients with SpS (P = 0.002). There was an increase in postoperative (P = 0.028) and intraoperative (P = 0.029) blood replacement in DS patients with diabetes. CONCLUSION: Diabetic patients with SpS and DS benefited from surgery, though older SpS patients with diabetes have more postoperative complications. IDH patients with diabetes did not benefit from surgical intervention. PMID- 21270716 TI - Differentiation of human bone marrow mesenchymal stem cells into neuron-like cells in vitro. AB - STUDY DESIGN: Responses of human mesenchymal stem cells from bone marrow (hBMSCs) were analyzed under chemical conditions, and then characterization of ion channels was evaluated by whole-cell patch clamp. OBJECTIVE: To explore the possibility of differentiation of human bone marrow-derived mesenchymal stem cells into neuron-like cells in vitro under different conditions. SUMMARY OF BACKGROUND DATA: The generation of mesenchymal stem cells into neuron-like cells has been studied. However, few of these studies characterized functional properties of the differentiated hBMSCs. METHODS: hBMSCs (Passage 2) were expanded and cultured in vitro. After Passage 5 was subcultured, the cells were induced by cytokines and antioxidants. Morphologic observation, immunocytochemistry, Western blot analysis, and patch-clamp techniques were performed to evaluate properties of treated and control groups. RESULTS: The differentiated neuronal cells from hBMSCs not only expressed neuron phenotype and membrane channel protein including Nav1.6, Kv1.2, Kv1.3, and Cav1.2 but also exhibited functional ion currents. Both hBMSCs and differentiated cells expressed Nav1.6, Kv1.2, Kv1.3, and Cav1.2 and voltage-activated potassium currents, including delayed rectifier, noise-like and transient outward currents. However, expression of channel proteins, such as sodium channel Nav1.6 and potassium channels Kv1.2 and Kv1.3, were upregulated. Consistently, their potassium currents were also enhanced in the differentiated cells. CONCLUSION: hBMSCs possess of great potential to differentiate into functional neurons, indicating that hBMSCs may be an ideal cell source in managing a variety of clinical diseases such as spinal cord injury. PMID- 21270717 TI - The course of work absenteeism involving neck pain: a cohort study of Ontario lost-time claimants. AB - STUDY DESIGN: Cohort study. OBJECTIVE: To describe the course of lost-time claims involving neck pain in workers compensated by the Ontario Workplace Safety and Insurance Board (WSIB). SUMMARY OF BACKGROUND DATA: The prevalence of neck pain in workers varies from 27.1% to 47.8%. Very little is known about the course of work absenteeism related to neck pain. METHODS: Our cohort included 5761 injured workers with an incident lost-time claim to the WSIB in 1997 and 1998. Claimants were followed for 2 years. We measured the cumulative time on lost-time benefits using the Kaplan-Meier method and described the number and duration of episodes on benefits. RESULTS: The median cumulative time-on-benefits for the cohort was 13 days (95% CI: 13-14). The cumulative time on benefits was shorter for men than women and for younger than older workers. 14.2% of claimants experienced multiple episodes of work absenteeism during the 2 years after the initial claim. The median time on benefits for claimants with a single episode was 11 days (95% CI: 10-11). The median length of the first episode on benefits was longer for claimants with multiple episodes (19-22 days) compared with those with a single episode (11 days). Age was positively associated with longer time-on-benefits in claimants with a single episode of work absenteeism. CONCLUSION: Most injured workers who make a workers' compensation claim that involves neck pain do not make a second claim in the subsequent 2 years. However, an important minority (14.2%) experience multiple episodes of work absenteeism and these workers accrue 40.4% of all lost-time days. Recurrent claims involving neck pain represent a significant burden of disability in Ontario. PMID- 21270718 TI - Reirradiation in head and neck cancers. AB - Salvage surgery is the mainstay of treatment for recurrences or secondary primary tumors in areas that were irradiated earlier. However, locoregional recurrence remains the main cause of death after surgery. Adjuvant reirradiation dramatically reduces locoregional recurrences but the risk-benefit ratio seems to be advantageous mostly for residual microscopic disease. In contrast, the rate of distant metastasis among reirradiated patients indicates that the local treatment alone is not sufficient. Full-dose exclusive chemo-reirradiation (over 60 Gy) can cure a subset of patients when surgery is not feasible. However, reirradiation is associated with a significant rate of severe toxicity and should, therefore, be compared with chemotherapy in randomized trials. Accrual may be difficult because of selection biases such as tumor volume, small volumes (largest axis less than 3 4 cm) being more likely to be irradiated. In addition, patients in poor general condition with severe comorbidities, organ dysfunction, or incomplete healing after salvage surgery, are unlikely to benefit from reirradiation. Noteworthy volumes to be reirradiated must be established between the head and neck surgeon and the radiation oncologist: the definition of the clinical target volume should be taken into account, the natural history of recurrent tumors, especially with regard to extension modalities, and the absence of strict correlation between imaging and histological real extension. This is even more critical with the advent of new irradiation techniques. Chemotherapy associations and new radiosensitizing agents are also under investigation. Comparison between reirradiation modalities is difficult because most trials are phase 2 mono institutional trials. As selection of patients is a key issue, only phase 3 multiinstitutional trials can provide definitive results. PMID- 21270719 TI - Newly designed, self-coiling catheters for regional anesthesia--an imaging study. AB - BACKGROUND AND OBJECTIVES: A major concern with the use of continuous peripheral nerve block is the difficulty encountered in placing the catheters close enough to the nerves to accomplish effective analgesia. The aim of this study was to investigate if a self-coiling catheter would remain close to the sciatic nerve once introduced through needles placed under ultrasound guidance and if contrast dye injected through the pigtail catheter made direct contact to the nerves. METHODS: First, Tuohy needles were placed anterior to the sciatic nerves under ultrasound guidance (needle-in-plane/nerve in short-axis approach). Next, the self-coiling catheters were blindly introduced through the needles. A total of 40 catheters were placed; 2 per sciatic nerve in the right and left legs of 10 human cadavers. To detect the exact catheter location, computer tomographic imaging of the legs was performed. Finally, the spread of injected contrast dye in relation to the nerves was assessed by magnetic resonance imaging. RESULTS: There was direct contact of the coil with the nerve in 37 cases. In the remaining cases, the shortest distances from the coil to the nerves were 5, 6, and 7 mm. In all but 1 case, the contrast dye was directly in contact with the nerves. The median circumferential covering of the nerve by contrast dye was 50% (25-interquartile range of 40%). CONCLUSIONS: By using self-coiling catheters, it is possible to blindly introduce the catheter through needles placed under ultrasound guidance with a low risk of catheter misplacement away from the targeted nerves. PMID- 21270720 TI - Progression of forearm intravenous regional anesthesia with ropivacaine. AB - The progression of sensory blockade in the hand following a forearm Bier block with ropivacaine is currently unknown. The hands of 10 healthy adult human subjects were anesthetized with ropivacaine, and their sensitivities to cold and touch were tested until the completion of anesthesia. On average, insensitivity to cold occurred uniformly throughout the hand within 9 mins; however, touch sensation was not complete until approximately 20 mins after injection. The spread of anesthesia occurred in a semisystematic way, spreading proximally and distally from the site of injection (mid-dorsum of the hand), and, at a slower rate, from the dorsum of the hand to the palm. PMID- 21270721 TI - Minimum effective volume of lidocaine for ultrasound-guided infraclavicular block. AB - BACKGROUND: The aim of this study was to determine the minimum effective volume of lidocaine 1.5% with epinephrine 5 MUg/mL in 90% of patients (MEV(90)) for single-injection ultrasound-guided infraclavicular block (ICB). METHODS: Using an in-plane technique, a single-injection ultrasound-guided ICB was performed: a 17 gauge, 8-cm Tuohy needle was advanced until the tip was located dorsal to the axillary artery. Volume assignment was carried out using a biased coin design up and-down sequential method, where the volume of local anesthetic administered to each patient depended on the response of the previous one. In case of failure, the next subject received a higher volume (defined as the previous volume with an increment of 2.5 mL). If the previous patient had a successful block, the next subject was randomized to a lower volume (defined as the previous volume with a decrement of 2.5 mL), with a probability of b=0.11, or the same volume, with a probability of 1-b=0.89. Lidocaine 1.5% with epinephrine 5 MUg/mL was used in all subjects. Success was defined, at 30 mins, as a minimal score of 14 of 16 points using a composite scale encompassing sensory and motor block. Patients undergoing surgery of the elbow, forearm, wrist, or hand were prospectively enrolled until 45 successful blocks were obtained. RESULTS: Fifty-five patients were included in the study. Using isotonic regression and bootstrap confidence interval (CI), the MEV(90) for single-injection ultrasound-guided ICB was estimated to be 35 mL (95% CI, 30-37.5 mL). The probability of a successful response at 35 mL was estimated to be 0.91 (95% CI, 0.8-1.0). All patients with a minimal composite score of 14 points at 30 mins achieved surgical anesthesia intraoperatively. CONCLUSIONS: For single-injection ultrasound-guided ICB, the MEV(90) of lidocaine 1.5% with epinephrine 5 MUg/mL is 35 mL. Further dose-finding studies are required for other concentrations of lidocaine, other local anesthetic agents as well as techniques involving multiple injections, a more medial approach to ICB, or precise location of all 3 cords of the brachial plexus. PMID- 21270722 TI - Ipsilateral brachial plexus block and hemidiaphragmatic paresis as adverse effect of a high thoracic paravertebral block. AB - BACKGROUND: Thoracic paravertebral block is regularly used for unilateral chest and abdominal surgery and is associated with a low complication rate. CASE REPORTS: We describe 2 patients with an ipsilateral brachial plexus block with Horner syndrome after a high continuous thoracic paravertebral block at T2-3. One patient also developed an ipsilateral hemidiaphragmatic paresis, an adverse effect that has not been reported before. Subsequent radiologic examination revealed a limited thoracic cephalad spread of the radiopaque dye and a laterally ascending spread from the thoracic paravertebral space toward and around the brachial plexus. We offer potential explanations for these phenomena. CONCLUSIONS: Brachial plexus block can occur by a route parallel to a nerve connecting the second intercostal nerve and T1 nerve, that is, Kuntz nerve. The hemidiaphragmatic paresis was attributed to the ascending spread of local anesthetic toward the area where the phrenic nerve bypasses the subclavian artery and vein. PMID- 21270723 TI - Combined versus sequential injection of mepivacaine and ropivacaine for supraclavicular nerve blocks. AB - BACKGROUND: An ideal local anesthetic with rapid onset and prolonged duration has yet to be developed. Clinicians use mixtures of local anesthetics in an attempt to combine their advantages. We tested the hypothesis that sequential supraclavicular injection of 1.5% mepivacaine followed 90 secs later by 0.5% ropivacaine speeds onset of sensory block and prolongs duration of analgesia compared with simultaneous injection of the same 2 local anesthetics. METHODS: We enrolled 103 patients undergoing surgery suitable for supraclavicular anesthesia. The primary outcome was time to 4-nerve sensory block onset in each of the 4 major nerve distributions: median, ulnar, radial, and musculocutaneous. Secondary outcomes included time to onset of first sensory block, time to complete motor block, duration of analgesia, pain scores at rest and with movement, and total opioid consumption. Outcomes were compared using the Kaplan-Meier analysis with the log-rank test or the analysis of variance, as appropriate. RESULTS: Times to 4-nerve sensory block onset were not different between sequential and combined anesthetic administration. The time to complete motor block onset was faster in the combined group as compared with the sequential. There were not significant differences between the 2 randomized groups in other secondary outcomes, such as the time to onset of first sensory block, the duration of analgesia, the pain scores at rest or with movement, or the total opioid consumption. CONCLUSIONS: Sequential injection of 1.5% mepivacaine followed 90 secs later by 0.5% ropivacaine provides no advantage compared with simultaneous injection of the same doses. PMID- 21270724 TI - Psoas compartment block for acute postoperative pain management after hip surgery in pediatrics: a comparative study with caudal analgesia. AB - BACKGROUND: Lower-limb peripheral nerve blocks in pediatrics have gained much more popularity in the last few decades. Our purpose of this study was to compare the postoperative analgesic effects between psoas compartment block (PCB) and caudal block in small children undergoing open hip reduction/osteotomies. METHODS: Forty American Society of Anesthesiologists physical status I-II children aged 1 to 6 years planned to undergo open hip reduction/osteotomies were administered general anesthesia and then randomly assigned to receive 1 of 2 regional anesthetics: caudal block (group C, n=20) or PCB (group P, n=20). Ropivacaine 0.25% with epinephrine (5 MUg/mL) was used in both blocks. The primary outcome of the study was the total consumption of morphine in the first 24 postoperative hrs. Secondary outcomes included dose of intraoperative fentanyl, occurrence of intraoperative hypotension or bradycardia, postoperative pain scores, time to first morphine analgesia, and occurrence of postoperative vomiting or urine retention. RESULTS: The cumulative dose of morphine administered in the ward in the first postoperative 24 hrs and the time to first rescue morphine dose were higher in group C than in group P (P<0.001). There were no differences between the 2 groups regarding intraoperative and postoperative complications except for the incidence of urine retention, which was higher in group C than in group P (P=0.037). CONCLUSIONS: Use of single-shot PCB is superior to single-shot caudal block regarding length of postoperative analgesia and cumulative dose of morphine in small children undergoing open hip reduction/osteotomies. PMID- 21270725 TI - Granulomatous conduit for intrathecal infusion of morphine and bupivacaine. AB - OBJECTIVE: Intrathecal drug delivery systems (IT-DDSs) have gained more widespread use in patients with non-cancer-related pain, notably failed back surgery syndrome and spinal arachnoiditis. Secondary to the longer life spans of these patients, more complications have been discovered with IT-DDSs. With an estimated incidence of 1% to 3%, an uncommon but serious complication is that of granuloma formation. CASE REPORT: We describe a case of a 38-year-old woman with a malfunctioning IT-DDS containing morphine and bupivacaine. The device had stopped providing relief for several months because of presumed leakage from the connection site between the pump and the proximal catheter. The IT-DDS spontaneously resumed functioning. The IT-DDS was explanted for low battery life, upon which we discovered that the leakage site had been encapsulated by drug concretion and granuloma formation, thus providing a sealed conduit that reestablished drug flow between the pump and the catheter. CONCLUSIONS: This case report reinforces the view that the infusate is the causal agent of this lesion. PMID- 21270726 TI - An evaluation of medications commonly used for epidural neurolysis procedures in a human fibroblast cell culture model. AB - BACKGROUND AND OBJECTIVES: Epidural injections are popular therapies for sciatica and low back pain. Local anesthetics and corticosteroids are commonly used for most injections techniques, but some treatments use a specific combination of several agents. The epidural lysis of adhesions procedure (Racz) uses a combination of bupivacaine, hyaluronidase, a corticosteroid, and hypertonic saline. Because severe complications, some with permanent neurologic deficits, have been observed, we considered the possibility that individual agents or a combination thereof might be capable of damaging or destroying cells in primarily the epidural tissues. METHODS: We used monolayer cell cultures of human fibroblasts in Dulbecco modified Eagle medium to study these pharmacological agents alone or in combination. Cell viability and proliferation were assessed by Trypan blue staining, cell counts, and the WST-1 assay. Time and concentration series were performed. RESULTS: With the corticosteroid, we observed the previously described proliferation-retarding effects. Hyaluronidase was not found to have a relevant effect on fibroblast proliferation. Bupivacaine and hypertonic saline were found to have a time- and concentration-dependent effect on cell viability and proliferation. Both were found to be toxic at concentrations well below the ones used clinically. CONCLUSIONS: We identified a potential for harm caused by commonly used pharmacological agents when applied epidurally. Animal studies will have to show whether the same can be observed in living tissues. PMID- 21270727 TI - Direct connections between the spinal epidural space and the venous circulation in humans. AB - BACKGROUND AND OBJECTIVES: Our previous studies in pigs indicate that direct connections exist between the spinal epidural space and the venous circulation. We wondered if similar connections occur in humans and have extended our investigations to human cadavers awaiting autopsy. METHODS: We studied 10 recently dead human bodies. We inserted 2 Tuohy needles into the epidural space of the lower thoracic spine at adjacent interspaces. We infused saline with a constant-flow pump into 1 needle and measured the resulting pressure through the other. Epidural pressure increased to a steady plateau during fluid infusion, and this value was recorded at several flow rates. The pressure decay after flow stopped was also recorded. Then we infused radiopaque contrast, removed the needles, and obtained a computed tomographic scan of the spine from the foramen magnum to the coccyx. RESULTS: Pressure in the epidural space increased to a plateau during saline infusion. Higher flow rates produced higher plateau pressures. Plots of plateau pressure versus infusion rate were linear in all bodies. The slope of the flow-pressure plot gave a steady-state resistance (543+/ 638 mm Hg.s/mL). The time constant of the pressure decay curve allowed calculation of initial capacitance (0.090+/-0.062 mL/mm Hg). Contrast could be identified in veins around the spinal column in all bodies. Contrast was found most commonly in the deep veins of the neck (7 bodies) and in veins originating in the area of the brachial plexus (7 bodies). Contrast was found less commonly and in smaller amounts in veins draining into the azygous system (5 bodies) and the lumbar veins (5 bodies). No contrast was found in veins in the sacral area. CONCLUSIONS: A direct connection between the spinal epidural space and the venous circulation has been demonstrated in human cadavers. The connection is most commonly found in the cervical and upper thoracic spine. PMID- 21270728 TI - Tensile strength decreases and perfusion pressure of 3-holed polyamide epidural catheters increases in long-term epidural infusion. AB - BACKGROUND AND OBJECTIVES: Epidural analgesia is an established method for pain management. The failure rate is 8% to 12% due to technical difficulties (catheter dislocation and/or disconnection; partial or total catheter occlusion) and management. The mechanical properties of the catheters, like tensile strength and flow rate, may also be affected by the analgesic solution and/or the tissue environment. METHOD: We investigated the tensile strength and perfusion pressure of new (n=20), perioperatively (n=30), and postoperatively (n=73) used epidural catheters (20-gauge, polyamide, closed tip, 3 side holes; Perifix [B. Braun]). To prevent dislocation, epidural catheters were taped (n=5) or fixed by suture (n=68) to the skin. After removal, mechanical properties were assessed by a tensile-testing machine (INSTRON 4500), and perfusion pressure was measured at flow rates of 10, 20, and 40 mL/h. RESULTS: All catheters demonstrated a 2-step force transmission. Initially, a minimal increase of length could be observed at 15 N followed by an elongation of several cm at additional forces (7 N). Breakage occurred in the control group at 23.5+/-1.5 N compared with 22.4+/-1.6 N in perioperative and 22.4+/-1.7 N in postoperative catheters (P<0.05). Duration of catheter use had no effect on tensile strength, whereas perfusion pressure at clinically used flow rates (10 mL/h) increased significantly from 19+/-1.3 to 44+/-72 mm Hg during long-term (>=7 days) epidural analgesia (P<0.05, analysis of variance). Fixation by suture had no influence on tensile strength or perfusion pressure. CONCLUSIONS: Epidural catheter use significantly increases the perfusion pressure and decreases the tensile strength. PMID- 21270729 TI - Compilation of secondary metabolites from Bidens pilosa L. AB - Bidens pilosa L. is a cosmopolitan annual herb, known for its traditional use in treating various diseases and thus much studied for the biological activity of its extracts, fractions and isolated compounds. Polyacetylenes and flavonoids, typical metabolite classes in the Bidens genus, predominate in the phytochemistry of B. pilosa. These classes of compounds have great taxonomic significance. In the Asteraceae family, the acetylene moiety is widely distributed in the Heliantheae tribe and some representatives, such as 1-phenylhepta-1,3,5-triyne, are noted for their biological activity and strong long-wave UV radiation absorbance. The flavonoids, specifically aurones and chalcones, have been reported as good sub-tribal level markers. Natural products from several other classes have also been isolated from different parts of B. pilosa. This review summarizes the available information on the 198 natural products isolated to date from B. pilosa. PMID- 21270730 TI - Irving-Williams order in the framework of connectivity index 3chiv enables simultaneous prediction of stability constants of bivalent transition metal complexes. AB - Logarithms of stability constants, log K1 and log beta2, of the first transition series metal mono- and bis-complexes with any of four aliphatic amino acids (glycine, alanine, valine and leucine) decrease monotonously with third order valence connectivity index, 3chiv, from Cu2+ to Mn2+. While stability of the complexes with the same metal is linearly dependent on 3chiv, stability constants of Mn2+, Fe2+, Co2+, and Ni2+complexes with the same ligand show a quadratic dependence on 3chiv. As Cu2+ complexes deviate significantly from quadratic functions, models for the simultaneous estimation of the stability constants, yielding r = 0.999 (S.E. = 0.05) and r = 0.998 (S.E. = 0.11), for log K1 and log beta2, respectively, were developed only for Mn2+, Fe2+, Co2+, and Ni2+ complexes with amino acids. PMID- 21270731 TI - Synthesis and anti-fungal activity of seven oleanolic acid glycosides. AB - In order to develop potential anti-fungal agents, seven glycoconjugates composed of alpha-L-rhamnose, 6-deoxy-alpha-L-talose, beta-D-galactose, alpha-D-mannose, beta-D-xylose-(1->4)-6-deoxy-alpha-L-talose, beta-D-galactose-(1->4)-alpha-L rhamnose, beta-D-galactose-(1->3)-beta-D-xylose-(1->4)-6-deoxy-alpha-L-talose as the glycone and oleanolic acid as the aglycone were synthesized in an efficient and practical way using glycosyl trichloroacetimidates as donors. The structures of the new compounds were confirmed by MS, 1H-NMR and 13C-NMR.Preliminary studies based on means of mycelium growth rate, indicated that all the compounds possess certain fungicidal activity against Sclerotinia sclerotiorum (Lib.) de Bary, Rhizoctonia solani Kuhn, Botrytis cinerea Pers and Phytophthora parasitica Dast. PMID- 21270732 TI - Cross-coupling reactions as valuable tool for the preparation of PET radiotracers. AB - The increasing application of positron emission tomography (PET) in nuclear medicine has stimulated the extensive development of a multitude of new radiotracers and novel radiolabeling procedures with the most prominent short lived positron emitters carbon-11 and fluorine-18. Radiolabeling with these radionuclides represents a remarkable challenge. Special attention has to be paid to synthesis time and specific labeling techniques due to the short physical half life of the respective radionuclides 11C (t(1/2) = 20.4 min) and 18F (t1/2) = 109.8 min). In the past, numerous transition metal-catalyzed reactions were employed in organic chemistry, even though only a handful of these coupling reactions were adopted in radiochemical practice. Thus, the implementation of modern synthesis methods like cross-coupling reactions offers the possibility to develop a wide variety of novel radiotracers. The introduction of catalysts based on transition metal complexes bears a high potential for rapid, efficient, highly selective and functional group-tolerating incorporation of carbon-11 and fluorine 18 into target molecules. This review deals with design, application and improvement of transition metal-mediated carbon-carbon as well as carbon heteroatom cross-coupling reactions as a labeling feature with the focus on the preparation of radiolabeled compounds for molecular imaging. PMID- 21270733 TI - Antitrypanasomal activity of novel benzaldehyde-thiosemicarbazone derivatives from kaurenoic acid. AB - A series of new thiosemicarbazones derived from natural diterpene kaurenoic acid were synthesized and tested against the epimastigote forms of Trypanosoma cruzi to evaluate their antitrypanosomal potential. Seven of the synthesized thiosemicarbazones were more active than kaurenoic acid with IC50 values between 2-24.0 mM. The o-nitro-benzaldehyde-thiosemicarbazone derivative was the most active compound with IC50 of 2.0 mM. The results show that the structural modifications accomplished enhanced the antitrypanosomal activity of these compounds. Besides, the thiocyanate, thiosemicarbazide and the p- methyl, p methoxy, p-dimethylamine, m-nitro and o-chlorobenzaldehyde-thiosemicarbazone derivatives displayed lower toxicity for LLMCK2 cells than kaurenoic acid, exhibing an IC50 of 59.5 mM. PMID- 21270734 TI - Seasonal variation in the chemical composition and antimicrobial activity of volatile oils of three species of Leptospermum (Myrtaceae) grown in Brazil. AB - This study investigates the seasonal variation of three species of Leptospermum (Myrtaceae) grown in Brazil. The chemical composition of the volatile oils of L. flavescens and L. petersonii did not show any significant seasonal variation in the major components, while for Leptospermum madidum subsp. sativum the levels of major constituents of the volatile oils varied with the harvest season. Major fluctuations in the composition of L. madidum subsp. sativum oil included alpha pinene (0-15.2%), beta-pinene (0.3-18.5%), alpha-humulene (0.8-30%), 1,8-cineole (0.4-7.1%) and E-caryophyllene (0.4-11.9%). Levels of beta-pinene (0.3-5.6%), terpinen-4-ol (4.7-7.2%) and nerolidol (55.1-67.6%) fluctuated seasonally in the L. flavescens oil. In L. petersonii, changes were noted for geranial (29.8 32.8%), citronellal (26.5-33.9%) and neral (22.7-23.5%). The activity of the volatile oils against the tested bacteria differed, depending on season the oils were obtained. In general, the volatile oils were more active against Gram positive bacteria. PMID- 21270735 TI - Self-assessed bruxism and phobic symptomatology. AB - AIM: The aim of this observational study was to compare two samples of patients (identified, from a previous survey carried out in 2007, as self-assessed bruxers and not) on the basis of the presence of anxious/phobic symptoms, general and linked to an oral surgery. METHODS: Forty-three bruxers and 207 non-bruxers were identified; among these last ones a sub-sample of 89 subjects was randomly selected as control and analyzed. The instruments for data collecting were two self-administered psychological questionnaires: STAI-Y1, Phobia Scale by Marks Sheehan, and supplementary items on specific dental fear/phobia. RESULTS: No significant differences were observed for age, gender and occupation data but interestingly bruxers are significantly more represented among widows/divorced and graduated in comparisons with non-bruxers. Alcohol consumers were more frequent in bruxers than in non-bruxers (55.8% and 12.4%, respectively; P=0.0001). Global anxiety (P=0.02), agoraphobia, claustrophobia, pathophobia, social phobia (P<0.05), are more frequent in bruxers as also a suffocation feeling (P=0.02). The severity of behaviours that aim to avoid the same situations that causes phobias is low and similar in the two groups. CONCLUSION: The involuntary habit of clenching is, in our opinion, reported by the patients who control their anxiety/phobias without avoiding behaviours, increasing the muscular activity at a level relevant to bruxism. PMID- 21270736 TI - Oral and non oral diseases and conditions associated with bad breath. AB - AIM: The causes of bad breath are numerous and related to conditions dependent or not on oral and general health. The aim of our observational study is the assessment of the simultaneous relationships between halitosis, oral and/or nonoral diseases, and lifestyles using the principal components analysis of categorical data (CATPCA) to identify the main components involved in the detection of the symptom. METHODS: A sample of 192 patients, who requested general dental examination at the Dental Clinic, participated at the study. Alimentary and voluptuary habits, general health information, drugs assumption, the status of teeth and intraoral medical devices including fillers, lesions of the oral mucosa, tongue coating score (TCS), plaque index (PI), probing bleeding index (PBI) and organoleptic tests were all evaluated. Data were analysed using CATPCA model. RESULTS: A strong relationship between halitosis and plaque, probing bleeding and tongue coating indexes was observed, whereas incongruous fillers, prostheses, systemic pathologies or diet were not clearly associated with halitosis probably because their effects on breath were clinically sheltered by the periodontal condition. CONCLUSION: The data of our observational study confirm that halitosis is more indicative of tongue coating and periodontal disease, rather than other oral and non oral associated conditions, like systemic pathologies or specific habits of life. PMID- 21270737 TI - Silica coating on alumina ceramic: comparison of three chairside air-abrasion devices working for different times and distances. AB - AIM: This study evaluated, by scanning electron microscope (SEM) and EDS, the effect of different strategies for silica coating (sandblasters, time and distance) of a glass-infiltrated ceramic (In-Ceram Alumina). METHODS: Forty-one ceramic blocks were produced. For comparison of the three air-abrasion devices, 15 ceramic samples were divided in three groups (N.=5): Bioart, Microetcher and Ronvig (air-abrasion parameters: 20 s at a distance of 10 mm). For evaluation of the time and distance factors, ceramic samples (N.=5) were allocated in groups considering three applied times (5 s, 13 s and 20 s) and two distances (10 mm and 20 mm), using the Ronvig device. In a control sample, no surface treatment was performed. After that, the micro-morphologic analyzes of the ceramic surfaces were made using SEM. EDS analyzes were carried out to detect the % of silica on representative ceramic surface. ANOVA and Tukey tests were used to analyze the results. RESULTS: One-way ANOVA showed the silica deposition was different for different devices (P=0.0054). The Ronvig device promoted the highest silica coating compared to the other devices (Tukey test). Two-way ANOVA showed the distance and time factors did not affect significantly the silica deposition (application time and distance showed no statistical difference). CONCLUSION: The Ronvig device provided the most effective silica deposition on glass-infiltrated alumina ceramic surface and the studied time and distance for air-abrasion did not affect the silica coating. PMID- 21270738 TI - Hard and soft tissue augmentation in implant surgery: a case report. AB - Correct pre- and postimplant hard and soft tissue management is prerequisite to achieving optimal esthetic and functional outcomes after implant-prosthesis treatment. Various different methods for preimplant hard tissue augmentation in alveolus maxillary atrophy are described. In some cases, non-resorbable titanium reinforced membranes are employed for vertical augmentation of the edentulous crest. Also well documented is soft tissue management through mucus-gingival surgery techniques that increase the thickness of peri-implant keratinized gingiva, enhancing soft tissue esthetic and health. These methods also include the use of epithelial-connectival grafts collected from the palate. Here we present a clinical case of severe bone vertical resorption in edentulous areas treated with two vertical ridge augmentations by means of non-resorbable membranes in the retromandibular area and deferred insertion of six implants. Peri-implant plastic surgery techniques to improve the quantity of keratinized mucosa during the second surgery phase are also discussed. Combination of the two techniques resulted in harmonic tissue architecture and adequate presence of keratinized gingiva. PMID- 21270739 TI - Solid variant of keratocystic odontogenic tumour: report of a case. AB - This case report presents a solid variant of keratocystic odontogenic tumour (KCOT), a benign uni- or multicystic intraosseous tumour of odontogenic origin, with a characteristic lining of parakeratinized stratified squamous epithelium and potential inflammatory infiltrate. A 52-year old female patient discovered occasionally, in an orthopantomography done for other reasons, the presence of a radiolucent lesion. A 2-3 cm wide lesion with well-demarcated margins was present in the premolar region of the left hemimandible. Under local anesthesia a biopsy was done and the diagnosis of odontogenic keratocyst was confirmed by histopathological examination. Under general anesthesia, the lesion was easily shelled-out and completely enucleated. The lesion had not recurred after a 6 years follow-up. The occurrence of a solid variant of KCOT could strengthen the hypothesis of a neoplastic rather than cystic nature of this lesion. PMID- 21270740 TI - Case report of oligodontia: long term stability of orthognatic surgery and prosthetic rehabilitation. AB - Oligodontia may compromise the harmonious development of the masticatory system. The quantity and quality of agenesis determines the type of approach and the complexity of rehabilitative therapy. We present a case of a patient affected by oligodontia and maxillo-mandibular skeletal alterations, corrected by orthodontic and orthognatic surgical treatment, assisted by prosthetic-presurgical rehabilitation of the lower arch. After surgery the occlusion was finally restored by a definitive prosthesis modeled on the presurgical one and supported by the same residual dental elements. Photographic and cephalometric analysis have shown the stability of the results at 20 years follow-up. The case presented shows that the final prosthesis on the residual teeth in patients affected by oligodontia may represent a possible alternative to implanto-prosthetic rehabilitation, presenting lower cost and requiring less time for definitive occlusal rehabilitation. PMID- 21270741 TI - Diverse clinical nature of cavernous lymphangioma: report of two cases. AB - Lymphangioma are uncommon hamartomatous congenital malformations of the lymphatic system that involve skin and subcutaneous tissue. They have marked predilection for head and neck region in 75% of cases. Around 50% of lesions are noticed at birth and 90% by 2 years of age. Oral lymphangioma may be present in tongue, palate, buccal mucosa, gingiva and lip. Lymphangioma are of 3 types-simplex, cavernous and cystic lymphangioma. Cavernous lymphangioma is usually seen in fairly dense tissue such as the tongue.We report two unusual cases of cavernous lymphangioma in 24-26 years age group with the site of involvement being floor of the mouth extending into the submandibular triangle in the first case, and the second manifesting as a bluish red swelling on the labial mucosa. PMID- 21270742 TI - Juvenile xanthogranuloma of the tongue: an unusual case report with immunohistochemical investigation. PMID- 21270743 TI - Interim guidance: preexposure prophylaxis for the prevention of HIV infection in men who have sex with men. AB - An estimated 56,000 human immunodeficiency virus (HIV) infections occur each year in the United States. Men who have sex with men (MSM) account for 53% of the estimated incident infections, and surveillance data suggest that the annual number of new HIV infections among MSM has been rising since the mid-1990s. Strategies for reducing acquisition of HIV infection by MSM have included 1) expanded HIV testing so that infected persons can be treated and their risk for transmitting infection minimized; 2) individual, small-group, and community-level behavioral interventions to reduce risk behaviors; 3) promotion of condom use; 4) detection and treatment of sexually transmitted infections; and 5) mental health and substance abuse counseling when needed. On November 23, 2010, investigators for the Pre-Exposure Prophylaxis Initiative (iPrEX) study announced results from a multinational, randomized, double-blind, placebo-controlled, phase III clinical trial of daily oral antiretrovirals (tenofovir disoproxil fumarate [TDF] and emtricitabine [FTC]) to prevent acquisition of HIV infection among uninfected but exposed MSM. This report provides interim guidance to health-care providers based on the reported results of that trial, which indicated that TDF plus FTC taken orally once a day as preexposure prophylaxis (PrEP) is safe and partially effective in reducing HIV acquisition among MSM when provided with regular monitoring of HIV status and ongoing risk-reduction and PrEP medication adherence counseling. PMID- 21270744 TI - Lead poisoning of a child associated with use of a Cambodian Amulet --- New York City, 2009. AB - Lead poisoning in children is a preventable public health problem that can adversely affect the developing nervous system and result in learning and behavior problems. The most common source of exposure for lead-poisoned children aged <6 years in the United States is lead-based paint. However, nonpaint sources have been identified increasingly as the cause of lead poisoning, particularly in immigrant communities. This report describes a case of lead poisoning in a child aged 1 year that was investigated by the New York City Department of Health and Mental Hygiene's (NYC DOHMH) Lead Poisoning Prevention Program in 2009. The likely source of exposure was an amulet made in Cambodia with leaded beads that was worn by the child. Health-care providers and public health workers should consider traditional customs when seeking sources of lead exposure in Southeast Asian populations. Health-care providers should ask parents about their use of amulets, especially those in Southeast Asian families and those with children found to have elevated blood lead levels (BLLs). Educational efforts are needed to inform Southeast Asian immigrants that amulets can be a source of lead poisoning. PMID- 21270745 TI - Updated recommendations for use of meningococcal conjugate vaccines --- Advisory Committee on Immunization Practices (ACIP), 2010. AB - On October 27, 2010, the Advisory Committee on Immunization Practices (ACIP) approved updated recommendations for the use of quadrivalent (serogroups A, C, Y, and W-135) meningococcal conjugate vaccines (Menveo, Novartis; and Menactra, Sanofi Pasteur) in adolescents and persons at high risk for meningococcal disease. These recommendations supplement the previous ACIP recommendations for meningococcal vaccination . The Meningococcal Vaccines Work Group of ACIP reviewed available data on immunogenicity in high-risk groups, bactericidal antibody persistence after immunization, current epidemiology, vaccine effectiveness (VE), and cost-effectiveness of different strategies for vaccination of adolescents. The Work Group then presented policy options for consideration by the full ACIP. This report summarizes two new recommendations approved by ACIP: 1) routine vaccination of adolescents, preferably at age 11 or 12 years, with a booster dose at age 16 years and 2) a 2-dose primary series administered 2 months apart for persons aged 2 through 54 years with persistent complement component deficiency (e.g., C5-C9, properidin, factor H, or factor D) and functional or anatomic asplenia, and for adolescents with human immunodeficiency virus (HIV) infection. CDC guidance for vaccine providers regarding these updated recommendations also is included. PMID- 21270746 TI - Notes from the field: respiratory diphtheria-like illness caused by toxigenic Corynebacterium ulcerans --- Idaho, 2010. AB - On September 12, 2010, the Idaho Department of Health and Welfare was notified of a case of respiratory diphtheria-like illness in an Idaho man aged 80 years whose pharyngeal specimens yielded Corynebacterium ulcerans. Although C. ulcerans is zoonotic, the patient reported no animal contact or consumption of an unpasteurized dairy product. His vaccination history was unknown. Respiratory diphtheria-like illness from C. ulcerans is uncommon but has been reported in industrialized countries where respiratory diphtheria is rare. The last case of diphtheria-like illness caused by C. ulcerans in the United States was reported in 2005. PMID- 21270747 TI - Hodgkin's lymphoma: the role of cell surface receptors in regulation of tumor cell fate. AB - The hallmark of Hodgkin's lymphoma (HL) are mononucleated Hodgkin's cells and multinucleated Reed-Sternberg (HRS) cells, which usually account for only about 1% of cells in the tumor tissue. The majority of HRS cells in classical HL are derived from germinal centre B cells that have acquired disadvantageous Ig variable chain gene mutations and escaped from apoptosis. Due to reprogramming of gene expression, these lymphoma cells have lost the expression of most B-cell specific genes and acquired expression of multiple genes that are typical for other hematopoietic cells. HRS cells attract various cells of immune system into lymphoma tissue resulting in an inflammatory microenvironment. Moreover, HRS cells are dependent on microenvironment, especially on survival signals from other cells. Despite the loss of BCR - the master-regulator of B cell fate, HRS cells express a number of receptors that regulate tumor cell survival. The rescue of HRS cells from apoptosis is a key event in HL pathogenesis. These cells express at least six receptors that belong to TNF receptor family: CD30, CD40, CD95, TACI, BCMA and RANK, co-stimulatory receptors CD80 and CD86, and E selectins ligand CD15. Due to the mutations in genes encoding proteins of CD95 mediated apoptotic signaling pathway, it is not functional in HRS cells. Ligands of TNF family receptors on cells in HL microenvironment contribute to the activation of canonical and non-canonical NF-kappaB signaling pathways and survival program of HRS cells. Moreover, in HRS cells a number of multiple mutations in negative NF-kappaB regulators, and also gains and amplifications of positive regulators, cooperate in deregulating these pathways. All TNF receptors may be linked to the activation of prosurvival gene expression programs via Akt and ERK pathways. HRS cells also express CD150 receptor with specific ITSM motifs in the cytoplasmic tail. Ligation of this receptor on HRS cells induced activation of Akt and ERK pathways, and moreover, it triggered activation of JNK signaling cascade. CONCLUSION: The review presents the current views on the role of cell surface receptors in maintenance of HL microenvironment favorable for HRS cells survival. PMID- 21270748 TI - At a crossroads of cancer risk and aging: the role of telomeres. AB - The risk of overall cancer inevitably increases with advancing age. The cancer incidence rate is not constant within the human life span (it exponentially increases with advancing age). Aging itself is a complex biological process with a poorly understood mechanism of its regulation. The aging process, as evidenced from the survey of the chances for death for the large cohort of people of various age groups, manifests probably due to a progressive accumulation of diverse adverse changes that increase the risk of death. While an increase of cancer risk due to aging cannot be fully explained, the length of telomeres (biomarker of aging) appears to be important to predict this risk. Cellular senescence, which is believed to be associated with dysfunctional (shortened) telomeres, may contribute to the aging of a whole organism. Here, based on recent literature data, we investigate the possible link between telomere dysfunction associated cellular senescence and tumorigenesis. PMID- 21270749 TI - Prostate cancer which affects an elderly man is a feature of senescence (cellular) - a biology phenomenon. AB - Some prostate cancers are clinically significant (i.e. life-threatening) but others are not. Small proportion of elderly men dies of prostate cancer while most of them harbor tumor lesions in their prostates. The aim of this paper was to present late-life form of the prostate cancer, which differs from its aggressive counterpart that affects men between 55-65 years old and younger. The differences can be found in carcinogenesis risk factors, cancer biology and finally patients' survival. The most important is that these two clinical (age related) forms of the prostate cancer are still undistinguishable in clinico pathology reports and patients bearing different diseases are offered the same treatment. Potential mechanisms leading to development of the late-life clinically indolent prostate cancer are discussed. It seems that the key abnormalities are proteins involved in control of regenerative potential and cell senescence. CONCLUSIONS: We postulate that late-life low-grade (clinically indolent) prostate cancer subcategory should be established. This type of "cancer" should rather be viewed as a senescence-related feature and probably not treated at all. PMID- 21270750 TI - Hyperflav - perspective photosensitizer for PDT: cell studies. AB - BACKGROUND: Application of hypericin (an alkaloid from Hypericum perforatum plants) as photodynamic agent may become the next successful step in photodynamic therapy of malignant tumors. Hyperflav - is a purified Hypericum extract designed for the purpose of photodynamic diagnosis. AIM: Present studies investigated the effectiveness in vitro of Hyperflav application as a photosensitizer for photodynamic therapy. METHODS: Hyperflav photodynamic activity was assessed in phototoxic cell tests on Jurkat, MT-4 and Namalwa leukemic cell lines. Spectroscopic measurements of Hyperflav solutions were performed. RESULTS: Hyperflav aqueous solubility was maintained in presence of polyvinylpyrrolidone with the most pronounced photodynamic activity at 1:5 (w/w) Hyperflav-PVP ratio. Hyperflav fluorescence spectrum in ethanol exhibits two main peaks around 597 and 647 nm, in accordance with the spectrum of pure hypericin. Fluorescence spectrum of aqueous solution exhibits peaks at 604 and 655 nm and indicates decreasing in fluorescence intensity. Hyperflav at drug dose range of 5 -25 MUg/ml and light dose 15 J/cm(2) showed a dose-dependent cytotoxicity on tested cell cultures, while dark cytotoxicity was not observed. Light irradiation of cell samples preincubated with 15 MUg/ml Hyperflav resulted in 69.9, 76.0 and 78.3% cell death of Jurkat, MT-4 and Namalwa cultures, respectively. Combined preparation of Hyperflav with gold nanoparticles showed low photocytotoxicity (24.2%) in comparison with Hyperflav alone (99.6%) on Namalwa cells. CONCLUSION: Hyperflav being solubilized in nontoxic aqueous media exhibits in vitro photodynamic activity at doses that do not have dark toxicity, and therefore it meets requirements as a perspective photosensitizer. Further studies, particularly in vivo, are warranted to fully evaluate photodynamic potential of Hyperflav. PMID- 21270751 TI - Inhibition of invasion and MMPs by a nutrient mixture in human cancer cell lines: a correlation study. AB - Matrix metalloproteinase (MMP)-2 and -9 secretion is elevated in various human cancers and their elevated expression has been associated with poor prognosis due to associated increased cancer cell invasion and metastasis. AIM: To examine the correlation between in vitro MMP-2 and MMP-9 secretion and Matrigel invasion in 42 different human cancer cell lines (selected on the basis of organ malignancies) treated with a nutrient mixture (NM). MATERIALS AND METHODS: The cells were cultured in their recommended media supplemented with 10% FBS and antibiotics in 24-well tissue culture plates. At near confluence, the cells were treated with NM dissolved in media at 0, 10, 50, 100, 500 and 1000 MUg/mL in triplicate. Parallel sets of cultures were also treated with phorbol 12-myristate 13-acetate (PMA) 100 ng/mL for induction of enzymes. After 24 h the media were collected and MMP-2 and MMP-9 levels were assayed by gelatinase zymography. Invasion studies were conducted using Matrigel in 24-well plates. RESULTS: Correlation of pooled data from different cancer cell line groups demonstrated dose-dependent inhibition of MMP-2 and -9 and Matrigel invasion with NM treatment and significant negative correlation between MMP-2 and MMP-9 levels and Matrigel invasion. Pooled data of cell lines expressing only MMP-2 and resistance to PMA induction of MMP-9 showed significant negative correlation (r = -0.77, p = 0.003) between MMP-2 secretion and inhibition of invasion through Matrigel. Cell lines expressing only MMP-9, showed significant negative correlation (r = -0.726, p = 0.003) between MMP-9 secretion and Matrigel invasion. Pooled data of cell lines expressing MMP-2 and MMP-9 demonstrated significant negative correlation (r = 0.821, p < 0.0001) between MMP-9 secretion and inhibition of invasion through Matrigel. Pooled data of cancer cell lines expressing no basal MMP- 9 secretion demonstrated significant negative correlation (r = -0.686, p < 0.0001) between PMA-induced MMP-9 secretion and inhibition of invasion through Matrigel. CONCLUSIONS: In conclusion, regardless of MMP-2 and MMP-9 patterns of expression, MMP modulation by NM was found to be significantly correlated with NM modulation of Matrigel invasion of these cell lines. PMID- 21270752 TI - Ultrastructural and some functional changes in tumor cells treated with stabilized iron oxide nanoparticles. AB - AIM: To study the ultrastructure and some functional indexes of tumor cells treated with stabilized iron nanoparticles in vitro. METHODS: 3 [4,5dimethylthiazol-2-1]-2,5-diphenyltetrazolium bromide (MTT)-test, electron microscopy, polarography with applying of closed Clark's electrode. RESULTS: It was shown that cultivation of cells with stabilized Fe(3)O(4) leads to intracellular accumulation of ferromagnetic nanoparticles. The most active ferromagnetic uptake by cells has been observed after 24 and 48 h of incubation. The presence of ferromagnetic in cells led to altered mitochondrial structure that caused the decrease of oxygen uptake rate in the cells of all studied lines. Ferromagnetic released from the majority of cells via exocytosis or clasmacytosis after a certain period of time. The number of dead cells or cells with severe damage was moderate, so cytotoxic action of stabilized iron oxide nanoparticles was minimal toward the studied cell lines. CONCLUSION: the presence of ferromagnetic nanoparticles in culture medium led to alterations in mitochondria ultrastructural organization and decrease of oxygen uptake by mitochondria in sensitive and anticancer-drugs resistant cells. PMID- 21270753 TI - The evaluation of prooxidant and antioxidant state of two variants of lewis lung carcinoma: a comparative study. AB - AIM: To study the functional activity of enzymatic component of antioxidant system and to evaluate an intensity of prooxidative processes in Lewis lung carcinoma variants (LLC and LLC/R9). METHODS: Activity of glutathione-S transferase (GST), glutathione peroxidase (GP), glutathione reductase (GR), catalase (Cat), content of lipid peroxidation (LP) byproducts were analyzed in tumor extracts at the 24(th) day after tumor transplantation, extracts of muscle tissues of tumor-bearing mice and intact mice using the method of optic spectrometry. RESULTS: It was revealed higher level of GST and GR activities, and lower level of GP activity, and a tendency for decrease of Cat activity level in LLC/R9 tumors compared to LLC tumors. The content of primary LP products was higher in LLC/R9 tumors while two tumor variants didn't differ significantly by the content of tiobarbiturate-active products. CONCLUSION: The pool of reduced glutathione in LLC/R9 tumors is more effectively replenished with GP involvement and is used by GST for detoxification of exogenous xenobiotics compared with LLC. Lower GP activity and the tendency to decreased Cat activity is characteristic property for LLC/R9 tumors compared to LLC. PMID- 21270754 TI - Influence of bacterial lectins on some reactions of nonspecific immunity in sarcoma 37 transplanted mice. AB - AIM: To study preventive effect of cytotoxic lectin from Bacillus subtilis B-7025 on the tumor growth and nonspecific immunity in sarcoma 37 transplanted mice. METHODS: Sarcoma 37 cells were transplanted in Balb/c mice. Cytotoxic lectin (CL) was isolated from cultural fluid of B.subtilis strain B-7025 and inoculated at a dose of 0.2 mg per animal in prophylactic or combined schedule. Functional activity of macrophages was evaluated by NBT-test and the level of cytotoxicity, cytotoxic activity of splenocytes was assayed against K562 cells. RESULTS: CL administration in prophylactic or combined schedule results in inhibition of sarcoma 37 growth in mice. Stimulating effect of CL on peritoneal macrophages of sarcoma 37-bearing mice, especially at early stages of tumor growth, has been observed. At the late stage of tumor growth, the effect of lectin on cytotoxic activity of spleen mononuclear cells has been registered. CONCLUSION: Upon the use of lectin from B. subtilis B-7025, positive shifts of antitumor immunity reactions leading to tumor growth inhibition and elevation of average life span of tumor-bearing mice, have been detected. PMID- 21270755 TI - DNA-PK, ATM and MDR proteins inhibitors in overcoming fludarabine resistance in CLL cells. AB - AIM: To perform the comparative study of the effects of DNA-dependent protein kinase (DNA-PK) inhibitors vanillin and NU7026, ataxia telangiectasia mutated kinase (ATM)/ ATM and Rad3 related (ATR) kinase inhibitor caffeine and multidrug resistance (MDR) protein modulator cyclosporine A (CsA) on fludarabine resistant and sensitive lymphocytes from chronic lymphocytic leukemia (CLL) patients. METHODS: Cells sensitivity in vitro was determined with 3-(4,5-dimethyl-2 thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT). DNA-PKs and ATM expression in CLL cells was evaluated using Western blotting. Multidrug tansporter protein expression and function was assessed by flow cytometry. Pro- or anti-apoptotic genes (BAX, LICE BCL-2, BCL-XS FLICE, FAS, TRAIL) expression on mRNA level was evaluated. RESULTS: Caffeine, vanillin, NU7026 and CsA increased fludarabine cytotoxicity against fludarabine-resistant CLL cells samples in comparison with sensitive cell samples. However, fludarabine-sensitive CLL samples were sensitized with inhibitors to a greater extent compared with resistant CLL samples. ATM expression increased in fludarabine-resistant CLL samples, but no apparent correlation between DNA-PKs level and fludarabine sensitivity in vitro or sensitization effect of DNA-PK inhibitors were observed. Fludarabine-resistant CLL lymphocytes showed tendency for depressed MDR efflux and decreased level of mRNA of pro-apoptotic gene BCL-XS. CONCLUSION: Absence of any definite conformity between fludarabine-resistant cell susceptibility to combined action of fludarabine and inhibitors, and molecular pathways that might be involved in this process does not exclude drugs synergy in fludarabine-resistant cells that could be used for overcoming resistance to nucleoside analogs in CLL. PMID- 21270756 TI - Expression of CK-19 and CEA mRNA in peripheral blood of gastric cancer patients. AB - AIM: To investigate the clinical and pathological relevance of detection of circulating tumor cells (CTC) in the peripheral blood of gastric carcinoma patients before operation. PATIENTS AND METHODS: Fifty patients with gastric adenocarcinoma were analysed prospectively. Patients were divided into two groups according to the extent of the tumor. Group I (unresectable) consisted of 22, and group II (resectable) consisted of 28 patients. Peripheral blood samples were collected pre-operatively from all 50 patients as well as from ten healthy controls and analyzed for carcinoembryonic antigen (CEA) and cytokeratin-19 (CK 19) messenger ribonucleic acids (mRNAs). Tumor localisation, stage, presence of signet cell formation, nodal metastases, serousal and lymphovascular invasion were recorded for all patients. RESULTS: Expression of CK-19 was detected in 24 (48%), and CEA in 10 (20%) cases. Nine patients (40%) in group I and 15 (53.6%) in group II were positive for CK-19 expression. CEA expression was more frequent among group I patients (6 vs. 4 cases). There was no significant difference between the groups in the expression of CK-19 and CEA mRNA, tumor localisation, presence of signet formation, and presence and extent of nodal metastases. Patients with major vascular invasion (MVI) expressed significantly higher levels of CTC mRNA compared to those without MVI (p = 0.023 for CEA, and p = 0.009 for CK-19). The median 1 and 2-year survival was 9.5 and 10.5 months for group I, and 20 and 28.5 months for group II, respectively (p = 0.001). The mean survival was 6.7 months for patients with MVI, and 30.2 months for those without MVI (p = 0.0001). CONCLUSIONS: High levels of CTCs were observed in patients with MVI invasion, rather than other causes of unresectability. It can be suggested that expression of both CEA and CK-19 in the peripheral blood of gastric cancer patients are strong predictors of MVI and significantly worse survival rates. PMID- 21270757 TI - Caspase-3 activity in papillary thyroid carcinomas. AB - AIM: The aim of this work was to assess caspase-3 activity in the tissue of papillary thyroid carcinomas of patients and analyze the peculiarities of changes in this activity depending upon a number of pathomorphological and clinical features of tumoral process. METHODS: Caspase-3 activity was determined by spectrophotometry with regard to acetyl-asp-glu-val-asp-paranitroanilide. RESULTS: At initial stages of tumor development, in the absence of metastases to lymph nodes, blood and lymphatic vessel invasion by tumor cells, extrathyroid spreading of tumor, sclerotic and fibrous changes in tumor stroma, and in the presence of tumor capsule, caspase-3 activity in papillary carcinoma tissue was higher compared to unchanged thyroid tissue of normofollicular structure. In case of a more aggressive behaviour of tumor, enzyme activity in carcinoma tissue did not differ significantly or (in case of extrathyroid spreading of tumor) was decreased compared to that in extratumoral tissue. In combination, this was expressed by a progressive decrease in caspase-3 activity in tumor tissue with increasing T category. Saspase 3 activity was found to be much higher in the tissue of papillary carcinomas of follicular-papillary structure and lower in the tissue of tumors of mixed structure with solid areas, compared to that in the tissue of papillary carcinomas of typical papillary structure. CONCLUSIONS: The data obtained in assessing caspase-3 activity suggest that the intensity of spontaneous apoptosis of human papillary thyroid carcinoma cells depends upon the stage and aggressiveness of tumoral process. PMID- 21270758 TI - Immunohistochemical analysis of beta-defensin-2 expression in human lung tumors. AB - AIM: The present research was directed on analysis of the expression patterns of human beta-defensin-2 (hBD-2) in human lung tumors. MATERIALS AND METHODS: Specimens of surgically resected human lung tumors (n = 31) of different histological type (1 case of small cell lung cancer, and 30 cases of non-small cell lung cancer (1 case of clear cell carcinoma, 9 cases of squamous cell carcinoma (SCC), and 20 cases of adenocarcinoma (AC)) were analyzed for expression of hBD-2 with the use of immunohistochemical analysis. RESULTS: Immunohistochemical analysis has revealed that all lung tumor samples independently on their histological type express hBD-2 peptide, however at different levels (from < 5% to 100% cells). According to our observations, low differentiated AC differs from moderately differentiated AC by significantly lower hBD-2 expression levels (p < 0.05). No correlation between hBD-2 expression patterns and PCNA or Bcl-2 expression has been found. CONCLUSION: Human beta defensin-2 expression levels may depend on differentiation grade of lung adenocarcinoma. PMID- 21270759 TI - Two cases with atypical metastasis in colorectal cancer: splenic and renal metastasis. AB - Atypical metastasis, such as splenic and renal metastasis is rare in colorectal cancer. There have been case reports of colorectal cancer patients with isolated splenic metastasis, even after years of surgery in the literature. AIM: To report two colorectal cancer cases with atypical metastasis. RESULTS: The first patient was a 58-year old man who had isolated splenic metastasis after 20 months of surgery. The other one was a 51-year old male patient with both lung and renal metastasis at rectal cancer diagnosis. Splenic and renal metastases have been histopathologically documented in both of them. The first patient was given chemotherapy after splenectomy. The other one had also multiple lung metastases besides renal metastasis. He received palliative chemotherapy. PMID- 21270760 TI - Surveillance of alloantibodies after transplantation identifies the risk of chronic rejection. AB - The monitoring of the levels of alloantibodies following transplantation might facilitate early diagnosis of chronic rejection (CR), the leading cause of renal allograft failure. Here, we used serial alloantibody surveillance to monitor patients with preoperative positive flow cytometric crossmatch (FCXM). Sixty-nine of 308 renal transplant patients in our center had preoperative positive FCXM. Blood was collected quarterly during the first postoperative year and tested by FCXM and single antigen bead luminometry, more sensitive techniques than complement-dependent cytotoxic crossmatching. Distinct post-transplant profiles emerged and were associated with different clinical outcomes. Two-thirds of patients showed complete elimination of FCXM and solid-phase assay reactions within 1 year, had few adverse events, and a 95% 3-year graft survival. In contrast, the remaining third failed to eliminate flow FCXM or solid-phase reactions directed against HLA class I or II antibodies. The inferior graft survival (67%) with loss in this latter group was primarily due to CR. Thus, systematic assessment of longitudinal changes in alloantibody levels, either by FCXM or solid-phase assay, can help identify patients at greater risk of developing CR. PMID- 21270761 TI - Tubular markers do not predict the decline in glomerular filtration rate in type 1 diabetic patients with overt nephropathy. AB - Recent studies have shown that both glomerular and tubulointerstitial damage are important factors in the pathophysiology and progression of diabetic nephropathy. To examine whether markers of tubular damage are useful in monitoring the progression of disease, we measured urinary levels of neutrophil gelatinase associated lipocalin (NGAL), liver-fatty acid-binding protein (LFABP), and kidney injury molecule-1 (KIM-1) in a 3-year intervention study of 63 type 1 diabetic patients with kidney disease. The baseline mean glomerular filtration rate (GFR) was 87 ml/min per 1.73 m(2) and urinary albumin excretion 1141 mg/24 h. Patients with the highest compared with the lowest quartile of urinary NGAL at baseline had higher urinary KIM-1 levels and a significant decrease in their GFR each year. Using linear regression analysis, we found that elevated urinary NGAL and KIM-1 concentrations were associated with a faster decline in GFR, but not after adjustment for known promoters of progression. Urinary LFABP was not related to decline in GFR. Losartan treatment (100 mg/day) reduced urinary KIM-1 by 43% over a 12-month period. Thus, urine biomarker measurements in patients with type 1 diabetic nephropathy did not provide additional prognostic information to that of known progression promoters. PMID- 21270762 TI - Fenofibrate, a PPARalpha agonist, has renoprotective effects in mice by enhancing renal lipolysis. AB - As renal lipotoxicity can lead to chronic kidney disease (CKD), we examined the role of peroxisome proliferator-activated receptor (PPAR)-alpha, a positive regulator of renal lipolysis. Feeding mice a high-fat diet induced glomerular injury, and treating them with fenofibrate, a PPARalpha agonist, increased the expression of lipolytic enzymes and reduced lipid accumulation and oxidative stress in glomeruli, while inhibiting the development of albuminuria and glomerular fibrosis. In mice given an overload of free fatty acid-bound albumin to induce tubulointerstitial injury, fenofibrate attenuated the development of oxidative stress, macrophage infiltration, and fibrosis, and enhanced lipolysis in the renal interstitium. Fenofibrate inhibited palmitate-induced expression of profibrotic plasminogen activator inhibitor-1 (PAI-1) in cultured mesangial cells, and the expression of both monocyte chemoattractant protein-1 and PAI-1 in proximal tubular cells along with the overexpression of lipolytic enzymes. Thus, fenofibrate can attenuate lipotoxicity-induced glomerular and tubulointerstitial injuries, with enhancement of renal lipolysis. Whether amelioration of renal lipotoxicity by PPARalpha agonists will turn out to be a useful strategy against CKD will require direct testing. PMID- 21270763 TI - Bardet-Biedl syndrome highlights the major role of the primary cilium in efficient water reabsorption. AB - Studies of the primary cilium, now known to be present in all cells, have undergone a revolution, in part, because mutation of many of its proteins causes a large number of diseases, including cystic kidney disease. Bardet-Biedl syndrome (BBS) is an inherited ciliopathy characterized, among other dysfunctions, by renal defects for which the precise role of the cilia in kidney function remains unclear. We studied a cohort of patients with BBS where we found that these patients had a urinary concentration defect even when kidney function was near normal and in the absence of major cyst formation. Subsequent in vitro analysis showed that renal cells in which a BBS gene was knocked down were unciliated, but did not exhibit cell cycle defects. As the vasopressin receptor 2 is located in the primary cilium, we studied BBS-derived unciliated renal epithelial cells and found that they were unable to respond to luminal arginine vasopressin treatment and activate their luminal aquaporin 2. The ability to reabsorb water was restored by treating these unciliated renal epithelial cells with forskolin, a receptor-independent adenylate cyclase activator, showing that the intracellular machinery for water absorption was present but not activated. These findings suggest that the luminal receptor located on the primary cilium may be important for efficient transepithelial water absorption. PMID- 21270764 TI - Induction of heat shock protein 70 inhibits ischemic renal injury. AB - Heat shock protein 70 (Hsp70) is a potent antiapoptotic agent. Here, we tested whether it directly regulates renal cell survival and organ function in a model of transient renal ischemia using Hsp70 knockout, heterozygous, and wild-type mice. The kidney cortical Hsp70 content inversely correlated with tubular injury, apoptosis, and organ dysfunction after injury. In knockout mice, ischemia caused changes in the activity of Akt and glycogen synthase kinase 3-beta (kinases that regulate the proapoptotic protein Bax), increased active Bax, and activated the proapoptotic protease caspase 3. As these changes were significantly reduced in the wild-type mice, we tested whether Hsp70 influences ischemia-induced apoptosis. An Hsp70 inducer, geranylgeranylacetone, increased Hsp70 expression in heterozygous and wild-type mice, and reduced both ischemic tubular injury and organ dysfunction. When administered after ischemia, this inducer also decreased tubular injury and organ failure in wild-type mice but did not protect the knockout mice. ATP depletion in vitro caused greater mitochondrial Bax accumulation and death in primary proximal tubule cells harvested from knockout compared with wild-type mice and altered serine phosphorylation of a Bax peptide at the Akt-specific target site. In contrast, lentiviral-mediated Hsp70 repletion decreased mitochondrial Bax accumulation and rescued Hsp70 knockout cells from death. Thus, increasing Hsp70 either before or after ischemic injury preserves renal function by attenuating acute kidney injury. PMID- 21270765 TI - The fate of Notch-deficient nephrogenic progenitor cells during metanephric kidney development. AB - To determine which nephron segments require Notch signals for development, we conditionally deleted Rbpj, a transcription factor required for canonical Notch signaling, in nephrogenic progenitors (NPs) of the metanephric mesenchyme. The retinoic acid receptor-beta2 (Rarb2) promoter efficiently directed Cre recombinase (Cre) activity to these progenitors. Conditional knockout of Rbpj in mice (Rarb2Cre(+)/Rbpj (f/-)) caused severe renal hypoplasia, as indicated by a 70-95% reduction in nephron number and the development of tubular cysts. To track the fate of NPs following Rarb2Cre expression, we labeled them with membrane associated enhanced green fluorescent protein (GFP). In TomatoGFP(+)/Rarb2Cre(+) control mice, NPs differentiated into epithelia of all nephron segments, except into collecting ducts. In TomatoGFP(+)/Rarb2Cre(+)/Rbpj (f/-) conditional knockout mice, NPs developed into podocytes or distal tubular epithelia, indicating that canonical Notch signals were not required for mesenchymal-to epithelial transition or for the specification of these nephron segments. Conversely, the few proximal tubules and associated cysts that developed in these mice were derived from the 5-10% of NPs that had failed to express Cre and, therefore, had intact Notch signaling. Thus, our fate mapping studies establish that the profound effect of Notch signaling on nephrogenesis is due to the specification of proximal but not distal tubules or podocytes. PMID- 21270766 TI - Defective renal maintenance of the vitamin D endocrine system impairs vitamin D renoprotection: a downward spiral in kidney disease. AB - In kidney disease, the progressive loss of renal capacity to produce calcitriol, the vitamin D hormone, is a key contributor to elevations in parathyroid hormone (PTH) and mineral and skeletal disorders predisposing to renal and cardiovascular damage, ectopic calcifications, and high mortality rates. Thus, the safe correction of calcitriol deficiency to suppress PTH has been the treatment of choice for decades. However, recent epidemiological and experimental data suggest that calcitriol replacement may improve outcomes through renal and cardioprotective actions unrelated to PTH suppression. Furthermore, a striking incidence of vitamin D deficiency occurs in kidney disease and associates more strongly than calcitriol deficiency with a higher risk for kidney disease progression and death. Despite the translational relevance of these findings, no prospective trials are currently available in support of the efficacy of vitamin D supplementation and/or calcitriol replacement to safely halt/moderate renal disease progression. This review updates the pathophysiology behind the vicious cycle by which kidney injury impairs the maintenance of normal vitamin D and calcitriol levels, which in turn impedes vitamin D/calcitriol renoprotective actions, a requirement for the design of prospective trials to improve current recommendations for vitamin D interventions at all stages of kidney disease. PMID- 21270767 TI - Carbon monoxide-releasing molecules protect against ischemia-reperfusion injury during kidney transplantation. AB - Carbon monoxide (CO) can provide beneficial antiapoptotic and anti-inflammatory effects in the context of ischemia-reperfusion injury (IRI). Here we tested the ability of pretreating the kidney donor with carbon monoxide-releasing molecules (CORM) to prevent IRI in a transplant model. Isogeneic Brown Norway donor rats were pretreated with CORM-2 18 h before kidney retrieval. The kidneys were then cold-preserved for 26 h and transplanted into Lewis rat recipients that had undergone bilateral nephrectomy. Allografts from Brown Norway to Lewis rats were also performed after 6 h of cold ischemic time with low-dose tacrolimus treatment. All recipients receiving CORM-2-treated isografts survived the transplant process and had near-normal serum creatinine levels, whereas all control animals died of uremia by the third post-operative day. This beneficial effect was also seen in isografted Lewis recipients receiving kidneys perfused with CORM-3, indicating that CORMs have direct effects on the kidney. Pretreatment of human umbilical vein endothelial cells in culture with CORM-2 for 1 h significantly reduced cytokine-induced nicotinamide adenine dinucleotide phosphate-dependent production of superoxide, activation of the inflammation relevant transcription factor nuclear factor-kappaB, upregulated expression of E selectin and intercellular adhesion molecule-1 adhesion proteins, and leukocyte adhesion to the endothelial cells. Thus, CORM-2-derived CO protects renal transplants from IRI by modulating inflammation. PMID- 21270768 TI - De novo malignancy is associated with renal transplant tourism. AB - Despite the objections to transplant tourism raised by the transplant community, many patients continue travel to other countries to receive commercial transplants. To evaluate some long-term complications, we reviewed medical records of 215 Taiwanese patients (touring group) who received commercial cadaveric renal transplants in China and compared them with those of 321 transplant recipients receiving domestic cadaveric renal transplants (domestic group) over the same 20-year period. Ten years after transplant, the graft and patient survival rates of the touring group were 55 and 81.5%, respectively, compared with 60 and 89.3%, respectively, of the domestic group. The difference between the two groups was not statistically significant. The 10-year cumulative cancer incidence of the touring group (21.5%) was significantly higher than that of the domestic group (6.8%). Univariate and multivariate stepwise regression analyses (excluding time on immunosuppression, an uncontrollable factor) indicated that transplant tourism was associated with significantly higher cancer incidence. Older age at transplantation was associated with a significantly increased cancer risk; however, the risk of de novo malignancy significantly decreased with longer graft survival. Thus, renal transplant tourism may be associated with a higher risk of post-transplant malignancy, especially in patients of older age at transplantation. PMID- 21270769 TI - Donor antigen-specific regulatory T-cell function affects outcome in kidney transplant recipients. AB - Chronic transplant dysfunction, a major impediment to long-term allograft survival, is caused by several factors including an ongoing alloimmune response termed chronic rejection. To define some of these factors further, we selected 107 patients mismatched to their donors from 623 patients transplanted at a single center. Patients were categorized according to their immunosuppressive treatment and further divided into those with stable or chronic allograft dysfunction. Donor human lymphocyte antigen allopeptide-specific T-cell lines were then generated from stable patients and those with biopsy-proven chronic allograft nephropathy. Increased amounts of CD4+CD25+ regulatory T cells (Tregs) and Treg-associated gene expression profiles were found in cell lines derived from the patients with stable compared with those with chronic allograft dysfunction. Furthermore, a higher percentage of Tregs was found in patients with stable graft function on tacrolimus-based compared with cyclosporine-based immunosuppression protocols. Patients with stable graft function had a significantly higher expression of interleukin (IL)-4 and IL-10, whereas the cytokines IL-2, IL-17, and interferon-gamma were significantly higher in patients with allograft dysfunction in vitro. Thus, enhancing the operational role of naturally occurring donor-specific Tregs in allograft recipients by adjusting the immunosuppression protocol may be advantageous particularly for patients with ongoing chronic rejection. PMID- 21270770 TI - Astrocyte and glutamate markers in the superficial, deep, and white matter layers of the anterior cingulate gyrus in schizophrenia. AB - Most studies of the neurobiology of schizophrenia have focused on neurotransmitter systems, their receptors, and downstream effectors. Recent evidence suggests that it is no longer tenable to consider neurons and their functions independently of the glia that interact with them. Although astrocytes have been viewed as harbingers of neuronal injury and CNS stress, their principal functions include maintenance of glutamate homeostasis and recycling, mediation of saltatory conduction, and even direct neurotransmission. Results of studies of astrocytes in schizophrenia have been variable, in part because of the assessment of single and not necessarily universal markers and/or assessment of non-discrete brain regions. We used laser capture microdissection to study three distinct partitions of the anterior cingulate gyrus (layers I-III, IV-VI, and the underlying white matter) in the brains of 18 well-characterized persons with schizophrenia and 21 unaffected comparison controls. We studied the mRNA expression of nine specific markers known to be localized to astrocytes. The expression of astrocyte markers was not altered in the superficial layers or the underlying white matter of the cingulate cortex of persons with schizophrenia. However, the expression of some astrocyte markers (diodinase type II, aquaporin 4, S100beta, glutaminase, excitatory amino-acid transporter 2, and thrombospondin), but not of others (aldehyde dehydrogenase 1 family member L1, glial fibrillary acidic protein, and vimentin) was significantly reduced in the deep layers of the anterior cingulate gyrus. These findings suggest that a subset of astrocytes localized to specific cortical layers is adversely affected in schizophrenia and raise the possibility of glutamatergic dyshomeostasis in selected neuronal populations. PMID- 21270771 TI - Dopamine D3-like receptors modulate anxiety-like behavior and regulate GABAergic transmission in the rat lateral/basolateral amygdala. AB - Central among the brain regions that regulate fear/anxiety behaviors is the lateral/basolateral amygdala (BLA). BLA output is tightly controlled by the relative activity of two populations of inhibitory GABAergic interneurons, local feedback cells distributed throughout the nucleus, and feedforward cells found along the lateral paracapsular border of this subdivision. Recent studies suggest that dopamine (DA) can modulate the BLA GABAergic system, thus linking fear/anxiety states with mesolimbic reward/attentional processes. However, the precise dopaminergic mechanisms regulating the activity of the two BLA GABAergic neuron populations have not been fully explored. We therefore examined the effects of DA D3-like receptors on BLA-dependent anxiety-like behavior and neurophysiology. After confirming the presence of D3-like receptors within the BLA, we found that microinjection of a D3-selective antagonist into the BLA decreased anxiety-like behavior expressed in both the light/dark transition test and the elevated plus maze. Consistent with this, we found that in vitro D3-like receptor activation selectively inhibits synaptic transmission at both BLA feedback and feedforward GABAergic interneuron populations, with no effect on glutamatergic transmission. This inhibition of GABAergic transmission is a result of a D3-like receptor-mediated, dynamin-dependent process that presumably reflects endocytosis of postsynaptic GABA(A) receptors found on principal BLA neurons. Because environmental cues alter both DA release and relative activity states of the BLA, our data strongly suggest that DA, potentially acting through D3-like receptors, may suppress the relative contribution by inhibitory processes in the BLA and modify the expression of BLA-related behaviors. PMID- 21270772 TI - Neural correlates of response inhibition and cigarette smoking in late adolescence. AB - Smoking is usually initiated in adolescence, and is the leading preventable cause of death in the United States. Little is known, however, about the links between smoking and neurobiological function in adolescent smokers. This study aimed to probe prefrontal cortical function in late adolescent smokers, using a response inhibition task, and to assess possible relationships between inhibition-related brain activity, clinical features of smoking behavior, and exposure to cigarette smoking. Participants in this study were otherwise healthy late adolescent smokers (15-21 years of age; n=25), who reported daily smoking for at least the 6 months before testing, and age- and education-matched nonsmokers (16-21 years of age; n=25), who each reported smoking fewer than five cigarettes in their lifetimes. The subjects performed the Stop-signal Task, while undergoing functional magnetic resonance imaging. There were no significant group differences in prefrontal cortical activity during response inhibition, but the Heaviness of Smoking Index, a measure of smoking behavior and dependence, was negatively related to neural function in cortical regions of the smokers. These findings suggest that smoking can modulate prefrontal cortical function. Given the late development of the prefrontal cortex, which continues through adolescence, it is possible that smoking may influence the trajectory of brain development during this critical developmental period. PMID- 21270773 TI - Urothelial antigen-specific CD4+ T cells function as direct effector cells and induce bladder autoimmune inflammation independent of CD8+ T cells. AB - The role of CD4(+) T cells in bladder autoimmune inflammation has not been identified because of the lack of a proper animal model. We investigated CD4(+) T cell responses to bladder urothelial ovalbumin (OVA), a model self-antigen (Ag), in transgenic URO-OVA mice. The expression of bladder urothelial OVA rendered mice unresponsive to OVA and resulted in quick clearance of Ag-specific CD4(+) T cells. Adoptive transfer of naive OVA-specific CD4(+) T cells led to exogenous T cell proliferation, activation, and bladder infiltration but no inflammatory induction. In contrast, adoptive transfer of preactivated OVA-specific CD4(+) T cells induced bladder inflammation. Studies further demonstrated that CD4(+) T cells induced bladder inflammation in URO-OVA mice depleted of CD8(+) T cells or deficient in the recombinase activating gene-1 (Rag-1(-/-)). These results indicate that urothelial Ag-specific CD4(+) T cells can function as direct effector cells to induce bladder autoimmune inflammation independent of CD8(+) T cells. PMID- 21270774 TI - Focus on computational and systems neuroscience. AB - We present a special focus on computational and systems neuroscience, highlighting recent advances in combining empirical and theoretical approaches, including work presented at the Cosyne meeting in past years. PMID- 21270775 TI - You get what you get and you don't get upset. PMID- 21270776 TI - Fighting the famine with an amine: synaptic strategies for smart search. PMID- 21270777 TI - Ubiquitin regulation of neuronal excitability. PMID- 21270778 TI - Integration and autonomy in axons. PMID- 21270779 TI - Attention points to the future. PMID- 21270780 TI - Multiple models to capture the variability in biological neurons and networks. AB - How tightly tuned are the synaptic and intrinsic properties that give rise to neuron and circuit function? Experimental work shows that these properties vary considerably across identified neurons in different animals. Given this variability in experimental data, this review describes some of the complications of building computational models to aid in understanding how system dynamics arise from the interaction of system components. We argue that instead of trying to build a single model that captures the generic behavior of a neuron or circuit, it is beneficial to construct a population of models that captures the behavior of the population that provided the experimental data. Studying a population of models with different underlying structure and similar behaviors provides opportunities to discover unsuspected compensatory mechanisms that contribute to neuron and network function. PMID- 21270781 TI - How advances in neural recording affect data analysis. AB - Over the last five decades, progress in neural recording techniques has allowed the number of simultaneously recorded neurons to double approximately every 7 years, mimicking Moore's law. Such exponential growth motivates us to ask how data analysis techniques are affected by progressively larger numbers of recorded neurons. Traditionally, neurons are analyzed independently on the basis of their tuning to stimuli or movement. Although tuning curve approaches are unaffected by growing numbers of simultaneously recorded neurons, newly developed techniques that analyze interactions between neurons become more accurate and more complex as the number of recorded neurons increases. Emerging data analysis techniques should consider both the computational costs and the potential for more accurate models associated with this exponential growth of the number of recorded neurons. PMID- 21270782 TI - A proposed common neural mechanism for categorization and perceptual decisions. AB - One of the most fascinating issues in neuroscience is how the brain makes decisions. Recent evidence points to the parietal cortex as an important locus for certain kinds of decisions. Because parietal neurons are also involved in movements, it has been proposed that decisions are encoded in an intentional, action-based framework based on the movements used to report decisions. An alternative or complementary view is that decisions represent more abstract information not linked to movements per se. Parallel experiments on categorization suggest that parietal neurons can indeed represent abstract categorical outcomes that are not linked to movements. This could provide a unified or complementary view of how the brain decides and categorizes. PMID- 21270783 TI - Hippocampal replay in the awake state: a potential substrate for memory consolidation and retrieval. AB - The hippocampus is required for the encoding, consolidation and retrieval of event memories. Although the neural mechanisms that underlie these processes are only partially understood, a series of recent papers point to awake memory replay as a potential contributor to both consolidation and retrieval. Replay is the sequential reactivation of hippocampal place cells that represent previously experienced behavioral trajectories and occurs frequently in the awake state, particularly during periods of relative immobility. Awake replay may reflect trajectories through either the current environment or previously visited environments that are spatially remote. The repetition of learned sequences on a compressed time scale is well suited to promote memory consolidation in distributed circuits beyond the hippocampus, suggesting that consolidation occurs in both the awake and sleeping animal. Moreover, sensory information can influence the content of awake replay, suggesting a role for awake replay in memory retrieval. PMID- 21270784 TI - From reinforcement learning models to psychiatric and neurological disorders. AB - Over the last decade and a half, reinforcement learning models have fostered an increasingly sophisticated understanding of the functions of dopamine and cortico basal ganglia-thalamo-cortical (CBGTC) circuits. More recently, these models, and the insights that they afford, have started to be used to understand important aspects of several psychiatric and neurological disorders that involve disturbances of the dopaminergic system and CBGTC circuits. We review this approach and its existing and potential applications to Parkinson's disease, Tourette's syndrome, attention-deficit/hyperactivity disorder, addiction, schizophrenia and preclinical animal models used to screen new antipsychotic drugs. The approach's proven explanatory and predictive power bodes well for the continued growth of computational psychiatry and computational neurology. PMID- 21270785 TI - Pharmacogenetics and clopidogrel response in patients undergoing percutaneous coronary interventions. PMID- 21270786 TI - CPIC: Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network. PMID- 21270787 TI - Lack of evidence for exposure-response relationship in the use of posaconazole as prophylaxis against invasive fungal infections. PMID- 21270788 TI - Immunogenicity and smoking-cessation outcomes for a novel nicotine immunotherapeutic. AB - NicVAX, a nicotine vaccine (3'AmNic-rEPA), has been clinically evaluated to determine whether higher antibody (Ab) concentrations are associated with higher smoking abstinence rates and whether dosages and frequency of administration are associated with increased Ab response. This randomized, double-blinded, placebo controlled multicenter clinical trial (N = 301 smokers) tested the results of 200 and 400-ug doses administered four or five times over a period of 6 months, as compared with placebo. 3'AmNic-rEPA recipients with the highest serum antinicotine Ab response (top 30% by area under the curve (AUC)) were significantly more likely than the placebo recipients (24.6% vs. 12.0%, P = 0.024, odds ratio (OR) = 2.69, 95% confidence interval (CI), 1.14-6.37) to attain 8 weeks of continuous abstinence from weeks 19 through 26. The five-injection, 400-ug dose regimen elicited the greatest Ab response and resulted in significantly higher abstinence rates than placebo. This study demonstrates, as proof of concept, that 3'AmNic-rEPA elicits Abs to nicotine and is associated with higher continuous abstinence rates (CAR). Its further development as a treatment for nicotine dependence is therefore justified. PMID- 21270789 TI - Induction of opioid-dependent individuals onto buprenorphine and buprenorphine/naloxone soluble-films. AB - A sublingual soluble-film formulation of buprenorphine/naloxone (B/N) has been approved by the US Food and Drug Administration for the treatment of opioid dependency. This preparation provides unit-dose, child-resistant packaging amenable to tracking and accountability, offers more rapid dissolution, and has a potentially preferred taste vs. tablets. This study compared the ability of buprenorphine (B) and B/N films to suppress spontaneous withdrawal in opioid dependent volunteers. Participants were maintained on morphine and underwent challenge sessions to confirm sensitivity to naloxone-induced opioid withdrawal. Subjects were randomized to receive either B (16 mg, n = 18) or B/N (16/4 mg, n = 16) soluble films for 5 days. The primary outcome measure was the Clinical Opiate Withdrawal Scale (COWS) score. Thirty-four subjects completed induction onto soluble films. There was a significant decrease in COWS scores but no significant differences between the groups. The results support the use of B and B/N soluble films as safe and effective delivery methods for opioid induction. PMID- 21270790 TI - The missing association: sequencing-based discovery of novel SNPs in VKORC1 and CYP2C9 that affect warfarin dose in African Americans. AB - It is well recognized that the genetic variants VKORC1-1639, CYP2C9*2, and CYP2C9*3 contribute to warfarin dose response. This has led to warfarin dosing algorithms that include these polymorphisms and explains between 47% and 56% of variability in dose in Caucasians. However, these polymorphisms explain significantly less of the variance in dose among African Americans. In order to identify novel variations that affect warfarin dose in African Americans, we used a targeted resequencing strategy that examined evolutionarily conserved sequences and regions of putative transcriptional binding. Through ethnicity-specific warfarin dose model building in 330 African Americans, we identified two novel genetic associations with higher warfarin dose, namely, VKORC1-8191 (rs61162043, P = 0.0041) and 18786 in CYP2C9 (rs7089580, P = 0.035). These novel finds are independent of the previous associations with these genes. Our regression model, encompassing both genetic and clinical variables, explained 40% of the variability in warfarin dose in African-American subjects, significantly more than any model thus far. PMID- 21270791 TI - Hepatocyte proliferation and hepatitis C virus kinetics during treatment. PMID- 21270792 TI - Early human screening of medications to treat drug addiction: novel paradigms and the relevance of pharmacogenetics. PMID- 21270793 TI - Rifampin enhances the glucose-lowering effect of metformin and increases OCT1 mRNA levels in healthy participants. AB - We evaluated the effect of the pregnane X receptor (PXR) agonist rifampin on metformin pharmacokinetics, organic cation transporter 1 (OCT1) and OCT2 mRNA levels, and glucose levels, using the oral glucose tolerance test (OGTT) in 16 healthy subjects. The glucose-lowering effects of metformin were evaluated by OGTT before and after metformin treatment on days 1 and 2 and again on days 13 and 14 after a 10-day course of rifampin. Rifampin increased the difference in maximum glucose levels (DeltaG(max)) by 41.9% (P = 0.024) and the area under the concentration-time curve (AUC) during the first 60 min after glucose ingestion (DeltaAUC(gluc60)) by 54.5% (P = 0.020). Renal clearance (CL(R)) of metformin was increased by 16% (P = 0.008), but the systemic exposure was only slightly increased (13%, P = 0.049), possibly because of increased absorption. Rifampin increased OCT1 mRNA levels 4.1-fold in peripheral blood cells (P = 0.001); however, OCT2 mRNA was not detected. Our results suggest that rifampin increases OCT1 expression and hepatic uptake of metformin, leading to enhanced glucose lowering action. PMID- 21270794 TI - Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. AB - Thiopurine methyltransferase (TPMT) activity exhibits monogenic co-dominant inheritance, with ethnic differences in the frequency of occurrence of variant alleles. With conventional thiopurine doses, homozygous TPMT-deficient patients (~1 in 178 to 1 in 3,736 individuals with two nonfunctional TPMT alleles) experience severe myelosuppression, 30-60% of individuals who are heterozygotes (~3-14% of the population) show moderate toxicity, and homozygous wild-type individuals (~86-97% of the population) show lower active thioguanine nucleolides and less myelosuppression. We provide dosing recommendations (updates at http://www.pharmgkb.org) for azathioprine, mercaptopurine (MP), and thioguanine based on TPMT genotype. PMID- 21270795 TI - Identification of adult nephron progenitors capable of kidney regeneration in zebrafish. AB - Loss of kidney function underlies many renal diseases. Mammals can partly repair their nephrons (the functional units of the kidney), but cannot form new ones. By contrast, fish add nephrons throughout their lifespan and regenerate nephrons de novo after injury, providing a model for understanding how mammalian renal regeneration may be therapeutically activated. Here we trace the source of new nephrons in the adult zebrafish to small cellular aggregates containing nephron progenitors. Transplantation of single aggregates comprising 10-30 cells is sufficient to engraft adults and generate multiple nephrons. Serial transplantation experiments to test self-renewal revealed that nephron progenitors are long-lived and possess significant replicative potential, consistent with stem-cell activity. Transplantation of mixed nephron progenitors tagged with either green or red fluorescent proteins yielded some mosaic nephrons, indicating that multiple nephron progenitors contribute to a single nephron. Consistent with this, live imaging of nephron formation in transparent larvae showed that nephrogenic aggregates form by the coalescence of multiple cells and then differentiate into nephrons. Taken together, these data demonstrate that the zebrafish kidney probably contains self-renewing nephron stem/progenitor cells. The identification of these cells paves the way to isolating or engineering the equivalent cells in mammals and developing novel renal regenerative therapies. PMID- 21270796 TI - Transient Hoogsteen base pairs in canonical duplex DNA. AB - Sequence-directed variations in the canonical DNA double helix structure that retain Watson-Crick base-pairing have important roles in DNA recognition, topology and nucleosome positioning. By using nuclear magnetic resonance relaxation dispersion spectroscopy in concert with steered molecular dynamics simulations, we have observed transient sequence-specific excursions away from Watson-Crick base-pairing at CA and TA steps inside canonical duplex DNA towards low-populated and short-lived A*T and G*C Hoogsteen base pairs. The observation of Hoogsteen base pairs in DNA duplexes specifically bound to transcription factors and in damaged DNA sites implies that the DNA double helix intrinsically codes for excited state Hoogsteen base pairs as a means of expanding its structural complexity beyond that which can be achieved based on Watson-Crick base-pairing. The methods presented here provide a new route for characterizing transient low-populated nucleic acid structures, which we predict will be abundant in the genome and constitute a second transient layer of the genetic code. PMID- 21270797 TI - Observation of scale invariance and universality in two-dimensional Bose gases. AB - The collective behaviour of a many-body system near a continuous phase transition is insensitive to the details of its microscopic physics; for example, thermodynamic observables follow generalized scaling laws near the phase transition. The Berezinskii-Kosterlitz-Thouless (BKT) phase transition in two dimensional Bose gases presents a particularly interesting case because the marginal dimensionality and intrinsic scaling symmetry result in a broad fluctuation regime and an extended range of universal scaling behaviour. Studies of the BKT transition in cold atoms have stimulated great interest in recent years, but a clear demonstration of critical behaviour near the phase transition has remained elusive. Here we report in situ density and density-fluctuation measurements of two-dimensional Bose gases of caesium at different temperatures and interaction strengths, observing scale-invariant, universal behaviours. The extracted thermodynamic functions confirm the existence of a wide universal region near the BKT phase transition, and provide a sensitive test of the universality predicted by classical-field theory and quantum Monte Carlo calculations. Our experimental results provide evidence for growing density density correlations in the fluctuation region, and call for further explorations of universal phenomena in classical and quantum critical physics. PMID- 21270798 TI - Transmembrane semaphorin signalling controls laminar stratification in the mammalian retina. AB - In the vertebrate retina, establishment of precise synaptic connections among distinct retinal neuron cell types is critical for processing visual information and for accurate visual perception. Retinal ganglion cells (RGCs), amacrine cells and bipolar cells establish stereotypic neurite arborization patterns to form functional neural circuits in the inner plexiform layer (IPL), a laminar region that is conventionally divided into five major parallel sublaminae. However, the molecular mechanisms governing distinct retinal subtype targeting to specific sublaminae within the IPL remain to be elucidated. Here we show that the transmembrane semaphorin Sema6A signals through its receptor PlexinA4 (PlexA4) to control lamina-specific neuronal stratification in the mouse retina. Expression analyses demonstrate that Sema6A and PlexA4 proteins are expressed in a complementary fashion in the developing retina: Sema6A in most ON sublaminae and PlexA4 in OFF sublaminae of the IPL. Mice with null mutations in PlexA4 or Sema6A exhibit severe defects in stereotypic lamina-specific neurite arborization of tyrosine hydroxylase (TH)-expressing dopaminergic amacrine cells, intrinsically photosensitive RGCs (ipRGCs) and calbindin-positive cells in the IPL. Sema6A and PlexA4 genetically interact in vivo for the regulation of dopaminergic amacrine cell laminar targeting. Therefore, neuronal targeting to subdivisions of the IPL in the mammalian retina is directed by repulsive transmembrane guidance cues present on neuronal processes. PMID- 21270799 TI - Milestones in investigative dermatology: the desmosome. PMID- 21270800 TI - Desmogleins and desmocollins as adhesive molecules. PMID- 21270801 TI - Skin needs plakophilin-1. PMID- 21270802 TI - Desmoplakin is essential for epidermal sheet formation. PMID- 21270803 TI - High-resolution mapping of the desmosomal plaque and adhesive interface. PMID- 21270804 TI - Identification of desmogleins as disease targets. PMID- 21270805 TI - Spotting desmosomes: the first 100 years. PMID- 21270806 TI - Biochemical characterization of the desmosome. PMID- 21270807 TI - Identification of desmoglein as a cadherin and analysis of desmoglein domain structure. PMID- 21270808 TI - Making connections: desmoplakin as an intermediate filament-binding protein. PMID- 21270810 TI - Special issue of The Journal of Antibiotics dedicated to the late Professor C Richard Hutchinson. PMID- 21270813 TI - Blood pressure components and risk for chronic kidney disease in middle-aged Japanese men: The Kansai Healthcare Study. AB - It is unclear which blood pressure (BP) components (that is, systolic BP (SBP), diastolic BP (DBP), pulse pressure (PP) and mean arterial pressure (MAP)) are superior predictors of chronic kidney disease (CKD). Furthermore it is unclear whether the combination of SBP+DBP or PP+MAP is superior to any of these four individual BP components in predicting CKD. We enrolled 9928 Japanese men aged 40 55 years who had a normal estimated glomerular filtration rate (eGFR), no proteinuria and no history of cardiovascular disease and were not taking any antihypertensive medications at baseline. CKD was defined as an eGFR of <60 ml min(-1) per 1.73 m(2) using the modified diet in renal disease equation. DeltaAkaike's information criterion (DeltaAIC) was used to compare the BP components-added model to the model without them in a Cox proportional hazards model. During the 52 428 person-years of follow-up, there were 434 cases of CKD. Of all four BP components, the model including DBP- or MAP-alone had the highest values of DeltaAIC (10.2 and 9.85, respectively). The PP-alone model had the lowest DeltaAIC value (-1.48). The combination models including SBP+DBP (DeltaAIC 8.42) or PP+MAP (8.42) were not superior to the models including DBP- or MAP alone. These findings suggested that, of the four BP components, both DBP and MAP were the most useful predictors for subsequent incidence of CKD, but PP was not an important predictor. The combination model, including SBP+DBP or PP+MAP, was not superior to the models including DBP- or MAP-alone for predicting CKD. PMID- 21270814 TI - Assessment of aortic stiffness by local and regional methods. AB - The stiffness of large arteries has an important role in cardiovascular hemodynamics. Aortic stiffness (AoStiff) can be assessed non-invasively with regional and local methods. In this paper, we compared these two techniques for evaluating AoStiff. Our subjects comprised of 118 consecutive patients (85 men, mean age: 49 +/- 14 years). We evaluated regional AoStiff with carotid-femoral pulse wave velocity (PWV) measured with a tonometric technique and by bioelectrical impedance (BI) wave velocity (IWV). The local AoStiff was calculated from BI signals recorded at the chest. We used glyceryl trinitrate (GTN) to test the effect of peripheral vasodilatation on both methods in a subgroup of 52 patients (37 men, mean age: 52 +/- 11 years). We found a significant correlation between IWV and PWV measurements (r = 0.88, P < 0.0001) as well as between AoStiff and PWV measurements (r = 0.75, P < 0.0001). GTN administration decreased mean arterial blood pressure by 4% (95% confidence interval: 2-8%, P = 0.002) without significant changes in AoStiff and regional IWV. Local AoStiff is correlated with regional measurements and is not influenced by changes in arterial pressure because of systemic peripheral vasodilatation. PMID- 21270815 TI - L/N-type calcium channel blocker cilnidipine ameliorates proteinuria and inhibits the renal renin-angiotensin-aldosterone system in deoxycorticosterone acetate salt hypertensive rats. AB - Cilnidipine, an N/L-type calcium channel blocker, has been reported to inhibit sympathetic nerve activity and has a greater renoprotective effect than L-type calcium channel blockers. To investigate the hypothesis that cilnidipine might ameliorate advanced hypertensive nephropathy and inhibit the renal renin angiotensin-aldosterone system, cilnidipine (1 mg per kg per day) or amlodipine (1 mg per kg per day) was administered to uninephrectomized deoxycorticosterone (DOCA)-salt hypertensive rats (DOCA-salt) for 4 weeks by gavage. Although the blood pressure in the DOCA-salt group was higher than that of control, neither cilnidipine nor amlodipine had any effect on the increase in blood pressure in the DOCA-salt group. The DOCA (40 mg per kg per week, subcutaneously (s.c.)) and salt (1% NaCl in drinking water) treatment significantly aggravated the levels of urinary protein excretion and creatinine clearance and increased glomerulosclerosis and collagen deposition in the tubulointerstitial area of the kidney. These effects were attenuated by cilnidipine treatment. Reverse transcription-polymerase chain reaction analysis revealed that the renal expression of mRNA for collagen I/IV and transforming growth factor-beta was enhanced in the DOCA-salt group and that the overexpression of these molecules was suppressed by cilnidipine. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived superoxide production in the kidney and urinary norepinephrine excretion, which were enhanced in the DOCA-salt group, were suppressed by cilnidipine. Cilnidipine also decreased the activity and expression of angiotensin-converting enzyme (ACE) and the aldosterone concentration in the renal homogenate. Although neither cilnidipine nor amlodipine had any effect on the increased blood pressure in the DOCA-salt group, these renal changes were not induced by treatment with amlodipine. In conclusion, cilnidipine inhibited renal dysfunction, sympathetic nerve activity and renal renin-angiotensin-aldosterone system in the DOCA-salt group. PMID- 21270816 TI - Combination of amlodipine and atorvastatin synergistically reduces leukocyte recruitment to mechanically injured mouse femoral artery. AB - Recent studies have demonstrated a potential synergistic effect of the combination of amlodipine with atorvastatin to reduce acute inflammation. The intraluminal wire injury of the mouse femoral artery induced significant leukocyte recruitment to the injured area and oxidative stress within 24 h. Administration of low-dose amlodipine (0.5 mg kg(-1) per day) or atorvastatin (1 mg kg(-1) per day) alone for 7 days failed to modulate leukocyte adhesion, whereas their co-administration for 7 days significantly inhibited leukocyte adhesion. Moreover, flow cytometric analysis showed that injury-induced oxidative stress and CD11b expression in three leukocyte fractions were elevated after injury and then reduced after the co-administration. Next, adoptive transfer of mononuclear cells (MNCs) was performed and MNCs were harvested from mice after wire injury exhibited adhesion to the recipient injured artery. Furthermore, the co-administration of low-dose atorvastatin and amlodipine to MNCs or the vasculature reduced the recruitment of MNCs to the injured artery. Our findings indicate that amlodipine and atorvastatin synergistically inhibit vascular inflammation. The underlying mechanisms of their effect involve, at least in part, stabilizing oxidative stress at the point of injury, suggesting the clinical efficacy of this drug combination for the treatment of vascular diseases. PMID- 21270817 TI - Angiotensin II induces human astrocyte senescence through reactive oxygen species production. AB - Angiotensin II (Ang II)-induced astrocyte senescence may be involved in cerebral ischemic injury and age-associated neurodegenerative disease. This study was conducted to determine the roles of reactive oxygen species production in Ang II induced cellular senescence in cultured human astrocytes. Human astrocytes were stimulated with Ang II either with or without an angiotensin type 1 receptor blocker, CV11974, or an antioxidant, tempol. Application of Ang II to human astrocytes resulted in a concentration-dependent increase in staining for dihydroethidium. Ang II (100 nM for 30 min) increased the translocation of two cytosolic components of NADPH oxidase, p47phox and p67phox, to the cell membrane and formation of the complex of p47phox, p67phox and p22phox. Ang II concentration-dependently induced an increase in beta-galactosidase staining. Pretreatment with CV11974 (100 nM) or tempol (3 mM) abolished Ang II-induced astrocyte beta-galactosidase staining. Moreover, Ang II significantly upregulated p16 mRNA expression, which was inhibited by pretreatment with CV11974 or tempol. These findings indicate that superoxide production contributes to Ang II-induced astrocyte senescence. PMID- 21270818 TI - Synergistic protection against vascular inflammation with a calcium channel blocker and a statin. PMID- 21270819 TI - The (pro)renin receptor is cleaved by ADAM19 in the Golgi leading to its secretion into extracellular space. AB - The (pro)renin receptor ((P)RR), which is a recently discovered molecule of the renin-angiotensin system, plays an important role in the development of cardiovascular diseases. However, the molecular properties and the subcellular distribution of (P)RR remain controversial. In this study, (P)RR-Venus in Chinese hamster ovary (CHO) cells ((P)RR-Venus-CHO) or endogenous (P)RR in human vascular smooth muscle cells (VSMC) were constitutively cleaved without any stimulation, and secretion of the amino-terminal fragment (NTF-(P)RR) into the media was determined using western blot analysis. Immunofluorescent analysis showed robust expression of (P)RR in the endoplasmic reticulum (ER) or the Golgi but not in the plasma membrane. Moreover, we identified ADAM19, which is expressed in the Golgi, as one of cleaving proteases of (P)RR. Transfected ADAM19 evoked the shedding of (P)RR, whereas transfected dominant negative ADAM19 suppressed it. Although (P)RR contains a furin cleavage site, neither the furin-deficient LoVo cells nor furin inhibitor-treated VSMC lost NTF-(P)RR in the media. The secreted NTF-(P)RR induced the renin activity of prorenin in the extracellular space. We describe that (P)RR is mainly localized in the subcellular organelles, such as the ER and Golgi, and (P)RR is cleaved by ADAM19 in the Golgi resulting in two fragments, NTF-(P)RR and CTF-(P)RR. These results may suggest that (P)RR is predominantly secreted into the extracellular space. PMID- 21270820 TI - A common variant in the CDKN2B gene on chromosome 9p21 protects against coronary artery disease in Americans of African ancestry. AB - A 58 kb region on chromosome 9p21.3 has consistently shown strong association with coronary artery disease (CAD) in multiple genome-wide association studies in populations of European and East Asian ancestry. In this study, we sought to further characterize the role of genetic variants in 9p21.3 in African American individuals. Apparently healthy African American siblings (n = 548) of patients with documented CAD < 60 years of age were genotyped and followed for incident CAD for up to 17 years. Tests of association for 86 single-nucleotide polymorphisms (SNPs) across the 9p21.3 region in a generalized estimating equation logistic framework under an additive model adjusting for traditional risk factors, family, follow-up time and population stratification were performed. A single SNP within the CDKN2B gene met stringent criteria for statistical significance, including permutation-based evaluations. This variant, rs3217989, was common (minor allele (G) frequency 0.242), conveyed protection against CAD (odds ratio (OR) = 0.19, 95% confidence interval (CI): 0.07 to 0.50, P = 0.0008) and was replicated in a combined analysis of two additional case/control studies of prevalent CAD/MI in African Americans (n = 990, P = 0.024, OR = 0.779, 95% CI: 0.626-0.968). This is the first report of a CAD association signal in a population of African ancestry with a common variant within the CDKN2B gene, independent from previous findings in European and East Asian ancestry populations. The findings demonstrate a significant protective effect against incident CAD in African American siblings of persons with premature CAD, with replication in a combination of two additional African American cohorts. PMID- 21270821 TI - Is there a role for phosphodiesterase type-5 inhibitors in the treatment of premature ejaculation? AB - Premature ejaculation (PE) is considered to be the most common male sexual dysfunction. The realization that PE may co-exist with ED prompted the use of PDE5-i's alone or in combination with selective serotonin reuptake inhibitors (SSRIs) for treating ejaculatory disorders. Until recently, there was little evidence that PDE5-i's alone may have a role in the treatment of PE in the absence of ED, and current available treatments include only on-demand dapoxetine. However, available data indicate that there is clinical, anatomical, physiological, pharmacological and genetic evidence to explain the efficacy of PDE5-i's. Nine manuscripts that examined the efficacy of PDE5-i's in the treatment of PE, alone or in combination with SSRIs, were retrieved. All studies reported some significant changes in the intravaginal ejaculatory latency time and sexual satisfaction scores, although not all were clinically meaningful. Well designed multicenter studies are urgently required to further elucidate the efficacy and safety, as well as the mechanisms of action of PDE5-i's in the treatment of PE. The aim of this review is to discuss basic rationale and to show clinical evidence sustaining the possibility to use off-label PDE5-i's to treat PE. PMID- 21270823 TI - Keratinocyte secretion of cyclophilin B via the constitutive pathway is regulated through its cyclosporin-binding site. AB - Cyclophilin B (CypB) is an endoplasmic reticulum (ER)-resident member of the cyclophilin family of proteins that bind cyclosporin A (CsA). We report that as in other cell types, CypB trafficked from the ER and was secreted by keratinocytes into the media in response to CsA. Concentrations as low as 1 pM of CsA induced secretion of CypB. Using brefeldin A, we showed that CypB is secreted from keratinocytes via the constitutive secretory pathway. We defined that substitution of tryptophan residue 128 in the CsA-binding site of CypB with alanine resulted in dissociation of CypB(W128A)-green fluorescent protein (GFP) from the ER. Photobleaching studies revealed a significant reduction in the diffusible mobility of CypB(W128A)-GFP compared with CypB(WT)-GFP, consistent with redistribution of CypB(W128A)-GFP into secretory vesicles disconnected from the ER/Golgi network. Furthermore, CsA significantly decreased the mobility of CypB(WT)-GFP but not CypB(W128A)-GFP. These studies demonstrate that therapeutically relevant concentrations of CsA regulate secretion of CypB by keratinocytes, and that a key residue within the CsA-binding site of CypB controls retention of CypB within the ER and regulates entry into the secretory pathway. As keratinocytes express CypB receptors (CD147) and CypB exhibits chemotactic properties, these data have implications for the therapeutic effects of CsA in inflammatory skin disease. PMID- 21270824 TI - RANK is expressed in metastatic melanoma and highly upregulated on melanoma initiating cells. AB - Melanoma accounts for ~ 79% of skin cancer-related deaths, and the receptor activator of NF-kappaB (RANK)-receptor activator of NF-kappaB ligand (RANKL) pathway has been shown to be involved in the migration and metastasis of epithelial tumor cells. In this study, we demonstrate that RANK was significantly increased in peripheral circulating melanoma cells, primary melanomas, and metastases from stage IV melanoma patients compared with tumor cells from stage I melanoma patients. However, upregulated RANK expression was not found in stage IV melanoma patients with bone metastases compared with stage IV melanoma patients without bone metastases, providing a possible explanation for the clinical observation that melanoma cells do not preferentially metastasize to bone tissue. Strikingly, RANK-expressing melanoma cells from peripheral blood, primary tumors, or metastases of stage IV patients coexpressed ATP-binding cassette (ABC) B5 and CD133, both markers characteristic of melanoma-initiating cells, suggesting a tumor stem cell-like phenotype. In support of this hypothesis, RANK-expressing melanoma cells showed a reduced Ki67 proliferation index compared with RANK(-) melanoma cells from the same patient and are able to induce tumor growth in immunodeficient mice. Together, our data demonstrate that RANK expression is increased in metastatic melanoma and highly upregulated on melanoma-initiating cells, suggesting that RANK might be involved in the development and maintenance of melanoma-initiating cells and possibly in metastatic spreading. PMID- 21270826 TI - Murine lupus susceptibility locus Sle2 activates DNA-reactive B cells through two sub-loci with distinct phenotypes. AB - The NZM2410-derived Sle2 lupus susceptibility locus induces an abnormal B-cell differentiation, which most prominently leads to the expansion of autoreactive B1a cells. We have mapped the expansion of B1a cells to three Sle2 sub-loci, Sle2a, Sle2b and Sle2c. Sle2 also enhances the breach of B-cell tolerance to nuclear antigens in the 56R anti-DNA immunoglobulin transgenic (Tg) model. This study used the Sle2 sub-congenic strains to map the activation of 56R Tg B cells. Sle2c strongly sustained the breach of tolerance and the activation of anti-DNA B cells. The production of Tg-encoded anti-DNA antibodies was more modest in Sle2a expressing mice, but Sle2a was responsible for the recruitment for Tg B cells to the marginal zone, a phenotype that has been found for 56R Tg B cells in mice expressing the whole Sle2 interval. In addition, Sle2a promoted the production of endogenously encoded anti-DNA antibodies. Overall, this study showed that at least two Sle2 genes are involved in the activation of anti-DNA B cells, and excluded more than two-thirds of the Sle2 interval from contributing to this phenotype. This constitutes an important step toward the identification of novel genes that have a critical role in B-cell tolerance. PMID- 21270827 TI - Revisiting the T-cell receptor alpha/delta locus and possible associations with multiple sclerosis. AB - A role for T cells in the pathogenesis of multiple sclerosis (MS) is well supported, evidenced by myriad immunological studies, as well as the unequivocal genetic influence of the major histocompatibility complex (MHC). Despite many attempts, no convincing genetic associations have been made between T-cell receptor (TCR) gene loci and MS. However, these studies may not be definitive because of small sample sizes and under-representative marker coverage of the chromosomal regions being investigated. To explore potential roles between the TCR alpha locus and MS, we have genotyped a large family-based cohort, including 1360 affected individuals and 1659 of their unaffected first-degree relatives, at 40 single-nucleotide polymorphism (SNP) markers within the TCR alpha/delta locus. This represents the largest TCR alpha-MS study to date. From this screen, we identified three potential loci of interest in TCR alpha variable and constant gene regions using the transmission disequilibrium test. Although SNPs implicating each of these regions of interest will require genotyping in independent replication cohorts, these findings suggest a role for TCR gene polymorphisms in MS susceptibility. In the context of these findings we review the evidence. PMID- 21270825 TI - Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort. AB - Systemic lupus erythematosus (SLE) is a prototypic autoimmune disorder with a complex pathogenesis in which genetic, hormonal and environmental factors have a role. Rare mutations in the TREX1 gene, the major mammalian 3'-5' exonuclease, have been reported in sporadic SLE cases. Some of these mutations have also been identified in a rare pediatric neurological condition featuring an inflammatory encephalopathy known as Aicardi-Goutieres syndrome (AGS). We sought to investigate the frequency of these mutations in a large multi-ancestral cohort of SLE cases and controls. A total of 40 single-nucleotide polymorphisms (SNPs), including both common and rare variants, across the TREX1 gene, were evaluated in ~8370 patients with SLE and ~7490 control subjects. Stringent quality control procedures were applied, and principal components and admixture proportions were calculated to identify outliers for removal from analysis. Population-based case control association analyses were performed. P-values, false-discovery rate q values, and odds ratios (OR) with 95% confidence intervals (CI) were calculated. The estimated frequency of TREX1 mutations in our lupus cohort was 0.5%. Five heterozygous mutations were detected at the Y305C polymorphism in European lupus cases but none were observed in European controls. Five African cases incurred heterozygous mutations at the E266G polymorphism and, again, none were observed in the African controls. A rare homozygous R114H mutation was identified in one Asian SLE patient, whereas all genotypes at this mutation in previous reports for SLE were heterozygous. Analysis of common TREX1 SNPs (minor allele frequency (MAF)>10%) revealed a relatively common risk haplotype in European SLE patients with neurological manifestations, especially seizures, with a frequency of 58% in lupus cases compared with 45% in normal controls (P=0.0008, OR=1.73, 95% CI=1.25 2.39). Finally, the presence or absence of specific autoantibodies in certain populations produced significant genetic associations. For example, a strong association with anti-nRNP was observed in the European cohort at a coding synonymous variant rs56203834 (P=2.99E-13, OR=5.2, 95% CI=3.18-8.56). Our data confirm and expand previous reports and provide additional support for the involvement of TREX1 in lupus pathogenesis. PMID- 21270828 TI - Complement factor H deficiency and endocapillary glomerulonephritis due to paternal isodisomy and a novel factor H mutation. AB - Complement factor H (CFH) is a regulator of the alternative complement activation pathway. Mutations in the CFH gene are associated with atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis type II and C3 glomerulonephritis. Here, we report a 6-month-old CFH-deficient child presenting with endocapillary glomerulonephritis rather than membranoproliferative glomerulonephritis (MPGN) or C3 glomerulonephritis. Sequence analyses showed homozygosity for a novel CFH missense mutation (Pro139Ser) associated with severely decreased CFH plasma concentration (<6%) but normal mRNA splicing and expression. The father was heterozygous carrier of the mutation, but the mother was a non-carrier. Thus, a large deletion in the maternal CFH locus or uniparental isodisomy was suspected. Polymorphic markers across chromosome 1 showed homozygosity for the paternal allele in all markers and a lack of the maternal allele in six informative markers. This combined with a comparative genomic hybridization assay demonstrated paternal isodisomy. Uniparental isodisomy increases the risk of homozygous variations in other genes on the affected chromosome. Therefore, we analyzed other susceptibility genes on chromosome 1 and found no sequence variation in membrane cofactor protein, but homozygosity for the common deletion of CFH-related proteins 1 and 3, which may contribute to the early onset of disease. PMID- 21270829 TI - Plasticity of the murine spleen T-cell cholinergic receptors and their role in in vitro differentiation of naive CD4 T cells toward the Th1, Th2 and Th17 lineages. AB - Acetylcholine (ACh) regulates vital functions of T cells by acting on the nicotinic and muscarinic classes of cholinergic receptors, nAChR and mAChRs, respectively. This study was performed in murine splenic T cells. In freshly isolated CD4 and CD8 T cells, we detected mRNAs encoding alpha5, alpha9, alpha10, beta1, beta2, beta4 nAChR subunits and M1, M3, M4 and M5 mAChR subtypes, whereas alpha2 was detected only in CD8 T cells. In vitro activation of CD4 T cells through T-cell receptor (TCR)/CD3 cross-linking was associated with the appearance of alpha4 and alpha7, upregulation of alpha5, alpha10, beta4, M1 and M5 and downregulation of alpha9 and beta2, whereas in vitro activation of CD8 T cells also featured the appearance of alpha4 and alpha7, as well as upregulation of alpha2, alpha5, beta4, M1 and M4, and downregulation of alpha10, beta1, beta2 and M3. In vitro polarization toward T helper (Th) 1 lineage was associated with a decrease of beta2, beta4 and M3 expression; that toward Th2 cells with downregulation of alpha9 and M3, and upregulation of M1 and M5; and that toward Th17 phenotype with downregulation of alpha9, alpha10, beta2 and M3 mAChR. Polarized T cells also expressed alpha4, but not alpha1, alpha2, alpha3, alpha6, beta3 or M2. To determine the role of cholinergic receptors in mediating the immunoregulatory action of autocrine/paracrine ACh, we analyzed the effects of nicotinic and muscarinic agonists+/-antagonists on cytokine production in the CD4+CD62L+ T cells co-stimulated via TCR/CD3 cross-linking. The nicotinergic stimulation upregulated interferon-gamma (IFN-gamma) and downregulated interleukin (IL)-17 secretion, whereas the muscarinic stimulation enhanced IL-10 and IL-17 and inhibited INF-gamma secretion. These results demonstrated plasticity of the T-cell cholinergic system. PMID- 21270830 TI - Cystic fibrosis modifier genes related to Pseudomonas aeruginosa infection. AB - Cystic fibrosis (CF) is one of the most common life-shortening genetic disorders, and the CF transmembrane conductance regulator (CFTR) is the major causal gene. However, a substantial clinical variability among patients with identical CFTR genotypes suggests the presence of modifier genes. We tested the effect of four genes involved in Pseudomonas aeruginosa infection. Analysis of a primary cohort detected eight candidate polymorphisms that were genotyped in the secondary cohort of 1579 patients; lung function and age at first infection with P. aeruginosa were considered as the phenotypes. Both additive and codominant models were considered, adjusting for confounding variables but not for multiple comparisons. In the secondary cohort, heme oxygenase-1 (HMOX1) rs2071749 had the most significant effect on lung function in the pediatric group (P=0.01; P(corrected)=0.03), and complement factor 3 (C3) rs11569393 and HMOX1 rs2071746 in the adult groups (P=0.03 for both variants; P(corrected)=0.16, 0.09). No polymorphism of complement factor B (CFB) or toll-like receptor 4 (TLR4) had a significant modifying effect on lung function in either group. We have identified two genes that showed nominal association with disease severity among CF patients. However, because of the multiple comparisons made, further studies are required to confirm the interaction between these modifying genes and CFTR. PMID- 21270832 TI - Chocolate and strawberries. PMID- 21270831 TI - Association between type 1 diabetes and GWAS SNPs in the southeast US Caucasian population. AB - The present study was conducted to assess genetic associations for type 1 diabetes (T1D) reported in previous genome-wide association studies (GWAS). A total of 21 previously reported single-nucleotide polymorphisms (SNPs) were genotyped by TaqMan assays in 1434 Caucasian T1D patients and 1864 normal controls from Georgia. Analysis of the samples identified 18 SNPs (PTPN22, INS, IFIH1, SH2B3, ERBB3, CTLA4, C14orf181, CTSH, CLEC16A, CD69, ITPR3, C6orf173, SKAP2, PRKCQ, RNLS, IL27, SIRPG and CTRB2) with putative association. PMID- 21270833 TI - A cornucopia of maize genes. PMID- 21270834 TI - The (new) new synthesis and epigenetic capacitors of morphological evolution. PMID- 21270835 TI - TRAPing a new gene for autoimmunity. PMID- 21270837 TI - Associations between reactive oxygen species, blood pressure and arterial stiffness in black South Africans: the SABPA study. AB - Many mechanisms, including oxidative stress, contribute to hypertension. This study investigated the possible associations between oxidative stress, blood pressure and arterial stiffness in black South Africans. Ambulatory blood pressure measurements were taken for 101 black South African men and 99 women. The stiffness indices included ambulatory arterial stiffness index (AASI) and pulse pressure (PP). Reactive oxygen species (ROS) levels (P<0.0001) were higher in the African women compared with men. ROS levels were also higher in hypertensive compared with normotensive men. The 24 h systolic blood pressure (SBP; P<0.01), 24 h diastolic blood pressure (DBP; P<0.0001) and pulse wave velocity (PWV; P<0.01) were significantly higher in African men compared with women. There were unadjusted positive associations of 24 h SBP (r=0.33; P=0.001), 24 h DBP (r=0.26; P=0.008) and 24 h PP (r=0.29; P=0.003) with ROS in African men only. A positive association between AASI and ROS existed only in hypertensive men (r=0.27; P=0.035), but became nonsignificant (B=0.0014; P=0.14) after adjustments. Adjusted, positive associations of 24 h SBP (B=0.181; P=0.018) and 24 h PP (B=0.086; P=0.050) with ROS were again only evident in African men. ROS is positively associated with SBP and PP in African men, suggesting that increased ROS levels may contribute to hypertension in this population group. PMID- 21270838 TI - C-reactive protein as a predictor of hypertension in the Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS) cohort. AB - Inflammation contributes to the development of hypertension. Whether C-reactive protein (CRP) has a causal role in hypertension remains unknown. We studied the relationship between circulating CRP levels and hypertension. The role of single nucleotide polymorphisms (SNPs) in the CRP gene as determinants of its plasma levels and the propensity to develop hypertension was investigated. Plasma CRP and genotypes of nine SNPs were determined in 1925 unrelated subjects from the Hong Kong Cardiovascular Risk Factor Prevalence Study-2 (CRISPS-2) in 2000-2004. Among 1378 subjects normotensive in CRISPS-2, 1115 subjects had been followed up in CRISPS-3 after a median interval of 5.3 years, 236 of whom had developed hypertension. Plasma CRP was independently associated with the development of hypertension in CRISPS-3 (odds ratio per quartile=1.26, P=0.010). Six SNPs were associated with plasma CRP (all P<0.001). However, none of the SNPs was significantly associated with blood pressure, prevalent or incident hypertension, or change in blood pressure. In conclusion, plasma CRP predicts the development of hypertension. Genetic variants in the CRP gene are significantly associated with plasma CRP but not with hypertension. The future risk of hypertension is therefore more related to plasma CRP than SNPs in the CRP gene in this population. PMID- 21270839 TI - The effect of conjugated linoleic acid, a natural trans fat from milk and meat, on human blood pressure: results from a randomized crossover feeding study. AB - Cis-9, trans-11 conjugated linoleic acid (CLA) is a natural trans fatty acid that is largely restricted to ruminant fats and consumed in foods and supplements. Its role in blood pressure (BP) regulation is still unclear. We examined the effect of cis-9, trans-11 CLA on BP compared with oleic acid. A total of 61 healthy volunteers were sequentially fed each of 3 diets for 3 weeks, in random order, for a total of 9 weeks. The diets were identical except for 7% of energy (18.9 g in a diet of 10 MJ day(-1)) that was provided either by oleic acid, by industrial trans fatty acids or by cis-9, trans-11 CLA. We measured BP on two separate days at the end of each intervention period. At baseline, mean BP was 113.8+/-14.4 mm Hg systolic and 66.3+/-9.6 mm Hg diastolic. The effect of the CLA diet compared with the oleic acid diet was 0.11 mm Hg (95% confidence interval: -1.27, 1.49) systolic and -0.45 mm Hg (-1.63, 0.73) diastolic. After the industrial trans fatty acid diet, the effect was 1.13 mm Hg (-0.25, 2.51) systolic and -0.44 mm Hg (-1.62, 0.73) diastolic compared with the oleic acid diet. Our study suggests that short-term high intakes of cis-9,trans-11 CLA do not affect BP in healthy volunteers. PMID- 21270842 TI - Atrial fibrillation in 2010: advances in treatment and management. AB - Clinical research into the management of atrial fibrillation-the most common serious arrhythmia-has mostly focused on arrhythmia prevention and the reduction of vascular events and death. In 2010, important advances have been made in stroke prevention with new anticoagulants and in atrial fibrillation rhythm management. PMID- 21270841 TI - Species sorting and neutral processes are both important during the initial assembly of bacterial communities. AB - Many studies have shown that species sorting, that is, the selection by local environmental conditions is important for the composition and assembly of bacterial communities. On the other hand, there are other studies that could show that bacterial communities are neutrally assembled. In this study, we implemented a microcosm experiment with the aim to determine, at the same time, the importance of species sorting and neutral processes for bacterial community assembly during the colonisation of new, that is, sterile, habitats, by atmospheric bacteria. For this we used outdoor microcosms, which contained sterile medium from three different rock pools representing different environmental conditions, which were seeded by rainwater bacteria. We found some evidence for neutral assembly processes, as almost every 4th taxon growing in the microcosms was also detectable in the rainwater sample irrespective of the medium. Most of these taxa belonged to widespread families with opportunistic growth strategies, such as the Pseudomonadaceae and Comamonadaceae, indicating that neutrally assembled taxa may primarily be generalists. On the other hand, we also found evidence for species sorting, as one out of three media selected a differently composed bacterial community. Species sorting effects were relatively weak and established themselves via differences in relative abundance of generalists among the different media, as well as media-specific occurrences of a few specific taxa. In summary, our results suggest that neutral and species sorting processes interact during the assembly of bacterial communities and that their importance may differ depending on how many generalists and specialists are present in a community. PMID- 21270840 TI - Coral-mucus-associated Vibrio integrons in the Great Barrier Reef: genomic hotspots for environmental adaptation. AB - Integron cassette arrays in a dozen cultivars of the most prevalent group of Vibrio isolates obtained from mucus expelled by a scleractinian coral (Pocillopora damicornis) colony living on the Great Barrier Reef were sequenced and compared. Although all cultivars showed >99% identity across recA, pyrH and rpoB genes, no two had more than 10% of their integron-associated gene cassettes in common, and some individuals shared cassettes exclusively with distantly related members of the genus. Of cassettes shared within the population, a number appear to have been transferred between Vibrio isolates, as assessed by phylogenetic analysis. Prominent among the mucus Vibrio cassettes with potentially inferable functions are acetyltransferases, some with close similarity to known antibiotic-resistance determinants. A subset of these potential resistance cassettes were shared exclusively between the mucus Vibrio cultivars, Vibrio coral pathogens and human pathogens, thus illustrating a direct link between these microbial niches through exchange of integron-associated gene cassettes. PMID- 21270843 TI - Acute coronary syndromes in 2010: progress from trials to practice. AB - Despite incremental progress in the treatment of acute coronary syndromes(acs), major uncertainties remain about the translation of evidence from trials into improved clinical practice. Key publications in 2010 have addressed this issue and questioned whether specific acs therapies should be targeted according to clinical and genetic characteristics. PMID- 21270844 TI - Atherosclerosis in 2010: new therapeutic insights. AB - Controversies in the treatment of atherosclerosis include uncertainty about the benefits of fibric acid derivatives, whether inhibition of cholesterol ester transfer protein is helpful or harmful, and about the benefits of statins in patients with renal failure. Key studies in 2010 contributed to the resolution of these long-standing controversies. PMID- 21270845 TI - Heart failure in 2010: one step forward, two steps back. AB - Patients with heart failure (HF) fall into two categories-those who are stable and ambulatory with a relatively low event rate, and patients requiring hospitalization who are characterized by high post-discharge mortality and rates of rehospitalization. HF trials in 2010 contributed to the advancement of outpatient management, whereas the development of novel therapies with a survival benefit remains an unmet need in acute HF syndromes. PMID- 21270846 TI - Hypertension in 2010: new challenges in blood pressure goals and assessment. AB - Provocative new studies have shown that tight blood pressure (BP) control (goal systolic BP <120 mmHg) in high-risk patients with diabetes mellitus confers no significant cardiovascular benefit other than stroke reduction, and that BP variability is important for the diagnosis and management of hypertension. the impact of these findings on future hypertension guidelines remains to be assessed. PMID- 21270848 TI - Vive la revolution. PMID- 21270847 TI - Valvular disease in 2010: evolution and revolution in risk stratification and therapy. AB - During 2010, several landmark studies, including the Partner trial,have made huge advances in the field of transcatheter aortic valve implantation. Other studies have made major contributions to the therapeutic management of young adult patients with severe aortic valve disease and of patients with asymptomatic severe mitral regurgitation. PMID- 21270849 TI - What comes first? PMID- 21270850 TI - Staring at the sun. PMID- 21270851 TI - Of course scientists can communicate. PMID- 21270863 TI - Brazil ignites telescope race. PMID- 21270864 TI - Tunisian scientists rejoice at freedom. PMID- 21270865 TI - China spurs quest for human variome. PMID- 21270866 TI - Probe keeps keen eye on Sun. PMID- 21270867 TI - Alzheimer's-disease probe nears approval. PMID- 21270868 TI - Marine science: China's unsinkable scientist. PMID- 21270869 TI - Central America: Panama's big ambition. PMID- 21270870 TI - Regulate trade in rare plants. PMID- 21270875 TI - Pitfalls of coal peak prediction. PMID- 21270876 TI - Scholars' awards go mainly to men. PMID- 21270878 TI - Treat ghostwriting as misconduct. PMID- 21270879 TI - Cognitive enhancement: A molecular memory booster. PMID- 21270880 TI - Quantum information: Entanglement on ice. PMID- 21270881 TI - Circadian rhythms: Redox redux. PMID- 21270882 TI - Medicine: diabetes in India. PMID- 21270883 TI - Cosmology: A glimpse of the first galaxies. PMID- 21270885 TI - Zoology: Why are whales big? PMID- 21270886 TI - The challenge of new drug discovery for tuberculosis. AB - Tuberculosis (TB) is more prevalent in the world today than at any other time in human history. Mycobacterium tuberculosis, the pathogen responsible for TB, uses diverse strategies to survive in a variety of host lesions and to evade immune surveillance. A key question is how robust are our approaches to discovering new TB drugs, and what measures could be taken to reduce the long and protracted clinical development of new drugs. The emergence of multi-drug-resistant strains of M. tuberculosis makes the discovery of new molecular scaffolds a priority, and the current situation even necessitates the re-engineering and repositioning of some old drug families to achieve effective control. Whatever the strategy used, success will depend largely on our proper understanding of the complex interactions between the pathogen and its human host. In this review, we discuss innovations in TB drug discovery and evolving strategies to bring newer agents more quickly to patients. PMID- 21270887 TI - A critical role for IGF-II in memory consolidation and enhancement. AB - We report that, in the rat, administering insulin-like growth factor II (IGF-II, also known as IGF2) significantly enhances memory retention and prevents forgetting. Inhibitory avoidance learning leads to an increase in hippocampal expression of IGF-II, which requires the transcription factor CCAAT enhancer binding protein beta and is essential for memory consolidation. Furthermore, injections of recombinant IGF-II into the hippocampus after either training or memory retrieval significantly enhance memory retention and prevent forgetting. To be effective, IGF-II needs to be administered within a sensitive period of memory consolidation. IGF-II-dependent memory enhancement requires IGF-II receptors, new protein synthesis, the function of activity-regulated cytoskeletal associated protein and glycogen-synthase kinase 3 (GSK3). Moreover, it correlates with a significant activation of synaptic GSK3beta and increased expression of GluR1 (also known as GRIA1) alpha-amino-3-hydroxy-5-methyl-4-isoxasolepropionic acid receptor subunits. In hippocampal slices, IGF-II promotes IGF-II receptor dependent, persistent long-term potentiation after weak synaptic stimulation. Thus, IGF-II may represent a novel target for cognitive enhancement therapies. PMID- 21270888 TI - Circadian clocks in human red blood cells. AB - Circadian (~24 hour) clocks are fundamentally important for coordinated physiology in organisms as diverse as cyanobacteria and humans. All current models of the molecular circadian clockwork in eukaryotic cells are based on transcription-translation feedback loops. Non-transcriptional mechanisms in the clockwork have been difficult to study in mammalian systems. We circumvented these problems by developing novel assays using human red blood cells, which have no nucleus (or DNA) and therefore cannot perform transcription. Our results show that transcription is not required for circadian oscillations in humans, and that non-transcriptional events seem to be sufficient to sustain cellular circadian rhythms. Using red blood cells, we found that peroxiredoxins, highly conserved antioxidant proteins, undergo ~24-hour redox cycles, which persist for many days under constant conditions (that is, in the absence of external cues). Moreover, these rhythms are entrainable (that is, tunable by environmental stimuli) and temperature-compensated, both key features of circadian rhythms. We anticipate that our findings will facilitate more sophisticated cellular clock models, highlighting the interdependency of transcriptional and non-transcriptional oscillations in potentially all eukaryotic cells. PMID- 21270889 TI - A candidate redshift z ~ 10 galaxy and rapid changes in that population at an age of 500 Myr. AB - Searches for very-high-redshift galaxies over the past decade have yielded a large sample of more than 6,000 galaxies existing just 900-2,000 million years (Myr) after the Big Bang (redshifts 6 > z > 3; ref. 1). The Hubble Ultra Deep Field (HUDF09) data have yielded the first reliable detections of z ~ 8 galaxies that, together with reports of a gamma-ray burst at z ~ 8.2 (refs 10, 11), constitute the earliest objects reliably reported to date. Observations of z ~ 7 8 galaxies suggest substantial star formation at z > 9-10 (refs 12, 13). Here we use the full two-year HUDF09 data to conduct an ultra-deep search for z ~ 10 galaxies in the heart of the reionization epoch, only 500 Myr after the Big Bang. Not only do we find one possible z ~ 10 galaxy candidate, but we show that, regardless of source detections, the star formation rate density is much smaller (~10%) at this time than it is just ~200 Myr later at z ~ 8. This demonstrates how rapid galaxy build-up was at z ~ 10, as galaxies increased in both luminosity density and volume density from z ~ 10 to z ~ 8. The 100-200 Myr before z ~ 10 is clearly a crucial phase in the assembly of the earliest galaxies. PMID- 21270890 TI - Hard-tip, soft-spring lithography. AB - Nanofabrication strategies are becoming increasingly expensive and equipment intensive, and consequently less accessible to researchers. As an alternative, scanning probe lithography has become a popular means of preparing nanoscale structures, in part owing to its relatively low cost and high resolution, and a registration accuracy that exceeds most existing technologies. However, increasing the throughput of cantilever-based scanning probe systems while maintaining their resolution and registration advantages has from the outset been a significant challenge. Even with impressive recent advances in cantilever array design, such arrays tend to be highly specialized for a given application, expensive, and often difficult to implement. It is therefore difficult to imagine commercially viable production methods based on scanning probe systems that rely on conventional cantilevers. Here we describe a low-cost and scalable cantilever free tip-based nanopatterning method that uses an array of hard silicon tips mounted onto an elastomeric backing. This method-which we term hard-tip, soft spring lithography-overcomes the throughput problems of cantilever-based scanning probe systems and the resolution limits imposed by the use of elastomeric stamps and tips: it is capable of delivering materials or energy to a surface to create arbitrary patterns of features with sub-50-nm resolution over centimetre-scale areas. We argue that hard-tip, soft-spring lithography is a versatile nanolithography strategy that should be widely adopted by academic and industrial researchers for rapid prototyping applications. PMID- 21270891 TI - Melt-induced speed-up of Greenland ice sheet offset by efficient subglacial drainage. AB - Fluctuations in surface melting are known to affect the speed of glaciers and ice sheets, but their impact on the Greenland ice sheet in a warming climate remains uncertain. Although some studies suggest that greater melting produces greater ice-sheet acceleration, others have identified a long-term decrease in Greenland's flow despite increased melting. Here we use satellite observations of ice motion recorded in a land-terminating sector of southwest Greenland to investigate the manner in which ice flow develops during years of markedly different melting. Although peak rates of ice speed-up are positively correlated with the degree of melting, mean summer flow rates are not, because glacier slowdown occurs, on average, when a critical run-off threshold of about 1.4 centimetres a day is exceeded. In contrast to the first half of summer, when flow is similar in all years, speed-up during the latter half is 62 +/- 16 per cent less in warmer years. Consequently, in warmer years, the period of fast ice flow is three times shorter and, overall, summer ice flow is slower. This behaviour is at odds with that expected from basal lubrication alone. Instead, it mirrors that of mountain glaciers, where melt-induced acceleration of flow ceases during years of high melting once subglacial drainage becomes efficient. A model of ice-sheet flow that captures switching between cavity and channel drainage modes is consistent with the run-off threshold, fast-flow periods, and later-summer speeds we have observed. Simulations of the Greenland ice-sheet flow under climate warming scenarios should account for the dynamic evolution of subglacial drainage; a simple model of basal lubrication alone misses key aspects of the ice sheet's response to climate warming. PMID- 21270892 TI - Comparative and demographic analysis of orang-utan genomes. AB - 'Orang-utan' is derived from a Malay term meaning 'man of the forest' and aptly describes the southeast Asian great apes native to Sumatra and Borneo. The orang utan species, Pongo abelii (Sumatran) and Pongo pygmaeus (Bornean), are the most phylogenetically distant great apes from humans, thereby providing an informative perspective on hominid evolution. Here we present a Sumatran orang-utan draft genome assembly and short read sequence data from five Sumatran and five Bornean orang-utan genomes. Our analyses reveal that, compared to other primates, the orang-utan genome has many unique features. Structural evolution of the orang utan genome has proceeded much more slowly than other great apes, evidenced by fewer rearrangements, less segmental duplication, a lower rate of gene family turnover and surprisingly quiescent Alu repeats, which have played a major role in restructuring other primate genomes. We also describe a primate polymorphic neocentromere, found in both Pongo species, emphasizing the gradual evolution of orang-utan genome structure. Orang-utans have extremely low energy usage for a eutherian mammal, far lower than their hominid relatives. Adding their genome to the repertoire of sequenced primates illuminates new signals of positive selection in several pathways including glycolipid metabolism. From the population perspective, both Pongo species are deeply diverse; however, Sumatran individuals possess greater diversity than their Bornean counterparts, and more species-specific variation. Our estimate of Bornean/Sumatran speciation time, 400,000 years ago, is more recent than most previous studies and underscores the complexity of the orang-utan speciation process. Despite a smaller modern census population size, the Sumatran effective population size (N(e)) expanded exponentially relative to the ancestral N(e) after the split, while Bornean N(e) declined over the same period. Overall, the resources and analyses presented here offer new opportunities in evolutionary genomics, insights into hominid biology, and an extensive database of variation for conservation efforts. PMID- 21270893 TI - Distinct physiological and behavioural functions for parental alleles of imprinted Grb10. AB - Imprinted genes, defined by their preferential expression of a single parental allele, represent a subset of the mammalian genome and often have key roles in embryonic development, but also postnatal functions including energy homeostasis and behaviour. When the two parental alleles are unequally represented within a social group (when there is sex bias in dispersal and/or variance in reproductive success), imprinted genes may evolve to modulate social behaviour, although so far no such instance is known. Predominantly expressed from the maternal allele during embryogenesis, Grb10 encodes an intracellular adaptor protein that can interact with several receptor tyrosine kinases and downstream signalling molecules. Here we demonstrate that within the brain Grb10 is expressed from the paternal allele from fetal life into adulthood and that ablation of this expression engenders increased social dominance specifically among other aspects of social behaviour, a finding supported by the observed increase in allogrooming by paternal Grb10-deficient animals. Grb10 is, therefore, the first example of an imprinted gene that regulates social behaviour. It is also currently alone in exhibiting imprinted expression from each of the parental alleles in a tissue specific manner, as loss of the peripherally expressed maternal allele leads to significant fetal and placental overgrowth. Thus Grb10 is, so far, a unique imprinted gene, able to influence distinct physiological processes, fetal growth and adult behaviour, owing to actions of the two parental alleles in different tissues. PMID- 21270894 TI - Bifidobacteria can protect from enteropathogenic infection through production of acetate. AB - The human gut is colonized with a wide variety of microorganisms, including species, such as those belonging to the bacterial genus Bifidobacterium, that have beneficial effects on human physiology and pathology. Among the most distinctive benefits of bifidobacteria are modulation of host defence responses and protection against infectious diseases. Nevertheless, the molecular mechanisms underlying these effects have barely been elucidated. To investigate these mechanisms, we used mice associated with certain bifidobacterial strains and a simplified model of lethal infection with enterohaemorrhagic Escherichia coli O157:H7, together with an integrated 'omics' approach. Here we show that genes encoding an ATP-binding-cassette-type carbohydrate transporter present in certain bifidobacteria contribute to protecting mice against death induced by E. coli O157:H7. We found that this effect can be attributed, at least in part, to increased production of acetate and that translocation of the E. coli O157:H7 Shiga toxin from the gut lumen to the blood was inhibited. We propose that acetate produced by protective bifidobacteria improves intestinal defence mediated by epithelial cells and thereby protects the host against lethal infection. PMID- 21270895 TI - Circadian rhythms persist without transcription in a eukaryote. AB - Circadian rhythms are ubiquitous in eukaryotes, and coordinate numerous aspects of behaviour, physiology and metabolism, from sleep/wake cycles in mammals to growth and photosynthesis in plants. This daily timekeeping is thought to be driven by transcriptional-translational feedback loops, whereby rhythmic expression of 'clock' gene products regulates the expression of associated genes in approximately 24-hour cycles. The specific transcriptional components differ between phylogenetic kingdoms. The unicellular pico-eukaryotic alga Ostreococcus tauri possesses a naturally minimized clock, which includes many features that are shared with plants, such as a central negative feedback loop that involves the morning-expressed CCA1 and evening-expressed TOC1 genes. Given that recent observations in animals and plants have revealed prominent post-translational contributions to timekeeping, a reappraisal of the transcriptional contribution to oscillator function is overdue. Here we show that non-transcriptional mechanisms are sufficient to sustain circadian timekeeping in the eukaryotic lineage, although they normally function in conjunction with transcriptional components. We identify oxidation of peroxiredoxin proteins as a transcription independent rhythmic biomarker, which is also rhythmic in mammals. Moreover we show that pharmacological modulators of the mammalian clock mechanism have the same effects on rhythms in Ostreococcus. Post-translational mechanisms, and at least one rhythmic marker, seem to be better conserved than transcriptional clock regulators. It is plausible that the oldest oscillator components are non transcriptional in nature, as in cyanobacteria, and are conserved across kingdoms. PMID- 21270896 TI - Structural basis for site-specific ribose methylation by box C/D RNA protein complexes. AB - Box C/D RNA protein complexes (RNPs) direct site-specific 2'-O-methylation of RNA and ribosome assembly. The guide RNA in C/D RNP forms base pairs with complementary substrates and selects the modification site using a molecular ruler. Despite many studies of C/D RNP structure, the fundamental questions of how C/D RNAs assemble into RNPs and how they guide modification remain unresolved. Here we report the crystal structure of an entire catalytically active archaeal C/D RNP consisting of a bipartite C/D RNA associated with two substrates and two copies each of Nop5, L7Ae and fibrillarin at 3.15-A resolution. The substrate pairs with the second through the eleventh nucleotide of the 12-nucleotide guide, and the resultant duplex is bracketed in a channel with flexible ends. The methyltransferase fibrillarin binds to an undistorted A form structure of the guide-substrate duplex and specifically loads the target ribose into the active site. Because interaction with the RNA duplex alone does not determine the site specificity, fibrillarin is further positioned by non specific and specific protein interactions. Compared with the structure of the inactive C/D RNP, extensive domain movements are induced by substrate loading. Our results reveal the organization of a monomeric C/D RNP and the mechanism underlying its site-specific methylation activity. PMID- 21270898 TI - Electrophysiological properties of spinal wide dynamic range neurons in neuropathic pain rats following spinal nerve ligation. AB - OBJECTIVE: The present study aimed to investigate the electrophysiological properties of wide dynamic range (WDR) neurons in spinal dorsal horn of rats with neuropathic pain induced by lumber 5 (L5) spinal nerve ligation (SNL) in a large size of samples. METHODS: Adult Sprague-Dawley rats were divided into normal and SNL groups. Electrophysiological technique was used to record the characteristics of WDR neurons in the spinal dorsal horn. RESULTS: Compared with the WDR neurons in normal rats, the WDR neurons in SNL rats showed an increase in excitability, manifested by an enlargement of the receptive field size, an increase in the proportion of neurons that exhibited spontaneous activities, decreases in the C response threshold and latency, and an increase in the C-response duration. In addition, the numbers of Abeta- and C-fiber-evoked discharges were smaller in SNL rats than in normal rats. CONCLUSION: The excitability of spinal WDR neurons increased in rats with neuropathic pain induced by L5 SNL. The increase in excitability of WDR neurons may contribute to the development of neuropathic pain. PMID- 21270899 TI - Decline of selectivity of V1 neurons to visual stimulus spatial frequencies in old cats. AB - OBJECTIVE: To examine whether the selectivity of visual cortical neurons to stimulus spatial frequencies would be affected by aging in cats. METHODS: In vivo extracellular single-unit recording techniques were employed to record the tuning responses of V1 neurons to different stimulus spatial frequencies in old and young adult cats. RESULTS: Statistical analysis showed that the mean optimal spatial frequency of grating stimuli that evoked the maximal response of V1 neurons in old cats was significantly lower than that in young adult cats. Furthermore, the mean high cut-off spatial frequency of grating stimuli that evoked the half amplitude of the maximal response of V1 neurons in old cats was also significantly lower than that in young adult cats. CONCLUSION: These results are consistent with those reported in the V1 of old monkeys, suggesting that the age-related decline in the selectivity of visual cortical cells to spatial frequency could be generalized to all mammalian species and might contribute to visual acuity reduction in senescent individuals. PMID- 21270900 TI - Expressions of Axl and Tyro-3 receptors are under regulation of nerve growth factor and are involved in differentiation of PC12 cells. AB - OBJECTIVE: Tyro-3 and Axl receptors are expressed in brain in a region-specific manner and their bioactivities in the central nervous system remain still elusive. The aim of the present study was to investigate their functions in neuronal differentiation. METHODS: PC12 cells overexpressing Tyro-3 or Axl were established by transfection with full-length CMV-Tyro-3-eCFP or CMV-Axl-eGFP plasmid, respectively. CMV-eGFP plasmid served as a control vector. After that, the fluorescence intensity and distributions of green fluorescent protein (GFP) and cyan fluorescent protein (CFP) in the cells with or without nerve growth factor (NGF) treatment were real-time monitored. RESULTS: Expressions of Tyro-3 and Axl receptors were under the regulation of NGF and associated with neuronal differentiation. This was not observed in CMV-eGFP-transfected PC12 cells. Besides, confocal microscopy revealed that NGF affected intracellular localization of full-length Axl-eGFP and Tyro-3-eCFP in PC12 cells. Moreover, the development of outgrowth of differentiated PC12 cells under stimulation of NGF was promoted by overexpression of Tyro-3 or Axl. CONCLUSION: Expressions of Tyro 3 and Axl receptors are under the regulation of NGF and are involved in NGF induced neuronal differentiation of PC12 cells. PMID- 21270901 TI - Research progress on neurobiology of neuronal nitric oxide synthase. AB - Neuronal nitric oxide synthase (nNOS) is mainly expressed in neurons, to some extent in astrocytes and neuronal stem cells. The alternative splicing of nNOS mRNA generates 5 isoforms of nNOS, including nNOS-alpha, nNOS-beta, nNOS-u, nNOS gamma and nNOS-2. Monomer of nNOS is inactive, and dimer is the active form. Dimerization requires tetrahydrobiopterin (BH4), heme and L-arginine binding. Regulation of nNOS expression relies largely on cAMP response element-binding protein (CREB) activity, and nNOS activity is regulated by heat shock protein 90 (HSP90)/HSP70, calmodulin (CaM), phosphorylation and dephosphorylation at Ser847 and Ser1412, and the protein inhibitor of nNOS (PIN). There are primarily 9 nNOS interacting proteins, including post-synaptic density protein 95 (PSD95), clathrin assembly lymphoid leukemia (CALM), calcium/calmodulin-dependent protein kinase II alpha (CAMKIIA), Disks large homolog 4 (DLG4), DLG2, 6 phosphofructokinase, muscle type (PFK-M), carboxy-terminal PDZ ligand of nNOS (CAPON) protein, syntrophin and dynein light chain (LC). Among them, PSD95, CAPON and PFK-M are important nNOS adapter proteins in neurons. The interaction of PSD95 with nNOS controls synapse formation and is implicated in N-methyl-D aspartic acid-induced neuronal death. nNOS-derived NO is implicated in synapse loss-mediated early cognitive/motor deficits in several neuropathological states, and negatively regulates neurogenesis under physiological and pathological conditions. PMID- 21270902 TI - Potassium channel blockers as an effective treatment to restore impulse conduction in injured axons. AB - Most axons in the vertebral central nervous system are myelinated by oligodendrocytes. Myelin protects and insulates neuronal processes, enabling the fast, saltatory conduction unique to myelinated axons. Myelin disruption resulting from trauma and biochemical reaction is a common pathological event in spinal cord injury and chronic neurodegenerative diseases. Myelin damage-induced axonal conduction block is considered to be a significant contributor to the devastating neurological deficits resulting from trauma and illness. Potassium channels are believed to play an important role in axonal conduction failure in spinal cord injury and multiple sclerosis. Myelin damage has been shown to unmask potassium channels, creating aberrant potassium currents that inhibit conduction. Potassium channel blockade reduces this ionic leakage and improves conduction. The present review was mainly focused on the development of this technique of restoring axonal conduction and neurological function of demyelinated axons. The drug 4-aminopyridine has recently shown clinical success in treating multiple sclerosis symptoms. Further translational research has also identified several novel potassium channel blockers that may prove effective in restoring axonal conduction. PMID- 21270903 TI - Down syndrome cell adhesion molecule and its functions in neural development. AB - The nervous system is a complex network with many types of neurons and numerous synaptic connections. The present knowledge on how neurons recognize specific targets and form such an intricate network is still limited. The Down syndrome cell adhesion molecule (DSCAM) belongs to the immunoglobulin superfamily and contributes to defects in the central nervous system in Down syndrome patients. DSCAM plays important roles in neural development, including dendritic patterning and self-avoidance, axon guidance and branching, axon target recognition and synaptic formation. However, the functional mechanisms and the underlying signaling pathways are still largely unknown. Here the functions of DSCAM in neural development were reviewed. Future research for better understanding DSCAM function and the relevance of DSCAM to human diseases was also discussed. PMID- 21270904 TI - Screening of treatment targets for Alzheimer's disease from the molecular mechanisms of impairment by beta-amyloid aggregation and tau hyperphosphorylation. AB - beta-Amyloid (Abeta) over-expression and tau hyperphosphorylation are considered to be the central events in the pathogenesis of Alzheimer's disease (AD). Studies on them may help elucidate the precise molecular pathogenesis of AD. Until now, although tau protein and Abeta remain the foci of AD research, the etiopathogenesis of AD and effective drugs for AD treatment are still largely unsolved. The present review was mainly focused on the molecular mechanism of Abeta aggregation-related impairment and the pathways leading to tau hyperphosphorylation, based on which some promising therapeutic targets for AD were also proposed. PMID- 21270905 TI - Behavioral assessments of the aversive quality of pain in animals. AB - Animals and humans share similar mechanisms of pain detection and similar brain areas involved in pain processing. Also, they show similar pain behaviors, such as reflexed sensation to nociceptive stimuli. Pain is often described in sensory discrimination (algosity) and affective motivation (unpleasantness) dimensions. Both basic and clinical findings indicate that individuals with chronic pain usually suffer more from pain-associated affective disturbances than from the actual pain sensations per se. Although the neural systems responsible for the sensory component of pain have been studied extensively, the neural mechanisms underlying negative affective component are not well understood. This is partly due to the relative paucity of animal paradigms for reliable examination of each component of pain. In humans, the experience of pain and suffering can be reported by language, while in animals, pain can only be inferred through physical and behavioral reactions. Animal behaviors, cognitive psychology and functional brain imaging have made it possible to assess pain affection and pain memory in animals. Animals subjected to either neuropathic injury or inflammatory insult display significant conditioned place aversion to a pain-paired environment in behaviors. The present review aims to summarize the common methods of affective unpleasantness assessment in rats. PMID- 21270906 TI - World Kidney Day 2011: protect your kidneys, save your heart. PMID- 21270907 TI - NEFRONA project: open-access database. PMID- 21270908 TI - The future of the artificial kidney: moving towards wearable and miniaturized devices. AB - New directions in dialysis research include cheaper treatments, home based therapies and simpler methods of blood purification. These objectives may be probably obtained with innovations in the field of artificial kidney through the utilization of new disciplines such as miniaturization, microfluidics, nanotechnology. This research may lead to a new era of dialysis in which the new challenges are transportability, wearability and why not the possibility to develop implantable devices. Although we are not there yet, a new series of papers have recently been published disclosing interesting and promising results on the application of wearable ultrafiltration systems (WUF) and wearable artificial kidneys (WAK). Some of them use extracorporeal blood cleansing as a method of blood purification while others use peritoneal dialysis as a treatment modality (ViWAK and AWAK.) A special mention deserves the wearable/portable ultrafiltration system for the therapy of overhydration and congestive heart failure (WAKMAN). This system will allow dehospitalization and treatment of patients with less comorbidity and improved tolerance. On the way to the wearable artificial kidney, new discoveries have been made such as a complete system for hemofiltration in newborns (CARPEDIEM). The neonate in fact is the typical patient who may benefit from miniaturization of the dialysis circuit. This review analyzes the rationale for such endeavour and the challenges to overcome in order to make possible a true ambulatory dialysis treatment. Some initial results with these new devices are presented. We would like to stimulate a collaborative effort to make a quantum leap in technology making the wearable artificial kidney a reality rather than a dream. PMID- 21270909 TI - Recommendations for the pharmacologic treatment of hyperglycemia in type 2 diabetes. Consensus document. PMID- 21270910 TI - Clinical evidence on the use of anti-mTOR drugs in renal transplantation. AB - Calcineurin inhibitor drugs (CNI) are the mainstay of modern immunosuppression in renal transplantation. However, they contribute significantly to the chronic loss of renal grafts and the high morbidity and mortality in this population due to their deleterious effects on the renal graft, cardiovascular profile and tumour pathology. Anti-mTOR drugs, sirolimus (SRL) and everolimus (EVE) are potent immunosuppressants with antiproliferative and anti-migratory capacities. These properties mean that they have a potential protective role in graft dysfunction, in renal function optimisation and the appearance of malignant tumours. Indeed, clinical trials and observational studies have demonstrated that conversion from CNI to anti-mTOR-based maintenance therapy has beneficial effects on transplant outcomes in terms of renal function, without significant increase in acute rejection rates. This review article examines the evidence of the use of anti mTOR in the following clinical situations following renal transplantation: 1) prevention of immune dysfunction and renal function preservation in de novo renal transplantation and after early or late CNI withdrawal; 2) chronic dysfunction of the renal graft; 3) cardiovascular effects; 4) de novo post-transplant diabetes, and 5) de novo tumour pathology. PMID- 21270911 TI - Molecular diagnosis of autosomal dominant polycystic kidney disease. AB - Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disorder. Its estimated prevalence is 1 per 800 individuals. ADPKD patients constitute 8% of the population on dialysis or kidney transplantation. The disease can be diagnosed using radiological or genetic procedures. Direct genetic diagnosis of the disease can now be performed in Spain; however, it is not an easy or cheap test. This is why every case should be considered individually to determine whether genetic testing is appropriate, and to determine which genetic test is most adequate. Genetic testing in ADPKD is of special interest for living donors and neonatal and sporadic cases. Genetic testing offers the chance of performing prenatal or pre-implantation testing of embryos in families with severe cases of the disease. Also, this will enable the disease to be treated, when specific treatment becomes available, in cases that would not be candidates for treatment without genetic confirmation. PMID- 21270912 TI - Hypouricemia and tubular transport of uric acid. AB - Hypouricemia is defined when a serum urate concentration is less than or equal 2.0mg/dl. Differential diagnosis is made by fractional uric acid excretion with the identification of urate transporters and intracellular proteins involved in the tubular transport of uric acid. This review examines current knowledge on uric acid tubular transport and the various clinical situations of hypouricemia. PMID- 21270913 TI - Dialysis after kidney transplant failure: do patients start in a worse condition than the general population with chronic kidney disease? AB - BACKGROUND: Patients with renal graft dysfunction constitute an increasingly prevalent group of end-stage kidney disease (ESKD) patients that require dialysis therapy. These patients have special characteristics that set them apart from the ESKD general population. The aim of this study was to analyse the clinical condition and evolution of patients entering dialysis with a failed kidney graft at the time of restarting dialysis and over a year of therapy according to the K/DOQI guidelines, and to compare them with incidental patients with end-stage kidney disease. We also investigated whether the modality of kidney replacement therapy may determine the clinical improvement of transplant patients. MATERIAL AND METHOD: This is a retrospective observational study of 106 patients with ESKD followed up in the Ramon y Cajal Hospital. They were classified in two groups. Group one was made up of 50 failed native kidney patients who started dialysis between 2000 and 2009. Group two was comprised of 56 transplant patients with graft dysfunction who returned to dialysis between 1997 and 2009. We studied parameters of kidney function, anaemia, calcium-phosphorus metabolism, cardiovascular risk factors and nutritional status at the time both groups started on dialysis and one year later. RESULTS: Both groups had a similar clinical status at the time they started on dialysis in most of the parameters analysed with the exception of anaemia. This was more severe in transplant patients, despite the fact that transplant patients received a higher dose of erythropoietin than non-transplant patients. One year later the main difference between both groups was the residual kidney function rate, higher in non transplant patients. There were no significant differences in the parameters analysed in patients with a failed graft according to the modality of kidney replacement therapy. CONCLUSION: Failed transplant patients start dialysis with more severe anaemia than patients entering dialysis for the first time. Twelve months later both groups present a similar clinical condition with the exception of residual kidney function, higher in failed native kidney patients. The method of dialysis treatment after kidney transplant failure did not have a bearing on the clinical improvement of our patients. PMID- 21270914 TI - Oral nicotinamide reduces serum phosphorus, increases HDL, and induces thrombocytopenia in hemodialysis patients: a double-blind randomized clinical trial. AB - BACKGROUND: Recently, nicotinamide has been suggested as an effective drug for hyperphosphatemia in hemodialysis patients. The authors assessed the efficacy and safety of nicotinamide in these patients with lower doses and longer duration than other studies. METHODS: Forty eight patients with fasting serum phosphorus >5 mg/dl enrolled in this randomized clinical trial study and were randomly assigned to two equal-sized groups of nicotinamide or placebo. The study lasted 8 weeks. In the first four weeks, nicotinamide was administered at 500 mg/day, and in the second four weeks at 1,000 mg/day. Blood samples were tested at baseline, week 4, and week 8. RESULTS: In nicotinamide group, the mean phosphorus level decreased from 5.9 +/- 0.58 mg/dl to 4.77 +/- 1.43 mg/dl in week 4 (P = 0.002) and to 4.66 +/- 1.06 mg/dl in week 8 (P = 0.000). The mean calcium-phosphorus product decreased significantly with the same pattern as phosphorus. High-density lipoprotein level increased from 42.46 +/- 8.01 mg/dl to 55.71 +/- 11.88 mg/dl in week 4 (P = 0.000) and to 65.25 +/- 20.18 mg/dl in week 8 (P = 0.000). Levels of serum calcium, uric acid, SGOT, SGPT, and iPTH didn't change significantly. Compared to baseline, the platelet counts were decreased in both week 4 and week 8. No significant changes were observed in placebo group. CONCLUSIONS: In our patients, nicotinamide effectively decreased phosphorus, increased high-density lipoprotein, and caused thrombocytopenia. Since nicotinamide lowered platelet counts and caused thrombocytopenia in lower doses than other studies in these patients, it is necessary to plan other studies for assessing the safety of the drug especially in different populations. PMID- 21270915 TI - Measurement of foveal thickness by optical coherence tomography in adult haemodialysis patients with diabetic nephropathy. AB - BACKGROUND: Several studies have demonstrated the efficacy of hemodialysis (HD) on macular edema in diabetic patients. OBJECTIVE: To study the effects of a HD session on foveal thickness by optical coherence tomography (OCT) in adult patients with type 2 diabetes mellitus with chronic renal failure (CRF) secondary to stage 5 diabetic nephropathy in HD. PATIENTS AND METHODS: We studied 25 eyes of 14 patients who underwent analytical studies and pre-HD and post-HD OCT. RESULTS: As a group, the foveal thickness did not change after one session of HD in the 25 eyes studied (245.28 +/- 52.21 MU versus 240.40 +/- 40.25 MU) (p = 0.428) (2% reduction) or correlated with any clinical or laboratory parameters analyzed.When comparing the subgroup of 13 eyes in which the foveal thickness did not change or decreased compared to the subgroup of 12 eyes in which the foveal thickness increased we found that in the first subgroup the bath temperature was significantly higher (37.00 +/- 0.00 versus 36.29 degrees C, p = 0.008) and the conductivity was significantly lower (14.00 +/- 0.00 versus 14.29 +/- 0.10 mS / cm, p = 0.030). CONCLUSION: HD may modify the foveal retinal thickness as a function of changing parameters such as bath temperature and conductivity. PMID- 21270916 TI - Undiagnosed kidney disease in hospitalised patients: an opportunity for improvement. AB - OBJECTIVES: In hospitalised patients, chronic kidney disease (CKD) is associated with a high risk of morbidity, mortality and drug toxicity. We identified care improvement opportunities in hospitalised patients with kidney disease in a regional hospital. MATERIAL AND METHOD: Clinical audit: 200 patients hospitalised for any reason in Alcaniz Hospital (Spain) were randomly selected. The data sources were laboratory data, clinical history and discharge reports. RIFLE criteria were applied to define kidney function deterioration. As process quality indicators we used: 1) percentage of hospitalised patients with at least one determination of kidney function during admission. 2) percentage of patients who met criteria for CKD and/or kidney function deterioration and who had this diagnosis recorded in clinical progress reports. 3) percentage of patients who met criteria for CKD and/or kidney function deterioration and who had this diagnosis recorded in the discharge report. RESULTS: Mean age was 71.1 (17) years, 42% women, 63% admitted to medical areas and 37% to surgical areas. Some 194 patients had a kidney function determination at admission; however during their stay kidney function was not monitored in 54 patients (27%), especially in surgical areas. CKD diagnosis by analyses prior to admission was available for 50 patients (25%); however this diagnosis figures in the clinical history in 14 of them (28%), and in the discharge report in 17 (34%). Kidney function deterioration was detected in 68 of the 146 patients who had kidney function monitoring during hospitalisation (46.5%). This information was contained in the clinical history in only 50% of cases and in the discharge report in 33.8%. CONCLUSIONS: The incidence of CKD prior to admission and deterioration of kidney function during hospitalisation are high. Often these diagnoses are not included in clinical progress reports or in the discharge report, reflecting poor condition awareness on the part of our colleagues. Implementation of a clinical protocol and its diffusion throughout the hospital may be important tools to achieving more efficient and consistent management of these conditions. PMID- 21270917 TI - Work climate in Mexican hemodialysis units: a cross-sectional study. AB - BACKGROUND: The work climate (WC) affects the performance of service providers and has an impact on the care provided to users. This is important in the case of conditions that affect the quality of life, as is the case of chronic kidney disease (CKD) treated with haemodialysis. In Mexico, the demand for the care of CKD cases is increasing and the haemodialysis offer is limited. The purpose of this study was to describe and compare the WC in public, private and social security haemodialysis units in Mexico and to validate a tool to measure WC in haemodialysis units (HU). METHOD: 372 professionals from 84 HU in 27 states were interviewed using a questionnaire. This included questions about the WC, quality of care and structure and organisation of the HU. Variables were compared by type of institution and profession. RESULTS: Significant correlations were observed between the WC and indicators of the quality of care. Nine out of fourteen variables presented important differences by type of unit, with a better perception of WC in private units and a poorer perception in social security ones. CONCLUSIONS: The perception of WC relies on the organisation and planning of the institutions, as well as on their infrastructure. In the case of Social Security HU in Mexico, these appear to be the areas that require improvement in order to encourage a better work climate. PMID- 21270918 TI - Results of a coordination and shared clinical information programme between primary care and nephrology. AB - INTRODUCTION: The high prevalence of chronic kidney disease (CKD) in the general population has created a need to coordinate specialised nephrology care and primary care. Although several systems have been developed to coordinate this process, published results are scarce and contradictory. OBJECTIVE: To present the results of the application of a coordinated programme between nephrology care and primary care through consultations and a system of shared clinical information to facilitate communication and improve the criteria for referring patients. METHODS: Elaboration of a coordinated care programme by the primary care management team and the nephrology department, based on the SEN-SEMFYC consensus document and a protocol for the study and management of arterial hypertension (AHT). Explanation and implementation in primary health care units. A directory of specialists' consultations was created, both in-person and via e mail. A continuous training programme in kidney disease and arterial hypertension was implemented in the in-person consultation sessions. The programme was progressively implemented over a three-year period (2007-2010) in an area of 426,000 inhabitants with 230 general practitioners. Use of a clinical information system named Salut en Xarxa that allows access to clinical reports, diagnoses, prescriptions, test results and clinical progression. RESULTS: Improved referral criteria between primary care and specialised nephrology service. Improved prioritisation of visits. Progressive increase in referrals denied by specialists (28.5% in 2009), accompanied by an explanatory report including suggestions for patient management. Decrease in first nephrology outpatient visits that have been referred from primary care (15% in 2009). Family doctors were generally satisfied with the improvement in communication and the continuous training programme. The main causes for denying referral requests were: patients >70 years with stage 3 CKD (44.15%); patients <70 years with stage 3a CKD (19.15%); albumin/creatinine ratio <500 mg/g (12.23%); non-secondary, non-refractory, essential AHT (11.17%). The general practitioners included in the programme showed great interest and no complaints were registered. CONCLUSIONS: The consultations improve adequacy and prioritisation of nephrology visits, allow for better communication between different levels of the health system, and offer systematic training for general practitioners to improve the management of nephrology patients. This process allows for referring nephrology patients with the most complex profiles to nephrology outpatient clinics. PMID- 21270919 TI - Quality of life in chronic kidney disease. AB - BACKGROUND: The evaluation of health-related quality of life (QOL) in chronic kidney disease intends to quantify its consequences, according to the patient's subjective perception. AIM: To evaluate the health-related QOL in four groups of patients followed at our Nephrology Department: chronic kidney disease (CKD) stages 1-4, kidney transplant (KT), haemodialysis (HD) and peritoneal dialysis (PD) patients. PATIENTS AND METHODS: Thirty patients with CKD stages 1-4 and 30 KT patients were randomly selected. All patients from our Haemodialysis and Peritoneal Dialysis Units with capacity to answer the inquiry (37 and 14, respectively) were also selected. The instruments applied were the SF-36 and KDQOL-SF 1.3. RESULTS: The four groups presented better results in the <> scale (77.68 +/- 18.46 in PD; 74.17 +/- 29.53 in KT; 66.81 +/- 31.39 in CKD 1-4; 62.16 +/- 32.84 in HD; p = 0.192). The lowest results appeared in the <> scale (39.92 +/- 19.12 in CKD; 45.95 +/- 21.56 in HD; 47.13 +/- 23.15 in KT; 51.79 +/- 18.89 in PD; p = 0.321). Peritoneal dialysis patients achieved the best results in the Physical Health Component, but this difference disappeared after adjustment to confounding factors. Age, gender and haemoglobin level were the variables related with QOL. However, PD patients obtained better scores comparing to HD patients in the following KDQOL-SF scales: <>, <> and <> (p <0.05). CONCLUSIONS: Health-related QOL was better in peritoneal dialysis patients comparing to haemodialysis patients in specific scales of chronic kidney disease. Age, gender and haemoglobin level interfered with health-related QOL. PMID- 21270920 TI - Psychological predictors for health-related quality of life in patients on peritoneal dialysis. AB - INTRODUCTION: It is currently recognized the impact of different clinical and sociodemographics variables on the health-related quality of life (HRQL) of patients undergoing peritoneal dialysis (DP), albeit the influence of psychological variable has not been thoroughly studied. The objective of this study is to identify the psychological predictors of HRQL in patients under DP. METHOD: 53 patients on DP participated in the study (49.54 +/- 17.03 years, 54.7% women) in whom HRQL was evaluated by the Kidney Disease Quality of Life Short Form and it was obtained information related with psychological variables (depressive and anxious symptoms , alexithymia, health-related locus of control and coping strategies) besides socio-demographical and clinical variables. RESULTS: Patients on DP presented a worse HRQL than general population, particularly in the physical dimension. The comorbility, the number of visits to urgency department, previous hospital admissions, serum albumin and previous treatment with hemodialysis showed a negative impact on several dimensions of HRQL, but depressive symptoms, alexithymia and particularly anxious symptoms were the main determinants of the variability of HRQL in DP patients. We did not obtain a significant relationship between HRQL and the locus of control or the coping strategies. CONCLUSIONS: Among patients undergoing DP, anxiety, depression and alexithymia are important determinants of HRQL and they should be considered both in the evaluation and the treatment of this population of patients. PMID- 21270921 TI - Page kidney Doppler ultrasound. PMID- 21270922 TI - Lactic acidosis and linezolid-induced pancytopaenia. PMID- 21270923 TI - Another patient with a natural history of diabetic nephropathy: current situation and means of prevention. PMID- 21270924 TI - Hydrothorax in peritoneal dialysis: a rare complication. PMID- 21270925 TI - Severe acute hypokalaemia secondary to voriconazole. Uncommon pharmacological causes of hypokalaemia. PMID- 21270926 TI - Extracapillary glomerulonephritis type I with the coexistence of positive anti GBM and p-ANCA antibodies. PMID- 21270927 TI - Late venous thrombosis of renal allograft: two cases with different treatment and outcome. PMID- 21270928 TI - Antisynthetase syndrome without myositis secondary to AA amyloidosis: a non described association. PMID- 21270929 TI - Cytomegalovirus colitis. PMID- 21270930 TI - Methanol poisoning. Evolution of blood levels with high-flux haemodialysis. PMID- 21270931 TI - Acute renal failure due to oxalate crystal deposition and enteric hyperoxaluria. PMID- 21270932 TI - Foetal hyper-echogenic colon as an early sign of cystinuria. PMID- 21270933 TI - Acute renal failure as a presentation of an aortocaval fistula associated with abdominal aortic aneurism. PMID- 21270934 TI - Cinacalcet in the treatment of hypercalcaemia and control of hyperparathyroidism due to ectopic parathyroid glands. PMID- 21270936 TI - Pregabalin in treatment-refractory fibromyalgia. AB - CONTEXT: Fibromyalgia is a chronic musculoskeletal pain disorder. The pain can be intractable and may not respond to commonly-used treatments, such as tricyclic antidepressants and opioids. OBJECTIVES: To evaluate pregabalin response in the subset of patients with fibromyalgia whose pain had been judged refractory to other treatments. METHODS: Patients had previously participated in a controlled trial of pregabalin and had moderate to severe pain despite treatment with gabapentin, a tricyclic antidepressant, and a third medication (e.g., other anticonvulsants, opioid, selective serotonin reuptake inhibitors, tramadol). Flexible-dose pregabalin 150-600 mg/day was added for 3-month treatment cycles, each followed by 3- to 28-day pregabalin "drug holiday" that lasted until a relapse occurred. Pain intensity was measured using the visual analogue scale of the Short-Form McGill Pain Questionnaire completed at baseline, the end of each 3 month treatment period and at the relapse visit. Analysis was at 15 months (after 5 cycles). RESULTS: In total, 25 patients were included and 19 completed the 15 month analysis period. At baseline, 88% were receiving >=1 pain medication. Pregabalin 150-600 mg/day was associated with statistically significant, clinically meaningful pain reduction during each treatment cycle. Pain quickly returned to baseline levels during the "drug holidays" in a median time of 2-4 days. Somnolence (n=5) and dizziness (n=4) were the most common adverse events. CONCLUSIONS: These results suggest that pregabalin may be beneficial in patients with fibromyalgia who have had an unsatisfactory response to treatment with other medications. PMID- 21270935 TI - An intercalation mechanism as a mode of action exerted by psychotropic drugs: results of altered phospholipid substrate availabilities in membranes? AB - Patients respond differently to psychotropic drugs, and this is currently a controversial theme among psychiatrists. The effects of 16 psychotropics on cell membrane parameters have been reported. These drugs belong to three major groups used in therapeutic psychiatry: antipsychotics, antidepressants, and anxiolytic/hypnotics. Human platelets, lacking dopamine (D(2)) receptors (proposed targets of most psychotropics), have been used as a cell model. Here we discuss the effects of these drugs on three metabolic phenomena and also results from Langmuir experiments. Diazepam, in contrast to the remaining drugs, had negligible effects on metabolic phenomena and had no effects in Langmuir experiments. Psychotropic drugs may work through intercalation in membrane phospholipids. It is possible that the fluidity of membranes, rich in essential fatty acids, the content being influenced by diet, could be a contributing factor to the action of psychotropics. This might in turn explain the observed major differences in therapeutic response among patients. PMID- 21270937 TI - Glycolipid-Dependent, Protease Sensitive Internalization of Pseudomonas aeruginosa Into Cultured Human Respiratory Epithelial Cells. AB - Internalization of PAK strain Pseudomonas aeruginosa into human respiratory epithelial cell lines and HeLa cervical cancer cells in vitro was readily demonstrable via a gentamycin protection assay. Depletion of target cell glycosphingolipids (GSLs) using a glucosyl ceramide synthase inhibitor, P4, completely prevented P. aeruginosa internalization. In contrast, P4 treatment had no effect on the internalization of Salmonella typhimurium into HeLa cells. Internalized P. aeruginosa were within membrane vacuoles, often containing microvesicles, between the bacterium and the limiting membrane. P. aeruginosa internalization was markedly enhanced by target cell pretreatment with the exogenous GSL, deacetyl gangliotetraosyl ceramide (Gg(4)). Gg(4) binds the lipid raft marker, GM1 ganglioside. Target cell pretreatment with TLCK, but not other (serine) protease inhibitors, prevented both P. aeruginosa host cell binding and internalization. NFkB inhibition also prevented internalization. A GSL-containing lipid-raft model of P. aeruginosa host cell binding/internalization is proposed. PMID- 21270938 TI - Insights into the development and treatment of cardiovascular disease: a role for animal models. PMID- 21270939 TI - Cortical brain regions associated with color processing: an FMRI study. AB - To clarify whether the neural pathways concerning color processing are the same for natural objects, for artifacts objects and for non-objects we examined brain responses measured with functional magnetic resonance imaging (FMRI) during a covert naming task including the factors color (color vs. black&white (B&W)) and stimulus type (natural vs. artifacts vs. non-objects). Our results indicate that the superior parietal lobule and precuneus (BA 7) bilaterally, the right hippocampus and the right fusifom gyrus (V4) make part of a network responsible for color processing both for natural objects and artifacts, but not for non objects. When color objects (both natural and artifacts) were contrasted with color non-objects we observed activations in the right parahippocampal gyrus (BA 35/36), the superior parietal lobule (BA 7) bilaterally, the left inferior middle temporal region (BA 20/21) and the inferior and superior frontal regions (BA 10/11/47). These additional activations suggest that colored objects recruit brain regions that are related to visual semantic information/retrieval and brain regions related to visuo-spatial processing. Overall, the results suggest that color information is an attribute that can improve object recognition (behavioral results) and activate a specific neural network related to visual semantic information that is more extensive than for B&W objects during object recognition. PMID- 21270940 TI - Comparison of the DiagCor GenoFlow Human Papillomavirus Array Test and Roche Linear Array HPV Genotyping Test. AB - Persistent infection of high-risk (HR) human papillomavirus (HPV) infection has been widely associated with cervical cancer. Monitoring HPV infection is therefore an important step against cervical cancer development. The DiagCor GenoFlow Human Papillomavirus Array Test (GenoFlow) is a novel HPV test based on PCR and "Flow-through" hybridization that can identify 33 HPV subtypes in 3 hours. In the present study, the GenoFlow Test was evaluated by comparing the genotyping results of 100 samples with Roche Linear Array HPV Genotyping Test (LA). The tests showed good agreement in detection of HPV-positive samples (concordance rate=95%, Cohen's Kappa=0.896), with good agreement in detection of HR HPVs (Cohen's Kappa=0.876). The GenoFlow Test showed high sensitivity (95%), high specificity (95%), low false positive rate (3.33%) and low false negative rate (7.50%). In conclusion, the novel GenoFlow Test showed comparable clinical performance to LA test, and offers advantages of reduction in turnaround time and manpower. PMID- 21270941 TI - Cervical artery dissection: emerging risk factors. AB - Cervical artery dissection (CAD) represents an increasingly recognized cause of stroke and the most common cause of ischemic stroke in young adults. Many factors have been identified in association with CAD such as primary disease of arterial wall (fibrodysplasia) and other non-specific diseases related to CAD like Ehlers Danlos-syndrome IV, Marfan's syndrome, vessel tortuosity. Moreover, an underlying arteriopathy which could be in part genetically determined, has been suspected. The rule of emerging risk factors for CAD such as recent respiratory tract infection, migraine and hyperhomocysteinemia are still a matter of research. Other known risks factors for CAD are major head/neck trauma like chiropractic maneuver, coughing or hyperextension injury associated to car. We examined emerging risks factors for CAD detected in the last years, as CAD pathogenesis is still not completely understood and needs further investigations. PMID- 21270943 TI - Features of Neurotoxicity on Brain CT of Acutely Intoxicated Unconscious Patients. AB - Diagnostic imaging is a valuable device in clinical management of poisoned patients presenting to emergency units in a comatose state. Some toxic agents have adverse effects on the central nervous system (CNS). Non-contrast computed tomography (CT) of the brain, as an available diagnostic method with a high resolution, can provide useful information about structural disturbances of unconscious patients with suspected drug or chemical intoxication. The authors would describe various presentations of toxic substances detected on the brain CT scans of ten patients with acute intoxication. While non-specific, CT findings of low-attenuation lesions in the basal ganglia, infarctions in young patients, or diffuse edema should raise suspicion for poisoning or overdose. PMID- 21270942 TI - Glycoxidative stress and cardiovascular complications in experimentally-induced diabetes: effects of antioxidant treatment. AB - Diabetes mellitus (DM) is a common metabolic disease, representing a serious risk factor for the development of cardiovascular complications, such as coronary heart disease, peripheral arterial disease and hypertension. Oxidative stress (OS), a feature of DM, is defined as an increase in the steady-state levels of reactive oxygen species (ROS) and may occur as a result of increased free radical generation and/or decreased anti-oxidant defense mechanisms. Increasing evidence indicates that hyperglycemia is the initiating cause of the tissue damage in DM, either through repeated acute changes in cellular glucose metabolism, or through long-term accumulation of glycated biomolecules and advanced glycation end products (AGEs). AGEs are formed by the Maillard process, a non-enzymatic reaction between ketone group of the glucose molecule or aldehydes and the amino groups of proteins that contributes to the aging of proteins and to the pathological complications of DM. In the presence of uncontrolled hyperglycemia, the increased formation of AGEs and lipid peroxidation products exacerbate intracellular OS and results in a loss of molecular integrity, disruption in cellular signaling and homeostasis, followed by inflammation and tissue injury such as endothelium dysfunction, arterial stiffening and microvascular complications. In addition to increased AGE production, there is also evidence of multiple pathways elevating ROS generation in DM, including; enhanced glucose auto-oxidation, increased mitochondrial superoxide production, protein kinase C dependent activation of NADPH oxidase, uncoupled endothelial nitric oxide synthase (eNOS) activity, increased substrate flux through the polyol pathway and stimulation of eicosanoid metabolism. It is, therefore, not surprising that the correction of these variables can result in amelioration of diabetic cardiovascular abnormalities. A linking element between these phenomena is cellular redox imbalance due to glycoxidative stress (GOS). Thus, recent interest has focused on strategies to prevent, reverse or retard GOS in order to modify the natural history of diabetic cardiovascular abnormalities. This review will discuss the links between GOS and diabetes-induced cardiovascular disorders and the effect of antioxidant therapy on altering the development of cardiovascular complications in diabetic animal models. PMID- 21270944 TI - Experimental models of abdominal aortic aneurysms. AB - Despite being a leading cause of death in the West, the pathophysiology of abdominal aortic aneurysms (AAA) is still incompletely understood. Pharmacotherapy to reduce the growth of small AAAs is limited and techniques for repairing aneurysms continue to evolve. Experimental models play a key role in AAA research, as they allow a detailed evaluation of the pathogenesis of disease progression. This review focuses on in vivo experimental models, which have improved our understanding of the potential mechanisms of AAA development and contributed to the advancement of new treatments. PMID- 21270945 TI - Ro 15-4513 Antagonizes Alcohol-Induced Sedation in Mice Through alphabetagamma2 type GABA(A) Receptors. AB - Ethyl alcohol (ethanol) has many molecular targets in the nervous system, its potency at these sites being low compared to those of sedative drugs. This has made it difficult to discover ethanol's binding site(s). There are two putative binding sites at gamma-aminobutyric acid (GABA) type A receptor subtypes for the proposed ethanol antagonist Ro 15-4513, the established gamma2 subunit-dependent benzodiazepine site and the recently reported delta subunit-dependent Ro 15 4513/ethanol binding site. Here, we aimed at clarifying the in vivo role of Ro 15 4513 at these two sites. We found that the antagonism of ethanol actions by Ro 15 4513 in wildtype mice was dependent on the test: an open field test showed that light sedation induced by 1.5-1.8 g/kg ethanol was sensitive to Ro 15-4513, whereas several tests for ethanol-induced anxiolytic effects showed that the ethanol-induced effects were insensitive to Ro 15-4513. Antagonism of ethanol induced sedation by Ro 15-4513 was unaffected in GABA(A) receptor delta subunit knockout mice. By contrast, when testing the GABA(A) receptor gamma2 subunit F77I knock-in mouse line (gamma2I77 mice) with its strongly reduced affinity of the benzodiazepine sites for Ro 15-4513, we found that the ethanol-induced sedation was no longer antagonized by Ro 15-4513. Indeed, gamma2I77 mice had only a small proportion of high-affinity binding of [(3)H]Ro 15-4513 left as compared to wildtype mice, especially in the caudate-putamen and septal areas, but these residual sites are apparently not involved in ethanol antagonism. In conclusion, we found that Ro 15-4513 abolished the sedative effect of ethanol by an action on gamma2 subunit-dependent benzodiazepine sites. PMID- 21270946 TI - In vitro assessment of developmental neurotoxicity: use of microelectrode arrays to measure functional changes in neuronal network ontogeny. AB - Because the Developmental Neurotoxicity Testing Guidelines require large numbers of animals and is expensive, development of in vitro approaches to screen chemicals for potential developmental neurotoxicity is a high priority. Many proposed approaches for screening are biochemical or morphological, and do not assess function of neuronal networks. In this study, microelectrode arrays (MEAs) were used to determine if chemical-induced changes in function could be detected by assessing the development of spontaneous network activity. MEAs record individual action potential spikes as well as groups of spikes (bursts) in neuronal networks, and activity can be assessed repeatedly over days in vitro (DIV). Primary cultures of rat cortical neurons were prepared on MEAs and spontaneous activity was assessed on DIV 2, 6, 9, 13, and 20 to determine the in vitro developmental profile of spontaneous spiking and bursting in cortical networks. In addition, 5 MUM of the protein kinase C inhibitor bisindolylmaleamide-1 (Bis-1) was added to MEAs (n = 9-18) on DIV 5 to determine if changes in spontaneous activity could be detected in response to inhibition of neurite outgrowth. A clear profile of in vitro activity development occurred in control MEAs, with the number of active channels increasing from 0/MEA on DIV 2 to 37 +/- 5/MEA by DIV 13; the rate of increase was most rapid between DIV 6 and 9, and activity declined by DIV 20. A similar pattern was observed for the number of bursting channels, as well as the total number of bursts. Bis-1 decreased the number of active channels/MEA and the number of bursting channels/MEA. Burst characteristics, such as burst duration and the number of spikes in a burst, were unchanged by Bis-1. These results demonstrate that MEAs can be used to assess the development of functional neuronal networks in vitro, as well as chemical-induced dysfunction. PMID- 21270947 TI - The Gender of Face Stimuli is Represented in Multiple Regions in the Human Brain. AB - Face perception in humans is mediated by activation in a network of brain areas. Conventional univariate fMRI data analysis has not localized differential responses to viewing male as compared with viewing female faces within this network. We tested whether we could detect neural response patterns specific to viewing male vs. female faces in 40 participants. Replicating earlier work, face stimuli evoked activation in the core (inferior occipital gyrus, IOG; fusiform gyrus, FG; and superior temporal sulcus, STS), as well as extended (amygdala, inferior frontal gyrus, IFG; insula, INS; and orbitofrontal cortex, OFC) regions of the face network. Multivariate pattern classification of activity within these regions revealed successful decoding of gender information, significantly above chance, in the IOG, FG, STS, IFG, INS, and OFC, but not in the amygdala. Multiple control regions indicated that this result might be restricted to face-responsive regions. Our findings suggest that gender information is distributed across the face network and is represented in the core regions that process invariant facial features, as well as the extended regions that process changeable aspects of faces. PMID- 21270948 TI - Intraoperative switch to a temporal surgical approach in 23- and 25-gauge microcannula-based sutureless transconjunctival vitrectomy. AB - PURPOSE: To illustrate a surgical method in which the infusion port during a three-port pars plana vitrectomy is moved intraoperatively from the traditional infra-temporal location and placed supra-nasally, thus permitting a temporal surgical approach to better tackle superior and inferior vitreoretinal pathology. METHODS: Description of surgical technique. RESULTS: When the location of the vitreoretinal pathology and/or the patient's anatomy prevents adequate visualization or surgical access and/or the instrument flexibility precludes sufficient maneuvering of the eyeball, a temporal approach to the vitrectomy may be employed by utilizing the interchangeable microcannulas of 23- and 25-gauge vitrectomy systems. The infusion port is dis-inserted from the traditional infra temporal microcannula and reaffixed in the supra-nasal microcannula. The surgeon, the operating microscope, and the foot pedals are then adjusted to a temporal orientation, and the instruments inserted through the temporally placed microcannulas. CONCLUSIONS: The flexibility of interchangeable microcannulas in 23- and 25-gauge PPV systems permits intraoperative switching between superior and temporal surgical sites to better manage posterior segment pathology. PMID- 21270949 TI - Effects of acetazolamide on infantile nystagmus syndrome waveforms: comparisons to contact lenses and convergence in a well-studied subject. AB - AIM: To determine if acetazolamide, an effective treatment for certain inherited channelopathies, has therapeutic effects on infantile nystagmus syndrome (INS) in a well-studied subject, compare them to other therapies in the same subject and to tenotomy and reattachment (T&R) in other subjects. METHODS: Eye-movement data were taken using a high-speed digital video recording system. Nystagmus waveforms were analyzed by applying an eXpanded Nystagmus Acuity Function (NAFX) at different gaze angles and determining the Longest Foveation Domain (LFD). RESULTS: Acetazolamide improved foveation by both a 59.7% increase in the peak value of the NAFX function (from 0.395 to 0.580) and a 70% broadening of the NAFX vs Gaze Angle curve (the LFD increased from 20 degrees to 34 degrees ). The resulting U-shaped improvement in the percent NAFX vs Gaze Angle curve, varied from ~60% near the NAFX peak to over 1000% laterally. The therapeutic improvements in NAFX from acetazolamide (similar to T&R) were intermediate between those of soft contact lenses and convergence, the latter was best; for LFD improvements, acetazolamide and contact lenses were equivalent and less effective than convergence. Computer simulations suggested that damping the central oscillation driving INS was insufficient to produce the foveation improvements and increased NAFX values. CONCLUSION: Acetazolamide resulted in improved-foveation INS waveforms over a broadened range of gaze angles, probably acting at more than one site. This raises the question of whether hereditary INS involves an inherited channelopathy, and whether other agents with known effects on ion channels should be investigated as therapy for this condition. PMID- 21270950 TI - Osteogenic predifferentiation of human bone marrow-derived stem cells by short term mechanical stimulation. AB - It is commonly accepted that bone marrow-derived stem cells (BMSCs) have to be expanded in vitro, but a prolonged time in culture decreases their multilineage potential. Mechanical and biological stimuli have been used to improve their osteogenic potential. While long-term stimulation has been shown to improve osteogenic differentiation, it remains to be seen whether short-term stimulation is also sufficient.We investigated the influence of 24 hours' cyclic loading (0.05Hz, 4kPa) on gene expression of human BMSCs in three-dimensional fibrin-DMEM constructs (n=7) in a compression bioreactor using DNA-array technology. Expression of the following genes showed a significant increase after mechanical stimulation: 2.6-fold osteopontin (OPN) and integrin-beta1 (ITGB1), 2.2-fold transforming growth factor-beta-receptor 1 (TGF-beta-R1) and 2.4-fold SMAD5 expression, compared to controls without mechanical stimulation (p<0.05 each). Platelet-derived growth factor-alpha (PDGF-alpha ) and annexin-V were also significantly overexpressed, the mechanical stimulation resulting in a 1.8-fold and 1.6-fold expression (p<0.05).Cells were identified as osteoblast precursors with a high proliferative capacity. Given the identical in-vitro environment for both groups, the increase in gene expression has been interpreted as a direct influence of cyclic mechanical stimulation on osteogenic differentiation. It may be postulated that short-term mechanical stimulation results in an improved osseous integration of tissue engineered grafts in bone defect healing. PMID- 21270951 TI - Malignant pigmented villonodular synovitis in the knee - report of a case with rapid clinical progression. AB - Malignant pigmented villonodular synovitis (PVNS) (or malignant giant cell tumor of tendon sheath (GCTTS) is an extremely rare condition defined as a malignant lesion occurring with concomitant or previously documented PVNS at the same site. To date, only less than 20 cases have been reported in English literatures. We report a case of malignant PVNS in the knee in a 56-year-old woman with unpredictable rapid progression. This case raised a caution that when atypical components in specimens of recurrent benign PVNS are detected, even if low-grade or tiny, both pathologists and surgeons should consider the risk of malignant PVNS, which could display aggressive clinical progression. PMID- 21270952 TI - Patella Infera in an HIV Positive Patient Following Total Knee Arthroplasty. AB - A lowering of the patella after total knee arthroplasty is accompanied by pain and a restriction of the range of motion. With its etiology being unclear at present, a multifactorial genesis is under discussion. For the first time, we present a case report describing an HIV infection as a possible cause of patella infera.A 54-year-old HIV-positive woman developed patella infera (Insall-Salvati ratio 0.6) with a painful restriction of motion 18 months after implantation of a bicondylar surface prosthesis. By changing to a partially coupled endoprosthesis, distalization of the joint line and partial patellar resection, the patient was free of symptoms with a ROM of 0 degrees /0 degrees /110 degrees .All risk factors known from the literature could be excluded in this case, so that the presence of an HIV infection has to be discussed as a possible cause. PMID- 21270953 TI - Traditional bonesetters and contemporary orthopaedic fracture care in a developing nation: historical aspects, contemporary status and future directions. AB - In developing nations such as Nigeria, where there is a shortage of surgeons formally trained in fracture care, many of the injured seek care from traditional bonesetters. We conducted a qualitative study of fracture care in two settings in Enugu, Nigeria: The National Orthopaedic Hospital Enugu (NOHE) and a traditional bonesetter practice. Primary assessment measures at the NOHE included evaluations of the structure and process of fracture care according to the Orthopaedic Trauma Association's Level 1 Trauma Center Requirements. Further, we conducted interviews of NOHE patients and hospital staff. We also observed fracture care at a traditional bonesetter practice. We observed the traditional care process and interviewed both bonesetters and patrons of the bonesetter practice.Although the NOHE does not qualify for certification as a Level 1 Trauma Center; the hospital does provide quality care. Our observations suggest a tension between Western and indigenous musculoskeletal practices. We propose that bonesetters not only be taught certain injury management techniques but also be incorporated into the Nigerian healthcare scheme. Bonesetters fill a void created by the severe lack of surgeons and further; bonesetters are primarily located in rural areas where they best care for underserved communities. In an integrated scheme, bonesetters would manage fractures for which they can achieve acceptable outcomes, referring others to local hospitals. An integrated model of fracture care is applicable in all developing countries where bonesetters perform a large proportion of fracture care. PMID- 21270954 TI - Treated Hypertension has No Influence on the Efficacy of Alendronate in the Therapy of Postmenopausal Osteoporosis: A Non-Randomized, Non-Blind, Controlled Prospective Study. AB - Changes in hormone metabolism during menopause are involved in the development of osteoporosis and arterial hypertension. A mutual influence of these two clinical pictures is evident on the basis of pathophysiological factors.In this study, we investigated whether a drug therapy of hypertension influences the efficacy of a bisphosphonate (alendronate) in the treatment of postmenopausal osteoporosis. For this purpose, 60 female patients were enrolled in the study, 30 of them on drug treatment for hypertension in addition to requiring treatment for osteoporosis, while the control group was only suffering from osteoporosis.Bone density was measured at the start of the study and 6 months after therapy (QCT).A significant increase in bone density was demonstrated in both groups, while a difference between the groups could not be seen.Treated arterial hypertension does not have a negative influence on the treatment of postmenopausal osteoporosis with alendronate. Rather, the concomitant treatment of these two clinical pictures would appear to make sense, in order to reduce morbidity and mortality. PMID- 21270955 TI - Reconstructing the knee joint mechanism from kinematic data. AB - The interpretation of joint kinematics data in terms of displacements is a product of the type of movement, the measurement technique and the underlying model of the joint implemented in optimization procedures. Kinematic constraints reducing the number of degrees of freedom (DOFs) are expected to compensate for measurement errors and noise, thus, increasing the reproducibility of joint angles. One approach already successfully applied by several groups approximates the healthy human knee joint as a compound hinge joint with minimal varus/valgus rotation. Most of these optimizations involve an orthogonality constraint. This contribution compares the effect of a model with and without orthogonality constraint on the obtained joint rotation angles. For this purpose, knee joint motion is simulated to generate kinematic data without noise and with normally distributed noise of varying size. For small noise the unconstrained model provides more accurate results, whereas for larger noise this is the case for the constrained model. This can be attributed to the shape of the objective function of the unconstrained model near its minimum. PMID- 21270956 TI - Pivotal role of anterior cingulate cortex in working memory after traumatic brain injury in youth. AB - In this fMRI study, the functions of the anterior cingulate cortex (ACC) were studied in a group of adolescents who had sustained a moderate to severe traumatic brain injury (TBI). A spatial working memory task with varying working memory loads, representing experimental conditions of increasing difficulty, was administered. In a cross-sectional comparison between the patients and a matched control group, patients performed worse than Controls, showing longer reaction times and lower response accuracy on the spatial working memory task. Brain imaging findings suggest a possible double-dissociation: activity of the ACC in the TBI group, but not in the Control group, was associated with task difficulty; conversely, activity of the left sensorimotor cortex (lSMC) in the Control group, but not in the TBI group, was correlated with task difficulty. In addition to the main cross-sectional study, a longitudinal study of a group of adolescent patients with moderate to severe TBI was done using fMRI and the same spatial working memory task. The patient group was studied at two time-points: one time point during the post-acute phase and one time-point 12 months later, during the chronic phase. Results indicated that patients' behavioral performance improved over time, suggesting cognitive recovery. Brain imaging findings suggest that, over this 12-month period, patients recruited less of the ACC and more of the lSMC in response to increasing task difficulty. The role of ACC in executive functions following a moderate to severe brain injury in adolescence is discussed within the context of conflicting models of the ACC functions in the existing literature. PMID- 21270957 TI - The role of mathematical modelling in guiding the science and economics of malaria elimination. AB - Unprecedented efforts are now underway to eliminate malaria from many regions. Despite the enormous financial resources committed, if malaria elimination is perceived as failing it is likely that this funding will not be sustained. It is imperative that methods are developed to use the limited data available to design site-specific, cost-effective elimination programmes. Mathematical modelling is a way of including mechanistic understanding to use available data to make predictions. Different strategies can be evaluated much more rapidly than is possible through trial and error in the field. Mathematical modelling has great potential as a tool to guide and inform current elimination efforts. Economic modelling weighs costs against characterised effects or predicted benefits in order to determine the most cost-efficient strategy but has traditionally used static models of disease not suitable for elimination. Dynamic mathematical modelling and economic modelling techniques need to be combined to contribute most effectively to ongoing policy discussions. We review the role of modelling in previous malaria control efforts as well as the unique nature of elimination and the consequent need for its explicit modelling, and emphasise the importance of good disease surveillance. The difficulties and complexities of economic evaluation of malaria control, particularly the end stages of elimination, are discussed. PMID- 21270958 TI - Nicotinamide-independent asymmetric bioreduction of CC-bonds via disproportionation of enones catalyzed by enoate reductases. AB - The asymmetric bioreduction of activated CC-bonds catalyzed by a single flavoprotein was achieved via direct hydrogen transfer from a sacrificial 2-enone or 1,4-dione as hydrogen donor without requirement of a nicotinamide cofactor. Due to its simplicity, this system has clear advantages over conventional FAD recycling systems. PMID- 21270959 TI - Visualization of interaction between inorganic nanoparticles and bacteria or fungi. AB - PURPOSE: The objective of the present investigation was to evaluate the morphologic characteristics of self-assemblies of diamond (nano-D), silver (nano Ag), gold (nano-Au), and platinum (nano-Pt) nanoparticles with Staphylococcus aureus (bacteria) and Candida albicans (fungi), to determine the possibility of constructing microorganism-nanoparticle vehicles. METHODS: Hydrocolloids of individual nanoparticles were added to suspensions of S. aureus and C. albicans. Immediately after mixing, the samples were inspected by transmission electron microscopy. RESULTS: Visualization of the morphologic interaction between the nanoparticles and microorganisms showed that nano-D, which are dielectrics and exhibit a positive zeta potential, were very different from the membrane potentials of microorganisms, and uniformly surrounded the microorganisms, without causing visible damage and destruction of cells. All metal nanoparticles with negative zeta potential had cell damaging properties. Nano-Ag showed the properties of self-organization with the cells, disintegrating the cell walls and cytoplasmic membranes, and releasing a substance (probably cytoplasm) outside the cell. Arrangement of nano-Au with microorganisms did not create a system of self organization, but instead a "noncontact" interaction between the nanoparticles and microorganisms was observed to cause damage to fungal cells. Nano-Pt caused both microorganisms to release a substance outside the cell and disintegrated the cytoplasmic membrane and cell wall. CONCLUSION: Nano-Ag, nano-Au, and nano-Pt (all metal nanoparticles) are harmful to bacteria and fungi. In contrast, nano-D bind closely to the surface of microorganisms without causing visible damage to cells, and demonstrating good self-assembling ability. The results indicate that both microorganisms could be used as potential carriers for nano-D. PMID- 21270960 TI - Local gene delivery via endovascular stents coated with dodecylated chitosan plasmid DNA nanoparticles. AB - Development of efficacious therapeutic strategies to prevent and inhibit the occurrences of restenosis after percutaneous transluminal coronary angioplasty is critical for the treatment of cardiovascular diseases. In this study, the feasibility and efficiency of stents coated with dodecylated chitosan-plasmid DNA nanoparticles (DCDNPs) were evaluated as scaffolds for localized and prolonged delivery of reporter genes into the diseased blood vessel wall. Dodecylated chitosan-plasmid DNA complexes formed stable positive charged nanospheres with mean diameter of approximately 90-180 nm and zeta potential of +28 +/- 3 mV. As prepared DCDNPs were spray-coated on stents, a thin layer of dense DCDNPs was successfully distributed onto the metal struts of the endovascular stents as demonstrated by scanning electron microscopy. The DCDNP stents were characterized for the release kinetics of plasmid DNA, and further evaluated for gene delivery and expression both in vitro and in vivo. In cell culture, DCDNP stents containing plasmid EGFP-C1 exhibited high level of GFP expression in cells grown on the stent surface and along the adjacent area. In animal studies, reporter gene activity was observed in the region of the artery in contact with the DCDNP stents, but not in adjacent arterial segments or distal organs. The DCDNP stent provides a very promising strategy for cardiovascular gene therapy. PMID- 21270961 TI - Pegylation of poly(gamma-benzyl-L-glutamate) nanoparticles is efficient for avoiding mononuclear phagocyte system capture in rats. AB - Poly(gamma-benzyl-L-glutamate) (PBLG) derivatives are synthetic polypeptides for preparing nanoparticles with well controlled surface properties. The aim of this paper was to investigate the biodistribution of pegylated PBLG in rats. For this purpose, nanoparticles were prepared by a nanoprecipitation method using mixtures of different PBLG derivates, including a pegylated derivate to avoid mononuclear phagocyte system uptake. The morphology, size distribution, and surface charge of the nanoparticles were investigated as a function of the amount of polymer employed for the preparation. Moderately polydispersed nanoparticles (polydispersity index less than 0.2) were obtained. Their size increased with polymer concentration. The zeta potential values were negative whatever the formulations. The availability of polyethylene glycol chains on the nanoparticles' surface was confirmed by measuring the decrease in bovine serum albumin adsorption. For in vivo distribution studies, pegylated and nonpegylated nanoparticles were prepared with polymer mixtures containing PBLG-fluorescein isothiocyanate and imaged by fluorescence microscopy to measure their accumulation in liver and spleen tissues of rats after intravenous administration. Injection of stealth formulations resulted in negligible fluorescence in liver and spleen compared with nonpegylated formulations, which suggests that these nanoparticles are promising candidates as a stealth-type long circulating drug carrier system and could be useful for active targeting of drugs while reducing systemic side effects. PMID- 21270963 TI - Cerebrovascular diseases: perspectives for the next decade. PMID- 21270962 TI - Andrographolide nanoparticles in leishmaniasis: characterization and in vitro evaluations. AB - Andrographolide (AG) is a diterpenoid lactone isolated from the leaves of Andrographis paniculata. AG is a potent and low-toxicity antileishmanial agent. Chemotherapy applications of AG are, however, seriously constrained because of poor bioavailability, short plasma half-life, and inappropriate tissue localization. Nanoparticulation of AG was therefore envisaged as a possible solution. AG nanoparticles (AGnp) loaded in 50:50 poly(DL-lactide-co-glycolic acid) were prepared for delivery into the monocyte-macrophage cells infested with the amastigote form of leishmanial parasite for evaluation in the chemotherapy of leishmaniasis. Particle characteristics of AGnp were optimized by proportionate application of a stabilizer, polyvinyl alcohol (PVA). Physicochemical characterization of AGnp by photon correlation spectroscopy exhibited an average particle size of 173 nm and zeta potential of -34.8 mV. Atomic force microscopy visualization revealed spherical nanoparticles with a smooth surface. Antileishmanial activity was found to be significant for the nanoparticle preparation with 4% PVA (IC50) 34 MUM) in about one-fourth of the dosage of the pure compound AG (IC50) 160 MUM). AGnp therefore have significant potential to target the infested macrophage cells and prove valuable in chemotherapy of neglected tropical diseases such as leishmaniasis. PMID- 21270964 TI - Gender differentials in the impact of parental death: Adolescent's sexual behaviour and risk of HIV infection in rural South Africa. AB - Using data from a longitudinal surveillance study from rural South Africa, we investigated the odds of sexual debut, pregnancy and HIV infection of 15- to 19 year-old adolescents by parental survival. Using descriptive statistics and logistic regressions, we examine the relative risk of orphans compared with non orphans to have ever had sex, being pregnant and being HIV infected, adjusting for age, sex, socio-economic status, education, being employed and residency. Of 8274 adolescents, 42% were orphaned (one or both parents died). Over 80% of adolescents remained in school, but orphans were significantly more likely to lag behind in grade for age. Female adolescent maternal (aOR 1.32, 95% CI 1.071.62), paternal (aOR 1.26, 95% CI 1.061.49) and dual (aOR 1.37, 95% CI 1.051.78) orphans were significantly more likely than non-orphaned females to have ever had sex; among males it was only paternal (aOR 1.27, 95% CI 1.051.53) orphans. Maternal (aOR 1.49, 95% CI 1.032.15) and dual (aOR 1.74, 95% CI 1.112.73) female orphans relative to non-orphaned females were significantly more likely to be HIV infected; male paternal (aOR 3.41, 95% CI 1.378.46) and dual (aOR 3.54, 95% CI 1.0611.86) orphans had over three-fold the odds of being infected. There was strong evidence that death of mother for girls was associated with increased vulnerability to earlier sexual debut and HIV infection, while fathers appeared to play a significant role in both their son's and daughter's lives. PMID- 21270966 TI - Rh isoimmunization in Sub-Saharan Africa indicates need for universal access to anti-RhD immunoglobulin and effective management of D-negative pregnancies. AB - Transplacental or fetomaternal hemorrhage (FMH) may occur during pregnancy or at delivery and lead to immunization to the D antigen if the mother is Rh-negative and the baby is Rh-positive. This can result in hemolytic disease of the fetus and newborn (HDFN) in subsequent D-positive pregnancies. The aim of this study is to highlight the challenges associated with the effective management and prevention of Rh alloimmunization among Rh-negative women in Sub-Saharan Africa. In most Sub-Saharan African countries, there is poor and sometimes no alloimmunization prevention following potentially sensitizing events and during medical termination of pregnancy in Rh-negative women. Information about previous pregnancies and termination are often lacking in patients' medical notes due to poor data management. These issues have made the management of Rh-negative pregnancy a huge challenge. Despite the fact that the prevalence of Rh-negative phenotype is significantly lower among Africans than Caucasians, Rh alloimmunization remains a major factor responsible for perinatal morbidity in Sub-Saharan Africa and may result in the compromise of the woman's obstetric care due to the unaffordability of anti-D immunoglobulin. There is the urgent need for the implementation of universal access to anti-D immunoglobulin for the Rh negative pregnant population in Africa. Anti-D immunoglobulin should be available in cases of potentially sensitizing events such as amniocentesis, cordocentesis, antepartum hemorrhage, vaginal bleeding during pregnancy, external cephalic version, abdominal trauma, intrauterine death and stillbirth, in utero therapeutic interventions, miscarriage, and therapeutic termination of pregnancy. There is also the need for the availability of FMH measurements following potentially sensitizing events. The low-cost acid elution method, a modification of the Kleihauer-Betke (KB) test, can become a readily available, affordable, and minimum alternative to flow cytometric measurement of FMH. Knowledge of anti-D prophylaxis among obstetricians, biomedical scientist, midwives, traditional birth attendants, pharmacists, and nurses in Africa needs to be improved. This will facilitate quality antenatal and postnatal care offered to Rh-negative pregnant population and improve perinatal outcomes. PMID- 21270965 TI - Clinical trials and progress with paclitaxel in ovarian cancer. AB - Paclitaxel is a front-line agent for ovarian cancer chemotherapy, along with the platinum agents. Derived from the Pacific yew tree, Taxus brevifolia, paclitaxel has covered significant ground from the initial discovery of its antineoplastic properties to clinical applications in many forms of human cancers, including ovarian cancer. Although much has been published about the unique mechanism of action of this agent, several issues remain to be resolved. Finding the appropriate dosage schedule for paclitaxel in chemo-naive and recurrent ovarian cancer, defining the role of paclitaxel in maintenance chemotherapy, and elucidating the mechanisms of taxane resistance are areas of intense research. Newer forms of taxanes are being manufactured to avoid troublesome adverse effects and to improve clinical efficacy. These issues are reviewed in detail in this paper with an emphasis on clinically relevant evidence-based information. PMID- 21270967 TI - Molecular mechanisms of hyperglycemia and cardiovascular-related events in critically ill patients: rationale for the clinical benefits of insulin therapy. AB - Newly recognized hyperglycemia frequently occurs with acute medical illness, especially among patients with cardiovascular disease (CVD). Hyperglycemia has been linked to increased morbidity and mortality in critically ill patients, especially when it is newly recognized. Increased rates of reinfarction, rehospitalization, major cardiovascular events, and death in CVD patients have also been found. An expanding body of literature describes the benefits of normalizing hyperglycemia with insulin therapy in hospitalized patients. This article reviews several underlying mechanisms thought to be responsible for the association between hyperglycemia and poor outcomes in critically ill patients and those with cardiovascular events, as well as the biologic rationale for the benefits of insulin therapy in these patients. PMID- 21270968 TI - Evaluation and Management of Posttraumatic Cognitive Impairments. AB - Psychiatrists are increasingly called upon to care for individuals with cognitive, emotional, and behavioral disturbances after TBI, especially in settings serving military service personnel and Veterans. In both the early and late post-injury periods, cognitive impairments contribute to disability among persons with TBI and are potentially substantial sources of suffering for persons with TBI and their families. In this article, the differential diagnosis, evaluation, and management of posttraumatic cognitive complaints is reviewed. The importance of pre-treatment evaluation as well as consideration of non-cognitive contributors to cognitive problems and functional limitations is emphasized first. The course of recovery after TBI, framed as a progression through posttraumatic encephalopathy, is reviewed next and used to anchor the evaluation and treatment of posttraumatic cognitive impairments in relation to injury severity as well as time post-injury. Finally, pharmacologic and rehabilitative interventions that may facilitate cognitive and functional recovery at each stage of posttraumatic encephalopathy are presented. PMID- 21270969 TI - Clinical and cytogenetic characteristics of choroidal melanoma in Vietnamese Asians. AB - PURPOSE: To report the clinical and cytogenetic characteristics of choroidal melanoma in Vietnamese Asians. METHODS: In three Vietnamese Asians with choroidal melanoma, transscleral fine needle aspiration biopsy (FNAB) was performed immediately before iodine-125 brachytherapy. Biopsy was examined for cytopathology, fluorescence in situ hybridization (FISH) for the centromere of chromosome 3, and analyzed by 250K whole genome Mapping Array and U133 plus 2.0 Expression Array. RESULTS: Three Vietnamese Asian men (50, 59, and 30 years of age) with clinical diagnosis of choroidal melanoma and no evidence of metastasis had FNAB immediately before Iodine-125 brachytherapy. Cytopathology showed heavily pigmented cells suggestive of or consistent with melanoma. Mapping Array and Expression Array revealed cytogenetic aberrations and gene expression profiles characteristic of choroidal melanoma. One patient (Case 2) with chromosome 3 loss and chromosome 8q gain developed biopsy-proven liver metastasis three years after brachytherapy. One patient (Case 1) with chromosome 6p, 9q and 17q gain and a second patient (Case 3) with 6p, 8q and 9q gains and losses in 6q and 8p have had no evidence of metastasis three years after brachytherapy. CONCLUSIONS: In this series of Vietnamese Asians with heavily pigmented choroidal melanoma, the clinical characteristics, cytogenetic aberrations and gene expression profiles were similar to characteristics in other ethnic/racial groups and the cytogenetic aberration of chromosome 3 loss was associated with the development of liver metastasis. PMID- 21270970 TI - In vitro ultraviolet-induced damage in human corneal, lens, and retinal pigment epithelial cells. AB - PURPOSE: The purpose was to develop suitable in vitro methods to detect ocular epithelial cell damage when exposed to UV radiation, in an effort to evaluate UV absorbing ophthalmic biomaterials. METHODS: Human corneal epithelial cells (HCEC), lens epithelial cells (HLEC), and retinal pigment epithelial cells (ARPE 19) were cultured and Ultraviolet A/Ultraviolet B (UVA/UVB) blocking filters and UVB-only blocking filters were placed between the cells and a UV light source. Cells were irradiated with UV radiations at various energy levels with and without filter protections. Cell viability after exposure was determined using the metabolic dye alamarBlue and by evaluating for changes in the nuclei, mitochondria, membrane permeability, and cell membranes of the cells using the fluorescent dyes Hoechst 33342, rhodamine 123, calcein AM, ethidium homodimer-1, and annexin V. High-resolution images of the cells were taken with a Zeiss 510 confocal laser scanning microscope. RESULTS: The alamarBlue assay results of UV exposed cells without filters showed energy level-dependent decreases in cellular viability. However, UV treated cells with 400 nm LP filter protection showed the equivalent viability to untreated control cells at all energy levels. Also, UV irradiated cells with 320 nm LP filter showed lower cell viability than the unexposed control cells, yet higher viability than UV-exposed cells without filters in an energy level-dependent manner. The confocal microscopy results also showed that UV radiation can cause significant dose-dependent degradations of nuclei and mitochondria in ocular cells. The annexin V staining also showed an increased number of apoptotic cells after UV irradiation. CONCLUSIONS: The findings suggest that UV-induced HCEC, HLEC, and ARPE-19 cell damage can be evaluated by bioassays that measure changes in the cell nuclei, mitochondria, cell membranes, and cell metabolism, and these assay methods provide a valuable in vitro model for evaluating the effectiveness of UV-absorbing ophthalmic biomaterials, including contact lenses and intraocular lenses. PMID- 21270971 TI - Small interfering RNA targeting of S phase kinase-interacting protein 2 inhibits cell proliferation of pterygium fibroblasts. AB - PURPOSE: Fibroblast cell proliferation is major reason for recurrence of pterygia. In the present study, we investigated if small interfering RNA (siRNA) mediated gene silencing of S phase-kinase-interacting protein 2 (Skp2) can be employed to inhibit protein 27 kinase inhibition protein 1 (p27(kip1)) down regulation in pterygium fibroblast cells (PFC) in vitro and in vivo. METHODS: A plasmid containing transgenes encoding Skp2 siRNA was used to decreasing the high constitutive levels of Skp2 protein in PFC and normal fibrboblast cells (NFC) in vitro and in vivo which can lead to consequent degradation of p27(kip1). Cell proliferation and viability were investigated using cell counts, 59 bromodeoxyuridine incorporation (BrdU assay) and tetrazolium reduction (MTT assay). RESULTS: Infection of PFC and NFC with Skp2 siRNA resulted in significant inhibition of cell proliferation and metabolic activity in vitro. Immunoflurescence showed decreased levels of Skp2 and increased levels of p27(kip1) in pSkp2 siRNA infected cells, but not in plasmid and uninfected cells. CONCLUSIONS: Skp2 siRNA inhibited the cell proliferation of PFC in vitro and in vivo. PMID- 21270972 TI - Predictors of implantable cardioverter-defibrillator use in patients with ischemic cardiomyopathy. AB - OBJECTIVES: The objective of this study was to identify and examine ICD utilization in a large group of eligible coronary artery bypass grafting (CABG) patients with impaired left ventricular function. METHODS: We conducted a retrospective study of ICD eligible patients who had previously undergone CABG surgery between March 1, 1995 and June 30, 2008 at a single tertiary care institution. All patients with a pre-operative left ventricular ejection fraction (LVEF) <= 35% were considered ICD eligible. The events of interest were ICD implantation and mortality, based on administrative data linkage. RESULTS: A total of 1,169 out of 11,931 CABG patients operated on during the same period had LVEF <= 35% and were defined as ICD eligible (mean EF = 27.3% +/- 6.4%). Of these eligible patients, only 101 received an ICD during follow-up (8.6%). The median time to implant was 255 days (14-1078). The single variable that independently predicted eventual ICD implantation was a history of arrhythmia (OR = 7.4; CI, 4.4-12.2). The variables that predicted not having an ICD implanted during follow up included the need for urgent CABG (OR = 0.5; CI, 0.2-0.9), age > 70 years (OR = 0.5; CI, 0.3-0.8), female gender (OR = 0.2; CI,0.1-0.6), or having chronic obstructive lung disease (OR = 0.5; CI,0.3-0.8). As a data validation step, a series of consecutive patient records were reviewed (n=80) showing that fewer than 23% underwent appropriate follow-up EF assessment post revascularization. CONCLUSION: Our findings suggest that CABG patients with ischemic cardiomyopathy have low rates of ICD utilization. This is particularly evident among females and elderly patients. Furthermore our data suggests that few patients post revascularization undergo follow-up EF assessment despite current guidelines likely contributing to the low rates of ICD utilization. PMID- 21270973 TI - [2nd Argentine consensus on the treatment of bipolar disorders 2010]. AB - The consensus guidelines of Argentine experts in the treatment of bipolar disorders are the result of three days of work of the 9 main local experts under the organization of the Argentine Association of Mood Disorders (ASATHU). This work is an update of the guidelines published on this journal in 2006. It was adopted a mixed criterion for its preparation: all the recent data of the evidence medicine based published until now were discussed and were balanced with the knowledge acquired from clinical experience of the local experts on the bipolar field. It presents general recommendations and suggested therapeutic sequences for maintenance, manic/hypomanic or mixed episode and depressive episode treatments. Bipolar disorders have been divided according to the international classifications in type I and II; with or without rapid cycling. This work also includes a series of recommendations for early and differential diagnosis of bipolar disorders. PMID- 21270974 TI - Simple synthesis of tetra-n-butylphosphonium benzimidazolate/benzimidazole mixture as a thermally stable proton conductor. AB - A mixture of tetra-n-butylphosphonium benzimidazolate and benzimidazole is readily prepared as a proton conductive liquid having thermal stability up to 300 degrees C. PMID- 21270975 TI - Integrated SPPS on continuous-flow radial microfluidic chip. AB - A novel integrated continuous-flow microfluidic system was designed and fabricated for solid phase peptide synthesis (SPPS) using conventional reactants. The microfluidic system was composed of a glass-based radial reaction chip, a diffluent chip, amino acid feeding reservoirs and continuous-flow reagent pathways. A tri-row cofferdam-fence structure was designed for solid phase supports trapping. Highly cross-linked, porous and high-loading 4 (hydroxymethyl)phenoxymethyl polystyrene (HMP) beads were prepared for microfluidic SPPS. The transfer losses, hazardous handling and time-consuming processes in traditional peptide cleavage steps were avoided by being replaced with the on-chip cleavage treatment. Six peptides from an antibody affinity peptide library against beta-endorphin with different lengths and sequences were obtained simultaneously on the constructed continuous-flow microfluidic system within a short time. This microfluidic system is automatic, integrated, effective, low-cost, recyclable and environment-friendly for not only SPPS but also other solid phase chemical syntheses. PMID- 21270976 TI - Catalytic asymmetric 1,3-dipolar cycloaddition of N-unprotected 2-oxoindolin-3 ylidene derivatives and azomethine ylides for the construction of spirooxindole pyrrolidines. AB - Asymmetric 1,3-dipolar cycloaddition of N-unprotected 2-oxoindolin-3-ylidene with azomethine ylides for the construction of spirooxindole-pyrrolidines bearing four contiguous stereogenic centers has been achieved with AgOAc/TF-BiphamPhos complexes for the first time. This catalytic system performance well over a broad scope of substrates, providing the synthetically useful adducts in high yields and excellent diastereoselectivities and moderate enantioselectivities. PMID- 21270977 TI - Wurtzite Cu2ZnSnS4 nanocrystals: a novel quaternary semiconductor. AB - A new wurtzite phase Cu(2)ZnSnS(4) was discovered and the corresponding nanocrystals have been successfully synthesized. They have been characterized in detail and showed the photoelectric response, which demonstrated their potential in the application of photovoltaic devices. PMID- 21270978 TI - Plaster-trodes for electro-analytical sensing via electrodeposition with electro catalytic metals. AB - We demonstrate that commercially available plasters (band aids), usually used for wound healing, can be electrolytically modified with a range of electro-catalytic metals for analytical sensing purposes. These 'Plaster-trodes' consist of a mesh type surface which have star-shaped type microelectrodes of ~150 micron radius in a hexagonal pattern which are separated from its nearest neighbours by ~1250 microns with interlinking connections between each microelectrode which are generally electrochemically active resulting in micro-band-type connections. Proof-of-concept is shown where the Plaster-trode is electrolytically modified with palladium for the sensing of hydrazine and nickel for the direct oxidation of ethanol. Given the low cost of the Plaster-trode which can be readily modified with electro-catalytic metals, we expect this new electrode to be widely utilised in electro-analysis. PMID- 21270979 TI - A novel paradigm for potential drug-targets discovery: quantifying relationships of enzymes and cascade interactions of neighboring biological processes to identify drug-targets. AB - Target discovery is the most crucial step in a modern drug discovery development. Our objective in this study is to propose a novel paradigm for a better discrimination of drug-targets and non-drug-targets with minimum disruptive side effects under a biological pathway context. We introduce a novel metric, namely, "pathway closeness centrality", for each gene that jointly considers the relationships of its neighboring enzymes and cross-talks of biological processes, to evaluate its probability of being a drug-target. This metric could distinguish drug-targets with non-drug-targets. Genes with lower pathway closeness centrality values are prone to play marginal roles in biological processes and have less lethality risk, but appear to have tissue-specific expressions. Compared with traditional metrics, our method outperforms degree, betweenness and bridging centrality under the human pathway context. Analysis of the existing top 20 drugs with the most disruptive side-effects indicates that pathway closeness centrality is an appropriate index to predict the probability of the occurrence of adverse pharmacological effects. Case studies in prostate cancer and type 2 diabetes mellitus indicate that the pathway closeness centrality metric could distinguish likely drug-targets well from human pathways. Thus, our method is a promising tool to aid target identification in drug discovery. PMID- 21270980 TI - Evaluation of tip-enhanced Raman spectroscopy for characterizing different virus strains. AB - Tip-enhanced Raman spectroscopy (TERS) is a highly sensitive spectroscopic technique which combines the advantages of optical spectroscopy with the requirements needed for the characterization of biological nano-structures. In this study, TERS was used to investigate the applicability of this spectroscopic technique for the detection of different virus strains like avipoxvirus and adeno associated virus. TERS spectra obtained from different particles of the same virus strain show variations in relative peak intensities and positions of most spectral features observed. These spectral variations were higher for the larger avipoxvirus particles (?~350 nm) than for the smaller adeno-associated virus particles (?~26 nm). PMID- 21270981 TI - Peptidomimetic bond formation by DNA-templated acyl transfer. AB - The efficiencies of DNA-templated acyl transfer reactions between a thioester modified oligonucleotide and a series of amine and thiol based nucleophiles are directly compared. The reactivity of the nucleophile, reaction conditions (solvent, buffer, pH) and linker length all play important roles in determining the efficiency of the transfer reaction. Careful optimisation of the system enables the use of DNA-templated synthesis to form stable peptide-like bonds under mild aqueous conditions close to neutral pH. PMID- 21270982 TI - Simultaneous sample washing and concentration using a "trapping-and-releasing" mechanism of magnetic beads on a microfluidic chip. AB - Simultaneous washing and concentration of functionalized magnetic beads in a complex sample solution were demonstrated by applying a rotational magnetic actuation system to a microfluidic chip under continuous flow conditions. The rotation of periodically arranged small permanent magnets close to the fluidic channel carrying a magnetic bead suspension allows trapping and releasing of the beads along the fluidic channel in a periodical manner. Each trapping and releasing event resembles one washing cycle. A purification efficiency of magnetic beads out of a mixed magnetic and non-magnetic bead sample solution of 83+/-4% at a flow rate of 0.5 uL min(-1), and a magnetic bead recovery or concentration efficiency of 91+/-5% were achieved using a flow rate of 0.2 uL min(-1). The detection performance of the device was experimentally evaluated with two different bioassays, using either streptavidin-coated magnetic beads in combination with biotinylated fluorescent isothiocyanate (FITC), or a mouse antigen (Ag)-antibody (Ab) system. PMID- 21270983 TI - Ionic strength and pH reversible response of visible and near-infrared fluorescence of graphene oxide nanosheets for monitoring the extracellular pH. AB - The visible and near-infrared (vis-NIR) fluorescence of graphene oxide nanosheets (GO) shows a reversible and sensitive response to ionic strength and pH, in particular a linear physiological pH dependence for monitoring extracellular pH evolution during growth and metabolism of normal and cancer cells. PMID- 21270984 TI - Phosphate mediated biomimetic synthesis of tetrahydroisoquinoline alkaloids. AB - A one-pot synthesis of tetrahydroisoquinoline alkaloids in a phosphate buffer has been achieved, and a reaction mechanism proposed. The utilisation of mild reaction conditions readily afforded a range of isoquinolines, including norcoclaurine. PMID- 21270985 TI - Cleavable beta-cyclodextrin nanocapsules incorporating Gd(III)-chelates as bioresponsive MRI probes. AB - Perthiolated beta-cyclodextrin-based nanocapsules incorporating diaquo Gd(III) complexes represent a promising new type of bioresponsive MRI contrast agent, showing a pronounced relaxivity change upon degradation in a reducing environment. PMID- 21270986 TI - Pre-nucleation dynamics of organic molecule self-assembly investigated by PEEM. AB - Pre-nucleation dynamics, nucleation and templated self-assembly of a conjugated planar aromatic molecule are investigated by photoemission electron microscopy (PEEM). The high resolution of individual molecular layers in PEEM, in combination with a numerical simulation, reveals the dynamic behaviour of molecules during the pre-nucleation deposition period and their temperature dependence. The in situ deposition of p-sexiphenyl (6P) molecules on Cu(110) and Cu(110) 2 * 1-O surfaces in ultrahigh vacuum, when monitored by PEEM in real-time allows (a) layer densities, (b) meta-stable layer filling by 6P molecules, (c) dynamic surface redistributions during layer filling and (d) critical density spontaneous dewetting to be accurately measured. The comparison of 6P deposited on Cu(110) to Cu(110) 2 * 1-O enables temperature dependent 6P nucleation processes on Cu(110) to be elucidated from PEEM. The interplay between energetically stable molecular arrangements and kinetically stabilised arrangements is shown to dominate the pre- and post-nucleation processes. In combination with additional data obtained during post-nucleation deposition times, such as surface diffusion anisotropies and nucleation energies, it is concluded that the pre-requisite for 6P nucleation, in a lying down orientation, is the formation of a double tilted layer with at least one layer being meta stable. PMID- 21270987 TI - Fe(z+) (z = 1-6) generation from ferrocene. AB - Multiply charged iron atoms up to Fe(6+) with few carbon ions were produced from ferrocene under intense femtosecond laser fields. The production of Fe(4+) and Fe(5+) from ferrocene requires much less laser intensity than theoretically expected for iron atoms. The dissociation of ferrocene and the generation mechanism of multiply charged iron atoms are discussed. PMID- 21270988 TI - Raman scattering by confined optical phonons in Si and Ge nanostructures. AB - A microscopic theory of the Raman scattering based on the local bond polarizability model is presented and applied to the analysis of phonon confinement in porous silicon and porous germanium, as well as nanowire structures. Within the linear response approximation, the Raman shift intensity is calculated by means of the displacement-displacement Green's function and the Born model, including central and non-central interatomic forces. For the porous case, the supercell method is used and ordered pores are produced by removing columns of Si or Ge atoms from their crystalline structures. This microscopic theory predicts a remarkable shift of the highest-frequency of first-order Raman peaks towards lower energies, in comparison with the crystalline case. This shift is discussed within the quantum confinement framework and quantitatively compared with the experimental results obtained from porous silicon samples, which were produced by anodizing p--type (001)-oriented crystalline Si wafers in a hydrofluoric acid bath. PMID- 21270989 TI - Graphene based gene transfection. AB - Graphene as a star in materials research has been attracting tremendous attentions in the past few years in various fields including biomedicine. In this work, for the first time we successfully use graphene as a non-toxic nano-vehicle for efficient gene transfection. Graphene oxide (GO) is bound with cationic polymers, polyethyleneimine (PEI) with two different molecular weights at 1.2 kDa and 10 kDa, forming GO-PEI-1.2k and GO-PEG-10k complexes, respectively, both of which are stable in physiological solutions. Cellular toxicity tests reveal that our GO-PEI-10k complex exhibits significantly reduced toxicity to the treated cells compared to the bare PEI-10k polymer. The positively charged GO-PEI complexes are able to further bind with plasmid DNA (pDNA) for intracellular transfection of the enhanced green fluorescence protein (EGFP) gene in HeLa cells. While EGFP transfection with PEI-1.2k appears to be ineffective, high EGFP expression is observed using the corresponding GO-PEI-1.2k as the transfection agent. On the other hand, GO-PEI-10k shows similar EGFP transfection efficiency but lower toxicity compared with PEI-10k. Our results suggest graphene to be a novel gene delivery nano-vector with low cytotoxicity and high transfection efficiency, promising for future applications in non-viral based gene therapy. PMID- 21270990 TI - A bio-inspired design strategy: Organization of tryptophan-appended naphthalenediimide into well-defined architectures induced by molecular interactions. AB - The chemistry of molecular assemblies involves weak yet complex non-covalent interactions, and the molecular organization of the pi-conjugated material is crucial in determining the performance of an organic electronic device. Herein we demonstrate a bioinspired design strategy to tune the self-assembly of naphthalenediimides (NDIs) by minute structural variations, pi-pi stacking, hydrophobic interactions and metal interactions. We address some of the limitations associated with current design strategies, such as restriction to a specific molecular interaction or the difficulty in controlling the assembly due to several complicated intermolecular interactions. Hydrophobic-effect-induced J type aggregation and sodium-interaction-induced H-type aggregation of tryptophan appended NDIs have been illustrated. (1)H NMR spectra further reveal sodium cation-pi interactions in tryptophan-appended NDIs, while NMR and IR spectroscopic studies confirm the structural variations associated with the molecular assembly. In summary, the molecular organization has been successfully transformed from nanospheres to particles, nanobelts, fibers and fractals. Such drastic changes in the morphology are clear and striking evidence of the importance of non-trivial weak non-covalent forces. PMID- 21270991 TI - Fabrication of biomimetic superhydrophobic surfaces inspired by lotus leaf and silver ragwort leaf. AB - Inspired by the self-cleaning lotus leaf and silver ragwort leaf, here we demonstrate the fabrication of biomimetic superhydrophobic fibrous mats via electrospinning polystyrene (PS) solution in the presence of silica nanoparticles. The resultant electrospun fiber surfaces exhibited a fascinating structure with the combination of nano-protrusions and numerous grooves due to the rapid phase separation in electrospinning. The content of silica nanoparticles incorporated into the fibers proved to be the key factor affecting the fiber surface morphology and hydrophobicity. The PS fibrous mats containing 14.3 wt% silica nanoparticles showed a stable superhydrophobicity with a water contact angle as high as 157.2 degrees , exceeding that (147 degrees ) of the silver ragwort leaf and approaching that (160 degrees ) of the lotus leaf. The superhydrophobicity was explained by the hierarchical surfaces increasing the surface roughness which trapped more air under the water droplets that fell on the fibers. PMID- 21270992 TI - Online transient isotachophoresis concentration by the pseudo-terminating electrolyte buffer for the separation of DNA-aptamer and its thrombin complex in poly(methyl methacrylate) microchip. AB - Online automatic transient isotachophoresis concentration of DNA-aptamer and its thrombin complex by using one kind of pseudo-terminating electrolyte buffer in a cross-channel poly(methyl methacrylate) microchip is reported. Sample injection, transient concentration and separation were done continuously and controlled by a sequential voltage switching program, time-consuming steps and complicated chip design were not required. Peak resolution between DNA-aptamer and its thrombin complex was influenced by this novel pseudo-terminating electrolyte buffer, which was prepared by the addition of chemical component with slow mobility into the same buffer as leading electrolyte buffer. 1100-fold signal enhancement of thrombin complex was achieved by this transient isotachophoresis on a standard cross-form microchip. The concentration effect or standing time of transient isotachophoresis was proved to be influenced by the concentration of leading electrolyte ion and the concentration of pseudo-terminating electrolyte buffer ion (glycine). The transient concentration was followed by on-chip nondenaturing gel electrophoresis in methylcellulose solution for the size-based separation. The detection limit, taken as the lowest thrombin concentration at threefold S/N, was determined to be 0.5 amol in mass by this method. PMID- 21270993 TI - Phase evolution in lithium disilicate glass-ceramics based on non-stoichiometric compositions of a multi-component system: structural studies by 29Si single and double resonance solid state NMR. AB - The crystallization mechanism of a high-strength lithium disilicate glass-ceramic in the SiO(2)-Li(2)O-P(2)O(5)-Al(2)O(3)-K(2)O-(ZrO(2)) system, used as restorative dentistry material, has been examined on the basis of quantitative (29)Si magic angle spinning (MAS) and (29)Si{(7)Li} rotational echo double resonance (REDOR) NMR spectroscopy. Crystallization occurs in two stages: near 650 degrees C a significant fraction of the Q(3) units disproportionates into crystalline Li(2)SiO(3) and Q(4) units. Upon further annealing of this glass ceramic to 850 degrees C the crystalline Li(2)SiO(3) phase reacts with the Q(4) units of the softened residual glass matrix, resulting in the crystallization of Li(2)Si(2)O(5). The NMR experiments provide detailed insight into the spatial distribution of the lithium ions suggesting the absence of lithium ion clustering in the residual glassy component of the final glass-ceramic. (31)P MAS-NMR spectra indicate that phosphate acts as a lithium ion scavenger, resulting in the predominant formation of orthophosphate (P(0)) and some pyrophosphate (P(1)) groups. Crystallization of Li(2)SiO(3) occurs concomitantly with the formation of a highly disordered Li(3)PO(4) phase as evidenced from strong linebroadening effects in the (31)P MAS-NMR spectra. Well-crystallized Li(3)PO(4) is only formed at annealing conditions resulting in the formation of crystalline lithium disilicate. These results argue against an epitaxial nucleation process previously proposed in the literature and rather suggest that the nucleation of both lithium metasilicate and lithium disilicate starts at the phase boundary between the disordered lithium phosphate phase and the glass matrix. PMID- 21270994 TI - Label-free aptamer-based sensors for L-argininamide by using nucleic acid minor groove binding dyes. AB - The nucleic acid minor groove binding dyes, DAPI and Hoechst 33258, were for the first time used in label-free aptamer-based sensors for L-argininamide. The synergy binding effect results in the enhancement of fluorescence of dyes. The method for detection of L-argininamide is simple, rapid and cost-effective. PMID- 21270995 TI - Continuous flow organometallic catalysis: new wind in old sails. AB - Organometallic catalysis is a powerful tool for chemical synthesis, and the field still evolves at a high pace continuously improving efficiencies and opening up new possibilities. However, despite increasing use in specialty and fine chemical production issues of catalyst recovery still hamper broader application and prevent tapping the full potential of this technology on industrial scale. Even though scientists have tackled this problem for decades practicable methods remained scarce. In this contribution we analyse the major challenges of performing organometallic catalysis in continuous flow from a conceptual point of view, and exemplify for recently developed concepts based on near- and supercritical fluids how the integration of molecular and engineering principles can offer new solutions to this persistent problem. PMID- 21270996 TI - Absolute quantification of transferrin in blood samples of harbour seals using HPLC-ICP-MS. AB - Harbour seals (Phoca vitulina) are bio-indicators for the assessment of their habitat and environmental changes. Besides population parameters and trends (survival, age structure, sex ratio), the individual health status represents a further important parameter for this assessment. The health status of seals is a complex and vague term, determined by a wide range of diagnostic parameters. Quantities of important blood proteins such as transferrin (Tf), as well as altered distribution patterns of its glycoforms, are frequently used as biomarkers in clinical diagnosis. Within this context Tf quantities and a varying pattern of its glycoforms are used as indicator for e.g. certain liver diseases, which also represents one of the most frequently observed pathological indication in harbour seals of the North Sea. Currently, most assay based quantification methods for Tf are limited since they often provide only information regarding the total Tf concentration rather than information of its different glycoforms. Due to a lack of suitable seal Tf antibodies also the application of more specific antibody based approaches is not possible. Within this background a new approach for the absolute quantification of the iron-transport protein Tf in the blood of harbour seals using its characteristic iron content and HPLC-ICP-MS detection is described. Method validation was performed using a certified human serum reference material (ERM-DA470K/IFCC). A Tf concentration of 2.33 +/- 0.03 g L(-1) (sum of all quantified glycoforms) has been calculated, which is in good agreement with the certified total Tf concentration of 2.35 +/- 0.08 g L(-1), confirming the accuracy of the proposed analytical method. Finally, different seal samples were analysed to demonstrate the suitability of the procedure for the quantification of Tf in real samples as well as to observe modified glycoform patterns. Compared to our previous studies for the first time it was possible to quantify the serum Tf baseline reference range for male (1.42-2.35 g L(-1)) and female German North Sea seals (1.93-2.74 g L(-1)) as well as a CDT level of 0.00 0.10 g L(-1), respectively, which provides valuable further diagnostic information regarding the health status of these specific marine mammals. Compared to assay based quantification approaches the proposed technique indicates great potential to obtain comparable and traceable absolute quantitative results, which are in particular important for long term investigations. This absolute quantification is based on an accurate, traceable element standard, while assay based approaches often show variations depending on the kit quality or changing activities of the used antibodies. PMID- 21270997 TI - Disorder in BaThF6--refinement of anharmonic displacement parameters from high pressure single-crystal X-ray diffraction data. AB - The structure of BaThF(6) has been investigated as a function of temperature and pressure with single-crystal X-ray diffraction using synchrotron radiation. The compound crystallizes in the tysonite structure, space group P6(3)/mmc (a = 4.296(1) A and c = 7.571(1) A at ambient conditions). It is stable at least down to 150 K and up to 4 GPa. In the entire range of pressures and temperatures studied here, the compound is characterized by a high degree of disorder, both on the cationic and anionic positions. Despite the different valence states and sizes, both cations occupy the same crystallographic site in the ideal tysonite structure. The cationic disorder is described by two alternative approaches. The first model corresponds to a split-atom position model in which Ba(2+) is maintained on a special position with site symmetry 6m2, while Th(4+) is slightly displaced from the respective position. In the second model, both cations are maintained on the ideal position and anharmonic displacement parameters using a tensor of third order are introduced. Anharmonic displacement parameters have been refined from high-pressure single-crystal X-ray data measured in situ in a diamond anvil cell for the first time. The feasibility and general problems of anharmonic refinements of high-pressure X-ray data are further commented. PMID- 21270998 TI - PBDEs and PCBs in the liver of the St Lawrence Estuary beluga (Delphinapterus leucas): a comparison of levels and temporal trends with the blubber. AB - Due to their lipophilic properties, persistent organic pollutants (POPs) are commonly assessed using the blubber of marine mammals. However, these chemicals are also accumulating in other tissues including the liver. Some pollutants, namely perfluorinated alkyl acids, are found predominately in the liver and blood of marine mammals, and thus monitored in those tissues. This raises the question whether any tissue would represent an identical trend of POPs in the SLE beluga. The current study reports the first temporal trends of PBDEs and PCBs in the liver of 65 SLE belugas. Neither ?7PBDEs nor major individual PBDE-homolog group concentrations showed significant trends between 1993 and 2007. Also, ?32PCBs did not change over years, although, tetra-, penta- and hepta-PCB decreased by 7.1, 6.8 and 8.5%, respectively, in males, whereas tetra-, penta- and octa-PCBs declined by 11, 12 and 12.9%, respectively, in females. In order to compare the distribution of POPs between liver and blubber, a lipid normalised concentration ratio R (blubber/liver) for PBDEs and PCBs was calculated for each individual beluga. For all PBDE and several PCB homolog groups, mean R values were not statistically different from unity indicating that the partitioning of these POPs is governed by the tissue lipid-content. Temporal trends of R ratios of PBDEs and PCBs were also examined. There were generally no significant temporal trends except for PBDEs in males where R increased in average by 12.7 +/- 2.9% yearly. The stratification of the blubber into a metabolically active (inner) and less active layers (outer blubber) may result in a slower response time of the blubber (full depth) than the liver to the recent change of contamination in the environment and explain the time trend differences between both tissues. This study suggests that the liver is more representative of recent exposure to lipophilic contaminants. PMID- 21270999 TI - Photoactivated capture molecule immobilization in plasmonic nanoapertures in the ultraviolet. AB - We demonstrate a photoactivated surface coupling scheme for achieving spatial overlap between biomolecules of interest and optical near field excitation. Using aluminium nanoapertures, we obtained increased coupling efficiency of biotinylated capture probe oligos to the photoactivated surface due to ~3* nanoaperture enhancement of UV light. We further validate DNA sensor functionality via the hybridization of Cy-5 labeled target oligos, with up to 8* fluorescence enhancement obtained from a commercial microarray scanner. This generic photoimmobilization strategy is an essential step to realizing miniaturized plasmon enhanced detection arrays by virtue of localizing capture molecules to the region of plasmonic enhancement. PMID- 21271000 TI - Deformability-based cell classification and enrichment using inertial microfluidics. AB - The ability to detect and isolate rare target cells from heterogeneous samples is in high demand in cell biology research, immunology, tissue engineering and medicine. Techniques allowing label-free cell enrichment or detection are especially important to reduce the complexity and costs towards clinical applications. Single-cell deformability has recently been recognized as a unique label-free biomarker for cell phenotype with implications for assessment of cancer invasiveness. Using a unique combination of fluid dynamic effects in a microfluidic system, we demonstrate high-throughput continuous label-free cell classification and enrichment based on cell size and deformability. The system takes advantage of a balance between deformability-induced and inertial lift forces as cells travel in a microchannel flow. Particles and droplets with varied elasticity and viscosity were found to have separate lateral dynamic equilibrium positions due to this balance of forces. We applied this system to successfully classify various cell types using cell size and deformability as distinguishing markers. Furthermore, using differences in dynamic equilibrium positions, we adapted the system to conduct passive, label-free and continuous cell enrichment based on these markers, enabling off-chip sample collection without significant gene expression changes. The presented method has practical potential for high throughput deformability measurements and cost-effective cell separation to obtain viable target cells of interest in cancer research, immunology, and regenerative medicine. PMID- 21271001 TI - Ischemia/reperfusion injury of primary porcine cardiomyocytes in a low-shear microfluidic culture and analysis device. AB - Ischemia/reperfusion (I/R) injury was induced in primary porcine cardiomyocytes in a low-shear microfluidic culture chip. The chip was capable of sustaining the cardiomyocyte culture and inducing I/R injury by subjecting the cells to periods of hypoxia lasting 3-4 hours followed by normoxia. Mitochondrial membrane potential was assayed using MitoTracker Red to follow mitochondrial depolarization, the earliest stage of apoptosis. Cell adhesion and morphology were also determined simultaneously with fluorescence measurements. Changes in membrane potential were observed earlier than previously reported, with mitochondria becoming depolarized as early as 2 hours into the ischemia period. The cells with depolarized mitochondria were deemed apoptotic. Out of 38-61 cells per time frame, the fraction of apoptotic cells was found to be similar to control samples (3%) at two hours of ischemia, which increased up to 22% at the end of the ischemia period as compared to 0% in the control samples. Morphological analysis of cells showed that 4 hours of ischemia followed by reperfusion produced blebbing cells within 2 hours of restoring oxygen to the chip. This approach is a versatile method for cardiomyocyte stress, and in future work additional analytical probes can be incorporated for a multi-analyte assay of cardiomyocyte apoptosis. PMID- 21271002 TI - A phosphorescent material with high and balanced carrier mobility for efficient OLEDs. AB - A phosphorescent material (Fppy)(2)Ir(dipba) possessing high PL efficiency in the solid state and superior hole/electron transporting property has acted successfully as an efficient neat phosphorescent emitter as well as an excellent host for high-performance PHOLEDs. PMID- 21271003 TI - A luminescent nanoscale metal-organic framework for sensing of nitroaromatic explosives. AB - The first nanoscale luminescent metal-organic framework has been realized for the straightforward and highly sensitive sensing of nitroaromatic explosives in enthanol solution. PMID- 21271004 TI - Bio-electrosprays: from bio-analytics to a generic tool for the health sciences. AB - Electrosprays or electrospraying is a process by which an aerosol is generated between two charged electrodes. This aerosol generation methodology has been known for well over a century, and has undergone exploration in aerosol and materials sciences, to many other areas of research and development. In one such exploration, electrosprays were partnered with mass spectrometry for the accurate characterisation of molecules. This technology now widely referred to as electrospray ionisation mass spectrometry (ESI MS) significantly contributes to molecular analysis and cancer biology to name a few. In fact these findings were recognised by the Chemistry Nobel Committee in 2002, and have catapulted electrosprays to many areas of research and development. In this review, the author wishes to introduce and discuss another such recent discovery, where electrosprays have been investigated for directly handling living cells and whole organisms. Over the past few years these electrosprays now referred to as "bio electrosprays" have undergone rigorous developmental studies both in terms of understanding all the associate physical, chemical and biological sciences for completely assessing their effects, if any on the direct handling of living biological materials. Therefore, the review will bring together all the work that has contributed to fully understanding that bio-electrosprays are an inert technology for directly handling living biological materials, while elucidating some unique features they possess over competing technologies. Hence, demonstrating this approach as a flexible methodology for a wide range of applications spanning bio-analytics, diagnostics to the possible creation of synthetic tissues, for repairing and replacing damaged/ageing tissues, to the targeted and controlled delivery of personalised medicine through experimental and/or medical cells and/or genes. Therefore, elucidating the far reaching ramifications bio-electrosprays have to our health sciences and well-being. PMID- 21271005 TI - Micronutrient supplementation for pulmonary tuberculosis. PMID- 21271006 TI - Short-term risk of cervical intraepithelial neoplasia grades 2 and 3 for women with normal cytology and human papillomavirus infection. AB - OBJECTIVE: To assess the risk of cervical intraepithelial neoplasia grades 2, 3 or higher (CIN 2/3+) for women with normal cytology and concurrent high-risk human papillomavirus infection (HR-HPV). MATERIAL AND METHODS: We examined 2 200 women every 6 months for an average of 9 years. Cervical smears and samples for HPV DNA were obtained at each visit. Absolute risk of subsequent CIN2/CIN3+ was estimated using the Kaplan-Meier method. RESULTS: The absolute risk of CIN2/CIN3+ among HR-HPV-positive women with normal Pap smear results was 1.06% (95%CI, 0.57 2.20), 5 times higher the risk among all women with normal Pap smears (0.20%; 95%CI, 0.12-0.32) but 7 times lower than that for women with HR-HPV infection and LSIL (7.24%; 95%CI, 3.78-15.2). CONCLUSION: Short-term absolute risk of CIN2/3+ after a normal Pap smear with concurrent HR-HPV infection is low (~1%), suggesting that the HR-HPV test has limited utility in short-term clinical decision-making for women with normal cytology. PMID- 21271007 TI - Estimating the cost of treating patients with liver cirrhosis at the Mexican Social Security Institute. AB - OBJECTIVE: To estimate the annual cost of treating patients with cirrhosis at the Mexican Institute of Social Security (IMSS per its abbreviation in Spanish). MATERIAL AND METHODS: The annual cost of treating three stages of cirrhosis (Child-Pugh A, Child-Pugh B and Child-Pugh C) was estimated using micro-costing techniques and medical experts. These results were compared and contrasted with prices reported by IMSS. RESULTS: The annual cost of treatment, in USA dollars, by Child-Pugh stage was: a) micro-costing results: $1110.17 stage A, $549.55 stage B and $348.16 stage C; b) opinion of medical experts: $1 633.64, $6564.04 and $19660.35, respectively; and c) IMSS costs: $4269.00, $16949.63 and $30249.25, respectively. CONCLUSIONS: The cost of treating patients with cirrhosis is considerable, and costs increase as the disease worsens. Cost estimates vary depending on the source of information, and the methodology used. There are discrepancies between the procedures reported in medical records and treatment recommendations by IMSS liver experts. PMID- 21271008 TI - [Use and non-use of pedestrian bridges in Mexico City. The pedestrian perspective]. AB - OBJECTIVE: To analyze the motives for using and not using pedestrian bridges (PB). MATERIAL AND METHODS: A cross-sectional survey was conducted of a sample of pedestrian users and non-users of PB; a logistic regression model was used to analyze the motives for use and non-use. RESULTS: The prevalence of non-use was 50.5 % of 813 surveyed pedestrians; the principal reason to use a PB was safety, and not to use it was "laziness". There were significant differences when analyzing the reason of non-use in the age groups 19 to 36 years, adjusted for education and physical characteristics of the PB ([aOR=1.7; 95 % CI=1.06-2.86] and [ORa.1.9; 95 % CI=1.14-3.33], respectively). CONCLUSIONS: The results of this study allow us to identify important aspects to consider--from the perspective of the pedestrians--when constructing new PB and improving existing PB to increase use in areas with a high risk of pedestrian injuries. PMID- 21271010 TI - [Importance of perceived competition and motivation to the mental health of college athletes]. AB - OBJECTIVE: This research analyzes the direct and indirect relationships among self-motivation, perceived competition and psychological well-being and ill being. MATERIAL AND METHODS: Data from 491 Spanish college students (299 men and 192 women) who practice sports were collected using a cross-sectional design. Statistical analyses were carried out using structural equation modeling. RESULTS: Psychological well-being was directly fostered by perceived competition and indirectly by self- motivation. Furthermore, perceived competition was negatively associated with psychological ill-being. CONCLUSIONS: Perceived competition and self-motivation are important to the psychological well-being of college students and to avoiding ill-being. PMID- 21271009 TI - Surveillance of nosocomial infections in a Mexican community hospital. How are we doing? AB - OBJECTIVE: To compare the nosocomial infection (NI) rate obtained from a retrospective review of clinical charts with that from the routine nosocomial infection surveillance system in a community hospital. MATERIAL AND METHODS: Retrospective review of a randomized sample of clinical charts.Results were compared to standard surveillance using crude and adjusted analyses. RESULTS: A total of 440 discharges were reviewed, there were 27 episodes of NIs among 22 patients. Cumulated incidence was 6.13 NI per 100 discharges. Diarrhea, pneumonia and peritonitis were the most common infections. Predictors of NI by Cox regression analysis included pleural catheter (HR 16.38), entry through the emergency ward, hospitalization in the intensive care unit (HR 7.19), and placement of orotracheal tube (HR 5.54). CONCLUSIONS: Frequency of NIs in this community hospital was high and underestimated. We identified urgent needs in the areas of training and monitoring. PMID- 21271011 TI - [Difficulties in the classification of metabolic syndrome. The example of adolescents in Mexico]. AB - OBJECTIVE: Determine the difference between the National Cholesterol Education Program Adult Treatment Panel (ATPIII) definition of the diagnosis of metabolic syndrome (MS) in Mexican adolescents and that by the International Diabetes Federation (IDF). MATERIAL AND METHODS: We conducted a cross-sectional study of 575 adolescents aged 14 to 16 years using the student's t test, chi square and Spearman correlation. RESULTS: The prevalence of MS was higher by ATPIII (18.6%) than by IDF (8.2%) (p <0.001) and there was a concordance of 41.1%. CONCLUSIONS: There is a statistical difference in the prevalence of MS depending on the definition. PMID- 21271012 TI - [Frequency of respiratory viruses and clinical characteristics in children attending a care center in Mexico City]. AB - OBJECTIVE: To describe the frequency of respiratory viruses and clinical characteristics in children with respiratory signs and symptoms in a tertiary care center in Mexico. MATERIAL AND METHODS: Patients with a clinical diagnosis of respiratory infection and a positive immunofluorescence result (Light Diagnostics) from January 2004 to October 2006 were included. RESULTS: From the 986 nashopharyngeal samples, 138 (14%) were positive by immunofluorescence. The frequency was: 80% RSV, 8% parainfluenza 1, 5% parainfluenza 3, 2% adenovirus, 2% influenza A, 1% parainfluenza 2 and 1% influenza B. CONCLUSIONS: Respiratory viruses were detected in 14% of samples tested. RSV was the most frequently identified virus and was associated with pneumonia and bronchiolitis in children younger than 3 years old. PMID- 21271013 TI - [Government actions for the early detection of breast cancer in Latin America. Future challenges]. AB - Documentary research carried out in 2009 aims to document the regulatory framework and existing programs for the early detection of breast cancer in Latin America and the Caribbean in order to establish the most important challenges for the containment of the epidemic in the region. The governments of the region have developed diverse efforts and initiatives to confront the rise in mortality due to said cause, including early detection, treatment and research strategies. Despite advances in the early detection of breast cancer, the challenge remains to link efforts to ensure continuity of care (diagnostic confirmation, treatment and monitoring) in order to achieve higher efficiency, effectiveness and benefits for women with this disease. PMID- 21271014 TI - [New paradigms and challenges in cervical cancer prevention and control in Latin America]. AB - Cervical cancer continues to be a significant health problem in Latin America. The use of conventional cytology to detect precancerous cervical lesions has had almost no major impact on reducing cervical cancer incidence and mortality rates, which are still high in the region. The availability of new screening tools to detect precancerous lesions provide great opportunities for cervical cancer prevention in the region, as do highly efficacious HPV vaccines able to prevent nearly all lesions associated with HPV-16 and -18 when applied before viral exposure. This paper summarizes the scientific evidence and regional experiences related to: i) the use of HPV testing and visual inspection after the application of acetic acid (VIA) in primary screening and ii) the implementation of adolescent HPV vaccination programs. Finally, we outline a number of recommendations for different resource settings. The feasibility of implementing successful and sustainable national cervical cancer prevention programs in Latin American countries in the region will depend on health priorities and the availability of infrastructure and health personnel--as determined by rigorous local situational analysis. PMID- 21271018 TI - [Operation and performance of the peer-review system]. PMID- 21271020 TI - [Influence of cataract surgical correction on working perception]. AB - PURPOSE: To analyze the benefits after cataract surgery in professional activities. METHODS: A prospective, randomized study was conducted at the Clinical Hospital of the University of Sao Paulo. The patients had cataract surgery by phacoemulsification (PHACO) and by extracapsular extraction (EECP). RESULTS: The sample consisted of 205 patients, 101 of these, submitted to phacoemulsification. The mean age in phacoemulsification group was 68.3 years +/- 9 years and 69.1 years +/- 8.5 years in extracapsular extraction group (p=0.70). The percentage of patients employed in phacoemulsification group was 16.83%, and in the extracapsular extraction group of 13.46%. Most patients who were not employed felt motivated to seek work. Most of the patients increased their productivity at work after surgery, 82.50% in the phacoemulsification group, and 78.60% in the other group (p=0.20). CONCLUSION: Cataract surgery of both techniques has improved the productivity at work and encouraged economically inactive individuals to seek employment. PMID- 21271021 TI - [Evolution and viability of an outpatient surgery center for cataract surgery on a large scale in a university hospital]. AB - PURPOSE: To analyze the number of surgeries performed in outpatient surgical center at a university hospital and to assess its financial viability during and after the interruption of the Cataract National Campaign in 2006. METHODS: Retrospective analytical study between 2005 and 2009 at the Clinical Hospital of the University of Sao Paulo (HC-FMUSP) which evaluated the economic viability of the outpatient surgical center, the number of cataract surgeries performed and the number of surgeons present daily in that unit. RESULTS: It would be necessary to perform at least 400 procedures monthly to ensure the financial viability of the outpatient surgical center. This number was lower than the expected in the years of 2008 and 2009 (average of 370.6 and 390.1 surgeries respectively). The number of cataract fellows decreased from 13 in 2005 to 3 in 2009. CONCLUSION: The main factor for the reduction in the number of cataract surgeries performed in the outpatient surgical center after 2006 was the difficulty of access of the population to the hospital due to restrictions on the development of screening projects. The increased use of the operating rooms by other clinics and the decrease in the admission of new surgeons, made the outpatient surgical center appropriate and viable for the new political-economic reality. PMID- 21271022 TI - Glaucoma anterior chamber morphometry based on optical Scheimpflug images. AB - PURPOSE: To compare the performance of gonioscopy and noncontact morphometry with anterior chamber tomography (High Resolution Pentacam - HR) using optical Scheimpflug images in the evaluation of the anterior chamber angle (ACA). METHODS: Transversal study. 112 eyes from 74 subjects evaluated at the Glaucoma Department, Fluminense Federal University, underwent gonioscopy and Pentacam HR. Using gonioscopy, the ACA was graded using the Shaffer Classification (SC) by a single experienced examiner masked to the Pentacam HR findings. Narrow angle was determined in eyes in which the posterior trabecular meshwork could not be seen in two or more quadrants on non-indentation gonioscopy (SC Grade 2 or less). Pentacam HR images of the nasal and temporal quadrants were evaluated by custom software to automatically obtain anterior chamber measurements, such as: anterior chamber angle (ACA), anterior chamber volume (ACV) and anterior chamber depth (ACD). RESULTS: Based on gonioscopy results, 74 (60.07%) eyes of patients classified as open-angle (SC 3 and 4) and 38 (33.93%) eyes of patients classified as narrow-angle (SC 1 and 2). Noncontact morphometry with Scheimpflug images revealed a mean ACA of 39.20 +/- 5.31 degrees for open-angle and 21.18 +/- 7.98 degrees for narrow-angle. The open-angle group showed significant greater ACV and ACD values when compared to narrow-angle group (ACV of 193 +/- 36 mm3 vs. 90 +/- 25 mm3, respectively, p<0.001; and ACD of 3,09 +/- 0,42 mm vs. 1,55 +/- 0,64 mm, respectively, p<0.0001.). In screening eyes with open-angle and narrow-angle with the Pentacam ACA of 20o (SC Grade 2) using the ROC curves, the analysis showed 52.6% of sensitivity and 100% of specificity. CONCLUSIONS: The Pentacam showed ability in detecting eyes at risk for angle closure analyzing ACV and ACD. PMID- 21271023 TI - [Litigation in ophthalmology: analysis of possible triggers]. AB - PURPOSE: To analyze the possible predisposing factors of lawsuits involving ophthalmologists. METHODS: Retrospective study of 70 lawsuits involving the practice of Ophthalmology. The patient's gender, age, medical and ophthalmic history were reviewed. The eye disorder that generated the prosecution, the pre existing ophthalmic diagnosis, the preoperative exams and the operating room data were also analyzed. The informed consent form, the outcome of the litigation and the value of compensation were recorded. RESULTS: Blindness was reported in 45 (64.3%) of the 70 lawsuits and was the principal eye disorder related to litigation. The pre-existing eye diseases associated with legal claims were: cataracts in 46 (65.7%) lawsuits, refractive errors in 12 (17.1%), ocular trauma in 8 (11.4%), glaucoma in 3 (4.3%) and retinal detachment in 1 (1.4%) lawsuit. The major surgical complications that possibly motivated the patient to sue the ophthalmologist were retinal detachment in 37 (52.8%) lawsuits, poor visual acuity after cataract surgery in 12 (17.1%), corneal disorders following refractive surgery in 8 (11.4%), endophthalmitis in 4 (5.7%), discomfort with refractive prescriptions in 4 (5.7%) and ocular atrophy in 4 (5.7%) lawsuits. Ophthalmic surgery was involved in 94.3% of the 70 prosecutions analyzed. Two or less visits to the ophthalmologist preceding the surgical or refractive event leading to legal dispute were recorded in 67.1% of the lawsuits. A pre-surgical Informed consent form was not used in 63% of the 66 surgical procedures leading to litigation. 62.9% of the lawsuits were unfavorable to the Ophthalmologist and the amount of compensation was less than R$ 50,000 in 72.7% of these legal claims. CONCLUSIONS: Blindness, surgery, retinal detachment, few pre-operative ophthalmic visits and the lack of informed consent forms were possible risk factors associated with lawsuits in the field of Ophthalmology. PMID- 21271024 TI - Incidence of endophthalmitis after cataract surgery (2002-2008) at a Brazilian university-hospital. AB - PURPOSE: To report on the incidence, diagnostic technique, and microbiological features of endophthalmitis at a university-setting in Brazil. METHODS: All cases of presumed postoperative endophthalmitis from 2002 to 2008 at a teaching hospital were included. Main data assessed were: number of cataract surgeries performed, incidence of endophthalmitis, microbiological outcome (aqueous and/or vitreous culture and Gram staining), and antimicrobial susceptibility testing of the positive cases. RESULTS: Seventy-three eyes of 73 patients (43 females and 30 males) developed endophthalmitis after 24,590 cataract surgeries. The incidence decreased from 0.49% in 2003 to 0.17% in 2006 and stabilized afterwards. Coagulase negative Staphylococci (CoNS) and Streptococcus viridans (56.5% and 15%, respectively) were the most common bacterial isolates. Culture and Gram stain were negative in 36.9%. CoNS presented susceptibility rates of 80% sensitivity to oxacillin, 90% to fourth-generation quinolones and 100% to vancomycin. CONCLUSIONS: The rate of endophthalmitis, diagnostic ability of conventional laboratory investigation, microbial isolates and antibiotic susceptibility are in accordance with other findings of the literature. Despite using prophylactic antibiotic drops, it was possible to identify cases that were susceptible to the antibiotics topically applied. PMID- 21271025 TI - Effect of bevel position on the corneal endothelium after phacoemulsification. AB - PURPOSE: To compare the extent of corneal endothelial (CE) cell loss changes in two groups of eyes submitted to phacoemulsification, with the conventional bevel up tip position in one eye and with the bevel-down tip position in the fellow eye. METHODS: This prospective clinical trial comprised 25 patients with bilateral cataracts subjected to lens removal by phacoemulsification with the conventional bevel-up tip position (GI) in one eye and with the bevel-down tip position (GII) in the fellow eye. The nuclei were graded clinically on the basis of hardness. The endothelial cell count (ECC) was evaluated preoperatively and 1, 3 and 6 months postoperatively. Total surgical time, effective ultrasound time and complications were also compared between the groups. Statistical analysis was performed by the Tukey Studentized Range test, with repeated measures for the selected periods. For the other parameters a paired t test was used. Data are presented as mean +/- SD, with the level of significance set at p<=0.05. RESULTS: The mean effective ultrasound time was 8.08 +/- 6.75 seconds in group I and 7.00 +/- 5.75 seconds in GII (P=0.1792) and total surgical time was 10.01 +/- 2.46 minutes in GI and 9.86 +/- 2.17 minutes in GII (p=0.6267), respectively. The paired t test revealed no statistical differences between the groups. Complications were also similar between the groups. Mean endothelial cell count loss was 6.9% in GI and 2.8% in GII at one month; 6.9% in GI and 3.6% in GII at three months and 11.9% in GI and 7.6% in GII at six months postoperatively. Comparison of endothelial cell count (ECC) showed a statistically significant difference between the groups during the postoperative period. CONCLUSION: The conventional bevel-up tip position has a negative effect on corneal endothelial cells compared with the bevel-down position. Since the results of other surgical parameters were similar, the bevel-down tip position should be considered as an option in non-complicated phacoemulsification. PMID- 21271026 TI - New comparative clinical and biometric findings between acute primary angle closure and glaucomatous eyes with narrow angle. AB - PURPOSE: To compare, clinically and biometrically, affected and fellow acute primary angle-closure (APAC) eyes and glaucomatous eyes with narrow angle (NA). METHODS: Comparative case series; 30 patients with APAC and 27 glaucomatous patients with NA were evaluated. Keratometry (K), central corneal thickness (CCT), lens thickness (LT), axial length (AL) and anterior chamber depth (ACD) were measured. Parameters defined as lens posisiton (LP) and relative lens position (RLP) were calculated. RESULTS: Biometric difference between APAC affected and fellow eyes was found only in LP (P=0.046). When fellow eyes were compared to glaucomatous eyes with NA, differences were found in ACD (P=0.009), AL (P=0.010), and LT/AL (P=0.005). The comparison between APAC-affected and glaucomatous eyes with NA showed significant differences in almost all biometric parameters, except for LT (P=0.148) and RLP (P=0.374). We found that the logistic regression model (LRM), built with three parameters (K, CCT and LT/AL), higher than 0.334 could be a reasonable instrument to differentiate APAC eyes from glaucomatous eyes with NA. CONCLUSIONS: This study showed that APAC-affected and fellow eyes have similar biometric features, and glaucomatous eyes with NA have a less crowded anterior segment. The LRM built showed promising results in distinguishing APAC from glaucomatous eyes with NA. PMID- 21271027 TI - [CBO/ALCON teaching method of phacoemulsification: results of Hospital de Olhos do Parana]. AB - PURPOSE: To analyze the results obtained with a new phacoemulsification teaching method in the specialization course of Hospital de Olhos do Parana. METHODS: A retrospective study evaluated the results of a "reversal" method used in the CBO/ALCON teaching program at the Hospital de Olhos do Parana. The method is based on the student progression through five checkpoints starting from the end of the surgery towards the beginning and analysis of intra- and postoperative complications at each one of the checkpoints. RESULTS: Of 84 operated eyes, 77 (91.67%) presented final visual acuity of 20/40 or better. Among the complications, the main one was the posterior capsular rupture and occurred in 11 (13.09%) of 13 (15.48%) eyes with complications. CONCLUSION: The "reversal" teaching method used in the CBO/ALCON teaching program is appropriate to the student, his instructor, as well as to the patient. PMID- 21271028 TI - [Impact of congenital versus acquired monocular vision as self-reported vision]. AB - PURPOSE: When the vision in one eye is preserved (monocular vision) and there is high risk, low prognosis and/or limited resources to the fellow eye surgery, it is unclear if the benefit of binocularity outweighs the reorientation for monocular vision. The goal is to quantify the impact of the quality of vision of both binocular and monocular condition, and in this latter case, between congenital and acquired. METHODS: Patients with visual acuity (VA)>0.5 in each eye underwent a structured questionnaire of 14 questions (VF-14), which the score 0-100 indicates the level of patient satisfaction with their vision, ranging from low to high respectively. Epidemiological data and scores of the four groups were recorded and analyzed statistically. RESULTS: The interview by the VF-14 with 56 subjects revealed that the highest score was similar between controls and patients with congenital monocular vision, and low and intermediate levels were obtained by individuals with acquired monocular vision and bilaterally blind, respectively (p<0.001). The more difficult activities for individuals with acquired monocular vision were to identify small print, recognize people, to distinguish traffic lights and watch TV. CONCLUSION: The study confirmed that the vision loss has an adverse impact on the performance of such activities being higher in congenital than in acquired monocular vision. The data suggest that rehabilitation measures should be considered to improve the quality of vision in intractable diseases, high risk or low prognosis. PMID- 21271029 TI - [Description of the neuropsychomotor and visual development of visually impaired children]. AB - PURPOSE: To assess the neuropsychomotor and visual development of visually impaired children. METHODS: Fourty-five children of both genders were evaluated in a 6-months period. The children were distributed into two study groups: experimental and control. The neuropsychomotor development and visual efficiency were evaluated in the two groups. RESULTS: In the control group, 86.66% of the sample was inappropriate on the coordination behavior, however, all aspects were considered inadequate. The differences among the groups were significant, since p values<0.05 were evidenced in the visual efficiency behavior as well as in the neuropsychomotor development. CONCLUSION: It was observed in the studied sample that the visually impaired were characterized by a global delay in the neuropsychomotor development, mostly in the coordination behavior. PMID- 21271030 TI - [Double Descemet's membrane after penetrating keratoplasty - surgical approach during phacoemulsification: case report]. AB - A case of inadvertent retention of Descemet's membrane after penetrating keratoplasty for Fuchs dystrophy is reported. The challenges to remove it during cataract surgery are commented, as well as a proposal of a new surgical approach. PMID- 21271031 TI - [Conjunctival fibrous histiocytoma simulating atipical pterygium in the Amazon region: case report]. AB - An inedited case in the Brazilian literature of conjunctival fibrous histiocytoma discovered during a wide scale community project accomplished by the team of the Center of Reference in Ophthalmology of the Hospital das Clinicas da Universidade Federal de Goias in the Amazon region is reported. A 38 year-old caucasian woman presented with a vascularized lesion on the medial portion of the bulbar conjunctiva and caruncular region of the right eye with extension for the limbus and invading about 2 mm of the medial cornea resembling a pterygium. Pathologic findings revealed that the lesion was constituted by spindle-shaped cells, with storiform arrangement, and large histocytelike cells. The immunohistochemistry revealed strong positivity for vimentin and the neoplastic cells were negative for AE1/AE3, HMB 45, S 100 protein. The histopathologic diagnosis was fibrous histiocytoma. The evolution demonstrated the tumoral growth and the possibility of a malignant lesion. PMID- 21271032 TI - Optic neuropathy secondary to cat scratch disease: case report. AB - Optic neuropathy due to cat scratch disease is a relatively infrequent occurrence associated with macular star formation and is characterized by sudden painless loss of vision mostly unilateral. Bartonella henselae is well recognized as the etiologic agent in cat scratch disease. Ocular complications of the disease occur in up to 10% of patients and include neuroretinitis. Ocular bartonelosis is usually self-limited with complete or near-complete recovery of vision in otherwise healthy patients. A case of a boy with neuroretinitis caused by B. henselae is reported. PMID- 21271033 TI - [Medial canthus necrosis associated with Hansen's disease: case report]. AB - In the present case we deal with a medial eyelid necrosis and injury of the canalicular system in a patient in treatment for lepromatous leprosy. Histology of the necrotic lesion showed granulomatous inflammatory reaction with accumulation of histiocytes and presence of alcohol-acid resistant bacilli. After medical treatment, the patient had a spontaneous recovery of the medial canthus architecture but with complete destruction of the canalicular system. PMID- 21271034 TI - [Use of stem cells cultured ex vivo for ocular surface reconstruction]. AB - Lesions on the ocular surface can destroy the stem cells from the limbus and cause limbal stem cell deficiency. The limbal stem cell deficiency is marked by conjunctivalization, which can be defined as the invasion of conjunctival epithelium over the cornea. This process is accompanied by varying degrees of corneal changes such as neovascularization, inflammation, recurrent erosions, persistent epithelial defects, destruction of basement membrane of epithelium and stromal healing. Often, these changes are associated with poor visual acuity, photophobia and ocular discomfort. The best treatment for this disease is not known and varies in unilateral or bilateral cases. Among the treatments available, transplantation of limbal autograft or allograft is one of the most used. To improve the outcome of allotransplantation, some researchers use the transplantation of corneal epithelium cultured in the laboratory by ex vivo expansion of limbal stem cells, but due to limited availability of autologous tissue from the limbus and the risk of complications associated with immunosuppression in allogeneic tissue transplantation, researches of others options of stem cell cultured ex vivo have been described in experimental and clinical stage. This review describes the new types of stem cells cultured ex vivo, their current results and future potential. PMID- 21271035 TI - [Immunology of the toxoplasmic retinochoroiditis]. AB - Toxoplasma gondii infection is an important cause of ocular disease in both immunocompromised and immunocompetent subjects. The pathogenesis of retinochoroidal lesion associated with this infection is not fully understood. In this review, the role of the immune system in the control of Toxoplasma infection, especially in the eye, is discussed. PMID- 21271036 TI - Influence of implant surfaces on osseointegration. AB - The biological fixation between the dental implant surfaces and jaw bones should be considered a prerequisite for the long-term success of implant-supported prostheses. In this context, the implant surface modifications gained an important and decisive place in implant research over the last years. As the most investigated topic in, it aided the development of enhanced dental treatment modalities and the expansion of dental implant use. Nowadays, a large number of implant types with a great variety of surface properties and other features are commercially available and have to be treated with caution. Although surface modifications have been shown to enhance osseointegration at early implantation times, for example, the clinician should look for research evidence before selecting a dental implant for a specific use. This paper reviews the literature on dental implant surfaces by assessing in vitro and in vivo studies to show the current perspective of implant development. The review comprises quantitative and qualitative results on the analysis of bone-implant interface using micro and nano implant surface topographies. Furthermore, the perspective of incorporating biomimetic molecules (e.g.: peptides and bone morphogenetic proteins) to the implant surface and their effects on bone formation and remodeling around implants are discussed. PMID- 21271037 TI - Biocompatibility evaluation of a new bioresorbable pin for membrane fixation. AB - The aim of this study was to morphometrically analyze the tissue response to a customized pin obtained from devitalized bovine cortical bone (DBCB-pin) implanted in the subcutaneous tissue of rats, as well as to assess its microstructural aspect by scanning electron microscopy (SEM). The pins were implanted in the subcutaneous tissue of 20 rats, which were killed at 7, 14, 28 and 60 days (5 rats/period) after implantation. In the subcutaneous tissue, DBCB pin promoted the formation of a fibrous capsule. At 7 days, capsule showed thickness of 70 +/- 3.2 um with higher density of newly formed capillaries and smaller density of collagen fibers. Between 14 and 60 days, more organized fibrous capsule exhibited smaller thickness (53 +/- 5.5 um) with higher density of fibroblasts and collagen fibers. In this period, a small and slow bioresorption of the DBCB-pin by macrophages and rare multinucleated giant cells without tissue damage was observed. The thickness of DBCB-pin resorbed was in mean only of 9.3 um. During all experimental periods not occurred presence of immune reaction cells as lymphocytes and plasma cells. It was concluded that the pin derived from cortical bovine bone was well tolerated by subcutaneous tissue of rats and slowly resorbed could be an alternative material for membrane fixation in the guided tissue regeneration procedures. PMID- 21271038 TI - Effects of low-level laser therapy on human osteoblastic cells grown on titanium. AB - The aim of this study was to investigate the effects of low-level laser therapy (LLLT) by using gallium aluminum arsenide (GaAlAs) diode laser on human osteoblastic cells grown on titanium (Ti). Osteoblastic cells were obtained by enzymatic digestion of human alveolar bone and cultured on Ti discs for up to 17 days. Cells were exposed to LLLT at 3 J/cm2 (wavelength of 780 nm) at days 3 and 7 and non-irradiated cultures were used as control. LLLT treatment did not influence culture growth, ALP activity, and mineralized matrix formation. Analysis of cultures by epifluorescence microscopy revealed an area without cells in LLLT treated cultures, which was repopulated latter with proliferative and less differentiated cells. Gene expression of ALP, OC, BSP, and BMP-7 was higher in LLLT treated cultures, while Runx2, OPN, and OPG were lower. These results indicate that LLLT modulates cell responses in a complex way stimulating osteoblastic differentiation, which suggests possible benefits on implant osseointegration despite a transient deleterious effect immediately after laser irradiation. PMID- 21271039 TI - Synthesis and biocompatibility of an experimental glass ionomer cement prepared by a non-hydrolytic sol-gel method. AB - The aims of this study were to demonstrate the synthesis of an experimental glass ionomer cement (GIC) by the non-hydrolytic sol-gel method and to evaluate its biocompatibility in comparison to a conventional glass ionomer cement (Vidrion R). Four polyethylene tubes containing the tested cements were implanted in the dorsal region of 15 rats, as follows: GI - experimental GIC and GII - conventional GIC. The external tube walls was considered the control group (CG). The rats were sacrificed 7, 21 and 42 days after implant placement for histopathological analysis. A four-point (I-IV) scoring system was used to graduate the inflammatory reaction. Regarding the experimental GIC sintherization, thermogravimetric and x-ray diffraction analysis demonstrated vitreous material formation at 110oC by the sol-gel method. For biocompatibility test, results showed a moderate chronic inflammatory reaction for GI (III), severe for GII (IV) and mild for CG (II) at 7 days. After 21 days, GI presented a mild reaction (II); GII, moderate (III) and CG, mild (II). At 42 days, GI showed a mild/absent inflammatory reaction (II to I), similar to GII (II to I). CG presented absence of chronic inflammatory reaction (I). It was concluded that the experimental GIC presented mild/absent tissue reaction after 42 days, being biocompatible when tested in the connective tissue of rats. PMID- 21271040 TI - Influence of high insertion torque on implant placement: an anisotropic bone stress analysis. AB - The aim of this study was to evaluate the influence of the high values of insertion torques on the stress and strain distribution in cortical and cancellous bones. Based on tomography imaging, a representative mathematical model of a partial maxilla was built using Mimics 11.11 and Solid Works 2010 softwares. Six models were built and each of them received an implant with one of the following insertion torques: 30, 40, 50, 60, 70 or 80 Ncm on the external hexagon. The cortical and cancellous bones were considered anisotropic. The bone/implant interface was considered perfectly bonded. The numerical analysis was carried out using Ansys Workbench 10.0. The convergence of analysis (6%) drove the mesh refinement. Maximum principal stress (deltamax) and maximum principal strain (epsilonmax) were obtained for cortical and cancellous bones around to implant. Pearson's correlation test was used to determine the correlation between insertion torque and stress concentration in the periimplant bone tissue, considering the significance level at 5%. The increase in the insertion torque generated an increase in the deltamax and epsilonmax values for cortical and cancellous bone. The deltamax was smaller for the cancellous bone, with greater stress variation among the insertion torques. The epsilonmax was higher in the cancellous bone in comparison to the cortical bone. According to the methodology used and the limits of this study, it can be concluded that higher insertion torques increased tensile and compressive stress concentrations in the periimplant bone tissue. PMID- 21271041 TI - Implant/abutment vertical misfit of one-piece cast frameworks made with different materials. AB - This study compared vertical and passive fit of one-piece cast frameworks made with 3 different materials: commercially pure titanium (CP Ti - G1), cobalt chromium alloy (Co-Cr - G2) and nickel-chromium-titanium alloy (Ni-Cr-Ti - G3). Fifteen frameworks were obtained simulating bars for fixed prosthesis in a model with 5 implants. The passive and vertical fit of the framework interface was measured using an optical microscope at x30 magnification. Data were statistically analyzed by ANOVA and LSD tests (alpha=0.05). Mean and standard deviation values for passive fit and vertical fit were, respectively: G1 [472.49 (109.88) um and 29.9 (13.24) um], G2 [584.84 (120.20) um and 27.05 (10.30) um], and G3 [462.70 (179.18) um and 24.95 (11.14) um]. For vertical fit, there were no significant differences among G1, G2 and G3 (p=0.285). There were no significant differences for passive fit between G1 and G3 (p=0.844), but both differed significantly from G2 (p=0.028 and p=0.035, respectively), which showed the highest misfit values. It may be concluded that the vertical fit of frameworks was not affected by the tested materials, and that one-piece cast frameworks resulted in inadequate passive fit. The Co-Cr alloy presented the worst values for passive fit. PMID- 21271042 TI - Inorganic particle analysis of dental impression elastomers. AB - The aim of this study was to determine quantitatively and qualitatively the inorganic particle fraction of commercially available dental elastomers. The inorganic volumetric fraction of two addition silicones (Reprosil Putty/Fluid and Flexitime Easy Putty/Fluid), three condensation silicones (Clonage Putty/Fluid, Optosil Confort/Xantopren VL and Silon APS Putty/Fluid), one polyether (Impregum Soft Light Body) and one polysulfide (Permlastic Light Body) was accessed by weighing a previously determined mass of each material in water before and after burning samples at 600 oC, during 3 h. Unsettled material samples were soaked in acetone and chloroform for removal of the organic portion. The remaining filler particles were sputter-coated with gold evaluation of their morphology and size, under scanning electron microscopy (SEM). Flexitime Easy Putty was the material with the highest results for volumetric particle fraction, while Impregum Soft had the lowest values. Silon 2 APS Fluid presented the lowest mean filler size values, while Clonage Putty had the highest values. SEM micrographs of the inorganic particles showed several morphologies - lathe-cut, spherical, spherical like, sticks, and sticks mixed to lathe-cut powder. The results of this study revealed differences in particle characteristics among the elastometic materials that could lead to different results when testing mechanical properties. PMID- 21271043 TI - Influence of grinding procedures on the flexural strength of zirconia ceramics. AB - The surface of zirconia may be damaged during grinding, influencing the mechanical properties of the material. The purpose of this study was to compare the flexural strength of zirconia after different grinding procedures. Twenty bar type zirconia specimens (21 x 5 x 2 mm) were divided into 4 groups and ground using a high-speed handpiece or a low-speed straight handpiece until the bars were reduced 1 mm using two different grinding times: continuous grinding and short-time grinding (n=5). Control specimens (n=5) were analyzed without grinding. The flexural strengths of the bars were determined by using 3-point bending test in a universal testing machine at a crosshead speed of 0.5 mm/min. The fracture load (N) was recorded, and the data were analyzed statistically by the Kruskal Wallis test at a significance level of 0.05. In the test groups, high speed handpiece grinding for a short time had produced the highest mean flexural strength (878.5 +/- 194.8 MPa), while micromotor continuous grinding produced the lowest mean flexural strength (733.8 +/- 94.2 MPa). The control group was the strongest group (928.4 +/- 186.5 MPa). However, there was no statistically significant differences among the groups (p>0.05). Within the limitations of the study, there was no difference in flexural strength of zirconia specimens ground with different procedures. PMID- 21271044 TI - Effect of etching and light-curing time on the shear bond strength of a resin modified glass ionomer cement. AB - The aim of this study was to assess the influence of etching and light-curing time on the shear bond strength (SBS) and adhesive remnant index (ARI) of a resin modified glass ionomer cement (RMGIC) upon debonding of orthodontic brackets. Sixty-eight bovine permanent incisors were obtained and embedded in acrylic resin. Edgewise metallic brackets were bonded to the teeth with Fuji Ortho LC RMGIC. The specimens were randomly assigned to 4 groups, using the following etching and light-curing times: G1: 10% polyacrylic acid and 40 s (control); G2: 37% phosphoric acid and 40 s; G3: 10% polyacrylic acid and 50 s; and G4: 37% phosphoric acid and 50 s. Shear test was performed at 0.5 mm/min and the ARI was assessed. G2 (3.6 +/- 0.98 MPa) presented significantly higher (p<0.05) SBS than G1 (2.76 +/- 0.86 MPa) and G4 (2.86 +/- 0.68 MPa), and there was no statistically significant difference (p>0.05) between G2 and G3 (2.94 +/- 0.67 MPa). ARI presented prevalence of scores 2 and 3 in all groups. RMGIC SBS enhanced with 37% phosphoric acid etching and 40 s light-curing time, but this did not occur when the light-curing time was increased, regardless of the acid used. RMGIC presented prevalence of failures at the adhesive/bracket interface. PMID- 21271045 TI - Comparison of silorane and methacrylate-based composite resins on the curing light transmission. AB - The aim of this study was to investigate the influence of different composite resins - Filtek P90 (silorane-based composite) and Heliomolar (methacrylate-based composite) - on light transmission and decrease in Knoop hardness between the bottom and top of cured specimens. The irradiance of a light-curing unit (LCU) was measured with a power meter (Ophir Optronics; 900 mw/cm2) and spectral distributions were obtained using a spectrometer (USB 2000). Twenty standardized cylindrical specimens (2 mm thick x 7 mm diameter) of each composite resin were obtained by curing using the LCU for 40 s. Light energy transmission through the composite was calculated (n=10). The Knoop hardness number for each surface was recorded as the mean of 3 indentations. The difference in Knoop hardness between the top and bottom (DKH) of the same specimen was calculated (n=10). The irradiance of light that passed through Filtek P90 (272 mW/cm2) was not significantly greater than that the passed through Heliomolar (271 mW/cm2). The DKH of Filtek P90 (25%) was significantly higher than that of Heliomolar (12%). There was a greater degree of subsurface polymerization of the methacrylate-based composite compared to the silorane-based composite. PMID- 21271046 TI - Procedural errors during root canal preparation using rotary NiTi instruments detected by periapical radiography and cone beam computed tomography. AB - This study detected procedural errors created by rotary nickel-titanium (NiTi) instruments during root canal preparation by two imaging methods. Forty extracted human maxillary and mandibular molars were divided randomly into two groups and treated by two endodontists (n=10) and two undergraduate dental students (n=10). The ProTaper Universal Rotary System was used to shape the canals and then they were filled using AH Plus sealer and gutta-percha. Periapical radiographs (PR) and cone beam computed tomography (CBCT) images were obtained and two examiners, who evaluated them to verify the occurrence of procedural errors (fractured instruments, perforations, and canal transportation). The Chi-square test at 0.05 level of significance was used for statistical analyses. There were no significant differences (p>0.05) between the imaging methods. In the analysis of procedural errors, there was no significant difference (p>0.05) between the groups of operators (endodontists vs. students) nor between tooth groups (maxillary molars vs. mandibular molars). In view of the low incidence of procedural errors during root canal preparation performed by students the introduction of rotary NiTi instruments has potential in undergraduate teaching. PR and CBCT permitted the detection of procedural errors, but the CBCT images offer more recourse for diagnosis. PMID- 21271047 TI - Patient with Down syndrome and implant therapy: a case report. AB - Patients with Down syndrome may not be cooperative during dental treatment and, in cases of complex treatment, it is necessary to use oral or inhaled sedation and/or general anesthesia, which represent safe and efficient treatment resources. There are few reports about oral rehabilitation with dental implants in patients with Down syndrome in the literature. This paper presents the case of a patient with Down syndrome and moderate mental retardation who suffered avulsion of the maxillary left central incisor after a fall, and was treated by means of a single dental implant with immediate load carried out under general anesthesia. After 4 years of follow up, there has been improvement in the sleep obstructive apnea syndrome due to the use of a tongue crib adapted for providing esthetics and preserving the implant placed. PMID- 21271048 TI - [Acoustic behavior of Fenestra bohlsii Giglio-Tos (Orthoptera: Acrididae: Gomphocerinae)]. AB - The acoustic behavior of Fenestra bohlsii Giglio-Tos is described for the first time. The sounds and behaviors were observed and registered in captivity. The signals were digitized with the Sound-Blaster AWE64 Gold program and analysed with the Avisoft SAS Lab Pro 30 PC for MS Windows software. Seven different types of sounds are described as produced by males: spontaneous song (also used during the courtship), two different types of courtship song, assault song, tapping associated to the courtship, interaction between males and fly crackling. For each one, the characteristic oscillograms and frequency spectra are given. Sounds are produced by different mechanisms: femoro-tegminal stridulation, typical for Gomphocerinae, fly crackling, hind tarsi tapping and alar beat, the last produced by the beat and clash of hind alae, that is, the castanet method which up to now was only known, among Orthoptera, in Stenobothrus rubicundulus Kruseman & Jeekel. A description of the stridulatory file of male and female is given, as well as that of the alar special structures. Behavioral units and their sequence during the courtship are defined. There, in addition to the acoustic signals, visual signals are present, referring to positions, hind legs, antennae and palpi movements and body vibrations. PMID- 21271049 TI - [Pollinators of Bertholletia excelsa (Lecythidales: Lecythidaceae): interactions with stingless bees (Apidae: Meliponini) and trophic niche]. AB - This paper presents an analysis of the foraging behavior and interactions of Xylocopa frontalis Olivier (Apidae: Xylocopini) and Eulaema mocsaryi (Friese) (Apidae: Euglossini) in the presence of stingless bees (Apidae: Meliponini) in flowers of Bertholletia excelsa, the Brazilian nut. The palynological load carried by both species was also examined. This study was conducted in the farm Aruana, Itacoatiara/ Amazonas state, Brazil, during the flowering peak of B. excelsa. The visitation by the main pollinators X. frontalis and E. mocsaryi were influenced by the presence and activities of stingless bees in the flowers of B. excelsa. Meliponini bees did not have any effect on the visits and collection of floral resources by X. frontalis, while negatively affecting the number of visits by E. mocsaryi. The stingless bees presented a variety of strategies to get access to pollen grains of B. excelsa, grouped into two categories: opportunism Frieseomelitta trichocerata Moure, Tetragona goettei (Friese), and Tetragona kaieteurensis (Schwarz), and stealing -Trigona branneri Cockerell, Trigona fuscipennis Friese, and Trigona guianae Cockerell. The palynological analysis from X. frontalis showed that the bee collected pollen in a few species of plants, but mainly on B. excelsa. The pollen grains of B. excelsa were poorly represented in the pollen shipments of E. mocsaryi, due to its large trophic niche in the locality. PMID- 21271050 TI - [Spatial distribution of nests of Acromyrmex crassispinus (Forel) (Hymenoptera: Formicidae) in Pinus taeda plantations]. AB - The spatial distribution of insects is essential to perform control strategies, to improve sample techniques and to estimate economic losses. We aimed to determine the spatial distribution of nests of Acromyrmex crassispinus (Forel) in Pinus taeda plantations. The experiments were carried out in P. taeda plantations with different ages (treatments: recently-planted, three and six-year old plants). The study took place in Rio Negrinho and in Tres Barras, SC. Three plots of one hectare were delimited in each treatment, and plots were divided in 64 sample units. The analysis of the dispersion index [variance/mean relationship (I), index of Morisita (Idelta) and k exponent of negative binomial distribution] showed that the majority of the samplings presented random distribution. Among the three distributions of probabilities studied: Poisson, positive binomial and negative binomial, the Poisson distribution was the best model to fit the spatial distribution of A. crassispinus nests in all samplings. The result was a random distribution in the plantings of different ages. PMID- 21271051 TI - Evaluation of water quality of an urban stream in southeastern Brazil using Chironomidae larvae (Insecta: Diptera). AB - In order to estimate the water quality of Sao Pedro stream, through distribution and composition of Chironomidae larvae present in the sediment four sampling sites were selected. In each sampling site, three sediment samples were collected within a period of twelve months using the Petersen (0.0189 m2) and the van Veen (0.0518 m2) dredges. Samples were washed through a sieve with a 0.21 mm mesh and the collected organisms were sorted in transparent trays, with a light shine being reflected into the tray. The sites located in the greatest urban mesh showed high densities of the genus Chironomus and lower values for diversity, uniformity and taxa richness, in relation to sites located in a less urbanized area. A significant difference in density of Chironomidae larvae (p = 0.02; H = 5.89) was observed between the sites without domestic sewage effluents (site I) and those with the input of the effluents (sites II, III and IV). The Chironomidae larvae composition and the physical and chemical parameters were effective as indicators of the environmental alterations in Sao Pedro stream. PMID- 21271052 TI - Floral preferences and climate influence in nectar and pollen foraging by Melipona rufiventris Lepeletier (Hymenoptera: Meliponini) in Ubatuba, Sao Paulo state, Brazil. AB - We describe the environment effects on the amount and quality of resources collected by Melipona rufiventris Lepeletier in the Atlantic Forest at Ubatuba city, Sao Paulo state, Brazil (44o48'W, 23o22'S). Bees carrying pollen and/or nectar were captured at nest entrances during 5 min every hour, from sunrise to sunset, once a month. Pollen loads were counted and saved for acetolysis. Nectar was collected, the volume was determined and the total dissolved solids were determined by refractometer. Air temperature, relative humidity and light intensity were also registered. The number of pollen loads reached its maximum value between 70% and 90% of relative humidity and 18oC and 23oC; for nectar loads this range was broader, 50-90% and 20-30oC. The number of pollen loads increased as relative humidity rose (rs = 0.401; P < 0.01) and high temperatures had a strong negative influence on the number of pollen loads collected (rs = 0.228; P < 0.01). The number of nectar loads positively correlated with temperature (rs = 0.244; P < 0.01) and light intensity (rs = 0.414; P < 0.01). The percentage of total dissolved solids (TDS) on nectar loads positively correlated with temperature and light intensity (rs = 0.361; P < 0.01 and rs = 0.245; P < 0.01), negatively correlated with relative humidity (rs = -0.629; P < 0.01), and it increased along the day. Most nectar loads had TDS between 11% and 30%, with an average of 24.7%. The volume measures did not show any pattern. Important pollen sources were Sapindaceae, Anacardiaceae, Rubiaceae, Arecaceae, Solanaceae and Myrtaceae; nectar sources were Sapindaceae, Fabaceae, Rubiaceae, Arecaceae and Solanaceae. PMID- 21271053 TI - Nesting behavior of Podium denticulatum Smith (Hymenoptera: Sphecidae). AB - The nesting behavior of Podium denticulatum Smith was studied on the campus of Ribeirao Preto of the Universidade de Sao Paulo, SP, Brazil, from September 2003 to August 2005. The wasps established their nests in bamboo canes ranging from 11.4 cm to 26.2 cm in length and from 0.7 cm to 1.8 cm in internal diameter. Podium denticulatum nested almost exclusively in the hot and wet season (September-April), producing at least five generations per year. The cell provisioning was made with adult and nymphal cockroaches (Blattellidae) which were arranged venter-up and with the head inward toward the inner end of the cell. The construction of a temporary closure occurred in cells that took more than one day to be provisioned. The cells provisioned with a greater number of prey were more likely to produce females than males. The nests included 1-6 brood cells separated by mud partitions and arranged in a linear series. The innermost cells of the nests produced females, and the outermost cells produced males. Nests were parasitized by Eulophidae (Melittobia sp.), Chrysididae and Tachinidae. PMID- 21271054 TI - [Oviposition behavior of Phymastichus coffea LaSalle (Hymenoptera: Eulophidae) on its natural host]. AB - Phymastichus coffea LaSalle is an African endoparasitoid of adults of the coffee berry borer, Hypothenemus hampei (Ferrari) that was introduced into Mexico for biological control purposes. The objective of this study was to investigate the oviposition behavior of P. coffea on its host under laboratory conditions. The results indicate that P. coffea females exhibited 12 behavioral acts during and after oviposition, such as, walking, cleaning, flying, surface landing, resting, host landing, host antennation, touching the host with forelegs, host recognition, walking on the host, oviposition and cleaning after oviposition. The sequence of each behavior is described in an ethogram. PMID- 21271055 TI - [Response of the ant community to attributes of fragments and vegetation in a northeastern Atlantic Rain Forest area, Brazil]. AB - The objective of this study was to determine the effects of forest fragmentation on ant richness in a landscape of Atlantic Forest in Northeast Brazil. More specifically, the ant richness was related to the attributes of fragments (area and distance from the fragment central point to the edge), landscape (forest cover surrounding the fragments), and tree community (plant density, richness, and percentage of shade tolerant species). The surveys were carried out in 19 fragments located in Alagoas State from October 2007 to March 2008. Samples were collected through a 300 m transect established in the center of each fragment, where 30 1-m2 leaf litter samples were collected at 10 m intervals. A total of 146 ant species was collected, which belonged to 42 genera, 24 tribes and nine subfamilies. The attributes of fragments and landscape did not influence ant richness. On the other hand, tree density explained ca. 23% of ant richness. In relation to functional groups, both density and richness of trees explained the richness of general myrmicines (the whole model explained ca. 42% of the variation in this group) and percentage of shade tolerant trees explained the richness of specialist predator ants (30% for the whole model). These results indicate that ant fauna is more influenced by vegetation integrity than by fragment size, distance to edge or forest cover surrounding fragments. PMID- 21271056 TI - [The bamboo Merostachys fischeriana (Bambusoideae: Bambuseae) as a canopy habitat for ants of Neotropical Montane Forest]. AB - Although Merostachys fischeriana is very abundant in the Brazilian Atlantic Rainforest, little attention has been paid to the biological interactions with other animals. The present study describes some of the interactions between ants and this bamboo species. The experiment was carried out in a fragment of a montane tropical forest in the Parque Estadual do Itacolomi, near Ouro Preto, MG, Brazil. Thirty culms of bamboo were randomly collected. The ants were obtained by direct collection from nodes and internodes. Morphometric variables of the bamboo were recorded for characterization of potential ant habitat. Merostachys fischeriana grows in rosettes as a thin bamboo (average = 1,0 cm; se = 0,27; n = 20) and is tall enough to reach the upper canopy of this low forest (average = 9,1 m; se = 2,72; n = 20). Fifteen ant species were sampled. Brachymyrmex heeri Forel was the most abundant in the nodes, while Camponotus crassus Mayr (Hymenoptera: Formicidae) was the most abundant in the internodes. The composition of the species that inhabit the internodes was different from the composition in the node (Q-test: Q = 3,76; P = 0,05). The level of occupation was defined by the number of holes (F = 10,33; P < 0,01), the number of internodes in the canopy (F = 6,84; P = 0,01) and the length of the culm (F = 7,52; P = 0,01). The plant's morphology allowed the occurrence of additional species of ants in the canopy and influenced the composition of the entire ant assemblage. PMID- 21271057 TI - Efficient sampling of ground-dwelling arthropods using pitfall traps in arid steppes. AB - Pitfall trapping is probably the most frequently used method for sampling ground dwelling arthropods. While the capture of specimens in pitfall traps largely depends on the number of individuals in the sampled area, trap design and trapping effort for a given environment, can also affect sampling success. The aim of this study was to determine the best pitfall trapping design for collecting ground-dwelling arthropods in the wind-blown and cold arid steppe areas of Patagonia. We tested four designs of traps, six types of preservative and different times of activation as well as the quantity of traps. Both preservation attributes and sampling efficiency differed between different trap designs and fluids compared. We conclude that in order to obtain reliable data on the structure of a community of ground-dwelling arthropods in Patagonia, at least three pitfall traps per experimental unit are required. In addition, traps should be opened for a minimum of 10 days filled with 300 ml of 30% ethylene glycol. We also suggested the use of a simple trap design (i. e. without funnel or roof). We believe these findings will contribute to more appropriate sampling of the ground dwelling fauna of Patagonia as well as other arid areas, leading to more reliable diversity studies. PMID- 21271058 TI - The acceptance rate of young wasps by alien colonies depends on colony developmental stages in the swarm-founding wasp, Polybia paulista von ihering (Hymenoptera: Vespidae). AB - In social insects, newly emerged individuals learn the colony-specific chemical label from their natal comb shortly after their emergence. These labels help to identify each individual's colony of origin and are used as a recognition template against which individuals can discriminate nestmates from non-nestmates. Our previous studies with Polybia paulista von Ihering support this general pattern, and the acceptance rate of young female and male wasps decreased as a function of their age. Our study also showed in P. paulista that more than 90% of newly emerged female wasps might be accepted by conspecific unrelated colonies. However, it has not been investigated whether the acceptance rate of newly emerged female wasps depends on colony developmental stage of recipient colonies. We introduced newly emerged female wasps of P. paulista into different colony developmental stags of recipient colonies, i.e., worker-producing and male producing colonies. We found that the acceptance rate of newly emerged female wasps by alien colonies was pretty lower by male-producing colonies than worker producing colonies. This is the first study to show that the acceptance rate of young female wasps depends on stages of recipient colonies. PMID- 21271059 TI - Host plant association and genetic differentiation of corn and rice strains of Spodoptera frugiperda Smith (Lepidoptera: Noctuidae) in Colombia. AB - Spodoptera frugiperda (Smith) is a polifagous insect of major economic impact in the western hemisphere and exhibits two strains (i.e., corn and rice) that are morphologically identical but differ in ecology, genetics and physiology. In this work we identified these strains and their respective hybrids by using a PCR-RFLP of the COI gene and PCR of the tandem region FR. Moreover, we performed a population structure analysis by using 253 larvae from Tolima, a region where S. frugiperda is a pest on corn, rice, sorghum and cotton. Corn strain was found on 42% in corn, 34% in cotton, 19% in sorghum and 0.04 % in rice and rice strain on 35% in corn, 0.06% in cotton, 0.06% in sorghum and 53% in rice, demonstrating that corn strain specificity is superior to rice strain. Hybrids between these strains were more abundant in corn. The distributions on their host plants reflect a population genetic differentiation in S. frugiperda with values of PhiPT (COI) = 0.31, P < 0.0001, PhiPT (FR) = 0.17, P < 0.0001 for all crops and PhiPT (COI) = 0.42, P < 0.01, PhiPT (FR) = 0.13, P < 0.01 for the sixteen sampled farms. The dendrograms showed two clusters representing both strains. The results obtained in this study suggest that the management of this insect must differ on each host plant, given the specialization that both strains present, particularly in corn and rice. PMID- 21271060 TI - Responses of coffee berry borer, Hypothenemus hampei (Ferrari)(Coleoptera: Scolytidae), to vertical distribution of methanol: ethanol traps. AB - Captures of the coffee berry borer (CBB) Hypothenemus hampei (Ferrari) were assessed in traps in the field. IAPAR designed traps [plastic bottles (2 L) lured with methanol:ethanol (1:1) in a vessel] were placed either at 0.5, 1.0 and 1.5m high from the ground or simultaneously tested in the 2004 fructification season. Traps placed at the three heights trapped 5.5 times more CBB than the others, mostly at the traps placed at 0.5 m (75%). Treatments using the IAPAR designed trap placed at 1.2 m high; IAPAR trap with a white plastic plate above (IAPAR modified I) at 1.2 m high; IAPAR at 0.5 m high and two additional vessels at 1.0 and 1.5m high (IAPAR modified II) and T-163 trap [three red plastic cups (300 ml) and a red plastic plate as a cover] lured with M:E (1:1) at 1.2m height were compared in the vegetative (2005) and fructification (2006) periods. IAPAR modified II (dispenser vessels placed at 0.5, 1.0 and 1.5 m) trapped more beetles than the remaining types (2.72 times more beetles than IAPAR design); and IAPAR modified I traps trapped more beetles than T 163 and IAPAR traps in the vegetative period. In the reproductive period, IAPAR modified II trapped less beetles than IAPAR and IAPAR modified I. In 2007 vegetative season, IAPAR modified II trap were compared with IAPAR trap and trapped 2.8 times more beetles. The positive responses to a vertical distribution of the volatile attractants in the vegetative period of the planting allow the development of more efficient trapping systems for CBB. PMID- 21271061 TI - [Habitat heterogeneity, richness and structure of assemblages of dung beetles (Scarabaeidae: Scarabaeinae) in areas of cerrado in the Chapada dos Parecis, Mato Grosso state, Brazil]. AB - Ecological theory of habitat heterogeneity and limited niche-similarity assumes that more heterogeneous environments provide a greater amount and diversity of resources than simple environments, resulting in a greater diversity of species. This study aimed to evaluate the effect of the habitat heterogeneity on the richness of dung beetles and to examine the spatial patterns of assemblage structure in relation to patterns of habitat heterogeneity. Dung beetles were collected using pitfall traps without bait in 30 points distributed in an area of cerrado sensu lato, in the region of Tangara da Serra, MT, Brazil, including areas of cerrado sensu stricto, campo sujo, cerradao and gallery forest. A total of 1,291 dung beetles were collected, distributed in 16 genera and 29 species. Overall habitat heterogeneity exerted a negative effect on patterns of dung beetles richness. Higher levels of species richness were observed in areas of cerrado campo sujo, while the areas of gallery forest were the most species poor. Regarding assembly structure, it was found that the dung beetles were separated into two major groups, one formed by the presence of specialized species in forest areas and other composed of species that occurred predominantly in cerrado. In conclusion, it was found that habitat complexity influenced the distribution of dung beetles, but the level of turnover in species composition along the heterogeneity gradient was relatively weak. PMID- 21271062 TI - Pollination of Adenocalymma bracteatum (Bignoniaceae): floral biology and visitors. AB - Adenocalymma bracteatum is a shrub of dense foliage and yellow flowers, easily found on grasslands areas in Central Brazil. The aim of this study was to determine the reproductive biology and the flower visitors of A. bracteatum in a pasture area nearby Ivinhema city, MS (Brazil). The flowering peak occurs in winter. The flower reflects ultraviolet light. Anthesis begins at 6:30h, and pollen and nectar are the resources to visitors. We captured 1,038 floral visitors. The bees Apis mellifera (L.), Trigona sp., Trigona spinipes (Fabricius), (Hymenoptera: Apoidea) and the ant Cephalotes sp. (Hymenoptera: Formicidae) were the main visitors. The reproductive tests indicate that A. bracteatum is self compatible, justifying its expansion in altered environments; however, the largest reproductive success was dependant on cross-pollination and self-pollination, evidencing the pollinators importance. Adenocalymma bracteatum presents melittophilous syndrome and bumblebees were the main pollinators in the area. The correlations observed between the climatic variables and the main pollinator species were low or medium. PMID- 21271063 TI - A new long-horned caddisfly in the genus Triplectides Kolenati (Trichoptera: Leptoceridae) from the Itatiaia massif, southeastern Brazil. AB - Triplectides itatiaia sp. nov. is described from specimens collected on the Itatiaia massif, Mantiqueira mountain range, Rio de Janeiro state, Brazil. The new species can be distinguished by the presence of hind wing fork I petiolate, the long dorsal excision of segment X and the flat, apically rounded mesal lobes. Female and immature stages are unknown. A key to the Brazilian species in the genus is provided. PMID- 21271064 TI - Aging and food source effects on mandibular stylets teeth wear of phytophagous stink bug (Heteroptera: Pentatomidae). AB - Studies were conducted to test the effect of age and food sources on wear of the mandibular teeth of the phytophagous pentatomid, Euschistus heros (F.). The total length (um) of the area bearing the mandibular teeth, the length of the 1st tooth, and the height of the 2nd tooth for teneral (< 1 day-old) adults were significantly greater than that of adults fed on natural [green bean, Phaseolus vulgaris pods, raw shelled peanuts, Arachis hypogaea, and mature soybean, Glycine max seeds] for 30 or 60 days. Adults fed on artificial dry diet showed, in general, similar results to those of teneral adults. Force (Newtons) required penetrating the natural foods was significantly greater than that required penetrating the artificial diet. The greater hardness of the natural foods caused increased mandibular serration wear. PMID- 21271065 TI - Sexual dimorphism in antennal receptors of Phyllophaga ravida Blanchard (Coleoptera: Scarabaeoidea: Melolonthidae). AB - The external morphology of sensilla on the antennae of males and females of Phyllophaga ravida Blanchard is described using scanning electron microscopy. Sexual dimorphism in body and antennal dimensions and in antennal receptor types was found. The female's body is slightly larger than the male's, although male antennal lamellae are longer than in females. Sixteen types of sensilla were identified on the proximal and distal surfaces of lamellae from both sexes, most of them in males: three types of placodea sensilla, four types of auricilica sensilla, five types of basiconica sensilla, and four types of coeloconica sensilla. Also, two types of mechanoreceptor sensilla were present on the lamellae periphery. Furthermore, males had larger placodea, auricilica and some types of basiconica sensilla. PMID- 21271066 TI - Comparative genetic diversity and genetic structure of three Chinese silkworm species Bombyx mori L. (Lepidoptera: Bombycidae), Antheraea pernyi Guerin Meneville and Samia cynthia ricini Donovan (Lepidoptera: Saturniidae). AB - The genetic diversity and genetic structure of three Chinese silkworm species Bombyx mori L., Antheraea pernyi Guerin-Meneville and Samia cynthia ricini Donovan were comparatively assessed based on RAPD markers. At the species level, A. pernyi and B. mori showed high levels of genetic diversity, whereas S. cynthia ricini showed low level of genetic diversity. However, at the strain level, A. pernyi had relatively highest genetic diversity and B. mori had lowest genetic diversity. Analysis of molecular variance (AMOVA) suggested that 60% and 72% of genetic variation resided within strains in A. pernyi and S. cynthia ricini, respectively, whereas only 16% of genetic variation occurred within strains in B. mori. In UPGMA dendrogram, individuals of A. pernyi and B. mori formed the strain specific genetic clades, whereas those of S. cynthia ricini were distributed in a mixed way. The implications of these results for the conservation and utilization in breeding programs of three silkworm species are discussed. PMID- 21271067 TI - [Selection of isolates of entomopathogenic fungi for controlling Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae) and their compatibility with insecticides used in tomato crop]. AB - The activity of Metarhizium anisopliae and Beauveria bassiana towards eggs and larvae of Tuta absoluta (Meyrick) was evaluated. Our data showed that the isolates were pathogenic to both developmental stages tested and the eggs were more susceptible than the 1st instars. The isolates URPE-6 and URPE-19 of M. anisopliae were more pathogenic to eggs and larvae, respectively. The compatibility of these two isolates with the insecticides chlorfenapyr, spinosad, indoxacarb, abamectin, and neem were evaluated. Spinosad and indoxacarb were compatible with the two M. anisopliae isolates in all tested concentrations. At the average recommended concentration, chlorfenapyr was compatible to URPE-6 and abamectin to UFPE-19. The use of entomopathogenic fungi associated with compatible insecticides may be a useful alternative to control T. absoluta. PMID- 21271068 TI - Selectivity of neem to Trichogramma pretiosum Riley and Trichogrammatoidea annulata De Santis (Hymenoptera: Trichogrammatidae). AB - Trichogramma pretiosum Riley and Trichogrammatoidea annulata De Santis are commonly found in avocado and persimmon orchards in northern Parana state. However, their abundance depends on whether insecticides are used or not to control the key lepidopteran pests Stenoma catenifer (Wals.) (Lepidoptera: Elachistidae) and Hypocala andremona (Stoll) (Lepidoptera: Noctuidae), respectively. The aim of this work was to evaluate the effects of an aqueous neem seed extract (ANSE) at 15, 3 and 1.5%, and of an emulsifiable concentrate neem oil (ECNO) at 2.5, 0.5 and 0.25% on lifetime parameters of these trichogrammatids as a way of testing the feasibility of integrating the biological and chemical control methods. Chemicals were applied on Anagasta kuehniella (Zeller) (Lepidoptera: Pyralidae) eggs before or after parasitization (one, three or five days). ANSE was more deleterious to both parasitoid species than ECNO, regardless of the concentration and the time of application. The chemicals acted on a concentration and time dependent manner. Treating the host with neem before parasitism was less deleterious to wasp emergence, especially for T. annulata. Pre-treatments (24h) of the host eggs with ECNO at concentrations varying from 0.5% to 0.25% did not affect T. pretiosum longevity, but 2.5% reduced T. annulata survival. Feeding wasps with honey mixed with 0.25% ECNO negatively affected T. annulata survival. PMID- 21271069 TI - Efficiency of Phytoseiulus longipes Evans as a control agent of Tetranychus evansi Baker & Pritchard (Acari: Phytoseiidae: Tetranychidae) on screenhouse tomatoes. AB - The spider mite Tetranychus evansi Baker & Pritchard can cause severe damage to tomato crops. The predatory mite Phytoseiulus longipes Evans was recently reported in association with T. evansi in Uruguaiana, Rio Grande do Sul State, Brazil. The objective of the present study was to evaluate the effects of P. longipes on the population of T. evansi on tomatoes under screenhouse condition. The study consisted on four experiments, in each of which 80 potted plantlets were distributed in two plots of 40 plantlets each. Two weeks later, each plantlet of both plots was infested with eight adult females of T. evansi; one week after, four adult females of P. longipes were released onto each plant of one plot. The population levels of T. evansi and the damage caused by these mites were significantly lower (P < 0.05; linear mixed-effect model) in the plots where P. longipes had been released. The results indicate the potential of this predator as a candidate for classical biological control of T. evansi by inoculative releases on tomato plants. PMID- 21271070 TI - [Oviposition, development, and reproduction of Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae) fed on different hosts of economic importance]. AB - The host selection for oviposition by Spodoptera frugiperda (J.E. Smith) among corn, millet, cotton and soybean, and its relationship with the biological characteristics were investigated. Free and non-choice tests for oviposition using plots containing five plants each, from each host in plastic greenhouse, resulted in similar oviposition preference among the host plants. In addition, selected biological characteristics of S. frugiperda were determined in the laboratory with larvae feeding on host leaves, and the combination of leaf and cotton boll. Neonate larvae exhibited low success of colonization on cotton boll compared to the leaves of all other hosts. Spodoptera frugiperda fed only on cotton bolls exhibited longer larval and pupal development, and longer adult life span; however with similar egg production. Larvae fed cotton leaves during six days and then transferred to cotton bolls, however, exhibited development and reproduction similar to those reared on corn or only on cotton leaves. Therefore, the variations on immature stages of S. frugiperda were not related with host selection for oviposition which was similar among the studied hosts. Based on our data, the millet as a winter, rotational, and cover crop is a potential host for S. frugiperda, while leaves and cotton bolls were diets of intermediate suitability as compared to corn and soybean leaves. PMID- 21271071 TI - Influence of trichomes on attractiveness and ovipositional preference of Bemisia tabaci (Genn.) B biotype (Hemiptera: Aleyrodidae) on tomato genotypes. AB - Brazil is one of the world's largest tomato producer, but considerable part of the production is lost due to the attack of Bemisia tabaci (Genn.) B biotype. Resistant germoplasm plants can be an important method for B. tabaci control in integrated pest management approaches. The attractiveness and ovipositional preference of B. tabaci for 17 tomato genotypes were evaluated in a free-choice test. Trials were set up in a randomized block design with ten replicates. Each replicate (one tomato plant per pot) was placed in a cage (80 x 50 x 50 cm) and infested with 1,000 adults during four days. Linear correlation tests were applied between the number of insects and eggs and number of trichomes in each tomato genotype. LA716, LA444-1 and PI134418 genotypes were the least attractive, while the 'Santa Clara' was the most attractive; PI134417 trapped the largest number of adults. LA716 genotype (4.1 eggs/leaflet and 2.1 cm2/eggs per leaflet) was the least preferred for whitefly oviposition; NAV1062, 'Fanny', LA1335, 'Santa Clara' and IAC294 were the most preferred genotypes. The glandular trichomes density was negatively correlated with whitefly's attractiveness and oviposition per leaflet and per leaf, and positively with the number of trapped insects. The non-glandular trichomes density was negatively correlated with the number of trapped insects and positively with whitefly's oviposition per cm2/leaflet andper cm2/leaf. LA716 had high antixenosis level (ovipositional nonpreference) toward B. tabaci B biotype related with type IV glandular trichome. PMID- 21271072 TI - [Resistance of potato cultivars to Myzus persicae (Sulz.) (Hemiptera: Aphididae)]. AB - Aphids are the most important vectors of viruses infecting potato (Solanum tuberosum). We focused on the response of the aphid vector Myzus persicae (Sulzer) to five commercial potatocultivars: Agata, Jaette Bintje, Mondial, Monalisa and Sante, by traditional antibiosis and antixenosis tests and by the EPG (Electrical Penetration Graph) technique, as a step forward to the design of effective management practices. Our aim was to identify plant factors involved in resistance of these cultivars against M. persicae, both at the surface and in deeper plant tissues. Results from the antixenosis test confirmed a strong preference of M. persicae for the Mondial cultivar. The antibiosis study indicated a lower population development of the aphid in 'Monalisa' when compared to 'Agata' and 'Jaette Bintje'. EPG assays indicated that 'Sante' inhibited the initial feeding process of M. persicae, whereas 'Monalisa' showed a physical-type of resistance as demonstrated by a very high number of short probes. The cultivar Mondial showed average values for all EPG variables analyzed. The behavior in 'Jaette Bintje' indicated this cultivar was an ideal host for aphid feeding and reproduction. Together, the EPG data revealed the existence of pre and post phloematics factors in the cultivars under study, which have important implications on the efficiency of transmission and spread of virus in potato by M. persicae. PMID- 21271073 TI - [The effect of water quality in the life cycle and in the attraction for the egg oviposition of Aedes aegypti (L.) (Diptera: Culicidae)]. AB - The present research aimed at evaluating the influence of the water quality in the life cycle and attraction of Aedes aegypti (L.) females to oviposit using different sources of water (raw sewage, effluent of UASB reactor, effluent of polishing lagoon, effluent of anaerobic filter, rain water and de-chlorinated water). The immature development time and survivorship were evaluated on a daily basis in two distinct feeding systems (with and without food). The quality of the water was shown to affect the egg and larval stages, but not the pupal or the adult. In the absence of food, no development was observed in rain water and de chlorinated water. Immature development was faster in water sources from raw sewage, although with the lowest survivorship (37.3%). Free-choice tests indicated that females preferred to lay most of their eggs on water collected from the effluent of a UASB reactor, achieving the highest oviposition activity index (OAI) of 0.57. In non-choice tests, females laid larger batches of eggs in water collected from anaerobic filters (204.8 eggs), with the lowest number of eggs being laid on de-chlorinated water (37.3 eggs). It can be concluded that A. aegypti does not demonstrate any particular preference to lay eggs on clean water. This has serious implications for developing strategies to manage populations of this important vector in urban areas as it was shown to lay eggs and successfully develop on several different sources of water. PMID- 21271074 TI - [Indicators of infestation, colonization and infection of Triatoma dimidiata (Latreille) (Hemiptera: Reduviidae) in Campeche, Mexico]. AB - Triatoma dimidiata (Latreille) is considered to be one of the primary vectors of Chagas disease in Southern Mexico and Central America. The objective of the present study was to obtain ecological information on T. dimidiata in two rural communities of Campeche, Mexico, where the vector is poorly studied. Our work consisted of monthly samplings carried out during one-year time at three levels: sylvatic, peridomestic and intradomestic, in order to estimate the population abundance of this species and its rate of infection with Trypanosoma cruzi. Triatoma dimidiata was the unique vector of this disease collected in San Juan Bautista Sakcabchen (SJBS) and Crucero San Luis (CSL). The total of 145 individuals were captured in SJBS; from these, 26.9%, 20% and 53.1% were collected in the sylvatic, peridomestic and intradomestic area, respectively. In CSL captures yielded 108 individuals: 40.7% in the sylvatic area, 20.4% peridomestic and 38.9% intradomestic. We found no correlation between climatic variables and population abundance of T. dimidiata. Dataset obtained suggests that individuals from the sylvatic area exhibit a high rate of natural infection by T. cruzi, with monthly percentages up to 61.5% for SJBS and 50% for CSL. At the peri and intradomestic level, the reservoirs apparently play an important role in the transmission, as the seroprevalence in dogs was 61.5% y 65.4%, for SJBS y CSL, respectively. Based on these findings, it was concluded that inhabitants of both communities are at a high risk of Chagas disease infection. PMID- 21271075 TI - Sand flies (Diptera: Psychodidae) in a Cerrado area of the Maranhao state, Brazil. AB - The present paper aims to increase the knowledge on the sand fly fauna in the cerrado areas of Maranhao state in urban, rural and forest environments. The research was carried out from October 2007 to September 2008, between 18:00h and 06:00h, in the municipality of Chapadinha, northeast Maranhao. For insect sampling, CDC light traps were set up in peridomicile and domicile areas of urban and rural zones as well as in Cerrado and Gallery forests. The total of 1,401 specimens belonging to 17 species were sampled, all within the genus Lutzomyia. Lutzomyia longipalpis (Lutz & Neiva) (52.5%), Lu. evandroi (Costa Lima & Antunes) (18.3%), Lu. whitmani (Antunes & Coutinho) (12.1%), Lu. lenti (Mangabeira) (4.7%) and Lu. termitophila (Martins, Falcao & Silva) (4.0%) were the most frequently collected. From an epidemiological viewpoint, five from all of the collected species are vectors of leishmaniasis: Lu. longipalpis, Lu. whitmani, Lu. flaviscutellata (Mangabeira), Lu. gomezi (Nitzulescu) and Lu. chagasi (Costa Lima). Lutzomyia chagasi was registered for the first time in Maranhao state and Lu. saulensis (Floch & Abonnenc), Lu. monstruosa (Floch & Abonnenc) and Lu. gomezi were found for the first time in the eastern part of the state, since they had been reported only in the Amazonian region of Maranhao. Regarding to the studied environments, the urban chicken house had the highest number of specimens collected (801), while the Gallery Forest was the most diverse (15 species). This study demonstrates that the northeast cerrado exhibits a mixed sand fly fauna characterized by an extremely important species vectors assortment involved in the epidemiological cycle of leishmaniasis in Maranhao state. PMID- 21271076 TI - Mosquito anthropophily: implications on malaria transmission in the Northern Brazilian Amazon. AB - Seasonal variation of adults and larvae of anophelines was studied during 2003 and 2004 in Roraima State, located in the Northern region of Brazilian Amazon. Species diversity increased with distance of capture to human dwellings. Greater diversity was found in extradomiciliary collections than in peridomiciliary or intradomiciliary. A significant association between Anopheles darlingi Root and An. albitarsis (s.l.) Arribalzaga (Diptera: Culicidae) breeding sites and the proximity to human dwellings was observed. Malaria Sporozoite Antigen Panel Assay (VectestTM Malaria) indicated An. albitarsis s.l. as one of the local vectors in the studied area. In this study, an index to describe the anthropophilic behavior of each anopheline species is proposed. PMID- 21271077 TI - Alternative techniques to study characters of the genitalia in Lepidoptera. AB - The present note aims to describe two alternative methods for observing genitalia in Lepidoptera. The first one provides means to examine both male and female genitalia without spoiling the scales of the abdomen, preserving it attached to the thorax and aesthetically similar to an unexamined specimen. The second one provides ways of observing certain characters on the male genitalia in a non destructive way, and does not depend on time-consuming removing and dissection of the abdomen. It is expected that the presented techniques will help on morphological studies and on identifying similar species which consistently differ in genitalic armatures. PMID- 21271078 TI - Epipona media cooper (Hymenoptera: Vespidae), a social wasp new to the Brazilian Atlantic Forest. AB - An occupied nest of Epipona media Cooper was discovered and collected in a cabruca (cocoa plantation with native tree cover). This is the first record of E. media from Bahia State. We described the nest structure and compared the adults with the closely related species Epipona tatua Cuvier. PMID- 21271079 TI - New host-plant records for the defoliator Ormiscodes amphimone (Fabricius) (Lepidoptera: Saturniidae). AB - Ormiscodes amphimone (Fabricius) is a phytophagous moth species known to severely defoliate woody species in Chile and Argentina. Here we document new records of O. amphimonehost associations emphasizing the role of Nothofagus pumilio as its primary host in our study area. This new record for Argentina is highly significant given the economic importance of N. pumilio as a timber resource and the potential of O. amphimone to generate extensive outbreaks. PMID- 21271080 TI - Frugivory by a stingless bee (Hymenoptera: Apidae). AB - Frugivory is not frequent among bees. Although stingless bees visit aged fruits for pulp, the use of fresh fruits is recorded only for Trigona hypogea Silvestri, a species that does not visit flowers. Here we report the occurrence of frugivory in Trigona amazonensis (Ducke), a flower-visiting stingless bee. PMID- 21271081 TI - Distribution and host range of Bephratelloides cubensis Ashmead (Hymenoptera: Eurytomidae) in Mexico. AB - The annona fruit borer wasp Bephratelloides cubensis Ashmead was recorded for the first time damaging "ilama" fruits Annona diversifolia (Anonaceae) in Coatlan del rio, Morelos, Cacahuamilpa and El Ocotillo, Guerrero, Mexico. Geographical distribution, hosts and damage are mentioned. PMID- 21271082 TI - Azteca barbifex Forel (Hymenoptera: Formicidae): potential pest of citrus crops in eastern Amazon. AB - Damage caused by the ant Azteca barbifex (Forel) was identified in orange trees (Citrus sinensis), in Capitao Poco County, Guama microregion, Para State. The damage caused by the scraping of stems and branches lead to reduction in yield with subsequent death of the plant. These characteristics indicate A. barbifex as a potential pest of citrus crops in the eastern region of Amazon. PMID- 21271083 TI - First record of Anastrepha pseudanomala Norrbom (Diptera: Tephritidae) and its host in Brazil. AB - Anastrepha pseudanomala Norrbom was reared in fruits of Couma utilis (Apocynaceae), and also collected in McPhail traps in Ferreira Gomes county, State of Amapa, Brazil. PMID- 21271085 TI - Interactive use of communication by verbal and non-verbal autistic children. AB - BACKGROUND: Communication of autistic children. AIM: To assess the communication functionality of verbal and non-verbal children of the autistic spectrum and to identify possible associations amongst the groups. METHOD: Subjects were 20 children of the autistic spectrum divided into two groups: V with 10 verbal children and NV with 10 non-verbal children with ages varying between 2y10m and 10y6m. All subjects were video recorded during 30 minutes of spontaneous interaction with their mothers. The samples were analyzed according to the functional communicative profile and comparisons within and between groups were conducted. RESULTS: Data referring to the occupation of communicative space suggest that there is an even balance between each child and his mother. The number of communicative acts per minute shows a clear difference between verbal and non-verbal children. Both verbal and non-verbal children use mostly the gestual communicative mean in their interactions. Data about the use of interpersonal communicative functions point out to the autistic children's great interactive impairment. CONCLUSION: The characterization of the functional communicative profile proposed in this study confirmed the autistic children's difficulties with interpersonal communication and that these difficulties do not depend on the preferred communicative mean. PMID- 21271086 TI - Written narrative practices in elementary school students. AB - BACKGROUND: Promotion of a written narratives production program in the third grade of an Elementary School. AIM: To analyze two written narrative practice proposals in order to verify which resources are more efficient in benefitting the textual productions of third grade Elementary School students. METHOD: Sixty students were selected from two third grade groups of a public Elementary School in Sao Paulo (Brazil). For the analysis, students were divided into two groups (Group A and Group B). Fourteen children's storybooks were used. In Group A, the story was orally told by the researchers in a colloquial manner, keeping the narrator role and the original structure proposed by the author. In Group B, the story was fully read. The book was projected onto a screen and read aloud so the students could follow the reading and observe the corresponding illustrations. Voice changing resources in the characters' dialogues were used. RESULTS: In the overall comparison, statistically significant results were found for moment (initial and final assessments) and for interaction between groups. It was observed that both groups presented substantial development from initial to final assessment. CONCLUSION: The Written Narratives Promotion Program based on the shared reading of children's storybooks constituted a more effective strategy than telling the stories using a single reader. PMID- 21271087 TI - Assessment of the swallowing function in older individuals referred to myocardial revascularization surgery. AB - BACKGROUND: Swallowing evaluation of older individuals with coronary disease referred to heart surgery. AIM: To identify the characteristics of the swallowing function in older individuals referred to myocardial revascularization surgery (MR), using an evaluating protocol composed by a water test, cervical auscultation and pulse oximetry. METHOD: The Assessment Protocol for Dysphagia Risk through a Combined Swallowing test and Vital Signs monitoring was used (PADTC)--measurements of HR and SpO2 (heart rate and oxygen saturation), water swallowing test with 1, 3, 5, 10, 15 e 20 ml, measurement of respiratory rate and cervical auscultation. The electronic stethoscope was used to analyze the number of swallows, response time and swallowing sound classification. In the Research Group (RG) older individuals with heart disease who were referred to MR were included. In the Control Group (CG) healthy older individuals were included. RESULTS: 38 older individuals were evaluated in the RG (mean age 68 years). In the CG, 30 older individuals were evaluated (mean age 70 years). There was a significant difference for the swallowing response time in older individuals with heart disease who presented HR below 60: swallowing response was shorter for 3 ml, 10 ml, 15 ml e 20 ml. HR was lower for individuals with heart disease. No significant difference was found between the groups for the other analyzed parameters. CONCLUSION: Older individuals with heart disease presented differences in the swallowing function when compared to healthy older individuals. Older individuals with heart disease presented alterations in the temporal coordination between breathing and swallowing, thus indicating risk for dysphagia. PMID- 21271088 TI - Oral narratives of children with typical language development. AB - BACKGROUND: Development of oral narrative. AIM: To verify narrative and pause duration, number of words and interlocutor's interventions in the oral narratives of children with typical development. METHOD: This study involved 31 subjects divided into four groups according to age: GI (3:1 to 4:0 years), GII (4:1 to 5:0 years), GIII (5:1 to 6:0 years) and GIV (6:1 to 7:0 years). Samples of spontaneous narrative and narrative based on a book without words were video recorded, transcribed and statistically analyzed using the Fisher's exact test (nonparametric) and the linear regression model with mixed effects. RESULTS: The results of pause duration, narrative duration and number of words were significantly higher for the narrative samples produced using a book than those obtained in the spontaneous narratives (p-value < 0.01). Regarding the number of interventions, a correlation (p-value = 0.03) between age and number of interventions was observed for the book context. It was observed that the number of interventions decrease with age. CONCLUSION: Children presented longer narratives in the book context. However, no significant differences were observed between the age groups. The results of the study also suggest that the interlocutor's interventions become less necessary with the aging process. PMID- 21271089 TI - Health sciences descriptors in the brazilian speech-language and hearing science. AB - BACKGROUND: Terminology in Speech-Language and Hearing Science. AIM: To propose a specific thesaurus about the Speech-Language and Hearing Science, for the English, Portuguese and Spanish languages, based on the existing keywords available on the Health Sciences Descriptors (DeCS). METHOD: Methodology was based on the pilot study developed by Campanatti-Ostiz and Andrade; that had as a purpose to verify the methodological viability for the creation of a Speech Language and Hearing Science category in the DeCS. The scientific journals selected for analyses of the titles, abstracts and keywords of all scientific articles were those in the field of the Speech-Language and Hearing Science, indexed on the SciELO. 1. Recovery of the Descriptors in the English language (Medical Subject Headings--MeSH); 2. Recovery and hierarchic organization of the descriptors in the Portuguese language was done (DeCS). The obtained data was analyzed as follows: descriptive analyses and relative relevance analyses of the DeCS areas. Based on the first analyses, we decided to select all 761 descriptors, with all the hierarchic numbers, independently of their occurrence (occurrence number--ON), and based on the second analyses, we decided to propose to exclude the less relevant areas and the exclusive DeCS areas. RESULTS: The proposal was finished with a total of 1676 occurrences of DeCS descriptors, distributed in the following areas: Anatomy; Diseases; Analytical, Diagnostic and Therapeutic Techniques and Equipments; Psychiatry and Psychology; Phenomena and Processes; Health Care. CONCLUSION: The presented proposal of a thesaurus contains the specific terminology of the Brazilian Speech-Language and Hearing Sciences and reflects the descriptors of the published scientific production. Being the DeCS a trilingual vocabulary (Portuguese, English and Spanish), the present descriptors organization proposition can be used in these three languages, allowing greater cultural interchange between different nations. PMID- 21271090 TI - Auditory measurements in parents of individuals with autosomal recessive hearing loss. AB - BACKGROUND: Audiological evaluation of parents of individuals with autosomal recessive hearing loss. AIM: To study the audiological profile of parents of individuals with autosomal recessive hearing loss, inferred by family history or by molecular tests that detected heterozygous mutations in the GJB2 gene. This gene codes Connexin 26. METHOD: Participants were 36 subjects, ranging between 30 and 60 years, who were divided into two groups: a control group composed by individuals without auditory complaints and without family history of hearing loss, and a research group composed by heterozygous parents of individuals with autosomal recessive hearing loss or heterozygous for connexin 26 mutations. All subjects underwent pure tone audiometry (0.25 to 8 kHz), high frequencies audiometry (9 to 20 kHz) and distortion product otoacoustic emissions (DPOAE). RESULTS: There were significant differences between the groups when considering the amplitude of DPOAE in the frequencies of 1001 and 1501 Hz. Amplitude was higher in the control group. There was no significant difference between the groups for pure tone thresholds from 0.25 to 20 KHz. CONCLUSION: The DPOAE were more effective, in comparison to the pure tone audiometry, to detect auditory differences between the groups. More studies of this type are necessary to confirm the observed results. PMID- 21271091 TI - Otoacoustic emissions growth rate threshold: distortion product in neonates. AB - BACKGROUND: Distortion product otoacoustic emission measures (DPOAE) verifies, among other characteristics, the emergence and growth rate of the DPOAE response according to sound stimulus intensity (growth curve). AIM: To estimate the DPOAE threshold in neonates according to the DPOAE growth curve at 2 kHz and 4 kHz, with stimulus presentation ranging between 35 and 70 dB SPL. METHOD: Participants were 51 neonates, with 24 to 84 hours of life and with no indication of risk for hearing impairment. The DPOAE were registered in the growth curve function at 2 kHz and at 4 kHz. Neonates were evaluated during the period of hospital stay, after birth. Three possible thresholds were considered (LIM 1, LIM 2 and LIM 3) based on the presence of response at 3 dB SPL in the signal to noise ratio. RESULTS: The average thresholds intensities ranged from 47.55 to 49.85 dB at 2 kHz and from 55.52 to 59.94 dB at 4 kHz. The mean amplitude response ranged from 6.67 to 8.27 dB at 2 kHz and from 6.99 to 11.35 dB at 4 kHz. There was significant difference between the three thresholds for the two studied frequencies. CONCLUSION: The procedure was feasible for the neonatal population revealing mean thresholds of up to 60 dB for both frequencies. Even though participants presented elevated thresholds, robust amplitude responses were observed. PMID- 21271092 TI - Computerized resources in language therapy with children of the autistic spectrum. AB - BACKGROUND: The use of computerized technology in language therapy with children of the autistic spectrum. AIM: To assess the interference of using computers and specific programs during language therapy in the functional communicative profile and socio-cognitive performance of children of the autistic spectrum. METHOD: 23 children with ages ranging between 3 and 12 years were individually video recorded prior to and after a set of 10 regular language therapy sessions (i.e. a total of two video samples per subject) using computerized games according to the child's choice. RESULTS: The following expressions were used by the therapists to describe the children's performance during the use of computers: more attentive, more communicative initiatives, more eye contact, more interactive, more verbalizations, more attention and more action requests. Qualitative and quantitative progresses were identified, although without statistical significance. Those progresses were observed after a time period that is smaller than the usually applied to this kind of comparison and it seems to be a promising result. CONCLUSION: More controlled associations and comparisons were not possible due to the groups' heterogeneity and therefore more consistent conclusions are not possible. It was clear that the subjects presented different reactions to the use of computerized resources during language therapy. PMID- 21271093 TI - Standardization of brainstem auditory evoked potential using a new device. AB - BACKGROUND: Standardization of Brainstem Auditory Evoked Potential (BAEP) using a new device. AIM: To standardize BAEP responses using a new device developed (NDD) in Brazil. METHOD: Analysis of absolute latencies, interpeaks and wave amplitudes of BAEP, using a new device developed to study normal-hearing groups (91 adults) and individuals (15 adults) with bilateral neurosensory hearing loss. Responses obtained in the EP15 hearing device/Interacoustics and the NDD were compared. For this, the following paramenters were used: non-filtered click of 100 microsecond (us), totaling 2000 stimuli in rarefied polarity, stimulation frequency of 13.1 clicks/s, intensity of 80 decibels normalized hearing level (dB nHL), with a window of 10 milliseconds and bandpass filter between 100 and 3000 Hertz (Hz). Significance level was set at 0.05. RESULTS: Absolute latency and interpeak means for 76 normal-hearing individuals with the NDD were: wave I=1.50, III=3.57, V=5.53, I-III=2.06, III-V=1.96 and I-V=4.02. When analyzing results according to gender, there was a statistically significant difference for the absolute latencies of waves III and V and in interpeaks I-III and I-V. Mean amplitude value of wave I=0.384 microvolt (uV) and of wave V=0.825 uV. There was no statistically significant difference between the absolute latencies and interpeaks of the two devices in the same individual. CONCLUSION: The components of BAEP with the NDD in normal-hearing subjects were similar regarding the tested ears, with statistically lower latencies in women. The BAEP latencies in the same individual with NDD were similar to those obtained with the EP15 / Interacoustics. Normal values of BAEP were obtained in normal-hearing adults. PMID- 21271094 TI - Impact of dizziness on the life quality of elderly with chronic vestibulopathy. AB - BACKGROUND: Dizziness impact on the quality of life (QoL) of elderly patients with chronic vestibular dysfunction. AIM: To evaluate the association between the impact of dizziness on the QoL of elderly patients with chronic vestibular dysfunction and demographic and clinical variables. METHOD: A prospective study. A hundred and twenty elderly patients with chronic vestibular dysfunction underwent the Brazilian version of the Dizziness Handicap Inventory (DHI). In order to verify the association between the QoL and the demographic and clinical variables, the following testes were used: Mann-Whitney, Kruskal-Wallis and Spearman's correlation coefficient. RESULTS: There were significant associations between the presence of rotating and non-rotating dizziness with the total score of the DHI (p = 0.010) and physical (p = 0.049) and functional (p = 0.009) subscales; between recurrent falls with total DHI (p = 0.004) and physical (p = 0.045), functional (p = 0.010) and emotional (p = 0.011) subscales. Significant correlations were found between functional incapacity and total DHI (r = + 0.557; p < 0.001) and physical (r = + 0.326; p < 0.001), functional (r = + 0.570; p < 0.001) and emotional (r = + 0.521; p < 0.001) subscales. CONCLUSIONS: The impact of dizziness on the QoL is higher in elderly patients with rotating and non rotating dizziness, recurrent falls and functional incapacity. PMID- 21271095 TI - Postural control of mouth breathing school aged children regarding gender. AB - BACKGROUND: Postural control of mouth breathing school aged children. AIM: To compare the posture and body balance of school aged children groups, with and without oral breathing considering the variable gender. METHOD: The study was developed at a municipal school in the city of Santa Maria (Brazil) and received prior approval of the ethics committee of the University of Santa Maria. The study group (with oral breathing) and the control group (without oral breathing) were selected based on an anamnesis, age (between 8 and 12 years), assessment of the stomatognathic system and auditory evaluation. The final sample was composed by 51 children in the study group (20 female and 31 male) and 58 in the control group (34 female and 24 male). Both groups were submitted to a dynamic posturography (sensory organization test--SOT) and to a postural assessment in right and left lateral view. RESULTS: Regarding the female gender, a statistically significant difference was observed for the angle that evaluates head horizontal alignment; for the SOT III value and for all SOT mean values. As for the male gender, a significant numerical difference was observed for the knee angle, for the ankle angle, for the SOT III value, for the SOT IV value and for all SOT mean values. CONCLUSION: School aged children with oral breathing present postural alterations; females present head positing alterations and males present alterations in the position of the inferior limbs. The body balance of school aged children with oral breathing, of both genders, demonstrated to be altered when compared to children without oral breathing, especially in the presence of sensorial conflict. PMID- 21271096 TI - Extralinguistic variables, gender and age, in the self-awareness of speech impairment. AB - BACKGROUND: Self-awareness of speech impairment according to the following extralinguistic variables: gender and age. AIM: To examine the influence of gender and age on the self-awareness of speech impairment. METHOD: Participants were 24 children with the diagnosis of phonological disorder, 15 boys and 9 girls, with ages ranging between 5:0 and 7:7 years. For this group the assessment of self-awareness of speech impairment was performed. RESULTS: Results indicated that 45.83% of the subjects presented self-awareness of speech impairment. There were no significant statistical differences between the studied extralinguistic variables and the self-awareness of speech impairment. However, a higher self awareness of speech impairment was observed for six-year-old male children. CONCLUSION: Children with phonological disorder can be self-aware of speech impairment; gender and age are not important factors for the development of this ability. PMID- 21271097 TI - Speech fluency profile in cluttering individuals. AB - BACKGROUND: Speech fluency in cluttering. AIM: To characterize and to compare the speech fluency in cluttering and fluent individuals. METHOD: Participants of this investigation were 14 individuals with ages between 8.0 and 40.11 years, of both genders, divided into two groups, paired by age and gender. GI was composed by 7 cluttering individuals and GII by 7 fluent individuals. The Speech Fluency Assessment Protocol was used to gather and to analyze the speech samples, taking into consideration the typology and frequency of speech disruption (SLD and OD) and speech rate, in words and syllables per minute. RESULTS: Data showed that the groups differed regarding the occurrence of the stuttering-like disfluencies and other disfluencies, number of words and syllables per minute. CONCLUSION: Cluttering individuals present a different fluency profile when compared to their fluent pairs. PMID- 21271098 TI - Maximum phonation time of vowels in adult women with vocal nodules. AB - BACKGROUND: Maximum phonation times (MPT) of vowels in adult women with vocal nodules. AIM: To verify and to correlate the values of MPT of vowels in young and middle-aged adult women with vocal nodules. METHOD: Database records from a speech therapy school-clinic were used, making up a total of 38 subjects. INCLUSION CRITERIA: female adults, aged between 20 and 53 years, with otorhinolaryngology diagnosis of vocal nodules. EXCLUSION CRITERIA: to present a laryngeal pathology other than vocal nodules; hearing loss ; oral breathing; history of neurological, psychiatric, endocrine or gastric disorders; flu or allergy history; drinking and/or smoking habits; previous speech therapy and/or otorhinolaryngology treatments. Anamnesis data, the otorhinolaryngology diagnosis, and the MPT measurements of vowels /a, i, u/ were verified for each subject. MPT evaluation consisted of the duration measurement of three emissions of the vowels, using habitual tone and intensity, until the end of exhalation, with the patient in a standing position, considering the highest value of each vowel. The results were statistically analyzed with a significance level of 5%. RESULTS: Representative age range; less representative MPT and mean, below normality and with a strong positive and meaningful correlation; moderate, positive and significant correlation between MPTs and their means. CONCLUSION: For the group of adult women with vocal nodules, the MPT values were reduced and positively correlated; the MPT of vowel /a/ presented a lower value when compared to the other investigated vowels. PMID- 21271099 TI - Perceptual analysis of adolescents' vocal stability during different phonation tasks. AB - BACKGROUND: Quality and frequency variability of adolescents' voice, during puberty, in different phonation tasks. AIM: To analyze the vocal stability of adolescents in three different phonation tasks using a voice perceptual analysis. METHOD: Participants were male students (n = 46 individuals), ranging in age from 13 to 15 years, from a public school in Campinas--SP. Voice samples were recorded using a digital recorder in three different tasks: speaking a sustained vowel /a/, counting from one to ten, and reading. Three voice specialists evaluated stability by means of voice perceptual analysis. For the voice samples that were considered unstable, the Analogical Visual Scale (AVS) of 10 cm was used to estimate the instability level, where zero means absence of instability and ten refers to maximum instability. RESULTS: 78.3% of the adolescents presented vocal instability when speaking the sustained vowel, varying from one to nine in the AVS. Only one adolescent presented unstable voice when counting numbers (level = 1). Vocal instability was not observed during reading for any of the participants. Vocal stability varied significantly among phonation tasks and adolescents showed greater instability during the sustained vowel (p<0.0001; g.l = 2). CONCLUSION: Counting numbers and reading do not detect vocal instability; the production of a sustained vowel demonstrated to be a better task. PMID- 21271100 TI - Oral language disorders and enuresis in children. AB - BACKGROUND: Co-occurrence of oral language disorders and enuresis in children. AIM: To identify and analyze the relationship between instances of oral language disorders and enuresis in children. METHOD: Clinical, quantitative and qualitative study, with a descriptive/interpretative outline, presented through two distinct situations. "Situation 1" refers to a group of 120 children between 3:0 and 10:0 years old, independently of gender and age, from a philanthropic Institution in Greater Sao Paulo. "Situation 2" refers specifically to the evaluation of children who have oral language disorders and enuresis. RESULTS: Results indicated that enuretic children present a higher percentage of oral language disorders when compared to non-enuretic children, especially phonological disorders and talking very little. These results support the studies on co-occurrence of enuresis and oral language disorders, presented in papers that attribute a bio-psychic etiology to this co-morbidity. CONCLUSION: Results indicated a relationship between enuresis and oral language disorders. Considering the interactions among language, body and psyche, it is suggested that speech therapists, when dealing with oral language disorders in children, also investigate the acquisition of their bladder sphincter control, in a bio psychical approach. PMID- 21271101 TI - Factors associated to bruxism in children from 4-6 years. AB - BACKGROUND: Bruxism has brought losses for the life quality of people. Its implications in the orofacial motricity and speech of children are still not well known. AIM: To investigate bruxism occurrence and associated factors concerning oral habits, orofacial motricity and functions of chewing, breathing and swallowing in children from 4 to 6 years. METHOD: 141 children from the referred age group who attend three education centers in Sao Paulo took part in the study. Parents filled in an investigation protocol on bruxism and the children were submitted to an orofacial motricity assessment. The research group was composed by children whose parents indicated habits of teeth clenching or grinding, during sleep or not. For the statistical analysis the Analysis of Variance, the Two Proportion Equality Test and the Odds Ratio calculation were used, with a significance level of 5%. RESULTS: A high occurrence of bruxism among the children (55.3%) was observed. The identified associated factors were: sialorrhea during sleep, pacifier use, habit of lip and fingernails biting, altered cheek tonus and bite, besides the participation of the perioral muscles during liquid swallowing. There was a high occurrence of children from both groups complaining about frequent headaches (76%) and who slept less hours than what is recommended for their age (35%). CONCLUSION: The findings corroborated the relationship among bruxism, oral habits and altered aspects of orofacial motricity in children from the studied age group, reinforcing the necessity of speech therapy actions next to the institutions and families. PMID- 21271102 TI - Cochlear implant: correlation of nerve function recovery, auditory deprivation and etiology. AB - BACKGROUND: The Auditory Nerve Recovery Function (REC) may be extracted from the Electrically Evoked Compound Action Potential (ECAP). ECAP may be influenced by the stimulation received (or the deprivation of stimulation) and by the etiology of the hearing loss, consequently it might affect the REC. AIM: To verify whether there is a correlation between the REC and each of the following factors: etiology, time of auditory deprivation and time of hearing aid use before cochlear implantation (CI). METHOD: Retrospective study. Data regarding etiology, time of auditory deprivation, time of hearing aid use before cochlear implantation were collected in children and adults who received a Nucleus(r)24. All patients who presented neural response at surgery and whose REC was assessed intraoperatively were included in this study. Fifty patients were selected, 26 children and 24 adults. Patients were divided according to the REC classification into three groups (GI: fast recovery; GII: intermediate recovery and GIII: slow recovery) to allow correlation analysis. RESULTS: Data analysis did not show any statistically significant correlation between the recovery function and the pre implant studied characteristics. Nevertheless, it was observed that there was a greater concentration of both, children and adults, in the intermediate recovery function values. GI did not present individuals with infectious etiologies, such as meningitis, rubella and cytomegalovirus. REC average scores were slower in infectious etiologies for both children and adults. CONCLUSION: There was no statistically significant correlation between the recovery function and factors such as etiology, time of auditory deprivation and time of hearing aid use prior to CI. PMID- 21271103 TI - Brainstem auditory evoked potential with speech stimulus. AB - BACKGROUND: Although clinical use of the click stimulus for the evaluation of brainstem auditory function is widespread, and despite the fact that several researchers use such stimulus in studies involving human hearing, little is known about the auditory processing of complex stimuli such as speech. AIM: To characterize the findings of the Auditory Brainstem Response (ABR) performed with speech stimuli in adults with typical development. METHOD: Fifty subjects, 22 males and 28 females, with typical development, were assessed for ABR using both click and speech stimuli. RESULTS: The latencies and amplitudes of the response components onset (V, A and complex VA), the area and slope that occur before 10 ms were identified and analyzed. These measurements were identified in all of the studied subjects and presented wave latency values (ms) of: V = 7.18 (SD = 1.08), A = 8.66 (SD = 1.13); Complex VA = 1.49 (SD = 0.43). For the wave amplitudes (uV), the values were: V = 0.29 (SD = 0.15), A = -0.3 (SD = 0.18); Complex VA = 0.58 (SD = 0. 25). The area measurements (uV X ms) and slope (uV / ms) were 0.27 (SD = 0.17) and 0.4 (SD = 0.17) respectively. CONCLUSION: Based on the gathered data it can be observed that this potential works as a new tool for understanding the encoding of sound at the brainstem level. PMID- 21271104 TI - Correlation between tracheoesophageal voice and speech and intraluminal pharyngoesophageal transition pressure. AB - BACKGROUND: Rehabilitation of individuals with total laryngectomy. AIM: To correlate the voice and speech proficiency of individuals with total laryngectomy, users of tracheoesophageal, prosthesis with the intraluminal pharyngoesophageal transition pressure at rest and during phonation. METHOD: Twelve individuals with total laryngectomy and with tracheoesophageal voice, users of speech prosthesis, were submitted to a voice and speech sample gathering and registration. These individuals were assessed by three experts using a specific protocol for the evaluation of tracheoesophageal communication. Individuals also underwent esophageal manometry in order to evaluate the intraluminal pharyngoesophageal transition pressure during rest and phonation. RESULTS: During phonation, individuals who had been characterized by the experts as good speakers (16.7%) presented average values of pressure amplitude during pharyngoesophageal transition of 27.48 mmHg. Average amplitude of 30.63 mmHg was observed for individuals classified as moderate speakers (52.5%), and of 38.72 mmHg for individuals classified as poor speakers (30.8%). During rest, the good speakers presented an average pressure of 14.72 mmHg, the moderate speakers of 13.04 mmHg and the poor speakers of 3.54 mmHg. CONCLUSION: The good speakers presented the lowest amplitude values of pharyngoesophageal transition pressure during phonation. However, the pressure observed in the rest condition was higher for the good speakers and lower for the poor speakers, suggesting that the raise in the pharyngoesophageal transition pressure during phonation damages the quality of tracheoesophageal communication when using speech prosthesis. PMID- 21271105 TI - Acoustical parameters of Brazilian Portuguese liquids in phonological disorder. AB - BACKGROUND: Phonological disorder is one of the most frequent speech and language deficit observed in children and therefore studies using objective evaluation measurements should be developed and implemented during the diagnostic process. AIM: To describe the acoustic characteristics of /l/ and /r/ liquid sounds. METHOD: Speech production samples of 20 children with and without phonological disorder were gathered and acoustically analyzed. Six words were selected for repetition: /se'bola/, /'lama/, [see text]. The analyzed acoustic parameters were F1, F2 and F3, duration and steady-state portion from the target sound and slope analysis. RESULTS: For words containing /l/, the duration parameter was the great differentiator between the two groups; values of the control group were higher than those found for the group with phonological disorder. Considering words containing /r/ that were correctly produced by the control group and that were always substituted by /l/ in the disordered group, parameters involving duration presented higher values in the disordered group. Slope analysis demonstrated higher values for the control group. CONCLUSION: Articulation accuracy of children in the control group was, overall, higher even when considering correctly produced words by the group with phonological disorder containing /l/. The analysis of other acoustic parameters, as well as the application of these parameters to other sounds of the Portuguese language, can help clinicians to make a precise evaluation and, consequently, to improve their therapeutic work. PMID- 21271106 TI - Auditory processing and phonological awareness in children with normal and deviant speech development. AB - BACKGROUND: Auditory processing (AP) and phonological awareness (PA) in children with and without phonological disorders. AIM: To compare the performance of children with and without phonological disorders in a PA test; to verify the possible relationship between performances in distinct tasks of this test with the performance in the AP evaluation. METHOD: Participants were 44 children with and without the diagnosis of phonological disorder, aged between 5:0 and 7:0 years, of both genders. After speech samples were gathered, subjects were divided into two groups: a study group (SG), composed by children with phonological disorders, and a control group (CG) with children without phonological disorders. PA was assessed through the Protocol Task Awareness Test (PTAT), and through the simplified AP evaluation (screening)--Disyllabic change--Staggered Spondaic Word (SSW), dichotic listening test and the binaural fusion test. RESULTS: In both PA and AP assessments, children of the CG obtained better results. When correlating the results of AP and PA, a greater number of correlations were observed for the SG. CONCLUSION: A significant relationship between the performance in the AP evaluation and success in PA tasks exists for children with phonological disorders. PMID- 21271107 TI - Story organization and narrative by school-age children with typical language development. AB - BACKGROUND: The narrative abilities provide valuable information about the linguistic, cognitive and social development of school-age children with typical language development (TLD). AIM: To examine the temporal ordering of figures and the narrative abilities of school-age children with TLD in relation to the type of discourse presented. METHOD: Participants of this study included 60 children with TLD aged between seven and ten years of age. Fifteen stories were used in the study. Each story was illustrated by four figures. The sequences of figures were created and classified as mechanical, behavioral and intentional according to the relationships presented among the characters. Data were transcribed and analyzed regarding the type of discourse (descriptive, causal and intentional) and the type of organization of the figures. RESULTS: No differences between age groups were observed for temporal ordering. For all age groups, the most frequently presented discourse type was the causal one. Statistically significant differences were observed among age groups for the causal and intentional discourse type. Inasmuch as the age increased, school-age children with TLD reduced the use of the descriptive discourse and increased the use of the intentional one. CONCLUSION: The ability of temporal ordering is already developed in children with TLD at seven-years of age. The type of discourse was influenced by age and by the type of story presented. PMID- 21271108 TI - Reading and writing assessment scales: preliminary reliability evidences. AB - BACKGROUND: Reliability of Reading and Writing Assessment Instruments. AIM: To investigate the reliability of two scales created to evaluate both reading and writing of children with ages between 8:0 and 11:11 years. METHOD: Two scales were created: a reading scale, composed of 12 testing items organized into four competency fields (letter knowledge and phonographemic relation, decoding of isolated items, reading fluency, reading comprehension), and a writing scale, with five items organized into three fields (letter writing and graphophonemic relation, codification of isolated items, writing construction). One hundred students (64 girls) from Public Schools, with ages raging between 8:0 and 11:11 years, were selected. Twenty students (12 girls) participated in the applicability study, resulting in the study version of the Scales. These scales were later applied to the remaining 80 students (52 girls). The obtained responses were assessed and computed for score assignment: item scores, competence field score (CFS) and raw scale score (RSS). Data were submitted to statistical analysis: the Cronbach's alpha coefficient was calculated and correlations between items (Pearson's correlation coefficient) were verified. A significance level of 0.05 was used. RESULTS: a = 0.866 and a = 0.461 were obtained for the Reading and Writing Scales, respectively. Correlations between the items were observed, ranging from weak to strong, and confirmed the alpha values. CONCLUSION: The Reading Scale was proven reliable, achieving acceptable levels for diagnostic instruments; the Writing Scale did not present an acceptable reliability level to measure the performance of the tested children. PMID- 21271109 TI - Spectral findings for vowels [a] and [a] at different velopharyngeal openings. AB - BACKGROUND: The size control of velopharyngeal opening is an important variable for the acoustic profile characterization of hypernasal speech. AIM: To investigate frequency spectral aspects of F1, F2, F3, nasal formant (FN) and anti formant, in Hertz, for vowels [a] and [a] at different velopharyngeal openings produced in the bulb of a palatal prosthesis replica used by a patient with velopharyngeal insufficiency. METHOD: Speech recordings were obtained for four words ("pato/mato" and "panto/manto") produced within a carrier phrase in 5 conditions of velopharyngeal functioning: prosthesis with no openings (control condition: CC); prosthesis with bulb opening of 10 mm2 (experimental condition with 10 mm2 opening: EC10), prosthesis with a 20 mm2 opening (EC20), prosthesis with a 30 mm2 opening (EC30), and without the prosthesis (ECO). Five speech language pathologists made a live rating of speech nasality during the reading of an oral passage. The recordings were used for spectral analysis. RESULTS: F1 values were significantly higher for [a] when compared to [a] in all conditions. F2 values for [a] in EC20 and EC30 were significantly lower than values in the other conditions, being closer to the values presented for [a]. F3 values were not significantly different between the testing conditions. There was a relationship between FN and anti-formants, and the auditory perception of nasality for conditions EC10 and EC20. CONCLUSION: Significant changes were observed in the studied spectral values according to changes in the velopharyngeal opening size. PMID- 21271110 TI - (Central) auditory processing disorders in individuals with and without dyslexia. AB - BACKGROUND: Comparison of (central) auditory processing disorders in children with and without dyslexia. AIM: To compare the (central) auditory processing disorders in Brazilian children with and without dyslexia using speech in noise, dichotic digits and pattern of frequency tests. METHOD: Forty-five children with ages ranging between 7:0 and 12:11 years were assessed; twenty children composed the dyslexic group and twenty composed the (Central) auditory processing disorder group. The tests used involved closing aural, auditory figure-ground and temporal ordering abilities. RESULTS: Individuals of the (Central) auditory processing disorder group presented a higher alteration probability in the speech in noise and dichotic digits tests than those from the dyslexic group. CONCLUSION: Subjects from the dyslexic group presented different patterns of (central) auditory processing disorder, with greater alteration in the tests that evaluate the temporal processing when compared to the tests that evaluate other auditory abilities. PMID- 21271111 TI - Expressive language and cognitive development: diversity and complexity of children's productions. AB - BACKGROUND: Objective and systematized analysis of cognitive and expressive language development. AIM: To characterize expressive language and cognitive development considering the diversity and complexity of children's productions. METHOD: This study involved 20 subjects (10 male and 10 female), who were adequate for gestational age and birth weight and had no pre, peri or post natal intercurrences. Participants were submitted to 30-minute sessions, once a month, for the observation of expressive language and cognitive development. The observations were made during the period that went from eight to 18 months of age, using the material and application procedures suggested by the PELCDO-r. RESULTS: The amount of different schemes, gestures and verbalizations that children were capable of producing (diversity and complexity) are presented and analyzed considering each one of the 30-minute sessions as well as the overall total during the period of observation (from eight to 18 months). CONCLUSION: The PELCDO-r allowed the characterization of expressive language and cognitive development by means of the objective observation of this process concerning the diversity and complexity of subjects' productions, considering the period between the fourth phase of sensorimotor stage and the beginning of preoperational stage. PMID- 21271112 TI - Contrast and covert contrast in the speech production of children. AB - BACKGROUND: Speech acoustics. AIM: To acoustically analyze the substitution between /t/ and /k/ in the speech production of children with typical and deviant acquisition process in order to identify and quantify the presence of covert contrast. METHOD: The experiment involved the repetition of words that combined /t/ and /k/ with /a/ and /u/ in stressed position. Participants were 9 children divided in three groups: children in the acquisition process of the phonological contrast (G1); children with phonological disorder (G2); and children with typical productions (G3). The speech productions were analyzed and edited using software Praat. The acoustic parameters adopted were: burst spectral characteristics; CV transition and durational characteristics. Duration parameters were analyzed by Friedman ANOVA while the other parameters were analyzed using two-way ANOVA and Hierarchical Linear Modeling. The adopted statistical significance level was of 0.05. RESULTS: Acoustic analysis indicated the presence of covert contrast in the productions of children in G1 and G2 (80% and 57.14% of substitutions respectively). In addition, acoustic analysis revealed differences in how well the children differentiated the two occlusives and which acoustic parameters were used to differentiate them. CONCLUSION: A lot of the substitutions presented in the speech of children in typical and deviant acquisition process are in fact covert contrasts. Moreover, the acoustic analyses allowed the detection of differences in the fine phonetic detail of children's speech production. PMID- 21271113 TI - Temporal auditory processing: correlation with developmental dyslexia and cortical malformation. AB - BACKGROUND: Temporal auditory processing and developmental dyslexia. AIM: To characterize the temporal auditory processing in children with developmental dyslexia and to correlate findings with cortical malformations. METHOD: Twenty school-aged children, ranging in age from 8 to 14 years were evaluated. These children were divided into two groups: the experimental group (EG) was composed by 11 children (eight were male) with developmental dyslexia and the control group (CG) was composed by nine normal children (six were male). After neurological assessment and verification of the intellectual level, language, reading and writing skills in order to determine the diagnosis, children underwent a peripheral audiological evaluation and Random Gap Detection Test and/or Random Gap Detection Test Expanded. RESULTS: A statistically significant difference between children in the EG and CG were observed, with children in the EG presenting worst performances. Most of the children in the EG presented perisylvian polymicrogyria. CONCLUSION: Children with developmental dyslexia may present temporal auditory processing disorders with deficits in phonological processing. Cortical malformations may be the anatomical substrate of these disorders. PMID- 21271114 TI - Acclimatization effect in speech recognition: evaluation without hearing aids. AB - BACKGROUND: After the adaptation of hearing aids, an improvement in speech understanding is expected to occur, called acclimatization. AIM: To determine the effect of acclimatization in sentences recognition threshold, for the conditions of silence (SRTQ) and noise (SRTN), in new users of hearing aids, evaluated prior to and after acclimatization, without the use of the hearing aids. METHOD: Participants were 40 individuals, aged between 28 and 78 years, with mild to moderate sensorineural hearing loss. Tests were conducted in three sessions: prior to the adaptation of the hearing aids, fourteen days and three months later.The Portuguese Sentences Lists test in free field was used for testing, and the SRTQ and SRTN were obtained (with noise level settled at 65 dB A). Results were expressed through the signal/noise ratios. RESULTS: The mean values for the SRTQ in the 1st, 2nd and 3rd sessions were 54.43, 51.71 and 52.22 dB A respectively,. The mean signal/noise ratios for the 1st, 2nd and 3rd sessions were 1.67, 0.30 and -0.03 dB A. When comparing the results obtained between the testing sessions, a statistically significant difference was observed between the 1st and 2nd sessions, and between the 1st and 3rd sessions for the values obtained in the testing conditions of silence and noise. CONCLUSION: There was a progressive reduction of sentences recognition thresholds and signal/noise ratios indicating an improvement in performance even when assessing the individuals without the hearing aids. This improvement can be related to the effect of acclimatization. PMID- 21271115 TI - Phonological changes obtained in the treatment of subjects comparing different therapy models. AB - BACKGROUND: There are many options of phonological disorder treatments that aim at improving children's communication. AIM: To analyze the Percentage of Consonants Correct-Revised, the number of acquired phonemes in the phonological system and the types of generalizations obtained in treatment, comparing different therapy models in subjects with different severity levels of phonological disorder. METHOD: Participants were 21 children, mean age 5:7 years. All subjects underwent speech, language and hearing evaluations and additional exams. Children were then divided into groups according to therapy model and severity level of phonological disorder. The Percentage of Consonants Correct Revised, the number of acquired phonemes and the types of generalizations were analyzed and compared within and between each therapeutic model, considering pre and post therapy evaluations. RESULTS: It was possible to observe improvement in the three analyzed therapy models. When comparing the therapy models, the greater improvement in percentage terms was observed for the ABAB-Withdrawal and Multiple Probes Model and the Maximal Oppositions Model, even though the statistical analysis indicated no significant difference. CONCLUSION: The three therapy models were effective for the treatment of children with phonological disorder because they all of them provided an increase in the Percentage of Consonants Correct-Revised, in the number of acquired phonemes and in the types of analyzed generalizations. PMID- 21271116 TI - School-aged children's performance in the Brazilian adaptation of the reading processes assessment. AB - BACKGROUND: Brazilian adaptation of the reading processes assessment (Prolec). AIM: To characterize and compare the performance of students from public and private teaching institutions from the 1st to the 4th grades in the adaptation of the reading processes assessment (Prolec). METHOD: 262 students from the 1st to the 4th grades of elementary school participated in this study. Participants were distributed as follows: Group I (GI) consisted of 122 students from the 1st to the 4th grades of public elementary schools and Group II (GII) consisted of 140 students from the 1st to the 4th grades of private elementary schools. The adapted version of the reading processes assessment (Prolec) was applied. RESULTS: The results indicated that GII performed better in tests of sound identification, word choosing, words reading, low-frequency words reading, pseudo words reading, sentences comprehension and text comprehension. Both groups presented a lower performance than the expected in Prolec tests Spanish version. CONCLUSIONS: The adaptation of the Prolec to the Brazilian reality appears to be appropriate for the establishment of a reading profile of students, from public and private teaching institutions, who are undergoing the initial phase of literacy. PMID- 21271117 TI - Long latency auditory evoked potentials in children with phonological disorder. AB - BACKGROUND: Auditory evoked potentials in children with phonological disorder. AIM: To characterize the long latency auditory evoked potentials (LLAEP) results N1, P2, N2 and P300 of children with phonological disorder and to verify the improvement of such potentials with speech therapy. METHOD: 25 children without phonological disorder (control group) and 41 with phonological disorder (study group) underwent a basic audiological evaluation and LLAEP. The study group was divided into two subgroups: subgroup A composed by 22 children, underwent 12 sessions of speech therapy and were submitted to audiological retesting after this period, and subgroup B composed by 19 children, who were also reassessed three months after the initial testing. RESULTS: Statistically significant differences between groups for the P2 and P300 latencies and P300 amplitude were observed. Comparison between the first and the second audiological assessments indicated no significant statistical differences between both subgroups regarding wave latencies. However, a significant statistical difference was verified for the P300 (study subgroup A) and P2/N2 (study subgroup B) wave amplitudes. The study group presented higher percentage of altered results in the P300; wave latency increase was the most frequent type of alteration. After speech therapy, the results of all components improved, however, there was no association between the improvement of LLAEP results with the background of otitis, as well as with the Percentage of Consonants Correct-Revised. CONCLUSION: Children with phonological disorder present altered P300 suggesting involvement of the central auditory pathway, probably due to alterations in the auditory processing, presenting improvement in all components of LLAEP results after speech therapy. PMID- 21271118 TI - The impact of stuttering on quality of life of children and adolescents. AB - BACKGROUND: Understanding the experience of people who stutter, both in and out treatment, will lead to improved outcomes. AIM: To investigate how stuttering affects the quality of life of children and adolescents who stutter. METHOD: The Overall Assessment of the Speaker's Experience of Stuttering--School-Age (OASES S) was used to assess the impact of stuttering and the Fluency Profile Protocol was used to stuttering severity. RESULTS: These age groups do experience moderate negative impact as measured by the OASES-S. The results showed a tendency toward a positive correlation between severity and the impact of stuttering on quality of life. CONCLUSION: A better understanding of the impact of stuttering in these age groups provides a needed guide for the development of stuttering treatments and treatment outcomes research. PMID- 21271119 TI - [Surgical treatment of morbid obesity gestational implications]. PMID- 21271120 TI - [What is the effectiveness of intracranial microcoil regarding surgical clipping in ruptured cerebral aneurysms ?]. PMID- 21271121 TI - Reviewing the guidelines from the Brazilian Ministry of Health for diagnosis of early pregnancy. PMID- 21271122 TI - [Borderline donors in liver transplantation]. PMID- 21271124 TI - [Bioethics at the bedside]. PMID- 21271125 TI - [Releasing Intrauterine System of Levonorgestrel and risk for breast cancer. ]. PMID- 21271126 TI - [Colon myiasis]. PMID- 21271127 TI - [Intradermal cerebriform nevus as cause of cutis verticis gyrata]. PMID- 21271128 TI - [Respiratory muscle training programs: impact on the functional autonomy of the elderly]. AB - OBJECTIVE: To compare two respiratory muscle training programs for improving the functional autonomy of institutionalized elderly. METHODS: Clinical randomized trial conducted at a long stay institution with 42 elderly volunteers that were divided into three groups: Group (r) Threshold (GT) with mean age (70.93 +/- 8.41), Group Voldyne (r) (GV) (70.54 +/- 7.73) and Control Group (CG) (73.92 +/- 7.28). Groups GT and GV were treated with breathing exercises and muscle training by Threshold and Voldyne, respectively while the CG did just breathing exercises. Training of groups took 10 weeks. To assess the functional autonomy, the elderly were evaluated before and after training, according to the GDLAM protocol. RESULTS: All intra-group comparison (pre x post-test) showed a significant difference in GT for all tests (C10M: Delta% = -20.57, p = 0.0001; LPS: Delta% = 13.53, p = 0.020; VTC: Delta% = -27.96, p = 0.0001; LCLC: Delta% = -18.71, p = 0.0001 and IG:% Delta = -18.43, p = 0.0001), except in LPDV. In GV there was a significant difference only (p <0.05) for the C10M (% Delta = -17.11, p = 0.004). In the comparison between (post x post), there was a statistical significance (p <0.05) for VTC test between the GT and GV (Delta = -3.62%, p = 0.017), with favorable results for the GT. Similarly, there was a statistical difference (p <0.05) in GT C10M (% Delta = -3.83, p = 0.023), LCLC (Delta = -34.02%, p = 0.012) and IG (Delta% = -13.63, p = 0.004) compared to GC. CONCLUSION: The trained groups improved functional autonomy, reaching 27.42; considered to be a weak level in both pre-and post-training. PMID- 21271129 TI - [Stress urinary incontinence in women belonging to the Family Health Program of Dourados/MS]. AB - OBJECTIVE: To describe prevalence of stress urinary incontinence (SUI) in women over 20 years of age, who participate in the Family Health Program (FHP) in Dourados, Mato Grosso do Sul, Brazil and to correlate with the following variables: age, body mass index (BMI), parity, number of pregnancies, hysterectomy, smoking and diabetes mellitus. METHODS: The study was cross sectional, using a household survey, where 336 women above 20 years of age and who did not have exclusion criteria were interviewed. Two forms were used in the interview: to complete demographic data and ICIQ-SF questionnaire, that evaluates impact on the quality of life (QL). For statistical analysis, the Chi-square test, Student's t test the corrected coefficient contingency and a forward stepwise logistic regression model were used. RESULTS: Prevalence of SUI in the study was 21.4%. In relation to the risk factors, age (p = 0.113), smoking (p = 0.796) and diabetes mellitus (p = 0.221) had no statistically significant association. On the other hand, the BMI (p = 0.007), number of pregnancies (p = 0.018), parity (p = 0.032) and hysterectomy (p = 0.024) presented association, however weak. Using logistic regression, only pairing of weight and hysterectomy were able to predict the outcome (SUI). The majority of patients (63.9%) had considered impairment in the QL as very serious. CONCLUSION: Prevalence of SUI observed was similar to that of other studies; BMI, parity, number of pregnancies and hysterectomy were associated with that pathology, which has a serious effect on the QL. PMID- 21271130 TI - Cardiovascular and renal anomalies in Turner syndrome. AB - OBJECTIVE: To evaluate the frequency and type of cardiovascular (CV) and renal/collecting system (R/CS) abnormalities seen in a sample of patients with Turner Syndrome (TS) and to verify the proportion of those anomalies detected only after diagnosis was established. METHODS: Retrospective study of 130 patients with TS diagnosed in an outpatient setting between 1989 and 2006. The mean age at diagnosis was 11.9 years. Data were obtained by personal history of CV and R/CS disorders and by results of echocardiogram and ultrasonography of the kidneys and collecting system performed after diagnosis. RESULTS: 25.6% of patients who underwent echocardiograms presented CV abnormalities. Among them, mitral regurgitation (21.4%), bicuspid aortic valve (19%) and aortic coarctation (19%) were the most frequent. R/CS anomalies were found in 29.3% of patients who underwent ultrasonography. Among them, duplication of the collecting system and hydronephrosis (25% each) and horseshoe kidney (21.2%) were the most frequent. In about 80% of cases there was no previous knowledge of these anomalies. CONCLUSION: The frequency of CV and R/CS abnormalities found in this study was similar to that of previous studies, but most were found in routine exams after TS diagnosis. Thus, early detection of associated anomalies depends on early detection of TS. PMID- 21271131 TI - [Severe injuries from falls on the same level]. AB - OBJECTIVE: Assess characteristics of trauma patients who sustained falls from their own height, more specifically focusing on presence of severe injuries, diagnosis and treatment. METHODS: Retrospective study including all adult blunt trauma patients admitted in the emergency room in a period of 9 months. Lesions with AIS (Abbreviated Injury Scale)>3 were considered "severe". Variables were compared between victims of fall from their own height (group I) and other blunt trauma mechanisms (group II). Student's t, chi square and Fisher exact tests were used for statistical analysis, considering p<0.05 as significant. RESULTS: Of the 1993 trauma patients included, 305 (15%) were victims of falls from their own height. In group I, mean age was 52.2 +/- 20.8 years and 64.8% were male. Injuries in the head segment were the most frequently observed (62.2%), followed by injuries in the extremities (22.3%), thorax (1.3%) and abdomen (0.7%). Severe injuries (AIS>3) were more frequent in the head (8.9%), followed by extremities (4.9%). In group I, craniotomies were needed in 2.3%. By comparing groups, we observed that victims of falls from their own height had significantly higher mean age, higher mean systolic blood pressure, and higher head AIS mean, as well as lower ISS mean, thorax AIS mean, abdomen AIS mean and extremities AIS mean. CONCLUSION: Importance of the trauma mechanism in victims of falls from own height should be emphasized due to a considerable possibility of occult severe injuries, mainly in the cephalic segment. PMID- 21271132 TI - [Waist circumference as indicator of body fat and metabolic alterations in teenagers: comparison among four references]. AB - OBJECTIVE: Assess diagnostic validity of four reference tables for waist circumference in female teenagers in order to detect lipid alterations, hyperinsulin, elevated homeostasis model assessment (HOMA), hyperleptinemia and excess of body adiposity. METHODS: A total of 133 female subjects, ranging from 14 to 19 years of age , were evaluated. All adolescents were recruited from public schools in Vicosa/MG. Blood samples were collected for determination of fasting plasma cholesterol total, LDL, HDL, triglycerides, insulin and leptin. Percentage of body fat was determined through tetrapolar electrical bioimpedance. Using the smallest abdominal measure it was possible to determine waist circumference and calculated values of sensibility, specificity, positive and negative predictive values. Waist circumference contingency tables were obtained using four criteria: Freedman et al., 1999; Taylor et al., 2000; McCarthy et al., 2001; and Moreno et al., 2007. RESULTS: In general, sensibility values were low for circumferences assessed and the highest values were obtained for the table of McCarthy et al., on the other hand, specificity values were high considering the table of Freedman et al. The positive predictive values were more relevant for total cholesterol and body fat percentage. CONCLUSION: Cutoffs for waist circumference used by McCarthy et al. were the most appropriate for populational assessments. Freedman's et al. proposal is appropriate for clinical use since it presents higher specificity. In addition, it can substitute high costs exams, out of the professionals' reach such as insulin and leptin. PMID- 21271133 TI - [Assessment of fetal vitality and perinatal results in pregnancies after gastroplasty with Roux-en-Y gastric bypass]. AB - OBJECTIVE: To study fetal vitality assessed in pregnancies after gastroplasty with Roux-en-Y gastric bypass and verify maternal complications and perinatal results. METHODS: Hospital charts of all pregnancies after gastroplasty with Roux en-Y gastric bypass were reviewed retrospectively. All cases followed at the specialized prenatal care that gave birth in this institution, between July 2001 and September 2009, were reviewed. The assessment of fetal vitality (cardiotocography, fetal biophysical profile and umbilical artery Doppler velocimetry) performed in the last week before delivery were analyzed. The maternal variables investigated were: demographic data, maternal complications, mode of delivery, complications during delivery and postpartum, maternal blood exams and perinatal results. RESULTS: During the study period 30 pregnancies after gastroplasty with Roux-en-Y gastric bypass were identified and 24 of them had undergone assessment of fetal vitality. All patients presented normal cardiotocography, normal fetal biophysical profile and normal results at the umbilical artery Doppler velocimetry. One case presented with oligohydramnios. The main complication observed was maternal anemia (Hb < 11.0 g/dL, 86.7%). Cesarean section was performed in 21 pregnancies (70%). Delivery complications included one case of adherences, one hematoma and infection of abdominal wall scar and one postpartum hysterectomy for myoma and uterine atony. The proportion of small infants for gestational age was 23.3%. CONCLUSION: Fetal vitality was not compromised in pregnancies after gastroplasty with Roux-en-Y gastric bypass. The main maternal complication was anemia, therefore these women require specific nutritional counseling and a broad evaluation for micronutrient deficiencies at early pregnancy. PMID- 21271134 TI - [Quality of prescriptions in a city of Minas Gerais: a pharmacoepidemiological approach]. AB - OBJECTIVE: To evaluate the quality of medical prescriptions dispensed in pharmacies. METHODS: This cross-sectional study was conducted to assess if prescriptions met all the necessary requirements. A total of 800 prescriptions was collected in four different pharmacies in the city of Muriae, MG. Prescriptions were assessed according to the requirements of the WHO indicators, including presence and legibility of essential information. RESULTS: Each prescription contains an average of 2.2 medications, and 22.1% of drugs were antibiotics. Drugs were prescribed by generic name in 33% of all prescriptions and 46.5% were part of RENAME. As for readability, 32% of prescriptions had poor legibility, 36% were illegible, and 32% readable. Essential information was lacking in several respects: the pharmaceutical form (64%), concentration (47%), dose (22%), interval between doses (63%), duration of treatment (30%) and route of administration (84%) were absent in prescriptions. CONCLUSION: The prescriptions assessed in this study did not provide all the information necessary for correct and safe use of medication and drugs. They were largely legible, showed a high percentage of trade names with limited presence in the RENAME and many were for antibiotics. PMID- 21271135 TI - [Cytogenetic analysis of material from spontaneous abortion]. AB - OBJECTIVE: To describe chromosomal abnormalities in spontaneous abortion material. METHODS: A retrospective compilation of karyotype analysis of slides stained with Band G was carried out by optical microscopy with materials of 428 abortion products referred for study. RESULTS: There were 145 normal results (33.9%) and 237 abnormal results (55.4%). In 46 samples there was no cell growth (10.7%). Numerical abnormalities were the most frequent, especially trisomy 16 (41 cases), triplodia (27 cases), monosomy X (26 cases), tetraploidy (13 cases) and trisomy 15 (13 cases). CONCLUSION: Cytogenetic alterations are an important cause of pregnancy loss and their detection helps the genetic counseling to the couple. Trisomy 16 is the most often found change. PMID- 21271136 TI - [Hospitalization due to motorcycle accidents in the Paraiba Valley using spatial analysis]. AB - OBJECTIVE: To identify clusters of municipalities with high rates of hospitalization due to motorcycle accidents in the "Vale do Paraiba". METHODS: This was an ecological study and exploratory data was obtained by DATASUS for the period 2001 to 2005 in 27 municipalities in the "Vale do Paraiba Paulista", covering a population of about one million inhabitants. The spatial analysis used the program Terraview and the Moran Global coefficients with respect to hospitalization rate and fleet of motorcycle were obtained. while the Pearson correlation was used for admission. Thematic maps of spatial distribution and of the BoxMap were constructed . Hospitalization data were addressed as rates per 100 thousand inhabitants. RESULTS: During the study period 1268 people were admitted, ranging from one to 608 hospital admissions per municipality. The coefficient of Moran Global IM = 0.34 (p = 0.02) for hospitalization rate and IM = 0.42 (p = 0.012) for admission rate according to the fleet. For hospitalization rate due to motorcycle accidents, there was also strong correlation between fleet of motorcycle and hospitalization (r = 0.94). CONCLUSION: A large cluster involving nine municipalities in the western region of the Paraiba Valley could be identified, thereby locating the residence of those hospitalized for motorcycle accidents, highlighting municipalities where preventive measures should be enforced. PMID- 21271137 TI - [Evaluation of factors related to the occurrence of female urinary incontinence]. AB - OBJECTIVE: To evaluate the risk factors related to occurrence of female urinary incontinence. METHODS: A case-control study that included 253 women (102 continent and 151 incontinent) invited to respond to an epidemiological questionnaire on possible risk factors for urinary incontinence. They were age, hormone status, race, body mass index, parity, types of deliveries (normal, forceps or cesarean), weight of largest newborn, use of episiotomy and/or analgesia during labor, history of hysterectomy, physical activity, smoking, diabetes mellitus, constipation, history of bronchial asthma and/or chronic obstructive pulmonary disease, use of diuretics and/or antidepressants. RESULTS: After application of binary logistic regression model we found, as risk factors for occurrence of urinary incontinence: age [OR = 1.07 (CI 1.03 to 1.1)], vaginal delivery [OR = 1.5 (CI 1.1 to 12.0)], forceps delivery [OR = 35.0 (CI 3.7 to 327)] and weight of largest newborn [OR = 1.001 (CI 1-1.002)]. Furthermore, we identified as a protective factor cesarean delivery [OR = 0.39 (CI 0.23 to 0.65)]. CONCLUSION: The independent risk factors for occurrence of urinary incontinence included age, vaginal delivery, forceps delivery and weight of largest infant and as a protective factor, cesarean section delivery. PMID- 21271138 TI - [Professional background and experience of antiretroviral prescribing physicians in the State of Sao Paulo]. AB - OBJECTIVE: Analysis of the professional profile of physicians who prescribe antiretroviral drugs (ARV) to HIV infected persons in the State of Sao Paulo. METHODS: Databases from different sources, namely Ministry of Health, Sao Paulo State Regional Medical Council, National Commission on Medical Residency and the Lattes platform, were consulted. Data concerning socio-demographic characteristics, academic and professional background and experience for the period from October 2007 to May 2009 were analyzed. RESULTS: The regular ARV prescription for 74 thousand patients was issued by 1,609 physicians whose characteristics are: evenly distributed according to gender, aged between 30 to 49 years, live in the metropolitan area of Greater Sao Paulo, graduated 16.1 years ago on the average, come from 93 different Brazilian medical schools, hold a specialty diploma in 67.5% of cases, most of them in the field of Infectious Diseases (38.9%). The mean number of patients per physician was 10, though 51.6% of physicians prescribed for 20 or more patients. Of these physicians 62% reported specific knowledge or experience with HIV care, although 2.7% of all prescriptions were issued by physicians without this specific qualification. Regions of high AIDS incidence showed a smaller number of prescribing physicians. The cities of Registro and Ribeirao Preto showed the highest concentration of physicians lacking proper credentials. CONCLUSION: The absolute majority of HIV patients receives their prescriptions from duly trained and experienced physicians. Nevertheless, the large number of non-qualified physicians together with the reduced number of physicians in HIV high incidence regions make up the major challenge for comprehensive and adequate care of HIV patients. PMID- 21271139 TI - [Physical activity in the prevention of diabetes in black ethnicity: how much is required?]. AB - OBJECTIVE: Analyze how much total physical activity (intensity and duration) is required and its different domains (work, commuting, household, and leisure time) as predictors of absence of diabetes in the black ethnicity population. METHODS: The design was cross-sectional with a sample of 2305 adults from 20 to 96 years of age, 902 (39.1%) male, living in the city of Salvador, Brazil. Receiver Operating Characteristic curves (ROC) were constructed to compare the areas of amount of physical activity in their different domains with absence of diabetes. Sensitivity and specificity were also established to identify the best cutoffs for the amount of physical activity related to absence of diabetes. Based on these cutoff points, a multivariate model was constructed to identify the association between physical activity and diabetes. RESULTS: Among the different amounts of physical activity greater significance was found in areas under the ROC curve for total physical activity, moderate activities performed during leisure time and work among men and commuting among women. Walking by itself was not a good predictor of absence of diabetes among men. It was also observed that 185 minutes/week of physical activity accumulated in different domains for men and 215 minutes/week for women were the best cutoffs for predicting absence of diabetes. CONCLUSION: Physical activity accumulated in different domains should be suggested in amounts suitable for a black ethnicity population in order to contribute to diabetes prevention. PMID- 21271140 TI - [Jehovah's Witnesses attitude towards hemocomponents and hemoderivatives]. AB - OBJECTIVE: To study extent of knowledge and acceptance of hemocomponents and hemoderivatives, fresh and stored, by Jehovah's Witnesses and also propose bioethical tools for any ethical and moral conflicts identified in their relationship with physicians and dentists. METHODS: A questionnaire was used to interview 150 Jehovah's Witnesses who attend "Saloes do Reino" in the Distrito Federal, Brazil. The questionnaire was directed towards information on socio demographic aspects related to the use (or not) of hemocomponents and hemoderivatives by those interviewed and also approach of healthcare professionals with patients of this belief. RESULTS: 74% believe that the use of blood causes more harm than benefits to health--refusal is essentially based on the Bible 96% do not support hemocomponents, but 76% support hemoderivatives in specific situations, showing that personal understandings do exist; 80% feel morally offended with use of stored blood and only 45% with fresh blood, confirming the religious interpretation that fresh products are in general more accepted; according to 83% of the interviewees dentists do not ask about patients' religion, whereas 71% of physicians do, showing little professional concern about this aspect. CONCLUSION: Jehovah's Witnesses are seen by their "moral outsiders" (here physicians and dentists) as the religious group that simply "does not use blood". Although, several blood treatments are nowadays permitted, it does not deprive them from a free conviction to refuse blood treatments. Their particular understandings frequently extend the list of blood prohibitions and, consequently, the number of moral conflicts, when considering that physicians and dentists usually do not ask about a patient's religion. PMID- 21271141 TI - [Assessment of endometrial morphology and histology in postmenopausal women]. AB - OBJECTIVE: Evaluate in outpatients, the endometrial morphology and histology of non-bleeding postmenopausal women. METHODS: We conducted a descriptive study where 52 menopausal women were selected, between 50 and 60 years of age, who had not used hormone replacement therapy in the last six months and did not present any kind of vaginal bleeding after menopause. These women underwent ultrasound examination, hysteroscopy and biopsy, and then endometrial findings were analyzed. RESULTS: Of the 52 women selected, thirty two (61.5%) had normal ultrasound, normal uterine cavity with atrophic endometrium, hysteroscopy, confirmed by endometrial biopsy. Twenty (38.4%) had hysteroscopic and histologic alterations and only five women showed by ultrasound an endometrial thickness of more than five millimeters. CONCLUSION: Diagnostic Hysteroscopy associated with aspiration biopsy (Pipelle) performed in the day care facility can reveal endometrial alterations that cannot be diagnosed by transvaginal ultrasound. PMID- 21271142 TI - [Melatonin: cell death modulator]. AB - Apoptosis or programmed death is a biological phenomenon, which is essential for the development and maintenance of a cell population. In this process, senescent or damaged cells are eliminated after activation of a cell death program involving participation of pro-apoptotic molecules (Fas, Fas-L, Bax, caspases 2, 3, 6, 7, 8 and 9). Molecule activation causes typical morphological changes, such as cell shrinkage, loss of adhesion to the extracellular matrix and neighboring cells, chromatin condensation, DNA fragmentation and formation of apoptotic bodies. Anti-apoptotic molecules (Bcl-2, FLIP) block the emergence and evolution of these cell changes and prevent cell death. The balance between molecules pro and anti-apoptotic ensures tissue homeostasis. When apoptosis is out of control, it contributes to the emergence of several neoplastic, autoimmune and neurodegenerative diseases. Several inducing and inhibitors of apoptosis agents are recognized as potential weapons in the fight against diseases related to proliferation and cell death disorders among which stand out hormones. Melatonin has been reported as important anti-apoptotic agent in various tissues by reducing cell calcium uptake, modulating expression of anti-oxidants and decreasing pro-apoptotic protein, such as Bax. The knowledge of new agents capable to act on the course pf apoptosis is important and of great value for developing further therapies against many diseases. Thus, the objective of this review was to elucidate the main aspects of cell death by apoptosis and the role of melatonin in this process. PMID- 21271143 TI - Lung volume reduction surgery: an overview. AB - This study intends to review the literature on the efficacy, safety and feasibility of lung volume reduction surgery (LVRS) in patients with advanced emphysema. Studies on LVRS from January 1995 to December 2009 were included by using Pubmed (MEDLINE) and Cochrane Library literature in English. Search words such as lung volume reduction surgery or lung reduction surgery, pneumoplasty or reduction pneumoplasty, COPD or chronic obstructive pulmonary disease and surgery, were used. We also compared medical therapy and surgical technique. Studies consisting of randomized controlled trials, controlled clinical trials (randomized and nonrandomized), reviews and case series were analyzed. Questions regarding validity of the early clinical reports, incomplete follow-up bias, selection criteria and survival, confounded the interpretation of clinical data on LVRS. Patients with upper, lower and diffuse distribution of emphysema were included; we also analyzed as key points perioperative morbidity and mortality and lung function measurement as FEV1. Bullous emphysema was excluded from this review. Surgical approach included median sternotomy, unilateral or bilateral thoracotomy, and videothoracoscopy with stapled or laser ablation. Results of prospective randomized trials between medical management and LVRS are essential before final assessment can be established. PMID- 21271145 TI - [Physical exercise and preterm birth]. PMID- 21271144 TI - [The molecular basis of RH system and its applications in obstetrics and transfusion medicine]. AB - The Rh system is the most polymorphic and immunogenic for all blood group systems. Currently more than 49 antigens were identified with five major antigens D, C, c, E, e. Knowledge of the Rh system's molecular basis, since its first cloning 17 years ago, allowed to understand the mechanism of Rh-negative phenotype and the variants of antigens as RHD and RHCE. Deletions, gene rearrangements and insertions are the main mutations. In Caucasians the primary mechanism of Rh-negative phenotype is the complete RHD gene deletion, while in African descendants it is the presence of pseudogene and gene RHDpsi hybrid RHD CE (4-7)-D. The authors analyze the structure of the Rh complex in red cells, molecular basis of the Rh system, mechanisms of Negativity RHD and weak and incomplete expression of RHD. PMID- 21271146 TI - [Comparison of fetal heart rate patterns in the second and third trimesters of pregnancy]. AB - PURPOSE: to compare the patterns of fetal heart rate (FHR) in the second and third trimesters of pregnancy. METHODS: a prospective and comparative study performed between January 2008 and July 2009. The inclusion criteria were: singleton pregnancy, live fetus, pregnant women without clinical or obstetrical complications, no fetal malformation, gestational age between 24 and 27 weeks (2nd trimester - 2T) or between 36 and 40 weeks (3rd trimester - 3T). Computerized cardiotocography (System 8002 - Sonicaid) was performed for 30 minutes and the fetal biophysical profile was obtained. System 8002 analyzes the FHR tracings for periods of 3.75 seconds (1/16 minutes). During each period, the mean duration of the time intervals between successive fetal heart beats is determined in milliseconds (ms); the mean FHR and also the differences between adjacent periods are calculated for each period. The parameters included: basal FHR, FHR accelerations, duration of high variation episodes, duration of low variation episodes and short-term variation. The dataset was analyzed by the Student t test, chi-square test and Fisher's exact test. Statistical significance was set at p<0.05. RESULTS: eighteen pregnancies on the second trimester were compared to 25 pregnancies on the third trimester. There was a significant difference in the FHR parameters evaluated by computerized cardiotocography between the 2T and 3T groups, regarding the following results: mean basal FHR (mean, 143.8 bpm versus 134.0 bpm, p=0.009), mean number of transitory FHR accelerations > 10 bpm (3.7 bpm versus 8.4 bpm, p <0.001) and >15 bpm (mean, 0.9 bpm versus 5.4 bpm, p <0.001), mean duration of high variation episodes (8.4 min versus 15.4 min, p=0.008) and mean short - term variation (8.0 ms versus 10.9 ms, p=0.01). The fetal biophysical profile showed normal results in all pregnancies. CONCLUSION: the present study shows significant differences in the FHR characteristics when the 2nd and 3rd trimesters of pregnancy are compared and confirms the influence of autonomic nervous system maturation on FHR regulation. PMID- 21271147 TI - [Assessment of the fetal mitral and tricuspid valves areas development by three dimensional ultrasonography]. AB - PURPOSE: to evaluate the areas of the atrioventricular valves (tricuspid and mitral) of normal fetuses by the use of three-dimensional ultrasound (3DUS) and the spatiotemporal image correlation (STIC) method. METHODS: a cross-sectional study was conducted on 141 women between the 18th and the 33rd week of pregnancy. Cardiac volumes were measured with a volumetric transabdominal transducer attached to the Voluson 730 Expert equipment. The four chamber plane was used as reference, with the region of interest (ROI) positioned from the ventricles, and the area of the valves was obtained manually. To determine the correlation of the areas with gestational age, scatter plots were constructed and the Pearson correlation coefficient (r) was calculated. Means, medians, standard deviations (SD) and maximum and minimum values were calculated. The simple linear regression model was used to determine reference ranges of valve areas according to the gestational age by the Altman method, with the level of significance set at p<0.05. To calculate the intraobserver reproducibility, we used the intraclass correlation coefficient (ICC) and the Bland-Altman graph. RESULTS: the mitral and tricuspid valve areas were correlated to the gestational age (r=0.80 for the tricuspid and r=0.79 for the mitral valve) and the mean value of the tricuspid and mitral valves increased from 0.22 +/- 0.10 cm2 and 0.23 +/- 0.10 cm2 on the 18th week to 0.92 +/- 0.29 cm2 and 1.08 +/- 0.41 cm2 on the 33rd of pregnancy, respectively. The intraobserver reproducibility resulted in an ICC=0.993 (95%CI 0.987; 0.996) and the mean difference was 0.01 cm2 (SD +/- 0.2 cm2 and CI95% +/- 0.4 cm2). CONCLUSION: reference intervals for the areas of the mitral and tricuspid valve between the 18th and the 33rd week of gestation were determined and proved to be highly reproducible. PMID- 21271148 TI - [Physical activity and quality of life in women aged 60 or older: associated factors]. AB - PURPOSE: to evaluate the level of physical activity, quality of life and associated factors in women aged 60 or older. METHODS: a cross-sectional study was conducted on 271 women who go to a Leisure Center and women attended at a menopause ambulatory in Campinas (SP). The women were invited to take part in the research, carried out through interviews. The instruments used were the version 8 of the International Physical Activity Questionnaire (IPAQ) modified for the elderly population in order to evaluate their physical activity, and the World Health Organization Questionnaire of Quality of Life specific for this group (WHOQOL-OLD) to evaluate their quality of life. IPAQ results were assessed using tertiles. The association between the WHOQOL-OLD and the IPAQ results and subject characteristics was assessed by the Student's t test, Mann-Whitney test and multiple analyses. RESULTS: the average age of women was 67.4 +/- 5.3 years. Among these women, 33% were classified as being less active. Analysis of each physical activity domain showed that 60.8% of the time was spent in sitting activities (1,701.6 +/- 986.1 minutes/week). Multiple analyses indicated that attending a leisure center in Campinas (SP) and being 70 years old or older increased the chances of engaging in moderate-intensity or vigorous-intensity physical activity by 11.4 and 2.8 times, respectively. The average quality of life score was 66.9 +/- 11.7. The highest value was observed in the domain related to sensory abilities (72.0 +/- 18.8) and the lowest value was related to autonomy (60.3 +/- 16.2). Linear regression showed that a good self-perception of health increased the quality of life score by 7.3 points, the use of a bigger amount of medication decreased it by 4.4 points and the performance of moderate or vigorous physical exercise increased the score by 4.8 points. CONCLUSION: women spend prolonged periods of time in sitting activities. The importance of engaging in moderate/vigorous-intensity physical activity is evident for obtaining a good quality of life. PMID- 21271149 TI - [Laparoscopy in the decision of treatment strategy for the infertile couple]. AB - PURPOSE: to evaluate the contribution of diagnostic laparoscopy to approach the infertile couple. METHODS: retrospective analysis of 86 consecutive cases of patients who were accompanied in the infertility appointments and were submitted to diagnostic laparoscopy from January 2004 to December 2006. Eighty-two of these patients had been submitted to hysterosalpingography (HSG) prior to laparoscopy. The laparoscopic findings were analyzed, as well as the accessory procedures, and the results of the hysterosalpingography and of the laparoscopy were correlated. Statistical analysis was performed by the use of the Statistical Package for the Social Sciences 15. The sensitivity and the specificity of HSG were determined and the confidence intervals were calculated with an alpha error of 0.05 (95%CI). RESULTS: the laparoscopy revealed 21 cases of endometriosis (24.4%), 14 cases of uni/bilateral inflammatory disease of the salpinx (16.3%), and 16 cases of pelvic inflammatory disease (18.6%). Adhesiolysis and ablation of endometrial lesions were performed in eight patients. There were also other accessory procedures: two salpingostomies, two paraovarian cystectomies, two ovarian cystectomies and three ovarian drillings. The tubal patency test during laparoscopy was normal in 44 cases (53%), revealed unilateral obstruction in 21 cases (25.3%) and bilateral obstruction in 17 cases (20.5%). The results of the hysterosalpingography were similar to those of the laparoscopy in 44 out of the 82 cases (53.7%). HSG sensitivity was 0.79 (95%CI=0.62-0.9) and its specificity was 0.58 (95%CI=0.42 0.73) when the disease was defined as any form of tubal occlusion detected with the laparoscopy, whether this occlusion was one-sided or two-sided. HSG sensitivity and specificity were 0.47 (95%CI=0.24-0.71) and 0.77 (95%CI=0.64 0.86), respectively, when the definition of the disease was limited to two-sided tubal occlusion. In nine cases (15.3%) in which HSG had shown normal findings or only a unilateral occlusion, laparoscopy revealed a two-sided occlusion. And in 15 cases (65.2%) in which HSG had shown a two-sided occlusion, laparoscopy revealed normal findings or one-sided occlusion. CONCLUSIONS: the laparoscopy demonstrated its diagnostic and therapeutic relevance, proving to have fundamental importance for the clarification of the tuboperitoneal status. It has permitted the development of concomitant accessory therapeutic procedures, thus defining the best treatment strategy for the infertile couples. PMID- 21271150 TI - [Concentration of steroid hormones in the follicular fluid of mature and immature ovarian follicles of patients with polycystic ovary syndrome submitted to in vitro fertilization]. AB - PURPOSE: to evaluate the concentration of steroid hormones in follicular fluid (FF) of small (10-14 mm) and large (> 18 mm) follicles of women with polycystic ovary syndrome (PCOS) submitted to controlled ovarian hyperstimulation (COH) and in vitro fertilization (IVF) cycles. METHODS: a case-control study was conducted on 13 infertile women with PCOS (17 cycles) and 31 infertile women due to male factor - Control Group (31 cycles). FF was aspirated individually and divided into four groups: G1 (FF of small follicles of the Control Group), G2 (FF of small follicles of the PCOS group), G3 (FF of large follicles of the Control Group) and G4 (FF of large follicles of the PCOS group). Estrogen, progesterone and beta-hCG were determined by chemiluminescence, and testosterone and androstenedione by radioimmunoassay. The unpaired t-test was used to compare the hormone determinations in the FF of the PCOS and Control Groups, and the four groups were compared by ANOVA. Fisher's exact test was used to compare the pregnancy rates. RESULTS: the small follicles of the two groups had lower progesterone levels (8,435 +/- 3,305 ng/mL) than large follicles (10,280 +/- 3,475 ng/mL), p-value <0.01. The progesterone levels of all follicles of group PCOS (8,095 +/- 4,151 ng/mL) were lower than Control (9,824 +/- 3,128 ng/mL), p value =0.03. Testosterone differed between G1 (326.6 +/- 124.4 ng/dL) and G3 (205.8 +/- 98.91 ng/dL), p-value <0.001, and between G3 (205.8 +/- 98.91 ng/dL) and G4 (351.10 +/- 122.1 ng/dL), p-value <0.001. Small follicles had higher testosterone levels (508.9 +/- 266 ng/dL) than large follicles (245.10 +/- 123 ng/dL), p-value <0.0001. The pregnancy rates did not differ between the PCOS (5/13, 38.5%) and the Control groups (9/31, 40.9%), p-value =072. CONCLUSIONS: women with PCOS had high testosterone concentrations in the FF, regardless of the stage of follicle development, and reduced progesterone levels, suggesting that paracrine factors may inhibit the secretion of the latter by follicular cells. The pregnancy rates showed that treatment with COH and IVF is a good option for women with infertility secondary to PCOS. PMID- 21271151 TI - [Body mass index influence in female urinary incontinence]. AB - PURPOSE: to evaluate and compare the effects of body mass index (BMI) on the severity of female urinary incontinence (UI) using the quality of life questionnaire King's Health Questionnaire (KHQ), variables of urodynamic studies and the medical history taken. METHODS: cross-sectional clinical study. We selected 65 patients with stress urinary incontinence (SUI) who were divided into three groups: Group I (BMI: 18-25 kg/m2), Group II (BMI: 25-30 kg/m2) and Group III (BMI>30 kg/m2). The KHQ domains were compared between these groups. In addition, some clinical history urodynamic data (presence of nocturia, enuresis, urgency and urge incontinence) were also related to BMI by calculating the Odds Ratio (OR). The BMI in the presence and absence of non-inhibited detrusor contractions and Valsalva leak point pressure (VLPP) <60 or > 60 cmH2O were evaluated. Finally, the correlation between BMI and the nine KHQ domains has been tested in order to detect some association. RESULTS: the KHQ did not record deterioration of quality of life in women with UI with increasing BMI in any of its areas. The OR for the presence of enuresis in relation to a BMI was 1.003 [CI: 0.897-1.121], p=0.962. The OR for nocturia was 1.049 [CI: 0.933-1.18], p=.425. The OR for urgency was 0.975 [CI: 0.826-1.151], p=0.762, and the OR for incontinence was 0.978 [CI: 0.85-1.126], p=0.76. We studied the BMI in patients with and without non-inhibited detrusor contractions and detected medians of 26.4 +/- 4.8 and 28.3 +/- 5.7 kg/m2, respectively (p=0.6). Similarly, the median BMI values for the groups with VLPP <60 and >60 cmH2O were 29.6 +/- 4.1 and 27.7 +/- 5.7 kg/m2, respectively (p=0.2). Finally, we failed to demonstrate an association between BMI and any of the nine KHQ domains by means of the Spearman correlation. CONCLUSION: there was no association of KHQ scores with BMI. There was also no correlation between the parameters of clinical history and of the urodynamic study with BMI. PMID- 21271152 TI - [Pre-eclampsia treatment according to scientific evidence]. AB - Hypertensive disorders in pregnancy deserve special attention in the setting of global public health. Currently, they represent the third cause of maternal mortality in the world and first in Brazil. From a practical standpoint, pre eclampsia remains a syndrome that leads to serious repercussions on maternal and fetal mortality and its etiology is not well known. Currently, the best treatment for forms of pre-eclampsia is being discussed at different times in pregnancy and puerperium, with the objective to reduce the high rates of maternal and fetal morbidity and mortality. Considering the pathophysiology of the event, anticipation of delivery is the best treatment for pre-eclampsia. The use of magnesium sulfate is recommended in all cases of severe pre-eclampsia and eclampsia for prevention and treatment of seizures. Likewise, treatment of hypertensive crises is recommended. Hydralazine, nifedipine and labetalol have been the most commonly used drugs for this purpose, but their use depends on the familiarity of the treating physician. Antenatal corticoid therapy is indicated whenever there is an imminent risk of preterm delivery between 24 and 34 weeks. In contrast, there is insufficient evidence to recommend bed rest and routine plasma volume expansion, and there is an urgent need for randomized clinical trials to determine whether maintenance antihypertensive treatment in pregnant women has benefits or risks for mothers and fetuses in all clinical forms of disease, particularly in cases of pure pre-eclampsia. PMID- 21271153 TI - [Perinatal mortality and traffic-related air pollution]. PMID- 21271154 TI - [Human papillomavirus cervical infection: viral genotyping and risk factors for high-grade squamous intraepithelial lesion and cervix cancer]. AB - PURPOSE: to analyze the characteristics of viral infection and the risk factors for high-grade squamous intraepithelial lesion and cervical carcinoma in women with cervical HPV infection. METHODS: a case-control study was conducted on women with cervical HPV at a Gynecology reference service enrolled at the Public Health System, located in Recife, Northeastern Brazil. The groups of cases (72 women with high-grade squamous intraepithelial lesion or cervical cancer) and controls (176 women with normal Pap smear or benign alterations) were investigated for six viral genotypes (HPV 16, 18, 31, 33, 6, 11) in ecto- and endocervical material using MY09/MY11 primers. The independent variables were ranked in three levels of determination: distal (sociodemographic), intermediate (behavioral) and proximal (previous Pap smear). The homogeneity of proportions was tested (chi2), unadjusted Odds Ratios (OR) were obtained and hierarchical logistic regression was applied to the final model, with adjustment of the effect of each variable to the outcome based on the variables in the same and previous levels of causality. RESULTS: the viral genotype of cervical infection was identified in 76.6% of the 248 women participating in the study. High-risk HPV genotypes (83.4% of cases and 67.1% of controls) were predominant, especially HPV 16 and 31. The distal risk factors identified were: living in a rural area (OR=2.71, 95%CI: 1.18-6.23), less than three years of study (OR=3.97, 95%CI: 2.09-7.54) and family income below two minimum wages (OR=3.30, 95%CI: 1.04-10.51); intermediate: four or more pregnancies (OR=2.00, 95%CI: 1.06-3.76); and proximal: absence of a previous Pap smear (OR=9.74, 95%CI: 2.48-38.28). CONCLUSIONS: genotypes 16 and 31 of cervical HPV infection are predominant among women assisted by the Public Health System in Northeastern Brazil. Socioeconomic and reproductive factors, as well as the absence of cytological screening, represent risk factors for the progression of infection to high-grade squamous intraepithelial lesion and cervical cancer. PMID- 21271155 TI - [Intraoperative injection of technetium-99m-dextran 500 for the identification of sentinel lymph node in breast cancer]. AB - PURPOSE: to determine the efficacy of intraoperative injection of Dextran-500-99m technetium (Tc) for the identification of the sentinel lymph node (SLN) in breast cancer and analyze time to label the SLN in the axillary region. METHODS: a prospective study between April 2008 and June 2009, which included 74 sentinel lymph node biopsies (SLNB) in patients with breast cancer in stages T1N0 and T2N0. After induction of anesthesia, 0.5 to 1.5 mCi of Dextran-500-99m-Tc filtered 0.22 um in a volume of 5 mL was injected intraoperative using the subareolar technique for SLNB. After labeling with the radioisotope, 2 mL of patent blue was injected. The time elapsed between injection and the axillary hot spot, the in vivo and ex vivo counts of the hottest nodes, the background count, and the number of SLN identified were documented. Data were analyzed using descriptive statistics with SPSS program, version 18. RESULTS: we identified the SLN in 100% of cases. The rate of SLN identification with the probe was 98% (73/74 cases). In one case (1.35%) the SLN was labeled only with the blue dye. The mean dose of radioisotope injected was 0.97 +/- 0.22 mCi. The average time to label the SLN was 10.7 minutes (+/- 5.7 min). We identified on average of 1.66 SLN labeled with the radioisotope. CONCLUSION: the procedure for SLN identification with an intraoperative injection of the radioisotope is oncologically safe and comfortable for the patient, providing agility to the surgical team. PMID- 21271156 TI - [Assessment of pain sensitivity and factors involved in the quality of the sample fluid cytologic papillary: preliminary results from the use of automated collection]. AB - PURPOSE: to evaluate painful sensitivity and factors involved in producing papillary fluid suitable for cytological analysis by means of automated collection. METHODS: we selected 50 asymptomatic women without a personal or family history of breast cancer, outside the pregnancy and childbirth cycle in order to collect papillary fluid by the automated system. We recorded and related to the production of papillary fluid patient age, smoking habit, previous breast surgery, parity, breastfeeding, menopausal status and age at menarche. All material collected was fixed in appropriate place, and sent separately for cytological analysis. The painful sensitivity of the collection procedure was assessed using the Borg Category-Ratio Scale (CR10 Scale). RESULTS: patient age ranged from 22 to 59 years, mean 41.6 +/- 8.6 years. Of the 50 patients, 20 (40%) showed no papillary fluid suitable for analysis in the breasts. In those patients from whom appropriate fluid was obtained for analysis of papillary cytology, parity was inversely related to the ability to obtain suitable cell samples with a level of statistical significance of p=0.035, OR=0.0032 (95%CI=0.0001-0.1388). Regarding soreness, the exam was well tolerated. CONCLUSIONS: the automated method of fluid collection for analysis of papillary cytology was well tolerated by the women; thus producing analyzable material in 60% of cases, a rate was inversely related to parity. PMID- 21271157 TI - [Preterm premature rupture of the fetal membranes: factors associated with bronchopulmonary dysplasia]. AB - PURPOSE: to analyze obstetric and neonatal factors associated with bronchopulmonary dysplasia outcome in patients with preterm premature amniorrhexis. METHODS: we analyzed 213 medical records of patients of Fernandes Figueira Institute who suffered premature amniorrhexis (<34 weeks of gestation) in the period from 1998 to 2002. Multiple gestations were excluded. Clinical obstetric and neonatal variables were considered in relation to the bronchopulmonary dysplasia outcome. Data were subjected to bivariate analysis, and the values showing statistical significance (p<0.05) were subjected to logistic regression analysis. RESULTS: the prevalence of bronchopulmonary dysplasia was 6.10%. Univariate analysis of the factors associated with the pulmonary dysplasia outcome were: neonatal mechanical ventilation for more than ten days(OR: 54.00 [11.55-278.25] p=0.000); birth gestational age of less than 30 weeks (OR: 6.33 [1.26- 43.06] p=0.017); birth weight <1,000 g (OR: 4.82 [1.34 17.53] p=0.010); birth weight <1.500 g (OR: 14.09 [1.82-300.50] p=0.003; patent ductus arteriosus (OR: 12.33 [3.07-50.10], p=0.000); hyaline membrane disease (OR: 8.46 [2.21-35.00] p=0.000); congenital pneumonia (OR: 7.48 [2.03-27.93] p=0.000); use of neonatal surfactant (OR: 19.66 [4.54-97.76] p=0.000), and neonatal infection (OR: 7.67 [0.99-163.79] p=0.049). In the final multivariate model, only the variables "neonatal mechanical ventilation">10 days (p=0.001) and "use of a surfactant" (p=0.040) remained independently associated with bronchopulmonary dysplasia. CONCLUSIONS: the factors associated with bronchopulmonary dysplasia are related to neonatal features, as prolonged mechanical ventilation and the use of a surfactant influence the development of the disease. PMID- 21271158 TI - [Application of multidisciplinary educational program in high-risk pregnancies due to endocrine diseases]. AB - PURPOSE: to investigate the application of a multidisciplinary educational program to high-risk pregnancies due to endocrine diseases. METHODS: we retrospectively evaluated the application of a multidisciplinary educational program to 185 pregnant women with endocrine diseases referred to a maternity specialized in high-risk pregnancy. All pregnant women received multidisciplinary prenatal care from a team consisting of endocrinologists, obstetricians, sonographers, nurses and dietitians. Oral and written information about healthy habits, diabetes care, use of artificial sweeteners and exercise during pregnancy was given to all patients at the first endocrine consultation. An individualized nutrition plan was prepared on the occasion of the first visit to the nutritionist. In bi-weekly and monthly endocrine and nutritional visits, respectively, information about healthy changes in lifestyle was emphasized and the weight was recorded. Adherence to physical activity and nutritional counseling was self-reported. We compared the weekly weight before and after the intervention, fetal weight at birth, rate of macrosomia and low birth weight, and frequency of cesarean delivery among the four categories of body mass index (BMI) before pregnancy (<18.5, from 18.5 to 24.9, from 25 to 29.9 and >30 kg/m2). RESULTS: the main disease of referral was diabetes (84.9%). One third of the pregnant women (31.2%) were overweight and 42.5% were obese before pregnancy. Most women was first seen by the multidisciplinary team in the third trimester of pregnancy (64.1%) and 50.5% exceeded the recommended weight gain at first evaluation. Obese women exceeded the recommended weight gain in 62.5% of cases. After the intervention, the percentage of women who exceeded the recommended weekly weight gain was reduced in all categories of pre-pregnancy BMI, although a statistically significant difference was found only in the group with normal pre pregnancy BMI (40.6 versus 21.9%, p = 0.03). At birth, average fetal weight was similar among the various BMI categories (p=0.277). Macrosomia was more frequent in women who were overweight and obese before pregnancy. Cesarean delivery was the most frequent route of delivery, regardless of pre-pregnancy BMI. CONCLUSIONS: in high-risk pregnancies due to endocrine disorders, a multidisciplinary educational approach limits excessive weekly weight gain despite the advanced gestational age. PMID- 21271159 TI - [Cerebroplacental ratio and acidemia to the birth in placental insufficiency detected before 34th week's gestation]. AB - PURPOSE: to evaluate the hypothesis that the fetal cerebroplacental ratio (CPR) is related to acidemia at birth in pregnancies complicated by placental insufficiency detected before 34 weeks of gestation. METHODS: this is a prospective cohort study of 55 patients between 26 and 34 weeks of gestation with a diagnosis of placental insufficiency characterized by abnormal umbilical artery Doppler (pulsatility index>95 p). Fetal assessment was performed for each patient by dopplervelocimetry of the umbilical artery, middle cerebral artery and ductus venosus, and by the fetal biophysical profile. CPR was calculated using the ratio between middle cerebral artery pulsatility index and umbilical artery pulsatility index, and the z-score was obtained (number of standard deviations of the mean value at each gestational age). Acidemia at birth was characterized when pH<7.2. RESULTS: of 55 patients, 29 (52.7%) presented acidemia at birth. In the group of fetal acidemia, when compared with the group with pH>7.2, a significant association was observed with CPR values (median 0.47 versus 0.58; p=0.009), pulsatility index of the umbilical artery (median 2.45 versus 1.93; p=0.003), ductus venosus pulsatility index for veins (PIV) (median 1.08 versus 0.85; p=0.034) and suspected or abnormal fetal biophysical profile (37 versus 8%; p=0.031). CPR analysis by z-score showed a negative tendency, but was not statistically significant (p=0.080). Significant correlations were found between pH at birth and CPR (r=0.45; p<0.01), z-score of CPR (r=0.27; p<0.05) and ductus venosus PIV (r=-0.35 p<0.01). CONCLUSION: CPR is associated with the presence of acidemia at birth in pregnancies with placental insufficiency detected before 34 weeks of gestation and this parameter could potentially represent a factor for assessing the severity of fetal involvement. PMID- 21271160 TI - [Acute abdomen in pregnant woman treated for bariatric surgery for obesity: case report]. AB - Bariatric surgery is currently considered as an alternative for the treatment of morbid obesity refractory to conventional clinical treatments. The surgeries more frequently used, which are radical and invasive, yield better and faster results, but are subject to clinical and surgical complications such as intestinal obstructions and subocclusions. Pregnancies in women submitted to this type of surgery are increasingly frequent, and the related complications have been increasingly reported. We present the case of a pregnant woman previously submitted to bariatric surgery who developed subocclusion with intestinal intussusception. This extremely serious complication requires attention for its diagnosis, i.e. , imaging and laboratory exams that are not usually employed during pregnancy. Gestation confuses and impairs their interpretation. In addition to the fact that the only treatment that reaches a good result is invasive, exploratory laparotomy is undesirable during this period. Maternal, fetal and perinatal mortality is usually high. In the present case, delivery occurred spontaneously during the first hours of hospitalization before the surgical procedure. Evolution was good and both mother and newborn, although premature, had good course and were discharged in good conditions. PMID- 21271161 TI - [The use of combined oral contraceptives in the polycystic ovary syndrome]. PMID- 21271162 TI - [Regularity of cycles and ovulatory pattern in young women with sickle cell anemia]. AB - PURPOSE: to evaluate the characteristics of the menstrual cycle and to identify the occurrence of ovulation in nulliparous young women with sickle cell anemia (SCA). METHODS: we conducted a case-control study including 26 nulliparous women of reproductive age, divided into two groups: "cases", consisting of 13 women with SCA, and "Control" Group, consisting of 13 healthy women with the same interval since menarche. The characteristics of the menstrual cycle were reported by the participants, who were also submitted to measurements of serum progesterone, basal body temperature curves and transabdominal ultrasound in three consecutive cycles (total: 78 cycles) in order to identify the occurrence of ovulation. The results were compared between groups using the nonparametric Mann-Whitney or Kruskal Wallis tests, and the differences were considered significant when p-value < 0.05. RESULTS: no significant difference was found in mean chronological age between the two groups (p = 0.2) in the pattern of the menstrual cycle when duration of flow (p = 0.4) and interval between cycles (p = 0.3) were compared. There was no difference between groups in age at menarche (p = 0.05). Mean hemoglobin value was 8.4 g/dL (+/- 0.9) in the group of women with SCA and 12.6 g/dL (+/- 0.8) in the control group (p < 0.01). The frequency of ovulatory cycles was similar for cases (76.9%) and controls (92.3%) (p = 0.5), with a predominance of individuals with three ovulatory cycles in the control group (84.6%) compared to 23.1% in the case group (p = 0.04). CONCLUSION: the findings justify the need for effective guidance for patients with SCA regarding sexual activity, the possibility of pregnancy and the alternatives for contraception. PMID- 21271163 TI - [Uterine fibroid embolization in women with giant fibroids]. AB - PURPOSE: to evaluate the effectiveness of uterine fibroid embolization (UFE) in patients with giant fibroids, with regard to both clinical outcomes and size reduction. METHODS: twenty-six patients with a mean age of 36.5 years, carrying symptomatic fibroids with a volume over 1,000 cm3, were referred for UFE. All patients had indication for percutaneous treatment. The procedures were performed under epidural anesthesia and sedation, using an institutional protocol. By unilateral femoral access, selective catheterization of uterine arteries and infusion of calibrated microspheres through microcatheter were carried out. Clinical evaluation was performed by means of regular outpatient gynecology consultation. All patients underwent magnetic resonance imaging (MRI) before the procedure and 15 patients underwent control MRI after 6 months. RESULTS: technical success was 100%. There was no complication related to the procedures. Mean uterine volume of the 15 patients studied was 1,401 cm3 before embolization (min 1,045 cm3, max 2,137 cm3) and 799 cm3 after 6 months (525 cm3 min, max. 1,604 cm3), resulting in a total reduction of 42.9%. Clinical improvement was observed in 25 of 26 patients. One woman with uterine volume of 1,098 cm3 who developed necrosis and partial fibroid expulsion underwent myomectomy. Another patient was submitted to myomectomy six months after the procedure because she wanted to become pregnant, despite partial fibroid size reduction. One patient with a uterine volume of 2,201 cm3 required a second intervention to achieve an adequate angiographic result. No patient underwent hysterectomy. On average, 9.2 microsphere syringes were used per patient. CONCLUSION: embolization of giant uterine fibroids is a feasible procedure with acceptable clinical and radiological outcomes. It can be considered an option for patients who desire to preserve the uterus, and it may serve as adjuvant therapy for high-risk myomectomy. PMID- 21271164 TI - [Impact of body mass index on in vitro fertilization outcomes]. AB - PURPOSE: to evaluate the impact of body mass index (BMI) on in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) outcomes performed at the Human Reproduction Center of Faculdade de Medicina do ABC. METHODS: retrospective data from 488 IVF cycles of 385 patients. Patients were classified into two groups according to BMI: normal weight (18.5-24.9 kg/m2) and overweight/obesity (>25 kg/m2). We evaluated the dose of recombinant follicle stimulating hormone (FSHr), the cancellation rates for ovarian cycle response, and the results of the assisted reproduction laboratory such as number of oocytes, number of good quality embryos, number of embryos transferred, and pregnancy rates, chemical pregnancy rates, miscarriage rate and live birth rate. The t test was used for comparison of quantitative variables between groups, and the chi2 test for comparison between qualitative variables. P values <0.05 were considered significant. RESULTS: considering ovulation induction characteristics, there was no statistically significant difference between groups regarding the FSHr dose administered or the cancellation rates, p=0.47 and p=0.85, respectively. Regarding laboratory findings, the number of oocytes retrieved per cycle was similar for both groups (p=0.09), as also was the number of good quality embryos obtained and transferred (p=0.7 and p=0.6). The pregnancy rate per embryo transfer was 27.6% for the group of normal weight and 29.6% for the overweight/obese group (p=0.76). Miscarriage rates and birth rates were similar for both groups, p=0.54 and p=0.94. CONCLUSION: BMI did not influence IVF/ICSI outcomes evaluated. PMID- 21271165 TI - [Adrenal androgen participation in the polycystic ovary syndrome]. AB - PURPOSE: to reassess the adrenal function of patients with PCOS after the introduction of the Rotterdam's criteria. METHODS: descriptive and cross sectional study including 53 patients 26 +/- 5.1 years old. Glucose, glycosylated hemoglobin, lipids, estradiol, progesterone, 17-OHP4, DHEAS, FSH, LH, TSH, PRL, androstenedione, free thyroxine, insulin, total testosterone, SHBG, and free androgen index were measured. Insulin resistance was considered to be present with a homeostatic model assessment index >2.8. The adrenal response to cortrosyn was assessed by the hormonal rise observed at 60 minutes, and by the area under the response curve. RESULTS: biochemical hyperandrogenism was found in 43 of 53 eligible patients (81.1%). Thirty-three women had adrenal hyperandrogenism (62.2%). The weight of these 33 women, aging 25.1 +/- 5.0 years, was 74.9 +/- 14.9 kg, BMI was 28.8 +/- 6.0 and the waist/hip ratio was 0.8 +/- 0.1. DHEAS was >6.7 nmol/L in 13 (39.4%) and androstenendione was >8.7 nmol/L in 31 (93.9%). The increments in 17-OHP4, cortisol, A, and progesterone were 163%, 153%, 32%, and 79%, respectively. The homeostatic insulin resistance model was >2.8 in 14 (42.4%). Insulin and estradiol were not correlated with cortisol or androgens. CONCLUSIONS: the use of multiple endocrine parameters showed a high prevalence of biochemical hyperandrogenism in patients with PCOS. Two thirds of the patients had adrenal hyperandrogenism, and estradiol and insulin did not influence adrenal secretion. PMID- 21271166 TI - [Echographic characteristics of the corpus luteum in early pregnancy: morphology and vascularization]. AB - PURPOSE: the purpose of this research was to evaluate the morphological aspects and vasculature of the corpus luteum (CL) based on ultrasound parameters during early pregnancy and to assess their relationship with early pregnancy loss. METHODS: this was a prospective cohort study of 90 pregnant patients between 6 and 8 weeks plus 6 days weeks of gestation. We included women at low risk, without acute or chronic systemic disease and with spontaneous conception. EXCLUSION CRITERIA: use of drugs or smoking, drugs inducing ovulation, history of more than one abortion, no heartbeat visible in the embryo and impossibility of visualization of the corpus luteum. The size, volume, morphological aspects, resistive index, and peak systolic velocity of the corpus luteum were measured by transvaginal sonography. RESULTS: ninety patients were included in the study. Maternal age ranged from 15 to 41 years (mean 28.6 +/- 5.8 years). The corpus luteum could be visualized in 87 patients (96.7%), 79 patients had normal pregnancies (90.1%), whereas spontaneous losses occurred in 8 cases (9.9%). In a comparison of the survivors and losses, there was no difference in mean CL diameter (21.8 versus 20.0 mm; p=0.108, Mann-Whitney test), mean CL volume (4.2 versus 3.0 cm3; p=0.076, Mann-Whitney test), mean resistive index (0.55 versus 0,58; p=0.220, Mann-Whitney test), peak systolic velocity (15 versus 15 cm/s; p=0.757, Mann-Whitney test). There was a positive relation between maternal age and resistive index. CONCLUSIONS: no apparent correlation was found between the morphological and vascular aspects of the corpus luteum in early normal pregnancies and first-trimester pregnancy losses. PMID- 21271167 TI - [Morphological and physiological analysis of livers and kidneys of pregnant rats and their fetuses treated by the association of zidovudine, lamivudine and ritonavir for the whole period of pregnancy]. AB - PURPOSE: to evaluate the effect of administration of three different doses of the zidovudine/lamivudine/ritonavir combination on the liver and kidneys of pregnant rats and their concepts from a morphological and physiological standpoint. METHODS: 40 pregnant EPM-1 Wistar rats were randomly divided into 4 groups: 1 control (Ctrl: drug vehicle control, n=10) and 3 experimental groups: Exp1x, Exp3x and Exp9x. An oral solution of the zidovudine/lamivudine/ritonavir combination was administered to the experimental groups from the day 0 to day 20 of pregnancy: Exp1x=10/5/20 mg/kg; Exp3x=30/15/60 mg/kg; Exp9x=90/45/180 mg/kg. On the 20th pregnancy day the rats were anesthetized and blood was taken directly from the ventricular chambers for further biochemical determinations: aspartate (AST) and alanine-(ALT) aminotransferases (Calorimetric method), urea nitrogen (BUN) by an enzymatic-kinetic method, and creatinine by a kinetic-calorimetric method. Maternal and fetal liver and kidney samples were taken, fixed in 10% formaldehyde and processed histologically for paraffin embedding. Five um-thick fragments of maternal and fetal livers and kidneys were stained with hematoxilyn eosin, being analyzed by light microscopy. To interpret the results, the well known pattern of normality for livers and kidneys was considered on the basis of the following structures: hepatocytes, portal structure, hepatic veins, renal corpuscles, renal tubules and loop of Henle. Regarding the fetal livers, we also considered the erythrocytes in their different stages of development as well as the megacariocytes. If there was a change in the established staining pattern for liver and kidney structures, changes in nuclear morphology, rupture of some cytoplasmic organelles, and presence of vascular congestion, this was considered to be due to the drug doses. Results were submitted to analysis of variance (ANOVA) and to the Tukey-Kramer multiple comparisons test (p<0.05). RESULTS: no morphological changes were observed in the maternal livers of the Ctrl, Exp1x and Exp3x groups. In the maternal liver of the Exp9x group, hepatocytes showed signs of atrophy and apoptosis (eosinophilic cytoplasm and pycnotic nuclei) and marked sinusoid capillary vasodilation (congestion) was observed. The maternal kidneys of the Ctrl and Exp1x groups were normal, with renal corpuscles, convoluted tubules and typical loops of Henle. In contrast, the Exp3x and Exp9x groups showed vascular congestion and small glomeruli rich in cells containing hyperchromatic nuclei which were more intense in Exp9x. Regarding the fetal organs, no morphological or physiological changes were observed. A significant increase of AST (305.70+/-55.80, p<0.05) and creatinine (0.50+/-0.09, p<0.05) was observed in group Exp9x. CONCLUSIONS: our results show that the administration of the zidovudine, lamivudine and ritonavir combination to pregnant rats at high doses caused morphological and physiological changes in the maternal liver and kidneys. On the other hand, there were no changes in fetal organs. PMID- 21271168 TI - [Monitoring the prenatal care process among users of the Unified Health Care System in a city of the Brazilian Southeast]. AB - PURPOSE: to evaluate the evolution of adequacy of the care process among pregnant users of the Brazilian Single Health System (SUS, acronym in Portuguese) and to consolidate a methodology for monitoring the prenatal care. METHODS: this is a multiple time series study with auditing of prenatal cards of pregnant women who were attended for prenatal care in a city of the Brazilian Southeast (Juiz de Fora, Minas Gerais) in the initial semesters of 2002 and 2004 (370 and 1,200 cards, respectively) and gave birth using SUS services in term pregnancies (p < 0.05). A three complementary level sequence was respected: utilization of prenatal care (beginning and number of visits) at level 1; utilization of prenatal care and obligatory clinical-obstetric procedures during prenatal visits (assessment of blood pressure (BP), weight, uterine fundal height (FH), gestational age (GA), fetal heart rate (FHR) and fetal presentation) at level 2; and utilization of prenatal care, obligatory clinical-obstetric procedures and basic laboratory tests, according to the Humanization Program of Prenatal Care and Birth (PHPN, acronym in Portuguese) (ABO/Rh, hemoglobin/hematocrit (Hb/Htc), VDRL, glycemia and urinalisys) at level 3. RESULTS: it was confirmed the high prenatal care coverage (99%), the increased mean number of visits per pregnant woman (6.4 versus 7.2%) and the decreased gestational age at the time of the first visit (17.4 versus 15.7 weeks). The proper registration of procedures and exams (exceptions: fetal presentation and blood typing) has significantly increased: BP (77.8 versus 83.9%); weight (75.4 versus 83.5%); FH (72.7 versus 81.3%); GA (58.1 versus 71.5%); FHR (79.5 versus 86.7%); Hb/Htc (14.9 versus 29%), VDRL (11.1 versus 20.7%), glycemia (16.5 versus 29%) and urinalisys (13.8 versus 29.8%). As a result, there was significant (p < 0.001) improvement of the adequacy between 2002 and 2004: 27.6 versus 44.8% (level 1); 7.8 versus 15.4% (level 2); 1.1 versus 4.5% (level 3). This trend was also noted in care provided by the majority of the municipal services/teams. CONCLUSIONS: the persistence of low adequacy, despite good coverage and PHPN implementation, confirmed the need to increase health managers, professionals and users' compliance with the rules and routines of care, including the institutionalization of a monitoring program of prenatal care. PMID- 21271169 TI - Influenza and pneumococcal vaccination in heart failure: a little applied recommendation. AB - BACKGROUND: Heart failure (HF) is associated with frequent decompensation and admissions to the emergency service. Influenza (INF) and Pneumococcal (pneumonia) vaccinations are recommended in the guidelines, however, respiratory infections are the third leading cause of hospitalization in heart failure. OBJECTIVE: To assess the frequency of vaccination against INF and PNM in patients with HF in government healthcare units. METHODS: An observational study carried out in Teresopolis, a mountain region in Rio de Janeiro, employed three strategies: (I) study of requests for vaccine against INF and/or PNM in the Health Department of Teresopolis between 2004 and 2006; (II) direct inquiry to 61 patients with heart failure treated in primary care about their vaccination status against INF and PNM; (III) direct inquiry about their vaccination status against INF and PNM to 81 patients with decompensated chronic heart failure treated in the only emergency service open to the public. RESULTS: In strategy I, INF and/or PNM vaccination was 15.3% of those with indications for cardiovascular and respiratory diseases. The median time between indication and vaccination was 32 days. In strategy II, the percentage of patients vaccinated against INF, aged > 60, was 23.1% and 24.6% against PMN at all ages. In strategy III, the percentage of patients vaccinated against INF was 35.8% and against PNM was 2.5%. CONCLUSION: The rate of vaccination against INF and PNM in patients with HF is very low and even lower in those with decompensated HF treated in emergency services. PMID- 21271170 TI - Epicardial mapping of sustained ventricular tachycardia in nonischemic heart disease. AB - BACKGROUND: The complexity of reentrant circuits related to ventricular tachycardias decreases the success rate of radiofrequency ablation procedures. OBJECTIVE: To evaluate whether the epicardial mapping with multiple electrodes carried out simultaneously with the endocardial mapping helps in ablation procedures of sustained ventricular tachycardia (VT) in patients with nonischemic heart disease. METHODS: Twenty-six patients with recurrent sustained VT, of which 22 (84.6%) presenting chronic chagasic cardiomyopathy, 2 (7.7%) with idiopathic dilated cardiomyopathy and 2 with right ventricular arrhythmogenic dysplasia (RVAD), were submitted to epicardial mapping with two or three microcatheters, with 8 electrodes each, simultaneously to the conventional endocardial mapping. A catheter with a 4-mm tip was used for the ablation by radiofrequency (RF) carried out during the induced VT. RESULTS: Of the 33 induced VT, 25 were mapped and 20 had their origin defined. Eleven had epicardial and 9 had endocardial origin. The programmed ventricular stimulation did not induce sustained VT in 11 (42.0%) of the 26 patients after the ablation. Events such as VT recurrence and death occurred in 10.0% of the patients submitted to successful ablation and in 59.0% of the unsuccessful cases, during a mean ambulatory follow-up of 357 +/- 208 days. CONCLUSION: Subepicardial circuits are frequent in patients with nonischemic heart disease. The epicardial mapping with multiple catheters carried out simultaneously with the endocardial mapping contributes to the identification of these circuits in a same procedure. PMID- 21271171 TI - Risk factors for mortality in octogenarians undergoing myocardial revascularization surgery. AB - BACKGROUND: Age over 80 years, by itself, is not the only risk factor for mortality in coronary artery bypass grafting. OBJECTIVE: To identify risk factors for mortality in octogenarian patients undergoing CABG. METHODS: We studied 164 patients aged 80 years and over. The variables studied were: gender; age (in years); ejection fraction (LVEF); reoperation; emergency surgery; number of revascularized arteries; use of the left internal thoracic artery (LITA); use of cardiopulmonary bypass (CPB); associated surgery; revascularization of the left anterior descending artery (DA); and use of intra-aortic balloon (IAB). Statistical analysis was done using descriptive analysis, univariate and multivariate logistic regression. A p value < 0.05 was considered statistically significant, and multivariate analysis was performed for variables whose value was p < 0.20. RESULTS: Mortality was 11%. Univariate analysis showed that low LVEF (p = 0.008), emergency surgery (p < 0.001), and use of intra-aortic balloon (p = 0.049) were related to higher mortality. When adjusted by logistic regression, age over 85 years was correlated with a 6.31 times greater mortality (p = 0.012), and emergency surgery was related to a 55.39 times greater mortality (p < 0.001). CONCLUSION: In octogenarians undergoing coronary artery bypass surgery, age over 85 years and emergency surgery are important predictors of mortality. PMID- 21271172 TI - Predictors of viability in patients with negative low-dose dobutamine stress echocardiograph. AB - BACKGROUND: Low-dose dobutamine stress echocardiography is specific for predicting reversible contractility dysfunction, but its sensitivity is lower than ideal. OBJECTIVE: We sought to explore the predictors of myocardial contractile recovery following revascularization, in patients with no viability by low-dose dobutamine stress echocardiography. METHODS: We prospectively enrolled 30 consecutive patients with significant coronary stenosis/occlusion amenable for revascularization, regional wall motion abnormality in the distribution of the affected artery and absence of viability by low-dose dobutamine stress echocardiography. They underwent resting 99mTc-sestamibi imaging study, and then underwent successful coronary revascularization. Follow up echocardiography was performed 3 months later. Patients were classified into 2 groups: group 1: with evidence of myocardial contractile recovery after revascularization at follow-up echocardiography and group 2: with no such evidence of recovery. The two groups were compared with respect to patients' clinical, echocardiographic and scintigraphic data. RESULTS: The mean age was 52.3 +/- 5.9 years, with 97% being males. The percentage of total 99mTc-sestamibi uptake was significantly higher in group 1 as compared to group 2 (p < 0.01), and it was the strongest independent predictor of myocardial contractile recovery at 3-month follow-up by multivariate regression analysis. Receiver operating characteristics curve revealed that a cutoff value of the percentage of total 99mTc-sestamibi uptake of 72% best predicted myocardial contractile recovery, with a sensitivity of 100% and specificity of 95.7%. CONCLUSION: In patients with no viability by low-dose dobutamine stress echocardiography, the percentage of total 99mTc-sestamibi uptake independently predicted myocardial contractile recovery following coronary revascularization. PMID- 21271173 TI - Tilt test--from the necessary to the indispensable. AB - The head-up tilt test (HUTT) is widely used for investigation of syncope and presyncope, since it allows diagnosing different types of dysautonomia. The main cause of syncope is the vasovagal syndrome, the most common diagnosis among patients with HUTT indication. The test has been used for nearly 20 years, but many doctors are unaware of the methodology. After the cardiac causes of syncope are ruled out, the appropriate indication of the test and instructions to patients are important to ensure that the test will be carried out in a safe and relaxed manner. There are controversies in the literature over the diagnostic capacity and reliability of results. Studies with various protocols may explain the variability of results. This review describes the guidelines-recommended methodology and indications, complications, limitations and perspectives of this test. PMID- 21271174 TI - Sedation with sufentanil and clonidine in patients undergoing heart catheterization. AB - BACKGROUND: Sedation for heart catheterization has been a cause for concern. Benzodiazepines, alpha-2 adrenergic agonists and opioids are used for this purpose. However, each drug has advantages and disadvantages. OBJECTIVE: To evaluate the efficacy of sufentanil and clonidine as sedative in patients undergoing heart catheterization, observing their impact on hemodynamic and respiratory parameters, the presence of side effects and satisfaction of the patient and interventional cardiologist with the examination. METHODS: This is a prospective, double-blind, randomized and controlled clinical trial involving 60 patients who received 0.1 ug/kg of sufentanil or 0.5 ug/kg of clonidine before heart catheterization. The score of sedation according to the Ramsay scale, the need for use of midazolam, side effects and hemodynamic and respiratory parameters were recorded, with the data being analyzed at 06 different moments. RESULTS: The behavior of blood pressure, heart rate and respiratory rate was similar in both groups, but, at moment 2, the patients in the sufentanil group (Group S) had a lower sedation score on the Ramsay scale, and the peripheral oxyhemoglobin saturation was lower than in the clonidine group (Group C) at time 6. Patients in Group S had higher incidence of nausea and vomiting after surgery than patients in Group C. Patient satisfaction was higher in the clonidine group. The interventional cardiologists were satisfied in both groups. CONCLUSION: Sufentanil and clonidine were effective as sedative in patients undergoing heart catheterization. PMID- 21271175 TI - Association between uric acid and cardiovascular risk variables in a non hospitalized population. AB - BACKGROUND: The association between uric acid (UA) and cardiovascular risk variables remains a controversial issue in epidemiological studies. OBJECTIVE: To evaluate the association between UA, blood pressure (BP), anthropometric indices and metabolic variables in a non-hospitalized population stratified by UA quintiles. METHODS: A cross-sectional observational study evaluated 756 individuals (369 males), aged 50.3 +/- 16.12 years, divided in UA quintiles. BP, body mass index (BMI), abdominal circumference (AC), UA, glucose, insulin, HOMA IR, total cholesterol (TC), LDL-c, HDL-c, triglycerides (TG) and creatinine (C) levels were obtained. The estimated glomerular filtration rate (eGFR) was calculated and arterial hypertension (AH) was considered when BP > 140x90 mmHg, overweight/obesity (OW/O) was considered when BMI > 25 kg/m2 and metabolic syndrome (MS) was established according to the I Brazilian Guideline of MS. RESULTS: 1) There was no difference between the groups regarding the distribution by sex and age range; 2) The highest UA quintiles presented higher mean age (p < 0.01), BMI, AC (p < 0.01), SBP, DBP (p < 0.001), TC, LDL-c, TG (p < 0.01), C and eGFR (p < 0.001) and lower mean HDL-c (p < 0.001); 3) The group with the highest UA quintile showed higher prevalence of AH, OW/O and MS (p < 0.001); 4) Higher percentages of the lowest quintiles of insulin (p < 0.02) and HOMA-IR (p < 0.01) were observed with the lowest quintiles of UA; 5) A logistic regression analysis showed that UA and the variables that compose MS were associated with the occurrence of MS (p < 0.01). CONCLUSION: Higher quintiles of uric acid were associated with a worse cardiovascular risk profile and a worse kidney function profile in the non-hospitalized population sample studied. PMID- 21271176 TI - Acute effects of smoking on autonomic modulation: analysis by Poincare plot. AB - BACKGROUND: Smoking affects the autonomic function. OBJECTIVE: To investigate the acute effects of smoking on the autonomic modulation and the post-smoking recovery of the heart rate variability (HRV) index through Poincare plot and linear indices. METHODS: A total of 25 young smokers underwent beat-to-beat analysis of heart rate in the sitting position after 8 hours of tobacco abstinence, for 30 minutes at rest, 20 minutes while smoking and 30 minutes after smoking. The analysis of variance for repeated measures, followed by Tukey's test or Friedman's test followed by Dunn's test, were applied depending on the normality of data, with p < 0.05. RESULTS: While smoking, there was a decrease in the indices: SD1 (23.4 +/- 9.2 vs 13.8 +/- 4.8), SD1/SD2 ratio (0.31 +/- 0.08 vs 0.2 +/- 0.04), RMSSD (32,7 +/- 13 vs 19.1 +/- 6.8), SDNN (47.6 +/- 14.8 vs 35.5 +/- 8.4), HFnu (32,5 +/- 11.6 vs 19 +/- 8.1) and the RR interval (816.8 +/- 89 vs 696.5 +/- 76.3) in relation to the rest period, whereas increases in the LFnu index (67.5 +/- 11.6 vs 81 +/- 8.1) and the LF/HF ratio (2.6 +/- 1.7 vs 5.4 +/- 3.1) were observed. The visual analysis of the plot showed a lower dispersion of RR intervals while smoking. Except for the SD1/SD2 ratio, the other indices presented recovery of values 30 minutes after smoking. CONCLUSION: Smoking resulted in acute modifications of the autonomic control, characterized by sympathetic activation and vagal withdrawal, presenting recovery 30 minutes after smoking. PMID- 21271177 TI - Mechanical evaluation of space closure loops in orthodontics. AB - This study evaluated the mechanical performance of teardrop-shaped loops and teardrop-shaped loops with helix used in orthodontic space closure. Sixty retraction loops made with 0.019" x 0.025" stainless steel (SS) and beta-titanium (BT) wires were used. They were attached to a testing machine to measure the magnitudes of the sagittal force and the load-deflection ratio necessary for 1 mm, 2 mm and 3 mm activation. The results demonstrated that the BT alloy presented significantly smaller mean values (p < 0.01) of sagittal force and load deflection than the SS alloy. The loop with the highest mean value of sagittal force and load-deflection was the teardrop-shaped loop (p < 0.01). Differences were observed in the mean values of sagittal force and load-deflection among activations, and the highest mean value was found in the activation of 3 mm, while the smallest mean value was evident in the activation of 1 mm (p < 0.01). It could be concluded that the metallic alloy used and the presence of a helix in configuration of the loops may have a strong influence on the sagittal force produced and on the load-deflection ratio; the teardrop-shaped loops and teardrop shaped loops with helix in BT presented the release of lighter forces; the teardrop-shaped loop in SS generated a high load-deflection ratio, providing high magnitudes of horizontal force during its deactivation. PMID- 21271178 TI - Comparison of two methods for alveolar bone loss measurement in an experimental periodontal disease model in rats. AB - There are many studies that evaluate possible risk factors for periodontal diseases in animals. Most of them have focused only on the biological aspects of disease occurrence; therefore, it has been difficult to compare studies of the different methodological approaches. The aim of the present study was to compare different methods - linear and area - of the evaluation of morphometrical alveolar bone loss. Sixty hemimaxillae, defleshed and stained with 1% methylene blue to delineate the cementoenamel junction and alveolar bone crest, were obtained from a previous study that induced periodontal disease by means of ligatures in two groups of fifteen Wistar rats during 9 weeks. Ligatures were placed around the right upper second molars, and the contra-lateral teeth remained as intra-group controls. Digital photographs were taken from the specimens and submitted to a single, calibrated, blind examiner who performed the morphometrical evaluation of alveolar bone loss using both linear and area methods. Mean values of linear and area measurements were obtained from each side - buccal and palatal - of the specimens. The degree of association between the two methods was determined by Pearson's Correlation Coefficient. An almost perfect association (0.98) was determined between the linear and area evaluations. A mathematical formula was subsequently created to estimate the total area of alveolar bone loss, from linear mean measurements. Both methods were suitable for detecting bone level alterations. The results of the present study allow for the transformation of data and better compilation of results from different studies. PMID- 21271179 TI - In vitro antifungal susceptibility of Candida spp. oral isolates from HIV positive patients and control individuals. AB - Oropharyngeal candidiasis is the most common fungal infection among HIV-positive patients. This condition can be treated with either systemic or topical antifungal agents; treatments are usually indicated empirically on the basis of clinical data. The knowledge of in vitro antifungal susceptibility is important to determine correct therapeutic guides for the treatment of fungal infections. Therefore, the objective of this study was to determine the antifungal susceptibility profile of oral Candida isolates from HIV-positive patients and control individuals. Amphotericin B, fluconazole, flucytosine, nystatin and ketoconazole were tested according to the methodology of microdilution proposed by the Clinical and Laboratory Standards Institute (CLSI); results were recorded in values of minimal inhibitory concentration (MIC). A total of 71 Candida isolates from HIV-positive patients were examined with the following species represented: C. albicans (59), C. tropicalis (9), C. glabrata (1), C. guilliermondii (1) and C. krusei (1). A total of 15 Candida isolates were evaluated from control individuals comprised of 11 C. albicans and 4 C. tropicalis samples. Our results demonstrated that the tested antifungal agents showed good activity for most isolates from both groups; however, variability in MIC values among isolates was observed. PMID- 21271180 TI - Vancomycin-dependent Enterococcus faecium vanA: characterization of the first case isolated in a university hospital in Brazil. AB - In this study, we report the characterization of a strain of Enterococcus faecium vanA, which grows only in the presence of vancomycin (VDEfm-UEL). The bacterium was isolated from the feces of a female patient who had undergone surgical treatment of Reinke's edema and was receiving intravenous vancomycin therapy for infection with methicillin/oxacillin-resistant Staphylococcus aureus, a postoperative complication. Antimicrobial dependence was further confirmed by the vancomycin E-test. VDEfm-UEL was also shown to be resistant to ampicillin, ciprofloxacin, chloramphenicol, erythromycin, levofloxacin, penicillin, rifampicin, and teicoplanin. The putative virulence genes efaA, gelE and esp were detected by PCR. The ddl gene from VDEfm-UEL was cloned and sequenced. Vancomycin dependence seems to be associated with the insertion of a nucleotide in that sequence, which results in a frame-shift mutation, introducing a premature stop codon. This is the first report of vancomycin-dependent E. faecium isolation in a university hospital in Brazil. PMID- 21271181 TI - Angiotensin II induces NF-kappaB, JNK and p38 MAPK activation in monocytic cells and increases matrix metalloproteinase-9 expression in a PKC- andRho kinase dependent manner. AB - Angiotensin II (ANG II), the main effector of the renin-angiotensin system, is implicated in endothelial permeability, recruitment and activation of the immune cells, and also vascular remodeling through induction of inflammatory genes. Matrix metalloproteinases (MMPs) are considered to be important inflammatory factors. Elucidation of ANG II signaling pathways and of possible cross-talks between their components is essential for the development of efficient inhibitory medications. The current study investigates the inflammatory signaling pathways activated by ANG II in cultures of human monocytic U-937 cells, and the effects of specific pharmacological inhibitors of signaling intermediates on MMP-9 gene (MMP-9) expression and activity. MMP-9 expression was determined by real-time PCR and supernatants were analyzed for MMP-9 activity by ELISA and zymography methods. A multi-target ELISA kit was employed to evaluate IkappaB, NF-kappaB, JNK, p38, and STAT3 activation following treatments. Stimulation with ANG II (100 nM) significantly increased MMP-9 expression and activity, and also activated NF kappaB, JNK, and p38 by 3.8-, 2.8- and 2.2-fold, respectively (P < 0.01). ANG II induced MMP-9 expression was significantly reduced by 75 and 67%, respectively, by co-incubation of the cells with a selective inhibitor of protein kinase C (GF109203X, 5 uM) or of rho kinase (Y-27632, 15 uM), but not with inhibitors of phosphoinositide 3-kinase (wortmannin, 200 nM), tyrosine kinases (genistein, 100 uM) or of reactive oxygen species (alpha-tocopherol, 100 uM). Thus, protein kinase C and Rho kinase are important components of the inflammatory signaling pathways activated by ANG II to increase MMP-9 expression in monocytic cells. Both signaling molecules may constitute potential targets for effective management of inflammation. PMID- 21271182 TI - Effect of maternal hydration on the increase of amniotic fluid index. AB - The objective of this study was to determine the effect of maternal hydration with oral isotonic solution and water on the amniotic fluid (AF) index of women with normohydramnios. Women with a normal AF index and gestational age between 33 and 36 weeks without maternal complications were randomized into three groups [isotonic solution (Gatorade((r))), water, control]. The isotonic solution and water groups were instructed to drink 1.5 L of the respective solution and the control group was instructed to drink 200 mL water over a period of 2 to 4 h. AF index was measured before and after hydration by Doppler ultrasonography. The investigator performing the AF index measurement was blind to the subject's group. Ninety-nine women completed the study without any adverse maternal effects. The median increase in AF index after hydration was significantly greater for the isotonic solution and water groups than for the control group. There was no significant difference between the isotonic solution and water groups. Hydration with isotonic solution and water caused a 10-fold (95%CI: 2.09 49.89) and 6-fold (95%CI: 1.16-30.95) increase in the chance of a 20% increase of AF index, respectively. Maternal hydration with isotonic solution or water increased the AF index in women with normohydramnios. PMID- 21271183 TI - Gender differences in serum CK-MB mass levels in healthy Brazilian subjects. AB - The creatine kinase-isoenzyme MB (CK-MB) mass assay is one of the laboratory tests used for the diagnosis of myocardial infarction. It is recommended, however, that reference limits should take gender and race into account. In the present study, we analyzed the plasma CK-MB mass and troponin levels of 244 healthy volunteers without a personal history of coronary artery disease and with no chronic diseases, muscular trauma or hypothyroidism, and not taking statins. The tests were performed with commercial kits, CK-MB mass turbo kit and Troponin I turbo kit, using the Immulite 1000 analyzer from Siemens Healthcare Diagnostic. The values were separated according to gender and showed significant differences by the Mann-Whitney test. Mean (+/- SD) CK-MB mass values were 2.55 +/- 1.09 for women (N = 121; age = 41.20 +/- 10.13 years) and 3.49 +/- 1.41 ng/mL for men (N = 123; age = 38.16 +/- 11.12 years). Gender-specific reference values at the 99th percentile level, according to the Medicalc statistical software, were 5.40 ng/mL for women and 7.13 ng/mL for men. The influence of race was not considered because of the high miscegenation of the Brazilian population. The CK-MB values obtained were higher than the 5.10 mg/mL proposed by the manufacturer of the laboratory kit. Therefore, decision limits should be related to population and gender in order to improve the specificity of this diagnostic tool, avoiding misclassification of patients. PMID- 21271184 TI - Case 6/2010 - 70-year-old hypertensive and diabetic female patient with interstitial and bilateral pulmonary alveolar infiltrate, dry cough, dyspnea, loss of appetite and no fever. PMID- 21271185 TI - Secondary hypertension to rare adrenal gland tumor. AB - The ganglioneuroma is a tumor of the sympathetic nervous system and may be associated with hypersecretion of vasoactive substances responsible for various symptoms and signs such as hypertension. The authors report a case of ganglioneuroma and a literature review, focusing on the most important aspects of diagnosis and therapy. The patient had recurrent symptomatic hypertensive crises, having performed an imaging study that found a nodule in the right adrenal gland. As neuroblastic tumors are radiologically undistinguishable, the patient underwent excision, confirming the diagnosis by pathology analysis. This case demonstrates the clinical variability of ganglioneuroma, the usefulness of imaging and the importance of histological study. PMID- 21271186 TI - Delayed right ventricular perforation in patient with implantable cardioverter - defibrillator. AB - We describe the case of a 62-year-old patient who returned for evaluation nine months after receiving an implantable cardioverter-defibrillator (ICD) with signs of delayed right ventricular (RV) perforation. The clinical signs that allowed the diagnosis of this late presentation to be achieved are discussed herein, as well as the conduct and the frequency of this complication in the literature. PMID- 21271187 TI - Determinants of neurological complications with the use of extracorporeal circulation (ECC). PMID- 21271188 TI - Risk prediction models: are they really necessary? PMID- 21271189 TI - Quality of life in patients with severe and stable coronary atherosclerotic disease. AB - BACKGROUND: There are few data on the factors decreasing quality of life (QoL) in patients with coronary artery disease (CAD) before a percutaneous coronary intervention (PCI). OBJECTIVE: To associate clinical variables with QoL scores in patients with stable CAD before the PCI and with unfavorable outcomes, 12 months after the procedure. METHODS: The present is a longitudinal study of 78 patients (43 men and 35 women), before an elective PCI. The associations between the QoL scores (SF-36 questionnaire) and age, sex, weight, body mass index, diabetes mellitus (DM), arterial hypertension, dyslipidemia, current smoking, previous cardiovascular event or PCI, glycemia control and blood pressure (BP) were analyzed by multivariate logistic regression. We also analyzed the associations between the clinical features and the unfavorable outcomes (death due to any cause, heart failure or nonfatal infarction). The level of significance was set at p < 0.05. RESULTS: The medians of the QoL scores were < 70 percentage in all domains. Female sex, age < 60 years, previous cardiovascular event or PCI, BMI >= 25 kg/m2, DM and high BP were associated with a higher degree of impairment of at least one QoL score. Female sex (OR: 7.19; 95%CI: 1.55 - 33.36; p = 0.012), previous cardiovascular event (OR: 3.97; 95%CI: 1.01 - 15.66; p = 0.049) and PCI failure (OR: 10.60; 95%CI: 1.83 - 61.46; p = 0.008) were associated with increased risk of combined outcome. CONCLUSION: In the presence of CAD, women and patients with comorbidities present a higher degree of QoL impairment. The unfavorable outcomes 12 months after the PCI are associated with the female sex, previous event or procedure failure. PMID- 21271190 TI - Cardiac magnetic resonance and its anatomical planes: how do I do it? AB - Due to the increasing use of the cardiac magnetic resonance (CMR) method and the frequent implementation of such method in new services, we describe herein, in a step-by-step format, the acquisition techniques that are necessary for a complete cardiac approach, of the main anatomical planes of the heart used by CMR. PMID- 21271191 TI - Relevant points for the evaluation of cardiovascular risk with the use of ABPM. PMID- 21271192 TI - Poll: Jehovah's witness patient. PMID- 21271193 TI - Older Brazilian patient with valvulopathy. PMID- 21271194 TI - 2009 H1N1 influenza virus and immunosuppressive drug. PMID- 21271195 TI - [The Brazilian Scientist Research Day]. PMID- 21271196 TI - Evaluation of optical density of bone defects filled with calcium phosphate cement and bioactive glass in rats. AB - PURPOSE: To evaluate new bone formation, by the analysis of optical density, in rat femoral defects filled with calcium phosphate cement (CPC) and bioactive glass (BG). METHODS: Twenty-one rats were divided into three groups, Group I (CPC), Group II (BG), and Group III (control), and assessed after 7, 15, and 30 days. Three bone cavities were made in the left femur and filled with CPC, BG, and no material (control). Digital images were obtained and the results were subjected to statistical analysis of variance (ANOVA), complemented by the Friedman and Kruskal-Wallis nonparametric tests, with a significance level of 5%. RESULTS: Regarding optical density, Group I showed statistical values significantly higher than Group III and also higher, although not statistically significant, than Group II, in all observation periods. When Groups II and III were compared, Group II showed higher optical density values, without statistically significant differences, in all periods. CONCLUSION: The biomaterials analyzed showed higher optical density in relation to the control group in all observation periods, calcium phosphate cement being the best option in the repair of bone defects, but without statistically significant differences in relation to bioactive glass. PMID- 21271197 TI - Use of calcium phosphate cement scaffolds for bone tissue engineering: in vitro study. AB - PURPOSE: To evaluate the ability of macroporous tricalcium phosphate cement (CPC) scaffolds to enable the adhesion, proliferation, and differentiation of mesenchymal stem cells derived from human bone marrow. METHODS: Cells from the iliac crest of an adult human donor were processed and cultured on macroporous CPC discs. Paraffin spheres sized between 100 and 250um were used as porogens. Cells were cultured for 5, 10, and 15 days. Next, we assessed cells' behavior and morphology on the biomaterial by scanning electron microscopy. The expression levels of the BGLA and SSP1 genes and the alkaline phosphatase (ALP) activity were quantified by the quantitative real-time polymerase chain reaction technique (QT-PCR) using the fluorophore SYBR GREEN((r)). RESULTS: QT-PCR detected the expression of the BGLA and SSP1 genes and the ALP activity in the periods of 10 and 15 days of culture. Thus, we found out that there was cell proliferation and differentiation in osteogenic cells. CONCLUSION: Macroporous CPC, with pore sized between 100 and 250um and developed using paraffin spheres, enables adhesion, proliferation, and differentiation of mesenchymal stem cells in osteogenic cells and can be used as a scaffold for bone tissue engineering. PMID- 21271198 TI - Histological analysis of low-intensity laser therapy effects in peripheral nerve regeneration in Wistar rats. AB - PURPOSE: Analyze the influence of low-intensity laser therapy in the sciatic nerve regeneration of rats submitted to controlled crush through histological analysis. METHODS: Were used 20 Wistar rats, to analyze the influence of low intensity laser therapy in the sciatic nerve regeneration, where the injury of the type axonotmesis was induced by a haemostatic clamp Crile (2nd level of the rack). The animals were randomly distributed in 2 groups. Control group (CG n = 10) and Laser group (LG n = 10). These were subdivided in 2 subgroups each, according to the euthanasia period: (CG14 - n = 5 and CG21 - n = 5) and (LG14 - n = 5 and LG21 - n = 5). At the end of treatment, the samples were removed and prepared for histological analysis, where were analyzed and quantified the following findings: Schwann cells, myelinic axons with large diameter and neurons. RESULTS: In the groups submitted to low-intensity laser therapy, were observed an increase in the number of all analyzed aspects with significance level. CONCLUSION: The irradiation with low intensity laser (904nm) influenced positively the regeneration of the sciatic nerve in Wistar rats after being injured by crush (axonotmesis), becoming the nerve recovery more rapid and efficient. PMID- 21271199 TI - Angiogenic activity of Calendula officinalis flowers L. in rats. AB - PURPOSE: In this work, angiogenic activity of Calendula officinalis L. (Asteraceae) ethanolic extract and dichloromethane and hexanic fractions were evaluated, considering medicinal properties, especially healing activity, are attributed to this plant. METHODS: Models using 36 rats and 90 embryonated eggs were used to evaluate healing and angiogenic activities of extracts and fractions of the plant, through the induction of skin wounds and the chorioallantoic membrane, respectively. The effect of vascular proliferation was also tested from the study to verify the intensity of expression of vascular endothelial growth factor (VEGF) in cutaneous wounds in rats. RESULTS: The angiogenic activity of the extract and the fractions was evidenced in both experimental models. It was verified that this effect is not directly related to the expression of VEGF and it could be associated to other pro-angiogenic factors. CONCLUSION: The healing activity referred to C. officinalis is related, among other factors, to its positive effect on angiogenesis, characterized by the induction of neovascularization. PMID- 21271200 TI - In vitro effect of 470 nm LED (Light Emitting Diode) in keloid fibroblasts. AB - PURPOSE: To quantify keloid fibroblasts after irradiation with 470nm blue LED, in vitro. METHODS: Fibroblasts from keloid and adjacent skin have been obtained from 6 patients. Cells have been cultivated and maintained in DMEM culture medium. In Petri dishes, they were irradiated with energy doses of 6J, 12J and 18J. After 24 h, counting was done by the average of the triplicates for each sample. RESULTS: There were no significant differences in the number of irradiated keloid fibroblasts at the studied doses (p=0.261). In adjacent skin fibroblasts, differences were observed (p=0.025) concerning the doses of 18 J and 6 J (p=0.03). CONCLUSIONS: There was a reduction in the number of adjacent skin fibroblasts irradiated with 470nm blue LED at the energy dose of 18 J compared to the ones irradiated at the energy dose of 6 J. There were no changes in keloid fibroblasts counting at any of the doses applied, 24 h after irradiation. PMID- 21271201 TI - Miniplate 1.5 fixation for the repair of mandibular osteotomies in cats. AB - PURPOSE: To evaluate the application of the maxillofacial miniplate 1.5 in the repair of unilateral mandibular osteotomies in cats. METHODS: Twelve adult cats were divided into two groups. In group 1 (n=6), the osteotomy was performed in the body of the mandible, behind the 1(st) molar. In group 2 (n=6), the osteotomy was performed between the 4(th) premolar and 1(st) molar. The osteotomy was fixed with a titanium miniplate 1.5. Oral alimentation was reinitiated 24 hours after surgery. Cats were euthanized at 12 weeks postoperative. RESULTS: Radiographs taken 1 week after surgery showed a radiolucent line. The osteotomy line was not more visible on the radiographs taken at 12 weeks postoperative. Macroscopic examination confirmed alignment and bone union of operated hemimandibles. Histological examination showed formation of woven bone within the osteotomy line. The percentage of bone tissue at these areas was measured by the histometry. There was no statistically significant difference between the values of group 1(75.07 +/- 5.99) and group 2 (74.76 +/- 8.54) (Mann-Whitney's test p= 0.469). CONCLUSION: We concluded that the use of miniplate 1.5 for the fixation of mandibular osteotomy in cats provided the main goals in the treatment of mandibular fractures: bone union, normal dental occlusion and immediate return to oral alimentation. PMID- 21271202 TI - Standardization of a method of prolonged thoracic surgery and mechanical ventilation in rats to evaluate local and systemic inflammation. AB - PURPOSE: To evaluate the immediate pulmonary and systemic inflammatory response after a long-term operative period. METHODS: Wistar rats in the experimental group were anaesthetized and submitted to tracheostomy, thoracotomy and remained on mechanical ventilation during three hours. Control animals were not submitted to the operative protocol. The following parameters have been evaluated: pulmonary myeloperoxidase activity, pulmonary serum protein extravasation, lung wet/dry weight ratio and measurement of levels of cytokines in serum. RESULTS: Operated animals exhibited significantly lower serum protein extravasation in lungs compared with control animals. The lung wet/dry weight ratio and myeloperoxidase activity did not differ between groups. Serum cytokines IL-1beta, TNF-alpha, and IL-10 levels were not detected in groups, whereas IL-6 was detected only in operated animals. CONCLUSION: The experimental mechanical ventilation in rats with a prolonged surgical time did not produce significant local and systemic inflammatory changes and permit to evaluate others procedures in thoracic surgery. PMID- 21271203 TI - Subtotal laparoscopic splenectomy in rats with preservation of the inferior pole. AB - PURPOSE: To evaluate the feasibility and safety of subtotal splenectomy by laparoscopy with inferior pole preservation and to determine the viability of the splenic remnant. METHODS: Twenty male Wistar rats weighing between 365 g and 474 g (mean 417.92 +/- 36.15g SD) were operated and randomly assigned to two groups : Group 1 rats were killed on postoperative day 10 (n = 10), and Group 2 on the postoperative day 80 (n = 10). Both the inferior splenic pole and the superior part of the spleen, which was used as a control to measure inferior pole viability, were weighed and morphologically examined. RESULTS: The technique was feasible in all cases. There were two postoperative deaths on immediate postoperative and one not well defined. The average weight percentage of the inferior pole, measured indirectly on the 10th day, was 53.67% +/- 11.59% and on the 80th day was 62.69% +/- 6.89%. The inferior pole was necrotic, with abscess formation in one case (5.9%) and appeared normal in all other cases. Microscopy showed features that were compatible with normality. CONCLUSIONS: Subtotal splenectomy with preservation of the inferior pole by laparoscopy was feasible and safety. The lower splenic pole was viable in 94.1% of animals. PMID- 21271204 TI - The comparison of methylene blue and vitamin E in prevention of abdominal postoperative adhesion formation in rat uterine horn models: Biochemical and histopathologic evaluation. AB - PURPOSE: To compare the effects of vitamin E and 1% methylen blue solutions on prevention of experimentally induced adhesions in rats. METHODS: Thirty seven female Spraque Dawley rats were randomized into four groups. First group was kept as sham operated group. An adhesion model was constituted on the left uterine horn of the other groups. The lesion areas of rats from the second, the third and the fourth groups were coated with 2 ml 0.9 % saline solution (C group), 10 mg vitamin E (VE group) and 1% methylen blue solutions (MB group), respectively. RESULTS: Histopathologically, adhesion scores, mononuclear cell infiltration, oedema and fibrosis were more prominent in the MB group compared with C and VE groups. There were no significant differences between the groups in tissue glutathione peroxidase (GPx), catalase (CAT) activities and glutation (GSH) level, these parameters were slightly increased in group with VE supplementation though. The administration of VE and MB significantly decreased NO (P<0.01) levels when compared to the C group. The level of malondialdehyde (MDA) in the VE group was significantly lower (P<0.05) than those of the Sh and C groups. CONCLUSION: Intraperitoneal methylen blue solutions treatments were more effective according to vitamin E in preventing the formation of intra-abdominal adhesion in a rat uterine horn model. PMID- 21271205 TI - Neovascularization after ischemic injury: evaluation with 99(m)Tc-HYNIC-RGD. AB - PURPOSE: Angiogenesis involves many mediators including integrins, and the tripeptide RGD is a target amino acid recognition sequence for many of them. Hindlimb ischemia is a simple and convenient animal model however standardization of the injection procedures in the devascularized and control limb is lacking, thus rendering difficult the interpretation of results. The aim of this investigations was to evaluate neovascularization in a hindlimb murine model by means of 99(m)Tc-HYNIC-beta-Ala-RGD. METHODS: 99(m)Tc-HYNIC-RGD analog was prepared using coligands. Ischemia was induced in Wistar rats by double- ligation of the common femoral artery. Radiolabeled RGD was injected after 2h, as well as 1, 3, 5, 7, 10 and 14 days. Uptake was evaluated by planar imaging and biodistribution studies. RESULTS: The highest ratio between ischemia and control was achieved at the 7th day (2.62 +/- 0.95), with substantial decrease by the 14th day. For pertechnetate the 7th day ratio was 0.87 +/- 0.23. Scintigraphic image confirmed different uptakes. CONCLUSION: 99(m)Tc-HYNIC-RGD analog concentrated in ischemic tissue by the time of widespread angiogenesis and pertechnetate confirmed reduction in blood flow. In this sense, the protocol can be recommended for ischemic models. PMID- 21271206 TI - Anal cancer precursor lesions in HIV-positive and HIV-negative patients seen at a tertiary health institution in Brazil. AB - PURPOSE: To investigate the prevalence of anal squamous intraepithelial lesions (ASIL) or anal cancer in patients attended at the Tropical Medicine Foundation of Amazonas. METHODS: 344 patients consecutively attended at the institution, in 2007/2008, were distributed in the following strata according to presence/abscense of at risk conditions for anal cancer: Group 1 - HIV-positive men-who-have-sex-with-men (101); Group 2 - HIV-positive females (49); Group 3 - patients without any at risk condition for anal cancer (53); Group 4 - HIV positive heterosexual men (38); Group 5 - HIV-negative patients, without anoreceptive sexual habits, but with other at risk conditions for anal cancer (45); Group 6 - HIV-negative men-who-have-sex-with-men (26); and Group 7 - HIV negative anoreceptive females (32). The histopathological results of biopsies guided by high-resolution anoscopy were analyzed by frequentist and bayesian statistics in order to calculate the point-prevalence of ASIL/cancer and observe any eventual preponderance of one group over the other. RESULTS: The point prevalence of ASIL for all the patients studied was 93/344 (27%), the difference between HIV-positive and negative patients being statistically significant (38.3% versus 13.5%; p < 0.0001). The prevalence of ASIL for each one of the groups studied was: Group 1 = 49.5%, Group 2 = 28.6%, Group 3 = 3.8%, Group 4 = 21.1%, Group 5 = 11.1%, Group 6 = 30.8% and Group 7 = 18.8%. Standard residual analysis demonstrated that ASIL was significantly prevalent in patients of Group 1 and high-grade ASIL in patients of Group 2. The odds for ASIL of Group 1 was significantly higher in comparison to Groups 2, 3, 4, 5 and 7 (p < 0.03). The odds for ASIL of Groups 2, 4 and 6 were significantly higher in comparison to Group 3 (p < 0.03). CONCLUSIONS: In the patients studied, ASIL (low and/or high grade) tended to be significantly more prevalent in HIV-positive patients. Nonetheless, HIV-negative anoreceptive patients also presented great probability to have anal cancer precursor lesions, mainly those of the male gender. PMID- 21271207 TI - Latero-lateral femoro-femoral arteriovenous fistula: a new surgical approach for hemodialysis patients with no vascular access. AB - PURPOSE: A new surgical approach for vascular access for hemodialysis using a latero-lateral arteriovenous fistula (AVF) in the thigh between the femoral artery (FA) and superficial femoral vein (SFV) transposed to the subcutaneous layer in patients with no other access options is described. METHODS: Ten patients (mean age: 37,9 years) for whom all possible sites for execution of any other procedure had been exhausted, underwent latero-lateral AVF close to the adductor channel between the FA and the SFV. The FSV was released and sectioned 2 cm from its confluence with the deep femoral vein and transposed in the subcutaneous tissue with extensions using saphenous vein or prosthetic material (PTFE) when needed. Follow -up included patency, flow evaluation and complications. RESULTS: Postoperative follow-up ranged from 3 to 96 months, with a mean of 38 months. The AVFs presented a flow of more than 350 ml/min and the AVFs remained patent for a mean period of 38 months. There were three failures of the procedures at 3, 5 and 7 months during postoperative follow-up due to graft infection and thrombosis (a case), anaphylactic shock and thrombosis (a case) and calf pain during dialysis (a case). Two patients developed slight inferior limb edema. CONCLUSION: The new surgical approach for access for hemodialysis represents a feasible procedure, with acceptable patency rates in exceptional cases where no other access option is available. PMID- 21271208 TI - Peer review, science, young investigators feelings and frustrations. PMID- 21271210 TI - Family Health Strategy doctors and nurses' perceptions of complementary therapies. AB - OBJECTIVE: To analyze Estrategia de Saude da Familia (Family Health Strategy) professionals' perception of complementary and integrative therapies. METHODS: A study with 177 doctors and nurses was conducted in 2008, based on a self administered questionnaire. The outcome variables were "interest in complementary and integrative therapies" and "agreement with the National Policy on Complementary and Integrative Therapies. Sex, age, graduate level of education, postgraduate level of education, length of time since graduation, length of time of work, having children, providing complementary and integrative therapies in the workplace, and using homeopathy or acupuncture comprised the independent variables. Data were analyzed using Chi-square test and Fisher's exact test. RESULTS: A total of 17 health centers provided complementary and integrative therapies; 12.4% of professionals had a specialization in homeopathy or acupuncture; 43.5% of doctors were specialists in family and community medicine/family health. Of all participants, 88.7% did not know the national directives for this area, although 81.4% agreed with their inclusion in the Sistema Unico de Saude (Unified Health System). The majority (59.9%) showed an interest in qualifications and all agreed that these therapies should be approached during the graduate course. Agreement with the inclusion of such therapies was significantly associated with the fact of being a nurse (p = 0.027) and using homeopathy for oneself (p = 0.019). Interest in complementary therapies was associated with the use of homeopathy for oneself (p = 0.02) and acupuncture by family members (p = 0.013). CONCLUSIONS: Complementary and integrative therapies are accepted by the professionals studied. This acceptance is associated with previous contact with such therapies and, probably, with residency/specialization in family and community medicine/family health. PMID- 21271211 TI - Mild traumatic brain injuries: a 10-year follow-up. AB - OBJECTIVE AND DESIGN: Long-term consequences of mild traumatic brain injuries were investigated based on a 10-year follow-up of patients from a previously published randomized controlled study of mild traumatic brain injuries. One aim was to describe changes over time after mild traumatic brain injuries in terms of the extent of persisting post-concussion symptoms, life satisfaction, perceived health, activities of daily living, changes in life roles and sick leave. Another aim was to identify differences between the intervention and control groups. PATIENTS: The intervention group comprised 142 persons and the control group 56 persons. METHODS: Postal questionnaires with a response rate of 56%. RESULTS: No differences over time were found for the intervention and control groups in terms of post-concussion symptoms. In the intervention group some variables in life satisfaction, perceived health and daily life were decreased. Some roles had changed over the years for both groups. No other differences between the intervention and control groups were found. However, in both groups sick leave decreased. CONCLUSION: Early individual intervention by a qualified rehabilitation team does not appear to impact on the long-term outcome for persons with symptoms related to mild traumatic brain injuries. The status after approximately 3 weeks is indicative of the status after 10 years. PMID- 21271212 TI - Fundamentals of prions and their inactivation (review). AB - Prion is an infectious particle composed of an abnormal isoform of the prion protein (PrPSc) and causes prion diseases such as bovine spongiform encephalopathy (BSE), Creutzfeldt-Jakob disease (CJD) and scrapie. Host cells express cellular prion protein (PrPC), which plays roles in normal functions such as anti-oxidative stress. PrPSc is derived from PrPC and produced by conformational conversion. Prion is notorious as a resistant pathogen, being difficult to inactivate with conventional sterilization procedures. Therefore, to prevent prion-caused iatrogenic diseases, the use of appropriate procedures to inactivate prions is important. For examples, alcohol treatment, autoclave (121C, 20 min) and gamma-ray irradiation, which are used for disinfection, antisepsis or sterilization of viruses and bacteria, are not effective against prion. This is a fundamental review of prions and methods of their inactivation. PMID- 21271213 TI - Estrogen receptor and progesterone receptor are prognostic factors in soft tissue sarcomas. AB - Estrogen (ER) and progesterone receptor (PgR) regulate growth and cell differentiation upon ligand-dependent and ligand-independent activation. In breast cancer and gynecological tumors their expression are known predictors of endocrine therapy benefits and a favourable therapy-independent prognosis. In soft tissue sarcomas, their expression profile is poorly defined and their significance is uncertain. We investigated the prognostic impact of ER and PgR in non-gastrointestinal stromal tumor soft tissue sarcomas (non-GIST STSs). Tumor samples and clinical data from 249 patients with non-GIST STS were obtained, and tissue microarrays (TMAs) were constructed for each specimen. Immunohistochemistry (IHC) was used to evaluate marker expression in tumor cells. In univariate analyses, the expression of neither ER nor PgR (P=0.333 and 0.067, respectively) were significant prognosticators in the total cohort. However, measured separately for each gender, ER positivity was a significant favourable indicator for disease specific survival (DSS) in women (P=0.017) while PgR positivity had inverse impact in men (P=0.001). Among the four possible coexpression profiles, ER-/PgR+ was significantly least favourable for survival in the univariate analysis (P<0.001). In the multivariate analysis, the ER-/PgR+ phenotype was an independent negative prognostic factor for DSS (HR=1.9, 95% CI=1.2-3.1, P=0.008) in addition to patient's nationality, tumor depth, histological entity, malignancy grade, metastasis at diagnosis, surgery and positive resection margins. The present findings indicate that ER and PgR have significant gender dependent impact on DSS in non-GIST STSs. PMID- 21271214 TI - Differential expression of invasion promoting genes in childhood rhabdomyosarcoma. AB - Expression profiling of tumor tissue allows a systematic search for targeted therapies and offers relevant prognostic information. Molecular studies on rhabdomyosarcoma (RMS) revealed a more differentiated classification than the histological subgrouping into embryonal (RME) and alveolar (RMA) rhabdomyosarcoma, and reflected the chromosomal aberrations found in RMS. We addressed biological processes like cell migration and emerging drug resistance by expression profiling to identify mechanisms of metastasic invasion and differential response to chemotherapy in RMS. Gene expression analysis was performed in 19 RMS samples using the Affymetrix U133 Plus2 array. Validation of target genes was performed by qRT-PCR. Data were analyzed using Pathway analysis software. Involvement of these genes in invasion processes was evaluated in knock down experiments using specific interference RNA and Matrigel(TM) invasion assay. In RMA tissues 211 of 534 genes were overexpressed, in RME tissues 323 genes were overexpressed. Pathway analysis software identified a group of genes involved in cell growth, morphology and motility. In patients with distant metastases especially transcription factors such as FOXF1 and LMO4 showed a high expression, which were described as determinants of tumor cell migration. Down-regulation of these factors inhibited the invasion of RMS cells >10-fold. Microarray technology is a powerful method not only to classify RMS samples, but also to identify major regulatory processes. Functional evaluation of LMO4 and FOXF1 identified targets of a molecular network for preventing metastatic invasion in RMS. PMID- 21271215 TI - Cantharidin induces G2/M phase arrest and apoptosis in human colorectal cancer colo 205 cells through inhibition of CDK1 activity and caspase-dependent signaling pathways. AB - Cantharidin (CTD) is a traditional Chinese medicine and an effective component isolated from blister beetle, and it has been demonstrated to have anticancer, antibiotic, antivirus activities and immune-regulated functions. It has been reported that CTD induces cell cycle arrest and apoptosis in many cancer cell types. However, there are no reports showing that CTD would induce cell cycle arrest and apoptosis in human colorectal cancer colo 205 cells. In this study, we studied colo 205 cells which were treated with CTD and demonstrated its molecular mechanisms in apoptosis. CTD induced growth inhibition, G2/M phase arrest and apoptosis in colo 205 cells. The IC50 is 20.53 uM in CTD-treated colo 205 cells. DAPI/TUNEL double staining and Annexin V assays were used to confirm the apoptotic cell death in colo 205 cells after CTD exposure. CTD caused G2/M arrest, down-regulated CDK1 activity, decreased Cyclin A, Cyclin B, CDK1 and increased CHK1 and p21 protein levels. Colorimetric assays also indicated that CTD triggered activities of casapse-8, -9 and -3 in colo 205 cells. Moreover, CTD increased ROS production and decreased the level of mitochondrial membrane potential (DeltaPsim) in colo 205 cells. Consequently, CTD-induced growth inhibition was significantly attenuated by N-acetylcysteine (NAC, a scavenger). CTD stimulated the protein levels of Fas/CD95, the caspase-3 active form, cytochrome c and Bax, but suppressed the protein levels of pro-caspase-8, pro caspase-9 and Bcl-2, determined by Western blot analysis. Based on our observations, we suggest that CTD is able to induce G2/M phase arrest and apoptosis in colo 205 cells through inhibition of CDK1 activity and caspase dependent signaling pathways. PMID- 21271216 TI - Expression of the forkhead transcription factor FOXL2 correlates with good prognosis in breast cancer patients treated with tamoxifen. AB - Aromatase is an important enzyme in the local synthesis of oestrogens and its expression has been shown to be increased in breast cancer through the activation of multiple promoters. However, the mechanisms behind this are not yet fully understood. A novel candidate in this context is the transcription factor forkhead box L2 (FOXL2), which has been recognised to be co-expressed with aromatase and transcriptionally active promoter II in developing goat and chicken ovaries. We propose that FOXL2 could be involved in the increased expression of aromatase in breast cancer. We examined FOXL2 and its relation to aromatase in 132 post-menopausal breast cancer patients by immunohistochemistry. Using in silico analysis, we further searched for FOXL2 binding-elements in the aromatase gene promoters. The results demonstrate that FOXL2 is expressed in breast cancer and influences clinical outcome with improved recurrence-free survival in cases with nuclear expression. In a multivariate Cox model, nuclear FOXL2 was a significant prognostic factor in ER-positive patients treated with tamoxifen (HR=0.18, 95% confidence interval (CI)=0.04-0.81, P=0.03). Tumours expressing nuclear FOXL2 were also more likely positive for stromal and/or cytoplasmic aromatase (P=0.03 and P=0.008, respectively). In silico analyses revealed binding elements of FOXL2 in promoters I.3, II and I.7 of the aromatase gene of which promoter I.7 was most significant. In conclusion, this is the first study to report that FOXL2 is expressed in breast cancer and correlates with aromatase as well as with clinical outcome. The results further strengthen a possible binding of FOXL2 to aromatase promoter I.7. Nevertheless, whether FOXL2 is a direct activator of aromatase requires further investigation. PMID- 21271217 TI - TNF-alpha is a novel target of miR-19a. AB - Many studies have demonstrated the overexpression and amplification of the miR-17 92 cluster in malignant human cancers, including B-cell lymphomas and lung cancers. The purpose of this study was to investigate for the first time, the expression of the miR-17-92 cluster in esophageal squamous cell carcinoma (ESCC). The miR-17-92 cluster was found to be overexpressed in 21 out of 28 (75%) esophageal cancer samples. It was also found that overexpression of the miR-17-92 cluster could promote cellular growth in vivo and in vitro. Furthermore, inhibition of miR-19a by antisense oligonucleotides (ONs) induced apoptosis, while antisense ONs against miR-17-5p, miR-18a, miR-20a and miR-92-1 did not exhibit such an effect. In addition, it was found that antagomir-19a treatment could impair tumor growth in vivo. Using Human Apoptosis RT2 Profiler PCR Array 384HT, we found that tumor necrosis factor-alpha (TNF-alpha) was up-regulated 12 fold in cells transfected with miR-19a antisense ONs compared to the cells treated with the control scramble ONs. MiR-19a was predicted to target the 3' untranslated region of TNF-alpha mRNA, and this was confirmed by luciferase reporter assay. Taken together, we conclude that the miR-17-92 cluster is overexpressed in ESCC and that TNF-alpha is a novel target of miR-19a. PMID- 21271218 TI - JS-K, a nitric oxide-releasing prodrug, induces breast cancer cell death while sparing normal mammary epithelial cells. AB - Targeted therapy with reduced side effects is a major goal in cancer research. We investigated the effects of JS-K, a nitric oxide (NO) prodrug designed to release high levels of NO when suitably activated, on human breast cancer cell lines, on non-transformed human MCF-10A mammary cells, and on normal human mammary epithelial cells (HMECs). Cell viability assay, flow cytometry, electron microscopy, and Western blot analysis were used to study the effects of JS-K on breast cancer and on mammary epithelial cells. After a 3-day incubation, the IC50s of JS-K against the breast cancer cells ranged from 0.8 to 3 uM. However, JS-K decreased the viability of the MCF-10A cells by only 20% at 10-uM concentration, and HMECs were unaffected by 10 uM JS-K. Flow cytometry indicated that JS-K increased the percentages of breast cancer cells under-going apoptosis. Interestingly, flow cytometry indicated that JS-K increased acidic vesicle organelle formation in breast cancer cells, suggesting that JS-K induced autophagy in breast cancer cells. Electron microscopy confirmed that JS-K-treated breast cancer cells underwent autophagic cell death. Western blot analysis showed that JS-K induced the expression of microtubule light chain 3-II, another autophagy marker, in breast cancer cells. However, JS-K did not induce apoptosis or autophagy in normal human mammary epithelial cells. These data indicate that JS-K selectively induces programmed cell death in breast cancer cells while sparing normal mammary epithelial cells under the same conditions. The selective anti-tumor activity of JS-K warrants its further investigation in breast tumors. PMID- 21271219 TI - Identification of recurrence-related microRNAs in the bone marrow of breast cancer patients. AB - Recently, bone marrow has been considered as playing a critical role in the generation of both metastasis and recurrent disease. The accumulation of a single microRNA in the bone marrow has the potential to regulate the translation of multiple genes in cancer metastasis and may therefore serve as a prognostic marker for cancer recurrence. MicroRNA microarray analysis was performed to compare microRNA levels in bone marrow from 4 breast cancer patients with recurrent disease and 4 patients without recurrence. Accumulation of two of these microRNAs, miR-21 and miR-181a, in the recurrent breast cancer cases was validated by RT-PCR in bone marrow from 291 additional breast cancer cases. Expression of a common target gene, PDCD4, was also determined in bone marrow from 291 breast cancer cases. Increased miR-21 and miR-181a levels were significantly associated with shortened disease-free survival (DFS; p=0.0003, 0.0007) and overall survival (OS; p=0.0351, 0.0443), respectively. While low PDCD4 expression was also significantly associated with poorer DFS (p=0.036). Multivariate analysis identified bone marrow miR-21 and mR-181a levels as valuable independent prognostic factors, with correlation coefficients that were significantly higher than that of the transcript of their common target gene. Accumulation of miR-21 and miR-181a in bone marrow appears to be associated with prognosis in breast cancer patients. The much higher significant correlation with microRNA levels and prognosis suggests epistatic effects on multiple target genes in the bone marrow of breast cancer patients. PMID- 21271220 TI - Triptolide-induced cell cycle arrest and apoptosis in human renal cell carcinoma cells. AB - Renal cell carcinoma (RCC) is the most frequent type of renal-originated malignancy. Although nephrectomy is successfully used to save the lives of patients with localized RCC, treatment of advanced and other refractory RCCs is poor and still inadequate. Here, we show that triptolide, a small molecule and a well-known anti-inflammatory and anti-immunity agent used in the clinic, is capable of inducing cell apoptosis via the mitochondrial pathway in the 786-0 RCC cell line. This induction occurred in concert with reduced expression of genes related to the stabilization of mitochondria such as Bcl-2 and Bcl-XL. Cell cycle analysis showed that exposure to triptolide decreased the proportion of cells in the G0/G1 and G2/M phases, and increased the proportion of cells in the S phase. Cell accumulation in the S phase can be attributed to reduced expression of cell cycle checkpoint regulators such as cyclin A, cyclin B, CDK1, CDK2 and retinoblastoma proteins (Rb). These results raise the possibility that triptolide induced apoptosis is mediated by cell cycle arrest. Similarly, in another human RCC cell line, OS-RC-2, triptolide-induced apoptosis and cell accumulation in S phase were also observed. Therefore, triptolide emerges as a stimulator of apoptosis by influencing coordinate regulation of proliferation and apoptosis, and may be applicable to the treatment of human renal cell carcinoma. PMID- 21271221 TI - Aberrant methylation of the CADM1 promoter is associated with poor prognosis in hepatocellular carcinoma treated with liver transplantation. AB - Approximately 20-40% of hepatocellular carcinoma (HCC) patients who undergo liver transplantation (LT) experience HCC recurrence within 5 years of the operation. Current predictors cannot sufficiently differentiate patients at risk for biochemical recurrence. The aim of the present study was to investigate the methylation status and expression levels of cell adhesion molecule 1 (CADM1) in HCC; to elucidate its regulation mechanisms; and finally, to evaluate the potential predictive value for tumor recurrence. Aberrant hypermethylation of CADM1 was frequently found in HCC cell lines with decreased CADM1 mRNA by bisulfite sequencing PCR. Re-expression of CADM1 was induced by treatment with demethylating agents. The promoter region of CADM1 was identified and the basal promoter activity was located in the -226 to -146 region relative to the transcriptional start site (TSS). Site-directed mutagenesis revealed that the consensus Sp1 binding site located in the basal promoter region was important for mediating CADM1 promoter activity. Furthermore, aberrant hypermethylation of CADM1 was detected in 34 of 82 (41.5%) of HCC tissues. The recurrence rate of the patients with CADM1 methylation was higher compared to that without CADM1 methylation (70.6% versus 33.3%; P=0.001). Multivariate analysis revealed that CADM1 methylation status (HR = 2.788; 95% CI, 1.043-5.063; P=0.010) was an independent prognostic factor for disease-free survival (DFS) of HCC patients treated with LT. In conclusion, CADM1 methylation may be used as a potential predictive biomarker for tumor recurrence of HCC after LT. PMID- 21271222 TI - KRAS-mutated non-small cell lung cancer cells are responsive to either co treatment with erlotinib or gefitinib and histone deacetylase inhibitors or single treatment with lapatinib. AB - The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors erlotinib and gefitinib provide significant clinical benefit for non-small cell lung cancer (NSCLC) patients whose tumors bear EGFR mutations/amplifications. However, anti EGFR therapy is largely ineffective in NSCLC with activating KRAS mutations. In this study, we investigated the treatment efficacy of erlotinib and gefitinib in combination with the histone deacetylase inhibitors (HDACi) vorinostat and sodium butyrate in the KRAS-mutated NSCLC cell line A549. For comparison, we tested the combination of HDACi with the dual tyrosine kinase inhibitor lapatinib. A549 cells proved to be resistant to erlotinib and gefitinib, but could be sensitized by cotreatment with HDACi, as assessed by flow cytometric analyses of cell death and mitochondrial depolarization. In contrast, A549 cells were a priori responsive to lapatinib treatment, but responsiveness to lapatinib could not be enhanced by HDACi cotreatment. These divergent effects of the different combination regimens may be explained by dissimilar types of cell death induced by the treatments: The use of the pan-caspase inhibitor z-VAD-fmk in the cell death and mitochondrial depolarization assays as well as fluorescence microscopy analyses indicated that erlotinib or gefitinib combined with HDACi elicited apoptosis, whereas lapatinib treatment induced a non-apoptotic type of cell death. Our study suggests that both HDACi/EGFR inhibitor-combination treatment and lapatinib-single treatment may be effective options for the therapy of NSCLC with KRAS mutations. PMID- 21271223 TI - Isolation and characterization of myofibroblast cell lines from oral squamous cell carcinoma. AB - Oral squamous cell carcinoma (OSCC) invasion is followed by several stromal events such as inflammatory and immune cell infiltration, neo-vascularization, fibroblast activation and occasionally myofibroblast emergence. Our previous studies demonstrated that myofibroblasts in the stroma of OSCC are associated with a more aggressive behavior, leading to shorter patient overall survival. Therefore, we evaluated whether OSCC-associated myofibroblasts have different characteristics compared to OSCC-associated fibroblasts. OSCC myofibroblast cell lines were isolated, cultured and characterized on the basis of the expression of specific isoform alpha of smooth muscle actin (alpha-SMA) and of the excessive production of type I collagen. To assess the proliferative potential of the cell lines, growth curves were constructed, whereas the production and activity of matrix metalloproteinases (MMP) were analyzed by ELISA and enzymography, respectively. Myofibroblast clones were positive for alpha-SMA and vimentin, and negative for pan-cytokeratin and CD34. In long time cultures, western blotting, flow cytometry and ELISA analysis revealed constant alpha-SMA expression and elevated production of type I collagen. There were no differences on proliferative potential between fibroblast and myofibroblast clones, but myofibroblast cells secreted significantly higher levels of MMP-1, -2, -9 and 13. Furthermore, MMP-2 gelatinolytic activity was significantly higher in myofibroblast clones. The results of this study suggest that myofibroblasts may contribute to OSCC invasion through elevation of MMP synthesis. PMID- 21271224 TI - Prognostic impact of AMP-activated protein kinase expression in ovarian carcinoma: correlation of protein expression and GC/TOF-MS-based metabolomics. AB - AMP-activated protein kinase (AMPK) plays a central role in regulating energy metabolism in cells. AMPK activation results in down-regulation of anabolic pathways (e.g., fatty acid biosynthesis) and switches on catabolic processes such as glucose uptake, glycolysis or fatty acid oxidation. Recent studies in cell culture models have shown that the growth of tumor cell lines was inhibited by AMPK activation, but the expression of AMPK in human ovarian tumors has not been reported so far. In this study we investigated AMPK expression in a cohort of 70 ovarian carcinomas, 14 borderline tumors and 5 normal ovaries and linked the protein expression data to Gas chromatography/ time of flight mass spectrometry (GC/TOF-MS) based metabolomics. We observed a significantly higher expression in ovarian carcinomas compared to borderline tumors and normal ovaries (p=0.038). Decreased AMPK expression correlated significantly with higher tumor grade (p=0.009) and was of adverse prognosis in patients with advanced tumor stages (p=0.016) as well as in patients with serous ovarian carcinomas (p=0.037). GC/TOF MS based metabolomics revealed a significantly higher concentration of glucose in AMPK-negative carcinomas (p=0.022) as well as overexpression of other metabolites from carbohydrate metabolism. Our results indicate a role for AMPK in progression of ovarian tumors and point towards a prognostic impact of AMPK expression for patient overall survival. Furthermore, our data suggest a deregulation of the AMPK-dependent energy metabolism in human ovarian carcinomas. In future clinical studies, activation of AMPK in ovarian carcinoma patients with advanced tumor stages might be an interesting therapeutic approach. PMID- 21271225 TI - GRObeta and its downstream effector EGR1 regulate cisplatin-induced apoptosis in WHCO1 cells. AB - Cisplatin is one of the most widely used chemotherapeutic agents employed for treatment of a wide variety of solid tumors, including human esophageal squamous cell carcinoma (ESCC). However, a major limitation of cisplatin-based chemotherapy of ESCC is the rather low-effective rate. Understanding the molecular events of limited efficacy of cisplatin-based chemotherapy of ESCC could lead to strategies resulting in improved therapeutic benefits. The CXC chemokine family has been reported to be related to inflammatory reaction, injure recovery, cell proliferation, apoptosis and even to be involved in the regulation of chemotherapeutic agent-induced apoptosis. CXCL2 chemokine, also known as GRObeta (growth-related gene product beta), belongs to the CXC chemokine group. The known functions of GRObeta are related to attracting neutrophils to sites of inflammation, modulation of the neurotransmitter release, cell proliferation and apoptosis. However, little is known about the relationship between GRObeta and chemotherapeutic agent-induced apoptosis. This study was designed to provide insights into the possible role of GRObeta in the regulation of cisplatin-induced apoptosis in ESCCs. We report here that inhibition of expression of GRObeta can decrease cisplatin-induced apoptosis in WHCO1 cells. EGR1 is a downstream factor regulated by GRObeta. Silencing expression of EGR1 can also decrease cisplatin induced apoptosis in WHCO1 cells. The activation of caspase 9 was delayed in cells in which GRObeta and EGR1 were knocked down after cisplatin treatment. All these results indicate that GRObeta and its downstream factor EGR1 are involved in regulating cisplatin-induced apoptosis in WHCO1 cells, and during this process the intrinsic apoptotic pathway is activated. It may be useful to examine the expression levels of GRObeta and EGR1 in ESCC patients to select those likely to respond well to cisplatin. PMID- 21271226 TI - Ultraviolet light exposure influences skin cancer in association with latitude. AB - The increase in the amount of solar ultraviolet (UV) light that reaches the earth is considered to be responsible for the worldwide increase in skin cancer. It has been reported that excessive levels of UVA and UVB light have multiple effects, which can be harmful to humans. Experimental measurements were obtained using wide-band solar light YES biometers from 2006 to 2009 in Arica, Chile and from 2003 to 2006 in Valdivia, Chile, both instruments having been calibrated according to the World Health Organization (WHO) criteria and integrated into the Chilean Meteorological Organization network. To explain the possible effect of radiation on skin cancer, revised pathological reports in Arica and Valdivia were analyzed. In Arica, data on men and women were collected between 1997 and 1998 2002, and in Valdivia, between 1997-2000 and 2001-2007. In this study, comparative values of ultraviolet index (UVI) from the above datasets, were analyzed. Arica is a city located in the subtropical zone of northern Chile, 25 meters above sea level, with a latitude of 1849'S and a longitude of 7019'W. It has a microclimate characterized by stable meteorological conditions throughout the year, including low precipitation (<5 mm per decade), predictable winds, a high percentage of clear sky days and high ground reflectivity due to the presence of light sand. Due to its location near sea level, the population performs a great number of outdoor activities. Valdivia is a city located in the southern part of Chile, 19 meters above sea level with a latitude of 3938'S and a longitude of 735'W. The aim of the present study was to determine the relationship between latitude and the risk of skin cancer in two cities with different latitudes. The incidence of skin cancer per 100,000 persons significantly (P<0.05) increased in both genders between the periods 1997-2000 and 2001-2007 in Arica. However, it decreased in men between the periods 1993 1997 and 1998-2002 in Valdivia. The results of this study indicate a steady increase in the incidence of skin cancer in Arica, most probably due to the high levels of UV light and the latitude to which individuals are exposed throughout the year, as well as the accumulative effect of this type of radiation on the skin. It can be concluded that Arica presented a greater UVI than Valdivia, which can explain the high prevalence of skin cancer in this population according to the pathological reports. PMID- 21271227 TI - Novel Carcinoembryonic-Antigen-(CEA)-Specific Pretargeting System to Assess Tumor Cell Viability after Irradiation of Colorectal Cancer Cells. AB - PURPOSE: To date, no valid imaging modality exists for early response prediction to neoadjuvant radiochemotherapy in carcinoembryonic-antigen-(CEA)-expressing rectal cancers (UICC stages II and III). It is hypothesized that the uptake of an anti-CEA antibody is directly related to the number of viable tumor cells and may be quantified by immuno-positron emission tomography (immuno-PET). Therefore, we evaluated a novel pretargeting system using TF2, a humanized bispecific trivalent monoclonal antibody (mAb), directed against CEA and the IMP-288-peptide, a hapten for binding radiometals for imaging. Uptake and kinetics of the pretargeting system were investigated in vitro prior to and after irradiation. METHODS: TF2 was labeled with 131I and IMP-288 with 111InCl3. The colorectal cancer cell lines HT29, SW480, and T84 with known varying CEA expression were incubated (<= 72 hours) with 131I-TF2 or the TF2-111In-IMP-288 pretargeting system. Parallel cultures were irradiated with 2-10 Gy high-energy photons. Tracer uptake, proliferation, apoptosis, and CEA-RNA expression of cancer cells were investigated. RESULTS: The uptake of tracers was dependent on CEA expression and cell count of the cell lines (uptake/106 cells: 0.3% in HT29, 1.5% in SW480, and 14% in T84, p < 0.001). The TF2-111In-IMP-288 pretargeting system showed a higher uptake after 4 and 72 hours compared to (131)I-TF2 in parallel cultures. Only in one cell line (SW480) an increased apoptosis after irradiation could be detected. Irradiation increased dose dependently both the specific uptake of 131I-TF2 and of the TF2-111In-IMP-288 system (4-fold in HT29 and T84 after 10 Gy (72 hours), p < 0.001). These results were CEA-mRNA independent. CONCLUSION: This novel pretargeting system allows the quantitative analysis of CEA-expressing colorectal cancer cells and represents a promising tool for evaluation of tumor cell viability after irradiation. PMID- 21271228 TI - [Perivascular brachial plexus block. Ultrasound versus nerve stimulator]. AB - BACKGROUND: Optimizing the needle position using ultrasound (US) instead of electrical nerve stimulation (NSt) is increasingly common for perivascular brachial plexus block. These two methods were compared in a prospective, randomized, single-blinded controlled trial regarding effectiveness and time of onset of peripheral nerve blockade. METHODS: After puncture (penetration of neurovascular sheath and complete insertion of needle) 56 patients were randomly assigned to either the US group (finding the needle tip in transpectoral section, short axis, correction of needle position if local anesthetic spread was insufficient) or the NSt group (target impulse reaction in median, ulnar or radial nerve of 0.3 mA/0.1 ms, if necessary correction of position before injection of local anesthetic) to verify the needle position. All patients received 500 mg 1% mepivacaine. Sensory and motor blocks were tested by single nerve measurements (SNM) 5, 10 and 20 min after finishing the injection, where 0 represents minimal and 2 maximal success of the block. RESULTS: Single nerve measurements were analyzed using repeated measures ANOVA. The mean results of cumulative SNMs were significantly higher in the US group at all measurement times. Sensitivity US/NSt: 5 min: 3.36+/-2.32/2.63+/-1.87; 10 min: 5.45+/ 2.41/4.21+/-2.45; 20 min: 7.30+/-2.02/6.43+/-2.43, p=0.015, motor function US/NSt: 5 min: 3.91+/-1.81/3.02+/-1.67; 10 min: 5.27+/-1.66/4.05+/-1.70; 20 min: 6.64+/-1.37/5.50+/-1.90, p<0.001. At the beginning of surgery complete nerve blockade was achieved in 89% in the US group and 68% in the NSt group (p=0.006), 3 (US) versus 7 (NSt) patients needed supplementation and 3 (US) versus 11 (NSt) patients needed general anesthesia (p=0.022). To achieve the nerve block took approximately 1 min more in the US group (p=0.003). CONCLUSION: The use of ultrasound in perivascular brachial plexus blocks leads to significantly higher success rates and shorter times of onset. PMID- 21271229 TI - [Well known but often forgotten. Effect of a neck roll on airway patency in deeply sedated children]. PMID- 21271230 TI - [Preclinical prediction of prehospital injury severity by emergency physicians : approach to evaluate validity]. AB - BACKGROUND: The prognosis of polytraumatized patients is basically dependent on the quality of emergency room (ER) management and a smooth transition from prehospital emergency therapy to ER therapy is essential. The accurate prediction of the prehospital injury severity by emergency physicians influences prehospital therapy and level of care of the destination hospital. Furthermore it helps to provide medical resources on time. Overestimation of injury severity wastes resources, underestimation puts patients at risk. Prehospital misjudgement of injury severity is common. The aim of this study was to evaluate reliability of the injury severity estimated by emergency physicians. MATERIALS AND METHODS: For comparison of the prehospital and hospital injury severity the Injury Severity Score (ISS) and Trauma-ISS (TRISS) were calculated. The TRISS consists of the ISS and the Revised Trauma Score (RTS). All diagnoses of the prehospital and admission charts were collected and an injury severity was allocated according to the Abbreviated Injury Scale (AIS). The concordance of prehospital and hospital injury severity at different ranges and according to different body regions was evaluated. A difference of more than 25% between the prehospital injury severity and the injury severity calculated after ER diagnostics was considered as being relevant and judged as overestimation or underestimation. The documented injury severity in the emergency physician protocol was judged as detailed, satisfactory and poor. RESULTS: Of the patients 73% reached the ER during on-call hours. The mean ER-ISS was 19 (1-50). At a range of +/-25% referring to the ER-ISS, 30% overestimation and 36% underestimation of the prehospital injury severity was observed. A concordance of 34% was found. At a range of +/-50% the concordance between the prehospital injury severity and the injury severity calculated after ER diagnostics was 57%, at a range of +/-75% the concordance was 73%. The mean ER TRISS was 6.9 points (0.3-98.6) and the mean ER-RTS was 7.569 points (0-7.841). Using the TRISS with a range of +/-25% a concordance of 28% was observed. A high concordance of the prehospital and hospital injury severity was found in the region of the face (70%) and external soft tissue injuries (80%). The concordance in the body region of the abdomen was 55%, of the thorax 40%, of the extremities and pelvis 37% and of the head 33%. Underestimation in the region of the abdomen was 32%, of the head 37%, of the thorax 42% and of the extremities and pelvis 47%. Missed injuries were the reason for underestimation in the body region of extremities and pelvis in half of the cases. Of the patients 61% suffered a traffic accident, 25% a fall of less than 3 m and 8% of more than 3 m. In 5% of the cases other mechanisms of injury were observed. Injury severity was documented in a detailed manner in 61% and satisfactory in 26%. CONCLUSIONS: The prediction of prehospital injury severity is difficult and less reliable. Relevant underestimation of injury severity was observed in visceral cavities. In order to evaluate injury severity the use of anatomical trauma scores alone might be not sufficient. In addition, the mechanism of injury and the deduced consequences, such as prehospital therapy, the choice of destination hospital and the need of ER treatment should be taken into account. PMID- 21271231 TI - [Nosocomial pneumonia. Prevention and diagnostic]. AB - Pneumonia occurring more than 48 h after induction of mechanical ventilation is called ventilator-associated pneumonia (VAP). VAP is the most common nosocomial infection in intensive care medicine and is associated with prolonged intensive care and hospital stay and a higher mortality. The main pathomechanism for development of ventilator-associated pneumonia is not so much the mechanical ventilation per se but more the pathogens passing along the tube towards the lungs. Avoidance of tracheal intubation, strict hygienic measures, reduction of oropharyngeal colonization and the avoidance of microaspiration are the most promising prevention strategies. Therapeutic success in treatment of VAP is coupled to an early diagnosis and therapy. Suspicion of pneumonia is based on clinical and radiologic criteria. Biomarkers and microbiological findings are important for follow-up and reevaluation of the suspected diagnosis. PMID- 21271232 TI - Hemodynamics in coronary artery bypass surgery: effects of intraoperative dexmedetomidine administration. AB - OBJECTIVE: Dexmedetomidine is an alpha2-receptor agonist which is increasingly being used in coronary artery bypass grafting (CABG) surgery due to its suppressive effect on the stress responses against intubation and surgery. In this study effects of dexmedetomidine administration as an adjuvant agent during induction and maintenance of anesthesia on intraoperative hemodynamic changes were studied in patients undergoing CABG. METHODS: A total of 20 patients undergoing CABG were included in the study. At the beginning dexmedetomidine infusion of 1 ug/kg body weight (BW)/h was performed for 10 min. After this the infusion dosage of dexmedetomidine was decreased to 0.2-0.4 ug/kgBW/h, 0.15 mg/kgBW of cisatracurium was administered for intubation and 0.5 MAC (minimum alveolar concentration) sevoflurane was administered as a volatile anesthetic. Heart rate (HR), mean arterial pressure (MAP), mean pulmonary artery pressure (MPAP), cardiac output (CO), systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR) were recorded 10 min after dexmedetomidine infusion, following intubation, during skin incision and sternotomy, before and after the bypass and in the postoperative period. RESULTS: With dexmedetomidine infusion HR and MAP were found to be moderately decreased in comparison to baseline values and no severe bradycardia or hypotension requiring intervention occurred. No increase in HR and MAP values were recorded during sternotomy and bypass. The MPAP evaluation showed no difference between the preoperative and intraoperative values (p>0.05). The cardiac output (CO) was found to be low starting from the time of skin incision to just before the bypass, compared to preoperative values (p<0.05) and SVR was moderately decreased with initial high dose infusion and after that increased to baseline values (p<0.05). CONCLUSION: Dexmedetomidine can be safely used in CABG operations delivering a stable hemodynamic status throughout the operative period. PMID- 21271234 TI - [Epidermolysis bullosa : Diagnosis and therapy]. AB - Hereditary epidermolysis bullosa is characterized by mechanically induced blistering of the skin and mucous membranes. The causative mechanisms are based on mutations in genes for structural proteins of the epidermis and the dermal epidermal junction zone. EB is genetically and clinically heterogeneous. Based on the clinical phenotype alone, the diagnosis is difficult in newborns and toddlers, and sometimes even in adults. A precise diagnosis is only possible with laboratory tests like immunofluorescence mapping, electron microscopy and mutation analysis in specialized centers. The treatment is symptomatic and based on the principles of good wound management and - for severe cases - on multidisciplinary care. New data on the pathogenetic mechanisms of epidermolysis bullosa deliver perspectives for development of novel molecular therapies. PMID- 21271233 TI - [Genetics of common chronic inflammatory skin diseases : An update on atopic dermatitis and psoriasis]. AB - Atopic dermatitis and psoriasis are two common chronic inflammatory skin diseases. Both are multifactorial disorders caused by an interaction between genetic and environmental factors. Epidemiological studies estimated a high heritability of up to 80% for both diseases, indicating a major role of genetic susceptibility factors in disease development and progression. However, in contrast to monogenic disorders, complex diseases are not caused by single gene mutations, but are the result of a complicated network of numerous susceptibility loci, many of which exert additive or synergistic effects, but have only a small role when considered in isolation. Knowledge on the genetic architecture of atopic dermatitis and psoriasis is still incomplete, but major advances have been made in the past years, in particular through genome-wide association approaches. PMID- 21271235 TI - Interventions to reduce central venous catheter-associated infections in children: which ones are beneficial? PMID- 21271237 TI - Relationship between serum estradiol and follicle-stimulating hormone levels and urodynamic results in women with stress urinary incontinence. AB - INTRODUCTION AND HYPOTHESIS: The purpose of the current study was to determine the relationship between the serum estradiol (E2) and follicle-stimulating hormone (FSH) levels and the urodynamic study results in women with stress urinary incontinence (SUI). METHODS: Eighty women were selected among patients who underwent urodynamic testing for SUI. Basic demographic features were evaluated and laboratory tests were performed. Multiple linear regression analyses were performed among the serum E2 and FSH levels and urodynamic results. RESULTS: E2 had a negative correlation with the Q-tip test in post-menopause. FSH had positive correlations with the post-void residual volume in the uroflowmetry and the voiding and flow times in the pressure-flow study in all of the patients and a negative correlation with the peak flow rate in the pressure-flow study in pre-menopause. CONCLUSIONS: E2 and FSH were associated with urodynamic parameters in female patients with SUI. PMID- 21271236 TI - Intervention to reduce catheter-related bloodstream infections in a pediatric intensive care unit. AB - OBJECTIVE: Identification of catheter-related bloodstream infection (CR-BSI) risk factors and determination of whether intervention related to identified risk factors would reduce CR-BSI rates. DESIGN: Prospective, observational, interventional and interrupted time-series study. SETTING: Pediatric Intensive Care Unit (PICU) in a university hospital. METHODS: During a 7-year period, 609 central venous catheters (CVC) were placed in 389 patients. CR-BSI risk factors were determined by multivariate analysis during two periods (January 2000 November 2002 and January 2003-April 2007). An intervention to reduce identified risk factors was performed after the first period. CR-BSI rates per 1,000 catheters-days were compared during the two periods. RESULTS: The CR-BSI rate was 11.94 [(95% CI 7.94-15.94)/1,000 catheter-days during the first period]. Weight [OR 0.96 (0.91-0.99)], parenteral nutrition (PN) [OR 3.38 (1.40-8.19)] and indwelling time (IT) [OR 1.08 (1.02-1.14)] were CR-BSI risk factors. Practice changes aimed at reducing PN and IT were introduced. PN decreased from 49.8% [95% CI (49.7-49.9)] to 26.7% [(95% CI 26.6-26.8)] (p < 0.001), and IT dropped from 9.92 (95% CI 9.09-10.75) to 8.13 (95% CI 7.47-8.79) days (p < 0.001). The CR-BSI rate was reduced to 3.05 (95% CI 0.93-5.17)/1,000 catheter-days. During the last period, PN and IT were no longer CR-BSI risk factors. Type of catheterisation (guide wire exchange) [OR 6.66 (1.40-31.7)] was the only CR-BSI risk factor. CONCLUSIONS: PN and IT were independent CR-BSI risk factors during the first period. An intervention focused on PN and IT reduction resulted in a sustained decrease of CR-BSI rates in our PICU. PMID- 21271238 TI - Analytical chemistry for cultural heritage: a key discipline in conservation research. PMID- 21271240 TI - Nuclear Overhauser effect challenge. PMID- 21271239 TI - HPLC-DAD-MS analysis of dyes identified in textiles from Mount Athos. AB - Organic colorants contained in 30 textiles (16th to early 20th century) from the monastery of Simonos Petra (Mount Athos) have been investigated using high performance liquid chromatography equipped with diode-array detection and mass spectrometry (HPLC-DAD-MS). The components of natural dyes identified in samples treated by the standard HCl dyestuff extraction method were: alizarin, apigenin, butein, carminic acid, chrysoeriol, dcII, dcIV, dcVII, ellagic acid, emodin, fisetin, flavokermesic acid, fustin, genistein, haematein derivative (Hae'), indigotin, indirubin, isoliquiritigenin, isorhamnetin, kaempferide, kaempferol, kermesic acid, luteolin, naringenin, purpurin, quercetin, rhamnazin, rhamnetin, sulfuretin, and type B and type C compounds (last two are markers for Caesalpinia trees). Early, semi-synthetic dyes, for example indigo carmine, fuchsin components, and rhodamine B were identified in objects dated late 19th to early 20th century. A dyestuff extraction method which involves use of TFA, instead of HCl, was applied to selected historical samples, showing that the mild method enables efficient extraction of weld (Reseda luteola L.) and dyer's broom (Genista tinctoria L.) glycosides. The marker compound (Hae') for logwood (Haematoxylum campechianum L.) identification after treatment with HCl was investigated by liquid chromatography coupled to mass spectrometry (LC-MS) in negative electrospray ionization (LC-MS-ESI(-)) mode. LC-MS in negative atmospheric pressure chemical ionization (LC-MS-APCI(-)) mode was used, probably for the first time, to investigate cochineal (Dactylopius coccus Costa) samples. Positive electrospray ionization (LC-MS-ESI(+)) mode was used for identification of fuchsin components. Detailed HPLC-DAD studies were performed on young fustic (Cotinus coggygria Scop.) and Persian berries (Rhamnus trees). PMID- 21271241 TI - Structural characterization by infrared multiple photon dissociation spectroscopy of protonated gas-phase ions obtained by electrospray ionization of cysteine and dopamine. AB - Structural characterization of protonated gas-phase ions of cysteine and dopamine by infrared multiple photon dissociation (IRMPD) spectroscopy using a free electron laser in combination with theory based on DFT calculations reveals the presence of two types of protonated dimer ions in the electrospray mass spectra of the metabolites. In addition to the proton-bound dimer of each species, the covalently bound dimer of cysteine (bound by a disulfide linkage) has been identified. The dimer ion of m/z 241 observed in the electrospray mass spectra of cysteine has been identified as protonated cystine by comparison of the experimental IRMPD spectrum to the IR absorption spectra predicted by theory and the IRMPD spectrum of a standard. Formation of the protonated covalently bound disulfide-linked dimer ions (i.e. protonated cystine) from electrospray of cysteine solution is consistent with the redox properties of cysteine. Both the IRMPD spectra and theory indicate that in protonated cystine the covalent disulfide bond is retained and the proton is involved in intramolecular hydrogen bonding between the amine groups of the two cysteine amino acid units. For cysteine, the protonated covalently bound dimer (m/z 241) dominated the mass spectrum relative to the proton-bound dimer (m/z 243), but this was not the case for dopamine, where the protonated monomer and the proton-bound dimer were both observed as major ions. An extended conformation of the ethylammonium side chain of gas-phase protonated dopamine monomer was verified from the correlation between the predicted IR absorption spectra and the experimental IRMPD spectrum. Dopamine has the same extended ethylamine side chain conformation in the proton bound dopamine dimer identified in the mass spectra of electrosprayed dopamine. The structure of the proton-bound dimer of dopamine is confirmed by calculations and the presence of an IR band due to the shared proton. The presence of the shared proton in the protonated cystine ion can be inferred from the IRMPD spectrum. PMID- 21271242 TI - Detailed imaging of the normal anatomy and pathologic conditions of the cavernous region at 3 Tesla using a contrast-enhanced MR angiography. AB - INTRODUCTION: The purpose of this study was to evaluate the potential of a high resolution contrast-enhanced magnetic resonance angiography (CE-MRA) at 3 Tesla for the delineation of the cavernous sinus (CS) anatomy both under normal and under pathological conditions. METHODS: Fifteen patients without pathologies in the CS and ten patients with pituitary adenomas were included. The CE-MRA was performed on a 3-Tesla scanner and analyzed collaboratively by two readers. The cranial nerves (CNs) within the CS, namely CNIII, CNIV, CNV1, CNV2, and CNVI, were identified in both patient groups. In the adenoma patients it was also assessed whether and to which extend the adenoma invaded the CS and the spatial relationship between tumor and CNs was determined. RESULTS: In the patients with normal CS anatomy, CNIII could be identified in 100%, CNIV in 86.7%, and CNV1, CNV2, as well as CNVI in 100% of analyzed sides. Pituitary adenomas invaded the CS unilaterally (right side) in four patients, and bilaterally in six patients. In patients with adenomas, the CN could be identified and differentiated from the tumor in the following percentages: CNIII in 100%, CNIV in 70%, both CNV1 and CNV2 in 90%, and CNVI in 100%. In all these cases, the tumor-nerve spatial relationship could be visualized. CONCLUSIONS: 3-Tesla CE-MRA allows detailed imaging of the complex anatomy of the CS and its structures. In adenoma patients, it clearly visualizes the spatial relationship between tumor and CNs, and thus might be helpful to optimize presurgical planning. PMID- 21271243 TI - Autoimmune-mediated encephalitis. AB - Autoimmune-mediated encephalitis may occur as a paraneoplastic or as a non paraneoplastic condition. The role of neuroimaging in autoimmune-mediated encephalitis has changed in the last decade partly due to improvements in sequence optimisation and higher field strength and partly due to the discovery of an increasing number of antibodies to neuronal cell and cell membrane antigens. Imaging is important since it can support the clinical diagnosis particularly in the absence of antibodies. Structural imaging findings can be subtle and are usually best seen on FLAIR images. A progressive as well as a relapsing-remitting course can be observed. Autoimmune-mediated encephalitis is classically linked to involvement of the hippocampus and amygdala, but extensive changes in the temporal cortex, basal ganglia, hypothalamus, brain stem, frontal and parietal cortex are not unusual. This report is based on a review of the literature (except the literature in Japanese) and own findings in patients with autoimmune-mediated encephalitis. PMID- 21271244 TI - Evolutionary changes in growth rate and toxin production in the cyanobacterium Microcystis aeruginosa under a scenario of eutrophication and temperature increase. AB - Toxic blooms of the cyanobacterium Microcystis aeruginosa affect humans and animals in inland water systems worldwide, and it has been hypothesized that the development of these blooms will increase under the future scenario of global change, considering eutrophication and temperature increase as two important consequences. The importance of genetic adaptation, chance and history on evolution of growth rate, and toxin production of M. aeruginosa was studied under these new conditions. The experiment followed the idea of "replaying life's tape" by means of the simultaneous propagation of 15 independent isolates of three M. aeruginosa strains, which were grown under doubled nutrient concentration and temperature during c. 87 generations. Adaptation by new mutations that resulted in the enhancement of growth rate arose during propagation of derived cultures under the new environmental conditions was the main component of evolution; however, chance also contributed in a lesser extension to evolution of growth rate. Mutations were selected, displacing the wild-type ancestral genotypes. In contrast, the effect of selection on mutations affecting microcystin production was neutral. Chance and history were the pacemakers in evolution of toxin production. Although this study might be considered an oversimplification of the reality, it suggest that a future scenario of global change might lead to an increase in M. aeruginosa bloom frequency, but no predictions about the frequency of toxicity can be made. PMID- 21271245 TI - The spatial distribution of fungi on decomposing woody litter in a freshwater stream, Western Ghats, India. AB - We mapped filamentous fungal association with mechanically "hard" and "soft" woody litter naturally deposited in a stream of the Western Ghats of India. Using a durometer (rubber hardness tester), the toughness of surface of wood collected from stream was determined by considering durometer reading from 60-72 to 30-37 as hardwood and softwood, respectively. From each wood (1.5 cm diameter), two segments each of 3 cm length were excised and vertically cut into nine sections comprising eight marginal and one central section. From three stream locations, hardwood and softwood sections were assessed for the occurrence of lignicolous and Ingoldian fungi. A first set of wood sections was incubated in damp chambers up to 4 months with periodical screening (every 2 weeks) for lignicolous fungi. Another set was incubated in bubble chambers up to 72 h to ascertain colonization of Ingoldian fungi. In hardwood sections, 17 lignicolous fungi (ascomycetes, four; mitosporic fungi, 13; mean, 6.8; range, 6-8/section) and ten Ingoldian fungi (mean, 2; range, 0-4/section) comprising nine lignicolous (11.1-40.7%) and three Ingoldian (11.1-14.8%) fungi as core-group taxa were recovered. In softwood, ten lignicolous fungi (ascomycetes, 0; mitosporic fungi, ten; mean, 3.8; range, 2-5/section) and 26 Ingoldian fungi (mean, 8.1; range, 5-10/section) comprising six lignicolous (11.1-85.2%) and 12 Ingoldian (11.1-88.9%) fungi as core-group taxa were recovered. The ratio of lignicolous fungi/Ingoldian fungi was higher in hardwood than softwood (1.7 vs. 0.4). The spore output of Ingoldian fungi was higher in softwood (mean, 901 g(-1); range, 80-2546 g(-1)) than hardwood (mean, 21 g(-1); range, 0-140 g(-1)). The Shannon diversity of lignicolous fungi was higher in hardwood than softwood (3.604 vs. 2.665), whereas it was opposite for Ingoldian fungi (3.116 vs. 3.918). The overall fungal diversity was higher in softwood than hardwood (4.413 vs. 4.219). The range of Jaccard's index of similarity among wood sections was higher in lignicolous fungi (8-71% and 13-75%) than Ingoldian fungi (0-50% and 8-55%) in hardwood and softwood. The rarefaction indices of expected number of taxa against hardwood sections revealed higher and persistent lignicolous fungi than the Ingoldian fungi, while the Ingoldian fungi were persistent in softwood sections, although they were lower than lignicolous fungi. Our study demonstrated the dominance of lignicolous fungi and Ingoldian fungi in hardwood and softwood, respectively. PMID- 21271246 TI - Automatic generation of absolute myocardial blood flow images using [15O]H2O and a clinical PET/CT scanner. AB - PURPOSE: Parametric imaging of absolute myocardial blood flow (MBF) using [(15)O]H(2)O enables determination of MBF with high spatial resolution. The aim of this study was to develop a method for generating reproducible, high-quality and quantitative parametric MBF images with minimal user intervention. METHODS: Nineteen patients referred for evaluation of MBF underwent rest and adenosine stress [(15)O]H(2)O positron emission tomography (PET) scans. Ascending aorta and right ventricular (RV) cavity volumes of interest (VOIs) were used as input functions. Implementation of a basis function method (BFM) of the single-tissue model with an additional correction for RV spillover was used to generate parametric images. The average segmental MBF derived from parametric images was compared with MBF obtained using nonlinear least-squares regression (NLR) of VOI data. Four segmentation algorithms were evaluated for automatic extraction of input functions. Segmental MBF obtained using these input functions was compared with MBF obtained using manually defined input functions. RESULTS: The average parametric MBF showed a high agreement with NLR-derived MBF [intraclass correlation coefficient (ICC) = 0.984]. For each segmentation algorithm there was at least one implementation that yielded high agreement (ICC > 0.9) with manually obtained input functions, although MBF calculated using each algorithm was at least 10% higher. Cluster analysis with six clusters yielded the highest agreement (ICC = 0.977), together with good segmentation reproducibility (coefficient of variation of MBF <5%). CONCLUSION: Parametric MBF images of diagnostic quality can be generated automatically using cluster analysis and a implementation of a BFM of the single-tissue model with additional RV spillover correction. PMID- 21271247 TI - Ethanol embolization of hemophilic pseudotumor of the mandible. PMID- 21271248 TI - Uterine artery embolization combined with local methotrexate and systemic methotrexate for treatment of cesarean scar pregnancy with different ultrasonographic pattern. AB - PURPOSE: This study was designed to compare the effectiveness of systemic methotrexate (MTX) with uterine artery embolization (UAE) combined with local MTX for the treatment of cesarean scar pregnancy (CSP) with different ultrasonographic pattern, and to indicate the preferable therapy in CSP patients. METHODS: The results of 21 CSP cases were reviewed. All subjects were initially administrated with systemic MTX (50 mg/m(2) body surface area). UAE combined with local MTX was added to the patients who had failed systemic MTX. The transvaginal ultrasonography data were retrospectively assessed, and two different ultrasonographic patterns were found: surface implantation and deep implantation of amniotic sac. The management and its effectiveness for patients with the two ultrasonographic patterns were studied retrospectively. Ultrasound scan and serum beta-hCG were monitored during follow-up. Data were analyzed with the Student's t test. RESULTS: Nine patients were successfully treated with systemic MTX. The remaining 12 cases were successfully treated with additional UAE combined with local MTX. According to the classification by Vial et al. of CSP on ultrasonography, most surface implanted CSPs (8/11, 72.7%) could be successfully treated with systemic MTX, whereas most deeply implanted CSPs (9/10, 90%) had failed systemic MTX but still could be successfully treated with additional UAE combined with local MTX. All patients recovered without severe side effects. Most patients with a future desire for reproduction achieved subsequent pregnancy. CONCLUSIONS: For CSP patients suitable for nonsurgical treatment, UAE combined with local MTX would be the superior option compared with systemic MTX in the cases with deep implantation of amniotic sac. PMID- 21271249 TI - The burden of hard atherosclerotic plaques does not promote endoleak development after endovascular aortic aneurysm repair: a risk stratification. AB - PURPOSE: To objectify the influence of the atherosclerotic burden in the proximal landing zone on the development of endoleaks after endovascular abdominal aortic aneurysm repair (EVAR) or thoracic endovascular aneurysm repair (TEVAR) using objective aortic calcium scoring (ACS). MATERIALS AND METHODS: This retrospective observation study included 267 patients who received an aortic endograft between 1997 and 2010 and for whom preoperative computed tomography (CT) was available to perform ACS using the CT-based V600 method. The mean follow-up period was 2 +/- 2.3 years. RESULTS: Type I endoleaks persisted in 45 patients (16.9%), type II in 34 (12.7%), type III in 8 (3%), and type IV or V in 3 patients, respectively (1.1% each). ACS in patients with type I endoleaks was not increased: 0.029 +/- 0.061 ml compared with 0.075 +/- 0.1349 ml in the rest of the patients, (p > 0.05; Whitney-Mann U-Test). There were significantly better results for the indication "traumatic aortic rupture" than for the other indications (p < 0.05). In multivariate logistic regression analyses, age was an independent risk factor for the development of type I endoleaks in the thoracic aorta (Wald 9.5; p = 0.002), whereas ACS score was an independent protective factor (Wald 6.9; p = 0.009). In the abdominal aorta, neither age nor ACS influenced the development of endoleaks. CONCLUSION: Contrary to previous assumptions, TEVAR and EVAR can be carried out without increasing the risk of an endoleak of any type, even if there is a high atherosclerotic "hard-plaque" burden of the aorta. The results are significantly better for traumatic aortic. PMID- 21271251 TI - Biocompatibility of implants: lymphocyte/macrophage interactions. AB - The monocyte-derived macrophage is recognized as a critical determinant in biocompatibility, but its appearance in the chronic inflammatory phase is accompanied by the presence of lymphocytes, which have been much less studied in this regard. Here, we first present an overview of the physiologic continuum comprising host reactions to the surgical implantation of biomaterial. Secondly, we describe our collective research efforts, which indicate that lymphocytes are additional and key cellular determinants of biocompatible outcome. Thus, bioengineering advances will require that lymphocyte responses be regarded as integral components of innate inflammatory and immune/immunotoxic cell interactions at sites of biomaterial implantation. PMID- 21271252 TI - Diagnostic benefits of presurgical fMRI in patients with brain tumours in the primary sensorimotor cortex. AB - OBJECTIVES: Reliable imaging of eloquent tumour-adjacent brain areas is necessary for planning function-preserving neurosurgery. This study evaluates the potential diagnostic benefits of presurgical functional magnetic resonance imaging (fMRI) in comparison to a detailed analysis of morphological MRI data. METHODS: Standardised preoperative functional and structural neuroimaging was performed on 77 patients with rolandic mass lesions at 1.5 Tesla. The central region of both hemispheres was allocated using six morphological and three functional landmarks. RESULTS: fMRI enabled localisation of the motor hand area in 76/77 patients, which was significantly superior to analysis of structural MRI (confident localisation of motor hand area in 66/77 patients; p < 0.002). FMRI provided additional diagnostic information in 96% (tongue representation) and 97% (foot representation) of patients. FMRI-based presurgical risk assessment correlated in 88% with a positive postoperative clinical outcome. CONCLUSION: Routine presurgical FMRI allows for superior assessment of the spatial relationship between brain tumour and motor cortex compared with a very detailed analysis of structural 3D MRI, thus significantly facilitating the preoperative risk-benefit assessment and function-preserving surgery. The additional imaging time seems justified. FMRI has the potential to reduce postoperative morbidity and therefore hospitalisation time. PMID- 21271250 TI - Lung transplantation: infection, inflammation, and the microbiome. AB - Lung transplantation is the only therapeutic option for patients with end-stage pulmonary disorders. Despite the improvements in surgical techniques and immunosuppressive therapy, allograft function and long-term survival are limited by the development of chronic lung transplant rejection. In this review, we focus on bronchiolitis obliterans syndrome (BOS) which is the major manifestation of chronic lung allograft rejection. We specifically review the effect of infection, a risk factor for BOS, cytokines/chemokines in the pathogenesis of BOS, and the potential link between the allograft microbiome and immune responses that may mediate the development of BOS. Understanding the allograft microbiome and how it relates to the pathologic mechanisms of BOS may suggest targeted therapies to improve long-term survival post-lung transplantation. PMID- 21271253 TI - [Acute loss of vision during therapy of chronic hepatitis C]. AB - A patient undergoing combined therapy of chronic hepatitis C with pegylated interferon-alpha-2a (PEG-IFN-alpha-2a) and ribavirin suddenly developed severe loss of visual acuity. A central vein occlusion with macular edema was found and intravitreal injections of bevacizumab were initiated. Retinal occlusion is a known complication of therapy with pegylated interferon-alpha-2a and ribavirin. An interdisciplinary assessment of patients treated for a chronic hepatitis C as well as an early anti-VEGF administration can be helpful in the therapy of this complication of chronic hepatitis C. PMID- 21271254 TI - [Worsening of vision with apparent changes of the posterior pole]. AB - The choroidal osteoma is a typically unilateral, benign ossifying tumor of the choroid. It is mostly located in the juxtapapillary area and usually found in females in the second or third decade of life. Most patients are asymptomatic. However, some can present with blurred vision, metamorphopsia, and visual field defects. Ultrasonography can show a calcified choroidal plaque with a typical shadowing posterior to the lesion. Fluorescein angiography and optical coherence tomography should be used if choroidal neovascularization is suspected as a possible complication of the choroidal osteoma. PMID- 21271255 TI - [Psychometric properties of the FKS : Reliability, validity, Rasch analysis, and descriptive results of the German version of the Children's Visual Function Questionnaire]. AB - BACKGROUND: Vision-related quality of life is an important endpoint for evaluation studies and quality assurance projects. The objective of this study is to conduct a psychometric test of the German version of the "Children's Visual Function Questionnaire" (FKS) in the version for children over age 3. METHODS: In a sample of n=236 children with various eye diseases distribution properties, internal consistency, unidimensionality, validity, and the fit of the FKS data to the Rasch model are tested. In addition, reference values are given for users. RESULTS: The FKS has satisfactory internal consistency and is valid in the sense that expected significant correlations occur with visual acuity. The weakness of the FKS, which provides impulses for further development, is primarily related to the scales for competence and personality in the following three areas: (1) high percentage of inapplicable questions, (2) ceiling effects, and (3) lack of unidimensionality. CONCLUSIONS: Overall, the FKS satisfactorily complies with psychometric standards. Therefore, it can be applied to assess children's vision related quality of life. PMID- 21271256 TI - [Antiangiogenic therapy at the ocular surface: when, what and why?]. AB - There are numerous indications for local antiangiogenic therapy at the ocular surface. These include vision-limiting corneal neovascularization, corneal blood and lymphatic vessels endangering corneal graft survival and tumor-associated lymphangiogenesis. A literature review in PubMed and own clinical and experimental data form the basis for a discussion of the indications, current therapeutic options and potential side-effects of local antiangiogenic therapy at the ocular surface. PMID- 21271258 TI - Family of CNP neuropeptides: common morphology in various invertebrates. AB - Neuropeptides expressed in the command neurons for withdrawal behavior were originally detected in the the central nervous system (CNS) of the terrestrial snail Helix (command neurons peptides, CNP). The family of CNP-like neuropeptides bears a C-terminal signature sequence Tyr-Pro-Arg-X. Using antisera against two of them, we have studied the CNS of various invertebrates belonging to the phyla of mollusks, annelids and insects. The immunoreactive neurons were detected in all studied species. Stained neurons were either interneurons projecting along the CNS ganglia chain, or sensory neurons, or neurohormonal cells. Beyond common morphological features, the immunoreactive cells had another similarity: the level of CNP expression depended on the functional state of the animal. Thus, the homologous neuropeptides in evolutionary distant invertebrate species possess some common morphological and functional features. PMID- 21271257 TI - Development and characterization of a mouse floxed Bmp2 osteoblast cell line that retains osteoblast genotype and phenotype. AB - Bone morphogenetic protein 2 (Bmp2) is essential for osteoblast differentiation and osteogenesis. Generation of floxed Bmp2 osteoblast cell lines is a valuable tool for studying the effects of Bmp2 on osteoblast differentiation and its signaling pathways during skeletal metabolism. Due to relatively limited sources of primary osteoblasts, we have developed cell lines that serve as good surrogate models for the study of osteoblast cell differentiation and bone mineralization. In this study, we established and characterized immortalized mouse floxed Bmp2 osteoblast cell lines. Primary mouse floxed Bmp2 osteoblasts were transfected with pSV3-neo and clonally selected. These transfected cells were verified by PCR and immunohistochemistry. To determine the genotype and phenotype of the immortalized cells, cell morphology, proliferation, differentiation and mineralization were analyzed. Also, expression of osteoblast-related gene markers including Runx2, Osx, ATF4, Dlx3, bone sialoprotein, dentin matrix protein 1, osteonectin, osteocalcin and osteopontin were examined by quantitative RT-PCR and immunohistochemistry. These results showed that immortalized floxed Bmp2 osteoblasts had a higher proliferation rate but preserved their genotypic and phenotypic characteristics similar to the primary cells. Thus, we, for the first time, describe the development of immortalized mouse floxed Bmp2 osteoblast cell lines and present a useful model to study osteoblast biology mediated by BMP2 and its downstream signaling transduction pathways. PMID- 21271259 TI - Novel expression of claudin-5 in glomerular podocytes. AB - Tight junctions are the main intercellular junctions of podocytes of the renal glomerulus under nephrotic conditions. Their requisite components, claudins, still remain to be identified. We have measured the mRNA levels of claudin subtypes by quantitative real-time PCR using isolated rat glomeruli. Claudin-5 was found to be expressed most abundantly in glomeruli. Mass spectrometric analysis of membrane preparation from isolated glomeruli also confirmed only claudin-5 expression without any detection of other claudin subtypes. In situ hybridization and immunolocalization studies revealed that claudin-5 was localized mainly in glomeruli where podocytes were the only cells expressing claudin-5. Claudin-5 protein was observed on the entire surface of podocytes including apical and basal domains of the plasma membrane in the normal condition and was inclined to be concentrated on tight junctions in puromycin aminonucleoside nephrosis. Total protein levels of claudin-5 in isolated glomeruli were not significantly upregulated in the nephrosis. These findings suggest that claudin-5 is a main claudin expressed in podocytes and that the formation of tight junctions in the nephrosis may be due to local recruitment of claudin-5 rather than due to total upregulation of the claudin protein levels. PMID- 21271260 TI - A 10-year-old boy with dark urine and acute kidney injury. PMID- 21271262 TI - Francis Murphey's theory on lumbar disc disease: upon reflection. PMID- 21271263 TI - Anatomic relations of the arachnoidea around the pituitary stalk: relevance for surgical removal of craniopharyngiomas. AB - PURPOSE: The growth pattern of craniopharyngiomas (CP) is yet to be understood due to challenges arising from the diversity of morphological features that exist. This in turn has had implications on the development of safe surgical strategies for management of these lesions. The aim of this study is to propose a morphological classification of CP based on their tumor-membrane relationship. It is hoped that this will contribute to better understanding of CP morphology and prediction of the intraoperative classification. METHODS: Histological techniques were used to study eight fetuses. Following Masson staining, the membranes around the pituitary stalk were observed under microscope. Pre-operative MRI and intraoperative images of 195 patients with CP were also analyzed. FINDINGS: The arachnoidal sleeve around the pituitary stalk (ASPS) was noted to be comprised of a compact fibrous component and a related loose trabecular component. The pituitary stalk was divided into four segments in accordance with the folds of the ASPS. Correspondingly, the growth of CPs was divided into four basic patterns infra-diaphragmatic (ID), extra-arachnoidal (EA), intra-arachnoidal (IA) and sub arachnoidal (SA) growth. The IA growth pattern can be further subdivided into two subtypes-namely, IA1 (with tumor growing within the fibrous component of the ASPS) and IA2 (with tumor growing within the trabecular component). This method of topographical division can be used to understand the growth of CP-infra diaphragmatic CP show growth pattern ID or ID together with EA. Suprasellar CP can show an extra-ventricular growth pattern (EA or IA2), an extra- and intra ventricular (IA2 + SA) growth pattern, a trans-infundibular growth pattern (ID + IA1 + SA) and an infundibulo-tuberal growth pattern (SA or SA + IA1). There is a statistically significant difference between CP growth patterns in children and adults. A predominance of ID growth is noted in children while adults tend to show a pattern of predominantly Extra-ventricular (EV) growth. CONCLUSION: Our proposed classification details the relationship of the surrounding structures to CPs and purports to predict and identify the intraoperative anatomical stratification. It also attempts to help predict the growth patterns of these tumors. A knowledge of the intimate relations of the tumor and its key surrounding structures allows for safe surgical removal. PMID- 21271264 TI - The surgery of craniopharyngiomas. PMID- 21271265 TI - Intraventricular craniopharyngioma: morphological analysis and outcome evaluation of 17 cases. AB - PURPOSE: There is still some confusion with regard to the tumor-third ventricle floor (3rd VF) relationship of craniopharyngiomas located exclusively within the third ventricle. This study aims to provide some evidence to clarify the growth pattern of intraventricular craniopharyngiomas (IVC), and to summarize the surgical strategy and outcome. METHODS: Seventeen cases of IVC were reviewed retrospectively in relation to preoperative imaging, clinical presentation, intraoperative findings, tumor pathology, and surgical outcome. The tumor-3rd VF relationship and the tumor's stratification were analyzed based on intraoperative inspection and histology. FINDINGS: Variable adherence patterns of IVC to the 3rd VF were found, which were classified as (a) purely IVC with pedicle attachment to 3rd VF (two cases), (b) intra-3rd VF tumors with wide-based attachment but a dissectible tumor boundary (seven cases), and (c) intra-3rd VF tumors with an undissectible wide, tight attachment (eight cases). Histological analysis revealed that both of the two cases with growth pattern "a" intruded into the third ventricular cavity without a covering layer of neural tissue (which only exists in the squamous-papillary subtype). Tumors with growth pattern "b" and "c," in contrast, were noted to have a thin layer of neural tissue. This occurred in both subtypes (11 adamantinomatous, 4 papillary). Total removal was accomplished in all tumors demonstrating growth pattern "a" and "b." There was also better preservation of the 3rd VF and consequently a better outcome. On the other hand, total removal was only achieved in 50% of tumors showing growth pattern "c" including one mortality. No recurrence has been encountered in patients whose tumors were totally removed. CONCLUSION: Variable adherence patterns and tumor subtypes were observed in IVCs, which were correlated to the tumor pathology, resectability, and subsequent prognosis. PMID- 21271266 TI - The Premenstrual Symptoms Screening Tool revised for adolescents (PSST-A): prevalence of severe PMS and premenstrual dysphoric disorder in adolescents. AB - The Premenstrual Symptoms Screening Tool was modified for use in adolescents and piloted in 578 girls at three international sites. Nearly one third (29.6%) reported experiencing severe PMS or PMDD, with irritability being the most commonly reported symptom. Rates of menstrual-related pain were high, particularly in those with severe PMS or PMDD. Severe PMS and PMDD present with similar rates and symptoms in adolescents as in adults, and the Premenstrual Symptoms Screening Tool modified for adolescents is a fast, reliable tool to screen for these syndromes in adolescents. PMID- 21271267 TI - Association between ER-alpha polymorphisms and bone mineral density in patients with Turner syndrome subjected to estroprogestagen treatment--a pilot study. AB - Reduced bone mineral density (BMD) is present in many women with Turner syndrome (TS), and hypo-estrogenism is known to play a vital role in bone mineralization disturbances. It has been suggested that genetic factors play an important role in the regulation of BMD. The aim of this study was to analyze the association between Pvu II and XbaI ER-alpha polymorphisms and BMD in TS patients subjected to estroprogestagen (EP) treatment. Thirty-two TS patients aged 17-38 (mean age 22.7 +/- 8.2) along with 82 healthy controls were the subjects for this study. Baseline values of hormonal parameters, BMD and bone density markers were measured in the subjects. Subsequently, TS patients underwent 4 years of EP therapy. The results of laboratory parameters and BMD were analyzed in regard to PvuII and XbaI polymorphic variants of the ER-alpha gene. The increase in BMD of TS subjects was the highest in the 1st (7.5%, p = 0.013) and 2nd (6.6%, p = 0.008) years of treatment. Four years of EP therapy was reflected by a significant increase in BMD z-scores in patients with xx and Xx genotypes of the XbaI gene and in those with with the pp and Pp genotypes of PvuII. In patients with haplotypes other than XXPP, BMD z-scores were significantly higher compared to their baseline after 2 (p = 0.002), 3 (p < 0.001) and 4 (p < 0.001) years of treatment. In conclusion, genotypes xx and pp were shown to be prognostic markers of a good response to EP treatment, whereas the XXPP haplotype carriers were revealed to have the risk factors for insufficient responsiveness against EP treatment in BMD control. PMID- 21271268 TI - Evaluation of the VITEK 2 AST-N111 card for detection of extended-spectrum beta lactamases (ESBLs) in Escherichia coli, Klebsiella pneumoniae, and Klebsiella oxytoca compared to ESBL Etests and combination disk methods. AB - The VITEK 2 AST-N111 card was evaluated for detection of extended-spectrum beta lactamases (ESBLs) by testing 51 ESBL positive and 50 ESBL negative isolates of E. coli, K. pneumoniae, and K. oxytoca. The occurrence of beta-lactamase genes was confirmed by PCR and sequencing. The advanced expert system (AES) of the VITEK 2 system achieved sensitivity and specificity values of 100% and 96.0%, respectively. The ESBL test of the VITEK 2 AST-N111 card showed a sensitivity of 92.1% and a specificity of 90.0%. Contradictory results obtained with the two VITEK 2 tools could be clarified by combination disk tests in nine of 11 isolates. The combined use of AES and ESBL tests of the AST-N111 card in association with combination disk tests in case of contradictory results seems to be a reliable method for ESBL detection. PMID- 21271269 TI - Adapting spa typing for national laboratory-based surveillance of methicillin resistant Staphylococcus aureus. AB - Laboratory-based surveillance of methicillin-resistant Staphylococcus aureus (MRSA) monitors the baseline occurrence of different genotypes and identifies strains and transmission chains responsible for outbreaks. The consequences of substituting pulsed-field gel electrophoresis (PFGE) with spa typing as a first line typing method were analyzed by typing 589 strains isolated between 1997 and 2006, with a focus on both short- and long-term correspondence between the PFGE and spa typing results. The study, covering these ten years, included all Finnish MRSA blood isolates and representatives of the two most prevalent MRSA strains (PFGE types FIN-4 and FIN-16) in Finland. In addition, all sporadic isolates from 2006 were included. spa typing was more expensive but approximately four times faster to perform than PFGE. Nearly 90% of FIN-4 and FIN-16 isolates showed consistent spa types, t172 and t067, respectively. spa typing predicted the PFGE result of the blood isolates by a Wallace coefficient of 0.9009, recognized internationally successful strains (t041, t067) to be common also in Finland, and identified a separate cluster of isolates, also related in time and place among the FIN-4 strains. Additional typing by another method was needed to provide adequate discrimination or to characterize isolates with a newly recognized spa type in Finland. PMID- 21271270 TI - Large differences between test strategies for the detection of anti-Borrelia antibodies are revealed by comparing eight ELISAs and five immunoblots. AB - We investigated the influence of assay choice on the results in a two-tier testing algorithm for the detection of anti-Borrelia antibodies. Eighty-nine serum samples from clinically well-defined patients were tested in eight different enzyme-linked immunosorbent assay (ELISA) systems based on whole-cell antigens, whole-cell antigens supplemented with VlsE and assays using exclusively recombinant proteins. A subset of samples was tested in five immunoblots: one whole-cell blot, one whole-cell blot supplemented with VlsE and three recombinant blots. The number of IgM- and/or IgG-positive ELISA results in the group of patients suspected of Borrelia infection ranged from 34 to 59%. The percentage of positives in cross-reactivity controls ranged from 0 to 38%. Comparison of immunoblots yielded large differences in inter-test agreement and showed, at best, a moderate agreement between tests. Remarkably, some immunoblots gave positive results in samples that had been tested negative by all eight ELISAs. The percentage of positive blots following a positive ELISA result depended heavily on the choice of ELISA-immunoblot combination. We conclude that the assays used to detect anti-Borrelia antibodies have widely divergent sensitivity and specificity. The choice of ELISA-immunoblot combination severely influences the number of positive results, making the exchange of test results between laboratories with different methodologies hazardous. PMID- 21271271 TI - Characterization of a non-fibrillar-related collagen in the mollusc Haliotis tuberculata and its biological activity on human dermal fibroblasts. AB - In invertebrates, members of the collagen family have been found in various phyla. Surprisingly, in mollusc, little is known about such molecules. In this study, we characterize the full-length abalone type IV collagen and we analysed its biological effects on human fibroblast in order to gain insights about this molecule in molluscs and particularly clues about its roles. We screened a cDNA library of Haliotis tuberculata hemocytes. The expression pattern of the transcript is determined using real-time polymerase chain reaction and in situ hybridization. The close identity between alpha1(IV) C-terminal domain and the vertebrate homologue led us to produce, purify and test in vitro a recombinant protein corresponding to this region using human dermal fibroblasts cell culture. The biological effects were evaluated on proliferation and on differentiation. We found that the 5,334-bp open reading frame transcript encodes a protein of 1,777 amino acids, including an interrupted 1,502-residue collagenous domain and a 232 residue C-terminal non-collagenous domain. The expression pattern of this transcript is mainly found in the mantle and hemocytes. The recombinant protein corresponding alpha1(IV) C-terminal domain increased fibroblast proliferation by 69% and doubled collagen synthesis produced in primary cultures. This work provides the first complete primary structure of a mollusc non-fibrillar collagen chain and the biological effects of its C-terminal domain on human cells. In this study, we prove that the NC1 domain from a molluscan collagen can improve human fibroblast proliferation as well as differentiation. PMID- 21271272 TI - A functional study of transforming growth factor-beta from the gonad of Pacific oyster Crassostrea gigas. AB - The transforming growth factor (TGF)-beta superfamily is a group of important growth factors involved in multiple processes such as differentiation, cell proliferation, apoptosis and cellular growth. In the Pacific oyster Crassostrea gigas, the oyster gonadal (og) TGF-beta gene was recently characterized through genome-wide expression profiling of oyster lines selected to be resistant or susceptible to summer mortality. Og TGF-beta appeared specifically expressed in the gonad to reach a maximum when gonads are fully mature, which singularly contrasts with the pleiotropic roles commonly ascribed to most TGF-beta family members. The function of og TGF-beta protein in oysters is unknown, and defining its role remains challenging. In this study, we develop a rapid bacterial production system to obtain recombinant og TGF-beta protein, and we demonstrate that og TGF-beta is processed by furin to a mature form of the protein. This mature form can be detected in vivo in the gonad. Functional inhibition of mature og TGF-beta in the gonad was conducted by inactivation of the protein using injection of antibodies. We show that inhibition of og TGF-beta function tends to reduce gonadic area. We conclude that mature og TGF-beta probably functions as an activator of germ cells development in oyster. PMID- 21271273 TI - A case of atypical hemolytic uremic syndrome due to anti-factor H antibody in a patient presenting with a factor XII deficiency identified two novel mutations. AB - A 9-year-old boy with pallor and macrohematuria showed hemolytic anemia, thrombocytopenia and renal failure. There was no history of diarrhea and the stool culture was negative. A diagnosis of atypical hemolytic uremic syndrome (HUS) was confirmed; however, the cause of the prolonged activated partial thromboplastin time (APTT) was unknown. Plasma exchange and hemodialysis were performed because of progressive hemolytic anemia and renal dysfunction. Fresh frozen plasma was administered frequently to correct the prolonged APTT after hemolysis was controlled and C3 levels had recovered. Factor H (FH) and factor I (IF) levels were normal and we did not detect mutations of FH, IF and membrane cofactor protein. Further investigation revealed the presence of anti-FH antibody in the patient's plasma and a deficiency of coagulation factor XII. Analysis of the patient's coagulation system displayed <3% functional activity of factor XII, whereas levels of other coagulation factors were within the normal range. Two novel mutations (W222G and R447S) were identified upon analysis of the factor XII gene in this patient. Moreover, further investigation revealed that compound heterozygous mutations were present in two of the patient's three siblings, while the third sibling only had a mutation at W222G. The patient was treated for atypical HUS; however, no treatment was required for factor XII deficiency as he did not display a hemorrhagic tendency. We report here a rare case of atypical HUS due to anti-FH antibody presenting with a coagulation factor XII deficiency. PMID- 21271274 TI - Relationship between behavioral and physiological spectral-ripple discrimination. AB - Previous studies have found a significant correlation between spectral-ripple discrimination and speech and music perception in cochlear implant (CI) users. This relationship could be of use to clinicians and scientists who are interested in using spectral-ripple stimuli in the assessment and habilitation of CI users. However, previous psychoacoustic tasks used to assess spectral discrimination are not suitable for all populations, and it would be beneficial to develop methods that could be used to test all age ranges, including pediatric implant users. Additionally, it is important to understand how ripple stimuli are processed in the central auditory system and how their neural representation contributes to behavioral performance. For this reason, we developed a single-interval, yes/no paradigm that could potentially be used both behaviorally and electrophysiologically to estimate spectral-ripple threshold. In experiment 1, behavioral thresholds obtained using the single-interval method were compared to thresholds obtained using a previously established three-alternative forced choice method. A significant correlation was found (r = 0.84, p = 0.0002) in 14 adult CI users. The spectral-ripple threshold obtained using the new method also correlated with speech perception in quiet and noise. In experiment 2, the effect of the number of vocoder-processing channels on the behavioral and physiological threshold in normal-hearing listeners was determined. Behavioral thresholds, using the new single-interval method, as well as cortical P1-N1-P2 responses changed as a function of the number of channels. Better behavioral and physiological performance (i.e., better discrimination ability at higher ripple densities) was observed as more channels added. In experiment 3, the relationship between behavioral and physiological data was examined. Amplitudes of the P1-N1 P2 "change" responses were significantly correlated with d' values from the single-interval behavioral procedure. Results suggest that the single-interval procedure with spectral-ripple phase inversion in ongoing stimuli is a valid approach for measuring behavioral or physiological spectral resolution. PMID- 21271275 TI - Integrated analysis of the conformation of a protein-linked spin label by crystallography, EPR and NMR spectroscopy. AB - Long-range structural information derived from paramagnetic relaxation enhancement observed in the presence of a paramagnetic nitroxide radical is highly useful for structural characterization of globular, modular and intrinsically disordered proteins, as well as protein-protein and protein-DNA complexes. Here we characterized the conformation of a spin-label attached to the homodimeric protein CylR2 using a combination of X-ray crystallography, electron paramagnetic resonance (EPR) and NMR spectroscopy. Close agreement was found between the conformation of the spin label observed in the crystal structure with interspin distances measured by EPR and signal broadening in NMR spectra, suggesting that the conformation seen in the crystal structure is also preferred in solution. In contrast, conformations of the spin label observed in crystal structures of T4 lysozyme are not in agreement with the paramagnetic relaxation enhancement observed for spin-labeled CylR2 in solution. Our data demonstrate that accurate positioning of the paramagnetic center is essential for high resolution structure determination. PMID- 21271277 TI - Why feed on fungi? The nutritional content of sporocarps consumed by buffy-headed marmosets, Callithrix flaviceps (Primates: Callitrichidae), in southeastern Brazil. AB - The typical diet of Callithrix marmosets is based on gums, although fungi are the dietary staple of a single group of Callithrix flaviceps studied in the Augusto Ruschi Biological Reserve, in southeastern Brazil. Here, we present the nutritional composition of two species of Mycocitrus fungi consumed by C. flaviceps, and discuss possible determinants of the preference of the marmosets for fungi over gums. The fungi were high in sugar/fiber and poor in proteins, and were similar in composition to the gums exploited by other marmosets and to the fungi consumed by Callimico goeldii. The reduced protein content of the fungi may be offset by the arthropod component of the diet of the Callithrix flaviceps study group. The low relative metabolic rate and enlarged cecum of Callithrix enable these marmosets to exploit foods with a high fiber content. In addition, the greater digestibility of chitin in comparison with plant fiber may make fungi a nutritionally more valuable resource to marmosets than gums. Marmosets, thus, may prefer to feed on fungi when an adequate supply of this resource is available in the environment. PMID- 21271278 TI - Task group differences in cuticular lipids in the honey bee Apis mellifera. AB - Social insects are defined by their ability to divide labor among their numerous nestmates. This is achieved via a complex system of chemical communication that allows colonies to organize task activity so as to maximize the productivity of the colony. However, the mechanism by which social insects distinguish task groups among morphologically identical individuals remains unknown. Using the honey bee, Apis mellifera, as our model species, we investigated the presence of task-specific patterns in the cuticular lipids (n-alkanes, fatty acids, and alkenes) of bees. Cuticular lipids are known to play an essential role in the recognition processes of insects. We found task-specific features in the n-alkane and alkene profiles of bees, but no task-specific patterns in the fatty acid profile. Foragers, in particular, had elevated levels of n-alkanes relative to nurse and newly emerged bees, suggesting increased waterproofing. Newly emerged bees had low levels of cuticular lipids, supporting the Blank Slate theory and potentially explaining their acceptance into foreign colonies. PMID- 21271280 TI - Mitochondrial energy metabolism in neurodegeneration associated with methylmalonic acidemia. AB - Methylmalonic acidemia is one of the most prevalent inherited metabolic disorders involving neurological deficits. In vitro experiments, animal model studies and tissue analyses from human patients suggest extensive impairment of mitochondrial energy metabolism in this disease. This review summarizes changes in mitochondrial energy metabolism occurring in methylmalonic acidemia, focusing mainly on the effects of accumulated methylmalonic acid, and gives an overview of the results found in different experimental models. Overall, experiments to date suggest that mitochondrial impairment in this disease occurs through a combination of the inhibition of specific enzymes and transporters, limitation in the availability of substrates for mitochondrial metabolic pathways and oxidative damage. PMID- 21271279 TI - Classical and alternative components of the mitochondrial respiratory chain in pathogenic fungi as potential therapeutic targets. AB - The frequency of opportunistic fungal infection has increased drastically, mainly in patients who are immunocompromised due to organ transplant, leukemia or HIV infection. In spite of this, only a few classes of drugs with a limited array of targets, are available for antifungal therapy. Therefore, more specific and less toxic drugs with new molecular targets is desirable for the treatment of fungal infections. In this context, searching for differences between mitochondrial mammalian hosts and fungi in the classical and alternative components of the mitochondrial respiratory chain may provide new potential therapeutic targets for this purpose. PMID- 21271281 TI - Hypothalamic inflammation and thermogenesis: the brown adipose tissue connection. AB - Hypothalamic inflammation and dysfunction are common features of experimental obesity. An imbalance between caloric intake and energy expenditure is generated as a consequence of this inflammation, leading to the progressive increase of body adiposity. Thermogenesis, is one of the main functions affected by obesity linked hypothalamic dysfunction and the complete characterization of the mechanisms involved in this process may offer new therapeutic perspectives for obesity. The brown adipose tissue is an important target for hypothalamic action in thermogenesis. This tissue has been thoroughly studied in rodents and hibernating mammals; however, until recently, its advocated role in human thermogenesis was neglected due to the lack of substantial evidence of its presence in adult humans. The recent demonstration of the presence of functional brown adipose tissue in adult humans has renovated the interest in this tissue. Here, we review some of the work that shows how inflammation and dysfunction of the hypothalamus can control brown adipose tissue activity and how this can impact on whole body thermogenesis and energy expenditure. PMID- 21271282 TI - Temporal and spectral analysis of ventricular fibrillation in humans. AB - PURPOSES: Analysing ventricular fibrillation (VF) rate and regularity at different sites and at different times may help understanding some of the mechanisms underlying VF in humans. METHODS: Twelve episodes of VF (19.4 +/- 5.6 s) were induced during electrophysiological study in eight men (63 +/- 14 years old). Calculation of dominant frequency (DF) by fast Fourier transform, short time Fourier transform, and analysis of the pitch frequency [VF cycle length duration (CL)] were performed. For each episode, we analysed the 12 lead-surface ECG, three unipolar, 10 near-field, and three far-field bipolar recordings by means of three quadripolar catheters positioned at the right ventricular apex (RV apex), right ventricular outflow tract, and at the coronary sinus (exploring the lateral left ventricular epicardium) (LV). RESULTS: Fast and regular discrete activation covered the whole duration of every intracardiac recording, whereas surface ECG consistently displayed chaotic and fibrillatory pattern. DF (5.25 +/- 0.64 Hz) was very similar on surface ECG recordings and in various intracardiac recordings. Intracardiac activation was rather regular during VF despite the fibrillatory process with very low SD of the CL. There were some significant inverse correlations between VF rate and VF regularity. Intracardiac sites displaying the fastest and most regular activations were those including the RV apex. VF rate and stability slightly increased over time. Finally, the parameters exploring the VF rate were found to be well correlated together, as well as parameters of VF regularity CONCLUSIONS: Human VF induced during electrophysiological study has a clear DF of activation and appears quite regular in intracardiac recordings. There is some spatial heterogeneity, which needs to be more detailed in order to localize possible driving sources. Fastest VF are the most regular. Rate and stability tend to increase during the initial phases of VF. PMID- 21271283 TI - Relationship of strength of social support and frequency of social contact with hypertension and general health status among older adults in the mobile care unit in Kuwait. AB - The major aim of this research is to examine the relationship between social support and hypertension and general health among older adults who live with their families and receiving care from the governmental institution in Kuwait related to the Ministry of Social Affairs, which is a home care unit. A total of 1,427 participants was selected. Some physical, sociocultural and demographic information was requested. Social support, frequency of contact, strength of relations, and self-rating health scales were used. The Somatic Symptoms Inventory was also used. The SPSS package was used to analyze the data. The findings indiated a direct relationship between social support and general health status among older adults in Kuwaiti society. Social support and social networking has a greater effect on the life of the elderly than on other age categories in the human population, given the decline in the general health of older adults due to psychological functions. PMID- 21271284 TI - Decline in co-residence of parents and children among older Kuwaiti men and women: what are the significant correlates? AB - A trend towards decline in co-residence with children is apparent in several countries while it is absent in others. The objectives of this paper are to address the patterns of co-residence with children among older Kuwaiti men and women aged 60+ and to assess the determinants of such patterns within the context of rapid socioeconomic changes occurring in the country (n = 1588). The data for this paper were collected as part of a household survey on the psychosocial health and disability among 2487 older Kuwaitis aged 50+. Forward step-wise logistic regression was run to assess the significant socio-demographic and health related correlates of living without any co-resident children. We found that the percentage living without any co-resident children increased from 5% in 1999 to 24% in 2005/6. About 13% women and 1% men were living alone in 2005/6. In the multivariate analysis, older age, female gender, non-Bedouin cultural background, a smaller number of children, higher educational level, and the presence of one or more domestic helpers were positively associated with the absence of co-resident children. On the other hand, those who were not married were less likely to reside without co-resident children, as were those with higher family incomes. Except for self-rated health none of the health related variables, such as chronic illnesses or depressive symptom experience, emerged as significant. Modernization forces seem to be at the core of the observed decline in co-residence with children. PMID- 21271285 TI - The structure of psychopathology in a community sample of preschoolers. AB - Despite growing interest in the development of alternative diagnostic classification systems for psychopathology in young children, little is known about the adequacy of the DSM symptom structure for describing psychopathology in this population. This paper examines the fit of the DSM-IV emotional (ED) and disruptive behavior disorder (DD) symptom structure in a community sample of 796 4-year-old children. Using the parent-report Child Symptom Inventory (CSI), the best model fit for ED included separate factors for Social Phobia, Separation Anxiety Disorder, Generalized Anxiety Disorder, and Major Depressive Disorder. For DD, the best model included separate Attention Deficit Hyperactivity Disorder Inattentive type (ADHD-I), Attention Deficit Hyperactivity Disorder Hyperactive/Impulsive type (ADHD-HI), and Oppositional Defiant Disorder diagnoses. These findings support using DSM-IV nosology to classify EDs in a community sample of preschool children, and suggest differentiation of ADHD into ADHD-I and ADHD-HI. PMID- 21271286 TI - Ringing the changes: emerging roles for DASH at the kinetochore-microtubule Interface. AB - Regulated interaction between kinetochores and the mitotic spindle is essential for the fidelity of chromosome segregation. Potentially deleterious attachments are corrected during prometaphase and metaphase. Correct attachments must persist during anaphase, when spindle-generated forces separate chromosomes to opposite poles. In yeast, the heterodecameric DASH complex plays a vital pole in maintaining this link. In vitro DASH forms both oligomeric patches and rings that can form load-bearing attachments with the tips of polymerising and depolymerising microtubules. In vivo, DASH localises primarily at the kinetochore, and has a role maintaining correct attachment between spindles and chromosomes in both Saccharomyces cerevisiae and Schizosaccharomyces pombe. Recent work has begun to describe how DASH acts alongside other components of the outer kinetochore to create a dynamic, regulated kinetochore-microtubule interface. Here, we review some of the key experiments into DASH function and discuss their implications for the nature of kinetochore-microtubule attachments in yeast and other organisms. PMID- 21271288 TI - A concern with regards to one of our publications previously published in Vet.Res. Commun. 2010;34(2):161-72. PMID- 21271289 TI - Energetic efficiency of milk synthesis in dual-purpose cows grazing tropical pastures. AB - The aim of this study was to assess the energetic efficiency of milk synthesis by grazing dual-purpose cows with or without a starch-based supplement in tropical South Mexico. Forty-six Holstein * Zebu cows were used in a 2 * 2 * 2 factorial design. Factors analysed were diet (supplemented, unsupplemented), age (young: 1 2 calvings, mature: >3 calvings) and day of lactation (21 and 84 days post calving). The supplement represented about 30% of estimated dry matter (DM) intake. Grass intake was measured using the n-alkane technique at 21 and 84 days post-calving when calculations of efficiency were performed. Efficiency for milk synthesis was reported as feed conversion efficiency (FCE, kilograms of milk per kilogram of DM intake), gross energetic efficiency (GEE, milk energy output/metabolisable energy (ME) intake) and efficiency of ME use for lactation (k(l), adjusted to zero energy balance). There were no interactions between factors. FCE and GEE were not different between diets, but supplemented cows had a lower (p < 0.01) k(l) value (0.62) than unsupplemented cows (0.67), suggesting a diverted partition of nutrients towards body tissue. Mature cows were more efficient (p < 0.001) than young cows in terms of FCE (1.13 vs 0.87) and GEE (0.34 vs 0.26), but equal in terms of k(l) (0.65). FCE (1.10 vs 0.90) and GEE (0.34 vs 0.27) were both higher on day 21 compared with day 84 post-calving, with a trend for a higher k(l) in early lactation. Dual-purpose cows used tropical grasses efficiently for milk synthesis, and higher milk yield observed in supplemented cows was due to a higher intake of nutrients rather than a higher energetic efficiency. PMID- 21271290 TI - Net change in periosteal strain during stance shift loading after surgery correlates to rapid de novo bone generation in critically sized defects. AB - In an ovine femur model, proliferative woven bone fills critically sized defects enveloped by periosteum within 2 weeks of treatment with the one-stage bone transport surgery. We hypothesize that mechanical loading modulates this process. Using high-definition optical strain measurements we determined prevailing periosteal strains for normal and surgically treated ovine femora subjected ex vivo to compressive loads simulating in vivo stance shifting (n = 3 per group, normal vs. treated). We determined spatial distribution of calcein green, a label for bone apposition in first the 2 weeks after surgery, in 15 degrees , 30 degrees , and 45 degrees sectors of histological cross sections through the middle of the defect zone (n = 6 bones, three to four sections per bone). Finally, we correlated early bone formation to either the maximal periosteal strain or the net change in maximal periosteal strain. We found that treatment with the one-stage bone-transport surgery profoundly changes the mechanical environment of cells within the periosteum during stance shift loading. The pattern of early bone formation is repeatable within and between animals and relates significantly to the actual strain magnitude prevailing in the periosteum during stance shift loading. Interestingly, early bone apposition after the surgery correlates well to the maximal net change in strain (above circa 2000 3000 MUepsilon, in tension or compression) rather than strain magnitude per se, providing further evidence that changes in cell shape may drive mechanoadaptation by progenitor cells. These important insights regarding mechanobiological factors that enhance rapid bone generation in critically sized defects can be translated to the tissue and organ scale, providing a basis for the development of best practices for clinical implementation and the definition of movement protocols to enhance the regenerative effect. PMID- 21271291 TI - White tea (Camellia sinensis Kuntze) exerts neuroprotection against hydrogen peroxide-induced toxicity in PC12 cells. AB - Tea is a popular beverage whose consumption is associated with prevention of certain disorders. The objective of the study was to investigate the potential neuroprotective effect of white tea extract (WTE) on hydrogen peroxide induced toxicity in PC12 cells. Cells were treated with various doses of WTE (10-250 MUg/ml) before exposition to 250 MUM hydrogen peroxide and cell survival was determined through the MTT and LDH assays. Oxidative stress was quantified in the cells after treatments as intracellular reactive oxygen species (ROS) production and the antioxidant activity of the extract was assessed in a cell free system in terms of free radical scavenging capacity. Results showed that WTE has a significant protective effect in the PC12 cell line against hydrogen peroxide as cell survival was significantly superior in WTE-treated cells compared to hydrogen peroxide-treated cells. A reduction on intracellular oxidative stress as well as radical scavenging properties were produced by WTE. Results suggest that WTE protects PC12 cells against H(2)O(2)-induced toxicity, and that an antioxidant mechanism through ROS scavenging may be in part responsible for cells neuroprotection. PMID- 21271292 TI - 3D spinal motion analysis during staircase walking using an ambulatory inertial and magnetic sensing system. AB - Previous research on spinal motion during walking has been restricted to the level walking condition in a gait lab although staircase walking (i.e., stair ascent and descent) exhibits unique biomechanical characteristics. A major difficulty in spinal motion capture during staircase walking is the in-the-lab limitation of measurement techniques. The purpose of this article is twofold: (i) to present an ambulatory spinal motion measurement system based on inertial and magnetic sensors (IMSs) to overcome this limitation and (ii) to demonstrate its application to 3D spinal motion analysis during staircase walking to fill a gap in the spinal kinematics literature. The proposed system is comprised of three tri-axial IMSs on the pelvis/spine measuring 3D angular motions of the pelvis, lumbar spine and thoracic spine and two uni-axial gyroscopes on the shanks providing gait cycle information. The proposed system was employed in comparing the spinal motion during the staircase walking to that of the level walking with respect to the motion pattern, variability, and range of motion (ROM). The test results showed clear differences in spinal motion between the level walking and staircase walking conditions, particularly in regards to the motion pattern and ROM of the flexion/extension and lateral bending of the spine. PMID- 21271293 TI - Analysis of retinal fundus images for grading of diabetic retinopathy severity. AB - Diabetic retinopathy (DR) is a sight threatening complication due to diabetes mellitus that affects the retina. In this article, a computerised DR grading system, which digitally analyses retinal fundus image, is used to measure foveal avascular zone. A v-fold cross-validation method is applied to the FINDeRS database to evaluate the performance of the DR system. It is shown that the system achieved sensitivity of >84%, specificity of >97% and accuracy of >95% for all DR stages. At high values of sensitivity (>95%), specificity (>97%) and accuracy (>98%) obtained for No DR and severe NPDR/PDR stages, the computerised DR grading system is suitable for early detection of DR and for effective treatment of severe cases. PMID- 21271294 TI - Free terminal time optimal control problem of an HIV model based on a conjugate gradient method. AB - The minimum duration of treatment periods and the optimal multidrug therapy for human immunodeficiency virus (HIV) type 1 infection are considered. We formulate an optimal tracking problem, attempting to drive the states of the model to a "healthy" steady state in which the viral load is low and the immune response is strong. We study an optimal time frame as well as HIV therapeutic strategies by analyzing the free terminal time optimal tracking control problem. The minimum duration of treatment periods and the optimal multidrug therapy are found by solving the corresponding optimality systems with the additional transversality condition for the terminal time. We demonstrate by numerical simulations that the optimal dynamic multidrug therapy can lead to the long-term control of HIV by the strong immune response after discontinuation of therapy. PMID- 21271295 TI - Accumulation and speciation of selenium in plants as affected by arbuscular mycorrhizal fungus Glomus mosseae. AB - Effects of arbuscular mycorrhizal fungus (Glomus mosseae) on the accumulation and speciation of selenium (Se) in alfalfa, maize, and soybean were investigated by using Se(IV)-spiked soil. Mycorrhizal inoculation decreased Se accumulation in roots and shoots of all the plants at Se spiked level of 0 or 2 mg kg(-1), while an increased Se accumulation was observed in alfalfa shoots and maize roots and shoots at the spiked level of 20 mg kg(-1). Concentration of inorganic Se (especially Se(VI)) in roots and shoots of the three plants was much higher in mycorrhizal than non-mycorrhizal treatment. Mycorrhizal inoculation decreased the portion of total organic Se in plant tissues with the exception of alfalfa and maize shoots at Se spiked level of 20 mg kg(-1), in which organic Se portion did not reduced greatly (<5%) for mycorrhizal treatment. Mycorrhizal effects on alfalfa and maize were more obvious than on soybean in terms of root colonization rate, biomass, and Se accumulation. PMID- 21271296 TI - Effect of mineral fortification on plasma biochemical profile in rats. AB - This study aimed at investigating the changes in biochemical profile of male rats following 8 weeks administration of different concentration of elemental iron, sodium iron ethylenediaminetetraacetate (NaFeEDTA), zinc sulfate (ZnSO(4)), and zinc oxide (ZnO) in whole wheat flour. Eight groups comprising five rats each were fed fortified whole wheat flour in the form of baked pallets, while one group served as control. Concentration of total cholesterol, high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), triglycerides, total proteins, albumin, globulin, plasma glucose, and blood urea nitrogen were assayed. Supplementing mineral-fortified diet to male rats did not indicate any significant (p <= 0.05) effect on total cholesterol concentration. Diets containing NaFeEDTA alone increased HDL-C and decreased LDL-C; however, the differences remained non significant. Likewise, plasma triglycerides content of male rats remained unchanged on feeding fortified diets. Diets containing iron as NaFeEDTA and elemental iron exerted little effect on total protein concentration in the plasma of rats. Plasma glucose and blood urea nitrogen levels did not exhibit any significant change as a result of ingesting mineral supplemented diets. The study concludes that the forms of fortificants and the fortification levels used in the current study are undamaging for lipid profile, renal function, and glucose levels in rats, suggesting that these may be safely used in wheat flour to combat iron and zinc deficiency in vulnerable groups. PMID- 21271297 TI - Toxic effect of terbium ion on horseradish cell. AB - The toxic effect of terbium (III) ion on the horseradish cell was investigated by scanning electron microscopy, gas chromatography, and standard biochemical methods. It was found that the activity of horseradish peroxidase in the horseradish treated with 0.2 mM terbium (III) ion decreased and led to the excessive accumulation of free radicals compared with that in the control horseradish. The excessive free radicals could oxidize unsaturated fatty acids in the horseradish cell and then increase the cell membrane lipid peroxidation of horseradish. The increase in the lipid peroxidation could lead to the destruction of the structure and function of the cell membrane and then damage of the horseradish cell. We propose that this is a possible mechanism for the toxic action of terbium in the biological systems. PMID- 21271298 TI - Plasma levels of zinc, copper, and ceruloplasmin in patients after undergoing laparoscopic adjustable gastric banding. AB - Laparoscopic adjustable gastric banding (LAGB) causes significant weight loss in morbidly obese adults. However, its consequences on nutritional status still remain unclear. There are a few studies determining the nutritional status after LAGB and none have focused on the serum levels of zinc (Zn), copper (Cu), and ceruloplasmin (CP). We aimed to investigate the effects of LAGB surgery on plasma Zn, Cu, and CP levels. Thirty patients with LAGB with morbid obesity were included. Blood samples were collected preooperatively and in the postoperative third month to determine plasma Zn, Cu, and CP levels. The mean preoperative and postoperative body mass indexes (BMI) were 44.9 +/- 7.4 kg/m(2) and 44.1 +/- 6.5 kg/m(2), respectively. The mean weight loss was 12.9 +/- 3.3 kg at the postoperative third month. The postoperative Zn (500 +/- 130 ng/ml), Cu (280 +/- 80 ng/ml), and CP (23.9 +/- 8.8 mg/dl) values were statistically significantly lower than the preooperative Zn (740 +/- 230 ng/ml), Cu (370 +/- 80 ng/ml) and CP (33.3 +/- 15.7 mg/dl) levels (p < 0.05). Decreases in the plasma levels of Zn, Cu, and CP were seen postoperatively following LAGB surgery. The nutritional status of LAGB-applied patients should be monitored and mineral supplementation may be considered. PMID- 21271299 TI - NACP-Rep1 relates to Beck Depression Inventory scores in healthy humans. AB - Alpha-synuclein (SNCA) is associated with a range of psychiatric diseases including neurodegeneration, alcohol craving, and depression. It regulates cellular homeostasis by virtue of its ability to interfere in dopaminergic, serotonergic, and noradrenergic pathways. To date, it is unclear whether the previously described association between SNCA and depressive symptomatology is limited to females with eating disorders or whether it could be extended to include healthy individuals. We included 105 women and 108 men. Genetic data and mRNA expression analyses were drawn from peripheral blood and the severity of depressive symptoms was quantified by the Beck's Depression Inventory (BDI). We found a significant association between the NACP-Rep1 length polymorphism and the BDI score (p = 0.004). Moreover, there was a significant gender dimorphism regarding mRNA expression of SNCA (p = 0.011). Our analysis revealed no further association between the In4 polymorphism or between the mRNA expression of SNCA and the BDI score. Since this investigation was limited to healthy individuals, conclusions concerning depression according to ICD-10 or DSM-IV cannot be drawn. The reported results may contribute to a better understanding of the molecular mechanisms linked to depressive symptoms. PMID- 21271300 TI - Promoter analysis of mouse Scn3a gene and regulation of the promoter activity by GC box and CpG methylation. AB - Voltage-gated sodium channel alpha-subunit type III (Na(v)1.3) is mainly expressed in the central nervous system and is associated with neurological disorders. The expression of mouse Scn3a product (Na(v)1.3) mainly occurs in embryonic and early postnatal brain but not in adult brain. Here, we report for the first time the identification and characterization of the mouse Scn3a gene promoter region and regulation of the promoter activity by GC box and CpG methylation. Luciferase assay showed that the promoter region F1.2 (nt -1,049 to +157) had significantly higher activity in PC12 cells, comparing with that in SH SY5Y cells and HEK293 cells. A stepwise 5' truncation of the promoter region found that the minimal functional promoter located within the region nt -168 to +157. Deletion of a GC box (nt -254 to -258) in the mouse Scn3a promoter decreased the promoter activity. CpG methylation of the F1.2 without the GC box completely repressed the promoter activity, suggesting that the GC box is a critical element in the CpG-methylated Scn3a promoter. These results suggest that the GC box and CpG methylation might play important roles in regulating mouse Scn3a gene expression. PMID- 21271301 TI - Acetylation as a transcriptional control mechanism-HDACs and HATs in pancreatic ductal adenocarcinoma. AB - INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors with a dismal prognosis. Although our understanding of the carcinogenesis of the disease increases continuously, no effective conservative therapeutic strategies exist. Therefore, novel targets have to be defined at the experimental level. Histone deacetylases (HDACs), especially the class I isoenzymes HDAC1, 2, and 3, are highly expressed in PDAC. CONCLUSION: This article summarizes the expression and functions of HDAC isoenzymes in PDAC, with a special focus on their promoter-specific mode of action. Although we have gained some molecular insight into the HDAC function in PDAC, less is known about the relevance of histone acetyltransferases (HATs) in PDAC. As an example, we will summarize function of the HAT p300, for which promoter-specific functions were described recently. Increasing the molecular insights into the functions of the acetylating and deacetylating machineries in PDAC are important, since this will lead to novel rationally based therapeutic strategies in the future. PMID- 21271302 TI - Tissue expression of the proteins fas and fas ligand in colorectal cancer and liver metastases. AB - BACKGROUND AND AIM: Our purpose is to study the clinical significance of Fas/FasL expression in colon cancer and liver metastases (LM). MATERIAL AND METHODS: The expression of Fas/FasL in 68 patients with colon cancer was examined immunohistochemically and correlated to the clinicopathological features of the tumors. RESULTS: High expression of FasL, was observed in stage D and in LM (p=0.024). Fas expression was reduced in stage D tumors and in LM, when compared to earlier stages of disease (p=0.024). LM had also shown a decreased expression of Fas (p=0.016). Tumors with low FasL expression upregulate more often their Fas expression (p = 0.028). No correlation could be established regarding the patients survival. CONCLUSIONS: Low expression of Fas and high expression of FasL are more often in colon tumor stage D and in liver metastasis; these imply tumor aggression, resistance against apoptosis, and could be held as negative prognostic factors. PMID- 21271303 TI - Evolution of the VEGF-regulated vascular network from a neural guidance system. AB - The vascular network is closely linked to the neural system, and an interdependence is displayed in healthy and in pathophysiological responses. How has close apposition of two such functionally different systems occurred? Here, we present a hypothesis for the evolution of the vascular network from an ancestral neural guidance system. Biological cornerstones of this hypothesis are the vascular endothelial growth factor (VEGF) protein family and cognate receptors. The primary sequences of such proteins are conserved from invertebrates, such as worms and flies that lack discernible vascular systems compared to mammals, but all these systems have sophisticated neuronal wiring involving such molecules. Ancestral VEGFs and receptors (VEGFRs) could have been used to develop and maintain the nervous system in primitive eukaryotes. During evolution, the demands of increased morphological complexity required systems for transporting molecules and cells, i.e., biological conductive tubes. We propose that the VEGF-VEGFR axis was subverted by evolution to mediate the formation of biological tubes necessary for transport of fluids, e.g., blood. Increasingly, there is evidence that aberrant VEGF-mediated responses are also linked to neuronal dysfunctions ranging from motor neuron disease, stroke, Parkinson's disease, Alzheimer's disease, ischemic brain disease, epilepsy, multiple sclerosis, and neuronal repair after injury, as well as common vascular diseases (e.g., retinal disease). Manipulation and correction of the VEGF response in different neural tissues could be an effective strategy to treat different neurological diseases. PMID- 21271304 TI - Collapsin response mediator protein-2: an emerging pathologic feature and therapeutic target for neurodisease indications. AB - Collapsin response mediator protein-2 (DPYSL2 or CRMP2) is a multifunctional adaptor protein within the central nervous system. In the developing brain or cell cultures, CRMP2 performs structural and regulatory functions related to cytoskeletal dynamics, vesicle trafficking and synaptic physiology whereas CRMP2 functions in adult brain are still being elucidated. CRMP2 has been associated with several neuropathologic or psychiatric conditions including Alzheimer's disease (AD) and schizophrenia, either at the level of genetic polymorphisms; protein expression; post-translational modifications; or protein/protein interactions. In AD, CRMP2 is phosphorylated by glycogen synthase kinase-3beta (GSK3beta) and cyclin dependent protein kinase-5 (CDK5), the same kinases that act on tau protein in generating neurofibrillary tangles (NFTs). Phosphorylated CRMP2 collects in NFTs in association with the synaptic structure-regulating SRA1/WAVE1 (specifically Rac1-associated protein-1/WASP family verprolin homologous protein-1) complex. This phenomenon could plausibly contribute to deficits in neural and synaptic structure that have been well documented in AD. This review discusses the essential biology of CRMP2 in the context of nascent data implicating CRMP2 perturbations as either a correlate of, or plausible contributor to, diverse neuropathologies. A discussion is made of recent findings that the atypical antidepressant tianeptine increases CRMP2 expression, whereas other, neuroactive small molecules including the epilepsy drug lacosamide and the natural brain metabolite lanthionine ketimine appear to bind CRMP2 directly with concomitant affects on neural structure. These findings constitute proofs-of concept that pharmacological manipulation of CRMP2 is possible and hence, may offer new opportunities for therapy development against certain neurological diseases. PMID- 21271305 TI - Hypertensive emergencies in children. AB - Hypertensive emergencies, though uncommon in children, are potentially life threatening. While targeting blood pressure reduction to below the 90th percentile for age, gender and height, mean arterial blood pressure should be gradually lowered by one-fourth of the planned reduction over 8-12 h, a further fourth over the next 8-12 h, and the final 50% over the 24 h after that. Frequent invasive or non-invasive blood pressure monitoring is essential, as is monitoring for sensorial alteration and loss of papillary reflexes. Few antihypertensive agents have been examined in children. Continuous intravenous infusions of short acting drugs such as nitroprusside, labetalol and nicardipine are preferred to intravenous boluses of hydralazine or diazoxide. If severe symptoms are absent, oral agents such as nifedipine, clonidine, minoxidil, hydralazine, labetalol, captopril, and prazosin may be used. Nicardipine and labetalol are particularly suited in emergencies with intracranial bleeding or ischemic stroke, while furosemide, sodium nitroprusside and nitroglycerine are useful in congestive cardiac failure. Therapy with oral antihypertensive drugs should be instituted within 6-12 h of parenteral therapy, and the latter gradually withdrawn over the next 12-48 h. Oral agents have limited application as primary therapy, except when administration of intravenous infusion is likely to be delayed. This article provides a summary of the clinical approach to evaluation and management of severe symptomatic hypertension in children. PMID- 21271307 TI - Chronic opioid therapy for chronic pain: an e-learning program to develop shared decision-making and communication skills. PMID- 21271306 TI - Serotonergic agents in the management of cluster headache. AB - Cluster headache is a highly disabling primary headache disorder, characterized by unilateral headache attacks occurring in association with cranial autonomic symptoms. Serotonergic agents, such as the ergot alkaloids, have traditionally been used for the acute and preventive treatment of cluster headache and other primary headaches. Although it initially was thought that their efficacy was due solely to the vasoconstriction of extracranial cerebral vessels, new mechanisms of action of these drugs have been ascertained as a consequence of advances in elucidation of the pathogenesis of primary headaches and the development of triptans. This article reviews the current knowledge about serotonergic agonists and antagonists used in the management of cluster headache, focusing on their mechanisms of action and on the possible role of serotonin system dysfunction in this complex disorder. PMID- 21271308 TI - Advances in primary CNS lymphoma: randomized clinical trials of chemotherapy and whole-brain radiotherapy. PMID- 21271309 TI - Modeling neurodegeneration in zebrafish. AB - The zebrafish, Danio rerio, has been established as an excellent vertebrate model for the study of developmental biology and gene function. It also has proven to be a valuable model to study human diseases. Here, we reviewed recent publications using zebrafish to study the pathology of human neurodegenerative diseases including Parkinson's, Huntington's, and Alzheimer's. These studies indicate that zebrafish genes and their human homologues have conserved functions with respect to the etiology of neurodegenerative diseases. The characteristics of the zebrafish and the experimental approaches to which it is amenable make this species a useful complement to other animal models for the study of pathologic mechanisms of neurodegenerative diseases and for the screening of compounds with therapeutic potential. PMID- 21271310 TI - The role of matrix metalloproteinases in atherothrombosis. AB - The matrix metalloproteinase (MMP) family of enzymes is involved in arterial wall extracellular matrix degradation and remodeling. The latter activities have been implicated in a number of normal and pathologic processes, such as atherosclerotic lesion formation and progression, plaque destabilization and rupture, but also in plaque stabilization and healing. As a result, the MMPs have been explored as both therapeutic targets and diagnostic tools for the treatment and diagnosis of atherosclerotic cardiovascular diseases. In this review, we summarize experimental findings, genetic associations, and the biomarker potential of MMPs in atherothrombosis. In addition, the regulation and expression of MMPs in atherosclerotic plaques is discussed, with an emphasis on the role of lipid-derived inflammatory mediators as modulators of MMP activity. PMID- 21271311 TI - The effect of sleep deprivation on BOLD activity elicited by a divided attention task. AB - Sleep loss, widespread in today's society and associated with a number of clinical conditions, has a detrimental effect on a variety of cognitive domains including attention. This study examined the sequelae of sleep deprivation upon BOLD fMRI activation during divided attention. Twelve healthy males completed two randomized sessions; one after 27 h of sleep deprivation and one after a normal night of sleep. During each session, BOLD fMRI was measured while subjects completed a cross-modal divided attention task (visual and auditory). After normal sleep, increased BOLD activation was observed bilaterally in the superior frontal gyrus and the inferior parietal lobe during divided attention performance. Subjects reported feeling significantly more sleepy in the sleep deprivation session, and there was a trend towards poorer divided attention task performance. Sleep deprivation led to a down regulation of activation in the left superior frontal gyrus, possibly reflecting an attenuation of top-down control mechanisms on the attentional system. These findings have implications for understanding the neural correlates of divided attention and the neurofunctional changes that occur in individuals who are sleep deprived. PMID- 21271312 TI - Upper Extremity Deep Vein Thrombosis: The Oft-forgotten Cousin of Venous Thromboembolic Disease. AB - OPINION STATEMENT: Upper extremity deep venous thrombosis (UEDVT) accounts for between 4% and 10% of all deep venous thromboses, and may be due to primary or secondary causes. The incidence of UEDVT is increasing, partly due to the exponential growth in the use of central venous catheters and the increasing placement of permanent cardiac pacemaker or defibrillator devices. UEDVT not only compromises future vascular access but results in significant morbidity and mortality, with symptomatic pulmonary embolus occurring in approximately 12%, post-thrombotic syndrome in 13%, and mortality ranging from 15-50%. Treatment of UEDVT depends on the underlying cause, primary or secondary. In this review, we will evaluate the management options and present a proposed treatment algorithm for primary UEDVT, involving catheter-directed thrombolysis, selective use of mechanical thrombectomy, anticoagulation and antithrombotic therapy, expeditious early first rib resection to decompress the thoracic outlet, and the role of adjunctive endovascular balloon angioplasty and stenting in improving axillo subclavian vein patency. With regard to secondary UEDVT, we will present a treatment algorithm for managing central venous catheter (CVC) thrombosis; review the options for antithrombotic and anticoagulant therapy; and discuss the role of endovascular therapy. Finally, we will review the data supporting the growing role of percutaneous transluminal angioplasty (PTA) or venoplasty and endovascular stenting as the modality of choice in managing SVC obstruction, whether due to benign or malignant causes, and provide a brief description of the role, benefits and potential complications of SVC filter placement. PMID- 21271313 TI - Limited diagnostic and predictive values of dual-time-point 18F FDG PET/CT for differentiation of incidentally detected thyroid nodules. AB - OBJECTIVE: To assess usefulness of dual-time-point (18)F FDG PET/CT to differentiate malignant from benign thyroid nodules and predict the potential factor for malignancy. METHODS: Fifty patients (age 38-83 years, mean 58 +/- 10.6 years) with thyroid nodule were recruited. The (18)F FDG PET/CT images were analyzed visually and quantitatively. RESULTS: The optimal visual grade of early and delayed images was >grade 3. When SUV(max1) of >2.9 was used as cut off point, the sensitivity and specificity were 55.5 and 63.4%. When SUV(max2) was >3.1, the sensitivity and specificity were 88.8 and 43.9%. When %DeltaSUV(max) was <=9.09%, the sensitivity and specificity were 33.3 and 87.8%. ROC analyses showed that all indices had similar efficacy without significances. No definite predictor could be found for malignant nodules. CONCLUSION: The dual-time-point (18)F FDG PET/CT is not a useful method for differentiating malignant and benign nodules. PMID- 21271314 TI - T-cell subset regulation in atopy. AB - Presentation of processed allergen by antigen-presenting cells to T-helper (Th) lymphocytes, which is influenced costimulatory signals, cytokines, chemokines, and regulatory T cells (Tregs), determines the development of different types of T-cell immunity. The discovery of Tregs revolutionized the primary concepts of immune regulation interpreted within the framework of a binary Th1/Th2 paradigm. Tregs play a central role in the maintenance of peripheral homeostasis, the establishment of controlled immune responses, and the inhibition of allergen specific effector cells. Recently, some other T-cell subsets appeared, including Th17 and Th9 cells, which control local tissue inflammation through upregulation of proinflammatory cytokines and chemokines. This review aims to discuss our understanding of the T-cell subset reciprocal interaction in atopy. PMID- 21271315 TI - Sublingual immunotherapy in patients with allergic rhinoconjunctivitis. AB - Sublingual immunotherapy (SLIT) is a well-established treatment option for allergic rhinitis in several European countries, but it is considered investigational in the United States. Studies conducted in Europe provided a large body of evidence supporting the safety and efficacy of SLIT, but those studies used allergen products that are different from those that are likely to be approved in the United States, and many of them were not controlled, randomized, double-blinded trials. This review summarize research conducted on the efficacy, safety, and mechanisms of SLIT published during the past year, with a focus on ragweed and grass antigens. Results of recent US studies document the safety and efficacy of SLIT and have started to yield insight into the mechanisms of SLIT. PMID- 21271316 TI - The effects of excipients and particle engineering on the biophysical stability and aerosol performance of parathyroid hormone (1-34) prepared as a dry powder for inhalation. AB - Pulmonary delivery of therapeutic peptides and proteins has many advantages including high relative bioavailability, rapid systemic absorption and onset of action and a non-invasive mode of administration which improves patient compliance. In this study, we investigated the effect of spray-drying (SD) and spray freeze-drying processes on the stability and aerosol performance of parathyroid hormone (PTH) (1-34) microparticles. In this study, the stabilisation effect of trehalose (a non-reducing sugar) and Brij 97 (a non-ionic surfactant) on spray-dried PTH particles was assessed using analytical techniques including circular dichroism (CD), fluorescence spectroscopy, modulated differential scanning calorimetry and an in vitro bioactivity assay. Physical characterisation also included electron microscopy, tap density measurement and laser light diffraction. The aerosol aerodynamic performance of the formulations was assessed using the Andersen cascade impactor. Based on these studies, a formulation for spray freeze-drying was selected and the effects of the two particle engineering techniques on the biophysical stability and aerosol performance of the resulting powders was determined. CD, fluorescence spectroscopy and bioactivity data suggest that trehalose when used alone as a stabilising excipient produces a superior stabilising effect than when used in combination with a non-ionic surfactant. This highlights the utility of CD and fluorescence spectroscopy studies for the prediction of protein bioactivity post-processing. Therefore, a method and formulation suitable for the preparation of PTH as a dry powder was developed based on spray-drying PTH with trehalose as a stabiliser with the bioactivity of SD PTH containing trehalose being equivalent to that of unprocessed PTH. PMID- 21271317 TI - On the control of visual fixation durations in free viewing of complex images. AB - The mechanisms for the substantial variation in the durations of visual fixations in scene perception are not yet well understood. During free viewing of paintings, gaze-contingent irrelevant distractors (Exp. 1) and non-gaze-related time-locked display changes (Exp. 2) were presented. We demonstrated that any visual change-its onset and offset-prolongs the ongoing fixation (i.e., delays the following saccade), strongly suggesting that fixation durations are under the direct control of the stimulus information. The strongest influence of distraction was observed for fixations preceded by saccades within the parafoveal range (<5 degrees of visual angle). We assume that these fixations contribute to the focal in contrast to the ambient mode of attention (Pannasch & Velichkovsky, Visual Cognition, 17, 1109-1131, 2009; Velichkovsky, Memory, 10, 405-419, 2002). Recent findings about two distinct "subpopulations of fixations," one under the direct and another under the indirect control of stimulation (e.g., Henderson & Smith, Visual Cognition, 17, 1055-1082, 2009), are reconsidered in view of these results. PMID- 21271318 TI - A multigenerational view of inequality. AB - The study of intergenerational mobility and most population research are governed by a two-generation (parent-to-offspring) view of intergenerational influence, to the neglect of the effects of grandparents and other ancestors and nonresident contemporary kin. While appropriate for some populations in some periods, this perspective may omit important sources of intergenerational continuity of family based social inequality. Social institutions, which transcend individual lives, help support multigenerational influence, particularly at the extreme top and bottom of the social hierarchy, but to some extent in the middle as well. Multigenerational influence also works through demographic processes because families influence subsequent generations through differential fertility and survival, migration, and marriage patterns, as well as through direct transmission of socioeconomic rewards, statuses, and positions. Future research should attend more closely to multigenerational effects; to the tandem nature of demographic and socioeconomic reproduction; and to data, measures, and models that transcend co-resident nuclear families. PMID- 21271319 TI - Dental pulp stem cells in regenerative dentistry. AB - Stem cells constitute the source of differentiated cells for the generation of tissues during development, and for regeneration of tissues that are diseased or injured postnatally. In recent years, stem cell research has grown exponentially owing to the recognition that stem cell-based therapies have the potential to improve the life of patients with conditions that span from Alzheimer's disease to cardiac ischemia to bone or tooth loss. Growing evidence demonstrates that stem cells are primarily found in niches and that certain tissues contain more stem cells than others. Among these tissues, the dental pulp is considered a rich source of mesenchymal stem cells that are suitable for tissue engineering applications. It is known that dental pulp stem cells have the potential to differentiate into several cell types, including odontoblasts, neural progenitors, osteoblasts, chondrocytes, and adipocytes. The dental pulp stem cells are highly proliferative. This characteristic facilitates ex vivo expansion and enhances the translational potential of these cells. Notably, the dental pulp is arguably the most accessible source of postnatal stem cells. Collectively, the multipotency, high proliferation rates, and accessibility make the dental pulp an attractive source of mesenchymal stem cells for tissue regeneration. This review discusses fundamental concepts of stem cell biology and tissue engineering within the context of regenerative dentistry. PMID- 21271320 TI - The effects of bisphosphonates on jaw bone remodeling, tissue properties, and extraction healing. AB - Bisphosphonate effects on the skeleton have been studied in the context of a broad range of disciplines, including endocrinology, orthopedics, oncology, and dentistry. The emergence of osteonecrosis of the jaw as a rare but serious side effect of bisphosphonate treatment has stimulated interest in understanding how this drug class affects the oral skeleton. This review focuses on recent work describing how bisphosphonates affect bone remodeling, tissue properties, and postsurgical healing in the oral cavity. PMID- 21271321 TI - Root and canal morphology of Indian maxillary premolars by a modified root canal staining technique. AB - The aim of this study was to investigate the root and canal morphology of maxillary first and second premolars in Indians by a modified canal staining and tooth clearing technique. Maxillary first (350) and second (350) premolars were collected, and the morphology and number of roots analyzed. After cleaning, the teeth were immersed in India ink and placed in a hyperbaric oxygen chamber at 0.6 MPa for 2 h. The teeth were then demineralized and cleared. Digital images of the teeth were examined under magnification to evaluate the number of root canals, root canal system configurations, number of apical foramina, and intercanal communications. Root canal configurations were identified based on Vertucci's classification and Gulabivala's additional classes. The most common root morphology of the first premolars was the classical two separate root morphology (a Caucasian trait) and that of the second premolars was a single-root morphology (a Mongoloid trait), though other morphologies such as singlerooted first premolars and three-rooted first and second premolars were also identified. A "radiculous" first premolar was identified in two samples. The buccal roots of the first premolar showed the maximum variation, the most common being type I (Vertucci's classification), followed by type IV. The highest incidence of intercanal communications was found in the single-rooted first premolars. All roots exhibiting type IV and V canal configurations showed two separate apical foramina, while additional type 2-3 canal configurations showed three separate apical foramina. The root number and morphology as well as the canal morphology of Indian maxillary premolars showed both Mongolian and Caucasian traits. PMID- 21271322 TI - Comparison of diameters at the cementoenamel junction between South Asians and Japanese. AB - Previously, sex differences among the various tooth types in Japanese skulls were examined to facilitate choosing an implant diameter similar to the cervical diameter of each tooth, and it was found that mesiodistal diameters at the cementoenamel junction were narrower in women than in men. Also interesting and relevant to the selection of implant diameter is the possible existence of racial differences in diameters at the cementoenamel junction. The purpose of this research was to test the hypothesis that the diameter at the cementoenamel junction of the tooth differs in humans of different races. We compared 106 skulls of unknown sex collected from South Asia with the skulls of Japanese women. Our conclusions are as follows: (1) Except for the lower canine, no significant racial differences were found in the labiolingual diameter of any teeth. (2) Except for the upper canine, upper central incisor, lower second premolar, and lower first premolar, a significant racial difference was found in the mesiodistal diameter. In all teeth in which this value differed, the mesiodistal diameters of South Asians were narrower than those of Japanese women, except for the lower canine. (3) The labiolingual and mesiodistal diameters of the lower canine were significantly larger in South Asians than in Japanese women. (4) Among South Asians, no significant left/right differences were found in the diameter at the cementoenamel junction of any tooth. PMID- 21271323 TI - The effects of oral xylitol administration on bone density in rat femur. AB - To examine the effects of oral xylitol administration on rat femur bone density, 36 four-week-old male Wistar rats divided into three groups were fed CE-2 diet (control, n = 12) alone or supplemented with 10% (n = 12) or 20% (n = 12) dietary xylitol for 40 days. Biochemical, morphological, and histological analyses were performed. The 10% and 20% xylitol groups showed higher levels of both serum Ca and alkaline phosphatase activity and lower levels of serum tartrate-resistant acid phosphatase than the control group. Although no significant differences in the three-dimensional bone structure or trabecular bone structure of the femur were observed, both xylitol groups showed significantly higher bone density than the control group. Compared to the control group, the 10% and 20% xylitol groups showed an increase in trabeculae. Thus, oral administration of xylitol appears to affect bone metabolism, leading to increased bone density in rat femur. PMID- 21271324 TI - Effect of CO2 laser irradiation on wound healing of exposed rat pulp. AB - This study examined the effects of direct pulp capping treatment using super pulsed CO2 laser preirradiation on the wound healing process of exposed rat pulp on days 1, 3, 7, 14, and 28 postoperatively. Group 1 was irradiated with a CO2 laser and directly capped with a self-etching adhesive system. The laser was operated in super-pulse mode (pulse duration, 200 MUs; interval, 5800 MUs; 0.003 J/pulse). The irradiation conditions were a power output of 0.5 W, an irradiation time of 3 s, and repeat mode (10 ms of irradiation at 10-ms intervals for a total beam exposure time of 1.5 s), defocused beam diameter of 0.74 mm (approximately 20 mm from the exposed pulp surface), energy density of 0.698 J/cm2 per pulse, total applied energy of 0.75 J, and an activated air-cooling system. Group 2 was capped with the self-etching adhesive system. Group 3 was capped with commercially available calcium hydroxide, and the self-etching adhesive system was applied to the cavity. The following parameters were evaluated: pulp tissue disorganization, inflammatory cell infiltration, reparative dentin formation, and bacterial penetration. The results were statistically analyzed using the Kruskal Wallis test for differences among the groups at each observation period (P < 0.05). There were no significant differences among the experimental groups in any parameters at any postoperative period (P > 0.05). CO2 laser irradiation was effective in arresting hemorrhaging but showed a tendency to delay reparative dentin formation compared with the application of calcium hydroxide. PMID- 21271325 TI - Comparative assessment of the sealing ability of Nd:YAG laser versus a new desensitizing agent in human dentinal tubules: a pilot study. AB - Dentinal hypersensitivity is a painful condition that occurs following periodontal treatment. Many treatment alternatives have been considered for this problem, including treatments with laser and dentinal adhesives. This study compared the sealing ability of Nd:YAG laser versus a new resin in scanning electron microscopy (SEM) micrographs. Ten human premolars were sectioned yielding 30 specimens of each premolar, which were randomly divided into three groups. The laser group was irradiated by Nd:YAG laser (1 W, 10 Hz, 60 s), the resin group was treated with the new Seal & Protect resin according to the manufacturer's instructions, and the third group served as the control group and did not receive any interventions. After preparation and gold coating of the samples, they were photographed by SEM at two magnifications (1500* and 4000*). The number and diameter (MUm) of the dentinal tubules were recorded in selected fields, and analysis of variance (ANOVA) and Tukey tests were used to determine significant differences between groups. The ANOVA results revealed significant differences in both the mean number (P < 0.001) and diameter (P < 0.05) among the three groups. Further statistical analysis showed a significant difference between the laser group and the resin group in both outcome measures (P < 0.05). Thus, both Nd:YAG laser and the new resin reduced the number and diameter of open dentinal tubules, a result that also explains the desensitization mechanism of these interventions. We further conclude that application of the new resin is more effective than Nd:YAG laser in minimizing the number and diameter of exposed dentinal tubules. PMID- 21271326 TI - Microleakage in Class V composite and compomer restorations following exposure to a colutory prescribed for the treatment of xerostomy. AB - The purpose of this study was to evaluate the effect of a colutory (XeroLacer, Lacer), prescribed for the treatment of xerostomy, on microleakage into class V cavities filled with a composite (Z100, 3M ESPE) or a compomer (F2000, 3M ESPE) in combination with either a two-step etch-and-rinse adhesive (Adper Scotchbond 1XT, 3M ESPE) or a self-etching adhesive (Adper Prompt L-Pop, 3M ESPE). Class V cavities were made in the buccal surfaces of 80 bovine lower incisors which were randomly divided into four groups (n = 20): (1) Adper Scotchbond 1XT/Z100; (2) Adper Scotchbond 1XT/F2000; (3) Adper Prompt L-Pop/Z100; and (4) Adper PLP/F2000. All specimens were immersed in distilled water for 3 months and ten specimens of each group were immersed and vibrated in XeroLacer for 2 min three times a day. The specimens were dyed with 1% methylene blue for 24 h. Longitudinal sections were made and percentages of microleakage were determined by image analysis. In distilled water, microleakage with the Adper Scotchbond 1XT/F2000 combination was significantly greater than with Adper Scotchbond 1XT/Z100 or Adper Prompt L Pop/Z100, and microleakage with Adper Prompt L-Pop/F2000 was significantly greater than that with Adper Prompt L-Pop/Z100. No significant differences were detected among the groups exposed to XeroLacer. However microleakage was significantly less with Adper Scotchbond 1XT/F2000 after exposure to XeroLacer than after immersion in distilled water only. In conclusion, exposure to XeroLacer decreased microleakage into cavities restored with the compomer. PMID- 21271327 TI - Performance of a fluorescence camera for detection of occlusal caries in vitro. AB - The aim of this study was to assess inter- and intra-examiner reproducibility and accuracy in the detection and assessment of occlusal caries in extracted human teeth using the newly developed fluorescence based camera VistaProof. Serial sectioning and microscopy are considered the gold standard. The occlusal surfaces of 53 teeth (99 investigation sites) were examined by two examiners with different levels of experience in cariology (one experienced dentist, one final year dental student) and the VistaProof. Thereafter, the teeth were serially sectioned and assessed for lesion depth. The intraclass correlation coefficients for inter- and intra-examiner reproducibility for the fluorescence-based examinations were 0.76-0.95. There was a significant correlation between the fluorescence and histological examinations for both examiners (r (s) = 0.47 and 0.55, P < 0.01). At the D1 diagnostic threshold (enamel and dentin lesions), sensitivity was 0.71-0.86 and specificity was between 0.32 and 0.76 at different cutoff values. At the D3 diagnostic threshold (dentin lesions), sensitivity was 0.04-0.91 and specificity was 0.56-0.99 for both examiners. When the areas under the receiver-operating characteristic curves were compared, there was no significant difference in the performance between the examiners (P = 0.52 at the D1 threshold, P = 0.81 at the D3 threshold). The VistaProof demonstrated high reproducibility and good diagnostic performance for the detection of occlusal caries at various stages of the disease process. Novice and experienced examiners were able to apply this system as a supportive device for caries diagnostic and monitoring purposes. Sensitivity and specificity values varied depending on the cutoff values. PMID- 21271328 TI - Early bond strength of two resin cements to Y-TZP ceramic using MPS or MPS/4-META silanes. AB - For cementation of yttrium-stabilized tetragonal zirconium polycrystal (Y-TZP) ceramic frameworks, protocols of surface-conditioning methods and available cements vary, resulting in confusion among clinicians regarding selection and effects of different conditioning methods on cement adhesion. This study evaluated the effect of two silanes (3-trimethoxysilylpropylmethacrylate (MPS) and 3-trimethoxysilylpropylmethacrylate/4-methacryloyloxyethyl trimellitate anhydride methyl methacrylate (MPS/4-META) on the adhesion of two resin-based cements (SuperBond and Panavia F 2.0) to Y-TZP ceramic and compared several protocols with those indicated by the manufacturer of each of these cements. Disks of Y-TZP ceramic (LAVA, 3M ESPE) (n = 60) were divided into six experimental groups (n = 10 per group) and treated as follows: (1) silica coating (SC) + MPS silane + SuperBond; (2) SC + MPS/4-META + silane + SuperBond); (3) SC + MPS silane + Panavia F 2.0); (4) SC + MPS/4-META silane + Panavia F 2.0); (5) no conditioning + MPS/4-META silane + Super-Bond (SuperBond instructions); and (6) 50-MUm Al(2)O(3) conditioning + Panavia F 2.0 (Panavia F 2.0 instructions). The specimens were subjected to shear-bond testing after water storage at 37 degrees C for 3 months in the dark. Data were analyzed by analysis of variance and Tukey's HSD (alpha = 0.05). After silica coating, the mean bond strength of SuperBond cement was not significantly different between MPS and MPS/4-META silanes (20.2 +/- 3.7 and 20.9 +/- 1.6 MPa, respectively), but the mean bond strength of Panavia F 2.0 was significantly higher with MPS silane (24.4 +/- 5.3 MPa) than with MPS/4-META (12.3 +/- 1.4 MPa) (P < 0.001). The SuperBond manufacturer's instructions alone resulted in significantly higher bond strength (9.7 +/- 3.1 MPa) than the Panavia F 2.0 manufacturer's instruction (0 MPa) (P < 0.001). When silica coating and silanization were used, both SuperBond and Panavia F 2.0 cements demonstrated higher bond strengths they did when the manufacturers' instructions were followed. With SuperBond, use of MPS or MPS/4 META silane resulted in no significant difference when the ceramic surface was silica coated, but with Panavia F 2.0, use of MPS silane resulted in a significantly higher bond strength than use of MPS/4-META. Use of chairside silica coating and silanization to condition the zirconia surface improved adhesion compared with the manufacturers' cementation protocols for SuperBond and Panavia F 2.0 resin cements. PMID- 21271329 TI - Effects of outdoor weathering on facial prosthetic elastomers. AB - Physical weathering is usually responsible for the degradation of maxillofacial prosthetic elastomers and the replacement of prostheses. The purpose of this study was to investigate the effects of outdoor weathering on the physical properties of four nonpigmented facial prosthetics after 1 year of exposure. In addition, simple mathematical models were developed to correlate the measured properties with irradiation time, including parameters with physical meaning. Three different medical-grade polydimethyl siloxanes (PDMSs) and an experimental chlorinated polyethylene (CPE) were examined in this study. The samples were exposed to solar radiation for 1 year in Athens, Greece. Mechanical tests (compression and tensile) were performed using universal-type testing machine, and hardness measurements were performed with a durometer (Shore A). Thermal tests were also performed with a differential scanning calorimeter. Simple mathematical models were developed to describe the examined properties. Changes observed in the properties of examined materials, before and after the exposure, reflected the effect of weathering. More specifically, two of the silicone prosthetics (Elastomer 42, TechSIL 25) seemed to become harder and more brittle, different from the other silicone (M511) sample and the CPE sample, which became softer and more ductile. Moreover mathematical models correlate the measured properties with irradiation time, and their constants indicate that duration of exposure seems to increase the degradation. Significant changes in the mechanical and thermal properties of the examined materials were observed as a result of outdoor weathering. The effect of weathering on samples' properties was introduced through its effect on the mathematical models' parameters. PMID- 21271330 TI - The effect of disinfecting solutions on bending properties and weight changes of Co-Cr and Ti-6Al-7Nb alloys for dentures. AB - We aimed to evaluate the effect of a denture cleanser and NaOCl 5.25% solution on the modulus of elasticity, the ultimate stress, and the weight changes of Co-Cr and Ti-6Al-7Nb alloys. To evaluate the modulus of elasticity and ultimate stress, 24 Co-Cr and 24 Ti-6Al-7Nb castings were fabricated, immersed in Corega Extradent, NaOCl 5.25%, or water in subgroups of six each. Thirty-six castings were produced to evaluate weight changes, 18 Co-Cr and 18 Ti-6Al-7Nb, and immersed in Corega Extradent, NaOCl 5.25%, or water in subgroups of six each. Changes in the modulus of elasticity, ultimate stress, and weight were calculated before and after immersion in the cleanser or NaOCl 5.25% solution for 45 cycles of 10 min each. Two-way analysis of variance ANOVA and Tukey's test at alpha = 0.05 were used to analyze the data. The modulus of elasticity and the ultimate stress of Co-Cr decreased after immersion in the solutions. The same properties of Ti-6Al-7Nb decreased in NaOCl 5.25% and increased in the other solutions. Weight loss was observed in Co-Cr alloy in both Corega Extradent and NaOCl 5.25%. A weight increase was observed in Co-Cr in water. An increase was observed in Ti 6Al-7Nb in Corega Extradent, NaOCl 5.25%, and water. The highest decrease (P = 0.05) in the modulus of elasticity and ultimate stress in Co-Cr were observed in NaOCl 5.25%, whereas no statistically significant differences (P > 0.05) were observed in Ti-6Al-7Nb in any of the solutions. A statistically significant weight loss (P < 0.05) was observed when Co-Cr was immersed in NaOCl 5.25%, and a statistically significant weight increase (P > 0.05) was observed when Ti-6Al-7Nb was immersed in Corega Extradent. The Co-Cr alloy bending properties after immersion fulfilled ADA Specification No. 14 for satisfactory clinical performance. PMID- 21271331 TI - Effects of tooth bleaching on shear bond strength of brackets rebonded with a self-etching adhesive system. AB - The purpose of this study was to ascertain the effects of tooth bleaching on the shear bond strength of orthodontic brackets rebonded with a self-etching adhesive system. A total of 39 premolars were collected and divided into three equal groups: in group 1 bracket bonding was performed without bleaching treatment; specimens in group 2 were bonded immediately after bleaching; and group 3 teeth were bleached, then immersed in artificial saliva and left for 7 days before bonding. The shear bond strength was measured, with the bonding/debonding procedures repeated once after the first debonding, and the bracket/adhesive failure modes were evaluated by the adhesive remnant index after each debonding. Excepting the mean shear bond strength for group 2 after the first debonding, the overall mean values reached the minimum clinical requirement of 6 MPa. The mean values at the first and second debondings were significantly higher in groups 1 and 3 than in group 2. Between groups 1 and 3, significant differences were noted at the first debonding, but not at the second debonding. Group 2 showed significant differences in mean shear bond strength between the first and second debondings. Bond failure at the enamel-adhesive interface occurred more frequently in group 2 than in groups 1 or 3 after the first debonding. The bracket-rebonding procedure can recover the reduced shear bond strength caused by immediate bonding after bleaching to a clinically acceptable level, but not to the prebleaching level. PMID- 21271332 TI - The perception of pain following interdental microimplant treatment for skeletal anchorage: a retrospective study. AB - During orthodontic therapy, patients frequently complain about pain and discomfort, especially during insertion of fixed appliances. Skeletal anchorage using an interdental microimplant is a new concept in orthodontic treatment. The purpose of this study was to investigate differences and changes in the level of pain among patients in relation to orthodontic microimplant treatments. Forty microimplants were applied to the maxilla as skeletal anchors in the orthodontic treatment. The visual analog scale (VAS) was used to evaluate the patients' perception of pain during this new modality treatment. The premolar extraction VAS core was used as a baseline for the complete orthodontic procedure. The mean VAS score was 35.8 mm at 24 h after premolar extraction. The mean VAS score for insertion and removal of the microimplant 24 h after the operation was 12.3 and 7.8 mm, respectively. Three months after removal of the skeletal anchors, the VAS score had decreased to 3.2 mm and was the same as with the traditional orthodontic treatment. By using the repeated-measure general linear model (GLM), we found that the score 1 day after microimplant placement was significantly less than that 1 day after first premolar extraction or that 1 day after fixed appliance insertion. This result indicates that interdental microimplant did not generate any greater pain than other orthodontic procedures. Therefore, patients were willing to adopt the new orthodontic treatment. PMID- 21271333 TI - Diagnostic implications of oral intravascular papillary endothelial hyperplasia. AB - This study examined the clinical, histological, and immunohistochemical features as well as the differential diagnoses of oral intravascular papillary endothelial hyperplasia (IPEH) to aid clinicians and pathologists in its diagnosis. Clinical features of five oral IPEH cases were obtained from medical records, and all histopathological diagnoses were reviewed. Immunohistochemical reactions, including anti-CD-34, laminin, vimentin, estrogen receptor alpha, and Ki-67, were assessed. Microscopically, a reactive proliferation of vascular cells composed of small papillary structures with hypocellular and hyalinized cores arising in an organized thrombus was seen. CD-34, vimentin, and laminin staining were strongly positive, while estrogen receptor alpha was negative in all cases. A low percentage of cells were positive for Ki-67 in four of five lesions, but one case was strongly positive. A diagnosis of angiosarcoma was investigated and rejected. IPEH presents specific microscopic characteristics that along with clinical data lead to an accurate diagnosis. The general dentist, the first to participate in the diagnostic process, must share the responsibility for diagnosis with the pathologist, and they must work together to determine the correct diagnosis and management. Oral lesions of IPEH are uncommon. Their main significance is that they show a microscopic resemblance to angiosarcoma. Thus, clinicians should have more information regarding this benign entity. Finally, we suggest that in recurrent cases exhibiting strong immunolabeling of proliferative markers the possibility of angiosarcoma should be investigated. PMID- 21271334 TI - Mechanical strength of orthodontic infrazygomatic mini-implants. AB - Orthodontic anchorages have recently been reinforced by newly developed mini implants. The aim of the present study was to investigate the mechanical strengths of infrazygomatic mini-implants. We measured the insertion torque and pull-out strength of three brands of infrazygomatic mini-implants (AbsoAnchors, Bioray, and Lomas). All three mini-implants were 2 mm in diameter, and five of each brand were manually driven 6 mm into artificial bone. Significant differences among the brands were investigated with Kruskal-Wallis tests. We found no significant relationship between insertion torque and pull-out strength in any individual brand. Among the three brands of infrazygomatic mini-implants, we found no significant difference in mechanical strength. The design of an infrazygomatic mini-implant may be the most important factor determining its mechanical strength. PMID- 21271335 TI - Ring fibers visualized by electron microscopy in a Japanese patient with malignant hyperthermia. AB - This report describes an episode of malignant hyperthermia (MH) in a 53-year-old Japanese man during general anesthesia that was triggered by isoflurane and succinylcholine. His past history and family history were unremarkable. From our analysis of ten exons, he had no recognizable mutation in the ryanodine receptor gene, but compatible with his MH reaction, he showed positive sensitivity to the Ca-induced Ca-release test. Histochemical and electron microscopic studies of muscle biopsy tissue demonstrated unusual "ring fibers," which have never before been reported to be associated with MH. The presence of ring fibers in this patient might indicate muscle regeneration, suggesting a recovery process from the MH episode. PMID- 21271337 TI - Defects in beta cell Ca2+ signalling, glucose metabolism and insulin secretion in a murine model of K(ATP) channel-induced neonatal diabetes mellitus. AB - AIMS/HYPOTHESIS: Mutations that render ATP-sensitive potassium (K(ATP)) channels insensitive to ATP inhibition cause neonatal diabetes mellitus. In mice, these mutations cause insulin secretion to be lost initially and, as the disease progresses, beta cell mass and insulin content also disappear. We investigated whether defects in calcium signalling alone are sufficient to explain short-term and long-term islet dysfunction. METHODS: We examined the metabolic, electrical and insulin secretion response in islets from mice that become diabetic after induction of ATP-insensitive Kir6.2 expression. To separate direct effects of K(ATP) overactivity on beta cell function from indirect effects of prolonged hyperglycaemia, normal glycaemia was maintained by protective exogenous islet transplantation. RESULTS: In endogenous islets from protected animals, glucose dependent elevations of intracellular free-calcium activity ([Ca(2+)](i)) were severely blunted. Insulin content of these islets was normal, and sulfonylureas and KCl stimulated increased [Ca(2+)](i). In the absence of transplant protection, [Ca(2+)](i) responses were similar, but glucose metabolism and redox state were dramatically altered; sulfonylurea- and KCl-stimulated insulin secretion was also lost, because of systemic effects induced by long-term hyperglycaemia and/or hypoinsulinaemia. In both cases, [Ca(2+)](i) dynamics were synchronous across the islet. After reduction of gap-junction coupling, glucose dependent [Ca(2+)](i) and insulin secretion was partially restored, indicating that excitability of weakly expressing cells is suppressed by cells expressing mutants, via gap-junctions. CONCLUSIONS/INTERPRETATION: The primary defect in K(ATP)-induced neonatal diabetes mellitus is failure of glucose metabolism to elevate [Ca(2+)](i), which suppresses insulin secretion and mildly alters islet glucose metabolism. Loss of insulin content and mitochondrial dysfunction are secondary to the long-term hyperglycaemia and/or hypoinsulinaemia that result from the absence of glucose-dependent insulin secretion. PMID- 21271338 TI - [Diagnostics and therapy of spinal metastases]. AB - Out of all skeletal metastases 30% are located in the spine as are 10% of primary bone tumors, whereby 52% of metastases occur in the lumbar region, 36% in the thoracic spine and 12% in the cervical spine. Patients suffer from local pain caused by irritation of the periosteum due to rapid growth of the tumor or subsequent pathologic fractures which may lead to compression and neurological impairment with paresthesia, paresis and paraplegia. If the diagnosis cannot be confirmed exactly by radiological imaging and laboratory tests, a biopsy should be performed. A precise diagnosis of the tumor entity as well as an estimation of the prognosis provides an important basis for further decision-making. The aim of therapy is pain relief and stabilization by operative and non-operative measures. Therapy is palliative with the aim of pain relief and preservation of mobility. In cases of solitary metastasis a curative operative treatment should be performed. PMID- 21271339 TI - Testing and treatment for osteoporosis following hip fracture in an integrated U.S. healthcare delivery system. AB - Older veterans with acute hip fracture do not receive adequate evaluation and treatment for osteoporosis, irrespective of their age and underlying health status. INTRODUCTION: Hip fractures are a serious complication of osteoporosis, leading to high mortality and morbidity. Prior studies have found significant undertreatment of osteoporosis in women with hip fracture. We examined the rate of bone density (BMD) testing and osteoporosis treatment among a predominantly male population hospitalized with hip fractures. METHODS: We conducted a retrospective cohort study of patients age 65 years and older hospitalized in U.S. Department of Veterans Affairs (VA) hospitals with hip fracture (N = 3,347) between 1 October, 2004 and 30 September, 2006. The primary outcome was receipt of BMD testing or initiation of pharmacotherapy within 12 months of fracture. RESULTS: The mean age of the study population was 79.0 years (SD = 6.7), 96.5% were male, and 83.3% were white. Only 1.2% of hip fracture patients underwent BMD testing and 14.5% received osteoporosis therapy within 12 months of fracture. Among fracture patients with minimal comorbid illness (N = 756) only 1.6% underwent BMD testing and 13.0% received pharmacotherapy. In logistic regression models, treatment rates were higher for women compared to men (odds ratio, 3.30; 95% CI, 2.16-5.04) and lower for blacks compared to whites (odds ratio, 0.67; 95% CI, 0.45-0.99). CONCLUSIONS: Evaluation and treatment of osteoporosis among patients with fractures is suboptimal even in an integrated healthcare delivery system with generous pharmaceutical coverage. This study suggests that the undertreatment of osteoporosis demonstrated in the private sector is also present within the VA. PMID- 21271340 TI - Intra-and inter-reader reliability of semi-automated quantitative morphometry measurements and vertebral fracture assessment using lateral scout views from computed tomography. AB - Intra-and inter-reader reliability of semi-automated quantitative vertebral morphometry measurements was determined using lateral computed tomography (CT) scout views. The method requires less time than conventional morphometry. Reliability was excellent for vertebral height measurements, good for height ratios, and comparable to semi-quantitative grading by radiologists for identification of vertebral fractures. INTRODUCTION: Underdiagnosis and undertreatment of vertebral fracture (VFx) is a well-known problem worldwide. Thus, new methods are needed to facilitate identification of VFx. This study aimed to determine intra- and inter-reader reliability of semi-automated quantitative vertebral morphometry based on shape-based statistical modeling (SpineAnalyzer, Optasia Medical, Cheadle, UK). METHODS: Two non-radiologists independently assessed vertebral morphometry from CT lateral scout views at two time points in 96 subjects (50 men, 46 women, 70.3 +/- 8.9 years) selected from the Framingham Heart Study Offspring and Third Generation Multi-Detector CT Study. VFxs were classified based solely on morphometry measurements using Genant's criteria. Intraclass correlation coefficients (ICCs), root mean squared coefficient of variation (RMS CV) and kappa (k) statistics were used to assess reliability. RESULTS: We analyzed 1,246 vertebrae in 96 subjects. The analysis time averaged 5.4 +/- 1.7 min per subject (range, 3.2-9.1 min). Intra-and inter reader ICCs for vertebral heights were excellent (>0.95) for all vertebral levels combined. Intra-and inter-reader RMS CV for height measurements ranged from 2.5% to 3.9% and 3.3% to 4.4%, respectively. Reliability of vertebral height ratios was good to fair. Based on morphometry measurements alone, readers A and B identified 51-52 and 46-59 subjects with at least one prevalent VFx, respectively, and there was a good intra-and inter-reader agreement (k = 0.59 0.69) for VFx identification. CONCLUSIONS: Semi-automated quantitative vertebral morphometry measurements from CT lateral scout views are convenient and reproducible, and may facilitate assessment of VFx. PMID- 21271341 TI - Bone health in healthy Indian population aged 50 years and above. AB - One thousand six hundred healthy subjects aged more than 50 years, residing in Delhi, were evaluated for bone mineral metabolic parameters. High prevalence of osteoporosis (35.1% subjects) was observed in this population. Bone mineral density (BMD) correlated positively with body mass index (BMI) and negatively with PTH levels. No correlation was observed with serum 25(OH)D levels. INTRODUCTION: To assess the bone health status in elderly Indians and compare peripheral DXA (pDXA) with central DXA in evaluation of osteoporosis. METHODS: The study involved 1,600 healthy subjects more than 50 years of age residing in Delhi, India, who underwent anthropometric, biochemical, and hormonal evaluation. BMD was measured by DXA at lumbar spine, hip, and distal radius; and by pDXA at forearm and calcaneum. RESULTS: Seven hundred ninety-two males and 808 postmenopausal females, with a mean age of 57.67 +/- 9.46 years were evaluated. Osteoporosis was present in 35.1% subjects (M-24.6%, F-42.5%) and osteopenia in 49.5% (M-54.3%, F-44.9%). Prevalence of osteoporosis increased with age in females, but not in males. BMD at all sites, except distal radius, was positively correlated with BMI (r=0.037, p=0.14). Total body BMD was negatively correlated with alkaline phosphatase (r= -0.184, p<0.00001) and PTH levels (r= -0.099, p<0.00001), respectively. No significant correlation was observed between serum 25(OH)D levels and BMD at any site. BMD at forearm and calcaneum, measured using pDXA, showed strong positive correlation with BMD measured by central DXA. pDXA had sensitivity of 88%, specificity of 55%, and negative and positive predictive values of 89% and 52%, respectively, at T-score -2.5 at peripheral sites compared to central DXA. CONCLUSIONS: A high prevalence of osteoporosis was observed in elderly Indian subjects. pDXA has high negative predictive value, making it a useful tool in population screening for osteoporosis. PMID- 21271342 TI - Modular MR-compatible lower leg exercise device for whole-body scanners. AB - PURPOSE: To develop a modular MR-compatible lower leg exercise device for muscle testing using a clinical 3 T MR scanner. MATERIALS AND METHODS: An exercise device to provide isotonic resistance to plantar- or dorsiflexion was constructed from nonferrous materials and designed for easy setup and use in a clinical environment. Validation tests were performed during dynamic MR acquisitions. For this purpose, the device was tested on the posterior lower leg musculature of five subjects during 3 min of exercise at 30% of maximum voluntary plantarflexion during 31-phosphorus MR spectroscopy ((31)P-MRS). Measures of muscle phosphocreatine (PCr), inorganic phosphate (Pi), and pH were obtained before, during, and after the exercise protocol. RESULTS: At the end of exercise regimen, muscle PCr showed a 28% decrease from resting levels (to 21.8 +/- 3.9 from 30.4 +/- 3.0 mM) and the average PCr recovery rate was 35.3 +/- 8.3 s. Muscle Pi concentrations increased 123% (to 14.6 +/- 4.7 from 6.5 +/- 3.3 mM) and pH decreased 1.5% (to 7.06 +/- 0.14 from 7.17 +/- 0.07) from resting levels. CONCLUSION: The described MR-compatible lower leg exercise was an effective tool for data acquisition during dynamic MR acquisitions of the calf muscles. The modular design allows for adaptation to other whole-body MR scanners and incorporation of custom-built mechanical or electronic interfaces and can be used for any MR protocol requiring dynamic evaluation of calf muscles. PMID- 21271343 TI - Perspective: the ISS boldly goes. PMID- 21271344 TI - Prolonged use of thromboprophylaxis may not be necessary in laparoscopic colorectal surgery. AB - PURPOSE: Patients undergoing colorectal resections are considered high risk for developing thromboembolic disease. We postulate, however, that the rapid recovery and swift mobilization after laparoscopic resections reduce this risk and that these patients therefore do not need prolonged thromboprophylaxis. This hypothesis was tested in this paper. METHODS: All patients who underwent laparoscopic colorectal surgery in our Colorectal Surgical Unit in the period from June 1991 until January 2010 were entered into a prospective database. The entire database was reviewed, and incidence of thromboembolic disease and significant bleeding complications were noted. RESULTS: Three thousand, three hundred sixty-four patients were laparoscopically operated on for colorectal disease and were entered in the database. Two thousand, one hundred twenty-seven patients were operated on for benign disease; 1,230, for colorectal cancer, and four, for other malignancies. Two deep venous thromboses were encountered (0.059%), and ten patients had pulmonary embolism (0.30%). The combined venous thromboembolism (VTE) risk for the overall group of patients undergoing laparoscopic colorectal operations is 0.36%. The combined VTE risk was 0.57% (7/1,230) in patients with colorectal cancer and 0.24% (5/2,127) in patients with benign disease (p = 0.118). Bleeding complications occurred in 44 patients (1.3%). CONCLUSIONS: In our group, the combined VTE risk for the overall group of patients undergoing laparoscopic colorectal operations is 0.36%. Therefore, we postulate that the prolonged use of thromboprophylaxis is not indicated in the vast majority of patients undergoing laparoscopic colorectal surgery. In particular, patients undergoing laparoscopic resections for benign disease and without other risk factors have such a low VTE risk that prolonged prophylaxis is probably not warranted. PMID- 21271345 TI - Lower albumin levels in African Americans at colon cancer diagnosis: a potential explanation for outcome disparities between groups? AB - BACKGROUND AND AIM: Colorectal cancer is the third most common cancer and 3rd leading cause of cancer-related death in the USA. African Americans (AA) have inferior outcomes when matched for diagnosis stage and socioeconomic situation. Nutritional status, at diagnosis and its contribution to the observed cancer outcome disparity, between AA and non-Hispanic whites (nHw) has not been evaluated to date. The aim of the investigation was to determine if differences in nutritional surrogate markers, such as serum albumin and body mass index (BMI), exist at the time of colorectal cancer diagnosis between AA and nHw. METHODS: The University of Florida College of Medicine-Jacksonville endoscopy database was reviewed for all patients with a biopsied colorectal mass between January 2000 and December 2007. Patients were excluded if histology did not reveal colorectal adenocarcinoma or albumin/BMI was unavailable. Demographic data, tumor location, serum albumin within 60 days of diagnosis, presence of diabetes along with serum HbA1c were obtained. RESULTS: During the study period, 321 patients had colorectal masses discovered and 156 met entry criteria. There was no difference between ethnic groups regarding gender distribution, tumor location, diabetes presence, or BMI. Mean albumin was significantly less in AA compared to nHw (p < 0.01). This persisted after adjustment for gender, presence/absence of diabetes, and BMI. CONCLUSIONS: Lower albumin levels in AA indicate poorer nutritional status at colorectal cancer diagnosis compared to nHw. This may contribute to the outcome disparities observed between AA and nHw. Aggressive nutritional interventions to reverse this disparity should be evaluated. PMID- 21271346 TI - Transanal endoscopic microsurgery for rectal cancer. Long-term oncologic results. AB - PURPOSE: Local excision of malignant rectal tumors remains controversial due to the lack of prospective studies. The principal aim of this paper is to analyze survival and recurrence of patients with rectal cancer who were operated by transanal endoscopic microsurgery with curative intention. METHODS: In 1997, we started a prospective protocol for patients who had T1/T2 rectal tumors: transanal local full-thickness excision was considered curative in T1 low risk (group A); patients with T1 high-risk and T2 low-risk tumors received postoperative radiotherapy (group B). From 1997 to 2006, 88 patients were enrolled. Sixty eight entered the study after the preoperative workup and 20 patients with an initial diagnosis of adenoma after postoperative definitive pathological assessment. RESULTS: After definitive histological findings, 54 patients were to group A, 28 to group B, and 6 had immediate radical surgery. One patient was lost for follow-up. At a mean follow-up of 71 months, 7 (4 from group A and 3 from group B) out of 81 patients recurred. Five-year overall survival was of 94% and cancer-specific survival of 96%. CONCLUSIONS: Our data support that transanal endoscopic microsurgery is an adequate treatment for T1 low-risk tumor, and no additional measures are required. For T2 low-risk lesions, our study showed a higher local recurrence rate than that reported after radical surgery but a similar survival outcome. PMID- 21271347 TI - A pilot phase II trial of magnesium supplements to reduce menopausal hot flashes in breast cancer patients. AB - BACKGROUND: We tested if magnesium would diminish bothersome hot flashes in breast cancer patients. METHODS: Breast cancer patients with at least 14 hot flashes a week received magnesium oxide 400 mg for 4 weeks, escalating to 800 mg if needed. Hot flash score (frequency * severity) at baseline was compared to the end of treatment. RESULTS: Of 29 who enrolled, 25 women completed treatment. The average age was 53.5 years; six African American, the rest Caucasian; eight were on tamoxifen, nine were on aromatase inhibitors, and 14 were on anti-depressants. Seventeen patients escalated the magnesium dose. Hot flash frequency/week was reduced from 52.2 (standard error (SE), 13.7) to 27.7 (SE, 5.7), a 41.4% reduction, p = 0.02, two-sided paired t test. Hot flash score was reduced from 109.8 (SE, 40.9) to 47.8 (SE, 13.8), a 50.4% reduction, p = 0.04. Of 25 patients, 14 (56%) had a >50% reduction in hot flash score, and 19 (76%) had a >25% reduction. Fatigue, sweating, and distress were all significantly reduced. Side effects were minor: two women stopped the drug including one each with headache and nausea, and two women had grade 1 diarrhea. Compliance was excellent, and many patients continued treatment after the trial. CONCLUSIONS: Oral magnesium appears to have helped more than half of the patients and was well tolerated. Side effects and cost ($0.02/tablet) were minimal. A randomized placebo controlled trial is planned. PMID- 21271348 TI - A three-dimensional comparison of a morphometric and conventional cephalometric midsagittal planes for craniofacial asymmetry. AB - Morphometric methods are used in biology to study object symmetry in living organisms and to determine the true plane of symmetry. The aim of this study was to determine if there are clinical differences between three-dimensional (3D) cephalometric midsagittal planes used to describe craniofacial asymmetry and a true symmetry plane derived from a morphometric method based on visible facial features. The sample consisted of 14 dry skulls (9 symmetric and 5 asymmetric) with metallic markers which were imaged with cone-beam computed tomography. An error study and statistical analysis were performed to validate the morphometric method. The morphometric and conventional cephalometric planes were constructed and compared. The 3D cephalometric planes constructed as perpendiculars to the Frankfort horizontal plane resembled the morphometric plane the most in both the symmetric and asymmetric groups with mean differences of less than 1.00 mm for most variables. However, the standard deviations were often large and clinically significant for these variables. There were clinically relevant differences (>1.00 mm) between the different 3D cephalometric midsagittal planes and the true plane of symmetry determined by the visible facial features. The difference between 3D cephalometric midsagittal planes and the true plane of symmetry determined by the visible facial features were clinically relevant. Care has to be taken using cephalometric midsagittal planes for diagnosis and treatment planning of craniofacial asymmetry as they might differ from the true plane of symmetry as determined by morphometrics. PMID- 21271349 TI - Long-term effects of tongue piercing--a case control study. AB - The aim of this study was to evaluate tooth and periodontal damage in subjects wearing a tongue piercing (TP) in comparison to matched control subjects without tongue piercing. Members of the German Federal Armed Forces who had TP (group TP) and a matched control group (group C) volunteered to take part in the study. The time in situ, localization and material of TP were documented. Dental examinations included DMF-T, oral hygiene, enamel fissures (EF), enamel cracks (EC) and recessions. Statistical analysis was determined by chi (2) test and the t test. Both groups had 46 male subjects (mean age 22.1 years). The piercings had been in situ for 3.8 +/- 3.1 years. Subjects in the TP group had a total of 1,260 teeth. Twenty-nine subjects had 115 teeth (9.1%) with EF (67% lingual). In group C (1,243 teeth), 30 subjects had 60 teeth with EF (4.8%, 78% vestibular) (p < 0.01). Thirty-eight subjects belonging to group TP had EC in 186 teeth (15%). In group C, 26 subjects with 56 teeth (4.5%) were affected by EC (p < 0.001). Twenty seven subjects in group TP had 97 teeth (7.7%) with recessions. Lingual surfaces of anterior teeth in the lower jaw were affected most frequently (74%). In group C, 8 subjects had 19 teeth (1.5%) with recessions (65% vestibular). Differences between the two groups were statistically significant (p < 0.001). Tongue piercing is correlated with an increased occurrence of enamel fissures, enamel cracks and lingual recessions. Patients need better information on the potential complications associated with tongue piercing. PMID- 21271350 TI - Perforated left-sided diverticulitis with faecal peritonitis: is the Hinchey classification the best guide for surgical decision making? AB - BACKGROUND: Although the Hinchey scoring system has guided surgical decision making for perforated diverticulitis, what constitutes optimal surgical management is controversial. We report our experience of selective primary closure of the perforation without use of a transverse colostomy and the specific circumstances in which this may be safe. METHODS: All cases of perforated diverticular disease of the sigmoid colon with Hinchey grade IV (faecal) peritonitis seen over a 4-year period from one surgical unit were reviewed. RESULTS: Primary closure without a diverting stoma was performed in six of the eight patients studied since the bowel was deemed healthy, and resection and primary end-to-end anastomosis were performed in the other two patients because there was associated scarring and stricture formation distally. In the primary closure patients, the site of the perforation was dissected and closed with attendant omentoplasty and a meticulous peritoneal toilet. In one of these cases, a diverting stoma was later fashioned after the patient developed a short-lived faecal fistula. CONCLUSION: The status of the underlying bowel, not the degree of peritoneal soiling, is the most significant consideration in defining the role of minimally invasive surgical treatment options for perforated diverticulitis. A new classification system that remains to be validated, taking into account the degree of colonic scarring and stricture formation, is proposed as a guide for surgical decision making in patients with perforated left-sided diverticulitis with faecal peritonitis. PMID- 21271351 TI - Tumor microenvironment is multifaceted. AB - Cancer initiation, progression, and invasion occur in a complex and dynamic microenvironment which depends on the hosts and sites where tumors develop. Tumors arising in mucosal tissues may progress in an inflammatory context linked to local viral and/or bacterial infections. At the opposite, tumors developing in immunoprivileged sites are protected from microorganisms and grow in an immunosuppressive environment. In the present review, we summarize and present our recent data on the influence of infectious context and immune cell infiltration organization in human Non-Small Cell Lung Cancers (NSCLC) progression. We show that stimulation of tumor cells by TLR for viral ssRNA, such as TLR7/8, or bacteria, such as TLR4, promotes cell survival and induces chemoresistance. On the opposite, stimulation by TLR3, receptor for double stranded viral RNA, decreases tumor cell viability and induces chemosensitivity in some lung tumor cell lines. Since fresh lung tumor cells exhibit a gene expression profile characteristic of TLR-stimulated lung tumor cell lines, we suspect that viral and bacterial influence may not only act on the host immune system but also directly on tumor growth and sensitivity to chemotherapy. The stroma of NSCLC contains tertiary lymphoid structures (or Tumor-induced Bronchus Associated Lymphoid Tissues (Ti-BALT)) with mature DC, follicular DC, and T and B cells. Two subsets of immature DC, Langerhans cells (LC) and interstitial DC (intDC), were detected in the tumor nests and the stroma, respectively. Here, we show that the densities of the three DC subsets, mature DC, LC, and intDC, are highly predictive of disease-specific survival in a series of 74 early-stage NSCLC patients. We hypothesize that the mature DC may derive from local activation and migration of the immature DC--and especially LC which contact the tumor cells--to the tertiary lymphoid structures, after sampling and processing of the tumor antigens. In view of the prominent role of DC in the immune response, we suggest that the microenvironment of early-stage NSCLC may allow the in situ activation of the adaptive response. Finally, we find that the eyes or brain of mice with growing B cell lymphoma are infiltrated with T cells and that the cytokines produced ex vivo by the tumoral tissues have an impaired Th1 cytokine profile. Our work illustrates that the host and external tumor microenvironments are multifaceted and strongly influence tumor progression and anti-tumor immune responses. PMID- 21271352 TI - Immunomodulating antibodies and drugs for the treatment of hematological malignancies. AB - The aim of cancer immunotherapy is to induce immune cells to kill tumor and promote immunological memory that protects against tumor recurrence. Most current immunotherapies, such as monoclonal antibodies (mAb), target the tumor cells directly. Advances in our understanding of the immune system such as the role of co-stimulatory and co-inhibitory receptors, and the advent of new immunomodulatory agents provide new opportunities to target the immune system and enhance anti-tumor immune responses. These promising agents include immunomodulating mAbs, Toll-like receptor agonists, IMiDs, and cytokines. In this review, we discuss the current results of immunomodulating agents in the treatment of hematological malignancies and propose applications that include targeting of the innate and adaptive immune systems as well as combinations with tumor-specific mAbs. PMID- 21271353 TI - Automated diagnosis of diabetes using heart rate variability signals. AB - An automated diagnostic system for diabetes mellitus (DM), from heart rate variability (HRV) measures, using feed forward neural network has been developed. Changes in autonomic nervous system activity caused by DM are quantified by means of time domain and frequency domain analysis of HRV. Electrocardiograms of 70 DM patients and 65 healthy volunteers were recorded. Nine time domain measures standard deviation of all NN intervals, square root of mean of sum of squares of differences between adjacent NN interval (RMSSD), number of adjacent NN intervals differing more than 50 ms. (NN50 count), percentage of NN50 count, R-R triangular index, triangular interpolation of NN intervals (TINN), standard deviation of the mean heart rate, mean R-R interval and mean heart rate-were used as the input features to the neural network. This diagnostic system classifies DM patients and normal volunteers from morphologically identical ECGs. Diagnostic results show that the system is performing well with an accuracy of 93.08%, specificity of 96.92% and sensitivity of 89.23%. PMID- 21271354 TI - In vivo conditions influence the coding of stimulus features by bursts of action potentials. AB - The functional role of burst firing (i.e. the firing of packets of action potentials followed by quiescence) in sensory processing is still under debate. Should bursts be considered as unitary events that signal the presence of a particular feature in the sensory environment or is information about stimulus attributes contained within their temporal structure? We compared the coding of stimulus attributes by bursts in vivo and in vitro of electrosensory pyramidal neurons in weakly electric fish by computing correlations between burst and stimulus attributes. Our results show that, while these correlations were strong in magnitude and significant in vitro, they were actually much weaker in magnitude if at all significant in vivo. We used a mathematical model of pyramidal neuron activity in vivo and showed that such a model could reproduce the correlations seen in vitro, thereby suggesting that differences in burst coding were not due to differences in bursting seen in vivo and in vitro. We next tested whether variability in the baseline (i.e. without stimulation) activity of ELL pyramidal neurons could account for these differences. To do so, we injected noise into our model whose intensity was calibrated to mimic baseline activity variability as quantified by the coefficient of variation. We found that this noise caused significant decreases in the magnitude of correlations between burst and stimulus attributes and could account for differences between in vitro and in vivo conditions. We then tested this prediction experimentally by directly injecting noise in vitro through the recording electrode. Our results show that this caused a lowering in magnitude of the correlations between burst and stimulus attributes in vitro and gave rise to values that were quantitatively similar to those seen under in vivo conditions. While it is expected that noise in the form of baseline activity variability will lower correlations between burst and stimulus attributes, our results show that such variability can account for differences seen in vivo. Thus, the high variability seen under in vivo conditions has profound consequences on the coding of information by bursts in ELL pyramidal neurons. In particular, our results support the viewpoint that bursts serve as a detector of particular stimulus features but do not carry detailed information about such features in their structure. PMID- 21271355 TI - Fluorescence immunoassay using an optical fiber for determination of Dermatophagoides farinae (Der f1). AB - Immunoassay methods are generally used for measuring of allergenic substances. However, they need special facilities, skilled handling, and time-consuming procedure. In this work, a fiber-optic immunoassay system which could measure allergen by fluorescent intensities of immune complexes formed by allergens and fluorescently labeled antibodies was established. Immune complexes absorbed on the optical fiber probe surface, and excitation light was injected into the probe, then evanescent field is created in the proximity of the probe. The fluorophores were excited by the evanescent light, and fluorescence was detected by a photo diode. The target allergen detected by our system was Der f1 derived from Dermatophagoides farinae that is one of the house dust mite and major source of inhaled allergens. The fluorophore used labeling on detecting antibody was cyanine 5. The system enabled to detect and quantitatively determine of Der f1. The measurement range was from 0.24 to 250 ng/ml, and the result competes with ELISA. The measurement time was 16 min/sample. The immunoassay system was applied to measurement of Der f1 from actual dust samples. Calculated values of Der f1 showed good correlations between the fiber-optic fluoroimmunoassay and ELISA. PMID- 21271356 TI - Effects of HealthWise South Africa on condom use self-efficacy. AB - The present study examines the impact of the HealthWise South Africa prevention intervention on condom use self-efficacy. Students from the Cape Town area were assessed at the beginning and end of each school year, beginning in the 8th grade and ending in the 11th. The intervention was delivered in 12 lessons during the 8th grade and 6 lessons during the 9th grade. Using three-level multiphase mixed effects models, we found that HealthWise had a statistically significant positive effect on condom use self-efficacy, although effects differed for boys and girls. HealthWise had an effect during the first phase of the intervention (8th grade) for girls and during the second phase (9th grade) for boys. We speculate that the gender differences occur because the 8th grade lessons of the intervention taught skills such as discussion, decision making, and negotiation, which may be more salient to girls, and a 9th grade lesson explicitly focused on condom use within the context of sexual relationships, which may have been more salient to boys. PMID- 21271357 TI - Assessing media campaigns linking marijuana non-use with autonomy and aspirations: "Be Under Your Own Influence" and ONDCP's "Above the Influence". AB - Two media-based interventions designed to reduce adolescent marijuana use ran concurrently from 2005 to 2009. Both interventions used similar message strategies, emphasizing marijuana's inconsistency with personal aspirations and autonomy. "Be Under Your Own Influence" was a randomized community and school trial replicating and extending a successful earlier intervention of the same name (Slater et al. Health Education Research 21:157-167, 2006). "Above the Influence" is a continuing national television, radio, and print campaign sponsored by the Office of National Drug Control Policy (ONDCP). This study assessed the simultaneous impact of the interventions in the 20 U.S. communities. Results indicate that earlier effects of the "Be Under Your Own Influence" intervention replicated only in part and that the most plausible explanation of the weaker effects is high exposure to the similar but more extensive ONDCP "Above the Influence" national campaign. Self-reported exposure to the ONDCP campaign predicted reduced marijuana use, and analyses partially support indirect effects of the two campaigns via aspirations and autonomy. PMID- 21271358 TI - Long target droplet polymerase chain reaction with a microfluidic device for high throughput detection of pathogenic bacteria at clinical sensitivity. AB - In this article we present a long target droplet polymerase chain reaction (PCR) microsystem for the amplification of the 16S ribosomal RNA gene. It is used for detecting Gram-positive and Gram-negative pathogens at high-throughput and is optimised for downstream species identification. The miniaturised device consists of three heating plates for denaturation, annealing and extension arranged to form a triangular prism. Around this prism a fluoropolymeric tubing is coiled, which represents the reactor. The source DNA was thermally isolated from bacterial cells without any purification, which proved the robustness of the system. Long target sequences up to 1.3 kbp from Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa have successfully been amplified, which is crucial for the successive species classification with DNA microarrays at high accuracy. In addition to the kilobase amplicon, detection limits down to DNA concentrations equivalent to 10(2) bacterial cells per reaction were achieved, which qualifies the microfluidic device for clinical applications. PCR efficiency could be increased up to 2-fold and the total processing time was accelerated 3-fold in comparison to a conventional thermocycler. Besides this speed-up, the device operates in continuous mode with consecutive droplets, offering a maximal throughput of 80 samples per hour in a single reactor. Therefore we have overcome the trade-off between target length, sensitivity and throughput, existing in present literature. This qualifies the device for the application in species identification by PCR and microarray technology with high sample numbers. Moreover early diagnosis of infectious diseases can be implemented, allowing immediate species specific antibiotic treatment. Finally this can improve patient convalescence significantly. PMID- 21271359 TI - Racism, health status, and birth outcomes: results of a participatory community based intervention and health survey. AB - Many community-based participatory research (CBPR) partnerships address social determinants of health as a central consideration. However, research studies that explicitly address racism are scarce in the CBPR literature, and there is a dearth of available community-generated data to empirically examine how racism influences health disparities at the local level. In this paper, we provide results of a cross-sectional, population-based health survey conducted in the urban areas of Genesee and Saginaw Counties in Michigan to assess how a sustained community intervention to reduce racism and infant mortality influenced knowledge, beliefs, and experiences of racism and to explore how perceived racism is associated with self-rated health and birth outcomes. We used ANOVA and regression models to compare the responses of intervention participants and non participants as well as African Americans and European Americans (N = 629). We found that intervention participants reported greater acknowledgment of the enduring and differential impact of racism in comparison to the non-intervention participants. Moreover, survey analyses revealed that racism was associated with health in the following ways: (1) experiences of racial discrimination predicted self-rated physical health, mental health, and smoking status; (2) perceived racism against one's racial group predicted lower self-rated physical health; and (3) emotional responses to racism-related experiences were marginally associated with lower birth-weight births in the study sample. Our study bolsters the published findings on perceived racism and health outcomes and highlights the usefulness of CBPR and community surveys to empirically investigate racism as a social determinant of health. PMID- 21271360 TI - Hand-sewn versus stapled oesophago-gastric anastomosis: systematic review and meta-analysis. AB - OBJECTIVE: In this meta-analysis, data from relevant randomised controlled trials has been pooled together to gain a consensus in the comparison of outcome following hand-sewn versus stapled oesophago-gastric (OG) anastomoses. METHODS: Medline, Embase, Cochrane, trial registries, conference proceedings and reference lists were searched for randomised controlled trials comparing hand-sewn and stapled OG anastomoses. Primary outcome measures were 30-day mortality, anastomotic leakage and stricture. Secondary outcomes were operative time, cardiac complications and pulmonary complications. RESULTS: Nine randomised trials were included in this meta-analysis. There was no significant difference between the groups for 30-day mortality (pooled odds ratio = 1.71; 95% CI = 0.822 to 3.56; P = 0.15) and anastomotic leakage (pooled odds ratio = 1.06; 95% CI = 0.62 to 1.80; P = 0.83). There was a significantly increased rate of anastomotic stricture associated with stapled OG anastomosis (pooled odds ratio = 1.76; 95% CI = 1.09 to 2.86; P = 0.02). DISCUSSION: Meta-analysis of randomised controlled trials comparing hand-sewn with stapled OG anastomosis demonstrates that a stapled anastomosis is associated with a shorter operative time but with an increased rate of post-operative anastomotic stricture. PMID- 21271361 TI - Diadem X: automated 4 dimensional analysis of morphological data. PMID- 21271362 TI - Stress and its role in sympathetic nervous system activation in hypertension and the metabolic syndrome. AB - Stress in several guises is evident in individuals with hypertension and in those with the metabolic syndrome and may account, at least in part, for the extent and pattern of sympathetic nervous activation. Importantly, elevated activity of the sympathetic nervous system is related to the development of obesity-related illnesses including hypertension, insulin resistance, and renal, cardiac, and vascular impairment. Notably, evidence of subclinical organ damage is evident even in young, normotensive, overweight persons, thereby reinforcing the need to develop and implement effective early intervention. PMID- 21271363 TI - Biomarkers in renal cell carcinoma: what next? PMID- 21271364 TI - Cholangiocarcinoma: epidemiology, risk factors, pathogenesis, and diagnosis. AB - Cholangiocarcinoma (CCA) is a rare tumor arising from the epithelium of the intrahepatic or the extrahepatic bile ducts. It is rarely diagnosed before 40 years of age except in patients with primary sclerosing cholangitis. CCA is usually clinically silent until the tumor obstructs the bile ducts. Carbohydrate antigen 19-9 is the most commonly used tumor marker, and magnetic resonance cholangiopancreatography is the best available imaging modality for CCA. Endoscopic retrograde cholangiopancreatography and cholangioscopy allow tissue acquisition. Positron emission tomography may play a role in identifying occult metastases. Tissue diagnosis is obtained by brush cytology or bile duct biopsy. PMID- 21271365 TI - A randomized controlled trial of a tailored interactive computer-delivered intervention to promote colorectal cancer screening: sometimes more is just the same. AB - BACKGROUND: There have been few studies of tailored interventions to promote colorectal cancer (CRC) screening. PURPOSE: We conducted a randomized trial of a tailored, interactive intervention to increase CRC screening. METHODS: Patients 50-70 years completed a baseline survey, were randomized to one of three groups, and attended a wellness exam after being exposed to a tailored intervention about CRC screening (tailored group), a public web site about CRC screening (web site group), or no intervention (survey-only group). The primary outcome was completion of any recommended CRC screening by 6 months. RESULTS: There was no statistically significant difference in screening by 6 months: 30%, 31%, and 28% of the survey-only, web site, and tailored groups were screened. Exposure to the tailored intervention was associated with increased knowledge and CRC screening self-efficacy at 2 weeks and 6 months. Family history, prior screening, stage of change, and physician recommendation moderated the intervention effects. CONCLUSIONS: A tailored intervention was not more effective at increasing screening than a public web site or only being surveyed. PMID- 21271368 TI - A note on partial report superiority. PMID- 21271369 TI - [Chinese standard for the diagnosis and treatment of colorectal cancer (2010)]. AB - To augment the levels of diagnosis and treatment for colorectal cancer and make them standardization in China, the Ministry of Health of the People's Republic of China released Chinese Standard for The Management of Colorectal Cancer (2010) in November 4, 2010. This standard incorporates the most recent progresses in colorectal cancer, and it provides standard guidelines with respect to diagnosis, pathologic examination, surgery, adjuvant therapy in the management of colorectal cancer in China. PMID- 21271370 TI - [Scientific research is the driving force for the advancement in surgery]. AB - The rapid progress in surgery in China has been closely related to government investment in public health care, construction of medical talents team, and basic and clinical research. The achievements of bench studies promote the development of clinical surgery. Translational medicine (bench-bedside-bench) has gained much attention in the medical community. The driving force promoting long-term development of surgery in China includes collaboration of basic scientists and surgeons, cultivation of surgeons with aptitude in scientific research, initiation of clinical research and popularization of multidisciplinary team. PMID- 21271371 TI - [Multidisciplinary therapy for gastric cancer]. AB - Accurate preoperative staging is imperative in the treatment of gastric cancer since diseases in different stages mandate different management strategies. Multi disciplinary therapy is important for gastric cancer. Endoscopic treatment has become the preferred treatment for patients with early gastric cancer. However, only when multiple disciplines is involved in the decision-making process, appropriate patients can be selected and benefit from the minimally invasive treatment. In China, 90% of gastric cancers are at advanced stage at diagnosis, which are associated with worse prognosis compared to early gastric cancer. The optimal treatment depends on the multi-disciplinary therapy including surgery, chemotherapy, radiotherapy, and molecular targeted therapy. PMID- 21271372 TI - ["Damage control surgery" concept in gastrointestinal surgery]. AB - In recent years, damage control is well established as a potentially life-saving procedure in a few selected critically injured patients. The "damage control" concept also has been shown to increase overall survival and is likely to modify the management of critically ill patients suffering from gastrointestinal disease. In these patients the "lethal triad" of hypothermia, acidosis, and coagulopathy acts as a vicious cycle that often can not be interrupted and marks the limit of the patient's ability to cope with the physiological consequences of traditional and extensive surgical procedures. The principles of damage control are to control bleeding, obstruction, and/or infection until the physiologic derangement has been restored and the patient could undergo a prolonged operation for definitive repair. This approach is unfolded in three phases. During the initial operation, the surgeon carries out only the absolute minimum necessary to improve patient's condition and to control bleeding, obstruction, and/or infection. The second phase consists of secondary resuscitation in the intensive care unit, characterized by maximization of hemodynamics, correction of coagulopathy, rewarming, and complete ventilatory support. During the third phase, definitive operation is performed. PMID- 21271373 TI - [Necessity and feasibility of screening for colorectal cancer in China]. AB - Incidence and mortality of colorectal cancer has increased significantly in recent years. Screening for colorectal cancer is the most effective method to decrease mortality. Colorectal adenoma is the precancerous lesion of colorectal cancer and can be detected through colonoscopy, which is the crucial in the early diagnosis and early treatment for colorectal cancer. The first step of screening is the selection of target population and the second step is colorectal examination. The selection of candidate for screening has direct effect on the efficacy of screening. The methods in common use include fecal occult blood test, questionnaire for high risk factors of colorectal cancer, colonoscopy, sigmoidoscopy, and CT virtual colonoscopy. Among those, colonoscopy is the most reliable method and widely used in the screening for colorectal cancer. PMID- 21271374 TI - [Laparoscopic-assisted anterior perineal plane for ultra-low anterior resection of the rectal cancer(APPEAR)]. AB - OBJECTIVE: To report a case of APPEAR performed using a laparoscopic-assisted approach. METHODS: A laparoscopic-assisted APPEAR was performed with end-to-end anastomosis on October 12, 2010 for a patient with low rectal cancer who received neoadjuvant chemoradiation. After total mesorectal excision was completed laparoscopically, a crescent-shape incision was then made in the middle perineum. The distal part of the rectum was dissected with electrocautery. An double stapling end-to-end anastomosis was performed after transaction of the rectum. RESULTS: Total operative time was 195 minutes. The perineal approach cost 30 minutes. The estimated blood loss was 50 ml. First stoma output with flatus was on postoperative day 3, and the patient resumed liquid diet. The patient was discharged on postoperative day 7. There were no complications including pelvic sepsis, perineal infection, or anastomotic leak. CONCLUSION: The APPEAR procedure can be performed safely with the abdominal approach completed laparoscopically. PMID- 21271375 TI - [Pilot study on MRI of human colon adenocarcinoma cells labeled with superparamagnetic iron oxide in vitro]. AB - OBJECTIVE: To study the feasibility of MRI of human colon adenocarcinoma cell line (Lovo) labeled with superparamagnetic iron oxide(SPIO) nanoparticles in vitro. METHODS: Lovo cells (5 * 10(5) and 1 * 10(6)) were cultured in medium containing different SPIO nanoparticles (50 microl and 500 microl). Transmission electron microscopy was used to observe cellular ultrastructure and to determine the uptake and distribution of particles in Lovo cells at 1-, 3-, 6-hours. MRI of Lovo cells was performed with T1WI, T2WI sequences. Unlabeled cells were used as controls. RESULTS: Uptake of SPIO nanoparticles occurred within 6 hours. On T1 weighted imaging, there was no significant difference in signal intensity between the experimental groups and the control group. On T2 weighted imaging, there was no significant difference in signal intensity between the experimental groups and the control group after culture of 1 h. Signal intensity began to decrease in 1 * 10(6) Lovo cells labeled with 500 microl SPIO nanoparticle after 3 hours culture. Signal intensity decreased in all the experimental groups after 6 hours culture. CONCLUSION: Human colon adenocarcinoma cell line (Lovo) can be labeled with SPIO nanoparticles, and the labeled cells can be imaged with MRI equipment. PMID- 21271376 TI - [Clinical significance of multi-slice spiral CT angiography in radical resection of gastric cancer]. AB - OBJECTIVES: To explore the clinical significance of preoperative abdominal multi slice spiral CT angiography (MSCTA) in radical resection of gastric cancer. METHODS: One hundred and three patients with gastric cancer were divided into two groups according to their desires. Group I( included 57 patients who underwent preoperative MSCTA and group II( included 46 patients who underwent surgery without preoperative MSCTA. All these patients were operated by the same surgical team. RESULTS: Six patients(10.5%) with abnormal gastric artery in group I( were discovered. The diagnostic concordance rate between MSCTA and intraoperative findings was 100% in group I( in the locations and alignments of main perigastric vessels and their relationship with cancer lesions. Operative time in group I( was shorter than that in group II( [(206 +/- 23) min vs. (257 +/- 32) min, P=0.044]. Operative time [(190 +/- 50) min] of patients with abnormal gastric artery of group I( was shorter than that [(255 +/- 62) min] of patients with abnormal gastric artery discovered during operation of group II( (P=0.048). However there were no differences in blood loss, extent of lymph node dissection, complication rate, length of hospital stay, and hospitalization cost between the two groups(P>0.05). CONCLUSION: Preoperative MSCTA is beneficial to the evaluation of vascular structure of the cancer and the adjacent tissues, which may reduce postoperative complications. PMID- 21271377 TI - [Transumbilical single-port access laparoscopic surgery for colorectal cancer]. AB - OBJECTIVE: To evaluate the surgical outcomes after transumbilical single-port access laparoscopic surgery for colorectal cancer. METHODS: Patients undergoing transumbilical single-port access laparoscopic radical resection for colorectal cancer at the Zhongshan Hospital of Xiamen University were included. RESULTS: Three patients underwent transumbilical single-port access laparoscopic radical resection for sigmoid colon cancer and 1 for rectal cancer between August 2010 and September 2010. There were no intraoperative or postoperative complications. No conversion was required. The mean operative time was 206 min and the mean estimated blood loss was 75 ml. The mean number of harvested lymph nodes was 21. Patients were ambulatory in the same day of surgery or postoperative day 1. Length of hospital stay ranged from 7 to 10 days. CONCLUSIONS: Transumbilical single-port access laparoscopic surgery is safe for colorectal cancer. Long-term outcomes warrant further investigation. PMID- 21271378 TI - [Outcomes after transanal endoscopic microsurgery for early rectal cancer and risk factors associated with recurrence]. AB - OBJECTIVE: To investigate outcomes after transanal endoscopic microsurgery (TEM) for early rectal cancer, identify risk factors associated with recurrence, and explore the indication of TEM for rectal cancer. METHODS: Sixty patients with rectal cancer undergoing TEM between June 2006 and June 2009 in the Provincial Qianfoshan Hospital of Shandong University were included in this study and data were retrospectively analyzed. RESULTS: There were 12 patients with pTis rectal cancer, 38 with pT1 and 10 with pT2. All the lesions were excised en bloc by full thickness TEM. No positive resection margins were reported. The operative time was(65.0 +/- 36.5) min. Estimated blood loss was (10.5 +/- 5.8) ml and hospital stay was(4.5 +/- 2.7) d. No perioperative mortality and complications occurred. The median follow-up was 28.5(range, 12-48) months. No recurrence developed in pTis lesions. There was significant difference in local recurrence rate between pT1 and pT2(2.6% vs. 40.0%, P<0.05). The recurrence rate in lesions larger than 3 cm in diameter(19.0%, 4/21) was significantly higher than that in lesions smaller than 3 cm in diameter (2.6%, 1/39) (P<0.05). Multivariate analysis showed that depth of tumour invasion(T stage) and tumour size were independently associated with recurrence after TEM. CONCLUSION: Local excision by TEM is oncologically safe and effective for pTis and pT1 rectal cancers and early lesions smaller than 3 cm in diameter. PMID- 21271379 TI - [A preliminary study of stenting followed by laparoscopic surgery for obstructing left-sided colon cancer]. AB - OBJECTIVE: To study the efficacy of stenting followed by laparoscopic surgery in the treatment of obstructing left-sided colon cancer. METHODS: Forty-nine patients with obstructing left-sided colon cancer were prospectively randomized into two groups. Twenty patients received emergent open surgery, while 15 underwent laparoscopic surgery 3 days after placement of the self-expanding metal stent (SEMS) and 14 of them received laparoscopic surgery 10 days after placement of SEMS. Outcomes evaluated included 1-stage operation rate, conversion rate, operative time, length of hospital stay, blood loss, postoperative pain score and use of analgesics, rates of permanent stoma, and postoperative complications. RESULTS: Compared with emergent open surgery, patients undergoing laparoscopic surgery had significantly less blood loss(P=0.000), lower permanent stoma rate (P=0.024), less pain(P=0.000), and lower incidence of postoperative complications. Laparoscopic surgery was associated with a significantly higher rate of 1-stage operation(P=0.004). Compared with patients undergoing laparoscopic surgery 3 days after SEMS placement, patients who underwent laparoscopic surgery 10 days after SEMS placement had a significantly higher 1 stage operation rate(P=0.001) and a lower conversion rate(P=0.046). CONCLUSIONS: Self-expanding metal stenting is a safe and effective bridge to laparoscopic surgery in patients with obstructing left-sided colon cancer. Laparoscopic surgery 10 days after SEMS placement may be more appropriate. PMID- 21271380 TI - [Anatomical observation of the 'holy plane' for total mesorectal excision]. AB - OBJECTIVE: To provide anatomic evidence for identification of "holy plane" between fascia propria and its adjacent fascia in total mesorectal excision. METHODS: A total of 26 pelvic specimens of adult male preserved in 10% formalin solution were used in this study. Twenty pelvis were employed for topographic anatomy, six for sectional anatomy. RESULTS: Rectovesical septum was formed by the ventral part of the fascia propria and Denonvilliers' fascia, with no blood vessel and nerve coursed between two layers. Dorsal part of the fascia propria parallelled with the presacral fascia, with no blood vessel and nerve coursed between two layers in 80% of the pelvis. However, anatomic variations was encountered occasionally--with muscle-like tissue or fusion of presacral fascia interposed between them for 20%. The lateral space of rectum was between lateral part of the fascia propria and parietal fascia which witnessed pelvic nerve plexus and lateral ligament of the rectum traveling. Pelvic nerve plexus was categorized as two types according the relation between fascia propria and nerve plexus: fusion type accounting for 85% and rarefaction type for 15%. CONCLUSION: 'holy plane' is sandwiched between the fascia propria and its adjacent fascia- ventrally Denonvilliers fascia, dorsally presacral fascia and laterally parietal fascia. PMID- 21271381 TI - [Factors associated with complications in patients undergoing surgery for obstructing colorectal cancer]. AB - OBJECTIVE: To evaluate risk factors associated with morbidity and mortality in patients undergoing surgery for obstructing colorectal cancer. METHODS: One hundred and eleven patients who underwent emergency surgery for obstructing colorectal cancer from January 2001 to December 2009 were retrospectively reviewed. RESULTS: Forty-nine patients had obstruction proximal to the splenic flexure and 62 patients at or distal to the splenic flexure. The morbidity and mortality rates of the emergency surgery for malignant obstruction were 21.6% and 5.4%, respectively. Twenty-three patients received resection with primary anastomosis with intraoperative lavage for left-sided lesions. There was no difference in morbidity between right-sided cancer and left-sided cancer(P>0.05). Univariable analysis showed that complications rate was higher in patients with higher ASA score (3-4) and in those aged over 60 years. Multivariate logistic regression analysis revealed that ASA score(3-4) was an independent risk factor. CONCLUSIONS: Emergency surgery for obstructing colorectal cancer is associated with high rates of morbidity and mortality. Selection of the proper operation and intensive treatment after surgery are recommended in high risk patients. PMID- 21271382 TI - [Gene methylation in stool for the screening of colorectal cancer and pre malignant lesions]. AB - OBJECTIVE: To evaluate association between DNA methylation of MAL, CDKN2A, and MGMT in stool and development of colorectal cancer, and to evaluate the screening value of these biomarkers in colorectal cancer and pre-malignant lesions. METHODS: Morning stool specimens were collected from 69 patients with colorectal cancer, 24 with colon adenoma, 19 with hyperplastic polyps, and 26 healthy controls. DNA was extracted and treated with bisulfite. Methylation-specific PCR(MSP) was performed for methylation analysis of MAL, CDKN2A and MGMT in DNA samples. Associations between clinicopathological features and gene methylation were analyzed. The sensitivity of diagnosis by combining three methylation markers was compared with fecal occult blood test(FOBT). RESULTS: The methylation frequencies of MAL, CDKN2A and MGMT were 78.3%, 52.5% and 55.1% in colorectal cancer, 58.3%, 41.7% and 37.5% in colon adenomas, 26.3%, 15.8% and 10.5% in hyperplastic polyps, and 3.8%, 0 and 3.8% in healthy controls, respectively. Significant differences in three genes were found between colorectal cancer and hyperplastic polyp, colorectal cancer and healthy control, colon adenoma and hyperplastic polyp, colon adenoma and healthy control(all P<0.05). The diagnostic sensitivity by combining three methylation markers was 92.8% in colorectal cancer, 70.8% in colon adenomas, significantly higher than FOBT examination (29.0% in colorectal cancer and 25.0% in colon adenomas, all P<0.05). No significant associations existed between three genes methylation of the three genes and clinical characteristic including sex, age, tumor location, lymph node metastases and TNM stage (all P>0.05). CONCLUSION: DNA methylations levels of MAL, CDKN2A, and MGMT in stools are significantly higher in colorectal cancer and colon adenoma, which may serve as an noninvasive approach for the screening of colorectal cancer and pre-malignant lesions. PMID- 21271383 TI - [Comparative observation of microcirculation and tissue healing process in gastrointestinal anastomosis with apposition or inverted suturing]. AB - OBJECTIVE: To compare microcirculation and tissue healing process in gastrointestinal anastomosis with apposition or inverted suture. METHODS: The study was performed in adult rabbits. Animals were randomly assigned to two groups. In group A, small intestine was transected at 20 cm and 40 cm from duodenojejunal ligament and apposition sutures were performed at 20 cm and inverted sutures at 40 cm. In group B, transaction and anastomosis were at the same location with group A while the suturing method was reversed. Anastomotic microcirculation and number of capillary were observed in vivo with naked eyes to evaluate inflammatory response, collagen proliferation and healing of epithelium and smooth muscle in both groups at postoperative day 3, 7, 14 and 28. RESULTS: In group A, tissue layers at the anastomosis were approximated tight and neat with mild inflammation and primary wound healing. In group B, displacement and poor alignment of layers were seen with severe inflammation and secondary wound healing. Low frequency of microcirculation was detected in group A at day 3, and blood flow velocity significantly increased at day 7. Blood flow velocity was close to normal at day 14 and completely restored to the normal level at day 28. Microcirculation was lower in group A than that in group B at each time point. There were more capillaries, lower number of inflammatory cells, less collagen proliferation, and better healing of anastomotic epithelium and smooth muscle in group A than group B. CONCLUSION: Apposition suturing is better than inverted suturing in restoring local anastomotic microcirculation and healing of intestinal tissues. PMID- 21271384 TI - [Influence of silencing Polo-like kinase 1 on migration and invasion of colorectal cancer cells]. AB - OBJECTIVE: To examine the role of Polo-like kinase 1(PLK1) in the migration and invasiveness of human colorectal cancer cells. METHODS: Nine colorectal cancer cell lines were cultured. Cell lines with the highest level of PLK1 expression was selected by PCR and Western blot. Three siRNA oligo segments targeting PLK1 were designed and selected cell lines transfected. Successful transfection was confirmed using real-time PCR and Western blot. Changes in migration and invasiveness of the selected cell line were evaluated by Transwell test. RESULTS: Colorectal cancer cell line SW1116 was selected with the highest expression of PLK1 at both mRNA level and protein level. The expression of PLK1 in SW1116 was reduced by the three siRNA oligo segments to varying degrees, and the No.1 siRNA oligo segment was the most efficient. In migration test, the number of cells crossing through chambers in PLK1-siRNA group was 44 +/- 14, which was lower than that in the negative control group (242 +/- 40) and in blank control group(240 +/ 38). In invasion test, the number of cells crossing through chambers in PLK1 siRNA group was 62 +/- 3, which was lower than that in negative control group (207 +/- 12) and in blank control group (211 +/- 15). These differences were statistically significant(P<0.01). CONCLUSION: PLK1 silencing by siRNA may inhibit the migration and invasiveness of colorectal cancer cells, suggesting that PLK1 might play an important role in the infiltration and metastasis of colorectal cancer. PMID- 21271385 TI - Quality of life and depression in carers of patients with early onset dementia. AB - OBJECTIVE: To investigate the quality of life (QoL) and depression and its correlates in carers living with early onset dementia (EOD) patients. METHOD: The subjects were 49 carers, either married to or cohabiting with EOD patients, 38 with Alzheimer's disease and 11 with other types of dementia. The Quality of Life - Alzheimer Disease scale (QoL-AD) and Geriatric Depression Scale-15 items (GDS 15) were used. RESULTS: The mean QoL score for the carers was 37.9 (SD 5.5) and the mean GDS-15 score 5.1 (SD 2.9). Linear regression analyses with QoL and GDS 15 score as dependent variables were performed. Increased age of the carer (B = 0.32) and greater insight of the patients (B = -0.186) were significantly associated with a better QoL for the carer. Being married (B = 2.10), having children together with the patient (B = 1.61) and being the carer of a patient with cardiovascular disease (B = 2.28) were associated significantly with a higher GDS-15 score, whereas being the carer of a patient who received domiciliary nursing care (B = -2.29) was significantly associated with a lower GDS-15 score. CONCLUSION: The QoL for carers of EOD patients corresponds positively with the increased age of carers and with patients' insight into their condition. Increased depressive symptomatology in carers was associated with being married, having offspring and caring for a patient with dementia and a co morbid cardiovascular disease. A reduction in depression was seen in carers when the patients received domiciliary nursing care. PMID- 21271386 TI - Memory services and memory clinics. PMID- 21271388 TI - Developing and implementing quality standards for memory services: The Memory Services National Accreditation Programme (MSNAP). AB - BACKGROUND: The lack of a consistent model means that the quality and characteristics of memory services can vary greatly. Quality standards have been successfully applied in a range of healthcare settings which allow services to implement improvements where necessary. A nationally agreed set of quality standards would help fulfil this need for UK memory services. OBJECTIVES: To develop a set of standards for memory services to form the basis of a quality improvement initiative (Memory Services National Accreditation Programme [MSNAP]). METHOD: The standards development process involved five main elements: Literature review/content analysis; key stakeholder workshop; email and postal consultation; consensus meeting; and final consultation/obtaining endorsements. Thirteen memory services in the northwest of England participated in the pilot programme, during which the draft set of quality standards were applied through the processes of self review and peer review. RESULTS: The finalised version consisted of 148 quality standards categorised along the following domains: management; resources available to support assessment and diagnosis; assessment and diagnosis; and ongoing care management and follow-up. The pilot stage highlighted standards representing common areas where improvements had been made, such as ascertaining whether the patient wished to know their diagnosis, and areas where more attention was still required, for example surveying referrers, patients and carers about their experiences of the service. CONCLUSION: It was possible to develop and field test nationally agreed quality standards for memory services. We believe that by implementing MSNAP it will be possible to improve the quality of UK memory services. PMID- 21271387 TI - Implementing innovative models of dementia care: The Healthy Aging Brain Center. AB - BACKGROUND: Recent randomized controlled trials have demonstrated the effectiveness of the collaborative dementia care model targeting both the patients suffering from dementia and their informal caregivers. OBJECTIVE: To implement a sustainable collaborative dementia care program in a public health care system in Indianapolis. METHODS: We used the framework of Complex Adaptive System and the tool of the Reflective Adaptive Process to translate the results of the dementia care trial into the Healthy Aging Brain Center (HABC). RESULTS: Within its first year of operation, the HABC delivered 528 visits to serve 208 patients and 176 informal caregivers. The mean age of HABC patients was 73.8 (standard deviation, SD 9.5), 40% were African-Americans, 42% had less than high school education, 14% had normal cognitive status, 39% received a diagnosis of mild cognitive impairment, and 46% were diagnosed with dementia. Within 12 months of the initial HABC visit, 28% of patients had at least one visit to an emergency room (ER) and 14% were hospitalized with a mean length of stay of five days. The rate of a one-week ER revisit was 14% and the 30-day rehospitalization rate was 11%. Only 5% of HABC patients received an order for neuroleptics and only 16% had simultaneous orders for both definite anticholinergic and anti-dementia drugs. CONCLUSION: The tools of 'implementation science' can be utilized to translate a health care delivery model developed in the research laboratory to a practical, operational, health care delivery program. PMID- 21271389 TI - Development of memory clinics in the Netherlands: 1998 to 2009. AB - OBJECTIVES: Memory clinics (MCs) are multidisciplinary teams involved with early diagnosis and treatment of people with dementia. The main aim of this study was to gain more insight into the development of MCs in the Netherlands since 1998. METHODS: In 1998, 2004 and 2009, an MC survey with questions about patient groups, organisation and working procedures of the MC were sent to all MCs in the Netherlands. RESULTS: The number of MCs increased from 12 in 1998, to 43 in 2004 and to 63 in 2009. In 2009, MCs were better embedded with other regional care and were delivering services for dementia with less emphasis on university-based research. While dementia was still the most common syndromal diagnosis, the proportion of subjects diagnosed with milder memory problems increased to 39%. Diagnostic tools, blood assessments and brain imaging were used in nearly all the facilities. There was an increase both in the use of extensive neuropsychological assessments and in the use of cerebrospinal fluid diagnostics. CONCLUSION: MCs in the Netherlands have outgrown the primarily university-based setting, have focussed less on scientific research, and have taken a place in the regular care of people with cognitive problems and people in early phases of dementia. PMID- 21271390 TI - Development of a dementia assessment quality database. AB - OBJECTIVE: Increased focus on the quality of health care requires tools and information to address and improve quality. One tool to evaluate and report the quality of clinical health services is quality indicators based on a clinical database. METHOD: The Capital Region of Denmark runs a quality database for dementia evaluation in the secondary health system. One volume and seven process quality indicators on dementia evaluations are monitored. Indicators include frequency of demented patients, percentage of patients evaluated within three months, whether the work-up included blood tests, Mini Mental State Examination (MMSE), brain scan and activities of daily living and percentage of patients treated with anti-dementia drugs. Indicators can be followed over time in an individual clinic. Up to 20 variables are entered to calculate the indicators and to provide risk factor variables for the data analyses. RESULTS: The database was constructed in 2005 and covers 30% of the Danish population. Data from all consecutive cases evaluated for dementia in the secondary health system in the Capital Region of Denmark are entered. The database has shown that the basic diagnostic work-up programme with MMSE, and a brain scan is performed in almost all patients. Differences in the prevalence of etiological diagnoses indicate differences in the application of the diagnostic criteria. This has initiated a process to harmonize the use of diagnostic criteria and the MMSE including administration guide. CONCLUSION: Clinical quality indicators based on all patients evaluated for dementia can be used to standardize and harmonize the evaluation process and improve clinical health services. PMID- 21271391 TI - Project REACH: a provider-delivered dual protection intervention for women using family planning services in New York City. AB - High rates of unintended pregnancies and sexually transmitted infection (STI), including HIV, highlight the importance of promoting dual protection (DP) - i.e., methods that offer concurrent protection against unintended pregnancies and STI - during contraceptive counseling. Using a Phase II quasi-experimental design, this study compared an individualized, clinic-based, nurse-delivered intervention designed to increase DP against standard of care among 101 HIV negative women accessing contraceptive services in medically under-served areas of New York City. Participants were evaluated at baseline, post-counseling, and six months later. Findings indicated that the intervention has possible benefit. At six month follow-up, there was greater perceived susceptibility to STI and fewer condom-unprotected vaginal sex occasions in the intervention arm. Women in the intervention also had five times the odds of reporting female condom use. Results suggest that this intervention has the potential for a larger population impact and should be more rigorously evaluated in a Phase III trial. PMID- 21271392 TI - Acceptability of rapid oral fluid HIV testing among male injection drug users in Taiwan, 1997 and 2007. AB - Rapid oral fluid HIV testing (rapid oral testing) is in the process of being adapted in Taiwan and elsewhere given its advantages over prior HIV testing methods. To guide this process, we examined the acceptability of rapid oral testing at two time points (i.e., 1997 and 2007) among one of the highest risk populations, male injection drug users (IDUs). For this purpose, an anonymous self-administered survey was completed by HIV-negative IDUs involved in the criminal justice system in 1997 (N (1)=137 parolees) and 2007 (N (2)=106 prisoners). A social marketing model helped guide the design of our questionnaire to assess the acceptability of rapid oral testing. This included assessing a new product, across four marketing dimensions: product, price, promotion, and place. Results revealed that in both 1997 and 2007, over 90% indicated that rapid oral testing would be highly acceptable, particularly if the cost was under US$6, and that a pharmacy would be the most appropriate and accessible venue for selling the rapid oral testing kits. The vast majority of survey respondents believed that the cost of rapid oral testing should be federally subsidized and that television and newspaper advertisements would be the most effective media to advertise for rapid oral testing. Both the 1997 and 2007 surveys suggested that rapid oral HIV testing would be particularly accepted in Taiwan by IDUs after release from the criminal justice system. PMID- 21271393 TI - Understanding locally, culturally, and contextually relevant mental health problems among Rwandan children and adolescents affected by HIV/AIDS. AB - In assessing the mental health of HIV/AIDS-affected children and adolescents in Sub-Saharan Africa, researchers often employ mental health measures developed in other settings. However, measures derived from standard Western psychiatric criteria are frequently based on conceptual models of illness or terminology that may or may not be an appropriate for diverse populations. Understanding local perceptions of mental health problems can aid in the selection or creation of appropriate measures. This study used qualitative methodologies (Free Listing, Key Informant interviews, and Clinician Interviews) to understand local perceptions of mental health problems facing HIV/AIDS-affected youth in Rwinkwavu, Rwanda. Several syndrome terms were identified by participants: agahinda kenshi, kwiheba, guhangayika, ihahamuka, umushiha, and uburara. While these local syndromes share some similarities with Western mood, anxiety, and conduct disorders, they also contain important culture-specific features and gradations of severity. Our findings underscore the importance of understanding local manifestations of mental health syndromes when conducting mental health assessments and when planning interventions for HIV/AIDS-affected children and adolescents in diverse settings. PMID- 21271394 TI - Assessing the psychological well-being of caregivers of people living with HIV/AIDS in Niger Delta region, Nigeria. AB - Despite the availability of anti-retroviral drugs and treatment, the care and support of people living with HIV/AIDS has continued to be a major challenge, with greater impact not only on the people living the disease. The burden associated with care often results in high level of stress among caregivers, usually manifesting as anxiety and/or depression. This study assesses the levels of stress among caregivers of people living with HIV/AIDS in Niger Delta region of Nigeria, in order to determine their coping strategies. Between July and December 2008, 322 caregivers of people living with HIV/AIDS attending HIV clinic of the University of Uyo Teaching Hospital were randomly assessed for stress (anxiety and depression), using Zung's Self-Rating Depression Scale (SDS) and Self-Report Questionnaire (SRQ-20). A total of 293 caregivers comprising 98 (33.4%) males and 195 (66.6%) females were analysed. Mean age of males was 44.0 +/- 4.5 years and females was 39.3 +/- 4.0 years. The difference in the mean was statistically significant (p<0.001). Of the 293 caregivers, 191 (65.2%) and 115 (39.2%) were scored high on SDS and SRQ-20, respectively (representing the levels of stress). Using SDS groups on SRQ-20 subscales, 134 (45.7%) had anxiety only, 23 (7.8%) depression only, 52 (17.7%) had a mixture of anxiety and depression, while 11 (3.7%) exhibited suicidal tendencies. There is increasing level of stress in caregiving. Therefore, adequate attention must be given to the psychological well-being of caregivers to enable them contribute positively to the care of people living with HIV/AIDS. PMID- 21271395 TI - Posttraumatic stress and depressive symptoms among people living with HIV in the Gambia. AB - This study aimed to assess the prevalence and clinical and psychosocial correlates of psychiatric symptoms in a sample of HIV patients in the Gambia. Data from 44 HIV-positive outpatients were collected at a Genito-Urinary Medicine clinic in Fajara, the Gambia. Translated versions of the Impact of Event Scale Revised and the Centre for Epidemiologic Studies Short Depression Scale were used to assess posttraumatic stress disorder (PTSD) symptoms and depressive symptoms, respectively. The Pictorial Representation of Illness and Self Measure revised was used to assess illness perception (IP). All other data (e.g., CD4 counts) were retrieved from medical charts or through standardised questions. The prevalence of PTSD symptoms (43.2%) and depressive symptoms (40.9%) was high. Not having an independent income and having a CD4 count under 200 cells/ul were independent correlates of depressive symptoms. Only IP was an independent correlate of PTSD symptoms. Finally, IP tended to moderate the relationship between CD4 cell counts and depressive symptoms. These findings indicate that routine screening for psychiatric symptoms is both necessary and feasible among HIV patients in the Gambia. In addition, any intervention targeting these symptoms should take IP into account. PMID- 21271396 TI - Employment status is associated with both physical and mental health quality of life in people living with HIV. AB - To evaluate the relationship between employment status and health-related quality of life (HRQOL) in HIV/AIDS. A total of 361 participants provided baseline data in the context of an ongoing cohort study examining the natural history of neurobehavioral functioning and its effects on HRQOL. We administered tests and collected laboratory data to determine demographic status, HIV disease markers, psychosocial symptom burden, neurocognitive function and HRQOL (MOS-HIV). We performed regression analyses to evaluate the contribution of employment status to the physical and mental health components of quality of life (QOL). Multivariate analyses showed that employment status was strongly related to better physical and mental health QOL after controlling for potential confounders. We found, however, that employment status had a greater impact on physical health than mental health QOL [physical health (beta = 6.8, 95% CI 4.6 to 9.1) and mental health QOL (beta = 3.3, 95% CI 0.93 to 5.7)]. The effect of employment for physical health QOL was stronger than that observed for ethnicity, social support, or having an AIDS diagnosis and was comparable to that observed with having many HIV-related symptoms. This cross-sectional study suggests that there may be physical and mental health benefits associated with obtaining or keeping employment, or more likely that both selection and causation mechanisms comprise an interactional and reinforcing process. PMID- 21271397 TI - Characteristics of Latino MSM who have sex in public settings. AB - Many men who have sex with men (MSM) have sexual encounters in public places, and some data suggest that this behavior is more common among Latino than non Hispanic white MSM in the USA. In a sample of 482 Latino MSM born in Brazil, Colombia, and the Dominican Republic, and living in the New York City metropolitan area, we examined how demographic and psychosocial characteristics are related to having sex in public venues. Logistic regression was performed with the dichotomous outcome of sex in a public place in the previous six months. Demographic variables included education, HIV-positive serostatus, unknown HIV serostatus, and years in the USA; psychosocial variables included self-efficacy for safer sex, depression, and gay community involvement. Results indicated that those individuals with unknown serostatus were more likely than those with HIV negative serostatus to have had sex in a public setting, as were men with lower self-efficacy for safer sex. These findings suggest that the partner pool may pose some risk to men who have sex in public sex venues, and therefore, low-risk sexual practices and condom use should be promoted in such settings. Contrary to expectations, higher education was related to sex in public settings, but neither depression nor more recent immigration was. Greater involvement in the gay community was also associated with having sex in public places, which may reflect the larger social function served by gay venues such as bathhouses and bars. PMID- 21271398 TI - Use of HIV primary care by HIV-positive Haitian immigrants in Miami, Florida. AB - Little is known about the use of HIV primary care among Haitian immigrants in the USA. The present study utilizes data from a survey of HIV-positive Haitians recruited from an HIV primary care clinic in Miami, Florida, to examine barriers and facilitators of regular use of HIV care by this population. Selection of measures was guided by the Andersen Model of Health Services Utilization for Vulnerable Populations. The dependent variable, regular use of HIV primary care, was operationalized as completion of four or more HIV primary care visits during the previous 12 months. Of the 96 participants surveyed, approximately three fourths did not graduate from high school and reported an annual income of up to $5000. Seventy-nine percent of participants completed four or more visits in the past year. On univariate as well as multivariate analyses, participants without formal education or those with high psychological distress were significantly less likely to have used HIV primary care regularly than those who attended school or who were less distressed, respectively. The findings emphasize the need for health care practitioners to pay close attention to the education level and the mental health status of their Haitian HIV patients. The data also suggest that once these individuals are linked to care and offered assistance with their daily challenges, they are very likely to stay connected to care and to take their antiretroviral medicines. PMID- 21271399 TI - Consistent condom use among Thai heterosexual adult males in Bangkok, Thailand. AB - Thai heterosexual males between 20 and 39 years old are at increased risk for HIV infection. Consistent condom use is effective against HIV transmission, but little is known about determinants of consistent condom use for these males. The purpose of this study is to explore determinants of consistent condom use for this population. The determinants of interest are age, educational level, marital status, income, and concepts from the theory of planned behavior: attitude toward condom use, subjective norm about consistent condom use, perceived behavioral control (PBC) of consistent condom use, and intention to use condoms consistently. We used a cross-sectional descriptive research design with a convenience sample of 400 heterosexual Thai males between 20 and 39 years. Our sample had a mean age of 28.71 years (SD = 6.33). During the last three months, 39.5% reported using condoms consistently, 23% reported using condoms inconsistently, and 37.5% reported never using condoms. The results from the regression analyses revealed that marital status, income, subjective norm about consistent condom use, PBC of consistent condom use, and intention to use condoms consistently were determinants of consistent condom use. Also the effect of subjective norm about consistent condom use and PBC of consistent condom use on consistent condom use was mediated by intention to use condoms consistently. These results suggest that interventions to increase consistent condom use should focus on enhancing intention to use condoms consistently by promoting subjective norm about consistent condom use and PBC of consistent condom use. PMID- 21271400 TI - Romantic relationships and sexual activities of the first generation of youth living with HIV since birth. AB - HIV-infected children, now maturing into adolescence and adulthood, must cope not only with adolescent developmental issues, but also with a chronic, socially stigmatised and sexually transmittable illness. Little research on this first generation of survivors has focused on romantic involvement and sexuality. This study, which employs a mixed-method embedded strategy (qualitative supported by quantitative), describes the perspectives of youth living with HIV since birth concerning: (1) romantic involvement and sexuality; and (2) risk management including the risk of HIV transmission and partner serostatus disclosure. Eighteen adolescents aged 13-22 from Montreal, Canada, participated in individual semi-structured interviews and completed self-report questionnaires. Most youths participated in non-penetrative sexual activities. Ten participants reported having had vaginal and three anal intercourses, at an average age of 14 for girls and 15 for boys. All sexually active youth reported having used a condom at least once. Of those who reported that their first sexual relationship was protected, over half had taken risks in subsequent relationships (e.g., unprotected sex, multiple partners, etc.). Interviews conducted with sexually inactive youths illustrate the interrelatedness of romantic involvement, sexual initiation and potential serostatus disclosure. Involvement in a sexual relationship would not be conceivable unless the partner was informed of their serostatus. For sexually active participants, risk management implies HIV transmission and partner disclosure. These youths have emotional issues regarding disclosure in romantic relationships and few risked potential rejection by disclosing. Condom use acts as a reminder of the infection and a barrier to intimacy. The narratives illustrate how risk perception changes and becomes relative with time and experience, especially when the viral load is undetectable and when past experience has convinced the adolescent that his/her partner might not become infected. Findings reinforce the need to prioritise sexual health issues for young people with perinatally acquired HIV. PMID- 21271401 TI - Paediatric HIV and elimination of mother-to-child transmission of HIV in the ASEAN region: a call to action. AB - Recent achievements in scaling up paediatric antiretroviral therapy (ART) have changed the life of children living with HIV, who now stay healthy and live longer lives. However, as it becomes more of a chronic infection, a range of new problems have begun to arise. These include the disclosure of HIV serostatus to children, adherence to ART, long-term toxicities of antiretroviral drugs and their sexual and reproductive health, which are posing significant challenges to the existing health systems caring for children with HIV with limited resources, experiences and capacities. While intensified efforts and actions to improve care and treatment for these children are needed, it is crucial to accelerate the prevention of mother-to-child transmission (PMTCT) of HIV, which is the main cause of paediatric HIV in the ASEAN region so as to eliminate the fundamental cause of the problem. This report argues that given over 70% of women have access to at least one antenatal care visit in the region and acceptance of HIV testing after receiving counselling on PMTCT could be as high as 90%, there is an opportunity to strengthen PMTCT services and eventually eliminate new paediatric HIV infections in the ASEAN countries. PMID- 21271402 TI - High HIV risk behavior among men who have sex with men in Kigali, Rwanda: making the case for supportive prevention policy. AB - Rwanda has responded strongly to HIV/AIDS, but prevention among men who have sex with men (MSM) has not yet been addressed due to a strong cultural resistance to homosexuality, and a lack of data showing the public health value of attending to the sexual health needs of this group. We conducted an exploratory study on HIV risk among MSM in Kigali using snowball sampling involving peer leaders. The 99 respondents were demographically, socially, and sexually diverse. Respondents reported relatively high numbers of male and female partners, and considerable HIV risk behaviors including commercial sex with men and women, low condom use during anal and vaginal sex, and high mobility. Many respondents reported verbal and/or physical abuse due to their sexuality. This first study of MSM in Rwanda has brought attention to a previously neglected HIV risk group and their potential driving role in the Rwandan epidemic, demonstrating the need for sensitive and targeted interventions. PMID- 21271403 TI - House/ball culture and adolescent African-American transgender persons and men who have sex with men: a synthesis of the literature. AB - Transgender persons and young men of color who have sex with men (YMSM of color) have been severely affected by HIV in the USA. Houses and balls in the USA have historically been a primary meeting ground for YMSM of color and transgender people, offering an opportunity for HIV prevention activities. Houses provide a familial structure for YMSM of color and transgender people, while balls provide them with events at which they can congregate for social support and entertainment. A comprehensive literature search was conducted using Scopus and PubMed, Internet websites, and HIV prevention and care resources for YMSM of color associated with a multisite evaluation. Houses and balls have been responsive to the HIV/AIDS epidemic and have developing networks that are critical in providing a social and familiar context for often-disenfranchised youth. The organizations have embraced the need for HIV prevention, and their methodology may be transferable to other prevention contexts. Future studies are needed to identify culturally appropriate and effective methods of integration of house/ball methods into HIV prevention services aimed at transgender persons and YMSM of color. PMID- 21271404 TI - Correlates of poor perceived health among individuals living with HIV and HBV chronic infections: a longitudinal assessment. AB - Chronic hepatitis B virus (HBV) infection affects up to 14% of people living with HIV and AIDS (PLWHA) and is associated with a higher risk of non-AIDS death. While great advances have been made in the therapeutic management of co-infection with HIV and HBV, nothing is known about perceived health in people living with HIV and HBV. This study aimed at characterizing individuals with poor perceived overall health among 308 HIV-HBV co-infected individuals enrolled between May 2002 and May 2003 in a three-year French cohort. A binary score for perceived overall health (good vs. poor) was calculated from individuals' responses to the COOP-WONCA charts at cohort enrolment and at quarterly visits throughout the follow-up. Mixed models were used to explore factors associated with this score. At enrolment, 190 individuals (62%) reported poor overall health. In the multivariate analysis, low CD4 percentage, co-infection with hepatitis C or D viruses, HIV diagnosis before 1996 and HBeAg positivity were independently associated with poor perceived overall health. Poor perceived health concerns a considerable portion of individuals living with HIV and HBV. Individuals with wild-type HBV and multiple hepatitis infection require better clinical management. Further research is needed for hepatitis D virus infection, for which treatment options are currently very limited. PMID- 21271405 TI - Ethnic differences in HIV-disclosure and sexual risk. AB - Little is known about ethnic differences in HIV-disclosure to sexual partners or the relationship between HIV-disclosure and sexual risk. Differences in HIV disclosure rates between African-American and White men who have sex with men (MSM) were analyzed using data from the Treatment Advocacy Program. In general, the findings suggest that African-Americans are less likely than Whites to disclose their HIV status to sexual partners. The findings also suggest that the African-American participants who disclosed to HIV-negative partners were significantly less likely to engage in unprotected anal sex with HIV-negative partners and partners whose HIV status was unknown than those participants who did not disclosure to HIV-negative partners. Although HIV-disclosure appears to be an important factor to consider in HIV-prevention efforts, there are unique factors that influence HIV-disclosure decisions for African-American MSM. Interventions should consider these unique challenges before focusing on HIV disclosure as a primary tool for reducing the transmission of HIV. PMID- 21271406 TI - An interdisciplinary HIV-adherence program combining motivational interviewing and electronic antiretroviral drug monitoring. AB - To ensure successful treatment, HIV patients must maintain a high degree of medication adherence over time. Since August 2004, patients who are (or are at risk of) experiencing problems with their HIV antiretroviral therapy (ART) have been referred by their physicians to an interdisciplinary HIV-adherence program. The program consists of a multifactorial intervention along with electronic drug monitoring (MEMS(TM)). The pharmacists organize individualized semi-structured motivational interviews based on cognitive, emotional, behavioral, and social issues. At the end of each session, the patient brings an adherence report to the physician. This enables the physician to use the adherence results to evaluate the treatment plan. The aim of this study was to retrospectively analyze this on going interdisciplinary HIV-adherence program. All patients who were included between August 2004 and the end of April 2008 were analyzed. One hundred and four patients were included (59% women, median age 39 (31.0, 46.0) years, 42% black ethnicity). Eighty (77%) patients were ART-experienced patients and 59% had a protease inhibitor-based treatment. The retention rate was high (92%) in the program. Patient inclusion in this HIV-adherence program was determined by patient issues for naive patients and by nonadherence or suboptimal clinical outcomes for ART-experienced patients. The median time spent by a subject at the pharmacy was 35 (25.0, 48.0) minutes, half for the medication handling and half for the interview. The adherence results showed a persistence of 87% and an execution of 88%. Proportion of undetectable subjects increased during study. In conclusion, retention and persistence rates were high in this highly selected problematic population. PMID- 21271407 TI - A simultaneous test of the relationship between identified psychosocial risk factors and recurrent events in coronary artery disease patients. AB - Psychosocial factors are increasingly recognized as risk indicators for coronary artery disease (CAD) prognosis and they are likely interrelated. The objective of this study is to simultaneously test the relationship between key psychosocial constructs as independent factor scores and recurrent events in CAD patients. There were 1268 CAD outpatients of 97 cardiologists surveyed at two points. Recurrent events or hospitalization in the intervening nine months were reported. Factor analysis of items from the Hospital Anxiety and Depression Scale, Perceived Stress Scale, the ENRICHD Social Support Inventory, and Hostile Attitudes Scale was performed to generate orthogonal factor scores. With adjustment for prognostic variables, logistic regression analysis was performed to examine the relationship between these factor scores and recurrent events. Factor analysis resulted in a six-factor solution: hostility, stress, anxiety, depressive symptoms, support, and resilience. Logistic regression revealed that functional status and anxiety, with a trend for depressive symptoms, were related to experiencing a recurrent event. In this simultaneous test of psychosocial constructs hypothesized to relate to cardiac prognosis, anxiety may be a particularly hazardous psychosocial factor. While replication is warranted, efforts to investigate the potential benefits of screening and to investigate treatments are needed. PMID- 21271408 TI - Effects of occupational stress, job characteristics, coping, and attributional style on the mental health and job satisfaction of university employees. AB - Well-being at work has been shown to be influenced by job characteristics and individual differences in coping styles. This study investigated the relationships between job demands, control, social support, efforts, rewards, coping, and attributional style in predicting anxiety, depression, and job satisfaction in a sample of 307 university employees from the UK. Results were compared to those from a sample of 120 members of the general population. Workplace demands, intrinsic and extrinsic effort, and negative coping and attributional behaviors were associated with high levels of depression and anxiety and low job satisfaction in university employees. Rewards, social support, job control, and positive coping and attributional behaviors were associated with lower levels of depression and anxiety and high job satisfaction. The study adds to the growing research on university samples by showing that a transactional approach should be adopted. This has implications for interventions and suggests that rather than just trying to change job characteristics one should identify at-risk individuals in this population and help them adopt appropriate positive coping styles. PMID- 21271409 TI - Effect of ultrasound on cyprids and juvenile barnacles. AB - Settlement inhibition of barnacle (Amphibalanus amphitrite) cypris larvae resulting from exposure to ultrasound was measured at three frequencies (23, 63, and 102 kHz), applied at three acoustic pressure levels (9, 15, and 22 kPa) for exposure times of 30, 150, and 300 s. The lowest settlement was observed for 23 kHz, which also induced the highest cyprid mortality. Cyprid settlement following exposure to 23 kHz at 22 kPa for 30 s was reduced by a factor of two. Observing surface exploration by the cyprids revealed an altered behaviour following exposure to ultrasound: step length was increased, while step duration, walking pace, and the fraction of cyprids exploring the surface were significantly reduced with respect to control cyprids. The basal area of juvenile barnacles, metamorphosed from ultrasound-treated cyprids was initially smaller than unexposed individuals, but normalised over two weeks' growth. Thus, ultrasound exposure effectively reduced cyprid settlement, yet metamorphosed barnacles grew normally. PMID- 21271410 TI - Larval metamorphosis of the mussel Mytilus galloprovincialis Lamarck, 1819 in response to neurotransmitter blockers and tetraethylammonium. AB - The metamorphic response of pediveliger larvae of Mytilus galloprovincialis to the neurotransmitter blockers chlorpromazine, amitriptyline, rauwolscine, idazoxan, atenolol and butoxamine, and to tetraethylammonium chloride (TEA) was investigated through a series of bioassays. Chlorpromazine, amitriptyline and idazoxin inhibited larval metamorphosis induced by 10-4 M epinephrine. The concentration that inhibited metamorphosis by 50% (IC50) for chlorpromazine and amitriptyline was 1.6 x 10-6 M and 6.6 x 10-5 M, respectively. Idazoxan was less effective with an IC50 of 4.4 x 1013 M. Moreover, these three inhibitors showed no toxicity at any of the concentrations tested. The larval metamorphic response to K+ was not inhibited by 10-3 M tetraethylammonium chloride after 96 h. Thus, the neurotransmitter blockers chlorpromazine and amitriptyline are inhibitors of larval metamorphosis, and will be useful tools for antifouling studies. PMID- 21271411 TI - Effects of modality presentation on working memory in school-age children: evidence for the pictorial superiority hypothesis. AB - This study investigated the effects of stimulus presentation modality on working memory performance in elementary school-age children ages 7-13. The experimental paradigm implemented a multitrial learning task incorporating three presentation modalities: Auditory, Visual, and simultaneous Auditory plus Visual. The first experiment compared the learning and memory performance of older and younger elementary school children. The second experiment compared verbal learning and memory performance in elementary school children with major depressive disorder (MDD) to the performance of nondepressed children. All participants benefited from the pictorial presentation of information during learning and recall of information as compared to the auditory presentation alone. Both age and socioeconomic status affected working memory performance in typically developing children. Children with depression demonstrated a more passive learning style during the auditory list acquisition. The present study supports the pictorial superiority hypothesis in verbal learning tasks and the theory that working memory matures during elementary school years. Furthermore, current results indicate that complex working memory measures are not entirely independent of previous experience. PMID- 21271412 TI - Development of cognitive skills in children with motor coordination impairments at 12-month follow-up. AB - The current study presents a 1-year follow-up investigation of the development of executive functions (i.e., inhibition, updating, and shifting) in children with motor coordination impairments. Cognitive and motor coordination skills of children (N = 94) aged between 5 and 7 years with and without motor coordination impairments were compared. A second focus of the study was on pre-academic skills. The results indicate marked stability of motor coordination impairments and persistent executive functioning deficits in motor-impaired children. Inhibition and shifting performance was consistently lower, compared to the children without motor coordination impairments. Moreover, children with motor coordination impairments showed lower pre-academic skills, facing a substantial disadvantage at the beginning of formal schooling. The combined cognitive and motor problems may be the result of an underlying inhibition deficit or a general automation deficit. Implications for intervention are discussed. PMID- 21271413 TI - Incorrigibility, jumping to conclusions, and decision threshold in schizophrenia. AB - INTRODUCTION: Previous studies confirmed a bias against disconfirmatory evidence (BADE) for both delusional and delusion-neutral events in paranoid schizophrenia. In the present study, we examined a potential relationship between the BADE and delusional ideation. METHODS: Fifty-five patients with schizophrenia (32 with current delusions), 20 patients with obsessive-compulsive disorder and 30 healthy participants were presented written scenarios composed of three successive sentences which increasingly disambiguated the situation. Participants were asked to rate interpretations presented along with the sentences. After each new sentence, participants could adjust their judgements in view of the new information. One interpretation ("true") did not seem to fit the first statement but became increasingly plausible, whereas "lure" interpretations appeared very likely initially but were eventually incorrect. Patients were given the option to decide for one of the statements. RESULTS: Patients with schizophrenia, irrespective of delusion severity, attenuated their ratings significantly less for lure interpretations in face of disconfirmatory evidence (BADE) compared to both control groups. We found no impairment regarding the integration of confirmatory evidence. Patients with schizophrenia made more incorrect decisions after the first sentence indicating jumping to conclusions relative to healthy controls. Participants with schizophrenia showed a lowered decision threshold compared to the controls. CONCLUSIONS: The findings lend further evidence to the claim that patients with schizophrenia are hastier and rather inflexible in their decision making. This response pattern may represent a trait-like vulnerability factor for the emergence of delusional incorrigibility, a hallmark symptom of schizophrenia. PMID- 21271414 TI - Moral reasoning in schizophrenia: an explorative study into economic decision making. AB - INTRODUCTION: Previous research has suggested that patients with schizophrenia are impaired in appreciating moral values and social norms. Here, we tested the hypothesis--using economic games--that patients with schizophrenia are similar to normals in their ability to recognise unfairness, but perhaps more tolerant towards the acceptance of unfair offers depending on the severity of negative symptoms. METHODS: Twenty-five patients with schizophrenia played an Ultimatum Game and a Dictator Game with punishment option to examine their ability to appreciate fairness rules and to reinforce equity in comparison to a healthy control group. RESULTS: As hypothesised, patients accepted significantly more unfair offers than controls. However, rejection rates increased in relation to the unfairness of proposals in both groups. Patients did not differ significantly from controls in the likelihood of punishing unfairness in the Dictator Game or in punishment investment itself. CONCLUSIONS: Patients with schizophrenia seem to be less sensitive towards unfairness to their own disadvantage, but punish unfairness at a comparable level to controls, which opposes the common view of a general lack of moral value appreciation in schizophrenia. PMID- 21271415 TI - Accuracy of a transformation method to estimate muscle attachments based on three bony landmarks. AB - In this work, the accuracy of a transformation method to estimate muscle attachments based on three bony landmarks was assessed. A concept of mathematical error was introduced and applied to a data-set of 17 muscles' attachment lines from the shoulders of seven cadavers. Within the muscles' attachment lines from the studied data-set, mathematical error and anatomical variability average percentage values were 37.3 and 62.7%, respectively, for the scapula, and 54.4 and 45.6%, respectively, for the humerus. To reduce mathematical error in the transformation method presented, the plane formed by the three landmarks of the segment corresponding to the scaled muscles should neither be too close to the origin of the global coordinate system, nor too far away from muscle attachment locations to be transformed. The procedure outlined in this work allows the researcher to analyse the anatomical variability within a data-set. PMID- 21271416 TI - Intraventricular vortex flow changes in the infarcted left ventricle: numerical results in an idealised 3D shape. AB - The cardiac diagnostic process is primarily based on the evaluation of myocardial mechanics whereas little is known about blood dynamics that is rarely considered to this purpose. The intraventricular blood flow is analysed here for akinetic and dyskinetic myocardial motion corresponding to the presence of an ischaemic pathology. This study is performed through a 3D numerical model of the left ventricular flow. Results show that the presence of an anterior-inferior wall infarction leads to the shortening and weakening of the diastolic mitral jet. A region of stagnating flow is found near the apex and close to the ischaemic wall. These results are in agreement with previous clinical findings based on echographic imaging. The described phenomena are also noticed for moderate degrees of the ischaemic pathology and suggest a potential value of the study of the intraventricular flow to develop early diagnostic indicators. PMID- 21271417 TI - The biomechanical effect of the collar of a femoral stem on total hip arthroplasty. AB - To investigate the biomechanical effect of collars, finite element analyses are carried out through two hip joints that are implanted using collared and collarless stems, respectively, and an intact hip joint model. For the analyses, the sacrum, coxal bone, and the cancellous and cortical bones of a femur are modelled using finite elements based on X-ray computed tomographic images taken from a 27-year-old woman. From the results, it is found that a collar with perfect calcar contact prevents stem subsidence and decreases the proximal lateral gap and the lateral stem tilting. Therefore, it can impart reasonable biomechanical stability for total hip arthroplasty. However, its low load transmission ability and increased stem tilting effect due to the imperfect contact between the collar and the calcar are found to be serious problems that need to be solved. Results of clinical follow-up are presented for supporting the computational results. PMID- 21271418 TI - CFD simulation of flow through heart: a perspective review. AB - The heart is an organ which pumps blood around the body by contraction of muscular wall. There is a coupled system in the heart containing the motion of wall and the motion of blood fluid; both motions must be computed simultaneously, which make biological computational fluid dynamics (CFD) difficult. The wall of the heart is not rigid and hence proper boundary conditions are essential for CFD modelling. Fluid-wall interaction is very important for real CFD modelling. There are many assumptions for CFD simulation of the heart that make it far from a real model. A realistic fluid-structure interaction modelling the structure by the finite element method and the fluid flow by CFD use more realistic coupling algorithms. This type of method is very powerful to solve the complex properties of the cardiac structure and the sensitive interaction of fluid and structure. The final goal of heart modelling is to simulate the total heart function by integrating cardiac anatomy, electrical activation, mechanics, metabolism and fluid mechanics together, as in the computational framework. PMID- 21271419 TI - Socio-economic status and malaria-related outcomes in Mvomero District, Tanzania. AB - While policies often target malaria prevention and treatment - proximal causes of malaria and related health outcomes - too little attention has been given to the role of household- and individual-level socio-economic status (SES) as a fundamental cause of disease risk in developing countries. This paper presents a conceptual model outlining ways in which SES may influence malaria-related outcomes. Building on this conceptual model, we use household data from rural Mvomero, Tanzania, to examine empirical relationships among multiple measures of household and individual SES and demographics, on the one hand, and malaria prevention, illness, and diagnosis and treatment behaviours, on the other. We find that access to prevention and treatment is significantly associated with indicators of households' wealth; education-based disparities do not emerge in this context. Meanwhile, reported malaria illness shows a stronger association with demographic variables than with SES (controlling for prevention). Greater understanding of the mechanisms through which SES and malaria policies interact to influence disease risk can help to reduce health disparities and reduce the malaria burden in an equitable manner. PMID- 21271420 TI - Perceived discrimination as a risk factor for Latina/o youth's substance use: do parent- and peer-based communication and relationship resources act as protective factors? AB - Based on general strain theory, it was hypothesized that as Latina/o youth experience perceived discrimination, they are more likely to develop acculturation stress and, in turn, more likely to use substances. Two additional hypotheses were set forth to examine how parent- and peer-based communication, relationship, and norm resources may function as buffers, thereby decreasing the likelihood that strained youth will use substances. Latina/o youth (N = 728) from 23 schools in Phoenix, AZ, completed surveys at three waves over 2 years. Structural equation modeling (SEM) results supported the first hypothesis. Yet, contrary to the second hypothesis, neither parent nor peer resources were significant moderators. Implications are discussed for theory and parent- and peer-based prevention research directed at perceived discrimination, acculturation stress, and substance use. PMID- 21271421 TI - Effects of entertainment (mis) education: exposure to entertainment television programs and organ donation intention. AB - This study investigates antecedents and outcomes of entertainment television consumption in organ donation with the Orientation1-Stimulus-Orientation2 Response (O1-S-O2 -R) model. It reveals that organ donation knowledge seems significantly related to recall of entertainment television programs and attitudes toward organ donation. Meanwhile, recall of entertainment television programs significantly predicts people's perception of medical mistrust, which in turn negatively predicts attitudes toward organ donation, while attitudes toward organ donation significantly predict behavioral intention in signing a donor card. It also suggests significant mediation relationships among the pre orientation variable, stimulus, post-orientation variable, and attitudinal and behavioral outcomes. This study provides an integrative theoretical framework to study media effects on organ donation and empirical evidence for "entertainment miseducation" (Morgan, Harrison, Chewning, Davis, & DiCorcia, 2007). PMID- 21271422 TI - Tracing the utility of injury surveillance data in Pretoria (South Africa) and Boras (Sweden). AB - Our research attempted to study the factors that influenced the use of injury data in two cities, representing different injury and socio-economic profiles. In Pretoria, the South African capital city, injury data uptake was constrained by, among other factors, the transitional institutional environment, stakeholders' suspicion of research and the absence of safety promotion champions. In the Swedish city of Boras, injury data uptake was facilitated by well-established research agency-municipality partnerships, injury prevention champions, a receptive political and knowledge driven environment and dedicated resources. The study signified the role of a range of content issues, contextual arrangements, social actors who may or may not operate from a perspective of sufficient consensus and institutional communication processes that may either facilitate or hinder the multiple employment and rapid movement of data along the 'ladder of knowledge utilisation'. Safety promotion researchers may need to expand their roles beyond data production to improve data utility. PMID- 21271423 TI - Differential response of two Pinus spp. to avian nitrogen input as revealed by nitrogen isotope analysis for tree rings. AB - Temporal variations in N concentration and delta(15)N value of annual tree rings (1 year of time resolution) of two Japanese Black Pine (Pinus thunbergii) and three Japanese Red Pine (Pinus densiflora) trees under current breeding activity of the Great Cormorant (Pharacrocorax carbo) and the Black-tailed Gull (Larus crassirostris), respectively, in central and northeastern Japan were studied. Both species from control sites where no avian input occurs show negative values (delta(15)N = around -4 0/00 to -2 0/00) which are common among higher plants growing under high rainfall regimes. The delta(15)N values of P. densiflora show uniformly positive values several years before and after the breeding event, indicating N translocation that moved the absorbed N of a given growth year to tree rings of the previous year while a clear historical value of soil N dynamics was kept intact in the annual rings of P. thunbergii. Long-term N trends inferred from tree rings must take into account tree species with limited translocation rates that can retain actual N annual acquisition. PMID- 21271424 TI - Mytilus galloprovincialis as a bioindicator of environmental conditions: the case of the eastern coast of the Adriatic Sea. AB - The marine mussel Mytilus galloprovincialis lives attached to the surface of hard substrata, where its exposure and relative immobility allow it to record changes in ambient seawater. It is also found along the eastern coast of the Adriatic Sea. Oxygen and carbon isotopes were analysed for calcite and aragonite in separate shell layers, while major, minor and trace elements in the bulk shell were analysed to evaluate environmental conditions such as the temperature of carbonate deposition, freshwater influence and locations of anthropogenic pollution. We found that, on average, aragonite is enriched by 1.10/00 in (13)C and by 0.20/00 in (18)O compared with calcite. The calculated temperatures for M. galloprovincialis shell growth from the investigated area range from 13.4 to 20.9 degrees C for calcite and from 16.6 to 23.1 degrees C for aragonite. According to the delta(18)O and delta(13)C values of shell layers, we can separate the investigated area into three locations: those with more influence of freshwater, those with less influence of freshwater and those with marine environments. The highest concentrations of manganese, barium, boron, arsenic, nickel and chromium were observed in shells from Omis, Bacvice and Zablace (Central Adriatic) and Sv. Ivan (South Adriatic), where chemical and heavy industries are located and where sewage is known to be discharged into coastal areas. The highest concentrations of zinc, lead and copper were measured in samples from Pula, Rijeka and Gruz, where there are also ports in addition to industry. PMID- 21271425 TI - A multiperspective approach to the conceptualization of executive functions. AB - The concept of executive function (EF) is deemed unclear and difficult to operationalize. We use a multiperspective approach to quantify and reduce the current proliferation of EFs. A literature review of 60 studies identified 68 subcomponents of EF: Through objective statistical techniques, these terms were reduced to 18 by removing semantic overlap (using latent semantic analysis) and psychometric overlap (using hierarchical cluster analysis). However, still such a large number of functions lacks parsimony. We therefore revisit the concept of EF and suggest that the many proposed subcomponents are not functions per se but rather a number of task-specific behaviors. PMID- 21271426 TI - The effects of drug-prevention messages on the accessibility of identity-related constructs. AB - Recent theoretical work has posited that the self-system guides behavior via currently activated self-concepts. The authors adopted this framework to the study of drug-prevention messages by examining the extent to which messages can alter the accessibility of views of self and of drugs that would support nonuse. Participants were exposed to 1 of 3 print-ad conditions: autonomy-themed prevention messages (treatment), health-information themed prevention messages (comparison), and informational consumer ads (control). Outcomes were reaction times to make dichotomous judgments. Relative to comparison and control ads, treatment ads were more successful at activating a self-view as a nonuser, a view that marijuana use is inconsistent with autonomy, and unwillingness to use marijuana. Post-hoc analysis revealed that the effect of ad condition on unwillingness was partially mediated by the accessibility of self-view as a nonuser. PMID- 21271427 TI - An assessment of printed diabetes-prevention materials available to a Northern Plains tribe. AB - The purpose of this study was to characterize the literacy demands of print materials used to encourage diabetes prevention on the Crow Reservation. Diabetes prevention materials included pamphlets, booklets, and fact sheets provided to Crow people. Readability was assessed using the SMOG formula. Diabetes related vocabulary was assessed to determine whether medical/scientific words were used and if they were defined. Numeracy demand was assessed by counting the number of times different numeracy concepts were used in each material. Lists, charts, and graphs were assessed using the PMOSE/IKIRSCH tool. We found that materials were written at a readability level higher than recommended. Across all materials, vocabulary terms were used often but not always defined. Numeric terms were not often used, but when used they were not defined. Most of the materials required the reader to read numbers or count. However, overall numeracy demand was relatively low. The PMOSE/IKIRSCH scores for materials were adequate. The authors found a mismatch between the level of skills required in some of the materials and the skills of the average person, including adults on the Crow Reservation. This study highlights the need for designing materials specifically for the intended audience, including rigorous pilot testing of materials. PMID- 21271428 TI - Organization development in community contexts. PMID- 21271429 TI - Helping organizations help others: organization development as a facilitator of social change. AB - This article explores organization development (OD) interventions and their likelihood of increasing social change outcomes in public agencies. The central argument of this work is that public and nonprofit organizations can deliver better social outcomes by systematically engaging in OD interventions. An in depth survey was conducted in 3 agencies of the Commonwealth of Pennsylvania at the end of the gubernatorial administration of Tom Ridge (1995-2002). During his administration, Governor Ridge led the agencies of Pennsylvania government through a large-scale change effort to improve the efficiency and effectiveness of service delivery to the citizens of the Commonwealth of Pennsylvania. The change effort was a remarkable event for the Commonwealth because no other governor in the history of the state had attempted to conceptualize and deliver a comprehensive large-scale change management initiative. The successes and setbacks served as a fertile context to shed light on the following research question: Do OD interventions increase the likelihood that public organizations will deliver better social outcomes? This question is important in that public organizations may need to engage in organization development activities to improve their internal operations, which in turn may help them provide exemplary social outcomes to those whom they serve. In short, organization development interventions might allow public organizations to help themselves to help others. PMID- 21271430 TI - Leading change through collaborative partnerships: a profile of leadership and capacity among local public health leaders. AB - Collaborative partnerships have grown in prominence as vehicles for systems change and organizational development among a network of organizations, particularly in the complex field of public health. Likewise, supporting the functioning and effectiveness of collaborative partnerships has become a key interest among organizational development scholars and community psychologists alike. In the question of capacity-building, no aspect of collaborative capacity has received greater attention than that of leadership. Research on collaborative partnerships has highlighted the importance of shared leadership while at the same time acknowledging that specific individuals do and often must emerge and assume more prominent roles in the partnership in order for the work of the partnership to move forward. However, we have limited knowledge of these key individuals and the roles that they play in non-hierarchical, voluntary partnerships. The present study is a comparative case study of prominent leaders in three regional public health partnerships. The aim of this investigation is to explore the questions: (1) What does it mean to be a leader in a context where no one is "in charge?" (2) What roles do those individuals identified as leaders play?, and (3) What are the specific capacities that enable the enactment of these roles? We find that those viewed as leaders by their partnerships shared a similar profile both in the range and types of roles they play and the capacities that enable them to carry out these roles. Further, we find that while individual attributes such as passion, knowledge, and leadership skills are important, some of the most prominent capacities are rooted in the organizational and institutional contexts within which the leader is nested. PMID- 21271431 TI - Testing a measure of organizational learning capacity and readiness for transformational change in human services. AB - Transformative organizational change requires organizational learning capacity, which we define in terms of (1) internal and (2) external organizational systems alignment, and promoting a culture of learning, including (3) an emphasis on exploration and information, (4) open communication, (5) staff empowerment, and (6) support for professional development. We shortened and adapted Watkins and Marsick's Dimensions of Learning Organizations Questionnaire into a new 16-item Organizational Learning Capacity Scale (OLCS) geared more toward nonprofit organizations. The OLCS and its subscales measuring each of the above 6 dimensions are unusually reliable for their brevity. ANOVAs for the OLCS and subscales clearly and consistently confirmed extensive participant observations and other qualitative data from four nonprofit human service organizations and one local human service funding organization. PMID- 21271432 TI - Promoting strengths, prevention, empowerment, and community change through organizational development: lessons for research, theory, and practice. AB - SPEC Learning and Changing by Doing is a three-year, action research, and organizational change project designed to ultimately promote social justice and well-being in the community. SPEC is an acronym that stands for Strengths, Prevention, Empowerment, and Community Change. The project consists of five organizations tackling internal organizational change in order to better promote justice and well-being in their respective constituencies. In this article we present a formative evaluation of this multicase study of organizational change in human services. This article contributes to the empirical and theoretical literature on organizational change in the nonprofit human service milieu. PMID- 21271433 TI - Using strategic planning and organizational development principles for health promotion in an Alaska native community. AB - Health promotion aims to support people in their efforts to increase control over factors that impact health and well-being. This emphasis on empowerment and contextual influences allows for a more holistic conceptualization of health and approaches to promoting health that are anchored in principles of community development and systems change. Piciryaratgun Calritllerkaq (Healthy Living Through A Healthy Lifestyle) is a collaboration between a Yup'ik village in rural Alaska and researchers from the University of Alaska Fairbanks. The goal was to improve nutrition, increase exercise, and decrease stress. The project utilized elements of organization development and strategic planning to develop a local infrastructure and process and to promote local expertise. The project team developed goals, objectives, action, and evaluation plans that integrated local traditions, Yup'ik culture, and research. PMID- 21271434 TI - The urban context: a place to eliminate health disparities and build organizational capacity. AB - This study seeks to examine the process of building the capacity to address health disparities in several urban African American neighborhoods. An inter organizational network consisting of a research university, community members, community organizations, media partners, and foundations was formed to develop a community-based intervention designed to provide health promotion and disease prevention strategies for type 2 diabetes and hypertension. In-depth qualitative interviews (n = 18) with foundation executives and project directors, civic organization leadership, community leaders, county epidemiologist, and university partners were conducted. Our study contextualizes a process to build a public health partnership using cultural, community, organizational, and societal factors necessary to address health disparities. Results showed 5 important factors to build organizational capacity: leadership, institutional commitment, trust, credibility, and inter-organizational networks. These factors reflected other important organizational and community capacity indicators such as: community context, organizational policies, practices and structures, and the establishment of new commitments and partnerships important to comprehensively address urban health disparities. Understanding these factors to address African American health disparities will provide lessons learned for health educators, researchers, practitioners, foundations, and communities interested in building and sustaining capacity efforts through the design, implementation, and maintenance of a community-based health promotion intervention. PMID- 21271435 TI - Comparison of styrene oxide enantiomers for hepatotoxic and pneumotoxic effects in microsomal epoxide hydrolase-deficient mice. AB - Styrene is hepatotoxic and pneumotoxic in mice. Styrene oxide, the active metabolite, is detoxified via hydrolysis by microsomal epoxide hydrolase (mEH). Racemic styrene oxide was previously found to be more lethal and produced increased toxicity in mEH-/- mice compared to wild-type mice. The hepatotoxicity and pneumotoxicity of the R- and S-styrene oxide (SO) enantiomers were compared in wild-type and mEH-deficient mice (mEH-/-). Twenty-four hours following administration of 150 mg/kg ip, neither enantiomer produced hepatotoxicity, but S SO was more pneumotoxic. However, in mEH-/- mice R-SO produced greater decreases in hepatic glutathione levels 3 h after administration. The basis for the unusual greater toxicity of S-SO, rather than the generally more toxic R-SO, in mEH-/- mice may be related to differences in detoxification by EH. PMID- 21271436 TI - Estimation of the percutaneous absorption of permethrin in humans using the parallelogram method. AB - The objective of this study was to develop an estimate of the percent dermal absorption of permethrin in humans to provide more accurate estimates of potential systemically absorbed dose associated with dermal exposure scenarios. Piperonyl butoxide (PBO) was used as a reference compound. The human percutaneous absorption estimate was based on the assumption that the ratio of in vivo dermal absorption (expressed as a percentage during a given time period) of permethrin through rat skin to in vitro dermal absorption through rat skin was the same as the ratio of in vivo dermal absorption in humans to in vitro dermal absorption with human skin, known as the parallelogram method. The ratio of dermal absorption by in vitro rat skin to absorption by in vitro human skin ranged from 6.7 to 15.4 (for a 24-h exposure period) with an average of 11. Data suggest in vivo human dermal absorption values for permethrin ranging from 1.4 to 3.3% when estimated based on 24-h in vivo rat values, and 2.5 to 5.7% based on 5-d in vivo rat values. The parallelogram method used to estimate dermal absorption of permethrin and PBO is supported by results from several other compounds for which in vivo and in vitro rat and human dermal absorption data exist. Collectively, these data indicate that estimating human dermal absorption from in vitro human and rat plus in vivo rat data are typically accurate within +/-3-fold of the values measured in human subjects. PMID- 21271437 TI - Fate and developmental effects of dietary uptake of methylmercury in Silurana tropicalis tadpoles. AB - Adverse effects of methylmercury (MeHg) exposure during amphibian metamorphosis remain to be fully characterized. Most previous investigations determined effects of short-term exposure to elevated dose rates, without information on mercury (Hg) depuration and degradation pathways. Since metamorphosis is primarily controlled by thyroid hormones (TH), alterations in this process suggest a disruption of the TH endocrine axis. The aim of this research was to (1) characterize patterns of MeHg accumulation and depuration in tadpoles and (2) examine effects of MeHg accumulation on metamorphosis and the TH axis. Silurana tropicalis tadpoles were exposed to environmental levels of dietary MeHg until metamorphic climax. Whole-body MeHg and total Hg (THg) levels were measured, as well as the number of metamorphs, rate of metamorphosis, body size, and whole body triiodothyronine (T3) levels at metamorphosis. Tadpoles exposed to a higher level of MeHg exhibited increased mortality and size, and reduced metamorphosis. At lower levels of MeHg, body burdens increased rapidly and eventually reached a plateau, whereas no plateau was reached at a higher level of MeHg exposure. T3 levels were not affected. Data indicate that at low and medium levels of exposure, depuration of MeHg may prevent toxicity in tadpoles. However, depuration mechanisms may be insufficient at high doses, producing disruption of metamorphosis and death. Although there were no marked effects of MeHg on whole body T3 levels, further investigation of other components of the TH axis is warranted. PMID- 21271438 TI - Topical metal chelation therapy ameliorates oxidation-induced toxicity in diabetic cataract. AB - Oxidative stress plays a critical role in cataractogenesis, the leading cause of blindness worldwide. Since transition metals generate reactive oxygen species (ROS) formation, metal chelation therapy has been proposed for treatment of cataracts. However, the effectiveness of most chelators is limited by low tissue penetrability. This study is the first to demonstrate that the topically applied divalent metal chelator ethylenediamine tetraacetic acid (EDTA) combined with the carrier and permeability enhancer methyl sulfonyl methane (MSM) ameliorates both oxidation-induced lens opacification and the associated toxic accumulation of protein-4-hydroxynonenal (HNE) adducts. Both in vitro (rat lens culture) and in vivo (diabetic rats), EDTA-MSM (1) significantly reduced lens opacification by about 40-50%, (2) significantly diminished lens epithelial cell proliferation and fiber cell swelling in early stages of cataract formation in vivo, and (3) notably decreased the levels of protein-HNE adducts. These findings have important implications specifically for the treatment of cataract and generally for other diseases in which oxidative stress plays a key pathogenic role. PMID- 21271439 TI - Magnesium in drinking water modifies the association between trihalomethanes and the risk of death from colon cancer. AB - The objectives of this study were to (1) examine the relationship between total trihalomethanes (TTHM) levels in public water supplies and death attributed to colon cancer and (2) determine whether magnesium (Mg) levels in drinking water modify the effects of TTHM on risk of colon cancer development. A matched case control study was used to investigate the relationship between the risk of death attributed to colon cancer and exposure to total trihalomethanes (TTHM) in drinking water in 53 municipalities in Taiwan. All colon cancer deaths of the 53 municipalities from 1998 through 2007 were obtained from the Bureau of Vital Statistics of the Taiwan Provincial Department of Health. Controls were deaths from other causes and were pair-matched to the cancer cases by gender, year of birth, and year of death. Each matched control was selected randomly from the set of possible controls for each cancer case. Data on TTHM levels in drinking water were collected from Taiwan Environmental Protection Administration. Information on the levels of Mg in drinking water was obtained from the Taiwan Water Supply Corporation. The municipality of residence for cancer cases and controls was presumed to be the source of the subject's TTHM and Mg exposure via drinking water. Relative to individuals whose TTHM exposure levels were <4.9 ppb, the adjusted odds ration (OR) (with 95% confidence interval [CI]) for colon cancer was 1.14 (1.01-1.28) for individuals who had resided in municipalities served by drinking water with a TTHM exposure>=4.9 ppb. Evidence of an interaction between drinking-water TTHM and Mg intake via drinking water was noted. This is the first study to report an effect modification by Mg intake from drinking water in association between TTHM exposure and risk of colon cancer occurrence. Better knowledge of this modifying factor will help in public policymaking and setting health standards. PMID- 21271440 TI - From the editor. Dealing with the needs of aged parents. PMID- 21271441 TI - Gender, marital power, and marital quality in later life. AB - This study uses data from the 1992 Health and Retirement Study to examine gender differences in marital power and marital quality among older adults and to assess whether there are gender differences in the correlates of marital quality and marital power in later life. Results show that women report lower marital happiness, marital interaction, and marital power than do men, on average. These differences persist even after controlling for a number of life-course events and transitions. Further, results show that gender differences are also evident in the relationship of employment, childrearing, caregiving, and health factors with marital quality and power. PMID- 21271442 TI - Psychosocial predictors of self-esteem in a multiethnic sample of women over 50 at risk for HIV. AB - Self-esteem is linked to high-risk behaviors in other populations but has not been examined in women aged 50 and older. This study explored how self-esteem is related to variables that can influence high-risk sexual behaviors in women over 50. A multiethnic community-based sample of 572 women aged 50 and older completed an anonymous questionnaire on sexual behaviors, sociodemographic characteristics, and psychosocial measures relevant to midlife and older women. Regression analysis showed sensation-seeking, HIV stigma, sexual assertiveness, and self silencing predicted self-esteem in women over 50 (F = 43.632, p < .001). Factors such as relational context, interpersonal power, and silencing can affect self esteem and may be contributing to HIV risk in this group. PMID- 21271444 TI - A pilot study of the application of the transtheoretical model during strength training in older women. AB - A Transtheoretical Model (TTM) goal-setting tool was used during strength training in women. Volunteers (mean age = 69, N = 27) were assigned to a strength training only or strength training/behavior change 12-week intervention. A pre/posttest, quasiexperimental design assessed TTM constructs, Health-Related Quality of Life, and functional fitness measurements. Multiple ANCOVAs revealed significant differences between groups on lower body strength (p = .001), upper body flexibility (p = .002), Decisional Balance (p = .024,) and Stage of Change for Exercise (p = .010). Stage of change progression may be enhanced using a goal setting tool during strength training in older women. PMID- 21271443 TI - Working beyond 65: predictors of late retirement for women and men MBAs. AB - Comparisons of those who planned to continue working after the age of 65 with those who did not were made for 145 women and 414 men working in managerial fields. All received MBA degrees between the years of 1973 and 1982. About 20% definitely wanted to work after age 65. More positive views of work were predictive of wanting to continue working as was having nontraditional gender role attitudes. Men who planned to continue working were particularly likely to have a spouse wanting to work past the age of 65. Several other factors appeared to operate differently for women and men. PMID- 21271445 TI - Experiences of veterans' widows following conjugal bereavement: a qualitative analysis. AB - This qualitative study analyzed the conjugal grief experience of veterans' widows. The narratives yielded several themes, including the decreased self reported symptoms of distress when widows reported having positive social support without negative social support, the development of an ongoing relationship with their deceased spouses with a mechanism for creating meaning from their loss, and the assumption of a new identity and new roles and responsibilities. Widows who ascribed a belief that external forces control their life events and those who have children with psychosocial issues reported increased symptoms of distress related to their spouses' death. PMID- 21271447 TI - Bibliometric study of Medical Reference Services Quarterly, 1982-2009. AB - Medical Reference Services Quarterly began publication in 1982, covering topics of current interest and practical value to public services librarians in medical and related specialties. Since then, it has expanded in scope to include more aspects of health sciences librarianship. This article is a systematic study of all 428 peer-reviewed articles published from 1982 through 2009, with a comprehensive description of content and a citation analysis. Content is extensively analyzed for article subject, and cited references are examined for subject, type of cited material, and average age. In addition, author, institutional, and regional productivity is determined and ranked. PMID- 21271448 TI - Engaging students in active learning: use of a blog and audience response system. AB - Librarians provide instruction to medical students as part of a core course in the medical school curriculum. Instruction was provided, in part, through didactic sessions covering professional-level medical information resources, PubMed search skills, psychosocial information, and evidence-based medicine. Librarians redesigned instructional sessions with the goals of increasing student engagement and minimizing the lecture format, maximizing the number of students receiving feedback on their search and evaluation skills, and permitting students to see a variety of possible responses as well as engage in peer- and self evaluation. Librarians integrated the use of a blog and an audience response system (ARS) into the instruction to help accomplish these goals. PMID- 21271449 TI - A hospital-based patient and family education center: if you build it, will they come? AB - Librarians located in a 560-bed, inner city academic medical center with 25,000 + admissions per year planned and opened a Patient and Family Education Center (PFEC) in the lobby of a new patient care pavilion. A review of use in the first 19 months revealed that expected needs were being met while a variety of unexpected needs were identified. Ongoing use continues to be monitored by a detailed log of patron visits maintained by library staff. This article describes the evolution of the Patient and Family Education Center, outreach to the hospital community, and plans for the future. PMID- 21271450 TI - Effectiveness of a liaison program in meeting information needs of college of pharmacy faculty. AB - This article describes the creation and implementation of focus groups to evaluate the effectiveness of a health sciences library's liaison program of the College of Pharmacy faculty and to better understand the faculty's information needs in order to design new and improved library services. The liaison services support the teaching and research needs of faculty and students through literature research, classroom teaching, and an extensive library collection of pharmacy literature. Focus group results demonstrated a high level of satisfaction with library liaison services and collections. Opportunities exist for expanded interaction with graduate students and greater marketing of library services to increase faculty awareness of specific library programs. PMID- 21271451 TI - ScienceDirect through SciVerse: a new way to approach Elsevier. AB - SciVerse is the new combined portal from Elsevier that services their ScienceDirect collection, SciTopics, and their Scopus database. Using SciVerse to access ScienceDirect is the specific focus of this review. Along with advanced keyword searching and citation searching options, SciVerse also incorporates a very useful image search feature. The aim seems to be not only to create an interface that provides broad functionality on par with other database search tools that many searchers use regularly but also to create an open platform that could be changed to respond effectively to the needs of customers. PMID- 21271452 TI - HTML5: a new standard for the Web. AB - HTML5 is the newest revision of the HTML standard developed by the World Wide Web Consortium (W3C). This new standard adds several exciting news features and capabilities to HTML. This article will briefly discuss the history of HTML standards, explore what changes are in the new HTML5 standard, and what implications it has for information professionals. A list of HTML5 resources and examples will also be provided. PMID- 21271453 TI - Going mobile: free and easy. AB - After almost two decades, mobile technologies are now such a part of the fabric of the hospital environment that hospital libraries must take this opportunity to continue to positively impact health outcomes by providing health professionals with valuable information and services via personal digital assistants (PDAs) and smartphones. This article provides background information on mobile technology use and handheld devices. It describes how hospital librarians, regardless of staff, budget, or access to technology, can position the hospital library to connect health professionals to clinically relevant mobile resources and library services. Suggestions for the promotion of mobile resources are included, as well as tips for keeping current. A significant amount of free content is identified. PMID- 21271454 TI - The introduction of a medical informatics course into a medical school curriculum. AB - Fulfilling the need for a course in medical informatics to be taught to medical students requires an effort on the part of the teaching faculty and administration. Creators of the curriculum must take into account contemporary pedagogical trends and the direction of medical education. Producing a course of study requires a firm conviction that practicing medicine in the 21st century demands currency, accuracy, and literacy with the available information sources. PMID- 21271458 TI - Prolonged sulforaphane treatment activates survival signaling in nontumorigenic NCM460 colon cells but apoptotic signaling in tumorigenic HCT116 colon cells. AB - Sulforaphane (SFN) is a naturally occurring chemopreventive agent; the induction of cell cycle arrest and apoptosis is a key mechanism by which SFN exerts its colon cancer prevention. However, little is known about the differential effects of SFN on colon cancer and normal cells. In this study, we demonstrated that SFN (15 MUmol/L) exposure (72 h) inhibited cell proliferation by up to 95% in colon cancer cells (HCT116) and by 52% in normal colon mucosa-derived (NCM460) cells. Our data also showed that SFN exposure (5 and 10 MUmol/L) led to the reduction of G1 phase cell distribution and an induction of apoptosis in HCT116 cells, but to a much lesser extent in NCM460 cells. Furthermore, the examination of mitogen activated protein kinase (MAPK) signaling status revealed that SFN upregulated the phosphorylation of extracellular-regulated kinase 1/2 (ERK1/2) in NCM460 cells but not in HCT116 cells. In contrast, SFN enhanced the phosphorylation of stress-activated protein kinase (SAPK) and decreased cellular myelocytomatosis oncogene (c-Myc) expression in HCT116 cells but not NCM460 cells. Taken together, the activation of survival signaling in NCM460 cells and apoptotic signaling in HCT116 cells may play a critical role in SFN's stronger potential of inhibiting cell proliferation in colon cancer cells than in normal colon cells. PMID- 21271460 TI - Decreasing treatment dropout by addressing expectations for treatment length. AB - Therapy dropout or premature termination is a significant problem which impedes the delivery of psychotherapy services. In this study, a method aimed to reduce the occurrence of premature termination by addressing clients' duration expectations was examined. Sixty-three adult clients seeking psychotherapy services from a psychology department training clinic were randomized into control (n=32) and education groups (n=31). On average, those clients in the education group, who were provided information about the dose-effect model prior to their intake appointment, were found to stay in treatment significantly longer (d=0.55) and were more likely to be classified as therapy completers (RR=3.55) when compared to clients in the control group. PMID- 21271459 TI - Macronutrient composition influence on breast cancer risk in Hispanic and non Hispanic white women: the 4-Corners Breast Cancer Study. AB - The association of dietary macronutrient composition with risk of breast cancer is not well understood. We investigated the macronutrient composition of diet in the 4-Corners Breast Cancer Study. Logistic regression models were used for case control comparisons adjusted for age, center, education, smoking, total activity, calories, dietary fiber, dietary calcium, height, parity, recent hormone exposure, reference year body mass index (BMI), and the interaction of BMI and recent hormone exposure. Breast cancer risk declined with increasing dietary fat and increased with carbohydrates similarly across ethnicity and menopausal status. Associations of carbohydrate (direct) and fat (inverse), particularly saturated and monounsaturated fat, with breast cancer were present among normal and overweight postmenopausal women and absent among obese postmenopausal women. No substantive differences were noted in the association of macronutrients with risk of breast cancer between non-Hispanic white and Hispanic women. Associations of the macronutrients carbohydrate and fat with breast cancer risk were attenuated among postmenopausal obese women. PMID- 21271461 TI - Therapist effects in routine psychotherapy practice: an account from chronic fatigue syndrome. AB - The effect of therapists in psychotherapy is a much debated topic, with a number of studies showing therapist variance being large while other studies show little or no variability in outcomes due to therapists. The aim of this study was to investigate therapist effects in a well-defined sample of patients and therapists from an outpatient service which specializes in providing cognitive behaviour therapy (CBT) for patients with chronic fatigue syndrome (CFS). Therapy was provided in a highly specialized clinical setting for CFS and was delivered by qualified CBT therapists with at least 2 years experience with this client group. Three hundred and seventy-four patients with CFS and 12 cognitive behavioural psychotherapists took part. Therapist effects on the primary outcomes of fatigue and disability were investigated with multilevel random effects models and variance component analysis. Different models were computed and compared. Results showed a reduction in fatigue and disability scores after therapy. Variance explained by therapists, when demographic covariates were accounted for, was 0% for fatigue and under 2% for disability. A number of important factors may have played a significant role in minimizing therapist effects in our study. These are: specialist setting, single centre, patients with the same primary diagnosis, therapists of the same orientation and training, shared environment and supervision. Future studies may stress the importance of these factors in the investigation of the therapist effect in psychotherapy. PMID- 21271462 TI - Neural evidence for "intuitive prosecution": the use of mental state information for negative moral verdicts. AB - Moral judgment depends critically on theory of mind (ToM), reasoning about mental states such as beliefs and intentions. People assign blame for failed attempts to harm and offer forgiveness in the case of accidents. Here we use fMRI to investigate the role of ToM in moral judgment of harmful vs. helpful actions. Is ToM deployed differently for judgments of blame vs. praise? Participants evaluated agents who produced a harmful, helpful, or neutral outcome, based on a harmful, helpful, or neutral intention; participants made blame and praise judgments. In the right temporo-parietal junction (right TPJ), and, to a lesser extent, the left TPJ and medial prefrontal cortex, the neural response reflected an interaction between belief and outcome factors, for both blame and praise judgments: The response in these regions was highest when participants delivered a negative moral judgment, i.e., assigned blame or withheld praise, based solely on the agent's intent (attempted harm, accidental help). These results show enhanced attention to mental states for negative moral verdicts based exclusively on mental state information. PMID- 21271463 TI - The acquisition of morphological knowledge investigated through artificial language learning. AB - Affix knowledge plays an important role in visual word recognition, but little is known about how it is acquired. The authors present a new method of investigating the acquisition of affixes in which participants are trained on novel affixes presented in novel word contexts (e.g., sleepnept). Experiment 1 investigated the role of semantic information on affix acquisition by comparing a form-learning condition with a condition in which participants also received definitions for each novel word. Experiment 2 investigated the role of long-term consolidation on affix acquisition by comparing knowledge of learned affixes two days and nearly two months after training. Results demonstrated that episodic knowledge of affixes can be acquired shortly after a single training session using either form or semantic learning, but suggested that the development of lexicalized representations of affixes requires the provision of semantic information during learning as well as a substantial period of offline consolidation. PMID- 21271464 TI - The relationship between allocentric and egocentric frames of reference and categorical and coordinate spatial information processing. AB - We report two experiments on the relationship between allocentric/egocentric frames of reference and categorical/coordinate spatial relations. Jager and Postma (2003) suggest two theoretical possibilities about their relationship: categorical judgements are better when combined with an allocentric reference frame and coordinate judgements with an egocentric reference frame (interaction hypothesis); allocentric/egocentric and categorical/coordinate form independent dimensions (independence hypothesis). Participants saw stimuli comprising two vertical bars (targets), one above and the other below a horizontal bar. They had to judge whether the targets appeared on the same side (categorical) or at the same distance (coordinate) with respect either to their body-midline (egocentric) or to the centre of the horizontal bar (allocentric). The results from Experiment 1 showed a facilitation in the allocentric and categorical conditions. In line with the independence hypothesis, no interaction effect emerged. To see whether the results were affected by the visual salience of the stimuli, in Experiment 2 the luminance of the horizontal bar was reduced. As a consequence, a significant interaction effect emerged indicating that categorical judgements were more accurate than coordinate ones, and especially so in the allocentric condition. Furthermore, egocentric judgements were as accurate as allocentric ones with a specific improvement when combined with coordinate spatial relations. The data from Experiment 2 showed that the visual salience of stimuli affected the relationship between allocentric/egocentric and categorical/coordinate dimensions. This suggests that the emergence of a selective interaction between the two dimensions may be modulated by the characteristics of the task. PMID- 21271465 TI - What is the most reliable imaging modality for small colonic polyp characterization? Study of white-light, autofluorescence, and narrow-band imaging. AB - BACKGROUND AND STUDY AIMS: In vivo optical diagnosis of small colorectal polyps has potential clinical and cost advantages, but requires accuracy and high interobserver agreement for clinically acceptability. We aimed to assess interobserver variability and diagnostic performance of endoscopic imaging modalities in characterizing small colonic polyps. METHODS: High quality still images of 80 polyps < 1 cm were recorded using white-light endoscopy (WLE), autofluorescence imaging (AFI) and narrow-band imaging with and without magnification (NBI and NBImag). All images were assessed for quality, prediction of polyp histology, and vascular pattern intensity (with NBI) by nine experienced colonoscopists (four experts in advanced imaging) from five UK centers. Interobserver agreement (kappa statistic), sensitivity, specificity, and accuracy were calculated compared with histopathological findings. RESULTS: Interobserver agreement for predicting polyp histology using NBImag was significantly better for experts (kappa = 0.63, substantial) compared with nonexperts (kappa = 0.30, fair; P < 0.001), and was moderate for all colonoscopists with WLE, AFI and NBI. Interobserver agreement for vascular pattern intensity using NBI was 0.69 (substantial) for experts and 0.57 (good) for nonexperts. NBImag had higher sensitivity than WLE (experts, 0.93 vs. 0.68, P < 0.001; nonexperts, 0.90 vs. 0.52, P < 0.001) and higher overall accuracy (experts, 0.76 vs. 0.64, P = 0.003; nonexperts 0.61 vs. 0.40, P < 0.001). AFI had worse accuracy than WLE for both expert colonoscopists (0.53 vs. 0.64, P = 0.02) and nonexperts (0.32 vs. 0.40, P = 0.04). CONCLUSIONS: Of the imaging modalities tested, NBImag appeared to have the best overall accuracy and interobserver agreement, although not adequate for in vivo diagnosis. NBI and AFI did not have better sensitivity, specificity, or accuracy compared with WLE. PMID- 21271466 TI - Sporadic duodenal polyps: classification, investigation, and management. AB - Sporadic duodenal polyps are uncommon, being found in up to 5% of patients referred for upper gastrointestinal endoscopy. They are often discovered incidentally and are usually asymptomatic. The histological subtype of polyps cannot always be determined on endoscopic appearance alone, and biopsy is advocated. The need for further imaging, endoscopic procedures, surgical resection, and surveillance is determined by the histological features, neoplastic potential and associated symptoms. This review describes the different subtypes of sporadic duodenal polyp: adenomas, hamartomas, gastric metaplasia, inflammatory fibroids, lipomas, leiomyomas, carcinoids, stromal tumors, solitary Peutz-Jeghers polyps, lymphomas, and other rare benign and malignant lesions. It describes the epidemiology, clinical presentation, investigation, management options, and screening and surveillance strategies for each, based on current evidence. PMID- 21271467 TI - Should we discard the needle stylet during EUS-FNA? PMID- 21271470 TI - ERCP for altered Roux-en-Y anatomy: a single-balloon or short double-balloon enteroscope? PMID- 21271472 TI - [The unity of internal medicine must be preserved and cultivated]. PMID- 21271473 TI - [Recent advances in the treatment of superficial vein thrombosis and extracranial carotid artery stenosis]. AB - Superficial vein thrombosis (SVT) occurs at least as frequent as deep vein thrombosis (DVT), and shares common risk factors with venous thromboembolism. The CALISTO trial was the first to provide specific recommendations for the pharmacologic treatment of SVT. Before treatment is initiated, an accompanying DVT must be excluded and the proximal extension of the SVT assessed. If the proximal extension of the thrombus is closer than 3 cm towards the deep vein system, it should be treated like DVT. Under certain conditions treatment with fondaparinux is indicated in acute symptomatic SVT. Furthermore, compression treatment is recommended. Extracranial carotid artery stenosis can be treated by either surgical thrombarterectomy or catheter based endovascular stent implantation. Trials comparing the two methods have not provided conclusive results on whether the two strategies are equally safe and effective. Considering the latest data from RCTs, careful patient selection (symptoms, comorbidities, age, anatomy, re-stenosis) including individual interdisciplinary discussion appears of ample importance. To date no information is available on whether patients with asymptomatic high grade carotid stenosis receiving "best medical therapy" should be considered for revascularisation in general or only in selected circumstances. PMID- 21271474 TI - [Recent advances in the treatment of type 1 diabetes mellitus]. AB - INTERVENTIONAL APPROACHES TO BETA CELL PRESERVATION: In a pilot study, initial attempts at primary prevention by preserving islet beta cells have been successful with highly hydrolyzed milk formula in children who are at high genetic risk of diabetes. Attempts at secondary prevention by intranasal application in children with a high-risk HLA genotype and positive islet autoantibodies have been disappointing. But in tertiary prevention anti inflammatory, antigen-directed and T-cell targeted treatment has been partially successful in slowing down the destruction of beta cells. BIOLOGICAL BETA CELL SUBSTITUTION: Transplantation of a vascularised pancreas or islet cells results in disease regression and the prevention of secondary/tertiary complications of diabetes. A principal aim is the avoidance of frequent, severe hypoglycaemic episodes resulting from markedly reduced awareness of hypoglycaemia or its counter-regulation. PMID- 21271475 TI - [Malnutrition in the elderly]. AB - Malnutrition, which occurs in 27.4% of all elderly persons, is a great burden to those affected and for the health services. There are multiple causes for malnutrition, such as loss of appetite, poorly balanced diet, dementia, dysphagia chewing problems, as well as gastrointestinal disorders. Presence of weight loss and/or anorexia point towards malnutrition. A prerequisite for properly targeted nutritional intervention is to distinguish between sarcopenia and kachexia. In addition the "Mini Nutritional Assessment" (MNA ((r))) questionnaire can be used quickly and reliably for diagnose malnutrition as recommended by the European Society for Clinical Nutrition and Metabolism. Treatment should be based on an individually designed nutritional regime, which incorporates eating habits and functional impairment of the patient. PMID- 21271476 TI - [Recent results of research on cancer of the colon, gastric cancer, sarcoma and bronchial carcinoma]. AB - In patients up to 70 years of age with colon carcinoma stage III adjuvant chemotherapy with infusions of fluorouracil (5-FU) or oral capecitabine combined with oxaliplatin should be the standard method. A new standard for the palliative treatment of Her2/newly positive advanced gastric cancer and cancer at the gastro esophageal junction is the administration of trastuzumab combined with chemotherapy. Patients with high-risk soft tissue sarcoma can be helped, in addition to surgical resection and subsequent radiotherapy, by neoadjuvant chemotherapy combined with regional deep hyperthermia. For patients with lung cancer additional individualized treatment is about to become routine. In addition to the EGFR mutation status, all non-smokers should in future be tested for aberration in the anaplastic lymphoma kinase (ALK) gene. PMID- 21271477 TI - [Bacteraemia and sepsis]. AB - Recent news in the field of bloodstream infection and sepsis relevant for the practitioner include the recommendation in the newly revised German sepsis guideline to introduce selective intestinal decontamination with non-absorbable antimicrobial substances for the prevention of secondary infections in ventilated patients. This intervention, however, remains controversial because there are indications of unfavourable effects (increased development of resistance), and because the effect size has been rather low. Other news indicate not only that procalcitonin can be reasonably used as an aid to determine the duration of antibiotic treatment in community-acquired respiratory infection and pneumonia. A procalcitonin-based algorithm can also be used in critical care patients to shorten the duration of antibiotic administration without worsening outcomes. Recent data indicate that E. coli and S. aureus continue to be the most frequent pathogens isolated in bloodstream infection. The proportion of E. coli strains producing extended-spectrum beta lactamase (ESBL) is increasing. New epidemiologic evidence shows that infections with this pathogen, resistant to many standard antibiotics, are associated with an increased mortality rate, similar to infections due to methicillin-resistant Staphylococcus aureus (MSRA). The incidence of MRSA bacteraemia in Germany can now be estimated better as it has become a notifiable infection. PMID- 21271478 TI - [Current approaches to the treatment of severe hypoxic respiratory insufficiency (acute lung injury; acute respiratory distress syndrome)]. AB - Lung-protective ventilation with a low tidal volume, plateau pressure < 30 cm H(2)O. oxygen saturation > 90% and permissive hypercapnia results in reduction of the mortality rate in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). The level of the positive end-expiratory pressure (PEEP) must be chosen in relation to oxygen requirement. High frequency oscillatory ventilation and neurally adjusted ventilatory assist are promising methods. However, further studies with firm end-points have to be awaited before a final judgment is possible. Veno-venous extracorporeal membrane oxygenation (ECMO) can ensure life-sustaining gas exchange in patients with severe vitally compromised pulmonary failure, to provide time for lung tissue to heal and reduce ventilatory stress. The latest guidelines for analgesia and sedation in intensive care medicine demand consistent monitoring of the level of sedation and the intensity of pain. The sedation should be interrupted daily, with phases of awakenings and, if possible, spontaneous breathing. Methods of supportive treatment: Positional treatment (prone position) and inhalation of vasodilators can improve ventilation/perfusion mismatch and thus oxygenation. However, administration of surfactant is currently not advised in adult respiratory failure. PMID- 21271479 TI - [Coronary heart disease - what is of importance after coronary intervention?]. AB - In the European Union Ticagrelor has recently been approved, as another P2Y12 receptor antagonist in addition to clopidogrel and prasugrel, in [corrected] the drug treatment after coronary intervention. [corrected] Dual antithrombotic treatment must be given for 4 weeks after elective implantation [corrected] of bare-metal stents, or for at least 6 months [corrected] with acetylsalicylic acid (ASA) plus clopidogrel after implantation of a drug-eluding stent. After an acute coronary syndrome ASA and clopidogrel (or prasugrel or ticagrelor) must be given for 12 months. In patients requiring urgent oral anticoagulation essential triple drug treatment should be given over as short a [corrected] space of time if possible. [corrected] Prasugrel and ticagrelor may, to protect against gastroduodenal bleeding, be given without restriction together with a proton-pump inhibitor. Preoperative coagulation management is essential for patients who have been on dual platelet-aggregation inhibitors, but premature withdrawal of this medication should be avoided. PMID- 21271480 TI - [Acute kidney injury]. AB - New guidelines of the "Kidney Disease: Improving Global Outcome" (KDIGO) working group standardize the definition of acute kidney injury (AKI) and acute kidney disease (AKD) allowing the assessment of prognosis and efficacy of prophylactic and therapeutic measures in different patient cohorts. The degree of severity and the duration of acute kidney injury are critical factors for the development of chronic kidney disease and mortality. The achievement of optimal fluid volumes is a cornerstone in the treatment during the early phase of AKI, while volume overload should be avoided in the late phase of established AKI. Recently employed biomarkers are promising for the early detection and prognosis of AKI, but cannot yet be used as routine tests. Microscopic urinalysis, a very old and cost-effective diagnostic measure, provides valuable informations about the severity and the course of AKI. PMID- 21271481 TI - [Asthma: new insights and advances in treatment]. AB - In mild asthma low-dose steroid inhalation treatment reduces severe exacerbations and exacerbation associated loss of lung function. In patients with mild asthma, symptom-driven use of a combination of inhaled steroid and short-acting beta-2 sympathomimetics in a single inhaler is feasible. In moderate and severe asthma the fixed combination of formoterol and budesonide can be used a maintenance therapy but also as treatment of acute symptoms. Monotherapy with long-acting beta 2-sympathomimetics should be completely avoided. Long-acting anticholinergic drugs are equally efficacious as long-acting beta-2-sympathomimetics, but have not yet been approved for use in patients with asthma. The correct identification of various phenotypes is especially important in severe asthma, because there are different specific treatment approaches. PMID- 21271482 TI - [Rheumatoid arthritis: milestones in classification and treatment]. AB - New classification criteria of rheumatoid arthritis (RA) by the American College of Rheumatology and the European League Against Rheumatism (EULAR) allow the early assignment of arthritides as RA and thus early start of therapy. This is an important step towards early diagnosis and treatment. The EULAR recommendations for the treatment of RA for the first time define the value of biologicals by means of therapeutic algorithms based on extensive scientific evidence and taking into account cost-effectiveness. As a result biologicals can be used after the first failure of disease-modifying anti-rheumatic drugs (DMARDs), if there are unfavourable prognostic factors. Methotrexate is, as a DMARD, at the centre of treatment. PMID- 21271483 TI - [Gastroenterological endoscopy]. AB - Endoscopy is often used in gastroenterology. It can prevent early recurrence of bleeding from esophageal varices. Computed virtual chromoendoscopy can diagnose pathological changes at the esophagogastric transitional zone in non-erosive reflux disease. In the buried bumper syndrome the internal bumper, which has migrate into the gastric wall, should be removed endoscopically. Double-balloon enteroscopy is one of the flexible enteroscopy techniques with an acceptable complication rate and remains the diagnostic and therapeutic gold standard for small bowel endoscopy. Hyperplastic polypoidal lesions of more than 1 cm in the colon should be removed, because it is not possible to distinguish definitively between hyperplastic polyps and serrated adenoma. Endoscopic ultrasound of the biliary tract makes it possible to remove biliary tract stones cost-effectively and without radiology. Endoscopic ultrasound-guided necrosectomy of the pancreas has become the standard method and has replaced percutaneous drainage and operative intervention. PMID- 21271484 TI - [21-year-old female patient with oral aphthosis and skin lesions]. PMID- 21271485 TI - [Giant paraesophageal herniation with intermittent prolapse into the thorax of the transverse colon]. AB - HISTORY AND ADMISSION FINDINGS: A 74-year-old woman was admitted with a history of recurring dyspnea for several months. During radiological examination of the chest computed tomography demonstrated a giant paraesophageal hernia containing transverse colon with a significant amount of paracolic fat tissue. Physical examination was unremarkable. INVESTIGATIONS: Routine blood tests and abdominal ultrasound were within the normal range. Endoscopy showed a normal upper and lower gastrointestinal tract and barium swallow was normal without any esophageal motor dysfunction. The esophagogastric junction and gastric fundus were below the diaphragm. TREATMENT AND COURSE: Laparoscopy revealed the colonic herniation and mediastinal adhesiolysis, complete resection of the hernia sac and reposition of the intrathoracic migrated transverse colon were undertaken. Hiatal repair was performed by anterior and posterior hiatoplasty and construction of an anterior 180 semifundoplication with fundopexy. CONCLUSION: Patients with giant paraesophageal hernias often present with nonspecific cardiac and respiratory symptoms and the condition is often misdiagnosed. If it is demonstrated, a possible abdominal involvement should be looked for. Minimally invasive surgery is feasible and efficacious in this condition and in addition to being better tolerated by the patient provides a far better visualization of the intrathoracic parts of a type IV hiatal hernia to the surgeon. PMID- 21271486 TI - [Unexpected complication following esophageal variceal hemorrhage - Case 2/2011]. AB - HISTORY AND ADMISSION FINDINGS: A 50-year-old patient with alcoholic liver cirrhosis was admitted due to hematemesis and melaena. DIAGNOSIS: Endoscopy showed esophageal variceal hemorrhage. A dose of erythromycin was administered before endoscopy for optimal endoscopic view. TREATMENT AND COURSE: After conservative treatment with hemopressin, ciprofloxacin, and substitution with blood and fresh frozen plasma, the patient had an episode of atrial fibrillation with rapid ventricular response. The episode was terminated by intravenous administration of amiodarone, with subsequent conversion to sinus rhythm. Later on, the patient suffered from torsades de pointes tachycardia. CONCLUSION: Secondary torsades de pointes tachycardias have a low incidence, but often fatal outcome. Torsades de pointes tachycardias mostly are the result of administration of QT-active drugs, and other cofactors. Emergency treatment addresses the reestablishment, and stabilization of sinus rhythm. Preferably, drug-induced torsades de pointes tachycardias are prevented by permanent critical review of administered drugs with respect to indications, interactions, and adverse reactions. PMID- 21271487 TI - [Prevention and private health insurance]. PMID- 21271488 TI - [Professional prospects for specialists in internal medicine in the hospital]. PMID- 21271489 TI - [New possibilities for internal medicine functions at the interface of ambulatory and hospital medicine]. PMID- 21271493 TI - Reproducibility of muscle oxygen saturation. AB - The present study evaluated the reproducibility of tissue oxygenation in relation to oxygen consumption (VO2) across cycle exercise intensities in a test-retest design. 12 subjects (25.7+/-2.1 years; 24.7+/-1.9 kg . m(-2)) twice performed an incremental bicycle exercise protocol, while tissue oxygen saturation (StO2) in the vastus lateralis muscle was monitored by a commercially available NIRS unit and VO2 determined by an open-circuit indirect calorimetric system. Coefficients of variation across rest, workloads corresponding to 25, 50 and 75% of individual maximum capacity, and maximum load were 5.8, 4.6, 6.1, 8.0, 11.0% (StO2) and 7.6, 6.0, 3.7, 3.4, 3.1% (VO2), respectively. 95 % CI of relative test-retest differences ranged from -5.6 to +5.4% at 25% load to -17.2 to +7.5% at maximum load for StO2 and from -7.3 to +7.7% at rest to -3.3 to +3.2% at maximum load for VO2. With advancing exercise intensity, within-subject variability of StO2 was augmented, whereas VO2 variability slightly attenuated. NIRS measurements at higher workloads need to be interpreted with caution. PMID- 21271494 TI - Validity of 3 protocols for verifying VO2 max. AB - The verification bout has emerged as a technique for confirming 'true' VO2 max; however, validity during a single visit is unknown. We evaluated 3 different GXT durations with severe intensity verification bouts. On 3 separate days, in counterbalanced order, 12 recreational-trained men completed short (9+/-1 min), middle (11+/-1 min), and long (13+/-2 min) duration GXTs followed by exhaustive, sine wave verification bouts during the same visit. Intensities for verification were set at speeds equivalent to 2-stages minus end-GXT speed. No differences (p<0.05) in VO2 max (mL/kg/min) were observed between short (49.1), middle (48.2), and long (48.8) protocols. In addition, no differences in verification bout duration occurred between protocols (3+/-1 min). Validity of VO2 max was strongest for the middle duration protocol (ICC alpha=0.97; typical error=1 mL/kg/min; CV=2%). A small, but significantly higher HR (max) (~1-2 bpm) was observed for the long protocol. Maximum respiratory exchange ratios were inconsistent (ICC alpha ranged 0.58-0.68). Our findings indicate GXT-verification bout testing during a single visit is a valid means of measuring 'true' VO2 max. The 10 min target for GXT duration was the optimum. PMID- 21271495 TI - Seasonal changes in stress indicators in high level football. AB - This study aimed at describing changes in stress and performance indicators throughout a competitive season in high level football. 15 players (19.5+/-3.0 years, 181+/-5 cm, 75.7+/-9.0 kg) competing under professional circumstances were tested at baseline and 3 times during the season 2008/09 (in-season 1, 2, 3). Testing consisted of the Recovery-Stress Questionnaire for Athletes (Total Stress and Recovery score), vertical jump tests (counter movement and drop jump (DJ)), and a maximal ramp-like running test. Average match exposure was higher during a 3-weeks period prior to in-season 3 compared to in-season 1 and 2 (1.5 vs. 1 h/week, p=0.05). Total Stress score was elevated at in-season 1 and 2 compared to baseline (p<0.01) with a further increase at in-season 3 (p<0.03; generalized eta squared (eta(2)(g))=0.37). Total Recovery score was decreased at in-season 1 and 3 compared to baseline (p<0.05; eta(2)(g)=0.21). Maximal running velocity (V(max)) and jumping heights were not significantly affected (eta(2)(g)<=0.04). Changes in DJ height and V (max) between baseline and in-season 3 were correlated with the corresponding changes in Total Stress score (r=-0.55 and r=-0.61, p<0.03). Usual match exposure during a professional football season does not induce relevant changes in performance indicators. Accumulated stress and a lack of recovery towards the end of a season might be indicated by psychometric deteriorations. PMID- 21271496 TI - Our experience on Actovegin, is it cutting edge? AB - Muscle injuries are one of the most common sport related injuries, their incidence varying from 30-55% in all sports injuries. They account for the loss of 90 training days and 15 matches per club per season in elite football (soccer). In recent years, the use of Actovegin(r) in sports medicine has caused a lot of controversy in many sports disciplines. Although it is unlikely for this deproteinised substance to have oxygen-enhancing capacity, there is an anecdotal belief that Actovegin(r) can increase an athlete's performance. Actovegin(r) is produced by Nycomed Austria GmbH and has been used by doctors across Europe, China and Russia for over 60 years. Nevertheless, very little is known regarding the effects of Actovegin on muscle injuries. This article reviews the current evidence on Actovegin(r), its legal status with sports governing bodies and its potential role in sport injuries. We will also report our experience with this drug in treating muscle injuries. In this pilot study, players in the Actovegin treatment group were able to return to play 8 days earlier (95% CI -1.249 to 14.7510) compared to physiotherapy alone (p=0.033). No adverse reactions were recorded in any of the participants. PMID- 21271497 TI - AQP-1 association with body fluid loss in 10-km runners. AB - Intrinsic body fluid regulation is critical for optimizing endurance performance. Aquaporins (AQPs) are a family of transmembrane proteins that transport water and glycerol across cellular membranes. A recent report revealed an association between a single nucleotide polymorphism (SNP) in the 3' untranslated region of the aquaporin-1 (AQP1) gene and endurance performance. The purpose of the study was to explore the association between the AQP1 SNP and acute body fluid loss in long distance runners. The subjects (N=91, Age=26+/-3 yrs; Ht=170+/-11 cm; Wt=61+/-5 kg; mean+/-SD) were biologically unrelated male long distance runners. Data were collected before and after an international 10 km road race. Body fluid loss was determined by the difference between nude body weight before and after the 10 km run. The AQP1 (G->C) gene variation was detected by the ARMS-PCR procedure. Genotypes were determined by PCR product size. Carriers of the AQP1 SNP had a significantly greater adjusted body fluid loss (3.7+/-0.9 kg) than non carriers (1.5+/-1.1 kg) (P<0.05). In conclusion, our study found an association between the AQP1 SNP and acute body fluid loss in long distance runners. PMID- 21271498 TI - First reported cases of exercise-associated hyponatremia in Asia. AB - There are no reported cases of exercise-associated hyponatremia (EAH) in tropical Asia. This study aimed to investigate the incidence of EAH at the on-site medical tent and fluid balance in long distance foot races in a warm and humid environment. Body mass was taken before and after the races (42-km marathon; 84 km ultra-marathon). Blood sodium concentration was measured for symptomatic runners admitted to the medical tent. Mean (SD) dry bulb temperature was 29.0 (0.6) degrees C, relative humidity 89 (2)% and wind speed 0.3 (0.5) m/s. Three out of the 8 symptomatic runners admitted to the medical tent were diagnosed with hyponatremia, with blood sodium concentrations of 134 mmol/L in a 42-km runner, and 131 and 117 mmol/L in two 84-km runners. In the 42-km race, mean % DeltaBM was -1.6 (1.2)%, ranging from -5.7 to 1.4%, and 22 runners (7%) gained weight. In the 84-km race, mean % DeltaBM was -2.3 (1.7)%, ranging from -8.0 to 1.4%, and 9 runners (8%) gained weight. In addition to the 3 cases of symptomatic hyponatremia observed, 8% of the 84-km runners and 7% of the 42-km runners gained weight during the race. This indicates the need to disseminate advice for the prevention and treatment of EAH for races held in the tropics. PMID- 21271499 TI - [Hormone-based classification and therapy concepts in psychiatry]. AB - This study retells key aspects of the history of the idea of hormone-based classification and therapy concepts in psychiatry. Different contributions to the history are not only represented from a historical, but also from a current medico-scientific perspective. One of the oldest, yet ethically most problematic, indications concerning hormonal methods to modify undesirable behaviour and sexuality was castration, which was widely used in the 20th century to "cure" homosexuality. Felix Platter, whose concept was humoral-pathological in nature, documented the first postpartum psychosis in the German-speaking countries, the pathogenesis of which according to present-day expertise is brought about by changes in female hormones. The concept of an "endocrine psychiatry" was developed at the beginning of the 20th century. Some protagonists for neuroendocrinology are highlighted, such as Paul Julius Mobius around 1900 or, in the 1950s, Manfred Bleuler, the nestor of this new discipline. Only the discovery of the hormones as such and the development of technologies like radioimmunassay to measure and quantify these hormone changes in mental illnesses allowed investigating these conditions properly. Ever since hormone-based therapeutic and classification concepts have played an important role, above all, in sexual, affective and eating disorders as well as alcohol dependence. PMID- 21271500 TI - Potential benefits from currently available three pneumococcal vaccines for children--population-based evaluation. AB - BACKGROUND: Currently there are 3 pneumococcal vaccines available in Germany. The aim of this study is to evaluate the potential of the three currently available pneumococcal vaccines to reduce the burden of invasive pneumococcal disease in children. SUBJECTS: Children younger than 16 years who have been hospitalized because of IPD between July 2007 and June 2009 in a German pediatric hospitals. METHOD: Surveillance of IPD in German pediatric hospitals and laboratories serving these hospitals. The case definition is isolation of Streptococcus pneumoniae from any normally sterile body site. The actual number of IPD cases is based on the capture recapture method combining information from both reporting systems. RESULTS: In the study period an estimated yearly number of 164 IPD cases occurred among children younger than 2 years compared to 144 and 116 cases among children aged 2-4 years and 5-15 years. Among children under 2 years of age, 69 cases were caused by serotypes covered by PCV10 compared to 103 cases potentially preventable by PCV13. Among children aged 2-4 years 94 IPD cases were caused by serotypes covered by PCV13 compared to 108 cases covered by PPV23. CONCLUSION: The newly available pneumococcal conjugate vaccines with better serotype coverage have the potential to further reduce IPD burden in Germany. The additional benefit of vaccination of children aged 2-4 years at high risk for pneumococcal infections with PPV23 is questionable. PMID- 21271501 TI - Unilateral facial flushing and sweating after physical exercise: Harlequin syndrome. PMID- 21271502 TI - [Frequency and influencing factors of ketoacidosis at diabetes onset in children and adolescents--a long-term study between 1995 and 2009]. AB - BACKGROUND: Diabetic ketoacidosis (DKA) is a frequent acute complication at onset of type 1 diabetes. It is assumed that increased public awareness about diabetes symptoms may reduce DKA rate at diabetes onset. To investigate the time-dependent trend in DKA prevalence we analysed the frequency and determinants of DKA at disease onset over 15 years in pediatric patients. PATIENTS AND METHODS: The prevalence of DKA at disease onset was analysed in individuals aged <=18 years treated for the first time from 1995-2009 within 7 days after diagnosis in pediatric centers. Simple and multiple logistic regression analysis was performed to investigate influencing factors on DKA prevalence. Change of the probability of ketoacidosis over years were modelled in the logistic regression as linear trend. RESULTS: 16 562 individuals from 170 institutions were studied with a mean age of 9.2 +/- 4.2 years. DKA (pH <7.3) was present in 20.8% of patients without a significant trend between 1995 and 2009 (p=0.222). DKA prevalence was higher in children <=5 years (26.3%) and in the age group 10-15 years (21.7%) than in individuals aged 5-10 years (16.4%) and 15-18 years (16.9%, p<0.001). Girls had DKA more often than boys (21.2% vs. 19.3%, p=0.002). DKA frequency was increased in individuals with migration background (26.5% vs. 19.2%, p<0.001). CONCLUSIONS: DKA prevalence at diabetes onset was constant at about 21% during the last 15 years. Very young children, pubertal adolescents, girls and individuals with migration background are at higher risk for DKA at diagnosis. To prevent DKA earlier diagnosis of type 1 diabetes is warranted especially in these patient groups. PMID- 21271503 TI - [Behavioral problems of somatic chronically ill adolescents: parent-child agreement and differences]. AB - BACKGROUND: Adolescents with a chronic somatic disease often show comorbid mental health problems which interfere with adherence and disease management. As adolescents often pass their rehabilitation treatment without their parents and therapists frequently lack resources necessary for assessing information from both the patients and their parents, the question arises what conclusions can be drawn on the basis of self report data only and how general agreement between parent and adolescents can be rated. METHODS: Parent-child-agreement of chronically ill adolescents and their families are analyzed using intra-class correlation (ICC). Data of 367 adolescents with obesity, chronic respiratory disease, skin disease and diabetes between the age of 12.0 and 16.11 years were collected at the beginning of rehabilitation treatment. Parents received their questionnaire via post. Psychological symptoms were identified using the German version of the Strength and Difficulties Questionnaire (SDQ-Deu). RESULTS: There was medium to high agreement between parent and child ratings regarding "emotional problems", "peer relationship problems" and "total difficulty score" for all diagnoses. CONCLUSIONS: Therapists of chronically ill adolescents can act on the assumption that parent-child-agreement is medium to high. Consequently, self-ratings appear a useful diagnostic indicator for rehabilitation treatment. PMID- 21271504 TI - [Prospective comparison of term small-for-gestational-age and appropriate-for gestational-age neonates during the first month of life]. AB - Aim of the prospective study was to investigate perinatal parameters and outcome of term SGA neonates. 100 term neonates were enrolled into 2 groups: group 1: 50 SGA neonates with birth weight below tenth percentile, group 2: 50 appropriate for-gestational-age neonates. Both groups were compared concerning parental anamnesis, perinatal parameters, postnatal adaptation and development during the first days of life. After discharge from the hospital all children were observed during the first 15 weeks. In all infants the gain of weight, length, head circumference and the amount and type of nutrition were recorded. It was observed that only 13% of the SGA neonates were small children of small parents. Most of the SGA neonates had a normal target high. We found a significantly increased number of mothers with disturbed uterine or placental perfusion in the SGA group as well as increased problems in postnatal adaptation. SGA children had a significantly faster increase of gaining weight and a higher amount of nutrition during the first 15 weeks of life. This could be an early sign of catch-up-growth in SGA neonates, which could be regard as a part of the complex risk for developing a metabolic syndrome in formerly SGA children. PMID- 21271505 TI - Hyperbilirubinemia and rapid fatal hepatic failure in severe combined immunodeficiency caused by adenosine deaminase deficiency (ADA-SCID). AB - Adenosin deaminase (ADA) deficiency is the cause for Severe Combined Immunodeficiency (SCID) in about 15% of patients with SCID, often presenting as T (-)B (-)NK (-)SCID. Treatment options for ADA-SCID are enzyme replacement, bone marrow transplantation or gene therapy. We here describe the first patient with ADA-SCID and fatal hepatic failure despite bone marrow transplantation from a 10/10 HLA identical related donor. As patients with ADA-SCID may be at yet underestimated increased risk for rapid hepatic failure we speculate whether hepatitis in ADA-SCID should lead to the immediate treatment with enzyme replacement by pegylated ADA. PMID- 21271506 TI - Decreased apoptosis despite severe CD4 depletion in the thymus of a human immunodeficiency virus-1 infected child. AB - Thymic epithelial space (TES), where thymopoiesis is located, and thymic perivascular space (PVS), where T lymphocytes are pooled, appear differentially involved in human immunodeficiency virus 1 (HIV-1)-infected children. The decline of CD4+ T cells during HIV-1 infection is probably due to a relative predominance of CD4+ T cell destruction on cell proliferation. Antiretroviral therapy (ART) typically increases circulating CD4+ T cell counts, but it is debated whether ART reduces the destruction of existing CD4+ T cells or enhances the production of new cells. We report on postmortem flow-cytometry, immunohistochemistry, and terminal deoxynucleotide transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) studies performed on thymus of an 11-year-old vertically HIV-1 infected child receiving ART. Thymus tissue sections showed that CD4+ and CD8+ cells were more numerous in PVS than in TES (p=0.0334 for CD4+ cells, p<0.0001 for CD8+ cells). Thymus cell suspension showed that CD4+ CD8+ cells (immature thymocytes) were 15.4% (age-related control: 80.5%). Very few apoptotic CD4+ cells were seen in TES. Very low to absent proliferation activity was demonstrated in both TES and PVS. We suggest that 1) lymphocyte depletion in HIV-1 infection is more pronounced in TES than in PVS, 2) immature thymocytes are not enhanced, and 3) an anti-apoptotic effect in the thymus seems to be a potential ART mechanism to explain the CD4+ pool increase. PMID- 21271507 TI - EUS-guided biliary drainage with placement of a new partially covered biliary stent for palliation of malignant biliary obstruction: a case series. AB - Endoscopic ultrasonography-guided biliary drainage (EUS-BD) has been developed as an alternative drainage technique in patients with obstructive jaundice where endoscopic retrograde cholangiopancreatography (ERCP) has failed. Between July 2008 and December 2009, 16 patients (9 men; median age 79 years) with biliopancreatic malignancy, who were candidates for alternative techniques of biliary decompression because ERCP had been unsuccessful, underwent EUS-BD with placement of a transmural or transpapillary partially covered nitinol self expandable metal stent (SEMS). EUS-assisted cholangiography was successful in all patients, with definition of the relevant anatomy, but biliary drainage was successfully performed in only 12 (75 %) of the 16 patients (9 choledochoduodenostomies with SEMS placement and 3 biliary rendezvous procedures with papillary SEMS placement), with regression of the cholestasis. No major complications and no procedure-related deaths occurred. There was one case of pneumoperitoneum which was managed conservatively. The median follow-up was 170 days. During the follow-up, eight patients of the 12 patients in whom biliary draining was successful died; four are currently alive. None of the patients required endoscopic reintervention. This series demonstrated that EUS-BD with a partially covered SEMS has a high rate of clinical success and low complication rates, and could represent an alternative choice for biliary decompression. PMID- 21271508 TI - [Innervation of the airways in asthma bronchiale and chronic obstructive pulmonary disease (COPD)]. AB - Airway nerves have the capacity to control airway functions via neuronal reflexes and through neuromediators and neuropeptides. Neuronal mechanisms are known to play a key role in the initiation and modulation of airway hyperresponsiveness and inflammation. Therefore, the nerve fibres may contribute to airway narrowing in asthma and COPD. In addition to the traditional transmitters such as norepinephrine in postganglionic sympathetic nerve fibres and acetylcholine in parasympathetic nerve fibres, a large number of neuropeptides have been identified to have different pharmacological effects on the muscle tone of the vessels and bronchi, mucus secretion and immune cells. Meanwhile, a broad range of stimuli including capsaicin, bradykinin, hyperosmolar saline, tobacco smoke, allergens, ozone, inflammatory mediators and even cold, dry air have been shown to activate sensory nerve fibres to release neuropeptides such as the tachykinins substance P (SP) and neurokinin A (NKA) to mediate neurogenic inflammation. Different aspects of the neurogenic inflammation have been well studied in animal models of chronic airway inflammation and anticholinergic agents such as ipratropium bromide (Atrovent ((r))) and tiotropium bromide (Spiriva ((r))) have been proved to be important when used as bronchodilators for the treatment of obstructive airway diseases such as COPD. However, little is known about the role of neurogenic airway inflammation in human diseases. In this review, we address the current knowledge of the airway sensory nerves in human asthma and COPD. PMID- 21271509 TI - [Results of single stage vs. two-stage total knee arthroplasty]. AB - BACKGROUND: The total knee arthroplasty (TKA) is a successful procedure. In cases of bilateral knee osteoarthritis, advantages of single stage TKA vs. two-stage TKA as well as the gap between the procedures in case of two-stage TKA are discussed controversially. The aim of the present study is to compare the clinical and radiographic results of single stage bilateral TKA and two-stage bilateral TKA. In cases of two-stage TKA the dependency on the gap between surgeries was determined. MATERIAL AND METHODS: In this retrospective study 43 patients with single stage TKA and 35 patients after two-stage TKA with a maximum of 12 months between surgeries were included. Follow-up was in mean 31 +/- 15 months. For clinical and radiological evaluation the Knee Society score (KSS) and Stolzalpen knee score were used. Quality of life was measured by the SF-36 score. The pain was determined using a visual analogue scale (VAS). Radiological evaluation was done by use of Knee Society roentgenographic evaluation and scoring system. RESULTS: The overall hospital stay for patients with two-stage TKA (26 +/- 5 days) was twice as long as for patients with single stage TKA (14 +/- 4 days). Patients with single stage bilateral TKA had a significantly higher KSS level (186 +/- 19 points) than patients after two-stage bilateral TKA (179 +/ 22 points). Within the two-stage group the best range of motion was achieved by patients with a gap of 4 to 6 months between surgeries and a decreased point value was measured in patients with a gap of 10 to 12 months between TKAs. Using the VAS patients with simultaneous bilateral TKA had significantly increased pain levels during passive motion. Within the two-stage group there were no differences in VAS. The results of Stolzalpen knee score were comparable in both groups. The analysis of radiological measurements showed a significantly higher number of radiolucent lines (1 mm) in patients with single stage TKA without any clinical relevance or progress in follow-up. Patients with single stage bilateral TKA had a higher complication rate than patients with a two-stage procedure. In the single stage group 6 patients had to be revised because of fracture, dislocation, peroneal nerve palsy, patella lateralisation or loosening. In the two-stage group only one patient had to be revised due to a quadriceps tendon rupture caused by a fall at day one after surgery. CONCLUSION: Analysis of clinical and radiological results shows only marginal differences between the two groups. In two-stage procedures functional results were best when the second surgery was done 4 to 6 months after the first procedure. Single stage TKA had a significantly higher complication rate. However, patient and surgeon should make the decision for single or two-stage bilateral TKA individually. PMID- 21271510 TI - [The role of external beam radiation therapy in the adjuvant treatment of pigmented villonodular synovitis]. AB - AIM: Pigmented villonodular synovitis (PVNS) is a rare proliferative disorder arising from synovial cells of the tendon sheets and joint capsules. The potential value of external beam radiation therapy in the interdisciplinary management of PVNS is demonstrated by a comprehensive literature review on the clinical use of radiotherapy and the results of national patterns of care study (PCS) which was conducted by the German Cooperative Group on Radiotherapy in Benign Diseases (GCG-BD) in 2008-2009. MATERIAL AND METHOD: A structured questionnaire was mailed to all 227 RT institutions in Germany to assess all previous treatments, the RT indication and techniques, the rate of local control, the functional outcome and the possible adverse effects related to the use of external beam radiation therapy (RT). For comparison of the clinical outcome data, a systematic literature research in several international electronic databases and a conventional library search were performed to identify publications addressing the use of RT for PVNS. RESULTS: Based on an overall response rate of 83.2%, the PCS was nationally representative. Ten percent of institutions presented clinical experience with the use of RT for PVNS; from this database a total of 41 treated sites from 14 institutions were evaluable for long term analysis. The primary therapeutic approach was cytoreductive surgery in all cases. In cases of residual tissue or complete resection of extensive local recurrences, RT was applied in 39 cases (95.1%). An excellent or good functional outcome was noted in 34 cases (82.9%). The use of RT was not associated with early or late toxicity larger than RTOG grade II. The literature review identified 19 published studies (1940-2009) which represented a total of 140 cases or patients, respectively. After follow-up periods ranging from 1-250 months and administration of total doses in the range of 16-50 Gy the overall rate of local control was 84.5%. CONCLUSION: Both the results of the national PCS and the literature review demonstrate that RT is a very safe and effective treatment option for the prevention of disease progression or recurrence in PVNS after primary surgical interventions. The planned treatment volume should include the whole synovial space and eventually all invasive components of the disease. Currently, total doses in the range of 30-36 Gy are recommended. PMID- 21271511 TI - [Disease management programs for adults with often diseases and competence networks for children and adolescents with rare diseases]. PMID- 21271512 TI - [Angiotensin II-receptor (type AT1)-antagonists and fetal impairment]. PMID- 21271513 TI - [Drooling in neuropediatric patients]. AB - Drooling is defined as an anterior salivary flow which can be insufficiently controlled due to dysphagia und orofacial motoric deficits. It leads to moistened lips, chin, hands and surrounding in diverse extent. Drooling can severely interfere social contacts and requires more nursing facilities. A multidisciplinary approach in diagnostics and therapy is essential. Key points are the evaluation of inhibited swallowing and of orofacial motoric deficits. In the therapy of drooling, scopolamine patches and oral stimulation plates are useful but within the last few years, the injection of botulinum toxin into the salivary glands produced positive effects, as this therapy is an effective, well tolerated and safe option in these children. Surgical corrections of the salivary glands are more and more reserved for isolated cases. PMID- 21271514 TI - Angiotensin II receptor blocker induced fetopathy: 7 cases. AB - BACKGROUND: During a period of 12 months 7 newborns with a partially severe fetopathy caused most probably by maternal sartan-intake in pregnancy were treated in 5 German teaching hospitals. Sartans antagonize the effect of angiotensin II at the AT1-receptor and are used to treat arterial hypertension. METHOD: We presented 2 cases at the yearly GNPI meeting 2010 and we were informed about similar cases in other German teaching hospitals which we brought together in this publication. RESULTS: In the presented cases, maternal sartan intake was noticed at different times in pregnancy and was in part discontinued some weeks before delivery. In all pregnancies oligohydramnios was present and fetal kidneys displayed a hyperechogenic structure on ultrasound. The newborns' postnatal course varied: oligohydramnios sequence with lung hypoplasia, arterial hypotension and renal insufficiency were the predominant problems of the first days of life. The majority (4/7) of infants did not survive this period, in other cases there was a complete (1/7) recovery of renal function whereas others survived with renal impairment (2/7), in part requiring chronic dialysis. Further distinctive features seen frequently were disturbances of cranial ossification and flaccid paralysis of hands and feet with deviations as well as sensorineural hearing loss. CONCLUSION: These case reports again underline the hazardousness of maternal sartan intake with potential fatal outcome for the newborn. Though the use of sartans in pregnancy is contraindicated and several case reports of sartan induced fetopathies exist, the risk of sartan treatment generally seems to be underestimated. PMID- 21271515 TI - Basophil activation test for the diagnosis of hymenoptera venom allergy in childhood: a pilot study. AB - INTRODUCTION: Cellular in vitro tests such as the CD63-based basophil activation test (BAT) have been successfully used to diagnose hymenoptera venom sensitization in adult patients while this has not been investigated in children so far. METHODS: 15 children (9 male, 6 female; 12.7+/-3.5 years) with suspected allergy to vespula (VE) or honey bee (HB) venom entered this study. Besides serum tryptase (ST) levels, sensitisation against VE and HB was assessed by titrated skin testing and determination of venom-specific serum IgE (sIgE) in all patients. After stimulation with 50 ng of insect venom, CD63-expression of activated basophils was measured by flow cytometry. RESULTS: Skin testing permitted identification of the culprit insect in 7 patients, 3 cases were diagnosed by additional sIgE measurements. In addition, BAT identified mono sensitization in 3 further patients with double sensitization upon skin and sIgE testing. Test sensitivity was lower for the BAT (67-75%) than for skin testing (89-100%) and sIgE determination (100%). Neither basophil activation nor sIgE serum levels were identified as reliable predictors of sting reaction severity. In all patients, ST measurements yielded values below the upper reference value. CONCLUSION: The current pilot study suggests a possible clinical benefit of BAT analysis in the diagnostic workup of pediatric insect venom allergy. However, further large-scale trials are required to investigate whether the BAT reliably contributes to the correct identification of the culprit insect venom. Due to its comparatively low sensitivity, the BAT should currently not be used in isolation from, but only in combination with established diagnostic instruments. PMID- 21271516 TI - Duodenum-penetrating toothpick with liver abscess: removal with single-balloon enteroscopy. PMID- 21271517 TI - Small-intestinal bleeding due to metastatic renal cell cancer. PMID- 21271518 TI - Inflammatory myofibroblastic tumor of the terminal ileum. PMID- 21271519 TI - Spontaneous disappearance of a giant colonic lipoma after endoscopic biopsy. PMID- 21271520 TI - A rare endoscopic feature of eosinophilic esophagitis. PMID- 21271521 TI - Loop-and-let-go technique for a bleeding, large sessile gastric gastrointestinal stromal tumor (GIST). PMID- 21271522 TI - Clinical acute pancreatitis following anterograde single balloon enteroscopy. PMID- 21271523 TI - Duodenal Crohn's disease successfully treated with adalimumab. PMID- 21271524 TI - A new method for placement of covered colorectal stents in the proximal colon using double balloon enteroscopy. PMID- 21271525 TI - A new method to facilitate bilateral hepatic duct drainage: simultaneous insertion of two thin 6-Fr self-expandable metal stents. PMID- 21271526 TI - Intestinal mantle cell lymphoma observed by double-balloon endoscopy with Fuji Intelligent Chromo Endoscopy. PMID- 21271527 TI - Endoscopic closure of a perforated peptic ulcer. PMID- 21271528 TI - Endoscopic hemostasis with multiple hemoclips and an endoloop for uncontrolled peptic ulcer bleeding. PMID- 21271529 TI - Endoscopic removal of a biliary covered metallic stent with the invagination method. PMID- 21271530 TI - Endocrinology through an endoscope: lesions in the esophagus, stomach, and duodenum in gastrinoma. PMID- 21271531 TI - Coil migration into the common bile duct as a cause of cholangitis. PMID- 21271532 TI - Analysis of cyst fluid obtained by endoscopic ultrasound-guided fine-needle aspiration supporting the diagnosis of a pancreatic neuroendocrine neoplasm. PMID- 21271533 TI - Treatment of a completely obstructed colonic anastomotic stricture using a CT guided endoscopic rendezvous technique. PMID- 21271534 TI - Endoscopy-assisted technique for removal of a transduodenal T-tube. PMID- 21271535 TI - Cladosporium macrocarpum brain abscess after endoscopic ultrasound-guided celiac plexus block. PMID- 21271536 TI - [The diagnosis of heart failure]. AB - The diagnosis of heart failure is essentially based upon the presence of typical symptoms and signs of congestion or a low cardiac output as well as the objective evidence of cardiac dysfunction. Basic tests include clinical examination, ECG, and chest x-ray. However, findings from these tests are neither absolutely specific nor sensitive for a diagnosis of heart failure. A low B-type natriuretic peptide concentration in a patient with acute dyspnoea makes the diagnosis of heart failure as the cause of a patient's symptoms unlikely. If HF is not unlikely based on ECG, x-ray, and BNP, an echocardiogram is recommended. Echocardiography is the single most useful tests to detect cardiac dysfunction and to identify the exact mechanism underlying the patient's symptoms of heart failure, which is essential to establish an appropriate treatment plan. PMID- 21271537 TI - [Drug treatment for chronic heart failure with reduced ejection fraction]. AB - Based on multiple randomized controlled trials performed in the last 20 years, drugs form the basis of treatment for heart failure with reduced ejection fraction (HFREF). Despite solid evidence for their efficacy and safety and publication of detailed national and international guidelines many patients with HFREF remain, who are not at all or only insufficiently treated. Treatment goals include reduction of mortality and hospitalizations, improvement of symptoms and exercise tolerance as well as prevention of disease progression. ACE-inhibitors and beta-adrenergic receptor blockers exert beneficial effects on all treatment goals and are therefore indicated in all patients with HFREF if tolerated. Diuretics allow control of fluid retention and maintenance of "euvolemia". Low dose spironolactone can be considered in persistent moderate to severe (NYHA 3 - 4) HFREF despite treatment. Angiotensin receptor blockers are indicated for ACE inhibitor intolerance or in addition to ACE-inhibitors and beta-adrenergic receptor blockers in case of persistent symptoms. Triple combination of ACE inhibitors, angiotensin receptor blockers and aldosterone antagonists should be avoided in view of the substantial risk of hyperkalemia. In current praxis digoxin is mainly used as an adjunctive agent for rate control of atrial fibrillation in combination with beta-adrenergic receptor blockers. Titration and maintenance of heart failure treatment requires continuous control of clinical parameters, renal function and electrolytes. It is recommended to use drugs and dosest hat have been shown to be effective in clinial trials. Despite the fact that heart failure is mainly a disease of the elderly, this population is underrepresented in clinical trials. The risk of side effects and drug-drug interactions is increased in elderly patients because of physiologic changes with age and frequent comorbidities with resultant polypharmacy. PMID- 21271538 TI - [Diagnosis and therapy of heart failure with normal ejection fraction]. AB - Diastolic heart failure, also termed as heart failure with normal or preserved ejection fraction has a high prevalence and mortality world wide. The clinical manifestation comprises typical symptoms and signs of heart failure along with normal or discretely reduced left ventricular ejection fraction. Though the etiology of diastolic heart failure is incompletely understood, functional and structural abnormalities of cardiomyocytes, the extracellular matrix, and the peripheral vasculature are assumed to contribute to the etiology of diastolic heart failure. The diagnosis requires typical symptoms and signs of heart failure, evidence of elevated natriuretic peptides and an impaired diastolic ventricular function, meanwhile left ventricular systolic function is normal or just slightly impaired. Catheter and MRI exams help to ensure the diagnosis. So far, no therapy has convincingly demonstrated a reduction of morbiditiy and mortality. Therefore, current guidelines emphasize the importance of an adequate treatment of risk factors and myocardial ischemia. PMID- 21271539 TI - [Device therapy in chronic heart failure]. AB - Besides optimal drug therapy, cardiac resynchronisation therapy offers a further therapy option for selected patients. Additional ICD implantation should be evaluated as well to prevent sudden cardiac death. PMID- 21271540 TI - [Surgical treatment options in end-stage heart failure]. AB - Despite significant improvements in pharmacological therapy heart failure is still one of the leading causes for death in the Western World. The gold standard treatment of end-stage heart failure remains cardiac transplantation, but there is a great excess of eligible candidates compared with the low number of suitable donor organs. The variety of surgical organ preserving treatment strategies has significantly increased during the last 20 years, intenting either to delay or even to prevent the need for cardiac transplantation. An individually tailored surgical concept should be considered as an alternative in any heart failure patient who has reached the limits of pharmacologic therapy. This article gives an overview about current and potential future therapeutic options in end-stage heart failure. PMID- 21271541 TI - [Comorbidity in heart failure]. AB - Noncardiac Comorbidities are frequent and may be overlooked during routine CHF management. They have great impact on hospitalisations and mortality. The most important comorbidities in heart failure patients are renal insufficiency, diabetes mellitus, chronic obstructive pulmonary disease, sleeping disorders like obstructive and central apnea syndrom, and anemia. The most powerful predictor for mortality is renal insufficiency. It's important to recognize the different causes of renal failure. Defining the volume status and the cardiac output is crucial for the guidance of therapy. The management of diuretic resistance is of special interest and often challenging. Diabetes mellitus is an independent risk factor for heart failure. The benefit of ACE inhibitors and Angiotensin receptor blockers for HF and DM is accepted. The management of Diabetes in HF depends on side-effect profiles of the numerous anti-diabetic drugs. Metformin is safe even in HF patients. Thiazolidinediones should be avoided in NYHA class III/IV because of fluid retention. In COPD patients there is an underuse of betablockers and the prediction of mortality with this comorbidity could be partially caused by that. The principle goal of treatment of sleeping disorders is to avoid hypoxia during night. CPAP therapy improves live quality and HF symptoms. Anemia is often diagnosed, the best therapy - erythropoetin plus iron or iron alone - remains controversial. Iron supplementation without anemia could be an option for better quality of life. To handle all these comorbidities in heart failure patients becomes more and mor complex. Heart failure nurses can help us to manage these growing population. PMID- 21271542 TI - [Heart failure in the elderly]. AB - The prevalence of heart failure substantially increases with advancing age. Nevertheless, heart failure in the elderly is commonly under-diagnosed, because dyspnoea and fatigue are often attributed to the natural process of aging. Age related alterations of the cardiovascular system and the presence of multiple comorbidities not only change the clinical features of heart failure, but also have an impact on heart failure treatment in this population. Cautious uptitration of the individual drugs and vigorous clinical and laboratory monitoring is mandatory to avoid undesired side effects. Although guideline recommended heart failure therapy is derived from trials that included mainly middle-aged patients with few comorbidities, it has proven beneficial even in the very elderly. Today, guideline-recommended heart failure therapy is still too often withheld from elderly patients out of fear of potential side effects. PMID- 21271543 TI - [Disease management for chronic heart failure patient]. AB - Patients with chronic heart failure (HF) are limited in their quality of life, have a poor prognosis and face frequent hospitalisations. Patient self-management was shown to improve quality of life, reduce rehospitalisations and costs in patients with chronic HF. Comprehensive disease management programmes are critical to foster patient self-management. The chronic care model developed by the WHO serves as the basis of such programmes. In order to develop self management skills a needs orientated training concept is mandatory, as patients need both knowledge of the illness and the ability to use the information to make appropriate decisions according to their individual situation. Switzerland has no established system for the care of patients with chronic diseases in particular those with HF. For this reason a group of Swiss experts for HF designed a model for disease management for HF patients in Switzerland. Since 2009 the Swiss Heart Foundation offers an education programme based on this model. The aim of this programme is to offer education and support for practitioners, patients and families. An initial pilot evaluation of the program showed mixed acceptance by practitioners, whereas patient assessed the program as supportive and in line with their requirements. PMID- 21271544 TI - [Cardiac rehabilitation in patients with heart failure--is there a treatment beyond pharmacotherapy, surgery and device implantation?]. AB - The reduced exercise capacity of patients with chronic heart failure cannot be explained solely on the basis of cardiac dysfunction. It seems to be the case that within the frame of the disease progression the importance of peripheral factors steadily increases. Chronic diminished perfusion of skeletal muscles, inactivity as well as harmful neuro-humoral activation leads to myopathy with loss of mitochondria and capillaries and to increased fibrosis. A systematic, controlled and properly dosed training improves in heart failure patients their cardiac symptoms like dyspnoe and exercise capacity. In addition an improved quality of life, augmented ejection fraction, diminished enddiastolic dimensions, improved respiratory efficiency will be achieved and the incidence of rehospitalization decreased. In the European guidelines there is a "class I recommendation" that is of the same class as the recommendation for a pharmacological standard therapy. The exact mechanism of the training of patients with heart failure is not known. In patients with ischemic heart failure training improves the myocardial perfusion due to a reduction of the endothelial dysfunction, and furthermore the training promotes collateralisation due to intermittend ischemic stimuli. The training is counteracting peripheral myopathy and it diminishes or even reverses the development of cardiac cachexia. In comparison of the prevalence of heart failure as well as the importance of training the referral pattern of some 500 patients per year encompasing all Swiss rehabilitation centers is considerably less than one would wish for. Heart failure exercise training should be started in a properly equipped center and evidenced with the advantage that it could be continued at home as a life long procedure. PMID- 21271545 TI - [Economic evaluation of neurological and mental disorders in Spain: systematic review and comparative analysis]. AB - AIM: We analyzed the trends over time and the characteristics of economic evaluation studies of neurological and mental disorders published in Spain between 1983 and 2008. MATERIALS AND METHODS: Systematic review and comparative analysis calculating odds ratios (OR). Electronic searches for literature were conducted in PubMed/Medline, Scopus, ISI Web of Knowledge, CRD, IME and IBECS, and manually in specialized journals and technical reports. RESULTS: The 52 studies included in the review showed heterogeneity in the quality of the information regarding methods of analysis and data sources. Economic evaluation studies of neurological and mental disorders showed the following associations, compared to a cohort of studies of other disease conditions (n = 425): cost utility analysis (OR = 1.57; 95% confidence interval, 95% CI = 0.77-3.22), treatments (OR = 3.02; 95% CI = 1.33-6.88), simulation mathematics models (OR = 2.51; 95% CI = 1.30-4.87), and healthcare system perspective (OR = 1.43; 95% CI = 0.80-2.54). CONCLUSIONS: Findings suggested that there is little research on economic evaluation research on neurological and mental disorders in Spain. In the future, more and better quality economic evaluation studies -according to their burden generated- are expected. PMID- 21271546 TI - [Nummular headache: clinical features and therapeutic experience in a series of 30 new cases]. AB - INTRODUCTION: Nummular headache (NH) is a mild or moderate pain, located in a small, well circumscribed, rounded or elliptical area. Temporal pattern is variable and pain exacerbations have been described. AIM. To analyze clinical characteristics and therapy requirement and response in a series of patients attended due to NH in a headache outpatient office. PATIENTS AND METHODS: 30 patients (18 females, 12 males) diagnosed as NH. We considered demographic and nosological characteristics, temporal pattern, presence and intensity of exacerbations, and requirement of symptomatic or preventive therapies. RESULTS: Age at onset 49.2 +/- 18.1 years (range: 21-79 years). Two of the patients presented a bifocal NH and we analyzed 32 areas, 28 rounded and 4 elliptical. Diameter: 4.7 +/- 1.1 cm. Regarding locations occipital (10 areas, 31.3%), parietal (9 areas, 28.1%) and frontal (6 areas, 18.8%). Pain intensity of 5.2 +/- 1.8 on a ten-point visual analogical scale. Regarding temporal profile, in 18 areas (56.3%) was chronic, in 5 (15.6%) episodic and undefined due to a scarce time from onset in 9 (28.1%). In 16 areas (50%) pain exacerbations lasting from 3 seconds to 15 minutes occurred. Nine (30%) patients did not improve with symptomatic drugs, and at least one preventative was prescribed in 23 (76.6%) patients without consistent effectiveness. CONCLUSIONS: NH is not an uncommon diagnosis in an outpatient headache office. In our series, basal pain intensity is moderate and symptomatic drugs commonly provide no relief. So, patients frequently need a preventive therapy. PMID- 21271547 TI - [West syndrome: aetiology, therapeutic options, clinical course and prognostic factors]. AB - INTRODUCTION: West syndrome is an age-specific form of epilepsy that associates infantile spasms, hypsarrhythmia and a delay in or the complete stoppage of psychomotor development, although this last case is not essential. AIMS: To define the profile of West syndrome in our environment by taking into account its aetiology, semiology, response to different therapeutic options and the appearance of side effects, as well as to establish prognostic factors that determine its course. PATIENTS AND METHODS: A data collection document stating the eligibility criteria was drafted. Data were collected by reviewing the medical records of patients diagnosed with West syndrome during the period between January 2003 and January 2009. Later, a statistical study was conducted with descriptive analysis and the level of statistical significance of the possible prognostic factors was established. RESULTS: The study included 70 patients. There was a predominance of symptomatic aetiology, with hypoxia ischaemia as the main cause. Regardless of the aetiology, 58% of patients responded to treatment with vigabatrine. Over 80% of patients being treated with adrenocorticotropic hormone were finally seizure-free and without hypsarrhythmia. Almost half the patients progressed to other epilepsies. CONCLUSIONS: The statistically significant poor prognostic factors were: existence of a prenatal history, neonatal history, symptomatic aetiology, age of onset below 4 months, epileptic seizures before the onset of the spasms and outside the neonatal period, and delayed psychomotor development prior to the onset of the spasms. PMID- 21271548 TI - [Recurrent painful ophthalmoplegia secondary to polyostotic fibrous dysplasia of the maxillary sinuses with involvement of the superior orbital fissure]. AB - INTRODUCTION: Fibrous dysplasia is a bone disease that is usually accompanied by asymptomatic lesions but which may sometimes display neurological manifestations due to the involvement of the craniofacial bones. CASE REPORT: A 25-year-old female, with a history of migraines, who visited at the age of 18 due to pain in the right retro-ocular and maxillary region, although with characteristics that were unlike those of her usual migraines, and which was associated with ipsilateral ophthalmoparesis. The condition had a self-limiting course and responded well to corticoids, although it was recurring. Examination revealed intense pain on palpation of the right-hand maxillary sinus and incomplete paralysis of the ipsilateral oculomotor nerve with palpebral ptosis. Results of complementary studies were normal, except for magnetic resonance imaging of the head and computerised axial tomography of the face, which revealed an expansive lesion with involvement of the right superior maxillary sinus and the greater wing of the sphenoid bone, with probable compromise of the superior orbital fissure, consistent with the diagnosis of fibrous dysplasia, which was confirmed by means of a pathology study. CONCLUSIONS: Fibrous dysplasia is a benign bone disorder, of unknown causation, in which normal bone tissue is replaced by amorphous conjunctive tissue. There is sometimes craniofacial involvement and a hypertrophic bone mass is formed which can fill the paranasal sinuses and the orbit, resulting in exophthalmus and visual disorders. To date the scientific literature does not include any reports of this disease manifesting as bouts of recurrent painful ophthalmoparesis which responds to corticoids, as happened in the case of our patient. PMID- 21271549 TI - [Memantine: the value of combined therapy]. AB - The symptomatic treatment of Alzheimer's disease is currently carried out using a twofold therapeutic approach involving acetylcholinesterase inhibitors, whose mechanism of action is based on the selective inhibition of this enzyme, and memantine, which acts by blocking the pathological tonic activation of NMDA receptors. Both drugs have been approved for the treatment of Alzheimer's disease and present a therapeutic indication spectrum that is shared in the moderate phase (MMSE: 10-20). Since both therapeutic approaches offer the same complementary mechanisms of action and share the same therapeutic indication over a wide symptomatic disease spectrum, the aim of this article is to review the existing evidence on the effectiveness of combined therapy so as to be able to discern its usefulness from the moment treatment begins. PMID- 21271550 TI - [HIV-1 neuropathogenesis: therapeutic strategies against neuronal loss induced by gp120/Tat glycoprotein in the central nervous system]. AB - Neuroinflammation is a key process in the neuropathogenesis of AIDS virus since as a result of the aberrant activation of the chemokine receptors (CXCR4, CX3CR1 and CR5) produces proinflammatory cytokine release by infected cells, increases microglial neurotoxicity and generates lipoperoxides and reactive oxygen species (ROS) that eventually damage the neuron. Moreover, the neurotoxin Tat produces dendritic loss by interacting with the low-density lipoprotein receptor (LRP) and also overstimulates N-methyl D-aspartate receptors (NMDA). Furthermore, the aberrant interaction of glycoprotein gp120 with the CXCR4 chemokine receptor causes caspase-3-dependent apoptosis (ceramide is also released) activating apoptotic proteins (p53 and retinoblastoma), which are part of the neurotoxic mechanisms associated to neuronal dysfunction in neuroAIDS. Similarly, gliosis/microglial activation and the release of neurotoxic factors by infected monocytes with elevated amounts of certain chemokines in the cerebrospinal fluid (MCP-1 and fractalkine, among others) contribute to the neuropathogenesis of HIV 1. Alpha-synuclein and beta amyloid deposits have also been detected in post mortem brains of seropositives patients. In addition, there are studies have detected several systemic markers related with the degenerative effects of the virus and its neurotoxins on the central nervous system; such as osteopontin, CD163 and fractalkine, among others. Lastly, clinical trials have been conducted using protective strategies related that attempt to inhibit apoptotic proteins (GSK-3 beta), microglial activation inhibitors (minocycline), antioxidants (selegiline) or trophic factors (IGF-1, growth hormone or erythropoietin). These trials have shown that their treatments are beneficial and complementary to treat complications of HIV/AIDS. PMID- 21271552 TI - [Reactivation of herpes zoster after electrocution]. PMID- 21271554 TI - [The social dimension of the quality of life in multiple sclerosis]. PMID- 21271555 TI - [On the composition of the pudendal nerve]. PMID- 21271556 TI - Infrainguinal percutaneous transluminal angioplasty or bypass surgery in patients aged 80 years and older with critical leg ischaemia. AB - BACKGROUND: Infrainguinal revascularization for critical leg ischaemia (CLI) in patients aged 80 years and over is associated with increased operative risk. The aim was to compare the results of percutaneous transluminal angioplasty (PTA) and bypass surgery in these patients. METHODS: Some 584 consecutive patients aged at least 80 years treated with either PTA (277) or bypass surgery (307) for CLI between 2000 and 2007 were included in this study. RESULTS: After 2 years PTA achieved better results than bypass surgery (leg salvage: 85.4 versus 78.7 per cent, P = 0.039; survival: 57.7 versus 52.3 per cent, P = 0.014; amputation-free survival (AFS): 53.0 versus 44.9 per cent, P = 0.005). Cox regression analysis showed that increased age (relative risk (RR) 1.05, 95 per cent confidence interval 1.02 to 1.08), decreased estimated glomerular filtration rate (RR 0.99, 0.99 to 1.00), diabetes (RR 1.30, 1.04 to 1.62), coronary artery disease (RR 1.36, 1.05 to 1.75) and bypass surgery (RR 1.55, 1.24 to 1.93) were associated with decreased AFS. In 95 propensity score-matched pairs, leg salvage at 2 years (88 versus 75 per cent; P = 0.010) and AFS (53 versus 45 per cent; P = 0.033) were significantly better after PTA. Classification and regression tree analysis suggested that PTA was associated with better 1-year AFS, especially in patients with coronary artery disease (63.8 versus 48.9 per cent; P = 0.008). CONCLUSION: When feasible, a strategy of PTA first appears to achieve better results than infrainguinal bypass surgery in patients aged 80 years and older. PMID- 21271559 TI - Germline mutations of the E-cadherin gene in families with inherited invasive lobular breast carcinoma but no diffuse gastric cancer. AB - BACKGROUND: Present data are highly suggestive but do not unequivocally prove the cosegregation of germ-line CDH1 mutations with inherited invasive lobular breast cancer (ILBC). METHODS: Two Caucasian families with 6 pathologically confirmed ILBC cases but no diffuse gastric cancer (DGC) were identified in our oncogenetics consultations. Screening for mutations of CDH1, BRCA1, and BRCA2 genes was performed on blood samples. When available, loss of heterozygosity (LOH) and immunohistochemistry (IHC) analyses were performed on tumor samples. RESULTS: No BRCA1 or BRCA2 mutation was found. Deleterious CDH1 germ-line mutations c.283C>T and c.1582del were found in all the 4 living women with ILBC in family 1 and family 2, respectively. The mutation c.283C>T was also present in a healthy 71-year-old male and 2 obligate carriers in family 1. No DGC was observed in the 2 families. Loss of the wild-type CDH1 allele in 1 of the breast tumors was confirmed by LOH and IHC studies, in accordance with the "2-hit" model of tumor suppressor genes. CONCLUSIONS: Germline CDH1 mutation can be cosegregated with ILBC in the absence of DGC. Present data do not support recommendation of prophylactic gastrectomy in CDH1 germline mutation carriers with ILBC. Cancer 2011. (c) 2011 American Cancer Society. PMID- 21271560 TI - Mother-pup interactions during a short olfactory deprivation period in young rats. AB - The effects of short-term bilateral naris occlusion (inducing olfactory deprivation) on mother-pup interactions, suckling behavior and hormonal status during post-natal development in Wistar rats were studied. Bilateral naris occlusion was performed on 8-day-old rat pups and its effects were evaluated at Day 9 and at Day 15. The narins opened spontaneously between Day 12 and 14. Olfactory-deprived pups exhibited a greater level of corticosterone at both ages versus untreated or sham animals. Olfactory deprivation via naris occlusion, in young rats, alters mother-pup interactions with a decrease in the duration of mother-pup retrieving and an increase in pup licking. Olfactory-deprived pups showed also a lower mean duration of nursing and a decrease in nipple attachment, which appeared related to difficulties in finding the nipple. Olfactory-deprived pups had difficulty recognizing their nest. These behavioral alterations were accompanied by a diminution in milk ingested and growth retardation associated with a reduced level of thyroxin at both 9 and 15 days of age. PMID- 21271561 TI - Neural signatures of face-voice synchrony in 5-month-old human infants. AB - Infants' unitary perception of their multisensory world, including learning from people (faces and speech), hinges on temporal synchrony. Despite its importance, relatively little work has investigated the brain processes involved in infants' perception of temporal synchrony. In two experiments, we examined event-related brain potentials (ERPs) to asynchronous and synchronous audio-visual speech in infants. Both experiments showed the early auditory P2 was greater for the synchronously presented pairings and later attentional processing (Nc) was greater for asynchronous pairings. In addition, dynamic stimuli used in Experiment 2 produced a greater early visual response (N1) to the asynchronous condition and an enhanced memory-related slow wave (PSW) later for the synchronous condition. These results suggest that, like adults, auditory-visual integration for young infants begins early during sensory processing rather than later during higher-level cognitive processing. However, unlike adults, infants' brain responses may be biased towards synchrony. Furthermore, effects of attentional and memory processing confirm interpretations of behavioral looking patterns suggesting infants find synchrony more familiar. PMID- 21271562 TI - Environmental enrichment delays pup-induced maternal behavior in rats. AB - Adult, virgin rats do not spontaneously display maternal behavior when exposed to foster pups. However, continuous daily exposure of the female to foster pups for about 5-7 days can induce a set of maternal behaviors similar to those shown by postpartum dams. Induction latencies depend upon a number of factors, including the stress and anxiety levels of the female. The goal of this study was to attempt to mitigate the likely stressfulness of being singly housed during testing by enriching the rat's home cage environment and to determine if the concomitant environmental change would alter the latency to express maternal behavior. In addition, the effect of varying the number of test pups used for testing was examined. Two groups of virgin Sprague-Dawley rats were first tested on the elevated plus maze after 1 week of exposure to either control (standard housing) or enriched conditions. One week later, maternal behavior testing began using one or three pups. Upon completion of maternal behavior testing, plasma corticosterone concentrations were determined following a mild stressor. The data indicate that enrichment tends to increase anxiety-like behaviors in the elevated plus maze. In addition, enrichment delayed the onset of maternal behavior irrespective of the number of test pups. There were no effects of environmental enrichment on plasma corticosterone levels following exposure to a stressor. These results indicate that what is considered a modestly enriched environment delays the expression of pup-oriented responses and does not apparently reduce stress or improve performance on all behavioral tasks. PMID- 21271563 TI - QSAR analysis of blood-brain distribution: the influence of plasma and brain tissue binding. AB - The extent of brain delivery expressed as steady-state brain/blood distribution ratio (log BB) is the most frequently used parameter for characterizing central nervous system exposure of drugs and drug candidates. The aim of the current study was to propose a physicochemical QSAR model for log BB prediction. Model development involved the following steps: (i) A data set consisting of 470 experimental log BB values determined in rodents was compiled and verified to ensure that selected data represented drug disposition governed by passive diffusion across blood-brain barrier. (ii) Available log BB values were corrected for unbound fraction in plasma to separate the influence of drug binding to brain and plasma constituents. (iii) The resulting ratios of total brain to unbound plasma concentrations reflecting brain tissue binding were described by a nonlinear ionization-specific model in terms of octanol/water log P and pK(a). The results of internal and external validation demonstrated good predictive power of the obtained model as both log BB and brain tissue binding strength were predicted with residual mean square error of 0.4 log units. The statistical parameters were similar among training and validation sets, indicating that the model is not likely to be overfitted. PMID- 21271564 TI - Molecular dynamics of the cryomilled base and hydrochloride ziprasidones by means of dielectric spectroscopy. AB - Cryomilling was applied to obtain amorphous forms of the base ziprasidone and its hydrochloride salt. Complete amorphization of both samples was confirmed by differential scanning calorimetry and X-ray measurements. As it turned out, cryogrinding is very effective way to obtain these drugs in the amorphous state, especially because melting of both ziprazidones accompanies significant chemical decomposition as revealed by ultra performance liquid chromatography examination. Consequently, the glassy state cannot be reached in conventional way, that is, by supercooling of melt. Broadband dielectric relaxation measurements were performed on both drugs to describe their molecular dynamics above as well as below their glass transition temperatures (T(g)). We found out that ziprasidone base and its hydrochloride salt differ in T(g) in the same way as it was previously reported for tramadol monohydrate and its hydrochloride. Moreover, our dielectric studies revealed that molecular mobility is not the main factor controlling kinetics of crystallization of both ziprasidones above their T(g) . Below the T(g) relaxation related to water as well as secondary relaxation process originating from the intermolecular interaction (Johari-Goldstein) were identified in the loss spectra of both materials. We have demonstrated that except of local mobility, water is the dominant factor moving both ziprasidones toward recrystallization process. Finally, we have also carried out solubility measurements to show that dissolution rate of the amorphous ziprasidones is much higher with respect to the crystalline samples. PMID- 21271566 TI - Is laryngeal electromyography useful in the diagnosis and management of vocal fold paresis/paralysis? PMID- 21271567 TI - Increased expression of arginase I and II in allergic nasal mucosa. AB - OBJECTIVES/HYPOTHESIS: It is known that arginase may be a regulator of diverse pathways, including production of nitric oxide (NO). Increased expression of arginase has been reported in several inflammatory lung diseases, including allergic asthma, suggesting that this may be a common feature underlying the pathophysiology of airway hyperreactivity. Thus, arginase I and II may play a role in the pathogenesis of allergic rhinitis. The distribution pattern and level of expression of arginase I and II were therefore determined in normal and allergic nasal mucosa. STUDY DESIGN: Controlled, prospective study. METHODS: The distribution pattern and level of expression of arginase I and II in normal and allergic nasal mucosa were evaluated using RT-PCR, immunohistochemistry, and Western blotting. RESULTS: The level of expression of arginase I and II mRNA was increased in allergic nasal mucosa in comparison with normal nasal mucosa. In normal nasal mucosa, arginase I and II were expressed in the surface epithelium, submucosal glands, vascular endothelium, and fibroblasts. In allergic nasal mucosa, both enzymes were also localized to similar sites, in addition to inflammatory cells, and the level of expression were greatly increased compared with normal nasal mucosa. These findings were verified by Western blotting. CONCLUSIONS: These results indicate that arginase I and II may play a role in the pathophysiology of allergic rhinitis, and suggest the possible role of the L arginine metabolic pathway through modulation of L-arginine availability as a substrate for nitric oxide synthase (NOS) and arginase in the pathogenesis of allergic rhinitis. PMID- 21271568 TI - Endoscopic surgical management of vidian nerve schwannoma. AB - Vidian nerve schwannomas are highly unusual, with only two reported cases in the world literature, and present with a constellation of symptoms that may be extremely vague. In the reported cases, open techniques have been utilized that required significant dismantling of the midfacial skeleton to access and manage these skull base lesions. Over the last 15 years, a paradigm shift in base of skull surgery has evolved with the advent of transnasal endoscopic techniques and instrumentation, improved surgical access and resectability of most skull-based pathologies, including vidian nerve lesions as reported here. We describe the varied clinical presentation and radiologic findings in two patients with such rare lesions. In addition, in one of these patients, we report on the first use of an expanded endonasal technique to access and remove vidian nerve schwannomas entirely endoscopically. PMID- 21271569 TI - Unilateral high vagal paralysis: relationship of the severity of swallowing disturbance and types of injuries. AB - OBJECTIVE: To evaluate the prognoses of high vagal lesions and their association with their clinical presentation, and seek to determine the best strategy of management for each patient. STUDY DESIGN: Retrospective case series with chart review. MATERIALS AND METHODS: Patients following laryngoplasty from 2001 to 2008 at a tertiary referral voice and swallowing center in Taiwan were reviewed. They were divided into two groups according to the etiologies of high vagal trauma. The pre- and posttreatment voice and swallowing functions were reviewed; swallowing status was compared between patient groups. RESULTS: Of 186 consecutive patients who underwent laryngoplasty, 8 females and 9 males were diagnosed of unilateral high vagal damage. One group of 11 patients suffered vagal damaging suddenly from skull base trauma, cerebrovascular accidents, and surgical complications; symptoms of vagal paralysis occurred immediately after those events. The second group was comprised of six patients who lost their high vagal functions gradually from a skull base tumor or mass compression. Feeding tube status was significantly different between the groups. All except one patient in group 2 recovered their voice and swallowing abilities after appropriate laryngoplasty. CONCLUSIONS: High vagal nerve damage from skull base surgery or trauma leads to a higher incidence of feeding tube dependency than that from skull base tumor compression. Patients can be treated successfully with an appropriate injection or medialization thyroplasty. Immediate laryngoplasty is suggested for cases right after skull base surgery or trauma. PMID- 21271570 TI - Facial determinants of female gender and feminizing forehead cranioplasty. AB - OBJECTIVE/HYPOTHESIS: Information determined by viewing a face includes familiarity, emotion, attractiveness, and gender. However, the specific facial characteristics that enable one to identify gender are largely unknown. Research suggests that femininity is a critical component of beauty; however, the most important identifiers of a woman's face are unknown. The objectives of this article were: 1) determine the area of the face most significant in identifying female gender, 2) determine if individuals with gender-confirming surgery of the face are identified as male or female, 3) review the efficacy and safety of a series of feminizing forehead cranioplasties. STUDY DESIGN: 1) Prospective evaluation of computer simulated changes and postoperative patient images, 2) retrospective review of medical records. METHODS: 1) Photographs of men were digitally altered to adjust (a) the forehead (b) the nose/lip, (c) the jaw. Each change a, b, or c is done in isolation in both frontal and profile views. Subjects were shown the three profile and the three frontal photographs and asked to rate which of each set is the most feminine. 2) Photographs of male-to-female (MTF) transgender patients who may have had forehead, midface, or jaw surgery were shown to subjects. Subjects were asked the gender of the person in each picture. 3) Medical records and operative reports of 168 patients who underwent feminizing forehead cranioplasty were evaluated for surgical technique, and complications. RESULTS: For Experiment 1, in frontal views of all subjects the forehead modification was selected as the most feminine, whereas in no cases was the forehead modification selected as least feminine by a majority of respondents. For the profile view, again the forehead modification was selected as most feminine by respondents for the majority of subjects, but surprisingly, the strength of the association between frontal modification and femininity, while strongly statistically significant, was more evident in the frontal view. For Experiment 2, among transgendered faces shown to viewers, 82% of postoperative forehead modifications were judged as women, 87% of postoperative midface modifications were judged as women, and 85% of postoperative lower faces were judged as women. For section 3, the review of safety and technique in 168 feminizing forehead cranioplasties, there were three basic surgical techniques utilized with only three complications for an overall complication rate of 1.8%. CONCLUSIONS: Feminization of the forehead through cranioplasty is safe and has a significant impact in determining the gender of the patient. The strong association between femininity and attractiveness can now be more specifically attributed to the upper third of the face and the interplay of the glabellar prominence of the forehead, along with the eyebrow shape and position, and hairline shape and position. These results have strong implications for a paradigm shift in the method of facial analysis used to select aesthetic procedures and illuminates the processes by which femininity and attractiveness are interpreted in faces. PMID- 21271571 TI - Site involvement as a predictor of airway intervention in angioedema. AB - OBJECTIVES/HYPOTHESIS: To look for a relationship between which sites are involved in angioedema and the need for airway intervention (intubation, tracheotomy). STUDY DESIGN: Retrospective chart review. METHODS: Charts of 140 patients who were admitted to two hospitals at an academic medical center between July 1, 2006 and June 30, 2008 with the diagnosis of angioedema were reviewed. Charts were reviewed for pertinent data, including demographics, sites of involvement along the upper airway, medical therapy, and airway intervention. Subsites included lips, anterior tongue, floor of mouth, soft palate, base of tongue (BOT), and larynx. RESULTS: The BOT was involved in 19 patients and the larynx was involved in 29 patients. Airway intervention was required in 21 patients (16%). Patients with laryngeal and/or BOT involvement required intervention in 38% of cases (vs. 7% in patients without involvement). Patients with more than three sites involved had a 39% rate of intervention, compared with only 12% in patients with less than three sites involved. Among those patients with laryngeal/BOT involvement, 56% with more than three sites involved required intervention, as compared to 30% of patients with less than three sites involved. CONCLUSIONS: Site of involvement was found to correlate with airway intervention. Involvement of anterior tongue, BOT, and larynx significantly increased the likelihood of intubation or tracheostomy, as did involvement of multiple sites. Thorough evaluation, including fiberoptic laryngoscopy, can aid in determining which patients require airway intervention. PMID- 21271572 TI - Diagnosis and treatment of 32 cases with aortoesophageal fistula due to esophageal foreign body. AB - OBJECTIVES/HYPOTHESIS: Aortoesophageal fistula is a rare but life-threatening complication of foreign body ingestion. In spite of several strategies for treatment, there is little consensus regarding the optimal management of the entity. In this article, we present our experience in the diagnosis and treatment of patients with aortoesophageal fistula. STUDY DESIGN: Retrospective study. METHODS: A total of 3,209 admissions due to esophageal foreign body impaction were recorded in Second Xiangya Hospital between 1963 and 2010. Of these, 32 cases were complicated with aortoesophageal fistula. In these 32 patients, 19 were treated by open surgery and 13 were managed with nonsurgical measures. We compared different treatments of the patients and their clinical outcomes. RESULTS: Foreign body and aortoesophageal fistula were found in all of these 32 cases in imaging examination and/or surgery. Three patients were completely cured and 16 patients died of fatal hemorrhage from the group of patients with surgical management. All 13 nonsurgically treated cases died. CONCLUSIONS: Early diagnosis and an aggressive surgical treatment without delay is the only form of effective therapy for the condition of aortoesophageal fistula. Imaging examination is helpful in diagnosis. In particular, three-dimensional computerized tomography is a safe, simple, and noninvasive examination method that has high sensitivity and specificity for the early diagnosis of aortoesophageal fistula. PMID- 21271573 TI - Temperature variations of nasal endoscopes. AB - OBJECTIVES: Advances in light sources and endoscopes have improved illumination during endoscopic sinus surgery. However, these advances have also increased the temperatures the equipment reaches during the course of procedures. Limited data exist on temperature variations of nasal endoscopes and the potential risks of burns to drapes and patients. We attempt to quantify temperature variations of nasal endoscopes and light cords. METHODS: Various endoscopes, light cords, and xenon light sources were used to measure temperature increases over time. Temperatures were measured with noncontact thermometers using different combinations of endoscopes, light cords, and light sources at multiple intervals up to 30 minutes over 30 trials. Variables assessed included endoscope age, light cord age, light source type, and light source age. Also, extended time trials were repeated up to 180 minutes. RESULTS: Endoscope tip temperatures peaked at 62.5 degrees C. Additional studies performed with the cord and light source alone reached a maximum temperature of nearly 200 degrees C. The ages of light cords and scopes do lead to statistically significant changes in heat production. Higher wattage light sources may increase potential temperatures. CONCLUSIONS: Patient safety is a preeminent concern for all procedures. Although the endoscope temperatures appear low risk for patient injury, the light cord itself creates extreme temperatures. It is important to monitor the endoscope and light cords for extreme temperatures to avoid patient injury. PMID- 21271574 TI - Risk factors for postoperative hemorrhage following tonsillectomy. AB - OBJECTIVES/HYPOTHESIS: To identify the main risk factors associated with postoperative hemorrhage following tonsillectomy. STUDY DESIGN: Prospective multicenter observational study. METHODS: The Surgical Instrument Surveillance Programme (SISP) was established in 2003 to monitor tonsil and adenoid surgery and the associated complications in all hospitals in Wales. Data were examined between April 1, 2003, and June 30, 2008, by using binary logistic regression, for risk factors that may contribute to primary (R1) or secondary (R2) postoperative hemorrhage of a severity sufficient to require a return to the operating theater. RESULTS: A total of 17,480 procedures were included. Patients aged >=12 years were 1.5 (1.0-2.1; P < .05) and 3 times (2.2-4.9; P < .0001) more likely to experience R1 and R2 complications, respectively. There were 2.5 times as many females as males aged >=12 years who underwent tonsillectomy, but males were almost twice as likely to experience R1 (1.4-2.8), P < .0001, or R2 (1.2 2.5), P < .001, postoperative hemorrhage. There was a 1.9-fold increased likelihood of R1 (1.1-3.3), P < .05, with the most junior surgeon, and no relationship with R2. All techniques that used heat had a significantly greater adjusted odds of R2 as compared with cold dissection, with odds ranging from 2.7 (1.5-4.7), P < .001, for dissection plus bipolar diathermy and ties, to 13.0 (5.8 29.1), P < .0001, with coblation when used with other techniques. No additional risk was associated with specified single-use instruments. CONCLUSIONS: Patient age and sex and operative technique were the most significant factors affecting the risk and timing of serious postoperative hemorrhage, with no additional risk associated with the use of specified single-use instruments. PMID- 21271575 TI - Interdigitation of the distal anastomosis between tubed fasciocutaneous flap and cervical esophagus for stricture prevention. AB - OBJECTIVES/HYPOTHESIS: Distal end circular stricture is a major complication following circumferential pharyngoesophageal reconstruction with tubed fasciocutaneous free flaps. To reduce the stricture rates, we have incorporated spatulation with interdigitation at the distal anastomosis site. This study investigated whether this procedure could decrease the stricture rate. STUDY DESIGN: Retrospective review. METHODS: There were 51 patients who underwent tubed fasciocutaneous free flap reconstruction following total laryngo-pharyngo esophagectomy between July 2002 and August 2008. The interdigitation technique was applied in 10 patients; the 41 remaining patients underwent simple circumferential anastomosis. This modification technique consists of incising both distal skin tube and cervical esophagus into three triangular parts, respectively, and interdigitation by interposition of these flaps. Of the 10 patients with this procedure, five patients were reconstructed with an anterolateral thigh flap and five with a radial forearm flap. All 10 patients received postoperative radiotherapy. The mean follow-up period was 30.2 months. RESULTS: Of the 41 patients without any modification, 12 patients (29.3%) developed a stricture; however, in our series of 10 patients undergoing this modification, there was no stricture formation except one (10.0%) who had been reconstructed with a radial forearm flap. The nine remaining patients all achieved a modified or unrestricted full oral diet without complications. Esophagography revealed a wide and patent anastomosis without stricture. CONCLUSIONS: This interdigitation technique could prevent circular contracture at the neopharyngoesophageal segment in reconstruction with tubed fasciocutaneous free flaps. PMID- 21271576 TI - The prevalence of occult metastases in nonsentinel lymph nodes after step-serial sectioning and immunohistochemistry in cN0 oral squamous cell carcinoma. AB - OBJECTIVES: To examine the prevalence of isolated tumor cells (ITC) and micrometastases (MM) in nonsentinel lymph nodes (NSN) using additional step serial sectioning and immunohistochemistry (IHC) as for sentinel lymph nodes (SN). STUDY DESIGN: Prospective, consecutive, and clinically controlled trial. METHODS: Fifty-one patients with oral cavity squamous cell carcinoma (OSCC) T1-T2 and clinically N0 neck underwent surgical treatment including sentinel-node biopsy (SNB) assisted selective neck dissection (SND). The location of the SN was determined using dynamic and planar lymphoscintigraphy and SPECT-CT. The harvested NSN from the neck dissections underwent the same histopathologic examinations as the SN using step-serial sectioning (SSS) at 150-micron intervals. Two sections from each level were stained with hematoxylin-eosin (H&E) and cytokeratin antibodies (AE1/AE3) and examined for tumor deposits. Results were compared with the previous routine examination of the NSN. RESULTS: A total of 403 NSN were examined with a median of 8 per patient. A total of 1/51 patients (2%) had involvement of an additional NSN not found on routine examination. This was the only lymph node with involvement not detected previously. However, this patient had metastases in SN and in another NSN detected on routine examination. The overall incidence of occult metastasis (SN + NSN) was 21.6% (11/51) as previously reported. CONCLUSIONS: The incidence of occult metastases in NSN after additional SSS and IHC was 2%. The risk of NSN involvement would seem to be extremely low in patients with early OSCC and negative SN. This study further validates SNB as an accurate staging tool for cN0 early OSCC. PMID- 21271577 TI - Diagnostic and interventional sialendoscopy: a preliminary experience. AB - OBJECTIVES/HYPOTHESIS: To review our preliminary experience with diagnostic and therapeutic sialendoscopy for the management of non-neoplastic disorders of the salivary gland. STUDY DESIGN: Retrospective chart review. METHODS: Thirty-three consecutive patients undergoing 36 sialendoscopy procedures performed at a tertiary medical center from July 2008 to July 2010 were included. RESULTS: The mean age of presentation was 43 years (range, 7-74 years), and 61% of patients were male. Indications included sialolithiasis (47%; 17 of 36), recurrent sialadenitis (44%, 16 of 36), and Sjogren's syndrome (8%; three of 36). Successful endoscopy was performed in 97% (35 of 36). A papillotomy for access was necessary in 25% (nine of 36). In patients with sialolithiasis (n = 17), the mean size of the stones was 7.3 mm (range, 1-20 mm). Complete stone removal was achieved in 76% (13 of 17) of cases. Endoscopic stone removal was possible in 29% (five of 17), and a combined approach technique was required in 47% (eight of 17). Seventy-two percent (26 of 36) of patients had complete resolution of symptoms after sialendoscopy, with 19% (seven of 36) having partial resolution of symptoms. Patients with partial improvement of symptoms had a mean duration of improvement of 4.7 months. The overall complication rate was 22% (eight of 36). The major and minor complication rates were 3% (one of 36) and 19% (seven of 36), respectively. CONCLUSIONS: Sialendoscopy is safe and effective in managing non neoplastic salivary gland disorders with low rates of major complications. Knowledge of options to navigate the rate-limiting steps, like dilation of the papilla and careful case selection, are key to successful outcomes. PMID- 21271578 TI - Synchronous second primary tumors in 2,016 head and neck cancer patients: role of symptom-directed panendoscopy. AB - OBJECTIVES/HYPOTHESIS: Second primary tumors (SPTs) are prevalent in head and neck cancer patients. Synchronous SPTs occur within the first 6 months after diagnosis of a first primary tumor. Work-up of first primary head and neck cancers may include panendoscopy if SPTs are suspected. It is unclear whether this strategy has significant impact on treatment results. STUDY DESIGN: Prospectively recorded data on head and neck cancer patients treated at an academic tertiary referral center. METHODS: The distribution of SPTs was retrieved from a database of 2,016 patients with head and neck cancer. Initial work-up included panendoscopy when an SPT was clinically suspected. RESULTS: Of 2,016 patients, 49 (2.4%) had synchronous SPTs. Of these, there were 26 diagnosed simultaneously with the first primary tumor, of which 18 (69%) were located in areas covered by panendoscopy. The remaining 23 were nonsimultaneous synchronous SPTs; 10 of them were located at sites accessible by panendoscopy, of which 6 were in the bronchial tree. Median survival after simultaneous SPTs was 9 months versus 3 months after nonsimultaneous synchronous SPTs (P = not significant). The highest frequency of synchronous SPTs was seen with first primary tumors of the hard palate, the dorsum of the tongue, and of the mandibular gingiva. CONCLUSIONS: Symptom-directed panendoscopy at initial work-up was successful at finding SPTs of the upper aerodigestive tract, but not SPTs located in the lower airways. Synchronous SPTs missed at initial work-up did not have significantly worse prognosis than simultaneous SPTs. PMID- 21271579 TI - A simple approach to facilitating fiberoptic intubation in the difficult airway. PMID- 21271580 TI - Long-term results of calcium hydroxylapatite for vocal fold augmentation. AB - OBJECTIVES/HYPOTHESIS: Studies have shown excellent results for 12-month post injection augmentation data for calcium hydroxylapatite (CaHA) for glottal incompetence; however, the longevity of the material past one year was unknown. Our objective was to report the long-term effectiveness of CaHA as a vocal fold injectable by assessing data from a cohort of patients who underwent injection for glottal insufficiency. STUDY DESIGN: Retrospective chart review. METHODS: Patients who underwent CaHA injection for glottal insufficiency of any etiology were considered for inclusion in the study. The change in Voice Handicap Index (VHI)-10 scores between preinjection scores and best postinjection scores as well as between the preinjection and the most recent VHI-10 scores were used as primary outcome measures to determine the persistence of benefit or the time to loss of benefit. Complications among the cohort were identified. RESULTS: Ninety patients who underwent 108 vocal fold injections with CaHA were evaluated for inclusion. Twenty patients with 22 injections met the criteria for inclusion. Fourteen of 22 (64%) subjects showed loss of benefit of the CaHA material. The average length of benefit was 18.6 months, with a range of 8 to 36 months. Three complications were identified among the original cohort of 108 injections. CONCLUSIONS: CaHA remains a safe and effective long-term vocal fold injectable with an average length of benefit of 18.6 months. Three complications were seen among 108 CaHA injections. CaHA is a long-term injectable with an excellent track record that does not appear to warrant concern for permanent or late complications. PMID- 21271581 TI - 532-nanometer potassium titanyl phosphate (KTP) laser-induced expression of selective matrix metalloproteinases (MMP) in the rat larynx. AB - OBJECTIVE/HYPOTHESIS: The 532-nm KTP laser is clinically useful to induce benign vocal fold lesion regression without a fibrotic response. Previously, we described an in vivo model for KTP-induced injury in the rat larynx. This study uses this model to correlate the KTP-induced histologic and biochemical changes with the absence of long-term vocal fold fibrosis seen in clinical scenarios. STUDY DESIGN: In vivo. METHODS: Unilateral vocal fold injury was induced via KTP laser at 10W (20mS pulse width) as described by our laboratory previously. Animals were subjected to serial endoscopic imaging from postoperative days 1 through 3. Animals were euthanized at 1 day, 4 weeks, and 12 weeks posttreatment and subjected to histologic analyses via hematoxylin and eosin and trichrome staining, as well as RT-PCR analyses for MMP-3, 9, transforming growth factor beta (TGF-beta), and COX-2 mRNA expression. Uninjured vocal folds were used as controls. RESULTS: Our study revealed gross healing of the vocal fold mucosa by 3 days posttreatment, and an immediate, moderate inflammatory infiltrate with no subsequent ultrastructural changes on histology. MMP-3 and COX-2 expression increased transiently, although no changes were seen in expression of MMP-9, an MMP involved in extracellular matrix remodeling, or TGF-beta, a profibrotic cytokine. CONCLUSIONS: These data suggest that the KTP laser induces a modest inflammatory response, selective MMP expression, and no long-term fibrotic processes in a clinically relevant simulation. PMID- 21271582 TI - Electromyographic and histologic evolution of the recurrent laryngeal nerve from transection and anastomosis to mature reinnervation. AB - OBJECTIVES: To describe the natural evolution of recurrent laryngeal nerve (RLN) reinnervation in an animal model. STUDY DESIGN: Twenty Sprague Dawley rats underwent unilateral RLN transection and anastomosis. Animals were sacrificed at 4, 8, 12, 16, and 20 weeks. Prior to sacrifice, each rat underwent electromyography (EMG) and visual grading of vocal fold motion. Bilateral RLNs were harvested and evaluated histologically. RESULTS: EMG revealed synkinetic reinnervation at all time periods except at 4 weeks. EMG evolution plateaued at 16 weeks. Vocal fold motion was slight in three rats at 4 weeks but was otherwise absent except for one rat at 12 weeks. Histologic changes of the axons and their myelin sheaths were consistent at each time period. At 16 weeks, histologic changes plateaued. CONCLUSIONS: Consistent EMG, histologic, and vocal fold motion changes occur at specific time periods during RLN reinnervation after transection and anastomosis in a rat model. Reinnervation is mature at 16 weeks. Findings corroborate theories of preferential and synkinetic reinnervation after RLN transection. Use of a rat model to investigate the effect of interventions on RLN reinnervation requires a minimum of 16 weeks between transection and investigation to allow for maturation of reinnervation. PMID- 21271583 TI - Central pontine myelinolysis as a cause of bilateral vocal fold immobility due to hyponatremia. AB - We report a patient admitted with severe dyspnea due to bilateral vocal fold immobility (BVFI), associated with hyponatremia and pneumonia that required emergency tracheotomy. Cerebral magnetic resonance imaging showed a pons lesion compatible with central pontine myelinolysis. Hyponatremia is thought to be caused by hypovolemia. The hyponatremia, and not its correction, is speculated to be the cause of central pontine myelinolysis in this patient. To our knowledge, this is the first case reported of a bilateral vocal fold immobility caused by central pontine myelinolysis induced by hyponatremia. PMID- 21271584 TI - The use of adalimumab for cricoarytenoid arthritis in ankylosing spondylitis--an effective therapy. AB - This report describes cartilaginous regeneration in a cricoarytenoid joint affected by spondyloarthropathy using tumor necrosis factor-alpha (TNF-alpha) blockade, monitored by magnetic resonance (MR) and computed tomography (CT) imaging. This case is interesting for several reasons. It is only the eighth case of destructive ankylosing spondylitis-related cricoarytenoid arthritis published in the English language literature. It describes, for the first time, full recovery of vocal cord mobility following TNF-alpha blockade. It is also the first case to be published with MR imaging demonstrating regeneration of the cricoarytenoid cartilage following treatment. This case represents a landmark in the treatment of patients presenting with destructive arthritis involving the cricoarytenoid joint. PMID- 21271585 TI - Optimal arytenoid adduction based on quantitative real-time voice analysis. AB - HYPOTHESIS: The optimal degree of arytenoid rotation for arytenoid adduction (AA) can be determined using quantitative real-time voice analysis. STUDY DESIGN: Repeated measures with each larynx serving as its own control. METHODS: Unilateral vocal fold paralysis (VFP) was modeled in five excised canine larynges. Medialization laryngoplasty (ML) was performed, followed by AA. The optimal degree of arytenoid rotation was determined using real-time measurements of vocal efficiency (V(E) ), percent jitter, and percent shimmer. After the optimal degree of rotation was determined, the arytenoid was hypo- and hyperrotated 10% +/- 2% of the optimal angle to mimic hypoadducted and hyperadducted states. Aerodynamic, acoustic, and mucosal wave measurements were recorded. RESULTS: Mean optimal angle of arytenoid adduction was 151.4 +/- 2.5 degrees . V(E) differed significantly across experimental conditions (P = .003). Optimal AA produced the highest V(E) of any treatment, but this value did not reach that produced in the normal condition. Percent jitter (P < .001) and percent shimmer (P < .001) differed across groups and were lowest for optimal AA. Mucosal wave amplitude of the normal (P = .001) and paralyzed fold (P = .043) differed across treatments. Amplitude of both folds was highest for optimal AA. CONCLUSIONS: V(E) and perturbation parameters were sensitive to the degree of arytenoid rotation. Using real-time voice analysis may aid surgeons in determining the optimal degree of arytenoid rotation when performing AA. Testing this method in patients and determining if optimal vocal outcomes are associated with optimal respiratory and swallowing outcomes will be essential to establishing clinical viability. PMID- 21271586 TI - Raised intensity phonation compromises vocal fold epithelial barrier integrity. AB - OBJECTIVES/HYPOTHESIS: We investigated the hypothesis that 30 minutes of raised intensity phonation alters transcript levels of vocal fold intercellular tight junction proteins and disrupts the vocal fold epithelial barrier. STUDY DESIGN: Prospective animal study. METHODS: Eighteen New Zealand white breeder rabbits were randomly assigned to receive 30 minutes of raised intensity phonation or approximation of the vocal folds without phonation. Quantitative polymerase chain reaction (qPCR) was used to investigate transcript levels of the epithelial intercellular tight junction proteins, occludin and zonula occludin-1 (ZO-1), and the adherens junction proteins beta-catenin and E-cadherin. Structural alterations to the vocal fold epithelium were further examined by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). RESULTS: Mann-Whitney U revealed significantly decreased occludin (P = .016) and beta catenin (P = .016) gene expression from rabbits undergoing raised intensity phonation compared with control. There were no significant differences in Z0-1 and E-cadherin gene expression between groups (P > .025). SEM revealed significant obliteration, desquamation, and evidence of microhole formation in rabbit vocal folds exposed to raised intensity phonation compared with control, whereas TEM revealed dilated intercellular morphology between groups. CONCLUSIONS: Results provide support for the hypothesis that a transient episode of raised intensity phonation alters transcript levels of vocal fold intercellular tight junction proteins and disrupts integrity of the epithelial barrier. The loss of barrier integrity may have significant consequences on epithelial defenses and compromise protection of the underlying mucosa from damage secondary to prolonged vibration exposure. PMID- 21271587 TI - Large vestibular aqueduct syndrome: anatomic and functional parameters. AB - OBJECTIVES/HYPOTHESIS: To correlate imaging and audiologic findings in patients with large vestibular aqueduct syndrome (LVAS). STUDY DESIGN: Retrospective analysis. METHODS: Thirty-eight patients with LVAS evident on magnetic resonance imaging with available clinical and audiometric data were selected from the databases of the study institution. Images were analyzed for endolymphatic sac and duct size, evidence of incomplete cochlear partitioning, and endolymphatic sac signal heterogeneity. The endolymphatic duct was measured in two different locations: near the vestibular aperture (ED(VA)) and at the midpoint between the common crus and the operculum (ED(MID)). Imaging data were correlated with audiologic variables. RESULTS: There was significant correlation between ears for the audiologic and anatomic variables collected. Twenty-one (62%) patients had a fluctuating or progressive hearing loss, and 13 (38%) remained stable (four were not evaluable). At the time of the analysis, 41% of ears had a profound loss. Significant correlation was identified between the presence of endolymphatic signal heterogeneity and worse pure tone average (PTA). ED(VA) measures were significantly larger among ears with a progressive pattern of hearing loss when compared to those that were stable. Also, ED(VA) correlated with PTA and the presence of progressive hearing loss, but ED(MID) had no such a relationship. CONCLUSIONS: Evidence of endolymphatic sac signal heterogeneity and larger measures of endolymphatic width when measured near the vestibule (ED(VA)) are markers of poorer hearing in these patients. By contrast, midpoint measures of the endolymphatic duct (ED(MID)) have no correlation with audiometric parameters. PMID- 21271588 TI - Cochlear implantation in a patient with Paget's disease. AB - Hearing loss in Paget's disease, a metabolic bone disease, has been reported in as many as 60% of cases, and is presumably related to changes in mineral density of the otic capsule. We describe a 59-year-old man with Paget's disease who had severe to profound hearing loss and was referred to us for cochlear implantation. Preoperative evaluation revealed poor communication skills despite significant residual hearing, raising concerns about postimplantation outcome. Nevertheless, implantation was successful. As our literature search yielded only one report of cochlear implantation in Paget's disease, we record our clinical experience and discuss the hearing rehabilitation dilemmas in this case. PMID- 21271589 TI - Expression of COX-2 and NMDA receptor genes at the cochlea and midbrain in salicylate-induced tinnitus. AB - OBJECTIVE/HYPOTHESIS: The expression of the genes for cyclooxygenase (COX) and NMDA receptor (NR) has seldom been reported in tinnitus. We hypothesized that expression of COX-2 and NR was altered in the cochlea and midbrain in salicylate induced tinnitus. STUDY DESIGN: Experimental study on mice. METHODS: We evaluated the tinnitus score and mRNA expression levels of COX-2 and NR subtype 2B (NR2B) in the cochlea and midbrain in response to intraperitoneal injections of salicylate for 4 days. RESULTS: At day 4 of tinnitus induction, the mean weights of the whole body and midbrain did not change greatly in both control and salicylate groups. The tinnitus score was not elevated from day 1 to day 4 in the control group, but increased day by day in the salicylate group. The mRNA expression level of COX-2 decreased slightly in the salicylate group in the cochlea (1.1 +/- 0.33 vs. 1.3 +/- 0.49, P = .0752) and in the midbrain (0.9 +/- 0.10 versus 1.0 +/- 0.35, P = .0489). Inversely, the expression levels of the NR2B gene increased moderately in the salicylate group in the cochlea (3.7 +/- 0.47 versus 2.3 +/- 1.13, P < 0.0001) and in the midbrain (1.6 +/- 0.64 versus 1.0 +/- 0.44, P = .0007). CONCLUSIONS: Salicylate induced tinnitus and altered the expression of the COX-2 and NR2B genes in the cochlea and midbrain of mice. These findings might contribute to further understanding of pathophysiology and therapy of tinnitus. PMID- 21271590 TI - Altered expression of middle and inner ear cytokines in mouse otitis media. AB - OBJECTIVES/HYPOTHESIS: The inner ear is at risk for sensorineural hearing loss in both acute and chronic otitis media (OM), but the mechanisms underlying sensorineural hearing loss are unknown. Previous gene expression array studies have shown that cytokine genes might be upregulated in the cochleas of mice with acute and chronic OM. This finding implies that the inner ear could manifest a direct inflammatory response to OM that may cause sensorineural damage. Therefore, to better understand inner ear cytokine gene expression during OM, quantitative real-time polymerase chain reaction and immunohistochemistry were used in mouse models to evaluate middle and inner ear inflammatory and remodeling cytokines. STUDY DESIGN: Basic science experiment. METHODS: An acute OM model was created in Balb/c mice by a transtympanic injection of Streptococcus pneumoniae in one ear; the other ear was used as a control. C3H/HeJ mice were screened for unilateral chronic OM, with the noninfected ear serving as a control. RESULTS: Both acute and chronic OM caused both the middle ear and inner tissues in these two mouse models to overexpress numerous cytokine genes related to tissue remodeling (tumor necrosis factor-alpha, bone morphogenetic proteins, fibroblast growth factors) and angiogenesis (vascular endothelial growth factor), as well as inflammatory cell proliferation (interleukin [IL]-1alpha,beta, IL-2, IL-6). Immunohistochemistry confirmed that both the middle ear and inner ear tissues expressed these cytokines. CONCLUSIONS: Cochlear tissues are capable of expressing cytokine mRNA that contributes to the inflammation and remodeling that occur in association with middle ear disease. This provides a potential molecular basis for the transient and permanent sensorineural hearing loss often reported with acute and chronic OM. PMID- 21271591 TI - Interleukin-8 production in response to tumor necrosis factor-alpha by cholesteatoma keratinocytes in cell culture. AB - OBJECTIVES/HYPOTHESIS: Keratinocytes harvested from acquired cholesteatoma and grown in cell culture will demonstrate increased interleukin-8 (IL-8) production in response to tumor necrosis factor (TNF)-alpha as compared with a control keratinocyte cell line. Immunohistochemical studies have identified IL-8 and TNF alpha, mediators of bony destruction, in tissue samples of cholesteatoma. TNF alpha stimulates IL-8 production in healthy epidermal keratinocyte cell lines. It is not known whether TNF-alpha stimulates IL-8 production in cultured cholesteatoma keratinocytes. STUDY DESIGN: Prospective controlled tissue culture experiment. METHODS: Tissue from an acquired cholesteatoma was dissociated and grown in keratinocyte serum-free media for 8 weeks. Cholesteatoma keratinocytes and a control cell line of skin epidermal keratinocytes were treated with TNF alpha. Conditioned media were harvested; production of IL-8 was measured by enzyme-linked immunosorbent assay, and cell counts were performed. RESULTS: At a zero concentration of TNF-alpha, mean production of IL-8 by cholesteatoma keratinocytes was 39,809 pg/mL/24hr/1 * 10(6) cells versus 1,907 pg/mL/24hr/1 * 10(6) cells from skin epidermal keratinocytes, a statistically significant difference (P < .05). The cholesteatoma keratinocytes showed a 2.1-fold increase in response to 2 pg/mL of TNF-alpha and a 2.44-fold increase in response to 20 pg/mL of TNF-alpha. The skin epidermal keratinocyte cell line demonstrated a 1.07 and 1.13-fold increase to respective concentrations of TNF-alpha. CONCLUSIONS: Cholesteatoma keratinocytes appear to retain cell signaling characteristics in vitro that distinguish them from skin epidermal keratinocytes. This finding may indicate that cholesteatoma keratinocytes undergo a change in behavior in vivo that is preserved after the cells are removed from the inflammatory environment of the middle ear. PMID- 21271592 TI - Hyaluronic acid fat graft myringoplasty: a minimally invasive technique. AB - OBJECTIVES: Hyaluronic acid fat graft myringoplasty (HAFGM) is a new technique for tympanic membrane perforation (TMP) treatment. It is simple, inexpensive, and performed under local anesthesia at the outpatient office department. We aim to evaluate the HAFGM on different TMP sizes, to compare the success rate of HAFGM with the underlay and overlay techniques, and to assess the hearing improvement at one year postoperatively. STUDY DESIGN: Prospective study. METHODS: Patients were divided into three groups depending on the patient's choice of technique: HAFGM (group I), underlay technique (group II), and overlay technique (group III). Perforations were classified into four grades. Postoperatively, the status of the eardrum, the improvement of hearing, and the incidence of complications were the main criteria for measuring outcome. RESULTS: Distribution of TMP was 131, 63, and 52 in group I, II, and III, respectively. Global successful rate and successful closure of the grade I, II, III, and IV were the same for the three groups. Postoperatively, no worsening of bone conduction threshold was noted. Air bone gap (ABG) was statistically similar for the three groups. No complications were noted for group I. The mean duration of the operative procedures was 16, 65, and 74 minutes for group I, II, and III, respectively (P = .02). The mean postoperative follow-up was 18.7, 20.6, and 15.5 months for groups I, II, and III, respectively. CONCLUSIONS: HAFGM success rate is comparable to that of the underlay and overlay techniques. Furthermore, it requires no hospitalization and avoids the difficulty of overlay and underlay tympanoplasty. PMID- 21271593 TI - Two cases of petrosquamosal sinus in the temporal bone presented as perioperative finding. AB - The petrosquamosal (PSS) is an embryonic emissary vein of the temporal bone in humans and connects the intra- and extracranial venous networks. Few reports in the recent literature provide detailed descriptions of PSSs that are found before or during surgeries. We report the presence of PSS in two patients with chronic otitis media. An abnormal vessel was found originating from the sigmoid sinus of each patient. The vessels coursed anteroinferiorly over the superior portion of the temporal bone and terminated near the posterior part of the temporomandibular joint. The clinical significance of PSS and a brief literature review are presented. PMID- 21271594 TI - Principles of inner ear sustained release following intratympanic administration. AB - OBJECTIVE/HYPOTHESIS: Previous studies revealed that intratympanic administration of the steroid dexamethasone in poloxamer 407 hydrogel, a class of thermoreversible polymers, resulted in significant and durable exposure in the inner ear. Interestingly, varying the concentrations of the poloxamer vehicle and of the steroid impacted the pharmacokinetic profile of dexamethasone in the perilymphatic compartment. Here, the respective contributions of different vehicles (aqueous solution, poloxamer hydrogel) and steroid drugs (dexamethasone, methylprednisolone) were investigated. In particular, various forms of the steroids, discriminated by their aqueous solubility, were compared. STUDY DESIGN: In vitro studies characterized the gelation profile and drug release kinetics of the various formulations. The inner ear pharmacokinetic profile of the different formulations was investigated in guinea pigs. RESULTS: Drugs formulated in poloxamer 407 shared significantly more prolonged exposure than those formulated in aqueous solutions both in vitro and in vivo in the inner ear. Furthermore, drugs with low aqueous solubility yielded increased degree and duration of exposure in the inner ear relative to water-soluble drugs. CONCLUSIONS: The inner ear pharmacokinetic profile of drugs administered intratympanically is not only highly dependent upon the nature of the vehicle but also upon the physicochemical properties of the drug delivered. PMID- 21271595 TI - Sensorineural hearing loss in sickle cell disease--a prospective study from Oman. AB - BACKGROUND: Sickle cell disease (SCD) is characterized by intermittent episodes of vascular occlusion and end-organ damage. Neurologic symptoms are frequent and auditory involvement is not unexpected. AIM: To study the prevalence and pattern of hearing loss in Omani patients with SCD. METHODS: We conducted a prospective case control study on SCD patients attending the outpatient department. Age and sex matched normal volunteer blood donor controls were recruited after an informed consent and Medical Ethics Committee approval. Pure tone audiometry was performed in all cases studied. RESULTS: Forty-six SCD patients (15 males, 32.6%) aged 16-45 years with a mean age of 26 years +/- 6.9 and 29 controls (10 males, 34.4%) aged 16-39 years with a mean age of 25.24 +/- 8.2 were enrolled in this study. The average hearing thresholds of SCD patients were consistently higher than controls in all frequencies tested in both ears. Of the 92 ears tested in SCD patients, 29.34% had SNHL. Ten patients had bilateral SNHL; whereas 3 and 4 cases had SNHL in left and right ears, respectively. All the control subjects had hearing thresholds within normal limits. SUMMARY/CONCLUSIONS: The study reveals a significant incidence of sensorineural hearing loss (SNHL) in SCD patients (36.95%), although the patients were clinically asymptomatic. The hearing loss was worse in the right ears and had a female preponderance. Also, the hearing loss was more severe at the higher frequencies, 2,000-8,000 Hz in SCD patients. HbS, HbF, or low hemoglobin levels did not discriminate SCD patients with SNHL, and the role of hemoglobin F in the cochlea is still not clear. Regular audiometric assessment should therefore be recommended in SCD patients routinely. PMID- 21271596 TI - Postcricoid vascular lesions: histopathological and immunohistochemical diagnosis. AB - OBJECTIVES/HYPOTHESIS: Postcricoid vascular lesions are a rare cause of dysphagia and stridor in the pediatric population. Currently, there is no clear consensus on what type of vascular lesions are common in the postcricoid area because adequate histological or immunohistochemistry studies are lacking. This study aimed to describe the histology and immunohistochemistry of postcricoid masses in our institutions' experience, and consolidate available data on the symptoms, management, and histology of these unusual malformations with a comprehensive literature review. STUDY DESIGN: Retrospective patient and literature review. METHODS: A retrospective review of patients with postcricoid vascular lesions was performed at two pediatric tertiary care institutions. Histology and immunohistochemistry studies were performed in patients undergoing a lesion biopsy. A complete literature review of the English language was completed for cases involving vascular lesions of the postcricoid area. RESULTS: Four patients were identified in our study with postcricoid vascular lesions. All patients presented with symptoms of dysphagia and intermittent stridor. Histology and immunohistochemistry studies were performed in three patients. GLUT-1 was negative in all three patients, and CD34 was positive in all patients tested. Lewis Y antigen was performed in one patient and was negative. A description of 19 cases reported in the English literature is included. CONCLUSIONS: Patients with postcricoid vascular lesions usually present with mild to moderate feeding difficulties, and stridor or dyspnea with agitation. Histopathology and immunohistochemistry results suggest that postcricoid vascular lesions may often represent congenital vascular malformations instead of infantile hemangiomas. PMID- 21271597 TI - Role of the mastoid in middle ear pressure regulation. AB - OBJECTIVES/HYPOTHESIS: Determine the role of mastoid volume in middle ear pressure (MEP) regulation. The hypothesis was that inert gas exchange between blood and middle ear (ME) is slower for larger mastoid volumes. STUDY DESIGN: Prospective. METHODS: For 21 enrolled subjects, the bilateral surface areas and volumes of the mastoid and tympanum were measured from computed tomography scans in 20 subjects with a wide range of mastoid volumes. Then, 19 subjects were reclined in a chair, fitted with a non-rebreathing mask and breathed room air for 20 minutes (acclimation), a gas composition of 25% N(2)O, 20% O(2), balance N(2) for 30 minutes (experiment), and room air for 30 minutes (recovery). Bilateral MEPs were recorded by tympanometry every 2 minutes. The slopes of the MEP-time functions during N(2)O breathing were calculated to the first observation of eustachian tube opening and divided by the estimated blood-ME N(2)O gradient to yield a N(2)O time constant. Sufficient data were available for 16 right and 11 left MEs to calculate the time constant. RESULTS: MEP did not change during the baseline period, but within 10 minutes of breathing the N(2)O mixture showed a progressive increase. The right-left correlation for the time constant was 0.87 (n = 10 ears, P = .001). Regression of the time constants on ME volume showed an inverse relationship (n = 23 ears, r = -41, P = .05). A better data fit was the curvilinear relationship predicted by a mathematical model of the mastoid acting as a ME ear gas reserve. CONCLUSIONS: These results support the tested hypothesis that the mastoid could serve as ME gas reserve. PMID- 21271598 TI - Causes of permanent childhood hearing impairment. AB - INTRODUCTION: The causes of Permanent Childhood Hearing Impairment (PCHI) are often quoted as being hereditary in 50%, acquired in 25%, and unknown in 25% of cases. Interest in the causes of PCHI has grown recently due to increasing diagnostic possibilities. We investigated the evidence for the reported distribution of these causes. METHODS: Population-based study and a systematic review. Inclusion criteria for population-based study: children born between 2003 and 2005, resident in The Netherlands at birth, known at an Audiology Center with PCHI at the age of 3-5 years. The causes of PCHI were determined prospectively by detection of congenital cytomegalovirus on dried blood spots and/or genetic diagnostic investigations in addition to reviewing data from medical records. A systematic review was carried out using three terms (hearing loss, infant, and etiology) and limited to articles published between January 1997 and July 2009. Main outcome measures were: the (weighted) proportions of the various causes of PCHI following diagnostic investigations. RESULTS: In the study-population (n = 185) a hereditary cause was found in 38.9%, acquired cause in 29.7%, miscellaneous cause in 7.1%, and the cause remained unknown in 24.3%. The systematic review of the literature (n = 9 articles) resulted in a weighted mean of 30.4% hereditary, 19.2% acquired, and 48.3% unknown causes of PCHI. DISCUSSION: The systematic review and the results of the population-based study provided little support for the generally accepted distribution of causes of PCHI. PMID- 21271599 TI - Low-stage computed tomography chronic rhinosinusitis: what is the role of endoscopic sinus surgery? AB - OBJECTIVES/HYPOTHESIS: To measure the change in quality-of-life (QoL) after endoscopic sinus surgery (ESS) in patients with medically recalcitrant chronic rhinosinusitis (CRS) and minimally affected computed tomography (CT) scans of the paranasal sinuses. STUDY DESIGN: Prospective, multicenter cohort study at three academic, tertiary care centers. METHODS: A total of 778 patients with CRS were enrolled between January 2001 and April 2009 after electing ESS. For the purposes of this analysis, patients with nasal polyposis, history of prior sinus surgery, or follow-up <6 months were excluded. Final study patients were categorized as low-stage CT CRS (Lund-Mackay <=3; n = 17) and high-stage CT CRS (Lund-Mackay >3; n = 207). Primary outcome measures included two disease-specific QoL instruments: the Rhinosinusitis Disability Index and the Chronic Sinusitis Survey. RESULTS: In patients with low-stage CT CRS, a statistically significant improvement was found across all disease-specific QoL scores (all P <= .012), with the exception of the CSS medication usage subscale (P = .073). These QoL improvements were comparable to those in patients with high-stage CT CRS. CONCLUSIONS: Some patients will present with CRS that is refractory to medical therapy even though their CT demonstrates relatively minimal disease. Based on the results of this study, ESS is associated with improved QoL in patients with low-stage CT CRS and can provide significant benefit to carefully selected patients with minimally affected CT scans. PMID- 21271600 TI - Systematic review of topical vasoconstrictors in endoscopic sinus surgery. AB - OBJECTIVE: The objective of this study is to systematically review the literature and examine the safety for the use of topical vasoconstrictors in endoscopic sinus surgery. STUDY DESIGN: Systematic review clinical trials. METHOD: A systematic literature search was performed in MEDLINE, EMBASE, The Cochrane Library, and National Guideline Clearinghouse, and references in the selected articles. RESULTS: The search criteria captured 42 manuscripts with relevant titles. A systematic review on the topical use of phenylephrine was found; however, no other systematic review, meta-analyses, or clinical guidelines were identified. Six randomized clinical trials or comparative studies, as well as multiple case reports and review articles were also identified. The literature supports the safety of oxymetazoline and epinephrine when used judiciously in carefully selected patients undergoing endoscopic sinonasal surgery; however, topical phenylephrine is not recommended because of its risk profile. CONCLUSION: In sinus or nasal surgery, topical vasoconstrictors should be used in a manner that minimizes the risk of cardiovascular morbidity. PMID- 21271601 TI - Efficacy of mitomycin C in endonasal endoscopic dacryocystorhinostomy. AB - OBJECTIVES/HYPOTHESIS: To evaluate the efficacy of intraoperative mitomycin C (MMC) in endonasal endoscopic dacryocystorhinostomy. STUDY DESIGN: Randomized controlled trial. METHODS: Fifty patients with primary acquired nasolacrimal duct obstruction were enrolled and randomly allocated into the treatment and control group. The patients underwent standard endonasal endoscopic dacryocystorhinostomy with mucosal flaps and mitomycin C or placebo on each group. The ostium size was measured at 3 months, 6 months, and 12 months to evaluate the effect of mitomycin C and placebo, and the patency of the lacrimal drainage system was assessed. RESULTS: There was no statistical significance in the success rate between the MMC group and the control group at 1-year follow-up (84.6% vs.79.2%, respectively, P = .59). At the 6-month and 12-month visits, the mean ostium size in the MMC group was 10.8 mm(2) (SD = 3.17) and 3.0 mm(2) (SD = 1.78), respectively, which were prominently larger than the control group at 7.1 mm(2) (SD = 2.62; P < .001, 95% CI, 0.84-5.45) and 1.6 mm(2) (SD = 1.18; P = .004, 95% CI, 0.49-2.38). CONCLUSIONS: There was no statistically significant difference in the success rates of both groups, but MMC seems to have a conspicuous effect on the healing process at the ostium. PMID- 21271602 TI - Addition of a minimally invasive medial orbital approach in the endoscopic management of advanced sino-orbital disease: cadaver study with clinical correlations. AB - OBJECTIVES: Access to the medial orbit traditionally has been gained transcutaneously, with potential for associated soft tissue and lacrimal disruption. Endoscopic transnasal approaches to the medial orbit may be limited in certain scenarios by tumor presence or patient-specific factors. The medial transconjunctival approach, or transcaruncular approach, has been recently described for access to the medial orbit in orbital decompression and repair of medial blowout fractures. The aim of this study is to determine the utility of this minimally invasive external approach in the endoscopic management of advanced sino-orbital disease. METHODS: This is a cadaver study with additional clinical correlations. The transcaruncular approach was combined with a transnasal endoscopic approach in cadaver dissections performed on eight sides. Five cases are described in which the transcaruncular approach was used as an adjunctive technique in advanced endoscopic sinus surgery. RESULTS: In cadaver dissection, the transcaruncular approach is a simple, reliable method to ligate the ethmoid arteries and place bony cuts along the medial orbital wall. In certain anatomic configurations, supraorbital dissection into the frontal sinus or anterior fossa may be achieved. In the cases examined, exposure of the medial orbital subperiosteal plane allowed for ligation of ethmoid arteries, assessment of periorbital invasion of disease, assistance in tumor dissection, and placement of a malleable retractor for protection of orbital contents. CONCLUSIONS: The transcaruncular approach to the medial orbit has certain advantages over the traditional open approach. Ligation of the ethmoid arteries, assessment of the lacrimal sac and periorbita for tumor invasion, protection of orbital contents, and en bloc resection of the periorbita and lamina papyrecea are possible through this route. PMID- 21271603 TI - Endoscopic modified Lothrop procedure: a radiographic anatomic study. AB - OBJECTIVE: Radiographic frontal recess and sinus anatomic measurements were obtained to evaluate the feasibility of the endoscopic modified Lothrop procedure. STUDY DESIGN: Computed tomography anatomic study. MATERIALS AND METHODS: Computed tomography (CT) scans from 97 patients, 39 male and 58 female, were analyzed in the sagittal plane. Four anatomic parameters were measured 1) midsagittal thickness of the nasal beak, 2) midsagittal distance from nasal beak to skull base, 3) accessible dimension of the frontal recess, and 4) anterior to posterior (AP) dimension of the frontal sinus. RESULTS: The average and range of each parameter are as follows: 1) midsagittal nasal beak thickness 0.8 cm (0.3 1.4 cm); 2) midsagittal beak to skull base 1.0 cm (0.4-2.4 cm); 3) left and right accessible dimension 0.8 cm (0.3-1.4 cm) and 0.8 cm (0.4-1.5 cm), respectively; 4) left and right AP diameter of the frontal sinus 1.0 cm (0.3-1.8 cm) and 1.1 cm (0.4-1.9 cm), respectively. There is statistically significant differences between the accessible dimension and AP dimension of the frontal sinus on male and female images. DISCUSSION: Preoperative frontal recess and sinus measurements can aid in the selection of patients for the endoscopic modified Lothrop procedure. A significant portion of the population, especially women, had limiting anatomic factors potentially excluding this procedure. PMID- 21271604 TI - Transcaruncular electrocoagulation of anterior ethmoidal artery for the treatment of severe epistaxis. AB - OBJECTIVE: The irrigation of the upper third of the nasal fossa is supplied by the anterior ethmoidal artery. We describe a surgical technique to deal with epistaxis due to anterior ethmoidal artery bleeding. PATIENTS AND METHODS: From January 2006 to March 2010 transcaruncular coagulation of the anterior ethmoidal artery was done on nine patients with epistaxis of the upper third of the nasal fossa. RESULTS: The procedure was successful on all cases. No bleeding relapse, major complications, or nasal or orbital sequelae were present in any of the patients. DISCUSSION/CONCLUSIONS: Transcaruncular electrocoagulation of the anterior ethmoidal artery is a safe and effective technique to deal with upper third nasal fossa bleeding. PMID- 21271605 TI - Soft palate sensory neuropathy in the pathogenesis of obstructive sleep apnea. AB - OBJECTIVES/ HYPOTHESIS: In general, obstructive sleep apnea (OSA) seems to be a progressive disorder whose pathogenesis is not fully understood. One hypothesis is that long-standing snoring vibrations cause a local neuropathy in the upper airway, which predisposes to obstructive events during sleep. The aim of this study was to investigate sensory function in the upper airway in a cohort of subjects comprising nonsnorers, snorers, and untreated subjects with OSA, and to correlate data to apnea-hypopnea index (AHI) and duration of snoring. STUDY DESIGN: Cross-sectional cohort study. METHODS: Subjects were recruited from primary care hypertension clinics. Whole-night respiratory recordings were performed to determine presence and degree of OSA. Three groups were formed based on AHI and snoring history: 1) nonsnorers (n = 25); 2) snorers, AHI < 10 (n = 32); 3) OSA subjects, AHI >= 10 (n = 33). Quantitative cold sensory testing of the soft palate and lip was used to assess neuropathy. RESULTS: There were no significant differences concerning lip sensory function between groups. Nonsnorers showed significantly lower thresholds for cold (i.e., better sensitivity) in the soft palate compared to both other groups (P < .01). Snorers had lower thresholds than OSA subjects (P < .05). There were significant correlations (P < .01) between decreased sensory function and AHI (r(s) = .41) and to duration of snoring (r(s) = .47). CONCLUSIONS: The degree of sensory neuropathy in the upper airway correlates with degree of obstructive sleep disorder. Our results strengthen the hypothesis that snoring vibrations may cause a neuropathy in the upper airway, which contributes to the progression and development of OSA. PMID- 21271606 TI - Local vascularized flaps for augmentation of Reinke's space. AB - OBJECTIVES/HYPOTHESIS: The purpose of this study is to describe and test a novel surgical strategy for augmentation of Reinke's space using vascularized flaps: a thyroid ala perichondrium flap (TAP) and a composite thyroid ala perichondrium flap (CTAP) from the anterior larynx. We hypothesized that these specially designed vascularized flaps would remain viable once inset into the lamina propria, and that they would not disrupt rheologic, biomechanical, and histologic properties of the native vocal fold. STUDY DESIGN: Experimental. In vivo canine model. METHODS: The length and volume of test flaps harvested in six adult human cadaveric larynges were analyzed to determine suitability for use in augmentation in the lamina propria. Also, 12 beagles randomly underwent unilateral placement of either TAP or CTAP, which were designed in accordance with the human adult cadaveric experiments. Flap perfusion was measured before and after harvest with laser Doppler. After 1 month, the beagles were humanely sacrificed and their larynges subjected to aerodynamic and acoustic evaluation using an excised larynx apparatus. The vocal fold lamina propria of four larynges--two TAP and two CTAP- underwent rheologic evaluation using a simple-shear rheometer. The remaining eight larynges underwent quantitative histologic and immunohistochemical evaluation. The survival and complication (swallowing, airway, local wound) rates of all dogs were noted. RESULTS: Initial studies with adult human cadaveric larynges established that TAP and CTAP possessed length and volume greater than native lamina propria. In the canine experiments, the perfusion change in the flaps was similar between flap groups. The damping ratio (zeta), dynamic viscosity (eta'), elastic shear modulus (G'), and viscous shear modulus (G") of treated and untreated native vocal folds were not statistically different. The glottic function measures of vocal efficiency, laryngeal resistance, jitter, shimmer, and harmonics-to-noise ratio (HNR) of treated and normal larynges were not statistically different. Similarly, the values for collagen, elastin, and glycosaminoglycans (GAGs) in treated and untreated vocal folds were not statistically different. Also, neither neochrondrogenesis nor neoosteogenesis was detected in any treated vocal fold. The values for vascular and cellular proliferation in treated and untreated vocal folds were not statistically different. All test dogs survived and had no complications related to swallowing, airway distress, or the local wound. CONCLUSIONS: The test flaps described and tested in this study appear to have conceptually attractive features for augmentation of Reinke's space. When placed in an in vivo setting TAP and CTAP did not reveal unfavorable vascular, rheologic, aerodynamic, acoustic, or histologic characteristics. There was no unanticipated morbidity or mortality to the test animals. Long-term viability of these flaps is unknown. TAP and CTAP may open novel pathways for correction of glottic defects and may offer crossover opportunities with tissue engineering techniques. PMID- 21271607 TI - Intestinal transport of bis(12)-hupyridone in Caco-2 cells and its improved permeability by the surfactant Brij-35. AB - The objective of the present study was to elucidate the mechanisms of intestinal transport of bis(12)-hupyridone (B12H) to predict its oral bioavailability. The effect of the B12H concentration and the contribution of the drug efflux transporters, P-glycoprotein (P-gp or ABCB1) and multidrug resistance-associated proteins (MRPs or ABCC) on B12H absorption were measured and evaluated using the human intestinal epithelial Caco-2 cell monolayer in the presence of transporter inhibitors. The results indicated that B12H was absorbed in a dose-dependent manner at concentrations ranging from 132 to 264 uM. However, only apical efflux was observed in the directional transport studies for B12H below 88 uM (P(app) (AP-to-BL): virtually zero; P(app) (BL-to-AP): 1.591 +/- 0.071 * 10(-5) cm s(-1) ). P-gp and mixed P-gp/MRP inhibitors significantly increased the absorptive transport (P(app) (AP-to-BL)) to 0.619 +/- 0.018 * 10(-5) and 0.608 +/- 0.025 * 10(-5) cm s(-1) , respectively, while decreasing secretory transport (P(app) (BL to-AP)) by >75%. A multiple-MRP inhibitor, probenecid, increased the P(app) (AP to-BL) to 0.329 +/- 0.015 * 10(-5) cm s(-1) while decreasing the P(app) (BL-to AP) by 50%. Another multiple-MRP inhibitor, indomethacin, only modestly decreased the P(app) (BL-to-AP) by ~30% and had no effect on the absorptive transport (P(app) (AP-to-BL): virtually zero). In addition, the effect of various pharmaceutical excipients (e.g. Pluronic F-68, Tween-80 and Brij-35) on B12H transport was determined and compared. Among them, Brij-35 effectively enhanced B12H absorption at a concentration lower than its critical micelle concentration (CMC, 60 uM). Therefore, Brij-35 can be used as a potential enhancer to improve intestinal absorption of B12H for oral administration. PMID- 21271608 TI - Changes in ultrastructure and properties of bracket slots after orthodontic treatment with bicuspid extraction. AB - This study examined the effects of an orthodontic treatment using a bicuspid extraction on the surface roughness and mechanical properties of stainless steel (SS) brackets adjacent to the extraction space. Four experimental groups were employed; groups 1 and 2 used the Archist((r)) SS brackets before and after the extraction treatment, respectively, and groups 3 and 4 used the Victory((r)) SS brackets before and after the extraction treatment, respectively. The slot surfaces of the bracket were scanned in air at a resolution of 512 * 512 pixels with a scan speed of 0.8 line/s. The visco-elasticity of the bracket slot was determined from the force-distance curves of atomic force microscopy. The orthodontic treatment with bicuspid extraction led to a significant increase (p<0.0001) in surface roughness in both groups. In particular, the Archist((r)) SS brackets showed more changes than the Victory((r)) SS brackets (p<0.0005). However, there was no significant difference in properties of the Victory((r)) and Archist((r)) brackets between before and after treatment. This suggests that the orthodontic treatment with bicuspid extraction is more responsible for the changes in surface roughness than the properties of the brackets. PMID- 21271609 TI - Snake venom: From fieldwork to the clinic: Recent insights into snake biology, together with new technology allowing high-throughput screening of venom, bring new hope for drug discovery. AB - Snake venoms are recognized here as a grossly under-explored resource in pharmacological prospecting. Discoveries in snake systematics demonstrate that former taxonomic bias in research has led to the neglect of thousands of species of potential medical use. Recent discoveries reveal an unexpectedly vast degree of variation in venom composition among snakes, from different species down to litter mates. The molecular mechanisms underlying this diversity are only beginning to be understood. However, the enormous potential that this resource represents for pharmacological prospecting is clear. New high-throughput screening systems offer greatly increased speed and efficiency in identifying and extracting therapeutically useful molecules. At the same time a global biodiversity crisis is threatening the very snake populations on which hopes for new venom-derived medications depend. Biomedical researchers, pharmacologists, clinicians, herpetologists, and conservation biologists must combine their efforts if the full potential of snake venom-derived medications is to be realized. PMID- 21271610 TI - The changing faces of HP1: From heterochromatin formation and gene silencing to euchromatic gene expression: HP1 acts as a positive regulator of transcription. AB - Heterochromatin protein 1 (HP1) is a positive regulator of active transcription in euchromatin. HP1 was first identified in Drosophila melanogaster as a major component of heterochromatin. Most eukaryotes have at least three isoforms of HP1, which are conserved in overall structure but localize differentially to heterochromatin and euchromatin. Although initial studies revealed a key role for HP1 in heterochromatin formation and gene silencing, recent progress has shed light on additional roles for HP1 in processes such as euchromatic gene expression. Recent studies have highlighted the importance of HP1-mediated gene regulation in euchromatin. Here, we focus on recent advances in understanding the role of HP1 in active transcription in euchromatin and how modification and localization of HP1 can regulate distinct functions for this protein in different contexts. PMID- 21271611 TI - IkappaB-Kinase-epsilon (IKKepsilon/IKKi/IkappaBKepsilon) expression and localization in prostate cancer tissues. AB - BACKGROUND: Advanced prostate cancer (PCa) remains a one of the leading causes of cancer related death and is often due to the progression from a hormone sensitive (HS) to a castrate resistant (CR) state for which therapeutic alternatives remain palliative. Molecular events involved in the progression to CR-PCa remain largely unknown. A previous study reported significantly higher levels of Ikappa-B kinase epsilon (IKKepsilon) expression in CR compared to androgen-responsive cell lines. In the present study, we evaluate IKKepsilon expression in human prostate tissue. METHODS: In order to evaluate the modulation of IKKepsilon expression in PCa tissue IKKepsilon immunostaining was performed on paraffin-embedded prostate tissue microarrays containing cores from normal tissues (n = 47), non-malignant tissues adjacent to the tumor (n = 53), prostatic intraepithelial neoplasia (PIN) (n = 28), HS (n = 62), and CR tumors (n = 31). RESULTS: We found a low cytoplasmic expression of IKKepsilon in non-malignant tissue. HS tumors showed a significant increase in cytoplasmic IKKepsilon expression compared to non malignant tissues. CR tissues presented the highest cytoplasmic IKKepsilon expression levels. We also report, for the first time, the presence of a nuclear localization of IKKepsilon in prostate epithelial cells, in particular we observed an increase of IKKepsilon nuclear localization in HS malignant tissues. Finally, we found a strong link between an increase of IKKepsilon cytoplasmic expression in PCa and metastatic progression. CONCLUSION: This study strongly suggests the role of IKKepsilon as a PCa oncogene that may be involved in the emergence of a CR state. PMID- 21271612 TI - Prostate cancer outcome and tissue levels of metal ions. AB - BACKGROUND: There are several studies examining prostate cancer and exposure to cadmium, iron, selenium, and zinc. Less data are available on the possible influence of these metal ions on prostate cancer outcome. This study measured levels of these ions in prostatectomy samples in order to examine possible associations between metal concentrations and disease outcome. METHODS: We obtained formalin fixed paraffin embedded tissue blocks of prostatectomy samples of 40 patients with PSA recurrence, matched 1:1 (for year of surgery, race, age, Gleason grading, and pathology TNM classification) with tissue blocks from 40 patients without recurrence (n = 80). Case-control pairs were compared for the levels of metals in areas adjacent to tumors. Inductively coupled plasma-mass spectrometry (ICP-MS) was used for quantification of Cd, Fe, Zn, and Se. RESULTS: Patients with biochemical (PSA) recurrence of disease had 12% lower median iron (95 ug/g vs. 111 ug/g; P = 0.04) and 21% lower zinc (279 ug/g vs. 346 ug/g; P = 0.04) concentrations in the normal-appearing tissue immediately adjacent to cancer areas. Differences in cadmium (0.489 ug/g vs. 0.439 ug/g; 4% higher) and selenium (1.68 ug/g vs. 1.58 ug/g; 5% higher) levels were not statistically significant in recurrence cases, when compared to non-recurrences (P = 0.40 and 0.21, respectively). CONCLUSIONS: There is an association between low zinc and low iron prostate tissue levels and biochemical recurrence in prostate cancer. Whether these novel findings are a cause or effect of more aggressive tumors, or whether low zinc and iron prostatic levels raise implications for therapy, remains to be investigated. PMID- 21271613 TI - Preliminary study of the specific endothelin a receptor antagonist zibotentan in combination with docetaxel in patients with metastatic castration-resistant prostate cancer. AB - BACKGROUND: This two-part study assessed the safety and tolerability of combined treatment with zibotentan (ZD4054), a specific endothelin A receptor antagonist, plus docetaxel in patients with metastatic castration-resistant prostate cancer. METHODS: Part A was an open-label, dose-finding phase to determine the safety and toxicity profile of zibotentan in combination with docetaxel. Patients received once-daily oral zibotentan 10 mg (initial cohort) or 15 mg in combination with docetaxel 75 mg/m(2) (administered on day 1 of each 21-day cycle) for up to 10 cycles. Part B was a double-blind phase which evaluated the safety and preliminary activity of zibotentan plus docetaxel. Patients were randomized 2:1 to receive zibotentan (at the highest tolerated dose identified in part A) plus docetaxel or placebo plus docetaxel. RESULTS: Six patients were enrolled in part A (n = 3, zibotentan 10 mg; n = 3, zibotentan 15 mg). No dose-limiting toxicity was observed, thus zibotentan 15 mg in combination with docetaxel was evaluated in part B (n = 20, zibotentan plus docetaxel; n = 11, placebo plus docetaxel). CTCAE grade >=3, most commonly neutropenia or leucopenia, were reported in 10 (50%) and nine (82%) patients in the zibotentan and placebo groups, respectively. One (17%) patient receiving placebo achieved complete response, two (22%) patients receiving zibotentan achieved partial response and stable disease occurred in six (67%) and three (50%) patients receiving zibotentan and placebo, respectively. CONCLUSIONS: The tolerability of zibotentan plus docetaxel was consistent with the known profiles of each drug. Sufficient preliminary activity was seen with this combination to merit continued development. PMID- 21271614 TI - Successful treatment of IgG and complement-mediated autoimmune hemolytic anemia with bortezomib and low-dose cyclophosphamide. PMID- 21271615 TI - Leptin, adiponectin, and resistin secretion and diurnal rhythmicity are unaltered in Parkinson's disease. PMID- 21271616 TI - Mirror helices and helicity switch at surfaces based on chiral triangular-shape oligo(phenylene ethynylenes). AB - The self-assembly of triangular-shaped oligo(phenylene ethynylenes) (OPEs), peripherally decorated with chiral and linear paraffinic chains, is investigated in bulk, onto surfaces and in solution. Whilst the X-ray diffraction data for the chiral studied systems display a broad reflection centered at 2theta ~20 degrees (lambda=Cu(Kalpha)), the higher crystallinity of OPE 3, endowed with three linear decyl chains, results in a diffractrogram with a number of well-resolved reflections that can be accurately indexed as a columnar packing arranged in 2D oblique cells. Compounds (S)-1 a and (R)-1 b-endowed with (S)- and (R)-3,7 dimethyloctyloxy chains-transfer their chirality to the supramolecular structures formed upon their self-assembly, and give rise to helical nanostructures of opposite handedness. A helicity switch is noticeable for the case of chiral (S)-2 decorated with (S)-2-methylnonyloxy chains which forms right-handed helices despite it possesses the same stereoconfiguration for their stereogenic carbons as (S)-1 a that self-assembles into left-handed helices. The stability and the mechanism of the supramolecular polymerization in solution have been investigated by UV/Vis experiments in methylcyclohexane. These studies demonstrate that the larger the distance between the stereogenic carbon and the aromatic framework is, the more stable the aggregate is. Additionally, the self-assembly mechanism is conditioned by the peripheral substituents: whereas compounds (S)-1 a and (R)-1 b self-assemble in a cooperative manner with a low degree of cooperativity, the aggregation of (S)-2 and 3 is well described by an isodesmic model. Therefore, the interaction between the chiral coil chains conditions the handedness of the helical pitch, the stability of the supramolecular structure and the supramolecular polymerization mechanism of the studied OPEs. PMID- 21271617 TI - Guanidine organocatalyst for the asymmetric Mannich-type reaction between alpha isothiocyanato imide and sulfonyl imines. PMID- 21271618 TI - Copper(I)-anilide complex [Na(phen)3][Cu(NPh2)2]: an intermediate in the copper catalyzed N-arylation of N-phenylaniline. AB - Complex [Na(phen)(3)][Cu(NPh(2) )(2)](2), containing a linear bis(N phenylanilide)copper(I) anion and a distorted octahedral tris(1,10 phenanthroline)sodium counter cation, has been isolated from the catalytic C-N cross-coupling reaction with the CuI/phen/tBuONa (phen=1,10-phenanthroline) catalytic system. Complex 2 can react with 4-iodotoluene to produce 4-methyl-N,N diphenylaniline (3 a) with 70.6 % yield. In addition, 2 can work as an effective catalyst for C-N coupling under the same reaction conditions, thus indicating that 2 is the intermediate of the catalytic system. Both [Cu(NPh(2))(2)](-) and [Cu(NPh(2))I](-) have been observed by in situ electron ionization mass spectrometry (ESI-MS) under catalytic reaction conditions, thus confirming that they are intermediates in the reaction. A catalytic cycle has been proposed based on these observations. The molecular structure of 2 has been determined by single crystal X-ray diffraction analysis. PMID- 21271619 TI - Direct hydrogenation of nitroaromatics and one-pot amidation with carboxylic acids over platinum nanowires. AB - A novel ultrathin platinum nanowire with uniform length and a diameter of 1.5 nm was synthesized by acidic etching of FePt nanowire in methanol. This nanowire was characterized by high-resolution transmission electron microscopy (HRTEM). X-ray diffraction (XRD) data indicated that the main plane is (111). The ability of this nanowire to catalyze the heterogeneous hydrogenation of nitroaromatics to give the corresponding amines has been investigated. The catalyst showed satisfactory activity in various solvents under mild conditions and showed excellent stability. The catalytic performance was also evaluated in the one-pot reduction of nitroaromatics and amidation with carboxylic acids under a hydrogen atmosphere at 100 degrees C. These methods for the hydrogenation of nitroaromatics and the direct amidation of nitroaromatics with carboxylic acids are simple, economical, and environmentally benign, and have practical advantages for the synthesis of amines and amides without the production of toxic byproducts. PMID- 21271620 TI - Ultrahigh density arrays of toroidal ZnO nanostructures by one-step cooperative self-assembly processes: mechanism of structural evolution and hybridization with Au nanoparticles. AB - A quick protocol for the fabrication of ultrahigh density arrays of toroidal ZnO nanostructures with tailored structures on a substrate surface is presented based on the one-step spin coating of a common solution composed of inverse micelles of polystyrene-block-poly(4-vinyl pyridine) copolymers (PS-b-P4VP) and sol-gel precursors without the need of conventional complex lithographic techniques. ZnO toroids decorated with gold nanoparticles are also obtained by subsequent loading and reduction of metallic precursors. It was elucidated that the diethanolamine moiety in the sol-gel precursors, which induces selective swelling and structural reorganization of the P4VP core blocks, plays a key role in the generation of toroidal nanostructures. Toroidal ZnO nanostructures embedded in a PS-b-P4VP matrix films or arrays of pure wurtzite ZnO nanorings are obtained by calcination under inert atmosphere. The structural parameters of the toroidal nanostructures such as the width, height, diameter of the rims as well as the spacing of their 2D arrays are controlled by employing PS-b-P4VP with different molecular weight and varying the mixing protocols. PMID- 21271621 TI - Ruthenium-catalyzed nitro and nitrile compounds coupling with alcohols: alternative route for N-substituted amine synthesis. PMID- 21271622 TI - The effect of the dynamics of revolving gates on the kinetics of molecular encapsulation--the activity/selectivity relationship. PMID- 21271623 TI - Multicomponent synthesis of chiral sulfinimines. AB - Two oxathiozolidine-S-oxide templates have been developed and used in a four component coupling protocol for the synthesis of a wide range of chiral sulfinimines in high enantiomeric excesses. The templates can be synthesized from cheap commodity chemicals in three steps in high yields. Furthermore the template is easily recovered in high yields for recycling. PMID- 21271624 TI - Most published and unpublished dissertations should be excluded from meta analyses: comment on Moyer et al. PMID- 21271625 TI - Uncovering molecular processes in crystal nucleation and growth by using molecular simulation. AB - Exploring nucleation processes by molecular simulation provides a mechanistic understanding at the atomic level and also enables kinetic and thermodynamic quantities to be estimated. However, whilst the potential for modeling crystal nucleation and growth processes is immense, there are specific technical challenges to modeling. In general, rare events, such as nucleation cannot be simulated using a direct "brute force" molecular dynamics approach. The limited time and length scales that are accessible by conventional molecular dynamics simulations have inspired a number of advances to tackle problems that were considered outside the scope of molecular simulation. While general insights and features could be explored from efficient generic models, new methods paved the way to realistic crystal nucleation scenarios. The association of single ions in solvent environments, the mechanisms of motif formation, ripening reactions, and the self-organization of nanocrystals can now be investigated at the molecular level. The analysis of interactions with growth-controlling additives gives a new understanding of functionalized nanocrystals and the precipitation of composite materials. PMID- 21271626 TI - 2-Iodoxybenzoic acid--a simple oxidant with a dazzling array of potential applications. AB - Since its discovery by Christoph Hartmann and Victor Meyer in 1893, 2 iodoxybenzoic acid (IBX) has emerged as a rather ubiquitous oxidant for organic synthesis. The past decade has seen the development of a large variety of applications that go far beyond the simple oxidation of alcohols. This Review is concerned with the synthetic potential of IBX, with particular emphasis on uncommon reactivity patterns and novel fields of application. PMID- 21271627 TI - Merging metal and N-heterocyclic carbene catalysis: on the way to discovering enantioselective organic transformations. PMID- 21271628 TI - Identification of CYP106A2 as a regioselective allylic bacterial diterpene hydroxylase. AB - The cytochrome P450 monooxygenase CYP106A2 from Bacillus megaterium ATCC 13368 catalyzes hydroxylations of a variety of 3-oxo-Delta(4) -steroids such as progesterone and deoxycorticosterone (DOC), mainly in the 15beta-position. We combined a high-throughput screening and a rational approach for identifying new substrates of CYP106A2. The diterpene resin acid abietic acid was found to be a substrate and was docked into the active site of a CYP106A2 homology model to provide further inside into the structural basis of the regioselectivity of hydroxylation. The products of the hydroxylation reaction were analyzed by HPLC and the V(max) and K(m) values were calculated. The corresponding reaction products were analyzed by NMR spectroscopy and identified as 12alpha- and 12beta hydroxyabietic acid. CYP106A2 was therefore identified as the first reported bacterial cytochrome P450 diterpene hydroxylase. Furthermore, an effective whole cell catalyst for the selective allylic 12alpha- and 12beta-hydroxylation was applied to produce the hydroxylated products. PMID- 21271629 TI - Baicalein inhibits formation of alpha-synuclein oligomers within living cells and prevents Abeta peptide fibrillation and oligomerisation. AB - Abnormal protein aggregation in the brain is linked to the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Recent studies revealed that the oligomeric form of aggregates is most likely the toxic species, and thus could be a good therapeutic target. To screen for potent inhibitors that can inhibit both oligomerisation and fibrillation of alpha-synuclein (alpha-syn), we systematically compared the antioligomeric and antifibrillar activities of eight compounds that were extracted from Chinese herbal medicines through three platforms that can monitor the formation of alpha-syn fibrils and oligomers in cell-free or cellular systems. Our results revealed that baicalein, a flavonoid extracted from the Chinese herbal medicine Scutellaria baicalensis Georgi ("huang qin" in Chinese), is a potent inhibitor of alpha-syn oligomerisation both in cell-free and cellular systems, and is also an effective inhibitor of alpha-syn fibrillation in cell free systems. We further tested the protective effect of baicalein against alpha syn-oligomer-induced toxicity in neuronal cells. Our data showed that baicalein inhibited the formation of alpha-syn oligomers in SH-SY5Y and Hela cells, and protected SH-SY5Y cells from alpha-syn-oligomer-induced toxicity. We also explored the effect of baicalein on amyloid-beta peptide (Abeta) aggregation and toxicity. We found that baicalein can also inhibit Abeta fibrillation and oligomerisation, disaggregate pre-formed Abeta amyloid fibrils and prevent Abeta fibril-induced toxicity in PC12 cells. Our study indicates that baicalein is a good inhibitor of amyloid protein aggregation and toxicity. Given the role of these processes in neurodegenerative diseases such as AD and PD, our results suggest that baicalein has potential as a therapeutic agent for the treatment of these devastating disorders. PMID- 21271630 TI - Engineering protein switches: sensors, regulators, and spare parts for biology and biotechnology. PMID- 21271632 TI - The effect of specific adsorption of cations and their size on the charge compensation mechanism in carbon micropores: the role of anion desorption. AB - Combined application of cyclic voltammetry (CV) and electrochemical quartz crystal microbalance (EQCM) technique reveals a complicated interplay between the adsorption of ammonium and lower molecular weight tetraalkyl ammonium cations and desorption of Cl(-) anions inside carbon micropores at low surface charge densities, which results in failure of their permselectivity. Higher negative surface charge densities induce complete exclusion (desorption) of the Cl(-) co ions, which imparts purely permselective behavior on the carbon micropores. The second fundamental effect discovered herein relates to the dominant role of anion desorption (as compared to cation adsorption), that is, overwhelming failure of permselectivity extends to high negative charge densities of the electrode in the presence of bulky tetraalkyl ammonium cations, which tend to be confined in the micropores of the carbon. The results obtained are important for advancement of high power density carbon-based supercapacitors, nanofiltration technologies with porous carbon membranes, and studies of ionic transport across biological membranes. PMID- 21271633 TI - Fluorescence correlation spectroscopy of fast chain dynamics within denatured protein L. AB - Intramolecular dynamics in the denatured state of a protein are of importance for protein folding. Native-like contact formation within the ensemble of denatured conformations of a protein may guide its transformation towards the native conformation. The efficiency of folding is thus dependent on the diffusion of chain fragments, which facilitates contact formation. Herein we investigate intramolecular diffusion of denatured molecules of the small two-state-folding protein L with fluorescence correlation spectroscopy (FCS). We utilize the specific quenching of the fluorescence of the oxazine dye Atto655 labeling a cysteine at position 64 (the C-terminus of the protein) by the side chain of a tryptophan at position 47. FCS measurements allow us to probe processes ranging in timescales from tens of nanoseconds to seconds. Two fast photophysical processes can be distinguished in the fluorescence correlation curves. The slower of the two is found to be due to triplet dynamics, while the faster process is attributed to the quenching of the Atto655 by the tryptophan upon transient ground-state complex formation. We study the dependence of the intrachain dynamics of the denatured protein on the concentration of the denaturant guanidinium chloride (GdmCl), and extract complex association and dissociation rates. While the dissociation rate does not depend on the denaturant, the association rate decreases as denaturant concentration is increased from 3 to 7 M GdmCl. This decrease in contact formation rate tracks the expansion of denatured protein L, measured in our previous work. Thus, the intramolecular diffusion coefficient calculated from the results is found to be essentially independent of the denaturant concentration over this range, even as the protein expands by more than 20%. PMID- 21271637 TI - Federal Advisory committee on genetics devises final recommendations. PMID- 21271634 TI - Direct electron transfer of hemoglobin and myoglobin at the bare glassy carbon electrode in an aqueous BMI.BF4 ionic-liquid mixture. AB - Direct and remarkably fast electron transfers between a bare glassy carbon electrode and heme proteins (hemoglobin or myoglobin) are obtained by using an aqueous 1-butyl-3-methyl imidazolium tetrafluoroborate (BMI.BF(4)) ionic-liquid mixture as electrolyte. The ionic liquid is observed to play a key role in the achievement of the electron transfer. The experimental data show that the proteins are not strongly adsorbed onto the electrode surface while giving rise to sharp and well-defined redox responses. Such a finding contrasts with most of the reported works found in literature and-beyond the fundamental aspect--it may be of interest in applications where adsorption is critical. Moreover, the electrocatalytic activity of the proteins toward the reduction of oxygen and nitrite in the aqueous BMI.BF(4) mixture is evidenced, showing the potential of this simple approach for bioelectroanalytical devices. PMID- 21271638 TI - Department of Justice opposes patents on isolated genes. PMID- 21271640 TI - Introduction to growth and development in craniofacial anomalies symposium and society of craniofacial genetics abstracts. PMID- 21271643 TI - Interparietal bone (Os Incae) in craniosynostosis. AB - The interparietal bone, Os Incae, is formed in a persistent mendosal suture. This suture is a normal variant in the human skull, well-known in anatomy and radiology textbooks. We report 11 children with craniosynostosis in the presence of an interparietal bone, five from Children's Hospital at Montefiore and six children from Children's Hospital Boston. The true incidence of an interparietal bone in patients with craniosynostosis or craniofacial anomalies is not known; nor are there recognized sequelae of an interparietal bone (bathrocephaly). Hypotheses regarding mechanisms that may contribute to the formation of an interparietal bone are discussed. PMID- 21271641 TI - Cranial neural crest cells on the move: their roles in craniofacial development. AB - The craniofacial region is assembled through the active migration of cells and the rearrangement and sculpting of facial prominences and pharyngeal arches, which consequently make it particularly susceptible to a large number of birth defects. Genetic, molecular, and cellular processes must be temporally and spatially regulated to culminate in the three-dimension structures of the face. The starting constituent for the majority of skeletal and connective tissues in the face is a pluripotent population of cells, the cranial neural crest cells (NCCs). In this review we discuss the newest scientific findings in the development of the craniofacial complex as related to NCCs. Furthermore, we present recent findings on NCC diseases called neurocristopathies and, in doing so, provide clinicians with new tools for understanding a growing number of craniofacial genetic disorders. PMID- 21271644 TI - In memoriam Ihsan Dogramaci (1915-2010). PMID- 21271645 TI - Arthrogryposis, perthes disease, and upward gaze palsy: a novel autosomal recessive syndromic form of arthrogryposis. AB - In this article, the unusual combination of arthrogryposis, upward gaze palsy, and Perthes disease in two sisters and their cousin who are all part of an extended consanguineous Saudi family is reported. All patients had difficult to control bronchial asthma and subtle facial dysmorphism. Two of the three had pyloric stenosis, two were intellectually normal, and one had academic problems but had a history of birth hypoxia. Pedigree is consistent with an autosomal recessive mode of inheritance. Lack of previous reports suggests this represents a novel syndromic form of arthrogryposis. PMID- 21271646 TI - A new syndrome with multiple capillary malformations, intractable seizures, and brain and limb anomalies. AB - We present two unrelated male infants with strikingly similar clinical features which have not previously been reported together. The most unusual feature was the presence of multiple small capillary malformations (port-wine stains) on the skin from birth. Both infants had intractable seizures, microcephaly with progressive cortical atrophy, severe developmental delay, dysmorphic facial features, and hypoplasia of the distal phalanges. To our knowledge, no other person with this unique constellation of features has been described. PMID- 21271647 TI - Back to the future: proceedings from the 2010 NF Conference. AB - The neurofibromatoses (NF) encompass the rare diseases NF1, NF2, and schwannomatosis. The NFs affect 100,000 Americans; over 2 million persons worldwide; and are caused by mutation of tumor suppressor genes. Individuals with NF1 in particular may develop tumors anywhere in the nervous system; additional manifestations can include learning disabilities, bone dysplasia, cardiovascular defects, unmanageable pain, and physical disfigurement. Ultimately, the NFs can cause blindness, deafness, severe morbidity, and increased mortality and NF1 includes a risk of malignant cancer. Today there is no treatment for the NFs (other than symptomatic); however, research efforts to understand these genetic conditions have made tremendous strides in the past few years. Progress is being made on all fronts, from discovery studies-understanding the molecular signaling deficits that cause the manifestations of NF-to the growth of preclinical drug screening initiatives and the emergence of a number of clinical trials. An important element in fuelling this progress is the sharing of knowledge, and to this end, for over 20 years the Children's Tumor Foundation has convened an annual NF Conference, bringing together NF professionals to share ideas and build collaborations. The 2010 NF Conference held in Baltimore, MD June 5-8, 2010 hosted over 300 NF researchers and clinicians. This paper provides a synthesis of the highlights presented at the Conference and as such, is a "state-of-the-field" for NF research in 2010. PMID- 21271648 TI - Richieri-Costa-Pereira syndrome: a unique acrofacial dysostosis type. An overview of the Brazilian cases. AB - We reported on 16 new Brazilian patients and review findings in 12 previously reported cases (25 apparently unrelated Brazilian families) from Hospital of Rehabilitation of Craniofacial Anomalies, presenting with Richieri-Costa-Pereira syndrome. All patients display a unique pattern of anomalies consisting of microstomia, micrognathia, abnormal fusion of mandible, cleft palate/Robin sequence, absence of central lower incisors, minor ears anomalies, hypoplastic first ray, abnormal tibiae, hypoplastic halluces, and clubfeet. Learning disability was also a common finding. The sex-ratio showed deviation toward to female (1.8F:1M). Recurrence in sibs was observed in nine instances and consanguinity in 11, supporting the hypothesis of autosomal recessive inheritance. Nineteen of the 25 families lived in Sao Paulo State, seven of them (10 affected individuals) from an isolated region named "Vale do Ribeira." The geographic barrier of this region associated with the high incidence of the consanguineous matting suggested that this condition is caused by a rare mutation with a founder effect. With the exception of one patient in France, all known cases are of Brazilian origin. The causative gene of this rare syndrome remains unknown. PMID- 21271649 TI - Al-Awadi-Raas-Rothschild (limb/pelvis/uterus-hypoplasia/aplasia) syndrome and WNT7A mutations: genetic homogeneity and nosological delineation. PMID- 21271650 TI - Identification of a novel C16orf57 mutation in Athabaskan patients with Poikiloderma with Neutropenia. AB - Poikiloderma with Neutropenia (PN), Clericuzio-Type (OMIM #604173) is characterized by poikiloderma, chronic neutropenia, recurrent sinopulmonary infections, bronchiectasis, and nail dystrophy. First described by Clericuzio in 1991 in 14 patients of Navajo descent, it has since also been described in non Navajo patients. C16orf57 has recently been identified as a causative gene in PN. The purpose of our study was to describe a spectrum of C16orf57 mutations in a cohort of PN patients including five patients of Athabaskan (Navajo and Apache) ancestry. Eleven patients from eight kindreds were enrolled in an IRB-approved study at Baylor College of Medicine. Five patients were of Athabaskan ancestry. PCR amplification and sequencing of the entire coding region of the C16orf57 gene was performed on genomic DNA. We identified biallelic C16orf57 mutations in all 11 PN patients in our cohort. The seven new deleterious mutations consisted of deletion (2), nonsense (3), and splice site (2) mutations. The patients of Athabaskan ancestry all had a common deletion mutation (c.496delA) which was not found in the six non-Athabaskan patients. Mutations in the C16orf57 gene have been identified thus far in all patients studied with a clinical diagnosis of PN. We have identified seven new mutations in C16orf57 in PN patients. One of these is present in all patients of Athabaskan descent, suggesting that c.496delA represents the PN-causative mutation in this subpopulation. PMID- 21271651 TI - Array-based MLPA to detect recurrent copy number variations in patients with idiopathic mental retardation. AB - Microdeletions, either subtelomeric or interstitial, are responsible for the mental handicap in approximately 10-20% of all patients. Currently, Multiplex Ligation-dependent Probe Amplification (MLPA) is widely used to detect these small aberrations in a routine fashion. Although cost-effective, the throughput is low and the degree of multiplexing is limited to maximally 40-50 probes. Therefore, we developed an array-based MLPA method, with probes identified by unique tag sequences, allowing the simultaneous analysis of 180 probes in a single experiment thereby covering all known mental retardation loci with at least two probes. We screened 120 patients with idiopathic mental retardation. In this group we detected 6 aberrations giving a detection rate of 5%, consistent with similar studies. In addition we tested 293 patients with mental retardation who were negative for fragile X syndrome and commercially available subtelomeric MLPA. We found seven causative rearrangements in this group (detection rate of 2.4%) thereby illustrating the value of including probes for interstitial microdeletion syndromes and additional probes in the telomeric regions in targeted screening sets for mental retardation. Array-based MLPA may thus be a good candidate to develop probe sets that rapidly detect copy number changes of disease associated loci in the human genome. This method may become a valuable tool in a routine diagnostic setting as it is a fast, user-friendly and relatively low-cost technique providing straightforward results requiring only 125 ng of genomic DNA. PMID- 21271652 TI - Pure and complete 12p trisomy due to a maternal centric fission of chromosome 12. AB - Pure and complete 12p trisomy are rare. Here, we report on a unique patient with trisomy 12p syndrome due to centric fission of maternal chromosome 12. Conventional cytogenetic and fluorescence in situ hybridization (FISH) techniques revealed the proposita's karyotype to be 47,XX,+fis(12)(p10)mat whereas the maternal one was 47,XX,-12,+fis(12)(p10),+fis(12) (q10). This is the first report on centric fission of chromosome 12 leading to stable telocentrics, each with a fully functional centromere. Our observation shows that the centric fission of chromosome 12 can be a new mechanism for generation of a partial centromere and trisomy 12p syndrome. PMID- 21271653 TI - Clinical follow-up of young adults affected by Williams syndrome: experience of 45 Italian patients. AB - Williams-Beuren syndrome (WBS) is a multisystem disorder that requires ongoing management by a primary care physician familiar with the natural history and specific medical problems associated with the condition. While the natural history of the disease during infancy is well known, data about the adult WBS population have been published only in the last few years, and show a wide range of medical, neurological, and psychiatric problems. We investigated 45 young adult WBS patients (mean age 23 years, range 17-39 years) using a well coordinated team which included a cardiologist, a nephrologist, an ophthalmologist, an endocrinologist, a gastroenterologist, orthodontist, and orthopedist. Here we describe the clinical features and medical complications in this cohort of patients. Most patients demonstrated a high frequency of multiple organ systems complications, in particular, abnormal body habitus; cardiovascular disease, and hypertension; sensorineural hearing loss; gastrointestinal symptoms including diverticular disease and abnormal glucose tolerance. We offer some suggestions for clinical monitoring which we propose will be useful in the overall care of adults with WBS. PMID- 21271654 TI - Why is the construction: Hypoplastic left heart "syndrome" a misnomer? And: What is a syndrome, anyhow? PMID- 21271655 TI - The severe end of the spectrum: Hypoplastic left heart in Potocki-Lupski syndrome. AB - Potocki-Lupski syndrome (PTLS) is a recently described microduplication syndrome associated with duplication 17p11.2, including the RAI1 gene. Features of PTLS include hypotonia, feeding difficulties, failure to thrive, developmental delay and behavioral abnormalities including autistic spectrum disorder, anxiety, and inattention. Cardiovascular anomalies were not recognized as a feature of duplication 17p11.2 until 2007 when noted in over 50% of a clinically characterized cohort. We report a patient with hypoplastic left heart syndrome whose diagnosis of PTLS was delayed until a genetic evaluation at age 4 years because of severe expressive language impairment. We suggest that array comparative genomic hybridization be performed in infants with severe congenital heart defects. PMID- 21271656 TI - Potocki-Lupski syndrome: an inherited dup(17)(p11.2p11.2) with hypoplastic left heart. AB - Low copy repeat (LCR) sequences in 17p11.2 predispose this region to genomic deletions and duplications. Duplication of 17p11.2, also known as Potocki-Lupski syndrome (PTLS), is a well-described microduplication syndrome featuring cognitive and language deficits, developmental delay, autistic behavior, structural cardiovascular anomalies, hypotonia, failure to thrive, apnea, and dysmorphism. We present a mother and her two children who share both dysmorphic features and the dup(17)(p11.2p11.2); the first child was born with hypoplastic left heart (HLH). The dup(17)(p11.2p11.2) was identified by GTG-banding analysis of peripheral blood specimens from all three individuals and confirmed by fluorescence in situ hybridization (FISH) and array comparative genomic hybridization (aCGH). Here we provide a thorough description of the phenotypes of the affected individuals, as well as describe physical features not reported previously for PTLS. PMID- 21271657 TI - Intragenic deletions of IL1RAPL1: Report of two cases and review of the literature. AB - IL1RAPL1 (interleukin-1 receptor accessory protein-like 1) located at Xp21.3-22.1 has repeatedly been shown to be deleted in patients with a contiguous gene syndrome also affecting neighboring genes, in particular DMD (dystrophin), DAX-1 (NR0B1, nuclear receptor subfamily 0, group B, member 1), and GK (glycerol kinase). In contrast, intragenic deletions of IL1RAPL1 or other mutations or cytogenetic aberrations affecting IL1RAPL1 have only rarely been identified. Up to date, they have mostly been associated with nonspecific mental retardation (MRX). We report on two nonrelated patients with MR and additional dysmorphic features who both show intragenic deletions of IL1RAPL1, one of them being de novo (exon 2) and the other one being inherited from his mother (exons 3-5). Deletions were identified by microarray-based chromosome analysis and confirmed by multiplex PCR and FISH, respectively. These data, along with recent functional studies indicating its role in neuronal development, provide further evidence for the relevance of IL1RAPL1 in the pathogenesis of X-linked MR and add knowledge to the phenotypic spectrum of IL1RAPL1 mutations. PMID- 21271658 TI - Cerebrovasculopathy in NF1 associated with ocular and scalp defects. AB - Vascular lesions are uncommon in children with neurofibromatosis 1 (NF1) but can cause serious complications. We report on a child with NF1 who presented at 18 months of age with symptomatic stenosis of the left middle cerebral artery and its branches, and associated moyamoya disease. She also had bilateral posterior embryotoxon, left corneal opacity (Peters anomaly), and cutis aplasia of the left scalp. All of these defects may have occurred as a result of disruption of the blood supply caused by NF1 vasculopathy prenatally. This constellation of vascular anomalies has not been previously reported in a patient with NF1. PMID- 21271659 TI - 47, XY, +der(Y),t(X;Y)(p21.1;p11.2): a unique case of XY sex reversal. AB - Translocations involving the short arms of the X and Y chromosomes are rare and can result in a functional disomy of the short arm of the X chromosome, including the dosage-sensitive sex reversal (DSS) locus. A result of such imbalance may be sex reversal with multiple congenital anomalies. We present the clinical and cytogenetic evaluation of a newborn infant with DSS and additional clinical findings of minor facial anomalies, left abdominal mass, 5th finger clinodactyly, and mild hypotonia. The external genitalia appeared to be normal female. The infant had bilateral corneal opacities and findings suggestive of anterior segment dysgenesis. Ultrasonography showed a small uterus with undetectable ovaries, and a left multicystic dysplastic kidney. High-resolution chromosome analysis identified the presence of a derivative Y chromosome, 47,XY, +der(Y)t(X;Y)(p21.1;p11.2), which was confirmed by fluorescence in situ hybridization studies. Array CGH showed a 35.1 Mb copy number gain of chromosome region Xp22.33-p21.1 and a 52.2 Mb copy number gain of Yp11.2-qter, in addition to the intact X and Y chromosomes. Previously reported patients with XY sex reversal have not had DSS with corneal opacities, dysgenesis of the anterior segment of the eye, and unilateral multicystic dysplastic kidney. These findings represent a new form of XY sex reversal due to an Xp duplication. PMID- 21271660 TI - A patient with a de novo distal 22q11.2 microdeletion and anxiety disorder. AB - We report on a young female with normal intelligence evaluated for long-term anxiety. Her history includes prematurity, neonatal feeding problems, surgical correction of congenital heart defects, recurrent upper airway and urinary tract infections, and delayed motor and developmental milestones. Physical examination disclosed small stature and minor dysmorphisms. Chromosome analysis, 22q11.2 FISH analysis, and subtelomeric MLPA testing did not detect any abnormalities. Genome wide SNP Array analysis showed a de novo deletion in 22q11.21q11.22, the so called distal 22q11 microdeletion that involves the MAPK1 gene. A diagnosis of panic disorder was made and the patient was successfully treated with a daily dose of 20 mg citalopram. To our knowledge, this is the first adolescent patient with a long history of complaints about anxiety and a distal 22q11 microdeletion. We speculate that genes from the deleted region, especially MAPK1, increase the neurobiological susceptibility to anxiety disorders that may be a part of the psychopathological phenotype of the distal 22q11.2 microdeletion syndrome. PMID- 21271661 TI - The nosology of Richieri-Costa/Guion-Almeida syndrome(s). AB - Richieri-Costa/Guion-Almeida syndrome type 1 (RCGAS1) is a rare MR/MCA syndrome comprising developmental and growth delay, microcephaly, prominent supraorbital ridges, asymmetric ptosis and eyebrows, esotropia, nystagmus, eye colobomas, and cleft lip/palate. It was originally described in three brothers and an additional sporadic male. The same authors also described a further family with a partially overlapping condition in two sisters (Richieri-Costa/Guion-Almeida syndrome type 2, RCGAS2). We report on a sporadic, mentally retarded patient strongly resembling those of the original report of RCGAS1, but lacking some manifestations such as short stature and, possibly, some ocular changes. Results of 200 kb CGH-array study were normal. By comparing the present and previously reported patients with RCGAS1 and 2, we tried to contribute to syndrome delineation and to separate them from conditions with similar facial anomalies. PMID- 21271662 TI - A translocation between Xq21.33 and 22q13.33 causes an intragenic SHANK3 deletion in a woman with Phelan-McDermid syndrome and hypergonadotropic hypogonadism. AB - Chromosome 22q13 monosomy has been described as a contiguous gene syndrome. Localized in the critical region, SHANK3 is likely to play a key role in the expression of the clinical phenotype. SHANK3 mutations have also been reported in autistic patients without a syndromic phenotype. We report on a 20-year-old woman with mental retardation carrying a de novo translocation between chromosome Xq21.33 and 22q13.33, associated with a duplication on Xq21.33 and deletion on 22q13.33. As a child her development was characterized by disturbed social interaction, stereotypic hand movements and ritualistic behavior and she was considered at one time to have autistic features. All these traits match the 22q13 deletion syndrome (Phelan-McDermid syndrome, OMIM 606232), likely due to the deletion overlapping the last two exons of the SHANK3 gene. Our patient harbors the smallest and most distal SHANK3 deletion described to date, yet resulting in the full spectrum of the Phelan-McDermid syndrome. In addition, she has hypergonadotropic hypogonadism with low estrogen level, high FSH level, and irregular menstruation. Intriguingly, chromosome translocations affecting the chromosome band Xq21 can result in premature ovarian failure. PMID- 21271663 TI - A de novo deletion of 20q11.2-q12 in a boy presenting with abnormal hands and feet, retinal dysplasia, and intractable feeding difficulty. AB - Proximal interstitial deletions involving 20q11-q12 are very rare. Only two cases have been reported. We describe another patient with 20q11.21-q12 deletion. We precisely mapped the 6.5-Mb deletion and successfully determined the deletion landmarks at the nucleotide level. Common clinical features among the three cases include developmental delay, intractable feeding difficulties with gastroesophageal reflux, and facial dysmorphism including triangular face, hypertelorism, and hypoplastic alae nasi, indicating that the 20q11.2-q12 deletion can be a clinically recognizable syndrome. This is also supported by the fact that the three deletions overlap significantly. In addition, unique features such as arthrogryposis/fetal akinesia (hypokinesia) deformation and retinal dysplasia are recognized in the patient reported herein. PMID- 21271664 TI - Fanconi-Bickel syndrome: report of life history and successful pregnancy in an affected patient. AB - Fanconi-Bickel syndrome (FBS, OMIM #227810) is a rare autosomal recessive disorder of carbohydrate transport originally described in 1949 [Fanconi and Bickel(1949);Helv Paediatr Acta 4: 359-396]. FBS is caused by mutations in the glucose and galactose transporter gene SLC2A2 (HGNC ID11006) [Santeret al.(1997); Nat Genet 17: 324-326] and is characterized by hepatic glycogen accumulation with hepatomegaly, fasting hypoglycemia, short stature, impaired glucose tolerance, hyperlipidemia, and tubular nephropathy. Although the described complications would not seem to preclude fertility in FBS patients, there has been no report of reproduction in affected individuals to date. We have followed a female with FBS for at least 20 years. She received a clinical diagnosis in adolescence, with recent molecular confirmation of two mutations in trans in the SLC2A2 gene. She has had glucosuria, proteinuria, impaired tubular reabsorption of phosphate, osteopenia, and hypercholesterolemia throughout her life, without any documented episodes of hypoglycemia. Hepatomegaly was initially noticed in infancy and resolved in late adolescence. She became pregnant at 31 years of age, had gestational diabetes treated with diet, and delivered a healthy boy. She had impaired glucose tolerance after her pregnancy.Her adult height was at the lower end of her target height range, and she had evidence of localized osteopenia at the left distal radius on DXA scan. This report describes the clinical history of an affected individual and highlights the importance of continued follow-up in order to extend our understanding of the history of this rare metabolic disorder. PMID- 21271665 TI - Microdeletion of 17q22q23.2 encompassing TBX2 and TBX4 in a patient with congenital microcephaly, thyroid duct cyst, sensorineural hearing loss, and pulmonary hypertension. AB - Microdeletions of the long arm of chromosome 17 are being reported with increasing frequency. Deletions of 17q22q23.2 may represent a genetically recognizable phenotype although its spectrum of genomic abnormalities, clinical manifestations, and critical regions are not fully delineated. Isolated reports and small case series suggest that deletions of 17q22q23.2 result in haploinsufficiency of dosage sensitive genes NOG, TBX2, and TBX4, which may be responsible for many aspects of the phenotype. Shared clinical features in this group of patients include microcephaly, prenatal onset growth restriction, heart defects, tracheoesophageal fistula, and esophageal atresia (TEF/EA), skeletal anomalies, and moderate to severe global developmental delay. We describe a female patient who presented with severe congenital microcephaly, thyroglossal duct cyst, sensorineural hearing loss, mild tracheomalacia, abnormal auricles, pulmonary hypertension, developmental delay, and postnatal onset growth delay. She had no TEF/EA or heart defects. Using a high density oligonucleotide microarray, we identified a microdeletion at 17q22q23.2, resulting in the heterozygous loss of several genes, including TBX2 and TBX4 but not NOG. The breakpoints did not lie within known segmental duplications. This case helps to further delineate the critical region for TEF/EA, which is likely confined to the chromosomal region proximal to 17q23.1, and suggests that genes in 17q23.1q23.2 may be associated with thyroglossal duct cysts. The role of TBX2 and TBX4 in pulmonary hypertension warrants investigation. PMID- 21271666 TI - 2q23 de novo microdeletion involving the MBD5 gene in a patient with developmental delay, postnatal microcephaly and distinct facial features. AB - We report on a female patient with a de novo interstitial deletion of chromosome region 2q23.1-23.3 identified by array-CGH. She had significant global delay with developmental regression at age 6 years. She developed seizures at age 3 years with progressive difficulties with balance, loss of fine motor skills and aggressive behavior. She had short stature, microcephaly, and distinct facial features. Her speech was dysarthric, and she demonstrated repetitive hand movements. In this article, we compare the clinical features of our patient with previously reported cases with a 2q23.1 deletion. PMID- 21271667 TI - Prenatal diagnosis and molecular characterization of two constitutional rings derived from one chromosome 22. PMID- 21271668 TI - Suspected trisomy 22: Modification, clarification, or confirmation of the diagnosis by aCGH. PMID- 21271669 TI - Novel L1CAM splice site mutation in a young male with L1 syndrome. PMID- 21271670 TI - De novo duplication 11p13 involving the PAX6 gene in a patient with neonatal seizures, hypotonia, microcephaly, developmental disability and minor ocular manifestations. PMID- 21271671 TI - De novo duplication of 18p11.21-18q12.1 in a female with anorectal malformation. PMID- 21271672 TI - A de novo cryptic 5p deletion and 9p duplication detected by subtelomeric MLPA in a boy with cri du chat syndrome. PMID- 21271673 TI - Cerebral dysgenesis does not exclude OFD I syndrome. PMID- 21271674 TI - Goldenhar syndrome phenotypes and 22q11 deletion. PMID- 21271675 TI - Amphioxus spawning behavior in an artificial seawater facility. AB - Owing to its phylogenetic position at the base of the chordates, the cephalochordate amphioxus is an emerging model system carrying immense significance for understanding the evolution of vertebrate development. One important shortcoming of amphioxus as a model organism has been the unavailability of animal husbandry protocols to maintain amphioxus adults away from the field. Here, we present the first report of successful maintenance and spawning of Branchiostoma lanceolatum adults in a facility run on artificial seawater. B. lanceolatum has been chosen for this study because it is the only amphioxus species that can be induced to spawn. We provide a step-by-step guide for the assembly of such a facility and discuss the day-to-day operations required for successful animal husbandry of B. lanceolatum adults. This work also includes a detailed description of the B. lanceolatum spawning behavior in captivity. Our analysis shows that the induced spawning efficiency is not sex biased, but increases as the natural spawning season progresses. We find that a minor fraction of the animals undergo phases of spontaneous spawning in the tanks and that this behavior is not affected by the treatment used to induce spawning. Moreover, the induced spawning efficiency is not discernibly correlated with spontaneous spawning in the facility. Last, we describe a protocol for long-term cryopreservation of B. lanceolatum sperm. Taken together, this work represents an important step toward further establishing amphioxus as a laboratory animal making it more amenable to experimental research, and hence assists the coming of age of this emerging model. PMID- 21271676 TI - Proteomic profiling of cerebrospinal fluid identifies prostaglandin D2 synthase as a putative biomarker for pediatric medulloblastoma: A pediatric brain tumor consortium study. AB - The aims of this study were to demonstrate the feasibility of centrally collecting and processing high-quality cerebrospinal fluid (CSF) samples for proteomic studies within a multi-center consortium and to identify putative biomarkers for medulloblastoma in CSF. We used 2-DE to investigate the CSF proteome from 33 children with medulloblastoma and compared it against the CSF proteome from 25 age-matched controls. Protein spots were subsequently identified by a combination of in-gel tryptic digestion and MALDI-TOF TOF MS analysis. On average, 160 protein spots were detected by 2-DE and 76 protein spots corresponding to 25 unique proteins were identified using MALDI-TOF. Levels of prostaglandin D2 synthase (PGD2S) were found to be six-fold decreased in the tumor samples versus control samples (p<0.00001). These data were further validated using ELISA. Close examination of PGD2S spots revealed the presence of complex sialylated carbohydrates at residues Asn(78) and Asn(87) . Total PGD2S levels are reduced six-fold in the CSF of children with medulloblastoma most likely representing a host response to the presence of the tumor. In addition, our results demonstrate the feasibility of performing proteomic studies on CSF samples collected from patients at multiple institutions within the consortium setting. PMID- 21271677 TI - Proteome analysis of Fusarium head blight in grains of naked barley (Hordeum vulgare subsp. nudum). AB - The effect of artificial Fusarium graminearum and F. culmorum infection at the level of the proteome on grains of naked barley (Hordeum vulgare subsp. nudum) was investigated in comparison to naturally infected samples. Fusarium infection in barley led to numerous host-specific biochemical responses. NEPHGE 2-D PAGE and MS were used to identify proteins that were differentially expressed in response to fungal infection and growing location of the plants. Moreover, the mycotoxin concentration of the grains was evaluated to characterize the infection degree. Inoculation of naked barley with Fusarium led to grain deoxynivalenol concentrations of up to 1.2 mg/kg. The carbon and nitrogen grain concentrations were not significantly changed after fungal infection, but differed between growing locations. Eleven proteins related to fungal infection were detected as were three proteins with effects based on growing location. These proteins belong to different protein groups involved in various cell functions: transcription regulation, defence response, nutrient reservoirs and starch biosynthesis. The results gave indications on plant defence strategies and changes as response to Fusarium infection in mature grains after a long infection period as well as being influenced by the growing location. PMID- 21271678 TI - Development of oleic acid-functionalized magnetite nanoparticles as hydrophobic probes for concentrating peptides with MALDI-TOF-MS analysis. AB - The oleic acid-functionalized magnetite nanoparticles (OA-Fe(3) O(4) ) with mean diameter of about 15 nm were synthesized through a low-cost, one-pot method and were designed as hydrophobic probes to realize the convenient, efficient and fast concentration of low-concentration peptides followed by MALDI-TOF-MS analysis. The capability of OA-Fe(3) O(4) nanoparticles in concentration of low-abundance peptides from simple and complex solutions were evaluated by comparing them with a sort of C8-modified magnetic microspheres. Samples of standard peptide solution, protein digest solution and human serum were introduced in the evaluating process, and the OA-Fe(3) O(4) nanoparticles exhibited good surface affinity toward low-concentration peptides. PMID- 21271679 TI - Global identification of miR-373-regulated genes in breast cancer by quantitative proteomics. AB - Although microRNAs (miRNAs) have been reported to play an important role in carcinogenesis, their molecular mechanism remains largely unknown because of our limited understanding of miRNA target genes. miR-373 was found to be capable of promoting breast cancer invasion and metastasis, but only a target gene was experimentally identified on the basis of mRNA expression analysis. In this study, we used SILAC-based quantitative proteomics to globally identify the genes regulated by miR-373. Totally, 3666 proteins were identified, and 335 proteins were found to be regulated by miR-373. Among the 192 proteins that were downregulated by miR-373, 27 (14.1%) were predicted to have at least one potential match site at their 3'-UTR for miR-373 seed sequence. However, miR-373 did not affect the mRNA level of the five selected candidate targets, TXNIP, TRPS1, RABEP1, GRHL2 and HIP1, suggesting that the protein expressions were regulated by miR-373 via translational inhibition instead of mRNA degradation. Luciferase and mutation assays validated that TXNIP and RABEP1 were the direct target genes of miR-373. More than 30 proteins reported to be involved in cancer invasion and metastasis were found to be regulated by miR-373 in breast cancer for the first time. PMID- 21271680 TI - Arginine-facilitated alpha- and pi-radical migrations in glycylarginyltryptophan radical cations. AB - We have used model tripeptides GXW (with X being one of the amino acid residues glycine (G), alanine (A), leucine (L), phenylalanine (F), glutamic acid (E), histidine (H), lysine (K), or arginine (R)) to study the effects of the basicity of the amino acid residue on the radical migrations and dissociations of odd electron molecular peptide radical cations M(.+) in the gas phase. Low-energy collision-induced dissociation (CID) experiments revealed that the interconvertibility of the isomers [G(.)XW](+) (radical centered on the N terminal alpha-carbon atom) and [GXW](.+) (radical centered on the pi system of the indolyl ring) generally increased upon increasing the proton affinity of residue X. When X was arginine, the most basic amino acid, the two isomers were fully interconvertible and produced almost identical CID spectra despite the different locations of their initial radical sites. The presence of the very basic arginine residue allowed radical migrations to proceed readily among the [G(.)RW](+) and [GRW](.+) isomers prior to their dissociations. Density functional theory calculations revealed that the energy barriers for isomerizations among the alpha-carbon-centered radical [G(.)RW](+), the pi centered radical [GRW](.+), and the beta-carbon-centered radical [GRW(beta)(.)](+) (ca. 32-36 kcal mol(-1)) were comparable with those for their dissociations (ca. 32-34 kcal mol(-1)). The arginine residue in these GRW radical cations tightly sequesters the proton, thereby resulting in minimal changes in the chemical environment during the radical migrations, in contrast to the situation for the analogous GGW system, in which the proton is inefficiently stabilized during the course of radical migration. PMID- 21271681 TI - Supramolecular chemical sensors based on pyrene monomer-excimer dual luminescence. AB - The past ten years have seen a spectacular development of chemical sensors based on the monomer-excimer dual luminescence of aromatic systems, such as pyrene. Either in the form of integrated or multicomponent molecular devices these chemosensors have been attracting a high interest above all because of their unique ratiometric properties. This review will focus on the latter systems, which can be classified into two classes: Firstly, the assembly of receptor effector conjugates is triggerred by the analyte of interest. As a result, the sensor shows monomer to excimer fluorescence switching upon substrate binding. Secondly, the supramolecular assembly that constitutes the sensor is perturbed by interaction with the analyte. This induces a conformational change or the exchange of a component of the system, which is the cause of the luminescence switch effect. PMID- 21271682 TI - Interconversion between formic acid and H(2)/CO(2) using rhodium and ruthenium catalysts for CO(2) fixation and H(2) storage. AB - The interconversion between formic acid and H(2)/CO(2) using half-sandwich rhodium and ruthenium catalysts with 4,4'-dihydroxy-2,2'-bipyridine (DHBP) was investigated. The influence of substituents of the bipyridine ligand was studied. Chemical shifts of protons in bipyridine linearly correlated with Hammett substituent constants. In the hydrogenation of CO(2) /bicarbonate to formate under basic conditions, significant activations of the catalysts were caused by the electronic effect of oxyanions generated by deprotonation of the hydroxyl group. Initial turnover frequencies of the ruthenium- and rhodium-DHBP complexes increased 65- and 8-fold, respectively, compared to the corresponding unsubstituted bipyridine complexes. In the decomposition of formic acid under acidic conditions, activity enhancement by the electronic effect of the hydroxyl group was observed for the ruthenium catalyst. The rhodium-DHBP catalyst showed high activity without CO contamination in a relatively wide pH range. Pressurized H(2) can be obtained using an autoclave reactor. The highest turnover frequency and number were obtained at 80 degrees C. The catalytic system provides valuable insight into the use of CO(2) as a H(2) storage material by combining CO(2) hydrogenation with formic acid decomposition. PMID- 21271683 TI - Selective oxidation of glycerol by using a hydrotalcite-supported platinum catalyst under atmospheric oxygen pressure in water. AB - A hydrotalcite-supported platinum (Pt/HT) catalyst was found to be a highly active and selective heterogeneous catalyst for glycerol oxidation in pure water under atmospheric oxygen pressure in a high glycerol/metal molar ratio up to 3125. High selectivity toward glyceric acid (78 %) was obtained even at room temperature under air atmosphere. The Pt/HT catalyst selectively oxidized the primary hydroxyl group of 1,2-propandiol to give the corresponding carboxylic acid (lactic acid) as well as glycerol. The activity of the catalyst was greatly influenced by the Mg/Al ratio of hydrotalcite. Glycerol conversion increased with increasing the Mg/Al ratio of hydrotalcite (from trace to 56 %). X-ray absorption fine structure (XAFS) measurements indicated that the catalytic oxidation activity was proportional to the metallic platinum concentration, and more than 35 % of metallic platinum was necessary for this reaction. TEM measurements and titration analysis by using benzoic acid suggested that the solid basicity of hydrotalcite plays important roles in the precise control of platinum size and metal concentration as well as the initial promotion of alcohol oxidation. PMID- 21271684 TI - The water oxidation bottleneck in artificial photosynthesis: how can we get through it? An alternative route involving a two-electron process. AB - The state-of-the-art of research on artificial photosynthesis is briefly reviewed. Insights into how Nature takes electrons from water, the photon-flux density of sunlight, the time scale for the arrival of the next photon (electron hole) at the oxygen-evolving complex, how Nature solves the photon-flux-density problem, and how we can get through the bottleneck of water oxidation are discussed. An alternate route for a two-electron process induced by one-photon excitation is postulated for getting through the bottleneck of water oxidation. PMID- 21271685 TI - NMR-based structural glycomics for high-throughput screening of carbohydrate active enzyme specificity. AB - We report here the development of a straightforward, sensitive, and quantitative NMR-based method for high-throughput characterization of carbohydrate structure and screening of carbohydrate active enzyme (CAZyme) specificity. Automated assays starting from gene library expression to carbohydrate structure determination directly from crude reaction media have been established and successfully used to screen a library of 4032 CAZymes obtained by combinatorial engineering, at a rate of 480 enzyme variants per day. This allowed one to accurately discriminate 303 enzyme variants with altered specificity. The results demonstrate the potential of high-throughput NMR technology in glycomics, to mine artificial and natural enzyme diversity for novel biocatalysts. PMID- 21271686 TI - Facile ring-opening of azabicyclic [3.1.0]- and [4.1.0]aminocyclopropanes to afford 3-piperidinone and 3-azepinone. AB - Azabicyclic [3.1.0] and [4.1.0] Kulinkovich products underwent a facile reduction/fragmentation to afford a variety of 3-piperidinones and 3-azepinones, respectively, in the presence of catalytic palladium on carbon and formic acid in an atmosphere of hydrogen. PMID- 21271687 TI - Studies toward the synthesis of maoecrystal V. AB - An approach toward the synthesis of maoecrystal V is described. The synthetic strategy for this approach was designed to address unique challenges posed by the strained tetrahydrofuran ring at the center of the target structure. PMID- 21271688 TI - Applications of organocatalytic asymmetric synthesis to drug prototypes--dual action and selective inhibitors of n-nitric oxide synthase with activity against the 5-HT1D/1B subreceptors. AB - The scope of MacMillan's organocatalytic asymmetric conjugate addition reaction of indoles and electron-rich aromatics to alpha,beta-unsaturated aldehydes has been extended to the use of 3-amino crotonaldehydes as substrates. The aromatics used include indoles as well as an aniline and a furan. The scope and effect of the groups on nitrogen (R, R') has also been studied. The method has been applied to the concise synthesis of an advanced precursor to S-(+)-1, a drug prototype for the treatment of migraine headaches. PMID- 21271689 TI - Cu-catalyzed one-pot synthesis of unsymmetrical diaryl thioethers by coupling of aryl halides using a thiol precursor. AB - An efficient Cu-catalyzed one-pot approach for the synthesis of unsymmetrical diaryl thioethers using potassium ethyl xanthogenate as a thiol surrogate is developed. This new protocol avoids usage of intricate thiols and makes use of its easily available xanthate as a precursor, and thiol will be generated in situ to prepare the diaryl thioethers through a Cu-catalyzed double arylation. This strategy was further successfully utilized for the synthesis of symmetrical diaryl thioethers, aryl alkyl thioethers, and benzothiazoles. PMID- 21271690 TI - A new class of structurally rigid tricyclic chiral secondary amine organocatalyst: highly enantioselective organocatalytic Michael addition of aldehydes to vinyl sulfones. AB - A new class of chiral secondary amine organocatalyst was rationally designed as an efficient catalyst to catalyze the elusive Michael addition of aldehydes to vinyl sulfones. High yield and excellent enantioselectivities could be obtained at room temperature without having to resort to high catalyst loading, anhydrous solvents, and low temperatures. Efficient control of enamine conformation and face shielding as well as the rigid nature of the tricyclic skeleton, with an inherent chiral pocket, provide a well-organized chiral environment to effect this elusive reaction efficiently. PMID- 21271691 TI - Contact angle hysteresis on superhydrophobic surfaces: an ionic liquid probe fluid offers mechanistic insight. AB - Silicon/silicon dioxide surfaces containing 3 MUm (width) * 6 MUm (length) * 40 MUm (height) staggered rhombus posts were prepared using photolithography and hydrophobized using a perfluoroalkyl-containing monofunctional silane. These surfaces exhibit water contact angles of theta(A)/theta(R) = 169 degrees /156 degrees . Water drops come to rest on a carefully aligned horizontal sample but roll when the surface is tilted slightly. No visible trail or evidence of water "left behind" at the receding edge of the drop is apparent on surfaces that water drops have rolled on or on samples removed from water through the air-water interface. When dimethylbis(beta-hydroxyethyl)ammonium methanesulfonate (N(+)S( ), a nonvolatile ionic liquid) is used as the liquid probe fluid (instead of water), contact angles of theta(A)/theta(R) = 164 degrees /152 degrees are observed and ~3-MUm-diameter sessile drops are visible (by scanning electron microscopy - SEM) on the top of every post of a sample drawn out of this liquid. We interpret the formation of these sessile microdrops as arising from microcapillary bridge failure that occurs during receding events and emphasize that the capillary bridges rupture in primarily a tensile failure mode. Smaller sessile drops could be prepared using mixtures of water and N(+)S(-). Microdroplets of N(+)S(-) were also observed to form selectively at particular features on surfaces containing square holes separated by ridges. This suggests that pinning sites can be identified using microscopy and this ionic liquid probe fluid. PMID- 21271692 TI - Preconcentration of f-elements from aqueous solution utilizing a modified carbon paste electrode. AB - An evaluation using paraffin oil based, Acheson 38 carbon paste electrodes modified with alpha-hydroxyisobutyric acid (HIBA) to preconcentrate f-elements cathodically is described. The modified paste was made by directly mixing solid HIBA into the carbon paste. A chemically reversible cyclic voltammogram for HIBA was observed on this modified carbon paste, which was found to be a non-Nerstian, single electron transfer process. Lanthanides (less promethium) were found to accumulate onto the electrode surface during a 30 s electrodeposition step at 0.4 V vs Ag/AgCl from 0.1 M LiCl. The elements were then stripped off into a 2% HNO(3) solution by an oxidative step at +0.8 V vs Ag/AgCl; quantitative removal from the electrode was confirmed by ICPMS. Ultratrace solutions with initial concentrations down to 5 parts per quadrillion (ppq) were preconcentrated in 5 min above our instrumental limit of detection (LOD) of around 1 ppt for lanthanides. PMID- 21271693 TI - Effect of dissolved organic matter on the transformation of contaminants induced by excited triplet states and the hydroxyl radical. AB - Dissolved organic matter (DOM) has recently been shown to reduce the transformation rate of various aqueous organic contaminants submitted to oxidation by excited triplet states, apparently by inhibiting the transformation of oxidation intermediates. The main goals of the present study were to evaluate in more detail the effect of concentration and type of DOM on the triplet-induced transformation rate of four selected organic compounds and to check for an analogous inhibition effect in the case of oxidation induced by hydroxyl radical. A marked inhibition by DOM of triplet-induced oxidation was observed for N,N dimethylaniline (DMA) and the two antibiotics sulfamethoxazole (SMX) and trimethoprim (TRI), with DOM of terrestrial origin being a more effective inhibitor than DOM of aquatic origin. The results are important to understand the role of DOM both as a photosensitizer and as an inhibitor for the triplet-induced transformation of aquatic contaminants. In contrast, no DOM-induced reduction in second-order rate constant could be observed in competition kinetics experiments for the reaction of hydroxyl radical with a series of 15 organic compounds, covering several classes of aromatic contaminants, indicating that Suwannee River fulvic acid (SRFA) used as reference DOM does not affect this reaction mechanism. PMID- 21271694 TI - Light-induced conformational change and product release in DNA repair by (6-4) photolyase. AB - Proteins of the cryptochrome/photolyase family share high sequence similarities, common folds, and the flavin adenine dinucleotide (FAD) cofactor, but exhibit diverse physiological functions. Mammalian cryptochromes are essential regulatory components of the 24 h circadian clock, whereas (6-4) photolyases recognize and repair UV-induced DNA damage by using light energy absorbed by FAD. Despite increasing knowledge about physiological functions from genetic analyses, the molecular mechanisms and conformational dynamics involved in clock signaling and DNA repair remain poorly understood. The (6-4) photolyase, which has strikingly high similarity to human clock cryptochromes, is a prototypic biological system to study conformational dynamics of cryptochrome/photolyase family proteins. The entire light-dependent DNA repair process for (6-4) photolyase can be reproduced in a simple in vitro system. To decipher pivotal reactions of the common FAD cofactor, we accomplished time-resolved measurements of radical formation, diffusion, and protein conformational changes during light-dependent repair by full-length (6-4) photolyase on DNA carrying a single UV-induced damage. The (6 4) photolyase by itself showed significant volume changes after blue-light activation, indicating protein conformational changes distant from the flavin cofactor. A drastic diffusion change was observed only in the presence of both (6 4) photolyase and damaged DNA, and not for (6-4) photolyase alone or with undamaged DNA. Thus, we propose that this diffusion change reflects the rapid (50 MUs time constant) dissociation of the protein from the repaired DNA product. Conformational changes with such fast turnover would likely enable DNA repair photolyases to access the entire genome in cells. PMID- 21271695 TI - Rational design of cyclic peptide modulators of the transcriptional coactivator CBP: a new class of p53 inhibitors. AB - The CREB binding protein (CBP) is a human transcriptional coactivator consisting of several conserved functional modules, which interacts with distinct transcription factors including nuclear receptors, CREB, and STAT proteins. Despite the importance of CBP in transcriptional regulation, many questions regarding the role of its particular domains in CBP functions remain unanswered. Therefore, developing small molecules capable of selectively modulating a single domain of CBP is of invaluable aid at unraveling its prominent activities. Here we report the design, synthesis, and biological evaluation of conformationally restricted peptides as novel modulators for the acetyl-lysine binding bromodomain (BRD) of CBP. Utilizing a target structure-guided and computer-aided rational design approach, we developed a series of cyclic peptides with affinity for CBP BRD significantly greater than those of its biological ligands, including lysine acetylated histones and tumor suppressor p53. The best cyclopeptide of the series exhibited a K(d) of 8.0 MUM, representing a 24-fold improvement in affinity over that of the linear lysine 382-acetylated p53 peptide. This lead peptide is highly selective for CBP BRD over BRDs from other transcriptional proteins. Cell-based functional assays carried out in colorectal carcinoma HCT116 cells further demonstrated the efficacy of this compound to modulate p53 stability and function in response to DNA damage. Our results strongly argue that these CBP modulators can effectively inhibit p53 transcriptional activity by blocking p53K382ac binding to CBP BRD and promoting p53 instability by changes of its post translational modification states, a different mechanism than that of the p53 inhibitors reported to date. PMID- 21271696 TI - Nondestructive sampling of living systems using in vivo solid-phase microextraction. PMID- 21271697 TI - Mild P4 activation to give an anionic diphosphorus complex with a dual binding ability at a single P site. AB - The anion [Mo(2)Cp(2)(MU-PCy(2))(MU-CO)(2)](-) (1; Li(+) salt) reacts at 290 K with P(4) to give the diphosphorus-bridged complex [Mo(2)Cp(2)(MU PCy(2))(CO)(2)(MU-kappa(2):kappa(2)-P(2))](-) (2). The latter reacts with MeI and ClSnPh(3) through a single P atom to give respectively diphosphenyl [Mo(2)Cp(2)(MU-PCy(2))(CO)(2)(MU-kappa(2):kappa(2)-P(2)Me)] (3) and stannyl [Mo(2)Cp(2)(MU-PCy(2))(CO)(2){MU-kappa(2):kappa(2)-P(2)(SnPh(3))}] (4) derivatives, with the P-P-Sn angle in 4 being unexpectedly acute [80.3(1) degrees ]. According to density functional theory calculations, this novel nucleophilic behavior of 1 is derived from its anionic nature, thus enabling the P(2) ligand to act in a pi-donor-like fashion. PMID- 21271698 TI - Simulations of micellization of sodium hexyl sulfate. AB - Micellization of the ionic surfactant sodium hexyl sulfate has been studied using atomistic explicit-solvent molecular dynamics simulations with and without excess NaCl or CaCl(2). Simulations were performed at surfactant loadings near the critical micellization concentration. Equilibrium micelle size distributions and estimates of the critical micellization concentration obtained from the simulations are in agreement with experimental data. In comparison to the sodium dodecyl sulfate surfactant, the shorter alkyl chain of sodium hexyl sulfate results in increased disorder of the micellar core and water exposure of the hydrocarbon tail groups. However, water and ions do not penetrate into the micellar core even for these weakly micellizing surfactants. Excess NaCl is observed to have a minor influence on the micelle structure but excess CaCl(2) induces drastic changes both in the structure and the dynamics of the micellar system. Furthermore, in the absence of excess salt, sodium hexyl sulfate forms predominantly spherical, disorganized aggregates but an increase in ionic strength drives an increase in aggregate size and leads to prolate aggregates. PMID- 21271699 TI - Spin crossover in tetranuclear cyanide-bridged iron(II) square complexes: a theoretical study. AB - Spin crossover in a series of six cyanide-bridged iron(II) tetranuclear square complexes was analyzed using density functional theory (DFT) methods. As the spin crossover between the low-spin (LS) and high-spin (HS) states can occur only for two of four iron ions, we characterized energetically and structurally the [LS LS], [HS-LS], and [HS-HS] spin-state isomers. For all studied complexes, the energy of the mixed [HS-LS] spin state does not deviate essentially from the halfway point between the energies of homogeneous spin states, thereby satisfying the conditions for an one-step transition between the [LS-LS] and [HS-HS]. This fact reflects the weak elastic coupling between the environments of transiting centers. The two-step spin transition observed in one complex can appear only due to the crystal packing effects. We also evaluated the strength of exchange coupling between the paramagnetic ions in the [HS-HS] state. PMID- 21271700 TI - 3D interconnected ionic nano-channels formed in polymer films: self-organization and polymerization of thermotropic bicontinuous cubic liquid crystals. AB - Thermotropic bicontinuous cubic (Cub(bi)) liquid-crystalline (LC) compounds based on a polymerizable ammonium moiety complexed with a lithium salt have been designed to obtain lithium ion-conductive all solid polymeric films having 3D interconnected ionic channels. The monomer shows a Cub(bi) phase from -5 to 19 degrees C on heating. The complexes retain the ability to form the Cub(bi) LC phase. They also form hexagonal columnar (Col(h)) LC phases at temperatures higher than those of the Cub(bi) phases. The complex of the monomer and LiBF(4) at the molar ratio of 4:1 exhibits the Cub(bi) and Col(h) phases between -6 to 19 degrees C and 19 to 56 degrees C, respectively, on heating. The Cub(bi) LC structure formed by the complex has been successfully preserved by in situ photopolymerization through UV irradiation in the presence of a photoinitiator. The resultant nanostructured film is optically transparent and free-standing. The X-ray analysis of the film confirms the preservation of the self-assembled nanostructure. The polymer film with the Cub(bi) LC nanostructure exhibits higher ionic conductivities than the polymer films obtained by photopolymerization of the complex in the Col(h) and isotropic phases. It is found that the 3D interconnected ionic channels derived from the Cub(bi) phase function as efficient ion-conductive pathways. PMID- 21271701 TI - Rhodium-catalyzed acylation with quinolinyl ketones: carbon-carbon single bond activation as the turnover-limiting step of catalysis. AB - The rhodium-catalyzed intramolecular carboacylation of quinolinyl ketones serves as an ideal subject for the mechanistic study of carbon-carbon bond activation. Combined kinetic and NMR studies of this reaction allowed the identification of the catalytic resting state and determination of the rate law, (12)C/(13)C kinetic isotope effects, and activation parameters. These results have identified the activation of a ketone-arene carbon-carbon single bond as the turnover limiting step of catalysis and provided quantitative detail into this process. PMID- 21271702 TI - Spatial bandgap engineering along single alloy nanowires. AB - Bandgap engineering of semiconductor nanowires is important in designing nanoscale multifunctional optoelectronic devices. Here, we report a facile thermal evaporation method, and realize the spatial bandgap engineering in single CdS(1-x)Se(x) alloy nanowires. Along the length of these achieved nanowires, the composition can be continuously tuned from x = 0 (CdS) at one end to x = 1 (CdSe) at the other end, resulting in the corresponding bandgap (light emission wavelength) being modulated gradually from 2.44 eV (507 nm, green light) to 1.74 eV (710 nm, red light). In spite of the existing composition (crystal lattice) transition along the length, these multicolor nanowires still possess high quality crystallization. These bandgap engineered nanowires will have promising applications in such as multicolor display and lighting, high-efficiency solar cells, ultrabroadly spectral detectors, and biotechnology. PMID- 21271703 TI - CO disrupts the reduced H-cluster of FeFe hydrogenase. A combined DFT and protein film voltammetry study. AB - Carbon monoxide is often described as a competitive inhibitor of FeFe hydrogenases, and it is used for probing H(2) binding to synthetic or in silico models of the active site H-cluster. Yet it does not always behave as a simple inhibitor. Using an original approach which combines accurate electrochemical measurements and theoretical calculations, we elucidate the mechanism by which, under certain conditions, CO binding can cause permanent damage to the H-cluster. Like in the case of oxygen inhibition, the reaction with CO engages the entire H cluster, rather than only the Fe(2) subsite. PMID- 21271704 TI - Light-activated kinases enable temporal dissection of signaling networks in living cells. AB - We report a general strategy for creating protein kinases in mammalian cells that are poised for very rapid activation by light. By photoactivating a caged version of MEK1, we demonstrate the specific, rapid, and receptor independent activation of an artificial subnetwork within the Raf/MEK/ERK pathway. Time-lapse microscopy allowed us to precisely characterize the kinetics of elementary steps in the signaling cascade and provided insight into adaptive feedback and rate determining processes in the pathway. PMID- 21271705 TI - Annealing-free high-mobility diketopyrrolopyrrole-quaterthiophene copolymer for solution-processed organic thin film transistors. AB - A donor-acceptor polymer semiconductor, PDQT, comprising diketopyrrolopyrrole (DPP) and beta-unsubstituted quaterthiophene (QT) for organic thin film transistors (OTFTs) is reported. This polymer forms ordered layer-by-layer lamellar packing with an edge-on orientation in thin films even without thermal annealing. The strong intermolecular interactions arising from the fused aromatic DPP moiety and the DPP-QT donor-acceptor interaction facilitate the spontaneous self-assembly of the polymer chains into close proximity and form a large pi-pi overlap, which are favorable for intermolecular charge hopping. The well interconnected crystalline grains form efficient intergranular charge transport pathways. The desirable chemical, electronic, and morphological structures of PDQT bring about high hole mobility of up to 0.97 cm(2)/(V.s) in OTFTs with polymer thin films annealed at a mild temperature of 100 degrees C and similarly high mobility of 0.89 cm(2)/(V.s) for polymer thin films even without thermal annealing. PMID- 21271706 TI - Synthesis of NHC complexes by oxidative addition of 2-chloro-N methylbenzimidazole. AB - The oxidative addition of 2-chloro-N-methylbenzimdazole to complexes of type [M(PPh(3))(4)] yields after N-protonation compounds with NH,NMe-substituted NHC ligands. For M = Pd complex compound trans-[3]BF(4) was obtained, while the oxidative addition for M = Pt yielded a mixture of cis-[4]BF(4) (major) and trans [4]BF(4) (minor). PMID- 21271707 TI - Multiple hindered rotators in a gyroscope-inspired tribenzylamine hemicryptophane. AB - A gyroscope-inspired tribenzylamine hemicryptophane provides a vehicle for exploring the structure and properties of multiple p-phenylene rotators within one molecule. The hemicryptophane was synthesized in three steps in good overall yield using mild conditions. Three rotator-forming linkers were cyclized to form a rigid cyclotriveratrylene (CTV) stator framework, which was then closed with an amine. The gyroscope-like molecule was characterized by (1)H NMR and (13)C NMR spectroscopy, and the structure was solved by X-ray crystallography. The rigidity of the two-component CTV-trismethylamine stator was investigated by (1)H variable temperature (VT) NMR experiments and molecular dynamics simulations. These techniques identified gyration of the three p-phenylene rotators on the millisecond time scale at -93 degrees C, with more dynamic but still hindered motion at room temperature (27 degrees C). The activation energy for the p phenylene rotation was determined to be ~10 kcal mol(-1). Due to the propeller arrangement of the p-phenylenes, their rotation is hindered but not strongly correlated. The compact size, simple synthetic route, and molecular motions of this gyroscope-inspired tribenzylamine hemicryptophane make it an attractive starting point for controlling the direction and coupling of rotators within molecular systems. PMID- 21271708 TI - Force-induced change in protein unfolding mechanism: discrete or continuous switch? AB - Mechanical stretching of proteins modifies their folding kinetics and may also cause a switch of folding mechanism from that at zero force. It is not clear from the kinetics alone whether the change is a continuous distortion of the zero force pathway or it occurs via a "discrete switch" to an alternative pathway. We use molecular simulations to dissect this switch of mechanism as a pulling force is applied to protein G via four different pairs of residues, or "pulling coordinates". Using a statistical clustering approach based on the pattern of native contact formation, we find distinct unfolding mechanisms at low and high force. For pulling coordinates for which the protein is resistant to the applied force, a marked "turnover" in the force-dependent unfolding kinetics is associated with an abrupt switch to a novel mechanical unfolding pathway. In contrast, pulling along coordinates where the protein has low resistance to force induces a smoother acceleration in the unfolding rate and a more gradual shift in the unfolding mechanism. The switch in folding pathway is captured by projection onto appropriate two-dimensional free energy surfaces, which separate the low and high force transition states. Remarkably, we find for a weak coordinate that the high force transition state is already accessible in the absence of force. Brownian dynamics simulations on these surfaces capture the force dependence of the kinetics, supporting the use of simplified low-dimensional models for interpreting mechanical unfolding experiments. We discuss the implications of the switch in pathway for the mechanical strength of proteins, and how such a switch may be experimentally tested. PMID- 21271709 TI - Metal contact engineering and registration-free fabrication of complementary metal-oxide semiconductor integrated circuits using aligned carbon nanotubes. AB - Complementary metal-oxide semiconductor (CMOS) operation is very desirable for logic circuit applications as it offers rail-to-rail swing, larger noise margin, and small static power consumption. However, it remains to be a challenging task for nanotube-based devices. Here in this paper, we report our progress on metal contact engineering for n-type nanotube transistors and CMOS integrated circuits using aligned carbon nanotubes. By using Pd as source/drain contacts for p-type transistors, small work function metal Gd as source/drain contacts for n-type transistors, and evaporated SiO(2) as a passivation layer, we have achieved n type transistor, PN diode, and integrated CMOS inverter with an air-stable operation. Compared with other nanotube n-doping techniques, such as potassium doping, PEI doping, hydrazine doping, etc., using low work function metal contacts for n-type nanotube devices is not only air stable but also integrated circuit fabrication compatible. Moreover, our aligned nanotube platform for CMOS integrated circuits shows significant advantage over the previously reported individual nanotube platforms with respect to scalability and reproducibility and suggests a practical and realistic approach for nanotube-based CMOS integrated circuit applications. PMID- 21271710 TI - F+ and F- affinities of simple N(x)F(y) and O(x)F(y) compounds. AB - Atomization energies at 0 K and heats of formation at 0 and 298 K are predicted for the neutral and ionic N(x)F(y) and O(x)F(y) systems using coupled cluster theory with single and double excitations and including a perturbative triples correction (CCSD(T)) method with correlation consistent basis sets extrapolated to the complete basis set (CBS) limit. To achieve near chemical accuracy (+/-1 kcal/mol), three corrections to the electronic energy were added to the frozen core CCSD(T)/CBS binding energies: corrections for core-valence, scalar relativistic, and first order atomic spin-orbit effects. Vibrational zero point energies were computed at the CCSD(T) level of theory where possible. The calculated heats of formation are in good agreement with the available experimental values, except for FOOF because of the neglect of higher order correlation corrections. The F(+) affinity in the N(x)F(y) series increases from N(2) to N(2)F(4) by 63 kcal/mol, while that in the O(2)F(y) series decreases by 18 kcal/mol from O(2) to O(2)F(2). Neither N(2) nor N(2)F(4) is predicted to bind F(-), and N(2)F(2) is a very weak Lewis acid with an F(-) affinity of about 10 kcal/mol for either the cis or trans isomer. The low F(-) affinities of the nitrogen fluorides explain why, in spite of the fact that many stable nitrogen fluoride cations are known, no nitrogen fluoride anions have been isolated so far. For example, the F(-) affinity of NF is predicted to be only 12.5 kcal/mol which explains the numerous experimental failures to prepare NF(2)(-) salts from the well-known strong acid HNF(2). The F(-) affinity of O(2) is predicted to have a small positive value and increases for O(2)F(2) by 23 kcal/mol, indicating that the O(2)F(3)(-) anion might be marginally stable at subambient temperatures. The calculated adiabatic ionization potentials and electron affinities are in good agreement with experiment considering that many of the experimental values are for vertical processes. PMID- 21271711 TI - From tetrahydroborate- to aminoborylvinylidene-osmium complexes via alkynyl aminoboryl intermediates. AB - The tetrahydroborate OsH(eta(2)-H(2)BH(2))(CO)(P(i)Pr(3))(2) (1) reacts with aniline and p-toluidine to give the aminoboryl derivatives [chemical structure: see text] (R = H (2), CH(3) (3)) and four H(2) molecules. Treatment of 2 and 3 with phenylacetylene gives Os{B(NHC(6)H(4)R)(2)}(C=CPh)(CO)(P(i)Pr(3))(2) (R = H (4), CH(3) (5)), which react with HBF(4) to afford the amino(fluoro)boryl species Os{BF(NHC(6)H(4)R)}(C=CPh)(CO)(P(i)Pr(3))(2) (R = H (6), CH(3) (7)). In contrast to HBF(4), the addition of acetic acid to 4 and 5 induces the release of phenylacetylene and the formation of the six-coordinate derivatives Os{B(NHC(6)H(4)R)(2)}(kappa(2)-O(2)CCH(3))(CO)(P(i)Pr(3))(2) (R = H (8), CH(3) (9)). The coordination number six for 4 and 5 can be also achieved by addition of CO. Under this gas Os{B(NHC(6)H(4)R)(2)}(C=CPh)(CO)(2)(P(i)Pr(3))(2) (R = H (10), CH(3) (11)) are formed. In toluene, these alkynyl-aminoboryl compounds evolve into the aminoborylvinylidenes Os{?C?C(Ph)B(NHC(6)H(4)R)(2)}(CO)(2)(P(i)Pr(3))(2) (R = H (12), CH(3) (13)) via a unimolecular 1,3-boryl migration from the metal to the C(beta) atom of the alkynyl ligand. Similarly to 4 and 5, complexes 6 and 7 coordinate CO to give Os{BF(NHC(6)H(4)R)}(C=CPh)(CO)(2)(P(i)Pr(3))(2) (R = H (15), CH(3) (16)), which evolve to Os{?C?C(Ph)BF(NHC(6)H(4)R)}(CO)(2)(P(i)Pr(3))(2) (R = H (17), CH(3) (18)). PMID- 21271712 TI - Treatment of mice with dextran sulfate sodium-induced colitis with human interleukin 10 secreted by transformed Bifidobacterium longum. AB - Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) the etiology of which has not yet been fully clarified. Cytokine interleukin-10 (IL-10) plays a central role in downregulating inflammatory cascade in UC and is likely a candidate for therapeutic intervention. However, its intravenous administration is costly and inconvenient. Therefore, we established a novel IL-10 delivery system by transforming a hIL-10-containing plasmid into B. longum (BL-hIL-10) and investigated its effects on 5% dextran sulfate sodium (DSS)-induced ulcerative colitis in mice and the possible underlying mechanism. Our results show that (1) hIL-10 was expressed and secreted into the culture supernatant of BL-hIL-10 after L-arabinose induction in vitro as examined by Western blot, enzyme-linked immunosorbent assay (ELISA) and RT-PCR; (2) addition of BL-hIL-10 culture supernatant had no cytotoxic effect and morphological alteration, but significantly inhibited the enhancement of proinflammatory cytokines by lipopolysaccharide (LPS) in THP-1 cells; (3) oral administration of BL-hIL-10 alleviated colitis syndrome of the model mice, attenuated colitis-activated NF kappaB pathway measured by DNA-binding assay and colitis-elevated expression of proinflammatory cytokines examined with CCK cytotoxic kits, and upregulated CD4+CD25+Foxp3+ Treg in blood and mesenteric lymph nodes measured by flow cytometry. In conclusion, BL-hIL-10 as a novel oral hIL-10 delivery system has been successfully established and oral administration of BL-hIL-10 alleviated inflammatory damage of colonic tissue in the model mice by blocking the colitis activated NF-kappaB pathway and upregulating CD4+CD25+Foxp3+ Treg in blood and mesenteric lymph nodes in mice. PMID- 21271713 TI - Functionalization of osmium arene anticancer complexes with (poly)arginine: effect on cellular uptake, internalization, and cytotoxicity. AB - Attaching peptides to metallodrugs may result in improved biological properties of the complexes. The potential use of cell penetrating peptides (CPPs) as cell delivery vectors is attractive, since directed cell uptake of (metallo)drugs remains a major challenge in anticancer drug design. In this work, we report the synthesis of peptide conjugates of the organometallic Os(II) anticancer complex [(eta(6)-biphenyl)Os(picolinate)Cl] with different arginine (Arg) chain lengths. Complexes conjugated to Arg(5) or Arg(8) at the 5-position of the picoline ring increase Os uptake into A2780 human ovarian cancer cells by ca. 2* and 10*, respectively, whereas a single Arg had no effect. Furthermore, a 15-fold increase in binding of Os to DNA, a potential target for these complexes, was observed for Arg(8) compared to the Arg(1) conjugate. The Arg(5) and Arg(8) conjugates exhibited fast kinetics of binding to calf thymus DNA and an ability to precipitate DNA at very low concentrations. In serum-free medium, the Arg(8) complex was cytotoxic (IC(50) 33 MUM) and appears to be a rare example of a bioactive organometallic peptide conjugate. Experiments on CHO cells deficient in DNA repair suggested that unrepaired DNA damage contributes to the cytotoxicity of the Arg(5) and Arg(8) conjugates. These studies demonstrate the potential for use of cell- and nucleus-penetrating peptides in targeting organometallic arene anticancer complexes. PMID- 21271714 TI - Simulation of the lo-ld phase boundary in DSPC/DOPC/cholesterol ternary mixtures using pairwise interactions. AB - Recently, a number of ternary phase diagrams of lipid mixtures have been constructed using various experimental techniques with a common goal of understanding the nature of lipid domains. An accurate experimental phase diagram can provide rich thermodynamic information and can also be used to extract molecular interactions using computer simulation. In this study, the liquid ordered and liquid-disordered (l(o)-l(d)) phase boundary of DSPC/DOPC/Cholesterol ternary mixtures is simulated in a lattice model using pairwise interactions. The block composition distribution (BCD) technique was used to locate accurately the compositions of coexisting phases and thermodynamics tie-lines in the two-phase region, and the Binder ratio method was used to determine the phase boundary in the critical region. In simulations performed along a thermodynamic tie-line, the BCD method correctly samples the compositions as well as the relative amounts of coexisting phases, which is in excellent agreement with the lever rule. A "best fit" phase boundary was obtained that has a top boundary closely resembling the experimental boundary. However, the width of the simulated two-phase region is significantly wider than the experimental one. The results show that pairwise interactions alone are not sufficient to describe the complexity of molecular interactions in the ternary lipid mixtures; more complex forms of interactions, possibly multibody interaction or domain interfacial energy, should be included in the simulation. PMID- 21271715 TI - In situ maleimide bridging of disulfides and a new approach to protein PEGylation. AB - The introduction of non-natural entities into proteins by chemical modification has numerous applications in fundamental biological science and for the development and manipulation of peptide and protein therapeutics. The reduction of native disulfide bonds provides a convenient method to access two nucleophilic cysteine residues that can serve as ideal attachment points for such chemical modification. The optimum bioconjugation strategy utilizing these cysteine residues should include the reconstruction of a bridge to mimic the role of the disulfide bond, maintaining structure and stability of the protein. Furthermore, the bridging chemical modification should be as rapid as possible to prevent problems associated with protein unfolding, aggregation, or disulfide scrambling. This study reports on an in situ disulfide reduction-bridging strategy that ensures rapid sequestration of the free cysteine residues in a bridge, using dithiomaleimides. This approach is then used to PEGylate the peptide hormone somatostatin and retention of biological activity is demonstrated. PMID- 21271716 TI - A catalytic, asymmetric formal synthesis of (+)-hamigeran B. AB - A concise asymmetric, formal synthesis of (+)-hamigeran B is reported. A Pd catalyzed, decarboxylative allylic alkylation, employing a trifluoromethylated derivative of t-BuPHOX, is utilized as the enantioselective step to form the critical quaternary carbon center in excellent yield and enantioselectivity. The product is converted in three steps to a late-stage intermediate previously used in the synthesis of hamigeran B. PMID- 21271717 TI - Inhibition of (+)-aristolochene synthase with iminium salts resembling eudesmane cation. AB - Trigonal iminium halides of (4aS,7S)-1,4a-dimethyl- and (4aS,7S)-4a-methyl-7 (prop-1-en-2-yl)-2,3,4,4a,5,6,7,8-octahydroquinolinium ions, aimed to mimic transition states associated with the aristolochene synthase-catalyzed cyclization of (-)-germacrene A to eudesmane cation, were evaluated under standard kinetic steady-state conditions. In the presence of inorganic diphosphate, these analogues were shown to competitively inhibit the enzyme, suggesting a stabilizing role for the diphosphate leaving group in this apparently endothermic transformation. PMID- 21271718 TI - Development of non-peptide ligands of growth factor receptor-bound protein 2-SRC homology 2 domain using molecular modeling and NMR spectroscopy. AB - We report a novel series of non-peptide ligands that inhibit the growth factor receptor-bound protein 2 (Grb2)-Src homology 2 (SH2) domain binding, designed using a combined computational and NMR-driven approach. We have identified a new lead compound, 1n (IC(50) = 56 MUM), which is cytotoxic in HER2-positive breast cancer cells and disrupts the interaction between HER2 and Grb2. Thus, 1n can be used as a scaffold for the development of efficient Grb2-SH2 domain binding inhibitors. PMID- 21271719 TI - Hemibonding between hydroxyl radical and water. AB - The ultraviolet absorption peak commonly used to identify OH radical in liquid water is mainly due to a charge-transfer-from-solvent transition that is prominent when OH is hemibonded, rather than more stable hydrogen bonded, to H(2)O. This work computationally characterizes the hemibonding interaction and the extent of the geometrical region over which it is significant. Hemibonding is found to be associated with an enlarged energy separation between the two lowest lying electronic states, which are otherwise always quite close to one another. The lower state, wherein the hemibonding occurs, retains an attractive interaction energy between OH and H(2)O that can be as much as one-half as strong as the optimum hydrogen-bonding interaction, while the enlarged separation between the states is mainly due to the upper state becoming repulsive over most of the hemibonding region. Hemibonding also leads to a considerable drop in the energy and a considerable increase in the oscillator strength of the characteristic charge-transfer transition. The region of significant hemibonding is found to lie within a moderate range of O-O azimuthal angles and over quite wide ranges of O-O separation distances and hydroxyl OH tilt angles. In particular, significant hemibonding interactions can extend down to surprisingly short O-O distances, where the oscillator strength for the charge-transfer-from solvent transition becomes very large. PMID- 21271720 TI - Phorbasones A and B, sesterterpenoids isolated from the marine sponge Phorbas sp. and induction of osteoblast differentiation. AB - Two new sesterterpenoids, phorbasones A (1) and B (2), were isolated from the Korean marine sponge Phorbas sp. Their complete structures were elucidated by spectral data and chemical reactions. Phorbasone A exhibited a positive effect on the calcium deposition activity in C3H10T1/2 cells. The biogenic origin of the core structure is believed to be through a novel rearrangement from the ansellone carbon structure. PMID- 21271721 TI - Ultrafast internal dynamics of flexible hydrogen-bonded supramolecular complexes. AB - Supramolecular chemistry is intimately linked to the dynamical interplay between intermolecular forces and intramolecular flexibility. Here, we studied the ultrafast equilibrium dynamics of a supramolecular hydrogen-bonded receptor substrate complex, 18-crown-6 monohydrate, using Fourier transform infrared (FTIR) and two-dimensional infrared (2DIR) spectroscopy in combination with numerical simulations based on molecular mechanics, density functional theory, and transition state theory. The theoretical calculations suggest that the flexibility of the macrocyclic crown ether receptor is related to an ultrafast crankshaft isomerization occurring on a time scale of several picoseconds and that the OH stretching vibrations of the substrate can serve as internal probes for the receptor's flexibility. The importance of population transfer among the vibrational modes of a given binding motif and of chemical exchange between spectroscopically distinguishable binding motifs for shaping the two-dimensional infrared spectrum and its temporal evolution is discussed. PMID- 21271722 TI - Solid state mutarotation of glucose. AB - It has been recently shown that mechanical milling can amorphize D-glucose without any mutarotation, giving rise to an anomerically pure amorphous sample. We have taken advantage of this exceptional possibility to study the kinetic of mutarotation in the amorphous solid state. The investigations have been performed in situ by time-resolved Raman spectroscopy. The results reveal an unexpected coupling between the mutarotation process and the structural relaxations involved in the glassy state. PMID- 21271723 TI - Proteolysis and bioconversion of cereal proteins to glutamate and gamma Aminobutyrate (GABA) in Rye malt sourdoughs. AB - This study aimed to achieve the conversion of cereal proteins to the alternative end products glutamate or gamma-aminobutyrate (GABA). Rye malt, fungal proteases, and lactobacilli were employed to convert wheat gluten or barley proteins. Glutamate and GABA formations were strain-dependent. Lactobacillus reuteri TMW1.106 and Lactobacillus rossiae 34J accumulated glutamate; L. reuteri LTH5448 and LTH5795 accumulated GABA. Glutamate and GABA accumulation by L. reuteri TMW1.106 and LTH5448 increased throughout fermentation time over 96 h, respectively. Peptides rather than amino acids were the main products of proteolysis in all doughs, and barley proteins were more resistant to degradation by rye malt proteases than wheat gluten. However, addition of fungal protease resulted in comparable degradation of both substrates. Glutamate and GABA accumulated to concentrations up to 63 and 90 mmol kg(-1) DM, respectively. Glutamate levels obtained through bioconversion of cereal proteins enable the use of hydrolyzed cereal protein as condiment. PMID- 21271724 TI - Differential effects of powdered whole soy milk and its hydrolysate on antiobesity and antihyperlipidemic response to high-fat treatment in C57BL/6N mice. AB - This study was performed to investigate the beneficial effects of powdered whole soy milk and its hydrolysate, compared to the processed soy milk and its hydrolysate, on the alteration of lipid metabolism and their possible effects on antiobesity in C57BL/6N mice fed a high-fat and -cholesterol diet. The mice were divided into a control group (20% casein) and four test groups for 5 weeks: soy milk (SM, 20% soy milk protein), soy milk hydrolysate (SMH, 20% hydrolyzed soy milk protein), whole soy milk (WSM, 20% whole soy milk protein), and whole soy milk hydrolysate (WSMH, 20% whole soy milk hydrolysate protein). The body weight and adipose tissue weights were significantly lowered in SMH, WSM, and WSMH groups compared to the control group despite providing an isoenergetic diet. Plasma lipid concentrations and hepatic fatty acid synthase (FAS) and glucose-6 phosphate dehydrogenase (G6PD) activities were significantly lowered in all soy milk groups; however, the hepatic lipid contents and malic enzyme (ME) activity were only significantly lowered in the WSM and WSMH groups, compared to the control group. Data suggest that powdered WSM or WSMH appears to be more beneficial than SM or SMH in overall antiobesity and antihyperlipidemic properties following in the order WSMH/WSM, SMH, SM, and casein. PMID- 21271725 TI - Facile amide formation via S-nitrosothioacids. AB - Here we report a novel amide bond formation strategy from simple thioacid and amine starting materials. The reaction is mediated by unstable but very reactive S-nitrosothioacid intermediates. This fast reaction under mild conditions should be useful in synthesis. PMID- 21271726 TI - Synthesis of (+/-)-7-hydroxylycopodine. AB - A six step synthesis of (+/-)-7-hydroxylycopodine has been achieved in 5% overall yield. In the key step, a Prins cyclization of a bicyclic keto alkyne in 60% H(2)SO(4) forms a tricyclic dihydroxy amino ketone. PMID- 21271727 TI - Tuning of intermolecular electron transfer reaction by modulating the microenvironment inside copolymer-surfactant supramolecular assemblies. AB - Photoinduced intermolecular electron transfer (ET) dynamics between various 7 aminocoumarin acceptors and N,N-dimethylaniline (DMAN) donor has been studied in copolymer-surfactant supramolecular assemblies prepared in aqueous 1% P123 triblock copolymer micellar solution with varying concentration of surfactants (sodium dodecyl sulfate (SDS), cetyl trimethyl ammonium chloride (CTAC), and triton-X-100 (TX100)). The aim of the present study is to modulate the reaction environment, especially the degree of micellar hydration inside the P123 micelle by the addition of the surfactants, which can modulate the ET reaction through the changes in the ET rates and the reaction exergonicity. Within the limited surfactant to copolymer molar ratios (n) used in the present study, fluorescence spectroscopy, dynamic light scattering (DLS), and small-angle neutron scattering (SANS) investigations indicate that the copolymer-surfactant supramolecular assemblies retain their micellar structure, although the micellar size gradually decreases with n. The redox potentials of the electron donor and acceptors are also found to change with n, although the extent of the effect is different for SDS, CTAC, and TX100 cosurfactants. In the presence of CTAC, the estimated exergonicity (-DeltaG(0)) of the ET reaction is found to increase with an increase in n compared with that in pure P123, whereas it decreases marginally with SDS and remains almost the same for TX100. Substantial quenching of coumarin fluorescence is observed in the presence of DMAN in all copolymer-surfactant micellar aggregates because of ET reaction. The ET rate is seen to increase gradually with an increase in SDS and CTAC concentration in the supramolecular assembly, although it remains unaffected on the addition of TX100. The increased ionic strength in the Corona region of the copolymer-surfactant supramolecular aggregates due to the addition of the ionic surfactants has been envisaged for the increase in the ET rates. A correlation of the quenching rate constants with the free-energy changes (DeltaG(0)) of the ET reactions shows the typical bell shaped curve as predicted by Marcus outersphere ET theory. A substantial shift along the exergonicity axis (~0.3 eV) for the appearance of the Marcus correlation is observed in some cases, although the extent of such shift depends on both the nature of the cosurfactant and the amount of cosurfactant used in the copolymer-surfactant supramolecular assembly. Therefore, these preliminary results suggest a possibility of not only modulating the ET rates but also tuning the appearance of Marcus inversion along the exergonicity scale by suitably tuning the reaction environment inside the copolymer-surfactant supramolecular assemblies with a relatively more hydrophilic cosurfactant. PMID- 21271728 TI - Density functional and spin-orbit ab initio study of CF3Br: molecular properties and electronic curve crossing. AB - Quantum chemical calculations of CF(3)Br and the CF(3) radical are performed using density functional theory (DFT) and time-dependent DFT (TDDFT). Molecular structures, vibrational frequencies, dipole moment, bond dissociation energy, and vertical excitation energies of CF(3)Br are calculated and compared with available experimental results. The performance of six hybrid and five hybrid meta functionals in DFT and TDDFT calculations are evaluated. The omegaB97X, B3PW91, and M05-2X functionals give very good results for molecular structures, vibrational frequencies, and vertical excitation energies, respectively. The omegaB97X functional calculates well the dipole moment of CF(3)Br. B3LYP, one of the most widely used functionals, does not perform well for calculations of the C Br bond length, bond dissociation energy, and vertical excitation energies. Potential energy curves of the low-lying excited states of CF(3)Br are obtained using the multiconfigurational spin-orbit ab initio method. The crossing point between 2A(1) and 3E states is located near the C-Br bond length of 2.45 A. Comparison with CH(3)Br shows that fluorination does not alter the location of the crossing point. The relation between the calculated potential energy curves and recent experimental result is briefly discussed. PMID- 21271729 TI - Combining horizontal and vertical substructure relationships in scaffold hierarchies for activity prediction. AB - For a systematic exploration of structural relationships between molecular scaffolds, ~24,000 unique scaffolds were extracted from 458 different target sets. Substructure relationships between these scaffolds were systematically determined. The scaffold tree data structure was utilized to study structural relationships between original scaffolds and derivative scaffolds obtained by rule-based decomposition. Leaf-to-root substructure relationships that resulted from rule-based decomposition were compared to leaf-to-leaf relationships between original scaffolds most of which were not part of the scaffold tree hierarchy. Decomposed scaffolds not contained in active target set compounds were prioritized on the basis of hierarchical scaffold patterns and additional substructure relationships. For high-priority virtual scaffolds, activity predictions were carried out, and these scaffolds were often found in external test compounds having the predicted activity. Taken together, our results suggest that leaf-to-root substructure relationships in scaffold trees should best be complemented with additional substructure relationships to determine high priority virtual scaffolds for activity prediction. PMID- 21271730 TI - Oral suspensions of morphine hydrochloride for controlled release: rheological properties and drug release. AB - Recent developments in pharmaceutical technology have facilitated the design and production of modified release formulas for drugs whose physical, chemical or biological properties impede release and thus might compromise their efficacy or safety. One such drug is morphine, whose short half-life requires repeated doses at short intervals. The use of biocompatible polymers such as ethylcellulose has made it possible to develop microencapsulated formulations which facilitate liquid, sustained-release pharmaceutical formulas for oral administration. We developed a stable final formulation of morphine with an acceptable release profile by comparing the rheological properties and stability of formulations with different thickeners (xanthan gum, Carbopol, and carboxymethylcellulose with microcrystalline cellulose) at different concentrations from 0.25% to 1.0%. Release assays in a Franz-type cell were done to determine the most suitable release profile for the formulation. PMID- 21271731 TI - Asymmetric dihydroxylations of enynes with a trisubstituted C?C bond. An unprecedented route to gamma-lactone building blocks with a quaternary stereocenter. AB - En route to a comprehensive set of hydroxylactone building blocks (4R,5R)-, (4R,5S)-, (4S,5R)-, and (4S,5S)-5a, Sharpless asymmetric dihydroxylations of allylic chlorides (E)- and (Z)-9 were performed. They delivered the four stereoisomers of diol 10 with up to 92% ee and absolute configurations, which were proven to be in accordance with the Sharpless mnemonic. PMID- 21271732 TI - Asymmetric dihydroxylations of 1-substituted (E)- and (Z)-3-methylpent-2-en-4 ynes: full compliance with the Sharpless mnemonic re-established and embellished. AB - Asymmetric dihydroxylations ("ADs") of the pentenynyl chlorides (E)- and (Z)-1 or the pentenyne-based ester (Z)-3 in the presence of (DHQ)(2)-containing ligands delivered diol stereoisomers (2R,3S)-2, (2R,3R)-2, and (3S,4R)-4, respectively. The ADs of pentenynyl ethers (E)-10 and (Z)-12, respectively, have the same stereochemical preference under analogous conditions; these reattributions correct previous reports of the contrary. The Sharpless mnemonic rationalizes all these results implying that each substrate prefers a Sharpless/Norrby instead of a Chapleur orientation in the transition state. PMID- 21271733 TI - New quinazolinone alkaloids within rare amino acid residue from coral-associated fungus, Aspergillus versicolor LCJ-5-4. AB - Cottoquinazoline D (3), a new alkaloid with a 1-aminocyclopropane-1-carboxylic acid residue rarely discovered in nature, was isolated and identified together with two new quinazolinone alkaloids, cottoquinazolines B (1) and C (2), from coral-associated fungus Aspergillus versicolor LCJ-5-4. Their structures including absolute configurations were elucidated based on spectroscopic methods, X-ray single crystal diffraction analysis, and chemical methods. A possible biogenetic pathway for them was proposed. PMID- 21271734 TI - NHC-catalyzed/titanium(IV)-mediated highly diastereo- and enantioselective dimerization of enals. AB - An NHC-catalyzed, diastereo- and enantioselective dimerization of enals has been developed. The use of Ti(Oi-Pr)(4) is a key element for the reactivity and selectivity of this process. The cyclopentenes are obtained with high levels of diastereo- and enantioselectivity and their synthetic utility is demonstrated by functionalization of the product alkene. PMID- 21271735 TI - High-resolution transmission electron microscopy study of electrically-driven reversible phase change in ge2sb2te5 nanowires. AB - By combining high-resolution transmission electron microscopy (HRTEM) characterization and electrical measurements on a unique device platform, we study the reversible electrically-driven phase-change characteristics of self assembled Ge(2)Sb(2)Te(5) nanowires. Detailed HRTEM analyses are used to correlate and understand the effect of full and intermediate structural transformations on the measured electrical properties of the nanowire devices. The study demonstrates that our unique approach has the potential to provide new information regarding the dynamic structural and electrical states of phase change materials at the nanoscale, which will aid the design of future phase change memory devices. PMID- 21271736 TI - Channel length scaling in graphene field-effect transistors studied with pulsed current-voltage measurements. AB - We investigate current saturation at short channel lengths in graphene field effect transistors (GFETs). Saturation is necessary to achieve low-output conductance required for device power gain. Dual-channel pulsed current-voltage measurements are performed to eliminate the significant effects of trapped charge in the gate dielectric, a problem common to all oxide-based dielectric films on graphene. With pulsed measurements, graphene transistors with channel lengths as small as 130 nm achieve output conductance as low as 0.3 mS/MUm in saturation. The transconductance of the devices is independent of channel length, consistent with a velocity saturation model of high-field transport. Saturation velocities have a density dependence consistent with diffusive transport limited by optical phonon emission. PMID- 21271737 TI - Surface morphology induced localized electric field and piezoresponse enhancement in nanostructured thin films. AB - Nanostructured piezoelectric and ferroelectric thin films are being increasingly used in sensing and actuating microdevices. In this work, we report the experimental discovery of localized electric field enhancement in nanocolumnar piezoelectric thin films and its significant impact on piezoresponse. The magnitude of electric field enhancement is associated with nonflat surface morphologies and is in agreement with theoretical and finite element models. The influence of this surface morphology induced enhancement on piezoresponse is demonstrated using phase field simulations, which also illustrates surface morphology induced strain enhancement. The observed enhancement can be effectively harnessed to improve the sensitivity of related piezoelectric thin film applications. PMID- 21271738 TI - Impermeable graphenic encasement of bacteria. AB - Transmission electron microscopy (TEM) of hygroscopic, permeable, and electron absorbing biological cells has been an important challenge due to the volumetric shrinkage, electrostatic charging, and structural degradation of cells under high vacuum and fixed electron beam.(1-3) Here we show that bacterial cells can be encased within a graphenic chamber to preserve their dimensional and topological characteristics under high vacuum (10(-5) Torr) and beam current (150 A/cm(2)). The strongly repelling pi clouds in the interstitial sites of graphene's lattice(4) reduces the graphene-encased-cell's permeability(5) from 7.6-20 nm/s to 0 nm/s. The C-C bond flexibility(5,6) enables conformal encasement of cells. Additionally, graphene's high Young's modulus(6,7) retains cell's structural integrity under TEM conditions, while its high electrical(8) and thermal conductivity(9) significantly abates electrostatic charging. We envision that the graphenic encasement approach will facilitate real-time TEM imaging of fluidic samples and potentially biochemical activity. PMID- 21271739 TI - Aqueous only route toward graphene from graphite oxide. AB - We report a new, simple, hydrazine-free, high-yield method for producing single layer graphene sheets. Graphene sheets were formed from graphite oxide by reduction with simple deionized water at 95 degrees C under atmospheric pressure. Over 65% of the sheets are single graphene layers; the average sheet diameter is 300 nm. We speculate that dehydration of graphene oxide is the main mechanism for oxygen reduction and transformation of C-C bonds from sp(3) to sp(2). The reduction appears to occur in large uniform interconnected oxygen-free patches so that despite the presence of residual oxygen the sp(2) carbon bonds formed on the sheets are sufficient to provide electronic properties comparable to reduced graphene sheets obtained using other methods. PMID- 21271740 TI - Excitation isotropy of single CdSe/ZnS nanocrystals. AB - We study the dimensionality of the excitation transition dipole moment for single CdSe/ZnS core-shell nanocrystals using azimuthally and radially polarized laser modes. The comparison of measured and simulated single nanocrystal excitation patterns shows that single CdSe/ZnS quantum dots possess a spherically degenerated excitation transition dipole. We show that the dimensionality of the excitation transition dipole moment distribution is the same for all individual CdSe/ZnS nanocrystals, disregarding the difference in core size and irrespective of variations in the local environment. In contrast to the emission transition dipole moment, which is oriented in one plane, the excitation transition dipole moment of a single CdSe/ZnS quantum dots possesses an isotropy in three dimensions. PMID- 21271741 TI - Hollow polyhedral structures in small gold-sulfide clusters. AB - Using ab initio methods, we investigate the structural evolution of a family of gold-sulfide cluster anions (Au(m)S(n)(-)). We show that this family of clusters exhibits simple size-evolution rules and novel hollow polyhedron structures. The highly stable Au(m)S(n)(-) species such as Au(6)S(4)(-), Au(9)S(5)(-), Au(9)S(6)( ), Au(10)S(6)(-), Au(11)S(6)(-), Au(12)S(8)(-), and Au(13)S(8)(-) detected in the recent ion mobility mass spectrometry experiment of Au(25)(SCH(2)CH(2)Ph)(18) (Angel et al. ACS Nano2010, 4, 4691) are found to possess either quasi tetrahedron, pyramidal, quasi-triangular prism, or quasi-cuboctahedron structures. The formation of these polyhedron structures are attributed to the high stability of the S-Au-S structural unit. A unique "edge-to-face" growth mechanism is proposed to understand the structural evolution of the small Au(m)S(n)(-) cluster. A 3:2 ratio rule of Au/S is suggested for the formation of a hollow polyhedron structure among small-sized Au(m)S(n) clusters. PMID- 21271742 TI - Intramolecular hydrogen bonding assisted charge transport through single rectifying molecule. AB - A novel diode molecule consisting of alpha-hydroxyphenyl pyridine motif was synthesized. Molecular self-assembly onto gold electrode surface leads to moderate rectifying behavior. The replacement of the hydroxyl proton by a methyl group leads to the disruption of intramolecular hydrogen bonding and yields a twisted molecular conformation. Comparing the current-voltage characteristics between these two compounds reveals that the presence of intramolecular hydrogen bonding substantially improves the molecular conductivity. PMID- 21271743 TI - Total synthesis of (+)-ent-cyclizidine: absolute configurational confirmation of antibiotic M146791. AB - The first total synthesis of the enantiomer of the indolizidine alkaloid, cyclizidine, was accomplished from readily available d-serine as the starting chiron. The relevant key reactions involve the stereocontrolled construction of the indolizidine ring system with the required functionality and further elaboration to install the cyclopropyl dienyl side chain. With this total synthesis, the absolute configuration of the natural product based on a redetermination of its X-ray structure has been confirmed. PMID- 21271744 TI - Vibrationally resolved photofragment translational spectroscopy of CH3I from 277 to 304 nm with increasing effect of the hot band. AB - The photodissociation dynamics of CH(3)I from 277 to 304 nm is studied with our mini-TOF photofragment translational spectrometer. A single laser beam is used for both photodissociation of CH(3)I and REMPI detection of iodine. Many resolved peaks in each photofragment translational spectrum reveal the vibrational states of the CH(3) fragment. There are some extra peaks showing the existence of the hot-band states of CH(3)I. After careful simulation with consideration of the hot band effect, the distribution of vibrational states of the CH(3) fragment is determined. The fraction sigma of photofragments produced from the hot-band CH(3)I varies from 0.07 at 277.38 nm to 0.40 at 304.02 nm in the I* channel and from 0.05 at 277.87 nm to 0.16 at 304.67 nm in the I channel . E(int)/E(avl) of photofragments from ground-state CH(3)I remains at about 0.03 in the I* channel for all four wavelengths, but E(int)/E(avl) decreases from 0.09 at 277.87 nm to 0.06 at 304.67 nm in the I channel . From the ground-state CH(3)I, the quantum yield Phi(I*) is determined to be 0.59 at 277 nm and 0.05 at 304 nm. The curve crossing probability P(cc) from the hot-band CH(3)I is lower than that from the ground-state CH(3)I. The potential energy at the curve-crossing point is determined to be 32,740 cm(-1). PMID- 21271745 TI - Experimental investigation of charge carrier transport in organic thin-film transistors with "buried surface layers". AB - We studied how the layers with different transport properties buried inside a semiconductor material affect the characteristics of organic thin film transistors (OTFT) using a well-defined multilayered structure fabricated by a contact film transfer method that we recently developed (ACS Appl. Mater. Interfaces 1, 2660 (2009)). A simple model with the charge distribution in the organic semiconductor film, the mobility dependence on the charge density, and the buried surface layers with a high mobility successfully reproduced the experimental mobility dependence on the thickness of the spin-coated films and the gate voltage. These results demonstrated that charge transport layers located far from the dielectric interface could contribute significantly to the total current in OTFTs. PMID- 21271746 TI - Metal-graphene interaction studied via atomic resolution scanning transmission electron microscopy. AB - Distributions and atomic sites of transition metals and gold on suspended graphene were investigated via high-resolution scanning transmission electron microscopy, especially using atomic resolution high angle dark field imaging. All metals, albeit as singular atoms or atom aggregates, reside in the omni-present hydrocarbon surface contamination; they do not form continuous films, but clusters or nanocrystals. No interaction was found between Au atoms and clean single-layer graphene surfaces, i.e., no Au atoms are retained on such surfaces. Au and also Fe atoms do, however, bond to clean few-layer graphene surfaces, where they assume T and B sites, respectively. Cr atoms were found to interact more strongly with clean monolayer graphene, they are possibly incorporated at graphene lattice imperfections and have been observed to catalyze dissociation of C-C bonds. This behavior might explain the observed high frequency of Cr-cluster nucleation, and the usefulness as wetting layer, for depositing electrical contacts on graphene. PMID- 21271747 TI - The pharmacokinetics of methanol in the presence of ethanol: a case study. AB - BACKGROUND AND OBJECTIVE: Methanol is a toxic alcohol that can cause significant morbidity and mortality in overdose, while ethanol is a readily available and effective antidote. Little is known about the pharmacokinetics of methanol in the presence of ethanol and vice versa. This paper explores the influence of methanol and ethanol on the pharmacokinetics of each other along with the effect of continuous venovenous haemodiafiltration (CVVHD) on alcohol removal. METHODS: Multiple plasma, urine and dialysate samples were collected from a 42-year-old male who ingested 166 g of methanol. Methanol and ethanol concentrations in both plasma and urine were assayed and the concentration-time data were modelled using nonlinear mixed-effects modelling software NONMEM(r) VI. Simulations were performed using the final model parameters in MATLAB(r) software where a variety of initial doses and ethanol infusions were assessed. RESULTS: The final model included a competitive metabolic interaction between methanol and ethanol as well as first-order elimination due to renal, CVVHD and an additional non-renal non CVVHD mechanism. Simulations from the model show a loading dose of 28.4 g/70 kg of ethanol results in a target plasma concentration of 1 g/L. Due to the competitive interaction between methanol and ethanol, higher amounts of methanol require lower maintenance doses of ethanol but for longer. CVVHD was shown to increase the dose rate of ethanol required but to decrease the duration of the maintenance phase. CONCLUSION: A detailed understanding of the pharmacokinetics of methanol and ethanol in the presence of each other is required to accurately determine the doses of ethanol required to treat different methanol poisonings. PMID- 21271749 TI - Influence of patient co-payments on atypical antipsychotic choice in Poland: implications once generic atypicals are available. AB - INTRODUCTION: Despite recent concerns over the effectiveness and safety of atypical antipsychotics compared with first-generation antipsychotics, prescribing of atypical antipsychotics continues to increase. The use of generic atypical antipsychotics is one way to address cost concerns, especially if there are no major differences in outcomes between generic and originator formulations. Market forces do appear to help lower prices if patients have to cover any difference between higher priced generics and originators and the current reference-priced products themselves, which they try to avoid, and if companies strive to gain market share. However, this approach may compromise individualizing atypical choice if reference classes consist of several atypicals between which there are significant co-payment differences. OBJECTIVES: First, to assess whether differences in patient co-payment levels between the various atypical antipsychotic formulations alter the atypical formulation prescribed and/or dispensed in practice in Poland. Second, to assess whether market forces in Poland help drive down generic prices in reality as successive generics are launched. Third, to assess the impact of the reduction in reference prices on the overall expenditure on atypicals by the National Health Fund in Poland. METHODS: Prescription and reimbursed expenditure data for olanzapine and risperidone were provided by the National Health Fund from 2002 to 2006, although no individual patient data were available. Reimbursement limits for the various presentations of olanzapine and risperidone were based on regulations from the Ministry of Health. RESULTS: Analysis of the data showed that the level of patient co-payment appeared to impact on the atypical antipsychotic dispensed, with utilization of olanzapine growing once its co-payment was reduced when generic olanzapine became available. The reverse was seen with risperidone, with only limited growth in utilization when co-payment levels increased.Market forces resulted in a 40% reduction in the reimbursed reference price (based on the defined daily dose) of olanzapine and a 77% reduction for risperidone from 2002 to July 2008. These price reductions helped moderate the growth in atypical expenditure in Poland despite appreciably increased utilization, especially for olanzapine. Continued moderation (or even a reduction) in the growth of expenditure on atypicals is envisaged, despite increasing utilization, as more generic formulations are launched, with further reductions in the reference price for both olanzapine and risperidone. CONCLUSIONS: Market forces appear to drive down the prices of generics and originators as more atypical formulations are launched. However, alternative approaches may be needed if significant co-payment differences compromise individualized care. PMID- 21271748 TI - Cost effectiveness of treatments for inflammatory bowel disease. AB - Traditionally, half of the direct costs associated with chronic inflammatory bowel diseases (IBD) [Crohn's disease (CD) and ulcerative colitis (UC)] have related to hospital inpatient treatment for a sub-group of more severely affected, often therapy-resistant individuals. The advent of effective but relatively expensive biological agents has increased the contribution of drugs to overall medical care costs. This has focussed interest on the relative cost effectiveness of rival therapies for IBD and, in particular, on the affordability of long-term biological therapy. The purpose of this article is to review the available literature on this topic and to identify areas for future research. Head-to-head trials of competing treatment options are uncommon and clinical trials have seldom addressed cost effectiveness. In UC, models have explored the cost utility of 'high-' versus 'standard-' dose 5-aminosalicylic acid (5-ASA) therapy and the theoretical impact of improved adherence with once-daily formulations. In CD, cost-utility models for anti-tumour necrosis factor (TNF) drugs versus standard care have suggested consistently that incremental benefits are achieved at increased overall cost. However, studies of varying design have produced a wide spectrum of incremental cost-effectiveness ratio estimates, which highlights the challenges and limitations of existing modelling techniques. PMID- 21271750 TI - Current and future economic burden of osteoporosis in New Zealand. AB - BACKGROUND: Osteoporosis is recognized as a serious health condition in developed as well as developing countries. There are no accurate estimates of the extent of the burden of osteoporosis in New Zealand. The purpose of this study was to estimate the economic burden of osteoporosis in New Zealand using data from international studies and population and health services information from New Zealand. OBJECTIVE: To estimate the number of osteoporotic fractures and cost of treatment and management of osteoporosis and osteoporotic fractures to the health system in New Zealand in 2007 and to project the future burden in 2013 and 2020. METHODS: Hospitalizations for hip fractures were combined with New Zealand census data and estimates from previous studies to estimate the expected number of osteoporotic vertebral, humeral, pelvic and other sites fractures in 2007. Health services usage and costs were estimated by combining data from New Zealand hospitals, the New Zealand Health Survey on the number of people diagnosed with osteoporosis, and the New Zealand Health Information Service (NZHIS) on pharmaceutical treatments. All prices are in New Zealand dollars ($NZ), year 2007 values. Losses in QALYs resulting from osteoporotic fractures were used to indicate the impact on morbidity and mortality. The lost QALYs and economic cost associated with osteoporosis were projected to 2013 and 2020 using population projections from the New Zealand census. RESULTS: There were an estimated 84 354 osteoporotic fractures in New Zealand in 2007, including 3803 hip and 27 994 vertebral fractures. Osteoporosis resulted in a loss of 11 249 QALYs. The total direct cost of osteoporosis was$NZ330 million, including $NZ212 million to treat the fractures, $NZ85 million for care after fractures and $NZ34 million for treatment and management of the estimated 70 631 people diagnosed with osteoporosis. Sensitivity analysis suggested the results were robust to assumptions regarding the number of fractures receiving medical treatment. Hospitalization costs represented a significant component of total costs. The cost of treatment and management of osteoporosis is expected to increase to over $NZ391 million in 2013 and $NZ458 million in 2020, with the number of QALYs lost increasing to 13 205 in 2013 and 15 176 in 2020. CONCLUSIONS: Osteoporosis and osteoporotic fractures create a significant burden on the health system in New Zealand. This study highlights the significant scope of the burden of osteoporosis and the potential gains that might be made from introducing interventions to mitigate the burden. PMID- 21271751 TI - Safe administration of celecoxib to a patient with repeated episodes of nephrotic syndrome induced by NSAIDs. AB - Nephrotic syndrome, with or without concomitant tubulointerstitial nephritis, is a rare renal adverse effect of NSAIDs. In the present report we describe a case of a 60-year-old Caucasian man who was admitted because of nephrotic syndrome following several days of use of meloxicam for hip osteoarthritis. Renal histopathology revealed minimal change disease, one of the commonest causes of nephrotic syndrome. The patient's condition resolved rapidly upon discontinuation of meloxicam. Because he had already experienced two episodes of nephrotic syndrome after administration of diclofenac several years previously, it was concluded that the patient had renal hypersensitivity to both diclofenac and meloxicam. While waiting for the hip arthroplasty, he was prescribed celecoxib for pain control. After 1 month of regular celecoxib use the patient remained in remission with respect to nephrotic syndrome and had normal renal function. We conclude that challenge with a structurally distinct NSAID (such as celecoxib in this case) may be an option, under close surveillance, in a patient with a history of nephrotic syndrome associated with use of an NSAID when continued treatment with an NSAID is indicated. PMID- 21271752 TI - Elective withdrawal from clozapine. PMID- 21271753 TI - Realizations of consonant clusters by children with phonological impairment. AB - Children with phonological impairment frequently have difficulty producing consonant clusters. Speech pathologists often use phonological processes to describe children's productions of consonant clusters, a commonly used description being cluster reduction. However, this description does not adequately address children's differing realizations of consonant clusters. The purpose of this paper is to develop and refine methods for the characterization of realizations of consonant clusters. The work of Greenlee (1974) and Chin and Dinnsen (1992) has been extended by examining the effect of syllable position, number of elements and constituents on children's realizations of consonant clusters. Specifically, word-initial fricative clusters, stop clusters, three element fricative + stop clusters, and word-final nasal clusters and fricative + stop clusters were examined. The results for 40 phonologically impaired children between the ages of 3;6 and 5;0 years are compared with those of Chin and Dinnsen (1992). The relationships found between child and adult representations of clusters suggest the importance of considering syllable position, number of elements and the constituents of consonant clusters when analysing phonologically impaired children's speech sounds. PMID- 21271754 TI - The narrative skills of primary school children with a unilateral hearing impairment. AB - The discourse skills of four boys with a unilateral hearing impairment (UHI), aged 7.2-10.7 years, were appraised over a 2-year period by examining their oral narrative use. All subjects exhibited delayed narrative skills, including features typical of children with a language disorder. These findings of language difficulties within this population were at variance with previous findings showing that children with UHI do not experience language problems. The subjects' language skills were discussed in relation to their academic performance. The implications of the findings for the process of narrative assessment were also discussed. PMID- 21271755 TI - Neuropsychological and neuroimaging findings of developmental dysphasia: A longitudinal case study. AB - This article presents an unusual and interesting neuropsychological and neuroimaging longitudinal study of a child who showed a relatively specific developmental language disorder in the absence of any other significant cognitive, emotional or neurological disturbance. The neuropsychological assessment included tests of intelligence, memory, language and frontal lobe functions. Our patient had a marked developmental language disorder characterized by severe impairment of oral and written language and a restricted vocabulary, even though the comprehension of both spoken and written language was relatively preserved. Moreover, his non-verbal intellectual ability was normal and he showed superior visuoconstructive and visuospatial abilities which suggested good development of right temporoparietal functions. On computerized tomography and magnetic resonance imaging there were no structural abnormalities in those cerebral areas concerned with language, although both neuroimaging studies did show a feasible reversed asymmetry or further atrophy on the left sylvian. It is noticeable that at age 17 a severe deficit in the expressive aspects of language remains. In contrast, visuo-constructive functions have improved. These results suggest a functional reorganization of the brain by increasing non-verbal capabilities. The prognosis in dysphasic syndromes is worse than in acquired aphasia in children, since despite speech therapy, an important language impairment persists during adulthood. PMID- 21271756 TI - Feature enhancement and phonological acquisition. AB - Distinctive features have been part of clinical work in phonological assessment and therapy. In almost all studies the set of features used was the Chomsky and Halle system. Stevens and Keyser (1989) offer a new look at distinctive features from the dimension of perceptual saliency, and account for the markedness relationship between segments. This paper explores to what extent it is possible to account for the substitution patterns in child phonologies based on the concepts of feature hierarchy, enhancement, and perceptual saliency as proposed by Stevens and Keyser. Concentrating on the consonantal substitutions in normal and disordered child speech, an attempt is made to distinguish between normal and unusual/idiosyncratic processes. Implications for assessment are discussed. PMID- 21271775 TI - Depressed levels of interferon-gamma and HLA-DR+CD3+ T cells in infants with transient hyperferritinemia. AB - Familial hemophagocytic lymphohistiocytosis (FHL), which typically has its onset during infancy, is uniformly fatal if not treated. It therefore requires prompt therapeutic intervention. Although hyperferritinemia has been emphasized as a useful marker for FHL, some nonfatal cases in infants with spontaneous remission also manifest with hyperferritinemia. However, distinguishing them is difficult because initial clinical features of these infants are similar. The authors encountered 14 infants with hyperferritinemia (serum ferritin >674 ng/mL), which normalized within 3 weeks following a benign clinical course. The authors compared the levels of HLA-DR+CD3+ T-cell subsets and interferon-gamma (IFN gamma) in the peripheral blood between these infants and FHL cases: one of the authors' own patients and others from the literature. Serum IFN-gamma was not detected in infants with hyperferritinemia. Moreover, levels of HLA-DR+CD3+ T cells were extremely depressed. In contrast, serum IFN-gamma was elevated and HLA DR+CD3+ T cells were not depressed in FHL. Measurement of activated T cells and serum IFN-gamma might help differentiate FHL in febrile infants with transient hyperferritinemia. PMID- 21271776 TI - Health-related quality of life in Egyptian children and adolescents with hemophilia A. AB - Quality of life (QoL) in hemophilia is an important area in hemophilia outcome assessment. The Haemo-QoL instrument is a set of questionnaires to measure QoL in those children. The objectives of this study was to assess health-related quality of life (HRQoL) in Egyptian hemophilic children and adolescents using an Arabic version of the Haemo-QoL questionnaire. Sixty patients with severe hemophilia A were recruited from 2 hemophilia treating centers in Egypt. Assessment of quality of life was done using the Haemo-QoL questionnaire. The scores of HRQoL were found to be for all dimensions widely above 50. It was highly significant in the 3 dimensions (physical health-family-treatment) in different age groups, but it was impaired in the dimension of "physical health" for 2 groups, and in the dimension of "family" for the oldest group, whereas the youngest group had highly impaired scores concerning the "treatment." The HRQoL in this study was not affected by the presence of factor VIII (FVIII) inhibitors. The QoL in hemophilic patients in Egypt needs strenuous efforts from hemophilia care-integrated teams of pediatric hematologists and psychiatrists in order to properly assess and improve QoL. PMID- 21271777 TI - Five Chinese pediatric patients with leukemias possibly arising from immature natural killer cells: clinical features and courses. AB - Leukemias arising from immature nature killer (NK) cells have been proposed as distinct entities and are rare. Treatment and prognosis of these diseases are controversial, and data on children are limited. According to the literature, one of these distinct leukemias may be myeloid/NK cell precursor acute leukemia (MNKPL), with the blasts being cytochemically myeloperoxidase negative (MPO(-)) and phenotypically CD56(+)CD3(-)CD7(+)CD34(+) and myeloid antigens(+). The other may be myeloid/NK cell acute leukemia (MNKL), in which the blasts were cytochemically MPO(dim) and phenotypically CD56(+)CD16(-)CD3(-)CD33(+)HLA-DR(-). Between 2005 and 2008, 4 MNKPL and 1 MNKL children aged 1.3 to 12.5 years were encountered in the First Affiliated Hospital of Sun Yat-Sen University. In those with MNKPL, remarkable extramedullary involvement usually occurring in adults was not observed; however, myelofibrosis was found in 2 children. The child with MNKL abandoned treatment. Those with MNKPL were treated with a protocol designed for childhood high-risk acute lymphoblastic leukemia (ALL) containing cytarabine, mitoxantrone, etoposide, l-asparaginase, and methotrexate according to the myeloid and lymphoid characteristics of MNKPL. They responded slowly to chemotherapy and were in complete remission (CR) for 26 to 63 months, except 1 who died in CR from pneumonia. They had longer survival and seemed to have a better outcome than those reported previously. In conclusion, childhood leukemias with immature NK cell markers may have different characteristics from their adult counterparts. A protocol including agents used for acute myeloid leukemia combined with those for ALL is seemingly effective for treatment of MNKPL. However, a modified treatment strategy designed more specifically for MNKPL and longer observations are needed. PMID- 21271778 TI - Hepatopathy-thrombocytopenia syndrome (HTS) after actinomycin-D therapy: report of three cases and review of the literature. AB - Hepatopathy-thrombocytopenia syndrome (HTS) is a severe complication very similar to vein occlusive disease (VOD), also known as hepatic sinusoidal obstructive syndrome (SOS), characterized by fever, hepatopathy (hepatomegaly with abnormal liver function tests), ascites, weight gain, jaundice, and thrombocytopenia (platelet count less than 25 * 10(3)/MUL). It has been generally observed in patients with Wilms tumor, and is commonly associated to administration of actinomycin D. We report three children with Wilms tumor, with severe HTS/SOS, but had a different outcome, in spite of vigorous supportive therapy. PMID- 21271779 TI - Treatment refusal and abandonment in children with acute lymphoblastic leukemia. PMID- 21271780 TI - A neonate with antiphospholipid syndrome and inherited thrombophilia. PMID- 21271782 TI - Correlation of 2nd trimester amniotic fluid amino acid profile with gestational age and estimated fetal weight. AB - OBJECTIVES: Our aim was to identify and quantitate free amino acids in human amniotic fluid (AF) specimens collected during 2nd trimester amniocentesis and determine the correlation between amino acid concentrations, gestational age, and estimated fetal weight. METHODS: Seventy-eight AF samples were retrieved between 18 and 22 weeks of gestation. Fetal weight estimation was based on fetal biometric measurements. RESULTS: Twenty-one amino acids were quantified. The concentration of glutamine exhibited the greatest correlation with gestational age (r = 0.477, p < 0.01). Additionally, significant negative correlations were recorded between gestational age and levels of alanine, proline, lysine, valine, taurine, leucine, glutamic acid, tyrosine, phenylalanine, isoleucine, ornithine, methionine, and tryptophane (p < 0.05). After adjusting for maternal age, fetal gender, intervals between consecutive pregnancies, pre-pregnancy body mass index, and smoking during pregnancy the strength of the correlation for proline and lysine decreased. A stepwise multiple linear regression model including gestational age as a first level predictor of fetal weight indicated that lysine and cysteine concentrations were additional predictors. CONCLUSIONS: Our results suggest that AF amino acids are crucial for fetal growth. Our purpose was not to establish an immediate diagnostic application. However, further exploration is likely to be fruitful, especially in high-risk pregnancies. PMID- 21271783 TI - The sequential effect of computerized delivery charting and simulation training on shoulder dystocia documentation. AB - OBJECTIVE: To estimate the effects of computerized charting and shoulder dystocia (SD) simulation drills on the documentation of SD. METHODS: 180 cases of SD were evaluated in three consecutive time periods: T1: 45 written delivery notes; T2: 48 delivery notes after the implementation of a standardized SD note in the computerized medical record; T3: 87 computerized delivery notes after SD simulation drills. RESULTS: A standardized SD computerized note resulted in a significant improvement in documentation of EFW, diabetic status, time of the body delivery, fetal head position, which shoulder was impacted, anesthesia, the length of each stage of labor, NICU admission, the birth weight, and that a discussion took place with the patient. The implementation of a SD simulation drill was associated with a further increase in the documentation of the instruments used for delivery, whether a cord pH was performed, and that a discussion took place with the patient. Additionally, the implementation of a SD simulation drill increased the rate of documented SD (1.61% vs. 2.37% of vaginal deliveries, p = 0.0275) and the number of obstetricians who documented a SD (32.35% vs. 60.29% of delivering obstetricians, p = 0.0020). CONCLUSIONS: Standardized SD notes as well as simulation drills improve documentation of SD events. PMID- 21271784 TI - Influence of water sorption of the underlying abutment on fracture resistance of zirconia copings. AB - OBJECTIVE: To investigate the influences of abutment water sorption and various aging parameters on the fracture resistance of zirconia copings. METHODS: Using a master die, identical replicas were made from three resin materials. The first was a melamine resin with very high water sorption (n = 48), the second an experimental resin core build-up composite with moderate water sorption (n = 40) and the third a commercially available core build-up composite with low water sorption (n = 40). On the abutment replicas, zirconia copings (n = 128) were made using a computer-aided design-computer-aided manufacturing system. The copings were luted onto the abutments using zinc oxide phosphate cement. In the melamine group, a subgroup of samples (n = 8) was cemented with a composite cement as controls. The forty specimens in every abutment material group were randomly divided into one of five subgroups, as follows: (i) not aged; (ii) mechanically (dry) loaded only (50 N; 1.2 * 10(6) cycles); (iii) stored for 10 days in water; (iv) thermally cycled (TC; 6000 * 5/55 degrees C); and (v) TC and mechanically loaded (TCML; 50 N, 1.2 * 10(6); 6000 * 5/55 degrees C). After aging, all copings were loaded to fracture. RESULTS: A statistically significant difference was found between the three abutment-die groups if the samples were aged by TCML. The zirconia copings cemented on abutments with high water sorption fractured during TCML, and the subgroup with moderate water sorption had significantly lower fracture resistance. A change of luting material had no impact on this behavior. CONCLUSION: Only the simultaneous combination of all chosen aging factors (TCML) was able to detect a difference in fracture behavior of a zirconia coping luted on abutments with varying water sorption. PMID- 21271785 TI - Persistence of gamma-H2AX and 53BP1 foci in proliferating and non-proliferating human mammary epithelial cells after exposure to gamma-rays or iron ions. AB - PURPOSE: To investigate gamma-H2AX (phosphorylated histone H2AX) and 53BP1 (tumour protein 53 binding protein No. 1) foci formation and removal in proliferating and non-proliferating human mammary epithelial cells (HMEC) after exposure to sparsely and densely ionising radiation under different cell culture conditions. MATERIAL AND METHODS: HMEC cells were grown either as monolayers (2D) or in extracellular matrix to allow the formation of acinar structures in vitro (3D). Foci numbers were quantified by image analysis at various time points after exposure. RESULTS: Our results reveal that in non-proliferating cells under 2D and 3D cell culture conditions, iron-ion induced gamma-H2AX foci were still present at 72 h after exposure, although 53BP1 foci returned to control levels at 48 h. In contrast in proliferating HMEC, both gamma-H2AX and 53BP1 foci decreased to control levels during the 24-48 h time interval after irradiation under 2D conditions. Foci numbers decreased faster after gamma-ray irradiation and returned to control levels by 12 h regardless of marker, cell proliferation status, and cell culture condition. CONCLUSIONS: The disappearance of radiation induced gamma-H2AX and 53BP1 foci in HMEC has different dynamics that depend on radiation quality and proliferation status. Notably, the general patterns do not depend on the cell culture condition (2D versus 3D). We speculate that the persistent gamma-H2AX foci in iron-ion irradiated non-proliferating cells could be due to limited availability of double-strand break (DSB) repair pathways in G0/G1-phase, or that repair of complex DSB requires replication or chromatin remodelling. PMID- 21271787 TI - Ankle foot orthoses for people with Charcot Marie Tooth disease--views of users and orthotists on important aspects of use. AB - PURPOSE: To explore important aspects of the benefits, important characteristics, barriers to use and disadvantages of using ankle foot orthoses (AFOs) as seen by people with Charcot Marie Tooth disease (CMT) and the orthotists who will fit and supply them. METHOD: This qualitative study used the nominal group technique and individual semi-structured interviews, according to participant preference and ability to travel. Propositions were put to 15 participants (eight females) with CMT regarding benefits, disadvantages, barriers to use and important characteristics of ankle foot orthoses AFOs and regarding benefits and disadvantages to seven orthotists. Priorities in these areas were ranked and a thematic analysis of the free text was made separately by two observers and a joint decision made of final themes. RESULTS: Fifteen people (eight females) with CMT and seven orthotists participated. Users' themes concerned functional mobility walking, pain/discomfort, choice of AFOs and associated footwear, custom made design, use in practical situations and support for foot and ankle. They noted that AFOs improved walking, but practical aspects of use and provision, as well as consideration of cosmetic aspects, were frequently problematic. Orthotists had similar themes, but with a difference in emphasis, that included prevention of future complications, education regarding device limitations and craftsmanship as a further theme. CONCLUSIONS: Users understood the potential benefits of AFOs and could identify disadvantages which might be remedied, but were frustrated by the difficulties in translating this into practice. Further refinement of current orthoses and delivery of orthotic services may assist in addressing these issues. PMID- 21271788 TI - Through-the-scope large diameter self-expanding metal stent placement as a safe and effective technique for palliation of malignant colorectal obstruction: a single center experience with a long-term follow-up. AB - OBJECTIVE: The aim of this study was to evaluate the outcomes of through-the scope (TTS) large diameter self-expanding metal stent (SEMS) placement for palliation of malignant colorectal obstruction. MATERIAL AND METHODS: Between January 2005 and December 2009, all patients who underwent endoscopic SEMS placement for palliation of malignant colorectal obstruction were prospectively enrolled. RESULTS: Thirty-nine patients (17M and 22F; mean age 75.9 +/- 10.6 years, range 50-91) were enrolled. The most frequent location was the sigmoid colon (13 cases). The causes of obstruction were colorectal malignancy in 32 patients and extracolonic malignancy in 7. Technical success was achieved in 36/39 patients (92.3%) and clinical success in 35/39 patients (89.7%). Technical failure was related to female sex (p = 0.04) and the extracolonic etiology of the stricture (p < 0.001). There were three early complications: two procedure related perforations successfully managed conservatively and one hemorrhage treated with APC. Early complications were related to the location of strictures at the recto-sigmoid junction (p < 0.001). Late complications occurred in 10 patients: 8 of these patients experienced occlusive symptoms (attributable to tumor ingrowth in 5 cases and stool impaction in 3 cases); the remaining 2 were one case of tumor ingrowth with sub-occlusive symptoms and hemorrhage, and one case of distal migration. There was no procedure-related mortality and all complications were managed without surgical intervention. SEMS patency duration was 236 +/- 128 days (range 31-497) and mean survival of the patients was 259 +/- 121 days (range, 32-511). CONCLUSIONS: In our experience, TTS large-diameter SEMS placement is a safe and effective treatment for palliation of malignant colorectal obstruction. PMID- 21271789 TI - The ALS Nutrition/NIPPV Study: design, feasibility, and initial results. AB - Our objective was to investigate the nutritional requirements in ALS and to determine the feasibility of early intervention with NIPPV. Subjects were enrolled into one of two arms. In the nutrition arm, total daily energy expenditure (TDEE) was determined longitudinally over 48 weeks using the Doubly Labeled Water method. In the NIPPV arm, NIPPV was offered at 80% vs. 50% FVC. Additional measurements were obtained in both arms to ultimately formulate equations to predict TDEE and to estimate sample size for a phase III study of early NIPPV. Eighty subjects were enrolled in the nutrition arm and 73 in the NIPPV arm. Baseline characteristics of the participants are described. TDEE was available for 80 subjects in 249 independent determinations during disease progression. Other variables were measured simultaneously for future modeling of ALS-specific equations to predict TDEE. In the NIPPV arm, rates of progression to the criteria for NIPPV intervention (80% or 50% predicted FVC) were computed. Additional factors were obtained longitudinally to develop indices of early ventilatory insufficiency. The results of this study will allow us to model equations to predict the energy requirements in ALS and to plan a study of early intervention with NIPPV. PMID- 21271790 TI - Neurophysiological index as a biomarker for ALS progression: validity of mixed effects models. AB - Our objective was to evaluate the neurophysiological index (NI) as a biomarker for amyotrophic lateral sclerosis (ALS) and to assess the validity of linear mixed effects models for describing longitudinal changes. Functional assessment and nerve conduction studies were undertaken in 58 ALS patients. Neurophysiological data were collected on four occasions over 12 weeks (baseline, weeks 4, 8 and 12). The NI was calculated for the abductor digiti minimi and ulnar nerve at the wrist. NI declined at a rate of 0.04 per week (S.E. 0.006, p < 0.0001). Patients with bulbar-onset disease had 0.88 greater NI than patients with upper limb-onset disease over the follow-up period (S.E. 0.39, p = 0.03). There were no differences in the rates of decline among patients with different disease phenotypes. Rates of change in NI and functional impairment were weakly correlated (Spearman's p = 0.29, p = 0.03). Linear mixed effects models were appropriate for detailing the longitudinal changes in NI. The present findings support incorporation of NI as an outcome measure for ALS clinical trials conducted over short time periods. PMID- 21271791 TI - Neuroanatomical correlates of apathy in ALS using 4 Tesla diffusion tensor MRI. AB - Our objective was to determine whether apathy in amyotrophic lateral sclerosis (ALS) relates to structural changes associated with the degenerative process or disease related factors such as illness duration, physical disability, or hypoxia. Using diffusion tensor imaging (DTI) with fractional anisotropy (FA), we conducted a voxel-based analysis of whole-brain changes to investigate decline in white matter integrity as it correlates with apathy in ALS. Twenty-four patients enrolled in the study were compared with 24 age- and gender-matched controls. The relationship between FA and apathy scores was tested using a general linear model accounting for age, gender and functional disability in 16 ALS patients. Results showed that, using a spatially unbiased voxel-wise approach and the statistical map-driven region of interest (ROI), a significant negative correlation existed between FA and apathy change scores in the right anterior cingulum region, whereas ALS disease severity was significantly correlated with FA alterations in bilateral motor areas. Apathy was not correlated with clinical depression, disease duration or respiratory dysfunction. In conclusion, our findings point towards a biological basis for apathy in the anterior cingulum, consistent with research on apathy in other neurological populations. PMID- 21271792 TI - Progressive and widespread brain damage in ALS: MRI voxel-based morphometry and diffusion tensor imaging study. AB - We investigated 17 patients with sporadic amyotrophic lateral sclerosis (ALS) using voxel-based morphometry (VBM) and voxel-based analysis of diffusion tensor images (DTI) at baseline and after a six-month follow-up. Compared with 17 healthy controls, ALS patients at baseline showed only minimal white matter volume decreases in the inferior frontal gyrus but marked decreases in the gray matter of several regions, especially in the bilateral paracentral lobule of the premotor cortex. DTI revealed reduced fractional anisotropy in the bilateral corticospinal tracts, insula, ventrolateral premotor cortex, and parietal cortex. Increased mean diffusivity was noted bilaterally in the motor cortex, ventrolateral premotor cortex, insula, hippocampal formation, and temporal gyrus. At the six-month follow-up, ALS patients showed widespread volume decreases in gray matter, and DTI abnormalities extended mainly into the bilateral frontal lobes, while volume changes in the white matter remained minimal but more distinct. Our combined VBM and DTI techniques revealed extra-corticospinal tract neuronal degeneration mainly in the frontotemporal lobe of ALS patients. In particular, follow-up examinations in these patients showed that whole-brain DTI changes occurred predominantly in the regions of brain atrophy. These objective analyses can be used to assess the disease condition of the ALS brain. PMID- 21271793 TI - The effect of simvastatin alone versus simvastatin plus ezetimibe on the concentration of small dense low-density lipoprotein cholesterol in subjects with primary hypercholesterolemia. AB - OBJECTIVE: To compare the effects of simvastatin alone versus simvastatin plus ezetimibe on small dense low-density lipoprotein cholesterol (sdLDL-C) concentration in subjects with primary hypercholesterolemia. RESEARCH DESIGN AND METHODS: Patients with LDL-C levels above those recommended by the National Cholesterol Education Program Adult Treatment Panel III were randomized to open label simvastatin 40 mg (n = 50) or simvastatin/ezetimibe 10/10 mg as a fixed combination (n = 50) daily. LDL particle size (estimated by electrophoresis), sdLDL-C levels, and lipid profile were blindly assessed at baseline and 3 months. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov NCT00932620. RESULTS: Both simvastatin 40 mg and simvastatin/ezetimibe 10/10 mg decreased total cholesterol (-31% and -36%, respectively), LDL-C (-43% and -49%, respectively), triglycerides (-17% and -19%, respectively), non-high-density lipoprotein cholesterol (non-HDL C; -40% and -46%, respectively), large LDL-C (-40 and -44%, respectively) and sdLDL-C levels (-42% and -46%, respectively, all p < 0.000 vs baseline) and increased LDL particle size (+0.5% and +0.7%, respectively, both p < 0.05 vs baseline). The changes in total cholesterol, LDL-C and non-HDL-C were greater in the simvastatin/ezetimibe group (all p < 0.05). Changes in triglycerides, large LDL-C, sdLDL-C levels and LDL particle size were similar in the two groups. In multivariate analysis, baseline sdLDL-C and triglyceride levels, but not the choice of treatment, were significantly and independently correlated with the changes in sdLDL-C levels. CONCLUSION: The combination of simvastatin 10 mg plus ezetimibe 10 mg is similarly effective to simvastatin 40 mg in improving sdLDL-C concentration and LDL particle size in subjects with primary hypercholesterolemia. PMID- 21271794 TI - Relationship between physician specialty and allopurinol prescribing patterns: a study of patients with gout in managed care settings. AB - OBJECTIVE: Allopurinol is used to lower serum uric acid (sUA) levels in gout patients. The objective of this study was to investigate the influence of physician specialty on allopurinol treatment patterns and sUA control. DESIGN AND METHODS: This was a retrospective study using claims from a managed care database of US health plan enrollees. Gout patients at least 18 years of age who received allopurinol were identified from the database between January 1, 2002 and April 30, 2007. The index date was defined as the date of the earliest allopurinol claim, and patients were required to have health plan enrollment for at least 365 days prior to and following the index date for inclusion. Physician specialty was determined using the index allopurinol claim. Dosage of allopurinol prescription(s) and number of gout flares were determined from claims data. sUA measurements were used to assess goal attainment over a period of at least one year following the index allopurinol prescription. RESULTS: There were 3363 patients with gout of whom 69.9% received an index allopurinol prescription from a generalist/internist, 5.7% from a rheumatologist, 2.6% from a nephrologist, and 21.8% from a physician with other specialty. Of patients receiving their index prescription from a nephrologist, 38.7% reached the sUA goal of <6 mg/dL (357 MUmol/L), as compared to patients prescribed by a rheumatologist, generalist/internist, or other physician (35.4%, 31.4%, and 39.4%, respectively; P = 0.015). When controlling for patient characteristics, multivariate analysis did not reveal statistically significant different odds of sUA goal attainment based on prescribing physician specialty, though separate analyses indicated that patients prescribed by a nephrologist had fewer gout flares. Change in allopurinol dosage from initial to final dose was more frequent among patients prescribed by rheumatologists and nephrologists. CONCLUSION: There is significant heterogeneity in the specialists' management of sUA levels in patients with gout, possibly reflecting differences in case mix and treatment approaches. Limitations related to the use of claims data, such as inability to observe medications filled over-the-counter, should be considered when interpreting study results. PMID- 21271795 TI - Focus on agomelatine. AB - BACKGROUND: Agomelatine is a novel antidepressant with agonist activity at melatonin receptors (MT(1) and MT(2)), and antagonistic effects at the 5HT(2c) serotonin receptor. SCOPE: This is a review of current evidence for clinical efficacy and safety, drawn from a literature review using Medline and PsycInfo in 2010 using search terms including agomelatine, melatonergic antidepressant and Valdoxan. FINDINGS: Agomelatine has antidepressant properties and from early on in its prescription agomelatine can improve sleep architecture and efficiency. Licensed for the treatment of depression in adults, other potential indications include seasonal affective disorder and anxiety disorders. Early controlled short term studies of agomelatine as an antidepressant indicate good efficacy and tolerability. There are fewer side effects on sexual health than with SSRI antidepressants. No withdrawal or discontinuation syndrome has yet been observed. Agomelatine is contraindicated in patients with impaired liver function and repeated liver function tests are suggested during prescription. CONCLUSION: Agomelatine is a useful and novel addition to the range of avialble antidepressants. Longer term post-marketing studies as to the effects of chronic exposure are required. PMID- 21271796 TI - Review of treatment response in rheumatoid arthritis: assessment of heterogeneity. AB - OBJECTIVE: Rheumatoid arthritis (RA) is a chronic, systemic, progressive, inflammatory disorder. The primary goals of treatment in RA are to reduce the signs and symptoms of disease, prevent progression of joint damage and improve patients' physical function. Patients with different sociodemographic characteristics, varying degrees of severity of illness, and comorbidities tend to exhibit differential response to treatment. The purpose of this review was to identify a broad set of factors that are associated with and/or predictive of RA treatment response and determine those that warrant further research. RESEARCH DESIGN AND METHODS: A comprehensive review of the literature from the last 10 years was performed using three key databases (PubMed, EMBASE, and Cochrane). All relevant articles that met the inclusion/exclusion criteria were selected and scored for their levels of evidence using the National Institute of Clinical Excellence (NICE) scoring method. Data on study design, interventions and treatment outcomes were abstracted using a structured abstraction table. RESULTS: A total of 30 articles were included in the review and data abstraction. Besides gender, baseline clinical variables such as C-reactive protein level, erythrocyte sedimentation rate, measures of disease activity, and Health Assessment Questionnaire scores (based on five patient-centered dimensions) were consistently associated with treatment response over time. CONCLUSIONS: This comprehensive literature review identified several factors associated with treatment response which might be valuable to include as relevant measures in future studies of RA treatment. Inclusion of these factors, particularly those in the clinical and sociodemographic domains, in the design of future trials will further the understanding that ultimately may help clinicians deliver targeted treatment to community practice RA patients, thus resulting in improved patient outcomes. PMID- 21271797 TI - Dorsal midbrain syndrome with loss of motor fusion: a rare association. AB - INTRODUCTION: Dorsal midbrain syndrome (DMS) is characterized by upgaze paralysis, convergence-retraction nystagmus, and eyelid retraction. Impaired downgaze and pupillary light-near dissociation may co-exist, while less common features including exotropia and convergence paralysis have also been described. However, loss of motor fusion is not a well recognised finding in DMS. PURPOSE: To describe DMS associated with loss of motor fusion. METHODS: Retrospective case series. RESULTS: Five patients (age 21-80 years) presented with features of DMS due to severe head injury (n=1), brainstem stroke (n=3) and pinealoma (n=1). All five complained of constant diplopia with horizontal and vertical separation and had an exotropia (range 20Delta to 70Delta), absent convergence and motor fusion. Two underwent strabismus surgery and subsequently had a variable improvement in their motor fusion. The remaining three patients were managed with occlusion. CONCLUSION: This case series illustrates the complexity of ocular motility findings associated with DMS and highlights the potential difficulties in the management of patients with loss of motor fusion. PMID- 21271798 TI - Quenching the quorum sensing system: potential antibacterial drug targets. AB - Emergence of antibiotic and multi-drug resistant pathogenic bacteria has created the need for new drugs and drug targets. During pathogenesis bacteria release signals which regulate virulence and pathogenicity related genes. Such bacteria co-ordinate their virulent behaviour in a cell density dependent phenomenon termed as quorum sensing (QS). In contrast, microbes interfere with QS system by quenching the signals, termed quorum quenching (QQ). As a consequence of disrupted QS, pathogens become susceptible to antibiotics and drugs. In this article, the biodiversity of organisms with potential to quench QS signals and the use of QQ molecules as antibacterial drugs have been reviewed. PMID- 21271799 TI - Otitis media with effusion and hearing loss in Chinese children with cleft lip and palate. AB - OBJECTIVE: To determine the incidence of otitis media with effusion and the associated hearing loss, the rate of ventilation tube insertion, and complications of ventilation tube insertion in Chinese cleft palate patients. DESIGN: Retrospective review in a tertiary care hospital in Hong Kong. PATIENTS: A total of 104 consecutive patients with cleft lip and/or cleft palate who were born between January 1996 and January 2006. RESULTS: The incidence of otitis media with effusion in Chinese cleft palate patients for the first 2 years after birth was 76.1%. Of these patients, 16.9% had otitis media with effusion associated with a moderate hearing loss (>40 decibels hearing level [dBHL]). Approximately half (53.2%) of our patients had ventilation tube insertion. Complications including retraction, tympanosclerosis, and perforation of the tympanic membrane were found in 15.7% of all ears with otitis media with effusion and ventilation tube insertion. CONCLUSIONS: The high incidence of otitis media with effusion in cleft palate infants found in this study is consistent with that reported in the Western literature. A small but significant proportion of otitis media with effusion was associated with moderate hearing loss that truly required surgical treatment. Cleft palate children are much more likely to develop otitis media with effusion than normal children, and they develop the condition at an earlier age. A protocol for the treatment of otitis media with effusion in cleft palate patients and further prospective studies are warranted. PMID- 21271800 TI - Dental arch relationship outcomes in children with complete unilateral cleft lip and palate treated at Princess Margaret Hospital for Children, Perth, Western Australia. AB - OBJECTIVES: To (1) audit dental arch relationships of all children born between 1982 and 1999 with complete unilateral cleft lip and palate (UCLP) treated at the Cleft Lip and Palate Unit, Princess Margaret Hospital for Children (PMH), Perth, Western Australia, (2) assess the distribution of GOSLON ratings from dental casts taken at 9 years, (3) compare the 9-year GOSLON ratings for "High" and "Low" caseload surgeons, and (4) compare the 9-year PMH GOSLON ratings with published ratings from other units. DESIGN: Retrospective audit of dental casts and medical charts. PATIENTS: Dental casts were retrieved for 71 children (47 boys and 24 girls) at 9 years of age. MAIN OUTCOME MEASURES: GOSLON ratings. RESULTS: Sixty-eight percent of patients had an excellent to satisfactory dental arch relationship (GOSLON Yardstick ratings 1 to 3) at 9 years with a mean rating of 2.85. High caseload surgeons achieved statistically better mean GOSLON ratings than low caseload surgeons (2.72 and 3.33, respectively). CONCLUSIONS: PMH Cleft Unit's dental arch relationship outcomes are comparable to published series of units using similar treatment protocols. High caseload surgeons achieved better dental arch relationships than low caseload surgeons. PMID- 21271801 TI - Endovascular treatment of the nutcracker syndrome: report of two cases. AB - The nutcracker syndrome (NS) is a rare condition characterized by the entrapment of the left renal vein (LRV) between the superior mesenteric artery (SMA) and the aorta. Clinically, it presents with flank pain, hematuria, and symptoms of pelvic venous congestion. Several surgical techniques have been described including left renal vein (LRV) transposition, autotransplantation, LRV bypass, superior mesenteric artery (SMA) transposition, gonadocaval bypass and nephrectomy. More recently, endovascular stenting of the renal vein has been proposed. We present two patients with NS who were successfully managed endovascularly, providing satisfactory mid-term clinical and imaging results. PMID- 21271802 TI - Cross-cultural adaptation and validation of the Chinese abbreviated profile of hearing aid benefit. AB - OBJECTIVE: The objective of the study was to investigate the cross-cultural validity and reliability of the Chinese version of the Abbreviated Profile of the Hearing Aid Benefit questionnaire (APHAB-CH). DESIGN: A convenience sampling method was used to identify and recruit subjects. The subjects completed a history form seeking demographic data, the APHAB-CH, and a questionnaire seeking a subjective rating of hearing aid performance and overall satisfaction with their hearing aid. STUDY SAMPLE: The subjects were 134 experienced hearing aid users. RESULTS: The APHAB-CH had a good internal consistency reliability estimate (alpha = 0.85) comparable to that of the original version. Significant correlation was observed between the APHAB-CH scores and other subjective ratings for hearing aid performance and the overall satisfaction measure. A high test retest reliability (intraclass correlation coefficient = 0.84) was observed. Confirmatory factor analysis revealed that the APHAB-CH had a two-factor structure comprising "hearing disability" and "averviseness." Normative data in terms of equal-percentile profiles were dervied for the APHAB-CH. CONCLUSION: The results suggest that the APHAB-CH is a reliable and valid measure of the outcomes of hearing aid fitting. PMID- 21271803 TI - Clinical evaluation of a new hearing aid anti-cardioid directivity pattern. AB - OBJECTIVE: The purpose of this research was to evaluate a new directional hearing aid algorithm which automatically adapts to an anti-cardioid pattern in background noise when a speech signal originates from behind the hearing aid user. DESIGN: Using the hearing-in-noise-test (HINT) in the soundfield, with the sentences delivered adaptively from the back (180 degrees ) and the standard HINT competing noise from the front (0 degrees ; 72 dB SPL), the participants were tested for three different hearing aid conditions: omnidirectional, conventional adaptive directional, and adaptive directional with the anti-cardioid algorithm enabled. STUDY SAMPLE: Adults (n = 21) with bilaterally symmetrical downward sloping sensorineural hearing loss; experienced hearing aid users and aided bilaterally for experimental testing. RESULTS: Results revealed a significant effect for the hearing aid microphone setting (p < .0001), with a HINT mean RTS of 4.2 dB for conventional adaptive directional, -0.1 dB for omnidirectional, and -5.7 dB when the anti-cardioid algorithm was active. This was a large effect size (Cohen's f2). CONCLUSION: The findings suggest that the signal classification system steered the algorithm correctly, and that when implemented, the anti cardioid polar pattern resulted in an improvement in speech recognition in background noise for this listening situation. PMID- 21271804 TI - Long-term, progressive, aerobic training increases adiponectin in middle-aged, overweight, untrained males and females. AB - Adipose tissue secretes the adipokine, adiponectin (ADPN), which increases insulin sensitivity. Because some of the metabolic effects of exercise and ADPN are similar, exercise has been proposed to increase ADPN. However, most short term (<=3 mos) and constant-effort exercise protocols have not produced increases in ADPN. Furthermore, no direct comparisons of male and female subjects on the effect of exercise on ADPN levels have been reported. We hypothesized that long term (6 mos), progressive training would increase ADPN levels in both males and females. We recruited middle-aged, untrained males and females to participate in an interventional study employing a marathon training regimen progressing from 9.7 to 88.5 km (6 to 55 miles) per week over 6 mos. At baseline, we matched the mean ages of the male and female groups. We collected and stored fasting plasma samples and recorded body measurements at 0 (baseline) and 6 mos. Stored samples were analysed for insulin, glucose, and ADPN. ADPN increased significantly among both males (from 5.89 +/- 2.46 (mean +/- SD) to 7.65 +/- 3.18 MUg/ml; p < 0.05) and females (from 8.48 +/- 3.22 to 10.56 +/- 4.05 MUg/ml; p < 0.05). The extent of the increase in ADPN was similar in the male (40.7 +/- 50%; median, 12.1%) and female (27.0 +/- 31.1%; median, 22.3%) groups. However, there was no significant reduction in insulin resistance as measured by the HOMA-IR scores in either group. We conclude that long-term, progressive aerobic training increases circulating ADPN levels in middle-aged, untrained males and females. PMID- 21271806 TI - Effect of pregnancy on topiramate pharmacokinetics in rabbits. AB - Pregnancy is associated with various physiological changes that may lead to significant alterations in the pharmacokinetic profiles of many drugs. The present study was designed to investigate the potential effects of pregnancy on the pharmacokinetics of topiramate (TPM) in the rabbit model. Nineteen female New Zealand white rabbits (nine pregnant and 10 non-pregnant) were used in this study. Blood samples were collected from the animals just before receiving TPM orally at a dose of 20 mg/kg and then serially for up to 24 h. TPM plasma samples were analysed using a validated tandem mass spectrometric (LC-MS/MS) method. The mean values of TPM pharmacokinetic parameters (t(1/2), T(max), AUC(0-infinity), and CL/F) were significantly modified in pregnant rabbits as compared with non pregnant group. Pregnancy significantly (P < 0.05) increased TPM half-life (t(1/2)), time to attain the maximum plasma concentration (T(max)), and the area under TPM plasma concentration-time curve (AUC(0-infinity)) and decreased the drug's oral clearance (CL/F) compared with non-pregnancy state in rabbits. The present study demonstrates that pregnancy alters the pharmacokinetics of TPM in rabbits in late gestational period and considerable inter-animal variability was observed. The findings of the present study indicate that TPM CL/F is decreased during late pregnancy in the rabbit model. PMID- 21271813 TI - The relationship between resting blood pressure, body mass index and lean body mass index in British children. AB - BACKGROUND: Elevated blood pressure (BP) in childhood is associated with overweight and obesity. However, lean body mass index (LBMI, cm(2)/kg) has been suggested as a better means than body mass index (BMI, kg/m(2)) by which to consider the relations between weight status and health indices in children. OBJECTIVE: To assess the relationship between resting BP and weight status in youth whilst considering BMI and LBMI when examining this issue. METHODS AND PROCEDURES: Height, body mass and resting blood pressure were assessed in 384 boys and 277 girls, aged 11-14 years from Central England. RESULTS: SBP was significantly lower in 'normal weight' children compared to overweight and obese children and in overweight compared to obese children (both p = 0.0001). DBP was significantly lower in 'normal weight' children compared to those classified as overweight (p = 0.006). BMI and LBMI were both significant predictors of SBP and DBP (p = 0.0001). However, LBMI was normally distributed, unlike BMI, and was a better predictor of BP than BMI. CONCLUSIONS: Overweight and obesity is associated with higher resting BP in British children. However, when examining the effect of weight status on BP, the researcher should consider use of LBMI over BMI. PMID- 21271814 TI - Body fat assessment in Sri Lankan adolescent girls; development of a simple field tool. AB - BACKGROUND: Development of accurate, simple measures of body fat is essential in developing countries due to the rising prevalence of overweight and obesity. Application of skin-fold thickness (SFT) to body fat prediction equations is an inexpensive method suitable for field settings. AIM: To determine percentage fat mass (%FM) of Sri Lankan adolescent girls using Fourier Transform Infrared spectrometry (FTIR) as a reference method and develop a SFT-prediction equation to estimate %FM. METHODS: Weight, height and SFT were measured and %FM determined by FTIR in 131 adolescent, post-menarcheal girls (15-19 years). SFT-measurements were applied to available body composition equations for validation in the population. A new equation for %FM was derived and validated. RESULTS: Mean %FM (FTIR) was 19.13 +/- 8.2.Selected body composition prediction equations over estimated %FM. The multiple regression procedure yielded a final equation consisting of two anthropometric and one demographic variable, % FM = 9.701 - (0.460)* age+(0.640)*TricepsSFT+(0.583)*Supra-iliacSFT. CONCLUSIONS: Existing SFT prediction-equations are unsuitable for predicting %FM in this population. The new equation utilizing one peripheral and one truncal skin-fold, is appropriate for prediction of %FM in this population and may be applicable to other South Asian/Asian-Indian adolescents following validation. PMID- 21271815 TI - Individual assessment of inherent arterial stiffness using nomogram and pulse wave velocity index: the Ohasama study. AB - We measured the brachial-ankle pulse wave velocity (baPWV) in 491 normotensives and determined the "PWV index" (measured baPWV-theoretical baPWV) in 491 normotensives and 83 controlled hypertensives. Linear regression analysis revealed that the theoretical baPWV (cm/sec) was 0.21 * age(2) (years(2))-13.73 * age (years) + 0.05 * mean arterial pressure(2) (mmHg(2)) + 3.95 * heart rate (bpm) + 36.49 * gender (1 male; 0 female) + 733 (R(2) = 0.53). The calculated PWV index was significantly higher in 13 smokers than 70 nonsmokers among controlled hypertensives. The calculated PWV index might provide more precise information about inherent arterial stiffness. PMID- 21271816 TI - Seasonal variation in home blood pressure measurements and relation to outside temperature in Japan. AB - Previous studies have suggested that outside temperature affects blood pressure (BP) levels. However, recently, due to a spreading heating system, the seasonal variation in BP levels might be smaller, especially in colder seasons when more heat is used. We used continuous measurements of home BP data to track seasonal variations of BP to analyze the relation between outside temperature and BP values. Among 213 volunteers who were asked to measure BP in September 2000, 79 participants (mean age 72.7 years, 60.0% women) measured BP at least once per month until August 2003 (36 months). The mean number of measurements was 19.0 times/month. Information on outside temperature was provided by the Japan Meteorological Agency. We used general linear models to analyze the relation between outside temperature and BP values. Blood pressure levels were lowest in the warmest months. However, the highest BP levels were not observed in the coldest month, but rather in March. A clear inverse association between temperature and BP values was evident only in periods when outside temperatures were above 10 degrees C. When the outside temperature was >= 10 degrees C, 1 degrees C increment of outside temperature correspond to 0.40 and 0.28 mmHg decrease of systolic blood pressure (SBP) and diastolic blood pressure (DBP), whereas the corresponding values were 0.06 and 0.01 mmHg when the outside temperature was <10 degrees C. In conclusion, inverse association between outside temperature and BP was observed only in warmer seasons. PMID- 21271817 TI - Associations between asymmetry and human attractiveness: Possible direct effects of asymmetry and signatures of publication bias. AB - BACKGROUND: Fluctuating asymmetry (FA), reflecting developmental instability (DI), may honestly signal individual quality and relate to human attractiveness and measures of sexual behaviour. The evolutionary importance of these associations, however, critically depends on the role of DI in driving these correlations. A direct effect of FA reduces the role of DI. AIM: To explore the direct effects of FA in determining human attractiveness, comparing the strength of associations whether the asymmetries could be observed during the attractiveness ratings or not. SUBJECTS AND METHODS: Literature search and meta analysis. RESULTS: This study found indications for such a direct role through stronger associations between FA and physical attractiveness when asymmetries are visible. Furthermore, a substantial publication bias emerged and correcting for it resulted in a reduction of 30-50% in effect sizes. When considering the few relatively large with sample size over 100 only, effect sizes were nearly zero. CONCLUSION: The current literature likely overstates the evolutionary importance of asymmetry in determining human (physical) attractiveness. This study discusses the possible consequences for presumed associations between DI and human sexual behaviour and fitness. PMID- 21271819 TI - Androgens alter brain catecholamine content and blood pressure in the testicular feminized male rat. AB - Androgens interact with catecholamines in the central nervous system (CNS) to regulate many physiological processes including blood pressure (BP). To test the hypothesis that testosterone (T) and 5a-dihydrotestosterone (DHT) modulate CNS catecholamines and BP through androgen receptor (AR)-dependent and independent mechanisms, we used the testicular feminized male (Tfm) rat. Females that carry the AR mutation (Tfm mutation) on the X chromosome were bred with spontaneously hypertensive rat (SHR) males. The normal AR male and Tfm offspring were divided into groups: control, castrated, castrated, and T or (DHT) replacement. In both AR normal and Tfm males, BP was reduced by castration, but T restored BP in both groups. In the amygdale, castration decreased dopamine (DA) in both strains and both T and DHT restored it. In the bed nucleus of the stria terminalis castration increased DA which was further increased by DHT and reduced to normal by T in both strains. In the frontal cortex, castration reduced DA content in both strains but only T restored it to normal in SHR but not in Tfm. Brain norepinephrine (NE) content showed a significant strain effect for the preoptic area (POA), but no treatment effect. Although castration did not change NE in the amygdala or POA in either strain, both T and DHT increased NE in the Tfm castrates. Blood pressure was influenced by T manipulation and correlated most significantly with DA content in the amygdala, frontal cortex, and stria terminalis. These data demonstrate an action of androgen on brain catecholamines and BP, which is independent of the classic androgen receptor. PMID- 21271820 TI - Introduction: knowledge is survival-the mission of the immune system and its stochastic simulations. AB - In this introduction the timeliness and interest of dedicating an issue of Autoimmunity to mostly "discrete" models is motivated by highlighting number of circumstances, observations encounters, that all have favored the rise of a family of agent based simulations of the Immune System. Franco Celada was among the first experimentalists to accept the challenge of interdisciplinarity and create a computational Immune System. He thinks that discrete models are especially useful in handling hypotheses: initiating them, representing their consequences, and revealing their plusses and minuses. He is sure that "looking at" the immune machinery as a cognitive system is useful both to the intuitive understanding and the creative development of models. PMID- 21271821 TI - Computer simulations of heterologous immunity: highlights of an interdisciplinary cooperation. AB - The relationship between biological research and mathematical modeling is complex, critical, and vital. In this review, we summarize the results of the collaboration between two laboratories, exploring the interaction between mathematical modeling and wet-lab immunology. During this collaboration several aspects of the immune defence against viral infections were investigated, focusing primarily on the subject of heterologous immunity. In this manuscript, we emphasize the topics where computational simulations were applied in conjunction with experiments, such as immune attrition, the growing and shrinking of cross-reactive T cell repertoires following repeated infections, the short and long-term effects of cross-reactive immunological memory, and the factors influencing the appearance of new clonal specificities. For each topic, we describe how the mathematical model used was adapted to answer specific biological questions, and we discuss the hypotheses that were generated by simulations. Finally, we propose rules for testing hypotheses that emerge from model experimentation in the wet lab, and vice-versa. PMID- 21271822 TI - Scientific English: ruminations on Dr. Johnson and Noah Webster. PMID- 21271823 TI - Developing an online psychoeducation package for bipolar disorder. AB - BACKGROUND: Medications are known to be effective for bipolar disorder but treatment non-adherence and psychosocial effects can impact adversely on long term outcome. Psychoeducation may help address some of these issues. AIMS: This article describes the development of a novel online psychoeducation programme ( www.BeatingBipolar.org ) for patients with bipolar disorder. METHOD: The programme was developed in three stages--a literature review, development of a draft outline of the programme and focus groups with mental health professionals and service users. RESULTS: Data highlighted the importance of presenting a supportive style of programme, realistic stories and positive role models within the programme and providing a variety of information delivery styles. Desired outcomes of the programme were an increased sense of control over bipolar disorder, reduced stigma and improved understanding for family and carers. CONCLUSION: The iterative development process using focus groups with service users and mental health professionals provided important insights into users' needs and preferences as well as identifying valued outcomes. Interactive online psychoeducation materials benefit from a systematic design process which is informed by a range of viewpoints. PMID- 21271824 TI - Assessing the relationship between therapeutic goal attainment and psychosocial characteristics for adolescents in crisis residence. AB - BACKGROUND: Adolescents in need of hospitalization often present with chronic and severe forms of psychopathology, placing the adolescent or someone else in danger. Extant research is limited related to the relationship of client symptoms and diagnoses to therapeutic goal attainment. AIMS: The purpose of this study was to evaluate the relationship between therapeutic goal attainment to symptomatology for adolescents in acute care psychiatric hospitalization. METHOD: Four canonical correlations were conducted utilizing the set of subscales for the Goal Attainment Scale of Stabilization (GASS) with each set of subscales for the (a) Suicide Probability Scale (SPS), (b) Target Symptom Rating (TSR), (c) Minnesota Multiphasic Personality Inventory-Adolescent (MMPI-A), and (d) Millon Adolescent Clinical Inventory (MACI). RESULTS: A statistically significant relationship was found between GASS subscales and the TSR subscales. The first canonical root was significant, lambda = 0.89, F(4, 232) = 3.55, p = 0.008, accounting for 11% (r(c) = 0.33) of the overlapping variance. CONCLUSIONS: Psychiatric symptoms appear to contribute to therapeutic goal attainment. For counselors working with adolescents in crisis residence, familiarity with client issues that promote or inhibit therapeutic progress may be helpful. PMID- 21271825 TI - Weak sense of coherence predicts depression: 1-year and 9-year follow-ups of the Finnish Outcomes of Depression International Network (ODIN) sample. AB - BACKGROUND: Previous studies show conflicting results on the role of weak sense of coherence (SOC) as a risk factor for depression. AIMS: The aim of this work was to study whether a weak SOC predicts depressive symptoms in a non-depressive population sample in the short or long perspective. METHOD: Participants without depressive symptoms (n = 1645) in the Finnish sample of the Outcomes of Depression International Network (ODIN) study were assessed at 1-year and 9-year follow-up. Depressive symptoms were assessed by the Beck Depression Inventory (BDI), and SOC by the 13-item Orientation to Life Questionnaire (SOC-13). Logistic regression analysis was used to test the association between baseline SOC and depressive symptoms measured at the follow-ups. RESULTS: In univariate analysis, there was a significant inverse association between baseline SOC and depressive symptoms at 1 year (p = 0.000) and at 9 years (p = 0.000). In multivariate analysis, weak SOC continued to predict depressive symptoms at 1 year (p = 0.022) and 9 years (p = 0.015). CONCLUSIONS: Weak SOC predicted depressive symptoms in the short and long perspective. It seems likely that a strong SOC represents a protective function, not only absence of current depression. PMID- 21271826 TI - An evaluation of the implementation of the FACE Health and Social Assessment in routine psychiatric practice. AB - BACKGROUND: Systematic assessment of patients is seen as an important aspect of mental health care. As yet few UK services have successfully implemented outcome measures. AIMS: To examine the feasibility of using FACE Health and Social Assessment in everyday practice and explore issues raised for staff. METHOD: This comprised a feasibility questionnaire completed by 52 staff, 3 focus groups involving 18 staff and an analysis of patient scores on routinely collected FACE data. RESULT: The questionnaire findings were positive yet only just over half of the patients on Assertive Outreach (AO) teams had some part of FACE completed in the previous year. The focus groups drew attention to many other calls on staff time and the importance of ongoing support. Staff were uncertain about the benefits of FACE for measuring change but believed that it promoted reflective practice. FACE subscores showed some ability to discriminate between patients on Rehabilitation and Recovery and AO teams but there were no significant differences for AO patients over time. CONCLUSIONS: Although competing demands and low priority may underpin the failure to implement FACE it is perhaps clinical staffs lack of conviction in its contribution to improving mental health care that is the fundamental issue. PMID- 21271827 TI - Using electronic patient records to assess the impact of swine flu (influenza H1N1) on mental health patients. AB - BACKGROUND: Electronic patient records are increasingly used in primary care research, but rarely in psychiatric research. Little is known about how people with pre-existing mental illness respond to public health threats. AIMS: To outline the swine flu related concerns and behaviours of mental health patients and to determine whether marked concern was associated with any specific demographic or diagnostic groups. METHODS: We searched a database containing electronic patient records from a large mental health trust for references to swine flu made between 15 April and 15 July 2009. Thematic analysis was used to code swine flu related concerns and behaviours. A case-control approach sought to determine whether there were demographic or diagnostic associations with expressing moderate/severe concern about swine flu. RESULTS: A range of swine flu related behaviours were noted and considerable impact was recorded for some patients. Children and patients with neurotic and somatoform disorders were over represented amongst those expressing moderate/severe swine flu concerns. CONCLUSION: Research databases using electronic clinical records are a useful way to track responses to emerging public health threats. Children receiving mental health care and patients with neurotic and somatoform disorders may be particularly psychologically vulnerable to infectious disease epidemics. PMID- 21271828 TI - Carers' experiences of assertive outreach services: an exploratory study. AB - BACKGROUND: Recent government policy has highlighted the needs of family and friends who provide support to mental health service users. Carers of assertive outreach (AO) service users may be particularly in need of support. However, little is known about their experiences and how services can support them. AIM: To explore the experiences of carers of individuals receiving an AO service. METHOD: Ten participants were interviewed using a semi-structured interview schedule. Interviews were transcribed and analysed using interpretative phenomenological analysis. RESULTS: Participants were positive about the service they and their relatives received from AO teams. They described the service as flexible and responsive to their needs and they had developed close collaborative relationships with AO workers. AO workers were considered by carers to be an extension of their family system. AO interventions helped their relatives to regain independence and enabled participants to feel less burdened by their caring role, thereby improving the carer's quality of life. CONCLUSIONS: The unique way in which AO teams engage and work alongside service users and their families is greatly valued by carers. PMID- 21271829 TI - Campaign appears to influence subjective experience of stigma. AB - BACKGROUND AND AIM: An English mental health trust implemented a strategy to dispel the stigma surrounding mental illness and service users. The purpose of this study was to evaluate its impact. METHOD: A questionnaire was mailed to 600 service users, selected at random, to evaluate the campaign's impact. Factor analysis of 243 responses yielded three factors which could be interpreted in relation to service users' perceptions of: public attitudes towards mental illness, service users' relationships with staff and other inter-personal relationships. RESULTS: Significant improvement was found in service users' perceptions of public attitudes towards mental illness. This can cautiously be related to the main thrust of the campaign. No change was found in the other two factors, which supports the inference that the campaign specifically influenced users' experience of public portrayals of mental illness. CONCLUSIONS: This study indicates that certain aspects of stigma may be amenable to change through a targeted campaign. While users' experience of public attitudes may be improved, at least in the short-term, other aspects of stigma did not appear to be amenable to change through community-level interventions. Different dimensions of stigma seem to demand different approaches. The intra-psychic roots of stigma may be the hardest elements to change. PMID- 21271838 TI - Strabismus surgery in the over 60s--an update. AB - BACKGROUND: The proportion of individuals above retirement age is expanding and consequently there is increased demand for ophthalmic surgery, including strabismus. In 2001 we published a pilot study reviewing all strabismus operations performed on patients aged 60 and over between 1992 and 1999. Almost a decade later, we repeated the analysis, aiming to identify any longitudinal trends. METHODS: Using the hospital information system, we conducted a retrospective review of all elective strabismus surgery in patients aged 60 years and over, performed by one surgeon (JPL) between January 2000 and September 2008. All operations were under general anesthesia. RESULTS: We identified 237 strabismus operations (9.1% of total operations) that were performed in patients aged 60 or over. This is significantly higher compared with the proportion of elderly patients in the previous study (111 patients, 7% of total operations, P=0.015). Gender distribution was similar to our previous study (105 females, 51% vs 59 females, 53.1%, P=0.814). Ages ranged from 60 to 96 years (mean 69.5 +/- 6.8). A decade ago, the more common diagnoses were fourth (22%) and sixth (10%) cranial nerve palsies, consecutive (14%) and secondary (9%) strabismus, whereas recently thyroid eye disease (18%), sixth nerve palsy (13%) and iatrogenic (11%) causes have overtaken the other categories (P=0.011). Adjustable sutures were undertaken in 144 patients (61%). CONCLUSION: Strabismus in elderly patients continues to be related to neurogenic etiologies but thyroid eye disease and iatrogenic causes are on the increase. This is the first 10-year longitudinal analysis to be presented, with the caveat that our data are obtained from a single practice. PMID- 21271839 TI - Functional properties of acetylated and succinylated cowpea protein concentrate and effect of enzymatic hydrolysis on solubility. AB - The present study was undertaken to improve functional properties of cowpea protein concentrate by acylation and partial hydrolysis with pepsin. The acylated concentrate showed significant improvement in protein solubility and water solubility index, at neutral pH. In addition, acylation increased fat absorption capacity compared with the untreated concentrate, and the maximum was obtained at 0.75 g succinic anhydride/g concentrate. Acetylation at concentrations of 0.25 0.50 g/g led to the higher emulsifying activity, and a markedly improvement in emulsifying stability was observed at 1.0 g anhydride/g concentrate. Foaming activity increased following acylation, particularly at 0.25 and 1.00 g/g succinic anhydride/g concentrate, while foam stability decreased. At pH 3.5, protein solubility of the acylated concentrates was low ( < 8%). Partial hydrolysis of cowpea protein concentrate with pepsin increased protein solubility at the isoelectric and neutral pH. PMID- 21271841 TI - Use of canonical variate analysis biplot in examination of choline content data of some foods. AB - Adequate intake (AI) of choline as part of the daily diet can help prevent major diseases. Low choline intake is a major risk factor for liver and several neurological disorders. Extreme choline consumption may cause diseases such as hypotension, sweating, diarrhea, and fishy body odor. The AI of choline is 425 mg/day for adult women; higher for pregnant and lactating women. The AI for adult men is 550 mg/day. The total choline content of foods is calculated as the sum of free choline, glycerophosphocholine, phosphocholine, phosphatidylcholine and sphingomyelin. These are called the choline variables. Observed values of choline variables may be different in amounts of nutrients. So different food groups in terms of choline variables are useful to compare. The present paper shows the advantages of using canonical variate analysis biplot to optimally separate groups and explore the differentiality of choline variables amounts in foods. PMID- 21271845 TI - Ovarian development of female-female pairs in the termite, Reticulitermes speratus. AB - In the rhinotermitid termite Reticulitermes speratus (Kolbe) (Isoptera: Rhinotermitidae), facultative parthenogenesis is known to occur occasionally and females cooperate with other females to found the colony. To elucidate the ovarian development in these two females, incipient female-female colonies were established under laboratory conditions, and the process of colony development was observed at 0.5, 1.5, 2.5, 3.5, and 7.5 months (stages I-V, respectively) after colony foundation. Ovarian development, vitellogenin gene expression, and juvenile hormone (JH) titers were examined. A precise reproductive cycle in both females was observed, in which the oviposition rate was relatively higher during stages I and II, decreased during stages III and IV, and then increased again at stage V. JH III titer and vitellogenin gene expression changed in parallel throughout the reproductive cycle of these queens. Ovarian maturation and vitellogenesis were similar in both females in a female-female colony at all stages examined, suggesting that no conflicts existed for two females in terms of oviposition. PMID- 21271846 TI - Threat to cedar, Cedrela odorata, plantations in Vietnam by the weevil, Aclees sp. AB - The recent decline and death of young cedar, Cedrela odorata L. (Sapindales: Meliaceae), plantations in Vietnam is caused by Aclees sp. (Coleoptera: Curculionidae), a wood-boring brown weevil. A field study was undertaken in three year-old plantations in two districts in Thanh Hoa province in August 2008. Trees were heavily impacted by the weevil, Aclees; the infestation level (P) ranged from 80 to 100% and the average damage index (R) ranged from 1.8 to 2.8. Observations over one year enabled the life history to be determined. Eggs were laid (February to March, September to November) inside the bark from the base of the trunk up to 60 cm in height. Larvae formed extensive feeding tunnels in the inner bark and sap wood. Pupation occurred in feeding tunnels or pupal chambers in the sapwood. Adults emerged twice a year, February to March and August to October. It is concluded that Aclees is a threat to C. odorata plantations in tropical regions of the world, and quarantine measures should be implemented to reduce the risk of spread. PMID- 21271847 TI - Nest architecture, colony productivity, and duration of immature stages in a social wasp, Mischocyttarus consimilis. AB - Tis study examined the nest architecture, colony productivity, and duration of the immature stages of the social wasp Mischocyttarus consimilis Zikan (Hymenoptera: Vespidae). The study was carried out under field conditions. Nests of M. consimilis consist of a single uncovered comb, which is attached to the substratum by a single petiole. The data for the nest architecture showed a positive and significant correlation between the size of the comb and the diameter of the petiole, and also between the height and diameter of the cells. The nests were constructed on horizontal, vertical, and sloping substrata with no apparent preference for a specific orientation. The colonies produced 72.9 cells and 40.7 adults on average. The mean frequency of productive cells was 33.3%, and 19.4% of the cells were reused. The mean duration of the immature stages combined was 69.7 days and the egg, larval, and pupal stages had mean durations of 14.9, 36.0, and 18.8 days, respectively. The duration of each immature stage was significantly shorter in the warm-humid season, and the larval and pupal stages were shorter during the colony pre-emergence stage. PMID- 21271848 TI - DNA barcoding of morid cods reveals deep divergence in the antitropical Halargyreus johnsoni but little distinction between Antimora rostrata and Antimora microlepis. AB - BACKGROUND AND AIMS: DNA barcoding strongly suggests that specimens of the slender codling (Halargyreus johnsonii) from New Zealand and Tasmania belong to a different species to H. johnsonii reported from other areas. RESULTS: Sequence divergence between the two groups averaged 3.95%, much higher than within-group divergences of 0.03 and 0.02% for specimens, respectively, from New Zealand Tasmania and from the North Pacific, Atlantic Ocean, and Southern Ocean. CONCLUSION: Meristic data for specimens from New Zealand and from the Southern Ocean north of the Ross Sea support the conclusion of two species. DNA barcodes for two sister taxa, Antimora rostrata and Antimora microlepis, show low intra species (0.3-0.06%) and inter-species (0.23%) divergence. PMID- 21271849 TI - DNA barcodes discriminate freshwater fishes from the Paraiba do Sul River Basin, Sao Paulo, Brazil. AB - BACKGROUND AND AIMS: Considering the promising use of DNA barcoding for species identification, the importance of the freshwater fish fauna of the Paraiba do Sul River Basin, and its advanced stage of degradation, the present study evaluated the effectiveness of DNA barcoding to identify the fish species in this basin. MATERIALS AND METHODS: A total of 295 specimens representing 58 species belonging to 40 genera, 17 families, and 5 orders were sequenced. RESULTS: The DNA barcodes discriminated all species analyzed without ambiguity. The results showed a pronounced difference between conspecific and congeneric pair-wise sequence comparisons, demonstrating the existence of a "barcode gap" for the species analyzed. The nearest-neighbor distance analysis showed only three cases with Kimura two-parameter values lower than a 2% divergence threshold. However, the patterns of divergence observed in each case remained sufficient to discriminate each species, revealing the accuracy of DNA barcoding even cases with relatively low genetic divergence. At the other extreme, three species displayed high genetic sequence divergence among conspecifics. For two cases, Characidium alipioi and Geophagus proximus, barcoding proved effective at flagging possible new species. For another case, Astyanax bimaculatus, the use of DNA barcoding of the comparison of shared freshwater fish fauna between different basins revealed itself as highly useful in disclosing that the previously identified A. bimaculatus "cluster A" probably represents the species Astyanax altiparanae. CONCLUSION: The present study is among the first to assess the efficiency of barcoding for the Brazilian freshwater fishes. The results demonstrate the utility of barcoding to identify the fauna from this basin, contribute to an enhanced understanding of the differentiation among species, and to help flag the presence of overlooked species. PMID- 21271850 TI - Five years of FISH-BOL: brief status report. AB - The Fish Barcode of Life Initiative (FISH-BOL) is a concerted global research project launched in 2005, with the goal to collect and assemble standardized DNA barcode sequences and associated voucher provenance data in a curated reference sequence library to aid the molecular identification of all fish species. This article is a detailed progress report (July 2010) on the number of fish species that have been assigned a DNA barcode. Of the approximately 31,000 currently known fish species, 25% have been processed successfully, with at least one species from 89% of all families barcoded; in this report we give a progress overview by taxonomy and geographic region. Using standard analytical protocols, differences in the barcoding completion rate between orders and families are observed, suggesting a potential PCR amplification bias. Overall, between 3 and 9% of the species analyzed failed to yield a "BARCODE compliant" sequence, depending upon how the data are filtered. When species with only a single representative specimen are included, the failure rate was 9%. This might derive from several sources such as mismatched primers and degraded DNA templates. In an attempt to account for the latter, when the analysis is restricted to species with at least two specimens examined, the observed failure rate is significantly lower (3%), suggesting that template quality is a source of concern for FISH-BOL. We, therefore, conclude that using a standard protocol with several specimens per species and PCR primer cocktails is an efficient and successful approach because failures were evenly distributed among orders and families. Only six orders with low species numbers (Pristiformes, Torpediniformes, Albuliformes, Batrachoidiformes, Gobiesociformes, and Petromyzontiformes) showed failure rates between 10 and 33%. Besides outlining an overarching approach for FISH-BOL data curation, the goal of the present article is to give guidance in directing sampling campaigns toward neglected or underrepresented families in order to complete the FISH-BOL campaign most efficiently. PMID- 21271851 TI - The MexBOL initiative. PMID- 21271852 TI - Molecular evidence that Langeronia macrocirra and Langeronia cf. parva (Trematoda: Pleurogenidae) parasites of anurans from Mexico are conspecific. AB - The genus Langeronia parasitizing the intestine of several species of anurans is distributed from North to Central America. We identified Langeronia macrocirra and Langeronia cf. parva from the same host and localities, and present here new data not applicable about their tegumental surface by scanning electron microscopy. We compared sequences of the rDNA ITS2 region and mtDNA cox1 gene for the two morphotypes. ITS2 exhibited a high degree of conservation. Phylogenetic reconstruction using cox1 revealed three clades (I, II, and III), which did not correspond to a previous identification or host. Little divergence was found within clades: sequences were identical in clade I, whereas clade II had 0.27% and clade III had 1.08%. Inter-clade divergence reached 8.69% (I vs. III). This pattern of genetic divergence indicated that both taxa probably belong to the same species, so we posit that the morphological changes could be correlated with development. Increasing sample size and geographical coverage will contribute to the taxonomy of the genus based on morphological and molecular evidence, and will open tracks toward the use of DNA barcodes to the genus in Mexico. PMID- 21271853 TI - Evidence of new species of Haematoloechus (Platyhelminthes: Digenea) using partial cox1 sequences. AB - BACKGROUND AND AIMS: Haematoloechus, digeneans parasites of amphibians, is a species-rich genus with more than 50 species around the globe. Establishing an accurate taxonomy for this group has been difficult due to high intraspecific variability. Nuclear DNA sequences have given independent information about species validity and phylogeny of the group. MATERIALS AND METHODS: In this paper, I test the performance of partial sequences of the mitochondrial cytochrome c oxidase subunit I (cox1) gene in the differentiation of recognized species of the genus and in the detection of potential new taxa. Samples from 13 nominal species were sequenced, plus four samples that could not be assigned to any described species based on morphology. RESULTS: Parsimony analysis of the amplified 360 bp fragment resulted in six most parsimonious trees showing the same grouping of samples, differing in the samples' arrangement within those groups. All 13 species were recovered on the trees, and five potential new species are shown. CONCLUSION: Additional sampling and sequencing is necessary to support this hypothesis, but with this preliminary information the search for diagnostic characters that allow the description of the new taxa is less difficult. PMID- 21271854 TI - DNA barcoding a highly diverse group of parasitoid wasps (Braconidae: Doryctinae) from a Mexican nature reserve. AB - BACKGROUND AND AIMS: The preliminary results of a DNA barcoding study of the doryctine fauna of parasitoid wasps from the Chamela-Cuixmala Biosphere Reserve in Mexico, a region dominated by tropical dry forest, are presented. So far, three field trips have been carried out to the reserve and 468 specimens have been collected, of which 407 cox1 sequences were obtained. MATERIALS AND METHODS: The general mixed Yule-coalescent model was applied to a phylogram to investigate the number of evolutionary units that can be detected from the DNA sequence data examined. RESULTS: A total of 185 barcoding species assigned to 20 identified doryctine genera were discriminated using the above model, 115 of which belong to the speciose genus Heterospilus, pointing out the extraordinary species richness of this subfamily of insects in a Mexican tropical dry forest. CONCLUSION: On the basis of the DNA barcodes generated, Ptesimogastroides Braet & van Achterberg is proposed to be a junior synonym of Ptesimogaster Marsh syn. nov. Neoheterospilus was also found deeply nested within a large Heterospilus clade, suggesting the paraphyly of the latter genus. PMID- 21271855 TI - DNA barcoding reveals Mexican diversity within the freshwater leech genus Helobdella (Annelida: Glossiphoniidae). AB - We investigated the genetic distances and taxonomic status among species of Helobdella, a genus of non-blood-feeding leeches, based on mitochondrial cytochrome c oxidase subunit I sequences. Sampling included 20 specimens representing nine nominal species collected in 11 states in Mexico as well as previously published sequences of different species of Helobdella from several places. A neighbor-joining tree, as well as identification of diagnostic nucleotides, was used to suggest the presence of seven species of Helobdella in Mexico including potentially two undescribed forms. PMID- 21271856 TI - Tropical montane nymphalids in Mexico: DNA barcodes reveal greater diversity. AB - MATERIALS AND METHODS: DNA sequences obtained for the Barcode of Life library in the All Lepidoptera Campaign project Nymphalidae of Central Mexico were analyzed as a test of species limits and to explore possible phylogenetic groupings in the Preponini tribe. Using specimens in the National Insect Collection of the Instituto de Biologia of the Universidad Nacional Autonoma de Mexico, 78 specimens were assayed for cytochrome oxidase c subunit 1. RESULTS: Disregarding the missing data, there were 458 conserved sites, 200 variable sites and 187 parsimony-informative sites. The neighbor-joining and maximum likelihood analyses indicate that none of the three genera of Preponini as currently circumscribed are reciprocally monophyletic. As per species limits, high levels of barcode variation in the Prepona deiphile complex suggest the existence of at least two new endemic species to Mexico. The divergent taxa were escalantiana from the Tuxtlas region in Veracruz, and ibarra from Sierra Madre del Sur in the Pacific states of southern Mexico. The genetic distance in the CO1 fragment between them and the other deiphile populations ranged from 2.7 to 8.0%. CONCLUSION: We recommend that morphological data need to be re-examined and that additional molecular data for species ought to be gathered before a particular biogeographic model can be proposed for the group in Mesoamerica. PMID- 21271857 TI - Genetic variation in avocado stem weevils Copturus aguacatae (Coleoptera: Curculionidae) in Mexico. AB - BACKGROUND AND AIM: The avocado stem weevil Copturus aguacatae is an important pest in avocado plantations. Its presence hinders the production and marketing of avocado in Mexico, the largest avocado producer worldwide. Biological control through pheromone synthesis, a strategy favored over chemical control in crops, is currently limited by difficult field identification of this species. MATERIALS AND METHODS: Using DNA barcoding, we examine the patterns of genetic variation of C. aguacatae in avocado trees in Mexico to help facilitate its identification and biological control. RESULTS: We show that there is one single species of avocado stem weevil throughout the sampled sites in Mexico. Overall, haplotype diversity is high, with Oaxaca forming one distinct group and all other sampled populations are admixed irrespective of geographic origin. CONCLUSION: The results suggest that high gene flow is maintained in this species and that a global strategy for biocontrol can be designed and implemented throughout the sampled range. PMID- 21271858 TI - DNA barcodes effectively identify the morphologically similar Common Opossum (Didelphis marsupialis) and Virginia Opossum (Didelphis virginiana) from areas of sympatry in Mexico. AB - Two morphologically similar species of opossum from the genus Didelphis-Didelphis virginiana and Didelphis marsupialis-cooccur sympatrically in Mexico. High intraspecific variation complicates their morphological discrimination, under both field and museum conditions. This study aims to evaluate the utility and reliability of using DNA barcodes (short standardized genome fragments used for DNA-based identification) to distinguish these two species. Sequences of the cytochrome c oxidase subunit I (Cox1) mitochondrial gene were obtained from 12 D. marsupialis and 29 D. virginiana individuals and were compared using the neighbor joining (NJ) algorithm with Kimura's two-parameter (K2P) model of nucleotide substitution. Average K2P distances were 1.56% within D. virginiana and 1.65% in D. marsupialis. Interspecific distances between D. virginiana and D. marsupialis varied from 7.8 to 9.3% and their barcode sequences formed distinct non overlapping clusters on NJ trees. All sympatric specimens of both species were effectively discriminated, confirming the utility of Cox1 barcoding as a tool for taxonomic identification of these morphologically similar taxa. PMID- 21271859 TI - Character-based, population-level DNA barcoding in Mexican species of Zamia L. (Zamiaceae: Cycadales). AB - BACKGROUND AND AIMS: With the recent proposal of matK and rbcL as core plant DNA barcoding regions by the Consortium for the Barcoding of Life Plant Working Group, the construction of reference libraries in the botanical DNA barcoding initiative has entered a new phase. However, in a recent DNA barcoding study in the three Mexican genera of the gymnosperm order Cycadales, we found that neither matK nor rbcL allow high levels of molecular identification of previously established species. MATERIALS AND METHODS: Our data analysis in that study rested on the "Characteristic Attributes Organization System" (CAOS), a character based algorithm for the definition of "DNA diagnostics." Here, we use CAOS to analyze a population-level molecular data set in Zamia, one of the three cycad genera occurring in Mexico, whose populations display contrasting biogeographic patterns. Our population-level study, which includes all species in the region formally known as Megamexico, is restricted to the genome region, which showed the best single-locus molecular identification performance in our previous study namely, the noncoding intergenic chloroplast spacer psbK-I. RESULTS: Our comparison of single-individual vs. population-level psbK-I datasets in Zamia indicates that CAOS analyses are sensitive to slight alignment changes, which in turn derive from the different amounts of molecular variation present in each matrix type. CONCLUSION: We, therefore, suggest that character-based studies that involve population-level data should contemplate this type of comparison between data matrices, before a set of DNA diagnostics in a given DNA barcoding reference library is considered definitive. PMID- 21271860 TI - Phospholipase A2 receptors in human leukemic blasts. PMID- 21271861 TI - Apoptotic induction in B-cell acute lymphoblastic leukemia cell lines treated with a protein kinase Cbeta inhibitor. AB - B-cell acute lymphoblastic leukemia (B-ALL) in adults exhibits a 5-year disease free survival rate of only 25-40% after currently available treatment. Protein kinase Cbeta (PKCbeta) is under active consideration as a rational therapeutic target in several B-cell malignancies, but studies of its possible utility in B ALL are lacking. Expression of PKCbeta1 and PKCbeta2 isoforms was demonstrated in five B-ALL cell lines characterized by distinctive chromosomal translocations, and sensitivity to PKCbeta-selective inhibition was examined. Inhibitor treatment resulted in a dose-dependent reduction in viability in all cell lines, although pro-B ALL with t(4;11)(q21;q23) was most sensitive. Apoptotic induction was evident after 24-48 h of treatment, and an inhibition of cell cycle progression was detected in one cell line. Treatment resulted in a rapid induction of poly(ADP-ribose) polymerase (PARP) cleavage, indicating caspase-3-mediated apoptosis, and a rapid reduction in phosphorylation of AKT and its downstream target glycogen synthase kinase 3beta (GSK3beta). These results indicate that PKCbeta targeting should be considered as a potential treatment option in B-ALL. PMID- 21271862 TI - A molecular and functional analysis of large granular lymphocyte expansions in patients with chronic myelogenous leukemia treated with tyrosine kinase inhibitors. AB - Tyrosine kinase inhibitor (TKI) therapy has become the standard treatment for chronic myelogenous leukemia (CML). Off-target kinase inhibition has been implicated in the appearance of unique adverse effects, such as colitis and pleural effusions. In addition, some patients present oligoclonal expansions of large granular lymphocytes (LGLs). We sought to further investigate this phenomenon in 64 patients treated with five different TKIs. Clonal expansions of cytotoxic T lymphocytes (CTLs) were identified in all TKI-treated patient groups, but only in dasatinib-treated patients were these expansions characterized as LGLs. Survival factors known to be important in LGL leukemia (interleukin-15 [IL 15] transpresentation, plasma platelet-derived growth factor [PDGF]-BB levels, nuclear factor-kappaB [NF-kappaB] and T-bet activation) were found to be associated with TKI-induced LGL expansions. Interestingly, patients with LGL expansions had increased cytotoxicity against non-transformed endothelial cells, which may play a role in observed autoimmune-like side effects. Our results indicate that patients with CML treated with TKIs can develop T cell expansions, which can in certain cases be related to some adverse effects. PMID- 21271863 TI - Chlorambucil in indolent mantle cell lymphoma--just another old drug for a new disease? PMID- 21271864 TI - Concomitant and antecedent deep venous thrombosis and cancer survival in male US veterans. AB - Survival is reportedly worse in patients with cancer concurrently diagnosed with deep venous thrombosis. However, information on specific malignancies is limited. From a cohort study of male US veterans we identified incident cancer cases (n = 412,008) and compared survival patterns among those with versus without a history of deep venous thrombosis. Using Cox proportional hazard models, we estimated hazard ratios (HRs) and 95% confidence intervals as measures of the relative risk of dying. Individuals with (versus without) a concomitant deep venous thrombosis and cancer diagnosis had a higher risk of dying (HR = 1.38; 1.28-1.49). The most prominent excess mortality (HR = 1.29-2.55) was observed among patients diagnosed with deep venous thrombosis at the time of diagnosis of lung, gastric, prostate, bladder, or kidney cancer. Increased risk of dying was also found among cancer patients diagnosed with deep venous thrombosis 1 year (HR = 1.14; 1.07-1.22), 1-5 years (HR = 1.14; 1.10-1.19), and >5 years (HR = 1.27; 1.23-1.31) before cancer; this was true for most cancer sites (HR = 1.17-1.64). In summary, antecedent deep venous thrombosis confers a worse prognosis upon cancer patients. Advanced stage at diagnosis, treatment effects, lifestyle factors, and comorbidity could explain differences by cancer site and time frame between a prior deep venous thrombosis diagnosis and cancer outcome. PMID- 21271865 TI - Ternary copper(II) complexes of levofloxacin and phenanthroline derivatives: in vitro antibacterial, DNA interactions, and SOD-like activity. AB - A series of ternary copper(II) complexes have been derived using levofloxacin and five phenanthroline derivatives. Complexes were characterized using infrared spectroscopy, Thermogravimetric (TG)-analysis, fast atom bombardment mass spectroscopy and reflectance spectra. Synthesized complexes exhibit the only d-d band at ~ 666 nm points toward a distorted square pyramidal geometry at metal centre with one unpaired electron responsible for paramagnetic behaviour of whole moiety. Binding behaviour of the complexes toward Herring Sperm DNA were determined using ultraviolet-Vis (UV-Vis) absorption titration and viscometric titration experiment, where as the cleavage efficacy of the complexes toward pUC19 DNA was determined by electrophoresis in presence of ethidium bromide. Complexes exhibit superoxide dismutase-like activity with their IC(50) values ranging from 0.7917 to 1.7432 uM. PMID- 21271866 TI - Synthesis and biological evaluation of some new pyridazinone derivatives. AB - A series of pyridazinone derivatives (19-34) were synthesized with an aim to synthesize safer anti-inflammatory agents. The compounds were evaluated for their anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation (LPO) actions. The percentage inhibition in edema at different time intervals indicated that compounds 20, 26, 28 and 34 exhibited good anti-inflammatory potential, comparable with that of ibuprofen (85.77%) within a range of 67.48-77.23%. The results illustrate that 5-(4-fluoro-benzyl)-3-(4-chloro-phenyl)-1,6-dihydro-6 pyridazinone (26) and 5-(4-chloro-benzyl)-3-(4-chloro-phenyl)-1,6-dihydro-6 pyridazinone (20) showed best anti-inflammatory activity. Furthermore, activity is more in case of chloro substitution as compared with methyl-substitution. The compounds synthesized were also evaluated for their ulcerogenic and LPO action and showed superior gastrointestinal safety profile along with reduction in LPO as compared with that of the ibuprofen. PMID- 21271871 TI - Prosthetic treatment of congenital hard and soft palate defects. AB - Obturator prostheses are used to improve mastication, speech, and swallowing by reestablishing oronasal separation and aesthetics in maxillary defect patients. A sectional and magnetically retained functional removable speech bulb prosthesis was planned to treat the congenitally cleft hard and soft palates of this patient. The obturator part, localized into lateral nasal undercuts covered with sound mucosa, was used to retain the complete denture. Two pieces of the prosthesis were joined together by a magnet in the mouth. A special hinge mechanism was added to join the complete denture and functional velopharyngeal parts of the prosthesis for the treatment of velopharyngeal inadequacy. Sufficient retention was obtained, and no major complications were seen in the patient's prosthesis in periodic controls. PMID- 21271872 TI - Effectiveness of a clinical intervention to eliminate barriers to pain and fatigue management in oncology. AB - BACKGROUND: Pain and fatigue are recognized as critical symptoms that impact quality of life (QOL) in cancer, particularly in palliative care settings. Barriers to pain and fatigue relief have been classified into three categories: patient, professional, and system barriers. The overall objective of this study was to test the effects of a clinical intervention on reducing barriers to pain and fatigue management in oncology. METHODS: This longitudinal, three-group, quasi-experimental study was conducted in three phases: phase 1 (usual care), phase 2 (intervention), and phase 3 (dissemination). A sample of 280 patients with breast, lung, colon, or prostate cancers, stage III and IV disease (80%), and a pain and/or fatigue of 4 or more (moderate to severe) were recruited. The intervention group received four educational sessions on pain/fatigue assessment and management, whereas the control group received usual care. Pain and fatigue barriers and patient knowledge were measured at baseline, 1 month, and 3 months post-accrual for all phases. A 3 * 2 repeated measures statistical design was utilized to derive a priori tests of immediate effects (baseline to 1 month) and sustained effects (baseline or 1 month to 3 months) for each major outcome variable, subscale, and/or scale score. RESULTS: There were significant immediate and sustained effects of the intervention on pain and fatigue barriers as well as knowledge. Measurable improvements in QOL were found in physical and psychological well-being only. CONCLUSION: A clinical intervention was effective in reducing patient barriers to pain and fatigue management, increasing patient knowledge regarding pain and fatigue, and is feasible and acceptable to patients. PMID- 21271873 TI - The impact of common tumor necrosis factor haplotypes on the development of asthma in children: an Egyptian model. AB - Conflicting results have arisen among different ethnic populations with regard to the ability of tumor necrosis factor (TNF) to control the development of bronchial asthma. We examined common TNF polymorphisms (TNFA -1031C>T, TNFA 308G>A, and TNFB +252A>G) to develop a model of the associations between these genetic markers and the development of the disease in Egypt. Amplified DNA from buccal mucosa was genotyped for 240 children using polymerase chain reaction restriction fragment length polymorphism. Skin prick test, total serum immunoglobulin E levels, and assessment of pulmonary functions were investigated. The onset age for one-third of the asthma patients in our study was between 7 and 10 years. The TNFA -1031C>T and TNFA -308G>A polymorphisms were strongly associated with the risk of asthma (p = 0.007, and p = 0.000, respectively), but the TNFB +252A>G polymorphism was not (p = 0.6). We detected a significant linkage between the +252A>G and -1031C>T, and another between the +252A>G and the -308G>A (p < 0.0001 for both). The -1031C>T and -308G>A polymorphisms were not linked (p = 0.14). The -308A/A genotype was absent, and the -308A allele was expressed only in patients with -308G/A heterozygosity (13%). All but the +252G/A genotype were also strongly associated with the severity of disease. Environmental factors, as genetic variations, clearly influence susceptibility, the onset, progression, and severity of bronchial asthma. More information is needed to develop genetic models of susceptibility for different ethnic populations. PMID- 21271900 TI - The influence of age, sex, and race on the incidence of esophageal cancer in the United States (1992-2006). AB - BACKGROUND: There is a striking male predominance in esophageal cancer patients. Sex hormones have been suggested as a contributing factor and these are influenced by age and race. In this study, we examined the male-to-female incidence rate ratios of esophageal cancer in the United States. METHODS: We used data from 13 registries in the Surveillance, Epidemiology, and End Results (SEER) database to calculate male-to-female incidence rate ratios of esophageal adenocarcinoma (EA) and esophageal squamous cell carcinoma (ESCC) diagnosed during 1992-2006 in different age and race groups. RESULTS: For EA, all races had similar sex and age-specific incidence patterns showing a peak in the male-to female incidence rate ratio in the age group 50-59, and an age-related decline thereafter. The highest male-to-female ratio was seen in Hispanics (20.5) and the lowest in Blacks (7.0) compared with 10.8 in Whites. By contrast, the male-to female incidence rate ratios were low and fairly stable throughout the different age groups in ESCC. CONCLUSION: The male-to-female incidence rate ratios in esophageal cancer vary considerably according to histology, age, and race. The highest sex ratios were seen in EA in the age group 50-59, rendering plausibility to the hypothesis that female sex hormone exposure may play a protective role in the development of this cancer. PMID- 21271901 TI - Adjuvant imatinib for gastrointestinal stromal tumors: the current situation and problems. AB - OBJECTIVE: To review the current situation and find out the current problems of adjuvant imatinib for gastrointestinal stromal tumors (GISTs). METHODS: Searching for articles and records about imatinib for GISTs, especially adjuvant imatinib for GISTs, on MEDLINE, EMBASE and international conference on gastrointestinal. RESULTS: GISTs are derived from mesenchymal cells of the gastrointestinal tract. The standard treatment for primary GISTs is to resect the tumor together with the negative margins completely without tumor rupture and spillage. Conventional chemotherapy and radiotherapy is ineffective for advanced GISTs. The introduction of imatinib has dramatically changed the natural history of advanced GISTs. Imatinib is generally safe and effective with doses of 400, 600 or 800 mg daily, and has become the standard drug in the treatment for patients with advanced GISTs. Furthermore, most of the toxicity of imatinib is minimal and manageable, almost no treatment-related deaths have been reported. Therefore, adjuvant imatinib therapy is safe and seems to improve recurrence-free survival after the resection of primary GISTs. CONCLUSIONS: Although U.S Food and Drug Administration and European Medicines Agency have approved the use of adjuvant imatinib for GISTs postoperatively, a series of questions about the use of adjuvant imatinib still exist, such as the impact of adjuvant imatinib on overall survival, the optimal dose, the best duration of treatment and the most suitable patients. Doctors and patients should weigh the pros (the decrease of relapse) and cons (drug toxicity and drug costs), especially in terms of the benefit of overall survival. PMID- 21271920 TI - Factors affecting the quality of sound recording for speech and voice analysis. AB - The importance and utility of objective evidence-based measurement of the voice is well documented. Therefore, greater consideration needs to be given to the factors that influence the quality of voice and speech recordings. This manuscript aims to bring together the many features that affect acoustically acquired voice and speech. Specifically, the paper considers the practical requirements of individual speech acquisition configurations through examining issues relating to hardware, software and microphone selection, the impact of environmental noise, analogue to digital conversion and file format as well as the acoustic measures resulting from varying levels of signal integrity. The type of recording environment required by a user is often dictated by a variety of clinical and experimental needs, including: the acoustic measures being investigated; portability of equipment; an individual's budget; and the expertise of the user. As the quality of recorded signals is influenced by many factors, awareness of these issues is essential. This paper aims to highlight the importance of these methodological considerations to those previously uninitiated with voice and speech acoustics. With current technology, the highest quality recording would be made using a stand-alone hard disc recorder, an independent mixer to attenuate the incoming signal, and insulated wiring combined with a high quality microphone in an anechoic chamber or sound treated room. PMID- 21271921 TI - The number of patients with communication related impairments in acute hospital stroke units. AB - Effective communication between patients who have had a stroke and their healthcare providers is vital. However, this may be difficult if patients have communication related impairments as a result of the stroke and/or have age related impairments that impact on their ability to communicate. This study sought to identify how many patients admitted into two acute hospital stroke units had a hearing, vision, speech, language and/or cognitive communicative impairment regardless of the cause. A total of 69 patients participated in this study. The majority (88%) of patients had one or more mild or more severe communication related impairments, 69% of patients had two or more communication related impairments and 39% of patients had three or more communication related impairments. The most common type of impairment was hearing impairment, followed by near vision impairment. That a high number of patients in acute hospital stroke units have communication related impairments suggests that many patients in acute stroke units may experience difficulty communicating their healthcare needs with healthcare providers and that alternative ways to support patients with communication related impairments in acute stroke units need to be available. PMID- 21271922 TI - Effects of audio-visual information and mode of speech on listener perceptions of alaryngeal speakers. AB - There is minimal research on listener perceptions of an individual with a laryngectomy (IWL) based on audio-visual information. The aim of this research was to provide preliminary insight into whether listeners have different perceptions of an individual with a laryngectomy based on mode of presentation (audio-only vs. audio-visual) and mode of speech (tracheoesophageal, oesophageal, electrolaryngeal, normal). Thirty-four naive listeners were randomly presented with a standard reading passage produced by one typical speaker from each mode of speech in both audio-only and audio-visual presentation mode. Listeners used a visual analogue scale (10 cm line) to indicate their perceptions of each speaker's personality. A significant effect for mode of speech was present. There was no significant difference in listener perceptions between mode of presentation using individual ratings. However, principal component analysis showed ratings were more favourable in the audio-visual mode. Results of this study suggest that visual information may only have a minor impact on listener perceptions of a speakers' personality and that mode of speech and degree of speech proficiency may only play a small role in listener perceptions. However, results should be interpreted with caution as results are based on only one speaker per mode of speech. PMID- 21271923 TI - Processing of wh-questions in a case of posterior cortical atrophy. AB - Posterior cortical atrophy (PCA) is a type of dementia that is characterized by visuo-spatial and memory deficits, dyslexia and dysgraphia, relatively early onset and preserved insight. Language deficits have been reported in some cases of PCA. Using an off-line grammaticality judgement task, processing of wh questions is investigated in a case of PCA. Other aspects of auditory language are also reported. It is shown that processing of wh-questions is influenced by syntactic structure, a novel finding in this condition. The results are discussed with reference to accounts of wh-questions in aphasia. An uneven profile of other language abilities is reported with deficits in digit span (forward, backward), story retelling ability, comparative questions but intact abilities in following commands, repetition, concept definition, generative naming and discourse comprehension. PMID- 21271924 TI - Speech-language pathology students' approaches to learning in a problem-based learning curriculum. AB - Problem-based learning (PBL) is hypothesized to enhance the development of deep learning. Most previous studies, however, have focused on outcomes (knowledge and skills) rather than students' approaches to learning, or how learning approach correlates with learning outcomes. Undergraduates in a speech-language pathology program (n = 114) completed the revised 2-factor Study Process Questionnaire (R SPQ-2F) twice in an academic year to identify their approaches to learning and to compare these results with academic outcomes. Two findings emerged. Although the mean of scores for the deep approach (DA) to learning was consistently higher than the mean of scores for the surface approach (SA) to learning, exposure to PBL led to significant increase in DA and SA to learning during an academic year for students in Years 1 to 3. Students who did well in a PBL examination showed a much stronger DA than SA to learning, while students who performed less well showed a smaller difference between DA and SA to learning. Possible explanations for these findings are evaluated and implications for further studies are discussed. PMID- 21271925 TI - A longitudinal case study of the effects of an integrated phonological awareness program for identical twin boys with childhood apraxia of speech (CAS). AB - This study is an examination of the longitudinal effects of an integrated phonological awareness approach for identical twin boys with childhood apraxia of speech (CAS). Genetic and environmental factors in the boys' responses to the intervention were also examined. Theo and Jamie (aged 4;5) each participated in 18 hours of intervention prior to school entry and were re-assessed at age 4;9, 5;3, and 5;9 respectively. Their speech, expressive morpho-syntactic, phonological awareness, reading, and spelling development were evaluated over their first year of schooling. Theo and Jamie experienced continued growth in speech and phonological awareness skills following participation in the intervention. They exhibited age-appropriate reading and spelling development during their first year of formal literacy instruction. They had persistent deficits in expressive morpho-syntactic skills despite speech production gains over the study. The results pointed to the benefit of integrating speech and phonological awareness goals within a preventative framework to ensure successful early literacy development for children with CAS. Findings suggested that language difficulties in children with CAS should be targeted during intervention as they do not resolve as the children's speech production difficulties minimize. PMID- 21271926 TI - Language planning disturbances in children who clutter or have learning disabilities. AB - The primary objective of this paper is to determine to what extent disturbances in the fluency of language production of children who clutter might be related to, or differ from difficulties in the same underlying processes of language formulation seen in children with learning disabilities. It is hypothesized that an increase in normal dysfluencies and sentence revisions in children who clutter reflect different neurolinguistic process to those of children with learning disabilities. To test this idea, 150 Dutch speaking children, aged 10;6 to 12;11 years, were divided in three groups (cluttering, learning difficulties and controls), and a range of speech and language variables were analysed. Results indicate differences in the underlying processes of language disturbances between children with cluttered speech and those with learning disabilities. Specifically, language production of children with learning disabilities was disturbed by problems at the conceptualizator and formulator stages of Levelt's language processing model, whilst language planning disturbances in children who clutter were considered to arise due to insufficient time to complete the editing phase of sentence structuring. These findings indicate that children who clutter can be differentiated from children with learning disabilities by both the number of main and secondary story plot elements and by the percentage of correct sentence structures. PMID- 21271927 TI - Effects of phonological awareness and semantic intervention on word-learning in children with SLI. AB - This study examined the effects of phonological awareness and semantic intervention on word-learning abilities in children with Specific Language Impairment (SLI) and whether treatment order influenced outcomes. An alternating treatment design was implemented to evaluate whether phonological awareness, semantic awareness, or a combination of both interventions positively influenced children's word-learning ability and whether the order of the treatments influenced outcomes. Nineteen children with SLI, aged between 6;3 and 8;2 years, and 19 age-matched children with typical language development participated in this study. The children with SLI were randomly assigned either to treatment condition A (phonological awareness intervention followed by semantic intervention) or treatment condition B (same interventions in reverse order). A word-learning paradigm was applied at pre-, mid-, and post-testing to evaluate which condition accelerated the receptive and expressive learning of novel words. Positive treatment effects on producing new words were found for the children who received phonological awareness intervention followed by semantic intervention. There was no improvement on the comprehension of new words for either group. The findings suggest that phonological awareness intervention may not only improve children's phonological skills, but may help to facilitate some aspects of word learning when followed by an additional semantic based intervention. PMID- 21271939 TI - Glucose tolerance of premenopausal women after menopause due to surgical removal of ovaries. AB - OBJECTIVE: To evaluate the influence of the abrupt withdrawal of ovarian function on glucose tolerance by studying premenopausal women before and after oophorectomy. METHODS: Thirty premenopausal women who needed hysterectomy for benign reasons volunteered for the study in our hospital in Istanbul, Turkey. An oral glucose tolerance test (OGTT) was performed before surgery and 3, 6 and 12 months after surgery. Fasting glucose, fasting insulin levels and insulin/glucose indexes, HOMA indexes, insulin and glucose levels were measured during OGTT. RESULTS: The mean fasting and 2-h glucose levels of the women did not change significantly during the 12 months of follow-up. However, the glucose levels during the glucose tolerance tests changed significantly after surgery (p<0.05). Insulin responses to the glucose tolerance test also increased significantly (p<0.005). Insulin/glucose indexes were significantly higher after surgery (p<0.005). Type 2 diabetes mellitus was detected in five women and impaired glucose tolerance was detected in 12 of the 30 patients after surgery in the 12 month period. CONCLUSION: The impairment of carbohydrate metabolism due to an abrupt decrease in natural estrogen levels should be considered before removing the ovaries during hysterectomy in premenopausal patients. PMID- 21271940 TI - Whole mouse blood microRNA as biomarkers for exposure to gamma-rays and (56)Fe ion. AB - PURPOSE: Biomarkers of ionising radiation exposure are useful in a variety of scenarios, such as medical diagnostic imaging, occupational exposures, and spaceflight. This study investigates to what extent microRNA (miRNA) expression signatures in mouse peripheral blood can be used as biomarkers for exposures to radiation with low and high linear energy transfers. MATERIALS AND METHODS: Mice were irradiated with doses of 0.5, 1.5, or 5.0 Gy gamma-rays (dose rate of 0.0136 Gy/s) or with doses of 0.1 or 0.5 Gy (56)Fe ions (dose rate of 0.00208 Gy/s). Total RNA was isolated from whole blood at 6 h or 24 h after irradiation. Three animals per irradiation condition were used. Differentially expressed miRNA were determined by means of quantitative real-time polymerase chain reaction. RESULTS: miRNA expression signatures were radiation type-specific and dose- and time dependent. The differentially expressed miRNA were expressed in either one condition (71%) or multiple conditions (29%). Classifiers based on the differentially expressed miRNA predicted radiation type or dose with accuracies between 75% and 100%. Gene-ontology analyses show that miRNA induced by irradiation are involved in the control of several biological processes, such as mRNA transcription regulation, nucleic-acid metabolism, and development. CONCLUSION: miRNA signatures induced by ionising radiation in mouse blood are radiation type- and radiation dose-specific. These findings underline the complexity of the radiation response and the importance of miRNA in it. PMID- 21271941 TI - Investigation of the effects of the chronic administration of some antihypertensive drugs on enzymatic and non-enzymatic oxidant/antioxidant parameters in rat ovarian tissue. AB - OBJECTIVE: In this study, effects of chronic antihypertensive drug (clonidine, methyldopa, amlodipine, ramipril, and rilmenidine) treatment on antioxidant oxidant parameters were investigated in rat ovarian tissue. STUDY DESIGN: Chronic drug administration for 30 days and at the end, biochemical examinations (total glutathione (tGSH), glutathione peroxidase (GPO), glutathione reductase (GR), glutathione s-transferase (GST), superoxide dismutase (SOD), nitric oxide (NO), catalase (CAT), malondialdehyde (MDA), and myeloperoxidase (MPO) analyses) were performed. RESULTS: The levels of glutathione (GSH) and NO, and the activities of GPO, GR, GST, SOD, and CAT were measured the lowest in ramiprile group. Also in ramiprile group, the level of MDA and the activity of MPO was the highest. CONCLUSION: We divided the drugs into four groups according to their biochemical side effect potentials in ovarian tissue: (I) Drugs which have no clear negative effect on ovarian tissue: clonidine, rilmenidine; (II) Drugs which have mild negative effect on ovarian tissue: methyldopa; (III) Drugs which have moderate negative effect on ovarian tissue: amlodipine; (IV) Drugs which have severe negative effect on ovarian tissue: ramipril. These data might be useful in the selection of the least toxic antihypertensive drug in pregnant and/or normal females. PMID- 21271942 TI - Original immunophenotype of blood endothelial progenitor cells and microparticles in patients with isolated arterial erectile dysfunction and late onset hypogonadism: effects of androgen replacement therapy. AB - OBJECTIVE: Blood endothelial progenitor cells (EPCs) and endothelial microparticles (EMPs) have been proposed as markers of endothelial dysfunction. Aim of this study was to evaluate an original immunophenotype of EPCs and EMPs in patients with isolated arterial erectile dysfunction (ED) and late onset hypogonadism (LOH) before and after androgen replacement therapy. MATERIALS AND METHODS: Fifty patients (50-64 years) with ED and LOH were selected. EPC (CD45(neg)/CD34(pos)/CD144(pos)) and EMP (CD45(neg)/CD34(neg)/CD144(pos)) blood concentrations were evaluated by flow cytometry. Thirty patients received androgen replacement therapy (Tostrex(r) ProStrakan) for 6 months (group A), other 20 patients not received androgen therapy for the contraindications in their clinical history (group B). RESULTS: After 6 months, group B showed IIEF-5 score, peak systolic velocity and acceleration time significantly worse than group A; in addition EPCs and EMPs were significantly higher in group B compared to group A. CONCLUSIONS: Patients with isolated arterial ED and LOH not treated with androgen therapy showed worst vascular parameters measured by penile Doppler and higher EPCs and EMPs compared to treated hypogonadal patients, hence, LOH appears to be an additional vascular risk factor, and these markers may be considered as predictors of cavernous artery disease. Finally, androgen therapy improves endothelial dysfunction. PMID- 21271943 TI - Granulocyte transfusions: where is the controversy? PMID- 21271944 TI - Treatment of asymptomatic pulmonary cryptococcosis in immunocompetent hosts with oral fluconazole. AB - BACKGROUND: Pulmonary cryptococcosis is occasionally detected on routine imaging studies in healthy hosts with no or mild symptoms. Isolated pulmonary cryptococcosis may be observed without specific therapy in asymptomatic immunocompetent hosts. However, considering that dissemination from a pulmonary infection can occur in patients with no immunologic defects, treatment of asymptomatic pulmonary cryptococcosis in immunocompetent hosts remains controversial. The aim of this study was to determine the role of fluconazole therapy in the management of isolated pulmonary cryptococcosis in asymptomatic healthy hosts. METHODS: We retrospectively analyzed the medical records and radiographic findings of 10 healthy subjects with isolated pulmonary cryptococcosis diagnosed incidentally and treated with oral fluconazole. RESULTS: All patients had no respiratory or constitutional symptoms. The most common radiological findings were pulmonary nodules, and the number of nodules in each patient was from 1 to 9. After histological confirmation, all patients were treated with oral fluconazole at a dosage of 400 mg per day for a median period of 6.4 months. No patient developed an adverse reaction to fluconazole. The mean interval between the initiation of antifungal therapy and final radiological response was 8.3 months. Seven of the 10 patients showed complete resolution, and the other 3 patients were assessed as having partial resolution. During the average follow-up period of 11.9 months, all patients showed a favourable outcome with no relapse. The overall cure rate was 70%. CONCLUSION: These results suggest that fluconazole may be an attractive therapeutic option for asymptomatic pulmonary cryptococcosis in immunocompetent hosts. PMID- 21271945 TI - Ertapenem for the treatment of urinary tract infections caused by extended spectrum beta-lactamase-producing bacteria in children. AB - BACKGROUND: Urinary tract infections (UTIs) are a problem frequently encountered by paediatric healthcare providers. Recent data suggest that extended-spectrum beta-lactamase (ESBL)-producing bacteria are an emerging cause of UTIs in non hospitalized patients. We report our experience of ertapenem use in 50 patients with complicated UTIs, mainly pyelonephritis, caused by ESBL-producing organisms. METHODS: Fifty patients aged <16 y who had a complicated UTI caused by ESBL producing organisms and who were treated with ertapenem at our hospital from 1 January 2009 to 31 December 2009, were included in the study. RESULTS: There were 20 (40%) males and 30 (60%) females with a mean +/- standard deviation age of 38.6 +/- 36.9 months (range 6-156 months). Twenty-eight patients had no urological abnormality. In 40 patients ertapenem was initiated after results of microbiological cultures became available. Ertapenem was initiated empirically for 10 patients known to be colonized with ESBL-producing bacteria. Urine cultures were negative at 3.3 +/- 0.7 days (range 2-5 days) after starting ertapenem treatment. The mean duration of ertapenem treatment was 7.8 +/- 1.2 days (range 7-14 days). No laboratory or clinical side effects were observed. CONCLUSIONS: Ertapenem is promising for the culture-guided treatment of ESBL producing Gram-negative complicated UTIs. Well-designed prospective studies are needed to define the role of ertapenem in treating complicated paediatric UTIs, especially upper UTIs. PMID- 21271947 TI - Vasopressin in definite Meniere's disease with positive electrocochleographic findings. AB - CONCLUSION: There was no evidence of a mean raised vasopressin level in 80 subjects suffering from definite Meniere's disease with positive electrocochleographic findings. There was no correlation with stress. The only group with a mildly raised level comprised those who had had a vertigo attack within a day. The most likely cause is nausea, which is the most potent trigger for vasopressin release. OBJECTIVE: It has been claimed that patients with Meniere's disease have raised vasopressin levels. This has been linked with a long-standing notion that that there is a link between stress and Meniere's disease, so that an increase in vasopressin could trigger a vertigo attack. METHODS: Serum vasopressin concentrations were measured in 80 patients with Meniere's disease whose diagnosis was based on conventional symptom criteria plus electrocochleographic evidence of endolymphatic hydrops. RESULTS: The community mean for vasopressin is 2.2 pmol/L (SD = 2.4). For all 80 Meniere's patients the mean vasopressin concentration was 2.1 pmol/L (SD = 1.6), and 2.8 pmol/L (SD = 0.9) when the last attack was within a day. PMID- 21271948 TI - Phenomenological differences between acute and chronic forms of major depression in inpatients. AB - BACKGROUND: Chronic forms of depression are highly prevalent especially in inpatient settings. Defined only by episode duration greater than 2 years, heterogeneous diagnoses like dysthymic disorder, double depression, major depression and recurrent major depression are included. Chronic depression is considered difficult to treat, although its distinguishing characteristics remain unclear. AIMS: The purpose of the present study was empirically to approach proposed differences between acute and chronic forms of depression. METHODS: 80 psychiatric inpatients positively screened for depression and diagnosed with the Composite International Diagnostic Interview (CIDI), completed a set of questionnaires regarding symptom severity (a simplified version of the Beck Depression Inventory), dysfunctional attitudes (Dysfunctional Attitudes Scale), ruminative response style (Response Styles Questionnaire, Why Ruminate Scale) and interpersonal problems (Inventory of Interpersonal Problems; IIP). RESULTS: 30 patients were diagnosed with chronic forms of depression; 34 patients with acute depression. Patients did not differ regarding symptom severity, ruminative response styles, all but one subscales of the IIP or presence of comorbid post traumatic stress disorder. However, chronic depression did show higher dysfunctional attitudes than acute depression, and reported higher rates of socially avoidant behavior. CONCLUSIONS: In line with previous findings, acute and chronic forms of depression differed in dysfunctional attitudes, which might actually reflect a distinguishing pattern of chronicity. Chronic depression patients also reported higher socially avoidant behavior, which might be crucial to focus in treatment. Surprisingly, other variables that are assumed to characterize chronic depression could not be confirmed as distinguishing features. Future research should take etiological aspects into account. PMID- 21271949 TI - Developments in schizophrenia genetics: from linkage to microchips, deletions and duplications. AB - BACKGROUND: There is strong evidence for significant contributions of genetic factors to the risk of schizophrenia. In the past 10 years, studies employing linkage and association approaches have identified multiple putative schizophrenia risk genes. For most of these, the evidence for association with schizophrenia remains weak and attempts of replication not always successful nor easy to interpret. AIM: To give an overview of new developments in genetic research of schizophrenia. METHODS: The present literature on schizophrenia genetics was reviewed with special emphasis on new developments such as genome wide association studies (GWAS), associations of copy number variations (CNVs) with schizophrenia and the role of endophenotypes in genetic research. RESULTS: The first GWAS of schizophrenia have identified new putative candidate risk genes and opened avenues for investigating how multiple genes may act in functional biological pathways forming the genetic basis of schizophrenia and other complex diseases. There is growing evidence that rare de novo CNVs as well as some inherited CNVs contribute to the susceptibility to several neuropsychiatric disorders including schizophrenia. Schizophrenia endophenotypes, which possibly better represent biological phenomena than the complex clinical phenotype, are turning out to be helpful for investigating neurobiological pathways of putative risk genes. CONCLUSIONS: Recent studies suggest that individual common gene variants make relatively small contributions to risk of schizophrenia but some rare CNVs may be associated with much higher risk when present. Future studies employing new technologies for identifying common and rare risk markers are likely to deepen our understanding of the genetic architecture of schizophrenia. PMID- 21271950 TI - ETC-216 for coronary artery disease. AB - INTRODUCTION: Increasing attention has focused on the role of high-density lipoprotein function as a target for cardiprotection. Apolipoprotein A-I(Milano) (AIM) involves a single amino-acid mutation of the major wild-type protein carried on high-density lipoprotein (HDL) particles. Early evidence of beneficial activities of AIM has stimulated support in its development as a potential therapy to reduce cardiovascular risk. AREAS COVERED: The importance of HDL as a target and early data supporting the beneficial effects of AIM are reviewed. All clinical studies of AIM found in PubMed are reviewed. EXPERT OPINION: ETC-216 represents a lipid-deplete form of HDL containing recombinant AIM. While early evidence suggests that administration of ETC-216 promotes rapid regression of coronary atherosclerosis, bringing this compound to clinical practice will require further trials that evaluate its impact on cardiovascular events. PMID- 21271952 TI - Evolution or revolution and the future of medical education: replacing the oak tree. PMID- 21271951 TI - Dendritic cell vaccination against ovarian cancer--tipping the Treg/TH17 balance to therapeutic advantage? AB - The pathology of ovarian cancer is characterized by profound immunosuppression in the tumor microenvironment. Mechanisms that contribute to the immunosuppressed state include tumor infiltration by regulatory T cells (Treg), expression of B7 H1 (PDL-1), which can promote T cell anergy and apoptosis through engagement of PD-1 expressed by effector T cells, and expression of indoleamine 2,3-dioxygenase (IDO), which can also contribute to effector T cell anergy. Expression of both B7 H1 and IDO has been associated with differentiation and recruitment of Treg, and clinical studies have shown that each of these mechanisms correlates independently with increased morbidity and mortality in patients with ovarian cancer. In a remarkable counterpoint to these observations, ovarian tumor infiltration with T(H)17 cells correlates with markedly improved clinical outcomes. In this Future Perspectives review, we argue that dendritic cell (DC) vaccination designed to drive tumor-antigen-specific T(H)17 T cell responses, combined with adjuvant treatments that abrogate immunosuppressive mechanisms operative in the tumor microenvironment, offers the potential for clinical benefit in the treatment of ovarian cancer. We also discuss pharmacological approaches to modulation of MAP kinase signaling for manipulation of the functional plasticity of DC, such that they may be directed to promote T(H)17 responses following DC vaccination. PMID- 21271953 TI - Selection for entry to medicine and specialist training. AB - The task of predicting professional performance during several decades of practice on the basis of any process which takes place a decade earlier is a virtual impossibility. Basically most Western medical schools seek some degree of academic excellence as predicted by school grades and pre-admission examinations. The data suggest that one need not be in the top 1-2% academically for success in medicine. One would therefore do better to place greater emphasis on the key personal qualities desirable in physicians in spite of even greater difficulty in assessing these factors. It seems that trained interviewers using a semi structured interview can improve the selection process at a considerable expenditure of manpower. Selection for specialty training has heretofore not attempted to seek to identify those qualities specific for each specialty. Application of techniques for this purpose may be the desired trend in the coming years. PMID- 21271954 TI - Postgraduate specialist training and continuing professional development. AB - Specialist education and continuing professional development are likely to change considerably over the next 20 years. This will reflect the context within which medicine is practised. This will include changes in disease patterns, population structure, medical advances, information technology and, perhaps most powerfully, public involvement. In speciality education there will be a need to define more clearly both the role of the specialist, and the competences to be achieved. CPD is the longest period of education and, as such, it is the phase during which there is likely to be greatest change in clinical practice. There is a need to develop mechanisms to assure the public that doctors continue to practice up-to date medicine, and that there is confidence and trust in the process. PMID- 21271955 TI - Scanning the horizon of training for general practice. PMID- 21271956 TI - The education and training of gastroenterologists for the 21st century: a paradigm for the education of medical specialists in technology-intensive fields an international and Israeli perspective. AB - Gastroenterology in the developed world as a paradigm for technologically intensive medical specialties has undergone dramatic changes during the last half century with expansion, proliferation and affluence followed by serious reactions on the part of cost-conscious and demanding governments, insurers and consumers. A review of events in several regions within the developed world reveals tremendous technological progress but inadequate attention to professional, economic and ethical issues, which are crucial for the education of a model gastroenterologist who will embody the qualities that will enable him/her to function well clinically, technologically, scientifically, professionally and ethically and thus enable him/her to cope with the increasingly complex challenges that are likely to arise during the next decades. The possibility and need for defining a specific ethic for technology-intensive medical specialists is discussed. PMID- 21271957 TI - Interprofessional education: evidence from the past to guide the future. AB - By reflecting on current systematic reviews of the evaluation of interprofessional education (IPE), this paper will consider the potential shape of IPE, for health and social care practitioners, in 2020. The reviews to be presented relate to evaluations of undergraduate, postgraduate and continuing education programmes. The patterns emerging from the data will be extrapolated into a vision of the developmental pathways that IPE might take. This will be done, within the context of, first, policy and practice for professional higher education and, second, strategies to enhance services to patients through closer collaboration. PMID- 21271958 TI - Scholarship in teaching and best evidence medical education: synergy for teaching and learning. AB - Medical education has lagged behind research and clinical care in developing a value system and social construct that promotes and stimulates the open discussion of the state of the art in teaching among teachers. The recent development of best evidence medical education (BEME) in Europe and the renewed attention to the concept of scholarship in North America provide a conceptual and strategic approach for enhancing the educational enterprise in the health professions. The similarities and differences between BEME and an approach to Scholarship in Teaching developed by a subcommittee of the Group on Educational Affairs of the Association of American Medical Colleges is examined. Combining these two approaches to medical teaching can maximize the potential for advancing the science and art of medical education. PMID- 21271959 TI - The role of assessment in expanding professional horizons. AB - This paper explores assessment innovations which have a system-wide effect on medical education and the medical profession. Important assessment approaches such as the objective structured clinical examination (OSCE), the portfolio, and hi-tech simulations are examples of reform-driven developments. A detailed account is provided on assessment areas that require further developments. The identified areas reflect current thinking in the Centre for Medical Education, University of Dundee Medical School.The assessment innovations are being developed alongside the implementation of the outcome-based curriculum. Areas that require extensive work are: assessment of progression towards defined outcomes, assessment of integrated abilities, assessment of different forms of medical knowledge, assessment of on-the-job learning, learning through assessment, assessment of error management and assessment of portfolio evidence. The identified areas for further assessment development are discussed and where appropriate a theoretical framework is provided. PMID- 21271960 TI - Investing in descriptive evaluation: a vision for the future of assessment. PMID- 21271961 TI - Community-based medical education. PMID- 21271962 TI - The PBL group: self-reflections and feedback for improved learning and growth. AB - The aims of the PBL group are briefly stated: the facilitation of learning, the fostering of self-directed and lifelong learners, and the developments of social skills that may enhance professional relations. These goals may only be reached by systematic and proficient work with the group processes in PBL; and this work has relevance in all the phases of the life of a group: in the initial formation and in the later renegotiations of interactive patterns. In working with the dynamics of a group, the importance of self-evaluation, reflection and feedback between students is emphasized. Inventories are suggested as a means to improve the feedback between students, and also changes in group interactions. The paper calls for a renewed interest in group dynamics in PBL. PMID- 21271963 TI - Patient safety and simulation-based medical education. AB - Continuous quality improvement is an accepted mandate in healthcare services. The delivery of the best, evidence based quality of care ultimately depends on the competences of practitioners as well as the system that supports their work. Medical education has been increasingly called upon to insure providers possess the skills and understanding necessary to fulfill the quality mission. Patient safety has in the past five years rapidly risen to the top of the healthcare policy agenda, and been incorporated into quality initiatives. Demand for curricula in patient safety and transfer of safety lessons learned in other risky industries have created new responsibilities for medical educators. Simulation based medical education will help fill these needs. Simulation offers ethical benefits, increased precision and relevance of training and competency assessment, and new methods of teaching error management and safety culture.Established and successful simulation methods such as standardized patients and task trainers are being joined by newer approaches enabled by improved technology. PMID- 21271964 TI - The marvelous medical education machine or how medical education can be 'unstuck' in time. PMID- 21271965 TI - Faculty development, teacher training and teacher accreditation in medical education: twenty years from now. AB - To address the issue of faculty development in the year 2020, an attempt is made to predict the structure of the future medical school and the profile of a future medical teacher. By projecting from the technological, sociological and structural processes that affect medical education, it can be envisaged that there will be several types of medical teachers, namely specialists, who will be resource people for the students, evaluators of student performance, and a minority of 'process teachers'. The role of the process teachers will be to tutor, facilitate learning, coach and guide the students in the only domain which cannot be self-learned by technological devices, namely: moral issues, interpersonal communication and crisis management. Each type of teacher requires a different training programme. All programmes, however, should be comprehensive, longitudinal or multiphasic, and lead the faculty member from orientation in both the institution and the educational field to a leadership position by successive approximations. It is further expected that societal demands will impose teacher accreditation and, perhaps, licensing. This, however, will remain in the medical profession's hands, and may bring about a resolution of the 'role-profession conflict', and a more favourable self-perception of faculty members as teachers. Finally, an optimistic conclusion is drawn for the future of medical education. PMID- 21271966 TI - The Institute for Learning and Teaching and UK approaches to accrediting teaching: looking to the future. PMID- 21271967 TI - Training and certification of teachers and trainers: the professionalization of medical education. AB - Economic constraints, profound changes in the healthcare system and insufficient educational expertise have gripped medical education. The objective of this study was to review professionalization of medical education and to contribute to an elaboration of a conceptual framework for understanding reforms. We developed a concept map based on information retrieved by searching the Medline/Knowledge Finder and the Cochrane Library databases. The descriptors used for the searches were 'certification, credentialing, education, faculty medical, quality assurance health care, research, staff development, teaching'. The endpoints for the study were: frequency, quality of studies and propositional content with regard to professionalization for developing a concept map. Thirty-one relevant studies were found in Medline.The Cochrane Library search returned no relevant studies. The evidence of the few studies was weak. The literature-derived concept map shows that faculty development is a prerequisite for certification leading to professionalization. Other related variables were resource allocation, intrinsic motivation to learn, educational research, study time, financial policy, organizational and staff development, and new specialized roles such as clinician educator. It is concluded that professionalization of medical education is needed. This deficit underscores the need for conceptually sound research approaches. The concept of intrinsic motivation explains how to comply with scientifically based standards, thus fostering professionality. Approaches facilitating compliance, such as evidence-based learning, potentially professionalize the practice of medical education. Novel approaches such as quality management and best evidence medical education could professionalize medical education. PMID- 21271968 TI - The global medical school, 2020. AB - With fast-developing technologies and communication, the future of the medical school is not clear. The definition of the graduate is shifting from what was forged in the past to a new doctor. The trends are towards more specialization, mastering of modern technologies and scientific achievements, versus community awareness and a return to family doctors. An innovative approach was taken with the development of a program in International Health and Medicine at Ben Gurion University, supplementing the regular curriculum of the Medical School. Such programs might bridge the gap between the doctor in industrial countries and the physician in Third World countries, by creating a physician who will be able to function in cultural environments other than his/her own. PMID- 21271969 TI - The medical teacher in the year 2020. PMID- 21271970 TI - The Medical Student in the year 2020. PMID- 21271971 TI - Do you know? PMID- 21271973 TI - What's new in medical education: items of interest to medical educators. PMID- 21271974 TI - News for AMEE members. PMID- 21271975 TI - Jottings. PMID- 21271976 TI - The effect of deleting a putative salt bridge on the properties of the thermostable subtilisin-like proteinase, aqualysin I. AB - Aqualysin I, is a subtilisin-like serine proteinase, from the thermophilic bacterium Thermus aquaticus. It is predicted that the enzyme contains a salt bridge, D17-R259, connecting the N- and C-terminal regions of the enzyme. Previously we reported on the stabilizing effect of the incorporation of a salt bridge at a corresponding site in VPR, a related cold adapted enzyme from a marine Vibrio sp. Here we describe the effect of the reverse change, i.e. the elimination of the salt bridge on the thermal stability and kinetic properties of aqualysin I. Deletion of the putative salt bridge in the D17N mutant of the enzyme destabilized the enzyme by 8-9 degrees C in terms of T50%, determined by thermal inactivation and over 4 degrees C in T(m), as measured from melting curves of the inhibited enzyme. The mutation, however, had no significant effect on the kinetic parameters of the enzyme under standard assay conditions. PMID- 21271977 TI - Isolation and compositional analysis of a CP12-associated complex of calvin cycle enzymes from Nicotiana tabacum. AB - Two Calvin Cycle enzymes, NAD(P)-dependent glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and phosphoribulokinase (PRK) form a multiprotein complex with CP12, a small intrinsically-unstructured protein. Under oxidizing conditions, association with CP12 confers redox-sensitivity to the otherwise redox-insensitive A isoform of GAPDH (GapA) and provides an additional level of down-regulation to the redox-regulated PRK. To determine if CP12-mediated regulation is specific for GAPDH and PRK in vivo, a high molecular weight complex containing CP12 was isolated from tobacco chloroplasts and leaves and its protein composition was characterized. Gel electrophoresis and immunoblot analyses after separation of stromal proteins by size fractionation verified that the GAPDH (both isoforms) and PRK co-migrated with CP12 in dark- but not light-adapted chloroplasts. Nano-liquid-chromatography-mass-spectrometry of the isolated complex identified only CP12, GAPDH and PRK. Since nearly all of the CP12 from darkened chloroplasts migrates with GADPH and PRK as a high molecular mass species, these data indicate that the tight association of tobacco CP12 with GAPDH and PRK is specific and involves no other Calvin Cycle enzymes. PMID- 21271978 TI - Using pseudo amino acid composition to predict protease families by incorporating a series of protein biological features. AB - Proteases are essential to most biological processes though they themselves remain intact during the processes. In this research, a computational approach was developed for predicting the families of proteases based on their sequences. According to the concept of pseudo amino acid composition, in order to catch the essential patterns for the sequences of proteases, the sample of a protein was formulated by a series of its biological features. There were a total of 132 biological features, which were sourced from various biochemical and physicochemical properties of the constituent amino acids. The importance of these features to the prediction is rated by Maximum Relevance Minimum Redundancy algorithm and then the Incremental Feature Selection was applied to select an optimal feature set, which was used to construct a predictor through the nearest neighbor algorithm. As a demonstration, the overall success rate by the jackknife test in identifying proteases among their seven families was 92.74%. It was revealed by further analysis on the optimal feature set that the secondary structure and amino acid composition play the key roles for the classification, which is quite consistent with some previous findings. The promising results imply that the predictor as presented in this paper may become a useful tool for studying proteases. PMID- 21271979 TI - An efficient support vector machine approach for identifying protein S nitrosylation sites. AB - Protein S-nitrosylation plays a key and specific role in many cellular processes. Detecting possible S-nitrosylated substrates and their corresponding exact sites is crucial for studying the mechanisms of these biological processes. Comparing with the expensive and time-consuming biochemical experiments, the computational methods are attracting considerable attention due to their convenience and fast speed. Although some computational models have been developed to predict S nitrosylation sites, their accuracy is still low. In this work,we incorporate support vector machine to predict protein S-nitrosylation sites. After a careful evaluation of six encoding schemes, we propose a new efficient predictor, CPR SNO, using the coupling patterns based encoding scheme. The performance of our CPR-SNO is measured with the area under the ROC curve (AUC) of 0.8289 in 10-fold cross validation experiments, which is significantly better than the existing best method GPS-SNO 1.0's 0.685 performance. In further annotating large-scale potential S-nitrosylated substrates, CPR-SNO also presents an encouraging predictive performance. These results indicate that CPR-SNO can be used as a competitive protein S-nitrosylation sites predictor to the biological community. Our CPR-SNO has been implemented as a web server and is available at http://math.cau.edu.cn/CPR -SNO/CPR-SNO.html. PMID- 21271980 TI - Nano-combinatorial and catalyst screening technologies. PMID- 21271981 TI - Atom probe tomography - a high throughput screening tool for atomic scale chemistry. AB - The objective of this paper is to examine the challenges and opportunities in high throughput screening of atomic scale chemistry via a technique known as atom probe tomography. While there are numerous methods that exist in the field of throughput screening, even at the nanoscale, most of the effort is on screening properties , rather than chemistry and/or structure. In this overview, we discuss the role atom probe tomography can have as a high throughput screening tool of atomic scale chemistry. Particular emphasis on the study of organic/ biological materials is given along with the needs and challenges to make atom probe tomography more widespread in the field of combinatorial chemistry. PMID- 21271982 TI - Characterizing the surface chemistry of nanoparticles: an analogy to solid-phase synthesis samples. AB - Chemical modifications of nanoparticle's (NP's) surfaces can be used to regulate their activities, remove their toxic effects, and enable them to perform desired functions. Similar to SPS samples, modified NPs also have small-molecules on the surface of a solid support. The need to monitor synthesis, optimize reaction conditions, and characterize the products is quite similar in both situations. FTIR, NMR, MS and other analytical methods have been used as effective methods to analyze surface bound molecules and monitor organic reactions directly, or indirectly, on a solid phase of a resin or a NPs. PMID- 21271983 TI - Impact of nanomaterials on high-throughput separation methodologies. AB - Due to the unique properties, such as their large surface to volume ratio and easy modification, nanomaterials have recently been studied as effective sorbents in the field of separation science. It has proven to be more effective and efficient to use nanoparticles (NPs) as a stationary phase in solid-phase extraction separation. In addition, NPs can be also used as buffer additives in capillary electrophoresis separation. This review highlights recent developments in high-throughput separation methodologies employing nanomaterials such as carbon nanotubes, gold nanoparticles and magnetic NPs etc. PMID- 21271984 TI - Glyconanoparticles for biomedical applications. AB - Over the past two decades, glycosylated nanoparticles (i.e., glyconanoparticles having sugar residues on the surface) received much attention for biomedical applications such as bioassays and targeted drug delivery. This minireview focuses on three aspects: (1) glycosylated gold nanoparticles, (2) glycosylated quantum dots, and (3) glyconanoparticles self-assembled from amphiphilic glycopolymers. The synthetic methods and the multivalent interactions between glyconanoparticles and lectins is shortly illustrated. PMID- 21271985 TI - Application of parallel synthesis and high-throughput characterization in photocatalyst discovery. AB - The last decade has seen significant progresses in the application of combinatorial approaches and high-throughput screening in photocatalyst discovery. This paper aims at providing a comprehensive review on the parallel synthesis and high-throughput characterization of photocatalysts, including the development of instrumentation, strategy of experiment, preparation of libraries, high-throughput screening technique and data analysis. The review ends with a summary of the remaining challenges and prospects on combinatorial photocatalyst discovery. PMID- 21271987 TI - Toll-like receptors in ocular surface diseases: overview and new findings. AB - The ocular surface is the first line of defence in the eye against environmental microbes. The ocular innate immune system consists of a combination of anatomical, mechanical and immunological defence mechanisms. TLRs (Toll-like receptors), widely expressed by the ocular surface, are able to recognize microbial pathogens and to trigger the earliest immune response leading to inflammation. Increasing evidence highlights the crucial role of TLRs in regulating innate immune responses during ocular surface infective and non infective inflammatory conditions. In addition, recent observations have shown that TLRs modulate the adaptive immune response, also playing an important role in ocular autoimmune and allergic diseases. One of the main goals of ocular surface treatment is to control the inflammatory reaction in order to preserve corneal integrity and transparency. Recent experimental evidence has shown that specific modulation of TLR pathways induces an improvement in several ocular inflammatory conditions, such as allergic conjunctivitis, suggesting new therapeutic anti-inflammatory strategies. The purpose of the present review is to summarize the current knowledge of TLRs at the ocular surface and to propose them as potential targets of therapy for ocular inflammatory conditions. PMID- 21271986 TI - Healthy aging and disease: role for telomere biology? AB - Aging is a biological process that affects most cells, organisms and species. Human aging is associated with increased susceptibility to a variety of chronic diseases, including cardiovascular disease, Type 2 diabetes, neurological diseases and cancer. Despite the remarkable progress made during the last two decades, our understanding of the biology of aging remains incomplete. Telomere biology has recently emerged as an important player in the aging and disease process. PMID- 21271989 TI - Preventing eczema flares with topical corticosteroids or tacrolimus: which is best? PMID- 21271990 TI - Infantile haemangioma: new aspects on the pathogenesis of the most common skin tumour in children. PMID- 21271991 TI - gamma-Secretase gene mutations link acne inversa with Alzheimer's disease. PMID- 21271992 TI - Nurse prescribing, concordance and the therapeutic consultation. PMID- 21271993 TI - Sun exposure induces rapid immunological changes in skin and peripheral blood in patients with psoriasis. AB - BACKGROUND: Ultraviolet (UV) radiation has immunosuppressive effects and heliotherapy is a well-described treatment modality for psoriasis. OBJECTIVES: To characterize early sun-induced immunological changes both local and systemic in patients with psoriasis. METHODS: Twenty patients with moderate to severe psoriasis were subjected to controlled sun exposure on Gran Canaria, Canary Islands, Spain. Psoriasis Area and Severity Index (PASI) scores were evaluated. Skin biopsies were obtained from lesional and nonlesional skin in 10 patients at baseline and on day 16 and from five additional patients on day 2. Specimens were examined with immunohistochemistry and polymerase chain reaction. Blood samples were obtained from all patients at the same time points and were examined for T cell subsets and cytokine production. RESULTS: Significant clinical improvement was achieved during the study period. CD4+ and CD8+ T cells in lesional skin were significantly reduced in both the epidermis and dermis. In contrast, dermal FOXP3+ T cells were relatively increased. In the peripheral blood skin homing cutaneous lymphocyte-associated antigen (CLA)+ T cells were significantly decreased after only 1 day in the sun and in vitro stimulated peripheral blood mononuclear cells demonstrated reduced capacity to secrete cytokines after 16 days. CONCLUSIONS: Our data show that clinical improvement of psoriasis following sun exposure is preceded by a rapid reduction in local and systemic inflammatory markers, strongly suggesting that immune modulation mediated the observed clinical effect. We cannot completely rule out that other mechanisms, such as stress reduction, may contribute, but it is extensively documented that UV irradiation is a potent inducer of immunosuppression and we therefore conclude that the observed effect was primarily due to sun exposure. PMID- 21271994 TI - Expanding the keratin mutation database: novel and recurrent mutations and genotype-phenotype correlations in 28 patients with epidermolytic ichthyosis. AB - BACKGROUND: Epidermolytic ichthyosis (EI) is a hereditary keratinization disorder caused by mutations in the keratin 1 (KRT1) or keratin 10 (KRT10) genes. In most cases of severe EI, heterozygous single point mutations are found at the highly conserved helix boundary motifs of KRT1 and KRT10 that play a critical role in filament formation. The presence of palmoplantar keratoderma suggests KRT1 mutations, whereas KRT10 mutations in most instances give rise to the nonpalmoplantar variants. OBJECTIVES: To identify the underlying mutations in patients with EI and to correlate genotype and phenotype. METHODS: Mutation analysis was performed in 28 patients with EI by direct sequencing of KRT1 and KRT10 genes. RESULTS: We identified 14 different mutations, of which four have not been published previously. CONCLUSIONS: Identification of novel mutations and genotype-phenotype correlations in EI allows improved understanding of disease pathogenesis as well as better patient management. PMID- 21271995 TI - Immunological activity of photodynamic therapy for genital warts. AB - BACKGROUND: An increasing body of evidence supports the usefulness of photodynamic therapy (PDT) in the treatment of non-neoplastic pathological conditions, including genital warts. In particular, PDT has demonstrated good clinical cure rates and low recurrence, and is now suggested as a safe alternative means of treating condylomata. OBJECTIVE: To confirm the suitability of aminolaevulinic acid (ALA)-PDT for the treatment of this condition and to investigate the recruitment and significance of immune cells in lesional areas by immunohistochemical analysis at different time intervals after treatment. METHODS: Fifteen subjects with histologically proven, recalcitrant condylomata acuminata of the penis, urethra, vulva or perianal area underwent several cycles of PDT following ALA application. Biopsies were taken at baseline and at different intervals during the trial, and infiltrating immune cells, CD3, CD4, CD8, CD1a and CD68, were evaluated by double immunocytochemical alkaline phosphatase antialkaline phosphatase (APAAP) staining. RESULTS: Our trial provided a complete cure rate of nine of 15 subjects after five PDT sessions. Perianal lesions showed a particularly rapid remission. While progressing towards total lesion clearance, the immunohistochemical pattern was dominated by dense CD4+ T lymphocytes infiltrating the superficial dermis, accompanied by an accumulation of Langerhans cells. Simultaneously, CD8 began to increase in the lesions of responding patients, and Langerhans cells seemed to migrate towards the dermis. CD68+ macrophages apparently did not participate in the immune inflammatory response. CONCLUSIONS: This study, to the best of our knowledge, represents the first attempt to clarify the effect of ALA-PDT on infiltrating immune cells in condylomata acuminata. Our results appear to confirm previously reported clinical data, suggesting that rapid activation of specific immunity in lesional skin, CD4+ T lymphocytes and dendritic cells could be responsible for healing. PMID- 21271996 TI - beta2-Adrenoceptors, NADPH oxidase, ROS and p38 MAPK: another 'radical' road to heart failure? AB - Persistent activation of the cardiac beta-adrenergic system may contribute to the pathogenesis of congestive heart failure. Both beta1- and beta2-adrenoceptors are known to mediate these noxious effects, yet the beta1-adrenoceptor-PKA axis has received greater attention with less information available on beta2-adrenoceptor driven pathways. In the present issue, Xu and colleagues provide new evidence, showing that beta2-adrenoceptor over-expression leads to increased reactive oxygen species (ROS) emission, mainly caused by up-regulation of reduced nicotinamide adenine dinucleotide phosphate oxidase (Nox) 2 and 4. Increase in ROS levels is accompanied by p38 mitogen-activated protein kinase activation, fibrosis, apoptosis and cardiac dysfunction. Both Nox inhibition and administration of the antioxidant N-acetyl cysteine prevent these adverse effects. Interestingly, antioxidant treatment also prevents the increase in Nox expression, suggesting that beta2-adrenoceptor stimulation triggers a vicious cycle eventually amplified by both Nox isoforms. The possible existence of a circuitry to enhance ROS signalling and detrimental consequences on myocardial remodelling are also discussed, in light of the recent description of intracellular localization of Nox4. PMID- 21271997 TI - Perceived sperm competition intensity influences seminal fluid protein production prior to courtship and mating. AB - Sperm competition is a potent postcopulatory selective force where sperm from rival males compete to fertilize a limited set of ova. Considering that sperm production is costly, we expect males to strategically allocate sperm in accordance with the level of competition. Accordingly, previous work has examined a male's strategic allocation in terms of sperm number. However, the seminal fluid proteins (Sfps) transferred along with sperm may also play a crucial role in competition. Surprisingly, the strategic allocation of Sfps has remained largely unexplored. Using Drosophila melanogaster, we examined the expression of three seminal fluid and four spermatogenesis genes in response to perceived sperm competition intensity by manipulating male density in a pre-mating and courtship environment. In the pre-mating environment, we found that males modified Sfp ratios by reducing the production of two spfs when potential rivals were present, while one Sfp and all spermatogenesis genes remained unaltered. In the courtship environment, males did not modify spermatogenesis or Sfp production in response to either rival males or female presence. Our data suggest that perceived competition in the pre-mating environment places a significant influence on Sfp allocation, which may be a general trend in promiscuous animal systems with internal fertilization. PMID- 21271998 TI - Evolutionary syndromes linking dispersal and mating system: the effect of autocorrelation in pollination conditions. AB - Self-fertilization is classically thought to be associated with propagule dispersal because self-fertilization is a boon to colonizers entering environments devoid of pollinators or potential mates. Yet, it has been theoretically shown that random fluctuations in pollination conditions select for the opposite association of traits. In nature, however, various ecological factors may deviate from random variations, and thus create temporal correlation in pollination conditions. Here, we develop a model to assess the effects of pollination condition autocorrelation on the joint evolution of dispersal and self-fertilization. Basically, two syndromes are found: dispersing outcrossers and nondispersing (partial) selfers. Importantly, (1) selfers are never associated with dispersal, whereas complete outcrossers are, and (2) the disperser/outcrosser syndrome is favored (resp. disfavored) by negative (resp. positive) autocorrelation in pollination conditions. Our results suggest that observed dispersal/mating system syndromes may depend heavily on the regime of pollination condition fluctuations. We also point out potential negative evolutionary effects of anthropic management of the environment on outcrossing species. PMID- 21271999 TI - Aposematic signal variation predicts male-male interactions in a polymorphic poison frog. AB - Many species use conspicuous "aposematic" signals to communicate unpalatability/unprofitability to potential predators. Although aposematic traits are generally considered to be classic examples of evolution by natural selection, they can also function in the context of sexual selection, and therefore comprise exceptional systems for understanding how conspicuous signals evolve under multifarious selection. We used males from a highly territorial poison frog species in a dichotomous choice behavioral test to conduct the first examination of how aposematic signal variation influences male-male interactions. Our results reveal two behavioral patterns: (1) male dorsal brightness influences the behaviors of male conspecifics such that males approach and call to brighter males more frequently and (2) a male's dorsal brightness predicts his own behavior such that bright males approach stimulus frogs faster, direct more calls to bright stimulus frogs, and exhibit lower advertising call pulse rates (a fitness-related trait). These findings indicate the potential for sexual selection by male-male competition to impact aposematic signal evolution. PMID- 21272000 TI - The local-clock permutation test: a simple test to compare rates of molecular evolution on phylogenetic trees. AB - Rates of molecular evolution vary substantially between lineages, and a growing effort is directed at uncovering the causes and consequences of this variation. Comparing local-clocks (rates of molecular evolution estimated from different sets of branches of a phylogenetic tree) is a common tool in this research effort. Here, I show that a commonly used test (the Likelihood Ratio Test, LRT) will not be statistically valid for comparing local-clocks in most cases. Instead, I propose the local-clock permutation test (LCPT), a simple test that can be used to test the significance of differences between local-clocks. The LCPT could also be used to test for differences between any parameter that can be assigned to individual branches on a phylogenetic tree. Using simulated data, I show that the LCPT has good power to detect differences between local-clocks. PMID- 21272001 TI - Field tests of interspecific competition in ant assemblages: revisiting the dominant red wood ants. AB - 1. There has been considerable debate on the importance of competition in ecological communities, but its importance in structuring ant assemblages has often been uncritically accepted. Here, we briefly review field experiments examining competition in ant assemblages and use a removal experiment to test the effect of the classical territorial dominant ant, Formica aquilonia. Ants of this species group are thought to structure communities through a dominance hierarchy. 2. First, we used pitfall traps to compare the abundance of other ants in replicated sites with low and high densities of F. aquilonia. We found differences in community composition, in particular, Camponotus herculeanus was more common in low-density sites, in accordance with predictions. Differences in ant assemblages were not owing to differences in measured habitat variables. 3. We removed F. aquilonia from a set of high-density sites, using physical and chemical methods, and repeated these procedures at procedural control sites. One year after removal, abundances of F. aquilonia at removal sites were similar to those at low-density sites. However, the composition of other species did not change in response to F. aquilonia removal. Replication rates were identical in the mensurative and experimental components of this study, so this is unlikely to be owing to the analysis being insufficiently powerful. 4. We suggest three possibilities for the lack of difference. First, the study may have been too short term or small scale to detect differences. However, previous studies have shown effects on smaller spatial- and temporal-scales. Second, priority effects may be important in the successful colonisation by F. aquilonia. Thirdly, boreal ant assemblages may be too depauperate for redundancy in ecological roles and for competition to play an important structuring role. 5. We thus recommend that long term large-scale experiments be considered essential if we are to distinguish between competing hypotheses in community ecology. PMID- 21272002 TI - The tyrosine phosphatase Shp-2 interacts with the dopamine D(1) receptor and triggers D(1) -mediated Erk signaling in striatal neurons. AB - We report a novel mechanism for dopamine D(1) receptor (D(1) R)-mediated extracellular signal-regulated kinases (Erk) activation in rat striatum. Erk signaling depends on phosphorylation and dephosphorylation events mediated by specific kinases and phosphatases. The tyrosine phosphatase Shp-2, that is required for Erk activation by tyrosine kinase receptors, has been recently shown to regulate signaling downstream of few G protein-coupled receptors. We show that the D(1) R interacts with Shp-2, that D(1) R stimulation results in Shp-2 tyrosine phosphorylation and activation in primary striatal neuronal cultures and that D(1) R/Shp-2 interaction is required for transmitting D(1) R-dependent signaling to Erk1/2 activation. D(1) R-mediated Erk1/2 phosphorylation in cultured striatal neurons is in fact abolished by over-expression of the inactive Shp-2(C/S) mutant and by small interfering RNA-induced Shp-2 silencing. Moreover, by using selective inhibitors we show that both D(1) R-induced Shp-2 activation and Erk1/2 phosphorylation are dependent on the cyclic AMP/protein kinase A pathway and require Src. These results, which were substantiated also in transfected human embryonic kidney 293 cells, provide a novel mechanism by which to converge D(1) R signaling to the Erk pathway and suggest that Shp-2 or the D(1) R/Shp-2 interface could represent a potential drug target for disorders of dopamine transmission involving malfunctioning of D(1) R signaling. PMID- 21272003 TI - Age-related changes of glycine receptor at the rat hippocampus: from the embryo to the adult. AB - Glycinergic inhibitory transmission has been described in spinal cord, but rather disregarded in the brain. The spatial-temporal characterization of glycine receptors (GlyR) in the hippocampus over development is herein reported. GlyR expression increases from late embryonic stage (E18) to 7 days postnatal (P7) and decreases from P7 on. Quantitative real-time PCR showed that GlyR subunit expression changes over neuronal maturation with a preponderance of alpha2 and alpha3, over alpha1 and beta. In immature stages, GlyR delineate the cell body of neurons at the Dentate Gyrus and Cornus Ammonis 1 and 3 (CA1/CA3) and are composed of alpha2 and alpha3 subunits. At P7, synaptic GlyRalpha2beta can already be observed in the dendritic areas of Dentate Gyrus and of CA1/CA3. In the mature hippocampus, synaptic GlyR decrease and, although a few synaptic GlyRalpha1beta can still be detected in the dendritic layers, extrasynaptic alpha2/alpha3-containing GlyR and somatic localized GlyRalpha3 are the most abundant. Our results point towards an important function of a slow tonic activation of extrasynaptic GlyR, over a fast phasic activation of synaptic GlyRalpha1beta. We clearly show that GlyR are widely expressed in hippocampus and that their subcellular localization and subunit composition change over development. PMID- 21272005 TI - Regulation of alpha-synuclein expression in cultured cortical neurons. AB - Alpha-synuclein (SNCA) is a predominantly neuronal protein involved in the control of neurotransmitter release. The levels of SNCA expression are closely linked to the pathogenesis of Parkinson's disease; however, the biochemical pathways and transcriptional elements that control SNCA expression are not well understood. We previously used the model system of neurotrophin-mediated PC12 cell neuronal differentiation to examine these phenomena. Although these studies were informative, they were limited to the use of a cell line; therefore, in the current work, we have turned our attention to cultured primary rat cortical neurons. In these cultures, SNCA expression increased with time in culture, as the neurons mature. Luciferase assays based on transient transfections of fusion constructs encoding components of the transcriptional control region of SNCA identified various promoter areas that have a positive or negative effect on SNCA transcription. Intron 1, previously identified by us as an important regulatory region in the PC12 cell model, cooperates with regions 5' to exon 1 to mediate gene transcription. Using selective pharmacological tools, we find that tyrosine kinase receptors and the phosphatidyl-inositol 3 kinase signaling pathway are involved in mediating these effects. The exogenous application of the neurotrophin brain-derived neurotrophic factor (BDNF) is sufficient on its own to promote the transcriptional activation of SNCA through this pathway, but a neutralizing antibody against BDNF failed to affect SNCA transcription in maturing cultures, suggesting that BDNF is not the main factor involved in maturation-induced SNCA transcription in this model. Further in vivo studies are needed to establish the role of neurotrophin signaling in the control of SNCA transcription. PMID- 21272004 TI - Acetate supplementation attenuates lipopolysaccharide-induced neuroinflammation. AB - Glyceryl triacetate (GTA), a compound effective at increasing circulating and tissue levels of acetate was used to treat rats subjected to a continual 28 day intra-ventricular infusion of bacterial lipopolysaccharide (LPS). This model produces a neuroinflammatory injury characterized by global neuroglial activation and a decrease in choline acetyltransferase immunoreactivity in the basal forebrain. During the LPS infusion, rats were given a daily treatment of either water or GTA at a dose of 6 g/kg by oral gavage. In parallel experiments, free CoA and acetyl-CoA levels were measured in microwave fixed brains and flash frozen heart, liver, kidney and muscle following a single oral dose of GTA. We found that a single oral dose of GTA significantly increased plasma acetate levels by 15 min and remained elevated for up to 4 h. At 30 min the acetyl-CoA levels in microwave-fixed brain and flash frozen heart and liver were increased at least 2.2-fold. The concentrations of brain acetyl-CoA was significantly increased between 30 and 45 min following treatment and remained elevated for up to 4 h. The concentration of free-CoA in brain was significantly decreased compared to controls at 240 min. Immunohistochemical and morphological analysis demonstrated that a daily treatment with GTA significantly reduced the percentage of reactive glial fibrillary acidic protein-positive astrocytes and activated CD11b-positive microglia by 40-50% in rats subjected to LPS-induced neuroinflammation. Further, in rats subjected to neuroinflammation, GTA significantly increased the number of choline acetyltransferase (ChAT)-positive cells by 40% in the basal forebrain compared to untreated controls. These data suggest that acetate supplementation increases intermediary short chain acetyl CoA metabolism and that treatment is potentially anti-inflammatory and neuroprotective with regards to attenuating neuroglial activation and increasing ChAT immunoreactivity in this model. PMID- 21272006 TI - Declining foliar and litter delta15N diverge from soil, epiphyte and input delta15N along a 120,000 yr temperate rainforest chronosequence. AB - Patterns in the natural abundance of nitrogen (N) isotopes (15N and 14N) can help in the understanding of ecosystem processes along environmental gradients, because some processes fractionate against the heavier isotope. We measured delta15N in many components of the Franz Josef soil chronosequence in New Zealand to see how each component varied along the sequence and within sites, and to see what this variation can tell us about how ecosystem processes such as N losses change with soil age. We analyzed delta15N in foliage from 18 woody species, abscised leaves from seven woody species, three soil horizons, bryophytes, lichens, bulk deposition, and nodules from the N-fixing tree Coriaria arborea (Coriariaceae). Foliar delta15N varied significantly across plant species. Foliage and bulk litter became 15N-depleted as soil age increased. Soil N from organic and mineral horizons was significantly more 15N-enriched than bulk litter N at each site. Increasing precipitation also decreased foliar and soil delta15N. Comparing input and whole ecosystem delta15N revealed limited evidence for net fractionation during N losses. These trends are consistent with some combination of increasing fractionation during plant N uptake, mycorrhizal transfer, within plant processing, and soil decomposition as soils age. PMID- 21272007 TI - Singlet Oxygen Sensor Green(r): photochemical behavior in solution and in a mammalian cell. AB - The development of efficient and selective luminescent probes for reactive oxygen species, particularly for singlet molecular oxygen, is currently of great importance. In this study, the photochemical behavior of Singlet Oxygen Sensor Green((r)) (SOSG), a commercially available fluorescent probe for singlet oxygen, was examined. Despite published claims to the contrary, the data presented herein indicate that SOSG can, in fact, be incorporated into a living mammalian cell. However, for a number of reasons, caution must be exercised when using SOSG. First, it is shown that the immediate product of the reaction between SOSG and singlet oxygen is, itself, an efficient singlet oxygen photosensitizer. Second, SOSG appears to efficiently bind to proteins which, in turn, can influence uptake by a cell as well as behavior in the cell. As such, incorrect use of SOSG can yield misleading data on yields of photosensitized singlet oxygen production, and can also lead to photooxygenation-dependent adverse effects in the system being investigated. PMID- 21272008 TI - Addiction reviews. Preface. PMID- 21272010 TI - Imaging brain response to reward in addictive disorders. AB - We compare the evidence from human neuroimaging studies for and against two of the major hypotheses of how alterations in the brain's reward system underlie addiction. One of these, the impulsivity hypothesis, proposes that addiction is characterized by excessive sensitivity to reward combined with a failure of inhibition. The other, the reward-deficiency hypothesis, proposes that addicted individuals have a reduced response to nondrug rewards that leads them to seek drugs in preference to more socially acceptable goals. Positron emission tomographic (PET) studies of dopamine receptor density and dopamine release strongly support the reward-deficiency hypothesis, while the more recent and numerous functional magnetic resonance imaging (fMRI) studies of goal-directed behavior provide both support and contradiction for each of the hypotheses. Differences in the time scale on which PET and fMRI make measurements probably account for differences in results, at least in part. It is likely that aspects of brain function described by both the impulsivity and reward-deficiency hypotheses contribute to the pathophysiology of addiction. PMID- 21272011 TI - The history and current state of drug abuse in Japan. AB - Drug abuse in Japan began after World War II and has been characterized by three epidemics of methamphetamine abuse; in addition, solvent abuse has been prominent for a long time. Since 1995, with the beginning of the third epidemic of methamphetamine abuse, drug abuse or dependence in Japan changed, with a marked decrease in solvent abuse, stabilization of methamphetamine abuse, an increase in the abuse of such drugs as cannabis or 3,4-methylenedioxymethamphetamine (which do not have high potential of causing drug-induced psychosis), and the emergence of designer drugs. Furthermore, the abuse of medical drugs such as Ritalin became a major issue in 2007. These changes reveal an increase in the abuse of drugs that do not as easily produce a psychotic state, underlain with a shift from personal conduct that leads to arrest to conduct that does not. Japan, therefore, needs to deal with drug abuse and dependence using not only a medical model, but also a criminal model as well. PMID- 21272012 TI - Individual vulnerability to addiction. AB - The process of addiction is often studied in the neurosciences as a function of the quantity or type of substance consumed, with the ultimate goal of counteracting these effects by other pharmacological means. However, epidemiology and clinical research have extensively demonstrated that most individuals who use drugs do not develop dependence. Numerous factors may explain an individual's propensity to addiction. This review discusses these paradigms and summarizes research on individual differences that encompass cultural and sociodemographic factors, psychiatric or psychological vulnerability, and biological or genetic propensity to addiction. Although these different factors often interact in the expression of vulnerable phenotypes, it is possible to alter or control specific sources of vulnerability. For these reasons, integrating individual vulnerability to addiction across different research disciplines is likely to provide the greatest advances for intervention and prevention efforts. PMID- 21272009 TI - Preclinical studies of alcohol binge drinking. AB - Binge drinking is prevalent and has serious biomedical consequences. In children, adolescents, and young adults, it is a prominent risk factor for later development of alcohol-use disorders. Many preclinical models have been employed to study the genetic risks for and biomedical consequences of alcohol drinking. However, these models historically did not result in blood-alcohol concentrations (BACs) exceeding 80 mg%; this relatively modest level is the threshold that currently defines a binge session, according to the NIAAA and CDC. Nevertheless, in alcohol-dependent rodents, binge drinking has been well documented. Key neurobiological substrates localized to brain reward and stress systems have been identified. Studies of newer models of binge drinking without dependence are reviewed here. In these models, rodents, non-human primates, and flies will drink enough to reach high BACs. They often display observable signs of intoxication. The neurobiological consequences of these episodes of binge drinking without dependence are reviewed, and preliminary evidence for roles for GABA, glutamate, opioid peptides, and corticotropin releasing factor are discussed, as is the need for more work to identify the antecedents and consequences of binge drinking in both animal models and humans. PMID- 21272013 TI - VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse. AB - The monoaminergic neuron, in particular the dopaminergic neuron, is central to mediating the hedonic and addictive properties of drugs of abuse. The effects of amphetamine (AMPH) and cocaine (COC), for example, depend on the ability to increase dopamine in the synapse, by effects on either the plasma membrane transporter DAT or the vesicular transporter for monoamine storage, VMAT2. The potential role of DAT as a target for AMPH and COC has been reviewed extensively. Here, we present VMAT2 as a target that enables the rewarding and addictive actions of these drugs, based on imaging, neurochemical, biochemical, cell biological, genetic, and immunohistochemical evidence. The presence of VMAT2 in noradrenergic, serotoninergic, histaminergic, and potentially trace aminergic neurons invites consideration of a wider role for aminergic neurotransmission in AMPH and COC abuse and addiction. PMID- 21272014 TI - The epigenetic landscape of addiction. AB - Drug-induced alterations in gene expression throughout the reward circuitry of the brain are likely components of the persistence of the drug-addicted state. Recent studies examining the molecular mechanisms controlling drug-induced transcriptional, behavioral, and synaptic plasticity have indicated a direct role for chromatin remodeling in the regulation and stability of drug-mediated neuronal gene programs, and the subsequent promulgation of addictive behaviors. In this review, we discuss recent advances in our understanding of chromatin phenomena--or epigenetics, by one definition--that contribute to drug addiction, with the hope that such mechanistic insights may aid in the development of novel therapeutics for future treatments of addiction. PMID- 21272015 TI - Hippocampus, amygdala, and stress: interacting systems that affect susceptibility to addiction. AB - Stress is one of the major factors in drug abuse, particularly in relapse and drug-seeking behavior. However, the mechanisms underlying the interactions between stress and drug abuse are unclear. For many years, studies have focused on the role of the dopaminergic reward system in drug abuse. Our results, for example, show that increased dopaminergic activity is induced by drug sensitization and different stressors via potentiation of the ventral subiculum nucleus accumbens (NAc) pathway. Although the role of the norepinephrine (NE) system in stress is well known, its involvement in drug abuse has received less attention. This review explores the different mechanisms by which stressors can modulate the ventral subiculum-accumbens pathway, and how these modulations can induce alterations in the behavioral response to drug administration. In particular, we will focus on two main afferents to the NAc, the basolateral amygdala and the ventral subiculum of the hippocampus, and their interactions with the locus coeruleus-norepinephrine system. PMID- 21272017 TI - Addictions in pain clinics and pain treatment. AB - A great deal of fear exists in the world of pain management on the part of both healthcare professionals and some patients where issues of abuse, misuse, and addiction are concerned. While it might be easy to consider all pain patients as "drug seekers" or addicts, the reality remains that most pain patients are genuine; we therefore must retain pain management efforts for the many, while being aware and cognizant of the few who have problems such as addiction. To begin to separate these entities, definitions and hallmarks of addiction are explored along with discussion of screening tools that can be employed to help identify problematic patients. In addition, the concepts of dependence and tolerance are defined and separated from old notions of addiction. Finally, issues related to engaging in a multidisciplinary approach are discussed along with caveats regarding prescribing to patients who have histories or ongoing issues of addiction. PMID- 21272016 TI - Pharmacological enhancement of drug cue extinction learning: translational challenges. AB - Augmentation of cue exposure (extinction) therapy with cognitive-enhancing pharmacotherapy may constitute a rational strategy for the clinical management of drug relapse. While certain success has been reported for this form of therapy in anxiety disorders, in this paper we highlight several obstacles that may undermine the efficacy of exposure therapy for substance use disorders. We also review translational studies that have evaluated the facilitative effects of the cognitive enhancer D-cycloserine on extinction targeting drug-related cues. Finally, important considerations for the design and implementation of future studies evaluating exposure therapy combined with pharmacotherapy for substance use disorders are discussed. PMID- 21272018 TI - Intramuscular extended-release naltrexone: current evidence. AB - Extended-release naltrexone (XR-NTX; Vivitrol), developed to address poor adherence in addictive disorders, is approved for use in alcohol and opioid dependence disorders. In alcohol-dependent adults with >= 4-day initial abstinence, XR-NTX increased initial and 6-month abstinence. An fMRI study found that XR-NTX attenuated the salience of alcohol visual and olfactory cues in the absence of alcohol, and post hoc analyses demonstrated efficacy even during high cue-exposure holiday periods. Safety and tolerability have generally been good, without adverse hepatic impact or intractable acute pain management. XR-NTX use appears feasible in primary care and public systems, and retrospective claims analyses have found cost savings and decreased intensive service utilization relative to oral agents. In opioid dependence, following detoxification, XR-NTX shows efficacy for maintaining abstinence, improving retention, decreasing craving, and preventing relapse. Trials are also exploring its use for the treatment of stimulant dependence. XR-NTX appears compatible with counseling and self-help attendance. While more research is needed, current findings suggest that a formulation of naltrexone that was sought beginning over three decades ago is fulfilling its promise as an extended-release pharmacotherapeutic. PMID- 21272019 TI - Nickel allergy is still frequent in young German females - probably because of insufficient protection from nickel-releasing objects. AB - BACKGROUND: Nickel contact allergy is still frequent both in patch-tested patients and in the general population. Objectives. To explain this observation by relating clinical epidemiological data with recent chemical analyses of nickel release from costume jewellery. METHODS: (i) The trend of nickel allergy was analysed using data registered between January 1994 and December 2009 in the Information Network of Departments of Dermatology. (ii) In 2008, different parts of items of costume jewellery purchased at random on the German market (n = 609) were analysed for nickel release according to EN 1811:1998 + A1:2008 in five official German laboratories of food and non-food INVESTIGATION. RESULTS: (i) Between 1994 and 2009, nickel allergy decreased in men (18-30 years) and in women (1-17 and 18-30 years); however, after 2000, there was no significant decrease in nickel allergy in the women aged 1-17 years. (ii) Of the post-assemblies, 28.0% exceeded the migration limit of >=0.2 ug/cm(2) per week, and 5% released >=26.8 ug/cm(2) per week. In articles with direct and prolonged contact with the skin, 12.8% of decorative parts and 17.1% of clasps exceeded the migration limit. If an adjustment factor was applied, according to the above norm, about half of the items otherwise rejected became acceptable. CONCLUSION: Exposure to nickel containing products exceeding the (unnecessarily relaxed) permitted limit may explain why nickel contact allergy remains a problem. PMID- 21272020 TI - Nickel deposited on the skin-visualization by DMG test. AB - BACKGROUND: Nickel is the most common cause of contact allergy and an important risk factor for hand eczema. Visualization techniques may be powerful in showing exposures. The dimethylglyoxime (DMG) test might be used to establish skin exposure to nickel. OBJECTIVES: To develop and evaluate methods for visualization of nickel on the skin by the DMG test and hand imprints. METHODS: Nickel solutions at different concentrations were applied in duplicate on the hands in healthy subjects (n = 5). The DMG test and acid wipe sampling for quantification were then performed. Hand imprints were taken after manipulation of nickel releasing tools (n = 1), and in workers performing their normal tasks (n = 7). The imprints were developed by the DMG test. RESULTS: The DMG test on hands gave positive results in all subjects. The lowest concentration giving rise to a colour change was set to 0.13 ug/cm(2) for DMG testing on skin. DMG test developed imprints worked well except when hands were heavily contaminated by other particles/dust. CONCLUSIONS: The DMG test may be used as a simple and powerful tool for visualization of nickel on skin. DMG test-developed hand imprints may, in the future, be used for semi-quantitative or quantitative exposure assessment. PMID- 21272021 TI - Occupational allergic contact dermatitis caused by rhodium solutions. PMID- 21272022 TI - Allergic contact dermatitis caused by tetrahydroxypropyl ethylenediamine in cosmetic products. PMID- 21272023 TI - A confidence interval for the difference between two reaction indices. PMID- 21272024 TI - Occupational allergic contact dermatitis caused by morphine. PMID- 21272025 TI - Allergic contact dermatitis caused by glycyrrhetinic acid and castor oil. PMID- 21272026 TI - Contact dermatitis and secondary systemic allergy to dimethindene maleate. PMID- 21272027 TI - Is matrix metalloproteinase-9 a culprit involved in dermatitis? Increased expression of gelatinolytic activity in allergic contact dermatitis. PMID- 21272028 TI - Age-related sensitization to p-phenylenediamine. PMID- 21272029 TI - Irritant contact dermatitis caused by Ranunculus kotschyi Boiss in 6 cases. PMID- 21272030 TI - The increase in p-phenylenediamine allergy in Denmark is not explained by an increase in contact allergy to para group chemicals. PMID- 21272031 TI - Anaphylactic reactions following Kenacort-A(r) injection: carboxymethylcellulose is involved once again. PMID- 21272032 TI - Occupational erythema multiforme-like contact reaction to iodoacetonitrile in a chemistry student. PMID- 21272033 TI - Photodermatitis caused by oral ketoprofen: two case reports. PMID- 21272034 TI - Allergic contact dermatitis caused by benzophenone-4 in a printer. PMID- 21272035 TI - Inhibition of ongoing allergic reactions using a novel anti-IgE DARPin-Fc fusion protein. AB - BACKGROUND: Aggregation of the high-affinity IgE receptor (FcepsilonRI) with the low-affinity IgG receptor (FcgammaRIIb) on basophils or mast cells has been shown to inhibit allergen-induced cell degranulation. Molecules cross-linking these two receptors might therefore be of interest for the treatment of allergic disorders. Here, we demonstrate the generation of a novel bispecific fusion protein efficiently aggregating FcepsilonRI-bound IgE with FcgammaRIIb on the surface of basophils to prevent pro-inflammatory mediator release. METHODS: Alternative binding molecules recognizing receptor-bound human IgE were selected from DARPin (designed ankyrin repeat protein) libraries. One of the selected DARPins was linked to the Fc-part of a human IgG(1) antibody for binding to FcgammaRIIb. RESULTS: The resulting anti-IgE DARPin-Fc fusion protein was not anaphylactogenic and inhibited allergen-induced basophil activation in whole blood assays. Both binding moieties of the fusion protein, namely the anti-IgE DARPin as well as the IgG(1) Fc-part, were required to achieve this inhibitory effect. Most importantly, inhibition was faster and more efficient than with Omalizumab, a humanized anti-IgE antibody currently used for the treatment of severe asthma. CONCLUSION: This novel anti-IgE DARPin-Fc fusion protein might represent a potential drug candidate for preventive or immediate treatment of allergic reactions. PMID- 21272036 TI - Explaining patterns of infection in free-living populations using laboratory immune experiments. AB - The host response to different helminth species can vary and have different consequences for helminth persistence. Often these differences are generated by changes in the dynamics and intensity of the immune components against parasites with distinct life history strategies. We examined the immune response of rabbits to primary infections of the gastrointestinal nematodes Trichostrongylus retortaeformis and Graphidium strigosum under controlled conditions for 120 days post-challenge. Results showed that rabbits developed a robust and effective immune response against T. retortaeformis and abundance quickly decreased in the duodenum and was completely cleared in the remaining sections of the small intestine within 4 months. Infected individuals exhibited an initial strong inflammatory response (IFN-gamma), IL-4 expression also increased and was coupled to a rapid serum and mucus IgG and IgA and eosinophilia. Strong IL-4, serum IgA and IgG responses and eosinophilia were also observed against G. strigosum. However, parasite abundance remained consistently high throughout the infection, and this was associated with relatively low mucus antibodies. These findings suggest that immunity plays a key role in affecting the abundance of these nematodes, and different immune mechanisms are involved in regulating the dynamics of each infection and their long-term persistence in free-living host populations. PMID- 21272037 TI - Low-level efficacy of cosmetic preservatives. AB - Preservation using combinations of preservatives has several advantages. This study shows that the concentration of some of the most frequently used allergenic preservatives can be markedly lowered when they are combined with phenoxyethanol. The antimicrobial efficacy of cosmetic preservatives and known allergens of various potency [diazolidinyl urea, methylchloroisothiazolinone/methylisothiazolinone (MCI/MI), methylisothiazolinone (MI) and phenoxyethanol] was tested alone and in various combinations of two or three preservatives together. The preservatives were tested for minimum inhibitory concentration (MIC) values and possible synergy using fractional inhibitory concentration. MCI/MI was the only preservative showing low-level MIC against all four tested microorganisms: Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans and Aspergillus niger. Different combinations of the preservatives indicated additive effects against the microorganisms. No combination of preservatives showed any inhibitory action on each other. Challenge tests with different concentrations and combinations were performed in a cosmetic cream. Diazolidinyl urea and MCI/MI alone were ineffective against C. albicans in a challenge test at concentrations up to 16 times higher than the observed MIC values. When combining phenoxyethanol with either one of the allergenic preservatives diazolidinyl urea, MCI/MI or MI, the cosmetic cream was adequately preserved at concentrations well below the preservatives' MIC values as well as 10-20 times below the maximum permitted concentrations. By using combinations of preservatives, effective preservation can be achieved with lower concentrations of allergenic preservatives. PMID- 21272038 TI - Sensory analysis of lipstick. AB - Sensory analysis of lipstick product by trained panellists started with recruiting female panels who are lipstick users, in good health condition and willing to be a part of sensory members. This group of people was further scrutinized with duo-trio method using commercial lipstick samples that are commonly used among them. About 40% of the 15 panels recruited were unable to differentiate the lipstick samples they usually use better than chance. The balance of nine panels that were corrected at least with 65% across all trials in panels screening process was formed a working group to develop sensory languages as a means of describing product similarities and differences and a scoring system. Five sessions with each session took about 90 min were carried out using 10 types of lipsticks with different waxes mixture ratio in the formulation together with six commercial lipsticks that are the most common to the panels. First session was focus on listing out the panels' perception towards the characteristic of the lipstick samples after normal application on their lips. Second session was focus on the refining and categorizing the responses gathered from the first session and translated into sensory attributes with its definition. Third session was focus on the scoring system. Fourth and fifth sessions were repetition of the third session to ensure consistency. In a collective effort of the panels, sensory attributes developed for lipstick were Spreadability, Off flavour, Hardness, Smoothness, Moist, Not messy, Glossy and Greasy. Analysis of variance was able to provide ample evidence on gauging the panel performance. A proper panels selecting and training was able to produce a reliable and sensitive trained panel for evaluating the product based on the procedures being trained. PMID- 21272039 TI - Efficacy of a piroctone olamine/climbazol shampoo in comparison with a zinc pyrithione shampoo in subjects with moderate to severe dandruff. AB - Dandruff is a chronic scalp disorder characterized by scaling and itching. A successful anti-dandruff shampoo not only has to provide superior anti-dandruff relief to ensure patient compliance. It also needs to offer excellent cosmetic and hair conditioning benefits at the same time. In this study, the efficacy of a shampoo containing 0.5% piroctone olamine and 0.45% climbazole (shampoo 1) was compared with a widely available commercial shampoo containing 1% zinc pyrithione (shampoo 2). In vitro studies investigating the anti-mycotic efficacy of a combination of 0.5% piroctone olamine and 0.45% climbazole as well as 1% zinc pyrithione were performed. To study substantivity, pig skin punches were used as a model system and a test of wet combability was performed to characterize combing ease. In vivo home-in-use studies were carried out to determine the efficacy of both shampoos to improve scalp condition and reduce itching in subjects suffering from moderate to severe dandruff. Results demonstrated a comparable anti-fungal effectiveness for 0.5% piroctone olamine plus 0.45% climbazole and 1% zinc pyrithione, respectively. Shampoo 1 showed a significantly higher anti-mycotics substantivity compared to shampoo 2. After treatment with shampoo 1, the wet combing force was significantly reduced compared with shampoo 2, suggesting a better combability following the use of shampoo 1. In an in vivo split head design study, shampoo 1 was shown to be equally effective in reducing the amount of dandruff on the scalp compared with shampoo 2. The approval rate of volunteers regarding the question 'The use of this shampoo decreases the itching of my scalp?' after a 4-week treatment with shampoo 1 equaled 90%. Overall, the shampoo formulation with 0.5% piroctone olamine and 0.45% climbazole effectively reduces the amount of dandruff and, at the same time, provides hair conditioning advantages. PMID- 21272040 TI - Design and application of water-in-oil emulsions for use in lipstick formulations. AB - The addition of water to lipsticks in the form of a water-in-oil emulsion is an attractive opportunity for cosmetics manufacturers to deliver hydrophilic molecules to the consumers, as well as improving the moisturizing properties. In this work, the effect of the emulsifier type and water content on the structural properties of the designed products was investigated. It has been shown that PGPR leads to smaller droplets than the other emulsifiers tested. This was attributed to the ability of PGPR to form elastic interfaces that slow the coalescence between droplets during the process. It was also observed that crystals of wax tend to form structures at the interface upon cooling that prevent coalescence during storage. These structures also prevent leakage of water into the continuous phase. No effect of the water content on the melting properties of the emulsions was observed. Upon addition of more than 10% water, softening of the material was measured, due to the overall decrease in solid content. Addition of crystalline material (hard paraffin) was successfully used to reinstate the material properties. PMID- 21272041 TI - Lysophospholipids improve skin moisturization by modulating of calcium-dependent cell differentiation pathway. AB - Recent studies have demonstrated that lysophospholipids (LPL) play critical roles in several biological signal transduction pathways to maintain the homoeostasis of cells, tissues and organs. Among them, lysophosphatidic acid (LPA) has been identified as a lipid mediator that induces morphological improvement in the epidermis in mice. In this study, we examined the effects of LPL (soybean-derived phospholipids modified with phospholipase A2 and C) compared with LPA. We initially examined the effects of LPA on normal human epidermal keratinocytes (NHEK) focusing on the expression of profilaggrin and serine palmitoyltransferase (SPT) mRNAs. LPA enhanced the expression of profilaggrin and SPT mRNAs via the modulation of Ca(2+) influx. Based on those results, the influence of LPL on NHEK was examined and was expanded to analyse the expression of two tight junction related proteins, occludin and claudin-1. LPL had similar effects to increase profilaggrin and SPT mRNA expression and also stimulated the expression of occludin and claudin-1 at the mRNA and protein levels. In accordance with these results, LPL elicited significant improvements in surface water content in human skin. These findings indicate that LPL has the potential to strengthen the skin moisturizing capability by up-regulating the expression of mRNAs encoding components important to skin barrier function and skin hydration. PMID- 21272042 TI - The response of subcutaneous connective tissue to newly developed calcium phosphate-based root canal sealers. AB - AIM: To evaluate the histopathologic biocompatibility of two new calcium phosphate-based sealers (CPS-1 & CPS-2) with a commercially available calcium hydroxide-based sealer (Acroseal). METHODOLOGY: Polyethylene tubes were filled with freshly mixed sealers and implanted subcutaneously in the dorsal connective tissue of rats. Empty tubes were used as controls. Histopathological examinations were conducted at 7, 15, 30, 60 and 90 days after the implantation procedure. The presence of inflammation and predominant cell types were analysed statistically with Mann-Whitney U and Kruskal-Wallis non-parametric tests. Fibrous connective tissue thickness adjacent to each sample was recorded. Differences were tested for significance using anova and 'Duncan's' multiple comparison test (P < 0.05). RESULTS: CPS-1 sealer was associated with severe inflammation and remained an irritation throughout the 90-day implantation period; the tissue reaction pattern was stromal fibrosis. The control, CPS-2 and Acroseal sealers had similar patterns of irritation, which were more severe initially and diminished with time creating a thin fibrous capsule around the implant with a complete absence of inflammatory cells. There was no difference in tissue reaction between the control, CPS-1, CPS-2 and Acroseal groups amongst the first two observation periods (P > 0.05). However, there was a highly significant difference between the same groups at the last two observation periods (P < 0.01). Also, there were highly significant differences between the observation periods within all four groups at 7, 15, 30, 60 and 90 days (P < 0.01). CONCLUSION: CPS-1 sealer was not biocompatible. CPS-2 sealer and Acroseal had a favourable biocompatibility level based on the histological findings. PMID- 21272043 TI - An investigation of a potential confounder in ex vivo microbiological studies- the bulk flow of fluid through apical foramina during tooth extraction. AB - AIMS: To investigate the factors affecting bulk flow of dye and bacterial suspensions into and out of apical foramina during simulated tooth extraction, using an ex vivo model. METHODOLOGY: Sixty extracted, single-rooted, human teeth were accessed, root canals located and in 50 the pulps dissolved; 10 teeth with attached periapical lesions were preserved. The size of apical foramina was determined digitally. The teeth were mounted in vials with polyvinylsiloxane impression material. Part 1: different dyes were inoculated in the coronal half of root canals or cervical 'gingival' margin, respectively, in separate experiments using the same teeth. Tooth extraction movements were simulated and apical penetration of the dye solutions with and without coronal restorations were examined in each case (20 teeth re-used 4 * ). Part 2: the same procedures were repeated on 30 more teeth but using a standard inoculum of Acidovorax sp. Part 3: 10 teeth with attached periapical lesions were inoculated with Acidovorax sp. in the absence of coronal restorations. Bacterial leakage into the periapical lesions was assessed. RESULTS: Coronal restorations significantly reduced the flow of dyes (P=0.002) or bacterial suspension (P=0.001) out of the canals and bacterial suspension into (P=0.02) the canals during simulated tooth extraction. The 'size of apical foramina' were positively correlated with passage of bacterial suspension out of the canal (P=0.04) and from the gingival trough into the canal (P=0.008), in the presence of a coronal restoration. CONCLUSIONS: The presence of coronal restorations, the size of apical foramina and presence of native canal contents with attached periapical lesions, all influenced fluid flow into and out of canals during simulated tooth extraction movements. PMID- 21272044 TI - The influence of a bisphosphonate on bone generation determined using a chick femur model. AB - AIM: To determine the direct influence of a bisphosphonate (pamidronate) delivered by one of two carriers, on bone generation in chick-femurs supported by chick egg chorio-allantoic membranes. METHODOLOGY: Twenty chick femurs freshly harvested from fertilized eggs were randomly allocated to two groups: (i) Affi Gel blue bead carrier (n=10); and (ii) hydroxyapatite bead carrier (n=10). The femurs in each group were further randomly divided into control (n=4) and experimental (n=6) subgroups. Carriers charged with PBS solution or 0.1 M pamidronate were delivered into the bone marrow of each femur at its mid-portion through a needle puncture. Each femur was then grafted onto the chorio-allantoic membrane of a chick egg and incubated for 7 days. Each experimental and control subgroup femur yielded four histological sections at the puncture site, constituting the test and inter-bone controls. In addition, two histological sections were also obtained from 400 to 450 MUm away from each end of the experimental puncture site to act as the intra-bone controls. Bone generation was quantified and the ratio of cross-sectional area of bone marrow to circumference of bone (outcome measure) was determined using a software package, Image-Pro((r)) Plus. The data were analysed using Mann-Whitney tests and Wilcoxon signed rank tests. RESULTS: The outcome ratio in the test group was significantly (P<0.001) smaller than both the inter-bone and intra-bone control groups. There was evidence of increased bone formation directly over the pamidronate-charged carriers. CONCLUSIONS: The test model established that pamidronate had a positive effect on bone generation over a period of 7 days, regardless of the carrier type. PMID- 21272045 TI - Alteration of reducing powers in an isogenic phosphoglucose isomerase (pgi) disrupted Escherichia coli expressing NAD(P)-dependent malic enzymes and NADP dependent glyceraldehyde 3-phosphate dehydrogenase. AB - AIMS: To understand the intracellular reducing power metabolism, growth and intracellular NAD(P)H concentrations of a phosphoglucose isomerase (pgi) disrupted Escherichia coli (KS002) were investigated with the expressions of redox enzymes. METHODS AND RESULTS: The isogenic pgi-mutation enabled E. coli to harbour two times both the intracellular NADPH and NADH at half the growth rate. The wild-type expressing NAD-dependent malic enzyme (maeA) was incapable of sufficient growth (<0.02 h(-1)), and the growth retardations were distinctively recovered when NADP-dependent glyceraldehyde-3-phosphate dehydrogenase (gapB) from Bacillus subtilis was coexpressed. The KS002 expressing maeA harboured the highest intracellular reducing powers (NADPH of 3.9 and NADH of 5.2 MUmol g DCW( 1) ) by three times each of those in wild type. The expression of NADP-dependent malic enzyme (maeB) enabled wild-type and KS002 strains to grow without significant alteration. CONCLUSIONS: The alterations of reducing powers and the growth were analysed in the genetic engineered E. coli strains. The potential application of the cells with the high intracellular NAD(P)H level is discussed based on the results. SIGNIFICANCE AND IMPACT OF THE STUDY: Metabolic engineering strategy for higher reducing power regeneration is provided. PMID- 21272046 TI - Viral metagenome analysis to guide human pathogen monitoring in environmental samples. AB - AIMS: The aim of this study was to develop and demonstrate an approach for describing the diversity of human pathogenic viruses in an environmentally isolated viral metagenome. METHODS AND RESULTS: In silico bioinformatic experiments were used to select an optimum annotation strategy for discovering human viruses in virome data sets and applied to annotate a class B biosolid virome. Results from the in silico study indicated that <1% errors in virus identification could be achieved when nucleotide-based search programs (BLASTn or tBLASTx), viral genome only databases and sequence reads >200 nt were considered. Within the 51,925 annotated sequences, 94 DNA and 19 RNA sequences were identified as human viruses. Virus diversity included environmentally transmitted agents such as parechovirus, coronavirus, adenovirus and aichi virus, as well as viruses associated with chronic human infections such as human herpes and hepatitis C viruses. CONCLUSIONS: This study provided a bioinformatic approach for identifying pathogens in a virome data set and demonstrated the human virus diversity in a relevant environmental sample. SIGNIFICANCE AND IMPACT OF THE STUDY: As the costs of next-generation sequencing decrease, the pathogen diversity described by virus metagenomes will provide an unbiased guide for subsequent cell culture and quantitative pathogen analyses and ensures that highly enriched and relevant pathogens are not neglected in exposure and risk assessments. PMID- 21272047 TI - An open-label, parallel, multiple-dose study comparing the pharmacokinetics and gastric acid suppression of rabeprazole extended-release with esomeprazole 40 mg and rabeprazole delayed-release 20 mg in healthy volunteers. AB - BACKGROUND: Novel rabeprazole extended-release (ER) formulations were developed to provide prolonged gastric acid suppression and potentially improved clinical outcomes in GERD patients. AIM: To evaluate the pharmacodynamics and pharmacokinetics of six rabeprazole-ER formulations vs. esomeprazole 40 mg and rabeprazole delayed-release (DR) 20 mg. METHODS: Helicobacter pylori-negative healthy subjects were randomised to receive one of eight treatments once daily for 5 days. Twenty-four-hour intragastric pH was monitored on days -1, 1 and 5. Rabeprazole plasma concentrations were measured on day 5. RESULTS: A total of 248 subjects (N=31/group) were enrolled in the study. On day 5, rabeprazole-ER groups provided mean durations of 18.5-20.2 h (77.0-84.1% of 24-h) with intragastric pH >4.0 vs. esomeprazole 40 mg (15.9 h/66.1% of 24-h) and rabeprazole-DR 20 mg (15.2 h/63.2% of 24-h). A similar increase was observed on day 1. While percentage of daytime (8 am-10 pm) with intragastric pH >4.0 on day 5 was overall similar across the groups, percentage of night-time (10 pm-8 am) with intragastric pH >4.0 was higher with the rabeprazole-ER groups (57.0-72.4%) vs. esomeprazole 40 mg (32.8%) and rabeprazole-DR 20 mg (34.0%). CONCLUSION: Rabeprazole-ER once daily for 5 days demonstrated a significantly longer duration of gastric acid suppression in 24 h vs. esomeprazole 40 mg and rabeprazole-DR 20 mg. The increase in acid suppression was predominantly due to prolonged acid suppression during the night-time; this was supported by the extended-release pharmacokinetic characteristics. PMID- 21272048 TI - A common promoter variant of TBX21 is associated with allele specific binding to Yin-Yang 1 and reduced gene expression. AB - T-bet is a key regulator for the lineage commitment in CD4 T helper (Th) 1 cells by activating the hallmark production of interferon-gamma, and its expression level is linked to autoimmune, infectious, and allergic diseases. A T to C base substitution has been identified at position -1993 in the TBX21 (encoding T-bet) promoter and has been associated with asthma and systemic lupus erythematosus. This study aimed to investigate the molecular mechanisms responsible for the influence of the T-1993C polymorphism on transcription and its functional effect by luciferase reporter, EMSAs, Chromatin immunoprecipitation assay, and flow cytometric analysis of intracellular T-bet, IFN-gamma and IL-4 expression in activated CD4(+) T cells. The presence of a -1993T allele obviously increases promoter activity compared with that of a promoter with a -1993C allele. TBX21 promoter carrying -1993C allele possesses significantly stronger binding affinity to the Yin Yang 1 (YY1) transcription factor than that carrying -1993T allele. YY1 overexpression decreased TBX21 promoter function in a T cell line, demonstrating that this element functions as a repressor. The C to T base exchange relieves the repression mediated by YY1. The individuals carrying -1993C allele were determined to have significantly diminished expression of TBX21 and IFN-gamma and increased IL-4 production in cells compared with the individuals carrying -1993T allele (P < 0.05). These findings demonstrate that the TBX21 T 1993C polymorphism represses TBX21 expression and Th1 cytokine production through control of YY1, which might result in the imbalance between Th1 and Th2 immune responses in autoimmune or allergic diseases. PMID- 21272049 TI - Deltamethrin Increases Candida albicans infection susceptibility in mice. AB - Deltamethrin, an alpha-cyano type II synthetic pyrethroid insecticide, is used to control a wide range of insects on a variety of crops and vectors of diseases. Deltamethrin has been previously reported for its immunotoxic effects and therefore its exposure may affect the host resistance to infection and tumour challenge. Effect of exposure of deltamethrin on host resistance to Candida albicans infection was examined in Swiss albino mice. The objective of this study was to investigate the modulatory action of deltamethrin in C. albicans infected mice. The dose of deltamethrin was initially tested and selected from our previous study (18 mg/kg). Percentage of infection in deltamethrin treated animals increased faster when compared to that of the controls. Deltamethrin exposure along with C. albicans infection caused alteration of humoral immune response. The number of colony forming unit in liver and spleen were also found to be significantly increased in the treated group. The results from our present study suggest that deltamethrin exhibits an immunosuppressive effect and has a negative impact on host resistance to C. albicans infection. PMID- 21272050 TI - Participation of iNKT cells in the early and late components of Tc1-mediated DNFB contact sensitivity: cooperative role of gammadelta-T cells. AB - Prior studies of classical 24 h responses in TNP-Cl (picryl chloride) allergic contact sensitivity (CS), showed mediation by Th1 cells in CBA mice, and established that 24 h elicitation of responses requires an early 2 h CS initiating component dependent on iNKT cells, IL-4 and B-1 B cells. Here, we studied the other form of cytotoxic T cell (Tc1) CS in DNFB sensitized BALB/c mice and determined that similar CS-initiation also is required. We systematically tested each step of the initiation pathway in this model. Thus, DNFB Tc1 CS was significantly impaired in iNKT cell deficient CD1d(-/-) and Jalpha18(-/-) mice, IL4Ralpha(-/-) and STAT-6(-/-) mice, and also in pan B-cell deficient JH(-/-) mice. Further, the Tc1 DNFB CS-initiating component, like Th1 response to TNP-Cl, was elicited by only 1-day after immunization, due to B-1 cells. In summary, we show that CS-Initiation also is required in Tc1 CS. Further, we have newly determined regulatory support of both the early and late components of DNFB induced Tc1 CS by iNKT cells and gammadelta-T cells. In summary, both iNKT cells and assisting gammadelta-T cells are involved in initiating and effector phases of DNFB induced CS. PMID- 21272051 TI - New roles for innate immune response in acute and chronic kidney injuries. AB - The innate immune system plays an important role as a first response to tissue injury. This first response is carried out via germline-encoded receptors. They can recognize exogenous Pathogen-Associated Molecular Patterns and endogenous Dangers-Associated Molecular Patterns. The Toll-Like Receptor (TLR) family is well-studied, but more recently another family in the cytoplasmic compartment, called nod-like receptor (NLR), was discovered. In addition to being present in inflammatory cells, these receptors are widely distributed in various cell types, including renal tissue, where these receptors have an important role in triggering the inflammatory response during renal diseases. This review summarizes the present data regarding the role of TLRs and NLRs in the course and development of various kidney pathologies. PMID- 21272052 TI - Immediate and conventional single implant treatment in the anterior maxilla: 1 year results of a case series on hard and soft tissue response and aesthetics. AB - AIM: The main objective of this clinical study was to document midfacial soft tissue dynamics following single immediate implant treatment (IIT) and conventional implant treatment (CIT) in the anterior maxilla when performed by experienced clinicians in well-selected patients. MATERIAL AND METHODS: Appropriate bone volume and ideal soft tissue levels were considered requirements for implant therapy. Additional prerequisites for IIT were intact socket walls and a thick gingival biotype. CIT included standard flap elevation whereas IIT was either performed with a flap or flapless procedure. All implants were provisionally restored using cemented acrylic crowns. Bone levels, papillae and midfacial soft tissue levels were monitored at regular intervals. The aesthetic outcome was assessed after 1 year using the pink aesthetic score (PES) and white aesthetic score (WES). RESULTS: Sixteen patients (10 men, six women; mean age 45) received an immediate implant and 23 patients (12 men, 11 women; mean age 40) had conventional implant surgery. One immediate implant failed in the early healing phase. The mean bone level from the implant-abutment interface was 0.85mm for IIT and 0.65mm for CIT after 1 year (p=0.144). Mesial papillae remained stable over time. Minute loss of distal papillae occurred following IIT (-0.38mm) and a tendency for re-growth was found following CIT (0.60mm). Midfacial soft tissues remained stable over time following IIT with only 7% showing advanced recession (>1mm). Flapless surgery induced less midfacial recession than flap surgery (p=0.023). Significant midfacial recession occurred following CIT (-1mm). Overall, 24% were aesthetic failures (PES<8 and/or WES<6) and 8% showed an (almost) perfect outcome (PES12 and WES9). The remainder (68%) demonstrated acceptable aesthetics. CONCLUSIONS: Immediate implants demonstrated fairly stable midfacial soft tissue levels with only a minority of cases showing advanced recession. Irrespective of the timing of implant placement, aesthetic failures seem to be rather common and only a strict minority may show perfection. PMID- 21272053 TI - Modelling of pain intensity and informative dropout in a dental pain model after naproxcinod, naproxen and placebo administration. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Modelling has been used to describe the pain relief and dropout for a few non-steroidal anti-inflammatory drugs. WHAT THIS STUDY ADDS: * This study shows the relationship between dose, plasma concentration, pain intensity and dropout for naproxen and naproxcinod. It also extends previous models by using a visual analogue scale for pain intensity instead of modelling pain relief on a categorical scale, and shows the value of including informative dropout in the simulations for visual predictive checks. AIMS: To describe pain intensity (PI) measured on a visual analogue scale (VAS) and dropout due to request for rescue medication after administration of naproxcinod, naproxen or placebo in 242 patients after wisdom tooth removal. METHODS Non-linear mixed effects modelling was used to describe the plasma concentrations of naproxen, either formed from naproxcinod or from naproxen itself, and their relationship to PI and dropout. Goodness of fit was assessed by simultaneous simulations of PI and dropout. RESULTS: Baseline PI for the typical patient was 52.7 mm. The PI was influenced by placebo effects, using an exponential model, and by naproxen concentrations using a sigmoid E(max) model. Typical maximal placebo effect was a decrease in PI by 20.2%, with an onset rate constant of 0.237 h(-1). EC(50) was 0.135 umol l(-1). A Weibull time-to-event model was used for the dropout, where the hazard was dependent on the predicted PI and by the PI at baseline. Since the dropout was not at random, it was necessary to include the simulated dropout in visual predictive checks (VPC) of PI. CONCLUSIONS: This model describes the relationship between drug effects, PI and the likelihood of dropout after naproxcinod, naproxen and placebo administration. The model provides an opportunity to describe the effects of other doses or formulations, after dental extraction. VPC created by simultaneous simulations of PI and dropout provides a good way of assessing the goodness of fit when there is informative dropout. PMID- 21272054 TI - Understanding the time course of pharmacological effect: a PKPD approach. AB - The key concepts that underpin the choice of drug and dosing regimen are an understanding of the drugs' effectiveness, the potential for adverse effects, and the expected time course over which both desired and adverse effects are likely to occur. Research in clinical pharmacology should therefore address three fundamental questions: (1) What is the magnitude of drug effects (beneficial or adverse) from a given dose? (2) How quickly will any given effects occur? (3) How long will these effects last? Under steady-state conditions, only the magnitude of drug effects can be examined. This requires researchers to consider non-steady state conditions, which require more complex models and an understanding of the mechanisms that drive the time course of drug effect. The aim of this review is to provide a conceptual framework for understanding the time course of drug effects using pharmacokinetic-pharmacodynamic models. Key examples will illustrate how this can inform the optimal use of drugs in the clinic. PMID- 21272055 TI - Family-centred care of children in hospital - a concept analysis. AB - AIM: This paper reports a concept analysis of family-centred nursing care of hospitalized children. BACKGROUND: Family-centred care describes a practice aimed towards involving the family in all aspects of care. Previous analyses explore the colloquial use of the concept. An increasing amount of scientific papers apply the concept with seemingly little consistency in use. DATA SOURCES: A systematic literature search including articles from 1951 to 2009 resulted in a sample of 25 research articles. REVIEW METHODS: A theoretical concept analysis influenced by Risjord's distinction between theoretical and colloquial analyses and based on the principles developed by Morse, Hupcey and Penrod was used to examine the structure and scientific maturity of the concept. FINDINGS: There is good agreement on the defining attributes of the concept, but they are described by sub concepts in need of clarification. The relationship between family and professionals is characterized by a mutual dependency and shared responsibility for the child's care, which may have both positive and negative consequences and holds potential areas of conflict not fully explained by the attribute of partnership. The nature of partnership remains unclear and it may therefore not yet be a relevant attribute. The concept is defined from the perspective of professionals and families, mostly represented by mothers. Few attempts have been made to operationalize the concept. CONCLUSION: Family-centred care is a partially mature and highly abstract concept. Developing a theory of family centred care could position the concept in a theoretical context and should also include the perspective of the sick child. PMID- 21272056 TI - Repetitive flood victims and acceptance of FEMA mitigation offers: an analysis with community-system policy implications. AB - Of all natural disasters, flooding causes the greatest amount of economic and social damage. The United States' Federal Emergency Management Agency (FEMA) uses a number of hazard mitigation grant programmes for flood victims, including mitigation offers to relocate permanently repetitive flood loss victims. This study examines factors that help to explain the degree of difficulty repetitive flood loss victims experience when they make decisions about relocating permanently after multiple flood losses. Data are drawn from interviews with FEMA officials and a survey of flood victims from eight repetitive flooding sites. The qualitative and quantitative results show the importance of rational choices by flood victims in their mitigation decisions, as they relate to financial variables, perceptions of future risk, attachments to home and community, and the relationships between repetitive flood loss victims and the local flood management officials who help them. The results offer evidence to suggest the value of a more community-system approach to FEMA relocation practices. PMID- 21272057 TI - Evaluating post-Katrina recovery in Mississippi using repeat photography. AB - Hurricane Katrina of August 2005 had extensive consequences for the state of Mississippi in the United States. Widespread infrastructure and property damage, massive social dislocation, and ecological loss remain among the many challenges faced by communities as they work towards 'normalcy'. This study employs repeat photography to understand differential recovery from Hurricane Katrina in Mississippi. Revealing change with conventional landscape photography, a process known as repeat photography, is common in the natural sciences. Simply stated, repeat photography is the practice of re-photographing the same scene as it appears in an earlier photograph. Photographs were taken at 131 sites every six months over a three-year period. Each photograph was assigned a recovery score and a spatially interpolated recovery surface was generated for each time period. The mapped and graphed results show disparities in the progression of recovery: some communities quickly entered the rebuilding process whereas others have lagged far behind. PMID- 21272058 TI - Social impact of the 2004 Manawatu floods and the 'hollowing out' of rural New Zealand. AB - The Manawatu floods of 2004 have had significant, long-lasting social consequences. This paper draws on findings from a series of detailed surveys of 39 farm households directly affected by the floods and 17 individuals directly involved in managing the flood recovery programme. The nature of the impact on rural families highlights how the 'hollowing out' of rural New Zealand has changed the capacity of rural communities to respond to natural hazards and increased their sense of isolation. In addition, the floods exposed the vulnerability of rural communities. This is shown to have implications for policies designed to build resilience and improve responses to adverse events, including the need to support local, community initiatives on self-reliance and mutual support. Approaches to manage better long-term flood risks should be designed within a context of ongoing rural decline that has compromised the health of both individuals and communities. PMID- 21272059 TI - Disaster coordination preparedness of soft-target organisations. AB - This paper introduces a network-enabled model to examine the disaster coordination preparedness of soft-target organisations (STOs). Little attention is devoted to this matter in recent research. This study places emphasis on such organisations and the proposed model tests hypotheses related to network relation and coordination preparedness. It analyses the data set entitled 'Preparedness of large retail malls to prevent and respond to terrorist attack, 2004', which contains 120 completed surveys of security directors of retail malls in the United States.(1) The following questions form the basis of this study: 'What do STOs need to be better prepared to respond to a disaster?'; 'How does network relationship between STOs and emergency agencies affect the coordination preparedness of STOs for disaster recovery?'; and 'Which centrality measure needs to be followed to measure network variables in order to analyse coordination preparedness?' The results show that STOs with a high level of connectedness and strong ties to other emergency agencies are better prepared for disaster response. PMID- 21272060 TI - Functional analysis of Borrelia burgdorferi uvrA in DNA damage protection. AB - Bacterial pathogens face constant challenges from DNA-damaging agents generated by host phagocytes. Although Borrelia burgdorferi appears to have much fewer DNA repair enzymes than pathogens with larger genomes, it does contain homologues of uvrA and uvrB (subunits A and B of excinuclease ABC). As a first step to exploring the physiologic function of uvrA(Bbu) and its possible role in survival in the host in the face of DNA-damaging agents, a partially deleted uvrA mutant was isolated by targeted inactivation. While growth of this mutant was markedly inhibited by UV irradiation, mitomycin C (MMC) and hydrogen peroxide at doses that lacked effect on wild-type B. burgdorferi, its response to pH 6.0-6.8 and reactive nitrogen intermediates was similar to that of the wild-type parental strain. The sensitivity of the inactivation mutant to UV irradiation, MMC and peroxide was complemented by an extrachromosomal copy of uvrA(Bbu). We conclude that uvrA(Bbu) is functional in B. burgdorferi. PMID- 21272061 TI - Decreased virulence of cystic fibrosis Pseudomonas aeruginosa in Dictyostelium discoideum. AB - The characteristics of clinical and environmental isolates of Pseudomonas aeruginosa from both hospital and community settings were analyzed in a eukaryotic virulence model employing the AX2 and X22 mutants of Dictyostelium discoideum. Thirty-one strains, including two Australian epidemic strains, of P. aeruginosa were analyzed, five from environmental sources, six from clinical sources other than cystic fibrosis (CF) patients and nineteen from CF patients' respiratory secretions. The majority of CF isolates almost uniquely supported the growth of D. discoideum. CF isolates of P. aeruginosa were found to be less virulent than isolates from other sources. Varying degrees of inhibition of the developmental cycle of D. discoideum when growing on CF isolates were also noted. This is the first description of P. aeruginosa isolates from clinical and environmental sources supporting the growth of D. discoideum. PMID- 21272062 TI - Effects of intravesical liposome-mediated human beta-defensin-2 gene transfection in a mouse urinary tract infection model. AB - The purpose of this study was to assess human beta-defensin-2 (hBD-2) gene transfection in human bladder epithelial cells and its therapeutic efficacy in a rat urinary tract infection (UTI) model via liposome mediated gene transfer. A large amount of hBD2 production (36.5 +/- 3.2 ng/10(6) cells) was demonstrated in transfected cells' supernatants. In addition, a detectable amount of hBD-2 was identified in rats' urine (4.77 +/- 1.4 ng/mL) by ELISA. Expression of the transgene hBD-2 in transfected cells and rats' bladders was also confirmed by RT PCR and Western blotting. Immunohistochemistry revealed that the transgene hBD-2 expressed in the entire epithelial layer of the transduced bladders. Numbers of bacterial colony-forming units in urine and bladders from hBD2 gene treated UTI rats were significantly lower than those from the UTI rats administered PBS at 24, 36, and 72 hr after infection (P < 0.05). In addition, in vivo expression of hBD-2 reduced mucosal damage, interstitial edema and inflammatory cell infiltration in UTI animals. The results indicate that successful inhibition of UTI progression can be produced by hBD2 gene therapy. The liposome-mediated hBD2 plasmid DNA transfection system appears to be a promising method for antimicrobial gene therapy of UTI. PMID- 21272063 TI - B-cell epitope KT-12 of enterohemorrhagic Escherichia coli O157:H7: a novel peptide vaccine candidate. AB - Enterohemorrhagic Escherichia coli (EHEC) O157:H7 is associated with hemorrhagic colitis, thrombotic thrombocytopenic purpura, and hemolytic-uremic syndrome in humans. B-cell epitopes of intimin gamma from EHEC O157:H7 were predicted and synthesized for evaluating their immunogenicity and protective effect and for screening a novel synthetic peptide vaccine. In the present study, five B-cell epitopes of IntC300 were predicted by Hopp-Woods, Chou-Fasman, Karplus-Schulz, Emini, Jameson-Wolf and Kolaskar-Tongaonakar analysis. One of them, KT-12 (KASITEIKADKT) was coupled with keyhole limpet hemocyanin, and used to immunize BALB/c mice three times by subcutaneous and intranasal injection. Mouse serum titers of IgG and IgA were assessed by indirect ELISA. Oral inoculation of EHEC O157:H7 resulted in infection and death of the mice. It was found that B-cell epitopes are located within or near the peptide segments 658-669, 711-723, 824 833, 897-914, 919-931. Both subcutaneous and intranasal immunization induced higher concentrations of IgG antibodies, as detected by indirect ELISA, and nasal mucosal immunization induced the production of high concentrations of IgA antibodies. After infection with a lethal dose of EHEC O157:H7, the survival rate of mice that had received subcutaneous immunization was not significantly different from that of the control group (P > 0.05). On the other hand, mice that received intranasal immunization showed a better survival rate than the group that received subcutaneous immunization (P < 0.05). The synthesized antigenic peptide KT-12 induced mice to produce higher concentrations of IgG and IgA after immunization, but only intranasal immunization of KT-12 succeeded in protecting most mice from infection with EHEC O157:H7. This study suggests that the synthesized antigenic peptide KT-12 is be a potential vaccine candidate against EHEC O157:H7. PMID- 21272064 TI - A comparative study of induction of pneumonia in mice with planktonic and biofilm cells of Klebsiella pneumoniae. AB - In the present study, the course of acute pneumonia in normal BALB/c mice infected by intranasal inoculation of planktonic and preformed biofilm cells (3 days old) of Klebsiella pneumoniae B5055 was studied and compared. With both cell forms the peak of infection was observed on the third post infection day, as assessed on the basis of lung bacterial load and corresponding pathology. There was an intense neutrophil infiltration in bronchoalveolar lavage fluid. Tissue damage was assessed on the basis of increased amounts of nitrite, malondialdehyde and lactate dehydrogenase in lung homogenates. The phagocytic potential of alveolar macrophages was lower in biofilm cell-induced infection than in that induced by planktonic cells. Biofilm cell induced infection generated significantly greater production of tumor necrosis factor-alpha and interleukin 1beta on the third and fifth days of infection, respectively. Production of interleukin-10 was, however, variable. There was no significant difference in the ability of planktonic and biofilm cell forms of K. pneumoniae to induce acute pneumonia in mice in terms of bacterial counts and histopathological changes. However, biofilm cell-induced infection showed delayed clearance as compared to infection induced with the planktonic form. PMID- 21272065 TI - German head circumference references for infants, children and adolescents in comparison with currently used national and international references. AB - AIM: To present valid head circumference (HC) percentiles from early infancy to 18 years and to compare them with percentiles currently used in Germany by Prader, as well as to international WHO and CDC references. METHODS: Nationally representative sample of 17,158 children and adolescents aged 0.25-17.98 years (KiGGS study 2003-2006) with standardized HC measurement. HC references were created using Cole's LMS method. RESULTS: The median growth of HC is largest in the first year of life. Adult HC is reached at age 16 years in girls, while in boys, HC growth continues through age 17 years and adult HC have to be derived from future KiGGS follow-up examinations. KiGGS percentiles are quite similar from early infancy to early school age compared to older Prader references, but higher thereafter (maximum difference of median HC: girls 1.4 cm, boys 0.9 cm). KiGGS percentiles are also higher than WHO and CDC percentiles over most of the compared age range, but differences are less pronounced compared to Prader. CONCLUSION: The KiGGS HC references presented here for boys and girls aged 4 months through 17 years are more valid than currently used German references. Because of the similarity of KiGGS and the currently used reference by Prader in early infancy, the currently used Prader reference for 0-4 months could complement KiGGS to cover the entire age range from birth to the end of adolescence. PMID- 21272066 TI - Bullying--a hidden factor behind somatic symptoms? PMID- 21272067 TI - Is phototherapy exposure associated with better or worse outcomes in 501- to 1000 g-birth-weight infants? AB - AIM: To compare risk-adjusted outcomes at 18- to 22-month-corrected age for extremely low birth weight (ELBW) infants who never received phototherapy (NoPTx) to those who received any phototherapy (PTx) in the NICHD Neonatal Research Network randomized trial of Aggressive vs. Conservative Phototherapy. METHODS: Outcomes at 18 to 22-month-corrected age included death, neurodevelopmental impairment (NDI) and Bayley Scales Mental Developmental Index (MDI). Regression models evaluated the independent association of PTx with adverse outcomes controlling for centre and other potentially confounding variables. RESULTS: Of 1972 infants, 216 were NoPTx and 1756 were PTx. For the entire 501- to 1000-g-BW cohort, PTx was not independently associated with death or NDI (OR 0.85, 95% CI: 0.60-1.20), death or adverse neurodevelopmental endpoints. However, among infants 501-750 g BW, the rate of significant developmental impairment with MDI < 50 was significantly higher for NoPTx (29%) than PTx (12%) (p = 0.004). CONCLUSIONS: Phototherapy did not appear to be independently associated with death or NDI for the overall ELBW group. Whether PTx increases mortality could not be excluded because of bias from deaths before reaching conservative treatment threshold. The higher rate of MDI < 50 in the 501- to 750-g-BW NoPTx group is concerning and consistent with NRN Trial results. PMID- 21272068 TI - Neonatal hyperbilirubinemia and Gly71Arg mutation of UGT1A1 gene: a Chinese case control study followed by systematic review of existing evidence. AB - AIM: To determine whether the UDP-glucuronosyltransferase 1A1 gene (UGT1A1) Gly71Arg (211G>A) mutation is associated with neonatal hyperbilirubinemia. METHODS: The study consisted of two parts. The case-control study included 112 hyperbilirubinemic infants and 105 control subjects from the Fifth People's Hospital of Shenzhen. Polymerase chain reaction, restriction fragment length polymorphisms and agarose gel electrophoresis techniques were used to detect the UGT1A1 211G>A mutation. Meta-analyses was performed to assess the association between neonatal hyperbilirubinemia and UGT1A1 211G>A. RESULTS: Our case-control study revealed that the likelihood of developing neonatal hyperbilirubinemia was 2.65 times higher in the infants with the A allele in the UGT1A1 211G>A than in the infants with the G allele (95% CI, 1.60-4.39). Meta-analyses (including data from our study) revealed that UGT1A1 211G>A is associated with an increased risk of neonatal hyperbilirubinemia [odds ratio (OR), 2.37; 95% CI, 2.05-2.74]. In the subgroup analyses based on ethnicity, significantly elevated risks were found in Asian populations (OR, 2.45; 95% CI, 2.10-2.84), but no significant associations were present in Caucasian populations (OR, 1.54; 95% CI, 0.87-2.75). CONCLUSION: The UGT1A1 211G>A mutation is associated with neonatal hyperbilirubinemia in Asians, but not in Caucasians. PMID- 21272069 TI - Persistent scrotal pain and suspected orchido-epididymitis of a young boy during pinworm (Enterobius vermicularis) infection in the bowel. AB - AIM: Pinworm (Enterobius vermicularis) is the most common parasite among mankind. Ectopic pinworm infections in number of organs are broadly reported. The aim of this report is to review the pinworm infection in the scrotum on the basis of our case. METHODS AND RESULTS: Our patient is a young boy with persistent pain in the scrotums together with abdominal symptoms. He underwent several urgent operations. Pinworm was finally found in appendix vermiformis. We hypothesize that concurrent unresponsive orchido-epididymitis was caused by pinworm as well. Eradication happened finally with pyvrinembonate. CONCLUSION: Pinworm is a parasite that lives usually in the bowel. Many ectopic locations, like scrotum, are known. Orchido-epididymitis by pinworm has to be kept in mind when treating boys with persistent scrotal pain. PMID- 21272070 TI - Exclusive enteral nutrition in the treatment of children with Crohn's disease in Sweden: a questionnaire survey. AB - AIM: The general use of exclusive enteral nutrition (EEN) as therapy for children with Crohn's disease (CD) in Sweden has not previously been studied. Thus, the aim of this study was to investigate how EEN is used as therapy in Sweden for children with CD. METHODS: A questionnaire was sent to all 37 paediatric units in Sweden that treat children with inflammatory bowel disease. RESULTS: The response rate was 78%, which covers nearly 90% of Sweden's paediatric population between 0 and 17 years of age. Ninety-six per cent of the units used EEN as a treatment option for children with CD, and 65% of the units used EEN as their primary therapy in newly diagnosed CD. The standard duration of EEN was 6 weeks, but the questionnaire revealed a span of 4-8 weeks. The use of polymeric formula was just as common as a combination of polymeric and elemental formulas. Fifty-seven per cent used oral nutrition supplements, and 81% allowed some extent of concomitant feeding, the addition of food and fluids, during EEN. All units used enteral nutrition to some extent as maintenance therapy after EEN was discontinued. CONCLUSIONS: In Sweden, EEN is used as therapy for children with Crohn's disease (CD), but the EEN protocols vary as to choice of formula and type of food and fluids allowed during EEN. Standardized EEN protocols would enable multicentre studies in Sweden, with the objective of investigating how EEN treatment can be improved and employed in the most efficient way. PMID- 21272071 TI - Clinical and laboratory findings in 220 children with recurrent abdominal pain. AB - AIM: To investigate the clinical and laboratory findings in children with recurrent abdominal pain (RAP). METHODS: Consecutive patients with RAP (Apley criteria), age 4-16 years, referred to a secondary medical centre were evaluated by a standardized history, physical examination and laboratory tests. The tests encompassed Helicobacter pylori (Hp), gastrointestinal bacterial infections, protozoa, coeliac disease, carbohydrate malabsorption, food intolerance, abdominal ultrasound and plain abdominal X-ray. More investigations were obtained if indicated. Patient characteristics were compared with surgical patients without abdominal pain (control group). RESULTS: A total of 220 consecutive patients were included (92 M, mean age 8.8 years [4.1-16.0 years]). In 88% of the patients, abnormalities were found that refer to possible causes. Especially, protozoa were present in 33% of the patients, mostly Dientamoeba fragilis, Yersinia enterocolitica in 12% and endoscopically proven infection with Hp in 11%. In 36%, a plain abdominal X-ray raised suspicion of constipation. CONCLUSION: In 220 consecutive patients with RAP, referred to secondary care, a standardized work-up yielded abnormal results in a high percentage. The clinical significance of these findings remains to be established. PMID- 21272072 TI - Outcomes of patients with cystic fibrosis undergoing lung transplantation with and without cystic fibrosis-associated liver cirrhosis. AB - People with severe cystic fibrosis (CF) lung disease with co-existent CF associated liver disease (CFLD) are often excluded from consideration of sole lung transplantation, largely because of the concerns that they will subsequently develop hepatic decompensation. This retrospective cohort study aimed at determining whether patients with severe cirrhosis caused by CFLD have any differences in perioperative and relevant post-transplant outcomes compared to CF patients without CFLD when undergoing sole lung transplantation. Six patients with CFLD were matched with 18 CF patients without CFLD undergoing sole lung transplant at the same institution. There were no differences in total operative time or intra-operative requirements for cardiopulmonary bypass or blood products. Over a period of five yr post-transplant, no differences were observed between the two groups in body mass index, six-min walk, lung function, and survival. None of the CFLD subjects developed variceal bleeding; however, one developed hepatocellular and renal failure at four yr post-transplant and is being assessed for liver-kidney transplant. One additional patient with CFLD required repeat lung transplantation for bronchiolitis obliterans syndrome. This study provides evidence that CF patients with liver cirrhosis caused by CFLD can safely be considered for sole lung transplantation provided there is no evidence of significant hepatocellular dysfunction with decompensated cirrhosis or hepatic synthetic failure. PMID- 21272073 TI - Blood transfusions in kidney transplant candidates are common and associated with adverse outcomes. AB - Surprisingly, there are no data regarding transfusion frequency, factors associated with transfusion administration in patients on the kidney transplant waiting list, or transfusion impact on graft and recipient outcomes. We used United States Renal Data System data to identify 43,025 patients added to the waiting list in 1999-2004 and followed through 2006 to assess the relative risk of post-listing transfusions. In 69,991 patients who underwent transplants during the same time period, we assessed the association between pre-transplant transfusions and level of panel-reactive antibody (PRA) at the time of transplant, and associations between PRA and patient outcomes. The three-yr cumulative incidence of transfusions was 26% for patients added to the waiting list in 1999, rising to 30% in 2004. Post-listing transfusions were associated with a 28% decreased likelihood of undergoing transplant, and a more than fourfold increased risk of death. There was a graded association between percent PRA at the time of transplant and adjusted risk of death-censored graft failure, death with function, and the combined event of graft failure and death. These data demonstrate that transfusions remain common and confirm the adverse association between transfusions and PRA, and high PRA and inferior graft and patient outcomes. PMID- 21272074 TI - Preemptive deceased donor kidney transplant not associated with patient survival benefit in minority kidney transplant recipients. AB - Previous studies have shown an inverse association between pre-transplant dialysis exposure and post-kidney transplant outcomes. Socioeconomic and allocation factors, in contrast to medical factors, play a greater role in dialysis exposure among minorities, and medical causes for delay may impact post transplant outcomes. This study sought to test whether minorities behaved similarly to Caucasians with regard to the effect of duration of dialysis on post transplant outcomes. All primary deceased donor kidney transplants between 1997 and 2004 (n = 54,162) were analyzed from the Organ Procurement and Transplant Network database and were categorized as either Caucasian or minority. Adjusted patient and graft survivals were determined in each subgroup based on the duration of pre-transplant dialysis. Caucasians recipients show a clear stepwise increase in risk of graft failure and death with increasing duration of dialysis. The risk of graft failure among minorities increased less without a clear stepwise pattern. The risk of death, however, showed a U-shaped risk profile with the highest risk of death among preemptive transplants and recipients with more than five yr of dialysis. The disparate effect of dialysis on minorities suggests that a selection bias and not a biologic effect may explain the association between dialysis duration and outcomes after kidney transplantation previously reported. PMID- 21272075 TI - Risk of colorectal neoplasia in patients with solid organ transplantation. AB - The incidence of colorectal adenomas and advanced neoplasia in the transplant population has not been well characterized. The aim of this study was to determine whether or not there was an increased incidence of colorectal adenomas and advanced neoplasia in solid organ transplantation (SOT) recipients compared with an average-risk population. We reviewed 360 patients with solid organ transplants who underwent colonoscopy between February 1995 and July 2008, and 360 age- and gender-matched patients in an average-risk population. The mean duration from transplantation to colonoscopy in the SOT group was 40.4 +/- 34.0 months. Ninety-three (25.8%) adenomas were detected in the SOT group, while 98 (27.2%) adenomas were detected in the control group (p = 0.763). There was a statistically significant difference (p < 0.0001) in the number of patients with advanced neoplasia in the SOT group (24 patients [6.7%]) compared with the control group (3 patients [0.8%]). The independent risk factors of advanced neoplasia were old age (odds ratio [OR], 1.067; 95% CI, 1.019-1.118) and transplantation (OR, 6.069; 95% CI, 1.455-25.314). In summary, there was a significant increase in the incidence of advanced colorectal neoplasia in SOT recipients. The reason for this finding is unclear, and studies with a larger number of patients are needed to further evaluate this group. PMID- 21272076 TI - Inhalation of expiratory droplets in aircraft cabins. AB - Airliner cabins have high occupant density and long exposure time, so the risk of airborne infection transmission could be high if one or more passengers are infected with an airborne infectious disease. The droplets exhaled by an infected passenger may contain infectious agents. This study developed a method to predict the amount of expiratory droplets inhaled by the passengers in an airliner cabin for any flight duration. The spatial and temporal distribution of expiratory droplets for the first 3 min after the exhalation from the index passenger was obtained using the computational fluid dynamics simulations. The perfectly mixed model was used for beyond 3 min after the exhalation. For multiple exhalations, the droplet concentration in a zone can be obtained by adding the droplet concentrations for all the exhalations until the current time with a time shift via the superposition method. These methods were used to determine the amount of droplets inhaled by the susceptible passengers over a 4-h flight under three common scenarios. The method, if coupled with information on the viability and the amount of infectious agent in the droplet, can aid in evaluating the infection risk. PRACTICAL IMPLICATIONS: The distribution of the infectious agents contained in the expiratory droplets of an infected occupant in an indoor environment is transient and non-uniform. The risk of infection can thus vary with time and space. The investigations developed methods to predict the spatial and temporal distribution of expiratory droplets, and the inhalation of these droplets in an aircraft cabin. The methods can be used in other indoor environments to assess the relative risk of infection in different zones, and suitable measures to control the spread of infection can be adopted. Appropriate treatment can be implemented for the zone identified as high-risk zones. PMID- 21272077 TI - Indoor Air: the first 10 years. AB - This paper recounts the first 10 years of the Indoor Air journal from the perspective of the founding editor. It represents personal recollections of the journal's founding and initial publication. It describes some of the amazing changes that have occurred since the decade of the 1990s when it was first published. PRACTICAL IMPLICATIONS: It is useful to reflect back periodically to earlier times when the Indoor Air journal was just beginning to understand the conditions that led to its founding. Wise people have contributed much to create this outstanding journal. Their contributions should not be forgotten. PMID- 21272078 TI - Qualification of a new and precise automatic tool for the assessment of hair diameters in phototrichograms. AB - BACKGROUND/PURPOSE: To automatically assess hair growth during cosmetic trials, incorporating parameters such as anagen-to-telogen rate, growth rate, and especially hair diameter. METHODS: We designed and qualified a new and automatic phototrichogram system based on a high-resolution DSLR camera system (theoretical resolution of 2.557 MUm/pixel) and modular macrolens system with fixed focus, combined with a trainable pattern recognition software for automated analysis. RESULTS: We improved the standard routine for dermatological phototrichogram technique to overcome inaccuracy in thickness measurements due to hair swelling by using an alternative immersion fluid, and increased the effective resolution for hair size and thickness measurement to <4 MUm. After having qualified manual measurements as gold standard for the determination of hair diameters, we established a new trainable automatic picture analysis software able to locate and measure individual hairs in length and thickness even in picture series taken from the same skin area at different time points. Comparisons between manual and automatic measurements of the same hairs showed a >90% correlation, and by comparing the automatic results with manual measurements of the same images without individual hair annotation, we could find a correlation of at least 80%. CONCLUSION: According to the results and findings generated in this qualification study, we have a reliable tool now that enables us to test cosmetic products for hair treatment in a highly automated way with a sufficient degree of precision and accuracy to detect even small changes in hair diameter during cosmetic trials. PMID- 21272079 TI - Acyclovir skin depot characterization following in vivo iontophoretic delivery. AB - BACKGROUND/PURPOSE: Current Herpes labialis infection treatment by oral, parenteral or topical routes is inefficient. The objective of this study was to investigate the use of iontophoresis for improved topical delivery of acyclovir (ACV) in vivo in hairless rat. METHODS: Iontophoresis was performed for 10 min using a 5% ACV gel formulation. Tape stripping and skin extractions were performed at different time points following treatment for drug quantification in stratum corneum (SC) and underlying skin, respectively. RESULTS: Fourfold more ACV was detected in the SC immediately following 10-min iontophoresis as compared with passive delivery. Similarly, high ACV levels (29.27+/-3.52 MUg/cm(2)) were achieved in the underlying skin following a single 10-min iontophoretic treatment while no drug detected following passive delivery (P<0.05). At 24-h post iontophoresis, ACV levels in the SC decreased with a corresponding increase in the underlying skin due to drug migration. After 24-h post-iontophoresis, drug levels gradually decreased in both skin compartments until no ACV was detected at 72-h post-iontophoresis. CONCLUSION: Iontophoretic delivery of ACV resulted in high drug levels in skin layers to form a drug depot, which persisted over 2-3 days. PMID- 21272080 TI - Investigation of hair shaft in seborrheic dermatitis using atomic force microscopy. AB - BACKGROUND/PURPOSE: We have investigated the changes of seborrheic dermatitis (SD) on the hair shaft in the morphological and physical properties using atomic force microscopy (AFM). METHODS: Hair samples were obtained from the lesional and perilesional regions in 15 patients with SD. Fifteen healthy adults were included as the control group. From the topography of hair obtained by AFM, the height of the scale, step height, roughness, diameter, and pit were determined. RESULTS: The scale thickness of the SD-affected hair was sevenfold more than in the control hair showing statistically significance. The lesional hair showed greater roughness parameters of Sa, Sq, and Sz than the perilesional and the control hair, but this difference was not significant. The cuticle of the lesional hair was significantly damaged while perilesional hair showed a very distinct cuticle structure with smooth edges and a regular interval between the cuticles. The diameter of the lesional hair was significantly lesser by 10-35% than that of the perilesional hair. The pit was rarely observed in the SD-affected hair collected from both the lesional and perilesional regions. CONCLUSION: The changes in the hair shaft affected SD was measured using AFM non-invasively. AFM could be a useful tool in monitoring the treatment response and the severity of SD. PMID- 21272081 TI - IJU this issue: An academic journal functions as a vector to convey messages and information among researchers around the world who share an interest. PMID- 21272082 TI - Editorial comment to Retroperitoneal laparoscopic anatrophic nephrolithotomy large staghorn calculi. PMID- 21272083 TI - Editorial comment to Impact of insulin resistance, insulin and adiponectin on kidney stones in the Japanese population. PMID- 21272084 TI - Editorial comment to Does performance of robot-assisted laparoscopic radical prostatectomy within 2 weeks after biopsy affect the outcome? PMID- 21272085 TI - Editorial comment to When should we expect no residual tumor (pT0) once we submit incidental T1a-b prostate cancers to radical prostatectomy? PMID- 21272086 TI - Two-stage repair with buccal mucosa for severe and complicated hypospadias in adults. AB - OBJECTIVES: To report the outcomes of two-stage repair for adult hypospadias using a buccal mucosa graft as a tube. METHODS: A total of 57 adult patients who underwent surgery for severe urethral defect at our institution from January 2002 to March 2010 were included in this analysis. The urethroplasty procedure included penile urethra reconstruction with the buccal mucosa graft used as a tube in the first stage, anastomosis of the unobstructed urethra in the second stage and a scrotal fascio-cutaneous flap transferred to resurface the reconstructed urethra for waterproofing. RESULTS: No complications occurred after the first stage, whereas postoperative infections occurred in six cases and distal necrosis of the scrotal flap occurred in two cases after the second stage. All eight of these patients had the complication of urethrocutaneous fistula, which healed after 2-4 weeks by cleaning and changing dressings in six patients. Twelve patients complained of straining at voiding in the early postoperative period. However, nine of these patients had an obvious increase in maximum flow rate without any intervention 3 months after the operation. Follow up ranged from 6 to 62 months (mean 28 months) in 46 patients. Most of the patients presented terminal meatus, no chordee, no urethral stricture and normal voiding. The majority of patients achieved excellent cosmetic and functional results. CONCLUSIONS: A buccal mucosa graft as a tube is a reliable and durable method of two-stage repair for severe and complicated hypospadias in adults. The use of scrotal flaps seems to contribute to a good vascularized waterproof cover. PMID- 21272087 TI - Photoselective vaporization for prostatic obstruction with the 120-W lithium triborate laser: 1-year clinical outcomes. AB - There are few reports of the clinical outcomes of photoselective vaporization of the prostate (PVP) for benign prostatic hyperplasia (BPH) using the 120-W lithium triborate (LBO) laser. The present study evaluates clinical outcomes of 76 men treated with the 120-W LBO laser by an experienced PVP surgeon with 12 months follow up. The International Prostate Symptom Score (IPSS), peak flow rate (Qmax) and post-void residual (PVR) were examined at baseline and at 3 and 12 months. These parameters at baseline and 12 months were 20 +/- 7.0, 7.6 +/- 3.5 mL/s, 155 +/- 155 mL and 8.1 +/- 6.1, 22.5 +/- 10.3 mL/s, 59 +/- 87 mL, respectively. Clinically, meaningful improvements in IPSS, Qmax and PVR were observed at 3 months and sustained at 12 months. There were few adverse events, with only 5.3% of patients requiring recatheterization. Clinical outcome at 12 months was similar to that at 3 months and to other published series. PMID- 21272088 TI - Surgical procedures for benign prostatic hyperplasia: a nationwide survey in Japan. AB - We investigated the trend in surgical procedures for benign prostatic hyperplasia (BPH) during the past 10 years in Japan. A questionnaire inquiring about the number of operations and surgical procedures for BPH in 1999, 2004 and 2009 was sent to 1824 institutes belonging to the Japanese Urological Association and/or the Japanese Clinical Urologists Association. Responses were obtained from 767 institutes (42.1%). The number of operations showed a gradual increase during the 10 years (n = 17,221 in 1999, 18,772 in 2004, 20,413 in 2009). Transurethral resection of the prostate, including transurethral resection in saline, was consistently the most common procedure (72.5% to 79.2%). Holmium laser enucleation of the prostate and transurethral enucleation with a bipolar system have dramatically increased, becoming the second most common in 2009 (n = 3416), although enucleation by open prostatectomy was still a viable option in 2009 (n = 555). Photoselective vaporization of the prostate was the third most common method in 2009 (n = 572). Coagulation and thermotherapy have become uncommon (n = 2039 in 1999, 217 in 2009), whereas incision and stenting were unchanged during the period. Thus, surgical procedures for BPH have been increasing in Japan during the past decade. Transurethral resection remains the standard, whereas enucleation and vaporization have been increasing. PMID- 21272089 TI - Primary adult intratesticular rhabdomyosarcoma: results of the treatment of six cases. AB - The aim of the present study was to assess the treatment outcomes in a cohort of adult patients with intratesticular rhabdomyosarcoma. Between 1999 and 2008, 296 patients underwent radical orchiectomy for intrascrotal mass. A retrospective chart review was carried out for adult patients diagnosed with intratesticular rhabdomyosarcoma. Overall, six patients (mean age 21 years, range 17-23) were included: five had embryonic rhabdomyosarcoma and one had pleomorphic rhabdomyosarcoma. Four patients underwent retroperitoneal lymph node dissection and five patients had postoperative chemotherapy. The mean length of follow up was 28 months (range 12-51 months). One patient was lost to follow up after 26 months, five cases remained alive at the end of the study. Surgical resection with chemotherapy was an effective way to achieve favorable outcomes and long term survival in adult patients with metastases from intratesticular rhabdomyosarcoma. PMID- 21272090 TI - Testis cancer gene D40 expression and its relationship with clinicopathological features in infertile men. AB - We previously identified a novel human cancer/testis gene, D40, which is dominantly expressed in testicular germ cells, various cancer cell lines and primary human tumors. The expression of D40 mRNA and proteins in various testicular tissues was quantified using the conventional reverse transcription polymerase chain reaction (RT-PCR), real-time quantitative RT-PCR and western blot analysis. The relationship between levels of D40 expression, serum follicle stimulating hormone (FSH) level and Johnsen's score was examined. D40 mRNA expression was observed in the testes of infertile men, except those with Sertoli cell-only syndrome or Klinefelter's syndrome. The quantity of D40 mRNA and protein was correlated with Johnsen's score and inversely correlated with serum FSH level. The present results show that the expression levels of D40 mRNA and proteins decrease according to the degree of spermatogenesis impairment in male infertile patients. PMID- 21272091 TI - Effects of three types of alpha-1 adrenoceptor blocker on lower urinary tract symptoms and sexual function in males with benign prostatic hyperplasia. AB - OBJECTIVES: The aim of the present study was to explore the effects of three different types of alpha-1 adrenoceptor blockers (alpha1-blocker) on lower urinary tract symptoms (LUTS), erectile dysfunction (ED) and ejaculatory dysfunction (EjD) in patients with benign prostatic hyperplasia. METHODS: A total of 136 male LUTS patients aged 50-80 years with International Prostate Symptom Score (IPSS) >=8 were enrolled. They were divided into three groups. Group S received silodosin at 4 mg twice a day; group T received tamsulosin at 0.2 mg once a day; and group N received naftopidil at 50 mg once a day. Assessment included IPSS, quality of life indexes (QOL), International Index of Erectile Function (IIEF-5), an ejaculation questionnaire, Qmax and post-void residual urine volume (PVR). These parameters were recorded at baseline, and at 1 and 3 months after treatment had ended. RESULTS: Mean IPSS and Qmax significantly improved after treatment in all groups without any significant difference among them. As for the IIEF-5 score, only group N significantly improved at 1 and 3 months. After treatment, 2.6 and 2.4% of patients complained of a de novo reduced volume of ejaculation in both groups T and N, respectively. Ten out of 41 patients (24.4%) complained of a total absence of antegrade ejaculation in group S after treatment. CONCLUSIONS: All three types of alpha1-blockers provided an objective and subjective improvement of LUTS in the present study population. However, erectile function only improved in patients treated with naftopidil and a higher rate of EjD was observed in those receiving silodosin. Because of their variable effects, we should consider the sexual dimension when prescribing alpha1 blockers for LUTS. PMID- 21272092 TI - Anogenital malignancies and pre-malignancies. AB - Anogenital pre-malignancies and malignancies are frequently encountered. Aetiopathogenetically, human papillomavirus (HPV) infection plays a critical role. However, there is a variable degree of association of HPV infection with the development of anogenital malignancies. In this context, the high level of clinically unapparent HPV infection should be considered. Therefore, the question arises if the association with HPV is always causative. Besides HPV, pre-existent lichen sclerosus is also an important aetiopathologic factor in the development of anogenital malignancies. Common anogenital pre-malignancies comprise Bowen's disease (BD), Bowenoid papulosis (BP) and erythroplasia of Queyrat (EQ). From a clinical point of view, these are clearly different entities, but from a histopathological point of view, BD, BP and EQ are indistinguishable. They all represent forms of squamous intraepithelial neoplasia (IN). Intraepithelial neoplasia (IN) is not only restricted to squamous variants, but also includes non squamous IN, Paget's disease (PD) and melanoma in situ. The risk of developing anogenital (pre)malignancies or other tumours is higher in immunocompromised and immunodeficient patients, in particular those suffering from human immunodeficiency virus (HIV) infection. Such risk factors will affect treatment and follow-up modalities. Regarding prophylactic measures, a relatively recent but very important development is the availability of HPV vaccination on a large scale. Momentarily, the effects of such vaccination, on a population-based scale, are not yet clear but will become apparent in the near future. Management of anogenital pre-malignancies and malignancies should be tailor-made and may be organized in a multidisciplinary fashion. PMID- 21272093 TI - Morphofunctional evaluation of thymus in hyperglycemic-hypoinsulinemic mice during dermatophytic infection. AB - Many works have shown that the enhanced susceptibility to infection seen in diabetic patients can be related to the hyperglycemia-hypoinsulinemia (HH) observed in this condition. Herein, we evaluated the HH effects on the morphofunctional features of the thymus as well as on dermatophytic infection. We demonstrated that, not only the HH condition but also the dermatophytic infection induced transitory alterations in the thymus; it was characterized by loss of cortical-medullar definition and disorganization of the extracellular matrix. These mice also showed a decrease of CD4(+) CD8(+) thymocytes and a higher percentage of CD4(+) CD8(+) lymphocytes in the peripheral blood. After 7 days, the thymus and peripheral lymphocytes subsets returned to normal values. Interestingly, when the two conditions, HH condition and the infection, were associated, the mice showed a decrease in the percentage of CD4(+) CD8(-) blood lymphocytes that are involved in the modulation of immune response and have direct cytotoxic effects on the fungus. Taken together, our results showed that both conditions transitorily changed the thymus, but only when both these conditions are present do they trigger persistent changes that might be responsible for the higher susceptibility to dermatophytosis seen in HH patients. PMID- 21272094 TI - Growth response, nutrient and mineral retention, bone mineralisation and walking ability of broiler chickens fed with dietary inclusion of various unconventional mineral sources. AB - Growth response, nutrient and mineral retention, bone mineral content and walking ability of broiler chicken fed dietary inclusion of various unconventional calcium sources were studied using 160-day-old broilers. Four isonitrogenous, isocaloric diets balanced for Ca and P were formulated such that oyster shell, snail shell, wood ash and limestone were used as main non-phytate (Ca from other sources apart from plant) calcium sources. Each dietary treatment consisted of 40 birds replicated four times with 10 birds per replicate. A single diet was fed to the broilers throughout the duration of the study which lasted for 8 weeks. Broilers fed diet containing oyster shell as calcium sources recorded the highest (p < 0.05) feed intake of 5863.30 g, while those fed diet containing limestone consumed the least intake (p < 0.05) of 5432.56 g. Occurrence of lameness and evidences of gaits were highest (p < 0.05) for broilers fed diet containing wood ash. Lowest (p < 0.05) Ca and ash retention were recorded for broiler fed diet containing wood ash as Ca sources. Similar tibia ash values were recorded for broilers fed oyster shell, snail shell and limestone. Wood ash inclusion resulted in a low Ca availability hence its inclusion in feeds for broilers should be discouraged. PMID- 21272095 TI - The effects of ghrelin on ovary histology in Barbus sharpeyi. AB - Ghrelin is expressed in key cells of the female reproductive organ in several species of fishes. It has a role in the control of fertility. In the present study, the histological effect of ghrelin on 48 female Barbus sharpeyi was tested. Twenty-four hours later, microscopic observations and histometric counting was done. The results indicated that ghrelin can increase the number of mature ovarian follicles and sexual maturation and reduce the average oocyte diameter. PMID- 21272096 TI - Effects of induction of ovulation with GnRH or HCG on follicular and luteal blood flow in Holstein-Friesian heifers. AB - The objective of this study was to compare the effects of gonadotropin-releasing hormone (GnRH) and human chorionic gonadotropin (hCG) on follicular blood flow (FBF) during the pre-ovulatory period and on luteal blood flow (LBF) during dioestrus in Holstein-Friesian heifers. Twelve animals were randomly divided into two groups and treated with either intramuscular injection of 100 MUg GnRH or intravenous (IV) injection of 5000 IU hCG on Day 0 (oestrus, 48 h after administration of PGF(2alpha) ) to induce ovulation. Follicular size (FS), FBF and time of ovulation were recorded with colour Doppler sonography at 0, 1, 3, 6, 12 and 24 h after GnRH and hCG treatment. Luteal size (LS) and LBF were investigated on Day 9 and 12 after ovulation. Plasma samples were taken to determine total oestrogens (E(tot) ) and progesterone (P(4) ) after each examination. Ovulation occurred between 24 and 48 h after treatment in all animals. No difference (p > 0.05) was observed in FS between the two treatment groups. Follicular blood flow was higher in the hCG group than that was in GnRH group at 1 h after treatment (p < 0.01). Total oestrogens were also higher (p < 0.01) in the hCG group than GnRH group; however, this difference was only obvious at 12 h after treatment. No difference (p > 0.05) was observed in LS, LBF or P(4) levels on Day 9 and 12 between treatment groups. In conclusion, the results suggest that induction of ovulation with hCG and GnRH has a temporary effect on FBF and oestrogen levels while no effect on the size of corpora lutea, LBF and P(4) levels was observed. PMID- 21272097 TI - Irreversible damage in ovine ovarian tissue after cryopreservation in propanediol: analyses after in vitro culture and xenotransplantation. AB - Current progress in cancer treatment has increased the incidence of long-term patient survival. Ovarian tissue cryopreservation (OT) is still the most promising fertility saving method offered to young female patients with cancer prior to the onset of radio-chemotherapy. Further follicular development of immature primordial follicles depends on transplantation or in vitro culture (IVC). Aim of this study was to evaluate the appropriateness of cryopreserved ovine OT with 1,2-propanediol (PROH) after short-term IVC and xenotransplantation (XT). Ovarian tissue fragments from young adult sheep were cryopreserved using a standard slow-freezing protocol with 1.5 M PROH. Cryopreserved OT was assessed by light- and transmission electron microscopic analyses after thawing, IVC or XT in severe immunodeficient mice. Control OT showed the presence of healthy preantral follicles (Mean: 78.8%; SE 2.9%) and normal structure of the stromal tissue. After thawing and IVC over 80% of damaged primordial follicles and poor preservation of the stromal tissue was observed. After XT, OT demonstrated deficient follicles and huge areas of vacuolization in the stromal tissue confirmed by ultrastructural assessment. In conclusion, because of the irreversible character of the follicular and stromal damage of cryopreserved ovine ovarian tissue after IVC and XT, strong improvement of the utilized protocol is needed to be suitable for the preservation of ovine ovarian tissue. The deleterious effects of PROH do not imply its exclusion as cryoprotectant, but more research is needed for the development of less toxic cryoprotectant mixtures and toxicity neutralizers with attested cryoprotectant capacity for the safe and feasible freezing of human ovarian tissue. PMID- 21272098 TI - In vitro maturation and fertilization in the Nilgai (Boselaphus tragocamelus) using oocytes and spermatozoa recovered post-mortem from animals that had died because of foot and mouth disease outbreak. AB - The ability to rescue gametes from endangered or wildlife species and to subsequently produce viable embryos holds tremendous potential as a means to increase the population size of endangered or wildlife species. The objective of this study was to assess the developmental competence of gametes recovered from nilgai that had died because of foot and mouth disease outbreak. Oocytes collected from the ovaries of seven dead nilgais were allowed to mature in vitro and were tested for developmental potential by in vitro fertilization (IVF) with epididymal spermatozoa collected also post-mortem. The average number of oocytes (n = 517) recovered per ovary was 36.9, and the side (right or left), size and weight of the ovaries had no significant effect on the number and quality of oocytes recovered. In vitro maturation studies indicated that the proportion of matured oocytes (MII stage) at 18, 24 and 30 h was 55.6%, 63.4% and 63.6%, respectively. Furthermore, 43% of the matured oocytes cleaved following in vitro fertilization and 12% of the cleaved oocytes (6/49) developed to the 4-8 cell stage. These findings suggest that the gametes recovered from nilgai post-mortem could be utilized for in vitro production of embryos. PMID- 21272101 TI - Lymphoblastic lymphoma with unusual cytological features in pericardial effusion fluid. PMID- 21272099 TI - Rad52 function prevents chromosome loss and truncation in Candida albicans. AB - RAD52 is required for almost all recombination events in Saccharomyces cerevisiae. We took advantage of the heterozygosity of HIS4 in the Candida albicans SC5314 lineage to study the role of Rad52 in the genomic stability of this important fungal pathogen. The rate of loss of heterozygosity (LOH) at HIS4 in rad52-DeltaDelta strains was ~10(-3) , at least 100-fold higher than in Rad52(+) strains. LOH of whole chromosome 4 or truncation of the homologue that carries the functional HIS4 allele was detected in all 80 rad52-DeltaDelta His auxotrophs (GLH -GL lab His(-)) obtained from six independent experiments. Isolates that had undergone whole chromosome LOH, presumably due to loss of chromosome, carried two copies of the remaining homologue. Isolates with truncations carried centric fragments of broken chromosomes healed by de novo telomere addition. GLH strains exhibited variable degrees of LOH across the genome, including two strains that became homozygous for all the heterozygous markers tested. In addition, GLH strains exhibited increased chromosomal instability (CIN), which was abolished by reintroduction of RAD52. CIN of GLH isolates is reminiscent of genomic alterations leading to cancer in human cells, and support the mutator hypothesis in which a mutator mutation or CIN phenotype facilitate more mutations/aneuploidies. PMID- 21272100 TI - Biochemical and morphological consequences of human alpha-synuclein expression in a mouse alpha-synuclein null background. AB - A consensus about the functions of human wild-type or mutated alpha-synuclein (alphaSYN) is lacking. Both forms of alphaSYN are implicated in Parkinson's disease, whereas the wild-type form is implicated in substance abuse. Interactions with other cellular proteins and organelles may meditate its functions. We developed a series of congenic mouse lines containing various allele doses or combinations of the human wild-type alphaSYN (hwalphaSYN) or a doubly mutated (A30P*A53T) alphaSYN (hm(2) alphaSYN) in a C57Bl/6J line spontaneously deleted in mouse alphaSYN (C57BL/6JOla). Both transgenes had a functional role in the nigrostriatal system, demonstrated by significant elevations in striatal catecholamines, metabolites and the enzyme tyrosine hydroxylase compared with null-mice without a transgene. Consequences occurred when the transgenes were expressed at a fraction of the endogenous level. Hemizygous congenic mice did not exhibit any change in the number or size of dopaminergic neurons in the ventral midbrain at 9 months of age. Human alphaSYN was predominantly located in neuronal cell bodies, neurites, synapses, and in intraneuronal/intraneuritic aggregates. The hm(2) alphaSYN transgene resulted in more aggregates and dystrophic neurites than did the hw5 transgene. The hwalphaSYN transgene resulted in higher expression of two striatal proteins, synaptogamin 7 and UCHL1, compared with the levels of the hm(2) alphaSYN transgene. These observations suggest that mutations in alphaSYN may impair specific functional domains, leaving others intact. These lines may be useful for exploring interactions between halphaSYN and environmental or genetic risk factors in dopamine-related disorders using a mouse model. PMID- 21272102 TI - Informed consent and patient understanding of blood transfusion. AB - BACKGROUND: Obtaining separate informed consent for blood transfusion is mandatory in some countries. Although patients should be informed about risks and benefits of transfusion, studies suggest this does not happen routinely in the UK and the patient perspective is lacking in the current literature. AIM: To explore provision of information and the consent process for patients receiving blood transfusions at our hospital. OBJECTIVES: To assess patient recall of the consent process, information conveyed, ease in understanding discussions and perceived knowledge of transfusion afterwards. METHODS: All 342 adult patients for whom blood was cross-matched between 1 March 2008 and 30 April 2008 were sent postal questionnaires. RESULTS: One hundred and sixty-four questionnaires were returned. Overall, 59.1% of patients said someone explained they might need a transfusion; of those 86.7% felt the reason had been explained. Only 58.8% of patients felt informed of what transfusion involves, with 67.0% told of the benefits and 27.8% informed of risks. Overall, 51.5% of patients said this information was easy to understand, but only 26.8% were aware of a transfusion information leaflet. Of those receiving leaflets, all said they read it and had no questions. Despite this, 61.9% were satisfied overall with the information received. CONCLUSION: Information leaflets could increase the information available to patients, with minimal impact on health care professionals' time. Leaflets are available, free of charge, from the National Health Service Blood and Transplant website. These have been introduced at each bedside, in pre-op packs and in outpatient clinics, with re-assessment planned in 6 months. PMID- 21272103 TI - Bacterial screening by flow cytometry offers potential for extension of platelet storage: results of 14 months of active surveillance. AB - BACKGROUND: Bacterial contamination is currently the major infectious hazard of platelet transfusion in developed countries. It has been demonstrated that a significant transfusion risk remains, in particular with older platelet concentrates (PCs). In 2009, the shelf life of PCs was therefore reduced in Germany to 4 days after the day of production according to Vote 38. The aim of the present study was the application and implementation of a recently developed flow cytometry-based rapid screening method (BactiFlow) for bacterial contamination at the end of PC shelf life as a routine in-process control. STUDY DESIGN AND METHODS: A total of 472 apheresis-derived PCs were tested using the BactiFlow flow cytometric assay to detect and count bacteria based on esterase activity in viable bacterial cells, while the BacT/Alert automated culture system served as the reference method. The automation potential of the flow cytometric assay was analysed by applying the semi-automated BactiFlow ALS system. RESULTS: An algorithm was developed for use in routine blood bank operations to extend the storage period of PCs. Two of the 472 apheresis PCs tested were positive in culture and identified as Propionibacterium species. One PC was positive for Staphylococcus aureus by both methods. All remaining specimens were tested negative by both methods. CONCLUSIONS: Our study demonstrates that routine bacterial testing of PCs was successfully implemented and the established algorithm proved efficient. The BactiFlow flow cytometric assay is the first rapid screening method which is suitable for a routine application combined with a high sensitivity. PMID- 21272104 TI - Ischaemia-reperfusion injury in orthotopic mouse lung transplants - a scanning electron microscopy study. AB - Lung ischaemia-reperfusion (I/R) injury remains a major cause of graft failure in lung transplantation (Tx). With the implementation of orthotopic lung Tx in mice, a physiological model on the base of a perfused and ventilated graft became available for the investigation of I/R injury. Using the scanning electron microscopy (SEM) technique, we here present an analysis of early and late morphological changes of pulmonary I/R injury. Syngeneic lungs were orthotopically transplanted between C57BL/6 mice. Grafts were exposed to 2 h of cold ischaemia. Transplants and right lungs were examined by SEM with corresponding haematoxylin-eosin histology 30 min and 4 h after reperfusion. Thirty minutes after reperfusion, the alveolar surface of transplants showed a discontinued lining of surfactant, while the lining of the non-transplanted lung was normal. Within the graft, leucocytes displayed an irregular surface with development of pseudopodia, and microvilli were detected on the membrane of pneumocytes. At 4 h after reperfusion, leucocytes significantly increased in numbers within the alveolar space. Also, the number of microvilli on pneumocytes increased significantly. Similar to these, the endothelium of vessels increasingly developed microvilli from 30 min towards 4 h after reperfusion. The airways of transplanted grafts showed mild changes with thickening of the bronchial epithelium and a destruction of kinocilia. Taken together, SEM detects pathological events of I/R that are previously not described in normal histology. These findings may influence the interpretation of studies investigating the I/R injury in the mouse model of lung Tx. PMID- 21272105 TI - Impaired glucose tolerance plus hyperlipidaemia induced by diet promotes retina microaneurysms in New Zealand rabbits. AB - With the increasing prevalence of diabetes mellitus and metabolic syndrome worldwide, experimental models are required to better understand the pathophysiology and therapeutic approaches to preserve pancreatic beta cells, attenuate atherosclerosis and protect target organs. The aims of this study were to develop an experimental model of impaired glucose tolerance combined with hypercholesterolaemia induced by diet and assess metabolic alterations and target organ lesions. New Zealand male rabbits were fed high-fat/high-sucrose (10/40%) and cholesterol-enriched diet for 24 weeks, when they were sacrificed. Biochemistry, fundus photographs with fluorescein angiography and pathological analyses were performed. Cholesterol-fed and normal animals of same age were compared. RESULTS: The animals with diet-induced impaired glucose tolerance combined with hypercholesterolaemia gained weight, increased blood glucose, total cholesterol, LDL-C and triglycerides and decreased HDL-C (P < 0.05 vs. baseline). Fructosamine levels and the homeostasis model assessment of insulin resistance (HOMA-IR) index were increased, while there was a reduction in the HOMA-beta (P < 0.05 for all vs. baseline). Histomorphologic findings of this model were aortic atherosclerosis, hepatic steatofibrosis and glomerular macrophage infiltration. Early clinical features of diabetic retinopathy with hyperfluorescent dots consistent with presence of retina microaneurysms were seen since week 12, progressing up to the end of the experiment (P < 0.0005 vs. baseline and 12 weeks). Our model reproduced several metabolic characteristics of human diabetes mellitus and promoted early signs of retinopathy. This non-expensive model is suitable for studying mechanistic pathways and allowing novel strategic approaches. PMID- 21272106 TI - Fifteen-year follow-up of thyroid status in adults with Down syndrome. AB - BACKGROUND: The natural history of thyroid function in adults with Down syndrome is relatively unknown with limited long-term follow-up data. METHOD: This study investigated annual thyroid function tests in 200 adults with Down syndrome over a 15-year period. RESULTS: For healthy adults with Down syndrome there is a gradual increase in thyroxine and possible gradual decline in thyroid-stimulating hormone with age. The 15-year incidence for definite hypothyroidism remains low and subclinical hypothyroidism is not a precursor for the onset of definite hypothyroidism. CONCLUSIONS: The incidence of thyroid dysfunction is markedly less than would be expected from prevalence studies. Subclinical hypothyroidism is not necessarily a precursor to definite hypothyroidism. Prevalence studies have overstated the association between thyroid dysfunction and Down syndrome. Routine screening for adults with Down syndrome who are euthyroid can be reduced to every 5 years rather than the 1-2 years, as is the present policy. PMID- 21272107 TI - Multimodel inference in ecology and evolution: challenges and solutions. AB - Information theoretic approaches and model averaging are increasing in popularity, but this approach can be difficult to apply to the realistic, complex models that typify many ecological and evolutionary analyses. This is especially true for those researchers without a formal background in information theory. Here, we highlight a number of practical obstacles to model averaging complex models. Although not meant to be an exhaustive review, we identify several important issues with tentative solutions where they exist (e.g. dealing with collinearity amongst predictors; how to compute model-averaged parameters) and highlight areas for future research where solutions are not clear (e.g. when to use random intercepts or slopes; which information criteria to use when random factors are involved). We also provide a worked example of a mixed model analysis of inbreeding depression in a wild population. By providing an overview of these issues, we hope that this approach will become more accessible to those investigating any process where multiple variables impact an evolutionary or ecological response. PMID- 21272108 TI - Building a child mental health workforce: what vision are we working toward? PMID- 21272109 TI - The concept of patient satisfaction in adolescent psychiatric care: a qualitative study. AB - PROBLEM: Few studies have asked how adolescents perceive the quality of psychiatric care. Therefore, the aim of the study was to explore adolescents' perception of quality of care and of satisfying treatment outcomes. METHODS: Fourteen adolescents participated in this hermeneutic study. FINDINGS: Several concepts describing adolescents' perspective of quality of care were found: secure place, tough love, peer solidarity, self-expression, and person not patient. Concepts describing satisfying treatment outcomes fell into four categories: improved mental health, personal development, strengthening of the self, and improved family relations. CONCLUSIONS: By casting light on users' perspectives, the study offers guidance for improvement of quality of care and for the development of patient satisfaction instruments. PMID- 21272110 TI - Effectiveness of six core strategies based on trauma informed care in reducing seclusions and restraints at a child and adolescent psychiatric hospital. AB - OBJECTIVE: The purpose of the study was to determine the effectiveness of six core strategies based on trauma informed care in reducing the use of seclusion and restraints with hospitalized youth. METHODS: The hospital staff received training in March 2005 in six core strategies that are based on trauma informed care. Medical records were reviewed for youth admitted between July 2004 and March 2007. Data were collected on demographics, including age, gender, ethnicity, number of admissions, type of admissions, length of stay, psychiatric diagnosis, number of seclusions, and restraints. RESULTS: Four hundred fifty eight youth (females 276/males 182) were admitted between July 2004 and March 2007. Seventy-nine patients or 17.2% (females 44/males 35) required 278 seclusions/restraints (159 seclusions/119 restraints), with average number of episodes 3.5/patient (range 1-28). Thirty-seven children and adolescents placed in seclusion and/or restraints had three or more episodes. In the first six months of study, the number of seclusions/restraints episodes were 93 (73 seclusions/20 restraints), involving 22 children and adolescents (females 11/males 11). Comparatively, in final six months of study following the training program, there were 31 episodes (6 seclusions/25 restraints) involving 11 children and adolescents (females 7/males 4). The major diagnoses of the youth placed in seclusion and/or restraints were disruptive behavior disorders (61%) and mood disorders (52%). CONCLUSIONS: This study shows downward trend in seclusions/restraints among hospitalized youth after implementation of National Association of State Mental Health Program Directors six core strategies based on trauma informed care. PMID- 21272111 TI - Recovery of normal body weight in adolescents with anorexia nervosa: the nurses' perspective on effective interventions. AB - PROBLEM: Little is known about effective nursing interventions for adolescents with anorexia nervosa. The purpose of this study was to discover which aspects of nursing care are most effective, according to nurses, in recovery of normal body weight in adolescents with anorexia nervosa. METHODS: A qualitative descriptive research design was applied with individual in-depth interviews and a focus group. Thematic analysis was used to analyze the data. FINDINGS: Nurses state that they are in a key position in guiding patients with anorexia nervosa toward a path of weight recovery. A good therapeutic relationship is essential to the implementation of targeted nursing interventions in the areas of eating and exercising, social support, and parent counseling. CONCLUSIONS: The results of this research can be used to define more detailed nursing interventions, the effectiveness of which can be tested in follow-up research. PMID- 21272112 TI - Psychometric properties of the Screen for Child Anxiety Related Emotional Disorders in a rural high school population. AB - PROBLEM: Evaluate psychometric properties of the 41-item SCARED (Screen for Child Anxiety Related Emotional Disorders) when used with a rural community dwelling sample. METHODS: As part of a randomized controlled trial, SCARED was administered to 193 adolescents in a rural high-school setting. Internal consistency, test-retest reliability, and factor structure were assessed. FINDINGS: Adequate internal consistency (alpha= 0.93) and test-retest reliability (r= 0.703) were demonstrated. Five factors were identified with a differing composition than previously reported. CONCLUSIONS: The SCARED was found to be a reliable tool in the rural adolescent population. Differences in some factors suggest further research is needed. PMID- 21272113 TI - Quality of eating disorders websites: what adolescents and their families need to know. AB - OBJECTIVE: The purpose of this study was to examine the accessibility and content quality of eating disorder websites. METHODS: A descriptive, exploratory study using four search engines and seven search terms was conducted to identify and evaluate the accuracy of eating disorder information available on consumer oriented websites. FINDINGS: One hundred fifteen (82.1%) websites were accessed. Few sites fully described the DSM diagnostic criteria for anorexia nervosa (13.2%), bulimia nervosa (15.8%), eating disorder not otherwise specified (6.9%), and binge eating disorder (8%), as well as associated treatment options. CONCLUSIONS: Results suggest that eating disorder websites do not adequately address diagnostic criteria or treatment options. PMID- 21272114 TI - An integrative review of adolescent depression screening instruments: applicability for use by school nurses. AB - BACKGROUND: Major depression is a significant yet underdiagnosed problem of adolescence. The consequences of undiagnosed and untreated depression in this vulnerable population can have detrimental effects. School nurses are in a prime position to perform early screening and referral. However, the school environment requires special consideration as the setting for screening of adolescent depression. OBJECTIVE: The purpose of this paper is to identify instruments that can be utilized by the school nurse to perform easily administered, rapid adolescent depression screenings that are valid, reliable, and economical. METHODS: An integrative review of current depression instruments used in adolescents was conducted. RESULTS: Of the seven most commonly used instruments, only four of those fit the criteria listed for conducting screening in the school setting by the school nurse. The four instruments include the Beck Depression Inventory-Youth (BDI-Y), the Children's Depression Inventory, the Center for Epidemiological Studies-Depression Scale for Children, and the Reynolds Adolescent Depression Scale. CONCLUSION: Although all four of the identified instruments provide reliability and validity in the school setting, it is the other criteria: affordability, ease of administration, and the ability of the instrument to be rapidly scored, that placed the Center for Epidemiological Studies-Depression Scale for Children and the BDI-Y as the reasonable choice of instruments for use by the school nurse. PMID- 21272115 TI - Anticipatory stress response in PTSD: extreme stress in children. AB - TOPIC: Anticipatory stress chronically activates the stress response in children with post-traumatic stress disorder (PTSD). Effects of the allostatic load may begin even before birth in a stressful environment. PURPOSE: The purpose of this paper is to discuss the anticipatory stress response in children with PTSD. The paper discusses the etiology, the impact of the disorder on long term health, cognitive and behavioral manifestations, and clinical management and treatment options. SOURCES USED: A review on current literature is presented and includes several key studies. CONCLUSIONS: Anticipatory stress in PTSD has acute and long-term health implications for the child. The psychiatric nurse plays a key role in preventing the long-term effects of PTSD. PMID- 21272116 TI - A report from the 6th World Conference. PMID- 21272118 TI - Allograft and overall survival of patients with posttransplant skin cancer. AB - BACKGROUND: Little is known about the possible association between nonmelanoma skin cancer (NMSC) and allograft survival and overall patient survival. OBJECTIVE: To determine the association between posttransplant NMSC and early to mid-term allograft survival and overall patient survival after kidney, liver, or heart transplantation. METHODS AND MATERIALS: We retrospectively reviewed patients identified from the Organ Procurement and Transplantation Network/United Network for Organ Sharing database. The study included adult recipients of kidney (n=46,216), liver (n=8,049), and heart (n=8,519) transplants from 1996 to 2001. RESULTS: Multivariate analysis showed that kidney recipients with NMSC had a significantly lower risk of allograft loss (relative risk (RR)=0.55, p<.001) and death (RR=0.55; p<.001) within 5 years of transplantation than recipients without NMSC. Significantly lower risk of death was also observed for liver recipients (RR=0.28, p<.001) and heart recipients (RR=0.25; p<.001) with NMSC. CONCLUSIONS: Longer early to mid-term allograft and overall survival was seen in patients with NMSC, but long-term survival rates must be examined to determine whether mortality rates increase later for patients with NMSC, as noted in previous studies. PMID- 21272119 TI - Comparative histology of intradermal implantation of mono and biphasic hyaluronic acid fillers. AB - BACKGROUND: Hyaluronic acid (HA) gels have been used as filler material in the aesthetic field. Although the native HA molecule is without specificity of species and organs, synthetic cross-linked gels have differences in chemical composition and three-dimensional structure. Different technologies are employed in cross-linking, and the products have varying rheological properties. OBJECTIVE: To determine whether the gels with differing chemical composition have differing histologic behavior when injected into human skin to determine if the histology changes after 14 days of implantation. MATERIALS AND METHODS: Human volunteers consented to having controlled placement of HA intradermally into forearm or buttock skin. The trials were conducted in a single clinic in association with the Hopitaux Universitaires de Geneve, Geneva, Switzerland. The biopsies were taken immediately after implantation of the product and at day 14. Standard paraffin sections were prepared and stained with hematoxylin and eosin and Alcian blue and examined by an independent pathologist. RESULTS: Results show that each type of HA has a predictable histologic behavior in the skin. Biphasic gel has demonstrated deposition in big pools, often deep in the reticular dermis. The pools compress the collagen fibers. The papillary dermis and superficial reticular dermis are free of HA. Monophasic monodensified gels show large pools of hyaluronans throughout all the thickness of the reticular dermis. This material breaks up the collagen fibers of most of the dermal plane. The papillary dermis is free of exogenous hyaluronans. Monophasic polydensified cohesive gel penetrates into the dermis in a diffuse, evenly distributed manner, except in the papillary dermis, which remains free of exogenous material. CONCLUSION: The different types of cross-linked HA have different behaviors in the dermis immediately after their injection. The patterns are consistent between patients and are predictable. These histologic patterns do not change when biopsies are examined at 2 weeks. PMID- 21272120 TI - Early postoperative treatment of thyroidectomy scars using a fractional carbon dioxide laser. AB - BACKGROUND: Ablative carbon dioxide fractional laser systems (CO(2) FS) have been effectively used to improve the appearance of scarring after surgical procedures, but an optimal treatment time has not been established. OBJECTIVE: To evaluate the efficacy and safety of CO(2) FS in early postoperative thyroidectomy scars. METHODS: Twenty-three Korean women with thyroidectomy scars were enrolled in this study. All patients underwent a single session of two passes of a CO(2) FS with a pulse energy setting of 50 mJ and a density of 100 spots/cm(2) 2 to 3 weeks after surgery. RESULTS: Mean Vancouver Scar Scale (VSS) scores were statistically significantly lower after laser treatment. Three months after CO(2) FS treatment of thyroidectomy scarring, 12 of 23 participants showed clinical improvement of more than 51% from 2 to 3 weeks after surgery. The mean grade of clinical improvement based on independent clinical assessment was 2.6 +/- 0.9. CONCLUSION: Early postoperative CO(2) FS treatment of thyroidectomy scars is effective and safe. PMID- 21272121 TI - Long-term follow-up of a case of cheek hyperpigmentation associated with McCune Albright syndrome treated with Q-switched ruby laser. PMID- 21272122 TI - World Kidney Day 2011: protect your kidneys, save your heart. PMID- 21272123 TI - Understanding crossmatch testing in organ transplantation: A case-based guide for the general nephrologist. AB - Crossmatching of potential renal donors against potential renal transplant recipients has been performed for over 40 years and is a mandatory component of the transplant work-up process. However, gone are the days when all that was available was the T-cell complement-dependent cytotoxicity crossmatch. There are now many more options available for determining the likelihood of donor-specific antibody-mediated responses including flow crossmatching and the 'virtual' crossmatch. In addition, assays to determine the extent of sensitization of cell mediated responses are being examined. This article builds an understanding of modern day crossmatch interpretation using a case-based approach in order to provide a framework for the general nephrologist to determine the likely immune consequences of a particular donor-recipient pairing. PMID- 21272124 TI - Preeclamptic nephropathy. AB - With the recent discovery of potential serum 'toxins' in human preeclampsia, it is timely to consider how these might relate to preeclamptic nephropathy. This review will discuss the clinical presentation of preeclampsia with an emphasis on renal involvement. It will explore the nature of the renal histological changes including endothelial and the more recently discovered podocyte changes, the implications of elevated anti-angiogenic molecules, anti-angiotensin-1 receptor agonistic antibodies and other proposed mechanisms in causing or exacerbating renal lesions. It will also explore the role of pre-existing renal disease in causing preeclampsia and the potential for new biomarkers, both serum and urinary, to inform clinical practice with regard to differentiating preeclampsia from pre-existing renal disease. Recommendations about the future of women who have had preeclampsia are unclear but the general consensus is that there are future cardiovascular risks, and to a lesser extent, future renal risks in these women. Regular review of proteinuria and glomerular filtration rate as well as overall cardiovascular risk status seems a logical step. PMID- 21272125 TI - Is the problem with the vehicle or the destination? Does high-dose ESA or high haemoglobin contribute to poor outcomes in CKD? AB - Randomized controlled trials have consistently demonstrated adverse outcomes from targeting higher haemoglobin levels in chronic kidney disease patients treated with erythropoiesis-stimulating agents (ESA). In contrast, observational studies have shown better survival in patients achieving high haemoglobin. Consequently, there is ongoing uncertainty as to whether high haemoglobin or high ESA dose contributes to poor outcomes in ESA-treated chronic kidney disease patients. The objectives of this article are to review the available evidence pertaining to this contentious area, provide recommendations where possible and suggest directions for future research efforts. PMID- 21272126 TI - Non-steroidal anti-inflammatory drugs and the risks of acute renal failure: Number needed to harm. PMID- 21272127 TI - Interactions of urate transporter URAT1 in human kidney with uricosuric drugs. AB - AIM: Hyperuricaemia is a significant factor in a variety of diseases, including gout and cardiovascular diseases. The kidney plays a dominant role in maintaining plasma urate levels through the excretion process. Human renal urate transporter URAT1 is thought to be an essential molecule that mediates the reabsorption of urate on the apical side of the proximal tubule. In this study the pharmacological characteristics and clinical implications of URAT1 were elucidated. METHODS: Madin-Darby canine kidney (MDCK) cells stably expressing URAT1 (MDCK-URAT1) were established and examined the interactions of URAT1 with various drugs such as benzbromarone and its metabolites including 6 hydroxybenzbromarone, angiotensin-converting enzyme inhibitors, non-steroidal anti-inflammatory drugs and urate transport inhibitors including E3040 and probenecid. RESULTS: MDCK-URAT1 cells exhibited a time- and dose-dependent increase in urate uptake, with a Km value of 570.7 umol/L. When an URAT1-green fluorescent protein fusion protein construct was expressed in MDCK cells, the protein was sorted mainly to the apical side of the membrane. The drugs except for captoril dose-dependently inhibited urate uptake mediated by URAT1, with half maximal inhibitory concentration (IC(50) ) values ranging 0.05-716 umol/L. CONCLUSION: Comparing these IC(50) values with intratubular concentrations of unbound drugs in humans, it is thought that URAT1 is a target molecule of uricosuric drugs, including 6-hydroxybenzbromarone, probenecid, indomethacin and salicylate, to inhibit urate reabsorption in vivo. In addition, a cell line that stably expressing URAT1 could be a useful tool for the development of uricosuric drugs. PMID- 21272128 TI - Sphingosine-1-phosphate reduces hepatic ischaemia/reperfusion-induced acute kidney injury through attenuation of endothelial injury in mice. AB - AIM: Hepatic ischaemia/reperfusion injury (IRI) frequently complicates acute kidney injury (AKI) during the perioperative period. This study was to determine whether hepatic IRI causes AKI and the effect of the sphingosine-1-phosphate (S1P) on AKI. METHODS: S1P and vehicle were given to mice before ischaemia and mice were subjected to hepatic IRI. Plasma creatinine (PCr), alanine transaminase (ALT), urinary neutrophil gelatinase-associated lipocalin (NGAL) and renal histological changes were determined. As a marker of endothelial injury, vascular permeability was measured. The effect of VPC 23019, a S1P(1) receptor antagonist, was also assessed. RESULTS: Hepatic IRI resulted in liver injury (increased ALT) and systemic inflammation. Kidneys showed elevated inflammatory cytokines, leucocyte infiltration, increased vascular permeability, tubular cell apoptosis and increased urinary NGAL, although PCr did not increase. Pretreatment with S1P resulted in an attenuation of systemic inflammation and kidney injury without any effect on plasma ALT or peripheral lymphocytes. The protective effect of S1P was partially reversed by VPC 23019, suggesting the important contribution of the S1P/S1P(1) pathway to protect against hepatic IRI-induced AKI. CONCLUSION: The study data demonstrate the important contribution of systemic inflammation and endothelial injury to AKI following hepatic IRI. Modulation of the S1P/S1P(1) receptor pathway might have some therapeutic potential in hepatic IRI-induced kidney injury. PMID- 21272129 TI - The clinical course of rapidly growing nontuberculous mycobacterial peritoneal dialysis infections in Asians: A case series and literature review. AB - INTRODUCTION: Peritoneal dialysis (PD)-related infections due to rapidly growing nontuberculous mycobacterium (RGNTM) are rare in Asians and have variable clinical outcomes. METHODS: We analysed retrospectively a series of RGNTM infections in a single-centre multi-ethnic Asian population over a 5-year period. Clinical features, treatment, risk factors and outcomes are discussed. RESULTS: Ten infections are described. They constituted 3% of all culture-positive exit site infection (ESI) and PD peritonitis. Seventy percent were due to Mycobacterium abscessus (three ESI and four peritonitis). There were two Mycobacterim fortuitum and one Mycobacterium chelonei peritonitis. No specific findings differentiated RGNTM infections from those caused by traditional organisms. Six cases had received prior antibiotics, two being topical gentamicin. Initial routine culture and alcohol acid fast bacillus were negative except for one case of M. abscessus. A confirmatory diagnosis was made a median 9 days post culture. No infection responded to routine antibiotics. Antibiotic resistance was variable but M. abscessus was universally sensitive to clarithromycin. Combined antibiotics based on sensitivity profile were successfully used in 70% of the cases. PD catheter loss was 80%. Three-month mortality was 40% (vs. 8.5% and 12% in non-RGNTM ESI and peritonitis, respectively). This may be related to the cohort high mean Charlson score of 7.5. CONCLUSION: RGNTM PD infections are commoner in Asians than previously reported. Their early diagnosis requires a high index of suspicion and appropriate treatment started promptly. They are associated with prior antibiotic use and refractory culture-negative infections, delayed diagnosis and lead to significant catheter loss and death. PMID- 21272130 TI - Relationship between the course of depression symptoms and the left ventricular mass index and left ventricular filling pressure in chronic haemodialysis patients. AB - AIM: Multiple measurements of depression symptoms over time were more predictive of cardiovascular mortality than a single time measurement performed at baseline. The aim of this study is to evaluate the association of the course of depression symptoms, based on repeated assessments of depression symptoms over time, with left ventricular mass index (LVMI) and left ventricular filling pressure (LVFP) in patients on haemodialysis (HD). METHODS: The level of depression symptoms in 61 patients on HD were prospectively assessed using the Beck Depression Inventory (BDI) at baseline and at three intervals (5, 10, 15 months). Doppler echocardiographic examinations were performed at the end of follow up. RESULTS: At the end of follow up, the patients were divided into three groups according to their course of depression symptoms: non-depression (n = 21), intermittent depression (n = 23) and persistent depression (n = 17). LVMI and LVFP were significantly increased in the persistent depression symptoms group compared to those of the non-depression symptoms group and the intermittent depression symptoms group. Persistent depression symptoms were independently associated with LVMI (beta-coefficient = 0.347, P = 0.017) and LVFP (beta-coefficient = 0.274, P = 0.048) after adjustment for age, sex, systolic blood pressure, diastolic blood pressure, diabetes and interdialytic weight gain. CONCLUSION: In our study, persistent depression symptoms were associated with left ventricular hypertrophy and diastolic dysfunction. Our data may provide a more complete understanding of cardiovascular risk associated with depression symptoms in patients on HD. PMID- 21272131 TI - Relation of ankle-brachial index to the rate of decline of residual renal function in peritoneal dialysis patients. AB - AIM: The aim of this study was to determine whether ankle-brachial index (ABI) predicts the rate of decline of residual renal function (RRF) in peritoneal dialysis (PD) patients. Previous studies demonstrated the importance of loss of RRF in predicting all-cause risk and cardiovascular mortality in PD patients. It is also known that patients with a low ABI value have a greater risk for deteriorating renal function in the general population. The relationship between ABI and the declining rate of RRF in PD patients with an additional dialysis specific risk factor is uncertain. METHODS: Seventy-four PD patients with RRF of more than 1 mL/min per 1.73 m(2) were analyzed. ABI was used as the surrogate measure of pre-existing cardiovascular disease and atherosclerosis burden to further determine the outcome of RRF in this study. The slope of decline of RRF was used to determine the outcome. RESULTS: Based on the multivariate analysis, only ABI (P < 0.001), diabetes (P = 0.02) and baseline RRF (P = 0.009) independently predicted a faster decline in RRF. A stepwise multiple linear regression analysis demonstrated that ABI was an independent predictor for the slope of decline of RRF (P < 0.001). CONCLUSION: A low ABI is an independent predictor of not only the known atherosclerotic events, but also of the rate of decline of RRF over time in PD patients. PMID- 21272132 TI - Changes in renal markers and acute kidney injury after marathon running. AB - BACKGROUND: The impact of marathon running on kidney function has not been previously described. METHODS: From 425 marathon runners, 13 women and 12 men were randomly selected and cardiovascular magnetic resonance imaging (MRI) and blood/urine biomarkers were performed 4 weeks before (baseline), immediately after (peak), and 24 h after the race (recovery). RESULTS: Participants were 38.7 +/- 9.0 years old and completed the marathon in 256.2 +/- 43.5 min. A total of 10/25 (40.0%) met the Acute Kidney Injury Network definition of acute kidney injury (AKI) based on a rise in serum creatinine. There were parallel and similar mean rises in serum creatinine and cystatin C from baseline, to peak, and return to normal in recovery. Urine neutrophil gelatinase-associated lipocalin rose from 8.2 +/- 4.0 to 47.0 +/- 28.6 and returned to 10.6 +/- 7.2 ng/mL, P < 0.0001. Likewise, the mean urinary kidney injury molecule-1 levels were 2.6 +/- 1.6, 3.5 +/- 1.6 and 2.7 +/- 1.6 ng/mL (P = 0.001). The mean and minimum pre- and post-IVC (inferior vena cava) diameters by MRI were 24.9, 18.8 and 25.3, 17.5 mm, respectively, suggesting that runners were not volume depleted at the first post race measurement. CONCLUSION: Approximately 40% of marathon runners experience a transient rise in serum creatinine that meets criteria of AKI with a parallel elevation of cystatin C, and supportive elevations of neutrophil gelatinase associated lipocalin and kidney injury molecule-1 in the urine. All biomarker elevations resolved by 24 h. These data suggest that AKI with a transient and minor change in renal filtration function occurs with the stress of marathon running. The impact of repetitive episodes of AKI with long-distance running is unknown. PMID- 21272133 TI - Triptolide attenuates renal interstitial fibrosis in rats with unilateral ureteral obstruction. AB - AIM: Extracts of Tripterygium wilfordii Hook F. have been used to treat glomerulonephritis for more than 30 years in China. Most of the anti-inflammatory and immunosuppressive activities of these extracts can be attributed to triptolide (Trip). The present study was to investigate the effect of Trip on renal interstitial fibrosis in a model of unilateral ureteral obstruction (UUO). METHODS: UUO or sham-operated rats were randomly assigned to receive mycophenolate mofetil (MMF), Trip or vehicle and were killed on days 7 and 14 after UUO or sham operation. Kidney specimens were fixed for immunohistochemistry for myofibroblasts (alpha-smooth muscle actin, alpha-SMA), macrophages (ED-1), monocyte chemoattractant protein-1 (MCP-1) and osteopontin. Interstitial collagen deposition and amounts of transforming growth factor-beta1 (TGF-beta1) were determined by Sirius red staining and enzyme-linked immunosorbent assay, respectively. The mRNA expression of TGF-beta1, connective tissue growth factor (CTGF), MCP-1 and osteopontin were measured by real-time polymerase chain reaction analysis. RESULTS: The scores for the density of alpha-SMA- and ED-1 positive cells, the staining of MCP-1 and osteopontin, interstitial collagen deposition and amounts of TGF-beta1 were significantly reduced by MMF or Trip. MMF or Trip significantly reduced the mRNA expression of TGF-beta1, CTGF, MCP-1 and osteopontin. CONCLUSION: Trip significantly attenuated tubulointerstitial fibrosis in a rat UUO model and the effect of Trip on renal fibrosis was similar to that of MMF. Trip may be useful as a potential candidate in the treatment of renal fibrosis. PMID- 21272134 TI - Injured kidney cells express SM22alpha (transgelin): Unique features distinct from alpha-smooth muscle actin (alphaSMA). AB - AIM: SM22alpha (transgelin) has been focused upon as a player in the process of phenotypic changes of types of cells. The SM22alpha expression in the rat anti glomerular basement membrane (GBM) nephritis model and differences from an established phenotypic marker for the myofibroblast, alpha-smooth muscle actin (alphaSMA), were investigated. METHODS: The rat kidney tissues were processed for histological studies, immunohistochemical and immunoelectronmicroscopy analyses on days 0, 7, 28, 42 and 56 after injection of rabbit anti-GBM serum for the disease induction. RESULTS: Immunohistochemistry with anti-SM22alpha antibodies (Ab) revealed that kidneys of the nephritic rats on day 7 expressed SM22alpha in podocytes, crescentic cells and epithelial cells of Bowman's capsule. After 28 days, SM22alpha was also expressed in peritubular interstitial cells. Double immunofluorescence with anti-SM22alpha Ab and anti-alphaSMA Ab showed that SM22alpha was preferentially expressed in podocytes, whereas alphaSMA was positive in mesangial cells on day 7. After day 28, both molecules became positive in peritubular interstitial cells. CONCLUSION: SM22alpha was expressed in epithelial cells of inflamed glomeruli in the early phase, and then also in peritubular interstitial cells in the later phase of anti-GBM nephritis model. SM22alpha presented unique kinetics of expression distinct from alphaSMA. PMID- 21272135 TI - The epidemiological association of altitude with chronic kidney disease: Evidence of protective effect. AB - AIMS: We sought to determine the association between living at high altitudes and the estimated glomerular filtration rate (eGFR) and also to determine the prevalence of end-stage renal disease (ESRD) at various altitudes. METHODS: In the first part of the study, we used data from the National Health and Nutrition Examination Survey III to examine the association between altitude of residence and eGFR. In the second part, we used the United States Renal Data System to study the association between altitude and prevalence of ESRD. The query revealed an ESRD prevalence of 485,012 for the year 2005. The prevalence rates were merged with the zip codes dataset. RESULTS: The mean eGFR was significantly increased at higher altitudes (78.4 +/- 21.6 vs 85.4 +/- 26.8 mL/min for categories 1 and 5, respectively; P < 0.05). In the analysis of the United States Renal Data System data for prevalence of ESRD, we found a significantly lower prevalence at the altitude of 523 feet and higher. CONCLUSION: Using a population-based approach, our study demonstrates an association between altitude and renal function. This association is independent of all factors studied and is reached at approximately 250 feet. There is also a negative association between the prevalence of ESRD and altitude of residence. Further studies are needed to elucidate the pathophysiological basis of these epidemiological findings. PMID- 21272136 TI - High incidence and recurrence of transitional cell carcinoma in Taiwanese patients with end-stage renal disease. AB - AIM: This study examines the epidemiology of transitional cell carcinoma (TCC) in end-stage renal disease (ESRD) population from Taiwan, the area with the highest incidence and prevalence of ESRD. METHODS: A total of 98 out of 10,890 ESRD patients were referred for management of TCC between 2000 and 2008. Demographic, clinical and laboratory data were collected and patient mortality and tumour recurrence rates were analyzed. RESULTS: TCC patients were aged 61.4 +/- 10.2 years and 66.3% were female. The average time from initiation of dialysis to tumour detection was 51.2 +/- 36.4 months. Hypertensive nephrosclerosis, diabetes mellitus, chronic glomerulonephritis and unknown aetiology accounted for 25.5%, 20.4%, 22.4% and 31.6% of the causes of renal failure, respectively. The aetiology of renal failure for the 31.6% of patients was unclear, but chronic tubulointerstitial nephritis following long-term consumption of Chinese herbs (19.4%) or analgesic compounds (3.1%) was considered in some patients. Almost all (98.0%) patients presented with gross haematuria. Most TCC were in early stage (stage 0, 3.1%; stage I, 56.1%) during diagnosis. At the end of this study, 17 of 98 (17.3%) patients died. Multivariate Cox regression analysis found that age (odds ratio =1.140, 95% confidence interval = 1.049-1.239, P = 0.002) and tumour pain (odds ratio = 0.234, 95% confidence interval = 0.057-0.961, P = 0.044) were significant risk factors for all-cause mortality. Furthermore, 35.7% of TCC recurred during follow up. The 5 year patient and tumour-free survival rates were 72.4% and 14.4%, respectively. CONCLUSION: The data shows that Taiwanese patients with ESRD had high incidence (0.9%) and recurrence (35.7%) of TCC. PMID- 21272137 TI - What do renal health-care professionals in Singapore think of advance care planning for patients with end-stage renal disease? AB - AIM: Previous studies have focused either on advance medical directives rather than advance care planning (ACP), or on patient's perspectives on ACP rather than those of the health-care providers. This study aimed to explore the knowledge, attitudes and experience of renal health-care professionals in Singapore on ACP for patients with end-stage renal failure. METHODS: A 41-item questionnaire was distributed to physicians, nurses, medical social workers (MSW) and other allied health professionals working in renal units. The questionnaire had four sections: demographics of the respondents, knowledge of, attitudes to and experience with ACP. RESULTS: Of a total of 620 survey forms, 562 were returned, giving a response rate of 90.6%. Medical social workers and physicians had higher knowledge scores than the rest. Of doctors and MSW, 82.4% and 100%, respectively, considered ACP discussions as part of their role, but only 37.1% of nurses and 38.1% of other allied health-care professionals thought likewise. Nurses appeared to be the least confident in conducting ACP discussions, and most fearful of upsetting patients and families. Medical social workers were the most confident. The main barriers for physicians appeared to be lack of time, concerns regarding family backlash and the perception that patients were not prepared to discuss ACP. CONCLUSION: Training of renal health-care professionals in ACP should aim to correct misunderstandings surrounding ACP, address potential barriers and impart communication skills. In particular, renal nurses will need encouragement to initiate discussions and be equipped with the skills to do so. PMID- 21272138 TI - Slow and steady. Reducing thrombotic events in renal transplant recipients treated with IVIg for antibody-mediated rejection. AB - Intravenous immunoglobulin (IVIg) therapy for antibody-mediated rejection (AMR) is increasing and is associated with a small but significant incidence of thrombosis. We determined thrombosis rates in patients treated with high-dose IVIg for AMR before and after alteration of an infusion protocol. The newer protocol introduced routine administration of aspirin 300 mg, enoxaparin 1 mg/kg, intravenous hydration and a maximum infusion rate of 100 mg/kg per hour (previously 200 mg/kg per hour). Nine thromboses in 275 infusions occurred before the protocol alteration (event rate 3.3%). Two were arterial thromboses including an acute myocardial infarct and a renal transplant artery thrombosis, which resulted in infarction of 2/3 of the graft. Seven venous thromboses occurred, six in arteriovenous fistulae and one case with bilateral above knee deep venous thromboses. Significant associations with thromboses were seen with higher IVIg dose and male sex. In the 6 months since the introduction of the new infusion protocol, 74 infusions have been administered with no thrombotic events. There have been no significant bleeding or fluid overload side-effects. Infusion times, however, have been doubled. A slower rate of infusion combined with antiplatelet and anticoagulation has thus far eliminated the small but significant IVIg related thrombosis rate previously observed in our patients treated for AMR without resulting in significant side-effects. Further study is now required to define which elements of this protocol are essential. PMID- 21272139 TI - Nephrogenic systemic fibrosis, in patients with end-stage kidney disease on dialysis, in the greater Auckland region, from 2000-2006. AB - AIM: Nephrogenic systemic fibrosis (NSF) is a rare and serious disease characterised by thickening and hardening of the skin with fibrosis of the dermis with CD34-positive fibrocytes. NSF occurs in patients with renal failure and has been linked to exposure of gadolinium contrast agents. The Auckland region has a population of 1.3 million with consultation and dialysis services for patients with end stage kidney disease provided by two separate renal units. The aim of this study was to determine the incidence and frequency of NSF in the Auckland region and determine the risk based on exposure to gadolinium based contrast agents. METHODS: A retrospective case notes review of all patients with end stage kidney disease under the care of the renal services between 1(st) January 2000 and 31(st) December 2006 was undertaken. All cases of proven or suspected NSF were identified. Using a picture archive and communications support system all imaging and exposure to contrast was identified. RESULTS: Three cases of biopsy proven NSF and two further cases of clinical NSF were identified. In all cases there was exposure to Gadolinium. This risk of NSF on exposure to any gadolinium based contrast agents was 0.67%. Gadodiamide was used in one institution where all five cases of NSF were seen, gadodiamide was used in 1% of patients in the other institution with no recognised cases. CONCLUSION: The incidence of NSF is low with the greatest risk on exposure to linear, non-ionic chelates, with no ethnic predisposition. PMID- 21272140 TI - Pyrexia of unknown origin and proteinuria: an enigma solved by renal biopsy. PMID- 21272141 TI - Cyclosporine and lactation. PMID- 21272142 TI - A hypothesis to phenotype COPD exacerbations by aetiology. AB - COPD exacerbations have traditionally been defined on the basis of symptoms or health-care utilization without specific reference to the suspected aetiology. Consequently, the term 'exacerbation' has been used to include all patients experiencing an acute deterioration of symptoms associated with COPD. However, exacerbations are known to result from a variety of causes and do not necessarily constitute an equivalent event in the same patient, between different patients or between individual research studies. We therefore hypothesize that phenotyping exacerbations by aetiology may identify exacerbation subgroups, clarify benefits of therapeutic intervention in the subgroups and overall improve clinical care. An acronym is proposed to facilitate phenotyping COPD exacerbations. PMID- 21272145 TI - Participation of BKCa2+ and KATP potassium ion channels in the contractility of human term pregnant myometrium in in vitro conditions. AB - AIM: The aim of this study was to assess the participation of ligand-sensitive potassium large conductance calcium-activated ion channels (BK(Ca2+) ) and adenosine triphosphate (ATP)-sensitive potassium ion channels (K(ATP) ) using its openers (NS1619 and pinacidil) in the contractility of human term pregnant myometrium in in vitro conditions. METHODS: Human myometrium tissue samples were collected from term pregnant laboring women who had to undergo cesarean section. The contractility of myometrium was induced by the application of oxytocin into the organ bath. Myometrial strips were incubated with the opener of BK(Ca2+) potassium ion channels NS1619 and its antagonist tetraethylammonium or with the opener of K(ATP) potassium ion channels pinacidil and its antagonist glibenclamide. RESULTS: K(ATP) potassium ion channel's opener pinacidil significantly decreased amplitude of myometrial contractions (P < 0.05) as well as frequency of myometrial contractions (P < 0.05) provoked by oxytocin in human term pregnant myometrium in in vitro conditions. The inhibition of the human myometrial contractions of pinacidil was significantly antagonized by its specific antagonist glibenclamide (P < 0.05). BK(Ca2+) potassium ion channel's opener NS1619 did not significantly affect the contractile activity of human term pregnant myometrium induced by the application of oxytocin in in vitro conditions. CONCLUSION: In our experimental study we found that the participation of BK(Ca2+) and K(ATP) potassium ion channels in the contractility of human term pregnant myometrium in labor is probably different. PMID- 21272146 TI - Vascular, renal and placental effects on pregnant offspring of protein-restricted rat dams. AB - AIM: Our previous study showed that a maternal low-protein diet induced hypertension and vascular dysfunction in rat offspring after day 175. In the present study, we hypothesized that these female offspring would develop hypertension in their own pregnancies even at ages less than 175 days because potential vascular dysfunction is exacerbated by the circulatory demands of pregnancy. MATERIAL AND METHODS: Wistar rats were fed an isocaloric diet containing either 18% (control group) or 9% (low-protein group) casein throughout pregnancy. The female offspring were fed standard chow and mated between days 70 and 125. At the end of pregnancy, blood pressure was measured, and the uterine arteries were dissected and investigated with a wire myograph. RESULTS: Placental weights were significantly lower in offspring of the low-protein group versus control. There were no significant differences in blood pressure. Renal expression of AT1 receptor mRNA was greater, and of AT2 receptor was less, in the low-protein group versus control. Vasoconstriction of uterine arteries to phenylephrine and U46619 was increased in the low-protein group, and vasodilatation to sodium nitroprusside was also increased. CONCLUSION: Low protein diet induces vascular effects on female offspring in their pregnancy, in terms of increased uterine artery vasoconstriction. This may be compensated for by increased sensitivity to nitric oxide (NO), maintaining blood pressure normal in the face of the demands of pregnancy. Such renal and vascular effects, combined with placental size, may transmit risk of vascular dysfunction to subsequent generations. PMID- 21272147 TI - Solitary metastasis of a clear cell ovarian adenocarcinoma to the small bowel mucosa. AB - Metastasis of ovarian carcinoma to the small bowel parenchyma without peritoneal dissemination is uncommon. A 63-year-old woman underwent surgery for a clear cell adenocarcinoma of the ovary and received adjuvant chemotherapy. Eighteen months after the operation, she presented with recurrent occult bowel hemorrhage without evidence of an abdominal mass. Nine months later, a rapidly growing abdominal mass was detected. Laparoscopy revealed a solitary tumor of the ileum covered with an intact serosal layer. Partial ileectomy was performed for tumor resection. Histological examination revealed cells resembling the primary ovarian tumor in the mucosal surface of the small bowel along with an intact serosa. The tumor cells were positive for cytokeratin 7 and negative for cytokeratin 20, suggesting an ovarian origin. This is the first report of solitary metastasis of an ovarian carcinoma to the small bowel parenchyma without peritoneal dissemination. Metastasis to the small bowel should be considered in ovarian carcinoma patients with occult gastrointestinal hemorrhage. PMID- 21272148 TI - Dietary folate intakes and effects of folic acid supplementation on folate concentrations among Japanese pregnant women. AB - AIM: To quantify the consumed amount of dietary folate and to evaluate effects of folic acid and balanced diets on serum folate concentrations. MATERIAL & METHODS: Food records collected from 641 pregnant women were assessed to quantify the consumed amount of dietary folate for a 6-year period from 2003 to 2008. Changes in serum folate concentrations were evaluated among 80 pregnant women who either took folic acid tablets or consumed balanced diets in 2008. RESULTS: Though the dietary folate intake averaged 331 ug daily, 200 women in the 1st trimester consumed the least amount of dietary folate, 294 ug daily. It was observed that 42% of the 200 women either consumed at least 440 ug of dietary folate daily or took 400 ug folic acid supplements daily, but that 58% of them neither consumed dietary folate of 440 ug nor took folic acid supplements. Intakes of 400 ug folic acid supplements for 5 weeks resulted in a significant increase in serum folate concentrations but the consumption of balanced diets had no effect on increasing folate concentrations. CONCLUSIONS: The average intake of dietary folate did not fulfill the Recommended Dietary Allowance of 440 ug. Serum folate concentration significantly increased only among pregnant women who took folic acid supplements. Recommendations to consume balanced diets do not seem effective to decrease the incidence of neural tube defects. PMID- 21272149 TI - Myomectomy for uterine myomas through ultramini-laparotomy. AB - Uterine fibroids are the most common benign tumors in the female reproductive tract during the reproductive years. Among the options in the treatment spectrum, myomectomy is always considered one of the best choices in the management of women with symptomatic uterine fibroids who wish to preserve future fertility. Myomectomy through conventional exploratory laparotomy may be the most familiar surgical approach. However, with the advances being made in techniques and instruments, there are many alternative approaches to myomectomy, including mini laparotomy, ultramini-laparotomy, laparoscopy, laparoscopy-aided, and vaginal and hysteroscopic approaches. The focus of this review article is limited to discussing the use of the ultramini-laparotomy approach to completing myomectomy in the management of the uterine fibroids. PMID- 21272150 TI - Case of atypical polypoid adenomyoma that possibly underwent a serial progression from endometrial hyperplasia to carcinoma. AB - Atypical polypoid adenomyoma is a rare uterine tumor composed of atypical endometrial glands, which often exhibit squamous metaplasia, and a cellular smooth muscle stroma. Although atypical polypoid adenomyoma is categorized as a benign lesion, it is reportedly associated with endometrial cancer, and it shows persistence and recurrence even after conservative medical treatment. We present a rare case of atypical polypoid adenomyoma that possibly underwent a serial pathological change from endometrial hyperplasia to carcinoma in a 40-year-old woman with no history of pregnancy. She was diagnosed with atypical polypoid adenomyoma during polypectomy surgery. After resecting the atypical polypoid adenomyoma, endometrial hyperplasia complex was detected. This condition eventually progressed from atypical hyperplasia complex to endometrial adenocarcinoma, and total abdominal hysterectomy was performed. A patient with atypical polypoid adenomyoma who wishes to preserve her fertility should be carefully monitored for endometrial carcinoma. If endometrial hyperplasia is detected in such a patient, a meticulous follow-up examination by performing endometrial biopsy is mandatory. PMID- 21272151 TI - Extensive uterovaginal prolapse during labor. AB - Uterovaginal prolapse complicating pregnancy is an extremely rare event. Obstetricians should be familiar with the condition as early recognition and close follow up is essential in order to avoid possible fetomaternal risks. We report a case of 35-year-old lady who presented to the emergency with complaints of labor pains, absent fetal movements and huge uterine cervical prolapse in active phase of labor. She was conservatively treated with bedrest, blood transfusions and irrigation of prolapsed cervix. A dead female fetus was delivered vaginally. Ring pessary was placed postnatally. We believe that an extensive uterovaginal prolapse needs close surveillance and can be managed conservatively. PMID- 21272152 TI - Understanding congenital heart defects through abdominal fetal electrocardiography: case reports and clinical implications. AB - AIMS: Congenital heart defects are the most common fetal structural anomalies of which a significant number remain unrecognized during postnatal life. Fetal electrocardiography (FECG) is an ideal clinical tool to complement ultrasonography for the screening and management of these cases where early and accurate diagnoses would allow definite rather than palliative treatment. The objective of this report was to correlate the particular FECG results found with the different types of congenital heart defects involved and to further demonstrate the usefulness of FECG in clinical settings. MATERIAL & METHODS: This is a report of four cases of prenatally diagnosed congenital heart defects seen at a university hospital in Sendai, Japan. Their complete and thorough evaluation included, among other tests, abdominal FECG analysis. RESULTS: The presence of premature ventricular contractions, a prolonged pre-ejection period (PEP > 75 msec), and prolonged QTc intervals (QTc > 440 msec) served as markers of hemodynamic alteration but were unlikely determinants of disease severity precluding further investigation. CONCLUSIONS: In practice, similar findings found on FECG should raise the index of suspicion for the presence of congenital heart disease and prompt a targeted ultrasound scan. PMID- 21272153 TI - Long-term cumulative pregnancy rate in women with unexplained infertility after laparoscopic surgery followed by in vitro fertilization or in vitro fertilization alone. AB - AIMS: Laparoscopy has been performed in women with unexplained infertility, but the recent trend is to commence in vitro fertilization (IVF) without prior laparoscopy. The aim of this study was to determine whether or not laparoscopic surgery is necessary for these patients. MATERIAL & METHODS: With a diagnosis of unexplained infertility, 51 women underwent laparoscopic surgery followed by IVF (laparoscopy group) and 41 women underwent IVF without prior laparoscopy (IVF group). We reviewed these two groups retrospectively and evaluated the cumulative pregnancy rate. RESULTS: In the laparoscopy group, 16 of the 51 women became pregnant spontaneously soon after surgery. Twenty-three patients became pregnant with IVF. In the IVF group, 32 patients became pregnant with IVF. Two of the 41 women became pregnant spontaneously while waiting to commence IVF. CONCLUSION: Laparoscopy should be offered as an option for younger patients who desire spontaneous pregnancy because there was no significant difference of the cumulative pregnancy rate between the groups. PMID- 21272154 TI - Changes in urodynamic parameters after tolterodine treatment for female overactive bladder syndrome with or without voiding dysfunction. AB - AIM: To investigate changes in urodynamic parameters after tolterodine treatment for female overactive bladder syndrome, especially in patients with voiding dysfunction. METHODS: Between January and December 2006, 44 patients were enrolled for six months of treatment with tolterodine. Pre-treatment and post treatment urodynamic studies were scheduled for the enrolled patients. RESULTS: Among the remaining 33 patients (11 dropped out), bladder capacity (P < 0.001) and post-void residual urine (P = 0.009) increased, and functional urethral length (P = 0.049) and pad weight test (P = 0.03) decreased after treatment. Besides this, detrusor pressure at maximal urine flow, functional urethral length, maximal urethral pressure and maximal urethral closure pressure were less affected by tolterodine in patients with voiding dysfunction, compared to those without voiding dysfunction. CONCLUSIONS: Tolterodine treatment increased bladder capacity and decreased urine leakage; however, some urodynamic parameters in patients with voiding dysfunction were less affected by tolterodine treatment. PMID- 21272155 TI - Factors affecting surgical margins in nonpalpable breast tumors excised with the radioguided occult lesion localization approach. AB - AIM: Most breast surgeons generally assume that obtaining negative margins in nonpalpable tumors is a matter of concern. The aim of this study was to examine whether it is easier to obtain negative margins in palpable tumors than in nonpalpable tumors excised with the radioguided occult lesion localization (ROLL) technique. METHODS: A retrospective review was made of nonpalpable breast cancers excised with the ROLL technique (ROLL group, n = 83) and palpable breast cancers in which breast conservative therapy was performed (Palpable group, n = 77). The margin status and the size of the minimum margin obtained when it was negative were reviewed. RESULTS: The percentage of resections with negative margins was similar in both groups: 51.9% in the Palpable group and 61.4% in the ROLL group. There was no difference between the two groups in the minimum margin obtained: mean +/- SD, 5.53 +/- 3.146 mm in the Palpable group and 5.96 +/- 3.039 mm in the ROLL group. Risk factors for failing to obtain negative margins were analyzed in both groups and were similar. These risk factors included histological grade, extensive intraductal carcinoma and c-erbB2 status. CONCLUSION: It is concluded that excision of nonpalpable breast tumors with the ROLL approach obtains similar results for margins as conservative surgery performed for palpable tumors. PMID- 21272157 TI - Assisted reproductive technologies in Thailand: 2001-2007 results generated from the ART Registry, Royal Thai College of Obstetricians and Gynaecologists. AB - AIM: To present the results of assisted reproductive technology (ART) performed in Thailand during 2001-2007. METHODS: All licensed ART centers are obliged to submit annual reports on the number of patients, cycles, ART techniques and treatment outcomes to the Reproductive Medicine Subcommittee of the Royal Thai College of Obstetricians and Gynaecologists. Data from all centers were aggregated and analyzed retrospectively. RESULTS: Cycles were categorized into fresh and frozen/thawed embryo transfer (FET) cycles. Initiated cycles in the first category for 2001 to 2007 were 2183, 2112, 2780, 2717, 3458, 3579 and 4288, respectively. FET cycles during the same period were 467, 558, 733, 768, 1136, 1210 and 1473, respectively. The average pregnancy rate for in vitro fertilization (IVF) was 28.9% per retrieval (range, 26-32.3%) or 33.8% per transfer (range, 30.7-38.6%). Multiple pregnancies (of which 89.3% were twins) from all treatment procedures during this period were 11.4% (range, 9.2-14.5%). A congenital abnormality was reported in 0.56% of live births. The number of embryos per transfer in IVF decreased from 4.1 to 2.9, with no drop in pregnancy rates. Oocyte insemination by intracytoplasmic sperm injection (ICSI) was utilized more often than standard IVF, while gamete intrafallopian transfer and zygote intrafallopian transfer were almost completely replaced by IVF/ICSI. There was a significant difference in pregnancy rates (P < 0.01) when clinics were classified by cycle volumes (<100, 100-400 and >400 cycles/year). CONCLUSIONS: Despite many limitations, the data provided in this report will help patients, clinicians and policy makers understand the current situation of ART practice in Thailand. PMID- 21272156 TI - Tumor hypoxia and genetic alterations in sporadic cancers. PMID- 21272158 TI - Curcumin analog GO-Y030 is a novel inhibitor of IKKbeta that suppresses NF-kappaB signaling and induces apoptosis. AB - Curcumin is a dietary constituent with tumor-suppressing potential, inhibiting various pathways involved in carcinogenesis. However, because of its low bioavailability, the use of curcumin in in vivo trials has been limited. To overcome this problem, we synthesized more than 50 analogs and identified a monoketone analog, GO-Y030, which has a 30-fold higher potential to suppress tumor cell growth compared with curcumin. We investigated the inhibitory effect of GO-Y030 on NF-kappaB activation. In thyroid, pancreatic cancers and cholangiocarcinoma cells, in which NF-kappaB is activated, NF-kappaB activation was suppressed to 8-62% of the control value following treatment with 1 MUM GO Y030, an effect comparable to that of 10 MUM curcumin. Direct inhibition of IKKbeta kinase activity and suppression of nuclear translocation of the NF-kappaB p65 subunit were observed. The 50% growth inhibition concentrations of GO-Y030 ranged from one-11th to one-14th of those of curcumin. GO-Y030 also induced cell death comparable to that induced by curcumin but at a 10-fold lower concentration. In pancreatic and thyroid cancer cells, the growth-inhibitory effect of GO-Y030 was 4- and 15-fold greater, respectively, than that of curcumin. GO-Y030 was a much stronger inducer of apoptosis compared with curcumin. The enhanced potency of GO-Y030 may make it more useful than curcumin, which suffers from low bioavailability. GO-Y030 is a good lead compound for the development of useful compounds for practical cancer chemotherapy. PMID- 21272159 TI - Efficacy of gefitinib for non-adenocarcinoma non-small-cell lung cancer patients harboring epidermal growth factor receptor mutations: a pooled analysis of published reports. AB - The efficacy of gefitinib for patients with non-adenocarcinoma non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations is unclear, because only a small percentage of patients enrolled in the clinical trials to evaluate the efficacy of gefitinib for tumors harboring EGFR mutation were non-adenocarcinoma NSCLC. A pooled analysis was conducted to clarify the efficacy of gefitinib for non-adenocarcinoma NSCLC patients harboring EGFR mutations. A systematic search of the PUBMED databases was conducted to identify all clinical reports that contained advanced non-adenocarcinoma NSCLC patients harboring EGFR mutations and treated with gefitinib. The selected patients were advanced non-adenocarcinoma NSCLC patients harboring EGFR mutations who were treated with gefitinib and described in reports containing the data of the histology, status of EGFR mutations and response to gefitinib. This study selected 33 patients from 15 reports. Twenty-seven and three of the 33 patients were squamous cell carcinoma and adenosquamous cell carcinoma, respectively. One patient each had large-cell carcinoma, pleomorphic carcinoma and spindle cell carcinoma. Twenty-one patients (64%) had sensitive EGFR mutations. The response rate (RR), disease control rate (DCR) and median progression-free survival (mPFS) was 27%, 67-70% and 3.0 months, respectively. These factors were statistically significantly inferior in the non-adenocarcinoma NSCLC patients harboring EGFR mutations to adenocarcinoma patients harboring EGFR mutations selected from the same published reports (RR: 27%vs 66%, P = 0.000028; DCR: 67-70%vs 92-93%, P = 0.000014; mPFS: 3.0 vs 9.4 months, P = 0.0001, respectively). Gefitinib is less effective in non-adenocarcinoma NSCLC harboring EGFR mutations than adenocarcinoma harboring EGFR mutations. PMID- 21272160 TI - Carboxyl terminus of Hsp70-interacting protein (CHIP) contributes to human glioma oncogenesis. AB - Malignant glioma is the most common adult primary brain tumor, and the mechanism of its oncogenesis is poorly understood. Growing evidence has shown that E3 ubiquitin ligases can promote tumorgenesis of glioma. CHIP is an E3 ubiquitin ligase that can induce ubiquitylation and degradation of many tumor-related proteins, and it has been reported to act as an upstream regulator in breast cancer; however, its role in human gliomas has not been evaluated yet. In this study, the expression of CHIP in glioma tissues was studied using immunohistochemistry. CHIP expression in glioma cells was studied by real-time RT PCR, western blot and double immunofluorescence staining. The role of CHIP in glioma oncogenesis was investigated by lentivirus-mediated RNA interference (RNAi) and overexpression in vitro and in vivo. We showed CHIP expression in glioma samples was related to tumor grades, with stronger staining in high-grade gliomas than in low-grade gliomas. Knocking down of CHIP suppressed proliferation, colony formation of U251 and U87 glioma cells, while overexpression of CHIP resulted in enhanced proliferation and colony formation in vitro. In a nude mouse xenograft model, intratumoral injection of CHIP RNAi lentivirus significantly delayed tumor growth. In contrast, overexpression of CHIP resulted in enhanced tumor growth in vivo. After CHIP RNAi, both survivin mRNA and protein were decreased, while CHIP overexpression induced increased mRNA and protein levels of survivin. This is the first study demonstrating CHIP contributes to oncogenesis of glioma. PMID- 21272161 TI - c-Jun N-terminal kinase activation by oxidative stress suppresses retinoid signaling through proteasomal degradation of retinoic acid receptor alpha protein in hepatic cells. AB - We previously reported that impaired retinoid signaling causes hepatocellular carcinoma (HCC) through oxidative stress. However, the interaction between oxidative stress and retinoid signaling has not been fully understood. To address this issue, the effects of hydrogen peroxide on the transcriptional activity of RAR/RXR heterodimers, RARalpha and RXRalpha proteins and intracellular signaling pathways were examined. The transcriptional activity of RAR/RXR examined by the DR5-tk-Luc reporter assay was significantly suppressed. The RARalpha protein level began to decrease at 6 h after treatment and declined thereafter. However, RARalpha mRNA were not changed. Activation of extracellular regulated kinases (ERK), p38, c-Jun N-terminal kinase (JNK) and Akt was observed after treatment of hydrogen peroxide. SP600125, an inhibitor of JNK, reversed the RARalpha protein level reduced by hydrogen peroxide. Anisomycin, an activator of JNK, reduced RARalpha protein. Transfection of wild-type JNK-constitutive actively expressing plasmid, but not kinase-negative JNK-expressing plasmid caused reduction of RARalpha protein. Proteasomal degradation of RARalpha was observed after anisomycin treatment; however, the mutant RARalpha, of which phosphorylation sites are replaced with alanines, was not degradated. In hepatitis C virus (HCV) related human liver tissues, phospho-JNK and RARalpha reciprocally expressed with the progression of liver disease. Finally, the staining of 8-OHdG and thioredoxin was increased with the disease progression. These data indicate that JNK activation by oxidative stress suppresses retinoid signaling through proteasomal degradation of RARalpha, suggesting that a vicious cycle between aberrant retinoid signaling and oxidative stress accelerates hepatocarcinogenesis. PMID- 21272162 TI - Failure to respond to physiologic challenge characterizes esophageal motility in erosive gastro-esophageal reflux disease. AB - BACKGROUND: Non-specific esophageal dysmotility with impaired clearance is often present in patients with gastro-esophageal reflux disease (GERD), especially those with erosive disease; however the physio-mechanic basis of esophageal dysfunction is not well defined. METHODS: Retrospective assessment of patients with erosive reflux disease (ERD; n=20) and endoscopy negative reflux disease (ENRD; n=20) with pathologic acid exposure on pH studies (>4.2% time/24 h) and also healthy controls (n=20) studied by high resolution manometry. Esophageal motility in response to liquid and solid bolus swallows and multiple water swallows (MWS) was analyzed. Peristaltic dysfunction was defined as failed peristalsis, spasm, weak or poorly coordinated esophageal contraction (>3cm break in 30 mmHg isocontour). KEY RESULTS: Peristaltic dysfunction was present in 33% of water swallows in controls, 56% ENRD and 76% ERD respectively (P<0.023 vs controls, P=0.185 vs ENRD). The proportion of effective peristaltic contractions improved with solid compared to liquid bolus in controls (18%vs 33%, P=0.082) and ENRD (22%vs 54%, P=0.046) but not ERD (62%vs 76%, P=0.438). Similarly, MWS was followed by effective peristalsis in 83% of controls and 70% ENRD but only 30% ERD patients (P<0.017 vs controls and P<0.031 vs ENRD). The association between acid exposure and dysmotility was closer for solid than liquid swallows (r=0.52 vs 0.27). CONCLUSIONS & INFERENCES: Peristaltic dysfunction is common in GERD. ERD patients are characterized by a failure to respond to the physiologic challenge of solid bolus and MWS that is likely also to impair clearance following reflux events and increase exposure to gastric refluxate. PMID- 21272163 TI - Treatment for ischaemic stroke within an unknown time window: how much imaging do we need? PMID- 21272164 TI - Tocilizumab: is there life beyond anti-TNF blockade? AB - Anti-TNF-alpha therapy has become the most effective biological treatment for rheumatoid arthritis. Despite having changed the prognosis of the disease establishing new targets for treatment strategy, there are several aspects that still remain unmatched. About 30% of the patients with rheumatoid arthritis have a less than satisfactory response to anti-TNF therapy, which has led the way for the pursuit of new targets and approaches to treatment. IL-6 is one of these alternative targets and data from the more recent clinical trials involving tocilizumab (an anti-IL-6 soluble receptor antibody) suggest advantages in relation to some clinical aspects which are not addressed by anti-TNF-alpha treatment. PMID- 21272165 TI - Clinicopathological significance of nuclear factor-kappaB activation in hepatocellular carcinoma. AB - AIM: Nuclear factor-kappaB (NF-kappaB) is a critical signaling mediator in inflammation, apoptosis resistance and oncogenesis. It has been reported that NF kappaB is activated in several cancers, including hepatocellular carcinoma (HCC). Studies of genetic disruptions in mice also suggest that NF-kappaB plays critical roles in hepatocarcinogenesis. The aim of the present study is to characterize NF kappaB activation and correlate it with the degree of malignancy in HCC. METHODS: To examine the correlation between the positivity of the nuclear p50 subunit and HCC recurrence, we analyzed immunostaining of the NF-kappaB p50 subunit in two groups of HCC samples with known prognosis and Akt phosphorylation status: 49 patients showing early recurrence within 6 months (group A) and 50 patients who were recurrence-free for at least for 3 years (group B). RESULTS: In group A, positive nuclear staining of p50 was shown in 18 cases (36.7%), whereas only one case (2.0%) in group B had positive nuclear staining of p50 (P = 2.48839 * 10(-5) ). This suggests a positive relationship between nuclear p50 and early recurrence and advanced HCC in humans. The presence of phosphorylated Akt correlated with nuclear staining of p50 in HCCs in group A (R(2) = 0.213, P < 0.001). CONCLUSION: Our results indicate that nuclear staining of p50 was clearly associated with early recurrent HCC, and the Akt pathway might play a role in NF kappaB activation in a subset of early recurrent HCC. PMID- 21272166 TI - Assessment of malignant potential of small hypervascular hepatocellular carcinoma using B-mode ultrasonography. AB - AIM: Evaluation of malignant potential is important to determine the treatment strategy for small hepatocellular carcinoma (HCC). The aim of the present study was to establish a method of assessing the malignant potential of small hypervascular HCC using B-mode ultrasonography. METHODS: One hundred and thirteen arterial hypervascular HCC nodules under 3 cm diagnosed by biopsy or surgical resection (20.5 +/- 6.3 mm) were classified into two groups ultrasonographically: type 1 with (n = 27) and type 2 without (n = 86) a halo. Type 2 was categorized into three subgroups: type 2a, homogenous hyperechoic (n = 9); type 2b, hypoechoic with a smooth margin (n = 35); and type 2c, hypoechoic with an irregular or unclear margin (n = 42). RESULTS: The mean diameter of type 2a nodules was significantly smaller than that of other HCC types (P < 0.05). Overall, moderately differentiated HCC was the predominant histological type, except for type 2a, all of which were well-differentiated HCC. The percentage of poorly differentiated HCC was significantly higher in type 2c nodules (19%) than in other HCC types (P < 0.01). The percentage of Lens culinaris agglutinin-reactive alpha-fetoprotein (AFP-L3) positivity was significantly higher in type 2c nodules (55%) than in other HCC types (P < 0.01). Classification on B-mode ultrasonography was correlated with the histological differentiation and serum level, an indicator of a poor prognosis. CONCLUSION: The malignant potential of type 2a is the lowest and that of type 2c is the highest, both histologically and serologically. Assessment of the malignant potential of small, hypervascular HCC is possible by B-mode ultrasonography. PMID- 21272167 TI - Impaired cellular immune response to diphtheria and tetanus vaccines in children after thoracic transplantation. AB - Safety and immunogenicity of diphtheria and tetanus booster vaccination were evaluated in 28 children after thoracic transplantation. Adverse events were documented in a patient diary. Blood was collected prior to and four wk after vaccination. Specific antibody concentrations were measured by ELISA. Lymphocytes were investigated for expression of activation markers (CD25, HLA-DR) by flow cytometry and proliferation assays with and without stimulation. Post-vaccination antibody titers were higher than prevaccination (p < 0.001), with more patients having protective antibody levels against diphtheria (p < 0.02) and tetanus (p < 0.001). There was no increased proliferation in non-stimulated or stimulated cultures after vaccination. The number of T-lymphocytes activated by the vaccination antigens was similar pre- and post-vaccination, whereas HLA-DR expression on stimulated and non-stimulated CD4(+) T-cells increased significantly. Increase in antibodies was negatively correlated with tacrolimus dose, and impaired cellular immunity was associated with higher tacrolimus dose and steroid use. Adverse events were similar to the general population; serious adverse events and rejection did not occur. Vaccination with inactivated vaccines can be performed safely in immunosuppressed children after thoracic transplantation and induces protective antibody levels in the majority of patients. Impaired induction of specific cellular immunity is correlated with intensity of immunosuppression and may explain reduced sustainability of antibodies. PMID- 21272168 TI - Majocchi's granuloma in solid organ transplant recipients. AB - Superficial fungal infections are fairly prevalent in transplant recipients and the incidence increases with more intense graft-conserving immunosuppressive therapy. Majocchi's granuloma is a deep folliculitis caused by dermatophytes that involves deeper layers of the dermis. Only a few case reports of the condition have been documented in transplant recipients. After an extensive review of the medical literature, 21 cases were retrieved and are summarized here, together with a new case that occurred in a recent heart transplant recipient from our institution. This report aims to provide a comprehensive analysis of Majocchi's granuloma in solid organ transplant (SOT) recipients, with special focus on potential risk factors, offending pathogens, clinical presentation, therapeutic approaches, and outcome. General observations are presented emphasizing the relevance of close clinical and dermatologic follow-up in high-risk SOT patients with specific comments regarding treatment regimens and outcomes. PMID- 21272169 TI - Securin and separase modulate membrane traffic by affecting endosomal acidification. AB - Securin and separase play a key role in sister chromatid separation during anaphase. However, a growing body of evidence suggests that in addition to regulating chromosome segregation, securin and separase display functions implicated in membrane traffic in Caenorhabditis elegans and Drosophila. Here we show that in mammalian cells both securin and separase associate with membranes and that depletion of either protein causes robust swelling of the trans-Golgi network (TGN) along with the appearance of large endocytic vesicles in the perinuclear region. These changes are accompanied by diminished constitutive protein secretion as well as impaired receptor recycling and degradation. Unexpectedly, cells depleted of securin or separase display defective acidification of early endosomes and increased membrane recruitment of vacuolar (V-) ATPase complexes, mimicking the effect of the specific V-ATPase inhibitor Bafilomycin A1. Taken together, our findings identify a new functional role of securin and separase in the modulation of membrane traffic and protein secretion that implicates regulation of V-ATPase assembly and function. PMID- 21272170 TI - Regulation of fusion pore closure and compound exocytosis in neuroendocrine PC12 cells by SCAMP1. AB - During exocytosis, neuroendocrine cells can achieve partial release of stored secretory products from dense core vesicles (DCVs) by coupling endocytosis directly at fusion sites and without full discharge. The physiological role of partial secretion is of substantial interest. Much is known about SNARE-mediated initiation of exocytosis and dynamin-mediated completion of endocytosis, but little is known about coupling events. We have used real-time microscopy to examine the role of secretory carrier membrane protein SCAMP1 in exo-endocytic coupling in PC12 cells. While reduced SCAMP1 expression is known to impede dilation of newly opened fusion pores during onset of DCV exocytosis, we now show that SCAMP1 deficiency also inhibits closure of fusion pores after they have opened. Inhibition causes accumulation of fusion figures at the plasma membrane. Closure is recovered by restoring expression and accelerated slightly by overexpression. Interestingly, inhibited pore closure resulting from loss of SCAMP1 appears to increase secondary fusion of DCVs to already-fused DCVs (compound exocytosis). Unexpectedly, reinternalization of expanded DCV membranes following compound exocytosis appears to proceed normally in SCAMP1-deficient cells. SCAMP1's apparent dual role in facilitating dilation and closure of fusion pores implicates its function in exo-endocytic coupling and in the regulation of partial secretion. Secondarily, SCAMP1 may serve to limit the extent of compound exocytosis. PMID- 21272171 TI - Introduction to the Australian consensus guidelines for the management of neutropenic fever in adult cancer patients, 2010/2011. Australian Consensus Guidelines 2011 Steering Committee. AB - The current consensus guidelines were developed to standardize the clinical approach to the management of neutropenic fever in adult cancer patients throughout Australian treating centres. The three areas of clinical practice covered by the guidelines, the process for developing consensus opinion, and the system used to grade the evidence and relative strength of recommendations are described. The health economics implications of establishing clinical guidance are also discussed. PMID- 21272172 TI - Use of risk stratification to guide ambulatory management of neutropenic fever. Australian Consensus Guidelines 2011 Steering Committee. AB - Utilization of risk-stratification tools in the setting of neutropenic fever is currently limited by inadequate knowledge and lack of awareness. Within this context, the approach to management of low-risk patients with neutropenic fever is inconsistent with the available evidence across many Australian treating centres. These clinical guidelines define and clarify an accepted standard of care for this patient group given the current evidence base. The Multinational Association for Supportive Care in Cancer risk index is presented as the preferred risk assessment tool for determining patient risk. Suitability of ambulatory care within specific patient populations is discussed, with defined eligibility criteria provided to guide clinical decision-making. Detailed recommendations for implementing appropriate ambulatory strategies, such as early discharge and outpatient antibiotic therapy, are also provided. Due consideration is given to infrastructural requirements and other supportive measures at a resourcing and operational level. An analysis of the relevant health economics is also presented. PMID- 21272173 TI - Use of empiric antimicrobial therapy in neutropenic fever. Australian Consensus Guidelines 2011 Steering Committee. AB - Administration of empiric antimicrobial therapy is standard practice in the management of neutropenic fever, but there remains considerable debate about the selection of an optimal regimen. In view of emerging evidence regarding efficacy and toxicity differences between empiric treatment regimens, and strong evidence of heterogeneity in clinical practice, the current guidelines were developed to provide Australian clinicians with comprehensive guidance for selecting an appropriate empiric strategy in the setting of neutropenic fever. Beta-lactam monotherapy is presented as the treatment of choice for all clinically stable patients while early treatment with combination antibiotic therapy is considered for patients at higher risk. Due consideration is given to the appropriate use of glycopeptides in this setting. Several clinical caveats, accounting for institution- and patient-specific risk factors, are provided to help guide the judicious use of the agents described. Detailed recommendations are also provided regarding time to first dose, timing of blood cultures, selection of a first-line antibiotic regimen, subsequent modification of antibiotic choice and cessation of therapy. PMID- 21272174 TI - Use of antibacterial prophylaxis for patients with neutropenia. Australian Consensus Guidelines 2011 Steering Committee. AB - The use of oral prophylactic antibiotics in patients with neutropenia is controversial and not recommended by this group because of a lack of evidence showing a reduction in mortality and concerns that such practice promotes antimicrobial resistance. Recent evidence has demonstrated non-significant but consistent, improvement in all-cause mortality when fluoroquinolones (FQs) are used as primary prophylaxis. However, the consensus was that this evidence was not strong enough to recommend prophylaxis. The evidence base for FQ prophylaxis is presented alongside current consensus opinion to guide the appropriate and judicious use of these agents. Due consideration is given to patient risk, as it pertains to specific patient populations, as well as the net effect on selective pressure from antibiotics if FQ prophylaxis is routinely used in a target population. The potential costs and consequences of emerging FQ resistance, particularly among Escherichia coli, Clostridium difficile and Gram-positive organisms, are considered. As FQ prophylaxis has been advocated in some chemotherapy protocols, specific regard is given to whether FQ prophylaxis should be used to support these regimens. The group also provides recommendations for monitoring and surveillance of emerging resistance in those centres that have adopted FQ prophylaxis. PMID- 21272175 TI - An Australian survey of clinical practices in management of neutropenic fever in adult cancer patients 2009. AB - BACKGROUND: An abundance of new evidence regarding treatment strategies for neutropenic fever is likely to contribute to variability in practice across institutions and clinicians alike. AIMS: To describe current clinical practices in Australia, by surveying haematologists, oncologists and infectious diseases physicians involved in cancer care. METHODS: Clinician members from Australian professional associations, accounting for the vast majority of Australian cancer specialists, were invited to participate in an electronic survey, comprising of a clinical case-based questionnaire. Clinical practice areas explored were: use of risk-assessment and empiric antibiotic strategies across various treatment settings; use of anti-bacterial prophylaxis; and use of granulocyte-colony stimulating factors for established neutropenic fever and for secondary prophylaxis. RESULTS: A total of 252 clinicians returned responses (approximately 30% response rate). The majority (>70%) were representative of practices in public, major city, tertiary referral hospitals. Less than half of clinicians were aware of risk-assessment tools and less than quarter currently used ambulatory care strategies. If adequate resources were made available, more than 80% were willing to use risk-assessment tools and 60% more clinicians were likely to use ambulatory care strategies. Most clinicians prescribed dual therapy parenteral antibiotics, even for clinically stable patients (53% haematologists, 56% oncologists). Granulocyte-colony stimulating factor was used frequently as secondary prophylaxis in the breast cancer case (91%), follicular lymphoma case (59%) and non-small cell lung cancer case (31%). Fluoroquinolone prophylaxis was infrequently prescribed (19% oncologists, 30% haematologists). CONCLUSIONS: Evidence-practice gaps were identified around the use of risk-assessment-based empiric therapy, and help to inform better clinical guidance. PMID- 21272176 TI - The disease and economic burden of neutropenic fever in adult patients in Australian cancer treatment centres 2008: analysis of the Victorian Admitted Episodes Dataset. AB - BACKGROUND: Although the incidence of neutropenic fever (FN) is estimated to be up to 80% for some malignancies, the epidemiological characteristics and economic burden are not well understood for Australian patients. AIMS: To describe underlying malignant conditions, potential aetiologies, clinical outcomes and healthcare utilization for an Australian population with FN, and to estimate the economic burden of this condition within the Australian healthcare sector. METHODS: Epidemiological features of FN were extracted from a population-based hospital morbidity dataset, the Victorian Admitted Episodes Dataset (VAED), for a 12-month period (2008). These were analysed according for a range of malignancy categories. Economic burden of hospitalizations was estimated according to data presented in the Round 12 National Hospital Cost Data Collection Report. RESULTS: A total of 2599 admitted episodes across 92 Victorian hospitals fulfilled inclusion criteria for FN. Metropolitan hospitalizations accounted for 79% episodes. FN illness comprised underlying solid tumours diagnoses (40%), followed by leukaemia (29.3%), lymphoma (22%) and myeloma (8.5%). Length of hospital stay was >15 days for approximately one-third of hospitalizations. intensive care unit admission rates were 5.9-11.7%. Weighted average costs of hospitalization (AUD) for solid tumours, lymphoma, myeloma and leukaemia were $8309 +/- $391, 18,145 +/ $1602, $21,764 +/- $1289 and $22,596 +/- $2618 respectively. CONCLUSIONS: Using VAED indices, epidemiological features of Australian patients with FN appear comparable with international reports. In contrast to US data, estimated healthcare costs are up to 50% lower in the Australian healthcare sector. These data offer important insights for prioritizing of research agendas and resource allocation. PMID- 21272178 TI - Causes of decreased activity of daily life in elderly patients who need daily living care. AB - AIM: The causes of decreased activity of daily life (ADL) in elderly patients include cerebrovascular diseases, bone fracture by falls, and dementia. The present study was conducted among elderly patients with decreased ADL who were hospitalized in nursing wards in order to investigate the causes of becoming early bedridden and to determine precautionary measures against decreased ADL. METHODS: The study subjects were 224 elderly patients with decreased ADL (mean age: 83.3 +/- 8.0 years) and 49 outpatients without decreased ADL (mean age: 76.8 +/- 5.3 years). Current age, age at the start of ADL decrease, medical history and history of smoking were investigated. RESULTS: In the groups with decreased ADL, current age and the age of becoming bedridden in non-diabetic versus diabetic groups were 84.7 +/- 7.9 versus 80.3 +/- 7.5 and 82.7 +/- 8.3 versus 77.6 +/- 8.0 years, respectively, both showing significantly lower values in the diabetic group (P < 0.05). Multiple regression analysis revealed that sex difference and diabetes were the factors determining the age of becoming early bedridden. Diabetic patients with smoking habit were significantly younger than diabetic and non-diabetic patients without smoking habit. CONCLUSION: Sex difference, smoking habit and presence of diabetes mellitus are independent risk factors of becoming early bedridden. Therefore, the major targets of medical care among elderly should be diabetic men with a smoking habit to lower the risks of decreased ADL. PMID- 21272179 TI - Central auditory processing in elderly with mild cognitive impairment. AB - AIM: The aim of the present study was to assess if central auditory processing affected patients with mild cognitive impairment (MCI) or not and to assess sensitivity and specificity of central auditory processing tests in detection of MCI. METHODS: This was a case-control study conducted at the Geriatrics Department and Audiology Unit, Ain Shams University Hospital. Participants were 150 elderly diagnosed as MCI compared with 150 normal subjects, based on a neuropsychological diagnostic test battery, the Cambridge Cognitive Examination (CAMCOG), and who were matched for age, sex and average threshold of hearing. Both cases and control groups were subjected to otological examination, immittancemetry, pure tone audiometry, speech audiometry and central auditory processing assessment by the use of a selective auditory attention test, dichotic digits test, auditory fusion test, pitch pattern sequences test and auditory memory battery of Goldman-Fristoe-Woodcock. RESULTS: The MCI group scored significantly lower than the control group in central auditory processing tests (P < 0.05). Sensitivity of dichotic digit test, pitch pattern sequence test and recognition memory test were 76.6%, 71.7% and 70.4%, respectively, while specificity were 56.2%, 81.2% and 92.2%, respectively. When the previous three tests were used together the sensitivity and specificity were 82.8% and 93.2%, respectively. CONCLUSION: Central auditory processing was affected in MCI patients. The dichotic digit test, pitch pattern sequence test and recognition memory test can be used in detection of MCI with high sensitivity and specificity. PMID- 21272180 TI - Effect of ferulic acid and Angelica archangelica extract on behavioral and psychological symptoms of dementia in frontotemporal lobar degeneration and dementia with Lewy bodies. AB - AIM: The behavioral and psychological symptoms of dementia place a heavy burden on caregivers. Antipsychotic drugs, though used to reduce the symptoms, frequently decrease patients' activities of daily living and reduce their quality of life. Recently, it was suggested that ferulic acid is an effective treatment for behavioral and psychological symptoms. We have also reported several patients with dementia with Lewy bodies showing good responses to ferulic acid and Angelica archangelica extract (Feru-guard). The present study investigated the efficacy of Feru-guard in the treatment of behavioral and psychological symptoms in frontotemporal lobar degeneration and dementia with Lewy bodies. METHODS: We designed a prospective, open-label trial of daily Feru-guard (3.0 g/day) lasting 4 weeks in 20 patients with frontotemporal lobar degeneration or dementia with Lewy bodies. Behavioral and psychological symptoms of dementia were assessed at baseline and 4 weeks after the start of treatment, using the Neuropsychiatric Inventory. The Neuropsychiatric Inventory scores were analyzed using the Wilcoxon rank sum test. RESULTS: Treatment with Feru-guard led to decreased scores on the Neuropsychiatric Inventory in 19 of 20 patients and significantly decreased the score overall. The treatment also led to significantly reduced subscale scores on the Neuropsychiatric Inventory ("delusions", "hallucinations", "agitation/aggression", "anxiety", "apathy/indifference", "irritability/lability" and "aberrant behavior"). There were no adverse effects or significant changes in physical findings or laboratory data. CONCLUSION: Feru-guard may be effective and valuable for treating the behavioral and psychological symptoms of dementia in frontotemporal lobar degeneration and dementia with Lewy bodies. PMID- 21272181 TI - Experience of elderly Spanish men with an implantable cardioverter-defibrillator. AB - AIM: An implantable cardioverter-defibrillator is the treatment of choice for ventricular arrhythmias and sudden death. Clinical trials and qualitative studies normally exclude elderly patients. The aim of this study was to describe the experience of elderly Spanish men with an implantable cardioverter-defibrillator. METHODS: This was a qualitative phenomenological study. Sampling was purposeful and used the snowball technique. Unstructured interviews and recipients' personal accounts were collected. Data collection finished with information saturation. Analysis was performed using the Giorgi proposal with triangulation between research-team members. Data were audited by an external researcher. RESULTS: The change and the need to adapt to the new situation can be perceived as a loss of independence by the elderly. The significance of the partner in the Spanish context is particularly relevant during the narration. Also, their view of the world is transformed, they experience an internal change. Additionally, the elderly patient may become confined to their home and shut off from their surroundings, accompanied by a sensation of being "stuck" and "imprisoned" by their own process. CONCLUSION: Elderly recipients can end up "clinging on" to customs as they are felt to define the recipient's identity and utility within their social and personal context. Their partner is of huge significance for elderly recipients. The geriatric health personnel must contribute to promote and maintain activities of daily living in elderly. Future qualitative studies taking an in-depth look at the experience and readjustment process of elderly recipients and the relationship among older people and technological equipment should be further conducted. PMID- 21272182 TI - Linking community and ecosystem dynamics through spatial ecology. AB - Classical approaches to food webs focus on patterns and processes occurring at the community level rather than at the broader ecosystem scale, and often ignore spatial aspects of the dynamics. However, recent research suggests that spatial processes influence both food web and ecosystem dynamics, and has led to the idea of 'metaecosystems'. However, these processes have been tackled separately by 'food web metacommunity' ecology, which focuses on the movement of traits, and 'landscape ecosystem' ecology, which focuses on the movement of materials among ecosystems. Here, we argue that this conceptual gap must be bridged to fully understand ecosystem dynamics because many natural cases demonstrate the existence of interactions between the movements of traits and materials. This unification of concepts can be achieved under the metaecosystem framework, and we present two models that highlight how this framework yields novel insights. We then discuss patches, limiting factors and spatial explicitness as key issues to advance metaecosystem theory. We point out future avenues for research on metaecosystem theory and their potential for application to biological conservation. PMID- 21272183 TI - Microbial diversity associated with four functional groups of benthic reef algae and the reef-building coral Montastraea annularis. AB - The coral reef benthos is primarily colonized by corals and algae, which are often in direct competition with one another for space. Numerous studies have shown that coral-associated Bacteria are different from the surrounding seawater and are at least partially species specific (i.e. the same bacterial species on the same coral species). Here we extend these microbial studies to four of the major ecological functional groups of algae found on coral reefs: upright and encrusting calcifying algae, fleshy algae, and turf algae, and compare the results to the communities found on the reef-building coral Montastraea annularis. It was found using 16S rDNA tag pyrosequencing that the different algal genera harbour characteristic bacterial communities, and these communities were generally more diverse than those found on corals. While the majority of coral-associated Bacteria were related to known heterotrophs, primarily consuming carbon-rich coral mucus, algal-associated communities harboured a high percentage of autotrophs. The majority of algal-associated autotrophic Bacteria were Cyanobacteria and may be important for nitrogen cycling on the algae. There was also a rich diversity of photosynthetic eukaryotes associated with the algae, including protists, diatoms, and other groups of microalgae. Together, these observations support the hypothesis that coral reefs are a vast landscape of distinctive microbial communities and extend the holobiont concept to benthic algae. PMID- 21272184 TI - Demethylation of methylarsonic acid by a microbial community. AB - Arsenic is one of the most widespread environmental carcinogens and has created devastating human health problems worldwide, yet little is known about mechanisms of biotransformation in contaminated regions. Methylarsonic acid [MAs(V)], extensively utilized as an herbicide, is largely demethylated to more toxic inorganic arsenite, which causes environmental problems. To understand the process of demethylation of methylarsenicals, soil samples commonly used on Florida golf courses were studied. Several soil extracts were found to demethylate MAs(V) to inorganic arsenite [As(III)]. From these extracts, a bacterial isolate was capable of reducing MAs(V) to MAs(III) but not of demethylating to As(III). A second bacterial isolate was capable of demethylating MAs(III) to As(III) but not of reducing MAs(V). A mixed culture could carry out the complete process of reduction and demethylation, demonstrating that demethylation of MAs(V) to As(III) is a two-step process. Analysis of the 16S ribosomal DNA sequences of the two organisms identified the MAs(V)-reducing and the MAs(III)-demethylating isolates as belong to Burkholderia and Streptomyces species respectively. This is the first report of a novel pathway of degradation of a methylarsenical herbicide by sequential reduction and demethylation in a microbial soil community, which we propose plays a significant role in the arsenic biogeocycle. PMID- 21272185 TI - Inhibition of NADPH oxidase alleviates experimental diabetes-induced myocardial contractile dysfunction. AB - AIM: O(2) (-) production is implicated in cardiac dysfunction for a number of diseases including diabetes. Activation of the O(2) (-)-producing enzyme NADPH oxidase is seen in diabetes, although its role in diabetic cardiomyopathy is unclear. This study was designed to evaluate the effect of NADPH oxidase inhibition on cardiac function in diabetes. METHODS: Experimental diabetes was induced in adult C57 mice using streptozotocin (STZ, 150 mg/kg, i.p.) prior to the administration of the NADPH oxidase inhibitor apocynin (4 mg/kg/day) for 2 weeks. Left ventricular (LV) and myocyte contractile functions were evaluated using echocardiography and edge-detection, respectively. RESULTS: STZ elicited hyperglycaemia and reduced body weight gain, which was unaffected by apocynin. STZ significantly reduced fractional shortening, LV wall thickness, peak shortening, maximal velocity and duration of shortening or relengthening, the effects of which - with the exception of wall thickness - were significantly attenuated or ablated by apocynin. Western blot analysis revealed that the effects of comparable Akt phosphorylation, reduced AMPK phosphorylation, downregulation of sarco(endo)plasmic reticulum Ca(2+)-ATPase and lessened phosphorylation of phospholamban in diabetic myocardium were unaffected by apocynin. Both apocynin and the nitric oxide synthase (NOS) inhibitor l-arginine methyl ester (L-NAME) inhibited elevated O(2) (-) production in diabetes without any additive effect between the two, indicating the presence of endothelial nitric oxide synthase (eNOS) uncoupling. However, neither diabetes nor apocynin altered the expression of heat shock protein 90 and eNOS phosphorylation (Ser(1177)). In addition, apocynin mitigated elevated levels of nitrotyrosine and nitric oxide in diabetes. CONCLUSION: Taken together, these data indicate the beneficial role of NADPH oxidase inhibition in diabetes-induced myocardial contractile dysfunction. PMID- 21272186 TI - Effects of intensive insulin therapy alone and in combination with pioglitazone on body weight, composition, distribution and liver fat content in patients with type 2 diabetes. AB - AIM: To evaluate the effects of intensive insulin therapy alone and with added pioglitazone on body weight, fat distribution, lean body mass (LBM) and liver fat in type 2 diabetic patients. METHODS: Twenty-five insulin-treated, obese patients with type 2 diabetes were randomized to addition of pioglitazone 45 mg (n = 12) or placebo (n = 13) and treated intensively for 12-16 weeks. Dual-energy X-ray absorptiometry/abdominal computed tomography scans were performed before/after treatment. LBM, visceral/subcutaneous adipose tissue (VAT/SAT) and liver/spleen (L/S) attenuation ratios were measured pre-/posttreatment (a ratio <1 represents fatty liver). RESULTS: Intensive insulin alone and insulin + pioglitazone significantly improved glycaemic control (7.8 +/- 0.3 to 7.2 +/- 0.3% and 7.6 +/- 0.3 to 7.1 +/- 0.4%, respectively). Body weight gain was greater with insulin + pioglitazone (4.9 +/- 4.5 kg) versus insulin therapy alone (1.7 +/- 0.7 kg). SAT increased significantly with pioglitazone + insulin therapy (393.9 +/- 48.5 to 443.2 +/- 56.7 cm(2) , p < 0.01) compared to a non-significant increase with insulin therapy alone (412.9 +/- 42.5 to 420.8 +/- 43.8 cm(2) ). VAT decreased non-significantly in both groups (240.3 +/- 41.7 to 223.8 +/- 38.1 cm(2) with insulin + pioglitazone and 266.6 +/- 27.4 to 250.5 +/- 22.2 cm(2) with insulin therapy). LBM increased significantly by 1.92 +/- 0.74 kg with insulin + pioglitazone treatment. The L/S attenuation ratio in the placebo + insulin group decreased from 1.08 +/- 0.1 to 1.04 +/- 0.1 (p = ns) and increased from 1.00 +/- 0.1 to 1.08 +/- 0.05 (p = 0.06) in the pioglitazone + insulin group. CONCLUSIONS: Intensification of insulin therapy in type 2 diabetic patients causes modest weight gain and no change in body fat distribution, LBM or liver fat. In contrast, the addition of pioglitazone, at equivalent glycaemia, increases weight gain, fat mass and SAT; increases LBM and tends to decrease liver fat. These changes in fat distribution may contribute to the beneficial effects of pioglitazone, despite greater weight gain. PMID- 21272187 TI - A new, highly selective murine peroxisome proliferator-activated receptor delta agonist increases responsiveness to thermogenic stimuli and glucose uptake in skeletal muscle in obese mice. AB - AIM: We investigated how GW800644, the first pharmacologically selective murine peroxisome proliferator-activated receptor delta (PPARdelta) agonist, affects energy balance, glucose homeostasis and fuel utilization by muscle in obese mice. METHODS: Potencies were determined in transactivation assays. Oral glucose tolerance was determined after 14 and 22 days' administration (10 mg/kg body weight, twice daily) to Lep(ob)/Lep(ob) mice. Food intake and energy expenditure were measured during a 26-day experiment, and plasma metabolites and 2 deoxyglucose uptake in vivo at termination. Palmitate oxidation and 2 deoxyglucose uptake by isolated soleus muscles were measured after 14 (in lean and obese mice) and 26 days. RESULTS: GW800644 activated murine PPARdelta (EC(50) 2 nM), but caused little to no activation of PPARalpha or PPARgamma up to 10 uM. It did not increase liver weight. GW800644 reduced food intake and body weight in obese mice after 8 days. It did not affect resting energy expenditure, but, compared to pair-fed mice, it increased the response to a beta(3)-adrenoceptor agonist. It improved glucose tolerance. GW800644, but not pair-feeding, reduced plasma glucose, insulin and triglyceride concentrations. It increased 2 deoxyglucose uptake in vivo in adipose tissue, soleus muscle, heart, brain and liver, and doubled 2-deoxyglucose uptake and palmitate oxidation in isolated soleus muscle from obese but not lean mice. CONCLUSIONS: PPARdelta agonism reduced food intake and independently elicited metabolic effects that included increased responsiveness to beta(3)-adrenoceptor stimulation, increased glucose utilization and fat oxidation in soleus muscle of Lep(ob)/Lep(ob) but not lean mice and increased glucose utilization in vivo in Lep(ob)/Lep(ob) mice. PMID- 21272188 TI - Insulin dose-response studies in severely insulin-resistant type 2 diabetes- evidence for effectiveness of very high insulin doses. AB - AIM: To combat diabetic complications strict glycaemic control is desirable in type 2 diabetes, but some patients are severely insulin resistant and it is not known whether high doses of insulin are effective. This study was designed to determine the acute dose-response effects of insulin in patients with type 2 diabetes and severe insulin resistance. METHODS: We included eight insulin resistant (mean insulin dose: 186 IU/day; body mass index: 35) subjects with type 2 diabetes in a single-blinded, randomized crossover study. Each subject was studied on two occasions. On each occasion, subjects underwent two 3-h hyperinsulinaemic euglycaemic clamps. The subjects were randomized to two low dose insulin infusions (0.5 and 1.5 mU/kg/min in random order) on one occasion and to two high-dose insulin infusions (3.0 and 5.0 mU/kg/min in random order) on another occasion. RESULTS: On all occasions, steady-state glucose infusion rates (SSGIRs) were accomplished and we observed a clear dose-response relationship with GIR values of 0.4 +/- 0.2 (s.e.), 2.6 +/- 0.6, 3.7 +/- 0.8 and 4.9 +/- 0.9 mg/kg/min during the 0.5, 1.5, 3.0 and 5.0 mU/kg/min insulin infusions, respectively (p < 0.001). Likewise, there was a dose-dependent suppression of endogenous glucose production (EGP) (p < 0.009), plasma free fatty acids (FFAs) (p < 0.001) and plasma glucagon (p = 0.001). CONCLUSIONS: Our results show that the insulin dose response in terms of GIR and EGP is preserved for insulin doses corresponding to >800 IU/day, suggesting effectiveness of very high insulin doses in severely insulin-resistant subjects. PMID- 21272189 TI - Association of beta-2 adrenergic agonist and corticosteroid injection in the treatment of lipomas. AB - AIM: The aim of this study was to evaluate the efficacy of isoproterenol and prednisolone in the treatment of subcutaneous lipomas. METHODS: The first experiment evaluated in vitro lipolysis induced by isoproterenol 10(-6) M alone and across a range of prednisolone concentrations to determine the optimal dose to maximize lipolysis. The second experiment evaluated lipolysis in a lipoma and subcutaneous fat by in vivo microdialysis in five subjects to isoproterenol 10( 6) M with and without prednisolone 10(-6) M. These five subjects and five additional subjects had a lipoma treated five times a week for 4 weeks in a 4-cm grid with 0.2 ml injections of 10(-6) M isoproterenol and 10(-6) M prednisolone. Lipoma size was followed monthly for 1 year or until surgical removal. RESULTS: Prednisolone increased in vitro lipolysis to isoproterenol and 10(-6) M was the optimal concentration of both drugs. Lipomas responded with less lipolysis to isoproterenol than subcutaneous fat during microdialysis, and prednisolone treatment increased lipolysis in both lipomas and subcutaneous fat. Injection treatment of the lipomas decreased their volume 50%. All but one lipoma grew after treatment. Eight of the 10 subjects elected for surgical treatment, and the histology of the lipomas was normal fat tissue. CONCLUSIONS: Prednisolone and isoproterenol in combination increased lipolysis, and injections of the combination into lipomas decreased their volume 50% over 4 weeks. Eight of the 10 subjects elected for surgical removal. PMID- 21272190 TI - Effects of an 11beta-hydroxysteroid dehydrogenase type 1 inhibitor, MK-0916, in patients with type 2 diabetes mellitus and metabolic syndrome. AB - AIM: We examined the effects of the 11beta-hydroxysteroid dehydrogenase type 1 (HSD1) inhibitor, MK-0916, on the multiple components of the metabolic syndrome (MetS) in patients with type 2 diabetes (T2DM) and MetS. METHODS: This was a 12 week, multicentre, randomized, double-blind, placebo-controlled study. Patients with T2DM (mean baseline A1C: 7.3%) and National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III)-defined MetS were randomized 1 : 1 : 1 : 1 to 0.5, 2 or 6 mg/day MK-0916 or placebo. The primary efficacy endpoint was a change from baseline at week 12 in fasting plasma glucose (FPG). Secondary endpoints included glycosylated haemoglobin A(1c) (A1C), 2-h postprandial glucose (2-h PPG), body weight, waist circumference, blood pressure and lipid profile. RESULTS: Treatment with MK-0916 had no significant effect relative to placebo on FPG at week 12. Compared to placebo, 6 mg MK-0916 produced a modest, significant (p = 0.049) reduction in A1C of 0.3% at week 12, but no significant difference was observed in 2-h PPG. Six milligram MK-0916 increased LDL-C relative to placebo by 10.4% (p = 0.041). Treatment with MK-0916 led to modest dose-dependent decreases in blood pressure and body weight. Overall, MK-0916 was generally well tolerated. MK-0916 produced mechanism-based activation of the hypothalamic pituitary-adrenal axis, resulting in mean increases in adrenal androgen levels that remained within the normal range at all doses tested. CONCLUSIONS: Inhibition of HSD1 with MK-0916 was generally well tolerated in patients with T2DM and MetS. Although no significant improvement in FPG was observed with MK 0916 compared to placebo, modest improvements in A1C, body weight and blood pressure were observed. PMID- 21272191 TI - Phenylbutyric acid reduces amyloid plaques and rescues cognitive behavior in AD transgenic mice. AB - Trafficking through the secretory pathway is known to regulate the maturation of the APP-cleaving secretases and APP proteolysis. The coupling of stress signaling and pathological deterioration of the brain in Alzheimer's disease (AD) supports a mechanistic connection between endoplasmic reticulum (ER) stress and neurodegeneration. Consequently, small molecular chaperones, which promote protein folding and minimize ER stress, might be effective in delaying or attenuating the deleterious progression of AD. We tested this hypothesis by treating APPswePS1delta9 AD transgenic mice with the molecular chaperone phenylbutyric acid (PBA) for 14 months at a dose of 1 mg PBA g(-1) of body weight in the drinking water. Phenylbutyric acid treatment increased secretase-mediated APP cleavage, but was not associated with any increase in amyloid biosynthesis. The PBA-treated AD transgenic mice had significantly decreased incidence and size of amyloid plaques throughout the cortex and hippocampus. There was no change in total amyloid levels suggesting that PBA modifies amyloid aggregation or pathogenesis independently of biogenesis. The decrease in amyloid plaques was paralleled by increased memory retention, as PBA treatment facilitated cognitive performance in a spatial memory task in both wild-type and AD transgenic mice. The molecular mechanism underlying the cognitive facilitation of PBA is not clear; however, increased levels of both metabotropic and ionotropic glutamate receptors, as well as ADAM10 and TACE, were observed in the cortex and hippocampus of PBA-treated mice. The data suggest that PBA ameliorates the cognitive and pathological features of AD and supports the investigation of PBA as a therapeutic for AD. PMID- 21272192 TI - Interaction between 24-hydroxycholesterol, oxidative stress, and amyloid-beta in amplifying neuronal damage in Alzheimer's disease: three partners in crime. AB - All three cholesterol oxidation products implicated thus far in the pathogenesis of Alzheimer's disease, 7beta-hydroxycholesterol, 24-hydroxycholesterol, and 27 hydroxycholesterol, markedly enhance the binding of amyloid-beta (Abeta) to human differentiated neuronal cell lines (SK-N-BE and NT-2) by up-regulating net expression and synthesis of CD36 and beta1-integrin receptors. However, only 24 hydroxycholesterol markedly potentiates the pro-apoptotic and pro-necrogenic effects of Abeta(1-42) peptide on these cells: 7beta-hydroxycholesterol and 27 hydroxycholesterol, like unoxidized cholesterol, show no potentiating effect. This peculiar behavior of 24-hydroxycholesterol at physiologic concentrations (1 MUm) depends on its strong enhancement of the intracellular generation of NADPH oxidase-dependent reactive oxygen species (ROS), mainly H(2) O(2) , and the consequent impairment of neuronal cell redox equilibrium, measured in terms of the GSSG/GSH ratio. Cell incubation with antioxidants quercetin or genistein prevents 24-hydroxycholesterol's pro-oxidant effect and potentiation of Abeta induced necrosis and apoptosis. Thus, the presence of 24-hydroxycholesterol in the close vicinity of amyloid plaques appears to enhance the adhesion of large amounts of Abeta to the plasma membrane of neurons and then to amplify the neurotoxic action of Abeta by locally increasing ROS steady-state levels. This report further supports a primary involvement of altered brain cholesterol metabolism in the complex pathogenesis of Alzheimer's disease. PMID- 21272193 TI - Age-dependent remodelling of ionotropic signalling in cortical astroglia. AB - Cortical astrocytes express fast ionotropic receptors for glutamate and ATP, although their role in neurone-glia communication remains controversial. Stimulation of neuronal afferents in mice neocortex triggers complex glial synaptic currents (GSCs) mediated by NMDA, P2X and AMPA receptors and glutamate transporters. In addition, astrocytes demonstrate spontaneous 'miniature' GSCs resulting from quantal release of neurotransmitters. Here, we demonstrate that maturation and aging of the brain of mice (from 1 to 21 months) affect the density of ionotropic receptors in astrocytes and their role in GSCs generation. The AMPA-receptor-mediated component is the largest in young animals and progressively declines with age. The P2X and NMDA components of GSC are smallest in young, maximal in adult (3 and 6 months old) and once more decrease in old mice, probably reflecting the remodelling of neuronal-glial circuitry. Our results demonstrate that fast synaptic transmission between neurones and astrocytes in neocortex that may be involved in information processing in neuronal-glial networks undergoes remodelling during brain maturation and aging. PMID- 21272194 TI - Barriers to blood pressure control: a STITCH substudy. AB - Despite improvements in blood pressure (BP) control, a substantial percentage of patients do not achieve target. The relative importance of determinants of poor BP control is unclear. Therefore, the authors conducted a post hoc exploratory analysis to assess determinants of BP control. Data were collected in 45 general practices, which enrolled patients with uncontrolled hypertension. Antihypertensive medication changes throughout the 6-month follow-up period were documented. Baseline and 6-month BPs were recorded. Of the 2030 patients analyzed, 320 had diabetes. Overall, 42% of patients did not achieve BP control. In multivariate analysis, failure to intensify therapy was identified as a significant independent predictor of lesser BP reduction. Of patients unable to reach target after 6 months, only 25% were prescribed >= 3 drugs. Patients with diabetes were significantly less likely to reach target than those without (26% vs 64%, P<.001). Antihypertensive therapy prescribed to patients with diabetes was only marginally more intensive than to those without. In patients with hypertension, whether with or without coexisting diabetes, poor BP control appears to be at least partially due to failure to uptitrate antihypertensive therapy. Clinical inertia is likely an important barrier to BP control. PMID- 21272195 TI - The comparative effects of azilsartan medoxomil and olmesartan on ambulatory and clinic blood pressure. AB - The current study assesses the antihypertensive efficacy and safety of the investigational angiotensin receptor blocker (ARB), azilsartan medoxomil (AZL-M), compared with placebo and the ARB olmesartan medoxomil (OLM-M). This randomized, double-blind, placebo-controlled, multicenter study assessed change from baseline in mean 24-hour ambulatory systolic blood pressure (SBP) following 6 weeks of treatment. Patients with primary hypertension (n=1275) and baseline 24-hour mean ambulatory systolic pressure >= 130 mm Hg and <= 170 mm Hg were studied; 142 received placebo and the remainder received 20 mg, 40 mg, or 80 mg AZL-M or 40 mg OLM-M. Mean age of participants was 58 +/- 11 years, baseline mean 24-hour SBP was 146 mm Hg. Dose-dependent reductions in 24-hour mean SBP at study end occurred in all AZL-M groups. Reduction in 24-hour mean SBP was greater with AZL M 80 mg than OLM-M 40 mg by 2.1 mm Hg (95% confidence interval, -4.0 to -0.1; P=.038), while AZL-M 40 mg was noninferior to OLM-M 40 mg. The side effect profiles of both ARBs were similar to placebo. AZL-M is well tolerated and more efficacious at its maximal dose than the highest dose of OLM-M. PMID- 21272196 TI - Improvements in insulin sensitivity and muscle blood flow in aerobic-trained overweight-obese hypertensive patients are not associated with ambulatory blood pressure. AB - To verify whether there are relationships between vascular and hormonal responses to aerobic training in hypertensive persons, sedentary hypertensive patients were randomized to an aerobic training or a callisthenic exercise group. The patients' 24-hour blood pressure, arterial compliance, forearm blood flow, and hormonal profile were evaluated at baseline and after 3-month training protocols. Mean maximal oxygen consumption (VO(2) max) increased by 8% in the aerobic group (P<.001), while no change was observed in the control group. There was a decrease in insulin resistance (homeostatic model assessment of insulin resistance, P=.039) and plasma cortisol (P=.006) in the aerobic group only, that also demonstrated an increase in forearm blood flow (P<.001) after training. No relationship was observed between change in blood pressure or change in body mass and other parameters. Aerobic training can promote a decrease in cardiovascular risk in hypertensive adults by improving vascular function and insulin resistance, despite no changes in ambulatory blood pressure after a 3-month intervention. PMID- 21272197 TI - Highly interactive multi-session programs impact physician behavior on hypertension management: outcomes of a new CME model. AB - There has been much discussion and study about the role of continuing medical education (CME) in improving patient care. The authors describe the processes used to develop and implement a series of live, half-day, highly interactive CME events that addressed knowledge, competency, and performance gaps in hypertension diagnosis and management in the primary care community and successfully changed physician behavior toward improved patient outcomes. Participation in an intensive, highly interactive, case-based didactic program was significantly associated with an increase in clinician knowledge and competency in diagnosing and managing patients with hypertension. Participation was also associated with a high likelihood for practice change and making guideline-driven and evidence based decisions to positively impact patient care. A greater portion of participants were able to identify the appropriate blood pressure goal and select the most appropriate pharmacotherapy regimen for specific patients. Quality of education index indicated that participants were 52% more likely to practice guideline-driven and evidence-based medicine than those who did not participate in the CME activity. PMID- 21272198 TI - Physician characteristics as predictors of blood pressure control in patients enrolled in the hypertension improvement project (HIP). AB - The authors sought to examine the relationship between physician characteristics and patient blood pressure (BP) in participants enrolled in the Hypertension Improvement Project (HIP). In this cross-sectional study using baseline data of HIP participants, the authors used multiple linear regression to examine how patient BP was related to physician characteristics, including experience, practice patterns, and clinic load. Patients had significantly lower systolic BP (SBP) (-0.2 mm Hg for every 1% increase, P=.008) and diastolic BP (DBP) (-0.1 mm Hg for every 1% increase, P=.0007) when seen by physicians with a higher percentage of patients with hypertension. Patients had significantly higher SBP (0.8 mm Hg for every 1% increase, P=.002) when seen by physicians with a higher number of total clinic visits per day. Patients had significantly lower DBP (-4.4 mm Hg decrease, P=.0002) when seen by physicians with inpatient duties. Physician's volume of patients with hypertension was related to better BP control. However, two indicators of a busy practice had conflicting relationships with BP control. Given the increasing time demands on physicians, future research should examine how physicians with a busy practice are able to successfully address BP in their patients. PMID- 21272199 TI - Influence of sex on the accuracy of oscillometric-derived blood pressures. AB - The effect of sex on the correlation between oscillometric and central aortic blood pressures (BP) is largely unknown. BP was simultaneously measured in the brachial artery using an oscillometric device and in the aorta using a fluid filled catheter in 98 patients undergoing coronary angiography. Mean age (+/- standard deviation) was 58 +/- 12 years, with 55% of the patients being male. Mean BP (MBP) measured by the oscillometric device and in the aorta were similar when the group was examined as a whole, but the oscillometric device overestimated MBP in men and underestimated MBP in women. Oscillometric pressures accurately estimated diastolic BP in women but overestimated diastolic BP in men and underestimated systolic BP in both sexes. The oscillometric device underestimated aortic pulse pressure in both sexes but less in men than in women. The accuracy of oscillometric MBP and diastolic BP varied as a function of aortic MBP, but sex-related differences in the accuracy of oscillometric pressures remained significant after adjusting for MBP, body mass index, height, age, race, heart rate, diabetes, smoking status, and BP-lowering therapies using a multivariate logistic regression model. Sex is an important determinant of the accuracy of oscillometric BP. PMID- 21272200 TI - Drug therapy for resistant hypertension: simplifying the approach. AB - Despite the availability of many effective antihypertensive drugs, the drug therapy for resistant hypertension remains a prominent problem. Reviews offer only the general recommendations of increasing dosage and adding drugs, offering clinicians little guidance with respect to the specifics of selecting medications and dosages. A simplified decision tree for drug selection that would be effective in most cases is needed. This review proposes such an approach. The approach is mechanism-based, targeting treatment at three hypertensive mechanisms: (1) sodium/volume, (2) the renin-angiotensin system (RAS), and (3) the sympathetic nervous system (SNS). It assumes baseline treatment with a 2-drug combination directed at sodium/volume and the RAS and recommends proceeding with one or both of just two treatment options: (1) strengthening the diuretic regimen, possibly with the addition of spironolactone, and/or (2) adding agents directed at the SNS, usually a beta-blocker or combination of an alpha- and a beta-blocker. The review calls for greater research and clinical attention directed to: (1) assessment of clinical clues that can help direct treatment toward either sodium/volume or the SNS, (2) increased recognition of the role of neurogenic (SNS-mediated) hypertension in resistant hypertension, (3) increased recognition of the effective but underutilized combination of alpha- + beta blockade, and (4) drug pharmacokinetics and dosing. PMID- 21272201 TI - Is there an increased cancer risk associated with the use of angiotensin receptor blockers and should it affect current prescribing? PMID- 21272202 TI - Taking a family history of hypertension: is there patient care benefit? PMID- 21272203 TI - Patient self-management improves blood pressure control. PMID- 21272220 TI - Burden of sodium abnormalities in patients hospitalized for heart failure. AB - Hyponatremia presumably is associated with adverse clinical outcomes in patients with congestive heart failure (CHF), but risk thresholds and economic burden are less studied. The authors analyzed 115,969 patients hospitalized for CHF and grouped them by serum sodium levels (severe hyponatremia, <=130 mEq/L; hyponatremia, 131-135 mEq/L; normonatremia, 136-145 mEq/L; hypernatremia, >145 mEq/L). Univariable and multivariable analyses on the associated clinical and economic outcomes were performed. The most common abnormality was hyponatremia (15.9%), followed by severe hyponatremia (5.3%) and hypernatremia (3.2%). Hospital mortality was highest for severe hyponatremia (7.6%), followed by hypernatremia (6.7%) and hyponatremia (4.9%) (P<.0001). Compared with normonatremia, risk-adjusted mortality was highest for severe hyponatremia (odds ratio [OR], 1.78; 95% confidence interval [CI], 1.59-1.99), followed by hypernatremia (OR, 1.55; 95% CI, 1.34-1.80) and hyponatremia (OR, 1.29; 95% CI, 1.19-1.40; all P<.0001). Risk-adjusted hospital prolongation was greater for each level of sodium abnormality than for normonatremia, ranging from 0.42 (CI, 0.26 0.60) days for hypernatremia to 1.28 (CI, 1.11-1.47) days for severe hyponatremia. Risk-adjusted attributable hospital cost increase was highest for severe hyponatremia ($1132; CI, $856-$1425; all (P<.0001). Sodium abnormalities were common in patients hospitalized for CHF. Adverse outcomes resulted not only from severe hyponatremia, but also from mild hyponatremia and hypernatremia. PMID- 21272221 TI - Primary role of B-type natriuretic peptide across the clinical spectrum: from emergency medicine to transitional care and beyond into the community. AB - Heart failure (HF), the most common reason for hospitalization in Medicare recipients, carries significant mortality and morbidity and is costly to the health care system. HF hospitalizations increase with the increasing age of the population and constitutes Medicare & Medicaid Services' largest expenditure. According to the Acute Decompensated Heart Failure National Registry (ADHERE), a database of more than 100,000 patients who were admitted with a diagnosis of HF, approximately 80% of these patients came from the emergency department (ED) and 89% had dyspnea at the time of ED presentation. Contrary to ADHERE data, the Biomarkers in Acute Heart Failure (BACH) trial indicates 34.6% of 1588 patients presenting to EDs with acute shortness of breath were diagnosed with HF. Although shortness of breath is thought to be predictive of HF, this idea is based on conclusions drawn from a registry enrolling patients with an established diagnosis. The ADHERE study reflects the population with confirmed diagnosis and not the at-risk population with symptoms suggestive of HF, thus emphasizing the need to distinguish and risk-stratify the population presenting to EDs prior to implementing early intervention. This is particularly desirable in patients with diagnosed acute HF for accurate diagnosis and better treatment outcomes. PMID- 21272222 TI - Blood volume measurements in patients with heart failure and a preserved ejection fraction: implications for diagnosing anemia. AB - Racial differences in the prevalence of anemia in patients with heart failure have been noted. The diagnosis of anemia in heart failure patients can be confounded by many factors. Plasma volume expansion is one of the most prominent confounders. The authors investigated the difference of anemia prevalence using two different diagnostic techniques: peripheral hemoglobin recommended by the World Health Organization criteria and blood volume (BV) analysis. Racial disparities in the prevalence of anemia using both measures were compared. Sixty patients with heart failure and preserved ejection fraction (HFPEF) underwent measurement of BV by a radio-labeled albumin technique. Anemia was defined by both WHO criteria and by measured red blood cell volume (RBCV) >10% below ideal. Anemia was found in 67% of patients by the peripheral hemoglobin technique with no racial disparity. Only 35% of the patients had anemia by the BV analysis, with a 2-fold higher prevalence among Hispanics compared with whites and blacks. In patients with HFPEF, the diagnosis of anemia based on hemoglobin is confounded by plasma volume derangements resulting in significant overdiagnosis in this cohort. Racial differences in the rate of anemia were found. Such data could have important implications for the diagnosis and management of anemia in ethnic minorities with HFPEF. PMID- 21272223 TI - Incidence of sleep-disordered breathing in patients with hypertrophic cardiomyopathy. AB - The authors investigated the prevalence of sleep-disordered breathing (SDB) together with its clinical correlations in patients with hypertrophic cardiomyopathy (HCM). A total of 113 consecutive patients including 63 patients with HCM (40 men; mean age, 59.5+/-13.0 years; New York Heart Association class, 2.0+/-0.9) underwent cardiorespiratory polygraphy in addition to their clinical work-up including echocardiography. Patients with an apnea-hypopnea-index (AHI) >=5/h were considered to have SDB. If thoracic and abdominal inspiration efforts were documented, SDB was considered to be obstructive sleep apnea (OSA), otherwise SDB was considered to be central sleep apnea (CSA). The age- and sex matched control group of 50 patients had exclusion of coronary artery disease by angiography, and normal left ventricular (ejection fraction >=55%) and valvular function. SDB was diagnosed in 52 patients (82.5% vs 72% in the control group; P =not significant) with a mean AHI of 23.0+/-17.8/h. Severity of SDB was higher in patients with HCM than in the control group (AHI 12.2+/-7.6/h; P =.003). OSA was documented in 39 patients (AHI 21.2+/-16.5/h) and CSA in 13 (AHI 28.4+/-20.9/h). The severity of SDB correlated with New York Heart Association functional class (eta=0.9, eta(2) =0.811) and with left ventricular end-diastolic (r=0.6, P <.01) and left atrial (r=0.4, P <.01) diameter. No correlations were found between SDB and other clinical or echocardiographic parameters. SDB is common in patients with hypertrophic cardiomyopathy, with a predominance of OSA and correlations with markers of left ventricular function. PMID- 21272224 TI - Uric acid as a predictor of all-cause mortality in heart failure: a meta analysis. AB - Serum uric acid (SUA) is a product of xanthine oxidase (XO). Apoptosis and tissue hypoxia lead to increased purine catabolism, which, in turn, increases XO activity and subsequently SUA levels. The purpose of this study was to perform a meta-analysis to evaluate the evidence supporting SUA as a predictor of all-cause mortality in patients with heart failure (HF) and to determine the SUA cut-off for the increase in risk. A search of the MEDLINE database (1966 to March 2009) supplemented by manual searches of bibliographies of key relevant articles was performed. The authors selected all cohort studies in which SUA was measured and mortality was reported in patients with HF. The pooled relative risk (RR) with the corresponding 95% confidence interval (CI) for all-cause mortality using the fixed-effects method was calculated. The effects of SUA on all-cause mortality at different SUA cut-offs using meta-regression was evaluated. The search strategy yielded 358 studies, of which only 6 met our eligibility criteria. The studies, however, comprised 1456 evaluable patients with HF, with a median ejection fraction of 32% (range, 26%-40%). The RR of all-cause mortality was 2.13 (95% CI, 1.78-2.55) for SUA>6.5 mg/dL compared with <6.5 mg/dL SUA level. There was a linear association (P<.01) between SUA and mortality after 7 mg/dL. Uric acid is an important prognostic marker for all-cause mortality in HF. SUA levels >7 mg/dL are associated with higher all-cause mortality. PMID- 21272225 TI - The meaningful use of the review of symptoms in heart failure patients. AB - Review of symptoms (ROS) is a time-honored tradition in medicine and has proved to be a case-finding maneuver in general medicine patients. The authors sought to investigate the prevalence of noncardiovascular symptoms in heart failure clinics by assessment of the ROS. Of the collected ROS, shortness of breath (SOB) represented the most frequent recalled symptom (8.6%), whereas fatigue (5.3%) was the most common noncardiac symptom. Multivariate regression analysis revealed that New York Heart Association class could, at least in part, explain the occurrence of SOB (R(2) =.4; P<.05). Importantly, alarm symptoms such as hemoptysis and bloody stools were present in <1% of the cohort. ROS evaluation remains a valuable tool for diagnostics; however, symptom-focused questionnaires should be routinely considered as a time-efficient strategy in the ambulatory specialty clinic. PMID- 21272226 TI - Not takotsubo: a different form of stress-induced cardiomyopathy--a case series. AB - The diagnosis of stress-induced cardiomyopathy requires wall motion abnormality, most typically apical ballooning. The authors report 3 cases of transient global left ventricular systolic dysfunction that developed over the course of severe medical illnesses. The cardiomyopathy that developed in each patient had all the features of takotsubo cardiomyopathy, including reversibility, mild troponin elevation, nonspecific electrocardiographic abnormalities, and a negative work-up for ischemia. The only difference was the absence of regional wall motion abnormalities. No patients developed sepsis or myocarditis. Stress-induced cardiomyopathy may present in different forms, including regional or global left ventricular dysfunction. Classic takotsubo syndrome may represent only part of the spectrum of this reversible condition. PMID- 21272230 TI - Nitroprusside and the treatment of hypertension. PMID- 21272227 TI - Use of metabolomic profiling in the study of arachidonic acid metabolism in cardiovascular disease. PMID- 21272231 TI - The Ty1 LTR-retrotransposon population in Saccharomyces cerevisiae genome: dynamics and sequence variations during mobility. AB - Transposable element (TE) evolution in genomes has mostly been deduced from comparative genome analyses. TEs often account for a large proportion of the eukaryotic nuclear genome (up to 50%, depending on the species). Among the many existing genomic copies, only a small fraction may contribute to the mobility of a TE family. We have identified here, using a genetic screening procedure to trap Ty1 long terminal repeat-retrotransposon insertions in Saccharomyces cerevisiae, which among the populations of resident Ty1 copies are responsible for Ty1 mobility. Although the newly inserted Ty1 copies resulting from a single round of transposition were found to originate from a limited subset of Ty1 resident copies, they showed a high degree of diversity at the nucleotide level, mainly due to the reverse transcription-mediated recombination. In this process, highly expressed and strikingly nonautonomous mutant Ty1 were found to be the most frequently used resident copies, which suggests that nonautonomous elements play a key role in the dynamics of the Ty1 family. PMID- 21272232 TI - The AJT report: news and issues that affect organ and tissue transplantation. AB - Is individualized organ repair in our future? This month, "The AJT Report" explores warm ex vivo lung perfusion, and what it might mean for the future of organ transplantation. PMID- 21272233 TI - Literature watch. PMID- 21272234 TI - Transplant surgery fellow perceptions about training and the ensuing job market are the right number of surgeons being trained? AB - The American Society of Transplant Surgeons (ASTS) sought whether the right number of abdominal organ transplant surgeons are being trained in the United States. Data regarding fellowship training and the ensuing job market were obtained by surveying program directors and fellowship graduates from 2003 to 2005. Sixty-four ASTS-approved programs were surveyed, representing 139 fellowship positions in kidney, pancreas and/or liver transplantation. One quarter of programs did not fill their positions. Forty-five fellows graduated annually. Most were male (86%), aged 31-35 years (57%), married (75%) and parents (62%). Upon graduation, 12% did not find transplant jobs (including 8% of Americans/Canadians), 14% did not get jobs for transplanting their preferred organ(s), 11% wished they focused more on transplantation and 27% changed jobs early. Half fellows were international medical graduates; 45% found US/Canadian transplant jobs, particularly 73% with US/Canadian residency training. Fellows reported adequate exposure to training volume, candidate selection, pre/postoperative care and organ procurement, but not to donor management/selection, outpatient care and core didactics. One-sixth noted insufficient 'mentoring/preparation for a transplantation career'. Currently, there seem to be enough trainees to fill entry-level positions. One-third program directors believe that there are too many trainees, given the current and foreseeable job market. ASTS is assessing the total workforce of transplant surgeons and evolving manpower needs. PMID- 21272235 TI - Experience of laparoscopic incisional hernia repair in kidney and/or pancreas transplant recipients. AB - Despite the wide popularity of laparoscopic incisional hernia repair (LIHR) in the nontransplant population, there are very few reports of LIHR available in abdominal organ transplant patients and none exclusively on kidney and/or pancreas (KP) transplant patients. We retrospectively reviewed a consecutive series of LIHR in KP transplant recipients performed over a period of 4 years and compared the results with LIHR in non-transplant patients during the same period. A total of 36 transplant patients were compared with 62 nontransplant patients. There were five patients converted to the open procedure in the transplant and four in nontransplant patients (p-NS). There were three seromas and one patient had a bowel perforation in the transplant group versus eight seromas, one bowel perforation and one small bowel obstruction noted in the nontransplant group. One patient in each group had a mesh infection requiring explant. Patients were followed up for a mean period of 2.2 years in the transplant group and 3 years in the nontransplant group. Overall there were five recurrences in the transplant group and four in the nontransplant group (p = NS). These results suggest that that LIHR is a safe and effective alternative to open repair. PMID- 21272236 TI - Cognitive and academic outcomes after pediatric liver transplantation: Functional Outcomes Group (FOG) results. AB - This multicenter study examined prevalence of cognitive and academic delays in children following liver transplant (LT). One hundred and forty-four patients ages 5-7 and 2 years post-LT were recruited through the SPLIT consortium and administered the Wechsler Preschool and Primary Scale of Intelligence, 3rd Edition (WPPSI-III), the Bracken Basic Concept Scale, Revised (BBCS-R), and the Wide Range Achievement Test, 4th edition (WRAT-4). Parents and teachers completed the Behavior Rating Inventory of Executive Function (BRIEF). Participants performed significantly below test norms on intelligence quotient (IQ) and achievement measures (Mean WPPSI-III Full Scale IQ = 94.7 +/- 13.5; WRAT-4 Reading = 92.7 +/- 17.2; WRAT-4 Math = 93.1 +/- 15.4; p < 0001). Twenty-six percent of patients (14% expected) had 'mild to moderate' IQ delays (Full Scale IQ = 71-85) and 4% (2% expected) had 'serious' delays (Full Scale IQ <= 70; p < 0.0001). Reading and/or math scores were weaker than IQ in 25%, suggesting learning disability, compared to 7% expected by CDC statistics (p < 0.0001). Executive deficits were noted on the BRIEF, especially by teacher report (Global Executive Composite = 58; p < 0.001). Results suggest a higher prevalence of cognitive and academic delays and learning problems in pediatric LT recipients compared to the normal population. PMID- 21272237 TI - Bile acids aspiration reduces survival in lung transplant recipients with BOS despite azithromycin. AB - Azithromycin (AZM) improved bronchiolitis obliterans syndrome (BOS) and reduced aspiration in lung transplant (LTx) recipients. We hypothesize that AZM could improve graft and overall survival more efficiently in LTx patients with BOS who have bile acid (BA) aspiration by protecting against the aspiration-induced progression of BOS. The goal was to compare FEV(1) (% baseline), BOS progression and overall survival in LTx recipients treated with AZM for BOS, both with versus without BA aspiration. Therefore, LTx recipients treated with AZM for BOS were recruited and broncho-alveolar lavage (BAL) samples were analyzed for the presence of BA and neutrophilia before the start of AZM treatment. Short-term effect of AZM on FEV(1) and BAL neutrophilia was assessed, progression of BOS and survival were followed-up for 3 years and results were compared between patients with/without BA aspiration. 19/37 LTx patients had BA in BAL. BA aspiration predisposed to a significantly worse outcome, in terms of decline in FEV(1) , progression of BOS >= 1 and survival. AZM does not seem to protect against the long-term allograft dysfunction caused by gastroesophageal reflux (GER) and aspiration and an additional treatment targeting aspiration may be indicated in those LTx patients. PMID- 21272238 TI - Transporting live donor kidneys for kidney paired donation: initial national results. AB - Optimizing the possibilities for kidney-paired donation (KPD) requires the participation of donor-recipient pairs from wide geographic regions. Initially it was envisaged that donors would travel to the recipient center; however, to minimize barriers to participation and simplify logistics, recent trends have involved transporting the kidneys rather than the donors. The goal of this study was to review outcomes of this practice. KPD programs throughout the United States were directly queried about all transplants involving live donor kidney transport. Early graft function was assessed by urine output in the first 8 h, postoperative serum creatinine trend, and incidence of delayed graft function. Between April 27, 2007 and April 29, 2010, 56 live donor kidneys were transported among 30 transplant centers. Median CIT was 7.2 h (IQR 5.5-9.7, range 2.5-14.5). Early urine output was robust (>100 cc/h) in all but four patients. Creatinine nadir was <2.0 mg/dL in all (including the four with lower urine output) but one patient, occurring at a median of 3 days (IQR 2-5, range 1-49). No patients experienced delayed graft function as defined by the need for dialysis in the first week. Current evidence suggests that live donor kidney transport is safe and feasible. PMID- 21272239 TI - Antifungal prophylaxis in lung transplantation--a world-wide survey. AB - While variations in antifungal prophylaxis have been previously reported in lung transplant (LTx) recipients, recent clinical practice is unknown. Our aim was to determine current antifungal prophylactic practice in LTx centers world-wide. One nominated LTx clinician from each active center was invited by e-mail to participate in a web-based survey between September 2009 and January 2010. Fifty seven percent (58/102) responded. The majority of responses were from medical directors of LTx centers (72.4%), and from the United States (44.8%). Within the first 6 months post-LTx, most centers (58.6%) employed universal prophylaxis, with 97.1% targeting Aspergillus species. Voriconazole alone, and in combination with inhaled amphotericin B (AmB), were the preferred first-line agents. Intolerance to side effects of voriconazole (69.2%) was the main reason for switching to alternatives. Beyond 6 months post-LTx, most (51.8%) did not employ antifungal prophylaxis. Fifteen centers (26.0%) conducted routine antifungal therapeutic drug monitoring during prophylactic period. There are differences in strategies employed between U.S. and European centers. Most respondents indicated a need for antifungal prophylactic guidelines. In comparison to earlier findings, there was a major shift toward prophylaxis with voriconazole and an increased use of echinocandins, posaconazole and inhaled lipid formulation AmB. PMID- 21272240 TI - Feasibility, reproducibility, risks and benefits of face transplantation: a prospective study of outcomes. AB - Composite tissue allotransplantations can be indicated when autologous transfers fail to restore human appearance. We report the reproducibility, difficulties, serious adverse events and outcomes of our patients. Five patients were included in a registered clinical research protocol after thorough screenings assessed by an independent expert committee systematically discussing the alternative options. One patient suffered from plexiform neurofibromas, two from third degree burns and two from gunshot injuries. They were included on a national waiting list with a dedicated face procurement procedure. Transplants were harvested from heart beating brain-dead donors before other tissues and organs. Induction immunosuppressive therapy included antithymocyte globulins, steroids, mycophenolate mophetil and tacrolimus. Maintenance therapy included the last three ones associated with extracorporeal-photopheresis. Four patients were transplanted with 7- to 38-month follow-up. One could not due to multiple panel reactive antibodies after 18 months on waiting list. Acute cellular rejections were controlled by conventional treatment. Opportunistic infections affected all patients and lead one patient to die two month after the transplantation. Voluntary facial activity appeared from 3 to 5 month. Face transplantation has been reproducible under conventional immunosuppression. Major improvements in facial aesthetic and function allowed patients to recover social relations and improved their quality of life. PMID- 21272241 TI - Cost analysis of conventional facial reconstruction procedures followed by face transplantation. AB - For the first time, this study analyzes the cost of multiple conventional reconstructions and face transplantation in a single patient. This patient is a 46-year-old female victim of a shotgun blast resulting in loss of multiple functional and aesthetic subunits. For over 5 years, she underwent multiple conventional reconstructions with suboptimal results. In December 2008, she became the recipient of the first U.S. face transplant. This has provided the unique opportunity to present the cost of 23 separate conventional reconstructive procedures and the first face transplant in the United States. The combined cost of conventional reconstructive procedures and the first U.S. face transplant was calculated to be $353 480 and $349 959, respectively. The combined cost posttransplant totaled $115 463. The direct cost pretransplant was $206 646, $232 893 peritransplant and $74 236 posttransplant. The two largest areas of cost utilization were surgical ($79 625; 38.5%) and nursing ($55 860; 27%), followed by anesthesia ($24 808; 12%) and pharmacy ($16 581; 8%). This study demonstrates that the cost of the first U.S. face transplant is similar to multiple conventional reconstructions. Although the cost of facial transplantation is considerable, the alleviation of psychological and physiological suffering, exceptional functional recovery and fulfillment of long-lasting hope for social reintegration may be priceless. PMID- 21272242 TI - HIV transmission through transfusion-Missouri and Colorado, 2008. PMID- 21272243 TI - A role for BDNF/TrkB signaling in behavioral and physiological consequences of social defeat stress. AB - Accumulating evidences underlie the importance of the interplay between environmental and genetic factors in contributing to the risk to develop mental illness. Brain-derived neurotrophic factor (BDNF) and its Tyrosine receptor kinase B (TrkB) receptor play a fundamental contribution to brain development and plastic adaptations to life events. In the present study, the potential for the BDNF/TrkB contribution in increasing vulnerability to negative social experiences was assessed by subjecting TrkB.T1 overexpressing mice to a chronic social defeat model. TrkB.T1 mice overexpress the dominant-negative truncated splice variant of TrkB receptor leading to decreased BDNF signaling. After repeated social defeat, mice were assessed in a longitudinal study for behavioral, physiological, endocrine and immune responses potentially related to psychiatric endophenotypes. TrkB.T1 overexpression corresponded to smaller changes in metabolic parameters such as body weight, food intake, feed efficiency and peripheral ghrelin levels compared with wild-type (wt) littermates following social defeat. Interestingly, 4 weeks after the last defeat, TrkB.T1 overexpressing mice exhibited more consistent social avoidance effects than what observed in wt subjects. Finally, previously unreported effects of TrkB mutations could be observed on lymphoid organ weight and on peripheral immune biomarker levels, such as interleukin 1alpha and regulated on activation, normal, T-cell expressed, and secreted (RANTES), thus suggesting a systemic role of BDNF signaling in immune function. In conclusion, the present data support a contribution of TrkB to stress vulnerability that, given the established role of TrkB in the response to antidepressant treatment, calls for further studies addressing the link between stress susceptibility and variability in drug efficacy. PMID- 21272244 TI - Best practice wound care. AB - This article describes the barriers, changes and achievements related to implementing one element of a wound care programme being best practice care. With the absence of a coordinated approach to wound care, clinical practice within our Area Health Service (AHS) was diverse, inconsistent and sometimes outdated. This was costly and harmful, leading to overuse of unhelpful care, underuse of effective care and errors in execution. The major aim was to improve the outcomes and quality of life for patients with wound care problems within our community. A collaborative across ten sites/services developed, implemented and evaluated policies and guidelines based on evidence-based bundles of care. Key barriers were local resistance and lack of experience in implementing structural and cultural changes. This was addressed by appointing a wound care programme manager, commissioning of a strategic oversight committee and local wound care committees. The techniques of spread and adoption were used, with early adopters making changes observable and allowing local adaption of guidelines, where appropriate. Deployment and improvement results varied across the sites, ranging from activity but no changes in practice to modest improvement in practice. Evaluating implementation of the leg ulcer guideline as an exemplar, it was demonstrated that there was a statistically significant improvement in overall compliance from 26% to 84%. However, only 7.7% of patients received all interventions to which they were entitled. Compliance with the eight individual interventions of the bundle ranged from 26% to 84%. Generic performance was evaluated against the wound assessment, treatment and evaluation plan with an average compliance of 70%. Early results identified that 20% of wounds were healed within the target of 10 days. As more standardised process are implemented, clinical outcomes should continue to improve and costs decrease. PMID- 21272246 TI - Review of Helicobacter pylori infection and chronic renal failure. AB - Chronic renal failure patients receiving hemodialysis and continuous ambulatory peritoneal dialysis often encounter gastrointestinal troubles over their long treatment period. Helicobacter pylori infection has close association with development of peptic ulcer, gastric cancer and gastric lymphoma, and is thought to be one of the major risk factors for gastrointestinal troubles in dialysis patients. However, it is unclear whether H. pylori infection is directly associated with progression of renal dysfunction and prognosis of chronic renal failure patients. Recent consensus shows that the prevalence of H. pylori infection in chronic renal failure patients is significantly lower than in subjects with normal renal function. In the natural history of H. pylori infection in hemodialysis patients, the prevalence of infection decreases as dialysis periods progressed, in particular within the first four years after the start of treatment. However, the chance of natural eradication becomes rare for patients receiving dialysis treatment for a long time. Moreover, chronic renal failure patients with H. pylori infection have a higher incidence of gastroduodenal diseases, and therefore, are recommended to receive eradication therapies, especially for those receiving treatment for a long time and with higher risks of complication. Intensive endoscopic check-ups for the prevention of gastrointestinal events and the discovery of peptic ulcer and neoplastic diseases at an early phase may be required. PMID- 21272247 TI - Therapeutic apheresis in the treatment of hemolytic uremic syndrome in view of pathophysiological aspects. AB - Hemolytic-uremic syndrome (HUS) is a disease that can lead to acute kidney injury and often to other serious sequelae, including death. The disease is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. In view of the different courses of HUS, a minimum of three different pathogenetic types leading to HUS can be subdivided as follows: HUS caused by infection, idiopathic HUS (non-Shiga toxin HUS), and HUS in systemic diseases and after toxin exposure. The etiology and pathogenesis of HUS are not completely understood and its therapy is complicated. After the introduction of therapeutic apheresis as a supportive therapy in HUS, several authors reported successful treatment in more than 87% of treated patients. The supportive therapy is indicated basically in severe courses of HUS and is superior to available therapy interventions. PMID- 21272248 TI - Lanthanum carbonate versus sevelamer hydrochloride: improvement of metabolic acidosis and hyperkalemia in hemodialysis patients. AB - Sevelamer hydrochloride (SH) has been reported to aggravate metabolic acidosis and hyperkalemia. This study was performed to evaluate acid-base status and serum potassium changes after replacing SH with lanthanum carbonate (LC) in hemodialysis patients. SH was prescribed for 24 weeks in 14 stable hemodialysis patients and replaced by LC in a similar treatment schedule. Laboratory tests, including indices of acid-base status, nutrition, bone/mineral metabolism, and dialysis adequacy, were performed monthly during the study. Dialysate bicarbonate, potassium and calcium concentrations remained constant. Serum bicarbonate and pH rose, and serum potassium dropped significantly under LC. Alkaline phosphatase also decreased significantly under LC. No significant differences were observed in the other studied parameters between the two treatment periods. Control of serum phosphate was similar under both phosphate binders and no differences were observed in calcium, Ca * P product, CRP, or lipid levels. Dialysis adequacy was constantly kept within K/DOQI target-range. Although full compliance to treatment was reported, three patients on LC complained of gastrointestinal upset and/or a metallic taste, and four had difficulty chewing the LC tablet. LC improves metabolic acidosis and hyperkalemia in hemodialysis patients previously under SH. Although both medications are well tolerated, the gastrointestinal side-effects appear to occur more frequently with LC; a fact that, together with difficulties in chewing the tablet, may result in decreased compliance. PMID- 21272249 TI - Pathological role of aminolevulinate in uremic patients. AB - Previous reports have demonstrated that delta-aminolevulinate (ALA) can promote iron release from horse spleen ferritin under conditions of high serum ALA levels in uremia; therefore, we speculated that the accumulated ALA in uremic patients would stimulate iron release from ferritin, resulting in accelerated oxidative stress and uremic complications. We measured the plasma ALA of uremic patients and examined the ALA-induced iron release from human ferritin. The participants consisted of 30 hemodialysis patients and 14 healthy subjects. Plasma malondialdehyde was measured as a surrogate marker of lipid peroxidation. The plasma exchange effluent from two patients who had undergone plasma exchange (for the treatment of systemic lupus erythematosus and acute myeloblastic leukemia) was collected and treated to obtain the human ferritin-rich fraction. Iron release from ferritin was examined using bathophenanthroline sulfate. The influence of antioxidants and different pH levels on iron release were investigated. Plasma ALA and malondialdehyde concentration in the hemodialysis patient was significantly higher than that in healthy subjects. ALA was positively correlated with malondialdehyde. The abundance of iron release was dependent on the ALA concentration and incubation time. Iron release at the high pH of 7.6 was decreased compared with that at pH 7.4. Citrate increased iron release at pH 7.4, but citrate-stimulated iron release was totally abolished at pH 7.6. Our study suggests that ALA accumulation may have a role to play in certain complications in uremic patients, such as oxidative stress, by releasing iron from ferritin. PMID- 21272250 TI - Association between platelet-related hemostasis impairment and functional iron deficiency in hemodialysis patients. AB - Hemostasis impairment and iron deficiency are relatively frequent in hemodialysis patients. Both conditions may contribute to anemia. The aim of our study was to explore possible associations between hemostasis impairment and iron deficiency by employing recently introduced methods for measurement of both conditions. Sixty-three hemodialysis patients were studied, with 30 age-matched, healthy controls. Hemostasis impairment was detected by in vitro closure time tests (collagen/epinephrine cartridge: CEPI; collagen/adenosine diphosphate (ADP) cartridge: CADP), whereas (functional) iron deficiency was measured by reticulocyte hemoglobin content (CHr) and the percentage of hypochromic red cells (HRC). We found that the patient group (N=14) with functional iron deficiency (CHr<29) had significantly delayed in vitro closure times in comparison to the patients (N=49) without functional iron deficiency. Furthermore, both types of closure time (CEPI and CADP) correlate highly significantly with CHr (P=0.002, and P=0.001). Such an association was not observed between in vitro closure time and HRC. We found a significant correlation between hemostasis impairment (measured by in vitro closure time) and iron deficiency (measured by CHr) in hemodialysis patients. This correlation has not previously been reported. It seems that in hemodialysis patients the hemostasis impairment affects (functional) iron deficiency, most likely by facilitating excessive blood loss and consequent iron deficiency. Thus, it appears that a delayed in vitro closure time along with decreased CHr may identify hemodialysis patients who suffer (occult) blood loss and/or excessive blood loss during hemodialysis procedure. The clinical value of this finding should be tested in larger studies. PMID- 21272251 TI - Role of thrombophilia in vascular access thrombosis among chronic hemodialysis patients in Tunisia. AB - Vascular access thrombosis represents a serious and common problem in hemodialysis patients. Therefore, identification of relevant thrombotic risk factors could lead to an improved antithrombotic therapy. This case control study was performed to evaluate the relationship between some thrombophilias and vascular access thrombosis in hemodialysis patients. Seventy-eight patients undergoing dialysis (between May 2007 and September 2009) were selected as subjects. This sample was divided into two groups; a case group of 28 patients who had sustained one or more thrombotic events that resulted in vascular access failure and a control group of 50 patients, who had never had a thrombotic occlusion of a functioning permanent dialysis access. Antithrombin, protein C and protein S levels were measured. Also, both groups were tested for the factor V Leiden mutation, the prothrombin G20210A mutation, the methylene tetrahydrofolate reductase C677T and A1298C mutations. Among genetic mutations of factor V Leiden, prothrombin G20210A and methylene tetrahydrofolate reductase genes, the C677T methylene tetrahydrofolate reductase mutation was the only significant genetic cause of vascular access thrombosis (P=0.005). Our data demonstrated a significantly increased risk of vascular access thrombosis in carriers of the C677T methylene tetrahydrofolate reductase mutation. PMID- 21272252 TI - Coronary plaque morphology using virtual histology-intravascular ultrasound analysis in hemodialysis patients. AB - Most dialysis patients have coronary artery disease at the initiation of dialysis therapy and these patients also have marked vascular calcification. Virtual histology-intravascular ultrasound (VH-IVUS) provides coronary tissue maps that are color coded by four major plaque components and facilitate the characterization of coronary plaque composition in vivo. The aim of this study was to identify coronary plaque characteristics in dialysis patients using VH IVUS. Twenty-three patients with coronary artery disease were included in this study. Of these, 12 patients had normal renal function or mild renal insufficiency (control group) and 11 patients were receiving maintenance dialysis therapy (hemodialysis group). We performed coronary angiography and VH-IVUS analysis on culprit lesions of all patients in the study. The result of VH-IVUS analysis showed that the hemodialysis group had a greater plaque volume, lower percentage of fibrous plaque, and higher percentage of dense calcium plaque compared with the control group. In addition, the serum phosphate levels were significantly associated with the percentage of necrotic core and dense calcium plaque in all study patients. Our findings suggest that the amount of necrotic core and dense calcium plaques increase significantly in hemodialysis patients, and that disordered mineral metabolism may be associated with coronary plaque morphology. PMID- 21272253 TI - Evidence for severe atherosclerotic changes in chronic hemodialysis patients: comparative autopsy study against cardiovascular disease patients without chronic kidney disease. AB - Atherosclerosis is a major cause of mortality and morbidity among hemodialysis patients, but whether it is more severe in hemodialysis patients than in cardiovascular disease patients without chronic kidney disease is unclear. We examined 46 autopsy patients who had undergone hemodialysis, and age and sex matched 46 patients with cardiovascular disease and an eGFR of >60 mL/min/1.73 m(2). There was no difference in the prevalence of diabetes or hypertension between the groups. We divided the aorta into four segments: A, ascending artery to arch; B, descending artery to diaphragm; C, suprarenal; and D, infrarenal. We used the classification of the American Heart Association to evaluate atherosclerosis progression. Distribution was scored by the extent to which each segment was damaged: 0, none; 1, less than 1/3; 2, more than 1/3 to less than 2/3; 3, more than 2/3. Histological examination revealed that the progression score (P < 0.05) and distribution score (P<0.005) were more severe in the hemodialysis group, especially in segment A. Regression analysis showed that atherosclerosis of segment A was related to age, gender, dyslipidemia, smoking, hemodialysis therapy, and hemodialysis duration. In hemodialysis patients, atherosclerotic changes in the aorta were more severe than in cardiovascular disease patients with an eGFR of >60 mL/min/1.73 m(2). Aortic atherosclerosis was aggravated by traditional and chronic kidney disease-related risk factors. PMID- 21272254 TI - Nutritional status evaluated by multi-frequency bioimpedance is not associated with quality of life or depressive symptoms in hemodialysis patients. AB - Hemodialysis therapy significantly impacts on patients' physical, psychological, and social performances. Such reduced quality of life depends on several factors, such as malnutrition, depression, and metabolic derangements. This study aims to evaluate the current nutritional status, quality of life and depressive symptoms, and determine the possible relationships with other risk factors for poor outcomes, in stable hemodialysis patients. This was a single-center, cross sectional study that enrolled 59 adult patients undergoing hemodialysis. Laboratory tests that included high-sensitivity c-reactive protein (CRP), and quality of life and depressive symptom evaluation, as well as malnutrition inflammation score, nutritional status and body composition (by direct segmental multi-frequency bioimpedance analysis) determinations were performed. Patients were classified as "underfat", "standard", "overfat", or "obese" by multi frequency bioimpedance analysis. Seven patients were underfat, 19 standard, 19 overfat, and 14 obese. Triglyceride levels significantly differed between the underfat, standard, overfat, and obese groups (1.06 [0.98-1.98]; 1.47 [1.16 1.67]; 2.53 [1.17-3.13]; 2.12 [1.41-2.95] mmol/L, respectively; P=0.026), as did Kt/V between the underfat, overfat, and obese groups (1.49 +/- 0.14; 1.23 +/- 0.19; 1.19 +/- 0.22; P=0.015 and P=0.006, respectively). Depressive symptoms, quality of life, and CRP and phosphate levels did not diverge among nutritional groups. Creatinine, albumin, and phosphate strongly correlated, as well as percent body fat, body mass index, and waist circumference (r=0.859 [P<0.001], and r=0.716 [P<0.001], respectively). Depressive symptoms and physical and psychological quality-of-life domains also strongly correlated (r(s) = -0.501 [P<0.001], r(s) = -0.597 [P<0.001], respectively). The majority of patients were overfat or obese and very few underfat. Inflammation was prevalent, overall. No association of nutritional status with malnutrition-inflammation, quality of life, or depressive symptoms could be established. PMID- 21272255 TI - Evaluation of dialyzer jacket structure and hollow-fiber dialysis membranes to achieve high dialysis performance. AB - The objective of this study was to determine the optimum dialyzer jacket structure and hollow-fiber dialysis membrane, both of which are indispensable factors for achieving high dialysis performance, by clarifying the relationship between the dialysis performance and the flow of dialysate and blood in a hollow fiber dialyzer. We evaluated the clearance, dialysate, and blood flow for four commercially available hollow-fiber dialyzers, namely, the APS-15S, APS-15SA, TS 1.6UL, and CX-1.6U. To evaluate dialysate and blood flow, we measured the residence-time distribution of dialysate and blood flow of these dialyzers by the pulse-response method. We also determined the clearances of urea, creatinine, vitamin B(12), and lysozyme to evaluate the dialysis performance of these dialyzers. While the baffle and taper structures allow effective supply of dialysate into the dialyzer jacket, the hollow-fiber shape, inner diameter, and packing density significantly influence the dialysate flow. In dialyzers with long taper-holding slits, the slit area is a key design parameter for achieving optimum dialysate flow. Similarly, the blood flow is significantly influenced by the structure of the inflowing and outflowing blood ports at the header of a dialyzer, and the shape and inner diameter of the hollow fibers. Hollow fibers with smaller inner diameters cause an increase in blood pressure, which causes blood to enter the hollow fibers more easily. The hollow-fiber shape hardly affects the blood flow. While improved dialysate and blood flow cause higher clearance of low molecular-weight substances, higher membrane area and pure-water permeability accelerate internal filtration, thereby causing an increase in the clearance of large molecular-weight substances. PMID- 21272256 TI - Stability of continuous renal replacement therapy solutions after phosphate addition: an experimental study. AB - The incidence of hypophosphatemia is high in critically ill children on continuous renal replacement therapy (CRRT) and the addition of phosphate supplements to the replacement and dialysis fluids reduces the frequency of hypophosphatemia. The objective of this study was to determine the in vitro stability of the CRRT solutions after phosphate addition. Three different concentrations of phosphate, 2.5, 4.6 and 7.7 mg/dL, in the replacement and dialysis fluids were analyzed. The pH, glucose, total calcium, phosphate, and magnesium were determined before adding the phosphate and at 2, 24, and 48 h after its addition. The bags were macroscopically observed for possible precipitation. After addition of the phosphate, its concentration remained stable and there were no significant changes in the concentrations of the other components. There were no visible signs of precipitation up to 48 h. The addition of phosphate to the CRRT fluids at concentrations of up to 7.7 mg/dL does not cause problems with precipitation or instability of the mixture. PMID- 21272257 TI - Cardiothoracic ratio association with mortality in patients on maintenance peritoneal dialysis. AB - The cardiothoracic ratio (CTR) indicates the left ventricular size; however, the significance of the CTR in patients on maintenance peritoneal dialysis (PD) remains unclear. In this study, 335 PD patients were enrolled and demographic, biochemical, co-morbidity, and dialysis-related data were obtained. The factors determining CTR were further analyzed. All patients were followed up for two years to investigate the mortality risks. We defined a normal CTR as less than the mean CTR value, mild cardiomegaly as a CTR between the mean and mean + 1 SD, and moderate-to-severe cardiomegaly as more than the mean CTR + 1 SD. Among the 335 patients, 163 patients were classified as having a normal CTR (<49.2%), 112 patients as having mild cardiomegaly (CTR 49.2-55.7%), and 60 patients as having moderate-to-severe cardiomegaly (CTR > 55.7%). chi(2) -analysis showed that the incidences of malnutrition and anemia were significantly higher in patients with severe cardiomegaly than in patients of the other groups. The CTR was positively correlated with age, but negatively correlated with albumin and hemoglobin levels. Twenty-six patients (7.7%) had died by the end of the study. Cox multivariate analysis revealed that the CTR significantly predicts all-cause two year mortality in PD patients on maintenance PD; therefore, the CTR correlates with the nutritional and anemic status of PD patients and is a reliable predictor for all-cause two-year mortality. The analytical results of this study support continued efforts to reduce the CTR and treat underlying causes in patients with cardiomegaly. PMID- 21272258 TI - Comparison of the acute rejection incidence rate in spousal donor transplantation before and after anti-CD20 antibody (rituximab) protocol as desensitization therapy. AB - Recipients of spousal donor transplantation (SDT) have poorer histocompatibility and higher human leukocyte antigen (HLA) sensitization due to pregnancy than those receiving related donor transplantation (RDT). Thus, SDT carries a higher risk of acute rejection (AR). In our department, patients at a high immunological risk, such as those with ABO incompatibility and HLA sensitization, were considered for desensitization by double filtration plasmapheresis and preoperative administration of rituximab. In this study we compared the AR incidence rates between SDT and RDT according to their immunological risk. We performed RDT in 279 and SDT in 100 patients, a total of 379 cases, between 2000 and 2008; 48.7% of RDT and 67.0% of SDT cases were considered to be at a high immunological risk and underwent preoperative desensitization (P=0.002). Even though the AR incident rate of SDT was higher than RDT in the low immunological risk group, in which the patients had undergone transplantation without desensitization (RDT 24.4%, SDT 37.0%, P=0.012), there was no significant difference between the two donor type groups in the high immunological risk group, in which transplantation with desensitization occurred (RDT 21.3%, SDT 31.3%, P>0.05). Preoperative administration of rituximab significantly reduced AR from 37.4% to 10.6% (P<0.001), especially T-cell mediated rejection (36.4% to 20.2%, P=0.01). SDT no longer carries a high risk when appropriate desensitization, including the use of rituximab, is performed. Overall, the five year graft survival rates were similar between RDT and SDT. PMID- 21272259 TI - Efficacy of cytokine removal by plasmadiafiltration using a selective plasma separator: in vitro sepsis model. AB - More effective removal of pro- and anti-inflammatory cytokines may play an important role in the treatment of sepsis. Plasmadiafiltration (PDF) with a larger selective plasma separator was performed to study the cytokine and plasma protein permeability profiles of the membrane in an in vitro sepsis model. The in vitro sepsis model was constructed by exposure of human whole blood to bacterial lipopolysaccharide. EVACURE 2A, a selective plasma separator, was placed in the blood circuit of PDF. Sieving coefficients of cytokines and plasma protein were tested in post-dilution PDF mode at the following operating parameters: blood flow rate 150 mL/min; dialysate flow rate 33.33 mL/min; replacing fluid flow rate 6.67 mL/min; ultrafiltration rate 5 mL/min. An enzyme linked immunoadsorbent assay was used to measure the concentrations of tumor necrosis factor-alpha (TNF alpha), high-mobility group box 1 protein (HMGB1), interleukin-1beta (IL-1beta), interleukin-1 receptor antagonist (IL-1ra), interleukin-2 (IL-2), interleukin-2 receptor (IL-2r), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL 10) in plasma and ultrafiltrate. Sieving coefficients of different solutes ranged from 0.1 to 1.0 at first, decreased 10%-60% after 1 h of PDF, and then remained stable. Total clearance rates of cytokines ranged from 15 to 80 mL/min. The concentrations of cytokines decreased 20-80% after 1 hour of PDF. The sieving coefficient of albumin was 0.1 at first and then decreased to 0.05 after 1 hour of therapy. Plasmadiafiltration with Evacure 2A plasma separator can effectively remove almost all of the inflammatory mediators with low albumin loss. PMID- 21272260 TI - Impact of lipid apheresis on Egr-1, c-Jun, c-Fos, and Hsp70 gene expression in white blood cells. AB - Lipid apheresis treatment has been suggested to cause oxidative stress. Cells respond to oxidative stress in many ways, including, among others, altered gene expressions. In the present investigation we investigated whether the gene expression of known stress genes was affected in the WBCs of patients undergoing lipid apheresis. For this purpose cellular early-growth-response gene-1 (Egr-1), c-Jun, c-Fos, and heat shock protein 70 (Hsp70) mRNA expression was followed before and immediately after lipid apheresis treatments (N=24). Gene expression was determined by quantitative reverse transcription-polymerase chain reaction. With the exception of c-Fos, the expression of Egr-1, c-Jun, and Hsp70 mRNA was not affected in WBCs by a single lipid apheresis treatment (median [16th percentile; 84 th percentile]): Egr-1, before 0.30 (0.13; 0.53), after 0.31 (0.14; 1.33); c-Jun, before 0.03 (0.03; 0.16), after 0.05 (0.03; 0.18); Hsp70, before 0.49 (0.23; 1.07), after 0.53 (0.20; 1.61)). Expression of c-Fos was significantly decreased (P<0.01) after lipid apheresis treatment (before 2.18 [1.06; 5.27], after 1.65 [0.74; 4.12]). Hsp70 and c-Fos expression in lipid apheresis patients was not different from that in 35 healthy blood donors, whereas Egr-1 and c-Jun were significantly decreased (P<0.05) in lipid apheresis patients when compared to controls (Egr-1 0.96 [0.42; 1.83], c-Jun 0.64 [0.40; 0.98], c-Fos 2.77 [1.32; 4,02], Hsp70 0.43 [0.28; 0.61]). These results show that lipid apheresis procedures do not induce stress gene expression in WBCs. Therefore, all the lipid apheresis systems used seem to be safe with respect to oxidative stress and other injuries induced in WBCs due to contact with extracorporeal tubing and membranes. PMID- 21272261 TI - Mycotic abdominal aortic aneurysm in a dialysis patient with catheter-related methicillin-resistant Staphylococcus aureus bacteremia. PMID- 21272262 TI - Occult disseminated malignancy presenting as microangiopathic hemolytic anemia. PMID- 21272263 TI - Peritoneal dialysis-related peritonitis caused by vancomycin-resistant Enterococcus faecium. PMID- 21272265 TI - The use of monoamine pharmacological agents in the treatment of sexual dysfunction: evidence in the literature. AB - INTRODUCTION: The monoamine neurotransmitters serotonin, dopamine, and norepinephrine play an important role in many medical and psychological conditions, including sexual responsiveness and behavior. Pharmacological agents that modulate monoamines may help alleviate sexual dysfunction. AIMS: To provide an overview of pharmacological agents that modulate monoamines and their use in the treatment of sexual dysfunction. METHODS: EMBASE and PubMed search for articles published between 1950 and 2010 using key words "sexual dysfunction,""monoamines,""monoaminergic receptors," and "generic names for pharmacological agents." MAIN OUTCOME MEASURES: To assess the literature evaluating the efficacy of monoamine pharmacologic agents used in the treatment of sexual dysfunction. RESULTS: The literature primarily cites the use of monoaminergic agents to treat sexual side effects from serotonergic reuptake inhibitors (SSRIs), with bupropion, buspirone and ropinirole providing the most convincing evidence. Controlled trials have shown that bupropion improves overall sexual dysfunction, but not frequency of sexual activity in depressed and nondepressed patients. Nefazodone and apomorphine have been used to treat sexual dysfunction, but their use is limited by significant side effect and safety profiles. New research on pharmacologic agents with subtype selectivity at dopaminergic and serotonergic receptors and those that possess dual mechanisms of action are being investigated. CONCLUSION: There has been tremendous progress over the past 50 years in understanding the role of monoamines in sexual function and the effect of pharmacologic agents which stimulate or antagonize monoaminergic receptors on sexual dysfunction. Nevertheless, large, double-blind, placebo-controlled studies evaluating the efficacy of currently available agents in populations without comorbid disorders are limited, preventing adequate interpretation of data. Continued research on sexual function and specific receptor subtypes will result in the development of more selective pharmacologic agents with the goal of increasing efficacy without the dose-limiting side effects of nonselective agents. PMID- 21272266 TI - The neurovascular unit in brain function and disease. AB - Neurovascular coupling, or functional hyperaemia, refers to complex mechanisms of communication between neurons, astrocytes and cerebral vessels which form the neurovascular unit that spatially and temporally adjusts blood supply to the needs in energy and oxygen of activated neurons. Neurovascular coupling is so precise that it underlies neuroimaging techniques to map changes in neuronal activity. Therefore, understanding its basis is indispensable for the proper interpretation of imaging signals from functional magnetic resonance imaging and positron emission tomography, routinely used in humans. Although neurovascular coupling mechanisms are not yet fully understood, considerable progress has been made over the last decade. In this review, we present recent knowledge from in vivo studies on the cortical cellular network involved in neurovascular coupling responses and the mediators implicated in these haemodynamic changes. Recent findings have emphasized the intricate interplay between both excitatory and inhibitory neurons in neurovascular coupling, together with an intermediary role of astrocytes, which are ideally positioned between neurons and microvessels. Finally, we describe latest findings on the alterations of neurovascular function encountered in neurodegenerative conditions such as Alzheimer's disease. PMID- 21272267 TI - Cisplatin decreases renal cyclooxygenase-2 expression and activity in rats. AB - AIM: Cisplatin (CP) induced acute renal failure (ARF) has previously been associated with decreased urinary prostaglandin E2 (PGE2) excretion and reduced aquaporin 2 (AQP2) expression in kidney collecting duct. In this study we examined the expression of cyclooxygenase (COX)-1 and -2 as well as AQP2 and the Na-K-2Cl cotransporter in kidneys from rats with CP induced ARF. METHODS: Rats were treated with either CP or saline and followed for 5 days. Kidneys were dissected into three zones and prepared for immunoblotting, quantitative polymerase chain reaction (QPCR) and immunohistochemistry. Renal content and urinary PGE2 excretion was measured. RESULTS: Cisplatin treatment was associated with polyuria and a significant decreased creatinine clearance. Inner medullary PGE2 content and urinary PGE2 excretion was decreased in CP-treated rats. QPCR and semiquatitative immunoblotting demonstrated that CP treatment reduced COX-2, AQP2 and Na-K-2Cl cotransporter abundance in the different kidney zones, whereas no change in COX-1 was observed. Results were confirmed by immunohistochemistry. CONCLUSION: Cyclooxygenase-2 expression is decreased in inner medulla and cortex. Consistent with this urinary PGE2 levels were reduced. These data suggest that downregulation of COX-2 is responsible for impaired de novo generation of vasodilatory prostaglandins which may play an important role for the CP induced renal vasoconstriction and development of nephropathy. PMID- 21272268 TI - Various patterns of IgH deletion identified by FISH using combined IgH and IgH/CCND1 probes in multiple myeloma and chronic lymphocytic leukemia. AB - INTRODUCTION: Interphase fluorescence in situ hybridization (FISH) can identify submicroscopic deletions adjacent to the breakpoints of rearrangements undetected by conventional cytogenetics. In this study, the characteristics and frequency of the IgH deletion identified by interphase FISH were investigated in patients with multiple myeloma (MM) and chronic lymphocytic leukemia (CLL). METHODS: The study group included 29 patients with MM and eight patients with CLL. Interphase FISH was performed with the IgH dual color, break-apart rearrangement probe and the IgH/CCND1 dual color, dual fusion translocation probe. RESULTS: The IgH deletion was found in 14% (4/29) of patients with MM and 13% (1/8) of the patients with CLL. Four patients had deletions of the whole or variable region of IgH on the native chromosome 14, whereas one patient had a deletion of the IgH variable region on a der(11)t(11;14). In two patients, the IgH break-apart FISH showed both patterns with and without IgH deletions. In cases showing the same pattern by IgH break-apart FISH, the IgH/CCND1 FISH showed different patterns, and vice versa. CONCLUSION: A variety of patterns of the IgH deletion were identified by interphase FISH using IgH break-apart and IgH/CCND1 probes in patients with MM and CLL. The results of this study suggest that the integrated information obtained with IgH break-apart and IgH/CCND1 FISH was needed to interpret FISH results unambiguously. PMID- 21272270 TI - Neurobiology and phenotypic expression in early onset schizophrenia. AB - AIM: Early-onset schizophrenia (onset before adulthood) is a rare and severe form of the disorder that shows phenotypic and neurobiological continuity with adult onset schizophrenia. Here, we provide a synthesis of keynote findings in this enriched population to understand better the neurobiology and pathophysiology of early-onset schizophrenia. METHODS: A synthetic and integrative approach is applied to review studies stemming from epidemiology, phenomenology, cognition, genetics and neuroimaging data. We provide conclusions and future directions of research on early-onset schizophrenia. RESULTS: Childhood and adolescent-onset schizophrenia is associated with severe clinical course, greater rates of premorbid abnormalities, poor psychosocial functioning and increased severity of brain abnormalities. Early-onset cases show similar neurobiological correlates and phenotypic deficits to adult-onset schizophrenia, but show worse long-term psychopathological outcome. Emerging technological advances have provided important insights into the genomic architecture of early-onset schizophrenia, suggesting that some genetic variations may occur more frequently and at a higher rate in young-onset than adult-onset cases. CONCLUSIONS: Clinical, cognitive, genetic and imaging data suggest increased severity in early-onset schizophrenia. Studying younger-onset cases can provide useful insights into the neurobiological mechanisms of schizophrenia and the complexity of gene-environment interactions leading to the emergence of this debilitating disorder. PMID- 21272271 TI - Criminal offending and distinguishing features of offenders among persons experiencing a first episode of psychosis. AB - AIMS: Persons with severe mental illness (SMI) are at increased risk of criminal offending, particularly violent offending, as compared with the general population. Most offenders with SMI acquire convictions prior to contact with mental health services. This study examined offending among 301 individuals experiencing their first episode of psychosis. METHODS: Patients provided information on sociodemographic and clinical variables and completed a neurological soft sign examination and neuropsychological tests. Additional information was extracted from clinical files and official criminal records. RESULTS: The results show that 33.9% of the men and 10.0% of the women had a record of criminal convictions, and 19.9% of the men and 4.6% of the women had been convicted of at least one violent crime. Proportionately more male and female patients than men and women in the general UK population had prior convictions for violent crimes. In a multivariate model including background and clinical variables, only one variable distinguished the male offenders. African Caribbean ethnicity was associated with a threefold increase in the odds of offending (odds ratio=3.84, 95% confidence interval 1.03-14.37). Offenders, as compared with non-offenders, obtained significantly lower premorbid and current intelligence quotient scores and similar scores on tests of neurological soft signs, working memory and executive functions. CONCLUSIONS: At contact with mental health services for a first episode of psychosis, significant numbers of patients have records of criminal convictions and thereby a high risk for future violent behaviour. These patients require specific interventions, in addition to medication, to reduce offending and aggressive behaviour. PMID- 21272272 TI - Early detection and intervention evaluation for people at high-risk of psychosis 2 (EDIE-2): trial rationale, design and baseline characteristics. AB - AIMS: Much research has begun to focus on the identification of people who are at high risk of developing psychosis, and clinical services have been initiated for this population. However, only a small number of studies have reported on the efficacy of interventions for preventing or delaying the onset of psychosis. The results of prior work suggest that cognitive therapy (CT) may be an effective, well-tolerated treatment. We report on the rationale and design for a large scale, multi-site randomized, controlled trial of CT for people who are assessed to be at high risk of psychosis because of either state or state-plus-trait risk factors. METHODS: The study employs a single-blind design in which all participants receive frequent mental-state monitoring, which will efficiently detect transition to psychosis, and half are randomized to weekly sessions of CT for up to 6 months. Participants will be followed-up for a minimum of 12 months and to a maximum of 2 years. RESULTS: We report the characteristics of the final sample at baseline (n=288). CONCLUSIONS: Our study aimed to expand the currently limited evidence base for best practice in interventions for individuals at high risk of psychosis. PMID- 21272273 TI - Personality traits in early psychosis: relationship with symptom and coping treatment outcomes. AB - AIMS: This study aimed to determine personality profiles of individuals with early psychosis based on the Five Factor Model of personality and assess the predictive value of personality traits or profiles on therapeutic outcomes of two group treatments for recent onset psychosis: cognitive behaviour therapy or skills training for symptom management. METHODS: One hundred and twenty-nine individuals with early psychosis were recruited to participate in a randomized controlled trial. The participants were randomized to one of two group treatments or to a wait-list control group. Measures included a personality inventory (NEO Five Factor Inventory) and outcome measures of symptomatology (Brief Psychiatric Rating Scale-Expanded) and coping strategies (Cybernetic Coping Scale). RESULTS: Cluster analyses revealed three different personality profiles (based on the Five Factor Model) - none specifically linked to psychotic symptoms. No links were revealed between personality traits and symptom change scores. Personality traits were linked to therapeutic improvements in active coping strategies, with extraversion accounting for 17% of the variance. Neuroticism was linked to increased use of passive coping strategies. Active coping strategies were also predicted by profile 1 (holding the highest openness score) with 26% of the variance explained and by profile 3 (the highest extraversion score), with 14% of the variance explained. CONCLUSIONS: Individuals with early psychosis can present with distinct personality profiles as would be expected in a non-clinical population. Personality traits do not appear to influence symptomatic treatment outcomes but are linked to behavioural changes, such as the use of coping strategies. PMID- 21272274 TI - Gender differences in perceptions of the severity and prevalence of eating disorders. AB - AIM: Gender differences in perceptions of the severity and prevalence of anorexia nervosa (AN) and bulimia nervosa (BN) were examined in young men (n=113) and women (n=289) recruited from a regional university campus in north-east Australia. METHODS: Participants viewed vignettes of fictional (female) sufferers of AN and BN and responded to the same series of questions in relation to each vignette. RESULTS: For both vignettes, a substantial minority of male, but not female, participants indicated that they would be a little or not at all sympathetic to someone with the problem described, that the problem described would be a little or not at all difficult to treat, and that having the problem described would be moderately or a little distressing. Men were also more likely than women to consider BN to be primarily a problem of 'lack of will-power/self control'. Perceptions of the prevalence of AN (modal response = 'very few women/10% or less') and BN ('10% to 30%') did not differ by gender and both male and female participants considered AN to be more severe and less common than BN. CONCLUSIONS: The findings suggest that there may be a need to target the attitudes and beliefs of young men in particular in the prevention and early intervention initiatives for eating disorders. PMID- 21272275 TI - 'Jumping to conclusions' in first-episode psychosis. AB - AIM: People with psychotic symptoms are reported to have a characteristic reasoning style in which they jump to conclusions (JTC). The aims of this research were threefold. The first was to establish how prevalent this style is in people with first-episode psychosis. The second was to examine the specificity of JTC to delusions. The third was to examine explanatory factors that may account for the JTC style. This was investigated by attempting to replicate, with a large sample, previous studies indicating that JTC is associated with specific psychotic and non-psychotic symptoms and processes. METHODS: Seventy-seven service users were recruited from a first-episode service and completed measures of reasoning and psychotic and non-psychotic symptomatologies. A well-established criterion was used to compare the JTC performance of those people with and without JTC. RESULTS: JTC was present in over 40% of the sample, which is consistent with previous studies of people with long-standing psychotic symptoms. Unlike previous research, no strong associations were found in relation to symptoms and other processes. CONCLUSIONS: JTC is a phenomenon common in many people in first-episode services. In this large cohort sample, no clear associations with symptoms or other psychological processes were evident. Hence, the reason people JTC is still unclear. PMID- 21272276 TI - Carer's education groups for relatives with a first episode of psychosis: an evaluation of an eight-week education group. AB - AIM: This study aimed to evaluate an eight-week carers group for people with first episode of psychosis receiving services from the Gloucestershire Recovery in Psychosis Early Intervention Team. Potential benefits for carers were assessed including changes in feelings of stress, isolation, recognition, and of being appreciated and valued. METHODS: Following completion of the group, all 12 carers participated in an independently facilitated focus group to evaluate the course. Transcripts were imported into the QSR NVivo 8 (QSR International, Doncaster, Victoria, Australia) software package for thematic analysis. An independent coding and correlational analysis of data was used to identify any common themes. RESULTS: Results identified five key themes reported by carers: the emotional impacts of being a carer (loss, grief, guilt, shock, acceptance), the wider impacts of mental illness within a family (isolation, stigma), the caring role and how this affected relationships (improved relationships), the design of the group (barriers, course content, timing of invitations, moving forward) and the wider impacts of participation (carer education, importance of sharing real-life experiences, navigating the National Health Service). CONCLUSIONS: Carers reported less isolation, improved confidence, greater understanding of psychosis, reduction in guilt and increased coping in their caring role after the group. Carers reported that they gained new knowledge, obtained support from staff and graduate carers, increased the recognition of their caring role and had improved relationships with their relative with mental illness. PMID- 21272277 TI - Matryoshka Project: lessons learned about early intervention in psychosis programme development. AB - AIM: This part of the Matryoshka project sought to understand the processes with which early intervention in psychosis (EIP) programmes were implemented and developed. The goals were to understand the key influences of programme implementation in the context of rapid EIP service growth and lack of specific provincial guidelines. METHODS: Sampling was purposive and data were collected with semi-structured interviews. Five Matryoshka Project programmes were successfully contacted. All interviews were conducted by phone, recorded and transcribed verbatim. Emerging themes were analysed iteratively and discussed among authors. Key themes were validated with participants. RESULTS: The new EIP services were significantly influenced by the provincial EIP network, advocacy groups and clinical mentors. EIP programme decision makers often relied on each other for guidance. Although the research evidence assisted programme decision makers to develop an effective EIP model for their region, implementation was often shaped by funding constraints. Programmes adapted their EIP models according to funding and local service characteristics. The lack of specific guidelines may have allowed innovation; programme creativity and diversity is consistent with EIP values. Despite the challenges related to geography and staffing, programmes experienced important successes such as partnerships across sectors, quality clinical service and the ability to engage hard-to-serve clientele. CONCLUSIONS: Although important, research evidence played only a secondary role. Relationships among providers and services, coupled with the dedication of front-line staff, were more critical to knowledge exchange than written documents alone. These findings stress the importance of researcher-front line relationships to the adoption of evidence-informed practice. PMID- 21272278 TI - First-episode psychosis patients recruited into treatment via early detection teams versus ordinary pathways: course and health service use during 5 years. AB - AIM: To compare the 5-year course and outcome of first-episode psychosis (FEP) patients recruited via active outreach detection teams (DTs) versus ordinary referral channels (not-DT). METHODS: Longitudinal comparison of two parallel consecutive samples on the Positive and Negative Syndrome Scale Score and the Global Assessment of Functioning Scale. Altogether, 203 FEP patients were identified, of whom 42 refused to participate. Included were 161 patients: 56 DT and 105 not-DT. RESULTS: After 2 years, the DT group developed more cases of schizophrenia with poorer prognostic features. However, the two groups did not differ significantly on outcome measures. More DT patients were treated as outpatients only and had fewer admissions and shorter total time as inpatients during the observation period. CONCLUSIONS: We have previously shown that detection teams recruited more chronic patients with poorer prognostic features, but fewer symptoms and better functioning at baseline. After 2 years, the DT patients functioned as well as the not-DT patients. At 5 years, both groups have stabilized to the same plateau of low symptom severity. PMID- 21272279 TI - Self-reported coping strategies in families of patients in early stages of psychotic disorder: an exploratory study. AB - AIM: Coping by families of patients with schizophrenia include 'approach' strategies considered to be adaptive (e.g. reinterpretation) and potentially maladaptive 'avoidant' strategies (denial/disengagement, use of alcohol and drugs). Little is known about coping strategies used by families of individuals with incipient or emergent psychosis. METHODS: Self-reported coping styles were assessed in family members of 11 ultra high risk and 12 recent-onset psychosis patients, using a modified version of Carver's Coping Orientations to Problems Experienced questionnaire. RESULTS: Families reported moderate use of 'approach' coping (e.g. planning, seeking social support, positive reinterpretation, acceptance and turning to religion) and rare use of 'avoidant' coping strategies (denial/disengagement and use of alcohol and drugs). CONCLUSIONS: The greater endorsement of 'approach' coping by these families is consistent with findings for families of first episode psychosis patients, and it is in contrast to more prevalent 'avoidant' coping by families of patients with more chronic psychotic illness. Early intervention could plausibly help families maintain the use of potentially more adaptive 'approach' coping strategies over time. PMID- 21272280 TI - MAKINGtheLINK: a school-based health promotion programme to increase help-seeking for cannabis and mental health issues among adolescents. AB - AIM: There is increasing concern regarding the use of cannabis among adolescents, especially given recent evidence highlighting its link with later mental disorders. Encouraging young people with mental health or drug issues to seek professional help is an important early intervention strategy; however, adolescents are typically reluctant to do so and instead turn to their peers for help. Peers may not have the skills or knowledge required to assist their friends to access professional help. This paper describes the development and evaluation of MAKINGtheLINK, a school-based health promotion programme that promotes help seeking behaviour for mental health and cannabis use issues among young people. METHODS: The MAKINGtheLINK programme was piloted with 182 Year 10 students at a secondary school in Melbourne, Australia. Forty teachers received the MAKINGtheLINK staff professional development session. RESULTS: The delivery of the MAKINGtheLINK programme was found to be both acceptable and feasible within a school setting. Students and teachers described it as a fun, engaging, helpful and important programme. Students reported increased confidence and awareness of how to seek help for themselves or a friend, and teachers indicated increased confidence and awareness of how to assist students to seek help for cannabis use and/or mental health problems. CONCLUSIONS: MAKINGtheLINK was successfully implemented within the school curriculum. We believe this is the first school based programme that specifically focuses on facilitating professional help seeking for cannabis use and mental health problems among young people, and demonstrates that utilizing peer models for help-seeking is a valuable resource for early intervention initiatives. PMID- 21272281 TI - Analysis of LOXL1 single nucleotide polymorphisms in Polish population with pseudoexfoliation syndrome. AB - PURPOSE: To assess the possible association of lysyl oxidase-like 1 (LOXL1) gene variants with pseudoexfoliation syndrome (PEX) in Polish population. METHODS: The group studied comprised of 36 patients with PEX (men and women) who presented to Department of Ophthalmology Collegium Medicum UMK in Bydgoszcz, Poland, and 30 control subjects. Blood samples were obtained from each patient via peripheral venipuncture, and genomic DNA was isolated according to the standard procedures. Three LOXL1 single nucleotide polymorphisms (SNPs) rs1048661 (R141L), rs3825942 (G153D) and rs216524 were genotyped in patient sample. RESULTS: The significant association with PEX was found for the G allele of rs3825942 (p = 0.0047) and for the T allele of rs216541 (p = 0.021). The haplotype (GGT) consisting of all three risk alleles was significantly overrepresented (87.5%) in patients with PEX. CONCLUSION: Single nucleotide polymorphisms in LOXL1 are associated with PEX in Polish population which confirms the association previously reported for Icelandic, Swedish, Indian and other populations. PMID- 21272282 TI - A comparison of basal and eye-flush tears for the analysis of cat tear proteins. AB - PURPOSE: To identify a rapid and effective tear collection method providing sufficient tear volume and total protein content (TPC) for analysis of individual proteins in cats. METHODS: Domestic adult short-haired cats (12-37 months; 2.7 6.6 kg) were used in the study. Basal tears without stimulation and eye-flush tears after instillation of saline (10 MUl) were collected using microcapillary tubes from animal eyes either unwounded control or wounded with 9-mm central epithelial debridement giving four groups with n = 3. Tear comparisons were based on total time and rate for tear collection, TPC using micro bicinchoninic acid (BCA), tear immunoglobulin A (IgA), total matrix-metalloproteinase (MMP)-9 concentration using sandwich enzyme-linked immunosorbent assay (ELISA) and MMP-9 activity. RESULTS: Eye-flush tears were collected significantly faster than basal tears in wounded eyes with higher rates for tear collection in unwounded control and wounded eyes. TPC was significantly lower in eye-flush tears compared to basal tears. The relative proportion of tear IgA normalized to TPC (% IgA of TPC) was not significantly different between basal and eye-flush tears. In unwounded control eyes, MMP-9 was slightly higher in eye-flush than in basal tears; activity of MMP-9 in both tear types was similar. In wounded eyes, eye-flush tears showed highest MMP-9 levels and activity on Day 1, which subsequently decreased to Day 7. MMP-9 activity in basal tears from wounded eyes did not display changes in expression. CONCLUSIONS: Eye-flush tears can be collected rapidly providing sufficient tear volume and TPC. This study also indicates that eye-flush tears may be more suitable than basal tears for the analysis of MMPs following corneal wounding. PMID- 21272283 TI - Training to improve reading speed in patients with juvenile macular dystrophy: a randomized study comparing two training methods. AB - PURPOSE: In this study, we examined the clinical application of two training methods for optimizing reading ability in patients with juvenile macular dystrophy with established eccentric preferred retinal locus and optimal use of low-vision aids. METHOD: This randomized study included 36 patients with juvenile macular dystrophy (35 with Stargardt's disease and one with Best's disease). All patients have been using individually optimized low-vision aids. After careful ophthalmological examination, patients were randomized into two groups: Group 1: Training to read during rapid serial visual presentation (RSVP) with elimination of eye movements as far as possible (n = 20); Group 2: Training to optimize reading eye movements (SM, sensomotoric training) (n = 16). Only patients with magnification requirement up to sixfold were included in the study. Training was performed for 4 weeks with an intensity of 1/2 hr per day and 5 days a week. Reading speed during page reading was measured before and after training. Eye movements during silent reading were recorded before and after training using a video eye tracker in 11 patients (five patients of SM and six of RSVP training group) and using an infrared reflection system in five patients (three patients from the SM and two patients of RSVP training group). RESULTS: Age, visual acuity and magnification requirement did not differ significantly between the two groups. The median reading speed was 83 words per minute (wpm) (interquartile range 74-105 wpm) in the RSVP training group and 102 (interquartile range 63-126 wpm) in the SM group before training and increased significantly to 104 (interquartile range 81-124 wpm) and 122, respectively (interquartile range 102 137 wpm; p = 0.01 and 0.006) after training, i.e. patients with RSVP training increased their reading speed by a median of 21 wpm, while it was 20 wpm in the SM group. There were individual patients, who benefited strongly from the training. Eye movement recordings before and after training showed that in the RSVP group, increasing reading speed correlated with decreasing fixation duration (r = -0.75, p = 0.03), whereas in the SM group, increasing reading speed correlated with a decreasing number of forward saccades (r = -0.9, p = 0.01). CONCLUSION: Although the median effect of both training methods was limited, individual patients benefited well. Our results may indicate a difference in the training effect between both methods on the reading strategy: the RSVP method reduces fixation duration, the SM method decreases the number of forward saccades. Patients can apply their newly learned reading strategy in the natural reading situation, e.g. in page reading without special presentation of the text. These results can be used as a basis for further improvement in training methods for optimizing reading performance in patients with a central scotoma. PMID- 21272285 TI - How to prevent retinopathy of prematurity. PMID- 21272286 TI - Circulating melanoma cells in peripheral blood of patients with uveal melanoma before and after different therapies and association with prognostic parameters: a pilot study. AB - PURPOSE: To evaluate whether tumour therapy for malignant uveal melanoma leads to a shedding of melanoma cells into the systemic circulation. METHODS: Ninety-four peripheral blood samples from 81 patients with malignant uveal melanoma were collected before and after different tumour therapies and the number of circulating melanoma cells (CMCs) was investigated (seven patients with enucleation, 49 patients with stereotactic radiotherapy, 19 patients with endoresection of the tumour, 15 patients with ruthenium-brachytherapy and four patients with transpupillary thermotherapy). A cellular approach was used to detect CMCs through an immunocytological assay with tumour cell enrichment by immunomagnetic cell sorting. The number of CMCs was analysed further according to specific patient characteristics, tumour parameters and the development of metastasis. RESULTS: There was no significant difference between the number of CMCs before and after the different therapies (p = 0.78). There was also no significant association between established prognostic parameters of primary uveal melanoma and the detection of CMCs (all p >0.05). The number of CMCs was not related to the development of metastasis in a short median follow-up time of 16 months (p > 0.05). CONCLUSION: No changes in CMC values were observed before and after different tumour therapies. In the majority of cases therapy does not lead to a shedding of detectable melanoma cells into the systemic circulation. PMID- 21272287 TI - Influence of a yellow-tinted intraocular lens on laser beam transmittance. AB - PURPOSE: To compare the transmittance of laser beams that are used for photocoagulation through a yellow-tinted intraocular lens (IOL) and a clear IOL. METHODS: The transmittance of laser beams of different wavelengths (488 + 514, 514, 521, 568 and 647 nm) through yellow-tinted and clear IOLs of varying dioptric powers [+10, +20 and +30 dioptres (D)] was measured using a laser power meter. The transmittance ratio was defined as the ratio of the transmittance thorough a tinted IOL to that through a clear IOL, assuming that the transmittance value of the latter is 1; this ratio was calculated for each IOL and each wavelength of the laser beam. RESULTS: There were no apparent differences in the transmittance values between the tinted and clear IOLs when the 521, 568 and 647 nm wavelengths were used. In contrast, the transmittance ratio decreased for the tinted IOL when the short wavelengths - 488 + 514 and 514 nm - were used, especially when an IOL of a higher dioptric power was used. This ratio was found to be 91.9% for a +10 D, 86.7% for a +20 D and 82.2% for a +30 D lens when a 488 + 514 nm wavelength beam was used. CONCLUSION: When treating patients using photocoagulation, we must bear in mind the decreased transmittance ratio of short-wavelength laser beams when passed through tinted IOLs and increase the setting power of the beam accordingly. PMID- 21272288 TI - Repeated intravitreal bevacizumab (Avastin((r))) treatment of persistent new vessels in proliferative diabetic retinopathy after complete panretinal photocoagulation. AB - PURPOSE: To evaluate the effect of repeated intravitreal injections of bevacizumab (Avastin((r))) in patients with proliferative diabetic retinopathy and persistent new vessels after panretinal photocoagulation. METHODS: In this prospective study we investigated 11 eyes of 10 diabetic patients with persistent new vessels after previous complete panretinal photocoagulation. Complete ophthalmological examinations were performed at baseline and during monthly follow-up visits until the final follow-up at 6 months. Colour fundus photography, fluorescein angiography (FA) and macular optical coherence tomography (OCT) were performed. The area of leakage (mm2) found in the FA was used to demonstrate the effect of bevacizumab on retinal new vessels. Patients received 1.0 mg of intravitreal bevacizumab at baseline and at each of the monthly follow-up visits when reappearance of retinal new vessels was documented. RESULTS: At the 1-week follow-up visit, 73% of the treated eyes showed complete regression of retinal new vessels. Eight eyes were assigned to retreatments at the 3-month follow-up because of the reappearance of retinal new vessels. After 6 months, 36% of the eyes were found to have reappearance of retinal new vessels. The retreatment rate was 1.9 +/- 0.7 and the mean interval to retreatment was 2.9 +/- 1.0 months. The mean leakage area decreased from 7.2 +/- 2.6 mm2 at baseline to 1.2 +/- 0.9 mm2 at the final follow-up visit. BCVA increased from 59.2 +/- 14.6 Early Treatment Diabetic Retinopathy Study (ETDRS) score (range 40-80) to 70.7 +/- 8.5 at the final visit (p = 0.017). CONCLUSION: Intravitreal bevacizumab led to a significant reduction of retinal new vessels for a mean period of 2.9 months. A 3-monthly retreatment regime might be a valid method to control retinal new vessels in diabetic patients with persistent new vessels. PMID- 21272289 TI - Clinical features in high myopia. A Danish cohort study of high myopia cases followed from age 14 to age 60. PMID- 21272290 TI - Spatial distribution of Na+-K+-ATPase in dendritic spines dissected by nanoscale superresolution STED microscopy. AB - BACKGROUND: The Na+,K+-ATPase plays an important role for ion homeostasis in virtually all mammalian cells, including neurons. Despite this, there is as yet little known about the isoform specific distribution in neurons. RESULTS: With help of superresolving stimulated emission depletion microscopy the spatial distribution of Na+,K+-ATPase in dendritic spines of cultured striatum neurons have been dissected. The found compartmentalized distribution provides a strong evidence for the confinement of neuronal Na+,K+-ATPase (alpha3 isoform) in the postsynaptic region of the spine. CONCLUSIONS: A compartmentalized distribution may have implications for the generation of local sodium gradients within the spine and for the structural and functional interaction between the sodium pump and other synaptic proteins. Superresolution microscopy has thus opened up a new perspective to elucidate the nature of the physiological function, regulation and signaling role of Na+,K+-ATPase from its topological distribution in dendritic spines. PMID- 21272291 TI - Hypericum perforatum treatment: effect on behaviour and neurogenesis in a chronic stress model in mice. AB - BACKGROUND: Extracts of Hypericum perforatum (St. John's wort) have been traditionally recommended for a wide range of medical conditions, in particular mild-to-moderate depression. The present study was designed to investigate the effect of Hypericum perforatum treatment in a mouse model of anxiety/depressive like behavior, induced by chronic corticosterone administration. METHODS: CD1 mice were submitted to 7 weeks corticosterone administration and then behavioral tests as Open Field (OF), Novelty-Suppressed Feeding (NSF), Forced Swim Test (FST) were performed. Cell proliferation in hippocampal dentate gyrus (DG) was investigated by both 5-bromo-2'-deoxyuridine (BrdU) and doublecortin (DCX) immunohistochemistry techniques and stereological procedure was used to quantify labeled cells. Golgi-impregnation method was used to evaluate changes in dendritic spines in DG. Hypericum perforatum (30 mg/Kg) has been administered for 3 weeks and then neural development in the adult hippocampus and behavioral changes have been examined. RESULTS: The anxiety/depressive-like state due to chronic corticosterone treatment was reversed by exogenous administration of Hypericum perforatum; the proliferation of progenitor cells in mice hippocampus was significantly reduced under chronic corticosterone treatment, whereas a long term treatment with Hypericum perforatum prevented the corticosterone-induced decrease in hippocampal cell proliferation. Corticosterone-treated mice exhibited a reduced spine density that was ameliorated by Hypericum perforatum administration. CONCLUSION: These results provide evidence of morphological adaptations occurring in mature hippocampal neurons that might underlie resilient responses to chronic stress and contribute to the therapeutic effects of chronic Hypericum perforatum treatment. PMID- 21272292 TI - Differential patterns of histone acetylation in inflammatory bowel diseases. AB - Post-translational modifications of histones, particularly acetylation, are associated with the regulation of inflammatory gene expression. We used two animal models of inflammation of the bowel and biopsy samples from patients with Crohn's disease (CD) to study the expression of acetylated histones (H) 3 and 4 in inflamed mucosa. Acetylation of histone H4 was significantly elevated in the inflamed mucosa in the trinitrobenzene sulfonic acid model of colitis particularly on lysine residues (K) 8 and 12 in contrast to non-inflamed tissue. In addition, acetylated H4 was localised to inflamed tissue and to Peyer's patches (PP) in dextran sulfate sodium (DSS)-treated rat models. Within the PP, H3 acetylation was detected in the mantle zone whereas H4 acetylation was seen in both the periphery and the germinal centre. Finally, acetylation of H4 was significantly upregulated in inflamed biopsies and PP from patients with CD. Enhanced acetylation of H4K5 and K16 was seen in the PP. These results demonstrate that histone acetylation is associated with inflammation and may provide a novel therapeutic target for mucosal inflammation. PMID- 21272293 TI - Genetic structure of Leptopilina boulardi populations from different climatic zones of Iran. AB - BACKGROUND: The genetic structure of populations can be influenced by geographic isolation (including physical distance) and ecology. We examined these effects in Leptopilina boulardi, a parasitoid of Drosophila of African origin and widely distributed over temperate and (sub) tropical climates. RESULTS: We sampled 11 populations of L. boulardi from five climatic zones in Iran and measured genetic differentiation at nuclear (Amplified Fragment Length Polymorphism; AFLP) and mitochondrial (Cytochrome Oxidase I; COI) loci. An Analysis of Molecular Variance (AMOVA) for the AFLP data revealed that 67.45% of variation resided between populations. No significant variation was observed between climatic zones. However, a significant difference was detected between populations from the central (dry) regions and those from the wetter north, which are separated by desert. A similarly clear cut genetic differentiation between populations from the central part of Iran and those from the north was observed by UPGMA cluster analysis and Principal Coordinates Analysis (PCO). Both UPGMA and PCO further separated two populations from the very humid western Caspian Sea coast (zone 3) from other northern populations from the temperate Caspian Sea coastal plain (zone 2), which are connected by forest. One population (Nour) was genetically intermediate between these two zones, indicating some gene flow between these two groups of populations. In all analyses a mountain population, Sorkhabad was found to be genetically identical to those from the nearby coastal plain (zone 2), which indicates high gene flow between these populations over a short geographical distance. One population from the Caspian coast (Astaneh) was genetically highly diverged from all other populations. A partial Mantel test showed a highly significant positive correlation between genetic and geographic distances, as well as separation by the deserts of central Iran. The COI sequences were highly conserved among all populations. CONCLUSION: The Iranian populations of L. boulardi showed clear genetic structure in AFLP profiles, but not in COI sequence data. The transfer of fruits containing Drosophila larvae parasitized by L. boulardi appears to have caused some unexpected gene flow and changed the genetic composition of populations, particularly in urban areas. Nevertheless, our results suggest that climate, geographic distance and physical barriers may all have contributed to the formation of genetically distinct populations of L. boulardi. Inevitably, there will be overlap between the portions of variance explained by these variables. Disentangling the relative contributions of climate and geography to the genetic structure of this species will require additional sampling. PMID- 21272294 TI - Targeting canine bladder transitional cell carcinoma with a human bladder cancer specific ligand. AB - OBJECTIVE: To determine if a human bladder cancer-specific peptide named PLZ4 can target canine bladder cancer cells. EXPERIMENTAL DESIGN: The binding of PLZ4 to five established canine invasive transitional cell carcinoma (TCC) cell lines and to normal canine bladder urothelial cells was determined using the whole cell binding assay and an affinitofluorescence assay. The WST-8 assay was performed to determine whether PLZ4 affected cell viability. In vivo tumor-specific homing/targeting property and biodistribution of PLZ4 was performed in a mouse xenograft model via tail vein injection and was confirmed with ex vivo imaging. RESULTS: PLZ4 exhibited high affinity and specific dose-dependent binding to canine bladder TCC cell lines, but not to normal canine urothelial cells. No significant changes in cell viability or proliferation were observed upon incubation with PLZ4. The in vivo and ex vivo optical imaging study showed that, when linked with the near-infrared fluorescent dye Cy5.5, PLZ4 substantially accumulated at the canine bladder cancer foci in the mouse xenograft model as compared to the control. CONCLUSIONS AND CLINICAL RELEVANCE: PLZ4 can specifically bind to canine bladder cancer cells. This suggests that the preclinical studies of PLZ4 as a potential diagnostic and therapeutic agent can be performed in dogs with naturally occurring bladder cancer, and that PLZ4 can possibly be developed in the management of canine bladder cancer. PMID- 21272295 TI - Phenotypic heterogeneity in mycobacterial stringent response. AB - BACKGROUND: A common survival strategy of microorganisms subjected to stress involves the generation of phenotypic heterogeneity in the isogenic microbial population enabling a subset of the population to survive under stress. In a recent study, a mycobacterial population of M. smegmatis was shown to develop phenotypic heterogeneity under nutrient depletion. The observed heterogeneity is in the form of a bimodal distribution of the expression levels of the Green Fluorescent Protein (GFP) as reporter with the gfp fused to the promoter of the rel gene. The stringent response pathway is initiated in the subpopulation with high rel activity. RESULTS: In the present study, we characterise quantitatively the single cell promoter activity of the three key genes, namely, mprA, sigE and rel, in the stringent response pathway with gfp as the reporter. The origin of bimodality in the GFP distribution lies in two stable expression states, i.e., bistability. We develop a theoretical model to study the dynamics of the stringent response pathway. The model incorporates a recently proposed mechanism of bistability based on positive feedback and cell growth retardation due to protein synthesis. Based on flow cytometry data, we establish that the distribution of GFP levels in the mycobacterial population at any point of time is a linear superposition of two invariant distributions, one Gaussian and the other lognormal, with only the coefficients in the linear combination depending on time. This allows us to use a binning algorithm and determine the time variation of the mean protein level, the fraction of cells in a subpopulation and also the coefficient of variation, a measure of gene expression noise. CONCLUSIONS: The results of the theoretical model along with a comprehensive analysis of the flow cytometry data provide definitive evidence for the coexistence of two subpopulations with overlapping protein distributions. PMID- 21272296 TI - Developing a Dementia Research Registry: a descriptive case study from North Thames DeNDRoN and the EVIDEM programme. AB - AIM: To describe the development of a dementia research registry, outlining the conceptual, practical and ethical challenges, and to report initial experiences of recruiting people with dementia to it from primary and secondary care. BACKGROUND: Women, the oldest old and ethnic minorities have been under represented in clinical trials in dementia. Such under-representation biases estimates of absolute effect, absolute harm and cost-effectiveness. Research on dementia should include patient populations that more exactly reflect the population at risk. One of the impediments to this is the lack of a suitable tool for identification of patients suitable for studies. CONSTRUCTION & CONTENTS: A technology development methodology was used to develop a registry of people with dementia and their carers. This involved phases of modelling and prototype creation, 'bench testing' the prototype with experts and then 'field testing' the refined prototype in exemplar sites. The evaluation of the field testing described here is based on a case study methodology. UTILITY: This case study suggests that construction and population of a dementia research registry is feasible, but initial development is complex because of the ethical and organisational difficulties. Recruitment from primary care is particularly costly in terms of staff time and only identifies a very small number of people with dementia who were not already known to specialist services. Recruiting people with dementia through secondary care is a resource intensive process that takes up to six months to complete. Identifying the components of a minimum dataset was easy but its usefulness for pre-screening potential research populations has yet to be established. Acceptance rates are very high in the first clinic to recruit to the registry, but this may reflect the efforts of registry 'champions'. DISCUSSION AND CONCLUSIONS: Easier recruitment may perpetuate potential selection biases and we are not yet able to assess the representativeness of the research ready population recruited to the registry. The need to recruit from wider populations, through primary and social care, remains. The success of this registry will be measured by the proportion of people from it who are recruited to research projects, and its impact on overall accrual to studies. PMID- 21272297 TI - Characterization of an H10N8 influenza virus isolated from Dongting lake wetland. AB - BACKGROUND: Wild birds, especially those in wetlands and aquatic environments, are considered to be natural reservoirs of avian influenza viruses. It is accepted that water is an important component in the transmission cycle of avian influenza virus. Monitoring the water at aggregation and breeding sites of migratory waterfowl, mainly wetland, is very important for early detection of avian influenza virus. The epidemiology investigation of avian influenza virus was performed in Dongting lake wetland which is an international important wetland. RESULTS: An H10N8 influenza virus was isolated from Dongting Lake wetland in 2007. Phylogenetic analysis indicated that the virus was generated by multiple gene segment reassortment. The isolate was lowly pathogenic for chickens. However, it replicated efficiently in the mouse lung without prior adaptation, and the virulence to mice increased rapidly during adaptation in mouse lung. Sequence analysis of the genome of viruses from different passages showed that multiple amino acid changes were involved in the adaptation of the isolates to mice. CONCLUSIONS: The water might be an important component in the transmission cycle of avian influenza virus, and other subtypes of avian influenza viruses (other than H5, H7 and H9) might evolve to pose a potential threat to mammals and even humans. PMID- 21272298 TI - The role of proboscis of the malaria vector mosquito Anopheles stephensi in host seeking behavior. AB - BACKGROUND: The proboscis is an essential head appendage in insects that processes gustatory code during food intake, particularly useful considering that blood-sucking arthropods routinely reach vessels under the host skin using this proboscis as a probe. RESULTS: Here, using an automated device able to quantify CO(2)-activated thermo (35 degrees C)-sensing behavior of the malaria vector Anopheles stephensi, we uncovered that the protruding proboscis of mosquitoes contributes unexpectedly to host identification from a distance. Ablation experiments indicated that not only antennae and maxillary palps, but also proboscis were required for the identification of pseudo-thermo targets. Furthermore, the function of the proboscis during this behavior can be segregated from CO(2) detection required to evoke mosquito activation, suggesting that the proboscis of mosquitoes divide the proboscis into a "thermo-antenna" in addition to a "thermo-probe". CONCLUSIONS: Our findings support an emerging view with a possible role of proboscis as important equipment during host-seeking, and give us an insight into how these appendages likely evolved from a common origin in order to function as antenna organs. PMID- 21272299 TI - Gravity models to classify commuting vs. resident workers. An application to the analysis of residential risk in a contaminated area. AB - BACKGROUND: The analysis of risk for the population residing and/or working in contaminated areas raises the topic of commuting. In fact, especially in contaminated areas, commuting groups are likely to be subject to lower exposure than residents. Only very recently environmental epidemiology has started considering the role of commuting as a differential source of exposure in contaminated areas. In order to improve the categorization of groups, this paper applies a gravitational model to the analysis of residential risk for workers in the Gela petrochemical complex, which began life in the early 60s in the municipality of Gela (Sicily, Italy) and is the main source of industrial pollution in the local area. RESULTS: A logistic regression model is implemented to measure the capacity of Gela "central location" to attract commuting flows from other sites. Drawing from gravity models, the proposed methodology: a) defines the probability of finding commuters from municipalities outside Gela as a function of the origin's "economic mass" and of its distance from each destination; b) establishes "commuting thresholds" relative to the origin's mass. The analysis includes 367 out of the 390 Sicilian municipalities. Results are applied to define "commuters" and "residents" within the cohort of petrochemical workers. The study population is composed of 5,627 workers. Different categories of residence in Gela are compared calculating Mortality Rate Ratios for lung cancer through a Poisson regression model, controlling for age and calendar period. The mobility model correctly classifies almost 90% of observations. Its application to the mortality analysis confirms a major risk for lung cancer associated with residence in Gela. CONCLUSIONS: Commuting is a critical aspect of the health-environment relationship in contaminated areas. The proposed methodology can be replicated to different contexts when residential information is lacking or unreliable; however, a careful consideration of the territorial characteristics ("insularity" and its impact on transportation time and costs, in our case) is suggested when specifying the area of application for the mobility analysis. PMID- 21272300 TI - PNAC: a protein nucleolar association classifier. AB - BACKGROUND: Although primarily known as the site of ribosome subunit production, the nucleolus is involved in numerous and diverse cellular processes. Recent large-scale proteomics projects have identified thousands of human proteins that associate with the nucleolus. However, in most cases, we know neither the fraction of each protein pool that is nucleolus-associated nor whether their association is permanent or conditional. RESULTS: To describe the dynamic localisation of proteins in the nucleolus, we investigated the extent of nucleolar association of proteins by first collating an extensively curated literature-derived dataset. This dataset then served to train a probabilistic predictor which integrates gene and protein characteristics. Unlike most previous experimental and computational studies of the nucleolar proteome that produce large static lists of nucleolar proteins regardless of their extent of nucleolar association, our predictor models the fluidity of the nucleolus by considering different classes of nucleolar-associated proteins. The new method predicts all human proteins as either nucleolar-enriched, nucleolar-nucleoplasmic, nucleolar cytoplasmic or non-nucleolar. Leave-one-out cross validation tests reveal sensitivity values for these four classes ranging from 0.72 to 0.90 and positive predictive values ranging from 0.63 to 0.94. The overall accuracy of the classifier was measured to be 0.85 on an independent literature-based test set and 0.74 using a large independent quantitative proteomics dataset. While the three nucleolar-association groups display vastly different Gene Ontology biological process signatures and evolutionary characteristics, they collectively represent the most well characterised nucleolar functions. CONCLUSIONS: Our proteome-wide classification of nucleolar association provides a novel representation of the dynamic content of the nucleolus. This model of nucleolar localisation thus increases the coverage while providing accurate and specific annotations of the nucleolar proteome. It will be instrumental in better understanding the central role of the nucleolus in the cell and its interaction with other subcellular compartments. PMID- 21272301 TI - Reverse end-diastolic flow in a fetus with a rare liver malformation: a case report. AB - INTRODUCTION: We describe a case of early and persistent reverse end-diastolic flow in the middle cerebral artery in a fetus with severe ascites. These features are associated with a rare liver malformation known as ductal plate malformation. CASE PRESENTATION: A 28-year-old Caucasian woman was referred to our high-risk obstetric unit at 24 weeks' gestation for fetal ascites detected during a routine ultrasound examination. During her hospitalization we performed medical investigations, including a fetal paracentesis, to detect the etiology of fetal ascites. The cause of fetal ascites (then considered non-immune or idiopathic) was not evident, but a subsequent ultrasound examination at 27 weeks' gestation showed a reverse end-diastolic flow in the middle cerebral artery without any other Doppler abnormalities. A cesarean section was performed at 28 weeks' gestation because of the compromised fetal condition. An autopsy revealed a rare malformation of intrahepatic bile ducts known as ductal plate malformation. CONCLUSION: Persistent reverse flow in the middle cerebral artery should be considered a marker of adverse pregnancy outcome. We recommend careful ultrasound monitoring in the presence of this ultrasonographic sign to exclude any other cause of increased intracranial pressure. To better understand the nature of these ultrasonographic signs, additional reports are deemed necessary. In fact in our case, as confirmed by histopathological examination, the fetal condition was extremely compromised due to failure of the fetal liver. Ductal plate malformation altered the liver structures causing hypoproteinemia and probably portal hypertension. These two conditions therefore explain the severe hydrops that compromised the fetal situation. PMID- 21272302 TI - Dental and craniofacial characteristics in a patient with Dubowitz syndrome: a case report. AB - INTRODUCTION: Dubowitz syndrome is a very rare, autosomal recessive disease characterized by microcephaly, growth retardation, a high sloping forehead, facial asymmetry, blepharophimosis, sparse hair and eyebrows, low-set ears and mental retardation. Symptoms vary between patients, but other characteristics include a soft high-pitched voice, dental and craniofacial abnormalities, partial webbing of the fingers and toes, palate deformations, genital abnormalities, eczema, hyperactivity, preference for concrete over abstract thinking, language difficulties and an aversion to crowds. CASE PRESENTATION: We describe the craniofacial and dental characteristics of a 12-year-old Caucasian Italian boy with both the typical and less common findings of Dubowitz syndrome. CONCLUSION: Diagnosis of Dubowitz syndrome is mainly based on the facial phenotype. Possible conditions for differential diagnosis include Bloom syndrome, Smith-Lemli-Opitz syndrome, and fetal alcohol syndrome. As there are few reports of this syndrome in the literature, we hope this case report will enable health professionals to recognize the phenotypic alterations of this syndrome, and allow early referral for the necessary multidisciplinary treatments. PMID- 21272303 TI - Differences in patient outcomes and chronic care management of oral anticoagulant therapy: an explorative study. AB - BACKGROUND: The oral anticoagulant therapy - provided to prevent thrombosis - is known to be associated with substantial avoidable hospitalization. Improving the quality of the oral anticoagulant therapy could avoid drug related hospitalizations. Therefore, this study compared the patient outcomes between Dutch anticoagulant clinic (AC) regions taking the variation in chronic care management into account in order to explore whether chronic care management elements could improve the quality of oral anticoagulant therapy. METHODS: Two data sources were combined. The first source was a questionnaire that was send to all ACs in the Netherlands in 2008 (response = 100%) to identify the application of chronic care management elements in the AC regions. The Chronic Care Model of Wagner was used to make the concept of chronic care management operational. The second source was the report of the Dutch National Network of ACs which contains patient outcomes of the ACs. RESULTS: Patient outcomes achieved by the ACs were good, yet differences existed; for instance the percentage of patients in the appropriate therapeutic ranges varied from 67 to 87% between AC regions. Moreover, differences existed in the use of chronic care management elements of the chronic care model, for example 12% of the ACs had multidisciplinary meetings and 58% of the ACs had formal agreements with at least one hospital within their region. Patient outcomes were significantly associated with patient orientation and the number of specialized nurses versus doctors (p-values < 0.05). Furthermore, the overall extent to which chronic care management elements were applied was positively associated with patient outcomes (p-values < 0.05). CONCLUSIONS: Substantial differences in the patient outcomes as well as chronic care management of oral anticoagulant therapy existed. Since our results showed a positive association between overall application of chronic care management and patient outcomes, additional research is needed to fully understand the working mechanism of chronic care management. PMID- 21272304 TI - Prevalence and characteristics of methicillin-resistant coagulase-negative staphylococci from livestock, chicken carcasses, bulk tank milk, minced meat, and contact persons. AB - BACKGROUND: Methicillin-resistant coagulase-negative staphylococci (MR-CNS) are of increasing importance to animal and public health. In veterinary medicine and along the meat and milk production line, only limited data were so far available on MR-CNS characteristics. The aim of the present study was to evaluate the prevalence of MR-CNS, to identify the detected staphylococci to species level, and to assess the antibiotic resistance profiles of isolated MR-CNS strains. RESULTS: After two-step enrichment and growth on chromogenic agar, MR-CNS were detected in 48.2% of samples from livestock and chicken carcasses, 46.4% of samples from bulk tank milk and minced meat, and 49.3% of human samples. Using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), 414 selected MR-CNS strains belonged to seven different species (S. sciuri, 32.6%; S. fleurettii, 25.1%; S. haemolyticus, 17.4%; S. epidermidis, 14.5%, S. lentus, 9.2%; S. warneri, 0.7%; S. cohnii, 0.5%). S. sciuri and S. fleurettii thereby predominated in livestock, BTM and minced meat samples, whereas S. epidermidis and S. haemolyticus predominated in human samples. In addition to beta-lactam resistance, 33-49% of all 414 strains were resistant to certain non-beta-lactam antibiotics (ciproflaxacin, clindamycin, erythromycin, tetracycline). CONCLUSIONS: A high prevalence of MR-CNS was found in livestock production. This is of concern in view of potential spread of mecA to S. aureus (MRSA). Multiresistant CNS strains might become an emerging problem for veterinary medicine. For species identification of MR-CNS isolated from different origins, MALDI-TOF MS proved to be a fast and reliable tool and is suitable for screening of large sample amounts. PMID- 21272305 TI - Antioxidative protection of dietary bilberry, chokeberry and Lactobacillus plantarum HEAL19 in mice subjected to intestinal oxidative stress by ischemia reperfusion. AB - BACKGROUND: Ischemia-reperfusion (I/R) in the intestines is an inflammatory condition which activates leukocytes and reactive oxygen species (ROS) and leads to lipid peroxidation and DNA damage. Bilberry and chokeberry fruits are rich sources of polyphenols which may act as antioxidants and prevent lipid peroxidation. Lactic acid bacteria (LAB) may improve microbial status in the intestines and increase the metabolic activity towards polyphenolic degradation. The aim of the study was to clarify antioxidative effects of bilberry and chokeberry fruits alone and with addition of a LAB-strain, Lactobacillus plantarum HEAL19, in an I/R-model in mice. METHODS: Male BALB/cJ mice were fed the experimental diets for 10 days. Diets consisted of standard chow supplemented with either bilberry (Vaccinium myrtillus) or chokeberry (Aronia * prunifolia) powder alone or in combination with the LAB-strain Lactobacillus plantarum HEAL19. I/R-injury was induced by holding superior mesenteric artery clamped for 30 minutes followed by reperfusion for 240 minutes. Thereafter, colonic and caecal tissues and contents were collected. Malondialdehyde (MDA) was used as indicator of lipid peroxidation and was measured by a calorimetric assay, lactobacilli were cultured on Rogosa agar plates and Enterobacteriaceae on VRBG agar plates, anthocyanins and phenolic acids were analysed by HPLC-DAD-ESI-MSn. RESULTS: MDA was significantly decreased in the colon of groups fed bilberry alone (p = 0.030) and in combination with L. plantarum HEAL19 (p = 0.021) compared to the IR-control but not in chokeberry-fed groups. Supplementation with bilberry or chokeberry alone reduced the total number of lactobacilli on the mucosa. Higher concentrations of anthocyanins were found in the colon than in the caecum content of mice. A more varied composition of different anthocyanins was also observed in the colon content compared to the caecum of bilberry-fed mice. Phenolic acids formed by microbial degradation of the dietary polyphenols in the gut could be detected. More phenolic metabolites were found in the intestines of bilberry-fed mice than in the chokeberry-fed ones. CONCLUSIONS: Bilberry alone and in combination with L. plantarum HEAL19 exerts a better protection against lipid peroxidation than chokeberry. These dietary supplements may be used to prevent or suppress oxidative stress. PMID- 21272306 TI - Relationship between amino acid composition and gene expression in the mouse genome. AB - BACKGROUND: Codon bias is a phenomenon that refers to the differences in the frequencies of synonymous codons among different genes. In many organisms, natural selection is considered to be a cause of codon bias because codon usage in highly expressed genes is biased toward optimal codons. Methods have previously been developed to predict the expression level of genes from their nucleotide sequences, which is based on the observation that synonymous codon usage shows an overall bias toward a few codons called major codons. However, the relationship between codon bias and gene expression level, as proposed by the translation-selection model, is less evident in mammals. FINDINGS: We investigated the correlations between the expression levels of 1,182 mouse genes and amino acid composition, as well as between gene expression and codon preference. We found that a weak but significant correlation exists between gene expression levels and amino acid composition in mouse. In total, less than 10% of variation of expression levels is explained by amino acid components. We found the effect of codon preference on gene expression was weaker than the effect of amino acid composition, because no significant correlations were observed with respect to codon preference. CONCLUSION: These results suggest that it is difficult to predict expression level from amino acid components or from codon bias in mouse. PMID- 21272307 TI - Early intra-intensive care unit psychological intervention promotes recovery from post traumatic stress disorders, anxiety and depression symptoms in critically ill patients. AB - INTRODUCTION: Critically ill patients who require intensive care unit (ICU) treatment may experience psychological distress with increasing development of psychological disorders and related morbidity. Our aim was to determine whether intra-ICU clinical psychologist interventions decrease the prevalence of anxiety, depression and posttraumatic stress disorder (PTSD) after 12 months from ICU discharge. METHODS: Our observational study included critical patients admitted before clinical psychologist intervention (control group) and patients who were involved in a clinical psychologist program (intervention group). The Hospital Anxiety and Depression Scale (HADS) and Impact of Event Scale-Revised questionnaires were used to assess the level of posttraumatic stress, anxiety and depression symptoms. RESULTS: The control and intervention groups showed similar demographic and clinical characteristics. Patients in the intervention group showed lower rates of anxiety (8.9% vs. 17.4%) and depression (6.5% vs. 12.8%) than the control group on the basis of HADS scores, even if the differences were not statistically significant. High risk for PTSD was significantly lower in patients receiving early clinical psychologist support than in the control group (21.1% vs. 57%; P < 0.0001). The percentage of patients who needed psychiatric medications at 12 months was significantly higher in the control group than in the patient group (41.7% vs. 8.1%; P < 0.0001). CONCLUSIONS: Our results suggest that that early intra-ICU clinical psychologist intervention may help critically ill trauma patients recover from this stressful experience. PMID- 21272308 TI - "Surface epithelial changes" in uterine endometrioid carcinoma mimicking micropapillary serous borderline tumor of ovary: report of two cases and review of the literature. AB - We encountered two cases of endometrioid carcinoma of uterus with extensive surface epithelial changes (SECs) mimicking serous borderline tumor (SBT) of the ovary. The first case was a well-differentiated endometrioid carcinoma arising in a background of complex atypical hyperplasia. The second case was moderately differentiated endometrioid carcinoma with squamous and mucinous differentiation. The SECs comprised of thin microapapillae without hierarchal branching, lined by cuboidal cells with eosinophilic cytoplasm and mild to moderate nuclear atypia. These areas were reminiscent of SBTs of ovary, micropapillary type. This report expands the existing spectrum of SECs. Serous borderline tumor of ovary like surface epithelial changes could be misleading if present in an endometrial biopsy or curettings. Therefore, knowledge of this morphologic variation is important. PMID- 21272309 TI - Comparative phylogeography of two related plant species with overlapping ranges in Europe, and the potential effects of climate change on their intraspecific genetic diversity. AB - BACKGROUND: The aim of the present study was to use a combined phylogeographic and species distribution modelling approach to compare the glacial histories of two plant species with overlapping distributions, Orthilia secunda (one-sided wintergreen) and Monotropa hypopitys (yellow bird's nest). Phylogeographic analysis was carried out to determine the distribution of genetic variation across the range of each species and to test whether both correspond to the "classic" model of high diversity in the south, with decreasing diversity at higher latitudes, or whether the cold-adapted O. secunda might retain more genetic variation in northern populations. In addition, projected species distributions based on a future climate scenario were modelled to assess how changes in the species ranges might impact on total intraspecific diversity in both cases. RESULTS: Palaeodistribution modelling and phylogeographic analysis using multiple genetic markers (chloroplast trnS-trnG region, nuclear ITS and microsatellites for O. secunda; chloroplast rps2, nuclear ITS and microsatellites for M. hypopitys) indicated that both species persisted throughout the Last Glacial Maximum in southern refugia. For both species, the majority of the genetic diversity was concentrated in these southerly populations, whereas those in recolonized areas generally exhibited lower levels of diversity, particularly in M. hypopitys. Species distribution modelling based on projected future climate indicated substantial changes in the ranges of both species, with a loss of southern and central populations, and a potential northward expansion for the temperate M. hypopitys. CONCLUSIONS: Both Orthilia secunda and Monotropa hypopitys appear to have persisted through the LGM in Europe in southern refugia. The boreal O. secunda, however, has retained a larger proportion of its genetic diversity in more northerly populations outside these refugial areas than the temperate M. hypopitys. Given that future species distribution modelling suggests northern range shifts and loss of suitable habitat in the southern parts of the species' current distributions, extinction of genetically diverse rear edge populations could have a significant effect in the rangewide intraspecific diversity of both species, but particularly in M. hypopitys. PMID- 21272310 TI - Back pain outcomes in primary care following a practice improvement intervention: a prospective cohort study. AB - BACKGROUND: Back pain is one of the UK's costliest and least understood health problems, whose prevalence still seems to be increasing. Educational interventions for general practitioners on back pain appear to have had little impact on practice, but these did not include quality improvement learning, involve patients in the learning, record costs or document practice activities as well as patient outcomes. METHODS: We assessed the outcome of providing information about quality improvement techniques and evidence-based practice for back pain using the Clinical Value Compass. This included clinical outcomes (Roland and Morris Disability Questionnaire), functional outcomes, costs of care and patient satisfaction. We provided workshops which used an action learning approach and collected before and after data on routine practice activity from practice electronic databases. In parallel, we studied outcomes in a separate cohort of patients with acute and sub-acute non-specific back pain recruited from the same practices over the same time period. Patient data were analysed as a prospective, split-cohort study with assessments at baseline and eight weeks following the first consultation. RESULTS: Data for 1014 patients were recorded in the practice database study, and 101 patients in the prospective cohort study. We found that practice activities, costs and patient outcomes changed little after the intervention. However, the intervention was associated with a small, but statistically significant reduction in disability in female patients. Additionally, baseline disability, downheartedness, self-rated health and leg pain had small but statistically significant effects (p < 0.05) on follow-up disability scores in some subgroups. CONCLUSIONS: GP education for back pain that both includes health improvement methodologies and involves patients may yield additional benefits for some patients without large changes in patterns of practice activity. The effects in this study were small and limited and the reasons for them remain obscure. However, such is the impact of back pain and its frequency of consultation in general practice that this kind of improvement methodology deserves further consideration. TRIAL REGISTRATION NUMBER: ISRCTN: ISRCTN30420389. PMID- 21272311 TI - An integrated molecular cytogenetic map of Cucumis sativus L. chromosome 2. AB - BACKGROUND: Integration of molecular, genetic and cytological maps is still a challenge for most plant species. Recent progress in molecular and cytogenetic studies created a basis for developing integrated maps in cucumber (Cucumis sativus L.). RESULTS: In this study, eleven fosmid clones and three plasmids containing 45S rDNA, the centromeric satellite repeat Type III and the pericentriomeric repeat CsRP1 sequences respectively were hybridized to cucumber metaphase chromosomes to assign their cytological location on chromosome 2. Moreover, an integrated molecular cytogenetic map of cucumber chromosomes 2 was constructed by fluorescence in situ hybridization (FISH) mapping of 11 fosmid clones together with the cucumber centromere-specific Type III sequence on meiotic pachytene chromosomes. The cytogenetic map was fully integrated with genetic linkage map since each fosmid clone was anchored by a genetically mapped simple sequence repeat marker (SSR). The relationship between the genetic and physical distances along chromosome was analyzed. CONCLUSIONS: Recombination was not evenly distributed along the physical length of chromosome 2. Suppression of recombination was found in centromeric and pericentromeric regions. Our results also indicated that the molecular markers composing the linkage map for chromosome 2 provided excellent coverage of the chromosome. PMID- 21272312 TI - Consistency of aortic distensibility and pulse wave velocity estimates with respect to the Bramwell-Hill theoretical model: a cardiovascular magnetic resonance study. AB - BACKGROUND: Arterial stiffness is considered as an independent predictor of cardiovascular mortality, and is increasingly used in clinical practice. This study aimed at evaluating the consistency of the automated estimation of regional and local aortic stiffness indices from cardiovascular magnetic resonance (CMR) data. RESULTS: Forty-six healthy subjects underwent carotid-femoral pulse wave velocity measurements (CF_PWV) by applanation tonometry and CMR with steady-state free-precession and phase contrast acquisitions at the level of the aortic arch. These data were used for the automated evaluation of the aortic arch pulse wave velocity (Arch_PWV), and the ascending aorta distensibility (AA_Distc, AA_Distb), which were estimated from ascending aorta strain (AA_Strain) combined with either carotid or brachial pulse pressure. The local ascending aorta pulse wave velocity AA_PWVc and AA_PWVb were estimated respectively from these carotid and brachial derived distensibility indices according to the Bramwell-Hill theoretical model, and were compared with the Arch_PWV. In addition, a reproducibility analysis of AA_PWV measurement and its comparison with the standard CF_PWV was performed. Characterization according to the Bramwell-Hill equation resulted in good correlations between Arch_PWV and both local distensibility indices AA_Distc (r = 0.71, p < 0.001) and AA_Distb (r = 0.60, p < 0.001); and between Arch_PWV and both theoretical local indices AA_PWVc (r = 0.78, p < 0.001) and AA_PWVb (r = 0.78, p < 0.001). Furthermore, the Arch_PWV was well related to CF_PWV (r = 0.69, p < 0.001) and its estimation was highly reproducible (inter-operator variability: 7.1%). CONCLUSIONS: The present work confirmed the consistency and robustness of the regional index Arch_PWV and the local indices AA_Distc and AA_Distb according to the theoretical model, as well as to the well established measurement of CF_PWV, demonstrating the relevance of the regional and local CMR indices. PMID- 21272313 TI - Comparative genomics allowed the identification of drug targets against human fungal pathogens. AB - BACKGROUND: The prevalence of invasive fungal infections (IFIs) has increased steadily worldwide in the last few decades. Particularly, there has been a global rise in the number of infections among immunosuppressed people. These patients present severe clinical forms of the infections, which are commonly fatal, and they are more susceptible to opportunistic fungal infections than non immunocompromised people. IFIs have historically been associated with high morbidity and mortality, partly because of the limitations of available antifungal therapies, including side effects, toxicities, drug interactions and antifungal resistance. Thus, the search for alternative therapies and/or the development of more specific drugs is a challenge that needs to be met. Genomics has created new ways of examining genes, which open new strategies for drug development and control of human diseases. RESULTS: In silico analyses and manual mining selected initially 57 potential drug targets, based on 55 genes experimentally confirmed as essential for Candida albicans or Aspergillus fumigatus and other 2 genes (kre2 and erg6) relevant for fungal survival within the host. Orthologs for those 57 potential targets were also identified in eight human fungal pathogens (C. albicans, A. fumigatus, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Paracoccidioides lutzii, Coccidioides immitis, Cryptococcus neoformans and Histoplasma capsulatum). Of those, 10 genes were present in all pathogenic fungi analyzed and absent in the human genome. We focused on four candidates: trr1 that encodes for thioredoxin reductase, rim8 that encodes for a protein involved in the proteolytic activation of a transcriptional factor in response to alkaline pH, kre2 that encodes for alpha 1,2-mannosyltransferase and erg6 that encodes for Delta(24)-sterol C methyltransferase. CONCLUSIONS: Our data show that the comparative genomics analysis of eight fungal pathogens enabled the identification of four new potential drug targets. The preferred profile for fungal targets includes proteins conserved among fungi, but absent in the human genome. These characteristics potentially minimize toxic side effects exerted by pharmacological inhibition of the cellular targets. From this first step of post genomic analysis, we obtained information relevant to future new drug development. PMID- 21272314 TI - Variety of transversus thoracis muscle in relation to the internal thoracic artery: an autopsy study of 120 subjects. AB - BACKGROUND: The transversus thoracis muscle is a thin muscular layer on the inner surface of the anterior thoracic wall that is always in concern during harvesting of the internal thoracic artery. Because the muscle is poorly described in the surgical literature, the aim of the present study is to examine in details its variations. METHODS: The data was obtained at standard autopsies of 120 Caucasian subjects (Bulgarians) of both sexes (97 males and 23 females), ranging in age from 18 to 91 years (mean age 52.8 +/- 17.8 years). The transversus thoracis morphology was thoroughly examined on the inner surface of the chest plates collected after routine incisions. RESULTS: An overall examination revealed that in majority of cases the transversus thoracis slips formed a complete muscular layer (left - 75.8%, right - 83.3%) or some of the slips (left - 22.5%, right - 15%) or all of them (left - 1.7%, right - 1.7%) were quite separated. Rarely (left - 3.3%, right - 5.8%), some fibrous slips of the transversus thoracis were noted. In 55.8% of the cases there was left/right muscle symmetry; 44.2% of the muscles were asymmetrical. Most commonly, the highest muscle attachment was to the second (left - 53.3%, right - 37.5%) or third rib (left - 29.2%, right - 46.7%). The sixth rib was the most common lowest attachment (left - 94.2%, right 89.2%). Most frequently, the muscle was composed of four (left - 31.7%, right - 44.2%) or fifth slips (left - 53.3%, right - 40.8%). CONCLUSIONS: This study provides detailed basic information on the variety of the transversus thoracic muscle. It also defines the range of the clearly visible, uncovered by the muscle part of the internal thoracic artery and the completeness of the muscular layer over it. The knowledge of these peculiar muscle-arterial relations would definitely be beneficial to cardiac surgeon in performing fast and safe arterial harvesting. PMID- 21272315 TI - Ancient DNA from lake sediments: bridging the gap between paleoecology and genetics. AB - BACKGROUND: Quaternary plant ecology in much of the world has historically relied on morphological identification of macro- and microfossils from sediments of small freshwater lakes. Here, we report new protocols that reliably yield DNA sequence data from Holocene plant macrofossils and bulk lake sediment used to infer ecological change. This will allow changes in census populations, estimated from fossils and associated sediment, to be directly associated with population genetic changes. RESULTS: We successfully sequenced DNA from 64 samples (out of 126) comprised of bulk sediment and seeds, leaf fragments, budscales, and samaras extracted from Holocene lake sediments in the western Great Lakes region of North America. Overall, DNA yields were low. However, we were able to reliably amplify samples with as few as 10 copies of a short cpDNA fragment with little detectable PCR inhibition. Our success rate was highest for sediments < 2000 years old, but we were able to successfully amplify DNA from samples up to 4600 years old. DNA sequences matched the taxonomic identity of the macrofossil from which they were extracted 79% of the time. Exceptions suggest that DNA molecules from surrounding nearby sediments may permeate or adhere to macrofossils in sediments. CONCLUSIONS: An ability to extract ancient DNA from Holocene sediments potentially allows exciting new insights into the genetic consequences of long term environmental change. The low DNA copy numbers we found in fossil material and the discovery of multiple sequence variants from single macrofossil extractions highlight the need for careful experimental and laboratory protocols. Further application of these protocols should lead to better understanding of the ecological and evolutionary consequences of environmental change. PMID- 21272316 TI - Meta regression analysis to indirectly compare dalteparin to enoxaparin for the prevention of venous thromboembolic events following total hip replacement. AB - BACKGROUND: Patients undergoing elective total hip replacement (THR) surgery are at an increased risk for venous thromboembolic events (VTEs). Dalteparin and enoxaparin are recommended as thromboprophylaxis for at least 10 days in these patients. Even though both agents have proven clinical effectiveness through placebo controlled studies, there have been no head to head trials to assess comparative effectiveness. Indirect statistical techniques were used to compare safety and efficacy between dalteparin and enoxaparin following THR surgery. METHODS: A literature search was conducted from January 1980 to November 2009 for randomized trials evaluating dalteparin or enoxaparin prophylaxis in THR patients. In trials where a common control was used (e.g. placebo), indirect statistical comparisons between dalteparin and enoxaparin were performed using meta regression analysis with active drug as the primary independent variable. RESULTS: A total of nine placebo controlled enoxaparin (n = 5) and dalteparin (n = 4) trials met the inclusion criteria. THR patients treated with enoxaparin or dalteparin had a 50% VTE risk reduction compared to the placebo control (RR = 0.50, p < 0.001). This benefit was achieved without a significant increase in the risk for major bleeds (RR = 1.19, p = 0.76), heparin induced thrombocytopenia (HIT) (RR = 1.13, p = 0.83) or death (RR = 0.72, p = 0.59). The indirect comparison was not able to find significant differences between enoxaparin and dalteparin in terms of VTEs (p = 0.36), major bleeds (p = 0.45), HIT (p = 0.48) and death (p = 0.86). CONCLUSIONS: The findings suggested comparable safety and efficacy between dalteparin and enoxaparin in TKR patients. Therefore, treatment decisions should be based on other considerations, such as patient or physician preference, ease of administration and cost. PMID- 21272317 TI - Cross-cultural adaptation and psychometric properties of the Brazilian-Portuguese version of the VSP-A (Vecu et Sante Percue de l'Adolescent), a health-related quality of life (HRQoL) instrument for adolescents, in a healthy Brazilian population. AB - BACKGROUND: Health-related quality of life (HRQoL) assessment, encompassing the adolescents' perceptions of their mental, physical, and social health and well being is increasingly considered an important outcome to be used to identify population health needs and to provide targeted medical care. Although validated instruments are essential for accurately assessing HRQoL outcomes, there are few cross-culturally adapted tools for use in Brazil, and none designed exclusively for use among adolescents. The Vecu et Sante Percue de l'Adolescent (VSP-A) is a generic, multidimensional self-reported instrument originally developed and validated in France that evaluates HRQoL of ill and healthy adolescents. PURPOSE: To cross-culturally adapt and validate the Brazilian-Portuguese version of the VSP-A, a generic HRQoL measure for adolescents originally developed in France. METHODS: The VSP-A was translated following a well-validated forward-backward process leading to the Brazilian version. The psychometric evaluation was conducted in a sample of 446 adolescents (14-18 years) attending 2 public high schools of Sao Goncalo City. The adolescents self-reported the Brazilian VSP-A, the validated Psychosomatic Symptom Checklist and socio-demographic information. A retest evaluation was carried out on a sub-sample (n = 195) at a two-week interval. The internal construct validity was assessed through confirmatory factor analysis (CFA), multi-trait scaling analyses, Rasch analysis evaluating unidimensionality of each scale and Cronbach's alpha coefficients. The reproducibility was evaluated by intra-class correlation coefficients (ICC). Zumbo's ordinal logistic regression analysis was used to detect differential item functioning (DIF) between the Brazilian and the French items. External construct validity was investigated testing expected differences between groups using one way analysis of variance (ANOVA), Mann-Whitney tests and the univariate general regression linear model. RESULTS: CFA showed an acceptable fit (RMSEA=0.05; CFI=0.93); 94% of scaling success was found for item-internal consistency and 98% for item discriminant validity. The items showed good fit to the Rasch model except 3 items with an INFIT at the upper threshold. Cronbach's Alpha ranged from 0.60 to 0.85. Test-retest reliability was moderate to good (ICC=0.55-0.82). DIF was evidenced in 4 out of 36 items. Expected patterns of differences were confirmed with significantly lower physical, psychological well being and vitality reported by symptomatic adolescents. CONCLUSIONS: Although DIF in few items and responsiveness must be further explored, the Brazilian version of VSP-A demonstrated an acceptable validity and reliability in adolescents attending school and might serve as a starting point for more specific clinical investigations. PMID- 21272318 TI - Mapping hospice patients' perception and verbal communication of end-of-life needs: an exploratory mixed methods inquiry. AB - BACKGROUND: Comprehensive "Total Pain" assessments of patients' end-of-life needs are critical for providing improved patient-clinician communication, assessing needs, and offering high quality palliative care. However, patients' needs-based research methodologies and findings remain highly diverse with their lack of consensus preventing optimum needs assessments and care planning. Mixed-methods is an underused yet robust "patient-based" approach for reported lived experiences to map both the incidence and prevalence of what patients perceive as important end of life needs. METHODS: Findings often include methodological artifacts and their own selection bias. Moving beyond diverse findings therefore requires revisiting methodological choices. A mixed methods research cross sectional design is therefore used to reduce limitations inherent in both qualitative and quantitative methodologies. Audio-taped phenomenological "thinking aloud" interviews of a purposive sample of 30 hospice patients are used to identify their vocabulary for communicating perceptions of end-of-life needs. Grounded theory procedures assisted by QSR-NVivo software is then used for discovering domains of needs embedded in the interview narratives. Summary findings are translated into quantified format for presentation and analytical purposes. RESULTS: Findings from this mixed-methods feasibility study indicate patients' narratives represent 7 core domains of end-of-life needs. These are (1) time, (2) social, (3) physiological, (4) death and dying, (5) safety, (6) spirituality, (7) change & adaptation. The prevalence, rather than just the occurrence, of patients' reported needs provides further insight into their relative importance. CONCLUSION: Patients' perceptions of end-of-life needs are multidimensional, often ambiguous and uncertain. Mixed methodology appears to hold considerable promise for unpacking both the occurrence and prevalence of cognitive structures represented by verbal encoding that constitute patients' narratives. Communication is a key currency for delivering optimal palliative care. Therefore understanding the domains of needs that emerge from patient-based vocabularies indicate potential for: (1) developing more comprehensive clinical patient needs assessment tools; (2) improved patient-clinician communication; and (3) moving toward a theoretical model of human needs that can emerge at the end of life. PMID- 21272319 TI - Cruciferous vegetable supplementation in a controlled diet study alters the serum peptidome in a GSTM1-genotype dependent manner. AB - BACKGROUND: Cruciferous vegetable intake is inversely associated with the risk of several cancers. Isothiocyanates (ITC) are hypothesized to be the major bioactive constituents contributing to these cancer-preventive effects. The polymorphic glutathione-S-transferase (GST) gene family encodes several enzymes which catalyze ITC degradation in vivo. METHODS: We utilized high throughput proteomics methods to examine how human serum peptides (the "peptidome") change in response to cruciferous vegetable feeding in individuals of different GSTM1 genotypes. In two randomized, crossover, controlled feeding studies (EAT and 2EAT) participants consumed a fruit- and vegetable-free basal diet and the basal diet supplemented with cruciferous vegetables. Serum samples collected at the end of the feeding period were fractionated and matrix assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry spectra were obtained. Peak identification/alignment computer algorithms and mixed effects models were used to analyze the data. RESULTS: After analysis of spectra from EAT participants, 24 distinct peaks showed statistically significant differences associated with cruciferous vegetable intake. Twenty of these peaks were driven by their GSTM1 genotype (i.e., GSTM1+ or GSTM1- null). When data from EAT and 2EAT participants were compared by joint processing of spectra to align a common set, 6 peaks showed consistent changes in both studies in a genotype-dependent manner. The peaks at 6700 m/z and 9565 m/z were identified as an isoform of transthyretin (TTR) and a fragment of zinc alpha2-glycoprotein (ZAG), respectively. CONCLUSIONS: Cruciferous vegetable intake in GSTM1+ individuals led to changes in circulating levels of several peptides/proteins, including TTR and a fragment of ZAG. TTR is a known marker of nutritional status and ZAG is an adipokine that plays a role in lipid mobilization. The results of this study present evidence that the GSTM1-genotype modulates the physiological response to cruciferous vegetable intake. PMID- 21272320 TI - FLT3 mutations in canine acute lymphocytic leukemia. AB - BACKGROUND: FMS-like tyrosine kinase 3 (FLT3) is a commonly mutated protein in a variety of human acute leukemias. Mutations leading to constitutively active FLT3, including internal tandem duplications of the juxtamembrane domain (ITD), result in continuous cellular proliferation, resistance to apoptotic cell death, and a poorer prognosis. A better understanding of the molecular consequences of FLT3 activation would allow improved therapeutic strategies in these patients. Canine lymphoproliferative diseases, including lymphoma and acute leukemias, share evolutionarily conserved chromosomal aberrations and exhibit conserved mutations within key oncogenes when compared to their human counterparts. A small percentage of canine acute lymphocytic leukemias (ALL) also exhibit FLT3 ITD mutations. METHODS: We molecularly characterized FLT3 mutations in two dogs and one cell line, by DNA sequencing, gene expression analysis via quantitative real time PCR, and sensitivity to the FLT3 inhibitor lestaurtinib via in vitro proliferation assays. FLT 3 and downstream mediators of FLT3 activation were assessed by Western blotting. RESULTS: The canine B-cell leukemia cell line, GL 1, and neoplastic cells from 2/7 dogs diagnosed cytologically with ALL were found to have FLT3 ITD mutations and FLT3 mRNA up-regulation. Lestaurtinib, a small molecule FLT3 inhibitor, significantly inhibited the growth of GL-1 cells, while not affecting the growth of two other canine lymphoid cell lines without the FLT3 mutation. Finally, western blots were used to confirm the conserved downstream mediators of FLT3 activating mutations. CONCLUSIONS: These results show that ALL and FLT3 biology is conserved between canine and human patients, supporting the notion that canine ALL, in conjunction with the GL-1 cell line, will be useful in the development of a relevant large animal model to aid in the study of human FLT3 mutant leukemias. PMID- 21272321 TI - The association between state mandates of colorectal cancer screening coverage and colorectal cancer screening utilization among US adults aged 50 to 64 years with health insurance. AB - BACKGROUND: Several states in the US have passed laws mandating coverage of colorectal cancer (CRC) screening tests by health insurance plans. The impact of these state mandates on the use of colorectal cancer screening has not been evaluated among an age-eligible target population with access to care (i.e., health care insurance coverage). METHODS: We collected information on state mandates implemented by December 31, 2008 and used data on insured adults aged 50 and 64 years from the Behavioral Risk Factor Surveillance System between 2002 and 2008 to classify individual-level exposure to state mandates for at least 1 year. Multivariate logistic regression models (with state- and year- fixed effects, and patient demographic and socioeconomic characteristics) were used to estimate the effect of state mandates on recent endoscopy screening (either flexible sigmoidoscopy or colonoscopy during the past year). RESULTS: From 1999-2008, twenty-two states in the US, including the District of Columbia passed comprehensive laws requiring health insurance coverage of CRC screening including endoscopy tests. Residence in states with CRC screening coverage mandates in place for at least 1 year was associated with a 1.4 percentage point increase in the probability of utilization of recent endoscopy (i.e., 17.5% screening rates in those with mandates versus 16.1% in those without, Adjusted OR = 1.10, 95% CI: 1.02-1.20, p = 0.02). CONCLUSIONS: The findings suggest a positive, albeit small, impact of state mandates on the use of recent CRC screening endoscopy among the target eligible population with health insurance. However, more research is needed to evaluate potential effects of mandates across health insurance types while including controls for other system-level factors (e.g. endoscopy and primary care capacity). National health insurance reform should strive towards a system that expands access to recommended CRC screening tests. PMID- 21272322 TI - Medical education and research environment in Qatar: a new epoch for translational research in the Middle East. AB - Recent advances in medical technology and key discoveries in biomedical research have the potential to improve human health in an unprecedented fashion. As a result, many of the Arab Gulf countries, particularly Qatar are devoting increasing resources toward establishing centers of excellence in biomedical research. However, there are challenges that must be overcome. The low profile of private medical institutions and their negligible endowments in the region are examples of such challenges. Business-type government controlled universities are not the solution for overcoming the challenges facing higher education and research programs in the Middle East.During the last decade, Qatar Foundation for Education, Science and Community Development has attracted six branch campuses of American Institutions of higher learning to the Education City in Qatar, a 2500 acre area, which is rapidly becoming a model of integrating higher education and research in the region. Not-for profit, time-tested education institutions from abroad in public-private partnership with local organizations offer favorable conditions to build robust research programs in the region. Weill Cornell Medical College in Qatar (WCMC-Q) of Cornell University is an example such an institution. It is the first and only medical school in Qatar.WCMC-Q's interwoven education, research and public health based framework lays a sturdy foundation for developing and implementing translational medicine research programs of importance to the State of Qatar and Middle Eastern nations. This approach is yielding positive results. Discoveries from this program should influence public policy in a positive fashion toward reducing premature mortality and morbidity due to diabetes, obesity, heart disease and cancer, examples of health conditions commonly encountered in Qatar. PMID- 21272323 TI - Attempting to distinguish between endogenous and contaminating cytokeratins in a corneal proteomic study. AB - BACKGROUND: The observation of cytokeratins (CK's) in mass spectrometry based studies raises the question of whether the identified CK is a true endogenous protein from the sample or simply represents a contaminant. This issue is especially important in proteomic studies of the corneal epithelium where several CK's have previously been reported to mark the stages of differentiation from corneal epithelial stem cell to the differentiated cell. METHODS: Here we describe a method to distinguish very likely endogenous from uncertain endogenous CK's in a mass spectrometry based proteomic study. In this study the CK identifications from 102 human corneal samples were compared with the number of human CK identifications found in 102 murine thymic lymphoma samples. RESULTS: It was anticipated that the CK's that were identified with a frequency of <5%, i.e. in less than one spot for every 20 spots analysed, are very likely to be endogenous and thereby represent a 'biologically significant' identification. CK's observed with a frequency >5% are uncertain endogenous since they may represent true endogenous CK's but the probability of contamination is high and therefore needs careful consideration. This was confirmed by comparison with a study of mouse samples where all identified human CK's are contaminants. CONCLUSIONS: CK's 3, 4, 7, 8, 11, 12, 13, 15, 17, 18, 19, 20 and 23 are very likely to be endogenous proteins if identified in a corneal study, whilst CK's 1, 2e, 5, 6A, 9, 10, 14 and 16 may be endogenous although some are likely to be contaminants in a proteomic study. Further immunohistochemical analysis and a search of the current literature largely supported the distinction. PMID- 21272324 TI - Transcriptional regulation of main metabolic pathways of cyoA, cydB, fnr, and fur gene knockout Escherichia coli in C-limited and N-limited aerobic continuous cultures. AB - BACKGROUND: It is important to understand the cellular responses emanating from environmental perturbations to redesign the networks for practical applications. In particular, the carbon (C) metabolism, nitrogen (N) assimilation, and energy generation are by far important, where those are interconnected and integrated to maintain cellular integrity. In our previous study, we investigated the effect of C/N ratio on the metabolic regulation of gdhA, glnL, glt B,D mutants as well as wild type Escherichia coli (Kumar and Shimizu, MCF, 1-17, 9:8,2010), where it was shown that the transcript levels of cyoA and cydB which encode the terminal oxidases, fnr and fur which encode global regulators were significantly up regulated under N-limited condition as compared to C-limited condition. In the present study, therefore, the effects of such single-gene knockout on the metabolic regulation were investigated to clarify the roles of those genes in the aerobic continuous culture at the dilution rate of 0.2 h(-1). RESULTS: The specific glucose consumption rates and the specific CO2 production rates of cyoA, cydB, fnr, and fur mutants were all increased as compared to the wild type under both C-limited and N-limited conditions. The former phenomenon was consistent with the up-regulations of the transcript levels of ptsG and ptsH, which are consistent with down-regulations of crp and mlc genes. Moreover, the increase in the specific glucose consumption rate was also caused by up-regulations of the transcript levels of pfkA, pykF and possibly zwf, where those are consistent with the down regulations of cra, crp and mlc genes. Moreover, the transcript levels of rpoN together with glnK, glnB, glnE were up-regulated, and thus the transcript levels of glnA,L,G, and gltB,D as well as nac were up-regulated, while gdhA was down-regulated. This implies the interconnection between cAMP-Crp and PII-Ntr systems. Moreover, cyoA, cydB, fnr and fur gene deletions up-regulated the transcript levels of respiration (nuoA, ndh, cyoA, cydB, and atpA) and the oxidative stress related genes such as soxR, S and sodA, where this was further enhanced under N-limitation. In the cases of cyoA and cydB mutants, arcA, fnr, fur, cydB (for cyoA mutant), and cyoA (for cydB mutant) genes were up-regulated, which may be due to incomplete oxidation of quinol. It was also shown that fur gene transcript level was up-regulated in accordance with the activation of respiratory chain genes. It was shown that the deletion of fur gene activated the enterobactin pathway. CONCLUSION: The present result demonstrated how the fermentation characteristics could be explained by the transcript levels of metabolic pathway genes as well as global regulators in relation to the knockout of such single genes as cyoA, cydB, fnr, and fur, and clarified the complex gene network regulation in relation to glycolysis, TCA cycle, respiration, and N regulated pathways. The present result is quite important in understanding the metabolic regulation for metabolic engineering. Moreover, the present result may be useful in improving the specific glucose consumption rate and activation of the TCA cycle by modulating the respiratory chain genes and the related global regulators. The result obtained under N-limited condition may be useful for the heterologous protein production under N-limitation. PMID- 21272325 TI - Cost-utility analysis of a one-time supervisor telephone contact at 6-weeks post partum to prevent extended sick leave following maternity leave in The Netherlands: results of an economic evaluation alongside a randomized controlled trial. AB - BACKGROUND: Working women of childbearing age are a vital part of the population. Following childbirth, this group of women can experience a myriad of physical and mental health problems that can interfere with their ability to work. Currently, there is little known about cost-effective post-partum interventions to prevent work disability. The purpose of the study was to evaluate whether supervisor telephone contact (STC) during maternity leave is cost-effective from a societal perspective in reducing sick leave and improving quality-adjusted life years (QALYs) compared to common practice (CP). METHODS: We conducted an economic evaluation alongside a randomized controlled trial. QALYs were measured by the EuroQol 5-D, and sick leave and presenteeism by the Health and work Performance Questionnaire. Resource use was collected by questionnaires. Data were analysed according to intention-to-treat. Missing data were imputed via multiple imputation. Uncertainty was estimated by 95% confidence intervals, cost-utility planes and curves, and sensitivity analyses. RESULTS: 541 working women from 15 companies participated. Response rates were above 85% at each measurement moment. At the end of the follow-up, no statistically significant between-group differences in QALYs, mean hours of sick leave or presenteeism or costs were observed. STC was found to be less effective and more costly. For willingness-to pay levels from ?0 through ?50,000, the probability that STC was cost-effective compared to CP was 0.2. Overall resource use was low. Mean total costs were ?3678 (95% CI: 3386; 3951). Productivity loss costs represented 37% of the total costs and of these costs, 48% was attributable to sick leave and 52% to work presenteeism. The cost analysis from a company's perspective indicated that there was a net cost associated with the STC intervention. CONCLUSIONS: STC was not cost-effective compared to common practice for a healthy population of working mothers; therefore, implementation is not indicated. The cost-utility of STC for working mothers with more severe post-partum health problems, however, needs to be investigated. Work presenteeism accounted for half of the total productivity loss and warrants attention in future studies. TRIAL REGISTRATION NUMBER: ISRCTN: ISRCTN73119486. PMID- 21272327 TI - Isolated sixth cranial nerve palsy as the presenting symptom of a rapidly expanding ACTH positive pituitary adenoma: a case report. AB - BACKGROUND: Pituitary adenoma may present with neuro-ophthalmic manifestations and, typically, rapid tumor expansion is the result of apoplexy. Herein, we present the first case of an isolated sixth cranial nerve palsy as initial feature of a rapidly expanding ACTH positive silent tumor without apoplexy. CASE PRESENTATION: A 44 year old female with a history of sarcoidosis presented with an isolated sixth cranial nerve palsy as the initial clinical feature of a rapidly expanding ACTH positive silent pituitary adenoma. The patient underwent emergent transsphenoidal hypophysectomy for this rapidly progressive tumor and subsequently regained complete vision and ocular motility. Despite tumor extension into the cavernous sinus, the other cranial nerves were spared during the initial presentation. CONCLUSIONS: This case illustrates the need to consider a rapidly growing pituitary tumor as a possibility when presented with a rapidly progressive ophthalmoplegia. PMID- 21272326 TI - Bioinformatic detection of E47, E2F1 and SREBP1 transcription factors as potential regulators of genes associated to acquisition of endometrial receptivity. AB - BACKGROUND: The endometrium is a dynamic tissue whose changes are driven by the ovarian steroidal hormones. Its main function is to provide an adequate substrate for embryo implantation. Using microarray technology, several reports have provided the gene expression patterns of human endometrial tissue during the window of implantation. However it is required that biological connections be made across these genomic datasets to take full advantage of them. The objective of this work was to perform a research synthesis of available gene expression profiles related to acquisition of endometrial receptivity for embryo implantation, in order to gain insights into its molecular basis and regulation. METHODS: Gene expression datasets were intersected to determine a consensus endometrial receptivity transcript list (CERTL). For this cluster of genes we determined their functional annotations using available web-based databases. In addition, promoter sequences were analyzed to identify putative transcription factor binding sites using bioinformatics tools and determined over-represented features. RESULTS: We found 40 up- and 21 down-regulated transcripts in the CERTL. Those more consistently increased were C4BPA, SPP1, APOD, CD55, CFD, CLDN4, DKK1, ID4, IL15 and MAP3K5 whereas the more consistently decreased were OLFM1, CCNB1, CRABP2, EDN3, FGFR1, MSX1 and MSX2. Functional annotation of CERTL showed it was enriched with transcripts related to the immune response, complement activation and cell cycle regulation. Promoter sequence analysis of genes revealed that DNA binding sites for E47, E2F1 and SREBP1 transcription factors were the most consistently over-represented and in both up- and down regulated genes during the window of implantation. CONCLUSIONS: Our research synthesis allowed organizing and mining high throughput data to explore endometrial receptivity and focus future research efforts on specific genes and pathways. The discovery of possible new transcription factors orchestrating the CERTL opens new alternatives for understanding gene expression regulation in uterine function. PMID- 21272328 TI - Influence of bi- and tri-compartmental knee arthroplasty on the kinematics of the knee joint. AB - BACKGROUND: The cruciate ligaments are important stabilizers of the knee joint and determine joint kinematics in the natural knee and after cruciate retaining arthroplasty.No in vitro data is available to biomechanically evaluate the ability of the anterior cruciate ligament (ACL) to maintain knee joint kinematics after bicruciate-retaining bi-compartmental knee arthroplasty (BKA).Therefore, the objective of the current study was to investigate the kinematics of the natural knee joint, before and after installing bicruciate-retaining BKA and posterior cruciate retaining total knee arthroplasty. Specifically, we incorporated a dynamic knee simulator to simulate weight-bearing flexions on cadaveric knee specimen before and after surgical manipulations. METHODS: In this cadaveric study we investigated rotational and translational tibiofemoral kinematics during simulated weight-bearing flexions of the intact knee, after bi compartmental knee arthroplasty (BKA+), after resecting the ACL in BKA (BKA-), and after posterior cruciate retaining total knee arthroplasty (TKA). RESULTS: Rotation of BKA+ is closest to the intact knee joint, whereas TKA shows significant differences from 30 to 90 degree of flexion. Within the tested flexion range (15 to 90 degree of flexion), there was no significant difference in the anterior-posterior translation among intact, BKA+, and TKA knees. Resecting the ACL in BKA leads to a significant anterior tibial translation. CONCLUSIONS: BKA with intact cruciate ligaments resembles rotation and translation of the natural knee during a simulated weight-bearing flexion. It is a suitable treatment option for medial and patellofemoral osteoarthritis with advantages in rotational characteristics compared to TKA. PMID- 21272329 TI - The G1 phase Cdks regulate the centrosome cycle and mediate oncogene-dependent centrosome amplification. AB - Because centrosome amplification generates aneuploidy and since centrosome amplification is ubiquitous in human tumors, a strong case is made for centrosome amplification being a major force in tumor biogenesis. Various evidence showing that oncogenes and altered tumor suppressors lead to centrosome amplification and aneuploidy suggests that oncogenes and altered tumor suppressors are a major source of genomic instability in tumors, and that they generate those abnormal processes to initiate and sustain tumorigenesis. We discuss how altered tumor suppressors and oncogenes utilize the cell cycle regulatory machinery to signal centrosome amplification and aneuploidy. PMID- 21272330 TI - A reference dataset for verifying numerical electrophysiological heart models. AB - BACKGROUND: The evaluation, verification and comparison of different numerical heart models are difficult without a commonly available database that could be utilized as a reference. Our aim was to compile an exemplary dataset. METHODS: The following methods were employed: Magnetic Resonance Imaging (MRI) of heart and torso, Body Surface Potential Maps (BSPM) and MagnetoCardioGraphy (MCG) maps. The latter were recorded simultaneously from the same individuals a few hours after the MRI sessions. RESULTS: A training dataset is made publicly available; datasets for blind testing will remain undisclosed. CONCLUSIONS: While the MRI data may provide a common input that can be applied to different numerical heart models, the verification and comparison of different models can be performed by comparing the measured biosignals with forward calculated signals from the models. PMID- 21272331 TI - Synchronized multiple regression of diagnostic radiation-induced rather than spontaneous: disseminated primary intracranial germinoma in a woman: a case report. AB - INTRODUCTION: Examples of the spontaneous regression of primary intracranial germinomas can be found in the literature. We present the case of a patient with disseminated lesions of primary intracranial germinoma which synchronously shrunk following diagnostic irradiation. We will discuss whether this regression was spontaneous or radiation-induced. CASE PRESENTATION: A 43-year-old Japanese woman presented to our hospital complaining of memory problems over a period of one year and blurred vision over a period of three months. Following magnetic resonance imaging, she was found to have a massive lesion in the third ventricle and small lesions in the pineal region, fourth ventricle, and in the anterior horn of the left lateral ventricle. Prior to an open biopsy to confirm the pathology of the lesions, she underwent a single cranial computed tomography scan and a single cranial digital subtraction angiography for a transcranial biopsy. Fourteen days after the first magnetic resonance image - 12 and eight days after the computed tomography scan and digital subtraction angiography, respectively - a pre-operative magnetic resonance image was taken, which showed a notable synchronous shrinkage of the third ventricle tumor, as well as shrinkage of the lesions in the pineal region and in the fourth ventricle. She did not undergo steroid administration until after a biopsy that confirmed the pathological diagnosis of pure germinoma. She then underwent whole craniospinal irradiation and went into a complete remission. CONCLUSIONS: In our case report, we state that diagnostic radiation can induce the regression of germinomas; this is the most reasonable explanation for the synchronous multiple regression observed in this case of germinoma. Clinicians should keep this non-spontaneous regression in mind and monitor germinoma lesions with minimal exposure to diagnostic radiation before diagnostic confirmation, and also before radiation treatment with or without chemotherapy begins. PMID- 21272333 TI - Pelvic actinomycosis presenting as a malignant pelvic mass: a case report. AB - INTRODUCTION: Pelvic actinomycosis constitutes 3% of all human actinomycosis infections. It is usually insidious, and is often mistaken for other conditions such as diverticulitis, abscesses, inflammatory bowel disease and malignant tumors, presenting a diagnostic challenge pre-operatively; it is identified post operatively in most cases. Here we present a case that presented as pelvic malignancy and was diagnosed as pelvic actinomycosis post-operatively. CASE PRESENTATION: A 48-year-old Caucasian Turkish woman presented to our clinic with a three-month history of abdominal pain, weight loss and difficulty in defecation. She had used an intra-uterine device for 16 years, however it had recently been removed. The rectosigmoidoscopy revealed narrowing of the lumen at 12 cm due to a mass lesion either in the wall or due to an extrinsic lesion that prevented the passage of the endoscope. On examination, there was no gynecological pathology. Magnetic resonance imaging showed a mass, measuring 5.5 * 4 cm attached to the rectum posterior to the uterus. The ureter on that side was dilated. Surgically there was a pelvic mass adhered to the rectum and uterine adnexes, measuring 10 * 12 cm. It originated from uterine adnexes, particularly ones from the left side and formed a conglomerated mass with the uterus and nearby organs; the left ureter was also dilated due to the pelvic mass. Because of concomitant tubal abscess formation and difficulty in dissection planes, total abdominal hysterectomy and bilateral salphingo-oophorectomy was performed (our patient was 48 years old and had completed her childbearing period). The cytology revealed inflammatory cells with aggregates of Actinomyces. Penicillin therapy was given for six months without any complication. CONCLUSIONS: Pelvic actinomycosis should always be considered in patients with a pelvic mass especially in ones using intra-uterine devices, and who have a history of appendectomy, tonsillectomy or dental infection. Surgeons should be aware of this infection in order to avoid excessive surgical procedures. PMID- 21272332 TI - Clinical outcomes of active specific immunotherapy in advanced colorectal cancer and suspected minimal residual colorectal cancer: a meta-analysis and system review. AB - BACKGROUND: To evaluate the objective clinical outcomes of active specific immunotherapy (ASI) in advanced colorectal cancer (advanced CRC) and suspected minimal residual colorectal cancer (suspected minimal residual CRC). METHODS: A search was conducted on Medline and Pub Med from January 1998 to January 2010 for original studies on ASI in colorectal cancer (CRC). All articles included in this study were assessed with the application of predetermined selection criteria and were divided into two groups: ASI in advanced CRC and ASI in suspected minimal residual CRC. For ASI in suspected minimal residual CRC, a meta-analysis was executed with results regarding the overall survival (OS) and disease-free survival (DFS). Regarding ASI in advanced colorectal cancer, a system review was performed with clinical outcomes. RESULTS: 1375 colorectal carcinoma patients with minimal residual disease have been enrolled in Meta-analysis. A significantly improved OS and DFS was noted for suspected minimal residual CRC patients utilizing ASI (For OS: HR = 0.76, P = 0.007; For DFS: HR = 0.76, P = 0.03). For ASI in stage II suspected minimal residual CRC, OS approached significance when compared with control (HR = 0.71, P = 0.09); however, the difference in DFS of ASI for the stage II suspected minimal residual CRC reached statistical significance (HR = 0.66, P = 0.02). For ASI in stage III suspected minimal residual CRC compared with control, The difference in both OS and DFS achieved statistical significance (For OS: HR = 0.76, P = 0.02; For DFS: HR = 0.81, P = 0.03). 656 advanced colorectal patients have been evaluated on ASI in advanced CRC. Eleven for CRs and PRs was reported, corresponding to an overall response rate of 1.68%. No serious adverse events have been observed in 2031 patients. CONCLUSIONS: It is unlikely that ASI will provide a standard complementary therapeutic approach for advanced CRC in the near future. However, the clinical responses to ASI in patients with suspected minimal residual CRC have been encouraging, and it has become clear that immunotherapy works best in situations of patients with suspected minimal residual CRC. PMID- 21272334 TI - Combined mirror visual and auditory feedback therapy for upper limb phantom pain: a case report. AB - INTRODUCTION: Phantom limb sensation and phantom limb pain is a very common issue after amputations. In recent years there has been accumulating data implicating 'mirror visual feedback' or 'mirror therapy' as helpful in the treatment of phantom limb sensation and phantom limb pain. CASE PRESENTATION: We present the case of a 24-year-old Caucasian man, a left upper limb amputee, treated with mirror visual feedback combined with auditory feedback with improved pain relief. CONCLUSION: This case may suggest that auditory feedback might enhance the effectiveness of mirror visual feedback and serve as a valuable addition to the complex multi-sensory processing of body perception in patients who are amputees. PMID- 21272335 TI - Pancreatic cancer: surgery is a feasible therapeutic option for elderly patients. AB - BACKGROUND: Compromised physiological reserve, comorbidities, and the natural history of pancreatic cancer may deny pancreatic resection from elderly patients. We evaluated outcomes of elderly patients amenable to pancreatic surgery. METHODS: The medical records of all patients who underwent pancreatic resection at our institution (1995-2007) were retrospectively reviewed. Patient, tumor, and outcomes characteristics in elderly patients aged >= 70 years were compared to a younger cohort (<70 y). RESULTS: Of 460 patients who had surgery for pancreatic neoplasm, 166 (36%) aged >= 70 y. Compared to patients < 70 y (n = 294), elderly patients had more associated comorbidities; 72% vs. 43% (p = 0.01) and a higher rate of malignant pathologies; 73% vs. 59% (p = 0.002). Operative time and blood products consumption were comparable; however, elderly patients had more post operative complications (41% vs. 29%; p = 0.01), longer hospital stay (26.2 vs. 19.7 days; p < 0.0001), and a higher incidence of peri-operative mortality (5.4% vs. 1.4%; p = 0.01). Multivariable analysis identified age >= 70 y as an independent predictor of shorter disease-specific survival (DSS) among patients who had surgery for pancreatic adenocarcinoma (n = 224). Median DSS for patients aged >= 70 y vs. < 70 y were 15 months (SE: 1.6) vs. 20 months (SE: 3.4), respectively (p = 0.05). One, two, and 5-Y DSS rates for the cohort of elderly patients were 58%, 36% and 23%, respectively. CONCLUSIONS: Properly selected elderly patients can undergo pancreatic resection with acceptable post-operative morbidity and mortality rates. Long term survival is achievable even in the presence of adenocarcinoma and therefore surgery should be seriously considered in these patients. PMID- 21272336 TI - Response to written feedback of clinical data within a longitudinal study: a qualitative study exploring the ethical implications. AB - BACKGROUND: There is a growing ethical imperative to feedback research results to participants but there remains a striking lack of empirical research on how people respond to individualised feedback. We sought to explore longitudinal study participants' response to receiving individual written feedback of weight related and blood results, and to consider the balance of harms against benefits. METHODS: A qualitative study with face-to-face and telephone interviews conducted with 50 men and women who had participated in the fifth and most recent wave of the cohort study 'West of Scotland Twenty-07' and received a feedback letter containing body mass index (BMI), body fat percentage, cholesterol and glycated haemoglobin A1c (HbA1c) results. RESULTS: Expectations of, and response to, the feedback of their individual results varied. Whilst half of the participants were on the whole 'pleased' with their results or held neutral views, half reported negative responses such as 'shock' or 'concern', particularly in relation to the weight-related results. Participants who were overweight and obese used the most negative language about their results, with some being quite distressed and reporting feelings of powerlessness, low self-image and anxiety over future health. Nevertheless, some people reported having implemented lifestyle changes in direct response to the feedback, resulting in significant weight-loss and/or dietary improvements. Others reported being motivated to change their behaviour. Age and gender differences were apparent in these narratives of behaviour change. CONCLUSIONS: The potential harm caused to some participants may be balanced against the benefit to others. More evaluation of the impact of the format, content and means of individualised feedback of research findings in non-trial studies is required given the growing ethical imperative to offer participants a choice of receiving their results, and the likelihood that a high percentage will choose to receive them. PMID- 21272337 TI - Differential cytopathogenesis of respiratory syncytial virus prototypic and clinical isolates in primary pediatric bronchial epithelial cells. AB - BACKGROUND: Human respiratory syncytial virus (RSV) causes severe respiratory disease in infants. Airway epithelial cells are the principle targets of RSV infection. However, the mechanisms by which it causes disease are poorly understood. Most RSV pathogenesis data are derived using laboratory-adapted prototypic strains. We hypothesized that such strains may be poorly representative of recent clinical isolates in terms of virus/host interactions in primary human bronchial epithelial cells (PBECs). METHODS: To address this hypothesis, we isolated three RSV strains from infants hospitalized with bronchiolitis and compared them with the prototypic RSV A2 in terms of cytopathology, virus growth kinetics and chemokine secretion in infected PBEC monolayers. RESULTS: RSV A2 rapidly obliterated the PBECs, whereas the clinical isolates caused much less cytopathology. Concomitantly, RSV A2 also grew faster and to higher titers in PBECs. Furthermore, dramatically increased secretion of IP-10 and RANTES was evident following A2 infection compared with the clinical isolates. CONCLUSIONS: The prototypic RSV strain A2 is poorly representative of recent clinical isolates in terms of cytopathogenicity, viral growth kinetics and pro-inflammatory responses induced following infection of PBEC monolayers. Thus, the choice of RSV strain may have important implications for future RSV pathogenesis studies. PMID- 21272338 TI - Eccentric exercise versus usual-care with older cancer survivors: the impact on muscle and mobility--an exploratory pilot study. AB - BACKGROUND: Resistance exercise programs with high compliance are needed to counter impaired muscle and mobility in older cancer survivors. To date outcomes have focused on older prostate cancer survivors, though more heterogeneous groups of older survivors are in-need. The purpose of this exploratory pilot study is to examine whether resistance exercise via negative eccentrically-induced work (RENEW) improves muscle and mobility in a diverse sample of older cancer survivors. METHODS: A total of 40 individuals (25 female, 15 male) with a mean age of 74 (+/- 6) years who have survived (8.4 +/- 8 years) since their cancer diagnosis (breast, prostate, colorectal and lymphoma) were assigned to a RENEW group or a non-exercise Usual-care group. RENEW was performed for 12 weeks and measures of muscle size, strength, power and mobility were made pre and post training. RESULTS: RENEW induced increases in quadriceps lean tissue average cross sectional area (Pre: 43.2 +/- 10.8 cm2; Post: 44.9 +/- 10.9 cm2), knee extension peak strength (Pre: 248.3 +/- 10.8 N; Post: 275.4 +/- 10.9 N), leg extension muscle power (Pre: 198.2 +/- 74.7 W; Post 255.5 +/- 87.3 W), six minute walk distance (Pre: 417.2 +/- 127.1 m; Post 466.9 +/- 125.1 m) and a decrease on the time to safely descend stairs (Pre: 6.8 +/- 4.5 s; Post 5.4 +/- 2.5 s). A significant (P < 0.05) group x time interaction was noted for the muscle size and mobility improvements. CONCLUSIONS: This exploration of RENEW in a heterogeneous cohort of older cancer survivors demonstrates increases in muscle size, strength and power along with improved mobility. The efficacy of a high-force, low perceived exertion exercise suggests RENEW may be suited to older individuals who are survivors of cancer. PMID- 21272339 TI - Reduction of exacerbations by the PDE4 inhibitor roflumilast--the importance of defining different subsets of patients with COPD. AB - BACKGROUND: As chronic obstructive pulmonary disease (COPD) is a heterogeneous disease it is unlikely that all patients will benefit equally from a given therapy. Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, has been shown to improve lung function in moderate and severe COPD but its effect on exacerbations in unselected populations was inconclusive. This led to the question of whether a responsive subset existed that could be investigated further. METHODS: The datasets of two previous replicate, randomized, double blind, placebo-controlled, parallel-group studies (oral roflumilast 500 MUg or placebo once daily for 52 weeks) that were inconclusive regarding exacerbations were combined in a post-hoc, pooled analysis to determine whether roflumilast reduced exacerbations in a more precisely defined patient subset. RESULTS: The pooled analysis included 2686 randomized patients. Roflumilast significantly decreased exacerbations by 14.3% compared with placebo (p = 0.026). Features associated with this reduction were: presence of chronic bronchitis with or without emphysema (26.2% decrease, p = 0.001), presence of cough (20.9% decrease, p = 0.006), presence of sputum (17.8% decrease, p = 0.03), and concurrent use of inhaled corticosteroids (ICS; 18.8% decrease, p = 0.014). The incidence of adverse events was similar with roflumilast and placebo (81.5% vs 80.1%), but more patients in the roflumilast group had events assessed as likely or definitely related to the study drug (21.5% vs 8.3%). CONCLUSIONS: This post-hoc, pooled analysis showed that roflumilast reduced exacerbation frequency in a subset of COPD patients whose characteristics included chronic bronchitis with/without concurrent ICS. These observations aided the design of subsequent phase 3 studies that prospectively confirmed the reduction in exacerbations with roflumilast treatment. TRIALS REGISTRATION: ClinicalTrials.gov identifiers: NCT00076089 and NCT00430729. PMID- 21272340 TI - PubChem3D: Conformer generation. AB - BACKGROUND: PubChem, an open archive for the biological activities of small molecules, provides search and analysis tools to assist users in locating desired information. Many of these tools focus on the notion of chemical structure similarity at some level. PubChem3D enables similarity of chemical structure 3-D conformers to augment the existing similarity of 2-D chemical structure graphs. It is also desirable to relate theoretical 3-D descriptions of chemical structures to experimental biological activity. As such, it is important to be assured that the theoretical conformer models can reproduce experimentally determined bioactive conformations. In the present study, we investigate the effects of three primary conformer generation parameters (the fragment sampling rate, the energy window size, and force field variant) upon the accuracy of theoretical conformer models, and determined optimal settings for PubChem3D conformer model generation and conformer sampling. RESULTS: Using the software package OMEGA from OpenEye Scientific Software, Inc., theoretical 3-D conformer models were generated for 25,972 small-molecule ligands, whose 3-D structures were experimentally determined. Different values for primary conformer generation parameters were systematically tested to find optimal settings. Employing a greater fragment sampling rate than the default did not improve the accuracy of the theoretical conformer model ensembles. An ever increasing energy window did increase the overall average accuracy, with rapid convergence observed at 10 kcal/mol and 15 kcal/mol for model building and torsion search, respectively; however, subsequent study showed that an energy threshold of 25 kcal/mol for torsion search resulted in slightly improved results for larger and more flexible structures. Exclusion of coulomb terms from the 94s variant of the Merck molecular force field (MMFF94s) in the torsion search stage gave more accurate conformer models at lower energy windows. Overall average accuracy of reproduction of bioactive conformations was remarkably linear with respect to both non-hydrogen atom count ("size") and effective rotor count ("flexibility"). Using these as independent variables, a regression equation was developed to predict the RMSD accuracy of a theoretical ensemble to reproduce bioactive conformations. The equation was modified to give a minimum RMSD conformer sampling value to help ensure that 90% of the sampled theoretical models should contain at least one conformer within the RMSD sampling value to a "bioactive" conformation. CONCLUSION: Optimal parameters for conformer generation using OMEGA were explored and determined. An equation was developed that provides an RMSD sampling value to use that is based on the relative accuracy to reproduce bioactive conformations. The optimal conformer generation parameters and RMSD sampling values determined are used by the PubChem3D project to generate theoretical conformer models. PMID- 21272341 TI - Clinical features, acute complications, and outcome of Salmonella meningitis in children under one year of age in Taiwan. AB - BACKGROUND: Salmonella meningitis remains a threat to children below two years of age in both developing and developed countries. However, information on such infections has not been well characterized. We analyzed data related to twelve years of experience in order to clarify the comprehensive features of Salmonella meningitis in our patients, including admission characteristics, acute complications, and long-term outcome. METHODS: The records of patients with spontaneous Salmonella meningitis from 1982 to 1994 were retrospectively reviewed. The long-term outcome was prospectively determined for survivors at school age by the developmental milestones reported by their parents and detailed neurological evaluation along with intelligence, hearing, visual, speech and language assessments. RESULTS: Of the twenty-four patients, seizures were noted in fifteen (63%) before admission and thirteen (54%) during hospitalization. Acute complications mainly included hydrocephalus (50%), subdural collection (42%), cerebral infarction (33%), ventriculitis (25%), empyema (13%), intracranial abscess (8%), and cranial nerve palsy (8%). Three patients (13%) died during the acute phase of Salmonella meningitis. The twenty-one survivors, on whom we followed up at school age, have sequelae consisting of language disorder (52%), motor disability (48%), intelligence quotient < 80 (43%), epilepsy (33%), sensorineural hearing loss (17%), visual deficits (10%), abducens nerve palsy (5%), microcephaly (5%), and hydrocephalus (5%). Overall, good outcome was noted in six (28.6%) of twenty-one survivors, mild sequelae in three (14.2%), moderate in six (28.6%), and severe in six (28.6%). CONCLUSION: Salmonella meningitis in neonates and infants had a wide spectrum of morbidity and acute complications, leading to a complicated hospital course and subsequently a high prevalence of permanent adverse outcome. Thus, early recognition of acute complications of Salmonella meningitis and a follow-up plan for early developmental assessment of survivors are vital. PMID- 21272342 TI - Purification and characterization of the first recombinant bird pancreatic lipase expressed in Pichia pastoris: the turkey. AB - BACKGROUND: The turkey pancreatic lipase (TPL) was purified from delipidated pancreases. Some biochemical properties and kinetic studies were determined using emulsified system and monomolecular film techniques. Those studies have shown that despite the accumulation of free fatty acids at the olive oil/water interface, TPL continues to hydrolyse efficiently the olive oil and the TC4 in the absence of colipase and bile salts, contrary to most classical digestive lipases which denaturate rapidly under the same conditions. The aim of the present study was to express TPL in the methylotrophic yeast Pichia pastoris in order to get a large amount of this enzyme exhibiting interesting biochemical properties, to purify and characterize the recombinant enzyme. RESULTS: The recombinant TPL was secreted into the culture medium and the expression level reached about 15 mg/l after 4 days of culture. Using Q-PCR, the number of expression cassette integrated on Pichia genomic DNA was estimated to 5. The purified rTPL, with molecular mass of 50 kDa, has a specific activity of 5300 U/mg on emulsified olive oil and 9500 U/mg on tributyrin. The optimal temperature and pH of rTPL were 37 degrees C and pH 8.5. The stability, reaction kinetics and effects of calcium ions and bile salts were also determined. CONCLUSIONS: Our results show that the expressed TPL have the same properties as the native TPL previously purified. This result allows us the use of the recombinant enzyme to investigate the TPL structure-function relationships. PMID- 21272343 TI - Fetal derived embryonic-like stem cells improve healing in a large animal flexor tendonitis model. AB - INTRODUCTION: Tendon injury is a common problem in athletes, with poor tissue regeneration and a high rate of re-injury. Stem cell therapy is an attractive treatment modality as it may induce tissue regeneration rather than tissue repair. Currently, there are no reports on the use of pluripotent cells in a large animal tendon model in vivo. We report the use of intra-lesional injection of male, fetal derived embryonic-like stem cells (fdESC) that express Oct-4, Nanog, SSEA4, Tra 1-60, Tra 1-81 and telomerase. METHODS: Tendon injury was induced using a collagenase gel-physical defect model in the mid-metacarpal region of the superficial digital flexor tendon (SDFT) of eight female adult Thoroughbred or Thoroughbred cross horses. Tendon lesions were treated one week later with intra-lesional injection of male derived fdESCs in media or media alone. Therapy was blinded and randomized. Serial ultrasound examinations were performed and final analysis at eight weeks included magnetic resonance imaging (MRI), biochemical assays (total DNA, glycosaminoglycan, collagen), gene expression (TNC, TNMD, SCX, COL1A1, COL3A1, COMP, DCN, MMP1, MMP3, MMP13, 18S) and histology. Differences between groups were assessed with Wilcoxon's rank sum test. RESULTS: Cell survival was demonstrated via the presence of the SRY gene in fdESC treated, but not control treated, female SDFT at the end of the trial. There were no differences in tendon matrix specific gene expression or total proteoglycan, collagen or DNA of tendon lesions between groups. Tissue architecture, tendon size, tendon lesion size, and tendon linear fiber pattern were significantly improved on histologic sections and ultrasound in the fdESC treated tendons. CONCLUSIONS: Such profound structural effects lend further support to the notion that pluripotent stem cells can effect musculoskeletal regeneration, rather than repair, even without in vitro lineage specific differentiation. Further investigation into the safety of pluripotent cellular therapy as well as the mechanisms by which repair was improved seem warranted. PMID- 21272344 TI - In vitro effects of relaxin on gene expression in porcine cumulus-oocyte complexes and developing embryos. AB - BACKGROUND: Relaxin hormone peptide is found in porcine follicular and utero tubal fluids, but its possible actions during early embryo development are still undetermined. Here, we investigated the effects of porcine relaxin during oocyte maturation and embryo development, and gene expression in the pig. METHODS: Immature cumulus-oocyte complexes (COCs) were obtained from ovarian follicles of sows. In experiment 1, COCs were matured in the presence of 0, 20, or 40 ng relaxin/ml, or 10% (v/v) porcine follicular fluid. In experiment 2, COCs were in vitro matured, fertilized and resulting embryos were cultured in the presence of 0, 20, or 40 ng relaxin/ml. In experiment 3, COCs were matured in the presence of 40 ng relaxin/ml, fertilized and zygotes were cultured as indicated in experiment 2. We evaluated the proportions of matured oocytes in experiment 1, cleaved and blastocysts on Day 2 and Day 7 post insemination in all experiments. The total cell number of blastocysts was also evaluated. In parallel, transcription levels of both relaxin and its receptors (RXFP1 and RXFP2), as well as a pro- (Bax) and anti- (Bcl2-like 1) apoptotic-related genes were determined. All data were analyzed by ANOVA and significant differences were fixed for P < 0.05. RESULTS: In experiment 1, relaxin significantly increased the proportions of matured oocytes and cleaved embryos, as well as the expression level of RXFP2 mRNA compared to RXFP1 (P < 0.05). There was no effect on endogenous expression of relaxin and Bcl2-like1/Bax ratios. In all experiments, relaxin did not affect the proportions of blastocysts, but did significantly increase their total cell numbers (P < 0.05). Furthermore, no effect of relaxin was observed on Bcl2 like1/Bax expression ratios, which were similar between groups. CONCLUSIONS: Exogenous relaxin influences its own receptors expression, improves oocyte nuclear maturation. Its beneficial effect on total cell number of blastocysts appears to be through a Bcl2-like1/Bax-independent mechanism. PMID- 21272345 TI - Youth mental health first aid: a description of the program and an initial evaluation. AB - BACKGROUND: Adolescence is the peak age of onset for mental illness, with half of all people who will ever have a mental illness experiencing their first episode prior to 18 years of age. Early onset of mental illness is a significant predictor for future episodes. However, adolescents and young adults are less likely than the population as a whole to either seek or receive treatment for a mental illness. The knowledge and attitudes of the adults in an adolescent's life may affect whether or not help is sought, and how quickly. In 2007, the Youth Mental Health First Aid Program was launched in Australia with the aim to teach adults, who work with or care for adolescents, the skills needed to recognise the early signs of mental illness, identify potential mental health-related crises, and assist adolescents to get the help they need as early as possible. This paper provides a description of the program, some initial evaluation and an outline of future directions. METHODS: The program was evaluated in two ways. The first was an uncontrolled trial with 246 adult members of the Australian public, who completed questionnaires immediately before attending the 14 hour course, one month later and six months later. Outcome measures were: recognition of schizophrenia or depression; intention to offer and confidence in offering assistance; stigmatising attitudes; knowledge about adolescent mental health problems and also about the Mental Health First Aid action plan. The second method of evaluation was to track the uptake of the program, including the number of instructors trained across Australia to deliver the course, the number of courses they delivered, and the uptake of the YMHFA Program in other countries. RESULTS: The uncontrolled trial found improvements in: recognition of schizophrenia; confidence in offering help; stigmatising attitudes; knowledge about adolescent mental health problems and application of the Mental Health First Aid action plan. Most results were maintained at follow-up. Over the first 3 years of this program, a total of 318 instructors were trained to deliver the course and these instructors have delivered courses to 10,686 people across all states and territories in Australia. The program has also spread to Canada, Singapore and England, and will spread to Hong Kong, Sweden and China in the near future. CONCLUSIONS: Initial evaluation suggests that the Youth Mental Health First Aid course improves participants' knowledge, attitudes and helping behaviour. The program has spread successfully both nationally and internationally. TRIAL REGISTRATION: ACTRN12609000033246. PMID- 21272346 TI - Statistical learning techniques applied to epidemiology: a simulated case-control comparison study with logistic regression. AB - BACKGROUND: When investigating covariate interactions and group associations with standard regression analyses, the relationship between the response variable and exposure may be difficult to characterize. When the relationship is nonlinear, linear modeling techniques do not capture the nonlinear information content. Statistical learning (SL) techniques with kernels are capable of addressing nonlinear problems without making parametric assumptions. However, these techniques do not produce findings relevant for epidemiologic interpretations. A simulated case-control study was used to contrast the information embedding characteristics and separation boundaries produced by a specific SL technique with logistic regression (LR) modeling representing a parametric approach. The SL technique was comprised of a kernel mapping in combination with a perceptron neural network. Because the LR model has an important epidemiologic interpretation, the SL method was modified to produce the analogous interpretation and generate odds ratios for comparison. RESULTS: The SL approach is capable of generating odds ratios for main effects and risk factor interactions that better capture nonlinear relationships between exposure variables and outcome in comparison with LR. CONCLUSIONS: The integration of SL methods in epidemiology may improve both the understanding and interpretation of complex exposure/disease relationships. PMID- 21272347 TI - Change in CD3 positive T-cell expression in psoriatic arthritis synovium correlates with change in DAS28 and magnetic resonance imaging synovitis scores following initiation of biologic therapy--a single centre, open-label study. AB - INTRODUCTION: With the development of increasing numbers of potential therapeutic agents in inflammatory disease comes the need for effective biomarkers to help screen for drug efficacy and optimal dosing regimens early in the clinical trial process. This need has been recognized by the Outcome Measures in Rheumatology Clinical Trials (OMERACT) group, which has established guidelines for biomarker validation. To seek a candidate synovial biomarker of treatment response in psoriatic arthritis (PsA), we determined whether changes in immunohistochemical markers of synovial inflammation correlate with changes in disease activity scores assessing 28 joints (DeltaDAS28) or magnetic resonance imaging synovitis scores (DeltaMRI) in patients with PsA treated with a biologic agent. METHODS: Twenty-five consecutive patients with PsA underwent arthroscopic synovial biopsies and MRI scans of an inflamed knee joint at baseline and 12 weeks after starting treatment with either anakinra (first 10 patients) or etanercept (subsequent 15 patients) in two sequential studies of identical design. DAS28 scores were measured at both time points. Immunohistochemical staining for CD3, CD68 and Factor VIII (FVIII) was performed on synovial samples and scored by digital image analysis (DIA). MRI scans performed at baseline and at 12 weeks were scored for synovitis semi-quantitatively. The DeltaDAS28 of the European League Against Rheumatism good response definition (>1.2) was chosen to divide patients into responder and non-responder groups. Differences between groups (Mann Whitney U test) and correlations between DeltaDAS28 with change in immunohistochemical and MRI synovitis scores (Spearman's rho test) were calculated. RESULTS: Paired synovial samples and MRI scans were available for 21 patients (8 anakinra, 13 etanercept) and 23 patients (8 anakinra, 15 etanercept) respectively. Change in CD3 (DeltaCD3) and CD68 expression in the synovial sublining layer (DeltaCD68sl) was significantly greater in the disease responders compared to non-responders following treatment (P = 0.005 and 0.013 respectively). DeltaCD3, but not DeltaCD68 or DeltaFVIII, correlated with both DeltaDAS28 (r = 0.49, P = 0.025) and DeltaMRI (r = 0.58, P = 0.009). CONCLUSIONS: The correlation of DeltaCD3 with DeltaDAS28 and DeltaMRI following biologic treatment in this cohort contributes to the validation of DeltaCD3 as a synovial biomarker of disease response in PsA, and supports the further evaluation of DeltaCD3 for predictive properties of future clinical outcomes. PMID- 21272348 TI - Malignant PEComa: a case report with emphasis on clinical and morphological criteria. AB - BACKGROUND: Malignant perivascular epitheliod cell tumor (PEComa) is a very rare entity composed of distinctive perivascular epitheliod cells with variable immunoreactivity for melanocytic and muscle markers. At present this neoplasm does not have a known normal cellular counterpart and the natural history is often unpredictable. Up to now, few cases of PEComa have been described and treatment modalities are still controversial, particularly in advanced conditions. CASE PRESENTATION: We handled the case of a 42-year-old man with unresectable PEComa of the abdomen. A 7 cm hepatic hypodense lesion between segment V and VIII of the liver and diffuse intraperitoneal nodules of 0,3-3,5 cm along the right subcapsular hepatic region, were documented by a CT scan. Radiological images showed abnormal lymph nodes of the right internal mammary chain and anterior mediastinum. The patient underwent an explorative laparotomy for uncontrolled intraabdominal hemorrhage without a well-defined preoperative tumor diagnosis. At surgery, multiple lobulated nodules containing hemorrhagic fluid on the liver surface, peritoneum and omentum were confirmed. The procedure had a palliative intent and consisted of hemostasis, hematomas evacuation and omentectomy. The diagnosis of PEComa was made after surgery on the basis of morphological and immunohistochemical criteria. Radiological and intra operative findings suggest that the mass has an hepatic origin with diffuse involvement of hepatic capsule and suspensory ligaments. The patient received medical support care with blood and plasma transfusions. In our experience, PEComa was clinically malignant, leading to a fatal outcome 25 days after hospital admission of patient. CONCLUSIONS: Here we report and discuss the peculiar clinical, radiological and morphological presentation of unresectable PEComa. Although in the majority of the reported series, PEComas show a more better prognosis, our case presents with a particular aggressive biological behaviour. The importance of a correct preoperative diagnosis, the need for more effective targeted therapies based on tumor molecular knowledge and evidence-based clinical studies are emphasized together with a revision of the concerning scientific literature. PMID- 21272349 TI - Longing for ground in a ground(less) world: a qualitative inquiry of existential suffering. AB - BACKGROUND: Existential and spiritual concerns are fundamental issues in palliative care and patients frequently articulate these concerns. The purpose of this study was to understand the process of engaging with existential suffering at the end of life. METHODS: A grounded theory approach was used to explore processes in the context of situated interaction and to explore the process of existential suffering. We began with in vivo codes of participants' words, and clustered these codes at increasingly higher levels of abstractions until we were able to theorize. RESULTS: Findings suggest the process of existential suffering begins with an experience of groundlessness that results in an overarching process of Longing for Ground in a Ground(less) World, a wish to minimize the uncomfortable or anxiety-provoking instability of groundlessness. Longing for ground is enacted in three overlapping ways: by turning toward one's discomfort and learning to let go (engaging groundlessness), turning away from the discomfort, attempting to keep it out of consciousness by clinging to familiar thoughts and ideas (taking refuge in the habitual), and learning to live within the flux of instability and unknowing (living in-between). CONCLUSIONS: Existential concerns are inherent in being human. This has implications for clinicians when considering how patients and colleagues may experience existential concerns in varying degrees, in their own fashion, either consciously or unconsciously. Findings emphasize a fluid and dynamic understanding of existential suffering and compel health providers to acknowledge the complexity of fear and anxiety while allowing space for the uniquely fluid nature of these processes for each person. Findings also have implications for health providers who may gravitate towards the transformational possibilities of encounters with mortality without inviting space for less optimistic possibilities of resistance, anger, and despondency that may concurrently arise. PMID- 21272350 TI - Outcomes and associated risk factors of patients traced after being lost to follow-up from antiretroviral treatment in Lilongwe, Malawi. AB - BACKGROUND: Loss to follow-up is a major challenge of antiretroviral treatment (ART) programs in sub-Saharan Africa. Our objective was to a) determine true outcomes of patients lost to follow-up (LTFU) and b) identify risk factors associated with successful tracing and deaths of patients LTFU from ART in a large public sector clinic in Lilongwe, Malawi. METHODS: Patients who were more than 2 weeks late according to their last ART supply and who provided a phone number or address in Lilongwe were eligible for tracing. Their outcomes were updated and risk factors for successful tracing and death were examined. RESULTS: Of 1800 patients LTFU with consent for tracing, 724 (40%) were eligible and tracing was successful in 534 (74%): 285 (53%) were found to be alive and on ART; 32 (6%) had stopped ART; and 217 (41%) had died. Having a phone contact doubled tracing success (adjusted odds ratio, aOR = 2.1, 95% CI 1.4-3.0) and odds of identifying deaths [aOR = 1.8 (1.2-2.7)] in patients successfully traced. Mortality was higher when ART was fee-based at initiation (aOR = 2.3, 95% CI 1.1 4.7) and declined with follow-up time on ART. Limiting the analysis to patients living in Lilongwe did not change the main findings. CONCLUSION: Ascertainment of contact information is a prerequisite for tracing, which can reveal outcomes of a large proportion of patients LTFU. Having a phone contact number is critical for successful tracing, but further research should focus on understanding whether phone tracing is associated with any differential reporting of mortality or LTFU. PMID- 21272351 TI - Genome-wide identification, classification and analysis of heat shock transcription factor family in maize. AB - BACKGROUND: Heat shock response in eukaryotes is transcriptionally regulated by conserved heat shock transcription factors (Hsfs). Hsf genes are represented by a large multigene family in plants and investigation of the Hsf gene family will serve to elucidate the mechanisms by which plants respond to stress. In recent years, reports of genome-wide structural and evolutionary analysis of the entire Hsf gene family have been generated in two model plant systems, Arabidopsis and rice. Maize, an important cereal crop, has represented a model plant for genetics and evolutionary research. Although some Hsf genes have been characterized in maize, analysis of the entire Hsf gene family were not completed following Maize (B73) Genome Sequencing Project. RESULTS: A genome-wide analysis was carried out in the present study to identify all Hsfs maize genes. Due to the availability of complete maize genome sequences, 25 nonredundant Hsf genes, named ZmHsfs were identified. Chromosomal location, protein domain and motif organization of ZmHsfs were analyzed in maize genome. The phylogenetic relationships, gene duplications and expression profiles of ZmHsf genes were also presented in this study. Twenty five ZmHsfs were classified into three major classes (class A, B, and C) according to their structural characteristics and phylogenetic comparisons, and class A was further subdivided into 10 subclasses. Moreover, phylogenetic analysis indicated that the orthologs from the three species (maize, Arabidopsis and rice) were distributed in all three classes, it also revealed diverse Hsf gene family expression patterns in classes and subclasses. Chromosomal/segmental duplications played a key role in Hsf gene family expansion in maize by investigation of gene duplication events. Furthermore, the transcripts of 25 ZmHsf genes were detected in the leaves by heat shock using quantitative real time PCR. The result demonstrated that ZmHsf genes exhibit different expression levels in heat stress treatment. CONCLUSIONS: Overall, data obtained from our investigation contributes to a better understanding of the complexity of the maize Hsf gene family and provides the first step towards directing future experimentation designed to perform systematic analysis of the functions of the Hsf gene family. PMID- 21272352 TI - Modeling RNA interference in mammalian cells. AB - BACKGROUND: RNA interference (RNAi) is a regulatory cellular process that controls post-transcriptional gene silencing. During RNAi double-stranded RNA (dsRNA) induces sequence-specific degradation of homologous mRNA via the generation of smaller dsRNA oligomers of length between 21-23nt (siRNAs). siRNAs are then loaded onto the RNA-Induced Silencing multiprotein Complex (RISC), which uses the siRNA antisense strand to specifically recognize mRNA species which exhibit a complementary sequence. Once the siRNA loaded-RISC binds the target mRNA, the mRNA is cleaved and degraded, and the siRNA loaded-RISC can degrade additional mRNA molecules. Despite the widespread use of siRNAs for gene silencing, and the importance of dosage for its efficiency and to avoid off target effects, none of the numerous mathematical models proposed in literature was validated to quantitatively capture the effects of RNAi on the target mRNA degradation for different concentrations of siRNAs. Here, we address this pressing open problem performing in vitro experiments of RNAi in mammalian cells and testing and comparing different mathematical models fitting experimental data to in-silico generated data. We performed in vitro experiments in human and hamster cell lines constitutively expressing respectively EGFP protein or tTA protein, measuring both mRNA levels, by quantitative Real-Time PCR, and protein levels, by FACS analysis, for a large range of concentrations of siRNA oligomers. RESULTS: We tested and validated four different mathematical models of RNA interference by quantitatively fitting models' parameters to best capture the in vitro experimental data. We show that a simple Hill kinetic model is the most efficient way to model RNA interference. Our experimental and modeling findings clearly show that the RNAi-mediated degradation of mRNA is subject to saturation effects. CONCLUSIONS: Our model has a simple mathematical form, amenable to analytical investigations and a small set of parameters with an intuitive physical meaning, that makes it a unique and reliable mathematical tool. The findings here presented will be a useful instrument for better understanding RNAi biology and as modelling tool in Systems and Synthetic Biology. PMID- 21272353 TI - Inflammatory and cytotoxic responses of an alveolar-capillary coculture model to silica nanoparticles: comparison with conventional monocultures. AB - BACKGROUND: To date silica nanoparticles (SNPs) play an important role in modern technology and nanomedicine. SNPs are present in various materials (tyres, electrical and thermal insulation material, photovoltaic facilities). They are also used in products that are directly exposed to humans such as cosmetics or toothpaste. For that reason it is of great concern to evaluate the possible hazards of these engineered particles for human health. Attention should primarily be focussed on SNP effects on biological barriers. Accidentally released SNP could, for example, encounter the alveolar-capillary barrier by inhalation. In this study we examined the inflammatory and cytotoxic responses of monodisperse amorphous silica nanoparticles (aSNPs) of 30 nm in size on an in vitro coculture model mimicking the alveolar-capillary barrier and compared these to conventional monocultures. METHODS: Thus, the epithelial cell line, H441, and the endothelial cell line, ISO-HAS-1, were used in monoculture and in coculture on opposite sides of a filter membrane. Cytotoxicity was evaluated by the MTS assay, detection of membrane integrity (LDH release), and TER (Transepithelial Electrical Resistance) measurement. Additionally, parameters of inflammation (sICAM-1, IL-6 and IL-8 release) and apoptosis markers were investigated. RESULTS: Regarding toxic effects (viability, membrane integrity, TER) the coculture model was less sensitive to apical aSNP exposure than the conventional monocultures of the appropriate cells. On the other hand, the in vitro coculture model responded with the release of inflammatory markers in a much more sensitive fashion than the conventional monoculture. At concentrations that were 10-100fold less than the toxic concentrations the apically exposed coculture showed a release of IL-6 and IL-8 to the basolateral side. This may mimic the early inflammatory events that take place in the pulmonary alveoli after aSNP inhalation. Furthermore, a number of apoptosis markers belonging to the intrinsic pathway were upregulated in the coculture following aSNP treatment. Analysis of the individual markers indicated that the cells suffered from DNA damage, hypoxia and ER-stress. CONCLUSION: We present evidence that our in vitro coculture model of the alveolar-capillary barrier is clearly advantageous compared to conventional monocultures in evaluating the extent of damage caused by hazardous material encountering the principle biological barrier in the lower respiratory tract. PMID- 21272354 TI - Model SNP development for complex genomes based on hexaploid oat using high throughput 454 sequencing technology. AB - BACKGROUND: Genetic markers are pivotal to modern genomics research; however, discovery and genotyping of molecular markers in oat has been hindered by the size and complexity of the genome, and by a scarcity of sequence data. The purpose of this study was to generate oat expressed sequence tag (EST) information, develop a bioinformatics pipeline for SNP discovery, and establish a method for rapid, cost-effective, and straightforward genotyping of SNP markers in complex polyploid genomes such as oat. RESULTS: Based on cDNA libraries of four cultivated oat genotypes, approximately 127,000 contigs were assembled from approximately one million Roche 454 sequence reads. Contigs were filtered through a novel bioinformatics pipeline to eliminate ambiguous polymorphism caused by subgenome homology, and 96 in silico SNPs were selected from 9,448 candidate loci for validation using high-resolution melting (HRM) analysis. Of these, 52 (54%) were polymorphic between parents of the Ogle1040 * TAM O-301 (OT) mapping population, with 48 segregating as single Mendelian loci, and 44 being placed on the existing OT linkage map. Ogle and TAM amplicons from 12 primers were sequenced for SNP validation, revealing complex polymorphism in seven amplicons but general sequence conservation within SNP loci. Whole-amplicon interrogation with HRM revealed insertions, deletions, and heterozygotes in secondary oat germplasm pools, generating multiple alleles at some primer targets. To validate marker utility, 36 SNP assays were used to evaluate the genetic diversity of 34 diverse oat genotypes. Dendrogram clusters corresponded generally to known genome composition and genetic ancestry. CONCLUSIONS: The high-throughput SNP discovery pipeline presented here is a rapid and effective method for identification of polymorphic SNP alleles in the oat genome. The current-generation HRM system is a simple and highly-informative platform for SNP genotyping. These techniques provide a model for SNP discovery and genotyping in other species with complex and poorly-characterized genomes. PMID- 21272355 TI - Animal model integration to AutDB, a genetic database for autism. AB - BACKGROUND: In the post-genomic era, multi-faceted research on complex disorders such as autism has generated diverse types of molecular information related to its pathogenesis. The rapid accumulation of putative candidate genes/loci for Autism Spectrum Disorders (ASD) and ASD-related animal models poses a major challenge for systematic analysis of their content. We previously created the Autism Database (AutDB) to provide a publicly available web portal for ongoing collection, manual annotation, and visualization of genes linked to ASD. Here, we describe the design, development, and integration of a new module within AutDB for ongoing collection and comprehensive cataloguing of ASD-related animal models. DESCRIPTION: As with the original AutDB, all data is extracted from published, peer-reviewed scientific literature. Animal models are annotated with a new standardized vocabulary of phenotypic terms developed by our researchers which is designed to reflect the diverse clinical manifestations of ASD. The new Animal Model module is seamlessly integrated to AutDB for dissemination of diverse information related to ASD. Animal model entries within the new module are linked to corresponding candidate genes in the original "Human Gene" module of the resource, thereby allowing for cross-modal navigation between gene models and human gene studies. Although the current release of the Animal Model module is restricted to mouse models, it was designed with an expandable framework which can easily incorporate additional species and non-genetic etiological models of autism in the future. CONCLUSIONS: Importantly, this modular ASD database provides a platform from which data mining, bioinformatics, and/or computational biology strategies may be adopted to develop predictive disease models that may offer further insights into the molecular underpinnings of this disorder. It also serves as a general model for disease-driven databases curating phenotypic characteristics of corresponding animal models. PMID- 21272356 TI - Thinking about going to the dentist: a Contemplation Ladder to assess dentally avoidant individuals' readiness to go to a dentist. AB - BACKGROUND: The Transtheoretical Model suggests that individuals vary according to their readiness to change behavior. Previous work in smoking cessation and other health areas suggests that interventions are more successful when they are tailored to an individual's stage of change with regards to the specific behavior. We report on the performance of a single-item measure ("Ladder") to assess the readiness to change dental-avoidant behavior. METHODS: An existing Contemplation Ladder for assessing stage of change in smoking cessation was modified to assess readiness to go to a dentist. The resulting Ladder was administered to samples of English-speaking adolescents (USA), Spanish-speaking adults (USA), and Norwegian military recruits (Norway) in order to assess construct validity. The Ladder was also administered to a sample of English speaking avoidant adolescents and young adults who were enrolled in an intervention study (USA) in order to assess criterion validity. All participants also had dental examinations, and completed other questionnaires. Correlations, chi square, t tests and one-way ANOVAs were used to assess relationships between variables. RESULTS: In two samples, participants who do not go to the dentist had significantly more teeth with caries; in a third sample, participants who do not go to the dentist had significantly worse caries. Ladder scores were not significantly related to age, gender, caries, or dental fear. However, Ladder scores were significantly related to statements of intention to visit a dentist in the future and the importance of oral health. In a preliminary finding, Ladder scores at baseline also predicted whether or not the participants decided to go to a dentist in the intervention sample. CONCLUSIONS: The data provide support for the convergent and divergent construct validity of the Ladder, and preliminary support for its criterion validity. The lack of relationship between dental fear and Ladder scores suggests that avoidant individuals may be helped to decide to go to a dentist using interventions which do not explicitly target their fear. PMID- 21272357 TI - Segmental duplication as one of the driving forces underlying the diversity of the human immunoglobulin heavy chain variable gene region. AB - BACKGROUND: Segmental duplication and deletion were implicated for a region containing the human immunoglobulin heavy chain variable (IGHV) gene segments, 1.9III/hv3005 (possible allelic variants of IGHV3-30) and hv3019b9 (a possible allelic variant of IGHV3-33). However, very little is known about the ranges of the duplication and the polymorphic region. This is mainly because of the difficulty associated with distinguishing between allelic and paralogous sequences in the IGHV region containing extensive repetitive sequences. Inability to separate the two parental haploid genomes in the subjects is another serious barrier. To address these issues, unique DNA sequence tags evenly distributed within and flanking the duplicated region implicated by the previous studies were selected. The selected tags in single sperm from six unrelated healthy donors were amplified by multiplex PCR followed by microarray detection. In this way, individual haplotypes of different parental origins in the sperm donors could be analyzed separately and precisely. The identified polymorphic region was further analyzed at the nucleotide sequence level using sequences from the three human genomic sequence assemblies in the database. RESULTS: A large polymorphic region was identified using the selected sequence tags. Four of the 12 haplotypes were shown to contain consecutively undetectable tags spanning in a variable range. Detailed analysis of sequences from the genomic sequence assemblies revealed two large duplicate sequence blocks of 24,696 bp and 24,387 bp, respectively, and an incomplete copy of 961 bp in this region. It contains up to 13 IGHV gene segments depending on haplotypes. A polymorphic region was found to be located within the duplicated blocks. The variants of this polymorphism unusually diverged at the nucleotide sequence level and in IGHV gene segment number, composition and organization, indicating a limited selection pressure in general. However, the divergence level within the gene segments is significantly different from that in the intergenic regions indicating that these regions may have been subject to different selection pressures and that the IGHV gene segments in this region are functionally important. CONCLUSIONS: Non-reciprocal genetic rearrangements associated with large duplicate sequence blocks could substantially contribute to the IGHV region diversity. Since the resulting polymorphisms may affect the number, composition and organization of the gene segments in this region, it may have significant impact on the function of the IGHV gene segment repertoire, antibody diversity, and therefore, the immune system. Because one of the gene segments, 3-30 (1.9III), is associated with autoimmune diseases, it could be of diagnostic significance to learn about the variants in the haplotypes by using the multiplex haplotype analysis system used in the present study with DNA sequence tags specific for the variants of all gene segments in this region. PMID- 21272358 TI - A comparison of the MOS-HIV and SF-12v2 for measuring health-related quality of life of men and women living with HIV/AIDS. AB - BACKGROUND: The purpose of this study was to examine the relationship between the Medical Outcomes Study-HIV Health Survey (MOS-HIV) and the SF-12v2 to determine if the latter is adequate to assess the health-related quality of life (HRQoL) of men and women living with HIV/AIDS. 112 men and women living with HIV/AIDS who access care at a tertiary HIV clinic in Hamilton, Ontario were included in this cross-sectional analysis. Correlation coefficients of the MOS-HIV physical and mental health summary scores (PHS and MHS) and the SF-12v2 physical and mental component summary scales (PCS and MCS) were calculated along with common sub domains of the measures including physical functioning (PF), bodily pain (BP), general health perceptions (GH), vitality (VT), social functioning (SF) and mental health (MH) to explore the relationship between these two HRQoL measures. The sub-domains role physical (RP) and role emotional (RE) of the SF-12v2 were compared separately to the sub-domain role functioning (RF) of the MOS-HIV. Weighted kappa scores were calculated to determine agreement beyond chance between the MOS-HIV and SF-12v2 in assigning a HRQoL state (i.e. low, moderate, good, very good). RESULTS: The MOS-HIV had mean PHS and MHS summary scores of 47.3 (SD = 11.5) and 49.2 (SD = 10.7) respectively. The mean SF-12v2 PCS and MCS scores were 47.7 (SD = 11.0) and 44.0 (SD = 10.4). The MOS-HIV and SF-12v2 physical and mental health summary scores were positively correlated (r = 0.84, p < 0.001 and r = 0.76, p < 0.001). All common sub-domains were significantly correlated at p values from < 0.001 to 0.034. Substantial agreement was observed in assigning a HRQoL state (Physical: kappa = 0.788, SE = 0.095; Mental: kappa = 0.707, SE = 0.095). CONCLUSIONS: This analysis validates the SF-12v2 for measuring HRQoL in adult men and women living with HIV/AIDS. PMID- 21272359 TI - Kin discrimination and possible cryptic species in the social amoeba Polysphondylium violaceum. AB - BACKGROUND: The genetic diversity of many protists is unknown. The differences that result from this diversity can be important in interactions among individuals. The social amoeba Polysphondylium violaceum, which is a member of the Dictyostelia, has a social stage where individual amoebae aggregate together to form a multicellular fruiting body with dead stalk cells and live spores. Individuals can either cooperate with amoebae from the same clone, or sort to form clonal fruiting bodies. In this study we look at genetic diversity in P. violaceum and at how this diversity impacts social behavior. RESULTS: The phylogeny of the ribosomal DNA sequence (17S to 5.8S region) shows that P. violaceum is made up of at least two groups. Mating compatibility is more common between clones from the same phylogenetic group, though matings between clones from different phylogenetic groups sometimes occurred. P. violaceum clones are more likely to form clonal fruiting bodies when they are mixed with clones from a different group than when they are mixed with a clone of the same group. CONCLUSION: Both the phylogenetic and mating analyses suggest the possibility of cryptic species in P. violaceum. The level of divergence found within P. violaceum is comparable to the divergence between sibling species in other dictyostelids. Both major groups A/B and C/D/E/F show kin discrimination, which elevates relatedness within fruiting bodies but not to the level of clonality. The diminished cooperation in mixes between groups suggests that the level of genetic variation between individuals influences the extent of their cooperation. PMID- 21272360 TI - Identification of novel conserved functional motifs across most Influenza A viral strains. AB - BACKGROUND: Influenza A virus poses a continuous threat to global public health. Design of novel universal drugs and vaccine requires a careful analysis of different strains of Influenza A viral genome from diverse hosts and subtypes. We performed a systematic in silico analysis of Influenza A viral segments of all available Influenza A viral strains and subtypes and grouped them based on host, subtype, and years isolated, and through multiple sequence alignments we extrapolated conserved regions, motifs, and accessible regions for functional mapping and annotation. RESULTS: Across all species and strains 87 highly conserved regions (conservation percentage > = 90%) and 19 functional motifs (conservation percentage = 100%) were found in PB2, PB1, PA, NP, M, and NS segments. The conservation percentage of these segments ranged between 94-98% in human strains (the most conserved), 85-93% in swine strains (the most variable), and 91-94% in avian strains. The most conserved segment was different in each host (PB1 for human strains, NS for avian strains, and M for swine strains). Target accessibility prediction yielded 324 accessible regions, with a single stranded probability > 0.5, of which 78 coincided with conserved regions. Some of the interesting annotations in these regions included sites for protein-protein interactions, the RNA binding groove, and the proton ion channel. CONCLUSIONS: The influenza virus has evolved to adapt to its host through variations in the GC content and conservation percentage of the conserved regions. Nineteen universal conserved functional motifs were discovered, of which some were accessible regions with interesting biological functions. These regions will serve as a foundation for universal drug targets as well as universal vaccine design. PMID- 21272361 TI - The use of ultra-dense array CGH analysis for the discovery of micro-copy number alterations and gene fusions in the cancer genome. AB - BACKGROUND: Molecular alterations critical to development of cancer include mutations, copy number alterations (amplifications and deletions) as well as genomic rearrangements resulting in gene fusions. Massively parallel next generation sequencing, which enables the discovery of such changes, uses considerable quantities of genomic DNA (> 5 ug), a serious limitation in ever smaller clinical samples. However, a commonly available microarray platforms such as array comparative genomic hybridization (array CGH) allows the characterization of gene copy number at a single gene resolution using much smaller amounts of genomic DNA. In this study we evaluate the sensitivity of ultra-dense array CGH platforms developed by Agilent, especially that of the 1 million probe array (1 M array), and their application when whole genome amplification is required because of limited sample quantities. METHODS: We performed array CGH on whole genome amplified and not amplified genomic DNA from MCF-7 breast cancer cells, using 244 K and 1 M Agilent arrays. The ADM-2 algorithm was used to identify micro-copy number alterations that measured less than 1 Mb in genomic length. RESULTS: DNA from MCF-7 breast cancer cells was analyzed for micro-copy number alterations, defined as measuring less than 1 Mb in genomic length. The 4-fold extra resolution of the 1 M array platform relative to the less dense 244 K array platform, led to the improved detection of copy number variations (CNVs) and micro-CNAs. The identification of intra-genic breakpoints in areas of DNA copy number gain signaled the possible presence of gene fusion events. However, the ultra-dense platforms, especially the densest 1 M array, detect artifacts inherent to whole genome amplification and should be used only with non-amplified DNA samples. CONCLUSIONS: This is a first report using 1 M array CGH for the discovery of cancer genes and biomarkers. We show the remarkable capacity of this technology to discover CNVs, micro-copy number alterations and even gene fusions. However, these platforms require excellent genomic DNA quality and do not tolerate relatively small imperfections related to the whole genome amplification. PMID- 21272362 TI - Label-free peptide profiling of OrbitrapTM full mass spectra. AB - BACKGROUND: We developed a new version of the open source software package Peptrix that can yet compare large numbers of OrbitrapTM LC-MS data. The peptide profiling results for Peptrix on MS1 spectra were compared with those obtained from a small selection of open source and commercial software packages: msInspect, SieveTM and ProgenesisTM. The properties compared in these packages were speed, total number of detected masses, redundancy of masses, reproducibility in numbers and CV of intensity, overlap of masses, and differences in peptide peak intensities. Reproducibility measurements were taken for the different MS1 software applications by measuring in triplicate a complex peptide mixture of immunoglobulin on the OrbitrapTM mass spectrometer. Values of peptide masses detected from the high intensity peaks of the MS1 spectra by peptide profiling were verified with values of the MS2 fragmented and sequenced masses that resulted in protein identifications with a significant score. FINDINGS: Peptrix finds about the same number of peptide features as the other packages, but peptide masses are in some cases approximately 5 to 10 times less redundant present in the peptide profile matrix. The Peptrix profile matrix displays the largest overlap when comparing the number of masses in a pair between two software applications. The overlap of peptide masses between software packages of low intensity peaks in the spectra is remarkably low with about 50% of the detected masses in the individual packages. Peptrix does not differ from the other packages in detecting 96% of the masses that relate to highly abundant sequenced proteins. MS1 peak intensities vary between the applications in a non linear way as they are not processed using the same method. CONCLUSIONS: Peptrix is capable of peptide profiling using OrbitrapTM files and finding differential expressed peptides in body fluid and tissue samples. The number of peptide masses detected in OrbitrapTM files can be increased by using more MS1 peptide profiling applications, including Peptrix, since it appears from the comparison of Peptrix with the other applications that all software packages have likely a high false negative rate of low intensity peptide peaks (missing peptides). PMID- 21272363 TI - Plasma incorporation, apparent retroconversion and beta-oxidation of 13C docosahexaenoic acid in the elderly. AB - BACKGROUND: Higher fish or higher docosahexaenoic acid (DHA) intake normally correlates positively with higher plasma DHA level, but recent evidence suggests that the positive relationship between intake and plasma levels of DHA is less clear in the elderly. METHODS: We compared the metabolism of 13C-DHA in six healthy elderly (mean - 77 y old) and six young adults (mean - 27 y old). All participants were given a single oral dose of 50 mg of uniformly labelled 13C DHA. Tracer incorporation into fatty acids of plasma triglycerides, free fatty acids, cholesteryl esters and phospholipids, as well as apparent retroconversion and beta-oxidation of 13C-DHA were evaluated 4 h, 24 h, 7d and 28d later. RESULTS: Plasma incorporation and beta-oxidation of 13C-DHA reached a maximum within 4 h in both groups, but 13C-DHA was transiently higher in all plasma lipids of the elderly 4 h to 28d later. At 4 h post-dose, 13C-DHA beta-oxidation was 1.9 times higher in the elderly, but over 7d, cumulative beta-oxidation of 13C-DHA was not different in the two groups (35% in the elderly and 38% in the young). Apparent retroconversion of 13C-DHA was well below 10% of 13C-DHA recovered in plasma at all time points, and was 2.1 times higher in the elderly 24 h and 7d after tracer intake. CONCLUSIONS: We conclude that 13C-DHA metabolism changes significantly during healthy aging. Since DHA is a potentially important molecule in neuro-protection, these changes may be relevant to the higher vulnerability of the elderly to cognitive decline. PMID- 21272364 TI - A multidisciplinary systematic review of the use of diagrams as a means of collecting data from research subjects: application, benefits and recommendations. AB - BACKGROUND: In research, diagrams are most commonly used in the analysis of data and visual presentation of results. However there has been a substantial growth in the use of diagrams in earlier stages of the research process to collect data. Despite this growth, guidance on this technique is often isolated within disciplines. METHODS: A multidisciplinary systematic review was performed, which included 13 traditional healthcare and non-health-focused indexes, non-indexed searches and contacting experts in the field. English-language articles that used diagrams as a data collection tool and reflected on the process were included in the review, with no restriction on publication date. RESULTS: The search identified 2690 documents, of which 80 were included in the final analysis. The choice to use diagrams for data collection is often determined by requirements of the research topic, such as the need to understand research subjects' knowledge or cognitive structure, to overcome cultural and linguistic differences, or to understand highly complex subject matter. How diagrams were used for data collection varied by the degrees of instruction for, and freedom in, diagram creation, the number of diagrams created or edited and the use of diagrams in conjunction with other data collection methods. Depending on how data collection is structured, a variety of options for qualitative and quantitative analysis are available to the researcher. The review identified a number of benefits to using diagrams in data collection, including the ease with which the method can be adapted to complement other data collection methods and its ability to focus discussion. However it is clear that the benefits and challenges of diagramming depend on the nature of its application and the type of diagrams used. DISCUSSION/CONCLUSION: The results of this multidisciplinary systematic review examine the application of diagrams in data collection and the methods for analyzing the unique datasets elicited. Three recommendations are presented. Firstly, the diagrammatic approach should be chosen based on the type of data needed. Secondly, appropriate instructions will depend on the approach chosen. And thirdly, the final results should present examples of original or recreated diagrams. This review also highlighted the need for a standardized terminology of the method and a supporting theoretical framework. PMID- 21272365 TI - Comparative evaluation of stroke triage algorithms for emergency medical dispatchers (MeDS): prospective cohort study protocol. AB - BACKGROUND: Stroke is a major cause of death and leading cause of disability in the United States. To maximize a stroke patient's chances of receiving thrombolytic treatment for acute ischemic stroke, it is important to improve prehospital recognition of stroke. However, it is known from published reports that emergency medical dispatchers (EMDs) using Card 28 of the Medical Priority Dispatch System protocols recognize stroke poorly. Therefore, to improve EMD's recognition of stroke, the National Association of Emergency Medical Dispatchers recently designed a new diagnostic stroke tool (Cincinnati Stroke Scale -CSS) to be used with Card 28. The objective of this study is to determine whether the addition of CSS improves diagnostic accuracy of stroke triage. METHODS/DESIGN: This prospective experimental study will be conducted during a one-year period in the 911 call center of Santa Clara County, CA. We will include callers aged >= 18 years with a chief complaint suggestive of stroke and second party callers (by stander or family who are in close proximity to the patient and can administer the tool) >= 18 years of age. Life threatening calls will be excluded from the study. Card 28 questions will be administered to subjects who meet study criteria. After completion of Card 28, CSS tool will be administered to all calls. EMDs will record their initial assessment of a cerebro-vascular accident (stroke) after completion of Card 28 and their final assessment after completion of CSS. These assessments will be compared with the hospital discharge diagnosis (ICD-9 codes) recorded in the Office of Statewide Health Planning and Development (OSHPD) database after linking the EMD database and OSHPD database using probabilistic linkage. The primary analysis will compare the sensitivity of the two stroke protocols using logistic regression and generalizing estimating equations to account for clustering by EMDs. To detect a 15% difference in sensitivity between the two groups with 80% power, we will enroll a total of 370 subjects in this trial. DISCUSSION: A three week pilot study was performed which demonstrated the feasibility of implementation of the study protocol. PMID- 21272366 TI - Modulation of TRAIL resistance in colon carcinoma cells: different contributions of DR4 and DR5. AB - BACKGROUND: rhTRAIL is a therapeutic agent, derived from the TRAIL cytokine, which induces apoptosis in cancer cells by activating the membrane death receptors 4 and 5 (DR4 and DR5). Here, we investigated each receptor's contribution to rhTRAIL sensitivity and rhTRAIL resistance. We assessed whether agonistic DR4 or DR5 antibodies could be used to circumvent rhTRAIL resistance, alone or in combination with various chemotherapies. METHODS: Our study was performed in an isogenic model comprised of the SW948 human colon carcinoma cell line and its rhTRAIL resistant sub-line SW948-TR. Effects of rhTRAIL and agonistic DR4/DR5 antibodies on cell viability were measured using MTT assays and identification of morphological changes characteristic of apoptosis, after acridine orange staining. Sensitivity to the different death receptor ligands was stimulated using pretreatment with the cytokine IFN-gamma and the proteasome inhibitor MG-132. To investigate the mechanisms underlying the changes in rhTRAIL sensitivity, alterations in expression levels of targets of interest were measured by Western blot analysis. Co-immunoprecipitation was used to determine the composition of the death-inducing signalling complex at the cell membrane. RESULTS: SW948 cells were sensitive to all three of the DR-targeting agents tested, although the agonistic DR5 antibody induced only weak caspase 8 cleavage and limited apoptosis. Surprisingly, agonistic DR4 and DR5 antibodies induced equivalent DISC formation and caspase 8 cleavage at the level of their individual receptors, suggesting impairment of further caspase 8 processing upon DR5 stimulation. SW948-TR cells were cross-resistant to all DR-targeting agents as a result of decreased caspase 8 expression levels. Caspase 8 protein expression was restored by MG-132 and IFN-gamma pretreatment, which also re-established sensitivity to rhTRAIL and agonistic DR4 antibody in SW948-TR. Surprisingly, MG 132 but not IFN-gamma could also increase DR5-mediated apoptosis in SW948-TR. CONCLUSIONS: These results highlight a critical difference between DR4- and DR5 mediated apoptotic signaling modulation, with possible implications for future combinatorial regimens. PMID- 21272367 TI - Anti-HSP90 autoantibodies in sera of infertile women identify a dominant, conserved epitope EP6 (380-389) of HSP90 beta protein. AB - BACKGROUND: We earlier reported a simple specific test for detection of anti ovarian antibodies in infertile women and identified number of specific molecular and cellular targets of which human heat shock protein 90-beta (HSP90 beta) was found to be the most immunodominant. The present study focuses on prediction and validation of the immunodominant epitope/s of this protein using sera from infertile women having anti-HSP90 autoantibodies. METHODS: Delineation of the immunodominant epitopes of HSP90 beta was done by using epitope prediction algorithms and 10 peptides (EP1-EP10) were custom synthesized. Their immunoreactivity was measured by ELISA using sera from patients and controls. To determine the most immunodominant epitope, the results were subjected to statistical analysis. The immunoreactivity of the immunodominant peptides were confirmed by dot blots using sera from patients. A rabbit polyclonal antibody against the immunodominant epitope was generated and its immunoreactivity to the parent protein in ovarian extracts as well in oocytes and embryos was investigated. RESULTS: Experimentally and statistically, peptide EP6 (380-389) seems to be the major antigenic epitope for the serum antibody binding followed by EP1 (1-12) and EP8 (488-498). Predicted 3D structures of these peptides demonstrated that they exist in the loop conformation which is the most mobile part of the protein. Also, analysis of the sequences of HSP90 beta across several species reveals that EP6 peptide forms a part of a well conserved motif. The polyclonal antibody generated to the immunodominant epitope- EP6 confirms similar biochemical and cellular immunoreactivity as seen with the patients' sera having anti-HSP90 autoantibodies. CONCLUSIONS: The decapeptide EP6 is a major immunogenic epitope of HSP90 followed by EP1 and EP8. Knowledge of binding epitopes on the autoantigen is necessary to understand the subsequent pathologic events. The study might generate new tools for the detection of disease-inducing epitopes and a possible therapeutic intervention. PMID- 21272368 TI - A review of public opinion towards alcohol controls in Australia. AB - BACKGROUND: Increasing concern about the negative impact of alcohol on the Australian community has renewed calls for tighter regulatory controls. This paper reviews levels of and trends in public support for liquor control regulations, regulation of alcohol promotions, and alcohol pricing and taxation reforms in Australia between 1998 and 2009. METHODS: Six electronic databases and twenty public health and alcohol organisation websites were searched for research literature, reports and media releases describing levels of public support for alcohol controls. Only studies which randomly selected participants were included. RESULTS: Twenty-one studies were included in the review. The majority of the Australian public support most proposed alcohol controls. Levels of support are divided between targeted and universal controls. CONCLUSIONS: Implementation of targeted alcohol policies is likely to be strongly supported by the Australian public, but universal controls are liable to be unpopular. Policy makers are provided with insights into factors likely to be associated with higher public support. PMID- 21272369 TI - Quantitative assessment of inter-observer variability in target volume delineation on stereotactic radiotherapy treatment for pituitary adenoma and meningioma near optic tract. AB - BACKGROUND: To assess inter-observer variability in delineating target volume and organs at risk in benign tumor adjacent to optic tract as a quality assurance exercise. METHODS: We quantitatively analyzed 21 plans made by 11 clinicians in seven CyberKnife centers. The clinicians were provided with a raw data set (pituitary adenoma and meningioma) including clinical information, and were asked to delineate the lesions and create a treatment plan. Their contouring and plans (10 adenoma and 11 meningioma plans), were then compared. In addition, we estimated the influence of differences in contouring by superimposing the respective contours onto a default plan. RESULTS: The median planning target volume (PTV) and the ratio of the largest to the smallest contoured volume were 9.22 cm3 (range, 7.17-14.3 cm3) and 1.99 for pituitary adenoma, and 6.86 cm3 (range 6.05-14.6 cm3) and 2.41 for meningioma. PTV volume was 10.1+/-1.74 cm3 for group 1 with a margin of 1-2 mm around the CTV (n=3) and 9.28+/-1.8 cm3 (p=0.51) for group 2 with no margin (n=7) in pituitary adenoma. In meningioma, group 1 showed larger PTV volume (10.1+/-3.26 cm3) than group 2 (6.91+/-0.7 cm3, p=0.03). All submitted plan keep the irradiated dose to optic tract within the range of 50 Gy (equivalent total doses in 2 Gy fractionation). However, contours superimposed onto the dose distribution of the default plan indicated that an excessive dose 23.64 Gy (up to 268% of the default plan) in pituitary adenoma and 24.84 Gy (131% of the default plan) in meningioma to the optic nerve in the contours from different contouring. CONCLUSION: Quality assurance revealed inter-observer variability in contour delineation and their influences on planning for pituitary adenoma and meningioma near optic tract. PMID- 21272370 TI - Use of cerebral state index to predict long-term unconsciousness in patients after elective craniotomy with delay recovery. AB - BACKGROUND: The major difficulty in postoperative care in patients after craniotomy is to distinguish the intracranial deficits from the residual effect of general anesthesia. In present study, we used cerebral state index (CSI) monitoring in patients after craniotomy with delayed recovery, and evaluated the prediction probability of CSI for long-term postoperative unconsciousness. METHODS: We enrolled 57 consecutive adult patients admitted to neurosurgical intensive care unit (NICU) after elective craniotomy with delayed recovery. CSI was continuously monitored for 6 hours after admission. Patient's level of consciousness was followed up for 24 hours. According to whether obeyed verbal command, patients were divided into awaken group and non-awaken group. CSI values were compared between the two groups. Prediction probability (PK) was calculated to determine the probability of CSI in predicting unconsciousness 24 hours after operation. RESULTS: In awaken group (n = 51), CSI increased significantly after the 2nd NICU admitted hour (P < 0.05). At each time point, CSI values in awaken group were significantly higher than those in non-awaken group (n = 6) (P < 0.05). The values of PK (SE) for CSI in the first 6 admitted hours ranged from 0.94 (0.06) to 0.99 (0.02). CONCLUSIONS: In patients after craniotomy with delayed recovery, CSI monitoring in early postoperative hours had high prediction probability for long-term unconsciousness. CSI monitoring may be a reliable objective method to predict level of consciousness after elective craniotomy. PMID- 21272371 TI - Development of a heart failure filter for Medline: an objective approach using evidence-based clinical practice guidelines as an alternative to hand searching. AB - BACKGROUND: Heart failure is a highly debilitating syndrome with a poor prognosis primarily affecting the elderly. Clinicians wanting timely access to heart failure evidence to provide optimal patient care can face many challenges in locating this evidence. This study developed and validated a search filter of high clinical utility for the retrieval of heart failure articles in OvidSP Medline. METHODS: A Clinical Advisory Group was established to advise study investigators. The study set of 876 relevant articles from four heart failure clinical practice guidelines was divided into three datasets: a Term Identification Set, a Filter Development Set, and a Filter Validation Set. A further validation set (the Cochrane Validation Set) was formed using studies included in Cochrane heart failure systematic reviews. Candidate search terms were identified via word frequency analysis. The filter was developed by creating combinations of terms and recording their performance in retrieving items from the Filter Development Set. The filter's recall was then validated in both the Filter Validation Set and the Cochrane Validation Set. A precision estimate was obtained post-hoc by running the filter in Medline and screening the first 200 retrievals for relevance to heart failure. RESULTS: The four-term filter achieved a recall of 96.9% in the Filter Development Set; 98.2% in the Filter Validation Set; and 97.8% in the Cochrane Validation Set. Of the first 200 references retrieved by the filter when run in Medline, 150 were deemed relevant and 50 irrelevant. The post-hoc precision estimate was therefore 75%. CONCLUSIONS: This study describes an objective method for developing a validated heart failure filter of high recall performance and then testing its precision post-hoc. Clinical practice guidelines were found to be a feasible alternative to hand searching in creating a gold standard for filter development. Guidelines may be especially appropriate given their clinical utility. A validated heart failure filter is now available to support health professionals seeking reliable and efficient access to the heart failure literature. PMID- 21272372 TI - Prediction of absolute risk of fragility fracture at 10 years in a Spanish population: validation of the WHO FRAX TM tool in Spain. AB - BACKGROUND: Age-related bone loss is asymptomatic, and the morbidity of osteoporosis is secondary to the fractures that occur. Common sites of fracture include the spine, hip, forearm and proximal humerus. Fractures at the hip incur the greatest morbidity and mortality and give rise to the highest direct costs for health services. Their incidence increases exponentially with age.Independently changes in population demography, the age - and sex- specific incidence of osteoporotic fractures appears to be increasing in developing and developed countries. This could mean more than double the expected burden of osteoporotic fractures in the next 50 years. METHODS/DESIGN: To assess the predictive power of the WHO FRAXTM tool to identify the subjects with the highest absolute risk of fragility fracture at 10 years in a Spanish population, a predictive validation study of the tool will be carried out. For this purpose, the participants recruited by 1999 will be assessed. These were referred to scan DXA Department from primary healthcare centres, non hospital and hospital consultations. STUDY POPULATION: Patients attended in the national health services integrated into a FRIDEX cohort with at least one Dual-energy X-ray absorptiometry (DXA) measurement and one extensive questionnaire related to fracture risk factors. MEASUREMENTS: At baseline bone mineral density measurement using DXA, clinical fracture risk factors questionnaire, dietary calcium intake assessment, history of previous fractures, and related drugs. Follow up by telephone interview to know fragility fractures in the 10 years with verification in electronic medical records and also to know the number of falls in the last year. The absolute risk of fracture will be estimated using the FRAXTM tool from the official web site. DISCUSSION: Since more than 10 years ago numerous publications have recognised the importance of other risk factors for new osteoporotic fractures in addition to low BMD. The extension of a method for calculating the risk (probability) of fractures using the FRAXTM tool is foreseeable in Spain and this would justify a study such as this to allow the necessary adjustments in calibration of the parameters included in the logarithmic formula constituted by FRAXTM. PMID- 21272373 TI - Neuronal degeneration in autonomic nervous system of Dystonia musculorum mice. AB - BACKGROUND: Dystonia musculorum (dt) is an autosomal recessive hereditary neuropathy with a characteristic uncoordinated movement and is caused by a defect in the bullous pemphigoid antigen 1 (BPAG1) gene. The neural isoform of BPAG1 is expressed in various neurons, including those in the central and peripheral nerve systems of mice. However, most previous studies on neuronal degeneration in BPAG1 deficient mice focused on peripheral sensory neurons and only limited investigation of the autonomic system has been conducted. METHODS: In this study, patterns of nerve innervation in cutaneous and iridial tissues were examined using general neuronal marker protein gene product 9.5 via immunohistochemistry. To perform quantitative analysis of the autonomic neuronal number, neurons within the lumbar sympathetic and parasympathetic ciliary ganglia were calculated. In addition, autonomic neurons were cultured from embryonic dt/dt mutants to elucidate degenerative patterns in vitro. Distribution patterns of neuronal intermediate filaments in cultured autonomic neurons were thoroughly studied under immunocytochemistry and conventional electron microscopy. RESULTS: Our immunohistochemistry results indicate that peripheral sensory nerves and autonomic innervation of sweat glands and irises dominated degeneration in dt/dt mice. Quantitative results confirmed that the number of neurons was significantly decreased in the lumbar sympathetic ganglia as well as in the parasympathetic ciliary ganglia of dt/dt mice compared with those of wild-type mice. We also observed that the neuronal intermediate filaments were aggregated abnormally in cultured autonomic neurons from dt/dt embryos. CONCLUSIONS: These results suggest that a deficiency in the cytoskeletal linker BPAG1 is responsible for dominant sensory nerve degeneration and severe autonomic degeneration in dt/dt mice. Additionally, abnormally aggregated neuronal intermediate filaments may participate in neuronal death of cultured autonomic neurons from dt/dt mutants. PMID- 21272374 TI - Caregiver awareness of reproductive health issues for women with intellectual disabilities. AB - BACKGROUND: Limited attention has been paid to the issue of reproductive health as it affects women with intellectual disabilities, despite reproductive health being a vital issue in public health policy for women in the general population. This paper describes caregiver awareness of reproductive health issues relative to women with intellectual disabilities who are being cared for in welfare institutions in Taiwan. METHODS: The study employed a cross-sectional, questionnaire-based study which recruited 1,152 caregivers (response rate = 71.87%) from 32 registered disability welfare institutions in Taiwan. We classified their understanding/awareness of reproductive health issues into four domains: menstrual (1) and menopause (2) issues, sex education (3), and reproductive health services (4). Each domain had five associated yes/no questions and the total score for the four domains was out of a maximum of 20. Data were analyzed using SPSS 15.0 software. RESULTS: We found that most of the caregivers were familiar with matters concerning sex education, menopause, and reproductive health services, but they lacked adequate understanding of issues associated with menstruation in women with ID. Many aspects of reproductive health such as "menstrual pain", "age at menarche", "masturbation", "diet during perimenopause", and "publicly available reproductive health services" were issues in which caregivers lacked adequate knowledge and required further instruction. Logistic regression analysis revealed that female caregivers with a university degree, and those who had experience assisting with reproductive health care were more inclined to have higher reproductive health awareness scores than their counterparts. CONCLUSIONS: This study highlights that service providers should offer appropriate reproductive health education to institutional caregivers, and that more attention be focused on the personal experiences and concerns of intellectually disabled women in future research. PMID- 21272375 TI - Evaluation of suitable reference genes for gene expression studies in bronchoalveolar lavage cells from horses with inflammatory airway disease. AB - BACKGROUND: The stability of reference genes has a tremendous effect on the results of relative quantification of genes expression by quantitative polymerase chain reaction. Equine Inflammatory Airway Disease (IAD) is a common condition often treated with corticosteroids. The diagnosis of IAD is based on clinical signs and bronchoalveolar lavage (BAL) fluid cytology. The aim of this study was to identify reference genes with the most stable mRNA expression in the BAL cells of horses with IAD irrespective of corticosteroids treatment. RESULTS: The expression stability of seven candidate reference genes (B2M, HPRT, GAPDH, ACTB, UBB, RPL32, SDHA) was determined by qRT-PCR in BAL samples taken pre- and post- treatment with dexamethasone and fluticasone propionate for two weeks in 7 horses with IAD. Primers' efficiencies were calculated using LinRegPCR. NormFinder, GeNorm and qBasePlus softwares were used to rank the genes according to their stability. GeNorm was also used to determine both the ideal number and the best combination of reference genes. GAPDH was found to be the most stably expressed gene with the three softwares. GeNorm ranked B2M as the least stable gene. Based on the pair-wise variation cut-off value determined with GeNorm, the number of genes required for optimal normalization was four and included GAPDH, SDHA, HPRT and RPL32. CONCLUSION: The geometric mean of GAPDH, HPRT, SDHA and RPL32 is recommended for accurate normalization of quantitative PCR data in BAL cells of horses with IAD treated with corticosteroids. If only one reference gene can be used, then GAPDH is recommended. PMID- 21272376 TI - DL- and PO-phosphatidylcholines as a promising learning and memory enhancer. AB - In the water maze test, oral administration with 1,2-dilynoleoyl-sn-glycero-3 phosphocholine (DLPhtCho)(5 mg/kg) alone or DLPhtCho (5 mg/kg) plus 1-palmitoyl-2 oleoyl-sn-glycero-3-phosphocholine (POPhtCho)(5 mg/kg) significantly shortened the prolonged acquisition latency for rats intraperitoneally injected with scopolamine, with more efficient effect than (POPhtCho)(5 mg/kg) alone, arachidonic acid (AA)(5 mg/kg) alone, docosahexaenoic acid (DHA)(5 mg/kg) alone, or 1-palmitoyl-2-linoleil-sn-glycero-3-phosphoserine (PLPhtSer)(5 mg/kg) alone. POPhtCho (5 mg/kg) alone or DLPhtCho (5 mg/kg) plus POPhtCho (5 mg/kg) also significantly shortened the prolonged retention latency for rats intraperitoneally injected with scopolamine, but otherwise no significant effect was obtained with DLPhtCho (5 mg/kg) alone, AA (5 mg/kg) alone, DHA (5 mg/kg) alone, or PLPhtSer (5 mg/kg) alone. Oral co-administration with DLPhtCho (5 mg/kg) and POPhtCho (5 mg/kg) significantly shortened the acquisition latency for rats untreated with scopolamine as compared with the latency for administration with polyethylene glycol (PEG), DLPhtCho alone at doses of 5 and 10 mg/kg, or POPhtCho alone at doses of 5 and 10 mg/kg, while no efficient effect on the retention latency was obtained. To assess the effect of DLPhtCho and POPhtCho on cognitive functions for humans, Mini Mental State Examination (MMSE) test was performed in subjects with cognitive disorders (the average MMSE score, 15). Oral co-intake with DLPhtCho (50 mg) and POPhtCho (45 mg) once after breakfast everyday raised the score to over 20, corresponding to normal cognitive functions, throughout 5 months after intake, and the increase in the score was significantly greater than that for oral intake with DLPhtCho (100 mg/day) alone or POPhtCho (90 mg/kg) alone. Taken together, the results of the present study show that co-intake with DLPhtCho and POPhtCho could enhance learning and memory ability and improve cognitive disorders for both the animals and humans with a promising efficacy. PMID- 21272377 TI - Expressions of COX-2 and VEGF-C in gastric cancer: correlations with lymphangiogenesis and prognostic implications. AB - BACKGROUND: Cyclooxygenase-2 (COX-2) has recently been considered to promote lymphangiogenesis by up-regulating vascular endothelial growth factor-C (VEGF-C) in breast and lung cancer. However, the impact of COX-2 on lymphangiogenesis of gastric cancer remains unclear. This study aims to test the expression of COX-2 and VEGF-C in human gastric cancer, and to analyze the correlation with lymphatic vessel density (LVD), clinicopathologic features and survival prognosis. METHODS: Using immunohistochemistry, COX-2, VEGF-C and level of LVD were analyzed in 56 R0 resected primary gastric adenocarcinomas, while paracancerous normal mucosal tissues were also collected as control from 25 concurrent patients. The relationships among COX-2 and VEGF-C expression, LVD, and clinicopathologic parameters were analyzed. The correlations of COX-2, VEGF-C and level of LVD with patient prognosis were also evaluated by univariate tests and multivariate Cox regression. RESULTS: The expression rates of COX-2 and VEGF-C were 69.64% and 55.36%, respectively, in gastric carcinoma. Peritumoral LVD was significantly higher than that in both normal and intratumoral tissue (P < 0.05). It was significantly correlated with lymph node metastasis and invasion depth (P = 0.003, P = 0.05). VEGF-C was significantly associated with peritumoral LVD (r = 0.308, P = 0.021). However, COX-2 was not correlated with VEGF-C (r = 0.110, P = 0.419) or LVD (r = 0.042, P = 0.758). Univariate analysis showed that survival time was impaired by higher COX-2 expression and higher peritumoral LVD. Multivariate survival analysis showed that age, COX-2 expression and peritumoral LVD were independent prognostic factors. CONCLUSIONS: Although COX-2 expression was associated with survival time, it was not correlated with VEGF-C and peritumoral LVD. Our data did not show that overexpression of COX-2 promotes tumor lymphangiogenesis through an up-regulation of VEGF-C expression in gastric carcinoma. Age, COX-2 and peritumoral LVD were independent prognostic factors for human gastric carcinoma. PMID- 21272378 TI - Interaction of annexin A6 with alpha actinin in cardiomyocytes. AB - BACKGROUND: Annexins are calcium dependent phospholipid binding proteins that are expressed in a wide variety of tissues and implicated in various extra- and intracellular processes. In myocardial tissue, annexins A2, A5 and A6 are particularly abundant, of which the expression levels of annexin A6 has been found to be maximal. Conflicting reports from transgenic mice overexpressing annexin A6 or null mice lacking annexin A6 showed imbalances in intracellular calcium turnover and disturbed cardiac contractility. However, few studies have focussed on the signalling module of annexin A6 in the heart either in normal or in pathological state. RESULTS: To identify the putative binding partners of annexin A6 in the heart, ventricular extracts were subjected to glutathione S transferase (GST)- annexin A6 pull down assay and the GST- annexin A6 bound proteins were identified by mass spectrometry. The pull down fractions of ventricular extracts with GST-full length annexin A6 as well as GST-C terminus deleted annexin A6 when immunoblotted with anti sarcomeric alpha (alpha)-actinin antibody showed the presence of alpha-actinin in the immunoblot which was absent when GST-N terminus deleted annexin A6 was used for pull down. Overexpression of green fluorescent protein (GFP) tagged full length annexin A6 showed z-line like appearance in cardiomyocytes whereas GFP-N termimus deleted annexin A6 was mostly localized to the nucleus. Overexpression of GFP-C terminus deleted annexin A6 in cardiomyocytes showed aggregate like appearance in the cytoplasm. Double immunofluorescent staining of cardiomyocytes with anti annexin A6 and anti sarcomeric alpha-actinin antibodies showed perfect co-localization of these two proteins with annexin A6 appearing like a component of sarcomere. Transient knockdown of annexin A6 in cardiomyocytes by shRNA significantly enhances the contractile functions but does not affect the z-band architecture, as revealed by alpha-actinin immunostaining in shRNA treated cells. CONCLUSIONS: In overall, the present study demonstrated for the first time that annexin A6 physically interacts with sarcomeric alpha-actinin and alters contractility of cardiomyocytes suggesting that it might play important role in excitation and contraction process. PMID- 21272379 TI - Eukaryote-wide sequence analysis of mitochondrial beta-barrel outer membrane proteins. AB - BACKGROUND: The outer membranes of mitochondria are thought to be homologous to the outer membranes of Gram negative bacteria, which contain 100's of distinct families of beta-barrel membrane proteins (BOMPs) often forming channels for transport of nutrients or drugs. However, only four families of mitochondrial BOMPs (MBOMPs) have been confirmed to date. Although estimates as high as 100 have been made in the past, the number of yet undiscovered MBOMPs is an open question. Fortunately, the recent discovery of a membrane integration signal (the beta-signal) for MBOMPs gave us an opportunity to look for undiscovered MBOMPs. RESULTS: We present the results of a comprehensive survey of eukaryotic protein sequences intended to identify new MBOMPs. Our search employs recent results on beta-signals as well as structural information and a novel BOMP predictor trained on both bacterial and mitochondrial BOMPs. Our principal finding is circumstantial evidence suggesting that few MBOMPs remain to be discovered, if one assumes that, like known MBOMPs, novel MBOMPs will be monomeric and beta signal dependent. In addition to this, our analysis of MBOMP homologs reveals some exceptions to the current model of the beta-signal, but confirms its consistent presence in the C-terminal region of MBOMP proteins. We also report a beta-signal independent search for MBOMPs against the yeast and Arabidopsis proteomes. We find no good candidates MBOMPs in yeast but the Arabidopsis results are less conclusive. CONCLUSIONS: Our results suggest there are no remaining MBOMPs left to discover in yeast; and if one assumes all MBOMPs are beta-signal dependent, few MBOMP families remain undiscovered in any sequenced organism. PMID- 21272380 TI - Usefulness of N-terminal pro-brain natriuretic peptide and C-reactive protein to predict ICU mortality in unselected medical ICU patients: a prospective, observational study. AB - INTRODUCTION: The performance of N-terminal pro-brain natriuretic peptide (NT proBNP) and C-reactive protein (CRP) to predict clinical outcomes in ICU patients is unimpressive. We aimed to assess the prognostic value of NT-proBNP, CRP or the combination of both in unselected medical ICU patients. METHODS: A total of 576 consecutive patients were screened for eligibility and followed up during the ICU stay. We collected each patient's baseline characteristics including the Acute Physiology and Chronic Health Evaluation II (APACHE-II) score, NT-proBNP and CRP levels. The primary outcome was ICU mortality. Potential predictors were analyzed for possible association with outcomes. We also evaluated the ability of NT proBNP and CRP additive to APACHE-II score to predict ICU mortality by calculation of C-index, net reclassification improvement (NRI) and integrated discrimination improvement (IDI) indices. RESULTS: Multiple regression revealed that CRP, NT-proBNP, APACHE-II score and fasting plasma glucose independently predicted ICU mortality (all P < 0.01). The C-index with respect to prediction of ICU mortality of APACHE II score (0.82 +/- 0.02; P < 0.01) was greater than that of NT-proBNP (0.71 +/- 0.03; P < 0.01) or CRP (0.65 +/- 0.03; P < 0.01) (all P < 0.01). As compared with APACHE-II score (0.82 +/- 0.02; P < 0.01), combination of CRP (0.83 +/- 0.02; P < 0.01) or NT-proBNP (0.83 +/- 0.02; P < 0.01) or both (0.84 +/- 0.02; P < 0.01) with APACHE-II score did not significantly increase C index for predicting ICU mortality (all P > 0.05). However, addition of NT-proBNP to APACHE-II score gave IDI of 6.6% (P = 0.003) and NRI of 16.6% (P = 0.007), addition of CRP to APACHE-II score provided IDI of 5.6% (P = 0.026) and NRI of 12.1% (P = 0.023), and addition of both markers to APACHE-II score yielded IDI of 7.5% (P = 0.002) and NRI of 17.9% (P = 0.002). In the cardiac subgroup (N = 213), NT-proBNP but not CRP independently predicted ICU mortality and addition of NT proBNP to APACHE-II score obviously increased predictive ability (IDI = 10.2%, P = 0.018; NRI = 18.5%, P = 0.028). In the non-cardiac group (N = 363), CRP rather than NT-proBNP was an independent predictor of ICU mortality. CONCLUSIONS: In unselected medical ICU patients, NT-proBNP and CRP can serve as independent predictors of ICU mortality and addition of NT-proBNP or CRP or both to APACHE-II score significantly improves the ability to predict ICU mortality. NT-proBNP appears to be useful for predicting ICU outcomes in cardiac patients. PMID- 21272381 TI - Research on health transition in Africa: time for action. AB - With rapidly increasing globalization, trends towards unhealthy diets, obesity, sedentary lifestyles and unhealthy habits are resulting in an increased worldwide burden of chronic non-communicable diseases (NCDs). In Africa this means that health systems face the challenge of an increasing burden of NCDs and of continuing high morbidity and mortality from communicable diseases. This health transition represents an enormous challenge to Africa as the region with the least resources for an effective response. Whereas previous epidemics, including HIV, have caught Africa unprepared, the opportunity now arises to take the advancing wave of health transition in Africa seriously. Health research has a key role to play in meeting health and development goals, and must be responsive to changing disease patterns, such as health transition. There is an urgent need for research on health transition in Africa to enable countries to respond effectively to rapidly changing health needs.Key areas of research include the following: epidemiological research so that a good understanding of the distribution in Africa of communicable and non-communicable diseases can inform health planning; research on the interactions between communicable and non communicable diseases; health system research with a particular focus on new approaches to improve the primary care response to health transition; and policy research to evaluate the more upstream measures addressing the population-level determinants of NCDs. It is time to capitalise on the global policy environment, which is becoming more favourable to action on health transition in Africa, and implement a research agenda for health transition. Alliances have a key role to play in Africa as well as in other regions in implementing the research agenda on health transition by building research capacity and mobilizing the necessary investments. PMID- 21272382 TI - The NKF-NUS hemodialysis trial protocol - a randomized controlled trial to determine the effectiveness of a self management intervention for hemodialysis patients. AB - BACKGROUND: Poor adherence to treatment is common in patients on hemodialysis which may increase risk for poor clinical outcomes and mortality. Self management interventions have been shown to be effective in improving compliance in other chronic populations. The aim of this trial is to evaluate the effectiveness of a recently developed group based self management intervention for hemodialysis patients compared to standard care. METHODS/DESIGN: This is a multicentre parallel arm block randomized controlled trial (RCT) of a four session group self management intervention for hemodialysis patients delivered by health care professionals compared to standard care. A total of 176 consenting adults maintained on hemodialysis for a minimum of 6 months will be randomized to receive the self management intervention or standard care. Primary outcomes are biochemical markers of clinical status and adherence. Secondary outcomes include general health related quality of life, disease-specific quality of life, mood, self efficacy and self-reported adherence. Outcomes will be measured at baseline, immediately post-intervention and at 3 and 9 months post-intervention by an independent assessor and analysed on intention to treat principles with linear mixed-effects models across all time points. A qualitative component will examine which aspects of program participants found particularly useful and any barriers to change. DISCUSSION: The NKF-NUS intervention builds upon previous research emphasizing the importance of empowering patients in taking control of their treatment management. The trial design addresses weaknesses of previous research by use of an adequate sample size to detect clinically significant changes in biochemical markers, recruitment of a sufficiently large representative sample, a theory based intervention and careful assessment of both clinical and psychological endpoints at various follow up points. Inclusion of multiple dependent variables allows us to assess the broader impact on the intervention including both hard end points as well as patient reported outcomes. This program, if found to be effective, has the potential to be implemented within the existing renal services delivery model in Singapore, particularly as this is being delivered by health care professionals already working with hemodialysis patients in these settings who are specifically trained in facilitating self management in renal patients. PMID- 21272383 TI - Scintigraphic features of Morquio's syndrome: a case report. AB - INTRODUCTION: To the best of our knowledge, we present for the first time the bone scintigraphy findings of a patient with Morquio's syndrome. CASE PRESENTATION: A 46-year-old Caucasian man with Morquio's syndrome presented with lower back pain six weeks after a left total hip replacement. A whole body bone scan demonstrated an anthropomorphic skeletal pattern consistent with a mucopolysaccharide storage disease, thereby showing the cause of the patient's pain. CONCLUSIONS: To the best of our knowledge, the bone scintigraphy findings of a case of Morquio's syndrome have never before been published. We present our case report to add to the knowledge we have of this rare disease. PMID- 21272385 TI - Improving the quality of meals eaten or prepared outside the home. PMID- 21272384 TI - Prevalence of resistance associated polymorphisms in Plasmodium falciparum field isolates from southern Pakistan. AB - BACKGROUND: Scarce data are available on Plasmodium falciparum anti-malarial drug resistance in Pakistan. The aim of this study was, therefore, to determine the prevalence of P. falciparum resistance associated polymorphisms in field isolates from southern Pakistan. METHODS: Blood samples from 244 patients with blood-slide confirmed P. falciparum mono-infections were collected between 2005-2007. Single nucleotide polymorphisms in the P. falciparum chloroquine resistance transporter (pfcrt K76T), multi drug resistance (pfmdr1 N86Y), dihydrofolate reductase (pfdhfr A16V, N51I, C59R, S108N, I164L) and dihydropteroate synthetase (pfdhps A436S, G437A and E540K) genes and pfmdr1 gene copy numbers were determined using PCR based methods. RESULTS: The prevalence of pfcrt 76T and pfmdr1 86Y was 93% and 57%, respectively. The prevalence of pfdhfr double mutations 59R + 108N/51R + 108N was 92%. The pfdhfr triple mutation (51I, 59R, 108N) occurred in 3% of samples. The pfdhfr (51I, 59R, 108N) and pfdhps (437G, 540E) quintuple mutation was found in one isolate. Pfdhps 437G was observed in 51% and 540E in 1% of the isolates. One isolate had two pfmdr1 copies and carried the pfmdr1 86Y and pfcrt 76T alleles. CONCLUSIONS: The results indicate high prevalence of in vivo resistance to chloroquine, whereas high grade resistance to sulphadoxine pyrimethamine does not appear to be widespread among P. falciparum in southern Pakistan. PMID- 21272386 TI - Adolescent development of psychosis as an outcome of hearing impairment: a 10 year longitudinal study. AB - BACKGROUND: It has long been acknowledged that hearing impairment may increase the risk for psychotic experiences. Recent work suggests that young people in particular may be at risk, indicating a possible developmental mechanism. METHOD: The hypothesis that individuals exposed to hearing impairment in early adolescence would display the highest risk for psychotic symptoms was examined in a prospective cohort study of a population sample of originally 3021 adolescents and young adults aged 14-24 years at baseline, in Munich, Germany (Early Developmental Stages of Psychopathology Study). The expression of psychosis was assessed at multiple time points over a period of up to 10 years, using a diagnostic interview (Munich Composite International Diagnostic Interview; CIDI) administered by clinical psychologists. RESULTS: Hearing impairment was associated with CIDI psychotic symptoms [odds ratio (OR) 2.04, 95% confidence interval (CI) 1.10-3.81], particularly more severe psychotic symptoms (OR 5.66, 95% CI 1.64-19.49). The association between hearing impairment and CIDI psychotic symptoms was much stronger in the youngest group aged 14-17 years at baseline (OR 3.28, 95% CI 1.54-7.01) than in the older group aged 18-24 years at baseline (OR 0.82, 95% CI 0.24-2.84). CONCLUSIONS: The finding of an age-specific association between hearing impairment and psychotic experiences suggests that disruption of development at a critical adolescent phase, in interaction with other personal and social vulnerabilities, may increase the risk for psychotic symptoms. PMID- 21272387 TI - Depression and anxiety in patients repeatedly referred to secondary care with medically unexplained symptoms: a case-control study. AB - BACKGROUND: One third of referrals from primary to secondary care are for medically unexplained symptoms (MUS). We aimed to determine the association of depression and anxiety disorders with high use of specialist services by patients with MUS. We did this by comparing their prevalence in patients who had been repeatedly referred with symptoms for which they had received repeated specialist diagnoses of MUS with that in two control groups. We also determined the adequacy of treatment received. METHOD: A case-control study in five general practices in Edinburgh, UK. Data collection was by case note review and questionnaire. Cases were 193 adults with three or more referrals over 5 years, at least two of which resulted in a diagnosis of MUS. Controls were: (a) patients referred only once over 5 years (n=152); (b) patients with three or more referrals for symptoms always diagnosed as medically explained (n=162). RESULTS: In total, 93 (48%) of the cases met our criteria for current depression, anxiety or panic disorders. This compared with 38 (25%) and 52 (35.2%) of the control groups; odds ratios (95% confidence intervals) of 2.6 (1.6-4.1) and 1.6 (1.01-2.4), respectively. Almost half (44%) of the cases with current depression or anxiety had not received recent minimum effective therapy. CONCLUSIONS: Depression, anxiety and panic disorders are common in patients repeatedly referred to hospital with MUS. Improving the recognition and treatment of these disorders in these patients has the potential to provide better, more appropriate and more cost-effective medical care. PMID- 21272388 TI - Effects of two dopamine-modulating genes (DAT1 9/10 and COMT Val/Met) on n-back working memory performance in healthy volunteers. AB - BACKGROUND: Impairments in working memory are present in many psychiatric illnesses such as attention-deficit hyperactivity disorder (ADHD) and schizophrenia. The dopamine transporter and catechol-O-methyltransferase (COMT) are proteins involved in dopamine clearance and the dopamine system is implicated in the modulation of working memory (WM) processes and neurochemical models of psychiatric diseases. The effects of functional polymorphisms of the dopamine transporter gene (DAT1) and the COMT gene were investigated using a visuospatial and numerical n-back working memory paradigm. Our n-back task was designed to reflect WM alone, and made no demands on higher executive functioning. METHOD: A total of 291 healthy volunteers (aged 18-45 years) were genotyped and matched for age, sex, and Barratt Impulsivity Scale (BIS) and National Adult Reading Test (NART) scores. To assess individual gene effects on WM, factorial mixed model analysis of variances (ANOVAs) were conducted with the between-subjects factor as genotype and difficulty level (0-, 1-, 2- and 3-back) entered as the within subjects factor. RESULTS: The analysis revealed that the DAT1 or COMT genotype alone or in combination did not predict performance on the n-back task in our sample of healthy volunteers. CONCLUSIONS: Behavioral effects of DAT1 and COMT polymorphisms on WM in healthy volunteers may be non-existent, or too subtle to identify without exceedingly large sample sizes. It is proposed that neuroimaging may provide more powerful means of elucidating the modulatory influences of these polymorphisms. PMID- 21272389 TI - IQ in children with autism spectrum disorders: data from the Special Needs and Autism Project (SNAP). AB - BACKGROUND: Autism spectrum disorder (ASD) was once considered to be highly associated with intellectual disability and to show a characteristic IQ profile, with strengths in performance over verbal abilities and a distinctive pattern of 'peaks' and 'troughs' at the subtest level. However, there are few data from epidemiological studies. METHOD: Comprehensive clinical assessments were conducted with 156 children aged 10-14 years [mean (s.d.)=11.7 (0.9)], seen as part of an epidemiological study (81 childhood autism, 75 other ASD). A sample weighting procedure enabled us to estimate characteristics of the total ASD population. RESULTS: Of the 75 children with ASD, 55% had an intellectual disability (IQ<70) but only 16% had moderate to severe intellectual disability (IQ<50); 28% had average intelligence (115>IQ>85) but only 3% were of above average intelligence (IQ>115). There was some evidence for a clinically significant Performance/Verbal IQ (PIQ/VIQ) discrepancy but discrepant verbal versus performance skills were not associated with a particular pattern of symptoms, as has been reported previously. There was mixed evidence of a characteristic subtest profile: whereas some previously reported patterns were supported (e.g. poor Comprehension), others were not (e.g. no 'peak' in Block Design). Adaptive skills were significantly lower than IQ and were associated with severity of early social impairment and also IQ. CONCLUSIONS: In this epidemiological sample, ASD was less strongly associated with intellectual disability than traditionally held and there was only limited evidence of a distinctive IQ profile. Adaptive outcome was significantly impaired even for those children of average intelligence. PMID- 21272390 TI - Cone synapses in macaque fovea: I. Two types of non-S cones are distinguished by numbers of contacts with OFF midget bipolar cells. AB - L and M cones, divided into two groups by absorption spectra, have not been distinguished by structure. Here, we report what may be such a difference. We reconstructed the synaptic terminals of 16 non-S cones and the dendritic arbors of their ON and OFF midget bipolar cells from high-magnification electron micrographs of serial thin sections of a small region of macaque fovea. Each cone terminal contacted a similar number (~16) of invaginating central elements provided by its ON midget bipolar cell. By contrast, the numbers of connections between a cone terminal and its OFF midget bipolar cell were grouped into two clusters: 30-37 versus 43-50 basal contacts in the triad-associated position and 41-47 versus 61-74 Outer Densities within those basal contacts. The coefficients of variation of these distributions were all in the range of 10% or lower, characteristic of single populations. If these two clusters correspond to M- and L-cone circuits, the results reveal structural differences between M and L cones and between their corresponding OFF midget bipolar cells. PMID- 21272391 TI - Cone synapses in macaque fovea: II. Dendrites of OFF midget bipolar cells exhibit Inner Densities similar to their Outer synaptic Densities in basal contacts with cone terminals. AB - As described in the companion paper, the synaptic terminal of a cone photoreceptor in macaque monkey makes an average of 35 or 46 basal contacts with the tips of the dendrites of its OFF midget bipolar cell. Each basal contact has one or more symmetrically thickened dense regions. These "Outer Densities," averaging 48 or 67 in number, harbor clusters of ionotropic glutamate receptors and are ~0.8 MUm (and ~1-ms diffusion time) from active zones associated with synaptic ribbons. Here, we show similarly appearing "Inner Densities," averaging 53 or 74 in number, located more proximally on the dendrites of these OFF midget bipolar cells, ~0.4 MUm inward from the tips of the dendrites and out of contact with the basal surface of the cone terminal. Compared to desmosome-like junctions, Inner Densities are closer to the terminal and are less dense and less thick. Each Inner Density is shared with another cell, the partners including diffuse bipolar cells, ON midget bipolar cells, and horizontal cells. Given the diversity of the partners, the OFF midget bipolar cells are unlikely to be in a synaptic relationship with the partners. Instead, Inner Densities are near enough to the active zones associated with synaptic ribbons to receive pulses of glutamate at concentrations effective for glutamate receptors. The role of Inner Densities is not known, but they might represent additional clusters of glutamate receptors. PMID- 21272393 TI - Computerized CBT (Think, Feel, Do) for depression and anxiety in children and adolescents: outcomes and feedback from a pilot randomized controlled trial. AB - BACKGROUND: Research has demonstrated the effectiveness of computerized cognitive behaviour therapy (cCBT) for depression and anxiety in adults, but there has been little work with children and adolescents. AIMS: To describe the development of a cCBT intervention (Think, Feel, Do) for young people, and preliminary outcomes and feedback from a pilot randomized controlled trial. METHOD: Twenty participants aged 11 to 16 with depression or anxiety were randomized to receive cCBT immediately or after a delay. Standardized measures were used to assess self reported anxiety, depression, self-esteem and cognitions, as well as parent rated strengths and difficulties. A feedback form was also completed to assess young people's views of the programme. RESULTS: A total of 15 participants completed the pre and post assessments in the trial, and 17 provided feedback on the intervention. Paired samples t-tests demonstrated significant improvements on 3 subscales in the control condition, compared to 7 subscales in the cCBT condition. Feedback showed moderate to high satisfaction for participants. CONCLUSIONS: This study provides encouraging preliminary results for the effectiveness and acceptability of cCBT with this age group. PMID- 21272392 TI - Synaptic release at mammalian bipolar cell terminals. AB - Bipolar cells play a vital role in the transfer of visual information across the vertebrate retina. The synaptic output of these neurons is regulated by factors that are extrinsic and intrinsic. Relatively little is known about the intrinsic factors that regulate neurotransmitter exocytosis. Much of what we know about intrinsic presynaptic mechanisms that regulate glutamate release has come from the study of the unusually large and accessible synaptic terminal of the goldfish rod-dominant bipolar cell, the Mb1 bipolar cell. However, over the past several years, examination of presynaptic mechanisms governing neurotransmitter release has been extended to the mammalian rod bipolar cell. In this review, we discuss the recent advances in our understanding of synaptic vesicle dynamics and neurotransmitter release in rodent rod bipolar cells and consider how these properties help to shape the synaptic output of the mammalian retina. PMID- 21272394 TI - Characterisation of DDT and pyrethroid resistance in Trinidad and Tobago populations of Aedes aegypti. AB - Insecticide resistance is an important factor in the effectiveness of Aedes aegypti control and the related spread of dengue. The objectives of this study were to investigate the status of the organochlorine dichlorodiphenyltrichloroethane (DDT) and pyrethroid (permethrin and deltamethrin) resistance in Trinidad and Tobago populations of Ae. aegypti and the underlying biochemical mechanisms. Nine populations of Ae. aegypti larvae from Trinidad and Tobago were assayed to DDT and PYs using the Centers for Disease Control and Prevention (CDC) time-mortality-based bioassay method. A diagnostic dosage (DD) was established for each insecticide using the CAREC reference susceptible Ae. aegypti strain and a resistance threshold (RT), time in which 98-100% mortality was observed in the CAREC strain, was calculated for each insecticide. Mosquitoes which survived the DD and RT were considered as resistant, and the resistance status of each population was categorised based on the WHO criteria with mortality <80% indicative of resistance. Biochemical assays were conducted to determine the activities of alpha and beta esterases, mixed function oxidases (MFO) and glutathione-S-transferases (GST) enzymes which are involved in resistance of mosquitoes to DDT and PYs. Enzymatic activity levels in each population were compared with those obtained for the CAREC susceptible strain, and significant differences were determined by Kruskal-Wallis and Tukey's non-parametric tests (P<0.05). The established DDs were 0.01 mg l(-1), 0.2 mg l( 1) and 1.0 mg l(-1) for deltamethrin, permethrin and DDT, respectively; and the RTs for deltamethrin, permethrin and DDT were 30, 75 and 120 min, respectively. All Ae. aegypti populations were resistant to DDT (<80% mortality); two strains were incipiently resistant to deltamethrin and three to permethrin (80-98% mortality). Biochemical assays revealed elevated levels of alpha-esterase and MFO enzymes in all Ae. aegypti populations. All, except three populations, showed increased levels of beta-esterases; and all populations, except Curepe, demonstrated elevated GST levels.Metabolic detoxification of enzymes is correlated with the manifestation of DDT and PY resistance in Trinidad and Tobago populations of Ae. aegypti. The presence of this resistance also suggests that knock down (kdr)-type resistance may be involved, hence the need for further investigations. This information can contribute to the development of an insecticide resistance surveillance programme and improvement of resistance management strategies aimed at combatting the spread of dengue in Trinidad and Tobago. PMID- 21272395 TI - DNA barcodes for two scale insect families, mealybugs (Hemiptera: Pseudococcidae) and armored scales (Hemiptera: Diaspididae). AB - Although DNA barcode coverage has grown rapidly for many insect orders, there are some groups, such as scale insects, where sequence recovery has been difficult. However, using a recently developed primer set, we recovered barcode records from 373 specimens, providing coverage for 75 species from 31 genera in two families. Overall success was >90% for mealybugs and >80% for armored scale species. The G.C content was very low in most species, averaging just 16.3%. Sequence divergences (K2P) between congeneric species averaged 10.7%, while intra-specific divergences averaged 0.97%. However, the latter value was inflated by high intra specific divergence in nine taxa, cases that may indicate species overlooked by current taxonomic treatments. Our study establishes the feasibility of developing a comprehensive barcode library for scale insects and indicates that its construction will both create an effective system for identifying scale insects and reveal taxonomic situations worthy of deeper analysis. PMID- 21272396 TI - Relationship between energy expenditure, nutritional status and clinical severity before starting enteral nutrition in critically ill children. AB - The objective of the present study was to investigate the relationship between energy expenditure (EE), biochemical and anthropometric nutritional status and severity scales in critically ill children. We performed a prospective observational study in forty-six critically ill children. The following variables were recorded before starting nutrition: age, sex, diagnosis, weight, height, risk of mortality according to the Paediatric Risk Score of Mortality (PRISM), the Revised Paediatric Index of Mortality (PIM2) and the Paediatric Logistic Organ Dysfunction (PELOD) scales, laboratory parameters (albumin, total proteins, prealbumin, transferrin, retinol-binding protein, cholesterol and TAG, and nitrogen balance) and EE measured by indirect calorimetry. The results showed that there was no relationship between EE and clinical severity evaluated using the PRISM, PIM2 and PELOD scales or with the anthropometric nutritional status or biochemical alterations. Finally, it was concluded that neither nutritional status nor clinical severity is related to EE. Therefore, EE must be measured individually in each critically ill child using indirect calorimetry. PMID- 21272397 TI - Dietary determinants for Hb-acrylamide and Hb-glycidamide adducts in Danish non smoking women. AB - Acrylamide (AA) is a probable human carcinogen that is formed in heat-treated carbohydrate-rich foods. The validity of FFQ to assess AA exposure has been questioned. The aim of the present cross-sectional study was to investigate dietary determinants of Hb-AA and Hb-glycidamide (GA) adducts. The study included 537 non-smoking women aged 50-65 years who participated in the Diet, Cancer and Health cohort (1993-97). At study baseline, blood samples and information on dietary and lifestyle variables obtained from self-administered questionnaires were collected. From blood samples, Hb-AA and Hb-GA in erythrocytes were analysed by liquid chromatography/MS/MS. Dietary determinants were evaluated by multiple linear regression analyses adjusted for age and smoking behaviour among ex smokers. The median for Hb-AA was 35 pmol/g globin (5th percentile 17, 95th percentile 89) and for Hb-GA 21 pmol/g globin (5th percentile 8, 95th percentile 49). Of the dietary factors studied, intakes of coffee and chips were statistically significantly associated with a 4 % per 200 g/d (95 % CI 2, 7; P < 0.0001) and an 18 % per 5 g/d (95 % CI 6, 31; P = 0.002) higher Hb-AA, respectively. This model explained 17 % of the variation in Hb-AA. Intakes of coffee and biscuits/crackers were statistically significantly associated with a 3 % per 200 g/d (95 % CI 1, 6; P = 0.005) and 12 % per 10 g/d (95 % CI 3, 23; P = 0.01) higher Hb-GA, respectively. This model explained 12 % of the variation in Hb-GA. In conclusion, only a few dietary determinants of Hb-AA and Hb-GA were identified. Thus, the present study implies that dietary intake measured by an FFQ explains only to a limited extent the variation in Hb-AA and Hb-GA concentrations. PMID- 21272398 TI - Early weaning causes undernutrition for a short period and programmes some metabolic syndrome components and leptin resistance in adult rat offspring. AB - Maternal malnutrition during lactation programmes for overweight and central leptin resistance in adulthood. The inhibition of lactation by maternal treatment with bromocriptine (a prolactin inhibitor) programmes for obesity, hyperleptinaemia and leptin resistance. Here, we evaluated the short- and long term effects of early weaning (EW) on body-weight regulation, leptin signalling, and hormone and lipid profiles in rats offspring. Lactating rats were separated into two groups: EW--dams were wrapped with a bandage to interrupt the lactation in the last 3 d of lactation; control--dams whose pups had free access to milk during all lactation (21 d). Data were significant at P < 0.05. At weaning, EW pups presented lower body weight (-10%), length (-4%), visceral fat (-40%), total fat (-30%), serum leptin (-73%), glycaemia (-10%), serum insulin (-20%) and insulin resistance index (IRI; -30 %), but higher total body protein content (+40%). At 180 d, EW offspring showed hyperphagia, higher length (+3%), body weight (+8%), visceral and total fat (+36 and 84%), serum TAG (+96%), glycaemia (+15%), leptinaemia (+185%) and IRI (+29%); however, they showed lower total protein content (-23%), leptin:body fat ratio (41%), prolactinaemia (-38%) and adiponectinaemia (-59%). Despite unchanged leptin receptor (OB-R) and signal transducer and activator of transcription 3 (STAT3), they displayed lower hypothalamic janus tyrosine kinase 2, phosphorylated STAT3 and a higher suppressor of cytokine signalling 3 levels, suggesting a central leptin resistance. Adult rats that were early weaned displayed higher adiposity, insulin resistance and dyslipidaemia, which are related to metabolic syndrome development. Our model reinforces the idea that neonatal malnutrition caused by shortening of the lactation period is important for metabolic programming of future diseases. PMID- 21272399 TI - Acute effects of whey protein isolate on blood pressure, vascular function and inflammatory markers in overweight postmenopausal women. AB - Previous evidence indicates that chronic consumption of dairy whey proteins has beneficial effects on CVD risk factors. The present study investigated the postprandial effects of whey protein isolate on blood pressure, vascular function and inflammatory markers in overweight and obese postmenopausal women. This was a randomised, three-way cross-over design study where twenty overweight and obese postmenopausal women consumed a breakfast meal in conjunction with one of three supplements: 45 g whey protein isolate, 45 g sodium caseinate or 45 g of a glucose control. Fasting and postprandial blood samples, blood pressure and pulse wave analysis readings were taken for up to 6 h. After consumption of the meal, both systolic and diastolic blood pressure, and augmentation index (AI) decreased initially for all interventions and gradually returned to baseline levels by 6 h. However, there were no significant differences in AI, systolic or diastolic blood pressure within or between the glucose control, casein or whey groups. There were also no significant group effects on plasma inflammatory markers (IL-6, TNF-alpha and C-reactive protein). The health effects previously seen with chronic whey protein ingestion were not seen in the acute 6 h postprandial period in relation to blood pressure, vascular function or inflammatory markers when compared with casein and a glucose control. This suggests that such effects are better observed from the long-term consumption of whey proteins. PMID- 21272400 TI - Effects of a supra-sustained gelatin-milk protein diet compared with (supra )sustained milk protein diets on body-weight loss. AB - Diets higher in protein content result in increased satiety and energy expenditure. In the short term, gelatin showed stronger hunger suppression and less subsequent energy intake compared with other proteins. The present study investigated whether a supra-sustained gelatin-milk protein (GMP) diet promotes weight loss compared with a sustained milk protein (SMP) diet and a supra sustained milk protein (SSMP) diet during an 8-week diet period. A total of seventy-two healthy subjects (31.2 (sd 4.8) kg/m2; 43 (sd 10) years) followed one of the three diets in a subject-specific amount: SMP, SSMP or GMP diet. During weeks 1-4, energy intake was 100 % of individual energy requirement: 10, 40 and 50 % of energy (En %) as protein, fat and carbohydrate, respectively (SMP diet), and 20, 30 and 50 En % as protein, fat and carbohydrate, respectively (SSMP diet or GMP diet). During weeks 5-8, energy intake was 33 % of individual energy requirement: 30, 35 and 35 En % as protein, fat and carbohydrate, respectively (SMP diet), and 60, 5 and 35 En % as protein, fat and carbohydrate, respectively (SSMP diet or GMP diet). Thus, absolute protein intake was kept constant throughout per subject. Significant decreases in BMI (P < 0.0001) were similar between the GMP ( - 1.7 (sd 0.5) kg/m2) and the SMP ( - 2.1 (sd 0.8) kg/m2) and SSMP ( - 1.6 (sd 0.5) kg/m2) diets. Decreases in fat-free mass (FFM), fat mass (FM) and FM %, and increases in FFM % were similar between the GMP and both control diets. Changes in RQ differed (P < 0.05) between the GMP ( - 0.01 (sd 0.06)) and SSMP ( - 0.04 (sd 0.04)) diets. Changes in HDL concentrations differed (P < 0.05) between the GMP ( - 0.21 (sd 0.18) mmol/l) and the SMP and SSMP diets ( - 0.08 (sd 0.18) mmol/l and - 0.09 (sd 0.26) mmol/l, respectively). In conclusion, a gelatin-milk protein diet does not induce more beneficial effects during an 8-week weight-loss period compared with a SMP or SSMP diet. PMID- 21272401 TI - Current guidelines for nut consumption are achievable and sustainable: a hazelnut intervention. AB - Nuts are known for their hypocholesterolaemic properties; however, to achieve optimal health benefits, nuts must be consumed regularly and in sufficient quantity. It is therefore important to assess the acceptability of regular consumption of nuts. The present study examined the long-term effects of hazelnut consumption in three different forms on 'desire to consume' and 'overall liking'. A total of forty-eight participants took part in this randomised cross-over study with three dietary phases of 4 weeks: 30 g/d of whole, sliced and ground hazelnuts. 'Overall liking' was measured in a three-stage design: a pre- and post exposure tasting session and daily evaluation over the exposure period. 'Desire to consume' hazelnuts was measured during the exposure period only. Ratings were measured on a 150 mm visual analogue scale. Mean ratings of 'desire to consume' were 92 (SD 35) mm for ground, 108 (SD 33) mm for sliced and 116 (SD 30) mm for whole hazelnuts. For 'overall liking', the mean ratings were 101 (SD 29) mm for ground, 110 (SD 32) mm for sliced and 118 (SD 30) mm for whole hazelnuts. Ground hazelnuts had significantly lower ratings than both sliced (P <= 0.034) and whole hazelnuts (P < 0.001), with no difference in ratings between sliced and whole hazelnuts (P >= 0.125). For each form of nut, ratings of 'overall liking' and 'desire to consume' were stable over the exposure period, indicating that not only did the participants like the nuts, but also they wished to continue eating them. Therefore, the guideline to consume nuts on a regular basis appears to be a sustainable behaviour to reduce CVD. PMID- 21272402 TI - A whole-grain cereal-rich diet increases plasma betaine, and tends to decrease total and LDL-cholesterol compared with a refined-grain diet in healthy subjects. AB - Epidemiological studies have repeatedly found that whole-grain (WG) cereal foods reduce the risk of several lifestyle-related diseases, though consistent clinical outcomes and mechanisms are elusive. To compare the effects of a WG-rich diet with a matched refined-grain (RG) diet on plasma biomarkers and bowel health parameters, seventeen healthy subjects (eleven females and six males) completed an exploratory cross-over study with a 2-week intervention diet based on either WG- or RG-based foods, separated by a washout of at least 5 weeks. Both diets were the same except for the use of WG (150 g/d) or RG foods. Subjects undertook a 4 h postprandial challenge on day 8 of each intervention diet. After 2 weeks, the WG diet tended to decrease plasma total and LDL-cholesterol (both P = 0.09), but did not change plasma HDL-cholesterol, fasting glucose, C-reactive protein or homocysteine compared with the RG diet. Plasma betaine and alkylresorcinol concentrations were elevated after 1 week of the WG diet (P = 0.01 and P < 0.0001, respectively). Clostridium leptum populations in faeces were increased after the WG diet, along with a trend for decreased faecal water pH (P = 0.096) and increased stool frequency (P < 0.0001) compared with the RG diet. A short controlled intervention trial with a variety of commercially available WG-based products tended to improve biomarkers of CVD compared with a RG diet. Changes in faecal microbiota related to increased fibre fermentation and increased plasma betaine concentrations point to both fibre and phytochemical components of WG being important in mediating any potential health effects. PMID- 21272403 TI - Major dietary patterns and their associations with cardiovascular risk factors among women in West Bengal, India. AB - Few studies have examined dietary patterns in relation to cardiovascular risk factors in Asian populations, particularly in India. The present study was undertaken to explore dietary patterns in a general urban Bengalee population of women in West Bengal, India, and their association with cardiovascular risk factors. We performed a cross-sectional study of 701 women (aged 35 years and above) selected by cluster sampling from twelve different wards of the Kolkata Municipal Corporation (Kolkata, India). The following three major dietary patterns were identified: the 'vegetable, fruits and pulses' pattern (characterised by higher intakes of dark-yellow and green leafy vegetables, sweets, fruits, pulses, nuts, poultry and eggs, and lower intake of mustard oil); the 'hydrogenated and saturated fat and vegetable oil' pattern (characterised by higher intakes of butter, hydrogenated oil, ghee, vegetable oil, mustard oil, condiments, sweets, fish, high-fat dairy and refined grain); the 'red meat and high-fat dairy' pattern (characterised by higher intakes of red meat, high-fat dairy products, whole grain, high-energy drinks and condiments, and lower intakes of fish, refined grain and low-fat dairy products). The vegetable, fruits and pulses pattern was inversely associated with serum total cholesterol (TC), LDL cholesterol and non-HDL-cholesterol (HDL-C) concentrations (P < 0.05 for all). The hydrogenated and saturated fat and vegetable oil pattern was positively associated with BMI, waist circumference (WC) and HDL-C concentration (P < 0.05 for all). In this Bengalee population, these three major dietary patterns were observed, and the dietary patterns were independently associated with BMI, WC and serum TC concentrations in women. PMID- 21272404 TI - Natural evolution of weight status in Duchenne muscular dystrophy: a retrospective audit. AB - The life expectancy of patients with Duchenne muscular dystrophy (DMD) has increased. A cross-sectional study of DMD patients showed that 54 % of 13-year old patients are obese and that 54 % of 18-year-old patients are underweight. We aimed to describe the natural evolution of weight status in DMD. This retrospective multi-centre audit collected body-weight measurements for seventy DMD patients born before 1992. The body-weight:age ratio (W:A) was used to evaluate weight status in reference to the Griffiths and Edwards chart. At the age of 13 years, 73 % were obese and 4 % were underweight. At maximal follow-up (age 15-26 years, mean 18.3 (sd 2.3) years), 47 % were obese and 34 % were underweight. Obesity at the age of 13 years was associated with later obesity, whereas normal weight status and underweight in 13-year-old patients predicted later underweight. A W:A >= 151 % in 13-year-old patients predicted later obesity, and a W:A <= 126.5 % predicted later underweight. Our audit provides the first longitudinal information about the spontaneous outcome of weight status in DMD. Patients (13 years old) with a W:A >= 151 % were more likely to become obese in late adolescence, but obesity prevented later underweight. These data suggest that mild obesity in 13-year-old DMD patients (W:A between 120 and 150 %) should not be discouraged because it prevents later underweight. PMID- 21272405 TI - Reparative properties of the traditional Chinese medicine Cordyceps sinensis (Chinese caterpillar mushroom) using HT29 cell culture and rat gastric damage models of injury. AB - Cordyceps sinensis (CS) is a traditional Chinese medicine and health food used to support many organ systems. It is commercially produced by cultivation in a liquid medium or on a solid (grain/potato) phase. We tested the effects of hot water extracts of liquid-phase and solid-phase commercially grown CS on its ability to influence proliferation (using Alamar blue, an oxidation/reduction indicator), migration (serial-wounded monolayer photomicroscopy), invasion through collagen gel (fluorometric assay) and indomethacin-induced apoptosis (active caspase-3 colorimetric assay) of human colon cancer HT29 cells. An in vivo study used a rat gastric damage model (indomethacin 20 mg/kg and 4 h restraint with oral administration). The CS extract stimulated cell proliferation threefold when added at 10 MUg/ml (P < 0.01). Cell migration increased by 69 % and invasion by 17 % when CS was added at 5 mg/ml (P < 0.01). The results also showed that 93 % of the pro-proliferative activity was soluble in ethanol, whereas pro-migratory activity was divided (61:49) into both ethanol-soluble and ethanol-insoluble sub-fractions. Indomethacin-induced apoptosis was not affected by the presence of CS. CS reduced the amount of gastric injury by 63 % when administered orally at 20 mg/ml (P < 0.01), the results being similar to using the potent cytoprotective agent epidermal growth factor at 25 MUg/ml (83 % reduction). We conclude that both methods of cultivated CS possess biological activity when analysed using a variety of gut models of injury and repair. Functional foods, such as CS, could provide a novel approach for the prevention and treatment of injury to the bowel. PMID- 21272406 TI - Modification of an in vitro model simulating the whole digestive process to investigate cellular endpoints of chemoprevention. AB - In vitro gut fermentation systems are relevant tools to study health benefits of foodstuffs. Most of them are commonly used to investigate the degradation of nutrients or the development of gut flora. Using these models, strong cytotoxic effects of the resulting samples on cultured cells were observed. Hence, the aim of the present study was to develop a modified in vitro fermentation model that simulates the whole digestive tract and generates fermented samples that are suitable for testing in cell culture experiments. Wholemeal wheat flour (wwf) was digested and fermented in vitro with a fermentation model using different ox gall concentrations (41.6 and 0.6 g/l). The resulting fermentation supernatants (fs) were characterised for metabolites and biological effects in HT29 cells. The fermentation of wwf increased chemopreventive SCFA and decreased carcinogenic deoxycholic acid (DCA). The strong cytotoxic effects of the fs, which were partly due to cholic acid and DCA, were diminished by lowering the ox gall concentration, allowing the use of the samples in cell culture experiments. In conclusion, an in vitro digestion model, which can be used to study the effects of foodstuffs on chemoprevention and gut health in colon cells, is introduced and its physiological relevance is demonstrated. PMID- 21272407 TI - Growth, body composition and hormonal status of growing pigs exhibiting a normal or small weight at birth and exposed to a neonatal diet enriched in proteins. AB - Small birth weight and excess of early protein intake are suspected to enhance later obesity risk. The present study was undertaken to determine the impact of neonatal diets differing in protein content on growth, body composition and hormonal status of 70-d-old pigs born with normal weight (NW) or small weight (SW). At 7 d of age, male and female suckled piglets were assigned to the NW (approximately 1.4 kg at birth) or SW (approximately 0.99 kg at birth) groups. They were fed milk replacers formulated to provide an adequate protein (AP) or a high protein (HP) supply for 3 weeks. From weaning to 70 d of age, all animals received ad libitum the same standard diet. Growth rates were higher (P < 0.05) in HP piglets than in AP piglets during formula feeding and remained higher (P < 0.05) only in HP male pigs thereafter. No difference in feed consumption was detected between groups during the periods examined. Carcass lipid content and the relative weight of perirenal adipose tissue did not differ between the AP and HP pigs. Whereas plasma leptin concentration was higher (P < 0.05) in HP pigs than in AP pigs with a marked difference in SW pigs, plasma insulin-like growth factor (IGF)-I concentration and expression of IGF system genes were not affected by the diets. In summary, a HP intake during the suckling period induced an increase in growth rate that persisted only in male pigs during the post-weaning period. This response was not associated with any difference in adiposity parameters in this period. PMID- 21272408 TI - Relative validity of fruit and vegetable intake estimated from an FFQ, using carotenoid and flavonoid biomarkers and the method of triads. AB - The aim of the present study was to validate the intakes of fruit, juice and vegetables from an FFQ. In sub-study I (n 147), intakes from the FFQ were evaluated against 7 d weighed food records (WR) and plasma carotenoid concentrations, whereas in sub-study II (n 85), the intakes were evaluated against plasma carotenoid concentrations and amounts of flavonoids in 24 h urine samples. Relative validity was evaluated by comparing median intakes, estimating correlation coefficients and validity coefficients using the method of triads. In sub-study I, we observed no significant difference in daily median fruit intake between the FFQ and the WR, whereas the intake of vegetables was higher from the FFQ than from the WR. The correlations between intakes from the FFQ and the WR ranged from 0.31 to 0.58. In sub-study II, the intakes of fruit and vegetables correlated significantly with plasma carotenoid concentrations and urinary flavonoids. The validity coefficients for the intakes of fruit and vegetables from the FFQ ranged from 0.61 to 0.88 in sub-study I and from 0.60 to 0.94 in sub study II. In summary, based on the associations observed between intakes from the FFQ and the biomarkers and the FFQ validity coefficients, the FFQ was found valid and suitable for ranking individuals according to their usual intake of fruit, juice and vegetables. PMID- 21272409 TI - Periconceptional folic acid supplementation and anthropometric measures at birth in a cohort of pregnant women in Valencia, Spain. AB - We examined the relationship between dietary folate intake and periconceptional use of folic acid (FA) supplements, and small-for-gestational age for weight (SGA W) and height (SGA-H). The study is based on 786 Spanish women aged 16 years or above, who attended the first-term prenatal population-based screening programme (10-13 weeks) at the reference hospital 'La Fe', Valencia, with singleton pregnancy. Periconceptional use of FA supplements was categorised as non-users, moderate users ( <= 1 mg/d) and high users (>1 mg/d). Babies born to mothers who used high doses of FA supplements had a significant reduction in mean birth height compared with babies of non-users (beta = - 0.53, 95 % CI - 0.96, - 0.09). As regards weight, mothers using moderate and high doses of FA supplements had lower-birth-weight babies for gestational age than non-users (beta = - 22.96, 95 % CI - 101.14, 55.23; beta = - 89.72, 95 % CI - 188.64, 9.21, respectively), although these decreases were not significant. Results from the multivariate logistic regression models showed that high FA supplement users had a higher significant risk for SGA-H (OR 5.33, 95 % CI 2.08, 13.7), and that users of moderate doses were not associated with a higher risk of either a SGA-W or a SGA H baby. In contrast, increased quintiles of the dietary intake of folate were associated with a decreased risk of SGA-W (P for trend = 0.002), although no association was observed for SGA-H. Our findings suggest that periconceptional use of FA supplements greater than 1 mg/d is associated with decreased birth height and may entail a risk of decreased birth weight. PMID- 21272410 TI - Holt-Oram syndrome: novel TBX5 mutation and associated anomalous right coronary artery. AB - The Holt-Oram syndrome was confirmed in an asymptomatic 36-year-old man by a novel TBX5-gene mutation (exon 8 acceptor splicing site, c.663-1G greater than A). Computed tomography showed an atrial septal defect and an anomalous right coronary artery crossing between the aorta and pulmonary arteries. Surgery corrected the septal defect and the initial segment of the anomalous vessel was unroofed and enlarged. Anomalous coronary arteries were not previously described in the Holt-Oram syndrome patients and should be added to the list of possible associated cardiac defects. PMID- 21272411 TI - Lichen planus of the larynx. AB - OBJECTIVE: We report an extremely rare case of laryngeal lichen planus. METHOD: A case report and literature review of the aetiopathogenesis, clinical features and management of laryngeal lichen planus are presented. RESULTS: A male patient presented with hoarseness and a history suggestive of squamous cell carcinoma of the larynx. However, characteristic histopathological findings demonstrated lichen planus. The patient responded very well to oral steroids, and at the time of writing had remained symptom-free for two years. CONCLUSION: This is the first English language report of laryngeal lichen planus. Lichen planus is a diagnosis of exclusion and responds well to steroids. However, patients should be followed up regularly as malignant change is known to occur. PMID- 21272412 TI - Immune-mediated pathology of nematode infection in sheep--is immunity beneficial to the animal? AB - Nematode parasitism is a severe impediment to sustainable and profitable sheep production in many countries in the world. Parasite resistance to anthelmintic treatment and consumer demand for organic agricultural products has led to much research into harnessing natural immunity as a long-term control measure. However, there is evidence that many of the clinical signs of nematode infection in sheep are due to immune-mediated pathology rather than direct effects of the parasite. Therefore, the desirability of promoting a strong natural immunity in sheep has been questioned. This review attempts to clarify some of the arguments for and against promoting strong natural immunity, particularly through selective breeding of parasite-resistant animals. It is concluded that the detrimental effects of immune-mediated pathology are outweighed by epidemiological and welfare benefits. Thus, control of nematode parasites through selection of naturally resistant sheep is a sustainable and desirable objective. PMID- 21272413 TI - Supplemented zinc does not alter mood in healthy older European adults--a randomised placebo-controlled trial: the Zenith study. AB - OBJECTIVE: Older people are vulnerable to zinc deficiency, which may impact upon their mood. This randomised, placebo-controlled, double-blind intervention study aimed to investigate the effect of oral zinc gluconate supplementation (15 mg/d; 30 mg/d; and placebo) on subjective mood (affect) in older Europeans. SUBJECTS: Healthy volunteers (n 387) aged 55-87 years were recruited. SETTING: Volunteers in Rome (Italy; n 108) and Grenoble (France; n 91) were aged 70-87 years and those in Coleraine (Northern Ireland; n 93) and Clermont-Ferrand (France; n 95) were aged 55-70 years. DESIGN: Mood was measured using the Positive and Negative Affect Scale on four occasions per day over 4 d at baseline, 3 and 6 months post intervention. RESULTS: Mixed ANOVA indicated that neither positive nor negative affect altered in response to zinc (15 mg/d or 30 mg/d) compared to placebo in either the 55-70 years or the >=70 years age group. CONCLUSIONS: These results suggest that zinc does not benefit mood in healthy older people. PMID- 21272414 TI - The meaning of 'fruits' and 'vegetables'. AB - OBJECTIVE: Fruit and vegetable consumption is a focus of research and nutrition education; yet, there is no universal agreement on the meaning of 'fruits' and 'vegetables'. Our objective was to describe survey respondent perceptions about a set of foods with regard to whether the food is a fruit, vegetable or something else. DESIGN: Three cross-sectional studies. SETTING: Two small studies involving cognitive interviewing sessions; and one large self-administered population survey. SUBJECTS: US adults in two small studies (n 55 and 80) and one large survey (n 3312), all with multiple race/ethnicities. RESULTS: Perceptions varied. In the survey, rice was considered a vegetable by about 20 % of respondents. In one small study, Spanish speakers were more likely to consider rice a vegetable, and Chinese speakers less likely, than were English speakers. Black beans were frequently classified as something other than vegetable or fruit. Among Hispanics, Spanish speakers were less likely than English speakers to consider beans a vegetable. Overall, tomatoes were classified as both fruit and vegetable, and these perceptions varied by race/ethnicity. CONCLUSIONS: Substantial disagreement among the fruit, vegetable and other food domains highlights the importance of clearly defining the desired constructs. Foods that require specific instruction include rice, dried beans, potatoes, tomatoes and fruits and vegetables in mixtures and condiments. For measurement, additional questions or explanations may be needed to clarify which foods are of interest. For communication, the global message to increase consumption of fruit and vegetables should be reinforced with specific guidance. PMID- 21272415 TI - Adaptation and validation of an FFQ for 6-10-year-old children. AB - OBJECTIVE: To adapt and test the relative validity of an instrument measuring the usual food intake of 6-10-year-old children. DESIGN: An FFQ encompassing the preceding 6 months was adapted and compared with the average of three 24 h dietary recalls. SETTING: Private and public schools in Porto Alegre, capital city of Rio Grande do Sul, the southernmost state in Brazil, with 1.5 million inhabitants. SUBJECTS: Children aged 6-10 years attending grades 1-4 in private and public schools in Porto Alegre. RESULTS: Ninety-one children were studied. The FFQ overestimated all nutrients. Correlations with the values obtained by 24 h dietary recalls were mostly above 0.50. The deattenuated correlations increased for all nutrients. The kappa coefficients for the adjusted nutrients varied from 0.12 (weak) to 0.34 (reasonable). Graphically, the FFQ was shown to underestimate some of the parameters and to overestimate others, with a wide CI for all nutrients. CONCLUSIONS: The FFQ does not have the required relative validity to classify the intake levels of schoolchildren, and further investigation is required to understand the sources of error. PMID- 21272416 TI - Individual and school environment factors associated with overweight in adolescents of the municipality of Rio de Janeiro, Brazil. AB - OBJECTIVE: To identify the association of individual and school environment factors with overweight among adolescents. DESIGN: Cross-sectional study. Sociodemographic and behavioural information was collected using an anonymous self-administered questionnaire. Indicators on human and physical resources of the schools were based on information collected in interviews with school principals. Overweight was defined based on the BMI Z-score for age and sex recommended by WHO. Logistic regression models were used for statistical analysis. SETTING: Rio de Janeiro, Brazil. SUBJECTS: By means of a two-stage (classrooms and students) probabilistic sampling, subjects comprised 1632 students enrolled in the last year of primary education of the municipal public school network, stratified by city region. RESULTS: The mean prevalence of overweight at schools was 17.2%, ranging from 0% to 50%. Adolescents more likely to be overweight were those who attended schools without knives and forks or ceramic/glass plates for students in the school refectory (prevalence odds ratio (POR) = 1.40; P = 0.04), those whose head of household had completed between 8 and 10 years of schooling (POR = 1.46; P = 0.03), those who did not live with both parents (POR = 1.24; P = 0.06) and those who had not practised physical activity outside school on at least 1 d in the 7 d before the study (POR = 1.56; P = 0.04). CONCLUSIONS: Sociodemographic and behavioural variables of adolescents and school characteristics were associated with overweight, confirming individual and context effects on this health disorder. Studies such as the present one, identifying variables in context, may support actions to prevent overweight among adolescents. PMID- 21272417 TI - Changes in lifestyle habits after counselling by nurse practitioners: 1-year results of the Groningen Overweight and Lifestyle study. AB - OBJECTIVES: The Groningen Overweight and Lifestyle (GOAL) study primarily aims at preventing weight gain by nurse practitioners (NP) guided by a standardized computerized software program. Since favourable changes in physical activity (PA) and diet may improve health independently of weight (loss), insight into effects on lifestyle habits is essential. We examined the 1-year effects of lifestyle counselling by NP on PA and diet, compared with usual care from the general practitioner (GP-UC). DESIGN: A randomized controlled trial. SETTING: Eleven general practice locations in the Netherlands. SUBJECTS: A total of 341 GOAL participants with overweight or obesity and either hypertension or dyslipidaemia, or both, who completed an FFQ and Short Questionnaire to Assess Health-Enhancing Physical Activity (SQUASH) at baseline and after 1 year. RESULTS: After 1 year, the NP group spent 33 min/week more on walking compared with the GP-UC group who spent -5 min/week on walking (P = 0.05). No significant differences were found between the NP and GP-UC groups on the percentage of persons complying with the PA guidelines. In both groups, nutrient intake changed in a favourable direction and participants complied more often with dietary guidelines, but without overall difference between the NP and GP-UC groups. CONCLUSIONS: With the exception of an increase in walking (based on self-reported data) in the NP group, no intervention effects on PA and diet occurred. Positive changes in nutrient intake were seen in both groups. PMID- 21272418 TI - First bite syndrome as presenting symptom of parapharyngeal adenoid cystic carcinoma. AB - INTRODUCTION: First bite syndrome refers to the development of pain in the parotid region after the first bite of each meal. CASE REPORT: A man was referred to our institution with first bite syndrome as his only symptom. Magnetic resonance imaging of the head and neck revealed a deep lobe parotid mass in close contact with the external carotid artery. Computed tomography guided fine needle biopsy indicated adenoid cystic carcinoma. Total parotidectomy was performed, with en bloc resection of the infiltrated external carotid artery and a selective neck dissection of levels Ib to III. High-weight ion radiotherapy was administered post-operatively. CONCLUSION: First bite syndrome has hitherto only been described following parapharyngeal space surgery. We present the first case of parotid gland adenoid cystic carcinoma presenting with first bite syndrome as the only symptom. The presence of first bite syndrome should prompt the clinician to investigate the parapharyngeal space and deep lobe of the parotid gland, especially in the absence of other signs or symptoms. PMID- 21272419 TI - Melanoma of the middle ear: initial presentation, Fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography imaging and follow up. AB - BACKGROUND: We present a rare case of primary mucosal melanoma of the middle ear imaged with 18F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (FDG-PET/CT). METHOD: Clinical, radiological, intra-operative and histological findings are discussed. RESULTS: An 88-year-old woman presented with intermittent otorrhoea of the left ear for several months. Otoscopy revealed a livid protrusion of the tympanic membrane. Melanoma was not suspected initially, but was established on transmembranous biopsy. Pre-operative 18F-fluoro-2-deoxy-D glucose positron emission tomography/computed tomography revealed a mass lesion in the left tympanic cavity with high fluoro-deoxyglucose uptake, as well as an ipsilateral intraparotid lymph node metastasis. The patient underwent surgical treatment. The diagnosis of melanoma was confirmed histologically. CONCLUSION: In this rare case, clinical, radiological and surgical findings led to the diagnosis of a primary mucosal melanoma of the middle ear. PMID- 21272420 TI - Anti-tuberculosis drug resistance patterns and trends in a tuberculosis referral hospital, 1997-2009. AB - Information about the changing epidemiology of drug-resistant tuberculosis (TB) in hospitals in China over the past decade remains largely unknown. This study examined the susceptibility patterns and trends of drug-resistant TB cases in the 309 Hospital in Beijing, China. Mycobacterium tuberculosis isolates were retrospectively identified, drug susceptibility test (DST) results and clinical data were analysed for the period 1997-2009. Of the 5523 culture-positive TB patients, 47.1% had resistance to any anti-TB drug, 14.8% had mono-resistant TB, 19.8% had poly-resistant TB, 19.4% had multidrug-resistant TB (MDR-TB), and 1.3% had extensively drug-resistant TB (XDR-TB). Drug-resistant TB was significantly associated with age group, residential situation, and TB treatment history (P<0.001). During 1997-2000, the percentage of TB patients with any resistance, mono-resistant TB, poly-resistant TB, MDR-TB and XDR-TB all increased significantly (P<0.001). During 2000-2003, the increasing trends of MDR-TB and XDR-TB cases were reversed. During 2004-2009, the percentage of TB patients with any resistance, mono-resistant TB, poly-resistant TB, MDR-TB and XDR-TB all declined significantly (P<0.001), but the prevalence of MDR-TB and poly-resistant TB cases remained high. Our study provides evidence demonstrating that intensive TB control measures have helped reverse the increasing trends of drug-resistant TB in China, but continuous surveillance of drug-resistant TB and better case management are still needed to further reduce the remaining high prevalence of drug-resistant TB. PMID- 21272421 TI - Nutrition transition and health status of Cretan women: evidence from two generations. AB - OBJECTIVE: Research has suggested the abandonment of the traditional Mediterranean diet (MD) by youngsters for a more Westernized regime. The present study aimed (i) to delineate differences in the consumption of traditional Cretan dishes and key nutrients in the MD between two contiguous generations of women and (ii) define how these dietary changes contribute to the morbidity of the younger generation. DESIGN: Cross-sectional. SETTING: The island of Crete, Greece. SUBJECTS: Eighty pairs of mothers and daughters, all living in their own households, were recruited from Crete. Information regarding the consumption of traditional Cretan dishes and two previous-day recalls were collected. The health status of the participants was also recorded. Simple correspondence analysis (SCA) was used to assess associations between differences in the food intake of daughters compared with their mothers and the prevalence of disease. RESULTS: The younger women showed increased intakes of rusks and meat dishes and decreased consumption of green vegetables, pulses and wine compared with their mothers. When nutrients were accounted for, only sugar consumption of the younger women surpassed the intake reported by their mothers. SCA associated hypercholesterolaemia in the daughters with increased cheese and meat intakes; allergies and respiratory problems were associated with lower cheese, fish and oil intakes; being overweight was associated with higher baked goods, oils, desserts, fish and alcohol intakes; and Fe-deficiency anaemia was associated with lower consumption of green vegetables. CONCLUSIONS: Results showed that, although a trend towards a more Westernized diet was noted in the younger women, the differences between the two generations appear to be small. Therefore, in Crete, the MD is still the primary diet regime. PMID- 21272422 TI - Healthy food availability and the association with BMI in Baltimore, Maryland. AB - OBJECTIVE: To study the association between the availability of healthy foods and BMI by neighbourhood race and socio-economic status (SES). DESIGN: Trained staff collected demographic information, height, weight and 24 h dietary recalls between 2004 and 2008. Healthy food availability was determined in thirty-four census tracts of varying racial and SES composition using the Nutrition Environment Measures Survey-Stores in 2007. Multilevel linear regression was used to estimate associations between healthy food availability and BMI. SETTING: Baltimore City, Maryland, USA. SUBJECTS: Adults aged 30-64 years (n 2616) who participated in the Healthy Aging in Neighborhoods of Diversity across the Life Span study. RESULTS: Among individuals living in predominantly white neighbourhoods, high availability of healthy foods was associated with significantly higher BMI compared with individuals living in neighbourhoods with low availability of healthy food after adjustment for demographic variables (beta = 3.22, P = 0.001). Associations were attenuated but remained significant after controlling for dietary quality (beta = 2.81, P = 0.012). CONCLUSIONS: Contrary to expectations, there was a positive association between the availability of healthy food and higher BMI among individuals living in predominantly white neighbourhoods. This result could be due to individuals in neighbourhoods with low healthy food availability travelling outside their neighbourhood to obtain healthy food. PMID- 21272423 TI - Short communicationKey differences between school lunches and packed lunches in primary schools in England in 2009. AB - OBJECTIVE: To compare the key differences between school lunches and packed lunches as consumed in a nationally representative sample of primary schools, 6-8 months after the nutrient-based standards for school lunch became mandatory. DESIGN: Data on 6580 pupils' school lunches and 3422 pupils' packed lunches were collected between February and April 2009 from pupils attending primary schools in England. Fieldwork was conducted over five consecutive school days. Fieldworkers randomly selected ten pupils taking a school lunch and five pupils bringing a packed lunch each day at each school, and recorded and weighed all food and drink items consumed, as well as any leftovers. SETTING: A nationally representative sample of 136 state-maintained primary schools in England. SUBJECTS: A total of 10 002 pupils aged 4-12 years. RESULTS: Mean intakes of protein, fat, saturated fat and vitamin C from both types of lunch met the nutrient-based standards. Pupils taking school lunches on average consumed significantly more protein, NSP, vitamin A, folate and Zn and less fat, saturated fat, non-milk extrinsic sugars (NMES), Na, Ca, vitamin C and Fe than pupils taking packed lunches. Energy intakes were low in both groups. CONCLUSIONS: Packed lunches were less likely to accord with food-based or nutrient-based standards than school lunches. Higher levels of Na, NMES, fat and percentage energy from saturated fat emphasise the difficulties associated with optimising nutrient intakes from packed lunches. PMID- 21272424 TI - Consumer segmentation based on the level and structure of fruit and vegetable intake: an empirical evidence for US adults from the National Health and Nutrition Examination Survey (NHANES) 2005-2006. AB - OBJECTIVE: To identify consumption patterns of fruit and vegetables within a representative sample of US adults with a focus on degree of produce processing and to explore sociodemographic, lifestyle and nutritional profiles associated with these patterns. DESIGN: Cross-sectional analysis. Fruit and vegetable (F&V) consumption data were collected using two non-consecutive 24 h recalls. For the purpose of the study, F&V intakes were aggregated into seven subgroups indicating degree of processing, which afterwards were used as inputs into cluster analysis. SETTING: The 2005-2006 National Health and Nutrition Examination Survey. SUBJECTS: The sample consisted of 2444 adults aged 20-59 years. RESULTS: Total average F&V intake of the adults was below the recommended level. Thereby, 20 % of the respondents consumed fruit only in the form of juice. Three F&V consumption patterns were identified: 'low-intake F&V consumers' (74 % of respondents), 'consumers of healthier F&V options' (13 %) and 'intensive fruit juice consumers' (13 %). These groups differed markedly in terms of their sociodemographic, lifestyle and health characteristics, such as gender, age, race/ethnicity, education, smoking, weight status, etc. Differences in nutrient profiles were also found, with the 'consumers of healthier F&V options' showing better nutritional quality compared with other clusters. CONCLUSIONS: Only a small share of US adults combines high F&V intakes with healthier F&V options that lead to a better nutritional profile. This raises discussion about a need to deliver more specific F&V promotion messages, including advice on healthier preparation methods, especially for the specific population groups. PMID- 21272425 TI - The changing occurrences of tetralogy of Fallot and simple transposition of the great arteries in Southern Nevada. AB - We analysed the occurrence of tetralogy of Fallot and simple transposition in the Hispanic and non-Hispanic populations of Clark County, Nevada, in the United States of America over a 30-year period from 1980 to 2009. We found a downward trend in the incidence of simple transposition of the great arteries in the non Hispanic population but an upward trend in the incidence in the Hispanic population. For tetralogy of Fallot, we found an upward trend in the incidence in both populations; the trend, however, was more dramatic in the Hispanic population. We also noted differences in the male to female ratios in the different groups. Even though we make no definitive conclusions regarding the causes of these incidence curves or the differences in occurrence between males or females, the data suggest an interplay of genetics and the environment. PMID- 21272426 TI - Prevalence and predictors of later feeding disorders in children who underwent neonatal cardiac surgery for congenital heart disease. AB - AIM: We thought of assessing the prevalence and predictors of feeding disorders in patients with congenital heart defects after neonatal cardiac surgery. METHODS: Retrospective study of 82 consecutive neonates (48 males, 34 females) who underwent surgery for congenital heart defects from 1999 to 2002. Information was taken from patient charts and nursing notes. The presence of a feeding disorder was assessed by a questionnaire sent to the paediatricians when the child was 2 years of age. A feeding disorder was defined as a need for tube feeding, inadequate food intake for age, or failure to thrive. Data were analysed with descriptive statistics and logistic regression. RESULTS: Feeding disorders occurred in 22% of the study population. Reoperation and early feeding disorders were identified as independent risk factors for later feeding disorders (odds ratio 5.8, p 0.01; odds ratio 20.7, p 0.02). There was a trend towards more feeding disorders in patients with neurological abnormalities during the first hospital stay. CONCLUSION: Feeding disorder is a frequent, long-term sequela after neonatal cardiac surgery. Patients with congenital heart defects who undergo multiple cardiac surgeries and those with early feeding disorders are at risk of developing later feeding disorders. Patients with these risk factors need to be selected for preventive strategies. PMID- 21272427 TI - The evolving approach to paediatric myocarditis: a review of the current literature. AB - Paediatric myocarditis remains challenging from the perspectives of diagnosis and management. Multiple aetiologies exist and the majority of cases appear to be related to viral illnesses. Enteroviruses are believed to be the most common cause, although cases related to adenovirus may be more frequent than suspected. The clinical presentation is extremely varied, ranging from asymptomatic to sudden unexpected death. A high index of suspicion is crucial. There is emerging evidence to support investigations such as serum N-terminal B-type natriuretic peptide levels, as well as cardiac magnetic resonance imaging as adjuncts to the clinical diagnosis. In the future, these may reduce the necessity for invasive methods, such as endomyocardial biopsy, which remain the gold standard. Management generally includes supportive care, consisting of cardiac failure medical management, with the potential for mechanical support and cardiac transplantation. Treatments aimed at immunosuppression remain controversial. The paediatric literature is extremely limited with no conclusive evidence to support or refute these strategies. This article summarises the current literature regarding aetiology, clinical presentation, diagnosis, and management of myocarditis in paediatric patients. PMID- 21272428 TI - Breaking bad news: an interview study of paediatric cardiologists. AB - Technical developments in paediatric cardiology over the last few decades have increased expectations on professionals, demanding of them more emotional competence and communicative ability. The aim of this study was to examine the approach of paediatric cardiologists in informing and communicating with the family of the patient. METHOD: A qualitative interview method was first tested in a pilot study with two paediatric cardiologists. There were nine subsequent semi structured interviews that were carried out with paediatric cardiologists. A researcher performed all the interviews, which were taped, transcribed, decoded, and analysed. RESULTS: Among paediatric cardiologists, how to break bad news to the family is an important concern, evident in findings regarding the significance of trust and confidence, the use of different emotional positions, and a common ambition to achieve skills to handle the situation. There is a need for reflection, education, and sharing of experiences. The cardiologists desire further development of teamwork and of skills in medical students and residents for delivering bad news. CONCLUSIONS: Doctors are expected to cope with the complexities of diagnoses and decisions, while simultaneously being sensitive to the feelings of the parents, aware of their own emotions, and able to keep it all under control in the context of breaking the bad news to the parents and keeping them informed. These conflicting demands create a need to expand the professional role of the doctor by including more training in emotional competence and communicative ability, beginning in medical school and continuing through consultancy. PMID- 21272429 TI - Current use of and attitudes to e-learning in otolaryngology: questionnaire survey of UK otolaryngology trainees. AB - INTRODUCTION: The E-lefENT programme is a collaborative e-learning project developed by the Department of Health and ENTUK. Prior to its introduction, we aimed to assess current use of and attitudes towards e-learning amongst UK otolaryngology trainees. METHOD: A web-based questionnaire was distributed to UK otolaryngology trainees via regional programme directors. RESULTS: A total of 117 responses was received (35 per cent response rate). Most trainees reported increasing exposure to e-learning throughout their training and rated their current computer literacy skills highly, although satisfaction with current e learning resources was found to vary widely for a variety of reasons. CONCLUSION: Meeting the educational needs of otolaryngology trainees in the current era continues to be a challenge. Most trainees are already familiar with e-learning, although the quality and delivery of available websites is currently variable. The majority of trainees who responded seemed receptive to the implementation of a free, otolaryngology-specific e-learning resource. PMID- 21272430 TI - IUD in a septated uterus. PMID- 21272431 TI - The acute treatment of maternal supraventricular tachycardias during pregnancy: a review of the literature. AB - OBJECTIVE: Since evidence-based guidelines for the treatment of acute supraventricular tachyarrhythmia (SVT) in pregnancy are not available, our objective was to document published reports and immediate outcomes in this patient population. DATA SOURCES: A search of the literature was performed using Medline, Embase, CINAHL, American College of Physicians Journal Club, Database of Abstracts of Reviews of Effects, and Cochrance Central Register of Controlled Trials, using key word searching and citations in the English language literature from January 1950 to March 2010, on the subject of SVT. STUDY SELECTION/DATA EXTRACTION: We reviewed 38 studies (case-controlled cohort studies, case series, and case reports) using the key words "supraventricular tachycardia," "paroxysmal tachycardia," and "atrial tachycardia," combined with "pregnancy" or "pregnancy complications." CONCLUSION: No randomized controlled trials have addressed the acute treatment of SVT in pregnancy. If non-invasive manoeuvres fail, adenosine should be the first-line agent for treatment if needed during the second and third trimester. There is a paucity of data on management of SVT in the first trimester. PMID- 21272432 TI - Traditional First Nations birthing practices: interviews with elders in Northwestern Ontario. AB - OBJECTIVES: Traditionally, First Nations maternity care was provided by community based midwives trained through apprenticeship. Obstetrical practices and beliefs were integrated to provide holistic care. The Sioux Lookout Meno Ya Win Health Centre has a mandate to be a centre of excellence for Aboriginal health care. We undertook a literature review and performed a qualitative research study to understand some of the traditional practices in maternity care. METHODS: We conducted qualitative semi-structured interviews in English and Oji-Cree with 12 elders who had knowledge and experience of historical birthing practices in their home communities. Research team members included nursing and medical personnel and Anishinabe First Nation members. Interviews were analyzed and themes developed and verified by member checking and triangulation. RESULTS: The hands on training for a community-based midwife often began in her teenage years with observation of childbirth practices. Practices were handed down by oral tradition and included prescriptions for healthy diet and moderate exercise during pregnancy; intrapartum care with preparation of clean cloths, moss, and scissors; the involvement of certain supportive family and community members; careful attention to the sacred handling of the placenta and umbilical cord; and careful wrapping of the newborn in fur. Complications, sometimes fatal, included retained placentas and stillbirths. CONCLUSION: The provision of modern maternity care to Aboriginal patients should include acknowledgement of, and respect for, traditional birthing practices. Facilities providing care for these patients should consult with the relevant Aboriginal communities to understand their needs and initiate appropriate programming. PMID- 21272433 TI - Retrospective review of predisposing factors and surgical outcomes in obstetric fistula patients at a single teaching hospital in Western Kenya. AB - OBJECTIVE: We examined success rates and complications of obstetric fistula (OF) surgical repairs in association with patient and fistula characteristics, including sociocultural and socioeconomic determinants of health. A better understanding of these associations will help guide surgical management and prevent predisposing factors. METHODS: We reviewed the medical records of 86 patients who underwent OF repair at Moi Teaching and Referral Hospital in Kenya between 1999 and 2007. RESULTS: Women with OF presented for repair with a variety of concurrent conditions. Seventy-eight percent had laboured for at least 24 hours; 29% had undergone previous unsuccessful surgery. Of the women who presented at postoperative follow-up, 54% still complained of incontinence. Persistent incontinence was associated with larger, more complicated fistulas and having had previous failed attempts at surgical repair. CONCLUSION: The association of factors such as duration of labour with OF reflects the limited availability of obstetrical care in Western Kenya. There is a significant difference in postoperative success of fistula repair between women with large fistulas or those who had previous failed surgery and other patients. This reflects the importance of primary and secondary prevention. PMID- 21272434 TI - [Rectal erosion caused by a prosthesis for treatment of vaginal prolapse (Prolift)]. AB - Contexte : La place des protheses non resorbables dans la chirurgie du prolapsus vaginal a pris beaucoup d'ampleur ces dernieres annees. Les complications tardives commencent a apparaitre. Cas : Nous vous presentons le cas d'une erosion tardive dans le bas rectum. Pour autant que nous sachions, il s'agit de la premiere mention de cette complication tardive de la prothese Prolift. Dans ce cas, il s'agit probablement d'une necrose de decubitus attribuable a une prothese trop longue. Conclusion : Les protheses non resorbables sont certainement une option dans le traitement des prolapsus vaginaux; toutefois, les complications de ces implants devraient etre connues et les patientes devraient etre avisees des risques. PMID- 21272435 TI - Making a case for abortion curriculum reform: a knowledge-assessment survey of undergraduate medical students. AB - OBJECTIVE: Recent evidence suggests that medical schools offer insufficient training to equip students with the knowledge and skills necessary to counsel patients about abortion and to become abortion providers. We conducted a knowledge-assessment survey of medical students before (second-year students) and after (fourth-year students) teaching related to abortion to evaluate the effectiveness of the undergraduate abortion curriculum. METHODS: Undergraduate medical students answered a knowledge-assessment survey about abortion epidemiology, practice guidelines, abortion methods and procedures, and student readiness to provide abortions. RESULTS: One hundred and twenty six of 266 second year students (47%) and 67 of 170 fourth-year students (39%) completed the survey. Fourth-year medical students scored higher on average than second-year students (P < 0.001), producing mean scores of 45% and 25%, respectively. Abortion epidemiology was the weakest area of performance for all students. Most medical students would either provide an abortion (37% of fourth-year students, 38% of second-year students) or refer to a provider (36% of fourth-year students and 34% of second-year students). There was no significant relationship between overall scores and student readiness to provide abortions. CONCLUSION: Medical students in both second and fourth year demonstrated a limited understanding of abortion. Most future physicians participating in this study indicated they would be willing to provide abortions. Curriculum reform to improve abortion training in undergraduate medical programs is essential to provide students with necessary learning opportunities and to ensure safe and effective reproductive health care for women. PMID- 21272436 TI - The fetal safety of benzodiazepines: an updated meta-analysis. AB - Benzodiazepines are commonly used by women of reproductive age, and hence many pregnant women are exposed to them. An updated meta-analysis of their fetal safety synthesized nine studies with over one million pregnancies, yielding an odds ratio of 1.07 (95% CI 0.91 to 1.25). While benzodiazepines do not appear to increase teratogenic risk in general, case-controls suggest a twofold increased risk of oral cleft. PMID- 21272437 TI - Ethical decision making in the resuscitation of extremely premature infants: the health care professional's perspective. AB - Across Canada, the rate of preterm birth (i.e., at < 37 weeks' gestation) has been steadily increasing. Advances in perinatal medicine and neonatal intensive care have resulted in an increased capacity to intervene at the extremes of prematurity, leading to an increase in the overall survival of infants born at early gestations. There has been little corresponding decrease in long-term complications. As a result, additional stresses are placed on neonatal intensive care units across the country, impacting families, health care professionals, and society as a whole. Moral distress and moral residue are often cited in the neonatal-perinatal literature as stressors experienced by those who participate in the resuscitation decision-making process. They are directly related to the challenge of making a concrete decision about life and death at extremely early gestations in the context of long-term uncertainty. In this review, we performed a systematic search of medical and ethics literature pertaining to resuscitation at the extremes of prematurity. The perspective of health care professionals is explored, including how definitions of viability and parental perspectives contribute to the decision-making process. We argue for the necessity of further research exploring the inter-professional context of ethical decision making at the extremes of prematurity. PMID- 21272438 TI - Genetic considerations for a woman's pre-conception evaluation. AB - OBJECTIVE: To give health care providers information about the genetic information that can be used as part of health surveillance for women undergoing a pre-conception evaluation for genetic risk assessment and possible genetic screening or testing. OPTIONS: This genetic information can be used for patient education and possible prenatal testing. OUTCOMES: The use of this genetic information may allow improved risk-benefit assessment for pre-conception counselling for individual patients and their families. EVIDENCE: PubMed or Medline and the Cochrane Database were searched in November 2009, using appropriate key words (pre-conception, genetic disease, maternal, family history, genetic health risk, genetic health surveillance, prenatal screening, prenatal diagnosis, birth defects, and teratogen). Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, and national and international medical specialty societies. BENEFITS, HARMS, AND COSTS: The benefits for the patient and her family include understanding of possible genetic risk and enhanced pregnancy outcomes. The harm includes increased anxiety or psychological stress associated with the possibility of identifying genetic risks. VALIDATION: The evidence obtained was reviewed by the Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada. RECOMMENDATIONS AND SUMMARY STATEMENTS: A review of the current literature does not provide enough information for this committee opinion to present evidence-based recommendations. PMID- 21272439 TI - Nasopharyngeal carcinoma as a paradigm of cancer genetics. AB - The unusual incidence patterns for nasopharyngeal carcinoma (NPC) in China, Northeast India, Arctic Inuit, Peninsular and island Southeast Asia, Polynesian Islanders, and North Africans indicate a role for NPC risk genes in Chinese, Chinese-related, and not-obviously Chinese-related populations. Renewed interest in NPC genetic risk has been stimulated by a hypothesis that NPC population patterns originated in Bai-Yue / pre-Austronesian-speaking aborigines and were dispersed during the last glacial maximum by Sundaland submersion. Five articles in this issue of the Chinese Journal of Cancer, first presented at a meeting on genetic aspects of NPC [National Cancer Center of Singapore (NCCS), February 20 21, 2010], are directed towards incidence patterns, to early detection of affected individuals within risk populations, and to the application of genetic technology advances to understanding the nature of high risk. Turnbull presents a general framework for understanding population migrations that underlie NPC and similar complex diseases, including other viral cancers. Trejaut et al. apply genetic markers to detail migration from East Asia through Taiwan to the populating of Island Polynesia. Migration dispersal in a westward direction took mongoloid peoples to modern day Northeast India adjacent to Western China (Xinjiang). NPC incidence in mongoloid Nagas ranks amongst the highest in the world, whereas elsewhere in India NPC is uncommon. Cao et al. detail incidence patterns in Southeast China that have occurred over recent decades. Finally, Ji et al. describe the utility of Epstein-Barr virus serostatus in early NPC detection. While genetic risk factors still remain largely unknown, human leukocyte antigen (HLA) genes have been a focus of attention since the discovery of an HLA association with NPC in 1973 and, two years later, that NPC susceptibility in highest-risk Cantonese involved the co-occurrence of multi-HLA locus combinations of HLA genes as chromosome combinations, or haplotypes (e.g. HLA-A2-B46), whereas in relatively lower-risk non-Cantonese Chinese (Hokkiens, Teochews) they appeared to act independently, a strength of association reflecting the 30-50-fold difference in incidence between highest risk Cantonese and lowest-risk Indians. The prototypic haplotype HLA-A2-B46 extends over megabases. An upstream DNA segment (near HLA-DPA1), has close similarity to Gorilla, with no obvious homology to Chimpanzee in current databases, suggesting that a reticulate model of primate evolution may be more appropriate than simple phylogeny. The DNA variation level in this segment is high enough for it to be a hominin remnant. HLA-B46 arose in mongoloids and remains largely limited to Chinese so the question arises as to whether the hominin candidate segment indicates an eastward trek of Homo neanderthalensis or the survival of much earlier Homo erectus? In 2011 sequencing technologies have finally caught up with the requirement to separate parental haplotypes. Recently achieved chromosome separation for whole genome di-haploid genetic and epigenetic analysis of parental inheritance in single individuals will reveal interacting patterns of multi-locus haplotypes as humans move in and through successive environments, thus providing definitive information on the genetic affinities between extant populations, and of the migrations that have led to the global distribution of modern Homo. The challenge can now be met of seeking HLA-associated locations both within and outside the HLA complex on each of the pair of chromosomes. More broadly, for every disease, genetic risk detection will require resolution of the diploid genome as a di-haplome. In the context of NPC, HLA genetic risk complete autosomal di-haplomic sequencing will enable testing of the Wee unitary origin hypothesis of NPC risk even among populations with no apparent mongoloid affinity. PMID- 21272440 TI - On the trails of markers and proxies: the socio-cognitive technologies of human movement, knowledge assemblage, and their relevance to the etiology of nasopharyngeal carcinoma. AB - Bacteria, pigs, rats, pots, plants, words, bones, stones, earrings, diseases, and genetic indicators of all varieties are markers and proxies for the complexity of interweaving trails and stories integral to understanding human movement and knowledge assemblage in Southeast Asia and around the world. Understanding human movement and knowledge assemblage is central to comprehending the genetic basis of disease, especially of a cancer like nasopharyngeal carcinoma. The problem is that the markers and trails, taken in isolation, do not all tell the same story. Human movement and knowledge assemblage are in constant interaction in an adaptive process of co-production with genes, terrain, climate, sea level changes, kinship relations, diet, materials, food and transport technologies, social and cognitive technologies, and knowledge strategies and transmission. Nasopharyngeal carcinoma is the outcome of an adaptive process involving physical, social, and genetic components. PMID- 21272441 TI - Ancient migration routes of Austronesian-speaking populations in oceanic Southeast Asia and Melanesia might mimic the spread of nasopharyngeal carcinoma. AB - Mitochondrial DNA (mtDNA) and non-recombining Y chromosome (NRY) are inherited uni-parentally from mother to daughter or from father to son respectively. Their polymorphism has initially been studied throughout populations of the world to demonstrate the "Out of Africa" hypothesis. Here, to correlate the distribution of nasopharyngeal carcinoma (NPC) in different populations of insular Asia, we analyze the mtDNA information (lineages) obtained from genotyping of the hyper variable region (HVS I & II) among 1400 individuals from island Southeast Asia (ISEA), Taiwan and Fujian and supplemented with the analysis of relevant coding region polymorphisms. Lineages that best represented a clade (a branch of the genetic tree) in the phylogeny were further analyzed using complete genomic mtDNA sequencing. Finally, these complete mtDNA sequences were used to construct a most parsimonious tree which now constitutes the most up-to-date mtDNA dataset available on ISEA and Taiwan. This analysis has exposed new insights of the evolutionary history of insular Asia and has strong implications in assessing possible correlations with linguistic, archaeology, demography and the NPC distribution in populations within these regions. To obtain a more objective and balanced genetic point of view, slowly evolving biallelic Y single nucleotide polymorphism (Y-SNP) was also analyzed. As in the first step above, the technique was first applied to determine affinities (macro analysis) between populations of insular Asia. Secondly, sixteen Y short tandem repeats (Y-STR) were used as they allow deeper insight (micro analysis) into the relationship between individuals of a same region. Together, mtDNA and NRY allowed a better definition of the relational, demographic, cultural and genetic components that constitute the make up of the present day peoples of ISEA. Outstanding findings were obtained on the routes of migration that occurred along with the spread of NPC during the settlement of insular Asia. The results of this analysis will be discussed using a conceptual approach. PMID- 21272442 TI - Nasopharyngeal carcinoma in the Northeastern states of India. AB - Nasopharyngeal cancer (NPC) is a rare disease in most parts of the world, except for Southeast Asia, some parts of North Africa and the Arctic. It is mostly seen in people of Chinese origin. In India, NPC is also rare, except for the Hill States of Northeast India, particularly Nagaland, Manipur, and Mizoram. The striking feature of NPC in Northeast India is that the incidence ranges over the complete spectrum from the lowest (as 0.5/100 000 to 2.0/100 000 among Caucasoid) to the highest (as about 20/100 000 among Cantonese/Zhongshan dialect Chinese). The age-adjusted rate of NPC in Kohima district of Nagaland State is 19.4/100 000, which is among the highest recorded rates. By contrast, in Assam, one of the so-called Hill States but not itself a hilly state, NPC is much less common. The Northeastern region is distinguished by a preponderance of the Tibeto-Burman languages and by variable mongoloid features among peoples of the region. The nature of the migratory populations who are presumed to be bearers of the mongoloid risk is unknown, but these NPC occurrence features provide an outstanding opportunity for NPC risk investigation, such as that of the hypothesis of Wee et al. for westward displacement of Chinese aborigines following the last glacial maximum. PMID- 21272443 TI - The prevalence and prevention of nasopharyngeal carcinoma in China. AB - Nasopharyngeal carcinoma (NPC) has remarkable epidemiological features, including regional, racial, and familial aggregations. The aim of this review is to describe the epidemiological characteristics of NPC and to propose possible causes for the high incidence patterns in southern China. Since the etiology of NPC is not completely understood, approaches to primary prevention of NPC remain under consideration. This situation highlights the need to conduct secondary prevention, including improving rates of early detection, early diagnosis, and early treatment in NPC patients. Since the 1970's, high-risk populations in southern China have been screened extensively for early detection of NPC using anti-Epstein-Barr virus (EBV) serum biomarkers. This review summarizes several large screening studies that have been conducted in the high-incidence areas of China. Screening markers, high-risk age range for screening, time intervals for blood re-examination, and the effectiveness of these screening studies will be discussed. Conduction of prospective randomized controlled screening trials in southern China can be expected to maximize the cost-effectiveness of early NPC detection screening. PMID- 21272444 TI - Detection of Stage I nasopharyngeal carcinoma by serologic screening and clinical examination. AB - In a prospective study, 42 048 adults residing in Zhongshan City, Guangdong, China, were followed for 16 years, and 171 of them developed nasopharyngeal carcinoma (NPC). Although Epstein-Barr virus (EBV) antibody levels of the cohort fluctuated, the antibody levels of 93% of the patients with NPC were raised and maintained at high levels for up to 10 years prior to diagnosis. This suggests that the serologic window affords an opportunity to monitor tumor progression during the preclinical stage of NPC development, facilitating early NPC detection. We reviewed the clinical records of the 171 patients with NPC in the prospective study to assess the efficacy of early NPC detection by serologic screening and clinical examination. Of the 171 patients, 51 had Stage I tumor (44 were among the 73 patients detected by clinical examination and 7 were among the 98 patients presented to outpatient department). Initial serologic screening predicted 58 (95.1%) of the 61 patients detected within 2 years. The risk of the screened population (58/3093) raised 13 times relative to cohort (61/42 048) during this period. Clinical examination detected all the 58 predicted cases, and 35 (60.3%) of which were diagnosed with Stage I tumor. The serologic prediction rate fell to 33.6% (37/110) 2 to 16 years after screening. The proportion of cases detected by clinical examination fell to 40.5% (15/37). The proportion of Stage I tumors among the cases detected by clinical examination during both periods remained at about 60%. We concluded that early detection of NPC can be accomplished by repeated serologic screening to maintain high prediction rates and by promptly examining screened subjects to detect tumors before the symptoms develop. PMID- 21272445 TI - Protein folding, protein homeostasis, and cancer. AB - Proteins fold into their functional 3-dimensional structures from a linear amino acid sequence. In vitro this process is spontaneous; while in vivo it is orchestrated by a specialized set of proteins, called chaperones. Protein folding is an ongoing cellular process, as cellular proteins constantly undergo synthesis and degradation. Here emerging links between this process and cancer are reviewed. This perspective both yields insights into the current struggle to develop novel cancer chemotherapeutics and has implications for future chemotherapy discovery. PMID- 21272446 TI - Association of a single nucleotide polymorphism at 6q25.1,rs2046210, with endometrial cancer risk among Chinese women. AB - A recent genome-wide association study identified a new susceptibility locus for breast cancer, rs2046210, which is a single nucleotide polymorphism (SNP) located upstream of the estrogen receptor alpha(ESR1) gene on chromosome 6q25.1. Given that endometrial cancer shares many risk factors with breast cancer and both are related to estrogen exposure and that rs2046210 is in close proximity to the ESR1 gene, we evaluated the association of SNP rs2046210 with endometrial cancer risk among 953 cases and 947 controls in a population-based, case-control study conducted in Shanghai, China. Logistic regression models were used to derive odds ratios (ORs) and 95% confidence intervals (95% CIs) after adjusting for potential confounders. We found that the A allele of rs2046210, linked to an increased risk of breast cancer, was associated with increased but not statistically significant risk of endometrial cancer (OR = 1.16, 95% CI = 0.96-1.41 for the GA and AA genotypes compared with the GG genotype); the association was stronger among post menopausal women (OR = 1.28, 95% CI = 1.00-1.65). The association tended to be stronger among women with higher or longer estrogen exposure than among women with relatively lower or shorter exposure to estrogen. Our study suggests that rs2046210 may play a role in the etiology of endometrial cancer. Additional studies are needed to confirm our findings. PMID- 21272447 TI - Nasal metastases from renal cell carcinoma are associated with Memorial Sloan Kettering Cancer Center poor-prognosis classification. AB - Unusual sites of metastases are recognized in patients with renal cell carcinoma (RCC). However, the prognostic implications of these sites are not well understood. We used the Memorial Sloan-Kettering Cancer Center (MSKCC) risk classification for metastatic RCC to evaluate 912 consecutive patients with RCC managed at the Singapore General Hospital between 1990 and 2009. Among these patients, 301 had metastases either at diagnosis or during the course of illness. Nasal metastases, all arising from clear cell RCC, were identified histologically in 4 patients (1.3% of those with metastasis). All 4 patients were classified as MSKCC poor prognosis by current risk criteria. Nasal metastases were significantly associated with lung and bone metastases. The frequency of nasal metastases in patients with metastatic RCC is about 1%, occurring predominantly in patients with clear cell RCC. Nasal metastases are associated with poor prognosis as estimated by the MSKCC risk classification, with attendant implications for selection of targeted therapy, and are usually associated with multi-organ dissemination, including concurrent lung and bone involvement. PMID- 21272448 TI - [The role of interferon in the treatment of viral hepatitis and its perspective]. PMID- 21272449 TI - [The combination administration of interferon in viral hepatitis]. PMID- 21272450 TI - [Efficacy forecast on interferon in the treatment of chronic viral hepatitis]. PMID- 21272451 TI - [Long-term outcomes of interferon therapy for chronic hepatitis]. PMID- 21272452 TI - [Application of interferon in the treatment of liver cancer]. PMID- 21272453 TI - [The guideline of prevention and treatment for chronic hepatitis B (2010 version)]. PMID- 21272454 TI - [A multicenter study of the effectiveness of interferon alpha-1b (Hapgen) in treating HBeAg positive chronic hepatitis B patients]. AB - To compare the efficacy and safety of interferon a-1b and interferon a-1b combined with lamivudine in the treatment of HBeAg positive chronic hepatitis B (CHB), to analyze the impact of variable factors on the efficacy, and to investigate the individualized anti-viral regimen for CHB patients. 111 CHB patients were enrolled and randomly divided into two groups. Group A: patients received interferon a-1b (49 patients, 50mug I. M. , qod. ) , Group B: interferon a-1b (idem) combined with lamivudine for 6-12 months or longer(62 patients, 100 mg, P.O. , q.d. ). (1) The HBeAg seroconversion rates of treatment by 12 and 18 months were 28.6% and 36.7% in group A, 29.0% and 38.7% in group B, respectively, no significant difference found between the two groups at the end of treatment (x2=0.003, P value is more than 0.05; x2=1.500, P value is more than 0.05). (2) The HBV DNA undetectable rates of treatment by 6 months, 12 months and 18 months were 8.2%, 53.1% and 57.1% in group A, 66.1%, 83.9% and 88.7% in group B, respectively, still no significant difference existed between the two groups (x2=38.150, P value is less than 0.05; x2=12.073, P value is less than 0.05, x2=14.459, P value is less than 0.05). (3) In group A, the HBeAg seroconversion rates for male and female patients were 34.5% and 40.0% respectively, no significant difference found between. As regard ages the rates were 34.9% and 50.0% for patients younger or more than 40 years of age, no significant difference existed between. The HBeAg seroconversion rate was higher in patients with lower baseline serum HBV DNA loads ( less than 6 log10 copies/ml) . (4) The rates of patients with fever and blood abnormality were 36.7% and 34.7% in group A, 32.3% and 27.4% in group B, respectively. The total incidences of adverse events were similar between group A and B (x2=0.244, P value is more than 0.05; x2=0.682, P value is more than 0.05). (5) The ratio of drug resistance in group B was only 1.6%. The adverse events of interferon a-1b treatment for CHB are low and mild. The HBeAg seroconversion rate persistently raises with the extension of interferon a-1b treatment course. The HBV DNA undetectable rate of interferon a 1b combined with lamivudine is significantly higher than that of interferon a-1b and the drug resistance of lamivudine can be reduced obviously by combination therapy. PMID- 21272455 TI - [Treatment with interferon and thymosin alpha-1 versus interferon monotherapy for HBeAg positive chronic hepatitis B: a meta-analysis]. AB - To compare the efficacy of interferon and thymosin alpha-1 combination therapy with interferon monotherapy for HBeAg positive chronic hepatitis B. The relevant randomized controlled trials were searched throughout PubMed, EBSCO, Cochrane Library, CBMdisc, VIP, WanFang since Janurary 1990. Studies were included if patients were followed up for at least 6 months after cessation of treatment. Meta-analysis was carried out with RevMan5.0 software. Subgroup analyses were used at different time of observation. Seven randomized controlled trials were included(535 patients in total). According to the results of meta-analysis, the combination therapy was remarkably more effective than monotherapy both at the end of the treatment and the follow-up in terms of HBV-DNA negative rate (54.9% vs 36.3%, OR=2.39, 95% CI=1.64-3.49, P value is less than 0.01; 58.6% vs 30.7%, OR=3.68, 95% CI=2.51-5.41, P value is less than 0.01, respectively), ALT normalization rate (74.5% vs 60.9%, OR=1.94, 95% CI=1.26-3.00, P value is less than 0.01; 74.0% vs 55.6%, OR=2.36, 95% CI=1.54-3.62, P value is less than 0.01, respectively), HBeAg loss rate (56.9% vs 36.7%, OR=2.38, 95% CI=1.61-3.51, P value is less than 0.01; 62.2% vs 33.2%, OR=3.42, 95% CI=2.31-5.06, P value is less than 0.01, respectively) , and HBeAg seroconversion rate (40.1% vs 29.0%, OR=1.65, 95% CI=1.10-2.47, P value is less than 0.05; 47.0% vs 29.5%, OR=2.13, 95% CI=1.43-3.16, P value is less than 0.01, respectively); the HBsAg loss rate of the combination therapy group was significantly higher than that of the monotherapy group only at the end of the follow-up (9.8% vs 3.7%, OR=2.92, 95% CI=1.09-7.76, P value is less than 0.05). Interferon and thymosin alpha-1 combination therapy achieves superior effect with no increase in the adverse effects as compared to interferon monotherapy for HBeAg positive chronic hepatitis B. PMID- 21272456 TI - [Association between the influential factors and the effectiveness of pegylated interferon alpha-2a plus ribavirin as a combination treatment for chronic hepatitis C patients]. AB - To evaluate the efficacy and to investigate the association between the length of the treatment period and the cumulative dose of pegylated interferon alpha-2a (PegIFN alpha-2a) plus ribavirin (RBV) and the effectiveness of antiviral therapy. We analyzed data from 117 patients treated for 48 weeks with PEG-IFN alpha-2a (135mug or 180mug/week) plus weight-based RBV (800 mg/d for patients is less than or equal to 65 kg, 1000 mg/d for patients 65-75 kg and 1200 mg/d for patients is more than or equal to 75 kg) under care at West China Hospital. HCV RNA was assessed at baseline, Week 4, 12 and 24, the end of treatment (EOT) and after 24 weeks follow-up (sustained virological response; SVR) with a test range of 1.0*10(3) to 5.0*10(7) IU/ml. Patients were stratified by age, gender, weight, route of transmission, duration of infection, baseline HCV RNA level and PegIFN alpha-2a or RBV dosage. HCV genotype was assessed in 29 patients (genotype 1b, 21; genotype 2a, 7; genotype 1b/2a, 1). Rapid virological response (RVR; HCV RNA negative at week 4), complete early virological response (cEVR; HCV RNA negative at week 12), EOT response, and SVR were achieved in 88 (75.2%), 110 (94%), 114 (97.4%) and 96 (82.1%) patients, respectively. Younger age, lower weight and shorter speculated infection years were associated with higher SVR rates (91.4% vs 72.9%, x2=6.796, P value is less than 0.05; 85% vs 50%, x2=5.433, P value is less than 0.05; 96.7% vs 77%, x2=5.852, P value is less than 0.05). SVR significantly increased with treatment length (38.5%, 66.7%, and 88.8% for is less than or equal to 29 weeks, 29-38 weeks, and is more than or equal to 38 weeks, respectively). SVR significantly increased with total cumulative treatment doses (38.5%, 66.7% and 88.8% for is less than or equal to 60%, 60%-80% and is more than or equal to 80% of PegIFN dose respectively; 33.3%, 85.3% and 96.8% for is less than or equal to 60%, 60%-80% and is more than or equal to 80% in RBV dose respectively) in all patients. Less than 80% of standard dose of RBV was not sufficient even if given enough PegIFN (is more than or equal to 80% cumulative treatment dose) in patients who achieved RVR. Chinese patients treated with peginterferon alpha-2a plus ribavirin have high rates of SVR. It is important to complete the target length of treatment and to continue the target dosage to achieve SVR. PMID- 21272457 TI - [Dynamic changes and clinical significance of HBcAg18-27 specific cytotoxic T lymphocytes in acute hepatitis B patients]. AB - This report aims to investigate the dynamical changes of HBcAg18-27 epitope specific cytotoxic T lymphocytes(CTL), alanine aminotransferase (ALT), HBV DNA and HBsAg in peripheral blood of acute hepatitis B patients, and to explore the roles of HBcAg18-27-specific CTLs in virus clearance and liver injury. Acute hepatitis B (AHB) and chronic hepatitis B (CHB) patients were divided into two groups according to results of HLA-A0201. Patients with positive HLA-A0201 were classified into HBcAg-specific CTL group and those with negative HLA-A0201 were referred as control group. The specific CTLs were stained with HLA-A0201 limited HBcAg18-27 epitope MHC-Pentamer and the frequencies of CTLs, T, B, NK and NKT cells were detected by flow cytometry (FCM). The serum ALT, HBV DNA and HBsAg were examined using speed analysis, quantitative PCR and abbott chemiluminescent technology. The frequencies of HBcAg18-27-specific CTLs in AHB patients were higher in the early three weeks as compared to the late three weeks. The apex time of HBV-specific CTL frequencies lagged behind those of HBV DNA, HBsAg and ALT. The loss of HBsAg in patients with high frequencies of HBV-specific CTL was earlier than that in patients with low frequencies (t = 2.018, P value is less than 0.05). In the second week the peak frequencies of CD3+CD8+ cells overlapped with that of HBcAg18-27-specific CTLs and with a positive correlation between (r = 0.420, P value is less than 0.05). During the early stages of AHB, the frequencies of NK and NKT cells were found significantly lower than that of control group and CHB group and the levels were back to normal after recovery. Moreover, a negative correlation existed between the frequencies of NK cells and the dynamic changes of HBcAg18-27-specific CTLs (r = -0.435, P value is less than 0.01) in AHB group. The frequencies of HBcAg18-27-specific CTLs were significantly higher as compared to CHB group in the first three weeks (z = 3.258, -4.04, and -3.259, P value is less than 0.01). The early loss of HBsAg was closely related to the high frequencies of HBcAg18-27 specific CTLs in AHB patients. HBcAg-specific CTL frequencies in peripheral blood could be used to predict clinical outcome after HBV infection. The frequencies of CD8+ T cells can reflect the changes of frequencies of HBcAg-specific CTL during acute HBV infection. PMID- 21272458 TI - [Long-fragment RNA inhibits hepatitis B virus gene replication and expression in HepG2.2.15 cells]. AB - To evaluate the inhibitory effects of long antisense RNA on HBV replication in HepG2.2.15 cells. The coding region of HBV S gene was cloned into pTARGET vector in sense and antisense orientations and the recombinant plasmids were transfected into HepG2.2.15 cells which were divided into HBS2 (antisense RNA) group, HBS4 (sense RNA) group and control group. HBsAg and HBeAg in the culture supernate were detected by ELISA. The HBV DNA in the supernate was quantified by real-time PCR. After treatment, the levels of HBsAg in HepG2.2.15 cell supernatants of three groups were 0.621+/-0.027, 3.399+/-0.018 and 2.232+/-0.187 respectively; the levels of HBeAg were 0.749+/-0.019, 1.548+/-0.025 and 1.570+/-0.044 respectively and the levels of HBV DNA were 1.597+/-0.082, 3.381+/-0.297 and 3.610+/-0.063 respectively. The expressions of HBsAg and HBeAg and the HBV DNA level in HBS2 group were remarkably reduced as compared to the control (Z = 2.309, P value is less than 0.05); whereas the sense plasmid transfection (HBS4) did not affect HBeAg (Z = -0.866) and HBV DNA (Z = -1.155) levels in the culture supernate but slightly increased the HBsAg level (Z = -2.309). Antisense RNA might be a useful tool to repress HBV replication. PMID- 21272459 TI - [Relative analysis of OPN and its related signal molecules in hepatocellular carcinoma]. AB - Osteopontin (OPN) has close relationship with metastasis in hepatocellular carcinoma but its downstream signal pathways have not been well defined in hepatocellular carcinoma. The object of this study is to identify the associated signal pathways in human HCC tissues. The expressions of OPN, intergrin aV, CD44v6, P-FAK, FAK, P-Src, Src, P-ERK and P-AKT were assayed using TMA analysis. The relationship of OPN with P-ERK, P-Src and P-AKT were explored and the role in HCC metastasis was analysed. The expression levels of OPN, intergrin aV, CD44v6, P-FAK, P-Src, Src, P-ERK and P-AKT in HCC tissue were significantly higher than that in normal tissue (P value is less than 0.05). No significant difference was found between the expression levels of FAK in HCC tissue and normal tissue (P value is more than 0.05). OPN expression was significantly associated with Integrin av (P value is less than 0.01), CD44V6 (P value is less than 0.01) and P ERK (P value is less than 0.05) but not with P-Src, P-FAK and P-AKT (P value is more than 0.05). The expressions of P-FAK (P value is less than 0.05), P-Src (P value is less than 0.01) and P-AKT (P value is less than 0.05) were significantly associated with Integrin av and the P-FAK expression was also significantly associated with CD44V6 (P value is less than 0.01). OPN promotes HCC metastasis though Integrin av/CD44V6/MAPK pathway in human HCC. PMID- 21272460 TI - [The diagnosis and treatment of abnormal uterine bleeding in nonpregnant patients with hepatic cirrhosis]. AB - To investigate the clinical characteristics of abnormal uterine bleeding (AUB) in nonpregnant hepatic cirrhosis patients and to assess the treatment and curative effects of AUB. A retrospective analysis was conducted on 72 nonpregant AUB patients treated in Ditan Hospital from October 2008 to October 2009. Data were assessed with SPSS 10.0 and the constituent ratio was examined by chi-square tests. 58 out of the 72 nonpregnant AUB patients were climacteric patients (80.56%). Approximately 42.5% and 68.8% (x2=7.189, P = 0.027) of the AUB patients were diagnosed with compensated and decompensated liver cirrhosis, respectively, which presents a statistical significance. Among the 18 cases of AUB with hypermenorrhea, 12 were with compensated cirrhosis and 6 with decompensated cirrhosis, which makes a statistical significance with a chi-square result of 7.189, P = 0.027. 41 out of the 52 cases with diagnostic curettage (75.00%) were observed with pathological changes in endomembrane. During the three months to one year follow-up,10 of 67 patients showed effective expectant treatment and 16 cases with hysterectomia complained no postoperative complications. A high frequency of AUB was observed in nonpregnant cirrhosis patients. The main bleeding pattern of the nonpregnant AUB patients with cirrhosis is hypermenorrhea. PMID- 21272461 TI - [Relationship between the expression of uncoupling protein 2 and the damage by oxygen free radicals in acute liver failure rats]. AB - To investigate the relationship between uncoupling protein 2 (UCP2) expression and the damage caused by oxygen free radicals in acute liver failure rat models. Thirty-five male Sprague-Dawley rats were randomly divided into two groups: the control group (15 rats) and liver failure group (20 rats). The rats were injected intraperitoneally with thioacetamide (TAA) to induce models of acute liver failure. The levels of endotoxin (ET) were detected by double antibody sandwich enzyme-linked immunosorbent assay. The expression of liver UCP2 mRNA was detected by reverse transcription polymerase chain reaction. The superoxide dismutase (SOD) and malonaldehyde (MDA) were detected by spectrophotometry. The expression of UCP2 protein was observed by immunohistochemistry. The data of the two groups were compared using Mann-Whitney U test or ANOVA. The expression of UCP2 mRNA in liver failure group was higher as compared to the control group (P value is less than 0.01); the level of MDA and endotoxin of liver failure group were higher than that of the control group (P value is less than 0.01). SOD of the liver failure group was lower (P value is less than 0.01). There was a certain correlation between UCP2 mRNA expression and ET, SOD and MDA (r = 0.952, -0.667, 0. 634 respectively, P value is less than 0.05 or 0.01). UCP2 is highly expressed in the livers of liver failure rats. A certain correlation perhaps existed between the expression of UCP2 mRNA and the serous SOD, MDA and ET. PMID- 21272462 TI - [The clinical significance of serum platelet-derived growth factor (PDGF-BB) in HBeAg positive and negative chronic hepatitis B patients]. PMID- 21272463 TI - [Plasma D-dimer changes in chronic severe hepatitis B patients]. PMID- 21272464 TI - [The immunostimulatory effects of CpG 1826 and HBsAg mixture on lymphocytes]. PMID- 21272465 TI - [Study on L-Ornithine-L-Aspartate in the treatment of acute-on-chronic liver failure]. PMID- 21272466 TI - [The neuropsychologic tests and the minimal hepatic encephalopathy investigations in liver cirrhotic patients]. PMID- 21272467 TI - [Transcatheter hyper-selective hepatic arterial embolization for the treatment of polycysitic liver disease]. PMID- 21272468 TI - [Treatment of chronic hepatitis C complicated with thyroid disease by peginterferon alfa-2a: 3 cases report]. PMID- 21272469 TI - [A case report of nephrotic syndrome caused by interferon alpha-2b in the treatment of chronic hepatitis B]. PMID- 21272470 TI - [A report from the Second Chinese National Symposium on Liver Fibrosis and Cirrhosis]. PMID- 21272471 TI - [A new mechanism of immune response mediated hepatocellular injury]. PMID- 21272472 TI - [The mechanisms and positions of anti-inflammatory drugs for liver diseases]. PMID- 21272473 TI - [Epidemiology of drug-induced liver injury]. PMID- 21272474 TI - [Effect of anti-VEGF165 ribozyme on biological behaviors of human lung adenocarcinoma cell]. AB - BACKGROUND: To investigate the biological effects of anti VEGF165 ribozyme on human lung adenocarcinoma cell. METHODS: Hammerhead ribozyme (VRz) against VEGF165 gene transcripts (site 212) and its paired mutant ribozyme (mVRz) were designed and synthesized, and the cleavage activity of the ribozymes on target RNA in a cell-free system was observed. The replication-incompetent adenovirus mediated eukaryotic expression vectors (rpAdVRz) containing VRz and mVRz gene were constructed and identified. Then the human lung adenocarcinoma cells (A549) were infected with recombinant adenovirus. The biological characteristics of A549 cell before and after infection in vitro were inspected by Northern blot, laser confocal imaging system analysis, flow cytometry and transmission electron microscopy. RESULTS: VRz specifically and efficiently cleaved the VEGF165 mRNA. The rpAdVRz was successfully constructed and infected A549 cell. The level of VEGF165 expression decreased 87% in rpAdVRz infected cells compared with the other groups, but their biological characteristics were not influenced by the expression of the exogenous gene. CONCLUSIONS: The adenovirus mediated hammerhead ribozyme against VEGF165 can significantly decrease the expression of VEGF165. This provides an experimental basis for human lung cancer gene therapy with antiangiogenesis method. PMID- 21272475 TI - [Study on anti-invasive effect and apoptosis induction of pentacyclic triterpenoid in human lung cancer cells]. AB - BACKGROUND: To study the anti-invasive effects and its mechanism and apoptosis induction of pentacyclic triterpenoid including glycyrrhizin (GL), 18beta glycyrrhetinic acid (GA), ursolic acid (UA) and oleanolic acid (OA) in highly potentially metastatic lung cancer cell line (PGCL3). METHODS: The invasive ability, the adhesive ability, the migration ability and the activity of cathepsin B (CB) of PGCL3 cells treated with the four drugs were determined by the invasion test of reconstituted basement membrane, the laminin adhesion test, the chemotactic migration test and the enzymological method of CB. The apoptosis of the cells was detected with acridine orange-ethidium bromide fluorescent stain (AO/EB) and TUNEL. RESULTS: The GL,GA, UA and OA could decrease the proliferative ability of PGCL3 cells, and their IC50 values were 1.83 mmol/L, 145.3 MUmol/L, 44.73 MUmol/L and 40.71 MUmol/L respectively. After treatment with 0.5 and 1.0 mmol/L GL, 25 and 50 MUmol/L GA, 30 and 40 MUmol/L UA, 35 and 45 MUmol/L OA for 96 h, the invasive ability of the PGCL3 cells was significantly decreased compared with that of the control groups ( P < 0.01 or P < 0.001). The adhesive and migration ability, the secretion of CB and the colony-formation number in semi solid agar were significantly decreased after PGCL3 cells were treated with the above concentration of the four drugs for 96 h ( P < 0.05, P < 0.01 or P < 0.001), and the inhibition was in a dose-dependent fashion. The percentages of apoptosis of the cells were obviously increased after treatment with the above concentration of the four durgs for 48 h, compared with the control group ( P < 0.05 or P < 0.01). CONCLUSIONS: All of the four drugs can inhibit the proliferative and invasive ability, and induce apoptosis of the PGCL3 human lung cancer cells. The mechanism of anti invasion may be to inhibit the adhesion, migration, and the CB secretion of the cells. PMID- 21272476 TI - [Research on radioimmunotherapy of lung cancer in nude mice using lung cancer monoclonal antibody LC-1 combined with 90Y]. AB - BACKGROUND: To evaluate potential clinical roles of monoclonal antibody (MoAb) based radioimmunotherapy in the treatment of lung cancer. METHODS: Anti-lung cancer monoclonal antibody LC-l IgM was combined with 90Y to produce radioimmunological targeting drug. Human lung cancer tissue was inoculated subcutaneously in 35 nude mice. They were randomized into seven groups while the tumor was 5 mm in diameter. The groups were divided by the dose of the drug injected to the tail vein of the mice: blank group, LC-1 IgM alone, 90Y 50 MUCi alone, 50 MUCi, 150 MUCi, 300 MUCi, and 400 MUCi combined therapy groups. The size of the tumor was measured weekly and the mice were killed in four weeks after treatment. The tumors were resected and weighed. RESULTS: As compared to blank group, therapy groups' tumor growth was inhibited and the inhibition was dose- and time-dependent. The inhibition rates of 300 MUCi and 400 MUCi groups were significantly different (P < 0.05). The nuclei of tumor cells showed karyopycnosis, structure disorder and rupture after treatment by pathological exam. In some regions, the tumor cells were necrotic or disappeared. CONCLUSIONS: The results indicate that the radioimmunological drug made from lung cancer monoclonal antibody LC-1 IgM and 90Y can specifically localise in tumor tissue and ensure radioimmunological targeting therapy, so has underlying clinical value. PMID- 21272477 TI - [Study on the growth-inhibiting effect of anticancer ketonon on lung cancer cell line and its mechanism]. AB - BACKGROUND: To observe the growth-inhibiting effect of anticancer ketonon on A549 cell line and PLA-801D cell line and to explore its mechanism based on the antineoplastic effects of Tanshinon. METHODS: A549 and PLA-801D cell lines were treated with anticancer ketonon by techniques of cell culture in vitro . The growth curves and dose-effect curves were drawn up. The ability of clone formation was determined. It was observed and analysed by light microscopy and flow cytometry. RESULTS: The growth of A549 and PLA 801D cell lines was evidently inhibited. Ability of clone formation was inhibited. The apoptosis index of cells was increased after treated with anticancer ketonon and the cell cycle was blocked at G0/G1 phase. CONCLUSIONS: Anticancer ketonon can significantly inhibit the growth of human lung cancer cells probably through inducing the apoptosis of cancer cells. PMID- 21272478 TI - [A multicenter randomized phase III trial of domestic product of rmhTNF in the treatment of non-small cell lung cancer]. AB - BACKGROUND: To evaluate and compare the effects and toxicity of the domestic product of recombinant mutant human tumor necrosis factor (rmhTNF) combined with chemotherapy and chemotherapy alone in the treatment of patients with non-small cell lung cancer (NSCLC). METHODS: Two hundred patients with NSCLC in multicenter were randomly devided into trial group (150 cases) and control group (50 cases). Chemotherapy with CAP regimen was given to the patients. Meanwhile, rmhTNF injection of 4*106U/m2 was also given from the 1st to 7th days, the 11th to 17th days on the chemotherapy cycle in the trial group. The control patients received chemotherapy alone. Twenty-one days were as a cycle, 2 cycles were given to each patient. The chemotherapeutic effects and toxicity were observed and compared between the two groups after the therapy. RESULTS: of the 200 patients, 5 cases in the trial group and 3 cases in the control group were out of the trial because of economy. The other 192 cases (145 cases in the trial group and 47 cases in the control group) could be analyzed and evaluated the clinical effects and toxicity. The response rate of chemotherapy was 46.90% (68/145) in the trial group and 17.02% (8/47) in the control group respectively ( P =0.001). The KPS scores was 86.02+/-9.74 in the trial group, and 80.14+/-9.10 in the control group ( P =0.025). No significant difference of degree III+IV toxicity was observed between the two groups ( P > 0.05). The side effects related to rmhTNF included slight fever, cold-like symptoms, pain and red and swelling in the injection site. All of them were mild and didn't need any treatment and disappeared after the therapy. There were no severe abnormality of liver and kidney function and ECG in both groups. CONCLUSIONS: The results demonstrate that the effects of domestic rmhTNF combined with chemotherapy are remarkably higher than that of chemotherapy alone in the treatment of NSCLC. rmhTNF can increase the sensitivity to chemotherapy and improve the quality of life of the patients with slight toxicity. Hence rmhTNF is worth expanding clinical use. PMID- 21272479 TI - [mRNA expressions of MAGE genes in human lung cancer]. AB - BACKGROUND: To investigate the expressions of MAGE-1,-2,-3 and -4 in lung cancer at mRNA level. METHODS: Using a reverse transcription-polymerase chain reaction assay (RT-PCR), the expressions of MAGE-1,-2,-3 and -4 in 35 lung cancer samples and non-tumorous lung tissues were examined. RESULTS: Of the 35 tumor samples, the MAGE-1,-2,-3 and -4 were expressed at mRNA level in 22.9% (8/35), 62.9% (22/35), 37.1% (13/35) and 77.1% (27/35) respectively. At least one of these genes was expressed in 85.7% (30/35) of the samples. Two or more of these genes were expressed in 71.4% (25/35) of the samples. None of the non-tumorous lung tissue was positive for these genes. No significant difference of the frequency of MAGE gene expression was found between adenocarcinoma and squamous cell carcinoma, between different tumor stages, and between groups with or without lymph node metastasis (P > 0.05). CONCLUSIONS: MAGE-1,-2,-3 and -4 are expressed at a high percentage in lung cancer. All of these genes are negative in the adjacent non tumorous lung tissue. These results indicate the possibility of a future specific immunotherapy for lung cancer based on these MAGE antigens. PMID- 21272480 TI - [The expression of Cx43 protein in non-small cell lung cancer tissues and its clinical significance]. AB - BACKGROUND: To investigate the expression feature of Cx43 protein in non-small cell lung cancer and its clinical significance. METHODS: Paraffin embedded tissues from 65 patients with primary non-small cell lung cancer and 20 adjacent non-cancerous lung tissues were investigated for expression of Cx43 protein by immunohistochemistry (ABC method). The relationship between Cx43 protein expression and clinicopathological characteristics of lung cancer was analyzed. RESULTS: Cx43 protein was positively expressed in 24 out of 65 lung cancer tissues (36.92%), and in all 20 adjacent non-cancerous lung tissues. There was a significant difference in Cx43 expression between stage I-II and stage III-IV groups ( P < 0.05), as well as between moderate-well and poor differentiation groups ( P < 0.01). Primary lung cancer tissues with lymph node metastasis showed lower expression of Cx43 than those without lymph node metastasis ( P < 0.01). The positive rate of Cx43 expression was not related to histological classification ( P > 0.05). CONCLUSIONS: Cx43 expression might play a role in the genesis, development and metastasis of lung cancer. It may be used to judge the biological behavior of lung cancer. PMID- 21272481 TI - [Expression of survivin gene and its significance in the carcinogenesis and development of non-small cell lung cancer]. AB - BACKGROUND: To study the expression of survivin mRNA in non-small cell lung cancer (NSCLC), and to explore its relationship with carcinogenesis, development invasion and metastasis of NSCLC. METHODS: In situ hybridization was applied to detect survivin mRNA expression in 12 normal bronchial epithelium, 9 dysplasia, 34 NSCLC and 12 metastatic lymph nodes. The relationship between survivin expression and clinicopathological characteristics was analyzed. RESULTS: In normal bronchial epithelium, dysplasia, NSCLC and metastatic lymph nodes, the positive rate of survivin mRNA expression were 16.67% (2/12), 33.33% (3/9), 61.76% (21/34), and 91.67% (11/12), respectively. There were significant differences in survivin mRNA expression between lung cancer and normal bronchial epithelium ( P < 0.01), as well as between metastatic lymph nodes and normal bronchial epithelium ( P < 0.001). There were remarkably higher survivin mRNA expressions in poor- and moderate-differentiated groups than that in well differentiated group ( P =0.003, P =0.004). The expression of survivin mRNA was not related to histologic classification and lymph node status ( P > 0.05, P > 0.05). CONCLUSIONS: Survivin mRNA expression may play an important role in the carcinogenesis and development of NSCLC. It may be a new target in gene therapy of lung cancer through blocking or down-regulating survivin mRNA expression to recover the normal regulation mechanism of apoptosis. PMID- 21272482 TI - [Expression and significance of matrix metalloproteinases and their tissue inhibitors in the infiltration and metastasis of lung cancer]. AB - BACKGROUND: To determine the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in lung cancer specimens, and to find out the possible roles of MMPs and TIMPs in the infiltration and metastasis of lung cancer. METHODS: The expression of MMP-1, MMP-2, MMP-9, MMP-13, TIMP-1, TIMP-2 were detected in 104 lung cancer tissues by immunohistochemical method. RESULTS: The expressions of MMPs and TIMPs were up-regulated in lung cancer tissues. The expression of MMP-2 was related to differentiated degree of tumor cells. MMP-9 correlated with lymph node metastasis of lung cancer. The positive rate of TIMP-1 was related to TNM stage and lymph node metastasis. In lung cancer tissues, there was positive correlation between MMP-2 and TIMP-2, and between MMP 9 and TIMP-2. CONCLUSIONS: MMPs and TIMPs may play the important roles in the development of lung cancer. MMP-9 and TIMP-1 might promote the infiltration and metastasis of lung cancer. PMID- 21272483 TI - [Immunohistochemical analysis of P14ARF protein expression in non-small cell lung cancer: its prognostic significance]. AB - BACKGROUND: To investigate immunoexpression of P14ARF protein in non-small cell lung cancer (NSCLC) and to evaluate the prognostic significance. METHODS: Thirty nine tumor specimens were immunohistochemically examined with FL-132 antibody against P14ARF protein. RESULTS: P14 nuclei immunoexpression was found in 25 tumor specimens (64.1%). The patients in stage I and II had a much higher P14 expression rate than the patients in stage III and IV [78.0%(18/23) vs 43.8%(7/16) P =0.043]. The P14 expression rate in patients with and without metastasis was 78.3%(18/23) and 43.8%(7/16) respectively (P=0.043). The mean survival time of patients without P14-immunopositive staining was significantly shorter than that of patients with P14-immunopositive staining (17 months vs 45 months, P=0.023 5). CONCLUSIONS: Patients with the expression of P14ARF protein have a better prognosis. Detection of P14ARF protein in lung cancer tissues may be helpful to predict the prognosis of NSCLC. PMID- 21272484 TI - [Proper operation mode of lung cancer: a clinicopathological study]. AB - BACKGROUND: To investigate pathologically the characteristics of proximal bronchial invasion of lung cancer, and to provide the theoretic basis for the selection of a proper operation mode. METHODS: A total of 398 patients with lung carcinoma underwent radical pulmonectomy and systematic lymphadenectomy. The proximal bronchi and the hilar and mediastinal lymph nodes of their operatively resected specimens were selected for pathological study. RESULTS: (1)The direct invasion of cancerous cells through mucous, submucous or multiple layers was the most frequent way during lung cancer spread, rating 9.3%, 21.8% and 68.9% respectively. 96.4% of the cancerous invasion occurred at the proximal bronchial wall less than 1.5 cm apart from the cancer margin. The extension of invasion correlated with the histopathologic type of cancer, mode of invasion and TNM classification. (2)The cancer infiltration by the nodes metastasizing into the bronchus wall (bronchial external tunica or cartilage) was also an important way for the cancer to spread, especially in adenocarcinoma. The poor differentiated adenocarcinoma has significantly higher metastatic rate and infiltration rate than the well differentiated ( P < 0.01, P < 0.01). There were 22 such cases, including 3 of lobar bronchus wall invaded by N1 metastasis and 19 of main bronchus wall by N2 metastasis. CONCLUSIONS: For radical removal of tumor, the key point for selecting a rational operation mode is to keep a distance of 1.5 cm or more between the excision margin of the bronchus and the tumor, to pay attention to the bronchial wall invasion caused by the metastatic lymph nodes, even in peripheral adenocarcinoma, and to dissect extensively and completely the lymph nodes of the hilar and upper and lower mediastinum at the homolateral thoracic cavity. PMID- 21272485 TI - [Long-term outcome of lung cancer patients treated with surgical resection: A report of 210 cases]. AB - BACKGROUND: To study the prognostic factors in patients with lung cancer after curative resection. METHODS: A retrospective study was conducted on 210 cases of clinicopathological survival data of lung cancer patients who underwent surgical resection from January 1987 to December 1999. Nine conventional prognostic factors were analyzed by COX model. RESULTS: The overall 3-, 5- and 10-year survival rates were 37.4%, 30.1% and 23.5% respectively. Univariate analysis showed that regional lymph nodes status (N), primary tumor status (T), histological type of lung cancer, the type of operation and curability of surgical resection were significantly related to disease specific survival. Multivariate analysis showed that regional lymph nodes status, primary tumor status and curability of surgical resection were the three independent predictors of long term outcome. The hazard ratio of death was 2.42 for patients with N2-3 vs N0-1( P =0.000 1), 3.50 for patients with T2-4 vs T1( P =0.033 0) and 1.77 for patients with incomplete resection vs complete resection ( P =0.022 4). CONCLUSIONS: Primary tumor status, regional lymph nodes status and curability of surgical resection are the three important prognostic factors of lung cancer. In order to improve long-term survival of lung cancer patients, it is very important to operate in the earlier stage of tumor, to extensively dissect intra-pulmonary and ipsilateral mediastinal lymph nodes and to avoid incomplete resection. PMID- 21272486 TI - [Research on cellular immune function of patients with lung cancer before and after operation]. AB - BACKGROUND: To explore the perioperative changes of T subsets and NK cell and analyze the related factors in patients with lung cancer. METHODS: The T subsets and NK cell from peripheral blood of 60 patients with lung cancer, 15 patients with lung benign tumor and 15 healthy people were detected by immunofluorescence. These indexes of the patients with lung cancer were detected also at postoperative 2nd, 7th, 14th and 28th days. RESULTS: 1.There were significant differences in the indexes between the lung cancer group and the groups of lung benign tumor and normal people except for CD8+ (P < 0.05). 2.At postoperative 2nd day CD3+, CD4+, CD4+/CD8+ and NK cell of the patients with lung cancer were decreased and CD8+ was increased significantly than those before operation (P < 0.05). During postoperative 1 to 2 weeks, all indexes had recovered basically to the preoperative level. At postoperative 28th day, CD3+, CD4+ , CD4+/CD8+ and NK cell were increased and CD8+ was decreased than those before operation (P < 0.05). 3. There was significant difference in the indexes among preoperative stage IIIA, IIIB and IB, and between preoperative N2 diseases and N0 group (P < 0.05). There was significant difference between the groups of radical and palliative operation and the group of thoracic exploration at postoperative 28th day (P < 0.05). There was significant difference in T subsets between the groups of blood transfusion and non-transfusion at postoperative 14th day (P < 0.05). CONCLUSIONS: The cellular immune function of the patients with lung cancer was lower than that of the patients with lung benign tumor and normal people. The perioperative immunity of patients with lung cancer decreases after operation and increases later. TNM stage and lymph node metastasis are relative to preoperative but not postoperative immunity. There is no significant correlation between cellular immune function and pathological type of the tumor. Radical and palliative operations can both significantly increase the patients' cellular immune function. Therefore the palliative operation is better than thoracic exploration. Blood transfusion can depress the immune function of the patients, so it is better to avoid perioperative blood transfusion. PMID- 21272487 TI - [Influencing factors of pathologic lymph node metastasis in clinical stage I non small cell lung cancer and their clinical significance]. AB - BACKGROUND: To explore predictors of mediastinal and intrapulmonary pathologic lymph node involvement in clinical stage I non-small cell lung cancer. METHODS: From July 1999 to April 2001, 159 patients with clinical stage I non-small cell lung cancer underwent lobectomy and complete mediastinal or intrapulmonary lymph node dissection. All the resected lymph nodes were pathologically analyzed to find out pathologic involvement. Univariate and multivariate analyses were used to clarify predictors of lymph node metastasis. RESULTS: Of all 159 patients, 37 (23%) had pathologic lymph node metastasis. According to logistic regression analysis, tumor size, grade of cell differentiation, and pleural invasion were the significant predictors of lymphatic metastasis ( P=0.003, P=0.004, P =0.005). Patients with 2 or more factors were more liable to have lymph node metastasis than those with less than 2 factors ( P < 0.001). CONCLUSIONS: When patients with clinical stage I non-small cell lung cancer have such clinical factors as tumor diameter > 2.0 cm, moderate or poor differentiation, or pleural invasion, they will be more liable to have lymph node metastasis. Therefore, it should be more prudent to select therapeutic way and judge their prognosis. PMID- 21272488 TI - [Perioperative respiratory and circulatory features in overweighted patients with lung cancer]. AB - BACKGROUND: To analyze the perioperative respiratory and circulatory features of overweighted patients with lung cancer. METHODS: The perioperative respiratory and circulatory features of 221 overweighted lung cancer patients were compared with those of 715 normal-weighted patients, by means of Chi-square analysis and t analysis. RESULTS: The abnormal incidence of MBB, Raw, SGaw, PEF, FEV1, V75 , and EEG, blood presure, serum cholesterol and glucose, was significantly higher in overweighted group than that in the normal weighted group ( P < 0.05), and FRC was significantly lower than that of the normal weighted group (3.46+/-0.87 vs 3.63+/-1.17, P < 0.01). There was no difference in D LCO, MMEF, V50 , V25 between the two groups. The odds of postoperative complication in respiratory or circulatory system was significantly increased in overweighted group than that in the normal weighted group. CONCLUSIONS: The obstruction of main airway, partial alveolar collapse and impotency of respiratory muscle may result in respiratory complication in overweighted patients, and increased cardiac burden and some pre existing diseases in overweighted patients might be the cause of increased incidence of circulatory complication. PMID- 21272489 TI - [Paclitaxel combined with platinum-based chemotherapy as second-line treatment in patients with advanced non-small cell lung cancer: A forty case-report]. AB - BACKGROUND: To evaluate the activity and toxicity of paclitaxel as second-line treatment for advanced non-small cell lung cancer (NSCLC). METHODS: Forty patients with recurrent advanced NSCLC were enrolled. Thirty-six patients were managed with regular regimen. Paclitaxel 135 mg/m2, 3 h, on day 1; DDP 75 mg/m2 or carboplatin 300-350 mg/m2 on day 2. Four patients were managed with weekly regimen. Paclitaxel 60 mg/m2,3 h, on days 1,8,15; DDP 75 mg/m2 on day 2. It was repeated every three or four weeks, up to two to four cycles. RESULTS: Thirty-six cases were evaluated for response and 27 for survival. The objective response rate was 13.9% (5/36). At least one tumor-related symptom relief was observed in 21 patients (58.3%). The median survival duration was 26.4 weeks and 1-year survival rate was 8% (4/36). The main toxicities included myelosuppression, fatigue and myalgia-arthralgia neuropathy. CONCLUSIONS: Paclitaxel has advantage to be well-tolerated and improve tumor-related symptom. Further studies with standardization of dose and regimen will be needed to clarify its role in the second-line treatment. PMID- 21272490 TI - [Combination of EP regimen and split-course hyperfractionated accelerated irradiation in locally advanced non-small cell lung cancer]. AB - BACKGROUND: To investigate the efficacy of EP regimen combined with split-course hyperfractionated accelerated irradiation for locally advanced non-small cell lung cancer. METHODS: The treatment was composed of 3 cycles of combined chemoradiotherapy at 4-week intervals. Chemotherapy with cisplatin ( 30 mg/m2) and etoposide (60 mg/m2) was administrated intravenously on days 1-3, followed by radiotherapy on days 4-8. A course of radiotherapy consisted of 1.5 Gy per fraction, twice a day (3 Gy per day) for 5 consecutive days, for a total dose of 15 Gy. In the third cycle, additional irradiotherapy consisted of 2 Gy once a day was performed on days 11-15, for a total dose up to 55 Gy during 10 weeks. After three cycles, patients were given 2 additional cycles of chemotherapy with MVP regimen. RESULTS: Of the 43 patients, 12 had a complete remission and 22 a partial response, resulting in an overall response rate of 79.1%. Of the 152 chemotherapeutic cycles administrated, there were 40 during which grade III-IV toxicities occurred, mainly consisting of leukopenia and vomiting. The 1- and 2 year survival rates were 66.7% and 57.2%, respectively. CONCLUSIONS: EP regimen combined with split-course hyperfractionated accelerated irradiation is effective and well tolerated for advanced locally non-small celll lung cancer. It should be investigated further. PMID- 21272491 TI - [Embolotherapy for the management of lung cancer with massive hemoptysis]. AB - BACKGROUND: To investigate the indication, complication and efficacy of bronchial artery embolization for the management of lung cancer with massive hemoptysis. METHODS: Thirty-eight cases of lung cancer with massive hemoptysis were retrospectively analyzed in our hospital from January 1996 to January 2003. All cases presented with acute hemoptysis from 220 to 980 ml daily, with a mean of 290 ml daily. A digital subtracted bronchial arteriogram was perfomed and bleeding arteries were embolized. RESULTS: Hemoptysis decreased gradually in all cases and ceased in 3 or 4 days after embolization. Recurrence was found only in one case 2 months after embolization and second embolization was applied to control hemoptysis. No serious complications occured. CONCLUSIONS: Bronchial artery embolization is safe and efficient for the management of lung cancer with massive hemoptysis. PMID- 21272492 TI - Acne in adolescents: quality of life, self-esteem, mood, and psychological disorders. AB - INTRODUCTION: Acne is a significant adolescent problem and may precipitate emotional and psychological effects. The impact of acne on psychological parameters and implications for acne treatment are not fully understood. METHODS: We performed a MEDLINE search using the terms "acne" and "adolescent" along with "psychological," "depression," or "psychiatric," which yielded 16 reviewed studies. RESULTS: Qualitative review of the selected articles revealed that the presence of acne has a significant impact on self-esteem and quality of life. Depression and other psychological disorders are more prevalent in acne patients and acne treatment may improve symptoms of these disorders. LIMITATIONS: The reviewed studies were semi-quantitative analyses utilizing various standardized surveys or questionnaires. Therefore, quantitative analysis of selected studies was not possible. CONCLUSION: The presence of co-morbid psychological disorders should be considered in the treatment of acne patients and future prospective trials are needed to assess the impact of treatment on psychological outcomes. PMID- 21272493 TI - Cutaneous sarcoidosis and malignancy: An association between sarcoidosis with skin manifestations and systemic neoplasia. AB - BACKGROUND: Whereas the association between multisystem and pulmonary sarcoidosis and malignancy has been documented, a relationship between cutaneous sarcoidosis and neoplasia has not yet been reported. Because cutaneous manifestations are seen in 20-25 percent of cases of sarcoidosis, this association deserves further investigation. METHODS: We reviewed the relevant literature, in addition to our case series, for a total of 110 cases of cutaneous and non-cutaneous sarcoidosis associated with malignancy with the aim of analyzing possible associations between cutaneous sarcoidosis and malignancy and to enhance the dermatologist's understanding of their critical role in the management of this disease. A search for consecutive cases, which were encountered during the past 20 years, identified 10 cases of confirmed cutaneous sarcoidosis. A review of the relevant literature was also conducted to identify cases of malignancy associated with cutaneous and non-cutaneous sarcoidosis. RESULTS: Cutaneous localization of sarcoidosis was identified in 58 of 100 patients with sarcoidosis and cancer found in the literature (58%) and in 4 of 10 patients in our series (40%). In our series, all cases manifested solid tumors, including breast (n=4 tumors), prostate cancer, colon cancer, kidney cancer, and squamous cell carcinoma of the skin (n=1 of each type). Among the 6 patients in our series with cancers and non cutaneous sarcoidosis, the types of neoplasias encountered were renal cancer (n=1), mycosis fungoides (n=1), diffuse large B-cell lymphoma (n=1), colon cancer (n=1), and ADK of parotid (n=2). Neoplasias developed after an average of 7.14 years in the literature cases and eight years in our series, following the diagnosis of sarcoidosis. Among the 100 cases of cutaneous (n=58) and non cutaneous (n=42) sarcoidosis associates with malignancy, which were extracted from the literature, hematologic malignancies accounted for 73 percent of cases and sarcoidosis preceded the detection of neoplasia in a majority (76%) of cases. Among 110 total cases analyzed in this paper, cutaneous sarcoidosis was confirmed in 56.4 percent of overall cases, a figure exceeding expected rates of cutaneous involvement (20-25%) in the general sarcoidosis population. CONCLUSIONS: Sarcoidosis with cutaneous manifestations appears to be associated with malignancy, possibly at a higher rate than other systemic forms of sarcoidosis. The predominant occurrence of sarcoidosis before the development of neoplasia may indicate that an immune dysregulation, such as impairment of cellular immunity mediated by sarcoidosis or the effects of treatment may contribute to an increased risk of malignancy in predisposed individuals. Physician recognition of this link between sarcoidosis and malignancy is critical. Dermatologists, in particular, play an important role, given that many of these associated cases manifest initially, or even solely, with cutaneous findings. PMID- 21272494 TI - Identification of a new mutation in the gene coding for hairless protein responsible for alopecia universalis: The importance of direct gene sequencing. AB - Mutations in the gene HR coding for the hairless protein are associated with atrichia with papular lesions (APL), an autosomal recessive form of alopecia universalis that is characterized by generalized scalp and body atrichia with papular lesions. We here describe a South Italian family of ancient Albanian heritage. The full phenotype with complete atrichia was expressed in 2 siblings, whereas the parents and one sister were unaffected. Direct sequencing of the gene coding for the hairless protein allowed the identification of a new mutation in exon 17. Consistent with the recessive inheritance of the disease, both the siblings were homozygous for the mutation, whereas the parents and the unaffected sister where heterozygous. A relevant discrepancy with a haplotype linkage study is reported, stressing the importance of gene sequencing in genetic diagnosis and counseling because linkage studies can be biased by recombination events. PMID- 21272495 TI - Complete regression of melanoma associated with vitiligo. AB - A 53-year-old woman presented with vitiligo. A pigmented lesion was disclosed in the physical examination. Its histopathologic study showed the presence of a band of melanophages in an uneven distribution. Fibroplasia and telangiectasias were also observed, but neither nevus nor melanoma cells were found. A short time afterwards, the patient developed a metastasis in an inguinal lymph node. In spite of high-dose interferon treatment, the patient died two years after the diagnosis. This case associates two uncommon events: a) the whole regression of a melanoma and b) vitiligo associated with melanoma. Although both processes have a similar pathogenic mechanism, this association is exceptional and probably influences the prognosis. PMID- 21272496 TI - Facial and bilateral acral porokeratosis with nail dystrophy: A case report. AB - Porokeratosis is a rare disorder of keratinization with unknown etiology. It exhibits both sporadic and autosomal dominant inheritance. The lesions are sharply demarcated, hyperkeratotic, and annular with distinct keratotic edges. The cornoid lamella is the histological hallmark of porokeratosis. Porokeratosis lesions on the face may have a superficial or a destructive nature. To our knowledge there are only a few cases of facial porokeratosis that have been reported. We report a sporadic form of facial and bilateral acral porokeratosis with nail dystrophy. PMID- 21272497 TI - Epidermolytic acanthoma of the scrotum: A rare mimicker of condyloma acuminatum. AB - Epidermolytic acanthoma is a rare benign tumor that is characterized by epidermolytic hyperkeratosis on histopathology. Epidermolytic acanthoma usually presents in adulthood as an asymptomatic tumor less than 1 cm in diameter with a verrucous surface. Whereas the lesions can present in either an isolated solitary, localized, or disseminated form, there tends to be a predilection for the genitoscrotal area. PMID- 21272498 TI - Annular erythematous papules in the neckline. AB - A 45-year-old woman with personal history of hypertension presented with an erythematous lesion in the neckline for a year and with a progressive growth. A physical examination revealed an annular lesion with erythematous papules in the edge. Histological exam showed phagocytosis of elastic fibers by multinucleated cells compatible with annular elastolytic giant-cell granuloma. The patient did not present any other associated systemic manifestation. Treatment with tacrolimus 0.1 percent ointment was prescribed with a very good response after two months. PMID- 21272499 TI - Extensive pigmented vulvar basal-cell carcinoma presenting as pruritus in an elderly woman. AB - Basal cell carcinoma (BCC), the most common human cancer, is seldom seen in the genital area. We present a case of an extensive pigmented BCC that developed on the mucosal surface of the vulva of an elderly woman and briefly review the relevant literature on vulvar BCC. PMID- 21272500 TI - Perianal dermatoses among men who have sex with men: A clinical profile of 32 Indian patients. AB - INTRODUCTION: A wide range of perianal dermatoses including different forms of sexually transmitted infections can occur in men who have sex with men (MSM). OBJECTIVE: To determine the relative frequencies and types of perianal lesions in a group of men from eastern India who had a history of receptive anal intercourse. METHODS: This was a cross-sectional clinical observational study. Consecutive MSM, presenting with perianal symptoms to the Sexually Transmitted Disease clinic of a tertiary care hospital of eastern India were studied. RESULTS: A total of 32 patients (age 15-54 years, mean 38.5 years) were evaluated. Perianal wart was the most common (16, 50%) lesion detected, followed by fissure (3, 9.4%), herpes simplex infection (2, 6.2%), molluscum contagiosum (2, 6.2%), abscess (1, 3.1%), condyloma lata (1, 3.1%), candidiasis (1, 3.1%), furuncle (1, 3.1%), gonococcal infection (1, 3.1%), irritant contact dermatitis (1, 3.1%), and perianal psoriasis (1, 3.1%). Two patients had perianal tuberculosis. Four patients (12.5%) were HIV positive and syphilis was found in one. CONCLUSION: A variety of dermatoses and infections can present in the perianal area of MSM, the most common being perianal wart. A thorough genital and perianal exam should be a part of a physical examination in these patients. PMID- 21272501 TI - On the missing link between inflammation and cancer. AB - A various array of cutaneous granulomatous disorders have been found to be associated with internal malignancy. Among them, sarcoidosis, granuloma anulare (GA), psoriasis, pyoderma gangrenosum (PG), or other neutrophilic dermatoses such as the Sweet syndrome and subcorneal pustular dermatosis may precede the development of a neoplastic process by months or years. Pathogenic links of inflammation with cancer are discussed, including inflammation, intrinsic immune dysfunction, cytokines and interleukins, angiogenetic factors, and epigenetic changes. PMID- 21272502 TI - Rapidly growing hemorrhagic papule on the cheek of a 54-year-old man. AB - A 54-year-old man sought medical attention for a growth on his right cheek that had been present for three months. The growth began as a small, brown "pimple" that gradually increased in size over time. Physical examination revealed a 9 mm well-circumscribed erythematous nodule with a hemorrhagic crust. On dermoscopy, the lesion was completely vascular appearing, with no pigment visualized. A clinical diagnosis of pyogenic granuloma was made. The lesion was biopsied and histopathologic examination revealed a 2.8 mm thick, Clark level IV, ulcerated, amelanotic nodular melanoma. Because the literature contains reports of nodular melanoma mimicking the presentation of a pyogenic granuloma, all such lesions should be biopsied for histopathologic diagnosis. PMID- 21272503 TI - Pink pigtail in a skin biopsy: What is your diagnosis? AB - Sarcoptes scabiei is an obligate ectoparasite, which burrows into the stratum granulosum of the epidermis and lays its eggs. The resultant host inflammatory response leads to intensely pruritic papules. CASE SYNOPSIS: A 63-year-old man undergoing treatment for immunoproliferative disease was suspected of having a pruritic drug eruption. Subsequent skin biopsy revealed an intracorneal burrow containing three pink, refractile pigtail-like structures, believed to be empty eggshells of S. scabiei. CONCLUSION: Traditionally, the presence of adult mites or eggs in skin scrapings or a skin biopsy is required for a definitive diagnosis of scabies. However, our case and similar cases suggest that the diagnosis of scabies can also be made on the basis of pink pigtail-like structures, remnants of eggshells, within the intracorneal burrow. PMID- 21272504 TI - [Childhood leprosy: Report of a case]. AB - Childhood leprosy is very common, especially in tropical and subtropical areas, such as Paraguay. Early symptoms can be missed in a routine examination and the diagnosis can pass unnoticed. Pediatricians and dermatologists should remember the manifestations of this disease in order to make an early diagnosis. We present the case of a 10-year-old child with borderline Hansen disease, considered unusual in children. She was treated with multibacillary therapy (MB WHO) with the combination of Rifampicin 600 mg, clofazimine 300 mg, and dapsone 100 mg once a month (the three drugs together on the same day once a month for 18 months); the remaining 28 days of the month, the child received clofazimine 50 mg/day and dapsone 100 mg/day (the two drugs together on the same day 28 days of the month for 18 months). This therapy produced complete remission of the lesions without reactional states. PMID- 21272505 TI - Letter: Erythema dyschromicum perstans revisited. AB - The recent Dermatology Online Journal article entitled, "Erythema dyschromicum perstans," is discussed to clarify the history of the disease and the contributions of those who have reported it. PMID- 21272506 TI - Letter: Acral-lentiginous melanoma: Report of 15 cases. PMID- 21272507 TI - Letter: Umbilical basal cell carcinoma in a 21-year-old man: Report of an exceptional case and dermatoscopic evaluation. AB - We report an exceptional case of umbilical basal cell carcinoma (BCC) in a 21 year-old man, whose correct diagnosis was suggested by dermoscopy during initial complete body mole mapping. Although BCC is a common skin tumor, only 7 cases of BCC arising within the umbilicus have been reported previously. To the best of our knowledge, our patient is unique because of his age, being the youngest case of umbilical BCC described in the literature. Complete examination and digital dermoscopic monitoring let us identify an asymptomatic, nonpigmented papule at the umbilicus. Dermoscopy images revealed signs of superficial ulceration and several types of vascular structures, which gave us the clue for the diagnosis and helped us differentiate it from other lesions such as Spitz nevus or amelanotic melanoma. The diagnosis was confirmed with histopathology after excision and there was no evidence of relapse in the following four years. PMID- 21272508 TI - Addressing adverse effects of antipsychotic treatment in young patients with schizophrenia. AB - Children and adolescents are at a greater risk than adults for antipsychotic induced adverse effects such as extrapyramidal symptoms, prolactin elevation, sedation, weight gain, and metabolic effects, which can have long-term health consequences for young patients. Clinicians should complete careful baseline assessments and perform dietary and lifestyle counseling when initiating antipsychotic treatment and then proactively monitor for adverse effects to optimize physical as well as psychiatric outcomes. Strategies to manage adverse effects that occur or worsen during treatment include switching medications, lowering the dosage of medications, and initiating targeted treatments to address clinically relevant changes. PMID- 21272509 TI - Strategies for selecting treatment and mitigating risk in patients with chronic pain. AB - Although opioid analgesics treat more types of pain and are usually more potent than other classes of analgesics, opioids are ineffective for some patients and can cause adverse physiologic or psychiatric effects in others. If a prescriber determines that opioid treatment is appropriate for a patient, opioid medications can be used chronically with both effectiveness and safety. Responsible opioid prescribing requires risk management, including assessing patients for abuse risk, identifying and measuring functional outcomes, and monitoring for adverse medication effects. Prescribers should follow the Federation of State Medical Boards model policy for using controlled substances and transparently document risk management when treating pain. PMID- 21272510 TI - Alternatives to antidepressants in treating acute bipolar depression. AB - Major depressive episodes and subsyndromal depressive symptoms are associated with significant psychosocial impairment for patients with bipolar disorder. However, insufficient evidence exists to support the efficacy of antidepressants for treating bipolar depression. Alternative pharmacotherapies have been approved for the treatment of bipolar depressive episodes, and adjunctive psychosocial interventions have proven efficacy when used with pharmacotherapy. PMID- 21272511 TI - Pharmacotherapy for late-life depression. AB - The 2001 expert consensus guidelines for treating major depressive disorder (MDD) in geriatric patients recommended antidepressant treatment in combination with psychotherapy. Recent evidence continues to support the use of selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors as first-line agents in the elderly, and although the transdermal monoamine oxidase inhibitor selegilene has shown promise in adult patients, it has not been studied in geriatric depression. Augmentation therapy with atypical antipsychotics or other agents may provide benefits for agitated, psychotic, or resistant MDD in the elderly. The few treatment studies that have been conducted in the geriatric population since the publication of the guidelines have had mixed results and high placebo response rates. More large controlled trials are needed. PMID- 21272513 TI - Suicidality in obsessive-compulsive disorder: prevalence and relation to symptom dimensions and comorbid conditions. AB - BACKGROUND: Suicidal thoughts and behaviors, also known as suicidality, are a fairly neglected area of study in patients with obsessive-compulsive disorder (OCD). OBJECTIVE: To evaluate several aspects of suicidality in a large multicenter sample of OCD patients and to compare those with and without suicidal ideation, plans, and attempts according to demographic and clinical variables, including symptom dimensions and comorbid disorders. METHOD: This cross-sectional study included 582 outpatients with primary OCD (DSM-IV) recruited between August 2003 and March 2008 from 7 centers of the Brazilian Research Consortium on Obsessive-Compulsive Spectrum Disorders. The following assessment instruments were used: the Yale-Brown Obsessive Compulsive Scale, the Dimensional Yale-Brown Obsessive Compulsive Scale, the Beck Depression and Anxiety Inventories, the Structured Clinical Interview for DSM-IV Axis I Disorders, and 6 specific questions to investigate suicidality. After univariate analyses, logistic regression analyses were performed to adjust the associations between the dependent and explanatory variables for possible confounders. RESULTS: Thirty-six percent of the patients reported lifetime suicidal thoughts, 20% had made suicidal plans, 11% had already attempted suicide, and 10% presented current suicidal thoughts. In the logistic regression, only lifetime major depressive disorder and posttraumatic stress disorder (PTSD) remained independently associated with all aspects of suicidal behaviors. The sexual/religious dimension and comorbid substance use disorders remained associated with suicidal thoughts and plans, while impulse-control disorders were associated with current suicidal thoughts and with suicide plans and attempts. CONCLUSIONS: The risk of suicidal behaviors must be carefully investigated in OCD patients, particularly those with symptoms of the sexual/religious dimension and comorbid major depressive disorder, PTSD, substance use disorders, and impulse-control disorders. PMID- 21272514 TI - The current crisis of confidence in antidepressants. PMID- 21272515 TI - Panic attacks and panic disorder in a population-based sample of active Canadian military personnel. AB - BACKGROUND: The factors contributing to psychiatric problems among military personnel, particularly for panic, are unclear. The objective of this study was to examine the prevalence and correlates of panic disorder and panic attacks in the Canadian military. METHOD: Statistics Canada and the Department of National Defense conducted the Canadian Community Health Survey-Canadian Forces Supplement in 2002 (May to December) with a representative sample of active Canadian military personnel (aged 16-54 years; N = 8,441; response rate, 81.5%). Comparisons were made between respondents with no past-year panic attacks, panic attacks without panic disorder, and panic disorder on measures of DSM-IV mental disorders, as well as validated measures of disability, distress, suicidal ideation, perceived need for mental health treatment, and mental health service use. Lifetime exposure to combat operations, witnessing of atrocities, and deployments were also assessed. RESULTS: Panic disorder and panic attacks were common in the military population, with past-year prevalence estimates of 1.8% and 7.0%, respectively. Both panic disorder and panic attacks were associated with increased odds of all mental disorders assessed, suicidal ideation, 2-week disability, and distress. Perceived need for mental health treatment and service use were common in individuals with panic attacks and panic disorder (perceived need: 46.3% for panic attacks, 89.6% for panic disorder; service use: 32.5% for panic attacks, 74.5% for panic disorder). CONCLUSIONS: Panic attacks and panic disorder in the military are associated with outcomes that could be detrimental to well-being and work performance, and early detection of panic in this population could help reduce these negative outcomes. PMID- 21272517 TI - Schizophrenia-related outpatient treatment of Medicaid-financed patients after hospital discharge. PMID- 21272519 TI - Risks of intermittent antipsychotic treatment in schizophrenia. PMID- 21272520 TI - Do antidepressants really beget more depressive episodes? PMID- 21272522 TI - The case for evidence-based pharmaceutical care. PMID- 21272523 TI - Prescribing trends for management of congestive heart failure from 2002 to 2004. AB - BACKGROUND: The incidence and prevalence of the patients diagnosed with congestive heart failure (CHF) continues to grow in the United States. The use of prescription drugs is a vital part of the management of CHF, and pharmacological regimens may vary among patients. OBJECTIVES: To examine the CHF prescription trends in the United States and to determine present prescribing patterns. METHODS: National Ambulatory Medical Care Survey and both divisions (outpatient and emergency department) of the National Hospital Ambulatory Medical Care Survey from 2002 to 2004 were used to acquire the appropriate data. All analyses used weighted data to represent national estimates. The unit of analysis was individual patient visits. Analysis of the data was accomplished using SPSS 14.0.2 and Stata/SE 9.2 statistical programs. RESULTS: During the 3 study years, 24,213,096 weighted visits were associated with a diagnosis of CHF. More than half (56.2%) of the study population were female; over 75% of the subjects were older than 65 years. Over one-quarter (27.3%; 6,618,208 visits) of CHF-related visits were not associated with being prescribed a CHF-related medication. Loop diuretics were the most commonly used medication (35%). Cardiovascular specialists (odds ratio [OR]=5.28; 95% confidence interval [CI]: 1.82-15.3; P=.002), general/family practice physicians (OR=4.5, 95% CI: 1.69-12.0; P=.003), and internal medicine physicians (OR=3.85, 95% CI: 1.39-10.7; P=.010) were more likely to prescribe CHF-related medication compared with other medical specialties. CHF patients who reside in the Northeast were more likely to receive CHF-related medications than other regions (Midwest OR=0.24; South OR=0.20; West OR=0.23; P<.05) of United States. CONCLUSIONS: There were regional and medical specialty-related variations for prescribing CHF-related medications. The results from this study suggest a need for increased awareness of the benefit of CHF related medications in the management of CHF. The increased implementation of the CHF management guidelines would improve overall patient care. PMID- 21272524 TI - Development of a new scale to measure self-reported medication nonadherence. AB - BACKGROUND: A major drawback in the medication adherence literature today is the absence of a gold standard for measuring medication adherence. Objective measures of nonadherence such as prescription claims and pill count, while quantifying nonadherence, do not provide the reasons for nonadherence, hence making it difficult to develop intervention strategies. Self-reported measures are helpful to determine reasons for nonadherence; however, widely used self-reported measures such as the Morisky scale are restricted to only few potential reasons. OBJECTIVES: The objective of this study was to develop a new scale to measure self-reported nonadherence and to compare it with the existing Morisky scale. METHODS: A cross-sectional study of adult U.S. population on cholesterol-lowering and asthma maintenance medications was used. Data on nonadherence were collected using (1) the newly developed Medication Adherence Reasons Scale (MARS), (2) Morisky scale, and (3) an objective self-reported measure. RESULTS: A total of 840 responses were collected. Factor analysis of MARS resulted in 5 subscales in cholesterol-lowering medications and 3 subscales in asthma maintenance medications. The level of agreement between both scales in identifying adherents and nonadherents as measured by kappa coefficient was 0.381 in cholesterol lowering medications and 0.545 in asthma medications. MARS was able to identify various other significant reasons for nonadherence than that identified by the Morisky scale. CONCLUSION: A new subjective measure of medication nonadherence based on the frequently reported reasons of nonadherence was developed, and it showed adequate reliability when compared with the Morisky scale to warrant future study. PMID- 21272525 TI - Patterns and predictors of antipsychotic medication use among the U.S. population: findings from the Medical Expenditure Panel Survey. AB - BACKGROUND: Given the importance of pharmacological treatment in mental disorders, it is important to have a thorough understanding of predictors and variations in antipsychotic use. OBJECTIVE: To provide a description of patient characteristics associated with antipsychotic use and to examine predictors of atypical antipsychotic use among antipsychotic users. METHODS: Data were obtained from the 2004 and 2005 Medical Expenditure Panel Survey. Dependent variables were annual, self-reported, atypical and typical antipsychotic use. Independent variables included predisposing, enabling, and need characteristics according to Andersen's Behavioral Model. In addition to descriptive statistics, logistic regression analyses were performed to examine the determinants of antipsychotic use. RESULTS: Patients aged 65 and older were 0.63 times as likely to use antipsychotics as patients aged 26-45. Poor and near-poor patients were 1.55 and 1.37 times as likely to use antipsychotics as middle- to high-income patients, respectively. The odds of antipsychotic use were 2.95 and 1.99 times for patients with public and prescription insurance coverage, respectively. Patients with a usual source of health care were 1.51 times as likely to use antipsychotics as those without. Compared with typical antipsychotic use, patients aged 25 and younger were 3.88 times as likely to use atypical antipsychotics as patients aged between 26 and 45. Urban residents were 1.87 times as likely as rural residents to use atypical antipsychotics. The odds of antipsychotic and atypical antipsychotic use for the poor mental health population were 8.73 and 3.87 times as patients with good to excellent mental health status. CONCLUSIONS: Predisposing and need factors play important roles in determining the use of antipsychotics. However, among antipsychotic users, the use of atypical versus typical antipsychotics appears to have been influenced primarily by need. These findings should be useful to clinicians and policy makers in directing antipsychotic treatments to patients in need. PMID- 21272526 TI - Prescription drug misuse in New Zealand: challenges for primary health care professionals. AB - BACKGROUND: Prescription drug misuse (PDM) is an international phenomenon. Prescription drugs sought for this purpose are often obtained through the primary health care network. OBJECTIVES: This study aimed to explore the challenges faced by community pharmacists (CPs) and general practitioners (GPs) when faced with the issue of "drug-seeking" and PDM. This forms part of a larger study of PDM issues for primary health care practitioners. METHODS: Qualitative interviews were carried out in New Zealand with 17 GPs and 16 CPs, purposively sampled to provide information from a variety of demographic and work environments. Interviews were tape-recorded, transcribed verbatim, and a thematic analysis conducted. Data collection took place between June 2007 and January 2008, and interviewees were offered an NZ$30 voucher in recognition of their contribution to the research. RESULTS: GPs and CPs faced a series of challenges in managing PDM, including identification of PDM, dealing with requests for inappropriate requests for psychoactive prescription drugs, verifying the legitimacy of requests and managing threatening behaviors. Specific issues were faced by rural practitioners, female practitioners and by locums and part-time staff. In particular, some participants reported feeling emotionally stressed after unpleasant drug-seeking incidents and some acknowledged that they may have missed identifying some drug-seeking because of lack of knowledge, "drug-seekers'" sophisticated strategies, or patients falling outside of their image of the archetypal "drug-seeker." CONCLUSION: This study demonstrated that PDM can be an issue for primary health care practitioners, and it can cause disruption to their work. Training in how to better manage threatening and escalating incidents may be useful as would increasing the level of awareness of PDM issues among health professional students. PMID- 21272527 TI - Physician beliefs and attitudes toward collaboration with community pharmacists. AB - BACKGROUND: Collaboration between pharmacists and physicians in ambulatory care clinics has been shown to improve patient outcomes. Although collaborative working relationships (CWRs) between community pharmacists and physicians have been studied, the beliefs and attitudes of physicians toward collaborating with pharmacists in this setting have yet to be described. The Theory of Reasoned Action provides a model for studying collaborative behavior. Beliefs were defined in terms of the value and expected outcomes associated with collaborating with community pharmacists. OBJECTIVE: The purpose of this study was to describe the beliefs, attitudes, and intentions of office-based physicians toward collaborating with community pharmacists to help patients manage their medications. METHODS: A cross-sectional study of Michigan office-based physicians was conducted. A total of 1109 internists, pulmonologists, endocrinologists, and cardiologists were surveyed. CWR measures, beliefs, attitudes, and intentions to collaborate were measured using a mailed survey. Regression analysis identified beliefs relevant to intentions to collaborate. RESULTS: There were 332 usable surveys returned (30% response rate). Overall, physicians' beliefs and attitudes toward collaborating with community pharmacists were moderately strong. Physicians' beliefs that collaborating with a community pharmacist would result in improved medication adherence was the strongest predictor of attitude toward collaboration. The belief that collaboration with a pharmacist would result in improved prescribing was another significant predictor. The results also found attitude toward collaboration significantly predicted intention to collaborate. CONCLUSIONS: Physicians' beliefs and attitudes play an important role in their intentions to collaborate with community pharmacists. The findings suggest a strategy that involves collaboration to improve medication adherence may be most effective. PMID- 21272528 TI - Access to multilingual prescription labels and verbal translation services in California. AB - BACKGROUND: The number of patients with limited English proficiency is on the rise in the United States, and conveying medication information to these individuals in an effective manner is crucial to improve adherence and reduce medication errors. OBJECTIVES: To examine (1) self-reported capability for and actual provision of prescription labels or verbal medication information in languages other than English by California pharmacies and (2) characteristics of pharmacies that provide such services. METHODS: In this cross-sectional, observational study, pharmacists in charge at 552 randomly selected retail pharmacies throughout California (US) were interviewed by phone. The main outcome measures of the study were number of pharmacies that could and did provide multilingual labels (MLs) and/or offer medication information verbally in the patient's preferred language. Chi-square tests and multivariate logistic regression analysis were used to determine associations between availability of MLs and verbal translation services and the demographic characteristics of pharmacies. RESULTS: Approximately, 69% of the pharmacies surveyed could provide MLs, and 67.9% did provide MLs routinely on patient request. Verbal translation of labels or other medication information such as leaflets, pamphlets, and guides was offered to patients who requested it in 82.4% of pharmacies. Chain pharmacies reported a significantly higher capability to provide MLs than independent pharmacies (Adjusted odds ratio [AOR]=0.28; 95% confidence interval [CI]=0.19, 0.42; P<.0001). Pharmacies located in rural areas reported higher availability of MLs (AOR=5.02; 95% CI=2.00, 12.6; P<.001) than pharmacies in urban areas. Pharmacies with higher number of estimated limited English proficient (LEP) patients reported higher availability of MLs (AOR=1.03; 95% CI=1.02, 1.05; P<.0001) and verbal translations (AOR=1.07; 95% CI=1.03, 1.09; P<.0001). CONCLUSIONS: There exists an unfulfilled need for providing MLs and/or verbal translations to LEP patients. Pharmacists and health care providers can fill this need to ensure appropriate medication usage and adherence and consequently reduce medication errors in this population. PMID- 21272529 TI - Results of the Arizona Medicaid health information technology pharmacy focus groups. AB - BACKGROUND: In 2007, a federal Medicaid Transformation Grant was awarded to design, develop, and deploy a statewide Health Information Exchange and Electronic Health Record in Arizona, United States. OBJECTIVE: To explore the health information technology needs, knowledge, and expectations of Arizona's health care professionals, moderated focus groups were conducted. This article describes the results of the pharmacist focus groups. METHODS: Focus group activities included a brief presentation, completion of a paper-based survey, and group discussion. The methods included solicitation by invitation, participant selection, meeting content, collaterals, focus group execution, recording, analysis, and discerning comparability among groups. RESULTS: Pharmacy focus group discussions centered on electronic prescribing, including the anticipated advantages: reducing handwriting interpretation errors, improving formulary compliance, improving communication with prescribers, increasing efficiency, and ensuring data accuracy. Disadvantages included: medication errors, inadequate training and knowledge of software applications, and inflated patient expectations. CONCLUSIONS: Pharmacists ranked e-prescribing as the highest priority feature of an electronic health system. PMID- 21272530 TI - Development and evaluation of an instrument to measure community pharmacists' self-efficacy beliefs about communicating with Spanish-speaking patients. AB - BACKGROUND: Hispanics are the largest growing population in the United States, and their use of prescription medications can be influenced by the education and counseling they receive from pharmacists. However, little is known about pharmacists' communication with patients who speak Spanish or factors that can influence such communication. OBJECTIVES: The objective of the study was to develop and validate an instrument to measure pharmacists' self-efficacy in communicating with Spanish-speaking patients. METHODS: An initial pool of 15 items developed from previous research and suggestions from communication experts and practicing pharmacists was subjected to cognitive interviewing. Nine retained items were administered to 1022 licensed pharmacists by mail survey. Summary statistics and exploratory factor analysis (EFA) were conducted. Retained factors were determined by the examination of eigenvalues and scree test results. Cronbach's alpha coefficients were calculated to assess internal consistency. RESULTS: A total of 540 community pharmacists completed the survey. Item means ranged from 2.93+/-1.47 to 1.58+/-0.88 based on a 5-point scale (1: not at all confident to 5: extremely confident). EFA resulted in a 2-factor solution, accounting for 71% of the variance. The 2 factors consisted of health and drug information (alpha=0.92) and opening the encounter (alpha=0.75). The alpha for the overall scale was 0.88. CONCLUSIONS: The results provide evidence to support the reliability and validity of an instrument to measure pharmacists' self efficacy beliefs about communicating with Spanish-speaking patients in community practice. Practitioners and researchers may use this instrument to inform pharmacy education, pharmacy practice improvement, and research efforts around communicating with Spanish-speaking clients. PMID- 21272531 TI - Examination of pharmacists' intention to report serious adverse drug events (ADEs) to the FDA using the theory of planned behavior. AB - BACKGROUND: Adverse drug event (ADE) reporting by pharmacists is an indispensable part of the drug safety system. U.S. pharmacists may submit reports of serious ADEs that they encounter to the Food and Drug Administration (FDA) through MedWatch. However, underreporting of serious ADEs is a common problem. Little is known about pharmacists' decision making with respect to ADE reporting. OBJECTIVES: This study explored the utility of the theory of planned behavior (TPB) model in predicting Texas pharmacists' intention to report serious ADEs to the FDA. METHODS: Data were collected from practicing Texas pharmacists using a mail questionnaire. A total of 1500 surveys were mailed, and 377 usable responses were obtained for a response rate of 26.4%. RESULTS: A majority (70.2%) of the 377 respondents were white/Caucasian, and 52.9% were male. Overall, pharmacists intended to report serious ADEs (mean=15.87+/-4.22; possible range: 3-21), had a positive attitude toward reporting (mean=4.62+/-4.92; possible range: -15 to +15), perceived that important others wanted them to report (subjective norm [SN] score=5.65+/-2.99; possible range: -9 to +9), and believed that they had control over their reporting behavior (perceived behavioral control [PBC] score=3.54+/ 2.69; possible/actual range: -6 to +6). Attitude (beta=0.221, P<.001) and SN (beta=0.438, P<.001) significantly predicted intent; however, PBC (beta=0.028, P>.05) did not. Attitude, SN, and PBC together accounted for 34.0% of the variance in intention to report serious ADEs (P<.001). The addition of past reporting behavior (P=.021) and perceived moral obligation (P<.001) significantly increased the variance in intention explained by the TPB model. CONCLUSIONS: Pharmacists showed a strong positive intent to report serious ADEs to the FDA. Strategies to increase pharmacists' intentions to report serious ADEs should focus on helping them see the value of reporting and altering their perception of social pressure toward reporting. The TPB may have utility in predicting ADE reporting behavior. PMID- 21272532 TI - Reexamining shift work pharmacists in Illinois. AB - BACKGROUND: Evidence suggests that pharmacists engaged in shift work might present unique characteristics, which has implications for labor supply and pharmacy services delivery. OBJECTIVES: To characterize shift-work pharmacists by comparing them: (1) with nonshift work pharmacists and (2) by type of shift schedule. METHODS: A 4-page self-administered Biennial Pharmacist Compensation Survey was mailed in late 2007 to a random sample of pharmacists licensed and residing in Illinois, United States. Pharmacists were classified as shift work pharmacists if they answered the question asking if their gross base earnings included a shift differential. Descriptive statistics, chi-square, and t tests were used to compare shift work pharmacists with nonshift work pharmacists. RESULTS: In Illinois, pharmacists receiving shift work differential pay were more likely to be staff hospital pharmacists who have children. Compared with nonshift pharmacists, they spent significantly more time dispensing and less time on business management activities and "other" functions. The most common types of alternative shifts reported were evening and night shifts. CONCLUSIONS: Repeated analysis of pharmacists engaged in shift work in Illinois evidences unique characteristics from pharmacists not involved in such work schedules. PMID- 21272533 TI - Pharmacists' acceptable levels of compensation for MTM services: a conjoint analysis. AB - BACKGROUND: The Medicare Modernization Act of 2003 requires prescription drug plans to provide medication therapy management (MTM) services to Medicare beneficiaries who are at high risk for inappropriate use of medications. However, inadequate compensation has been a barrier for MTM expansion among pharmacists. OBJECTIVES: The objective of this study was to determine pharmacists' acceptable levels of compensation for MTM services. METHODS: A preference-based fractional factorial design of conjoint analysis was used by surveying 1524 active pharmacists in Tennessee. Pharmacists were asked to select between packages (scenarios) of MTM services that represented combinations of MTM attributes (characteristics). The MTM attributes included type of patient (new or returning), patient's number of chronic conditions (1, 3, or 6), patient's number of medications (4, 8, or 16), patient's annual drug costs ($2000, $3000, or $4000), service duration (15 minutes, 30 minutes, or 45 minutes), and price of MTM services ($30, $60, or $120). A survival analysis model was used to predict pharmacists' willingness to select 1 versus another MTM service package. Pharmacists' acceptable level of compensation was estimated as the marginal rate of substitution between the parameter estimates of an attribute and the price attribute of MTM. RESULTS: The parameter estimates were -0.0303 (P<.0001) for service duration and 0.0210 (P<.0001) for price of MTM services, respectively, so pharmacists were willing to accept $1.44/min (0.0303/0.0210), or $86.4/h, for MTM services. Pharmacists' characteristics were associated significantly with their acceptable levels of compensation: years of practice was associated with a higher need for compensation, pharmacy ownership (vs nonowner) associated with a lower need, and having provided MTM previously (vs having not provided MTM) was associated with a higher need. CONCLUSIONS: Pharmacists' acceptable level of compensation is in the higher part of current ranges from $30 to $100/h. To increase participation in MTM services, pharmacist compensation needs to be increased. Future studies might continue to corroborate the generalizability of findings from this study. PMID- 21272534 TI - The role of information technology in the development of community pharmacy services: visions and strategic views of international experts. AB - BACKGROUND: Community pharmacy's strategic vision has been to extend practice responsibilities beyond dispensing and provide patient care services. Few studies have evaluated the strategic and long-term development of information technology (IT) systems to support this vision. OBJECTIVE: The objective of this study was to explore international experts' visions and strategic views on IT development needs in relation to service provision in community pharmacies. METHOD: Semistructured interviews were conducted with a purposive sample of 14 experts from 8 countries in 2007-2008. These experts had expertise in the development of community pharmacy services and IT. The interviews were content analyzed using a constant comparison approach and a SWOT (strengths, weaknesses, opportunities, threats) analysis was undertaken. RESULTS: Most of the experts shared the vision for community pharmacy adopting a patient care orientation; supported by IT-based documentation, new technological solutions, access to information, and shared patient data. Opportunities to achieve this vision included IT solutions, professional skills, and interprofessional collaboration. Threats included costs, pharmacists' attitude, and the absence of IT solutions. CONCLUSIONS: Those responsible for IT development in community pharmacy sector should create long term IT development strategies that are in line with community pharmacy service development strategies. PMID- 21272535 TI - Immigrant pharmacists in Portugal: a qualitative exploration of their work related attitudes. AB - BACKGROUND: There are no data about the immigrant pharmacist population in Portugal, including their perceptions on adaptation to the Portuguese professional and social context. OBJECTIVE: To explore the perceptions and adaptation of the immigrant pharmacists' community in Portugal, with regards to their practice and life, in general. METHOD: A cross-sectional mail questionnaire was sent to all immigrant community pharmacists registered with the Portuguese Pharmaceutical Society (N=771). Descriptive statistics and an iterative reflexive coding process were used to characterize participants' perceptions and attitudes. RESULTS: Of 36 valid questionnaires 75.0% were females, with a median age of 33 years, mostly citizens from Europe (eg, France) and South America (eg, Brazil). Immigrant pharmacists reported 61.1% overall satisfaction with their decision of coming to Portugal. However, the general perception of the immigrant pharmacists was that the attitudes of their Portuguese colleagues and managers were negative towards them. Nevertheless, positive beliefs, as compared to those in their home country (e.g., strong professional bodies), were also reported. CONCLUSION: Portuguese pharmaceutical authorities need to consider immigrant colleagues' concerns. Further research is needed to determine the prevalence of these and other findings. PMID- 21272536 TI - Social pharmacy as a field of study: the needs and challenges in global pharmacy education. AB - The practice of pharmacy and, consequently, pharmacy curricula have undergone significant changes over the past years in response to a rapidly changing economic, political, and social environment. Within this context, the pharmacist's role had expanded to include more direct interaction with the public in terms of the provision of health information and advice on the safe and rational use of medications. To carry out these roles effectively, pharmacists need to be well prepared on how to deal with patients' behavior and psychology. The understanding of patient sociobehavioral aspects in the medication use process is paramount to achieving optimal clinical and humanistic outcomes from therapy. The concept of behavioral sciences and health psychology are embedded as the fundamental concepts in the field of social pharmacy, and thus it is imperative that this should be taught and nurtured to future pharmacy practitioners. Based on the growing needs for future pharmacists to be exposed to issues in social pharmacy, many pharmacy schools around the world have adopted this subject to be part of their standard curriculum. In this commentary, a discussion of the needs of social pharmacy courses in pharmacy curriculum will be addressed in the context of both developed and developing countries. PMID- 21272537 TI - Patient awareness of specialized diabetes services provided in community pharmacies. AB - BACKGROUND: Community pharmacists are increasingly seeking advanced certification in various clinical areas, including diabetes. However, it is unclear as to how much patients are aware of this advanced training and how they would like specialized services to be provided. OBJECTIVES: To discern patients' level of awareness and understanding of the Certified Diabetes Educator (CDE) designation, the level of support for CDE pharmacists' services, and if the CDE designation would have any influence on patronage patterns. METHODS: A convenience sample of people with diabetes was asked to complete a self-administered questionnaire at 1 of 10 community pharmacies. Questionnaires were completed and returned in a self addressed envelope. Descriptive statistics were performed, followed by post hoc analysis including principal component analysis to evidence questionnaire validity and discern latent attitudinal structure. RESULTS: There were 121 completed questionnaires returned (37.1% response rate). Fifty-four percent of respondents reported knowing of the CDE designation, whereas 82% were unaware that pharmacists could become a CDE. On learning of a CDE pharmacist in their community, 59% would likely schedule an appointment, whereas 27% would schedule an appointment if a fee was charged. The 2 constructs emerging from analysis were the patient/pharmacist relationship and pharmacist as CDE. Those who reported a relationship with their pharmacist were more likely to discuss their diabetes with a CDE pharmacist and schedule an appointment if a fee was charged. Respondents who reported a high level of importance of pharmacists as CDEs felt that a CDE pharmacist improves the image of the pharmacy. CONCLUSIONS: There appears to be little awareness that pharmacists may become CDEs. The patient pharmacist relationship and whether a fee is being charged influence whether respondents' would see a CDE pharmacist. Many indicated that they would be willing to see a CDE pharmacist if they knew one was available, yet it may not be a big enough factor to influence where their prescriptions are filled. PMID- 21272538 TI - Pharmacy ownership in Canada: implications for the authority and autonomy of community pharmacy managers. AB - BACKGROUND: In recent years, the number of independently owned pharmacies has declined even as the total number of pharmacies in Canada has increased. With increasing corporate ownership, there is concern that this trend will adversely affect the profession's ability to influence pharmacy practice and practice change. OBJECTIVE: To examine the relationship between ownership type and community pharmacy managers in terms of professional and employer authority, managerial autonomy, decision making, and amount of control. METHODS: This study consisted of a cross-sectional survey of community pharmacy managers in Canada by means of a self-administered postal questionnaire sent to a stratified sample of community pharmacies. Statistical analysis consisted of exploratory factor analysis with reliability testing on identified constructs. Frequencies, 1-way analyses of variance, Scheffe post hoc tests, and general linear modeling were used to determine significant differences among groups based on ownership type. RESULTS: In total, 646 of 1961 questionnaires from pharmacy managers were completed and returned (response rate 32.9%). Respondents rated their authority similarly across ownership types. Autonomy, decision-making capabilities, and control needed to carry out the professional role appear most limited among corporate respondents and, to a lesser extent, franchise managers. CONCLUSIONS: Pharmacy managers currently perceive a high level of authority; but with limited autonomy among corporate managers, it is unclear whether this authority is sufficient to prevent the subordination of both patient and professional interests to financial interests. PMID- 21272539 TI - An examination of pharmacists' labor supply and wages. AB - BACKGROUND: For the last decade, there has been a shortage of pharmacists for most of the United States. This shortage is in part because of demand-side phenomena (eg, increasing prescription drug use, increases in the complexity of drug regimens, and an aging population). However, there also may be supply-side causes. Although the number of pharmacy school graduates has increased, most graduates are women, many of whom may choose to work part-time. Because of the change in sex composition of the workforce, some researchers conclude that pharmacist shortages will be even more critical in the future. OBJECTIVES: The goals of this article are to model pharmacists' decisions to work, estimate pharmacists' wages, and identify influences on the number of hours worked by pharmacists in the United States. METHODS: Pharmacist labor supply is examined using a static, 3-step, empirical labor supply model that estimates the decision to work, hourly wages, and number of hours worked for U.S. pharmacists. RESULTS: Pharmacists have high starting wages but flat wage trajectories. Although many pharmacists are working part-time, this is true for women and men. Income effects do not dominate substitution effects, even at the high level of compensation found here. CONCLUSIONS: Results indicate that previous predictions brought about by the changing sex composition of the pharmacist labor force might not come to pass, and additional pharmacists may be attracted to the profession by higher wages and flexible schedules. PMID- 21272540 TI - Relationship between diet, exercise habits, and health status among patients with diabetes. AB - BACKGROUND: The American Diabetes Association recommends that people with diabetes should engage in physical activity and healthy eating. Similarly, diets rich in fruits or vegetables (5-13 servings) have been found to lower the risk of stroke, cardiovascular conditions, cancer, and diabetes. OBJECTIVES: To examine the associations between eating fruits and vegetables and exercising on physical/mental health among diabetes patients. A secondary objective was to describe the relationship between socioeconomic status and physical/mental health. Finally, we used the Health Belief Model (HBM) to help providers understand how they can work best with their patients to implement healthy lifestyle. METHODS: The 2005 Centers for Disease Control's Behavioral Risk Factor Surveillance System was used to determine the relationship between eating fruits/vegetables and exercise on physical and mental health. The sample was restricted to individuals who self-reported being diagnosed with diabetes (N=33,320) in 2005. Eating fruits and vegetables was categorized by the number of fruit and vegetable servings consumed daily (0, 1-2, 3-4, and >=5). Poisson regression was used to assess these associations. RESULTS: Only 26% of individuals ate 5 or more servings of fruits and vegetables, whereas only 33% met exercise recommendations. Individuals who ate 5 or more servings of fruits and vegetables reported better mental health but poor physical health. Compared with meeting exercise recommendations, no exercise was associated with more days of poor physical/mental health. CONCLUSIONS: Reinforcement of daily exercise is helpful to patients with diabetes (PWDS); meeting exercise recommendations was associated with better outcomes of physical and mental health. Pharmacists and other public health providers should focus on interventions that incorporate the promotion of healthy lifestyles. The HBM can be used to improve health behavior among PWDS. Pharmacists are in a unique position to advocate change with consistent access to care. PMID- 21272541 TI - New Zealand community pharmacists' views of their roles in meeting medicine related needs for people with mental illness. AB - BACKGROUND: Mental illness is common among the New Zealand population. Several roles have been identified for community pharmacists in providing care to people with mental illness; however, the specifics of these roles have not been studied in New Zealand. OBJECTIVES: To explore the services currently provided by community pharmacists, the barriers that may be encountered, and possible solutions when providing care to people with mental illness. METHODS: Community pharmacists across the North Island of New Zealand, who expressed a special interest in mental health or had a clozapine-dispensing contract, were invited to participate. Eleven participants were interviewed using a semistructured format guided by principles of inductive analysis. Using a thematic approach, transcripts from the interviews were analyzed with the assistance of NVivo 7(r) (QSR International Pty Ltd 2007). RESULTS: Four major themes were identified: provision of care, relationships, challenges within the health care system and resources, and future roles for pharmacists. Provision of care was associated with the type of services pharmacists provided, patient-focused care, family involvement, education, psychological support, referrals, and culturally appropriate practice. Building effective relationships was described by participants as adopting a nonjudgmental and culturally sensitive manner, respecting patient privacy, spending more time with patients, and using varied communication techniques. Significant challenges involved working at the end of the health care chain, inadequate patient information and contact time, prescription and payment issues, and difficulties ensuring compliance with medication. Participants identified education, support, and funding as resources that needed to be improved. Their perspectives about future roles of the pharmacists included providing more education and acting as medicine managers for patients. CONCLUSIONS: Pharmacists provided a variety of services to people with mental illness despite the barriers they encountered. If the roles of community pharmacists within mental health were to be expanded, solutions to these barriers would need to be identified and implemented. PMID- 21272542 TI - Primary care physicians' perceptions of medication errors and error prevention in cooperation with community pharmacists. AB - BACKGROUND: Physicians and community pharmacists play a major role in safe use of medication in primary outpatient care. Still, little is known about primary care physicians' perceptions of medication errors and error prevention and how they would like to cooperate with community pharmacists in error prevention and management. OBJECTIVES: To explore primary outpatient care physicians' perceptions of medication errors and error prevention and to examine physicians' perceptions and expectations of cooperation with community pharmacists in error prevention and management. METHODS: A national mail survey containing structured and open-ended questions to a random sample of 15% of Finnish public health care physicians and occupational health physicians (n=639) was carried out. RESULTS: A total of 179 responses were entered into the study (29% response rate). The potential causes of medication errors were most often related to physicians (39%), followed by the causes related to the organization (23%) and patient (19%). The factors concerning physicians' unawareness of patients' comedication arose as the major causes of medication errors. The respondents considered workload as a primary cause for medication errors. The most frequently mentioned actions to prevent medication errors were related to the physician (31%), organization (28%), and information technology (22%). The respondents expected more contacts from community pharmacists than actually occurred, particularly in the cases of potential drug abuse and problems in drug use. CONCLUSIONS: Problems related to polypharmacy because of physicians' unawareness of patients' entire current medication were considered as most challenging in medication safety. Many of the problems were contributed to communication and coordination issues, which could be ameliorated by appropriate use of information technology. The study also indicated a need to develop the cooperation between primary care physicians and community pharmacists to enhance medication safety. PMID- 21272543 TI - The decision to continue or discontinue treatment: experiences and beliefs of users of selective serotonin-reuptake inhibitors in the initial months--a qualitative study. AB - BACKGROUND: Little is known about patients' views on taking selective serotonin reuptake inhibitors (SSRIs) and their decision-making processes regarding either continuation or discontinuation within a few months of initiating therapy. OBJECTIVE: To explore the experiences and beliefs of SSRI users in relation to initiation and execution of treatment, with the intention to identify patterns leading to discontinuation or continuation of treatment. METHODS: Semistructured qualitative interview study. Eighteen patients, older than 18 years, were interviewed 3 months after starting SSRI treatment prescribed by a general practitioner (GP), 9 of whom had discontinued (discontinuers) and 9 of whom continued treatment (continuers). RESULTS: Two main patterns lead to either discontinuation or continuation of use. Continuers were satisfied with the GP's role during initiation and execution of SSRI treatment and fully trusted their decision. Continuers' attitudes toward treatment were predominantly positive; they seemed to have little doubt about the necessity of using an SSRI and hardly considered discontinuing for fear of relapse. Discontinuers, on the other hand, seemed to be less involved in decision making and often appeared to have little confidence in their GPs. Most discontinuers felt that they lacked knowledge, and their attitude toward taking SSRIs was rather negative. Discontinuers often were unconvinced about the necessity of using an SSRI and appeared to have a strong desire to discontinue treatment. CONCLUSION: Lack of shared decision making between patient and GP, limited counseling during treatment, lack of knowledge, and patients' negative attitudes toward SSRI use and the disease itself, hampered the acceptance of the SSRI and brought on the decisional conflict to discontinue treatment. Health care professionals could be more supportive during the initial months of SSRI treatment by eliciting patients' considerations for continuing or discontinuing treatment. PMID- 21272544 TI - Evaluation of online consumer medication information. AB - BACKGROUND: Millions of Americans search the Internet for health-related information; however, the readability and comprehensiveness of consumer medication information (CMI) on the Internet has not been widely studied. OBJECTIVE: The purpose of this study was to evaluate the readability and comprehensiveness of online CMI. METHODS: The readability and comprehensiveness of consumer drug information found on 3 well-known Web sites (Medline Plus, Yahoo Health, and WebMD) was evaluated; in particular, information related to 10 commonly prescribed medications. Readability was assessed using the Simple Measure of Gobbledygook (SMOG) and Fry Readability Graph (FRG) tools; comprehensiveness of information was evaluated using the Keystone action plan criteria. RESULTS: Using SMOG, the mean reading level of each Web site was 13th grade level or higher. Using the FRG, the mean reading level was 10th grade or higher. Out of the 24 points in the Keystone action plan criteria, information found on each of the Web sites was deemed accurate with mean score of 21, 21, and 19 for Medline Plus, Yahoo Health, and WebMD, respectively. CONCLUSIONS: For the medications reviewed, CMI found on Web sites was accurate when assessed using the Keystone action plan criteria. The readability levels were higher than the recommended sixth grade level. PMID- 21272545 TI - Perception and knowledge of patients with type 2 diabetes in Malaysia about their disease and medication: a qualitative study. AB - BACKGROUND: Diabetic patients' experience and knowledge about their medication play an important role in determining the success of long-term adherence in their disease management. OBJECTIVE: This study aimed to explore diabetic patients' experience and knowledge about diabetes and its medication and to understand the factors contributing to medication adherence in Malaysian population. METHODS: A qualitative research approach was adopted to gain a better understanding of the current perceptions and knowledge held by diabetic patients. Twelve patients were interviewed using a semi-structured interview guide. Saturation point of the interview was reached after the 10th interview, and no more new themes emerged from the subsequent 2 interviews. All interviews were transcribed verbatim and analyzed by means of a standard content analysis framework. RESULTS: A total of 4 themes were identified from the interview analysis: knowledge about diabetes and its medication, experiences of adverse effects of medication, issues related to adherence, and the impact of medical and family relationships on well-being. Most of the patients were aware of the disease known as diabetes but unaware which type of diabetes they were suffering from. None of the participants knew the adverse effects of their medication, and most of them considered it to be safe. Financial barriers, forgetfulness, self-medication, and quality of relationships with doctor and family members seem to be the factors that challenge adherence in our sample of diabetic patients. CONCLUSION: This study identified a number of key themes that might be useful in enhancing the awareness of experiences, knowledge, adherence, and attitudes of Malaysian patients with diabetes. More efforts should be taken to estimate how diabetic patients take their medication, and a well-planned educational program is also required to educate and encourage patients to practice a healthy lifestyle. PMID- 21272546 TI - Research funding expectations as a function of faculty teaching/administrative workload. AB - BACKGROUND: Persistent faculty shortages at US pharmacy schools make faculty recruitment and retention a perennial priority. The literature indicates that a key retention issue is whether the faculty member's scholarship is compromised because of a heavy teaching or service workload. OBJECTIVE: Assess US pharmacy faculty perceptions concerning their views of appropriate expectations of research grant support given their teaching/administrative workloads. METHODS: Data and opinions were collected using a multiple-choice, cross-sectional survey instrument (SurveyMonkey(r); Menlo Park, CA), e-mailed to 1047 faculty members, randomly selected from all Accreditation Council of Pharmacy Education (ACPE) accredited US pharmacy schools. Statistical analyses were performed using SPSS(r) (Chicago, IL) for Windows, Version 17.0. RESULTS: Of the researcher respondents, a majority felt that the amount of teaching expected was too much to be a competitive researcher. Teaching commitment was found more likely to increase than decrease after achieving tenure. Reported new faculty start-up funding was well below that typically found at nonpharmacy research schools. CONCLUSIONS: This information is anticipated to help pharmacy faculty members gauge their workload and productivity relative to a national peer group, and to help pharmacy schools improve in faculty recruitment and retention. The survey findings may assist pharmacy schools in clarifying reasonable teaching and funding expectations for pre- and post-tenure faculty, which in turn may help attract more pharmaceutical scientists to academic pharmacy positions. PMID- 21272547 TI - Pharmacist supplementary prescribing: a step toward more independence? AB - BACKGROUND: Supplementary prescribing (SP) is a drug therapy management model implemented in the United Kingdom since 2003. It is a voluntary partnership between an independent prescriber; a supplementary prescriber, for example, nurse or pharmacist; and the patient, to implement an agreed patient-specific clinical management plan (CMP). OBJECTIVE: To investigate pharmacist prescribers' views and experiences of the early stages of SP implementation. METHODS: A qualitative, longitudinal study design was used. A purposive, maximum variability sample of 16 pharmacist supplementary prescribers, trained in Southern England, participated. Eleven were hospital pharmacists, owing to the overrepresentation of hospital pharmacists in the first cohort. Two semistructured interviews were conducted with each participant, at 3 and 6 months after their registration as prescribers. The Framework approach was used for data collection, management, and analysis. RESULTS: Three typologies of pharmacists' experiences were identified: "a blind alley", "a stepping stone" and "a good fit". Despite some delays in its implementation, SP was seen as a step forward. Some participants also believed that it improved patient care and pharmacists' integration in the health care team and increased their job satisfaction. However, there was a concern that SP, as first implemented, was bureaucratic and limited pharmacists' freedom in their decision making. Hence, pharmacists were more supportive of the then imminent introduction of a pharmacist independent prescribing (IP) role. CONCLUSIONS: Despite challenges, the SP role represented a step forward for pharmacists in the United Kingdom. It is possible that pharmacist SP can coexist with IP in the areas suitable for CMP use. Elsewhere, SP is likely to become more of a "stepping stone" to an IP role than the preferred model for pharmacist prescribing. Future research needs to objectively assess the outcomes of pharmacist SP, preferably in comparison with IP, to inform decision making among pharmacists regarding the adoption of such an innovative role. PMID- 21272548 TI - Physician-pharmacist collaborative care in dyslipidemia management: the perception of clinicians and patients. AB - BACKGROUND: Collaborative practices allow physicians and pharmacists to comanage pharmacotherapy to maximize the benefits of medication regimens. The Trial to Evaluate an Ambulatory primary care Management program for patients with dyslipidemia (TEAM) study compared the efficacy of a physician-pharmacist collaborative primary care (PPCC) intervention, where pharmacists requested laboratory tests and adjusted medication dosage, to the usual care (UC) for patients under treatment with lipid-lowering medication. OBJECTIVE: In a qualitative study nested within the TEAM study, the perceptions of physicians, pharmacists, and patients regarding the PPCC model, interprofessional collaboration, and the clinicians' willingness to implement the model in their practice were explored. METHODS: In the area of Montreal (Quebec, Canada), TEAM study participants assigned to the PPCC group were invited to participate. Individual semistructured interviews with physicians (n=7) and 2 six-member focus groups with pharmacists (n=12) and patients (n=12) were analyzed using a phenomenological approach. RESULTS: The vast majority of participants reported PPCC was more structured and systematic than the UC they had received previously, wherein physicians prescribe and adjust pharmacotherapy and pharmacists provide the counseling and dispense medications. Many patients felt they received better follow-up and reported being reassured and well informed, making them more inclined to care for themselves better. These feelings were attributed largely to the pharmacists' accessibility and ability to communicate with them easily. Given the physician shortage, physicians perceived interprofessional collaboration as almost inevitable. They considered PPCC to be safe and effective. However, obstacles were also identified. Physicians were concerned that it might alter their special relationship with patients and threaten their overall medical follow-up. Pharmacists felt enthusiastic about their new role, but found PPCC time consuming and thought it might not be applicable to all the patients. CONCLUSIONS: PPCC model was highly appreciated by patients, and clinicians saw it as beneficial to patients. However, several obstacles still have to be overcome before the model can be implemented in the current health care context. PMID- 21272549 TI - An organizational culture gap analysis in 6 New Zealand community pharmacies. AB - BACKGROUND: The barriers to moving forward and meeting the expectations of policy makers and professional pharmacy bodies appear to relate to the organizational culture of community pharmacy. Despite the importance of cultural change for business transformation, organizational culture has largely gone unnoticed in community pharmacy practice research. OBJECTIVES: To perform an organizational culture gap analysis in 6 New Zealand community pharmacies. METHODS: Mean scores from a cultural rating survey (n=47) were calculated for 8 cultural clusters and mapped onto a typical and a beneficial pattern match (ladder diagram) for each case site. These ladder diagrams provide an understanding of the gap between the 2 ratings based on the gradient of the lines joining cultural clusters-the rungs of the ladder. Software can be used to generate a Pearson correlation describing the strength of the relationship between the typical and beneficial ratings. RESULTS: Eight cultural clusters were mapped: "leadership and staff management"; "valuing each other and the team"; "free-thinking, fun and, open to challenge"; "trusted behavior"; "customer relations"; "focus on external integration"; "provision of systematic advice"; and the "embracing of innovation." Analysis suggested a high level of correlation between the means of the typical and beneficial ratings. Although the variance between average ratings might be quite small, the relative difference can still be meaningful to participants in the cultural setting. The diagrams suggest a requirement for external integration, the provision of systematic advice, and the embracing of innovation to become more typical in most pharmacies. Trusted behavior is the most typical and most beneficial cultural dimension in most pharmacies, whereas valuing each other and the team is the least beneficial. CONCLUSIONS: Gaps in organizational culture have been identified through the use of a rating survey. The dimensions of focus on external integration, providing systematic advice, and embracing innovation require further exploration through interviews in case site pharmacies. PMID- 21272550 TI - Media coverage of off-label promotion: a content analysis of US newspapers. AB - BACKGROUND: Promotion of drugs for off-label use is newsworthy, because it is an illegal but all too common strategy used by pharmaceutical companies. The print media are an important source of information about coverage of off-label promotion of drugs and devices and can influence public perceptions of the practice. OBJECTIVES: Print media coverage of off-label promotion during the years 1990-2008 were described and quantified. The primary themes and general tones relating to off-label promotion articles were evaluated. General concerns associated with off-label promotion and complaints about specific brand name drugs were also identified. METHODS: Content analyses of the top 6 US newspapers were conducted over the period of 1990-2008 to analyze the media coverage given to off-label promotion of drugs and devices. Headlines and full text of articles were analyzed for primary themes and tones of the coverage. Intercoder reliability tests were performed on all the study variables. RESULTS: One hundred and one articles were identified meeting the study inclusion criteria. Coverage varied by newspaper. The Wall Street Journal had the most coverage on the topic (45%), and USA Today and Chicago Tribune had the least coverage (5%). Overall, most of the stories sampled were deemed to have a negative tone in coverage (77%), focusing mainly on lawsuits against drug companies for promoting their drugs for off-label uses. Pfizer's Neurontin((r)) (Pfizer Inc., New York, NY 10017, USA) and Johnson & Johnson's Retin-A((r)) (Orthoneutrogena, Los Angeles, CA 90045, USA) received the most media attention. CONCLUSION: The news media helps shape public understanding of promotional practices of pharmaceutical companies and their potential benefits and harms. This study suggests that print media coverage is generally negative about off-label promotion, focusing on legal actions taken against drug companies and the negative consequences of such promotional practices. PMID- 21272551 TI - Evaluating pharmacists' views, knowledge, and perception regarding generic medicines in New Zealand. AB - BACKGROUND: Generic medicines are commonly used in New Zealand; however, Pharmaceutical Management Agency of New Zealand (PHARMAC) has indicated a need for better information to the public. Studies on consumers' perceptions suggest that pharmacists play an important role in consumers' choice; hence, "quality use of generic medicines" can be promoted with a better understanding of pharmacists' views, knowledge, and perception. OBJECTIVES: (1)To evaluate pharmacists' perceptions, views, and knowledge of and willingness to recommend generic medicines. (2) To explore pharmacists perceptions of the safety, quality, and efficacy of generic medicines. (3) To assess pharmacists' views on current policy with respect to substitution of generic medicines. METHODS: A cross-sectional survey using a postal questionnaire was conducted, and questionnaires were sent to 625 randomly selected pharmacists from a list of 1594 pharmacists who had agreed to release their details for research purposes. RESULTS: Three-hundred and sixty pharmacists responded to the questionnaire (a response rate of 58%). Seventy percent of pharmacists stated there is no difference in safety between original brand and generic medicines. However, 65% stated that original brand medicines were of higher quality than their generic counterparts, and half stated that generic medicines and original brand medicines are equally effective. A large number of pharmacists reported concerns regarding brand substitution and offered suggestions, such as the need for advertising campaigns, patient pamphlets, updating prescribers' software, and distinct packaging for generic medicines. It was found that pharmacists' perceptions of generic medicines are primarily driven by PHARMACs policies and their experiences with consumers. CONCLUSIONS: About one-third of pharmacists correctly defined the term "generic medicines," suggesting discrepancies in pharmacists' knowledge and perceptions of generic medicines. Concerns were raised regarding: quality, safety, and effectiveness; however, most of the pharmacists acknowledged the economic benefits to the health care system. PMID- 21272552 TI - The theoretical basis for practice-relevant medication use research: patient centered/behavioral theories. AB - BACKGROUND: There is an urgent need for research to improve the quality of medication use among those who require pharmacotherapy. OBJECTIVE: To describe how behavioral science theories can help to achieve this goal. METHODS: We begin by describing what a theory is and the functions that theories serve. We then provide 8 guiding principles that are crucial for investigators to understand if they are to use theory appropriately. We conclude by discussing the need for a new model of patient medication self-management that incorporates information concerning factors operating at all levels of the ecological framework, ranging from patient-level to societal-level factors. RESULTS: The 8 guiding principles discussed are the following: (1) There is no single theory that is appropriate for guiding all medication use research; (2) Behavioral science theories are probabilistic, not deterministic; (3) When trying to influence a health behavior, the health behavior of interest must be defined precisely; (4) Many factors outside of patient control influence patient medication use; (5) Every patient is unique; (6) Patient motivation is a fundamental ingredient required to optimize medication use, especially when maintenance of long term behavior is the goal; (7) Health care providers can have a profound effect on patient medication use, and this effect can operate through several possible causal pathways; and (8) When planning an intervention to optimize medication use, it is important to develop a conceptual model that links intervention inputs to the ultimate outcomes that are desired. CONCLUSION: Medication use can be influenced by a wide variety of factors acting at different levels of the ecological model. The quality of research on medication use could be improved by development of an ecological model specific to medication self-management. PMID- 21272553 TI - Violence among persons diagnosed with schizophrenia: how pharmacists can help. AB - Violence among those diagnosed with schizophrenia has been reported but is not a diagnostic component of the disorder. The position of the courts regarding fulfillment of the requisite intent to commit violent acts has not been extensively reported. This article discusses the impact of a diagnosis of schizophrenia in an individual and how the pharmacist can help integrate information into the health care system. The recent Supreme Court case of Clark versus Arizona and the older case of Patterson versus Cockrell are discussed with respect to the concept of intent (to commit the act) and the implications this has on an individual in the midst of a psychotic episode. Quality of life, the perception of the stigma associated with a diagnosis of schizophrenia, and pharmacotherapy are briefly discussed. The origin of schizophrenia is multifactorial. Persons with schizophrenia are not innately violent, but alteration in perception may precipitate aggressive acts. Given the complex and diverse nature of schizophrenia and the fact that even with successful pharmacological treatment residual symptoms may still be present, there is a need to provide information to health care practitioners and the court. PMID- 21272554 TI - Functional dyspepsia: eosinophils, macrophages, and the postinfectious state. PMID- 21272555 TI - Confocal endomicroscopy in celiac disease. PMID- 21272556 TI - Reversal of multifocal low- and high-grade dysplasia in patients with an ileoanal pouch. PMID- 21272558 TI - Esophageal papillomas and skin abnormalities. Focal dermal hypoplasia (Goltz syndrome) manifesting with esophageal papillomatosis. PMID- 21272559 TI - Artifact-inducing enrichment of ethylenediaminetetraacetic acid and ethyleneglycoltetraacetic acid on anion exchange resins. AB - Multivalent metal chelators, ethylenediaminetetraacetic acid (EDTA) and ethyleneglycoltetraacetic acid (EGTA), are used extensively during protein purification. Both strong (Q) and weak (DEAE) anion exchange resins were found to adsorb surprisingly large quantities of EDTA and EGTA that elute from the resin at NaCl concentrations of approximately 240 mM (EDTA) and 140 mM (EGTA). The EDTA/EGTA elution and saturation parameters were determined for five commonly used anion exchange resins. The resulting concentration of eluted EDTA was 10- to 200-fold higher than that originally present in the sample or in the mobile phase. Samples from fractions containing such a high concentration of EDTA were found to inhibit Mg(2+)-dependent polymerase chain reaction (PCR). EDTA binding to the anion exchange resins could saturate the resin, decrease its binding capacity, and displace weakly bound proteins such as green fluorescent protein (GFP). Several steps are suggested to minimize on-column EDTA concentration, including column equilibration in the absence of any EDTA, lower concentrations (0.1-0.5mM) of EDTA, monitoring eluate absorbance at 280 nm as well as at 215 nm, adding EDTA back into fractions eluting before the EDTA peak, and performing blank column runs to control for the effect of changes in EDTA concentration in downstream assays. PMID- 21272560 TI - A sensitive mass spectrometry method for simultaneous quantification of DNA methylation and hydroxymethylation levels in biological samples. AB - The recent discovery of 5-hydroxymethyl-cytosine (5 hmC) in embryonic stem cells and postmitotic neurons has triggered the need for quantitative measurements of both 5-methyl-cytosine (5 mC) and 5 hmC in the same sample. We have developed a method using liquid chromatography electrospray ionization tandem mass spectrometry with multiple reaction monitoring (LC-ESI-MS/MS-MRM) to simultaneously measure levels of 5 mC and 5 hmC in digested genomic DNA. This method is fast, robust, and accurate, and it is more sensitive than the current 5 hmC quantitation methods such as end labeling with thin layer chromatography and radiolabeling by glycosylation. Only 50 ng of digested genomic DNA is required to measure the presence of 0.1% 5 hmC in DNA from mouse embryonic stem cells. Using this procedure, we show that human induced pluripotent stem cells exhibit a dramatic increase in 5 mC and 5 hmC levels compared with parental fibroblast cells, suggesting a dynamic regulation of DNA methylation and hydroxymethylation during cellular reprogramming. PMID- 21272561 TI - Quantitative and selective polymerase chain reaction analysis of highly similar human alpha-class glutathione transferases. AB - Alpha-class glutathione transferases (GSTs) found expressed in human tissues constitute a family of four homologous enzymes with contrasting enzyme activities. In particular, GST A3-3 has been shown to contribute to the biosynthesis of steroid hormones in human cells and is selectively expressed in steroidogenic tissues. The more ubiquitous GST A1-1, GST A2-2, and GST A4-4 appear to be primarily involved in detoxification processes and are expressed at higher levels than GST A3-3. We are interested in studying the cell and tissue expression of the GST A3-3 gene, yet the existence of highly expressed sequence similar homologs and of several splice variants is a serious challenge for the specific detection of unique transcript species. We found that published polymerase chain reaction (PCR) primers for GST A3-3 lack the specificity required for reliable quantitative analysis. Therefore, we designed quantitative PCR (qPCR) primers with greatly increased discrimination power for the human GSTA3 full-length transcript. The improved primers allow accurate discrimination between GST A3-3 and the other alpha-class GSTs and so are of great value to studies of the expression of the GSTA3 gene. The novel primers were used to quantify GSTA3 transcripts in human embryonic liver and steroidogenic cell lines. PMID- 21272562 TI - Liver kinase B1 (LKB1) in the pathogenesis of UVB-induced murine basal cell carcinoma. AB - LKB1, a known tumor suppressor, is mutated in Peutz-Jeghers Syndrome (PJS). It is responsible for the enhanced cancer risk in patients with PJS. Dysregulation of LKB1-dependent signaling also occurs in various epithelial cancers. UVB alters the expression of LKB1, though its role in the pathogenesis of skin cancer is unknown. Here we describe upregulation of LKB1 expression in UVB-induced murine basal cell carcinoma (BCC) and in human skin tumor keratinocytes. AMP-kinase and acetyl Co-A carboxylase, the downstream LKB1 targets, are also enhanced in this neoplasm. In addition, p-Akt, a kinase which inactivates GSK3beta by its phosphorylation, is enhanced in BCCs. Consistently, an accumulation of p-GSK3beta and an increase in activated nuclear beta-catenin are found. mTOR signaling, which is also inhibited by LKB1, remains upregulated in BCCs. However, a marked decrease in the expression of sestrins, which function as potent negative regulators of mTOR is observed. Metformin, a known chemical inducer of this pathway, was found effective in immortalized HaCaT keratinocytes, but failed to activate the LKB1-dependent signaling in human carcinoma A431 cells. Thus, our data show that the LKB1/AMPK axis fails to regulate mTOR pathway, and a complex regulatory mechanism exists for the persistent mTOR activation in murine BCCs. PMID- 21272563 TI - Rapid induction of REDD1 expression by endurance exercise in rat skeletal muscle. AB - An acute bout of exercise induces repression of protein synthesis in skeletal muscle due in part to reduced signaling through the mammalian target of rapamycin complex 1 (mTORC1). Previous studies have shown that upregulated expression of regulated in DNA damage and development (REDD) 1 and 2 is an important mechanism in the regulation of mTORC1 activity in response to a variety of stresses. This study investigated whether induction of REDD1/2 expression occurs in rat skeletal muscle in response to a burst of endurance exercise. In addition, we determined if ingestion of glucose or branched chain amino acids (BCAA) before exercise changes the expression of REDD1/2 in muscle. Rats ran on a motor-driven treadmill at a speed of 28 mmin(-1) for 90 min, and then the gastrocnemius muscle was removed and analyzed for phosphorylation of the eukaryotic initiation factor (eIF) 4E binding protein 1 (4E-BP1) and expression of REDD1/2. Exercise repressed the mTORC1-signaling pathway regardless of the ingestion of nutrients before the exercise, as shown by dephosphorylation of 4E-BP1. In addition, exercise induced the expression of REDD1 mRNA (~8-fold) and protein (~3-fold). Exercise-induced expression of REDD1 was not affected by the ingestion of glucose or BCAA. Expression of REDD2 mRNA was not altered by either exercise or nutrients. These findings indicated that enhanced expression of REDD1 may be an important mechanism that could partially explain the downregulation of mTORC1 signaling, and subsequent inhibition of protein synthesis in skeletal muscle during exercise. PMID- 21272564 TI - Limited expression of reticulocalbin-1 in lymphatic endothelial cells in lung tumor but not in normal lung. AB - Lymphatic endothelial cells in tumors (T-LECs) are considered to have different characteristics from LECs in non-tumor tissues (N-LECs). However, differences between the two types have not been well analyzed at molecular level. In this report, we performed differential proteome analysis of T-LEC and N-LEC models prepared by cultivation of LECs in tumor conditioned medium. By expression profiling of identified proteins using tissue microarrays, reticulocalbin-1 was found to be expressed in clinical specimen-derived T-LECs and lung cancer cells but not N-LECs. It is suggested that reticulocalbin-1 may be an important molecule in understanding T-LEC function and control of lymphatic metastasis. PMID- 21272565 TI - Phagocytosis is inhibited by autophagic induction in murine macrophages. AB - Recent studies have demonstrated that communication takes place between the autophagic and phagocytic pathways, indicating that the convergence of these two pathways plays an important role in the innate immune response against intracellular microbes. The present study investigated the effect of autophagic induction on the phagocytic capacity of murine macrophages. Autophagy induced by physiological and pharmacological means was shown to reduce the phagocytic capacity of murine macrophages, regardless of cell origin or the nature of the phagocytosed particles themselves. This autophagic inhibitory effect on phagocytosis was shown to be an early and reversible event that results in no loss of cell viability. Furthermore, the data presented herein demonstrate that the induction of autophagy does not affect a macrophage's capacity to recognize and bind to particles, indicating that autophagy does not inhibit the particle recognition process, even though particle internalization is suppressed. The findings herein support the notion that phagocytosis and autophagy may be interdependent and complementary processes. PMID- 21272566 TI - Sensitive non-radioactive determination of aminotransferase stereospecificity for C-4' hydrogen transfer on the coenzyme. AB - A sensitive non-radioactive method for determination of the stereospecificity of the C-4' hydrogen transfer on the coenzymes (pyridoxal phosphate, PLP; and pyridoxamine phosphate, PMP) of aminotransferases has been developed. Aminotransferase of unknown stereospecificity in its PLP form was incubated in (2)H(2)O with a substrate amino acid resulted in PMP labeled with deuterium at C 4' in the pro-S or pro-R configuration according to the stereospecificity of the aminotransferase tested. The [4'-(2)H]PMP was isolated from the enzyme protein and divided into two portions. The first portion was incubated in aqueous buffer with apo-aspartate aminotransferase (a reference si-face specific enzyme), and the other was incubated with apo-branched-chain amino acid aminotransferase (a reference re-face specific enzyme) in the presence of a substrate 2-oxo acid. The (2)H at C-4' is retained with the PLP if the aminotransferase in question transfers C-4' hydrogen on the opposite face of the coenzyme compared with the reference aminotransferase, but the (2)H is removed if the test and reference aminotransferases catalyze hydrogen transfer on the same face. PLP formed in the final reactions was analyzed by LC-MS/MS for the presence or absence of (2)H. The method was highly sensitive that for the aminotransferase with ca. 50 kDa subunit molecular weight, only 2mg of the enzyme was sufficient for the whole test. With this method, the use of radioactive substances could be avoided without compromising the sensitivity of the assay. PMID- 21272567 TI - Evaluation of the bitterness of green tea catechins by a cell-based assay with the human bitter taste receptor hTAS2R39. AB - Catechins have a broad range of physiological functions and act as the main taste ingredient of green tea. Although catechins show a strong bitterness, the bitter taste receptor for catechins has not been fully understood. The objective of this study was to identify the receptor for the major green tea catechins such as (-) epicatechin (EC), (-)-epicatechin gallate (ECg), (-)-epigallocatechin (EGC), and (-)-epigallocatechin gallate (EGCg). By the cell-based assay using cultured cells expressing human bitter taste receptor, a clear response of hTAS2R39-expressing cells was observed to 300MUM of either ECg or EGCg, which elicit a strong bitterness in humans. The response of hTAS2R39-expressing cells to ECg was the strongest among the tested catechins, followed by EGCg. Because the cellular response to EC and EGC is much weaker than those of ECg and EGCg, galloyl groups was strongly supposed to be involved in the bitter intensity. This finding is similar to the observations of taste intensity obtained from a human sensory study. Our results suggest the participation of hTAS2R39 in the detection of catechins in humans, indicating the possibility that bitterness of tea catechins can be evaluated by using cells expressing hTAS2R39. PMID- 21272568 TI - Plasma YKL-40 levels in healthy subjects from the general population. AB - BACKGROUND: Plasma YKL-40 is a new biomarker in patients with cancer and inflammatory diseases. High plasma YKL-40 is associated with poor prognosis. Our aim was to determine reference levels in healthy subjects. METHODS: Plasma YKL-40 was determined in 3130 participants aged 20-80 years from the Danish general population, the Copenhagen City Heart Study. They had no known disease at time of blood sampling in 1991-1994 and remained healthy and alive during a 16-year follow-up period. In 644 participants, YKL-40 was measured again in samples taken 10 years after the first. RESULTS: The median plasma YKL-40 was 40 MUg/L (2.5 97.5% reference levels: 14-155) with no difference between sexes. YKL-40 increased exponentially with age. For age-adjusted reference levels, the YKL-40 percentile as a function of age in years and plasma YKL-40 in MUg/L was derived: percentile=100/(1+(YKL-40^-3)*(1.062^age)*5000). In subjects with two YKL-40 measurements 10 years apart, the mean increase in YKL-40 was 1.5 MUg/L/year (SE: 0.2), while the mean change in the calculated age percentile was minimal (-0.3; SE: 0.1). CONCLUSIONS: Plasma YKL-40 increases with age within and across healthy individuals from the general population. Age-stratified or age-adjusted reference levels are important when YKL-40 test results are evaluated. PMID- 21272569 TI - Consequences of metaphase II oocyte cryopreservation on mRNA content. AB - INTRODUCTION: We studied the consequences of freezing/thawing processes on mRNA contents in MII oocytes after slow-freezing/rapid thawing (SF/RT) and vitrification/warming (V/W) protocols, and compared the results to fresh MII oocytes. We quantified the nuclear transcript mRNA responsible for the translation of proteins belonging either to trans-regulatory protein family or to functional structural proteins such as proteins involved in DNA structural organization (NAP1L1, TOP1, H1F0H1), chromosomal structure maintenance (SMC, SCC3, RAD21, SMC1A, SMC1B, STAG3, REC8), mitochondrial energetic pathways (ATP5GJ, SDHC), cell cycle regulation and processes (CLTA, MAPK6, CKS2) and staminal cell potency-development competence stage (DPPA3, OCT4, FOXJ2). MATERIAL AND METHODS: Surplus MII oocytes were donated from patients in IVF cycles and divided in three groups of 15 oocytes. Group 1 was comprised of non-cryopreserved oocytes and Groups 2 and 3 underwent SF/RT and V/W procedures, respectively. RESULTS: There was an overall decrease of mRNA extracted from cryopreserved oocytes compared to control group. Only 39.4% of mRNA content were preserved after SF/RT while 63.3% of mRNA content were maintained after V/W. CONCLUSIONS: Oocyte cryopreservation is associated with molecular injury associated with the decrease of stored mRNA. However the V/W protocol is more conservative than SF/RT resulting in a level of mRNA sufficient to maintain biologic functions in the subsequent fertilized oocyte. PMID- 21272570 TI - Galacto-oligosaccharides as protective molecules in the preservation of Lactobacillus delbrueckii subsp. bulgaricus. AB - In this work, the protective capacity of galacto-oligosaccharides in the preservation of Lactobacillus delbrueckii subsp. bulgaricus CIDCA 333 was evaluated. Lactobacillus bulgaricus was freeze-dried or dried over silica gel in the presence of three commercial products containing galacto-oligosaccharides. The freeze-dried samples were stored at 5 and 25 degrees C for different periods of time. After desiccation, freeze-drying or storage, samples were rehydrated and bacterial plate counts were determined. According to the results obtained, all galacto-oligosaccharides assays demonstrated to be highly efficient in the preservation of L. bulgaricus. The higher content of galacto-oligosaccharides in the commercial products was correlated with their higher protective capacity. Galacto-oligosaccharides are widely known by their prebiotic properties. However, their role as protective molecules have not been reported nor properly explored up to now. In this work the protective capacity of galacto-oligosaccharides in the preservation of L. bulgaricus, a strain particularly sensitive to any preservation process, was demonstrated. The novel role of galacto oligosaccharides as protective molecules opens up several perspectives in regard to their applications. The supplementation of probiotics with galacto oligosaccharides allows the production of self-protected synbiotic products, galacto-oligosaccharides exerting both a prebiotic and protecting effect. PMID- 21272571 TI - Histamine H(3) receptor-mediated modulation of perivascular nerve transmission in rat mesenteric arteries. AB - The rat mesenteric artery has been shown to be innervated by adrenergic vasoconstrictor nerves and calcitonin gene-related peptide (CGRP)-containing (CGRPergic) vasodilator nerves. The present study was designed to investigate the involvement of histamine H(3) receptors in the neurotransmission of perivascular adrenergic and CGRPergic nerves. The mesenteric vascular beds without an endothelium isolated from male Wistar rats were perfused with Krebs solution and perfusion pressure was measured. In preparations with resting tension, the selective H(3) receptor agonist (R)-alpha-methylhistamine (alpha-methylhistamine; 10-100nM) significantly reduced periarterial nerve stimulation (2-8Hz)-induced vasoconstriction and noradrenaline release in the perfusate without an effect on the vasoconstriction induced by exogenously injected noradrenaline (0.5, 1.0nmol). In preparations with active tone produced by methoxamine (2MUM) and in the presence of guanethidine (5MUM), the periarterial nerve stimulation (1, 2Hz) induced vasodilator response was inhibited by alpha-methylhistamine (0.1-1MUM) perfusion without affecting vasodilation induced by exogenously injected CGRP (5pmol). Clobenpropit (histamine H(3) receptor antagonist, 1MUM) canceled the alpha-methylhistamine-induced decrease in the periarterial nerve stimulation induced vasoconstriction and noradrenaline release and periarterial nerve stimulation-induced vasodilation. These results suggest that the stimulation of H(3) receptors located in rat perivascular nerves inhibits presynaptically the neurotransmission of not only adrenergic nerves, but also CGRP nerves, by decreasing neurotransmitters. PMID- 21272572 TI - Characterization of bencycloquidium bromide, a novel muscarinic M(3) receptor antagonist in guinea pig airways. AB - In this study we have investigated the antagonist affinity, efficacy and duration of action of bencycloquidium bromide (BCQB), a selective muscarinic M(3) receptor antagonist, as a possible clinical bronchodilator for the treatment of chronic obstructive pulmonary disease (COPD) and asthma. In competition studies, BCQB showed high affinity toward the M(3) receptor in Chinese hamster ovary (CHO) cells (M(3) pKi=8.21, M(2) pKi=7.21, and M(1) pKi=7.86); pA(2)=8.85, 8.71 and 8.57 in methacholine-induced contraction of trachea, ileum and urinary bladder, 8.19 in methacholine-induced bradycardia of right atrium in vitro, respectively. In function studies, duration of inhibition of carbachol-induced tonic contraction, BCQB and ipratropium had a very similar onset and offset of action, but onset faster and offset slower than that of tiotropium. After treatment with intratracheally instilled or the inhalation route, BCQB protects against methacholine or antigen-induced bronchoconstriction in a dose-dependent manner in the normal and sensitized guinea pigs in vivo. BCQB and ipratropium-induced inhibitory activity was short lasting, as it declined quickly when compared to tiotropium. These results suggest that BCQB bind muscarinic M(3) receptors with high affinity. On this basis we speculate that a putative BCQB-based therapy for COPD might require more than once-a-day administration to be as effective as the currently employed once-daily therapy with tiotropium. Nevertheless, Inhalable M(3)-selective compounds may spare M(2)-cardiac receptors and reduce the risks of cardiovascular events associated with the long-term treatment of these agents. PMID- 21272573 TI - Interference between insulin and estradiol signaling pathways in the regulation of cardiac eNOS and Na(+)/K(+)-ATPase. AB - Insulin and estradiol share some of signaling pathways and regulate same target molecules exerting mostly beneficial cardiac effects. In order to study their cardiac interaction, ovariectomized female rats were treated with hormones, separately or simultaneously (20, 30 or 40min before analysis), and the phosphorylations of protein kinase B (Akt), extracellular signal-regulated kinases 1 and 2 (ERK 1/2), endothelial nitric oxide synthase (eNOS) were analyzed, as well as the plasma membrane content of alpha2 subunit of Na(+)/K(+) ATPase. Insulin, particularly, and estradiol stimulate Ser(473) Akt phosphorylation. The combined treatment was stimulatory, but less than insulin alone was. The general increase of Thr(308) Akt phosphorylation by insulin was stronger than at Ser(473) and reduced in the presence of estradiol, which also stimulated this phosphorylation given alone. The estradiol induction of ERK 1/2 phosphorylation was inverted to the decrease by the combined treatment, while insulin had no effect. Only insulin increased the plasma membrane content of alpha2. Estradiol did increase the phosphorylation of eNOS, whereas the insulin effect was controversial. The effect of the combined treatment on target molecules was generally opposite to single hormone treatment. In summary, both hormones exerted an effect on Akt phosphorylation, but only estradiol stimulated ERK 1/2 phosphorylation. The alpha2 plasma membrane content was increased only by insulin, while estradiol increased eNOS phosphorylation more consistently. Finally, if these hormones were administered together, it seems that they disturb each other in having a full effect on cardiac Akt, ERK 1/2, and downstream effectors, eNOS and Na(+)/K(+)-ATPase. PMID- 21272575 TI - Connexin39 deficient mice display accelerated myogenesis and regeneration of skeletal muscle. AB - During muscle development and regeneration of skeletal muscle in mice connexin43 (Cx43) and connexin39 (Cx39) are specifically expressed: Cx43 in satellite cells and myoblasts, whereas Cx39 is exclusively expressed in myogenin-positive cells. We generated Cx39 deficient mice by replacing the coding region of the Gjd4 gene by DNA coding for the enhanced green fluorescent protein eGFP. Adult Cx39 deficient mice exhibit no obvious phenotypic alterations of skeletal muscle compared to wild type mice in the resting state. However, myogenesis in Cx39 deficient embryos is accelerated as indicated by increased myogenin expression on ED13.5 and ED16.5 and increased expression of Cx43 in developing skeletal muscle. In addition, the regeneration process of skeletal muscle in Cx39 deficient mice is accelerated as shown by a 2day earlier onset of MyoD and myogenin expression, relative to wild type littermates. Interestingly, Cx43 expression was also upregulated in Cx39 deficient mice during regeneration of skeletal muscle. We hypothesize that Cx43 may compensate for the loss of Cx39 during myogenesis and regeneration. PMID- 21272574 TI - Atypical chemokine receptors. AB - Atypical chemokine receptors (ACRs) are cell surface receptors with seven transmembrane domains structurally homologous to chemokine G-protein coupled receptors (GPCRs). However, upon ligation by cognate chemokines, ACRs fail to induce classical signaling and downstream cellular responses characteristic for GPCRs. Despite this, by affecting chemokine availability and function, ACRs impact on a multitude of pathophysiological events and have emerged as important molecular players in health and disease. This review discusses individual characteristics of the currently known ACRs, highlights their similarities and differences and attempts to establish their group identity. It summarizes the progress made in mapping ACR expression, understanding their diverse in vitro and in vivo functions of ACRs and uncovering their contributions to disease pathogeneses. PMID- 21272576 TI - Lack of neuroprotection against experimental glaucoma in c-Jun N-terminal kinase 3 knockout mice. AB - To determine if the absence of c-Jun N-terminal kinase 3 (JNK3) in the mouse retina would reduce retinal ganglion cell (RGC) loss in mice with experimental glaucoma. C57BL/6 mice underwent experimental intraocular pressure (IOP) elevation with a bead/viscoelastic injection into one eye. One-half of the mice were Jnk3 homozygous knockouts (KO) and were compared to wild type (WT) mice. IOP was measured under anesthesia with the TonoLab, axial length was measured post mortem with calipers after inflation to 15mmHg, and RGC layer counts were performed on retinal whole mount images stained with DAPI, imaged by confocal microscopy, and counted by masked observers in an image analysis system. Axon counts were performed in optic nerve cross-sections by semi-automated image analysis. Both WT and Jnk3(-/-) mice had mean elevations of IOP of more than 50% after bead injection. Both groups underwent the expected axial globe elongation due to chronic IOP elevation. The absence of JNK3 in KO retina was demonstrated by Western blots. RGC layer neuron counts showed modest loss in both WT and Jnk3( /-) animals; local differences by retinal eccentricity were detected, in each case indicating greater loss in KO animals than in WT. The baseline number of RGC layer cells in KO animals was 10% higher than in WT, but the number of optic nerve axons was identical in KO and WT controls. A slightly greater loss of RGC in Jnk3(-/-) mice compared to controls was detected in experimental mouse glaucoma by RGC layer counting and there was no protective effect shown in axon counts. Counts of RGC layer cells and optic nerve axons indicate that Jnk3(-/-) mice have an increased number of amacrine cells compared to WT controls. PMID- 21272577 TI - Quantitative analysis of pupillary light reflex by real-time autofluorescent imaging in a diabetic mouse model. AB - Here we (i) introduce a novel laser-based quantitative method of measuring pupillary light reflex (PLR) and applied it for the in vivo PLR monitoring of early diabetic retinopathy (DR) in a mouse model, (ii) investigate if melanopsin expressing retinal ganglion cells (mRGCs) are implicated in the early progression of DR and, if so, is there an impact on PLR and (iii) determine if changes in PLR precede the onset of retinal hypoperfusion. A base-line PLR measurement is captured from C57BL/6J wild type mice followed by a single intraperitoneal administration of 200 mg/kg streptozotocin (STZ) and citrate buffer (vehicle) for the "diabetic" (n=5) and "control" (n=5) mice respectively, the very next day. PLR measurements are repeated once a week for four weeks. The PLR data comprises retinal autofluorescence intensity (AFI) values sampled over a 5-min period under confocal excitation with 488 nm high intensity blue laser light. AFI is used here as an indirect measure of pupil size since the amount of excitation light entering and emission light leaving the eye is proportional to the pupil area. Immunohistochemistry (IHC) staining of mRGCs and RT-PCR of melanopsin mRNA are performed at the end-point. The vascular calibre of both control and STZ-treated diabetic mice is assessed via in vivo fluorescein angiography (FA) on day 0 (base line), 1/2, 1 and 4 months post-STZ treatment. The PLR profile shows a more rapid pupil constriction and slower dilation in diabetic mice compared to the control. Changes in PLR coincide or even precede the onset of retinal hypoperfusion. Extensive dendritic network of the mRGCs in retinal whole-mounts and increased melanopsin mRNA from the whole eye are also observed in diabetic mice. These pathological changes to mRGCs during early DR may in turn contribute towards changes in PLR. We present here a quantitative method of measuring PLR which enables an early detection of DR with potential application in the clinical setting. In contrast to conventional measurements of PLR, we are able to calibrate the amount of light reaching the retina which is a crucial parameter in longitudinal studies. PMID- 21272578 TI - Further evidence of olfactory ensheathing glia facilitating axonal regeneration after a complete spinal cord transection. AB - Spinal Wistar Hannover rats injected with olfactory ensheathing glia (OEG) have been shown to recover some bipedal stepping and climbing abilities. Given the intrinsic ability of the spinal cord to regain stepping with pharmacological agents or epidural stimulation after a complete mid-thoracic transection, we asked if functional recovery after OEG injections is due to changes in the caudal stump or facilitation of functional regeneration of axons across the transection site. OEG were injected rostral and caudal to the transection site immediately after transection. Robotically assisted step training in the presence of intrathecal injections of a 5-HT(2A) receptor agonist (quipazine) was used to facilitate recovery of stepping. Bipedal stepping as well as climbing abilities were tested over a 6-month period post-transection to determine any improvement in hindlimb functional due to OEG injections and/or step training. The ability for OEG to facilitate regeneration was analyzed electrophysiologically by transcranially stimulating the brainstem and recording motor evoked potentials (MEP) with chronically implanted intramuscular EMG electrodes in the soleus and tibalis anterior with and without intrathecal injections of noradrenergic, serotonergic, and glycinergic receptor antagonists. Analyses confirmed that along with improved stepping ability and increased use of the hindlimbs during climbing, only OEG rats showed recovery of MEP. In addition the MEP signals were eliminated after a re-transection of the spinal cord rostral to the original transection and were modified in the presence of receptor antagonists. These data indicate that improved hindlimb function after a complete transection was coupled with OEG-facilitated functional regeneration of axons. This article is part of a Special Issue entitled: Understanding olfactory ensheathing glia and their prospect for nervous system repair. PMID- 21272579 TI - A suitable model for the utilization of Duddingtonia flagrans fungus in small flock-size sheep farms. AB - Effective alternatives to anthelmintic treatment of nematode parasite infections of sheep are required because of the high prevalence of drug resistance. Within this context, the nematode-trapping fungus Duddingtonia flagrans has become a valuable component of various integrated control strategies. Toward this objective, a small quantity of lyophilized D. flagrans chlamydospores (10(6) spores per animal) was administered to sheep in a one-year plot study. Animals grazing on native pasture were divided into two homogeneous groups and were kept in 1-ha paddocks in the southern region of Brazil. The oral administration of chlamydospores led to a significant reduction (p<0.05) in the number of nematode eggs per gram of feces and in the larval availability on herbage (difference of 37.6%) in comparison to the control group. Control animals needed to be dewormed three times during the experiment, whereas the fungus-treated animals maintained a low parasite load, independent of seasonal variation. Although D. flagrans cannot serve as a panacea for nematode parasite control of livestock, it represents a significant advance toward rationalizing the use of endoparasitic drugs in small animals. PMID- 21272580 TI - Anti-Giardia activity of Syzygium aromaticum essential oil and eugenol: effects on growth, viability, adherence and ultrastructure. AB - The present work evaluates the anti-Giardia activity of Syzygium aromaticum and its major compound eugenol. The effects were evaluated on parasite growth, adherence, viability and ultrastructure. S. aromaticum essential oil (IC(50)=134 MUg/ml) and eugenol (IC(50)=101 MUg/ml) inhibited the growth of G. lamblia. The essential oil inhibited trophozoites adherence since the first hour of incubation and was able to kill almost 50% of the parasites population in a time dependent manner. The eugenol inhibited G. lamblia trophozoites adherence since the third hour and not induce cell lyses. The main morphological alterations were modifications on the cell shape, presence of precipitates in the cytoplasm, autophagic vesicles, internalization of flagella and ventral disc, membrane blebs, and intracellular and nuclear clearing. Taken together, our findings lead us to propose that eugenol was responsible for the anti-giardial activity of the S. aromaticum essential oil and both have potential for use as therapeutic agents against giardiasis. PMID- 21272581 TI - Leishmania mexicana: LACK (Leishmania homolog of receptors for activated C kinase) is a plasminogen binding protein. AB - Leishmania mexicana is able to interact with the fibrinolytic system through its component plasminogen, the zymogenic form of the protease plasmin. In this study a new plasminogen binding protein of this parasite was identified: LACK, the Leishmania homolog of receptors for activated C-kinase. Plasminogen binds recombinant LACK with a K(d) value of 1.6+/-0.4 MUM, and binding is lysine dependent since it is inhibited by the lysine analog epsilon-aminocaproic acid. Inhibition studies with specific peptides and plasminogen binding activity of a mutated recombinant LACK have highlighted the internal motif (260)VYDLESKAV(268), similar to those found in several enolases, as involved in plasminogen binding. Recombinant LACK and secreted proteins, in medium conditioned by parasites, enhance plasminogen activation to plasmin by the tissue plasminogen activator (t PA). In addition to its localization in the cytosol, in the microsomal fraction and as secreted protein in conditioned medium, LACK was also localized on the external surface of the membrane. The results presented here suggest that LACK might bind and enhance plasminogen activation in vivo promoting the formation of plasmin. Plasminogen binding of LACK represents a new function for this protein and might contribute to the invasiveness of the parasite. PMID- 21272582 TI - Concomitant and protective immunity in mice exposed to repeated infections with Echinostoma malayanum. AB - Concomitant immunity and its consequence against infection play roles in regulating worm burdens in helminthiasis. Under natural conditions, this immunity is generated by exposure to repeated low dose or trickle infection. In this study, concomitant immunity was induced in mice exposed repeatedly to infection with Echinostoma malayanum and its protective effect on a challenge infection evaluated. A profile of worm burden from exposure to 10 metacercariae/mouse/week rose rapidly during the first 2 weeks reaching a plateau from week 3 to 8 post infection. Based on a cumulative dose of infection, worm recoveries were around 75% in the first 2 weeks, dropped to 50% at week 3 and 19% at week 8. After week 2, adult worm burden was constant and no juvenile worms were found after week 3 of the experiment. To examine the effect of resistance against reinfection, mice in the experimental group were primarily infected with 10 metacercariae/week for 5 weeks, treated with praziquantel and were challenged with 75 metacercariae/animal. The number of worms recovered from the experimental groups was significantly lower than that from naive control groups beginning from 24 h to 28 days post challenge. The worms in the experimental group showed growth retardation and the proportion of adult worms was lower than that in the control animals especially during the first 3 weeks of the experiment. Parasite fecundity was also suppressed compared with that in the control group. The selective effects of protective immunity on establishment, growth, and fecundity of challenged worms affected the population dynamics of E. malayanum which is a similar phenomenon to concomitant immunity in schistosomiasis. PMID- 21272583 TI - Trypanocidal properties, structure-activity relationship and computational studies of quinoxaline 1,4-di-N-oxide derivatives. AB - Pyrazole and propenone quinoxaline derivatives were tested against intracellular forms of Leishmania peruviana and Trypanosoma cruzi. Both series were tested for toxicity against proliferative and non-proliferative cells. The pyrazole quinoxaline series was quite inactive against T. cruzi; however, the compound 2,6 dimethyl-3-f-quinoxaline 1,4-dioxide was found to inhibit 50% of Leishmania growth at 8.9 MUM, with no impact against proliferative kidney cells and with low toxicity against THP-1 cells and murine macrophages. The compounds belonging to the propenone quinoxaline series were moderately active against T. cruzi. Among these compounds, two were particularly interesting, (2E)-1-(7-fluoro-3-methyl quinoxalin-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propenone and (2E)-3-(3,4,5 trimethoxy-phenyl)-1-(3,6,7-trimethyl-quinoxalin-2-yl)-propenone. The former possessed selective activity against proliferative cells (cancer and parasites) and was inactive against murine peritoneal macrophages; the latter was active against Leishmania and inactive against the other tested cells. Furthermore, insilico studies showed that both series respected Lipinski's rules and that they confirmed a linear correlation between trypanocidal activities and LogP. Docking studies revealed that compounds of the second series could interact with the poly (ADP-ribose) polymerase protein of Trypanosoma cruzi. PMID- 21272584 TI - Anti-oxidant activity of superoxide dismutase and glutathione peroxidase enzymes in skeletal muscles from slaughter cattle infected with Taenia saginata. AB - It is known that highly reactive oxygene species produced during normal cellular metabolism represent a powerful effector mechanism against parasites. Superoxide dismutase (SOD) and glutathione peroxidase (GPx) belong to the main defense anti oxidants that prevent the formation of new free radical species. The aim of this study was to assess the activities of SOD and GPx in cattle tissues infected with Taenia saginata. We observed a statistically significant increase in the SOD and GPx activities (p=0.00003, 0.00008, respectively, Student's t-test) in skeletal muscles infected with T. saginata in spectrophotometric analysis. With the use of western blot technique, SOD synthesis stimulation has appeared in the host tissues containing cysticerci in contrast with the control samples. There was no statistically significant increase in the GPx band intensity observed in the studied samples in comparison to controls (Gene Tools Version 4.01 program). These results support the significance of anti-oxidant processes in host defense mechanism during parasitic infections. PMID- 21272585 TI - The varied nature of women's sexuality: unresolved issues and a theoretical approach. AB - During the 20th century there were clear indications that the socio-cultural suppression of women's sexuality had lessened, revealing a marked variability of women's sexual expression. In this article we review the recent literature to explore explanations for this variability. It is clear that we know little about the nature of sexual desire, and in particular, what it is that is desired. There is also now substantial evidence that vaginal response, as measured by vaginal pulse amplitude, is a relatively automatic response to perception of sexual stimuli, regardless of whether these stimuli are perceived positively or result in subjective arousal. This is considered as a possible mechanism that allows vaginal intercourse without pain, even when the woman is not sexually aroused. The roles of androgens and estrogen in women's sexuality remain uncertain. The evidence is, however, consistent with there being a testosterone-dependent component of women's sexuality that is more important for some women than others. Finally, a new theoretical model is presented that aims to resolve these uncertainties and that proposes different types of women's sexuality. Once we have a better understanding of "normal" female sexuality, in its various forms, our ability to develop effective treatments for women's sexual problems should improve. PMID- 21272586 TI - The stress-response-dampening effects of placebo. AB - This experiment used both biological and self-report measures to examine how alcohol modifies stress responses, and to test whether the interaction between these two factors alters risk-taking in healthy young adults. Participants were divided into stress or no-stress conditions and then further divided into one of three beverage groups. The alcohol group consumed a binge-drinking level of alcohol; the placebo group consumed soda, but believed they were consuming alcohol; the sober group was aware that they were not consuming alcohol. Following beverage consumption, the stress group was subjected to the Trier Social Stress Test (TSST) while the no-stress group completed crossword puzzles; all participants subsequently completed a computerized risk-taking task. Exposure to the TSST significantly increased salivary levels of the hormone cortisol and the enzyme alpha-amylase, as well as subjective self-ratings of anxiety and tension. In the stress condition, both placebo and intoxicated groups reported less tension and anxiety, and exhibited a smaller increase in cortisol, following the TSST than did the sober group. Thus, the expectation of receiving alcohol altered subjective and physiological responses to the stressor. Neither alcohol nor stress increased risk taking, however the sober group demonstrated lower risk taking on the computer task on the second session. These findings clearly demonstrate that the expectation of alcohol (placebo) alters subsequent physiological responses to stress. PMID- 21272587 TI - Cloning, sequence identification and expression profile analysis of alpha-L fucosidase gene from the Mediterranean fruit fly Ceratitis capitata. AB - The Mediterranean fruit fly Ceratitis capitata (Diptera: Tephritidae) is one of the most destructive agricultural pests, a polyphagus insect of relevant economic importance and is widespread in many regions around the world. It is the best studied fruit fly pest at genetic and molecular level and much has been learned on its ecology and behaviour. An alpha-L-fucosidase has been recently hypothesized to be involved in sperm-egg interactions in Drosophila melanogaster and in other Drosophila species. Here, a complete cDNA encoding a putative alpha L-fucosidase of the medfly was amplified using the reverse polymerase chain reaction (RT-PCR) with degenerate based on the conserved coding sequence information of several insect alpha-L-fucosidases, cloned and sequenced (GenBank accession no. FJ177429). The coding region consisted of 1482 bp which encoded a 485-residues protein (named CcFUCA) with a predicted molecular mass of 56.1 kDa. The deduced protein sequence showed 75% amino acid identity to D. melanogaster alpha-L-fucosidase, and in fact the phylogenetic tree analysis revealed that CcFUCA had closer relationships with the alpha-L-fucosidases of drosophilid species. The tissue expression analysis indicated that CcFuca was expressed in a single transcript in all tissues, suggesting a ubiquitous localization pattern of the encoded protein. Our findings provide novel insights on a gene encoding a protein potentially involved in primary gamete interactions in C. capitata. PMID- 21272588 TI - Operating on chromatin, a colorful language where context matters. AB - Histones, the fundamental packaging elements of eukaryotic DNA, are highly decorated with a diverse set of post-translational modifications (PTMs) that are recognized to govern the structure and function of chromatin. Ten years ago, we put forward the histone code hypothesis, which provided a model to explain how single and/or combinatorial PTMs on histones regulate the diverse activities associated with chromatin (e.g., gene transcription). At that time, there was a limited understanding of both the number of PTMs that occur on histones and the proteins that place, remove, and interpret them. Since the conception of this hypothesis, the field has witnessed an unprecedented advance in our understanding of the enzymes that contribute to the establishment of histone PTMs, as well as the diverse effector proteins that bind them. While debate continues as to whether histone PTMs truly constitute a strict "code," it is becoming clear that PTMs on histone proteins function in elaborate combinations to regulate the many activities associated with chromatin. In this special issue, we celebrate the 50th anniversary of the landmark publication of the lac operon with a review that provides a current view of the histone code hypothesis, the lessons we have learned over the last decade, and the technologies that will drive our understanding of histone PTMs forward in the future. PMID- 21272589 TI - Fixation of a deleterious allele under mutation pressure and finite selection intensity. AB - The mean fixation time of a deleterious mutant allele is studied beyond the diffusion approximation. As in Kimura's classical work [M. Kimura, Proc. Natl. Acad. Sci. USA. 77, 522 (1980)], that was motivated by the problem of fixation in the presence of amorphic or hypermorphic mutations, we consider a diallelic model at a single locus comprising a wild-type A and a mutant allele A' produced irreversibly from A at small uniform rate v. The relative fitnesses of the mutant homozygotes A'A', mutant heterozygotes A'A and wild-type homozygotes AA are 1-s, 1-h and 1, respectively, where it is assumed that v<0) and discuss three situations: when the mutant is (i) completely dominant (s=h); (ii) completely recessive (h=0), and (iii) semi-dominant (h=s/2). Our theoretical predictions for the mean fixation time and the quasi-stationary distribution of the mutant population in the coexistence state, are shown to be in excellent agreement with numerical simulations. Furthermore, when s is finite, we demonstrate that our results are superior to those of the diffusion theory, while the latter is shown to be an accurate approximation only when N(e)s(2)<<1, where N(e) is the effective population size. PMID- 21272590 TI - Limiting genotype frequencies of Y-linked genes through bisexual branching processes with blind choice. AB - The limiting genotype growth rates and the limiting genotype frequencies of Y linked genes are studied in a two-sex monogamous population. To this end, the evolution of the numbers of females, males, and mating units of each genotype is modelled by a multitype bisexual branching process in which it assumed that the gene has no influence on the mating process. It is deduced from this model that the average numbers of female and male descendants per mating unit of a genotype determine its growth rate, which does not depend on the behaviour of the other genotypes. Hence, the dominant genotype is found. Conditions for the simultaneous survival of genotypes to have positive probability are also investigated. Finally, the main results are illustrated by means of examples. PMID- 21272591 TI - Distinct effects of pramipexole on the proliferation of adult mouse sub ventricular zone-derived cells and the appearance of a neuronal phenotype. AB - Pramipexole (PPX) is a dopamine agonist with an 8-fold higher affinity for D3 than D2 receptor, whose efficacy in the treatment of Parkinson's disease is based on dopamine agonistic activity. PPX has also been recently shown to be endowed with neuroprotective activity and neurogenic potential. The aim of this study was a more detailed characterization of PPX-induced neurogenesis. Both D2 and D3 receptors are expressed in floating and differentiated neurospheres obtained from the sub-ventricular zone (SVZ) of adult mice. Treatment of secondary neurospheres with 10 MUM PPX causes a marked induction of cell proliferation, assessed by enhanced cell number and S phase population at cell cycle analysis. Stimulation of proliferation by PPX is still detectable in plated neurospheres before the onset of migration and differentiation, as by enhanced BrdU incorporation. This effect is sensitive to the selective D3 dopamine receptor antagonist U99194A, as well as to sulpiride. A 24 h treatment with PPX does not modify the morphology of neurosphere-derived cells, but causes an increase of glial fibrillary acidic protein (GFAP)-positive cells, an effect sensitive to both D2 and D3 antagonism. Differentiation toward the neuronal lineage is increased by PPX as shown by enhancement of the cell population positive to the early neuronal marker doublecortin (DCX) at 24 h and the mature neuronal marker microtubule associated protein (MAP2) at 72 h. This effect is not modified by treatment with U99194A and is mimicked by BDNF. Accordingly, PPX increases BDNF release with a mechanism involving D2 but not D3 receptors. PMID- 21272592 TI - Augmentation of immune response by chicoric acid through the modulation of CD28/CTLA-4 and Th1 pathway in chronically stressed mice. AB - This study demonstrates the protective effect of chicoric acid (CA) on chronic restraint stress-induced altered T lymphocyte subset distribution and corresponding cytokine secretion patterns in experimental Swiss albino mice. CA has the potential to restore diminished immune response and Th1/Th2 homeostasis in chronically stressed mice as evident by significant increase in lymphocyte proliferation and CD3(+), CD4(+) and CD8(+) T cell population. Interestingly, chicoric acid imparted immunostimulation mainly by upregulating the expression of CD28 and CD80 and downregulating CTLA-4. It exerted stimulatory effect on IL-12, IFN-gamma and IL-2 and suppressed the increased IL-10 levels in chronically stressed mice. It also exhibited a significant lowering effect on raised corticosterone levels and reversed the chronic stress-induced hypertrophy of adrenal glands and atrophy of thymus and spleen, thereby showing its normalizing effect on HPA axis. Our results reveal that CA has the potential to reverse the impact of chronic restraint stress on immune status by normalizing corticosterone levels and augmenting Th1 cytokine profile along with the co-stimulatory molecules particularly CD28/CTLA-4 pathway that plays a very important role in generation of an effective immune response in immune compromised situations. PMID- 21272593 TI - Opiates and plasticity. AB - Opiates are among the most powerful analgesics and pain-relieving agents. However, they are potentially extremely addictive thereby limiting their medical use, making them exceedingly susceptible to abuse and adding to the global drug problem. It is believed that positive memories associated with the pleasurable effects of opiates and negative memories associated with dysphoria during opiate withdrawal contribute to compulsive opiate-seeking behavior characterizing addiction. There is a vast amount of available data regarding the neuroadaptations in response to opiates during opiate tolerance, dependence and withdrawal that contribute to opiate addiction, yet it is still a major challenge to identify the neurobiological adaptations that underlie the hallmarks of opiate addiction such as compulsive drug use, and relapse to drug seeking. Since the discovery of synaptic plasticity as the cellular correlate of learning and memory, strong overlaps between neural and cellular substrates of learning and addiction have been recognized. Consequently, the current notion of addiction supports the idea that aberrant forms of drug-induced synaptic plasticity and learning in the brain drive addictive behaviors. Here we discuss current progress on some of the recently identified forms of synaptic plasticity at excitatory and inhibitory synapses in opioid-sensitive areas of the brain that are targeted by opiates and other addictive drugs. The neuroadaptations involved in opiate tolerance, dependence and withdrawal will be re-visited since they share many features with synaptic learning mechanisms. PMID- 21272594 TI - Enhancement of apamin-sensitive medium afterhyperpolarization current by anandamide and its role in excitability control in cultured hippocampal neurons. AB - Although endocannabinoid anandamide (AEA) plays an important role in synaptic signaling and neuronal survival, the underlying mechanism is not fully understood. Afterhyperpolarization (AHP) is the critical modulator of cell excitability and in turn shapes the neuronal output. Here, we examined the effects of AEA on AHP current and action potential firing in cultured rat hippocampal neurons. In whole-cell patch-clamp recording, AEA applied in the extracellular medium at nanomolar concentration enhanced medium AHP (mAHP) current and spike-frequency adaptation. Activation of apamin-sensitive, small conductance Ca(2+)-activated K(+) (SK) channels, probably SK2 and SK3 as the immunofluorescence analysis indicated, attributed largely to the AEA action on mAHP. Interestingly, AEA-induced potentiation of mAHP current was abolished by inositol 1,4,5-trisphosphate receptors (IP(3)Rs) blockade. However, the potentiation was not affected by inhibiting Ca(2+) influx or Ca(2+) release from internal store through ryanodine receptors. In addition, blockade of CB1, TRPV1 or Gi/o-protein did not attenuate the potentiation. Thus, AEA might enhance the SK mAHP currents mainly in a non-CB1/TRPV1 receptor way. Our study provides the first evidence that a functional cascade might lie among AEA, IP(3)Rs and SK channels, which may keep the membrane excitability stable in a negative-feedback manner. PMID- 21272596 TI - The efficacy of local luminance amplitude in disambiguating the origin of luminance signals depends on carrier frequency: further evidence for the active role of second-order vision in layer decomposition. AB - When an undulating surface bearing a painted texture is illuminated the resulting shading pattern produces in-phase modulations of the mean luminance (LM) and luminance amplitude (AM) of the texture. Experimentally, in-phase combinations of LM and AM (LM+AM) are seen as undulating surfaces whereas anti-phase combinations (LM-AM) are more ambiguous; being seen as undulating when presented alone but as flat when presented in a plaid with LM+AM. AM is a second-order cue and its influence on shape-from-shading can be explained with a bottom-up layer decomposition model containing second-order mechanisms. However, the role of second-order vision in layer decomposition has not been established. If second order vision is involved in layer decomposition then the perceptual differences between LM+AM and LM-AM should depend on the properties of the carrier texture in a way that is consistent with the known properties of second-order vision. Here we find a preference for carrier frequencies 3 octaves above the modulation frequency and take this as an indication that second-order (filter-rectify filter) mechanisms are involved in processing our LM/AM mixes. We introduce a modified model which takes into account the selectivity of second-order vision for carrier frequency. PMID- 21272595 TI - An expectation-based memory deficit in aging. AB - Memory performance can be enhanced by expectations regarding the appearance of ensuing stimuli. Here, we investigated the influence of stimulus-category expectation on memory performance in aging, and used fMRI to explore age-related alterations in associated neural mechanisms. Unlike younger adults, who demonstrated both working memory (WM) and long-term memory (LTM) performance benefits for face stimuli when this stimulus category was expected, older adults did not exhibit these memory benefits. Concordantly, older adults did not exhibit expectation-period activity modulation in visual association cortex (i.e., fusiform face area (FFA)), unlike younger adults. However, within the older population, individuals who demonstrated face-expectation memory benefits also exhibited expectation-period FFA activity modulation equivalent to younger adults. The older cohort also displayed diminished expectation-related functional connectivity between regions of the prefrontal cortex and the FFA, relative to younger adults, suggesting that network alterations underlie the absence of expectation-mediated cortical modulation and memory benefits. This deficit may have broader consequences for the effective utilization of predictive cues to guide attention and engender optimal cognitive performance in older individuals. PMID- 21272597 TI - Conservation of characteristics and functions of CD4 positive lymphocytes in a teleost fish. AB - The presence of helper and cytotoxic T cells in fish has been suggested, although T cell subsets have yet to be identified at the cellular level. In order to investigate the functions of CD4 and CD8alpha positive T cells we attempted to produce and characterize monoclonal antibodies (mAbs) against teleost CD4 and CD8alpha. Here we report the successful production of mAbs against CD4 and CD8alpha in clonal ginbuna crucian carp Carassius auratus langsdorfii and the function of CD4 positive T cells. In this study we demonstrate the presence of teleost CD4- and CD8alpha-positive T cell subsets with morphology, tissue distribution and gene expression similar to those of mammalian CD4- and CD8 positive T lymphocytes. Using mAbs we found that CD4/CD8 double positive T cells are only present in the thymus, suggesting that it is the site of T cell development. We further demonstrated in vitro proliferation of CD4 positive T cells by allogeneic combination of mixed leukocyte culture and antigen-specific proliferation of CD4 positive T cells after in vitro sensitization with OVA. In our previous study we showed that CD8alpha-positive lymphocytes are the primary cell type showing specific cytotoxicity against allogeneic targets. Collectively, these findings suggest that CD4 and CD8alpha positive T cells in ginbuna are equivalent to helper and cytotoxic T lymphocytes (CTL) in mammals, respectively. This is the first report to show the characteristics and functions of CD4 positive T cells in fish and these findings shed light into the evolutionary origins and primordial functions of helper T cells. PMID- 21272598 TI - Cholinergic influences on cortical development and adult neurogenesis. AB - In this review, we focus on immature neurons and their regulation by the cholinergic system, both during cortical development as well as during adult neurogenesis. We discuss various studies that indicate roles for acetylcholine in precursor development and neuronal differentiation. Cholinergic neurons projecting from the basal forebrain innervate the cerebral cortex during critical periods of neuronal development. Acetylcholine stimulation may help to promote a favourable environment for neuronal maturation. Afferents and their cortical target cells interact and are likely to influence each other during the establishment and refinement of connections. Intracortical cholinergic interneurons similarly have a local effect on cortical circuits. Reduced cholinergic innervation during development hence leads to reduced cortical thickness and dendritic abnormalities. Acetylcholine is also likely to play a critical role in neuronal plasticity, as shown in the visual and barrel cortices. Spontaneous nicotinic excitation is also important during a brief developmental window in the first postnatal weeks leading to waves of neural activity, likely to have an effect on neurite extension, target selection and synaptogenesis. In the hippocampus such activity plays a role in the maturation of GABAergic synapses during the developmental shift from depolarizing to hyperpolarizing transmission. The cholinergic system also seems likely to regulate hippocampal neurogenesis in the adult, positively promoting proliferation, differentiation, integration and potentially survival of newborn neurons. PMID- 21272599 TI - Medical doctors' attitudes and beliefs about diet and health are more like those of their lay countrymen (France, Germany, Italy, UK and USA) than those of doctors in other countries. AB - The relation between diet and health has become a public health concern in Western/developed countries. Physicians are influenced in their views about health by their medical training and membership in a particular culture/nation to one extent or another. Their medical training is itself influenced by both a common body of accepted formal knowledge and practice and culture- or nation specific influences on medical education. In this study, we compared physicians from different countries and physicians and lay individuals from the same country with regard to beliefs and attitudes about the relation between diet and health and other health-related issues. Telephone interviews about diet and health conducted with randomly sampled physicians and laypersons in France, Germany, Italy, the United Kingdom, and the USA revealed substantial cultural/national differences and few differences between physicians and laypersons of the same country. Three different measures of similarity converged in supporting the claim that in the areas of diet and health, physicians resemble their countrymen more than they resemble physicians from other Western countries. The degree to which differences in culture- and nation-mediated medical education influence these results is to be determined. PMID- 21272600 TI - Development of a highly immunogenic recombinant candidate vaccine against human chorionic gonadotropin. AB - Human chorionic gonadotropin (hCG) is synthesized soon after fertilization and is essential for embryonic implantation. A vaccine targeting hCG would be an ideal choice for immuno-contraception; an anti-hCG vaccine developed by Talwar et al., has previously undergone Phase II efficacy trials, providing proof of principle. These trials established the threshold levels of bio-neutralizing anti-hCG antibody titers required to prevent pregnancy; however, these titers (>50 ng/ml) were achieved in only 80% of immunized women. In this communication, we report a novel recombinant anti-hCG vaccine which demonstrates improved immunogenicity. hCGbeta was genetically fused at C-terminal to the B-subunit of E. coli heat labile enterotoxin. The recombinant fusion protein (hCGbeta-LTB) was expressed in Pichia pastoris and, upon adsorption on Alhydrogel along with Mycobacterium indicus pranii (MIP) as an immuno-modulator, evoked a very high anti-hCG immune response in 100% of immunized BALB/c mice. This recombinant vaccine is expected to reduce cost as well as facilitate production of a molecularly consistent conjugate on a large scale. PMID- 21272601 TI - An M2 cytoplasmic tail mutant as a live attenuated influenza vaccine against pandemic (H1N1) 2009 influenza virus. AB - The 2009 influenza pandemic brought home the importance of vaccines in infection control. Previously, we demonstrated an M2 cytoplasmic tail mutant H5N1 influenza virus could serve as a live-attenuated vaccine. Here, we adapted that strategy, generating a mutant pandemic (H1N1) 2009 virus that grew well in cell culture, but replicated less well in mice than did wild-type virus. The mutant virus elicited sterile immunity in mice, completely protecting them from challenge with a pandemic (H1N1) 2009 virus. Our results indicate that M2 cytoplasmic tail mutants are suitable for live-attenuated vaccines against pandemic viruses. PMID- 21272602 TI - A novel retinoic acid, catechin hydrate and mustard oil-based emulsion for enhanced cytokine and antibody responses against multiple strains of HIV-1 following mucosal and systemic vaccinations. AB - Non-replicating protein- or DNA-based antigens generally require immune-enhancing adjuvants and delivery systems. It has been particularly difficult to raise antibodies against gp120 of HIV-1, which constitutes an important approach in HIV vaccine design. While almost all effort in adjuvant research has focused on mimicking the pathogens and the danger signals they engender in the host, relatively little effort has been spent on nutritive approaches. In this study, a new nutritive immune-enhancing delivery system (NIDS) composed of vitamin A, a polyphenol-flavonoid, catechin hydrate, and mustard oil was tested for its adjuvant effect in immune responses against the gp120 protein of HIV-1(CN54). Following a combination of two mucosal and two systemic vaccinations of mice, we found significant enhancement of both local and systemic antibodies as well as cytokine responses. These data have important implications for vaccine and adjuvant design against HIV-1 and other pathogens. PMID- 21272603 TI - Exploring the vaccine potential of Dec-205 targeting in Mycobacterium tuberculosis infection in mice. AB - Protein subunit vaccines are an attractive mode of immunisation against infectious diseases but the approach is hampered by the lack of suitable adjuvants for human use. We investigated if antigen targeting to the endocytic cell receptor Dec-205 on dendritic cells (DCs) could induce a protective immune response to Mycobacterium tuberculosis (MTB) infection in the absence of conventional adjuvants. Dec-205 receptor expressed by several subsets of DC has been shown in previous studies to be an efficient endocytic receptor for inducing both humoral and cellular immune responses, but this immunisation approach has not been tested in an experimental model of infection. We therefore prepared chemical conjugates of an anti-mouse Dec-205 monoclonal antibody (mAb) and the highly immunogenic antigen 85B (Ag85B) of MTB and showed that they bound efficiently to bone-marrow derived DC. Moreover, DC stimulated in vitro with Dec 205 conjugates could induce proliferation of splenocytes from Ag85B-immunised mice, while the negative control conjugates failed to do so. Following immunisation of mice with the anti-Dec-205-Ag85B conjugates administered together with a co-stimulatory anti-CD40 mAb, antigen-specific humoral and cellular responses were detected. Although the conjugates induced a strong Ag85B-specific humoral response, T cell proliferation and interferon-gamma production were observed only when the conjugates were used to boost BCG vaccine. Importantly though, the conjugate vaccine did not offer significant protection against MTB challenge when used on its own or as a boost to BCG. Therefore, we conclude that Ag85B-based vaccine targeting to Dec-205 alone is not a sufficiently robust vaccination strategy for tuberculosis, although this approach might be more successful with other antigens or infections. PMID- 21272604 TI - Vaccine eligibility and acceptance among ambulatory obstetric and gynecologic patients. AB - OBJECTIVE: To assess vaccine eligibility and factors associated with vaccine acceptance among ambulatory obstetric and gynecologic patients. METHODS: An anonymous office-based survey was administered to women seeking ambulatory obstetric and gynecologic care at a large women's hospital from December 2007 to July 2008. Information collected included: demographics, medical and vaccination history, interest in receiving vaccines and attitudes towards vaccine providers. Vaccine eligibility was based on age and/or self-reported risk factors in accord with the 2007-2008 Center for Disease Control and Prevention (CDC) adult immunization schedule. Vaccine eligibility was examined using descriptive statistics, and demographic characteristics were compared using chi-squared analysis. A multivariable logistic regression model was developed to assess factors associated with participants' willingness to accept vaccines from their obstetrician-gynecologist. RESULTS: A total of 1441 women completed the survey. The majority of participants (87%) would accept vaccines if recommended by their obstetrician-gynecologist. The primary factors associated with vaccine acceptance were having less than a high school education, being privately insured, currently being pregnant, reporting a history of vaccinations and previously receiving vaccinations from an obstetrician-gynecologist. A significant portion of participants were eligible for the hepatitis B, influenza and HPV vaccines (>= 50% for each). The type of vaccine did not influence willingness to accept vaccines from an obstetrician-gynecologist. CONCLUSION: A majority of women appear eligible for, and will accept, vaccinations regardless of specific vaccine, if recommended by their obstetrician-gynecologist. These findings justify ongoing efforts to expand immunization services offered by obstetrician gynecologists. PMID- 21272605 TI - Re: The health technology assessment of bivalent HPV vaccine Cervarix(r) in Italy. PMID- 21272606 TI - Delivery route, MyD88 signaling and cross-priming events determine the anti-tumor efficacy of an adenovirus based melanoma vaccine. AB - Adenovirus (Ad)-based vaccines are considered for cancer immunotherapy, yet, detailed knowledge on their mechanism of action and optimal delivery route for anti-tumor efficacy is lacking. Here, we compared the anti-tumor efficacy of an Ad-based melanoma vaccine after intradermal, intravenous, intranasal or intraperitoneal delivery in the B16F10 melanoma model. The intradermal route induced superior systemic anti-melanoma immunity which was MyD88 signaling dependent. Predominant transduction of non-professional antigen-presenting cells at the dermal vaccination sites and draining lymph nodes, suggested a role for cross-presentation, which was confirmed in vitro. We conclude that the dermis provides an optimal route of entry for Ad-based vaccines for high-efficacy systemic anti-tumor immunization and that this immunization likely involves cross priming events in the draining lymph nodes. PMID- 21272607 TI - Immunogenicity and protective efficacy in dogs of an MF59TM-adjuvanted vaccine against recombinant canine/porcine coronavirus. AB - Recently, canine coronavirus (CCoV) strains with putative recombinant origin with porcine transmissible gastroenteritis virus (TGEV) were shown to be widespread in Europe. In this study, a killed vaccine against TGEV-like CCoV strains, included in the new subtype CCoV-IIb, was developed through inactivation with betapropiolactone and emulsification with MF59TM adjuvant. Safety, immunogenicity and efficacy of the developed vaccine were evaluated in vivo. Five 10-week-old beagle pups were administered (three weeks apart) two vaccine doses, whereas two animals served as unvaccinated controls. The vaccine was shown to be safe as no local neither systemic reactions were observed after first and second dose administration. Serum antibodies against CCoV were detected in vaccinates starting from study day 14 (by enzyme-linked immunosorbent assay) or 28 (by virus neutralisation test). Subsequent challenge with virulent CCoV-IIb resulted in the development of mild gastroenteric disease in control pups, whereas vaccinates did not display clinical signs. Faecal shedding of the challenge virus occurred in both treatment groups, but vaccinated dogs were found to shed very low viral titres in comparison to controls. The developed vaccine may help control the CCoV IIb-induced disease (and active virus circulation) in environments, such as kennels and shelters, where the pathogenic potential of this virus is greater as a consequence of predisposing factors and concurrent infections. PMID- 21272608 TI - Effect of lappaconitine on neuropathic pain mediated by P2X3 receptor in rat dorsal root ganglion. AB - ATP facilitates initiation and transmission of the neuropathic pain at the dorsal root ganglion (DRG) level via the P2X receptors, especially the subtype P2X(3). Lappaconitine (LA) is an active principle isolated from Chinese herbal medicine and possesses analgesic effect. The aim of this study was to investigate the effect of LA on chronic constriction injury (CCI)-induced neuropathic pain mediated by P2X(3) receptor in the DRG neurons. In the presence of CCI and/or LA, the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were measured and P2X(3) receptor expression in the DRG neurons was evaluated by immunohistochemistry and Western blotting. Following intrathecal administration of P2X(3) receptor oligonucleotide, the effect of LA on pain thresholds was assessed. Furthermore, the effect of LA on the P2X(3) receptor agonists ATP- and alpha,beta-meATP-induced inward currents (I(ATP) and I(alpha,beta-meATP)) in the acutely dissociated rat DRG neurons was investigated by whole cell patch-clamp. The results included: (1) There showed reduction of pain thresholds, enhancement of I(ATP) and I(alpha,beta-meATP) and up-regulation of P2X(3) receptor expression in rat DRG neurons when neuropathic pain occurred. (2) In the presence of LA, the decreased pain thresholds, the up-regulated P2X(3) receptor expression and the enhanced I(ATP) and I(alpha,beta-meATP) were reversible in the CCI rats. (3) The down-regulated P2X(3) receptor expression with pretreatment of P2X(3) receptor antisense oligonucleotide significantly attenuated the analgesic effect of LA. These results indicate that the analgesic effect of LA involves decrease of expression and sensitization of the P2X(3) receptors of the rat DRG neurons following CCI. PMID- 21272609 TI - Separation and preconcentration system based on microextraction with ionic liquid for determination of copper in water and food samples by stopped-flow injection spectrofluorimetry. AB - In this work, an efficient in situ solvent formation microextraction (ISFME) was combined with stopped-flow injection spectrofluorimetry (SFIS) for the determination of copper. In the proposed approach, thiamine was oxidized with copper(II) to form hydrophobic and highly fluorescent thiochrome (TC), which was subsequently extracted into ionic liquid as an extractant phase. A small amount of an ion-pairing agent (NaPF(6)) was added to the sample solution containing a water-miscible ionic liquid ([Hmim][BF(4)]) to obtain a hydrophobic ionic liquid ([Hmim][PF(6)]), which acted as the extraction phase. After centrifuging, phase separation was performed and the enriched analyte was determined by SFIS. ISFME is an efficient method for separation and preconcentration of metal ions from aqueous solutions with a high ionic strength. Variables affecting the analytical performance were studied and optimized. Under optimum experimental conditions, the proposed method provided a limit of detection (LOD) of 0.024MUgL(-1) and a relative standard deviation (RSD) of 2.1%. The accuracy of the combined methodology was evaluated by recovery experiments and by analyzing certified reference material (GBW 07605 Tea). Finally, the proposed method was successfully applied to copper determination in water and food samples. PMID- 21272610 TI - Anti-inflammatory activity of Angelica dahurica ethanolic extract on RAW264.7 cells via upregulation of heme oxygenase-1. AB - In this study, we analyzed the anti-inflammatory effects of Angelica dahurica Bentham et Hooker ethanolic extract (ADEE) on RAW264.7 cells, to understand the mechanism underlying its observed effects. ADEE inhibited cyclooxygenase 2 (COX 2) and inducible nitric oxide synthase (iNOS) expression, leading to the suppression of COX-2-derived prostaglandin E(2) and iNOS-derived production in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. These inhibitory effects of ADEE were accompanied by the reduced production of tumor necrosis factor alpha and interleukin (IL)-6. ADEE also inhibited nuclear factor kappaB (NFkappaB) translocation to the nucleus by interrupting inhibitor kappa Balpha (IkappaBalpha) degradation. ADEE upregulated heme oxygenase 1 expression, and treatment with tin protoporphyrin IX (SnPP), a selective inhibitor of HO-1, reversed the LPS-induced generation of proinflammatory cytokines. ADEE also induced IL-4 and IL-5 expression in concanavalin-A-stimulated splenocytes. These results suggest that ADEE has anti-inflammatory activity, which acts via the suppression of the NF-kappaB pathway. PMID- 21272611 TI - TCDD adsorbed on silica as a model for TCDD contaminated soils: Evidence for suppression of humoral immunity in mice. AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), the prototypical aryl hydrocarbon receptor (AhR) ligand, exhibits immune suppression in vivo and in vitro. Suppression of primary humoral immune responses in particular has been well characterized as one of the most sensitive functional immune endpoints in animals treated with TCDD. Previous studies have used purified TCDD to elucidate the mechanisms by which TCDD and dioxin-like compounds (DLC) impair IgM production by B cells, but did not represent the route by which animals and humans are likely to be exposed environmentally. In the studies reported here, mice were treated with TCDD adsorbed onto a well-defined synthetic silica phase of known purity and physical properties, followed by sensitization with sheep erythrocytes to initiate a humoral immune response. We found that surfactant-templated mesoporous forms of amorphous silica provided an ideal combination of purity, dispersibility and textural properties for immobilizing TCDD. TCDD-adsorbed silica distributed to the spleen and liver after oral administration as assessed by induction of cyp1a1 gene expression. Most notably, TCDD delivered in the adsorbed state on amorphous silica and as a solute in corn oil (CO) produced similar suppression of the anti-sheep red blood cell immunoglobulin M antibody forming cell (sRBC IgM AFC) response at equivalent doses of TCDD. These results suggest that TCDD immobilized on silicate particles found in soils distributes to the spleen and suppresses humoral immunity. PMID- 21272612 TI - Pharmacologic amelioration of severe hypoglycemia-induced neuronal damage. AB - Hypoglycemia is a common complication for insulin treated people with diabetes. Severe hypoglycemia, which occurs in the setting of excess or ill-timed insulin administration, has been shown to cause brain damage. Previous pre-clinical studies have shown that memantine (an N-methyl-d-aspartate receptor antagonist) and erythropoietin can be neuroprotective in other models of brain injury. We hypothesized that these agents might also be neuroprotective in response to severe hypoglycemia-induced brain damage. To test this hypothesis, 9-week old, awake, male Sprague-Dawley rats underwent hyperinsulinemic (0.2 U kg(-1)min(-1)) hypoglycemic clamps to induce severe hypoglycemia (blood glucose 10-15 mg/dl for 90 min). Animals were randomized into control (vehicle) or pharmacological treatments (memantine or erythropoietin). One week after severe hypoglycemia, neuronal damage was assessed by Fluoro-Jade B and hematoxylin and eosin staining of brain sections. Treatment with both memantine and erythropoietin significantly decreased severe hypoglycemia-induced neuronal damage in the cortex by 35% and 39%, respectively (both p<0.05 vs. controls). These findings demonstrate that memantine and erythropoietin provide a protective effect against severe hypoglycemia-induced neuronal damage. PMID- 21272613 TI - Longitudinal analysis of the behavioural phenotype in R6/1 (C57BL/6J) Huntington's disease transgenic mice. AB - Huntington's disease is caused by a single mutation on the HTT gene which produces an expansion in the number of glutamine repeats present in the huntingtin protein. This mutation results in an array of motor, cognitive and behavioural problems mediated by a progressive loss of striatal neurons and brain atrophy. The identification of behavioural phenotypes in mouse models of the disease provides a baseline of efficacy for therapeutic interventions. The R6/1 mouse line carries ~115 CAG repeats and has an aggressive form of the disease. The aim of the present study was to undertake longitudinal behavioural characterisation of this mouse line in order to quantify the time course and severity of disease progression. In the present study, when compared to wildtype littermates, male R6/1 heterozygous mice demonstrated a progressive weight loss from 3 months of age. The R6/1 carriers also demonstrated a relatively stable motor coordination deficit on the rotarod, and progressive impairments on each aspect of the balance beam test: latency to orientate and traverse the beam; number of fore- and hind-limb footslips. The R6/1 carriers were less reactive to acoustic startle stimuli and displayed less inhibition to prepulse warning stimuli than their wildtype littermates. In the Morris water maze, the R6/1 carriers demonstrated a deficit on latency to find the platform and path length measures, which was apparent by 3 months of age but not further progressive. They also demonstrated fewer entries into the target zone during probe trials. The data from the present study demonstrate that the R6/1 mouse has a profound behavioural phenotype that includes motor and cognitive deficits, but that not all of these deficits were robustly progressive in nature. PMID- 21272614 TI - Orphenadrine induces secondarily generalized convulsive status epilepticus in rats. AB - The current study was aimed to assess the convulsant potency of orphenadrine (ORPH) in rats together with a screen of different conventional antiepileptic drugs (AEDs) on their efficacy to suppress it. ORPH was administered intraperitoneally (i.p.) in doses of 50-80 mg/kg in male Wistar rats. The latency to first seizure, the number of seizure episodes and the duration of overt status epilepticus (SE) as well as the incidence of deaths was scored with simultaneous electroencephalographic (EEG) recordings. Subsequently, the effects of conventional AEDs on ORPH-evoked (80 mg/kg) seizure incidence were studied. ORPH dose-dependently induced seizures in increasing number of animals, reaching 100% at a dose of 80 mg/kg, associated with low mortality and no drug-related neurotoxicity. Epileptic attacks started as complex partial fits consisting of stereotyped behavior, limb movements, head shaking and myoclonic twitches of the body. Subsequently, an overt generalized convulsive SE appeared, lasting for approximately 2h. Among conventional AEDs: carbamazepine, ethosuximide and phenytoin had no effect while valproate (p<0.001), diazepam (p<0.01), and phenobarbital (p<0.001) dose-dependently suppressed seizure activity. All the above characteristics make the new model, a useful, easy to perform experimental tool to study the pathophysiology of SE as well as the effects of new AEDs. PMID- 21272615 TI - Proteomic changes in the brains of Huntington's disease mouse models reflect pathology and implicate mitochondrial changes. AB - Mouse models of Huntington's disease (HD) have been used extensively to recapitulate the pathological cascade of events in human HD. Mutant huntingtin interacts with many other proteins and has a well documented effect on gene expression. We were interested in whether changes in gene expression were translated into changes in the protein abundance in the brains of mouse models of HD. In two different HD knock in mouse models, the HdhQ150 and the HdhQ92, we detected changes in the abundance of proteins in mouse brain between wild-type and homozygous mutant animals. The numbers of changes detected rose with age and phenotypic severity. There were regional differences with most changes seen in the caudate and fewest in the cerebellum, reflecting the known pattern of gene expression changes in human HD and mouse models of HD and the known pathology. However, while some changes in the proteome followed changes in gene expression others did not directly reflect changes in gene expression seen in these animal models. Seven of the sixteen proteins detected have a known mitochondrial function, an enrichment of six-fold over that expected (p=0.001): these mitochondrial proteins show both increases and decreases in abundance implying that a straightforward alteration in mitochondrial number is unlikely to account for this finding. PMID- 21272616 TI - TPH2 in the ventral tegmental area of the male rat brain. AB - This study surveyed the distribution of tryptophan hydroxylase 2 (TPH2) mRNA, protein, and enzymatic activity throughout the male Sprague-Dawley rat brain. TPH2 is the genetic isoform of TPH that catalyzes the rate-limiting step in serotonin biosynthesis within the central nervous system. Although cell bodies of serotonergic neurons are located mainly in the raphe, serotonin-containing axons innervate many regions of the brain. In the present study, we assessed the levels of mRNA, protein expression, and enzyme activity of TPH2 in the rat raphe, ventral tegmental area (VTA), substantia nigra, hippocampus, cerebellum, dorsal striatum, nucleus accumbens, amygdala, and medial prefrontal cortex to more fully understand the distribution of this enzyme throughout the central nervous system. The pineal gland was used as a control tissue that expresses TPH1 (the peripheral enzyme), but not TPH2. As expected, the raphe showed the highest brain TPH2 activity and protein expression. In the contrast to other reports, however, the VTA followed the raphe as the region with the second-highest amount of TPH2 activity, mRNA and protein expression. There were significantly lower TPH activities and levels of TPH2 protein in the other regions. In addition, TPH2 immunocytochemistry demonstrated the presence of TPH-positive cell bodies within the VTA. The results of this study indicate that TPH2 and serotonergic signaling may play an important role in the mesolimbic/mesocortical reward pathway. PMID- 21272617 TI - Immunohistochemical localization of receptor for advanced glycation end (RAGE) products in the R6/2 mouse model of Huntington's disease. AB - The receptor for advanced glycation end (RAGE) products is a multi-ligand receptor that belongs to the immunoglobulin superfamily of cell surface receptors, whose ligands are known to be upregulated in neuropathological conditions. RAGE upregulation has been described in neurodegenerative diseases, such as Alzheimer's disease, Creutzfeldt-Jakob's disease and Huntington's disease (HD). To analyze in detail the implication of RAGE in HD, we studied the immunohistochemical distribution of RAGE in the striatum of the R6/2 mouse model of HD, with particular attention to the neuronal subpopulations and their relative vulnerability to HD neurodegeneration. We show that RAGE immunoreactivity is evenly distributed to the cytoplasm of neurons in the wild type mouse, while it is finely granular in the cytoplasm of striatal neurons of R6/2 mouse. RAGE is distributed in 98% of spiny projection neurons, both in the normal mouse and in the R6/2. RAGE co-localizes with all of the striatal interneuron subsets both in the wild-type and in the R6/2 mouse. However, the intensity of RAGE immunoreactivity is significantly higher in the spiny neurons and in the PARV neurons of R6/2 mouse, whereas it is comparable between R6/2 and wild-type in the cholinergic and somatostatinergic interneurons. These data support the concept that RAGE is upregulated in the neurodegenerative process of HD, and suggests that its activation is related to the individual vulnerability of the striatal neuronal subtype. PMID- 21272618 TI - Total oligomeric flavonoids of Cyperus rotundus ameliorates neurological deficits, excitotoxicity and behavioral alterations induced by cerebral ischemic reperfusion injury in rats. AB - Interactions between neurons and astrocytes play a critical role in the central nervous system homeostasis. Cyperus rotundus (family: Cyperaceae), a traditional Indian medicinal herb, used as nervine tonic and nootropic in the Ayurvedic system of medicine. The present study was undertaken to investigate the neuroprotective effect of total oligomeric flavonoids (TOFs), prepared from C. rotundus, in rat model of cerebral ischemia and reperfusion. Male Sprague Dawley rats (290-340g) were subjected to middle cerebral artery occlusion (MCAO) for 2h and reperfusion for 70h. Experimental animals were divided into four groups: Group I - sham operated (n=7); Group II - vehicle treated ischemic-reperfusion (IR) (n=9), and Group III and IV - TOFs treated (100 and 200mg/kg body weight, p.o., respectively; n=7 in each group). Vehicle or TOFs were pretreated for four days before the induction of ischemia and continued for next three days after the ischemia i.e. treatment was scheduled totally for a period of 7 days. MCAO surgery was performed on day 4, 1h after TOFs administration. Neuroprotective effect of TOFs was substantiated in terms of neurological deficits, excitotoxicity (glutamate, glutamine synthetase and Na(+)K(+)ATPase levels), oxidative stress (malondialdehyde, super oxide dismutase, and glutathione) and neurobehavioral functions in the experimental animals. TOFs decreased glutamate, glutamine synthetase (GS) and increased Na(+)K(+)ATPase activity in a dose dependent manner when compared to the IR rats. Treatment with TOFs significantly reduced the neurological deficits and reversed the anxiogenic behavior in rats. Further, it also significantly decreased MDA and increased superoxide dismutase (SOD) and glutathione content in brains of experimental rats. Histopathological examination using cresyl violet staining revealed the attenuation of neuronal loss by TOFs in stroke rats. The present study demonstrates the unswerving involvement of TOFs on ischemia-reperfusion triggered biochemical alterations in MCAO/R rats. Hence, TOFs might be an attractive candidate for further studies in the development of new drugs for cerebral stroke treatment. PMID- 21272619 TI - Number of synapses increased in the rat spinal dorsal horn after sciatic nerve transection: a stereological study. AB - We recently found that the number of synapses in the spinal dorsal horn, as estimated by stereological techniques, increased by 86% after chronic constriction injury of sciatic nerve in rats. In this study, we aimed to reveal whether transection of sciatic nerve was also associated with a plasticity change in the number of synapses. 18 adult SD rats were randomly divided into 3 groups undergoing (i) unilateral sham operation, (ii) unilateral sciatic nerve transection, and (iii) unilateral sciatic nerve transection with postoperative medication (parecoxib) for 3 days, respectively. 28 days postoperation, the L4-6 segment of the spinal cord was removed; paraffin-embedded sections were prepared and stained with Nissl's method and synaptophysin immunohistochemistry. The optical disector (a contemporary stereological technique) was used to estimate the numbers of neurons and synapses in the spinal dorsal horn. Compared to the non-operated side, the axotomy induced a 74.3% increase in the number of synapses per unit length of spinal cord or a 67.4% increase in the ratio between the numbers of synapses and neurons in the middle tissue block from the L4-6 segment on the operated side but not in either the rostral or caudal tissue block. Parecoxib had no effect on the parameters. In conclusion, peripheral nerve injury, model for neuropathic pain, is associated with a synaptic plasticity (numerical increase) in the spinal dorsal horn. PMID- 21272620 TI - Tamoxifen and mifepriston modulate nicotine induced conditioned place preference in female rats. AB - An increasing number of studies suggest that nicotine/tobacco addiction is modulated by ovarian hormones. The levels of estrogen and progesterone appear to be important in the success of quit attempts and smoking cessation. In women smokers with the diagnosis or risk of breast cancer, the estrogen receptor modulator tamoxifen (TAM) is widely used, and even though the detrimental health effects of smoking are known, this vulnerable group has difficulty quitting and continues to smoke. The current study tested the effect of the estrogen receptor modulator TAM and the progesterone receptor antagonist mifepriston (RU486) on nicotine-induced conditioned place preference (CPP) in adult female rats. A three chambered CPP apparatus was used and nicotine was paired with the initially non preferred chamber. Rats received nicotine or saline and hormone receptor modulators (vehicle, TAM, RU486) in a 2*3 experimental design. We have previously shown that nicotine induces CPP in male Sprague-Dawley rats but not in females. Our results show that while nicotine alone does not induce CPP in female rats, rats treated with TAM exhibit nicotine-induced CPP. Although RU486 has an aversive effect when applied alone, this is ameliorated by nicotine. These results confirm the role of ovarian hormone receptors in nicotine-induced CPP and may have clinical implications for developing more efficient smoking cessation approaches in women smokers. PMID- 21272621 TI - Effects of oxymatrine on sympathoexcitatory reflex induced by myocardial ischemic signaling mediated by P2X3 receptors in rat SCG and DRG. AB - Sympathoexcitatory reflex is characterized by an increase in blood pressure and sympathetic nerve activity. P2X3 receptors in SCG neurons are involved in increasing sympathoexcitatory reflex after myocardial ischemic (MI) injury. The present study is aimed to explore the effects of oxymatrine (Oxy) on the transmission of myocardial ischemic signaling mediated by P2X3 receptors in rat superior cervical ganglia (SCG) and cervical dorsal root ganglia (DRG) in the sympathoexcitatory reflex after myocardial ischemic injury. In this study, the expression levels of P2X3 immunoreactivity, mRNA and protein were analyzed in SCG and DRG neurons by immunohistochemistry, in situ hybridization and Western blotting. The results show that the myocardial ischemic injury induces the increase of the systolic blood pressure and heart rate and upregulates the expression of P2X3 receptors in SCG and DRG neurons. Upregulated expression of P2X3 receptors in SCG and DRG neurons subsequently leads to the aggravated sympathoexcitatory reflex. Oxymatrine reduces the systolic blood pressure and heart rate in myocardial ischemic rats. After myocardial ischemic rats are treated with oxymatrine, the expression levels of P2X3 immunoreactivity, mRNA and protein are lower than those in myocardial ischemic rats. Oxymatrine may decrease the expression of P2X3 receptor and depress the aggravated sympathoexcitatory reflex induced by the nociceptive transmission of myocardial ischemic injury via P2X3 receptors of rat SCG and DRG neurons. PMID- 21272622 TI - Expressed 2-5A synthetase genes and pseudogenes in the marine sponge Geodia barretti. AB - The 2',5'-oligoadenylate synthetases (2-5A synthetases, OAS) form a family of proteins presented in many branches of Metazoa. The phylum Porifera (sponges) contains OAS proteins which are different from those in vertebrates and form a distinct OAS subfamily. In turn, OAS proteins from different genera of Demospongia show rather low similarities in their primary structures. To ascertain divergence of the OAS genes within a particular sponge genus, we identified the OAS genes from the marine sponge Geodia barretti and compared them with those from another member of the genus Geodia, Geodia cydonium. The identity and similarity of the OAS sequences found in G. barretti with those from G. cydonium were considerably higher than identities and similarities compared with those from other sponges, 75% and 85% versus 27-30% and 42-47%, respectively. We also established the presence of a transcriptionally active polymorphic OAS pseudogene in the genome of G. barretti. The transcripts of the OAS pseudogene(s) lack several internal exons encoding necessary motifs for OAS enzymatic activity. The maintenance and further diversification of OAS gene(s) and pseudogene(s) suggest the prevalence of gene duplication events over the loss of gene duplicates in Geodia genomes during the evolution. PMID- 21272623 TI - Identification of genes involved in bamboo fiber development. AB - Recently bamboo has gained reputation as a major resource of non-wood fiber. The present study was undertaken to generate information about fiber development process in bamboo (Bambusa balcooa) using PCR-based suppressive subtractive hybridization (PCR-SSH) technique, as molecular mechanism of its fiber development is yet to be explored. SSH was performed between cDNA isolated from leaf (as driver) and internodes (as tester) of B. balcooa which indicated up regulation of 521 ESTs. Among these 41 were contigs and 65 ESTs were singletons. On the basis of BLASTX search 307 ESTs with known functions were classified into several functional categories including transport, metabolism, information, perception and response to stimuli while others were either non-significant (120) or hypothetical proteins (94). A total of 51 out of 307 functional ESTs were found fiber specific and their global distribution among different plant species like maize, rice, cotton and Arabidopsis ESTs were determined. Net distributions and differential expression patterns of 13 important B. balcooa fiber specific cDNAs among different internodes during bamboo development were studied using RNA slot-blot, semi-quantitative RT-PCR and real time PCR. In-situ localization of mRNA transcript for few selected bamboo fiber ESTs namely, V1Bb147 (protein kinase-like protein) and V1Bb88 (myb domain-containing protein) were detected using Confocal Laser Scanning Microscope. Transcript levels of these genes exhibited an orchestral turn-over during bamboo development, suggesting their close association with fiber development, an event associated with several metabolic and physiological changes. The results clearly suggest that these genes are involved in several concerted mechanisms involving Ca(+) signaling pathway, cell wall synthesis, hormone regulation, system maintaining cell turgor pressure and cytoskeleton synthesis pathway accountable for bamboo fiber development signifying fiber development as a complex but ordered metabolic process involving differential expression of large scale fiber associated genes. This is the first report on systematic analysis of genes involved in bamboo fiber development. PMID- 21272624 TI - Development and characterisation of modified poloxamer 407 thermoresponsive depot systems containing cubosomes. AB - The purpose of this study is to develop a thermoresponsive sustained release delivery system combining phytantriol cubosomes and poloxamer 407 (P407). P407 undergoes thermoreversible gelation, where it exists as a free-flowing liquid at low temperature and gels upon heating. However, this polymer has the major draw back of fast erosion in aqueous environments which needs to be addressed. Three different concentrations of P407 (12%, 15% and 17% (w/v)) were formulated with various additives (methyl cellulose (MC), dextran, carrageenan and Pluronic-R (25R4)). The rheological characteristics and in vitro stability were investigated. The sol-gel transition temperature of P407 was lowered in the presence of the phytantriol cubosomes. The addition of MC and dextran did not affect the sol-gel transition temperature whereas 25R4 increased the gelation temperature. No transition was observed for the carrageenan formulations. The presence of 25R4 allowed the development of formulations that were free flowing liquid at working temperature (22 degrees C), gelled at body temperature (37 degrees C) and had improved stability in an aqueous environment. Both rheological and in vitro stability studies suggested that cubosome-loaded 17% (w/v) P407 with 25R4 in 1:1 molar ratio may have a potential as sustained release delivery system. PMID- 21272625 TI - Solubility and in vitro transdermal diffusion of riboflavin assisted by PAMAM dendrimers. AB - PAMAM dendrimers of full generation (Gn) and half generation (Gn.5) were used as solubility enhancers of riboflavin (B2 vitamin) in methanol. They were found to weakly enhance solubility of B2 (7.2-10.3 times) according to the order: G2?G2.5>G3?G3.5>G4. The homogeneous mixtures of Gn (or Gn.5) with B2 of 1:1 molar ratio were obtained by removal of methanol to form oily host-guest complexes. The complexes were released from o/w emulsions and the transdermal permeation of B(2) through polyvinyldifluoride (PVDF) and pig ear skin (PES) membranes was estimated. PAMAM dendrimers were demonstrated to promote permeation of B2 according to the order: G2>G3?G2.5>G3.5>G4 (none). The permeation of fluorescein labeled dendrimers is faster than B2; the diffusion of G2 dendrimer through PES was the slowest of all studied Gn dendrimers, presumably due to absorption inside the skin. On the other hand the G2 was the best permeation enhancer for B2. The water soluble PAMAM dendrimers G2 and G3 can be successfully applied in cosmetic and dermatologic emulsions for this weakly water soluble vitamin. PMID- 21272626 TI - Porphyrin-containing polyaspartamide gadolinium complexes as potential magnetic resonance imaging contrast agents. AB - Porphyrin-containing polyaspartamide ligands (APTSPP-PHEA-DTPA) were synthesized by the incorporation of diethylenetriaminepentaacetic acid (DTPA) and 5-(4' aminophenyl)-10,15,20-tris(4'-sulfonatophenyl) porphyrin, trisodium salt (APTSPP) into poly-alpha,beta-[N-(2-hydroxyethyl)-l-aspartamide] (PHEA). These ligands were further reacted with gadolinium chloride to produce macromolecule-gadolinium complexes (APTSPP-PHEA-DTPA-Gd). Experimental data of (1)H NMR, IR, UV and elemental analysis evidenced the formation of the polyaspartamide ligands and gadolinium complexes. In vitro and in vivo property tests indicated that APTSPP PHEA-DTPA-Gd possessed noticeably higher relaxation effectiveness, less toxicity to HeLa cells, and significantly higher enhanced signal intensities (SI) of the VX2 carcinoma in rabbits with lower injection dose requirement than that of Gd DTPA. Moreover, APTSPP-PHEA-DTPA-Gd was found to greatly enhance the contrast of MR images of the VX2 carcinoma, providing prolonged intravascular duration, and distinguished the VX2 carcinoma and normal tissues in rabbits according to MR image signal enhancements. These porphyrin-containing polyaspartamide gadolinium complexes can be used as the candidates of contrast agents for targeted MRI to tumors. PMID- 21272627 TI - Evaluation of a crystalline nanosuspension: polymorphism, process induced transformation and in vivo studies. AB - The aim of this work was to evaluate a crystalline nanosuspension of an investigational anticancer compound, SN 30191. Solid forms of SN 30191 were prepared and characterized by thermal analysis, infrared spectroscopy, 13C CP/MAS SSNMR spectroscopy, SEM and powder XRD. Wet milling was performed using a high pressure homogenizer and process induced transformations were studied as a function of time and pressure using infrared spectroscopy. Dose-toxicity and pharmacokinetics (PK) of the nanocrystal formulation were evaluated in mice after intravenous administration. SN 30191 was found to exist in two polymorphic forms (I and II) and a hydrate with an equilibrium solubility < 0.1 MUg/ml (pH 1.3 11.0, 37 degrees C). Wet milling resulted in solid state transformation as a function of pressure. Form II was found to transform into form I at intermediate pressures. A further increase in pressure resulted in formation of a hydrate. The final nanosuspension consisted of SN 30191 as a hydrate. The dose-toxicity studies revealed higher tolerance (~4 times) for the nanosuspension (10 mg/kg) when compared with a solution formulation (2.5 mg/kg). Compared with solution formulation, the nanosuspension allowed the delivery of a higher dose and rendered possible the performance of PK and tissue distribution studies in animals. PMID- 21272628 TI - Optimization of microdermabrasion for controlled removal of stratum corneum. AB - Microdermabrasion has been shown to increase skin permeability for transdermal drug delivery by damaging or removing skin's outer layer, stratum corneum. However, relationships between microdermabrasion parameters and effects on the stratum corneum barrier have not been developed. In this study, we determined the effect of microdermabrasion crystal flow rate, time, and suction pressure applied in both static and dynamic modes on the extent of stratum corneum removal from excised porcine skin. In addition to controlling the depth of tissue removal by microdermabrasion parameters, we also controlled the area of tissue removal by applying a metal mask patterned with 125- or 250-MUm holes to selectively expose small spots of tissue to microdermabrasion. We found that the extent of stratum corneum removal depended strongly on the crystal flow rate and exposure time and only weakly on pressure or static/dynamic mode operation. Masking the skin was effective to localize stratum corneum removal to exposed sites. Overall, this study demonstrates that optimized microdermabrasion in combination with a mask can be used to selectively remove stratum corneum with three-dimensional control, which is important to translating this technique into a novel method of transdermal drug delivery. PMID- 21272629 TI - Old mice lacking high-affinity nicotine receptors resist acoustic trauma. AB - There is presently no clearly effective preventative medication against noise induced hearing loss (NIHL). However, negative feedback systems that presumably evolved to modulate the sensitivity of the organ of Corti may incidentally confer protection. One feedback system implicated in protection from NIHL involves synaptic connections between the lateral olivocochlear efferent terminals and the afferent fibers of spiral ganglion neurons (SGNs). These connections operate via high-affinity nicotinic acetylcholine receptors containing the beta2 subunit. We unexpectedly observed protection from NIHL in 9-month old knockout mice lacking the beta2 subunit (beta2(-/-)); however, the same protection was not observed in 2-month old beta2(-/-) mice. This enigmatic observation led to the discovery that protection from acoustic trauma in older beta2(-/-) mice is mainly mediated by an age-related increase of corticosterone, not disruption of efferent cholinergic transmission. Significant protection of inner hair cells after acoustic trauma in beta2(-/-) mice was linked to the activation of glucocorticoid signaling pathways. However, significant loss of SGNs was observed in animals with chronically high systemic levels of corticosterone. These results suggested a "double-edge sword" nature of glucocorticoid signaling in neuronal protection, and a need for caution regarding when to apply synthetic glucocorticoid drugs to treat neural injury such as accompanies acoustic trauma. PMID- 21272630 TI - Observer weighting of interaural cues in positive and negative envelope slopes of amplitude-modulated waveforms. AB - The auditory system can encode interaural delays in highpass-filtered complex sounds by phase locking to their slowly modulating envelopes. Spectrotemporal analysis of interaurally time-delayed highpass waveforms reveals the presence of a concomitant interaural level cue. The current study systematically investigated the contribution of time and concomitant level cues carried by positive and negative envelope slopes of a modified sinusoidally amplitude-modulated (SAM) high-frequency carrier. The waveforms were generated from concatenation of individual modulation cycles whose envelope peaks were extended by the desired interaural delay, allowing independent control of delays in the positive and negative modulation slopes. In experiment 1, thresholds were measured using a 2 interval forced-choice adaptive task for interaural delays in either the positive or negative modulation slopes. In a control condition, thresholds were measured for a standard SAM tone. In experiment 2, decision weights were estimated using a multiple-observation correlational method in a single-interval forced-choice task for interaural delays carried simultaneously by the positive, and independently, negative slopes of the modulation envelope. In experiment 3, decision weights were measured for groups of 3 modulation cycles at the start, middle, and end of the waveform to determine the influence of onset dominance or recency effects. Results were consistent across experiments: thresholds were equal for the positive and negative modulation slopes. Decision weights were positive and equal for the time cue in the positive and negative envelope slopes. Weights were also larger for modulations cycles near the waveform onset. Weights estimated for the concomitant interaural level cue were positive for the positive envelope slope and negative for the negative slope, consistent with exclusive use of time cues. PMID- 21272631 TI - Microbial 2,3-butanediol production: a state-of-the-art review. AB - 2,3-butanediol is a promising bulk chemical due to its extensive industry applications. The state-of-the-art nature of microbial 2,3-butanediol production is reviewed in this paper. Various strategies for efficient and economical microbial 2,3-butanediol production, including strain improvement, substrate alternation, and process development, are reviewed and compared with regard to their pros and cons. This review also summarizes value added derivatives of biologically produced 2,3-butanediol and different strategies for downstream processing. The future prospects of microbial 2,3-butanediol production are discussed in light of the current progress, challenges, and trends in this field. Guidelines for future studies are also proposed. PMID- 21272632 TI - Sleep and fatigue in mice infected with murine gammaherpesvirus 68. AB - Fatigue, a common symptom of many acute and chronic medical conditions, reduces both quality of life and workplace productivity and can be disabling. However, the pathophysiologic mechanisms that underlie fatigue can be difficult to study in human populations due to the patient heterogeneity, the variety of underlying causes and potential triggering events, and an inability to collect samples that may be essential to elucidation of mechanisms (e.g., brain). Although the etiology of chronic fatigue syndrome (CFS) remains elusive, some studies have implicated viral infections, including Epstein-Barr virus (EBV), a human gammaherpesvirus, as a potential factor in the pathogenesis of CFS. Murine gammaherpesvirus 68 (gammaHV68) is a mouse pathogen that shares many similarities with human gammaHVs, including EBV. In this study, we use gammaHV68-infected C57BL/6J mice as a model system for studying the impact of chronic viral infection on sleep-wake behavior, activity patterns, and body temperature profiles. Our data show that gammaHV68 alters sleep, activity, and temperature in a manner suggestive of fatigue. In mice infected with the highest dose used in this study (40,000plaque forming units), food intake, body weight, wheel running, body temperature, and sleep were normal until approximately 7days after infection. These parameters were significantly altered during days 7 through 11, returned to baseline levels at day 12 after infection, and remained within the normal range for the remainder of the 30-day period after inoculation. At that time, both infected and uninfected mice were injected with lipopolysaccharide (LPS), and their responses monitored. Uninfected mice given LPS developed a modest and transient febrile response during the initial light phase (hours 12 through 24) after injection. In contrast, infected mice developed changes in core body temperatures that persisted for at least 5days. Infected mice showed an initial hypothermia that lasted for approximately 12h, followed by a modest fever that persisted for several hours. For the remainder of the 5-day recording period, they showed mild hypothermia during the dark phase. Running wheel activity of infected mice was reduced for at least 5days after injection of LPS, but for only 12h in uninfected mice. Collectively, these observations indicate that (1) physiologic and behavioral processes in mice are altered and recover during an early phase of infection, and (2) mice with latent gammaHV68 infection have an exacerbated response to challenge with LPS. These findings indicate that laboratory mice with gammaHV68 infections may provide a useful model for the study of fatigue and other physiologic and behavioral perturbations that may occur during acute and chronic infection with gammaherpesviruses. PMID- 21272633 TI - The agrochemical fungicide triadimefon induces abnormalities in Xenopus laevis embryos. AB - The dysmorphogenic activity of the triazole fungicide triadimefon (FON) has been evaluated using Xenopus laevis development. Embryos, exposed to 500 MUM FON during early neurulation phases (stages 13-17, Nieuwkoop and Faber), were allowed to develop until stage 47. Larvae revealed serious craniofacial defects, bent forebrain, and abnormal hindbrain segmentation. CRABP and CYP26 (markers related to retinoic acid homeostasis) gene and protein expression and protein distribution have been evaluated at stage 17 and at the end of the branchial arch morphogenesis (stage 27) by real-time PCR, western blot and whole-mount immunostaining. A significant increase of CYP26 transcript has been observed at both embryonic stages. A co-localization of the two markers has been observed at the cephalic region. Embryos exposed to FON showed abnormal distribution of positive tissues. Due to the strict similarity of these results with those previously described in rodents, a FON-related alteration of mechanism conserved during vertebrate evolution is suggested. PMID- 21272634 TI - Detection of Escherichia coli O157:H7 virulence genes in isolates from beef, pork, water, human and animal species in the northwest province, South Africa: public health implications. AB - The aim of the present study was to isolate and identify Escherichia coli O157:H7 from pigs, cattle, humans, beef, pork and water samples and to determine their putative virulence genes by PCR analysis. A total of 220 samples were analysed; 5600 presumptive E. coli O157:H7 were screened for the presence of rfb(O157) and fliC(H7) gene fragments by PCR and 130 isolates were confirmed. The prevalence of E. coli O157:H7 was higher in pigs and pork 88(67.7%) than in cattle and beef 36(27.7%), water 3(2.3%) or humans 1 (0.77%). Moreover, the pathogen was more frequently isolated from faecal (16.9%-43.1%) than from meat samples (10.8% 24.6%). A large proportion--73 (56.2%)--of the isolates possessed the hlyA gene, while 48 (36.9%) harboured the eaeA gene. Although there were no major differences in the number of isolates harbouring the stx(1) and stx(2) genes, respectively, only a small proportion 13(10%) harboured both shiga toxin genes. Despite this, the proportion of isolates that possessed the stx(1) 29(22.3%) was higher than those possessing the stx(2) gene. None of the E. coli O157:H7 isolates harboured all four shiga-toxin producing E. coli (STEC) virulence genes investigated. When comparing the proportion of isolates obtained from the different sample sources and/or stations, significant positive correlations were observed between isolates from Mafikeng and Lichtenburg (r = 0.981, p < 0.05) and those from Mafikeng and Rustenburg (r = 0.991, p < 0.05). These results therefore indicate that meat and faeces samples obtained from major cities in the northwest province were contaminated with E. coli O157:H7. We suggest that there is a need for improving the sanitary conditions of farms, abattoirs and butcher shops. This could reduce transmission of E. coli O157:H7 to humans. PMID- 21272635 TI - The involvement of Importin-beta and peroxiredoxin-6005 in mitochondrial biogenesis. AB - Importin-beta is encoded by the Ketel gene in Drosophila. Upon running out of the maternal Importin-beta dowry larvae without the Ketel gene slow down and before dying possess symptoms characteristic for mitochondrial cytopathies. Death of the larvae is almost certainly the consequence of ceasing import of proteins, including some of the transcription factors, into the nuclei. We report here that the ensuing altered gene expression pattern leads to cessation of mitochondrial biogenesis. A transcriptome comparison between larvae with and without Ketel gene revealed altered expression level for 30 genes that are all nuclear. The seven downregulated genes have C/EBP transcription factor binding site in their promoter. RNAi silencing the function of peroxiredoxin-6005, one of the 23 upregulated genes, leads to excessive mitochondrial biogenesis, free radical production and death of the larvae. It appears that peroxiredoxin-6005 is engaged in mitochondrial biogenesis possibly as a component of redox-signaling. PMID- 21272636 TI - Gellan gum blended PEI nanocomposites as gene delivery agents: evidences from in vitro and in vivo studies. AB - Branched Polyethylenimine, 25 kDa (PEI), was blended with gellan gum, an anionic heteropolysaccharide, for partial neutralization of its excess positive charge to form gellan gum-polyethylenimine (GP) nanocomposites (NCs). Subsequently, we manipulated the amount of gellan gum for obtaining a series of NCs and characterized them for their size, charge and morphology. Among all the NCs, one member, named GP3, showed the best transfection efficiency in tested cell lines in comparison with the rest of the series, PEI, Lipofectamine and other commercial transfection agents and also exhibited minimum cytotoxicity. It was found to transfect primary cells of mouse skin with better efficiency than PEI and Lipofectamine and was able to protect the plasmid DNA from nucleases and serum proteins present in the blood. GP3 exhibited efficient intracellular delivery of plasmid as revealed by confocal studies while its intracellular presence was also confirmed by the knockdown of GFP expression (using GFP specific siRNA) and JNKII by quantifying proteins in cell lysates and by western blotting and hybridization, respectively. In vivo cytotoxicity studies in Drosophila showed lack of induction of stress response in the exposed organisms. Further, exposed organisms did not show any developmental delay or mortality and no morphological defects were observed in the emerged flies. In vivo gene expression studies in Balb/c mice revealed maximum expression of luciferase enzyme in spleen. The study suggests that GP3 may act as an efficient non-viral gene carrier with diverse biomedical applications. PMID- 21272637 TI - Cisplatin-loaded gelatin-poly(acrylic acid) nanoparticles: synthesis, antitumor efficiency in vivo and penetration in tumors. AB - Cisplatin (CDDP)-loaded gelatin-poly(acrylic acid) (GEL-PAA) nanoparticles were successfully prepared by polymerizing acrylic acid in the presence of gelatin in aqueous solution followed by incorporating CDDP into the formed GEL-PAA nanoparticles through polymer-metal complex formation of CDDP with carboxylic groups in the nanoparticles. The obtained nanoparticles had a spherical shape, with a mean size of about 100 nm, and high drug payload as well as stability. It is found that CDDP can be released from the nanoparticles in a sustained manner with a small initial burst release. In vitro cytotoxicity revealed that CDDP loaded nanoparticles had similar cytotoxicity to free CDDP after 48 h co incubation with human colorectal cancer cell line LoVo. In vivo antitumor activity indicated that the nanoparticle formulation was superior in anticancer effect to free CDDP on murine hepatic H22 tumor-bearing mice model through intraperitoneal (i.p.) administration and displayed a dose-dependent antitumor efficacy. Further, the penetration examination of the nanoparticles through tumor tissue revealed that the CDDP-loaded GEL-PAA nanoparticles could only affect the cells near the tumor vasculature after they entered into the tumor tissue. PMID- 21272638 TI - Skin penetration behaviour of liposomes as a function of their composition. AB - Deformable liposomes have been developed and evaluated as a novel topical and transdermal delivery system. Their mechanism of drug transport into and through the skin has been investigated but remains a much debated question. The present study concerns ex vivo diffusion experiments using pig ear skin in order to explain the penetration mechanism of classical and deformable liposomes. Classical and deformable vesicles containing betamethasone in the aqueous compartment through the use of cyclodextrin inclusion complexes were compared to vesicles encapsulating betamethasone in their lipid bilayer. Deformable liposomes contained sodium deoxycholate as the edge activator. Liposomes were characterised by their diameter, encapsulation efficiency, deformability, stability (in terms of change in diameter) and release of encapsulated drug. Ex vivo diffusion studies using Franz diffusion cells were performed. Confocal microscopy was performed to visualise the penetration of fluorescently labelled liposomes into the skin. This study showed that liposomes do not stay intact when they penetrate the deepest layers of the skin. Betamethasone is released from the vesicles after which free drug molecules can diffuse through the stratum corneum and partition into the viable skin tissue. PMID- 21272639 TI - Comparison of analytical methods to detect instability of etanercept during thermal stress testing. AB - The aim was comparing the capability of a set of analytical methods to detect physical instability (focus on aggregation and structural changes) of etanercept during thermal stress testing as early as possible. Pre-filled syringes of Enbrel(r) 50mg from three batches were thermally stressed for one week at 50 degrees C. Samples were taken at days 0, 1, 2, 3, 4 and 7, and analyzed with high performance liquid size exclusion chromatography (HP-SEC), SDS-PAGE gel electrophoresis, dynamic light scattering (DLS), light obscuration, extrinsic fluorescence (Bis-ANS), far-UV circular dichroism (CD) spectroscopy, second derivative UV spectroscopy (UV), and enzyme-linked immunosorbent assay (ELISA). Thermal stress resulted in the formation of small soluble aggregates (HP-SEC, DLS) which were in part covalent (SDS-PAGE), and conformationally changed (Bis ANS, CD, UV). No significant increase in subvisible particles was detected by light obscuration. An apparent increase in TNF-alpha binding to etancercept in the stressed formulations was found by ELISA. The three batches were comparable when unstressed, but showed slight differences in aggregation tendency. Bis-ANS fluorescence was most sensitive with respect to early-stage detection of heat induced instability of etanercept (significant changes already at day 1), followed by HP-SEC (day 2) and DLS (day 3). This points towards a degradation mechanism involving exposure of hydrophobic patches due to partial unfolding followed by aggregation. PMID- 21272641 TI - Influence of anabolic combinations of an androgen plus an estrogen on biochemical pathways in bovine uterine endometrium and ovary. AB - The application of anabolic steroids in food producing animals is forbidden in the EU since 1988, but the abuse of such drugs is a potential problem. The existing test systems are based on known compounds and can be eluded by newly emerging substances. The examination of physiological effects of anabolic hormones on different tissues to indirectly detect misuse might overcome this problem. Two studies were conducted with post-pubertal 24-months old Nguni heifers and pre-pubertal female 2-4 weeks old Holstein Friesian calves, respectively. The animals of the accordant treatment groups were administered combinations of estrogenic and androgenic compounds. The measurement of the gene expression pattern was undertaken with RT-qPCR. Target genes of different functional groups (receptors, angiogenesis, steroid synthesis, proliferation, apoptosis, nutrient metabolism and others) have been quantified. Several biochemical pathways were shown to be influenced by anabolic treatment. Both studies identified significant regulations in steroid and growth factor receptors (AR, ERbeta, LHR, FSHR, Flt-1, PR, IGF-1R, Alk-6), angiogenic and tissue remodeling factors (VEGFs, FGFs, BMPs, ANGPT-2, MMPs, TIMP-2, CTSB), steroid synthesis (S5A1, HSD17, CYP19A1), proliferation (TNFalpha, IGF-1, IGFBPs, p53, c fos; CEBPD, c-kit), apoptosis (CASP3, FasL, p53) and others (C7, INHA, STAR). Several genes were regulated to opposite directions in post-pubertal compared to pre-pubertal animals. PCA for Nguni heifers demonstrated a distinct separation between the control and the treatment group. In conclusion, anabolics modify hormone sensitivity and steroid synthesis, and they induce proliferative effects in the whole reproductive tract (uterus and ovary) as well as anti-angiogenic effects in the ovary. However, the extent will depend on the developmental stage of the animals. PMID- 21272642 TI - Smooth muscle neurokinin-2 receptors mediate contraction in human saphenous veins. AB - Substance P (SP) and neurokinin A (NKA) are members of the tachykinin peptides family. SP causes endothelial-dependant relaxation but the contractile response to tachykinins in human vessels remains unknown. The objective was to assess the expression and the contractile effects of tachykinins and their receptors in human saphenous veins (SV). Tachykinin expression was assessed with RT-PCR, tachykinin receptors expression with RT-PCR and immunohistochemistry, and functional studies were performed in organ bath. Transcripts of all tachykinin and tachykinin receptor genes were found in SV. NK(1)-receptors were localized in both endothelial and smooth muscle layers of undistended SV, whereas they were only found in smooth muscle layers of varicose SV. The expression of NK(2)- and NK(3)-receptors was limited to the smooth muscle in both preparations. NKA induced concentration-dependent contractions in about half the varicose SV. Maximum effect reached 27.6+/-5.5% of 90 mM KCl and the pD(2) value was 7.3+/ 0.2. NKA also induced the contraction of undistended veins from bypass and did not cause the relaxation of these vessels after precontraction. The NK(2) receptor antagonist SR48968 abolished the contraction induced by NKA, and a rapid desensitization of the NK(2)-receptor was observed. In varicose SV, the agonists specific to NK(1)- or NK(3)-receptors did not cause either contraction or relaxation. The stimulation of smooth muscle NK(2)-receptors can induce the contraction of human SV. As SV is richly innervated, tachykinins may participate in the regulation of the tone in this portion of the low pressure vascular system. PMID- 21272640 TI - Human hydroxysteroid dehydrogenases and pre-receptor regulation: insights into inhibitor design and evaluation. AB - Hydroxysteroid dehydrogenases (HSDs) represent a major class of NAD(P)(H) dependent steroid hormone oxidoreductases involved in the pre-receptor regulation of hormone action. This is achieved by HSDs working in pairs so that they can interconvert ketosteroids with hydroxysteroids resulting in a change in ligand potency for nuclear receptors. HSDs belong to two protein superfamilies the aldo keto reductases and the short-chain dehydrogenase/reductases. In humans, many of the important enzymes have been thoroughly characterized including the elucidation of their three-dimensional structures. Because these enzymes play fundamental roles in steroid hormone action they can be considered to be drug targets for a variety of steroid driven diseases, e.g. metabolic syndrome and obesity, inflammation, and hormone dependent malignancies of the endometrium, prostate and breast. This article will review how fundamental knowledge of these enzymes can be exploited in the development of isoform specific HSD inhibitors from both protein superfamilies. Article from the Special issue on Targeted Inhibitors. PMID- 21272643 TI - Development of a Bayesian estimator for the therapeutic drug monitoring of mycophenolate mofetil in children with idiopathic nephrotic syndrome. AB - The use of mycophenolate mofetil (MMF) in children with idiopathic nephrotic syndrome (INS) is increasing. However, the clinical benefit of its monitoring has been scarcely studied, and little is known about its pharmacokinetics in this context. The objectives of the present study were: (i) to study and model the pharmacokinetics of mycophenolic acid (MPA; the active moiety of MMF) in paediatric patients with INS given MMF, at all stages of the disease; (ii) to develop a Bayesian estimator (MAP-BE) for individual inter-dose area under the concentration-time curve (AUC) prediction in this population, using a limited blood sampling strategy (LSS). Full-pharmacokinetic (PK) profiles of MPA collected in paediatric inpatients with INS already treated with a maintenance immunosuppressive therapy based on MMF (with no calcineurin inhibitors; CNI) were studied. A classical iterative two-stage (ITS) method was applied to model the data and develop MAP-BEs using a one-compartment open model where the absorption is described by a double gamma law allowing the description of a potential enterohepatic recirculation. The performance of the MAP-BE developed for individual exposure assessment was evaluated by the bias and precision of predicted AUCs with respect to measured, trapezoidal AUCs (reference value), and by the proportion of predicted AUCs with absolute error >20%. These PK tools were tested in an independent group of patients. Sixty PK profiles of MPA from children receiving MMF in association to corticosteroids or given alone were included in the study. Forty-five of these PK profiles were used to develop a PK model and a MAP-BE, and 15 for their validation. In the building group, the PK model fitted accurately the PK profiles of MPA: mean residual error of modelled vs. reference AUC was m+/-SD=-0.015+/-0.092 (range: -0.153 to 0.204). The MAP-BE which allowed the estimation of MPA AUC on the basis of a 20 min-60 min-180 min LSS was then developed. In the independent group of patients, its mean residual error vs. reference AUCs was m+/-SD=-0.036+/-0.145 (range: -0.205 to 0.189). Thus, a PK model and its derived MAP-BE for MMF (without any associated CNI) when given to children with INS have been developed. Clinical trials using these PK tools could test the potential impact of the therapeutic drug monitoring of MMF based on the AUC on the clinical evolution of INS. PMID- 21272644 TI - Triton X-114 phase separation in the isolation and purification of mouse liver microsomal membrane proteins. AB - Integral membrane proteins (IMPs) mediate several cellular functions including cell adhesion, ion and nutrient transport, and cell signalling. IMPs are typically hard to isolate and purify due to their hydrophobic nature and low cellular abundance, however, microsomes are small lipid vesicles rich in IMPs, which form spontaneously when cells are mechanically disrupted. In this study, we have employed mouse liver microsomes as a model for optimising a method for IMP isolation and characterisation. Microsomes were collected by differential centrifugation, purified with sodium carbonate, and subjected to GeLC-MS/MS analysis. A total of 1124 proteins were identified in the microsome fraction, with 47% (524/1124) predicted by TMHMM to contain at least one transmembrane domain (TMD). The ability of phase partitioning using the detergent Triton X-114 (TX-114) to further enrich for membrane proteins was evaluated. Microsomes were subjected to successive rounds of solubility-based phase separation, with proteins partitioning into the aqueous phase, detergent phase, or TX-114 insoluble pellet fraction. GeLC-MS/MS analysis of the three TX-114 fractions identified 1212 proteins, of which 146 were not detected in the un-fractionated microsome sample. Conspicuously, IMPs partitioned to the detergent phase, with 56% (435/770) of proteins identified in that fraction containing at least one TMD. GO Slim characterisation of the microsome proteome revealed enrichment of proteins from the endoplasmic reticulum, mitochondria, Golgi apparatus, endosome, and cytoplasm. Further, enzymes including monooxygenases were well represented with 35 cytochrome P450 identifications (CYPs 1A2, 2A5, 2A12, 2B10, 2C29, 2C37, 2C39, 2C44, 2C50, 2C54. 2C67, 2C68, 2C70, 2D10, 2D11, 2D22, 2D26, 2D9, 2E1, 2F2, 2J5, 2U1, 3A11, 3A13, 3A25, 4A10, 4A12A, 4A12B, 4F13, 4F14, 4F15, 4V3, 51,7B1, and 8B1). Evaluation of biological processes showed enrichment of proteins involved in fatty acid biosynthesis and elongation, as well as steroid synthesis. In addition, transport proteins including 24 members of the Rab family of GTPases were identified. Comparison of this dataset with the current mouse liver microsome proteome contributes an additional 648 protein identifications, of which 50% (326/648) contain at least one TMD. PMID- 21272645 TI - Effects of co-expression of molecular chaperones on heterologous soluble expression of the cold-active lipase Lip-948. AB - The cold-active lipase gene Lip-948, cloned from Antarctic psychrotrophic bacterium Psychrobacter sp. G, was ligated into plasmid pColdI. The recombinant plasmid pColdI+Lip-948 was then transformed into Escherichia coli BL21. SDS-PAGE analysis showed that there was substantive expression of lipase LIP-948 in E. coli with a yield of about 39% of total protein, most of which was present in the inclusion body. The soluble protein LIP-948 only consisted of 1.7% of total LIP 948 with a specific activity of 66.51U/mg. Co-expression of molecular chaperones with the pColdI+Lip-948 were also carried out. The results showed that co expression of different chaperones led to an increase or decrease in the formation of soluble LIP-948 in varying degrees. Co-expression of pColdI+Lip-948 with chaperone pTf16 and pGro7 decreased the amount of soluble LIP-948, while the soluble expression was enhanced when pColdI+Lip-948 was co-expressed with "chaperone team" plasmids (pKJE7, pG-Tf2, pG-KJE8), respectively. LIP-948 was most efficiently expressed in soluble form when it was co-expressed with pG-KJE8, which was up to 19.8% of intracellular soluble proteins and with a specific activity of 108.77U/mg. The soluble LIP-948 was purified with amylase affinity chromatography and its enzymatic characters were studied. The optimal temperature and pH of LIP-948 was 35 degrees C and 8, respectively. The activity of LIP-948 dropped dramatically after incubation at 50 degrees C for 15min and was enhanced by Sr(2+), Ca(2+). It preferentially hydrolyzed 4-nitrophenyl esters with the shorter carbon chain. PMID- 21272646 TI - The chiral structure of porous chitin within the wing-scales of Callophrys rubi. AB - The structure of the porous three-dimensional reticulated pattern in the wing scales of the butterfly Callophrys rubi (the Green Hairstreak) is explored in detail, via scanning and transmission electron microscopy. A full 3D tomographic reconstruction of a section of this material reveals that the predominantly chitin material is assembled in the wing scale to form a structure whose geometry bears a remarkable correspondence to the srs net, well-known in solid state chemistry and soft materials science. The porous solid is bounded to an excellent approximation by a parallel surface to the Gyroid, a three-periodic minimal surface with cubic crystallographic symmetry I4132, as foreshadowed by Stavenga and Michielson. The scale of the structure is commensurate with the wavelength of visible light, with an edge of the conventional cubic unit cell of the parallel Gyroid of approximately 310 nm. The genesis of this structure is discussed, and we suggest it affords a remarkable example of templating of a chiral material via soft matter, analogous to the formation of mesoporous silica via surfactant assemblies in solution. In the butterfly, the templating is achieved by the lipid protein membranes within the smooth endoplasmic reticulum (while it remains in the chrysalis), that likely form cubic membranes, folded according to the form of the Gyroid. The subsequent formation of the chiral hard chitin framework is suggested to be driven by the gradual polymerisation of the chitin precursors, whose inherent chiral assembly in solution (during growth) promotes the formation of a single enantiomer. PMID- 21272647 TI - Retrofit implementation of Zernike phase plate imaging for cryo-TEM. AB - In-focus phase-plate imaging is particularly beneficial for cryo-TEM because it offers a substantial overall increase in image contrast, without an electron dose penalty, and it simplifies image interpretation. We show how phase-plate cryo-TEM can be implemented with an appropriate existing TEM, and provide a basic practical introduction to use of thin-film (carbon) phase plates. We point out potential pitfalls of phase-plate operation, and discuss solutions. We provide information on evaluating a particular TEM for its suitability. PMID- 21272648 TI - Protective effect of herbal and probiotics enriched diet on haematological and immunity status of Oplegnathus fasciatus (Temminck & Schlegel) against Edwardsiella tarda. AB - This study determines the effect of diet enriched with the herb Baical skullcap Scutellaria baicalensis, and/or probiotics Lactobacillus sakei BK19 in rock bream, Oplegnathus fasciatus (32 +/- 3 g) against Edwardsiella tarda. The changes in haematological parameters, innate immune response, and disease resistance were investigated after 1, 3, and 6 weeks. The white blood cell count (WBC: 10(4) mm( 3)), red blood cell count (RBC: 10(6) mm(-3)), and haemoglobin (Hb: g dl(-1)) levels significant increased (P < 0.05) with mixed diet on 3rd and 6th week and probiotics enriched diet on 6th week. The haematocrit (Ht: %) level significantly increased (P < 0.05) when fed with mixed diet on weeks 1-6. Interestingly, in mixed diet group the lymphocytes (LYM), monocytes (MON), and neutrophils (NEU) significantly increased from week 1-6. The eosinophils (EOS) significantly increased in all the treated groups. In the probiotics or mixed diet groups the total protein (TP: g dl(-1)) increased significantly on weeks 3 and 6. The serum lysozyme activity significantly was enhanced in all the treated groups indicating an increase in the innate immunity level. Serum complement, antiprotease activities, reactive oxygen species (ROS) and reactive nitrogen species (RNS) production significantly increased from week 1-6 with mixed diet. The maximum protection against E. tarda was recorded in mixed diet group with a minimum cumulative mortality of 20% and a high relative percent survival (RPS) of 72.84. In the probiotics and herbal diet groups the cumulative mortality was 25% and 35% and RPS was 68.63 and 59.42, respectively. This study indicates that administration of probiotics or mixed diets can effectively minimize the mortality and restore the altered hematological parameters and enhancing the innate immunity in O. fasciatus against E. tarda. PMID- 21272649 TI - Expression and applications of recombinant crustacean hyperglycemic hormone from eyestalks of white shrimp (Litopenaeus vannamei) against bacterial infection. AB - Crustacean hyperglycemic hormone (CHH) has many functions to regulate carbohydrate metabolism, ecdysis and reproduction including ion transport in crustaceans. The cDNA encoding CHH peptides containing 369 bp open reading frame encoding 122 amino acids was cloned from eyestalk of white shrimp (Litopenaeus vannamei) and was produced by a bacterial expression system. The biological activity of recombinant L. vannamei crustacean hyperglycemic hormone (rLV-CHH) was tested. The hemolymph glucose level of shrimp increased two-fold at 1h after the rLV-CHH injection and then returned to normal after 3h. In addition to the effect of rLV-CHH administration (25 MUg/shrimp) on immunological responses of white shrimp against pathogenic bacteria, Vibrio harveyi was studied. Results showed that the blood parameters of shrimp injected with rLV-CHH; the THC, PO activity, serum protein level and clearance ability to V. harveyi, were also higher than those of Neg-protein and PBS-injected shrimp. The survival of shrimp injected with rLV-CHH was significantly higher (66.0%) than shrimp that injected with Neg-protein (33.3%) and PBS (28.9%) after 14 days. It is possible that the administration of rLV-CHH in L. vannamei exhibited a higher immune response related to resistance against V. harveyi infection. PMID- 21272650 TI - Channel catfish CD8alpha and CD8beta co-receptors: characterization, expression and polymorphism. AB - In this study we report the identification and characterization of channel catfish, Ictalurus punctatus CD8alpha and CD8beta genes. Both genes encode predicted proteins containing a leader, a immunoglobulin superfamily V domain, a stalk/hinge region, a transmembrane region and a positively charged cytoplasmic tail (CYT) containing the conserved teleost C-X-H motif. Catfish CD8alpha and CD8beta are encoded as single copy genes and as in other vertebrates exhibit a conserved head to tail synteny; the CD8beta gene is found 14.1kb upstream of the CD8alpha gene. Both CD8alpha and CD8beta transcripts showed a low degree of polymorphism. Finally, as determined by q-PCR both CD8alpha and CD8beta are expressed in various catfish lymphoid tissues with the highest expression observed in thymus from 2 month old catfish-fry. In the future these results will provide the basis for evaluating the role of CD8(+) CTL and other CD8-bearing cells in response to immunization or infection in the catfish. PMID- 21272651 TI - Cellular and humoral factors involved in the response of rainbow trout gills to Ichthyophthirius multifiliis infections: molecular and immunohistochemical studies. AB - The parasitic ciliate Ichthyophthirius multifiliis infecting skin, fins and gills of fish induces a protective immune response in rainbow trout (Oncorhynchus mykiss) surviving the infection and a similar protection can be conferred by i.p. injection of live theronts. A combined molecular and immunohistochemical approach has been used in this work for pinpointing cellular and humoral immune factors in gill tissue involved in the response and indicating interactions between the systemic and local responses. Fish were immunized by intra-peritoneal injection of live I. multifiliis theronts, control fish were injected with PBS and subgroups were treated with the immuno-suppressant hydrocortisone before fish were challenged with live theronts. Significant up-regulations of genes encoding IgM, IgT, C3, SAA, IL-8, IL-22 and IFN-gamma were induced by immunization and challenge. Hydrocortisone treatment had a significant down-regulating effect on genes incoding IgT, IgM, CD4, CD8, IFN-gamma, IL-8 and IL-22 in all groups. Immunohistochemistry, using monoclonal antibodies to detect cellular markers, demonstrated active involvement of CD8, MHC II, IgT and IgM positive cells in gill tissue. Putative T-cells (CD8 positive cells) were detected in the intraepithelial lymphoid tissue located at the base of gill filaments and in hyperplastic gill tissue but following infection a clear efflux of these cells was detected. MHC II positive cells were distributed across the gill filaments and accumulated in hyperplastic tissue but hydrocortisone treatment affected their density negatively in both immunized and non-immunized fish. IgT positive cells were present in the epithelial lining of the gill lamellae (suggesting a primary role of this protein in the mucosal defence against the ciliate) whereas IgM positive cells were found only in gill arterioles and the lamellar capillaries. The present work indicates an intensive activity and specialized function of immune cells (B-cells, T-cells and macrophages) and humoral elements such as immunoglobulins IgT and IgM which are orchestrated by cytokines in gill tissue reacting against I. multifiliis. PMID- 21272652 TI - Activation of cytokine expression occurs through the TNFalpha/NF-kappaB-mediated pathway in birnavirus-infected cells. AB - The infectious pancreatic necrosis virus (IPNV) belongs to the Birnaviridae family of viruses and causes acute contagious diseases in a number of economically important freshwater and marine fish. In this study, we infected zebrafish embryonic cells (ZF4) with IPNV and analyzed the gene expression patterns of normal and infected cells using quantitative real-time PCR. We identified a number of immune response genes, including ifna, ifng, mx, irf1, irf2, irf4, tnfa, tnfb, il-1b, il-15, il-26, ccl4 and mmp family genes, that are induced after viral infection. Transcriptional regulators, including cebpb, junb, nfkb and stat1, stat4 and stat5, were also upregulated in IPNV-infected cells. In addition, we used Pathway Studio software to identify TNFalpha as having the greatest downstream influence among these altered genes. Treating virus-infected cells with an siRNA targeting TNFalpha inhibited NF-kappaB expression. To further interrupt the TNFalpha/NF-kappaB-mediated pathway, the expression levels of cytokines and metalloproteinases were inhibited in IPNV-infected cells. These data suggest that, during IPNV infection, the expression of cytokines and metalloproteinases might be initiated through the TNFalpha/NF-kappaB-mediated pathway. The modulation of TNFalpha/NF-kappaB-related mechanisms may provide a therapeutic strategy for inhibiting viral infection in teleosts. PMID- 21272653 TI - An Mpeg (macrophage expressed gene) from the Pacific oyster Crassostrea gigas: molecular characterization and gene expression. AB - Mpegs (macrophage expressed genes) encode members of the MACPF (membrane-attack complex/perforin) protein superfamily that play essential roles in innate immunity. In the present study, a homolog of Mpeg1 was identified in Crassostrea gigas and designed Cg-Mpeg1. The complete cDNA of Cg-Mpeg1 is 2781 bp in length, containing an ORF of 2226 bp, which encodes a putative protein of 742 amino acids with a predicted 19-aa hydrophobic signal peptide, an MACPF domain, and a transmembrane domain. Phylogenetic analysis shows that Cg-Mpeg1 is similar to other mollusk MACPF proteins and might originate in an ancient ancestor gene before the divergence of protostomes and deuterostomes. Localization study revealed that Cg-Mpeg1 protein is found primarily in late endosomes. The MACPF domain from Cg-Mpeg1 exhibits significant antibacterial activity to both Gram negative and positive bacteria. Furthermore, Real-time Quantitative PCR analysis showed that Cg-Mpeg1 is expressed in all tissues detected with highest expression in gill and gonads. Moreover, Mpeg1 mRNA levels are significantly up-regulated following infection with Vibrio alginolyticus. These results highlight that Cg Mpeg1 plays an essential role in host defense and elimination of pathogens in C. gigas. PMID- 21272655 TI - Fear and stop: a role for the amygdala in motor inhibition by emotional signals. AB - Rapid interruption of ongoing motor actions is crucial to respond to unexpected and potentially threatening situations. Yet, it remains unclear how motor inhibition interacts with emotional processes. Here we used a modified stop signal task including an emotional component (fearful faces) to investigate whether neural circuits engaged by action suppression are modulated by task irrelevant threat-related signals. Behavioral performance showed that reaction times were prolonged in the presence of incidental threat information, and this emotional slowing was enhanced when incorrect responses were made following stop signals. However, the speed and efficacy of voluntary inhibition was unaffected by emotion. Brain imaging data revealed that emotional cues during stop trials interacted with activity in limbic regions encompassing the basal amygdala and sublenticular extended amygdala region, as well as with the supplementary motor area (SMA). In addition, successful motor inhibition to threat signals selectively recruited a region in lateral orbitofrontal cortex, distinct from areas in inferior frontal gyrus typically associated with voluntary inhibition. Activity in primary motor cortex was lower when incorrect responses were made on stop signal trials accompanied by a fearful face, relative to neutral, in parallel with the slower response times observed behaviorally. Taken together, our findings suggest that the amygdala may not only promote protective motor reactions in emotionally-significant contexts (such as freezing or defensive behavior) but also influence the execution of ongoing actions by modulating brain circuits involved in motor control, so as to afford quick and adaptive changes in current behavior. PMID- 21272654 TI - Automated hippocampal shape analysis predicts the onset of dementia in mild cognitive impairment. AB - The hippocampus is involved at the onset of the neuropathological pathways leading to Alzheimer's disease (AD). Individuals with mild cognitive impairment (MCI) are at increased risk of AD. Hippocampal volume has been shown to predict which MCI subjects will convert to AD. Our aim in the present study was to produce a fully automated prognostic procedure, scalable to high throughput clinical and research applications, for the prediction of MCI conversion to AD using 3D hippocampal morphology. We used an automated analysis for the extraction and mapping of the hippocampus from structural magnetic resonance scans to extract 3D hippocampal shape morphology, and we then applied machine learning classification to predict conversion from MCI to AD. We investigated the accuracy of prediction in 103 MCI subjects (mean age 74.1 years) from the longitudinal AddNeuroMed study. Our model correctly predicted MCI conversion to dementia within a year at an accuracy of 80% (sensitivity 77%, specificity 80%), a performance which is competitive with previous predictive models dependent on manual measurements. Categorization of MCI subjects based on hippocampal morphology revealed more rapid cognitive deterioration in MMSE scores (p<0.01) and CERAD verbal memory (p<0.01) in those subjects who were predicted to develop dementia relative to those predicted to remain stable. The pattern of atrophy associated with increased risk of conversion demonstrated initial degeneration in the anterior part of the cornus ammonis 1 (CA1) hippocampal subregion. We conclude that automated shape analysis generates sensitive measurements of early neurodegeneration which predates the onset of dementia and thus provides a prognostic biomarker for conversion of MCI to AD. PMID- 21272656 TI - Monophyletic origin of brood care in damselfishes. AB - The absence of a pelagic larval stage and brood care has evolved very few times in coral reef fishes. Damselfishes, a widely represented group with more than 380 species, includes only three such species, the monotypic Acanthochromis polyacanthus, and the two Altrichthys species, Altrichthys azurelineatus and Altrichthys curatus. In a recent study, Cooper et al. provided a comprehensive phylogenetic hypothesis for the damselfish family, based on mitochondrial and nuclear sequences, with more than 100 species that included all extant genera (Cooper et al., 2009). A. polyacanthus and sequences from formalin-preserved tissue of A. curatus did not cluster together, indicating that brood care may have evolved independently twice in damselfishes. Here, we use mitochondrial and nuclear molecular markers from fresh specimens of both Altrichthys species. We found that Altrichthys and Acanthochromis are closest relatives, which suggests that brood care may have evolved only once in damselfishes. Due to the limited geographic range of Altrichthys (western Philippines) and the abundant presence of Acanthochromis in that region, we also suggest that brood care may have originated in that region. PMID- 21272657 TI - Determinants of range of joint motion in patients with early symptomatic osteoarthritis of the hip and/or knee: an exploratory study in the CHECK cohort. AB - OBJECTIVE: Reduced range of motion (ROM) is supposed to be a characteristic feature of osteoarthritis (OA). Because little is known about determinants of ROM, the objective of the present study was to explore the association between demographic, articular, and clinical factors and ROM in patients with early symptomatic knee and/or hip OA. DESIGN: Baseline data of 598 participants of the Cohort Hip and Cohort Knee (CHECK) study were used in this cross-sectional study. METHODS: Separate analyses were performed for participants with knee and participants with hip symptoms. Active knee flexion, and hip internal rotation, external rotation, flexion, adduction, and abduction were assessed using a goniometer. Participants underwent a standardised physical and radiographic examination, and completed a questionnaire. Exploratory regression analyses were performed to explore the association between ROM and demographic [i.e., age, gender, body mass index (BMI)], articular [i.e., osteophytosis, joint space narrowing (JSN)], and clinical (i.e., pain, stiffness) factors. RESULTS: In patients with early symptomatic knee OA, osteophytosis, bony enlargement, crepitus, pain, and higher BMI were associated with lower knee flexion. JSN was associated with lower ROM in all planes of motion. In addition, osteophytosis, flattening of the femoral head, femoral buttressing, pain, morning stiffness, male gender, and higher BMI were found to be associated with lower hip ROM in two planes of motion. CONCLUSION: Features of articular degeneration are associated with lower knee ROM and lower hip ROM in patients with early OA. Pain, stiffness, higher BMI, and male gender are associated with lower ROM as well. PMID- 21272658 TI - Aberrant genome size and instability of Phytophthora ramorum oospore progenies. AB - The functionality of the sexual cycle in the heterothallic pathogen Phytophthora ramorum, causal agent of Sudden Oak Death, has recently been demonstrated. Sexual reproduction could create genotypic variation and increase the pathogen's ability to adapt to other host plants or changing environments. Genetic characterization using co-dominant microsatellite markers and flow cytometry of single-oospore progeny of crosses between a European A1 isolate and North American or European A2 isolates revealed a considerable number of non-Mendelian inheritance events. This includes inheritance of more than two alleles at a locus and non-inheritance of alleles from one parent at another locus. The progenies were mitotically unstable: zoospore and hyphal tip derivatives of the progenies showed genotypic rearrangements and phenotypic variation. Flow cytometry confirmed variation and instability in DNA content of the single-oospore progenies. This indicates that single-oospore progenies not only display aberrant genomic and phenotypic variation due to meiotic irregularities, but also extra variation as a result of post-meiotic genomic rearrangements. PMID- 21272659 TI - Voluntary and reflex cough: similarities and differences. AB - Cough is defensive airway reflex subjected to a high degree of cortical control. Not surprisingly, all cough motor patterns can be mimicked and reflex cough be inhibited up to complete suppression, at least to a certain extent. Reflex cough differentiates from other airway reflex responses for its characteristic 3-phase motor pattern, and such pattern is maintained when coughing is produced voluntarily. Despite these and some other similarities, voluntary and reflex cough differ in many important respects, suggesting different neural control of the respiratory and non-respiratory musculature implicated in the generation of the cough modalities. This paper focuses the motor features that differentiate voluntary and reflex cough efforts, and highlights the importance of functional assessment of coughing in the diagnostic workup of respiratory and extra respiratory diseases affecting the production of voluntary and reflex cough. PMID- 21272660 TI - Functional implications of the multiple afferent pathways regulating cough. AB - At least 2 airway vagal afferent nerve subtypes can directly initiate coughing upon activation. The capsaicin-insensitive, acid-sensitive mechanoreceptors innervating the larynx, trachea and large bronchi regulate coughing in both conscious and anesthetized animals. Activation of capsaicin-sensitive C-fibers innervating these airways will also produce coughing, but C-fiber dependent cough is prevented entirely by anesthesia. The different stimuli activating these afferent nerve subtypes and their differential sensitivity to anesthesia implies the existence of 2 parallel pathways for cough, and by extension, 2 types of cough, one essential and homeostatic, the second nonessential and pathophysiologic. The basic properties of the afferent nerves regulating cough, their interactions both centrally and peripherally and their responsiveness to tussive stimuli are briefly reviewed. Also reviewed is evidence against the notion of 2 completely separate types of cough regulated by parallel afferent pathways, asserting instead that multiple afferent nerve subtypes contribute to all types of cough. PMID- 21272661 TI - Analysis of micronuclei, histopathological changes and cell proliferation in nasal epithelium cells of rats after exposure to formaldehyde by inhalation. AB - The frequencies of micronuclei (MN), histopathological changes and cell proliferation were determined in the nasal epithelium of male Fischer-344 rats after exposure to formaldehyde (FA) by whole-body inhalation for four weeks (6h/day, 5 days/week). Groups of 12 rats each were exposed to the target concentrations of 0, 0.5, 1, 2, 6, 10 and 15ppm. The micronucleus test (MNT) was performed with nasal epithelial cells prepared from six animals per group. Two thousand cells per animal were analysed for the presence of MN. The other six rats per group were subcutaneously implanted with osmotic pumps containing 5 bromo-2'-deoxyuridine (BrdUrd), three days prior to necropsy. Paraffin sections were made from the nasal cavity (four levels) of these animals for histopathology and cell-proliferation measurements. The frequency of cells with MN was not increased in any of the groups. However, there was also no induction of MN in nasal cells of rats exposed to a single dose of cyclophosphamide (CP, 20mg/kg) by gavage and analysed 3, 7, 14 or 28 days after the treatment. In contrast, nasal epithelial cells from rats exposed to 10 or 15ppm FA vapour showed clear site specific pathological changes (focal epithelial degeneration, inflammation and squamous metaplasia) in a decreasing gradient (anterior to posterior). Analysis of slides after anti-BrdUrd antibody staining clearly indicated increased cell proliferation (unit length labelling indices, ULLI) after exposure to 6ppm and higher. No treatment-related effects were measured after exposure to 0.5, 1 and 2ppm. When comparing the cell-proliferation rate of normal epithelium with that of directly adjacent metaplastic epithelium, no consistent pattern was found: depending on the location, cell proliferation of normal epithelia was either higher or lower. Our results support previous findings demonstrating local cytotoxic effects in the nose of rats after inhalation of FA. However, induction of MN in the nasal epithelium as an indicator of a mutagenic effect was not seen. Because only limited experience exists for the MNT with rat nasal epithelial cells, this result has to be interpreted with great care. The contribution of mutagenicity to FA's carcinogenicity in rat nasal epithelium remains unclear. PMID- 21272662 TI - Distribution of serotonin (5-HT) and its receptors in the insect brain with focus on the mushroom bodies: lessons from Drosophila melanogaster and Apis mellifera. AB - The biogenic amine serotonin (5-hydroxytryptamine, 5-HT) plays a key role in regulating and modulating various physiological and behavioral processes in both protostomes and deuterostomes. The specific functions of serotonin are mediated by its binding to and subsequent activation of membrane receptors. The vast majority of these receptors belong to the superfamily of G-protein-coupled receptors. We report here the in vivo expression pattern of a recently characterized 5-HT(1) receptor of the honeybee Apis mellifera (Am5-HT(1A)) in the mushroom bodies. In addition, we summarize current knowledge on the distribution of serotonin and serotonin receptor subtypes in the brain and specifically in the mushroom bodies of the fruit fly Drosophila melanogaster and the honeybee. Functional studies in these two species have shown that serotonergic signaling participates in various behaviors including aggression, sleep, circadian rhythms, responses to visual stimuli, and associative learning. The molecular, pharmacological, and functional properties of identified 5-HT receptor subtypes from A. mellifera and D. melanogaster will also be summarized in this review. PMID- 21272663 TI - Novel Cu(II)-RGD-octapeptides: Synthesis, coordination mode, in vitro anti platelet aggregation/in vivo anti-thrombotic evaluation and correlation of sequence with nano-structure. AB - The synthesis, bioassays and nano-structure characterization of Cu(II)-RGD octapeptide complexes Cu(II)-Arg-Gly-Asp-Ser-Arg-Gly-Asp-Ser [Cu(II)-4a], Cu(II) Arg-Gly-Asp-Val-Arg-Gly-Asp-Val [Cu(II)-4b] and Cu(II)-Arg-Gly-Asp-Phe-Arg-Gly Asp-Phe [Cu(II)-4c] were investigated. UV-vis, CD and CD/ESI-MS spectra suggested that the coordination of Cu(II)-4a-c met a 3 N mode. In the in vitro anti platelet aggregation assay the IC(50) values of Cu(II)-RGD-octapeptide complexes were 10 - 110 folds lower than that of RGD-octapeptides. In the in vivo anti thrombotic assay the effective dose of Cu(II)-RGD-octapeptide complexes was 5000 folds lower than that of RGD-octapeptides. In transmission electron microscopy measurement Cu(II)-4a-c offered distinct nano-images. The effect of the sequence on the in vitro anti-platelet aggregation/in vivo anti-thrombotic activity and the nano-structure of Cu(II)-4a-c was discussed. FROM THE CLINICAL EDITOR: This basic science paper discusses the synthesis, coordination mode, in vitro anti platelet aggregation and in vivo anti-thrombotic evaluation of novel Cu(II)-RGD octapeptides. PMID- 21272664 TI - Portable nanofiber meshes dictate cell orientation throughout three-dimensional hydrogels. AB - In this study, a new technique that controls individual cell orientation using nanofiber meshes within three-dimensional (3D) hydrogels is reported. Highly aligned and fragile electrospun nanofibers (average diameter 500 nm) were manufactured into portable and handleable meshes with average line density of 45 nanofibers per 100 MUm and thickness ranging between 0.5 and 3.0 MUm. Through a facile and reproducible fabrication process, the nanofiber meshes can be incorporated into 3D hydrogels via a bottom-up, layer-by-layer assembly process, resulting in macroscopic and highly organized scaffolds. The nanofibers dictated the orientation of the cytoskeleton of individual cells in a very precise manner, allowing altering of the orientation of a cell population throughout the thickness of the hydrogel. Addition of nanofibers affected cell phenotype and protein synthesis. This nanofiber-cell-hydrogel composite enables replication of the cellular and matrix architecture found in many natural tissues, offering a novel protocol for electrospun nanofibers in regenerative medicine and bioengineering. FROM THE CLINICAL EDITOR: A novel protocol for highly organized nanofiber meshes incorporated into 3D hydrogels can be used to direct the overlying cell population cytoskeleton direction, phenotype, and protein synthesis. Nanospun matrices offers a significant advancement for controlled tissue bioengineering and regenerative medicine applications. PMID- 21272665 TI - Cetuximab-labeled liposomes containing near-infrared probe for in vivo imaging. AB - A new liposome-based near-infrared probe that combines both imaging and targeting abilities was developed for application in medical imaging. The near-infrared fluorescent molecule indocyanine green (ICG), and the cetuximab monoclonal antibody for epidermal growth factor receptor (EGFR) were attached to liposomes by passive adsorption. It was found that ICG molecules adsorbed to the liposomes are more fluorescent than free ICG and have a larger quantum yield. Cetuximab adsorbed fluorescent liposomes preserved EGFR recognition, as is evident from internalization and selective binding to A431 colon carcinoma cells overexpressing EGFR. The binding of cetuximab-targeted fluorescent liposomes to A431 compared with IEC-6 cells (normal enterocytes expressing physiological EGFR levels) was greater by a factor of 3.5, ensuring imaging abilities with available fluorescent equipment. Due to relatively high quantum yield and specific tumor cell-recognizing ability, this technology deserves further in vivo evaluation for imaging and diagnostic purposes. FROM THE CLINICAL EDITOR: A new liposome-based near-infrared probe combining both imaging and targeting abilities is reported. Due to relatively high quantum yield and EGFR-expressing tumor cell specificity, this technology deserves further in vivo evaluation for imaging and diagnostic purposes. PMID- 21272666 TI - Modulation of collagen alignment by silver nanoparticles results in better mechanical properties in wound healing. AB - Our previous study has revealed that silver nanoparticles (AgNPs) have potential to promote wound healing by accelerated re-epithelization and enhanced differentiation of fibroblasts. However, the effect of AgNPs on the functionality of repaired skin is unknown. The aim of this study was to explore the tensile properties of healed skin after treatment with AgNPs. Immunohistochemical staining, quantitative assay and scanning electron microscopy (SEM) were used to detect and compare collagen deposition, and the morphology and distribution of collagen fibers. Our results showed that AgNPs improved tensile properties and led to better fibril alignments in repaired skin, with a close resemblance to normal skin. Based on our findings, we concluded that AgNPs were predominantly responsible for regulating deposition of collagen and their use resulted in excellent alignment in the wound healing process. The exact signaling pathway by which AgNPs affect collagen regeneration is yet to be investigated. FROM THE CLINICAL EDITOR: The aim of this study was to explore the tensile properties of healed skin after treatment with AgNPs. These nanoparticles improved tensile properties and led to better fibril alignments in repaired skin, with a close resemblance to normal skin. The exact signaling pathway by which AgNPs affect collagen regeneration is yet to be investigated. PMID- 21272667 TI - Micellar nanomedicine of human neuropeptide Y. AB - Human neuropeptide Y (NPY) is an important biologics that regulates a multitude of physiological functions and could be amenable to therapeutic manipulations in certain disease states. However, rapid (within minutes) enzymatic degradation and inactivation of NPY precludes its development as a drug. Accordingly, we determined whether self-association of NPY with biocompatible and biodegradable sterically stabilized phospholipid micelles (SSM) improves its stability and bioactivity. We found that in saline NPY spontaneously aggregates; however, in the presence of SSM it self-associates with the micelles as monomers. Three NPY molecules self-associate with 1 SSM at saturation. This process stabilizes the peptide in alpha-helix conformation, abrogates its degradation by dipeptidyl peptidase-4 and potentiates NPY-induced inhibition of cAMP elaboration in SK-N-MC cells. Collectively, these data indicate that self-association of NPY with SSM stabilizes and protects the peptide in active monomeric conformation, thereby amplifying its bioactivity in vitro. We propose further development of NPY in SSM as a novel, long-acting nanomedicine. FROM THE CLINICAL EDITOR: Human neuropeptide Y (NPY) regulates a multitude of physiological functions and could be amenable to therapeutic manipulations, which is currently limited by its short half life. Self-association of NPY with spherically stabilized micelles (SSM) protects and stabilizes the peptide in active monomeric conformation, thereby amplifying its bioactivity in vitro, enabling future therapeutic considerations. PMID- 21272668 TI - Cancer-cell-specific cytotoxicity of non-oxidized iron elements in iron core-gold shell NPs. AB - Gold-coated iron nanoparticles (NPs) selectively and significantly (P <0.0001) inhibit proliferation of oral- and colorectal-cancer cells in vitro at doses as low as 5 MUg/mL, but have little adverse effect on normal healthy control cells. The particle treatment caused delay in cell-cycle progression, especially in the S-phase. There was no significant difference in the NP uptake between cancer and control cells, and cytotoxicity resulted primarily from the iron core, before oxidation, rather than from the Fe ions released from the core. In contrast with magnetic NPs that usually serve as drug carriers, diagnostic probes or hyperthermia media, the iron, before oxidation, in the NPs selectively suppressed cancer cell growth and left healthy control cells unaffected in vitro and in vivo. This novel nanomaterial holds great promise as a therapeutic tool in nanomedicine. FROM THE CLINICAL EDITOR: Gold-coated iron nanoparticles (NPs) selectively suppressed squamous cell carcinoma (SCC) and colorectal cancer (CRC) cell growth, but left healthy control cells unaffected both in vitro and in vivo. The particles were equally uptaken by all cells, but delayed cell progression only for cancer cells. The origin is related to the iron core: neither iron ions nor the oxidized NPs have the same outcome. PMID- 21272669 TI - Polyethylenimine-conjugated gold nanoparticles: Gene transfer potential and low toxicity in the cornea. AB - This study examined the gene transfer efficiency and toxicity of 2-kDa polyethylenimine conjugated to gold nanoparticles (PEI2-GNPs) in the human cornea in vitro and rabbit cornea in vivo. PEI2-GNPs with nitrogen-to-phosphorus ratios of up to 180 exhibited significant transgene delivery in the human cornea without altering the viability or phenotype of these cells. Similarly, PEI2-GNPs applied to corneal tissues collected after 12 hours, 72 hours, or 7 days exhibited appreciable gold uptake throughout the rabbit stroma with gradual clearance of GNPs over time. Transmission electron microscopy detected GNPs in the keratocytes and the extracellular matrix of the rabbit corneas. Additionally, slit-lamp biomicroscopy in live animals even 7 days after topical PEI2-GNP application to the cornea detected no inflammation, redness, or edema in rabbit eyes in vivo, with only moderate cell death and immune reactions. These results suggest that PEI2-GNPs are safe for the cornea and can potentially be useful for corneal gene therapy in vivo. FROM THE CLINICAL EDITOR: This study examined the gene transfer efficiency and toxicity of 2-kDa polyethylenimine conjugated to gold nanoparticles in the human cornea in vitro and rabbit cornea in vivo. The results suggest that PEI2-GNPs are safe for the cornea and can potentially be useful for corneal gene therapy in vivo. PMID- 21272670 TI - Characterization and expression of a novel Frizzled 9 gene in Schistosoma japonicum. AB - Wnt signaling regulates a diverse array of eukaryotic development processes, which are mediated by the Frizzled family receptors. However, the role of this signaling pathway in the development of Schistosoma japonicum remains poorly understood. We isolated a novel S. japonicum Frizzled member (SjFz9), which encodes a 923 amino acid protein, sharing the general feature of Frizzled proteins. We investigated its mRNA and protein expression patterns during different life stages in definitive hosts. Quantitative real-time PCR analysis revealed that SjFz9 transcripts were highly expressed in the schistosomulum. In adult stages, SjFz9 expression exhibited high level at day 23 and day 42 in both male and female, compared to other adult stages. The immunohistochemical localization pattern of the SjFz9 protein showed a broad tissue distribution in the subtegumental musculature and acetabulum musculature of schistosomulum and adult worms. Furthermore, SjFz9 was found prominently expressed in the testes of the male and the ovary as well as the vitellarium of the female. Our data suggest that SjFz9 may be an important Wnt receptor with potential functions in regulating the cell differentiation and proliferation within the musculature, as well as the development of the reproductive organs of both sexes. PMID- 21272671 TI - Macromolecular deterioration as the ultimate constraint on human lifespan. AB - A number of tissues and organs in the human body contain abundant proteins that are long-lived. This includes the heart, lung, brain, bone and connective tissues. It is proposed that the accumulation of modifications to such long-lived proteins over a period of decades alters the properties of the organs and tissues in which they reside. Such insidious processes may affect human health, fitness and ultimately may limit our lifespan. The human lens, which contains proteins that do not turnover, is used to illustrate the impact of these gradual deleterious modifications. On the basis of data derived from the lens, it is postulated that the intrinsic instability of certain amino acid residues, which leads to truncation, racemisation and deamidation, is primarily responsible for the age-related deterioration of such proteins. Since these post-translational modifications accumulate over a period of many years, they can only be studied using organisms that have lifespans measured in decades. One conclusion is that there may be important aspects of human aging that can be studied only using long lived animals. PMID- 21272672 TI - Synergistic enhancement of human bone marrow stromal cell proliferation and osteogenic differentiation on BMP-2-derived and RGD peptide concentration gradients. AB - Rational design of bioactive tissue engineered scaffolds for directing bone regeneration in vivo requires a comprehensive understanding of cell interactions with the immobilized bioactive molecules. In the current study, substrates possessing gradient concentrations of immobilized peptides were used to measure the concentration-dependent proliferation and osteogenic differentiation of human bone marrow stromal cells. Two bioactive peptides, one derived from extracellular matrix protein (ECM), GRGDS, and one from bone morphogenic protein-2 (BMP-2), KIPKASSVPTELSAISTLYL, were found to synergistically enhance cell proliferation, up-regulate osteogenic mRNA markers bone sialoprotein (BSP) and Runt-related transcription factor 2, and produce mineralization at densities greater than 130 pmol cm(-2) (65 pmol cm(-2) for each peptide). In addition, COOH-terminated self assembled monolayers alone led to up-regulated BSP mRNA levels at densities above 200 pmol cm(-2) and increased cell proliferation from day 3 to day 14. Taking further advantage of both the synergistic potentials and the concentration dependent activities of ECM and growth-factor-derived peptides on proliferative activity and osteogenic differentiation, without the need for additional osteogenic supplements, will enable the successful incorporation of the bioactive species into biorelevant tissue engineering scaffolds. PMID- 21272673 TI - Role of toll-like receptor 4 in the inflammation reaction surrounding silicone prosthesis. AB - The inflammation which occurs around the silicone prosthesis is a complex process that can provoke the failure of the device and compromise the health of the implanted patient. Toll-like receptors (TLRs), which are transmembrane proteins, are now known to act in the innate immune response and in endogenous inflammation. The aim of our study was to assess the role of TLR4 in the foreign body reaction to a silicone shell prosthesis. Disks of shell silicone prosthesis were implanted in the subcutaneous tissue of C57BL6-TLR4-/- and C57BL6-WT mice. At day 14, inflammatory cell infiltrate and vessel sections around the prosthesis were less numerous in TLR4-/- than in WT mice. A histomorphometric analysis showed that the capsule around the implant was 1.96-fold less thick in depleted TLR4 than in wild-type mice. In addition, vascular endothelial growth factor and transforming growth factor 1 were underexpressed in the surrounding tissue of the prosthesis in TLR4-/- mice. Our study suggests, from this foreign body response model against silicone in mice, that TLR4 plays a key role in the reaction process around silicone implants. PMID- 21272674 TI - The impact of the EU regulatory constraint of transgenic crops on farm income. AB - World population and the need for nutritious food continue to grow. For 14 years farmers from a range of countries across the globe have been accessing transgenic technologies either to reduce crop production costs, increase yield and/or to exploit a range of rotational benefits. In 2009 134 Mha of transgenic crops was grown. The arable area of the EU 27 is approximately 102 Mha; however, only about 0.1 Mha of transgenic crops, mainly maize in Spain, is grown in the EU. This is in part due to limited approvals before the establishment of a moratorium on the cultivation of transgenic crops. In this paper we estimate the revenue foregone by EU farmers, based on the potential hectarages of IR and HT transgenic crops that have been economically successful elsewhere if they were to be grown in areas of the EU where farmers could expect an overall financial benefit. This benefit would accrue primarily from reduced input costs. We estimate that if the areas of transgenic maize, cotton, soya, oil seed rape and sugar beet were to be grown where there is agronomic need or benefit then farmer margins would increase by between ?443 and ?929 M/year. It is noted that this margin of revenue foregone is likely to increase if the current level of approval and growth remains low, as new transgenic events come to market and are rapidly taken up by farmers in other parts of the world. PMID- 21272675 TI - High resolution TOF MS coupled to CE for the analysis of isotopically resolved intact proteins. AB - Intact protein analysis by mass spectrometry is of great interest for the characterisation of biotechnological products. Exact mass measurement in combination with isotopic resolution allows the detection of modifications leading to small mass changes like deamidation or reduction of disulfide bonds directly on the level of the intact protein. Here, a concept is presented based on time-of-flight mass spectrometry. A bench top TOF MS and a high resolution TOF MS were used to resolve the isotopes of intact recombinant human growth hormone and intact human erythropoietin, respectively. Thus, these 22 and around 30kDa large proteins can be characterised sensitively in great detail and along with capillary electrophoretic separation unambiguous identification of minor protein modifications like deamidation is possible. PMID- 21272677 TI - Administration of adenovirus encoding anti-CD20 antibody gene induces B-cell deletion and alleviates lupus in the BWF1 mouse model. AB - Increasing evidence demonstrates that pathological B cells play an essential role in the triggering and development of human systemic lupus erythematosus (SLE). A rational strategy for treating SLE might be to delete B cells thereby suppressing autoimmunity. Commercial monoclonal anti-CD20 antibody is widely used for treatment of B cell-related autoimmune disorders. However its long term use is limited by several factors including short half-life, high cost, and possible side effects of antibody protein therapy. Therefore, we constructed a recombinant adenovirus encoding the murine anti-CD20 antibody gene, and used it to immunize lupus-prone (BWF1) mice. Our data demonstrated that administration of adenovirus encoding the murine anti-CD20 antibody gene generated murine anti-CD20 antibody, which resulted in elimination of B cells in BWF1 mice. In addition, the anti-CD20 reduced serum anti-dsDNA antibody levels, impeded the development of proteinuria and improved the survival of BWF1 mice. These findings suggested that the adenovirus encoding murine anti-CD20 antibody gene might provide an alternative strategy for B cell-mediated diseases. PMID- 21272676 TI - PHOSPHO1 is essential for mechanically competent mineralization and the avoidance of spontaneous fractures. AB - Phosphatases are essential for the mineralization of the extracellular matrix within the skeleton. Their precise identities and functions however remain unclear. PHOSPHO1 is a phosphoethanolamine/phosphocholine phosphatase involved in the generation of inorganic phosphate for bone mineralization. It is highly expressed at sites of mineralization in bone and cartilage. The bones of Phospho1(-/-) mice are hypomineralized, bowed and present with spontaneous greenstick fractures at birth. In this study we show that PHOSPHO1 is essential for mechanically competent mineralization that is able to withstand habitual load. Long bones from Phospho1(-/-) mice did not fracture during 3-point bending but deformed plastically. With dynamic loading nanoindentation the elastic modulus and hardness of Phospho1(-/-) tibiae were significantly lower than wild type tibia. Raman microscopy revealed significantly lower mineral:matrix ratios and lower carbonate substitutions in Phospho1(-/-) tibia. The altered dihydroxylysinonorleucine/hydroxylysinonorleucine and pyridinoline/deoxypyridinoline collagen crosslink ratios indicated possible changes in lysyl hydroxylase-1 activity and/or bone mineralization status. The bone formation and resorption markers, N-terminal propeptide and C-terminal telopeptide of Type I collagen, were both increased in Phospho1(-/-) mice and this we associated with increased bone remodeling during fracture repair or an attempt to remodel a mechanically competent bone capable of withstanding physiological load. In summary these data indicate that Phospho1(-/-) bones are hypomineralized and, consequently, are softer and more flexible. An inability to withstand physiological loading may explain the deformations noted. We hypothesize that this phenotype is due to the reduced availability of inorganic phosphate to form hydroxyapatite during mineralization, creating an undermineralized yet active bone. PMID- 21272678 TI - Isoforskolin pretreatment attenuates lipopolysaccharide-induced acute lung injury in animal models. AB - Isoforskolin was isolated from Coleus forskohlii native to Yunnan in China. We hypothesize that isoforskolin pretreatment attenuates acute lung injury induced by lipopolysaccharide (endotoxin). Three acute lung injury models were used: situ perfused rat lung, rat and mouse models of endotoxic shock. Additionally, lipopolysaccharide stimulated proinflammatory cytokine production was evaluated in human mononuclear leukocyte. In situ perfused rat lungs, pre-perfusion with isoforskolin (100, and 200 MUM) and dexamethasone (65 MUM, positive control) inhibited lipopolysaccharide (10 mg/L) induced increases in lung neutrophil adhesion rate, myeloperoxidase activity, lung weight Wet/Dry ratio, permeability surface area product value, and tumor necrosis factor (TNF)-alpha levels. In rats, pretreatments with isoforskolin (5, 10, and 20 mg/kg, i.p.) and dexamethasone (5mg/kg, i.p.) markedly reduced lipopolysaccharide (6 mg/kg i.v.) induced increases of karyocyte, neutrophil counts and protein content in bronchoalveolar lavage fluid, and plasma myeloperoxidase activity. Lung histopathology showed that morphologic changes induced by lipopolysaccharide were less pronounced in the isoforskolin and dexamethasone pretreated rats. In mice, 5 mg/kg isoforskolin and dexamethasone caused 100% and 80% survival, respectively, after administration of lipopolysaccharide (62.5mg/kg, i.v., 40% survival if untreated). In human mononuclear leukocyte, isoforskolin (50, 100, and 200 MUM) and dexamethasone (10 MUM) pre-incubation lowered lipopolysaccharide (2 MUg/mL) induced secretion of the cytokine TNF-alpha, and interleukins (IL)-1beta, IL-6, and IL-8. In conclusion, pretreatment with isoforskolin attenuates lipopolysaccharide-induced acute lung injury in several models, and it is involved in down-regulation of inflammatory responses and proinflammatory cytokines TNF-alpha, IL-1beta, IL-6, and IL-8. PMID- 21272679 TI - Letter from the editors: Controversies and changing concepts in thyroid cancer management. PMID- 21272681 TI - Lymph node dissection in papillary thyroid carcinoma. AB - The management of papillary thyroid carcinoma continues to evolve. Although the debate over the extent of thyroidectomy has largely faded, the role of elective neck dissection in the surgical management of papillary thyroid cancer has become a topic of contention. The current standard of care for patients with papillary thyroid cancer includes total thyroidectomy and a therapeutic lymph node dissection for patients presenting with clinically evident nodal disease. However, many surgeons advocate prophylactic central neck lymph node dissections in patients who present with no clinical or radiographic evidence of lymph node involvement. Proponents of prophylactic central compartment neck dissection argue that the incidence of central neck metastases is high and the sensitivity of preoperative ultrasound is low. Furthermore, central neck dissection advocates argue that clearing the central neck at the initial operation improves staging accuracy, assists in deciding on postoperative radioactive iodine treatment, and potentially avoids a higher-risk reoperative central neck dissection. Selective lateral neck dissections, as well as modified radical neck dissections, are accepted as necessary therapy in patients with clinically or radiographically positive lateral compartment disease. An essential component of any discussion on the extent of lymphadenectomy is whether patients derive any additional benefit from having a lymphadenectomy with total thyroidectomy and whether this can be done without significantly increasing the morbidity of the operation. Here we discuss the surgical options for approaching lymphadenectomy in patients presenting with papillary thyroid carcinoma. PMID- 21272682 TI - Similarities and differences in follicular cell-derived thyroid cancer management guidelines used in Europe and the United States. AB - The management of thyroid cancer has become more refined and complex over the last thirty years. In an effort to provide guidance to both clinicians and patients, several organizations have developed clinical management guidelines that provide specific advice regarding the diagnosis, treatment and follow-up of differentiated thyroid cancer. In this review, we compare and contrast the major management recommendations provided in the guidelines of the European Thyroid Association with those published by thyroid cancer specialty organizations in the United States (American Thyroid Association and National Comprehensive Cancer Network). By carefully examining treatment and management approaches that are applied in other areas of the world, we can identify equally effective alternative treatment or follow-up options that may find applicability to specific patients in our own practice. Despite significant difference in cultures, economies, and health care delivery systems, thyroid cancer management recommendations from the European experts and the American experts are far more similar than they are different. Each of the guidelines strongly endorses an initial management approach that is guided by individualized estimates of risk of recurrence and risk of death. Furthermore, follow up and additional therapeutic recommendations are based on revised risk estimates that reflect an individual patient's response to therapy. PMID- 21272683 TI - To ablate or not to ablate: issues and evidence involved in 131I ablation of residual thyroid tissue in patients with differentiated thyroid carcinoma. AB - Ablation of residual thyroid tissue after total or near-total thyroidectomy is widely accepted by many practitioners and endorsed by relevant professional societies in the United States and the international community for patients with defined risk factors, including age greater than 45 years, large tumors; tumors with undesirable histopathology; lymph node involvement; positive surgical margins; gross and possibly microscopic extrathyroidal extension; and, of course, evidence or suspicion of distal metastases, including mediastinal lymphadenopathy, pulmonary or osseous metastases or involvement of other organs. (131)I therapy doses of 3.7-5.5 GBq (100-150 mCi) should be used, and additional activity should be used in the event there are additional findings on pretreatment whole-body scans. Depending upon the patient's age, general medical condition, and renal function, nuclear medicine practitioners should be prepared to perform whole body (blood or bone marrow) dosimetry in the event doses >5.5 GBq (150 mCi) are being considered to assure patient safety. Still unresolved is the role of (131)I ablation in the so-called "low risk" patient--particularly in a patient who has undergone a near-total thyroidectomy in the hands of a skilled surgeon. If an ablative dose is to be administered, 0.9-1.8 MBq (25-50 mCi) appears to be sufficient to eliminate most if not all thyroid tissue. The problem is defining the "low-risk" patient. After review of the extensive literature on this subject, it appears that the thoughtful and informed practitioner must make a patient specific decision in this setting on the basis of his/her experience and review of the details in each case and continue to review the evidence on this subject as it becomes available. PMID- 21272684 TI - Thyroid stunning: fact or fiction? AB - Stunning of thyroid tissue by diagnostic activities of (131)I has been described by some investigators and refuted by others. The support both for and against stunning has at times been enthusiastic and vigorous. We present the data from both sides of the debate in an attempt to highlight the strengths and deficiencies in the investigations cited. Clinical, animal, and in vitro studies are included. There are considerable differences in clinical practice, such as the administered activity for diagnostic whole-body scan, delay between diagnostic scan and treatment, time between treatment and posttherapy scanning, and timing of follow-up studies, that have to be analyzed with care. Other factors that often cannot be judged, such as levels of thyroid-stimulating hormone and serum iodine at time of diagnostic testing versus treatment could have an influence on stunning. Larger diagnostic doses and longer delays to therapy appear to increase the likelihood of stunning. The stunning effect of early-absorbed radiation from the therapy should also be considered. PMID- 21272685 TI - The problem of the patient with thyroglobulin elevation but negative iodine scintigraphy: the TENIS syndrome. AB - The available data upon which to act in caring for patients with functioning thyroid cancer and thyroglobulin elevation/negative iodine scintigraphy (TENIS) are imperfect, almost never coming from randomized, blinded studies. When the serum thyroglobulin exceeds 2-10 ng/mL, one should use the latest imaging equipment available to find metastatic disease, especially in areas in which it is potentially resectable, ie, neck, bone, and occasionally brain, and collaborate with an experienced surgeon in removing such metastases. If one cannot locate operable metastases and/or tumor location remains elusive, empiric high-dose (131)I therapy, preceded by dosimetry, should be considered. There are no randomized studies to prove that this treatment prolongs life, although there is definite evidence of cell killing, because the serum thyroglobulin level frequently diminishes after radioiodine therapy. In selected cases External beam radiotherapy will be helpful when the tumor has been located but cannot be fully removed, for example, with invasion of the trachea, spine, or muscles. There are several tyrosine kinase inhibitors that have shown some effectiveness against the TENIS syndrome, but these should ideally be used in the context of a clinical trial. Tyrosine kinase inhibitor drugs should be preferred to conventional chemotherapy at this time; data on lenalidominde have only appeared in abstract form. The return of NIS function, to permit functioning thyroid cancer with the TENIS syndrome to again concentrate therapeutic amounts of (131)I, remains an elusive goal, with few drugs showing real promise. Gene therapy to restore the function of the NIS gene and enhance cellular immunomodulatory and tumor suppressive activity has not yet succeeded clinically. Physicians caring for patients with the TENIS syndrome are urged to enter them into clinical therapeutic studies whenever possible. PMID- 21272686 TI - Thyroid cancer--indications and opportunities for positron emission tomography/computed tomography imaging. AB - Although thyroid cancer is a comparatively rare malignancy, it represents the vast majority of endocrine cancers and its incidence is increasing. Most differentiated thyroid cancers have an excellent prognosis if diagnosed early and treated appropriately. Aggressive histologic subtypes and variants carry a worse prognosis. During the last 2 decades positron emission tomography (PET) and PET/computed tomography (CT), mostly with fluorodeoxyglucose (FDG), has been used increasingly in patients with thyroid cancers. Currently, the most valuable role FDG-PET/CT exists in the work-up of patients with differentiated thyroid cancer status post thyroidectomy who present with increasing thyroglobulin levels and a negative (131)I whole-body scan. FDG-PET/CT is also useful in the initial (post thyroidectomy) staging of high-risk patients with less differentiated (and thus less iodine-avid and clinically more aggressive) subtypes, such as tall cell variant and Hurthle cell carcinoma, but in particular poorly differentiated and anaplastic carcinoma. FDG-PET/CT may help in defining the extent of disease in some patients with medullary thyroid carcinoma and rising postoperative calcitonin levels. However, FDOPA has emerged as an alternate and more promising radiotracer in this setting. In aggressive cancers that are less amenable to treatment with (131)iodine, FDG-PET/CT may help in radiotherapy planning, and in assessing the response to radiotherapy, embolization, or experimental systemic treatments. (124)Iodine PET/CT may serve a role in obtaining lesional dosimetry for better and more rationale planning of treatment with (131)iodine. Thyroid cancer is not a monolithic disease, and different stages and histologic entities require different approaches in imaging and individualized therapy. PMID- 21272687 TI - Alternative therapeutic approaches in the treatment of primary and secondary dedifferentiated and medullary thyroid carcinoma. AB - The prognosis of patients with surgically unresectable differentiated thyroid tumors deteriorates significantly if radioiodine therapy is or becomes ineffective, considering the limited role of conventional chemotherapies in these patients. Several alternative approaches have been investigated for the treatment of patients with advanced thyroid malignancies in recent years. Among targeted therapies, tyrosine kinase inhibitors have resulted in the most encouraging responses and could soon be, along with redifferentiation therapy, the possible palliative strategies. Radiopeptide therapy, especially with beta emitter-labeled DOTANOC, which shows a great affinity to the somatostatin receptors expressed by thyroid tumor cells, might also be an attractive approach considering its comparatively low rate of side effects. However, the indication should be evaluated on individual basis. Medullary thyroid carcinoma shows a worse overall prognosis compared with the other differentiated thyroid tumors especially because of its natural resistance to radioiodine therapy. However, among possible palliative strategies, (131)I-meta-iodobenzylguanidine therapy is a noteworthy therapeutic approach in patients experiencing metastasized medullary thyroid carcinoma. In summary, recent developments in the treatment of patients with advanced thyroid malignancies have shown promising results, raising the hope for better outcomes in these patients in future. PMID- 21272688 TI - Eating pattern analyses: the whole is more than the sum of its parts. PMID- 21272689 TI - Successes in Washington, still more to accomplish. PMID- 21272690 TI - 2010 Journal reader survey results. PMID- 21272691 TI - It all adds up: nutrition analysis software can open the door to professional opportunities. PMID- 21272692 TI - Is fructose a story of mice but not men? PMID- 21272694 TI - Labeling solid fats and added sugars as empty calories. PMID- 21272696 TI - Understanding the eating behaviors of adolescents: application of dietary patterns methodology to behavioral nutrition research. PMID- 21272697 TI - Multiple sociodemographic and socioenvironmental characteristics are correlated with major patterns of dietary intake in adolescents. AB - BACKGROUND: Few studies have used dietary pattern analysis, a useful method to summarize dietary intake, in adolescents. OBJECTIVE: Examine sociodemographic and socioenvironmental correlates of habitual dietary patterns. DESIGN: Data for this cross-sectional/prospective analysis were drawn from Project EAT (Eating Among Teens), a population-based study. SUBJECTS/SETTING: Project EAT-I (Time 1), collected data on 4,746 adolescents in 1998-1999. Project EAT-II (Time 2) resurveyed 53% (n=2,516) of the original cohort 5 years later in 2003-2004. Dietary intake was assessed using the Youth/Adolescent Food Frequency Questionnaire. MAIN OUTCOME MEASURES/STATISTICAL ANALYSIS PERFORMED: Factor analysis identified four dietary patterns at Time 1 (vegetable, fruit, starchy food, and snack food) and Time 2 (vegetable and fruit, fast food, starchy food, and snack food). Linear regression was used to examine the relationship of Time 1 socioeconomic status and race (mutually adjusted) on factor scores for each dietary pattern, and then of Time 1 socioenvironmental characteristics (adjusted for socioeconomic status and race) on these factor scores. RESULTS: In prospective analyses, socioeconomic status, family meal frequency, and home availability of healthy food were positively associated with the vegetable and fruit and starchy food patterns and inversely associated with the fast food pattern. Home availability of unhealthy food was inversely associated with the vegetable and fruit and starchy food patterns and positively associated with the fast food and snack food patterns. Maternal, paternal, and peer support for healthy eating were positively associated with the vegetable and fruit pattern and inversely associated with the fast food pattern. Similar associations were seen in cross-sectional analyses. CONCLUSIONS: Multiple correlates of dietary patterns were identified. Health professionals should target these factors to improve the dietary quality of habitual eating practices in adolescents by encouraging parents to decrease home availability of unhealthy food while increasing availability of healthy food, family meal frequency, and parental support for healthy eating. PMID- 21272698 TI - Major habitual dietary patterns are associated with acute myocardial infarction and cardiovascular risk markers in a southern European population. AB - BACKGROUND: Most dietary pattern analyses in southern Europe have relied on a priori food approaches using Mediterranean-style diet indexes. These methods may not reflect the current population's food consumption. OBJECTIVE: To assess the association of a posteriori dietary patterns with acute myocardial infarction (AMI) and cardiovascular risk markers in the general adult population of Porto, Portugal. DESIGN: A population-based case-control study was conducted. Information was collected by trained interviewers. Diet was assessed with a validated 82-item food frequency questionnaire. PARTICIPANTS/SETTING: Cases were patients consecutively hospitalized for an incident non-fatal AMI (n=820), and controls were individuals free of previous AMI selected from the hospitals' catchment area (n=2,196). STATISTICAL ANALYSES: Dietary patterns, representing mutually exclusive clusters of individuals, were identified by multivariate finite mixture models among controls. Odds ratios (OR) and their 95% confidence intervals (CIs) were obtained from unconditional logistic regression, with adjustment for main confounders. RESULTS: In comparison to women with a "healthy" dietary pattern, those with a "low fruit and vegetables" pattern and a "red meat and alcohol" (also characterized by lower intake of dairy products and vegetables) pattern showed a higher risk of AMI (OR 1.85, 95% CI 1.01 to 3.39 and OR 1.91, 95% CI 1.17 to 3.12, respectively). Female controls with the "red meat and alcohol" pattern also had a higher total to high-density lipoprotein cholesterol ratio. In comparison to men with a "healthy" pattern, those with the "red meat and alcohol" pattern, similar to the counterpart found in women, were more likely to experience an AMI (OR 1.98, 95% CI 1.35 to 2.92); male controls with this pattern had higher diastolic and systolic blood pressure, C-reactive protein, and uric acid levels. CONCLUSIONS: A dietary pattern with lower fruit and vegetable intakes in women, and a pattern characterized by higher consumption of red meat and alcohol (and lower of dairy products and vegetables) in both sexes, were associated with an increased risk of AMI and adverse cardiovascular risk profiles. These findings highlight the importance of sustained recommendations for fruit and vegetable intake and cautious guidance on consumption of alcoholic beverages, which clusters with less healthy dietary patterns of men and women. PMID- 21272699 TI - Salty-snack eating, television or video-game viewing, and asthma symptoms among 10- to 12-year-old children: the PANACEA study. AB - BACKGROUND: Salty-snack consumption, as well as the amount of time children spend watching television or playing video games, have been implicated in the development of asthma; however, results are still conflicting. OBJECTIVE: The aim of this work was to evaluate the association of salty-snack eating and television/video-game viewing with childhood asthma symptoms. DESIGN: Cross sectional study. SETTINGS: Seven hundred children (323 male), 10 to 12 years old, from 18 schools located in the greater area of Athens were enrolled. Children and their parents completed questionnaires, which evaluated, among other things, dietary habits. Adherence to the Mediterranean diet was evaluated using the KIDMED (Mediterranean Diet Quality Index for Children and Adolescents) score. STATISTICAL ANALYSIS: The association of children's characteristics with asthma symptoms was performed by calculating the odds ratios and corresponding 95% confidence intervals. RESULTS: Overall lifetime prevalence of asthma symptoms was 23.7% (27.6% boys, 20.4% girls; P=0.03). Forty-eight percent of children reported salty-snack consumption (>= 1 times/week). Salty-snack consumption was positively associated with the hours of television/video-game viewing (P=0.04) and inversely with the KIDMED score (P=0.02). Consumption of salty snacks (>3 times/week vs never/rare) was associated with a 4.8-times higher likelihood of having asthma symptoms (95% confidence interval: 1.50 to 15.8), irrespective of potential confounders. The associations of salty-snack eating and asthma symptoms were more prominent in children who watched television or played video games >2 hours/day. In addition, adherence to the Mediterranean diet was inversely associated with the likelihood of asthma symptoms. CONCLUSIONS: Unhealthy lifestyle behaviors, such as salty-snack eating and television/video-game viewing were strongly associated with the presence of asthma symptoms. Future interventions and public health messages should be focused on changing these behaviors from the early stages of life. PMID- 21272700 TI - Diet and asthma: nutrition implications from prevention to treatment. AB - Asthma is characterized by lung airway inflammation initiated and perpetuated by an inappropriate immune response, increased airway responsiveness, and variable airflow obstruction. In Western countries there has been a marked increase in asthma prevalence such that it has become a public health concern. It has been hypothesized that the increase may be due to changing antioxidant intake, increasing dietary ratio of n-6:n-3 polyunsaturated fatty acids (PUFA), and vitamin D deficiency (and supplementation). Observational studies have reported associations between asthma and dietary antioxidants (vitamin E, vitamin C, carotenoids, selenium, polyphenols, and fruit), PUFA, and vitamin D. However, supplementing the diets of adults with asthma with antioxidants and n-3 PUFA has minimal, if any, clinical benefit. Currently there is insufficient evidence to support the use of nutrient supplements to complement conventional treatment; however, results of ongoing studies are awaited, and additional research is required, particularly in children. Interest in the potential of dietary intervention during pregnancy to reduce the likelihood of childhood asthma has increased. A small number of cohort studies have highlighted associations between childhood asthma and reduced maternal intake of some nutrients (vitamin E, vitamin D, selenium, zinc, and PUFA) during pregnancy. Although vitamin D intervention studies during pregnancy are ongoing and two intervention studies suggest that dietary PUFA manipulation during pregnancy may be advantageous, further trials are needed to establish if modification of maternal nutrient intake during pregnancy can be used as a healthy, low cost, public health measure to reduce the prevalence of childhood asthma. PMID- 21272701 TI - Characteristics of family mealtimes affecting children's vegetable consumption and liking. AB - Research has documented an association between family mealtimes and higher dietary quality in school-aged children and adolescents. However, there is little understanding of the specific characteristics of mealtimes that are beneficial and a lack of research with preschool-aged children. This cross-sectional study conducted in the United Kingdom in 2008 examined associations between mealtime characteristics and preschoolers' vegetable consumption and liking. Four hundred and thirty-four primary caregivers of children aged 2 to 5 years reported on children's vegetable intake and liking and completed a questionnaire on frequency of family meals, food preparation, and the social and environmental context of family mealtimes. Univariate and multiple linear regression analyses assessed mealtime variables and children's vegetable intake and liking. Multiple regression analysis revealed children's vegetable consumption was predicted by eating approximately the same food as their parents (beta=.14; P <= 0.01), using ready-made sauces (beta=-.12; P <= 0.05), and cooking from scratch (beta=.11; P <= 0.05), accounting for 21% of the variance (with covariates). Children's liking for vegetables was predicted by eating approximately the same food as their parents (beta=.15; P <= 0.01) and use of preprepared dishes (beta=-.15; P <= 0.01), accounting for 8% of the variance (with covariates). Frequency of family mealtimes was unrelated to children's vegetable consumption or liking in this sample. This contrasts with findings in older children and adolescents, where frequency of family mealtimes is related to dietary quality and intake. In preschool-aged children, it seems emphasis should be placed on encouraging parents to provide home-cooked meals that mirror those eaten by the adults in the family to improve vegetable intake. PMID- 21272702 TI - Associations between neighborhood availability and individual consumption of dark green and orange vegetables among ethnically diverse adults in Detroit. AB - Diets rich in dark-green and orange vegetables have been associated with a reduction in chronic diseases. However, most Americans do not consume the number of daily servings recommended by the 2005 Dietary Guidelines for Americans. An increasing number of studies suggest that changes to the neighborhood food environment may be critical to achieving population-wide improvements in eating. The objective of this study was to examine the relationship between observed neighborhood availability and individual consumption of dark-green and orange vegetables among low- to moderate-income and ethnically diverse adults in Detroit. This study used a cross-sectional design that drew upon a 2002-2003 community survey and 2002 in-person audit of food stores. A total of 919 adults (mean age 46.3 years, 52.2% female) including African Americans (56.7 %), Latinos (22.2%), and whites (18.7%) residing in three Detroit communities participated in the survey. Two-level weighted, hierarchical linear regression was used to analyze the data. On average, survey respondents ate 0.61 daily servings of dark green and orange vegetables. Residents of neighborhoods with no stores carrying five or more varieties of dark-green and orange vegetables were associated with an average of 0.17 fewer daily servings of these foods compared with residents of neighborhoods with two stores carrying five or more varieties of dark-green and orange vegetables (P=0.047). These findings suggest that living in a neighborhood with multiple opportunities to purchase dark-green and orange vegetables may make an important contribution toward meeting recommended intakes. PMID- 21272703 TI - Comparing the nutrient rich foods index with "Go," "Slow," and "Whoa," foods. AB - The US National Heart, Lung, and Blood Institute has grouped foods and beverages into three classes: "Go," "Slow," and "Whoa," as part of a children's guide to eating right. Using nutrient composition data in the 2004 Food and Nutrient Database for Dietary Studies, this descriptive study compared the Go, Slow, and Whoa food classes to tertiles of food rankings generated by the Nutrient Rich Foods Index. A total of 1,045 foods and beverages were first assigned into Go, Slow, and Whoa classes and then ranked by the Nutrient Rich Foods Index nutrient profile model. The Nutrient Rich Foods Index model was based on nine nutrients to encourage: protein, fiber, vitamins A, C, and E, calcium, iron, magnesium, and potassium; and on three nutrients to limit: saturated fat, added sugar, and sodium, all calculated per 100 calories. Both the Go, Slow, and Whoa and the Nutrient Rich Foods Index models readily distinguished between energy-dense and nutrient-rich beverages and foods, and the three Go, Slow, and Whoa classes closely corresponded to tertiles of Nutrient Rich Foods Index scores. There were some disagreements in the class assignment of fortified cereals, some dairy products, and diet beverages. Unlike the Go, Slow, and Whoa model, the Nutrient Rich Foods Index model produced continuous scores that could be used to rank foods within a given class. The study provides an illustration of how diverse nutrient profiling systems can be used to identify healthful foods and beverages. PMID- 21272704 TI - Vitamin, fluoride, and iron use among US children younger than 12 years of age: results from the Slone Survey 1998-2007. AB - Pediatric vitamin and mineral supplements are thought to be used commonly in the United States, but details of their use are lacking. Using data from the Slone Survey (a cross-sectional national random-digit-dial medication use survey), this study sought to define the prevalence and patterns of use of supplemental vitamins, fluoride, and iron among US children younger than 12 years of age. Primary statistical analyses involved descriptive statistics and calculation of weighted prevalence of use estimates with 95% confidence intervals. Between February 1998 and April 2007, there were 2,857 children 0 to 11 years of age enrolled from the 48 contiguous United States with weighted prevalence of use of vitamins, iron, and fluoride as the primary outcome. The response rate to the survey was 61%. Overall, 23.1% of children had used a vitamin, fluoride, or iron supplement in the 7 days before the interview, with use being highest among 2- to 5-year-olds. Almost all vitamins and most fluoride and iron were taken in the form of multicomponent products. The most commonly taken specific vitamins were C, D, B-12, B-6, and B-2, each by >20% of children. Overall, 3.3% of study participants took supplemental fluoride and 9.7% took supplemental iron. In conclusion, this study found that almost one-quarter of US children younger than 12 years of age, and 30% of 2-year-olds, use supplemental vitamins, fluoride, and iron in a given week. These data should be combined with what is known about the need for pediatric supplementation with vitamins, fluoride, and iron to help clinicians and policy makers counsel parents about the optimal use of these products. PMID- 21272705 TI - Increasing the protein content of meals and its effect on daily energy intake. AB - High-protein preloads have been shown to enhance satiety, but little is known about the satiating effects of protein in more typical situations when meals are consumed ad libitum. To investigate the effects of protein in amounts commonly consumed over a day, a crossover study was conducted in 2008. In this experiment, 18 normal-weight women consumed ad libitum lunch and dinner entrees 1 day a week that were covertly varied in protein content (10%, 15%, 20%, 25%, or 30% energy). Entrees were manipulated by substituting animal protein for starchy ingredients and were matched for energy density, fat content, palatability, and appearance. Unmanipulated breakfasts and evening snacks were consumed ad libitum. Participants rated their hunger and fullness before and after meals as well as the taste and appearance of entrees. Data were analyzed using a mixed linear model. Results showed that mean 24-hour protein intake increased significantly across conditions, from 44+/-2 g/day in the 10% protein condition to 82+/-6 g/day in the 30% condition. Daily energy intake did not differ significantly across the 10% to 30% protein conditions (means 1,870+/-93, 1,887+/-93, 1,848+/-111, 1,876+/ 100, and 1,807+/-98 kcal in the 10%, 15%, 20%, 25%, and 30% energy groups, respectively). There were no significant differences in hunger and fullness ratings across conditions or in taste and appearance ratings of the manipulated entrees. This study showed that varying the protein content of several entrees consumed ad libitum did not differentially influence daily energy intake or affect ratings of satiety. PMID- 21272706 TI - Awareness of Federal Dietary Guidance in persons aged 16 years and older: results from the National Health and Nutrition Examination Survey 2005-2006. AB - The National Health and Nutrition Examination Survey 2005-2006 included questions on awareness of the Dietary Guidelines for Americans (DGA), the Food Guide Pyramid, and the 5 A Day for Better Health Program. Prevalence of awareness of federal dietary guidance was estimated and differences were tested across demographic traits, health characteristics, and diet-related attitudes and behavior. The continuous National Health and Nutrition Examination Survey uses a nationally representative cross-sectional sample design. The analytic sample consisted of 5,499 persons aged 16 years and older with complete data. Among persons aged 16 years and older, 83.8% had heard of at least one of the initiatives: 49.2% had heard of the DGA, 80.6% had heard of the Food Guide Pyramid, and 51.2% had heard of the 5 A Day program. There was a linear trend of decreasing awareness of at least one of the guidance efforts with increasing age. Differences by sex, race/ethnicity, education, and income were also observed. Differences by body mass index were not statistically significant; however, significant differences were seen with fatalistic beliefs about body weight. Differences by smoking, self-assessed diet quality, and eating out frequency were not statistically significant after adjustment for sex, age, race/ethnicity, education, and income. These results may be useful in promotion of the upcoming edition of the DGA and to suggest population groups that may benefit from strengthened and more innovative education efforts at the public health program level and at the clinic level. PMID- 21272707 TI - Peanut allergy: case of an 11-year-old boy with a selective diet. PMID- 21272708 TI - Ethics opinion: eliminating dietetics-related inequalities. PMID- 21272710 TI - Is red yeast rice safe and effective for lowering serum cholesterol? PMID- 21272711 TI - Fulfilling the promise: supporting participation in daily life. AB - Participation is a central concept in rehabilitation, and by addressing it in science and practice, rehabilitation professionals and scientists provide a link between biomedical science and care and population health. This lecture traces the history of the development of participation and proposes language that includes, but expands, the International Classification of Functioning, Disability and Health language to foster communication of rehabilitation scientists. It also presents a model of rehabilitation service that focuses on participation that can be developed from evidence generated by rehabilitation scientists. PMID- 21272712 TI - Motivational enhancement therapy in addition to physical therapy improves motivational factors and treatment outcomes in people with low back pain: a randomized controlled trial. AB - OBJECTIVES: To examine whether the addition of motivational enhancement treatment (MET) to conventional physical therapy (PT) produces better outcomes than PT alone in people with chronic low back pain (LBP). DESIGN: A double-blinded, prospective, randomized, controlled trial. SETTING: PT outpatient department. PARTICIPANTS: Participants (N=76) with chronic LBP were randomly assigned to receive 10 sessions of either MET plus PT or PT alone. INTERVENTION: MET included motivational interviewing strategies and motivation-enhancing factors. The PT program consisted of interferential therapy and back exercises. MAIN OUTCOME MEASURES: Motivational-enhancing factors, pain intensity, physical functions, and exercise compliance. RESULTS: The MET-plus-PT group produced significantly greater improvements than the PT group in 3 motivation-enhancing factors; proxy efficacy (P<.001), working alliance (P<.001), and treatment expectancy (P=.011). Furthermore, they performed significantly better in lifting capacity (P=.015), 36 Item Short Form Health Survey General Health subscale (P=.015), and exercise compliance (P=.002) than the PT group. A trend of a greater decrease in visual analog scale and Roland-Morris Disability Questionnaire scores also was found in the MET-plus-PT group than the PT group. CONCLUSION: The addition of MET to PT treatment can effectively enhance motivation and exercise compliance and show better improvement in physical function in patients with chronic LBP compared with PT alone. PMID- 21272713 TI - Inspiratory muscular training in chronic stroke survivors: a randomized controlled trial. AB - OBJECTIVE: To assess the effectiveness of inspiratory muscular training (IMT) on measures of strength, resistance, functional performance, and quality of life (QOL) for chronic stroke survivors. DESIGN: Double-blinded randomized controlled trial. SETTING: Research laboratory. PARTICIPANTS: Subjects (N=21) with stroke (11 men, 10 women; maximal inspiratory pressure [MIP] <90% of predicted values) were randomly assigned to the experimental (n=11) and control groups (n=10); 18 participants completed all testing and training. INTERVENTIONS: Interventions were based on home-based training, with resistance adjusted biweekly to 30% of MIP for the experimental group. The control group underwent the same protocol without the threshold resistance valve. Both groups received home training 30 minutes a day 5 times a week for 8 weeks. MAIN OUTCOME MEASURES: MIP, inspiratory muscular endurance (IME), functional performance, and QOL. RESULTS: There were significant between-group differences for the MIP and IME measures. Significant changes were observed for only the experimental group for MIP (67.8+/-14.6 at baseline to 102.2+/-26.0cmH(2)O at posttraining) and IME (31.8+/-19.3 to 49.2+/ 21.1cmH(2)O). No statistically significant differences were observed for measures of functional performance and QOL. CONCLUSIONS: Significant short-term effects of the IMT program for inspiratory strength and endurance were observed in chronic stroke survivors. These findings gave some indications that IMT may benefit people with stroke, and it is feasible to be included in rehabilitation interventions with this population. PMID- 21272714 TI - Single blind, prospective, randomized controlled trial comparing dorsal aluminum and custom thermoplastic splints to stack splint for acute mallet finger. AB - OBJECTIVE: To compare Stack, dorsal, and custom splinting techniques in people with acute type 1a or b mallet finger. DESIGN: Multi-center randomized controlled trial. SETTING: Outpatient hand therapy clinics (2 public hospitals and 1 private clinic). PARTICIPANTS: Patients (N=64) with acute type 1a or b mallet finger. INTERVENTIONS: Prefabricated Stack splint (control), dorsal padded aluminum splint, or custom-made thermoplastic thimble splint. All were worn for 8 weeks continuously, with a 4 week graduated withdrawal and exercise program. MAIN OUTCOME MEASURES: The primary outcome was extensor lag at 12 and 20 weeks. Secondary outcomes were incidence of treatment failure, complications, range of motion of the distal interphalangeal joint, pain (visual analog scale) patient compliance, and patient satisfaction. RESULTS: There was no difference in the primary outcome between groups at 12 or 20 weeks; however, the Stack and dorsal splints had significant rates of treatment failure (23.8% in both groups, compared to none in the thermoplastic group; P=.04). There was a medium negative correlation between patient compliance and degree of extensor lag. No significant differences between groups were observed for patient satisfaction or pain. CONCLUSIONS: As splints for mallet finger must be worn continuously for 6 to 8 weeks, and compliance correlates with favorable outcomes, treating practitioners must ensure the splint provided is robust enough for daily living requirements and does not cause complications, which are intolerable to the patient. In this study, no extensor lag difference was found between the 3 splint types, but custom-made thermoplastic splints were significantly less likely to result in treatment failure. PMID- 21272715 TI - Effect of plantar vibration stimuli on the balance of older women: a randomized controlled trial. AB - OBJECTIVE: To identify the effect of vibratory stimuli applied to the plantar region on the balance of women 60 years or older. DESIGN: A randomized controlled trial (blinded assessor). SETTING: University research laboratory. PARTICIPANTS: All women (N=30; age, >=60y) selected had a balance deficit, assessed by using the One-Leg Stance test with eyes open (EO). INTERVENTIONS: Participants were randomly divided into an experimental group, which received vibratory stimuli, and a control group, which received no intervention. MAIN OUTCOME MEASURES: Functional reach (FR) test and center-of-pressure (CoP) sway area (force platform). RESULTS: There was a significant difference in the time factor of the experimental group for the FR test and CoP sway area with eyes closed (EC). For the group * time interaction, there was improvement in balance in anterior posterior (AP) CoP sway velocity with EO and EC. There also was improvement in CoP sway area with EC. CONCLUSION: Vibratory stimuli applied to the plantar region have beneficial effects on balance in women 60 years or older, with greater effectiveness in anterior displacement, postural control of the AP axis, and the EC condition. PMID- 21272716 TI - Trajectories in the course of life satisfaction after spinal cord injury: identification and predictors. AB - OBJECTIVE: To identify different life satisfaction trajectories in the period between the start of active spinal cord injury (SCI) rehabilitation and 5 years after discharge, and to find predictors for distinguishing between trajectories. The hypotheses were that different life satisfaction trajectories would be identified and that demographic, lesion, physical, and social characteristics would be predictors of life satisfaction trajectory membership. DESIGN: Multicenter prospective cohort study with measurements at the start of active rehabilitation, after 3 months, at discharge, and 1, 2, and 5 years after discharge. SETTING: Eight Dutch rehabilitation centers with specialized SCI units. PARTICIPANTS: Persons (N=225) with recently acquired SCI between the ages of 18 and 65 years were included, and data from 206 persons were analyzed. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Life satisfaction was measured as the sum score of "current life satisfaction" and "current life satisfaction compared with life satisfaction before SCI" (range, 2-13). RESULTS: Five life satisfaction trajectories were identified by using latent class growth mixture modeling: (1) low median scores (3-5) at all time points (27%), (2) intermediate scores (6-7) at all time points (31%), (3) high scores (8-10.5) at all time points (17%), (4) improvements from 3 to 9 (23%), and (5) deterioration from 9 to 4 (2%). Logistic regression showed that predictors of the low versus high life satisfaction trajectory were functional independence and pain. Predictors of the low life satisfaction versus the recovery trajectory were sex and functional independence. These predictors explained only a small part of the total variance. CONCLUSIONS: Life satisfaction in people with SCI follows distinct trajectories. Monitoring life satisfaction at the start of active rehabilitation and 3 months later might allow identification of persons at risk for poor long-term adjustment. PMID- 21272717 TI - Measuring upper limb capacity in poststroke patients: development, fit of the monotone homogeneity model, unidimensionality, fit of the double monotonicity model, differential item functioning, internal consistency, and feasibility of the stroke upper limb capacity scale, SULCS. AB - OBJECTIVES: To develop an easy-to-use scale that measures upper limb capacity, according to the International Classification of Functioning, Disability and Health definition, in patients after stroke, and to investigate certain psychometric properties of this scale. DESIGN: Cohort study. SETTING: Inpatient department of a rehabilitation center. PARTICIPANTS: Patients (N=546; mean age +/ SD, 60.1+/-11.2y; 56% men) undergoing rehabilitation after stroke. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Mokken scale analysis was used to investigate the following psychometric properties: (1) fit of the monotone homogeneity model, indicating that the items form a scale; (2) unidimensionality, indicating that the items measure only 1 concept (or construct); (3) fit of the double monotonicity model, indicating invariant (hierarchical) item ordering; (4) differential item functioning (DIF), indicating the validity of comparison between subgroups; and (5) internal consistency, indicating the degree of interrelatedness of the items. The mean time needed to complete the scale was calculated to indicate (6) feasibility. RESULTS: The Stroke Upper Limb Capacity Scale (SULCS) was developed on the basis of interviews with experts. Ten of 15 items had (1) good fit of the monotone homogeneity model (coefficient H=.88), were (2) unidimensional, and had (3) good fit of the double monotonicity model (coefficient H(T)=.71), (4) absence of DIF (Crit-values <40), and (5) good internal consistency (coefficient rho=.96). When applying start-and stop rules, the (6) feasibility of the SULCS was good (6min). CONCLUSIONS: The SULCS is an easy-to-use, unidimensional, hierarchical, and internally consistent scale that assesses upper limb capacity in patients after stroke. PMID- 21272718 TI - Lower extremity physical performance, self-reported mobility difficulty, and use of compensatory strategies for mobility by elderly women. AB - OBJECTIVE: To describe the relationship between lower extremity physical performance, self-reported mobility difficulty, and self-reported use of compensatory strategies (CSs) for mobility inside the home. DESIGN: Cross sectional exploratory study. SETTING: Community-dwelling elders. PARTICIPANTS: Disabled, cognitively intact women 65 years or older (N=1002), from the Women's Health and Aging Study I. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: CS scale: no CS, behavioral modifications (BMs) only, durable medical equipment (DME) with or without use of BMs, and any use of human help (HH); and 3 dichotomous CS measures: any CS (vs none); DME+HH (vs BMs only, among users of any CS); any HH (vs DME only, among users of any DME/HH). RESULTS: Self-reported mobility difficulty and physical performance were significantly correlated with one another (r=-.57, P<.0001) and with the CS scale ([r=.51, P<.001] and [r=-.54, P<.0001], respectively). Sequential logistic regressions showed self-reported difficulty and physical performance were significant independent predictors of each category of CS. For the any CS and DME+HH models, the odds ratio for self reported difficulty decreased by approximately 50% when physical performance was included in the model, compared with difficulty alone ([18.0 to 8.6] and [7.3 to 3.8], respectively), but both physical performance and difficulty remained significant predictors (P<.0001). The effects of covariates differed for the various CS categories, with some covariates having independent relationships to CS, and others appearing to have moderating or mediating effects on the relationship of self-reported difficulty or physical performance to CS. CONCLUSIONS: Physical performance, self-reported difficulty, health conditions, and contextual factors have complex effects on the way elders carry out mobility inside the home. PMID- 21272719 TI - Preoperative quadriceps strength as a predictor for short-term functional outcome after total hip replacement. AB - OBJECTIVE: To determine the preoperative strength of the muscle group of the lower extremity that is most important in predicting functional recovery after primary unilateral total hip replacement (THR). DESIGN: Prospective observational study with inception cohort. SETTINGS: Joint care program (hospital care/clinical division of a nursing home/outpatient physical therapy). PARTICIPANTS: Patients (N=55) undergoing primary unilateral THR. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Baseline measures within 2 weeks preoperative and follow-up at 6 and 12 weeks postoperative included isometric strength measurement of the hip (flexors, extensors, abductors, adductors) and knee (flexors, extensors) musculature using a handheld dynamometer. Functional outcome was tested using performance-based (Timed Up and Go Test, 6-Minute Walk Test) and self-report measures (Western Ontario and McMaster Universities Osteoarthritis Index, subscale Physical Function [WOMAC PF], 36-Item Short Form Health Survey subscale Mental Health, visual analog scale for pain). RESULTS: Of the patients (N=55; mean age, 72.7+/-6.8y; 41 women) included; 18 dropped out, leaving 37 patients for analyses. After correction for WOMAC PF score at baseline, body mass index, sex, and age, the preoperative knee extensors strength measure of the operated site was the only muscle group showing a significant effect on functional outcome measured by using the WOMAC PF at 12 weeks postoperatively (R(2)=.355; beta= .105; P for beta=.004). CONCLUSION: Preoperative greater knee extensor strength of the operated site is associated with better physical function, measured by using the WOMAC PF at 12 weeks postoperative. PMID- 21272720 TI - Enhancing muscle force and femur compressive loads via feedback-controlled stimulation of paralyzed quadriceps in humans. AB - OBJECTIVE: To compare paralyzed quadriceps force properties and femur compressive loads in an upright functional task during conventional constant-frequency stimulation and force feedback-modulated stimulation. DESIGN: Crossover trial. SETTING: Research laboratory. PARTICIPANTS: Subjects (N=13; 12 men, 1 woman) with motor-complete spinal cord injury. INTERVENTIONS: Subjects performed 2 bouts of 60 isometric quadriceps contractions while supported in a standing frame. On separate days, subjects received constant-frequency stimulation at 20Hz (CONST) or frequency-modulated stimulation triggered by a change in force (FDBCK). During FDBCK, a computer algorithm responded to each 10% reduction in force with a 20% increase in stimulation frequency. MAIN OUTCOME MEASURES: A biomechanical model was used to derive compressive loads on the femur, with a target starting dose of load equal to 1.5 times body weight. RESULTS: Peak quadriceps force and fatigue index were higher for FDBCK than CONST (P<.05). Within-train force decline was greater during FDBCK bouts, but mean force remained above CONST values (P<.05). As fatigue developed during repetitive stimulation, FDBCK was superior to CONST for maintenance of femur compressive loads (P<.05). CONCLUSIONS: Feedback modulated stimulation in electrically activated stance is a viable method to maximize the physiologic performance of paralyzed quadriceps muscle. Compared with CONST, FDBCK yielded compressive loads that were closer to a targeted dose of stress with known osteogenic potential. Optimization of muscle force with FDBCK may be a useful tactic for future training-based antiosteoporosis protocols. PMID- 21272721 TI - Assessment of breathing patterns and respiratory muscle recruitment during singing and speech in quadriplegia. AB - OBJECTIVES: To explore how respiratory impairment after cervical spinal cord injury affects vocal function, and to explore muscle recruitment strategies used during vocal tasks after quadriplegia. It was hypothesized that to achieve the increased respiratory support required for singing and loud speech, people with quadriplegia use different patterns of muscle recruitment and control strategies compared with control subjects without spinal cord injury. DESIGN: Matched, parallel-group design. SETTING: Large university-affiliated public hospital. PARTICIPANTS: Consenting participants with motor-complete C5-7 quadriplegia (n=6) and able-bodied age-matched controls (n=6) were assessed on physiologic and voice measures during vocal tasks. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Standard respiratory function testing, surface electromyographic activity from accessory respiratory muscles, sound pressure levels during vocal tasks, the Voice Handicap Index, and the Perceptual Voice Profile. RESULTS: The group with quadriplegia had a reduced lung capacity (vital capacity, 71% vs 102% of predicted; P=.028), more perceived voice problems (Voice Handicap Index score, 22.5 vs 6.5; P=.046), and greater recruitment of accessory respiratory muscles during both loud and soft volumes (P=.028) than the able-bodied controls. The group with quadriplegia also demonstrated higher accessory muscle activation in changing from soft to loud speech (P=.028). CONCLUSIONS: People with quadriplegia have impaired vocal ability and use different muscle recruitment strategies during speech than the able-bodied. These findings will enable us to target specific measurements of respiratory physiology for assessing functional improvements in response to formal therapeutic singing training. PMID- 21272722 TI - Revisiting length of stay in stroke rehabilitation in Turkey. AB - OBJECTIVE: To investigate the parameters influencing length of stay (LOS) in stroke rehabilitation in Turkey. DESIGN: Retrospective study. SETTING: Rehabilitation ward in a university hospital, a referral center in the capital of Turkey. PARTICIPANTS: Consecutive inpatient stroke survivors (N=142) after ischemic or hemorrhagic cerebrovascular events rehabilitated in a university rehabilitation center between January 2005 and October 2009. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: The primary study outcome measurement is LOS on the rehabilitation ward. RESULTS: LOS was best predicted by Brunnstrom's motor recovery stages (BMRS) lower extremity on admission, BMRS hand on admission, and the presence of infections (LOS in days = 70.6 - 5 * BMRS lower extremity - 3.2 * BMRS hand + 10.3 * presence of infections [infection; present=2, absent=1]; R(2)=.37). CONCLUSIONS: Motor impairments and infections were the parameters that most affected LOS in stroke rehabilitation. Prevention strategies for infections should be pursued more aggressively. The prevention of infections, which is an essential component of a patient's general well-being, also shortened LOS in stroke rehabilitation. High medical costs urge LOS to shorten in the developing countries hereafter. A national rehabilitation policy should be implemented to reach the same functional outcome with shorter LOS in stroke patients. PMID- 21272723 TI - Relationship between walk tests and parental reports of walking abilities in children with cerebral palsy. AB - OBJECTIVES: To test the strength of association between 2 clinic-based measures of walking ability, the 1-minute walk test (1MWT) and the six-minute walk test (6MWT), and the parental report of usual walking performance, measured by the ABILOCO-Kids logit score, in children with cerebral palsy (CP). DESIGN: Observational study. SETTING: Tertiary level outpatient clinics. PARTICIPANTS: Children and youth with CP (N=60; 32 boys, 28 girls; mean age, 11.2y [range, 5 18y]), Gross Motor Function Classification System (GMFCS) level I to IV. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The 10-item ABILOCO-Kids questionnaire, the 1MWT, and the 6MWT. RESULTS: ABILOCO-Kids logit scores were significantly correlated with the 1MWT (rho=.70, P<.01) and the 6MWT (rho=.70, P<.01) but not with age or sex. Linear models revealed a possibly significant difference in the strength of the relationship of the ABILOCO-Kids logit score with walking distance, depending on GMFCS level (P=.06 1MWT; P=.14 6MWT). The strongest relationship was observed at GMFCS level II, where ABILOCO-Kids score predicted 33% of variance in 1MWT (P=.003) and 31% of 6MWT (P=.003). The weakest relationship was at GMFCS level I, where ABILOCO-Kids score predicted only 5% of the variance in 1MWT (P=.33) and 16% of the variance in 6MWT (P=.08). CONCLUSIONS: Parental perceptions of their child's walking ability in the community correlate with clinic-based walking tests in ambulatory children with CP, providing evidence of convergent validity for the 1MWT and 6MWT. However, parents report a much wider range of walking abilities in children who function at a high level (GMFCS I) than is reflected by their walk test results. PMID- 21272724 TI - Appendicular lean mass does not mediate the significant association between vitamin D status and functional outcome in hip-fracture women. AB - OBJECTIVE: To investigate whether muscle mass mediates the significant association between vitamin D status and functional recovery after hip fracture in women. DESIGN: Observational study. SETTING: Rehabilitation hospital in Italy. PARTICIPANTS: We investigated white women (N=280) of 305 who were consecutively admitted to a rehabilitation hospital because of their first fracture of the hip. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: To assess muscle mass, we measured appendicular lean mass (aLM) by dual-energy x-ray absorptiometry (DXA), 21.2+/-6.2 (mean +/- SD) days after hip fracture occurrence in the 280 women. On the same day, we assessed serum levels of 25-hydroxyvitamin D and parathyroid hormone (PTH). Ability to function in activities of daily living was evaluated by the Barthel Index both before and after acute inpatient rehabilitation. RESULTS: After adjustment for 8 confounders, including age, cognitive impairment, pressure ulcers, neurologic impairment, infections, fracture type, Barthel Index score at admission to rehabilitation, and aLM/height(2) (aLM/ht(2)), 25-hydroxyvitamin D levels were significantly associated both with Barthel Index scores after rehabilitation (P=.003) and their changes during rehabilitation (P=.008). Similar results were obtained when the 25-hydroxyvitamin D/PTH ratio was substituted for 25-hydroxyvitamin D levels. Conversely, aLM/ht(2) was not significantly correlated with Barthel Index scores and their changes during rehabilitation. Furthermore, we found no significant associations between either 25 hydroxyvitamin D levels or the 25-hydroxyvitamin D/PTH ratio and aLM/ht(2). CONCLUSIONS: The significant association between 25-hydroxyvitamin D levels (and 25-hydroxyvitamin D/PTH ratio) and the ability to function in women with hip fractures was not mediated by aLM assessed by DXA. PMID- 21272725 TI - Prediction of peak oxygen consumption from the ratings of perceived exertion during a graded exercise test and ramp exercise test in able-bodied participants and paraplegic persons. AB - OBJECTIVE: To assess the accuracy of predicting peak oxygen consumption (Vo(2)peak) from a graded exercise test (GXT) and a ramp exercise test during arm exercise in able-bodied persons and persons with paraplegia using ratings of perceived exertion (RPEs). DESIGN: Each participant performed a GXT (started at 30W and increased by 15W every 2min) and a ramp exercise test (started at 0W and increased by 15W.min(-1)). SETTING: Universities' laboratories. PARTICIPANTS: Able-bodied men (n=13; mean +/- SD, 27.2+/-4.3y) and men with paraplegia (n=12; 31.1+/-5.7y). Six of the persons with paraplegia had flaccid paralysis as a result of poliomyelitis infection. The other 6 persons had complete spinal cord injuries with neurologic levels at and below T6. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Prediction of Vo(2)peak by extrapolating submaximal oxygen consumption (Vo(2)) and RPE values to RPE 20 on the Borg 6 to 20 RPE scale. RESULTS: This study showed a very strong linear relationship between RPE and Vo(2) during the GXT and the ramp test for able-bodied persons (R(2)>=.95 and R(2)>=.96, respectively) and persons with paraplegia (R(2)>=.96 and R(2)>=.95, respectively). There was no significant difference between measured and predicted Vo(2)peak from RPEs before and including RPE 13, 15, and 17 during the GXT for persons with paraplegia (P>.05). For the able-bodied participants, there was no significant difference between measured and predicted Vo(2)peak from RPEs before and including RPE 15 and 17 during the ramp exercise test (P>.05). CONCLUSION: The GXT provided acceptable predictions of Vo(2)peak for persons with paraplegia, and the ramp test provided acceptable predictions of Vo(2)peak for able-bodied persons. PMID- 21272726 TI - Transcultural adaptation and psychometric properties of a Spanish-language version of physical activity instruments for patients with fibromyalgia. AB - OBJECTIVES: To develop a transcultural adaptation of the Leisure Time Physical Activity Instrument (LTPAI) and the Physical Activity at Home and Work Instrument (PAHWI) in Spanish and to assess their psychometric properties in women with fibromyalgia syndrome (FS). DESIGN: A cross-sectional transcultural adaptation and validation study. SETTING: Testing was completed at the university. PARTICIPANTS: Seventy-five (N=75) women with FS (median age=51y; 25th-75th percentiles, 45-55y) and a median symptom duration of 16 years (25th-75th percentiles, 10-25y) were recruited for the study. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Cognitive function (Paced Auditory Serial Addition Task), physical activity habits (LTPAI, PAHWI, International Physical Activity Questionnaire [IPAQ]), and active energy expenditure using a multiple-sensor body monitor were used for the evaluations. The differences between the readings (test 1 - test 2) and the SD of the differences, intraclass correlation coefficient (ICC), 95% confidence interval (CI) for the ICC, coefficient of repeatability, intrapatient SD, standard error of the mean, minimal detectable change, Wilcoxon signed-rank test, and Bland-Altman graphs were used to examine reliability. The magnitude of the associations between LTPAI-PAHWI and IPAQ, and between LTPAI PAHWI and the body monitoring device, were used to examine the validity of the construct. RESULTS: The median time that the study population spent performing physical activities during their leisure time was 5h/wk (25th-75th percentiles, 3 9h/wk). A satisfactory test-retest reliability was found for the total score of the LTPAI (ICC=.84; 95% CI, .76-.90) and for the workplace subscale of the PAHWI (ICC=.87; 95% CI, .81-.92). A significant association was observed between LTPAI and both the leisure time domain of the IPAQ (rho=.61; P<.001) and the active energy expenditure of the body monitoring device (rho=.27; P=.021). A significant association was found between the workplace subscale of the PAHWI and the work domain of the IPAQ (rho=.58; P<.001) as well as between the subscale for housework of the PAHWI and the domestic domain of the IPAQ (rho=.43; P<.001). However, no association was observed between PAHWI and the SenseWear Armband. CONCLUSIONS: The Spanish version of the LTPAI and PAHWI is understandable, and its administration is feasible in patients with FS. LTPAI can be considered a fairly reliable and valid tool to assess leisure physical activities in Spanish women with FS. The PAHWI does not appear to be a reliable and valid tool to assess physical activities associated with work in Spanish women with FS. Although the PAHWI demonstrated acceptable test-retest reliability for the workplace subscale, a lower reliability was observed for the total score and for the housework subscale. PMID- 21272727 TI - Is fatigue after stroke associated with physical deconditioning? A cross sectional study in ambulatory stroke survivors. AB - OBJECTIVE: To determine the relationship between a measure of fatigue and 2 indices of physical fitness, lower limb extensor power (LLEP) and walking economy. DESIGN: This was a cross-sectional study of patients with stroke. Fatigue was assessed by vitality (VIT) score of the Medical Outcomes Study 36 Item Short-Form Health Survey version 2 (SF-36v2). LLEP of the unaffected limb was measured using a lower leg extensor power rig. Walking economy was calculated by measuring oxygen consumption (mL.kg(-1).m(-1)) during walking at a comfortable speed. Bivariate analyses were performed relating VIT to indices of fitness. Multiple regression analyses were also performed and included age, sex, and either SF-36v2 emotional role function or SF-36v2 mental health, as predictors of VIT. SETTING: Community setting. PARTICIPANTS: Participants (N=66; 36 men; mean age +/- SD, 71.0+/-9.9y) were all community dwelling, had survived a stroke, were able to walk independently, and had completed their stroke rehabilitation. INTERVENTIONS: Not applicable MAIN OUTCOME MEASURES: The main outcome measure is SF-36v2 (VIT), with walking economy and LLEP of the limb unaffected by the stroke being independent variables. RESULTS: Walking economy was not significantly related to VIT (R=-.024, P=.86, n=60). LLEP was positively related to VIT in bivariate analysis (R=.38, P=.003, n=58). After controlling for age, sex, and SF 36 emotional role function (or SF-36v2 mental health if the extreme outlier was excluded), LLEP remained a significant predictor of VIT. CONCLUSIONS: We found an association between fatigue and reduced LLEP. If a larger study confirms these findings, it would support the need to develop and test interventions to increase LLEP as a treatment for fatigue after stroke. PMID- 21272728 TI - Level of evidence in four selected rehabilitation journals. AB - OBJECTIVE: To investigate the methodologic quality and level of evidence of publications in major peer-reviewed general rehabilitation journals (Archives of Physical Medicine and Rehabilitation [APMR], American Journal of Physical Medicine and Rehabilitation [AJPMR], Clinical Rehabilitation [CR], and Physical Therapy [PT]). DESIGN: Descriptive, comparative. MAIN OUTCOME MEASURES: All the articles published in AJPMR, APMR, CR, and PT between January 2005 and December 2009 were investigated. Type of study and level of evidence were recorded for all articles. Selection and assessment of articles were based on the title and abstract by 2 independent raters. RESULTS: The most frequently published reports were randomized controlled trials (12.7%), followed by cross-sectional studies (12.1%), case reports/case series (10.3%), validation studies (9.3%), cohort studies (8.9%), clinical trials (7.5%), case-control studies (6.8%), and other study types (32.4%). When the articles were classified according to their level of evidence, level I studies most frequently appeared in CR (29.1%), followed by PT (11.0%), APMR (10.5%), and AJPMR (7.1%). Most of the meta-analyses (10) were in APMR, and there were none in AJPMR. CONCLUSIONS: Randomized controlled trials and meta-analyses form only a small proportion of articles published in the current rehabilitation literature. The numbers of randomized controlled trials and meta-analysis are comparable with those in other fields. PMID- 21272729 TI - Invited commentary on "Level of evidence in four selected rehabilitation journals". AB - Level of evidence has been studied in 4 selected rehabilitation journals in the article by Kocak, Unver, and Karatosun. However, other journals within the rehabilitation field would also have been relevant to study to get a more comprehensive analysis. Examples of such journals are mentioned in this commentary. The limitations of the traditional impact factor are discussed, and the use of a 5-year impact factor is suggested. The categorization of journals used and the lack of definitions of the categories are criticized. The importance of publishing more randomized controlled trials and systematic reviews in rehabilitation is supported. PMID- 21272730 TI - Sample size calculation in physical medicine and rehabilitation: a systematic review of reporting, characteristics, and results in randomized controlled trials. AB - OBJECTIVE: To assess systematically the reporting of sample size calculation in randomized controlled trials (RCTs) in 5 leading journals in the field of physical medicine and rehabilitation (PM&R). DATA SOURCES: The data source was full reports of RCTs in 5 leading PM&R journals (Journal of Rehabilitation Medicine, Archives of Physical Medicine and Rehabilitation, American Journal of Physical Medicine and Rehabilitation, Clinical Rehabilitation, and Disability and Rehabilitation) between January and December of 1998 and 2008. Articles were identified in Medline. STUDY SELECTION: A total of 111 articles met our inclusion criteria, which include RCTs of human studies in the 5 selected journals. DATA EXTRACTION: Sample size calculation reporting and trial characteristics were collected for each trial by independent investigators. DATA SYNTHESIS: In 2008, 57.3% of articles reported sample size calculation as compared with only 3.4% in 1998. The parameters that were commonly used were a power of 80% and alpha of 5%. Articles often failed to report effect size or effect estimates for sample size calculation. Studies reporting sample size calculation were more likely to describe the main outcome and to have a sample size greater than 50 subjects. The study outcome (positive vs negative) was not associated with the likelihood of sample size reporting. Trial characteristics of the 2 periods (1998 vs 2008) were similar except that in 1998 there were more negative studies compared with 2008. CONCLUSIONS: Although sample size calculation reporting has improved dramatically in 10 years and is comparable with other fields in medicine, it is still not adequate given current publication guidelines. PMID- 21272731 TI - Serial ultrasonographic findings of plantar fasciitis after treatment with botulinum toxin a: a case study. AB - Plantar fasciitis is a common cause of heel pain and is the result of a degenerative process of the plantar fascia at its calcaneal attachment. A case study of a preliminary experience with local injections of botulinum toxin A (BTX A) for the treatment of chronic plantar fasciitis in a 43-year-old woman is presented. We injected the patient with 70 units of BTX-A (0.7mL) in 2 divided doses: 40 units (0.4mL) in the tender region of the heel, and 30 units (0.3mL) in the most tender point of the foot arch. Visual analog scale (VAS) and pressure pain threshold (PPT) were measured to evaluate the efficacy of BTX-A injections. Real-time, high-resolution ultrasonographic findings of the plantar fascia after BTX-A injections were also used for serial follow-ups. After BTX-A injection, decreased VAS values were reported and increased PPT was observed. In ultrasonographic studies, the thickness of the plantar fascia and the hypoechogenicity of the fascia were reduced. Decreased plantar fascia thickness was observed on the first and third week after BTX-A injections. The findings were compatible with the changes in pain assessed by VAS and PPT. Ultrasonographic findings also indicated a progressive decrease in the thickness of the underlying muscle belly. Ultrasonography seems to be a valuable, noninvasive diagnostic tool for the evaluation of plantar fasciitis treated with BTX-A injections. It can offer objective measurements of therapeutic effects and is feasible for serial follow-ups. PMID- 21272732 TI - Near-normal gait pattern with peroneal electrical stimulation as a neuroprosthesis in the chronic phase of stroke: a case report. AB - In recent years, the use of functional electrical stimulation (FES) of the peroneal nerve has increased as an alternative for an ankle-foot orthosis (AFO) to treat stroke-related drop foot. We present a chronic stroke patient demonstrating an almost normal gait pattern with peroneal FES as a neuroprosthesis. A 60-year-old survivor of a right hemisphere infarction 21 months ago, who regularly used a polypropylene AFO, was provided with a surface based peroneal FES device for severe drop foot. In a second instance, he received an implanted FES system because of skin problems with the surface stimulator. With both FES devices, the patient achieved an adequate foot elevation. Moreover, his hip and knee flexion angles during walking increased to normal values and his ankle push-off power increased. His gait pattern became almost symmetrical and less variable than with the AFO. Furthermore, his ability to avoid a sudden obstacle improved to normal values with FES. Our patient showed benefits from peroneal FES beyond what can be attributed to improved foot lift alone. With regard to the potential working mechanisms underlying this response to FES, biomechanical benefits related to improved ankle push-off are suggested as the main mechanism. PMID- 21272733 TI - Equivalent benefits/risks of cervical manipulation and mobilization. PMID- 21272735 TI - Genetic variation in PCLO is associated with prefrontal cortex expression and bipolar disorder. PMID- 21272736 TI - Structural trait markers of bipolar disorder: disruption of white matter integrity and localized gray matter abnormalities in anterior fronto-limbic regions. PMID- 21272737 TI - Unilateral RS3PE with young-onset rheumatoid arthritis. PMID- 21272739 TI - Food and Chemical Toxicology. Editorial. PMID- 21272738 TI - Camillo Golgi and modern neuroscience. PMID- 21272740 TI - [Editorial. The choice to maintain the French language]. PMID- 21272741 TI - Right-to-left shunting in the right lateral decubitus and upright positions: a variant of platypnea-orthodeoxia syndrome. PMID- 21272742 TI - Percutaneous leaflet repair and annuloplasty for mitral regurgitation. AB - Percutaneous therapy for the treatment of mitral regurgitation has emerged rapidly over the past few years. Most of the percutaneous approaches are modifications of existing surgical approaches to mitral annuloplasty or leaflet repair. Catheter-based devices mimic these surgical approaches with less procedural morbidity and mortality as a consequence of their less invasive nature. Percutaneous annuloplasty can be achieved indirectly via the coronary sinus or directly from retrograde left ventricular access. Catheter-based leaflet repair is accomplished using an implantable clip to mimic the surgical edge-to edge technique. Several of these percutaneous approaches have been successfully used in patients to demonstrate proof of concept, while others have already stopped further development. There is increasing experience in both trials and practice to begin to define the clinical utility of percutanenous leaflet repair, and annuloplasty approaches are undergoing significant development. PMID- 21272743 TI - Randomized comparison of percutaneous coronary intervention with sirolimus eluting stents versus coronary artery bypass grafting in unprotected left main stem stenosis. AB - OBJECTIVES: The purpose of this randomized study was to compare sirolimus-eluting stenting with coronary artery bypass grafting (CABG) for patients with unprotected left main (ULM) coronary artery disease. BACKGROUND: CABG is considered the standard of care for treatment of ULM. Improvements in percutaneous coronary intervention (PCI) with use of drug-eluting stents might lead to similar results. The effectiveness of drug-eluting stenting versus surgery has not been established in a randomized trial. METHODS: In this prospective, multicenter, randomized trial, 201 patients with ULM disease were randomly assigned to undergo sirolimus-eluting stenting (n = 100) or CABG using predominantly arterial grafts (n = 101). The primary clinical end point was noninferiority in freedom from major adverse cardiac events, such as cardiac death, myocardial infarction, and the need for target vessel revascularization within 12 months. RESULTS: The combined primary end point was reached in 13.9% of patients after surgery, as opposed to 19.0% after PCI (p = 0.19 for noninferiority). The combined rates for death and myocardial infarction were comparable (surgery, 7.9% vs. stenting, 5.0%; noninferiority p < 0.001), but stenting was inferior to surgery for repeat revascularization (5.9% vs. 14.0%; noninferiority p = 0.35). Perioperative complications including 2 strokes were higher after surgery (4% vs. 30%; p < 0.001). Freedom from angina was similar between groups (p = 0.33). CONCLUSIONS: In patients with ULM stenosis, PCI with sirolimus-eluting stents did not show noninferiority [corrected] to CABG at 12 month follow-up with respect to freedom from major adverse cardiac events, which is mainly influenced by repeated revascularization, whereas for hard endpoints, [corrected] PCI results are favorable. A longer follow-up is warranted. [corrected] PMID- 21272744 TI - Are all end points created equal? The case for weighting. PMID- 21272745 TI - Impaired renal function is associated with echocardiographic nonresponse and poor prognosis after cardiac resynchronization therapy. AB - OBJECTIVES: Aims of this study were to investigate the effect of renal function on left ventricular (LV) reverse remodeling and long-term outcome after cardiac resynchronization therapy (CRT), and to explore the relation between LV reverse remodeling and changes in renal function at 6-month follow-up. BACKGROUND: Renal insufficiency is highly prevalent in heart failure patients, including patients eligible for CRT, and is associated with poor prognosis. METHODS: The study comprised 490 patients undergoing CRT. Response to CRT was defined as a decrease in LV end-systolic volume >=15% at 6-month follow-up. Primary end point during long-term follow-up was all-cause mortality. RESULTS: At baseline, mean estimated glomerular filtration rate (eGFR) was 70 +/- 28 ml/min/1.73 m2. At 6-month follow up, 263 patients (54%) demonstrated response to CRT. Responders had an eGFR of 74 +/- 26 ml/min/1.73 m2 versus 64 +/- 28 ml/min/1.73 m2 in nonresponders (p < 0.001). During long-term follow-up, patients with an eGFR <60 ml/min/1.73 m2 had higher mortality than patients with an eGFR of 60 to 90 ml/min/1.73 m2 or an eGFR >90 ml/min/1.73 m2 (p < 0.001). Finally, responders to CRT had preservation of renal function (DeltaeGFR -0.6), whereas nonresponders had a slight worsening in renal function (DeltaeGFR -4.7, p < 0.05). CONCLUSIONS: Impaired renal function in CRT candidates is associated with nonresponse during 6-month follow-up. Additionally, patients with impaired renal function have worse long-term survival after CRT. Response to CRT results in preservation of renal function. PMID- 21272746 TI - Inappropriate implantable cardioverter-defibrillator shocks: incidence, predictors, and impact on mortality. AB - OBJECTIVES: The purpose of this study was to assess the incidence, predictors, and outcome of inappropriate shocks in implantable cardioverter-defibrillator (ICD) patients. BACKGROUND: Despite the benefits of ICD therapy, inappropriate defibrillator shocks continue to be a significant drawback. The prognostic importance of inappropriate shocks outside the setting of a clinical trial remains unclear. METHODS: From 1996 to 2006, all recipients of defibrillator devices equipped with intracardiac electrogram storage were included in the current analysis and clinically assessed at implantation. During follow-up, the occurrence of inappropriate ICD shocks and all-cause mortality was noted. RESULTS: A total of 1,544 ICD patients (79% male, age 61 +/- 13 years) were included in the analysis. During the follow-up period of 41 +/- 18 months, 13% experienced >=1 inappropriate shocks. The cumulative incidence steadily increased to 18% at 5-year follow-up. Independent predictors of the occurrence of inappropriate shocks included a history of atrial fibrillation (hazard ratio [HR]: 2.0, p < 0.01) and age younger than 70 years (HR: 1.8, p = 0.01). Experiencing a single inappropriate shock resulted in an increased risk of all cause mortality (HR: 1.6, p = 0.01). Mortality risk increased with every subsequent shock, up to an HR of 3.7 after 5 inappropriate shocks. CONCLUSIONS: In a large cohort of ICD patients, inappropriate shocks were common. The most important finding is the association between inappropriate shocks and mortality, independent of interim appropriate shocks. PMID- 21272747 TI - Prevention and reversal of atrial fibrillation inducibility and autonomic remodeling by low-level vagosympathetic nerve stimulation. AB - OBJECTIVES: We hypothesized that autonomic atrial remodeling can be reversed by low-level (LL) vagosympathetic nerve stimulation (VNS). BACKGROUND: Previously, we showed that VNS can be antiarrhythmogenic. METHODS: Thirty-three dogs were subjected to electrical stimulation (20 Hz) applied to both vagosympathetic trunks at voltages 10% to 50% below the threshold that slowed sinus rate or AV conduction. Group 1 (n = 7): Programmed stimulation (PS) was performed at baseline and during 6-h rapid atrial pacing (RAP). PS allowed determination of effective refractory period (ERP) and AF inducibility measured by window of vulnerability (WOV). LL-VNS was continuously applied from the 4th to 6th hours. Group 2 (n = 4): After baseline ERP and WOV determinations, 6-h concomitant RAP+LL-VNS was applied. Sustained AF was induced by injecting acetylcholine (ACh) 10 mM into the anterior right ganglionated plexus (Group 3, n = 10) or applying ACh 10 mM to right atrial appendage (Group 4, n = 9). RESULTS: Group 1: The ERP progressively shortened and the SigmaWOV (sum of WOV from all tested sites) progressively increased (p < 0.05) during 3-h RAP then returned toward baseline during 3-h RAP+LL-VNS (p < 0.05). Group 2: 6-h concomitant RAP+LL-VNS did not induce any significant change in ERP and SigmaWOV. Group 3 and Group 4: AF duration (AF-D) and cycle length (AF-CL) were markedly altered by 3-h LL-VNS (Group 3: baseline: AF-D = 389 +/- 90 s, AF-CL = 45.1 +/- 7.8 ms; LL-VNS: AF-D = 50 +/- 15 s, AF-CL = 82.0 +/- 13.7 ms [both p < 0.001]; Group 4: baseline: AF-D = 505 +/- 162 s, AF-CL = 48.8 +/- 6.6 ms; LL-VNS: AF-D = 71 +/- 21 s, AF-CL = 101.3 +/- 20.9 ms [both p < 0.001]). CONCLUSIONS: LL-VNS can prevent and reverse atrial remodeling induced by RAP as well as suppress AF induced by strong cholinergic stimulation. Inhibition of the intrinsic cardiac autonomic nervous system by LL VNS may be responsible for these salutary results. PMID- 21272748 TI - Endocardial radiofrequency ablation for hypertrophic obstructive cardiomyopathy: acute results and 6 months' follow-up in 19 patients. AB - OBJECTIVES: The purpose of this study was to examine the efficacy and safety of endocardial radiofrequency ablation of septal hypertrophy (ERASH) for left ventricular outflow tract (LVOT) gradient reduction in hypertrophic obstructive cardiomyopathy (HOCM). BACKGROUND: Anatomic variability of the vessels supplying the obstructing septal bulge can limit the efficacy of transcoronary ablation of septal hypertrophy in HOCM. Previous studies showed that inducing a local contraction disorder without reducing septal mass results in effective gradient reduction. We examined an alternative endocardial approach to transcoronary ablation of septal hypertrophy by using ERASH. METHODS: Nineteen patients with HOCM were enrolled; in 9 patients, the left ventricular septum was ablated, and in 10 patients, the right ventricular septum was ablated. Follow-up examinations (echocardiography, 6-min walk test, bicycle ergometry) were performed 3 days and 6 months after ERASH. RESULTS: After 31.2 +/- 10 radiofrequency pulses, a significant and sustained LVOT gradient reduction could be achieved (62% reduction of resting gradients and 60% reduction of provoked gradients, p = 0.0001). The 6-min walking distance increased significantly from 412.9 +/- 129 m to 471.2 +/- 139 m after 6 months, p = 0.019); and New York Heart Association functional class was improved from 3.0 +/- 0.0 to 1.6 +/- 0.7 (p = 0.0001). Complete atrioventricular block requiring permanent pacemaker implantation occurred in 4 patients (21%); 1 patient had cardiac tamponade. CONCLUSIONS: ERASH is a new therapeutic option in the treatment of HOCM, allowing significant and sustained reduction of the LVOT gradient as well as symptomatic improvement with acceptable safety by inducing a discrete septal contraction disorder. It may be suitable for patients not amenable to transcoronary ablation of septal hypertrophy or myectomy. PMID- 21272749 TI - Obesity induces signs of premature cardiac aging in younger patients: the role of mitochondria. AB - OBJECTIVES: The purpose of the present study was to investigate the influence of obesity on cardiac aging. BACKGROUND: Obesity is associated with an increased incidence of left ventricular hypertrophy, diastolic dysfunction, heart failure, and atherosclerosis. METHODS: Sixty male cardiac surgery patients were included in the study according to body mass index (18.5 to 25 kg/m2: normal weight; 30 to 35 kg/m2: obese) and age (<55 years: young; >70 years: old) and divided into 4 groups of 15 patients each. Right atrial cardiomyocytes were analyzed for mitochondrial function, markers of apoptosis, cardiac load or metabolism, and oxidative stress parameters. The metabolic state was further characterized in fasting blood samples. RESULTS: Obesity resulted in disturbed mitochondrial biogenesis and function (respiratory chain complex I) in the cardiomyocytes of young and old patients. Disturbed mitochondrial function was associated with signs of increased oxidative stress (protein carbonyl content, 8-hydroxy-2' deoxyguanosine) as well as telomere shortening by up to 30%. Cardiomyocytes from older (obese and normal-weight) and young obese patients demonstrated higher levels of load-induced markers (atrial natriuretic peptide and brain natriuretic peptide) and proapoptotic activation with increased Bax and Bcl-xS expression, cytochrome C release, and caspase 3/9 activation. Disturbances in glucose metabolism and adipocytokine release were detectable in old (obese and normal weight) and young obese patients. However, only minor deteriorations in most parameters were observed in obese subjects older than 70 years of age compared with normal-weight, age-matched patients. CONCLUSIONS: These data indicate that obesity results in premature cardiac aging in younger patients, which may contribute to an increased risk for heart failure. PMID- 21272750 TI - Obesity stresses cardiac mitochondria even when you are young. PMID- 21272751 TI - Antihypertensive efficacy of hydrochlorothiazide as evaluated by ambulatory blood pressure monitoring: a meta-analysis of randomized trials. AB - OBJECTIVES: The purpose of this study was to evaluate the antihypertensive efficacy of hydrochlorothiazide (HCTZ) by ambulatory blood pressure (BP) monitoring. BACKGROUND: HCTZ is the most commonly prescribed antihypertensive drug worldwide. More than 97% of all HCTZ prescriptions are for 12.5 to 25 mg per day. The antihypertensive efficacy of HCTZ by ambulatory BP monitoring is less well defined. METHODS: A systematic review was made using Medline, Cochrane, and Embase for all the randomized trials that assessed 24-h BP with HCTZ in comparison with other antihypertensive drugs. RESULTS: Fourteen studies of HCTZ dose 12.5 to 25 mg with 1,234 patients and 5 studies of HCTZ dose 50 mg with 229 patients fulfilled the inclusion criteria. The decrease in 24-h BP with HCTZ dose 12.5 to 25 mg was systolic 6.5 mm Hg (95% confidence interval: 5.3 to 7.7 mm Hg) and diastolic 4.5 mm Hg (95% confidence interval: 3.1 to 6.0 mm Hg) and was inferior compared with the 24-h BP reduction of angiotensin-converting enzyme inhibitors (mean BP reduction 12.9/7.7 mm Hg; p < 0.003), angiotensin-receptor blockers (mean BP reduction 13.3/7.8 mm Hg; p < 0.001), beta-blockers (mean BP reduction 11.2/8.5 mm Hg; p < 0.00001), and calcium antagonists (mean BP reduction 11.0/8.1 mm Hg; p < 0.05). There was no significant difference in both systolic (p = 0.30) and diastolic (p = 0.15) 24-h BP reduction between HCTZ 12.5 mg (5.7/3.3 mm Hg) and HCTZ 25 mg (7.6/5.4 mm Hg). However, with HCTZ 50 mg, the reduction in 24-h BP was significantly higher (12.0/5.4 mm Hg) and was comparable to that of other agents. CONCLUSIONS: The antihypertensive efficacy of HCTZ in its daily dose of 12.5 to 25 mg as measured in head-to-head studies by ambulatory BP measurement is consistently inferior to that of all other drug classes. Because outcome data at this dose are lacking, HCTZ is an inappropriate first line drug for the treatment of hypertension. PMID- 21272752 TI - Nebivolol exerts beneficial effects on endothelial function, early endothelial progenitor cells, myocardial neovascularization, and left ventricular dysfunction early after myocardial infarction beyond conventional beta1-blockade. AB - OBJECTIVES: The aim of this study was to investigate whether nebivolol has added effects on left ventricular (LV) dysfunction and remodeling early after myocardial infarction (MI) beyond its beta1-receptor-blocking properties. BACKGROUND: Nebivolol is a third-generation selective beta1-adrenoreceptor antagonist that stimulates endothelial cell nitric oxide (NO) production and prevents vascular reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation. Both endothelial NO synthase-derived NO production and NADPH oxidase activation are critical modulators of LV dysfunction early after MI. METHODS: Mice with extensive anterior MI (n = 90) were randomized to treatment with nebivolol (10 mg/kg/day), metoprolol-succinate (20 mg/kg/day), or placebo for 30 days starting on day 1 after surgery. RESULTS: Infarct size was similar among the groups. Both beta1-adrenergic receptor antagonists caused a similar decrease in heart rate. Nebivolol therapy improved endothelium-dependent vasorelaxation and increased early endothelial progenitor cells 4 weeks after MI compared with metoprolol and placebo. Nebivolol, but not metoprolol, inhibited cardiac NADPH oxidase activation after MI, as detected by electron spin resonance spectroscopy analysis. Importantly, nebivolol, but not metoprolol, improved LV dysfunction 4 weeks after MI (LV ejection fraction: nebivolol vs. metoprolol vs. placebo: 32 +/- 4% vs. 17 +/- 6% vs. 19 +/- 4%; nebivolol vs. metoprolol: p < 0.05) and was associated with improved survival 4 weeks post-MI compared with placebo. Nebivolol had a significantly more pronounced inhibitory effect on cardiomyocyte hypertrophy after MI compared with metoprolol. CONCLUSIONS: Nebivolol improves LV dysfunction and survival early after MI likely beyond the effects provided by conventional beta1-receptor blockade. Nebivolol induced effects on NO-mediated endothelial function, early endothelial progenitor cells and inhibition of myocardial NADPH oxidase likely contribute to these beneficial effects of nebivolol early after MI. PMID- 21272753 TI - Genetic warfarin dosing: tables versus algorithms. AB - OBJECTIVES: The aim of this study was to compare the accuracy of genetic tables and formal pharmacogenetic algorithms for warfarin dosing. BACKGROUND: Pharmacogenetic algorithms based on regression equations can predict warfarin dose, but they require detailed mathematical calculations. A simpler alternative, recently added to the warfarin label by the U.S. Food and Drug Administration, is to use genotype-stratified tables to estimate warfarin dose. This table may potentially increase the use of pharmacogenetic warfarin dosing in clinical practice; however, its accuracy has not been quantified. METHODS: A retrospective cohort study of 1,378 patients from 3 anticoagulation centers was conducted. Inclusion criteria were stable therapeutic warfarin dose and complete genetic and clinical data. Five dose prediction methods were compared: 2 methods using only clinical information (empiric 5 mg/day dosing and a formal clinical algorithm), 2 genetic tables (the new warfarin label table and a table based on mean dose stratified by genotype), and 1 formal pharmacogenetic algorithm, using both clinical and genetic information. For each method, the proportion of patients whose predicted doses were within 20% of their actual therapeutic doses was determined. Dosing methods were compared using McNemar's chi-square test. RESULTS: Warfarin dose prediction was significantly more accurate (all p < 0.001) with the pharmacogenetic algorithm (52%) than with all other methods: empiric dosing (37%; odds ratio [OR]: 2.2), clinical algorithm (39%; OR: 2.2), warfarin label (43%; OR: 1.8), and genotype mean dose table (44%; OR: 1.9). CONCLUSIONS: Although genetic tables predicted warfarin dose better than empiric dosing, formal pharmacogenetic algorithms were the most accurate. PMID- 21272754 TI - Parental history and myocardial infarction risk across the world: the INTERHEART Study. PMID- 21272755 TI - Family history of heart disease: the re-emergence of a traditional risk factor. PMID- 21272756 TI - Right ventricular myxoma. PMID- 21272757 TI - The ACC looks globally to tackle cardiovascular disease. PMID- 21272758 TI - CoreValve transcatheter aortic valve implantation via the subclavian artery: comparison with the transfemoral approach. PMID- 21272759 TI - Multicenter experience with extraction of the Sprint Fidelis implantable cardioverter-defibrillator lead. PMID- 21272761 TI - The Legacy of Giving--IFSHT President's lecture. PMID- 21272762 TI - Clinical commentary in response to: Severity of contracture and self-reported disability in patients with Dupuytren's contracture referred for surgery. PMID- 21272763 TI - Association of disturbances in the thoracic outlet in subjects with carpal tunnel syndrome: a case-control study. AB - INTRODUCTION: A limited amount of research has investigated the potential relationship between carpal tunnel syndrome (CTS) and thoracic outlet dysfunction. PURPOSE OF THE STUDY: To compare the prevalence of positive clinical tests suggestive of disputed neurogenic thoracic outlet syndrome (TOS) in subjects with CTS (CTS+) with that of subjects without CTS (control). STUDY DESIGN: Case-control study. METHODS: Subjects with electrodiagnostically confirmed CTS (CTS+) were recruited consecutively and matched by age (+/-2 years) and gender with asymptomatic (control) subjects. Subjects underwent clinical testing for neurogenic TOS using two provocative tests: modified Cyriax release test and elevated arm stress test (EAST). Subjects were tested for the presence of an elevated first rib using cervical rotation lateral flexion (CRLF) test. RESULTS: A total of 32 investigational subjects and 32 matched control subjects was included in each group (mean age: 43.5+5.9 years). A significantly greater number of CTS+ subjects presented with positive provocative testing for TOS (modified Cyriax release test p=0.005; EAST approached significance p=0.027) and for the presence of an elevated first rib (CRLF test p=0.003) as compared with controls. The likelihood of neck pain, shoulder pain, or an elevated first rib was 16 times greater in the CTS+ group as compared with that in the control group. CONCLUSIONS: A greater number of subjects with CTS presented with proximal dysfunctions suggestive of TOS and history of neck and shoulder pain. Evaluation of proximal structures involved with thoracic outlet dysfunction in persons with CTS has clinical merit. LEVEL OF EVIDENCE: Level III-b. PMID- 21272764 TI - Identification of shoulder-specific patient acceptable symptom state in patients with rheumatic diseases undergoing shoulder surgery. AB - STUDY DESIGN: Clinical measurement study with a longitudinal design. OBJECTIVE: Estimate Patient Acceptable Symptom State (PASS) thresholds in six shoulder outcome measures and two pain scales. METHODS: Patients with rheumatic diseases undergoing shoulder surgery were assessed at baseline and one-year follow-up (with Bostrom Shoulder Movement Impairment Scale, Constant, Disability of the Arm, Shoulder and Hand [DASH], Oxford Shoulder Score [Oxford], Shoulder Function Assessment Scale, Shoulder Pain and Disability Index [Spadi], and two visual analog pain scales [VAS]). PASS thresholds were estimated using the 75th percentile and the receiver operating characteristic curve approach. RESULTS: One hundred patients were included; 74 (74%) patients considered their shoulder function to be acceptable (PASS+), which was significantly associated with being female, odds ratio (OR) 4.54, and having better functional status (Health Assessment Questionnaire), OR 0.17 (p<0.05). Activity-related pain (VAS), the Oxford, and the Spadi showed best discriminative accuracy for PASS. All measures estimated changes exceeding the minimal clinical important difference. CONCLUSION: The Oxford and the Spadi showed better discriminant ability for PASS than the more commonly used Constant score and the DASH. The PASS thresholds for pain showed that patients accepted less pain at rest than during activity, underlining the importance of assessing both aspects of pain. LEVEL OF EVIDENCE: 3. Diagnostic study. PMID- 21272765 TI - Preface. Reoperative oral and maxillofacial surgery. PMID- 21272766 TI - Reoperative mandibular trauma: management of posttraumatic mandibular deformities. AB - Mandibular fractures are one the most common maxillofacial injuries. Diagnostic errors, poor surgical technique, healing disorders, or complications may lead to the establishment of posttraumatic mandibular deformities. Nonunion, malunion/malocclusion, or facial asymmetry can be found early during the healing process or as long-term sequelae after the initial mandibular fracture repair. Although occasionally these problems can be solved in a nonsurgical manner, reoperations play an important role in the management of these untoward outcomes. This article discusses the reoperative techniques used for the management of these deformities. PMID- 21272767 TI - Reoperative soft tissue trauma. AB - Trauma remains the leading cause of death in the first 4 decades of life and is surpassed only by cancer and atherosclerotic disease as the overall leading causes of death in the United States. Many of the injuries involve the facial region, including soft tissue trauma. This article highlights the current available modalities used in the management of unsightly scars or those scars whose location and appearance compromise function. PMID- 21272768 TI - Considerations in revision rhinoplasty: lessons learned. AB - This article is intended to deal with the difficult subject matter of revision rhinoplasty. Since there is consensus that rhinoplasty is one of the most difficult aesthetic surgery procedures, one would make the inference that a revision rhinoplasty should also be one of the more difficult revision surgeries. The intent of this article is to share with the readers a few pearls and lessons learned dealing with revision rhinoplasty. PMID- 21272769 TI - Reoperative face and neck lifts. AB - The complexity of the reoperative facelift or neck lift is directly related to the way the primary procedure was performed. Regardless of the primary technique used, the secondary procedure should be directed to the specific problems that the patient exhibits, such as scars, earlobe deformity, hair pattern changes, laxity in the upper face or neck, jowling, or deepening of the nasolabial folds. Contour should be restored within the deep layer support via the elevation of the superficial musculoaponeurotic system and platysma rather than rotating skin flaps in an exaggerated manner in a cephalad direction, producing a tight unnatural look. PMID- 21272770 TI - Reoperative temporomandibular joint surgery. AB - TMJ surgeries are not always successful. Many potential pitfalls can occur during any phase of the treatment and can lead to complications, less than desirable results, and short- or long-term failures. Unsatisfactory results can occur for multiple reasons, including misdiagnosis of the original pathologic condition, incorrect selection of surgical technique, technical failures, complications, systemic disease, and unrealistic expectations. This article focuses on the reoperation of the TMJ primarily in cases of internal derangement and discusses TMJ arthrocentesis, arthroscopy, modified condylotomy, and open joint procedures. PMID- 21272771 TI - Reoperative mandibular reconstruction. AB - Ideal reconstruction of the mandible is important for a multitude of reasons and has been and continues to be among the most common surgical challenges for reconstructive surgeons of the head and neck. Historically, pedicle flaps, such as the pectoralis major and deltopectoral myocutaneous flaps, were workhorse flaps for lower facial third head and neck reconstruction. This article outlines the relevant anatomy of the perimandibular region, reconstructive options including second free flaps, relevant workup, and complications pertaining to reoperative mandibular surgery. PMID- 21272772 TI - Reoperative maxillofacial oncology. AB - Approximately 36,000 people in the United States will be diagnosed with oral or oropharyngeal cancer in 2010. In more than 90% of the cases of oral cavity and oropharyngeal cancers, histopathologic examination reveals squamous cell carcinoma (SCCA). Despite appropriate initial treatment, oral SCCA recurs in 25% to 48% of cases. Several studies have shown that most cancers recur within about 2 years after the initial treatment. Hence, close follow-up of patients is important for the timely detection of recurrences.This article discusses the types of recurrence and the surveillance and treatment of recurrent oral SCCA. PMID- 21272773 TI - Reoperations in cleft lip and cleft palate treatment. AB - The surgical management of cleft lip and palate is a difficult and complex endeavor. Several surgical techniques for the treatment of this deformity have been described around the world; each one, when properly done by expert surgeons, renders good and predictable results most of the times. However, the fact that there are so many techniques means that there is no universal procedure that will always deliver great esthetic and functional results. This article discusses the causes of inadequate results in primary cleft lip and palate surgery and describes the various secondary surgical techniques to correct the same. PMID- 21272774 TI - Twenty-five years old and only getting better. PMID- 21272775 TI - The post-BART anti-fibrinolytic dilemma? PMID- 21272776 TI - The year in cardiothoracic and vascular anesthesia: selected highlights from 2010. AB - The aortic valve treatment revolution continues with the maturation of aortic valve repair and the dissemination of transcatheter aortic valve implantation. The recent publication of comprehensive multidisciplinary guidelines for diseases of the thoracic aorta has assigned important roles for the cardiovascular anesthesiologist and perioperative echocardiographer. Although intense angiotensin blockade improves outcomes in heart failure, it might further complicate the maintenance of perioperative systemic vascular tone. Ultrafiltration as well as intensive medical management guided by the biomarker brain natriuretic peptide improves outcomes in heart failure. Continuous-flow left ventricular assist devices have further improved outcomes in the surgical management of heart failure. Major risk factors for bleeding in the setting of these devices include advanced liver disease and acquired von Willebrand syndrome. The metabolic modulator perhexiline improves myocardial diastolic energetics to achieve significant symptomatic improvement in hypertrophic cardiomyopathy. A landmark report was also published recently that outlines the major areas for future research and clinical innovation in this disease. Landmark trials have documented the outcome importance of perioperative cerebral oxygen saturation monitoring as well as the outcome advantages of the Sano shunt over the modified Blalock-Taussig shunt in the Norwood procedure. Furthermore, the development and evaluation of pediatric-specific ventricular assist devices likely will revolutionize the mechanical management of pediatric heart failure. A multidisciplinary review has highlighted the priorities for future perioperative trials in congenital heart disease. These pervasive developments likely will influence the future training models in pediatric cardiac anesthesia. PMID- 21272777 TI - Seizures after open heart surgery: comparison of epsilon-aminocaproic acid and tranexamic acid. AB - OBJECTIVE: Although the lysine analogs tranexamic acid (TXA) and aminocaproic acid (EACA) are used widely for antifibrinolytic therapy in cardiac surgery, relatively little research has been performed on their safety profiles, especially in the setting of cardiac surgery. Two antifibrinolytic protocols using either TXA or aminocaproic acid were compared according to postoperative outcome. DESIGN: A retrospective analysis. SETTING: A university-affiliated hospital. PARTICIPANTS: Six hundred four patients undergoing cardiac surgery. INTERVENTIONS: One cohort of 275 consecutive patients received TXA; a second cohort of 329 consecutive patients was treated with EACA. Except for antifibrinolytic therapy, the anesthetic and surgical teams and their protocols remained unchanged. MEASUREMENTS AND MAIN RESULTS: Besides major outcome criteria, namely postoperative bleeding, the need for allogeneic transfusions, operative revision because of bleeding, postoperative renal dysfunction, neurologic events, heart failure, and in-hospital mortality, the authors specifically sought differences between the groups concerning seizures. The 2 cohorts were comparable over a range of perioperative factors. Postoperative seizures occurred significantly more frequently in TXA patients (7.6% v 3.3%, p = 0.019), whereas EACA patients had a higher incidence of postoperative renal dysfunction (20.0% v 30.1%, p = 0.005). There were no differences in all other measured major outcome factors. CONCLUSION: Both lysine analogs are associated with significant side effects, which must be taken into account when performing risk-benefit analyses of their use. Their use should be restricted to patients at high risk for bleeding; routine use on low-risk patients undergoing standard surgeries should face renewed critical reappraisal. PMID- 21272778 TI - Stars of the future. PMID- 21272779 TI - Case 1-2011: The challenges posed by a complicated pulmonary thromboendarterectomy. PMID- 21272780 TI - Late arrival: recruiting coreceptors to the T cell receptor complex. AB - In this issue of Immunity, Jiang et al. (2011) provide evidence that the CD8 coreceptor is recruited to the T cell receptor (TCR) complex after initial TCR triggering where it stabilizes the TCR-peptide-major histocompatibility complex interaction. PMID- 21272781 TI - CNS autoimmune inflammation: RICK must NOD! AB - In this issue of Immunity, Shaw et al. (2011) report that the NOD-RICK signaling axis is required for the activation of dendritic cells infiltrating the central nervous system, leading to reactivation of antigen-specific T cells and autoimmune inflammation. PMID- 21272782 TI - Erythropoietin surprises: an immune saga. AB - Erythropoietin (EPO) an erythropoietic stimulating agent also exerts effects on other cell systems. Nairz et al. (2011) now link EPO and intracellular signaling through the EPO receptor (EPOR) to innate immune cell activity via macrophages. PMID- 21272783 TI - Deflating the lymph node. AB - Although the lymph node lymphatic vessel growth and development is positively regulated by B cells and macrophages, Kataru et al. (2011), in this issue of Immunity, show negative regulation of lymphatic vessels by interferon-gamma from T cells. PMID- 21272784 TI - Blood relatives of follicular helper T cells. AB - Expression of the chemokine receptor CXCR5 identifies B follicular helper T cells. In this issue of Immunity, Morita et al. (2011) describe a heterogeneous circulating CXCR5(+)CD4(+) B cell helper population overrepresented in juvenile dermatomyositis patients. PMID- 21272785 TI - A new market to save lives from pneumococcal disease. PMID- 21272786 TI - Science in court: the myth of HIV fingerprinting. PMID- 21272787 TI - Herpes simplex encephalitis. PMID- 21272788 TI - Long-term outcome of Q fever endocarditis. PMID- 21272789 TI - An addition to the effect of treating co-infections on HIV-1 viral load. PMID- 21272791 TI - Prevention of Q fever endocarditis. PMID- 21272792 TI - Effective management in clusters of pneumococcal disease: a systematic review. AB - Outbreaks of serious pneumococcal disease can occur with high attack rates in certain settings. We systematically reviewed studies of interventions implemented in pneumococcal clusters and those reporting the effect of antibiotics on carriage reduction to assess the effectiveness of interventions. Evidence was graded according to the Scottish Intercollegiate Guidelines Network system. Of 28 identified cluster reports, one showed that administration of antibiotics to close contacts reduced risk of pneumococcal disease. In three of four clusters where rifampicin chemoprophylaxis was used and in four of five clusters where penicillin was used no further cases were seen after intervention. In clusters where pneumococcal polysaccharide vaccine was used, subsequent cases occurred, all within around 2 weeks of vaccination, which suggests delayed benefit with this approach (evidence grade D). Use of infection control measures alone was reported in eight clusters, with no further cases being reported in seven (grade D). From 21 selected carriage studies, large carriage reductions were observed consistently with use of penicillin and azithromycin, with median values being 90% and 73%, respectively (grade C). The findings were presented to a working group for pneumococcal cluster guidelines and used to develop key recommendations on the management of clusters that supported prompt use of amoxicillin or azithromycin chemoprophylaxis, pneumococcal vaccination for close contacts, and implementation of infection control measures. PMID- 21272793 TI - Urbanisation and infectious diseases in a globalised world. AB - The world is becoming urban. The UN predicts that the world's urban population will almost double from 3.3 billion in 2007 to 6.3 billion in 2050. Most of this increase will be in developing countries. Exponential urban growth is having a profound effect on global health. Because of international travel and migration, cities are becoming important hubs for the transmission of infectious diseases, as shown by recent pandemics. Physicians in urban environments in developing and developed countries need to be aware of the changes in infectious diseases associated with urbanisation. Furthermore, health should be a major consideration in town planning to ensure urbanisation works to reduce the burden of infectious diseases in the future. PMID- 21272794 TI - Emerging opportunistic yeast infections. AB - A growing population of immunosuppressed patients has resulted in increasingly frequent diagnoses of invasive fungal infections, including those caused by unusual yeasts. The incidence of non-albicans species of Candida is increasing compared with that of Candida albicans, and several species, such as Candida glabrata and Candida krusei, may be resistant to azole antifungal therapy. Trichosporon species are the second most common cause of fungaemia in patients with haematological malignant disease and are characterised by resistance to amphotericin and echinocandins and poor prognosis. Rhodotorula species belong to the family Cryptococcaceae, and are a cause of catheter-related fungaemia, sepsis, and invasive disease in severely immunosuppressed patients. An increasing number of sporadic cases of invasive fungal infections by non-neoformans cryptococci have been reported in immunocompromised hosts, especially for patients with advanced HIV infection or cancer who are undergoing transplant. Other uncommon yeasts that can cause invasive disease in severely immunosuppressed patients include Geotrichum, Hansenula, Malassezia, and Saccharomyces. Host immune status is a crucial determinant of the type of invasive fungal infection a patient is at risk for. Diagnosis can be challenging and relies heavily on traditional cultures of blood and other sterile sites, although serum (1,3)-beta-D-glucan testing might have an adjunctive role. Although rare yeasts are emerging as opportunistic human pathogens, diagnosis remains challenging and treatment suboptimal. PMID- 21272795 TI - Weil's disease in a rat owner. PMID- 21272796 TI - In favour of early surgery in Crohn's disease: a hypothesis to be tested. PMID- 21272797 TI - IBD in the elderly population: results from a population-based study in Western Hungary, 1977-2008. AB - BACKGROUND AND AIMS: Limited data are available on the incidence and disease course of IBD in the elderly population. Our aim was to analyze the incidence and disease course of IBD according to the age at diagnosis in the population-based Veszprem province database, which included incident patients diagnosed between January 1, 1977 and December 31, 2008. METHODS: Data of 1420 incident patients were analyzed (UC: 914, age at diagnosis: 38.9 SD 15.9 years; CD: 506, age at diagnosis: 31.5 SD 13.8 years). Both hospital and outpatient records were collected and comprehensively reviewed. RESULTS: 106 (11.6%) of UC patients and 21 (4.2%) of CD patients were diagnosed with >60 years of age. In UC, the incidence increased from 1.09 to 10.8/10(5) in the elderly, while CD increased to 3.04/10(5) in 2002-2007. In CD, colonic location (elderly: 61.9% vs. pediatric: 24.3%, p=0.001, and adults: 36.8%, p=0.02) and stenosing disease (elderly: 42.9% vs. pediatric: 14.9%, p=0.005, and adults: 19.5%, p=0.01) were more frequent in the elderly. A change in disease behavior was absent in the elderly, while in pediatric and adult CD population it was 20.3% (p=0.037), 19.8% (p=0.036) after 5 years. In UC, extensive disease was more frequent in pediatric patients compared to the elderly (p=0.003, OR: 2.73, 95%CI: 1.38-5.41). In addition, pediatric (57.3%, p<0.001, OR: 6.58; 95%CI: 3.22-12.9) and adult (39.8%, p<0.001, OR: 3.24; 95%CI: 1.91-5.49) patients required more often systemic steroids during follow-up compared to the elderly (17%). Proximal extension at 10 years was 11.6%, but time to extension was not different according to the age at onset. CONCLUSIONS: Elderly patients represent an increasing proportion of the IBD population. Stenosing and colon-only disease were characteristic for elderly CD patients, while the disease course in UC was milder. PMID- 21272798 TI - Association between bactericidal/permeability increasing protein (BPI) gene polymorphism (Lys216Glu) and inflammatory bowel disease. AB - BACKGROUND: Increasing evidence suggests that innate immune system may have a key role in the pathogenesis of the inflammatory bowel disease (IBD). Bactericidal/permeability increasing protein (BPI) has an important role in the recognition and neutralization of gram-negative bacteria by host innate immune system. The polymorphism on BPI gene called Lys216Glu is on the suspected list of IBD pathogenesis. METHODS: We studied the Lys216Glu polymorphism on BPI gene, in a Turkish IBD patient population. A total of 238 IBD patients; 116 Crohn's disease (CD) and 122 ulcerative colitis (UC), besides 197 healthy controls were included in this study. RESULTS: The Glu/Glu genotype and allele frequencies were found to be statistically higher compared to healthy control group not only in CD patients [P: 0.03, OR: 1.87 (CI 95% 1.02-3.42) and P: 0.00001 (OR: 2.07 CI 95% 1.47-2.91) respectively] but also in UC patients [P: 0.0002, OR: 2.71 (CI 95% 1.53-4.80) and P: 0.00002 (OR: 2.71 CI 95% 1.53-4.80) respectively]. CONCLUSIONS: BPI polymorphism (Lys216Glu) is associated both to CD and UC. Our findings differ from the two Western European studies; one without any association and the other indicating an association only with CD. Our study is the first one reporting a novel association between BPI gene mutation (Lys216Glu) and UC. PMID- 21272799 TI - Prevalence of inflammatory bowel disease related dysplasia and cancer in 1500 colonoscopies from a referral center in northwestern Greece. AB - BACKGROUND AND AIM: To report on the prevalence of inflammatory bowel disease (IBD) related intestinal dysplasia and cancer in northwestern Greece. PATIENTS AND METHODS: Single referral center retrospective study. The policy among all gastroenterologists of the area regarding medical treatment, patient follow up and bowel surveillance strategies including risk factors is the same. RESULTS: We analyzed 1494 colonoscopies from 696 consecutive IBD patients (494 UC). The follow up time [median, IQR] was 16 [8-23] years and the age at diagnosis was 28 [21-49] years. The number of patient years at risk was 16.219. Disease location for UC was: pancolitis 761 (59%), left sided colitis 455 (35%), and proctitis 69 (6%). Disease location for CD was: colitis 142 (66%), ileitis 45 (22%) and ileocolitis 21 (10%). Disease activity was in remission in 1240 (83%) of them. In total, 498 (72%) patients were on mesalazine, 169(24%) on immunosuppression and 29 (4%) on biologicals. Biopsies were taken randomly in 1429 (96%) endoscopies and were targeted in 65 (4%) of them. We recorded 69 (9.4%) cases with dysplasia and 10 (1.4%) cases with intestinal cancer (9 in UC). No difference was found for dysplasia and cancer in patients who followed up for 10-20 years or for more than 20 years. CONCLUSIONS: The prevalence of dysplasia and cancer is increased in UC compared to CD but the prevalence of high-grade dysplasia is comparatively low. Intestinal cancer prevalence is increasing after the first decade and then practically remains stable. PMID- 21272800 TI - Is the length of postoperative recurrence on the neo ileum terminal ileum predictable in Crohn's disease? AB - Crohn's disease (CD) often has a stricturing phenotype on the terminal ileum requiring surgery due to obstruction. Recurrence is frequent, creating a risk of multiple surgeries. We studied patients with ileal or ileo-colic CD who had undergone at least two surgical bowel resections between 1968 and 2008 for obstructive symptoms. AIMS: The aim of this retrospective study was to determine if the length of the removed diseased bowel varied from one surgical resection to the next. The measurements obtained from radiology (small bowel follow-up), surgery and histology were compared. RESULTS: Twenty four patients were included. Seventeen had 2 resections, 5 patients had 3 resections and two had 4 resections. The resected length of the diseased ileum was significantly shorter for the second intervention than for the first as assessed by radiology (median 16 cm vs 37 cm; p=0.0005), surgery (20 cm vs 40 cm; p=0.005) and histology (15 cm vs 25 cm; p=0.02) while there was no difference between the second and third resections (16 cm, 13 cm, 19.5 cm respectively) for the three types of measurements (p=NS). The surgeon's assessment of the diseased segment was longer than the histologist's (p=0.003). No factor was found to be significantly associated with the length of the diseased bowel on recurrence. CONCLUSION: This study shows that the length of the excised neo-terminal ileum during the first episode of recurrence was shorter than during the first episode of disease and remained stable for the third episode. This is an important prognostic finding that could influence the therapeutic choices for this disease and reduce hesitation to indicate surgery. PMID- 21272801 TI - Treatment of acute ulcerative colitis with infliximab, a retrospective study from three Danish hospitals. AB - BACKGROUND: In acute steroid-refractory ulcerative colitis, rescue therapy with infliximab has become a therapeutic option in patients facing colectomy. Data on efficacy and safety in this setting are sparse. METHODS: Patients with ulcerative colitis and acute and severe steroid-refractory disease, who were given infliximab as rescue therapy, were identified by a review of patients' records and databases of infliximab-treated patients. Data on patient background, concomitant medication, endoscopic and laboratory results, clinical activity and adverse events were collected. RESULTS: Fifty-six patients, all admitted because of high disease activity of short duration, and failing high-dose glucocorticoid treatment, received infliximab treatment and were followed up for a median of 538 days (range 2-1769). Colectomy was avoided in 61% of cases. No fatalities were observed. Concomitant medication at the end of follow-up indicated a low number of relapses in patients without colectomies. CONCLUSIONS: Our results show a lasting benefit of infliximab rescue therapy in 61% of patients with acute, steroid-refractory ulcerative colitis, a low incidence of late colectomies, and low frequency of steroid use in patients who avoided colectomy. High levels of C reactive protein on admittance and at the first infliximab infusion were associated with colectomy. Our study adds to the growing experience of infliximab treatment of patients with acute, steroid-refractory ulcerative colitis. PMID- 21272802 TI - Impact of Clostridium difficile infection in patients with ulcerative colitis. AB - BACKGROUND: Clostridium difficile infection (CDI) is becoming prevalent in general population as well as in patients with inflammatory bowel disease (IBD). AIM: The aim of the study was to identify risk factors for CDI in patients with ulcerative colitis (UC) and to assess outcome of UC in patients following CDI. METHODS: UC inpatients or outpatients who had positive results for C. difficile toxins A and B between 2000 and 2006 were identified (N=39) and matched for age and gender to UC patients who were negative C. difficile toxins and had never been diagnosed with CDI (N=39). Records were reviewed for adverse clinical outcome, defined as colectomy within 3 months of C. difficile testing. Conditional logistic regression was used to analyze multivariable association to identify risk factors for CDI and for adverse clinical outcome. RESULTS: A total of 78 subjects were analyzed, 60% were males. Median age was 39. Among 39 patients with CDI, 20 (47.2%) were diagnosed as outpatients, 50% failed treatment with the first antibiotic monotherapy, and 21.2% had recurrent infection. Antibiotic exposure within 30 days prior to C. difficile testing was found to be associated with an increased risk for CDI with an odds ratio of 12.0 (95% CI 1.2, 124.2) Subsequent colectomy within 3 months after CDI diagnosis, was not associated with CDI in both univariable and multivariable analyses. After adjusting for CDI, lack of 5-aminosalicylic acid (ASA) in the treatment regimen was significantly associated with colectomy with an odds ratio of 3.3 (95% CI: 1.2, 9.4). There was no UC- or CDI-associated mortality in this case series. CONCLUSIONS: Recent antibiotic exposure was a risk factor for CDI in UC patients. Interestingly, CDI does not seem to adversely affect short-term adverse clinical outcome (colectomy). PMID- 21272803 TI - Increased risk for coronary heart disease, asthma, and connective tissue diseases in inflammatory bowel disease. AB - BACKGROUND AND AIMS: Patients with inflammatory bowel diseases (IBD) show increased risk for other immune-mediated diseases such as arthritis, ankylosing spondylitis, and some pulmonary diseases. Less is known about the prevalence of other chronic diseases in IBD, and the impact of comorbidity on health-related quality of life (HRQoL). METHODS: The study population comprised 2831 IBD patients recruited from the National Health Insurance register and from a patient association register. Study subjects completed generic 15D and disease-specific IBDQ questionnaires. The Social Insurance Institution of Finland provided data on other chronic diseases entitling patients to reimbursed medication. For each study subject, two controls, matched for age, sex, and hospital district, were chosen. RESULTS: A significant increase existed in prevalence of connective tissue diseases, pernicious anemia and asthma. Furthermore, coronary heart disease (CHD) occurred significantly more frequently in IBD patients than in their peers (p=0.004). The difference was, however, more clearly seen in females (p=0.014 versus 0.046 in males). Active and long-lasting IBD were risk factors. Concomitant other chronic diseases appeared to impair HRQoL. Asthma, hypertension and psychological disorders had an especially strong negative impact on HRQoL, as observed with both the generic and disease-specific HRQoL tools. CONCLUSIONS: In addition to many immune-mediated diseases, CHD appeared to be more common in IBD than in control patients, especially in females. The reason is unknown, but chronic inflammation may predispose to atherosclerosis. This finding should encourage more efficacious management of underlying cardiovascular risk factors, and probably also inflammatory activity in IBD. PMID- 21272804 TI - Assessment of non-cirrhotic portal hypertension associated with thiopurine therapy in inflammatory bowel disease. AB - Thiopurines represent an effective and widely used immunosuppressant in the therapeutic armamentarium of inflammatory bowel disease. However up to 25% of patients may be unable to continue the drug due to side effects. The incidence of hepatotoxicity associated with thiopurine use is reported between 0% and 32%. Veno-occlusive disease, peliosis hepatis, perisinusoidal fibrosis and nodular regenerative hyperplasia have all been described with thiopurines. Recent trials of 6-tioguanine, although successful in patients with allergies to azathioprine or mercaptopurine, have been compromised by increased hepatotoxicity, either veno occlusive disease or nodular regenerative hyperplasia. We describe a report of nodular regenerative hyperplasia in a Crohn's disease patient associated with 6 mercaptopurine therapy and have reviewed the management and the literature regarding this complication. Our report strengthens the importance of further safety studies to evaluate the etiology, prevalence, risk factors and screening modalities for hepatotoxicity, in particular of nodular regenerative hyperplasia, in patients treated with thiopurines for inflammatory bowel disease. PMID- 21272805 TI - Dysplasia surveillance in an ulcerative colitis patient: successful detection with narrow band imaging and magnification. AB - One of the contemporary challenges gastroenterologists face is cancer screening and surveillance in long-term colitis patients. The search for a consensually practical and effective method to routinely detect dysplastic mucosa persists. In recent years, publications demonstrating the applicability of narrow band imaging (NBI) in this setting have sparked further research. We present a case report where NBI with magnification played a fundamental role in the detection of dysplasia in an ulcerative colitis patient. This case reinforces the potential widespread applicability of NBI as a surveillance tool in distinguishing dysplastic from nondysplastic colorectal lesions in ulcerative colitis. PMID- 21272806 TI - Internal iliac vein thrombosis in pediatric Crohn's disease. AB - Thromboembolic events are one of the important extraintestinal manifestations of inflammatory bowel diseases that are associated with considerable morbidity and mortality. Iliac vein thrombosis is rarely reported in inflammatory bowel diseases. A 9.5 year-old girl was presented with joint pain, nausea, vomiting and weight loss. She was diagnosed with Crohn's disease and right internal iliac vein thrombosis. With the implementation of immunosuppressive and anticoagulant therapies clinical picture has improved and thrombosis has resolved. Timely diagnosis and early treatment of extraintestinal complications of inflammatory bowel diseases might be lifesaving. PMID- 21272807 TI - Disseminated Cryptococcus neoformans infection and Crohn's disease in an immunocompetent patient. AB - Cryptococcus neoformans is a human pathogen ubiquitously present in the environment. It primarily affects immunocompromised patients, but individuals with no underlying disease or immunodeficiency can also be affected. We herein describe the case of a patient found to have Crohn's disease and disseminated cryptococcosis simultaneously. She had no predisposing underlying cause for impaired immunity. Our patient showed signs that would have make it hard to discriminate between an inflammatory bowel disease and an infection if bowel only would have been involved. The patient underwent surgical intervention; medical therapy was effective against Cryptococcus. She is at now being followed-up for Crohn's disease. When dealing with patient affected with inflammatory bowel diseases, careful history taking, objective and instrumental examination are demandable in order not to overlook associated conditions or infectious diseases. Diagnosis and therapy of cryptococcosis infection in patient with Crohn's disease are herein discussed. PMID- 21272808 TI - Association between Cogan's syndrome and inflammatory bowel disease: a case series. AB - BACKGROUND AND AIMS: Cogan's syndrome (CS) is a rare autoimmune disease with less than 250 cases reported. It mainly affects the audiovestibular system and the eyes frequently resulting in deafness. Inflammatory bowel disease (IBD) consists of two subtypes, Crohn's disease (CD) and ulcerative colitis (UC), and represents a common form of chronic intestinal inflammation. Here, we report an association between CS and IBD in four patients. METHODS: Patient data were collected using a questionnaire that was sent to one of our outpatients and three of the 13 members of the German CS self-help group. RESULTS: In all Cogan patients with IBD (3 female with UC, 1 male with CD), intestinal disease was diagnosed years before the onset of CS. After suffering from a complicated IBD disease course, they suddenly developed CS-related symptoms, such as hearing loss, tinnitus or eye inflammation. Three of them went deaf within a few years after diagnosis. Although all of them had been on immunosuppressive IBD therapy, these treatment regimens did not prevent the onset of CS. CONCLUSIONS: Our data suggest a strong association of IBD and CS. Since CS rapidly leads to bilateral deafness, it seems to be a rare, but nevertheless important disease that can occur in association with IBD. However, neither an early diagnosis nor an immunosuppressive therapy seems to efficaciously prevent disease progression. PMID- 21272809 TI - An unusual case of Crohn's disease with isolated gastric involvement. PMID- 21272810 TI - A case of early eosinophilic gastroenteritis with dramatic response to steroids. PMID- 21272811 TI - Safety and usefulness of balloon endoscopy in Crohn's disease patients with postoperative ileal lesions. PMID- 21272812 TI - Rapid onset of ulcerative colitis after treatment with interferon beta1a in a patient with multiple sclerosis. PMID- 21272813 TI - Increased fatigability of external anal sphincter in inflammatory bowel disease. PMID- 21272815 TI - Providing health supervision to support high-quality primary care: the time is now. PMID- 21272816 TI - It's not what you say, its how you say it: improving the effectiveness of anticipatory guidance. PMID- 21272817 TI - The Joseph W. St. Geme Jr lecture: striving for "polygamy". PMID- 21272818 TI - The role of supervision in creating responsible and competent physicians. PMID- 21272819 TI - Books and reading: evidence-based standard of care whose time has come. AB - Reach Out and Read (ROR) is the only systematically evaluated clinical activity to promote child development in primary care used throughout the United States. The ROR intervention is straightforward: clinicians provide advice about the benefits of reading aloud, as well as directly giving books to high-risk children and parents to take home at each pediatric visit of children aged 6 months to 5 years. ROR builds upon a significant evidence base of the value of reading aloud to young children. The studies evaluating ROR from different sites from subjects from different racial backgrounds and numerous outcome measures are consistently positive. From its initial single site at Boston City Hospital in 1989, to over 4600 clinical sites in 2010, over 30 000 clinicians distributed over 6.2 million books a year to 3.9 million children across the United States. The future efforts for ROR include integrating mental health competencies found in American Academy of Pediatrics guidelines as part of residency and clinician training into the ROR paradigm, quality improvement to ensure fidelity to the intervention, and expanded pediatric clinician involvement in local early childhood/school readiness community efforts. Finally, the most important future goal is the adoption of giving advice about reading aloud and giving developmentally appropriate books to high-risk families as best practice by official bodies. PMID- 21272820 TI - Delivery of well-child care: a look inside the door. AB - OBJECTIVE: To describe the delivery of well-child care and its components; to compare that delivery with recommendations in Bright Futures; and to compare delivery of well-child care for children with special health care needs with that for children without special needs. METHODS: Over a 10-week period, 2 medical students observed and documented characteristics of well-child care visits by general pediatricians and midlevel pediatric providers. Parents completed a demographic questionnaire and a screener for children with special health care needs. RESULTS: A total of 483 visits by 43 pediatricians and 9 midlevel providers with patients from 0 to 19 years of age were observed. Adjusted mean visit duration was 20.3 minutes; 38.9% of visits began with an open-ended question about parent/child concerns. A mean of 7.2 health supervision/anticipatory guidance topics were addressed per visit. Clinicians addressed a mean of 42% of Bright Futures-recommended age-specific health supervision/anticipatory guidance topics. Topics addressed less frequently than recommended included family support, parental well-being, behavior/discipline, physical activity, media screen time, risk reduction/substance use, puberty/sex, social-peer interactions, and violence. Shorter visits were associated with asking about parent/child concerns and with addressing greater proportions of recommended health supervision/anticipatory guidance topics. Well-child care visits with children with special health care needs were 36% longer than those with children without special needs and addressed similar numbers of age-specific health supervision/anticipatory guidance topics. More time was spent with children with special health care needs addressing health supervision/anticipatory guidance topics, other conditions (usually their chronic condition), and testing, prescriptions, and referrals. CONCLUSIONS: Utilizing direct observation of visits with pediatric clinicians, we found that solicitation of parent/child concerns occurred less frequently than recommended. Fewer than half of recommended visit-specific health supervision/anticipatory guidance topics were addressed, and there was little congruence with some Bright Futures age group-specific recommendations. Notably, both solicitation of patient/parent concerns and greater adherence to health supervision/anticipatory guidance recommendations were associated with shorter visits. Well-child care visits with children with special health care needs were longer than those with children without special needs; more time was spent addressing similar numbers of health supervision/anticipatory guidance topics as well as their chronic conditions. PMID- 21272821 TI - Innovative delivery of newborn anticipatory guidance: a randomized, controlled trial incorporating media-based learning into primary care. AB - OBJECTIVE: Recent initiatives seek to incorporate efficient, evidence-based practices into primary care. This study tested the feasibility, impact, and acceptance of incorporating a DVD of newborn anticipatory guidance into routine well-child care. METHODS: This randomized trial tested a 15-minute educational DVD intervention versus control condition with paper handouts on newborn anticipatory guidance. We recruited parents of newborns <=1 month old presenting for their first visit. Blinded research assistants conducted telephone follow-up 2 weeks later and medical chart reviews 2 months after enrollment. Clinic staff and providers completed semistructured surveys to rate the intervention. Primary outcomes included parent knowledge of infant development, self-efficacy with infant care skills, and problem-solving competence. RESULTS: We enrolled 137 subjects (response rate 82%). Scores on knowledge, self-efficacy, and problem solving were high at baseline for both groups and did not significantly change. More parents in the DVD group reported feeling prepared to care for their baby after the visit (94% vs 81%, P = .03), feeling high confidence bathing their baby (93% vs 78%, P = .01), and recognizing congestion (70% vs 52%, P = .03) compared to the control group. Those in the DVD group also had fewer additional office visits between birth and 2 months (P = .01). Staff and providers agreed the DVD was useful for patients (88%) and did not disrupt patient flow (93%). CONCLUSIONS: A DVD of newborn anticipatory guidance was feasible, well accepted, and had a positive impact in a pediatric practice. Video and other technologies represent an efficient, innovative way to reach parents as part of the office encounter. PMID- 21272822 TI - Using baby books to increase new mothers' safety practices. AB - OBJECTIVE: To determine whether educational baby books are an effective method for increasing low-income, first-time mothers' safety practices during their child's first 18 months. METHODS: Primiparous women (n = 167) were randomly assigned to 1 of 3 groups: an educational book group, a noneducational book group, or a no-book group. Home visits and interviews measured safety practices when women were in their third trimester of pregnancy (baseline) and when their children were 2, 4, 6, 9, 12, and 18 months of age. RESULTS: Women in the educational book group had fewer risks in their homes and exercised more safety practices than the no-book group (- 20% risk reduction; effect size = -.30). When the safety practices involved little time or expense (eg, putting away sharp objects), the educational book group was significantly more likely to engage in these behaviors than the no-book group (40% higher practices; effect size = 0.19) or noneducational book group (27% higher practices; effect size = 0.13). However, no differences were found between groups for behaviors that required high effort in time, money, or hassle (eg, installing latches on cabinets). CONCLUSIONS: Educational baby books appear to be an easy and low-cost way to increase the safety practices of new mothers, especially if the practices involve little to no time, money, or hassle. PMID- 21272823 TI - Getting under the hood: exploring issues that affect provider-based recall using an immunization information system. AB - OBJECTIVE: To assess 1) pediatric practices' use of provider-based recall using an immunization information system 8 months after training on the recall process; 2) initiation and sustainability barriers to provider-based recall using an immunization information system; 3) strategies that facilitated recall initiation; and 4) recommendations for alternative approaches for conducting recall. METHODS: In 2008, 11 practices received training on the automatic recall function in the Colorado Immunization Information System (CIIS) for both infants and adolescents. The 2-hour computer-based training provided an opportunity for attendees to run real-time recall reports with CIIS staff assistance. Eight months later, key informant interviews were conducted with 24 providers and staff from these practices. RESULTS: Eight months after training, only 4 of 11 practices had implemented recall using CIIS: 3 practices recalled children <=2 years of age, and 1 practice recalled adolescent girls for human papillomavirus vaccine. Initiation barriers included lack of awareness of baseline immunization rates, distrust in the accuracy of CIIS-generated data, and perceived difficulties recalling adolescents. Having unrealistic expectations about recall effectiveness was a barrier to sustainability. Strategies that facilitated recall included having a dedicated staff person for recall efforts and recalling children <=2 years of age. Most key informants viewed population-based recall conducted by public health departments or schools as an acceptable alternative to provider-based recall. CONCLUSIONS: Even with a promising tool to assist pediatric offices, implementing provider-based recall is challenging for pediatric practices. Given existing barriers, providers expressed support for alternative recall methods. PMID- 21272824 TI - Use of a pictographic diagram to decrease parent dosing errors with infant acetaminophen: a health literacy perspective. AB - OBJECTIVE: Medication dosing errors by parents are frequent. We sought to whether a pictographic dosing diagram could improve parent ability to dose infant acetaminophen, and to determine whether pictogram benefit varies by health literacy level. METHODS: We conducted an experimental study of parents presenting with their children to an urban public hospital pediatric clinic. Caregivers were randomized to dose infant acetaminophen with a standard dropper using text-only or text-plus-pictogram instructions (pictographic diagram of dose). The primary outcome variable was dosing accuracy (error defined as >20% deviation above/below dose; large overdosing error defined as >1.5 times recommended dose). Caregiver health literacy was assessed by means of the Newest Vital Sign measure. RESULTS: A total of 299 parents were assessed (144 text-only instructions; 155 text plus pictogram); 77.9% had limited health literacy (Newest Vital Sign score 0-3). Text plus-pictogram recipients were less likely to make an error compared to text-only recipients (43.9% vs 59.0%, P = .01; absolute risk reduction, 15.2% [95% confidence interval, 3.8-26.0]; number needed to treat, 7 [4-26]). Of text-plus pictogram recipients, 0.6% made a large overdosing error compared to 5.6% of text only recipients (absolute risk reduction, 4.9% [0.9-10.0]; number needed to treat, 20 [10-108]). Pictogram benefit varied by health literacy, with a statistically significant difference in dosing error evident in the text-plus pictogram group compared to the text-only group among parents with low health literacy (50.4% vs 66.4%; P = .02), but not for parents with adequate health literacy (P = .7). CONCLUSIONS: Inclusion of pictographic dosing diagrams as part of written medication instructions for infant acetaminophen may help parents provide doses of medication more accurately, especially those with low health literacy. High error rates, even among parents with adequate health literacy, suggest that additional study of strategies to optimize dosing is needed. PMID- 21272825 TI - Quality improvement for asthma care within a hospital-based teaching clinic. AB - OBJECTIVE: The aim of this study was to determine if a quality improvement intervention in a teaching clinic was associated with the following: 1) improved asthma action plan creation and distribution, 2)increased classification of asthma patients as intermittent or persistent, 3) increased prescriptions of asthma controller medications, 4) decreased emergency department visits and hospitalizations, and 5) sustainable changes in outcomes after the intervention year. METHODS: A retrospective analysis was conducted of a quality improvement project involving children aged >2 years who were diagnosed with asthma, evaluated in a large hospital-based teaching clinic. Outcomes were assessed for 1 year before and 3 years after quality improvement intervention. RESULTS: Data from children with asthma seen in the clinic over the 4 years of the study (N = 1797) were analyzed. Mixed effects model regressions showed that children after the intervention were over twofold more likely to receive an asthma action plan (using 2006 as referent, adjusted risk ratio [ARR] 2.29, 95% confidence interval [CI] 2.03-2.56 in 2007; ARR 2.40, 95% CI 2.15-2.66 in 2008; ARR 2.86, 95% CI 2.60 3.20 in 2009). Recorded assessment of asthma severity was 31% to 47% more likely post-intervention (ARR 1.31, 95% CI 1.26-1.36 in 2007, ARR 1.44 95% CI 1.38-1.50 in 2008, ARR 1.47 95% 1.41-1.54 in 2009). Controller medication prescribing increased postintervention ARR 1.08, 95% CI, 1.02-1.14 in 2007; ARR 1.11, 95% CI, 1.04-1.17 in 2008; ARR 1.11, 95% CI, 1.05-1.19 in 2009. Emergency department visits and hospitalizations trended lower postintervention (not significant). CONCLUSIONS: A quality improvement intervention in a hospital-based teaching clinic was associated with increased use of asthma action plans, classification of asthma severity, and controller medications, and possibly a trend toward fewer emergency visits and hospitalizations. PMID- 21272826 TI - Natural history of pandemic H1N1 2009 influenza infection in healthy pediatric outpatients. AB - OBJECTIVE: The pandemic influenza H1N1 2009 (pH1N1) virus is expected to remain a prominent circulating strain in the current and subsequent influenza seasons. The objective of this study was to compare the clinical course of infection with laboratory-confirmed pH1N1 and seasonal influenza A and B in a cohort of previously healthy children managed in the outpatient setting without antiviral therapy. METHODS: Previously healthy children 17 years of age or younger were prospectively enrolled during the first wave of the 2009 pandemic (May-July 2009) and the 2 preceding influenza seasons from a single primary care physician office and a tertiary children's hospital emergency department. Inclusion criteria were: age <=17 years; laboratory-confirmed influenza; and not receiving antiviral agents. Follow-up telephone interviews were conducted approximately 2 days and 14 days after presentation to assess symptom duration. RESULTS: A total of 251 patients (101 with pH1N1, 90 with seasonal influenza A, 60 with seasonal influenza B) were included. Presenting symptoms and duration of symptoms associated with pH1N1 were similar to those with seasonal influenza. Median fever duration in pH1N1 was 3 days and had resolved within 8 days in 95% of patients. Among patients with pH1N1, abnormalities on chest auscultation (10 of 101), the hospitalization rate (2 of 101), the proportion of children receiving intravenous fluid therapy (1 of 101) or supplemental oxygen (1 of 101) were not significantly different from patients with seasonal influenza. CONCLUSIONS: In most children without underlying risk factors for severe influenza, pH1N1 virus causes an uncomplicated respiratory tract illness, no more severe than seasonal influenza. PMID- 21272827 TI - Breastfeeding education and support services offered to pediatric residents in the US. AB - OBJECTIVE: The American Academy of Pediatrics (AAP) encourages pediatricians to support the practice of breastfeeding and residency educators to develop formal curricula in breastfeeding education. Few studies, however, describe breastfeeding education or support services currently provided to pediatric residents in the United States. The goals of this study were to investigate breastfeeding training offered during 3-year pediatric residency programs and to describe residency programs' policies and services for residents who breastfeed. METHODS: We conducted a cross-sectional study using a Web-based survey of pediatric program directors regarding breastfeeding education and support services for residents. RESULTS: Seventy percent of program directors (132 of 189) completed the survey, with 77.3% of respondents (n = 102) estimating the amount of breastfeeding education offered to their pediatric residents. Residents are provided with a median total of 9.0 hours of breastfeeding training over 3 years, primarily in continuity clinic and in lectures and rounds with attendings. At the programs' primary teaching hospitals, breastfeeding residents are provided breastfeeding rooms (67.0%), breast pumps (75.3%), and breast milk storage facilities (87.6%). Only 10 programs reported having an official policy to accommodate breastfeeding residents. CONCLUSIONS: Pediatric residents receive approximately 3 hours of breastfeeding training per year. In addition, there is less than universal implementation by residency programs of AAP recommendations for supporting breastfeeding in the workplace. Pediatric residency programs should find ways to improve and assess the quality of breastfeeding education and workplace support to better role model this advocacy standard. PMID- 21272828 TI - The impact of child care problems on employment: findings from a national survey of US parents. AB - OBJECTIVES: Many parents struggle to secure high-quality, consistent child care services, and this may impact employment decisions. Our objectives were to determine the type of employment problems that parents attribute to difficulties in securing child care and to identify whether having a child with behavior problems and/or chronic illness is independently associated with child care related employment problems in the United States. METHODS: This study included parents of children aged 0 to 13 years by using household-level sampling from the nationally representative random digit dial survey Gallup panel. We included 9 measures of child care-related employment problems. Poststratification weights were applied based on census region, income, and education by using Stata's poststratification commands. RESULTS: A survey was conducted of 1431 households with at least 1 parent employed. Overall, 46% of households reported 1 or more child care-related employment change. Being absent from work (21%) and changing the work schedule (27%) were the most prevalent changes reported. Two-parent households were significantly less likely to report child care-related employment changes compared with single parent households. Households with a stay-at-home parent were less likely to report child care-related absenteeism but more likely to report recently quitting work compared with households without a stay-at-home parent. Having a child with behavior problems or a serious chronic health condition was associated with double to triple odds of many child care-related employment problems. CONCLUSIONS: Child care-related employment problems are common among families with a child with chronic illness or behavior problems. These findings support the need for pediatricians and policy makers to strive for the implementation of more parent-friendly labor conditions. PMID- 21272829 TI - The Future of Nursing report: let's resolve to keep up the momentum. PMID- 21272830 TI - Development of high-fidelity simulated clinical experiences for baccalaureate nursing students. AB - High-fidelity simulators offer a teaching tool for nurse educators to provide lifelike simulated clinical experiences for baccalaureate nursing students. A group of faculty teaching a variety of clinical courses followed similar steps within frameworks of the American Association of Colleges of Nursing essentials and education theories to create case scenarios. The benefits of simulation experiences for students are discussed and a template for the nurse educator is provided to help develop simulations. This system is illustrated by an example from a high-risk antepartum obstetric scenario. PMID- 21272831 TI - Improving health-care quality through an AFPNP National Nursing Education Collaborative to strengthen PNP curriculum in mental/behavioral health and EBP: lessons learned from academic faculty and clinical preceptors. AB - In 2004, the Association of Faculty of Pediatric Nurse Practitioners was awarded a grant by the Commonwealth Fund to plan, implement, and evaluate a strengthened national curriculum for students in 20 pediatric nurse practitioner programs throughout the United States. Curricular changes focused on increasing the knowledge and skills of students in the area of evidence-based mental and behavioral health care for children and adolescents. The processes through which this national initiative was undertaken were described in "Strengthening PNP Curricula in Mental/Behavioral Health and Evidence-Based Practice" (B. M. Melnyk et al., 2010). This article focuses on the important perspectives of academic faculty and clinical preceptors and provides critical insight for nursing faculty when planning implementation of significant curricular change. The purpose of this descriptive study was to determine the challenges and facilitators of implementing a strengthened curriculum in didactic and clinical courses to inform nationwide dissemination of this curriculum to all PNP programs throughout the country. Confidential, structured, individual telephone interviews were conducted with academic and clinical preceptors from the schools that had participated in the implementation study. Curricular change presents challenges in most schools of nursing and will be affected by characteristics unique to each institution. Faculty need to be educated regarding the factors that are likely to enhance the process of making important and timely changes in curriculum. Finally, valuable lessons regarding the necessary early engagement of clinical preceptors should inform future curricular change initiatives. PMID- 21272832 TI - Second degree prelicensure master's graduates: what attracts them to nursing, their views on the profession, and their contributions. AB - This qualitative study explored second degree prelicensure master's graduates' attraction to the nursing profession, views on nursing, and thoughts regarding their contribution to nursing. Fourteen individuals participated from a cohort of master's students enrolled in a second degree program with a Clinical Nurse Leader focus. Data were collected through researcher-participant interviews. The researchers categorized data according to interview questions using constant comparison. Within each category, central themes emerged. Findings revealed that participants were drawn to nursing because of the opportunities and the caring nature of nursing. Participants felt prepared and excited to start a second career despite having to overcome challenges. They believed that their previous education enhanced their communication abilities and broadened their views; however, they encountered difficulties integrating previously held perspectives into a nursing worldview. They found poor nurse-to-nurse relationships among some experienced nurses and the difficulty of nursing education surprising. The opportunity to help others and the people for whom they provided care were the two features the participants most liked about nursing. Understanding such insights is important to continue to attract individuals from other careers to nursing. Findings highlight the important contributions that these individuals bring to the profession. PMID- 21272833 TI - The difference between professional image and job satisfaction of nurses who studied in a post-basic education program and nurses with generic education: a questionnaire survey. AB - To compare nurses' perceptions of the contribution of post-basic education (PBE) programs to nurses' professional image, job satisfaction, and clinical practice between two groups, nurses who had participated in PBE programs and nurses who had not. This is a cross-sectional study. A study conducted with 419 nurses employed in two major hospitals in Israel. Data were collected using structured questionnaires containing perception on professional self-image and clinical image, job satisfaction, and PBE contributions to nursing practice. Nurses who had completed a PBE in comparison to those who had not completed such a program rated higher the contribution of the program to independent decision making (40% and 50%, respectively, P < .001) as well as to specialized skills and proficiencies (38% and 55%, respectively, P < .01). Significant differences between the two groups were also found regarding professional image. Professional self-image and image of the clinical area were positively associated with professionalization. No differences regarding job satisfaction were found between the two groups. The study indicated that the model of PBE applied allows nurses to acquire greater self-confidence and improves professional self-image when making decisions. The model likewise helped nurses acquire greater authority to decide and intervene in clinical practice. PMID- 21272834 TI - A clinical teaching technique for nurse preceptors: the five minute preceptor. AB - Although preceptorship is the leading approach to the clinical education of senior undergraduate nursing students in the westernized world, few specific nursing preceptor-focused clinical teaching techniques are reported in the literature. One promising preceptor-specific teaching strategy is the Five Step "Microskills" Model of Clinical Teaching (J.O. Neher, K.C. Gordon, B. Meyer, & N. Stevens, 1992). This technique, also known as the One Minute Preceptor (OMP; J.O. Neher & N. Stevens, 2003), has been used for more than 15 years in clinical medical education. In this article, we trace the origins of the OMP and describe an adaptation to nursing education, referred to as the Five Minute Preceptor (5MP). The 5MP steps are the following: (1) get the student to take a stand, (2) probe for supporting evidence, (3) teach general rules, (4) reinforce the positives, and (5) correct errors or misinterpretations. In addition, we explore the relationship between the 5MP and experiential learning and provide a detailed example of the 5MP's use in undergraduate clinical nursing education. Recommendations are provided for the development of a 5MP educational package and the evaluation of the 5MP's use in baccalaureate nursing programs. PMID- 21272835 TI - Lost in translation: student perceptions of cultural competence in undergraduate and graduate nursing curricula. AB - The rapidly changing demographics of the United States require nurses who are equipped with knowledge and skills to meet the needs of an increasingly diverse patient population. Nurse educators seek to meet this challenge through integrating cultural competence into nursing course curricula. Few studies have examined student perceptions of the integration of this material. As part of a larger school-wide assessment, this qualitative descriptive study used focus groups of doctoral and bachelor of science in nursing students to evaluate their perceptions of the integration of cultural competence in the nursing curriculum. We sought to answer two questions: (a) what the students' perceptions were and (b) what recommendations they had for improvement. The results of the focus groups yielded three themes: (a) broadening definitions, (b) integrating cultural competence, and (c) missed opportunities. Student suggestions and recommendations for enhancing cultural competence in the curricula are provided. PMID- 21272836 TI - Analysis of graduates' perceptions of an accelerated bachelor of science program in nursing. AB - Rapid expansion of second-degree programs as one approach to addressing the nursing shortage by increasing the number of graduates in shorter periods of time prompted the need for program evaluation to identify the outcomes, strengths, and best practices of these programs. This study used both quantitative and qualitative methods of inquiry to analyze the responses of 28 of 56 recent graduates of an accelerated baccalaureate program. Respondents rated components of the program from preadmission to graduation on a Likert scale and responded to open-ended questions regarding strengths and weaknesses of the program. Analysis included descriptive statistics for quantitative data and content analysis for qualitative data. The analysis showed a high degree of similarity between the quantitative and qualitative data. Highly rated program components, that is, opportunity for graduate course work and integration with graduate students, clinical skill practice and experiences, variety of teaching methodologies, peer and faculty support, were reflected in the themes of cohort bonding, variety of clinical experiences, and supportive faculty and staff. Outcomes of program satisfaction, National Council Licensure Examination pass rates, successful nursing employment, and graduate school attendance were supported by the data. PMID- 21272837 TI - Gender discrimination and nursing: alpha literature review. AB - This article aims to examine gender stereotypes in relation to men in nursing, discuss gender discrimination cases in nursing, and explore methods used for promoting equal educational opportunities during nursing studies. The literature review was based on related databases, such as CINAHL, Science Direct, MEDLINE, and EBSCO. Legal case studies are included in order to provide a more practical example of those barriers existing for men pursuing nursing, as well as statistical data concerning gender discrimination and male attrition to nursing schools in relation to those barriers. These strengthen the validity of the manuscript. Literature review showed that gender discrimination is still prevalent within nursing profession. Nursing faculty should prepare male nursing students to interact effectively with female clients as well. Role modeling the therapeutic relationship with clients is one strategy that may help male students. In general, the faculty should provide equal learning opportunities to nursing students. PMID- 21272838 TI - Don't forget about Benner. PMID- 21272839 TI - Target-directed visual attention is a prerequisite for action-specific perception. AB - Witt et al. (2008) have recently shown that golfers who putt with more success perceive the hole to be bigger than golfers who putt with less success. In three experiments, we systematically examined whether this phenomenon, labelled action specific perception, depends on directing visual attention towards the action target. In Experiment 1 we replicated previously reported action-specific effects on perception in golf putting. In Experiments 2 and 3 we directly assessed whether action-specific effects on perception in golf putting are dependent on focusing visual attention on the target. To this end, the participants performed the putting task while visual attention towards the target was either completely withheld (Experiment 2) or divided over the target and other task-relevant objects (Experiment 3). No action-specific effects were found when visual attention towards the action target was occluded or partially diverted from the target. Together, our results provide evidence to suggest that focusing visual attention on the target while performing the action is a prerequisite for the emergence of action-specific perception. PMID- 21272840 TI - Extending end-state comfort effect: do we consider the beginning state comfort of another? AB - Sharing a drink or passing a tool to another person is frequently done in our daily lives. However, a second thought is rarely given about how the object should be handed; instead we pay attention to other factors (e.g., the company). This interaction (handing a tool to someone) is interesting, since it may give insight to how motor intentions are predicted. Research has demonstrated that individuals exhibit an end-state comfort effect when manipulating objects, and it is of interest to determine how this is applied to a joint-action paradigm. The purpose of this experiment was to determine if participants would anticipate the confederate's postural requirements and pass tools in a manner that allowed the confederate to have beginning state comfort and thus facilitate the motion sequence as a whole. That is, would the participant incur the cost of the movement by adopting an awkward posture to facilitate the use of the tool by the confederate? The results demonstrated that participants allowed the confederate to adopt a comfortable beginning state comfort on 100% of the trials for all the tools. However, the participants did not sacrifice end-state comfort, demonstrating that the participants were able to plan ahead to both maximize their own end-state comfort and the beginning state comfort of the confederate. PMID- 21272841 TI - Electro-optic effects of colloidal crystals. AB - Many kinds of electro-optic effects of colloidal crystals are observed and discussed on the basis of the fundamental properties of colloidal crystals themselves. Several electro-optic effects of colloidal crystals have been found by the authors mainly by use of light-scattering, reflection- and transmitted light intensity measurements in an electric field, (a) waveform deformation, (b) phase-shift effects, (c) second-order harmonics generation, (d) self-resonance frequency generation (characteristic frequency and harmonic oscillation), (e) peak wavelength-shift effects and (f) waveform transformation. These electro optic responses are explained successfully by the resonance-, visco-elastic- and structural relaxation-parameters of colloidal crystals. PMID- 21272842 TI - Kinetics of adsorption of metal ions on inorganic materials: A review. AB - It is necessary to establish the rate law of adsorbate-adsorbent interactions to understand the mechanism by which the solute accumulates on the surface of a solid and gets adsorbed to the surface. A number of theoretical models and equations are available for the purpose and the best fit of the experimental data to any of these models is interpreted as giving the appropriate kinetics for the adsorption process. There is a spate of publications during the last few years on adsorption of various metals and other contaminants on conventional and non conventional adsorbents, and many have tried to work out the kinetics. This has resulted from the wide interest generated on using adsorption as a practical method for treating contaminated water. In this review, an attempt has been made to discuss the kinetics of adsorption of metal ions on inorganic solids on the basis of published reports. A variety of materials like clays and clay minerals, zeolites, silica gel, soil, activated alumina, inorganic polymer, inorganic oxides, fly ash, etc. have been considered as the adsorbents and cations and anions of As, Cd, Co, Cr, Cu, Fe, Hg, Mn, Ni, Pb, Se, and Zn as adsorbate have been covered in this review. The majority of the interactions have been divided into either pseudo first order or second order kinetics on the basis of the best fit obtained by various groups of workers, although second order kinetics has been found to be the most predominant one. The discussion under each category is carried out with respect to each type of metal ion separately. Application of models as given by the Elovich equation, intra-particle diffusion and liquid film diffusion has also been shown by many authors and these have also been reviewed. The time taken for attaining equilibrium in each case has been considered as a significant parameter and is discussed almost in all the cases. The values of the kinetic rate coefficients indicate the speed at which the metal ions adsorb on the materials and these are discussed in all available cases. The review aims to give a comprehensive picture on the studies of kinetics of adsorption during the last few years. PMID- 21272843 TI - Chronic fetal hypoxia produces selective brain injury associated with altered nitric oxide synthases. AB - OBJECTIVE: The purpose of this study was to investigate the impact of chronic hypoxia on the nitric oxide synthase isoenzymes in specific brain structures. STUDY DESIGN: Time-mated pregnant guinea pigs were exposed to 10.5% molecular oxygen for 14 days (animals with chronic fetal hypoxia; HPX) or room air (control animals; NMX); L-N6-(1-iminoethyl)-lysine (L-NIL; an inducible nitric oxide synthase inhibitor, 1 mg/kg/d) was administered to HPX group for 14 days (L-NIL + HPX). Fetal brains were harvested at term. Multilabeled immunofluorescence was used to generate a brain injury map. Laser capture microdissection and quantitative polymerase chain reaction were applied; cell injury markers, apoptosis activation, neuron loss, total nitric oxide, and the levels of individual nitric oxide synthase isoenzymes were quantified. RESULTS: Chronic hypoxia causes selective fetal brain injury rather than global. Injury is associated with differentially affected nitric oxide synthases in both neurons and glial cells, with inducible macrophage-type nitric oxide synthase up regulated at all injury sites. L-NIL attenuated the injury, despite continued hypoxia. CONCLUSION: These studies demonstrate that chronic hypoxia selectively injures the fetal brain in part by the differential regulation of nitric oxide synthase isoenzymes in an anatomic- and cell-specific manner. PMID- 21272844 TI - A randomized trial of day-case vs inpatient laparoscopic supracervical hysterectomy. AB - OBJECTIVE: To determine whether women having day-case laparoscopic supracervical hysterectomy are more or less satisfied with the length of hospital stay compared with women who stayed overnight after the procedure. STUDY DESIGN: An randomized control trial of 49 women randomized to day-case or overnight hospital stay after laparoscopic supracervical hysterectomy. Satisfaction with length of hospitalization and quality of life were compared using the Mann-Whitney U test. RESULTS: No group differences were found in satisfaction with length of hospital stay (P = .13). There was a nonsignificant trend toward greater anxiety in the day-case group (P = .06 on day 1 postoperative). Quality of life was lower in the day-case group on days 2 (P = .02) and 4 (P = .03), postoperatively. CONCLUSION: Women having a day-case hysterectomy were discharged after median of 5 hours postoperative and were similarly satisfied as women hospitalized overnight. Quality of life, however, does appear to be compromised by day-case surgery. PMID- 21272845 TI - Maternal immunization with tetanus-diphtheria-pertussis vaccine: effect on maternal and neonatal serum antibody levels. AB - OBJECTIVE: We sought to determine whether tetanus-diphtheria-pertussis vaccination (Tdap) in pregnancy provides newborns antibodies against pertussis when compared to mothers who did not receive Tdap. STUDY DESIGN: Paired maternal and umbilical cord blood samples were collected at the time of delivery and the serum stored at -86 degrees C. For each paired sample of maternal and cord blood, the medical chart and vaccine history was reviewed to determine whether Tdap was received or not. RESULTS: Newborns born from mothers who received Tdap during pregnancy had significantly higher concentrations of diphtheria antitoxin (P < .001), tetanus antitoxin (P = .004), and antibodies to pertussis toxin (P < .001), filamentous hemagglutinin (P = .002), pertactin (P < .001), and fimbriae 2/3 (P < .001) when compared to newborns from mothers who did not receive Tdap. There was a significant increase in the odds that newborns from mothers who received Tdap during pregnancy have antibodies that may provide protection against diphtheria (P = .0141), pertussis toxin (P < .0001), and fimbriae 2/3 (P = .0146). CONCLUSION: Administering Tdap during pregnancy increases antibody titers against diphtheria and pertussis antigens. Maternal Tdap may prevent neonatal pertussis infection. PMID- 21272846 TI - Magnesium sulfate ameliorates maternal and fetal inflammation in a rat model of maternal infection. AB - OBJECTIVE: Magnesium sulfate is proposed to have neuroprotective effects in the offspring. We examined the effects of maternal magnesium sulfate administration on maternal and fetal inflammatory responses in a rat model of maternal infection. STUDY DESIGN: Pregnant rats were injected with saline, Gram-negative bacterial endotoxin lipopolysaccharide or lipopolysaccharide with magnesium sulfate (pre- and/or after lipopolysaccharide) to mimic infection. Maternal blood, amniotic fluid, fetal blood, and fetal brains were collected 4 hours after lipopolysaccharide and assayed for tumor necrosis factor, interleukin-6, monocyte chemoattractant protein-1, and growth-related oncogene-KC. In addition, the effect of magnesium sulfate on cytokine production by an astrocytoma cell line was assessed. RESULTS: Lipopolysaccharide administration induced tumor necrosis factor, interleukin-6, monocyte chemoattractant protein-1, and growth-related oncogene-KC expression in maternal and fetal compartments. Maternal magnesium sulfate treatment significantly attenuated lipopolysaccharide-induced multiple proinflammatory mediator levels in maternal and fetal compartments. CONCLUSION: Antenatal magnesium sulfate administration significantly ameliorated maternal, fetal, and gestational tissue-associated inflammatory responses in an experimental model of maternal infection. PMID- 21272847 TI - Training to reduce adverse obstetric events with risk of cerebral palsy. PMID- 21272848 TI - Microarray-based identification of clinically relevant vaginal bacteria in relation to bacterial vaginosis. AB - OBJECTIVE: The objective was to examine the use of a tailor-made DNA microarray containing probes representing the vaginal microbiota to examine bacterial vaginosis. STUDY DESIGN: One hundred one women attending a health center for HIV testing in South Africa were enrolled. Stained, liquid-based cytology slides were scored for bacterial vaginosis. An inventory of organisms was obtained using microarray technology, probing genera associated with bacterial vaginosis in more detail, namely Gardnerella, Atopobium, Dialister, Leptotrichia, Megasphaera, Mobiluncus, Peptostreptococcus, Prevotella, and Sneathia. RESULTS: Of 101 women, 34 were diagnosed positive for bacterial vaginosis. This condition was associated with an increased microbial diversity. It is no longer useful to base the diagnosis of bacterial vaginosis on Gardnerella alone. Rather, its presence with Leptotrichia and Prevotella species, and especially Atopobium was more indicative of an aberrant state of the vaginal flora. CONCLUSION: To understand the vaginal microbiota in more detail, microarray-based identification can be used after microscopic scoring. PMID- 21272849 TI - Is transcervical Foley catheter actually slower than prostaglandins in ripening the cervix? A randomized study. AB - OBJECTIVE: The purpose of this study was to determine whether the maximum time for cervical ripening (from 24-12 hours) would influence the efficacy of a transcervical Foley catheter and to compare efficacy to that of a prostaglandin E(2) vaginal insert. STUDY DESIGN: Three hundred ninety-seven women were assigned randomly to (1) Foley catheter left in place for a maximum of 24 hours, (2) Foley catheter left in place for a maximum of 12 hours, or (3) prostaglandin E(2) controlled-release vaginal insert. Primary outcome was vaginal delivery within 24 hours. RESULTS: There were no differences in vaginal delivery rates. The proportion of women who achieved vaginal delivery in 24 hours was lower in the 24 hour Foley catheter group than in the other 2 groups (24-hour Foley catheter, 21.0%; 12-hour Foley catheter, 59.8%; vaginal prostaglandin E(2), 48.5%; P < .0001). CONCLUSION: Cutting the ripening time with a Foley catheter by one-half increases the proportion of women who deliver vaginally within 24 hours and yields efficacy similar to that of prostaglandin E(2) vaginal insert. PMID- 21272850 TI - [Detection of induced myocardial ischemia during stress cardiovascular magnetic resonance]. AB - In the past decade, cardiovascular magnetic resonance (CMR) has evolved considerably. Its clinical applications enable the diagnosis and prognostic assessment of patients with ischemic heart disease. CMR is safe, with absence of any ionizing radiation, and offers the greatest information from a single test, allowing the assessment of myocardial morphology, myocardial function and viability. Stress-CMR can be used for detection and quantification of ischemia. This article analyses the technical approach, the limits and reviews the available literature about diagnostic performance of stress CMR testing and its results in the prognostication of cardiac patients. With further improvements in CMR techniques and the establishment of a standardized study protocol, stress-CMR will play a pivotal role in managing patients with ischemic heart disease. PMID- 21272851 TI - [Pulmonary embolism mimicking acute anterior myocardial infarction: diagnostic trap]. AB - Pulmonary embolism remains the major malingerer of acute chest disease. The clinical and electrocardiographic manifestations may deviate to a diagnosis of myocardial infarction. We report a case of bilateral pulmonary embolism in a patient of 50 years. The electrocardiogram showed ST elevation in anteroseptal and lateral leads. The diagnosis of acute myocardial infarction was selected and a fibrinolysis achieved. Getting out under beta-blocker therapy, antiplatelet, statin and angiotensin-converting enzyme inhibitors after 10 days hospitalization, the patient was readmitted one month later for a massive pulmonary embolism. Coronary angiography performed after the second hospitalization was normal. PMID- 21272852 TI - [Isolated non-compaction of the right ventricular myocardium: two cases report]. AB - BACKGROUND: The noncompaction of myocardium is a rare myocardiopathy. The isolated right ventricular involvement is exceptional. We report two cases of isolated noncompaction of the right ventricular myocardium. CASE 1: I., 2 years old, investigated for a congenital cyanosis with severe functional repercussion. Her echocardiography revealed a complex congenital heart disease associated with isolate noncompaction of the right ventricle. CASE 2: A., 5 years old, was referred for history of syncope for the 2 last years. The echocardiography showed a severe pulmonary hypertension and an isolate noncompaction of the right ventricle. CONCLUSION: Due to the rarity of the isolate non-compaction of the right ventricle, it diagnosis remains difficult. The treatment and the outcomes of this disease are still unclear. An early diagnosis may help to reduce its complication. PMID- 21272853 TI - [Infective endocarditis as the only manifestation of Whipple's disease: an atypical presentation]. AB - Diagnosis of Whipple's disease is difficult, and thus its frequency is probably underestimated, particularly in culture-negative infective endocarditis. However, it must be systematically searched for in such a situation, first because it is associated with a poor natural outcome, and second because Tropheryma whipplei is not covered by the conventional empirical therapy recommended for culture negative infective endocarditis. Whipple's disease endocarditis is usually associated with weight loss, intestinal and joint involvement. Nevertheless, it is sometimes the only manifestation of the disease, which makes the diagnosis much more difficult. We report the case of a 66-year-old patient with Barlow's disease, who underwent mitral valve replacement for severe mitral regurgitation. Vegetations were observed on the resected valve, both macroscopically and histologically. No microorganism was found at first. The diagnosis of Whipple's disease endocarditis was finally obtained by Polymerase Chain Reaction on valve tissue, and later confirmed by Periodic Acid Schiff staining. The outcome was favorable after a prolonged antibiotic therapy including doxycycline and hydroxychloroquine. PMID- 21272854 TI - [Evaluation of blood pressure control by ambulatory blood pressure monitoring and study of factors associated with poor blood pressure control in 300 treated hypertensive type 2 diabetic patients]. AB - Hypertension is frequently associated with type 2 diabetes and is often difficult to control. AIM: Evaluate the frequency of controlled hypertension in our type 2 diabetic patients with known and treated hypertension and determine the factors associated with poor blood pressure control. SUBJECTS AND METHODS: Prospective study concerning 300 type 2 diabetic patients with a known and treated hypertension, sex-ratio: 0.64, mean age: 61.2+/-9.1 years (37-86). All subjects underwent physical examination, biological investigations and a 24 hours ambulatory blood pressure monitoring (ABPM). RESULTS: Hypertension was well controlled in 70 patients (23.3%). The concordance rate between clinical measure of blood pressure and ABPM was 70.3%. Subjects with uncontrolled hypertension were older (61.8+/-8.9 vs 59.1+/-9.3 years, P<0.05), more frequently of male sex (sex-ratio: 0.77 vs 0.34, P<0.01), smokers (36.4 vs 21.7%, P<0.05) and with abdominal adiposity (P<0.05). Duration of diabetes, body mass index and the frequency of peripheral neuropathy, retinopathy and coronary insufficiency were not different between the two groups. Diabetic nephropathy was more frequent (29.8 vs 16.1%, P<0.05) in the group with uncontrolled hypertension. Loss of circadian blood pressure rhythm was noted in 239 patients (79.6%) and it was more frequently observed in patients with uncontrolled hypertension (84 vs 66%, P<0.001). CONCLUSION: Our type 2 diabetic patients had a poorly controlled hypertension. Close monitoring of blood pressure with adjustment of antihypertensive treatment are necessary to improve cardiovascular prognosis of our patients. PMID- 21272855 TI - [Heart and Steinert's disease]. AB - Myotonic dystrophy type 1 (Steinert disease) is an autosomal dominant disease characterized by myotonia and multiorgan damage. This latter is the most frequent of the adult-onset muscular dystrophies. Heart involvement is often associated, including cardiomyopathies, atrioventricular block, atrial and ventricular arrhythmias. PMID- 21272856 TI - [Cardiologic emergencies and natural disaster. Prospective study with Xynthia tempest]. AB - BACKGROUND: Stress-induced cardiomyopathy and ischemic cardiopathy have been described after natural disasters such as earthquakes. OBJECTIVES OF THE STUDY: Count stress-induced cardiomyopathies and ischemic cardiopathies just after Xynthia tempest which damaged the Vendean coast on February2010, in order to study epidemiology. PATIENTS AND METHOD: Included patients were living in a tempest damaged village, and admitted in Vendee hospital just after or in the week following the tempest, and presenting a suspected acute coronary syndrome or stress-induced cardiomyopathy. RESULTS: Among 3350 inhabitants of the two damaged Vendean towns, we count three acute coronary syndromes, two Tako-Tsubo cardiomyopathies, and one coronary spasm. We count five women and one man, average age is 76. CONCLUSION: The diagnosis of ischemic cardiopathy and stress induced cardiomyopathy is over-represented in this tempest damaged population, that have been little described. PMID- 21272857 TI - [Infective endocarditis complicating patent ductus arteriosus: emergency surgical treatment of two cases]. AB - Infective endocarditis is a rare complication of patent ductus arteriosus nowadays. About two patients, aged 7 and 5 years old, we diagnosed and treated a patent ductus arteriosus complicated with an infective vegetative endocarditis with a risk of pulmonary embolism. We report in this observation this clinical and surgical experience. PMID- 21272858 TI - [Intermediate lesion and multivessels disease: Interest of fractional flow reserve (FFR) to determine the strategy of revascularization]. AB - Most patients undergoing a catheterization did not have any previous non-invasive testing. Therefore, most decisions about revascularization are taken solely on the basis of the angiogram. Nowadays, it is possible to gain reliable functional information during catheterization by measuring fractional flow reserve (FFR). FFR is obtained by simple pressure measurements distal to the stenosis during maximal hyperemia. FFR-guided revascularization provides better clinical outcomes than angiographically-guided decisions. This is especially relevant in patients with multi-vessel disease and mild to moderate coronary plaque burden. FFR is able to determine the hemodynamic significance of each lesion individually and enables therefore guidance of the revascularization treatment. The case of a 62 year-old man with stable angina is reported. He underwent percutaneous coronary intervention of the left anterior descending 10 years ago. Repeat coronary angiogram revealed multi-vessel disease with a moderate stenosis in all main coronary arteries. Non-invasive functional assessment by myocardial perfusion imaging was inconclusive to evaluate presence or absence of ischemia. The use of FFR in this clinical scenario may be very useful to determine treatment strategy. PMID- 21272859 TI - In vitro synergism between berberine and miconazole against planktonic and biofilm Candida cultures. AB - OBJECTIVES: To investigate the antimycotic activity of the plant alkaloid berberine (BBR), alone and in combination with antifungal azoles, against planktonic and biofilm Candida cultures. DESIGN: The minimum inhibitory concentrations (MICs) of BBR, miconazole (MCZ), and fluconazole (FLC) towards Candida albicans, Candida glabrata, Candida kefyr, Candida krusei, Candida parapsilosis, and Candida tropicalis were determined by a microdilution method. For C. albicans, the synergistic effects of BBR combined with MCZ or FLC were examined in a paper disc agar diffusion assay and checkerboard microdilution assay. The effect of the BBR/MCZ combination was further investigated in a C. albicans biofilm formation model with a dual-chamber flow cell. The effect on metabolic activity of biofilm cells was established using 2,3-bis(2-methoxy-4 nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT)/menadione. RESULTS: Berberine inhibited the growth of various Candida species (MICs 0.98-31.25mg/L) in the following order of susceptibility: C. krusei > C. kefyr > C. glabrata > C. tropicalis > C. parapsilosis and C. albicans. Synergism between BBR and MCZ or FLC was observed in the disc diffusion assay as well as in suspension showing an FIC index <0.5 (?FIC=0.19). Whilst neither BBR (16 mg/L) nor MCZ (0.8 mg/L) alone significantly inhibited biofilm formation of C. albicans, their combination reduced biofilm formation by >91% after 24 h, as established from the reduction in surface area coverage (P<0.01). The BBR/MCZ combination also exhibited synergy against the metabolic activity of pre-formed C. albicans biofilms in polystyrene microtiter plates (?FIC=0.25). CONCLUSION: Berberine exhibits synergistic effects with commonly used antimycotic drugs against C. albicans, either in planktonic or in biofilm growth phases. PMID- 21272860 TI - Return of fear after retrospective inferences about the absence of an unconditioned stimulus during extinction. AB - We examined whether the effect of an extinction phase can be influenced retrospectively by information about the cause of the absence of the unconditioned stimulus (US) during that phase. Participants were subjected to a differential fear conditioning procedure, followed by an extinction procedure. Afterwards, half of the participants were presented with information about a technical failure, which explained why the US had been absent during the extinction phase. The other participants received information that was unrelated to the US. During a subsequent presentation of the target conditioned stimulus (CS), only the former group of participants showed renewed anticipatory skin conductance responding and a return of US expectancy. The results are in accordance with a propositional account of associative learning and highlight the importance of retrospective reasoning as a cause of relapse after exposure therapy. PMID- 21272861 TI - Dysfunctional reward circuitry in obsessive-compulsive disorder. AB - BACKGROUND: Obsessive-compulsive disorder (OCD) is primarily conceived as an anxiety disorder but has features resembling addictive behavior. Patients with OCD may develop dependency upon compulsive behaviors because of the rewarding effects following reduction of obsession-induced anxiety. Reward processing is critically dependent on ventral striatal-orbitofrontal circuitry and brain imaging studies in OCD have consistently shown abnormal activation within this circuitry. This is the first functional imaging study to investigate explicitly reward circuitry in OCD. METHODS: Brain activity during reward anticipation and receipt was compared between 18 OCD patients and 19 healthy control subjects, using a monetary incentive delay task and functional magnetic resonance imaging. Reward processing was compared between OCD patients with predominantly contamination fear and patients with predominantly high-risk assessment. RESULTS: Obsessive-compulsive disorder patients showed attenuated reward anticipation activity in the nucleus accumbens compared with healthy control subjects. Reduced activity of the nucleus accumbens was more pronounced in OCD patients with contamination fear than in patients with high-risk assessment. Brain activity during reward receipt was similar between patients and control subjects. A hint toward more dysfunctional reward processing was found in treatment-resistant OCD patients who subsequently were successfully treated with deep brain stimulation of the nucleus accumbens. CONCLUSIONS: Obsessive-compulsive disorder patients may be less able to make beneficial choices because of altered nucleus accumbens activation when anticipating rewards. This finding supports the conceptualization of OCD as a disorder of reward processing and behavioral addiction. PMID- 21272863 TI - Experimental and theoretical study of a Diels-Alder reaction between a sugar derived nitroalkene and cyclopentadiene. AB - The Diels-Alder reaction of a pyranose-derived nitroalkene 1 with cyclopentadiene is described, and the unexpected facial selectivity of the cycloaddition is analyzed by a computational study. PMID- 21272864 TI - Stereoselective synthesis of N-galactofuranosyl amides. AB - alpha- or beta-Galactofuranosyl (Galf) amides can be synthesized with high stereoselectivity by traceless Staudinger ligation starting from unprotected beta galactofuranosyl azide or tetra-O-acetyl-beta-galactofuranosyl azide, respectively. The resulting Galf amides are hitherto unknown molecules, with interesting potential as inhibitors of mycobacterial growth. PMID- 21272865 TI - An association between urinary cadmium and urinary stone disease in persons living in cadmium-contaminated villages in northwestern Thailand: a population study. AB - Excessive urinary calcium excretion is the major risk of urinary stone formation. Very few population studies have been performed to determine the relationship between environmental cadmium exposure and urinary stone disease. This population based study examined an association between urinary cadmium excretion, a good biomarker of long-term cadmium exposure, and prevalence of urinary stones in persons aged 15 years and older, who lived in the 12 cadmium-contaminated villages in the Mae Sot District, Tak Province, northwestern Thailand. A total of 6748 persons were interviewed and screened for urinary cadmium and urinary stone disease in 2009. To test a correlation between urinary excretion of cadmium and calcium, we measured urinary calcium content in 1492 persons, who lived in 3 villages randomly selected from the 12 contaminated villages. The rate of urinary stones significantly increased from 4.3% among persons in the lowest quartile of urinary cadmium to 11.3% in the highest quartile. An increase in stone prevalence with increasing urinary cadmium levels was similarly observed in both genders. Multiple logistic regression analysis revealed a positive association between urinary cadmium levels and stone prevalence, after adjusting for other co variables. The urinary calcium excretion significantly increased with increasing urinary cadmium levels in both genders, after adjusting for other co-variables. Elevated calciuria induced by cadmium might increase the risk of urinary stone formation in this environmentally exposed population. PMID- 21272866 TI - Distinct expression of the soluble and the membrane-bound forms of interleukin-1 receptor accessory protein in the endometrium of women with endometriosis. AB - OBJECTIVE: To investigate interleukin (IL) 1 receptor accessory protein (IL1RAcP) expression in the eutopic endometrium of women with endometriosis. DESIGN: Retrospective study. SETTING: Human reproduction research laboratory. PATIENT(S): Sixty-six women with endometriosis and 60 healthy women with no laparoscopic evidence of endometriosis. INTERVENTION(S): Endometrial tissue samples were obtained during laparoscopic surgery. MAIN OUTCOME MEASURE(S): IL1RAcP protein expression was analyzed by immunohistochemistry, Western blot, and ELISA, and IL1RAcP mRNA expression was analyzed by quantitative real-time polymerase chain reaction. RESULT(S): This study showed a significant downregulation of soluble (s)IL1RAcP expression in the eutopic endometrium of women with endometriosis compared to normal women, occurring at the protein or mRNA level. This finding appeared to vary according to endometriosis stage, being more obvious in the earliest (I and II) than the latest (III and IV) stages of the disease. However, the membrane-bound IL1RAcP did not show any noticeable endometriosis-related change, neither at the protein or mRNA level. CONCLUSION(S): In view of the wide spectrum of IL-1 inflammatory and growth-promoting effects, downregulation of sIL1RAcP, which is known for inhibiting IL1, indicates a profound defect in the capability of endometrial cells of women with endometriosis to counterregulate IL 1 effects and may represent an important mechanism underlying the ability of these cells to implant and develop into host tissues. PMID- 21272867 TI - Breast cancer and fertility preservation. AB - OBJECTIVE: To review the benefits of adjuvant systemic therapy given to women with breast cancer of reproductive age, its effects on fertility, and options for fertility preservation. DESIGN: Publications relevant to fertility preservation and breast cancer were identified through a PubMed database search. CONCLUSION(S): Most women who develop invasive breast cancer under age 40 will be advised to undergo adjuvant chemotherapy with or without extended antihormonal therapy to reduce the risk of recurrence and death from breast cancer. Adjuvant chemotherapy particularly with alkylating agents such as cyclophosphamide is gonadotoxic and markedly accelerates the rate of age-related ovarian follicle loss. Although loss of fertility is an important issue for young cancer survivors, there is often little discussion about fertility preservation before initiation of adjuvant therapy. Greater familiarity with prognosis and effects of different types of adjuvant therapy on the part of infertility specialists and fertility preservation options such cryopreservation of embryos, oocytes, and ovarian tissue on the part of oncologists would facilitate these discussions. Establishment of rapid fertility consultation links within cancer survivorship programs can help ensure that every young woman who is likely to undergo gonadotoxic cancer treatment is counseled about the effects of therapy and options available to her to increase the likelihood of childbearing after cancer treatment. PMID- 21272868 TI - Successful pregnancy with preimplantation genetic diagnosis in a woman with mosaic Turner syndrome. AB - OBJECTIVE: To determine the efficacy of the preimplantation cytogenetic analysis of the embryos obtained from patient with mosaic Turner syndrome before an IVF program. DESIGN: Prospective cytogenetic analysis. SETTING: University-based tertiary medical center. PATIENT(S): A 29 year-old female, a partner in a couple with male factor infertility, was diagnosed with mosaic Turner syndrome with a 45,X [17]/46,XX [13] karyotype. INTERVENTION(S): Preimplantation genetic diagnosis was performed on four blastomeres obtained from four different embryos by fluorescence in situ hybridization probes specific to chromosomes X, Y, 13, 18, 21 in an intracytoplasmic sperm injection cycle. MAIN OUTCOME MEASURE(S): Blastomeres with normal signals. RESULT(S): Two blastomeres detected as normal were transferred and pregnancy was achieved. CONCLUSION(S): Preimplantation Genetic Diagnose should be considered in the infertility treatment of the patient with mosaic Turner Syndrome. PMID- 21272870 TI - Endoscopic removal of a gastric trichobezoar in a pediatric patient. PMID- 21272869 TI - The great debate: varicocele treatment and impact on fertility. AB - OBJECTIVE: To evaluate the current literature on the impact and potential mechanisms of varicocele repair on male fertility. DESIGN: Pertinent articles were identified through computer PubMed search on varicocele repair and male factor infertility. References of selected articles were hand searched for additional citations. CONCLUSION(S): Varicocele repair has been shown to reverse a spectrum of effects contributing to men with impaired fertility. Clinical studies on the intervention have illustrated variable effects on postoperative sperm parameters and pregnancy rates (PR). Studies with conflicting results suffer from a significant number of confounding variables such as variable repair technique or lack of controls. Additional studies are warranted on the role of modern microsurgical varicocelectomy given the improvements in assisted reproductive technologies (ART). PMID- 21272871 TI - Success and complications associated with placement of fully covered removable self-expandable metal stents for benign esophageal diseases (with videos). AB - BACKGROUND: Fully covered esophageal self-expandable metal stents (FCSEMSs) are thought to induce less mucosal hyperplasia and are potentially removable. They may constitute an attractive alternative for the treatment of benign esophageal diseases. OBJECTIVE: To evaluate the efficacy and safety of FCSEMSs in the treatment of benign esophageal diseases. DESIGN: Patients referred for management of benign esophageal disease underwent placement of an FCSEMS and were entered into a prospective database and analyzed retrospectively for clinical response, efficacy, and morbidity. SETTING: Two tertiary care centers with long-standing experience in the management of benign esophageal strictures. PATIENTS: Between January 2006 and September 2007, 35 patients (mean age 61 years, range 20-85 years) underwent FCSEMS placement for benign esophageal diseases at 2 tertiary academic medical centers. There were 19 patients with benign esophageal strictures and 16 patients with leaks/perforations. INTERVENTION: Temporary placement of FCSEMS until stricture resolution. MAIN OUTCOME MEASUREMENTS: Clinical response, efficacy, and morbidity. RESULTS: Indications for stent placement were esophageal leak/fistulae (n = 12), refractory benign strictures (n = 10), anastomotic strictures (n = 7), perforations (n = 4), and radiation induced strictures (n = 2). Immediate complications were chest pain (2 patients), stent migration (2 patients), dysphagia (1 patient), respiratory compromise (1 patient), and arrhythmia (1 patient). Long-term complications included recurrent dysphagia (6 patients), aspiration pneumonia (2 patients), globus sensation (2 patients), abdominal pain (2 patients), and fever (1 patient). Stent migration was observed in 12 patients (34%). After placement, dysphagia scores at 1 month improved significantly from 3.1 +/- 1.0 to 1.2 +/- 1.3 (P < .0001). A total of 11 of 35 patients (31%) were treated successfully. Specifically, 21% of patients with refractory strictures and 44% of patients with leaks/fistulae had successful long-term outcomes without any need for reinterventions. All stents were retrieved successfully, except for 1 stent, which fractured and was retrieved in 2 pieces without any complications. CONCLUSION: Use of FCSEMSs for benign esophageal conditions was associated with frequent stent migration and long-term improvement in only one third of patients. Further investigation is required before recommending FCSEMS placement to treat benign diseases of the esophagus and to further characterize the subgroup that might benefit from these interventions. PMID- 21272872 TI - Acute pancreatitis and aspiration pneumonia after administration of synthetic human secretin (with video). PMID- 21272873 TI - Migrated anchoring gastric band removed by double-balloon enteroscopy. PMID- 21272874 TI - Use of adipose tissue-derived stromal cells for prevention of esophageal stricture after circumferential EMR in a canine model. AB - BACKGROUND: EMR is an accepted treatment for early esophageal carcinoma. However, resection of a large mucosal area often causes postoperative esophageal stricture. OBJECTIVE: To investigate the efficacy of autologous adipose tissue derived stromal cells (ADSCs) for prevention of stricture formation after EMR in dogs. DESIGN: Animal study. SETTING: University research center. INTERVENTION: Ten beagle dogs were randomized into a control group and an ADSCs-injected (ADSC) group. The ADSCs were isolated from autologous adipose tissue. Immediately after circumferential esophageal EMR, about 5 * 10(6) ADSCs suspended in 8 mL of phosphate-buffered saline solution were injected endoscopically into the residual submucosa of the ADSC group, whereas the control group received only 8 mL of phosphate-buffered saline solution. MAIN OUTCOME MEASUREMENTS: Dysphagia score, weight loss, rate of mucosal constriction, and histologic assessments. RESULTS: In the control and ADSC groups, the median dysphagia scores were 4 and 1 (P < .043), the mean degrees of mucosal constriction were 75.7% and 45.3% (P < .008), and the numbers of nascent microvessels in the submucosal layer were 7.4 and 16.2 per unit area (P = .007), respectively. Atrophy and fibrosis of the muscularis propria layer were observed in the control group. LIMITATIONS: Animal study, small sample size. CONCLUSION: Injection therapy with autologous ADSCs suppresses constriction of the esophageal mucosa and improves clinical symptoms after circumferential EMR in this canine model. PMID- 21272875 TI - Single-balloon versus double-balloon endoscopy for achieving total enteroscopy: a randomized, controlled trial. AB - BACKGROUND: Balloon endoscopy has been accepted as an effective tool for examining the small intestine. Two types of balloon endoscopy, single and double, are commercially available. The difference in performance between these 2 types of balloon endoscopy has not yet been elucidated. OBJECTIVE: To compare the yield of single-balloon endoscopy (SBE) and double-balloon endoscopy (DBE). DESIGN: Single-center, randomized, controlled trial. SETTING: University hospital in Tokyo, Japan. PATIENTS: Patients with suspected small-bowel disease. INTERVENTIONS: SBE and DBE. MAIN OUTCOME MEASUREMENTS: Outcomes were the total enteroscopy rate, diagnostic yield, complication rate, and clinical outcomes. Analysis was done by intent to treat. RESULTS: The study started in April 2008 and was terminated in April 2010 because of an obvious disadvantage for the SBE group. Thirty-eight patients were enrolled in the study; 18 patients were assigned to the SBE group and 20 to the DBE group. The total enteroscopy rate was 0% in the SBE group and 57.1% in the DBE group (P = .002). In terms of complications, the DBE group had 1 patient with Mallory-Weiss syndrome, and the SBE group had 1 patient with hyperamylasemia. There was no difference in the overall diagnosis rate between the SBE and DBE groups (61.1% vs 50.0%, P = .49). There was no difference in therapeutic outcome between the SBE and DBE groups (27.8% vs 35.0%, P = .63). LIMITATIONS: Relatively small number of study patients. CONCLUSIONS: Total enteroscopy is more easily performed with DBE than with SBE. PMID- 21272876 TI - Do we still need EUS in the workup of patients with early esophageal neoplasia? A retrospective analysis of 131 cases. AB - BACKGROUND: EUS is often used for locoregional staging of early esophageal neoplasia. However, its value compared with that of endoscopic examination and diagnostic endoscopic resection (ER) may be questioned because diagnostic ER allows histological assessment of submucosal invasion and other risk factors for lymph node metastasis, eg, poor differentiation/lymphovascular invasion. OBJECTIVE: To evaluate how often patients were excluded from endoscopic treatment of esophageal neoplasia based on EUS findings. DESIGN: Retrospective cohort study. SETTING: Tertiary care institution. PATIENTS: Patients with early esophageal neoplasia. INTERVENTIONS: EUS, diagnostic ER. MAIN OUTCOME MEASUREMENTS: Number of patients excluded from endoscopic treatment based on EUS results. RESULTS: A total of 131 patients were included (98 men, 33 women; age 66 +/- 13 years). In 105 of 131 patients (80%), EUS findings were unremarkable. In 25 of 105 patients (24%), diagnostic ER showed submucosal invasion (n = 17), deep resection margins positive for cancer (n = 2, confirmed at surgery), or poor differentiation/lymphovascular invasion (n = 6). In 26 of 131 patients (20%), EUS findings raised the suspicion of submucosal invasion and/or lymph node metastasis. In the 14 of 26 patients (54%) with abnormal EUS findings, endoscopy results were unremarkable. Diagnostic ER showed submucosal invasion in 7 of 14 (50%) patients, whereas no lymph node metastasis risk factors were found in 7 of 14 patients (50%), who subsequently underwent curative endoscopic treatment. In 12 of 26 patients (46%) with abnormal EUS, endoscopy also raised doubts on whether curative endoscopic treatment could be achieved. After diagnostic ER, no risk factors for lymph node metastasis were found in 3 of 12 patients (25%). LIMITATION: Retrospective study. CONCLUSIONS: This study shows that EUS has virtually no clinical impact on the workup of early esophageal neoplasia and strengthens the role of diagnostic ER as a final diagnostic step. PMID- 21272877 TI - Cicatricial stenosis after endoscopic submucosal dissection of esophageal cancer effectively treated with a temporary self-expandable metal stent. PMID- 21272878 TI - Efficient method for time-domain simulation of the linear feedback systems containing fractional order controllers. AB - One main approach for time-domain simulation of the linear output-feedback systems containing fractional-order controllers is to approximate the transfer function of the controller with an integer-order transfer function and then perform the simulation. In general, this approach suffers from two main disadvantages: first, the internal stability of the resulting feedback system is not guaranteed, and second, the amount of error caused by this approximation is not exactly known. The aim of this paper is to propose an efficient method for time-domain simulation of such systems without facing the above mentioned drawbacks. For this purpose, the fractional-order controller is approximated with an integer-order transfer function (possibly in combination with the delay term) such that the internal stability of the closed-loop system is guaranteed, and then the simulation is performed. It is also shown that the resulting approximate controller can effectively be realized by using the proposed method. Some formulas for estimating and correcting the simulation error, when the feedback system under consideration is subjected to the unit step command or the unit step disturbance, are also presented. Finally, three numerical examples are studied and the results are compared with the Oustaloup continuous approximation method. PMID- 21272879 TI - Backstepping sliding mode tracking control of a vane-type air motor X-Y table motion system. AB - Air motors are increasingly being used in pneumatic related industries because of their advantages of low operating cost and low maintenance. The DSP controller and the backstepping sliding mode control method were utilized in this study to control an X-Y pneumatic table for tracking trajectory. Due to the effects of the compressibility of air, friction between the motor and ball screw table and the dead-zone effect caused by the proportional valve, the system will yield different responses even with the same inlet pressure and will chatter at low speed. Hence under certain conditions, this method of backstepping sliding mode control can be applied to achieve better results than with the PID controller, such as for tracking circle error and tracking error of the two axes. According to the results, a steady-state error of 0.5 MUm can be achieved. The proposed method of backstepping sliding mode control can accomplish accurate tracking circle trajectory performance, offering an improvement in the tracking error of more than 50% over that of the PID controller. PMID- 21272880 TI - Difficulties in establishing long-term trauma outcomes data collections. Could trauma outcomes be routinely monitored in New South Wales, Australia: piloting a 3 month follow-up? AB - Injuries represent a significant health burden in Australia. In New South Wales (NSW), no routine follow-up of post-injury health outcomes is conducted. This article describes the development of a protocol and the conduct of a pilot study to collect information on trauma outcomes at 3 months post-injury at two trauma centres. A modified Victorian model of trauma outcomes monitoring was adopted, with potential participants required to 'opt in' to the collection. Fifty-three percent of individuals contacted consented to opt in, with 75% of these completing an interview. The data items collected were able to provide an indicator of the impact of trauma on individuals. This study has highlighted that there are important methodological issues to be addressed in terms of recruitment in establishing long-term trauma outcomes data collections that are representative of the trauma population. Ultimately, information from a long-term trauma outcomes collection could be linked to data collections to conduct research across the injury continuum. PMID- 21272881 TI - Postpartum contraceptive needs in northern Haiti. AB - OBJECTIVE: To assess the knowledge of, attitudes toward, and practices regarding postpartum contraception among healthcare providers and postpartum women in northern Haiti. METHODS: Six focus groups were conducted with postpartum patients and 3 were conducted with maternity service providers; a structured questionnaire was then administered to postpartum patients. RESULTS: In total, 282 postpartum women were included in the present study: 249 in the survey and 33 in focus groups. Although 97.9% of women expressed a desire for family-planning counseling before discharge from the postpartum ward, only 6.0% of women received such counseling. Most women wanted to space or limit their pregnancies; 79.8% of women, including those with only 1 child, wanted to choose a contraceptive method before discharge. Providers expressed concern for the volume of induced abortions and maternal deaths within the hospital, which many felt could be averted by improving postpartum family planning. However, there was no postpartum contraceptive counseling or method provision in the present setting, and no providers had experience in initiating methods immediately postpartum. CONCLUSION: Efforts to integrate family planning into postpartum care services could help to reduce the unmet need for family planning, and help patients and providers reach their goals. PMID- 21272882 TI - Descriptive epidemiology of Pap test results from women with gynecologic symptoms in Georgia. PMID- 21272883 TI - Length of the endometrial cavity and intrauterine contraceptive device expulsion. AB - OBJECTIVE: To evaluate the correlation between endometrial cavity length and expulsion rate in acceptors of the TCu380A intrauterine device (IUD) or the levonorgestrel-releasing intrauterine system (LNG-IUS). METHODS: The study included 235 nulligravida and parous women who received a TCu380A IUD or LNG-IUS and who were observed for up to 1 year. The length of the uterine cavity was measured by uterine sounding and ultrasonography. RESULTS: The endometrial cavity was shorter than 3.2 cm in 2 LNG-IUS users and at least 3.2 cm long in 87 LNG-IUS users, with expulsions occurring in 0 (0.0%) and 2 (2.3%) of these women, respectively (P>0.999). Among the TCu380A IUD users, the endometrial cavity was shorter than 3.6 cm in 63 women and at least 3.6 cm long in 83 women, with expulsions occurring in 3 (4.8%) and 5 (6.0%) of these women, respectively (P>0.999). The mean length of the endometrial cavity-evaluated via ultrasonography-among the 10 women whose devices were expelled was 3.9 +/- 0.3 cm, compared with 3.9 +/- 0.0 cm in those who retained their devices (P=0.799). CONCLUSION: The present results do not support the hypothesis of an association between uterine length and risk of intrauterine contraceptive expulsion. PMID- 21272884 TI - Adequacy of visual inspection with acetic acid in women of advancing age. AB - OBJECTIVE: The present study assessed the adequacy and predictive performance of visual inspection with acetic acid (VIA) in women over the age of 50 years and compared the specificity and sensitivity of VIA with that of the conventional cytology. METHODS: In total, 588 Salvadoran women ages 50-79 underwent VIA, Pap smear, and cervical biopsy. VIA was considered adequate if the squamocolumnar junction was completely visible. A positive biopsy was defined as cervical intraepithelial neoplasia (CIN) 2 or worse. RESULTS: Age was negatively correlated with VIA adequacy (P=0.04). Nevertheless, the majority of women-even in the older age groups-had adequate examinations. The adequacy of VIA was positively correlated with gravida (P=0.01) and was higher in women who had been treated by cryotherapy (P=0.02). The rate of positive biopsies was unexpectedly low (n=6 [1%]) making it difficult to assess the predictive performance of VIA. In this small sample, the sensitivities of VIA (17%) and Pap (33%) were low; the high number of false negatives could not be fully explained by inadequacy of the examinations. CONCLUSIONS: Adequacy of VIA declined with age. However, the squamocolumnar junction was visible to the naked eye in the majority of women, indicating that they are good candidates for VIA. PMID- 21272885 TI - Could intra-tendinous hyperthermia during running explain chronic injury of the human Achilles tendon? AB - Chronic tendinopathy of the human Achilles tendon (AT) is common but its injury mechanism is not fully understood. It has been hypothesised that heat energy losses from the AT during running could explain the degeneration of AT material seen with injury. A mathematical model of AT temperature distribution was used to predict what temperatures the core of the AT could reach during running. This model required input values for mechanical properties of the AT (stiffness, hysteresis, cross-sectional area (CSA), strain during running) which were determined using a combination of ultrasound imaging, kinematic and kinetic data. AT length data were obtained during hopping and treadmill running (12 kmph) using ultrasound images of the medial gastrocnemius (50 Hz) and kinematic data (200 Hz). AT force data were calculated from inverse dynamics during hopping and combined with AT length data to compute AT stiffness and hysteresis. AT strain was computed from AT length data during treadmill running. AT CSA was measured on transverse ultrasound scans of the AT. Mean +/- sd tendon properties were: stiffness = 176 +/- 41 Nmm(-1), hysteresis =17 +/- 12%, strain during running =3.5 +/- 1.8% and CSA = 42 +/- 8 mm(2). These values were input into the model of AT core temperature and this was predicted to reach at least 41 degrees C during running. Such temperatures were deemed to be conservative estimates but still sufficient for tendon hyperthermia to be a potential cause of tendon injury. PMID- 21272886 TI - Chiral separation of metalaxyl and benalaxyl fungicides by electrokinetic chromatography and determination of enantiomeric impurities. AB - The enantiomers of two acylamine fungicides (metalaxyl and benalaxyl) were separated by EKC using CDs as chiral selectors. The use of 15 mM succinyl-gamma CD for metalaxyl and 5 mM succinyl-beta-CD for benalaxyl dissolved in a 50 mM 2 morpholinoethanesulfonic acid buffer (pH 6.5), enabled the chiral separation of metalaxyl enantiomers in 11.5 min with a resolution of 3.1 and the enantiomeric separation of benalaxyl in 7.5 min with a resolution close to 15. Under these conditions, the two enantiomers of each of the chiral compound studied were also separated from folpet, very commonly present in fungicide formulations containing metalaxyl or benalaxyl. The analytical characteristics of the two developed methods were studied in terms of precision, linearity, selectivity, limits of detection (LODs) and limits of quantitation (LOQs) showing their suitability for the determination of these compounds in commercial agrochemical formulations. Finally, the development of an in-capillary preconcentration strategy allowed the detection of enantiomeric impurities up to 1.2% in commercial products labeled as enantiomerically pure in metalaxyl-M. PMID- 21272887 TI - Surface functionalized silica as a toolkit for studying aqueous phase palladium adsorption and mineralization on thiol moiety in the absence of external reducing agents. AB - Biological templates such as virions or protein assemblies have several surface functional groups that can complicate the elucidation of the fundamental mechanism(s) governing the sorption and mineralization of metals on the surface of the template. Surface functionalized silica nanoclusters with hydroxyl, amine, or thiol groups serve as surrogates for understanding the interaction between individual amino acid functionalities and inorganic precursors. Analysis of palladium ion uptake on the functionalized silica enabled the investigation of a new palladium mineralization strategy using thiol surface moieties in the absence of external reducing agents. This study reveals the nature of the palladium-thiol interaction and the resulting self-reduction mechanism that produces the metal palladium nanolayer on the thiol-terminated silica. This surface functionalized silica approach is thus an effective toolkit for exploring the fundamentals of metal precursor sorption on surface functional groups, and for developing new metal deposition methodologies. PMID- 21272888 TI - Transition metal complexes on mesoporous silica nanoparticles as highly efficient catalysts for epoxidation of styrene. AB - We have synthesized a series of catalysts for epoxidation of styrene by immobilizing salicylaldimine transition metal (copper, manganese, and cobalt) complexes on mesoporous silica nanoparticles (MSNs) with diameters of 120-150 nm. The prepared catalysts are characterized by infrared (IR) spectra, thermal gravimetric analyses (TGA), inductively coupled plasma (ICP), CHN elemental analysis, nitrogen adsorption-desorption, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). These catalysts possess excellent catalytic efficiency in epoxidation of styrene when using tert-BuOOH (TBHP) as oxidant. Styrene shows a high conversion (~99%) as well as epoxide selectivity (~80%) over Cu-MSN catalysts, and high conversion (~99%) and moderate epoxide selectivity (~65%) over Mn-MSN and Co-MSN catalysts. The recycling experiment results indicate that these catalysts maintain catalytic activity even after being used for three cycles. Our results indicate that MSNs can serve as better catalyst supports. PMID- 21272889 TI - Growth of gold nanorods in gelled surfactant solutions. AB - Gold nanorods have been actively studied for new nanotechnological materials and industrial applications. It is well known that gold nanorods grow spontaneously in surfactant solutions, and a number of procedures for their preparation have been reported; however, the factors that determine the morphology have not been well understood. In this study, we observed the time series of the growth process of gold nanorods in gelled surfactant solutions by completely stopping the growth reaction. This growth process was compared to that in solution without gelation. The comparison indicates that the self-assembly of surfactant molecules affected the resulting shape, especially the short-axis length, of the nanorods. Small angle neutron scattering (SANS) experiments revealed that the gelled solutions form lamellar structures, whereas nongelled systems form spherical micelles. On the bases of these results, we present a model showing that the short-axis length of gold nanorods is affected by a decrease in the spontaneous curvature of the outer surfactant layer and/or an increase in the bending modulus of the surfactant membrane neighboring the gold surface. PMID- 21272890 TI - Preparation of electrospun luminescent polyimide/europium nanofibers by simultaneous in situ sol-gel and imidization processes. AB - Luminescent polyimide (PI)/europium nanofibers have been successfully prepared by electrospinning combined with an in situ sol-gel technique. The possible reaction mechanism of the simultaneous imidization of polyamide acid and gelation of europium phase was analyzed by thermogravimetric analysis (TG) and differential scanning calorimetry (DSC). The results showed that chemical coupling and noncovalent interaction existed between the polymer and the europium which formed during the preparative process. Fourier-transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), and scanning electronic spectroscopy (SEM) studies also indicated the successful incorporation of europium into PI matrix and various morphologies could be achieved by controlling the calcination temperature and the europium content. Nanofibers with necklace-like structures were obtained after calcination under high temperatures. These PI/europium nanofibers were further demonstrated to have strong fluorescence emission. The intensity ratio for the PI/europium nanofibers, labeled as ((5)D(0) >(7)F(2))/((5)D(0)->(7)F(1)), which is well known as the asymmetry parameter, was lower than that in pure Eu(2)O(3) powder, indicating that there were highly symmetric coordination spheres around europium in the nanofibers. PMID- 21272891 TI - Diffusion of sodium dodecyl sulfate micelles in agarose gels. AB - The gradient diffusion of ionic sodium dodecyl sulfate micelles in agarose gel was investigated at moderate concentrations above the CMC. Of particular interest were the effects of micelle, gel, and sodium chloride concentration on the micelle diffusivity. Holographic interferometry was used to measure the gradient diffusion coefficient at three sodium chloride concentrations (0, 0.03, 0.10 M), three gel concentrations (0, 1, 2 wt%), and several surfactant concentrations. Time-resolved fluorescence quenching was used to measure aggregation numbers both in solution and gel. The micelle diffusivity increased linearly with surfactant concentration at the two larger sodium chloride concentrations and all gel concentrations. In general, the strength of this effect increased with decreasing sodium chloride concentration and increased with gel concentration. This behavior is evidence of decreasing micelle-micelle electrostatic interactions with increasing sodium chloride concentrations, and increasing excluded volume effects and hydrodynamic screening with increasing gel concentration, respectively. The only exception was at 0.1M sodium chloride and 2 wt% agarose, which showed a slight reduction in the slope compared to 1 wt% agarose. It was found that the concentration effect is quite strong for charged solutes: at a NaCl concentration of 0.03 M in a 2% agarose gel, in a solution with 3% SDS micelles by volume, the micelle diffusion coefficient is doubled relative to its value in the same gel at infinite dilution. The extrapolated, infinite-dilution diffusion coefficients and the rate at which the micelle diffusivity increased with surfactant concentration were compared with predictions of previously published theories in which the micelles are treated as charged, colloidal spheres and the gel as a Brinkman medium. The experimental data and theoretical predictions were in good agreement. PMID- 21272892 TI - Microemulsion-mediated sol-gel synthesis of mesoporous rutile TiO2 nanoneedles and its performance as anode material for Li-ion batteries. AB - Mesoporous rutile TiO(2) nanoneedles have been successfully synthesized using a reverse microemulsion-mediated sol-gel method at room temperature. The materials were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), and the Bruauner-Emmet-Teller (BET) adsorption method, and their electrochemical properties were investigated by galvanostatic charge and discharge tests. XRD observations revealed the formation of a pure rutile TiO(2) phase. Furthermore, TEM observation revealed the presence of a highly porous needle-like morphology. The electrochemical measurements show that the nanoneedles deliver an initial capacity of 305 mA h g(-1) as anode material for Li-ion batteries and sustain a capacity value of 128 mA h g(-1) beyond 15 cycles. The reported synthesis is simple, mild, energy efficient, and without postcalcination. PMID- 21272893 TI - Concentration- and pH-dependence of highly alkaline sodium silicate solutions. AB - In this study two routes for the gelation of water glass have been investigated; the destabilization by a change in pH and by an increase in concentration through evaporation. Both methods produce optically transparent, highly viscous, homogeneous solutions. The structure and dynamics of the solutions along the two routes have been investigated with dynamic light scattering, (29)Si-Nuclear Magnetic Resonance spectroscopy, viscosity measurements and infrared spectroscopy. We find that the two routes are fundamentally different. Increasing the concentration of the sodium silicate system leaves the silica speciation apparently unchanged. Lowering the pH leads to condensation reactions, thus a change in the silica speciation. PMID- 21272894 TI - Applying the WHO ICF framework to communication assessment and goal setting in Huntington's disease: a case discussion. AB - PURPOSE: Huntington's Disease (HD) is a fatal, hereditary neurodegenerative disorder that is characterized by a triad of motor, cognitive and psychiatric symptoms that impact on both communicative effectiveness and the treatment techniques used to maximize communicative participation. The purpose of this article is to describe the application of the World Health Organization's International Classification of Functioning, Disability and Health (ICF) to communication assessment and goal setting for a 37 year old man with HD. METHOD: Communication assessment consisted of qualitative interviews based on the ICF framework with the client and his mother, supplemented with quantitative communication assessments. Analysis and conceptualization of assessment information was completed with a modified version of the Rehabilitation Problem Solving Form (RPS-Form) (Steiner et al., 2002). RESULTS: While impairments in body structures and functions were evident, analysis revealed that environmental factors such as family support were both key barriers and facilitators to communicative participation. CONCLUSIONS: This case illustrates the potential of using the ICF to conceptualize communicative functioning and disability in HD and particularly highlights the importance of consideration of personal and environmental factors in revealing contributions to activity limitations and participation restrictions. Further investigation of applications of ICF for individuals with HD is suggested. LEARNING OUTCOMES: As a result of this activity, readers will recognize the application of the WHO ICF to assessment and goal setting in a complex hereditary condition, Huntington Disease. As a result of this activity, readers will describe the use of the Rehabilitation Problem Solving Form (RPS-Form) for communication disorders. As a result of this activity, readers will identify relevant issues in comprehensive communication assessment of a fatal, degenerative neurological condition such as the advantages and challenges of clinical use of the ICF and its coding. As a result of this activity, readers will introduce life storybooks as a potential legacy item in degenerative diseases. PMID- 21272895 TI - Stroke in tuberculous meningitis. AB - Stroke in tuberculous meningitis (TBM) occurs in 15-57% of patients especially in advance stage and severe illness. The majority of strokes may be asymptomatic because of being in a silent area, deep coma or associated pathology such as spinal arachnoiditis or tuberculoma. Methods of evaluation also influence the frequency of stroke. MRI is more sensitive in detecting acute (DWI) and chronic (T2, FLAIR) stroke. Most of the strokes in TBM are multiple, bilateral and located in the basal ganglia especially the 'tubercular zone' which comprises of the caudate, anterior thalamus, anterior limb and genu of the internal capsule. These are attributed to the involvement of medial striate, thalamotuberal and thalamostriate arteries which are embedded in exudates and likely to be stretched by a coexistent hydrocephalus. Cortical stroke can also occur due to the involvement of proximal portion of the middle, anterior and posterior cerebral arteries as well as the supraclinoid portion of the internal carotid and basilar arteries which are documented in MRI, angiography and autopsy studies. Arteritis is more common than infarction in autopsy study. The role of cytokines especially tumor necrosis factor (TNFalpha), vascular endothelial growth factor (VEGF) and matrix metaloproteineases (MMPs) in damaging the blood brain barrier, attracting leucocytes and release of vasoactive autocoids have been suggested. The prothrombotic state may also contribute to stroke in TBM. Corticosteroids with antitubercular therapy were thought to reduce mortality and morbidity but their role in reducing strokes has not been proven. Aspirin also reduces mortality and its role in reducing stroke in TBM needs further studies. PMID- 21272896 TI - Endovascular repair of arterio-bronchial fistula of the outflow graft of HeartMate II left ventricular assist device. PMID- 21272897 TI - Effect of remote ischemic preconditioning on renal dysfunction after complex valvular heart surgery: a randomized controlled trial. AB - OBJECTIVE: Acute kidney injury after cardiac surgery with cardiopulmonary bypass is closely related to systemic inflammatory reactions and oxidative stresses. Remote ischemic preconditioning is a systemic protective strategy whereby brief limb ischemia confers systemic protection against prolonged ischemia and inflammatory reactions in distant organs. This study investigated whether remote ischemic preconditioning provides systemic protective effect on kidneys that are not directly exposed to ischemia-reperfusion injury during complex valvular heart surgery. METHODS: Seventy-six adult patients undergoing complex valvular heart surgery were randomly assigned to either remote ischemic preconditioning group (n = 38) or control group (n = 38). Remote ischemic preconditioning consisted of 3 10-minute cycles of lower limb ischemia and reperfusion with an automated cuff inflator. Primary end points were comparisons of biomarkers of renal injury including serum creatinine, cystatin C and neutrophil gelatinase-associated lipocalin, and incidence of acute kidney injury. Secondary end points were comparisons of myocardial enzyme release and pulmonary parameters. RESULTS: There were no significant differences in serum levels of biomarkers of renal injury between groups throughout the study period. The incidence of acute kidney injury did not differ between groups. Creatine kinase isoenzyme MB at 24 hours after surgery was lower, and intensive care unit stay was shorter in the remote ischemic preconditioning group than in the control group. CONCLUSIONS: In patients undergoing complex valvular heart surgery, remote ischemic preconditioning did not reduce degree of renal injury or incidence of acute kidney injury whereas it did reduce myocardial injury and intensive care unit stay. PMID- 21272898 TI - Early systemic-to-pulmonary artery shunt intervention in neonates with congenital heart disease. AB - OBJECTIVE: To determine the incidence, risk factors, and outcomes after early, unplanned intervention on systemic-to-pulmonary artery shunts in neonates. METHODS: We retrospectively studied all neonates undergoing systemic-to-pulmonary artery shunt placement at The Children's Hospital of Philadelphia between September 1, 2002, and May 1, 2005. Patients requiring transcatheter or surgical systemic-to-pulmonary artery shunt intervention before discharge were compared with those not undergoing shunt intervention. RESULTS: A total of 206 patients underwent shunt placement. Diagnoses included hypoplastic left heart syndrome (62.1%), pulmonary atresia (15%), tricuspid atresia (4.9%), tetralogy of Fallot (2.4%), and other lesions with obstruction to systemic (10.7%) or pulmonary blood flow (4.9%). Twenty-one interventions occurred in 20 patients (9.7%). Risk factors for intervention included heterotaxy syndrome (P = .04), congenital abnormality (P = .04), and a trend toward lower birthweight. In patients with a modified Blalock-Taussig shunt, similar risk factors were identified and the incidence of intervention decreased with increasing shunt size. In-hospital mortality was 30% (6/20) for the cases and 8.1% (15/186) for the nonintervention group (P = .02). Long-term survival was significantly lower in patients requiring intervention (P = .002). This group also had a higher incidence of infections (P < .001) and extracorporeal membrane oxygenation (P < .001), and longer hospital stay (P = .001). CONCLUSIONS: In neonates undergoing systemic-to-pulmonary artery shunt placement, approximately 10% underwent shunt intervention before discharge. Some factors, such as low birthweight, shunt size, noncardiac congenital abnormalities, and heterotaxy syndrome, may help identify patients at risk. Patients undergoing intervention experienced increased morbidity and mortality. PMID- 21272899 TI - Enhanced left ventricular mass regression after aortic valve replacement in patients with aortic stenosis is associated with improved long-term survival. AB - BACKGROUND: Aortic valve replacement in patients with aortic stenosis is usually followed by regression of left ventricular hypertrophy. More complete resolution of left ventricular hypertrophy is suggested to be associated with superior clinical outcomes; however, its translational impact on long-term survival after aortic valve replacement has not been investigated. METHODS: Demographic, operative, and clinical data were obtained retrospectively through case note review. Transthoracic echocardiography was used to measure left ventricular mass preoperatively and at annual follow-up visits. Patients were classified according to their reduction in left ventricular mass at 1 year after the operation: group 1, less than 25 g; group 2, 25 to 150 g; and group 3, more than 150 g. Kaplan Meier and multivariable Cox regression were used. RESULTS: A total of 147 patients were discharged from the hospital after aortic valve replacement for aortic stenosis between 1991 and 2001. Preoperative left ventricular mass was 279 +/- 98 g in group 1 (n = 47), 347 +/- 104 g in group 2 (n = 62), and 491 +/- 183 g in group 3 (n = 38) (P < .001). Mean time to last echocardiogram was 6.2 +/- 3.2 years. Left ventricular mass at late follow-up was 310 +/- 119 g in group 1, 267 +/- 107 g in group 2, and 259 +/- 96 g in group 3 (P = .05). Transvalvular gradients at follow-up were not significantly different among the groups (group 1, 24.8 +/- 23 mm Hg; group 2, 21.4 +/- 16 mm Hg; group 3, 14.7 +/- 9 mm Hg) (P = .31). There was no difference in the prevalence of other factors influencing left ventricular mass regression such as ischemic heart disease or hypertension, valve type, or valve size used. Ten-year actuarial survival was not statistically different in patients with enhanced left ventricular mass regression when compared with the log-rank test (group 1, 51% +/- 9%; group 2, 54% +/- 8%; and group 3, 72% +/- 10%) (P = .26). After adjustment, left ventricular mass reduction of more than 150 g was demonstrated as an independent predictor of improved long-term survival on multivariate analysis (P = .02). CONCLUSIONS: Our study is the first to suggest that enhanced postoperative left ventricular mass regression, specifically in patients undergoing aortic valve replacement for aortic stenosis, may be associated with improved long-term survival. In view of these findings, strategies purported to be associated with superior left ventricular mass regression should be considered when undertaking aortic valve replacement. PMID- 21272900 TI - Assessment of Hurricane Ivan impact on chlorophyll-a in Pensacola Bay by MODIS 250 m remote sensing. AB - The impact of Hurricane Ivan on water quality in Pensacola Bay was investigated by MODIS 250m remote sensing of chlorophyll-a concentrations at different time slots before and after the hurricane event. Before the hurricane, the mean chlorophyll-a in the Bay was 5.3 MUg/L. Heavy rainfall occurred during the hurricane landfall. The 48 h rainfall reached 40cm and the peak storm surge reached 3m on 9/16. After the rainstorm and during the storm surge on 9/17/2004, the mean chlorophyll-a concentration substantially increased to 14.7 MUg/L. 26.3% water area was in the poor-water-quality condition (chl-a>20 MUg/L). This indicates that heavy nutrient loads from urban stormwater runoff and storm-surge inundation simulated chlorophyll bloom. After the end of the storm surge on 9/18/2004, the mean chlorophyll dropped to 2.0 MUg/L, suggesting the effective flushing of polluted water from the bay to the Gulf of Mexico by the storm-surge. The good water quality condition lasted for almost several weeks after the storm surge. The peak river flow, arriving on the 4th day after the peak storm surge, did not alter the good water quality situation in the bay. This indicates that urban stormwater runoff rather than the river inflow is the major pollutant source for water quality in Pensacola Bay during the hurricane. PMID- 21272901 TI - Altered multihormone synchrony in obese patients with polycystic ovary syndrome. AB - Luteinizing hormone (LH) concentrations and pulsatility are increased in obese women with polycystic ovary syndrome (PCOS). In addition, patients have hyperandrogenemia and insulin resistance. The mechanisms involved in aberrant hormone regulation in PCOS are still unclear. We investigated 15 obese PCOS women with a body mass index between 30 and 54 kg/m(2) and 9 healthy obese controls (body mass index, 31-60 kg/m(2)) with regular menstrual cycles. Subjects underwent 24-hour blood sampling at 10-minute intervals for later measurements of LH, leptin, testosterone, and insulin concentrations. Data were analyzed with a new deconvolution program, approximate entropy (and bivariate approximate entropy), and a cross-correlation network. Patients had increased LH pulse frequency and more than 2-fold greater daily LH secretion, with diminished pattern regularity. Testosterone secretion was increased 2-fold, but pattern regularity was similar to that in controls. In the network construct, insulin was correlated positively with LH, whereas leptin and testosterone were correlated negatively with LH. Bivariate synchrony of LH with insulin was decreased. Short term caloric restriction paradoxically increased LH secretion by 1.5-fold and pattern irregularity, and reduced interpulse variability. Testosterone secretion and fasting concentrations of estradiol and sex hormone-binding globulin levels remained unchanged. Correlations between LH and insulin, leptin, and calculated free testosterone decreased. This study demonstrates marked alterations in the control of LH secretion in PCOS in the fed and calorie-restricted states. The ensemble results point to abnormal feedback control of not only the GnRH gonadotrope complex, but also LH's relationships with leptin, insulin, and testosterone. PMID- 21272902 TI - Effect of food prices on the prevalence of obesity among young adults. AB - OBJECTIVE: To examine the extent to which various food prices were associated with the obesity status of young adults. STUDY DESIGN: Retrospective cohort study of 6537 men and 5324 women in the USA using panel data from the Monitoring the Future Surveys (1992-2003), which were merged with two food-at-home and one food away-from-home price measures from the American Chamber of Commerce Researchers Association. METHODS: Longitudinal individual random effect and fixed effect models were estimated. RESULTS: This study found that food prices did not have a significant effect on the prevalence of obesity among young female adults. For young adult men, an individual random effect estimator suggested that a 10% increase in the price of fast food was associated with a 13.2% decrease in the probability of obesity, but this effect lost its economic and statistical significance once individual fixed effects were controlled for in the estimation. CONCLUSIONS: Overall, the results imply that observed time-varying individual characteristics, such as working status, marital status and school enrolment status, may over-ride the effect of changes in food prices for young adults. More research employing longitudinal data is necessary to determine if food subsidies or taxes, particularly soft drink and fast food taxes or subsidies for fruit and vegetables, could be effective policy measures to curtail the increasing prevalence of obesity among young adults. PMID- 21272903 TI - [A custom-made nasal splint designed with 3D modelisation]. PMID- 21272904 TI - [Unusual zygomatic fracture in infants]. PMID- 21272905 TI - Lamb waves in two-dimensional phononic crystal plate with anisotropic inclusions. AB - An analysis is given to the band structure of the two-dimensional phononic crystal plate constituted of a square array of elastic anisotropic, circular Pb cylinders embedded in elastic isotropic epoxy. The numerical results show that the band gap can be tuned by rotating the anisotropic material orientation. It is found that the influence of anisotropy on band gap of Lamb wave is clearly different from that on the band gap of bulk waves. The thickness of the system under study is a sensitive parameter to affect the influence of anisotropic materials on the normalized gap width. PMID- 21272906 TI - Insertion of CTCF-binding sites into a first-generation adenovirus vector reduces the innate inflammatory response and prolongs transgene expression. AB - We have made improvements to E1-deleted adenovirus (Ad) transducing vectors that both substantially reduce the innate inflammatory response provoked by the virus in BALB/c mouse ears and increase the duration of expression of the GFP transgene in BALB/c mouse liver. These improvements result from testing the hypothesis that induction of strong innate responses is primarily a result of the powerful enhancer contained within the strong CMV promoter activating expression of Ad genes retained within the vector. A DNA fragment containing four CTCF-binding sites, which was expected to act as a chromatin insulator, was introduced 5', 3', or both 5' and 3' of a CMV-GFP cassette in an attempt to reduce activation of Ad gene expression by the enhancer. The presence of this sequence in any of the configurations led to reduction of the innate immune response, as assayed by mouse ear swelling, to the low level induced by a virus deleted for the E1 region and carrying no introduced sequence. In addition, the duration of GFP expression in the liver more than doubled. The prolonged GFP expression indicates that GFP does not play the limiting role in shutting down vector expression. The CTCF binding sequence introduced appears to act as a chromatin insulator in Ad DNA, but position-independence of the elements in reducing the innate immune response indicate unanticipated complexities in the mechanism by which Ad vectors induce innate immune responses. PMID- 21272907 TI - Isolation and characterization of cynomolgus macaque (Macaca fascicularis) cytomegalovirus (CyCMV). AB - Cynomolgus macaques have been widely used as an animal model in preclinical biomedical research and are becoming more popular among HIV/SIV vaccine researchers. Here we report the isolation and characterization of a cytomegalovirus from cynomolgus macaques (CyCMV). CyCMV was isolated from a healthy captive-bred 4-year-old cynomolgus macaque of Filipino origin. The virus was identified by its characteristic growth properties in cell culture, ultrastructural morphology and sequence of viral DNA polymerase and glycoprotein B (gB). CyCMV gB shows 77% identity and 88% homology to rhesus cytomegalovirus (RhCMV) gB and 58% identity and 76% homology to human cytomegalovirus gB at the amino acid level. Phylogenetic analysis using known CMV gB protein sequences show that CyCMV is more closely related to RhCMV than to other primate CMVs. CyCMV down-regulates MHC class I expression on infected cells and we show that the colony-bred cynomolgus macaques have detectable CyCMV-specific humoral and cell mediated immune responses. PMID- 21272908 TI - An antiviral RISC isolated from Tobacco rattle virus-infected plants. AB - The RNAi model predicts that during antiviral defense a RNA-induced silencing complex (RISC) is programmed with viral short-interfering RNAs (siRNAs) to target the cognate viral RNA for degradation. We show that infection of Nicotiana benthamiana with Tobacco rattle virus (TRV) activates an antiviral nuclease that specifically cleaves TRV RNA in vitro. In agreement with known RISC properties, the nuclease activity was inhibited by NaCl and EDTA and stimulated by divalent metal cations; a novel property was its preferential targeting of elongated RNA molecules. Intriguingly, the specificity of the TRV RISC could be reprogrammed by exogenous addition of RNA (containing siRNAs) from plants infected with an unrelated virus, resulting in a newly acquired ability of RISC to target this heterologous genome in vitro. Evidently the virus-specific nuclease complex from N. benthamiana represents a genuine RISC that functions as a readily employable and reprogrammable antiviral defense unit. PMID- 21272909 TI - Associations between maternal phthalate exposure and cord sex hormones in human infants. AB - It has been speculated that maternal phthalate exposure may affect reproductive development in human newborns. However, the mechanism awaits further investigation. The aim is to evaluate the association between maternal phthalate exposure and cord sex steroid hormones in pregnant women and their newborns from the general population. A total of 155 maternal and infant pair were recruited and analyzed. Levels of urinary phthalate metabolites and sex steroid hormones were determined using liquid chromatography/electrospray tandem mass spectrometry (LC-ESI-MS/MS) and radioimmunoassay (RIA), respectively. No significant correlation was found between each steroid hormones and phthalate metabolites for male newborns, except MMP was marginally significantly correlated with E(2). After adjusting for maternal age, estradiol (E(2)) levels in cord serum from male newborns were not correlated with maternal urinary phthalate metabolites. In female newborns, the maternal urinary levels of mono-(2-ethylhexyl) phthalate (MEHP) and mono-(2-ethyl-5-hydroxyhexyl) phthalate (5OH-MEHP) were negatively correlated with the free testosterone (fT) and fT/E(2) levels in cord serum with Pearson correlation coefficients ranging between -0.24 and -0.29 (p<0.05). Additionally, after gestational age was adjusted, the maternal urinary level of DEHP was negatively correlated with the free testosterone (fT) and fT/E(2) levels in cord serum. We suggest that maternal exposure to phthalates may affect sex steroid hormones status in fetal and newborn stage. PMID- 21272910 TI - Comparison of polyurethane foam and biodegradable polymer as carriers in moving bed biofilm reactor for treating wastewater with a low C/N ratio. AB - This paper presents a comparison between two different materials used as carriers: inert polyurethane (PU) foam and biodegradable polymer polycaprolactone (PCL) particles for the removal of organics and nitrogen from wastewater with a low C/N ratio using moving bed biofilm reactors. The results, during a monitoring period of four months, showed that TOC and ammonium removal efficiency was higher in reactor 2 filled with PU carriers than in reactor 1 filled with PCL carriers (90% and 65% in the former, compared with 72% and 56% in the latter at an hydraulic retention time of 14 h). Reactor 1 showed good behavior in terms of total nitrogen removal as the biodegradable polymer was an effective substrate providing reducing power for denitrification. From three-dimensional excitation emission matrix analysis, it was shown that the effluent from reactor 1 contained mainly protein-like and soluble microbial product-like substances. PMID- 21272911 TI - Passive dosing: an approach to control mutagen exposure in the Ames fluctuation test. AB - One of the major challenges for mutagenicity assessment of environmental samples and individual compounds for example in the Ames fluctuation test (AFT) is the establishment and control of a well defined exposure concentration. Thus, a combination of passive dosing with silicone O-rings (SRs) together with an analytical confirmation of the freely dissolved concentration (FDC) is presented. FDCs are often determined with a combination of solid phase micro-extraction (SPME) with gas chromatography (GC). For compounds with poor performance in GC, a high performance liquid chromatography-mass spectrometry (HPLC-MS) analysis of bi distilled water dosed with identically loaded SRs is suggested to avoid interference of the bacterial culture. The approach was tested for six amino-, nitro-, and keto-substituted polycyclic aromatic compounds with a logK(OW) range of 2.5-5.1 without metabolic activation. The method provided reliable concentration-effect relationships and freely dissolved 50% effect concentrations (DEC(50)) 3-33 times lower than nominal effect concentrations (NEC(50)) derived in parallel solvent-dosed AFT. Partition coefficients and NEC(50)/DEC(50) ratios were well correlated with lipophilicity. PMID- 21272912 TI - Role of microbial exopolymeric substances (EPS) on chromium sorption and transport in heterogeneous subsurface soils: I. Cr(III) complexation with EPS in aqueous solution. AB - Chromium (III) binding by exopolymeric substances (EPS) isolated from Pseudomonas putida P18, Pseudomonas aeruginosa P16 and Pseudomonas stutzeri P40 strains were investigated by the determination of conditional stability constants and the concentration of functional groups using the ion-exchange experiments and potentiometric titrations. Spectroscopic (EXAFS) analysis was also used to obtain information on the nature of Cr(III) binding with EPS functional groups. The data from ion-exchange experiments and potentiometric titrations were evaluated using a non-electrostatic discrete ligand approach. The modeling results show that the acid/base properties of EPSs can be best characterized by invoking four different types of acid functional groups with arbitrarily assigned pK(a) values of 4, 6, 8 and 10. The analysis of ion-exchange data using the discrete ligand approach suggests that while the Cr binding by EPS from P. aeruginosa can be successfully described based on a reaction stoichiometry of 1:2 between Cr(III) and HL(2) monoprotic ligands, the accurate description of Cr binding by EPSs extracted from P. putida and P. stutzeri requires postulation of 1:1 Cr(III)-ligand complexes with HL(2) and HL(3) monoprotic ligands, respectively. These results indicate that the carboxyl and/or phosphoric acid sites contribute to Cr(III) binding by microbial EPS, as also confirmed by EXAFS analysis performed in the current study. Overall, this study highlights the need for incorporation of Cr-EPS interactions into transport and speciation models to more accurately assess microbial Cr(VI) reduction and chromium transport in subsurface systems, including microbial reactive treatment barriers. PMID- 21272913 TI - Polybrominated diphenyl ethers and organochlorine compound levels in brown trout (Salmo trutta) from Andean Patagonia, Argentina. AB - Polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), DDTs and endosulfan residues were analyzed in muscle, liver, gonads, gills and stomach content of brown trout (Salmo trutta) from the Andean Patagonia. PBDEs, PCBs and DDTs levels were positively correlated with lipid content, while less hydrophobic endosulfans showed a poor correlation. Endosulfan levels were about 99.9% of total contaminant (highest levels in liver 500*10(3)ng g(-1) lipid weight), with alpha-/beta-isomers ratio >1 in all organs. These results are in agreement to the current-use of the technical endosulfan and also suggest acute exposure to this insecticide. Conversely, DDT/DDE ratio reflects fish exposure to old DDT sources, showing a DDE predominance. Gills had the highest levels of DDTs, PCBs and PBDEs, indicating they represent the main uptake pathway for such hydrophobic compounds from water column. PCBs showed the lowest levels in all organs and the PBDEs/PCBs ratios >1 agree with worldwide trends. PBDEs levels in gonads, gills, liver and muscle exceeded 80 ng g(-1) (lipid weight) and were higher than other values reported in the Southern Hemisphere. BDE-47 was the predominant congener, suggesting higher bioaccumulation potential and possible brown trout metabolism of higher congeners. Since there is no point source of PBDEs in the region and residues were dominated by lower brominated congeners, atmospheric transport could be the main source of these compounds. This first report of PBDEs levels in fish from Argentina contributes to the knowledge about environmental trends of these persistent organic pollutants (POPs) in remote areas such as the Andean Patagonia. PMID- 21272914 TI - Mercury species of sediment and fish in freshwater fish ponds around the Pearl River Delta, PR China: human health risk assessment. AB - This study investigated total mercury (THg) and methylmercury (MeHg) concentrations in five species of freshwater fish and their associated fish pond sediments collected from 18 freshwater fish ponds around the Pearl River Delta (PRD). The concentrations of THg and MeHg in fish pond surface sediments were 33.1-386 ng g(-1) dry wt and 0.18-1.25 ng g(-1) dry wt, respectively. The age of ponds affected the surface sediment MeHg concentration. The vertical distribution of MeHg in sediment cores showed that MeHg concentrations decreased with increasing depth in the top 10 cm. In addition, a significant correlation was observed between %MeHg and DNA from Desulfovibrionacaea or Desulfobulbus (p<0.05) in sediment cores. Concentrations of THg and MeHg in fish muscles ranged from 7.43-76.7 to 5.93-76.1 ng g(-1) wet wt, respectively, with significant linear relationships (r=0.97, p<0.01, n=122) observed between THg and MeHg levels in fish. A significant correlation between THg concentrations in fish (herbivorous: r=0.71, p<0.05, n=7; carnivorous: r=0.77, p<0.05, n=11) and corresponding sediments was also obtained. Risk assessment indicated that the consumption of largemouth bass and mandarin fish would result in higher estimated daily intakes (EDIs) of MeHg than reference dose (RfD) for both adults and children. PMID- 21272915 TI - Reversed association between levels of prostate specific antigen and levels of blood cadmium and urinary cadmium. AB - Prostate cancer associated with cadmium exposure may indicate a link between prostate specific antigen (PSA) and levels of blood cadmium (BCd) and urinary cadmium (UCd). Thus, these associations were investigated. We recruited 295 men, 50 years of age and above from a health check-up program at a health center as subjects of the study. They completed a self-reported questionnaire and provided fasting samples of blood and urine for cadmium assay. The assay was performed using atomic absorption spectrophotometry. Blood samples were also collected for the assays of total cholesterol and high-density lipoprotein measures. The means of BCd and UCd increased with age and the means of all subjects were 1.19+/-1.04 MUg L(-1) and 1.37+/-1.76 MUg g(-1) creatinine, respectively. The PSA levels were positively associated with the lipid levels, but reversely associated with BCd and UCd levels. The multivariate logistic regression analysis showed that men with PSA>=4.0 ng m L(-1) had an odds ratio (OR) of 0.4 (95% CI=0.1-0.9) to have BCd>0.49 MUg L(-1), and an OR of 0.4 (95% CI=0.2-1.0) to have UCd>0.45 MUg g(-1) creatinine. In conclusion, the PSA levels are reversely associated with BCd and UCd levels. PMID- 21272916 TI - Microcalorimetric studies of perchlorate on heat production by hepatocytes and mitochondria isolated from Carassius auratus. AB - As a new threat to environment all through the world, perchlorate (ClO(4)(-)) was predominantly a thyrotoxin, and its toxic manifestations in non-thyroid were also documented. However, little is known about the effects of ClO(4)(-) on cell and organelle. Therefore, the present study was designed to investigate the effects of ClO(4)(-) on hepatocytes and mitochondria isolated from Carassius auratus from the direct viewpoint of energy by using the microcalorimetric method. The metabolic thermogenic curves of hepatocytes and mitochondria at 25 degrees C were obtained. And the thermokinetic parameters, such as growth rate constant (k), inhibitory ratio (I), maximum thermal power (P(max)) and total thermal effect (Q(total)) have been calculated. The results indicated that the toxicity of ClO(4)(-) on hepatocytes was relevant to the concentration of ClO(4)(-). However, 10-100mgL(-1)ClO(4)(-) stimulated the metabolic activity of mitochondria and the toxicity of ClO(4)(-) on mitochondria only occurrenced when treated with higher concentration of ClO(4)(-). This study shown that mitochondria has a major impact on the metabolic thermogenic of hepatocytes, but not the only factor. Meanwhile, it demonstrated that microcalorimetry was a powerful tool for understanding biological processes and studying on the toxic action of environmental contaminants in cell or subcellular level. PMID- 21272917 TI - Geno-toxicity assay of sediment and water samples from the Upper Silesia post mining areas, Poland by means of Allium-test. AB - Genotoxic potential of two environmental compartments (water and sediment) from the Upper Silesia Coal Basin (USCB), Poland were evaluated and compared by employing root meristem cells of Allium cepa. The clear genotoxic effect of water and sediment sampled was shown, with an important contribution of severe types of cytogenetic abnormalities. The most biologically relevant pollutants were revealed through multivariate statistical analysis of relationships between biological effects registered and the environment contamination. Overall, results of simultaneous use of conventional monitoring methods and biological tests suggested that contemporary levels of persistent pollutants in post-mining areas of the USCB may enhance the risk both for human health and biological components of natural ecosystems. PMID- 21272918 TI - Effects of salinities on the gene expression of a (NAD+)-dependent glycerol-3 phosphate dehydrogenase in Dunaliella salina. AB - Glycerol-3-phosphate dehydrogenase (G3pdh) is a key enzyme in the pathway of glycerol synthesis, which converts dihydroxyacetone phosphate (DHAP) to glycerol 3-phosphate. In this study, the effects of salinity changes on variation of cell shape and single cell glycerol content of Dunaliella salina were observed, and the effects of salinity changes on the gene expressions of a (NAD+)-dependent G3pdh (EC1.1.1.8) among G3pdh isozymes in D. salina were detected by real-time quantitative PCR. Results showed that the changes of shape and volume of D. salina cell cultured chronically at various salinities were minor, but when the salinity was changed rapidly, the variations of cell shape and cell volume of D. salina were significant, which were recovered basically after 2h except treating by high salinity. Also, it was found some lipid globules in the surface of D. salina cells when the salinity increased from 2.0 to 4.0-5.0 M NaCl rapidly. When D. salina was cultured chronically at various salinities, the accumulation of single cell glycerol increased with increased salinity, and D. salina also could rapidly decrease or increase single cell glycerol contents to adapt to hypoosmotic or hyperosmotic shock. The expression level of G3pdh in D. salina grown at various salinities was significantly inversely correlated to the salinity, but there was no significant correlation between the expression level of G3pdh and salinity after 2 h of treatment by hyperosmotic or hypoosmotic shock. PMID- 21272919 TI - Scale-dependency of macroinvertebrate communities: responses to contaminated sediments within run-of-river dams. AB - Due to their nutrient recycling function and their importance in food-webs, macroinvertebrates are essential for the functioning of aquatic ecosystems. These organisms also constitute an important component of biodiversity. Sediment evaluation and monitoring is an essential aspect of ecosystem monitoring since sediments represent an important component of aquatic habitats and are also a potential source of contamination. In this study, we focused on macroinvertebrate communities within run-of-river dams, that are prime areas for sediment and pollutant accumulation. Little is known about littoral macroinvertebrate communities within run-of-river dam or their response to sediment levels and pollution. We therefore aimed to evaluate the following aspects: the functional and structural composition of macroinvertebrate communities in run-of-river dams; the impact of pollutant accumulation on such communities, and the most efficient scales and tools needed for the biomonitoring of contaminated sediments in such environments. Two run-of-river dams located in the French alpine area were selected and three spatial scales were examined: transversal (banks and channel), transversal x longitudinal (banks/channel x tail/middle/dam) and patch scale (erosion, sedimentation and vegetation habitats). At the patch scale, we noted that the heterogeneity of littoral habitats provided many available niches that allow for the development of diversified macroinvertebrate communities. This implies highly variable responses to contamination. Once combined on a global 'banks' spatial scale, littoral habitats can highlight the effects of toxic disturbances. PMID- 21272920 TI - Arsenic trioxide induces procoagulant activity through phosphatidylserine exposure and microparticle generation in endothelial cells. AB - BACKGROUND: Coagulopathy is a major cause of early death when arsenic trioxide (As(2)O(3)) therapy fails. In addition to the procoagulant properties of blast cells, the cytotoxic therapy may contribute to the coagulation disorders. The aim of the present study was to evaluate the possible impact of As(2)O(3) on membrane alterations, including phosphatidylserine (PS) exposure and microparticle generation, and the consequent procoagulant properties of endothelial cells. METHODS: Procoagulant activity (PCA) of human umbilical vein endothelial cells (HUVECs) was assessed by measuring clotting time and through purified coagulation complex assays. PS exposure on HUVEC membrane was observed by confocal microscopy and quantified with flow cytometry. In addition, counts and PCA of endothelial microparticles were determined by flow cytometry and plasma coagulation assay. RESULTS: As(2)O(3) increased the ability of HUVECs to accelerate coagulation process and promote formation of coagulation complexes. Procoagulant activity corresponded to PS exposed on HUVECs. In coincidence with the PS externalization, As(2)O(3) increased the production of PS-bearing microparticles, which then accelerated fibrin strand formation significantly. By blocking PS, lactadherin was able to inhibit over 90% of the intrinsic tenase/prothrombinase activity of As(2)O(3)-treated HUVECs, and restored coagulation times of As(2)O(3)-treated cells and microparticles to control levels. CONCLUSIONS: As(2)O(3) increases PCA of HUVECs through PS exposure and PS-bearing microparticle generation, which might cause thrombosis and act as a contributing factor in As(2)O(3) therapy related coagulopathy. PMID- 21272922 TI - Elevated numbers and altered subsets of procoagulant microparticles in breast cancer patients using endocrine therapy. AB - INTRODUCTION: Microparticles (MP) can be elevated in cancer and thromboembolic disease. We hypothesized a role for MP in the hypercoagulable state in breast cancer patients using endocrine therapy, in whom both cancer and the use of endocrine therapy are independent risk factors for the development of thrombosis. DESIGN AND METHODS: Plasma samples were collected from 40 breast cancer patients using endocrine therapy (20 patients without metastases receiving adjuvant therapy and 20 patients with metastatic disease treated in a palliative setting) and from 20 female healthy controls. The endocrine therapy used was either an anti-estrogen or an aromatase inhibitor. Numbers and cellular origin of MP subsets were analyzed by flowcytometry. MP-associated procoagulant activity was measured using a thrombin generation assay using conditions that allow analysis of MP induced thrombin generation. RESULTS: Breast cancer patients using endocrine therapy had higher levels of MP positive for Annexin V (median 10000 vs 6500*10E6/l), P-selectin (330 vs 200*10E6/l), tissue factor (33 vs 15*10E6/l), and of MP derived from platelets (CD41) and leukocytes (CD45). Thrombin generation in plasma was dependent on the presence of MP and thrombin generation performed after addition of isolated MP to normal plasma showed a higher endogenous thrombin potential (1105 vs 1029 nM.min) in breast cancer patients. No differences were observed in MP levels and thrombin generation parameters between the metastatic and adjuvant group. CONCLUSION: Breast cancer patients using endocrine therapy have an increased MP number and a higher MP-dependent thrombin generation, irrespective of the presence of metastatic disease. Altered MP subset characteristics in these patients, especially the higher number of (activated) platelet derived MP and leukocyte derived MP, may in part explain a heightened procoagulant state in breast cancer patients using endocrine therapy. PMID- 21272923 TI - The Feverfew plant-derived compound, parthenolide enhances platelet production and attenuates platelet activation through NF-kappaB inhibition. AB - INTRODUCTION: Few treatments are available that can safely and effectively stimulate new platelet production for thrombocytopenic patients. Additionally, recipients of transfused platelets may experience an inflammatory response due to stored platelets becoming unnecessarily activated, thus creating the need for suitable agents that will dampen undesirable platelet activation. We investigated the effect of the feverfew plant-derived compound, parthenolide on platelet production and platelet activation because of its well-studied ability to induce apoptosis or differentiation in some types of cancer. METHODS: Parthenolide was used to treat human megakaryoblastic cell lines, primary human and mouse megakaryocytes. Resulting platelet production and function was measured via flow cytometry. The two most common parthenolide signaling mechanisms, oxidative stress and nuclear factor-kappaB inhibition, were assessed within the megakaryocytes using reactive oxygen species, glutathione and luciferase reporter assays. The influence of parthenolide on ex vivo platelet activation was tested with parthenolide pretreatment followed by collagen or thrombin activation. The resulting P-selectin surface expression and released soluble CD40 ligand was measured. RESULTS: Parthenolide stimulates functional platelet production from human megakaryocyte cell lines, and from primary mouse and human megakaryocytes in vitro. Parthenolide enhances platelet production via inhibition of nuclear factor-kappaB signaling in megakaryocytes and is independent of the parthenolide induced oxidative stress response. Additionally, parthenolide treatment of human peripheral blood platelets attenuated activation of stimulated platelets. CONCLUSION: Overall, these data reveal that parthenolide has strong potential as a candidate to enhance platelet production and to dampen undesirable platelet activation. PMID- 21272924 TI - Overexpression of Thy1/CD90 in human hepatocellular carcinoma is associated with HBV infection and poor prognosis. AB - Thy1/CD90 is an important marker of many types of stem cells. It functions as a tumor suppressor in ovarian cancer and in nasopharyngeal carcinoma. In this study, the expression status of Thy1 in clinical hepatocellular carcinoma (HCC) tissue samples was investigated. Relationships of Thy1 expression with clinical parameters and patient survival rate were analyzed. The quantities of Thy1 mRNA were statistically higher in tumor tissues than those in the adjacent non-tumor tissues (p<0.001). Immunohistochemical data confirmed that Thy1 protein was increased in 73% of HCC samples. Thy1 expression was not influenced by chronic alcohol exposure or cirrhosis. Overexpression in Thy1 was correlated with age (p=0.006), hepatitis B virus (HBV) infection (p=0.044), and histological grade (p=0.014). Patients with the highest level of Thy1 expression showed the poorest prognosis (p=0.040). In conclusion, overexpression of Thy1 may not suppress the development of HCC. Thy1 could provide a clinical prognostic marker for HCC. PMID- 21272925 TI - Semirigid ureteroscopy in management of large proximal ureteral calculi: is there still a role in developing countries? AB - OBJECTIVES: To evaluate the outcome and complications of the use of semirigid ureteroscopy (URS) together with intracorporeal pneumatic lithotripsy in the management of upper ureteral calculi >10 mm in diameter. METHODS: A total of 75 patients (41 women and 34 men), with a mean age of 48 years (range 25-60), underwent primary URS for solitary radiopaque proximal ureteral calculi 10-20 mm in diameter (average 13.1). Dilation of the intramural ureter was done in 60 cases (80% of patients), and intracorporeal lithotripsy was required in 56 (74.6%). Ureteral catheters were left for drainage in 60% of patients, 26.7% were left unstented, and only 13.3% required an indwelling stent. RESULTS: Of the 75 stones, 60 (80%) were successfully cleared after a single endoscopic procedure. Our initial stone-free rate was 90.6% at 2 weeks after the primary endoscopic procedure and had reached 98.6% at 3 months. Antegrade URS for migrating stones was done successfully in 6 cases in a tubeless fashion, and open ureterolithotomy was required in 1 case. No major complications were encountered. The minor complications included only mild extravasation and self-limited postoperative fever and hematuria. The risk factors for URS failure included male gender, the severity of the hydronephrosis, the severity of impaction, and the occurrence of extravasation. CONCLUSIONS: The results of our study have shown that semirigid URS is a safe and successful alternative to open ureterolithotomy in the management of large proximal ureteral calculi in the absence of flexible instruments. PMID- 21272926 TI - Side population is increased in paclitaxel-resistant ovarian cancer cell lines regardless of resistance to cisplatin. AB - OBJECTIVES: In recent years, cancer stem cells (CSCs) have been reported to be correlated with chemoresistance and may also be enriched in side populations (SPs). In this study, the relationship between resistance to paclitaxel (PTX) and cisplatin (CDDP) and side populations was examined in three parental PTX- and CDDP-sensitive ovarian cancer cell lines (2008, KF28, and TU-OM-1) and several other cell lines derived from these as well as the additional effects of interferon-alpha (INF-alpha). METHODS: SP of three different parental cell lines and PTX- and/or CDDP-resistant cell lines derived from these was analyzed with flow cytometry. The expression of ABCB1 and ABCG2 in KF28 and its derived cell lines was examined. Additional cell-death effect of INF-alpha with PTX was also examined. RESULTS: In the three parental cell lines and the PTX-sensitive cell lines derived from these lines, SP was very low. Conversely, in PTX-resistant cell lines, regardless of CDDP resistance, SP increased. ABCB1 was strongly expressed in the PTX-resistant cells, but not in their parental lines, which are sensitive to PTX. While INF-alpha showed only slight enhancement of the cell death effect of PTX in PTX-sensitive cells, INF-alpha itself strongly induced apoptosis in PTX-resistant cells regardless of PTX concentration. CONCLUSIONS: The SP could be correlated with resistance to PTX. SP could be a target of INF alpha, and resistance to PTX might be overcome by INF-alpha. PMID- 21272927 TI - Mite allergen is a danger signal for the skin via activation of inflammasome in keratinocytes. AB - BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disorder caused by multiple factors. Among them, house dust mite (HDM) allergens are important in the development of AD. In airway allergy, HDM allergens activate innate immunity. However, information regarding the activation of innate immunity by HDM allergens in the skin is limited. OBJECTIVES: The inflammasome is a key regulator of pathogen recognition and inflammation. We investigated whether HDM allergens activate the inflammasome in epidermal keratinocytes. METHODS: Keratinocytes were stimulated with Dermatophagoides pteronyssinus, and the activation of caspase-1 and secretion of IL-1beta and IL-18 were examined. Formation of the inflammasome was studied by analyzing the subcellular distributions of inflammasome proteins. The importance of specific inflammasome proteins was studied by knocking down their expression through transfection of keratinocytes with lentiviral particles carrying short hairpin RNAs (shRNAs). RESULTS: D pteronyssinus activated caspase 1 and induced caspase-1-dependent release of IL-1beta and IL-18 from keratinocytes. Moreover, D pteronyssinus stimulated assembly of the inflammasome by recruiting apoptosis-associated specklike protein containing a caspase recruitment domain (ASC), caspase-1, and nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin-domain containing 3 (NLRP3) to the perinuclear region. Finally, infection with lentiviral particles carrying ASC, caspase-1, or NLRP3 shRNAs suppressed the release of IL-1beta and IL-18 from the keratinocytes. Activation of the NLRP3 inflammasome by D pteronyssinus was dependent on cysteine protease activity. CONCLUSION: House dust mite allergens are danger signals for the skin. In addition, HDM-induced activation of the NLRP3 inflammasome may play a pivotal role in the pathogenesis of AD. PMID- 21272928 TI - Quantification of specific IgE to whole peanut extract and peanut components in prediction of peanut allergy. PMID- 21272929 TI - Leukocyte nicotinamide adenine dinucleotide phosphate-reduced oxidase is required for isocyanate-induced lung inflammation. AB - BACKGROUND: Isocyanates are low-molecular-weight compounds noted for inducing occupational and environmental asthma. Isocyanate-induced lung disease, an oxidant stress-dependent pulmonary inflammation, is the leading cause of occupational asthma. OBJECTIVES: To address the role of leukocyte-produced oxidants in airway inflammation induced by toluene diisocyanate (TDI), and to elucidate the role of leukocyte nicotinamide adenine dinucleotide phosphate reduced (NADPH) oxidase in pathogenesis by TDI. METHODS: Wild-type mice and NADPH oxidase-deficient mice (neutrophil cytosolic factor 1 mutant, Ncf1(-/-)) were intranasally injected, challenged with inhalatory TDI, and then investigated for lung inflammation. RESULTS: Cell infiltration in lung tissue and leukocytes in bronchoalveolar lavage, airway reactivity to a methacholine challenge, and TDI induced inflammatory cytokine expression and nuclear factor activation in the lung tissue were all markedly lower in Ncf1(-/-) mice. Wild-type mice treated with blocking antibodies against CD4 and IL-17 showed markedly lower TDI-induced airway hyperresponsiveness. CONCLUSION: Leukocyte NADPH oxidase is an essential regulator in TDI-induced airway inflammation through redox modification of immune responses. PMID- 21272930 TI - The N400 effect in children: relationships with comprehension, vocabulary and decoding. AB - Using event-related potentials (ERPs), we investigated the N400 (an ERP component that occurs in response to meaningful stimuli) in children aged 8-10 years old and examined relationships between the N400 and individual differences in listening comprehension, word recognition and non-word decoding. Moreover, we tested the claim that the N400 effect provides a valuable indicator of behavioural vocabulary knowledge. Eighteen children were presented with picture word pairs that were either 'congruent' (the picture depicted the spoken word) or 'incongruent' (they were unrelated). Three peaks were observed in the ERP waveform triggered to the onset of the picture-word stimuli: an N100 in fronto central channels, an N200 in central-parietal channels and an N400 in frontal, central and parietal channels. In contrast to the N100 peak, the N200 and N400 peaks were sensitive to semantic incongruency with greater peak amplitudes for incongruent than congruent conditions. The incongruency effects for each peak correlated positively with listening comprehension but when the peak amplitudes were averaged across congruent/incongruent conditions they correlated positively with non-word decoding. These findings provide neurophysiological support for the position that sensitivity to semantic context (reflected in the N400 effect) is crucial for comprehension whereas phonological decoding skill relates to more general processing differences reflected in the ERP waveform. There were no correlations between ERP and behavioural measures of expressive or receptive vocabulary knowledge for the same items, suggesting that the N400 effect may not be a reliable estimate of vocabulary knowledge in children aged 8-10 years. PMID- 21272931 TI - pH-responsive endosomolytic pseudo-peptides for drug delivery to multicellular spheroids tumour models. AB - Endosomolytic polymers can aid in the endosomal release of therapeutics to improve intracellular drug delivery. pH-responsive biomimetic pseudo-peptides were synthesised by grafting l-phenylalanine onto the pendant carboxylic acids of a polyamide, poly(l-lysine isophthalamide). PP-75 (stoichiometric l-phenylalanine grafting of 75 mol%) was determined to have the best endosomolytic property. The mean hydrodynamic size of PP-75 decreased with lower pH as the polymers adopted a more compact conformation due to protonation of acidic groups and increase in hydrophobicity. PP-75 was demonstrated to deliver model drugs effectively in three dimensional (3D) magnetic HeLa multicellular spheroids used as in vitro tumour models. These spheroids can be isolated easily and quickly by magnetic separation. Due to its relatively small size, PP-75 was able to penetrate from the exterior to the interior of these spheroids and was internalised by the cells in the spheroids. It could retain its pH-mediated membrane-lytic capability in 3D drug delivery by releasing internalised calcein from intracellular endosomes in the tumour models. Furthermore, cell viability results suggest that PP-75 showed no significant cytotoxicity towards cells in the spheroids. The pH-responsive PP 75 can potentially enhance the extracellular and intracellular delivery of therapeutics in tumours. PMID- 21272932 TI - Enhanced endosomal escape of siRNA-incorporating hybrid nanoparticles from calcium phosphate and PEG-block charge-conversional polymer for efficient gene knockdown with negligible cytotoxicity. AB - Development of safe and efficient short interfering RNA (siRNA) delivery system for RNA interference (RNAi)-based therapeutics is a current critical challenge in drug delivery field. The major barriers in siRNA delivery into the target cytoplasm are the fragility of siRNA in the body, the inefficient cellular uptake, and the acidic endosomal entrapment. To overcome these barriers, this study is presenting a hybrid nanocarrier system composed of calcium phosphate comprising the block copolymer of poly(ethylene glycol) (PEG) and charge conversional polymer (CCP) as a siRNA vehicle. In these nanoparticles, the calcium phosphate forms a stable core to incorporate polyanions, siRNA and PEG CCP. The synthesized PEG-CCP is a non-toxic endosomal escaping unit, which induces endosomal membrane destabilization by the produced polycation through degradation of the flanking cis-aconitylamide of CCP in acidic endosomes. The nanoparticles prepared by mixing of each component was confirmed to possess excellent siRNA-loading efficiency (~80% of dose), and to present relatively homogenous spherical shape with small size. With negligible cytotoxicity, the nanoparticles efficiently induced vascular endothelial growth factor (VEGF) mRNA knockdown (~80%) in pancreatic cancer cells (PanC-1). Confocal laser scanning microscopic observation revealed rapid endosomal escape of siRNA with the nanoparticles for the excellent mRNA knockdown. The results obtained demonstrate our hybrid nanoparticle as a promising candidate to develop siRNA therapy. PMID- 21272933 TI - Spatially directed guidance of stem cell population migration by immobilized patterns of growth factors. AB - We investigated how engineered gradients of exogenous growth factors, immobilized to an extracellular matrix material, influence collective guidance of stem cell populations over extended time (>1 day) and length (>1 mm) scales in vitro. Patterns of low-to-high, high-to-low, and uniform concentrations of heparin binding epidermal growth factor-like growth factor were inkjet printed at precise locations on fibrin substrates. Proliferation and migration responses of mesenchymal stem cells seeded at pattern origins were observed with time-lapse video microscopy and analyzed using both manual and automated computer vision based cell tracking techniques. Based on results of established chemotaxis studies, we expected that the low-to-high gradient would most effectively direct cell guidance away from the cell source. All printed patterns, however, were found to direct net collective cell guidance with comparable responses. Our analysis revealed that collective "cell diffusion" down a cell-to-cell confinement gradient originating at the cell starting lines and not the net sum of directed individual cell migration up a growth factor concentration gradient is the principal driving force for directing mesenchymal stem cell population outgrowth from a cell source. These results suggest that simple uniform distributions of growth factors immobilized to an extracellular matrix material may be as effective in directing cell migration into a wound site as more complex patterns with concentration gradients. PMID- 21272934 TI - Review: Placental syncytiotrophoblast membranes--domains, subdomains and microdomains. AB - Human placental syncytiotrophoblast (STB) is an epithelium responsible for materno-fetal exchange. Ions play multiple roles in STB, as in other transport epithelia. We have been interested in the character and functional expression of ion channels in STB membrane fractions. Characterization of ion channels and their relationship with different domains, subdomains and microdomains of STB membranes is important to explain the intracellular mechanisms operating in the placental barrier. The aim of this paper is to summarize our work on this subject. We isolated and purified basal membrane (BM) and two fractions from the apical membrane, a classical fraction (MVM) and a light fraction (LMVM). They were used either for reconstitution into giant liposomes or for transplantation into Xenopus oocyte membranes followed by electrophysiological recordings to characterize chloride and cationic channels in STB from term human placenta. In addition, Western blot analysis, using ion channel antibodies, was performed on purified apical and basal membrane fractions. We also reported the presence of two functional microdomains (lipid rafts) in LMVM and MVM, using detergent resistant membranes (DRMs) and cholesterol-sensitive depletion. Moreover we found evidence of cytoskeletal participation in lipid rafts of different composition. Our results contribute to knowledge of the ion channels present in STB membranes and their participation in the physiology of this epithelium in normal and pathological pregnancies. PMID- 21272935 TI - Pancreatic cancer bears overexpression of neurotensin and neurotensin receptor subtype-1 and SR 48692 counteracts neurotensin induced cell proliferation in human pancreatic ductal carcinoma cell line PANC-1. AB - The presence of neurotensin and neurotensin receptors has been demonstrated in human pancreatic carcinomas using autoradiography and Northern blot analysis. In vitro studies have reported that the neurotensin antagonist SR 48692 could inhibit the growth of MIA PaCa-2 cells in a neurotensin mediated fashion, and neurotensin could overcome this inhibition or stimulate proliferation. However, it is currently unknown whether such actions are exerted on PANC-1 cells. In addition, the immunolocation of neurotensin and neurotensin receptors is still unclear in human pancreatic ductal carcinoma tissues. Immunohistochemistry was applied to detect the distribution of neurotensin and neurotensin receptor subtype-1 in human pancreatic ductal carcinoma and normal pancreatic tissues. Furthermore, an in vitro study was carried out to test the pharmacological profile of neurotensin and SR 48692 in human pancreatic ductal carcinoma cell line PANC-1. Compared with normal pancreatic tissues, pancreatic ductal carcinoma tissues have higher neurotensin and neurotensin receptor subtype-1 expression rates. Pancreatic ductal carcinomas (32/40) bear the expression of both neurotensin and neurotensin receptor subtype-1. We observed that neurotensin (10 11-10-7 M) significantly stimulated the proliferation of PANC-1 and SR 48692 (10 11-10-7 M) alone had no effect on the growth of PANC-1 cells; however, SR 48692 (10-10-10-6 M) inhibited the stimulatory effect of neurotensin (10-9 M). Considering the overexpression of both neurotensin and neurotensin receptor subtype-1 in pancreatic ductal carcinomas, it could enable us to develop markers for pancreatic cancer diagnosis. As SR 48692 could inhibit neurotensin induced cell growth, neurotensin receptor subtype-1 may serve as a therapeutic target for the therapy of pancreatic carcinomas. Furthermore, our study indicates that the counteraction of neurotensin and neurotensin receptor subtype-1 regulates the genesis and development of pancreatic carcinomas. PMID- 21272936 TI - Histopathological effects and EROD induction in common carp exposed to dietary heavy oil. AB - Common carp, Cyprinus carpio, was exposed to 1% and 5% dietary heavy oil for 2 weeks. Higher polyaromatic hydrocarbons (PAHs) accumulation induced higher hepatic EROD activity in exposure groups compared with the control group. Significant histological alternations were observed in the liver such as nuclear and cellular hypertrophy, accumulation of eosinophilic granules in cytoplasm, nuclear degeneration and fibrillar inclusion in cytoplasm. Severe damage of the kidney was indicated by nuclear and cellular degeneration, and ultimately necrosis in the tubular epithelium cells. In addition, dilated glomerulus with hemorrhage was found in the renal capsule. The mean assessment value (MAV) and degree of tissue changes (DTC), as semi-quantitative analyses, were significantly increased with concentration and duration of exposure. Likewise, frequencies of pathological lesions in both liver and kidney were also increased with concentration and duration of exposure. PMID- 21272937 TI - Fronto-limbic dysfunction in borderline personality disorder: a 18F-FDG positron emission tomography study. AB - INTRODUCTION: Several functional neuroimaging studies have demonstrated abnormalities in fronto-limbic pathways when comparing borderline personality disorder (BPD) patients with controls. The present study aimed to evaluate regional cerebral metabolism in euthymic BPD patients with similar measured impulsivity levels by means of 18F-FDG PET during resting state and to compare them against a control group. METHODS: The present study evaluates regional cerebral metabolism in 8 euthymic BPD patients with 18F-FDG PET during resting state as compared to 8 controls with similar socio-geographic characteristics. RESULTS: BPD patients presented a marked hypo-metabolism in frontal lobe and showed hyper-metabolism in motor cortex (paracentral lobules and post-central cortex), medial and anterior cingulus, occipital lobe, temporal pole, left superior parietal gyrus and right superior frontal gyrus. No significant differences appeared in basal ganglia or thalamus. CONCLUSIONS: Results reveal a dysfunction in patients' frontolimbic network during rest and provide further evidence for the importance of these regions in relation to BPD symptomatology. PMID- 21272938 TI - Full and partial PTSD among young adult survivors 10 months after the L'Aquila 2009 earthquake: gender differences. AB - BACKGROUND: Earthquakes are one of the most frequently occurring natural disasters and extensive research has been conducted on mental disorders on exposed populations, particularly on post-traumatic stress disorder (PTSD). On April 6th 2009, the town of L'Aquila (Abruzzo), in central Italy, was struck by an earthquake with a strength of 5.9 on the Richter scale. In the town of L'Aquila many buildings collapsed and large parts of the town were destroyed. Overall, 309 people were killed, 1600 injured among which 200 severely injured and hospitalized, more than 65,000 people were displaced. METHODS: The aim of the present study was to investigate prevalence rates of PTSD, either full-blown or partial PTSD, among 512 students attending the last year of high school in L'Aquila about 10 months after the earthquake. According to the literature, partial PTSD was defined as the presence of symptoms in the DSM-IV Criterion B and C or D for PTSD diagnosis. Gender differences in the symptoms reported were investigated. Assessments included the Trauma and Loss Spectrum-Self Report (TALS SR) and the Impact of Event Scale (IES). RESULTS: The results of the present study showed the presence of a diagnosis of PTSD in 192 (37.5%) of the students examined, with significantly (p=.000) higher rates in women than men (N=120, 51.7% and N=72, 25.7%, respectively). Moreover, 153 (29.9%) students reported partial PTSD (75, 32.3% women and 78, 27.9% men respectively). Significantly higher PTSD symptoms were reported by women with respect to men. LIMITATIONS: The lack of information on the impact of the earthquake on subjects and on the presence of Axis I psychiatric comorbidities are two major limitations besides the use of self-report instruments. CONCLUSIONS: Our results show high rates of full or partial PTSD in adolescents who survived the April 2009 L'Aquila earthquake, with women being the most affected. Thus, these results highlight the need to carefully explore these conditions. PMID- 21272939 TI - Daily variations in sleep-wake patterns and severity of psychopathology: a pilot study in community-dwelling individuals with chronic schizophrenia. AB - The daily co-occurrence of change in sleep characteristics and psychopathology was examined in six individuals with schizophrenia and seven healthy controls using a prospective assessment of rest-activity patterns conducted in the person's home for up to 28 days. The results provide preliminary evidence that a change in sleep-wake timing is followed by a change in symptom severity. PMID- 21272940 TI - Why do some voluntary patients feel coerced into hospitalisation? A mixed-methods study. AB - This study aimed to investigate factors linked to perceived coercion at admission and during treatment among voluntary inpatients. Quantitative and qualitative methods were used. Two hundred seventy patients were screened for perceived coercion at admission. Those who felt coerced into admission rated their perceived coercion during treatment a month after admission. Patient characteristics and experiences were tested as predictors of coercion. In-depth interviews on experiences leading to perceived coercion were conducted with 36 participants and analysed thematically. Thirty-four percent of patients felt coerced into admission and half of those still felt coerced a month later. No patient characteristics were associated with perceived coercion. Those whose satisfaction with treatment increased more markedly between baseline and a month later were less likely to feel coerced a month after admission. In the qualitative interviews three themes leading to perceived coercion were identified: viewing the hospital as ineffective and other treatments as more appropriate, not participating in the admission and treatment and not feeling respected. Involving patients in the decision-making and treating them with respect may reduce perceived coercion. PMID- 21272941 TI - Detection of colostrum-derived alloantibodies in calves with bovine neonatal pancytopenia. AB - Bovine neonatal pancytopenia (BNP) is an emerging calf disease of unknown cause characterized by a pronounced susceptibility to bleeding as a result of a pancytopenia and bone marrow depletion. In this study we investigated whether this phenomenon is related to colostrum-derived alloantibodies directed against neonatal leukocytes. In a first experiment and using a flow cytometric approach sera from 6 BNP-dams (had given birth to BNP-calves; vaccinated against bovine viral diarrhea virus [BVDV]) and 6 control-dams (no herd history of BNP; no BVDV vaccination) were analyzed for the presences of alloantibodies (IgG) able to bind to the surface of leukocytes isolated from 7 calves from a herd with no history of BNP (no BVDV vaccination). In a second experiment, 4 neonates from 3 BNP-dams were fed colostrum from their corresponding mothers and sampled on a regular basis from birth up to day 21 of life under clinically controlled conditions. Sample analysis of the 4 neonates included hematology (white blood cell count and platelets), bone marrow cytology and histopathology as well as the flow cytometric detection of the percentage of IgG+-lymphocytes/monocytes in the peripheral blood. Experiment #1 showed that all BNP-dam sera harbored significantly higher alloantibody titers than the control dam sera (p<0.001). In the peripheral blood of the two neonates (Experiment #2), the percentage of IgG+ cells increased dramatically within 12h post colostrum intake (p.c.i.), remaining at over 95% for up to 3 days. Both calves developed BNP-associated clinical symptoms, one died. Both twin calves showed no clinical symptoms accompanied by a minor increase of IgG+ cells for up to 12h. Thus, the level of IgG+-cells and the duration of the detection thereof correlated with the severity of BNP developed by these animals. The results show that BNP-dams harbor alloantibodies against surface antigens of neonatal leukocytes in their sera that are readily transferred to the offspring via colostrum. These alloantibodies probably play a crucial role in the pathogenesis of BNP. PMID- 21272942 TI - Establishment of a novel feline leukemia virus (FeLV)-negative B-cell cell line from a cat with B-cell lymphoma. AB - We established a novel feline B-cell line, MS4, from the neoplastic pleural effusion of a cat with cutaneous B-cell lymphoma. Immunophenotype staining of the MS4 cells was positive for CD20, CD79alpha, and IgA and negative for CD3, CD4, CD5, CD8alpha, CD18, CD21, CD22, IgM, IgG, Ig light chain, and MHC class II. PCR analysis for immunoglobulin heavy chain gene rearrangements revealed a monoclonal rearrangement, whereas no clonal rearrangement of the T-cell receptor gamma gene was detected. Southern blotting with an exogenous feline leukemia virus (FeLV) U3 probe revealed no integration of exogenous FeLV provirus. The MS4 cell line is the first FeLV-negative feline B-cell lymphoma cell line, and may be used to investigate the pathogenesis of spontaneously occurring feline lymphoma and the development of new therapies. PMID- 21272943 TI - Polymorphism of the ovine FOXP3 gene (FOXP3). AB - FOXP3 is a transcription factor predominantly expressed in CD4(+) CD25(+) thymocytes and CD4(+) CD25(+) peripheral T cells. It has been reported that variation in the FOXP3 gene (FOXP3) could cause impaired immune regulation. Using PCR-SSCP, variation in exon 4, exon 9-10 and exon 13-14 of ovine FOXP3, covering three functional domains (a proline rich domain, a leucine zipper-like motif and the forkhead domain, respectively) was investigated. Four SSCP banding patterns were observed for the exon 13-14 amplicon, while no variation was detected in either exon 4 or exon 9-10. Either one or two SSCP banding patterns were observed in the sheep studied. In accordance with the X chromosome location of FOXP3, ewes were homozygous or heterozygous, while rams were hemizygous. Sequencing of DNA corresponding to the four PCR-SSCP patterns for exon 13-14, revealed four unique DNA sequences which resulted from both sequence and length variation. These comprised of two SNPs (one in intron 13 and the other in exon 14), and variation in copy number for a hexa-nucleotide repeat (TGGCCC)(n) in intron 13. These results indicate that ovine FOXP3 is polymorphic and the variation detected in this region may have implications for immune regulation in sheep. PMID- 21272944 TI - A modified live PRRSV vaccine and the pathogenic parent strain induce regulatory T cells in pigs naturally infected with Mycoplasma hyopneumoniae. AB - The lack of heterologous protection by porcine reproductive and respiratory syndrome virus (PRRSV) vaccines is currently a major problem in the field. Heterologous protection by PRRS vaccines depends on the ability of the vaccine to induce an interferon gamma (IFN-gamma) response. One mechanism by which the virus evades the immune system is by activating regulatory T cells (T(regs)), resulting in induction of interleukin 10 rather than IFN-gamma. Our hypothesis that current PRRS vaccines do not differ from pathogenic strains in the ability to induce T(regs) was tested by inoculating three groups of pigs with two pathogenic viruses and an attenuated vaccine strain and evaluating the number of T(regs) in peripheral blood mononuclear cells. Before inoculation, the pigs, although vaccinated became infected naturally with Mycoplasma hyopneumoniae before shipment to our research facility. Our results show that the PRRSV vaccine strain and parent strain are equally able to induce T(regs) in pigs naturally infected with M. hyopneumoniae. Pigs in the vaccine and PRRSV groups had higher lung lesion scores than pigs in the control groups. The results suggest that the exacerbation M. hyopneumoniae respiratory disease may be due to the ability of PRRSV vaccination and viral infection to induce regulatory T cells. PMID- 21272945 TI - Reduced thymic output and peripheral naive CD4 T-cell alterations in primary progressive multiple sclerosis (PPMS). AB - We compared naive CD4 and CD8 T-cell homeostasis in primary progressive multiple sclerosis (PPMS), relapsing-remitting MS (RRMS) and controls. Quantitation of signal joint T-cell receptor (TCR) excision circles (sjTRECs) and quantitative estimates of daily thymic export confirm our previous report of reduced thymic output in RRMS and demonstrate reduced thymic output in PPMS. In PPMS, the decreasing % CD31+ naive CD4 T-cells but constant sjTRECs and constant naive CD4 T-cell numbers with age, together with increased Bcl-2 expression suggest increased TCR signaling with increased naive T-cell survival. We conclude PPMS patients have peripheral immune alterations related to reduced thymic output. PMID- 21272946 TI - Outcomes of surgery for laryngotracheal stenosis-the parents perspective. AB - Reconstructive laryngeal surgery has been very successful in the treatment of laryngotracheal stenosis. Traditionally authors have used survival and decannulation rates as markers of success. OBJECTIVE: To evaluate the outcome of paediatric laryngotracheal surgery from the parents perspective. METHOD: Retrospective audit of all children undergoing laryngotracheal reconstruction or cricotracheal resection for laryngotracheal stenosis in a three year period at the Royal Hospital for Sick Children, Glasgow. An open-ended questionnaire was used to assess parental concerns regarding their child's airway, post-operative results and the current status of their voice, breathing and swallowing. RESULTS: 30 patients were eligible for the inclusion of which there were 17 responses (56%). The most common concerns pre-operatively were difficulty breathing, tracheostomy and survival. Post-operatively parents felt that breathing, voice and a reduction in the number of lower respiratory tract infections were the main improvements. We also identified the high level of importance that the parents assigned to their child's independence and ability to lead a normal life. CONCLUSION: This study has given us a unique insight into the concerns of parents who have children with laryngotracheal stenosis. It has also allowed us to evaluate our post-operative results from a qualitative perspective through the eyes of the parents. PMID- 21272947 TI - Changes in the swimming behavior of Eurytemora affinis (Copepoda, Calanoida) in response to a sub-lethal exposure to nonylphenols. AB - Estuarine waters are continuously loaded with chemicals which affect the physiology of aquatic organisms to various extents. They also have adverse effects on a wide range of behaviors. Nonylphenols and related compounds are biodegradation products of the nonionic surfactants nonylphenol polyethoxylates. They are commonly found in the aquatic environment. We observed immediate alterations of the free swimming activity of the calanoid copepod Eurytemora affinis from the Seine estuary in response to a sub-lethal concentration of nonylphenols (4-NP and NP1EC) at environmentally realistic concentrations (2 MUg/L). Swimming speed and activity increased for both males and females. The use of copepod kinematic proved to be a sensitive indicator of sub-lethal exposure to pollutants. PMID- 21272948 TI - Haptics in teaching handwriting: the role of perceptual and visuo-motor skills. AB - Two studies were carried out in order to better understand the role of perceptual and visuo-motor skills in handwriting. Two training programs, visual-haptic (VH) and visual (V), were compared which differed in the way children explored the letters. The results revealed that improvements of VH training on letter recognition and handwriting quality were higher than improvements after V training. We suppose that VH training was more efficient because it improved both perceptual and visuo-motor skills. In the second experiment, in order to investigate the part of each component, we assessed the link between visuo-motor skills, perceptual skills and handwriting. The results showed that only the visuo motor tasks predict handwriting copying performance. These results are discussed in relation to the respective roles of the perceptual and visuo-motor skills on letter shape learning and handwriting movement execution. PMID- 21272949 TI - The importance of expressing antimicrobial agents on water basis in growth/no growth interface models: a case study for Zygosaccharomyces bailii. AB - In a previous study on Zygosaccharomyces bailii, three growth/no growth models have been developed, predicting growth probability of the yeast at different conditions typical for acidified foods (Dang, T.D.T., Mertens, L., Vermeulen, A., Geeraerd, A.H., Van Impe, J.F., Debevere, J., Devlieghere, F., 2010. Modeling the growth/no growth boundary of Z. bailii in acidic conditions: A contribution to the alternative method to preserve foods without using chemical preservatives. International Journal of Food Microbiology 137, 1-12). In these broth-based models, the variables were pH, water activity and acetic acid, with acetic acid concentration expressed in volume % on the total culture medium (i.e., broth). To continue the previous study, validation experiments were performed for 15 selected combinations of intrinsic factors to assess the performance of the model at 22 degrees C (60days) in a real food product (ketchup). Although the majority of experimental results were consistent, some remarkable deviations between prediction and validation were observed, e.g., Z. bailii growth occurred in conditions where almost no growth had been predicted. A thorough investigation revealed that the difference between two ways of expressing acetic acid concentration (i.e., on broth basis and on water basis) is rather significant, particularly for media containing high amounts of dry matter. Consequently, the use of broth-based concentrations in the models was not appropriate. Three models with acetic acid concentration expressed on water basis were established and it was observed that predictions by these models well matched the validation results; therefore a "systematic error" in broth-based models was recognized. In practice, quantities of antimicrobial agents are often calculated based on the water content of food products. Hence, to assure reliable predictions and facilitate the application of models (developed from lab media with high dry matter contents), it is important to express antimicrobial agents' concentrations on a common basis-the water content. Reviews over other published growth/no growth models in literature are carried out and expressions of the stress factors' concentrations (on broth basis) found in these models confirm this finding. PMID- 21272950 TI - Analysis of bacterial communities of traditional fermented West African cereal foods using culture independent methods. AB - In this study, the microbial composition of kunu-zaki and ogi, two popular foods in Nigeria produced after natural, uncontrolled fermentation of cereals, was assessed by culture-independent molecular profiling methods. In particular, PCR denaturing gradient gel electrophoresis and construction of 16S rRNA gene clone libraries revealed the presence of diverse bacterial communities. DNA sequencing of the highly variable V3 region of the 16S rRNA genes obtained from PCR-DGGE fingerprints identified species related to Weissella confusa, Lactobacillus fermentum, Lactobacillus amylolyticus, Lactobacillus delbrueckii subsp. bulgaricus, Bacillus spp. and Lactococcus lactis spp lactis from food samples obtained from northern and southern geographical locations. A more comprehensive analysis of 272 full-length 16S rRNA gene inserts revealed that 70% of them were assigned to the Lactobacillaceae family and 19% to the Streptococcaceae family. Interestingly, sequences associated with a particular food type were also identified. For example, L. plantarum, L. pantheris and L. vaccinostercus were found in ogi but not in kunu-zaki while W. confusa, Streptococcus lutetiensis and Streptococcus gallolyticus subsp. macedonicus were found in kunu-zaki but not in ogi. Phylotypes corresponding to potentially pathogenic bacteria, such as Clostridium perfringens and Bacillus cereus were also detected highlighting the need for controlled fermentation processes. PMID- 21272951 TI - The utility of hemoglobin A1c at diagnosis for prediction of future glycemic control in children with type 1 diabetes. AB - INTRODUCTION: We evaluated the relationships of hemoglobin A1c (A1c) at diagnosis of type 1 diabetes (T1DM) to future glycemic control and to a series of clinical variables in children with T1DM. MATERIALS AND METHODS: Patients <18 years old diagnosed with T1DM during a one year period who had an A1c at diagnosis and at least one follow-up visit at our center were eligible for inclusion. Baseline variables examined included age, race, gender, symptom duration, admission acuity, anthropometrics, bicarbonate, and A1c. Annual anthropometric and A1c data were also obtained from clinic visits through 4 years after diagnosis. RESULTS: We identified 120 children (53 males). Mean age at diagnosis was 7.6+/-3.9 years. Mean A1c at diagnosis was 10.9+/-1.9%. A1c at diagnosis correlated with age at diagnosis, symptom duration, and A1c at 3-years, with trends towards correlations at 6 weeks and 4 years. A1c at 1 year correlated highly with A1c at subsequent visits. No other baseline variables correlated with subsequent glycemic control. CONCLUSIONS: In children with newly diagnosed diabetes, A1cs at diagnosis and one year post diagnosis are related to subsequent glycemic control. Children with high A1cs particularly at one year post diagnosis may benefit from targeted intensification of resources. PMID- 21272952 TI - Associations of intra-renal arterial resistance index with chronic kidney disease and carotid intima-media thickness in type 2 diabetes mellitus. AB - Renal dysfunction can be evaluated by increased intra-renal arterial resistance index (RI). We evaluated 113 Chinese men with type 2 diabetes on their RI. Results suggest that RI is associated with chronic kidney disease and subclinical arteriosclerosis. RI may help monitoring the deterioration of intra-renal hemodynamics. PMID- 21272953 TI - Duration of prior gefitinib treatment predicts survival potential in patients with lung adenocarcinoma receiving subsequent erlotinib. AB - PURPOSE: We investigated survival potential in patients receiving erlotinib after failure of gefitinib, focusing on response and time to progression (TTP) with gefitinib. METHODS: We retrospectively reviewed lung adenocarcinoma patients who received erlotinib after experiencing progression with gefitinib. Our primary objective was to evaluate the prognostic significance of erlotinib therapy. RESULTS: A total 42 lung adenocarcinoma patients were included in this study. Overall disease control rate was 59.5% (partial response [PR], 2.4%; stable disease [SD], 57.1%). Median overall survival was 7.1 months, and median progression-free survival was 3.4 months. The number of patients who achieved PR and non-PR (SD+ progressive disease [PD]) with gefitinib were 22 (52%) and 20 (48%), respectively. Patients with PR for gefitinib showed significantly longer survival times than those with non-PR (9.2 vs. 4.7 months; p=0.014). In particular, among PR patients, those with TTP <12 months on gefitinib showed significantly longer survival times than those with TTP >=12 months (10.3 vs. 6.4 months; p=0.04). CONCLUSIONS: Erlotinib may exert survival benefit for lung adenocarcinoma patients with less than 12 months of TTP of prior gefitinib who achieved PR for gefitinib. PMID- 21272954 TI - Lung cancer in never smokers: change of a mindset in the molecular era. AB - Lung cancer is a leading cause of cancer-related mortality across the world. Although the majority of lung cancer is attributed to tobacco smoke, approximately 25% of lung cancers worldwide occur in lifelong never smokers. Over the past decades, the bulk of research on this disease suggested that several genetic, environmental, hormonal, and viral factors might increase the risk of lung cancer among never smokers. However, there has been no dominant risk factor whose significance has been validated across racial and ethnic groups. However, this subset of lung cancers has received renewed attention due to the introduction of the epidermal growth factor receptor-tyrosine kinase (EGFR-TK) inhibitors showing the dramatic therapeutic response on selected patients with activating EGFR mutations which occur more commonly in never smokers. The treatment strategy blocking EGFR pathway in EGFR-mutant lung cancer represents a remarkable example of molecular targeted therapies which completely repress tumor by inhibition of driving oncogenes. More recently, a surprising positive effect of an ALK inhibitor on EML4-ALK-positive lung cancer has been suggested that lung cancer in never smokers is likely to be an assemblage of molecularly defined subsets which would be a good candidate for personalized diagnostic and therapeutic approaches. PMID- 21272955 TI - Overexpression of HEMA1 encoding glutamyl-tRNA reductase. AB - 5-Aminolevulinic acid (ALA) synthesis has been shown to be the rate limiting step of tetrapyrrole biosynthesis. Glutamyl-tRNA reductase (GluTR) is the first committed enzyme of plant ALA synthesis and is controlled by interacting regulators, such as heme and the FLU protein. Induced inactivation of the HEMA1 gene encoding GluTR by RNAi expression in tobacco resulted in a reduced activity of Mg chelatase and Fe chelatase indicating a feed-forward regulatory mechanism that links ALA synthesis posttranslationally with late enzymes of tetrapyrrole biosynthesis (Hedtke et al., 2007). Here, the regulatory impact of GluTR was investigated by overexpression of AtHEMA1 in Arabidopsis and tobacco plants. Light-dependent ALA synthesis cannot benefit from an up to 7-fold induced expression of GluTR in Arabidopsis. While constitutive AtHEMA1 overexpression in tobacco stimulates ALA synthesis by 50-90% during light-exposed growth of seedlings, no increase in heme and chlorophyll contents is observed. HEMA1 overexpression in etiolated and dark-grown Arabidopsis and tobacco seedlings leads to additional accumulation of protochlorophyllide. As excessive accumulation of GluTR does not correlate with increased ALA formation, it is hypothesized that ALA synthesis is additionally limited by other effectors that balance the allocation of ALA with the activity of enzymes of chlorophyll and heme biosynthesis. PMID- 21272956 TI - Foodborne gastroenteritis outbreak in an Austrian healthcare facility caused by asymptomatic, norovirus-excreting kitchen staff. AB - An outbreak of norovirus GGII.4 2006b affected an Austrian 600-bed healthcare facility from 15 to 27 March 2009. A total of 204 patients, residents and staff fitted the outbreak case definition; 17 (8.3%) were laboratory-confirmed. Foodborne origin was suspected in the 114 patient and resident cases with onset 15-18 March. A case-cohort study was performed to test the hypothesis that consumption of dishes offered on 14, 15 and 16 March (risk days) was associated with increased risk of infection. Data on food exposure of 62% (317/510) of the patient and resident cohort were available for a simultaneous retrospective cohort study. The case-cohort analysis revealed that consumption of sliced cold sausage offered on 15 March [odds ratio (OR): 3.98; 95% confidence interval (CI): 1.18-14.1], a meat dish with salad (adjusted OR: 2.2; 95% CI: 1.19-4.08) and a rolled spinach pancake (adjusted OR: 2.17; 95% CI: 1.27-3.71) on 16 March were independent risk factors. It is likely that one of the five asymptomatic excretors among the kitchen staff on duty on the risk days was the source of food contamination. The case-cohort study design was found to be a valid alternative to the retrospective cohort study design for the investigation of a suspected foodborne outbreak in a large cohort. PMID- 21272957 TI - The 2007 Model of the Clinical Practice of Emergency Medicine: the 2009 update 2009 EM Model Review Task Force. PMID- 21272958 TI - The effect of cognitive impairment on the accuracy of the presenting complaint and discharge instruction comprehension in older emergency department patients. AB - STUDY OBJECTIVE: We seek to determine how delirium and dementia affect the accuracy of the presenting illness and discharge instruction comprehension in older emergency department (ED) patients. METHODS: This cross-sectional study was conducted at an academic ED from May 2008 to July 2008 and included non-nursing home patients aged 65 years and older. Two open-ended interviews were performed to assess patients' ability to accurately provide their presenting illness and comprehension of their ED discharge instructions. The surrogates' version of the presenting illness and printed discharge instructions were the reference standards. Concordance between the patient and the reference standards was determined by 2 reviewers using a 5-point scale ranging from 1 (no concordance) to 5 (complete concordance). Proportional odds logistic regression was performed to determine whether cognitive impairment was associated with presenting complaint accuracy and discharge instruction comprehension. All models were adjusted for age, health literacy, education, nonwhite race, and hearing impairment. RESULTS: For the presenting illness analysis, 202 patients participated. Compared with patients without cognitive impairment, those with delirium superimposed on dementia (DSD) had lower odds of agreeing with their surrogates with regard to why they were in the ED (adjusted proportional odds ratio=0.20; 95% confidence interval [CI] 0.09 to 0.43). For the discharge instruction comprehension analysis, 115 patients participated. Patients with DSD had significantly lower odds of comprehending their discharge diagnosis (adjusted proportional odds ratio=0.13; 95% CI 0.04 to 0.47), return to the ED instructions (adjusted proportional odds ratio=0.18; 95% CI 0.04 to 0.82), and follow-up instructions (adjusted proportional odds ratio=0.09; 95% CI 0.02 to 0.35) compared with patients without cognitive impairment. CONCLUSION: DSD is associated with decreased accuracy of the older patient's presenting illness and decreased comprehension of ED discharge instructions. PMID- 21272959 TI - In vivo molecular imaging of the GABA/benzodiazepine receptor complex in the aged rat brain. AB - The GABA-ergic system, known to regulate neural tissue genesis during cortical development, has been postulated to play a role in cerebral aging processes. Using in vivo molecular imaging and voxel-wise quantification, we aimed to assess the effects of aging on the benzodiazepine (BDZ) recognition site of the GABA(A) receptor. To visualize BDZ site availability, [(11)C]-flumazenil microPET acquisitions were conducted in young and old rats. The data were analyzed and region of interest analyses were applied to validate the voxel-wise approach. We observed decreased [(11)C]-flumazenil binding in the aged rat brains in comparison with the young control group. More specifically, clusters of reduced radioligand uptake were detected in the bilateral hippocampus, cerebellum, midbrain, and bilateral frontal and parieto-occipital cortex. Our results support the pertinence of voxel-wise quantification in the analysis of microPET data. Moreover, these findings indicate that the aging process involves declines in neural BDZ recognition site availability, proposed to reflect alterations in GABA(A) receptor subunit polypeptide expression. PMID- 21272960 TI - Discriminant analysis of longitudinal cortical thickness changes in Alzheimer's disease using dynamic and network features. AB - Neuroimage measures from magnetic resonance (MR) imaging, such as cortical thickness, have been playing an increasingly important role in searching for biomarkers of Alzheimer's disease (AD). Recent studies show that, AD, mild cognitive impairment (MCI) and normal control (NC) can be distinguished with relatively high accuracy using the baseline cortical thickness. With the increasing availability of large longitudinal datasets, it also becomes possible to study the longitudinal changes of cortical thickness and their correlation with the development of pathology in AD. In this study, the longitudinal cortical thickness changes of 152 subjects from 4 clinical groups (AD, NC, Progressive-MCI and Stable-MCI) selected from Alzheimer's Disease Neuroimaging Initiative (ADNI) are measured by our recently developed 4 D (spatial+temporal) thickness measuring algorithm. It is found that the 4 clinical groups demonstrate very similar spatial distribution of grey matter (GM) loss on cortex. To fully utilize the longitudinal information and better discriminate the subjects from 4 groups, especially between Stable-MCI and Progressive-MCI, 3 different categories of features are extracted for each subject, i.e., (1) static cortical thickness measures computed from the baseline and endline, (2) cortex thinning dynamics, such as the thinning speed (mm/year) and the thinning ratio (endline/baseline), and (3) network features computed from the brain network constructed based on the correlation between the longitudinal thickness changes of different regions of interest (ROIs). By combining the complementary information provided by features from the 3 categories, 2 classifiers are trained to diagnose AD and to predict the conversion to AD in MCI subjects, respectively. In the leave-one-out cross validation, the proposed method can distinguish AD patients from NC at an accuracy of 96.1%, and can detect 81.7% (AUC = 0.875) of the MCI converters 6 months ahead of their conversions to AD. Also, by analyzing the brain network built via longitudinal cortical thickness changes, a significant decrease (p < 0.02) of the network clustering coefficient (associated with the development of AD pathology) is found in the Progressive-MCI group, which indicates the degenerated wiring efficiency of the brain network due to AD. More interestingly, the decreasing of network clustering coefficient of the olfactory cortex region was also found in the AD patients, which suggests olfactory dysfunction. Although the smell identification test is not performed in ADNI, this finding is consistent with other AD-related olfactory studies. PMID- 21272962 TI - Herpes simplex virus type I induces the accumulation of intracellular beta amyloid in autophagic compartments and the inhibition of the non-amyloidogenic pathway in human neuroblastoma cells. AB - Mounting evidence suggests that herpes simplex virus type 1 (HSV-1) is involved in the pathogenesis of Alzheimer's disease (AD). Epidemiological analyses have shown that HSV-1 is a risk factor for AD in people with at least 1 type 4 allele of the apolipoprotein E gene. Recent studies have also suggested that HSV-1 contributes to the appearance of the biochemical anomalies characteristic of AD brains. In addition, autophagic activity appears to be reduced with aging, and the final stages of autophagy in neurodegenerative process appear to be impaired. The present work reports that HSV-1 provokes the strong intracellular accumulation of both the main species of beta-amyloid (Abeta) in the autophagic compartments and that it is associated with a marked inhibition of Abeta secretion. Autophagosomes containing Abeta failed to fuse with lysosomes in HSV-1 infected cells, indicating the impaired degradation of Abeta localized in the autophagic vesicles. In addition, HSV-1 infection was associated with the inhibition of the nonamyloidogenic pathway of amyloid precursor protein (APP) processing without significantly affecting the activity of the secretases involved in the amyloidogenic pathway. Taken together, these data suggest that HSV-1 infection modulates autophagy and amyloid precursor protein processing, contributing to the accumulation of Abeta characteristic of AD. PMID- 21272963 TI - Synthesis, molecular docking and binding studies of selective serotonin transporter inhibitors. AB - With the aim of obtaining compounds possessing high SERT selectivity, in the present work we synthesized and studied the inhibition of serotonin (SERT), dopamine (DAT) and norepinephrine (NET) transporters by docking studies and experimental binding measurements of a series of 4-(aryl)piperidin-3-one O-4 benzyl oxime hydrochlorides (1-10) of both E and Z configuration. E configuration compounds showed high SERT binding affinities (K(i) = 10-98 nM) and high SERT selectivities over both NET and DAT. The molecular docking studies allowed a rationalization of the molecular basis of drug-SERT interactions both of the synthesized compounds and paroxetine and fluoxetine used as reference antidepressant drugs. PMID- 21272964 TI - Virtual screening studies on HIV-1 reverse transcriptase inhibitors to design potent leads. AB - The purpose of this study is to identify novel and potent inhibitors against HIV 1 reverse transcriptase (RT). The crystal structure of the most active ligand was converted into a feature-shaped query. This query was used to align molecules to generate statistically valid 3D-QSAR (r(2) = 0.873) and Pharmacophore models (HypoGen). The best HypoGen model consists of three Pharmacophore features (one hydrogen bond acceptor, one hydrophobic aliphatic and one ring aromatic) and further validated using known RT inhibitors. The designed novel inhibitors are further subjected to docking studies to reduce the number of false positives. We have identified and proposed some novel and potential lead molecules as reverse transcriptase inhibitors using analog and structure based studies. PMID- 21272965 TI - Anti-tubercular agents. Part 6: synthesis and antimycobacterial activity of novel arylsulfonamido conjugated oxazolidinones. AB - As a part of investigation of new anti-tubercular agents in this laboratory, herein we describe the synthesis of a new class of arylsulfonamido conjugated oxazolidinones. The in vitro activity of these conjugated (6a-f, 7a-d, 9a-c and 11a-c) molecules against Mycobacterium tuberculosis H(37)Rv by using rifampicin and linezolide as positive controls is discussed, compounds 7c and 9a-c are found to be the most active members in this series. Further, cytotoxicity of the potent conjugates of the series (7c, and 9a-c) was evaluated on human foreskin fibroblast (HFF) cells by using MTT assay. Finally, these studies suggest that compounds 7c and 9a may serve as promising lead scaffolds for further generation of new as anti-TB agents. PMID- 21272966 TI - [Which are the predictive factors to be ranked within the 500 first medical students at the national ranking exam? A cross-sectional study of the 2009 class]. AB - PURPOSE: The objective of this study was to analyze, during a transversal study, the predictive sociodemographic and individual factors to be ranked within the first 500 medical students in the 2009 French national ranking exam (NRE). METHODS: In September 2009, 5570 medical students have chosen their subspecialty. They were invited to fill-up a questionnaire that included sociodemographics and educational items. Logistic regression was used to identify factors that were associated with being ranked within the first 500 medical students. RESULTS: A total of 4712 students (two third of women) responded to the questionnaire (92.3% response rate). The mean age of respondents was 24.7 years (+/-1.79). In the multivariate analysis, independent factors associated with being ranked within the first 500 medical students at the NRE were: being less than 25-year-old (odds ratio [OR]: 1.8; 95%CI: 1.3-2.5; P<0.001), region of origin (Ile de France) (OR: 3.7; 95%CI: 2.3-5.8; P<0.0001), to succeed at the first medical year examination for the first time (OR: 1.7; 95%CI: 1.2-2.4; P<0.001), being in the first 20% of the medical students during externship (P<0.0001), critical reading test (CRT) teaching by graduate doctors (OR: 1.5; 95%CI: 1.05-2.1; P<0.001), and to participate in a national practicing ranking exam with a CRT (OR: 1.96; 95%CI: 1.3-3.03; P=0.002). CONCLUSION: Our study identified six factors independently associated with being ranked within the first 500 medical students in the French NRE. Education and training of the CRT, newly introduced test in 2009, seem to play an important role. PMID- 21272967 TI - Potential risks of pro-eating disorder websites. AB - Although dangers of pro-eating disorder (pro-ED) websites have recently been discussed in the popular press, no integration of research findings on this topic yet exists. After completing a systematic search for peer-reviewed articles about pro-ED websites, we identified three possible risks as themes: operation under the guise of "support," reinforcement of disordered eating, and prevention of help-seeking and recovery. Pro-ED websites tend to be perceived as supportive by users, but instead appear to exacerbate or maintain users' eating disorder symptoms. We discuss research and clinical implications of these dangers. Future research should clarify how specific features of pro-ED websites contribute to the development, exacerbation, and maintenance of eating pathology, e.g., by employing experimental techniques and prospective designs with clinical samples and various ages. Despite limited empirical research on the topic, existing findings should prompt clinicians, parents, and researchers to remain vigilant about potential negative influences of pro-ED websites on users. PMID- 21272968 TI - Access to primary mental health care for hard-to-reach groups: from 'silent suffering' to 'making it work'. AB - Equitable access to primary care for people with common mental health problems in the UK remains problematic. The experiences of people from hard-to-reach groups offer important insights into barriers to accessing care. In this study, we report on secondary analysis of qualitative data generated within seven previously-reported studies. Thirty-three of ninety-two available transcripts were re-analysed using a new heuristic of access, generated to frame narrative based comparative case analysis. The remaining transcripts were used to triangulate the findings via a process of collaborative analysis between a secondary researcher, naive to research findings of the original studies, and primary researchers involved in data generation and analysis within the original studies. This method provided a rich body of 'fine grain' insights into the ways in which problem formulation, help-seeking, use of services and perceptions of service quality are interlinked in a recursive and socially embedded matrix of inequitable access to primary mental health care. The findings indicate both extensive commonalities between experiences of people from different 'hard-to reach groups', and considerable diversity within each group. An idiographic generalisation and aggregation of this variety of experiences points to one main common facilitator (communicated availability of acceptable mental health services) and two main common barriers (lack of effective information and multiple forms of stigma) to equitable access to primary mental health care. We conclude that there is a need to provide local care that is pluralistic, adaptive, holistic, resonant and socially conscious in order to ensure that equitable access to mental health services can become a reality. PMID- 21272969 TI - Periosteal osteosarcoma of the mandible: case report and review of the literature. PMID- 21272970 TI - Influence of mandibular reconstruction on patients' health-related quality of life. AB - PURPOSE: To evaluate and compare the influence of different types of mandibular reconstruction on health-related quality of life (HR-QoL) of nonrecurrence patients. PATIENTS AND METHODS: We recruited 252 patients who underwent mandibular reconstruction between 1994 and 2007 for this cross-sectional study. They were classified into groups based on reconstruction technique: free bone graft (FBG) group, particulate bone cancellous marrow graft (PBCMG) group, reconstruction plate (RP) group, and microvascular free flap group. The University of Washington Head and Neck Quality of Life Questionnaire and 5 supplemental domains regarding the donor sites were used to evaluate and compare HR-QoL among the groups. RESULTS: The outcomes of the University of Washington Head and Neck Quality of Life Questionnaire differed significantly among the groups (P < .0001). The results of the additional donor site domains also differed greatly among the groups (P < .0001). Appearance, chewing, activity, appearance-donor site, and function-donor site were the domains that were most frequently chosen by the patients as the most important issues. Most of the patients rated their HR-QoL as somewhat better compared with their experience the month before they underwent reconstruction. The HR-QoL and overall quality of life (QoL) during the past 7 days were rated as very good in the FBG group and PBCMG group and good in the RP group and microvascular free flap group. CONCLUSIONS: HR-QoL of patients in the FBG and PBCMG groups did not differ significantly with regard to any of the domains, and these 2 groups consistently had the highest mean scores. Both groups differed significantly from the RP group, which tended to report the lowest mean scores for the domains. PMID- 21272971 TI - Delayed complications of tooth extraction in patients taking warfarin, antibiotics, and other medications. PMID- 21272972 TI - Prospective randomized clinical trial comparing bite force in 2-mm locking plates versus 2-mm standard plates in treatment of mandibular fractures. AB - PURPOSE: To compare the efficacy of the 2-mm locking miniplates to 2-mm standard miniplates in the osteosynthesis of mandibular fractures on the basis of clinical parameters and bite force recording. PATIENTS AND METHODS: A prospective randomized clinical trial was conducted at the Faculty of Dental Science, CSMMU (formerly King Georges Medical College), Lucknow, India, from January 1, 2007, to January 31, 2008, to treat consecutive mandible fractures. The patients were randomly divided into 2 groups. The patients underwent osteosynthesis--group 1 with Synthes 2-mm locking titanium miniplates and group 2 with Synthes 2-mm nonlocking titanium miniplates. The cause of trauma, the number of days from injury to surgery, average age, gender, and site distribution were all reviewed. The assessment of the patients was done at 1, 3, and 6 weeks and 3 months using the clinical parameters and bite force recording. RESULTS: A total of 20 patients with 32 fractures met the inclusion criteria. In our study, a statistically significant difference was not found in the clinical parameters such as pain, swelling, infection, paresthesia, hardware failure, and mobility between the fracture segments. A statistically significant difference was found between the change in bite force from the previous follow-up visit in groups 1 and 2. From 1 week to 3 months, the change in the incisor bite force was significantly greater for group 1 than for group 2. At 6 weeks and 3 months, the change in right molar bite force from the previous follow-up visit was significantly greater for group 1 than for group 2. At the 1-, 3-, 6-week and 3-month follow-up visits, the change in left molar bite force from the previous follow-up visit was significantly greater for group 1 than for group 2. CONCLUSION: These findings show that the use of locking miniplates plate in mandibular fracture was efficacious enough to bear the masticatory loads during osteosynthesis of the fracture. The locking miniplates provide the advantage of a greater bite force, with clinical results almost similar to those seen with nonlocking miniplate osteosynthesis. PMID- 21272973 TI - Glossopharyngeal neuralgia: a presentation of 14 cases. AB - OBJECTIVE: The aim of this study was to present a series of clinical cases on glossopharyngeal neuralgia as well as the therapeutic approach used. PATIENTS AND METHODS: This observational, descriptive, and retrospective study was carried out on 14 patients who were diagnosed with glossopharyngeal neuralgia between the years 1997 and 2007 at the Oral-Facial and Implant Surgery Department and at the Otorhinolaryngology, Neurology, and Neurosurgery Departments of the Madrid University Hospital. RESULTS: The study consisted of 8 women and 6 men. The neuralgia was found predominantly on the left side, and considering the 4 areas of topographical distribution into which the distribution of the ninth nerve is divided, the results of our study showed that the maximum of the areas affected was 3, with 2 areas being the most common. Accompanying symptoms were only recorded in 4 of the cases. In 12 of the cases, initial treatment was with prescription drugs consisting of different doses of carbamazepine. In the remaining cases, or once the other course of treatment was proven to be unsuccessful, surgical treatment was used, applying different techniques and obtaining a high rate of success with them. CONCLUSIONS: Glossopharyngeal neuralgia is an uncommon pathology that is treated with medicine or surgery, with carbamazepine and vascular microdecompression being the treatments of choice. PMID- 21272974 TI - The use of an ultrasonic bone curette in the surgery of jaw tumors involving the inferior alveolar nerve. AB - BACKGROUND: Preservation of lip sensation is crucial in ablative surgery of mandibular tumors. When tumor control does not necessitate sacrifice of the inferior alveolar nerve (IAN), as in some cases of benign tumors of the lower jaw, attempts may be made to spare the nerve. The authors present and discuss their experience with an ultrasonic device in the treatment of benign tumors of the jaw in correspondence of the IAN. MATERIALS AND METHODS: Five patients with tumoral lesions involving the IAN underwent surgery with an ultrasonic surgical device (Sonopet Omni Surgical System; Stryker, Kalamazoo, MI). RESULTS: Fine, delicate movements allowed the surgeon to remove bone without damage to surrounding tissue. Three of 5 patients did not present intraoperative or postoperative complications that could be attributed to the Sonopet. Two cases were partial failures. In 1 case, postoperative dysesthesia was encountered, and in the other case, intraoperative transection of the nerve occurred. CONCLUSION: The Sonopet ultrasonic bone curette proved to be highly useful in surgical procedures close to the IAN because it does not produce heat or cause mechanical injury to the neurovascular bundle. Application of this instrument may provide improved ability to preserve sensibility of the chin and lower lip in patients affected by lesions in proximity to the IAN. PMID- 21272975 TI - Reconstruction of severe medial orbital wall fractures using titanium mesh plates placed using transcaruncular-transconjunctival approach: a successful combination of 2 techniques. AB - PURPOSE: To prospectively evaluate the use of titanium mesh plates in a combined transcaruncular-transconjunctival approach for severe medial orbital wall fractures. PATIENTS AND METHODS: We analyzed the clinical and radiologic data of 10 patients with isolated blow-out orbital fractures. The fracture location was the medial wall in 5 (50%) and the floor/medial wall in 5 (50%). Of the 10 patients, 8 (80%) were treated using 3-dimensionally preformed orbital titanium mesh plates and 2 (20%) with nonpreformed radial orbital mesh plates fixed at the inferior orbital rim with 1 or 2 monocortical screws (diameter 1.3 mm). RESULTS: All the patients had satisfactory and anatomically correct orbital wall reconstruction as assessed on the immediate postoperative computed tomography scan. None of the patients experienced ophthalmic complications related to the transcaruncular-transconjunctival approach or developed enophthalmos as determined using Hertel exophthalmometry. One patient (10%) developed a nonhandicapping diplopia related to post-traumatic muscular contusion of the medial rectus muscle. CONCLUSIONS: The present study has demonstrated that titanium mesh plates placed using a combined transcaruncular-transconjunctival approach for the reconstruction of severe medial orbital wall fractures results in a high rate of success. PMID- 21272976 TI - Sclerotherapy for vascular malformations in the oral and maxillofacial region: treatment and follow-up of 66 lesions. AB - PURPOSE: The aim of the present study was to relate the use of 5% monoethanolamine oleate in sclerotherapy for vascular malformations and to suggest a protocol for its use. PATIENTS AND METHODS: A total of 53 patients with 66 vascular malformation lesions were treated with an intralesional injection of 5% monoethanolamine oleate at 0.1 mL/cm of lesion with at least a 15-day interval and as many as 4 applications. A descriptive statistical analysis was performed using SigmaPlot, version 9.0, software. RESULTS: The treatment with the protocol suggested was effective in 65 cases, and in 1 case, surgical intervention was required. CONCLUSIONS: Sclerotherapy was effective in the treatment of vascular malformations, and the method chosen was adequate for lesion resolution without complications. PMID- 21272977 TI - Mandibular reconstruction using a tray with particulate cancellous bone and marrow and platelet-rich plasma by an intraoral approach. AB - PURPOSE: To evaluate the possibility of immediate mandibular reconstruction using particulate cancellous bone and marrow (PCBM), platelet-rich plasma (PRP), and a tray, we compared the postsurgical infection rate and bone formation in patients who received mandibular reconstruction with this method using either an intraoral or extraoral approach. PATIENTS AND METHODS: We conducted a retrospective study of a series of 18 patients who underwent the mandibular reconstruction procedure using a mesh tray with PCBM and PRP, all performed by 1 surgeon. These cases were further divided into those treated by the intraoral approach and those treated by the extraoral approach. Clinical data, postoperative bone formation, and complications in the 2 groups were evaluated. The chi(2) examination and the Mann Whitney U test were used for statistical analysis. RESULTS: We could not detect any statistically significant differences in clinical data between the 2 groups, except for the timing of reconstruction. There were postoperative complications such as wound dehiscence and tray exposure, as well as infection of the reconstructed bone. The overall complication rate of the recipient sites in the intraoral group was 30% (3 of 10), whereas in the extraoral group, it was 0%. However, satisfactory bone formation was seen in all cases in the intraoral group (100% [10 of 10]) but only 87.5% (7 of 8) in the extraoral group. CONCLUSION: We conclude that mandibular reconstruction using a tray with PCBM and PRP is a safe and reliable method for cases of benign tumor and trauma, even if immediate reconstruction is performed by an intraoral approach. PMID- 21272978 TI - Development of nano-hydroxyapatite graft with silk fibroin scaffold as a new bone substitute. AB - PURPOSE: This study involves a comparison between the bone regeneration of nano hydroxyapatite (nHA), as derived from eggshells either with or without silk fibroin scaffolds, and the unfilled control in the rabbit calvarial bony defect model. MATERIALS AND METHODS: Sixteen 4-month-old New Zealand white rabbits, with a mean weight of 2.8 kg (range, 2.5-3.0 kg), were used in this experiment. After the formation of bilateral parietal bony defects (diameter, 8.0 mm), either an nHA or an nHA+silk fibroin combination (nHA+silk) was grafted. The control was unfilled defect. The bone regeneration was evaluated by micro-computed tomography (MUCT) and histomorphometric analyses at 4 and 8 weeks. RESULTS: All measured variables of the MUCT analysis were significantly higher in the grafted groups (nHA and nHA+silk) than in the unfilled control groups at both 4 and 8 weeks after operation (P < .05). On histomorphometric analysis, there was no significant difference between the groups at 4 weeks after operation. However, the nHA group exerted significantly higher bone regeneration (40.16% +/- 8.27%) compared with the unfilled control group (25.66% +/- 10.98%) or the nHA+silk group (16.62% +/- 3.05%) (P < .05). CONCLUSION: The nHA from eggshells exerted better bone formation than the unfilled control group on both MUCT and histomorphometric analyses. Considering the rapid healing in bony defect and easy availability, the nHA from the eggshells could prove to be a good new bone substitute. PMID- 21272979 TI - Hospital Universiti Sains Malaysia experience in orbital floor reconstruction: autogenous graft versus Medpor. AB - PURPOSE: A normally restored orbital structure after reconstructive surgery would accelerate the return of orbital function. The aim of the present study was to compare the outcomes of 2 orbital implants: autogenous grafts and porous polyethylene (Medpor). MATERIALS AND METHODS: A longitudinal study was conducted of all patients who had undergone orbital floor reconstruction using an autogenous graft or Medpor. The study participants were divided into 2 groups, and the postoperative outcomes were assessed clinically. RESULTS: Of the 26 patients, 14 (53.0%) had undergone surgery with an autogenous graft and 12 (46.2%) with Medpor. Postoperatively, no diplopia in the primary gaze was noted in any patient. However, down gaze and peripheral diplopia was found in 11.5% and 26.9% in the autogenous group and in 3.8% and 26.9% in the Medpor group, respectively (P = 1.24). Enophthalmos was present in 11.4% of the autogenous graft group and 15.3% of the Medpor group (P = .465). The Hess chart findings were abnormal in 11.4% of both groups (P = .062). Restriction of movement was observed in 1 patient (3.8%) from the autogenous group and 7.7% of the Medpor group (P = .574). CONCLUSIONS: Orbital floor reconstruction using an autogenous graft or Medpor showed comparable results. PMID- 21272980 TI - Biomechanical analysis of the strength of the mandible after marginal resection. AB - PURPOSE: This study investigated the biomechanical behavior of the mandible after marginal resection by tensile test in a human cadaveric mandible and finite element (FE) analysis. MATERIALS AND METHODS: Human cadaveric mandibular models after marginal resection were prepared with residual heights of 5, 10, and 15 mm. The strength in each of these mandibular models was examined by tensile testing. In addition, FE models of the mandible after marginal resection were prepared with residual heights of 5, 7.5, 10, 12.5, and 15 mm. Distribution and magnitude of von Mises stress were analyzed by applying bite forces of 151 N as a point load on the incisal region and 355.2 and 478.1 N on the premolar and molar regions on the nonresected and resected sides, respectively. At the molar region of the resected side, bite forces of 368.5 N and 286.9 N (80% and 60%, respectively, of 478.1 N) were also applied. RESULTS: On tensile testing, all cadaveric mandibular models were broken at the posterior resection corner. The tensile force was significantly larger in the model with a residual height of 15 mm compared with that of those with a 5- or 10-mm residual height. On FE analysis, von Mises stress was concentrated at the resection corner. The region of maximal von Mises stress concentration in FE models was consistent with that showing destruction on tensile testing. The relationship between the residual height and von Mises stress in the resection area was linear in models of the incisal, premolar, and molar loading on the nonresected side and quadratic in models of the premolar and molar loading on the resected side. The maximal von Mises stress in the resection area was highest during molar loading on the resected side under the present loading condition and exceeded the threshold for the development of pathologic fracture in the model with a residual height of around 10 mm or less. However, the maximal von Mises stress decreased in parallel with the reduction of bite force in the molar region of the resected side. CONCLUSIONS: The residual height and bite force are critical factors for the prevention of pathologic fracture of the mandible after marginal resection. Currently, a residual height of more than 10 mm and reduction of bite force are recommended to reduce the risk of fracture. PMID- 21272981 TI - Garre's osteomyelitis in a patient with chromosome 22q11.2 syndrome: a case report. PMID- 21272982 TI - The effects of mothers' past infant-holding preferences on their adult children's face processing lateralisation. AB - Face processing development is negatively affected when infants have not been exposed to faces for some time because of congenital cataract blocking all vision (Le Grand, Mondloch, Maurer, & Brent, 2001). It is not clear, however, whether more subtle differences in face exposure may also have an influence. The present study looked at the effect of the mother's preferred side of holding an infant, on her adult child's face processing lateralisation. Adults with a mother who had a left-arm preference for holding infants were compared with adults with a mother who had a right-arm holding preference. All participants were right-handed and had been exclusively bottle-fed during infancy. The participants were presented with two chimeric faces tests, one involving emotion and the other one gender. The left-arm held individuals showed a normal left-bias on the chimeric face tests, whereas the right-arm held individuals a significantly decreased left bias. The results might suggest that reduced exposure to high quality emotional information on faces in infancy results in diminished right-hemisphere lateralisation for face processing. PMID- 21272983 TI - Effect of opening a new catheterization laboratory on 30-day and 2-year survival rates in myocardial infarction patients. AB - INTRODUCTION AND OBJECTIVES: To determine the effect of opening an on-site diagnostic catheterization facility on 30-day and 2-year mortality rates in patients with myocardial infarction (MI). METHODS: The study included 1539 consecutive MI patients aged 25-74 years who were recruited before and after the catheterization laboratory opened in 1998: during 1995-1997 and 1999-2003, respectively. RESULTS: The 641 consecutive MI patients recruited in 1995-1997 had worse 30-day mortality than the 898 recruited between 1999-2003 (11.2% versus 6.35%, respectively; P=.001). The number of coronary angiographies and percutaneous coronary interventions carried out was greater in the second period (19.4% versus 3.3%, and 54.8% versus 23.0%, respectively; P<.001). Two-year survival curves were significantly better in the second period for all-cause and cardiovascular death. The adjusted odds ratio for death at 30 days was 0.58 (95% confidence interval [CI] 0.36-0.95) for the second period compared with the first and the adjusted hazard ratio for cardiovascular death at 2 years for patients still alive at 30 days was 0.62 (95%CI 0.39-0.99). After adjustment for the prescription of statins, angiotensin-converting enzyme inhibitors, beta-blockers and antiplatelet drugs at discharge, the effect observed at 2 years was no longer significant. CONCLUSIONS: Opening a new on-site diagnostic catheterization unit significantly increased the 30-day survival of MI patients. However, the increase in 2-year survival of 30-day survivors observed was largely explained by the implementation of better secondary prevention. PMID- 21272984 TI - Role of a new cardiac catheterization laboratory in advancing cardiovascular care and outcomes in post-myocardial infarction patients. PMID- 21272985 TI - Outcome of very-low-birth-weight infants who received epinephrine in the delivery room. AB - BACKGROUND: In recent years, there has been an increase in the number of very low birth weight (VLBW) infants and an improvement in their survival. However, there are no specific recommendations regarding the use of resuscitative efforts for VLBW infants, and there is scant data in the literature on morbidity and mortality in relation to epinephrine administration. Due to the vulnerability of VLBW infants, studies that examine the effects and consequences of cardiovascular resuscitation and epinephrine administration are needed. STUDY AIM: The objective of this study is to determine the outcome of VLBW infants, who received epinephrine in the delivery room. METHODS: Medical records of VLBW infants admitted to neonatal intensive care unit (NICU) from 1999 to 2007 were reviewed, and infants who received epinephrine in the delivery room were identified and included in the study. RESULTS: Infants who received epinephrine are smaller in terms of gestational age and birth weight and have decreased survival. After adjusting for gestational age and birth weight, infants who received epinephrine presented lower 1 and 5 min APGAR (Appearance, Pulse, Grimace, Activity, Respiration) scores, more respiratory distress syndrome, lower survival (26% vs. 43%, p<0.01) and lower survival without severe brain injury (17% vs. 32%, p<0.01). CONCLUSIONS: VLBW infants, who require epinephrine in the delivery room, are smaller in terms of gestational age and birth weight. The requirement of epinephrine in the delivery room during resuscitation may be associated to worst outcomes and decreased survival without severe brain injury. These findings lead to more questions on how aggressive resuscitation efforts should be for these infants. PMID- 21272986 TI - Glidescope((r)) videolaryngoscope improves intubation success rate in cardiac arrest scenarios without chest compressions interruption: a randomized cross-over manikin study. AB - AIM: The aim of this study was to assess the performance of the Glidescope((r)) in a manikin cardiopulmonary resuscitation (CPR) scenario. METHODS: Following a brief didactic session, 45 volunteer doctors inexperienced with airway management, attempted to intubate a manikin using a Macintosh laryngoscope and Glidescope((r)) with uninterrupted and without chest compressions. Primary endpoints were intubation times and success rate with each device. Dental compression and level of self-confidence in using each device were also assessed. RESULTS: In the scenario without chest compressions the cumulative success rate related to time to intubation was significantly higher with the Macintosh blade than with the Glidescope((r)) (p<0.001). On the contrary, in the scenario with continuous chest compressions, the cumulative rate related to time to intubation was significantly higher with the Glidescope((r)) (p=0.035). Significantly fewer attempts were required for the first successful intubation with the Macintosh blade in the non-CPR scenario versus the CPR scenario (p=0.007). Moreover, the number of attempts for the first successful intubation was significantly lower for the Glidescope((r)) in the non-CPR (p=0.001) and the CPR scenario (p<0.001). Dental compression was significantly lower with the Glidescope((r)) in both scenarios (p<0.001). CONCLUSIONS: Using the GlideScope((r)) in a manikin CPR scenario provides extremely high intubation success rates in short times with the first attempt, in medical practitioners inexperienced in intubation. PMID- 21272988 TI - Serum total IgE level during pregnancy and postpartum. AB - BACKGROUND: Studies on serum IgE levels during pregnancy are limited. OBJECTIVE: To investigate the course of serum total IgE levels during pregnancy and postpartum. METHODS: 159 pregnant subjects provided 218 serum samples during various stages of pregnancy and the postpartum period. Serum total IgE geometric means were compared at various trimesters and postpartum. In addition, the postpartum IgE data were analysed according to the method of delivery. Analysis was also done according to history of allergy. RESULTS: The geometric mean serum total IgE was 20.5 IU/ml in the first trimester, 20.8 IU/ml in the second and 22.2 IU/ml in the third. Postpartum serum IgE level showed a lower mean, 14.9 IU/ml during the early postpartum period (less than 30 days) compared to 30.3 IU/ml during the late postpartum period (30 days-25 weeks). However this was not statistically significant. Serum IgE in the postpartum period also did not differ according to method of delivery. A history of allergy was positive in 98 samples, negative in 61 and unclear in 59. Using analysis of variance, none of these three groups showed significant change in serum total IgE level during pregnancy or postpartum. CONCLUSION: In this cross-sectional study, serum total IgE levels showed no statistically significant changes during pregnancy or postpartum. This finding would be of greater weight if reproduced in a larger number of subjects with multiple serial samples at fixed regular time intervals during pregnancy and postpartum. PMID- 21272987 TI - Allergic hypersensitivity to cannabis in patients with allergy and illicit drug users. AB - BACKGROUND: Cannabis is the illicit drug most widely used by young people in high income countries. Allergy symptoms have only occasionally been reported as one of the adverse health effects of cannabis use. OBJECTIVES: To study IgE-mediated response to cannabis in drug users, atopic patients, and healthy controls. METHODS: Asthmatic patients sensitised to pollen, and all patients sensitised to tobacco, tomato and latex, considered as cross-reacting allergens, were selected from a data base of 21,582 patients. Drug users attending a drug-rehabilitation clinic were also included. Controls were 200 non-atopic blood donors. Specific IgE determination, prick tests and specific challenge with cannabis extracts were performed in patients and controls. RESULTS: Overall, 340 patients, mean age 26.9+/-10.7 years, were included. Males (61.4%) were the most sensitised to cannabis (p<0.001). All cannabis-sensitised patients were alcohol users. Eighteen (72%) of the patients allergic to tomato were sensitised to cannabis, but a positive specific challenge to cannabis was highest in patients sensitised to tobacco (13/21, 61.9%), (p<0.001). Pollen allergy was not a risk factor for cannabis sensitisation. Prick tests and IgE for cannabis had a good sensitivity (92 and 88.1%, respectively) and specificity (87.1 and 96%) for cannabis sensitisation. CONCLUSIONS: Cannabis may be an important allergen in young people. Patients previously sensitised to tobacco or tomato are at risk. Cannabis prick tests and IgE were useful in detecting sensitisation. PMID- 21272989 TI - Cervical hydatidiform mole pregnancy after missed abortion presenting with severe vaginal bleeding: case report and review of the literature. AB - We report a 28-year-old woman presenting with a complete hyaditiform mole localized to the cervix. She had undergone curettage of missed abortion two months previously and the aborted material showed normal placental tissue on histopathologic examination. Two months after curettage she presented with sudden severe vaginal bleeding. Clinical examination revealed a lesion of the epithelial outer surface of the cervix. Due to the bleeding, immediate surgical intervention was necessary. Histological examination revealed a complete hydatidiform mole. Currently, only three cases of this exceedingly rare diagnosis have been published: two reported a partial mole and one a complete hydatidiform mole. In our case, we hypothesize that the pathogenesis took place in two steps. Initially the curettage of the missed abortion damaged the endometrial lining. During a new rapid re-fertilization after the missed abortion, a hydatidiform molar pregnancy developed. Normally this abnormal trophoblast tissue would adhere to the endometrium but in this case we assume that intrauterine implantation was not possible because of endometrial damage at the prior curettage, allowing the abnormal trophoblast tissue to pass the endocervix and emerge into the vaginal vault. Presumably, during the curettage an epithelial defect was produced on the outer surface of the cervix, due to clamping the cervix during dilatation. We speculate that this weak spot on the epithelial surface was responsible for the adherence to the cervix and subsequent bleeding was caused by injury of maternal blood vessels. We propose that careful holding of the cervix with atraumatic clamps during curettage is important to avoid subsequent complications. PMID- 21272990 TI - High grade CIN diagnosis by combined visual inspection with Lugol's iodine and cytology in symptomatic women. AB - OBJECTIVE: To investigate the diagnostic performance of combining the visual inspection with Lugol's iodine (VILI) and cytology screening to detect high-grade cervical intraepithelial neoplasia (CIN-2 or CIN-3) in symptomatic women, using histological examination as the standard reference test. STUDY DESIGN: Cross sectional referral study utilizing secondary data from 538 medical records from a clinic specialized in cervical pathology in Brazil. RESULTS: Although the sensitivity reached 96.8%, the specificity was only 8.1%, with positive predictive value of 18.3% and negative predictive value of 92.3%. CONCLUSION: The combination of both tests proved to be highly sensitive, leading to a large decrease in the false negative results. This was achieved, however, at the cost of an excess in the rate of false positive results, thus making the combination unviable for screening in symptomatic women. PMID- 21272991 TI - User behaviour, best practice and the risks of non-target exposure associated with anticoagulant rodenticide use. AB - Usage of anticoagulant rodenticides (ARs) is an integral component of modern agriculture and is essential for the control of commensal rodent populations. However, the extensive deployment of ARs has led to widespread exposure of a range of non-target predatory birds and mammals to some compounds, in particular the second-generation anticoagulant rodenticides (SGARs). As a result, there has been considerable effort placed into devising voluntary best practice guidelines that increase the efficacy of rodent control and reduce the risk of non-target exposure. Currently, there is limited published information on actual practice amongst users or implementation of best practice. We assessed the behaviour of a typical group of users using an on-farm questionnaire survey. Most baited for rodents every year using SGARs. Most respondents were apparently aware of the risks of non-target exposure and adhered to some of the best practice recommendations but total compliance was rare. Our questionnaire revealed that users of first generation anticoagulant rodenticides rarely protected or checked bait stations, and so took little effort to prevent primary exposure of non targets. Users almost never searched for and removed poisoned carcasses and many baited for prolonged periods or permanently. These factors are all likely to enhance the likelihood of primary and secondary exposure of non-target species. PMID- 21272992 TI - Prevention of recurrent urinary tract infections by intravesical administration of hyaluronic acid and chondroitin sulphate: a placebo-controlled randomised trial. AB - BACKGROUND: Urinary tract infection (UTI) is a prevalent condition in women during their lifetime with a high rate of recurrence within 3-6 mo. OBJECTIVES: Our aim was to investigate the efficacy and tolerability of the intravesical administration of combined hyaluronic acid (HA) and chondroitin sulphate (CS) in female patients with a history of recurrent UTI. DESIGN, SETTING, AND PARTICIPANTS: We conducted a prospective, randomised, double-blind, placebo controlled study comparing the intravesical instillation of HA-CS with placebo in women with recurrent UTI. INTERVENTION: Participants were randomised to receive 50 ml of sterile sodium HA 1.6% and CS 2.0% solution (IALURIL((r))) weekly for 4 wk and then monthly for 5 mo. MEASUREMENTS: The primary end point of the study was defined as the mean number of UTI per patient per year. Participants were evaluated addressing UTI status/urinary symptoms and with a general health related quality-of-life (QoL) questionnaire at baseline and after 3, 6, 9, and 12 mo. RESULTS AND LIMITATIONS: In the intention-to-treat analysis, 57 women were randomly allocated to HA-CS (n=28) or placebo (n=29). The UTI rate per patient per year at the end of the study (12 mo) (mean+/-SD: -86.6%+/-47.6 vs -9.6%+/ 24.6; mean difference: 77%; 95% confidence interval, 72.3-80.8; p=0.0002) and the mean time to UTI recurrence (52.7+/-33.4 vs 185.2+/-78.7 d; p<0.001) were significantly reduced after treatment with HA-CS compared with placebo. Overall urinary symptoms and QoL measured by questionnaires significantly improved compared with placebo (Pelvic Pain and Urgency/Frequency questionnaire symptom score: 14.53+/-4.32 vs 9.88+/-6.77; p=0.004; SF-36 QoL score: 78.6+/-6.44 vs 53.1+/-4.72; p<0.001). No serious adverse event was reported. CONCLUSIONS: Compared with placebo, HA-CS intravesical instillations significantly reduced UTI rate without severe side effects while improving symptoms and QoL over a 12-mo period in patients with recurrent UTI. TRIAL REGISTRATION: ISRCTN 76354426. PMID- 21272993 TI - Accurate molecular classification of kidney cancer subtypes using microRNA signature. AB - BACKGROUND: Renal cell carcinoma (RCC) encompasses different histologic subtypes. Distinguishing between the subtypes is usually made by morphologic assessment, which is not always accurate. OBJECTIVE: Our aim was to identify microRNA (miRNA) signatures that can distinguish the different RCC subtypes accurately. DESIGN, SETTING, AND PARTICIPANTS: A total of 94 different subtype cases were analysed. miRNA microarray analysis was performed on fresh frozen tissues of three common RCC subtypes (clear cell, chromophobe, and papillary) and on oncocytoma. Results were validated on the original as well as on an independent set of tumours, using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis with miRNA-specific primers. MEASUREMENTS: Microarray data were analysed by standard approaches. Relative expression for qRT-PCR was determined using the DeltaDeltaC(T) method, and expression values were normalised to small nucleolar RNA, C/D box 44 (SNORD44, formerly RNU44). Experiments were done in triplicate, and an average was calculated. Fold change was expressed as a log(2) value. The top-scoring pairs classifier identified operational decision rules for distinguishing between different RCC subtypes and was robust under cross validation. RESULTS AND LIMITATIONS: We developed a classification system that can distinguish the different RCC subtypes using unique miRNA signatures in a maximum of four steps. The system has a sensitivity of 97% in distinguishing normal from RCC, 100% for clear cell RCC (ccRCC) subtype, 97% for papillary RCC (pRCC) subtype, and 100% accuracy in distinguishing oncocytoma from chromophobe RCC (chRCC) subtype. This system was cross-validated and showed an accuracy of about 90%. The oncogenesis of ccRCC is more closely related to pRCC, whereas chRCC is comparable with oncocytoma. We also developed a binary classification system that can distinguish between two individual subtypes. CONCLUSIONS: MiRNA expression patterns can distinguish between RCC subtypes. PMID- 21272994 TI - Fenton treatment of complex industrial wastewater: optimization of process conditions by surface response method. AB - Remediation of industrial wastewaters represents a stringent problem in modern society, which requires particular understanding and ad hoc solutions. In this work, we performed extensive experimental study of chemical Fenton oxidation in order to understand the optimal operative conditions to be applied in real industrial wastewaters treatment. We analyzed the effectiveness of chemical oxygen demand (COD) removal from different wastewaters within a wide range of initial COD content. We observed a maximum COD % removal of about 80%, assessing the efficiency of the process. In order to understand the role of different reagents in the final yield, we performed a factorial experimental approach on the Fenton's reagents (H(2)O(2) and Fe(2+)) and analyzed the results developing an analytical second-order model. The model depends on three variables, namely: the initial [COD(i)] of the sample, the [COD(i)]/[H(2)O(2)] ratio and [H(2)O(2)]/[Fe(2+)] ratio. We obtained an accurate description of the COD % removal in different initial conditions, with a R(2)=0.85. In particular, we observed that optimal quantities of Fenton's reagents are a function of the initial COD of the treated wastes. PMID- 21272995 TI - Synthesis of Cr(VI)-imprinted poly(4-vinyl pyridine-co-hydroxyethyl methacrylate) particles: its adsorption propensity to Cr(VI). AB - The aim of this study is to prepare ion-imprinted polymers, which can be used for the selective removal of Cr(VI) anions from aqueous media. 4-Vinyl pyridine (4 VP) was used as functional monomer. The Cr(VI)-imprinted poly(4-vinyl pyridine-co 2-hydroxyethyl methacrylate), poly(VP-HEMA), particles were prepared by bulk polymerization. The Cr(VI)-imprinted polymer particles were grained from the bulk polymer, and the template ions (i.e., Cr(VI)) were removed using thiourea (0.5%, v/v) in 0.5M HCl. The Cr(VI)-imprinted polymer contained 21.4 MUmol 4-VP/g polymers. The specific surface area of the IIP2 particles was found to be 34.5m(2)/g (size range of 75-150 MUm), and the swelling ratio was about to 108%. The effect of initial concentration of Cr(VI) anions, the adsorption rate and the pH of the medium on adsorption capacity of Cr(VI)-imprinting polymer were studied. The maximum experimental adsorption capacity was 3.31 mmol Cr(VI)/g polymer. Under competitive condition, the adsorption capacity of Cr(VI)-imprinted particles for Cr(VI) is 13.8 and 11.7 folds greater than that of the Cr(III) and Ni(II) ions, respectively. The first- and second order kinetics models were estimated on the basis of comparative analysis of the corresponding rate parameters, equilibrium capacity and correlation coefficients. The Langmuir adsorption isotherm model was well described the Cr(VI)-imprinted system and the maximum adsorption capacity (Q(max)) was found to be 3.42 mmol/g. Moreover, the reusability of the poly(VP-HEMA) particles was tested for several times and no significant loss in adsorption capacity was observed. PMID- 21272996 TI - Mothers' and fathers' responses to their child's pain moderate the relationship between the child's pain catastrophizing and disability. AB - Preliminary evidence suggests that pain catastrophizing in children may be important in understanding how parents respond to their child's pain. However, no study has investigated whether parental responses, in turn, moderate the impact of child's catastrophizing upon pain outcomes. The present study was designed to address this, and investigated the association of the child's catastrophizing with different types of parental responses (ie, solicitousness, discouragement and coping promoting responses) and the extent to which parental responses moderate the association between the child's catastrophizing and disability. Participants were 386 school children and their parents. Analyses revealed significant associations between the child's pain catastrophizing and parental responses, but with mothers and fathers evidencing different patterns; ie, higher levels of the child's catastrophizing were significantly associated with lower levels of solicitousness by fathers, and with higher levels of discouragement by mothers. Moderation analyses indicated that father's solicitiousness moderated the association between catastrophizing and disability; the positive association between catastrophizing and the child's disability was further strengthened when fathers reported low levels of solicitousness, but became less pronounced when fathers reported high levels of solicitousness. Findings also revealed a moderating impact of mothers' and fathers' promotion of their child's well behaviour/coping. Specifically, the detrimental impact of child catastrophizing upon disability was less pronounced when parents reported high promotion of their child's well behaviours/coping. The findings of the present study suggest the importance of assessing and targeting parental responses to their child's pain to alter the adverse impact of the child's pain catastrophizing on pain outcomes. PMID- 21272997 TI - Screening tools for neuropathic pain: can they be of use in individuals with spinal cord injury? AB - Pain of both neuropathic and nociceptive aetiology is common after spinal cord injury (SCI), and classifying pain is sometimes a challenge. The objective of this study was to test the usefulness of the Swedish version of the screening tools Douleur Neuropathique 4 questions (DN4), the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS), the Neuropathic Pain Questionnaire (NPQ), and the painDETECT Questionnaire (PD-Q) in individuals with SCI and pain. A further objective was to define pain descriptors able to discriminate neuropathic pain from nonneuropathic pain. Forty individuals with SCI >=1 year and pain >=6 months were examined by a specialised physician and assessed twice using the 4 screening tools. The analysis included tests of reliability (test-retest) and validity (calculation of sensitivity, specificity, and overall agreement), an explorative analysis of the cutoff scores and regression analysis for identifying predictors of diagnostic accuracy. Our results indicate that reliability was good to very good for 3 of the screening tools, DN4, LANSS, and NPQ with a Cohen's kappa coefficient between 0.70 and 1.00. DN4 showed the highest sensitivity (93%), followed by PD-Q (68%), NPQ (50%), and LANSS (36%). LANSS and NPQ demonstrated the highest specificity (100%), followed by PD-Q (83%) and DN4 (75%). Diagnostic accuracy for the tools was for DN4 88%, PD-Q 78%, NPQ 65%, and LANSS 55%. A final model showed that 3 items, hypoesthesia to touch, burning pain, and numbness, could discriminate pain in this cohort of individuals with SCI with a high goodness of fit. PMID- 21272998 TI - From transduction to pain sensation: defining genes, cells, and circuits. PMID- 21272999 TI - Central poststroke pain: a population-based study. AB - Central poststroke pain (CPSP) is a specific pain condition arising as a direct consequence of a cerebrovascular lesion. There is limited knowledge about the epidemiology and clinical characteristics of this often neglected but important consequence of stroke. In this population-based study, a questionnaire was sent out to all (n=964) stroke patients identified through the Danish National Indicator Project Stroke Database in Aarhus County, Denmark, between March 2004 and February 2005. All surviving patients who fulfilled 4 questionnaire criteria for possible CPSP (n=51) were selected for further clinical examination, and their pain was classified by using stringent and well-defined criteria and a detailed, standardized clinical examination. The minimum prevalence of definite or probable CPSP in this population is 7.3% and the prevalence of CPSP-like dysesthesia or pain is 8.6%. Pinprick hyperalgesia was present in 57%, cold allodynia in 40%, and brush-evoked dysesthesia in 51% of patients with CPSP. Because of its negative impact on quality of life and rehabilitation, pain is an important symptom to assess in stroke survivors. PMID- 21273000 TI - Infection of humans and animals with Echinococcus granulosus (G1 and G3 strains) and E. ortleppi in Southern Brazil. AB - The Rio Grande do Sul state, in Southern Brazil, is one of the foci of human cystic echinococcosis (CE). The sheep strain (G1) of Echinococcus granulosus and Echinococcus ortleppi (also known as cattle strain G5) have been reported before to infect livestock. However, up to the present, no molecular data are available on isolates of the E. granulosus complex from humans and dogs. The present study analyzed hydatid cysts from 6 CE patients and adult worms from 12 dogs. Sequencing of the mitochondrial cox1 and 12S rRNA genes detected the E. granulosus G1 genotype from four human cases, the G3 genotype (or buffalo strain) from one human case and E. ortleppi from another human case, respectively. Ten of the twelve dogs were found infected with the G1 genotype, and one dog each harbored worms of the G3 genotype and E. ortleppi. Obvious morphological differences were recognized between the G1 and E. ortleppi adult worms from dogs in this region. The buffalo strain (G3) is for the first time reported from South America. PMID- 21273001 TI - Serological prevalence of Babesia caballi and Theileria equi in horses of Lara State, Venezuela. AB - The main objective of this study was to demonstrate the occurrence of equine piroplasmosis (EP) in horses of Lara State, Venezuela, and to correlate it with the factors host's sex and age in order to know the epidemiology of this disease at the Venezuelan Centroccidental Region. Antibody levels to Babesia caballi and Theileria equi were assessed in 360 equine serum samples, collected from 9 municipalities of Lara State, using an ELISA technique with recombinant antigens and monoclonal antibodies (Mabs). Antibodies to B. caballi were found in 254 horses (70.6%), whereas 181 animals (50.3%) were detected as seropositives to T. equi. In addition, 128 samples (35.56%) were seropositives to both hemoparasites. There were no significant differences between the seropositivity to B. caballi and T. equi with the factors sex and age of the horses. These results show that Lara State is an enzootic area for equine piroplasmosis, and are a contribution to a partial knowledge of the dynamic of this disease in Venezuela. PMID- 21273002 TI - Prevalence of trypanosome infections in dogs from Chagas disease endemic regions in Panama, Central America. AB - The prevalence of canine trypanosomosis was investigated in two Chagas disease endemic rural communities located in the central region of Panama. Serologic tests for Trypanosoma cruzi infection revealed a prevalence of 11.1%. Hemocultures coupled with PCR analysis demonstrated a Trypanosoma rangeli infection rate of 5.1%. An overall trypanosome infection index of 16.2% (16/99) was detected in this canine population. One dog had a mixed infection of T. cruzi and T. rangeli. Six of the trypanosome-infected dogs belong to people who were diagnosed of Chagas disease. We conclude that dogs from this rural area of Panama are frequently infected with trypanosomes transmitted by the sylvatic vector, Rhodnius pallescens, and suggest that dogs are important in the peridomestic transmission cycle of trypanosomes as reservoirs and hosts. The epidemiological implications of these findings are discussed. PMID- 21273003 TI - Activities of adenine nucleotide and nucleoside degradation enzymes in platelets of rats infected by Trypanosoma evansi. AB - Nucleotide and nucleoside-degrading enzymes, such as nucleoside triphosphate diphosphohydrose (NTPDase), 5'-nucleotidase and adenosine deaminase (ADA) are present in the surface membranes of platelets, involved in clotting disturbances of Trypanosoma evansi-infected animals. Thus, this study was aimed at evaluating the activities of these enzymes in platelets of rats experimentally infected with T. evansi. Animals were divided into four groups, according to the level of parasitemia. Blood samples were collected on days 3 (group A: at the beginning of parasitemia), 5 (group B: high parasitemia) and 15 (group C: chronic infection), post-infection. Group D (control group) was composed of non-infected animals for platelet count, separation and enzymatic assays. Animals from groups A and B showed marked thrombocytopenia, but platelet count was not affected in chronically infected rats. NTPDase, 5'-nucleotidase and ADA activities decreased (p<0.05) in platelets from rats of groups A and B, when compared to the control group. In group C, only NTPDase and 5'-nucleoside activities decreased (p<0.001). The correlations between platelet count and nucleotide/nucleoside hydrolysis were positive and statistically significant (p<0.05) in groups A and B. Platelet aggregation was decreased in all infected groups, in comparison to the control group (p<0.05). It is concluded that the alterations observed in the activities of NTPDase, 5'-nucleotidase and ADA in platelets of T. evansi-infected animals might be related to thrombocytopenia, that by reducing the number of platelets, there was less release of ATP and ADP. Another possibility being suggested is that changes have occurred in the membrane of these cells, decreasing the expression of these enzymes in the cell membrane. PMID- 21273004 TI - An interaction between a neuropeptide Y gene polymorphism and early adversity modulates endocrine stress responses. AB - Interindividual variability in the regulation of the human stress system accounts for a part of the individual's liability to stress-related diseases. These differences are influenced by environmental and genetic factors. Early childhood adversity is a well-studied environmental factor affecting an individual's stress response which has been shown to be modulated by gene-environment interaction (GxE). Neuropeptide Y (NPY) plays a role in stress regulation and genetic variation in NPY may influence stress responses. In this study, we analyzed the association of a common variant in the NPY gene promoter, rs16147, with cortisol and ACTH responses to acute psychosocial stress in young adults from the Mannheim Study of Children at Risk (MARS), an ongoing epidemiological cohort study following the outcome of early adversity from birth into adulthood. We found evidence of a GxE interaction between rs16147 and early adversity significantly affecting HPA axis responses to acute psychosocial stress. These findings suggest that the neurobiological mechanisms linking early adverse experience and later neuroendocrine stress regulation are modulated by a gene variant whose functional relevance is documented by increasing convergent evidence from in vitro, animal and human studies. PMID- 21273005 TI - Changes in the sleep electroencephalogram (EEG) during male to female transgender therapy. AB - Steroids, including estrogens, participate in sleep regulation. For example estrogen replacement therapy improved sleep quality in postmenopausal women. Patients, who undergo a cross-gender hormone therapy, receive high doses of estrogens. The effects of this treatment on sleep are unknown. To clarify this issue, we examined seven male to female transsexual patients (age range 31-44 years, mean+/-SD 35.9+/-4.2 years). The patients spent two nights on 2 separate occasions in our sleep laboratory. The first night of each session served for adaptation to laboratory conditions. In the second night sleep electroencephalogram [EEG] was recorded from 2300h to 0700h. The first examination was performed before and the second about 3 months after initiation of cross-gender hormone therapy with a dose of 80-100mg estrogen applied every 2 weeks. Additionally patients were treated with a starting dose of the anti androgen cyproteronacetate of 100mg/day and after about 6 weeks with a maintenance therapy of 50mg/d in order to suppress androgenic effects. Statistical analysis was performed with the Wilcoxon rank test. Under this estrogen therapy we found a significant increase in stage 1 sleep during the whole night (at baseline [b]: 33.29+/-9.94min; treatment [t]: 51.57+/-24.26min; p<0.05) Beta activity in nonREM sleep was significantly increased (p=0.02) during hormone therapy compared to before treatment. Other sleep EEG parameters showed no significant changes. Administration of estrogen and anti-androgens in male to female transsexual patients had only a small influence on sleep EEG, with an increase in the duration of shallow sleep. PMID- 21273006 TI - Regional lymphatic spread in women with pelvic endometriosis. AB - Endometriosis is defined by the presence of endometrial tissue outside the uterine cavity and is associated with chronic pelvic pain and infertility. After surgical and/or medical treatment, endometriosis has a high recurrence rate which increases with the length of follow-up. To delay or to eliminate recurrence is a main task in the control of this disease. To date, little is known about the mechanism of recurrence and its management is not efficacious. Recently, it has been observed that regional lymph node involvement by endometriosis is a common phenomenon in women with endometriosis. Endometriotic cells in regional lymph node are a potential target of hormonal stimulation in the postoperative period and may be a major source of disease recurrence. We hypothesize that the resection of regional lymph nodes can decrease the recurrence rate of endometriosis and hence should become part of the surgical treatment of this disease. PMID- 21273007 TI - [Ballantyne syndrome caused by materno-fetal Parvovirus B19 infection: about two cases]. AB - Ballantyne's syndrome also known as Mirror syndrome is the association of fetal hydrops and maternal hydric retention. The maternal condition is often misdiagnosed as preeclampsia. We report two cases of Ballantyne syndrome associated with materno-fetal Parvovirus B19 infection. In the first case, the syndrome occurred at 26GW in a context of premature rupture of membranes. Parents and medical staff opted for termination of pregnancy because of the poor fetal prognosis. Maternal symptoms regressed after delivery. In the second case, the patient presented a Ballantyne's syndrome at 25GW. Intrauterine transfusions reversed symptomatology. Fetal hydrops of any etiology can be associated with this syndrome. Specific treatment of the fetus can avoid maternal complication allowing continuation of the pregnancy. PMID- 21273008 TI - Microbiology of equine wounds and evidence of bacterial biofilms. AB - Horse wounds have a high risk of becoming infected due to their environment. Infected wounds harbour diverse populations of microorganisms, however in some cases these microorganisms can be difficult to identify and fail to respond to antibiotic treatment, resulting in chronic non-healing wounds. In human wounds this has been attributed to the ability of bacteria to survive in a biofilm phenotypic state. Biofilms are known to delay wound healing, principally due to their recalcitrance towards antimicrobial therapies and components of the innate immune response. This study describes the presence of bacterial biofilms within equine wounds. Thirteen 8-mm diameter tissue samples were collected from (n=18) chronic wounds. Following histological staining, samples were observed for evidence of biofilms. Fifty one wounds and control skin sites were sampled using sterile swabs. Control skin sites were on the uninjured side of the horse at the same anatomical location as the wound. The isolated bacteria were cultured aerobically and anaerobically. The biofilm forming potential of all the isolated bacteria was determined using a standard crystal violet microtitre plate assay. Stained tissue samples provided evidence of biofilms within 61.5% (8 out of 13) equine wounds. In total 340 bacterial isolates were identified from all the equine wound and skin samples. Pseudomonas aeruginosa and Enterococcus faecium were the most predominantly isolated bacterial species from equine wound and skin samples respectively. Staphylococcus was the most commonly isolated genus in both environments. Bacteria cultured from chronic and acute wounds showed significantly (P<0.05) higher biofilm forming potential than bacteria isolated from skin. This paper highlights preliminary evidence supporting the presence of biofilms and a high microbial diversity in equine chronic wounds. The presence of biofilms in equine wounds partly explains the reluctance of many lower limb wounds to heal. Non-healing limb wounds in horses are a well documented welfare and economic concern. This knowledge can be used to shape future treatments in order to increase the healing rate and decrease the costs and suffering associate with equine wounds. PMID- 21273009 TI - Host specific differences alter the requirement for certain Salmonella genes during swine colonization. AB - The pathogenic potential of Salmonella is determined during the complex interaction between pathogen and host, requiring optimal regulation of multiple bacterial genetic systems within variable in vivo environments. The mouse model of systemic disease has been an extremely productive model to investigate the pathogenesis of Salmonella enterica serovar Typhimurium (S. Typhimurium). Although the mouse model is a widely used paradigm for studying the pathogenesis of systemic disease caused by Salmonella, investigations concerning food safety interventions should employ natural hosts to examine gastrointestinal colonization by Salmonella. Recent research has demonstrated specific differences in the attenuation of certain S. Typhimurium mutants in mice compared to swine. This variation in pathogenesis between the mouse model and pigs for the S. Typhimurium mutants is presumably dependent upon either the requirements for specific gene products during systemic disease (mouse) versus gastrointestinal colonization (pig) or host specific differences. In addition, host specific diversity in Salmonella colonization of swine has also been described in comparison to other food-producing animals, including cattle and chickens. Differences in Salmonella colonization and pathogenesis across diverse animal species highlight the importance of species-specific studies of gastrointestinal colonization for the development of Salmonella interventions to enhance pork safety. PMID- 21273010 TI - Detection of PRRSV circulation in herds without clinical signs of PRRS: comparison of five age groups to assess the preferred age group and sample size. AB - A cross-sectional study was conducted to find the most effective diagnostic approach to detect circulation of porcine reproductive and respiratory syndrome virus (PRRSV). The study was performed in 10 Dutch swine herds, with sows and fattening pigs or breeding stock. Herds did not experience clinical signs of PRRS during the last 6 months before sampling, but a PRRSV infection was confirmed at most 2 years before sampling. Blood samples were collected from 5 age groups: sows during early and late gestation, weaners at 9 weeks of age, fatteners or breeding stock at 16 and 22 weeks of age. For each category, 20 serum samples were examined; in total 100 serum samples per herd. Samples were analysed for PRRSV antibodies with ELISA (n=1002), and rt-PCR when ELISA S/P-ratios were above 1.5 (n=307) or below 0.4 (n=187; random selection from each age group). A logistic regression analysis was used to obtain factors associated with the probability of virus detection in a pig (PCR positive test result). Herd, ELISA result, and age group were included as explanatory variables. Variables remained in the model when statistically significant. ELISA results showed that none of the herds could be considered to be free of PRRSV infection. Mean PRRSV seroprevalence in unvaccinated animals varied between 18% and 82%, and mean PRRS virus prevalence varied between 0% and 41%. In only one of the 10 herds, no PRRS virus could be detected. The odds of finding PRRS-virus in blood samples were 8.6 (95% CI, 5.3-13.9) in pigs of 9 weeks of age and 4.6 (95% CI, 3.0-7.0) in pigs of 16 weeks of age, compared with fatteners of 22 weeks of age. This result indicates that 9- to 16-week-old pigs are the preferred age group to detect PRRS virus, in herds without clinical signs of PRRS. We concluded that PRRS-virus circulation could be detected in 8 out of 9 of the study-herds, with a relatively low number of blood samples. Testing 12 blood samples in both rt-PCR and ELISA, with 6 samples in pigs 9 weeks of age and 6 samples in pigs 16 weeks of age, will lead to a cost-efficient first evaluation of the PRRSV infection-status in herds without clinical signs of PRRS. PMID- 21273011 TI - Isolation of an equine coronavirus from adult horses with pyrogenic and enteric disease and its antigenic and genomic characterization in comparison with the NC99 strain. AB - A new equine coronavirus was isolated from the feces of adult horses with pyrogenic and enteric disease. The disease outbreak was mainly observed among 2- to 4-year-old horses living in stables of a draft-horse racetrack in Japan. On comparing the isolated virus (isolate Tokachi09) with the equine coronavirus NC99 strain, no significant differences were observed in several biological properties such as hemagglutinating activity, antigenicity (in indirect immunofluorescence and neutralization tests), and one-step growth (in cell culture). The sequences of the nucleocapsid and spike genes of isolate Tokachi09 showed identical size (1341 and 4092 nucleotides, 446 and 1363 amino acids, respectively) and high similarity (98.0% and 99.0% at the nucleotides, 97.3% and 99.0% at the amino acids, respectively) to those of strain NC99. However, the isolate had a 185 nucleotide deletion from four bases after the 3'-terminal end of the spike gene, resulting in the absence of the open reading frame predicted to encode a 4.7-kDa nonstructural protein in strain NC99. These results suggest that the 4.7-kDa nonstructural protein is not essential for viral replication, at least in cell culture, and that the Japanese strain probably originated from a different lineage to the North American strain. This is the first equine coronavirus to be isolated from adult horses with pyrogenic and enteric disease. PMID- 21273012 TI - Special populations: do we need evidence from randomized controlled trials to support the need for respiratory syncytial virus prophylaxis? AB - Congenital abnormalities and impaired mechanisms that govern the normal coordinated physiology of breathing, sucking, swallowing and airway clearance, place infants with underlying medical disorders at high risk for respiratory morbidity following respiratory syncytial virus (RSV) lower respiratory tract infection. The use of RSV prophylaxis in premature infants' <= 35 weeks gestational age, infants with chronic lung and hemodynamically significant heart disease is firmly established through randomized controlled clinical trials (RCT's). RSV prophylaxis in infants with serious medical illnesses must be justified based on emerging scientific literature and the overriding concept of achieving a balance between benefit and harm with treatment. This article will explore the current evidence for palivizumab prophylaxis in a variety of disorders and examine existing differences between pediatric advisory body recommendations and real world practice. PMID- 21273013 TI - Bone freezing and bisphosphonates. PMID- 21273014 TI - DCIS of the breast: Are we over-diagnosing it? Are we over-treating it? PMID- 21273015 TI - Expression of aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocators in human adenoid tissue. AB - OBJECTIVE: The aim of this study was to determine whether aryl hydrocarbon receptor (AhR) and AhR nuclear translocators (ARNTs) are expressed in human adenoid tissue. METHODS: Paraffin-embedded human adenoid tissue specimens were obtained from eight children with adenoid hypertrophy. Sections were stained immunohistochemically with specific polyclonal antibodies to evaluate the expression pattern of AhR, ARNT1 and ARNT2 were evaluated. RESULTS: AhR immunoreactivity was ubiquitously seen in human adenoid tissue such as the epithelium, subepithelial layer, germinal center, mantle zone and interfollicular area. ARNT1 was also widely expressed in the same regions as AhR. Although ARNT2 was expressed in the human adenoid, the expression level was significantly lower than that of ARNT1. CONCLUSION: These data suggest that the relationship between AhR and ARNTs may play an important role in the local immune response in adenoid and that ARNT1 may be more important than ARNT2 especially in adenoid tissue. PMID- 21273016 TI - Modified tongue base suspension for multilevel or single level obstructions in sleep apnea: clinical and radiologic results. AB - OBJECTIVES: To investigate the radiologic and polysomnographic success in opening the airway using a tongue base suspension procedure alone or in combination with uvulopalatal flap in obstructive sleep apnea syndrome (OSAS) patients. METHODS: This study was conducted in 20 patients with moderate or severe OSAS in a prospective manner. The tongue base suspension technique alone or with a uvulopalatal flap (UPF) technique was applied. Magnetic resonance imaging (MRI) scans of patients obtained during the preoperative period and at the 5th week of the postoperative period were compared. Changes in pain and swallowing difficulties were assessed. Polysomnography (PSG) was applied at the 12th postoperative month, and body mass index (BMI) and Epworth sleepiness scale (ESS) values were determined. The degree of satisfaction relative to the surgery was assessed with 4 questions. RESULTS: Preoperative apnea-hypopnea index (AHI) level was found to be 24.55+/-9.87, whereas postoperative AHI level was 12.40+/-9.87 (P<0.01). The success rate was determined to be 60%. Preoperative ESS values were 13.90+/-2.67 and were reduced to 6.55+/-3.13 postoperatively (P<0.01), and the preoperative posterior airway space (PAS) level was 10.08+/-1.23, which was increased to 11.64+/-1.46 postoperatively (P<0.01). Visual analog scale (VAS) values for swallowing difficulty were 8.62 at day 1 and decreased to 3.98 at day 7. The VAS values for pain were 9.14 at day 1, but were reduced to 4.18 at day 7. CONCLUSIONS: Patients with OSAS who have hypertrophy of the tongue base may safely receive a tongue base suspension procedure, which is a minimally invasive method. The postoperative hospital stay is short and the success rate is high, as shown with both PSG and MRI. PMID- 21273017 TI - Comparative analysis of perinatal and postnatal factors, and general movement in extremely preterm infants. AB - STUDY AIM: To describe general movement in extremely premature infants and examine correlations with risk factors for antenatal, perinatal, and postnatal morbidity. STUDY TYPE: Prospective, single-center study. Nineteen patients were followed up. METHODOLOGY: The infants' general movement was analyzed using video recordings. Qualitative and quantitative assessments were performed during the writhing movement (WM) period and fidgety movement (FM) period. The quality of the general movements (GMs) and the scores achieved were then correlated with antenatal, perinatal, and postnatal factors. RESULTS: Infants' motor activity fluctuated during the WM period, especially in extremely premature infants where poor repertoire is often observed. No correlations were found between WMs and obstetric factors. Gestational age correlated with WMs' quality (p=0.023). WMs correlated with factors of postnatal morbidity such as chronic lung disease (CLD) (p=0.034) and nosocomial infections (p=0.05). At 3 months corrected age, the spontaneous movement quality are correlated with neurological explorations such as US brain (p=0.032), MRI (p=0.039), EEG (p=0.036), and neurological follow-up assessments (p=0.015). CONCLUSION: Prudence must be used when performing the analysis of general movement in extremely preterm infants. WMs may be influenced by perinatal morbidity, and possibly by the severe brain immaturity of these infants. WMs correlate with CLD and nosocomial infections. Analysis of general movement in infants of 3 months corrected age is a valuable means to detect neurological disorders. PMID- 21273018 TI - A case of clinically mild encephalitis with a reversible splenial lesion (MERS) after mumps vaccination. AB - We describe for the first time an 8-year-old male patient who demonstrated clinically mild encephalitis with a reversible splenial lesion after mumps vaccination. He suffered from transient hallucinations, nuchal rigidity, and inappropriate antidiuretic hormone secretion syndrome. On the 5th day of admission, his head MRI showed symmetrical high-signal-intensity lesions on T2, FLAIR, and diffusion-weighted images in the splenium of the corpus callosum and in the periventricular white matter, while an apparent diffusion coefficient map showed reduced diffusion. The images were not enhanced by gadolinium. Follow-up MRI on the 16th day of admission revealed none of these abnormalities. His serum IgM and IgG antibodies against the mumps virus were positive according to an enzyme immunoassay. Mumps Torii vaccine strain was isolated from the patient's cerebrospinal fluid. Previous reports demonstrated that transient delirious behavior, the syndrome of inappropriate antidiuretic hormone secretion, and good prognosis were the main clinical features of mild encephalitis with a reversible splenial lesion. This case shows that mild encephalitis with a reversible splenial lesion could occur after mumps vaccination. PMID- 21273019 TI - How accurate is CT morphometry of airway? Phantom and clinical validation study. AB - OBJECTIVE: To assess the reliability of CT airway measurement using phantom and to evaluate its reproducibility using clinical chest CT images. MATERIALS AND METHODS: The phantom consisted of six tubes with different diameters and wall thicknesses was used. The wall area ratio (%WA) and wall thickness ratio (%WT) were calculated and the difference from the actual value (error ratio) was assessed. In vivo validation was performed with MDCT data of consecutive 10 patients and inter- and intra-rater agreements of the measurement were evaluated. RESULTS: The error ratio of %WA and %WT increased for the phantom tube with a 1mm or thinner wall thickness. The FOV size has an influence on the airway measurement especially for the tube with 1mm wall thickness. Inter-rater reliabilities between two observers for %WA and %WT were excellent and good intra class correlation coefficient for %WA and %WT were obtained as 0.825 and 0.811, respectively. Intra-rater reliabilities of measurement also showed good intra class correlation coefficient for %WA and %WT as 0.822 and 0.800, respectively. CONCLUSION: Although the phantom study showed there is a tendency to overestimate the wall area of an airway with a thickness 1mm or less, the software has a potential to be used in assessing longitudinal observation of the same patient, as well as, comparison among different patients due to good intra- and inter rater reliability. PMID- 21273020 TI - WITHDRAWN: Endorectal MRI accuracy in auguring tumour location, tumour extent, capsular perforation and seminal vesicle invasion of prostate cancer in north African men. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 21273021 TI - Real-time contrast-enhanced ultrasound in diagnosing of focal spleen lesions. AB - OBJECTIVE: To investigate the features of focal spleen lesions (FSLs) on contrast enhanced ultrasound (CEUS) imaging. MATERIALS AND METHODS: CEUS with a blot injection of SonoVue was performed in 48 patients with 75 FSLs (median diameter 2.6cm) and their perfusion characteristics were analyzed by using contrast pulse sequences (CPS) technique. RESULTS: Among 19 malignant lesions (10 metastases, 7 lymphoma, 1 hemangiosarcoma, 1 epithelioid hemangioendothelioma) and 56 benign lesion (23 hemangiomas, 14 cysts, 8 infarctions, 4 splenic ruptures, 3 tuberculosis, 2 abscess, 1 pseudoaneurysm, 1 lymphangioma), 25 benign lesions were demonstrated nonenhancement. For malignancy, 50.0% (5/10) metastases and 57.1% (4/7) lymphomas were showed hypoenhancement in the arterial phase, and 18 (94.7%) of malignant lesions were hypo-enhancement in the parenchymal phase. Among 31 benign lesions with enhancement, 27 (87.1%) were showed isoenhancement or hyperenhancement in the arterial phase and 22 (71.0%) lesions were isoenhancement or hyperenhancement in the parenchymal phase. The sensitivity, specificity and accuracy of diagnosis for FSLs were 91.1%, 95.0% and 92.0% for CEUS and 75.0%, 84.2% and 77.3% respectively, for the conventional baseline ultrasound (BUS). CONCLUSION: Real-time CEUS can provide valuable information for the diagnosis and differential diagnosis of FSLs. PMID- 21273022 TI - Changes in thalamus connectivity in mild cognitive impairment: evidence from resting state fMRI. AB - PURPOSE: The subcortical region such as thalamus was believed to have close relationship with many cerebral cortexes which made it especially interesting in the study of functional connectivity. Here, we used resting state functional MRI (fMRI) to examine changes in thalamus connectivity in mild cognitive impairment (MCI), which presented a neuro-disconnection syndrome. MATERIALS AND METHODS: Data from 14 patients and 14 healthy age-matched controls were analyzed. Thalamus connectivity was investigated by examination of the correlation between low frequency fMRI signal fluctuations in the thalamus and those in all other brain regions. RESULTS: We found that functional connectivity between the left thalamus and a set of regions was decreased in MCI; these regions are: bilateral cuneus, middle occipital gyrus (MOG), superior frontal gyrus (SFG), medial prefrontal cortex (MPFC), precuneus, inferior frontal gyrus (IFG) and precentral gyrus (PreCG). There are also some regions showed reduced connectivity to right thalamus; these regions are bilateral cuneus, MOG, fusiform gyrus (FG), MPFC, paracentral lobe (PCL), precuneus, superior parietal lobe (SPL) and IFG. We also found increased functional connectivity between the left thalamus and the right thalamus in MCI. CONCLUSION: The decreased connectivity between the thalamus and the other brain regions might indicate reduced integrity of thalamus-related cortical networks in MCI. Furthermore, the increased connectivity between the left and right thalamus suggest compensation for the loss of cognitive function. Briefly, impairment and compensation of thalamus connectivity coexist in the MCI patients. PMID- 21273023 TI - Bias field reduction by localized Lloyd-Max quantization. AB - Bias field reduction is a common problem in medical imaging. A bias field usually manifests itself as a smooth intensity variation across the image. The resulting image inhomogeneity is a severe problem for posterior image processing and analysis techniques such as registration or segmentation. In this article, we present a novel debiasing technique based on localized Lloyd-Max quantization (LMQ). The local bias is modeled as a multiplicative field and is assumed to be slowly varying. The method is based on the assumption that the global, undegraded histogram is characterized by a limited number of gray values. The goal is then to find the discrete intensity values such that spreading those values according to the local bias field reproduces the global histogram as good as possible. We show that our method is capable of efficiently reducing (even strong) bias fields in 3D volumes. PMID- 21273024 TI - Lomefloxacin promotes the interaction between human serum albumin and transferrin: a mechanistic insight into the emergence of antibiotic's side effects. AB - Human serum albumin (HSA) and serum transferrin (TF) are two drug carrier proteins in vivo. In this study it was investigated how lomefloxacin (LMF) binding affected the HSA-TF interaction using different spectroscopic, calorimetric and molecular modeling techniques. Fluorescence, circular dichroism and synchronous fluorescence revealed that LMF could bind to both proteins, resulting in protein conformational changes. Moreover, HSA and TF could interact so that some fluorescence residues were positioned at the interface and were shielded from quenching by LMF. The interaction between HSA and TF was further confirmed by fluorescence resonance energy transfer. Quantitative analyses of the far-UV CD spectra of the HSA-TF interaction in the presence and absence of LMF revealed secondary structural changes in detail. Resonance light-scattering studies demonstrated that the HSA-TF interaction resulted in a new species with a larger size, and that the presence of LMF could further favor this reaction. Isothermal titration calorimetry revealed that electrostatic interaction was dominant in the absence of LMF, whereas van der Waals forces and hydrogen bonding become significant in its presence. On the other hand, it was found that the binding constant of TF bound to HSA was stronger in the presence of LMF. ANS fluorescence further indicated that hydrophobic interactions play a minor part in the HSA-TF system. Molecular modeling studies confirmed the presence of fluorophore residues, hydrogen bonding and electrostatic interactions at the interface of the HSA-TF complex. It also suggested that the binding sites of LMF were not located there. These data indicate that LMF can modify the interaction between HSA and TF as two model proteins present in serum. The relevance to drugs' side effects, pharmacokinetic of drugs and selection of diagnostic biomarker is discussed. PMID- 21273025 TI - Methodological diversity to reach patients along the margins, in the shadows, and on the cutting edge. AB - OBJECTIVE: There is extensive research on novel uses of visual and social media to disseminate health information, but fewer researchers have considered how to use new communication channels to listen to health care consumers and gather data for research purposes. METHODS: Current statistics and literature were reviewed to assess potential uses of interactive and visual media for health communication data collection. RESULTS: This essay examines the topic of methodological diversity by offering a few examples from current literature and practice on how interactive media can be more fully utilized to engage with research participants, discover appropriate research questions, and collect quantitative and qualitative health communication data. CONCLUSION: Social networks, mobile based technology, photovoice, and microblogging have potential benefits for collecting patient feedback for research, but there are also limitations of using technology-based collection methods. PRACTICAL IMPLICATIONS: Researchers should explore advantages and barriers for using interactive technology to access marginalized populations. PMID- 21273026 TI - Overexpression of HMGA2 in bladder cancer and its association with clinicopathologic features and prognosis HMGA2 as a prognostic marker of bladder cancer. AB - PURPOSE: To examine HMGA2 expression and investigate its clinical and prognostic significance in human urothelial bladder cancer (BUC). METHODS: We detected HMGA2 mRNA and protein expression by quantitative reverse-transcription polymerase chain reaction and western blotting, respectively in 44 frozen bladder cancer tissues and 18 adjacent normal bladder tissues. HMGA2 protein expression was assessed by immunohistochemical analysis of 148 paraffin-embedded specimens of human BUC and 30 specimens of adjacent normal bladder tissue. Correlations between HMGA2 and clinicopathologic features and prognosis were tested by statistical analyses. RESULTS: HMGA2 mRNA and protein levels in bladder cancer samples were significantly increased compared with adjacent normal bladder tissues (P < 0.001). mRNA overexpression correlated with high stage and grade of the bladder cancer (P < 0.001 and P = 0.002 respectively). HMGA2 protein expression was negative in all normal urothelial tissue samples, but positive in 52% (77/148) of bladder cancers (P < 0.001). HMGA2 expression correlated with tumor grade and stage (P < 0.001 and P = 0.003 respectively), Overexpression of HMGA2 protein in non-muscle-invasive bladder cancer was significantly associated with shorter recurrence-free survival (P < 0.001), and progression-free survival (P = 0.0004). Multivariate analysis showed that HMGA2 expression was an independent prognostic factor for both tumor recurrence (P < 0.001) and tumor progression (P = 0.006). CONCLUSIONS: HMGA2 is up-regulated in bladder cancer at both the transcriptional and translational levels compared with normal bladder tissue, HMGA2 protein is thus a potential prognostic marker for predicting tumor recurrence and progression. PMID- 21273027 TI - Professionals' opinion on follow-up in breast cancer patients; perceived purpose and influence of patients' risk factors. AB - AIM: To provide insight into professionals' opinions on breast cancer follow-up to facilitate implementation of new follow-up strategies. The study focuses on current practice, purpose and perceived effects, and preferred frequency and duration of follow-up. DESIGN: A 29-item questionnaire on professionals' demographics, current practice, opinion on the current guideline, preferences in frequency and duration of tailored follow-up, and the purpose and perceived effects of follow-up was sent to 633 Dutch professionals. RESULTS: The current national guideline is followed by 81% of respondents. All different specialists are involved in follow-up. Sixty-nine percent of respondents' report nurse practitioners to be involved in follow-up. When asked for tailored follow-up, professionals indicate more factors for increased follow-up (age<40 years, pT3-4 tumour, pN2-3, treatment related morbidity, and psychosocial support), than for reduced schedules (age >70 years and DCIS histology). Alternative forms of follow up are not endorsed by >90% of respondents. Detection of a new primary tumour of the breast is considered the most important purpose of follow-up (98%), 57% still indicates detecting metastases as a goal. CONCLUSIONS: Professionals tend towards longer and more intensive follow-up than the current guideline for a large group of patients. Limitations and developments in follow-up need to be considered to facilitate alternative follow-up strategies. PMID- 21273028 TI - Adult orbital masses: a pictorial review. PMID- 21273029 TI - Suppression of high-mobility group box-1 and receptor for advanced glycation end product axis by polymyxin B-immobilized fiber hemoperfusion in septic shock patients. AB - PURPOSE: Endotoxin plays a role in organ failure in septic shock patients. High mobility group box 1 (HMGB1) and receptor for advanced glycation end-products (RAGE) axis is also involved in septic shock. We investigated here the effects of endotoxin removal by polymyxin B-immobilized polystyrene fiber (PMX-F) treatment on circulating levels of HMGB1, soluble RAGE (sRAGE), and interleukin-6 (IL-6) in septic shock patients. MATERIALS AND METHODS: Fifteen septic shock patients (70.1 +/- 8.5 years) and 15 age- and sex-matched healthy volunteers were included in this study. Polymyxin B-immobilized polystyrene fiber treatment was repeated twice, separated by an interval of 24 hours. Blood samples were collected before and immediately after the second PMX-F treatment for determinations of biochemical variables. RESULTS: Systolic and diastolic blood pressures were significantly lower, and endotoxin, IL-6, HMGB1, and sRAGE levels were higher in septic shock patients compared with healthy volunteers. These parameters were significantly improved by PMX-F treatment. The changes in endotoxin obtained by PMX-F treatment were correlated with those in HMGB1, sRAGE, and IL-6. Multiple stepwise regression analysis revealed that IL-6 was a sole independent correlate of endotoxin. CONCLUSIONS: Our present study suggests that PMX-F treatment could block the HMGB1-RAGE axis in patients with septic shock via removal of endotoxin induced inflammatory reactions. PMID- 21273030 TI - The safety of synthetic colloid in critically ill patients with severe traumatic brain injuries. AB - PURPOSE: Although 4% albumin is associated with increased mortality in patients with traumatic brain injury (TBI), evidence concerning the safety of synthetic colloids is lacking. We aimed to determine if there is an association between synthetic colloids and mortality in patients with severe TBI. MATERIALS AND METHODS: A retrospective cohort study of patients with severe TBI was conducted. Data were collected on all intravenous fluids administered during the first 14 days of admission. Multivariable Cox proportional hazards regression was used to model the association between daily cumulative pentastarch quintiles and mortality. RESULTS: Patients receiving pentastarch had higher Acute Physiology and Chronic Health II scores (23.9 vs 21.6, P < .01), frequency of craniotomy (42.5% vs 21.6%, P = .02), longer duration of intensive care unit stay (12 vs 4 days, P < .01), and mechanical ventilation (10 vs 3 days, P < .01). On unadjusted Cox regression, patients in the highest quintile of cumulative pentastarch administration had a higher rate of mortality compared with those receiving no colloid (hazard ratio, 3.8; 95% confidence interval, 1.2-12.4; P = .03). However, this relationship did not persist in the final multivariable model (hazard ratio 1.0; 95% confidence interval, 0.25-4.1; P = .98). CONCLUSION: There was no association between cumulative exposure to pentastarch and mortality in patients with severe TBI. PMID- 21273031 TI - Correlation between coagulopathy and outcome in severe head trauma in neurointensive care and trauma units. AB - BACKGROUND: Abnormal blood coagulation after traumatic brain injury is a common finding. Some studies have proposed these changes as useful predictors of outcome in patients with head trauma. This study aimed at evaluating the association of the routine tests of blood coagulation within the first hours after severe head trauma with prognosis of patients with severe head trauma. MATERIALS AND METHODS: A total of 52 patients with severe head trauma (Glasgow Coma Scale [GCS], <=8) were admitted at Tabriz University Hospital for 1 year. Patients with major accompanying trauma were excluded. On admission, serum levels of hemoglobin and hematocrit as well as the platelet count, prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ratio (INR) were documented. The relation between these parameters with final outcome and also with GCS at admission, 24 hours, 48 hours, and 1 week after admission and discharge time and Glasgow Outcome Scale (GOS) were studied. RESULTS: Thirty three patients were discharged, and 19 died. There were significant negative correlations between PT, PTT, and INR with all GCS and GOS scores. These correlations were significant and positive between the platelet count and all GCS and GOS scores. Median PT, PTT, and INR were significantly higher in nonsurvivors. Median serum platelets count was significantly lower in nonsurvivors. CONCLUSION: On-admission PT, PTT, INR and platelet count may be used as predictors of outcome and prognosis of patients with severe head trauma. PMID- 21273032 TI - Validation of the Intensive Care Delirium Screening Checklist in nonintubated intensive care unit patients in a resource-poor medical intensive care setting in South India. AB - OBJECTIVE: Delirium is a common, difficult-to-diagnose clinical condition in critical care units. The lack of recognition of delirium often results in increased morbidity and mortality. The study aimed to determine the validity and reliability of the Intensive Care Delirium Screening Checklist (ICDSC) in a resource-poor medical intensive care setting in South India. MATERIALS AND METHODS: Fifty-three patients admitted into the medical intensive care unit of a teaching hospital who were neither mute nor intubated were recruited for the study. Trained residents administered the ICDSC to screen for delirium. A consultant psychiatrist used the International Classification of Diseases, 10th Revision diagnostic criteria for research to determine the presence of delirium. RESULTS: The optimal threshold for screening, as ICDSC total score of 3 or more, was obtained by using a receiver operating characteristic curve. Although a sensitivity and specificity of 75% and 74%, respectively, were obtained at the original cutoff of 4, a sensitivity of 90% and specificity of 61.54% were achieved with a cutoff of 3. In a subsample of 21 patients, interrater reliability was evaluated and found to be 0.947 (95% confidence interval, 0.870 0.979). The ICDSC had good internal consistency, with Cronbach alpha of .754 and Guttman split-half coefficient of 0.71. Factor analysis revealed a 2-factor structure, namely, altered sensorium/psychopathology and sleep-wake cycle problems. CONCLUSIONS: Our findings indicate that in nonintubated intensive care unit patients, the ICDSC can be used to screen for delirium but should not be used as a diagnostic instrument in this patient population and that residents can be trained in the use of the instrument in resource-poor critical care settings. Using a different threshold for positivity of 3 rather than 4 appeared to offer improved screening characteristics in this resource-poor critical care setting. PMID- 21273033 TI - Prevention of extubation failure in high-risk patients with neuromuscular disease. AB - BACKGROUND: A substantial proportion of patients with neuromuscular disease (NMD) who undergo positive pressure ventilation via endotracheal intubation for acute respiratory failure fail to pass spontaneous breathing trials and should be considered at high risk for extubation failure. In our study, we prospectively investigated the efficacy of early application of noninvasive ventilation (NIV) combined with assisted coughing as an intervention aimed at preventing extubation failure in patients with NMD. METHODS: This study is a prospective analysis of the short-term outcomes of 10 patients with NMD who were treated by NIV and assisted coughing immediately after extubation and comparison with the outcomes of a population of 10 historical control patients who received standard medical therapy (SMT) alone. The participants were composed of 10 patients with NMD who were submitted to NIV and assisted coughing after extubation (group A) and 10 historical control patients who were administered SMT (group B), who were admitted to a 4-bed respiratory intensive care unit (RICU) in a university hospital. Need for reintubation despite treatment was evaluated. Mortality during RICU stay, need for tracheostomy, and length of stay in the RICU were also compared. RESULTS: Significantly fewer patients who received the treatment protocol required reintubation and tracheostomy compared with those who received SMT (reintubation, 3 vs 10; tracheostomy, 3 vs 9; P = .002 and .01, respectively). Mortality did not differ significantly between the 2 groups. Patients in group A remained for a shorter time in the RICU compared with group B (7.8 +/- 3.9 vs 23.8 +/- 15.8 days; P = .006). CONCLUSIONS: Preventive application of NIV combined with assisted coughing after extubation provides a clinically important advantage to patients with NMD by averting the need for reintubation or tracheostomy and shortening their stay in the RICU; its use should be included in the routine approach to patients with NMD at high risk for postextubation respiratory failure. PMID- 21273034 TI - Physical examination, central venous pressure, and chest radiography for the prediction of transpulmonary thermodilution-derived hemodynamic parameters in critically ill patients: a prospective trial. AB - PURPOSE: Physical examination, assessment of central venous pressure (CVP) and chest radiography are diagnostic tools for estimation of volume status in intensive care unit (ICU) patients. Passive leg raising (PLR) is a test to estimate fluid responsiveness. Transpulmonary thermodilution (TPTD) is established for measurement of cardiac index (CI), global end-diastolic volume index (GEDVI), and extravascular lung water index (EVLWI). This study compares the estimation of volume status using physical examination, CVP, chest radiography, PLR, and TPTD. MATERIALS AND METHODS: This study was a prospective trial. Seventy-one patients in a medical ICU were studied. Interventions were as follows: physical examination by 2 independent examiners. CVP was measured. TPTD was performed. In 2 patient subgroups PLR and chest radiography was performed. Comparison of clinical and x-ray-based estimation of volume status, CVP, PLR, and TPTD variables was performed. RESULTS: Estimation of volume status based on physical examination showed a poor interobserver agreement between the examiners. There was no significant correlation between physical examination-based estimation of volume status and CVP or TPTD-derived GEDVI. There was no significant correlation between CVP and GEDVI, EVLWI or CI. PLR did not indicate fluid responsiveness. Radiographically estimated and TPTD-GEDVI/EVLWI values were significantly different. CONCLUSIONS: In ICU patients, assessment of volume status remains difficult. Physical examination, CVP, and portable radiography do not correlate with TPTD assessment of volume status, preload, or pulmonary hydration. PMID- 21273035 TI - Toward less sedation in the intensive care unit: a prospective observational study. AB - PURPOSE: Excessive sedation is associated with prolonged mechanical ventilation and longer intensive care unit (ICU) and hospital stays. We evaluated the feasibility of using minimal sedation in the ICU. METHODS: Prospective observational study in a university hospital 34-bed medico-surgical department of intensive care. All adult patients who stayed in the ICU for more than 12 hours over a 2-month period were included. Intensive care unit admission diagnoses, severity scores, use of sedatives and/or opiates, duration of mechanical ventilation, length of ICU stay, and 28-day mortality were recorded for each patient. RESULTS: Of the 335 patients (median age, 61 years) admitted during the study period, 142 (42%) received some sedation, most commonly with midazolam and propofol. Sedative agents were administered predominantly for short periods of time (only 10% of patients received sedation for >24 hours). One hundred fifty five patients (46%) received mechanical ventilation, generating 15,240 hours of mechanical ventilation, of these, only 2993 (20%) hours were accompanied by a continuous sedative infusion. Self-extubation occurred in 6 patients, but only 1 needed reintubation. CONCLUSIONS: In a mixed medical-surgical ICU, minimal use of continuous sedation seems feasible without apparent adverse effects. PMID- 21273036 TI - Pantoprazole for the prevention of gastrointestinal bleeding in high-risk patients with acute coronary syndromes. AB - PURPOSE: The aim of this study is to evaluate the preventive effect of proton pump inhibitors on gastrointestinal (GI) bleeding in patients with acute coronary syndromes (ACS) who are at high risk for GI bleeding. MATERIALS AND METHODS: We enrolled 665 patients with ACS who had one or more of the following risk factors for GI bleeding: 75 years of age or older, history of peptic ulcer disease, history of GI bleeding, cardiogenic shock, and chronic renal dysfunction (serum creatinine, >2 mg/dL). Patients were randomly assigned to receive 40 mg of pantoprazole or placebo twice daily for 7 days, in addition to standard treatment of ACS. The primary end point was the occurrence of GI bleeding during hospitalization. RESULTS: During a median time of hospitalization of 12 days, 12 (3.6%) of 332 patients in the placebo group had an occurrence of GI bleeding, as compared with 4 (1.2%) of the 333 patients in the pantoprazole group (P = .046, Fisher exact test). The log-rank test showed a significant difference between the 2 groups in the time to the occurrence of GI bleeding (P = .015). Major GI bleeding occurred in 5 (1.5%) patients in the placebo group but only in 1 (0.3%) in the pantoprazole group (P = .12). Pneumonia developed in 22 (6.6%) patients in the placebo group and 24 (7.2%) in the pantoprazole group (chi(2) = 0.077, P = .88). The 30-day mortality was 10.2% (34/332) in the placebo group and 10.5% (35/333) in the pantoprazole group. CONCLUSIONS: In patients with ACS who are at high risk for GI hemorrhage, prophylactic treatment with pantoprazole could reduce the risk of GI bleeding with no significant effects on the incidence of hospital-acquired pneumonia and 30-day mortality. PMID- 21273037 TI - Pseudoaneurysm of the anterior tibial artery after a tibial bone true-cut needle biopsy treated by an arterial resection and anastomosis. AB - We report the case of a 38-year-old man who developed a false aneurysm of the anterior tibial artery after a true-cut needle biopsy of the shinbone. Although arterial damages are a known theoretical risk of such a procedure, to our knowledge, this is the first case to be reported. Repair was achieved by means of an arterial resection and anastomosis. PMID- 21273038 TI - Hepatic artery dissection in a 65-year-old woman with acute pancreatitis. AB - We describe a case of hepatic artery dissection in a 65-year-old woman. This is the 22nd reported case of hepatic artery dissection, and the first associated with mild acute pancreatitis. The incidence of this condition may be increasing with rising rates of intervention affecting the biliary system. Recognition may also be increasing with growing use of high-quality radiography. Treatment should prevent rupture and ameliorate cardiovascular risk. Surgery should be considered in patients with complications or those likely to have them in future. There is a paucity of data regarding hepatic artery dissection, limiting evidence for guiding management. PMID- 21273039 TI - Salvaging vascular access and treatment of severe limb edema: case reports on the novel use of the hemodialysis reliable outflow vascular access device. AB - We report two cases in which patients on chronic hemodialysis presented with morbid unilateral edema of the upper extremity and chest on the side of a currently functioning arteriovenous access. Both patients were known to the vascular surgery service and had previously undergone multiple attempts to create and maintain vascular access. Both severe and disabling edema and the need to maintain dialysis access were of significant concern. These patients were taken to the operating room to address both issues. Upper extremity venography with central venous runoff revealed central vein stenosis and/or occlusion resistant to angioplasty and stenting. Ultimately, these two patients received the Hemodialysis Reliable Outflow vascular access device. The experiences in this study demonstrate the novel use of a relatively new vascular access device for salvage of a malfunctioning arteriovenous fistula or graft as well as treatment of symptoms and complications resulting from long standing vascular access. PMID- 21273040 TI - Horseshoe kidney and inflammatory abdominal aortic aneurysm: a case report and literature review. AB - The combined presence of an inflammatory abdominal aortic aneurysm and a horseshoe kidney is a rare event with only one reported case in previously published data. We present a case of a horseshoe kidney with a concomitant 6-cm inflammatory abdominal aortic aneurysm and a 3.6-cm right iliac artery aneurysm repaired through a transperitoneal approach with aortoiliac reconstruction. PMID- 21273041 TI - Prevalence and functioning of children with cerebral palsy in four areas of the United States in 2006: a report from the Autism and Developmental Disabilities Monitoring Network. AB - AIM: To estimate the prevalence of cerebral palsy (CP) and the frequency of co occurring developmental disabilities (DDs), gross motor function (GMF), and walking ability using the largest surveillance DD database in the US. METHODS: We conducted population-based surveillance of 8-year-old children in 2006 (N=142,338), in areas of Alabama, Georgia, Wisconsin, and Missouri. This multi site collaboration involved retrospective record review at multiple sources. We reported CP subtype, co-occurring DDs, Gross Motor Function Classification System (GMFCS) level, and walking ability as well as CP period prevalence by race/ethnicity and sex. RESULTS: CP prevalence was 3.3 (95% confidence interval [CI]: 3.1-3.7) per 1000 and varied by site, ranging from 2.9 (Wisconsin) to 3.8 (Georgia) per 1000, 8-year olds (p<0.02). Approximately 81% had spastic CP. Among children with CP, 8% had an autism spectrum disorder and 35% had epilepsy. Using the GMFCS, 38.1% functioned at the highest level (I), with 17.1% at the lowest level (V). Fifty-six percent were able to walk independently and 33% had limited or no walking ability. INTERPRETATION: Surveillance data are enhanced when factors such as functioning and co-occurring conditions known to affect clinical service needs, quality of life, and health care are also considered. PMID- 21273042 TI - Self-reports of Pap smear screening in women with physical disabilities. AB - We collected self reported rate of cervical smear testing and to examine the affecting factors in women with physical disabilities in the study, to define the reproductive health care for this group of people. The study population recruited 521 women with physical disabilities aged more than 15 years who were officially registered as having physical disabilities in Taipei County, Taiwan. Those people with physical disabilities include following: upper and low limb, spinal cord injury and other nervous system impairments. Results found that there were 71.5% participants had ever used the Pap smear tests in their life time and mean age of the first screening was 39.21+/-10.16 years (range=20-85 years). Nearly 41% of participants expressed that they had accepted the screening within 1 year and 28.1% reported they used the Pap smear screening regularly. Our study also found women with physical disabilities have higher use of Pap smear tests than does the general population in Taiwan (74% vs. 64% in aged>=30 years). Logistic regression model for the use of Pap smear test indicated that those married women (OR=12.06, 95% CI=6.85-21.22), with mild level of disability (OR=2.10, 95% CI=1.05-4.21) and high cognitive level toward Pap smear information were factors to affect the use of Pap smear in the study participants. We suggest the further study should conduct to examine the quality perception and follow-up service of Pap smear test for women with physical disabilities, to ensure the health care right for this group of women. PMID- 21273043 TI - Emergence of hierarchical structure mirroring linguistic composition in a recurrent neural network. AB - We show that a Multiple Timescale Recurrent Neural Network (MTRNN) can acquire the capabilities to recognize, generate, and correct sentences by self-organizing in a way that mirrors the hierarchical structure of sentences: characters grouped into words, and words into sentences. The model can control which sentence to generate depending on its initial states (generation phase) and the initial states can be calculated from the target sentence (recognition phase). In an experiment, we trained our model over a set of unannotated sentences from an artificial language, represented as sequences of characters. Once trained, the model could recognize and generate grammatical sentences, even if they were not learned. Moreover, we found that our model could correct a few substitution errors in a sentence, and the correction performance was improved by adding the errors to the training sentences in each training iteration with a certain probability. An analysis of the neural activations in our model revealed that the MTRNN had self-organized, reflecting the hierarchical linguistic structure by taking advantage of the differences in timescale among its neurons: in particular, neurons that change the fastest represented "characters", those that change more slowly, "words", and those that change the slowest, "sentences". PMID- 21273045 TI - Symptom cluster among hemodialysis patients in Taiwan. AB - This cross-sectional study aimed to investigate the prevalence and severity of symptom disturbance and to identify symptom clusters among hemodialysis patients. A convenience sample of 117 Taiwanese dialysis patients completed the Somatic Symptoms Disturbance Index, the Taiwanese Depression Scale, and a demographic questionnaire. Findings indicated that four symptom clusters emerged from the factor analysis. Relationships within symptom clusters were offered and explored. PMID- 21273044 TI - Virus expanded regulatory T cells control disease severity in the Theiler's virus mouse model of MS. AB - Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease (TMEV-IDD) serves as virus-induced model of chronic progressive multiple sclerosis. Infection of susceptible SJL/J mice leads to life-long CNS virus persistence and a progressive autoimmune demyelinating disease mediated by myelin specific T cells activated via epitope spreading. In contrast, virus is rapidly cleared by a robust CTL response in TMEV-IDD-resistant C57BL/6 mice. We investigated whether differential induction of regulatory T cells (Tregs) controls susceptibility to TMEV-IDD. Infection of disease-susceptible SJL/J, but not B6 mice, leads to rapid activation and expansion of Tregs resulting in an unfavorable CNS ratio of Treg:Teffector cells. In addition, anti-CD25-induced inactivation of Tregs in susceptible SJL/J, but not resistant B6, mice results in significantly decreased clinical disease concomitant with enhanced anti-viral CD4(+), CD8(+) and antibody responses resulting in decreased CNS viral titers. This is the first demonstration that virus-induced Treg activation regulates susceptibility to autoimmune disease differentially in susceptible and resistant strains of mice and provides a new mechanistic explanation for the etiology of infection-induced autoimmunity. PMID- 21273046 TI - The use of TMJ Concepts prostheses to reconstruct patients with major temporomandibular joint and mandibular defects. AB - Temporomandibular joint (TMJ) reconstruction may be required in complex cases in which there are additional mandibular or zygomatic arch defects. The reconstructive options include autogenous tissue, alloplastic material, or combinations of these. The authors describe 4 cases in which TMJ reconstruction was performed with TMJ Concepts customized joint prostheses. The prosthetic components were designed to restore major defects in the zygomatic arch and the mandibular ramus and body, including one case in which the mandibular component was used to restore total mandibular continuity. The prosthetic components used in these cases provided excellent anatomical reconstruction, and were a viable treatment option in cases in which the pathological process made autogenous grafts unsuitable. The prostheses have been functioning for up to 6 years. In one case a revision operation was required because the lack of a pterygomasseteric sling resulted in the condyle dropping out of the fossa. The authors' clinical experience with these cases suggests that a customized prosthesis combined with TMJ reconstruction can be a reliable treatment alternative for bridging complex, major maxillo-mandibular defects. PMID- 21273047 TI - The circulating microRNA-221 level in patients with malignant melanoma as a new tumor marker. AB - BACKGROUND: MicroRNA-221 (miR-221) is known to be abnormally expressed in malignant melanoma (MM) cells, and it favors the induction of the malignant phenotype through down-modulation of p27Kip1/CDKN1B and the c-KIT receptor. This suggests that the serum level of miR-221 might increase in patients with MM and thus could be used as a new tumor marker. OBJECTIVE: To evaluate the possibility that the serum miR-221 level can be a marker of MM. METHODS: Serum samples were obtained from 94 MM patients and 20 healthy controls. MicroRNAs were purified from serum, and miR-221 levels were measured by quantitative real-time polymerase chain reaction. RESULTS: Circulating miR-221 was detectable and could be quantified in serum samples. MM patients had significantly higher miR-221 levels than healthy controls. Among the MM patients, the miR-221 levels were significantly increased in patients with stage I-IV MM compared to those with MM in situ, and the levels were correlated with tumor thickness. Moreover, a longitudinal study revealed a tendency for the miR-221 levels to decrease after surgical removal of the primary tumor, and to increase again at recurrence. CONCLUSIONS: Serum levels of miR-221 were significantly increased in MM patients and may be useful not only for the diagnosis of MM, but also for the differentiating MM in situ from stage I-IV MM, and for evaluating tumor progression and monitoring patients during the follow-up period. In addition, considering that the serum levels of miR-221 were correlated with tumor thickness, miR-221 might also be useful as a prognostic marker for patients with MM. PMID- 21273048 TI - Monosize microbeads for pseudo-affinity adsorption of human insulin. AB - Affinity adsorption technique is increasingly used for protein purification, separation and other biochemical applications. Therapeutic molecules such as antibodies, cytokines, therapeutic DNA and plasma proteins must be purified before characterization and utilization. The aim of this study was to prepare micronsized spherical polymeric beads and to investigate the extent of their human insulin adsorption capability. Monosize poly(ethylene glycol dimethacrylate N-methacryloyl-(L)-histidine) [poly(EDMA-MAH)] beads were prepared by modified suspension copolymerization. Functional monomer (MAH) was synthesized using methacryloyl chloride and L-histidine. The beads were characterized using scanning electron microscopy (SEM), Fourier transform infrared spectroscopy, swelling test and elemental analysis. MAH incorporation into monosize polymeric beads, having an average size around 2-3 MUm, was estimated as 55.3 MUmol MAH/g bead. Equilibrium swelling ratios of poly(EDMA-MAH) and poly(EDMA) beads were 65% and 55%, respectively. Adsorption experiments were performed under different conditions (i.e., pH, temperature, protein concentration and ionic strength). It was found that adsorption characteristics are strongly depend on these conditions. Maximum insulin adsorption capacity was achieved as 24.7 mg insulin/g poly(EDMA-MAH) beads. Results were well fitted to the Langmuir isotherm model. Compared with poly(EDMA-MAH), nonspecific insulin adsorption onto poly(EDMA) beads was very low (0.61 mg insulin/g bead) and can be negligible. It was observed that insulin could be repeatedly adsorbed and desorbed (at least 10 times) without significant loss in adsorption capacity. PMID- 21273049 TI - Micelle formation of Tyr-Phe dipeptide and Val-Tyr-Val tripeptide in aqueous solution and their influence on the aggregation of SDS and PEO-PPO-PEO copolymer micelles. AB - The aggregation properties of Tyr-Phe dipeptide and Val-Tyr-Val tripeptide were studied in aqueous solution and in the presence of SDS and SDS-polymer environments using UV-visible, surface tension, fluorescence and circular dichroism (CD) techniques. Both the peptides formed micelles. The cmc values obtained for dipeptide and tripeptide are 2*10(-5) and 4*10(-5) M, respectively in aqueous solution at 25 degrees C. The presence of additives (SDS and polymer) hindered the micelle formation of peptides. The cmc values obtained by various methods are in good agreement with each other. Effect of peptides on the aggregation properties of SDS also was investigated. The cmc of SDS was decreased in presence of peptides and were reduced with increase in temperature. Using monophasic micellization concept, the association constant (K(A)) for the SDS peptide mixed micellar systems was determined. Using biphasic model, the thermodynamic parameters viz; DeltaG degrees (m), DeltaH degrees (m) and DeltaS degrees (m) for SDS-water and SDS-peptide-water mixed micellar systems, the standard free energy for transfer of SDS from aqueous to peptide additive environments were estimated at various temperatures. These results suggest that the SDS is more stable in micellized form in the SDS-water-peptide ternary systems compared to the situation in the corresponding SDS-water binary systems. PMID- 21273050 TI - A novel polyacrylamide nanocomposite hydrogel reinforced with natural chitosan nanofibers. AB - Polyacrylamide (PAM) was used as a matrix material for fabricating novel nanocomposite hydrogels reinforced with natural chitosan nanofibers (CNFs) via in situ free-radical polymerization. The nanocomposite's structure, strength, morphology and rheological properties were investigated. The results showed that the CNFs had a strong interaction with PAM through hydrogen and covalent bondings. The CNFs acted as a multifunctional cross-linker and a reinforcing agent in the hydrogel system. The compression strength and storage modulus of the nanocomposite hydrogels were significantly higher than those of the pure PAM hydrogels and the corresponding PAM/chitosan semi-interpenetrating polymer network (PAM-SIPN) hydrogels. The swelling ratio (SR) of the nanocomposite hydrogels was lower than that of the PAM hydrogel, but was similar to that of the PAM-SIPN hydrogel. Among the CNF contents used, the 1.5 wt% CNF loading level showed the best combined swelling and mechanical properties for the hydrogels. PMID- 21273051 TI - Covalent immobilization of liposomes on plasma functionalized metallic surfaces. AB - A method was developed to functionalize biomedical metals with liposomes. The novelty of the method includes the plasma-functionalization of the metal surface with proper chemical groups to be used as anchor sites for the covalent immobilization of the liposomes. Stainless steel (SS-316) disks were processed in radiofrequency glow discharges fed with vapors of acrylic acid to coat them with thin adherent films characterized by surface carboxylic groups, where liposomes were covalently bound through the formation of amide bonds. For this, liposomes decorated with polyethylene glycol molecules bearing terminal amine-groups were prepared. After ensuring that the liposomes remain intact, under the conditions applying for immobilization; different attachment conditions were evaluated (incubation time, concentration of liposome dispersion) for optimization of the technique. Immobilization of calcein-entrapping liposomes was evaluated by monitoring the percent of calcein attached on the surfaces. Best results were obtained when liposome dispersions with 5mg/ml (liposomal lipid) concentration were incubated on each disk for 24h at 37 degrees C. The method is proposed for developing drug-eluting biomedical materials or devices by using liposomes that have appropriate membrane compositions and are loaded with drugs or other bioactive agents. PMID- 21273052 TI - Regulation of cellular responses to macroporous inorganic films prepared by the inverse-opal method. AB - Regenerative medicine for repairing damaged body tissues has recently become critically important. Cell culture scaffolds are required for the control of cell attachment, proliferation, and differentiation in in vitro cell cultures. A new strategy to control cell adhesion, morphology, and proliferation was developed by culturing mouse osteoblast-like MC3T3-E1 cells on novel cell culture scaffolds fabricated using ordered nanometer-sized pores (100, 300, 500, and 1000 nm). Results of this study indicate that after 72 h of incubation, the number of cells cultured on a silica film with a pore size of 1000 nm was similar to or slightly lower than that cultured on a non-porous control silica film. Films with 100-500 nm pore sizes, however, resulted in the cell growth inhibition. Morphology of the cultured cells revealed increased elongation and the formation of actin stress fibers was virtually absent on macroporous silica films with 100-500 nm pore size. Vinculin molecules expressed in cells cultured on the non-porous silica films showed many clear focal adhesions, whereas focal contacts were insufficiently formed in cells cultured on macroporous films. The influence of hydroxyapatite (HAp) and alumina scaffolds on the behavior of MC3T3-E1 cells was also evaluated. The proliferation rate of MC3T3-E1 cells cultured on HAp films with 1000 nm pore size was increased to approximately 20% above than that obtained of cells cultured on non-porous HAp films. These results demonstrate that the pore size and constituents of films play a role in controlling the morphology and proliferation rate of MC3T3-E1 cells. PMID- 21273053 TI - The antidepressant effects and mechanism of action of total saponins from the caudexes and leaves of Panax notoginseng in animal models of depression. AB - Total saponins extracted from the caudexes and leaves of Panax notoginseng (SCLPN) have been used in the clinic for improving mental function, treating insomnia, and alleviating anxiety. The present study evaluated the potential antidepressant activity of SCLPN in rodent models of depression and the mechanism of action of SCLPN. Mice were received SCLPN at doses of 10-1000 mg/kg daily for 1, 7, and 14 days and then were subjected to the forced swim test and locomotor activity test. The results showed that SCLPN decreased immobility time in the forced swim test, with little effect on locomotion. In the chronic mild stress model, chronic SCLPN treatment (70 mg/kg) reversed the rats' depression-like behavior. Furthermore, SCLPN exerted its antidepressant-like effect by increasing the levels of 5-hydroxytryptamine, dopamine, and noradrenaline. Additionally, SCLPN treatment reduced intracellular Ca(2+) in cultured neurons. The present study suggests that SCLPN may function as an antidepressant, and the antidepressant-like effects of SCLPN may be mediated by modulation of brain monoamine neurotransmitters and intracellular Ca(2+) concentration. PMID- 21273054 TI - Treatment of pulmonary arterial hypertension: the role of prostacyclin and prostaglandin analogs. AB - Pulmonary arterial hypertension is a progressive, fatal disease characterized by elevated pulmonary arterial pressure >=25 mm Hg and normal pulmonary capillary wedge pressure <= 5 mm Hg. Physiological features of pulmonary arterial hypertension are characterized clinically by the presence of pre-capillary pulmonary hypertension not caused by other conditions such as lung diseases or chronic thromboembolic pulmonary hypertension. There are several therapies currently available that have been shown to improve hemodynamics and improve outcomes in patients with pulmonary arterial hypertension. These therapies include synthetic prostacyclin and prostaglandin analogs, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors. Multiple prostacyclin and prostaglandin analog formulations are currently in use (both branded and generic), available for parenteral, inhaled, or oral administration. This review discusses the pharmacology, clinical effects, and routes of administration of prostacyclin and prostaglandin analogs, emphasizing the advantages and disadvantages of each from the clinical perspective. PMID- 21273055 TI - The protective effects of nutritional antioxidant therapy on Ehrlich solid tumor bearing mice depend on the type of antioxidant therapy chosen: histology, genotoxicity and hematology evaluations. AB - Strong evidence indicates that reactive oxygen species (ROS) play an important role in the initiation as well as the promotion phase of carcinogenesis. Studies support the role of ROS in cancer, in part, by showing that dietary antioxidants act as cancer-preventive agents. Although results are promising, the research on this topic is still controversial. Thus, the aim of this study was to investigate whether vitamins C, E and pequi oil can, individually, provide prevention and/or be used afterward as an adjuvant in cancer therapy. Ehrlich solid tumor-bearing mice received antioxidant as follows: before tumor inoculation, before and after tumor inoculation (continuous administration), and after tumor inoculation; morphometric analyses of tumor, genotoxicity and hematology were then carried out. Antioxidant administrations before tumor inoculation effectively inhibited its growth in the three experimental protocols, but administrations after the tumor's appearance accelerated tumor growth and favored metastases. Continuous administration of pequi oil inhibited the tumor's growth, while the same protocol with vitamins E and C accelerated it, favoring metastasis and increasing oxidative stress on erythrocytes. Except for continuous administration with vitamin E, the development of ascites tumor metastases was linked with increased inflammation. Results suggest that the efficiency and applicability of antioxidants in the medical clinic can depend not only on the nature of the antioxidant, the type and stage of cancer being treated and the prevailing oxygen partial pressure in the tissues, but also on the type of antioxidant therapy chosen. PMID- 21273056 TI - Genetic and cellular mechanisms of oncogenesis. PMID- 21273057 TI - Young age and a positive family history of colorectal cancer are complementary selection criteria for the identification of Lynch syndrome. AB - Families at high risk for Lynch syndrome can effectively be recognised by microsatellite instability (MSI) testing. The aim of the present study is to compare the effectiveness of a MSI test for the identification of Lynch syndrome in patients selected by a pathologist mainly based on young age at diagnosis (MSI testing-indicated-by-a-Pathologist; MIPA), with that of patients selected by a clinical geneticist mainly based on family history (MSI-testing-indicated-by Family-History; MIFH). Patients with a Lynch syndrome associated tumour were selected using MIPA (n=362) or MIFH (n=887). Germline DNA mutation testing was performed in 171 out of 215 patients (80%) with a MSI positive tumour. MSI was tested positive in 20% of the MIPA-group group compared to 16% in the MIFH-group (P=0.291). In 91 of 171 patients with MSI positive tumours tested for germline mutations were identified as Lynch syndrome patients: 42% in the MIPA-group and 56% in the MIFH-group (P=0.066). Colorectal cancer (CRC) or endometrial cancer (EC) presenting at an age below 50 years would have led to the diagnosis of Lynch syndrome in 89% of these families (CRC below 50 years: 88% and EC below 50 years: 12%). Families detected by MIPA were characterised more often by extracolonic Lynch syndrome associated malignancies, especially EC (P<0.001). Our results indicate that recognition of Lynch syndrome by CRC or EC below 50 years is as effective as a positive family history. Families from patients selected by individual criteria more often harbour extracolonic Lynch syndrome associated malignancies. PMID- 21273058 TI - Prognostic value of opioid binding protein/cell adhesion molecule-like promoter methylation in bladder carcinoma. AB - The OPCML gene (opioid binding protein/cell adhesion molecule-like), a putative tumour suppressor gene, is frequently inactivated in carcinomas, namely through aberrant promoter methylation. Herein, we aimed to determine whether OPCML altered expression mediated by epigenetic mechanisms was implicated in bladder carcinogenesis and to assess its potential as a bladder cancer epi-marker. OPCML promoter methylation levels from 91 samples of bladder urothelial carcinoma, 25 normal bladder tissues and bladder cancer cell lines were assessed by quantitative methylation-specific polymerase chain reaction, and correlated with OPCML mRNA expression, determined by quantitative reverse-transcription polymerase chain reaction. To prove the epigenetic regulation of OPCML, five bladder cancer cell lines were exposed to 5-aza-2'deoxycytidine (5-aza-dC), a specific DNA methyltransferase inhibitor and trichostatin A (TSA), a histone deacetylase inhibitor. In bladder tumours, the overall frequency of methylation was 60% and methylation levels were significantly higher when compared with normal mucosa (P=0.0001). No correlation was found between methylation levels and clinicopathological parameters. Interestingly, OPCML promoter methylation was associated with worse disease-specific survival (P=0.022) in univariate analysis. Furthermore, a significant inverse correlation between OPCML promoter methylation and mRNA expression levels was found, although a significant re-expression was only achieved when 5-aza-dC and TSA were used simultaneously. The high frequency of OPCML promoter methylation in urothelial carcinomas suggests an important role for this epigenetic alteration in bladder carcinogenesis, highlighting its potential as an epigenetic biomarker for bladder urothelial carcinoma with prognostic significance. PMID- 21273059 TI - Differentiation of human rhabdomyosarcoma RD cells is regulated by reciprocal, functional interactions between myostatin, p38 and extracellular regulated kinase signalling pathways. AB - Rhabdomyosarcoma (RMS) includes heterogeneous tumours of mesenchymal derivation which are genetically committed to the myogenic lineage, but fail to complete terminal differentiation. Previous works have reported on deregulated myostatin, p38 and extracellular regulated kinase (ERK) signalling in RMS cell lines; however, the functional link between these pathways and their relative contribution to RMS pathogenesis and/or maintenance of the transformed phenotype in vitro are unclear. Herein we show that the constitutive expression of a dominant-negative form of activin receptor type IIb (dnACTRIIb), which inhibits myostatin signalling, decreased proliferation and promoted differentiation of the human RMS RD cell line. DnACTRIIb-dependent differentiation of RD cells correlated with a reduced SMAD2/3 (small mother against decapentaplegic) and ERK signalling and the activation of p38 pathway. Conversely, the expression of a constitutively activated ALK5 (activin receptor-like kinase) (caALK5) form, activating SMAD3 and ERK pathways, led to further impairment of RD differentiation. Pharmacological blockade of ERK pathway in RD cells was sufficient to replicate the biological phenotype observed in dnACTRIIb-expressing RD cells, and also recovered the differentiation of caALK5-expressing RD cells. Conversely, deliberate activation of p38 signalling mimics the effect of dnActRIIb and overcame the differentiation block in RD cells. These data indicate the existence of a network formed by myostatin/SMAD2/3, ERK and p38 pathways that, when deregulated, might contribute to the pathogenesis of RMS. The components of this network might, therefore, be a valuable target for interventions towards correcting the malignant phenotype of RMS. PMID- 21273060 TI - Primary resistance to cetuximab in a panel of patient-derived tumour xenograft models: activation of MET as one mechanism for drug resistance. AB - Cetuximab (Erbitux(r)) targets the epidermal growth factor receptor (EGFR) and is approved for treatment of colorectal and head and neck cancer. Despite wide expression of EGFR, only a subgroup of cancer patients responds to cetuximab therapy. In the present study we assessed the cetuximab response in vivo of 79 human patient-derived xenografts originating from five tumour histotypes. We analysed basic tumour characteristics including EGFR expression and activation, mutational status of KRAS, BRAF and NRAS, the expression of EGFR ligands and the activation of HER3 (ErbB3) and the hepatocyte growth factor receptor MET. Based on these results, a cetuximab response score including positive and negative factors affecting therapeutic response is proposed. Positive factors are high expression and activation of EGFR and its ligands epiregulin or amphiregulin, negative factors are markers for downstream pathway activation independent of EGFR. In cetuximab resistant NSCL adenocarcinoma LXFA 526 and LXFA 1647, overexpression due to gene amplification and strong activation of MET was identified. Knock-down of MET by siRNA in the corresponding cell lines showed that anchorage-independent growth and migration are dependent on MET. MET knock down sensitized LXFA 526L and LXFA 1647L to EGF. Combined treatments of a MET inhibitor and cetuximab were additive. Therefore, combination therapy of cetuximab and a MET inhibitor in selected lung cancer patients could be of high clinical significance. PMID- 21273061 TI - Comparison of some new pretreatment methods for second generation bioethanol production from wheat straw and water hyacinth. AB - Pretreatment of lignocellulosic residues like water hyacinth (WH) and wheat straw (WS) using crude glycerol (CG) and ionic liquids (IL) pretreatment was evaluated and compared with conventional dilute acid pretreatment (DAT) in terms of enzymatic hydrolysis yield and fermentation yield of pretreated samples. In the case of WS, 1-butyl-3-methylimidazolium acetate pretreatment was found to be the best method. The hydrolysis yields of glucose and total reducing sugars were 2.1 and 3.3 times respectively higher by IL pretreatment than DAT, while it was 1.4 and 1.9 times respectively higher with CG pretreatment. For WH sample, CG pretreatment was as effective as DAT and more effective than IL pretreatment regarding hydrolysis yield. The fermentation inhibition was not noticeable with both types of pretreatment methods and feedstocks. Besides, CG pretreatment was found as effective as pure glycerol pretreatment for both feedstocks. This opens up an attractive economic route for the utilization of CG. PMID- 21273062 TI - Increasing power generation for scaling up single-chamber air cathode microbial fuel cells. AB - Scaling up microbial fuel cells (MFCs) requires a better understanding the importance of the different factors such as electrode surface area and reactor geometry relative to solution conditions such as conductivity and substrate concentration. It is shown here that the substrate concentration has significant effect on anode but not cathode performance, while the solution conductivity has a significant effect on the cathode but not the anode. The cathode surface area is always important for increasing power. Doubling the cathode size can increase power by 62% with domestic wastewater, but doubling the anode size increases power by 12%. Volumetric power density was shown to be a linear function of cathode specific surface area (ratio of cathode surface area to reactor volume), but the impact of cathode size on power generation depended on the substrate strength (COD) and conductivity. These results demonstrate the cathode specific surface area is the most critical factor for scaling-up MFCs to obtain high power densities. PMID- 21273063 TI - Design of potent and selective GPR119 agonists for type II diabetes. AB - Screening of the Merck sample collection identified compound 1 as a weakly potent GPR119 agonist (hEC(50)=3600 nM). Dual termini optimization of 1 led to compound 36 having improved potency, selectivity, and formulation profile, however, modest physical properties (PP) hindered its utility. Design of a new core containing a cyclopropyl restriction yielded further PP improvements and when combined with the termini SAR optimizations yielded a potent and highly selective agonist suitable for further preclinical development (58). PMID- 21273064 TI - Design and synthesis of highly solvatochromic fluorescent 2'-deoxyguanosine and 2'-deoxyadenosine analogs. AB - We synthesized various substituted 8-styryl-2'-deoxyguanosine and 8-styryl-2' deoxyadenosine derivatives. Among them only acetyl substituted 8-styryl-2' deoxyguanosine analog 5b showed a remarkable solvatochromicity (Deltalambda(max)(em)=91 nm),that is, strong fluorescence at 477 nm in 1,4 dioxane, but in methanol the fluorescence was red shifted to 558 nm with very low intensity. Such environmentally sensitive solvatochromic fluorescent guanosine analogs may be useful as a sensor for investigating interactions of DNA with DNA binding proteins. PMID- 21273065 TI - Synthesis and pharmacological evaluation of the individual stereoisomers of 3 [methyl(1,2,3,4-tetrahydro-2-naphthalenyl)amino]-1-indanone, a potent mast cell stabilising agent. AB - Each stereoisomer of 3-[methyl(1,2,3,4-tetrahydro-2-naphthalenyl)amino]-1 indanone, 1a-d, was prepared and evaluated in vitro for its ability to prevent mediator release induced by different degranulating agents from rodent mast cells and also in vivo against passive cutaneous anaphylaxis. The manner in which the stereoisomers prevented direct membrane activation was found to be highly dependent on the stereochemistry of the individual isomers. Stereoisomer 1b was the most active isomer in vivo, exhibiting superior activity to disodium cromoglycate. PMID- 21273066 TI - Isosteric replacement of the Z-enone with haloethyl ketone and E-enone in a resorcylic acid lactone series and biological evaluation. AB - The synthesis of a small library of resorcylic acid lactones and evaluation of their biological properties as kinase inhibitors is described. Within the series E-enones were found more active than corresponding Z-enones as inhibitors of a subset of kinases containing a conserved cysteine. Replacement of the enone moiety with a beta-haloketone group led to compounds with an interesting kinase selectivity profile and also antiproliferative activity against Jurkat cells. An E-enone derivative also showed activity against capillary tube formation based on a co-culture of primary human umbilical cord endothelial cells (HUVECs) and vascular smooth muscle cells (vSMCs). PMID- 21273067 TI - Design and synthesis of potent Gram-negative specific LpxC inhibitors. AB - Antibiotic resistant hospital acquired infections are on the rise, creating an urgent need for novel bactericidal drugs. Enzymes involved in lipopolysaccharide (LPS) biosynthesis are attractive antibacterial targets since LPS is the major structural component of the outer membrane of Gram-negative bacteria. Lipid A is an essential hydrophobic anchor of LPS and the first committed step in lipid A biosynthesis is catalyzed by a unique zinc dependent metalloamidase, UDP-3-O-(R-3 hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC). LpxC is an attractive Gram-negative only target that has been chemically validated by potent bactericidal hydroxamate inhibitors that work by coordination of the enzyme's catalytic zinc ion. An exploratory chemistry effort focused on expanding the SAR around hydroxamic acid zinc-binding 'warheads' lead to the identification of novel compounds with enzyme potency and antibacterial activity similar to CHIR 090. PMID- 21273068 TI - Identification and initial SAR of silybin: an Hsp90 inhibitor. AB - Through Hsp90-dependent firefly luciferase refolding and Hsp90-dependent heme regulated eIF2alpha kinase (HRI) activation assays, silybin was identified as a novel Hsp90 inhibitor. Subsequently, a library of silybin analogues was designed, synthesized and evaluated. Initial SAR studies identified the essential, non essential and detrimental functionalities on silybin that contribute to Hsp90 inhibition. PMID- 21273069 TI - 6''-Azido-6''-deoxy-UDP-N-acetylglucosamine as a glycosyltransferase substrate. AB - 6''-Azido-6''-deoxy-UDP-N-acetylglucosamine (UDP-6Az-GlcNAc) is a potential alternate substrate for N-acetylglucosaminyltransferases. This compound could be used to generate various glycoconjugates bearing an azide functionality that could in turn be subjected to further modification using Staudinger ligation or Huisgen cycloaddition. UDP-6Az-GlcNAc is synthesized from alpha-benzyl-N acetylglucosaminoside in seven-steps with an overall yield of 6%. It is demonstrated to serve as a substrate donor for the glycosyl transfer reaction catalyzed by the human UDP-GlcNAc:polypeptidyltransferase (OGT) to the acceptor protein nucleoporin 62 (nup62). PMID- 21273070 TI - Pyrrolidinone diterpenoid from Isodon excisus and inhibition of nitric oxide production in lipopolysaccharide-induced macrophage RAW264.7 cells. AB - A new pyrrolidinone diterpenoid, excisusin F (1), was isolated from the aerial parts of Isodon excisus (Lamiaceae), together with four known compounds, and their structures were determined mainly by NMR (1D and 2D) and mass spectrometry. Excisusin F (1) and inflexarabdonin E (3) showed potent inhibitory effects of LPS induced nitric oxide production in RAW264.7 cells with the IC(50) value of 10.4 and 3.8 MUM, respectively. PMID- 21273071 TI - Aromatic ring functionalization of benzolactam derivatives: new potent dopamine D3 receptor ligands. AB - Since the discovery of the dopamine D(3) receptor, an intensive effort has been directed toward the development of potent and selective ligands in order to elucidate the function and potential therapeutic advantages of targeting D(3) receptors. As a part of our efforts, a novel series of substituted benzolactams derivatives was synthesized mostly through palladium-catalyzed reactions. Their affinities on D(1)-D(4) receptors were evaluated and the data led us to highly potent D(3) ligands, some of them highly selective for D(3) receptor, compared to the related dopamine receptor subtypes. Functional D(3) activity assays of the most relevant compounds have been carried out revealing antagonist as well as partial agonist activity. PMID- 21273072 TI - Efficient synthesis and biological evaluation of 1,3-benzenedicarbonyl dithioureas. AB - The synthesis and biological activity of 1,3-benzenedicarbonyl dithioureas are described. Bioassay results indicated that these compounds exhibited cytotoxicity against various cancer cells. For example, compounds 4a showed the best inhibition activities against KB and CNE2 with IC(50) 10.72 and 9.91 MUM, respectively. PMID- 21273073 TI - Investigation on a host-guest inclusion system by beta-cyclodextrin derivative and its analytical application. AB - The host-guest inclusion system of ethyl substituted beta-cyclodextrin (DE-beta CD) with mangiferin (MA) was investigated by fluorescence spectra in solution. The results showed that the MA was encapsulated in the DE-beta-CD's cavity to form a 2:1 stoichiometry host-guest inclusion complex (DE-beta-CD/MA) and the inclusion constant (K=3.04*10(6)L(2)/mol(2)) was confirmed by the typical double reciprocal plots. Furthermore, several experimental conditions were optimized in order to obtain the maximum fluorescence signal. In addition, the thermodynamic parameters, Gibbs free energy (DeltaG degrees ), enthalpy change (DeltaH degrees ) and entropy change (DeltaS degrees ) of DE-beta-CD/MA were obtained by the Van't Hoff equation. A spectrofluorimetric method for the determination of MA in solution in the presence of DE-beta-CD was developed based on the remarkable enhancement of the fluorescence intensity of MA. The linear range was 2.00*10(-8) 7.00*10(-6)mol/L and the detection limit was 4.05*10(-9)mol/L. The proposed method was successfully applied to the analysis of MA in serum with the satisfactory result. PMID- 21273074 TI - Discovery of dual binding site acetylcholinesterase inhibitors identified by pharmacophore modeling and sequential virtual screening techniques. AB - Dual binding site acetylcholinesterase (AChE) inhibitors are promising for the treatment of Alzheimer's disease (AD). They alleviate the cognitive deficits and AD-modifying agents, by inhibiting the beta-amyloid (Abeta) peptide aggregation, through binding to both the catalytic and peripheral anionic sites, the so called dual binding site of the AChE enzyme. In this Letter, chemical features based 3D pharmacophore models were developed based on the eight potent and structurally diverse AChE inhibitors (I-VIII) obtained from high-throughput in vitro screening technique. The best 3D-pharmacophore model, Hypo1, consists of two hydrogen-bond acceptor lipid, one hydrophobe, and two hydrophobic aliphatic features obtained by Catalyst/HIPHOP algorithm adopted in Discovery studio program. Hypo1 was used as a 3D query in sequential virtual screening study to filter three small compound databases. Further, a total of nine compounds were selected and followed on in vitro analysis. Finally, we identified two leads--Specs1 (IC(50)=3.279 MUM) and Spec2 (IC(50)=5.986 MUM) dual binding site compounds from Specs database, having good AChE enzyme inhibitory activity. PMID- 21273075 TI - The impact of attentional, auditory, and combined cues on walking during single and cognitive dual tasks in Parkinson disease. AB - Auditory and attentional cues improve gait in Parkinson disease (PD), but it is unclear if combining the two cueing strategies offers additional benefit. Further, the effect of a secondary cognitive task on cue efficacy is unknown. Therefore, this study aimed to assess the effects of cue type and task complexity on gait in PD. 11 participants with PD, 11 age-matched controls, and 11 young controls performed 3 walking trials on a GAITRite walkway under the following cueing conditions: no cue (baseline), rhythmic auditory cue at 10% below (AUD-10) and 10% above (AUD+10) self selected cadence, attentional cue (ATT; "take long strides"), and a combination of AUD and ATT (COM-10, COM+10). Each condition was also performed concurrently with a secondary word generation task (dual task, DT). Baseline gait velocity and stride length were less for those with PD and age matched controls compared to young controls, and the ability of those with PD to use cues differed from the other groups. Gait velocity and stride length increased in PD with ATT, but not with auditory cues. Similar increases in gait velocity and stride length were observed with the combined cues, but additional benefit beyond ATT alone was not observed. Cues did not improve gait velocity during dual task walking, although stride length did increase with COMB+10. It appears persons with PD are able to benefit from attentional cueing and can combine attentional and auditory cues, but do not gain additional benefit from such a combination. During walking while performing a secondary cognitive task, attentional cues may help to facilitate a longer stride length. PMID- 21273076 TI - Postural instability caused by extended bed rest is alleviated by brief daily exposure to low magnitude mechanical signals. AB - Loss of postural stability, as exacerbated by chronic bed rest, aging, neuromuscular injury or disease, results in a marked increase in the risk of falls, potentiating severe injury and even death. To investigate the capacity of low magnitude mechanical signals (LMMS) to retain postural stability under conditions conducive to its decline, 29 healthy adult subjects underwent 90 days of 6-degree head down tilt bed-rest. Treated subjects underwent a daily 10 min regimen of 30 Hz LMMS at either a 0.3g-force (n=12) or a 0.5g-force (n=5), introduced by Low Intensity Vibration (LIV). Control subjects (n=13) received no LMMS treatment. Postural stability, quantified by dispersions of the plantar based center of pressure, deteriorated significantly from baseline in control subjects, with displacement and velocity at 60 days increasing 98.7% and 193%, respectively, while the LMMS group increased only 26.7% and 6.4%, reflecting a 73% and 97% relative retention in stability as compared to control. Increasing LMMS magnitude from 0.3 to 0.5 g had no significant influence on outcomes. LMMS failed to spare loss of muscle extension strength, but helped to retain flexion strength (e.g., 46.2% improved retention of baseline concentric flexion strength vs. untreated controls; p=0.01). These data suggest the potential of extremely small mechanical signals as a non-invasive means of preserving postural control under the challenge of chronic bed rest, and may ultimately represent non pharmacologic means of reducing the risk of debilitating falls in elderly and infirm. PMID- 21273077 TI - Intramedullary conus medullaris metastasis of periurethral adenocarcinoma. AB - Intramedullary spinal cord metastasis to the conus medullaris is very rare. We report a 44-year-old woman with an intra-axial conus medullaris metastasis from periurethral adenocarcinoma. To our knowledge, this is the first report in the literature. We also discuss the clinical features, possible pathophysiological mechanisms and treatment options for intramedullary spinal cord metastasis to the conus medullaris. PMID- 21273078 TI - Akinetic-rigid syndrome due to extrapontine and pontine myelinolysis following appropriate correction of hyponatraemia. AB - Extrapontine myelinolysis in association with the more common central pontine variety is increasingly reported. Although typically associated with rapid correction of hyponatraemia, myelinolysis is also seen when sodium correction occurs at recommended rates. We present a 60-year-old man who developed hyponatraemia and hypokalaemia due to repeated vomiting. An acute symmetric akinetic-rigid syndrome followed correction of hyponatraemia, performed in line with current guidelines. There were no clinical features of pontine involvement even though a typical lesion was seen on MRI. Bilateral putaminal and caudate lesions were seen. He recovered well with only symptomatic treatment. Myelinolysis can present with features of extrapontine involvement with the pontine lesions remaining asymptomatic. Current guidelines for the correction of hyponatraemia do not prevent development of myelinolysis in all instances. In contrast to the generally expected poor outcome in this condition, patients do make a good recovery with symptomatic treatment and good nursing care. PMID- 21273079 TI - Detection of infundibula using three-dimensional time-of-flight magnetic resonance angiography with volume rendering at 3.0 Tesla compared to digital subtraction angiography. AB - We aimed to prospectively evaluate the effectiveness of unenhanced, three dimensional time-of-flight magnetic resonance angiography (3D-TOF-MRA) with volume rendering (VR) at 3.0 Tesla in the detection of infundibula (IF). A total of 136 consecutive patients with suspected or known aneurysms detected by MRA were examined using DSA, and IF were identified. A 3D specialist adjusted window width to the appropriate threshold, took level and MR source images and performed MRA post-processing techniques, including VR and the single artery highlighting method. VR-DSA was obtained from the rotational DSA data, and two-dimensional (2D)-DSA and VR-DSA were combined as the gold standard. Three blinded readers evaluated the diagnostic sensitivity and accuracy of 3D-TOF-MRA with VR. The 2D DSA and VR-DSA revealed 44 IF in 34 of the 136 patients and no cerebral IF in 102 patients. For MRA, sensitivity per patient for all readers ranged from 89.5% to 97.1%, while accuracy per patient ranged from 97.1% to 99.3%. Per IF sensitivity for all readers ranged from 91.7% to 97.7%, while the per IF accuracy ranged from 97.3% to 99.3%. For detection of IF at the internal carotid artery, sensitivity for all readers ranged from 89.5% to 97.1%, and accuracy from 89.5% to 97.4%. For detection of IF at the anterior choroidal arteries, sensitivity and accuracy was 100% in all patients. There were no significant differences in the sensitivity or accuracy of all readers in the detection of single and multiple IF (p>0.05). One false-negative was found for IF by reader 1, two for reader 2 and four for reader 3. We conclude that VR 3D-TOF-MRA at 3.0 T is an ideal, non-invasive imaging exam for the detection of IF and can be used effectively in its diagnosis. PMID- 21273080 TI - Lipophilic derivatives of leu-enkephalinamide: in vitro permeability, stability and in vivo nasal delivery. AB - Leu-enkephalin is an endogenous pain modulating opioid pentapeptide. Its development as a potential pharmaceutic has been hampered by poor membrane permeability and susceptibility to enzymatic degradation. The addition of an unnatural amino acid containing a lipidic side chain at the N-terminus and the modification of the C-terminus to a carboxyamide was performed to enhance the nasal delivery of the peptide. Two lipidic derivatives with varying side chain lengths (C(8)-Enk-NH(2) (1), C(12)-Enk-NH(2) (2)) and their acetylated analogues were successfully synthesised. Caco-2 cell monolayer permeability and Caco-2 cell homogenate stability assays were performed. C(8)-Enk-NH(2) (1) and its acetylated analogue Ac-C8-Enk-NH(2) (3) exhibited apparent permeabilities (mean+/-SD) of 2.51+/-0.75*10(-6)cm/s and 1.06+/-0.62*10(-6), respectively. C12-Enk-NH(2) (2) exhibited an apparent permeability of 2.43+/-1.26*10(-6) cm/s while Ac-C12-Enk NH(2) (4) was not permeable through the Caco-2 monolayers due to its poor solubility. All analogues exhibited improved Caco-2 homogenate stability compared to Leu-Enk-NH(2) with t(1/2) values of: C8-Enk-NH(2) (1): 31.7 min, C(12)-Enk NH(2) (2): 14.7 min, Ac-C8-Enk-NH(2) (3): 83 min, Ac-C(12)-Enk-NH(2) (4): 27 min. However, plasma stability assays revealed that the diastereoisomers of C8-Enk NH(2) (1) did not degrade at the same rate, with the l isomer (t(1/2)=8.9 min) degrading into Leu-enkephalinamide and then des-Tyr-Leu-Enk-NH(2), whereas the d isomer was stable (t(1/2)=120 min). In vivo nasal administration of C(8)-Enk NH(2) to male rats resulted in concentrations of 5.9+/-1.84*10(-2) MUM in the olfactory bulbs, 1.35+/-1.01*10(-2) MUM in the brain and 6.53+/-1.87*10(-3) MUM in the blood 10 min after administration. PMID- 21273082 TI - Modelling topoisomerase I inhibition by minor groove binders. AB - Topoisomerase inhibition is an extremely useful target for anticancer and antimicrobial drugs, and an undesirable side effect of some drugs targeting other proteins. Published modelling studies are sparse, and have used small data sets with relatively low molecular diversity. Given the important role of minor groove binding in the mechanism of topoisomerase I inhibition, we have conducted the first 3D QSAR study of topoisomerase I inhibition of a large, diverse set of minor groove binders using the minor groove binding conformation as the alignment template. The highly significant QSAR models resulting from this alignment identify the roles played by molecular features, most importantly the hydrogen bond donor properties. PMID- 21273081 TI - A competition assay to identify amyloidogenesis inhibitors by monitoring the fluorescence emitted by the covalent attachment of a stilbene derivative to transthyretin. AB - Herein we demonstrate that competition between candidate kinetic stabilizer binding to transthyretin (TTR) and stilbene binding to and reaction with the same thyroxine sites within TTR can be utilized to discover potent and highly selective non-covalent TTR amyloidogenesis inhibitors. We report two stilbenes, S1 and S2, for use in distinct competition assays. Each bind selectively to TTR and then chemoselectively react to form an amide bond with the Lys-15 residue of TTR, creating a fluorescent conjugate. We used 28 TTR kinetic stabilizers exhibiting a known spectrum of plasma TTR binding selectivities and TTR amyloid fibril inhibition efficacies to validate the 'TTR fluorescence conjugate competition assay'. The kinetic stabilizers competed with S1 for binding to recombinant TTR in buffer and with S2 for binding to endogenous levels of TTR in human blood serum. In both assay scenarios, we demonstrate that the lower the TTR stilbene conjugate fluorescence after a 3 h competition, the greater the binding selectivity and potency of the candidate TTR kinetic stabilizer. These assays, particularly the assay utilizing S2 in human serum, replace two assays previously utilized to gather the same information. While not the focus of this manuscript, it is clear that the 'TTR fluorescence conjugate competition assay' could be adapted for high throughput screening applications. PMID- 21273083 TI - Synthesis and antimycobacterial properties of N-substituted 6-amino-5 cyanopyrazine-2-carboxamides. AB - A series of fifteen new compounds related to pyrazinamide (PZA) were synthesized, characterized with analytical data and screened for antimycobacterial, antifungal and antibacterial activity. The series consists of 6-chloro-5-cyanopyrazine-2 carboxamide and N-substituted 6-amino-5-cyanopyrazine-2-carboxamides, derived from the previous by nucleophilic substitution with various non-aromatic amines (alkylamines, cycloalkylamines, heterocyclic amines). Some of the compounds exerted antimycobacterial activity against Mycobacterium tuberculosis equal to pyrazinamide (12.5-25 MUg/mL). More importantly, 6-chloro-5-cyanopyrazine-2 carboxamide and 5-cyano-6-(heptylamino)pyrazine-2-carboxamide were active against Mycobacterium kansasii and Mycobacterium avium, which are unsusceptible to PZA. Basic structure-activity relationships are presented. Only weak antifungal and no antibacterial activity was detected. PMID- 21273084 TI - Melampomagnolide B: a new antileukemic sesquiterpene. AB - Melampomagnolide B has been identified as a new antileukemic sesquiterpene. A biotin-conjugated derivative of melampomagnolide B was designed and synthesized in order to elucidate its mechanism of action. A study of the biochemical interactions of the biotin probe suggests that melampomagnolide B derives its remarkable selectivity for leukemic cells over normal hematopoietic cells from its unique ability to exploit biochemical differences between the two cell types. PMID- 21273085 TI - Practical synthesis of precursor of [N-methyl-11C]vorozole, an efficient PET tracer targeting aromatase in the brain. AB - A practical method to prepare precursor of [N-methyl-(11)C]vorozole ([(11)C]vorozole), an efficient positron emission tomography (PET) tracer for imaging aromatase in the living body, was established. Sufficient amount of the racemate including norvorozole, a demethylated vorozole derivative used as a precursor of [(11)C]vorozole, became available by means of high-yield eight-step synthesis. The enantiomers were separated by preparative HPLC using a chiral stationary phase column to give optically pure norvorozole and its enantiomer. From the latter, ent-[(11)C]vorozole, an enantiomer of [(11)C]vorozole, was prepared and used in the PET study for the first time, which was shown to bind very weakly to aromatase in rhesus monkey brain supporting the previous pharmacological results. The stable supply of norvorozole will facilitate further researches on aromatase in the living body including brain by the PET technique. PMID- 21273086 TI - Off-pump coronary artery bypass and avoidance of hypothermic cardiac arrest improves early left ventricular function in patients with systolic dysfunction. AB - OBJECTIVE: Off-pump coronary artery bypass surgery (OPCAB) and beating-heart coronary artery bypass grafting (BH-CAB) performed with cardiopulmonary bypass support are used with increasing frequency in the treatment of coronary artery occlusive disease. The utility of OPCAB and BH-CAB in treating high-risk patients has been studied, but the effects of these procedures on ventricular function have not been thoroughly investigated. METHODS: Data were collected from a database encompassing all patients who underwent isolated coronary revascularization performed by a single surgeon between August 2002 and March 2007. All procedures (n = 507) began as OPCAB operations, but 99 were converted to BH-CAB during surgery. Each patient's ejection fraction (EF) was measured preoperatively and postoperatively (median, 5.0 days after surgery). RESULTS: We found that although the BH-CAB patients tended to be in worse health and to have a lower preoperative EF than the OPCAB patients, both groups of patients had similar improvements in postoperative EF (6.8% vs 5.4%; p = 0.65). In addition, multivariable linear regression showed that a lower preoperative EF, age >= 70 years, and cardiomegaly predicted less postoperative EF improvement after coronary revascularization by either OPCAB or BH-CAB. CONCLUSIONS: Both OPCAB and BH-CAB procedures produce significant and similar short-term improvement in EF in patients with coronary disease. This change in EF may account for the subjective clinical improvements seen early after both procedures. PMID- 21273087 TI - Transaortic migration of a Steinman wire from the shoulder. AB - Orthopedic pins and wires are regularly used for the treatment of bone fractures and dislocations. Migration of these devices from the shoulder into the thoracic cavity is an uncommon but well-known complication. However, great vessels' injuries by a migrated wire are extremely rare. We report the case of a 78-year old woman with a penetrating injury of the ascending thoracic aorta and the superior vena cava caused by migration of a Steinman wire that was used for percutaneous fixation of a left-shoulder dislocation 5 years earlier. There was no hemothorax, hemomediastinum, or hemopericardia, but hemoptysis was present. Such a case has not been previously described. The patient was treated by an emergency median sternotomy with a favorable outcome. PMID- 21273088 TI - The role of Tc-99m-2-Methoxy-Isobutyl-Isonitrile Single Photon Emission Computed Tomography in visualizing anterior mediastinal tumor and differentiating histologic type of thymoma. AB - OBJECTIVE: To evaluate the usefulness of (99m)Tc-2-Methoxy-Isobutyl-Isonitrile Single Photon Emission Computed Tomography (MIBI-SPECT) for assessing anterior mediastinal mass, and distinguishing the grade of malignancy of thymic epithelial tumors to offer guidance for decision making. METHODS: From January 2006 to November 2009, 31 consecutive patients with an anterior mediastinal mass at CT were enrolled. All patients underwent (99m)Tc-MIBI-SPECT before invasive diagnostic procedures and/or surgical resection. The uptake of the mediastinal tumor (T) was compared with the normal tissue (N) and the T/N ratio was calculated to define the metabolic activity of the lesions. Patients were divided into six groups according histologic patterns, which were then correlated to the T/N value: benign tumor (BT), lymphoma (LYM), other malignant tumor (OMT), and low-risk thymoma (LRT) including types A, AB, and B1, high-risk thymoma (HRT) including types B2 and B3, and thymic carcinoma (TC). RESULTS: There were five BT, eight LRT (four = A, two = AB, and two = B1), four HRT (three = B2 and one = B3), four thymic carcinoma, six LYM and four OMT. The T/N value of BT, LRT, HRT, CT, LYM, and OMT was 1.3 +/- 0.3, 1.3 +/- 0.2, 1.8 +/- 0.3, 2.7 +/- 0.5, 2.8 +/- 0.1, and 2.9 +/- 0.2, respectively. The T/N ratio of BT and of LRT was significantly lower than that of HRT, of CT, of LYM, and of OMT (p < 0.05), while there is no significant difference of MIBI uptake between BT and LRT. MIBI uptake in HRT was significantly lower than that in TC, LYM, and OMT (p < 0.05), whereas no significant difference was found between the different types of malignant lesions (TC, LYM, and OMT). Regarding thymoma, the degree of MIBI accumulation significantly increased as the World Health Organization (WHO) classification shifted from type A to type B and to TC. Yet, the T/N value of stages I and II was significantly lower than that of stages III and IV. The size of the lesion and the presence of myasthenia were not correlated with MIBI uptake. CONCLUSION: (99m)Tc-MIBI-SPECT seems to be useful in the evaluation of malignancy in anterior mediastinal mass, and is significantly correlated with the WHO classification and the Masaoka stage. Thus, this technique may add further information to morphological studies for decision making. PMID- 21273089 TI - Hairy trachea!! PMID- 21273090 TI - Keeping an 'eye' on type A dissections. PMID- 21273091 TI - Partnerships in intensive care unit (ICU): a new model of nursing care delivery. AB - AIM: The purpose of this project was to explore an alternate nursing workforce model in major public hospital in Melbourne, Australia. Drivers for this project included improving patient care, facilitating access to intensive care (ICU) beds and managing the changing nursing workforce challenges. METHODS: Using an exploratory descriptive design completed over two stages, a nursing partnership model with Enrolled Nurses (ENs) and experienced ICU nurses was piloted over a nine month period from May 2006. FINDINGS: Overall the partnership model was not sustainable. The positive outcomes included an improved focus on standards of patient care, maintaining access to ICU beds, skill enhancement for participating nurses and a general acceptance by staff to pilot alternate models of care in ICU. The challenges identified included managing changing patient acuity and patient allocation, staff turnover, and barriers to effectively transitioning the appointed Enrolled Nurses into this ICU setting. CONCLUSION: The resources and leadership required to implement the pilot were immense and the requirement did not lessen over time resulting in the pilot being unsustainable after nine months. PMID- 21273092 TI - Current technologies for HER2 testing in breast cancer. AB - BACKGROUND: Molecular techniques play an increasingly important role in breast cancer detection and help in the prediction of prognosis and treatment response. HER-2/neu predicts the sensitivity of breast tumors to trastuzumab and lapatinib. Presently there are several ways to assess HER2 status at the protein level (e.g. ELISA), at the RNA level (RT-PCR, microarray) and at the DNA level (fluorescence in situ hybridization, chromogenic in situ hybridization (ISH), silver in situ hybridization or multiplex ligation-dependent probe amplification). DESIGN: This paper provides an overview of new developments in HER2 testing. RESULTS: Although these techniques correlate well in comparative studies, discrepancies remain. Each technique has its own (dis)advantages and thus there is no real gold standard. Not surprisingly, there is no consensus at present on which of the protein- or gene-based techniques is superior, on the use of mono- or duo-probe ISH systems, nor on the use of manual or fully-automated staining- and scoring systems. CONCLUSION: Until large clinical trials clearly point out one strategy as the best predictive one for trastuzumab response, the choice for a testing strategy will probably be based on local preferences which consider both practical and economic issues. Standardization, proper internal and external quality control assessment, laboratory accreditation and automation of tissue processing (autostainers) and interpretation methods (image analysis) will play an increasingly important role in HER2 testing. PMID- 21273093 TI - Lymphoblastic lymphoma. AB - Lymphoblastic lymphoma (LBL) is a neoplasm of immature B cells committed to the B (B-LBL) or T-cell lineage (T-LBL) that accounts for approximately 2% of all lymphomas. From a histopathological point of view, blasts may be encountered in tissue biopsy and/or bone marrow (BM). In tissue sections, LBL is generally characterized by a diffuse or, as in lymph nodes and less commonly, paracortical pattern. Although histological features are usually sufficient to distinguish lymphoblastic from mature B- or T-cell neoplasms, a differential diagnosis with blastoid variant of mantle cell lymphoma, Burkitt lymphoma or myeloid leukemia may arise in some cases. Of greater importance is the characterization of immunophenotype by flow cytometry. In B-LBL, tumour cells are virtually always positive for B cell markers CD19, CD79a and CD22. They are positive for CD10, CD 24, PAX5, and TdT in most cases, while the expression of CD20 and the lineage independent stem cell antigen CD34 is variable and CD45 may be absent. Surface immunoglobulin is usually absent. In T-LBL, neoplastic cells are usually TdT positive and variably express CD1a, CD2, CD3, CD4, CD5, CD7 and CD8. The only reliable lineage-specific is surface CD3. Most B-LBL have clonal rearrangements of the Ig heavy chain or less frequently of light chain genes. T-cell receptor gamma or beta chain gene rearrangements may be seen in a significant number of cases, but rearrangements are not helpful for lineage assignment. LBL occurs more commonly in children than in adults, mostly in males. Although 80% of precursor B cell neoplasms present as acute leukemias, with BM and peripheral blood (PB) involvement, a small proportion present with a mass lesion and have <25% blasts in the BM. Unlike precursor T-LBL, mediastinal masses and involvement of BM are rare, but lymph nodes and extranodal sites are more frequently involved. T-LBL patients, compared to those with B-LBL, show younger age, a higher rate of mediastinal tumours or BM involvement. Patients are usually males in their teens to twenties and present with lymphadenopathy in cervical, supraclavicular and axillary regions, or with a mediastinal mass. In most patients the mediastinal mass is anterior, bulky, and associated with pleural effusions, superior vena cava syndrome, tracheal obstruction, and pericardial effusions. They frequently present with advanced disease, B symptoms and elevated serum LDH levels. Abdominal involvement (liver and spleen) is unusual. LBL is highly aggressive, but frequently curable with current therapy. The prognosis in all age groups has dramatically improved with the use of intensive ALL-type chemotherapy regimes, with a disease-free survival of 73-90% in children and 45-72% in adults. Intensive intrathecal chemotherapy prophylaxis is required to reduce the CNS relapse incidence, while the role of prophylactic cranial irradiation is unclear. Consolidation mediastinal irradiation may decrease mediastinal relapse. Patients with adverse prognostic features should be considered for high-dose chemotherapy and SCT. Autologous SCT has been shown to produce similar good results as chemotherapy alone, and allogeneic SCT is likely to be a more appropriate option for patients who are beyond first remission or with more advanced disease. PMID- 21273094 TI - Tacrolimus preserves vasomotor function and maintains vascular homeostasis. AB - BACKGROUND: Post-transplant immunosuppression is associated with endothelial dysfunction that may lead to vasculopathy. We have previously demonstrated that cyclosporine causes vascular dysfunction. In this we study examined the effect of tacrolimus (Tac) in an identical model. METHODS: Lewis rats (n = 8 per group) were injected with Tac (low, medium or high dose) or saline (Con) daily for 2 weeks. Segments of thoracic aorta (TAo) were assessed for endothelium-dependent (Edep) and -independent (Eind) vasorelaxation (E(max)) and sensitivity to endothelin (ET)-induced vasoconstriction (C(max)). ET(A) and ET(B) receptor (Rc) expression levels were determined in TAo. Tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta) expression were determined in myocardial (LV) tissue. Plasma ET levels and tissue oxidative injury were quantified by enzyme-linked immunoassay. RESULTS: Tac did not impair Edep relaxation when compared with Con (p = 0.69). Impairment of sodium nitroprusside mediated Eind vasorelaxation was noted with Tac (E(max): Con 69 +/- 2%, Tac high 54 +/- 2%; p = 0.0001), whereas no such impairment was seen with diltiazem mediated Eind vasorelaxation (p = 0.06). Tac decreased sensitivity to ET (C(max): Con 222 +/- 19%, Tac high 162 +/- 11%; p = 0.0002) and ET levels (Con 0.8 +/- 0.1 fmol/ml, Tac 0.4 +/- 0.1 fmol/ml; p = 0.02). Tac did not alter ET(A) Rc expression (p = 0.28), but increased ET(B) Rc levels (p = 0.02). Oxidative injury was similar in both LV (p = 0.43) and Ao (p = 0.73) tissue. Similarly, TNF-alpha expression (p = 0.16) was not different between groups, whereas expression of TGF beta demonstrated a significant decrease with Tac treatment (p = 0.02). CONCLUSION: Our findings suggests that tacrolimus has beneficial effects with respect to endothelial function. PMID- 21273095 TI - Eye movements reveal solution knowledge prior to insight. AB - In two experiments, participants solved anagram problems while their eye movements were monitored. Each problem consisted of a circular array of five letters: a scrambled four-letter solution word containing three consonants and one vowel, and an additional randomly-placed distractor consonant. Viewing times on the distractor consonant compared to the solution consonants provided an online measure of knowledge of the solution. Viewing times on the distractor consonant and the solution consonants were indistinguishable early in the trial. In contrast, several seconds prior to the response, viewing times on the distractor consonant decreased in a gradual manner compared to viewing times on the solution consonants. Importantly, this pattern was obtained across both trials in which participants reported the subjective experience of insight and trials in which they did not. These findings are consistent with the availability of partial knowledge of the solution prior to such information being accessible to subjective phenomenal awareness. PMID- 21273096 TI - Maintaining binding in working memory: comparing the effects of intentional goals and incidental affordances. AB - Much research on memory for binding depends on incidental measures. However, if encoding associations benefits from conscious attention, then incidental measures of binding memory might not yield a sufficient understanding of how binding is accomplished. Memory for letters and spatial locations was compared in three within-participants tasks, one in which binding was not afforded by stimulus presentation, one in which incidental binding was possible, and one in which binding was explicitly to be remembered. Some evidence for incidental binding was observed, but unique benefits of explicit binding instructions included preserved discrimination as set size increased and drastic reduction in false alarms to lures that included a new spatial location and an old letter. This suggests that substantial cognitive benefits, including enhanced memory for features themselves, might occur through intentional binding, and that incidental measures of binding might not reflect these advantages. PMID- 21273097 TI - Efficacy of vagus nerve stimulation for refractory epilepsy among patient subgroups: a re-analysis using the Engel classification. AB - Optimal candidates for VNS as a treatment for refractory epilepsy have not been identified. In this retrospective two-center study, we used the Engel classification for evaluating seizure outcome, and tried to identify predictive factors for outcome by means of subgroup analysis. The medical records of patients who have been treated with VNS for at least one year at Dartmouth Hitchcock Medical Center and Ghent University Hospital were evaluated. Seizure frequency outcome was assessed using the Engel classification for the study population as a whole, and for patient subgroups with regard to mental functioning, seizure type, predisposing factors for developing epilepsy, age at time of VNS implantation and epilepsy duration. 189 patients (102M/87F) were included in the study (mean FU: 41 months). 6% had a class I outcome (seizure free), 13% a class II outcome (almost seizure-free), 49% a class III outcome (worthwhile improvement) and 32% had a class IV outcome (no improvement). When patients were divided into specific subgroups, a statistically significant better outcome was found patients with normal mental functioning (p=0.029). In our series, results for VNS are clearly inferior to resective surgery, but comparable to other treatment modalities for refractory epilepsy. With combined class I and II outcomes around 20%, and another 50% of patients having worthwhile improvement, VNS is a viable alternative when resective surgery is not feasible. PMID- 21273098 TI - Determining the technical and clinical factors associated with pain for children undergoing botulinum toxin injections under nitrous oxide and anesthetic cream. AB - AIMS: To determine technical and clinical factors associated with pain when using an analgesic protocol with 50% nitrous oxide/oxygen and anesthetic cream (lidocaine and prilocaine, Emla((r))) for children with cerebral palsy undergoing botulinum toxin injections. METHODS: Monocentric prospective study including 50 children newly injected with a mean age of 6.6 years (+/- 4.32, range 1-18) and 199 injected muscles. Pain was evaluated using the Children's Hospital of Eastern Ontario Pain Scale (CHEOPS). The following variables were noted: gender, age, weight, Gross Motor Function Classification System, type of cerebral palsy (hemiplegic, diplegic, tetraplegic), muscles injected and severe cognitive impairment. The procedure was broken down into three phases for the purpose of pain evaluation: puncture, muscle localization using electrostimulation and injection of botulinum toxin. RESULTS: The mean CHEOPS score was 8.16 (+/- 3.5) and 38% of scores were above the therapeutic threshold of 9. The injection phase was significantly more painful (6.77 +/- 3.30) than the puncture (4.88 +/- 2.03) and localization (5.46 +/- 2.68) phases. The adductor muscles were less painful than other muscles. Children with more severe cognitive impairment seemed to perceive higher levels of pain than the others. Other clinical factors were not associated with pain score. CONCLUSION: Clinical characteristics seem not strongly correlated to the success or failure of the 50% nitrous oxide/oxygen Emla((r)) protocol and this pain treatment protocol does not prevent equally all phases of botulinum toxin injections. Future research on the products and its dilution might help to reduce pain level. PMID- 21273099 TI - Self-, parent-, and teacher-reported behavioral symptoms in youngsters with Tourette syndrome: a case-control study. AB - AIMS: Tourette syndrome (TS) is a neurodevelopmental disorder characterized by multiple tics and associated with co-morbid behavioral problems (TS-plus). We investigated the usefulness of self-report versus parent- and teacher-report instruments in assisting the specialist assessment of TS-plus in a child/adolescent population. METHODS: Twenty-three patients diagnosed with TS (19 males; age 13.9 +/- 3.7 years) and 69 matched healthy controls participated in this study. All recruited participants completed a standardized psychometric battery, including the Children's Depression Inventory (CDI), the Self Administrated Psychiatric Scales for Children and Adolescents (SAFA) and the State-Trait Anger Expression Inventory (STAXI). Parents completed the Child Behavior Checklist (CBCL) and Conners' Parent Rating Scales-Revised (CPRS-R). Participants' teachers completed the Conners' Teacher Rating Scales-Revised (CTRS R). Results were compared with similar data obtained from controls. RESULTS: Nineteen patients (82.6%) fulfilled DSM-IV-TR criteria for at least one co-morbid condition: obsessive-compulsive disorder (OCD, n = 8; 34.8%); attention deficit hyperactivity disorder (ADHD, n = 6; 26.1%); OCD + ADHD (n = 5; 21.7%). Scores on self-report instruments failed to show any significant differences between TS and controls. Most subscores of the CPRS-R, CTRS-R, and CBCL were significantly higher for the TS group than controls. The TS + OCD subgroup scored significantly higher than the TS-OCD subgroup on the CBCL-Externalizing, Anxious/Depressed and Obsessive-Compulsive subscales. CONCLUSIONS: Self-report instruments appear to have limited usefulness in assisting the assessment of the behavioral spectrum of young patients with TS. However, proxy-rated instruments differentiate TS populations from healthy subjects, and the CBCL can add relevant information to the clinical diagnosis of co-morbid OCD. PMID- 21273100 TI - Sex differences in sleep pattern of rats in an experimental model of osteoarthritis. AB - BACKGROUND: Osteoarthritis (OA) is a major healthcare burden with increasing incidence, and is characterised by the degeneration of articular cartilage. OA is associated with chronic pain and sleep disturbance. OBJECTIVE: The current study examined and compared the long-term effects of chronic articular pain on sleep patterns between female and male rats in an experimental model of OA. METHODS: Rats were implanted with electrodes for electrocorticography and electromyography and assigned to control, sham or OA groups. OA was induced by the intra-articular administration of (2 mg) monosodium iodoacetate into the left knee joint in male and female rats (at estrus and diestrus phases). RESULTS: Sleep was monitored at days 1, 10, 15, 20 and 28 after iodoacetate injection during light and dark periods. The results showed that the overall sleep architecture changed in both sexes. These alterations occurred during the light and dark periods, began on D1 and persisted until the end of the study. OA rats, regardless of sex, showed a fragmented sleep pattern with reduced sleep efficiency, slow-wave sleep and paradoxical sleep, and fewer paradoxical sleep bouts. However, the males showed lower sleep efficiency and reduced slow-wave sleep compared to females during the dark period. Additionally, OA affected the hormonal levels in male rats, as testosterone levels were reduced in comparison to the control and sham groups. In females, progesterone and estradiol remained unchanged throughout the study. CONCLUSIONS: Our results suggest that the chronic model of OA influenced the sleep patterns in both sexes. However, males appeared to be more affected. PMID- 21273101 TI - Coherence times and Rabi oscillations in CaWO4:Cr(5+) crystal. AB - The coherence times of dopant pentavalent chromium ions in CaWO4 single crystal (0.0006at.% Cr(5+)) were investigated both theoretically and experimentally. Temperature dependences of spin-lattice relaxation time T1 and phase memory time T(M) were measured in the temperature range 6-30 K at high (94 GHz, W band) and low (3.5 GHz, S band) frequencies of electron spin resonance. It follows from T(M) calculations that phase relaxation of Cr(5+) ion arises mainly from magnetic dipole interactions between the chromium ions. Anomalously fast damping of Rabi oscillations is detected in both S- and W-band experiments. It is shown that this phenomenon is caused by microwave field inhomogeneity inside the resonator. Relations between the damping time of Rabi oscillations, Rabi frequency and the crystal sample size are obtained. Lumped-element resonators and smaller sample dimensions are suggested to lower spin dephasing during transient nutations. PMID- 21273102 TI - Integrated refocused virtual ESEEM: detection of nuclear transition spectra without dead time and blind spots. AB - General expressions describing the refocused stimulated (RS) and refocused virtual (RV) electron spin echo envelope modulations (ESEEM) generated with the same basic four-pulse sequence are derived. It is shown that integration of the 3D time domain trace over the two "low-resolution" time intervals (those between the first and second and between the third and fourth microwave pulses) results in a dead time-free 1D ESEEM trace in the "high-resolution" dimension (i.e., the time interval between the second and third microwave pulses) that only contains harmonics with the fundamental frequencies of nuclear transitions. The practical implementation of the integrated RS ESEEM requires pulse swapping, which leads to unrecoverable distortions in the ESEEM traces and the resulting spectra. The integrated RV ESEEM is free from such distortions and represents a robust practical technique for obtaining dead time- and blind spots-free spectra of nuclear transitions, without homonuclear combination lines. As an application example, the integrated RV ESEEM was used to obtain the spectrum of a strongly coupled proton of the OH ligand of the Mo(V) active center of the low-pH form of the molybdoenzyme sulfite oxidase. PMID- 21273103 TI - Development of quantitative structure-activity relationships for explanatory modeling of fast reacting (meth)acrylate monomers bearing novel functionality. AB - The photoinitiated polymerization of (meth)acrylate monomers bearing novel carbamate functionality exhibits significantly greater reaction rate when compared to more traditional acrylate monomers undergoing similar polymerization. This unusually fast reactivity has been the subject of much investigation. In order to suggest an explanatory mechanism for the enhanced polymerization rates we have conducted quantitative structure-activity relationship investigations of these novel monomers. These studies have resulted in statistically sound models with coefficients of multiple determination of R(2)>0.93. Principal component and k nearest neighbor similarity analysis were also conducted on the multiple regression models. These results are discussed in light of published experimental investigations of the photopolymerization reactivity of the novel monomers. PMID- 21273104 TI - Studies of tricyclic piperazine/piperidine furnished molecules as novel integrin alphavbeta3/alphaIIbbeta3 dual antagonists using 3D-QSAR and molecular docking. AB - The development of injectable integrin alpha(v)beta(3)/alpha(IIb)beta(3) dual antagonists attracts much attention of research for treating of acute ischemic diseases in recent years. In this work, based on a dataset composed of 102 tricyclic piperazine/piperidine furnished dual alpha(v)beta(3) and alpha(IIb)beta(3) antagonists, a variety of in silico modeling approaches including the comparative molecular field analysis (CoMFA), comparative similarity indices analysis (CoMSIA), and molecular docking were applied to reveal the requisite 3D structural features impacting the biological activities. Our statistical results show that the ligand-based 3D-QSAR models for both the alpha(v)beta(3) and alpha(IIb)beta(3) studies exhibited satisfactory internal and external predictability, i.e., for the CoMFA models, results of Q(2)=0.48, R(ncv)(2)=0.87, R(pred)(2)=0.71 for alpha(v)beta(3) and Q(2)=0.50, R(ncv)(2)=0.85, R(pred)(2)=0.72 for alpha(IIb)beta(3) analysis were obtained, and for the CoMSIA ones, the outcomes of Q(2)=0.55, R(ncv)(2)=0.90, R(pred)(2)=0.72 for alpha(v)beta(3) and Q(2)=0.52, R(ncv)(2)=0.88, R(pred)(2)=0.74 for alpha(IIb)beta(3) were achieved respectively. In addition, through a comparison between 3D-QSAR contour maps and docking results, it is revealed that that the most crucial interactions occurring between the tricyclic piperazine/piperidine derivatives and alpha(v)beta(3)/alpha(IIb)beta(3) receptor ligand binding pocket are H-bonding, and the key amino acids impacting the interactions are Arg214, Asn215, Ser123, and Lys253 for alpha(v)beta(3), but Arg214, Asn215, Ser123 and Tyr190 for alpha(IIb)beta(3) receptors, respectively. Halogen-containing groups at position 15 and 16, benzene sulfonamide substituent at position 23, and the replacement of piperazine with 4-aminopiperidine of ring B may increase the alpha(v)beta(3)/alpha(IIb)beta(3) antagonistic activity. The potencies for antagonists to inhibit isolated alpha(v)beta(3) and alpha(IIb)beta(3) are linear correlated, indicating that similar interaction mechanisms may exist for the series of molecules. To our best knowledge this is the first report on 3D-QSAR modeling of these dual alpha(v)beta(3)/alpha(IIb)beta(3) antagonists. The results obtained should provide information for better understanding of the mechanism of antagonism and thus be helpful in design of novel potent dual alpha(v)beta(3)/alpha(IIb)beta(3) antagonists. PMID- 21273105 TI - Pulmonary rhodococcosis in a cat. AB - Feline Rhodococcus equi infection is rare, despite the bacteria is widespread in the environment. R equi infection is typically observed in equine species but the infection has also been reported in dogs, cats and other domestic animals. There are a few reports regarding pulmonary R equi infection in cats and the disease appears to be limited to the skin and the subcutaneous tissue. This report describes the pathological, microbiological and the virulence features associated with an acute necrosuppurative pneumonia in a cat. To the best of our knowledge, this is the first report of feline pulmonary R equi infection in Italy. PMID- 21273106 TI - The prevalence, characteristics and metabolic consequences of renal insufficiency in very old hospitalized diabetic patients. AB - AIMS: We aimed to characterize the determinants and characteristics of renal disease in very old diabetic patients in geriatric care. METHODS: Consecutive diabetic patients (96 women, 38 men) admitted to a geriatric service were studied. Glomerular filtration rate (GFR), albuminuria, vascular and general comorbidities, glycaemic control, malnutrition (using the Mini-Nutritional Assessment [MNA], serum albumin and cholesterol levels), haemoglobin and inflammation (CRP levels) were assessed. RESULTS: (a) 51.2 and 12.4% patients had moderate or severe renal insufficiency. The prevalence of normo-, micro- and macroalbuminuria was 45.0, 38.9 and 16.0% in the whole population, and was similar in patients with or without moderate renal insufficiency. Renal insufficiency was associated with previous stroke (P=0.024), heart failure (P=0.024), and atrial fibrillation (P=0.008), and possibly myocardial infarction (P=0.059, Mann-Whitney test). (b) Albuminaemia was associated with albuminuria, MNA scores, haemoglobin, total and HDL-cholesterol and CRP. However, in multiple linear regression analysis CRP was the only robust determinant of albuminaemia (P<0.0001). (c) Renal insufficiency was not associated with the MNA, serum albumin, haemoglobin and cholesterol levels. CONCLUSION: Renal insufficiency often occurs without albuminuria, suggesting aetiologies distinct from classical diabetic nephropathy, and is strongly associated with vascular comorbidities. Hypoalbuminaemia is more strongly associated with inflammation than with albuminuria and malnutrition. Malnutrition, hypoalbuminaemia, low cholesterol levels and anaemia are not associated with renal insufficiency, likely due to the very high prevalence of these abnormalities in the whole population. These features must be taken into account when organizing the global care of elderly diabetic patients. PMID- 21273107 TI - The role for radicular veins in nerve root pain is underestimated: limitations of imaging studies. PMID- 21273108 TI - Incidence of tuberculosis in patients with rheumatoid arthritis. A systematic literature review. AB - OBJECTIVES: To determine the incidence and risk of tuberculosis in rheumatoid arthritis (RA) patients exposed or unexposed to TNFalpha antagonists, the impact of recommendations about managing latent tuberculosis, the time to diagnosis of active tuberculosis, and the proportion of extrapulmonary forms. METHODS: Systematic review of articles retrieved using Medline. From each article, we abstracted the incidence and risk of tuberculosis in RA patients exposed or unexposed to TNFalpha antagonists, the duration of TNFalpha antagonist exposure at the diagnosis of tuberculosis, and the distribution of the tuberculosis foci. RESULTS: We selected 14 articles. The risk of tuberculosis was increased 2- to 10 fold in RA patients unexposed to TNFalpha antagonists and 2- to 4-fold in those exposed to TNFalpha antagonists, compared to the general population. The incidence of tuberculosis in TNFalpha antagonist-treated patients varied across studies (9.3 to 449/100,000) according to the country, observation period, and TNFalpha antagonist used. The risk was greater with monoclonal antibodies than with the soluble receptor. Official recommendations have decreased the risk of tuberculosis in TNFalpha antagonist-treated patients. Over half the cases of active tuberculosis were diagnosed during the first treatment year. Among TNFalpha antagonist-treated patients with tuberculosis, 60% had extrapulmonary lesions. Disseminated tuberculosis was more common with monoclonal antibodies. CONCLUSIONS: The risk of tuberculosis is increased during TNFalpha antagonist therapy, and the increase is larger with the monoclonal antibodies than with the soluble receptor. Tuberculosis during TNFalpha antagonist therapy is a rare event that occurs early after treatment initiation. Extrapulmonary involvement is common and potentially severe. Therefore, clinicians should direct careful attention to the risk of tuberculosis associated with TNFalpha antagonist therapy. PMID- 21273109 TI - Second reported case of human infection with Streptococcus equi subsp. ruminatorum. AB - The field of zoonoses changes constantly. Streptococcus equi subsp. ruminatorum is a group C Streptococcus subspecies first identified in 2004. The first case of human infection with this agent was reported in 2007. Here, we report a second case. A 70-year-old man had acute spondylodiscitis and endocarditis involving the anterior mitral valve leaflet. S. equi subsp. ruminatorum was identified in the blood cultures. Antibiotic therapy was successful in eradicating the infection. The workup showed hypogammaglobulinemia with stage I myeloma. He reported frequent contacts with horses including two that exhibited symptoms of upper airway infection a few days before his symptoms started. Serological tests indicated S. equi infection in both animals. This unusual case confirms that S. equi subsp. ruminatorum can cause human disease. In addition, our patient was probably contaminated via the skin, a mode of transmission that has not been described previously. It also highlights the usefulness of molecular biology tests, which should be performed routinely in patients with group C streptococcus infections and evidence suggesting a zoonosis. PMID- 21273110 TI - Detection of basic calcium phosphate crystals in osteoarthritis. AB - Osteoarthritis (OA) is the most common human joint disorder. Its complex pathogenesis remains poorly understood but appears multifactorial. To date, no specific pharmacological agent has been identified to alter the disease course of OA. Calcification of articular cartilage is a hallmark of OA and evidence suggests it contributes directly to joint degeneration. Calcium crystals are frequently found in OA synovial fluid but their exact role in the disease process is unclear. Basic calcium phosphate (BCP) crystals are the predominant crystal type found in OA and recent data indicate a pathogenic role for these crystals in OA. However, information on the exact frequency and distribution of BCP crystals vary considerably, mainly due to the lack of simple and reliable methods of detection. The purpose of this review is to describe the current available methods for detecting BCP crystals and to highlight their obvious advantages and limitations. Recent developments in the field are also discussed with particular reference to their potential clinical applicability. Improved methods of detection for BCP crystals could potentially aid the diagnosis of OA and the development of novel therapies. PMID- 21273111 TI - Down-regulation of the Wnt, estrogen receptor, insulin-like growth factor-I, and bone morphogenetic protein pathways in osteoblasts from rats with chronic spinal cord injury. AB - OBJECTIVES: To investigate the anabolic response of osteoblasts to chronic spinal cord injury and to identify potential signaling pathways that are associated with the osteogenic response after spinal cord injury by using in-house microarray analyses in osteoblasts. METHODS: Ten young male Sprague-Dawley rats were randomized into spinal cord injury (SCI) and SHAM groups. The tibiae were assessed for DXA and bone histomorphometry, and osteoblasts from femora were used for microarray analysis. RESULTS: SCI rats showed lower BMD and deteriorated microstructure in the proximal tibiae as compared with SHAM rats. The Wnt, BMP/TGF, estrogen receptor (ER), and IGF-I pathways were down-regulated in osteoblasts from spinal cord-injured rats. CONCLUSION: Down-regulation of the Wnt, BMP/TGF, ER, and growth hormone/IGF-I pathways is associated with decreased bone formation after spinal cord injury. PMID- 21273112 TI - Enzymatic synthesis of ascorbyl palmitate in ultrasound-assisted system: process optimization and kinetic evaluation. AB - This work is focused on the optimization of reaction parameters for the synthesis of ascorbyl palmitate catalyzed by Candida antarctica lipase in different organic solvents under ultrasound irradiation. The sequential strategy of experimental design proved to be useful in determining the optimal conditions for reaction conversion in tert-butanol system using Novozym 435 as catalyst. The optimum production was achieved at 70 degrees C, ascorbic acid to palmitic acid molar ratio of 1:9, enzyme concentration of 5 wt% at 3h of reaction, resulting in an ascorbyl palmitate conversion of about 27%. Reaction kinetics for ascorbyl palmitate production in ultrasound device showed that satisfactory reaction conversions (~26%) could be achieved in short reaction times (2h). The empirical kinetic model proposed is able to satisfactorily represent and predict the experimental data. PMID- 21273113 TI - Assessment and stenting of tracheal stenosis using deformable shape models. AB - This work presents a decision support system for the assessment of tracheal stenosis. In the proposed method, a statistical shape model of healthy tracheas is registered to a 3D CT image of a patient with tracheal stenosis. The registration yields an estimation of the shape of the patient's trachea as if stenosis was not present. From this point, the extent and the severity of the stenosis is assessed and stent parameters are obtained automatically. The method was extensively evaluated on simulation as well on real data and the results showed that it is accurate and fast enough to be used in the clinical setting. PMID- 21273116 TI - Vibrational spectroscopic (FTIR and FTRaman) investigation using ab initio (HF) and DFT (LSDA and B3LYP) analysis on the structure of Toluic acid. AB - The FTRaman and FTIR spectra for Toluic acid (TA) have been recorded in the region 4000-100 cm(-1) and compared with the harmonic vibrational frequencies calculated using HF/DFT (LSDA and B3LYP) method BY employing 6-311G (d, p) basis set with appropriate scale factors. IR intensities and Raman activities are also calculated by HF and DFT (LSDA/B3LYP) methods. Optimized geometries of the molecule have been interpreted and compared with the reported experimental values for benzoic acid and some substituted benzoic acids. The experimental geometrical parameters show satisfactory agreement with the theoretical prediction from HF and DFT. The scaled vibrational frequencies at B3LYP/6-311G (d, p) seem to coincide with the experimentally observed values with acceptable deviations. The theoretical spectrograms (IR and Raman) have been constructed and compared with the experimental FT-IR and FT-Raman spectra. Some of the vibrational frequencies of the TA are effected upon profusely with the methyl substitutions in comparison to benzoic acid and these differences are interpreted. PMID- 21273115 TI - Determination of lysozyme at the nanogram level in food sample using Resonance Rayleigh-scattering method with Au nanoparticles as probe. AB - A new method for determination of lysozyme with high sensitivity based on Resonance Rayleigh scattering (RRS) by using Au nanoparticles as a probe was proposed in this experiment. The RRS spectrum, nonlinear scattering (second-order scattering (SOS), frequency doubling scattering (FDS)) spectra and absorption spectrum of the Au nanoparticles-lysozyme system have been analyzed. In addition, the effects of several factors on scattering intensities were investigated, including pH value of solution, amount of Au nanoparticles, mixing sequence of each reagent and the coexisting substances. The results showed that the coexisting substances have little influence on the RRS intensities of the systems. Moreover, the possible mechanism for the RRS enhancement of Au nanoparticles-lysozyme system was preliminary discussed. The RRS method for determination of lysozyme has good sensitivity and selectivity with the detection limits 30.1 ng/ml. The contents of lysozyme were determined with recoveries of 98.2-105.4% and relativity relative standard deviation (RSD) of 0.3-3.7%, respectively. It proved that the method established in our study is suitable for the determination of lysozyme in synthetic sample and natural chicken egg white sample. PMID- 21273114 TI - Cognitive neuroscience of self-regulation failure. AB - Self-regulatory failure is a core feature of many social and mental health problems. Self-regulation can be undermined by failures to transcend overwhelming temptations, negative moods and resource depletion, and when minor lapses in self control snowball into self-regulatory collapse. Cognitive neuroscience research suggests that successful self-regulation is dependent on top-down control from the prefrontal cortex over subcortical regions involved in reward and emotion. We highlight recent neuroimaging research on self-regulatory failure, the findings of which support a balance model of self-regulation whereby self-regulatory failure occurs whenever the balance is tipped in favor of subcortical areas, either due to particularly strong impulses or when prefrontal function itself is impaired. Such a model is consistent with recent findings in the cognitive neuroscience of addictive behavior, emotion regulation and decision-making. PMID- 21273117 TI - Correlation between the Elecsys HBsAg II assay and the Architect assay for the quantification of hepatitis B surface antigen (HBsAg) in the serum. AB - BACKGROUND: Hepatitis B surface antigen (HBsAg) clearance during chronic hepatitis B (CHB) infection is associated with improved long-term clinical outcome, so is considered an important therapeutic goal in CHB. Studies have shown that serum HBsAg quantification during, and at end of, treatment may predict long-term HBsAg loss. OBJECTIVES: Performance comparison of the qualitative Elecsys HBsAg II assay using a quantitative research protocol and an established quantitative HBsAg assay. STUDY DESIGN: A dilution algorithm was developed for the Elecsys HBsAg II assay to allow quantification of HBsAg levels; this was used to measure HBsAg levels in a range of samples including sera from patients infected with different HBV genotypes, HBV mutants, and longitudinal samples from patients undergoing antiviral treatment. Results were compared with those from the quantitative Architect HBsAg assay. RESULTS: There was significant overall correlation between Elecsys and Architect assays (correlation coefficient [r]=0.97; p<0.001). HBsAg levels measured with both assays correlated well in all phases of infection (r=0.80-0.96), across all genotypes tested (HBV genotype A, r=0.89; HBV genotype D, r=0.97), and in samples with lamivudine-resistant mutations (r=0.94). Bland-Altman analysis showed only minor discordance between assays in different phases of chronic HBV-infection (3.8-5.1%). This strong correlation was also present for sera with lower HBsAg concentrations. On treatment HBsAg levels were similar when measured with either assay. CONCLUSIONS: Using a simple dilution algorithm, the quantitative Elecsys HBsAg II assay reliably determined serum HBsAg levels in a wide range of samples, and showed very high correlation with the Architect HBsAg assay. PMID- 21273118 TI - Automated high throughput DNA isolation for detection of human papillomavirus in oral rinse samples. AB - BACKGROUND: Oral HPV infection elevates risk of oropharyngeal cancer, but its natural history is unknown. Natural history studies necessitate validation of an automated, high-throughput method for HPV genomic DNA detection in oral rinse samples (ORS). OBJECTIVES: To compare agreement of oral HPV detection in ORS processed by a magnetic-bead based automated platform to a previous gold standard, manual protein-precipitation method. Agreement was compared to that of repeat sampling and repeat HPV testing. STUDY DESIGN: HIV-infected individuals (n=100) provided two ORS collected 15 min apart. DNA was isolated from equal aliquots by either a protein-precipitation based (Puregene, Qiagen) or magnetic bead-based (QIAsymphonyTM SP, Qiagen) method. HPV DNA was detected and type specified by consensus primer PCR and reverse line blot hybridization. The kappa statistic was used to assess overall agreement (OA) and agreement on a positive test (Ps+). RESULTS: The DNA purification methods had very high agreement for categorizing an individual as HPV infected (OA=0.95; Ps+=0.94) as well as for detection of HPV type-specific infection (OA=0.99; Ps+=0.88) in ORS. Agreement for detection of HPV type-specific infection was greater than that observed with repeat oral rinse sampling (OA=0.99, Ps+=0.76) but comparable to inter-assay agreement (OA=1.00, Ps+=0.90). CONCLUSIONS: HPV detection in ORS processed with a magnetic-bead based automated platform will facilitate large natural history studies of oral HPV infection necessary to evaluate the potential use of oral HPV detection in oral cancer screening. PMID- 21273119 TI - Contribution of Listeria monocytogenes RecA to acid and bile survival and invasion of human intestinal Caco-2 cells. AB - The food-borne pathogen Listeria monocytogenes is able to colonize the human gastro-intestinal tract and subsequently cross the intestinal barrier. Thus, for L. monocytogenes to become virulent, it must survive the low pH of the stomach, high bile concentrations in the small intestine, and invade the epithelial cells. In this study, we show that RecA, which is an important factor in DNA repair and the activator of the SOS response, contributes to the resistance against acid and bile and to the ability of L. monocytogenes to adhere and invade human intestine epithelial cells. Activation of recA was shown with a promoter reporter after exposure to low pH and high bile concentrations and during adhesion and invasion of Caco-2 intestinal epithelial cells. Furthermore, an in-frame recA deletion mutant showed reduced survival after exposure to low pH and high bile concentrations. This mutant also showed a deficiency in adhesion and invasion of Caco-2 cells. These results suggest that RecA may contribute to the colonization of the human gastro-intestinal tract and crossing of the intestinal barrier. PMID- 21273120 TI - Staphylococcus aureus ClpC is involved in protection of carbon-metabolizing enzymes from carbonylation during stationary growth phase. AB - The ability of Staphylococcus aureus to adapt to various conditions of stress is the result of a complex regulatory response. Among them, ClpC, belonging to the Hsp100/Clp ATPase family, seems to play an important role. For instance, we previously demonstrated that a functional clpC deletion resulted in enhanced survival in the late stationary phase (death phase period) compared to the parental S. aureus strain. However, the mechanisms for the enhanced survival of a S. aureus clpC mutant during the death phase period are still elusive. In Escherichia coli, among the factors that might lead to bacterial cell death during stationary phase, the amount of protein aggregates and/or oxidized proteins appears to be of major importance. Thus, in the present study, we have evaluated protein aggregates and carbonylated protein (as a marker of protein oxidation) contents both in the wild type and in an S. aureus clpC mutant during the exponential growth phase and the death phase. Whereas at all time points the tested clpC mutant exhibits the same amount of protein aggregates as the WT strain, the total amount of carbonylated proteins appears to be lower in the clpC mutant. Moreover, we observed that at the entrance of the death phase carbon metabolizing enzymes [such as the TCA cycle enzymes Mqo2 (malate: quinone oxidoreductase) and FumC/CitG (fumarate hydratase)] albeit not the bulk proteins are carbonylated to a larger extent in the clpC mutant. Reduced activity of the TCA cycle due to specific carbonylation of these proteins will result in a decrease of endogenous oxidative stress which in turn might confer enhanced survival of the clpC mutant during the death phase period thus contributing to bacterial longevity and chronic infection. PMID- 21273121 TI - Can we repair the mitral valve from outside the heart? A novel extra-cardiac approach to functional mitral regurgitation. AB - BACKGROUND: Functional mitral regurgitation (FMR) is primarily due to abnormalities of the ventricular muscle in the presence of normal mitral leaflets. Present surgical treatment options address the mitral valve annulus and leaflets but not the ventricular muscle. We discuss the evolution of a concept that describes a ventricular solution to this problem, and report preliminary clinical results from the first five subjects implanted with the latest version of this device. METHODS: Evaluation of safety and efficacy of the latest version of the BACETM (Basal Annuloplasty of the Cardia Externally) Device was done first in sheep with rapid ventricular pacing to induce severe MR. The BACE Device was implanted around the base of the heart and chambers on the device filled with normal saline through the subcutaneous ports under echocardiogram until there was no evidence of MR. Once MR was effectively reduced, the chest was closed and the animals recovered, with clinical and echocardiographic analysis through six months of follow-up. Human studies were done with in a similar manner, with subjects that were already undergoing concomitant open-chest coronary artery bypass graft (CABG) surgery. Five subjects with ischaemic MR and triple vessel coronary artery disease were first implanted with the BACE Device, applied epicardially on a beating heart without use of cardiopulmonary bypass, before coronary artery bypass grafting was done. RESULTS: In five sheep, epicardial application of the BACE Device effectively reduced mitral regurgitation from Grade 4 to Grade 0, and the effect was sustained through six months despite ongoing pacing. Terminal studies at six months showed no adhesion to the silicone band. All five human subjects were male, NYHA Class III, with LVEF of 20-40%. Epicardial application and adjustment of the BACE Device was performed safely on a beating heart with effective reduction in FMR to grade <1. All five subjects had three bypass grafts. Reduction in MR was sustained for at least six months and there were no unanticipated or device-related adverse events. CONCLUSION: Epicardial application and adjustment of the BACE Device can be performed safely without CPB with effective reduction in MR. PMID- 21273122 TI - Trematode families and genera: have we found them all? AB - The proposal of new trematode families has almost stopped. Many new genera are still being proposed, but the number has fallen below historical rates. For most of the history of description of trematodes there have been more genera known from tetrapods than from fishes, but this pattern has reversed recently. These reductions are argued to be more of a reflection of the law of diminishing returns than diminution of effort. Thus, at the family level the classification of trematodes is becoming mature, and at the genus level we are seeing the 'beginning of the end' of the discovery of diversity. However, work for generations of scientists remains in other aspects of trematode biodiversity research, especially in life cycles, phylogeny and biogeography. PMID- 21273123 TI - Atomic force microscopy: a tool to analyze the structural organization of pathogenic protozoa. AB - The fine structure of parasitic protozoa has been the subject of intense investigation with the use of electron microscopy. The recent development of atomic force microscopy (AFM) and all of the techniques associated with AFM has created new ways to further analyze the structure of cells. In this review, the various, presently-available modalities of AFM are discussed, as well as the results obtained in analysis of: (i) the structure of intact and detergent extracted protozoa; (ii) the surface of infected cells; (iii) the structure of parasite macromolecules; (iv) the measurement of surface potential; and (v) force spectroscopy, the measurement of elasticity and ligand-receptor interactions. PMID- 21273124 TI - Live birth after transfer of a twice-vitrified warmed blastocyst that had undergone trophectoderm biopsy. AB - A 28-year-old patient presented for preimplantation genetic screening (PGS) for family balancing utilizing previously vitrified blastocysts and day-2 embryos. To synchronize endometrial development with the embryos to be transferred, five embryos vitrified on day 2 were warmed 3 days prior to scheduled transfer. Three of them developed to 8-, 8- and 7-cell stages, respectively, and were biopsied the next day, during which three vitrified blastocysts were warmed and the two surviving blastocysts underwent trophectoderm biopsy. The five biopsied embryos were subjected to two-probe fluorescence in-situ hybridization for chromosomes X and Y. As there were still 2 days before the scheduled embryo transfer following biopsy, the two biopsied blastocysts were re-vitrified. One blastocyst and two of the embryos vitrified on day 2 were normal for sex chromosomes; of these, one of the day-2 vitrified embryos was arrested and the other did not favour the patient's wish. The re-vitrified blastocyst, which was normal for sex chromosomes, was therefore warmed and transferred, resulting in delivery of one healthy boy. As far as is known, this is the first-reported live birth developed from a re-vitrified blastocyst that had been previously vitrified, warmed and undergone trophectoderm biopsy. PMID- 21273125 TI - New candidate gene POU5F1 associated with premature ovarian failure in Chinese patients. AB - Premature ovarian failure (POF) is defined as a cessation of ovarian function in women before the age of 40 years. POU5F1 has a critical role in regulating pluripotency in embryonic development and POU5F1 transcription factor is down regulated more than 30-fold in the POF candidate gene Nobox knockout ovaries. In order to identify the potential correlation between POU5F1 and the development of POF, the exon regions of POU5F1 were amplified and sequenced in 115 POF patients and 149 healthy controls. One non-synonymous variant of POU5F1 (c. C37A, p. Pro13Thr) was identified and confirmed in one of the POF patients. The substitution replacing a hydrophobic amino acid, proline, with a hydrophilic amino acid, threonine. As far as is known, the present study is the first to identify a potential association between POU5F1 and the development of POF. PMID- 21273126 TI - Progesterone rise on HCG day in GnRH antagonist/rFSH stimulated cycles affects endometrial gene expression. AB - Premature progesterone rise during gonadotrophin-releasing hormone (GnRH) antagonist cycles for IVF is a frequent phenomenon and has been associated with lower pregnancy and implantation rates. This study evaluated endometrial gene expression on the day of oocyte retrieval according to the concentration of serum progesterone on the day of human chorionic gonadotrophin (HCG) administration in GnRH-antagonist/recombinant FSH IVF cycles with fresh embryo transfer. Endometrial biopsies (n=14) were analysed with Affymetrix HG U133 Plus 2.0 Arrays. Patients were divided into three groups according to their progesterone serum concentration on the day of HCG administration: <= 0.9 ng/ml (group A), 1 1.5 ng/ml (group B) and >1.5 ng/ml (group C). Gene expression analysis showed a small number of significantly differentially expressed probe sets between groups A and B (five up/23 down in B) and a large difference between groups B and C (607 up/212 down; P <= 0.05, fold change >= 1.4). Validation was performed with quantitative real-time PCR on selected genes. As far as is known, this is the first study to demonstrate a distinct difference in endometrial gene expression profile between patients with a progesterone serum concentration above and below the threshold of 1.5 ng/ml on the day of HCG administration. PMID- 21273127 TI - Effect of bisphenol A on human endometrial stromal fibroblasts in vitro. AB - This study evaluated the effects of bisphenol A (BPA) on human endometrial stromal fibroblast (ESF) differentiation and expression of genes involved in oestrogen metabolism. Human ESF from eight hysterectomy specimens were cultured and treated with 5-100 MUmol/l of BPA +/- oestradiol or 8-br-cAMP for 48 h. mRNA expression was analysed by real-time reverse-transcription PCR. 8-br-cAMP-induced human ESF decidualization was confirmed by expression of insulin-like growth factor binding protein-1 (IGFBP1) and prolactin secretion. Short-term exposure (48 h) decreased human ESF proliferation (P<0.04) not due to apoptosis. High doses of BPA significantly induced IGFBP1 mRNA and protein, decreased P450scc mRNA, reversed the 8-br-cAMP-induced increase in HSD17B2 (oestradiol to oestrone conversion) in a dose-dependent manner and down-regulated HSD17B1 expression (oestrone to oestradiol conversion; P <= 0.03). 8-br-cAMP significantly potentiated this effect (P=0.028). BPA had no significant effect on aromatase and PPAR gamma expression. The oestrogen-receptor antagonist ICI had no effect on gene expression in BPA-treated cells, and oestrogen receptor alpha, but not oestrogen receptor beta, was significantly down-regulated by high doses of BPA (P=0.028). BPA has an endocrine-disrupting effect on human ESF function and gene expression but the underlying mechanisms appear not to involve oestrogen-mediated pathways. PMID- 21273128 TI - Depot GnRH-agonist trigger for breast-cancer patient undergoing ovarian stimulation resulted in mature oocytes for cryopreservation: a case report. AB - This report describes the case of a 27-year-old woman with breast cancer who underwent ovarian stimulation for fertility preservation with recombinant FSH in conjunction with a gonadotrophin-releasing hormone (GnRH) antagonist and an aromatase inhibitor from the beginning of the treatment. A 3.75-mg triptorelin depot formulation was given intramuscularly when the follicular diameter of three follicles reached >= 20 mm and a total of 13 follicles reached >= 15 mm. Oocyte retrieval was scheduled for 36 h later and 10 mature oocytes were collected and vitrified. This case report demonstrates that a depot GnRH-agonist trigger effectively leads to mature oocyte retrieval, with the advantage of initiating ovarian suppression for the purpose of fertility preservation during adjuvant chemotherapy in breast-cancer patients. PMID- 21273129 TI - Fixing oocytes? A bovine model provides new hope. AB - In a previous issue of Reproductive BioMedicine Online, Chiaratti and co-workers presented a bovine model for ooplasmic transfer, which demonstrated a positive effect on early development. Developmental deficits resulting from artificial treatment of recipient eggs with a toxic compound were ameliorated by the addition of small volumes of healthy donor cytoplasm. This model provides an important advance in the understanding of ooplasmic effects in early development and addresses issues about the prior human trials in this area. PMID- 21273130 TI - Coverage of malaria protection in pregnant women in sub-Saharan Africa: a synthesis and analysis of national survey data. AB - BACKGROUND: Insecticide-treated nets and intermittent preventive treatment with sulfadoxine-pyrimethamine are recommended for the control of malaria during pregnancy in endemic areas in Africa, but there has been no analysis of coverage data at a subnational level. We aimed to synthesise data from national surveys about these interventions, accounting for disparities in malaria risk within national borders. METHODS: We extracted data for specific strategies for malaria control in pregnant women from national malaria policies from endemic countries in Africa. We identified the most recent national household cluster-sample surveys recording intermittent preventive treatment with sulfadoxine pyrimethamine and use of insecticide-treated nets. We reconciled data to subnational administrative units to construct a model to estimate the number of pregnant women covered by a recommended intervention in 2007. FINDINGS: 45 (96%) of 47 countries surveyed had a policy for distribution of insecticide-treated nets for pregnant women; estimated coverage in 2007 was 4.7 million (17%) of 27.7 million pregnancies at risk of malaria in 32 countries with data. 39 (83%) of 47 countries surveyed had an intermittent preventive treatment policy; in 2007, an estimated 6.4 million (25%) of 25.6 million pregnant women received at least one dose of treatment and 19.8 million (77%) visited an antenatal clinic (31 countries). Estimated coverage was lowest in areas of high-intensity transmission of malaria. INTERPRETATION: Despite success in a few countries, coverage of insecticide-treated nets and intermittent preventive treatment in pregnant African women is inadequate; increased efforts towards scale-up are needed. FUNDING: The Malaria in Pregnancy Consortium and Wellcome Trust. PMID- 21273131 TI - Malaria control in pregnancy: still a long way to go. PMID- 21273132 TI - Can a community-based intervention improve the home food environment? parental perspectives of the influence of the delicious and nutritious garden. AB - OBJECTIVE: To examine changes in parental report of the home food environment during the course of a garden-based fruit and vegetable (FV) intervention for grade school children. METHODS: Self-administered pre-post surveys were completed by parents/caregivers (n = 83). Main outcome measures included: child asking behavior, FV availability/accessibility, parental encouragement, and value of FV consumption. RESULTS: Process evaluation results indicate children shared their garden experiences at home, and as a result, the children's home food environment became increasingly supportive of FV consumption. Parents reported an increase (P < .01) in the frequency that their child asked for FVs. Parental value for FV consumption also improved (P < .01), as did home availability of fruit (P < .05), vegetables (P < .001), and parental encouragement of FVs (P = .06). CONCLUSIONS AND IMPLICATIONS: Community-based interventions that provide activities to engage parents may provide added benefit by improving the home food environment. PMID- 21273133 TI - Evaluation of 131I-anti-MIF mAb as a reporter for allograft rejection. AB - Finding a specific agent will be useful for monitoring allorejection in clinic. The macrophage migration inhibitory factor (MIF) was reported to be one of the major cytokines involved in allorejection. In this study, we evaluated whether (131)I-anti-MIF mAb could be an efficient imaging reporter for monitoring allorejection. (131)I-anti-MIF mAb or control (131)I-IgG was injected to skin allotransplantation mice and T/NT ratios were evaluated. The imaging changes of grafts were dynamically displayed by whole-body images. The results showed that up-regulation of MIF expression was found in allografts but not in isografts. During the whole progression of rejection, the T/NT ratio in the (131)I-anti-MIF mAb group was significantly higher than that in the (131)I-IgG group and markedly increased on the top of rejection. The graft-rejection could also be shown more clearly in the (131)I-anti-MIF mAb group by whole-body imaging. These results implied that (131)I-anti-MIF mAb may be a valid method for facilitating the development of protocols to monitor allorejection. PMID- 21273135 TI - Managing epilepsy well: self-management needs assessment. AB - Epilepsy self-management interventions have been investigated with respect to health care needs, medical adherence, depression, anxiety, employment, and sleep problems. Studies have been limited in terms of representative samples and inconsistent or restricted findings. The direct needs assessment of patients with epilepsy as a basis for program design has not been well used as an approach to improving program participation and outcomes. This study investigated the perceived medical and psychosocial problems of adults with epilepsy, as well as their preferences for self-management program design and delivery format. Results indicated a more psychosocially challenged subgroup of individuals with significant depressive and cognitive complaints. A self-management program that involves face-to-face individual or group meetings led by an epilepsy professional and trained peer leader for 60 minutes weekly was preferred. Six to eight sessions focused on diverse education sessions (e.g., managing disability and medical care, socializing on a budget, and leading a healthy lifestyle) and emotional coping strategies delivered on weeknights or Saturday afternoons were most highly endorsed. Emotional self-management and cognitive compensatory strategies require special emphasis given the challenges of a large subgroup. PMID- 21273134 TI - The effects of left or right hemispheric epilepsy on language networks investigated with semantic decision fMRI task and independent component analysis. AB - Chronic and progressive brain injury, as seen in epilepsy, may alter brain networks that underlie cognitive functions. To evaluate the effect of epilepsy on language functions we investigated the neuroanatomical basis of semantic processing in patients with left (LHE) or right (RHE) hemispheric onset epilepsy using semantic decision fMRI paradigm and group independent component analysis (ICA); we then compared the results of our investigations with language networks in healthy subjects examined with the same language task (Kim K, Karunanayaka P, Privitera M, Holland S, Szaflarski J. Semantic association investigated with fMRI and independent component analysis. In press). Group ICA is a data-driven technique capable of revealing the functional organization of the human brain based on fMRI data. In addition to providing functional connectivity information, ICA can also provide information about the temporal dynamics of underlying networks subserving specific cognitive functions. In this study, we implemented two complementary analyses to investigate group differences in underlying network dynamics based on associated independent component (IC) time courses (a priori defined criterion or a posteriori identified maximum likelihood descriptor). We detected several differences between healthy controls and patients with epilepsy not previously observed with standard fMRI analysis methods. Our analyses confirmed the presence of different effects of LHE or RHE on the behavior of the language network. In particular, a major difference was noted in the nodes subserving verbal encoding and retrieval in the bilateral medial temporal regions. These effects were dependent on the side of the epilepsy onset; that is, effects were different with left or right hemispheric epilepsy. These findings may explain the differences in verbal and nonverbal memory abilities between patients with left and those with right hemispheric epilepsy. Further, although the effects on other nodes of the network were more subtle, several deviations from normal network function were observed in patients with LHE (e.g., alterations in the functions of the primarily left frontotemporal network module) or in patients with RHE (e.g., differences in the medial retrosplenial module responsible for mental imagery or in the anterior cingulate module subserving attention control). These findings not only highlight the negative effects of epilepsy on the main left hemispheric language network nodes in patients with LHE, but also document the effects of epilepsy on other language network nodes whether exerted by LHE or RHE. Further, these results document the advantages of using group ICA for investigating the effects of disease state (e.g., epilepsy) on the network subserving cognitive processing and provide an interesting avenue for further exploration. PMID- 21273136 TI - Transient epileptic amnesia in a memory clinic setting: a report of three cases. AB - Transient epileptic amnesia (TEA) is a recently described, typically misdiagnosed at presentation, distinctive syndrome, characterized by recurrent, brief attacks of memory loss in middle-aged or elderly people, accompanied by significant interictal memory difficulties. We describe the clinical, neuroimaging, electrophysiological, and neuropsychological characteristics of three patients fulfilling the proposed criteria for TEA, initially referred to our memory clinic for evaluation and treatment of probable dementia. Neuropsychological performance on admission and 6 months after treatment demonstrated a broad range of performance on measures of executive function, lower than expected visuospatial perception, and poor autobiographical memory. TEA should be included in the differential diagnosis of dementia to avoid misdiagnosis and needless medication. It is a benign and treatable condition, yet the associated decline in autobiographical and remote memory despite antiepileptic therapy poses challenges for further research. PMID- 21273137 TI - Seizure semiology and aging. AB - The incidence of epilepsy is high in older individuals. However, epilepsy in the elderly may be underdiagnosed and undertreated because of diagnostic difficulties. The main goal of this study was to determine whether seizure semiology differs between older and younger adults with epilepsy in the outpatient setting. Fifty patients with focal epilepsy aged 55 years and older and 50 patients aged between 18 and 45 years were included. Review of medical records contained detailed seizure description. There were no differences in seizure semiology between groups, except that subtle perceptions of transient confusion were seen in older patients but not in younger patients (P=0.0028). Older patients had less generalized motor seizures, but the differences between groups did not reach significance (P=0.01). Older patients may present with subtle symptoms of seizures characterized by brief periods of confusion, which may contribute to greater difficulty diagnosing seizures in the elderly. PMID- 21273138 TI - Central auditory processing impairment in patients with temporal lobe epilepsy. AB - In temporal lobe epilepsy (TLE) there may be functional abnormalities or structural lesions that can manifest as a central auditory processing disorder, which is defined as a disorder in the recognition, discrimination, ordering, grouping, and localization of sounds, with emphasis on the processing of nonspeech sounds. We performed frequency pattern, duration pattern, and dichotic tests in 28 patients with TLE with normal hearing on pure tone audiometry. The scores on the frequency pattern, duration pattern, and dichotic tests were abnormal in 78.6, 57.1, and 20.6% of patients, respectively, with no significant differences with the laterality of TLE. Patients with hippocampal sclerosis performed significantly worse than patients with normal MRI findings in frequency tests. Longer duration of epilepsy is negatively correlated with both the duration pattern and dichotic tests (P<0.05). Our results suggest that patients with TLE may be at risk for impairment of central auditory processing, which is increased in patients with hippocampal sclerosis or a longer duration of epilepsy. PMID- 21273139 TI - Identifying epilepsy surgery candidates in the outpatient clinic. AB - Epilepsy is the most prevalent disabling neurological disorder across the life span, and is not controlled by medications in more than one-third of patients. Epilepsy surgery is an accepted treatment, with guidelines supporting utilization in patients with recurrent temporal lobe seizures after two or more trials of antiepileptic medications. Unfortunately, the average delay in presurgical evaluation of appropriate candidates is more than 20 years, and this delay has not improved in recent decades. This offers the international neurological community the opportunity to improve disability, mortality, and quality of life by more effective application of epilepsy surgery and earlier identification of potential candidates. Optimal use of MRI and video/EEG monitoring should allow cost-effective screening of persons with recurrent seizures prior to more detailed presurgical evaluation when indicated. PMID- 21273140 TI - Effect of bariatric surgery on normal and abnormal renal function. AB - BACKGROUND: Obesity has been associated with hypertension, diabetes mellitus, and metabolic syndrome, risk factors for chronic kidney disease. In addition, obesity has been found to have an independent, negative effect on renal function and the progression of renal insufficiency. METHODS: The serum creatinine (CR) in 813 patients who had undergone obesity surgery from 2003 to 2009 at a large academic medical center and had been followed up for >=24 months was retrospectively monitored. Renal function, as measured by the CR level, was assessed at baseline and at 6, 12, and >=24 months of follow-up. The groups were stratified by the baseline CR as follows: normal (CR <1.3 mg/dL), mild impairment (CR 1.3-1.6 mg/dL), and moderate impairment (CR >1.6 mg/dL). RESULTS: Of the 813 patients, 757 had a CR <1.3 mg/dL at baseline. Of those 757 patients, 97.6% had maintained a CR of <1.3 mg/dL, 1.3% had a CR of 1.3-1.6 mg/dL, 1.1% had a CR of >1.6 mg/dL (n = 757) at 6 months of follow-up. At 1 year of follow-up, 99% had maintained a CR of <1.3 mg/dL and 1% had a CR of >1.3% (n = 509). At 2 years of follow-up, 100% had a CR value of <1.3 mg/dL (n = 388). Of the remaining 56 patients, 71.4% had been classified as having mild impairment (CR 1.3-1.6 mg/dL) and 28.5% as having moderate impairment (CR >1.6 mg/dL) before weight loss surgery. Examination of the CR values at >=2 years after weight loss surgery demonstrated that 76.7% had a normal CR level, 12.5% had mild impairment, and 10.7% had moderate impairment. CONCLUSION: Bariatric surgery does not have a negative effect on renal function as measured by the CR, whether CR at baseline is <1.3 or >=1.3 mg/dL when monitored for >=24 months. For those with impaired renal function and a CR >=1.3 mg/dL, improvement in CR was seen in 76.7% at >=2 years postoperatively, at a point at which the weight loss velocity, hydration, and nutritional status have stabilized. The weight loss associated with bariatric surgery could potentially have a positive effect on renal function at >=24 months, such as was found in the present study by a stable or reduced CR level. The etiology for this might be a direct effect of weight loss on impaired renal function or an indirect effect by reducing the rates of co-morbidities, such as diabetes mellitus and hypertension, both risk factors for renal disease. Additional prospective studies, including weight-matched controls, are needed. PMID- 21273141 TI - Long-term follow-up of multivessel percutaneous coronary intervention with drug eluting stents for de novo lesions with correlation to the SYNTAX score. AB - BACKGROUND: Stent thrombosis (ST) and restenosis are concerns after percutaneous coronary intervention (PCI). Limited information exists concerning clinical and angiographic outcomes following multiple stent insertion. We therefore present the long-term outcome from drug-eluting stent (DES) insertion and correlate this with the Syntax score. METHODS AND RESULTS: Between April 2002 and 2006, all patients that underwent multilesion PCI (defined as >=4 DES) were included for analysis, and follow-up commenced from the point where the fourth stent was inserted. Three hundred and seventy-four patients were identified, comprising 1972 lesions; 99% had clinical (30+/-16 months), and 72% had angiographic follow up. The mean number of stents implanted was 5.7+/-1.9 and with length of 137+/-50 mm and Syntax Score of 24+/-8. The Syntax score (SS) did not predict major adverse cardiac events (MACE) at long-term follow-up, which occurred in 33% in the low SS (<22), 34% intermediate SS (22-32) and 40% in the high SS (>33); P=ns. However, the number of stents implanted correlated with events [MACE: 12% (4 DES), 35% (4-6 DES), 61% (>6 DES)]. There were 11 (2.9%) definite and probable ST: four acute and subacute, three late, and four very late. CONCLUSIONS: This study demonstrates an acceptable occurrence of myocardial infarction, death, repeat revascularisation, and ST in patients with multivessel de novo lesions, which had better correlation with the number of DES inserted than the Syntax score. PMID- 21273142 TI - Reliability using the universal classification of acute myocardial infarction compared to ST-segment classification. AB - OBJECTIVES: To study the inter-physician reliability using the universal classification (UC) of acute myocardial infarction (AMI) compared to the ST segment classification (STC). The UC is based on clinical, electrocardiographic (ECG), and pathophysiologic characteristics compared to the STC, which is mainly ECG based. METHODS: In this registry of consecutive patients with AMI presenting to a tertiary hospital, we studied the inter-physician reliability [weighted kappa (wK)] using the UC and the STC. Two physician investigators independently classified each patient with AMI according to the UC and STC, and a third senior physician investigator resolved any disagreement. RESULTS: The study included Type 1=226 (89.7%), Type 2=16 (6.3%), Type 3=3 (1.2%), Type 4a=1 (0.4%), Type 4b=4 (1.6%), Type 5=2 (0.8%), ST-segment-elevation AMI (STEMI)=140 (55.6%), and non-ST-segment-elevation AMI (NSTEMI)=112 (44.4%). Inter-physician reliability using the UC was very good (wK=0.84, 95% CI 0.68-0.99) and using the STC was good (wK=0.78, 95% CI 0.70-0.86). Of patients with Type 1 AMI, 57.1% were STEMI and 42.9% were NSTEMI. In contrast, of patients with Type 2 AMI, 18.8% were STEMI and 81.2% were NSTEMI. CONCLUSION: The UC is a reliable method to classify patients with AMI and performs better than the STC in this study. Validation of the two classifications should be performed in large prospective studies. PMID- 21273143 TI - A new stent design with multiple radio-opaque markers for protection of side branch vessels in bifurcation lesions: HJ stents. AB - BACKGROUND: Loss of side-branch vessels is a serious complication following stent implantation in parent vessels of bifurcation lesions. The purpose of this study was to introduce and test a new stent design for the protection of side-branch vessels in the management of bifurcation lesions. METHODS AND MATERIALS: This stent has multiple radio-opaque markers in its central portion, whose presence is useful in avoiding stent-strut placement across the side-branch orifice and in correctly directing the insertion of a second guide wire through the struts into the side branch to minimize jailing of side branches during stent deployment in the parent vessel. In vitro tests of the acrylic resin bifurcation phantom model were performed under fluoroscopic guidance in the catheterization laboratory with 10 stents with multiple radio-opaque markers and 10 stents without. Kissing balloon angioplasty was performed across the side branch after stent implantation in the parent vessel in both groups. Side-branch jailing by the stent (presence of any stent struts crossing the side-branch orifice) was determined visually and compared between the two groups. RESULTS: The jailed side branch with the stent struts was observed in one of 10 new stents and in five of 10 conventional stents without them. CONCLUSIONS: The in vitro tests demonstrated the superiority of a new stent design for the reduction of side-branch jailing in bifurcation lesions. PMID- 21273144 TI - Kissing inflation is feasible with all second-generation drug-eluting balloons. AB - OBJECTIVE: To assess the feasibility of kissing second-generation drug-eluting balloons (DEB), which have better mechanical properties than the first-generation DEB, in order to optimize provisional bare-metal stenting (BMS) when treating coronary bifurcation lesions in patients with contraindication to drug-eluting stents. METHODS: Consecutive patients with anticipated low compliance to dual antiplatelet therapy who are undergoing provisional stenting with an open-cell design BMS and final kissing balloon with second-generation DEB were enrolled in this feasibility study. Angiographic success and procedural success (i.e., angiographic success in absence of in hospital major cardiovascular events) were registered. Clinical follow-up was also attempted in all patients. RESULTS: A total of 14 patients (mean age 66+/-9 years, nine men) participated on the study. The DEB used were SeQuent Please (B. Braun Melsungen, Berlin, Germany) in six patients, In.Pact Falcon (Medtronic Invatec, Roncadelle, Italy) in four patients, New Dior (Eurocor, Bonn, Germany) in two patients and Pantera Lux (Biotronik, Berlin, Germany) in another two patients. All procedures, but one, were performed by transradial access through a 6-French high-flow guiding catheter. True bifurcation was present in 50% of the patients. Angiographic and procedural success was obtained in all patients. At a mean follow-up of 234+/-81 days, all contacted patients were asymptomatic and free from major adverse cardiac events (including cardiac death, nonfatal myocardial infarction and target bifurcation revascularization). CONCLUSION: At the advent of dedicated bifurcation stents, kissing DEB appears safe and effective and can be used to implement innovative, simpler, safer and possibly more effective bifurcation techniques. These remarkable results have laid the ground for an ongoing prospective registry of the kissing DEB technique (KISSING DEBBIE study, ClinicalTrials.gov NCT01009996). PMID- 21273145 TI - Accelerated coronary atherosclerosis after execution of percutaneous coronary intervention in patient with HIV/HCV coinfection: case report and review of the literature. AB - Highly active antiretroviral therapy has greatly reduced AIDS-related morbidity and mortality; however, its widespread use has been associated with a marked rise in the frequency of cardiovascular diseases in patients with HIV. Moreover, HIV infection is associated with accelerated coronary atherosclerosis and vasculopathy, although the mechanisms underlying these findings have not been determined. We describe the case of a 45-year-old woman with HIV/HCV coinfection, irritable bowel syndrome, and accelerated progression of coronary atherosclerosis after execution of percutaneous coronary intervention (PCI). In this case, the rapidity of progression of atherosclerosis seems linked principally to chronic inflammation and excess immune activation that can depend by a concourse of factors (chronic C hepatitis, irritable bowel syndrome, PCI execution) not directly associated with traditional risk factors. Caregivers following HIV infected patients should be aware of the increased risk of accelerated atherogenesis in these subjects, principally in case of presence of causes of intense immune activation. PMID- 21273146 TI - Beneficial effect of ischemic preconditioning on post-infarction left ventricular remodeling and global left ventricular function. AB - BACKGROUND: Preinfarction angina (PA) is a clinical analogue of ischemic preconditioning that improves postinfarct prognosis. Data concerning the association of PA with post infarction left ventricular (LV) remodeling and LV diastolic function are limited. We aimed to evaluate this association in patients with acute myocardial infarction (AMI) in the modern clinical era of widespread use of revascularization and antiremodeling medical treatment. METHODS: We studied 53 patients with anterior AMI who underwent complete reperfusion and received up to date antiremodeling medical treatment. LV remodeling, systolic and diastolic function were assessed using 2D echocardiography at baseline and 6 at months follow-up. Patients were divided into two groups regarding the presence or absence of PA. RESULTS: LV remodeling at follow-up was less frequent in the PA group (25 vs. 55 %, P<.05). Patients with PA had lower end-systolic volume index at baseline and follow up (24.1+/-6 vs. 30.1+/-14 ml/m(2), P<.001 and 25.3+/-8 vs. 35.6+/-2 ml/m(2), P=.001 respectively). Additionally at 6 months, they had better LV ejection fraction (52.1+/-9 vs. 42.9+/-10 %, P=.002) and exhibited improved diastolic filling as reflected by mitral E/e' (14.6+/-5 vs. 18.8+/-8, P=.05). CONCLUSIONS: Ischemic preconditioning in the form of PA promotes better LV systolic and diastolic function in the mid-term and is associated with less postinfarct LV remodeling in this specific study population. The results of the study underline the possible need for further risk stratification of AMI patients regarding the absence of PA. PMID- 21273147 TI - Bifurcation stenting: the current state of play. PMID- 21273148 TI - In-hospital outcomes and cost comparison of femoropopliteal reopening strategies. AB - PURPOSE: Atherectomy has emerged as an alternative to percutaneous transluminal angioplasty (PTA) for endovascular reopening. Despite increasing use of atherectomy (and higher cost of atherectomy catheters compared with balloon catheters), few studies have compared outcomes and costs with other reopening strategies. METHODS: We performed a retrospective cohort study involving all patients undergoing isolated femoropopliteal PTA (n=69) or atherectomy (n=92) at our institution from 1/2005 to 4/2006. The choice of reopening strategy was left to the treating physician, and no patients with relative contraindications to stent placement (specifically common femoral artery lesions) were included. Device and supply costs were calculated using the hospital resource-based accounting system, and other costs were calculated using the hospital micro-cost accounting system. Professional fees were calculated from the Medicare Fee Schedule. RESULTS: Baseline characteristics were generally well matched. There were no significant differences in complications (vascular complications, urgent repeat reopening, death, myocardial infarction, or stroke) between groups (PTA 8.7% vs. atherectomy 5.4%, P=.53). PTA required more balloons (2.0+/-0.8 vs. 0.7+/-1.0, P<.001) and stents (1.5+/-0.8 vs. 0.2+/-0.5, P<.001), but fewer atherectomy catheters (0.0+/-0.0 vs. 1.2+/-0.4, P<.001). Neither procedural supply costs (PTA $3137+/-1459 vs. atherectomy $3338+/-1505, P=.20) nor total costs differed between PTA and atherectomy patients ($10,945+/-4521 vs. $10,783+/ 3857, P=.42). CONCLUSIONS: Initial outcomes and costs are comparable for femoropopliteal PTA and atherectomy. The choice of reopening strategy should therefore be based on operator experience and anatomic suitability. Further studies are required to determine whether there are differences in long-term outcomes or costs between these approaches. PMID- 21273149 TI - [Immunosuppressive treatments: mechanisms of action and clinical use]. AB - Renal transplantation is the treatment of choice of end stage renal failure. It both improves the quality and the quantity of life compared to other techniques, such as hemodialysis. These results are partly related to the use of immunosuppressive therapy more effective and whose handling has improved over time. Advances in understanding the mechanisms of lymphocyte activation and the phenomena of rejection have in fact better defined the use of these treatments and their associations. Treatments can be broadly classified according to their characteristics (biological or chemical). Among chemical treatments, steroids are widely used, although the question of their avoidance or spearing is still a matter of debate. The cornerstone of immunosuppressive regimens remains the calcineurin inhibitors, characterized by a narrow therapeutic index and the need for therapeutic drug monitoring. Inhibitors of mammalian target of rapamycin (mTOR) have interesting antiproliferative effects that could be important against chronic allograft dysfunction and/or carcinogenesis. However, their safety profile makes them difficult to handle. Inhibitors of purine synthesis are largely based on inhibitors of inosine monophosphate dehydrogenase (IMPDH). Their effectiveness makes them privileged partners of other therapeutic classes. Among biological treatments, it is possible to separate the depleting and non depleting antibodies. Among the former, antithymocyte globulins are mainly active in T cells, whereas rituximab, a monoclonal anti-CD20, is active in B cells involved in the phenomena of humoral rejection. The non depleting antibodies are represented by anti-CD25, directed against the receptor for interleukin-2. In the near future it is likely that the belatacept, a costimulation blockade fusion protein will be used to allow calcineurin inhibitors sparing. Other immunosuppressive agents, acting at different levels of the immune response are being evaluated. In addition, advances in pharmacology offered hope of a better individualization of immunosuppressive therapies and better definition of therapeutic strategies used. PMID- 21273150 TI - [Phosphocalcic metabolism: regulation and explorations]. AB - Calcium and phosphate play a key role in bone mineralization but have also many other physiological functions. The control of serum phosphate concentration is mandatory to avoid the occurrence of severe metabolic disorders, but is less tightly regulated than serum ionized calcium concentration, which is maintained in a very limited range thanks to parathyroid hormone (PTH) and the active vitamin D metabolite calcitriol. Any change in serum ionized calcium concentration is detected by the calcium sensing receptor (CaSR), a membranous protein located principally in the parathyroid glands and the kidney. A decrease in ionized calcium level inactivates the CaSR, thus stimulating PTH secretion. PTH in turn stimulates the release of calcium and phosphate from bone, renal calcium reabsorption and calcium and phosphate intestinal absorption by inducing renal calcitriol production. Moreover, PTH inhibits phosphate reabsorption in proximal tubular cells, thus contributing towards phosphate homeostasis. Fibroblast growth factor 23 (FGF23) is a circulating factor that decreases serum levels of inorganic phosphate by inhibiting renal phosphate reabsorption and calcitriol production and may have a great physiological role in phosphate homeostasis. Recently, vitamin D actions independent of calcium and phosphate homeostasis were discovered. Basal exploration of phosphocalcic metabolism abnormalities consists in measurement of serum calcium (ionized calcium if possible), phosphate, 25-hydroxy vitamine D and PTH and of 24 hours urinary calcium excretion as well as renal function. Hence, the understanding of physiopathological mechanisms has been improved by newly identified genetic disorders responsible for phophocalcic homeostasis disturbances. PMID- 21273151 TI - [The role of psychological interventions in dialysis: an exploratory study]. AB - Patients suffering from end-stage renal disease (ESRD) have a very reduced quality of life accompanied by a severe emotional distress (high worries-anxiety depression). However, in Belgium, no regular psychological intervention is proposed to dialyzed patients. Our objective is to show that psychological intervention can significantly decrease the emotional distress of patients with ESRD. Eleven sessions of structured interventions are proposed to ESRD patients. Eligibility criteria are to be major, to not present confusion or/and dementia, to have been on dialysis treatment for at least 3months, to have obtained 14 or more on HAD-scale. Interventions carry on the management of anxious and depressive symptoms and of the disease itself. This constitutes three independent modules. Questionnaires are filled in by the patients at various stages to evaluate the anxiety and the depression (HADS), the worries (Penn State) and the quality of life (KDQoL-SF). Results for the 47 ESRD patients show a significant reduction of the scores of anxiety, depression and worries and a significant growth of quality of life. In parallel, a decrease in the serum calcium phosphorus product analyzed before dialysis has been noted. PMID- 21273152 TI - Addressing the midwifery workforce crisis: evaluating an employment model for undergraduate midwifery students at a tertiary maternity hospital in Melbourne, Australia. AB - BACKGROUND AND AIMS: In Victoria, maternity services are under significant strain due to increased numbers of women giving birth and critical workforce shortages. Hospitals have experienced challenges in adequately staffing maternity units, particularly on postnatal wards. In 2008, a tertiary maternity hospital in Melbourne introduced a model where undergraduate midwifery students were employed as Division 2 nurses (SMW_Div2) (enrolled nurses), to work in the postnatal area only. This study explored the pilot employment model from the perspective of the SMW_Div2 and hospital midwives. METHODS: A web-based survey was administered to hospital midwives and the SMW_Div2s in the employment model in January 2010. The survey explored the views of midwives and SMW_Div2s regarding the perceived impact of the model on workforce readiness, recruitment and retention, and clinical competence and confidence. FINDINGS: Forty-seven of 158 midwives (30%) and five of nine SMW_Div2s employed in the model responded to the survey. Both groups considered the model to have benefits for the organisation, including increased: student workforce readiness; clinical confidence and competence; and organisational loyalty. Both groups also considered that the model would facilitate: workforce recruitment; a teaching and learning culture within the organisation; and enhanced partnerships between students, hospitals and universities. Caution was expressed regarding workload and the need for ongoing support for SMW_Div2s working in the model. DISCUSSION AND CONCLUSION: SMW_Div2s and midwives were positive about the introduction of the paid employment model at the Women's. The findings are consistent with evaluations of similar programs in the nursing setting. The employment model has potential short and long term individual and organisational advantages, which is important in the context of increasing births and workforce shortages. Progression of such models will be contingent on the collaboration and cooperation of the various stakeholders involved in maternity workforce and education. PMID- 21273153 TI - Allele frequencies of nine non-CODIS STR loci in Chinese Uyghur ethnic minority group. PMID- 21273154 TI - Survivor of a traumatic atlanto-occipital dislocation. AB - Atlanto-occipital dislocation is a devastating ligamentous injury that most often turns fatal. However, because of on-site resuscitation improvements, the emergency teams are increasingly dealing with this condition. We report a rare case of atlanto-occipital dislocation (AOD) in a surviving patient with more than one-year follow-up. The mechanism of injury appears to be an extreme hyperextension applied to the head. This injury occurs more frequently in children since they are anatomically predisposed (flat articulation between the occiput and the atlas, increased ligamentous laxity). The diagnosis should be suggested by severe neurological injury after high trauma but also post-traumatic cardiorespiratory deficit. There have been reports of atlanto-occipital dilocations without neurologic impairment. A radiographic examination must be performed and lateral cervical radiographs should be acquired. However, additional imaging with CT or MRI may be required to aid diagnosis of AOD in cases in which radiographic findings are equivocal. Once the diagnosis of AOD has been confirmed, an anatomical classification should be made according to the magnitude of displacement. Fatal lesions are of neurological and vascular origin and some authors advocate the systematic use of angiography. Consensus regarding the management of AOD in adults has been achieved. Occipito-cervical arthrodesis is the recommended treatment option. We advocate a two-stage surgery: the patient is initially fitted with a halo vest then occipitocervical fusion is performed. Surgical treatment should be combined with cardiorespiratory management. The emergency teams should get familiar with this injury since they will be increasingly confronted to it. Early recognition and standard appropriate management is essential to avoid delayed treatment and complications. PMID- 21273155 TI - Open and subcutaneous recent tibialis anterior tendon ruptures: does postoperative immobilization method influence outcome? AB - We report on seven traumatic lesions of the tibialis anterior tendon (one subcutaneous rupture and six open tears) in seven injured patients of mean age 45 years [17-79] all managed by direct suture and immobilization either using a cast boot (four cases) or a lower leg external fixator (three cases). After a mean follow-up of 31 months (6-50), external fixation achieved favourable clinical results with no specific complication. External fixation improves the conditions for suture efficiency, provides full immobilization and facilitates wound care in patients at a high risk of developing cutaneous complications. In accordance with data published in the literature, immobilization by means of a windowed cast boot achieved satisfactory results in patients with no risk factors. This method compatible with early mobilization avoids placement of a posterior splint which could induce slackening and weakening of tendon repair. LEVEL OF EVIDENCE: Retrospective study (Level IV). PMID- 21273156 TI - Treatment of recurrent THR dislocation using of a cementless dual-mobility cup: a 59 cases series with a mean 8 years' follow-up. AB - INTRODUCTION: Instability is one of the most feared complications following total hip replacement (THR). In France, dual-mobility cups are widely used in acetabular revision for instability; few studies, however, have focused on this type of implant. HYPOTHESIS: The gain in stability provided by the dual-mobility implant allows the risk of dislocation to decrease by the sole revision of the acetabular component in case of recurrent instability. OBJECTIVES: This hypothesis was tested over medium-term follow-up of a series of cementless dual mobility cups implanted during isolated acetabular revision for recurrent dislocation. PATIENTS AND METHODS: A series of THR revision for instability was analyzed retrospectively. Inclusion criteria were: recurrent THR dislocation treated by cementless dual-mobility cup, between 1995 and 2001. Radiological analysis used ImagikaTM software. Fifty-nine patients were included; nine died before radioclinical follow-up could be performed; none of the survivors were lost to follow-up. Mean follow-up was 8 years (range, 6-11 years). RESULTS: There was one early dislocation without recurrence; the dislocation rate was 1.7%. At follow-up, mean PMA score was 16.5 (12-18) and mean Harris score 86.7 (49-99). Radiologically, there was no loosening or migration, but 19% of X-ray views showed less than 1mm wide peri-acetabular radiolucency. With dislocation as censoring criterion, 8-year survivorship was 98% (95% CI: 95-100%). DISCUSSION: The dislocation rate (1.7%) and clinical results were better than in most series of revision by constrained cup for recurrent dislocation. The high rate of peri acetabular radiolucency would seem to relate to the external coating of the cup: aluminum oxide in the Novae-1 implant and aluminum oxide/hydroxyapatite in the Novae-E. CONCLUSION: The use of dual-mobility cups to treat THR instability gave satisfactory results. We recommend dual-mobility cups with hydroxyapatite surface treatment over a porous metallic substrate, rather than with an aluminum oxide or an aluminum oxide/hydroxyapatite bilayer coating. LEVEL OF EVIDENCE: Level IV. Retrospective Study. PMID- 21273157 TI - Descriptive characteristics of a colon disease family registry at an urban hospital. AB - BACKGROUND: Hospital registries are an important component of cancer screening efforts of individuals and communities. This paper describes the structure and goals of a Colon Disease Family Registry at a metropolitan hospital. Patient characteristics, differences between gastrointestinal diseases among probands, subjective distress in relation to perception of colorectal cancer, and quality of life were examined. METHODS: Participants were patients with colorectal cancer (CRC), familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal carcinoma (HNPCC) and inflammatory bowel disease ulcerative colitis (UC) and Crohn's disease representing a range of colonic diseases. A total of 630 probands were recruited into the registry and administered a questionnaire. RESULTS: Of the 630 probands, 198 (31.4%) were diagnosed with CRC, 36 (5.3%) with FAP or HNPCC and 272 (43.2%) with UC or Crohn's. The majority of all three groups had some level of college education, was white, and reported a household income greater then $70,000. The Impact of Event Scale score was found to be of notable significance when categorized by relation to proband (p<0.01) and proband diagnoses (p <= 0.000). On the quality of life item, the largest difference was between FAP or HNPCC and UC or Crohn's without CRC. CONCLUSION: Subjective distress scores were higher for CRC probands in comparison to probands with other colorectal diseases. Quality of life was relatively high for all probands. Psychological distress should be explored in more depth and more frequently to screen for any concomitant psychiatric disorders like post-traumatic symptoms that have been linked to a cancer diagnosis. PMID- 21273158 TI - BMI and lifestyle changes as correlates to changes in self-reported diagnosis of hypertension among older Chinese adults. AB - Nutrition transition theory attributes increased prevalence of high blood pressure to excess body weight associated with lifestyle changes in recent decades. We examined the association of changes in self-reported hypertension diagnoses with changes in body mass index (BMI), health-related behaviors, health status, and social risk factors among older Chinese adults from 1997 to 2006. Data from the longitudinal China Health and Nutrition Survey (CHNS) were analyzed for adults who were age 60 years and older, had a BMI exceeding 18.6 kg/m(2), and reported no diagnosis of hypertension at baseline (n = 1928). Logistic regression models identified factors contributing to staying nonhypertensive or developing hypertension over time. Approximately 17.8% (n = 324) of study participants developed self-reported hypertension, whereas 83.2% (n = 1604) remained without hypertension. Those who stayed overweight or obese or became overweight or obese were more likely to report a new hypertension diagnosis. Incident diagnoses were also observed among those who developed acute conditions, sustained memory loss, or increased their income, whereas remaining nonhypertensive was more likely among rural residents and those who became more physically active and quit drinking alcohol. Study findings provided partial support for the nutrition transition theory whereby changing demographics and lifestyle factors were associated with increases in incident hypertension. PMID- 21273163 TI - Health education issues, problems, methodologies, assessment and evaluation. PMID- 21273162 TI - Impacts of climate change on public health in India: future research directions. AB - BACKGROUND: Climate change and associated increases in climate variability will likely further exacerbate global health disparities. More research is needed, particularly in developing countries, to accurately predict the anticipated impacts and inform effective interventions. OBJECTIVES: Building on the information presented at the 2009 Joint Indo-U.S. Workshop on Climate Change and Health in Goa, India, we reviewed relevant literature and data, addressed gaps in knowledge, and identified priorities and strategies for future research in India. DISCUSSION: The scope of the problem in India is enormous, based on the potential for climate change and variability to exacerbate endemic malaria, dengue, yellow fever, cholera, and chikungunya, as well as chronic diseases, particularly among the millions of people who already experience poor sanitation, pollution, malnutrition, and a shortage of drinking water. Ongoing efforts to study these risks were discussed but remain scant. A universal theme of the recommendations developed was the importance of improving the surveillance, monitoring, and integration of meteorological, environmental, geospatial, and health data while working in parallel to implement adaptation strategies. CONCLUSIONS: It will be critical for India to invest in improvements in information infrastructure that are innovative and that promote interdisciplinary collaborations while embarking on adaptation strategies. This will require unprecedented levels of collaboration across diverse institutions in India and abroad. The data can be used in research on the likely impacts of climate change on health that reflect India's diverse climates and populations. Local human and technical capacities for risk communication and promoting adaptive behavior must also be enhanced. PMID- 21273164 TI - Using vouchers to increase access to maternal healthcare in Bangladesh. AB - The maternal mortality ratio (322) is comparatively high in Bangladesh. The utilization of maternity care provided by trained professionals during and after delivery is alarmingly low, primarily due to lack of knowledge and money. The overall objective of this operations research project was to test the feasibility and effectiveness of introducing financial support (voucher scheme) for poor rural women to improve utilization of antenatal care (ANC), delivery and postnatal check-up (PNC) from trained service providers. A pretest-posttest design was utilized. A total of 436 women were interviewed before and 414 after the intervention to evaluate the impact of interventions. In-depth interviews were conducted with users and non-users of vouchers. Findings show that institutional deliveries have increased from 2% to 18%. Utilization of ANC from trained providers has increased from 42% to 89%. Similarly, utilization of PNC from trained providers has increased from 10% to 60%. PMID- 21273165 TI - HIV knowledge and stigmatization among adolescents in Yemeni schools. AB - The number of assessments on HIV knowledge and stigmatization among adolescents in Yemen is still very limited. This cross-sectional study aimed to have a better understanding on the level of knowledge on HIV transmission and prevention. Also, this study explored the level of stigma and discrimination among students toward people living with HIV (PLWH). The study sample consisted of 2,274 male and female students (mean age 16.6 years) randomly selected from 27 high schools in Aden, Yemen. The results revealed low levels of knowledge on major prevention measures, such as condoms, where only 49.4% knew that condoms could protect from HIV infection; and high levels of misconceptions on the modes of transmission. In addition, the study revealed a high level of stigma and discrimination toward people living with HIV. The results would serve as a baseline for implementing a school-based educational program on HIV/AIDS. PMID- 21273166 TI - Using the theory of planned behavior to predict safer sexual behavior by ghanaian immigrants in a large midwestern U.S. city. AB - Ghanaian immigrant population in the United States is at a high risk for developing HIV/AIDS. This study uses the Theory of Planned Behavior to predict safer sexual behavior among Ghanaian immigrants in a large Midwestern city in the United States. A 55-item questionnaire was developed and tested for validity (face, content, and construct) and reliability (stability and test-retest). A total of 137 Ghanaian immigrants completed the questionnaire. The constructs of perceived behavioral control (p < 0.001) and subjective norm (p < 0.001) were significant predictors for intention to use condoms and they accounted for 38% of the variance. Behavioral intention for condom use (p < 0.001) was the significant predictor for condom use and it accounted for 21% of the variance. Health education interventions based on constructs of the Theory of Planned Behavior must promote consistent and correct use of condoms in this population. PMID- 21273167 TI - Sexual harassment experiences of female graduates of Nigerian tertiary institutions. AB - The sexual harassment experiences of female graduates from tertiary institutions in Nigeria, were explored using self-administered questionnaires. Information was obtained on the respondents' socio-demographic characteristics and experiences of sexual harassment while in their various tertiary institutions. The majority (69.8%) of the respondents had been sexually harassed, with the main perpetrators being male classmates and lecturers. About two-thirds experienced the non physical type of sexual harassment; 48.2% experienced the physical type. Non physical harassment included sexual comments (57.8%) and requests to do something sexual in exchange for academic favors (32.2%). Physical forms of sexual harassment included unwanted sexual touching (29.4%) and being intentionally brushed against in a sexual way (28.9%). The effects experienced by victims were depression and perceived insecurity on campus. Sexual harassment is a common occurrence in Nigerian tertiary institutions. Appropriate institutional interventions should be developed to reduce these occurrences. PMID- 21273168 TI - Intimate partner violence: prevalence and perceptions of married men in Ibadan, Nigeria. AB - In sub-Saharan Africa rates of intimate partner violence (IPV) are high. Thus, identifying reasons for abuse is crucial in ensuring women's health. Hence, mens perception of IPV was assessed, and prevalence of abuse determined. Survey of 820 married men from six urban communities in Ibadan was done using interviewer administered questionnaire. Four focus group discussions were conducted. Lifetime prevalence of perpetration of physical abuse was 25.1%, while psychological violence was 44.4%. Two hundred and forty (29.3%) had ever perpetrated sexual violence and 23.2% economic violence. At least one of these forms of violence had been perpetrated by 44.1% of the respondents. "Being rude" (66.4%) and "insufficient care of the children" (54.3%) were common justifications for IPV. Motive of the abuse were "to make partner responsible" (60.3%) and "to obtain respect" (59.9%). Predictors of perpetrating violence were being in polygamous unions (OR 1.83, 95% CI: 1.11-3.03), consuming alcohol (AOR 1.67; 95% CI: 1.10 2.53), and being Moslem (AOR = 1.87, 95% CI: 1.21-2.910). Men with inadequate knowledge and negative attitudes had greater likelihood of perpetrating IPV (AOR = 2.11, 95% CI: 1.37-3.26 and AOR = 2.09, 95% CI: 1.33-3.27). IPV was also associated with young age. Premarital counseling on how to resolve conflict without resulting to violence and early education of boys on violence to women is recommended. PMID- 21273169 TI - Literacy for good health: pre-menopause women in Cross River State, Nigeria. AB - This article examines the influence of literacy on the health of menopausetting (or pre-menopause) women in urban Calabar Metropolis of Cross River State, Nigeria. Two null hypotheses were formulated with a 45-item questionnaire from a representative sample size of 500 urban women between ages 35 and above, using purposive, stratified, and simple random sampling procedures. The research design is survey inferential, while data analysis was by one-way analysis of variance (ANOVA). Fisher's multiple comparison (LSD) and Independent t-test techniques were carried out. The analysis revealed that literacy level significantly influences the health of menopausetting women and that menopausetting women who are highly literate live healthier lives than their counterparts who are averagely and lowly literate. Some recommendations were made which will enhance longevity and ultimate well-being of menopausetting women. PMID- 21273174 TI - Circulating microRNAs: possible prediction biomarkers for personalized therapy of non-small-cell lung carcinoma. PMID- 21273172 TI - Effects of lenalidomide and dexamethasone treatment duration on survival in patients with relapsed or refractory multiple myeloma treated with lenalidomide and dexamethasone. AB - BACKGROUND: In two randomized phase III trials (MM-009 and MM-010), lenalidomide plus dexamethasone significantly prolonged time to progression and overall survival (OS) in patients with relapsed/refractory multiple myeloma compared with dexamethasone alone. In both trials the treatment was continued until disease progression or unacceptable toxicity. We conducted a subanalysis to determine if continuing therapy after achieving>=partial response (PR) improved survival. PATIENTS AND METHODS: Data were collected on 212 patients who were treated with lenalidomide plus dexamethasone and achieved>=PR. Kaplan-Meier survival estimates were compared between patients on continued treatment versus patients discontinuing therapy because of adverse events, withdrawal of consent, or other reasons. Time-dependent multivariate regression analyses were used to determine the benefit of continuing treatment with lenalidomide. RESULTS: A total of 174 patients received continued treatment until disease progression or death, and 38 patients discontinued therapy without progression. There was a trend toward longer median OS in patients who continued therapy (50.9 months vs. 35.0 months; P=.0594). When controlling for the number of previous antimyeloma therapies, beta2-microglobulin levels, and Durie-Salmon stage (which adversely affected survival in these patients), continued lenalidomide treatment (HR, 0.137; 95% CI, 0.045-0.417; P=.0005) or each additional cycle of lenalidomide (HR, 0.921; 95% CI, 0.886-0.957; P<.0001) were both associated with longer survival. CONCLUSION: Continued lenalidomide treatment until disease progression after achievement of >=PR is associated with a significant survival advantage when controlling for patient characteristics. These findings should be confirmed in a prospectively designed trial. PMID- 21273175 TI - Classification and toxicities of vascular disrupting agents. AB - Vascular disrupting agents (VDAs) are an exciting new group of targeted therapies under active clinical research in many solid tumors, in particular, lung cancer. Small-molecule VDAs are the focus of current clinical research, and consist of the flavonoids and the tubulin-binding agents. Toxicities of single-agent VDAs are characterized by acute, transient, and generally noncumulative side effects including headaches, nausea and vomiting, tumor pain, hypertension, and tachycardia. Flavonoid agents can also cause infusion site pain, visual disturbances, electrocardiac abnormalities, and symptoms consistent with an acute release of serotonin. Tubulin-binding agents can result in cardiac ischemia, abdominal pain, neuromotor abnormalities and cerebellar ataxia, and acute hemodynamic changes. Clinical trials investigating VDAs in combination with traditional chemotherapy have also shown the potential for significant pharmacologic and adverse toxicity interactions. Further research will need to focus on pharmacokinetic and pharmacodynamic parameters to optimize dosing schedules, determine effective combinations with chemotherapy, and minimize toxicities associated with VDAs. PMID- 21273176 TI - The potential application of zoledronic acid as anticancer therapy in patients with non-small-cell lung cancer. AB - Non-small-cell lung cancer (NSCLC) is frequently characterized by metastases to bone. Bisphosphonates have demonstrated efficacy in reducing the risk of skeletal related events in cancer patients with bone metastases, including those with NSCLC. Zoledronic acid (ZA) is one of the most potent bisphosphonates and is approved for the first-line treatment of patients with multiple myeloma and bone metastases from solid tumors. Recent preclinical and clinical data suggest that ZA may also have direct and indirect anticancer effects. Several preclinical studies have provided insight into the potential mechanisms responsible for the anticancer activity of ZA, including inhibiting farnesyl pyrophosphate or geranylgeranyl pyrophosphate and activation of immune-mediated anticancer response by gammadelta T cells. In patients with NSCLC, ZA has been shown to reduce vascular endothelial growth factor levels with a direct correlation to clinical response. Clinical studies in this setting have shown that ZA may also provide a survival benefit and prolong time to progression. Ongoing studies are evaluating the efficacy of ZA for anticancer activity and prevention of bone metastases. Bisphosphonates, particularly ZA, are generally well tolerated and may likely offer an adjunct therapeutic option for patients with NSCLC. PMID- 21273177 TI - Randomized phase II trial of concurrent versus sequential bortezomib plus docetaxel in advanced non-small-cell lung cancer: a California cancer consortium trial. AB - BACKGROUND: The proteasome inhibitor bortezomib sensitizes tumor cells to chemotherapy-induced apoptosis. In preclinical non-small-cell lung cancer (NSCLC) models, p53-dependent growth arrest after bortezomib treatment resulted in reduced cytotoxicity if bortezomib preceded docetaxel. The reverse sequence of docetaxel before bortezomib was associated with increased apoptosis, cleavage of caspase-3 and PARP (poly [ADP-ribose] polymerase), and reduction in Bcl-2. A prospective randomized phase II trial of concurrent versus sequential docetaxel and bortezomib was conducted to assess whether administration sequence resulted in measurable clinical differences. PATIENTS AND METHODS: Previously treated patients with advanced NSCLC were randomized to concurrent (CON) or sequential (SEQ) docetaxel (75 mg/m2 intravenous [I.V.]) followed by bortezomib, every 3 weeks. In the CON arm, bortezomib (1.6 mg/m2 I.V.) was given on days 1 and 8, and in the SEQ arm, it was given on days 2 and 8. Previous erlotinib as well as treated or controlled brain metastases were allowed. The primary endpoint was objective response rate (RR); progression-free (PFS) and overall survival (OS) were secondary endpoints. RESULTS: Eighty-one patients were randomized (40 CON and 41 SEQ). Grade 3+ toxicities were mostly due to myelosuppression. One patient each had grade 4 hyponatremia and syncope. Toxicities were similar between the arms. There was 1 treatment-related death in the SEQ arm. There were 8 partial responders, 4 in each arm, for an overall RR of 10%. Disease control rate was similar in both arms (50% vs. 49%). Median PFS was 12 weeks in the CON arm and 11 weeks in the SEQ arm. Median OS times in the CON and SEQ arms were 13.3 and 10.5 months, respectively. CONCLUSION: Docetaxel plus bortezomib given sequentially or concurrently has similar RR and PFS. Median survival in the SEQ arm exceeds published survival estimates for either agent alone or in combination. Any further studies in this population would require molecular characterization of a phenotype most likely to benefit from proteasome inhibitor therapy. PMID- 21273178 TI - A role for IGF-1R-targeted therapies in small-cell lung cancer? AB - BACKGROUND: Small-cell lung cancer (SCLC) is an aggressive disease with a poor prognosis. The insulin-like growth factor-1 receptor (IGF-1R) is an autocrine growth factor and an attractive therapeutic target in many solid tumors, but particularly in lung cancer. PATIENTS AND METHODS: This study examined tumor samples from 23 patients diagnosed with SCLC, 11 resected specimens and 12 nodal biopsies obtained by mediastinoscopy, for expression of IGF-1R using the monoclonal rabbit anti-IGF-1R (clone G11, Ventana Medical Systems, Tucson, AZ) and standard immunohistochemistry (IHC). RESULTS: All 23 tumor samples expressed IGF-1R with a range of stain intensity from weak (1+) to strong (3+). Ten tumors had a score of 3+, 7 tumors 2+, and 6 tumors 1+. Patient survival data were available for all 23 patients. Two patients died < 30 days post biopsy, therefore, the intensity of anti-IGF-1R immunostaining for 21 patients was correlated to survival. Patients with 3+ immunostaining had a poorer prognosis (P = .003). The overall survival of patients who underwent surgical resection was significantly better (median survival not reached) than patients who were not resected (median survival, 7.4 months) (P = .006). CONCLUSION: IGF-1R targeted therapies may have a role in the treatment of SCLC in combination with chemotherapy or as maintenance therapy. Further studies on the clinical benefit of targeting IGF-1R in SCLC are needed. PMID- 21273179 TI - Cell cycle protein cyclin Y is associated with human non-small-cell lung cancer proliferation and tumorigenesis. AB - BACKGROUND: The role of cell cycle protein cyclin Y (CCNY) in non-small-cell lung cancer (NSCLC) is not clear. Hence, the aim of this study was to explore the potential role of CCNY in lung cancer. PATIENTS AND METHODS: Real-time quantitative polymerase chain reaction was used for detecting the expression of CCNY mRNA in 60 samples from patients with NSCLC. The functional role of CCNY in NSCLC cells was evaluated by small interfering RNA-mediated depletion of the protein followed by analysis of cell proliferation, anchorage-independent growth, and xenograft growth. RESULTS: CCNY mRNA is overexpressed (N = 60) in samples from patients with NSCLC. Furthermore, CCNY mRNA expression positively correlated with histologic types (squamous cell carcinoma vs. adenocarcinomas; P = .048) and with the tumor size (size > 3 cm vs. size <= 3 cm; P = .010) in NSCLC. Functionally, CCNY depletion was shown to inhibit cell proliferation and anchorage-independent growth in lung cancer cells. Moreover, the proliferation effects were increased when CCNY was overexpressed in lung cancer cells. Finally, CCNY was shown to support H1299 and 95D xenograft growth in nude mice. CONCLUSION: We reported for the first time (to the best of our knowledge) that CCNY was overexpressed in samples of NSCLC. CCNY mRNA expression associated with histologic types of NSCLC and promoted the malignant growth of lung cancer cell line in vivo and in vitro. Thus, these results validated the role of CCNY as a clinically relevant human oncoprotein and warrant further investigation of CCNY as a biomarker and a therapeutic target in NSCLC. PMID- 21273180 TI - Role of computed tomography fluoroscopy-guided cutting needle biopsy of lung lesions after transbronchial examination resulting in negative diagnosis. AB - INTRODUCTION: Computed tomography (CT)-guided lung biopsy is occasionally used for the lesions that were diagnosed as nonmalignant by transbronchial examination despite the fact that other clinical data suggested those as malignant. The purpose of this study is to evaluate the outcomes of CT fluoroscopy-guided cutting needle biopsy of lung lesions after transbronchial examination resulting in negative diagnosis. PATIENTS AND METHODS: We retrospectively evaluated the outcomes of CT fluoroscopy-guided lung biopsy for 351 lesions (mean size, 2.8 cm) that were found to be nonmalignant by transbronchial examination. Diagnostic yield, including sensitivity and specificity for the diagnosis of malignancy, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated. Various variables were analyzed to determine the factors for diagnostic failure. RESULTS: The biopsy result was nondiagnostic, true-positive, true-negative, false-positive, or false-negative for 2, 262, 70, 0, or 17 lesions, respectively. Thus, the sensitivity, specificity, PPV, NPV, and accuracy of CT fluoroscopy-guided cutting needle biopsy was found to be 93% (262/281), 100% (70/70), 100% (262/262), 80% (70/87), and 94% (332/351), respectively. There was no significant risk factor for diagnostic failure. CONCLUSION: Computed tomography fluoroscopy-guided cutting needle lung biopsy is a useful technique to correct or confirm negative diagnosis by transbronchial examination. PMID- 21273181 TI - Clinicopathologic factors affecting the progression-free survival of patients with advanced non-small-cell lung cancer after gefitinib therapy. AB - BACKGROUND: The aim of this study was to analyze the factors independent of epidermal growth factor (EGFR) gene mutations that affect the progression-free survival (PFS) of patients with advanced non-small-cell lung cancer (NSCLC) after gefitinib therapy. PATIENTS AND METHODS: Eighty patients with advanced NSCLC between January 2003 and April 2010 at Kyoto University Hospital were analyzed for EGFR somatic mutations and treated with gefitinib. We adopted the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method for determination of EGFR mutation status. To evaluate risk factors associated with PFS, Cox proportional hazards regression model with a step-down procedure was used. Proportional hazards assumptions were checked and satisfied; only those variables with statistically significant results in univariate analysis were included in a multivariate analysis. RESULTS: The median PFS of patients with EGFR mutations were significantly longer than in patients with wild-type EGFR. The median PFS of patients after first-line gefitinib therapy was significantly longer than those who received treatment as a second-line therapy. The median PFS of patients over 75 years of age was significantly longer than in younger patients. Based on multivariate analysis, wild-type EGFR status and age < 75 years were significant and independent negative factors that affect PFS after gefitinib therapy. CONCLUSION: In this study, we showed the EGFR mutants and age > 75 years were good predictive factors for PFS after gefitinib therapy, suggesting that first-line gefitinib treatment for older patients is efficacious regardless of EGFR mutational status. PMID- 21273182 TI - Addition of darbepoetin alfa to dose-dense chemotherapy: results from a randomized phase II trial in small-cell lung cancer patients receiving carboplatin plus etoposide. AB - Darbepoetin alfa, an erythropoiesis-stimulating agent (ESA), is used in cancer patients as a supportive care for anemia. For small-cell lung cancer (SCLC), several studies have shown that the administration of ESAs does not affect survival but decreases the need for blood transfusions and improves the quality of life (QOL) of patients receiving chemotherapy. The present randomized phase II study assessed the feasibility, efficacy, and safety of the administration of darbepoetin alfa to patients with SCLC receiving dose-dense (every 2 weeks) standard chemotherapy consisting of carboplatin plus etoposide, pegfilgrastim prophylactically. Seventy-four chemotherapy-naive patients with limited or extensive SCLC received combination chemotherapy for 6 cycles, and half of the patients additionally received darbepoetin to achieve a target hemoglobin concentration of 12-13 g/dL. The primary study outcome, progression-free survival, showed no difference between the 2 arms of the study. Among the secondary endpoints, objective response was similar in the presence and absence of darbepoetin (best response rates = 75.0% vs. 77.8%). Likewise, 1-year survival rates were not different between the 2 treatment arms (40.1% vs. 45.9%). There were no significant differences in grade 3/4 toxicities. As expected, the need for blood transfusions differed significantly: 19.4% of patients in the darbepoetin arm received transfusions versus 38.9% in the control arm. Analysis of European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30) scales at different time points showed that the darbepoetin group's QOL was significantly better for certain readouts and never significantly worse than that of the control group. Thus, the combination of darbepoetin alfa with dose-dense carboplatin plus etoposide was feasible and well tolerated. Addition of darbepoetin alfa to chemotherapy lowered the need for blood transfusions and did not affect measures of survival and objective response. PMID- 21273183 TI - Treatment, rationale, and study design of TALISMAN study: a randomized phase II open-label study of second-line erlotinib versus intermittent erlotinib dosing with docetaxel in the treatment of former-smoker men affected by recurrent squamous non-small-cell lung cancer. AB - We present the treatment rationale and study design of the TALISMAN (TArceva and docetaxeL In former-Smokers MAle patients with recurrent Non-small-cell lung cancer) study, an open-label, randomized phase II trial of erlotinib (arm A) or intermittent erlotinib and docetaxel (arm B) in male former smokers affected by recurrent squamous non-small-cell lung cancer (NSCLC). In arm A, treatment consists of erlotinib 150 mg daily orally until progression or inacceptable toxicity; in arm B, treatment consists of docetaxel 75 mg/m2 on day 1 and erlotinib 150 mg orally on days 2-16, recycled every 3 weeks up to 4 cycles followed, in patients not progressed, by erlotinib 150 mg daily orally until disease progression or inacceptable toxicity. The primary endpoint of this study is the rate of patients without progression at 6 months, and secondary objectives include median progression-free survival, median overall survival, activity, and toxicity. In addition, translational research evaluating EGFR and KRAS mutational status will be investigated for both arms. PMID- 21273184 TI - Acceptability of a clinician-assisted computerized psychological intervention for comorbid mental health and substance use problems: treatment adherence data from a randomized controlled trial. AB - BACKGROUND: Computer-delivered psychological treatments have great potential, particularly for individuals who cannot access traditional approaches. Little is known about the acceptability of computer-delivered treatment, especially among those with comorbid mental health and substance use problems. OBJECTIVE: The objective of our study was to assess the acceptability of a clinician-assisted computer-based (CAC) psychological treatment (delivered on DVD in a clinic setting) for comorbid depression and alcohol or cannabis use problems relative to a therapist-delivered equivalent and a brief intervention control. METHODS: We compared treatment acceptability, in terms of treatment dropout/participation and therapeutic alliance, of therapist-delivered versus CAC psychological treatment. We randomly assigned 97 participants with current depression and problematic alcohol/cannabis use to three conditions: brief intervention (BI, one individual session delivered face to face), therapist-delivered (one initial face-to-face session plus 9 individual sessions delivered by a therapist), and CAC interventions (one initial face-to-face session plus 9 individual CAC sessions). Randomization occurred following baseline and provision of the initial session, and therapeutic alliance ratings were obtained from participants following completion of the initial session, and at sessions 5 and 10 among the therapist delivered and CAC conditions. RESULTS: Treatment retention and attendance rates were equal between therapist-delivered and CAC conditions, with 51% (34/67) completing all 10 treatment sessions. No significant differences existed between participants in therapist-delivered and CAC conditions at any point in therapy on the majority of therapeutic alliance subscales. However, relative to therapist delivered treatment, the subscale of Client Initiative was rated significantly higher among participants allocated to the BI (F(2,54) = 4.86, P = .01) and CAC participants after session 5 (F(1,29) = 9.24, P = .005), and this domain was related to better alcohol outcomes. Linear regression modeled therapeutic alliance over all sessions, with treatment allocation, retention, other demographic factors, and baseline symptoms exhibiting no predictive value. CONCLUSIONS: Participants in a trial of CAC versus therapist-delivered treatment were equally able to engage, bond, and commit to treatment, despite comorbidity typically being associated with increased treatment dropout, problematic engagement, and complexities in treatment planning. The extent to which a client feels that they are directing therapy (Client initiative) may be an important component of change in BI and CAC intervention, especially for hazardous alcohol use. PMID- 21273185 TI - The effectiveness of interventions to establish smoke-free homes in pregnancy and in the neonatal period: a systematic review. AB - This review considers the effectiveness of interventions to encourage the establishment of smoke-free homes during pregnancy and the neonatal period. A comprehensive search of the literature was undertaken to find relevant studies via electronic databases, citations and reference lists of included studies. The searches identified 17 papers that met the inclusion criteria. These were quality assessed and data extracted. Due to heterogeneity of the papers, a narrative synthesis was completed. Interventions were categorized in terms of those based on counselling, counselling plus additional elements, individually adapted programmes and motivational interviewing. The findings suggest inconclusive evidence relating to these intervention types, with a range of outcome measures reported. There were limitations throughout the papers in terms of study quality (especially sample size) and poor reporting of results in relation to effectiveness. The review was limited by its very specific population; however, it suggests that currently there is mixed evidence for the effectiveness of interventions to reduce parental environmental tobacco smoke in early infancy. PMID- 21273186 TI - Determinants of preventive health behavior in relation to cervical cancer screening among the female population of Belgrade. AB - Identifying the factors that deter or stimulate the women to participate in screening activities is very important in order to design effective education and motivation strategies, particularly in the countries without an organized system. The study employed a case-control design. The participants were recruited in four primary health care institutions in Belgrade over a month. The study group comprised all women aged 18-70 years, who demonstrated an initiative for a PAP- smear. The controls were women with no Pap smears within the last 4 years, matched by age (+/-2 years), education and marital status with the study group participants. The study instrument was the 62-item self-administered questionnaire. According to multivariate analysis, adherence to cervical cancer screening practices is significantly related to better financial status [odds ratio (OR) = 10.8, P = 0.001], no gender preference for a gynecologist (OR = 3.1, P = 0.015), consultations with a gynecologist (OR = 4.7, P = 0.029), conversation with the women with cervical cancer about that disease (OR = 2.8, P = 0.029) and higher media exposure to information about cervical cancer prevention (OR = 5.0, P = 0.004). Open communication, social networks and improving social-economic status of women in our society are the most prominent factors, most of which are mainly outside the health services' domain and require multisectoral collaboration to improve women's reproductive health. PMID- 21273187 TI - Correlation between risk factors and musculoskeletal disorders among classical musicians. AB - BACKGROUND: Musculoskeletal disorders in humans may originate from biomechanical, environmental, psychosocial and personal risk factors encountered in the working environment. These disorders in musicians are designated as playing related musculoskeletal disorders (PRMD). AIMS: To investigate the correlation between biomechanical, environmental, psychosocial and personal risk factors and potential incidence of PRMD arising in professional classical musicians. METHODS: Fifty-nine orchestral classical musicians were observed: They also filled out questionnaires providing information regarding musculoskeletal symptoms, psychosocial factors and demography. RESULTS: Clinical observation using the Rapid Upper Limb Assessment (RULA) showed significantly higher scores in string musicians compared with woodwind and brass players (right RULA score F = 4.77, P < 0.05; left RULA score, F = 3.90, P < 0.05). A multivariate regression model showed statistical significance for five of the six dependent variables regarding prevalence of painful joints, severity of musculoskeletal symptoms and functional limitation. The regression analysis revealed that biomechanical risk factors, perceived physical environment risk factors, instrument weight and average playing hours per week, were the main predictors of PRMD. CONCLUSIONS: The biomechanical risk factors that predict PRMD are mainly associated with the upper limbs. A high association between PRMD and clinical observation emphasizes the need for further investigation of these risk factors and to study possible implementations in order to define 'prevention strategies' for musical routines and patterns, as used by classical musicians. PMID- 21273188 TI - Human herpesvirus 8 infection in children and adults in a population-based study in rural Uganda. AB - BACKGROUND: Human herpesvirus 8 (HHV-8) infection is endemic in sub-Saharan Africa. We examined sociodemographic, behavioral, and biological factors associated with HHV-8 infection in children and adults to determine HHV-8 seroprevalence and potential routes of transmission. METHODS: Participants were 1383 children and 1477 adults from a population-based sample in a rural community in Uganda. Serum samples were tested for HHV-8 antibodies with use of an enzyme immunoassay against K8.1. RESULTS: HHV-8 seroprevalence increased from 16% among children aged 1.5-2 years to 32% among children aged 10-13 years (P <.001) and from 37% among participants aged 14-19 years to 49% among adults aged >= 50 years (P <.05). HHV-8 seropositivity in children was independently associated with residing with a seropositive parent (P < .001) and residing with >= 1 other seropositive child aged <14 years (P < .001). History of sharing food and/or sauce plates was marginally associated with HHV-8 infection in children (P = .05). Among 1404 participants aged >= 15 years , there was no association between correlates of sexual behavior (eg, number of lifetime sex partners and HIV infection) and HHV-8 seropositivity (P > .10). CONCLUSIONS: Our data suggest that HHV-8 is acquired primarily through horizontal transmission in childhood from intrafamilial contacts and that transmission continues into adulthood potentially through nonsexual routes. PMID- 21273190 TI - Sign language users' education and employment levels: keeping pace with changes in the general Australian population? AB - This article draws on data from the 2006 Australian census to explore the education and employment outcomes of sign languages users living in Victoria, Australia, and to compare them with outcomes reported in the general population. Census data have the advantage of sampling the entire population on the one night, avoiding problems of population comparability and sampling errors that may affect survey-based research. The analysis shows that sign language users are approaching parity with the general population on some measures of educational attainment, but there remains a gap in employment levels and particularly income. Sign language users aged 25-44 years show higher attainment than those in the 45 64 age group, suggesting that educational reforms in the last 30 years are having a positive impact on both education and employment levels. However, younger sign language users are still struggling to keep pace with improvements in certain employment outcomes that are seen in the general population. PMID- 21273189 TI - Human herpesvirus 8 seropositivity in rural Uganda: maturation of sero epidemiological studies. PMID- 21273191 TI - The importance of morphemic awareness to reading achievement and the potential of signing morphemes to supporting reading development. AB - The ability to access and understand the meaning of multi-morphemic words is essential for age-appropriate literacy growth as well as for achievement in other participants, such as science and social studies, which are so print-dependent. This paper provides a theoretical basis for focusing on the morphology of English when teaching students who are deaf or hard of hearing to read through a review of the literature on the role of morphology in reading for both hearing students and those with a hearing loss. In addition, the authors review the empirical literature on Signing Exact English (SEE), a system of signing English constructed in which the morphology of words is made visible to children who might not be able to hear them. The authors propose that students' use of SEE can provide a bridge to developing the morphemic awareness so necessary for age appropriate reading development and achievement. PMID- 21273192 TI - Ablation for persistent atrial fibrillation: do we know who to turn away? PMID- 21273193 TI - Multiple inappropriate rate drop responses triggered by ventricular premature beats. AB - We report the case of a 70-year-old patient presenting with palpitations who was found to have recurrent inappropriate rate drop responses on interrogation of his pacemaker. These were found to be triggered by interpolated premature ventricular complexes (PVCs). We discuss the drop detect algorithm and how interpolated PVCs triggered the rate drop response. PMID- 21273194 TI - A new method of filtering T waves to detect hidden P waves in electrocardiogram signals. AB - AIMS: A correct identification of the P wave is crucial for the diagnosis of narrow QRS tachycardias. This is sometimes difficult because atrial activity is hidden in the T wave. The aim of this study is to evaluate the usefulness of a T wave filtering technique based on wavelet transformation to identify atrial activity. METHODS AND RESULTS: Forty-two patients with narrow QRS tachycardias and regular atrial activity were studied. A surface electrocardiogram (ECG), intra-atrial recording, and the T wave filtering ECG were compared simultaneously to check the accuracy of the filtering system in detecting atrial activity. The sensitivity of the T wave filtering and P wave detection algorithm was 85.8% [95% confidence interval (CI): 81.2-89.4%] and the specificity was 89.4% (95% CI: 87.1 91.4%), with a global accuracy of 88.5% (95% CI: 86.5-90.3%). The expert cardiologist's accuracy in distinguishing between atrioventricular nodal reentry tachycardia and atrioventricular reentry tachycardia was 75% in the surface ECG vs. 100% in the ECG with the T wave filtering process (P<0.01). CONCLUSIONS: T wave filtering based on wavelet transformation improves the capacity of the surface ECG to identify atrial activity in cases of regular narrow QRS supraventricular tachycardias. PMID- 21273195 TI - Facilitatory and inhibitory effects of SCN5A mutations on atrial fibrillation in Brugada syndrome. AB - AIMS: Brugada syndrome (BrS) is associated with increased risk for atrial fibrillation (AFib). However, the role of SCN5A mutations in the occurrence of AFib remains unclear. Cardiac sodium current reduction caused by SCN5A mutations may facilitate AFib by slowing intra-atrial conduction and inducing structural changes, but also prevent it by suppressing atrial ectopic activity. Here, we examined the relation between SCN5A mutations, atrial conduction velocity, atrial structural changes, and atrial ectopic activity in BrS. METHODS AND RESULTS: Data from 214 BrS patients [78 with an SCN5A mutation (patients with an SCN5A mutation, BrSSCN5A+) and 136 without an SCN5A mutation (patients without an SCN5A mutation, BrSSCN5A-)] were collected. Intra-atrial conduction velocity was assessed by measuring P-wave durations at baseline and during sodium channel provocation testing. Atrial structural changes were assessed by measuring atrial dimensions using cardiac magnetic resonance imaging. Atrial ectopic activity was assessed by determining the incidence of atrial ectopic beats using 24 h Holter recordings. Clinical characteristics (including AFib occurrence) did not differ between BrSSCN5A+ and BrSSCN5A-. Baseline P-wave durations were longer in BrSSCN5A+ than in BrSSCN5A-, but lengthened markedly in BrSSCN5A- during provocation testing. Atrial dimensions did not differ. Atrial ectopic beats occurred more often in BrSSCN5A-, and the proportion of patients experiencing one or more atrial ectopic beats was larger in BrSSCN5A- than in BrSSCN5A+. CONCLUSION: In BrS, the presence of an SCN5A mutation is associated with intra atrial conduction slowing and suppressed atrial ectopic activity. Intra-atrial conduction slowing may provide a plausible substrate for AFib maintenance, while reduced atrial ectopic activity may constitute inhibition of the trigger for AFib initiation. PMID- 21273196 TI - The effect of electronic repositioning on left ventricular pacing and phrenic nerve stimulation. AB - AIMS: Cardiac resynchronization therapy (CRT) improves survival and reduces heart failure symptoms. However, phrenic nerve stimulation and high pacing thresholds are common problems that limit CRT effectiveness. Current technology allows reprogramming of left ventricular (LV) pacing vectors, permitting 'electronic repositioning' to overcome both phrenic nerve stimulation and high pacing output without the need for re-operation. METHODS AND RESULTS: Patients underwent prospective evaluation of a CRT system implantation with a bipolar LV. Optimal LV threshold and avoidance of phrenic nerve stimulation were determined at baseline and at 6 months. A subset of 48 patients underwent more detailed evaluation of pacing threshold and phrenic nerve stimulation at baseline and at 6 months. Between 2004 and 2007, 228 patients underwent CRT implantation (64 CRT pacemakers, 164 CRT defibrillators). At baseline, electronic reprogramming to determine an alternate configuration compared with standard LVtip to LVring found a >= 1.0 V reduction in pacing threshold in 80 patients (35%). Of the 17 patients who had an LVtip to LVring configuration and high pacing threshold (>5.0 V), 16 could be reduced by >1.0 V (94%) and 11 could be reduced by >2.0 V through electronic repositioning alone without repositioning the lead (65%). At implant, there were 48 patients with phrenic nerve stimulation at less than maximum pacing output (21%) using the standard LVtip to LVring configuration. In 37 cases (77%), there was at least one other configuration with no phrenic nerve stimulation, which prevented the need for lead revision. CONCLUSIONS: Electronic repositioning is an important tool in the management of CRT patients which may help to lower thresholds, avoid phrenic nerve stimulation, and prevent unnecessary re operations for LV lead repositioning. PMID- 21273197 TI - Survey of ELF magnetic field levels in households near overhead power lines in Serbia. AB - During the last eight years, 'VINCA' Institute--Radiation and Environmental Protection Laboratory has performed environmental 'spot' broadband measurements of extremely low frequency (ELF-50 Hz) electric and magnetic fields and RF (100 kHz-3 GHz) electromagnetic fields in over 35 municipalities in Serbia. These investigations were motivated by the local population requesting information about levels of general public exposure to time-varying electric and magnetic fields in living spaces. This paper presents a summary of values measured in households under overhead power lines. These measurements will be useful in determining the exposure levels of the general public, which in turn determines whether the exposure levels are within reference levels recommended by International Commission on Non-Ionizing Radiation Protection (ICNIRP) Guidelines. It has turned out that measured values are far below the recommended safe levels. PMID- 21273198 TI - Evaluation of radiographic image quality parameters obtained with the REX simulator. AB - The PTW REX phantom was used to study the radiographic image quality parameters in X-ray devices in the X-ray Diagnostics Department, as well as the system of film processing at the University Hospital of Rio de Janeiro State. X-ray devices were evaluated by performing tests on 11 screen-film combinations from X-ray devices in 3 rooms. The results showed that six film-screen combinations exhibited poor performances. For determination of air kerma output in the X-ray field, two devices presented significant variation >2 %. The grid attenuation factor in three devices had been approved, while two films were within the limits of sensitometric specifications. The modulation transfer function, which evaluates the level of image degradation, revealed that five film-screen combinations exhibited bad performance. The tests with the REX phantom revealed that the X-ray equipment and the system of processing at the University Hospital presented discrepancies in relation to the expected values, contributing to loss of quality of the radiographs. PMID- 21273199 TI - Using an optimised OSL single-aliquot regenerative-dose protocol for low-dose retrospective dosimetry on household salt. AB - The single-aliquot regenerative-dose (SAR) protocols used in retrospective dosimetry for optically stimulated luminescence measurements have been mainly developed for archaeological and geological dating of quartz and feldspar. The aim in this study is to find a read-out protocol that can generate the most reproducible signal for household salt (NaCl) at absorbed doses below 100 mGy. The relation between the reproducibility of the signal, in terms of the ratio between given absorbed dose and SAR-calculated dose, and parameters such as test dose pre-heat temperature has been studied. It was found that a temperature of 200 degrees C yielded the best reproducibility in the SAR-calculated dose, which is a somewhat higher pre-heat temperature than what is used for dating of quartz. PMID- 21273200 TI - Renovascular hypertension: screening and modern management. AB - The diagnosis and management of patients with renovascular disease and hypertension continue to elude healthcare providers. The advent of novel imaging and interventional techniques, and increased understanding of the pathways leading to irreversible renal injury and renovascular hypertension, have ushered in commendable attempts to optimize and fine-tune strategies to preserve or restore renal function and control blood pressure. Large randomized clinical trials that compare different forms of therapy, and smaller trials that test novel experimental treatments, will hopefully help formulate innovative concepts and tools to manage the patient population with atherosclerotic renovascular disease. PMID- 21273201 TI - Percutaneous pulmonary valve implantation: two-centre experience with more than 100 patients. AB - AIMS: Dysfunction of valved conduits in the right ventricular outflow tract (RVOT) limits durability and enforces repeated surgical interventions. We report on our combined two-centre experience with percutaneous pulmonary valve implantation (PPVI). METHODS AND RESULTS: One hundred and two patients with RVOT dysfunction [median weight: 63 kg (54.2-75.9 kg), median age: 21.5 years (16.2 30.1 years), diagnoses: TOF/PA 61, TAC 14, TGA 9, other 10, AoS post-Ross-OP 8] were scheduled for PPVI since December 2006. Percutaneous pulmonary valve implantation was performed in all patients. Pre-stenting of the RVOT was done in 97 patients (95%). The median peak systolic RVOT gradient decreased from 37 mmHg (29-46 mmHg) to 14 mmHg (9-17 mmHg, P < 0.001) and the ratio RV pressure/AoP decreased from 62% (53-76%) to 36% (30-42%, P < 0.0001). The median end-diastolic RV-volume index (MRI) decreased from 106 mL/m(2) (93-133 mL/m(2)) to 90 mL/m(2) (71-108 mL/m(2), P = 0.001). Pulmonary regurgitation was significantly reduced in all patients. One patient died due to compression of the left coronary artery. The incidence of stent fractures was 5 of 102 (5%). During follow-up [median: 352 days (99-390 days)] one percutaneous valve had to be removed surgically 6 months after implantation due to bacterial endocarditis. In 8 of 102 patients, a repeated dilatation of the valve was done due to a significant residual systolic pressure gradient, which resulted in a valve-in-valve procedure in four. CONCLUSION: This study shows that PPVI is feasible and it improves the haemodynamics in a selected patient collective. Apart from one coronary compression, the rate of complications at short-term follow-up was low. Percutaneous pulmonary valve implantation can be performed by experienced interventionalists with similar results as originally published. The intervention is technically challenging and longer clinical follow-up is needed. PMID- 21273202 TI - In vivo critical fibrous cap thickness for rupture-prone coronary plaques assessed by optical coherence tomography. AB - AIMS: The widely accepted threshold of <65 MUm for coronary plaque fibrous cap thickness was derived from postmortem studies of ruptured plaques and may not be appropriate for in vivo rupture-prone plaques. We investigated the relationship between fibrous cap thickness and plaque rupture using optical coherence tomography (OCT). METHODS AND RESULTS: We studied 266 lesions (103 from patients with acute coronary syndrome and 163 from patients with stable angina) before percutaneous coronary intervention using OCT. Ruptured and non-ruptured lipid rich plaques were identified and the thinnest and most representative fibrous cap thickness were determined. Cap thickness was reliably measured in 71 ruptured and 111 non-ruptured plaques. From the ruptured plaques, the median thinnest cap thickness was 54 MUm (50-60). The median most representative cap thickness was 116 MUm (103-136). For non-ruptured plaques, the median thinnest cap thickness was 80 MUm (67-104) and 182 MUm (156-216) for most representative cap thickness. In 95% of ruptured plaques, the thinnest cap thickness and most representative cap thickness were <80 and <188 MUm, respectively. The best cut-offs for predicting rupture were <67 MUm (OR: 16.1, CI: 7.5-34.4, P < 0.001) for the thinnest cap thickness and <151 MUm (OR: 35.6, CI: 15.0-84.3, P < 0.001) for most representative cap thickness. These two measures were modestly correlated (r(2) = 0.39) and both independently associated with rupture. CONCLUSION: In vivo critical cap thicknesses were <80 MUm for the thinnest and <188 MUm for most representative fibrous cap thickness. Prospective imaging studies are required to establish the significance of these values. PMID- 21273203 TI - Percutaneous implantation of an Edwards SAPIEN valve in a failing pulmonary bioprosthesis in palliated tetralogy of Fallot. PMID- 21273204 TI - An improved bimolecular fluorescence complementation tool based on superfolder green fluorescent protein. AB - Bimolecular fluorescence complementation (BiFC) has been widely used in the analysis of protein-protein interactions (PPIs) in recent years. There are many notable advantages of BiFC such as convenience and direct visualization of PPI in cells. However, BiFC has one common limitation: the separated non-fluorescent fragments can be spontaneously self-assembled into an intact protein, which leads to false-positive results. In this study, a pair of complementary fragments (sfGFPN and sfGFPC) was constructed by splitting superfolder GFP (sfGFP) between the 214 and 215 amino acid residue, and sfGFPC was mutated by site-directed gene mutagenesis to decrease the signal of negative control. Our results showed that mutations in sfGFPC (sfGFPC(m12)) can effectively decrease the signal of negative control. Thus, we provide an improved BiFC tool for the analysis of PPI. Further, since the self-assembly problem is a common shortcoming for application of BiFC, our research provides a feasible strategy for other BiFC candidate proteins with the same problem. PMID- 21273205 TI - Diurnal variation of cortisol in people with dementia: relationship to cognition and illness burden. AB - Cortisol patterns in nursing home residents with dementia are described and examined in relation to cognition and comorbid illnesses. Saliva was sampled 4 times in a 24-hour period (week 1) and at the same times 1 week later (week 2). In general, cortisol levels decreased from morning to evening, with 50% exhibiting a negative slope. In contrast, 38% of the participants had a relatively flat cortisol diurnal rhythm, and 7% exhibited an afternoon increase. The cortisol pattern was consistent between weeks 1 and 2 for 39% with a negative slope, 13% with a flat profile, and for 2% with an afternoon increase pattern. Cortisol rhythm was not statistically significantly related to cognition or illness burden. While this study contributes to the understanding of differences in the diurnal pattern of cortisol for older adults with dementia, more research is needed to understand the etiology of the differences and the biological mechanisms involved. PMID- 21273206 TI - Knowledge of documented dementia diagnosis and treatment in veterans and their caregivers. AB - We studied perceptions of dementia diagnosis and treatment in patient-caregiver dyads enrolled in a care coordination intervention trial for veterans with dementia. We compared patient and caregiver perceptions of diagnosis and treatment to information in the medical record and assessed concordance between patient and caregiver perceptions. Data were derived from medical record abstraction and structured interviews with 132 patients and 183 caregivers. Most caregivers, but only about one fourth of patients, reported having received information about a diagnosis related to memory loss. Caregivers were more accurate than patients in recalling the patient's use of memory-enhancing medications. Within dyads there was poor agreement regarding a diagnosis of dementia. Our findings suggest that there is substantial room for improvement in disclosure and education of dementia diagnosis, especially at the level of the patient-caregiver dyad. PMID- 21273207 TI - Use of services by community-dwelling patients with dementia: a systematic review. AB - Dementia is a complicated disease requiring medical, psychological, and social services. Services to address these needs include medical care (outpatient physician/specialist, inpatient, emergency) and community care (home health, day care, meal preparation, transportation, counseling, support groups, respite care, physical therapy). This systematic review of articles published in English from 1991 to the present examines studies of ambulatory, community-dwelling dementia patients with established dementia diagnoses. Searches of the Medline database using 13 combinations of search terms, plus searches of Embase and PsycINFO databases using 3 combinations of terms and examination of reference lists of related articles, resulted in identification of 15 studies dealing with healthcare utilization among community-dwelling dementia patients in both medical and community care settings. Patients with dementia frequently use the full spectrum of medical services. Community resources are used less frequently. Community healthcare services may be a valuable resource in alleviating some burden of dementia care for physicians. PMID- 21273208 TI - Association of delirium post-stroke with early and late mortality. PMID- 21273209 TI - Effects of ageing on cerebral haemodynamics assessed during respiratory manoeuvres. AB - BACKGROUND: cerebral autoregulation (CA) is the ability to control cerebral blood flow during fluctuations in arterial blood pressure (ABP). It is impaired in a number of conditions including acute stroke, though studies so far have not found a decline in CA with age. CA is very sensitive to changes in pCO2. OBJECTIVE: this study investigates the effect of ageing on CA using a moving-window autoregressive moving average (MW-ARMA) to calculate CA as autoregulatory index (ARMA-ARI) during hypercapnia and hypocapnia, to ascertain whether this method would detect age-related differences in CA due to change in pCO2. METHOD: ECG was used to measure R-R interval, Finapres to measure ABP and capnography to measure end-tidal CO2. Transcranial Doppler ultrasonography was used to measure left and right middle cerebral artery cerebral blood flow velocity (CBFV). Hypercapnia was induced by a breath-hold, hypocapnia by hyperventilation. RESULTS: thirty volunteers of mean age 25 +/- 6 years and 30 volunteers of mean age 64 +/- 4 years were recruited. CBFV was higher and change in CBFV due to respiratory manoeuvre was significantly greater in the younger group compared with the older group. However, no difference in ARMA-ARI was found between the groups. CONCLUSION: these findings suggest that CA is not affected by healthy ageing. PMID- 21273210 TI - Taking the next step: combining incrementally valid indicators to improve recidivism prediction. AB - The possibility of combining indicators to improve recidivism prediction was evaluated in a sample of released federal prisoners randomly divided into a derivation subsample (n = 550) and a cross-validation subsample (n = 551). Five incrementally valid indicators were selected from five domains: demographic (age), historical (prior convictions), adjustment (prior incident reports), rating scale (Violation scale of the Lifestyle Criminality Screening Form), and self-report (General Criminal Thinking score from the Psychological Inventory of Criminal Thinking Styles). After converting scores on the five indicators to a common scale (z score), two combined scores were calculated: a simple summed score (unweighted summed score) and a score computed using beta weights from a Cox survival analysis of the derivation subsample (weighted summed score). Correlational and receiver operating characteristic analyses revealed that the unweighted and weighted summed scores produced equivalent results and that both improved significantly on the results of the five contributing indicators. PMID- 21273211 TI - Social inequalities in residential exposure to road traffic noise: an environmental justice analysis based on the RECORD Cohort Study. AB - OBJECTIVES: To explore social inequalities in residential exposure to road traffic noise in an urban area. METHODS: Environmental injustice in road traffic noise exposure was investigated in Paris, France, using the RECORD Cohort Study (n = 2130) and modelled noise data. Associations were assessed by estimating noise exposure within the local area around participants' residence, considering various socioeconomic variables defined at both individual and neighbourhood level, and comparing different regression models attempting or not to control for spatial autocorrelation in noise levels. RESULTS: After individual-level adjustment, participants' noise exposure increased with neighbourhood educational level and dwelling value but also with proportion of non-French citizens, suggesting seemingly contradictory findings. However, when country of citizenship was defined according to its human development level, noise exposure in fact increased and decreased with the proportions of citizens from advantaged and disadvantaged countries, respectively. These findings were consistent with those reported for the other socioeconomic characteristics, suggesting higher road traffic noise exposure in advantaged neighbourhoods. Substantial collinearity between neighbourhood explanatory variables and spatial random effects caused identifiability problems that prevented successful control for spatial autocorrelation. CONCLUSIONS: Contrary to previous literature, this study shows that people living in advantaged neighbourhoods were more exposed to road traffic noise in their residential environment than their deprived counterparts. This case study demonstrates the need to systematically perform sensitivity analyses with multiple socioeconomic characteristics to avoid incorrect inferences about an environmental injustice situation and the complexity of effectively controlling for spatial autocorrelation when fixed and random components of the model are correlated. PMID- 21273212 TI - Calcification in retinoblastoma: histopathologic findings and statistical analysis of 302 cases. AB - AIM: To evaluate the histopathologic factors statistically associated with the presence of calcification in eyes with retinoblastoma. METHODS: Retrospective, consecutive and observational case series. Three hundred and two enucleated eyes with retinoblastoma examined between the years 1960 and 2008. Five representative histopathologic slides of the pupil-optic nerve section and three cross optic nerve sections were retrospectively reviewed. The presence and degree of calcification as well as other histopathologic features were evaluated. Demographic data including age, gender and country of origin of the case were also reviewed. Univariate and multivariate statistical analyses were performed to search for a possible correlation between calcification and the other histopathologic factors and/or demographic data. RESULTS: Calcification was present in 84.9% of cases. Age, tumour size, necrosis, basophilic staining, iris neovascularisation, choroidal, scleral and/or optic nerve invasion were correlated significantly with calcification. Multivariate analysis showed a significant correlation between the presence of calcification and the amount of necrosis and choroidal invasion only. CONCLUSIONS: In this series, calcification was more frequent in cases with more necrosis and cases with choroidal invasion, a known poor histopathologic risk factor for metastatic disease. The possible clinical implication of the findings from this study deserves additional studies. PMID- 21273213 TI - Inhibition of vascular endothelial growth factor (VEGF) is sufficient to completely restore barrier malfunction induced by growth factors in microvascular retinal endothelial cells. AB - BACKGROUND: Deregulated expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) or insulin-like growth factor-1 (IGF-1) is associated with the pathogenesis of diabetic retinopathy. The VEGF(165)-induced increase in permeability of retinal endothelial cells (REC), probably resulting in diabetic macular oedema (DME), could be completely restored by the VEGF binding Fab fragment ranibizumab in vitro. We investigated whether bFGF and IGF-1 as single factors or in combination with VEGF(165) influence permeability and tight junctions in immortalised bovine REC (iBREC) and if these effects could be restored by inhibition of VEGF. METHODS: As a measure of changes in cellular permeability, transendothelial electrical resistance (TER) was monitored during long-term treatment of iBREC with growth factors in the absence or presence of ranibizumab or KRN951 (an inhibitor of VEGF receptors). Expression of claudin-1, as an indicator of functional tight junctions, was assessed by western blot analysis. RESULTS: Whereas VEGF(165) decreased TER and expression of claudin-1 in a concentration-dependent manner, long-term treatment of iBREC with 10-100 ng/ml bFGF or/and IGF-1 did not. Changes in claudin-1 expression or TER, induced by 25 ng/ml VEGF(165), were slightly enhanced by bFGF and/or IGF-1 and were accompanied by a slightly increased secretion of VEGF. Complete reversion of these effects was achieved by prolonged treatment with ranibizumab and partly by exposure to KRN951. CONCLUSION: Our findings indicate that VEGF(165), but not IGF-1 or bFGF, is mainly responsible for changes in cellular permeability observed in REC. This supports VEGF targeting as a therapeutic concept for DME. PMID- 21273214 TI - Chromosomal mapping and candidate gene discovery of chicken developmental mutants and genome-wide variation analysis of MHC congenics. AB - The chicken has been widely used in experimental research given its importance to agriculture and its utility as a model for vertebrate biology and biomedical pursuits for over 100 years. Herein we used advanced technologies to investigate the genomic characteristics of specialized chicken congenic genetic resources developed on a highly inbred background. An Illumina 3K chicken single nucleotide polymorphism (SNP) array was utilized to study variation within and among major histocompatibility complex (MHC)-congenic lines as well as investigate line specific genomic diversity, inbreeding coefficients, and MHC B haplotype-specific GGA 16 SNP profiles. We also investigated developmental mutant-congenic lines to map a number of single-gene mutations using both the Illumina 3K array and a recently developed Illumina 60K chicken SNP array. In addition to identifying the chromosomes and specific subregions, the mapping results affirmed prior analyses indicating recessive or dominant and autosomal or sex chromosome modes of inheritance. Priority candidate genes are described for each mutation based on association with similar phenotypes in other vertebrates. These single-gene mutations provide a means of studying amniote development and in particular serve as invaluable biomedical models for similar malformations found in human. PMID- 21273215 TI - Homogeneity at nuclear microsatellite loci masks mitochondrial haplotype diversity in the endangered fanshell pearlymussel (Cyprogenia stegaria). AB - We report on multiple patterns of differentiation and connectivity in the fanshell pearlymussel (Cyprogenia stegaria), based on different markers. Knowledge of genetic variation and genetic connectivity among remaining populations of this federally endangered species is needed to initiate implementation of the species recovery plan. We collected tissue samples from 96 specimens from the Green, Rolling Fork, and Licking Rivers, tributaries to the Ohio River, and the Clinch River, a tributary to the Tennessee River, providing broad coverage of the current distributional range of the species. Results from 7 nuclear DNA microsatellite markers suggested minimal population-level differentiation, whereas a mitochondrial DNA (mtDNA) marker (ND1) exhibited significant differentiation between C. stegaria in the Clinch River and the Ohio River populations. The ND1 data also confirm the existence of 2 distinct mtDNA lineages in the genus that transcends species boundaries. Further analyses suggest that the disproportionally strong signal from 2 very divergent ND1 lineages possibly masks finer-grained structure in the Ohio River population, based on one of the mtDNA lineages only. We recommend further sampling to confirm the absence of one lineage from the upper Clinch River drainage and suggest that provisional management guidelines should limit reciprocal exchanges among C. stegaria populations from the Clinch River and those in the Ohio River system. PMID- 21273216 TI - Evolution of 2 reproductive proteins, ZP3 and PKDREJ, in cetaceans. AB - The rapid evolution of proteins involved in reproduction has been documented in several animal taxa. This is thought to be the result of forces involved in sexual selection and is expected to be particularly strong in promiscuous mating systems. In this study, a range of cetacean species were used to analyze the patterns of evolution in 2 reproductive proteins involved in fertilization: the zona pellucida 3 (ZP3), present in the egg coat, and PKDREJ, localized in the sperm head. We targeted exons 6 and 7 of ZP3 and a part of the REJ domain in PKDREJ for a total of 958 bp in 18 species. We found very low levels of amino acid sequence divergence in both proteins, a very weak signal of positive selection in ZP3 and no signal in PKDREJ. These results were consistent with previous reports of a slow rate of molecular evolution in cetaceans but unexpected due to the existence of promiscuous mating systems in these species. The results raise questions about the evolution of reproductive isolation and species recognition in whales and dolphins. PMID- 21273217 TI - Bacterial colonization of rings and cell phones carried by health-care providers: are these mobile bacterial zoos in the hospital? AB - Our objective was to assess the presence of pathogenic organisms on the rings (worn on fingers) and cell phones carried by health-care workers (HCWs) and the public. Forty-two percent of mobile phones carried by HCWs and 18% carried by the general public were found to carry one or more organisms; 82% of the rings worn by HCWs and 36% of those worn by the general public were found to be positive for the presence of at least one type of microbe. PMID- 21273218 TI - Getting a diagnosis v. learning to live with it? The case of the progressive ataxias. AB - OBJECTIVES: To examine the perceptions and experiences of the diagnosis process in people with a progressive ataxia, a group of rare complex neurological conditions usually leading to disturbances in balance and speech. METHODS: An explorative qualitative study involving analysis of public accounts posted to specialist Internet discussion forums by people with symptoms of ataxia. Internet data were utilized partly because ataxia is a rare condition. RESULTS: The main themes that emerged were diagnosis as an arduous process, achieving diagnosis as a privilege, the importance of getting a medical label, being believed with regard to symptoms and 'idiopathic' diagnosis as a non-diagnosis. The accounts of people who were not able to secure a definitive diagnosis suggested that their priorities had changed from getting a diagnosis to managing and learning to live with their progressive disabilities. CONCLUSIONS: The diagnosis of the progressive ataxias presents challenges for patients, clinicians and in terms of the extensive use of finite healthcare resources. Our findings suggest there are varied views on the importance of diagnosis to people with progressive ataxia. This warrants further in-depth research to understand how people rate the relative utility of diagnostics. PMID- 21273219 TI - Qualitative study of high-cost patients in an urban primary care centre. AB - OBJECTIVES: We examined patient accounts of illness and care among primary care patients whose medical services costs were high in order to illuminate factors associated with high cost. METHODS: Thirty-three primary care patients with multiple chronic illnesses in an urban clinic serving a resource poor neighbourhood were selected from a range of high medical cost patients. Participants were interviewed with open-ended questions to investigate experiences of illnesses and care; their responses were examined for prominent themes using qualitative analysis methodology. RESULTS: Patients sorted themselves into two categories based on the dominant focus of the roles of the care givers: one termed 'professional', in which the focus was on the competence and effectiveness of the care giver; and the second, 'personal', in which the focus was on the interpersonal relationship. DISCUSSION: We examine similarities with other recent studies, suggest factors influencing these two different types of relationships such as intensity of involvement in the healthcare system as well as personality characteristics, and explore the challenge for healthcare programme development. We also noted that these two ways of conceptualizing the doctor-patient relationship may have adaptive or maladaptive consequences depending on the match between physician and patient. PMID- 21273220 TI - Shared decision-making in palliative care: a systematic mixed studies review using narrative synthesis. AB - The aim of this study is to synthesize knowledge about the process of shared decision-making (SDM) in palliative care. Medline, EMBASE, CINAHL, PsychInfo, Web of Science were searched with core concepts: shared decisions, patient participation in decision-making, and palliative care. Titles and abstracts were screened according to inclusion criteria (original research, adult patients, Western contexts, decision-making, palliative treatment or setting), yielding 37 articles for analysis. A narrative synthesis was created using the methods of thematic analysis, conceptual mapping, and critical reflection on the synthesis process. Results demonstrate that while a majority of patients want to participate in treatment decisions to some extent, most do not achieve their preferred levels of involvement because decisions are delayed and alternative treatment options are seldom discussed. The literature regarding the process of SDM itself remains scarce in palliative care. Further research is needed in order to better understand the longitudinal, interactive, and interdisciplinary process of decision-making in palliative care. PMID- 21273221 TI - Perceived barriers and facilitators for general practitioner-patient communication in palliative care: a systematic review. AB - While effective general practitioner (GP)-patient communication is required for the provision of good palliative care, barriers and facilitators for this communication are largely unknown. We aimed to identify barriers and facilitators for GP-patient communication in palliative care. In a systematic review seven computerized databases were searched to find empirical studies on GP-patient communication in palliative care. Fifteen qualitative studies and seven quantitative questionnaire studies were included. The main perceived barriers were GPs' lack of availability, and patients' and GPs' ambivalence to discuss 'bad prognosis'. Main perceived facilitators were GPs being available, initiating discussion about several end-of-life issues and anticipating various scenarios. Lack of availability and failure to discuss former mistakes appear to be blind spots of GPs. GPs should be more forthcoming to initiate discussions with palliative care patients about prognosis and end-of-life issues. Empirical studies are needed to investigate the effectiveness of the perceived barriers and facilitators. PMID- 21273222 TI - Captopril suppression: limitations for confirmation of primary aldosteronism. AB - INTRODUCTION: The aldosterone/renin ratio (ARR) is the first line screening test for primary aldosteronism (PA). However, in hypertensive patients with an increased ARR, PA needs to be confirmed by other means. METHODS: A 25 mg oral captopril test was performed in 16 healthy subjects to obtain reference values for aldosterone and ARR at 120 minutes after the test. Subsequently these data were applied to 46 hypertensive patients screened for PA with an increased ARR. RESULTS: At 120 minutes after the captopril test ARR decreased in healthy subjects within a narrow range, but remained high in patients with PA and in patients with primary hypertension, especially for those with low renin characteristics. At 120 minutes after captopril, the range of ARR in primary hypertensive patients overlapped in 88% of the cases with the range of the ARR in the PA patients. Sensitivity and specificity of basal ARR and ARR after the captopril test to diagnose PA, calculated as receiver operator characteristics, showed an area under the curve of 0.595 for basal ARR and 0.664 for ARR at 120 minutes after the test. CONCLUSION: The ARR at 120 minutes after the captopril test is only marginally better than basal ARR in diagnosing PA in hypertensive patients screened with an increased ARR. Owing to an overall limited capacity to clearly discriminate PA from primary hypertension, the test could not therefore be recommended for the confirmatory diagnosis of PA. PMID- 21273223 TI - Association of echocardiographic left ventricular structure with the ACE D/I polymorphism: a meta-analysis. AB - INTRODUCTION: : In a previous meta-analysis, we derived pooled estimates for the association of left ventricular mass (LVM) and hypertrophy (LVH), as diagnosed by electrocardiography or echocardiography, with the ACE D/I polymorphism. We updated this meta-analysis until May 2009 only considering echocardiographic phenotypes. METHODS: : We computed pooled estimates from a random-effects model. RESULTS: : Across 38 studies, both DD homozygotes (n = 2440) and DI heterozygotes ( n = 4310) had higher (p <= 0.002) LVM or LVM index than II homozygotes (n = 2229). Across 21 studies with available data, this was due to increased mean wall thickness (MWT) with no difference in left ventricular internal diameter (LVID). Standardised differences (DD versus II) were 0.39 (p < 0.001) for LVM, 0.34 (p = 0.009) for MWT, and 0.066 (p = 0.26) for LVID. Across 16 studies (4894 participants), the pooled odds ratios of LVH (versus II homozygotes) were 1.11 (p = 0.29) and 1.02 (p = 0.88) for the DD and DI genotypes, respectively. Sensitivity analyses were confirmatory. CONCLUSIONS: : Our meta-analysis supports the hypothesis that the enhanced ACE activity associated with the D allele is associated with higher LV mass. Smaller sample size might explain the lack of significant association with LVH. PMID- 21273224 TI - The association between circulating angiotensin-converting enzyme and cardiovascular risk in the elderly: a cross-sectional study. AB - INTRODUCTION: A polymorphism in the angiotensin-converting enzyme gene (ACE I/D polymorphism) has been associated with increased risk for cardiovascular disease (CVD). This polymorphism affects the level of circulating ACE, but there is great individual variation, even between those with the same genotype. Few previous studies have investigated the link between circulating ACE and cardiovascular risk. The aim of this study was to investigate this association, and to examine the relationship between ACE level, ACE genotype and CVD. MATERIALS AND METHODS: The study population consisted of 322 men and 350 women aged 69-87. Plasma ACE level was determined using enzyme-linked immunosorbent assay (ELISA), and ACE genotype was analysed using PCR followed by gel electrophoresis. RESULTS: In men, ACE levels increased with increasing number of cardiovascular risk factors (p = 0.003). There was a significant association in men between increased ACE level and both diabetes (p = 0.007) and smoking (p = 0.037). CONCLUSIONS: This study shows that cardiovascular risk factors (such as smoking and diabetes) are associated with higher levels of circulating ACE in men. High ACE levels may represent one of the cellular mechanisms involved in producing the vascular damage associated with cardiovascular risk factors. PMID- 21273225 TI - Breast cancer screening: ''reassuring'' the worried well? AB - BACKGROUND: One of the suggested benefits of cancer screening is the peace of mind and reassurance experienced by those women who are given negative results. The aim of the present study was to investigate whether there was a difference in the expression of psychosocial aspects in a population of women offered screening compared to a population of women not offered screening for breast cancer. METHODS: One thousand women, aged 50-69 years, were randomly drawn from the Danish Civil Registration System to receive part I of the questionnaire Consequences of Screening in Breast Cancer (COS-BC1): the sample consisted of 500 women living in a geographical area where screening mammography had been offered for more than 10 years and 500 women living in an area where the public health authorities had never invited women to breast cancer screening. RESULTS: A total of 759 women returned the questionnaire. Those living in areas where screening was not offered reported more negative psychosocial aspects compared to women living in areas where screening was offered. CONCLUSIONS: The results indicate that women tend to perceive breast cancer screening as a reassuring preventive initiative. Alternatively, the results indicate that the lack of invitation to breast cancer screening may have a negative psychosocial impact. PMID- 21273226 TI - Nature-assisted therapy: systematic review of controlled and observational studies. AB - BACKGROUND: Nature's potentially positive effect on human health may serve as an important public health intervention. While several scientific studies have been performed on the subject, no systematic review of existing evidence has until date been established. METHODS: This article is a systematic evaluation of available scientific evidence for nature-assisted therapy (NAT). With the design of a systematic review relevant data sources were scrutinised to retrieve studies meeting predefined inclusion criteria. The methodological quality of studies and abstracted data were assessed for intervention studies on NAT for a defined disease. The final inclusion of a study was decided by the authors together. RESULTS: The included studies were heterogeneous for participant characteristics, intervention type, and methodological quality. Three meta-analyses, six studies of high evidence grade (four reporting significant improvement), and 29 studies of low to moderate evidence grade (26 reporting health improvements) were included. For the studies with high evidence grade, the results were generally positive, though somewhat ambiguous. Among the studies of moderate to low evidence grade, health improvements were reported in 26 cases out of 29. CONCLUSIONS: This review gives at hand that a rather small but reliable evidence base supports the effectiveness and appropriateness of NAT as a relevant resource for public health. Significant improvements were found for varied outcomes in diverse diagnoses, spanning from obesity to schizophrenia. Recommendations for specific areas of future research of the subject are provided. PMID- 21273227 TI - Macro-environmental factors associated with leisure-time physical activity: a cross-national analysis of EU countries. AB - BACKGROUND: Although there is a growing agreement among researchers that the modern environment contributes to the current trend of decreasing leisure-time physical activity (LTPA), there are very few studies addressing environmental and policy correlates of LTPA within a cross-national European context. This study describes LTPA patterns across the European Union and identifies some macro environmental factors associated with LTPA rates at a national level. METHODS: Data on LTPA and indicators of the economic, physical, and policy environment were assembled from international databases for the 27 European member states. To examine the association of each of the independent macro-environmental variables and LTPA as a continuous dependent variable, bivariate linear regression models were employed. Separate analyses were done for the overall, male, and female groups. RESULTS: With respect to LTPA, striking differences between European member states and genders were found, with higher rates in Western and Northern European countries, and among males. Statistical significant associations were observed between overall LTPA and variables from the economic (GDP, real GDP, and public expenditures on health), food (available fat, available fruit, and vegetables), urbanisation (urban population, total and new passenger cars), and policy (all governance indicators) domains. Associations for male and female LTPA were similar, except that for males available fruit and vegetables, and for females available fat and urban population were not significant. CONCLUSIONS: This exploratory study seeks to plead for the need for cross-nationally comparable LTPA data and more sophisticated research in order to understand the role of macro-economic environments, with a special focus on policy-related variables and gender-specific differences. PMID- 21273228 TI - Using pictures as vignettes to assess stages of change in weight management. AB - AIMS: To evaluate the association between descriptions of the stage of change in weight management (using pictures as vignettes) and the changes in the restriction of amount of food and body weight. The goal is to develop counselling methods for helping people to change their lifestyles. METHODS: A total of 74 people at high risk of type 2 diabetes participated in six months of group counselling. The data were collected through questionnaires and video-recordings at the beginning and the end of the counselling process, and were analyzed using both deductive content analysis and statistical analysis. RESULTS: Most of the participants were at the contemplation stage at the beginning of the study, and nearly half were at the action stage at six months. There were associations between progression in the lifestyle change process, the restriction of food amount, and weight changes. Judging from this, the descriptions of the change process of weight management using pictures were well made, because the change process progressed in parallel with the changes in weight and restriction of the amount of food eaten. CONCLUSIONS: Assessing the stages of change in weight management by using pictures as vignettes is easy to carry out, and feasible. The descriptions of the stages of change were parallel with the changes in restriction of food and changes in weight. PMID- 21273229 TI - District nurses' use for an assessment tool in their daily work with elderly patients' medication management. AB - AIM: To explore the capability of the Safe Medication Assessment (SMA) tool in identifying factors highly related to unsafe medication management among elderly patients and to investigate the district nurses' (DNs) opinions of the SMA's usefulness as a tool in their daily primary healthcare practice. INTRODUCTION: Elderly patients who experience many medical conditions often use multiple drugs. As well as the combined decline in physical and cognitive functions, the elderly are at high risk for medication-related problems. It is essential to develop a screening procedure to distinguish elderly at risk of an unsafe medication management. METHODS: An explorative study. During a 3-6-month period, 25 voluntary DNs used SMA with 160 patients (consecutively chosen and meeting four specified criteria) in their daily practice. Furthermore, DNs responded to questions regarding SMA's usefulness. RESULTS: The result showed that SMA had the capability to identify factors highly related to unsafe medication management among the elderly included in the study. In 64% of assessments DNs identified areas of new information and in 23% of the assessments DNs intervened. They found SMA to be satisfactory regarding its level of simplicity, relevance, completeness, intelligibility, and time for implementation. CONCLUSIONS: SMA alerted the DNs to patients' attitudes about medication and empowered them in identifying elderly patients who had unsafe medication management. SMA was also perceived as a useful assessment tool by the DNs. PMID- 21273230 TI - Remifentanil does not impair left ventricular systolic and diastolic function in young healthy patients. AB - BACKGROUND: Experimental studies and investigations in patients with cardiac diseases suggest that opioids at clinical concentrations have no important direct effect on myocardial relaxation and contractility. In vivo data on the effect of remifentanil on myocardial function in humans are scarce. This study aimed to investigate the effects of remifentanil on left ventricular (LV) function in young healthy humans by transthoracic echocardiography (TTE). We hypothesized that remifentanil does not impair systolic, diastolic LV function, or both. METHODS: Twelve individuals (aged 18-48 yr) without any history or signs of cardiovascular disease and undergoing minor surgical procedures under general anaesthesia were studied. Echocardiographic examinations were performed in the spontaneously breathing subjects before (baseline) and during administration of remifentanil at a target effect-site concentration of 2 ng ml(-1) by target controlled infusion. Analysis of systolic function focused on fractional area change (FAC). Analysis of diastolic function focused on peak early diastolic velocity of the mitral annulus (e') and on transmitral peak flow velocity (E). RESULTS: Remifentanil infusion at a target concentration of 2 ng ml(-1) did not affect heart rate or arterial pressure. There was no evidence of systolic or diastolic dysfunction during remifentanil infusion, as the echocardiographic measure of systolic function (FAC) was similar to baseline, and measures of diastolic function remained unchanged (e') or improved slightly (E). CONCLUSION: Continuous infusion of remifentanil in a clinically relevant concentration did not affect systolic and diastolic LV function in young healthy subjects during spontaneous breathing as indicated by TTE. PMID- 21273231 TI - Association of -27T>C and its haplotype at the putative promoter for IgA-specific receptor gene with IgA nephropathy among the Chinese Han population. AB - BACKGROUND: One-third to half of IgA nephropathy (IgAN) patients have raised serum IgA levels. Decreased clearance of IgA/IgA complex has been observed in IgAN patients. FCAR codes for IgA-specific receptor and plays an important role in IgA metabolism. Previous small sample-sized studies reported controversial findings in its association with IgAN. METHODS: We re-sequenced the FCAR in 107 IgAN patients and 112 controls. Association of -27T/C and their haplotypes were performed in 606 patients versus 606 controls, its two independent subsets: 293 single patients with family members and 313 cases versus 606 controls. Functional impact of -27T>C and their haplotypes were analyzed by bioinformatics, allelic differential expression and luciferase activity assays. Cell surface FCAR density between -27T/C heterozygous patients and -27T/T homozygous controls was assessed by flow cytometry. RESULTS: -27T>C, on the consensus TATA box of transcription factor-binding motif in the putative promoter of the gene was the only variation identified in all coding, splice-site and known protein-binding sequence in re sequencing. -27C and its haplotype were associated with IgAN (P = 0.0034/0.0013, 0.0099/0.0054, 0.0129/0.0076 and 0.00039/0.00014 in 606 cases versus 606 controls, family-based study, 313 cases versus 606 controls and meta-analysis, respectively). Bioinformatics predicted 2 bp binding changes by -27C. Allelic differential expression and luciferase activity assays showed a reduced expression/activity by the associated haplotype/allele (P < 0.001). -27T/C heterozygous patients had a lower receptor density on cell surface compared to 27T/T homozygous controls (P < 0.001). CONCLUSIONS: Our results provide evidence for genetic variation at the putative promoter region of FCAR conferring susceptibility to IgAN, suggesting -27C and its haplotype may be causative for the susceptibility among the Chinese Han population. PMID- 21273233 TI - Immunostaining findings in IgA nephropathy: correlation with histology and clinical outcome in the Oxford classification patient cohort. AB - BACKGROUND: IgA nephropathy is defined by the presence of IgA-dominant glomerular deposits. Within this definition, there is variation in the location of IgA and the presence of other immunoglobulins. The Oxford classification of IgA nephropathy identifies four histological features that are independent predictors of clinical outcome but does not include immunostains. Here, we investigate the potential clinical significance of immunostaining data. METHODS: Original biopsy reports from the patients in the Oxford classification study were reviewed. The location of IgA deposits (mesangial versus mesangial + capillary wall) and the presence of IgG >trace were correlated with histological and clinical features. RESULTS: Original biopsy reports were available for 211 of 265 patients in the Oxford classification cohort, of which 175 included sufficient details to subclassify immunostaining findings. The presence of capillary wall IgA deposits was associated with a higher mesangial cellularity score (1.3 +/- 0.6 versus 0.9 +/- 0.5 for mesangial-only IgA, P = 0.007) and endocapillary proliferation (per cent of patients with any endocapillary proliferation of 62 versus 35% for mesangial-only IgA, P = 0.01). Similarly, the presence of IgG was associated with a higher mesangial cellularity score (1.2 +/- 0.6 versus 0.9 +/- 0.5, P = 0.03) and endocapillary proliferation (per cent of patients with endocapillary proliferation of 57 versus 31% with no IgG, P = 0.009). There was no significant association between the location of IgA or the presence of IgG and rate of loss of renal function and association between the location of IgA and renal survival although patients with these immunofluorescence findings tended to receive more immunosuppression. There was a trend towards poorer renal survival in those patients with glomerular IgG (hazard ratio of 2.1, 95% confidence interval, 1.0 4.6, P = 0.06). CONCLUSIONS: We conclude that the location of glomerular IgA and the presence of IgG correlate with mesangial and endocapillary cellularity. This supports the role of IgG and capillary wall IgA in the development of proliferative changes in IgA nephropathy. PMID- 21273232 TI - Epidemiology, clinical features and outcomes of pneumonia in patients with chronic kidney disease. AB - BACKGROUND: Although infection remains among the most common causes of morbidity and mortality in patients with chronic kidney disease (CKD), data on epidemiology, clinical features and outcomes of pneumonia in this population are scarce. METHODS: Observational analysis of a prospective cohort of hospitalized adults with pneumonia, between 13 February 1995 and 30 April 2010, in a tertiary teaching hospital. CKD patients, defined as patients with a baseline glomerular filtration rate <60 mL/min/1.73 m(2), were compared with non-CKD patients. RESULTS: During the study period, 3800 patients with pneumonia required hospitalization. Two-hundred and three (5.3%) patients had CKD, of whom 46 were on dialysis therapy. Patients with CKD were older (77 versus 70 years; P < 0.001), were more likely to have comorbidities (82.3 versus 63.3%; P < 0.001) and more commonly classified into high-risk pneumonia severity index classes (89.6 versus 57%; P < 0.001) than were the remaining patients. Streptococcus pneumoniae was the most frequent pathogen (28.1 versus 34.7%; P = 0.05). Mortality was higher in patients with CKD (15.8 versus 8.3%; P < 0.001). Among CKD patients, age [+1 year increase; adjusted odds ratio, 1.25; 95% confidence interval (CI) 1.07-1.46] and cardiac complications during hospitalization (adjusted odds ratio, 9.23; 95% CI 1.39-61.1) were found to be independent risk factors for mortality, whereas prior pneumococcal vaccination (adjusted odds ratio, 0.05; 95% CI 0.005 0.69) and leukocytosis at hospital admission (adjusted odds ratio, 0.10; 95% CI 0.01-0.64) were protective factors. CONCLUSIONS: Pneumonia is a serious complication in CKD patients. Independent factors for mortality are older age and cardiac complications, whereas prior pneumococcal vaccination and leucokytosis at hospital admission are protective factors. These findings should encourage physicians to increase pneumococcal vaccine coverage among CKD patients. PMID- 21273234 TI - Fluid overload correction and cardiac history influence brain natriuretic peptide evolution in incident haemodialysis patients. AB - OBJECTIVES: Brain natriuretic peptide (BNP) is a cardiac peptide secreted by ventricle myocardial cells under stretch constraint. Increased BNP has been shown associated with increased mortality in end-stage renal disease patients. In patients starting haemodialysis (HD), both fluid overload and cardiac history are frequently present and may be responsible for a high BNP plasma level. We report in this study the evolution of BNP levels in incident HD patients, its relationship with fluid removal and cardiac history as well as its prognostic value. METHODS: Forty-six patients (female/male: 21/25; 68.6 +/- 14.5 years old) surviving at least 6 months after HD treatment onset were retrospectively analysed. Plasma BNP (Chemoluminescent Microparticule ImmunoAssay on i8200 Architect Abbott, Paris, France; normal value < 100 pg/mL) was assessed at HD start and during the second quarter of HD treatment (Q2). RESULTS: At dialysis start, the plasma BNP level was 1041 +/- 1178 pg/mL (range: 14-4181 pg/mL). It was correlated with age (P = 0.0017) and was significantly higher in males (P = 0.0017) and in patients with cardiac disease history (P = 0.001). The plasma BNP level at baseline was not related to the mortality risk. At Q2, predialysis systolic blood pressure (BP) decreased from 140.5 +/- 24.5 to 129.4 +/- 20.6 mmHg (P = 0.0001) and the postdialysis body weight by 7.6 +/- 8.4% (P < 0.0001). The BNP level decreased to 631 +/- 707 pg/mL (P = 0.01) at Q2. Its variation was significantly correlated with systolic BP decrease (P = 0.006). A high BNP level was found associated with an increased risk of mortality. CONCLUSIONS: Hence, plasma BNP levels decreased during the first months of HD treatment during the dry weight quest. Whereas initial BNP values were not associated with increased mortality risk, the BNP level at Q2 was independently predictive of mortality. Hence, BNP is a useful tool to follow patient dehydration after dialysis start. Initial fluid overload may act as a confounding factor for its value as a prognostic marker because of cardiac disease. PMID- 21273235 TI - Different kinetics of HBV and HCV during haemodialysis and absence of seronegative viral hepatitis in patients with end-stage renal disease. AB - BACKGROUND: Hepatitis C virus (HCV) and hepatitis B virus (HBV) infections are common in haemodialysis units. Moreover, some studies reported seronegative cases of viral hepatitis. We and others have previously shown an HCV RNA decline during haemodialysis; however, limited data on HBV viraemia during haemodialysis are available. METHODS: A total of 142 haemodialysis patients participated in this study, 11 were anti-HCV positive and 7 were HBsAg positive. HCV RNA and HBV DNA were determined in all patients irrespective of hepatitis serology. HBV DNA, HCV RNA, HBsAg and HCV core antigen (HCVcoreAg) were quantified repeatedly in anti HCV- and HBsAg-positive patients before and after haemodialysis. RESULTS: No case of seronegative viral hepatitis could be identified. HCV RNA was detected in 9 of the 11 anti-HCV-positive patients, while HBV DNA tested positive in all 7 HBsAg positive patients. A decrease of HCVcoreAg was observed during four dialysis sessions in 8/9 patients (-24.4 +/- 22.7%, P < 0.001) parallelled by HCV RNA decline in most individuals (-10.1 +/- 48.6%, P = 0.22). In contrast, HBV DNA and HBsAg declined only in 1/7 patients during all four independent measurements. The remaining six patients showed heterogeneous patterns of HBV DNA and HBsAg before and after haemodialysis without a significant change in mean HBV DNA and HBsAg levels (+14 +/- 60.6% and -0.2 +/- 25.3%, P > 0.05, respectively). HCVcoreAg correlated strongly with HCV RNA (r = 0.937; P < 0.001, n = 72), while there was no correlation between HBV DNA and HBsAg (r = -0.234; P = 0.131, n = 43). CONCLUSIONS: Seronegative viral hepatitis is rare in German maintenance haemodialysis patients. HCV RNA and HCVcoreAg decline during haemodialysis indicating a potential beneficial effect of haemodialysis during antiviral therapy of hepatitis C, which does not apply to HBV infection. PMID- 21273236 TI - Immunogenicity of an adjuvanted 2009 pandemic influenza A (H1N1) vaccine in haemodialysed patients. AB - BACKGROUND: The 2009 pandemic of influenza A (H1N1) prompted an urgent worldwide vaccination campaign, especially of high-risk subjects, such as maintenance haemodialysis (HD) patients. Still the immunogenicity of the pandemic A (H1N1) vaccine in HD patients is unknown. METHODS: We prospectively studied the immunogenicity of a monovalent adjuvanted influenza A/California/2009 (H1N1) vaccine (Pandemrix, GSK Biologicals, Rixensart, Belgium) in HD patients and controls. Antibody level was measured using a seroneutralization assay before (D(0)) and 30 days after (D(30)) a single 3.75 MUg vaccine dose. Specimens were tested in quadruplicates. Geometric mean (GM) antibody titers were determined in each subject at D(0) and D(30). Seroconversion was defined as an increase in GM titers by a factor 4 or more. RESULTS: Fifty-three adult HD patients [aged 71 +/- 10, 58.5% males, on HD for a median of 38 (3 - 146) months] and 32 control subjects (aged 47.3 +/- 14, 31.3% males) were analyzed. Baseline GM titers were similar in HD patients and controls [7.9 (6.6 - 9.6) vs 10 (6 - 17); p = 0.69]. Seroconversion was observed in 30 (93.8%) controls and 34 (64.2%) HD patients (p = 0.002). In addition, GM titers at D(30) were significantly higher in controls than in HD patients [373 (217 - 640) vs 75.5 (42.5 - 134); p = 0.001]. HD patients were significantly older than controls (p < 0.001) and more likely to be males (p = 0.02). However, by multivariate analysis, HD status [OR 0.13 (0.02 0.78), p = 0.03], but neither age [OR 0.99 (0.96 - 1.03); p = 0.7] nor male gender [OR 1.31 (0.45 - 3.85); p = 0.63] was independently associated with seroconversion. The vaccine was generally well tolerated by HD patients. CONCLUSIONS: Only 64% of chronic HD patients developed seroconversion after a single dose of adjuvanted influenza A (H1N1) vaccine, a much lower rate than in controls (94%). These results underscore the substantial immunodeficiency associated with End-Stage Renal Disease. The persistence of protective antibodies as well as the effect of a booster dose remain to be investigated in HD patients. PMID- 21273237 TI - ANCA vasculitis meets epigenetics--closing in on the molecular roots of disease. PMID- 21273238 TI - World Kidney Day 2011: protect your kidneys, save your heart. PMID- 21273239 TI - TMP revisited: the importance of plasma colloid osmotic pressure in high-flux dialyzers. PMID- 21273240 TI - In search of early events in the development of chronic kidney disease: the emerging role for lipocalin-2/NGAL. PMID- 21273241 TI - Kidney diseases beyond nephrology: intensive care. PMID- 21273242 TI - Kidney disease in diabetology: lessons from 2010. PMID- 21273243 TI - The relationship between arrhythmogenesis and impaired contractility in heart failure: role of altered ryanodine receptor function. AB - AIMS: In heart failure (HF), abnormal myocyte Ca(2+) handling has been implicated in cardiac arrhythmias and contractile dysfunction. In the present study, we investigated the relationships between Ca(2+) handling, reduced myocyte contractility, and enhanced arrhythmogenesis during HF progression in a canine model of non-ischaemic HF. METHODS AND RESULTS: Key Ca(2+) handling parameters were determined by measuring cytosolic and intra-sarcoplasmic reticulum (SR) [Ca(2+)] in isolated ventricular myocytes at different stages of HF. The progression of HF was associated with an early and continuous increase in ryanodine receptor (RyR2)-mediated SR Ca(2+) leak. The increase in RyR2 activity was paralleled by an increase in the frequency of diastolic spontaneous Ca(2+) waves (SCWs) in HF myocytes under conditions of beta-adrenergic stimulation. In addition to causing arrhythmogenic-delayed afterdepolarizations, SCWs decreased the amplitude of subsequent electrically evoked Ca(2+) transients by depleting SR Ca(2+). At late stages of HF, Ca(2+) release oscillated essentially independent of electrical pacing. The increased propensity for the generation of SCWs in HF myocytes was attributable to reduced ability of the RyR2 channels to become refractory following Ca(2+) release. The progressive alterations in RyR2 function and Ca(2+) cycling in HF myocytes were associated with sequential modifications of RyR2 by CaMKII-dependent phosphorylation and thiol oxidation. CONCLUSION: These findings suggest that destabilized RyR2 activity due to excessive CaMKII phopshorylation and oxidation resulting in impaired post-release refractoriness is a common mechanism involved in arrhythmogenesis and contractile dysfunction in the failing heart. PMID- 21273244 TI - Enhanced expression of DYRK1A in cardiomyocytes inhibits acute NFAT activation but does not prevent hypertrophy in vivo. AB - AIMS: The calcineurin and nuclear factor of activated T cells (NFAT) pathway can mediate pro-hypertrophic signalling in the heart. Recently, it has been shown that dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) phosphorylates NFAT, which limits calcineurin/NFAT signal transduction in T cells and hypertrophy in cultured cardiomyocytes. The hypothesis tested in this study was that DYRK1A prevents calcineurin/NFAT-mediated cardiac hypertrophy in vivo. METHODS AND RESULTS: In cultured rat cardiomyocytes, adenovirus-mediated overexpression of DYRK1A antagonized calcineurin-mediated nuclear NFAT translocation and the phenylephrine-induced hypertrophic growth response. To test the ability of DYRK1A to reduce hypertrophic cardiac growth in vivo, we created tetracycline-repressible Dyrk1a transgenic mice to avoid the cardiac developmental defects associated with embryonic DYRK1A expression. However, in the mouse model, histological determination of myocyte diameter, heart weight/body weight ratio, and echocardiographic measurements revealed that myocardial expression of DYRK1A failed to reduce hypertrophy induced via aortic banding or co-expression of calcineurin. This discrepancy is explained, at least in part, by insufficient long-term inhibition of NFAT and the activation of DYRK1A-resistant maladaptive genes in vivo. CONCLUSION: Isolated augmentation of DYRK1A can be compensated for in vivo, and this may significantly limit anti hypertrophic interventions aimed at enhancing DYRK1A activity. PMID- 21273245 TI - PC6 levels in uterine lavage are closely associated with uterine receptivity and significantly lower in a subgroup of women with unexplained infertility. AB - BACKGROUND Embryo implantation requires a healthy embryo and a receptive uterus. Uterine incompetence contributes significantly to implantation failure and infertility. To date, there are no reliable biochemical methods that can determine whether the uterus is receptive. Proprotein convertase 5/6 (PC6) is tightly regulated in the uterus and critical for receptivity and implantation; its secretory nature predicts PC6 to be secreted into the uterine cavity. The present study examines whether PC6 is detectable in uterine lavage and whether there is any correlation between secreted PC6 levels and uterine receptivity. METHODS Western blotting determined the presence of PC6 protein in uterine lavage. A sensitive and high-throughput activity assay was established and validated. This assay was applied to 103 lavages collected from different phases of the menstrual cycle from women with proven fertility or unexplained infertility. RESULTS Uterine lavage contained PC6 protein with levels paralleling enzymatic activity. PC6 levels were significantly higher in the receptive than in the non-receptive phase in fertile women, and the putative receptive phase levels in a subgroup of women with unexplained infertility were significantly lower than in the fertile counterparts. CONCLUSIONS PC6 levels in uterine lavage are significantly elevated in the luteal phase of fertile women and markedly reduced in a subgroup of women with unexplained infertility. Uterine fluid is a valuable source of material to evaluate uterine function. Detection of PC6 in uterine fluid may lead to the development of a rapid and relatively non-surgical assessment of uterine receptivity. PMID- 21273246 TI - Emw1p/YNL313cp is essential for maintenance of the cell wall in Saccharomyces cerevisiae. AB - There are six essential genes in the Saccharomyces cerevisiae genome which encode proteins bearing the tetratricopeptide repeat (TPR) domain that mediates protein protein interaction. Thus far, the function of one of them, YNL313c, remains unknown. Our conditional mutants of YNL313c display osmoremedial temperature sensitivity, hypersensitivity to both Calcofluor White and low concentrations of SDS, and osmoremedial caffeine sensitivity. These are hallmarks of mutants that display cell wall defects. Accordingly we rename the gene as EMW1 (essential for maintenance of the cell wall). Loss of Emw1p function is not associated with abrogation of the cell wall integrity (CWI) MAP kinase cascade. Instead, emw1(ts) mutants activate this cascade even at permissive temperature, indicating that loss of Emw1p function does not cause a defect in sensors and effectors of cell wall signalling, but leads to a cell wall defect directly. Constitutive activation of the CWI cascade is reflected by the overproduction of chitin by emw1(ts) mutants, a compensatory response frequently displayed by cell wall mutants. Growth is restored to emw1(ts) mutants incubated at otherwise non permissive temperature when GFA1 is overexpressed. GFA1 encodes the hexosephosphate aminotransferase that catalyses the rate-limiting step in the pathway that synthesizes the chitin precursor UDP-GlcNAc. The possibility that Emw1p is required for function of Gfa1p was ruled out, because the emw1(ts) phenotype persists when the requirement for Gfa1p is bypassed. Furthermore, if loss of Emw1p function leads to loss of function of Gfa1p, then chitin synthesis would be diminished. Instead, a stimulation of the synthesis of this polymer is detected. Consequently, the defect associated with emw1(ts) mutants may be associated with compromise in one of the remaining processes that depend on UDP GlcNAc, namely N-glycosylation or glycosylphosphatidylinositol (GPI)-anchor synthesis. PMID- 21273247 TI - The role of the antimicrobial compound 2,4-diacetylphloroglucinol in the impact of biocontrol Pseudomonas fluorescens F113 on Azospirillum brasilense phytostimulators. AB - Pseudomonads producing the antimicrobial metabolite 2,4-diacetylphloroglucinol (Phl) can control soil-borne phytopathogens, but their impact on other plant beneficial bacteria remains poorly documented. Here, the effects of synthetic Phl and Phl(+) Pseudomonas fluorescens F113 on Azospirillum brasilense phytostimulators were investigated. Most A. brasilense strains were moderately sensitive to Phl. In vitro, Phl induced accumulation of carotenoids and poly-beta hydroxybutyrate-like granules, cytoplasmic membrane damage and growth inhibition in A. brasilense Cd. Experiments with P. fluorescens F113 and a Phl(-) mutant indicated that Phl production ability contributed to in vitro growth inhibition of A. brasilense Cd and Sp245. Under gnotobiotic conditions, each of the three strains, P. fluorescens F113 and A. brasilense Cd and Sp245, stimulated wheat growth. Co-inoculation of A. brasilense Sp245 and Pseudomonas resulted in the same level of phytostimulation as in single inoculations, whereas it abolished phytostimulation when A. brasilense Cd was used. Pseudomonas Phl production ability resulted in lower Azospirillum cell numbers per root system (based on colony counts) and restricted microscale root colonization of neighbouring Azospirillum cells (based on confocal microscopy), regardless of the A. brasilense strain used. Therefore, this work establishes that Phl(+) pseudomonads have the potential to interfere with A. brasilense phytostimulators on roots and with their plant growth promotion capacity. PMID- 21273248 TI - RpoE1, an extracytoplasmic function sigma factor, is a repressor of the flagellar system in Brucella melitensis. AB - The genome of Brucella melitensis contains genes coding for the sigma factors RpoD, RpoN, RpoH1, RpoH2, RpoE1 and RpoE2. Previously published data show that B. melitensis is flagellated and that an rpoE1 mutant overexpresses the flagellar protein FlgE. In this study, we demonstrate that mutation of rpoE1 causes an overexpression of the flagellar genes fliF, flgE, fliC, flaF and flbT, correlating with the production of a longer filament and thereby demonstrating that RpoE1 acts as a flagellar repressor. Moreover, mutation of rpoE1 increases the promoter activity of the flagellar master regulator ftcR, suggesting that RpoE1 acts upstream of ftcR. Together, these data show that RpoE1 represses the flagellar synthesis and filament length in B. melitensis. PMID- 21273249 TI - Role of FlbT in flagellin production in Brucella melitensis. AB - It was recently demonstrated that the pathogen Brucella melitensis produces a polar sheathed flagellum under the control of the master regulator FtcR. However, the regulatory mechanism controlling the flagellar assembly remains unknown. In this work, we investigate the flagellar hierarchy of B. melitensis as well as the flagellin FliC regulation. We show that a mutation in fliF or flgE (coding for the basal body structure and the hook, respectively) does not affect FliC synthesis, suggesting that production of FliC does not depend on the flagellar assembly. We demonstrate that FlbT is a FliC activator since inactivation of flbT causes a decrease in fliC expression by using a fliC-lacZ translational reporter construct. Moreover, the quantitative real-time PCR and Western blot analysis show a marked decrease in fliC mRNA and FliC protein level, respectively. Conversely, the B. melitensis wild-type strain overexpressing flaF fails to produce FliC, suggesting an opposite function. Interestingly, the expression of the flbT gene in an ftcR or an flbT mutant restores FliC production, demonstrating that FlbT plays a regulatory checkpoint role in FliC synthesis. This mechanism could be conserved in the Rhizobiales since complementation of an flbT or an ftcR mutant with flbT from Sinorhizobium meliloti restores FliC synthesis. PMID- 21273250 TI - Dissection of the relative contribution of the Schizosaccharomyces pombe Ctr4 and Ctr5 proteins to the copper transport and cell surface delivery functions. AB - The Ctr1 family of proteins mediates high-affinity copper (Cu) acquisition in eukaryotic organisms. In the fission yeast Schizosaccharomyces pombe, Cu uptake is carried out by a heteromeric complex formed by the Ctr4 and Ctr5 proteins. Unlike human and Saccharomyces cerevisiae Ctr1 proteins, Ctr4 and Ctr5 are unable to function independently in Cu acquisition. Instead, both proteins physically interact with each other to form a Ctr4-Ctr5 heteromeric complex, and are interdependent for secretion to the plasma membrane and Cu transport activity. In this study, we used S. cerevisiae mutants that are defective in high-affinity Cu uptake to dissect the relative contribution of Ctr4 and Ctr5 to the Cu transport function. Functional complementation and localization assays show that the conserved Met-X(3)-Met motif in transmembrane domain 2 of the Ctr5 protein is dispensable for the functionality of the Ctr4-Ctr5 complex, whereas the Met-X(3) Met motif in the Ctr4 protein is essential for function and for localization of the hetero-complex to the plasma membrane. Moreover, Ctr4/Ctr5 chimeric proteins reveal unique properties found either in Ctr4 or in Ctr5, and are sufficient for Cu uptake on the cell surface of Sch. pombe cells. Functional chimeras contain the Ctr4 central and Ctr5 carboxyl-terminal domains (CTDs). We propose that the Ctr4 central domain mediates Cu transport in this hetero-complex, whereas the Ctr5 CTD functions in the regulation of trafficking of the Cu transport complex to the cell surface. PMID- 21273251 TI - Predictors of the perceived impact of a patient safety collaborative: an exploratory study. AB - OBJECTIVE: The aim of this study was to evaluate the influence of various factors on the perceived impact of a patient safety improvement collaborative in the UK, the Safer Patients Initiative (SPI). STUDY DESIGN: A cross-sectional survey design was used. Study setting Twenty National Health Service organizations from the UK that participated in the main phase of the SPI programme, which ran from September 2007 to 2008. PARTICIPANTS: Senior executive leads, clinical operational leads in the four clinical areas targeted by the programme, programme coordinators and any other staff involved in the SPI (n = 635). INTERVENTION: The SPI is a patient safety improvement intervention based on the Breakthrough Series Collaborative model (Institute of Healthcare Improvement, 2004) aimed at improving patient safety in four clinical areas (general ward care, intensive care, perioperative care and pharmacy) through implementing a number of evidence based clinical practices and a focus on organizational leadership. Outcome measures Participant perceptions of the impact of the programme on their organizations. RESULTS: Exploratory regression analysis showed that programme management, the value assigned to programme methodology and length of data collection contributed the largest variance in perceived impact of the SPI followed by perceived support from junior doctors, inter-professional collaboration, difference of the programme from existing safety improvement practices and organizational readiness. CONCLUSIONS: The resulting model suggests hierarchical importance for a range of variables to support future research concerning the mechanisms by which large-scale organizational programmes, such as the SPI, impact on the care systems they are designed to influence. PMID- 21273252 TI - Pulmonary embolism due to biological glue after repair of type A aortic dissection. AB - Biological glue is increasingly used in cardiac surgery. We report a case of type A aortic dissection repair that was complicated by subsequent pulmonary embolism due to BioGlue((r)) (Cryolife Inc, Hennesaw, GA, USA). To our knowledge this is the first report of a case with this complication. PMID- 21273253 TI - Coronary graft patency after perioperative myocardial infarction: a study with multislice computed tomography. AB - A total of 55 consecutive patients who experienced perioperative myocardial infarction (MI) after coronary artery bypass grafting were studied using multislice computed tomography (MSCT) angiography to evaluate for graft patency. The MSCT detected acute graft occlusion in 23% grafts. Of the 55 patients, 40% patients had occluded grafts and perioperative MI in the area of the grafted vessels; remaining 60% had patent grafts with infarction in the area of the grafted vessels. Compared with the patients with patent grafts, those with occluded grafts had a higher blood sugar level. In addition, graft occlusion was higher in grafts with severe distal disease. Among the patients with patent grafts, luminal stenosis of the native vessels supplying the infarcted myocardium was higher than that in the native vessels supplying the non-infarcted myocardium. In conclusion, MSCT is feasible for the assessment of graft patency in the setting of perioperative MI. Graft occlusion is detected in less than half of the cases and usually occurs in the grafts with severe distal involvement and the patients with uncontrolled hyperglycemia. In patients with patent grafts, the severity of luminal stenosis of the native grafted vessel is the main predisposing factor for perioperative MI. PMID- 21273254 TI - Aortic valve reconstruction using self-developed aortic valve plasty system in aortic valve disease. AB - Aortic valve disease is usually treated by prosthetic valve replacement. We have performed aortic valve plasty (AVP) using glutaraldehyde-treated autologous pericardium. AVP was performed for 88 patients from April 2007 through August 2009. Sixty-five patients had aortic stenosis, and 23 patients had aortic regurgitation (AR). Twenty-one patients showed bicuspid aortic valves, and one patient showed quadricuspid valve. There were 43 males and 45 females. Their mean age was 70.6+/-10.5 years old. First, diseased leaflets excised. Then, the distance between each commissure was measured. The new leaflet were trimmed with an original template from a glutaraldehyde-treated autologous pericardium sample. Finally, the annular margin of the pericardial leaflet was running sutured to each annulus. There was no operative mortality or embolic event. Postoperative echocardiography revealed a mean peak pressure gradient (PG) of 19.0+/-9.1 mmHg one week after surgery. Thirty-two patients had echocardiography one year after surgery. The peak PG became 12.9+/-5.8 mmHg. Ten patients showed no AR, 20 patients showed trivial AR, and two patients showed mild AR. Freedom from reoperation is 100% at three years follow-up. PMID- 21273255 TI - Modified French-window thoracotomy for exposure of the anterior thoracic spine. AB - Due to the limited exposure, technical challenges, and postoperative pain of thoracic spine surgery, open thoracotomy and video-assisted thoracic surgery (VATS) are associated with significant morbidity and mortality. The modified French-window thoracotomy approach with the aid of a thoracoscope is a useful technique for approaching diseases of the anterior spinal. This approach allows for specific exposure of the spine with a reduction in postoperative pain, morbidity, and mortality and avoids the limitations of VATS. PMID- 21273256 TI - Left atrial and right ventricular myxoma: an uncommon presentation of a rare tumour. AB - Myxomas are rare tumours but are the most common benign tumours of the heart. They can arise from any heart chamber. However, they arise more frequently from the left atrium. They have rarely been described as originating from two different chambers. Their clinical presentation is varied and may mimic arterial embolism or symptoms of cardiac, infectious, malignant and immune diseases, therefore making their diagnosis challenging. We report a case of a young female patient with left atrial and right ventricular myxomas who initially presented with neurological symptoms (visual and speech disturbances). Transoesophageal echocardiography has become an invaluable tool to diagnose myxomas and plan the surgical approach. PMID- 21273257 TI - Structural characteristics of small intestinal submucosa constructs dictate in vivo incorporation and angiogenic response. AB - The rate of angiogenesis and cellular infiltration into degradable biomaterials determines scaffold persistence in vivo. The ability to tune the degradation properties of naturally derived biomaterials has been a popular goal in tissue engineering, yet has often depended on chemical crosslinking. Small intestinal submucosa (SIS) is a naturally derived, collagen-based, bioactive scaffold that has broad clinical success in many therapeutic applications. Two methods for producing multilayer, non-crosslinked SIS constructs were compared in vitro and in vivo. Traditional and cryo SEM, mercury intrusion porosimetry, and a novel enzymatic degradation assay determined that lyophilization produced an open, porous scaffold, in contrast to the collapsed, denser structure of SIS constructs produced using a vacuum press process. The angiogenic responses to lyophilized and vacuum-pressed SIS constructs were evaluated in vivo using a subcutaneous implant assay in mice. Explanted samples were compared after 7 and 21 days using fluorescence microangiography and light microscopy. Capacity of the implant neovasculature was also determined. These experiments revealed that the lyophilized SIS was infiltrated and vascularized more rapidly than the vacuum pressed. These data demonstrate the tunable incorporation of a non-crosslinked ECM-based biomaterial, which may have implications for the persistence of this degradable scaffold in tissue engineering. PMID- 21273258 TI - Development of conical soluble phosphate glass fibers for directional tissue growth. AB - One of the challenges of tissue engineering is the regulation of vascularization and innervations of the implant by the host. Here, we propose that using soluble phosphate glass (SPG) fibers, incorporated in dense collagen constructs will allow us to control the rate and direction of tissue ingrowth. The idea here was to generate channels with tailored direction using conical phosphate glass fibers. The changing surface area-to-mass ratio of conical fibers will make them to dissolve faster from their narrow ends opening up channels in that direction ahead of any ingrowing cells. In this study, we show that SPG fibers can be manipulated to produce conical shape fibers using graded dissolution. Our result shows that 40 um fibers of composition ratio 0.5 (P(2)O(5)):0.25 (CaO):0.25 (Na(2)O) and dissolution time of 8-10 h have a mean reduction in fiber diameter of 8.85 +/- 2.8 um over 19.5 mm fiber length, i.e., a mean rate of 0.5 um/mm (n=20) change. These conically shaped fibers can also be manipulated and potentially used to promote uniaxial cell-tissue ingrowth for improved innervations and vascularization of tissue engineered constructs. PMID- 21273259 TI - Phase development during setting and hardening of a bone cement based on alpha tricalcium and octacalcium phosphates. AB - In this study, the phase development in the cement system alpha-TCP-OCP with phosphoric acid as a setting liquid was studied. The most promising formulation of alpha-TCP (60 wt%) and OCP (40 wt%) is proposed. This cement has the following characteristics: setting time 10 min, pH = 6.7, the compressive strength about 30 MPa, and high dissolution rate in an isotonic solution; the final wt% composition of alpha-TCP/DCPD/HA/OCP equals 27/38/20/15. Energy dispersive X-ray diffraction techniques were used for in situ monitoring of the processes taking place in the cement in real time. PMID- 21273260 TI - Thermal, dynamic mechanical, and dielectric analyses of some polyurethane biocomposites. AB - Polymer biocomposites based on segmented poly(ester urethane) and extracellular matrix components have been prepared for the development of tissue engineering applications with improved biological characteristics of the materials in contact with blood and tissues for long periods. Thermal, dynamical, and dielectrical analyses were employed to study the molecular dynamics of these materials and the influence of changing the physical network morphology and hydrogen bond interactions accompanied by phase transitions, interfacial effects, and polarization or conductivity. All phenomena that concur in the tested materials are evaluated by cross-examination of the dynamic mechanical characteristic properties (storage modulus, loss modulus, and loss factor) and dielectric properties (relative permittivity, relative loss factor, and loss tangent) as a function of temperature. Comparative aspects were elucidated by calculating the apparent activation energies of multiplex experiments. PMID- 21273261 TI - In vivo assessment of bone ingrowth potential of three-dimensional e-beam produced implant surfaces and the effect of additional treatment by acid etching and hydroxyapatite coating. AB - The bone ingrowth potential of three-dimensional E-beam-produced implant surfaces was examined by histology and compared to a porous plasma-sprayed control. The effects of acid etching and a hydroxyapatite (HA) coating were also evaluated by histology. Specimens were implanted in the distal femur of 10 goats. Histological analysis of bone ingrowth was performed 6 weeks after implantation. The E-beam produced surfaces showed significantly better bone ingrowth compared to the plasma-sprayed control. Additional treatment of the E-beam surface structures with a HA coating, further improved bone ingrowth potential of these structures significantly. Acid etching of the E-beam structures did not influence bone ingrowth significantly. In conclusion, the HA-coated, E-beam-produced structures are promising potential implant surfaces. PMID- 21273262 TI - Investigation of PEG-PLGA-PEG nanoparticles-based multipolyplexes for IL-18 gene delivery. AB - Nanoparticles were formulated with biodegradable monomethoxy (poly ethylene glycol)-poly(lactide-co-glycolide)-monomethoxy (poly ethylene glycol) of three different proportional (PEG-PLGA-PEG, lactic acid: glycolic acid = 80/20, 70/30, 50/50) and the cytotoxicity of nanoparticle was characterized according to US Pharmacopoeia XXIII recommendations on various cell lines, including L929, Chang's hepatocytes, primary mouse myoblasts, osteoblasts, and renal vascular endothelial cells. mIL-18 gene was first condensed by polycationic peptide polylysine (PLL), and then encapsulated in the PEG-PLGA-PEG NPs as a novel multi polyplex gene delivery system - Polymer-PLL-DNA. (PPDs) After lyopholization, the morphology, particle size, zeta potential, and the integrity of DNA in the NPs were investigated. The expression of mIL-18 gene on CT-26 cells in vitro were determined by western blot, while in vivo efficacy was evaluated by tumor inhibition rate, histological section, and survival curve in pulmonary metastasis of colon cancer in BALB/c mice model. Results showed that the cytotoxicity of blank nanoparticles was related to the degradation properties of the polymers with different compositions. The NPs with LA:GA = 70/30 (NPs-73) was optimal for intravenous injection due to its low cytotoxicity. Physicochemical properties of the PPDs were not changed during the lyopholization, while mIL-18 was successfully expressed in vitro. The anti-tumor efficacy in vivo of PPDs showed improvement especially combined with chemotherapy of cisplatin, and confirmed the promising application of the PPDs system, which compared with any single treatment. PMID- 21273263 TI - Enhanced mechanical properties and in vitro cell response of surface mechanical attrition treated pure titanium. AB - Surface mechanical attrition treatment (SMAT) was used to fabricate nanocrystalline surface layers on the commercial purity titanium. X-ray diffraction and transmission electron microscopy results indicate that the top layer contained nanograins. Enhanced strength and microhardness were achieved due to the surface nanostructure. Cell culture tests have shown a greater adhered cell density and more extensively spreading morphologies of Saos-2 cells on the SMAT substrates compared to those on the as-received Ti counterparts. Enhanced cell viability and cell cycle were also achieved on the SMAT Ti substrates. These could be attributed to the nanostructure grains with the increased surface hydrophilicity and roughness on the SMAT Ti. PMID- 21273264 TI - Characterizations of chondrocyte attachment and proliferation on electrospun biodegradable scaffolds of PLLA and PBSA for use in cartilage tissue engineering. AB - The influence of physical characteristics of electrospun three-dimensional (3D) fibrous scaffolds based on polybutylene succinate-co-adipate (PBSA) and poly l lactic acid (PLLA) on the culture of primary human chondrocytes (PHCs) in terms of cell attachment, proliferation, and re-differentiation was investigated. Physical characteristics assessed for two polymers electrospun at two different delivery rates (PBSA-3, PBSA-16, PLLA-3, and PLLA-16) including average fiber diameter, average pore diameter, porosity, and contact angle. Results demonstrated that 3D fibrous scaffolds are better for PHCs' attachment than two dimensional (2D) casting films made of the same polymeric materials. It was also found that 3D fibrous scaffolds are appropriate architecture for the proliferation of PHCs than 2D casting films and dependent upon the polymer used. Histological analysis revealed that a significant amount of PHC was found to be growing only within layers of PLLA fibrous scaffolds. The mitochondrial ribonucleic acid (mRNA) expression of both aggrecan and type II collagen by PHCs cultured in tissue culture polystyrene for 28 days decreased significantly. The mRNA expression of both aggrecan and type II collagen by PHCs cultured in PBSA scaffolds increased from 14 to 28 days, whereas only mRNA expression of aggrecan cultured in both PLLA scaffolds increased from 14 to 28 days. PMID- 21273265 TI - Global income-related inequalities in HIV testing. AB - BACKGROUND: Voluntary counseling and testing (VCT) is an important prevention initiative in reducing HIV/AIDS transmission. Despite current global prevention efforts, many low- and middle-income countries continue reporting low VCT levels. Little is known about the association of within- and between-country socioeconomic inequalities and VCT. Based on the 'inverse equity hypothesis,' this study examines the degree to which low socioeconomic groups in developing countries are disadvantaged in VCT. METHODS: Using recently released data from the 2002 to 2003 World Health Survey (WHS) for 106 705 individuals in 49 countries, this study used multilevel logistic regression to examine the association of individual- and national-level factors with VCT, and whether national economic development moderated the association between individual income and VCT. Individual income was based on country-specific income quintiles. National economic development was based on national gross domestic product per capita (GDP/c). Effect modification was evaluated with the likelihood ratio test (G(2)). Individuals eligible for the VCT question of the WHS were adults between the ages of 18-49 years; women who had given birth in the last 2 years were excluded from this question. RESULTS: VCT was more likely among higher income quintiles and in countries with higher GDP/c. GDP/c moderated the association between individual income and VCT whereby relative income differences in VCT were greater in countries with lower GDP/c (G(2)= 9.21; P= 0.002). Individual socio demographic characteristics were also associated with the likelihood of a person having VCT. CONCLUSIONS: Relative socioeconomic inequalities in VCT coverage appear to decline when higher SES groups reach a certain level of coverage. These findings suggest that changes to international VCT programs may be necessary to moderate the relative VCT differences between high- and low-income individuals in lower GDP/c nations. PMID- 21273266 TI - Extent of hematopoietic involvement by TET2 mutations in JAK2V617F polycythemia vera. AB - TET2 mutations are found in polycythemia vera and it was initially reported that there is a greater TET2 mutational burden than JAK2(V617F) in polycythemia vera stem cells and that TET2 mutations precede JAK2(V617F). We quantified the proportion of TET2, JAK2(V617F) mutations and X-chromosome allelic usage in polycythemia vera cells, BFU-Es and in vitro expanded erythroid progenitors and found clonal reticulocytes, granulocytes, platelets and CD34(+) cells. We found that TET2 mutations may also follow rather than precede JAK2(V617F) as recently reported by others. Only a fraction of clonal early hematopoietic precursors and largely polyclonal T cells carry the TET2 mutation. We showed that in vitro the concomitant presence of JAK2(V617F) and TET2 mutations favors clonal polycythemia vera erythroid progenitors in contrast with non-TET2 mutated progenitors. We conclude that loss-of-function TET2 mutations are not the polycythemia vera initiating events and that the acquisition of TET2 somatic mutations may increase the aggressivity of the polycythemia vera clone. PMID- 21273267 TI - Compound heterozygosity for KLF1 mutations associated with remarkable increase of fetal hemoglobin and red cell protoporphyrin. AB - The persistence of high fetal hemoglobin level in adults may ameliorate the clinical phenotype of beta-thalassemia and sickle cell anemia. Several genetic variants responsible for hereditary persistence of fetal hemoglobin, linked and not linked to the beta globin gene cluster, have been identified in patients and in normal individuals. Monoallelic loss of KLF1, a gene with a key role in erythropoiesis, has been recently reported to be responsible for persistence of high levels of fetal hemoglobin. In a Sardinian family, high levels of HbF (22.1 30.9%) were present only in compound heterozygotes for the S270X nonsense and K332Q missense mutations, while the isolated S270X nonsense (haploinsufficiency) or K332Q missense mutation were associated with normal HbF levels (<1.5%). Functionally, the K332Q Klf1 mutation impairs binding to the BCl11A gene and activation of the gamma- and beta-globin promoters. Moreover, we report for the first time the association of KLF1 mutations with very high levels of zinc protoporphyrin. PMID- 21273268 TI - A modeling approach to evaluate long-term outcome of prophylactic and on demand treatment strategies for severe hemophilia A. AB - BACKGROUND: Severe hemophilia requires life-long treatment with expensive clotting factor concentrates; studies comparing effects of different therapeutic strategies over decades are very difficult to perform. A simulation model was developed to evaluate the long-term outcome of on demand, prophylactic and mixed treatment strategies for patients with severe hemophilia A. DESIGN AND METHODS: A computer model was developed based on individual patients' data from a Dutch cohort study in which intermediate dose prophylaxis was used and a French cohort study in which on demand treatment was used, and multivariate regression analyses. This model simulated individual patients' life expectancy, onset of bleeding, life-time joint bleeds, radiological outcome and concentrate use according to the different treatment strategies. RESULTS: According to the model, life-time on demand treatment would result in an average of 1,494 joint bleeds during the hemophiliac's life, and consumption of 4.9 million IU of factor VIII concentrate. In contrast, life-time intermediate dose prophylaxis resulted in a mean of 357 joint bleeds and factor consumption of 8.3 million IU. A multiple switch strategy (between prophylactic and on demand treatment based on bleeding pattern) resulted in a mean number of 395 joint bleeds and factor consumption of 6.6 million IU. The estimated proportion of patients with Pettersson scores over 28 points was 32% for both the prophylactic and the multiple switching strategies, compared to 76% for continuous on demand treatment. CONCLUSIONS: The present model allows evaluation of the impact of various treatment strategies on patients' joint bleeds and clotting factor consumption. It may be expanded with additional data to allow more precise estimates and include economic evaluations of treatment strategies. PMID- 21273269 TI - Predicting response to immunosuppressive therapy in childhood aplastic anemia. AB - In aplastic anemia, predictive markers of response to immunosuppressive therapy have not been well defined. We retrospectively evaluated whether clinical and laboratory findings before treatment could predict response in a pediatric cohort from the multicenter AA-97 study in Japan. Between 1997 and 2006, 312 newly diagnosed children were enrolled and treated with a combination of antithymocyte globulin and cyclosporine. In multivariate analyses, lower white blood cell count was the most significant predictive marker of better response; patients with white blood cell count less than 2.0*10(9)/L showed a higher response rate than those with white blood cell count of 2.0*10(9)/L or more (P=0.0003), followed by shorter interval between diagnosis and therapy (P=0.01), and male sex (P=0.03). In conclusion, pre-treatment clinical and laboratory findings influence response to therapy. The finding that response rate worsens with increasing interval between diagnosis and treatment highlights the importance of prompt immunosuppressive therapy for patients with aplastic anemia. PMID- 21273270 TI - Designing colour-coded measuring tapes based on mid-arm and chest circumference to predict low birth weight in the field. AB - BACKGROUND: In developing countries, 80% of the births take place in the community. METHODS: Birthweight, mid-arm and chest circumferences were measured in 294 newborns admitted in a tertiary-level hospital in Kolkata between April and August 2010. Colour-coded measuring tapes were devised using receiver operating characteristic curves to calculate the most sensitive and specific cut off values to identify birthweight <2.5 and 1.8 kg. RESULT: There is no significant difference in accuracy of Mid-arm circumference (MAC) and Chest circumference (CC) for prediction of low birth weight and birthweight <1.8 kg. The tape has three zones, green [weight (wt) > 2.5 kg, MAC > 8.4 cm, CC > 30 cm], yellow (wt 2.5-1.8 kg, MAC 8.4-6.7 cm, CC 30-25.5 cm) indicating some risk, and red (wt < 1.8 kg, MAC < 6.7 cm, CC < 25.5 cm) indicating babies needing referral and admission in Level II neonatal care unit. PMID- 21273271 TI - Adverse outcomes from IVF. PMID- 21273272 TI - Does poor health justify NHS reform? PMID- 21273273 TI - Chronic alcohol exposure induces genome damage measured using the cytokinesis block micronucleus cytome assay and aneuploidy in human B lymphoblastoid cell lines. AB - Excessive alcohol consumption is associated with an increased risk of a variety of cancers. The specific association between alcohol consumption and increased risk of breast cancer has been a consistent finding in numerous studies to date; however, the biological mechanism remains unknown. One possibility is that alcohol induces chromosome instability and aneuploidy events commonly seen in cancer. The cytokinesis-block micronucleus cytome assay was used to assess the ability of alcohol to induce DNA damage and aneuploidy in two human B lymphoblastoid cell lines--WIL2-NS and GM13705. The cells were treated chronically with physiologically relevant levels of alcohol (0.36 and 1.35% v/v) for a period of 6 weeks. Results demonstrate that in these cell lines, chronic treatment with alcohol induces micronuclei, nucleoplasmic bridges and nuclear buds, indicative of the various genome damaging events of chromosome loss and breakage, asymmetric chromosome rearrangement and gene amplification, respectively. Using chromogenic in situ hybridisation, we measured chromosome 17 aneuploidy in these cell lines. Results from this assay indicate that chronic treatment of alcohol induces aneuploidy (measured as chromosome 17 aneuploidy) in both cell lines. The results from this study support the hypothesis that alcohol is a probable cause of cancer initiation by inducing chromosomal instability and aneuploidy, which may be a result of multiple indirect mechanisms. PMID- 21273274 TI - High smoking rates in 1940s, 1950s and 1960s in US explain comparatively lower life expectancy of older Americans. PMID- 21273275 TI - Russians are unable to buy aspirin, paracetamol, and other basic drugs because of official bungle. PMID- 21273276 TI - Last US manufacturer of drug used in executions stops production. PMID- 21273277 TI - Experts express doubts that food and drink industries have the motives to improve health. PMID- 21273279 TI - Outcomes of chest compression only CPR versus conventional CPR conducted by lay people in patients with out of hospital cardiopulmonary arrest witnessed by bystanders: nationwide population based observational study. AB - OBJECTIVE: To compare the effectiveness of cardiopulmonary resuscitation (CPR) with chest compression only and conventional CPR on outcomes after cardiopulmonary arrest out of hospital. DESIGN: Nationwide population based observational study. SETTING: A nationwide emergency medical service system in Japan. Population All consecutive patients with out of hospital cardiopulmonary arrest, January 2005 to December 2007 in Japan, witnessed at the moment of collapse. Lay people attempted chest compression only CPR (n = 20,707) or conventional CPR (mouth to mouth ventilation and chest compression) (n = 19,328), and patients were transferred to hospital by ambulance. MAIN OUTCOME MEASURES: Factors associated with better outcomes (assessed with chi(2), multiple logistic regression analysis, odds ratios and their 95% confidence intervals): one month survival and neurologically favourable one month survival rates defined as category one (good cerebral performance) or two (moderate cerebral disability) of the cerebral performance categories. RESULTS: Conventional CPR was associated with better outcomes than chest compression only CPR, for both one month survival (adjusted odds ratio 1.17, 95% confidence interval 1.06 to 1.29) and neurologically favourable one month survival (1.17, 1.01 to 1.35). Neurologically favourable one month survival decreased with increasing age and with delays of up to 10 minutes in starting CPR for both conventional and chest compression only CPR. The benefit of conventional CPR over chest compression only CPR was significantly greater in younger people in non-cardiac cases (P = 0.025) and with a delay in start of CPR after the event was witnessed in non-cardiac cases (P = 0.015) and all cases combined (P = 0.037). CONCLUSIONS: Conventional CPR is associated with better outcomes than chest compression only CPR for selected patients with out of hospital cardiopulmonary arrest, such as those with arrests of non-cardiac origin and younger people, and people in whom there was delay in the start of CPR. PMID- 21273280 TI - Chest compression or conventional CPR after out of hospital cardiac arrest? PMID- 21273282 TI - Legal action delays ban on tobacco displays in Scotland. PMID- 21273283 TI - The effect of supplemental vitamins and minerals on the development of prostate cancer: a systematic review and meta-analysis. AB - BACKGROUND: Vitamin supplementation is used for many purposes with mainly alleged benefits. One of these is the use of various vitamins for the prevention of prostate cancer. METHODS: We conducted a systematic review and meta-analysis on this topic. Pubmed, Embase and the Cochrane Database were searched; as well, we hand searched the references in key articles. Randomized controlled trials (RCTs), cohort studies and case-control studies were included. The review assessed the effect of supplemental vitamins on the risk of prostate cancer and on disease severity and death in men with prostate cancer. RESULTS: Fourteen articles were included in the final assessment. Individually, a few of these studies showed a relationship between the ingestion of supplemental vitamins or minerals and the incidence or severity of prostate cancer, especially in smokers. However, neither the use of multivitamin supplementation nor the use of individual vitamin/mineral supplementation affected the overall occurrence of prostate cancer or the occurrence of advanced/metastatic prostate cancer or death from prostate cancer when the results of the studies were combined in a meta analysis. We also conducted several sensitivity analyses by running meta-analysis using just the higher quality studies and just the RCTs. There were still no associations found. CONCLUSIONS: There is no convincing evidence that the use of supplemental multivitamins or any specific vitamin affects the occurrence or severity of prostate cancer. There was high heterogeneity among the studies so it is possible that unidentified subgroups may benefit or be harmed by the use of vitamins. PMID- 21273284 TI - Attitudes towards obesity treatment in GP training practices: a focus group study. AB - BACKGROUND: Both patients and government expect the GP to treat obesity. Previous studies reported a negative attitude of GPs towards this task. Little is known about the attitude of GP trainees. OBJECTIVES: To assess the attitude and other factors that influence the willingness and ability of GP trainees to provide lifestyle interventions for overweight patients. METHODS: A qualitative study was performed using focus groups, consisting of first- and third-year trainees, GP trainers and teachers. Two researchers analysed the data independently. RESULTS: First-year trainees lack knowledge and a positive attitude. Third-year trainees, although trained in motivational interviewing techniques, lack specific knowledge and feel cheated when discussing eating habits. Trainers are despondent as they rarely observe long-lasting results. Teachers warn the trainees not to have high hopes. The trainers and trainees fear ruining the relationship with their patient, and all make a request for evidence-based multidisciplinary treatment programmes, joint responsibility and an image change in society to stop the epidemic. CONCLUSIONS: Trainees do not feel more competent in treating overweight patients successfully over the course of their GP specialty training and GP trainers are not convinced of the success of the treatment of overweight patients. Therefore, it could be equally important to reflect on the GP trainer as a role model as to concentrate on the education of the trainee. Both need a revived attitude and evidence-based treatment programmes, help from policy makers and an attitude change in society are desired. PMID- 21273285 TI - The monitoring of gingival crevicular fluid volume during orthodontic treatment: a longitudinal randomized split-mouth study. AB - This randomized split-mouth study was aimed at evaluating whether an orthodontic appliance per se or orthodontic tooth movement can induce detectable changes in gingival crevicular fluid (GCF) volume, and thus whether GCF volume is a predictable biomarker for tissue remodelling incident to orthodontic tooth movement. MATERIALS AND METHODS: Sixteen healthy orthodontic patients (7 females and 9 males; mean age, 17.7 years; range, 13-27 years) with the need for extraction of the first upper premolars were enrolled. One randomly chosen maxillary canine was subjected to a distalizing force by a 0.017 * 0.025 inch titanium-molybdenum alloy archwire and considered as the test tooth (TT). The contralateral canine, which was not subjected to any force but was included in an orthodontic appliance, was used as a control (CT). GCF sampling was performed at both mesial and distal sites of the CTs and TTs at baseline, immediately before applying the orthodontic appliance, and after 1 hour, 24 hours, and 7, 14, and 21 days. A Periotron was used to measure the GCF volume. A modest but significant increase in the GCF volume over time was seen in both the CTs (mesial sites) and the TTs (both mesial and distal sites) with no differences between the experimental teeth. Subclinical tissue inflammation consequent to the placement of the orthodontic appliance might be responsible for these GCF volume changes. The GCF volume does not appear to be a reliable biomarker for tissue remodelling during orthodontic treatment. PMID- 21273286 TI - Left/right asymmetries and open/closed differences of interdental forces in the mandible. AB - The aim of the present investigation was to study the variation in interdental forces between mandibular canines and lateral incisors of 19 volunteers (9 males and 10 females) aged 20-26 years for four configurations (mandible open/closed and left/right side). These forces were derived by pulling a stainless steel matrix strip between these teeth, six times per configuration, and registering the time variation with a high-resolution transducer. The repeated median smoothing algorithm was applied to find the maximum of each curve and a bootstrap method estimated the 95 per cent confidence intervals (CIs) for all 76 configurations. Seventy-six per cent of all paired force differences were found to be significant. Asymmetry phenomena were observed: the interdental forces differed significantly between the left and right sides and also between the open and closed position of the mandible. The interdental forces (4-21 N) showed a pattern modulated by volunteer-specific features: in 91 per cent of the configurations, the interdental forces were larger when the mouth was open. This observed pattern contributes to the instability observed in clinical practice, thus necessitating permanent fixed lower retainer wear. PMID- 21273287 TI - Ethnic differences in the soft tissue profiles of Turkish and European-American young adults with normal occlusions and well-balanced faces. AB - The aim of this study was to evaluate soft tissue differences between Turkish and North American adults by comparing two sample populations with ideal occlusion and well-balanced faces. Lateral cephalometric radiographs of 117 Anatolian Turkish adults (65 female and 52 male, mean age: 23.9 +/- 2.8 years) were compared with a sample of 116 adults of European-American ancestry (64 female and 52 male, mean age: 25.0 +/- 6.8 years). The cephalometric analyses of Holdaway, Epker, and Legan and Burstone were performed using Dolphin Image Software 9.0. Thirty-two measurements (27 linear and 5 angular) were analysed. For statistical evaluation, independent samples t-tests were performed. Distinct differences were found between the two samples in facial convexity, upper lip position and length, lower lip position, chin prominence, and chin thickness. Vertical proportional findings were similar between groups. Ethnic differences were found between Turkish and North American adults in the soft tissue profile. It is appropriate to consider these differences during routine diagnosis and treatment planning of a Turkish patient or an American patient of European ancestry. PMID- 21273288 TI - Genome-wide association analysis and fine mapping of NT-proBNP level provide novel insight into the role of the MTHFR-CLCN6-NPPA-NPPB gene cluster. AB - High blood concentration of the N-terminal cleavage product of the B-type natriuretic peptide (NT-proBNP) is strongly associated with cardiac dysfunction and is increasingly used for heart failure diagnosis. To identify genetic variants associated with NT-proBNP level, we performed a genome-wide association analysis in 1325 individuals from South Tyrol, Italy, and followed up the most significant results in 1746 individuals from two German population-based studies. A genome-wide significant signal in the MTHFR-CLCN6-NPPA-NPPB gene cluster was replicated, after correction for multiple testing (replication one-sided P-value = 8.4 * 10(-10)). A conditional regression analysis of 128 single-nucleotide polymorphisms in the region of interest identified novel variants in the CLCN6 gene as independently associated with NT-proBNP. In this locus, four haplotypes were associated with increased NT-proBNP levels (haplotype-specific combined P values from 8.3 * 10(-03) to 9.3 * 10(-11)). The observed increase in the NT proBNP level was proportional to the number of haplotype copies present (i.e. dosage effect), with an increase associated with two copies that varied between 20 and 100 pg/ml across populations. The identification of novel variants in the MTHFR-CLCN6-NPPA-NPPB cluster provides new insights into the biological mechanisms of cardiac dysfunction. PMID- 21273289 TI - Impairment of the tRNA-splicing endonuclease subunit 54 (tsen54) gene causes neurological abnormalities and larval death in zebrafish models of pontocerebellar hypoplasia. AB - Pontocerebellar hypoplasia (PCH) represents a group (PCH1-6) of neurodegenerative autosomal recessive disorders characterized by hypoplasia and/or atrophy of the cerebellum, hypoplasia of the ventral pons, progressive microcephaly and variable neocortical atrophy. The majority of PCH2 and PCH4 cases are caused by mutations in the TSEN54 gene; one of the four subunits comprising the tRNA-splicing endonuclease (TSEN) complex. We hypothesized that TSEN54 mutations act through a loss of function mechanism. At 8 weeks of gestation, human TSEN54 is expressed ubiquitously in the brain, yet strong expression is seen within the telencephalon and metencephalon. Comparable expression patterns for tsen54 are observed in zebrafish embryos. Morpholino (MO) knockdown of tsen54 in zebrafish embryos results in loss of structural definition in the brain. This phenotype was partially rescued by co-injecting the MO with human TSEN54 mRNA. A developmental patterning defect was not associated with tsen54 knockdown; however, an increase in cell death within the brain was observed, thus bearing resemblance to PCH pathophysiology. Additionally, N-methyl-N-nitrosourea mutant zebrafish homozygous for a tsen54 premature stop-codon mutation die within 9 days post-fertilization. To determine whether a common disease pathway exists between TSEN54 and other PCH related genes, we also monitored the effects of mitochondrial arginyl-tRNA synthetase (rars2; PCH1 and PCH6) knockdown in zebrafish. Comparable brain phenotypes were observed following the inhibition of both genes. These data strongly support the hypothesis that TSEN54 mutations cause PCH through a loss of function mechanism. Also we suggest that a common disease pathway may exist between TSEN54- and RARS2-related PCH, which may involve a tRNA processing related mechanism. PMID- 21273290 TI - FGFR3 is a target of the homeobox transcription factor SHOX in limb development. AB - The short stature homeobox gene SHOX encodes a transcription factor which is important for normal limb development. In humans, SHOX deficiency has been associated with various short stature syndromes including Leri-Weill dyschondrosteosis (LWD), Langer mesomelic dysplasia and Turner syndrome as well as non-syndromic idiopathic short stature. A common feature of these syndromes is disproportionate short stature with a particular shortening of the forearms and lower legs. In our studies employing microarray analyses and cell culture experiments, we revealed a strong positive effect of SHOX on the expression of the fibroblast growth factor receptor gene FGFR3, another well-known factor for limb development. Luciferase reporter gene assays show that SHOX activates the extended FGFR3 promoter, and results from chromatin immunoprecipitation (ChIP) sequencing, ChIP and electrophoretic mobility shift assay experiments suggest a direct binding of SHOX to multiple upstream sequences of FGFR3. To further investigate these regulations in a cellular system for limb development, the effect of viral overexpression of Shox in limb bud derived chicken micromass cultures was tested. We found that Fgfr3 was negatively regulated by Shox, as demonstrated by quantitative real-time polymerase chain reaction and in situ hybridization. This repressive effect might explain the almost mutually exclusive expression patterns of Fgfr3 and Shox in embryonic chicken limbs. A negative regulation that occurs mainly in the mesomelic segments, a region where SHOX is known to be strongly expressed, offers a possible explanation for the phenotypes seen in patients with FGFR3 (e.g. achondroplasia) and SHOX defects (e.g. LWD). In summary, these data present a link between two frequent short stature phenotypes. PMID- 21273291 TI - IKAP/Elp1 involvement in cytoskeleton regulation and implication for familial dysautonomia. AB - Deficiency in the IKAP/Elp1 protein leads to the recessive sensory autosomal congenital neuropathy which is called familial dysautonomia (FD). This protein was originally identified as a role player in transcriptional elongation being a subunit of the RNAPII transcriptional Elongator multi-protein complex. Subsequently, IKAP/Elp1 was shown to play various functions in the cytoplasm. Here, we describe experiments performed with IKAP/Elp1 downregulated cell lines and FD-derived cells and tissues. Immunostaining of the cytoskeleton component alpha-tubulin in IKAP/Elp1 downregulated cells revealed disorganization of the microtubules (MTs) that was reflected in aberrant cell shape and process formation. In contrast to a recent report on the decrease in alpha-tubulin acetylation in IKAP/Elp1 downregulated cells, we were unable to observe any effect of IKAP/Elp1 deficiency on alpha-tubulin acetylation in the FD cerebrum and in a variety of IKAP/Elp1 downregulated cell lines. To explore possible candidates involved in the observed aberrations in MTs, we focused on superior cervical ganglion-10 protein (SCG10), also called STMN2, which is known to be an MT destabilizing protein. We have found that SCG10 is upregulated in the IKAP/Elp1-deficient FD cerebrum, FD fibroblasts and in IKAP/Elp1 downregulated neuroblastoma cell line. To better understand the effect of IKAP/Elp1 deficiency on SCG10 expression, we investigated the possible involvement of RE-1-silencing transcription factor (REST), a known repressor of the SCG10 gene. Indeed, REST was downregulated in the IKAP/Elp1-deficient FD cerebrum and IKAP/Elp1 downregulated neuroblastoma cell line. These results could shed light on a possible link between IKAP/Elp1 deficiency and cytoskeleton destabilization. PMID- 21273292 TI - Pleural fluid analysis and radiographic, sonographic, and echocardiographic characteristics of hepatic hydrothorax. AB - BACKGROUND: There are limited published data defining complete pleural fluid analysis, echocardiographic characteristics, or the presence or absence of ascites on sonographic or CT imaging in patients with hepatic hydrothorax. METHODS: We reviewed pleural fluid analysis and radiographic, sonographic, and echocardiographic findings in 41 consecutive patients with hepatic hydrothorax referred to the Pleural Procedure Service for thoracentesis. RESULTS: Ascites was detected on sonographic or CT imaging in 38 of 39 patients (97%). Diastolic dysfunction was found in 11 of 21 patients (52%). Contrast echocardiography with agitated saline demonstrated an intrapulmonary shunt in 18 of 23 cases (78%). Solitary hepatic hydrothorax had a median pleural fluid pH of 7.49 (fifth to 95th percentile, 7.40-7.57), total protein level of 1.5 g/dL (0.58-2.34), and lactate dehydrogenase (LDH) level of 65 IU/L (36-138). The median pleural fluid/serum protein ratio and pleural LDH/upper limit of normal serum LDH ratio were 0.25 (0.10-0.43) and 0.27 (0.14-0.57), respectively. The median absolute neutrophil count (ANC) was 26 cells/MUL (1-230). Only a single patient had a protein discordant exudate despite 83% of patients receiving diuretics. When comparing solitary hepatic hydrothorax and spontaneous bacterial pleuritis, there was no statistically significant difference among pleural fluid total protein (P = .99), LDH (P = .33), and serum albumin (P = .47). ANC was higher in patients with spontaneous bacterial pleuritis (P < .0001). CONCLUSIONS: Hepatic hydrothorax virtually always presents with ascites that is detectable on sonographic or CT imaging. The development of an "exudate" from diuretic therapy is a rare phenomenon in hepatic hydrothorax. In contrast, diastolic dysfunction and intrapulmonary shunting are common in patients with hepatic hydrothorax. There was no statistically significant change in pleural fluid parameters with spontaneous bacterial pleuritis, except an increased ANC. PMID- 21273293 TI - Weight loss via diet and exercise improves exercise breathing mechanics in obese men. AB - BACKGROUND: Obesity alters breathing mechanics during exercise. Weight loss improves lung function at rest, but the effect of weight loss, especially regional fat loss, on exercise breathing mechanics is unclear. We hypothesized that weight loss, especially a decrease in abdominal fat, would improve breathing mechanics during exercise because of an increase in end-expiratory lung volume (EELV). METHODS: Nine obese men were studied before and after weight loss (13% +/ 8% of total fat weight, mean +/- SD). Subjects underwent pulmonary function testing, underwater weighing, fat distribution estimates (MRI), and graded cycle ergometry before and after a 12-week diet and exercise program. In seven men, esophageal and gastric pressures were measured. The effects of weight loss were analyzed at rest, at ventilatory threshold (VTh), and during peak exercise by dependent Student t test, and the relationship among variables was determined by correlation analysis. RESULTS: Subjects lost 7.4 +/- 4.2 kg of body weight (P < .001), but the distribution of fat remained unchanged. After weight loss, lung volume subdivisions at rest were increased (P < .05) and were moderately associated (P < .05) with changes in chest, waist, and hip circumferences. At VTh, EELV increased, and gastric pressure decreased significantly (P < .05). The changes in waist circumference, hip circumference, BMI, and sum of chest, waist, and hip circumferences were also consistently and significantly correlated (P < .05) with changes in gastric pressure during exercise at VTh. CONCLUSIONS: Modest weight loss improves breathing mechanics during submaximal exercise in otherwise healthy obese men, which is clinically encouraging. Improvement appears to be related to the cumulative loss of chest wall fat. PMID- 21273294 TI - Physical activity is the strongest predictor of all-cause mortality in patients with COPD: a prospective cohort study. AB - BACKGROUND: Systemic effects of COPD are incompletely reflected by established prognostic assessments. We determined the prognostic value of objectively measured physical activity in comparison with established predictors of mortality and evaluated the prognostic value of noninvasive assessments of cardiovascular status, biomarkers of systemic inflammation, and adipokines. METHODS: In a prospective cohort study of 170 outpatients with stable COPD (mean FEV(1), 56% predicted), we assessed lung function by spirometry and body plethysmography; physical activity level (PAL) by a multisensory armband; exercise capacity by 6 min walk distance test; cardiovascular status by echocardiography, vascular Doppler sonography (ankle-brachial index [ABI]), and N-terminal pro-B-type natriuretic peptide level; nutritional and muscular status by BMI and fat-free mass index; biomarkers by levels of high-sensitivity C-reactive protein, IL-6, fibrinogen, adiponectin, and leptin; and health status, dyspnea, and depressive symptoms by questionnaire. Established prognostic indices were calculated. The median follow-up was 48 months (range, 10-53 months). RESULTS: All-cause mortality was 15.4%. After adjustments, each 0.14 increase in PAL was associated with a lower risk of death (hazard ratio [HR], 0.46; 95% CI, 0.33-0.64; P < .001). Compared with established predictors, PAL showed the best discriminative properties for 4-year survival (C statistic, 0.81) and was associated with the highest relative risk of death per standardized decrease. Novel predictors of mortality were adiponectin level (HR, 1.34; 95% CI, 1.06-1.71; P = .017), leptin level (HR, 0.81; 95% CI, 0.65-0.99; P = .042), right ventricular function (Tei index) (HR, 1.26; 95% CI, 1.04-1.54; P = .020), and ABI < 1.00 (HR, 3.87; 95% CI, 1.44-10.40; P = .007). A stepwise Cox regression revealed that the best model of independent predictors was PAL, adiponectin level, and ABI. The composite of these factors further improved the discriminative properties (C statistic, 0.85). CONCLUSIONS: We found that objectively measured physical activity is the strongest predictor of all-cause mortality in patients with COPD. In addition, adiponectin level and vascular status provide independent prognostic information in our cohort. PMID- 21273295 TI - Circulating microparticles in children with sleep disordered breathing. AB - BACKGROUND: Endothelial dysfunction is a common complication of pediatric obstructive sleep apnea (OSA). Circulating cell-derived microparticles (MPs) have emerged as reliable biomarkers of endothelial dysfunction and atherosclerosis. METHODS: Children underwent blood drawing the morning after a sleep study. Endothelial function was assessed using a modified hyperemic test after cuff induced occlusion of the brachial artery. Circulating MP levels in plasma, including levels of endothelial MPs, endothelial progenitor MPs, leukocyte MPs, and platelet MPs, were measured using flow cytometry after staining with cell specific antibodies. RESULTS: The levels of endothelial MPs, endothelial progenitor MPs, leukocyte MPs, and platelet MPs were significantly different according to the severity of OSA in children. Leukocyte CD11b+ MPs and platelet CD41a+ MPs correlated with the apnea-hypopnea index (AHI) (r = 0.334, P < .001; and r = 0.301, P < .001, respectively), and associations emerged between leukocyte CD11b+ MPs and apolipoprotein B (r = 0.206, P < .05) and between endothelial MPs and low-density lipoprotein cholesterol (r = 0.240, P < .01). In a multivariate regression model, the BMI z score (beta +/- SE, 0.045 +/- 0.020; P = .020) and the CD41a MPs to leukocyte CD45 MPs ratio (beta +/- SE, 0.074 +/- 0.032; P = .021) were independently associated with peak hyperemic responses. After controlling for age, gender, race, BMI z score, and apolipoprotein B levels, endothelial MPs, endothelial progenitor MPs, and leukocyte MPs showed independent associations with the AHI. Complex significant associations emerged between endothelial function, the AHI, and CD41a MPs. CONCLUSIONS: Childhood OSA is associated with higher circulating MP levels that can promote cardiovascular risk. Platelet-derived MPs emerge as being significantly associated with the vascular dysfunction associated with OSA in children and could potentially account for increased risk for altered endothelial function. However, the clinical use of MPs as reliable biomarker indicators of vascular risk will have to await further studies. PMID- 21273296 TI - Mechanism of greater oxygen desaturation during walking compared with cycling in patients with COPD. AB - BACKGROUND: Patients with COPD exhibit greater oxyhemoglobin desaturation during walking than with cycling. The purpose of this investigation was to investigate differences in ventilatory responses and gas exchange as proposed mechanisms for this observation. METHODS: Arterial blood gas and lactate levels were measured in 12 patients with COPD (aged 68 +/- 6 years) during incremental treadmill and cycle exercise. The primary outcome to assess the ventilatory response to exercise was Pao2. The primary outcome to assess impairment in exercise gas exchange was the difference between partial pressures of alveolar and arterial oxygen (Pao2 - Pao2). RESULTS: Pao2 in patients was significantly lower at peak exercise for treadmill walking (51.4 +/- 6.8 mm Hg) compared with cycling (60.4 +/- 10.7 mm Hg) (P = .002). The initial increase in Pao2 with cycling occurred prior to the onset of the anaerobic threshold. At peak exercise, Pao2 was significantly higher with cycling compared with walking (P = .004). The anaerobic threshold occurred at a lower oxygen consumption during cycling than walking (P = .001), and peak lactate levels were higher with cycling (P = .019). With progressive exercise, Pao2 - Pao2 increased similarly during treadmill and cycle exercise. CONCLUSIONS: The higher Pao2 during cycling minimized the magnitude of oxyhemoglobin desaturation compared with walking. The enhanced respiratory stimulation during cycling appears due to an initial neurogenic process, possibly originating in receptors of exercising muscles, and a subsequent earlier onset of anaerobic metabolism with higher lactate levels during cycling. PMID- 21273297 TI - Varicella reinfection in a seropositive physician following occupational exposure to localized zoster. AB - A 32-year-old physician with a history of chickenpox at age 5 and seropositivity to varicella-zoster virus (VZV) at age 30 developed fever and vesicular rash 14 days after examining an immunocompetent patient with localized herpes zoster ophthalmicus. Vesicular viral culture grew VZV, and the physician was diagnosed with VZV reinfection. PMID- 21273298 TI - Association of vitamin D insufficiency with carotid intima-media thickness in HIV infected persons. AB - We observed an independent association between vitamin D insufficiency and higher carotid intima-media thickness in a cross-sectional analysis of 139 HIV-infected persons. If confirmed, these findings support a clinical trial of vitamin D supplementation to reduce cardiovascular events in HIV-infected persons. PMID- 21273299 TI - Scale for the measurement of attitudes towards alcohol. AB - AIMS: The aim was to analyse the characteristics of, and validate, a new instrument in Italian, 'Scale for the measurement of attitudes towards alcohol'. The instrument is a means for assessing young people's risk profile regarding the use of alcohol and identifying the factors that contribute to determining this attitude. METHODS: The test was initially composed of 60 items divided into three domains and administered to a sample of 41 subjects. The results revealed the necessity of adapting the test's conceptual structure: consequently, the items were reduced to 35, divided into five domains. This second version was administered to a sample of 467 students attending upper secondary schools and vocational training schools in the municipality of Siena. Following this second experiment, a third version was realized, which comprised 25 items divided into the same five domains; it was administered to 100 subjects, with an equal number of males and females and an age range of 14-30 years. Analysis of the data obtained resulted in a final structure formed of 15 items in three domains. RESULTS: The final structure of the test has good psychometric properties in terms of both reliability and validity. CONCLUSIONS: The 'Scale for the measurement of attitudes towards alcohol' can be seen as an instrument for evaluating the factors capable of conditioning the behaviour of people between 18 and 26 years of age towards alcoholic substances. PMID- 21273300 TI - Decline in alcohol consumption in Estonia: combined effects of strengthened alcohol policy and economic downturn. AB - AIMS: To describe alcohol policy changes in parallel to consumption changes in 2005-2010 in Estonia, where alcohol consumption is among the highest in Europe. METHODS: Review of pertinent legislation and literature. RESULTS: Alcohol consumption decreased since 2008, while alcohol excise tax, sales time restrictions and ad bans have increased since 2005. An economic downturn started in 2008. CONCLUSION: The precise roles of policy changes and the economic downturn in the decline of alcohol consumption, and whether the decrease will be sustained, are still unclear. PMID- 21273301 TI - Early Treatment for Women with Alcohol Addiction (EWA) reduces mortality: a randomized controlled trial with long-term register follow-up. AB - AIMS: To compare the mortality of female alcoholics randomly assigned to the woman-only programme 'Early treatment for Women with Alcohol Addiction' (EWA) versus those who received mixed gender 'Treatment As Usual' (TAU). METHODS: Randomized controlled trial involving 2-year follow-up by personal interview and mortality register data through 27 years of 200 women first time treated for alcohol use disorder (AUD; EWA, n = 100 and TAU, n = 100), who were consecutively recruited during 1983-1984. Data from the Causes of Death Register were used to test for mortality differences related to group interaction predictors such as age, inpatient versus outpatient status at intake and 2-year drinking outcome. RESULTS: Significantly lower mortality was found among younger women who participated in EWA compared with those who received TAU. This difference lasted nearly 20 years after intake to treatment. For women who only needed outpatient treatment, reduced mortality was found in the EWA group, even for older women. Increased mortality was found for TAU women who did not attend the 2-year follow up compared with those who attended; no such difference was found for EWA women. This indicates different attrition mechanisms in the two groups. Thus, previously reported treatment effects may have been underestimated. EWA was a more comprehensive programme than TAU while also being single gender. CONCLUSIONS: EWA, specifically developed to meet a broad spectrum of problems among women with AUDs, was more effective than TAU, a mixed gender programme. It was not possible to separate whether this was in part because it was a more comprehensive programme, as well as being single gender. PMID- 21273302 TI - Neonatal diagnosis of severe combined immunodeficiency leads to significantly improved survival outcome: the case for newborn screening. AB - Severe combined immunodeficiency (SCID) carries a poor prognosis without definitive treatment by hematopoietic stem cell transplantation. The outcome for transplantation varies and is dependent on donor status and the condition of the child at the time of transplantation. Diagnosis at birth may allow for better protection of SCID babies from infection and improve transplantation outcome. In this comparative study conducted at the 2 designated SCID transplantation centers in the United Kingdom, we show that SCID babies diagnosed at birth because of a positive family history have a significantly improved outcome compared with the first presenting family member. The overall improved survival of more than 90% is related to a reduced rate of infection and significantly improved transplantation outcome irrespective of donor choice, conditioning regimen used, and underlying genetic diagnosis. Neonatal screening for SCID would significantly improve the outcome in this otherwise potentially devastating condition. PMID- 21273303 TI - A microRNA expression signature of osteoclastogenesis. AB - MicroRNAs (miRs) are small noncoding RNAs that principally function in the spatiotemporal regulation of protein translation in animal cells. Although emerging evidence suggests that some miRs play important roles in osteoblastogenesis and skeletal homeostasis, much less is known in osteoclastogenesis. Here, we show that receptor activator of nuclear factor kappaB ligand (RANKL)-induced osteoclastogenesis is mediated by miR-21. MiR-21 was identified as an miR expression signature of RANKL-induced osteoclastogenesis that down-regulates programmed cell death 4 (PDCD4) protein levels. Diminished PDCD4 removes a repression from c-Fos, a critical transcription factor for osteoclastogenesis and osteoclast-specific downstream target genes. In addition, RANKL-induced c-Fos up-regulates miR-21 gene expression. Bone marrow-derived monocyte/macrophage precursors deficient of DiGeorge syndrome critical region gene 8, an RNA binding protein associated with miR biogenesis, and Dicer, an endoribonuclease in the RNaseIII family associated with miR biogenesis, possessed significantly decreased miR-21 levels and increased PDCD4 protein levels so that RANKL-induced osteoclastogenesis was impaired in those cells. However, forced expression of miR-21 rescued osteoclast development because of down-regulation of PDCD4 protein expression levels. Thus, our studies provide a new molecular mechanism, including a positive feedback loop of c-Fos/miR-21/PDCD4, regulating osteoclastogenesis. PMID- 21273304 TI - Origin, functional role, and clinical impact of Fanconi anemia FANCA mutations. AB - Fanconi anemia is characterized by congenital abnormalities, bone marrow failure, and cancer predisposition. To investigate the origin, functional role, and clinical impact of FANCA mutations, we determined a FANCA mutational spectrum with 130 pathogenic alleles. Some of these mutations were further characterized for their distribution in populations, mode of emergence, or functional consequences at cellular and clinical level. The world most frequent FANCA mutation is not the result of a mutational "hot-spot" but results from worldwide dissemination of an ancestral Indo-European mutation. We provide molecular evidence that total absence of FANCA in humans does not reduce embryonic viability, as the observed frequency of mutation carriers in the Gypsy population equals the expected by Hardy-Weinberg equilibrium. We also prove that long distance Alu-Alu recombination can cause Fanconi anemia by originating large interstitial deletions involving FANCA and 2 adjacent genes. Finally, we show that all missense mutations studied lead to an altered FANCA protein that is unable to relocate to the nucleus and activate the FA/BRCA pathway. This may explain the observed lack of correlation between type of FANCA mutation and cellular phenotype or clinical severity in terms of age of onset of hematologic disease or number of malformations. PMID- 21273305 TI - KIT signaling regulates MITF expression through miRNAs in normal and malignant mast cell proliferation. AB - Activating mutations in codon D816 of the tyrosine kinase receptor, KIT, are found in the majority of patients with systemic mastocytosis. We found that the transcription factor, microphthalmia-associated transcription factor (MITF), is highly expressed in bone marrow biopsies from 9 of 10 patients with systemic mastocytosis and activating c-KIT mutations. In primary and transformed mast cells, we show that KIT signaling markedly up-regulates MITF protein. We demonstrate that MITF is required for the proliferative phenotype by inhibiting colony-forming units with sh-RNA knockdown of MITF. Furthermore, constitutively active KIT does not restore growth of primary MITF-deficient mast cells. MITF mRNA levels do not change significantly with KIT signaling, suggesting posttranscriptional regulation. An array screen from mast cells identified candidate miRNAs regulated by KIT signaling. We found that miR-539 and miR-381 are down-regulated by KIT signaling and they repressed MITF expression through conserved miRNA binding sites in the MITF 3'-untranslated region. Forced expression of these miRNAs suppressed MITF protein and inhibited colony-forming capacity of mastocytosis cell lines. This work demonstrates a novel regulatory pathway between 2 critical mast cell factors, KIT and MITF, mediated by miRNAs; dysregulation of this pathway may contribute to abnormal mast cell proliferation and malignant mast cell diseases. PMID- 21273306 TI - E47 regulates hematopoietic stem cell proliferation and energetics but not myeloid lineage restriction. AB - The immune system is replenished by self-renewing hematopoietic stem cells (HSCs) that produce multipotent progenitors (MPPs) with little renewal capacity. E proteins, the widely expressed basic helix-loop-helix transcription factors, contribute to HSC and MPP activity, but their specific functions remain undefined. Using quantitative in vivo and in vitro approaches, we show that E47 is dispensable for the short-term myeloid differentiation of HSCs but regulates their long-term capabilities. E47-deficient progenitors show competent myeloid production in short-term assays in vitro and in vivo. However, long-term myeloid and lymphoid differentiation is compromised because of a progressive loss of HSC self-renewal that is associated with diminished p21 expression and hyperproliferation. The activity of E47 is shown to be cell-intrinsic. Moreover, E47-deficient HSCs and MPPs have altered expression of genes associated with cellular energy metabolism, and the size of the MPP pool but not downstream lymphoid precursors in bone marrow or thymus is rescued in vivo by antioxidant. Together, these observations suggest a role for E47 in the tight control of HSC proliferation and energy metabolism, and demonstrate that E47 is not required for short-term myeloid differentiation. PMID- 21273307 TI - Potent inhibition of anoxic depolarization by the sodium channel blocker dibucaine. AB - Recurring waves of peri-infarct depolarizations (PIDs) propagate across gray matter in the hours and days following stroke, expanding the primary site of injury. Ischemic depolarization (termed anoxic depolarization or AD in live brain slices) is PID-like but immediately arises in the more metabolically compromised ischemic core. This causes dramatic neuronal and astrocyte swelling and dendritic beading with spine loss within minutes, resulting in acute cell death. AD is evoked in rodent neocortical slices by suppressing the Na(+)/K(+)-ATPase pump with either oxygen/glucose deprivation (OGD) or exposure to ouabain. The process driving AD and PIDs remains poorly understood. Here we show that dibucaine is a potent drug inhibiting AD because of its high binding affinity to the Na(+) channel. Field recording reveals that, when superfused with ouabain (5 min), neocortical slices pretreated with 1 MUM dibucaine for 45 min display either no AD or delayed AD onset compared with untreated controls. If ouabain exposure is extended to 10 min, 1 MUM dibucaine is still able to delay AD onset by ~ 60%. Likewise, it delays OGD-evoked AD onset by ~ 54% but does not depress action potentials (APs) or evoked orthodromic field potentials. Increasing dibucaine to 10 MUM inhibits AP firing, gradually putting the slice into a stasis that inhibits AD onset but also renders the slice functionally quiescent. Two-photon microscopy reveals that 10 MUM dibucaine pretreatment prevents or helps reverse ouabain-induced structural neuronal damage. Although the therapeutic range of dibucaine is quite narrow, dibucaine-like drugs could prove therapeutically useful in inhibiting PIDs and their resultant neuronal damage. PMID- 21273308 TI - Do premotor interneurons act in parallel on spinal motoneurons and on dorsal horn spinocerebellar and spinocervical tract neurons in the cat? AB - It has previously been established that ventral spinocerebellar tract (VSCT) neurons and dorsal spinocerebellar tract neurons located in Clarke's column (CC DSCT neurons) forward information on actions of premotor interneurons in reflex pathways from muscle afferents on alpha-motoneurons. Whether DSCT neurons located in the dorsal horn (dh DSCT neurons) and spinocervical tract (SCT) neurons are involved in forwarding similar feedback information has not yet been investigated. The aim of the present study was therefore to examine the input from premotor interneurons to these neurons. Electrical stimuli were applied within major hindlimb motor nuclei to activate axon-collaterals of interneurons projecting to these nuclei, and intracellular records were obtained from dh DSCT and SCT neurons. Direct actions of the stimulated interneurons were differentiated from indirect actions by latencies of postsynaptic potentials evoked by intraspinal stimuli and by the absence or presence of temporal facilitation. Direct actions of premotor interneurons were found in a smaller proportion of dh DSCT than of CC DSCT neurons. However, they were evoked by both excitatory and inhibitory interneurons, whereas only inhibitory premotor interneurons were previously found to affect CC DSCT neurons [as indicated by monosynaptic excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) in dh DSCT and only IPSPs in CC DSCT neurons]. No effects of premotor interneurons were found in SCT neurons, since monosynaptic EPSPs or IPSPs were only evoked in them by stimuli applied outside motor nuclei. The study thus reveals a considerable differentiation of feedback information provided by different populations of ascending tract neurons. PMID- 21273310 TI - The motor system plays the violin: a musical metaphor inferred from the oscillatory activity of the alpha-motoneuron pools during locomotion. AB - Despite substantial advances in the field, particularly resulting from physiological studies in animals, the neural mechanisms underlying the generation of many motor behaviors in humans remain unclear. A recent study (Cappellini G et al. J Neurophysiol 104: 3064-3073, 2010) sheds more light on this topic. Like the string of a violin, the alpha-motoneuron pools in the spinal cord during locomotion show continuous and oscillatory patterns of activation. In this report, the implications and relevance of this finding are discussed in a general framework that includes neurophysiology, optimal control theory, and robotics. PMID- 21273309 TI - Network recruitment to coherent oscillations in a hippocampal computer model. AB - Coherent neural oscillations represent transient synchronization of local neuronal populations in both normal and pathological brain activity. These oscillations occur at or above gamma frequencies (>30 Hz) and often are propagated to neighboring tissue under circumstances that are both normal and abnormal, such as gamma binding or seizures. The mechanisms that generate and propagate these oscillations are poorly understood. In the present study we demonstrate, via a detailed computational model, a mechanism whereby physiological noise and coupling initiate oscillations and then recruit neighboring tissue, in a manner well described by a combination of stochastic resonance and coherence resonance. We develop a novel statistical method to quantify recruitment using several measures of network synchrony. This measurement demonstrates that oscillations spread via preexisting network connections such as interneuronal connections, recurrent synapses, and gap junctions, provided that neighboring cells also receive sufficient inputs in the form of random synaptic noise. "Epileptic" high-frequency oscillations (HFOs), produced by pathologies such as increased synaptic activity and recurrent connections, were superior at recruiting neighboring tissue. "Normal" HFOs, associated with fast firing of inhibitory cells and sparse pyramidal cell firing, tended to suppress surrounding cells and showed very limited ability to recruit. These findings point to synaptic noise and physiological coupling as important targets for understanding the generation and propagation of both normal and pathological HFOs, suggesting potential new diagnostic and therapeutic approaches to human disorders such as epilepsy. PMID- 21273311 TI - Effects of cortical activation on sensory responses in barrel cortex. AB - Neocortex network activity changes from a deactivated state during quiescence to an activated state during arousal and vigilance. In urethane-anesthetized rats, cortical activation is readily produced by either stimulating the brainstem reticular formation or by application of cholinergic agonists into the thalamus. We studied the effects of cortical activation on spontaneous activity and sensory responses in the barrel cortex. Cortical activation leads to a suppression of low frequency sensory responses and to a reduction in their variability due to the abolishment of up and down membrane potential fluctuations in cortical cells. Overall, sensory responses become sharper and more reliable during cortical activation. PMID- 21273312 TI - Cc2d1a, a C2 domain containing protein linked to nonsyndromic mental retardation, controls functional maturation of central synapses. AB - Cc2d1a is an evolutionarily conserved protein composed of NH(2)-terminal Drosophila melanogaster 14 domain (DM14) domains and a COOH-terminal C2 domain. Human patients with homozygotic mutation in the gene suffer from nonsyndromic mental retardation, implying that Cc2d1a functions in the central nervous system. To examine the physiological role of the Cc2d1a, we generated and analyzed Cc2d1a knockout (KO) mice. Cc2d1a KO mice die soon after birth, apparently because of their inability to breathe. Histological analysis of Cc2d1a KO animals did not identify any structural defects in the peripheral respiratory apparatus. However, functional analysis of synapses formed between Cc2d1a-deficient cortical neurons revealed a robust increase in the pace of maturation of evoked synaptic responses as well as synaptic vesicle trafficking. This synaptic anomaly was rescued by reintroducing full-length Cc2d1a but not C2-domain-deletion mutant, underscoring the functional importance of C2 domain. Our data suggest that Cc2d1a is required for mouse survival and performs essential function in controlling functional maturation of synapses. PMID- 21273314 TI - Direction and speed tuning to visual motion in cortical areas MT and MSTd during smooth pursuit eye movements. AB - When tracking a moving target in the natural world with pursuit eye movement, our visual system must compensate for the self-induced retinal slip of the visual features in the background to enable us to perceive their actual motion. We previously reported that the speed of the background stimulus in space is represented by dorsal medial superior temporal (MSTd) neurons in the monkey cortex, which compensate for retinal image motion resulting from eye movements when the direction of the pursuit and background motion are parallel to the preferred direction of each neuron. To further characterize the compensation observed in the MSTd responses to the background motion, we recorded single unit activities in cortical areas middle temporal (MT) and MSTd, and we selected neurons responsive to a large-field visual stimulus. We studied their responses to the large-field stimulus in the background while monkeys pursued a moving target and while fixated a stationary target. We investigated whether compensation for retinal image motion of the background depended on the speed of pursuit. We also asked whether the directional selectivity of each neuron in relation to the external world remained the same even during pursuit and whether compensation for retinal image motion occurred irrespective of the direction of the pursuit. We found that the majority of the MSTd neurons responded to the visual motion in space by compensating for the image motion on the retina resulting from the pursuit regardless of pursuit speed and direction, whereas most of the MT neurons responded in relation to the genuine retinal image motion. PMID- 21273313 TI - Relationships among low-frequency local field potentials, spiking activity, and three-dimensional reach and grasp kinematics in primary motor and ventral premotor cortices. AB - A prominent feature of motor cortex field potentials during movement is a distinctive low-frequency local field potential (lf-LFP) (<4 Hz), referred to as the movement event-related potential (mEP). The lf-LFP appears to be a global signal related to regional synaptic input, but its relationship to nearby output signaled by single unit spiking activity (SUA) or to movement remains to be established. Previous studies comparing information in primary motor cortex (MI) lf-LFPs and SUA in the context of planar reaching tasks concluded that lf-LFPs have more information than spikes about movement. However, the relative performance of these signals was based on a small number of simultaneously recorded channels and units, or for data averaged across sessions, which could miss information of larger-scale spiking populations. Here, we simultaneously recorded LFPs and SUA from two 96-microelectrode arrays implanted in two major motor cortical areas, MI and ventral premotor (PMv), while monkeys freely reached for and grasped objects swinging in front of them. We compared arm end point and grip aperture kinematics' decoding accuracy for lf-LFP and SUA ensembles. The results show that lf-LFPs provide enough information to reconstruct kinematics in both areas with little difference in decoding performance between MI and PMv. Individual lf-LFP channels often provided more accurate decoding of single kinematic variables than any one single unit. However, the decoding performance of the best single unit among the large population usually exceeded that of the best single lf-LFP channel. Furthermore, ensembles of SUA outperformed the pool of lf-LFP channels, in disagreement with the previously reported superiority of lf-LFP decoding. Decoding results suggest that information in lf-LFPs recorded from intracortical arrays may allow the reconstruction of reach and grasp for real-time neuroprosthetic applications, thus potentially supplementing the ability to decode these same features from spiking populations. PMID- 21273315 TI - Physiological changes underlying bilateral isometric arm voluntary contractions in healthy humans. AB - Many bilateral motor tasks engage simultaneous activation of distal and proximal arm muscles, but little is known about their physiological interactions. Here, we used transcranial magnetic stimulation to examine motor-evoked potentials (MEPs), interhemispheric inhibition at a conditioning-test interval of 10 (IHI(10)) and 40 ms (IHI(40)), and short-interval intracortical inhibition (SICI) in the left first dorsal interosseous (FDI) muscle during isometric index finger abduction. The right side remained at rest or performed isometric voluntary contraction with the FDI, biceps or triceps brachii, or the tibialis anterior. Left FDI MEPs were suppressed to a similar extent during contraction of the right FDI and biceps and triceps brachii but remained unchanged during contraction of the right tibialis anterior. IHI(10) and IHI(40) were decreased during contraction of the right biceps and triceps brachii compared with contraction of the right FDI. SICI was increased during activation of the right biceps and triceps brachii and decreased during activation of the right FDI. The present results indicate that an isometric voluntary contraction with either a distal or a proximal arm muscle, but not a foot dorsiflexor, decreases corticospinal output in a contralateral active finger muscle. Transcallosal inhibitory effects were strong during bilateral activation of distal hand muscles and weak during simultaneous activation of a distal and a proximal arm muscle, whereas GABAergic intracortical activity was modulated in the opposite manner. These findings suggest that in intact humans crossed interactions at the level of the motor cortex involved different physiological mechanisms when bilateral distal hand muscles are active and when a distal and a proximal arm muscle are simultaneously active. PMID- 21273316 TI - Physiological clustering of visual channels in the mouse retina. AB - Anatomy predicts that mammalian retinas should have in excess of 12 physiological channels, each encoding a specific aspect of the visual scene. Although several channels have been correlated with morphological cell types, the number of morphological types generally exceeds the known physiological types. Here, we attempted to sort the ganglion cells of the mouse retina purely on a physiological basis. The null hypothesis was that the outputs of the ganglion cells form a continuum or should be divided into only a few types. We recorded the spiking output of 471 retinal ganglion cells on a multielectrode array while presenting 4 classes of visual stimuli. Five parameters were chosen to describe each cell's response characteristics, including relative amplitude of the ON and OFF responses, response latency, response transience, direction selectivity, and the receptive field surround. We compared the results of four clustering routines and judged the results using the relevant validation indices. The optimal partition was the 12-cluster solution of the Fuzzy Gustafson-Kessel algorithm. This classification contained three visual channels that carried predominately OFF responses, six that carried ON responses, and three that carried both ON and OFF information. They differed in other parameters as well. Other evidence suggests that the true number of cell types in the mouse retina may be somewhat larger than 12, and a definitive typology will probably require broader stimulus sets and characterization of more response parameters. Nonetheless, the present results do allow us to reject the null hypothesis: it appears that in addition to well-known cell types (such as the ON-OFF direction selectivity cells) numerous other cell classes can be identified in the mouse retina based solely on their responses to a standard set of simple visual stimuli. PMID- 21273317 TI - Controlling Spike Timing and Synchrony in Oscillatory Neurons. AB - We describe an algorithm to control synchrony between two periodically firing neurons. The control scheme operates in real-time using a dynamic clamp platform. This algorithm is a low impact stimulation method that brings the neurons toward the desired level of synchrony over the course of several neuron firing periods. As a proof of principle, we demonstrate the versatility of the algorithm using real- time conductance models, and then show its performance with biological neurons of hippocampal region CA1 and entorhinal cortex. PMID- 21273318 TI - Glucose-dependent insulinotropic polypeptide receptor knockout mice are impaired in learning, synaptic plasticity, and neurogenesis. AB - Glucose-dependent insulinotropic polypeptide (GIP) is a key incretin hormone, released from intestine after a meal, producing a glucose-dependent insulin secretion. The GIP receptor (GIPR) is expressed on pyramidal neurons in the cortex and hippocampus, and GIP is synthesized in a subset of neurons in the brain. However, the role of the GIPR in neuronal signaling is not clear. In this study, we used a mouse strain with GIPR gene deletion (GIPR KO) to elucidate the role of the GIPR in neuronal communication and brain function. Compared with C57BL/6 control mice, GIPR KO mice displayed higher locomotor activity in an open field task. Impairment of recognition and spatial learning and memory of GIPR KO mice were found in the object recognition task and a spatial water maze task, respectively. In an object location task, no impairment was found. GIPR KO mice also showed impaired synaptic plasticity in paired-pulse facilitation and a block of long-term potentiation in area CA1 of the hippocampus. Moreover, a large decrease in the number of neuronal progenitor cells was found in the dentate gyrus of transgenic mice, although the numbers of young neurons was not changed. Together the results suggest that GIP receptors play an important role in cognition, neurotransmission, and cell proliferation. PMID- 21273319 TI - Developmental plasticity of descending motor pathways. AB - Juvenile animal brains are highly plastic and thus often achieve better functional recovery after injury compared with adult brains. Recently, Umeda et al. (Umeda T, Takahashi M, Isa K, Isa T. J Neurophysiol 104: 1707-1716, 2010) have shown that the remodeling of both corticospinal and extra-pyramidal pathways can contribute to the recovery of grasping and reaching ability in hemidecorticated juvenile rats. They have further unveiled the strengthening of the cortico-reticulo-spinal pathway after injury, that mediates the fast excitation of ipsilateral motoneurons for functional recovery. PMID- 21273320 TI - L-arginine via nitric oxide is an inhibitory feedback modulator of Aplysia feeding. AB - An increase in L-arginine hemolymph concentration acts as a postingestion signal inhibiting Aplysia feeding. At physiological concentrations (a 10-MUM increase over background), the inhibitory effect of L-arginine is too weak to block feeding in hungry animals. However, a 10-MUM increase in L-arginine concentration acts along with another inhibitory stimulus, the sustained presence of food odor, to inhibit feeding after a period of access to food. A physiological concentration of L-arginine also blocked the excitatory effect of a stimulus enhancing feeding, pheromones secreted by mating conspecifics. High concentrations of L-arginine (2.5 mM) alone also inhibited ad libitum feeding. L arginine is the substrate from which nitric oxide synthase (NOS) produces nitric oxide (NO). Both an NO donor and a 10-MUM increase in L-arginine inhibited biting in response to a weak food stimulus. Treatment with NOS inhibitors initiated food finding and biting in the absence of food, indicating that food initiates feeding against a background of tonic nitrergic inhibition. Increased feeding in response to blocking NOS is accompanied by firing of the metacerebral (MCC) neuron, a monitor of food arousal. The excitatory effect on the MCC of blocking NOS is indirect. The data suggest that L-arginine acts by amplifying NO synthesis, which acts as a background stimulus inhibiting feeding. Background modulation of neural activity and behavior by NO may also be present in other systems, but such modulation may be difficult to identify because its effects are evident only in the context of additional stimuli modulating behavior. PMID- 21273321 TI - Competition and convergence between auditory and cross-modal visual inputs to primary auditory cortical areas. AB - Sensory neocortex is capable of considerable plasticity after sensory deprivation or damage to input pathways, especially early in development. Although plasticity can often be restorative, sometimes novel, ectopic inputs invade the affected cortical area. Invading inputs from other sensory modalities may compromise the original function or even take over, imposing a new function and preventing recovery. Using ferrets whose retinal axons were rerouted into auditory thalamus at birth, we were able to examine the effect of varying the degree of ectopic, cross-modal input on reorganization of developing auditory cortex. In particular, we assayed whether the invading visual inputs and the existing auditory inputs competed for or shared postsynaptic targets and whether the convergence of input modalities would induce multisensory processing. We demonstrate that although the cross-modal inputs create new visual neurons in auditory cortex, some auditory processing remains. The degree of damage to auditory input to the medial geniculate nucleus was directly related to the proportion of visual neurons in auditory cortex, suggesting that the visual and residual auditory inputs compete for cortical territory. Visual neurons were not segregated from auditory neurons but shared target space even on individual target cells, substantially increasing the proportion of multisensory neurons. Thus spatial convergence of visual and auditory input modalities may be sufficient to expand multisensory representations. Together these findings argue that early, patterned visual activity does not drive segregation of visual and auditory afferents and suggest that auditory function might be compromised by converging visual inputs. These results indicate possible ways in which multisensory cortical areas may form during development and evolution. They also suggest that rehabilitative strategies designed to promote recovery of function after sensory deprivation or damage need to take into account that sensory cortex may become substantially more multisensory after alteration of its input during development. PMID- 21273322 TI - A tingling sanshool derivative excites primary sensory neurons and elicits nocifensive behavior in rats. AB - Szechuan peppers contain hydroxy-alpha-sanshool that imparts desirable tingling, cooling, and numbing sensations. Hydroxy-alpha-sanshool activates a subset of sensory dorsal root ganglion (DRG) neurons by inhibiting two-pore potassium channels. We presently investigated if a tingle-evoking sanshool analog, isobutylalkenyl amide (IBA), excites rat DRG neurons and, if so, if these neurons are also activated by agonists of TRPM8, TRPA1, and/or TRPV1. Thirty-four percent of DRG neurons tested responded to IBA, with 29% of them also responding to menthol, 29% to cinnamic aldehyde, 66% to capsaicin, and subsets responding to two or more transient receptor potential (TRP) agonists. IBA-responsive cells had similar size distributions regardless of whether they responded to capsaicin or not; cells only responsive to IBA were larger. Responses to repeated application of IBA at a 5-min interstimulus interval exhibited self-desensitization (tachyphylaxis). Capsaicin did not cross-desensitize responses to IBA to any greater extent than the tachyphylaxis observed with repeated IBA applications. These findings are consistent with psychophysical observations that IBA elicits tingle sensation accompanied by pungency and cooling, with self-desensitization but little cross-desensitization by capsaicin. Intraplantar injection of IBA elicited nocifensive responses (paw licking, shaking-flinching, and guarding) in a dose-related manner similar to the effects of intraplantar capsaicin and serotonin. IBA had no effect on thermal sensitivity but enhanced mechanical sensitivity at the highest dose tested. These observations suggest that IBA elicits an unfamiliar aversive sensation that is expressed behaviorally by the limited response repertoire available to the animal. PMID- 21273323 TI - Nonlinear effects of noradrenergic modulation of olfactory bulb function in adult rodents. AB - The mammalian main olfactory bulb receives a significant noradrenergic input from the locus coeruleus. Norepinephrine (NE) is involved in acquisition of conditioned odor preferences in neonatal animals, in some species-specific odor dependent behaviors, and in adult odor perception. We provide a detailed review of the functional role of NE in adult rodent main olfactory bulb function. We include cellular, synaptic, network, and behavioral data and use computational simulations to tie these different types of data together. PMID- 21273324 TI - Separate representations of dynamics in rhythmic and discrete movements: evidence from motor learning. AB - Rhythmic and discrete arm movements occur ubiquitously in everyday life, and there is a debate as to whether these two classes of movements arise from the same or different underlying neural mechanisms. Here we examine interference in a motor-learning paradigm to test whether rhythmic and discrete movements employ at least partially separate neural representations. Subjects were required to make circular movements of their right hand while they were exposed to a velocity dependent force field that perturbed the circularity of the movement path. The direction of the force-field perturbation reversed at the end of each block of 20 revolutions. When subjects made only rhythmic or only discrete circular movements, interference was observed when switching between the two opposing force fields. However, when subjects alternated between blocks of rhythmic and discrete movements, such that each was uniquely associated with one of the perturbation directions, interference was significantly reduced. Only in this case did subjects learn to corepresent the two opposing perturbations, suggesting that different neural resources were employed for the two movement types. Our results provide further evidence that rhythmic and discrete movements employ at least partially separate control mechanisms in the motor system. PMID- 21273325 TI - MPs or ICs? AB - In this issue of Blood, Gyorgy and colleagues used multiple methods to characterize cell-derived microparticles (MPs) in the plasma and synovial fluid of arthritis patients and discovered that MPs and immune complexes (ICs) have overlapping biophysical properties. PMID- 21273326 TI - HDAC inhibitors block innate immunity. AB - In this issue of Blood, Roger and colleagues present data on the magnitude of influence that broad-spectrum HDAC inhibitors exert on TLR-driven immune responses, thus demonstrating that HDAC inhibitors are immunosuppressive drugs. PMID- 21273327 TI - MPO and neutrophils: a magnetic attraction. AB - In this issue of Blood, Klinke et al demonstrate the ability of myeloperoxidase (MPO) to attract neutrophils to the vascular wall, a process that might contribute to the pathogenesis of atherosclerosis and other inflammatory vascular disorders. PMID- 21273328 TI - Bacteria and HIT: a close connection? AB - HIT is caused by antibodies specific to PF4/heparin complexes. In this issue of Blood, Krauel et al report novel findings supporting the hypothesis that primary synthesis of these antibodies results from bacterial infections. HIT, therefore, appears to be a misdirected antibacterial host defense response. PMID- 21273329 TI - Clues to DVT pathogenesis. AB - In this issue of Blood, Brill and colleagues demonstrate that von Willebrand factor (VWF) release and subsequent platelet adhesion to endothelial cells are required for thrombus formation in a mouse model of deep venous thrombosis (DVT). PMID- 21273331 TI - Search for nodulation-related CLE genes in the genome of Glycine max. AB - CLE peptides are potentially involved in nodule organ development and in the autoregulation of nodulation (AON), a systemic process that restricts nodule number. A genome-wide survey of CLE peptide genes in the soybean glycine max genome resulted in the identification of 39 GmCLE genes, the majority of which have not yet been annotated. qRT-PCR analysis indicated two different nodulation related CLE expression patterns, one linked with nodule primordium development and a new one linked with nodule maturation. Moreover, two GmCLE gene pairs, encoding group-III CLE peptides that were previously shown to be involved in AON, had a transient expression pattern during nodule development, were induced by the essential nodulation hormone cytokinin, and one pair was also slightly induced by the addition of nitrate. Hence, our data support the hypothesis that group-III CLE peptides produced in the nodules are involved in primordium homeostasis and intertwined in activating AON, but not in sustaining it. PMID- 21273332 TI - Exploring nitrogen remobilization for seed filling using natural variation in Arabidopsis thaliana. AB - Nineteen Arabidopsis accessions grown at low (LOW N) and high (HIGH N) nitrate supplies were labelled using (15)N to trace nitrogen remobilization to the seeds. Effects of genotype and nutrition were examined. Nitrate availability affected biomass and yield, and highly modified the nitrogen concentration in the dry remains. Surprisingly, variations of one-seed dry weight (DW(1S)) and harvest index (HI) were poorly affected by nutrition. Nitrogen harvest index (NHI) was highly correlated with HI and showed that nitrogen use efficiency (NUE) was increased at LOW N. Nitrogen remobilization efficiency (NRE), as (15)N partitioning in seeds ((15)NHI), was also higher at LOW N. The relative specific abundance (RSA) in seeds and whole plants indicated that the (14)NO(3) absorbed post-labelling was mainly allocated to the seeds (SEEDS) at LOW N, but to the dry remains (DR) at HIGH N. Nitrogen concentration (N%) in the DR was then 4-fold higher at HIGH N compared with LOW N, whilst N% in seeds was poorly modified. Although NHI and (15)NHI were highly correlated to HI, significant variations in NUE and NRE were identified using normalization to HI. New insights provided in this report are helpful for the comprehension of NUE and NRE concepts in Arabidopsis as well as in crops and especially in Brassica napus. PMID- 21273333 TI - Role of magnesium in alleviation of aluminium toxicity in plants. AB - Magnesium is pivotal for activating a large number of enzymes; hence, magnesium plays an important role in numerous physiological and biochemical processes affecting plant growth and development. Magnesium can also ameliorate aluminium phytotoxicity, but literature reports on the dynamics of magnesium homeostasis upon exposure to aluminium are rare. Herein existing knowledge on the magnesium transport mechanisms and homeostasis maintenance in plant cells is critically reviewed. Even though overexpression of magnesium transporters can alleviate aluminium toxicity in plants, the mechanisms governing such alleviation remain obscure. Possible magnesium-dependent mechanisms include (i) better carbon partitioning from shoots to roots; (ii) increased synthesis and exudation of organic acid anions; (iii) enhanced acid phosphatase activity; (iv) maintenance of proton-ATPase activity and cytoplasmic pH regulation; (v) protection against an aluminium-induced cytosolic calcium increase; and (vi) protection against reactive oxygen species. Future research should concentrate on assessing aluminium toxicity and tolerance in plants with overexpressed or antisense magnesium transporters to increase understanding of the aluminium-magnesium interaction. PMID- 21273334 TI - Additive effects of Na+ and Cl- ions on barley growth under salinity stress. AB - Soil salinity affects large areas of the world's cultivated land, causing significant reductions in crop yield. Despite the fact that most plants accumulate both sodium (Na(+)) and chloride (Cl(-)) ions in high concentrations in their shoot tissues when grown in saline soils, most research on salt tolerance in annual plants has focused on the toxic effects of Na(+) accumulation. It has previously been suggested that Cl(-) toxicity may also be an important cause of growth reduction in barley plants. Here, the extent to which specific ion toxicities of Na(+) and Cl(-) reduce the growth of barley grown in saline soils is shown under varying salinity treatments using four barley genotypes differing in their salt tolerance in solution and soil-based systems. High Na(+), Cl(-), and NaCl separately reduced the growth of barley, however, the reductions in growth and photosynthesis were greatest under NaCl stress and were mainly additive of the effects of Na(+) and Cl(-) stress. The results demonstrated that Na(+) and Cl(-) exclusion among barley genotypes are independent mechanisms and different genotypes expressed different combinations of the two mechanisms. High concentrations of Na(+) reduced K(+) and Ca(2+) uptake and reduced photosynthesis mainly by reducing stomatal conductance. By comparison, high Cl(-) concentration reduced photosynthetic capacity due to non stomatal effects: there was chlorophyll degradation, and a reduction in the actual quantum yield of PSII electron transport which was associated with both photochemical quenching and the efficiency of excitation energy capture. The results also showed that there are fundamental differences in salinity responses between soil and solution culture, and that the importance of the different mechanisms of salt damage varies according to the system under which the plants were grown. PMID- 21273335 TI - Drought alters timing, quantity, and quality of wood formation in Scots pine. AB - Drought has been frequently discussed as a trigger for forest decline. Today, large-scale Scots pine decline is observed in many dry inner-Alpine valleys, with drought discussed as the main causative factor. This study aimed to analyse the impact of drought on wood formation and wood structure. To study tree growth under contrasting water supply, an irrigation experiment was installed in a mature Scots pine (Pinus sylvestris L.) forest at a xeric site in a dry inner Alpine valley. Inter- and intra-annual radial increments as well as intra-annual variations in wood structure of pine trees were studied. It was found that non irrigated trees had a noticeably shorter period of wood formation and showed a significantly lower increment. The water conduction cells were significantly enlarged and had significantly thinner cell walls compared with irrigated trees. It is concluded that pine trees under drought stress build a more effective water conducting system (larger tracheids) at the cost of a probably higher vulnerability to cavitation (larger tracheids with thinner cell walls) but without losing their capability to recover. The significant shortening of the growth period in control trees indicated that the period where wood formation actually takes place can be much shorter under drought than the 'potential' period, meaning the phenological growth period. PMID- 21273336 TI - Demethylation of oligogalacturonides by FaPE1 in the fruits of the wild strawberry Fragaria vesca triggers metabolic and transcriptional changes associated with defence and development of the fruit. AB - Ectopic expression of the strawberry (Fragaria*ananassa) gene FaPE1 encoding pectin methyl esterase produced in the wild species Fragaria vesca partially demethylated oligogalacturonides (OGAs), which conferred partial resistance of ripe fruits to the fungus Botrytis cinerea. Analyses of metabolic and transcriptional changes in the receptacle of the transgenic fruits revealed channelling of metabolites to aspartate and aromatic amino acids as well as phenolics, flavanones, and sesquiterpenoids, which was in parallel with the increased expression of some genes related to plant defence. The results illustrate the changes associated with resistance to B. cinerea in the transgenic F. vesca. These changes were accompanied by a significant decrease in the auxin content of the receptacle of the ripe fruits of transgenic F. vesca, and enhanced expression of some auxin-repressed genes. The role of these OGAs in fruit development was revealed by the larger size of the ripe fruits in transgenic F. vesca. When taken together these results show that in cultivated F. ananassa FaPE1 participates in the de-esterification of pectins and the generation of partially demethylated OGAs, which might reinforce the plant defence system and play an active role in fruit development. PMID- 21273337 TI - Assessing the applicability of the earth impedance method for in situ studies of tree root systems. AB - Several electrical methods have been introduced as non-invasive techniques to overcome the limited accessibility to root systems. Among them, the earth impedance method (EIM) represents the most recent development. Applying an electrical field between a cormus and the rooted soil, the EIM measures the absorptive root surface area (ARSA) from grounding resistance patterns. Allometric relationships suggested that this method was a valuable tool. Crucial assumptions for the applicability of the EIM, however, have not been tested experimentally. Focusing on tree root systems, the present study assesses the applicability of the EIM. Six hypotheses, deduced from the EIM approach, were tested in several experiments and the results were compared with conventional methods. None of the hypotheses could be verified and the results allow two major conclusions. First, in terms of an analogue electrical circuit, a tree-root-soil continuum appears as a serial circuit with xylem and soil resistance being the dominant components. Allometric variation in contact resistance, with the latter being the proxy for root surface area, are thus overruled by the spatial and seasonal variation of soil and xylem resistances. Second, in a tree-root-soil continuum, distal roots conduct only a negligible portion of the electric charge. Most of charge carriers leave the root system in the proximal parts of the root soil interface. PMID- 21273338 TI - Large changes in anatomy and physiology between diploid Rangpur lime (Citrus limonia) and its autotetraploid are not associated with large changes in leaf gene expression. AB - Very little is known about the molecular origin of the large phenotypic differentiation between genotypes arising from somatic chromosome set doubling and their diploid parents. In this study, the anatomy and physiology of diploid (2x) and autotetraploid (4x) Rangpur lime (Citrus limonia Osbeck) seedlings has been characterized. Growth of 2x was more vigorous than 4x although leaves, stems, and roots of 4x plants were thicker and contained larger cells than 2x that may have a large impact on cell-to-cell water exchanges. Leaf water content was higher in 4x than in 2x. Leaf transcriptome expression using a citrus microarray containing 21 081 genes revealed that the number of genes differentially expressed in both genotypes was less than 1% and the maximum rate of gene expression change within a 2-fold range. Six up-regulated genes in 4x were targeted to validate microarray results by real-time reverse transcription PCR. Five of these genes were apparently involved in the response to water deficit, suggesting that, in control conditions, the genome expression of citrus autotetraploids may act in a similar way to diploids under water-deficit stress condition. The sixth up-regulated gene which codes for a histone may also play an important role in regulating the transcription of growth processes. These results show that the large phenotypic differentiation in 4x Rangpur lime compared with 2x is not associated with large changes in genome expression. This suggests that, in 4x Rangpur lime, subtle changes in gene expression may be at the origin of the phenotypic differentiation of 4x citrus when compared with 2x. PMID- 21273339 TI - Determination of the site of CO2 sensing in poplar: is the area-based N content and anatomy of new leaves determined by their immediate CO2 environment or by the CO2 environment of mature leaves? AB - Exposure to an elevated CO(2) concentration ([CO(2)]) generally decreases leaf N content per unit area (N(area)) and stomatal density, and increases leaf thickness. Mature leaves can 'sense' elevated [CO(2)] and this regulates stomatal development of expanding leaves (systemic regulation). It is unclear if systemic regulation is involved in determination of leaf thickness and N(area)-traits that are significantly correlated with photosynthetic capacity. A cuvette system was used whereby [CO(2)] around mature leaves was controlled separately from that around expanding leaves. Expanding leaves of poplar (Populus trichocarpa*P. deltoides) seedlings were exposed to elevated [CO(2)] (720 MUmol mol(-1)) while the remaining mature leaves inside the cuvette were under ambient [CO(2)] of 360 MUmol mol(-1). Reverse treatments were performed. Exposure of newly developing leaves to elevated [CO(2)] increased their thickness, but when mature leaves were exposed to elevated [CO(2)] the increase in thickness of new leaves was less pronounced. The largest response to [CO(2)] was reflected in the palisade tissue thickness (as opposed to the spongy tissue) of new leaves. The N(area) of new leaves was unaffected by the local [CO(2)] where the new leaves developed, but decreased following the exposure of mature leaves to elevated [CO(2)]. The volume fraction of mesophyll cells compared with total leaf and the mesophyll cell density changed in a manner similar to the response of N(area). These results suggest that N(area) is controlled independently of the leaf thickness, and suggest that N(area) is under systemic regulation by [CO(2)] signals from mature leaves that control mesophyll cell division. PMID- 21273340 TI - Changing the substrate specificity of P450cam towards diphenylmethane by semi rational enzyme engineering. AB - A focused library comprising nine residues of the active site of P450cam monooxygenase resulting in ~ 300,000 protein variants was screened for activity on diphenylmethane (DPM). The assay was based on the depletion of NADH by an in vitro reconstituted P450cam system in a 96-well scale. The throughput was increased by the parallel cultivation, purification and analysis of 20 variants per well (cluster screening). Thus ~ 20,000 protein variants could be screened in summary of which five were found to transform DPM with a specific activity of up to 75% of the wild-type activity on d-camphor and a coupling rate of 7-18%. One variant converting DPM to 4-hydroxydiphenylmethane (4HDPM) was subjected to site directed mutagenesis and saturation mutagenesis, which revealed the particular importance of positions F87, Y96 and L244 for substrate selectivity and the possibility for further improvements of this variant. Moreover, a reduction in size of the amino acid at position 396 decreased specific activity dramatically but increased coupling and switched the main product formation from 4HDPM towards diphenylmethanol. PMID- 21273341 TI - Modulating the pH-activity profile of cellulase A from Cellulomonas fimi by replacement of surface residues. AB - One industrial process for the production of cellulosic ethanol and or value added products involves exposing the cellulose content of plant materials by steam explosion in the presence of strong acid, followed by its neutralization and subsequent digestion with a cocktail of cellulolytic enzymes. These enzymes typically have activity optima at slightly acidic or neutral pH and so generating enzymes that are more active and tolerant in more acidic conditions would help to reduce associated costs. Here, we describe the engineering of cellulase A from Cellulomonas fimi as a model to replace residues that were identified as potentially influencing the pH-activity profile of the enzyme based on sequence alignments and analysis of the known three-dimensional structures of other CAZy family 6 glycoside hydrolases with the aim to lower its pH optimum. Twelve specific residues and a sequence of eight were identified and a total of 30 mutant enzymes were generated. In addition to being replaced with natural amino acids, some of the identified residues were substituted with cysteine and subsequently oxidized to cysteinesulfinate. Of the four single amino acid replacements that produced enhancements of activity at acidic pH, three involved the removal of charged groups from the surface of the enzyme. The generation of double mutations provided mixed results but the combination of Glu407 -> Ala and Tyr321 -> Phe replacements had an additive effect on the enhancement, reaching a total activity that was 162% of the wild-type level. This study thus illustrated the utility of altering the surface charge properties of the family 6 glycoside hydrolases to enhance activity at low pH and thereby an avenue for further protein engineering. PMID- 21273342 TI - Aromatase inhibitor-induced loss of grip strength is body mass index dependent: hypothesis-generating findings for its pathogenesis. AB - BACKGROUND: Our preliminary results showed that tenosynovial changes and decrease in grip strength are associated with the aromatase inhibitor-induced musculoskeletal syndrome (AIMSS). Here, we report the final results and assess the relationship between grip strength and body mass index (BMI). PATIENTS AND METHODS: We conducted a prospective study including postmenopausal early breast cancer patients receiving either an aromatase inhibitor (AI) or tamoxifen. Primary end point was change from baseline in tenosynovial abnormalities. Secondary end points were changes from baseline in morning stiffness, intra articular fluid and grip strength and its association with BMI. RESULTS: After 6 months of therapy, 74% [95% confidence interval (CI) 51% to 89%] of AI-treated patients had worsened tenosynovial abnormalities, 56% (95% CI 34% to 75%) had increased intra-articular fluid, and 22% (95% CI 9% to 45%) had increased morning stiffness. Grip strength decreased 8% for the left hand (95% CI 2% to 21%) and 11% for the right (95% CI 4% to 17%). Regression analysis suggested that grip strength decreased more for subjects with high or with low BMI. CONCLUSIONS: AIMSS is characterized by tenosynovial changes, intra-articular fluid and morning stiffness. We hypothesize that the quadratic association between BMI and loss of grip strength reflects AI-induced changes on the endocrine control of the growth hormone insulin-like growth factor-I pathway. PMID- 21273343 TI - Functional organ preservation in patients with locoregionally advanced head and neck squamous cell carcinoma treated by platinum-based multidrug induction chemotherapy and concurrent chemoradiotherapy. AB - BACKGROUND: The objective of this study was to evaluate the feasibility, safety, and efficacy in terms of functional organ preservation of multidrug induction chemotherapy and concurrent chemoradiotherapy (IC-CCRT) protocol in patients with locoregionally advanced head and neck squamous cell carcinoma (LA-HNSCC). PATIENTS AND METHODS: Patients with previously untreated, inoperable, histologically proven nonmetastatic stage III or IV HNSCC were eligible. Following one cycle of IC, two cycles of cisplatinum and 5-fluorouracil CCRT with conventional fractionated radiotherapy up to a dose of 66-70 Gy were administrated. RESULTS: Between January 2000 and July 2007, a total of 139 patients were candidates to receive IC-CCRT for LA-HNSCC. Overall, 83% of the patients completed the treatment. Three-year overall survival estimate was 68% [95% confidence interval (CI) 57% to 79%]. Three-year progression-free survival (PFS) estimate was 62% (95% CI 50% to 74%). Three-year functional PFS was 57% (95% CI 44% to 69%). There were no cases of treatment-related deaths. The most frequent severe acute toxicity was pharyngeal mucositis. CONCLUSIONS: Cisplatinum based multidrug IC-CCRT can result in functional organ preservation and curative treatment in most patients with LA-HNSCC. The toxicity profile and patients' compliance to treatment confirmed the safety and tolerability of this approach. PMID- 21273344 TI - Should diagnostic laparoscopy be conducted before hormonal treatment in early stage endometrial cancer? PMID- 21273345 TI - An economic analysis of the INTEREST trial, a randomized trial of docetaxel versus gefitinib as second-/third-line therapy in advanced non-small-cell lung cancer. AB - BACKGROUND: The INTEREST (IRESSA NSCLC Trial Evaluating Response and Survival against Taxotere) trial compared gefitinib with docetaxel (Taxotere) in pretreated advanced non-small-cell lung cancer (NSCLC). Noninferiority for overall survival was concluded. Gefitinib had a better toxicity profile and greater improvements in quality of life (QoL). We undertook a cost-consequence analysis to estimate the direct medical costs of gefitinib compared with docetaxel. PATIENTS AND METHODS: Summary data from INTEREST were used to derive resource utilization and direct costs from treatment start until drug discontinuation. Costs for treatment, adverse events, outpatient visits and investigations were calculated. Mean total cost-per-patient-per-arm was determined, and incremental cost was calculated. Utility values were generated from Functional Assessment of Cancer Therapy - Lung scores and compared between arms. RESULTS: Incremental mean overall cost per patient for gefitinib over docetaxel was CAD $5161. Drug was the major contributor to overall cost in both arms. Longer mean duration of gefitinib therapy (134 versus 91 days) contributed to the incremental cost difference. The cost per 21-day cycle was similar in both arms ($1963 docetaxel, $2095 gefitinib). CONCLUSION: The modest increase in cost associated with gefitinib supports its use as an alternative to docetaxel as second-line treatment of advanced NSCLC, particularly given the improvements in QoL, patient preference for oral therapy and better toxicity profile with gefitinib. PMID- 21273346 TI - Circulating biomarker tissue kallikrein-related peptidase KLK5 impacts ovarian cancer patients' survival. AB - BACKGROUND: Effective cancer biomarkers for early detection, prognosis, or therapy response prediction are urgently needed in ovarian cancer. Kallikrein related peptidases, including KLK5, have been reported to play an important role in the course of the disease. PATIENTS AND METHODS: KLK5 antigen content was determined by enzyme-linked immunosorbent assay in ovarian cancer patients' [FIGO (International Federation of Gynecology and Obstetrics) stages I-IV, n = 52] serum as well as ascitic fluid and compared with KLK5 content in serum of patients with benign ovarian tumors (n = 45). RESULTS: KLK5 antigen content was significantly elevated in the serum of ovarian cancer patients compared with the serum of patients with benign ovarian tumors. Forty-two of 52 ovarian cancer serum samples, 42 of 43 benign ovarian tumor serum samples, and all 41 ascitic fluid samples were KLK5 positive. Elevated KLK5 antigen in serum and ascitic fluid of ovarian cancer patients was a prognostic factor for progression-free survival. CONCLUSIONS: Our data support the finding that ovarian cancer patients release significant amounts of KLK5 into serum and ascitic fluid but KLK5 antigen is low in serum of patients with benign ovarian tumors. Increased serum and ascitic fluid KLK5 levels are associated with poor patient outcome, thus underlining the importance of KLK5 as a biomarker for early detection as well as for disease management in ovarian cancer. PMID- 21273347 TI - Risk of arterial thromboembolic events in patients with advanced colorectal cancer receiving bevacizumab. AB - BACKGROUND: Bevacizumab is an antiangiogenic mAb with efficacy against several cancers, but it is associated with risk of arterial thromboembolism (ATE). Further data are needed to determine the safety of bevacizumab. PATIENTS AND METHODS: We recorded grade 3, 4, or 5 ATE events and other data (including age, baseline cardiovascular risk factors, history of ATE, and aspirin use) from 471 patients with metastatic colorectal cancer in the MAX (Mitomycin, Avastin, Xeloda) trial of capecitabine monotherapy versus capecitabine with bevacizumab with or without mitomycin C. RESULTS: Bevacizumab-treated patients had 12 grade 3, 4, or 5 ATEs (3.8% incidence). ATEs occurred in 2.1% of patients >65 years, 5% of those with a history of ATE, and 5% of those with cardiac risk factors. Age, history of ATE, or vascular risk factors did not increase risk. Aspirin users had a higher incidence than nonusers (8.9% versus 2.7%) but had higher rates of vascular risk factors. CONCLUSIONS: Bevacizumab was associated with a modestly higher risk of ATE, but safety was not significantly worse in older patients or patients with a history of ATE or vascular risk factors. The effect of aspirin in preventing ATE in patients receiving bevacizumab could not be determined from this study. PMID- 21273348 TI - Phase II trial of combretastatin A4 phosphate, carboplatin, and paclitaxel in patients with platinum-resistant ovarian cancer. AB - BACKGROUND: A previous dose-escalation trial of the vascular disrupting agent combretastatin A4 phosphate (CA4P) given before carboplatin, paclitaxel, or both showed responses in 7 of 18 patients with relapsed ovarian cancer. PATIENTS AND METHODS: Patients with ovarian cancer that had relapsed and who could start trial therapy within 6 months of their last platinum chemotherapy were given CA4P 63 mg/m(2) minimum 18 h before paclitaxel 175 mg/m(2) and carboplatin AUC (area under the concentration curve) 5, repeated every 3 weeks. RESULTS: Five of the first 18 patients' disease responded, so the study was extended and closed after 44 patients were recruited. Grade >=2 toxic effects were neutropenia in 75% and thrombocytopenia in 9% of patients (weekly blood counts), tumour pain, fatigue, and neuropathy, with one patient with rapidly reversible ataxia. Hypertension (23% of patients) was controlled by glyceryl trinitrate or prophylactic amlodipine. The response rate by RECIST was 13.5% and by Gynecologic Cancer InterGroup CA 125 criteria 34%. CONCLUSIONS: The addition of CA4P to paclitaxel and carboplatin is well tolerated and appears to produce a higher response rate in this patient population than if the chemotherapy was given without CA4P. A planned randomised trial will test this hypothesis. PMID- 21273349 TI - Is mechanical clot removal or disruption a cost-effective treatment for acute stroke? AB - BACKGROUND AND PURPOSE: It is unclear whether the costs and risks of mechanical therapies make them cost-effective. We examined whether interventions such as mechanical clot removal or disruption with angioplasty are cost-effective for acute ischemic stroke compared with best medical therapy. MATERIALS AND METHODS: We performed a cost-utility analysis of patients with acute stroke due to large intracranial artery occlusion presenting beyond the 3-hour window for IV tPA. Model inputs for the mechanical arm were derived from Multi MERCI trial data and a recent meta-analysis. For best medical therapy, we used rates of spontaneous recanalization, ICH, and functional outcomes based on a systematic literature review. Discounted QALYs were determined by using the Markov modeling for 65-year old patients with acute ischemic stroke. RESULTS: On the basis of a systematic literature review, we modeled an 84% rate of recanalization with mechanical intervention and a 6.3% rate of symptomatic ICH. For best medical therapy, we modeled a spontaneous recanalization rate of 24% with a 2% rate of symptomatic ICH. Mechanical therapies were associated with a $7718 net cost and a gain of a 0.82 QALYs for each use, thus yielding a net of $9386/QALY gained. In sensitivity analyses, results were dependent on the rates of recanalization, symptomatic ICH rates, and costs of treatment. CONCLUSIONS: On the basis of available data, mechanical therapies in qualified patients with acute stroke beyond the window for IV tPA appear to be cost-effective. However, the inputs are not derived from randomized trials, and results are sensitive to several assumptions. PMID- 21273350 TI - Percutaneous balloon kyphoplasty with the patient under intravenous analgesia and sedation: a feasibility study. AB - BACKGROUND AND PURPOSE: Kyphoplasty is a minimally invasive procedure for the treatment of malignant or osteoporotic vertebral compression fractures, normally performed with the patient under general anesthesia. This may cause a therapeutic dilemma because these patients often have a very high risk for general anesthesia due to concomitant diseases. The aim of this study was to evaluate the safety and feasibility of percutaneous kyphoplasty by using IV anesthesia and sedation with midazolam and piritramide. MATERIALS AND METHODS: From June 2007 to June 2009, we prospectively included 133 patients (77 women, 56 men; mean age, 69.18 +/- 11.45 years) who were referred for BKP. Kyphoplasty was always performed under fluoroscopic guidance with a biplane angiographic system by using a transpedicular or extrapedicular approach. The individual anesthesia risk was assessed by using the ASA criteria. All procedures were performed with the patient under IV anesthesia and sedation with fractionated administration of midazolam and piritramide. Pain was assessed before and after treatment by using a VAS. RESULTS: Ninety-nine patients (74.4%) had a significantly increased risk for general anesthesia (ASA score, >= 3). A total of 162 kyphoplasty procedures were performed. The mean amounts of midazolam and piritramide used were 11.3 +/- 4.38 mg and 11.8 +/- 3.98 mg, respectively. No complications related to IV anesthesia and sedation occurred. Periprocedural pain management was rated as sufficient, and all patients would undergo the procedure again. CONCLUSIONS: Percutaneous BKP with the patient under IV anesthesia and sedation with midazolam and piritramide is a safe and feasible method for treating vertebral compression fractures in patients with an increased risk for general anesthesia. PMID- 21273351 TI - Reversible cerebral vasoconstriction syndrome: treatment with combined intra arterial verapamil infusion and intracranial angioplasty. AB - We report a case of severe RCVS treated with a combination of selective intra arterial verapamil infusions and intracranial angioplasty, resulting in angiographic and clinical improvement. Endovascular techniques more commonly used in the treatment of SAH-induced vasospasm are potentially important adjuncts to systemic drug therapy in the management of severe RCVS. PMID- 21273352 TI - Age-related metabolic profiles in cognitively healthy elders: results from a voxel-based [18F]fluorodeoxyglucose-positron-emission tomography study with partial volume effects correction. AB - BACKGROUND AND PURPOSE: Functional brain variability has been scarcely investigated in cognitively healthy elderly subjects, and it is currently debated whether previous findings of regional metabolic variability are artifacts associated with brain atrophy. The primary purpose of this study was to test whether there is regional cerebral age-related hypometabolism specifically in later stages of life. MATERIALS AND METHODS: MR imaging and FDG-PET data were acquired from 55 cognitively healthy elderly subjects, and voxel-based linear correlations between age and GM volume or regional cerebral metabolism were conducted by using SPM5 in images with and without correction for PVE. To investigate sex-specific differences in the pattern of brain aging, we repeated the above voxelwise calculations after dividing our sample by sex. RESULTS: Our analysis revealed 2 large clusters of age-related metabolic decrease in the overall sample, 1 in the left orbitofrontal cortex and the other in the right temporolimbic region, encompassing the hippocampus, the parahippocampal gyrus, and the amygdala. The division of our sample by sex revealed significant sex specific age-related metabolic decrease in the left temporolimbic region of men and in the left dorsolateral frontal cortex of women. When we applied atrophy correction to our PET data, none of the above-mentioned correlations remained significant. CONCLUSIONS: Our findings suggest that age-related functional brain variability in cognitively healthy elderly individuals is largely secondary to the degree of regional brain atrophy, and the findings provide support to the notion that appropriate PVE correction is a key tool in neuroimaging investigations. PMID- 21273353 TI - Hemodynamics and anatomy of elastase-induced rabbit aneurysm models: similarity to human cerebral aneurysms? AB - BACKGROUND AND PURPOSE: Animal models provide a mechanism for fundamental studies of the coupling between hemodynamics and pathophysiology in diseases such as saccular aneurysms. In this work, we evaluated the capability of an elastase induced saccular aneurysm model in rabbits to reproduce the anatomic and hemodynamic features typical for human intracranial aneurysms. MATERIALS AND METHODS: Saccular aneurysms were created in 51 rabbits at the origin of the RCCA. Twelve weeks' postcreation, the lumen geometry of the aneurysm and surrounding vasculature was acquired by using 3DRA. Geometric features of these models were measured. Pulsatile 3D CFD studies were performed with rabbit-specific inlet profiles. RESULTS: Geometric features, including aneurysm height, width, neck diameter, aspect ratio, and NSI of all 51 rabbit aneurysm models fell within the range reported for human IAs. The distribution and range in values of pressure, WSS, and OSI were also typical for human IAs. A single recirculation region was observed in 33 (65%) of 51 cases, whereas a second transient recirculation zone was observed in 18 (35%) cases. Both of these flow types are commonly observed in human IAs. CONCLUSIONS: Most hemodynamic and geometric features in a commonly used elastase-induced rabbit saccular aneurysm model are qualitatively and quantitatively similar to those seen in large numbers of human cerebral aneurysms. PMID- 21273354 TI - Correlating quantitative MR imaging with histopathology in X-linked adrenoleukodystrophy. AB - BACKGROUND AND PURPOSE: Quantitative MR imaging techniques may improve the pathologic specificity of MR imaging regarding white matter abnormalities. Our purposes were to determine whether ADC, FA, MTR, and MRS metabolites correlate with the degree of white matter damage in patients with X-ALD; whether differences in ADC, FA, and MTR observed in vivo are retained in fresh and formalin-fixed postmortem brain tissue; and whether the differences predict histopathology. MATERIALS AND METHODS: MRS metabolites, MTR, ADC, and FA, were determined in 7 patients with X-ALD in 3 white matter areas (NAWM, active demyelination, and complete demyelination) and were compared with values obtained in 14 controls. MTR, ADC, and FA were assessed in postmortem brains from 15 patients with X-ALD and 5 controls. Values were correlated with the degree of astrogliosis and density of myelin, axons, and cells. Equations to estimate histopathology from MR imaging parameters were calculated by linear regression analysis. RESULTS: MRS showed increased mIns, Lac, and Cho and decreased tNAA in living patients with X-ALD; the values depended on the degree of demyelination. MTR, ADC, and FA values were different in postmortem than in vivo white matter, but differences related to degrees of white matter damage were retained. ADC was high and FA and MTR were low in abnormal white matter. Correlations between histopathologic findings and MR imaging parameters were strong. A combination of ADC and FA predicted pathologic parameters best. CONCLUSIONS: Changes in quantitative MR imaging parameters, present in living patients and related to the severity of white matter pathology, are retained in postmortem brain tissue. MR imaging parameters predict white matter histopathologic parameters. PMID- 21273355 TI - Prolonged carotid sinus reflex is a risk factor for contrast-induced nephropathy following carotid artery stenting. AB - BACKGROUND AND PURPOSE: Although many studies have demonstrated that CIN is associated with in-hospital and long-term mortality, the incidence of CIN following CAS is unclear. We investigated the incidence of CIN, defined as an increase from a baseline creatinine value of at least 0.5 mg/dL or 25% within 72 hours of contrast administration, and we also examined renal function in the late phase after CAS. MATERIALS AND METHODS: We examined 80 patients who underwent CAS between April 2005 and December 2009. Clinical background, laboratory data, contrast volume, and clinical course were collected and analyzed. RESULTS: The incidence of CIN was 8.8% (7/80), and no patients required hemodialysis. In the group that developed CIN, prolonged CSR after CAS was found in 57.1% (4/7) of cases; this incidence differed significantly (P = .001) from that in the group without development of CIN. Neither preoperative renal function, contrast volume, nor history was related to the incidence of CIN, while on multivariate analysis, prolonged CSR was found to be an independent risk factor for CIN. The incidence of elevation in creatinine values at 6 months after CAS was 8.2% (6/73). All patients who developed delayed renal impairment had pre-existing CKD; this finding differed significantly (P = .04) from that in the group without development of delayed renal impairment. CONCLUSIONS: Because patients who develop prolonged CSR after CAS are at increased risk of perioperative major adverse clinical events including CIN, patients at high risk for this condition should be carefully managed to prevent increased morbidity and mortality. PMID- 21273356 TI - Reproducibility of single-subject functional connectivity measurements. AB - BACKGROUND AND PURPOSE: Measurements of resting-state functional connectivity have increasingly been used for characterization of neuropathologic and neurodevelopmental populations. We collected data to characterize how much imaging time is necessary to obtain reproducible quantitative functional connectivity measurements needed for a reliable single-subject diagnostic test. MATERIALS AND METHODS: We obtained 100 five-minute BOLD scans on a single subject, divided into 10 sessions of 10 scans each, with the subject at rest or while watching video clips of cartoons. These data were compared with resting state BOLD scans from 36 healthy control subjects by evaluating the correlation between each pair of 64 small spheric regions of interest obtained from a published functional brain parcellation. RESULTS: Single-subject and group data converged to reliable estimates of individual and population connectivity values proportional to 1 / sqrt(n). Dramatic improvements in reliability were seen by using <=25 minutes of imaging time, with smaller improvements for additional time. Functional connectivity "fingerprints" for the individual and population began diverging at approximately 15 minutes of imaging time, with increasing reliability even at 4 hours of imaging time. Twenty-five minutes of BOLD imaging time was required before any individual connections could reliably discriminate an individual from a group of healthy control subjects. A classifier discriminating scans during which our subject was resting or watching cartoons was 95% accurate at 10 minutes and 100% accurate at 15 minutes of imaging time. CONCLUSIONS: An individual subject and control population converged to reliable different functional connectivity profiles that were task-modulated and could be discriminated with sufficient imaging time. PMID- 21273357 TI - Nocturnal saturation and glucose tolerance in children with cystic fibrosis. AB - BACKGROUND: Glucose intolerance is common in cystic fibrosis (CF), and is associated with worsening pulmonary function and nutritional status, and increased mortality. As sleep-disordered breathing is associated with disorders of glucose metabolism, it was hypothesised that recurrent episodes of hypoxaemia during sleep, and sleep disruption, would be associated with inflammation and glucose intolerance in CF. METHODS: 25 children (aged 14+/-4 (mean+/-SD) years) with CF underwent polysomnography, actigraphy, measurement of serum inflammatory markers and oral glucose tolerance testing. Blood glucose area under the curve (AUC), as a cumulative measure of glucose response, was determined. Polysomnography data were compared with retrospective data from 25 healthy controls. RESULTS: Forced expiratory volume in 1 s was 92+/-14% predicted. 24 subjects underwent glucose tolerance testing, of whom 29% had impaired glucose tolerance and 4% had diabetes. The mean nocturnal oxygen saturation correlated negatively with glucose AUC at 120 min (r=-0.49, p=0.015). Partial correlations and regression models including age, body mass index, nocturnal saturation and pulmonary function indicated that nocturnal saturation accounted for the majority of the predictive power for glucose AUC (R(2)=0.24, p=0.001). There were no meaningful relationships between sleep quality, inflammation and glucose tolerance. CONCLUSIONS: Lower oxyhaemoglobin saturation is associated with worse glucose regulation in children with CF. Further studies are needed to determine whether lower saturation negatively impacts glucose regulation or, alternatively, whether abnormalities in glucose metabolism are an early sign of pulmonary dysfunction. PMID- 21273358 TI - Use of briefings and debriefings as a tool in improving team work, efficiency, and communication in the operating theatre. AB - INTRODUCTION: Team work, communication, and efficiency in the operating theatre are widely recognised to be suboptimal. Poor communication is the single biggest cause of medical error. The surgical operating theatre is a potentially highly stressed environment where poor communication can lead to fatal errors. The objectives of this study were to assess the effects briefings and debriefings had on theatre start time, list lengths, and the staff's impression of these meetings. MATERIALS AND METHODS: Briefings and debriefings were conducted before the start of theatre lists over a 6 month period in 2007 in a district general hospital in north Bristol, UK. Both quantitative and qualitative data were collected. Using the hospital theatre database, theatre start and finish time was found and list length calculated. A questionnaire was devised and used to assess staff attitude to the briefings and debriefings. RESULTS: Staff felt that the briefings highlighted potential problems, improved the team culture, and led to organisational change. Theatre start times tended to be earlier and lists lengths were shorter when briefings were conducted, although this only reached statistical significance on one type of list. DISCUSSION: Briefings and debriefings had a positive impact on teamwork and communication. The lists ran more efficiently and briefings did not delay the theatre start times-in fact, the lists tended to start earlier. PMID- 21273359 TI - Prescribing in pregnancy and during breast feeding: using principles in clinical practice. AB - Prescribing in pregnancy often causes uncertainty and anxiety for the clinician and may lead to the omission of necessary treatment. Many drugs have inadequate data to assure safety, and therefore the clinician is left with a dilemma as to where the balance of risks and benefits lie with respect to the mother and her fetus. Understanding under what circumstances women can be prescribed medication and using principles of prescribing in pregnancy to further clarify the potential risks will aid good clinical decision-making. An appreciation of the available resources and the conviction to find the best available evidence will best serve the patient and her fetus. Teratogenicity refers to the potential for a drug to cause fetal malformations and affects the embryo 3-8 weeks after conception. Teratogenic drugs are associated with an increased risk of malformations, but the majority of babies are born with no abnormalities. In addition, approximately 2 3% of infants are born with major malformations with no association with maternal medication, and this and other confounding factors need to be addressed during counselling of a woman. Fetotoxicity refers to the functional changes that can occur to the fetus as a result of medication in the second and third trimesters. These effects are more subtle and more difficult to assess and therefore there are fewer data to support or refute these types of associations. For the majority of drugs, the neonatal dose from breast feeding is a fraction of the dose exposure in utero. PMID- 21273360 TI - Comparison of aortic dissection in Chinese patients with and without Marfan syndrome. AB - BACKGROUND: Aortic dissection is a life-threatening cardiovascular disease with high mortality. Little is known about comparisons of the clinical characteristics or the factors that influence the long-term prognosis of Chinese patients with aortic dissection with and without Marfan syndrome (MFS). METHODS: The authors studied the data of 246 patients with aortic dissection. The patients were hospitalised for aortic abnormalities from 2004 to 2008 in Fuwai Hospital. Medical charts were reviewed to obtain clinical data using a standardised data collection sheet. RESULTS: Of the 246 patients with acute aortic dissection, 56 had MFS. Compared with the non-MFS patients, those with MFS were considerably younger (mean +/- SD age 35.27 +/- 11.11 vs 54.11 +/- 11.96 years, p<0.001) and had pre-existing hypertension much less commonly (5.4% vs 80.0%, p<0.001). The patients with MFS presented with a wider ascending aorta diameter (63.60 +/- 9.00 vs 38.55 +/- 9.44 mm, p<0.001) and a lower body mass index (20.14 +/- 2.00 vs 25.62 +/- 3.41, p<0.001) than the non-MFS patients. Overall, 91.1% of the MFS patients underwent surgical treatment, whereas 55.78% of the non-MFS patients accepted medical treatment. However, mortality in the two groups did not differ significantly (6 vs 17, p=0.527). Multivariate analysis showed that the aortic diameter (OR=1.072) was a risk factor and surgical treatment (OR=0.006) was a protective factor for the survival of MFS patients with aortic dissection. With increased diastolic blood pressure, mortality decreased in non-MFS patients with aortic dissection (OR=0.905). CONCLUSIONS: These clinical results could be useful for rapid assessment of the treatment and prognosis of patients with aortic dissection. PMID- 21273361 TI - The novel use of fast track CT to select patients for lung cancer clinics: effect on clinic efficiency, waiting times, and patient satisfaction. AB - BACKGROUND: Lung cancer is the most common cause of cancer death in the UK, and triaging patients 'straight to test' is recommended to improve patient experience and outcomes. While such pathways are likely to lead to earlier diagnosis and treatment, the data to support this assumption are limited. OBJECTIVES: To assess the impact of a fast track CT pathway to select patients for lung cancer clinics on clinic efficiency, diagnostic and treatment delays, and patient satisfaction. METHODS: Retrospective comparative cohort study of patients referred to lung cancer clinics for investigation of suspicious imaging from January to December 2006 and June to December 2007. RESULTS: The proportion of patients seen in clinic subsequently diagnosed with lung cancer increased from 124/399 (31%) to 86/168 (51%) (p<0.001). Time from referral to diagnosis reduced from 22 to 17 days (p<0.001). Time from referral to first discussion at the multidisciplinary team (MDT) meeting fell from 32 to 22 days (p<0.001). Time from referral to decision to treat reduced from 42 to 35 days (p<0.05). Time from referral to first treatment fell from 55 to 49 days (p=0.095). The proportion of patients who felt the diagnostic process took too long fell from 15/80 (19%) to 3/49 (6%) (p<0.05). CONCLUSIONS: The new pathway led to more effective use of clinic appointments, reduced diagnostic delay, and more rapid treatment decision times. Patient satisfaction with the speed of the diagnostic process increased. It is recommended that hospital trusts in England consider adopting similar 'straight to test' triaging to select patients for lung cancer clinics. PMID- 21273362 TI - Peripheral arterial disease: the evolving role of non-invasive imaging. AB - Peripheral arterial disease is usually secondary to stenotic or occlusive atherosclerosis and is both common and increasing in western society. The majority of symptomatic patients have intermittent claudication and only a minority (<2% and typically those with diabetes mellitus or renal failure) progress to critical limb ischaemia, heralded by the onset of rest pain and/or tissue loss. Imaging is largely reserved for patients with disabling symptoms in whom revascularisation is planned. In these patients, accurate depiction of the vascular anatomy is critical for clinical decision making as the distribution and severity of disease are key factors determining whether revascularisation should be by endovascular techniques or open surgery. Driven by advances in technology, non-invasive vascular imaging has recently undergone significant refinement and has replaced conventional digital subtraction angiography for many clinical indications. In this review, the relative merits and limitations of duplex ultrasound, CT angiography, and magnetic resonance angiography are discussed, emerging imaging techniques are described, and complications relating to the use of intravascular contrast agents are highlighted. PMID- 21273363 TI - Efficiency of anthropometric indicators of obesity for identifying cardiovascular risk factors in a Chinese population. AB - OBJECTIVE: To evaluate the predictive value of the body mass index (BMI), waist circumference (WC), and waist-to-height ratio (WHtR) for the presence of several cardiovascular risk conditions-hypertension, dyslipidaemia, metabolic syndrome (MS), and type 2 diabetes-in a Chinese population in Jinan, China. METHODS: Data for a representative, cross-sectional sample of 3006 adults (mean age; range 20 74 years) in Jinan from 2007 to 2008 were studied. The association of BMI, WC, and WHtR with cardiovascular risk conditions was assessed by use of receiver operating characteristic curve (ROC) analysis and by calculating the area under the ROC (AUC) and age adjusted odds ratios (ORs) for metabolic syndrome, dyslipidaemia, type 2 diabetes, and hypertension. RESULTS: AUC cut-off values showed that the association of WHtR and WC was higher than that for BMI for all risk conditions for both sexes, except for hypertension in men. The AUC values for WC showed a higher association with hypertension and metabolic syndrome for women than men (p<0.01 for hypertension, p<0.05 for metabolic syndrome). The ORs were highest for WHtR for metabolic syndrome, diabetes, and hypertension in women. The ORs were highest for BMI for hypertension in men. CONCLUSIONS: Compared with BMI, measures of central obesity, particularly WHtR, show a better association with obesity related cardiovascular risk conditions for both sexes, except for hypertension in men, in Jinan, China. PMID- 21273364 TI - 2011 Hippocrates Prize. PMID- 21273365 TI - The efficacy of strabismus surgery in adults: a review for primary care physicians. AB - Many adult patients with strabismus are under the misconception that nothing can be done to correct the problem or that treatment is associated with a high degree of risk. Moreover, many optometrists, comprehensive ophthalmologists and primary care physicians are similarly misinformed. In fact, most adult patients with strabismus can be successfully treated, with ~80% of patients achieving satisfactory alignment with one surgical procedure. In addition, adult strabismus surgery carries a relatively low risk, with serious complications being anecdotal and rare. The majority of adults will experience some improvement in binocular function after strabismus surgery even if the strabismus has been longstanding. Most commonly this takes the form of an expansion of binocular visual fields; however, some patients may also regain stereopsis. Consequently, strabismus surgery in adults is not merely cosmetic in most cases. There are many psychological and interpersonal benefits to adult strabismus surgery. These benefits are highlighted by the finding that the majority of adults with strabismus would trade a portion of their life expectancy to be rid of their ocular misalignment. Although adult strabismus surgery has been shown to be highly cost-effective, many adults with strabismus can be successfully managed by non-surgical means. If an adult with strabismus is under the impression, or was told, they cannot be treated, or that treatment is risky, they should consider a referral to an ophthalmologist specifically specialising in strabismus. PMID- 21273366 TI - Kisspeptin activates the hypothalamic-adenohypophyseal-gonadal axis in prepubertal ewe lambs. AB - The onset of puberty in mammals involves an increase in the pulsatile release of GNRH and LH. The KISS1 gene is essential for pubertal development, and its product, kisspeptin, stimulates the release of LH. The objective of this study was to determine the effects of kisspeptin in the hypothalamic-adenohypophyseal gonadal axis of prepubertal ewe lambs. Ewe lambs (28 weeks of age) were treated intravenously with saline (control, n=6) or kisspeptin (20 MUg kisspeptin; n=6) every hour for 24 h. Kisspeptin stimulated pulse-like release of LH within 15 min following injections, and increased the frequency and amplitude of LH pulses, and mean circulating concentrations of LH and estradiol. A surge-like release of LH was observed in four kisspeptin-treated lambs beginning 17 h after the onset of treatment, and all four lambs had elevated circulating concentrations of progesterone within 5 days post-treatment. However, circulating concentrations of progesterone decreased within 2 days after the initial rise in three of the four ewe lambs, indicating that induced luteal activity was of short duration. The proportion of lambs that were pubertal (defined by circulating concentrations of progesterone above 1 ng/ml for at least 7 days) by 35 weeks of age (8/11) and the mean age at puberty (32 +/- 1 weeks) for those reaching puberty within the experimental period did not differ between treatments. Results support a role for kisspeptin in the activation of the hypothalamic-adenohypophyseal axis leading to the onset of puberty in ewe lambs. PMID- 21273367 TI - Islet transplantation reverses the effects of maternal diabetes on mouse oocytes. AB - Maternal diabetes adversely affects preimplantation embryo development and oocyte maturation. Thus, it is important to identify ways to eliminate the effects of maternal diabetes on preimplantation embryos and oocytes. The objectives of this study were to investigate whether islet transplantation could reverse the effects of diabetes on oocytes. Our results revealed that maternal diabetes induced decreased ovulation; increased the frequency of meiotic spindle defects, chromosome misalignment, and aneuploidy; increased the relative expression levels of Mad2 and Bub1; and enhanced the sensitivity of oocytes to parthenogenetic activation. Islet transplantation prevented these detrimental effects. Therefore, we concluded that islet transplantation could reverse the effects of diabetes on oocytes, and that this technique may be useful to treat the fundamental reproductive problems of women with diabetes mellitus. PMID- 21273368 TI - Placental development during early pregnancy in sheep: cell proliferation, global methylation, and angiogenesis in the fetal placenta. AB - To characterize early fetal placental development, gravid uterine tissues were collected from pregnant ewes every other day from day 16 to 30 after mating. Determination of 1) cell proliferation was based on Ki67 protein immunodetection; 2) global methylation was based on 5-methyl-cytosine (5mC) expression and mRNA expression for DNA methyltransferases (DNMTs) 1, 3a, and 3b; and 3) vascular development was based on smooth muscle cell actin immunolocalization and on mRNA expression of several factors involved in the regulation of angiogenesis in fetal membranes (FMs). Throughout early pregnancy, the labeling index (proportion of proliferating cells) was very high (21%) and did not change. Expression of 5mC and mRNA for DNMT3b decreased, but mRNA for DNMT1 and 3a increased. Blood vessels were detected in FM on days 18-30 of pregnancy, and their number per tissue area did not change. The patterns of mRNA expression for placental growth factor, vascular endothelial growth factor, and their receptors FLT1 and KDR; angiopoietins 1 and 2 and their receptor TEK; endothelial nitric oxide synthase and the NO receptor GUCY13B; and hypoxia inducing factor 1 alpha changed in FM during early pregnancy. These data demonstrate high cellular proliferation rates, and changes in global methylation and mRNA expression of factors involved in the regulation of DNA methylation and angiogenesis in FM during early pregnancy. This description of cellular and molecular changes in FM during early pregnancy will provide the foundation for determining the basis of altered placental development in pregnancies compromised by environmental, genetic, or other factors. PMID- 21273369 TI - Characterization of mouse sperm TMEM190, a small transmembrane protein with the trefoil domain: evidence for co-localization with IZUMO1 and complex formation with other sperm proteins. AB - TMEM190, a small transmembrane protein containing the trefoil domain, was previously identified by our proteomic analysis of mouse sperm. Two structural features of TMEM190, 'trefoil domain' and 'small transmembrane protein', led us to hypothesize that this protein forms a protein-protein complex required during fertilization, and we characterized TMEM190 by biochemical, cytological, and genetic approaches. We showed in this study that the mouse Tmem190 gene exhibits testis-specific mRNA expression and that the encoded RNA is translated into a 19 kDa protein found in both testicular germ cells and cauda epididymal sperm. Treatment of the cell surface with proteinase K, subcellular fractionation, and immunofluorescence assay all revealed that mouse TMEM190 is an inner-acrosomal membrane protein of cauda epididymal sperm. During the acrosome reaction, TMEM190 partly relocated onto the surface of the equatorial segment, on which sperm oocyte fusion occurs. Moreover, TMEM190 and IZUMO1, which is an immunoglobulin like protein required for gamete fusion, co-localized in mouse sperm both before and after the acrosome reaction. However, immunoprecipitates of TMEM190 contained several sperm proteins, but did not include IZUMO1. These findings suggest that a mouse sperm protein complex(es) including TMEM190 plays an indirect role(s) in sperm-oocyte fusion. The role(s), if any, is probably dispensable since Tmem190 null male mice were normally fertile. PMID- 21273370 TI - Comparative studies of placentation and immunology in non-human primates suggest a scenario for the evolution of deep trophoblast invasion and an explanation for human pregnancy disorders. AB - Deep trophoblast invasion in the placental bed has been considered the hallmark of human pregnancy. It occurs by two routes, interstitial and endovascular, and results in transformation of the walls of the spiral arteries as they traverse the decidua and the inner third of the myometrium. Disturbances in this process are associated with reproductive disorders such preeclampsia. In contrast, trophoblast invasion in Old World monkeys occurs only by the endovascular route and seldom reaches the myometrium. Recently, it was shown that this pattern is maintained in gibbons, but that the human arrangement also occurs in chimpanzee and gorilla. There is an interesting parallel with results from placental immunology regarding the evolution of the major histocompatability complex class I antigen HLA-C and its cognate receptors. HLA-C is not present in Old World monkeys or gibbons. It emerged in the orangutan and became polymorphic in the lineage leading to gorilla, bonobo, chimpanzee, and human. Interaction between HLA-C1 and HLA-C2 on the surface of trophoblast and killer immunoglobulin-like receptors (KIRs) expressed by uterine natural killer cells are important regulators of trophoblast invasion. Evolution of this system in great apes may have been one prerequisite for deep trophoblast invasion but seems to have come at a price. The evidence now suggests that certain combinations of maternal genotype for KIRs and fetal genotype for HLA-C imply an increased risk of preeclampsia, fetal growth restriction, and recurrent abortion. The fetal genotype is in part derived from the father providing an explanation for the paternal contribution to reproductive disorders. PMID- 21273372 TI - Cell surface hydrophobicity: a predictor of biofilm production in Candida isolates? PMID- 21273371 TI - Stimulation of tube formation mediated through the prostaglandin EP2 receptor in rat luteal endothelial cells. AB - To explore the role of prostaglandin E(2) (PGE(2)) in angiogenesis in the developing corpus luteum, luteal microvascular endothelial-like cells (luteal ECs) were prepared from highly luteinizing ovaries of rats using the percoll density gradient method. The cells abundantly expressed the mRNAs of the endothelial markers CD31 (PECAM-1) and responded to the vascular endothelial growth factor (VEGF) to form in vitro tube structures on Matrigel. Cyclooxygenase (COX) inhibitors significantly suppressed tube formation in luteal ECs, whereas PGE(2) counteracted the COX inhibitor-induced blockage. PGE(2)-induced tube formation was blocked by a cyclic AMP-dependent protein kinase A (PKA) inhibitor, H89. The antagonist against the PGE receptor type 2 (EP2 receptor), AH6809, completely inhibited PGE(2)-induced tube formation and partly suppressed the VEGF induced tube formation but did not attenuate PGE(2)-induced phosphorylation of both AKT kinase and extracellular signal-regulated kinase 1/2. VEGF significantly enhanced the expression of COX-2 mRNAs detected by real-time RT-PCR and PGE(2) secretion into the media measured by ELISA in luteal ECs. In turn, PGE(2) stimulated VEGF expression. In vitro co-culture of luteal ECs with steroidogenic luteal cells (SLCs) promoted tube formation. Pre-treatment of SLCs with VEGF further enhanced tube formation of ECs, and this effect was blocked by the COX-2 inhibitor. This stimulatory effect was inhibited by treatment with AH6809. These data indicate that PGE(2) exerts a direct stimulatory effect on tube formation mainly via the EP2 receptor/PKA signaling in luteal ECs. Our results suggest the possibility that the endogenous PGE(2) that is produced from luteinizing follicular cells as well as ECs may stimulate luteal angiogenesis. PMID- 21273373 TI - Retrospective study of Pneumocystis pneumonia over half a century in mainland China. AB - A retrospective study was performed on case reports of Pneumocystis pneumonia (PCP) from 1959 to 2009 in mainland China. The epidemiological characteristics of PCP over half a century were investigated over two time spans. The first was from 1959, when the first incidence of PCP was reported, to 1984, before the emergence of AIDS in mainland China. The second was from 1985, when the first AIDS case was reported in mainland China, to the end of 2009. A total of 2351 PCP cases were reported during these two time spans, covering a 51-year period. Only seven PCP cases were reported during the first time span. Six were diagnosed by autopsy, accordingly without treatment, whilst the other was diagnosed by open lung biopsy in a living patient who eventually recovered following treatment with sulfadiazine and pyrimethamine. The other 2344 PCP cases were reported during the second time span (1985-2009) from 21 provinces, four municipalities and three autonomous regions. Among the 2344 PCP cases, 70.22 % (1646/2344) were identified together with human immunodeficiency virus (HIV) infection or were in AIDS patients. The remaining 698 non-HIV-infected patients had undergone organ transplantation, had other underlying diseases such as malignancy or hypoimmunity, or had undetermined diagnosis. The results of statistical analysis indicated that AIDS was the most common underlying disease of PCP for patients <1 year and >14 years. For patients aged between 1 and 14 years, haematological malignancy was the most common underlying disease. The trend of the underlying diseases changed with time, showing that the number of PCP patients afflicted by HIV/AIDS increased dramatically, reaching almost threefold during the most recent 5 years compared with the level of the previous 10 years. The number of patients undergoing organ transplantation or with other underlying diseases rose constantly, but the number of malignancies tended to decline from 1995-2004 to 2005-2009. During the second time span (1995-2009), most of the patients (97.61 %) were diagnosed alive and only 56 cases (2.39 %) were identified by autopsy. The mortality of PCP patients treated with anti-Pneumocystis drugs was 14.61 % for those with HIV/AIDS and 15.84 % for those without HIV/AIDS. For the PCP patients without anti-Pneumocystis treatment, all (100 %) of the HIV/AIDS associated PCP patients died, whilst 13.79 % (4/29) of non-HIV-infected PCP patients survived. These data from epidemiological investigation of PCP in China over a period of half a century may provide useful information for prevention and the development of treatment of PCP. PMID- 21273374 TI - Role of twenty-four-hour ambulatory blood pressure monitoring in children on dialysis. AB - BACKGROUND AND OBJECTIVES: Pre- or postdialysis BP recordings are imprecise, can be biased, and have poor test-retest reliability in children on dialysis. We aimed to examine the possible differences between pre- and postdialysis BP levels and 24-hour ambulatory BP monitoring (ABPM) in diagnosis of hypertension (HTN). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Twenty-four children on dialysis had 24-hour ABPM in the interdialytic period, and values were compared with average pre- and postdialysis systolic BP (SBP) and diastolic BP (DBP) recordings that week. Each patient had an echocardiogram to determine presence of left ventricular hypertrophy (LVH). RESULTS: By ABPM, 8% of patients had white coat HTN and 12% had masked HTN. There was no significant difference in diagnosis of systolic HTN based on ABPM daytime SBP mean or load and postdialysis SBP. However, only 15% of patients had diastolic HTN based on postdialysis measures, whereas 46% of patients had significantly elevated daytime DBP loads and 71% had high nighttime DBP loads on ABPM. Forty-eight percent of patients were SBP nondippers. Children with LVH had higher daytime and nighttime SBP loads, significantly higher daytime and nighttime DBP loads, and lesser degree of nocturnal dipping of SBP compared with those who did not. CONCLUSION: ABPM is more informative than pre- and postdialysis BPs and improves the predictability of BP as a risk factor for target organ damage. Diagnosis and treatment monitoring of HTN among pediatric dialysis patients is enhanced with addition of ABPM. PMID- 21273375 TI - Race disparities in U.S. nephrology fellowship training. AB - BACKGROUND AND OBJECTIVES: Renal disease disproportionately affects African American patients. Trust has been implicated as an important factor in patient outcomes. Higher levels of trust and better interpersonal care have been reported when race of patient and physician are concordant. The purpose of this analysis was to examine trends in the racial background of U.S. medical school graduates, internal medicine residents, nephrology fellows, and patients with ESRD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data for medical school graduates were obtained from the Association of American Medical Colleges and data for internal medicine and nephrology trainees from GME Track. ESRD data were obtained from U.S. Renal Data System (USRDS) annual reports. RESULTS: A significant disparity continues to exist between the proportional race makeup of African-American nephrology fellows (3.8%) and ESRD patients (32%). The low numbers of African American nephrology fellows, and consequently new nephrologists, in light of the increase in ESRD patients has important implications for patient-centered nephrology care. CONCLUSIONS: Efforts are needed to increase minority recruitment into nephrology training programs, to more closely balance the racial background of trainees and patients in hopes of fostering improved trust between ESRD caregivers and patients, increasing access to care, alleviating ESRD health care disparities, and improving patient care. PMID- 21273376 TI - Multidisciplinary team care may slow the rate of decline in renal function. AB - BACKGROUND AND OBJECTIVES: A multidisciplinary team (MDT) approach to chronic kidney disease (CKD) may help optimize care of CKD and comorbidities. We implemented an MDT quality improvement project for persons with stage 3 CKD and comorbid diabetes and/or hypertension. Our objective was to decrease the rate of decline of GFR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We used a 4-year historical cohort to compare 1769 persons referred for usual nephrology care versus 233 referred for MDT care within an integrated, not-for-profit Health Maintenance Organization (HMO). Usual care consisted of referral to an outside nephrologist. The MDT consisted of an HMO-based nephrologist, pharmacy specialist, diabetes educator, dietitian, social worker, and nephrology nurse. Both groups received usual primary care. The primary outcome was rate of decline of GFR. Secondary outcomes were LDL, hemoglobin A1c, and BP. RESULTS: In multivariate repeated-measures analyses, MDT care was associated with a mean annual decline in GFR of 1.2 versus 2.5 ml/min per 1.73 m(2) for usual care. In stratified analyses, the significant difference in GFR decline persisted only in those who completed their referrals. There were no differences in the secondary outcomes between groups. CONCLUSIONS: In this integrated care setting, MDT care resulted in a slower decline in GFR than usual care. This occurred despite a lack of significant differences for secondary disease-specific measures, suggesting that other differences in the MDT population or care process accounted for the slower decline in GFR in the MDT group. PMID- 21273377 TI - Trends in the incidence of primary intracranial tumors in Osaka, Japan. AB - We analyzed the trends in the age-standardized incidence rates of 10,460 cases of primary intracranial tumors diagnosed during 1975 and 2004, Osaka, Japan using the Joinpoint regression analysis. During the period 1975-2004, the age standardized incidence rates of total intracranial tumors increased until 1987 at 3.1% per year and then decreased significantly at -1.8% per year. The time trends were different according to the age groups. In the age group 0-19, the rate did not exhibit substantial increase or decrease. In the age group 20-74, the rates increased significantly until 1988 and then leveled off until 1999 and finally decreased. Whereas in the age group 75 and over, the rates increased drastically until 1984 and then leveled off. During the recent 10 year period 1995-2004, the age-standardized incidence rates of meningioma decreased significantly, but those of glioblastoma did not. PMID- 21273378 TI - A case of bronchial lipoma. PMID- 21273379 TI - Comparison of time trends in brain and central nervous system cancer mortality (1990-2006) between countries based on the WHO mortality database. PMID- 21273380 TI - Contrast summation across eyes and space is revealed along the entire dipper function by a "Swiss cheese" stimulus. AB - Previous contrast discrimination experiments have shown that luminance contrast is summed across ocular (T. S. Meese, M. A. Georgeson, & D. H. Baker, 2006) and spatial (T. S. Meese & R. J. Summers, 2007) dimensions at threshold and above. However, is this process sufficiently general to operate across the conjunction of eyes and space? Here we used a "Swiss cheese" stimulus where the blurred "holes" in sine-wave carriers were of equal area to the blurred target ("cheese") regions. The locations of the target regions in the monocular image pairs were interdigitated across eyes such that their binocular sum was a uniform grating. When pedestal contrasts were above threshold, the monocular neural images contained strong evidence that the high-contrast regions in the two eyes did not overlap. Nevertheless, sensitivity to dual contrast increments (i.e., to contrast increments in different locations in the two eyes) was a factor of ~1.7 greater than to single increments (i.e., increments in a single eye), comparable with conventional binocular summation. This provides evidence for a contiguous area summation process that operates at all contrasts and is influenced little, if at all, by eye of origin. A three-stage model of contrast gain control fitted the results and possessed the properties of ocularity invariance and area invariance owing to its cascade of normalization stages. The implications for a population code for pattern size are discussed. PMID- 21273381 TI - Low responsiveness to clopidogrel increases risk among CKD patients undergoing coronary intervention. AB - Patients with CKD are at higher risk for major events after percutaneous coronary intervention (PCI) compared with subjects with normal renal function. The aims of this study were to evaluate responsiveness to clopidogrel in patients with CKD and to examine the effect of antiplatelet drug response on post-PCI outcome. We retrospectively evaluated a consecutive cohort of 1567 patients with symptomatic coronary artery disease undergoing PCI, 648 (41%) of whom had stage 3 to 5 CKD. We assessed responsiveness to clopidogrel by ADP-induced platelet aggregation after oral administration of a 600-mg clopidogrel loading dose and 100 mg of aspirin. In a multivariate survival analysis that included 1335 (85%) of the cohort, stage 3 to 5 CKD and low response to clopidogrel were independent predictors of the primary end point (composite of myocardial infarction, ischemic stroke, and death within 1 year). In summary, a low response to clopidogrel might be an additional risk factor for the poorer outcomes in patients with stage 3 to 5 CKD compared with patients with better renal function. PMID- 21273382 TI - Nonossifying fibroma in the mandible of a goat. AB - An 8-year-old male Nubian goat was presented with a peracute history of straining to urinate and unilateral mandibular swelling. At necropsy, the rostral half body of the left mandible was distorted by fusiform swelling that, on sagittal section, had marked medullary bone loss and replacement with a well-demarcated fibrous mass. Histologically, the mass comprised streaming spindloid cells with whorls and storiform patterns, interspersed with numerous multinucleated giant cells. Bone formation was not present in the neoplasm. The mandibular mass was diagnosed as nonossifying fibroma, a relatively common tumor in children but seldom reported in domestic animals. PMID- 21273383 TI - Encephalitis and neuronal necrosis in a 3-month-old suckled beef calf. AB - A 3-month-old suckled beef calf from the west coast of Scotland showed neurologic clinical signs for 1 week and was euthanized after failing to respond to treatment. Blood and tissue samples, including the brain, were submitted for diagnosis. Histologic examination of the brain showed neuronal chromatolysis and necrosis in the hind brain and loss of Purkinje cells in the cerebellum, accompanied by mild nonsuppurative encephalitis in the hind brain with a striking lack of inflammation in the cerebellar layers. Other microscopic lesions present were mild nonsuppurative meningitis with perivascular cuffs, diffuse hypergliosis, and occasional foci of neuronophagia. Polymerase chain reaction amplification of viral nucleic acids and specific immunohistochemical labeling allowed the identification of louping ill virus, and serology showed high titers of immunoglobulin M, indicating a recent infection. PMID- 21273384 TI - Bacterial osteomyelitis in a 3-week-old broiler chicken associated with Enterococcus hirae. AB - Enterococcus hirae infections are reported to cause growth depression, encephalomalacia, endocarditis, and septicemia in chickens. This report describes osteomyelitis in the proximal femur of a 3-week-old broiler chicken that also suffered from valvular endocarditis and liver necrosis. Histologically, clusters of gram-positive coccoid bacteria were found in many organs, including bone lesions. In tissues from 5 of 6 examined chickens from the same flock, E hirae was isolated in large numbers. To the authors' knowledge, this is the first report of spontaneous bacterial osteomyelitis where E hirae was cultured from bone and where coccoid bacteria consistent with Enterococcus spp were simultaneously demonstrated within bone lesions. PMID- 21273385 TI - Mycobacterial hypersensitivity pneumonitis requires TLR9-MyD88 in lung CD11b+ CD11c+ cells. AB - Mycobacteria are among the most common causes of hypersensitivity pneumonitis (HP), but controversy persists with regard to the involvement of the infectious potency of the organism in mycobacterial HP (hot tub lung). This study aimed to establish a mouse model of hot tub lung to clarify its pathophysiology. Mice were exposed intranasally to formalin-killed Mycobacterium avium from a patient with hot tub lung (HP strain) or chronic pulmonary infection (non-HP strain), and bronchoalveolar lavage fluids and lung tissues were evaluated for allergic inflammation. Dead M. avium HP strain, but not non-HP strain, elicited marked HP like pulmonary inflammation in wild-type mice. Although the inflammation was induced in mice lacking CD4 or CD8, the induction of HP-like responses was prevented in mice lacking myeloid differentiation factor (MyD)88 or Toll-like receptor (TLR)9. Cultured lung CD11c+ cells responded to M. avium in a TLR9 dependent manner, and reconstitution of TLR9-/- mice with lung CD11c+ cells from wild-type mice restored the inflammatory responses. Further investigation revealed that pulmonary exposure to M. avium HP strain increased the number of lung CD11b+ CD11c+ cells (dendritic cells) through TLR9 signalling. Our results provide evidence that hot tub lung develops via the mycobacterial engagement of TLR9-MyD88 signalling in lung CD11b+ dendritic cells independent of the mycobacterial infectious capacity. PMID- 21273386 TI - Elevation of surfactant protein A in plasma and sputum in cigarette smokers. AB - Serum surfactant protein (SP)-A has been postulated to associate with pulmonary fibrosis, but its role in cigarette smoking-related lung diseases is undefined. SP-A levels in plasma and induced sputum in nonsmokers, smokers with respiratory symptoms (cough and/or phlegm) and symptom-free smokers were assessed using a validated EIA method. A total of 474 current smokers without any diseases or medications were enrolled and followed for 2 yrs with 111 of them succeeding in stopping. Plasma SP-A level was detectable in all subjects and elevated in smokers independently of the symptoms compared to nonsmokers (p = 0.001). After 2 yrs of follow-up, the SP-A level was higher in those who continued smoking compared to the quitters (p<0.001). Plasma SP-A levels were associated with age, smoking history and lung function. Sputum (n = 109) SP-A was nondetectable in most nonsmokers, whereas smoking and symptoms increased sputum SP-A highly significantly (p = 0.001). In conclusion, SP-A may be involved in pathogenesis of cigarette smoking-related lung diseases. Further studies are needed to elucidate the role of SP-A in chronic obstructive pulmonary disease. PMID- 21273387 TI - All-trans retinoic acid results in irregular repair of septa and fails to inhibit proinflammatory macrophages. AB - All-trans retinoic acid (ATRA) is controversially discussed in emphysema therapy. We re-evaluated ATRA in the elastase model and hypothesised that beneficial effects should be reflected by increased alveolar surface area, elastin expression and downregulation of inflammatory mediators and matrix metalloproteinases (MMPs). Emphysema was induced by porcine pancreatic elastase versus saline in Sprague-Dawley rats. On days 26-37, rats received daily intraperitoneal injections with ATRA (500 MUg . kg(-1) body weight) versus olive oil. Lungs were removed at day 38. Rat alveolar epithelial L2 cells were incubated with/without elastase followed by ATRA- or vehicle-treatment, respectively. ATRA only partially ameliorated structural defects. Alveolar walls exhibited irregular architecture: increased arithmetic mean thickness, reduction in surface coverage by alveolar epithelial cells type II. ATRA only partially restored reduced soluble elastin. It tended to increase the ratio of ED1(+):ED2(+) macrophages. Bronchoalveolar lavage (BAL) cells exhibited a proinflammatory state and high expression of interleukin-1beta, cytokine-induced neutrophil chemoattractant-1, tumour necrosis factor-alpha, nuclear factor kappaB, MMP-2, MMP-9, MMP-12, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 in emphysema, with ATRA exerting only few effects. MMP-7 was highly induced by ATRA in healthy but not in emphysematous lungs. ATRA reduced both MMP 2 and TIMP-1 activity in BAL fluid of emphysematous lungs. ATRA-therapy may bear the risk of unwanted side-effects on alveolar septal architecture in emphysematous lungs. PMID- 21273388 TI - Nasal nitric oxide and nitric oxide synthase expression in primary ciliary dyskinesia. AB - No study has evaluated the correlation between different expression of nitric oxide synthase (NOS) isoforms in nasal epithelial cells and nasal NO (nNO) level in primary ciliary dyskinesia (PCD). Gene expression of endothelial (NOS3) and inducible NOS (NOS2) and their correlation with nNO level, ciliary function and morphology were studied in patients with PCD or secondary ciliary dyskinesia (SCD). NOS3 gene polymorphisms were studied in blood leukocytes. A total of 212 subjects were studied (48 with PCD, 161 with SCD and three normal subjects). nNO level correlated with mean ciliary beat frequency (p = 0.044; r = 0.174). The lower the nNO level the higher was the percentage of immotile cilia (p<0.001; r = -0.375). A significant positive correlation between NOS2 gene expression and nNO levels was demonstrated in all children (p = 0.001; r = 0.428), and this correlation was confirmed in patients with PCD (p = 0.019; r = 0.484). NOS2 gene expression was lower in PCD than in SCD (p = 0.04). The NOS3 isoform correlated with missing central microtubules (p = 0.048; r = 0.447). nNO levels were higher in PCD subjects with the NOS3 thymidine 894 mutation, and this was associated with a higher ciliary beat frequency (p = 0.045). These results demonstrate a relationship between nNO level, NOS mRNA expression and ciliary beat frequency. PMID- 21273389 TI - Volumetry: an alternative to assess therapy response for malignant pleural mesothelioma? AB - The purpose of our study was to assess robustness of volumetric measurement of malignant pleural mesothelioma (MPM) before and after chemotherapy to modified RECIST (response evaluation criteria in solid tumours) criteria. 30 patients with digitally available chest computed tomography (CT) scans before and after three cycles of chemotherapy were included. Three readers independently assessed tumour response using two different methods: 1) the modified RECIST criteria; and 2) the tumour volumetric approach using dedicated software (Myrian; Intrasense, Paris, France). Inter-rater reliability of unidimensional and volumetric measurements was assessed using intraclass correlation. Tumour response classification for modified RECIST was compared to the volumetric approach applying unidimensional RECIST volumetric equivalent criteria. The determination of unidimensional tumour measurement (RECIST) revealed a low inter-rater reliability (0.55) and a low interobserver agreement for tumour response classification (general kappa 0.33). Only 14 patients were classified equally. A high inter-rater reliability (0.99) and interobserver agreement (general kappa 0.9) were found for absolute tumour volumes (volumetric measurements). 27 cases were classified equally. The number of cases classified as "stable disease" was higher for the volumetric approach using tumour-equivalent criteria compared to modified RECIST. Volumetric measurement of MPM on CT using Myrian software is a reliable, reproducible and sensitive method to measure tumour volume and, thus, therapy response after induction chemotherapy. PMID- 21273390 TI - Idiopathic nonspecific interstitial pneumonia: an interstitial lung disease associated with autoimmune disorders? AB - Recent evidence suggests that idiopathic nonspecific interstitial pneumonia (iNSIP) is a distinct clinical entity amongst other idiopathic interstitial pneumonias, and some data seem to suggest a possible pathogenetic role of autoimmunity. The aim of the present study was to assess if iNSIP might represent an early lung manifestation of an autoimmune disease. After initial review of cases found in the medical records database by searching for the term "NSIP" (n = 63), 37 iNSIP cases were identified, and were re-evaluated using a dynamic integrated multidisciplinary approach. 27 cases with iNSIP were selected for the study. Mean +/- sd age at first respiratory symptom was 54.2 +/- 8 yrs, 70% were females, and 59% were never-smokers. At follow-up (mean +/- sd 59.7 +/- 29 months, range 12-138 months), autoimmune diseases occurred in 14 (52%) patients, with seven (26%) cases of autoimmune thyroiditis, six (22%) of undifferentiated connective tissue disease and three (11%) of connective tissue disease. Patients developing autoimmune diseases were older and more frequently never-smoking females. In >50% of patients diagnosed with iNSIP, evidence of autoimmune diseases develops within 2 yrs, suggesting a probable link between the clinical entity of iNSIP and autoimmune disorders. PMID- 21273391 TI - Comparison of cardiac and pulmonary-specific quality-of-life measures in pulmonary arterial hypertension. AB - Studies systematically comparing the performance of health-related quality-of life (HRQoL) instruments in pulmonary arterial hypertension (PAH) are lacking. We sought to address this by comparing cardiac and respiratory-specific measures of HRQoL in PAH. We prospectively assessed HRQoL in 128 patients with catheterisation-confirmed PAH at baseline and at 6, 12 and post-24 month follow up visits. Cardiac-specific HRQoL was assessed using the Minnesota Living with Heart Failure Questionnaire (LHFQ); respiratory-specific HRQoL was assessed using the Airways Questionnaire 20 (AQ20); and general health status was assessed using the 36-item Short Form physical component summary (SF-36 PCS). The LHFQ and AQ20 were highly intercorrelated. Both demonstrated strong internal consistency and converged with the SF-36 PCS. Both discriminated patients based on World Health Organization (WHO) functional class, 6-min walking distance (6MWD) and Borg dyspnoea index (BDI), with the exception of a potential floor effect associated with low 6MWD. The LHFQ was more responsive than the AQ20 to changes over time in WHO functional class, 6MWD and BDI. In multivariate analyses, the LHFQ and AQ20 were each longitudinal predictors of general health status, independent of functional class, 6MWD and BDI. In conclusion, both cardiac-specific and respiratory-specific measures appropriately assess HRQoL in most patients with PAH. Overall, the LHFQ demonstrates stronger performance characteristics than the AQ20. PMID- 21273392 TI - Blockade of Th1 chemokine receptors ameliorates pulmonary granulomatosis in mice. AB - Sarcoidosis is a granulomatous disease of unknown aetiology. We identified immunological targets for the treatment of pulmonary granulomatosis using a murine model generated with Propionibacterium acnes. Sensitisation and challenge using heat-killed P. acnes and dendritic cells (DCs) were performed to produce pulmonary granulomatosis in C57BL/6 mice. Immunological analyses using ELISA as well as cDNA microarray analysis were used to search for cytokines or chemokines associated with the formation of granulomas in the lungs. Co-administration of P. acnes and DCs reproducibly induced the formation of pulmonary granulomas, which resembled sarcoid granulomas. The cDNA microarray assay demonstrated that the gene expression of CXCL9 and CXCL10, ligands for CXCR3, and of CCL4, a ligand for CCR5, was strongly upregulated during granulomatosis. ELISA confirmed that levels of CXCL9 and CXCL10 as well as T-helper (Th)1 cytokines and chemokines including tumour necrosis factor-alpha and interferon-gamma were elevated in bronchoalveolar lavage fluid (BALF). The blockade of Th1 chemokine receptors using TAK-779, a dual blocker for CXCR3 and CCR5, led to reduced numbers of CXCR3+CD4+ and CCR5+CD4+ T-cells in BALF. Furthermore, administration of TAK-779 ameliorated the granulomatosis. The targeted inhibition of Th1 chemokines might be useful for inhibiting Th1-biased granulomatous diseases, including sarcoidosis. PMID- 21273393 TI - Variation in hydrogen cyanide production between different strains of Pseudomonas aeruginosa. AB - There is increasing interest in using the cyanogenic properties of Pseudomonas aeruginosa to develop a nonmicrobiological method for its detection. Prior to this, the variation in cyanide production between different P. aeruginosa strains needs to be investigated. Hydrogen cyanide (HCN) released into the gas phase by 96 genotyped P. aeruginosa samples was measured using selected ion flow tube-mass spectrometry after 24, 48, 72 and 96 h of incubation. The HCN produced by a range of non-P. aeruginosa cultures and incubated blank plates was also measured. All P. aeruginosa strains produced more HCN than the control samples, which generated extremely low levels. Analysis across all time-points demonstrated that nonmucoid samples produced more HCN than the mucoid samples (p=0.003), but this relationship varied according to strain. There were clear differences in the headspace HCN concentration for different strains. Multivariate analysis of headspace HCN for the commonest strains (Liverpool, Midlands_1 and Stoke-on Trent, UK) revealed a significant effect of strain (p<0.001) and a borderline interaction of strain and phenotype (p=0.051). This evidence confirms that all P. aeruginosa strains produce HCN but to varying degrees and generates interest in the possible future clinical applications of the cyanogenic properties of P. aeruginosa. PMID- 21273394 TI - Mannose efflux from the cells: a potential source of mannose in blood. AB - All mammals have 50-100 MUM mannose in their blood. However, the source of the dynamic pool of mannose in blood is unknown. Most of it is thought to be derived from glucose in the cells. We studied mannose uptake and release by various cell types. Interestingly, our results show that mannose taken up by the cells through transporters is handled differently from the mannose released within the cells due to glycan processing of protein-bound oligosaccharides. Although more than 95% of incoming mannose is catabolized, most of the mannose released by intracellular processing is expelled from the cells as free mannose predominantly via a nocodazole-sensitive sugar transporter. Under physiological conditions, incoming mannose is more accessible to hexokinase, whereas mannose released within the cells is protected from HK and therefore has a different fate. Our data also suggest that generation of free mannose due to the processing of glycoconjugates composed of glucose-derived mannose and its efflux from the cells can account for most of the mannose found in blood and its steady state maintenance. PMID- 21273395 TI - The pharmacokinetics, pharmacodynamics, and tolerability of liraglutide, a once daily human GLP-1 analogue, after multiple subcutaneous administration in healthy Chinese male subjects. AB - In this single-center, randomized, double-blind, within dose group, placebo controlled, dose escalation trial, the pharmacokinetics, pharmacodynamics, tolerability, and safety of liraglutide were evaluated in 37 healthy Chinese subjects. Subjects were randomized to 1 of 3 dose groups (0.6, 1.2, or 1.8 mg), and within each group, randomized to liraglutide or placebo (3:1). All subjects started at 0.6 mg liraglutide (or placebo) once daily for 1 week, and the dose was increased for dose groups 1.2 mg and 1.8 mg in weekly steps of 0.6 mg to the predefined dose targets. Liraglutide or placebo was administered once daily by subcutaneous injection for 21 consecutive days. The dose relationships of AUC(0 24h), C(max), and C(trough) at steady state do not deviate in a relevant way from dose proportionality. t(max) and t(1/2) were 8 hours (median) and 11.2 to 12.2 hours (geometric mean), respectively. The plasma glucose levels in all liraglutide groups were decreased, while reduced serum insulin level was observed in the 1.2- and 1.8-mg groups after liraglutide treatment. The most common adverse events were of gastrointestinal origin. Other adverse events were comparable between the liraglutide and placebo groups. Liraglutide was well tolerated in healthy Chinese subjects. No major safety concerns were identified. PMID- 21273396 TI - Trends in cardiovascular risk factor levels in the Minnesota Heart Survey (1980 2002) as compared with the National Health and Nutrition Examination Survey (1976 2002): A partial explanation for Minnesota's low cardiovascular disease mortality? AB - The authors compared trends in and levels of coronary heart disease (CHD) risk factors between the Minneapolis-St. Paul, Minnesota, metropolitan area (Twin Cities) and the entire US population to help explain the ongoing decline in US CHD mortality rates. The study populations for risk factors were adults aged 25 74 years enrolled in 2 population-based surveillance studies: the Minnesota Heart Survey (MHS) in 1980-1982, 1985-1987, 1990-1992, 1995-1997, and 2000-2002 and the National Health and Nutrition Examination Survey (NHANES) in 1976-1980, 1988 1994, 1999-2000, and 2001-2002. The authors found a continuous decline in CHD mortality rates in the Twin Cities and nationally between 1980 and 2000. Similar decreasing rates of change in risk factors across survey years, parallel to the CHD mortality rate decline, were observed in MHS and in NHANES. Adults in MHS had generally lower levels of CHD risk factors than NHANES adults, consistent with the CHD mortality rate difference. Approximately 47% of women and 44% of men in MHS had no elevated CHD risk factors, including smoking, hypertension, high cholesterol, and obesity, versus 36% of women and 34% of men in NHANES. The better CHD risk factor profile in the Twin Cities may partly explain the lower CHD death rate there. PMID- 21273397 TI - Questionnaire predictors of atopy in a US population sample: findings from the National Health and Nutrition Examination Survey, 2005-2006. AB - Allergic conditions and biochemical measures are both used to characterize atopy. To assess questionnaires' ability to predict biochemical measures of atopy, the authors used data on 5 allergic conditions (allergy, hay fever, eczema, rhinitis, and itchy rash) and serum-specific immunoglobulin E (IgE) levels from the 2005 2006 National Health and Nutrition Examination Survey. Atopy was defined as 1 or more positive specific IgEs (>=0.35 kU/L). Questionnaire responses were assessed for sensitivity, specificity, and positive and negative predictive values for atopy. In this population-based US sample, 44% of participants were specific IgE positive and 53% reported at least 1 allergic condition. Discordance between atopy and allergic conditions was considerable; 37% of persons with atopy reported no allergic condition, and 48% of persons who reported an allergic condition were not atopic. Thus, no combination of self-reported allergic conditions achieved both high sensitivity and high specificity for IgE. The positive predictive value of reported allergic conditions for atopy ranged from 50% for eczema to 72% for hay fever, while the negative predictive value ranged from 57% for eczema to 65% for any condition. Given the high proportion of asymptomatic participants who were specific IgE-positive and persons who reported allergic conditions but were specific IgE-negative, it is unlikely that questionnaires will ever capture the same participants as those found to be atopic by biochemical measures. PMID- 21273398 TI - Predictors of measurement error in energy intake during pregnancy. AB - Nutrition plays a critical role in maternal and fetal health; however, research on error in the measurement of energy intake during pregnancy is limited. The authors analyzed data on 998 women living in central North Carolina with singleton pregnancies during 2001-2005. Second-trimester diet was assessed by food frequency questionnaire. Estimated energy requirements were calculated using Institute of Medicine prediction equations, with adjustment for energy costs during the second trimester. Implausible values for daily energy intake were determined using confidence limits of agreement for energy intake/estimated energy requirements. Prevalences of low energy reporting (LER) and high energy reporting (HER) were 32.8% and 12.9%, respectively. In a multivariable analysis, pregravid body mass index was related to both LER and HER; LER was higher in both overweight (odds ratio = 1.96, 95% confidence interval: 1.26, 3.02; P = 0.031) and obese (odds ratio = 3.29, 95% confidence interval: 2.33, 4.65; P < 0.001) women than in normal-weight counterparts. Other predictors of LER included marriage and higher levels of physical activity. HER was higher among subjects who were underweight, African-American, and less educated and subjects who had higher depressive symptom scores. LER and HER are prevalent during pregnancy. Identifying their predictors may improve data collection and analytic methods for reducing systematic bias in the study of diet and reproductive outcomes. PMID- 21273399 TI - Antigen-specific splenic CD4+ and CD8+ regulatory T cells generated via the eye, suppress experimental autoimmune encephalomyelitis either at the priming or at the effector phase. AB - The injection of antigen into the ocular anterior chamber (AC) induces the generation of splenic CD4(+) and CD8(+) regulatory T (Treg) cells, specific for the antigen injected into the AC. These Treg cells inhibit the induction (CD4(+)) and also the expression (CD8(+)) of a delayed-type hypersensitivity response. The ability of AC-induced self-antigen-specific Treg cells in modulating autoimmunity is not well defined. Here we show that an injection of encephalitogenic myelin oligodendrocyte glycoprotein (MOG(35-55)) peptide into the anterior chamber of the eye (AC-MOG), before the induction of or during established experimental autoimmune encephalomyelitis (EAE) induced by MOG(35-55), suppresses the induction or progression of EAE, respectively. CD4(+) or CD8(+) splenic Treg cells induced by an injection of AC-MOG prevent EAE either at the inductive (priming) or at the progressive (effector) phase, respectively. This suppression of EAE by an AC-MOG injection or by intravenous transfer of splenic regulatory cells induced by an AC-MOG injection is specific for the antigen injected into the AC. Additionally, our data suggest that splenic CD8(+) Treg cells that suppress active EAE may use a transforming growth factor (TGF)-beta-dependent suppression mechanism while the suppression of the induction of EAE by the AC induced CD4(+) Treg cells is independent of TGF-beta. Thus, we show for the first time that regulation of EAE at the priming or the chronic phase requires different phenotypes of Treg cells. Hence, it is important to consider the phenotype of Treg cells while designing effective cell-based therapies against autoimmune disorders. PMID- 21273400 TI - Adult-onset autosomal dominant leukodystrophy: linking nuclear envelope to myelin. PMID- 21273401 TI - The spatiotemporal structure of population coding in monkey parietal cortex. PMID- 21273402 TI - Differential electrophysiological changes in striatal output neurons in Huntington's disease. AB - There is considerable evidence that alterations in striatal medium-sized spiny neurons (MSSNs) giving rise to the direct (D1 receptor-expressing) and indirect (D2 receptor-expressing) pathways differentially contribute to the phenotype of Huntington's disease (HD). To determine how each subpopulation of MSSN is functionally affected, we examined spontaneous excitatory postsynaptic currents (sEPSCs) and dopamine (DA) modulation in two HD mouse models, the YAC128 and the BACHD (a bacterial-artificial chromosome). These mice also expressed enhanced green fluorescent protein (EGFP) under the control of the promoter for either DA D1 or D2 receptors to identify neurons. In early symptomatic YAC128 and BACHD mice, glutamate transmission was increased in both D1 and D2 MSSNs, but in different ways. D1 cells displayed increased sEPSC frequencies and decreased paired-pulse ratios (PPRs) while D2 cells displayed larger evoked glutamate currents but no change in sEPSC frequencies or PPRs. D1 receptor modulation of sEPSCs was absent in D1-YAC128 cells at the early symptomatic stage but was restored by treating the slices with tetrabenazine. In contrast, in fully symptomatic YAC128 mice, glutamate transmission was decreased specifically in D1 cells, and D1 receptor modulation was normal in D1-YAC128 cells. Behaviorally, early symptomatic mice showed increased stereotypies that were decreased by tetrabenazine treatment. Together, these studies support differential imbalances in glutamate and DA transmission in direct and indirect pathway MSSNs. Stereotypic behavior at an early stage could be explained by increased glutamate activity and DA tone in direct pathway neurons, whereas hypokinesia at later stages could result from reduced input onto these neurons. PMID- 21273403 TI - Functional connectome of the striatal medium spiny neuron. AB - Dopamine system disorders ranging from movement disorders to addiction and schizophrenia involve striatal medium spiny neurons (MSNs), yet their functional connectivity has been difficult to determine comprehensively. We generated a mouse with conditional channelrhodopsin-2 expression restricted to medium spiny neurons and assessed the specificity and strength of their intrinsic connections in the striatum and their projections to the globus pallidus and the substantia nigra. In the striatum, medium spiny neurons connected with other MSNs and tonically active cholinergic interneurons, but not with fast-spiking GABA interneurons. In the globus pallidus, medium spiny neurons connected strongly with one class of electrophysiologically identified neurons, but weakly with the other. In the substantia nigra, medium spiny neurons connected strongly with GABA, but not with dopamine neurons. Projections to the globus pallidus showed solely D2-mediated presynaptic inhibition, whereas projections to the substantia nigra showed solely D1-mediated presynaptic facilitation. This optogenetic approach defines the functional connectome of the striatal medium spiny neuron. PMID- 21273404 TI - Theta-burst transcranial magnetic stimulation alters cortical inhibition. AB - Human cortical excitability can be modified by repetitive transcranial magnetic stimulation (rTMS), but the cellular mechanisms are largely unknown. Here, we show that the pattern of delivery of theta-burst stimulation (TBS) (continuous versus intermittent) differently modifies electric activity and protein expression in the rat neocortex. Intermittent TBS (iTBS), but not continuous TBS (cTBS), enhanced spontaneous neuronal firing and EEG gamma band power. Sensory evoked cortical inhibition increased only after iTBS, although both TBS protocols increased the first sensory response arising from the resting cortical state. Changes in the cortical expression of the calcium-binding proteins parvalbumin (PV) and calbindin D-28k (CB) indicate that changes in spontaneous and evoked cortical activity following rTMS are in part related to altered activity of inhibitory systems. By reducing PV expression in the fast-spiking interneurons, iTBS primarily affected the inhibitory control of pyramidal cell output activity, while cTBS, by reducing CB expression, more likely affected the dendritic integration of synaptic inputs controlled by other classes of inhibitory interneurons. Calretinin, the third major calcium-binding protein expressed by another class of interneurons was not affected at all. We conclude that different patterns of TBS modulate the activity of inhibitory cell classes differently, probably depending on the synaptic connectivity and the preferred discharge pattern of these inhibitory neurons. PMID- 21273405 TI - Discrete neuroanatomical networks are associated with specific cognitive abilities in old age. AB - There have been many attempts at explaining age-related cognitive decline on the basis of regional brain changes, with the usual but inconsistent findings being that smaller gray matter volumes in certain brain regions predict worse cognitive performance in specific domains. Additionally, compromised white matter integrity, as suggested by white matter hyperintensities or decreased regional white matter fractional anisotropy, has an adverse impact on cognitive functions. The human brain is, however, a network and it may be more appropriate to relate cognitive functions to properties of the network rather than specific brain regions. We report on graph theory-based analyses of diffusion tensor imaging tract-derived connectivity in a sample of 342 healthy individuals aged 72-92 years. The cognitive domains included processing speed, memory, language, visuospatial, and executive functions. We examined the association of these cognitive assessments with both the connectivity of the whole brain network and individual cortical regions. We found that the efficiency of the whole brain network of cortical fiber connections had an influence on processing speed and visuospatial and executive functions. Correlations between connectivity of specific regions and cognitive assessments were also observed, e.g., stronger connectivity in regions such as superior frontal gyrus and posterior cingulate cortex were associated with better executive function. Similar to the relationship between regional connectivity efficiency and age, greater processing speed was significantly correlated with better connectivity of nearly all the cortical regions. For the first time, regional anatomical connectivity maps related to processing speed and visuospatial and executive functions in the elderly are identified. PMID- 21273406 TI - Thalamic ryanodine receptors are involved in controlling the tonic firing of thalamocortical neurons and inflammatory pain signal processing. AB - Ryanodine receptors (RyRs) are highly conductive intracellular Ca(2+) release channels which are widely expressed in the CNS. They rapidly increase the intracellular Ca(2+) concentrations in neuronal cells in response to Ca(2+) influx through voltage-gated Ca(2+) channels. A previous study reported that RyRs were expressed in thalamocortical (TC) neurons, but their physiological function has remained elusive. Here, we show that the activation of RyRs in TC neurons in mice decreases their tonic firing rate while blocking them induces the opposite response. Furthermore, activation of RyRs in ventroposteriomedial/ventroposteriolateral nuclei reduces the behavioral responses to inflammatory pain and blocking them increases the responses. This study highlights the importance of the intracellular Ca(2+) release via RyRs in controlling the excitability of TC neurons and in inflammatory pain signal processing in the thalamus. PMID- 21273407 TI - Flexible, task-dependent use of sensory feedback to control hand movements. AB - We tested whether changing accuracy demands for simple pointing movements leads humans to adjust the feedback control laws that map sensory signals from the moving hand to motor commands. Subjects made repeated pointing movements in a virtual environment to touch a button whose shape varied randomly from trial to trial-between squares, rectangles oriented perpendicular to the movement path, and rectangles oriented parallel to the movement path. Subjects performed the task on a horizontal table but saw the target configuration and a virtual rendering of their pointing finger through a mirror mounted between a monitor and the table. On one-third of trials, the position of the virtual finger was perturbed by +/-1 cm either in the movement direction or perpendicular to the movement direction when the finger passed behind an occluder. Subjects corrected quickly for the perturbations despite not consciously noticing them; however, they corrected almost twice as much for perturbations aligned with the narrow dimension of a target than for perturbations aligned with the long dimension. These changes in apparent feedback gain appeared in the kinematic trajectories soon after the time of the perturbations, indicating that they reflect differences in the feedback control law used throughout the duration of movements. The results indicate that the brain adjusts its feedback control law for individual movements "on demand" to fit task demands. Simulations of optimal control laws for a two-joint arm show that accuracy demands alone, coupled with signal-dependent noise, lead to qualitatively the same behavior. PMID- 21273408 TI - Distances between real-world locations are represented in the human hippocampus. AB - Spatial navigation is believed to be guided in part by reference to an internal map of the environment. We used functional magnetic resonance imaging (fMRI) to test for a key aspect of a cognitive map: preservation of real-world distance relationships. University students were scanned while viewing photographs of familiar campus landmarks. fMRI response levels in the left hippocampus corresponded to real-world distances between landmarks shown on successive trials, indicating that this region considered closer landmarks to be more representationally similar and more distant landmarks to be more representationally distinct. In contrast, posterior visually responsive regions such as retrosplenial complex and the parahippocampal place area were sensitive to landmark repetition and encoded landmark identity in their multivoxel activity patterns but did not show a distance-related response. These data suggest the existence of a map-like representation in the human medial temporal lobe that encodes the coordinates of familiar locations in large-scale, real-world environments. PMID- 21273409 TI - Vascularization of cytochrome oxidase-rich blobs in the primary visual cortex of squirrel and macaque monkeys. AB - The close correlation between energy supply by blood vessels and energy consumption by cellular processes in the brain is the basis of blood flow-related functional imaging techniques. Regional differences in vascular density can be detected using high-resolution functional magnetic resonance imaging. Therefore, inhomogeneities in vascularization might help to identify anatomically distinct areas noninvasively in vivo. It was reported previously that cytochrome oxidase rich blobs in the striate cortex of squirrel monkeys are characterized by a notably higher vascular density (42% higher than interblob regions). However, blobs have so far never been identified in vivo on the basis of their vascular density. Here, we analyzed blobs of the primary visual cortex of squirrel monkeys and macaques with respect to the relationship between vascularization and cytochrome oxidase activity. By double staining with cytochrome oxidase enzyme histochemistry to define the blobs and collagen type IV immunohistochemistry to quantify the blood vessels, a close correlation between oxidative metabolism and vascularization was confirmed and quantified in detail. The vascular length density in cytochrome oxidase blobs was on average 4.5% higher than in the interblob regions, a difference almost one order of magnitude smaller than previously reported. Thus, the vascular density that is closely associated with local average metabolic activity is a structural equivalent of cerebral metabolism and blood flow. However, the quantitative differences in vascularization between blob and interblob regions are small and below the detectability threshold of the noninvasive hemodynamic imaging methods of today. PMID- 21273410 TI - Neural characterization of the speed-accuracy tradeoff in a perceptual decision making task. AB - Decisions often necessitate a tradeoff between speed and accuracy (SAT), that is, fast decisions are more error prone while careful decisions take longer. Sequential sampling models assume that evidence for different response alternatives is accumulated over time and suggest that SAT modulates the decision system by setting a lower threshold (boundary) on required accumulated evidence to commit a response under time pressure. We investigated how such a speed accuracy tradeoff is implemented neurally under different levels of sensory evidence. Using magnetoencephalography (MEG) and a face-house categorization task, we show that the later decision- and motor-related systems rather than the early sensory system are modulated by SAT. Source analysis revealed that the bilateral supplementary motor areas (SMAs) and the medial precuneus were more activated under the speed instruction and correlated negatively (right SMA) with the boundary parameter, whereas the left dorsolateral prefrontal cortex (DLPFC) was more activated under the accuracy instruction and showed a positive correlation with the boundary. The findings are interpreted in the sense that SMA activity dynamically facilitates fast responses during stimulus processing, potentially by disinhibiting thalamo-striatal loops, whereas DLPFC reflects accumulated evidence before response execution. PMID- 21273411 TI - The mouse cochlea expresses a local hypothalamic-pituitary-adrenal equivalent signaling system and requires corticotropin-releasing factor receptor 1 to establish normal hair cell innervation and cochlear sensitivity. AB - Cells of the inner ear face constant metabolic and structural stress. Exposure to intense sound or certain drugs destroys cochlea hair cells, which in mammals do not regenerate. Thus, an endogenous stress response system may exist within the cochlea to protect it from everyday stressors. We recently described the existence of corticotropin-releasing factor (CRF) in the mouse cochlea. The CRF receptor type 1 (CRFR1) is considered the primary and canonical target of CRF signaling, and systemically it plays an essential role in coordinating the body wide stress response via activation of the hypothalamic-pituitary-adrenal (HPA) axis. Here, we describe an essential role for CRFR1 in auditory system development and function, and offer the first description of a complete HPA equivalent signaling system resident within the cochlea. To reveal the role of CRFR1 activation in the cochlea, we have used mice carrying a null ablation of the CRFR1 gene. CRFR1(-/-) mice exhibited elevated auditory thresholds at all frequencies tested, indicating reduced sensitivity. Furthermore, our results suggest that CRFR1 has a developmental role affecting inner hair cell morphology and afferent and efferent synapse distribution. Given the role of HPA signaling in maintaining local homeostasis in other tissues, the presence of a cochlear HPA signaling system suggests important roles for CRFR1 activity in setting cochlear sensitivity, perhaps both neural and non-neural mechanisms. These data highlight the complex pleiotropic mechanisms modulated by CRFR1 signaling in the cochlea. PMID- 21273412 TI - Improved motion perception and impaired spatial suppression following disruption of cortical area MT/V5. AB - As stimulus size increases, motion direction of high-contrast patterns becomes increasingly harder to perceive. This counterintuitive behavioral result, termed "spatial suppression," is hypothesized to reflect center-surround antagonism-a receptive field property ubiquitous in sensory systems. Prior research proposed that spatial suppression of motion signals is a direct correlate of center surround antagonism within cortical area MT. Here, we investigated whether human MT/V5 is indeed causally involved in spatial suppression of motion signals. The key assumption is that a disruption of neural mechanisms that play a critical role in spatial suppression could allow these normally suppressed motion signals to reach perceptual awareness. Thus, our hypothesis was that a disruption of MT/V5 should weaken spatial suppression and, consequently, improve motion perception of large, moving patterns. To disrupt MT/V5, we used offline 1 Hz transcranial magnetic stimulation (TMS)-a method that temporarily attenuates normal functioning of the targeted cortex. Early visual areas were also targeted as a control site. The results supported our hypotheses and showed that disruption of MT/V5 improved motion discrimination of large, moving stimuli, presumably by weakening surround suppression strength. This effect was specific to MT/V5 stimulation and contralaterally presented stimuli. Evidently, the critical neural constraints limiting motion perception of large, high-contrast stimuli involve MT/V5. Additionally, our findings mimic spatial suppression deficits that are observed in several patient populations and implicate impaired MT/V5 processes as likely neural correlates for the reported perceptual abnormalities in the elderly, patients with schizophrenia and those with a history of depression. PMID- 21273413 TI - Insulin modulates cocaine-sensitive monoamine transporter function and impulsive behavior. AB - Because insulin acutely enhances the function of dopamine transporters, the tyrosine kinase receptors activated by this hormone may modulate transporter dependent neurochemical and behavioral effects of psychoactive drugs. In this respect, we examined the effects of insulin on exocytotic monoamine release and the efficacy of the monoamine transporter blocker cocaine in rat nucleus accumbens. Whereas insulin reduced electrically evoked exocytotic [(3)H]dopamine release in nucleus accumbens slices, the hormone potentiated the release enhancing effect of cocaine thereon. The phosphatidylinositol 3-kinase inhibitor LY294002 abolished these effects, indicating the involvement of insulin receptors. Similar insulin effects were observed on the release of [(3)H]norepinephrine in nucleus accumbens slices, but not on that of [(3)H]serotonin, and were also apparent in medial prefrontal cortex slices. As might then be expected, insulin also potentiated the dopamine and norepinephrine release-enhancing effects of the selective monoamine uptake inhibitors GBR12909 and desmethylimipramine, respectively. In subsequent behavioral experiments, we investigated the role of insulin in motor impulsivity that depends on monoamine neurotransmission in the nucleus accumbens. Intracranial administration of insulin in the nucleus accumbens alone reduced premature responses in the five choice serial reaction time task and enhanced the stimulatory effect of peripheral cocaine administration on impulsivity, resembling the observed neurochemical effects of the hormone. In contrast, cocaine-induced locomotor activity remained unchanged by intra-accumbal insulin application. These data reveal that insulin presynaptically regulates cocaine-sensitive monoamine transporter function in the nucleus accumbens and, as a consequence, impulsivity. Therefore, insulin signaling proteins may represent targets for the treatment of inhibitory control deficits such as addictive behaviors. PMID- 21273414 TI - PreBotzinger complex neurokinin-1 receptor-expressing neurons mediate opioid induced respiratory depression. AB - The analgesic properties of the opium poppy Papever somniferum were first mentioned by Hippocrates around 400 BC, and opioid analgesics remain the mainstay of pain management today. These drugs can cause the serious side-effect of respiratory depression that can be lethal with overdose, however the critical brain sites and neurochemical identity of the neurons mediating this depression are unknown. By locally manipulating neurotransmission in the adult rat, we identify the critical site of the medulla, the preBotzinger complex, that mediates opioid-induced respiratory depression in vivo. Here we show that opioids at the preBotzinger complex cause respiratory depression or fatal apnea, with anesthesia and deep-sleep being particularly vulnerable states for opioid-induced respiratory depression. Importantly, we establish that the preBotzinger complex is fully responsible for respiratory rate suppression following systemic administration of opioid analgesics. The site in the medulla most sensitive to opioids corresponds to a region expressing neurokinin-1 receptors, and we show in rhythmically active brainstem section in vitro that neurokinin-1 receptor expressing preBotzinger complex neurons are selectively inhibited by opioids. In summary, neurokinin-1 receptor-expressing preBotzinger complex neurons constitute the critical site mediating opioid-induced respiratory rate depression, and the key therapeutic target for its prevention or reversal. PMID- 21273415 TI - Thalamocortical pathfinding defects precede degeneration of the reticular thalamic nucleus in polysialic acid-deficient mice. AB - The modification of the neural cell adhesion molecule (NCAM) with polysialic acid (polySia) is tightly linked to neural development. Genetic ablation of the polySia-synthesizing enzymes ST8SiaII and ST8SiaIV generates polySia-negative but NCAM-positive (II(-/-)IV(-/-)) mice characterized by severe defects of major brain axon tracts, including internal capsule hypoplasia. Here, we demonstrate that misguidance of thalamocortical fibers and deficiencies of corticothalamic connections contribute to internal capsule defects in II(-/-)IV(-/-) mice. Thalamocortical fibers cross the primordium of the reticular thalamic nucleus (Rt) at embryonic day 14.5, before they fail to turn into the ventral telencephalon, thus deviating from their normal trajectory without passing through the internal capsule. At postnatal day 1, a reduction and massive disorganization of fibers traversing the Rt was observed, whereas terminal deoxynucleotidyl transferase dUTP nick end labeling and cleaved caspase-3 staining indicated abundant apoptotic cell death of Rt neurons at postnatal day 5. Furthermore, during postnatal development, the number of Rt neurons was drastically reduced in 4-week-old II(-/-)IV(-/-) mice, but not in the NCAM deficient N(-/-) or II(-/-)IV(-/-)N(-/-) triple knock-out animals displaying no internal capsule defects. Thus, degeneration of the Rt in II(-/-)IV(-/-) mice may be a consequence of malformation of thalamocortical and corticothalamic fibers providing major excitatory input into the Rt. Indeed, apoptotic death of Rt neurons could be induced by lesioning corticothalamic fibers on whole-brain slice cultures. We therefore propose that anterograde transneuronal degeneration of the Rt in polysialylation-deficient, NCAM-positive mice is caused by defective afferent innervation attributable to thalamocortical pathfinding defects. PMID- 21273416 TI - Multiple targets of MU-opioid receptor-mediated presynaptic inhibition at primary afferent Adelta- and C-fibers. AB - Agonists at MU-opioid receptors (MORs) represent the gold standard for the treatment of severe pain. A key element of opioid analgesia is the depression of nociceptive information at the first synaptic relay in spinal pain pathways. The underlying mechanisms are, however, largely unknown. In spinal cord slices with dorsal roots attached prepared from young rats, we determined the inhibitory effect of the selective MOR agonist [d-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin (DAMGO) on monosynaptic Adelta- and C-fiber-evoked EPSCs in lamina I neurons. DAMGO depressed presynaptically Adelta- and C-fiber-mediated responses, indicating that MORs are expressed on central terminals of both fiber types. We next addressed the mechanisms of presynaptic inhibition. The effect of DAMGO at both Adelta- and C-fiber terminals was mainly mediated by an inhibition of N-type voltage-dependent Ca(2+) channels (VDCCs), and to a lesser extent of P/Q-type VDCCs. Inhibition by DAMGO was not reduced by K(+) channel blockers. The rate of miniature EPSCs was reduced by DAMGO in a dose-dependent manner. The opioid also reduced Ca(2+)-dependent, ionomycin-induced EPSCs downstream of VDCCs. DAMGO had no effect on the kinetics of vesicle exocytosis in C-fiber terminals, but decreased the rate of unloading of Adelta-fiber boutons moderately, as revealed by two-photon imaging of styryl dye destaining. Together, these results suggest that binding of opioids to MORs reduces nociceptive signal transmission at central Adelta- and C-fiber synapses mainly by inhibition of presynaptic N-type VDCCs. P/Q-type VDCCs and the transmitter release machinery are targets of opioid action as well. PMID- 21273417 TI - AKAP79/150 impacts intrinsic excitability of hippocampal neurons through phospho regulation of A-type K+ channel trafficking. AB - Kv4.2, as the primary alpha-subunit of rapidly inactivating, A-type voltage-gated K(+) (Kv) channels expressed in hippocampal CA1 pyramidal dendrites, plays a critical role in regulating their excitability. Activity-dependent trafficking of Kv4.2 relies on C-terminal protein kinase A (PKA) phosphorylation. A-kinase anchoring proteins (AKAPs) target PKA to glutamate receptor and ion channel complexes to allow for discrete, local signaling. As part of a previous study, we showed that AKAP79/150 interacts with Kv4.2 complexes and that the two proteins colocalize in hippocampal neurons. However, the nature and functional consequence of their interaction has not been previously explored. Here, we report that the C terminal domain of Kv4.2 interacts with an internal region of AKAP79/150 that overlaps with its MAGUK (membrane-associated guanylate kinase)-binding domain. We show that AKAP79/150-anchored PKA activity controls Kv4.2 surface expression in heterologous cells and hippocampal neurons. Consistent with these findings, disrupting PKA anchoring led to a decrease in neuronal excitability, while preventing dephosphorylation by the phosphatase calcineurin resulted in increased excitability. These results demonstrate that AKAP79/150 provides a platform for dynamic PKA regulation of Kv4.2 expression, fundamentally impacting CA1 excitability. PMID- 21273418 TI - Disentangling scene content from spatial boundary: complementary roles for the parahippocampal place area and lateral occipital complex in representing real world scenes. AB - Behavioral and computational studies suggest that visual scene analysis rapidly produces a rich description of both the objects and the spatial layout of surfaces in a scene. However, there is still a large gap in our understanding of how the human brain accomplishes these diverse functions of scene understanding. Here we probe the nature of real-world scene representations using multivoxel functional magnetic resonance imaging pattern analysis. We show that natural scenes are analyzed in a distributed and complementary manner by the parahippocampal place area (PPA) and the lateral occipital complex (LOC) in particular, as well as other regions in the ventral stream. Specifically, we study the classification performance of different scene-selective regions using images that vary in spatial boundary and naturalness content. We discover that, whereas both the PPA and LOC can accurately classify scenes, they make different errors: the PPA more often confuses scenes that have the same spatial boundaries, whereas the LOC more often confuses scenes that have the same content. By demonstrating that visual scene analysis recruits distinct and complementary high level representations, our results testify to distinct neural pathways for representing the spatial boundaries and content of a visual scene. PMID- 21273419 TI - The deubiquitinating enzyme USP-46 negatively regulates the degradation of glutamate receptors to control their abundance in the ventral nerve cord of Caenorhabditis elegans. AB - Ubiquitin-mediated endocytosis and post-endocytic trafficking of glutamate receptors control their synaptic abundance and are implicated in modulating synaptic strength. Ubiquitination is a reversible modification, but the identities and specific functions of deubiquitinating enzymes in the nervous system are lacking. Here, we show that the deubiquitinating enzyme ubiquitin specific protease-46 (USP-46) regulates the abundance of the glutamate receptor GLR-1 in the ventral nerve cord of Caenorhabditis elegans. Mutants lacking usp-46 have decreased GLR-1 in the ventral nerve cord and corresponding defects in GLR-1 dependent behaviors. The amount of ubiquitinated GLR-1 is increased in usp-46 mutants. Mutations that block GLR-1 ubiquitination or receptor degradation in the multi-vesicular body/lysosome prevent the decrease in GLR-1 observed in usp-46 mutants. These data support a model in which USP-46 promotes GLR-1 abundance at synapses by deubiquitinating GLR-1 and preventing its degradation in the lysosome. This work suggests that the balance between the addition and removal of ubiquitin is important for glutamate receptor trafficking. PMID- 21273421 TI - Errors and conflict at the task level and the response level. AB - In the last decade, research on error and conflict processing has become one of the most influential research areas in the domain of cognitive control. There is now converging evidence that a specific part of the posterior frontomedian cortex (pFMC), the rostral cingulate zone (RCZ), is crucially involved in the processing of errors and conflict. However, error-related research has focused primarily on a specific error type, namely, response errors. The aim of the present study was to investigate whether errors on the task level rely on the same neural and functional mechanisms. Here we report a dissociation of both error types in the pFMC: whereas response errors activate the RCZ, task errors activate the dorsal frontomedian cortex. Although this last region shows an overlap in activation for task and response errors on the group level, a closer inspection of the single subject data is more in accordance with a functional anatomical dissociation. When investigating brain areas related to conflict on the task and response levels, a clear dissociation was perceived between areas associated with response conflict and with task conflict. Overall, our data support a dissociation between response and task levels of processing in the pFMC. In addition, we provide additional evidence for a dissociation between conflict and errors both at the response level and at the task level. PMID- 21273420 TI - CD45 deficiency drives amyloid-beta peptide oligomers and neuronal loss in Alzheimer's disease mice. AB - Converging lines of evidence indicate dysregulation of the key immunoregulatory molecule CD45 (also known as leukocyte common antigen) in Alzheimer's disease (AD). We report that transgenic mice overproducing amyloid-beta peptide (Abeta) but deficient in CD45 (PSAPP/CD45(-/-) mice) faithfully recapitulate AD neuropathology. Specifically, we find increased abundance of cerebral intracellular and extracellular soluble oligomeric and insoluble Abeta, decreased plasma soluble Abeta, increased abundance of microglial neurotoxic cytokines tumor necrosis factor-alpha and interleukin-1beta, and neuronal loss in PSAPP/CD45(-/-) mice compared with CD45-sufficient PSAPP littermates (bearing mutant human amyloid precursor protein and mutant human presenilin-1 transgenes). After CD45 ablation, in vitro and in vivo studies demonstrate an anti-Abeta phagocytic but proinflammatory microglial phenotype. This form of microglial activation occurs with elevated Abeta oligomers and neural injury and loss as determined by decreased ratio of anti-apoptotic Bcl-xL to proapoptotic Bax, increased activated caspase-3, mitochondrial dysfunction, and loss of cortical neurons in PSAPP/CD45(-/-) mice. These data show that deficiency in CD45 activity leads to brain accumulation of neurotoxic Abeta oligomers and validate CD45 mediated microglial clearance of oligomeric Abeta as a novel AD therapeutic target. PMID- 21273422 TI - Activation of TREK currents by the neuroprotective agent riluzole in mouse sympathetic neurons. AB - Background K2P channels play a key role in stabilizing the resting membrane potential, thereby modulating cell excitability in the central and peripheral somatic nervous system. Whole-cell experiments revealed a riluzole-activated current (I(RIL)), transported by potassium, in mouse superior cervical ganglion (mSCG) neurons. The activation of this current by riluzole, linoleic acid, membrane stretch, and internal acidification, its open rectification and insensitivity to most classic potassium channel blockers, indicated that I(RIL) flows through channels of the TREK [two-pore domain weak inwardly rectifying K channel (TWIK)-related K channel] subfamily. Whole-ganglia and single-cell reverse transcription-PCR demonstrated the presence of TREK-1, TREK-2, and TRAAK (TWIK-related arachidonic acid-activated K(+) channel) mRNA, and the expression of these three proteins was confirmed by immunocytochemistry in mSCG neurons. I(RIL) was enhanced by zinc, inhibited by barium and fluoxetine, but unaffected by quinine and ruthenium red, strongly suggesting that it was carried through TREK-1/2 channels. Consistently, a channel with properties identical with the heterologously expressed TREK-2 was recorded in most (75%) cell-attached patches. These results provide the first evidence for the expression of K2P channels in the mammalian autonomic nervous system, and they extend the impact of these channels to the entire nervous system. PMID- 21273423 TI - Expectations change the signatures and timing of electrophysiological correlates of perceptual awareness. AB - Previous experience allows the brain to predict what comes next. How these expectations affect conscious experience is poorly understood. In particular, it is unknown whether and when expectations interact with sensory evidence in granting access to conscious perception, and how this is reflected electrophysiologically. Here, we parametrically manipulate sensory evidence and expectations while measuring event-related potentials in human subjects to assess the time course of evoked responses that correlate with subjective visibility, the properties of the stimuli, and/or perceptual expectations. We found that expectations lower the threshold of conscious perception and reduce the latency of neuronal signatures differentiating seen and unseen stimuli. Without expectations, this differentiation occurs ~300 ms and with expectations ~200 ms after stimulus in occipitoparietal sensors. The amplitude of this differentiating response component (P2) decreases as visibility increases, regardless of whether this increase is attributable to enhanced sensory evidence and/or the gradual buildup of perceptual expectations. Importantly, at matched performance levels, responses to seen and unseen stimuli differed regardless of the physical stimulus properties. These findings indicate that the latency of the neuronal correlates of access to consciousness depend on whether access is driven by stimulus saliency or by a combination of expectations and sensory evidence. PMID- 21273424 TI - Necessity is the mother of invention: reconstructing missing sensory information in multiple, concurrent reference frames for eye-hand coordination. AB - When aligning the hand to grasp an object, the CNS combines multiple sensory inputs encoded in multiple reference frames. Previous studies suggest that when a direct comparison of target and hand is possible via a single sensory modality, the CNS avoids performing unnecessary coordinate transformations that add noise. But when target and hand do not share a common sensory modality (e.g., aligning the unseen hand to a visual target), at least one coordinate transformation is required. Similarly, body movements may occur between target acquisition and manual response, requiring that egocentric target information be updated or transformed to external reference frames to compensate. Here, we asked subjects to align the hand to an external target, where the target could be presented visually or kinesthetically and feedback about the hand was visual, kinesthetic, or both. We used a novel technique of imposing conflict between external visual and gravito-kinesthetic reference frames when subjects tilted the head during an instructed memory delay. By comparing experimental results to analytical models based on principles of maximum likelihood, we showed that multiple transformations above the strict minimum may be performed, but only if the task precludes a unimodal comparison of egocentric target and hand information. Thus, for cross-modal tasks, or when head movements are involved, the CNS creates and uses both kinesthetic and visual representations. We conclude that the necessity of producing at least one coordinate transformation activates multiple, concurrent internal representations, the functionality of which depends on the alignment of the head with respect to gravity. PMID- 21273425 TI - Serotonin receptor 5-HT2B mediates serotonin-induced mechanical hyperalgesia. AB - Serotonin [5-hydroxytryptamine (5-HT)] released from mast cells or platelets in peripheral tissues is one of the important inflammatory mediators in pain and hyperalgesia. The involvement of 5-HT in pain is complex because it could inhibit or facilitate nociceptive transmission, reflecting the presence of multiple 5-HT subtype receptors on peripheral and central nociceptors. The present study aimed to investigate the involvement of 5-HT(2B) in 5-HT-induced pain and whether the subtype exists in dorsal root ganglion (DRG) neurons. Injecting the 5-HT or 5 HT(2) agonist in hindpaws of mice induced significant hyperalgesia to mechanical stimuli, which was inhibited by the 5-HT(2B/2C) antagonist but not by 5-HT(1A), 5 HT(2A), or 5-HT(3A) antagonists. Therefore, 5-HT(2B) or 5-HT(2C) may be involved in 5-HT-induced mechanical hyperalgesia. The 5-HT(2B/2C) antagonist also blocked 5-HT-induced transient [Ca(2+)] signaling in DRG neurons. All subtypes of 5-HT receptors except 5-HT(2C) and 5-HT(6) are present in DRGs. In situ hybridization also demonstrated 5-HT(2B) mainly expressed in small- to medium-diameter DRG neurons that respond to pain. Likely, 5-HT(2B) mediates 5-HT-induced mechanical hyperalgesia in mice. PMID- 21273426 TI - Crystal structure of the amyloid-beta p3 fragment provides a model for oligomer formation in Alzheimer's disease. AB - Alzheimer's disease is a progressive neurodegenerative disorder associated with the presence of amyloid-beta (Abeta) peptide fibrillar plaques in the brain. However, current evidence suggests that soluble nonfibrillar Abeta oligomers may be the major drivers of Abeta-mediated synaptic dysfunction. Structural information on these Abeta species has been very limited because of their noncrystalline and unstable nature. Here, we describe a crystal structure of amylogenic residues 18-41 of the Abeta peptide (equivalent to the p3 alpha/gamma secretase fragment of amyloid precursor protein) presented within the CDR3 loop region of a shark Ig new antigen receptor (IgNAR) single variable domain antibody. The predominant oligomeric species is a tightly associated Abeta dimer, with paired dimers forming a tetramer in the crystal caged within four IgNAR domains, preventing uncontrolled amyloid formation. Our structure correlates with independently observed features of small nonfibrillar Abeta oligomers and reveals conserved elements consistent with residues and motifs predicted as critical in Abeta folding and oligomerization, thus potentially providing a model system for nonfibrillar oligomer formation in Alzheimer's disease. PMID- 21273427 TI - FMRP regulates the transition from radial glial cells to intermediate progenitor cells during neocortical development. AB - During vertebrate cortical neurogenesis, radial glial cells (RGCs) serve as neural stem cells that generate neurons directly or indirectly through intermediate progenitor cells (IPCs). The transition from RGCs to IPCs is a key step in determining overall neuronal production and may underlie evolutionary expansion of the cerebral cortex. Here we show that this transition is controlled by fragile X mental retardation protein (FMRP), an RNA-binding protein whose deficiency causes fragile X syndrome. Analysis of mouse embryos electroporated with FMRP small hairpin RNA and knock-out mouse embryos lacking FMRP reveals that specific loss of FMRP causes depletion of neocortical RGCs due to an RGC-to-IPC cell fate change. The RGC depletion is associated with altered F-actin organization and can be largely rescued by overexpressing profilin 1 (Pfn1), a core actin regulatory protein promoting F-actin formation. Our data suggest that FMRP suppresses the transition from RGCs to IPCs during neocortical development by an actin-dependent mechanism. PMID- 21273428 TI - Spatiotemporal evolution of the functional magnetic resonance imaging response to ultrashort stimuli. AB - The specificity of the hemodynamic response function (HRF) is determined spatially by the vascular architecture and temporally by the evolution of hemodynamic changes. The stimulus duration has additional influence on the spatiotemporal evolution of the HRF, as brief stimuli elicit responses that engage only the local vasculature, whereas long stimuli lead to the involvement of remote vascular supply and drainage. Here, we used functional magnetic resonance imaging to investigate the spatiotemporal evolution of the blood oxygenation level-dependent (BOLD), cerebral blood flow (CBF), and cerebral blood volume (CBV) HRF to ultrashort forelimb stimulation in an anesthetized rodent model. The HRFs to a single 333-MUs-long stimulus were robustly detected and consisted of a rapid response in both CBF and CBV, with an onset time (OT) of 350 ms and a full width at half-maximum of 1 s. In contrast, longer stimuli elicited a dispersive transit of oxygenated blood across the cortical microvasculature that significantly prolonged the evolution of the CBV HRF, but not the CBF. The CBF and CBV OTs suggest that vasoactive messengers are synthesized, released, and effective within 350 ms. However, the difference between the BOLD and CBV OT (~100 ms) was significantly smaller than the arteriolar-venular transit time (~500 ms), indicating an arterial contribution to the BOLD HRF. Finally, the rapid rate of growth of the active region with stimulus elongation suggests that functional hyperemia is an integrative process that involves the entire functional cortical depth. These findings offer a new view into the spatiotemporal dynamics of functional hemodynamic regulation in the brain. PMID- 21273429 TI - Regulation of synapse structure and function by distinct myosin II motors. AB - Ongoing synaptic function and rapid, bidirectional plasticity are both controlled by regulatory mechanisms within dendritic spines. Spine actin dynamics maintain synapse structure and function, and cytoskeletal rearrangements in these structures trigger structural and functional plasticity. Therefore, proteins that interact with actin filaments are attractive candidates to regulate synaptic actin dynamics and, thus, synapse structure and function. Here, we have cloned the rat isoform of class II myosin heavy chain MyH7B in brain. Unexpectedly, this isoform resembles muscle-type myosin II rather than the ubiquitously expressed nonmuscle myosin II isoforms, suggesting that a rich functional diversity of myosin II motors may exist in neurons. Indeed, reducing the expression of MyH7B in mature neurons caused profound alterations to dendritic spine structure and excitatory synaptic strength. Structurally, dendritic spines had large, irregularly shaped heads that contained many filopodia-like protrusions. Neurons with reduced MyH7B expression also had impaired miniature EPSC amplitudes accompanied by a decrease in synaptic AMPA receptors, which was linked to alterations of the actin cytoskeleton. MyH7B-mediated control over spine morphology and synaptic strength was distinct from that of a nonmuscle myosin, myosin IIb. Interestingly, when myosin IIb expression and MyH7B expression were simultaneously knocked-down in neurons, a third, more pronounced phenotype emerged. Together, our data provide evidence that distinct myosin II isoforms work together to regulate synapse structure and function in cultured hippocampal neurons. Thus, myosin II motor activity is emerging as a broad regulatory mechanism for control over complex actin networks within dendritic spines. PMID- 21273430 TI - Protein quantification at the single vesicle level reveals that a subset of synaptic vesicle proteins are trafficked with high precision. AB - Protein sorting represents a potential point of regulation in neurotransmission because it dictates the protein composition of synaptic vesicles, the organelle that mediates transmitter release. Although the average number of most vesicle proteins has been estimated using bulk biochemical approaches (Takamori et al., 2006), no information exists on the intervesicle variability of protein number, and thus on the precision with which proteins are sorted to vesicles. To address this, we adapted a single molecule quantification approach (Mutch et al., 2007) and used it to quantify both the average number and variance of seven integral membrane proteins in brain synaptic vesicles. We report that four vesicle proteins, SV2, the proton ATPase, Vglut1, and synaptotagmin 1, showed little intervesicle variation in number, indicating they are sorted to vesicles with high precision. In contrast, the apparent number of VAMP2/synaptobrevin 2, synaptophysin, and synaptogyrin demonstrated significant intervesicle variability. These findings place constraints on models of protein function at the synapse and raise the possibility that changes in vesicle protein expression affect vesicle composition and functioning. PMID- 21273431 TI - Reduced neuronal inhibition and coordination of adolescent prefrontal cortex during motivated behavior. AB - Adolescence is a time of both cognitive maturation and vulnerability to several major psychiatric illnesses and drug dependence. There is increasing awareness that behavioral or pharmacological intervention during this period may be critical for disease prevention in susceptible individuals. Therefore, we must attain a deeper understanding of how the adolescent brain processes salient events relevant to motivated behavior. To do this, we recorded single-unit and local field potential activity in the orbitofrontal cortex of rats as they performed a simple reward-driven operant task. Adolescents encoded basic elements of the task differently than adults, indicating that neuronal processing of salient events differs in the two age groups. Entrainment of local field potential oscillations, variance in spike timing, and relative proportions of inhibitory and excitatory responses differed in an event-specific manner. Overall adolescent phasic neural activity was less inhibited and more variable through much of the task. Cortical inhibition is essential for efficient communication between neuronal groups, and reduced inhibitory control of cortical activity has been implicated in schizophrenia and other disorders. Thus, these results suggest that reduced inhibitory responses of adolescent cortical neurons to salient events could be a critical mechanism for some of the increased vulnerabilities of this period. PMID- 21273432 TI - Tracking vocal pitch through noise: neural correlates in nonprimary auditory cortex. AB - In natural environments, a sound can be heard as stable despite the presence of other occasionally louder sounds. For example, when a portion in a voice is replaced by masking noise, the interrupted voice may still appear illusorily continuous. Previous research found that continuity illusions of simple interrupted sounds, such as tones, are accompanied by weaker activity in the primary auditory cortex (PAC) during the interruption than veridical discontinuity percepts of these sounds. Here, we studied whether continuity illusions of more natural and more complex sounds also emerge from this mechanism. We used psychophysics and functional magnetic resonance imaging in humans to measure simultaneously continuity ratings and blood oxygenation level dependent activity to vowels that were partially replaced by masking noise. Consistent with previous results on tone continuity illusions, we found listeners' reports of more salient vowel continuity illusions associated with weaker activity in auditory cortex (compared with reports of veridical discontinuity percepts of physically identical stimuli). In contrast to the reduced activity to tone continuity illusions in PAC, this reduction was localized in the right anterolateral Heschl's gyrus, a region that corresponds more to the non-PAC. Our findings suggest that the ability to hear differently complex sounds as stable during other louder sounds may be attributable to a common suppressive mechanism that operates at different levels of sound representation in auditory cortex. PMID- 21273433 TI - Concerted action of CB1 cannabinoid receptor and deleted in colorectal cancer in axon guidance. AB - Endocannabinoids (eCBs) are retrograde neurotransmitters that modulate the function of many types of synapses. The presence of eCBs, their CB1 receptor (CB1R), and metabolizing enzymes at embryonic and early postnatal periods have been linked to developmental processes such as neuronal proliferation, differentiation, and migration, axon guidance, and synaptogenesis. Here, we demonstrate the presence of a functional eCB system in the developing visual system and the role of CB1R during axon growth and retinothalamic development. Pharmacological treatment of retinal explants and primary cortical neuron cultures with ACEA, a selective CB1R agonist, induced a collapse of the growth cone (GC). Furthermore the application of AM251, a CB1R inverse agonist, to the neuronal cultures increased the surface area of GC. In vivo, intraocular injection of ACEA diminished retinal projection growth, while AM251 promoted growth and caused aberrant projections. In addition, compared with their wild type littermates, CB1R-deficient adult mice revealed a lower level of eye specific segregation of retinal projections in the dorsal lateral geniculate nucleus. Finally, we found that pharmacological modulation of CB1R affected the trafficking of Deleted in colorectal cancer (DCC) receptor to the plasma membrane in a PKA-dependent manner. Moreover, pharmacological inhibition or genetic inactivation of DCC abolished the CB1R-induced reorganization of the GC. Overall, these findings establish a mechanism by which the CB1R influences GC behavior and nervous system development in concerted action with DCC. PMID- 21273434 TI - Early maturation of the linguistic dorsal pathway in human infants. AB - Human infants, unlike even closely related primates, exhibit a remarkable capacity for language learning. Yet how the underlying anatomical network matures remains largely unknown. The classical view is that of a largely immature brain comprising only a few islands of maturity in primary cortices. This view has favored a description of learning based on bottom-up algorithms and has tended to discard the role of frontal regions, which were assumed to be barely functional early on. Here, using an index based on the normalized T2-weighted magnetic resonance signal, we have quantified maturation within the linguistic network in fourteen 1- to 4-month-old infants. Our results show first that the ventral superior temporal sulcus (STS), and not the inferior frontal area, is the less mature perisylvian region. A significant difference of maturation in the STS favoring the right side is an early testimony of the distinctive left-right development of this structure observed during the whole life. Second, asymmetries of maturation in Broca's area were correlated with asymmetries in the posterior STS and in the parietal segment of the arcuate fasciculus, suggesting that an efficient frontotemporal dorsal pathway might provide infants with a phonological loop circuitry much earlier than expected. PMID- 21273435 TI - The role of striatal tonically active neurons in reward prediction error signaling during instrumental task performance. AB - The detection of differences between predictions and actual outcomes is important for associative learning and for selecting actions according to their potential future reward. There are reports that tonically active neurons (TANs) in the primate striatum may carry information about errors in the prediction of rewards. However, this property seems to be expressed in classical conditioning tasks but not during performance of an instrumental task. To address this issue, we recorded the activity of TANs in the putamen of two monkeys performing an instrumental task in which probabilistic rewarding outcomes were contingent on an action in block-design experiments. Behavioral evidence suggests that animals adjusted their performance according to the level of probability for reward on each trial block. We found that the TAN response to reward was stronger as the reward probability decreased; this effect was especially prominent on the late component of the pause-rebound pattern of typical response seen in these neurons. The responsiveness to reward omission was also increased with increasing reward probability, whereas there were no detectable effects on responses to the stimulus that triggered the movement. Overall, the modulation of TAN responses by reward probability appeared relatively weak compared with that observed previously in a probabilistic classical conditioning task using the same block design. These data indicate that instrumental conditioning was less effective at demonstrating prediction error signaling in TANs. We conclude that the sensitivity of the TAN system to reward probability depends on the specific learning situation in which animals experienced the stimulus-reward associations. PMID- 21273436 TI - Analysis of development of direction selectivity in retinotectum by a neural circuit model with spike timing-dependent plasticity. AB - The development of direction selectivity in the visual system depends on visual experience. In the developing Xenopus retinotectal system, tectal neurons (TNs) become direction selective through spike timing-dependent plasticity (STDP) after repetitive retinal exposure to a moving bar in a specific direction. We investigated the mechanism responsible for the development of direction selectivity in the Xenopus retinotectal system using a neural circuit model with STDP. In this retinotectal circuit model, a moving bar stimulated the retinal ganglion cells (RGCs), which provided feedforward excitation to the TNs and interneurons (INs). The INs provided delayed feedforward inhibition to the TNs. The TNs also received feedback excitation from neighboring TNs. As a synaptic learning rule, a molecular STDP model was used for synapses between the RGCs and TNs. The retinotectal circuit model reproduced experimentally observed features of the development of direction selectivity, such as increase in input to the TN. The peak of feedforward excitation from RGCs to TNs shifted earlier as a result of STDP. Together with the delayed feedforward inhibition, a stronger earlier transient feedforward signal was generated, which exceeded the threshold of the feedback excitation from the neighboring TNs and resulted in amplification of input to the TN. The suppression of the delayed feedforward inhibition resulted in the development of orientation selectivity rather than direction selectivity, indicating the pivotal role of the delayed feedforward inhibition in direction selectivity. We propose a mechanism for the development of direction selectivity involving a delayed feedforward inhibition with STDP and the amplification of feedback excitation. PMID- 21273437 TI - Cytoplasmic linker proteins regulate neuronal polarization through microtubule and growth cone dynamics. AB - Axon formation is a hallmark of initial neuronal polarization. This process is thought to be regulated by enhanced microtubule stability in the subsequent axon and changes in actin dynamics in the future axonal growth cone. Here, we show that the microtubule end-binding proteins cytoplasmic linker protein (CLIP)-115 and CLIP-170 were enriched in the axonal growth cone and extended into the actin rich domain of the growth cone. CLIPs were necessary for axon formation and sufficient to induce an axon. The regulation of axonal microtubule stabilization by CLIPs enabled the protrusion of microtubules into the leading edge of the axonal growth cone. Moreover, CLIPs positively regulated growth cone dynamics and restrained actin arc formation, which was necessary for axon growth. In fact, in neurons without CLIP activity, axon formation was restored by actin destabilization or myosin II inhibition. Together, our data suggest that CLIPs enable neuronal polarization by controlling the stabilization of microtubules and growth cone dynamics. PMID- 21273438 TI - Tuning the period of the mammalian circadian clock: additive and independent effects of CK1epsilonTau and Fbxl3Afh mutations on mouse circadian behavior and molecular pacemaking. AB - Circadian pacemaking in the suprachiasmatic nucleus (SCN) revolves around a transcriptional/posttranslational feedback loop in which period (Per) and cryptochrome (Cry) genes are negatively regulated by their protein products. Genetically specified differences in this oscillator underlie sleep and metabolic disorders, and dictate diurnal/nocturnal preference. A critical goal, therefore, is to identify mechanisms that generate circadian phenotypic diversity, through both single gene effects and gene interactions. The individual stabilities of PER or CRY proteins determine pacemaker period, and PER/CRY complexes have been proposed to afford mutual stabilization, although how PER and CRY proteins with contrasting stabilities interact is unknown. We therefore examined interactions between two mutations in male mice: Fbxl3(Afh), which lengthens period by stabilizing CRY, and Csnk1epsilon(tm1Asil) (CK1epsilon(Tau)), which destabilizes PER, thereby accelerating the clock. By intercrossing these mutants, we show that the stabilities of CRY and PER are independently regulated, contrary to the expectation of mutual stabilization. Segregation of wild-type and mutant alleles generated a spectrum of periods for rest-activity behavior and SCN bioluminescence rhythms. The mutations exerted independent, additive effects on circadian period, biased toward shorter periods determined by CK1epsilon(Tau). Notably, Fbxl3(Afh) extended the duration of the nadir of the PER2-driven bioluminescence rhythm but CK1epsilon(Tau) reversed this, indicating that despite maintained CRY expression, CK1epsilon(Tau) truncated the interval of negative feedback. These results argue for independent, additive biochemical actions of PER and CRY in circadian control, and complement genome-wide epistatic analyses, seeking to decipher the multigenic control of circadian pacemaking. PMID- 21273439 TI - NrCAM deletion causes topographic mistargeting of thalamocortical axons to the visual cortex and disrupts visual acuity. AB - NrCAM is a neural cell adhesion molecule of the L1 family that has been linked to autism spectrum disorders, a disease spectrum in which abnormal thalamocortical connectivity may contribute to visual processing defects. Here we show that NrCAM interaction with neuropilin-2 (Npn-2) is critical for semaphorin 3F (Sema3F) induced guidance of thalamocortical axon subpopulations at the ventral telencephalon (VTe), an intermediate target for thalamic axon sorting. Genetic deletion of NrCAM or Npn-2 caused contingents of embryonic thalamic axons to misproject caudally in the VTe. The resultant thalamocortical map of NrCAM-null mutants showed striking mistargeting of motor and somatosensory thalamic axon contingents to the primary visual cortex, but retinogeniculate targeting and segregation were normal. NrCAM formed a molecular complex with Npn-2 in brain and neural cells, and was required for Sema3F-induced growth cone collapse in thalamic neuron cultures, consistent with a vital function for NrCAM in Sema3F induced axon repulsion. NrCAM-null mice displayed reduced responses to visual evoked potentials recorded from layer IV in the binocular zone of primary visual cortex (V1), particularly when evoked from the ipsilateral eye, indicating abnormal visual acuity and ocularity. These results demonstrate that NrCAM is required for normal maturation of cortical visual acuity, and suggest that the aberrant projection of thalamic motor and somatosensory axons to the visual cortex in NrCAM-null mutant mice impairs cortical functions. PMID- 21273440 TI - Ligand-dependent degradation of SRC-1 is pivotal for progesterone receptor transcriptional activity. AB - The progesterone receptor (PR), a ligand-activated transcription factor, recruits the primary coactivator steroid receptor coactivator-1 (SRC-1) gene promoters. It is known that PR transcriptional activity is paradoxically coupled to its ligand dependent down-regulation. However, despite its importance in PR function, the regulation of SRC-1 expression level during hormonal exposure is poorly understood. Here we report that SRC-1 expression level (but not other p160 family members) is down-regulated by the agonist ligand R5020 in a PR-dependent manner. In contrast, the antagonist RU486 fails to induce down-regulation of the coactivator and impairs PR agonist-dependent degradation of SRC-1. We show that SRC-1 proteolysis is a proteasome- and ubiquitin-mediated process that, predominantly but not exclusively, occurs in the cytoplasmic compartment in which SRC-1 colocalizes with proteasome antigens as demonstrated by confocal imaging. Moreover, SRC-1 was stabilized in the presence of leptomycin B or several proteasomal inhibitors. Two degradation motifs, amino-acids 2-16 corresponding to a PEST motif and amino acids 41-136 located in the basic helix loop helix domain of the coactivator, were identified and shown to control the stability as well as the hormone-dependent down-regulation of the coactivator. SRC-1 degradation is of physiological importance because the two nondegradable mutants that still interacted with PR as demonstrated by coimmunoprecipitation failed to stimulate transcription of exogenous and endogenous target genes, suggesting that concomitant PR/SRC-1 ligand-dependent degradation is a necessary step for PR transactivation activity. Collectively our findings are consistent with the emerging role of proteasome-mediated proteolysis in the gene-regulating process and indicate that the ligand-dependent down-regulation of SRC-1 is critical for PR transcriptional activity. PMID- 21273441 TI - Lysine methylation and functional modulation of androgen receptor by Set9 methyltransferase. AB - Lysine methyltransferases modulate activities of transcription factors and transcription coregulators by methylating specific lysine residue(s). We report that the androgen receptor (AR) is methylated at lysine-630 by Set9, which was originally identified as a histone H3K4 monomethyltransferase. Alanine substitution of lysine-630 prevented AR methylation in vitro and in vivo. Set9 methylated the nuclear and cytoplasmic AR utilizing the cofactor S-adenosyl methionine. A pan-methyllysine antibody recognized endogenous AR, and Set9 coimmunoprecipitated with nuclear and cytoplasmic AR. Set9 overexpression potentiated AR-mediated transactivation of the probasin promoter, whereas Set9 depletion inhibited AR activity and target gene expression. Similar to AR, chromatin occupancy of Set9 at androgen response elements (AREs) was androgen dependent, and associated with methylated histone H3K4 chromatin activation marks and p300/CBP associated factor acetyltransferase recruitment. Set9 depletion increased the histone H3K9-dimethyl repressive mark at AREs and reduced histone activation marks and occupancy of p300/CBP associated factor. K630A mutation reduced amino- and carboxy-terminal (N-C) interaction in Set9-intact cells, whereas N-C interaction for wild-type AR was reduced upon Set9 depletion. The K630A mutant was resistant to loss of activity from Set9 silencing and to increase of activity from Set9 overexpression. The K630 dependence of Set9 regulated N-C interaction and AR activity suggests that Set9 directly acts on AR at the amino acid level. Chromatin recruitment of Set9 to AREs is suggestive of its additional role as a transcriptional coactivator. Because the cellular metabolic state determines the level of S-adenosylmethionine and consequently the activity of Set9, the enhanced activity of methylated AR may have special significance in certain metabolic contexts. PMID- 21273442 TI - Testosterone, not 5alpha-dihydrotestosterone, stimulates LRH-1 leading to FSH independent expression of Cyp19 and P450scc in granulosa cells. AB - Androgens are crucial for normal folliculogenesis and female fertility as evidenced in androgen receptor-null and granulosa cell conditional knockout mice. It is thought, however, that the multiple effects of androgens in the ovary are mainly complementary to the actions of gonadotropins. Using primary rat granulosa cells, we demonstrated that in the absence of gonadotropins, testosterone (T) increases aromatase (Cyp19) and P450 side-change cleavage expression, two enzymes crucial for normal ovarian function. T can be converted into estradiol, a classical estrogen, by Cyp19 and into 5alpha-dihydrotestosterone, a pure androgen, by 5alpha-reductase. However, inhibition of Cyp19 and/or 5alpha reductase did not prevent the stimulatory effects of T. In contrast, the effect of this steroid was potentiated by blocking 5alpha-reductase. Additionally, T, not 5alpha-dihydrotestosterone, stimulates liver receptor homolog-1 (LRH-1) expression, whereas the expression of steroidogenic factor-1 (SF-1) was not affected by either steroid. LRH-1 and SF-1 are transcription factors known to be involved in the regulation of Cyp19. Accordingly, small interference RNA against LRH-1 prevented Cyp19 and P450 side-change cleavage up-regulation whereas anti-SF 1 small interference RNA had no effects. Chromatin immunoprecipitation demonstrated that T stimulation of LRH-1 leads to the recruitment of LRH-1 to the native Cyp19 promoter, which was not affected by cotreatment with 5alpha reductase and Cyp19 inhibitors. Finally, gel shift and supershift analysis demonstrated that the androgen receptor binds to an androgen response element located within the LRH-1 promoter. These results provide novel evidence that T has a direct effect on the expression of genes involved in granulosa cell differentiation. PMID- 21273443 TI - Research resource: Comparative nuclear receptor atlas: basal and activated peritoneal B-1 and B-2 cells. AB - Naive murine B cells are typically divided into three subsets based on functional and phenotypic characteristics: innate-like B-1 and marginal zone B cells vs. adaptive B-2 cells, also known as follicular or conventional B cells. B-1 cells, the innate-immune-like component of the B cell lineage are the primary source of natural antibodies and have been shown to modulate autoimmune diseases, human B cell leukemias, and inflammatory disorders such as atherosclerosis. On the other hand, B-2 cells are the principal mediators of the adaptive humoral immune response and represent an important pharmacological target for various conditions including rheumatoid arthritis, lupus erythematosus, and lymphomas. Using the resources of the Nuclear Receptor Signaling Atlas program, we used quantitative real-time PCR to assess the complement of the 49 murine nuclear receptor superfamily expressed in quiescent and toll-like receptor (TLR)-stimulated peritoneal B-1 and B-2 cells. We report the expression of 24 nuclear receptors in basal B-1 cells and 25 nuclear receptors in basal B-2 cells, with, in some cases, dramatic changes in response to TLR 4 or TLR 2/1 stimulation. Comparative nuclear receptor profiling between B-1 and peritoneal B-2 cells reveals a highly concordant expression pattern, albeit at quantitatively dissimilar levels. We also found that splenic B cells express 23 nuclear receptors. This catalog of nuclear receptor expression in B-1 and B-2 cells provides data to be used to better understand the specific roles of nuclear receptors in B cell function, chronic inflammation, and autoimmune disease. PMID- 21273444 TI - N-cadherin loss in POMC-expressing cells leads to pituitary disorganization. AB - Pituitary tumors are the third most common intracranial tumor in humans and can cause altered hormone secretions leading to hypercortisolism, acromegaly, and infertility. Reduced expression of the cell adhesion molecule N-cadherin has been linked with the formation of pituitary tumors, but its role in normal pituitary gland physiology or tumor initiation is unknown. In the murine pituitary, N cadherin expression is detected in virtually all cells of the posterior, intermediate, and anterior lobes. N-cadherin may function to initiate important cues such as controlling proliferation, directing cell placement, and promoting formation of cell networks that coordinately release hormones into the bloodstream. To address this, we generated mice lacking N-cadherin in proopiomelanocortin-expressing melanotrope and corticotrope cells of the intermediate and anterior lobes of the pituitary. We observed that intermediate lobe cells can aberrantly displace SOX2-containing progenitor cells in the N cadherin conditional knockout mice at postnatal d 1. By postnatal d 30, although a reduction in alpha- and beta-catenin membrane staining occurs, there is little effect on intermediate lobe architecture with N-cadherin loss. Also, despite these changes in adherens junction molecules, no alterations in cell proliferation occur. In contrast, loss of N-cadherin in the corticotropes leads to aberrant cell clustering and a reduction in Pomc mRNA. Taken together, our data reveal important roles of N-cadherin in pituitary cell placement and that loss of N-cadherin alone does not lead to pituitary tumor formation. PMID- 21273445 TI - ROS signaling by NOX4 drives fibroblast-to-myofibroblast differentiation in the diseased prostatic stroma. AB - Stromal remodeling, in particular fibroblast-to-myofibroblast differentiation, is a hallmark of benign prostatic hyperplasia (BPH) and solid tumors, including prostate cancer (PCa). Increased local production of TGFbeta1 is considered the inducing stimulus. Given that stromal remodeling actively promotes BPH/PCa development, there is considerable interest in developing stromal-targeted therapies. Microarray and quantitative PCR analysis of primary human prostatic stromal cells induced to undergo fibroblast-to-myofibroblast differentiation with TGFbeta1 revealed up-regulation of the reactive oxygen species (ROS) producer reduced nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) and down regulation of the selenium-containing ROS-scavenging enzymes glutathione peroxidase 3, thioredoxin reductase 1 (TXNRD1), and the selenium transporter selenoprotein P plasma 1. Consistently, NOX4 expression correlated specifically with the myofibroblast phenotype in vivo, and loss of selenoprotein P plasma 1 was observed in tumor-associated stroma of human PCa biopsies. Using lentiviral NOX4 short hairpin RNA-mediated knockdown, pharmacological inhibitors, antioxidants, and selenium, we demonstrate that TGFbeta1 induction of NOX4 derived ROS is required for TGFbeta1-mediated phosphorylation of c-jun N-terminal kinase, which in turn is essential for subsequent downstream cytoskeletal remodeling. Significantly, selenium supplementation inhibited differentiation by increasing ROS-scavenging selenoenzyme biosynthesis because glutathione peroxidase 3 and TXNRD1 expression and TXNRD1 enzyme activity were restored. Consistently, selenium depleted ROS levels downstream of NOX4 induction. Collectively, this work demonstrates that dysregulated redox homeostasis driven by elevated NOX4-derived ROS signaling underlies fibroblast-to-myofibroblast differentiation in the diseased prostatic stroma. Further, these data indicate the potential clinical value of selenium and/or NOX4 inhibitors in preventing the functional pathogenic changes of stromal cells in BPH and PCa. PMID- 21273446 TI - Plastid stromule branching coincides with contiguous endoplasmic reticulum dynamics. AB - Stromules are stroma-filled tubules extending from plastids whose rapid extension toward or retraction from other plastids has suggested a role in interplastidic communication and exchange of metabolites. Several studies point to sporadic dilations, kinks, and branches occurring along stromule length but have not elucidated the underlying basis for these occurrences. Similarly, although specific details on interacting partners have been missing, a consensus viewpoint suggests that stromules increase the interactive surface of a plastid with its cytoplasmic surroundings. Here, using live imaging, we show that the behavior of dynamic, pleomorphic stromules strongly coincides with that of cortical endoplasmic reticulum (ER) tubules. Covisualization of fluorescent protein highlighted stromules and the ER in diverse cell types clearly suggests correlative dynamics of the two membrane-bound compartments. The extension and retraction, as well as directional changes in stromule branches occur in tandem with the behavior of neighboring ER tubules. Three-dimensional and four dimensional volume rendering reveals that stromules that extend into cortical regions occupy channels between ER tubules possibly through multiple membrane contact sites. Our observations clearly depict coincidental stromule-ER behavior and suggest that either the neighboring ER tubules shape stromules directly or the behavior of both ER and stromules is simultaneously dictated by a shared cytoskeleton-based mechanism. These new observations strongly implicate the ER membrane in interactions with stromules and suggest that their interacting surfaces might serve as major conduits for bidirectional exchange of ions, lipids, and metabolites between the two organelles. PMID- 21273447 TI - Structures of SAS-6 suggest its organization in centrioles. AB - Centrioles are cylindrical, ninefold symmetrical structures with peripheral triplet microtubules strictly required to template cilia and flagella. The highly conserved protein SAS-6 constitutes the center of the cartwheel assembly that scaffolds centrioles early in their biogenesis. We determined the x-ray structure of the amino-terminal domain of SAS-6 from zebrafish, and we show that recombinant SAS-6 self-associates in vitro into assemblies that resemble cartwheel centers. Point mutations are consistent with the notion that centriole formation in vivo depends on the interactions that define the self-assemblies observed here. Thus, these interactions are probably essential to the structural organization of cartwheel centers. PMID- 21273448 TI - The magnitude and duration of Late Ordovician-Early Silurian glaciation. AB - Understanding ancient climate changes is hampered by the inability to disentangle trends in ocean temperature from trends in continental ice volume. We used carbonate "clumped" isotope paleothermometry to constrain ocean temperatures, and thereby estimate ice volumes, through the Late Ordovician-Early Silurian glaciation. We find tropical ocean temperatures of 32 degrees to 37 degrees C except for short-lived cooling by ~5 degrees C during the final Ordovician stage. Evidence for ice sheets spans much of the study interval, but the cooling pulse coincided with a glacial maximum during which ice volumes likely equaled or exceeded those of the last (Pleistocene) glacial maximum. This cooling also coincided with a large perturbation of the carbon cycle and the Late Ordovician mass extinction. PMID- 21273449 TI - Global food supply. Linking policy on climate and food. PMID- 21273450 TI - Microtubule stabilization reduces scarring and causes axon regeneration after spinal cord injury. AB - Hypertrophic scarring and poor intrinsic axon growth capacity constitute major obstacles for spinal cord repair. These processes are tightly regulated by microtubule dynamics. Here, moderate microtubule stabilization decreased scar formation after spinal cord injury in rodents through various cellular mechanisms, including dampening of transforming growth factor-beta signaling. It prevented accumulation of chondroitin sulfate proteoglycans and rendered the lesion site permissive for axon regeneration of growth-competent sensory neurons. Microtubule stabilization also promoted growth of central nervous system axons of the Raphe-spinal tract and led to functional improvement. Thus, microtubule stabilization reduces fibrotic scarring and enhances the capacity of axons to grow. PMID- 21273451 TI - New views on news and research. PMID- 21273458 TI - U.S. science policy. Collins sparks furor with proposed NIH reshuffling. PMID- 21273459 TI - Human evolution. Did modern humans travel out of Africa via Arabia? PMID- 21273460 TI - Epidemiology. Despite sensitivities, scientists seek to solve Haiti's cholera riddle. PMID- 21273461 TI - Eradication. Pressure growing to set a date to destroy remaining smallpox stocks. PMID- 21273462 TI - Primatology. Last-ditch effort to save embattled ape. PMID- 21273463 TI - Cell biology. Telling time without turning on genes. PMID- 21273464 TI - Anthropology. A new view of the birth of Homo sapiens. PMID- 21273465 TI - Anthropology. The species problem. PMID- 21273466 TI - Physiology. Going the distance. PMID- 21273467 TI - Physiology. Treading air. PMID- 21273468 TI - Origins of biodiversity. PMID- 21273469 TI - Genetics-based field studies prioritize safety. PMID- 21273470 TI - Recognizing scientists and technologists. PMID- 21273473 TI - Computer science. Cloud computing--what's in it for me as a scientist? PMID- 21273472 TI - Science education. Defeating creationism in the courtroom, but not in the classroom. PMID- 21273474 TI - Genomics. The genomic view of bacterial diversification. PMID- 21273475 TI - Microbiology. A tail of division. PMID- 21273476 TI - Cell biology. Why starving cells eat themselves. PMID- 21273477 TI - Chemistry. Chemical kinetics under test. PMID- 21273478 TI - SPORE series winner. Penguins and polar bears integrates science and literacy. PMID- 21273479 TI - The newest synthesis: understanding the interplay of evolutionary and ecological dynamics. AB - The effect of ecological change on evolution has long been a focus of scientific research. The reverse--how evolutionary dynamics affect ecological traits--has only recently captured our attention, however, with the realization that evolution can occur over ecological time scales. This newly highlighted causal direction and the implied feedback loop--eco-evolutionary dynamics--is invigorating both ecologists and evolutionists and blurring the distinction between them. Despite some recent relevant studies, the importance of the evolution-to-ecology pathway across systems is still unknown. Only an extensive research effort involving multiple experimental approaches-particularly long-term field experiments--over a variety of ecological communities will provide the answer. PMID- 21273481 TI - Rotational symmetry breaking in the hidden-order phase of URu2Si2. AB - A second-order phase transition is characterized by spontaneous symmetry breaking. The nature of the broken symmetry in the so-called "hidden-order" phase transition in the heavy-fermion compound URu(2)Si(2), at transition temperature T(h) = 17.5 K, has posed a long-standing mystery. We report the emergence of an in-plane anisotropy of the magnetic susceptibility below T(h), which breaks the four-fold rotational symmetry of the tetragonal URu(2)Si(2). Two-fold oscillations in the magnetic torque under in-plane field rotation were sensitively detected in small pure crystals. Our findings suggest that the hidden order phase is an electronic "nematic" phase, a translationally invariant metallic phase with spontaneous breaking of rotational symmetry. PMID- 21273482 TI - High-gain backward lasing in air. AB - The compelling need for standoff detection of hazardous gases and vapor indicators of explosives has motivated the development of a remotely pumped, high gain air laser that produces lasing in the backward direction and can sample the air as the beam returns. We demonstrate that high gain can be achieved in the near-infrared region by pumping with a focused ultraviolet laser. The pumping mechanism is simultaneous resonant two-photon dissociation of molecular oxygen and resonant two-photon pumping of the atomic oxygen fragments. The high gain from the millimeter-length focal zone leads to equally strong lasing in the forward and backward directions. Further backward amplification is achieved with the use of earlier laser spark dissociation. Low-divergence backward air lasing provides possibilities for remote detection. PMID- 21273480 TI - Rapid pneumococcal evolution in response to clinical interventions. AB - Epidemiological studies of the naturally transformable bacterial pathogen Streptococcus pneumoniae have previously been confounded by high rates of recombination. Sequencing 240 isolates of the PMEN1 (Spain(23F)-1) multidrug resistant lineage enabled base substitutions to be distinguished from polymorphisms arising through horizontal sequence transfer. More than 700 recombinations were detected, with genes encoding major antigens frequently affected. Among these were 10 capsule-switching events, one of which accompanied a population shift as vaccine-escape serotype 19A isolates emerged in the USA after the introduction of the conjugate polysaccharide vaccine. The evolution of resistance to fluoroquinolones, rifampicin, and macrolides was observed to occur on multiple occasions. This study details how genomic plasticity within lineages of recombinogenic bacteria can permit adaptation to clinical interventions over remarkably short time scales. PMID- 21273483 TI - Magnetic bistability of molecules in homogeneous solution at room temperature. AB - Magnetic bistability, as manifested in the magnetization of ferromagnetic materials or spin crossover in transition metal complexes, has essentially been restricted to either bulk materials or to very low temperatures. We now present a molecular spin switch that is bistable at room temperature in homogeneous solution. Irradiation of a carefully designed nickel complex with blue-green light (500 nanometers) induces coordination of a tethered pyridine ligand and concomitant electronic rearrangement from a diamagnetic to a paramagnetic state in up to 75% of the ensemble. The process is fully reversible on irradiation with violet-blue light (435 nanometers). No fatigue or degradation is observed after several thousand cycles at room temperature under air. Preliminary data show promise for applications in magnetic resonance imaging. PMID- 21273484 TI - Kinetic isotope effects for the reactions of muonic helium and muonium with H2. AB - The neutral muonic helium atom may be regarded as the heaviest isotope of the hydrogen atom, with a mass of ~4.1 atomic mass units ((4.1)H), because the negative muon almost perfectly screens one proton charge. We report the reaction rate of (4.1)H with (1)H(2) to produce (4.1)H(1)H + (1)H at 295 to 500 kelvin. The experimental rate constants are compared with the predictions of accurate quantum-mechanical dynamics calculations carried out on an accurate Born-Huang potential energy surface and with previously measured rate constants of (0.11)H (where (0.11)H is shorthand for muonium). Kinetic isotope effects can be compared for the unprecedentedly large mass ratio of 36. The agreement with accurate quantum dynamics is quantitative at 500 kelvin, and variational transition-state theory is used to interpret the extremely low (large inverse) kinetic isotope effects in the 10(-4) to 10(-2) range. PMID- 21273485 TI - Enhanced modern heat transfer to the Arctic by warm Atlantic Water. AB - The Arctic is responding more rapidly to global warming than most other areas on our planet. Northward-flowing Atlantic Water is the major means of heat advection toward the Arctic and strongly affects the sea ice distribution. Records of its natural variability are critical for the understanding of feedback mechanisms and the future of the Arctic climate system, but continuous historical records reach back only ~150 years. Here, we present a multidecadal-scale record of ocean temperature variations during the past 2000 years, derived from marine sediments off Western Svalbard (79 degrees N). We find that early-21st-century temperatures of Atlantic Water entering the Arctic Ocean are unprecedented over the past 2000 years and are presumably linked to the Arctic amplification of global warming. PMID- 21273486 TI - The southern route "out of Africa": evidence for an early expansion of modern humans into Arabia. AB - The timing of the dispersal of anatomically modern humans (AMH) out of Africa is a fundamental question in human evolutionary studies. Existing data suggest a rapid coastal exodus via the Indian Ocean rim around 60,000 years ago. We present evidence from Jebel Faya, United Arab Emirates, demonstrating human presence in eastern Arabia during the last interglacial. The tool kit found at Jebel Faya has affinities to the late Middle Stone Age in northeast Africa, indicating that technological innovation was not necessary to facilitate migration into Arabia. Instead, we propose that low eustatic sea level and increased rainfall during the transition between marine isotope stages 6 and 5 allowed humans to populate Arabia. This evidence implies that AMH may have been present in South Asia before the Toba eruption. PMID- 21273487 TI - Effects of experimental seaweed deposition on lizard and ant predation in an island food web. AB - The effect of environmental change on ecosystems is mediated by species interactions. Environmental change may remove or add species and shift life history events, altering which species interact at a given time. However, environmental change may also reconfigure multispecies interactions when both species composition and phenology remain intact. In a Caribbean island system, a major manifestation of environmental change is seaweed deposition, which has been linked to eutrophication, overfishing, and hurricanes. Here, we show in a whole island field experiment that without seaweed two predators--lizards and ants--had a substantially greater-than-additive effect on herbivory. When seaweed was added to mimic deposition by hurricanes, no interactive predator effect occurred. Thus environmental change can substantially restructure food-web interactions, complicating efforts to predict anthropogenic changes in ecosystem processes. PMID- 21273488 TI - Metagenomic discovery of biomass-degrading genes and genomes from cow rumen. AB - The paucity of enzymes that efficiently deconstruct plant polysaccharides represents a major bottleneck for industrial-scale conversion of cellulosic biomass into biofuels. Cow rumen microbes specialize in degradation of cellulosic plant material, but most members of this complex community resist cultivation. To characterize biomass-degrading genes and genomes, we sequenced and analyzed 268 gigabases of metagenomic DNA from microbes adherent to plant fiber incubated in cow rumen. From these data, we identified 27,755 putative carbohydrate-active genes and expressed 90 candidate proteins, of which 57% were enzymatically active against cellulosic substrates. We also assembled 15 uncultured microbial genomes, which were validated by complementary methods including single-cell genome sequencing. These data sets provide a substantially expanded catalog of genes and genomes participating in the deconstruction of cellulosic biomass. PMID- 21273490 TI - Big and mighty: preverbal infants mentally represent social dominance. AB - Human infants face the formidable challenge of learning the structure of their social environment. Previous research indicates that infants have early developing representations of intentional agents, and of cooperative social interactions, that help meet that challenge. Here we report five studies with 144 infant participants showing that 10- to 13-month-old, but not 8-month-old, infants recognize when two novel agents have conflicting goals, and that they use the agents' relative size to predict the outcome of the very first dominance contests between them. These results suggest that preverbal infants mentally represent social dominance and use a cue that covaries with it phylogenetically, and marks it metaphorically across human cultures and languages, to predict which of two agents is likely to prevail in a conflict of goals. PMID- 21273489 TI - Cleavage of NIK by the API2-MALT1 fusion oncoprotein leads to noncanonical NF kappaB activation. AB - Proper regulation of nuclear factor kappaB (NF-kappaB) transcriptional activity is required for normal lymphocyte function, and deregulated NF-kappaB signaling can facilitate lymphomagenesis. We demonstrate that the API2-MALT1 fusion oncoprotein created by the recurrent t(11;18)(q21;q21) in mucosa-associated lymphoid tissue (MALT) lymphoma induces proteolytic cleavage of NF-kappaB inducing kinase (NIK) at arginine 325. NIK cleavage requires the concerted actions of both fusion partners and generates a C-terminal NIK fragment that retains kinase activity and is resistant to proteasomal degradation. The resulting deregulated NIK activity is associated with constitutive noncanonical NF-kappaB signaling, enhanced B cell adhesion, and apoptosis resistance. Our study reveals the gain-of-function proteolytic activity of a fusion oncoprotein and highlights the importance of the noncanonical NF-kappaB pathway in B lymphoproliferative disease. PMID- 21273491 TI - Increased insulin requirements during exercise at very high altitude in type 1 diabetes. AB - OBJECTIVE: Safe, very high altitude trekking in subjects with type 1 diabetes requires understanding of glucose regulation at high altitude. We investigated insulin requirements, energy expenditure, and glucose levels at very high altitude in relation to acute mountain sickness (AMS) symptoms in individuals with type 1 diabetes. RESEARCH DESIGN AND METHODS: Eight individuals with complication-free type 1 diabetes took part in a 14-day expedition to Mount Meru (4,562 m) and Mount Kilimanjaro (5,895 m) in Tanzania. Daily insulin doses, glucose levels, energy expenditure, and AMS symptoms were determined. Also, energy expenditure and AMS symptoms were compared with a healthy control group. RESULTS: We found a positive relation between AMS symptoms and insulin requirements (r = 0.78; P = 0.041) and AMS symptoms and glucose levels (r = 0.86; P = 0.014) for Mount Kilimanjaro. Compared with sea level, insulin doses tended to decrease by 14.2% (19.7) (median [interquartile range]) (P = 0.41), whereas glucose levels remained stable up to 5,000 m altitude. However, at altitudes >5,000 m, insulin dose was unchanged (36.8 +/- 17 vs. 37.6 +/- 19.1 international units [mean +/- SD] P = 0.75), but glucose levels (7.5 +/- 0.6 vs. 9.5 +/- 0.8 mmol/L [mean +/- SD] P = 0.067) and AMS scores (1.3 +/- 1.6 vs. 4.4 +/- 4 points [mean +/- SD] P = 0.091) tended to increase. Energy expenditure and AMS symptoms were comparable in both groups (P = 0.84). CONCLUSIONS: Our data indicate that in complication-free individuals with type 1 diabetes, insulin requirements tend to increase during altitudes above 5,000 m despite high energy expenditure. This change may be explained, at least partly, by AMS. PMID- 21273492 TI - The possible protective role of glucagon-like peptide 1 on endothelium during the meal and evidence for an "endothelial resistance" to glucagon-like peptide 1 in diabetes. AB - OBJECTIVE: Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion. However, GLP-1 also improves endothelial function in diabetes. RESEARCH DESIGN AND METHODS: Sixteen type 2 diabetic patients and 12 control subjects received a meal, an oral glucose tolerance test (OGTT), and two hyperglycemic clamps, with or without GLP-1. The clamps were repeated in diabetic patients after 2 months of strict glycemic control. RESULTS: During the meal, glycemia, nitrotyrosine, and plasma 8-iso prostaglandin F2alpha (8-iso-PGF2a) remained unchanged in the control subjects, whereas they increased in diabetic patients. Flow-mediated vasodilation (FMD) decreased in diabetes, whereas GLP-1 increased in both groups. During the OGTT, an increase in glycemia, nitrotyrosine, and 8-iso-PGF2a and a decrease in FMD were observed at 1 h in the control subjects and at 1 and 2 h in the diabetic patients. In the same way, GLP-1 increased in both groups at the same levels of the meal. During the clamps, in both the control subjects and the diabetic patients, a significant increase in nitrotyrosine and 8-iso-PGF2a and a decrease in FMD were observed, effects that were significantly reduced by GLP-1. After improved glycemic control, hyperglycemia during the clamps was less effective in producing oxidative stress and endothelial dysfunction and the GLP-1 administration was most effective in reducing these effects. CONCLUSIONS: Our data suggest that during the meal GLP-1 can simultaneously exert an incretin effect on insulin secretion and a protective effect on endothelial function, reasonably controlling oxidative stress generation. The ability of GLP-1 in protecting endothelial function seems to depend on the level of glycemia, a phenomenon already described for insulin secretion. PMID- 21273493 TI - Accelerated insulin pharmacokinetics and improved postprandial glycemic control in patients with type 1 diabetes after coadministration of prandial insulins with hyaluronidase. AB - OBJECTIVE: To compare the pharmacokinetics, pharmacodynamics, and safety of insulin lispro or regular human insulin (RHI) with or without recombinant human hyaluronidase (rHuPH20) administered before a standardized meal. RESEARCH DESIGN AND METHODS: In this four-way, crossover study, 22 patients with type 1 diabetes received injections of individually optimized doses of lispro or RHI with and without rHuPH20 before a liquid meal. RESULTS: With rHuPH20 coadministration, early insulin exposure (0-60 min) increased by 54% (P = 0.0011) for lispro and 206% (P < 0.0001) for RHI compared with the respective insulin alone. Peak blood glucose decreased 26 mg/dL for lispro (P = 0.002) and 24 mg/dL for RHI (P = 0.017), reducing hyperglycemic excursions (area under the curve for blood glucose >140 mg/dL) by 79% (P = 0.09) and 85% (P = 0.049), respectively. Rates of hypoglycemia were comparable for lispro with or without rHuPH20, whereas coadministration of RHI and rHuPH20 reduced hypoglycemia. CONCLUSIONS: Lispro or RHI with rHuPH20 produced earlier and greater peak insulin concentrations and improved postprandial glycemic control. PMID- 21273494 TI - Clinical significance of urinary liver-type fatty acid-binding protein in diabetic nephropathy of type 2 diabetic patients. AB - OBJECTIVE: Urinary liver-type fatty acid-binding protein (L-FABP) is a promising indicator of tubular but not glomerular damage. The aim of this study was to evaluate the clinical usefulness of urinary L-FABP as a prognostic biomarker in impaired diabetic nephropathy in type 2 diabetes. RESEARCH DESIGN AND METHODS: This investigation involved a cross-sectional and longitudinal analysis of the relationship between urinary L-FABP levels and progressive nephropathy. Urinary L FABP was measured with enzyme-linked immunosorbent assay. In the cross-sectional analysis, the association of urinary L-FABP, with the severity of diabetic nephropathy, was investigated in 140 patients with type 2 diabetes and in 412 healthy control subjects. Of the patients in the former study, 104 have been followed for 4 years. The progression of diabetic nephropathy was defined as progressive albuminuria, end-stage renal disease, or induction of hemodialysis. RESULTS: Urinary L-FABP levels were progressively increased in subjects with normo-, micro-, or macroalbuminuria and further increased in patients with end stage renal disease. In the longitudinal analysis, high urinary L-FABP levels were associated with the increase in albuminuria, progression to end-stage renal disease, or induction of hemodialysis. This was particularly demonstrated in the subgroup of patients without renal dysfunction (n = 59), where high urinary L FABP levels were associated with the progression of diabetic nephropathy. CONCLUSIONS: Urinary L-FABP accurately reflected the severity of diabetic nephropathy in type 2 diabetes, and its level was high in the patients with normoalbuminuria. Moreover, higher urinary L-FABP was a risk factor for progression of diabetic nephropathy. PMID- 21273495 TI - The cost-effectiveness of personalized genetic medicine: the case of genetic testing in neonatal diabetes. AB - OBJECTIVE: Neonatal diabetes mellitus is a rare form of diabetes diagnosed in infancy. Nearly half of patients with permanent neonatal diabetes have mutations in the genes for the ATP-sensitive potassium channel (KCNJ11 and ABCC8) that allow switching from insulin to sulfonylurea therapy. Although treatment conversion has dramatic benefits, the cost-effectiveness of routine genetic testing is unknown. RESEARCH DESIGN AND METHODS: We conducted a societal cost utility analysis comparing a policy of routine genetic testing to no testing among children with permanent neonatal diabetes. We used a simulation model of type 1 diabetic complications, with the outcome of interest being the incremental cost-effectiveness ratio (ICER, $/quality-adjusted life-year [QALY] gained) over 30 years of follow-up. RESULTS: In the base case, the testing policy dominated the no-testing policy. The testing policy was projected to bring about quality-of life benefits that enlarged over time (0.32 QALYs at 10 years, 0.70 at 30 years) and produced savings in total costs that were present as early as 10 years ($12,528 at 10 years, $30,437 at 30 years). Sensitivity analyses indicated that the testing policy would remain cost-saving as long as the prevalence of the genetic defects remained >3% and would retain an ICER <$200,000/QALY at prevalences between 0.7 and 3%. CONCLUSIONS: Genetic testing in neonatal diabetes improves quality of life and lowers costs. This paradigmatic case study highlights the potential economic impact of applying the concepts of personalized genetic medicine to other disorders in the future. PMID- 21273496 TI - The 25-year cumulative incidence of lower extremity amputations in people with type 1 diabetes. AB - OBJECTIVE: To examine the 25-year cumulative incidence of lower-extremity amputation (LEA) in people with type 1 diabetes. RESEARCH DESIGN AND METHODS: Cumulative incidence of LEA was ascertained in Wisconsin Epidemiologic Study of Diabetic Retinopathy participants (n = 943) using the Kaplan-Meier approach accounting for competing risk of death. Relationships of baseline characteristics with incidence of LEA were explored using a proportional hazards approach with discrete linear regression modeling. RESULTS: The overall 25-year incidence of LEA was 10.1%. In multivariate analyses (results reported as odds ratio; 95% CI), being male (3.90; 2.29-6.65), heavy smoking (2.07; 1.11-3.85), having hypertension (3.36; 1.91-5.93), diabetic retinopathy (2.62; 1.13-6.09), neuropathy (1.68; 1.02-2.76), and higher HbA(1c) (per 1% 1.40; 1.24-1.58) were independently associated with the incidence of LEA. CONCLUSIONS: Our results show a high 25-year incidence of LEA and suggest that glycemic control and blood pressure control and preventing heavy smoking may result in reduction in its incidence. PMID- 21273497 TI - Underdiagnosed and undertreated depression among racially/ethnically diverse patients with type 2 diabetes. AB - OBJECTIVE: To examine racial/ethnic differences in the prevalence of depressive symptoms and in provider recognition of depression among Latino, Asian, and non Hispanic white patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Patients (n = 1,209) with type 2 diabetes were recruited from five university affiliated primary care clinics for an observational study. RESULTS: Vietnamese American (133, 59.4%) and Mexican American (351, 50.2%) patients were more likely to report symptoms consistent with clinical depression (Center for Epidemiological Studies Depression [CES-D] scale score >= 22) than non-Hispanic whites (119, 41.6%; F [2, 1206] = 8.05, P < 0.001). Despite comparable diabetes care, Vietnamese and Mexican patients with high depressive symptoms were less likely to be diagnosed and treated than non-Hispanic whites (all P values < 0.001). Minority patients who reported low levels of trust in their provider were less likely to have been diagnosed or treated for depression (adjusted odds ratio 0.65, 95% CI 0.44-0.98, P < 0.05). CONCLUSIONS: Innovative strategies are needed to improve recognition of depressive symptoms in minority patients. PMID- 21273498 TI - Associations between concentrations of vitamin D and concentrations of insulin, glucose, and HbA1c among adolescents in the United States. AB - OBJECTIVE: Our objective was to examine the associations between concentrations of vitamin D and concentrations of insulin, glucose, and HbA(1c) in a nationally representative sample of adolescents in the U.S. RESEARCH DESIGN AND METHODS: We used data for 1,941 adolescents, aged 12-17 years, who participated in the National Health and Nutrition Examination Survey between 2001 and 2006. RESULTS: Adjusted concentrations of insulin were ~24% lower among male subjects with a concentration of vitamin D >= 75 nmol/L than among male subjects with a concentration of vitamin D <50 nmol/L (P = 0.003). Concentrations of vitamin D were inversely associated with concentrations of glucose only among Mexican American male subjects (P = 0.007). No significant associations between concentrations of vitamin D and HbA(1c) were detected. CONCLUSIONS: Our results support an inverse association between concentrations of vitamin D and insulin primarily in adolescent male subjects. PMID- 21273499 TI - Diabetes and risk of prostate cancer: a study using the National Health Insurance. AB - OBJECTIVE: The link between diabetes and prostate cancer is rarely studied in Asians. RESEARCH DESIGN AND METHODS: The trend of age-standardized prostate cancer incidence in 1995-2006 in the Taiwanese general population was calculated. A random sample of 1,000,000 subjects covered by the National Health Insurance in 2005 was recruited. A total of 494,630 men for all ages and 204,741 men >= 40 years old and without prostate cancer at the beginning of 2003 were followed to the end of 2005. Cumulative incidence and risk ratio between diabetic and nondiabetic men were calculated. Logistic regression estimated the adjusted odds ratios for risk factors. RESULTS: The trend of prostate cancer incidence increased significantly (P < 0.0001). The cumulative incidence markedly increased with age in either the diabetic or nondiabetic men. The respective risk ratio (95% CI) for all ages and age 40-64, 65-74, and >= 75 years was 5.83 (5.10-6.66), 2.09 (1.60-2.74), 1.35 (1.07-1.71), and 1.39 (1.12-1.71). In logistic regression for all ages or for age >= 40 years, age, diabetes, nephropathy, ischemic heart disease, dyslipidemia, living region, and occupation were significantly associated with increased risk, but medications including insulin and oral antidiabetic agents were not. CONCLUSIONS: Prostate cancer incidence is increasing in Taiwan. A positive link between diabetes and prostate cancer is observed, which is more remarkable in the youngest age of 40-64 years. The association between prostate cancer and comorbidities commonly seen in diabetic patients suggests a more complicated scenario in the link between prostate cancer and diabetes at different disease stages. PMID- 21273500 TI - Consumption of sugar-sweetened beverages among adults with type 2 diabetes. AB - OBJECTIVE: To examine patterns of sugar-sweetened beverage (SSB) consumption among U.S. adults with type 2 diabetes in 2003-2006. RESEARCH DESIGN AND METHODS: We analyzed 24-h dietary recall data from the National Health and Nutrition Examination Survey 2003-2006 to estimate SSB consumption levels among 1,090 adults (aged >= 20 years) with type 2 diabetes overall and by diagnosis and control status of their diabetes. RESULTS: In 2003-2006, 45% of adults with diabetes consumed SSBs on a given day, obtaining an average of 202 calories and 47 g of sugar. Undiagnosed adults with diabetes were significantly more likely to consume SSBs than diagnosed adults (60 vs. 38% diagnosed/uncontrolled [P < 0.001] and 43% diagnosed/controlled [P = 0.001]) and were less likely to consume diet beverages (18 vs. 50% diagnosed/uncontrolled [P < 0.001] and 40% diagnosed/controlled [P < 0.001]). Men consumed significantly more SSBs than women (P = 0.027), younger adults (aged 20-44) more than older adults (45-64 and >= 65; P < 0.001), non-Hispanic black more than whites (P = 0.010); and low income individuals (quartile 1) more than higher-income individuals (quartile 3, P = 0.040; quartile 4, P = 0.013). For most demographic and body weight categories, adults who were undiagnosed consumed more sugar from SSBs than adults who were diagnosed. CONCLUSIONS: SSB consumption is high among adults with diabetes, particularly among those who are undiagnosed. PMID- 21273501 TI - Social activity and depressive symptoms in Korean American older adults: the conditioning role of acculturation. AB - OBJECTIVE: This study examined the independent and interactive effects of acculturation and social activity on depressive symptoms. METHOD: Using a sample of community-dwelling Korean American older adults (N = 675), hierarchical regression models of depressive symptoms were estimated with an array of predictors: (a) demographic variables, (b) health-related variables, (c) acculturation, (d) social activity, and (e) an interaction between acculturation and social activity. RESULTS: After controlling for the effects of demographic and health-related variables, both acculturation and social activity were identified as significant predictors. Moreover, their interaction was significant (beta = .09, p < .05). Further analysis showed that the beneficial effect of social activity on mental health was particularly strong among those with lower levels of acculturation. DISCUSSION: Our findings suggest that enhancing opportunities for social engagement may serve to protect and promote the mental health of vulnerable older immigrants, particularly those who are less acculturated. PMID- 21273502 TI - Socioeconomic status, marital status continuity and change, marital conflict, and mortality. AB - OBJECTIVE: The authors investigated (a) whether being continuously married compared with other marital status trajectories over 5 years attenuates the adverse effects of lower education and lower income on longevity, (b) whether being in higher conflict as well as lower conflict marriage compared with being single provides a buffer against socioeconomic status inequalities in mortality, and (c) whether the conditional effects of marital factors on the SES-mortality association vary by gender. METHOD: The authors estimated logistic regression models with data from adults aged 30 or above who participated in the National Survey of Families and Households 1987- 2002. RESULTS: Being continuously married, compared with being continuously never married or making a transition to separation/divorce, buffered mortality risks among men with low income. Mortality risk for low-income men was also lower in higher conflict marriages compared with being never married or previously married. DISCUSSION: Marriage ameliorates mortality risks for some low-income men. PMID- 21273503 TI - Negative effect of increased body weight on sperm conventional and nonconventional flow cytometric sperm parameters. AB - Although with some discrepancy, obese men have been reported to have the worst conventional sperm parameters, but little is known about the effects of body weight on sperm mitochondrial function, chromatin condensation and apoptosis. This study was undertaken to evaluate conventional and nonconventional sperm parameters in nonsmoking overweight or obese men without any other cause known to alter sperm parameters. Fifty overweight, 50 obese, and 50 normal-weight healthy nonsmoking men were carefully selected. Each man underwent up to 2 sperm analyses and evaluation of mitochondrial membrane potential (MMP), phosphatidylserine (PS) externalization, chromatin compactness, and DNA fragmentation by flow cytometry. Overweight and obese men had significantly lower sperm progressive motility and normal forms than controls. They also had a significantly higher percentage of spermatozoa with low MMP. Obese, but not overweight, men showed a significantly higher percentage of spermatozoa with PS externalization, an early sign of apoptosis, and a lower percentage of viable spermatozoa. A significant increased percentage of spermatozoa with abnormal chromatin compactness was found in both overweight and obese men, whereas only obese men had a significantly higher number of spermatozoa with DNA fragmentation compared with controls. Healthy nonsmoking overweight and obese men have worse conventional and nonconventional sperm parameters than normal weight controls. The important role played by these parameters in a couple's fertility suggests a program of body weight loss among the therapeutic repertoire for male infertility. PMID- 21273504 TI - Local expression of epidermal growth factor-like growth factors in human testis and its role in spermatogenesis. AB - Microdissection testicular sperm extraction (micro-TESE) has revealed that spermatogenesis in nonobstructive azoospermia (NOA) patients is heterogeneous, even in the same testis, but there is no information regarding growth factors to support spermatogenesis. We investigated the involvement of epidermal growth factor (EGF)-like growth factors, which play important roles in cell proliferation and differentiation in NOA patients who underwent micro-TESE. Testicular samples were obtained from 5 fertile men (15 samples), 5 prostate cancer patients receiving maximum androgen blockade (10 samples), and 13 NOA patients who underwent micro-TESE (50 samples). The expression of the mRNA for EGF, heparin binding (HB)-EGF, amphiregulin, epiregulin, betacellulin, and transforming growth factor (TGF)-alpha were analyzed by real-time polymerase chain reaction analysis and adjusted using the expression of glyceraldehyde-3 phosphate dehydrogenase. Heterogeneous expression of these EGF-like growth factors were observed even in the same testis. The expression of HB-EGF, amphiregulin and TGF-alpha in NOA and prostate cancer patients was significantly lower than observed in fertile controls. In NOA patients, expression in the testicular sample comprising mature sperm was significantly higher than those without mature sperm, indicating that HB-EGF, amphiregulin, and TGF-alpha are considered to participate in creating a suitable niche for spermatogenesis. Considering the findings that ablation of gonadotropin inhibited and human chorionic gonadotropin stimulation increased these EGF-like growth factors, the expressions are presumably under gonadotropin regulation. PMID- 21273505 TI - On the role of frustration in the energy landscapes of allosteric proteins. AB - Natural protein domains must be sufficiently stable to fold but often need to be locally unstable to function. Overall, strong energetic conflicts are minimized in native states satisfying the principle of minimal frustration. Local violations of this principle open up possibilities to form the complex multifunnel energy landscapes needed for large-scale conformational changes. We survey the local frustration patterns of allosteric domains and show that the regions that reconfigure are often enriched in patches of highly frustrated interactions, consistent both with the idea that these locally frustrated regions may act as specific hinges or that proteins may "crack" in these locations. On the other hand, the symmetry of multimeric protein assemblies allows near degeneracy by reconfiguring while maintaining minimally frustrated interactions. We also anecdotally examine some specific examples of complex conformational changes and speculate on the role of frustration in the kinetics of allosteric change. PMID- 21273506 TI - Primary cilia membrane assembly is initiated by Rab11 and transport protein particle II (TRAPPII) complex-dependent trafficking of Rabin8 to the centrosome. AB - Sensory and signaling pathways are exquisitely organized in primary cilia. Bardet Biedl syndrome (BBS) patients have compromised cilia and signaling. BBS proteins form the BBSome, which binds Rabin8, a guanine nucleotide exchange factor (GEF) activating the Rab8 GTPase, required for ciliary assembly. We now describe serum regulated upstream vesicular transport events leading to centrosomal Rab8 activation and ciliary membrane formation. Using live microscopy imaging, we show that upon serum withdrawal Rab8 is observed to assemble the ciliary membrane in ~100 min. Rab8-dependent ciliary assembly is initiated by the relocalization of Rabin8 to Rab11-positive vesicles that are transported to the centrosome. After ciliogenesis, Rab8 ciliary transport is strongly reduced, and this reduction appears to be associated with decreased Rabin8 centrosomal accumulation. Rab11 GTP associates with the Rabin8 COOH-terminal region and is required for Rabin8 preciliary membrane trafficking to the centrosome and for ciliogenesis. Using zebrafish as a model organism, we show that Rabin8 and Rab11 are associated with the BBS pathway. Finally, using tandem affinity purification and mass spectrometry, we determined that the transport protein particle (TRAPP) II complex associates with the Rabin8 NH(2)-terminal domain and show that TRAPP II subunits colocalize with centrosomal Rabin8 and are required for Rabin8 preciliary targeting and ciliogenesis. PMID- 21273507 TI - Bilateral perisylvian polymicrogyria with cerebellar dysplasia and ectopic neurohypophysis. AB - Polymicrogyria (involving or not the sylvian scissure) with cerebellar cortical dysplasia or vermis hypoplasia has been reported in few cases. In addition, the association between ectopic neurohypophysis and other cortical malformations, including bilateral perisylvian polymicrogyria, has been documented. We describe a girl affected by focal epilepsy since the age of 2 years. Magnetic resonance imaging (MRI) at 11 and 22 years of age showed bilateral perisylvian polymicrogyria, dysplasia of the left cerebellar hemisphere, and ectopic neurohypophysis. Genetic tests, including fluorescent in situ hybridization 22q11.2 and array-comparative genomic hybridization, and pituitary hormones (at the age of 20 years) were normal. The patient is now 22 years old, and she is seizure free under therapy with lamotrigine and levetiracetam. To the best of our knowledge, this is the first description of this complex cerebral malformation. This finding confirms that bilateral perisylvian polymicrogyria can be associated with other cerebral malformations; cerebellum and neurohypophysis must be carefully evaluated in patients with polymicrogyria. PMID- 21273508 TI - An unusual presentation of copper metabolism disorder and a possible connection with Niemann-Pick type C. AB - Abnormal copper metabolism has been linked with neurological disorders, such as Wilson and Menkes disease. Another disorder causing symptoms similar to copper metabolism disorder is Niemann-Pick type C. However, a definite pathophysiological connection between Niemann-Pick type C and copper metabolism disorders has never been established. The authors present an adolescent with an unusual presentation of copper deficiency-dysarthria, ataxia, and vertical gaze paresis, without significant cognitive degeneration or pathological magnetic resonance imaging (MRI). The patient was found to carry 2 mutations in the NPC1 gene. A possible link, explaining how copper deficiency might induce the Niemann Pick phenotype might involve overproduction of cholesterol and inhibition of acid sphingomyelinase. We suggest that copper metabolism disorders be included in the differential diagnosis for ataxia and dysarthria, even in cases with unusual presentations. Moreover, should the connection between copper and Niemann-Pick be validated, screening for copper metabolism disorders may be advisable in Niemann Pick type C patients and vice-versa. PMID- 21273509 TI - Plasma N-glycan profiling by mass spectrometry for congenital disorders of glycosylation type II. AB - BACKGROUND: Determination of the genetic defect in patients with a congenital disorder of glycosylation (CDG) is challenging because of the wide clinical presentation, the large number of gene products involved, and the occurrence of secondary causes of underglycosylation. Transferrin isoelectric focusing has been the method of choice for CDG screening; however, improved methods are required for the molecular diagnosis of patients with CDG type II. METHODS: Plasma samples with a typical transferrin isofocusing profile were analyzed. N-glycans were released from these samples by PNGase F [peptide-N4-(acetyl-beta-glucosaminyl) asparagine amidase] digestion, permethylated and purified, and measured on a MALDI linear ion trap mass spectrometer. A set of 38 glycans was used for quantitative comparison and to establish reference intervals for such glycan features as the number of antennae, the level of truncation, and fucosylation. Plasma N-glycans from control individuals, patients with known CDG type II defects, and patients with a secondary cause of underglycosylation were analyzed. RESULTS: CDGs due to mannosyl (alpha-1,6-)-glycoprotein beta-1,2-N acetylglucosaminyltransferase (MGAT2), beta-1,4-galactosyltransferase 1 (B4GALT1), and SLC35C1 (a GDP-fucose transporter) defects could be diagnosed directly from the N-glycan profile. CDGs due to defects in proteins involved in Golgi trafficking, such as subunit 7 of the conserved oligomeric Golgi complex (COG7) and subunit V0 a2 of the lysosomal H(+)-transporting ATPase (ATP6V0A2) caused a loss of triantennary N-glycans and an increase of truncated structures. Secondary causes with liver involvement were characterized by increased fucosylation, whereas the presence of plasma sialidase produced isolated undersialylation. CONCLUSIONS: MALDI ion trap analysis of plasma N-glycans documents features that discriminate between primary and secondary causes of underglycosylation and should be applied as the first step in the diagnostic track of all patients with an unsolved CDG type II. PMID- 21273510 TI - Prognosis and prognostic factors of the micropapillary pattern in patients treated for stage II and III serous borderline tumors of the ovary. AB - BACKGROUND: To determine the prognosis of a micropapillary (MP) pattern in patients with stage II and stage III serous borderline tumor of the ovary (SBOT). METHODS: Review of patients with stage II and stage III SBOT treated or referred to our institution with characterization of an MP pattern and its clinical impact. RESULTS: In 1969-2006, 168 patients were reviewed. Fifty-six patients had SBOT-MP. The rate of conservative surgery was lower in the SBOT-MP group than in the typical SBOT group, but the rate of patients with more than three peritoneal sites with implants was higher in the SBOT-MP group. The rate of invasive implants was not statistically different between the two groups. Eighteen recurrences were observed (six of them in the form of invasive disease) in the SBOT-MP group. Only one death was observed. The overall survival times and recurrence-free intervals were similar in both groups. The only prognostic factor for recurrence in the SBOT-MP group was the use of conservative surgery. CONCLUSIONS: In the present series, an MP pattern doesn't appear to signify a poor prognosis. The only prognostic factor for recurrence in SBOT-MP was the use of conservative surgery. Further studies on the MP pattern are needed to evaluate prognosis and the results of conservative surgery. PMID- 21273511 TI - Management of skin toxicity associated with cetuximab treatment in combination with chemotherapy or radiotherapy. AB - BACKGROUND: Cetuximab was demonstrated by clinical trials to improve response rate and survival of patients with metastatic and nonresectable colorectal cancer or carcinoma of the head and neck. Appropriate management of skin toxicity associated with epidermal growth factor receptor inhibitor (EGFR-i) therapy is necessary to allow adequate drug administration and to improve quality of life and outcomes. METHODS: A group of Italian Experts produced recommendations for skin toxicity management using the RAND/UCLA Appropriateness Method. Statements were generated on the basis of a systematic revision of the literature and voted twice by a panel of 40 expert physicians; the second vote was preceded by a meeting of the panelists. RESULTS: Skin toxicity included skin rash, skin dryness, pruritus, paronychia, hair abnormality, and mucositis. Recommendations for prophylaxis and therapeutic interventions for each type of toxicity were proposed. CONCLUSIONS: Interventions that were considered appropriate to improve compliance and outcomes of cancer patients treated with EGFR-i were identified. PMID- 21273512 TI - Accurate classification of metastatic brain tumors using a novel microRNA-based test. AB - BACKGROUND: Identification of the tissue of origin of a brain metastatic tumor is vital to its management. Carcinoma of unknown primary (CUP) is common in oncology, representing 3%-5% of all invasive malignancies. We aimed to validate a recently developed microRNA-based quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) test for identifying the tumor tissue of origin, first in a consecutive cohort of metastatic tumors of known origin and then in a cohort of CUP cases resected from the central nervous system (CNS). PATIENTS AND METHODS: One hundred two resected CNS metastatic tumors with known origin, previously classified based on the patient's clinical history and pathological data, as well as a second cohort of resected CNS tumors from 57 patients originally diagnosed as CUP were studied. A qRT-PCR diagnostic assay that measures the expression level of 48 microRNAs was used to classify the tissue of origin of these metastatic tumors. RESULTS: In this blinded study, the test predictions correctly identified the reference diagnosis of the samples of known origin, excluding samples from prostate origin, in 84% of cases. In the second CUP patient cohort, the test prediction was in agreement with the diagnosis that was later confirmed clinically or with pathological evaluation in 80% of cases. CONCLUSION: In a cohort of brain and spinal metastases, a previously developed test based on the expression of 48 microRNAs allowed accurate identification of the tumor tissue of origin in the majority of cases. The high accuracy of this test in identifying the tissue of origin of metastases of unknown primary is demonstrated for the first time and may have broad clinical application. PMID- 21273513 TI - Micropapillary pattern in newly diagnosed borderline tumors of the ovary: what's in a name? PMID- 21273514 TI - Report of a phase II study of clofarabine and cytarabine in de novo and relapsed and refractory AML patients and in selected elderly patients at high risk for anthracycline toxicity. AB - PURPOSE: To determine the efficacy and safety of clofarabine and cytarabine (Ara C) in adult patients with relapsed or refractory acute myeloid leukemia (AML) and in elderly patients with untreated AML and heart disease. PATIENTS AND METHODS: Patients with relapsed/refractory AML and older patients for whom there was a concern over toxicity from additional anthracyclines received 5 days of clofarabine, 40 mg/m(2) per day i.v. over 1 hour, followed 4 hours later by Ara C, 1,000 mg/m(2) per day i.v. over 2 hours. RESULTS: Thirty patients were enrolled. The median age was 67 years (range, 38-82 years) and 18 (60%) had received at least one prior therapy. Eleven (37%) patients had a history of cardiovascular disease and were considered to be at high risk for anthracycline toxicity. High-risk cytogenetic abnormalities were present in 14 (47%) patients. The overall response rate (complete remission [CR] plus partial remission) was 53%, including a CR in 14 patients (47%). Responses were observed in all cytogenetic risk groups and in patients who had received up to five prior therapies. The median disease-free survival interval was 9.5 months. The 30-day mortality rate was 20% (de novo AML, 8%; relapsed/refractory AML, 28%). Of the 14 patients achieving a CR, half were able to proceed to curative hematopoietic stem cell transplantation. CONCLUSIONS: Clofarabine in combination with Ara-C is effective in both untreated and previously treated patients with AML. In addition, it represents a useful remission induction strategy to serve as a bridge to transplantation in older patients with AML. PMID- 21273515 TI - Teaching nutrition integration: MUST screening in cancer. AB - RATIONALE: Nutritional risk screening should be routine in order to select patients in need of nutrition care; this conduct change has to rely on education. In this project, radiotherapy department health professionals were trained on how to use the Malnutrition Universal Screening Tool (MUST), to foster its integration into cancer outpatient management; we also aimed to identify those more adherent to screening. METHODS: Research dieticians (the standard) conducted interactive sessions with all physicians, nurses, and radiotherapy (RT) technicians, who were closely supervised to facilitate routine MUST integration. There were two phases: after the first session, phase 1 assessed 200 patients over 4 months; after the second session, phase 2 screened 450 patients, always before RT. Validity was evaluated comparing results from the standard against all other health professionals, adjusted for number. RESULTS: RT technicians were most adherent to the MUST: 80% of patients in phase 1, increasing to 85% in phase 2. Nurses doubled their input, from 19% to 36%. Physicians had poor MUST integration, yet they progressively incorporated percentage weight loss into patient records, increasing from 57% in phase 1 to 84% in phase 2, independently of diagnosis and stage. The highest concordance (kappa coefficient) with dieticians was found with RT technicians' use of the MUST (p < .002) and percentage weight loss determination by physicians (p < .001). CONCLUSIONS: We show that systematic screening in cancer is feasible by all professionals involved, once a proximity teaching project is put into practice. RT technicians, who daily treat patients, were highly adherent to integrate the MUST and might be in charge of selecting at-risk patients. Physicians are unlikely to use the MUST, but acknowledged nutrition value and changed their routine by integrating recent percentage weight loss into their approach to patients. Our structured methodology may be used as a model for the development of teaching adapted to different departments with other realities. PMID- 21273516 TI - Science to practice: Will Gadolinium--enhanced MR imaging be useful in assessment of at-risk pregnancies? PMID- 21273517 TI - Coronary CT versus MR angiography: pro CT--the role of CT angiography. PMID- 21273518 TI - Coronary CT versus MR angiography: the role of MR angiography. PMID- 21273519 TI - Principles of and advances in percutaneous ablation. AB - Image-guided tumor ablation with both thermal and nonthermal sources has received substantial attention for the treatment of many focal malignancies. Increasing interest has been accompanied by continual advances in energy delivery, application technique, and therapeutic combinations with the intent to improve the efficacy and/or specificity of ablative therapies. This review outlines clinical percutaneous tumor ablation technology, detailing the science, devices, techniques, technical obstacles, current trends, and future goals in percutaneous tumor ablation. Methods such as chemical ablation, cryoablation, high-temperature ablation (radiofrequency, microwave, laser, and ultrasound), and irreversible electroporation will be discussed. Advances in technique will also be covered, including combination therapies, tissue property modulation, and the role of computer modeling for treatment optimization. PMID- 21273520 TI - Reduction in false-positive results after introduction of digital mammography: analysis from four population-based breast cancer screening programs in Spain. AB - PURPOSE: To evaluate the effect of the introduction of digital mammography on the recall rate, detection rate, false-positive rate, and rates of invasive procedures in a cohort of women from four population-based breast cancer screening programs in Spain. MATERIALS AND METHODS: The study was approved by the ethics committee; informed consent was not required. A total of 242,838 mammograms (171,191 screen film [screen-film mammography group] and 71,647 digital [digital mammography group]) obtained in 103,613 women aged 45-69 years were included. False-positive results for any additional procedure and for invasive procedures, the breast cancer rate, and the positive predictive value in each group were compared by using Pearson chi(2) test. The effect of the mammographic technology used (screen-film or digital) on the false-positive results and cancer detection risk was evaluated with multivariate logistic regression models, adjusted according to women's and the screening program's characteristics and time trends. RESULTS: The false-positive rate was higher for screen-film than for digital mammography (7.6% and 5.7%, respectively; P < .001). False-positive results after an invasive procedure were significantly higher for screen-film than for digital mammography (1.9% and 0.7%, respectively; P < .001). No significant differences were observed in the overall cancer detection rate between the two groups (0.45% and 0.43% in the screen-film and digital mammography groups, respectively; P = .59). The adjusted risk of a false-positive result was higher for screen-film than for digital mammography (odds ratio = 1.32). The adjusted risk was also lower for the digital mammography group when time trends were taken into account. CONCLUSION: The lower false-positive risk with use of digital mammography should be taken into account when balancing the risks and benefits of breast cancer screening. PMID- 21273521 TI - Globalization of P4 medicine: predictive, personalized, preemptive, and participatory--summary of the proceedings of the Eighth International Symposium of the International Society for Strategic Studies in Radiology, August 27-29, 2009. AB - In August 2009, the International Society for Strategic Studies in Radiology held its eighth biennial meeting. The program focused on the globalization of predictive medicine--or P4 medicine--as it relates to the practice of radiology and radiology research. P4 medicine refers to predictive, personalized, preemptive, and participatory medicine and was the inspiration of Elias Zerhouni, MD, former director of the National Institutes of Health. This article is a summary of some of the key concepts presented at the meeting by an international group of radiologists, imaging scientists, and leaders of industry. In predictive medicine, imaging and imaging-related technologies will likely play an increasing role in the early detection of disease and, thus, the preemption of the development of advanced, hard-to-treat disease. Research into systems biology and molecular imaging promises to personalize medicine, facilitating the provision of the right care to the right patient at the right time. In participatory medicine, increasing interactions with referring physicians and patients will be helpful in raising awareness and recognition of the role of radiologists and will have a positive effect on professionalism. There is also a need to increase awareness of the vital role of radiologists as imaging and radiation safety experts who evaluate the necessity and appropriateness of examinations, monitor performance quality, and are available for postexamination consultations. PMID- 21273522 TI - Differentiation of malignant and benign pulmonary nodules with quantitative first pass 320-detector row perfusion CT versus FDG PET/CT. AB - PURPOSE: To prospectively compare the capability of quantitative first-pass perfusion 320-detector row computed tomography (CT) (ie, area-detector CT) with that of combined positron emission tomography and CT (PET/CT) for differentiation between malignant and benign pulmonary nodules. MATERIALS AND METHODS: This prospective study was approved by the institutional review board, and written informed consent was obtained from 50 consecutive patients with 76 pulmonary nodules. All patients underwent dynamic area-detector CT, PET/CT, and microbacterial and/or histopathologic examinations. All pulmonary nodules were divided into three groups: malignant nodules (n = 43), benign nodules with low biologic activity (n = 6), and benign nodules with high biologic activity (n = 27). For each dynamic area-detector CT data set, the perfusion derived by using the maximum slope model (PF(MS)), extraction fraction derived by using the Patlak plot model (EF(PP)), and blood volume derived by using the Patlak plot model (BV(PP)) were calculated. These parameters were statistically compared among the three nodule groups. Receiver operating characteristic (ROC) analyses were used to compare the diagnostic capability of the CT and PET/CT indexes. Finally, the sensitivity, specificity, and accuracy of each index were compared by using the McNemar test. RESULTS: All indexes in the malignant nodule group were significantly different from those in the low-biologic-activity benign nodule group (P < .05). Areas under the ROC curve for PF(MS) and EF(PP) were significantly larger than those for BV(PP) (P < .05) and maximal standard uptake value (SUV(max)) (P < .05). The specificity and accuracy of PF(MS) and EF(PP) were significantly higher than those of BV(PP) and SUV(max) (P < .05). CONCLUSION: Dynamic first-pass area-detector perfusion CT has the potential to be more specific and accurate than PET/CT for differentiating malignant from benign pulmonary nodules. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100245/-/DC1. PMID- 21273523 TI - Liver fibrosis in patients with chronic hepatitis C: noninvasive diagnosis by means of real-time tissue elastography--establishment of the method for measurement. AB - PURPOSE: To prospectively measure liver stiffness with real-time tissue elastography in patients with chronic hepatitis C and to compare the results with those of clinical assessment of fibrosis by using histologic stage as the reference standard. MATERIALS AND METHODS: All subjects gave informed consent, and the study was approved by the institutional ethics committee. Seventy hospitalized patients (46 men, 24 women; mean age, 65.5 years +/- 11.7 [standard deviation]; age range, 33-87 years) with chronic hepatitis C underwent real-time elastography between January 2009 and September 2009. Elastography was performed at four liver locations by two independent observers. The elastic ratio (ratio of the value in the intrahepatic venous small vessels divided by the value in the hepatic parenchyma) was calculated and was compared with histologic fibrosis stage at liver biopsy. The elastic ratio and clinical fibrosis markers were assessed by using receiver operating characteristic (ROC) analysis. The differences between body site and observers were assessed with kappa statistics and intraclass correlation coefficients (ICCs). RESULTS: Real-time tissue elastography cutoff values were 2.73 for F of 2 or greater, 3.25 for F of 3 or greater, and 3.93 for F of 4. No site differences were observed (kappa = 0.835, ICC = 0.966), and the elastic ratio measurement was correlated between the two examiners (r(2) = 0.869, P < .0001). The areas under the ROC curves for elastic ratio, hyaluronic acid, type IV collagen, aspartate aminotransferase-to-platelet ratio index, FibroIndex, Forns score, and Hepascore were 0.95, 0.32, 0.73, 0.76, 0.76, 0.87, and 0.70, respectively; the elastic ratio performed better than the serum fibrosis markers and other scores. CONCLUSION: Real-time tissue elastography is not invasive and could be used to evaluate liver fibrosis in patients with chronic hepatitis C. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100319/-/DC1. PMID- 21273524 TI - Transarterial chemoembolization can be safely performed in patients with hepatocellular carcinoma invading the main portal vein and may improve the overall survival. AB - PURPOSE: To determine the efficacy and safety of transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC) and main portal vein (MPV) invasion. MATERIALS AND METHODS: This study was approved by the institutional review board, and the requirement to obtain informed consent was waived. The authors retrospectively assessed the electronic medical records of patients in whom HCC with MPV invasion was newly diagnosed from January 2004 to December 2007 at a single tertiary medical center. Patients with decompensated hepatic function were excluded. Outcomes of patients treated with TACE were compared with those of patients given supportive care according to Child-Pugh class. RESULTS: One hundred twenty-five patients (104 men and 21 women; mean age, 55.7 years; age range, 33.4-83.0 years) were included. The median overall survival was 3.7 months (range, 0.2-33.3 months). Eighty-three of the 125 patients (66.4%) were treated with TACE and 42 (33.6%) received supportive care. Repeated TACE showed significant survival benefits compared with supportive care in patients with Child-Pugh class A (median survival, 7.4 months vs 2.6 months, respectively; P < .001) and class B (median survival, 2.8 months vs 1.9 months, respectively; P = .002) disease. Results of multivariate analysis showed that treatment with TACE (hazard ratio, 0.263; 95% confidence interval [CI]: 0.164, 0.424; P < .001) and Child-Pugh class A status (hazard ratio, 0.550; 95% CI: 0.368, 0.822; P = .004) were independent predictive factors of a favorable outcome. There were no procedure-related deaths within 4 weeks after TACE, and patient morbidity was 28.9% (24 of 83 patients). CONCLUSION: TACE can be performed safely and may improve the overall survival of patients with HCC and MPV invasion. PMID- 21273525 TI - Pulmonary radiofrequency ablation in patients with a single lung: feasibility, efficacy, and tolerance. AB - PURPOSE: To evaluate the feasibility, efficacy, and tolerance of pulmonary radiofrequency (RF) ablation for the treatment of lung tumors in patients with a single lung. MATERIALS AND METHODS: This was a retrospective study from four institutions, with waiver of institutional review board approval and of informed consent. From July 2003 to March 2009, 15 single-lung patients (nine men and six women; mean age, 64 years; age range, 42-82 years) with one to three lung tumors underwent 16 sessions of RF ablation. One patient underwent two sessions due to occurrence of new tumors. Eleven patients had primary lung cancer and four patients had metastases. The previous pneumonectomy was performed for the treatment of primary or secondary lung tumors. Twenty-one tumors measuring 4-37 mm (mean, 15.5 mm +/- 8 [standard deviation]) were treated. All procedures were performed by using general anesthesia with intubation. Electrodes were expandable in 13 procedures and straight in three. The efficacy was evaluated with computed tomography (CT) or positron emission tomography (PET)/CT, performed 3, 6, 12, and 18 months and 2 years after treatment. The median follow-up was 17.6 months, with seven patients being followed at 1 year and three being followed at 2 years. Treatment tolerance was evaluated from results of clinical examination, follow-up CT, and CT performed immediately after completion of RF ablation. RESULTS: No procedural deaths occurred. Procedural complications observed at CT during RF ablation were mild parenchymal hemorrhages (n = 5; 31%). All pneumothoraces (n = 6; 37%) resolved after chest tube placement. Postprocedural complications included one case of pulmonary infection and two cases of limited hemoptysis. Complete tumor ablation was obtained in all RF sessions but one (15 of 16; 95%). Overall survival rate was 71.4% (95% confidence interval [CI]: 36%, 92%) at 2 years; cancer-specific survival was 100% at 2 years. The tumor-free survival was 58.7% (95% CI: 32%, 81%) at 1 year and 19.6% (95% CI: 4%, 58%) at 2 years. CONCLUSION: RF ablation appears to be a reasonable and safe option in patients with a single lung. PMID- 21273527 TI - Case 166: Metastatic left pulmonary artery sarcoma. PMID- 21273528 TI - Trends in radiologic training. PMID- 21273529 TI - Contrast-enhanced dedicated breast CT. PMID- 21273530 TI - The coffee bean sign in sigmoid volvulus. PMID- 21273531 TI - Epidermal growth factor upregulates serotonin transporter in human intestinal epithelial cells via transcriptional mechanisms. AB - Serotonin transporter (SERT) regulates extracellular availability of serotonin and is a potential pharmacological target for gastrointestinal disorders. A decrease in SERT has been implicated in intestinal inflammatory and diarrheal disorders. However, little is known regarding regulation of SERT in the intestine. Epidermal growth factor (EGF) is known to influence intestinal electrolyte and nutrient transport processes and has protective effects on intestinal mucosa. Whether EGF regulates SERT in the human intestine is not known. The present studies examined the regulation of SERT by EGF, utilizing Caco 2 cells grown on Transwell inserts as an in vitro model. Treatment with EGF from the basolateral side (10 ng/ml, 24 h) significantly stimulated SERT activity (~2 fold, P < 0.01) and mRNA levels compared with control. EGF increased the activities of the two alternate promoter constructs for human SERT gene: SERT promoter 1 (hSERTp1, upstream of exon 1a) and SERT promoter 2 (hSERTp2, upstream of exon 2). Inhibition of EGF receptor (EGFR) tyrosine kinase activity by PD168393 (1 nM) blocked the stimulatory effects of EGF on SERT promoters. Progressive deletions of the SERT promoter indicated that the putative EGF responsive elements are present in the -672/-472 region of the hSERTp1 and regions spanning -1195/-738 and -152/+123 of hSERTp2. EGF markedly increased the binding of Caco-2 nuclear proteins to the potential AP-1 cis-elements present in EGF-responsive regions of hSERTp1 and p2. Overexpression of c-jun but not c-fos specifically transactivated hSERTp2, with no effects on hSERTp1. Our findings define novel mechanisms of transcriptional regulation of SERT by EGF via EGFR at the promoter level that may contribute to the beneficial effects of EGF in gut disorders. PMID- 21273532 TI - Muscarinic receptor agonists stimulate human colon cancer cell migration and invasion. AB - Muscarinic receptors (CHRM) are overexpressed in colon cancer. To explore a role for muscarinic receptor signaling in colon cancer metastasis, we used human H508 and HT29 colon cancer cells that coexpress epidermal growth factor (ERBB) and CHRM3 receptors. In a wound closure model, following 8-h incubation of H508 cells with 100 MUM ACh we observed a threefold increase in cell migration indistinguishable from the actions of epidermal growth factor (EGF). Atropine blocked the actions of ACh but not of EGF. In SNU-C4 colon cancer cells that express ERBB but not CHRM, EGF caused a threefold increase in migration; ACh had no effect. ACh-induced cell migration was attenuated by chemical inhibitors of ERBB1 activation, by anti-ERBB1 antibody, and by inhibitors of ERK and phosphatidylinositol 3-kinase (PI3K) signaling. Consistent with matrix metalloproteinase-7 (MMP7)-mediated release of an ERBB1 ligand, heparin binding epidermal growth factor-like growth factor (HBEGF), ACh-induced migration was inhibited by an MMP inhibitor and by anti-MMP7 and -HBEGF antibodies. ACh-induced cell migration was blocked by inhibiting RhoA and ROCK, key proteins that interact with the actin cytoskeleton. ACh-induced RhoA activation was attenuated by agents that inhibit ERBB1, ERK, and PI3K activation. Collectively, these findings indicate that ACh-induced cell migration is mediated by MMP7-mediated release of HBEGF, an ERBB ligand that activates ERBB1 and downstream ERK and PI3K signaling. In a cell invasion model, ACh-induced HT29 cell invasion was blocked by atropine. In concert with previous observations, these findings indicate that muscarinic receptor signaling plays a key role in colon cancer cell proliferation, survival, migration, and invasion. PMID- 21273533 TI - Copy number variations in candidate genes in neovascular age-related macular degeneration. AB - PURPOSE: The pathogenesis of age-related macular degeneration (AMD) is strongly influenced by genetic factors, and single nucleotide polymorphisms have been consistently linked to AMD. Copy number variation (CNV), or variation in the number of copies of a particular segment of DNA, may also contribute to AMD pathogenesis. This study evaluated CNVs in candidate genes that have been reported to be linked to AMD. METHODS: Study participants were 131 patients with neovascular AMD and 103 elderly persons without AMD who were evaluated by retinal specialists at the National Eye Institute. DNA was collected from peripheral whole blood, and duplex RT-PCR based copy number (CN) assays were performed for the genes CCR3, CFH, CX3CR1, ERCC6, HTRA1, and VEGF. Quantitative CNs (CN = 0, 1, 2, or 3+) were determined. RESULTS: Novel CNVs were discovered in CCR3, CX3CR1, and ERCC6. The unadjusted data suggested that CN = 3+ for CX3CR1 might be mildly protective against AMD, but this trend did not persist after adjustment for age. AMD patients appeared to have an elevated mean CFH CN relative to controls (2.13 [95% confidence interval (CI), 2.05-2.21] vs. 2.01 [95% CI, 1.92-2.09 copies]; P = 0.05). No significant associations between CNV and AMD were observed for the remaining genes. CONCLUSIONS: The methods described are suitable for quantitative characterization of CNV in candidate genes. The authors identified CNVs in AMD associated genes but did not find strong evidence for a link with neovascular AMD. PMID- 21273535 TI - A clinical description of Ocular Response Analyzer measurements. AB - PURPOSE: To examine the interrelationships among the Ocular Response Analyzer (ORA; Reichert Ophthalmic Instruments, Buffalo, NY), Goldmann applanation tonometer (GAT), and corneal geometry measurements in a young, healthy sample. METHODS: Central corneal radius, ORA, GAT, and central corneal thickness (CCT) measurements were taken in 99 subjects (age, 21 +/- 2 years) who were free of ocular and systemic disease. RESULTS: The mean +/- SD corneal hysteresis (CH) and corneal resistance factor (CRF) were 10.4 +/- 1.2 and 10.1 +/- 1.5 mm Hg, respectively. The Bland-Altman 95% limits of agreement of ORA Goldmann-correlated IOP (ORAg) and ORA corneal-compensated (ORAcc) IOP with reference to GAT were 4.5 to +6.0 and -4.1 to +6.8 mm Hg, respectively. The full equations used by the ORA to calculate ORAcc and CRF were reconstructed. The statistically significant effect of CCT on GAT became redundant if CRF was included in a multivariate regression analysis. Both CH and CRF were associated with CCT (R(2) = 0.252 and 0.290, respectively). CONCLUSIONS: Sample CH and CRF were consistent with those reported in the literature. ORAg and ORAcc agreed poorly with GAT. CRF appears to be at least a partial description of corneal rigidity. The ocular determinants of CH are unclear. PMID- 21273534 TI - Pharmacological cholinergic blockade stimulates inflammatory cytokine production and lymphocytic infiltration in the mouse lacrimal gland. AB - PURPOSE: To investigate the effects of cholinergic blockade on inflammatory cell infiltration and cytokine production in the mouse lacrimal gland (LG). METHODS: C57BL/6 mice were untreated (UT) or received subcutaneous injections of either scopolamine hydrobromide (SCOP; 0.5 mg/0.2 mL) or saline (SAL) four times daily for 2 or 5 days (2D, 5D). This was followed by a 7-day rest period in separate groups. Tear volume (cotton thread) and tear epidermal growth factor (EGF, by ELISA) concentrations were measured. Extraorbital LGs were surgically excised and sectioned or lysed for gene expression analysis. Immunohistochemistry evaluated immunophenotype of infiltrating cells. Expression of EGF and T helper (Th)-1, -2, and -17-associated cytokines in LGs was evaluated by real-time PCR. Goblet cell density was evaluated in periodic acid Schiff-stained conjunctival sections. RESULTS: Tear volume and EGF protein levels were significantly reduced in SCOP5D mice compared with controls, indicating that cholinergic blockade decreased LG secretory function. LGs of SCOP2D and SCOP5D mice showed an increased density of CD4(+), CD11c+, CD11b+, and myeloperoxidase+ cells compared with UT controls. At day 5, these cells were significantly elevated compared with SAL-treated counterparts. Elevated levels of IL-17A, IL-17R, IFN-gamma, IL-12Rbeta1, IL-2, IL 13, IL-6, IL-1beta, and TNF-alpha transcripts were noted in SCOP2D mice and IFN gamma, TGF-beta1, and IL-18R transcripts in SCOP5D mice. CONCLUSIONS: Pharmacological blockade of lacrimal secretion induced a significant CD4(+) infiltration in the LG, mimicking Sjogren's syndrome. The mRNA expression profile revealed elevations of a mix of inflammatory cytokines and Th-1-associated factors. PMID- 21273536 TI - Cross-talk between miR-29 and transforming growth factor-betas in trabecular meshwork cells. AB - PURPOSE: To investigate the interactions between microRNA-29 (miR-29), a negative regulator of extracellular matrix (ECM), and transforming growth factors (TGF)beta-1 and TGFbeta-2. METHODS: Changes in expression of the miR-29 family were analyzed by quantitative-PCR (Q-PCR) after treatment with TGFbeta1 and TGFbeta2 (1 ng/mL). TGFbeta1 and TGFbeta2 were evaluated at gene expression and protein levels by Q-PCR and ELISA, respectively, in human trabecular meshwork (HTM) cells transfected with miR-29b or scramble control. TGFbeta1 promoter activity was analyzed using an adenovirus with the reporter SEAP. The effects of miR-29b and TGFbeta2 on ECM gene expression were evaluated in cells transfected with miR-29b or scramble control and treated with TGFbeta2, and the expression of ECM genes was analyzed by Q-PCR. RESULTS: TGFbeta2 but not TGFbeta1, downregulated the three members of the miR-29 family. Overexpression of miR-29b antagonized the effects of TGFbeta2 on the expression of several ECM components. MiR-29b decreased the expression of TGFbeta1 at the promoter, transcript, and protein levels but had only a minor effect on the expression of active TGFbeta2. The inhibition of TGFbeta1 by miR-29b was partially recovered after co transfection with a plasmid-expressing bone morphogenetic protein 1. CONCLUSIONS: Results showed some level of crosstalk between TGFbetas and miR-29. Specifically, the downregulation of miR-29 by TGFbeta2 contributed to the induction of several ECM components by this cytokine in TM cells. This observation, together with the inhibitory effects of miR-29b on the expression of TGFbeta1, suggests that the miR-29 family could play an important role in modulating TGFbetas on the outflow pathway. PMID- 21273537 TI - Ocular pathology relevant to glaucoma in a Gja1(Jrt/+) mouse model of human oculodentodigital dysplasia. AB - PURPOSE: Oculodentodigital dysplasia (ODDD) is a human disorder caused by mutations in the gap junction alpha 1 (GJA1) gene encoding the connexin43 (Cx43) gap junction protein. Causal links between GJA1 mutations and glaucoma are not understood. The purpose in this study was to examine the ocular phenotype for Gja1(Jrt/+) mice harboring a Cx43 G60S mutation. METHODS; In young Gja1(Jrt/+) mice, Cx43 abundance was assessed with a Western blot, and Cx43 localization was visualized using immunohistochemistry and confocal microscopy. Intraocular pressure (IOP) was measured by rebound tonometry, and eye anatomy was imaged using ocular coherence tomography (OCT). Hematoxylin and eosin (H&E)-stained eye sections were examined for ocular histopathology related to the development of glaucoma. RESULTS: Decreased Cx43 protein levels were evident in whole eyes from Gja1(Jrt/+) mice compared with those of wild-type mice at postnatal day 1 (P = 0.005). Cx43 immunofluorescence in ciliary bodies of Gja1(Jrt/+) mice was diffuse and intracellular, unlike the gap junction plaques prevalent in wild-type mice. IOP in Gja1(Jrt/+) mice changed during postnatal development, with significantly lower IOP at 21 weeks of age in comparison to the IOP of wild-type eyes. Microphthalmia, enophthalmia, anterior angle closure, and reduced pupil diameter were observed in Gja1(Jrt/+) mice at all ages examined. Ocular histology showed prominent separations between the pigmented and nonpigmented ciliary epithelium of Gja1(Jrt/+) mice, split irides, and alterations in the number and distribution of nuclei in the retina. CONCLUSIONS: Detailed phenotyping of Gja1(Jrt/+) eyes offers a framework for elucidating human ODDD ocular disease mechanisms and evaluating new treatments designed to protect ocular synaptic network integrity. PMID- 21273538 TI - Combined blockade of VEGFR-2 and VEGFR-3 inhibits inflammatory lymphangiogenesis in early and middle stages. AB - PURPOSE: Lymphangiogenesis (LG) accompanies many corneal diseases after inflammatory, infectious, or chemical insults and is a primary mediator of transplant rejection. The purpose of this study was to investigate whether there is a time window for therapeutic intervention of corneal LG and whether a combined blockade of VEGFR-2 and VEGFR-3 effectively suppresses early-, middle-, or late-stage LG. METHODS: Corneal inflammatory neovascularization was induced by a standard suture placement model in mice. Neutralizing antibodies against VEGFR 3 and/or VEGFR-2 were administrated systemically with the treatment started at postoperative day 0, day 7, or day 14. Whole mount corneas were sampled for immunofluorescence microscopic studies using LYVE-1 (a lymphatic marker) antibodies. Digital images were analyzed by software. RESULTS: Both VEGFR-3 and VEGFR-2 were involved in corneal suture-induced inflammatory LG. Their combined blockade led to a significant inhibition of both early- and middle-stage LG while demonstrating no effect on late-stage LG. CONCLUSIONS: Corneal inflammatory LG has a discrete time window for intervention therapy. Although it is important to start the treatment as soon as possible, interventions initiated in the middle of the LG process are still effective. These novel findings will shed some light on our understanding of inflammatory LG and the development of new therapeutic protocols for LG-related diseases at different stages. PMID- 21273539 TI - Treatment of experimental anterior and intermediate uveitis by a dexamethasone intravitreal implant. AB - PURPOSE: To assess the efficacy of a dexamethasone (DEX) intravitreal implant in a rabbit model of anterior and intermediate uveitis. METHODS: Experimental anterior and intermediate uveitis was induced by a unilateral intracameral injection of Mycobacterium tuberculosis H37Ra antigen in preimmunized rabbits. Four days after uveitis induction, rabbits received DEX implant or underwent a sham procedure (no implant). Clinical and histopathologic signs of uveitis were assessed for 13 days, and levels of inflammatory markers in the iris/ciliary body were measured after 21 days. RESULTS: All signs of anterior and intermediate uveitis were reduced by the DEX implant compared with sham procedure. At day 13, mean anterior chamber cell scores +/- SD for the DEX implant versus the sham procedure were, respectively, 1.9 +/- 1.3 versus 4.0 +/- 0.0 (P = 0.04), and mean total histologic inflammatory scores were 3.9 +/- 2.5 versus 15.4 +/- 6.0 (P = 0.026). Similarly, at day 13, mean vitreous haze severity scores (SD) for the DEX implant versus the sham procedure were, respectively, 0.1 +/- 0.2 versus 2.7 +/- 1.5 (P = 0.026), and mean vitreous inflammatory cell infiltration scores were 0.0 +/- 0.0 versus 1.5 +/- 1.3. Treatment with the DEX intravitreal implant also significantly reduced the proinflammatory immune response, as measured by cytokine levels in iris/ciliary body. CONCLUSIONS: A single administration of DEX implant significantly reduced inflammation in an animal model of anterior and intermediate uveitis. PMID- 21273540 TI - Multivariate analyses of inflammatory cytokines in eyes with branch retinal vein occlusion: relationships to bevacizumab treatment. AB - PURPOSE: To characterize the differential expression of intraocular inflammatory cytokines in eyes with branch retinal vein occlusion (BRVO) and to assess their roles as prognostic determinants of BRVO. METHODS: A prospective cohort study of 38 eyes with BRVO. Aqueous humor samples were collected just before the intravitreal injection of bevacizumab and were assessed for 18 cytokines, chemokines, and growth factors. For control, aqueous humor was collected from 28 eyes before cataract surgery. RESULTS: In the aqueous of eyes with BRVO, the IL 23, IL-8, IL-6, IL-15, IL-12, and IL-17 levels were significantly higher than that in control eyes. Pretreatment visual acuity was significantly correlated with the concentrations of IL-8, IL-10, IL-2, IL-1beta, IL-5, IL-6, IL-23, IL-4, MCP-1, IL-1alpha, IL-12, IL-13, IFN-gamma, and IL-15. The pretreatment nonperfused area (NPA) was significantly correlated with the concentrations of IL 8, IL-2, MCP-1, and IL-6. Logistic regression analyses revealed significant associations between the BRVO and the concentrations of IL-8, IL-23, IL-12, IL 15, IL-10, IL-1beta, and IL-13. IL-8 had the highest odds ratio (OR) and was significantly associated with NPA, central retinal thickness (CRT), and visual acuity. Bevacizumab treatment significantly improved visual acuity and CRT after 1 month. Refractoriness to bevacizumab (defined as CRT recovery 1 month after treatment by <90%) was significantly associated with the IL-12 level. CONCLUSIONS: Of the induced cytokines in eyes with BRVO, IL-8 was the most significantly associated with the disease parameters of BRVO. IL-12 is most likely a factor that blocks the effect of bevacizumab treatment. (www.umin.ac.jp/ctr number, UMIN000003854.). PMID- 21273541 TI - Three-dimensional visualization of ocular vascular pathology by optical coherence angiography in vivo. AB - PURPOSE: To demonstrate the clinical application of a noninvasive, three dimensional, vascular imaging technique called Doppler optical coherence angiography (OCA). To evaluate the vascular architecture of polypoidal choroidal vasculopathy (PCV) using Doppler OCA. METHODS: The authors prospectively examined the eyes of four healthy subjects and 15 PCV patients. Three-dimensional vascular flow imaging was performed using high-speed, high-resolution, and high penetration spectral-domain Doppler optical coherence tomography. Two-dimensional images of the retina, choroid, and vascular lesions were obtained simultaneously. RESULTS: Distribution of blood flow detected by Doppler OCA imaging corresponded well with that by indocyanine angiographic imaging. PCV lesions were localized in the space between the retinal pigment epithelium and the Bruch's membrane. CONCLUSIONS: The authors found using Doppler OCA that PCV lesions are similar in architecture to choroidal neovascularization in age-related macular degeneration. Doppler OCA facilitates rapid and noninvasive examination of exudative macular diseases. PMID- 21273542 TI - Mitochondrial DNA damage and repair in RPE associated with aging and age-related macular degeneration. AB - PURPOSE: Mitochondrial DNA (mtDNA) damage may be associated with age-related diseases, such as age-related macular degeneration (AMD). The present study was designed to test whether the frequency of mtDNA damage, heteroplasmic mtDNA mutations, and repair capacity correlate with progression of AMD. METHODS: Macular and peripheral RPE cells were isolated and cultured from human donor eyes with and without AMD. The stages of AMD were graded according to the Minnesota Grading System. Confluent primary RPE cells were used to test the frequency of endogenous mtDNA damage by quantitative PCR. Mutation detection kits were used to detect heteroplasmic mtDNA mutation. To test the mtDNA repair capacity, cultured RPE cells were allowed to recover for 3 and 6 hours after exposure to H(2)O(2), and repair was assessed by quantitative PCR. The levels of human OGG1 protein, which is associated with mtDNA repair, were analyzed by Western blot. RESULTS: This study showed that mtDNA damage increased with aging and that more lesions occurred in RPE cells from the macular region than the periphery. Furthermore, mtDNA repair capacity decreased with aging, with less mtDNA repair capacity in the macular region compared with the periphery in samples from aged subjects. Most interestingly, the mtDNA damage was positively correlated with the grading level of AMD, whereas repair capacity was negatively correlated. In addition, more mitochondrial heteroplasmic mutations were detected in eyes with AMD. CONCLUSIONS: These data show macula-specific increases in mtDNA damage, heteroplasmic mutations, and diminished repair that are associated with aging and AMD severity. PMID- 21273543 TI - AAV-mediated gene replacement, either alone or in combination with physical and pharmacological agents, results in partial and transient protection from photoreceptor degeneration associated with betaPDE deficiency. AB - PURPOSE: Mutations in the PDE6B gene cause recessive, severe retinitis pigmentosa (RP). PDE6B encodes the beta subunit of the rod-specific phosphodiesterase (betaPDE), which, when absent, results in toxic levels of intracellular Ca(2+) and photoreceptor cell death. Ca(2+) blockers, such as nilvadipine, as well as light restriction, slow photoreceptor degeneration in animal models of betaPDE deficiencies. The goal of the study was to evaluate the efficacy of AAV2/5- or AAV2/8-mediated gene replacement in combination with nilvadipine and/or with light restriction in the rd10 mouse bearing homozygous pde6b mutations. METHODS: AAV vectors encoding either betaPDE or EGFP were subretinally administered at postnatal day (P)2. Nilvadipine was administered from P7 to P28. For light restriction, pregnant rd10 mice were kept in a dark environment until their pups were 28 days old. All functional and histologic analyses were performed at P35. RESULTS: Significant morphologic photoreceptor protection was observed after subretinal administration of AAV vectors encoding EGFP. This protection further increased after administration of AAV2/8 or -2/5 encoding for betaPDE and was not associated with significant functional improvement. Photoreceptor protection was higher after AAV2/8- than after AAV2/5-mediated delivery and was not significantly augmented by additional drug therapy and/or light restriction. The protective effect was lost after P35. CONCLUSIONS: In conclusion, more efficient gene transfer tools than those used in this study, as well as a better understanding of the disease pathogenesis, should be explored to increase the effect of gene replacement and to design gene-based strategies that block the apoptotic pathways activated by betaPDE deficiency. PMID- 21273544 TI - Engagement of TLR2 reverses the suppressor function of conjunctiva CD4+CD25+ regulatory T cells and promotes herpes simplex virus epitope-specific CD4+CD25- effector T cell responses. AB - PURPOSE. The authors recently reported that Foxp3(+)CD4(+) CD25(+(Bright)) "natural" regulatory T cells (nT(reg) cells) are abundant in rabbit conjunctiva and suppress herpes simplex virus (HSV)-1-specific CD4(+) and CD8(+) effector T cells (T(eff) cells). However, little is known about the overall regulatory mechanisms of these nT(reg) cells. The authors investigate the regulation of conjunctiva-resident nT(reg) cells through Toll-like receptors (TLRs) and their effect on ocular mucosal T(eff) cell immunity. METHODS. CD4(+)CD25(+) nT(reg) cells were purified from naive rabbit conjunctivas, and their TLR expression profile was determined. The effects of TLR engagement on nT(reg) cell-mediated suppression of CD4(+) T(eff) cells were determined in vitro and in vivo. RESULTS. The authors found that conjunctiva-resident nT(reg) cells express high levels of TLR2 and TLR9; exposure to the TLR2 ligand lipoteichoic acid (LTA) led to the increased activation and proliferation of nT(reg) cells, and the addition of autologous APCs further increased nT(reg) cell expansion; in contrast, the TLR9 ligand CpG(2007) inhibited the proliferation of nT(reg) cells, and the addition of autologous APCs had no effect on such inhibition; nT(reg) cells treated with LTA, but not with CpG(2007), expressed IFN-gamma and IL-10 mRNA, but not TGF beta; consistent with in vitro data, rabbits immunized by topical ocular drops of HSV-gD peptides + TLR2 ligand (LTA) displayed enhanced CD4(+)CD25(-) T(eff) cell immune responses when compared with HSV-gD peptides + TLR9 ligand (CpG(2007)). CONCLUSIONS. Although conjunctiva-resident CD4(+)CD25(+) nT(reg) cells express high level of TLR2 and TLR9, their suppressive function is more significantly reversed after the administration of TLR2 ligand (LTA; P < 0.005) than of TLR9 ligand (CpG(200); P > 0.005). These findings will likely help optimize the topical ocular administration of immunotherapies. PMID- 21273545 TI - Smad4 is required predominantly in the developmental processes dependent on the BMP branch of the TGF-beta signaling system in the embryonic mouse retina. AB - PURPOSE: The present study was aimed at defining developmental roles of Smad4, a key mediator of the TGF-beta superfamily signaling system, in the embryonic mouse retina. METHODS: Using a Cre/loxP-mediated conditional gene targeting approach, Smad4 gene function was deleted from the embryonic mouse retina. Mutant phenotypes were morphologically and molecularly examined. RESULTS: Loss of Smad4 in the developing retina led to varying degrees of microphthalmia at birth, presumably because of elevated apoptosis observed transiently at embryonic day 12.5 in the developing retina. This was also associated with an apparent delay in accumulation of retinal ganglion cells. Smad4 conditional mutants also exhibited alterations of retinal spatial patterning along the dorsal-ventral axis, consistent with a known function of BMP signaling in the embryonic retina. However, despite a known role for BMP signaling in retinal cell survival, proliferation, and differentiation, Smad4 mutant retinal progenitor cells were capable of maintaining growth and neurogenesis throughout embryonic development. We also found that the loss of Smad4 led to abnormal targeting of retinal ganglion cell axons to the optic nerve head, a phenotype consistent with reduced BMP signaling in the developing retina. CONCLUSIONS: These results suggest that Smad4 is essential for a subset of, but not all, TGF-beta/BMP-dependent developmental processes in the embryonic retina. In addition, genetic requirements for Smad4 in the embryonic retina are evident predominantly in the developmental events regulated by the BMP branch of the TGF-beta signaling pathway. PMID- 21273546 TI - The effect of induced intraocular straylight on perimetric tests. AB - PURPOSE: To investigate the effect of intraocular straylight (IOS) on threshold measurements made by four types of perimetry: standard automated perimetry (SAP), frequency-doubling technology (FDT) perimetry, flicker-defined form (FDF) perimetry, and the Moorfields Motion Displacement Test (MDT). METHODS: Six healthy young (21-29 years) psychophysically experienced observers were tested five times with each perimeter, each time with one of five different white opacity filters (WOFs), to induce various levels of IOS. Each WOF gave rise to an increase in IOS, measured with a straylight meter, of between 10% and 200% from baseline and ranging in effect from normal ageing to significant cataract. The change in sensitivity from baseline was normalized, allowing comparison of standardized (z) scores (change divided by the standard deviation of normative values) for each instrument. RESULTS: Average SAP, FDT, and FDF thresholds were significantly affected (P < 0.001) by moderate to large increases in IOS (50% 200%), whereas MDT remained largely unaffected over the same range of straylight levels. CONCLUSIONS: The Moorfields MDT shows greater resilience to the effects of additional straylight compared with SAP, FDT, or FDF. PMID- 21273547 TI - Early-onset, slow progression of cone photoreceptor dysfunction and degeneration in CNG channel subunit CNGB3 deficiency. AB - PURPOSE: To investigate the progression of cone dysfunction and degeneration in CNG channel subunit CNGB3 deficiency. METHODS: Retinal structure and function in CNGB3(-/-) and wild-type (WT) mice were evaluated by electroretinography (ERG), lectin cytochemistry, and correlative Western blot analysis of cone-specific proteins. Cone and rod terminal integrity was assessed by electron microscopy and synaptic protein immunohistochemical distribution. RESULTS: Cone ERG amplitudes (photopic b-wave) in CNGB3(-/-) mice were reduced to approximately 50% of WT levels by postnatal day 15, decreasing further to approximately 30% of WT levels by 1 month and to approximately 20% by 12 months of age. Rod ERG responses (scotopic a-wave) were not affected in CNGB3(-/-) mice. Average CNGB3(-/-) cone densities were approximately 80% of WT levels at 1 month and declined slowly thereafter to only approximately 50% of WT levels by 12 months. Expression levels of M-opsin, cone transducin alpha-subunit, and cone arrestin in CNGB3(-/-) mice were reduced by 50% to 60% by 1 month and declined to 35% to 45% of WT levels by 9 months. In addition, cone opsin mislocalized to the outer nuclear layer and the outer plexiform layer in the CNGB3(-/-) retina. Cone and rod synaptic marker expression and terminal ultrastructure were normal in the CNGB3(-/-) retina. CONCLUSIONS: These findings are consistent with an early-onset, slow progression of cone functional defects and cone loss in CNGB3(-/-) mice, with the cone signaling deficits arising from disrupted phototransduction and cone loss rather than from synaptic defects. PMID- 21273548 TI - Dexamethasone-associated cross-linked actin network formation in human trabecular meshwork cells involves beta3 integrin signaling. AB - PURPOSE: To determine whether cross-linked actin networks (CLANs) formed in dexamethasone (DEX)-treated human trabecular meshwork (HTM) cells are structurally similar to those formed after beta3 integrin activation and involve alphavbeta3 integrin signaling. METHODS: Two HTM cell strains and an alphavbeta3 integrin-overexpressing immortalized TM cell line were used. DEX- or ethanol pretreated HTM cells were plated on fibronectin with or without beta3 integrin activating mAb AP-5. Immunofluorescence microscopy was used to identify phalloidin-labeled CLANs and to ascertain the presence of alpha-actinin, PIP(2), and syndecan-4 within them. beta3 Integrin signaling involvement was determined using a PI3-kinase (LY294002) or Rac1 (NSC23766) inhibitor. alphavbeta3 Integrin expression levels and the beta3 integrin activation state were determined by fluorescence-activated cell sorter analysis and immunofluorescence microscopy. RESULTS: CLANs associated with either DEX treatment or beta3 integrin activation contained syndecan-4, PIP(2), and alpha-actinin. In the absence of mAb AP-5, LY294002 did not affect DEX-associated CLAN formation, whereas NSC23766 decreased the percentage of CLAN-positive cells by 80%. In the presence of mAb AP-5, both inhibitors decreased DEX-associated CLAN formation. DEX pretreatment increased beta3 integrin-induced CLAN formation nearly sixfold and the level of alphavbeta3 integrin expression and activation threefold compared with control cells. Activated beta3 integrin-positive adhesions increased nearly fivefold in DEX treated cells. alphavbeta3 Integrin overexpression in TM-1 cells increased CLAN formation twofold. CONCLUSIONS: DEX-associated CLANs were structurally similar to those induced by mAb AP-5 and involved both increased expression and activation of alphavbeta3 integrins. Thus, glucocorticoid-induced CLAN formation may involve enhanced beta3 integrin signaling in HTM cells, possibly by an inside-out signaling mechanism. PMID- 21273549 TI - Sonoporation enhances chemotherapeutic efficacy in retinoblastoma cells in vitro. AB - PURPOSE: To study the ability of ultrasound (US) and microbubbles (MB) to enhance chemotherapeutic efficacy against retinoblastoma Y79 cells in vitro. METHODS: The experiment was performed in three stages. The authors first compared cell viability of Y79 cells exposed to doxorubicin versus cells exposed to doxorubicin combined with low-intensity, low-frequency US + MB. They then evaluated enhanced cell permeability by studying the intensity of intracellular fluorescence in cells exposed to doxorubicin versus those exposed to doxorubicin with US + MB. Lastly they evaluated the morphologic characteristics of the cells by scanning electron microscopy (SEM) to identify the presence of pores. RESULTS: The Y79 cells exposed to doxorubicin with US + MB showed a significant decrease in cell viability at 72 hours compared with those exposed to doxorubicin alone (P = 0.02). Cells also showed immediate increased permeability to doxorubicin with the addition of US + MB compared with doxorubicin alone, which continued to increase over 60 minutes. SEM did not demonstrate physical pores at the lowest US + MB intensity shown to enhance intracellular doxorubicin fluorescence. CONCLUSIONS: US + MB facilitates the uptake of chemotherapy in retinoblastoma Y79 cells in vitro. This occurs in the absence of visible pores, suggesting a possible secondary mechanism for increased drug delivery. This experiment is the first step toward enhancing chemotherapy with sonoporation in the treatment of intraocular tumors. This technique may lead to more effective chemotherapy treatments with less collateral damage to ocular tissues and may allow reduced systemic dosage and systemic side effects. PMID- 21273550 TI - Differential effects of rapamycin on rods and cones during light-induced stress in albino mice. AB - PURPOSE: Autophagy is a lysosomal machinery-dependent process that catabolizes cellular components/organelles and proteins in an autophagic vacuole (AV) dependent and -independent manner, respectively. Short-term exposure of the retina to bright light results in shortening of the outer segments, concomitant with AV formation. Autophagy is also induced by continuous long-term light damage, leading to photoreceptor cell death. Here the authors examined two questions: is autophagy induced during light damage proapoptotic or antiapoptotic, and are rods and cones affected differently? To this end, Balb/c mice exposed to light damage were treated with rapamycin to increase autophagy. METHODS: Balb/c and GFP-LC3 mice were treated with rapamycin/vehicle. Photoreceptor degeneration was induced by 10-day light damage. Autophagy was documented by histologic, biochemical, and molecular tools; rod and cone survival was assessed by histology and electroretinography. RESULTS: Light damage resulted in rod, but not cone, cell loss. Autophagy and AV formation was elicited in response to light damage, which was amplified by rapamycin. Rapamycin treatment significantly improved rod survival and function, reduced apoptosis, and normalized cytokine production that was increased in light damage. However, AV formation in GFP-LC3 mice revealed that light damage or rapamycin treatment induced AVs in cones, concomitant with reduced cone-mediated electroretinograms. CONCLUSIONS: Systemic rapamycin treatment provided rod protection; however, AV formation was induced only in cones. Thus, rapamycin may act differentially in stressed photoreceptors; rapamycin might protect rods by normalizing cytokine production, removing damaged proteins by AV-independent autophagy, or both, whereas cones might be protected by AV-dependent autophagy, possibly involving reduced photon capture. PMID- 21273551 TI - Pathogenic spectrum of fungal keratitis and specific identification of Fusarium solani. AB - PURPOSE: To investigate the predominant causative pathogens and epidemiologic features of fungal keratitis and establish a rapid, specific molecular method to detect fungal keratitis caused by Fusarium solani. METHODS: A total of 174 patients with presumed fungal keratitis and 174 affected eyes were examined. Isolates from corneal specimens were identified according to morphologic and physiological characteristics. The primers that were designed for F. solani were tested to confirm whether they had species specificity. Multiplex PCR with universal fungal and F. solani-specific primers was performed with fungal and bacterial strains and was used to detect microorganisms in the clinical specimens. RESULTS: A total of 160 patients (92.0%) were diagnosed with fungal infection by either potassium hydroxide wet-mount or microbiologic culture. Fungal cultures were positive in 128 patients (73.6%) with 139 fungal isolates. Fusarium (48.2%) was the most frequently isolated genus, in which F. solani (35.2%) was the most common species, followed by the Aspergillus (18.7%) and Candida (16.6%) genera. The PCR results showed that the designed primers were species specific and suitable for specific identification of F. solani. The multiplex PCR of 3-day broth cultures could identify and distinguish F. solani from other pathogens rapidly and specifically from clinical specimens. CONCLUSIONS: Fusarium species, especially F. solani, were found to be the predominant cause of fungal keratitis in northeast China. The established multiplex PCR method could have potential advantages for rapid detection of F. solani. These findings might have significance for early diagnosis and treatment of fungal keratitis. PMID- 21273552 TI - Dicer plays essential roles for retinal development by regulation of survival and differentiation. AB - PURPOSE: Much attention has been paid to the roles of microRNA in developmental and biological processes. Dicer plays essential roles in cell survival and proliferation in various organs. We examined the role of Dicer in retinal development using retina-specific conditional knockout of Dicer in mice. METHODS: Dkk3-Cre expressed the Cre gene in retinal progenitor cells from an early embryonic stage. The authors analyzed Dkk-Cre/Dicer-flox (Dicer-CKO) mice for their survival, proliferation, and differentiation. To analyze the role of Dicer in later stages of retinal development, a Cre expression plasmid was introduced into the neonatal retina by electroporation, and retinal differentiation was examined. RESULTS: Dicer-CKO mice were born at the numbers we expected, based on Mendelian genetics, but their eyes never opened. Massive death of retinal progenitor cells occurred during embryogenesis, resulting in microphthalmia, and most retinal cells had disappeared by postnatal day 14. In vitro reaggregation culture of Dicer-CKO retinal cells showed that cell death and the suppression of proliferation by Dicer inactivation occurred in a cell-autonomous manner. Cell differentiation markers were expressed in the Dicer-CKO retina; however, these cells localized abnormally, and the inner plexiform layer was absent, suggesting that cell migration and morphologic differentiation, especially process extension, were perturbed. Forced neonatal expression of Cre induced apoptosis and affected the expression of differentiation markers. CONCLUSIONS: Taken together, these results show that Dicer is essential during early retinal development. PMID- 21273553 TI - Soluble M6P/IGF2R released by TACE controls angiogenesis via blocking plasminogen activation. AB - RATIONALE: The urokinase plasminogen activator (uPA) system is among the most crucial pericellular proteolytic systems associated with the processes of angiogenesis. We previously identified an important regulator of the uPA system in the mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R). OBJECTIVE: Here, we wanted to clarify whether and how did the soluble form of M6P/IGF2R (sM6P/IGF2R) contribute to modulation of the uPA system. METHODS AND RESULTS: By using specific inhibitors and RNA interference, we show that the tumor necrosis factor alpha convertase (TACE, ADAM-17) mediates the release of the ectodomain of M6P/IGF2R from human endothelial cells. We demonstrate further that sM6P/IGF2R binds plasminogen (Plg) and thereby prevents Plg from binding to the cell surface and uPA, ultimately inhibiting in this manner Plg activation. Furthermore, peptide 18-36 derived from the Plg-binding site of M6P/IGF2R mimics sM6P/IGF2R in the inhibition of Plg activation and blocks cancer cell invasion in vitro, endothelial cell invasion in vivo, and tumor growth in vivo. CONCLUSIONS: The interaction of sM6P/IGF2R with Plg may be an important regulatory mechanism to inhibit migration of cells using the uPA/uPAR system. PMID- 21273554 TI - A peptide mimetic of the connexin43 carboxyl terminus reduces gap junction remodeling and induced arrhythmia following ventricular injury. AB - RATIONALE: Remodeling of connexin (Cx)43 gap junctions (GJs) is linked to ventricular arrhythmia. OBJECTIVES: A peptide mimetic of the carboxyl terminal (CT) of Cx43, incorporating a postsynaptic density-95/disks-large/ZO-1 (PDZ) binding domain, reduces Cx43/ZO-1 interaction and GJ size remodeling in vitro. Here, we determined: (1) whether the Cx43-CT mimetic alphaCT1 altered GJ remodeling following left ventricular (LV) injury in vivo; (2) whether alphaCT1 affected arrhythmic propensity; and (3) the mechanism of alphaCT1 effects on arrhythmogenicity and GJ remodeling. METHODS AND RESULTS: A cryoinjury model generating a reproducible wound and injury border zone (IBZ) in the LV was used. Adherent methylcellulose patches formulated to locally release alphaCT1 (< 48 hours) were placed on cryoinjuries. Relative to controls, Cx43/ZO-1 colocalization in the IBZ was reduced by alphaCT1 by 24 hours after injury. Programmed electric stimulation ex vivo and optical mapping of voltage transients indicated that peptide-treated hearts showed reduced inducible arrhythmias and increased ventricular depolarization rates 7 to 9 days after injury. At 24 hours and 1 week after injury, alphaCT1-treated hearts maintained Cx43 in intercalated disks (IDs) in the IBZ, whereas by 1 week after injury, controls demonstrated Cx43 remodeling from IDs to lateralized distributions. Over a postinjury time course of 1 week, alphaCT1-treated IBZs showed increased Cx43 phosphorylation at serine368 (Cx43-pS368) relative to control tissues. In biochemical assays, alphaCT1 promoted phosphorylation of serine368 by protein kinase (PK)C-epsilon in a dose-dependent manner that was modulated by, but did not require ZO-1 PDZ2. CONCLUSIONS: alphaCT1 increases Cx43-pS368 in vitro in a PKC-epsilon-dependent manner and in the IBZ in vivo acutely following ventricular injury. alphaCT1 mediated increase in Cx43-pS368 phosphorylation may contribute to reductions in inducible-arrhythmia following injury. PMID- 21273555 TI - Chronic fine particulate matter exposure induces systemic vascular dysfunction via NADPH oxidase and TLR4 pathways. AB - RATIONALE: Chronic exposure to ambient air-borne particulate matter of < 2.5 MUm (PM2.5) increases cardiovascular risk. The mechanisms by which inhaled ambient particles are sensed and how these effects are systemically transduced remain elusive. OBJECTIVE: To investigate the molecular mechanisms by which PM2.5 mediates inflammatory responses in a mouse model of chronic exposure. METHODS AND RESULTS: Here, we show that chronic exposure to ambient PM2.5 promotes Ly6C(high) inflammatory monocyte egress from bone-marrow and mediates their entry into tissue niches where they generate reactive oxygen species via NADPH oxidase. Toll like receptor (TLR)4 and Nox2 (gp91(phox)) deficiency prevented monocyte NADPH oxidase activation in response to PM2.5 and was associated with restoration of systemic vascular dysfunction. TLR4 activation appeared to be a prerequisite for NAPDH oxidase activation as evidenced by reduced p47(phox) phosphorylation in TLR4 deficient animals. PM2.5 exposure markedly increased oxidized phospholipid derivatives of 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (oxPAPC) in bronchioalveolar lavage fluid. Correspondingly, exposure of bone marrow derived macrophages to oxPAPC but not PAPC recapitulated effects of chronic PM2.5 exposure, whereas TLR4 deficiency attenuated this response. CONCLUSIONS: Taken together, our findings suggest that PM2.5 triggers an increase in oxidized phospholipids in lungs that then mediates a systemic cellular inflammatory response through TLR4/NADPH oxidase-dependent mechanisms. PMID- 21273556 TI - Impaired phosphatidylcholine biosynthesis reduces atherosclerosis and prevents lipotoxic cardiac dysfunction in ApoE-/- Mice. AB - RATIONALE: Phosphatidylcholine (PC) is the predominant phospholipid component of circulating lipoproteins. The majority of PC is formed by the choline pathway. However, approximately one-third of hepatic PC can also be synthesized by phosphatidylethanolamine N-methyltransferase (PEMT). PEMT is required for normal secretion of very-low-density lipoproteins from the liver. We hypothesized that lack of PEMT would attenuate atherosclerosis and improve myocardial function. OBJECTIVE: Investigate the contribution of PEMT to atherosclerotic lesion formation and cardiac function in mice that lack apolipoprotein E. METHODS AND RESULTS: Mice deficient in apolipoprotein E (Pemt(+/+)/Apoe(-/-)) and mice lacking both PEMT and apoE (Pemt(-/-)/Apoe(-/-)) were fed a chow diet for 1 year. The atherogenic lipoprotein profile of plasma of Apoe(-/-) mice was significantly improved by PEMT deficiency, with lower levels of triacylglycerol (45%) and cholesterol (~25%) in the very-low-density lipoprotein and low density/intermediate-density lipoprotein fractions, respectively (P < 0.05). Atherosclerotic lesion area was reduced by ~30%, and aortic cholesteryl ester and cholesterol content were also reduced by ~40% by PEMT deficiency (P < 0.05). By in vivo echocardiography, we detected a ~50% improvement in systolic function in the Pemt(-/-)/Apoe(-/-) compared with Pemt(+/+)/Apoe(-/-) mice (P < 0.05). This was accompanied by a significant reduction in cardiac triacylglycerol (34%) in mice lacking PEMT. CONCLUSIONS: These results indicate that treatment strategies aimed at inhibition of PEMT might prevent the accumulation of cardiac triacylglycerol that predisposes individuals to compromised cardiac function. PMID- 21273557 TI - Circulating proprotein convertase subtilisin/kexin 9 (PCSK9) regulates VLDLR protein and triglyceride accumulation in visceral adipose tissue. AB - OBJECTIVE: Proprotein convertase subtilisin/kexin 9 (PCSK9) promotes the degradation of the low-density lipoprotein receptor (LDLR), and its gene is the third locus implicated in familial hypercholesterolemia. Herein, we investigated the role of PCSK9 in adipose tissue metabolism. METHODS AND RESULTS: At 6 months of age, Pcsk9(-/-) mice accumulated ~80% more visceral adipose tissue than wild type mice. This was associated with adipocyte hypertrophy and increased in vivo fatty acid uptake and ex vivo triglyceride synthesis. Moreover, adipocyte hypertrophy was also observed in Pcsk9(-/-) Ldlr(-/-) mice, indicating that the LDLR is not implicated. Rather, we show here by immunohistochemistry that Pcsk9( /-) males and females exhibit 4- and ~ 40-fold higher cell surface levels of very low-density lipoprotein receptor (VLDLR) in perigonadal depots, respectively. Expression of PCSK9 in the liver of Pcsk9(-/-) females reestablished both circulating PCSK9 and normal VLDLR levels. In contrast, specific inactivation of PCSK9 in the liver of wild-type females led to ~ 50-fold higher levels of perigonadal VLDLR. CONCLUSIONS: In vivo, endogenous PCSK9 regulates VLDLR protein levels in adipose tissue. This regulation is achieved by circulating PCSK9 that originates entirely in the liver. PCSK9 is thus pivotal in fat metabolism: it maintains high circulating cholesterol levels via hepatic LDLR degradation, but it also limits visceral adipogenesis likely via adipose VLDLR regulation. PMID- 21273558 TI - Primary monocytes regulate endothelial cell survival through secretion of angiopoietin-1 and activation of endothelial Tie2. AB - OBJECTIVE: Monocyte recruitment and interaction with the endothelium is imperative to vascular recovery. Tie2 plays a key role in endothelial health and vascular remodeling. We studied monocyte-mediated Tie2/angiopoietin signaling following interaction of primary monocytes with endothelial cells and its role in endothelial cell survival. METHODS AND RESULTS: The direct interaction of primary monocytes with subconfluent endothelial cells resulted in transient secretion of angiopoietin-1 from monocytes and the activation of endothelial Tie2. This effect was abolished by preactivation of monocytes with tumor necrosis factor-alpha. Although primary monocytes contained high levels of both angiopoietin 1 and 2, endothelial cells contained primarily angiopoietin 2. Seeding of monocytes on serum-starved endothelial cells reduced caspase-3 activity by 46 +/- 5.1%, and 52 +/- 5.8% after tumor necrosis factor-alpha treatment and decreased detected single-stranded DNA levels by 41 +/- 4.2% and 40 +/- 3.5%, respectively. This protective effect of monocytes on endothelial cells was reversed by Tie2 silencing with specific short interfering RNA. The antiapoptotic effect of monocytes was further supported by the activation of cell survival signaling pathways involving phosphatidylinositol 3-kinase, STAT3, and AKT. CONCLUSIONS: Monocytes and endothelial cells form a unique Tie2/angiopoietin-1 signaling system that affects endothelial cell survival and may play critical a role in vascular remodeling and homeostasis. PMID- 21273560 TI - Macrophage activation is responsible for loss of anticontractile function in inflamed perivascular fat. AB - OBJECTIVE: The aim of this study was to determine whether macrophages dispersed throughout perivascular fat are crucial to the loss of anticontractile function when healthy adipose tissue becomes inflamed and to gain an understanding of the mechanisms involved. METHODS AND RESULTS: Pharmacological studies on in vitro small arterial segments from a mouse model of inducible macrophage ablation and on wild-type animals were carried out with and without perivascular fat using 2 physiological stimuli of inflammation: aldosterone and hypoxia. Both inflammatory insults caused a similar loss of anticontractile capacity of perivascular fat and increased macrophage activation. Aldosterone receptor antagonism and free radical scavengers were able to restore this capacity and reduce macrophage activation. However, in a mouse deficient of macrophages CD11b-diptheria toxin receptor (CD11b-DTR), there was no increase in contractility of arteries following aldosterone incubation or hypoxia. CONCLUSIONS: The presence and activation of macrophages in adipose tissue is the key modulator of the increase in contractility in arteries with perivascular fat following induction of inflammation. Despite multiple factors that may be involved in bringing about the vascular consequences of obesity, the ability of eplerenone to ameliorate the inflammatory effects of both aldosterone and hypoxia may be of potential therapeutic interest. PMID- 21273559 TI - RhoA-mediated signaling in Notch-induced senescence-like growth arrest and endothelial barrier dysfunction. AB - OBJECTIVE: Notch signaling has a critical role in vascular development and morphogenesis. Activation of Notch in endothelial cells led to a senescence-like phenotype with loss of barrier function. Our objective was to understand the molecular pathways mediating this phenotype. METHODS AND RESULTS: Human primary endothelial cells increase expression of Notch receptors and ligands during propagation in vitro toward natural senescence. This senescence was induced at low passage with Notch activation. We characterized the pathways activated downstream of Notch signaling. Notch was activated by Delta-like 4 ligand or constitutively active Notch receptors and measured for cell proliferation, migration, and sprouting. Notch signaling triggered early senescence in low passage cells, characterized by increased p53 and p21 expression. The senescence phenotype was associated with hyperpermeability of the monolayer, with disrupted vascular endothelial cadherin and beta-catenin levels and localization. Consistent with changes in cell shape and contact, we demonstrated that Notch activation increases myosin light chain phosphorylation by activating Rho kinase. Inhibition of Rho abrogated Notch-induced myosin light chain phosphorylation and led to enhanced barrier function by reorganizing F-actin to beta-catenin containing cell-cell adherens junctions. CONCLUSIONS: Our findings show that RhoA/Rho kinase regulation by Notch signaling in endothelial cells triggers a senescence phenotype associated with endothelial barrier dysfunction. PMID- 21273561 TI - Genetic inactivation of prokineticin receptor-1 leads to heart and kidney disorders. AB - OBJECTIVE: Prokineticins are potent angiogenic hormones that use 2 receptors, prokineticin receptor-1 (PKR1) and PKR2, with important therapeutic use in anticancer therapy. Observations of cardiac and renal toxicity in cancer patients treated with antiangiogenic compounds led us to explore how PKR1 signaling functioned in heart and kidney in vivo. METHODS AND RESULTS: We generated mice with a conditional disruption of the PKR1 gene. We observed that PKR1 loss led to cardiomegaly, severe interstitial fibrosis, and cardiac dysfunction under stress conditions, accompanied by renal tubular dilation, reduced glomerular capillaries, urinary phosphate excretion, and proteinuria at later ages. Abnormal mitochondria and increased apoptosis were evident in both organs. Perturbation of capillary angiogenesis in both organs was restored at the adult stage potentially via upregulation of hypoxia-inducible factor-1 and proangiogenic factors. Compensatory mechanism could not revoke the epicardial and glomerular capillary networks, because of increased apoptosis and reduced progenitor cell numbers, consistent with an endogenous role of PKR1 signaling in stimulating epicardin+ progenitor cell proliferation and differentiation. CONCLUSIONS: Here, we showed for the first time that the loss of PKR1 causes renal and cardiac structural and functional changes because of deficits in survival signaling, mitochondrial, and progenitor cell functions in found both organs. PMID- 21273562 TI - Identification of peroxiredoxin-1 as a novel biomarker of abdominal aortic aneurysm. AB - OBJECTIVE: In the search of novel biomarkers of abdominal aortic aneurysm (AAA) progression, proteins released by intraluminal thrombus (ILT) were analyzed by a differential proteomic approach. METHODS AND RESULTS: Different layers (luminal/abluminal) of the ILT of AAA were incubated, and the proteins released were analyzed by 2-dimensional difference in-gel electrophoresis. Several differentially expressed proteins involved in main AAA pathological mechanisms (proteolysis, oxidative stress, and thrombosis) were identified by mass spectrometry. Among the proteins identified, peroxiredoxin-1 (PRX-1) was more released by the luminal layer compared with the abluminal layer of the ILT, which was further validated by Western blot, ELISA, and immunohistochemistry. We demonstrated increased PRX-1 serum levels in AAA patients compared with healthy subjects and also positive correlation among PRX-1 and AAA diameter, plasmin antiplasmin, and myeloperoxidase levels. Finally, a prospective study revealed a positive correlation between PRX-1 serum levels and AAA expansion rate. Moreover, the combination of PRX-1 and AAA size had significantly additive value in predicting growth. CONCLUSIONS: Several proteins associated with AAA pathogenesis have been identified by a proteomic approach in ILT-conditioned medium. Among them, PRX-1 serum levels are increased in AAA patients and correlate with AAA size and growth rate, suggesting the potential use of PRX-1 as a biomarker for AAA evolution. PMID- 21273563 TI - Histamine deficiency decreases atherosclerosis and inflammatory response in apolipoprotein E knockout mice independently of serum cholesterol level. AB - OBJECTIVE: Histamine and histamine receptors are found in atherosclerotic lesions, and their signaling and subsequent proatherogenic or proinflammatory gene expression are involved in atherogenesis. In the present study, we generated apolipoprotein E (apoE) and histamine synthesizing histidine decarboxylase double knockout (DKO) mice on a C57BL/6J (wild-type mice) background to clarify the roles of histamine in atherosclerosis. METHODS AND RESULTS: Wild-type, apoE knockout (KO), and DKO mice were fed a high-cholesterol diet to analyze hyperlipidemia-induced atherosclerosis. Compared with wild-type mice, apoE-KO mice showed increased expression of histamine and its receptors, corresponding to increased atherosclerotic lesion areas and expression of inflammatory regulators, such as nuclear factor-kappaB, scavenger receptors, inflammatory cytokines, and matrix metalloproteinases. Histamine deficiency after deletion of histidine decarboxylase reduced atherosclerotic areas and expression of a range of the inflammation regulatory genes, but serum cholesterol levels of DKO mice were higher than those of apoE-KO mice. CONCLUSIONS: These results indicate that histamine is involved in the development of atherosclerosis in apoE-KO mice by regulating gene expression of inflammatory modulators, an action that appears to be independent of serum cholesterol levels. In addition to acute inflammatory response, histamine participates in chronic inflammation, such as hyperlipidemia induced atherosclerosis, and might be a novel therapeutic target for the treatment of atherosclerosis. PMID- 21273564 TI - A 5-item scale to predict stroke outcome after cortical middle cerebral artery territory infarction: validation from results of the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) Study. AB - BACKGROUND AND PURPOSE: Various clinical, laboratory, and radiographic parameters have been identified as predictors of outcome for ischemic stroke. The purpose of this study was to combine these parameters into a validated scale for outcome prognostication in patients with a middle cerebral artery territory infarction. METHODS: We retrospectively reviewed 129 patients over a 2-year period and considered demographic, clinical, laboratory, and radiographic parameters as potential predictors of outcome. Inclusion criteria were unilateral hemispheric infarcts within the middle cerebral artery territory >15 mm in diameter. Our primary outcome measure was a favorable recovery defined as a modified Rankin Score was <=2 at 30 days. A multivariable model was used to determine independent predictors of outcome and weighted to create a 5-item scale to predict stroke recovery. External validation of this model was done using data from the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) study. RESULTS: The 5 independent predictors of outcome were as follows: age (OR, 1.09; 95% CI, 1.03 to 1.14; P=0.001), National Institutes of Health Stroke Scale score (OR, 1.17; 95% CI, 1.06 to 1.30; P=0.003), infarct volume (OR, 1.01; 95% CI, 1.00 to 1.02; P=0.03), admission white blood cell count (8.5*10(3)/mm(3); OR, 1.16; 95% CI, 1.03 to 1.27; P=0.04), and presence of hyperglycemia (OR, 4.2; 95% CI, 1.1 to 16.4; P=0.04). Combining these variables into a point scale significantly improved prediction over the individual variables accounted alone as evidenced by the area underneath the receiver operating curve (OR, 0.91; 95% CI, 0.87 to 0.96; P=0.0001). When applied to the DEFUSE study population for validation, the model achieved a sensitivity of 83% and specificity of 86%. CONCLUSIONS: With validation from a prospective study of similar patients, this model serves as a useful clinical and research tool to predict stroke recovery after cortical middle cerebral artery territory infarction. PMID- 21273565 TI - Changes in intracortical excitability after transient ischemic attack are associated with ABCD2 score. AB - BACKGROUND AND PURPOSE: A transient ischemic attack (TIA) is a brief ischemic episode characterized by rapid clinical resolution and not associated with permanent cerebral infarction. Whether changes in intracortical excitability persist and are related to clinical predictors of stroke risk after TIA remains unknown. METHODS: Participants were individuals with clinically resolved motor TIA with no structural lesions and healthy age-matched control participants. Single and paired-pulse transcranial magnetic stimulation was used to measure intracortical excitability. Recruitment curves for percent inhibition and facilitation were used to derive excitability thresholds. Correlations between threshold asymmetries and ABCD(2) score were performed. RESULTS: Results showed a significant 3-way interaction with reduced inhibition and enhanced facilitation in the affected compared with unaffected hemisphere after TIA. No significant differences were present in healthy participants. Asymmetries in intracortical inhibition and facilitation were significantly correlated with ABCD(2) score. CONCLUSIONS: The present study is the first, to our knowledge, to demonstrate altered intracortical inhibition and facilitation in the affected hemisphere after TIA. These changes occurred on average 2 weeks after clinical signs of TIA resolved and in the absence of structural lesions and were not present in healthy age-matched control participants. Furthermore, this study is the first, to our knowledge, to report that changes in intracortical excitability after TIA are associated with ABCD(2) score. PMID- 21273566 TI - The role of vitamin B in stroke prevention: a journey from observational studies to clinical trials and critique of the VITAmins TO Prevent Stroke (VITATOPS). PMID- 21273567 TI - Osteopontin reduced hypoxia-ischemia neonatal brain injury by suppression of apoptosis in a rat pup model. AB - BACKGROUND AND PURPOSE: Osteopontin (OPN) is neuroprotective in ischemic brain injuries in adult experimental models; therefore, we hypothesized that OPN would provide neuroprotection and improve long-term neurological function in the immature brain after hypoxic-ischemic (HI) injury. METHODS: HI was induced by unilateral ligation of the right carotid artery followed by hypoxia (8% O(2) for 2 hours) in postnatal Day 7 rats. OPN (0.03 MUg or 0.1 MUg) was injected intracerebroventricularly at 1 hour post-HI. Temporal expression of endogenous OPN was evaluated in the normal rat brain at the age of 0, 4, 7, 11, 14, and 21 days and in the ipsilateral hemisphere after HI. The effects of OPN were evaluated using 2-3-5-triphenyl tetrazolium chloride staining, apoptotic cell death assay, and cleaved caspase-3 expression. Neurological function was assessed by the Morris water maze test. RESULTS: Endogenous OPN expression in the brain was the highest at the age of 0 day with continuous reduction until the age of 21 days during development. After HI injury, endogenous OPN expression was increased and peaked at 48 hours. Exogenous OPN decreased infarct volume and improved neurological outcomes 7 weeks after HI injury. OPN-induced neuroprotection was blocked by an integrin antagonist. CONCLUSIONS: OPN-induced neuroprotection was associated with cleaved-caspase-3 inhibition and antiapoptotic cell death. OPN treatment improved long-term neurological function against neonatal HI brain injury. PMID- 21273568 TI - Stroke Council and American Stroke Association update. PMID- 21273570 TI - Letter by Wachter et al regarding article "Cost-effectiveness of outpatient cardiac monitoring to detect atrial fibrillation after ischemic stroke". PMID- 21273569 TI - Stem Cell Therapy as an Emerging Paradigm for Stroke (STEPS) II. AB - Cell-based therapies represent a new therapeutic approach for stroke. In 2007, investigators from academia, industry leaders, and members of the National Institutes of Health crafted recommendations to facilitate the translational development of cellular therapies as a novel, emerging modality for stroke from animal studies to clinical trials. This meeting was called Stem Cell Therapies as an Emerging Paradigm in Stroke (STEPS) and was modeled on the format of the Stroke Therapy Academic Industry Roundtable (STAIR) meetings. Since publication of the original STEPS guidelines, there has been an explosive growth in the number of cellular products and in the number of new laboratory discoveries that impact the safety and potential efficacy of cell therapies for stroke. Any successful development of a cell product will need to take into consideration several factors, including the preclinical safety and efficacy profile, cell characterization, delivery route, in vivo biodistribution, and mechanism of action. In 2010, a second meeting called STEPS 2 was held to bring together clinical and basic science researchers with industry, regulatory, and National Institutes of Health representatives. At this meeting, participants identified critical gaps in knowledge and research areas that require further studies, updated prior guidelines, and drafted new recommendations to create a framework to guide future investigations in cell-based therapies for stroke. PMID- 21273571 TI - Poor performance of current prognostic scores for early risk of recurrence after minor stroke. AB - BACKGROUND AND PURPOSE: The ABCD(2) score predicts the early risk of stroke after transient ischemic attack. The early risk of recurrence after minor stroke is as high but the only validated prognostic scores for use in minor stroke predict long-term risk of recurrence: the Essen Stroke Risk Score and the Stroke Prognosis Instrument II. METHODS: We determined the prognostic value of the ABCD(2) score, Essen Stroke Risk Score, and Stroke Prognosis Instrument II in a prospective population-based study in Oxfordshire, UK, of all incident and recurrent stroke (Oxford Vascular Study). Minor stroke was defined as an National Institutes of Health Stroke Scale score <=5 at the time of first assessment. The 90-day risks of recurrent stroke were determined in relation to each score. Areas under the receiver operator curves indicated predictive value. RESULTS: Of 1247 first events in the study period, 488 were transient ischemic attacks, 520 were minor strokes, and 239 were major strokes. The ABCD(2) score was modestly predictive (area under the receiver operator curve, 0.64; 0.53 to 0.74; P=0.03) of recurrence at 7 days after minor stroke and at 90 days (0.62; 0.54 to 0.70; P=0.004). Neither Essen Stroke Risk Score (0.50; 0.42 to 0.59; P=0.95) nor Stroke Prognosis Instrument II (0.48; 0.39 to 0.60; P=0.92) were predictive of 7-day or 90-day risk of recurrent stroke. Of the traditional vascular risk factors, etiologic classification (Trial of ORG 10172 in Acute Stroke Treatment) and variables in the ABCD(2) score, only blood pressure >140/90 mm Hg (hazard ratio, 2.75; 1.18 to 6.38; P=0.02) and large artery disease (hazard ratio, 2.21; 1.00 to 4.88; P=0.05) were predictive of 90-day risk. CONCLUSIONS: The predictive power of the ABCD(2) score is modest in patients with minor stroke, and neither the Essen Stroke Risk Score nor the Stroke Prognosis Instrument II predicts early recurrence. More reliable early risk prediction after minor stroke is required. PMID- 21273572 TI - Novel dynamic four-dimensional CT angiography revealing 2-type motions of cerebral arteries. AB - BACKGROUND AND PURPOSE: We developed a novel dynamic 4-dimensional CT angiography to accurately evaluate dynamics in cerebral aneurysm. METHODS: Dynamic 4 dimensional CT angiography achieved high-resolution 3-dimensional imaging with temporal resolution in a beating heart using dynamic scanning data sets reconstructed with a retrospective simulated R-R interval reconstruction algorithm. RESULTS: Movie artifacts disappeared on dynamic 4-dimensional CT angiography movies of 2 kinds of stationary phantoms (titanium clips and dry bone). In the virtual pulsating aneurysm model, pulsation on the dynamic 4 dimensional CT angiography movie resembled actual movement in terms of pulsation size. In a clinical study, dynamic 4-dimensional CT angiography showed 2-type motions: pulsation and anatomic positional changes of the cerebral artery. CONCLUSIONS: This newly developed 4-dimensional visualizing technique may deliver some clues to clarify the pathophysiology of cerebral aneurysms. PMID- 21273573 TI - Innovative approaches helpful to enhance knowledge on weather-related stroke events over a wide geographical area and a large population. AB - BACKGROUND AND PURPOSE: Results on the effect of weather on stroke occurrences are still confusing and controversial. The aim of this study was to retrospectively investigate in Tuscany (central Italy) the weather-related stroke events through the use of an innovative source of weather data (Reanalysis) together with an original statistical approach to quantify the prompt/delayed health effects of both cold and heat exposures. METHODS: Daily stroke hospitalizations and meteorologic data from the Reanalysis 2 Achieve were obtained for the period 1997 to 2007. Generalized linear and additive models and an innovative modeling approach, the constrained segmented distributed lag model, were applied. RESULTS: Both daily averages and day-to-day changes of air temperature and geopotential height (a measure that approximates the mean surface pressure) were selected as independent predictors of all stroke occurrences. In particular, a 5 degrees C temperature decrease was associated with 16.5% increase of primary intracerebral hemorrhage of people >=65 years of age. A general short term cold effect on hospitalizations limited to 1 week after exposure was observed and, for the first time, a clear harvesting effect (deficit of hospitalization) for cold-related primary intracerebral hemorrhage was described. Day-to-day changes of meteorologic parameters disclosed characteristic U- and J shaped relationships with stroke occurrences. CONCLUSIONS: Thanks to the intrinsic characteristic of Reanalysis, these results might simply be implemented in an operative forecast system regarding weather-related stroke events with the aim to develop preventive health plans. PMID- 21273575 TI - Frequent absence of tumor suppressor FUS1 protein expression in human bone and soft tissue sarcomas. AB - BACKGROUND: FUS1 is a tumor suppressor gene located on human chromosome 3p21.3. Frequent loss of FUS1 protein expression is associated with lung cancer development. This study examined FUS1 expression and its possible tumor suppressive role in bone and soft tissue sarcomas. MATERIALS AND METHODS: The expressions of FUS1 mRNA and FUS1 protein were assessed in sarcoma cell lines, sarcoma tissues, benign bone and soft-tissue tumor (BST) tissues, and healthy tissues. Exogenous FUS1 gene transfection was performed on sarcoma cell lines. RESULTS: FUS1 mRNA expression was detected in all sarcoma cell lines, all benign BSTs and healthy tissues, and almost all sarcoma tissues. In contrast, FUS1 protein expression was frequently lost in sarcoma cells and sarcoma tissues. The exogenous FUS1 gene delivery induced strong FUS1 protein expression, inhibition of cell viability and apoptosis in sarcoma cells. CONCLUSION: FUS1 may act as a tumor suppressor in bone and soft-tissue sarcomas. PMID- 21273576 TI - Measuring IGF-1, ER-alpha and EGFR expression can predict tamoxifen-resistance in ER-positive breast cancer. AB - In vitro studies have suggested that tamoxifen resistance may be due to altered expression and downstream signalling of insulin-like growth factor-1 (IGF-1) receptor (IGF-1l), oestrogen receptor-alpha (ERalpha), epidermal growth factor receptor (EGFR) and HER-2. We investigated which gene expressions could predict tamoxifen resistant breast cancer. Expression of IGF-1R, IGF-1 ligand (IGF-1), ERalpha, EGFR and HER-2 in 91 ER-positive breast cancer tumours were measured using real-time PCR and correlated with clinical outcome. The tamoxifen resistant group (n=20) consisted of: i) tumours which were resistant to neoadjuvant tamoxifen treatment and ii) tumours which were excised from patients who later developed recurrence or metastasis during adjuvant tamoxifen treatment. These were compared with tamoxifen sensitive tumours which were surgical excision specimens from patients who did not develop recurrence/metastasis during adjuvant tamoxifen treatment. Tumours with higher IGF-1 ligand and ERalpha expression took longer to develop tamoxifen resistance. Tamoxifen resistant tumours had lower IGF 1 and ERalpha expression compared to tamoxifen-sensitive tumours. IGF-1 expression strongly correlated with ERalpha expression in the tamoxifen sensitive group only. ERalpha inversely correlated with EGFR expression in the tamoxifen resistant group only. We conclude that IGF-1 ligand and ERalpha expression in breast carcinomas can be measured to predict tamoxifen resistance. Measuring ERalpha expression using RT-PCR may be more sensitive than immunohistochemistry in determining anti-oestrogen sensitivity. PMID- 21273574 TI - Inhibition of tumor cellular proteasome activity by triptolide extracted from the Chinese medicinal plant 'thunder god vine'. AB - AIMS: The molecular mechanisms of triptolide responsible for its antitumor properties are not yet fully understood. The ubiquitin/proteasome system is an important pathway of protein degradation in cells. This study investigated whether triptolide may inhibit proteasomal activity and induce apoptosis in human cancer cells. MATERIALS AND METHODS: In vitro proteasome inhibition was measured by incubation of a purified 20S proteasome with triptolide. Human breast and prostate cancer cell lines were also treated with different doses of triptolide for different times, followed by measurement of proteasome inhibition (levels of the chymotrypsin-like activity, ubiquitinated proteins and three well-known proteasome target proteins, p27, IkappaB-alpha and Bax) and apoptosis induction (caspase-3 activity and PARP cleavage). RESULTS: Triptolide did not inhibit the chymotrypsin-like activity of purified 20S proteasome. However, treatment of triptolide was able to cause decreased levels of cellular proteasomal chymotrypsin-like activity and accumulation of ubiquitinated proteins and three well-known proteasome target proteins in human breast and prostate cancer cells, associated with apoptosis induction. CONCLUSION: It is possible that at least one of metabolites of triptolide has proteasome-inhibitory activity. PMID- 21273577 TI - Human lymphoma cells develop resistance to radiation in the presence of astrocytes in vitro. AB - BACKGROUND: Lymphomas growing in the central nervous system exhibit resistance to radiotherapy compared to lymphomas of the lymph nodes. Because astrocytes have been shown to reduce radiation-induced neuronal toxicity, this study hypothesized that astrocytes might protect lymphoma cells from radiation-induced cell killing. MATERIALS AND METHODS: A human lymphoma cell line, H9, and normal human astrocytes were grown in culture, exposed to radiation and assessed for cell viability, radiation sensitivity, glutathione content, induction of apoptosis and cell-cycle distribution. RESULTS: Cell survival assays demonstrated that H9 cells growing in an astrocyte-monolayer and also in an astrocyte-conditioned medium displayed radioresistance compared with H9 cells growing under standard conditions. The radioresistance correlated with accumulation of H9 cells in the G(2) phase of the cell cycle, suppression of radiation-induced apoptosis and coincided with a moderate increase in glutathione. CONCLUSION: The findings of this study suggest that astrocytes may play a role in the radioresistance exhibited by lymphomas of the central nervous system. PMID- 21273578 TI - Apoptosis of SAS cells induced by sonodynamic therapy using 5-aminolevulinic acid sonosensitizer. AB - BACKGROUND: 5-Aminolevulinic acid (ALA) has been used as a photodynamic sensitizer for cancer treatment using photodynamic therapy. However, the light has markedly limited penetration depth. It was found that ALA also responds to low energy ultrasound, which has the capability to penetrate deep into tissues. Therefore, sonodynamic therapy (SDT) is a promising method for noninvasive treatment of tumors embedded deep in the tissue. It is desirable to kill the cancer cells via apoptosis rather than necrosis, and therefore, it is necessary to gain a better understanding of the mechanisms of treating cancer using SDT. MATERIALS AND METHODS: The apoptosis of SAS cells induced by pulsed 1.05MHz ultrasound in combination with ALA was investigated in vitro. RESULTS: The cells exposed to SDT with 10 MUg/ml ALA displayed significantly higher apoptosis than cells treated by ultrasound alone. There was notably increased reactive oxygen species (ROS) production in the cells treated by SDT with ALA than by ultrasound alone, resulting in higher lipid peroxidation (LPO) level and more cells losing their mitochondrial membrane potential (MMP). CONCLUSION: ALA-mediated SDT produced strong apoptotic effects on SAS cells, which were mainly related to the excessive intracellular ROS production followed by LPO increase and MMP decrease. PMID- 21273579 TI - Procathepsin D and cytokines influence the proliferation of lung cancer cells. AB - Enzymatically inactive procathepsin D (pCD) has been established as an important factor in the development of lung cancer. In addition to serving as a growth factor, pCD is also involved in communication between cancer cells and surrounding cells. In the present investigation, a possible combination of autocrine and paracrine actions of pCD was investigated. pCD initiated secretion of interleukin (IL)-4, IL-8, IL-10 and IL-13 from lung cancer cells. These cytokines participated in the proliferation of the cancer cells, as demonstrated both by adding the cytokines and by inhibition using specific anti-cytokine antibodies. Using several clones of lung cancer cells differing in production of activation peptide, the pCD/cytokine cooperation and action was shown to be dependent on pCD secretion. Further proof that pCD is one of the key molecules involved in cancer development is presented. PMID- 21273580 TI - Feulgen staining remains the gold standard for precise DNA image cytometry. AB - AIM: The suitability of Papanicolaou staining and of hematoxylin staining for DNA single-cell cytometry was investigated in comparison to Feulgen staining. MATERIALS AND METHODS: Ten normal cervical smears and ten cervical smears containing cells of a squamous cell carcinoma in situ were analyzed. The integrated optical density (IOD) of 200 epithelial cells, chosen per random, was determined using a CM-1 TV-image analysis system (Hund, Wetzlar, Germany). Various DNA cytometric variables, accepted by the European Society for Analytical and Cellular Pathology (ESACP), and the mean nuclear area were calculated. Two measurements were performed after Papanicolaou staining (wavelengths: 530 nm and 590 nm), followed by measurements after hematoxylin re-staining (wavelength: 590 nm) and after Feulgen restaining (wavelength: 570 nm). RESULTS: All histograms of Feulgen-stained normal squamous epithelia revealed a regular DNA distribution. The corresponding histograms after Papanicolaou staining or hematoxylin staining showed a wide scatter of values instead of a clear-cut diploid peak and an increased number of values >4c. Similar findings were observed in the carcinomatous smears. In particular, the mean values of the dispersion parameters (2cDI, entropy, ploidy imbalance and 2,5cEE) were significantly increased as compared to Feulgen staining. CONCLUSION: Diagnostic or prognostic conclusions cannot be drawn from DNA measurements on Papanicolaou-stained or hematoxylin stained specimens; Feulgen staining remains the gold standard for such purposes. PMID- 21273581 TI - EGFR codon 497 polymorphism - implications for receptor sensitivity to inhibitors in HNSCC cell lines. AB - BACKGROUND: The epidermal growth factor receptor (EGFR, ErbB-1, HER-1) is overexpressed in many epithelial tumors, particularly head and neck squamous cell carcinomas (HNSCCs) and is related to poor prognosis. For non-small cell lung cancer (NSCLC) it was found that activating mutations in the kinase domain of the receptor predicted a high response-rate to EGFR-specific kinase inhibitors. The goal of the present study was to investigate potential sequence changes of EGFR in HNSCC cells and to determine their possible role in tumor biology. MATERIALS AND METHODS: The whole EGFR coding sequence of eleven previously well characterized HNSCC cell lines was determined by RT-PCR sequencing. The response of the cells to the kinase inhibitor AG1478 and the monoclonal anti-EGFR antibody cetuximab was evaluated by cell cycle and Western blot analysis. RESULTS: None of the cell lines exhibited EGFR mutations. However, 4 out of the 11 (36%) cell lines harboured the K497 polymorphism in the receptor. The R497 cell lines were more frequently (71%) derived from N(+) tumors than the K497 cell lines (25%), whereas the K497 cells, although not reaching significance, appeared on average to be more sensitive to inhibitor treatment. This effect was particularly pronounced in the AG1478-treated tumor cells and was associated with the level of extracellular-signal regulated kinase-1/2 phosphorylation which appeared more efficiently inhibited in the cell lines exhibiting the K497 EGFR polymorphism. CONCLUSION: EGFR mutations are a rare event in HNSCC cell lines and, consistent with previous studies the EGFR codon 497 polymorphism could play a significant role in HNSCC disease and therapy response. PMID- 21273582 TI - Overexpression of Interleukin-6 suppresses cisplatin-induced cytotoxicity in esophageal squamous cell carcinoma cells. AB - Interleukin-6 (IL-6) expression at local tumor sites or in systemic circulation is associated with disease progression and poor prognosis of esophageal cancer. The aim of this study was to investigate the possible influence of IL-6 on biological activities of esophageal cancer cells in terms of chemosensitivity. Human esophageal cancer cell lines TE13 and KYSE170 were transfected with a plasmid vector expressing IL-6 and stable transfectants overexpressing IL-6 were thus established. The sensitivity of IL-6 transfectants to cisplatin was evaluated using a WST-8 assay and cell-cycle analysis. In addition, the inhibitory effects of IL-6-specific siRNAs were investigated. IL-6 transfectants showed significantly reduced sensitivity to cisplatin compared to control transfectants. In addition, the reduced cisplatin sensitivity of IL-6 transfectants was restored by pretreatment with IL-6-specific siRNA. These results suggest that intracellular IL-6 expression in tumor cells may acts as a resistance factor against cisplatin-based treatments for esophageal cancer. PMID- 21273583 TI - TIP60 as a potential marker for the malignancy of gastric cancer. AB - BACKGROUND: Recently, it has been shown that the loss of the human histone acetyl transferase, TIP60, led to an accumulation of double-strand DNA breaks and has been linked to a growing number of cancer types. MATERIALS AND METHODS: TIP60 expression levels were examined in 46 gastric cancer samples using a quantitative real-time polymerase chain reaction (QRT-PCR). Subsequently, clinicopathological data were correlated with the TIP60 expression score. RESULTS: A down-regulation of the TIP60 gene was observed in 28 out of 46 (61%) specimens of primary gastric cancer. TIP60 down-regulation showed significant correlation with patient age (p=0.0224), depth of tumor invasion (p=0.0401) and lymph node metastasis (p=0.0481). CONCLUSION: The down-regulation of TIP60 is important for the malignant pathway of gastric carcinogenesis. PMID- 21273584 TI - Cytotoxicity of Thymus vulgaris essential oil towards human oral cavity squamous cell carcinoma. AB - BACKGROUND: Oral cavity squamous cell carcinoma (OCSCC) accounts for 2% to 3% of all malignancies and has a high mortality rate. The majority of anticancer drugs are of natural origin. However, it is unknown whether the medicinal plant Thymus vulgaris L. (thyme) is cytotoxic towards head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: Cytotoxicity of thyme essential oil was investigated on the HNSCC cell line, UMSCC1. The IC50 of thyme essential oil extract was 369 MUg/ml. Moreover, we performed pharmacogenomics analyses. RESULTS: Genes involved in the cell cycle, cell death and cancer were involved in the cytotoxic activity of thyme essential oil at the transcriptional level. The three most significantly regulated pathways by thyme essential oil were interferon signaling, N-glycan biosynthesis and extracellular signal-regulated kinase 5 (ERK5) signaling. CONCLUSION: Thyme essential oil inhibits human HNSCC cell growth. Based on pharmacogenomic approaches, novel insights into the molecular mode of anticancer activity of thyme are presented. PMID- 21273585 TI - Thyroid hormones (T3 and T4): dual effect on human cancer cell proliferation. AB - Several findings suggest that the patient's hormonal context plays a crucial role in determining cancer outcome. The exact nature of thyroid hormone action on tumour growth has not been established yet, in fact contrasting data show thyroid hormones have a promotory or an inhibitory action on cancer cell proliferation depending on the case. We hypothesized that not only tissue specificity, but also specific mutations occurring during tumoral development in different thyroid hormone cellular targets are responsible for this dual effect. To test our hypothesis we analysed, by time-course and bromodeoxyuridine assay, thyroid hormone effects on the proliferation of six cancer cell lines originating from the same tissue or organ but carrying different mutations (in phospho-inositide 3 kinase or beta-catenin genes). The data obtained in this study show how mutations that affect the balance between degradation and stabilization of beta-catenin assume a remarkable importance in determining the cell-specific thyroid hormone effect on cell growth. PMID- 21273586 TI - Prognostic value of mitotic counts in breast cancer of Saudi Arabian patients. AB - BACKGROUND: Quantitative methods in combination with other objective prognostic criteria can improve the evaluation of a cancer patient's prognosis, and possibly predict response to therapy. One of the important prognostic and predictive markers is the mitotic count, which has proven valuable in many aspects. In this study, the prognostic value of the mitotic count was assessed in breast cancer (BC) patients in Saudi Arabia. PATIENTS AND METHODS: The study comprised a series of 87 patients diagnosed and treated for breast cancer at the Departments of Surgery and Oncology, King Abdul-Aziz University Hospital, between 2000 and 2008. Mitotic counts were carried out using a standard laboratory microscope (objective, * 40; field diameter, 420 MUm). The number of mitotic figures in 10 consecutive high-power fields (hpf) from the most cellular area of the sample gave the mitotic activity index (MAI, mitotic figures/10 hpf). The standardized mitotic index (SMI) recorded the mitotic count as the number of mitotic figures by area of the neoplastic tissue in the microscopic field, thus the number of mitoses in 10 consecutive fields was corrected for the volume fraction and field size (mitotic figures/mm2). RESULTS: The means of MAI and SMI of the tumors in the entire series of 87 patients were 15 mitotic figures/10 hpf (range 4-45) and 4 mitotic figures/mm2 (range 1-9), respectively. The mitotic counts were higher in advanced stages than in early cancer (p < 0.04). The mitotic counts were significantly larger in patients with high-grade tumor (p < 0.004) and in cases with tumor metastasis (p < 0.004). The mitotic counts were also significantly larger in the recurrent cases than in non-recurrent ones (p < 0.02). CONCLUSION: The quantitatively measurable mitotic counts of cancer cell nuclei are of significant prognostic value in invasive ductal carcinoma of the breast in Saudi Arabia and the mean cut-off values of MAI and SMI can be applied as objective (quantitative) criteria to distinguish breast cancer patients into groups with favorable and less favorable prognosis. PMID- 21273587 TI - NK4 gene therapy combined with cisplatin inhibits tumour growth and metastasis of squamous cell carcinoma. AB - BACKGROUND: NK4 inhibits vascularisation in tumour tissues, thereby arresting tumour growth. However, the antitumour efficacy of individual antiangiogenic molecules expressed in vivo is not sufficiently potent to induce regression in animal models. One of the strategies to overcome this disadvantage is to use chemotherapy. MATERIALS AND METHODS: This study evaluated the efficacy of combining NK4 gene therapy with cisplatin to treat experimental squamous cell carcinomas. For gene therapy, biodegradable cationised gelatin microspheres were used for the controlled release of NK4 plasmid DNA. RESULTS: A combined regimen of antiangiogenic gene therapy and low-dose cisplatin led to a marked decrease in tumour volume and vascularity, and caused increased apoptosis compared to NK4 gene therapy alone. Moreover, combination treatment of NK4 gene therapy and low dose cisplatin dramatically inhibited the formation of lung metastases. CONCLUSION: NK4 gene therapy combined with low-dose cisplatin may be an effective regimen for treating oral squamous cell carcinoma. PMID- 21273588 TI - Constitutively active FGFR3 with Lys650Glu mutation enhances bortezomib sensitivity in plasma cell malignancy. AB - The ectopically expressed fibroblast growth factor receptor 3 (FGFR3) and its constitutively active mutations have been detected in patients with multiple myeloma (MM). This study investigated whether the cytotoxic effects of bortezomib on malignant plasma cells are associated with FGFR3 expression and the existence of mutations of FGFR3. MATERIALS AND METHODS: Cell apoptosis assays were performed in a plasmacytoma cell line, FR4 cells and a myeloma cell line, RPMI8226 cells overexpressing wild-type FGFR3 (FGFR3(WT)) or two different mutants, FGFR3(K650E) or FGFR3(Y373C), and the induction of endoplasmic reticulum (ER) stress protein was compared between each type of cell. RESULTS: FR4 cells with FGFR3(K650E) showed enhanced sensitivity to bortezomib together with increased induction of ER stress proteins, compared to FR4 cells with mock, FGFR3(WT) or FGFR3(Y373C). RPMI8226 cells with FGFR3(K650E) also showed enhanced bortezomib sensitivity. CONCLUSION: This study indicated that FGFR3K650E is associated with bortezomib sensitivity in malignant plasma cells via ER stress pathways. PMID- 21273589 TI - The tumor suppressive effect of angiotensin II type 1 receptor antagonist in a murine osteosarcoma model. AB - BACKGROUND: Angiogenesis is involved in the growth and metastasis of most solid tumors. Several reports have demonstrated that angiotensin II stimulates growth and migration of certain cancer cell lines and induces angiogenesis through up regulation of vascular endothelial growth factor. This study examined whether an angiotensin II type 1 receptor (AT1R) antagonist (CV11974) inhibits osteosarcoma progression and distant metastasis. MATERIALS AND METHODS: Osteosarcoma (LM8) was transplanted into subcutaneous dorsal tissue of C3H mice. The mice were administered CV11974 daily by intraperitoneal injections at 0.1 mg/kg, 1 mg/kg, or 10 mg/kg, or saline for 28 days. RESULTS: Subcutaneous tumor size was smaller in the CV11974 treatment groups than in the control group. Lung and liver metastases were significantly reduced in the CV11974 treatment groups when compared with the control group. CONCLUSION: CV11974 is widely used to treat hypertension clinically and therefore may be a novel antiangiogenic therapy for osteosarcoma through blocking AT1R-mediated signaling. PMID- 21273590 TI - New sarcomatoid cancer cell line SAR-HCV established from a hepatitis C virus related liver tumour lesion. AB - A sarcomatoid carcinoma cell line (SAR-HCV) was established from a malignant liver lesion of a patient infected with hepatitis C virus. SAR-HCV cells were successfully xenografted in SCID mice. Vimentin was strongly positive in cultured SAR-HCV cells, the primary tumour lesion and the xenografts. Hepatocyte paraffin 1 protein and certain cytokeratin markers, CK8, CK18 and AE1/AE3 were not detected in cultured cells, but were focally positive in the tumour lesion and xenografts, suggesting that this cancer cell line preserves some features of hepatocyte differentiation when grown in vivo. HLA class I, N-cadherin, vascular endothelial growth factor, CD44, and heat-shock protein 70 were moderately expressed in this cell line. Spectral karyotyping analysis revealed a nearly triploid karyotype, 34-63<3n>, XXY[12] with complicated genetic abnormalities of chromosomal structure in all metaphases examined. This cell line will be useful in further studying hepato-sarcomatoid carcinoma cells and in understanding carcinogenesis and epithelial-mesenchymal transition in hepatitis C virus-related liver tumour. PMID- 21273591 TI - Oncogramme, a new promising method for individualized breast tumour response testing for cancer treatment. AB - BACKGROUND: Breast cancer is the most widely spread cancer in the world, attracting much research and individualized tumour response testing (ITRT) methods are now used to individualize patient chemotherapeutic administrations. A new ITRT method was developed with optimized processing. MATERIALS AND METHODS: Breast tumour fragments were separated and the cells seeded in a foetal calf serum-free defined medium. After various chemotherapeutic treatments, cytotoxicity was determined by cell death detection with calcein acetoxymethyl and ethidium homodimer labelling. RESULTS: The culture medium allowed breast tumour cell proliferation in culture, while preventing fibroblastic cell survival. Moreover, the cell death analysis gave rise to a chemoresistance profile called an Oncogramme, with statistically significant values. CONCLUSION: The Oncogramme is a new ITRT method which can predict patient cell sensitivities to chemotherapeutics and should be validated by a new phase I clinical trial. PMID- 21273592 TI - Hepatic arterial infusion in the treatment of liver metastases with PEG liposomes in combination with degradable starch microspheres (DSM) increases tumor 5-FU concentration. an animal study in CC-531 liver tumor-bearing rats. AB - The regional application of cytostatics in liver metastases leads to increased concentrations in the tumor tissue. The effect of flow retardation by temporary occlusion and drug targeting with liposome encapsulation (PEG liposomes) on tumor 5-fluorouracil (5-FU) concentrations was investigated. MATERIALS AND METHODS: Tumor-bearing rats were submitted to i.v. or intraarterial (i.a.) therapy with liposome-encapsulated or non-encapsulated 5-FU. The i.a. groups were additionally treated with or without Spherex(r) degradable starch microspheres (DSM). The tumor 5-FU concentrations were determined by high-performance liquid chromatography (HPLC) as area under the curve (AUC). RESULTS: A comparison with i.v. in administered 5-FU yielded the following increases tumor concentrations: 5 FU-PEG liposomes i.v. 27-fold, 5-FU i.a. 19-fold, 5-FU i.a. + DSM 1760-fold, 5-FU PEG liposomes i.a. 110-fold, 5-FU-PEG liposomes i.a. + DSM 7665-fold. CONCLUSION: Liver intratumoral 5-FU concentration increases to >7,500 times that following i.v. administration by a combination of regional administration via the hepatic artery with temporary embolization by DSM and drug targeting by liposome encapsulated 5-FU. PMID- 21273593 TI - Improvement of biodistribution with PEGylated liposomes containing docetaxel with degradable starch microspheres for hepatic arterial infusion in the treatment of liver metastases: a study in CC-531 liver tumor-bearing WAG RIJ rats. AB - AIM: To improve the drug concentration in liver metastases, docetaxel was encapsulated in polyethyleneglycol-liposomes and administered regionally with degradable starch microspheres (DSM). MATERIALS AND METHODS: A rodent model of solitary metastasis (CC-531 adenocarcinoma) was studied. The animals were randomized into six groups and treated with 15 ng/kg docetaxel: I: intravenous (i.v.). II: PEG-liposomes i.v.; III: intraartial (i.a.) via the hepatica artery; IV: i.a.) + DSM; V: PEG-liposomes i.a.; and VI: PEG-liposomes i.a. + DSM. The docetaxel concentration in the serum, liver and liver tumor at defined times (5, 15, 30, 60,120 240 min and 24 h) was measured using HPLC. RESULTS: The area under the concentration (AUC) versus time curves showed an 11-fold higher concentration in the tumor tissue when comparing the docetaxel-PEG-liposomes i.a. + DSM group to the i.v. group (p<0.01). CONCLUSION: Compared to intravenous therapy, i.a. therapy with docetaxel-PEG-liposomes + DSM results in higher tumor tissue concentrations. PMID- 21273594 TI - Neem leaf extract induces radiosensitization in human neuroblastoma xenograft through modulation of apoptotic pathway. AB - Induction of apoptosis is directly correlated with the biological effectiveness of ionizing radiation (IR). Accordingly, we investigated the efficacy of neem leaf extract (NLE) on IR-associated apoptotic transcriptional modulation and cell death in neuroblastoma (NB). MATERIALS AND METHODS: NB xenografts exposed to single dose (SDR, 10 Gy) or fractionated (FIR, 2 Gy/d*5d) with or without NLE were examined for transcriptional activation of 84 apoptotic pathway genes using quantitative polymerase chain reaction. Apoptosis was measured using TdT nick-end labeling. RESULTS: FIR induced 55 and suppressed 10 genes, while SDR induced 49 and suppressed 5 genes. Of these, 46 and 4 genes were commonly up/down-regulated after FIR and SDR. NLE inhibited IR-induced NAIP, BIRC6, BIRC8, NOL3 and enhanced BAK1, BAX, BCL10, CASP1, CASP10 CARD8 and CRADD. Furthermore, NLE conferred FIR- and SDR-induced cell death. CONCLUSION: These data imply that NLE may exert radiosensitization by activating pro-apoptotic signaling and negating survival signaling and may thus potentiate radiotherapy in NB. PMID- 21273595 TI - MAGE expressions mediated by demethylation of MAGE promoters induce progression of non-small cell lung cancer. AB - BACKGROUND: The MAGE gene encodes cancer/testis antigens that are recognized on melanoma cells by autologous cytolytic T lymphocytes. These genes are expressed in various tumor cells, but not in healthy tissues except for the testis and placenta. MAGE expression is known to be activated by promoter demethylation. MATERIALS AND METHODS: The expression of MAGE-A1 and -A3 and promoter methylation of MAGE-A1 and -A3 was investigated in 67 non-small cell lung cancer (NSCLC) specimens and their correlation with clinicopathological parameters was elucidated. RESULTS: Expression of MAGE-A1 and -A3 was detected in 29.9% and 38.8% of the cases. Demethylation of MAGE-A1 and -A3 was detected in 41.8% and 46.3% of the cases. In 18 (of 20) cases, MAGE-A1 expression showed demethylation of MAGE-A1 and in 24 (of 26) cases MAGE-A3 expression showed demethylation of MAGE-A3. The patients with MAGE expression had a worse prognosis than those with no MAGE expression. CONCLUSION: MAGE expression mediated by demethylation of MAGE promoters is associated with aggressive progression of NSCLC. PMID- 21273596 TI - Oleic acid is the active component in the mushroom Daedalea gibbosa inhibiting Bcr-Abl kinase autophosphorylation activity. AB - The hallmark of chronic myeloid leukemia (CML) is the abnormal activity of p210(Bcr-Abl) kinase. Selective kinase inhibitors such as imatinib or nilotinib have been established successfully for the treatment of CML. Despite high rates of clinical response, CML patients can develop resistance to these kinase inhibitors mainly due to point mutations within the Abl kinase domain of the fusion protein. Previously, we reported that a crude extract of the mushroom Daedalea gibbosa inhibited kinase activity of Bcr-Abl kinase. Here we report on the identification of the active component of Daedalea gibbosa, oleic acid, which inhibited Bcr-Abl kinase autophosphorylation in Ba/F3 cells and exhibited anti CML activity in a BCR/ABL-positive mouse model. PMID- 21273597 TI - Chemical Composition and antiproliferative activity of essential oil from the leaves of a medicinal herb, Levisticum officinale, against UMSCC1 head and neck squamous carcinoma cells. AB - BACKGROUND: Oral squamous cell carcinoma (OSCC) is a challenging disease with a high mortality rate. Natural products represent a valuable source for the development of novel anticancer drugs. We investigated the cytotoxic potential of essential oil from the leaves of a medicinal plant, Levisticum officinale (lovage) on head and neck squamous carcinoma cells (HNSCC). MATERIALS AND METHODS: Cytotoxicity of lovage essential oil was investigated on the HNSCC cell line, UMSCC1. Additionally, we performed pharmacogenomics analyses. RESULTS: Lovage essential oil extract had an IC50 value of 292.6 MUg/ml. Genes involved in apoptosis, cancer, cellular growth and cell cycle regulation were the most prominently affected in microarray analyses. The three pathways to be most significantly regulated were extracellular signal-regulated kinase 5 (ERK5) signaling, integrin-linked kinase (ILK) signaling, virus entry via endocytic pathways and p53 signaling. CONCLUSION: Levisticum officinale essential oil inhibits human HNSCC cell growth. PMID- 21273598 TI - Anticancer and antimetastatic activities of Renieramycin M, a marine tetrahydroisoquinoline alkaloid, in human non-small cell lung cancer cells. AB - BACKGROUND: Renieramycin M, has been shown to exhibit promising anticancer activity against some cancer cell lines; however, the underlying mechanism remains unknown. MATERIALS AND METHODS: Renieramycin M was isolated from the blue sponge Xestospongia sp. Anticancer and antimetastatic activities of renieramycin M were investigated in human non-small cell lung cancer cells. RESULTS: Renieramycin M treatment caused p53 activation, which subsequently down-regulated anti-apoptotic MCL-1 and BCL-2 proteins, while the level of pro-apoptotic BAX protein was not altered. The subtoxic concentrations of renieramycin M significantly decreased invasion and migration abilities of cancer cells. In addition, this compound showed a strong inhibitory effect on anchorage independent growth of the cells. CONCLUSION: These results reveal that renieramycin M induced lung cancer cells apoptosis through p53-dependent pathway and the compound may inhibit progression and metastasis of lung cancer cells. PMID- 21273599 TI - ATM/ATR and SMAD3 pathways contribute to 3-indole-induced G1 arrest in cancer cells and xenograft models. AB - BACKGROUND: 3-Indole inhibits lung cancer growth by apoptosis. Here, the growth inhibition mechanism besides apoptosis was further characterized. MATERIALS AND METHODS: The Comet assay was used to examine 3-indole-induced DNA damage. Cell cycle distribution and protein expression were analyzed using flow cytometry, Western blotting and immunohistochemistry in cell and animal models. RESULTS: 3 Indole induced dose-dependent DNA damage, which was reversed by reactive oxygen species (ROS) inhibitor in lung cancer cells. Cell cycle G1 arrest was observed in the 3-indole-treated cells. DNA damage-responsive proteins involved in the ataxia telangiectasia mutated/ataxia telangiectasia and Rad3-related (ATM/ATR) pathway and G1 regulation proteins such as p21 and SMA- and MAD-related protein 3 (SMAD3) were induced in the cell models. The altered expression of ATM, ATR, checkpoint kinase 2 (CHK2), and cell division cycle 25 homolog A (CDC25A) were confirmed in xenograft models. Importantly, the 3-indole-induced ATM/ATR and transforming growth factor (TGF)-beta/SMAD pathways were attenuated by ROS inhibitor. CONCLUSION: 3-Indole causes DNA damage and triggers ATM/ATR and SMAD3 signaling pathways to arrest lung cancer cells at the G1-phase. PMID- 21273600 TI - Effect of genistein on p90RSK phosphorylation and cell proliferation in T47D breast cancer cells. AB - BACKGROUND: The molecular mechanisms of genistein's proliferative effects on breast cancer cells are largely unknown. This study aimed to examine estrogen receptor (ER)-related signaling molecules involved in genistein-associated cell proliferation and survival (ERK1/2, p90RSK, JNK, Akt and NFkappaB) and to correlate these results to cell proliferation. MATERIALS AND METHODS: The effect of genistein on cell-signaling molecules was determined in T47D breast cancer cells by a Bioplex phosphoprotein detection kit. These results were confirmed by Western blotting and were correlated to cell proliferation by MTT assay. RESULTS: Low and high concentrations of genistein induced an ERK1/2-independent decrease in phosphorylated p90RSK. This effect was accompanied by decreased cell proliferation at high concentrations and an increased response at low concentrations of genistein following a 48-hour exposure. CONCLUSION: Concentration-dependent actions of genistein in T47D cells may be due to differential activation of signaling molecules. PMID- 21273601 TI - Increased efficacy and reduced cardiotoxicity of metronomic treatment with cyclophosphamide in rat breast cancer. AB - BACKGROUND/AIM: It has been reported that continuous low-dose (metronomic) administration of cytotoxic drugs may be better tolerated and may have greater antitumor effects than a single high-dose chemotherapy. The aim of this study was to examine the efficacy and cardiotoxicity of metronomic administration of two of the most commonly used anticancer agents, cyclophosphamide (CPA) and doxorubicin (DOX), on an experimental breast cancer of rats. MATERIALS AND METHODS: Breast tumors were induced in Fisher 344 female rats by implanting Mat B III cells. Rats with tumors were randomized into three groups and were treated with a total dose of 160 mg/kg CPA and a total dose of 12 mg/kg DOX, administered twice per week for four weeks. Control rats were injected with saline according to the same schedule. Echocardiography was performed before the start of treatment and before sacrifice, which took place two weeks after the last injection, when plasma troponin was also measured. RESULTS: The metronomic CPA eradicated the tumors and preserved body weight and echocardiographic parameters. The metronomic DOX slowed tumor growth, but was not able to prevent DOX-induced cardiotoxicity. CONCLUSION: These results suggest that the success of a metronomic chemotherapy in terms of both efficacy and toxicity depends on the target, the class and the route of administration of the anticancer agent. PMID- 21273602 TI - Association of cyclooxygenase 2 polymorphic genotypes with prostate cancer in taiwan. AB - The aim of this study was to evaluate the association of polymorphic genotypes in the cyclooxygenase 2 gene (COX2), which is reported to be overexpressed in prostate tumors, with Taiwan prostate cancer patients. MATERIALS AND METHODS: Six polymorphic variants of COX2 were analyzed for their association with prostate cancer susceptibility. A total of 218 patients with prostate cancer and 436 healthy controls in central Taiwan were enrolled in this investigation. P-values and odds ratios with 95% confidence intervals were used to assess the strength of the association. RESULTS: Among the six polymorphic sites examined, only the Cox 2 promoter G-765C (rs14133) genotypes were distributed differently between the prostate cancer and control groups. The COX2 -765GG genotype was associated with higher prostate cancer risk than -765GC. CONCLUSION: These findings provide evidence that the G allele of COX2 promoter G-765C may be associated with the development of prostate cancer and may be a useful marker for early detection of prostate cancer. PMID- 21273603 TI - Significant association of cyclin D1 single nucleotide polymorphisms with oral cancer in taiwan. AB - The cell cycle regulator cyclin D1 (CCND1) is thought to play a major role in the transition of the cell cycle from G(1) to S-phase. It is known that cancer cells have unbalanced cell cycle regulation. This study aimed to investigate the association of CCND1 single nucleotide polymorphisms A870G (rs9344) and C1722G (rs678653) with oral cancer risk and examine the interaction between CCND1 and smoking habit. MATERIALS AND METHODS: In this hospital-based case-control study, the CCND1 polymorphisms were investigated in 620 patients and 620 age- and gender matched controls. RESULTS: Significant differences were shown between the oral cancer and control groups in the distribution of the genotypes (p=0.0014) and allelic frequency (p=0.0027) in the CCND1 rs9344 genotype. Individuals who carried at least one G allele (GG or AG) had a 0.64-fold decreased risk of developing oral cancer compared to those who carried the AA wild-type genotype (95% CI: 0.50-0.81). There was an obvious joint effect of CCND1 rs9344 genotype with smoking habit on oral cancer. CONCLUSION: Cell cycle regulation may play a role in oral carcinogenesis and CCND1 rs9344 polymorphism maybe a useful biomarker for oral oncology. PMID- 21273605 TI - Detection and significance of parametrial micrometastases in early-stage cervical cancer. AB - BACKGROUND: Parametrial metastases are rare in women with small, node-negative cervical tumors. We examined the incidence of micrometastases in women with pathologically negative parametria. PATIENTS AND METHODS: Patients with IA-IB cervical cancer who underwent radical hysterectomy and had no evidence of parametrial metastases were examined. Immunohistochemistry (IHC) using a cytokeratin antibody was performed in parametrial sections. RESULTS: Among 46 patients, a parametrial micrometastasis was identified in 1 (2.2%). Micrometastases were seen in 5% of women with lymphvascular space invasion (LVSI) and in 0 (0%) patients without LVSI (p=0.43). The patient with a parametrial micrometastasis experienced recurrence and died from her disease. In a previous report, we defined patients with tumors <2 cm, negative pelvic lymph nodes, and no LVSI as being at low-risk for parametrial disease. There were no micrometastases in this group of women in the current series. CONCLUSION: Parametrial micrometastases are uncommon in early-stage cervical cancer. PMID- 21273604 TI - Ruta graveolens extract induces DNA damage pathways and blocks Akt activation to inhibit cancer cell proliferation and survival. AB - BACKGROUND: Ruta graveolens is a medicinal herb that has been used for centuries against various ailments. This study examined the anticancer properties of the herb using cancer cell lines. MATERIALS AND METHODS: Methanolic extract of R. graveolens was tested on colon, breast and prostate cancer cells. Viability, cell cycle profiles, clonogenicity and capase activation were measured. Induction and subcellular localizations of p53, 53BP1 and gamma-H2AX proteins were examined. RESULTS: The extract dose-dependently decreased the viability and the clonogenicity of treated cells and induced G2/M arrest, aberrant mitoses, and caspase-3 activation. It also induced the p53 pathway and focal concentration of the DNA damage response proteins 53BP1 and gamma-H2AX. Moreover, the levels of phospho-Akt and cyclin B1 were reduced by treatment, whereas only cyclin B1 was reduced in normal dermal fibroblasts. CONCLUSION: R. graveolens extract contains bioactive compounds which, independently of known photoactivatable mechanisms, potently inhibit cancer cell proliferation and survival through multiple targets. PMID- 21273606 TI - Phase II study of saracatinib (AZD0530) for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). AB - BACKGROUND: Saracatinib (AZD0530) is an orally available Src kinase inhibitor. A phase II study was conducted to evaluate saracatinib in patients with recurrent or metastatic head and neck squamous cell cancer (HNSCC). PATIENTS AND METHODS: This was an open-label, single-arm, phase II study. Patients received 175 mg saracatinib daily either orally or by percutaneous gastrostomy tube. Radiologic imaging for response was planned at the end of each eight-week cycle. RESULTS: Nine patients were enrolled. All patients had received prior radiotherapy and six patients had received prior chemotherapy for recurrent or metastatic disease. The most common adverse event was fatigue. Eight patients had progression of disease by response evaluation criteria in solid tumors (RECIST) within the first eight week cycle and one patient was removed from the study after 11 days due to clinical decline with stable disease according to the RECIST criteria. Median overall survival was six months. The study was closed early due to lack of efficacy according to the early stopping rule. CONCLUSION: Single-agent saracatinib does not merit further study in recurrent or metastatic HNSCC. PMID- 21273607 TI - A phase II study of capecitabine, oxaliplatin, bevacizumab and cetuximab in the treatment of metastatic colorectal cancer. AB - AIM: This study was designed to determine the efficacy and tolerability of capecitabine, oxaliplatin and bevacizumab in combination with cetuximab as first line therapy for advanced colorectal cancer. PATIENTS AND METHODS: Patients with previously untreated advanced colorectal cancer received oxaliplatin 130 mg/m2 and bevacizumab 7.5 mg/kg every three weeks, capecitabine 850 mg/m2 twice daily on days 1-14, and cetuximab at 400 mg/m2 load and 250 mg/m2 weekly. KRAS, BRAF and PI3K mutation status from paraffin-embedded tumor samples were assessed using real-time polymerase chain reaction. RESULTS: Thirty patients were evaluable for safety and efficacy. One patient had a complete response and 12 patients had a partial response, giving an overall response rate of 43% (95% confidence interval (CI) 25%-63%). Fifteen patients had stable disease. The median time to progression was 10.3 months (95% CI, 6.8-16.3 months). The median overall survival was 18.8 months (95% CI, 14.2-23.7 months). Common grade >= 3 non hematological toxicities were skin rash (37%), sensory neuropathy (27%) and diarrhea (17%). Grade >= 3 hematological toxicities were uncommon. Mutations in KRAS, BRAF and PI3K occurred in 34.5%, 10.3% and 10.3% of patients respectively, but did not correlate with treatment outcome. CONCLUSION: The addition of cetuximab to capecitabine, oxaliplatin and bevacizumab did not improve the three drug regimen activity compared to published data and was associated with significant toxicities requiring frequent dose modifications. KRAS, BRAF, and PI3K mutation status were consistent with published literature, but did not affect outcome in this small study. PMID- 21273608 TI - Expression of LGR5, an intestinal stem cell marker, during each stage of colorectal tumorigenesis. AB - BACKGROUND: The Wnt target LGR5 has been recently identified as a murine intestinal stem cell marker. Its role during each stage of human colorectal tumorigenesis remains to be determined. PATIENTS AND METHODS: LGR5 expression was investigated by immunohistochemical analysis in 17 low-grade and 13 high-grade intraepithelial neoplasias and 30 adenocarcinomas. RESULTS: The number of LGR5 positive cells increased tumor, with clustering of the cells to form patches. An apparent difference in their distribution among the tumorigenesis stages was observed. LGR5 expression in luminal surface showed a negative association with the progressive grade of tumors, while that in lower crypt exhibited a positive association with grade. In adenocarcinomas, LGR5 expression in luminal surface was negatively associated with pStage, while it was almost invariably high in lower crypt during advanced pStage disease. CONCLUSION: These results suggest that the shifts in the distribution of LGR5-positive cells towards the lower crypt play a role in the development and progression of colorectal cancer. PMID- 21273609 TI - The role of pelvic lymph node dissection during radical cystectomy for bladder cancer. AB - BACKGROUND: Radical cystectomy is the standard treatment for patients with invasive bladder cancer. Many aspects regarding the role of concomitant pelvic lymph node dissection (PLND), its extension and the oncological impact are still under discussion. MATERIALS AND METHODS: A detailed literature review is presented to assess the impact of pelvic lymph node dissection during radical cystectomy in terms of staging and therapeutic procedure. Analysis of evidence: The study presented the role of imaging in the assessment of lymph node status, the anatomical account of bladder lymphatic drainage and the techniques for dissection. The evidence from the literature examined showed that pathological stage of the bladder, the extent of PLND in both node-negative and - positive disease, the lymph node density and the extracapsular involvement of metastatic lymph nodes are significant independent prognostic factors for disease-free survival. CONCLUSION: Radical cystectomy with bilateral pelvic iliac lymphadenectomy is a standard treatment for high-grade, invasive bladder cancer, providing the best survival outcomes and the lowest local recurrence rates. Even if the precise extent of lymph node dissection is still not standardized, many studies support a more extended lymphadenectomy to obtain better cancer-specific survival rates without significantly increasing the morbidity or mortality of the surgery. The concept of lymph node density may become a useful prognostic variable in high-risk node-positive patients. PMID- 21273610 TI - Two cases with a long-term survival following multidisciplinary treatment for recurrent breast cancer after surgery. AB - Recurrent breast cancer (BC) tends to show an aggressive behavior and the number of cases of long-term survival is limited. Two rare cases of recurrent breast cancer were treated with a multidisciplinary approach. The outcome of the two cases indicated an excellent survival period of more than 13 years after recurrence. These findings suggest that patients who experience a recurrence after tumor resection have a chance of achieving long-term survival when treated with aggressive therapy, even in the presence of extensive metastases involving multiple organs. PMID- 21273611 TI - C-erbB-3 expression in non-small cell lung cancer (NSCLC) patients treated by Erlotinib. AB - BACKGROUND: The clinical impact of c-erbB-3 has seldom been assessed in patients with non small cell lung cancer (NSCLC). PATIENTS AND METHODS: Forty-three NSCLC patients treated by erlotinib for c-erbB-3 and EGFR expression were investigated by immunohistochemistry analysis. RESULTS: Two partial responses, one minor response, two stable diseases and twenty progressive diseases were observed at the first evaluation. Seventeen patients died before evaluation. Median EGFR expression was 70% of the cancer cells. Forty-two percent of the tumours co expressed c-erbB-3 and EGFR without any difference according to histology or disease stage. There was no correlation between c-erbB-3 and EGFR expression. Median survival time was 2.6 months and the six months survival rate was 21%. There was no detectable impact of EGFR (p=0.94) or c-erbB-3 (p=0.93) expression on survival. CONCLUSION: In this small particular cohort of NSCLC patients receiving salvage therapy with erlotinib, there was no correlation between c-erbB 3 expression and clinical parameters, nor between cerbB-3/EGFR expression and outcome. PMID- 21273612 TI - A phase II study of weekly paclitaxel and doxifluridine combination chemotherapy for advanced/recurrent gastric cancer. AB - BACKGROUND: Paclitaxel and doxifluridine (5'-DFUR) have distinct mechanisms of action and toxicity profiles. This study evaluated the antitumor activity and toxicities of combination chemotherapy with these drugs in patients with advanced/recurrent gastric cancer (AGC). PATIENTS AND METHODS: Patients with histologically confirmed AGC, which was either unresectable or metastatic, were included in this study. The treatment consisted of 80 mg/m2 paclitaxel given i.v. on days 1, 8, and 15 every 4 weeks, and 533 mg/m2 doxifluridine given orally on days 1-5 every week. RESULTS: One hundred and four patients were evaluated for toxicity and 93 patients were evaluated for a therapeutic response. The overall response rate was 33.3% (1st line: 41.7%, 2nd line: 25.0%), including a complete remission in two patients, a partial remission in 29, stable disease in 39, progressive disease in 17; the response was not evaluable in six patients. The median overall survival was 287 days. Commonly observed grade 3/4 adverse events were leukopenia (13.5%), anorexia (3.8%), fatigue (3.8%) and diarrhea (2.9%). CONCLUSION: Paclitaxel and doxifluridine combination chemotherapy is a well tolerated and convenient treatment regimen that can be given on an outpatient basis with promising efficacy for AGC. PMID- 21273613 TI - Cortactin in breast cancer: analysis with tissue microarray. AB - BACKGROUND: Tissue microarray (TMA) allows the rapid immunohistochemical analysis of thousands of tissue samples in a parallel fashion. This study was designed to analyze the cortactin status in breast cancer using TMA and to investigate the relationship of cortactin status to breast cancer biology. PATIENTS AND METHODS: Archival tissue specimens from 99 patients with primary invasive breast cancer were selected. The cortactin expression was analyzed by TMA. Age, estrogen receptor status, histological grading and TNM staging data were also collected. RESULTS: There were 23 patients (23.2%) with low (+) expression of cortactin, 60 patients (60.6%) with intermediate (++) expression and 16(16.2%) with strong (+++) expression. There was no significant relationship between cortactin expression and age, histological grading, primary tumor staging, lymph node status, estrogen receptor and TNM stage. By multivariate analysis, estrogen receptor status and TNM staging were found to be significantly related to the overall five-year survival rate. CONCLUSION: Cortactin expression failed to demonstrate a prognostic value for patients with breast cancer. PMID- 21273614 TI - Successful S-1 monotherapy for chemorefractory thymic carcinoma. AB - The optimal chemotherapeutic regimen for inoperable thymic carcinoma remains uncertain and little information is available regarding the usefulness of salvage chemotherapy. S-1, a newly developed oral fluorouracil antitumor drug, has been reported to be effective in the treatment of gastrointestinal tumors and non small cell lung cancer. This case study reports a case of chemorefractory thymic cancer with a good response to S-1 monotherapy. S-1 was used as sixth-line chemotherapy and the response was the first remarkable tumor regression in the patient's clinical course. S-1 appears to have significant activity against thymic carcinoma. PMID- 21273615 TI - Prognostic value of the human antigen R (HuR) in human breast cancer: high level predicts a favourable prognosis. AB - BACKGROUND: The role of human antigen R (HuR) and its prognostic value in breast cancer is currently only partially understood. This study aimed to determine the levels of expression of HuR in breast cancer and assess its prognostic value. MATERIALS AND METHODS: HuR expression levels were assessed in a cohort of human breast cancer specimens and cell lines using both quantitative and qualitative analysis along with immunohistochemical techniques and the results were compared to the patient details. RESULTS: Immunohistochemical staining revealed a weak HuR staining pattern in breast tumour sections compared to the intense epithelial staining of the normal breast tissues. The levels of HuR transcripts were lower in the more advanced TNM4 and TNM3, poor outcome NPI-2 (Nottingham Prognostic Index) and NPI-3 and node-positive tumours compared with the early stage TNM2 and TNM1, NPI-1, and node-negative tumours, although these values did not reach statistical significance. The patients with metastasis, those who died of breast cancer and those with bone metastasis had significantly decreased levels of HuR transcripts, (p=0.031, p=0.018 or p=0.038 respectively) compared to the disease free patients. The patients with poor prognosis, including those with metastasis and those who died of breast cancer, had a significantly lower level of HuR transcripts compared to the disease-free patients (p=0.021). High levels of HuR correlated with longer overall survival, although the values did not reach statistical significance (p=0.06). CONCLUSION: While no significant association of the levels of HuR expression with pathological status of breast cancer is reported, HuR may represent a prognostic factor in human breast cancer, as patients expressing high levels of HuR have a favourable prognosis, and the prognostic role of HuR for breast cancer metastasis, particularly bone metastasis is supported. PMID- 21273616 TI - Pronounced tumour regression after radiotherapy is associated with negative/weak glucose transporter-1 expression in rectal cancer. AB - The aim of this study was to assess glucose transporter-1 (GLUT-1) expression as a predictor of disease outcome in rectal cancer treated by preoperative radio- or chemoradiotherapy. PATIENTS AND METHODS: Operative samples from 175 rectal cancer patients and 78 preoperative biopsies were analysed for GLUT-1 expression using immunohistochemistry. Forty-six patients received long-course radiotherapy, with/without chemotherapy and tumour regression grade was analysed in these specimens. RESULTS: Negative GLUT-1 expression was seen in 25/78 (32%) of the preoperative biopsies and in 38/78 (49%) of the operative samples. There was no significant correlation of GLUT-1 with common clinicopathological factors. A trend towards longer disease-free survival (DFS) for the long-course radiotherapy group patients was seen with negative/weak GLUT-1 staining intensity (p=0.066) and excellent tumour regression grade (p=0.068) in operative samples. Disease free survival (p=0.068) and disease-specific survival (p=0.024) of the patients with excellent tumour regression were longer than among the patients with moderate or less regression. CONCLUSION: A trend towards longer DFS among patients in favour of negative/weak GLUT-1 staining in the operative samples after long-course radiotherapy is demonstrated. PMID- 21273617 TI - Randomized phase II study of paclitaxel and carboplatin or vinorelbine in advanced non-small cell lung cancer. AB - BACKGROUND: A randomized phase II trial was conducted to determine if two non platinum protocols are able to yield a similar efficacy and toxicity profile as compared to two platinum-based doublets in advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: A total of 61 patients were randomly assigned to a reference regimen of carboplatin and paclitaxel (repeated every 3 weeks) or to one of three experimental regimens: paclitaxel plus vinorelbine (repeated every 3 or 4 weeks) and carboplatin plus paclitaxel (repeated every 4 weeks). RESULTS: The objective remission rate for all the patients was 34.1%. The median progression-free survival for all the patients was 3 months. The median overall survival and one-year overall survival were 6 months and 21.5%, respectively. Toxicity was moderate and manageable. Response, survival and toxicity did not significantly differ between the four treatment groups. CONCLUSION: The efficacy and toxicity profile of platinum-free combinations is comparable to that of platinum-based doublets. PMID- 21273618 TI - Clinical significance of STC1 gene expression in patients with colorectal cancer. AB - BACKGROUND: Recent studies suggest that altered patterns of stanniocalcin 1 (STC1) gene expression have a role in human carcinogenesis. This study examined the relationship between the relative expression of the STC1 gene and clinicopathological factors in patients with colorectal cancer. PATIENTS AND METHODS: Surgical specimens of cancer tissue and adjacent normal mucosa were obtained from 202 patients with colorectal carcinomas. The relative expression levels of STC1 mRNA in the cancer and the normal adjacent mucosa were measured by quantitative real-time, reverse-transcriptase polymerase chain reaction. RESULTS: The relative expression levels of the STC1 gene were higher in the cancer tissue than in the normal adjacent mucosa and high expression of STC1 correlated with poor postoperative survival. CONCLUSION: High expression of the STC1 gene might be a useful predictor of poor postoperative outcome in patients with colorectal cancer. PMID- 21273619 TI - Temsirolimus in metastatic chromophobe renal cell carcinoma after interferon and sorafenib therapy. AB - Chromophobe renal cell carcinoma (chRCC) is a common subtype of renal cell carcinoma (RCC), occurring in 6-11% of renal carcinoma patients. Limited clinical trial data have shown minimal activity with cytokines and chemotherapy, although small-molecule inhibitors of the vascular endothelial growth factor and platelet derived growth factor pathways such as sunitinib and sorafenib, which are associated with significant clinical activity in clear-cell RCC (ccRCC), have been associated with a 25% response rate in chRCC. The mammalian target of rapamycin kinase inhibitor temsirolimus demonstrates good clinical activity in ccRCC patients with poor prognosis, with further data suggesting it is an effective treatment for all RCC tumour histologies. This report describes the case of a patient with chRCC who experienced rapid improvement in his general condition and stable disease on treatment with temsirolimus, following disease progression on interferon alfa and sorafenib treatment. This case report suggests that temsirolimus is an effective and appropriate treatment for this RCC tumour subtype. PMID- 21273620 TI - 5-FU-induced hyperammonemic encephalopathy in a case of metastatic rectal adenocarcinoid successfully rechallenged with the fluoropyrimidine analog, capecitabine. AB - Neurological complications of both fluorouracil (5-FU) and its oral prodrug, capecitabine, have been described in the literature. This study reported the case of a 70-year-old female with metastatic adenocarcinoid of the rectum who developed hyperammonemic encephalopathy, following infusional 5-FU therapy, manifesting itself as intractable nausea, vomiting, confusion and disorientation. Interestingly, when the patient was rechallenged with the fluoropyrimidine analog, capecitabine, neither hyperammonemia nor symptom recurrence was observed. 5-FU is an integral component of effective anti-neoplastic treatment for metastatic colorectal cancer, but is often discontinued when neurotoxicity develops. This case highlighted the use of capecitabine as an alternative for patients who have demonstrated evidence of 5-FU-induced hyperammonemic encephalopathy. Re-challenging the patient with capecitabine, at a low daily dose intensity, accounted for the overall tolerability of the treatment, as demonstrated by normal ammonia levels and the lack of neurological symptoms. PMID- 21273621 TI - Predictive value of serum biomarkers in patients after portal vein embolization (PVE): a pilot study. AB - BACKGROUND/AIM: Insufficient growth of the liver or tumor progression is an important issue of portal vein embolization (PVE) in some patients. This study evaluated the predictive value of serum biomarkers for liver hypertrophy and tumor progression after PVE. PATIENTS AND METHODS: Serum levels of tumor markers, growth factors and cytokines were determined in 40 patients with malignant liver tumors in the pre- and post-PVE period. The values were compared with contralateral liver hypertrophy and tumor progression. RESULTS: Liver tissue hypertrophy occurred in 26 (65%), tumor progression in 11 (27.5%) and insufficient liver hypertrophy in 3 (7.5%) of the patients. The significant predictive biomarkers of PVE included serum TPA levels, monototal, IGF-BP3, IGF1, TGF-alpha, EGF, HGF, VEGF, TNFa and IL-10 before PVE; and TK, TPA, monototal, IGF BP3, TGFa and IL-8 over the course of 28 days after PVE. CONCLUSION: Certain serum biomarkers have an important predictive value for the result of PVE. PMID- 21273622 TI - The dynamics of serum tumor markers in predicting metastatic uveal melanoma (part 1). AB - AIM: To examine the kinetics of the tumor marker levels: osteopontin (OPN), S 100beta, melanoma inhibitory activity (MIA) and tissue polypeptide-specific antigen (TPS), and to evaluate their potential for predicting earlier liver metastasis in patients with uveal melanoma (UM). PATIENTS AND METHODS: Forty three UM patients who remained disease-free (DF) for at least 10 years, 32 patients with metastatic UM and 53 healthy controls were enrolled. Median and mean levels of the tumor markers OPN, S-100beta, MIA and TPS at the time periods of 0-6, 6-12, 12-18, 18-24 and >24 months prior to confirmation of metastasis by liver ultrasound, CT scan and biopsy, served in a box and whiskers analysis and were compared by Students t-test. Trends of changes in marker levels of DF and metastatic UM groups were calculated and compared by ANOVA. RESULTS: The lead time for predicting metastasis was: 12-18 months both for OPN (p=0.005) and MIA (p=0.37), for S-100beta 18-24 months first increase (p=0.5) followed by a second one 0-6 months (p=0.01) and for TPS 18-24 months (p=0.1). The gradient of the trendlines for the metastatic group was significantly steeper for MIA (p=0.02) and S-100beta (p=0.018) than for the DF group and not statistically significant for OPN (p=0.168). For TPS, the trendline was negative. The overall increase in the levels of OPN and S-100beta was significant, while for TPS and MIA, it was not. CONCLUSION: Significant increases in OPN and S-100beta levels were demonstrated by a major lead time. Trendlines of the metastasis group were steeper than of the DF group predicting liver metastasis. The routine use of those markers in the follow up of UM patients, can enable earlier diagnosis of liver metastasis and effective therapeutic intervention, with an impact on survival. PMID- 21273623 TI - Trends in liver function tests: a comparison with serum tumor markers in metastatic uveal melanoma (part 2). AB - AIM: To compare trends in liver function test (LFT) levels over consecutive visits before detection of liver metastasis (LM) from uveal melanoma (UM) with such trends in the serum tumor markers S-100beta, melanoma inhibitory activity (MIA), osteopontin (OPN), and tissue polypeptide-specific antigen (TPS). PATIENTS AND METHODS: Blood was drawn from 32 patients with metastatic UM and 43 disease free (DF) patients semi-annually for levels of S-100beta, MIA, OPN, and TPS. Abdominal ultrasonography (US) and LFTs were used to detect LM. Median LFT levels were calculated at 6-month intervals prior to the clinical detection of LM. Trends in LFT levels over consecutive visits in the groups were compared with trends in the tumor markers for these groups. RESULTS: Only LDH gave a statistically significant difference between the trends of the metastasis and DF groups (p=0.0041). When calculating the lead time, all of the elevations were non significant except for gamma glutamyltransferase which showed a statistically significant elevation at time 0, the time of detection of metastasis. LDH showed a rise at 0-6 months before detection, but this was not significant. For the tumor markers, steeper trendlines were shown for the metastasis group for MIA and S-100beta, and most of the markers showed a lead time of more than six months, although this was statistically significant only for OPN. CONCLUSION: Following the dynamics of tumor markers and LFTs may help to find metastatic disease in UM patients before the metastases are detectable by imaging, enabling earlier treatment. PMID- 21273624 TI - Pharmacogenetic tailoring of irinotecan-based first-line chemotherapy in metastatic colorectal cancer: results of a pilot study. AB - BACKGROUND: Tolerability to irinotecan may be explained by pharmacogenomic polymorphisms. The purpose of this pharmacogenetic trial was to study the relevance of thymidylate synthase (TS) genotyping and of the isoform 1A1 of uridine diphosphate glucuronosyltransferase (UGT1A1) in order to tailor a combination chemotherapy regimen of 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) in metastatic colorectal cancer. PATIENTS AND METHODS: Patients with favourable TS and UGT1A1 profiles received high-dose (HD) FOLFIRI. Patients with TS-3R/3R could not receive HD-FOLFIRI, and those with UGT1A1-7/7 received standard FOLFIRI. The endpoints were overall response rate and safety. RESULTS: Sixty-nine patients were enrolled in the study. Sixty-five patients received chemotherapy. Twenty patients (30.8%) achieved a partial response. The haematological toxicity was less in the HD-FOLFIRI subgroup. Patients having received HD-FOLFIRI did not experience increased levels of nausea-vomiting, asthenia or alopecia. Diarrhoea was more frequent with HD-FOLFIRI. CONCLUSION: The genotypic assessment allowed a safer use of HD-FOLFIRI. Further investigations may target patients who benefit from intensification. PMID- 21273625 TI - Risk of Ipsilateral breast tumor recurrence in patients treated with Tamoxifen or Anastrozole following breast-conserving surgery with or without radiotherapy. AB - BACKGROUND: It is unknown whether anastrozole (Ana) is superior to tamoxifen (Tam) with regard to local control after breast-conserving surgery without radiotherapy (RT). PATIENTS AND METHODS: Two hundred and ninety-two breast cancer patients who had undergone breast-conserving surgery and been treated with Tam or Ana, with or without RT, were retrospectively analyzed. Ipsilateral breast tumor recurrence (IBTR)-free survival rates were compared according to the treatment drug and RT. RESULTS: In the Tam group, IBTR-free survival rates did not significantly differ according to the use or absence of RT (p=0.08), whereas in the Ana group, a significant difference (5-year IBTR-free survival rate, 98.8% in the RT group vs. 65.7% in the no RT group, p<0.0001) was found. In addition, multivariate analysis showed that RT use was an independent prognostic factor for IBTR-free survival (p=0.01) among the patients treated with Ana. CONCLUSION: Caution is needed when RT is omitted for patients undergoing breast-conserving surgery and receiving Ana for adjuvant treatment. PMID- 21273626 TI - Parameters of biological activity in colorectal cancer. AB - BACKGROUND: The aim of this study was to measure several parameters in patients with early-stage colorectal cancer (CRC) and to evaluate them for their utility in routine clinical practice. PATIENTS AND METHODS: Pre-operative serum levels of the following parameters were measured in 174 patients with CRC (clinical stage I III): carcinoembryonic antigen (CEA), carbohydrate antigen CA 19-9, proliferative marker thymidine kinase (TK), tissue polypeptide antigen (TPA), tissue polypeptide-specific antigen (TPS), interleukin-6 (IL-6), interleukin-10 (IL-10), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP 1), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), vascular endothelial growth factor (VEGF), C-peptide, insulin, adiponectin and leptin. The control group consisted of 50 patients who were undergoing a complete preventive medical examination and in these patients at the time of blood collection there was no evidence of any cancer disease. RESULTS: Significant increase of the following parameters was found in patients with CRC: CEA, CA 19-9, TPA, IL-6, IL-10, TIMP-1, C-peptide, insulin and adiponectin. Only two of these, CA 19-9 and adiponectin, represent highly unfavorable prognostic factors. If elevated, they affect both progression-free interval and overall survival. CONCLUSION: Based on our results, we can conclude that none of the measured parameters fulfills the criteria for use for screening nor for primary diagnosis of CRC. Some of the parameters are important for prognosis estimate: Elevated CA 19-9 is related to an unfavorable prognosis, in terms of cancer recurrence and mortality rate. Angiogenetic factor VEGF represents a prognostic factor important for OS. CEA represents a parameter which is related to disease progression. Interleukins seem to be prospective complementary tumor markers. Adiponectin may be used for estimation of advanced stage of cancer and for estimate of risk of cancer recurrence. PMID- 21273627 TI - A tool for clinical reasoning and reflection using the international classification of functioning, disability and health (ICF) framework and patient management model. AB - BACKGROUND AND PURPOSE: Professional development is a cornerstone of physical therapist practice. As the profession moves toward the ideals of Vision 2020, more emphasis is being placed on the process of clinical decision making. Although reflection and mentorship are widely regarded as important instruments to facilitate the progression of clinical reasoning skills, little guidance exists in the postprofessional arena to assist clinicians with these essential needs. As more organizations develop formal mentoring programs, a need arises for a tool that will engage mentors, proteges, and clinicians of all abilities in thoughtful reflection and discussion that will help develop clinical reasoning skills. CASE DESCRIPTION: The process of developing reflective clinical decision making skills in physical therapist practitioners is described, and how this process was used at one institution is illustrated. A tool for clinical reasoning and reflection is proposed that incorporates the existing conceptual frameworks of the Guide to Physical Therapist Practice and the International Classification of Functioning, Disability and Health (ICF). OUTCOMES: This case report discusses how the tool was implemented by staff with varying levels of expertise, their outcomes in regard to the development of their clinical reasoning skills, and how the tool facilitated mentoring sessions around patient cases to improve care. DISCUSSION: This case report describes a practical application of a postprofessional educational process designed to develop reflective and patient centered clinical reasoning skills. Although this process has shown some preliminary success, more research is warranted. By cultivating reflective thinking and critical inquiry, the physical therapy profession can help develop autonomous practitioners of physical therapy and promote the ideals of Vision 2020. PMID- 21273628 TI - Limb collapse, rather than instability, causes failure in sit-to-stand performance among patients with parkinson disease. AB - BACKGROUND: Previous studies focused on describing successful sit-to-stand (STS) performance in patients with Parkinson disease (PD). Little is known about why these patients fail to perform this transfer activity. Objective This study aimed to determine the role of dynamic stability and limb support in governing successful STS performance in patients with PD and to determine the limits of recovery for discriminating between successful and failed STS trials. DESIGN: This was a cross-sectional study. METHODS: Twenty-eight patients with PD were instructed to perform the STS task. Kinematic data on 18 successful trials and 14 failed trials (when the patients fell backward) were collected with a motion analysis system. Dynamic stability was determined by the anteroposterior position of the body's center of mass (COM) relative to the base of support (BOS) and by the anteroposterior velocity of the COM relative to the BOS (Velocity(COM/BOS,AP)). Limb support was characterized by the hip height (Height(hip)). RESULTS: /b> The findings revealed no between-group ("risers" versus "fallers") differences in dynamic stability. The fallers shifted their COM in a significantly more anterior position to compensate for their lower Velocity(COM/BOS,AP) at seat-off. It was in the vertical direction that the fallers had significantly reduced peak COM velocity (Velocity(COM,vertical)) and lower corresponding Height(hip) than the risers. Results of a stepwise regression model showed that Velocity(COM/BOS,AP) and Height(hip) at the instant of peak Velocity(COM,vertical) could best predict the STS outcome (success versus failure), with an overall prediction accuracy of 87.5%. The limit differentiating successful from failed STS trials was: Height(hip)=-0.814 Velocity(COM/BOS,AP) + 0.463. Limitations All of the patients were community dwelling and had a moderate level of disease severity. The results cannot be generalized to those who are institutionalized or with advanced PD. CONCLUSIONS: Limb support and ill-timed peak forward COM velocity, rather than dynamic stability, play the dominant roles in determining successful STS performance in patients with PD. PMID- 21273629 TI - Responsiveness to change of 10 physical tests used for patients with back pain. AB - BACKGROUND: Few studies have examined the responsiveness of physical tests. OBJECTIVE: The purpose of this study was to explore the responsiveness of 10 physical tests used for patients with back pain in order to illuminate the significance of changes in scores. DESIGN: Cross-sectional and longitudinal designs within a prospective cohort study were applied. METHODS: Distribution based and anchor-based methods were used. Ninety-eight patients (18-65 years of age) with long-lasting back pain were recruited consecutively at an outpatient spine clinic. Measurements The participants were assessed using 10 physical tests and 2 questionnaires (Hannover Functional Ability Questionnaire and Roland-Morris Disability Questionnaire) at inclusion and after rehabilitation. Six predefined hypotheses for each test were examined regarding the association between changes in scores on the physical tests and the self-report measures of functioning and regarding the relationship of changes in scores on the physical tests and external anchors of important change. RESULTS: Five physical tests demonstrated responsiveness by both distribution-based and anchor-based methods: spondylometry, lateral flexion test, fingertip-to-floor test, lift test, and Back Performance Scale (4 hypotheses confirmed). The minimal important change values were all within the range of the smallest detectable change for individual patients. Responsiveness by distribution-based methods only (3 hypotheses confirmed) was shown for the Biering-Sorensen test and the loaded reach test, whereas little evidence of responsiveness (1 hypothesis confirmed) was shown for the Global Physiotherapy Examination flexibility subscale, the Progressive Isoinertial Lifting Evaluation, and the 15-m (50-ft) walk test. Limitations The smallest detectable change values were examined in a small sample of patients and need further exploration. CONCLUSIONS: Responsiveness varied among the 10 physical tests. PMID- 21273630 TI - Information for decision making by patients with early-stage prostate cancer: a comparison across 9 countries. AB - PURPOSE: To describe decisional roles of patients with early-stage prostate cancer in 9 countries and to compare the information they rated important for decision making (DM). METHOD: A survey of recently treated patients was conducted in Canada, Italy, England, Germany, Poland, Portugal, Netherlands, Spain, and Turkey. Participants indicated their decisional role in their actual decision and the role they would prefer now. Each participant also rated (essential/desired/no opinion/avoid) the importance of obtaining answers, between diagnosis and treatment decision, to each of 92 questions. For each essential/desired question, participants specified all purposes for that information (to help them: understand/decide/plan/not sure/other). RESULTS: A total of 659 patients participated with country-specific response rates between 58%-77%. Between 83% 96% of each country's participants recalled actually taking an active decisional role and, in most countries, that increased slightly if they were to make the decision today; there were no significant differences among countries. There was a small reliable difference in the mean number of questions rated essential for DM across countries. More striking, however, was the wide variability within each country: no question was rated essential for DM by even 50% of its participants but almost every question was rated essential by some. CONCLUSIONS: Almost all participants from each country want to participate in their treatment decisions. Although there are country-specific differences in the amount of information required, wide variation within each country suggests that information that patients feel is essential or desired for DM should be addressed on an individual basis in all countries. PMID- 21273631 TI - Two nuclear life cycle-regulated genes encode interchangeable subunits c of mitochondrial ATP synthase in Podospora anserina. AB - An F(1)F(O) ATP synthase in the inner mitochondrial membrane catalyzes the late steps of ATP production via the process of oxidative phosphorylation. A small protein subunit (subunit c or ATP9) of this enzyme shows a substantial genetic diversity, and its gene can be found in both the mitochondrion and/or nucleus. In a representative set of 26 species of fungi for which the genomes have been entirely sequenced, we found five Atp9 gene repartitions. The phylogenetic distribution of nuclear and mitochondrial Atp9 genes suggests that their evolution has included two independent transfers to the nucleus followed by several independent episodes of the loss of the mitochondrial and/or nuclear gene. Interestingly, we found that in Podospora anserina, subunit c is exclusively produced from two nuclear genes (PaAtp9-5 and PaAtp9-7), which display different expression profiles through the life cycle of the fungus. The PaAtp9-5 gene is specifically and strongly expressed in germinating ascospores, whereas PaAtp9-7 is mostly transcribed during sexual reproduction. Consistent with these observations, deletion of PaAtp9-5 is lethal, whereas PaAtp9-7 deletion strongly impairs ascospore production. The P. anserina PaAtp9-5 and PaAtp9-7 genes are therefore nonredundant. By swapping the 5' and 3' flanking regions between genes we demonstrated, however, that the PaAtp9 coding sequences are functionally interchangeable. These findings show that after transfer to the nucleus, the subunit c gene in Podospora became a key target for the modulation of cellular energy metabolism according to the requirements of the life cycle. PMID- 21273632 TI - Rampant purifying selection conserves positions with posttranslational modifications in human proteins. AB - Posttranslational modifications (PTMs) are chemical alterations that are critical to protein conformation and activation states. Despite their functional importance and reported involvement in many diseases, evolutionary analyses have produced enigmatic results because only weak or no selective pressures have been attributed to many types of PTMs. In a large-scale analysis of 16,836 PTM positions from 4,484 human proteins, we find that positions harboring PTMs show evidence of higher purifying selection in 70% of the phosphorylated and N-linked glycosylated proteins. The purifying selection is up to 42% more severe at PTM residues as compared with the corresponding unmodified amino acids. These results establish extensive selective pressures in the long-term history of positions that experience PTMs in the human proteins. Our findings will enhance our understanding of the historical function of PTMs over time and help in predicting PTM positions by using evolutionary comparisons. PMID- 21273633 TI - Spectrum of MHC class II variability in Darwin's finches and their close relatives. AB - The study describes >400 major histocompatibility complex (MHC) class II B exon 2 and 114 intron 2 sequences of 36 passerine bird species, 13 of which belong to the group of Darwin's finches (DFs) and the remaining 23 to close or more distant relatives of DFs in Central and South America. The data set is analyzed by a combination of judiciously selected statistical methods. The analysis reveals that reliable information concerning MHC organization, including the assignment of sequences to loci, and evolution, as well as the process of species divergence, can be obtained in the absence of genomic sequence data, if the analysis is taken several steps beyond the standard phylogenetic tree construction approach. The main findings of the present study are these: The MHC class II B region of the passerine birds is as elaborate in its organization, divergence, and genetic diversity as the MHC of the eutherian mammals, specifically the primates. Hence, the reported simplicity of the fowl MHC is an oddity. With the help of appropriate markers, the divergence of the MHC genes can be traced deep in the phylogeny of the bird taxa. Transspecies polymorphism is rampant at many of the bird MHC loci. In this respect, the DFs behave as if they were a single, genetically undifferentiated population. There is thus far no indication of alleles that could be considered species, genus, or even DF group specific. The implication of these findings is that DFs are in the midst of adaptive radiations, in which morphological differentiation into species is running ahead of genetic differentiation in genetic systems such as the MHC or the mitochondrial DNA. The radiations are so young that there has not been enough time to sort out polymorphisms at most of the loci among the morphologically differentiating species. These findings parallel those on Lake Victoria haplochromine fishes. Several of the DF MHC allelic lineages can be traced back to the MHC genes of the species Tiaris obscura, which we identified previously as the closest extant relative of DFs in continental America. PMID- 21273634 TI - Intragene higher order repeats in neuroblastoma breakpoint family genes distinguish humans from chimpanzees. AB - Much attention has been devoted to identifying genomic patterns underlying the evolution of the human brain and its emergent advanced cognitive capabilities, which lie at the heart of differences distinguishing humans from chimpanzees, our closest living relatives. Here, we identify two particular intragene repeat structures of noncoding human DNA, spanning as much as a hundred kilobases, that are present in human genome but are absent from the chimpanzee genome and other nonhuman primates. Using our novel computational method Global Repeat Map, we examine tandem repeat structure in human and chimpanzee chromosome 1. In human chromosome 1, we find three higher order repeats (HORs), two of them novel, not reported previously, whereas in chimpanzee chromosome 1, we find only one HOR, a 2mer alphoid HOR instead of human alphoid 11mer HOR. In human chromosome 1, we identify an HOR based on 39-bp primary repeat unit, with secondary, tertiary, and quartic repeat units, fully embedded in human hornerin gene, related to regenerating and psoriatric skin. Such an HOR is not found in chimpanzee chromosome 1. We find a remarkable human 3mer HOR organization based on the ~1.6 kb primary repeat unit, fully embedded within the neuroblastoma breakpoint family genes, which is related to the function of the human brain. Such HORs are not present in chimpanzees. In general, we find that human-chimpanzee differences are much larger for tandem repeats, in particularly for HORs, than for gene sequences. This may be of great significance in light of recent studies that are beginning to reveal the large-scale regulatory architecture of the human genome, in particular the role of noncoding sequences. We hypothesize about the possible importance of human accelerated HOR patterns as components in the gene expression multilayered regulatory network. PMID- 21273635 TI - Calprotectin testing in the community. PMID- 21273636 TI - Paradoxical decrease in serum high-density lipoprotein cholesterol and lipid lowering drugs. PMID- 21273637 TI - A transient IgE monoclonal protein in a child. PMID- 21273638 TI - Complex actions of estradiol-3-sulfate in late gestation fetal brain. AB - The most abundant form of estrogen circulating in fetal plasma is sulfo conjugated estrogen; for example, estradiol-3-sulfate (E(2)SO(4)) is more highly abundant than estradiol (E(2)). The present study investigated the ontogeny of the deconjugating (steroid sulfatase [STS]) and conjugating (estrogen sulfotransferase [STF]) enzymes in ovine fetal brain and tested the hypothesis that treatment with E(2)SO(4) would alter the expression of one or both enzymes. Steroid sulfatase was more highly expressed than STF, and both changed as a function of gestational age. Estradiol-3-sulfate infused intracerebroventricularly (icv) significantly increased plasma adrenocorticotropic hormone (ACTH) and cortisol concentrations. Plasma E(2) and E(2)SO(4) were increased, and brain expression of estrogen receptor alpha was decreased. The proteins STS and STF were up- and downregulated, respectively. Pituitary proopiomelanocortin (POMC) and follicle-stimulating hormone (FSH) and hypothalamic corticotrophin-releasing hormone (CRH) messenger RNA (mRNA) was decreased. We conclude that E(2)SO(4) has complex actions on the fetal brain, which might involve deconjugation by STS, but that the net result of direct E(2)SO(4) icv infusion is more complex than can be accounted for by infusion of E(2) alone. PMID- 21273639 TI - Proliferating cell nuclear antigen as a molecular biomarker for spermatogenesis in PTU-induced hypothyroidism of rats. AB - The thyroid hormone has few serious effects on the testes except during the neonatal stage. There is little knowledge concerning the prolonged effect of thyroid hormone deficiency throughout the rat's life span and its effect on spermatogenesis. Proliferating cell nuclear antigen (PCNA) is a nuclear matrix protein, which is essential for multiple cell cycle pathways. Here we used PCNA immunohistochemistry as a marker to differentiate between the testes of control and hypothyroid rats. About 20 rats were equally divided into 2 groups; the first group was the control group, while the second group was the experimental group in which rats were fed 0.05% 6-n-propyl thiouracil (PTU) in drinking water for 6 weeks. Immunohistochemistry, using an antibody against PCNA, showed at least 3 differences in the pattern of PCNA immunoreactivity (PCNA-ir). First, PCNA-ir was not detected in Sertoli and Leydig cells in the testes of control rats and detected in some of the hypothyroid rats. Second, in the control group more than 96% of spermatogonia were PCNA-positive cells; however, hypothyroidism caused the reduction to approximately 25% PCNA staining in spermatogonia. The third difference was in the abnormal distribution of spermatogonia seen in the hypothyroid rat testis, not in the control one. These results suggest that prepubertal hypothyroidism affects the proliferation of spermatogenic cells leading to impaired spermatogenesis and that PCNA index is a useful marker for assessing germ cell kinetics and spermatogenesis in prepubertal hypothyroidism. PMID- 21273640 TI - The role of lipocalin 2 and its concernment with human nonmetastatic clone 23 type 1 and p53 in carcinogenesis of uterine cervix. AB - To investigate the novel role of lipocalin 2 and its concernment with human nonmetastatic clone 23 type 1 (nm23-H1) and p53 in cervical carcinogenesis, SiHa cervical cancer cells were knocked down for nm23-H and lipocalin 2 or overexpressed by lipocalin 2 genes. We found that the overexpression of lipocalin 2 or knockdown of nm23-H1 genes increased the proliferation of SiHa cancer cells, while knocking down of lipocalin 2 decreased the proliferation of SiHa. Furthermore, knockdown of nm23-H1 or overexpression of lipocalin 2 was associated with reduced expression of p53 and its downstream gene p21. Using tissue microarrays, lipocalin 2 immunoreactivity was significantly elevated in cancer tissues as compared with it in high- or low-grade dysplasia or normal tissues. Serum secreted form lipocalin 2 from patients with cervical cancer increased in comparison with normal controls. Conclusively, secreted form lipocalin 2 reflects its implication in cervical cancer tissues and may be utilized as an adjuvant biomarker. PMID- 21273641 TI - Maternal undernourished fetal kidneys exhibit differential regulation of nephrogenic genes including downregulation of the Notch signaling pathway. AB - Maternal undernutrition results in offspring nephron number reduction and hypertension that are hypothesized to begin as compensatory changes in fetal gene expression during gestation. To evaluate mechanisms of dysregulated nephrogenesis, pregnant Sprague Dawley rats were 50% food restricted from embryonic day (E) 10 to E20. At E20, fetal male kidneys were examined by microarray analysis. A total of 476 differentially expressed transcripts were detected including those regulating development and differentiation, mitosis and cell cycle, chromatin assembly, and steroid hormone regulation. Differentially regulated genes were detected in MAPK/ERK, Wnt, and Notch signaling pathways. Validation of the microarray results was performed for the Notch signaling pathway, an important pathway in nephron formation. Protein expression of Notch pathway factors by Western blotting showed significantly decreased Notch2 and downstream effector Hey1 protein expression, while Ctbp1 co-repressor was increased. These data together show that maternal undernutrition results in developmental disruption in fetal nephrogenesis gene expression signaling. PMID- 21273642 TI - Enhanced inhibition of lung adenocarcinoma by combinatorial treatment with indole 3-carbinol and silibinin in A/J mice. AB - In earlier studies, we demonstrated the efficacy of indole-3-carbinol (I3C) against lung adenocarcinoma in A/J mice. However, these effects were accompanied by reductions in body weight gain. We therefore assessed if combinations of low doses of I3C with silibinin could inhibit lung tumorigenesis without causing undesirable side effects. In in vitro assays with A549 and H460 lung cancer cells, exposure of the cells to a mixture of low concentrations of I3C (50 MUM) plus silibinin (50 MUM) for 72 h caused inhibition of cell growth and extracellular signal-regulated kinase (ERK) and Akt activation and induction of apoptosis, whereas the individual agents did not have any effect. In mice pretreated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and given I3C (10 MUmol/g diet) plus silibinin (7 MUmol/g diet), multiplicities of tumors on the surface of the lung and adenocarcinoma were reduced by 60 and 95%, respectively. The individual effects of I3C and silibinin were relatively weaker: 43 and 36% reductions, respectively, in the multiplicity of tumors on the surface of the lung and 83 and 50% reductions, respectively, in the number of adenocarcinoma. Also, the expression of phospho-Akt, phospho-ERK and cyclin D1 and poly (ADP ribose) polymerase cleavage were strongly modulated by I3C plus silibinin than by I3C or silibinin alone, suggesting that the chemopreventive activities of the mixture could be mediated, at least partly, via modulation of the level of these proteins. Taken together, our findings showed that mixtures of I3C and silibinin are more potent than the individual compounds for the chemoprevention of lung cancer in A/J mice. PMID- 21273643 TI - In vitro functional effects of XPC gene rare variants from bladder cancer patients. AB - The XPC gene is involved in repair of bulky DNA adducts formed by carcinogenic metabolites and oxidative DNA damage, both known bladder cancer risk factors. Single nucleotide polymorphisms (SNPs) in XPC have been associated with increased bladder cancer risk. Recently, rarer genetic variants have been identified but it is difficult to ascertain which are of functional importance. During a mutation screen of XPC in DNA from 33 bladder tumour samples and matched blood samples, we identified five novel variants in the patients' germ line DNA. In a case-control study of 771 bladder cancer cases and 800 controls, c.905T>C (Phe302Ser), c.1177C>T (Arg393Trp), c.*156G>A [3' untranslated region (UTR)] and c.2251-37C>A (in an intronic C>G SNP site) were found to be rare variants, with a combined odds ratio of 3.1 (95% confidence interval 1.0-9.8, P=0.048) for carriage of one variant. The fifth variant was a 2% minor allele frequency SNP not associated with bladder cancer. The two non-synonymous coding variants were predicted to have functional effects using analytical algorithms; a reduced recruitment of GFP tagged XPC plasmids containing either c.905T>C or c.1177C>T to sites of 408 nm wavelength laser-induced oxidative DNA damage was found in vitro. c.*156G>A appeared to be associated with reduced messenger RNA stability in an in vitro plasmid-based assay. Although the laser microbeam assay is relevant to a range of DNA repair genes, our 3' UTR assay based on Green fluorescent protein(GFP) has widespread applicability and could be used to assess any gene. These assays may be useful in determining which rare variants are functional, prior to large genotyping efforts. PMID- 21273644 TI - New concepts in the aetiology of primary osteoarthritis of the hip caused by femoroacetabular impingement. AB - The paper presents modern concepts in the aetiology and development of osteoarthritis of the hip. Femoroacetabular impingement (FAI) is a condition characterized by a repetitive abnormal contact of the acetabular rim with the femoral head-neck region, which leads to the development of early osteoarthritis of the hip. There are three types of FAI: cam type, pincer type, and mixed type. FAI is diagnosed on the basis of history, clinical assessment and imaging evidence from radiographs, magnetic resonance imaging, ultrasound scans and computed tomography. Early diagnosis and appropriate treatment of FAI make it possible to halt the development of osteoarthritis of the hip. PMID- 21273645 TI - Anterior approach according to Ganz--surgical dislocation of hip joint. AB - The surgical technique of an anterior approach to the hip joint according to Ganz is described. The procedure preserves the deep branch of the medial circumflex artery, which, combined with greater trochanter osteotomy, allows for safe hip joint dislocation without a risk of avascular necrosis of the femoral head. This approach makes it possible to inspect the femoral head and the entire acetabulum. It is suitable for the treatment of early stages of coxarthrosis. PMID- 21273646 TI - Osteochondroplasty as a treatment of femoroacetabular impingement. AB - BACKGROUND: Femoroacetabular impingement (FAI) is a condition characterized by repetitive abnormal contact of the femoral acetabulum with the femoral head-neck region, which leads to the development of early-stage coxarthrosis. Early diagnosis and appropriate treatment of FAI can halt the development of coxarthrosis. MATERIAL AND METHODS: We present the early results of surgical treatment of 13 patients with FAI by osteochondroplasty of the head-neck region. An anterior approach to the hip joint was employed without surgical dislocation of the femoral head. The follow-up period ranged from 1.5 to 4 years. Clinical assessment was conducted according to the Harris classification. The FAI index was measured during radiographic evaluation. RESULTS: Clinical assessment revealed an improvement in 12 patients. Radiographically, the value of FAI index was normal in all the patients who underwent the surgery. CONCLUSIONS: Osteochondroplasty of the head-neck region appears to be an effective treatment of FAI in early-stage coxarthrosis. PMID- 21273647 TI - Operative technique and results of core decompression and filling with bone grafts in the treatment of osteonecrosis of femoral head. AB - BACKGROUND: The aim of this paper is to present the operative technique and results of core decompression and clearing of a necrotic zone in the femoral head followed by filling the defect with impacted autologous or synthetic bone grafts. This procedure allows for mechanical prevention of further collapse of the femoral head and loss of its spherical shape. It also creates conditions for the incorporation of the biological graft or synthetic bone. MATERIALS AND METHODS: A series of 63 patients (72 hips) were treated for aseptic osteonecrosis of the femoral head between 1996 and 2009. This group comprised 42 men and 21 women aged 19 to 60 years (average age: 35 years). Radiographic staging of necrosis was based on the ARCO (Association Research Circulation Osseous) classification. All patients were treated with core decompression followed by filling the bone defect with autologous or synthetic (Wright ProDense) bone grafts. RESULTS: Average follow-up was 5 years (from 1 to 12 years). After one year of follow-up, pain relief with preservation of a spherical femoral head was obtained in 45 hips (63%). Sixteen hips (22%) had significant limitation of the range of motion that, however, did not exceed preoperative values, with no significant pain during walking, and loss of the spherical shape of the femoral head on radiographs. CONCLUSIONS: Filling the defect with morsellized or synthetic bone grafts followed by graft impaction creates mechanical and biological conditions for graft incorporation. Where collapse has not occurred during the first six post operative months, a good and lasting result can be expected. PMID- 21273648 TI - Functional benchmarking of rehabilitation outcomes following anterior cruciate ligament reconstruction. AB - BACKGROUND: The aim of the study was to use selected functional benchmarks (FBs) to assess the level of physical fitness in patients undergoing rehabilitation following anterior cruciate ligament (ACL) reconstruction surgery. MATERIAL AND METHODS: The study involved 115 patients (51 women) after ACL reconstruction surgery. The patients (aged 18-43) were monitored by an orthopedist during their rehabilitation. In order to supplement the clinical examination results, we applied our own classification of functional benchmarks and examination methods which allowed objective assessment of the degree of restoration of locomotor function at individual stages of rehabilitation. The following FBs were established: minimum (MFB), standard (SFB), optimal (OFB) and sports (SPFB). RESULTS: A poor clinical outcome was noted in 6 patients (5.2%). 104 patients had a stable knee on physical examination, and a significant restoration of the range of motion and circumference of the operated knees was noted in this group in the 12th week compared with the healthy knees. The patients walked 4 km on a treadmill, with female patients covering an additional 1.13 km, and male patients 2.04 km at an inclination angle of 10 degrees . They climbed 116 steps when going up and then down stairs (separate counts). Between rehabilitation weeks 20 and 21, 81 patients (including 33 women) achieved significant improvement in muscle torques, which now approximated those of the non-operated limbs. Female patients covered a distance of 600 metres on a treadmill at the speed of 12 kph, and male patients covered 625 metres at 16 kph. Patients were also able to perform full knee bends and jumps with both feet. CONCLUSIONS: 1. SFB-level function was attained by 104 patients during 12 weeks of rehabilitation. 2. The optimal functional benchmark (OFB) was achieved by 83 patients between the 13th and 21st week of rehabilitation. 3. These results show the usefulness of functional benchmarking for assessing rehabilitation outcomes in patients planning to resume sports and recreational activity after an injury. PMID- 21273649 TI - Influence of various forms of physical exercise on bioelectric activity of quadriceps femoris muscle. Pilot study. AB - BACKGROUND: Recent years have seen a dynamic development of treatment methods targeting the knee joint region. Surgical interventions are becoming increasingly less invasive, being at the same time ever more diverse, which offers the patients possibility of living their lives without any limitations. This is being made possible thanks to diagnostic progress and advances in bioengineering. A rehabilitation programme has to be tailored to the chosen method of treatment, to each patient, his/her lifestyle and expectations. The objective of the present study is to evaluate various forms of physical activity used in rehabilitation following knee surgery with regard to the electrical activity of the quadriceps femoris muscle. MATERIAL AND METHODS: The study group was composed of 28 healthy adults (13 men and 15 women) aged 21 to 29 years. The participants were asked to perform 17 kinesiotherapeutic activities that are most commonly administered in the rehabilitation of patients following knee surgery. During the exercises, percutaneous EMG (sEMG) traces were obtained for the vastus medialis (VM) and vastus lateralis muscle (VL). RESULTS: Activity of the quadriceps femoris muscle was highest during isometric exercises performed in extension. Similar activity levels were noted during isometric exercises against resistance applied to the adductor and abductor muscles. Equally high values were obtained during open kinetic chain exercises. CONCLUSIONS: The study revealed that the exercises under investigation were useful in postoperative rehabilitation following knee surgery. Isometric exercises performed with the knee in extension and possibly with resistance applied to the adductor and abductor muscles of the hip are the most effective in the early postoperative phase because they generate only minor loads. PMID- 21273650 TI - Factors determining health awareness in persons after spinal injury with neurological complications. Pilot study. AB - BACKGROUND: Dedicated health education is a core intervention in comprehensive rehabilitation programmes. Health awareness of those disabled as a result of a spinal injury with neurological complications (SINC) has rarely been the subject of scientific analyses despite its importance for designing dedicated educational programs. PURPOSE: To evaluate factors determining the health awareness of persons after SINC. MATERIAL AND METHODS: 133 SINC patients (32 women) between 0.5 and 31 years after injury. An ad hoc questionnaire designed by the authors consisting of 150 detailed questions about the diagnosis, prophylaxis and management of typical health consequences of SINC. RESULTS: The mean test score (TS) was 56.6 points. TS correlated inversely with age in a statistically significant manner (correlation coefficient (CC) = -0.31). TS increased with the time elapsed since injury, with distinct increments at 1 year and 10 years after the event. Significantly higher TSs were noted in persons with university (64.6) and secondary education (65.7) compared with the rest of the group (37.9). Those unable to walk but able to use the wheelchair for independent locomotion had a higher TS (59.7) compared to wheelchair-bound persons unable to drive the wheelchair (47.5) and to persons with preserved walking ability (46.2). Significantly higher scores were achieved by inhabitants of towns above 100,000 population, those employed, members of an association for disabled persons, and respondents capable of independent self-care. There was an inverse correlation between TS and Beck's depression score (CC=-0.36). TS did not depend on gender. Interaction with other persons with SINC is perceived as the most important source of health related knowledge. CONCLUSIONS: Predictors of better health awareness in SINC persons include a young age, at least secondary education, more than 10 years since injury, participation in community rehabilitation organised by an association of persons with disability, being employed, being unable to walk, effective self-care, and absence of depression. PMID- 21273651 TI - A new syndrome sheds light on old medical & rehabilitative dilemmas: paraparesis due to rhabdomyolysis and bilaterally symmetric compartment syndrome in four patients. Cases study. AB - Via our description of a seemingly heterogeneous group of four patients who presented to our rehabilitation facility with a rather unusual clinical presentation of compartment syndrome with development of a flaccid paraparesis and rhabdomyolysis immediately after awakening from a prolonged sleep episode in an unusual posture - which might, in fact, be a 'new syndrome' - we have also come to address an important issue linking our group of patients - specifically, the complexities which present to a rehabilitative facility in the cases of unusual and unclear diagnoses. Eventually, all four of our patients remained severely disabled. All had suffered sensorimotor axonal demyelinative polyneuropathies and two patients had subclinical hypothyroidism. Prior to the prolonged sleep episode, they had all consumed alcohol and drugs. Using these four rather demanding diagnostic rehabilitative cases we address the ever important issue of timely mutual communication and patience. For when a rehabilitative facility is confronted with patients whose diagnoses are not clear, the scope of the long-term comprehensive rehabilitation management faces some major obstacles with respect to how the rehabilitative team can succeed in designing a 'tailor-made' rehabilitation program for these patients, which often times proves to be a rather tricky task requiring innovative and creative efforts on the parts of all those involved in the care of the patient. Quite a challenging task, indeed, yet one genuinely necessary to attempt to achieve so that the patient, family and, of course, the 'payer agency/provider' can all prepare themselves, realistically so as to obtain the best overall rehabilitative outcome for these patients. We conclude that what is most necessary for these unique patients is patience. PMID- 21273652 TI - Total hip arthroplasty following Ganz periacetabular osteotomy. Cases study. AB - The Ganz periacetabular osteotomy (PAO) is currently the most popular hip-sparing procedure in adults with acetabular dysplasia. If this procedure fails and a total hip arthroplasty is necessary, spatial reorientation of the acetabulum alters the conditions of implanting the acetabular component of the prosthesis. In our study, we present two cases of total hip arthroplasty in patients who had undergone PAO. PMID- 21273653 TI - Patient rehabilitation following hand transplantation at forearm distal third level. AB - The results of hand transplantations in terms of both graft survival (49/52, i.e. 94.3%) and hand function recovery are very inspiring. The degree of functional recovery is similar to that achieved after hand replantation at the same level. With regard to function recovery, the most favorable level of replantation seems to be the distal third of the forearm, with 75% of hand transplantations performed at this level. The aim of this paper was to present the process of limb rehabilitation following a hand transplantation at the level of the forearm's distal third. The recipient, a 29-year-old male, lost his right dominant hand 6 years before the operation in a drum flaker accident. The donor was a 52-year-old female. The limb was transplanted in a standard manner, with an uneventful postoperative period. The multidirectional rehabilitation focused on motor and sensory function as well as the recipient's psychological status. First passive finger movements were introduced on postoperative day 2, followed by assisted active movements from day 21 post-transplant onwards, and from day 28 we implemented exercises with an outrigger extension splint. Favorable hand position positioning was ensured by changing ortheses frequently. Motor rehabilitation relied on Perfetti's visual-motor training (from d 28 p-op.) together with continuous passive motion (Artromot F device). We also used electrical stimulation of the nerve trunks and intrinsic muscles of the hand as well as discrimination exercises of tactile sensation. The rehabilitation process was very similar to the one we use in patients after limb replantation. We assessed the motor and sensory functions of the grafted limb as very good despite diminished muscle strength, which does not affect the general functional result. The recipient adapted perfectly to living with a transplanted limb. The outcomes achieved by the hand transplant recipient confirm the need of early and multidirectional rehabilitation. PMID- 21273654 TI - Interleukin-1 (IL-1) in stress-induced activation of limbic-hypothalamic pituitary adrenal axis. AB - Proinflammatory cytokine interleukin-1 (IL-1) produced during psychological and immunological stress, plays a significant role in the neuroendocrine and stress responses. Brain IL-1 is an important mediator in stress-induced stimulation of the limbic-hypothalamic-pituitary-adrenal axis and secretion of ACTH and corticosterone. This review aims to describe some signaling pathways between the limbic-hypothalamic-pituitary structures during prolonged stress responses including their sensitization and adaptation. Interleukin-1 represents an important central component operating in neurochemical and immune network for efficient coping in preventing stress-associated psycho- and neuropathology. PMID- 21273655 TI - Important role of 3-methoxytyramine in the inhibition of cocaine sensitization by 1-methyl-1,2,3,4-tetrahydroisoquinoline: an in vivo microdialysis study. AB - 1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) is an endogenous compound with neuroprotective and antidopaminergic activities. Our previous research has shown that 1MeTIQ prevents morphine addiction and abates the expression of the reinstatement of cocaine self-administration. The current study investigated the mechanism of action of 1MeTIQ that is responsible for its considerable anticraving potential. Accordingly, we performed behavioral tests that measured the influence of 1MeTIQ on the locomotor activity of rats (Wistar) after a single cocaine (15 mg/kg, i.p.) dose and during cocaine sensitization (15 mg/kg, i.p.). In a neurochemical study, we examined the influence of 1MeTIQ on dopamine release in the rat striatum after a single cocaine administration and during cocaine sensitization using an in vivo microdialysis methodology. The data showed that 1MeTIQ (50 mg/kg, i.p.) only slightly inhibited cocaine-induced hyperactivity but completely antagonized the expression of locomotor cocaine sensitization. The in vivo microdialysis study demonstrated that the administration of 1MeTIQ before the acute cocaine injection intensified the cocaine-induced increase in dopamine release and produced a huge and long-lasting elevation of the extraneuronal concentration of dopamine (by approximately 1400%, p < 0.01) in the rat striatum. A significant increase in 3-methoxytyramine (3-MT) (by approximately 400%, p < 0.01) was also observed. During the expression of cocaine sensitization, the administration of 1MeTIQ before the reminder dose of cocaine produced an additional elevation of dopamine release but considerably more strongly increased the concentration of 3-MT in the synaptic cleft (by about 800%, p < 0.01). In light of these data and of our earlier in vitro and in vivo experiments showing a physiological role of 3-MT in the inhibitory regulation of excessive stimulation, we suggest that locomotor hyperactivity is dependent not only on dopamine concentration in the extracellular space, but also on the ratio of [DA/3-MT]. 1MeTIQ administered before the reminder dose of cocaine to cocaine-experienced rats plainly normalized the [DA/3-MT] ratio, which was increased by cocaine, and this effect may be responsible for its anti-addictive action. The results strongly support the view that 1MeTIQ may have a more general anti-abuse potential, and the extraneuronal metabolite of dopamine, 3-MT, may play a crucial role in its anti-craving effects. PMID- 21273656 TI - Chronic ecstasy use increases neurotrophin-4 gene expression and protein levels in the rat brain. AB - Ecstasy is a widely abused psychoactive recreational drug that is known to induce neuroplastic effects. The molecular basis of addiction remains poorly understood, but diverse lines of evidence suggest that neurotrophins (BDNF, NT-3 and NT-4) play a role in the regulation of synaptic plasticity. The present study was designed to evaluate the alteration of NT-4 protein levels and gene expression in the brain stem, cerebellum and cerebral hemisphere of rat brains in the context of ecstasy dependence. Ecstasy addiction was induced by intraperitoneal injection of ecstasy (10 mg/kg) for 5 days. After chronic ecstasy treatment, the NT-4 levels in the abovementioned areas of the brain were determined by ELISA. There was a significant increase in the NT-4 protein concentration in the brain stem, cerebellum and cerebral hemisphere when compared with control group. Additionally, these regions were assayed for the transcription of NT-4 using semi quantitative RT-PCR normalized to beta-actin gene transcription. The results show that chronic administration of ecstasy significantly increased NT-4 gene expression in the abovementioned areas of brain. The current work demonstrates that ecstasy induced-maladaptations may be regulated by NT-4. PMID- 21273657 TI - Effects of serotonin (5-HT)6 receptor ligands on responding for cocaine reward and seeking in rats. AB - The endogenous brain serotonin (5-HT) system is believed to have an important modulatory influence in mediating drug reward and seeking mechanisms. Data from preclinical behavioral studies have provided emerging evidence that 5-HT(6) receptors, among other 5-HT receptors, may play a significant role in the mechanisms of action of psychostimulant addicted drugs. The aim of the present study was to investigate whether the selective pharmacological blockade or activation of 5-HT(6) receptors altered the maintenance of cocaine self administration, reinstatement of cocaine-seeking behavior following an extinction of cocaine self-administration or cocaine-evoked conditioned place preference in rats. We also evaluated the effects of 5-chloro-N-(4-methoxy-3-piperazin-1 ylphenyl)-3-methyl)-2-benzothiophene-sulfonamide (SB 271046, a 5-HT(6) receptor antagonist) or N-1-(6-chloroimidazo-[2,1-b]-[1,3]thiazole-5-sulfonyl)tryptamine (WAY 181187, a potent 5-HT(6) receptor agonist) on locomotor activity in rats. Our results indicate that SB 271046 (1-10 mg/kg) altered cocaine-maintained self administration as well as cocaine-evoked reinstatement of cocaine seeking and expression of cocaine place preference in rats.We also demonstrate that pharmacological stimulation of 5-HT(6) receptors by WAY 181187 (3-30 mg/kg) attenuated the expression of cocaine conditioned place preference but not cocaine self-administration and reinstatement of cocaine seeking. WAY 181187 at the highest dose used (30 mg/kg) reduced basal locomotor activity. Despite current results, the precise function and therapeutic relevance of 5-HT(6) receptors need further clarification. PMID- 21273658 TI - Effect of metyrapone on the fluoxetine-induced change in extracellular dopamine, serotonin and their metabolites in the rat frontal cortex. AB - Major depression is frequently associated with the hyperactivity of the hypothalamic-pituitary-adrenocortical axis, and glucocorticoid synthesis inhibitors have been shown to exert antidepressant action. Metyrapone (an inhibitor of the enzyme 11-beta-hydroxylase) has been found to be effective as an adjunctive therapy in combination with other antidepressants (ADs) in both treatment-resistant depression and animal models. To understand the mechanism of the clinical efficacy of a combination of an AD and metyrapone in treatment resistant depression, the present study was aimed at determining the influence of fluoxetine (FLU; a selective serotonin reuptake inhibitor) and metyrapone, given separately or jointly, on the extracellular level of dopamine (DA), serotonin (5 HT) and their metabolites in rat frontal cortex of freely moving rats using microdialysis and high performance liquid chromatography (HPLC) with electrochemical detection. FLU (10 mg/kg) given alone increased the extracellular level of DA and 5-HT in the rat frontal cortex. Metyrapone (100 mg/kg) alone did not change the level of monoamines. A combination of FLU and metyrapone produced the same change in the efflux of both DA and 5-HT as did FLU alone. However, the latter combination (FLU and metyrapone) produced significantly bigger increases in the levels of extracellular DA metabolites (3,4-dihydroxyphenylacetic acid, homovanillic acid) and a 5-HT metabolite (5-hydroxyindoleacetic acid) than did FLU alone. The above findings suggest that--among other mechanisms--increases in the levels of extracellular DA and 5-HT metabolites may play a role in the enhancement of FLU efficacy by metyrapone, and may be of crucial importance to the pharmacotherapy of drug-resistant depression. PMID- 21273659 TI - Effects of melatonin in a place preference conditioning depend on the time of administration. AB - A conditioned place preference paradigm was used to assess potential rewarding properties of melatonin. The conditioning with melatonin was carried out at two periods of the 12-h light/dark cycle: in the morning (08.30-10.00) and in the evening (18.30-20.00). Morning administration of melatonin (2.5, 5 and 10 mg/kg) did not support conditioned place preference. In contrast, evening conditioning with melatonin caused a clear shift towards the drug-paired side. This effect was dose-dependent; higher doses of 2.5, 5, 10 and 50 mg/kg induced conditioned preference while lower doses of 0.5 and 1 mg/kg were ineffective. The increase in the side preference induced by the two most effective doses of melatonin (10 and 50 mg/kg) were comparable to that induced by 1 mg/kg of amphetamine, and was significantly attenuated by the melatonin antagonist, S 22153 (20 mg/kg). In chronic experiment, melatonin (10 mg/kg) caused similar increase of the time spent on conditioned side both in animals administered vehicle for 7 days and in rats receiving 10 mg/kg of melatonin for the same period of time. Potent activity in the conditioned preference model suggests that melatonin may have rewarding properties, which moreover, is not tolerated following repeated pre-exposure to the drug. These findings may indicate potential abuse liability of melatonin, and therefore, its use by humans should require a careful monitoring for abuse and/or dependency. PMID- 21273660 TI - Effects of neurosteroids on the human corticotropin-releasing hormone gene. AB - Increased activity of hypothalamic-pituitary-adrenal (HPA) axis and hypersecretion of corticotropin-releasing hormone (CRH) are known to be important factors in pathogenesis of some stress-related diseases. Some neurosteroids exert anxiolytic and antidepressant effects probably by inhibition of HPA axis activity. The aim of our study was to find out if neurosteroids can directly affect human CRH gene transcription. The effect of allopregnanolone (ALLO), allotetrahydrodeoxycorticosterone (THDOC), pregnenolone (PGL), PGL sulfate (PGL S), dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S) on CRH expression was determined in differentiated Neuro-2A cells stably transfected with plasmid containing a fragment of human CRH promoter (-663 to + 124 bp) linked to the chloramphenicol acetyltransferase (CAT) reporter gene. It was found that PGL (0.3 30 MUM), ALLO (1-30 MUM) and THDOC (1-30 MUM) present in the culture medium for 5 days in the concentration-dependent manner inhibited CRH-CAT activity. These neurosteroids also inhibited forskolin-stimulated CRH gene transcription with similar potency. In contrast, PGL-S, DHEA and DHEA-S in a concentration from 0.01 to 10 MUM had no effect on basal and forskolin-stimulated CRH activity. Further experiments revealed that wortmannin (an inhibitor of phosphatidylinositol 3 kinase; PI3-K) at concentrations of 0.01 and 0.02 MUM did not change the inhibitory effect of ALLO (3 MUM) and PGL (1 MUM) on CRH gene transcription. Moreover, ALLO (3 MUM) and PGL (1 MUM) present in the culture medium for 5 days did not change the amount of active, phosphorylated form of protein kinase B (PKB, Akt) and extracellular signal-regulated kinase (ERK). The obtained results indicate that PGL, ALLO and THDOC inhibited basal and forskolin-induced CRH gene promoter activity in the differentiated Neuro-2A cells and that these effects did not depend on the activation of PI3-K/Akt and ERK-MAPK pathways. PMID- 21273661 TI - 1-Methyl-1,2,3,4-tetrahydroisoquinoline and established uncompetitive NMDA receptor antagonists induce tolerance to excitotoxicity. AB - The aim of this study was to establish the antagonistic effects of 1-methyl 1,2,3,4-tetrahydroisoquinoline (1MeTIQ) on NMDA receptors and its neuroprotective abilities on primary cultures of rat cerebellar granule cells exposed for 30 min to 250 or 100 MUM glutamate. Neuronal viability was tested after 24 h with propidium iodide or calcein/ethidium homodimer-1 staining. The neuroprotective potential of 100, 250 or 500 MUM 1MeTIQ was compared with established uncompetitive NMDA receptor antagonists, 0.5 MUM MK-801, or 5 MUM memantine. These substances were applied for 30 min either together with glutamate, 24 or 48 h before glutamate, or 0.5 h, 1 h and 3 h after exposure to the excitotoxin. The results demonstrated that MK-801, memantine and 500 MUM 1MeTIQ induced an almost complete neuroprotection when co-applied with glutamate, but lower concentrations of 1MeTIQ were slightly less effective. Similar effects for 1MeTIQ and the established NMDA receptor antagonists were observed in the pretreatment experiments, even with a 48-h lag between the application of the tested substances and the excitotoxic challenge. In the post-treatment experiments, MK 801 and memantine and 500 MUM 1MeTIQ applied up to 3 h after the exposure to glutamate significantly reduced the excitotoxic lesion, but 1MeTIQ in lower concentrations was ineffective. These results indicate that 1MeTIQ shares neuroprotective abilities with established uncompetitive NMDA receptor antagonists, which suggests that its inhibitory effect on NMDA receptors plays a key role in its anti-excitotoxic activity. Moreover, our data disclose a new mechanism of 1MeTIQ-evoked neuroprotection based on the induction of neuronal tolerance to excitotoxicity. PMID- 21273662 TI - Neuroprotective potential of mGluR5 antagonist MTEP: effects on kainate-induced excitotoxicity in the rat hippocampus. AB - Extensive research into glutamate receptors in the central nervous system has shown important role of metabotropic glutamate receptors (mGluR) as potential targets for neuroprotective drugs. The aim of the present study was to investigate neuroprotective potential of the highly selective mGlu5 antagonist 3 [(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP) against kainate (KA)-induced excitotoxicity in vivo. Our attention was focused mainly on the effectiveness of delayed treatment. In order to evoke neuronal injury, rats were unilaterally injected with kainic acid (KA; 2.5 nmol/1 MUl) into the CA1 region of the hippocampus. MTEP (1, 5 or 10 nmol/1 MUl) was administered into CA1 30 min, 1, 3 and 6 h after KA. Additionally, other rats were injected intraperitoneally (i.p.) with MTEP in a dose of 1 mg/kg, once daily for 7 days. The first injection of MTEP was 1 h after KA. Seven days after treatment, the brains were taken out and analyzed histologically to estimate the total number of neurons in CA region of dorsal hippocampus using stereological methods. The study was also aimed at determining a possible influence of MTEP on neuronal glutamate release induced by KA in the hippocampus, using microdialysis method. The obtained results showed that MTEP had neuroprotective effect after both intrahippocampal and intraperitoneal injection. It was found that MTEP could prevent excitotoxic neuronal damage even when it was applied 1-6 h after the toxin. Moreover, it was observed that MTEP significantly reduced the KA-induced glutamate release in the hippocampus. It seems to play a role in mediating neuroprotective effects of MTEP. PMID- 21273663 TI - Influence of antidepressant drugs on chlorpromazine metabolism in human liver--an in vitro study. AB - The aim of the present study was to investigate the possible effects of antidepressant drugs (fluvoxamine, imipramine) on the metabolism of the aliphatic type phenothiazine neuroleptic chlorpromazine in the human liver. The experiment was performed in vitro using human liver microsomes. The kinetic analysis of chlorpromazine metabolism carried out in the absence or presence of antidepressants showed that fluvoxamine potently inhibited chlorpromazine 5 sulfoxidation (K(i) = 2.8 MUM), mono-N-demethylation (K(i) = 1.4 MUM) and di-N demethylation (K(i) = 1.1 MUM) via a competitive mechanism at therapeutic antidepressant concentrations. Imipramine moderately diminished the rate of chlorpromazine 5-sulfoxidation (K(i) = 8.7 MUM, competitive inhibition), mono-N demethylation (K(i) = 16.0 MUM, non-competitive inhibition) and di-N demethylation (K(i) = 13.5 MUM mixed inhibition). Considering the serious side effects of chlorpromazine and some of its metabolites, metabolic interactions between this neuroleptic and antidepressant drugs (especially the chlorpromazine fluvoxamine interaction) may be of pharmacological and clinical importance. PMID- 21273664 TI - Amino acid metabolic processes in the temporal lobes assessed by proton magnetic resonance spectroscopy (1H MRS) in children with Down syndrome. AB - Down syndrome (DS), or trisomy 21, is one of the most common autosomal mutations. The overexpression of the beta-amyloid precursor protein gene, located on chromosome 21, causes an increased production of the specific amyloid. The current study is a continuation of our earlier investigations relating to the profile of metabolic changes in the frontal lobes of DS patients as assessed by proton magnetic resonance spectroscopy ((1)H MRS). The aims of the study were the morphological assessment of the brain using magnetic resonance imaging (MRI) and the evaluation of metabolic disorders of the temporal lobes using (1)H MRS in DS children. The study group included 20 children with DS aged 3-15 years and treated in the Department of Pediatric Neurology and Rehabilitation, Medical University of Bialystok. The control group included healthy children (n = 20). MRI scans of the heads of DS children were performed using a 1.5 T MR scanner under standard conditions. (1)H MRS investigations were also carried out to assess metabolic changes in the temporal lobes. Metabolites, such as N acetylaspartate (NAA), glutamate-glutamine complex (Glx), choline (Cho), myoinositol (mI) and gamma-aminobutyric acid (GABA), were determined in both temporal lobes with reference to the internal marker creatine (Cr). Results were compared with the control group.We found a statistically significant decrease in NAA/Cr, Cho/Cr, mI/Cr and GABA/Cr ratios. The Glx/Cr ratio in both temporal lobes of DS patients did not differ from the control group. Our results indicate metabolic neurotransmitter disorders in the central nervous system in children with DS. PMID- 21273665 TI - Modulatory effect of high saturated fat diet-induced metabolic disturbances on angiogenic response in hepatocyte RXRalpha knockout mice. AB - Metabolic syndrome and diabetes lead to pathological angiogenesis and angiopathy. Metabolic disturbances occur as an effect of genetic and environmental interaction. Hyperleptinemia accompanies obesity and leptin is a potent proangiogenic factor. The aim of the study was to investigate the effect of high fat diet-induced alterations in gene expression and angiogenic response in the hRXRalpha ko mice lacking of hyperglycemia. hRXRalpha ko and control mice were fed either standard or high saturated fat (HF) diet for 7 weeks. Body weight and biochemical parameters (glucose, triglycerides, cholesterol), insulin and adipokines (leptin, adiponectin) were monitored. At sixth week of feeding, mice were subcutaneously injected for 6 days with matrigel containing bFGF. Then, matrigel plugs were used for immunohistochemical staining of cells with CD31 antibody and gene expression assessment (by microarray confirmed for some genes with quantitative real time PCR). For description of angiogenesis CD31 positive structures were counted in the matrigel sections. HF diet feeding of the hRXRalpha ko mice resulted in increased serum cholesterol and leptin level and in tendency to decrease angiogenesis (number of vessels with lumen). The microarray studies revealed that HF diet down-regulated genes related to angiogenesis (Nos3, Kdr) and up-regulated genes connected with apoptosis (activators of caspase 3, proapoptotic genes Bcl2) and proinflammatory pathway (NfkappaB pathway, Tnfalpha). Summing up, HF diet feeding of hRXRalpha ko mice resulted in dyslipidemia and hyperleptinemia as well as impaired angiogenic response, and cell apoptosis. These results argue for independent participation of dyslipidemia and hyperleptinemia in pathology of angiogenic response associating metabolic syndrome. PMID- 21273666 TI - Hemostatic effects of simvastatin in subjects with impaired fasting glucose. AB - The aim of our study was to compare the effect of simvastatin on a range of hemostatic variables in subjects with impaired fasting glucose (IFG) and isolated hypercholesterolemia. We enrolled 28 subjects with IFG, 25 primary hypercholesterolemic patients and 24 age-, sex- and weight-matched control subjects with normal lipid profile and glucose metabolism. The tested parameters (lipid profile, fasting and 2-h post-glucose load plasma glucose levels, the homeostasis model assessment (HOMA) ratio, glycated hemoglobin, the prothrombin and partial thromboplastin time, plasma fibrinogen, PAI-1 levels and factor VII coagulant activity) were determined at baseline and after 4 and 12 weeks of simvastatin treatment (20 mg/daily). Compared to the control subjects, hypercholesterolemic and IFG patients exhibited increased plasma levels of fibrinogen and PAI-1 and increased factor VII activity. PAI-1 was higher in hypercholesterolemic than in IFG patients. Simvastatin improved lipid profile in both groups of patients, but it did not influence glucose metabolism. In both IFG and hypercholesterolemic patients, simvastatin reduced fibrinogen and PAI-1 levels and factor VII activity, and it prolonged the prothrombin and partial thromboplastin time in a lipid- and glucose-independent manner. The main conclusion of our study is that early glucose metabolism abnormalities are associated with disturbed coagulation and fibrinolysis, which contribute to the development and progression of atherosclerosis. Treatment with a lipid lowering agent may bring multidirectional beneficial effects on hemostasis in IFG patients. PMID- 21273667 TI - Hemostatic effects of fenofibrate in patients with mixed dyslipidemia and impaired fasting glucose. AB - Our study aimed to compare the effect of fenofibrate on hemostasis between patients with isolated impaired fasting glucose (IFG) and isolated mixed dyslipidemia and to examine the action of this agent on glucose and lipid metabolism. Twenty-two IFG and 23 mixed dyslipidemic patients were treated for 90 days with micronized fenofibrate (267 mg/day) and were compared with 22 age-, sex and weight-matched control subjects without lipid and glucose metabolism abnormalities. The lipid profile, fasting and 2-h post-glucose challenge glucose levels, HOMA and glycated hemoglobin as well as the plasma levels/activities of fibrinogen, factor VII and PAI-1 were determined at the beginning and after 30 and 90 days of treatment. Compared to the control subjects, mixed dyslipidemic and IFG patients exhibited increased plasma levels of fibrinogen and PAI-1 as well as increased factor VII activity. Fibrinogen, factor VII and PAI-1 were higher in mixed dyslipidemic than IFG subjects. Not only did fenofibrate improve plasma lipids, but it also increased glucose sensitivity and normalized the IFG- and mixed dyslipidemia-induced changes in coagulation and fibrinolysis. Our study shows that IFG is associated with abnormal hemostasis, which is disturbed to a lesser extent in IFG than in mixed dyslipidemia. Fenofibrate seems to produce a complex beneficial effect on hemostasis in this group of patients. PMID- 21273668 TI - Effects of standard treatment on the dynamics of matrix metalloproteinases gene expression in patients with acute coronary syndromes. AB - Inflammation plays a critical role in the pathology of acute coronary syndrome (ACS). Matrix metalloproteinases (MMP)--proteolytic enzymes participating in plaque destabilization--are the crucial effectors of proinflammatory mechanisms leading to plaque rupture. Numerous reports have confirmed the significance of these factors both in circulating blood and locally in the plaque. There is, however, a lack of information on the molecular mechanisms leading to these disturbances, and the effect of standard treatment for ACS on these processes. The aim of the study was to assess the gene expression of MMP-2, -9 and TIMP-2, and the effect of standard treatment on the expression of the studied genes. The study was conducted in 32 patients with ACS and 15 healthy subjects (control group). Monocytes were isolated using Rosette-Sep kits. Gene expression of MMP-2, MMP-9 and TIMP-2 was evaluated on days 1 and 5 in the studied group and once in controls. Total mRNA was extracted from monocytes and the number of mRNA copies was assessed by QRT-PCR. Monocytes of ACS patients present with significantly higher gene expression of MMP-2, -9 and TIMP-2 compared to healthy controls (0.0915 +/- 0.037 vs. 0.001 +/- 0.0002, p < 0.01; 0.81 +/- 0.279 vs. 0.10 +/- 0.057, p < 0.05; 0.84 +/- 0.140 vs. 0.42 +/- 0.126, p < 0.05, respectively). After the 5-day standard treatment, a significant decrease in MMP-2 gene expression was observed. Other studied genes did not show relevant changes during the observation period. No significant correlation was found between classical atherosclerosis risk factors and the expression of the studied genes. Monocytes of ACS patients significantly overexpressed MMP-2, MMP-9 and TIMP-2. Five days of standard treatment resulted in downregulation of the MMP-2 gene. MMP gene overexpression appears to be an independent factor concerning the pathogenesis of ACS. PMID- 21273669 TI - Calcium mobilization by the plant estrogen ferutinin does not induce blood platelet aggregation. AB - Platelet activation is closely associated with an increase in intracellular Ca(2+) concentration. Various compounds including Ca(2+) ionophores are able to trigger platelet aggregation by increasing intracellular Ca(2+) concentration in platelets. In the present study, we monitored the effect of the phytoestrogen ferutinin, which acts as a Ca(2+) ionophore in human blood platelets; its ionophore-like properties include upregulation of [Ca(2+)](in), activation of fibrinogen receptors and increased fibrinogen binding. Using spectrofluorometry and triple-color flow cytometry, we demonstrate that ferutinin increases [Ca(2+)](in) in both isolated platelets and platelets in whole blood from humans. This effect was almost completely blocked by the Ca(2+) chelator EGTA and was not sensitive to either Gd(3+) or econazole, which inhibit VOC and SOC channels, respectively. Nor was the effect sensitive to thapsigargin, an inhibitor of endoplasmic reticulum Ca(2+) ATPases. Ferutinin stimulated the expression of the active form of the GPIIb-IIIa complex and whole blood platelet aggregation only weakly and had no statistically significant effect on the binding of fibrinogen. These results demonstrate apparently inconsistent effects of ferutinin, which raises intraplatelet Ca(2+) concentration but fails to have an effect on spontaneous blood platelet aggregation. This pattern of responses may be caused by the combination of ferutinin's Ca(2+) ionophoric and estrogenic properties. PMID- 21273670 TI - Role of beta-adrenoceptors, cAMP phosphodiesterase and external Ca2+ on polyamine induced relaxation in isolated bovine tracheal strips. AB - Polyamines relax several smooth muscles and elicit cardiotonic effects in the rat heart via interactions with beta-adrenoceptors. The aim of this work was to establish whether beta(2)-adrenoceptors were involved in polyamine-relaxation of bovine tracheal strips. Endogenous polyamines displaced the specific radioligand, [(3)H]dihydroalprenolol, but spermine was the most potent. The polyamines elicited an acute transient relaxation, which was independent of beta adrenoceptor activation, followed by a maintained component, which was shown to be dependent on beta-adrenoceptor activation because it was antagonized and reversed by propranolol. Polyamines did not alter salbutamol-induced acute relaxation. Polyamines modified the salbutamol-induced long-term effect on airway tone, which was shown by a partial reversal of beta-adrenoceptor desensitization. This process was delayed by alpha-difluoromethylornithine, but spermine increased the latency and time of reversal and decreased receptor desensitization. Putrescine prolonged the time-constant without changes in the desensitization. Spermine, but not putrescine, might block Ca(2+) channels, because it relaxed KCl or electrical stimulated-contractions, which are related to Ca(2+) influx, and the inhibition of cAMP phosphodiesterase activity. These differences might explain the functional differences observed between putrescine and spermine. Therefore, polyamines may modulate airway smooth muscle tone and interfere with the mechanism of receptor desensitization via several mechanisms involving beta(2)-adrenoceptors, Ca(2+) influx and cAMP phosphodiesterase. PMID- 21273671 TI - Lactoferrin inhibits the growth of nasal polyp fibroblasts. AB - The aim of this study was to evaluate the effects of lactoferrin (LF) on the growth of fibroblasts derived from nasal polyps. We showed that the proliferation of fibroblasts was inhibited in a dose-dependent manner by both native and recombinant LF. The greatest inhibition of proliferation was caused by human milk derived, iron-saturated LF. The inhibition of fibroblast proliferation was not species specific because bovine LF also was active. The interaction between LFs and a putative cell receptor did not depend on the sugar composition of the glycan moiety of the LF molecule because lactoferrins of different origins were active and the addition of monosaccharides to the cultures did not block proliferation. However, the treatment of fibroblasts with sodium chlorate (an inhibitor of glycosaminoglycan sulfation) or the addition of heparin abolished the inhibitory effect of LF, suggesting that LF binds heparan sulfate-containing proteoglycans. The significance of LF in nasal excretions in controlling polyp formation is discussed. PMID- 21273672 TI - Modulating effects of nonselective and selective phosphodiesterase inhibitors on lymphocyte subsets and humoral immune response in mice. AB - Phosphodiesterase (PDE) inhibitors can regulate the activity of immune cells by increasing intracellular levels of cyclic nucleotides. The aim of this study was to determine the effects of milrinone, a selective PDE3 inhibitor, sildenafil, a selective PDE5 inhibitor, and aminophylline, a nonselective PDE inhibitor, on lymphocyte subsets and humoral immune response in mice when administered in vivo. Aminophylline (20 mg/kg, i.m.), milrinone (1 mg/kg, i.m.) or sildenafil (1 mg/kg, p.o.) were administered to mice either once or five times at 24 h intervals. Some mice were immunized with a sheep red blood cell (SRBC) suspension administered i.p. either 2 h after the single dose or 2 h after the second of the five doses. In non-immunized mice treated five times with PDE inhibitors, the subsets of T lymphocytes in the thymus and T and B lymphocytes in the spleen and mesenteric lymph nodes were determined 12, 24 or 72 h after the last dose. The humoral immune response was determined on days 4, 7 and 14 after SRBC injection in SRBC immunized mice treated with PDE inhibitors. A modulating effect of the drugs on lymphocyte subpopulations was observed. The greatest impact was observed in splenocyte subpopulations, and resulted in decreased percentages of B cells (CD19(+)) and increased percentages of T cells (CD3(+), CD4(+), CD8(+)). No effect or slight influence of the drugs on anti-SRBC hemagglutinins was observed, but the number of plaque-forming splenocytes was increased. The drugs under investigation did not show a significant immunosuppressive effect. PMID- 21273673 TI - Frequencies and roles of CYP3A5, CYP3A4 and ABCB1 single nucleotide polymorphisms in Italian teenagers after kidney transplantation. AB - The main genes involved in the pharmacokinetics of immunosuppressive drugs are those encoding cytochrome P450 (CYP) family enzymes and multidrug resistance 1 (ABCB1). In this study, 87 Italian teenagers with transplanted kidneys (mean age 11.6 +/- 4.8 years) receiving calcineurin inhibitors (CNIs) were genotyped for the single nucleotide polymorphisms (SNPs) CYP3A5*1/3 and CYP3A4*1B for CYP3A, and C1236T, G2677T/A, C3435T and IVS21+49 for ABCB1, and retrospectively evaluated for the influence of the screened SNPs on CNI blood level at different post-transplantation times. The CYP3A5*1 allele was present in 7% of the patients, and the CYP3A4*1B allele was present in 3% of patients. The ABCB1 C1236T, G2677T/A and C3435T SNPs C, G and T occurred frequently (55%, 53% and 54%, respectively). The frequency of the T allele of IVS21+49 was 86%. The frequency of SNPs in both genes was comparable with that reported in other European Caucasian populations but different from that found in Asians or Afro Americans. None of the cyclosporine (CsA) pharmacokinetic parameters were associated with the CYP3A5 genetic polymorphism, whereas the presence of the A allele in some patients was responsible for the required administration of a significantly increased dose of tacrolimus (Tac) that was necessary to reach therapeutic target levels. None of the Tac pharmacokinetic parameters were associated with ABCB1 SNPs, but ABCB1 SNPs had early effects on the CsA exposure index and dose requirements. In conclusion, because SNPs of the CYP3A and ABCB1 genes may be associated with CNI pharmacokinetic parameters and exposure indices, pre-transplant genetic screening should be considered in order to avoid immunosuppressant-related adverse events. PMID- 21273674 TI - Anti-clastogenic potential of carnosic acid against 7,12 dimethylbenz(a)anthracene (DMBA)-induced clastogenesis. AB - Carnosic acid, a primary phenolic compound found in the leaves of rosemary (Rosmarinus officinalis), has diverse pharmacological and biological activities. The aim of the present study was to investigate the anti-clastogenic effect of carnosic acid in DMBA-induced clastogenesis. The frequency of bone marrow micronucleated polychromatic erythrocytes (MnPCEs), chromosomal aberrations (cytogenetic end points), the status of Phase I and II detoxification enzymes, lipid peroxidation by-products and antioxidants (biochemical endpoints) were analyzed to assess the anti-clastogenic effect of carnosic acid in DMBA-induced clastogenesis. Oral pretreatment of carnosic acid for five days to DMBA-treated hamsters significantly protected DMBA-induced clastogenesis as well as biochemical abnormalities. Although the exact mechanism of anti-clastogenic effects of carnosic acid is unclear, the antioxidant potential and effect on modulation of Phase I and II detoxification enzymes could play a possible role. PMID- 21273675 TI - Chemopreventive and antioxidant efficacy of (6)-paradol in 7,12 dimethylbenz(a)anthracene induced hamster buccal pouch carcinogenesis. AB - The present study evaluated the chemopreventive potential of (6)-paradol, a pungent phenolic constituent of ginger, on 7,12-dimethylbenz(a)anthracene (DMBA) induced hamster buccal pouch carcinogenesis. The mechanistic pathway for the chemopreventive potential of (6)-paradol was evaluated by measuring the status of tumor incidence, volume and burden as well as by analyzing the status of phase II detoxification agents, lipid peroxidation and antioxidants. Oral squamous cell carcinoma was induced in hamster buccal pouches by painting them with 0.5% DMBA in liquid paraffin three times a week for 14 weeks. We observed 100% tumor formation with marked biochemical abnormalities in tumor-bearing animals compared to control animals. Oral administration of 30 mg/kg b.w. (6)-paradol to DMBA treated hamsters on alternate days from DMBA painting for 14 weeks, significantly reduced the formation of tumors and improved the status of detoxification agents, lipid peroxidation and antioxidants. Therefore, the present study suggests that (6)-paradol has potent chemopreventive, anti-lipid peroxidative and antioxidant potentials as well as a modulating effect on phase II detoxification enzyme and reduced glutathione (GSH) in DMBA-induced hamster buccal pouch carcinogenesis. PMID- 21273676 TI - NMDA but not AMPA glutamatergic receptors are involved in the antidepressant-like activity of MTEP during the forced swim test in mice. AB - Several lines of evidence suggest an antidepressant-like activity for 3-[(methyl 1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP), a highly selective, non-competitive antagonist of metabotropic glutamate receptors subtype 5 (mGluR(5)). This effect has been observed following both acute and chronic MTEP treatments in behavioral tests and experimental models of depression, such as the forced swim test (FST), the tail suspension test, and the olfactory bulbectomy model of depression. However, the mechanism of action for mGluR(5) antagonists remains unclear. The aim of this study was to investigate whether the antidepressant-like action of MTEPis dependent on ionotropic glutamatergic receptors. Male Albino Swiss mice were used, and antidepressant-like activity was evaluated using the FST. The antidepressant-like effect of MTEP (0.3 mg/kg) was significantly antagonized by pre-treatment with the NMDA receptor agonist N-methyl-D-aspartic acid (NMDA, 75 mg/kg, i.p.). The AMPA receptor antagonist NBQX (10 mg/kg, i.p.) did not affect the MTEP activity. Our results indicate that the antidepressant-like activity of MTEP in the FST involves NMDA but not AMPA receptors and suggest that the interaction between mGluR(5) and NMDA receptors plays an important role in the underlying antidepressant mechanism(s). PMID- 21273677 TI - Effects of co-treatment with mirtazapine and low doses of risperidone on immobility time in the forced swimming test in mice. AB - The aim of the present study was to examine the effect of mirtazapine (MIR) and risperidone (an atypical antipsychotic drug), given separately or jointly, on immobility time in the forced swimming test in male C57BL/6J mice. Fluoxetine (FLU) was used as a reference drug. MIR (2.5, 5 and 10 mg/kg) and FLU (5 and 10 mg/kg), or risperidone in low doses (0.05 and 0.1 mg/kg) given alone did not change the immobility time of mice in the forced swimming test. Joint administration of MIR (5 and 10 mg/kg) or FLU (10 mg/kg) and risperidone (0.1 mg/kg) produced antidepressant-like activity in the forced swimming test. WAY100636 (a 5-HT(1A) receptor antagonist) inhibited, while yohimbine (an alpha(2)-adrenergic receptor antagonist) potentiated the antidepressant-like effect induced by co-administration of MIR and risperidone. Active behavior in that test did not reflect an increase in general activity, since combined administration of antidepressants and risperidone failed to enhance the locomotor activity of mice. The obtained results indicate that risperidone applied in a low dose enhances the antidepressant-like activity of MIR and that, among other mechanisms, 5-HT(1A)-, and alpha(2)-adrenergic receptors may play a role in this effect. PMID- 21273678 TI - Effects of morphine and methadone treatment on mRNA expression of Galpha(i) subunits in rat brains. AB - Methadone is clinically effective as substitution therapy in patients with opioid dependence. The diversity of methadone and morphine in their intracellular activity is postulated. We compared the effects of repeated daily treatment of Sprague-Dawley rats with morphine (10 mg/kg) and methadone (1 mg/kg) on the expression of the Galpha(i1-i3) mRNAs in several rat brain areas using RT-qPCR. We found that both opioid receptor agonists decreased Galpha(i3) mRNA in only the nucleus accumbens. Although there was no difference in the influence of morphine and methadone on Galpha(i), our results indicate that among Galpha(i) subunits, the Galpha(i3) is specifically involved in the mechanism of action of both drugs. PMID- 21273679 TI - Alterations in hippocampal calcium-binding neurons induced by stress models of depression: a preliminary assessment. AB - In this study, the neuropathological changes induced by chronic unpredictable stress (CUS) and chronic mild stress (CMS) in calbindin D-28K (CB) and parvalbumin (PV) immunoreactive neurons in the rat hippocampus were demonstrated. We used immunohistochemical techniques to quantify the numerical density and morphological changes of PV immunoreactive and CB immunoreactive neurons in the dentate gyrus (DG) and the CA1 and CA3 regions of the hippocampus. We also assessed cell proliferation (Ki-67) and apoptotic processes (active caspase-3) in the DG. We found a significant decrease (16.6% for CUS and 13.3% for CMS) in the numerical density of granule cells (GC), alterations in the CB immunoreactive cells of the GC in the DG and an impairment of mossy fiber CB immunolabelling in the CA3. These changes were not accompanied by a decrease in Ki-67 labeling or the level of caspase-3 in the DG. These data indicate a stress-induced reduction of calcium binding neuron parameters, which may be related to the behavioral paradigms exhibited in these models. PMID- 21273680 TI - Early lifetime zinc supplementation protects zinc-deficient diet-induced alterations. AB - Preclinical and clinical data indicate the involvement of zinc in the pathophysiology and therapy of depression. A relationship between zinc-deficiency and depression symptoms was recently proposed. The present study investigated alterations in spontaneous locomotor activity and zinc concentrations in the serum, hippocampus and frontal cortex; these alterations were induced by subjecting rats to a zinc-deficient diet, prior subjected after birth to zinc supplemented diet. Body weight was significantly reduced in animals subjected to the four-week zinc-deficient diet compared to those subjected to the zinc adequate diet. The two-week zinc-deficient diet induced a significant increase in locomotor activity in all measured time periods (5, 30 and 60 min by 44-62%). The four-week zinc-deficient diet did not affect locomotor activity, while the six week zinc-deficient diet resulted in a 45% increase in the 5 min time period. Serum zinc concentrations were significantly reduced (by 29%) in animals subjected to the four-week zinc-deficient diet but not in those subjected to the two- or six-week zinc-deficient diets. The zinc-deficient diet did not influence the zinc concentration in the examined brain regions regardless of the length. These results indicate that post-birth supplementation with zinc may protect zinc deficient diet-induced rapid alterations in zinc homeostasis. PMID- 21273681 TI - Impact of maternal separation on neural cell adhesion molecules expression in dopaminergic brain regions of juvenile, adolescent and adult rats. AB - Stressful experiences in the early stages of life can influence brain development and maturation, and they can also increase the risk for some psychiatric disorders; however, the specific mechanisms of this effect are still poorly understood. Neural cell adhesion molecules (NCAM 120, 140, 180 kDa) are known to play an important role in normal brain development and synaptic plasticity. Therefore, we decided to investigate whether maternal separation (MS) in rats, a paradigm which models an early life stress, has any impact on the expression of NCAM proteins in the juvenile, adolescent and adult brains of both male and female rats. Specifically, we focused our efforts on the brain regions associated with dopaminergic neurotransmission. In juvenile rats, MS decreased the levels of NCAM-140 in the substantia nigra (SN) of females and NCAM-180 in the ventral tegmental area of males. During adolescence, a reduction in NCAM-180 levels in the SN and medial prefrontal cortex (mPFC) of MS females was revealed. Finally, in adulthood, a decrease in NCAM-180 expression was observed in the mPFC of MS males. The results that we obtained indicate that early life stress can affect maturation and NCAM-driven plasticity in dopaminergic brain areas at different stages of ontogenesis and with a sex-specific manner. PMID- 21273682 TI - Effects of low doses of intracerebroventricular 6-OHDA on the levels of monoaminergic neurotransmitters in rat brain structures. AB - The objective of this study was to determine the degree and specificity of noradrenergic lesions in different areas of the rat brain after intracerebroventricular administration of low doses of 6-hydroxydopamine (6-OHDA) into both lateral ventricles. Our interest focused on the induction of an effective hypothalamic lesion. The results suggest that small doses of 6-OHDA (25 or 50 MUg per ventricle) could effectively damage the noradrenergic system in the hypothalamus without significant interfering with the dopamine level and with only a modest reduction in the serotonin concentration. PMID- 21273683 TI - Anticonvulsant effects of four linear furanocoumarins, bergapten, imperatorin, oxypeucedanin, and xanthotoxin, in the mouse maximal electroshock-induced seizure model: a comparative study. AB - The aim of this study was to determine and compare the anticonvulsant activities of four natural furanocoumarins [bergapten (5-methoxypsoralen), imperatorin (8 isopentenyloxypsoralen), oxypeucedanin (5-epoxy-isopentenyloxypsoralen) and xanthotoxin (8-methoxypsoralen)] in the maximal electroshock-induced seizure test in mice. The anticonvulsant effects of bergapten, imperatorin, oxypeucedanin, and xanthotoxin were evaluated at 15, 30, 60 and 120 min after their systemic (intraperitoneal) administration. Tonic hind limb extension (seizure activity) was evoked in adult albino Swiss mice by a current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2 s stimulus duration) delivered via auricular electrodes. The time courses of protection by bergapten, imperatorin, oxypeucedanin and xanthotoxin against maximal electroshock-induced seizures revealed that 300 mg/kg imperatorin and xanthotoxin (C-8 substituted derivatives of psoralen) exerted strong anticonvulsant activity, whereas 300 mg/kg bergapten and oxypeucedanin (C-5 substituted derivatives of psoralen) did not produce any anticonvulsant activity in this model. In conclusion, imperatorin and xanthotoxin protected the animals against maximal electroshock-induced seizures, whereas bergapten and oxypeucedanin, despite their chemical and structural similarities to xanthotoxin and imperatorin, exerted no anticonvulsant activity in this seizure test. PMID- 21273684 TI - Gain of function of Kir4.1 channel increases cell resistance to changes of potassium fluxes and cell volume evoked by ammonia and hypoosmotic stress. AB - The Kir4.1 channel is an inward rectifying potassium channel involved in the control of potassium and water movement in mammalian cells. To evaluate independently the role of Kir4.1 alone and without interaction with other cellular effectors, we compared (86)Rb fluxes and cell volume in Kir4.1 transfected cells (Kir4.1(+)) with cells transfected with an empty vector (Kir4.1(-)). Transfection with Kir4.1 neither increased (86)Rb uptake nor (86)Rb efflux from cells in isotonic medium. Pretreatment with ammonia (5 mM ammonium chloride) in isotonic medium produced a pronounced increase of (86)Rb uptake and a moderate decrease of cell volume in Kir4.1(-) but not in Kir4.1(+) cells. However, pretreatment evoked no change in (86)Rb efflux in either cell type. Hypotonic treatment (HT) markedly increased (86)Rb efflux in Kir4.1(-) cells and increased cell volume in both cell types. Although pretreatment with ammonia did not alter the effect of HT on (86)Rb efflux in either Kir4.1(+) or Kir4.1(-) cells, it potentiated the effect of hypotonic treatment in increasing cell volume in Kir4.1(-) cells. The results demonstrate that the presence of Kir4.1 in cells increases their resistance to alterations of potassium fluxes and/or cell volume imposed by ammonia and hypotonicity. PMID- 21273685 TI - Effects of ethylene glycol ethers on cell viability in the human neuroblastoma SH SY5Y cell line. AB - Ethylene glycol ethers (EGEs) are a class of chemicals used extensively in the manufacture of a wide range of domestic and industrial products, which may result in human exposure and toxicity. Hematologic and reproductive toxicity of EGEs are well known whereas their action on neuronal cell viability has not been studied so far. In the present study, we investigated the effects of some EGEs on cell viability and on the hydrogen peroxide-induced damage in the human neuroblastoma (SH-SY5Y) cells. It has been found that 2-phenoxyethanol in a concentration dependent manner (5-25 mM, 24 h) increased the basal and H(2)O(2)-induced lactate dehydrogenase (LDH) release and 3-[4,5-dimethylthiazol-2-yl]2,5-diphenyl tetrazolium bromide (MTT) reduction. 2-Butoxyethanol given alone did not affect LDH release and MTT reduction but concentration-dependently enhanced the cytotoxic effect of H(2)O(2). 2-Isopropoxyethanol significantly and concentration dependently (1-25 mM) increased the basal LDH release and attenuated MTT reduction, but did not potentiate the cytotoxic effect of H(2)O(2). Contrary to this, 2-methoxyethanol did not show a cytotoxic effect while 2-ethoxyethanol at high concentrations intensified the hydrogen peroxide action. This study demonstrated that among the EGEs studied, 2-phenoxyethanol showed the most consistent cytotoxic effect on neurons in in vitro conditions and enhanced the hydrogen peroxide action. 2-Isopropoxyethanol had also a potent cytotoxic effect, but it did not enhance the hydrogen peroxide action, whereas 2-butoxyethanol only potentiated cytotoxic effect of H(2)O(2). It is concluded that the results of the present study should be confirmed in in vivo conditions and that some EGEs, especially 2-phenoxyethanol, 2-butoxyethanol and 2-isopropoxyethanol, may be responsible for initiation or exacerbation of neuronal cell damage. PMID- 21273686 TI - Anti-inflammatory effect of atorvastatin in patients with aortic sclerosis or mild aortic stenosis independent of hypercholesterolemia. AB - The aim of our study was to assess the effect of atorvastatin (20 mg) on inflammatory biomarkers in patients with aortic sclerosis or mild aortic stenosis. Additionally, the anti-inflammatory effect of statin therapy was compared between hypercholesterolemic and non-hypercholesterolemic patients. We enrolled 33 patients with aortic sclerosis or mild aortic stenosis (AS) (18 males and 15 females, mean age 70 +/- 8 years). Plasma levels of the following biomarkers were measured: C-reactive protein (CRP), interleukin (IL-6) and monocyte chemoattractant protein-1 (MCP-1). Atorvastatin (20 mg) was used for four weeks. All three biomarkers of inflammation significantly decreased after atorvastatin: CRP from 4.08 +/- 3.72 to 2.97 +/- 3.26 MUg/ml (p < 0.05), IL-6 from 20.66 +/- 20.05 to 13.36 +/- 11.21 pg/ml (p < 0.05) and MCP-1 from 271.08 +/ 85.72 to 213.24 +/- 115.09 pg/ml (p < 0.05). No differences in the levels of these biomarkers were shown in a comparison between 17 patients with hypercholesterolemia and 16 patients without hypercholesterolemia. In patients in the early stages of aortic valve disease (with aortic sclerosis or mild AS), atorvastatin at a dose of 20 mg reduced the biomarkers of inflammation. PMID- 21273687 TI - Numerical analysis of a unique mode of locomotion: vertical climbing by Pacific lamprey. AB - Pacific lampreys are capable of climbing vertical wetted surfaces through a two phase (bending and stretching) locomotion mode using the oral disc for adherence. We investigate the physical mechanism and performance of this process by using a continuous beam model. Two mechanisms, one akin to the jumping process and the other related to the fast stretching of the body, have been identified. This locomotion mode may inspire biomimetic designs of anguilliform swimming devices capable of overcoming steep obstacles. By using a genetic algorithm simulation we identify the combination of kinematic parameters corresponding to optimal efficiency (defined as the gravitational potential energy gained in each climbing step divided by the energy spent to activate the motion). These parameters are similar to laboratory observations of lamprey motion, suggesting that this type of locomotion has been optimized for maximum efficiency through evolution. PMID- 21273689 TI - Molecular systematics and conservation of the langurs and leaf monkeys of South Asia. AB - Numerous morphology-based classification schemes have been proposed for langurs and leaf monkeys of South Asia but there is very little agreement between them. An incorrect classification scheme when used as a basis for biogeographic studies can support erroneous hypotheses. Further, lack of taxonomic resolution will also confound conservation efforts, given that conservation biologists use traditional morphology-based-classification schemes to prioritize species for conservation. Here, I have revisited recent molecular phylogenetic studies done on langurs and leaf monkeys of South Asia. Results from these studies are in turn used to derive a rational and scientific basis for prioritizing species for conservation. Molecular data support the classification of langurs of the Indian subcontinent Hanuman, Nilgiri and purple-faced langurs-in the genus Semnopithecus, whereas Phayre's leaf monkey along with other Southeast Asian leaf monkeys form another distinct clade (Trachypithecus). The phylogenetic position of capped and golden langurs remains unresolved. Molecular data suggest that they are closely related to each other but this group might have evolved through past hybridization between Semnopithecus and Trachypithecus. Additionally, genetic data also support the splitting of the so-called Hanuman langurs into at least three species. The scores for taxonomic uniqueness of langurs and leaf monkeys of South Asia were revised using this molecular phylogeny-based classification. According to the revised scores, Phayres leaf monkey and golden langur are priority species for conservation followed by capped and Nilgiri langurs. PMID- 21273690 TI - Meiotic behaviour of tetraploid wheats (Triticum turgidum L.) and their synthetic hexaploid wheat derivates influenced by meiotic restitution and heat stress. AB - Meiotic restitution is considered to be a common mechanism of polyploidization in plants and hence is one of the most important processes in plant speciation. Meiotic behaviour of plant chromosomes is influenced by both genetic and environmental factors. In this study, the meiotic behaviour of cereal crops was investigated, which includes tetraploid wheat genotypes (with and without the meiotic restitution trait) and their derivates (synthetic hexaploid wheats and a doubled haploid (DH) line), grown at two planting dates in the field. In addition, two local landraces of emmer wheat (Triticum turgidum ssp. dicoccum), one wheat cultivar (Chinese spring), one DH triticale cultivar (Eleanor) and one rye accession were included. Immature spikes of mid-autumn and end-winter sowing plants were collected in April and May 2008, respectively, fixed in Carnoy's solution and stained with hematoxylin. Pollen mother cells (PMCs) from anthers at different stages of meiotic process were analysed for their chromosomal behaviour and irregularities. Meiotic aberrations such as laggards, chromosome bridges, micronuclei, abnormal cytokines, chromatin pulling and meiotic restitution were observed and the studied genotypes were accordingly ranked as follows: triticale > synthetic hexaploid wheats > tetraploid wheats possessing meiotic restitution > tetraploid wheats lacking meiotic restitution > rye. The results indicated that the samples that had been planted in the autumn, thus experiencing an optimum temperature level at the flowering stage, exhibited less meiotic irregularities than winter planting samples that encountered heat stress at the flowering period. PMID- 21273691 TI - Mapping of QTL for tiller number at different stages of growth in wheat using double haploid and immortalized F2 populations. AB - Effective tiller number is one of the most important traits for wheat (Triticum aestivum L.) yield, but the inheritance of tillering is poorly understood. A set of 168 doubled haploid (DH) lines derivatives of a cross between two winter wheat cultivars (Huapei 3 and Yumai 57), and an immortalized F(2) (IF(2)) population generated by randomly permutated intermating of these DHs were investigated, and QTLs of tillering related to the maximum tillering of pre-winter (MTW), maximum tillering in spring (MTS), and effective tillering in harvest (ETH) were mapped. Phenotypic data were collected for the two populations from two different environments. Using inclusive composite interval mapping (ICIM), a total of 9 and 18 significant QTL were detected across environments for tillering in the DH and IF(2) populations, respectively. Four QTLs were common between two populations. A major QTL located on the 5D chromosome with the allele originating from Yumai 57 was detected and increased 1.92 and 3.55 tillers in MTW and MTS, respectively. QTLs (QMts6D, QEth6D) having a neighbouring marker interval at Xswes679.1 and Xcfa2129 on chromosome 6D was detected in MTS and ETH. These results provide a better understanding of the genetic factors for selectively expressing the control of tiller number in different growth stages and facilitate marker assisted selection strategy in breeding. PMID- 21273692 TI - Comparing genetic ancestry and self-reported race/ethnicity in a multiethnic population in New York City. AB - Self-reported race/ethnicity is frequently used in epidemiological studies to assess an individual's background origin. However, in admixed populations such as Hispanic, self-reported race/ethnicity may not accurately represent them genetically because they are admixed with European, African and Native American ancestry. We estimated the proportions of genetic admixture in an ethnically diverse population of 396 mothers and 188 of their children with 35 ancestry informative markers (AIMs) using the STRUCTURE version 2.2 program. The majority of the markers showed significant deviation from Hardy-Weinberg equilibrium in our study population. In mothers self-identified as Black and White, the imputed ancestry proportions were 77.6% African and 75.1% European respectively, while the racial composition among self-identified Hispanics was 29.2% European, 26.0% African, and 44.8% Native American. We also investigated the utility of AIMs by showing the improved fitness of models in paraoxanase-1 genotype-phenotype associations after incorporating AIMs; however, the improvement was moderate at best. In summary, a minimal set of 35 AIMs is sufficient to detect population stratification and estimate the proportion of individual genetic admixture; however, the utility of these markers remains questionable. PMID- 21273693 TI - Transcriptome atlas of eight liver cell types uncovers effects of histidine catabolites on rat liver regeneration. AB - Eight liver cell types were isolated using the methods of Percoll density gradient centrifugation and immunomagnetic beads to explore effects of histidine catabolites on rat liver regeneration. Rat Genome 230 2.0 Array was used to detect the expression profiles of genes associated with metabolism of histidine and its catabolites for the above-mentioned eight liver cell types, and bioinformatic and systems biology approaches were employed to analyse the relationship between above genes and rat liver regeneration. The results showed that the urocanic acid (UA) was degraded from histidine in Kupffer cells, acts on Kupffer cells itself and dendritic cells to generate immune suppression by autocrine and paracrine modes. Hepatocytes, biliary epithelia cells, oval cells and dendritic cells can convert histidine to histamine, which can promote sinusoidal endothelial cells proliferation by GsM pathway, and promote the proliferation of hepatocytes and biliary epithelia cells by GqM pathway. PMID- 21273694 TI - Polymorphisms in the pituitary growth hormone gene and its receptor associated with coronary artery disease in a predisposed cohort from India. AB - We investigated the promoter polymorphisms of the pituitary growth hormone gene (GH1) and exon 3 deletion polymorphism (GHRd3) in its receptor gene (GHR) in 299 angiographically proven patients with coronary artery disease (CAD) and 231 asymptomatic controls enrolled in the ongoing Indian Atherosclerosis Research Study. Real time PCR based analysis of the GHR variant showed significant association of the GHRd3 deletion allele with CAD (OR 0.48, 95% CI: 0.30-0.76, P = 0.0014) and a dominant model of inheritance (Akaike information criterion = 482). The deletion allele showed significant association with high plasma HDL-c levels (P = 0.001). Sequencing of the proximal promoter region of GH1 revealed 12 novel polymorphisms and a TAGA haplotype constituted by the functional SNPs rs2005171, rs11568828, rs2005172 and rs6171, that showed significant association with CAD alone (adjusted OR of 3.31 (95% CI = 1.33-8.29, P = 0.011) and in CAD patients with diabetes (P = 0.019). Mean standardized height was associated with three of the four haplotype-tagging SNPs in the cohort (P <= 0.03). Eleven of the 12 polymorphic promoter SNPs contributed to 14.7% of variation in height in females in the whole dataset (P = 0.029). CAD patients with history of stroke exhibited marginally significantly lower mean height as compared to rest of the cohort (P < 0.006). In conclusion, genetic polymorphisms in the GHR gene and its ligand, GH1, may modulate the risk of CAD in the Asian Indian population. PMID- 21273695 TI - Novel alleles of 31-bp VNTR polymorphism in the human cystathionine beta-synthase (CBS) gene were detected in healthy Asians. AB - A 31-bp variable number of tandem repeats (VNTR) polymorphism of the cystathionine beta-synthase (CBS) gene was earlier reported in Caucasians of predominantly European descent and Indo-Caucasoid populations. We report here for the first time, the detection of allele 20, which was absent in Caucasian and Indo-Caucasoid populations, as a common allele present in Singaporean Chinese (6.25%), Indians (11.7%), and Malays (11.5%). Hence, allele 20 might be a specific allele for Asian populations. A relatively common allele 19 found in the Caucasian and Indo-Caucasoid populations (10.4%-10.6%) was absent in the Asian samples of this study. Therefore, allele 19 might be a specific allele for the Caucasian populations. A novel and rare allele 13, which was not reported before in the Caucasian and Indo-Caucasoid populations, was found in 0.5% of Singaporean Chinese as genotype 13/17 heterozygotes. The presence of alleles 13 and 20 were verified by DNA sequencing. There were five new genotypes (13/17, 16/20, 17/20, 18/20 and 20/20) not reported before in the Caucasian and Indo-Caucasoid populations, detected in this study. Nine genotypes (15/18, 16/18, 16/21, 17/19, 18/19, 18/21, 19/19, 19/21 and 21/21) which were present in the Caucasian and/or Indo-Caucasoid populations were absent in this study. Our results showed that CBS 31-bp VNTR polymorphism has a distinct genetic difference in allele and genotype frequencies between the European Caucasians, Indo-Caucasoid and Asian populations. PMID- 21273696 TI - Chromosome region 2p25 is linked and associated with type 1 diabetes in Colombia. PMID- 21273697 TI - Middle-aged heterozygous carriers of Wilson's disease do not present with significant phenotypic deviations related to copper metabolism. PMID- 21273698 TI - Common variants in the gene for the serotonin receptor 6 (HTR6) do not contribute to obesity. PMID- 21273699 TI - Novel mutation in ATP-binding domain of ABCD1 gene in adrenoleukodystrophy. PMID- 21273700 TI - Analysis of genetic diversity in a close population of Zandi sheep using genealogical information. PMID- 21273701 TI - Alpha-1 antitrypsin phenotypes in patients with Klinefelter's syndrome. PMID- 21273702 TI - Isolation of rye-specific DNA fragment and genetic diversity analysis of rye genus Secale L. using wheat SSR markers. PMID- 21273703 TI - Chromosomal localization of rDNA and DAPI bands in solanaceous medicinal plant Hyoscyamus niger L. PMID- 21273705 TI - Application of RNA interference in treating human diseases. AB - Gene silencing can occur either through repression of transcription, termed transcriptional gene silencing (TGS), or through translation repression andmRNA degradation, termed posttranscriptional gene silencing (PTGS). PTGS results from sequence-specific mRNA degradation in the cytoplasm without dramatic changes in transcription of corresponding gene in nucleus. Both TGS and PTGS are used to regulate endogenous genes. Interestingly, mechanisms for gene silencing also protect the genome from transposons and viruses. In this paper, we first review RNAi mechanism and then focus on some of its applications in biomedical research such as treatment for HIV, viral hepatitis, cardiovascular and cerebrovascular diseases, metabolic disease, neurodegenerative disorders and cancer. PMID- 21273706 TI - Molecular characterization and functional analysis of elite genes in wheat and its related species. AB - The tribe Triticeae includes major cereal crops (bread wheat, durum wheat, triticale, barley and rye), as well as abundant forage and lawn grasses. Wheat and its wild related species possess numerous favourable genes for yield improvement, grain quality enhancement, biotic and abiotic stress resistance, and constitute a giant gene pool for wheat improvement. In recent years, significant progress on molecular characterization and functional analysis of elite genes in wheat and its related species have been achieved. In this paper, we review the cloned functional genes correlated with grain quality, biotic and abiotic stress resistance, photosystem and nutrition utilization in wheat and its related species. PMID- 21273707 TI - GAL4 enhancer trap strains with reporter gene expression during the development of adult brain in Drosophila melanogaster. PMID- 21273708 TI - MAO-A promoter polymorphism and idiopathic pulmonary arterial hypertension. PMID- 21273704 TI - Modifiers and mechanisms of multi-system polyglutamine neurodegenerative disorders: lessons from fly models. AB - Polyglutamine (polyQ) diseases, resulting from a dynamic expansion of glutamine repeats in a polypeptide, are a class of genetically inherited late onset neurodegenerative disorders which, despite expression of the mutated gene widely in brain and other tissues, affect defined subpopulations of neurons in a disease specific manner. We briefly review the different polyQ-expansion-induced neurodegenerative disorders and the advantages of modelling them in Drosophila. Studies using the fly models have successfully identified a variety of genetic modifiers and have helped in understanding some of the molecular events that follow expression of the abnormal polyQ proteins. Expression of the mutant polyQ proteins causes, as a consequence of intra-cellular and inter-cellular networking, mis-regulation at multiple steps like transcriptional and posttranscriptional regulations, cell signalling, protein quality control systems (protein folding and degradation networks), axonal transport machinery etc., in the sensitive neurons, resulting ultimately in their death. The diversity of genetic modifiers of polyQ toxicity identified through extensive genetic screens in fly and other models clearly reflects a complex network effect of the presence of the mutated protein. Such network effects pose a major challenge for therapeutic applications. PMID- 21273709 TI - Diversity in Indian barley (Hordeum vulgare) cultivars and identification of genotype-specific fingerprints using microsatellite markers. PMID- 21273710 TI - More than meets the eye: digital fraud in dentistry. AB - INTRODUCTION: Digital photographs play a substantial role in the presentation and validation of clinical cases for documentation and research purposes in esthetically oriented professions such as dentistry. The introduction of sophisticated cameras and "easy to use" computer software readily available on today's market has enabled digital fraud to emerge as a common and widely used practice. Hence, it is essential that both dentists and editorial circles are aware and cautious with regard to the possibility of digital fraud. MATERIALS AND METHODS: A set of 10 routine "pre-" and "post" treatment dental procedure photographs were taken and randomly manipulated using standard desktop software. A team of 10 dental professionals were selected and each one of them was individually requested to review and evaluate the authenticity of the photographs. RESULTS: An assessment of expert opinion revealed an overall sensitivity of 60% and a sensitivity of 15% in correctly identifying a manipulated photograph, which is considered low. Furthermore, there was poor interobserver agreement. CONCLUSION: Advanced technology that is easily available has resulted in adept digital fraud that is difficult to detect. There is a need for awareness among both dental practitioners and the editorial circle regarding misrepresentation due to image manipulation. It is therefore necessary to follow a skeptical approach in the assessment of digitalized photos used in research and as a part of clinical dentistry. PMID- 21273711 TI - A comparative study of retentive strengths of zinc phosphate, polycarboxylate and glass ionomer cements with stainless steel crowns - an in vitro study. AB - An in vitro study was conducted to compare the retentive strengths of zinc phosphate, polycarboxylate and glass ionomer cements using Instron universal testing machine. Thirty preformed and pretrimmed stainless steel crowns were used for cementation on 30 extracted human primary molars which were divided into three groups of 10 teeth in each group. Then the teeth were stored in artificial saliva and incubated at 37 degrees C for 24 h. A load was applied on to the crown and was gradually increased till the crown showed dislodgement, and then the readings were recorded using Instron recorder and analyzed for statistical significance. The surface area of crown was measured by graphical method. The retentive strength was expressed in terms of kg/cm 2 , which was calculated by the equation load divided by area. Retentive strengths of zinc phosphate (ranged from a minimum of 16.93 to amaximum of 28.13 kg/cm 2 with mean of 21.28 kg/cm 2 ) and glass ionomer cement (minimum of 13.69 - 28.15 kg/cm 2 with mean of 20.69 kg/cm 2 ) were greater than that of polycarboxylate cement (minimum of 13.26 - 22.69 kg/cm 2 with mean of 16.79 kg/cm 2 ). Negligible difference (0.59 kg/cm 2 ) of retentive strength was observed between zinc phosphate (21.28 kg/cm 2 ) and glass ionomer cements (20.69 kg/cm 2 ). Glass ionomer cements can be recommended for cementation of stainless steel crowns because of its advantages and the retentive strength was almost similar to that of zinc phosphate cement. PMID- 21273712 TI - Antimicrobial activity of different endodontic sealers: an in vitro evaluation. AB - BACKGROUND: Microbes are considered as the primary etiological agents in endodontic diseases. The ways of reducing these agents are root canal debridement, antimicrobial irrigants, and antibacterial filling materials. But the complexity of the pulp canal system presents a problem for chemomechanical preparation. One of the factors determining the success of endodontic treatment is the sealing material with a potent bactericidal effect. AIM: The aim of the present study was to assess the antimicrobial activity of endodontic sealers of different bases - in vitro. MATERIALS AND METHOD: The antimicrobial activity of three root canal sealers (endomethasone, AH 26, and apexit) was evaluated against seven strains of bacteria at various time intervals using the agar diffusion test. The freshly mixed sealers were placed in prepared wells of agar plates inoculated with the test microorganisms. The plates were incubated for 24, 48, 72 hours, and 7 and 15 days. The mean zones of inhibition were measured. STATISTICAL ANALYSIS: All statistical analysis was performed using the SPSS 13 statistical software version. The analysis of variance (ANOVA), post-hoc Bonferroni test, and paired t test were performed to reveal the statistical significance. RESULTS: Statistically significant zones of bacterial growth inhibition were observed in descending order of antimicrobial activity: endomethasone, AH 26, and apexit. CONCLUSION: Zinc oxide eugenol based root canal sealer produced largest inhibitory zones followed in decreasing order by epoxy resin based sealer and least by calcium hydroxide based root canal sealer. PMID- 21273713 TI - Comparative evaluation of the effect of cavity disinfectants on the fracture resistance of primary molars restored with indirect composite inlays: an in vitro study. AB - A study was conducted to evaluate and compare the effect of cavity disinfectants on the fracture resistance of primary molars restored with indirect composite inlays. Thirty-six non-carious primary second molars were selected and divided randomly into three groups (n = 12): control group (no disinfectant), chlorhexidine group (disinfected with 2% chlorhexidine for 40 seconds) and sodium hypochlorite group crowns (disinfected with 2% chlorhexidine for 40 seconds). The inlays were fabricated by indirect method using Ceram X nanocomposite on plaster die. All the groups were submitted to compression mechanic test in a Hounsfield universal testing machine at 1 mm/min cross-head speed and the results were calculated in Newtons. Descriptive statistics, independent t test, and one way analysis of variance (ANOVA) test revealed the mean fracture resistance of three groups, i.e., control group, chlorhexidine group and sodium hypochlorite group to be 2260.66, 1858.08 and 1310.66, respectively. When intragroup comparisons were made, a significant difference was observed in all the groups (P<0.001). Scheffe's post hoc test revealed that control group had the highest fracture resistance, followed by chlorhexidine group, and sodium hypochlorite group had the least fracture resistance. Each value differed significantly from the other (P<0.05). Cavity disinfectants used in the present study had detrimental effect on the fracture resistance of primary molars. Among the disinfectants employed in the present study, chlorhexidine showed a better resistance to fracture than sodium hypochlorite. PMID- 21273714 TI - In vivo remineralization of artificial enamel carious lesions using a mineral enriched mouthrinse and a fluoride dentifrice: a polarized light microscopic comparative evaluation. AB - BACKGROUND: Remineralization process is accelerated by the presence of fluoride ions in the oral environment, but this mechanism of caries reversal will be further enhanced if the concentration of calcium, phosphate and fluoride ions is supersaturated with respect to that of oral fluids. AIM: This in vivo study was carried out to evaluate and compare the remineralizing efficacy of a urea-based mineral-enriched mouthrinse and a fluoridated dentifrice using an in vivo intraoral appliance model and polarized light microscopic evaluation technique. MATERIALS AND METHODS: The specimens were prepared from sound teeth and artificial caries was produced using an artificial caries medium in vitro and enamel specimens were inserted in removable orthodontic appliances that were to be worn by 14 children of 10-15 years of age. They were divided into three groups - nonfluoridated dentifrice, fluoridated dentifrice and mineral-enriched mouthrinse groups. After the 6-month experimental period, during which the enamel specimens inserted in the intraoral appliance were subjected to one of the agents (either fluoride, nonfluoride dentifrice or mouthrinse) in vivo, the specimens were retrieved from the patients and were evaluated using the polarized light microscopic technique. OBSERVATIONS AND RESULTS: On analysis, mineral gain occurred in all groups, viz. nonfluoride dentifrice group, fluoride dentifrice and mineral-enriched mouthrinse group. However, it was found to be complete in the mouthrinse group, i.e. both at the surface and at the subsurface (67%), while in the fluoridated dentifrice group, 43% of the samples showed mineral gain in both zones. In the nonfluoridated dentifrice group also, remineralization occurred but was limited either to the surface or the subsurface zone. CONCLUSIONS: Urea-based mineral-enriched mouthrinse was shown to be more efficacious in the process of remineralization of artificial carious lesions. PMID- 21273715 TI - Efficacy of various root canal irrigants on removal of smear layer in the primary root canals after hand instrumentation: a scanning electron microscopy study. AB - AIM: The purpose of this in-vitro study is to determine the efficacy of various irrigants in removing the smear layer in primary teeth root canals after hand instrumentation. MATERIALS AND METHODS: The present study consisted of 30 human primary incisors which were sectioned at the cementoenamel junction horizontally. The specimens were divided randomly into four experimental and one control group having six teeth each and each group was treated with the specific irrigant. 5.25% NaOCl, 5.25% NaOCl + 10% EDTA, 6% citric acid, 2% chlorhexidine, saline (control) were the irrigants evaluated for efficacy in removal of smear layer. The specimens were split along the longitudinal axis using a chisel after placing superficial grooves in cementum not extending to the root canal. The exposed surface was subjected to scanning electron microscopic analysis to reveal the efficacy of irrigants in removal of smear layer. The representative areas were evaluated twice at 15 days interval by a single evaluator. The scale for the smear layer removal by Rome et al was modified and used in the present study. RESULTS: The pictures from the scanning electron microscopy showed that among the tested irrigants, citric acid has the best efficacy to remove the smear layer without altering the normal dentinal structures, which was supported by the lowest mean smear scores. The pictures from the 10%EDTA + 5.25% sodium hypochlorite group showed that even though it removed the smear layer, it adversely affected the dentine structure. SEM pictures of the other groups like sodium hypochlorite, chlorhexidine revealed that these irrigants does not have the capacity to remove the smear layer in primary teeth. CONCLUSIONS: The results of the present study clearly indicate the superior efficacy of 6% citric acid than the other tested irrigants on removing the smear layer in primary teeth root canals. PMID- 21273716 TI - A study of influence of sugars on the modulations of dental plaque pH in children with rampant caries, moderate caries and no caries. AB - The present study is undertaken to find out the pH of resting plaque in children with no caries, moderate caries and rampant caries and to determine the modulations of plaque pH with different sugar solution rinses viz: sucrose, glucose and fructose. The study was carried out on forty five children, in the age group of 3-10 years (25 males and 20 females). The child was given 10 ml of test solution and was asked to rinse and swish it in the mouth for a period of 30 sec. Plaque samples were taken from 20 different spots after 5, 10, 20 and 30 min of the rinse and pH values of all the samples were determined. Results show that there was a statistically significant (P<0.05) difference between the pH values of plaque at different intervals of time with sucrose, fructose and glucose solution rinse in children with moderate caries, rampant caries as compared to the caries free group. Sucrose was found to be highly cariogenic in all the children with a greater potentiating effect in moderate and rampant caries. Glucose also appeared to have a cariogenic role while fructose had the least of it all. PMID- 21273717 TI - Mother's knowledge about pre-school child's oral health. AB - Children under the age of 5 years generally spend most of their time with their parents and guardians, especially mothers, even when they attend pre-schools or nurseries. It has been found that young children's oral health maintenance and outcomes are influenced by their parent's knowledge and beliefs. This study was done to assess the mother's knowledge about the oral health of their pre-school children in Moradabad, India. Mothers of children aged 1-4 years, attending the hospital for vaccination or regular checkups in the pediatric division of government hospitals, were invited to participate in the study. A 20-item questionnaire covering socio-demographic characteristics, dietary practices, oral hygiene practices and importance of deciduous teeth, was distributed to their mothers, during their visit to the hospital. Responses of the mothers were recorded on a Likert Scale. The sample comprised 406 mothers, with the mean age of children being 3.8 years. Three hundred (73.8%) mothers had a good knowledge about diet and dietary practices, while only 110 (27.1%) and 103 (25.4%) mothers were found to have a good knowledge about the importance of oral hygiene practices and importance of deciduous teeth, respectively. Mothers with higher educational qualification and information gained through dentist had a better knowledge about child's oral health. Oral hygiene habits and dietary habits are established during pre-school days and the parents, especially mothers, function as role models for their children. PMID- 21273718 TI - Management of recurrent fracture of central incisor with internal resorption using light transmitting (luminex) post. AB - The normal root canal anatomy may be altered in various pathological processes and making it very difficult and at times impossible to achieve ideal obturation by normal methods. Internal resorption is one among them. There are several treatment protocols advised for this pathological condition. A crown-root fracture is defined as a fracture involving enamel, dentin and cementum and accounts for 5% of all traumatic injuries to the permanent dentition. In anterior teeth, these fractures are usually caused by direct trauma and often complicated in fully erupted teeth. In cases where the fracture line extends down along the long axis of the root, extraction of the tooth is indicated. The purpose of this report is to present the use of light transmitting post system to reinforce the crown root fractured maxillary central incisor due to trauma and internal resorption. PMID- 21273719 TI - Peripheral giant cell granuloma. AB - Peripheral giant cell granuloma is a benign reactive lesion of gingiva. It manifests as a firm, soft, bright nodule or as a sessile or pedunculate mass. This article reports the management of peripheral giant cell granuloma in a 12 year-old boy by surgical excision. PMID- 21273720 TI - Psoriatic triad in a patient presenting with oligodontia. AB - Psoriasis is a common dermatological disease. It can occur at any age but usually develops between 15 and 35 years of age and may persist throughout a person's lifetime with periods of exacerbation and remission. The hyperproliferative state of the affected epidermis produces a turnover rate that is up to eight times greater than normal. Instead of being shed, the skin cells pile up, causing the visible lesions. Oral manifestations of psoriasis are rare clinical observations. Lesions have been reported on the lips, buccal mucosa, palate, gingiva, and floor of the mouth. We document a presentation of psoriasis showing a triad: skin lesions, arthritis, and oral manifestations (oligodontia being patient's chief concern). Dental rehabilitation done was in the form of partial dentures. This was done to address the immediate concern of the patient, that is, inability to chew properly. As put forth through this case report, a potential link between psoriasis and oligodontia has scope for further study. PMID- 21273721 TI - Familial hypophosphatemic rickets. AB - Rickets is the failure of mineralization of osteoid and newly formed bones in a child skeleton. It is commonly associated with vitamin D deficiency; however, it can be because of a decrease in the serum phosphate levels leading to inadequate mineralization of cartilage and bone, consequent skeletal deformities, and growth retardation. The hypophosphatemic conditions that interfere in bone mineralization comprise many hereditary or acquired diseases. One of the hereditary types of hypophosphatemic rickets is the familial hypophosphatemic rickets. This rare variety was diagnosed in a 9-year-old patient who had come with a chief complaint of a missing tooth. In the present case, radiographic aspects of oral and systemic manifestations of familial hypophosphatemic rickets are highlighted. PMID- 21273722 TI - Maxillary aneurysmal bone cyst: report of a rare case. AB - Everyone likes to see, hear, and know about rare things. An aneurysmal bone cyst (ABC) is an uncommon non-neoplastic lesion of the bone, mostly affecting long bones and spine. This rare jaw lesion usually affects the mandible but origin from the maxillary anterior region is even rarer. This paper describes a case of an ABC in an 8-year-old female child with a progressively increasing swelling in the right nasomaxillary region developed over a period of 1.5 months. Treatment consisted of the excision and enucleation of the lesion through an intraoral approach under general anesthesia. The higher prevalence in young adulthood has made the role of pedodontists vital in diagnosing ABCs, at the earliest. PMID- 21273723 TI - A new technique of impression making for an obturator in cleft lip and palate patient. AB - Cleft lip and palate is a birth defect occurring in the orofacial region. One of the immediate problems to be addressed in a newborn with this defect would be to aid in suckling and swallowing. Here we present a case of a 5-day-old infant with unilateral cleft lip and palate for whom feeding obturator was made by using a simplified impression technique to facilitate feeding. PMID- 21273724 TI - Regional odontodysplasia. AB - Regional odontodysplasia (ROD) is a rare developmental anomaly involving both mesodermal and ectodermal components in a group of contiguous teeth. It affects the primary and permanent dentitions in the maxilla and the mandible or both, however, the maxilla is frequently involved. Although the etiology of the ROD is uncertain, it has been suggested that numerous other factors play a role. The treatment plan should be based on the degree of involvement as well as the functional and esthetic needs in each case. This article reports the case of a 5 year-old boy presenting a rare anomaly on the right side of the maxillary arch. The treatment performed was rehabilitation with temporary partial acrylic denture and periodic checkups. The extraction was followed by rehabilitation with dental implants. The main aim of this article is to provide valuable information to pediatric dentists about the review and treatment alternatives for ROD. PMID- 21273725 TI - Congenital absence of multiple primary teeth. AB - Idiopathic agenesis of primary dentition is very rare. This is a case report of a 2-year and 6-month-old girl child who presented with 14 missing primary teeth. A review of the previous case reports is done and the management of these cases is discussed. PMID- 21273726 TI - Apert syndrome. AB - Apert syndrome (acrocephalosyndactyly) is a rare developmental malformation characterized by craniosynostosis, mid-face hypoplasia, symmetrical syndactyly of hands and feet. The prodromal characteristics for the typical cranio-facial appearance are early craniosynostosis of the coronal suture, cranial base and agenesis of the sagittal suture. The purpose of this paper is to report a case of Apert syndrome with emphasis on craniofacial and oral features in an eighteen month-old male child. The patient presented with several craniofacial deformities, including brachycephaly, midface hypoplasia, flat face, hypertelorism, ocular proptosis, downslanting palpebral fissures. Syndactylies with osseous fusion of the hands and feet were also observed. Intraoral findings included delayed eruption of teeth, high arched palate with pseudo cleft in the posterior one third. PMID- 21273727 TI - Pierre Robin sequence: report of two cases. AB - Pierre Robin sequence (PRS) or anomalad, a well-recognized presentation, is the association of the first brachial arch malformation. It presents with a classic triad of micrognathia, glossoptosis, and cleft palate. In a neonate with a complete cleft palate, problems with feeding are commonly encountered. Presented here are two cases with PRS in whom palatal obturators were constructed. PMID- 21273730 TI - Pharmacodynamics of cibenzoline-induced hypoglycemia in rats. AB - Hypoglycemia is one of the serious adverse effects induced by cibenzoline (CBZ), an antiarrhythmic agent. In order to clarify the pharmacodynamics of CBZ-induced hypoglycemia, CBZ was administered intravenously to conscious rats at a dose of 5, 10 or 20 mg/kg and serum samples were collected periodically to determine the concentrations of CBZ, insulin and glucose. The pharmacokinetics of CBZ showed nonlinear characteristics and could be described by a two-compartment model with Michaelis-Menten elimination kinetics. CBZ induced a rapid increase in the serum concentration of insulin. As the CBZ dose was increased, a greater hypoglycemic effect occurred. The indirect response model was applied to account for the CBZ induced increase in insulin secretion and the subsequent decrease in serum glucose. A linear relationship was assumed between the serum concentration of CBZ and its stimulating effect on insulin secretion. A nonlinear relationship was assumed between the serum concentration of insulin and its stimulating effect on the elimination of serum glucose. The time courses of serum concentrations of CBZ, insulin and glucose after intravenous injection of CBZ could be described by the pharmacokinetic and pharmacodynamic model developed. This approach will be useful for the identification of variable factors related to CBZ-induced hypoglycemia. PMID- 21273731 TI - A newly developed DNA microarray is useful to assess induction of cytochromes p450 in the cynomolgus monkey. AB - Cytochromes P450 (P450s or CYPs) are a gene family of highly homologous genes and include the CYP1-4 family, which is relevant to drug metabolism. In the cynomolgus monkey (which is frequently used in drug metabolism studies), numerous CYPs (mfCYPs) have been identified in the CYP1-4 family. DNA microarrays are useful for high-throughput screening assays; however, there is a potential problem with cross-hybridization of highly homologous genes in the gene family. This problem might be solved with the use of low-density DNA microarrays, with which specific validation can be performed for the genes on the microarray. We have developed a DNA microarray for the 20 mfCYPs and have evaluated and validated its specificity and usefulness. First, in both DNA microarray and quantitative polymerase chain reaction (qPCR) analyses, hepatic expression of each mfCYP correlated well, and similar tissue expression patterns were observed for five representative mfCYPs, confirming the specificity of the DNA microarray. Second, the usefulness of this DNA microarray was validated by induction analysis of mfCYPs in primary hepatocytes, which successfully detected known responders, but also novel responders (mfCYP2C43, mfCYP2C75, and mfCYP3A5 for rifampicin), as confirmed by qPCR analysis. This DNA microarray can thus be utilized for high throughput assays during drug development. PMID- 21273732 TI - Regional distribution of drug-metabolizing enzyme activities in the liver and small intestine of cynomolgus monkeys. AB - The cynomolgus monkey is an animal species widely used to study drug metabolism because of its evolutionary closeness to humans. However, drug-metabolizing enzyme activities have not been compared in various parts of the liver and small intestine in cynomolgus monkeys. In this study, therefore, drug-metabolizing enzyme activities were analyzed in the liver (the five lobes) and small intestine (six sections from the duodenum to the distal ileum). 7-Ethoxyresorufin O deethylation, coumarin 7-hydroxylation, paclitaxel 6alpha-hydroxylation, diclofenac 4'-hydroxylation, tolbutamide methylhydroxylation, S-mephenytoin 4' hydroxylation, bufuralol 1'-hydroxylation, chlorzoxazone 6-hydroxylation, midazolam 1'-hydroxylation, and testosterone 6beta-, 16alpha-, 16beta-, and 2alpha-hydroxylation were used as the probe reactions for this investigation. In liver, all probe reactions were detected and enzyme activity levels were similar in all lobes, whereas, in the small intestine, all enzyme activities were detected (except for coumarin 7-hydroxylase and testosterone 16alpha-hydroxylase activity), but from jejunum to ileum there was a decrease in the level of enzyme activity. This includes midazolam 1'-hydroxylation and testosterone 6beta hydroxylation, which are catalyzed by cynomolgus monkey cytochrome P450 (CYP) 3A4/5, orthologs of human CYP3A4/5, which are important drug-metabolizing enzymes. The data presented in this study are expected to facilitate the use of cynomolgus monkeys in drug metabolism studies. PMID- 21273733 TI - Pharmacokinetics of tolterodine in Japanese and Koreans: physiological and stochastic assessment of ethnic differences. AB - Tolterodine is known as a drug which exhibits ethnic differences in pharmacokinetics between Japanese and Koreans despite genetic similarities among the populations of East Asian countries. Tolterodine is mainly metabolized by CYP2D6 to a 5-hydroxymethyl metabolite (5-HM), and 5-HM is also metabolized by CYP2D6. The reduced-function allele CYP2D6*10 is frequently observed in Asian populations. We investigated differences in the pharmacokinetics of tolterodine between small Japanese and Korean study populations by physiological and stochastic approaches with consideration of the CYP2D6 genotype. The genotype frequencies of CYP2D6*10/*10 and CYP2D6*5/*10 were found to be higher in Koreans than in Japanese, which suggested that this frequency difference occurred incidentally. The effects of CYP2D6 genotype and ethnicity on the intrinsic clearance of tolterodine by CYP2D6 were tested and only genotype was found to be a significant factor by ANCOVA. A simulation was conducted to confirm whether the observed differences in tolterodine exposure could be explained by the differences in genotype frequency found in this study. It was confirmed that the variability of intrinsic clearance could be responsible for the incidental exposure differences. In conclusion, apparent differences in exposure were found between small Japanese and Korean study populations because of the variability of intrinsic clearances and genotype frequencies. PMID- 21273734 TI - Effect of the VKORC1 genotype on warfarin dose requirements in Japanese pediatric patients. AB - The primary aim of the present study was to evaluate the effect of the genotype of vitamin K epoxide reductase complex 1 (VKORC1) on warfarin dose requirements in Japanese pediatric patients. Forty-eight pediatric patients (0.42-19.25 years old) in whom stable anticoagulation was achieved by warfarin were enrolled in this study, and the polymorphic alleles of VKORC1 and CYP2C9 were determined for each subject. The relative impact of covariates on the anticoagulant effect of warfarin was evaluated by multiple regression analysis. It was found that VKORC1 genotype and age were major factors affecting the relationship between the weight normalized warfarin dose and the therapeutic prothrombin time-international normalized ratio (PT-INR). Because only one patient had the CYP2C9*3 allele, we could not evaluate the effect of CYP2C9 polymorphisms on the anticoagulant effect of warfarin. In contrast, the anticoagulant effect of warfarin in patients with the VKORC1 1173CT or 1173CC genotype was 52.3% of that in patients with the 1173TT genotype. In addition, the anticoagulant effect of warfarin was shown to increase by 10.5% per year in Japanese pediatric patients. In conclusion, genotyping of VKORC1 will be useful in establishing individual anticoagulant therapy with warfarin, and it should be noted that a higher weight-normalized dose of warfarin is required in younger pediatric patients. PMID- 21273735 TI - Clinical backgrounds and morbidity of cognitive impairment in elderly diabetic patients. AB - Despite numerous reports that have linked diabetes with cognitive impairment (CI), there are few studies that have attempted to clarify the morbidity of CI among elderly diabetic patients. The Mini-Mental State Examination (MMSE) was performed on 240 diabetic patients aged 65 years or older who had no diagnosis of dementia. The MMSE scores were 28-30 (normal range) in 151 patients (63%), 24-27 (suspected CI) in 77 (32%), and <= 23 (definite CI) in 12 (5%). Eight of the 12 patients with MMSE scores <= 23 underwent further detailed examination: the final diagnosis was Alzheimer's disease (AD) (N = 5), vascular dementia (N = 2), and mixed dementia (N = 1). Among 24 of the 77 patients with MMSE scores of 24-27 who were referred for further detailed examination, the final diagnosis was early AD (N = 5), cerebrovascular disease (CVD) (N = 10), and mild CI (N = 7). Only 2 of the patients were judged as being normal. The percentage of patients with a history of CVD, the rate of diuretic use, and the serum levels of non-high density lipoprotein cholesterol were higher, and the percentage of patients with a history of habitual alcohol consumption was lower in the low MMSE score group than in the normal MMSE score group. Among elderly diabetic patients aged 65 years or older, 5% had evident CI and 32% had suspected CI. Medical staff involved in the care of diabetic patients should be highly aware of possible CI in this patient population. PMID- 21273736 TI - Work form affects maximum oxygen uptake for one year in workers. AB - Our previous study suggested that the work form is related to the maximum oxygen uptake (VO(2)max). Therefore, we test the hypothesis by a longitudinal study that, besides these lifestyle-related factors, the work form increases VO(2)max among workers. Seven hundred and ninety nine males aged 37.1 +/- 10.6 and 395 females aged 37.7 +/- 10.5 (range: 20 to 59 yr old), who participated in The Total Health Promotion Plan (THP) at their respective workplaces twice in one year from 1997 to 1998, were selected. Data on VO(2)max were analyzed for age, systolic blood pressure (SBP), body mass index (BMI), work form (sedentary, standing, and ambulatory), exercise, and smoking. Age and the baseline variables for BMI and for VO(2)max showed significant negative relationships with a change in VO(2)max in males and females. Further, a change in the BMI showed a significant negative relationship with a change of VO(2)max in males. However, exercise habit and an ambulatory work form showed significant positive relationships with a change of VO(2)max in males. It was suggested that after adjusting for other factors in males, an ambulatory work form may be associated with an increase in VO(2)max in one year. PMID- 21273737 TI - Effects of edaravone on a rat model of punch-drunk syndrome. AB - Punch-drunk syndrome (PDS) refers to a pathological condition in which higher brain dysfunction occurs in a delayed fashion in boxers who have suffered repeated blows to the head. However, the underlying mechanisms remain unknown. This study attempted to elucidate the mechanism of higher brain dysfunction observed following skull vibration in two experiments involving a rat model of PDS. Experiment 1 evaluated the effects of edaravone on histological changes in the rat brain tissue after skull vibration (frequency 20 Hz, amplitude 4 mm, duration 60 minutes). The amount of free radicals formed in response to skull vibration was very small, and edaravone administration reduced the number of glial fibrillary acidic protein and advanced glycation end product-positive cells. Experiment 2 examined the time course of change in learning ability following skull vibration in Tokai High Avoider rats. The learning ability of individual rats was evaluated by the Sidman-type electric shock avoidance test 5 days after the last session of skull vibration or final anesthesia and once a month for 9 consecutive months. Delayed learning disability was not observed in rats administered edaravone immediately after skull vibration. These results suggest that free radical-induced astrocyte activation and subsequent glial scar formation contribute to the occurrence of delayed learning disabilities. Edaravone administration after skull vibration suppressed glial scar formation, thereby inhibiting the occurrence of delayed learning disabilities. PMID- 21273738 TI - Efficacy of motor cortex stimulation for intractable central neuropathic pain: comparison of stimulation parameters between post-stroke pain and other central pain. AB - Motor cortex stimulation (MCS) has now become the preferred option for neurosurgical management of intractable central neuropathic pain such as post stroke pain and trigeminal neuropathic pain. However, the efficacy of MCS for other central neuropathic pain such as pain resulting from spinal cord or brainstem lesions is unclear. We retrospectively reviewed 11 consecutive patients with intractable central neuropathic pain who underwent MCS in our institution. Eight patients had poststroke pain caused by thalamic hemorrhage (n = 5) or infarction (n = 3) (thalamic group). Two patients had postoperative neuropathic pain caused by spinal cord lesions, and one patient had facial pain caused by a brainstem lesion associated with multiple sclerosis (brainstem-spinal group). Visual analog scale and stimulation parameters were evaluated at 1 and 6 months postoperatively. MCS was effective for six of eight patients in the thalamic group, and all three patients in the brainstem-spinal group. These efficacies continued for 6 months after surgery without significant change in the stimulation parameters compared with the parameters at 1 month in both groups. The mean amplitude at 1 month and frequency at 6 months after surgery were significantly higher in the brainstem-spinal group than the thalamic group, although the patient number was small. MCS is effective for other central neuropathic pain, but higher intensity stimulation parameters may be necessary to gain adequate pain reduction. PMID- 21273739 TI - Evaluation of combined use of transcranial and direct cortical motor evoked potential monitoring during unruptured aneurysm surgery. AB - The feasibility and reliability of combined use of transcranial and direct cortical motor evoked potential (MEP) monitoring during unruptured aneurysm surgery were evaluated. Forty-eight patients with unruptured cerebral aneurysms underwent craniotomy and neck clipping accompanied by muscle MEP monitoring. MEPs were elicited successfully by transcranial electrical stimulation in all patients. Direct cortical stimulation elicited MEPs in 44 patients. Reduction in MEP amplitude to less than 50% of baseline was considered significant. No postoperative motor paresis occurred in 39 patients in whom transcranial and direct MEPs remained unchanged. Four patients in whom direct MEPs could not be recorded had no intraoperative abnormality in transcranial MEPs and no postoperative motor dysfunction. Four of the other 5 patients manifested significant transient direct MEP changes without transcranial MEP changes. The transient MEP changes were observed in 3 patients during temporary clipping of the parent artery and in one patient with inadequate clipping of an middle cerebral artery aneurysm, and were considered due to insufficiency of blood flow. Decrease or disappearance of direct MEP waves recovered immediately after re application of the clip and release of the temporary clip. Direct MEP waves disappeared and did not recover until the end of microsurgical procedures in one patient, although transcranial MEP amplitude remained at less than 50% of baseline. She developed hemiparesis postoperatively, which recovered within 6 hours. The duration of temporary occlusion in patients with direct MEP changes was significantly longer than that in patients without (p < 0.05). Direct MEP was sensitive in detecting ischemic stress to descending motor pathways during aneurysm surgery. Transcranial MEPs could be elicited in patients in whom direct MEPs could not be obtained, and during periods such as craniotomy or after dural closure, in which direct MEPs could not be recorded. These findings suggest that combined transcranial and direct cortical MEP recording may improve the feasibility and reliability of MEP monitoring during unruptured aneurysm surgery. PMID- 21273740 TI - Treatment selection for ruptured aneurysm and outcomes: clipping or coil embolization. AB - The International Subarachnoid Aneurysm Trial has shown that coil embolization achieves a better outcome for aneurysms treatable by either clipping or coil embolization. However, many ruptured aneurysms are hardly treatable by either clipping or coil embolization. Selection of either clipping or coil embolization will affect the treatment outcome for ruptured aneurysms. The relationship between patient selection and treatment outcome in a so-called "regional center hospital" in Japan must be clarified. This study included 113 patients with ruptured intracranial saccular aneurysms measuring less than 10 mm. Selection criteria for coil embolization were principally paraclinoid or posterior circulation aneurysm, Hunt and Hess grade IV or over, and patient age 75 years or older. Other aneurysms were principally treated by clipping. Aneurysms with a dome/neck ratio of less than 1.5, distorted aneurysms, Hunt and Hess grades I III, patient age 74 years or younger, and middle cerebral artery aneurysm were actively treated by clipping. A few exceptional indications were considered in detail. Low invasiveness coil embolization is better than clipping to obtain good neurological outcome for patients with perforators difficult to dissect, aneurysms difficult to dissect due to previous open surgery, and aneurysms requiring bilateral open surgery, despite the slightly higher rebleeding rate in coil embolization. Overall outcomes were modified Rankin Scale (mRS) 0-2 in 82 of 113 patients (73%) and mRS 3-6 in 31 (27%). Appropriate selection of clipping or coil embolization can achieve acceptable treatment outcomes for ruptured aneurysm. PMID- 21273741 TI - Cortical subarachnoid hemorrhage caused by cerebral venous thrombosis. AB - Patients with non-traumatic, non-aneurysmal, and non-perimesencephalic subarachnoid hemorrhage (SAH) tend to have clots circumscribed along the cortical convexity, a condition referred to as acute cortical SAH. Cerebral venous thrombosis (CVT) is a potential cause of cortical SAH. The study tried to establish the diagnosis and management of cortical SAH caused by CVT. Retrospective review of 145 patients with non-traumatic SAH identified 15 patients with no ruptured aneurysm. Clinical features were investigated with a specific focus on patients with SAH caused by CVT. Eight of the 15 patients had perimesencephalic SAH, and 7 had cortical SAH. SAH caused by CVT was diagnosed in 4 of the 7 patients with cortical SAH. The cortical SAH involved the unilateral convexity or sylvian cistern and spared the basal cistern on computed tomography in all 4 patients. CVT occurred in the transverse sinus and cortical vein (1 patient), insular vein (1 patient), and cortical vein (2 patients). Identification of thrombosed veins or sinuses was established directly by T(2)* weighted and diffusion-weighted magnetic resonance (MR) imaging in the acute stage and diffusion-weighted and T(1)-weighted MR imaging in the subacute stage. All patients had cortical swelling without findings of venous hemorrhagic infarction on T(2)*-weighted MR imaging. None of the 4 patients received active treatment, and all had favorable outcomes. CVT in patients with non-traumatic cortical SAH should be first excluded as a potential hemorrhagic cause by MR imaging for thrombosed veins or sinuses before initiating antifibrinolytic therapy. PMID- 21273742 TI - Traumatic carotid-cavernous fistula associated with persistent primitive trigeminal artery treated by transarterial coil embolization--case report. AB - A 30-year-old woman presented with traumatic carotid-cavernous fistula associated with persistent primitive trigeminal artery (PPTA) manifesting as right conjunctival chemosis, exophthalmos, and diplopia. The lesion was treated successfully by trans-arterial coil embolization using the double catheter method with balloon assist. Injury to the PPTA is relatively rare and the PPTA should be sacrificed together with the fistula during the repair. PMID- 21273743 TI - Ruptured anterior communicating artery aneurysm associated with anterior cranial fossa dural arteriovenous fistula--case report. AB - A 77-year-old man presented with an extremely rare association of anterior cranial fossa dural arteriovenous fistula (AVF) with anterior communicating artery (ACoA) aneurysm manifesting as consciousness deterioration due to intracerebral hemorrhage in the left frontal lobe and diffuse subarachnoid hemorrhage. Angiography confirmed the association of a dural AVF fed by both ethmoidal arteries and an ACoA aneurysm. Surgery for these two lesions was performed concurrently, and the ACoA aneurysm was found to be responsible for the hemorrhage. This association seems incidental, but is clinically significant since the preoperative determination of the bleeding point is difficult. We conclude that these two lesions should be treated simultaneously, to avoid leaving the ruptured point untreated. PMID- 21273744 TI - Arteriovenous fistula involving the inferior petroclival vein--case report. AB - A 68-year-old man presented with an extremely rare extracranial arteriovenous fistula (AVF) involving the inferior petroclival vein (IPCV) with retrograde venous drainage into an ophthalmic vein through the anterior condylar confluence and inferior petrosal sinus manifesting as ocular symptoms. The AVF was successfully treated by selective transvenous embolization with platinum coils. AVF involving the IPCV should be recognized as a possible extracranial lesion manifesting as clinical symptoms similar to cavernous sinus dural AVF. PMID- 21273745 TI - Pituitary apoplexy causing internal carotid artery occlusion--case report. AB - A 50-year-old man presented with pituitary apoplexy resulting in internal carotid artery occlusion manifesting as sudden onset of severe headache, right ptosis, and left hemiparesis, associated with visual impairment. Computed tomography showed a nodular mass, located in the sellar and suprasellar regions with early signs of acute cerebral ischemia. Magnetic resonance (MR) imaging indicated that the mass compressed the bilateral cavernous sinuses, resulting in obliteration of the cavernous portion of the right internal carotid artery. Right middle cerebral artery territory infarction was also found. Conservative therapy with steroids was given in the acute stage and repeated MR imaging showed recanalization of the internal carotid artery with reduction of the tumor size. The tumor was removed through the transsphenoidal approach to obtain a definitive diagnosis in the chronic stage. The histological diagnosis was consistent with non-functioning pituitary adenoma. Eye movement of this patient showed full recovery after the operation. Pituitary apoplexy resulting in internal carotid artery occlusion is rare. Surgical decompression through the transsphenoidal approach is appropriate, but the optimal timing should consider severe disturbance of visual acuity and visual field in the acute stage. PMID- 21273746 TI - Chronic encapsulated intracerebral hematoma associated with cavernous angioma- case report. AB - An 80-year-old male presented with a chronic encapsulated intracerebral hematoma (CEIH) with surrounding edema under the right frontal lobe manifesting as slow exacerbation of disturbance of orientation and gait. He had a history of cerebral infarction with an asymptomatic cavernous angioma in the right frontal lobe. The CEIH was diagnosed as bleeding from the cavernous angioma, and surgical removal was performed. The hematoma was chronic and covered by a thick capsule. In addition, mass tissue covered with the organized hematoma was found near the capsule, which was excised and found to be a cavernous angioma. CEIH is a special type of intracerebral hemorrhage, and bleeding from a cavernous angioma is occasionally seen. CEIH should be considered in the case of a hemorrhagic intracranial lesion with a chronic, progressive course with capsule formation and edema around the lesion. The source of bleeding is unknown in about half of the reported cases, and occult vascular malformation may be involved, necessitating care in diagnosis. PMID- 21273747 TI - Primary angiitis of the central nervous system mimicking tumor-like lesion--case report. AB - A 60-year-old man presented with a rare case of primary angiitis of the central nervous system mimicking a tumor-like lesion and manifesting as slight disorientation, left hemiparesis, and motor aphasia. Computed tomography showed multiple low density lesions in the left frontal lobe, brain stem, and right parietal lobe. Magnetic resonance images revealed a slightly enhanced mass lesion in the right parietal lobe with surrounding brain edema. Serum, cerebrospinal fluid, and other image examinations did not show any abnormal findings, so surgical removal of the right parietal mass was performed. Histological examination revealed that the mass consisted of hemorrhagic infarction without cellular atypia. Proliferations of endothelial cells in small and medium arteries, and infiltration of macrophages in the perivascular space were detected in the infarction tissues. The histological diagnosis was primary angiitis of the central nervous system. PMID- 21273748 TI - Severe parkinsonism following endoscopic third ventriculostomy for non communicating hydrocephalus--case report. AB - A 23-year-old male with non-communicating hydrocephalus caused by intraventricular hemorrhage from an arteriovenous malformation was treated by endoscopic third ventriculostomy (ETV) after repeated ventricular cerebrospinal fluid drainage and removal of ventriculoperitoneal shunt due to infection. Postoperatively, the patient developed robust rigidity and akinesia with mutism, suggesting secondary parkinsonism. These symptoms showed marked improvement after administration of levodopa, and were not aggravated after discontinuation. The pathophysiology of this case might involve dysfunction of the dopaminergic system caused by repeated compression and release of the paraventricular white matter. Careful perioperative management not leading to excessive dilation of the the ventricles should be considered for ETV for non-communicating hydrocephalus to avoid this unexpected complication. PMID- 21273749 TI - Atypical osteomyelitis of the skull base and craniovertebral junction caused by Actinomyces infection--case report. AB - A 44-year-old man presented with a very rare case of skull base osteomyelitis manifesting as persistent diplopia. He initially had the symptom with fever after dental extraction. Biopsy from the cervix and upper pharynx performed in a previous hospital had showed negative findings by histological and bacterial examinations. Magnetic resonance (MR) imaging disclosed enhanced lesions in the right cavernous sinus, clivus, and right cervical regions. Computed tomography revealed osteolysis, and fluorodeoxyglucose positron emission tomography (FDG PET) showed areas of increased uptake. Bacteriological examination of the isolated clival lesion disclosed Actinomyces israelii, and he was treated with intravenous penicillin, 18 million units a day for 6 weeks. MR imaging revealed reduction of intensity in the enhanced areas, and FDG-PET showed disappearance of the increased uptake. After 6 months of oral antibiotics administration, MR imaging disclosed disappearance of the enhanced lesions, and the patient had no sign of neurological deficits. Skull base osteomyelitis resembles neoplasm or inflammatory disease of this region in neurological and radiographic findings. The biopsy specimen should be ideally obtained from an isolated region, and prepared to identify a wide range of organisms and to differentiate other diseases. The serum level of C-reactive protein and FDG-PET are useful to follow up the efficacy of antibiotic therapy. PMID- 21273750 TI - Thoracic disk herniation manifesting as sciatica-like pain--two case reports. AB - Two patients presented with sciatica-like pain caused by thoracic disk herniation. Sciatica-like pain was the initial and major symptom in both patients, but careful neurological examination showed vague signs of upper motor neuron disturbance, and thoracic magnetic resonance (MR) imaging revealed disk herniations at the mid-thoracic level. After video-assisted thoracoscopic discectomy, the pain was completely improved. Thorough neurological examination and MR imagery of the thoracic spine, and if needed, even the cervical spine, are required if lumbar image findings do not correlate with the symptoms or physical examination. PMID- 21273751 TI - Cerebral infarction along the distribution of perforating arteries during aneurysm surgery in a patient with pheochromocytoma--case report. AB - A 58-year-old woman with refractory hypertension presented with subarachnoid hemorrhage. Digital subtraction angiography and three-dimensional computed tomography (CT) angiography revealed a ruptured left vertebral artery (VA) aneurysm and an unruptured left middle cerebral artery (MCA) aneurysm. The patient successfully underwent neck clipping of the left VA aneurysm. However, CT obtained just after the operation showed an asymptomatic cerebral infarction along the distribution of medial striate arteries of the right anterior cerebral artery in the caudate nucleus. The pathogenesis of the infarction was unknown. Before clipping surgery of the left MCA aneurysm, detailed examinations to find the cause of her refractory hypertension were performed. Laboratory tests revealed plasma serum level of norepinephrine at 15,521 pg/ml (normal range 100 450 pg/ml). Abdominal magnetic resonance imaging revealed a pheochromocytoma in the right adrenal gland. After preoperative management of the pheochromocytoma, the neck of the left MCA aneurysm was successfully clipped. When the patient awakened from anesthesia, she noticed right hemiparesis and motor aphasia. CT showed cerebral infarction along the distribution of lenticulostriate arteries of the left MCA in the putamen. Her symptoms gradually improved, and the pheochromocytoma was removed by laparoscopic surgery. Sustained severe hypertension and depletion of blood volume resulting from excess catecholamine release from the pheochromocytoma may have caused the complications. Hypervolemic fluid infusion and maintenance of normotensive blood pressure during surgery may avoid such ischemic events. PMID- 21273752 TI - Third ventricular meningioma--case report. AB - A 63-year-old man presented with headache. Magnetic resonance imaging showed a mass lesion homogeneously enhanced with gadolinium, which occluded the route from the third ventricle to the aqueduct. The patient underwent surgery for removal of the tumor via the right frontal transcortical-transventricular approach to the third ventricle via the transchoroidal route. Intraoperative diagnosis was meningioma. Total removal of the tumor was achieved in piecemeal fashion (Simpson grade 1). The histological diagnosis was meningothelial meningioma. The patient was discharged without neurological deficits. Third ventricle is a rare and difficult site to remove tumor totally. However, total removal was needed in this case of benign meningioma, so the operative strategy and the differential diagnosis before operation is considered to be very important. PMID- 21273753 TI - Inflammatory myofibroblastic tumor of the cerebellar hemisphere--case report. AB - A 60-year-old man presented with a rare cerebellar inflammatory myofibroblastic tumor (IMT) manifesting as gait disturbance and dysarthria. Brain magnetic resonance imaging demonstrated an intra-axial round-shaped isointense mass homogeneously enhanced with gadolinium in the right cerebellar hemisphere, as well as perifocal edema extending to the brain stem and right thalamus. The tumor was elastic hard and was resected en bloc with a clear margin. Histological examination revealed IMT with spindle cells and collagen, but negative for anaplastic lymphoma kinase expression. IMT most commonly affects the lung, but may involve many other parts of the body. There is some debate regarding the disease entity of IMT in the central nervous system (IMT-CNS) because of its rarity and high frequency of recurrence. IMT-CNS is an important differential diagnosis among tumor-like intracranial lesions and total resection is required. PMID- 21273754 TI - Subarachnoid hemorrhage caused by pilocytic astrocytoma--case report. AB - A 20-year-old woman presented with subarachnoid hemorrhage (SAH) in the frontal interhemispheric fissure, and a cystic lesion in the left frontal lobe. Cerebral angiography demonstrated no aneurysm or vascular abnormalities. T(1)-weighted magnetic resonance imaging with contrast medium revealed an enhanced lesion along the falx. The lesion and cyst were removed, and histological examination revealed a pilocytic astrocytoma. Spontaneous intracranial hemorrhage from pilocytic astrocytoma is rare, with only 15 reported cases mostly involving intratumoral hemorrhage in the parenchyma of hypothalamic and cerebellar tumors. SAH caused by cerebral hemisphere pilocytic astrocytoma is extremely rare. This case suggests that interhemispheric fissure SAH, not associated with aneurysm or abnormal vascularity, could originate from small, low-grade glioma in the superficial cerebral hemisphere. PMID- 21273755 TI - Posterior fossa epidermoid cysts presenting with unusual radiological appearances -two case reports. AB - Intracranial epidermoid cysts generally appear as hypodense on computed tomography (CT), hypointense on T(1)-weighted magnetic resonance (MR) imaging, and hyperintense on diffusion-weighted MR imaging. We report two cases of posterior fossa epidermoid cysts with unusual radiological features. A 49-year old male presented with facial dysesthesia and a 12-year-old male presented with diplopia and internuclear ophthalmoplegia. CT of both cases revealed hyperdense lesions. MR imaging showed the first case as hypointense in the posterior part and hyperintense in the anterior part of the tumor on diffusion-weighted imaging, and the second case as hyperintense on diffusion-weighted and T(1)-weighted MR imaging. Surgical exploration revealed that the tumors consisted of creamy materials, instead of the usual semi-solid or flaky texture in epidermoid cysts. Xanthochromic serous fluid was also contained in the superoposterior half of the cyst of the first case. These unusual contents of the cyst may be responsible for the unusual neuroimaging findings. Histological examination showed both cysts were lined with stratified squamous epithelium and contained keratinaceous materials. Therefore, epidermoid cysts can occasionally present with unusual radiological characteristics giving rise to a diagnostic pitfall. PMID- 21273756 TI - Electrocautery skin incision for neurosurgery procedures--technical note. AB - The reluctance to incise skin with electrocautery is partly attributable to concerns about excessive scarring and poor wound healing. However, recently no difference was reported in wound complications between the cold scalpel and electrocautery scalpel. We assessed the safety and efficacy of electrocautery skin incision in 22 scalp incisions, including 4 cases of reoperation. Electrocautery skin incisions were created using a sharp needle electrode. The generator unit was set on cutting mode, with power of 6 W and 330 kHz sinusoid waveform. Subcutaneous dissections also used the sharp needle electrode, set on coagulating mode, with power of 10 W and 1 MHz pulse-modulated waveform. Galea incisions used a standard blade tip, set on coagulating mode, with power of 20 W and 1 MHz pulse-modulated waveform. Skin incision with the sharp needle electrode caused no charring of the wound. Little bleeding or oozing were observed and skin clips were not necessary. No wound complication such as necrosis or infection occurred. Electrocautery skin incisions for re-operations were also performed safely without complications. Electrocautery skin incision is sufficiently safe procedure not only for first operation but also for re-operation. Electrocautery skin incision is efficacious, especially for extended operation times, because of little blood loss from the edges of skin incision and possible avoidance of skin edge necrosis or alopecia caused by skin clips. PMID- 21273757 TI - Does finasteride have a preventive effect on chronic bacterial prostatitis? Pilot study using an animal model. AB - AIM: To evaluate the preventive effect of finasteride on chronic bacterial prostatitis (CBP), Wistar rats were divided into four groups: control, ciprofloxacin, finasteride, and ciprofloxacin/finasteride. METHODS: All drug pretreatments were conducted for 4 weeks, and then experimental CBP was induced by instillation of a bacterial suspension (Escherichia coli Z17 O2:K1;H-). RESULTS: After 4 weeks, results of microbiological cultures of prostate and urine samples as well as histological findings of the prostate in each group were analyzed. Finasteride significantly reduced bacterial infection and decreased inflammatory cell infiltration in prostatic tissue compared with the control group. The group given both finasteride and antibiotic showed a greater inhibition of bacterial infection in the tissue than those given either finasteride or antibiotic alone. CONCLUSION: Our experiments suggest the possibility that finasteride has a preventive effect on development of CBP, although there is as yet no consensus on the mechanism of this effect. PMID- 21273758 TI - Safety of a new compact male intermittent catheter: randomized, cross-over, single-blind study in healthy male volunteers. AB - INTRODUCTION: A new compact male intermittent catheter was compared with a regular intermittent male catheter in terms of safety and acceptability. METHODS: In this randomized, single-blind, cross-over study, healthy male volunteers were catheterized twice with a compact catheter and twice with a regular catheter. RESULTS: 28 participants were enrolled. Mean +/- SD discomfort (visual analogue scale; primary objective) was 2.25 +/- 1.5 and 2.52 +/- 1.8 for the compact and regular catheters, respectively (difference -0.27; 95% confidence interval -0.73 to 0.19); there was no significant difference in hematuria (p = 0.54) or discomfort/stinging/pain at first micturition (p = 0.56). During insertion, handling was easier (p = 0.0001) and touching the coating was necessary less often (2.2 vs. 81.3% of catheterizations; p < 0.0001) with the compact catheter; it was preferred by nurses for 20 of 23 participants. No adverse events were reported. CONCLUSIONS: Short-term safety of the new compact catheter was at least as good as that of the regular male intermittent catheter and handling was improved. PMID- 21273759 TI - Phosphatidylinositol 3-kinase inhibitor LY294002 suppresses proliferation and sensitizes doxorubicin chemotherapy in bladder cancer cells. AB - BACKGROUND: Phosphatidylinositol 3-kinase (PI3K)-AKT signaling is a well characterized pathway involved in control of cell proliferation, apoptosis and oncogenesis. LY294002 is a commonly used pharmacologic inhibitor which acts at the ATP-binding site of the PI3K enzyme, and thus selectively inhibits the PI3K AKT nexus. The purpose of the study was to examine whether PI3K inhibited by LY294002 had effects in human bladder cancer cells. METHODS: After treatment with LY294002, MTT assay, a chemosensitivity test, colony formation assay, apoptosis assay and Western blot analysis were conducted in EJ cells. RESULT: EJ cells treated with LY294002 showed significant AKT phosphorylation suppressing in a dose-response manner. Additionally, the PI3K/AKT signaling inhibitor LY294002 suppressed cell proliferation and enhanced chemosensitivity to doxorubicin in human bladder cancer EJ cells. Furthermore, LY294002 increased cell apoptosis to doxorubicin. CONCLUSION: The augmentation of doxorubicin with the PI3K inhibitor LY294002 may resolve the multidrug resistance of bladder cancer, and this may be a new strategy for achieving tolerance for chemotherapeutic agents in bladder cancer therapy. PMID- 21273760 TI - Influence of age on the relationship between alcohol consumption and metabolic syndrome. AB - BACKGROUND: Relationships between alcohol consumption and risks for metabolic syndrome in general populations are very controversial. It is unknown whether age influences the relationship between alcohol intake and the prevalence of metabolic syndrome. OBJECTIVE: The purpose of this study was to determine whether age influences the relationship between alcohol consumption and metabolic syndrome. METHODS: Men aged >=35 and <45 years (younger group) and those aged >=65 years (older group), matched for alcohol intake and smoking history, were divided into four subgroups by alcohol intake [non-, light (<22 g ethanol/day), heavy (>=22 and <44 g ethanol/day) and very heavy (>=44 g ethanol/day) drinkers]. Odds ratios (ORs) versus nondrinkers for each risk factor and metabolic syndrome were compared between the younger and older groups. RESULTS: Both in the younger and older groups, ORs for high blood pressure and low HDL cholesterol were significantly high and low, respectively, in all drinker groups. In younger subjects, the OR for large waist circumference was significantly low in light drinkers, and the OR for high hemoglobin A(1c) was significantly low in light and heavy drinkers, while these associations were not found in older subjects. The OR for metabolic syndrome was significantly low in light and heavy drinkers in the younger subjects but was not significant in any drinker groups in older subjects. CONCLUSION: Age influences the relationships between alcohol consumption and atherosclerotic risk factors, and there is a significant association between alcohol intake and a lower risk for metabolic syndrome in young men but not in elderly men. PMID- 21273761 TI - The GH/IGF-I axis and pituitary function and size in adults with Prader-Willi syndrome. AB - BACKGROUND: In adults with Prader-Willi syndrome (PWS), limited information is available about pituitary function, more specifically the prevalence of growth hormone deficiency (GHD). The aim of this study was to gain more insight into endocrine function in PWS adults, with emphasis on GH secretion. METHODS: 15 randomly selected adult PWS individuals were included and 14 healthy brothers and sisters served as a control group. Main outcome measures were IGF-I, IGFBP-3 and peak GH level after a combined GHRH-arginine test. Other pituitary hormone deficits are diagnosed based on serum levels of the concerning hormones. The size of the pituitary gland was measured on MRI images. RESULTS: In PWS adults, IGF-I levels were low and IGFBP-3 levels normal when compared to healthy controls. GHD was diagnosed in 8-38% of the PWS patients, depending on the criteria used. Hypogonadism was present in 87% of the patients. Hypothyroidism and adrenal insufficiency could also be demonstrated. Anterior pituitary size was lower in PWS individuals when compared to healthy controls. CONCLUSION: In this study, pituitary hormone deficiencies are demonstrated in a considerable number of adults with PWS, hypogonadism and GHD being most prominent. Furthermore, the anterior pituitary is smaller in comparison with healthy controls. PMID- 21273762 TI - Composition and epigenetic markers of heterochromatin in the aphid Aphis nerii (Hemiptera: Aphididae). AB - A detailed karyotype analysis of the oleander aphid Aphis nerii focusing on the distribution, molecular composition and epigenetic modifications of heterochromatin was done in order to better understand the structure and evolution of holocentric/holokinetic chromosomes in aphids. The female karyotype (2n = 8) consisted of 3 pairs of autosomes and a pair of X chromosomes that were the longest elements in the karyotype and carried a single, terminally located nucleolar organizer region. Males showed 2n = 7 chromosomes due to the presence of a single X chromosome. Heterochromatin was located in the X chromosomes only and consisted of 4 satellite DNAs that have been identified. A. nerii constitutive heterochromatin was enriched in mono-, di- and tri-methylated H3 histones and HP1 proteins but, interestingly, it lacked DNA methylation that was widespread in euchromatic chromosomal regions. These results suggest that aphid heterochromatin is assembled and condensed without any involvement of DNA methylation. PMID- 21273763 TI - A survey conducted on patients' and urologists' perceptions of benign prostatic hyperplasia. AB - OBJECTIVES: To better understand the discrepancy that may exist between urologists and patients on various aspects of their perception of benign prostatic hyperplasia (BPH). SUBJECTS AND METHODS: Questionnaires on BPH for patients and urologists and a BPH patient education brochure were developed. 141 patients with symptoms of BPH completed a set of two questionnaires, to be filled out before and after reading the education brochure. 172 urologists practicing in Korea were randomly selected to complete the questionnaire. RESULTS: Nearly 60% of patients misunderstood the risk for BPH to progress to prostate cancer. In addition, the perceived risks of untreated BPH, desirable treatment effects and undesirable side effects were significantly different between the patients and the urologists. Among the discrete attributes of available medical therapy, the 5alpha-reductase inhibitor monotherapy was the preferred method chosen by patients. Although the patient brochure significantly improved most of the patients' misconceptions about BPH, the patient preference did not change significantly. CONCLUSIONS: Patients with BPH do not have accurate information about their disease and their expectations of treatment may be very different from their urologist. PMID- 21273764 TI - The role of shugoshin in meiotic chromosome segregation. AB - During meiosis, DNA replication is followed by 2 successive chromosome segregation events, resulting in the production of gametes with a haploid number of chromosomes from a diploid precursor cell. Faithful chromosome segregation in meiosis requires that sister chromatid cohesion is lost from chromosome arms during meiosis I, but retained at centromeric regions until meiosis II. Recent studies have begun to uncover the mechanisms underlying this stepwise loss of cohesion in meiosis and the role of a conserved protein, shugoshin, in regulating this process. PMID- 21273765 TI - Chromosome abnormalities in the human oocyte. AB - Aneuploidy is the most commonly occurring type of chromosome abnormality and the most significant clinically. It arises mostly due to segregation errors taking place during female meiosis and is also closely associated with advancing maternal age. Two main aneuploidy-causing mechanisms have been described: the first involves the non-disjunction of entire chromosomes and can take place during both meiotic divisions, whereas the second involves the premature division of a chromosome into its 2 sister chromatids, followed by their random segregation, upon completion of meiosis I. To elucidate the causal mechanisms of maternally derived aneuploidy and the manner with which they affect the 2 meiotic divisions, a large number of oocytes and their corresponding polar bodies have been examined. Various classical and molecular cytogenetic methods have been employed for this purpose, and valuable data have been obtained. Moreover, research into the gene expression patterns of oocytes according to maturity, maternal age, and chromosome status has provided a unique insight into the complex nature of the biological processes and genetic pathways regulating female meiosis. Findings obtained from the cytogenetic and molecular analysis of oocytes will be reviewed in this article. PMID- 21273766 TI - A case of well-tolerated and safe deferasirox administration during the first trimester of a spontaneous pregnancy in an advanced maternal age thalassemic patient. AB - In this report, we present a case of a spontaneous pregnancy in a 42-year-old thalassemic woman referred to our Microcythemic Unit while she was on deferasirox (DFX) therapy. The patient had been on treatment with DFX since March 2008 and in March 2009 realized that she was pregnant at 12 weeks of gestation. The conception was spontaneous and the baby was born at full term without complications or malformations. PMID- 21273767 TI - Recovery of systolic dysfunction in duchenne muscular dystrophy due to the point mutation c.4213C>T. AB - OBJECTIVES: So far, a beneficial effect of combined angiotensin-converting enzyme inhibitors (ACEI) and beta-blocker therapy for systolic dysfunction in Duchenne muscular dystrophy (DMD) has been reported only in patients in whom DMD was due to deletions in the dystrophin gene. CASE REPORT: In a 24-year-old male with DMD due to the point mutation c.4213C>T (p.Gln1405X) in exon 30 of the dystrophin gene, cardiologic examination at the age of 23 years revealed asymptomatic severely reduced systolic dysfunction with a fractional shortening of 14% in the absence of dilated cardiomyopathy. A combined therapy with enalapril (2.5 mg/day) and bisoprolol (1.25 mg/day) was initiated. After a slow increase in the dosage to 10 mg enalapril/day and 2.5 mg bisoprolol/day, systolic dysfunction resolved to a fractional shortening of 26% already after 7 months. CONCLUSIONS: This case shows that asymptomatic reduced systolic function also in patients with DMD due to a point mutation responds favourably to a combination therapy with ACEI and beta-blockers. PMID- 21273768 TI - Seasonal variation in hospital admission in patients with heart failure and its effect on prognosis. AB - BACKGROUND: A seasonal variation in hospital admissions in patients with heart failure (HF) has been described and most admissions occur during the winter season. The effect of this seasonal variation on prognosis is less clear. OBJECTIVES: To evaluate the effect of the seasonal timing of hospital admission on clinical outcome in patients with HF. METHODS: We prospectively enrolled 362 consecutive patients hospitalized with a definite clinical diagnosis of HF during a 2-year period. Patients were followed clinically for a period of 1 year. RESULTS: There was a prominent seasonal variation in hospital admissions in patients with HF with peak admissions during the winter. The admission rate inversely correlated with the average monthly temperature. Admission during the summer season was a significant predictor of reduced survival (59 vs. 75%, p < 0.01). Cox regression analysis demonstrated that independent predictors of reduced survival after adjustment for other predictors were admission during the hottest 6 months or admission during the summer. In addition, increased mean environmental admission temperature was an independent predictor of reduced survival. CONCLUSIONS: Seasonal temperature has a significant effect on the rate of hospital admission in patients with HF. Admission during warmer weather is a sign of a poor prognosis. PMID- 21273769 TI - Acute disabling low-back pain during intravenous administration of amiodarone: could intravenous to oral switch therapy be a safe strategy? AB - We report for the first time a case of an acute disabling low-back pain episode during intravenous administration of amiodarone in a patient with atrial fibrillation. The symptoms completely resolved after terminating the infusion, and switching amiodarone from intravenous to oral administration was well tolerated. PMID- 21273770 TI - Linkage analysis of autopsy-confirmed familial Alzheimer disease supports an Alzheimer disease locus in 8q24. AB - BACKGROUND/AIMS: We have previously reported the results of an extended genome wide scan of Swedish Alzheimer disease (AD)-affected families; in this paper, we analyzed a subset of these families with autopsy-confirmed AD. METHODS: We report the fine-mapping, using both microsatellite markers and single-nucleotide polymorphisms (SNPs), in the observed maximum logarithm of the odds (LOD)-2 unit (LOD(max)-2) region under the identified linkage peak, linkage analysis of the fine-mapping data with additionally analyzed pedigrees, and association analysis of SNPs selected from candidate genes in the linked interval. The subset was made on the criterion of at least one autopsy-confirmed AD case per family, resulting in 24 families. RESULTS: Linkage analysis of a family subset having at least one autopsy-confirmed AD case showed a significant nonparametric single-point LOD score of 4.4 in 8q24. Fine-mapping under the linkage peak with 10 microsatellite markers yielded an increase in the multipoint (mpt) LOD score from 2.1 to 3.0. SNP genotyping was performed on 21 selected candidate transcripts of the LOD(max) 2 region. Both family-based association and linkage analysis were performed on extended material from 30 families, resulting in a suggestive linkage at peak marker rs6577853 (mpt LOD score = 2.4). CONCLUSION: The 8q24 region has been implicated to be involved in AD etiology. PMID- 21273771 TI - Changes in vascular risk factors from midlife to late life and white matter lesions: a 20-year follow-up study. AB - BACKGROUND/AIMS: This study investigated the relation of midlife blood pressure, total cholesterol, body mass index (BMI), their changes over time, apolipoprotein E, and white matter lesions (WML). METHODS: Participants of the Cardiovascular Risk Factors, Aging and Incidence of Dementia study were derived from random, population-based samples previously surveyed in 1972, 1977, 1982 or 1987. In 1998, 1,449 (73%) individuals aged 65-79 years were re-examined (average follow up 21 years). A subpopulation (n = 112) was scanned with a 1.5-tesla MRI scanner in 1998, and WML were assessed from fluid-attenuated inversion recovery images using a semi-quantitative visual rating scale. RESULTS: Risk of late-life WML was related to midlife overweight (relative risk = 2.53; 95% CI = 1.70-2.89), obesity (2.94; 2.44-3.03), and hypertension (2.73; 1.81-3.08), even after adjustments for several confounding factors. Elevated BMI (>25) (2.26; 1.42-2.62) and hypertension (3.14; 1.83-3.40) from midlife to late life also increased the risk of WML. In addition, an association with WML was seen for decreasing blood pressure (hypertension at midlife but not at late life) (3.25; 2.46-3.41), even after controlling for antihypertensive treatment. Lipid-lowering drugs had a protective effect against WML (0.13; 0.02-0.59). CONCLUSIONS: These results indicate that early and sustained vascular risk factor control is associated with a lower likelihood of having more severe WML in late life. PMID- 21273772 TI - Role of DNA methylation in the development of diffuse-type gastric cancer. AB - Cancer cells exhibit two opposing methylation abnormalities: genome-wide hypomethylation and gene promoter hypermethylation. Downregulation of E-cadherin (CDH1) plays a key role in the development of diffuse-type gastric cancer, and DNA methylation is a major cause of the gene's silencing. Hereditary diffuse gastric cancer is caused by germline mutation of CDH1 gene, and DNA methylation frequently serves as the second hit completely inactivating the gene. In sporadic diffuse-type gastric cancer, methylation of CDH1 is more prevalent than mutation of the gene. Epstein-Barr virus (EBV)-associated gastric carcinoma (EBV associated GC) is characterized by concurrent methylation of multiple genes, and diffuse-type gastric cancer is frequently seen among EBV-associated GCs. Patients with pangastritis or enlarged-fold gastritis, which are both caused by Helicobacter pylori infection, reportedly have an increased risk for diffuse-type gastric cancer. Notably, the gastric mucosa of enlarged-fold gastritis patients exhibits CDH1 hypermethylation and genome-wide hypomethylation. These data suggest that aberrant DNA methylation is an essential promoter of carcinogenesis in individuals at high risk for diffuse-type gastric cancer. PMID- 21273773 TI - Gastric atrophy reversible or irreversible after Helicobacter pylori eradication an open question. PMID- 21273774 TI - Is this stricture inflammatory? PMID- 21273775 TI - Assessment of inflammatory and fibrotic stenoses in patients with Crohn's disease using contrast-enhanced ultrasound and computerized algorithm: a pilot study. AB - PURPOSE: The development of stenosis is a typical complication of Crohn's disease and represents a serious diagnostic and therapeutic challenge. The aim of the present study was to define objective quantitative measures of stricture characteristics (fibrostenotic/cicartricial vs. inflammatory) using contrast enhanced ultrasound (CEUS) in patients with stenotic Crohn's disease. MATERIALS AND METHODS: During a period of 18 months, 18 consecutive patients with Crohn's disease and manifestation of a localized significant small bowel stenosis were prospectively recruited. Standardized ultrasound (US) examination, color-coded duplex sonography and CEUS using SonoVue(r) were performed. Quantitative measurements of bowel wall vascularity were determined using computerized algorithms (Bracco QONTRAST software). The quality of stenosis (fibrostenotic vs. inflammatory) was classified in a 4-point scale, and the diagnostic/prognostic power of the US and clinical tests upon initial presentation were compared. RESULTS: We established a novel standardized CEUS procedure using computerized algorithms to quantitatively examine stenoses in Crohn's disease. An inflammatory origin of stenosis correlated significantly with a high Crohn's Disease Activity Index (CDAI) (p < 0.01), the length of stenosis (p < 0.01) as well as the Limberg score (p < 0.01). There was no correlation between the type of stenosis and quantitative results of CEUS. CONCLUSION: Although bowel wall vascularity can be quantitatively assessed in stenotic areas by CEUS, this analysis does not improve the diagnostic power for the objective determination of the quality of stenosis at a single measurement. Semiquantitative analysis of bowel wall vascularity, length of stenosis, and CDAI may help to discriminate the origin of small bowel stenosis in Crohn's disease. PMID- 21273776 TI - Interleukin-18 gene polymorphisms in tunisian patients with inflammatory bowel disease. AB - AIM: Interleukin (IL)-18 can regulate the Th2-mediated immune response and it may be involved in the pathogenesis of Th1 and Th2 chronic inflammatory diseases. This study sought to detect a possible association between two single nucleotide polymorphisms (SNPs) (-137G/C and -607C/A) in the IL-18 gene promoter region and susceptibility to inflammatory bowel disease (IBD) including Crohn's disease (CD) and ulcerative colitis (UC) in the Tunisian population. METHODS: The (-137G/C and -607C/A) IL-18 polymorphism was analyzed in 105 patients with CD, 59 patients with UC, and 100 controls using the sequence-specific polymerase chain reaction method. RESULTS: The distribution of allele and genotype frequencies illustrate that the -137G/G genotype frequency was significantly higher in UC than in controls (p value corrected (pc) = 0.038). On the other hand, we found a statistically significant association (pc = 0.033) between genotype AA of the IL 18 gene promoter (-607C/A) polymorphism in UC patients and the distal localization of the lesions. In CD, no significant differences were observed at positions -607 and -137. The analysis of IBD patients according to clinical behavior revealed no difference. CONCLUSION: The two SNPs at position -607 (C/A) and -137 (G/C) in the promoter region of the IL-18 gene was associated with the development of UC but not CD, providing a strong support for an IBD susceptibility gene in the region surrounding IL-18. It remains to be determined precisely how the IL-18 alleles influence the pathogenesis of IBD. PMID- 21273777 TI - Mild-to-moderate neurogenic pyrexia in acute cerebral infarction. AB - BACKGROUND: Pyrexia is often associated with unfavorable stroke outcomes. However, limited information is available on the relationship between the causes of poststroke hyperthermia and stroke prognosis, especially for mild-to-moderate neurogenic pyrexia in acute cerebral infarction. AIMS: To compare the differences in the clinical features and characteristics of pyrexia as well as its prognosis among acute cerebral infarction patients with mild-to-moderate neurogenic pyrexia, with infectious pyrexia, and without pyrexia. The focus was on mild-to moderate neurogenic pyrexia. METHODS: A total of 709 patients with acute cerebral infarction were prospectively recruited and their clinical data were analyzed. RESULTS: No significant difference was detected in age, gender, history of smoking, hypertension, or diabetes among the 3 groups (p > 0.05). Patients with mild-to-moderate neurogenic pyrexia and those with infectious pyrexia had higher baseline National Institutes of Health Stroke Scale (NIHSS) scores (15.1 +/- 6.7, p = 0.003; 14.3 +/- 8.1, p = 0.002, respectively), lower 3-month Barthel index (BI) values (64.2 +/- 40.7, p < 0.001; 61.9 +/- 49.3, p < 0.001, respectively) and higher 3-month mortality rates (13%, p = 0.026; 16%, p < 0.001, respectively) than patients without pyrexia (NIHSS score 11.4 +/- 7.9; BI 82.6 +/- 39.8, and mortality rate 6%, respectively). No difference existed in these parameters between the 2 pyrexia groups (p > 0.05), but mild-to-moderate neurogenic pyrexia had an earlier onset and a shorter duration than infectious pyrexia (p < 0.001). CONCLUSIONS: Acute cerebral infarction patients with mild-to-moderate neurogenic pyrexia had a similar prognosis compared to those with infectious pyrexia. Mild to-moderate neurogenic pyrexia is possibly associated with stroke severity. PMID- 21273778 TI - The prevalence of long spinal cord lesions and anti-aquaporin 4 antibodies in neuromyelitis optica patients in Taiwan. AB - BACKGROUND AND OBJECTIVE: It was the aim of this study to determine the prevalence of anti-aquaporin 4 antibody (anti-AQP4 Ab) and long spinal cord lesions in neuromyelitis optica (NMO) and multiple sclerosis (MS) patients in Taiwan. Asia has a relatively high rate of NMO compared with MS patients. Anti AQP4 Ab is an important marker for NMO worldwide, but serological data and clinical profiles of NMO patients in Taiwan have not been reported. METHODS: This retrospective study compared the clinical symptoms, demographics, spinal cord lesion length and AQP4 Ab status of 34 patients with NMO with 34 patients diagnosed with conventional MS. RESULTS: Our NMO patients were predominantly middle-aged women (median age 45 years), exhibited many relapses (1.0/year) and displayed a higher Expanded Disability Status Scale score (4.75) than conventional MS patients. NMO patients exhibited long spinal cord lesions as detected by MRI. Forty-one percent of the NMO patients had detectable anti-AQP4 Ab. The Expanded Disability Status Scale score was significantly higher in AQP4 Ab- NMO patients. CONCLUSION: The prevalence of AQP4 Ab in a Taiwanese NMO group was 41%. Long spinal cord lesions and detection of AQP4 Ab helped to differentiate NMO patients from MS patients. Long spinal cord lesions with the anti-AQP4 Ab test may allow for an earlier diagnosis of NMO and improve therapeutic decisions. PMID- 21273779 TI - Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry combined with magnetic beads for detecting serum protein biomarkers in parkinson's disease. AB - BACKGROUND: Biomarkers for neurodegenerative diseases are essential to facilitate disease diagnosis. Application of proteomics has greatly hastened the search for novel biomarkers. In this study, new potential biomarkers were discovered, and a diagnostic pattern was established for idiopathic Parkinson's disease (PD) by using proteomic technology. METHODS: Serum proteins from PD patients and controls were captured by magnetic bead-based weak cation exchange. The molecular weight of the proteins in bead-binding fraction was detected by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Biomarker Wizard 3.1 and Biomarker Patterns Software were used for data analysis and constructing a model of biomarkers. A blinded testing set was used to validate the model. RESULTS: A total of 17 discriminating m/z peaks related to PD were identified. The model based on the 5 biomarkers generated an excellent separation between PD and healthy controls with 98.36% for the sensitivity and 83.05% for the specificity. Blind test data demonstrated the model could recognize patients with PD with a sensitivity of 85.0% and a specificity of 70.0%. CONCLUSIONS: The preliminary data suggested a potential application of MALDI-TOF-MS combined with magnetic beads. The model comprising 5 promising biomarkers can differentiate individuals with PD and the healthy subjects precisely. PMID- 21273781 TI - Speech inconsistency index in Brazilian Portuguese-speaking children. AB - OBJECTIVE: Speech inconsistency is characterised by variable productions of the same lexical items within the same context. This study aimed to describe inconsistencies among Brazilian Portuguese (BP)-speaking children with and without phonological disorder (PD) as well as the effectiveness of a speech inconsistency test (SIT). METHODS: The study sample included children between 5 years 0 months (5;0 years) and 10;10 years of age, both genders, 51 children with PD and 50 without speech-language disorders. The SIT includes 25 pictures, each named 3 times in different sequences within the same session. RESULTS: The inconsistency average of children with PD (27.4%) was higher than that of typically developing children (9.8%). Linear regression showed age and gender effects, receiver operating characteristic curves were built for speech inconsistency with combined gender and age cutoff values. Inconsistent subjects among typically developing children included 2 younger boys and 2 older girls. Inconsistencies were found among children with PD, including 10 boys up to 7;6 years and 11 over this age, and 7 girls up to 7;6 years and 6 over this age. CONCLUSION: Speech inconsistency in BP-speaking children seems to be an effective measure for differentiating children with PD from those with typically developing phonology. PMID- 21273782 TI - Vascular dysfunction in streptozotocin-induced experimental diabetes strictly depends on insulin deficiency. AB - OBJECTIVE: In previous studies we and others have shown that streptozotocin (STZ) induced diabetes in rats is associated with vascular oxidative stress and dysfunction. In the present study, we sought to determine whether vascular dysfunction and oxidative stress strictly depend on insulin deficiency. METHODS: The effects of insulin (2.5 U/day s.c., 2 weeks) therapy on vascular disorders in STZ-induced (60 mg/kg i.v., 8 weeks) diabetes mellitus (type I) were studied in Wistar rats. The contribution of NADPH oxidase to overall oxidative stress was investigated by in vivo (30 mg/kg/day s.c., 4 days) and in vitro treatment with apocynin. RESULTS: Insulin therapy completely normalized blood glucose, body weight, vascular dysfunction and oxidative stress as well as increased cardiac reactive oxygen and nitrogen species formation in diabetic rats, although diabetes was already established for 6 weeks before insulin therapy was started for the last 2 weeks of the total treatment interval. Apocynin normalized cardiac NADPH oxidase activity, and L-NAME effects suggest a role for uncoupled endothelial nitric oxide synthase in diabetic vascular complications. CONCLUSIONS: Our findings indicate that STZ-induced diabetes is a model of insulin-dependent diabetes (type 1) and that cardiovascular complications are probably not associated with systemic toxic side effects of STZ. PMID- 21273783 TI - Heme oxygenase-1 does not mediate the effects of extracellular acidosis on vascular smooth muscle cell proliferation, migration, and susceptibility to apoptosis. AB - BACKGROUND: Unbalanced vascular smooth muscle cell (VSMC) proliferation, migration, and apoptosis contribute to vascular disorders such as atherosclerosis, restenosis, and pulmonary hypertension. The effect of extracellular acidosis (EA) on VSMC homeostasis is incompletely understood but we previously reported that EA increases heme oxygenase-1 (HO-1) expression in VSMCs. Since HO-1 regulates VSMC proliferation and apoptosis we sought to define the role of HO-1 in VSMC responses to EA. METHODS: Mouse aortic smooth muscle cells (MASMCs) were isolated from wild-type and HO-1-null mice. Cell proliferation and migration assays were done in a physiologic pH (7.4) or EA (pH 6.8). VSMC apoptosis in response to hydrogen peroxide was assessed by JC-1 staining, caspase-3 cleavage, annexin V, and Hoechst staining. RESULTS: Wild-type MASMCs showed decreased proliferation and migration at pH 6.8 compared to pH 7.4. This observation was also true in HO-1-null MASMCs. Although wild-type and HO-1 null cells showed differences in the mode and kinetics of cell death, both genotypes exhibited increased susceptibility to hydrogen peroxide-induced apoptosis at pH 6.8 compared to 7.4. CONCLUSIONS: EA inhibits VSMC proliferation and migration and increases susceptibility to oxidant-induced apoptosis. These effects of acidosis on VSMC homeostasis are independent of HO-1. PMID- 21273784 TI - Endothelial glycocalyx structure in the intact carotid artery: a two-photon laser scanning microscopy study. AB - BACKGROUND: The endothelial glycocalyx (EG) is the carbohydrate-rich luminal lining of endothelial cells that mediates permeability and blood cell-vessel wall interactions. To establish an atheroprotective role of the EG, adequate imaging and quantification of its properties in intact, viable, atherogenesis-prone arteries is needed. METHODS: Carotid arteries of C57Bl6/J mice (n=22) were isolated including the bifurcation, mounted in a perfusion chamber, and perfused with fluorescent lectin wheat germ agglutinin-fluorescein isothiocyanate. The EG was visualized through the vessel wall using two-photon laser scanning microscopy. An image quantification protocol was developed to assess EG thickness, which was sensitive to hyaluronidase-induced changes. RESULTS: In the lesion-protected common carotid artery, EG thickness was found to be 2.3 +/- 0.1 MUm (mean +/- SEM), while the surface area devoid of (wheat germ agglutinin sensitive) EG was 8.9 +/- 4.2%. Data from the external carotid artery were similar (2.5 +/- 0.1 MUm; 9.1 +/- 5.0%). In the atherogenesis-prone internal carotid artery the EG-devoid surface area was significantly higher (27.4 +/- 5.5%, p<0.05); thickness at the remaining areas was 2.5 +/- 0.1 MUm. CONCLUSION: The EG can be adequately imaged and quantified using two-photon laser scanning microscopy in intact, viable mounted carotid arteries. Spatial EG differences could underlie atherogenesis. PMID- 21273785 TI - Increased vascular injury reduces the degree of intimal hyperplasia following angioplasty in rabbits. AB - BACKGROUND/AIMS: Formation of intimal hyperplasia following angioplastic procedures can lead to complications, including restenosis and accelerated atherosclerosis. The vessel wall media is a main source of neointimal cells. However, evidence suggests that there are additional cell sources, such as the adventitia. Here we investigate whether an extensive loss of vascular smooth muscle cells (VSMCs) in the media results in less intimal hyperplasia or if there is compensatory cell recruitment from the adventitia. METHODS: A balloon catheter was pulled through the rabbit carotid artery 4 times (major injury) or 2 times (minor injury). Adventitial cells were labeled with 5-bromo-2-deoxyuridine or PKH26. RESULTS: The major injury, but not the minor injury, resulted in a complete loss of VSMCs in large parts of the media and significant leukocyte infiltration. The major injury resulted in less neointima compared with the minor injury. The thinnest neointima was seen at the most injured parts of the media in the major injury group. Cell-tracking experiments showed that the media, but not the adventitia, served as a source of neointimal cells. CONCLUSION: An augmented angioplastic injury with extensive VSMC loss in rabbits reduced the degree of intimal hyperplasia. No compensatory recruitment of neointimal cells from the adventitia occurred. PMID- 21273786 TI - Long-term ouabain treatment impairs vascular function in resistance arteries. AB - BACKGROUND/AIMS: The purpose of this study was to examine the cardiovascular effects of long-term ouabain treatment at different time points. METHODS: Systolic blood pressure (SBP) was measured by tail-cuff method in male Wistar rats treated with ouabain (approx. 8.0 MUg.day(-1)) or vehicle for 5, 10 and 20 weeks. Afterwards, vascular function was assessed in mesenteric resistance arteries (MRA) using a wire myograph. ROS production and COX-1 and COX-2, TNF alpha, and IL-6 protein expression were investigated. RESULTS: SBP was increased by ouabain treatment up to the 6th week and remained stable until the 20th week. However, noradrenaline-induced contraction increased only in MRA in rats treated with ouabain for 20 weeks. NOS inhibition and endothelium removal increased the noradrenaline response, but to a smaller magnitude in MRA in the ouabain group. Moreover, inhibition of COX-2 or incubation with superoxide dismutase restores noradrenaline-induced contraction in the 20-week ouabain group to control levels. ROS production as well as COX-2, IL-6 and TNF-alpha protein expression increased in MRA in this group. CONCLUSION: Although ouabain treatment induced hypertension in all groups, a larger noradrenaline induced contraction was observed over 20 weeks of treatment. This vascular dysfunction was related to COX-2-derived prostanoids and oxidative stress, increased pro- inflammatory cytokines and reduced NO bioavailability. PMID- 21273787 TI - The GPER1 agonist G-1 attenuates endothelial cell proliferation by inhibiting DNA synthesis and accumulating cells in the S and G2 phases of the cell cycle. AB - G protein-coupled receptor 30 (GPR30) or G protein-coupled estrogen receptor 1 (GPER1) is expressed in the vasculature, but the importance of vascular GPER1 remains to be clarified. Here we investigate effects of the GPER1 agonist G-1 on endothelial cell proliferation using mouse microvascular endothelial bEnd.3 cells. The bEnd.3 cells express mRNA for GPER1. The bEnd.3 cells expressed both ERalpha and ERbeta immunoreactivities. Treatment with G-1 reduced DNA synthesis and cell number with IC(50) values of about 2 MUM. GPER1 siRNA prevented G-1 induced attenuation of DNA synthesis. G-1 accumulated cells in S and G2 phases of the cell cycle, suggesting that G-1 blocks transition between G2 and M. G-1 had no effect on DNA synthesis in COS-7 cells only weakly expressing GPER1 mRNA. 17beta-Estradiol had no effect on DNA synthesis in physiological concentrations (nM). The ER blocker ICI182780 reduced DNA synthesis with similar potency as G-1. Treatment with the ERK/MAP kinase inhibitor PD98059 had no effect on G-1-induced attenuation of DNA synthesis. G-1- induced antiproliferation was observed not only in bEnd.3 cells but also in human umbilical vein endothelial cells and HMEC 1 endothelial cells. We conclude that the GPER1 agonist G-1 attenuates endothelial cell proliferation via inhibition of DNA synthesis and by accumulation of cells in S and G2. PMID- 21273788 TI - Circulating endothelial cell protein C receptor: endothelial regulation and cumulative impact of gender and A3 haplotype. AB - BACKGROUND: The endothelial cell (EC) protein C receptor (EPCR) negatively regulates coagulation and inflammation. Factors and mechanisms regulating the expression of cell-bound EPCR and the release of soluble (s) EPCR are still unclear. METHODS: We investigated the reciprocal regulation of membrane-bound and sEPCR upon inflammation using primary cultures of vascular EC. The impact of 2 parameters, gender and EPCR gene A3 haplotype, on sEPCR plasma basal level and endothelial expression was examined by Elisa and flow cytometry. RESULTS: Exposure of EC to tumor necrosis factor alpha causes a rapid downregulation of membrane-associated EPCR expression without affecting markedly the spontaneous release of sEPCR by EC. In a cohort of 100 healthy donors, we show that males express significantly higher basal sEPCR in plasma than females (194 +/- 12 vs. 145 +/- 9 ng/ml, respectively, p<0.01). Both gender and EPCR A3 haplotype affect sEPCR plasma levels but have no apparent effect on EPCR expression by EC. No quantitative correlation between cellular expression and circulating blood sEPCR was observed, suggesting that endothelial expression may not reflect the plasma level. CONCLUSION: Male gender is another parameter with A3 haplotype associated with elevated sEPCR levels in blood, and both parameters may contribute to selective regulatory mechanisms of EPCR release upon inflammation. PMID- 21273789 TI - Comparison of combination therapy of olmesartan plus azelnidipine or hydrochlorothiazide on renal and vascular damage in SHR/NDmcr-cp rats. AB - BACKGROUND: Although the recommended target blood pressure for patients with chronic kidney disease is <130/80 mm Hg, this is difficult to achieve by treatment with an angiotensin receptor blocker alone. Addition of either a calcium channel blocker or a diuretic is suggested as second-line medication; however, which combination is most beneficial for target-organ protection remains unknown. METHODS: SHR/NDmcr-cp rats were administered no medications (control) or low-dose olmesartan for 2 weeks and then either olmesartan at an increased dose, azelnidipine, or the hydrochlorothiazide for 3 weeks. We assessed oxidative stress in the kidney and aorta, and endothelial function. RESULTS: Urinary protein excretion was lower in all treated rats than in control rats. Oxidative stress caused by activation of NAD(P)H oxidase was observed in the glomeruli and aorta of control rats and was significantly suppressed in the olmesartan/azelnidipine (Olm/Azl) groups. Combination therapy with olmesartan and hydrochlorothiazide (Olm/HCTZ) however failed to suppress oxidative stress. The Olm/Azl groups maintained the endothelial surface layer in the glomeruli and protected endothelial function in the aorta. CONCLUSION: In an animal model of metabolic syndrome, a combination of Olm/Azl is superior to a combination of Olm/HCTZ in terms of prevention of glomerular and vascular injuries. PMID- 21273790 TI - Renal function in patients treated with cinacalcet for persistent hyperparathyroidism after kidney transplantation. AB - BACKGROUND AND AIM: Cinacalcet effectively reduces calcium in patients with persistent hyperparathyroidism (HPT) after kidney transplantation. We aimed to assess the association of cinacalcet with a decrease in renal function based on a meta-analysis of observational studies in kidney transplant patients with persistent HPT. METHOD: Meta-analysis of observational studies, no randomized controlled studies were available. We calculated the mean difference between renal function before cinacalcet and at 3 months on cinacalcet treatment for each study. Pooled analyses are based on random effects models. RESULTS: Pooling the studies on kidney transplant patients with persistent HPT (8 studies, n = 115), we found a significant reduction in renal function (p = 0.008). The effect size was 5 MUmol/l (p < 0.0001) when pooling the 7 studies where serum creatinine levels were reported. Meta-regression analysis revealed that there was an association between renal function and the amount of calcium reduction under treatment with cinacalcet. A higher delta change in serum calcium levels was associated with a decrease in renal function at 3 months of cinacalcet treatment. CONCLUSION: Cinacalcet treatment was associated with a decline of renal function in kidney transplant recipients with persistent HPT. Our meta-analysis underscores the need for frequent monitoring of creatinine and calcium levels during cinacalcet treatment. PMID- 21273791 TI - Cloning of a gene encoding beta-glucosidase from Chaetomium thermophilum CT2 and its expression in Pichia pastoris. AB - A new thermostable beta-glucosidase gene (bgl) from Chaetomium thermophilum CT2 was cloned, sequenced and expressed. The full-length DNA of bgl was 3,101 bp and included three introns. The full-length cDNA contained an open reading frame of 2,604-bp nucleotides, encoding 867 amino acids with a potential secretion signal. The C. thermophilum CT2 beta-glucosidase gene was functionally expressed in Pichia pastoris. The purified recombinant beta-glucosidase was a 119-kDa glycoprotein with an optimum catalytic activity at pH 5.0 and 60 degrees C. The enzyme was stable at 50 degrees C, and retained 67.7% activity after being kept at 60 degrees C for 1 h; the half-time of the enzyme at 65 degrees C was approximately 55 min, and even retained 29.7% activity after incubation at 70 degrees C for 10 min. PMID- 21273792 TI - Sustained inflations: comparing three neonatal resuscitation devices. AB - BACKGROUND: Some national resuscitation guidelines advocate using sustained initial inflations (2-3 s) for babies requiring resuscitation. Inflation times >=10 s have been used for preterm infants. OBJECTIVES: This study examines the ability of operators of varying experience to provide a sustained inflation using three different manual ventilation devices. METHODS: We compared a self-inflating bag, a flow-inflating bag and a pressure-limited T-piece device. Fifty clinical staff members from five professional groups gave a sustained inflation with a target peak pressure of 30 cm H2O and target duration of 10 s to an internal leak free manikin. We measured peak inflating pressure (PIP) and mean inflating pressure (MIP) during the sustained inflation, and the duration of inflating pressure (IP) >20 and 25 cm H2O. RESULTS: Median (IQR) duration of IP >25 cm H2O was: self-inflating bag 2.5 s (0.8-5.7), flow-inflating bag 10.6 s (8.4-12.9) and the T-piece 10.7 s (8.9-11.9). There was a weak correlation between experience using a self-inflating bag and longer inflation times (R = 0.290, p = 0.041). When compared with the T-piece, the flow-inflating bag had lower mean MIP (27.0 +/- 1.8 vs. 28.8 +/- 2.0 cm H2O) and higher mean PIP (32.3 +/- 3.7 vs. 29.8 +/- 1.8 cm H2O). There were no differences in performance between operator groups. CONCLUSION: The T-piece provided consistent PIP during a single 10 s sustained inflation with less variation in pressure compared with the flow-inflating bag. Sustained inflations >3 s were difficult to achieve with a self-inflating bag. PMID- 21273793 TI - Systolic right ventricular function in preterm and term neonates: reference values of the tricuspid annular plane systolic excursion (TAPSE) in 258 patients and calculation of Z-score values. AB - BACKGROUND: The tricuspid annular plane systolic excursion (TAPSE) is an echocardiographic measurement to assess right ventricular systolic function in adults and children. OBJECTIVE: We determined growth- and birth weight-related changes of TAPSE to establish reference values in preterm and term neonates. METHODS: A prospective study was conducted in a group of 258 preterm and term neonates (age: 25+0 to 40+6 weeks of gestation, birth weight: 530-4200 g). RESULTS: The TAPSE ranged from a mean of 0.44 cm (Z-score +/-2: 0.30-0.59 cm) in preterm neonates in the 26th week of gestation to 1.03 cm (Z-score +/-2: 0.85 1.21 cm) in term neonates in the 41st week of gestation. The TAPSE values increased in a linear way from the 26th to 41st week of gestation. TAPSE, week of gestation and weight are strongly correlated: Pearson's correlation coefficient was 0.93 for week of gestation - TAPSE (p < 0.001), 0.93 for week of gestation - birth weight (p < 0.001), and 0.89 for birth weight - TAPSE (p < 0.001). There was no statistically significant difference of normal TAPSE values between female and male patients (p = 0.987). CONCLUSION: Z-scores of TAPSE values were calculated and percentile charts were established to serve as reference data for ready application in preterm and term neonates with structurally normal hearts and with congenital heart disease in the future. PMID- 21273794 TI - Changes in serum adiponectin levels from birth to term-equivalent age are associated with postnatal weight gain in preterm infants. AB - BACKGROUND: Adiponectin, one of the adipocytokines, is postulated to play a key role in fetal growth, probably enhancing the growth-promoting effect of insulin through insulin-sensitizing action. OBJECTIVES AND METHODS: To examine how different intrauterine or postnatal growth patterns relate to adiponectin secretion, we measured serum adiponectin concentrations in 30 appropriate-for gestational-age (AGA) and 19 small-for-gestational-age (SGA) preterm infants on the first day of life and at term-equivalent age. RESULTS: The serum levels of adiponectin increased significantly in all preterm infants from birth to term equivalent age. The adiponectin levels at term-equivalent age were significantly higher in the AGA than in the SGA group [mean (SD) 40.4 (12.3) vs. 28.4 (10.4) MUg/ml; p < 0.01] after adjustment for gestational age or term-equivalent body weight. The increase in adiponectin levels from birth to term-equivalent age was significantly higher in the AGA than in the SGA group, and was positively correlated with the weight gain rate (g/kg/day) in the combined groups (r = 0.37, p < 0.01). A multiple regression analysis with the adiponectin increase from birth to term-equivalent age as the dependent variable for all the subjects revealed that only weight gain rate was independently associated with the adiponectin increase. CONCLUSIONS: Our results suggest that the change in serum adiponectin levels may reflect postnatal growth from birth to term-equivalent age in preterm infants. PMID- 21273795 TI - Photodynamic therapy combined with intravitreal injection of vascular endothelial growth factor antibody for polypoidal choroidal vasculopathy. AB - BACKGROUND/AIMS: To evaluate the efficacy of photodynamic therapy (PDT) combined with intravitreal injection of anti-vascular-endothelial-growth-factor (anti VEGF) antibody in patients with polypoidal choroidal vasculopathy (PCV). METHODS: Twenty-two eyes of 22 patients with PCV followed for 12 months after combination therapy with PDT and anti-VEGF were retrospectively reviewed. Patients received intravitreal anti-VEGF (1.25 mg bevacizumab or 0.5 mg ranibizumab) within 7 days after PDT. Retreatment with PDT and intravitreal anti-VEGF injections, or with intravitreal anti-VEGF alone, was performed when indicated. The main outcome measures were best-corrected visual acuity (BCVA) and central foveal thickness (CFT). RESULTS: Mean logMAR BCVA was 0.43 at baseline and 0.45, 0.36, 0.30 and 0.28 at 1, 3, 6 and 12 months, respectively, after the initial combination therapy. Mean BCVA was significantly improved at 6 and 12 months after treatment (p < 0.05). Mean CFT was 269.4 MUm at baseline and 180.1, 136.7, 127.5 and 139.6 MUm at 1, 3, 6 and 12 months, respectively, after the initial combination therapy. CFT decreased significantly throughout the follow-up period. At 12 months, mean BCVA improved by 1.5 lines, and mean CFT decreased by 129.8 MUm. Polypoidal lesions disappeared in 7 of the 13 eyes in which indocyanine green angiography was performed at 12 months. No changes in the branching vascular network were observed in any of these 13 eyes. Patients were treated with PDT a mean of 1.3 times and injected with intravitreal anti-VEGF a mean of 3.4 times over the 12-month period. CONCLUSION: Combined PDT and intravitreal anti-VEGF may improve visual acuity and decrease CFT at 12 months. Large long-term prospective studies are needed to evaluate the efficacy and safety of combination therapy. PMID- 21273796 TI - Effects of flickering light on refraction and changes in eye axial length of C57BL/6 mice. AB - AIMS: To investigate the effectiveness and feasibility of inducing myopia in mice by flickering-light (FL) stimulation. METHODS: Forty-five 28-day-old C57BL/6 (B6) mice were randomly assigned to three groups: control group, FL stimulation group and form deprivation (FD) group. Mice in the control group were raised under 250 lux illumination from 8:00 a.m. to 8:00 p.m. Mice in the FL group were raised under illumination with a duty cycle of 50% at a flash rate of 2 Hz from 8:00 a.m. to 8:00 p.m. for 6 weeks. Mice in the FD group were raised under the same conditions as the control group; the right eyes of the mice were covered with semitransparent hemispherical plastic shells serving as eye diffusers. The refractive state and axial length (AL) of the right eyes were measured by eccentric infrared photorefraction and A-scan ultrasonography, respectively, before treatment and after 2, 4, 6 or 8 weeks' treatment. RESULTS: After 6 weeks' exposure to FL, the refraction became more myopic compared with the control group as indicated by longer AL compared with the control group (p < 0.05); the FD eyes were more myopic than the FL eyes (p < 0.05). However, some mice lost their eye diffusers, and lens opacities were found. CONCLUSION: Myopia can be induced by FL in B6 mice. The myopic shift induced by FL is less than that induced by FD, but FL causes fewer side effects, and is safery and easier to manipulate. PMID- 21273797 TI - Quantifying FITC-labeled latex beads opsonized with photoreceptor outer segment fragments: an easy and inexpensive method of investigating phagocytosis in retinal pigment epithelium cells. AB - The retinal pigment epithelium (RPE) is the most active phagocyte in the human body, and this function is indispensable for vision. In this study, we introduce an easy and inexpensive way to quantify RPE phagocytosis by opsonizing FITC labeled latex beads of a defined size with a crude mixture of photoreceptor outer segment fragments, using cells of porcine origin. After performance of the desired experiment, phagocytosis can easily be quantified by counting the ingested particles. With this protocol, we combine the advantage of a natural target with the advantages of the defined properties of latex beads. Moreover, in order to conduct these phagocytosis experiments, as laboratory equipment, in addition to cell culture equipment, only a centrifuge and a simple fluorescence microscope are needed. PMID- 21273798 TI - Elevated Nepsilon-(carboxymethyl)lysine is associated with apoptosis of retinal pericytes in streptozotocin-induced diabetic rats. AB - Advanced glycation end products including Nepsilon-(carboxymethyl)lysine (CML) are believed to contribute to retinal pericyte loss in diabetic retinopathy. Nuclear factor-kappaB (NF-kappaB) activation has been considered as a potential cytotoxic modulator of retinal pericytes. Herein, we investigated whether CML accumulation can trigger NF-kappaB activation and apoptosis of retinal pericytes in streptozotocin (STZ)-induced diabetic rats. Seven-week-old Sprague-Dawley rats were made diabetic (STZ, 60 mg/kg). After 5 months, CML level and NF-kappaB activation were measured in trypsin-digested retinal vessels. In diabetic rats, TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) positive and caspase 3-positive retinal pericytes were significantly increased. CML and NF-kappaB activation was also markedly increased in diabetic retinal vessels. Moreover, the immunoreactivity of NF-kappaB was localized within the region where CML were accumulated. Apoptosis occurred in CML-accumulating retinal pericytes. These results suggest that NF-kappaB could be activated in CML accumulating pericytes from diabetic retina. CML accumulation is responsible, at least in part, for the apoptosis of retinal pericytes. PMID- 21273799 TI - Complications of pediatric auditory brain stem implantation via retrosigmoid approach. AB - OBJECTIVE: We aimed to present the complications of auditory brain stem implantations (ABI) in pediatric patients which were performed via retrosigmoid approach. METHODS: Between March 2007 and February 2010, five prelingually deaf children underwent ABI (Medel device) operation via retrosigmoid approach. All children had severe cochlear malformations. The ages ranged from 20 months to 5 years. The perioperative complications encountered in 2 patients were evaluated retrospectively. RESULTS: No intraoperative complication was observed in the patients. Cerebrospinal fluid (CSF) leakage was the most common postoperative complication that was seen in 2 patients. The CSF leak triggered a cascade of comorbidities, and elongated the hospitalization. CONCLUSION: Pediatric ABI surgery can lead to morbidity. The CSF leak is the most common complication encountered in retrosigmoid approach. The other complications usually result from long-term hospital stay during treatment period of the CSF leak. Therefore, every attempt must be made to prevent occurrence of CSF leaks in pediatric ABI operations. PMID- 21273800 TI - Ear and further anatomic anomalies in children undergoing stapedotomy. AB - PURPOSE: Aim of this study was to examine any stapes fixation-related clinical, intraoperative and high-resolution computed tomography (HRCT) findings in children undergoing stapedotomy. PROCEDURES: Detailed diagnostic assessment was performed in 12 children (18 ears) who underwent stapedotomy within the period 2005-2008. RESULTS: Ear malformations such as malleus-incus anomalies, malleus epitympanum fixation and absence of the stapedius tendon, small external auditory canal and auricle malformations were clinically and/or intraoperatively diagnosed. HRCT identified a petrous high jugular bulb and malformed inner auditory canal in 4 ears; however, it failed to recognize ossicular fixation. Systemic anomalies, namely kyphoscoliosis, esophageal atresia and finger malformations were identified in 2 children. Summing up, additional anatomic anomalies were found in 8 patients (66.7%). CONCLUSIONS: Ear malformations may coexist in children with stapes fixation. Ossicular fixation is not easily recognized with HRCT, and therefore, ossicular mobility should always be tested intraoperatively. In a few cases, pediatric stapes fixation can coexist with systemic dysplasias; in such patients, additional referral to geneticists is recommended. PMID- 21273801 TI - Audiological findings in celiac disease. AB - OBJECTIVE: Celiac disease (CD) is a gluten-triggered immune enteropathy caused by a genetic predisposition. Recent papers suggest that CD is increasingly recognized by extraintestinal findings. The aim of this study was to investigate the effect of CD on hearing pathway including the olivocochlear efferent system in children. METHODS: Forty-one pediatric CD patients and 31 controls were included in the study. Both groups were evaluated with audiometry, tympanometry, transiently evoked otoacoustic emission (TEOAE), distortion product otoacoustic emission (DPOAE), and contralateral suppression of the TEOAE. RESULTS: The threshold at 250 Hz of the patients with CD was significantly higher (p < 0.05 in CD compared to control group, p < 0.0001). The signal to noise ratio (SNR) amplitudes in DPOAE testing and the SNR amplitudes with and without contralateral acoustic stimulus in TEOAE testing were significantly lower at 1,000 Hz in the CD compared to the control group. There was no significant difference between the CD and the control group regarding contralateral suppression amplitudes. CONCLUSION: CD seems to have an important impact on the auditory system, and results in an elevation of the thresholds at 250 Hz on audiometry and a decrease in the amplitudes of DPOAE and linear TEOAE at 1,000 Hz in children. PMID- 21273802 TI - Pain-associated adaptive cortical reorganisation in chronic pancreatitis. AB - BACKGROUND/AIMS: In various chronic pain conditions cortical reorganisation seems to play a role in the symptomatology. The aims of this study were to investigate cortical reorganisation in patients with pain caused by chronic pancreatitis (CP) and to correlate putative cortical reorganisation to clinical pain scores. METHODS: 24 patients suffering from CP and 14 healthy volunteers were included. Patients' daily experience of pain was recorded in a pain diary. The sigmoid was stimulated electrically with simultaneous recording of evoked brain potentials (EPs). The brain source localisations reflecting direct neuronal activity were fitted by a five-dipole model projected to magnetic resonance imaging of the individual brains. RESULTS: Patients showed prolonged latencies of the EPs confined to the frontal region of the brain (p < 0.01). The corresponding brain sources were located in the bilateral insula, cingulate gyrus and bilateral secondary somatosensory area. The insular dipoles were localised more posterior in the patients than in healthy subjects (p < 0.01). The shift in insular dipole localisation was negatively correlated with the patients' clinical pain scores (p < 0.05). CONCLUSIONS: The findings indicate that sustained pain in CP leads to functional reorganisation of the insular cortex. We suggest its physiological correlate to be an adaptive response to chronic pain. and IAP. PMID- 21273803 TI - Delayed production of IL-18 in lungs and pancreas of rats with acute pancreatitis. AB - BACKGROUND/AIMS: During acute pancreatitis, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 and IL-6 play a pivotal role in promoting injury in the pancreas and remote organs. IL- 18 is a more recently discovered proinflammatory cytokine whose expression is also increased in serum. However, the profile of IL 18 expression in the pancreas and lung is unknown, and the aim of our study was to investigate such expression in rats with pancreatitis. METHODS: Acute pancreatitis was induced by taurocholic acid and endotoxin. Pulmonary and pancreatic injury was measured by biological and histological parameters. Lung injury was also evaluated in ex vivo lung preparations. RESULTS: Pancreatic and pulmonary injury appeared within 2 h after pancreatitis induction and persisted until the end of the protocol (18 h). TNF-alpha, IL-1 and IL-6 expression increased early in the lungs and pancreas, with a partial recovery by the end of the study. In contrast, IL-18 increased mostly by the end of the protocol (18 h after pancreatitis induction). CONCLUSION: IL-18 may serve as an additional marker to monitor the severity of inflammation during pancreatitis since its tissue production is delayed and appears after that of more commonly investigated cytokines. and IAP. PMID- 21273804 TI - Innovative sunscreen formulation based on benzophenone-3-loaded chitosan-coated polymeric nanocapsules. AB - AIM: To evaluate the effect of cationic coating of polymeric nanocapsules in sunscreen formulations on the in vitro skin penetration of benzophenone-3. METHODS: Benzophenone-3-loaded nanocapsules were prepared by the interfacial deposition of poly(epsilon-caprolactone) and coated by using a chitosan solution. The nanoparticles were characterized and incorporated in hydrogels. The presence of nanoparticles in hydroxyethyl cellulose gels was observed by transmission electron microscopy and photon correlation spectroscopy. Penetration studies were carried out using Franz cells with porcine skin membranes. RESULTS: Benzophenone 3-loaded chitosan-coated nanocapsules presented a mean size of 202 +/- 7 nm and positive zeta potential (+21 +/- 1 mV), while these values for the uncoated nanocapsules were 175 +/- 1 nm and -8 +/- 1 mV. Penetration profiles showed that a higher amount of benzophenone-3 remained at the skin surface and a lower amount was found in the receptor compartment after the application of the formulation containing chitosan-coated nanocapsules compared to a formulation containing its free form. CONCLUSIONS: Hydrogel containing benzophenone-3 chitosan-coated nanocapsules represents an innovative formulation to overcome limitations of sunscreen daily use. PMID- 21273805 TI - [The effects of dutasteride on voiding and storage symptoms in men with benign prostatic hyperplasia]. AB - We investigated the effects of dutasteride on voiding and storage symptoms by a post-hoc analysis from two randomized, placebo-controlled, parallel-group studies (Japanese phase II study and phase III study) which assessed the efficacy and safety of dutasteride in Japanese men with benign prostatic hyperplasia (BPH). Men aged 50 years and older, with a prostate volume of 30 cc or greater, an International Prostate Symptom Score (IPSS) of 8 or higher and maximal urinary flow rate of 15 ml/sec or lower were randomized to placebo or dutasteride groups. The number of subjects for the placebo and dutasteride groups was respectively 72 and 72 in the phase II study, and 185 and 193 in the phase III study. Questions 1, 3, 5 and 6 of IPSS were related to voiding symptoms, and Questions 2, 4 and 7 were related to storage symptoms. Changes between pre- and post-treatments were evaluated. In the phase II study, dutasteride significantly improved voiding symptoms and numerically improved storage symptoms compared with the placebo at week 24. In the phase III study, dutasteride significantly improved voiding and storage symptoms compared with the placebo after 52 weeks. These consistent results suggest that dutasteride is effective for both voiding and storage symptoms in Japanese men with BPH. PMID- 21273806 TI - [Clinical outcome of microsurgical varicocelectomy done for pain]. AB - Surgical ligation for varicocele is primarily used in the management of male infertility patients. However, effectiveness of the ligation for painful varicocele is still controversial. We reviewed record s from 18 patients (average age 17.8 years) who underwent varicocele ligation done for pain at our institution from June 1999 to May 2010. The varicocele was on the left side and was grade III in 15 cases and grade II in 3 cases. The pain was classified into three types ; discomfort, dull pain and sharp pain. Microsurgical varicocelectomy was done with inguinal or subinguinal approach. Evaluation of postoperative pain was available in 17 patients, and 15 patients (88%) reported complete resolution of the pain with averaged follow up duration of 11 months (3 to 53 months). We concluded that microsurgical varicocelectomy using the inguinal or subinguinal approach was an effective treatment modality for varicocele-associated pain. PMID- 21273807 TI - [Leiomyosarcoma of the kidney with tumor thrombus to the inferior vena cava]. AB - A 76-year-old female presented with edema in the bilateral lower legs and computed tomography (CT) subsequently revealed a tumor under the right side of the kidney that extended to the inferior vena cava. Under suspicion of a right renal sarcoma or malignant teratoma, we performed a right nephrectomy and tumor thrombectomy. Histopathological features of the resected specimen were compatible with a leiomyosarcoma originating from either extrarenal blood vessels or muscle fibers of the renal pelvis. Immunohistological findings showed that the tumor cells were spindle-shaped, arranged in bundles, and stained positive for alpha smooth muscle actin and desmin. The patient was free from recurrence 10 months after surgery. The prognosis of patients with a renal leiomyosarcoma with venous thrombus has been considered to be poor. Herein, we provide details of our case and conclude that radical tumor resection is necessary for a long-term cure. PMID- 21273808 TI - [Disseminated nocardiosis presenting as retroperitoneal abscess: a case report]. AB - A 64-year-old man presented to our emergency room with right back pain on July 10, 2009. At the emergency room, abdominal enhanced computed tomography revealed a cystic lesion in the retroperitoneum. Then he was referred to our department. We performed percutaneous drainage of the retroperitoneal lesion and aspirated white pus. The retroperitoneal cystic lesion proved to be an abscess. Microscopic examination of a Gram stained specimen of the abscess revealed gram-positive bacillary fragments ; therefore, we suspected the pathogen to be Nocardia. He had a history of chronic glomerulonephritis and had received treatment consisting of 20 mg prednisolone, and 75 mg cyclosporine per day. He was regularly visiting the department of cardiovascular for follow-up of chronic heart failure. On the day before his visit to our emergency room, his chest X-ray medicine had revealed a nodular shadow. Then he was referred to the department of respiratory medicine and was scheduled to receive a bronchoscopy later. We suspected the nodule of the lung also to be an abscess of Nocardia. Later, head computed tomography (CT) revealed a brain abscess the pathogen of which was Nocardia. Nocardia is a filamentous, gram-positive, branched bacterium and classified as an aerobic actinobacteria. Nocardia species are difficult to diagnose due to non-specific clinical and histological manifestation. We report this case of disseminated nocardiosis presenting as retroperitoneal abscess. The disseminated nocardiosis was diagnosed without delay by percutaneous drainage and appropriate treatment was provided. PMID- 21273809 TI - [A case of retroperitoneal well-differentiated liposarcoma with metaplastic bone formation]. AB - A 43-year-old female was referred to our hospital from a local doctor. Her chief complaints were weight gain and abdominal fullness. Computed tomography and magnetic resonance imaging showed a huge tumor in the right retroperitoneal space, which adhered to the right kidney. It was resected with concomitant resection of the right kidney. It measured 30*15 cm and weighed 3.0 kg. Histological examination revealed well differentiated liposarcoma with metaplastic bone formation. She has survived 22 months since the operation with no evidence of recurrence. A retoroperitoneal liposarcoma with metaplastic bone formation is rare. Twenty cases have been reported in Japan including our case. PMID- 21273810 TI - [Metastatic renal tumor originating from thyroid cancer: a case report]. AB - A 82-year-old female was referred to our department for close examination and treatment of a right renal tumor incidentally found by computed tomography. Her past history included partial thyroidectomy for follicular thyroid carcinoma 20 years earlier. Enhanced computed tomography showed a hypervascular mass with a diameter of 3 cm at the lower pole of the right kidney. We carried out radical nephrectomy for diagnosis of renal cell carcinoma. Pathological findings revealed a metastatic renal tumor of follicular thyroid carcinoma. It is rare to find metastatic renal tumors arising from thyroid carcinoma in clinical practice. Thirty cases have been reported in the Japanese literature. PMID- 21273811 TI - [A case of bladder paraganglioma managed by transurethral approach, using holmium laser]. AB - A 78-year-old man was referred to our hospital with a bladder tumor. He suffered from headaches and palpitations after voiding. Cystoscopy and MRI showed a submucosal bladder tumor which localized submucosally without invasion to the muscular layer. The tumor was positive for 131I-MIBG scintigraphy and we diagnosed it as a bladder paraganglioma. We enucleated the tumor en bloc from the bladder using holmium laser via transurethral approach, with minimal alteration of blood pressure during the procedure. The enucleated tumor was evacuated out of the bladder with a morcellator. PMID- 21273812 TI - [A case of prostatic abscess]. AB - A 53-year-old man presented with high fever and urinary retention. The patient had diabetes, and alcoholic liver cirrhosis. Clinical diagnosis was prostatic abscess by magnetic resonance imaging (MRI), and we performed anti-biotic therapy. Because there was no improvement of symptoms, we performed percutaneous cystostomy and transurethral resection (TUR) of the abscess walls. Drainage by TUR is suggested to be a useful strategy for prostatic abscess. PMID- 21273813 TI - [A case of segmental testicular infarction]. AB - A 39-year-old man presented with left scrotal pain which lasted for 3 days. The laboratory test showed slightly elevated C-reactive protein and lactate dehydrogenase whereas alpha-fetoprotein and beta-human chorionic gonadotropin were normal. Scrotal Doppler ultrasound test demonstrated an oval-shaped hypoechoic lesion and enhanced magnetic resonance imaging revealed an avascular lesion in the left testis with the rim enhancement. He underwent left high orchiectomy. The histopathological examination revealed segmental testicular infarction with partial necrosis. PMID- 21273814 TI - MassSQUIRM: An assay for quantitative measurement of lysine demethylase activity. AB - In eukaryotes, DNA is wrapped around proteins called histones and is condensed into chromatin. Post-translational modification of histones can result in changes in gene expression. One of the most well-studied histone modifications is the methylation of lysine 4 on histone H3 (H3K4). This residue can be mono-, di- or tri-methylated and these varying methylation states have been associated with different levels of gene expression. Understanding exactly what the purpose of these methylation states is, in terms of gene expression, has been a topic of much research in recent years. Enzymes that can add (methyltransferases) and remove (demethylases) these modifications are of particular interest. The first demethylase discovered, LSD1, is the most well-classified and has been implicated in contributing to human cancers and to DNA damage response pathways. Currently, there are limited methods for accurately studying the activity of demethylases in vitro or in vivo. In this work, we present MassSQUIRM (mass spectrometric quantitation using isotopic reductive methylation), a quantitative method for studying the activity of demethylases capable of removing mono- and di-methyl marks from lysine residues. We focus specifically on LSD1 due to its potential as a prime therapeutic target for human disease. This quantitative approach will enable better characterization of the activity of LSD1 and other chromatin modifying enzymes in vitro, in vivo or in response to inhibitors. PMID- 21273815 TI - Shedding light on Toll signaling through live imaging. AB - The Toll receptor propagates the ventralizing signal designating dorsal/ventral cell fate in the Drosophila embryo. The application of live-imaging approaches to this classical developmental signaling pathway is yielding some surprising new insights into Toll receptor signaling. In addition to its previously known plasma membrane localization, Toll is present in Rab5+ early endosomes. Dominant, constitutively active forms of Toll preferentially partition into endosomes. Blocking endocytosis locally prevents Toll from signaling suggesting that endocytosis is required for Toll to signal. Augmenting endocytosis increases Toll signaling. Both interventions alter the shape of the Dorsal gradient globally indicating an important role of endocytosis in fixing spatial information for the Dorsal gradient. PMID- 21273816 TI - A database for the analysis of immunity genes in Drosophila: PADMA database. AB - While microarray experiments generate voluminous data, discerning trends that support an existing or alternative paradigm is challenging. To synergize hypothesis building and testing, we designed the Pathogen Associated Drosophila MicroArray (PADMA) database for easy retrieval and comparison of microarray results from immunity-related experiments (www.padmadatabase.org). PADMA also allows biologists to upload their microarray-results and compare it with datasets housed within PADMA. We tested PADMA using a preliminary dataset from Ganaspis xanthopoda-infected fly larvae, and uncovered unexpected trends in gene expression, reshaping our hypothesis. Thus, the PADMA database will be a useful resource to fly researchers to evaluate, revise, and refine hypotheses. PMID- 21273840 TI - Serum sepsis, not sickness. AB - Rarely taught in medical schools, clinical reasoning is the ability to discern the important from the unimportant and to arrive at accurate and efficient clinical conclusions. Identifying errors in reasoning is difficult; however, undetected clinical reasoning errors can have exponential consequences. As quality and patient safety come into focus, identifying and preventing clinical reasoning errors have become imperative. The authors present a case of a man sent for admission from a subspecialty clinic diagnosed with infliximab-induced serum sickness. Not countering the expert's diagnosis, initial workup failed to diagnose joint abscess and sepsis. Heuristics are mental shortcuts used to make decision making more efficient but can lead to error. The anchoring heuristic, premature closure, confirmation bias and the blind obedience heuristic are examples. Introspective surveillance and interactive hypothesis testing defend against heuristics. The authors conclude by discussing 4 types of hypersensitivity reactions, serum sickness in particular, and the chimeric nature of infliximab. PMID- 21273841 TI - Undoing Flexner: the beginning of the end of academic medicine in America. PMID- 21273842 TI - Respiratory stress response: A Novel diagnostic method for detection of significant coronary artery disease from finger pulse wave analysis during brief respiratory exercise: RETRACTION. PMID- 21273893 TI - Early phase 2 inpatient rehabilitation after acute coronary syndrome treated with primary percutaneous coronary intervention: short- and long-term effects on blood pressure and metabolic parameters. AB - OBJECTIVE: The aim of this study was to assess the 1-yr follow-up effects of inpatient rehabilitation and its prolongation with an ambulatory training program on blood pressure and metabolic risk factors in patients after an acute coronary syndrome. DESIGN: A controlled (n = 20) prospective study was undertaken. The study group consisted of 54 consecutive patients participating in a 3-wk inpatient rehabilitation. Of these, 14 chose to continue the training for 3 mos (CR_In+Amb group) and 40 declined (CR_In group). RESULTS: Body mass index increased in the CR_In and control groups. The magnitude of change was greater in controls (2.2 +/- 2.14 vs. 0.7 +/- 1.70 kg/m; P < 0.05). Waist circumference increased only in the control group, and at 12 mos, it was higher than in the CR_In and CR_In+Amb groups (P < 0.05). Mean systolic and diastolic blood pressure increased in the CR_In (from 121/76 to 130/82 mm Hg; P < 0.01) and control (from 122/74 to 139/87 mm Hg; P < 0.01) groups. At 12 mos, blood pressure in the CR_In group was lower than in the control group but higher than in the CR_In+Amb group (119/77 mm Hg; P < 0.05). Total cholesterol, low-density lipoprotein cholesterol level, and triglyceride level at 12 mos were higher in the control group than in the CR_In and CR_In+Amb groups (P < 0.05). C-reactive protein decreased in the CR_In and CR_In+Amb groups (P < 0.01). CONCLUSIONS: Inpatient rehabilitation was associated with beneficial effects on blood lipids and C-reactive protein in coronary patients and attenuated the rise in blood pressure and adiposity indices observed in nonparticipants. Prolongation of rehabilitation with an ambulatory program improved blood pressure control. PMID- 21273894 TI - Survey results of pain treatments in adults with cerebral palsy. AB - OBJECTIVE: The aims of this study were to identify the types and frequencies of pain treatments used by individuals with cerebral palsy, examine the perceived effectiveness of these treatments, and identify the types of healthcare providers that were accessed for pain-related services. DESIGN: A cross-sectional survey design was used. A total of 83 adults (mean [SD] age, 40.3 [13.6] yrs) with cerebral palsy indicated their pain location and intensity during the past 3 mos. Next, they indicated their use of 24 different pain treatments and the effectiveness of each. Finally, participants indicated the frequency of pain related healthcare visits to specific providers over the past 6 mos. RESULTS: Of the participants, 63% reported experiencing chronic pain and rated their pain intensity over the past week as 5.1 of 10, on average. The most common pain locations were the lower back, hips, and legs. Physical interventions (e.g., physical therapy, strengthening) were the most common pain treatments reportedly used and were rated as moderately effective. Many other treatments were also used, and participants sought pain-related care from a variety of providers. CONCLUSIONS: Although participants reportedly accessed pain care from a variety of providers and perceived that several types of treatments were effective, many of the treatments rated as effective were rarely used or provided. Future research using clinical trial methods would further elucidate the specific pain treatments that are most beneficial for adults with cerebral palsy. PMID- 21273895 TI - Inpatient rehabilitation improved functional status in asthenic patients with solid and hematologic malignancies. AB - OBJECTIVE: The aim of this study was to compare functional outcomes in asthenic patients with hematologic malignancies with those of asthenic patients with solid tumors after inpatient rehabilitation. We hypothesized that asthenic patients with hematologic malignancies are less likely than patients with solid tumors to make functional improvement after rehabilitation. DESIGN: The records of 60 asthenic cancer patients (30 consecutive patients with solid tumors and 30 consecutive patients with hematologic malignancies) who underwent inpatient rehabilitation at a comprehensive cancer center between October 2005 and October 2007 were retrospectively reviewed. Patients with focal neurologic deficits were excluded. All patients admitted to the inpatient rehabilitation unit received 3 hrs of more of therapy per weekday. The main outcomes included total, motor, and cognitive Functional Independence Measure (FIM) scores, hospital and rehabilitation length of stay, and FIM efficiency. RESULTS: The mean total FIM score significantly improved in patients with solid tumors (mean, 15; range, -6 to 38) and in patients with hematologic malignancies (mean, 17; range, -3 to 27); however, between-group differences in FIM scores were not significant (P = 0.31). The solid tumor patients were significantly older than the hematologic malignancy patients (71 +/- 11 vs. 64 +/- 12 yrs; P = 0.02), but the mean rehabilitation lengths of stay were the same for each group (9.5 days; P = 0.82). The mean FIM efficiency in the hematologic malignancy group was higher than that of the solid tumor group (1.9 vs.1.4; P = 0.049). CONCLUSIONS: Asthenic patients with solid tumors or hematologic malignancies could benefit from inpatient rehabilitation and make significant functional gain. PMID- 21273896 TI - Spondyloepiphyseal dysplasia tarda with progressive arthropathy complicated with paraplegia. AB - Spondyloepiphyseal dysplasia tarda with progressive arthropathy is characterized by short stature resulting from platyspondylia and progressive arthropathy. This disorder may cause a predisposition to disk herniations, which may rarely lead to spastic paraplegia. We report a 21-yr-old male patient with spondyloepiphyseal dysplasia tarda with progressive arthropathy who developed spastic paraplegia because of spinal stenosis caused by thoracic disk herniations. PMID- 21273897 TI - Effect of vibration treatment on symptoms associated with eccentric exercise induced muscle damage. AB - OBJECTIVE: : The aim of this study was to test the hypothesis that vibration treatment reduces delayed-onset muscle soreness and swelling and enhances recovery of muscle function after eccentric exercise. DESIGN: : A randomized crossover design was used. Fifteen young men performed ten sets of six maximal eccentric contractions of the elbow flexors with the right arm for one occasion and the left arm for the other occasion separated by 4 wks. One arm received a 30 min vibration treatment at 30 mins after and 1, 2, 3, and 4 days after the exercise (treatment group), and the other arm did not receive any treatment (control group). The order of the treatment and control conditions and the use of the dominant and nondominant arms were counterbalanced among subjects. Changes in indirect markers of muscle damage were compared between arms by a two-way repeated-measures analysis of variance. RESULTS: : Compared with the control group, the treatment group showed significantly (P < 0.05) less development and faster reduction in delayed-onset muscle soreness at 2 to 5 days after exercise. The recovery of range of motion was significantly (P < 0.05) faster for the treatment than for the control group. However, no significant effects on the recovery of muscle strength and serum creatine kinase activity were evident. Immediately after the vibration treatment, a significant (P < 0.05) decrease in the magnitude of delayed-onset muscle soreness and muscle strength and an increase in pressure pain threshold and range of motion were found. CONCLUSIONS: : These results showed that the vibration treatment was effective for attenuation of delayed-onset muscle soreness and recovery of range of motion after strenuous eccentric exercise but did not affect swelling, recovery of muscle strength, and serum creatine kinase activity. PMID- 21273898 TI - Exercise paradigms to study brain injury recovery in rodents. AB - Exercise has been found to influence molecular systems important for maintaining neural function and plasticity as well as treatment of neurologic disorders. The stimuli required to elicit plasticity are thought to be activity dependent. Several protocols of physical exercise have been used to explore its effects on brain function. However, it is becoming increasingly recognized that no single physical exercise model is likely to fulfill all therapeutic needs. Varied interpretations of data derived from animal models have given rise to the lack of uniformity in the description and control of various features of the physical exercise stimulus, ranging from low to high intensity, intermittent to sustained, short to long durations, and different modes of activity. This article first describes the characteristics of the most frequently used animal models and goes on to review brain plasticity in intact animals and the usefulness of these models for the study of brain disorders. In this regard, animal models that investigate the beneficial effects of exercise on the brain before and after brain injury are discussed. A challenge for future studies is to better evaluate the usefulness of physical exercise protocols for preventing or treating brain disorders. PMID- 21273899 TI - Vitamin d deficiency-induced vertebral fractures may cause stooped posture in Parkinson disease. AB - OBJECTIVE: To determine the pathogenesis of the stooped posture in Parkinson disease (PD), we prospectively studied fractures in a cohort of patients with Parkinson disease for 5 yrs. DESIGN: At baseline, we recorded the dietary intake of vitamin D and serum concentrations of parathyroid hormone and 25 hydroxyvitamin D. Bone mineral density and lateral thoracic and lumbar spine radiographs were obtained at baseline and every year for 5 yrs. RESULTS: During the 5-yr study period, stooped posture developed in 34 patients; the rest of the 58 patients did not show stooped posture. At baseline, mean serum 25 hydroxyvitamin D and parathyroid hormone levels were 10.9 ng/ml and 73.1 pg/ml, respectively, in the stooped group and 18.6 ng/ml and 56.4 pg/ml, respectively, in the nonstooped group. Bone mineral density in the stooped group was significantly lower than in the nonstooped group. Dietary intake of vitamin D in the stooped group was significantly lower than in the nonstooped group. During the study period, 19 (22%) patients in the nonstooped group developed new vertebral fracture, compared with 23 (100%) patients in the stooped group. The mean +/- SD percentage changes in bone mineral density were -6.5 +/- 0.6 in the stooped group and -3.8 +/- 0.8 in the nonstooped group. Mean serum levels of 25 hydroxyvitamin D after 5 yrs were 7.0 ng/ml in the stooped group and 14.1 ng/ml in the nonstooped group. CONCLUSIONS: Stooped posture in Parkinson disease may be caused by vertebral fractures resulting from vitamin D deficiency with compensatory hyperparathyroidism. Vitamin D supplementation may reduce stooped posture in patients with Parkinson disease. PMID- 21273900 TI - The effectiveness of triamcinolone acetonide vs. procaine hydrochloride injection in the management of carpal tunnel syndrome: a double-blind randomized clinical trial. AB - OBJECTIVE: Corticosteroid injection into the carpal tunnel is frequently used for the treatment of carpal tunnel syndrome (CTS). Steroids are usually mixed with local anesthetics, which have positive effects that can aid the treatment of CTS by inhibiting the spontaneous discharge ability of excitable cells. The aim of this study was 3-fold: (1) to determine the efficacy of triamcinolone acetonide injection in the treatment of CTS, (2) to determine the efficacy of procaine hydrochloride (HCl) in the treatment of CTS, and (3) to compare the efficacy of triamcinolone acetonide and that of procaine HCl in the treatment of CTS. DESIGN: This prospective, randomized, double-blind clinical trial included 99 patients (120 median nerves) with clinical and electrophysiologic evidence of CTS. The 120 median nerves were randomly assigned to one of three groups: group 1 received 40 mg of triamcinolone acetonide, group 2 received 4 ml of 1% procaine HCl, and group 3 received both 40 mg of triamcinolone acetonide and 4 ml of 1% procaine HCl. Clinical and electrophysiologic evaluations were performed at the study onset and at 2 and 6 mos after treatment. RESULTS: At the study onset, there were no statistically significant differences between the groups with respect to distal motor latency, compound motor action potential, compound sensory action potential, sensory nerve conduction velocity, or visual analog scale score; however, distal motor latency, compound sensory action potential amplitude, sensory nerve conduction velocity, and visual analog scale scores improved significantly in each group 2 mos after treatment (P < 0.05), and these improvements persisted at 6 mos after treatment (P < 0.05). Significant differences were not observed between groups 1 and 2 or between groups 1 and 3 with respect to electrophysiologic findings at baseline or 2 or 6 mos after treatment (P > 0.05). Group 3 had better compound sensory action potential amplitude and sensory nerve conduction velocity scores than group 2 did at 6 mos (P < 0.05) and better visual analog scale scores than group 2 did at 2 and 6 mos (P < 0.05). CONCLUSIONS: Local procaine HCl injection and steroid injection effectively reduced the symptoms of CTS and equally improved electrophysiologic findings. As such, procaine HCl can be used in CTS patients in whom steroid use is contraindicated. PMID- 21273901 TI - A wheelchair workshop for medical students improves knowledge and skills: a randomized controlled trial. AB - OBJECTIVE: To test the hypothesis that a multicomponent workshop about wheelchairs, tailored for undergraduate medical students, is effective in improving medical students' wheelchair-related knowledge, skills, and attitudes. DESIGN: A randomized controlled trial of 24 first- and second-year medical students randomly allocated into intervention and control groups was undertaken. The intervention group received a 4-hr workshop that included didactic, practical, community, and reflective elements. The educational objectives were validated by a focus group. The main outcome measures were a written knowledge test, a practical examination, the Scale of Attitudes Toward Disabled Persons, and students' perceptions. RESULTS: The baseline characteristics of the groups were comparable. After the workshop, the mean scores on the written knowledge test and practical examination for the intervention group were higher than for the control group by 23.9% (95% confidence interval, 17.6%-30.3%; P < 0.0001) and 34.4% (95% confidence interval, 26.3%-42.5%; P < 0.0001), respectively. The difference (-1.6%) for the Scale of Attitudes Toward Disabled Persons scores was not significant (P = 0.93), but there may have been a ceiling effect (both groups' mean scores were >87%). The perceptions of the students who took the workshop were highly positive. CONCLUSIONS: A wheelchair workshop designed for medical students was practical, well received by students, and effective at improving students' knowledge and skills. Although students' attitudes were not measurably affected by the intervention, there was qualitative evidence of a positive effect. PMID- 21273902 TI - Efficacy of knee braces and foot orthoses in conservative management of knee osteoarthritis: a systematic review. AB - A systematic analysis was conducted on the effectiveness of knee braces and foot orthoses in conservative management of knee osteoarthritis. The methodologic quality of the randomized clinical trials, controlled clinical trials, and observational studies were systematically reviewed using the Structured Effectiveness Quality Evaluation Scale. Twenty-five studies met the inclusion criteria. The orthoses used in the studies included Generation II osteoarthritis knee brace, valgus knee braces, functional off-loading knee braces, knee sleeves, lateral-wedged insoles with subtalar strapping, medial-wedged insoles, and specialized footwear. Results suggest that knee braces and foot orthoses are effective in decreasing pain, joint stiffness, and drug dosage. They also improve proprioception, balance, Kellgren/Lawrence grading, and physical function scores in subjects with varus and valgus knee osteoarthritis. Knee braces and foot orthoses could be cautiously considered as conservative management for relief of pain and stiffness and improving physical function for persons with knee osteoarthritis. The conclusions of this review are limited by methodologic considerations like poor quality of trials and heterogeneity of interventions. PMID- 21273903 TI - Efficacy of a midcurricular examination for predicting nursing student academic success. AB - The purpose of this study was to investigate the usefulness of the HESI midcurricular examination in identifying at-risk students earlier in their nursing career. This study used quantitative measures to examine the relationship between the HESI midcurricular examination and the student's success in the nursing program and their performance on the HESI-E2 and the NCLEX-RN. In logistic regression models, the score attained on the HESI midcurricular examination was a significant predictor of academic and NCLEX-RN success, with significant differences in scores between those who were and were not successful. Statistically significant correlations were found between the HESI midcurricular examination score and the score on the HESI-E2 and their performance in the capstone nursing courses. An analysis of the data supported the belief that the HESI midcurricular examination was a useful predictive tool that can identify students at risk for nonsuccess prior to the senior year of nursing so that measures to ensure success can be implemented. PMID- 21273904 TI - Triaging women with acute coronary syndrome: a review of the literature. AB - AIMS AND OBJECTIVES: This article analyzes the literature describing factors affecting nurses' triage of emergency department (ED) patients with potential acute coronary syndrome (ACS), with particular attention paid to gender-based differences. INTRODUCTION: Acute coronary syndrome is one of the most time critical conditions requiring ED nurse triage. This literature review will provide examination of how triage nurses prioritize patients with possible ACS, reflecting on challenges specifically associated with evaluating women for ACS in the ED. The article presents a description of the research findings that may help improve the timely revascularization of ACS in women. METHODS: An electronic search of EBSCOhost CINAHL, Health Source Nursing Academic Edition, MEDLINE, Psychology and Behavioral Sciences Collection databases, online theses, the Cochrane Library, the Joanna Briggs Institute, and National Guideline Clearinghouse resources were used to identify all relevant scientific articles published between 1990 and 2010. Google and Google Scholar search engines were used to undertake a broader search of the World Wide Web to improve completeness of the search. This search technique was augmented by hand searching these articles' reference lists for publications missed during the primary search. RESULTS: : Review of the literature suggests factors such as patient age, sex, and symptoms at ED presentation affect the accuracy of nurses' triage of ACS, particularly for women. However, research examining delays due to ED triage is scant and has predominantly been undertaken by one researcher. Little research has examined triage of ACS specifically in women. CONCLUSIONS: The literature search revealed a small number of articles describing challenges associated with nurse triage of women with ACS. Although most of this published research is North American, the themes uncovered are well supported by broader international research on acute assessment and management of women's ACS. These include the following: gender-based differences in the presentation of ACS can preclude early identification of ACS, advanced patient age often correlates with missed or delayed diagnosis of ACS, and there appears to be a general bias against managing women for ACS in parity with men's disease. RELEVANCE TO PRACTICE: : Early reperfusion therapy is critical for optimal health outcomes in ACS. Triage nurses are ideally placed to minimize time to treatment for ACS. An understanding of the issues related to clinical decision making and triage allocation of women with ACS at triage is necessary to ensure appropriate treatment. PMID- 21273905 TI - Bridging the gap between hospital and home: a new model of care for reducing readmission rates in chronic heart failure. AB - Advanced cardiovascular interventions and an aging population contribute to the growing prevalence of patients with heart failure (HF). Improved medical management, while decreasing mortality, has increased morbidity and cost, with a majority of expense related to preventable hospitalizations. Evidence-based guidelines for discharge instruction, when successfully administered, reduce readmission rates in high-risk HF patients, leading to improved quality of life and economic savings. Unfortunately, effective delivery is complex and time consuming, placing a high demand on already overworked bedside nurses. Failure to provide complete discharge instructions results in nonadherence to treatment regimens and lack of essential follow-up, the most commonly identified reasons for acute HF exacerbations and readmissions. To improve quality of care, hospitals need to adopt a new model that incorporates delivery of intensive, 1-on 1 education to high-risk HF patients during the hospital stay with continuing support, guidance, and education throughout the transition from hospital to home. This can be achieved through implementation of a 2-tiered model that incorporates a risk-assessment tool with utilization of a HF nurse educator. The simple, evidence-based bedside screening tool will allow medical-surgical nurses to quickly identify and refer HF patients at high risk of readmission to a HF nurse educator. With an advanced degree and specialized training, the nurse educator is responsible for providing in-depth discharge teaching and bridging the gap from hospital to home. The end result is improved self-management, increased quality of life, reduced hospital admissions, and an associated decrease in societal costs of HF. PMID- 21273906 TI - Mechanical scale and load cell underwater weighing: a comparison of simultaneous measurements and the reliability of methods. AB - Both load cell and mechanical scale-based hydrostatic weighing (HW) systems are used for the measurement of underwater weight. However, there has been no direct comparison of the 2 methods. The purpose of the current investigation was to simultaneously compare a load cell and mechanical scale for use in HW. Twenty seven men and women (mean +/- SD, age: 22 +/- 2 years) participated in the 2-day investigation. Each subject completed 2 HW assessments 24 hours apart. Single-day comparisons of all trials for both days revealed no significant difference between the mechanical scale and the load cell (mean difference < 0.016 kg, p > 0.05). True underwater weight values were not significantly different between methods for either days (mean difference < 0.014 kg, p > 0.05) and accounted for a mean difference in percent fat (%FAT) of <0.108%. The 95% limits of agreement indicated a maximum difference between methods of 0.53% FAT. Both methods produced similar reliability SEM values (mechanical SEM < 0.72%FAT, load cell SEM < 0.75%FAT). In conclusion, there was no difference between mechanical scale and load cell measurements of underwater weights and the added precision of the load cell only marginally (<0.16%FAT) improved day-to-day reliability. Either a mechanical scale or load cell can be used for HW with similar accuracy and reliability in young adults with a body mass index of 18.7-34.4 (5-25%FAT). PMID- 21273907 TI - Comparison of player movement patterns between 1-day and test cricket. AB - Physical demands of cricket presumably vary by both game format and performance level. Differences in player movement patterns between 2 game formats (1 day and multiday) and 2 levels of elite performance (state and international) were quantified with global positioning system technology. Five movement categories were established, and 15 movement pattern variables were reported. Data from state (n = 42, 200 files) and international (n = 12, 63 files) cricketers were scaled to hourly values to compare movement demands. Cricketers generally covered similar distances in both formats, except for state 1-day fielders who covered moderately greater distance (~0.7 km.h-1 more; 21 +/- 8%; mean +/- 90% confidence interval) than state multiday (first-class) fielders. State 1-day cricketers also covered small to moderately greater distances (running 41 +/- 13%; striding 38 +/ 16%; sprinting 39 +/- 36%) in the faster movement patterns and consequently had moderately less recovery time (13-67%) between high-intensity efforts as first class cricketers. Comparisons of movements between performance levels revealed similar total distances between state and international cricketers. However, Test fielders covered moderately greater (29-48%) distances at the higher-intensity movement patterns (running, striding, and sprinting) than first-class fielders. In summary, although movement patterns were broadly similar between formats and levels, it appears that one day cricket (compared with multiday games) and test matches (compared with state-level competition) require more higher-intensity running. Conditioning coaches should train state and international 1-day cricket players similarly, but should account for the higher physical demands of international multiday cricket. PMID- 21273908 TI - Parasympathetic nervous activity mirrors recovery status in weightlifting performance after training. AB - Heart rate variability (HRV) and parasympathetic power are closely related to the well-being and health status in humans. The main goal of the study was to determine whether these measures can reflect recovery status after weight training. After a 10-day detraining period, 7 weightlifters were challenged with a 2-hour weight training which elicited approximately fourfold increases in circulating muscle creatine kinase level and protracted pain feeling (p < 0.05). Weightlifting performance was then evaluated 3, 24, 48, and 72 hours after training to determine the degree of recovery from fatigue. Heart rate variability, circulating dehydroepiandrostendione sulfate (DHEA-S), and muscle damage markers were measured before each performance test. An electrocardiogram was recorded for 5 minutes continuously at rest in seated positions. After training, weightlifting performance of the subjects decreased below baseline in paralleled with suppressed parasympathetic power (high-frequency [HF] HRV), whereas sympathetic power (normalized low-frequency HRV) was slightly elevated at 3 hours of recovery (p < 0.05). Both weightlifting performances and parasympathetic power returned to baseline values in 24 hours and further increased above baseline during 48-72 hours of recovery in a similar fashion (p < 0.05). Circulating DHEA-S level dropped at 24 hours (p < 0.05) and returned to normal values by 48 hours. Muscle pain increased at 3 hours after training and remained higher than baseline values for the 72-hour recovery period (p < 0.05). Our data suggest that parasympathetic power, indicated by HF HRV, is able to reflect the recovery status of weightlifters after training. PMID- 21273909 TI - Sling exercise and traditional warm-up have similar effects on the velocity and accuracy of throwing. AB - Throwing is a complex motion that involves the entire body and often puts an inordinate amount of stress on the shoulder and the arm. Warm-up prepares the body for work and can enhance performance. Sling-based exercise (SE) has been theorized to activate muscles, particularly the stabilizers, in a manner beneficial for preactivity warm-up, yet this hypothesis has not been tested. Our purpose was to determine if a warm-up using SE would increase throwing velocity and accuracy compared to a traditional, thrower's 10 warm-up program. Division I baseball players (nonpitchers) (16 men, age: 19.6 +/- 1.3, height: 184.2 +/- 6.2 cm, mass: 76.9 +/- 19.2 kg) volunteered to participate in this crossover study. All subjects underwent both a warm-up routine using a traditional method (Thrower's 10 exercises) and a warm-up routine using closed kinetic chain SE methods (RedCord) on different days separated by 72 hours. Ball velocity and accuracy measures were obtained on 10 throws after either the traditional and SE warm-up regimens. Velocity was recorded using a standard Juggs radar gun (JUGS; Tualatin, OR, USA). Accuracy was recorded using a custom accuracy target. An Analysis of covariance was performed, with the number of throws recorded before the testing was used as a covariate and p < 0.05 was set a priori. There were no statistical differences between the SE warm-up and Thrower's 10 warm-up for throwing velocity (SE: 74.7 +/- 7.5 mph, Thrower's 10: 74.6 +/- 7.3 mph p = 0.874) or accuracy (SE: 115.6 +/- 53.7 cm, Thrower's 10: 91.8 +/- 55 cm, p = 0.136). Warming up with SE produced equivalent throwing velocity and accuracy compared to the Thrower's 10 warm-up method. Thus, SE provides an alternative to traditional warm-up. PMID- 21273910 TI - Cardiorespiratory and metabolic alterations during exercise and passive recovery after three modes of exercise. AB - The objective of this study was to investigate the potential variations in cardiorespiratory and metabolic parameters and running performance among 3 modes of exercise of the same duration, namely, intermittent running with active recovery (AR) or passive recovery (PR) and continuous running (CR) and whether these variations could affect passive recovery time (PRT). Fifteen male physical education students with a subspecialty in soccer were studied (mean age 22.3 +/- 2.5 years, training experience 12.3 +/- 2.5 years) in the middle of the playing season. The results showed that during exercise, the highest heart rate (HR) and VO2 values were observed in CR, whereas the lowest values in PR followed by AR. Blood lactate (BLa) concentration was higher in PR by 38% compared to that in AR (p < 0.05). The exercise duration was similar between PR and AR tests and longer than in CR. With regard to PRT, the highest HR (186 +/- 9 b . min(-1)), VO2 (55.5 +/- 5.2 ml . kg(-1) . min(-1)), and BLa (5.1 +/- 1.7 mmol . L(-1)) values were found in CR. No differences in HR and VO2 between PR and AR were detected. However, despite the differences in BLa concentration between AR and PR during exercise, the PRT BLa values between these 2 exercise modes were not different. Among the 3 running protocols, only CR appeared to have fully challenged the cardiorespiratory system inducing maximal HR and VO2 responses during exercise and high BLa values in PRT, yet these responses were not associated with better exercise performance compared to intermittent running. Therefore, intermittent exercise, regardless of implementing passive or active interval, might be the preferable exercise mode particularly in activities extended over 30 minutes. PMID- 21273911 TI - Seasonal changes in jump performance and body composition in women volleyball players. AB - The present study aimed to evaluate the effects of different resistance training programs on jump performance and body composition of female volleyball players of the highest Spanish division league over 24 weeks of training. Ten female volleyball players (27.41 +/- 4.94 years; 72.2 +/- 8.5 kg; 179.7 +/- 6.4 cm) completed 24 weeks of training and testing using a linear periodization, progressing from general conditioning (weeks 1-4), to hypertrophy (weeks 5-8), then to maximum strength and power (weeks 9-16) and concluding with a specific strength training (weeks 17-24). Body composition was measured using bioelectrical-impedance analysis, and neuromuscular capacity was estimated by squat jump, countermovement jump, Abalakov jump, and 2 repetition maxima (2RM). After initial evaluation (PRE), the players were tested on 3 different occasions (POST: fourth week, POST 1: eighth week and POST 2: 24th week) of the training cycle. Muscle mass increased on (4.5%, p < 0.05) and fat-free mass (4.38%, p < 0.05), whereas fat percent decreased (13.90%, p < 0.05). All neuromuscular performance tests were increased from PRE to POST 2 (ranging from 17.64 to 20.89%, p < 0.01) and from POST 1 to POST 2 (ranging from 4.62 to 7.56% p < 0.01). The results suggest that the volleyball players studied continued improving power and strength capacity together with body composition during the course of the study. Finally, as major application, these data provide normative and performance standards for female volleyball players. PMID- 21273912 TI - The effects of circadian rhythmicity of salivary cortisol and testosterone on maximal isometric force, maximal dynamic force, and power output. AB - The study investigated the effects of circadian rhythm of cortisol (C) and testosterone (T) on maximal force production (Fpeak) and power output (Ppeak). Twenty male university students (mean age = 23.8 +/- 3.6 years, height = 177.5 +/ 6.4 cm, weight = 78.9 +/- 11.2 kg) performed 4 time-of-day testing sessions consisting of countermovement jumps (CMJs), squat jumps (SJ), isometric midthigh pulls (IMTPs), and a 1-repetition maximum (1RM) squat. Saliva samples were collected at 0800, 1200, 1600, and 2000 hours to assess T and C levels on each testing day. Session rate-of-perceived exertion (RPE) scores were collected after each session. The results showed that Fpeak and Ppeak presented a clear circadian rhythm in CMJ and IMTP but not in SJ. One repetition maximum squat did not display a clear circadian rhythm. Session RPE scores collected at 0800 and 2000 hours were significantly (p <= 0.05) higher than those obtained at 1200 and 1600 hours. Salivary T and C displayed a clear circadian rhythm with highest values at 0800 hours and lowest at 2000 hours; however, no significant correlation was found between T and C with Fpeak and Ppeak. A very strong correlation was found between Taural with Fpeak of CMJ and IMTP and Ppeak of CMJ (r = 0.86, r = 0.84 and r = 0.8, p <= 0.001). The study showed the existence of a circadian rhythm in Fpeak and Ppeak in CMJ and IMTP. The evidence suggests that strength and power training or testing should be scheduled later during the day. The use of Taural seemed to be a more effective indicator of physical performance than hormonal measures, and the use of session RPE should also be closely monitored because it may present a circadian rhythm. PMID- 21273913 TI - Effects of aging and training status on ventilatory response during incremental cycling exercise. AB - The aim of this study was to examine the effect of aging and training status on ventilatory response during incremental cycling exercise. Eight young (24 +/- 5 years) and 8 older (64 +/- 3 years) competitive cyclists together with 8 young (27 +/- 4 years) and 8 older (63 +/- 2 years) untrained individuals underwent a continuous incremental cycling test to exhaustion to determine ventilatory threshold (VT), respiratory compensation point (RCP), and maximal oxygen uptake (VO2max). In addition, the isocapnic buffering (IB) phase was calculated together with the hypocapnic hyperventilation. Ventilatory threshold occurred at similar relative exercise intensities in all groups, whereas RCP was recorded at higher intensities in young and older cyclists compared to the untrained subjects. The IB phase, reported as the difference between VT and RCP and expressed either in absolute (ml.min-1.kg-1 VO2) or in relative terms, was greater (p < 0.01) in both young and older trained cyclists than in untrained subjects, who were also characterized by a lower exercise capacity. Isocapnic buffering was particularly small in the older untrained volunteers. Although young untrained and older trained subjects had a similar level of VO2max, older athletes exhibited a larger IB. In addition, a higher absolute but similar relative IB was observed in young vs. older cyclists, despite a higher VO2max in the former. In conclusion, the present study shows that aging is associated with a reduction of the IB phase recorded during an incremental exercise test. Moreover, endurance training induces adaptations that result in an enlargement of the IB phase independent of age. This information can be used for the characterization and monitoring of the physiological adaptations induced by endurance training. PMID- 21273914 TI - Upward squatting in individuals with and without patellofemoral pain syndrome: a biomechanical study. AB - The purpose of the study was to test the hypothesis on whether individuals with patellofemoral pain syndrome (PFPS) try to avoid knee position during upward squatting so as not to aggravate this syndrome. Also, we tested whether PFPS would generate changes in the kinetic and electromyographic (EMG) strategies used to perform this task. Eight healthy subjects and 8 subjects with PFPS, but without a history of pain for at least 30 days, took part in the experiment. They were asked to perform upward squatting with knees initially flexed at 60 degrees (very flexed) until reaching an upright position. Angle, velocity, and acceleration (kinematic) were reconstructed for knee and ankle joints. The torques at these joints were calculated using inverse dynamics, taking into account anthropometric and inertial characteristics of each subject, including records from force data. Only activities of major muscles were recorded. The kinetic and EMG profiles were quantified during acceleration and deceleration phases of the upward squatting. Both healthy and PFPS subjects used the same kinetic and EMG strategies to perform the upward squatting, even though the magnitude of the muscle activities were decreased for the latter group. Compared to the control group, the PFPS subjects presented larger joint ankle torques and smaller knee joint torques. However, the subjects avoided keeping their knees very flexed at the initial position. Group differences in the kinetic and EMG strategies can be explained by differences in the initial position, suggesting a protective strategy used by subjects with PFPS. Therefore, for these subjects, coaches and therapists should avoid using this exercise when the knee is required to move above 40 degrees flexion. PMID- 21273915 TI - Comparison of training and game demands of national level cricketers. AB - Although the physiological demands of cricket match play are emerging, the demands of contemporary training practices have not been reported. The aim of this study was to quantify the physiological demands of selected cricket training activities and compare these to known match demands. Twenty-eight different training activities were monitored in national academy level cricketers (n = 42) using global positioning system units during a 14-week residential training program. The training activities were classified into 3 categories: conditioning sessions (n = 8), skill sessions (n = 9), and game simulations (n = 11). Conditioning sessions were further classified into high- (n = 4) and low- (n = 4) intensity drills. Time-motion measures included movement patterns (walk, jog, run, stride, and sprint distances), total distance covered, number of sprints, number of high-intensity efforts, maximum speed, and recovery time between high intensity efforts. Inferential statistics were used to quantify magnitudes of difference between various training drills. Movement patterns were then compared to recently published game data (Twenty20, One-Day, and Multiday games) from the same sample group of cricketers. Conditioning drills were twice as long in duration as skill drills and twice as intense as both the skill and game simulation drills. Exercising heart rates were 9-26% and lactate levels up to 3.5 times higher in conditioning compared to other training drills. Conditioning drills matched or exceeded (up to 10 b.min-1; 5%) peak game heart rates. Conversely, skill and simulation drills replicated mean game heart rates for some, but not all positions. In conclusion, training replicates or exceeds cricket match demands in conditioning-type drills but not in simulation or skill based drills. Modification of skill and simulation training drill practices will ensure closer replication of match and training demands. PMID- 21273916 TI - Pacing patterns in competitive rowing adopted in different race categories. AB - Data from 7 World Rowing Championships between 2001 and 2009 were analyzed to determine the time distribution during 2,000-m heavyweight races (from 500-m quarter times) and to assess whether pacing patterns differ between boat classes (single vs. team boats) and qualifying rounds (heats vs. finals). Analyses of variance with repeated measures on quarter times revealed that pacing patterns in heat races were better described (i.e., higher amount of variance explained) by a linear trend line with a positive slope (women: eta2 = 0.76, men: eta2 = 0.68) but followed a quadratic trend line (parabolic-shaped pattern) during finals (women: eta2 = 0.81, men: eta2 = 0.60). Not using a spurt at the end of the heat races may indicate an attempt to conserve energy for subsequent rounds or reflect reduced effort made by losing crews or both aspects. In single boats, the pacing pattern was better represented by a linear trend line with a positive slope (women: eta2 = 0.76, men: eta2 = 0.68), but the amount of variance explained was virtually the same for both the linear and the quadratic trend component in team boats. The absence of a final spurt in single boat races suggests that the physiological status of the athlete plays an important role to control the timing and rate of decline in rowing speed. PMID- 21273917 TI - Muscle-damaging exercise affects isokinetic torque more at short muscle length. AB - The aim of this study was to investigate the differences in the length-dependent changes in quadriceps muscle torque during voluntary isometric and isokinetic contractions performed after severe muscle-damaging exercise. Thirteen physically active men (age = 23.8 +/- 3.2 years, body weight = 77.2 +/- 4.5 kg) performed stretch-shortening cycle (SSC) exercise comprising 100 drop jumps with 30-second intervals between each jump. Changes in the voluntary and electrically evoked torque in concentric and isometric conditions at different muscle lengths, muscle soreness, and plasma creatine kinase (CK) activity were assessed within 72 hours after SSC exercise. Isokinetic knee extension torque decreased significantly (p < 0.05) at all joint angles after SSC exercise. At 2 minutes and at 72 hours after SSC exercise, the changes in knee torque were significantly smaller at 80 degrees (where 180 degrees = full knee extension) than at 110-130 degrees . At 2 minutes after SSC exercise, the optimal angle for isokinetic knee extension torque shifted by 9.5 +/- 8.9 degrees to a longer muscle length (p < 0.05). Electrically induced torque at low-frequency (20-Hz) stimulation decreased significantly more at a knee joint angle of 130 degrees than at 90 degrees . The subjects felt acute muscle pain and CK activity in the blood increased to 1,593.9 +/- 536.2 IU.L-1 within 72 hours after SSC exercise (p < 0.05). This study demonstrates that the effect of muscle-damaging exercise on isokinetic torque is greatest for contractions at short muscle lengths. These findings have practical importance because the movements in most physical activities are dynamic in nature, and the decrease in torque at various points in the range of motion during exercise might affect overall performance. PMID- 21273918 TI - Stereotactic radiosurgery of cranial nonvestibular schwannomas: results of single and multisession radiosurgery. AB - BACKGROUND: Surgical resection of nonvestibular cranial schwannomas carries a considerable risk of postoperative complications. Stereotactic radiosurgery (SRS) offers a non-invasive treatment alternative. The efficacy and safety of multi session SRS of nonvestibular cranial schwannomas has not been well studied. OBJECTIVE: To analyze the results of single- and multi-session SRS of nonvestibular cranial schwannomas. METHODS: From 2001 to 2007, 42 lesions in 40 patients were treated with SRS at Stanford University Medical Center, targeting schwannomas of cranial nerves IV (n = 1), V (n = 18), VII (n = 6), X (n = 5), XII (n = 2), jugular foramen (n = 8), and cavernous sinus (n = 2). SRS was delivered to a median marginal dose of 18 Gy (range, 15-33 Gy) in 1 to 3 sessions, targeting a median tumor volume of 3.2 cm (range, 0.1-23.7 cm). The median doses for treatments in 1 (n = 18), 2 (n = 9), and 3 (n = 15) sessions were 17.5, 20, and 18 Gy, respectively. RESULTS: With a median follow-up of 29 months (range, 6 84 months), tumor control was achieved in 41 of the 42 lesions. Eighteen of 42 lesions (43%) decreased in size; 23 tumors (55%) remained stable. There were 2 cases of new or worsening cranial nerve deficits in patients treated in single session; no patient treated with multi-session SRS experienced any cranial nerve toxicity (P = 0.18). CONCLUSION: SRS of nonvestibular cranial schwannomas provides excellent tumor control with minimal risk of complications. There was a trend towards decreased complications with multi-session SRS. PMID- 21273919 TI - Epilepsy after bypass surgery in adult moyamoya disease. AB - BACKGROUND: Postoperative seizure, well-known in association with other pathologies, has been rarely discussed in adult moyamoya disease. OBJECTIVE: We evaluated postoperative seizures in adult patients with moyamoya undergoing revascularization surgery. METHODS: From 2001 to 2007, 43 adult patients with moyamoya disease underwent 53 revascularization surgeries, consisting of direct bypass with or without indirect bypass. Incidence and profile of postoperative seizures were investigated, with evaluation of influencing factors. Multivariable analysis using a generalized estimation equation was performed to determine which factors were related to postoperative seizure. RESULTS: Seizures developed in 10 sides (18.9%) after revascularization for moyamoya disease, including immediate (<24 hours, n = 0), early (1-7 days, n = 5), late (8-30 days, n = 0), and delayed seizures (>=1 month, n = 7). Early and subsequent delayed seizures developed in the same lesions in 2 patients. Seizures developed only in the patients with combined direct and indirect revascularization. Postoperative temporary neurological deficits with imaging abnormalities were significantly related to postoperative nondelayed seizures (P = .02). Delayed seizures were significantly different according to the location of the recipient artery (P = .03), especially with the frontal branches. By multivariable analysis, revascularization using frontal branches trended toward increased incidence of delayed postoperative seizure, with adjusted odds ratio of 13.78 (95% confidence interval, 1.7-114.1). CONCLUSION: In adult patients with moyamoya disease, the incidence of delayed postoperative seizure seems to be higher than that of other pathologies. The delayed, pronounced formation of synangiosis in moyamoya disease may be related to the development of such delayed postoperative seizures, especially when the location of the recipient artery is frontal. PMID- 21273920 TI - Surgical mortality at 30 days and complications leading to recraniotomy in 2630 consecutive craniotomies for intracranial tumors. AB - BACKGROUND: In order to weigh the risks of surgery against the presumed advantages, it is important to have specific knowledge about complication rates. OBJECTIVE: To study the surgical mortality and rate of reoperations for hematomas and infections after intracranial surgery for brain tumors in a large, contemporary, single-institution consecutive series. METHODS: All adult patients from a well-defined population of 2.7 million inhabitants who underwent craniotomies for intracranial tumors at Oslo University Hospital from 2003 to 2008 were included (n = 2630). The patients were identified from our prospectively collected database and their charts studied retrospectively. Follow up was 100%. RESULTS: The overall surgical mortality, defined as death within 30 days of surgery, was 2.3% (n = 60). The mortality rates for high- and low-grade gliomas, meningiomas, and metastases were 2.9%, 1.0%, 0.9%, and 4.5%, respectively. Age >60 (odds ratio 1.84, P < 0.05) and biopsy compared with resection (odds ratio 4.67, P < 0.01) were significantly positively associated with increased surgical mortality. Hematomas accounted for 35% of the surgical mortality. Postoperative hematomas needing evacuation occurred in 2.1% (n = 54). Age >60 was significantly correlated to increased risk of postoperative hematomas (odds ratio 2.43, P < 0.001). A total of 39 patients (1.5%) were reoperated for postoperative infection. Meningiomas had an increased risk of infections compared with high-grade gliomas (odds ratio 4.61, P < 0.001). CONCLUSION: The surgical mortality within 30 days of surgery was 2.3%, with age >60 and biopsy vs resection being the 2 factors significantly associated with increased mortality. Postoperative hematomas caused about one third of the surgical mortality. PMID- 21273921 TI - Newly synthesized radical-containing nanoparticles enhance neuroprotection after cerebral ischemia-reperfusion injury. AB - BACKGROUND: Antioxidant nitroxyl radicals such as 2,2,6,6-tetramethylpiperidine-1 oxyl (TEMPO) have been investigated for their ability to scavenge free radicals produced by ischemia-reperfusion injury. However, the short in vivo half-life and toxicity of TEMPO have limited their clinical application. OBJECTIVE: We developed a core-shell-type nanoparticle, termed a radical-containing nanoparticle (RNP), to deliver nitroxyl radicals with prolonged in vivo half-life and pH-sensitivity. We evaluated the ability of RNP to deliver TEMPO radicals to the ischemic brain and scavenge free radicals in cerebral ischemia-reperfusion injury using rats. METHODS: When RNPs were administrated to middle cerebral artery occlusion rats, the delivery and clearance of RNPs were detected using electron paramagnetic resonance (EPR) assay. The production of superoxide anion in neuronal cells was observed with dihydroethidium staining. The treatment effects were evaluated by measuring the cerebral infarction volumes, lipid peroxidation and protein oxidation, and neurological symptom scoring. RESULTS: The TEMPO radicals contained in RNPs were detected for 6 hours after intravenous administration as a triplet EPR signal in the ischemic brain, and RNPs significantly reduced the production of superoxide anion in neuronal cells compared with saline and 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyls (TEMPOL). The infarction volumes of rats treated by RNPs were significantly lower than those of rats treated by saline, micelles, and TEMPOL. In addition, RNP treatment suppressed lipid peroxidation and protein oxidation, and limited the adverse effects of TEMPO radicals such as hypotension. CONCLUSION: RNPs could be a promising neuroprotective agent with their enhanced ability to scavenge free radicals and reduced toxicity. PMID- 21273922 TI - Autologous adult cortical cell transplantation enhances functional recovery following unilateral lesion of motor cortex in primates: a pilot study. AB - BACKGROUND: Although cell therapy is a promising approach after cerebral cortex lesion, few studies assess quantitatively its behavioral gain in nonhuman primates. Furthermore, implantations of fetal grafts of exogenous stem cells are limited by safety and ethical issues. OBJECTIVE: To test in nonhuman primates the transplantation of autologous adult neural progenitor cortical cells with assessment of functional outcome. METHODS: Seven adult macaque monkeys were trained to perform a manual dexterity task, before the hand representation in motor cortex was chemically lesioned unilaterally. Five monkeys were used as control, compared with 2 monkeys subjected to different autologous cells transplantation protocols performed at different time intervals. RESULTS: After lesion, there was a complete loss of manual dexterity in the contralesional hand. The 5 "control" monkeys recovered progressively and spontaneously part of their manual dexterity, reaching a unique and definitive plateau of recovery, ranging from 38% to 98% of prelesion score after 10 to 120 days. The 2 "treated" monkeys reached a first spontaneous recovery plateau at about 25 and 40 days postlesion, representing 35% and 61% of the prelesion performance, respectively. In contrast to the controls, a second recovery plateau took place 2 to 3 months after cell transplantation, corresponding to an additional enhancement of functional recovery, representing 24% and 37% improvement, respectively. CONCLUSIONS: These pilot data, derived from 2 monkeys treated differently, suggest that, in the present experimental conditions, autologous adult brain progenitor cell transplantation in a nonhuman primate is safe and promotes enhancement of functional recovery. PMID- 21273923 TI - Awake craniotomy vs surgery under general anesthesia for resection of supratentorial lesions. AB - BACKGROUND: The use of an awake craniotomy in the treatment of supratentorial lesions is a challenge for both patients and staff in the operation theater. OBJECT: To assess the safety and effectiveness of an awake craniotomy with brain mapping in comparison with a craniotomy performed under general anesthesia. METHODS: We prospectively compared 2 groups of patients who underwent surgery for supratentorial lesions: those in whom an awake craniotomy with intraoperative brain mapping was used (AC group, n = 214) and those in whom surgery was performed under general anesthesia (GA group, n = 361, including 72 patients with lesions in eloquent areas). The AC group included lesions in close proximity to the eloquent cortex that were surgically treated on an elective basis. RESULTS: Globally, the 2 groups were comparable in terms of sex, age, American Society of Anesthesiologists score, pathology, size of lesions, quality of resection, duration of surgery, and neurological outcome, and different in tumor location and preoperative neurological deficits (higher in the AC group). However, specific data analysis of patients with lesions in eloquent areas revealed a significantly better neurological outcome and quality of resection (P < .001) in the AC group than the subgroup of GA patients with lesions in eloquent areas. Surgery was uneventful in AC patients and they were discharged home sooner. CONCLUSION: AC with brain mapping is safe and allows maximal removal of lesions close to functional areas with low neurological complication rates. It provides an excellent alternative to craniotomy under GA. PMID- 21273924 TI - Granulocyte colony-stimulating factor enhances the angiogenetic effect of indirect bypass surgery for chronic cerebral hypoperfusion in a rat model. AB - BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) mobilizes hematopoietic bone marrow cells into systemic circulation and has been used clinically to treat chemotherapy-induced neutropenia. Recently, G-CSF was shown to have neuroprotective and angiogenetic effects in acute cerebral infarction. OBJECTIVE: To evaluate the effects of G-CSF for angiogenesis after indirect bypass surgery. METHODS: : Chronic cerebral hypoperfusions were induced in male Wistar rats by permanent bilateral internal carotid artery occlusion (BICAO). After BICAO, unilateral indirect bypass and encephalogaleosynangiosis (EGS) were performed, and human recombinant G-CSF (10 MUg/kg) or saline was injected intramuscularly for 5 consecutive days. We measured regional cerebral blood flow (rCBF) by laser Doppler flowmetry and performed immunohistochemical analysis 21 days after BICAO. RESULTS: BICAO decreased rCBF to 62.52% +/- 5.8% of control (P < .01). The rCBF increased significantly 21 days after BICAO in all treatment groups (n = 10; P < .05) except the G-E- group. The rCBF increase observed in the G+E+ group was significantly higher than that observed in other groups. Both G-CSF and EGS treatments significantly increased the number of small vessels (P < .01), and G CSF and EGS showed additive effect in increasing the number of small vessels. CONCLUSION: Combined use of G-CSF and indirect bypass surgery induces an increase in rCBF and angiogenesis under conditions of cerebral chronic hypoperfusion. This is the first report to demonstrate that G-CSF can enhance angiogenesis induced by indirect bypass surgery, and that this combined therapy is a safe and easy method of treatment. PMID- 21273925 TI - Early recognition of lumbar overdrainage by lumboventricular pressure gradient. AB - BACKGROUND: Lumbar drainage (LD) represents a promising treatment strategy for prevention of vasospasm after aneurysmal subarachnoid hemorrhage (SAH). OBJECTIVE: To report on transient herniation caused by lumbar overdrainage in 3 patients with severe SAH who were treated with early LD within an ongoing feasibility study. METHODS: Patients with first-time aneurysmal SAH received LD within 72 hours of symptom onset, after aneurysm clipping or coiling. LD, with a target drainage amount of 5 to 10 mL, was continued for 6 to 9 days. External ventricular drainage (EVD) was begun on admission when hydrocephalus was present. With both catheters in place, intracranial pressure (ICP) and lumbar pressure (LP) were monitored simultaneously. RESULTS: Three of 22 patients developed a progressive lumboventricular pressure gradient, likely due to cerebrospinal fluid (CSF) overdrainage. Two patients showed signs of herniation. Clamping of LD resulted in complete reversal of symptoms in those patients. The lumboventricular pressure gradient began to evolve at least 12 hours before clinical symptoms developed, and gradually disappeared in all 3 patients after LD clamping. CONCLUSION: Lumbar overdrainage should be avoided in severe SAH, and lumboventricular pressure measurement may be a useful monitoring tool. Herniation due to lumbar overdrainage is a feared complication that can be avoided by following a strict LD management protocol. PMID- 21273926 TI - Optic radiation fiber tracking using anteriorly angulated diffusion tensor imaging: a tested algorithm for quick application. AB - BACKGROUND: Fiber tracking (FT) of the optic pathways (OPs) is difficult because there is no standard for the parameters of diffusion tensor imaging (DTI), placement of seed volumes, or interpreting the results. OBJECTIVE: To determine optimal conditions and parameters for DTI and FT of the optic radiation under intraoperative conditions, we performed a multivariate prospective study. METHODS: A healthy man underwent magnetic resonance imaging and DTI scans using various scan parameters. The slice thicknesses were 2.7 mm, 5 mm, and 7 mm, and the gantry of the slices was 0 degrees and 44 degrees. The OPs were tracked using different settings for focal anisotropy and minimal length of the visualized fibers. The time needed for DTI, image processing, and uploading as well as the difficulty of depicting the OPs, the time needed for FT, quality, and volume of the tracked fiber object were registered and analyzed. RESULTS: The DTI took between 2 minutes 14 seconds for the axial scan with 7-mm slice thickness and 6 minutes 14 seconds for the 44-degree angulated scan with 2.7-mm slice thickness. Splitting the data into a 3-dimensional mosaic data set took between 1 minute 42 seconds (44 degrees, 7 mm; 0 degrees, 7 mm) and 4 minutes 21 seconds (44 degrees, 2.7 mm). The best results were achieved using 44-degree, 2.7-mm DTI. The optimal setting for focal anisotropy was 0.1 and 11 mm for minimal length. Using these parameters, tracking of the OPs was possible in 1 minute 22 seconds and with high quality and correlating with anatomic studies. CONCLUSION: The use of anteriorly angulated DTI improves the FT work flow and the results of tractography of the OP. The quality of the resulting objects can be judged by anatomic landmarks. PMID- 21273927 TI - Weight changes in subthalamic nucleus vs globus pallidus internus deep brain stimulation: results from the COMPARE Parkinson disease deep brain stimulation cohort. AB - BACKGROUND: Parkinson's patients, on average, gain weight after deep brain stimulation (DBS). OBJECTIVE: To determine potential differences in weight gain when comparing the subthalamic nucleus and the globus pallidus internus target. METHODS: A retrospective analysis was performed on the prospective, randomized cohort of National Institutes of Health COMPARE trial DBS patients who received unilateral subthalamic nucleus or globus pallidus internus DBS. Baseline weights were recorded before DBS surgery and at 6, 12, and 18 months postoperatively. Relationships between weight change and changes in Beck Depression Inventory score, Unified Parkinson's Disease Rating Scale (UPDRS) motor score (part III) (also the dyskinesia duration and disability subscores from UPDRS IV), and Hoehn Yahr stage were determined via Spearman's rank-order correlation coefficients. Regression analyses were performed to investigate the effects of potential factors on weight change over time. RESULTS: Patients in the COMPARE DBS cohort gained a significant amount of weight, a mean of 4.86 lb (standard deviation = 8.73) (P = .001), but there was no significant difference between subthalamic nucleus and globus pallidus internus targets (weight gain of 4.29 +/- 6.79 and 5.38 +/- 10.32 lb, respectively; P = .68). Weight gain did not correlate with Beck Depression Inventory score change, UPDRS motor score, dyskinesia duration, dyskinesia disability change, or the Hoehn-Yahr stage (P = .62, .21, and .31, respectively). No specific variable was associated with weight gain, and there were no differences in binge eating post-surgery in either target. CONCLUSION: There were significant changes in weight over time after DBS therapy. However, neither Beck Depression Inventory score change nor UPDRS score change or dyskinesia was correlated with weight gain. No significant factor was associated with the weight change. PMID- 21273928 TI - Computed tomography imaging of transferrin targeting liposomes encapsulating both boron and iodine contrast agents by convection-enhanced delivery to F98 rat glioma for boron neutron capture therapy. AB - BACKGROUND: To achieve potent tumor-selective antitumor efficacy by boron neutron capture therapy (BNCT), it is important to have a significant differential uptake of 10B between tumor cells and normal cells. This should enable BNCT to reduce damage to normal tissues compared with other radiation therapies. OBJECTIVE: To augment the therapeutic efficacy of BNCT, we used transferrin-conjugated polyethylene glycol (PEG) (TF-PEG) liposome encapsulating sodium borocaptate and Iomeprol, an iodine contrast agent, with intratumoral convection-enhanced delivery (CED) in a rat glioma tumor model. METHODS: The in vitro (10)B concentration of F98 rat glioma cells was determined by inductively coupled plasma atomic emission spectrometry after incubation with either TF-PEG or PEG liposomes. For in vivo biodistribution studies, (10)B concentrations within blood, normal brain tissue, and intracerebrally transplanted F98 cells were measured with inductively coupled plasma-atomic emission spectrometry after CED of the compounds, and computed tomography was performed at selected time intervals. RESULTS: (10)B concentrations of F98 cultured glioma cells in vitro 6 hours after exposure to PEG and TF-PEG liposome were 16.1 and 51.9 ng (10)B/10(6) cells, respectively. (10)B concentrations in F98 glioma tissue 24 hours after CED were 22.5 and 82.2 MUg/g, by PEG and TF-PEG liposome, respectively, with lower (10)B concentrations in blood and normal brain. Iomeprol provided vivid and stable enhanced computed tomography imaging of the transplanted tumor even 72 hours after CED by TF-PEG liposome. Conversely, tissue enhancement had already washed out at 24 hours after CED of the PEG liposomes. CONCLUSION: The combination of TF-PEG liposome encapsulating sodium borocaptate and Iomeprol and intratumoral CED enables not only a precise and potent targeting of boron delivery to the tumor tissue, but also the ability to follow the trace of boron delivery administered intratumorally by real-time computed tomography. PMID- 21273929 TI - Navigated transcranial magnetic stimulation and functional magnetic resonance imaging: advanced adjuncts in preoperative planning for central region tumors. AB - BACKGROUND: Tumor resection in the vicinity of the motor cortex poses a challenge to all neurosurgeons. For preoperative assessment of eloquent cortical areas, functional magnetic resonance imaging (fMRI) is used, whereas intraoperatively, direct cortical stimulation (DCS) is performed. Navigated transcranial magnetic stimulation (nTMS) is comparable to DCS in activating cortical pyramidal neurons. OBJECTIVE: To evaluate the reliability of nTMS compared with fMRI and DCS for preoperative resection planning of centrally located tumors. METHODS: In a prospective series, 11 patients (ages, 20-63 years; mean, 41.9 +/- 14.9 years, 2 women) with tumors located in or adjacent to the motor cortex were evaluated for surgery. fMRI and nTMS were applied for preoperative assessment of the extent of tumor resection. A 3-dimensional anatomic data set with superimposed fMRI data was integrated in the eXimia Navigated Brain Stimulation station for ensuing motor cortex mapping by nTMS. Responses from nTMS were evaluated by electromyographic response. During surgery, the coordinates of each DCS site were unambiguously defined and integrated into neuronavigation. A post hoc comparison of the coordinates of nTMS, fMRI, and DCS was performed. RESULTS: Distances from nTMS to DCS (10.5 +/- 5.67 mm) were significantly smaller than those from fMRI to DCS (15.0 +/- 7.6 mm). CONCLUSION: nTMS anticipates information usually only enabled by DCS and therefore allows surgical planning in eloquent cortex surgery. PMID- 21273930 TI - Stereotactic 125iodine brachytherapy for the treatment of singular brain metastases: closing a gap? AB - BACKGROUND: Brain metastases represent the most common intracranial tumors and are associated with very poor prognosis. OBJECTIVE: To investigate the feasibility, survival, and cerebral disease control of patients with singular brain metastases treated with stereotactic 125iodine brachytherapy (SBT), to identify prognostic factors, and to compare results with other local treatment methods. METHODS: Complications, survival (overall and separated by recursive partitioning analysis [RPA] classes), and local and distant disease control were evaluated retrospectively in 90 patients. Prognostic factors were identified by forming subgroups of patients based on age, Karnofsky Performance Status, status of extracranial disease, interval since initial diagnosis, absence/presence of prior whole-brain radiation therapy, localization, morphology, and tumor volume. RESULTS: There was no treatment-related mortality, and morbidity was transient and low (3.3%). Median survival was 8.5 months overall and 18.1 months for RPA class 1 patients. After 1 year, the actuarial incidence of local and distant cerebral relapse was 5.4% and 46.4%, respectively. Karnofsky Performance Status >= 70 (P < .002), stable systemic disease (P < .02), RPA class 1 (P < .02), and a prolonged (> 12 month) interval between initial diagnosis and SBT (P < .05) significantly improved survival. No significant influence of previous whole-brain radiation therapy on survival or cerebral disease relapse was found. CONCLUSION: SBT represents a safe, minimally invasive, and, compared with SRS and microsurgery, a similarly effective local treatment option in terms of survival and cerebral disease control. It allows histological (re-)evaluation and treatment within 1 stereotactic operation. Because it is less restricted by tumor localization or size, it greatly advances local treatment options, and on the basis of its favorable biological irradiation effect, SBT does not limit additional irradiation treatment in the event of disease relapse. PMID- 21273931 TI - Geometry of the internal carotid artery and recurrent patterns in location, orientation, and rupture status of lateral aneurysms: an image-based computational study. AB - BACKGROUND: Intracranial aneurysm development and rupture may be associated to the morphology of the parent vessel. OBJECTIVE: To quantitatively characterize the geometry of the internal carotid artery (ICA) in relation to the location and orientation of lateral aneurysms and to identify recurrent patterns associated with their rupture status. METHODS: The geometry of 54 ICAs hosting lateral aneurysms was analyzed by means of computational geometry techniques. The ICA was split into individual bends, and the bend hosting the aneurysm was described in terms of curvature, torsion, length, and radius. Aneurysm position and orientation with respect to the parent vessel and specifically the hosting bend were characterized, as well as angles between the portions of the parent artery immediately upstream of and downstream from the aneurysm and the aneurysm ostium. Differences in geometric parameters with respect to rupture status and their performance as classifiers were evaluated. RESULTS: ICA bends hosting ruptured aneurysms were shorter with a smaller radius, lower maximum curvature, and lower proximal torsion compared with those hosting unruptured lesions. Ruptured aneurysms occurred in more distal portions of the ICA, along the outer wall of the vessel, and closer to the curvature peak within the hosting bend than unruptured ones. The proximal portions of ICAs hosting ruptured aneurysms approached the ostium region at a smaller angle. CONCLUSION: Geometric factors relative to the ICA were associated with the distribution of aneurysms and their rupture status. The present work has potential implications in the quest for hemodynamic factors contributing to the development, progression, and rupture of intracranial aneurysms. PMID- 21273932 TI - World Health Organization Grade II gliomas and subventricular zone: anatomic, genetic, and clinical considerations. AB - BACKGROUND: Recent studies suggest a possible origin of human gliomas from subventricular zone (SVZ) stem cells. OBJECTIVE: To evaluate the relationship of World Health Organization grade II gliomas (GIIGs) with the SVZ and to investigate the presence of different genetic patterns, depending on their relationship with the SVZ. METHODS: Forty-three consecutive patients were operated on for GIIG. Preoperative fluid-attenuated inversion recovery-weighted magnetic resonance images were reviewed to assess the presence of cortical involvement and the relationship between gliomas and the SVZ. Patients were divided into 2 groups: group 1, tumors in contact with the SVZ; and group 2, tumors not in contact with the SVZ. Preoperative and postoperative tumor volumes were calculated. Genetic analysis was performed to study 1p19q allelic loss. RESULTS: Twenty-four patients were in group 1 and 19 in group 2. All tumors were in contact with the cortex. Preoperative volume was significantly larger in group 1 than in group 2 (P = .003). The proportion of total and subtotal resections was higher in group 2 (P = .01). Insular tumors never showed 1p19q codeletions. Noninsular tumors exhibited a significantly different incidence of complete 1p19q codeletion, with allelic loss more common in group 1 (P = .03). CONCLUSION: GIIGs showed a constant relationship with the cortex and a larger volume when they came in contact with the ventricles. A distinct genetic pattern was found in noninsular SVZ GIIGs. This parameter can be considered for therapeutic management. PMID- 21273934 TI - Open and endovascular treatment of unruptured carotid-ophthalmic aneurysms: clinical and radiographic outcomes. AB - BACKGROUND: Aneurysms of the carotid-ophthalmic artery present unique challenges to cerebrovascular neurosurgeons given their proximity to vital anatomic structures. OBJECTIVE: To report our experience with a combined-modality treatment of unruptured carotid-ophthalmic aneurysms over a 12-year period. METHODS: A retrospective review of 161 patients who underwent open, endovascular, or combined treatment of 170 aneurysms from January 1997 to July 2009 was conducted. Medical records, operative reports, office notes, and follow-up angiograms were reviewed to obtain data on patient demographics, angiographic results, and clinical outcomes. RESULTS: One hundred forty-seven aneurysms were treated via endovascular techniques; 17 aneurysms (10%) were treated with microsurgical clip ligation; and 6 aneurysms (3.5%) were treated with a combined approach. Of the aneurysms treated via an endovascular approach alone, 81.6% of aneurysms had evidence of >= 95% occlusion on initial angiogram. There was a 1.4% rate of major complications associated with the initial procedure. Twenty-six of these aneurysms (18.9%) required further intervention on the basis of early angiographic results. Major complications occurred after 6 of 23 open microsurgical procedures (26.1%), including 2 instances of permanent visual loss. Nine clipped patients had long-term angiographic follow-up; none required further intervention. CONCLUSION: Endovascular treatment of carotid-ophthalmic aneurysms with modern endovascular techniques can be performed safely and efficaciously in the elective setting. PMID- 21273935 TI - Endoscopic port surgery for resection of lesions of the cerebellar peduncles: technical note. AB - BACKGROUND: Mass lesions of the inferior, middle, and superior cerebellar peduncles (cerebellar peduncle complex [CPC]) present numerous surgical pitfalls when resection or debulking is warranted. Success has been achieved through multiple approaches, but complications can be severe. OBJECTIVE: To report the surgical technique for and clinical results of the treatment of lesions in the CPC with an endoscopic port via a lateral transcerebellar corridor. METHODS: Three patients underwent resection of intrinsic lesions of the CPC via a lateral transcerebellar approach with an endoscopic port. Deployment of the port was performed with frameless image-guided placement into the area of interest. Resection was performed using bimanual microsurgical technique under parallel endoscopic visualization. RESULTS: Three patients 43, 27, and 13 years of age underwent successful resection of lesion in the CPC. Histopathological diagnosis consisted of cavernous malformation, glioblastoma multiforme, and a juvenile pilocytic astrocytoma. All had complete gross total resection except for the patient with a high-grade glioma. Clinically, all had excellent outcomes, with 1 patient suffering postoperative facial palsy after resection of her high-grade glioma. CONCLUSION: The lateral transcerebellar approach to the CPC with an endoscopic port may be a feasible alternative to standard microsurgical resection in such difficult cases. Careful patient selection is critical to identify those who may be suitable for endoscopic port surgery on the basis of clinical, radiographic, and anatomical considerations. PMID- 21273936 TI - The effect of pulse width and contact configuration on paresthesia coverage in spinal cord stimulation. AB - BACKGROUND: In spinal cord stimulation for the management of chronic, intractable pain, a satisfactory analgesic effect can be obtained only when the stimulation induced paresthesias cover all painful body areas completely or partially. OBJECTIVE: To investigate the effect of stimulus pulse width (PW) and contact configuration (CC) on the area of paresthesia (PA), perception threshold (VPT), discomfort threshold (VDT), and usage range (UR) in spinal cord stimulation. METHODS: Chronic pain patients were tested during a follow-up visit. They were stimulated monopolarly and with the CC giving each patient the best analgesia. VPT, VDT, and UR were determined for PWs of 90, 210, and 450 microseconds. The paresthesia contours at VDT were drawn on a body map and digitized; PA was calculated; and its anatomic composition was described. The effects of PW and CC on PA, VPT, VDT, and UR were tested statistically. RESULTS: Twenty-four of 31 tests with low thoracic stimulation and 8 of 9 tests with cervical stimulation gave a significant extension of PA at increasing PW. In 14 of 18 tests (low thoracic), a caudal extension was obtained (primarily in L5-S2). In cervical stimulation the extension was predominantly caudal as well. In contrast to VPT and VDT, UR is not significantly different when stimulating with any CC. CONCLUSION: PA extends caudally with increasing PW. The mechanism includes that the larger and smaller dorsal column fibers have a different mediolateral distribution and that smaller dorsal column fibers have a smaller UR and can be activated only when PW is sufficiently large. A similar effect of CC on PA is unlikely as long as electrodes with a large intercontact distance are applied. PMID- 21273937 TI - Robotic digital subtraction angiography systems within the hybrid operating room. AB - BACKGROUND: Fully equipped high-end digital subtraction angiography (DSA) within the operating room (OR) environment has emerged as a new trend in the fields of neurosurgery and vascular surgery. OBJECTIVE: To describe initial clinical experience with a robotic DSA system in the hybrid OR. METHODS: A newly designed robotic DSA system (Artis zeego; Siemens AG, Forchheim, Germany) was installed in the hybrid OR. The system consists of a multiaxis robotic C arm and surgical OR table. In addition to conventional neuroendovascular procedures, the system was used as an intraoperative imaging tool for various neurosurgical procedures such as aneurysm clipping and spine instrumentation. RESULTS: Five hundred one neurosurgical procedures were successfully conducted in the hybrid OR with the robotic DSA. During surgical procedures such as aneurysm clipping and arteriovenous fistula treatment, intraoperative 2-/3-dimensional angiography and C-arm-based computed tomographic images (DynaCT) were easily performed without moving the OR table. Newly developed virtual navigation software (syngo iGuide; Siemens AG) can be used in frameless navigation and in access to deep-seated intracranial lesions or needle placement. CONCLUSION: This newly developed robotic DSA system provides safe and precise treatment in the fields of endovascular treatment and neurosurgery. PMID- 21273938 TI - Immunogenicity of trivalent influenza vaccine in extremely low-birth-weight, premature versus term infants. AB - BACKGROUND: Influenza vaccine immunogenicity in premature infants is incompletely characterized. OBJECTIVE: To assess the immunogenicity of trivalent, inactivated influenza vaccine (TIV) in extremely low-birth-weight (<= 1000 g birth weight) premature (<30 weeks gestation) infants. We hypothesized that geometric mean titers of influenza antibody would be lower in premature than in full-term (FT) (>= 37 week) infants. DESIGN/METHODS: In this prospective multicenter study, former premature and FT infants who were 6 to 17 months of age received 2 doses of TIV during the 2006-2007 or 2007-2008 influenza seasons. Sera were drawn before dose 1, and 4 to 6 weeks after dose 2. Antibody was measured by hemagglutination inhibition. RESULTS: Over 2 years, 41 premature and 42 FT infants were enrolled; 36 and 33 of these infants, respectively, had postvaccination titers available. Premature infants weighed less (mean, 1.3-1.8 kg difference) at the time of immunization than FT infants. Prevaccination titers did not differ between groups. Premature infants had higher postvaccination antibody geometric mean titers than FT infants to H1 (2006-2007, 1:513 vs. 1:91, P = 0.03; 2007-2008, 1:363 vs. 1:189, P = 0.02) and B/Victoria (2006-2007, 1:51 vs. 1:10, P = 0.02). More premature than FT infants had antibody titers >= 1:32 to B/Victoria (85% vs. 60%, P = 0.04) in 2007-2008. Two (5%) premature and 8 (19%) FT infants had adverse events, primarily fever, within 72 hours after vaccination. No child had medically diagnosed influenza. CONCLUSIONS: Former premature infants had antibody responses to 2 TIV doses higher than or equal to those of FT children. Two TIV doses are immunogenic and well tolerated in extremely low-birth-weight, premature infants 6 to 17 months old. PMID- 21273939 TI - Immunogenicity and safety of human papillomavirus-16/18 AS04-adjuvanted vaccine administered according to an alternative dosing schedule compared with the standard dosing schedule in healthy women aged 15 to 25 years: results from a randomized study. AB - BACKGROUND: The human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine is immunogenic, has a clinically acceptable safety profile, and prevents incident and persistent HPV-16/18 infection and cervical precancerous lesions. This study (NCT00552279) evaluated the vaccine when administered according to an alternative dosing schedule (0-1-12 months) compared with the standard dosing schedule (0-1-6 months). METHODS: The study was of randomized open design and was conducted at multiple centers in Europe. Healthy women aged 15 to 25 years were randomized (1:1) to receive HPV-16/18 vaccine according to the standard schedule at months 0, 1, and 6 (n = 401) or an alternative schedule at months 0, 1, and 12 (n = 403). HPV-16 and -18 antibodies were measured by enzyme-linked immunosorbent assay at months 0, 2, and 7 or 13 (depending on group); noninferiority evaluation was performed sequentially for seroconversion rates and geometric mean antibody titers. Primary analysis of immunogenicity was based on the according-to-protocol cohort. Vaccine safety and reactogenicity were assessed on the total vaccinated cohort. RESULTS: Predefined noninferiority criteria were met 1 month after the third vaccine dose when the HPV-16/18 vaccine was administered according to the 0 1-12 month schedule compared with the 0-1-6 month schedule in terms of seroconversion rates for HPV-16 (100% and 100%) and HPV-18 (99.7% and 100%) and geometric mean antibody titers for HPV-16 (11884.7 and 10311.9 ELISA units/mL) and HPV-18 (4501.3 and 3963.6 ELISA units/mL), respectively. The HPV-16/18 vaccine had a clinically acceptable safety profile when administered according to either schedule. CONCLUSIONS: The third dose of the HPV-16/18 vaccine can be administered any time between 6 and 12 months after the first dose, with adequate immunogenicity and a clinically acceptable safety profile. PMID- 21273940 TI - Autosomal recessive vitelliform macular dystrophy in a large cohort of vitelliform macular dystrophy patients. AB - PURPOSE: To report 11 cases of autosomal recessive vitelliform macular dystrophy and to compare their molecular findings and phenotypic characteristics with those of patients with the more common and well-described dominant form of the disease. METHODS: Blood samples were obtained from 435 unrelated individuals with a clinical diagnosis of vitelliform macular dystrophy and screened for mutations in the coding sequences of BEST1. Medical records and retinal photographs of selected patients were reviewed. RESULTS: Nine of the 435 probands were found to have 2 plausible disease-causing variations in BEST1, while 198 individuals were found to have heterozygous variations compatible with autosomal dominant inheritance. Inheritance phase was determined in three of the recessive families. Six novel disease-causing mutations were identified among these recessive patients: Arg47Cys, IVS7-2A>G, IVS7+4G>A, Ile205del12ATCCTGCTCCAGAG, Pro274Arg, and Ile366delCAGGTGTGGC. Forty-four novel disease-causing mutations were identified among the patients with presumed autosomal dominant disease. The phenotype of patients with recessive alleles for BEST1 ranged from typical vitelliform lesions to extensive extramacular deposits. CONCLUSION: The authors provide evidence that two abnormal BEST1 alleles, neither of which causes macular disease alone, can act in concert to cause early-onset vitelliform macular dystrophy. PMID- 21273941 TI - Occurrence of sectoral choroidal occlusive vasculopathy and retinal arteriolar embolization after superselective ophthalmic artery chemotherapy for advanced intraocular retinoblastoma. AB - BACKGROUND: Superselective ophthalmic artery chemotherapy (SOAC) has recently been proposed as an alternative to intravenous chemoreduction for advanced intraocular retinoblastoma. Preliminary results appear promising in terms of tumor control and eye conservation, but little is known regarding ocular toxicity and visual prognosis. In this study, we report on the vascular adverse effects observed in our initial cohort of 13 patients. METHODS: The charts of 13 consecutive patients with retinoblastoma who received a total of 30 injections (up to 3 injections of a single agent per patient at 3-week interval) of melphalan (0.35 mg/kg) in the ophthalmic artery between November 2008 and June 2010 were retrospectively reviewed. RetCam fundus photography and fluorescein angiography were performed at presentation and before each injection. Vision was assessed at the latest visit. RESULTS: Enucleation and external beam radiotherapy could be avoided in all cases but one, with a mean follow-up of 7 months. Sectoral choroidal occlusive vasculopathy leading to chorioretinal atrophy was observed temporally in 2 eyes (15%) 3 weeks to 6 weeks after the beginning of SOAC and retinal arteriolar emboli in 1 eye 2 weeks after injection. There was no stroke or other clinically significant systemic side effects except a perioperative transient spasm of the internal carotid artery in one patient. Vision ranged between 20/1600 and 20/32 depending on the status of the macula. CONCLUSION: Superselective ophthalmic artery chemotherapy was effective in all patients with no stroke or other systemic vascular complications. Unlike intravenous chemoreduction, SOAC is associated with potentially sight-threatening adverse effects, such as severe chorioretinal atrophy secondary to subacute choroidal occlusive vasculopathy or central retinal artery embolism, not to mention the risk of ophthalmic artery obstruction, which was not observed in this series. Further analysis of the risks and benefits of SOAC will define its role within the therapeutic arsenal. Meanwhile, we suggest that SOAC should be given in one eye only and restricted to advanced cases of retinoblastoma, as an alternative to enucleation and/or external beam radiotherapy. PMID- 21273942 TI - Feasibility of intrasurgical spectral-domain optical coherence tomography. AB - PURPOSE: To evaluate the feasibility of intrasurgical spectral-domain optical coherence tomography in a pilot study. METHODS: Using a Carl Zeiss Meditec Cirrus HD-OCT system adapted to the optical pathway of a Zeiss OPMI VISU 200 surgical microscope, 512 * 128 macular cube scans were performed during various steps of microsurgical procedures in 25 cases. The acquired volume data were postprocessed and visualized using a ray-traced three-dimensional display system. RESULTS: The surgical procedures included pars plana vitrectomies for epiretinal membranes (n = 8), macular holes (n = 4), primary rhegmatogenous retinal detachment (n = 1), proliferative diabetic retinopathy (n = 3), silicone oil removal (n = 2), and cataract surgery only (n = 7). It was possible to acquire intraretinal scans with sufficient quality from all patients. Decisions for additional membrane peeling, knowledge about the behavior of the macular hole and the foveal depression during and after membrane removal, information about clinically invisible fluid accumulation under silicone oil or in a clinically diagnosed "macula-on" retinal detachment, and the condition of the fovea immediately after cataract removal could be gained. CONCLUSION: Intrasurgical spectral-domain optical coherence tomography evaluation is feasible using the tested system and may positively influence surgical decisions and techniques resulting in an improved patient outcome. PMID- 21273943 TI - Vitreous surgery for impending macular hole. AB - PURPOSE: In a study conducted 15 years ago, the "Vitrectomy for Prevention of Macular Hole Study Group" was not able to prove the benefits and advantages of vitrectomy for treatment of impending macular holes; however, during the interim period, notable improvements have been achieved concerning diagnosis and efficacy of treatment. This study aims to identify the effect of current vitreous surgery for treatment of symptomatic impending macular holes. METHODS: Nineteen eyes of 17 consecutive patients who had undergone vitrectomy with internal limiting membrane peeling and short-acting gas tamponade for treatment of symptomatic impending macular holes were reviewed. Outer foveal defects on preoperative optical coherence tomography were demonstrated in all cases. We analyzed visual outcome and postoperative change in foveal appearance on optical coherence tomography. RESULTS: The follow-up period ranged from 3 months to 41 months, with a mean of 13.5 months. Mean logarithm of the minimum angle of resolution best corrected visual acuity improved postoperatively from 0.42 +/- 0.18 to 0.11 +/- 0.11 (P < 0.01). Postoperative optical coherence tomography examination revealed anatomical closure with complete disappearance of outer foveal defects in all patients. CONCLUSION: In symptomatic patients with impending macular holes, current vitreous surgery may prevent progression to a full-thickness macular hole and improve visual outcome. A randomized trial is warranted. PMID- 21273944 TI - Intraoperative choroidal detachment during 23-gauge vitrectomy. AB - PURPOSE: To review intraoperative choroidal detachments during 23-gauge vitrectomy and examine possible mechanism(s) involved. METHODS: A retrospective consecutive case review of 23-gauge vitrectomies was performed. Main outcomes included choroidal detachment incidence, location, extent, relation to infusion cannula, and postoperative course. Laboratory study of human donor eyes was conducted by placing 23-gauge cannulas at various angles through the pars plana and injecting viscoelastic material after cannula retraction. RESULTS: Among 338 consecutive 23-gauge vitrectomy cases, 12 (3.55%) intraoperative choroidal detachments occurred. These included 6 (1.77%) serous detachments, 4 (1.18%) limited hemorrhagic detachments, and 1 case each of gas and silicone oil during an exchange. In four of six serous detachments and three of four hemorrhagic detachments, the detachment originated from the infusion cannula site. Intraoperative infusion cannula retraction (5 of 12 cases) and blockage (2 of 12 cases) caused transient hypotony. All cases of serous, hemorrhagic, and gas detachment resolved without intervention. Cannulas were placed at various angles to the sclera in human donor eyes. Choroidal detachments were produced after injecting viscoelastic material through obliquely placed cannulas after 1 mm of retraction. CONCLUSION: Infusion cannula retraction is an important mechanism and risk factor for the development of intraoperative choroidal detachment during 23 gauge vitrectomy. Precautions to prevent retraction and intraoperative repositioning may help avoid this complication. PMID- 21273945 TI - Pores of the inner limiting membrane in flat-mounted surgical specimens. AB - PURPOSE: To demonstrate the incidence of pores in the inner limiting membrane (ILM) in flat-mounted ILM specimens and to show the immunocytochemical properties of cellular proliferation associated with them. METHODS: One hundred and twelve ILM specimens from patients with idiopathic macular holes were flat mounted and screened for pores. The ILM was assessed by phase-contrast and interference microscopy. Various antibodies were used against glial cells, hyalocytes, and retinal pigment epithelial cells. RESULTS: In total, only three pores were found. They were characterized by a full-thickness defect of the ILM with irregular borders and cellular proliferation on the ILM. Glial cells were seen in direct association with the ILM pore. Glial cell and hyalocyte markers were the main immunologic features observed. CONCLUSION: Inner limiting membrane pores are a rare finding. Glial cells are likely to cross the ILM through these pores on their way from the retina to the vitreoretinal border. Given the frequency of cellular proliferation and the rare finding of ILM pores, other pathways have to be considered in playing the leading role in epiretinal proliferation. They might include migration of cells through ILM thinning along retinal vessels and proliferation of vitreous cortex hyalocytes at the vitreoretinal border. PMID- 21273946 TI - Finasteride for chronic central serous chorioretinopathy. AB - PURPOSE: To evaluate the safety and efficacy of finasteride, an inhibitor of dihydrotestosterone synthesis, in the treatment of chronic central serous chorioretinopathy. METHODS: Five patients with chronic central serous chorioretinopathy were prospectively enrolled in this pilot study. Patients were administered finasteride (5 mg) daily for 3 months, after which study medication was withheld and patients were observed for 3 months. Main outcome measures included best-corrected visual acuity, central subfield macular thickness, and subretinal fluid volume as assessed by optical coherence tomography. Serum dihydrotestosterone, serum testosterone, and urinary cortisol were also measured. RESULTS: There was no change in mean best-corrected visual acuity. Mean center subfield macular thickness and subretinal fluid volume reached a nadir at 3 months and rose to levels that were below baseline by 6 months. The changes in both optical coherence tomography parameters paralleled those in serum dihydrotestosterone level. In four patients, center-subfield macular thickness and/or subretinal fluid volume increased after discontinuation of finasteride. In the remaining patient, both optical coherence tomography parameters normalized with finasteride and remained stable when the study medication was discontinued. CONCLUSION: Finasteride may represent a novel medical treatment for chronic central serous chorioretinopathy. Larger controlled clinical trials are needed to further assess the efficacy of finasteride for the treatment of central serous chorioretinopathy. PMID- 21273947 TI - The relationship between diabetic retinopathy and serum levels of ischemia modified albumin and malondialdehyde. AB - PURPOSE: To establish the correlation between ischemia-modified albumin (IMA) and malondialdehyde (MDA) and the development of diabetic retinopathy (DRP) in patients with diabetes mellitus. METHODS: Seventy Type 2 diabetic patients, 35 with DRP, and 36 healthy controls were enrolled in this study. Serum IMA and MDA levels were compared statistically. Receiver operating characteristic curve analysis was also performed to calculate the value of IMA and MDA in distinguishing DRP. RESULTS: Mean serum IMA levels were 0.658 +/- 0.128 absorbance units in the non-DRP group, compared with 0.767 +/- 0.074 absorbance units in the DRP group and 0.619 +/- 0.044 absorbance units in the control group. Mean serum MDA levels were 0.325 +/- 0.172 nmol/mL, 0.244 +/- 0.152 nmol/mL, and 0.178 +/- 0.131 nmol/mL, respectively. The differences in IMA and MDA levels were statistically significant for all groups (P < 0.05 for all). The areas under the receiver operating characteristic curves for the determination of DRP in diabetic patients were 0.789 (95% confidence interval, 0.682-0.896) for IMA and 0.3 (95% confidence interval, 0.175-0.426) for MDA. CONCLUSION: Both serum IMA and serum MDA levels were higher in the diabetic patients compared with the control group. In particular, the high sensitivity of IMA toward DRP showed that it reflected retinal vascular complication better than MDA. Ischemia-modified albumin may be a useful marker in monitoring the risk of DRP development. PMID- 21273948 TI - Toxic epidermal necrolyis after vancomycin use: a case report and discussion of management. AB - Vancomycin is a commonly used antibiotic for severe Gram-positive bacterial infections, especially for methicillin-resistant Staphylococcus Aureus and coagulase-negative staphylococci infections. Nevertheless, only few cases of toxic epidermal necrolysis have been reported since the introduction of Vancomycin into clinical practice. We report a case of a 35-year-old man who presented with multiple facial abscesses and methicillin-resistant Staphylococcus Aureus bactermia and who was started on Vancomycin and later developed toxic epidermal necrolysis. PMID- 21273949 TI - A review of economic evaluations of genetic testing services and interventions (2004-2009). AB - To review economic evaluations of genetic interventions published between 2004 and 2009 and assess the quality of the identified studies, we searched for economic evaluations of genetic testing and interventions published between 2004 and 2009. Studies that met inclusion criteria were reviewed and their quality then assessed using a validated instrument-the Quality of Health Economic Studies. Of 54 articles identified, 26 met study criteria and were included in the review. These studies span a number of clinical indications, genetic tests, and interventions, but the majority (92%) focuses on genetic interventions for preventive screening and increasing treatment efficacy. The mean quality score for the reviewed studies was 89.8. Comparison of the quality of different study types revealed that cost-utility studies and studies that used a combined decision tree and Markov model had the highest mean quality scores. Clear statements regarding bias, funding source, and study perspective were commonly lacking in the reviewed studies. Although the reviewed studies were of fairly high quality, we found Quality of Health Economic Studies methodology for grading the quality of economic evaluations challenging and observed no statistically significant improvement in quality of studies between the periods of 1995-2004 and 2004-2009. PMID- 21273950 TI - Crystal structure and hydrogen bonding study of (10E)-2,2-dimethyl-3,4-dihydro-2H benzo[g]chromene-5,10-dione 10-oxime derived from alpha-lapachone. AB - The compound (10E)-2,2-dimethyl-3,4-dihydro-2H-benzo[g]chromene-5,10-dione-10 oxime (1) was synthesized from a-lapachone and hydroxylamine chloride in alkaline medium. Single-crystals suitable for X-ray diffraction measurements were grown from an ethanol solution, and the crystal structure of the title molecule is reported for the first time. The title molecule was also characterized by 1H- and 13C-NMR in CDCl3 solution, FTIR and MS. The crystal structure of 1 shows an E stereochemistry and dimers formed through classical hydrogen bonds. PMID- 21273951 TI - Preparative isolation of three anthraquinones from Rumex japonicus by high-speed counter-current chromatography. AB - Three anthraquinones--emodin, chrysophanol, and physcion--were successfully purified from the dichloromethane extract of the Chinese medicinal herb Rumex japonicus by high-speed counter-current chromatography (HSCCC). The extract was separated with n-hexane-ethanol-water (18:22:3, v/v/v) as the two-phase solvent system and yielded 3.4 mg of emodin, 24.1 mg of chrysophanol, and 2.0 mg of physcion from 500 mg of sample with purities of 99.2 %, 98.8% and 98.2%, respectively. The HSCCC fractions were analyzed by high-performance liquid chromatography (HPLC) and the chemical structures of the three anthraquinones were confirmed by 1H-NMR and 13C-NMR analysis. This is the first time these anthraquinones have been obtained from R. japonicus by HSCCC. PMID- 21273952 TI - Visually-impaired children in Havana: challenges of education, rehabilitation and inclusion. PMID- 21273953 TI - In the eye of the Cuban epidemic neuropathy storm: Rosaralis Santiesteban MD PhD, Neurology and Neurosurgery Institute. Interview by Christina Mills. AB - When Cuba was hit by a neuropathy epidemic two decades ago, Dr Rosaralis Santiesteban was one of the Cuban health professionals who played a key role in its management, as reflected in a recent issue of Seminars in Ophthalmology. She was well prepared for her part: trained in medicine at the University of Havana before completing a residency in ophthalmology and eventually a doctorate in medical sciences, she has received multiple honors for her research, publishing and teaching. In 2007, she was named Distinguished Researcher by the Cuban Ministry of Science, Technology and the Environment. She has headed the Department of Neuro-ophthalmology at Cuba's Neurology and Neurosurgery Institute since 1977. Now called Cuban Epidemic Neuropathy, the 1990s epidemic that affected over 50,000 Cubans is the largest and best-documented of its kind in history. As researchers pressed to unravel the mystery of its etiology to hasten the epidemic's end, Dr Santiesteban recognized that similar outbreaks had occurred during Cuba's wars of independence in the late 1800s--described in her book, Epidemias y Endemias de neuropatia en Cuba. In the proverbial eye of the storm during the 1990s epidemic, she shares her reflections below on the context, causes, evolution and lessons learned from the challenge that put Cuba's health system to the test. PMID- 21273954 TI - A Cuban NGO perspective on disabilities: Jose Blanch MD MPH, National Association of Blind Persons. Interview by Gail Reed. AB - Dual specialties in epidemiology and labor medicine, as well as an advanced degree in public health, gave Dr Jose Blanch expertise on disabilities in Cuba from a population health perspective. However, when he began losing his sight due to a diabetic retinopathy while serving in Africa, he also began a difficult journey that would transform his life and career, giving him new personal and professional perspectives on disability and the potential of disabled persons. Active for the past several years in the National Association of Blind Persons (ANCI, its Spanish acronym), in 2010 Dr Blanch was elected President of the non governmental organization. He spoke with MEDICC Review about ANCI's role and challenges in the context of Cuba today. PMID- 21273955 TI - Improved visual acuity after frontalis sling surgery for simple congenital ptosis. AB - INTRODUCTION: Congenital ptosis is malpositioning of the eyelids that, when moderate or severe, can negatively affect visual development during its critical period, resulting in amblyopia: diminished visual acuity with no apparent organic cause. Early diagnosis and timely treatment are essential for preventing amblyopia. Congenital ptosis is uncommon but poses a challenge to any ophthalmologist; the only treatment is surgical. Among these patients in Cuba, those with the most complex clinical characteristics are generally referred to the Ramon Pando Ferrer Ophthalmology Institute in Havana. OBJECTIVE: Characterize visual acuity outcomes obtained in patients seen at this Institute who received surgery for simple congenital ptosis using the frontalis sling procedure. METHOD: A descriptive prospective longitudinal study was conducted to describe visual acuity outcomes in 11 patients with a diagnosis of isolated congenital ptosis seen in the Oculoplastic Service of the Ramon Pando Ferrer Ophthalmology Institute between January and July 2009 and operated on using the frontalis sling procedure. The majority exhibited severe visual acuity impairment (0.1-0.5) prior to surgery. Variables employed were age, sex, degree of ptosis, degree of ptosis correction, visual acuity, and complications during surgery and postoperatively. RESULTS: Male patients aged 1-4 years predominated. Visual acuity improved in 100% of patients, to varying degrees. Prior to surgery, 72% had visual acuity of 0.1-0.5. Six months post-surgery, with visual rehabilitation, 90.9% exhibited visual acuity of >0.5. In 81.8% of patients, palpebral ptosis was fully corrected. Complications were minimal: injury to the palpebral tarsus and undercorrection were the most common and did not affect final surgical outcome or interfere with rehabilitation. CONCLUSIONS: Correction of congenital ptosis using the frontalis sling technique yielded satisfactory visual acuity outcomes, contributing to visual rehabilitation of the affected patients. PMID- 21273956 TI - Clinical and epidemiological profile of diabetes mellitus in pregnancy, Isle of Youth, 2008. AB - INTRODUCTION: Diabetes in pregnancy threatens both maternal and neonatal health, with risks of lung immaturity, fetal macrosomia, dystocia and impaired maternal kidney function. Before insulin, diabetes resulted in maternal mortality rates of 30-50% and perinatal mortality rates of 50-60%. Global prevalence estimates vary by population, geographical area and diagnostic criteria. Diabetes accounts for some 90% of endocrine complications in pregnancy. OBJECTIVES: Determine diabetes mellitus prevalence in pregnancy and characterize the population of diabetic women who gave birth in the Isle of Youth Special Municipality in 2008. METHODS: A descriptive retrospective study was carried out from January to December 2008. Clinical records were reviewed of 180 diabetic women who gave birth on the Isle of Youth in 2008, their diagnosis based on WHO criteria modified by municipal health authorities. Study variables were: maternal age, nutritional status, glucose tolerance, gestational age at diagnosis, history of diabetes, and pregnancy outcome; as well as risk factors such as diabetes family history, pregnancy weight gain and comorbidities. RESULTS: Overall prevalence (pregestational and gestational diabetes) among these cases was 17.3%; highest in the group aged >= 35 years. Gestational diabetes was more frequent (96.1% of cases) than pre-gestational diabetes. Multiparity (62.1%), a first-degree family history of diabetes mellitus (26.1%), excess weight before pregnancy (50%) and adequate weight gain during pregnancy (54.4%) were the most frequent conditions found. Among gestational diabetics, diabetes was most frequently detected at 20 28 weeks gestation (31.8%). Fetal macrosomia appeared in 4.4% of cases and a high percentage of deliveries were by Cesarean section (30%). There were no low Apgar scores or congenital abnormalities among neonates. CONCLUSIONS: Despite using modified, more inclusive, WHO diagnostic criteria, the clinical and demographic characteristics of the population studied were comparable to those in other studies of diabetes in pregnancy, except for the low frequency of fetal macrosomia and absence of birth defects present in our study. PMID- 21273958 TI - Cuba's National Clinical Trials Coordinating Center: emergence, evolution, and main results. Translated from the Spanish and reprinted with permission from the Revista Cubana de Farmacia. Vol. 44 No. 2 (special supplement), Apr-Jun 2010. AB - The rapid development of Cuba's pharmaceutical industry in the 1990s created a need for structures to ensure clinical evaluation of products before their introduction into medical practice and subsequent marketing. One of the centers founded for this purpose was the National Clinical Trials Coordinating Center. This paper summarizes the factors that motivated the creation of the Center and presents a brief history of its organizational development over the last 17 years. It also describes the main components of the system for designing and conducting clinical trials, and the most significant contributions of each toward achieving the Center's objectives. PMID- 21273957 TI - Introduction of imatinib as first-line therapy for chronic myeloid leukemia in Cuba. AB - INTRODUCTION: Chronic myeloid leukemia is the first malignant disease to be associated with a genetic lesion and is the first leukemia to provide a genotype model conducive to targeted molecular therapy. It is a chronic clonal myeloproliferative disorder, originating in a pluripotent stem cell common to all three hematopoietic lineages, characterized by overproduction of myeloid cells in all stages of maturation. Approval of the use of imatinib in the United States in 2001 and its introduction in the treatment of chronic myeloid leukemia changed the evolution and prognosis of the disease and began the era of molecular therapy for malignancies. Imatinib is highly effective and causes fewer adverse reactions than earlier treatments based on interferon and hydroxyurea. In Cuba, chronic myeloid leukemia has been treated with interferon since 1998. Starting in 2003, imatinib was gradually introduced for use in newly-diagnosed chronic myeloid leukemia patients. OBJECTIVE: Evaluate the use of imatinib as first-line therapy for chronic myeloid leukemia in a group of Cuban patients, based on hematologic, cytogenetic, and molecular response; overall and event-free survival rates; and most frequency and severity of adverse reactions. METHODS: During May 2003 to May 2008, 33 newly-diagnosed chronic myeloid leukemia patients (25 adults, 8 children; <6 months from diagnosis) received a single daily oral dose of imatinib 400 mg from the time of study enrollment. Variables used: (1) to evaluate treatment efficacy: hematologic, cytogenetic, and molecular response; overall and event-free survival; and (2) to evaluate safety: presence of adverse reactions leading to definitive interruption of treatment or death. RESULTS: Complete hematologic response occurred in 100% of patients, major cytogenetic response in 90.9%, and complete cytogenetic response in 48.5%. Molecular response occurred in 36.4% of patients. With a mean follow-up of 39 months, overall survival was 96% and estimated five-year event-free survival was 85%. No adverse reactions occurred in 39.5% of patients. Adverse reactions most frequently observed were myelosuppression (24.2%) and digestive disorders (21.2%). These were followed, in decreasing order, by edema, primarily orbital (9.1%), skin depigmentation (3%), and cardiac arrhythmias (3%). CONCLUSIONS: In the present study, imatinib was effective first-line therapy for patients with newly-diagnosed chronic myeloid leukemia, as determined by overall and event-free survival rates. No severe adverse reactions were observed. PMID- 21273959 TI - Haiti one year later: Cuban medical team draws on experience and partnerships. PMID- 21273960 TI - Addressing Cuba's aging population: why epimapping needs to go local. PMID- 21273961 TI - Simulation based training of airway management with Macintosh blade and Glidescope video laryngoscope. PMID- 21273962 TI - Obesity hypoventilation syndrome and acute hypercapnia and role of noninvasive positive-pressure ventilation: a call of caution to intensivists for selecting the best strategy. PMID- 21273963 TI - Mortality following mechanical ventilation in the Intensive Care Unit: a puzzle under construction. PMID- 21273964 TI - Postoperative non-invasive ventilation outside the ICU: do not go too far! PMID- 21273965 TI - The influence of severe obesity on non-invasive ventilation (NIV) strategies and responses in patients with acute hypercapnic respiratory failure attacks in the ICU. AB - BACKGROUND: Obesity rates are increasing in the general population and are also prevalent in intensive care units (ICUs). Patients are sometimes admitted to ICUs for hypercapnic respiratory failure or cor pulmonale, but more often, they are admitted for pneumonia, excessive daytime sleepiness, heart failure, chronic obstructive pulmonary disease (COPD), asthma attacks or pulmonary embolism, and hypercapnic respiratory failure is coincidentally noticed during this period. The optimal noninvasive mechanical ventilation strategy is often not used during ICU treatment. The aim of this study was to assess the differences between non invasive ventilation (NIV) strategies and the outcomes of obese and non-obese patients with acute hypercapnic respiratory failure. METHODS: In this retrospective cohort study, 73 patients who were ventilated with a face mask were studied. Patients were divided into two groups: obese (BMI>35 kg/m2) and non obese (BMI<35 kg/m2), and the differences between these two groups in necessary pressure, volume, mode, ventilator and time to reduce PaCO2 <50 mmHg were investigated. RESULTS: The mean age of the patients was 66 +/- 14 years, and the mean admission APACHE II score was 18 +/- 4. Forty-one (56%) of the patients were female. For the obese patients, the reason for ICU admission was more frequently pulmonary edema and less frequently pulmonary infections, which was significantly different (P=0.003 and 0.043, respectively) than the rates for the non-obese patients. While there was no significant difference across the groups between the ventilators, modes and inspiratory pressure levels, obese patients required higher end-expiratory pressure levels and more time to reduce their PaCO2 levels below 50 mmHg than non-obese patients. The lengths of NIV and ICU stay and intubation and the mortality rates were similar in both groups. CONCLUSION: These results suggest that improvement in hypercapnia in obese patients may require higher PEEP levels and longer times than that of non-obese patients during acute hypercapnic respiratory failure attack. PMID- 21273966 TI - Intraneural injections and regional anesthesia: the known and the unknown. AB - Peripheral nerve injury is a rare complication of regional anesthesia. Intraneural injections were once considered harbingers of neural injury with practitioners focusing on their avoidance. With ultrasound guidance, it is now possible to visualize the difference between perineural (outside the nerve), intraneural (below the epineurium), and intrafascicular (within the perineurium) injections and to determine their association with postoperative neurological complications. We also now have a better understanding of the multifactorial nature of neurologic injury based on the nerve anatomy, site of needle insertion, bevel type, location of the needle tip, pressure achieved during injection, and underlying patient factors. Using ultrasound guidance during nerve blocks has revealed that not all intraneural injections result in injury, and its use will continue to provide insight into the mechanism of anesthetic-related nerve injury. PMID- 21273967 TI - When is the risk acceptable to proceed to noncardiac surgery following an acute myocardial infarction? AB - There is a large degree of uncertainty regarding the optimal time delay between an acute (<= 7 days) or recent (8-30 days) myocardial infarction and a patient undergoing scheduled, noncardiac surgery. Historically, the re-infarction rate for patients undergoing non-cardiac surgery within three months of a myocardial infarction has been 5%, with a very high associated mortality rate. The American Heart Association has suggested that non-cardiac surgery is acceptable six weeks after a myocardial infarction. This review considers the pathophysiology of resolution, the therapeutic responses to acute myocardial infarctions and the predictors of outcome, which may assist with the risk-benefit analysis concerning an appropriate time to proceed with non-cardiac surgery following an acute myocardial infarction. These predictors include the presence of cardiac failure, as evaluated clinically by cardiac echocardiography and increases in B-type natriuretic proteins, and the presence of persistent ischemia, as evaluated by elevations in troponin levels and ST-segment depression. PMID- 21273968 TI - Subarachnoid hemorrhage: an update for the intensivist. AB - Subarachnoid hemorrhage (SAH) remains a serious condition with high mortality and disability. In the past decades, there have been improvements in the techniques to secure aneurysms both surgical and endovascular techniques aimed at reducing the risk of future bleeding events. Nevertheless, securing the aneurysm is only the starting point in the care of SAH patients. Intracranial and extracranial complications following SAH are common and impact long-term outcomes. Intensive care management of patients with SAH offers the opportunity to reduce morbidity by reducing secondary insults and preventing complications. PMID- 21273969 TI - Lung recruitment maneuvers during acute respiratory distress syndrome: is it useful? AB - Although significant advances have been made in approaches to manage the acute respiratory distress syndrome (ARDS), reported overall mortality for ARDS is still high. Recruitment maneuvers (RM) have been recommended by some as potential adjuncts to lung protective ventilatory approaches in ARDS. In this point of view issues surrounding the use of RM in ARDS are addressed. Specifically, the ability of RM to open the lung, the safety of RM, and their affect on outcome are addressed. Finally, a specific approach to performing RM with the use of a decremental PEEP trial is outlined. PMID- 21273970 TI - An unusual airway device obstruction. PMID- 21273971 TI - Anesthesia out of surgical area in a child with Marshall-Smith Syndrome. PMID- 21273972 TI - Obstructive sleep apnea is a risk factor for difficult endotracheal intubation. PMID- 21273973 TI - A year in review in Minerva Anestesiologica 2010. Critical care. Experimental and clinical studies. PMID- 21273974 TI - Ovarian cancer: a bright future. PMID- 21273975 TI - Microarray-based gene expression studies in ovarian cancer. AB - BACKGROUND: DNA microarray technology is a powerful genomic tool that has the potential to elucidate the relationship between clinical features of cancers and their underlying biological alterations. METHODS: We performed a systemic search in PubMed and Medline databases for recently published articles. The search terms used included "genome-wide," "microarrays," "ovarian cancer," "prognosis, " "gene expression profiling, " "molecular marker, " and "molecular biomarker. " RESULTS: Genome-wide expression profiling using DNA microarray technology has enhanced our understanding of the genes that influence ovarian cancer development, histopathologic subtype, progression, response to therapy, and overall survival. CONCLUSIONS: Gene expression profiling has demonstrated its utility in ovarian cancer research. It is hoped that with technologic, statistical, and bioinformatic advances, the reliability and reproducibility of this technique will increase, spawning clinical applications that may enhance our understanding of the disease and our ability to care for patients in the future. PMID- 21273976 TI - Screening for ovarian cancer. AB - BACKGROUND: Ovarian cancer remains the most deadly of the gynecologic cancers. It is difficult to diagnose until in advanced stages. An effective screening test may help to decrease mortality from ovarian cancer. Due to the low incidence of ovarian cancer in the general population, a good screening test must have high sensitivity and specificity to allow accurate detection without excessive false positive results. Thus, effective screening for ovarian cancer has remained elusive. METHODS: Studies evaluating screening methods for ovarian cancer are reviewed. Screening methods investigated include ultrasound, CA-125, and serum proteins. RESULTS: The use of CA-125 or ultrasound alone does not result in adequate sensitivity or specificity for routine screening. A combination of the two modalities improves sensitivity, specificity, and positive predictive value. Using a combination of serum proteins may also improve sensitivity, specificity, and positive predictive value, but such studies have yet to be validated. CONCLUSIONS: No effective screening methods for ovarian cancer that have been adequately validated are available. Routine screening for ovarian cancer in the general population is not currently recommended. PMID- 21273977 TI - The role of surgery in the management of epithelial ovarian cancer. AB - BACKGROUND: Epithelial ovarian cancer is the most deadly gynecologic cancer in the United States. Multiple modalities of therapy are utilized in the management of the disease. The role of surgery remains important in the treatment of this disease and is described herein. METHODS: Medline and PubMed were utilized to search the English language medical literature up to March 2010. A broad range of studies and quality of data were analyzed, including prospective studies, case control analyses, and meta-analyses. When possible, the highest level of evidence was reviewed and presented. RESULTS: For the medically fit patient, optimal cytoreductive surgery positively impacts survival. For some highly selected patients, there is a role for a minimally invasive approach. In the recurrent setting, factors such as interval to recurrence and the distribution of disease will determine the utility of secondary cytoreductive surgery. A subgroup of patients may benefit from palliative surgical procedures in the recurrent setting. CONCLUSIONS: Despite advances in the use of chemotherapy and biologic agents, surgery remains an important modality in the diagnosis and treatment of ovarian cancer. PMID- 21273978 TI - Antiangiogenic therapies in epithelial ovarian cancer. AB - BACKGROUND: Angiogenesis is a critical component of tumor development and proliferation, and increased angiogenesis has been associated with a worse clinical outcome in a number of solid tumors, including ovarian cancer. Therefore, agents that target the angiogenic process are of considerable interest in the treatment of ovarian cancer. METHODS: Studies evaluating the efficacy of antiangiogenic agents in ovarian cancer are reported. Antiangiogenic agents examined include vascular endothelial growth factor (VEGF) pathway inhibitors, including monoclonal antibodies, tyrosine kinase inhibitors (TKIs), and a soluble receptor decoy, as well as inhibitors of other angiogenic factors and vascular disrupting agents. RESULTS: The VEGF inhibitor bevacizumab has been shown to have efficacy in ovarian cancer in phase II trials and a progression-free survival advantage in one phase III trial. TKIs block the VEGF receptors and secondary angiogenic pathways and have shown activity in phase I and II trials. Alternative angiogenesis inhibitors include EphA2 inhibitors and a selective angiopoietin 1/2 neutralizing peptibody. Another strategy is to destroy the existing tumor vasculature, and a number of vascular disrupting agents are being studied in preclinical and phase I trials. Antiangiogenic agents have a unique side effect profile, likely due to inhibition of normal physiologic angiogenesis. CONCLUSIONS: Phase II and early phase III trials have demonstrated that antiangiogenic therapies have significant activity in ovarian cancer. The results of phase III trials in the front-line and recurrent settings will determine the extent of clinical benefit of antiangiogenic therapies in combination with chemotherapy. Antiangiogenic agents have a distinct side effect profile, and further studies are necessary to evaluate how to minimize the incidence of these events and to identify women most likely to benefit from these therapies. PMID- 21273979 TI - Current and future directions of clinical trials for ovarian cancer. AB - BACKGROUND: The management of ovarian cancer includes a combination of surgery and chemotherapy. The majority of clinical trials have historically addressed questions pertaining to the selection, dosing, and schedule of chemotherapy agents. METHODS: In this report, a comprehensive review of the major clinical trials in ovarian cancer is performed. The increasing data and clinical experience in the management of ovarian cancer, as it sets the stage for currently active protocols and future clinical trial design, are emphasized. RESULTS: Paclitaxel plus carboplatin is the primary intravenous treatment strategy in the front-line setting. Recent data show an improvement in overall survival for intravenous dose-dense treatment. Multiple randomized controlled trials support the use of intraperitoneal treatment. For recurrent disease, a growing number of new agents including targeted therapeutics are now available. Increasingly, surgical approach, biologic targets, and quality of life endpoints are included in clinical trial design. CONCLUSIONS: Over the last several decades, clinical trials have defined the current therapeutic approach for ovarian cancer. Paclitaxel with a platinum-based agent is currently the preferred front-line therapy, with encouraging data to support either dose-dense or intraperitoneal drug delivery. Future trials will determine the role of biologic agents and vaccine therapies, as well as their impact on quality of life. PMID- 21273980 TI - Quality of life in ovarian cancer. AB - BACKGROUND: Ovarian cancer and its management interventions can produce significant impairments in health-related quality of life (HRQOL). These effects have been studied in both localized and advanced disease settings. METHODS: The authors assessed research reports that focus on the evaluation of HRQOL in patients with ovarian cancer in order to describe the findings and to suggest approaches that might maintain or maximize the quality of life in these patients. RESULTS: Evaluation of quality of life and functional impairment can include consideration of several issues such as the effects of the disease and its treatments on symptomatology, systemic therapy effects, the balance between life prolonging but toxic protocols, and the sexual, psychosocial, social, and financial effects of treatment. The Gynecologic Oncology Group is actively studying these issues in its protocols. CONCLUSIONS: HRQOL evaluation is a valuable measure in optimizing care of patients with ovarian cancer, but more research is needed to make such evaluations sufficiently inexpensive and easy to perform so that they can be more fully incorporated into general oncologic practice. PMID- 21273981 TI - A review of cost-effectiveness studies in ovarian cancer. AB - BACKGROUND: Ovarian cancer is the fifth leading cause of all cancer-related deaths among women. While the costs of diagnosis and treatment impact the affected individual and the health system, the most important costs for the patient are often the pain and suffering associated with ovarian cancer. The quality of life associated with any management decision should be closely examined. Cost-effectiveness models take into account costs, effects, and quality of life and provide clinicians with useful tools to aid in making these difficult decisions. METHODS: A comprehensive review of cost-effectiveness analyses was undertaken concerning screening for and treatment of ovarian cancer. RESULTS: Screening methods to detect ovarian cancer are unproven, and the majority of women present with advanced-stage disease. Multimodal screening strategies with high specificities targeted at the highest-risk individuals are the most likely strategies to be cost-effective. Primary treatment with intravenous paclitaxel and platinum regimens has proven to be cost-effective in multiple studies. Studies evaluating intraperitoneal chemotherapy show that this strategy is potentially cost-effective over a long-term time horizon. A cost-effectiveness analysis of the management of recurrent platinum-sensitive ovarian cancer showed that treatment with carboplatin and paclitaxel is cost-effective compared to single-agent therapy. However, the preferred option for patients with recurrent platinum-resistant ovarian cancer appears to be supportive care (no chemotherapy) or single-agent therapy. CONCLUSIONS: Many therapeutic choices are cost-effective in the treatment of ovarian cancer. Cost-effectiveness models offer one way to examine options in the management of a disease. The quality of life of the patient should be the most important factor in any management decision and is incorporated into well-designed studies on cost-effectiveness. PMID- 21273982 TI - An examination of educational gaps in the diagnosis and treatment of myelodysplastic syndromes. AB - BACKGROUND: Myelodysplastic syndromes (MDS) comprise a heterogeneous group of hematologic malignancies, with an incidence rate of 3.4 cases per 100,000 in the United States. MDS affects patients predominantly over 60 years of age. As these syndromes are not well understood by many medical practitioner, patients with MDS may be underrecognized or underdiagnosed. The availability of new MDS treatment options further establishes the need to more closely assess gaps in clinical practice and underscores the necessity to develop educational activities to address those gaps. METHODS: A multidisciplinary panel was convened to examine current educational needs and gaps. A group consensus approach incorporating a modified nominal group technique was utilized to prioritize and review needs identified in the pre-meeting survey and to evaluate data provided by panelists prior to the meeting. RESULTS: The panel identified and prioritized seven educational areas of need: (1) MDS disease awareness, (2) diagnosis, (3) classification and risk stratification, (4) treatment issues, (5) referral to stem cell transplantation or new treatment protocols, (6) clinical monitoring and toxicity management, and (7) translation of new data into patient care. CONCLUSIONS: In-depth knowledge is critical to the timely diagnosis and optimal care of MDS patients. A number of key educational needs exist. Educational programs should be practical in orientation to integrate data into practice, and they should be tailored for the intended audience. In addition, an effective educational program must be easily applied by participants. PMID- 21273983 TI - Association of necrotizing enterocolitis with anemia and packed red blood cell transfusions in preterm infants. AB - OBJECTIVE: To determine association of anemia and red blood cell (RBC) transfusions with necrotizing enterocolitis (NEC) in preterm infants. STUDY DESIGN: A total of 111 preterm infants with NEC >= stage 2a were compared with 222 matched controls. In all, 28 clinical variables, including hematocrit (Hct) and RBC transfusions were recorded. Propensity scores and multivariate logistic regression models were created to examine effects on the risk of NEC. RESULT: Controlling for other factors, lower Hct was associated with increased odds of NEC (odds ratio (OR)=1.10, P=0.01). RBC transfusion has a temporal relationship with NEC onset. Transfusion within 24 h (OR=7.60, P=0.001) and 48 h (OR=5.55, P=0.001) has a higher odds of developing NEC but this association is not significant by 96 h (OR=2.13, P=0.07), post-transfusion. CONCLUSION: Anemia may increase the risk of developing NEC in preterm infants. RBC transfusions are temporally related to NEC. Prospective studies are needed to better evaluate the potential influence of transfusions on the development of NEC. PMID- 21273984 TI - Early postnatal hypotension is not associated with indicators of white matter damage or cerebral palsy in extremely low gestational age newborns. AB - OBJECTIVE: To evaluate, in extremely low gestational age newborns (ELGANs), relationships between indicators of early postnatal hypotension and cranial ultrasound indicators of cerebral white matter damage imaged in the nursery and cerebral palsy diagnoses at 24 months follow-up. STUDY DESIGN: The 1041 infants in this prospective study were born at <28 weeks gestation, were assessed for three indicators of hypotension in the first 24 postnatal hours, had at least one set of protocol cranial ultrasound scans and were evaluated with a structured neurological exam at 24 months corrected age. Indicators of hypotension included: (1) lowest mean arterial pressure (MAP) in the lowest quartile for gestational age; (2) treatment with a vasopressor; and (3) blood pressure lability, defined as the upper quartile of the difference between each infant's lowest and highest MAP. Outcomes included indicators of cerebral white matter damage, that is, moderate/severe ventriculomegaly or an echolucent lesion on cranial ultrasound and cerebral palsy diagnoses at 24 months gestation. Logistic regression was used to evaluate relationships among hypotension indicators and outcomes, adjusting for potential confounders. RESULT: Twenty-one percent of surviving infants had a lowest blood pressure in the lowest quartile for gestational age, 24% were treated with vasopressors and 24% had labile blood pressure. Among infants with these hypotension indicators, 10% percent developed ventriculomegaly and 7% developed an echolucent lesion. At 24 months follow-up, 6% had developed quadriparesis, 4% diparesis and 2% hemiparesis. After adjusting for confounders, we found no association between indicators of hypotension, and indicators of cerebral white matter damage or a cerebral palsy diagnosis. CONCLUSION: The absence of an association between indicators of hypotension and cerebral white matter damage and or cerebral palsy suggests that early hypotension may not be important in the pathogenesis of brain injury in ELGANs. PMID- 21273985 TI - A meta-analysis of dopamine use in hypotensive preterm infants: blood pressure and cerebral hemodynamics. AB - OBJECTIVE: Dopamine administration results in variable effects on blood pressure in hypotensive preterm infants. The clinical benefits of dopamine administration in increasing cerebral blood flow (CBF) and reducing adverse neurological outcomes in hypotensive preterm neonates are unclear. The objective of this study was to examine the efficacy of dopamine for treatment of hypotension and investigate the changes in cerebral hemodynamics and central nervous system injury in hypotensive preterm infants following dopamine administration. STUDY DESIGN: Standard meta-analytic techniques, including random and fixed effects models, were used to calculate combined effect size correlations and significance levels. RESULT: Random effects meta-analysis found that dopamine increases mean arterial blood pressure (12 studies; N=163; r=0.88, 95% confidence interval (CI)=0.76 to 0.94) and systolic blood pressure (8 studies; N=142; r=0.81, 95% CI=0.42 to 0.94). For the increase in blood pressure, dopamine administration was associated with a significantly greater overall efficacy than dobutamine (seven studies; N=251; r=0.26; 95% CI=0.20 to 0.32), colloid (two studies; N=67; r=0.60; 95% CI=0.41 to 0.74) and hydrocortisone (one study; N=28; r=0.40; 95% CI=0.034 to 0.67). CBF increased following dopamine administration (five studies; N=75; r=0.36; 95% CI=-0.059 to 0.67) and the increase in CBF was greater in hypotensive than normotensive preterm infants (eight studies; N=153; r=0.16; 95% CI=-0.0080 to 0.32). There were no statistically significant differences in adverse neurological outcome between dopamine and dobutamine (three studies; N=118; r= 0.13; 95% CI=-0.31 to 0.059), epinephrine (two studies; N=46; r=0.06; 95% CI= 0.23 to 0.34), colloid (two studies; N=80; r=0.0070; 95% CI=-0.218 to 0.23) or hydrocortisone administration (one study; N=40; r=-0.10; 95% CI=-0.40 to 0.22). CONCLUSION: Dopamine administration increases mean and systolic blood pressure in hypotensive preterm infants, and is more effective than dobutamine, colloid or hydrocortisone alone. Dopamine administration is associated with increased CBF, with greater increases in CBF in hypotensive than in normotensive preterm infants. Dopamine is not associated with a greater incidence of adverse effects than other therapies used to treat hypotension. PMID- 21273986 TI - Impact of balloon atrial septostomy in neonates with transposition of great arteries. AB - OBJECTIVE: To examine the impact of balloon atrial septostomy (BAS) on cardio respiratory status, need for prostaglandin E(1) (PGE(1)) and postoperative outcomes in infants with transposition of great arteries (TGA). STUDY DESIGN: Single-center retrospective review of consecutive neonates with dTGA. RESULT: BAS was performed in 42 (70%) infants and resulted in a significant increase in minimum (61 to 76%) and maximum (80 to 90%) oxygen (O(2)) saturations and a drop in FiO(2). BAS was 'successful,' that is, PGE(1) was discontinued in 16 (38%) infants. Three infants died; four infants developed strokes, all of whom had undergone BAS. The duration of hospitalization, ventilation and O(2) need did not differ between infants without BAS, 'successful' BAS and unsuccessful BAS. PGE(1) duration correlated with duration of hospitalization, ventilation, O(2) need and peak respiratory severity score (P<0.03). CONCLUSION: We speculate that limiting BAS for clinical hypoxemia and aggressive weaning of PGE(1) following BAS would improve outcomes. PMID- 21273987 TI - Direct breast-feeding in the neonatal intensive care unit: is it important? AB - OBJECTIVE: Rates of breast milk feeding at hospital discharge are low in premature infants due to the many associated challenges. Although there are many benefits associated with breast milk, the effects of direct breast-feeding in the neonatal intensive care unit (NICU) have not been identified. The purpose of this study was to investigate the relationship between direct breast-feeding (infant sucking directly from the breast) and duration and success with breast milk feedings until discharge in premature infants. STUDY DESIGN: This retrospective cohort was conducted on 66 very-low birth weight infants whose mothers initiated breast milk feedings in the NICU. Chart review revealed documented type (breast milk with or without fortifiers or type of infant formula), volume and mode (nasogastric tube, breast or bottle) of all gastric feeds for each day of NICU hospitalization. From this documentation, whether the mother initiated breast milk feedings, the number of times the mother put the infant to breast, the gestational age of the first direct breast-feeding, whether the first oral feeding was at the breast, the duration of breast milk feedings and whether breast milk feedings continued until NICU discharge were determined. Associations between breast-feeding participatory factors and breast milk feeding outcomes were investigated using linear and logistic regression. RESULT: Positive associations were found between breast milk feedings at discharge and mothers putting their infants directly to breast in the NICU (P=0.0005). The duration of breast milk feedings was associated with: mothers putting their infants directly to breast (P=0.0110), whether the first oral sucking feeding was at the breast (P=0.0108) and the gestational age of the first breast-feeding attempt (P<0.0001). CONCLUSION: Breast milk feedings are encouraged in most NICU's, but direct breast-feeding is often overlooked as an important area of research in the tightly controlled environment of the NICU. This study demonstrates a link between direct breast-feeding behaviors in the NICU and success with provision of milk at discharge, as well as how early participation can be an important factor in the breast-feeding process for mothers of NICU infants. More research on the effects of direct breast-feeding is warranted. PMID- 21273988 TI - The age of necrotizing enterocolitis onset: an application of Sartwell's incubation period model. AB - OBJECTIVE: Model age of necrotizing enterocolitis (NEC) onset applying Sartwell's model of incubation periods, and examine its relationship to gestational age (GA). STUDY DESIGN: Retrospective chart review of St Louis Children's Hospital neonates diagnosed with NEC (>=Bell's stage II) from 2004 to 2008, inclusive. RESULT: The relationship between age of NEC (N=84 cases) onset and GA best fits a non-linear model, with infants <=28 weeks having a disproportionately longer time to onset than older GA groups and explained 50.3% of the variability in age of NEC onset. Additional clinical variables provided no improvement in explaining age of NEC onset. Application of Sartwell's model to age of NEC onset proved a good fit, when birth is used as the common exposure episode, and age is equivalent of the incubation period. CONCLUSION: The relationship between day of NEC diagnosis and GA is non-linear, with lower GA infants having disproportionately longer time to onset. Despite these GA differences, the fit to Sartwell's model for incubation periods model is consistent with NEC being a consequence of an event that occurs at or soon after birth. PMID- 21273989 TI - Why do families of sick newborns accept hospital care? A community-based cohort study in Karachi, Pakistan. AB - OBJECTIVE: Sick young infants are at high risk of mortality in developing countries, but families often decline hospital referral. Our objective was to identify the predictors of acceptance of referral for hospital care among families of severely ill newborns and infants <59 days old in three low-income communities of Karachi, Pakistan. STUDY DESIGN: A cohort of 541 newborns and infants referred from home by community health workers conducting household surveillance, and diagnosed with a serious illness at local community clinics between 1 January and 31 December 2007, was followed-up within 1 month of referral to the public hospital. RESULT: Only 24% of families accepted hospital referral. Major reasons for refusal were financial difficulties (67%) and father/elder denying permission (65%). Religious/cultural beliefs were cited by 20% of families. Referral acceptance was higher with recognition of severity of the illness by mother (odds ratio=12.7; 95% confidence interval=4.6 to 35.2), family's ability to speak the dominant language at hospital (odds ratio=2.0; 95% confidence interval=1.3-3.1), presence of grunting in the infant (odds ratio=3.3; 95% confidence interval=1.2-9.0) and infant temperature <35.5 degrees C (odds ratio=4.1; 95% confidence interval=2.3 to 7.4). No gender differential was observed. CONCLUSION: Refusal of hospital referral for sick young infants is very common. Interventions that encourage appropriate care seeking, as well as community-based management of young infant illnesses when referral is not feasible are needed to improve neonatal survival in low-income countries. PMID- 21273990 TI - Impact of electronic medical record integration of a handoff tool on sign-out in a newborn intensive care unit. AB - OBJECTIVE: To evaluate the impact of integrating a handoff tool into the electronic medical record (EMR) on sign-out accuracy, satisfaction and workflow in a neonatal intensive care unit (NICU). STUDY DESIGN: Prospective surveys of neonatal care providers in an academic children's hospital 1 month before and 6 months following EMR integration of a standalone Microsoft Access neonatal handoff tool. RESULT: Providers perceived sign-out information to be somewhat or very accurate at a rate of 78% with the standalone handoff tool and 91% with the EMR-integrated tool (P < 0.01). Before integration of neonatal sign-out into the EMR, 35% of providers were satisfied with the process of updating sign-out information and 71% were satisfied with the printed sign-out document; following EMR integration, 92% of providers were satisfied with the process of updating sign-out information (P < 0.01) and 98% were satisfied with the printed sign-out document (P<0.01). Neonatal care providers reported spending a median of 11 to 15 min/day updating the standalone sign-out and 16 to 20 min/day updating the EMR integrated sign-out (P = 0.026). The median percentage of total sign-out preparation time dedicated to transcribing information from the EMR was 25 to 49% before and <25% after EMR integration of the handoff tool (P < 0.01). CONCLUSION: Integration of a NICU-specific handoff tool into an EMR resulted in improvements in perceived sign-out accuracy, provider satisfaction and at least one aspect of workflow. PMID- 21273991 TI - Relationship between trajectories of trunk fat mass development in adolescence and cardiometabolic risk in young adulthood. AB - To examine developmental trajectories of trunk fat mass (FM) growth of individuals categorized as either low or high for cardiometabolic risk at 26 years, a total of 55 males and 76 females from the Saskatchewan Pediatric Bone Mineral Accrual Study (1991-2007) were assessed from adolescence (11.5 +/- 1.8 years) to young adulthood (26.2 +/- 2.2 years) (median of 11 visits per individual) and had a measure of cardiometabolic risk in young adulthood. Participants were categorized as low or high for blood pressure and cardiometabolic risk as adults using a sex-specific median split of continuous standardized risk scores. Individual trunk FM trajectories of participants in each risk group were analyzed using multilevel random effects models. Males and females in the high blood pressure group had significantly steeper (accelerated) trajectories of trunk FM development (0.61 +/- 0.14 and 0.52 +/- 0.10 log g, respectively) than those in the low blood pressure group for females in the high cardiometabolic risk group trajectory of trunk FM was significantly steeper (0.52 +/- 0.10 log g) than those females in the low cardiometabolic risk group. Dietary fat was positively related (0.01 +/- 0.003 g/1,000 kcal) and physical activity negatively related (-0.16 +/- 0.05 physical activity score) to trunk FM development in males. Young adults with high cardiometabolic risk, compared to low, have greater trunk FM as early as 8 years of age, which supports the need for early intervention. PMID- 21273993 TI - The contribution of visceral adiposity and mid-thigh fat-rich muscle to the metabolic profile in postmenopausal women. AB - This study explored the relationship between muscle fat infiltration derived from mid-thigh computed tomography (CT) scan, central fat distribution and insulin sensitivity in postmenopausal women. Mid-thigh CT scans were used to measure low attenuation muscle surface (LAMS) (0-34 Hounsfield units (HU)), which represented a specific component of fat-rich muscle. Whole-body insulin sensitivity (M/I) was evaluated by an euglycemic-hyperinsulinemic clamp. A group of 103 women aged 57.0 +/- 4.4 years was studied. Women with higher levels of LAMS presented higher metabolic risk features, particularly elevated fasting, 2-h plasma glucose (2hPG) concentrations and diminished M/I (P < 0.05). To further study the contribution of muscle fat infiltration and central adiposity on metabolic parameters, we divided the whole group based on the median of LAMS and visceral adipose tissue (VAT). As expected, the best metabolic profile was found in the Low-LAMS/Low-VAT group and the worst in the High-LAMS/High-VAT group. Women with Low-LAMS/High-VAT presented similar metabolic risks to those with High-LAMS/High-VAT. There was no difference between High-LAMS/Low-VAT and Low-LAMS/Low-VAT, which presents the most healthy metabolic and glycemic profiles as reflected by the lowest levels of cardiovascular disease risk variables. This suggests that High-LAMS/Low-VAT is also at low risk of metabolic deteriorations and that High-LAMS, only in the presence of High-VAT seems associated with deteriorated risks. Although increased mid-thigh fat-rich muscle was related to a deteriorated metabolic profile, VAT appears as a more important contributor to alterations in the metabolic profile in postmenopausal women. PMID- 21273992 TI - ADIPOQ, ADIPOR1, and ADIPOR2 polymorphisms in relation to serum adiponectin levels and BMI in black and white women. AB - Adiponectin is an adipose-secreted protein with influence on several physiologic pathways including those related to insulin sensitivity, inflammation, and atherogenesis. Adiponectin levels are highly heritable and several single nucleotide polymorphisms (SNPs) in adiponectin-related genes (ADIPOQ, ADIPOR1, ADIPOR2) have been examined in relation to circulating adiponectin levels and obesity phenotypes, but despite differences in adiponectin levels and obesity prevalence by race, few studies have included black participants. Using cross sectional interview data and blood samples collected from 990 black and 977 white women enrolled in the Southern Community Cohort Study (SCCS) from 2002 to 2006, we examined 25 SNPs in ADIPOQ, 19 in ADIPOR1, and 27 in ADIPOR2 in relation to serum adiponectin levels and BMI using race-stratified linear regression models adjusted for age and percentage African ancestry. SNP rs17366568 in ADIPOQ was significantly associated with serum adiponectin levels in white women only (adjusted mean adiponectin levels = 15.9 for G/G genotype, 13.7 for A/G, and 9.3 for A/A, P = 0.00036). No other SNPs were associated with adiponectin or BMI among blacks or whites. Because adiponectin levels as well as obesity are highly heritable and vary by race but associations with polymorphisms in the ADIPOQ, ADIPOR1, and ADIPOR2 genes have been few in this and other studies, future work including large populations from diverse racial groups is needed to detect additional genetic variants that influence adiponectin and BMI. PMID- 21273994 TI - Sleep apnea, reproductive hormones and quality of sexual life in severely obese men. AB - The effect of sleep apnea on the reproductive function of obese men is not entirely elucidated. The objective of this study was to define the effect of sleep apnea on the reproductive hormones and sexual function in obese men. This study included 89 severely obese men with BMI >=35 kg/m2 considering gastric bypass surgery. Anthropometrics (weight, and BMI), reproductive hormones, and sleep studies were measured. The sexual quality of life was assessed using the Impact of Weight on Quality of Life-Lite questionnaire (IWQOL-Lite). The mean age of our patients was 46.9 +/- 11.0 years, the mean BMI was 47.8 +/- 8.7 kg/m2 and the mean weight was 337.7 +/- 62.4 lb. After correction for age and BMI, means of free testosterone per severity group of sleep apnea were as follows: no or mild sleep apnea 74.4 +/- 3.8 pg/ml, moderate sleep apnea 68.6 +/- 4.2 pg/ml, and severe sleep apnea 60.2 +/- 2.92 pg/ml, P = 0.014. All other parameters of sleep apnea including hypopnea index, percent time below a SpO2 of 90%, and percent time below a SpO2 of 80% were also negatively correlated with testosterone levels after correction for age and BMI. BMI and presence of coronary artery disease decreased the sexual quality of life. Sleep apnea was associated with reduced sexual quality of life. In summary, sleep apnea negatively affects testosterone levels independent of BMI. Severely obese men had decreased sexual quality of life. PMID- 21273995 TI - Ecological momentary assessment of obesogenic eating behavior: combining person specific and environmental predictors. AB - Obesity has been promoted by a food environment that encourages excessive caloric intake. An understanding of how the food environment contributes to obesogenic eating behavior in different types of individuals may facilitate healthy weight control efforts. In this study, Ecological Momentary Assessment (EMA) via palmtop computers was used to collect real-time information about participants' environment and eating patterns to predict overeating (i.e., greater than usual intake during routine meals/snacks, and eating outside of a participant's normal routine) that could lead to weight gain. Thirty-nine women (BMI = 21.6 +/- 1.8; age = 20.1 +/- 2.0 years; 61% white) of normal weight (BMI 18.5-25) completed the Three Factor Eating Questionnaire and the Power of Food Scale (PFS), and carried a palmtop computer for 7-10 days, which prompted them to answer questions about eating events, including a count of the types of good tasting high-calorie foods that were available. None of the self-report measures predicted overeating, but BMI interacted with the number of palatable foods available to predict overeating (P = 0.035). Compared to leaner individuals who reported a relatively low frequency of overeating regardless of the availability of palatable food, the probability of overeating among heavier individuals was very low in the absence of palatable food, but quickly increased in proportion to the number of palatable foods available. Our findings suggest that the eating behavior of those with higher relative weights is susceptible to the presence of palatable foods in the environment. Individuals practicing weight control may benefit from limiting their exposure to good tasting high-calorie food in their immediate environment. PMID- 21273996 TI - Weight loss goals among African-American women with type 2 diabetes in a behavioral weight control program. AB - African-American women with type 2 diabetes experience limited weight loss in behavioral weight control programs. Some research suggests that overly ambitious weight loss expectations may negatively affect weight losses achieved but it is unknown whether they affect weight loss among African-American women. The current study examined personal weight loss goals and expected satisfaction with a reasonable weight loss among African-American women with type 2 diabetes starting a behavioral obesity treatment. We also explored associations among these factors and weight loss treatment outcomes. Self-identified African-American women (N = 84) in a 24-session group program were assessed at baseline and 6-month follow up. At baseline, women indicated weight loss goals of 14.1 +/- 6.6 kg (14% of initial weight). They also reported relatively high expected satisfaction with a reasonable weight loss (7-10%). On average, participants lost 3.0 +/- 3.9 kg (3% of initial weight) and attended 73 +/- 21% of group sessions. Neither weight loss goals nor expected satisfaction with a reasonable weight loss was correlated with either actual weight loss outcome or attendance. Having higher personal weight loss goals was associated with lower expectations of satisfaction with a reasonable weight loss. This suggests that African-American women with type 2 diabetes enter treatment hoping to lose far more weight than they are likely to achieve. It is important to understand the psychosocial sequelae of failing to reach these goals on subsequent weight maintenance and future weight loss attempts within this population. PMID- 21273997 TI - DNA methylation variability at growth-related imprints does not contribute to overweight in monozygotic twins discordant for BMI. AB - Defective genomic imprinting is often associated with syndromes that include abnormal growth as a clinical phenotype. However, whether differential methylation at imprinted loci also contributes to nonsyndromic abnormal body weight regulation is yet unknown. In this study, we investigated a potential contribution of aberrant DNA methylation at nine differentially methylated regions (DMRs) to the development of nonsyndromic overweight. Sixteen monozygotic (MZ) twins discordant for BMI (BMI difference ranging from 2.9-9.5 kg/m(2)) were recruited from the East Flanders Prospective Twin Survey. DNA extracted from saliva samples was bisulfite-treated followed by PCR amplification of target regions in DMRs most representative for abnormal growth syndromes: KvDMR1, H19 CTCF4, H19 CTCF6, IGF2 DMR0, IGF2 DMR2, GRB10, MEST, SNRPN, GNAS XL-alpha-s and GNAS Exon1A. At the DMRs analyzed, methylation-dependent primer extension experiments revealed only small intrapair differences in methylation indexes (MI) between the heavy and lean co-twins. In addition, no significant correlations between intrapair BMI differences and intrapair differences in MI were observed. In conclusion, DNA methylation variability at the nine DMRs analyzed does not seem to contribute to the discordancy in BMI observed in these MZ twins. PMID- 21273998 TI - High-resolution genome-wide linkage mapping identifies susceptibility loci for BMI in the Chinese population. AB - The genetic loci affecting the commonly used BMI have been intensively investigated using linkage approaches in multiple populations. This study aims at performing the first genome-wide linkage scan on BMI in the Chinese population in mainland China with hypothesis that heterogeneity in genetic linkage could exist in different ethnic populations. BMI was measured from 126 dizygotic twins in Qingdao municipality who were genotyped using high-resolution Affymetrix Genome Wide Human SNP arrays containing about 1 million single-nucleotide polymorphisms (SNPs). Nonparametric linkage analysis was performed with Merlin software package for linkage analysis using variance components approach for quantitative trait loci mapping. We identified a strong linkage peak at the end of chromosome 7 (7q36 at 186 cM) with a lod score of 4.06 which overlaps with that reported by a large multicenter study in western countries. Multiple loci showing suggestive linkage were found on chromosome 1 (lod score 2.38 at 242 cM), chromosome 8 (2.48 at 95 cM), and chromosome 14 (2.2 at 89.4 cM). The strong linkage identified in the Chinese subjects that is consistent with that found in populations of European origin could suggest the existence of evolutionarily preserved genetic mechanisms for BMI whereas the multiple suggestive loci could represent genetic effect from gene-environment interaction as a result of population-specific environmental adaptation. PMID- 21273999 TI - Factors associated with early atherosclerosis and arterial calcifications in young subjects with a benign phenotype of obesity. AB - We assessed (i) the association between early arterial disease and factors linked to adiposity, dietary habits, and family in a young cohort of 151 obese children and adolescents with less than or equal to one cardiovascular (CV) risk factor, (ii) whether in subjects with carotid calcifications there was an imbalance of calcium-phosphorus homeostasis. Measurement included: carotid ultrasound, oral glucose tolerance test, anthropometry, body composition, dietary history, white blood cells count, lipids, uric acid, adiponectin, insulin, C-reactive protein, plasminogen activator inhibitor 1 (PAI-1), 25-hydroxyvitamin D, parathyroid hormone (PTH), calcium and phosphorus. Obese children with carotid artery intima media thickness (cIMT) values >75 degrees percentile (0.55 mm), compared to those with lower cIMT, were more obese, more often pubertal and had higher prevalence of family history of CV disease (CVD) (P < 0.05), higher plasma PAI-1 and uric acid (P < 0.001) and lower adiponectin (P < 0.05) and high-density lipoprotein (HDL) cholesterol levels (P < 0.05). After adjustment for sex, age, puberty, obesity, and insulin levels, only PAI-I remained significantly different between the two groups (10.9 (7.2-29.8) vs. 6.2 (4.3-10.6) ng/ml, P < 0.001). Dietary intake did not affect cIMT values. Eight percent of subjects showed nonatherosclerotic carotid calcifications with patchy pattern. These children had a worse lipid profile (P < 0.05) and higher plasma PTH levels (48.6 +/- 21.5 vs 38.5 +/- 16.9 pg/ml, P < 0.05) that were inversely associated with 25 hydroxyvitamin D levels (r = 0.245, P < 0.01). Present results suggest that (i) several adiposity-related factors may play a role in promoting the development of early arterial diseases in young subjects with a benign phenotype of obesity, (ii) a PTH rise resulting from a subclinical imbalance in calcium-phosphorus homeostasis may affect the biological process of vascular calcifications. PMID- 21274000 TI - CD200 expression suppresses natural killer cell function and directly inhibits patient anti-tumor response in acute myeloid leukemia. AB - Upregulation of the immunosuppressive cell surface glycoprotein, CD200, is a common feature of acute myeloid leukemia (AML) and is associated with poor patient outcome. We investigated whether CD200 overexpression on AML cells could specifically compromise patient natural killer (NK) cell anti-tumor responses. We found that CD200(hi) patients showed a 50% reduction in the frequency of activated NK cells (CD56(dim)CD16(+)) compared with CD200(lo) patients. Additionally, NK receptor expression (NKp44 and NKp46) on these cells was also significantly downregulated in CD200(hi) patients. To assess whether NK cell activity was directly influenced by CD200 expression, we examined the effect of ectopic expression of CD200. These assays revealed that both NK cell cytolytic activity and interferon-gamma response were significantly reduced toward CD200(+) leukemic targets and that these targets showed increased survival compared with CD200(-) cells. Similarly, NK cells isolated from AML patients were less functionally active toward CD200(hi) autologous blasts from both cytolytic and immunoregulatory perspectives. Finally, blocking CD200 alone was sufficient to recover a significant proportion of NK cell cytolytic activity. Together, these findings provide the first evidence that CD200 has a direct and significant suppressive influence on NK cell activity in AML patients and may contribute to the increased relapse rate in CD200(+) patients. PMID- 21274001 TI - HAX-1 expression in human B lymphoma. PMID- 21274002 TI - Interferon-alpha in acute myeloid leukemia: an old drug revisited. AB - Interferon-alpha (IFN-alpha), a type I IFN, is a well-known antitumoral agent. The investigation of its clinical properties in acute myeloid leukemia (AML) has been prompted by its pleiotropic antiproliferative and immune effects. So far, integration of IFN-alpha in the therapeutic arsenal against AML has been modest in view of the divergent results of clinical trials. Recent insights into the key pharmacokinetic determinants of the clinical efficacy of IFN along with advances in its pharmaceutical formulation, have sparked renewed interest in its use. This paper reviews the possible applicability of IFN-alpha in the treatment of AML and provides a rational basis to re-explore its efficacy in clinical trials. PMID- 21274003 TI - Comprehensive array CGH of normal karyotype myelodysplastic syndromes reveals hidden recurrent and individual genomic copy number alterations with prognostic relevance. AB - About 40% of patients with myelodysplastic syndromes (MDSs) present with a normal karyotype, and they are facing different courses of disease. To advance the biological understanding and to find molecular prognostic markers, we performed a high-resolution oligonucleotide array study of 107 MDS patients (French American British) with a normal karyotype and clinical follow-up through the Duesseldorf MDS registry. Recurrent hidden deletions overlapping with known cytogenetic aberrations or sites of known tumor-associated genes were identified in 4q24 (TET2, 2x), 5q31.2 (2x), 7q22.1 (3x) and 21q22.12 (RUNX1, 2x). One patient with a 7q22.1 deletion had an additional 5q31.2 deletion of the acute myeloid leukemia/MDS region, the smallest deletion identified so far and including the putative tumor suppressor (ts) genes, EGR1 and CTNNA1. One TET2 deletion was homozygous and one heterozygous, with a missense mutation in the remaining allele, further supporting its role as a ts gene. Besides these recurrent alterations, additional individual imbalances were found in 34 cases; in total, 42/107 (39%) cases had genomic imbalances. These patients had an inferior survival as compared with the rest of the patients (P=0.002). This study emphasizes the heterogeneity of MDS, but points to interesting genes that may have diagnostic and prognostic impact. PMID- 21274004 TI - A deep-sequencing study of chronic myeloid leukemia patients in blast crisis (BC CML) detects mutations in 76.9% of cases. PMID- 21274005 TI - Inner-membrane proteins PMI/TMEM11 regulate mitochondrial morphogenesis independently of the DRP1/MFN fission/fusion pathways. AB - Mitochondria are highly dynamic organelles that can change in number and morphology during cell cycle, development or in response to extracellular stimuli. These morphological dynamics are controlled by a tight balance between two antagonistic pathways that promote fusion and fission. Genetic approaches have identified a cohort of conserved proteins that form the core of mitochondrial remodelling machineries. Mitofusins (MFNs) and OPA1 proteins are dynamin-related GTPases that are required for outer- and inner-mitochondrial membrane fusion respectively whereas dynamin-related protein 1 (DRP1) is the master regulator of mitochondrial fission. We demonstrate here that the Drosophila PMI gene and its human orthologue TMEM11 encode mitochondrial inner membrane proteins that regulate mitochondrial morphogenesis. PMI-mutant cells contain a highly condensed mitochondrial network, suggesting that PMI has either a pro-fission or an anti-fusion function. Surprisingly, however, epistatic experiments indicate that PMI shapes the mitochondria through a mechanism that is independent of drp1 and mfn. This shows that mitochondrial networks can be shaped in higher eukaryotes by at least two separate pathways: one PMI-dependent and one DRP1/MFN-dependent. PMID- 21274006 TI - A new meiosis-specific cohesin complex implicated in the cohesin code for homologous pairing. AB - We identify a new mammalian cohesin subunit, RAD21-like protein (RAD21L), with sequence similarity to RAD21 and REC8. RAD21L localizes along axial elements in early meiotic prophase, in a manner that is spatiotemporally different to either REC8 or RAD21. Remarkably, RAD21L and REC8 have symmetrical, mutually exclusive localization on the not-yet-synapsed homologues, implying that the cohesin patterning could provide a code for homologue recognition. RAD21 transiently localizes to axial elements after the dissociation of RAD21L and REC8 in late pachytene, a period of recombination repair. Further, we show that the removal of cohesins and synaptonemal complex during late meiotic prophase is promoted by Polo-like kinase 1, which is similar to the mitotic prophase pathway. PMID- 21274007 TI - Phospho-DeltaNp63alpha is a key regulator of the cisplatin-induced microRNAome in cancer cells. AB - Head and neck squamous cell carcinoma (HNSCC) cells exposed to cisplatin (CIS) displayed a dramatic ATM-dependent phosphorylation of DeltaNp63alpha that leads to the transcriptional regulation of downstream mRNAs. Here, we report that phospho (p)-DeltaNp63alpha transcriptionally deregulates miRNA expression after CIS treatment. Several p-DeltaNp63alpha-dependent microRNA species (miRNAs) were deregulated in HNSCC cells upon CIS exposure, including miR-181a, miR-519a, and miR-374a (downregulated) and miR-630 (upregulated). Deregulation of miRNA expression led to subsequent modulation of mRNA expression of several targets (TP53-S46, HIPK2, ATM, CDKN1A and 1B, CASP3, PARP1 and 2, DDIT1 and 4, BCL2 and BCL2L2, TP73, YES1, and YAP1) that are involved in the apoptotic process. Our data support the notion that miRNAs are critical downstream targets of p DeltaNp63alpha and mediate key pathways implicated in the response of cancer cells to chemotherapeutic drugs. PMID- 21274008 TI - MTBP plays a crucial role in mitotic progression and chromosome segregation. AB - Murine double minute 2 (MDM2) binding protein (MTBP) has been implicated in tumor cell proliferation, but the underlying mechanisms remain unclear. The results of MTBP expression analysis during cell cycle progression demonstrated that MTBP protein was rapidly degraded during mitosis. Immunofluorescence studies revealed that a portion of MTBP was localized at the kinetochores during prometaphase. MTBP overexpression delayed mitotic progression from nuclear envelope breakdown (NEB) to anaphase onset and induced abnormal chromosome segregation such as lagging chromosomes, chromosome bridges, and multipolar chromosome segregation. Conversely, MTBP downmodulation caused an abbreviated metaphase and insufficient mitotic arrest, resulting in abnormal chromosome segregation, aneuploidy, decreased cell proliferation, senescence, and cell death, similar to that of Mad2 (mitotic arrest-deficient 2) downmodulation. Furthermore, MTBP downmodulation inhibited the accumulation of Mad1 and Mad2, but not BubR1 (budding uninhibited by benzimidazoles related 1), on the kinetochores, whereas MTBP overexpression inhibited the release of Mad2 from the metaphase kinetochores. These results may imply that MTBP has an important role in recruiting and/or retaining the Mad1/Mad2 complex at the kinetochores during prometaphase, but its degradation is required for silencing the mitotic checkpoint. Together, this study indicates that MTBP has a crucial role in proper mitotic progression and faithful chromosome segregation, providing new insights into regulation of the mitotic checkpoint. PMID- 21274009 TI - Derivation of neural precursor cells from human ES cells at 3% O(2) is efficient, enhances survival and presents no barrier to regional specification and functional differentiation. AB - In vitro stem cell systems traditionally employ oxygen levels that are far removed from the in vivo situation. This study investigates whether an ambient environment containing a physiological oxygen level of 3% (normoxia) enables the generation of neural precursor cells (NPCs) from human embryonic stem cells (hESCs) and whether the resultant NPCs can undergo regional specification and functional maturation. We report robust and efficient neural conversion at 3% O(2), demonstration of tri-lineage potential of resultant NPCs and the subsequent electrophysiological maturation of neurons. We also show that NPCs derived under 3% O(2) can be differentiated long term in the absence of neurotrophins and can be readily specified into both spinal motor neurons and midbrain dopaminergic neurons. Finally, modelling the oxygen stress that occurs during transplantation, we demonstrate that in vitro transfer of NPCs from a 20 to 3% O(2) environment results in significant cell death, while maintenance in 3% O(2) is protective. Together these findings support 3% O(2) as a physiologically relevant system to study stem cell-derived neuronal differentiation and function as well as to model neuronal injury. PMID- 21274010 TI - Amblyopia and quality of life: a systematic review. AB - Amblyopia is a common condition, which can affect up to 5% of the general population. Health-related quality-of-life (HRQoL) implications of amblyopia and/or its treatment have been explored in the literature. A systematic literature search was undertaken during the period of 7-14 May 2010 to identify the HRQoL implications of amblyopia and/or its treatment. A total of 35 papers were included in the literature review. The HRQoL implications of amblyopia related specifically to amblyopia treatment, rather than to the condition itself. These included impact on family life, social interactions, difficulties in undertaking daily activities, as well as feelings and behaviour. The identified studies adopted a number of methodologies. The study populations included children with the condition, parents of children with amblyopia, and adults who had undertaken amblyopia treatment as a child. Some studies developed their own measures of HRQoL, and others determined HRQoL through proxy measures. The reported findings of the HRQoL implications are of importance when considering the management of cases of amblyopia. The issues identified in the literature review are discussed with respect to how HRQoL is measured (treatment compliance vs proxy measures), and whether HRQoL is taken from a child's or a parent's perspective. Changing societal views over glasses and occlusion therapy are also discussed. Further research is required to assess the immediate and long-term effects of amblyopia and/or its treatment on HRQoL using a more standardised approach. PMID- 21274011 TI - Visual perceptions induced by intravitreous injections of therapeutic agents. AB - PURPOSE: The purpose of this study was to conduct a questionnaire-based survey of subjective visual perceptions induced by intravitreous (IVT) injections of therapeutic agents. PATIENTS AND METHODS: Patients undergoing an IVT injection of ranibizumab, pegaptanib sodium, or triamcinolone acetonide were administered a questionnaire in the immediate post-injection period and at 2 weeks of follow-up. RESULTS: In the immediate post-injection period (75 IVT injections, 75 eyes, 75 patients), lights and floaters were reported after 20 (27%) and 24 (32%) IVT injections, respectively. In comparison, at the 2-week follow-up, the incidence of reported lights (11; 15%) was similar (P>0.05), but the incidence of reported floaters was higher (48; 64%; P=0.00). Subgroup analysis for various injection subgroups (no previous injection vs previous injection(s) in the study eye; injections in study eyes with good VA (logarithm of minimal angle of resolution [logMAR] <= 0.3) vs moderate VA (0.7 0.3) vs poor VA (logMAR >= 0.7); injections according to pharmacological agent (ranibizumab vs pegaptanib vs triamcinolone acetonide); injections in study eyes with choroidal neovascularization (of various causes) vs study eyes with macular edema (of various causes); and injections in phakic vs pseudophakic eyes) did not reveal any statistically significant associations. Visual perceptions experienced following 15% of IVT injections gave cause for concern to the patient (mean visual analog scale score (+/- SD): 4.5 (+/- 1.7)), and in 64% of cases, the patients believed that preoperative counseling would have averted the concern. CONCLUSIONS: Lights and floaters are frequent visual perceptions following IVT injections of therapeutic agents. They can give rise to concern that could be alleviated with preinjection counseling. PMID- 21274012 TI - Antiviral treatment following penetrating keratoplasty for herpetic keratitis. AB - PURPOSE: To assess the effect of antiviral treatment on corneal graft survival following penetrating keratoplasty for herpetic keratitis. METHODS: Retrospective cohort study of 454 patients receiving primary penetrating keratoplasties (PKs) for viral infection reported to NHS Blood and Transplant (NHSBT) between April 1999 and June 2005. Follow-up data were available on 403 PKs. Kaplan-Meier survival estimates were used to determine graft survival for the three treatment groups: no medication, topical antiviral, and oral antiviral medication. A Cox regression model was used to investigate the combined effects of all additional factors on graft failure. The model was fitted using all pre-operative factors first and then post-operative factors including type of antiviral medication were included. RESULTS: Patients who received oral antiviral medication post operatively had consistently better graft survival than those receiving no medication or only topical medication. Patients receiving oral antivirals were less than a third as likely to have a failed graft at 5 years compared with those on no antiviral medication (relative risk (RR) 0.3, CI: 0.2-0.7, P=0.002). Other factors that were found to influence the risk of graft failure were the presence of deep corneal vascularisation (P=0.009), PK performed for therapeutic reasons (P=0.03), large diameter grafts (P=0.04), and experiencing a rejection episode (P=0.003). CONCLUSION: Oral antiviral treatment reduces the risk of graft failure in patients undergoing primary PK for herpetic keratitis and should be routinely used in this group of patients post-operatively unless contra-indicated. PMID- 21274014 TI - Screening for symptomatic optic pathway glioma in children with neurofibromatosis type 1. PMID- 21274016 TI - Struck by a thought. PMID- 21274017 TI - Hemoccult Screening: We'll Find Time. PMID- 21274015 TI - A [c.566-2A>G] heterozygous mutation in the PAX6 gene causes aniridia with mild visual impairment. PMID- 21274018 TI - Spinal manipulation: a further debate. PMID- 21274019 TI - Misadventure or negligence at sigmoidoscopy? PMID- 21274021 TI - Perforation at Sigmoidoscopy: Was the FP Negligent? PMID- 21274020 TI - Filing reprints: can office staff help? AB - Filing systems for reprints must be tailored to the individual's practice profile, to maximize usefulness as a resource for clinical problem solving. However, the clerical time involved often reduces the physician's ability to maintain such a filing system. The authors tested two hypotheses that using the International Classification of Health Problems in Primary Care (ICHPPC) nurses or receptionists could code, cross reference and file reprints after the physician has selected the articles. Contents pages of five primary care journals were given to two academic family physicians, two practicing physicians, a research assistant and two receptionists, one of whom had used ICHPPC to record patient encounters. All coders except the second receptionist, who was unfamiliar with ICHPPC, reached good agreement in coding. Filing reprints may therefore be done by trained staff for groups of physicians. PMID- 21274022 TI - Controlling blood sugars. AB - Management of the diabetic patient has undergone a minor revolution in the past decade. Better understanding of insulin's physiology, its interaction with glucose and other aspects of metabolism, and knowledge of hyperglycemia's detrimental effects, have contributed to a drive to keep blood glucose levels as close to non-diabetic norms as possible. One of the most important therapeutic advances has been the realization that patients must become their own chief therapists. They therefore must be adequately and intensively educated to understand the interrelationships of diet, insulin, and activity in controlling blood glucose levels. Self blood glucose monitoring is essential to gauge these interrelationships and allows the educated patient to make daily therapeutic decisions. PMID- 21274023 TI - The management of diabetic eye disease. AB - Many diabetics go through life without ocular examination until complications begin. Ophthalmological consultation should be annual, and ocular complications are best prevented by tight control of blood sugar, best achieved at present with the insulin pump. This article describes diagnosis and management of diabetic retinopathy according to type of diabetes. It also describes indications for pars plana vitrectomy, cataract removal and lens implant. Close cooperation between family physician and ophthalmologist ensures prompt intervention to preserve vision. PMID- 21274024 TI - The insulin pump. AB - Subcutaneous continuous insulin infusion systems deliver insulin at a basal rate designed to keep blood glucose levels normal in the non-fed state. Additional insulin is delivered at meal time. Pumps can provide near optimal control of blood glucose concentrations in selected, highly motivated patients. The pump provides better diabetic control than once daily insulin injections, although several daily injections can provide comparable control. Optimal control with the pump causes some short-term beneficial metabolic changes, but there are no controlled clinical trials evaluating the long-term effect on complications. Insulin pump therapy should be initiated only for highly motivated, well instructed patients in a supportive clinical setting. The hazards include rapid development of uncontrolled diabetes when insulin infusion stops, and development of hypoglycemia in the basal rate mode. PMID- 21274025 TI - Chlamydia trachomatis and the fitz-hugh-curtis syndrome. AB - Right upper abdominal pain in the presence of pelvic inflammatory disease is called Fitz-Hugh-Curtis syndrome. It is due to perihepatitis secondary to transperitoneal spread of Neisseria gonorrhoeae or Chlamydia trachomatis. Twenty five percent of all patients present with right upper abdominal pain as their sole complaint. In order to recognize and manage Fitz-Hugh-Curtis syndrome, the clinician must carefully consider that young, sexually active women may have occult pelvic inflammatory disease. A case history demonstrates how clinical recognition allows effective management before the results of laboratory investigations are available. The Fitz-Hugh-Curtis syndrome is readily treated with conventional antibiotic regimens. PMID- 21274027 TI - Who wrote this? The question of authorship. PMID- 21274026 TI - Postgraduate training route and content of subsequent practice. AB - This study compared the practices of family medicine residency graduates with those of graduates from rotating internship programs. Proportions of medical services billed to the provincial government in each of 15 service classes formed the data base. No significant differences were observed between the groups in general, across groups for any class of medical services. Although the two groups appear to provide the same services, these results do not indicate that the two groups perform in the same manner or with the same results. Practice content, however, appears to be patient dictated rather than physician dictated. The issue is not, then, which training is better, but rather, are any of the present routes adequate. PMID- 21274029 TI - Beer Drinker's Finger. PMID- 21274028 TI - Sex assault exam: too complicated? PMID- 21274030 TI - How not to get saddle sore cycling. PMID- 21274031 TI - How representative are volunteer physicians in collaborative research projects? AB - Few family physicians can generate large samples for statistically significant research, which has led to multicentre collaborative studies. Are the volunteers for these studies typical of family physicians as a whole? If they are not, results will be biased. This preliminary study examines the differences between a group of volunteers and non-volunteers, using several variables. The only statistically significant difference was in place of practice: volunteers were far more likely to come from small towns than from metropolitan or rural areas. Discriminate analysis showed it was possible to predict correctly to which group the physician belonged in only 62% of cases. Further study must be done on other potentially sensitive variables. PMID- 21274032 TI - Managing pain caused by neurological disease. AB - Stabbing paroxysmal pain due to neurological disease can often be controlled by anticonvulsants, whereas steady burning pain is often responsive to tricyclic antidepressants, and to neuroleptics. Overuse of opiates may actually aggravate the pain, necessitating detoxification. Transcutaneous electrical nerve stimulation is helpful for conditions in which pain is localized, especially if there is a 'trigger area' or neuroma, or if paresthesias can be stimulated within the painful area. Local anesthetic injection, possibly with corticosteroid, relieves painful scars and neuromas, neuritis, and tender trigger points. Sympathetic blocks are used for post-herpetic neuralgia and sympathetic dystrophies. Relaxation therapy is a very useful psychological treatment. PMID- 21274033 TI - Wheelchair users' problems with community living. AB - Those confined to wheelchairs face many frustrations when attempting to become more active in their communities. Many community and health facilities are inaccessible and available transportation is limited. Wheelchair users may have difficulty obtaining appropriate wheelchair prescriptions. Their quality of life and health may be jeopardized by pressure sores. Painful conditions in the arms may further increase the degree of disability. A special approach to fitness training may be required. The wheelchair user's self-image will be affected by society's general negativism toward the disabled. Knowledgeable and sympathetic medical care can reduce the stresses inevitable for patients confined to wheelchairs. PMID- 21274034 TI - Stroke rehabilitation: would your patient benefit? AB - Stroke is a common event with major implications for functional loss for the patient, the family, and society. Very little can be done medically or surgically to enhance neurological function, so rehabilitation on functional grounds becomes paramount. It is very difficult to predict if a patient will benefit from rehabilitation on neurological grounds; any patient who is alert, can learn, and can cooperate should be offered a stroke rehabilitation program as soon as he is able to participate in it. PMID- 21274035 TI - Rehabilitation of stroke patients in a day hospital. AB - A comprehensive rehabilitation program for stroke patients strives to rectify deficits in communication, cognition, sensation and motor function. Day hospitals can provide diagnostic and remedial therapy services daily or for several hours a week. At the same time, patients can live at home, maintaining their place in the family and community. Day hospitals can also benefit patients who were not introduced to a rehabilitation program soon after suffering a stroke, and provide intermittent upgrading and maintenance therapy for those with recurrent or remote strokes. The day hospital can help the family physician to assess patients' functional status, and assist with caregiving. The experience of a Toronto day hospital is described. PMID- 21274036 TI - Parkinson's disease: a pharmacological update. AB - The primary biochemical defect in Parkinsonism is dopamine depletion. Anticholinergics (except in the elderly) and amantadine are useful in treating early symptomatic disease. L-dopa remains the most effective drug, but experience has led to more modest use due to its late complications, particularly dyskinesias. Bromocriptine, a dopamine agonist, is relatively effective, but when it should be used is undecided. Beta-blockers may control tremor. Treatment should be tailored to each patient, and focus on functional motor ability. Dyskinesias and neuropsychiatric complications are the major limiting factors with most of these drugs. Several drugs are under investigation. PMID- 21274037 TI - Injuries arising from aerobic fitness classes. AB - Aerobic fitness classes are a popular form of exercise for many people. A questionnaire survey of 410 participants and a clinical review of 100 patients presenting for treatment, showed that 67.3% of respondents had significant pain resulting from the classes, but only 21% stopped exercising because of it. The majority of injuries are to the lower extremities, including tibial stress syndrome and patellofemoral pain. This study suggests that most of these injuries are preventable, especially by advice on proper footwear, pace of activity, how many classes to attend and how frequently to increase activity. PMID- 21274038 TI - Effects of oral contraceptive usage on b(12) and folate levels. AB - Evidence shows a fall in folate and vitamin B(12) levels in women taking oral contraceptives. These levels do not return to normal until about three months after usage has stopped, but many women become pregnant during this time. This paper examines the evidence for an effect on such pregnancies of lowered folate and B(12) levels, and concludes that nutritional counselling should begin in schools, should continue in the medical care of women in their childbearing years, and folic acid supplementation should begin as soon as pregnancy is confirmed. This supplementation should be periconceptional in women at higher risk of bearing a child with neural tube defects, and greater in multiple pregnancy, malabsorption, hemolytic anemia and concomitant use of drugs known to be folate antogonists. PMID- 21274039 TI - Diagnosing infectious mononucleosis: avoiding the pitfalls. AB - Infectious mononucleosis may be diagnosed with confidence only when Hoagland's diagnostic criteria have been met. The illness must be compatible with the known clinical features of infectious mononucleosis; there should be absolute and relative lymphocytosis on differential white cell count; there should be more than 20% atypical lymphocytes and serological tests should be positive-either a Paul-Bunnell Davidsohn or a rapid slide test for heterophil antibody. Failure to diagnose this common viral infection accurately may lead to inappropriate and perhaps harmful management, and may delay recognition of potentially life threatening complications. PMID- 21274040 TI - Talking to patients about sex. PMID- 21274041 TI - Writing for Scientific Journals: Why Can't I Say I? PMID- 21274042 TI - [Not Available]. AB - Moral philosophy is often more frustrating than helpful to family physicians who come to it seeking solutions to the everyday moral dilemmas that their practices present. Continuity of care and comprehensive care are features of family medicine that require the nurturing of close doctor-patient relationships. They also present family physicians with unique moral dilemmas which require decision and action with insufficient information or time to apply the careful thought associated with moral philosophy. Decisions can often be made only on the basis of the personal and professional relationships existing between doctor and patient. There is a rigor and legitimacy to this process that better reflects the process of moral decision-making in family medicine than does that of traditional moral philosophy. PMID- 21274043 TI - Gee, thanks. PMID- 21274044 TI - Antibiotics in sexual assault. PMID- 21274045 TI - [Not Available]. PMID- 21274046 TI - Anesthesia part of family practice history. PMID- 21274047 TI - Generic substitution and allergic reaction. PMID- 21274048 TI - Causes of red stools. PMID- 21274049 TI - For the record. PMID- 21274051 TI - When in doubt, ask the patient. PMID- 21274050 TI - Immunization: Public Health or FP? PMID- 21274052 TI - Immunization: Public Health or FP? PMID- 21274053 TI - Immunization: Public Health or FP? PMID- 21274054 TI - Immunization: Public Health or FP? PMID- 21274055 TI - Immunization: Public Health or FP? PMID- 21274056 TI - Immunization: Public Health or FP? PMID- 21274057 TI - Family Practice vs. Public Health: Who Cares? PMID- 21274058 TI - Sexual health care in family medicine. AB - Although patients frequently present with sexual concerns, family doctors generally do not handle them well. Sexual issues may present in many ways: as specific concerns; as a component of non-sexual complaints or as a factor in relationship or marital problems. The family doctor must include sexual enquiry and counselling as part of overall health care, and in the management of illnesses. In order to be effective counsellors, physicians must examine their own attitudes, and become knowledgeable about sexuality and myths influencing sexual behavior, and skillful at interviewing and sexual history-taking. The family doctor can become adept at giving patients permission to discuss their sexuality, and at providing information and strategies to enhance sensual enjoyment and communication with partners. Small group training sessions incorporating discussion and role-playing effectively teach physicians skills and strategies in sexual counselling. PMID- 21274059 TI - The sexual assault examination. AB - The sexual assault examination poses many problems for physicians. They must deal not only with the patient's physical and emotional trauma, but also collect forensic evidence, and provide proper treatment and follow-up. Patient management has been simplified and improved in Ontario by a standardized sexual assault examination kit. It has been used at McMaster University's Regional Sexual Assault Centre since its establishment in 1979. The first step in managing victims is ensuring their wellbeing, and treating them sympathetically. The kit provides information on consent, taking the sexual assault history, recording the patient's emotional status, and treatment guidelines. It also contains equipment and instructions on collecting clothing and body evidence, and on the genital and anal examination. The collection of good forensic evidence can decrease the need for doctors and nurses to testify in court. PMID- 21274060 TI - Inhibited sexual desire and sexual avoidance. AB - Inhibited sexual desire (ISD) is one of the most common sexual dysfunctions, especially in women. Family physicians have an opportunity to recognize ISD before the associated problems become entrenched, and to guide couples toward satisfactory resolution. A summary is presented of current thinking on ISD and its causes. Case reports and observations about frequency of and treatment for ISD are included. Much less has been written about sexual avoidance in the presence of desire. A definition is offered of simple sexual avoidance in the absence of genital dysfunction. Frequency, treatment response, and specific cases are described. A newly identified entity-mutual unwillingness to importune for sex-is discussed briefly. Counselling which focuses on communication, self responsibility, and sex education is very helpful to patients with sexual problems. PMID- 21274061 TI - How physicians can introduce sex education in schools. AB - In 1981 the author described the introduction of a Human Growth and Development section in a school health program in Dartmouth, Nova Scotia. This article describes the step by step progress a community physician can take to negotiate with school boards the introduction of such a program. The emphasis is on preventive medicine in the community where the physician practices. PMID- 21274062 TI - The homosexual male patient: the ten percent factor. AB - There are problems with physicians' knowledge of homosexuality, both in concept and in medical factors. Many physicians do not know what to consider in dealing with a gay patient, nor how to search out the problems. A fictional case history illustrates that a lack of empathy, awareness and clinical suspicion can have negative results. PMID- 21274063 TI - Premenstrual syndrome: diagnosis and management. AB - Premenstrual syndrome is a recurrent set of disabling symptoms that occur in a definite relation to the menstrual cycle. Patients chart the severity of symptoms over time during consecutive menstrual cycles while the physician should rule out other possible gynecological and psychiatric disorders. Management is through education, environmental manipulation and symptomatic relief of stressors, using a variety of medications. Often a multidisciplinary approach of family physician, psychiatrist and gynecologist is needed. PMID- 21274064 TI - The use of estrogens. AB - The pathways of production of estrogen are described, as well as its actions. Its use in childhood, puberty, adolescence, childbearing years and the menopause is detailed, together with the actions of the available estrogens. Special emphasis is placed on their employment in states of deficiency, such as genital atrophy and osteoporosis. Diagnostic features of estrogen deficiency are described and appropriate therapy suggested. PMID- 21274065 TI - Changes in sexually transmitted disease. AB - Patterns of sexually transmitted diseases have changed, but the incidence has not decreased. The commonest STD (nonspecific urethritis) has only recently become reportable. The ratio of gonorrhea to NSU has reversed. Common childhood diseases have now become sexually transmitted diseases, for example, molluscum contagiosum and warts. Some venereal diseases have become less virulent, but acquired immune deficiency syndrome (AIDS) is almost uniformly fatal. Most infectious enteric diseases have now become sexually transmitted diseases. The key to eradicating STD is intelligent and persistent public health personnel. Some STD are multisystem diseases; a broad range of interested consultants will be useful to the family physician. PMID- 21274066 TI - Identifying sexual dysfunction. AB - Many patients present sexual concerns, which they may express openly or in various covert ways. Identifying sexual dysfunction is therefore an important part of family practice. All family doctors must be sexual counsellors at some time, and their effectiveness or lack of it will influence patients' lives. In order to maintain patients' confidence, the family physician must have empathy, non-judgmental counselling skills, and up-to-date information on sexuality. PMID- 21274067 TI - Recognizing battered wife syndrome. AB - Battered wife syndrome is difficult to detect because the women usually do not volunteer the diagnosis. They often present with vague somatic complaints such as headache, lower back pain, abdominal pain, pelvic pain and dyspareunia. Four case histories demonstrate the difficulty in recognizing the cause of these complaints. The diagnosis was often missed because straight-forward, non threatening, open-ended questions were not asked initially. The family physician's primary role is to identify the syndrome and initiate psychotherapy. Psychotherapy is centred on reversing "learned helplessness" and developing a new self-concept. This can be enhanced by an interval or transition house. PMID- 21274068 TI - Dyspareunia. AB - Painful coitus is a distressing symptom for both sexes. Often, physician and patient avoid this issue because of their own inability to deal with such problems. Dyspareunia may be caused by a variety of conditions, mainly related to the reproductive system. However, even where medical or surgical treatment is contemplated, therapy will usually require some form of sex counselling. A sex oriented history which resembles the usual medical format is used in the assessment. The PLISSIT model of therapy allows the practitioner to begin treatment, and to make a referral when his or her "comfort index" may be exceeded. PMID- 21274069 TI - Sex education for patients. AB - Sex education evokes a wide variety of responses in the community and from teachers. Consequently, physicians have a responsibility to present sex education material in a factual, objective way. Many people are misinformed about sexual behavior. Physicians can help patients and the community by being aware of appropriate sex education for each age group. A curriculum for sex education, and opportunities to provide sex information for patients of different ages and stages in the lifecycle, are described. PMID- 21274070 TI - A randomized trial of three approaches to smoking cessation. AB - Three hundred and sixty-six patients volunteered for a smoking cessation trial and were randomly allocated to a control group or to three interventions: a single counselling visit to a physician, eight sessions of group health education or eight sessions of group behavior modification. Progress was assessed by smoking diaries, supported by saliva thiocyanate tests, before and after the intervention and six and 12 months later. Only the two group approaches showed a significant improvement compared to the control group immediately after the intervention; these differences were no longer statistically significant six or 12 months later. The group methods proved to be more cost-effective than the physician intervention. However, when different sub-groups were examined, such as heavy or light smokers, a different pattern of results emerged. For very heavy smokers, the physician-led intervention proved almost as successful as the group approaches. Overall quitting results were disappointing, but the programs appear to be more successful at helping people reduce smoking. PMID- 21274071 TI - Assessing the quality of care in family physicians' practices. AB - This feasibility study by the Practice Assessment Committee of the College of Family Physicians of Canada was conducted to define and produce instruments that could be used to assess quality of care rendered in family physicians' offices. The favorable response to these evaluations and the acceptance of the results indicates that this method can be useful to family physicians. The instruments identify family physicians' strengths and deficiencies so that with appropriate changes in the quality and efficiency of care, they are able to achieve higher levels of professional satisfaction. These methods may ultimately be used to establish acceptable standards for care given by family physicians in their offices. PMID- 21274072 TI - The psychosocial profile: a history-taking aid. AB - Family physicians need a good history-taking model. All diagnostic possibilities, both physiological and psychological, have to be considered during the history taking process, with a reliable system of hypothesis formation and testing. A psychosocial profile incorporated into the history correlates symptoms of anxiety and situational depression with significant concerns in the patient's life. This temporal correlation helps to differentiate functional symptoms from organic pathology. PMID- 21274073 TI - A cancer patient and his family face the future. PMID- 21274074 TI - Senokot and red stools: no cause for alarm. PMID- 21274075 TI - Public health and immunization. PMID- 21274076 TI - Home visits essential in providing home care? PMID- 21274077 TI - Cancer in Canada: an epidemiological perspective. AB - The incidence of cancer has risen steadily over the past 20 years, with a percentage increase per year of 1.3 in males and 0.5 in females. In 1980 the incidence was 333 per 100,000 in males and 259 per 100,000 in females. Over age 45, the incidence of cancers of the larynx and lung increased in both sexes, as did that of cancer of the prostate in males. The incidence of melanoma and other skin cancer is also rising in both sexes. Although the incidence of cervical cancer among women aged 35 and over fell during the decade 1970-80, the incidence among younger women increased. The trends over time and the regional differences in incidence are generally in keeping with what is known (and what is not known) about the etiology of cancer. PMID- 21274078 TI - Multiple myeloma. AB - The features of multiple myeloma are due to plasma cell proliferation and the production of a monoclonal antibody. Skeletal disease with hypercalcemia, bone marrow dysfunction, sepsis, and renal failure are the commonest problems noted. The diagnosis is suggested by the demonstration of monoclonal gammopathy in the serum or the presence of free immunoglobulin light chains in the urine. Other diagnostic features are bone marrow plasmacytosis, hypogammaglobulinemia and lytic bone lesions. Beneficial responses are seen with supportive care of complications, radiotherapy for severe bone disease and chemotherapy to decrease the tumor burden. PMID- 21274079 TI - Lung cancer: to treat or not to treat? AB - Surgical resection is the best form of treatment for primary non-small cell lung cancer. In resected cases the overall five year survival rate is 35%. The prognosis depends on cell type, nodal status and tumor size. Palliation of symptoms can be controlled in most instances by chemotherapy, radiation therapy or a combination of both. Presently there is no proven role for adjuvant irradiation therapy and chemotherapy after curative resection. Small cell carcinoma should be treated with combination chemotherapy and prophylactic cranial radiation; these therapies prolong survival and control symptoms. Patients' questions should be answered specifically and in no greater depth than the patient desires. Close communication should be maintained between physician, patient and a designated member of the family. PMID- 21274080 TI - Cutaneous malignant melanoma. AB - In Canada melanoma causes 400 deaths a year, often in young adult patients. Excessive ultraviolet radiation to unprotected skin is an important cause. Certain moles should be removed as a precautionary measure; an experienced clinician can recognize many melanomas. Both microstaging by the pathologist and clinical staging must be carried out before definitive treatment is planned. The only 'curative' treatment is surgical. Any patient so treated requires ten years of careful follow up. The results of chemotherapy for disseminated disease are poor. PMID- 21274081 TI - Hypodermoclysis for symptom control in terminal care. AB - Subcutaneous infusions of fluid and electrolytes can be used for replacement and correction of imbalance, by a method known as hypodermoclysis (HDC). Since April 1982, the Palliative Care Unit of the Edmonton General Hospital has been using this method for symptom control, titrating the rate of infusion against the severity of the symptoms, when the oral route was no longer available. If incompatible drugs have to be given at the same time, or if two drugs have to be given at different rates, two sites are used simultaneously. HDC is an adequate method of symptom control for terminal patients; it has advantages over intravenous, intermittent subcutaneous or intramuscular routes and rectal infusion, when used as described. PMID- 21274082 TI - Practical cancer chemotherapy: venous access and extravasation. AB - Cancer chemotherapy is becoming more effective, and therefore more widely used. Treatment is frequently begun at a cancer centre and continued by the patient's family physician in the home town. In larger centres, trained intravenous or chemotherapy nurses may be available, but in many areas the physician may not have such assistance. This article reviews the intravenous delivery of cancer chemotherapy and the procedure to follow if accidental extravasation should occur. PMID- 21274083 TI - Hodgkin's Disease 1985. AB - Most patients with Hodgkin's disease will present with painless lymphadenopathy; 50% will have some degree of mediastinal involvement. Diagnosis is made on finding Reed-Sternberg cells or atypical reticulum cells. Accurate staging is crucial and should be done jointly by medical and radiation oncologists. Treatment is by radiation or chemotherapy, or combinations of the two. Cure rates are high. PMID- 21274084 TI - Carcinoma of the prostate. AB - Prostatic carcinoma is the third most common cause of death from cancer among males. Selection of appropriate therapy and evaluation of results is often difficult, since patients present at different stages of the disease. Methods of staging, diagnosis, treatment of localized tumor, radiation, surgery and treatment of metastases are described. PMID- 21274085 TI - Testicular carcinoma. AB - Testis cancer is most commonly discovered because of painless testicular enlargement. Careful examination remains the best non-invasive diagnostic procedure. Accurate definition of pathological type and clinical stage determines management and defines prognosis. Surgical removal of the testis by an inguinal incision after spermatic cord occlusion is mandatory, and scrotal needling or biopsy must be avoided. Seminomas are the most common. When confined to the testis or when spread is limited to a few small retroperitoneal nodes, cure rates of 90% or more are produced by orchiectomy and radiation. Non-seminomatous germinal tumors should be staged surgically using retroperitoneal lymphadenectomy if clinical staging implies minimal tumor spread. Where tumor spread is found, aggressive chemotherapy produces a cure rate of greater than 95%. For advanced disease, chemotherapy is the primary treatment post-orchiectomy. PMID- 21274086 TI - Nutritional considerations for cancer patients. AB - Although weight loss is a frequent, though not invariable, component of the cancer syndrome, the associated malnutrition is a poor prognostic sign among both children and adults. This article describes the possible mechanisms of cancer cachexia; reviews the present state of nutritional support in cancer patients; identifies nutritional problems and workable approaches during the pre- and post treatment periods; discusses the unconventional nutritional practices commonly encountered and lists resource materials for patients and families. PMID- 21274087 TI - Diet and cancer prevention: separating fact from myth. AB - Public belief about the role of diet in cancer ranges from the opinion that cancer is genetically determined through to the idea that a specific diet will prevent all cancer. This article examines current knowledge about food additives, vitamins and nutritional pharmacology in relation to present knowledge of cancer incidence. PMID- 21274088 TI - Team sports: a place for primary care. AB - Physicians' role in team sports goes beyond the traditional 'Doc' who attends the game for stitching and primary injury management. Injury and illness prevention, ongoing supervision of rehabilitation, education, fitness evaluation, and training prescription are roles which have often fallen, by default, to paramedicals. The author recounts his experience in medical supervision of major junior hockey in the Western Hockey League. PMID- 21274089 TI - Breast self-examination: programs and materials available for teaching and research. AB - There is an abundance of information of breast self-examination (BSE) as a method of detecting breast cancer. This article describes the various teaching programs and sources of information available to physician, nurse and patient. Materials featuring old, young, black or white women are available; many can be obtained in English, French, Spanish and Braille. These materials range from annotated bibliographies, pamphlets and research reports to programs of continuing education for physicians, nurses and patients. PMID- 21274090 TI - Gastric cancer in young people. AB - Gastric carcinoma occurs in young people as well as old; incidence in various studies of patients from different age groups suggests that incidence varies more according to location than to age-incidence in young people can be up to 3% in some areas. Diaries of two women who were under age 35 at the time of diagnosis of gastric cancer are presented. Because the disease is relatively rare in the young and the symptoms are very similar to benign ulcers, the diagnosis is often made late. Radiological investigation, signs, symptoms and family history must be carefully scrutinized; if medical ulcer therapy has no effect, every attempt must be made to reach a further diagnosis as soon as possible. PMID- 21274091 TI - The Hypertension Symposium: One Observer's Impressions. PMID- 21274092 TI - From research to readers: genesis of a journal. PMID- 21274093 TI - [Not Available]. PMID- 21274094 TI - Malpractice injustices. PMID- 21274095 TI - Undiagnosed twins: malpractice or bonus? PMID- 21274096 TI - Study credits: too complex? PMID- 21274097 TI - Cross-cultural Meds: Getting the Message. PMID- 21274098 TI - Tutorial groups unite. PMID- 21274099 TI - 'Jaundiced view' a pleasure to read. PMID- 21274100 TI - Immunization status of preschool children in a teaching practice. AB - Of preschool children registered at a university family medicine centre, 82% were found to be adequately immunized. A review of patient charts, however, showed that 31% contained immunization information that was difficult to interpret; extensive home follow-up was required to confirm immunization data. Special emphasis must be placed on producing accurate, easily retrievable chart information. Practices where nurses had a major role in infant care had better immunization records. Given that immunization is now a requirement for school admission in Ontario, the cost and feasibility of a recall system of child immunization should be explored. PMID- 21274101 TI - Mild Hypertension: Should it be Treated? AB - Mild hypertension-diastolic blood pressure (DBP) of 90-104 mmHg-has an important prognostic significance. Results of randomized clinical trials evaluating effects of antihypertensive treatment show that DBP at or above 100 mmHg always requires pharmacological intervention. Further evidence is accumulating which would probably further lower the threshold at which therapy would be considered mandatory. PMID- 21274102 TI - The clinical evaluation of hypertension. AB - The incidence of secondary hypertension in clinical practice is probably below 5%. The majority of those cases are of renal origin. Extensive and costly investigations for rarer forms of hypertension therefore do not appear justified. A comprehensive medical history, plus a good physical exam and some critical laboratory analyses can uncover the great majority of primary and secondary forms of hypertension, allowing for the detection of additional risks factors. Current research trends will eventually provide newer approaches which may permit a better evaluation of the prognosis of hypertension, as well as the development of more efficient therapies. PMID- 21274103 TI - Problems with hypertension detection in family practice. AB - The family physician's office is the preferred site for case-detection of hypertension. However, certain problems interfere with case-detection efforts. There have been conflicting messages about the levels of blood pressure needed to diagnose hypertension and institute therapy. Given the natural history of hypertension, an appropriate goal would be a blood pressure measurement on every patient every two years. The problem-solving approach to patients is another factor which interferes with case-detection. Certain office organization factors are relevant. Blood pressure measurements taken in the office may not fairly represent true 'blood' pressure; a case can be made for increased use of home blood pressures. Finally, care must be taken in the techniques of blood pressure measurement. PMID- 21274104 TI - Initial therapy for patients with uncomplicated hypertension. AB - Although commonly prescribed for hypertension, nonpharmacologic treatments have, at best, a minor adjunctive role to play. Current Canadian recommendations call for either a diuretic or beta blocker. If the diastolic blood pressure does not fall below 90 mmHg, a beta blocker or diuretic, respectively, should be added. Medications should be carefully adjusted until the BP is well controlled without adverse effects. About one-third of patients will experience side effects from a medication, but these often subside with time or can be overcome by switching medications. In the long run, antihypertensive therapy does much more good than harm for most patients. Optimizing the cost/benefit ratio for individual patients is the most important challenge. PMID- 21274105 TI - Management of more severe cases of hypertension. AB - Despite the use of general guidelines for non-pharmacologic and pharmacologic therapy of hypertension, special problems do arise. In some instances the hypertension may be unresponsive or so severe that a different mode of intervention might be necessary. For such instances special considerations in therapy are needed. PMID- 21274106 TI - Compliance with antihypertensive medication. AB - Although we have efficacious treatment for hypertension many patients do not take their medication or even follow through with their physician visits, thereby negating potential benefits. Detecting patients who do not take their medications is as important as diagnosing and treating the hypertension itself. This paper outlines methods of detecting and 'treating' non-compliance and discusses the role of the physician/patient relationship in compliance. PMID- 21274107 TI - The Physician's Approach to Hypertension in the Office. AB - The family physician must take a comprehensive approach to managing hypertension in the office, to prevent the cardiovascular complications of atherosclerosis. Many risk factors interact to produce the vascular damage which culminates in stroke, myocardial infarction and heart failure. With each patient all the risk factors must be assessed and a specific treatment plan developed. Reduction of elevated blood pressure alone has no consistent effect on the incidence of heart attacks. Pharmacological therapy is usually required for patients with persistently elevated diastolic pressure; this should not exclude the concurrent use of non-pharmacological interventions. As the side effects of hypotensive drugs are common and non-specific, step-down therapy should be considered in those patients whose blood pressure has been controlled for one year. PMID- 21274108 TI - Organizing the office for effective detection and management of hypertension. AB - An effective office organization for screening and follow-up of hypertensives can be simple. The physician must first adopt a policy of regularly taking blood pressures of patients who attend for any reason. Notations on the outside of the chart are a visible record and reminder. A tickler file with 12 monthly divisions provides an efficient follow-up system. There are no ethical barriers to instituting this approach. PMID- 21274109 TI - Community health programming for hypertension control in Canada. AB - High blood pressure is one of the four major risk factors in the development of cardiovascular disease. Canadian surveys suggest that 10-15% of Canadians have high blood pressure, controlled or uncontrolled. Hypertension accounts for substantial use of health services, without optimal value obtained. Community strategies are needed-education, bringing into care, surveillance, and maintaining patients in care. Coordination between health care professionals, voluntary health organizations and volunteers is critical to the success of these efforts. PMID- 21274110 TI - Predicting and preventing hypertension and associated cardiovascular disease. AB - THE DEVELOPMENT OF HYPERTENSION CAN BE PREDICTED BY SUCH FACTORS AS: age, salt, alcohol and fiber intake, obesity, physical activity, psychosocial factors, and family history of hypertension or premature cardiovascular disease. Blood pressure response to stressful stimuli is also an important predictor. Research should focus on better assessment and management of predictors including psychosocial factors which increase blood pressure, and personality characteristics that increase sensitivity to stressful stimuli. Since inheritance of blood pressure may be considerable, detecting a hypertensive patient should stimulate the family physician to measure blood pressure of other family members. Future management of hypertension may involve increased public health activity to improve detection, education and management in the community while more efficient office management integrates the patient into the decision making process. PMID- 21274111 TI - The family physician and special groups of hypertensives. AB - Future hypertension research will include not only fundamental pathophysiology and new methods of drug therapy but also research into which groups require special treatment. Hypertension is most common in the elderly, but after age 70 is only weakly associated with cardiovascular morbidity and mortality, mainly in females, and more related to systolic hypertension than diastolic. Hypotensive therapy has not yet proven to be of benefit in this age group. Trials of therapy, perhaps especially in systolic hypertension, in women and in previous stroke victims could well be carried out cooperatively by family physicians. The effectiveness of salt reduction and weight reduction in lowering blood pressure is controversial, but could be tested in cooperative trials, especially for borderline hypertensives and possibly for children of hypertensive parents. PMID- 21274112 TI - Methods of transmitting information on hypertension to family physicians: a review. AB - FAMILY PHYSICIANS ARE MIRED IN A HOPELESS FLOOD OF INFORMATION UNLESS THEY UNDERTAKE REGULAR CONTINUING MEDICAL EDUCATION BASED ON ANSWERS TO THE QUESTIONS: What do I need to learn? How do I learn best? What format is best suited to me? How can I evaluate my learning? This paper examines answers to these questions, and looks ahead to methods which may become the preferred choices in future. PMID- 21274114 TI - Medical work in the Caribbean. PMID- 21274113 TI - Clothing for sports: part 1: fashion foils phidippides, proves fatal at finish. AB - The choice of clothing for any particular sport can be made on a reasonably scientific basis, taking into account hot, cold or wet conditions, effects on temperature regulating mechanism, ability to enhance athletic performance, safety and comfort. Part 1 of this two-part article discusses the selection of garments for any sports activity according to specific properties of certain fabrics and also covers safety gear, sports brassieres and shoes. PMID- 21274115 TI - Family medicine: into the future. PMID- 21274117 TI - [Not Available]. PMID- 21274116 TI - Three cheers for peer review. PMID- 21274118 TI - Who cares for the physician? PMID- 21274119 TI - Abstinence only answer for teen contraception. PMID- 21274120 TI - Research on old drugs: expand indications. PMID- 21274121 TI - Keep obstetrics in family practice. PMID- 21274122 TI - Benzodiazepines: no cause for complacency. PMID- 21274123 TI - Prophylaxis for the international traveller. AB - Travellers should know as much as possible about the quality of food and drink in the areas of travel, and be prepared with safety measures if necessary. Routine immunization should be up to date; cholera and yellow fever vaccinations are required for travel to certain areas. Such prophylaxis should be sought, ideally, several months before departure. Resurgences of malaria are occurring in areas where the disease had previously been controlled, making prophylaxis essential for travel to endemic areas. Other mild disorders may be treated with medication appropriate to the type of travel and area. Patients may appreciate cautionary advice about behavior, to lessen the likelihood of physical or social harm. PMID- 21274124 TI - Medical problems related to air travel. AB - Air travel has become the preferred method of transportation for many Canadians, some of whom would otherwise be unable to travel long distances. Airline medical departments will provide advice and assistance with prior notification. The pressurized cabin has a slightly hypoxic atmosphere, so cardiac and chronic pulmonary patients require individual evaluations before departure. Severely anemic patients and those with neurological disorders may need to take special precautions, as will those with conditions affected by pressure changes. Aside from a few contraindications, the majority of patients can enjoy the benefits of commercial air travel, with proper guidance from their family physician. PMID- 21274125 TI - Advice for travellers to tropical and subtropical countries. AB - Travellers to areas where political instability, poverty or inadequate public health measures render them at risk of exposure to infections and diseases they are unlikely to meet at home should seek prophylaxis and protection before departure. Inoculation is the best form of protection for certain diseases; since protocols change frequently, a reliable local source of current information should be found. Prophylaxis against malaria involves both mechanical protection against mosquito bites, and appropriate chemoprophylaxis. Water safety must be considered where chlorinated water is not available; a protocol for decontamination is presented, and guidelines for avoiding gastrointestinal disorders are listed. PMID- 21274126 TI - Overcoming jet lag. AB - Jet lag is a symptom complex resulting from travel across time zones, which can incapacitate travellers for several days. It is a result of the abrupt changes forced on travellers' sense of time, place and wellbeing, and on their internal cycles. It is manifested in its early phase by exhaustion out of proportion to the length of the flight, disorientation to time, and disruption in sense of wellbeing, memory and performance. In the later phase, profound exhaustion, constipation or diarrhea, anorexia, insomnia, headache, and limited night and peripheral vision may be experienced. Light, food, methylated xanthines (coffee, tea, etc.), physical and mental activity, alcohol and smoking affect bodily rhythms. Awareness and manipulation of these 'cues' before, during and after a flight can significantly reduce jet lag. PMID- 21274127 TI - Malnutrition and dehydration in the third world: practical treatment. AB - Malnutrition coupled with dehydration (usually secondary to diarrhea) is one of the major causes of morbidity and death in the Third World. The mortality rate is high, especially in children; four to five million die each year. However, diagnosis and treatment of these problems has improved in the past decade. In therapeutic feeding programs, which are designed for markedly malnourished children, oral rehydration solution is likely the most important medicine that can be offered. After initial rehydration, the malnutrition can be treated with six to nine meals daily, and/or nasal-gastric feeding and special high energy milk formulas. Patients usually require four to six weeks before moving to a supplementary program, which supplies an additional 350-500 kilocalories and an extra 15 g of protein to the daily diet. This program is for those at high risk: children under age five, pregnant and lactating women, and certain debilitated patients. PMID- 21274128 TI - A canadian medical team in ethiopia. AB - In February 1985, a Canadian medical relief team was established in a northern Ethiopia refugee camp. Volunteer physicians, nurses, and support staff have worked in the camp since February 1985. Their activities range from supervising intensive feeding programs, to controlling infections, to educating patients. About 300-400 patients visit the outpatient clinics daily. Malnutrition, vitamin A and B deficiencies, scurvy, rickets, gastroenteritis, malaria, leprosy, tuberculosis, pneumonia, trachoma and tetanus are commonly seen. The continuing presence of the medical team depends on donations and volunteer participation. PMID- 21274129 TI - Diabetes and travel. AB - Travel can be therapeutic, but for the diabetic patient, it necessitates careful preparation. The family physician should be coordinator of the team that prepares the patient for the trip. The patient is a central member of this team, and must know as much as possible about the places to be visited, modes of transportation, facilities, etc. Current medication must be reviewed, and possible medical problems anticipated, taking climate and change of exercise pattern into account. Careful attention must be paid to current medical problems with good education concerning potential emergencies. Diabetes therapy during travelling times and the holiday must be carefully reviewed with the patient. The necessary referrals to other physicians and health professionals involved in the care of diabetes should be arranged well in advance of the holiday. Every assistance must be given to the patient to help him travel with diabetes-not from it. PMID- 21274130 TI - Stool examination and reports in the traveller. AB - Diarrhea is by far the most common illness in a returning traveller, so family physicians frequently request stool examination for these patients. Appropriate history and adequate specimens, obtained on three or four different days, are crucial to proper interpretation of results. Decisions on treatment will depend on the patient's current symptoms and type of pathogen. Not all pathogens require treatment and not all reported parasites are pathogenic. The patient's lifestyle and occupation may influence decision-making on treatment of asymptomatic carriers of certain parasites or bacterial intestinal pathogens. Guidelines for such decision-making are presented. PMID- 21274131 TI - Medical aspects of scuba diving. AB - Scuba divers may encounter dangerous levels of stress, due to increased ambient pressures and hostile environments. Divers therefore require a high level of mental and cardiorespiratory fitness. They must be informed of specific contraindications to diving. Family physicians with a basic knowledge of the medical aspects of scuba diving are in a very good position to examine and advise sports divers. Screening mainly involves an assessment of emotional stability and cardiorespiratory fitness, and an ear, nose and throat examination. Common problems suffered by scuba divers are discussed, as are temporary and permanent contraindications to diving. PMID- 21274132 TI - Space travel: bringing medical discoveries down to Earth. AB - Space travel has necessitated intensive study of certain physical conditions, notably cardiovascular deconditioning, motion sickness, musculoskeletal atrophy and psychological isolation. Benefits of this research are beginning to be available to terrestrial medicine, for example in research on osteoporosis and motion sickness. Other space technology of benefit to medicine includes diagnostic and therapeutic devices, transmission of medical data and satellite communications. A permanently inhabited space station is planned for the 1990s and further research into isolation, occupational hazards in remote locations, transportation of accident victims and stabilization awaiting transportation can be expected, all with probable spinoffs for terrestrial medicine. Space is also a good environment for production of very pure, specific pharmaceuticals, such as alpha1-antitrypsin, interferon and pancreatic beta cells. PMID- 21274133 TI - Risks of baby walkers and options for prevention. AB - Recent studies have reported fatal head injuries associated with baby walkers. Skull fractures and hospital admissions are significantly higher for infants who have received head injuries while using a walker. Thirty to 50% of infants regularly placed in walkers experience an accident or injury related to the device. Most injuries are minor cuts, abrasions and contusions. While there are many hazards, no benefits have been documented. The walkers do not help children learn to walk. Options for preventing injury including banning baby walkers, product design regulations, and public education about the risks. An outright ban would be difficult, because walkers are not considered inherently dangerous; they become so when parental supervision is lacking. Although design specifications will decrease some walker-related injuries, they will not prevent severe or fatal head injuries associated with falls down stairs. Public awareness of hazards from baby walkers and discouragement of their use are recommended preventive measures at this time. PMID- 21274134 TI - Acetaminophen liver injury. AB - Acetaminophen can produce potentially fatal liver necrosis, via an intermediate toxic metabolite. Hepatic injury usually requires acute ingestion of at least 10 15 g of the drug. The patient typically feels well for one to three days before evidence of liver damage appears. Striking elevation of aminotransferases is characteristic, reflecting acute hepatocellular necrosis. In non-fatal cases, recovery is usually rapid. Liver damage can be completely prevented by oral or IV N-acetylcysteine (Mucomyst), which blocks the effect of the toxic metabolite. However, treatment is effective only if given within eight to 12 hours of acetaminophen ingestion. Hence, prompt action by the physician can prevent acetaminophen liver necrosis. PMID- 21274135 TI - Malaria: an important emergency room diagnosis. AB - Fever in a traveller returning from an area endemic with malaria is a medical emergency. Although malaria is rare in Canada, it is one of the commonest communicable diseases in the world. A history of prophylaxis is no guarantee that malaria has not been contracted. This case history details an example of failed prophylaxis, emergency room presentation, and emergency treatment for Plasmodium falciparum. Clinical manifestations of the disease can occur up to six months after return from a malarial region, especially if chemoprophylaxis delays initial presentation. Symptoms include the sudden onset of chills, rigor, fever, profuse sweating, prostration, malaise, myalgia, headache, anorexia, nausea, vomiting and diarrhea. A single negative blood film does not exclude the diagnosis. PMID- 21274137 TI - Genetic counselling in family practice. PMID- 21274136 TI - Asymptomatic microscopic hematuria revisited. AB - The literature states that asymptomatic microscopic hematuria (AMH) is a sensitive indicator of underlying pathology and deserves investigation. However, studies to date have been done on urological outpatients and, because of referral and sampling bias, the findings may not be applicable to a family practice population. The positive predictive value of AMH may be very low in a family practice. The recommended investigations are invasive, expensive, and cause morbidity and mortality. Further studies must examine the significance of AMH in the general population. Such studies would help to identify at risk patients and, perhaps, allow investigations to be tailored to these patients, while the physician maintains a high degree of suspicion and keeps a watchful eye on the others. PMID- 21274138 TI - [Not Available]. PMID- 21274139 TI - Hemoccult 'disappointing'. PMID- 21274140 TI - Boost screening for hypertension. PMID- 21274141 TI - Nutrition info and the family doctor. PMID- 21274142 TI - Who sends junk mail? PMID- 21274143 TI - Child health care in Canada. AB - Canadian family medicine and pediatrics have much in common, yet increasing interspecialty competition in the U.S. threatens to spill over into Canada. Geographic, demographic and manpower considerations make it imperative that family physicians continue to provide most of the health care for children in this country. Restrictive entry into traditional specialty programs, subspecialty domination of pediatric training and a shift in the age structure of pediatricians vs family physicians will ensure that the primary care of children will remain with Canadian family doctors. Research has revealed no superiority of one type of provider. Nevertheless the training of family physicians in behavioral and ambulatory areas could be improved. Maintenance of obstetrical activity is key to continued involvement in child health. Areas of collaboration between the two disciplines are explored. PMID- 21274144 TI - Use of cimetidine in hospitalized patients: the role of continuing medical education. AB - In 1983, the highest selling drug in Canada was cimetidine (Tagamet(r)-Smith Kline & French). A clinical review was initially conducted in 1981-82 to assess how physicians in a rural hospital in British Columbia prescribed cimetidine. The study was repeated and showed that prescribing patterns improved. Attempts to improve quality of care through continuing medical education are extremely important, particularly in light of escalating medical costs. PMID- 21274145 TI - Well baby visits: screening and health promotion. AB - Traditional child care consists of periodic health examinations and treatment for episodic illness. It is important to ensure that prevention, detection and early treatment of developmental problems are always done, especially in children with frequent illnesses. Educational and psychosocial factors, nutrition and physical assessment must also be stressed to promote child and family health. The authors have developed flow sheets for screening visits at age two weeks to two years, to check growth, nutrition, education, parenting, behavior, development, symptoms, examination procedures, and assessment. The sheets are a memory and charting aid in a busy office, allow other office staff to participate, and can be modified to suit the practice and the patient. PMID- 21274146 TI - The Heartsaver-Baby: A CPR Course for Young Parents. AB - Accidents are the leading cause of death in infancy and childhood from ages one through 24. Parental training programs in the prevention and management of pediatric emergencies may effectively decrease the morbidity and mortality of sudden accidental death in children. The Heartsaver-Baby course is a course in cardiopulmonary resuscitation specifically designed for young parents. It includes training in the prevention of childhood emergencies resulting in sudden death, recognition of the most common emergencies in different age groups, practical training in CPR and obstructed airway maneuvers. Widespread implementation of this community program may help decrease the incidence of accidents in children and provide parents with a better background to deal with life-threatening emergencies. PMID- 21274147 TI - The Pre-term Infant: Outcome 1985. AB - Improvements in neonatal mortality rates have occurred as a result of regionalized perinatal care, neonatal intensive care and improved socioeconomic standards. Some of this can be ascribed to specific advances in neonatal management, including the introduction of new formulae, and drugs such as indomethacin. The increased survival has produced a new morbidity which presents a new set of challenges in continuing child and family care. PMID- 21274148 TI - Diagnosing and managing neonatal respiratory depression. AB - There are four types of neonatal respiratory depression. Most infants who require resuscitation have clearly depressed respiration at birth. The onset is prenatal in these cases. However, other infants appear normal at birth, cough and breathe a few times, but become acutely depressed in the first minute or so. A third group deteriorates gradually over the first few minutes, making little or no effort to breathe. A fourth group appears normal or fairly normal at birth, and while breathing strenuously develops signs of asphyxia. The pre- and postnatal signs, causes and differential diagnosis of the four types of neonatal depression are described, and guidelines for resuscitation are provided. PMID- 21274149 TI - An update on the sudden infant death syndrome. AB - Sudden infant death syndrome (SIDS) is a term applied to the sudden death of an infant that defies explanation. The infant apnea syndrome (formerly the near-miss for SIDS) has come to apply to a different population of infants who are unlikely to have died from SIDS. The use of monitoring devices in the home is logical in the apnea syndrome, but evidence for its use for the prevention of SIDS is presently lacking. There is no information yet on methods by which to predict or to prevent SIDS. Support and counselling of grieving parents requires an updated knowledge of advances in SIDS research. PMID- 21274150 TI - Common congenital anomalies. AB - Congenital anomalies account for a substantial proportion of childhood morbidity and mortality. They have become proportionately larger because of the decline of such other categories as infections or birth trauma. Approximately 3% of newborns have a serious handicapping or potentially lethal condition; in longterm studies the frequency is much higher. There is no good evidence to suggest that the rates of congenital anomalies are increasing, although this is a common perception. This article discusses diagnosis and management (especially genetic implications) of heart defects, neural tube defects, orofacial clefting, dislocated hip, clubfoot, and hypospadias. PMID- 21274151 TI - Growth retardation: an approach to management. AB - The physician who looks after children and teenagers is often confronted with the problem of short stature or growth failure. A major concern is when, and how extensively, to investigate the problem. From a practical standpoint, assessment can be related to height percentiles. The aims of treatment are to identify and treat appropriately the patients in whom there is an organic cause and to provide psychologic counselling and support. Common causes of growth failure are identified and a simple approach to management is outlined. PMID- 21274152 TI - Childhood cardiac murmurs: innocent or not? AB - Cardiac murmurs may be detected in as many as half of the pediatric patients in an office practice. Careful history taking and clinical cardiovascular system examination will usually separate those patients who warrant further investigations from those who do not. Tips are provided on how to examine various age groups to elicit the most information. Full disclosure of the cardiac findings should be made to the family at the time, to prevent conflicts at a later date. PMID- 21274153 TI - Differential diagnosis of upper airway disease in children. AB - Upper airway disease in childhood is very common and can be life-threatening. It is important to differentiate between the various causes of airway obstruction in children. A croupy cough can signal acute laryngotracheobronchitis (croup), acute epiglottitis, or aspiration of a foreign body. The problem must be quickly and accurately diagnosed, followed by appropriate management and careful monitoring. Morbidity and mortality can be high in certain instances. Therefore, the physician must know the indications for hospitalization. PMID- 21274154 TI - Infections in refugee children from developing countries. AB - Refugee children, although in generally good health, may present with unfamiliar infectious or hematological problems, primarily tuberculosis, hepatitis B, intestinal parasites, malaria, eosinophilia and anemia. Prevalence, clinical features and treatment are discussed, together with the features of some less common infections. In the symptomatic refugee child, both common and exotic infectious diseases should be considered in the differential diagnosis. Iron deficiency and hemoglobinopathies should be considered in the differential diagnosis of microcytic anemia. PMID- 21274155 TI - Limp affecting the hip and knee in children. AB - Limp and pain are common findings about the hip and knee in growing children. Epiphyseal growth peculiarities in children account for many of the specific disease entities. Simple but specific physical examination and mandatory simple X rays will virtually always give or exclude a diagnosis. problems about the hip are usually serious, for example Legg-Perthes, slipped epiphysis and septic arthritis. Most childhood knee problems are annoying but not serious. Chondromalacia patellae and Osgood-Schlatter's disease seldom require treatment but the knee is the most common site for osteogenic sarcoma. PMID- 21274156 TI - The unusual but benign in pediatric surgery. AB - The problem of what is normal and what is not is closely related to whether or not, if something is indeed abnormal, it matters. Anticipating the outcome will affect the management in infants and children of such relatively benign conditions as hydroceles, umbilical hernias, diseases of the male and female breasts, lymphadenopathy and the intact prepuce. Unnecessary investigations such as barium studies which do not affect management are inadvisable. Congenital torticollis and undescended testis, seemingly benign, must be appropriately treated, however, in order to avoid lifelong sequelae. PMID- 21274157 TI - Allergy in pediatrics. AB - Given the current understanding of allergic mechanisms, more precise recent descriptions of clinical symptoms in relationship to these mechanisms and modern pharmacology, the family physician can become very comfortable with the diagnosis and management of allergic problems after proper training. The physician must be familiar with the concepts of modern allergy, be able to distinguish between IgE mediated and non-IgE-mediated mechanisms, especially in relation to foods, and above all, be able to recognize and manage all of the non-wheezing presentations of asthma. PMID- 21274158 TI - Donald ingram rice: the man, the doctor, the official. PMID- 21274159 TI - Miscarriage: how to help in the crisis. AB - Miscarriage is a frequent outcome of pregnancy, with major emotional implications to the couple experiencing such an event. This review examines common emotional sequelae to miscarriage, drawing on both the medical literature and reports of women's responses in the public press. Commonly asked questions stress the need for patient information and education. PMID- 21274160 TI - Atypical severe muscular dystrophy in a male: genetic implications for female relatives. AB - Genetic counselling of two younger sisters of a 32-year-old man with a 28-year history of severe progressive muscular dystrophy stimulated efforts to determine his diagnosis and the mode of inheritance. The investigation was complicated by the patient's sudden death during the period of investigation. However, genetic and neurological evaluation, electromyography and nerve conduction studies, serum enzymes and reinterpretation of a muscle biopsy 23 years earlier made it unlikely that inheritance was X-linked, thereby substantially reducing his sisters' risk of bearing affected children. Precise diagnosis, especially of what is not likely in atypically presenting genetic disease, is of paramount importance in managing families at risk for genetic disease in future children. It is an important responsibility of family physicians concerned with preventive genetic medicine. PMID- 21274162 TI - Bad news can be good news. PMID- 21274161 TI - Videotapes as continuing medical education for physicians in isolated communities. AB - The lack of available and appropriate continuing medical education is a major problem for physicians practicing in isolated communities. This paper describes a pilot project in the use of videotapes as one method of meeting this need. The tapes were well received by the physicians who participated in the project and highly rated as being an effective learning method, appropriate to their practices. Videotapes provide an educational opportunity for physicians working in isolated communities at a relatively low cost and with little disruption of practice or personal life. PMID- 21274163 TI - [Not Available]. PMID- 21274164 TI - Pneumococcal Vaccine And Hodgkin's Disease. PMID- 21274165 TI - Drug names: a real headache. PMID- 21274166 TI - Team sports and primary care. PMID- 21274168 TI - Victims of violence. PMID- 21274167 TI - Support group formed. PMID- 21274169 TI - Is there a problem with benzodiazepine prescribing in maritime Canada? AB - The benzodiazepine prescribing habits of 64 maritime doctors were studied through collection and examination of carbon copies of all prescriptions over a 22 week period. Diazepam was the most frequently prescribed anxiolytic benzodiazepine, followed by chlordiazepoxide, then oxazepam. These three drugs accounted for almost 60% of all benzodiazepine prescriptions. Triazolam and flurazepam were prescribed eight times more frequently than the other hypnotics, nitrazepam and temazepam. The number of prescriptions judged to be inappropriately excessive was small (3.3% of 7,066). Efforts by drug manufacturers, pharmaceutical sales representatives and CME providers are needed to make the practicing physician aware of the phamacokinetics of the different benzodiazepines, so that an appropriate choice of drug and frequency of daily doses can be made. PMID- 21274170 TI - Illness behavior and anomie in family practice. AB - Patients who present with physical complaints that have a psychosocial source are often dissatisfied with reassurance that nothing is physically wrong. This is frustrating to the physician, who may elect to refer the patient, do nothing further-or address the issue of illness behavior. This article analyzes the effects of the physician's response on the doctor/patient relationship, and outlines several methods of psychotherapy which can be used to change illness behavior. PMID- 21274171 TI - Divorce: a fact in your practice. AB - Although the divorce rate has risen dramatically, marriage is still the lifestyle of the majority of adults. Divorce disrupts one's identity, economic and emotional dependancy and disturbs primary relationships with family of origin, children, friends and colleagues. Physicians may have trouble adjusting to new circumstances in their patients' lives. Serious emotional adjustments are necessary in resuming the status of being single. The physician can help by focusing on the support system, by emphasizing that the turmoil of adjustment is normal and by helping set realistic goals. Studies show that suicidal and even homicidal behavior is present in a significant percentage of divorcing spouses. PMID- 21274172 TI - Assessing the single-parent family. AB - The increase of single-parent families causes an increase in psychosocial problems and illness associated with stress. Divorce, separation, and lone parenting have now surpassed death as a cause of single-parent families. They are major life events, and the family physician who helps anticipate them and facilitates adaptation of the family can help prevent associated morbidity and mortality. A non-judgmental approach and understanding of system theory helps in assessing the single-parent family and its stresses. As in medical areas, diagnosis precedes treatment, appropriate assessment indicates management strategies. The acronym 'PRACTICE' describes an assessment tool for the areas likely to be problematic in single-parent families. The difference between the divorced, widowed and the never-married and their coping strategies are described. PMID- 21274173 TI - Marriage as a stage in the family life cycle. AB - The life cycle of a family goes through well recognized developmental stages, each of which causes some disruption. At certain stages, preventive intervention by the family physician would be most fruitful. The transition to marriage is a case in point. Knowing the tasks of this stage can help the family physician anticipate any problems, particularly ones which may affect health. Research into the effects of education for marriage has shown that such education helps couples resolve conflicts constructively. Research is now focusing on the next stage of family development: the birth of the first child. PMID- 21274174 TI - [Not Available]. AB - The author proposes the system approach as a means of understanding and action for the family doctor. Different clinical situations are considered: the interview with the whole family, the interview with part of the family and the individual encounter. These examples show the utility of the system approach for the family doctor. The tools can also be used in individual consultation-the most common situation for the family doctor. In family medicine, the family is often identified as the 'patient'. Some believe that individual care should be given 'in the context of the family'. The author believes that the missing link between these two viewpoints is the use of the system approach in the individual encounter. PMID- 21274175 TI - Helping families deal with adolescent sexuality. AB - Developing an independent sexual identity is one of the psychosocial tasks of adolescence. The only recent change in adolescent sexual activity is an increased percentage of teenage girls having intercourse. Coitus carries the risk of pregnancy and sexually transmitted diseases. It is also an area of conflict with parents. There are healthy and unhealthy approaches to these problems. Family physicians must demystify adolescent sexuality. They must give the adolescent non judgmental, confidential, and comprehensive care. They must pursue the many possible underlying causes for parental conflict with their teenagers over sexuality. Community involvement is very important in this aspect of practice. PMID- 21274176 TI - Suicidal behavior in the emergency room part 1: assessment of risk. AB - Emergency physicians have a significant responsibility in the recognition, management and prevention of suicide behavior. A comprehensive clinical assessment should include a systematic review of high risk factors. Five important aspects associated with high risk factors are reviewed in this paper: the patient's suicidal intention; the lethality of the attempt; psychiatric diagnosis; demographic and clinical characteristics, and attitudes toward the suicidal attempt, significant others and health care providers. PMID- 21274177 TI - Suicidal behavior in the emergency room part 2: treatment and disposition. AB - Emergency physicians have a significant responsibility in recognizing, managing and preventing suicidal behavior. This paper proposes a theoretical model for disposition of patients with suicidal ideas and behavior. This model is based on five well documented predictors of suicide: intention and lethality of the suicide attempt, psychiatric diagnosis, demographic and clinical factors, attitude towards the attempt and support system. Treatment recommendations are based on initial assessment of these factors. Inpatients must be carefully supervised; the commonest forms of suicide in hospital are hanging and jumping from heights. Treatment plans should be implemented immediately. Since compliance with follow-up is very low in these patients, outpatient treatment should be implemented with an outreach program and integrated with community psychiatric and mental health services. PMID- 21274178 TI - 'No resuscitation' orders: perspectives, policies, problems and procedures. AB - Chedoke-McMaster Hospitals in Hamilton have evolved a 'No CPR' Policy for over seven years. This article describes some of the important ethical, administrative and practical clinical factors in successful application of a 'No CPR' order to the management of terminally ill patients. The role of the attending physician is critical in negotiating 'No CPR' decisions with patients and families. Physicians' attitudes toward death and their perceptions of their professional responsibilities for patients determine if and how an order will be written. Several clinical strategies are suggested to help negotiate a 'no CPR' decision. PMID- 21274180 TI - What would you have done? Teenage pregnancy. PMID- 21274179 TI - Breast-feeding and the Working Mother. AB - Despite the resurgent popularity and known benefits of breast-feeding, most Canadian women do not consider the possibility of continuing breast-feeding when they return to work. This paper examines the reasons why many women make this choice, and what factors are involved in continuing to breast-feed. The long range goal of our society should be to increase the percentage of mothers who continue to breast-feed their babies until at least six months of age, and to increase the percentage of places of employment where it is possible for an employee to continue to breast-feed after returning to work. PMID- 21274181 TI - Whither artificial reproduction? AB - Artificial reproduction now offers sub fertile couples a number of options which raise scientific and ethical questions. This article discusses the Canadian and British experiences in formulating regulations and legislation in this important field. Current work on mammalian embryo research foretells the direction which human research will take. This article stresses the need for family physicians' participation in the ethical decisions that accompany these new developments. PMID- 21274182 TI - A child or our child? Ethical dimensions of artificial insemination by donor. AB - This paper advocates redefining parenting in terms of commitment and nurture rather than biological affinity. Legal precedents involve a geneological bias, but this is unrealistic in the light of the increasing variety of modes of reproduction now open to prospective parents. Commitment and nurture favor social rather than biological affinity as the foundation of family life. Whether we can insist on commitment and nurture as conditions of "parenting" is moot, hinging on whether parenting is viewed as a privilege or a right. However that question is resolved, justice demands that artificial insemination by donor and natural parents be treated alike. PMID- 21274183 TI - Differences in work plans of graduating family medicine residents. AB - Much subjective evidence has compared productivity of male and female physicians. Given that enrollment of female students is now much higher, manpower planners have to look carefully at the implications, ensuring that they have accurate information. This study surveyed 1984 graduates of one Ontario and four western residency training programs in family practice. Although many men had no fulltime plans and intended to take at least three months off, women were more likely not to have any work plans, to be intending to practice in an urban area, and to be intending to limit their practices (e.g. no obstetrics, no emergency room, no surgical assisting). While traditional role conflicts may account for these differences, there may also be different confidence levels by sex for certain aspects of family medicine. PMID- 21274184 TI - Comments. PMID- 21274185 TI - The company doctor: whose side are you on? PMID- 21274186 TI - Family physician manpower in alberta. PMID- 21274187 TI - Les mauvaises nouvelles peuvent s'averer de bonnes nouvelles. PMID- 21274189 TI - Folate and b(12) levels: are supplements given too late? PMID- 21274188 TI - Pharmacists and the 'real world'. PMID- 21274190 TI - Harms patients? Then don't do it. PMID- 21274191 TI - Teach and Reassure: Don't Proscribe BSE. PMID- 21274192 TI - No cure for the cancerphobics. PMID- 21274193 TI - Patient feedback has been positive. PMID- 21274194 TI - A logical step in detecting cancer. PMID- 21274195 TI - Need to increase patient awareness. PMID- 21274196 TI - Forestall fear with a good patient/doctor relationship. PMID- 21274197 TI - Cancerphobia? That's A Copout. PMID- 21274199 TI - BSE Cancerphobia? Not Seen by this FP. PMID- 21274198 TI - Cancerphobia is a red herring. PMID- 21274200 TI - Compare BSE To Brushing Teeth. PMID- 21274201 TI - Banning BSE? Most FPs Say No. PMID- 21274202 TI - Genital Chlamydia trachomatis: detection, treatment and patient education. AB - To determine the frequency of genital chlamydial infections in the patients of an Ontario family planning clinic, endocervical swabs for tissue culture of Chlamydia trachomatis were taken. Incidence of this infection in our patient population was 7%. Most patients were asymptomatic. Treatment with two different regimens of tetracycline proved equally effective. Male partners of positive cases were encouraged to attend for urethral culture and treatment. The major challenge of this study was to educate patients about a disease of which most had never heard. Recommendations include: routine screening of all sexually active women under 25; culture for Chlamydia in all symptomatic patients, and treatment of sexual partner(s) of Chlamydia-positive patients. PMID- 21274203 TI - Family physicians' attitudes towards obstetrics in alberta. AB - Concerned about family physicians' changing role in obstetrics, the Alberta Chapter of the College of Family Physicians of Canada conducted a survey of a 10% sample of Alberta family physicians. Practices and attitudes about various aspects of obstetrical care were determined, including procedures, technology, alternative birthing methods, payment, Canadian Medical Protective Association fees, and continuing education. The response (89% of surveyed family physicians) showed that 66.7% were providing obstetrical care, 24.8% had stopped, and 8.5% had never practiced obstetrics. Ten percent were planning to quit within the next two years, mainly for economic reasons, but three (2.3%) would have liked to start if privileges were available. Respondents wanted more 'hands-on' experience in training and practice, were satisfied with the availability of tertiary care, and were not averse to trying alternate birthing methods if they were safe and occurred in hospital. PMID- 21274204 TI - Developing an occupational health program: the team approach. AB - Occupational health and safety programs involve professionals in occupational medicine and nursing, industrial hygiene, safety and accident prevention, psychology, sociology and health physics. Occupational health programs should allow regular health evaluations of workers, and the recognition, evaluation, and control of environmental hazards. When designing in-plant medical facilities, accommodation should be made for possible future expansion, disabled people, and an access route for an ambulance. Treatment and prevention facilities should be separate. Patients' records must be complete and kept confidential. The occupational health program must also be evaluated regularly. Education of management and the work force is necessary to ensure that the environment is safe and to prevent accidents. Special programs may be introduced, based on the particular risks, toxicants, and problems in different industries. PMID- 21274205 TI - Doctors' notes to employers and insurers. AB - If physicians do not write notes for employers and disability insurers carefully, patients may lose employment and/or disability benefits. Employers want to know whether workers can perform the job adequately and safely under reasonable conditions. Whether the inability to do the job is due to a legitimate medical problem is irrelevant for protecting jobs. The physician should therefore be careful to distinguish between 'hurt', which may cause workers pain, but allow them to do a job, and 'harm', which means a particular job may worsen the patient's condition. The physician must also be well informed about eligibility for disability payment. When writing a note, doctors should ask themselves several questions: Is there a definite diagnosis? Is the patient receiving optimal medical therapy? What are the irreducible limitations imposed by the patient's disease? What are the contraindications? Is the disability temporary or permanent? PMID- 21274206 TI - Disability insurance. AB - A disability insurance policy provides specified income benefits when the insured person becomes unable to work because of illness or accident. With an individual policy, the insured person is generally the policy holder. With a group plan, the employer is the policy holder. An individual policy can provide several optional benefits in addition to disability benefits, which are not available in a group plan. In assessing risk, the insurer uses the application, the agent's report, a physical examination, the attending physician's report, and sometimes a consumer investigation company's inspection report. Records from the Medical Information Bureau, an association of American and Canadian life insurance companies, may also be used. The process of claims adjudication is described, as are differences between short-term and long-term disability claims. Many group policies have a rehabilitation provision; payments may continue while the claimant undergoes rehabilitation or retraining. PMID- 21274207 TI - The company doctor: an endangered species. AB - Company doctors are both managers and clinicians. They are responsible for managing human resources, occupational health professionals, technicians, and clerical staff. They are involved in prevention programs, and are expected to advise management of changes in occupational health, workers' compensation, and human rights legislation. As clinicians, company doctors conduct preplacement and periodic examinations, and provide on-the-job treatment, counselling, and rehabilitation. However, fewer than 10% of Canadian workers are cared for by full time occupational health physicians, and most workers do not have access to formal, occupational health programs. There is a need for better resources and occupational medical training, particularly for part-time company physicians. PMID- 21274208 TI - Preventing hepatitis B in health care workers. AB - Exposure to hepatitis B virus (HBV) infection is a potentially serious occupational hazard for health care workers. Data indicate an increased risk of HBV infection in health care workers. This risk appears to be related to the frequency of contact with patients' blood and exposure to high risk patient populations. Strategies available for preventing HBV infection in the health care setting include HBV vaccine, which is the most efficacious and practical strategy. In view of the potential consequences of HBV infection, health care employers have a responsibility to provide education, serological testing and vaccination. Health care workers have a responsibility to use these programs, and to assess their own risk of infection. PMID- 21274209 TI - Premenstrual syndrome: approaches to diagnosis and treatment. AB - There has been much confusion in the literature over the definition, diagnosis and treatment of premenstrual syndrome (PMS). This article discusses definitions of PMS, incidence, etiology and symptomatology. Diagnosis depends on the timing of symptoms rather than the type. Symptoms commonly occur during the late premenstruum; at ovulation and during the premenstruum; or at ovulation, gradually increasing in severity throughout the luteal phase. To diagnose PMS, three consecutive menstrual cycles must be charted, the symptoms must be limited to the luteal phase, and there must be a complete absence of symptoms for at least one week in the postmenstruum. Rational treatment programs for mild, moderate and severe PMS are proposed. The role of progesterone in treatment is discussed. PMID- 21274210 TI - A comprehensive approach to male homosexual disorders. AB - AIDS, hepatitis, and gay bowel syndrome are among the many problems which occur more frequently in male homosexuals. The physician should have a routine screening program for such patients and be aware of all patients' sexual preferences. Counselling on lifestyle and an awareness of psychosocial issues in homosexuality are important in preventing many of these disorders. Hepatitis B vaccine is a significant breakthrough and its use should be actively encouraged. PMID- 21274212 TI - Que feriez-vous? Un cancer de poumon. PMID- 21274211 TI - The community pharmacist as a resource for the family physician. AB - The family physician's relationship with the community pharmacist has tended to be biased. The physician sees the pharmacist simply as a dispenser of drugs. Physicians and pharmacists are usually physically separated, lessening their chances of a collaborative working relationship. Family physicians' traditional sources of drug information include journals, colleagues and drug company literature. However, when they have some form of regular interaction with a pharmacist, physicians tend to see the pharmacist as a main source of drug information. The proper use of medication involves three critical relationships: doctor/patient, doctor/pharmacist, and pharmacist/patient. The doctor/pharmacist relationship has several components: individual consultations, regular team meetings, and establishment of a limited formulary for physicians and residents. There is evidence that compliance is improved when the pharmacist is involved in patient education. PMID- 21274213 TI - Teaching core content in family medicine. AB - Core content in family medicine has been difficult to define, given that family practice has differed widely from physician to physician, according to locale and availability of resources. Since family medicine has been taught, educators have been attempting to define its core content-and find ways of teaching it. At the McMaster University Medical Centre Family Practice Unit we have put the problems first: residents present a problem in patient care and the group discusses the problem in relation to a precirculated article on the topic. Lecturing is kept to a minimum, and articles are chosen according to the principles of critical appraisal. An attempt at evaluation generated a positive response. PMID- 21274214 TI - The responsible family physician: rule bound or risk-taking? AB - Moral philosophy is often more frustrating than helpful to family physicians who come to it seeking solutions to the everyday moral dilemmas that their practices present. Continuity of care and comprehensive care are features of family medicine that require the nurturing of close doctor-patient relationships. They also present family physicians with unique moral dilemmas which require decision and action with insufficient information or time to apply the careful thought associated with moral philosophy. Decisions can often be made only on the basis of the personal and professional relationships existing between doctor and patient. There is a rigor and legitimacy to this process that better reflects the process of moral decision-making in family medicine than does that of traditional moral philosophy. PMID- 21274215 TI - [Not Available]. PMID- 21274216 TI - [Not Available]. PMID- 21274217 TI - 'Gynegadgetry'. PMID- 21274218 TI - Breast Examination: What's Reasonable? PMID- 21274219 TI - Breast Examination: What's Reasonable? PMID- 21274220 TI - Single tablet treatment of urinary tract infections in women. AB - Non-pregnant women presenting to a family practice clinic with symptoms of lower urinary tract infection were randomly assigned to a single dose of one, two or three tablets of sulfadiazine/trimethoprim 410 mg/90 mg. All three regimens were equally effective and caused no serious side effects. Overall cure rates were 93% at seven days and 81% at 14 days. Single tablet treatment with appropriate follow up appears to be an effective treatment of lower urinary tract infections in non pregnant women. PMID- 21274221 TI - Cough: bronchospasm or not? AB - Cough is a frequent presenting complaint, often with a history very similar to that of asthma. This study examines the incidence of bronchospasm among coughers in a family practice. The pathophysiology of cough shows that the irritant receptors for cough and bronchospasm are identical; epithelial damage may result in cough, or bronchospasm, or both. Of 32 patients presenting with cough as their chief complaint, eight were found to have bronchospasm. Since effective treatment depends on correct diagnosis, a precise history of the cough is necessary to differentiate different causes. PMID- 21274222 TI - Scoliosis screening and treatment. AB - Scoliosis-a spinal curve of 5 degrees or more, with a rotational deformity-may be present in up to 4% of patients aged 12-14. However, only about 0.3% require treatment, for progressive curves of 20 degrees or more. About 70% of all scoliosis in North America is idiopathic. Non-idiopathic varieties include congenital and neuromuscular scoliosis, mesenchymal disorders, non-structural scoliosis, juvenile kyphosis and Scheuermann's disease. A clinical evaluation for early detection of scoliosis need take only a few seconds during an office visit. Treatment can include periodic check-ups and X-rays, exercises, braces, electrical stimulation and surgery. Scoliosis associated with other conditions can be discovered in patients of any age, and recognition early is important for proper treatment. PMID- 21274223 TI - Spinal manipulation in the treatment of low-back pain. AB - Spinal manipulation, one of the oldest forms of therapy for back pain, has mostly been practiced outside of the medical profession. Over the past decade, there has been an escalation of clinical and basic science research on manipulative therapy, which has shown that there is a scientific basis for the treatment of back pain by manipulation. Most family practitioners have neither the time nor inclination to master the art of manipulation and will wish to refer their patients to a skilled practitioner of this therapy. Results of spinal manipulation in 283 patients with low back pain are presented. The physician who makes use of this resource will provide relief for many patients. PMID- 21274224 TI - A behavioral approach to managing chronic low back pain. AB - Most patients with chronic back pain have no defined disease for which there is a specific treatment. These patients demonstrate excessive illness behavior. The initial approach must be to rule out a treatable disease. Then the patient must accept that while activity may hurt, it will not harm. The patient and spouse must both understand that no further investigation or specific therapy will help. The family physician must teach patients to change their lifestyle through a program of progressive activity. Realistic expectations must be set, with return to a normal lifestyle and work as the ultimate goals. PMID- 21274225 TI - Temporomandibular joint dysfunction: a dental overview. AB - Temporomandibular joint dysfunction is common and often acutely painful. Because of the large and diverse symptom complex created by this disorder, patients frequently first seek relief from their physician rather than their dentist. In this article temporomandibular joint (TMJ) dysfunction is defined and the presenting signs and symptoms are discussed. Their etiology is described in relation to the anatomy of the temporomandibular joint. Examination techniques can help in the differential diagnosis. Current treatment ranges from heat, local anesthesia and ultrasound to anxiolytics, transcutaneous nerve stimulation and nutritional supplementation. PMID- 21274226 TI - Acute management for the injured hand. AB - If not optimally treated, a hand injury can lead to disability which often has considerable economic and social implications. The role of the primary care physician is to diagnose the injury correctly and initiate management which will keep this disability to a minimum. This is best achieved by making a composite diagnosis to include all the injured components of the hand. The emphasis must be on early mobilization of the injured area and the maintenance of mobility in all joints of the upper limb. Early referral to physiotherapy and occupational therapy departments is highly desirable. The major pitfall in managing hand injuries is over zealous treatment of the fracture at the expense of the soft tissue injury, resulting in iatrogenic stiffness. PMID- 21274227 TI - Surgery for the arthritic knee. AB - The optimal surgical procedure for the arthritic knee depends upon the type of arthritis and the patient. If the patient is 'high demand' (i.e., relatively active and young), and has incongruous arthritis (in either the medial or lateral compartments but not both), then realignment by osteotomy transfers the weight to the healthy compartment. If the osteotomy is successful, the patient may continue a physically demanding lifestyle. Knee replacement is indicated if the patient is 'low demand' (i.e., elderly or suffering from multiple joint disease) and has congruous arthritis, with destruction of both weight-bearing compartments. Knee replacement does not allow the same activity level as realignment but, fortunately, the low demand patient tends to have congruous disease (e.g., rheumatoid arthritis) and the high demand patient incongruous disease (e.g., osteoarthritis). PMID- 21274228 TI - Patellofemoral arthralgia, overuse syndromes of the knee, and chondromalacia patella. AB - Patellofemoral arthralgia is a very common syndrome affecting athletes. Most often, examination fails to define true pathology. Conservative treatment, an active exercise program, and sports may be undertaken without harm to the knee. The patellofemoral arthralgia syndrome must be differentiated from true chondromalacia patella, where there is actual degeneration of the patella's articular cartilage, and from other sources of internal derangement such as meniscal disease or osteochondral lesions. Careful attention to the history of onset, and provoking activities such as climbing stairs, kneeling, and crouching, will allow the physician to recognize patellofemoral arthralgia. Other common overuse syndromes also should be looked for, and differentiated from problems due to true internal derangement. PMID- 21274229 TI - Minor surgery of the foot. AB - Ingrown toenails, hallux valgus and Morton's neuroma are common problems in family practice. All are amenable to surgical treatment. Ingrown toenails, in particular, are easily treated in the office. The indications for conservative treatment, surgical management, and some surgical techniques are discussed. PMID- 21274230 TI - Fractures and soft tissue injuries of the feet and ankle. AB - An accurate clinical diagnosis of foot and ankle pain can be made by a history, physical examination and routine X-rays of the affected part. Each problem has a specific treatment; however, fractures and dislocations around the foot and ankle can be thought of in an organized fashion by proper physical examination and then the appropriate treatment. Fractures and soft tissue injuries can be treated rationally by understanding the mechanism of injury and the possibility of subsequent deformity. This article classifies specific injuries as a group and indicates a treatment program for each problem. PMID- 21274231 TI - Assessing Children's Legs and Feet. AB - Shoes are necessary for protection and warmth. Normal children do not require shoes for support. There is no scientific evidence that shoes-'orthopedic' or otherwise-influence or alter the growth or shape of the normal child's foot except, perhaps, adversely if they fit poorly. Family physicians must understand common variations of normal foot and leg development if they are to effectively advise and reassure parents about appropriate footwear. Flat feet, knock knees, bow legs, in-toeing, and out-toeing in otherwise normal children can easily be distinguished from similar but more serious deformities associated with disease or congenital anomaly. PMID- 21274232 TI - Clothing for sports: part 2: stridalongapos loses shorts, wins in style. AB - The choice of clothing for sports must take into account the climate, movement, ability to enhance athletic performance, safety and comfort. Part 2 of this two part article describes the clothing needed for running, cycling, skiing, windsurfing, triathlon, aerobic dancing and hot air ballooning. PMID- 21274233 TI - The patient in poetry: an exercise in clinical problem solving. AB - Meeting a patient for the first time, a physician must sort through an often complex, jumbled array of information. This process can be replicated in reading: literature abounds with medical examples which, when analyzed, reveal similar diagnostic challenges to those faced in practice. This article examines the poem "To An Old Jaundiced Woman" by Dr. William Carlos Williams. The conclusions of fourth year Dalhousie medical students are presented, together with the viewpoint of a practicing family physician. Readers are invited to compare their responses. PMID- 21274234 TI - Issues at the edge of life: a case report. AB - A 78-year-old man suffered a non-terminal cerebrovascular accident and was admitted to the in-hospital service of a family practice teaching unit. His family requested that he be allowed to die, in order to honor his previously expressed wishes and to spare him the "indignities of intervention". They were informed that treatment was relatively simple and non-invasive, but remained adamant. The case is discussed from the perspectives of the attending physician and a physician observer, who witnessed the 'ripple effect' that the case had on staff and students of the teaching unit. PMID- 21274235 TI - Who should do routine immunizations? PMID- 21274236 TI - Dear reader: farewell. PMID- 21274237 TI - Midwifery and the family physician. AB - Midwives have provided care for thousands of women who have given birth in their homes over the past 15 years in Canada. Their request for legalization of midwifery services is receiving serious consideration by the governments of Ontario and Quebec. Fewer family physicians are practicing obstetrics, and those who are express concern for the safety of their patients who choose home birth. Consumers, however, argue that planned, midwife-attended birth at home is a safe option. Perinatal mortality rates are consistently low when the statistics on planned are separated from those on unexpected home births. Midwifery services can complement the role of the family physician in providing continuity of care to the laboring woman. The Dutch domiciliary midwifery service demonstrates the possibility of this service being successful, but Canada must build a service designed for Canadian needs. PMID- 21274238 TI - Pill-takers: At Special Risk Of Chlamydial Infection? PMID- 21274239 TI - Pharmacists and family physicians. PMID- 21274240 TI - Three Cheers for CFP's Editor. PMID- 21274241 TI - When to treat acetaminophen overdose. PMID- 21274242 TI - Can fundal height predict birth weight or twins? AB - To determine how well symphysis fundal height measurements correlated with birth weight, the authors retrospectively reviewed 100 records of pregnancy from a family practice. The sensitivity and specificity of symphysis fundal height in identifying small and large for gestational age babies were determined. While symphysis fundal height measurements correlated well with birth weight, the sensitivity was too low and the number of false positives too high, for symphysis fundal height measurement alone to be clinically useful. On reviewing all twin pregnancies in the same setting, the authors found that symphysis fundal height measurements facilitated early diagnosis of twin gestation. PMID- 21274243 TI - Pertussis: the disease and the vaccine. AB - PERTUSSIS STILL CAUSES SIGNIFICANT MORBIDITY: average duration of the illness is six to eight weeks. Almost one third of infants have complications including weight loss, apneic spells, otitis media, pneumonia, and seizures. Encephalopathy occurs in approximately one in 2000 infants: one third die and one third sustain permanent brain damage. The mortality rate is one in 1000 infants. Pertussis vaccine consists of heat and formalin-killed whole bacteria. Minor reactions of fever, irritability, crying, and local reactions occur after 40-60% of injections. Major reactions include prolonged screaming, seizures, collapse, fever over 40.5 degrees C, and encephalopathy. Permanent brain damage occurs in association with one in 310,000 injections, so the benefits clearly outweigh the risks. All young children should be immunized. PMID- 21274244 TI - Palliative care: cure versus palliation. AB - The decision to ease symptoms without curing causes stress in physician and patient alike. Palliative care must involve the patient, family and family physician. Proper care will involve awareness of the physician's and society's attitudes to death and dying, education, useful denial, when to palliate, patient selection, and palliative care as an alternative to 'curative' therapy. The role of the family physician is defined, and check lists are presented to facilitate patient selection. The patient must maintain control of the situation with the physician as informant, advisor and coordinator of care for the terminal phase of the patient's life. PMID- 21274245 TI - Lipid screening in family practice: a critical appraisal of recent evidence. AB - Applying principles of critical appraisal to evidence for lipid screening in family practice, one concludes that elevations of triglyceride are not a defined risk for coronary heart disease at present and screening cannot be justified. In contrast, there is now good evidence that elevated cholesterol is not only a primary risk factor for, but also a cause of coronary heart disease. There has been no randomized trial of cholesterol screening to date, leaving the physician in the position of knowing something should be done about the problem, but the best methods are yet to be clarified. PMID- 21274246 TI - Management of breast cancer: what do I tell the patient? AB - Controversies exist about management of breast cancer because different conclusions are drawn from the same sets of data. Evidence now shows that conservative methods of treatment give the same results as aggressive surgery, especially when combined with radiation, so the question is not which operation is best, but how this knowledge can be disseminated. The surgeon and patient should be fully aware of the options for reconstruction. The next big question concerns prophylactic radiotherapy, which awaits a convincing randomized controlled trial of its effectiveness. Long-term benefits of adjuvant chemotherapy are unknown, but costs (both physical and financial) are well known. Patients must be given access to data on risk factors for developing breast cancer, especially so-called 'precancerous' lesions. Screening of all women is still a debatable topic, although all women with risk factors should be screened. They should be frankly told that prognosis can only be based on statistical probability. PMID- 21274247 TI - Prenatal diagnosis by amniocentesis and chorionic villus biopsy. AB - Prenatal diagnosis forms only a small part of day-to-day family practice, but the techniques are of critical importance to couples at risk of having a child affected by genetic disorder. Second trimester amniocentesis will probably be replaced by first trimester chorionic villus biopsy and recombinant DNA technology, but the ethical and moral problems related to prenatal diagnosis are not so easily solved. Family physicians need to examine their own attitudes toward the handicapped before they offer counselling to couples at risk of bearing handicapped children. The controversy over abortion is central to the issue of prenatal diagnosis, and may only be resolved by development of prenatal treatments for certain genetic disorders. Sometimes the only thing we can offer patients is to be with them, in whatever their decisions bring. PMID- 21274248 TI - Chemonucleolysis as treatment for herniated lumbar disc. AB - Herniated disc, while not the most common cause of low back pain, is the most common reason for surgery to relieve back pain. An alternative to surgery when sciatic pain is the result of disc herniation is chemonucleolysis with chymopapain. Since this enzyme is effective only in very specific circumstances, proper patient selection is crucial. Five criteria for selection are presented, emphasizing that since chemonucleolysis is not conservative treatment, it should be reserved for patients whose pain is unrelieved by conservative methods. There are several important contraindications to chemonucleolysis: allergy to chymopapain, risk of injury to the cauda equina, disc lesions at cord levels, pregnancy, patient's age (not recommended for adolescents) and sequestrated disc. Technique is exacting and should be limited to surgeons with the opportunity for concentrated experience. PMID- 21274249 TI - Immunotherapy: critical appraisal, effectiveness and cost/benefit ratio. AB - A critical appraisal of the literature shows that allergy skin testing is safe, economical and useful when correlated by a meticulous medical history and physical examination. Immunotherapy is beneficial in appropriately selected patients, if properly performed using licensed and preferably standardized allergenic extracts. This article reviews the labelling and standardization of those extracts, the guidelines in determining their degree of effectiveness, their current status and their different nature through inhalation, contact, injection or ingestion. It emphasizes the basic steps in dealing with potential allergic complaints, enumerating the specific indications for immunotherapy, in which conditions it gives results and the extent of these results. The cost/benefit ratio of immunotherapy and the future prospects for allergy skin testing and immunotherapy are discussed. PMID- 21274250 TI - Alcohol and the fetus: a reasoned approach. AB - Evidence relating adverse pregnancy outcome to maternal alcohol use seldom focuses on nonabusive levels of drinking, yet this is what the majority of patients seek information about. Outcomes of the hypothesized mechanisms of action appear related to pattern of exposure and timing during pregnancy. Methodological problems encountered in human studies include determination of exposure, method of analysis, and outcome measurement. Physicians should be aware of drinking habits of women in the childbearing years, and the reported adverse effects of moderate drinking. Guidelines for alcohol use in pregnancy are suggested. PMID- 21274251 TI - Is exercise a 'good thing'? AB - Exercise has emerged as a central concern in longevity and good health in the past 25 years, partly due to national pride, partly to business entrepreneurship and partly to scientific fact. There is still little hard evidence that exercise can prevent cardiovascular diseases. Any attempts at sound enquiry into the effects of exercise are hampered by the lack of specific regimens and reliable measuring devices. On the other hand, there is considerable morbidity associated with injudicious exercise activities. PMID- 21274252 TI - Are criticisms of exercise well-founded? AB - As with many decisions in public health, reasons for the advocacy of vigorous exercise can never be demonstrated by a large-scale, randomized controlled experiment. Nevertheless, there is strong evidence that physicians should be more active in commending regular physical activity to their patients, not only for its impact on mood state and thus perceived health, but also for its value in preventing and treating such common organic conditions as coronary heart disease, hypertension, maturity onset diabetes, and osteoporosis. For these problems, exercise is more effective and has fewer side effects than many alternative forms of therapy. Although some risks from injudicious exercise remain, they have been greatly exaggerated by those opposed to exercise. The advantages of a well planned regimen (which should be centred on the enhancement of normal daily activity) far outweigh the risks that a musculoskeletal problem may be provoked or worsened by the prescribed activity. PMID- 21274253 TI - Preventing nuclear war: what physicians can achieve. AB - On its fifth anniversary, the International Physicians for the Prevention of Nuclear War was awarded the Nobel Peace Prize. The organization was conceived by two Boston cardiologists who joined with some Soviet colleagues to create an international forum for considering the medical consequences of and means for preventing nuclear war. This article by the organization's archivist documents its difficult progress yet remarkable growth. Overcoming serious obstacles has added to its strength and credibility: now involving organizations with 145,000 members in 41 countries, IPPNW has become the international voice of medicine's concern about nuclear war. PMID- 21274254 TI - Psychological effects of the threat of nuclear war. AB - Systematic studies are emerging on the prevailing harmful psychological effect of the threat of nuclear war. The most recent surveys have identified populations which are particularly vulnerable. Anxiety was found to be a factor in criminal behavior, and threat of nuclear war to be a factor in anxiety. Psychiatric morbidity has been correlated with work deprivation and threat of annihilation. Many studies have focused on children, finding that anxiety about social issues is high, but that cynicism and apathy set in rapidly. Conclusions from such studies show that denial and avoidance are some of the worst results, since they are a barrier to meaningful reaction. The most vulnerable groups are children, adolescents, the unemployed, and those responsible for the welfare of others. Appropriate action is seen to be acknowledgement of fear and disillusionment as valid feelings, education towards a stronger sense of reality, and mobilization of goal-directed activity. PMID- 21274255 TI - What would you have done? Outcome of the teenage pregnancy. PMID- 21274256 TI - Bridging the gap between fluxomics and industrial biotechnology. AB - Metabolic flux analysis is a vital tool used to determine the ultimate output of cellular metabolism and thus detect biotechnologically relevant bottlenecks in productivity. 13C-based metabolic flux analysis (13C-MFA) and flux balance analysis (FBA) have many potential applications in biotechnology. However, noteworthy hurdles in fluxomics study are still present. First, several technical difficulties in both 13C-MFA and FBA severely limit the scope of fluxomics findings and the applicability of obtained metabolic information. Second, the complexity of metabolic regulation poses a great challenge for precise prediction and analysis of metabolic networks, as there are gaps between fluxomics results and other omics studies. Third, despite identified metabolic bottlenecks or sources of host stress from product synthesis, it remains difficult to overcome inherent metabolic robustness or to efficiently import and express nonnative pathways. Fourth, product yields often decrease as the number of enzymatic steps increases. Such decrease in yield may not be caused by rate-limiting enzymes, but rather is accumulated through each enzymatic reaction. Fifth, a high-throughput fluxomics tool hasnot been developed for characterizing nonmodel microorganisms and maximizing their application in industrial biotechnology. Refining fluxomics tools and understanding these obstacles will improve our ability to engineer highly efficient metabolic pathways in microbial hosts. PMID- 21274257 TI - Chemoprevention of Head and Neck Cancer by Green Tea Extract: EGCG-The Role of EGFR Signaling and "Lipid Raft". AB - Over the past decade dose-intensified chemo-radiotherapy or molecular targeted therapy has been introduced into the treatments of head and neck squamous cell carcinoma (HNSCC) to improve the outcomes of this dismal disease. However, these strategies have revealed only limited efficacy so far. Moreover, the frequent occurrences of second primary tumor further worsen the prognosis of patients. In this context, early detection and chemoprevention appear to be a realistic and effective method to improve the prognosis as well as quality of life in patients with HNSCC. In this short paper, we discuss the potential of green tea extract, ( )-epigallocatechin-3-galate (EGCG) in HNSCC chemoprevention, focusing on two aspects that are provided recently: (1) evidence of clinical efficacy and (2) unique biological effects on "lipid raft" that emerged as an important platform of numerous biophysical functions, for example, receptor tyrosin kinases (RTKs) signalings including epidermal growth factor receptor (EGFR), which play critical roles in HNSCC carcinogenesis. PMID- 21274259 TI - Screening for EGFR Mutations in Patients with Head and Neck Cancer Treated with Gefitinib on a Compassionate-Use Program: A Hellenic Cooperative Oncology Group Study. AB - Background and Aim. EGFR is commonly expressed in cancers of the head and neck (H and N), and anti-EGFR agents have demonstrated improvements in outcomes (TTP and OS). The aim of this study was to determine EGFR gene status in H and N cancer patients treated with gefitinib and to correlate mutational status with clinico pathological data and response. Patients and Methods. Patients with histologically confirmed H and N cancer having failed prior treatment for advanced disease entered this compassionate-use-program. Nineteen patients received gefitinib. EGFR expression was assessed by IHC, gene copy number by FISH, and mutation analysis was conducted for EGFR (18-21), KRAS, BRAF (V600E), and HER-2 exon 20. An additional TKI naive cohort of 73 patients was also screened. Results. Mutations were detected in 6/19 patients (3* EGFR, 1* KRAS, and 2* HER2-exon 20). There were no significant differences in TTP or OS for patients with somatic EGFR mutations. No BRAF mutations were detected. Conclusions. The incidence of EGFR mutations in H and N cancer in this study was 5.3%. No statistically relevant correlations between mutation or gene gain and response or survival were observed. Due to the limited number of patients and low incidence of genetic aberrations in the genes analyzed, additional studies are warranted. PMID- 21274258 TI - Hydrodynamic delivery of chitosan-folate-DNA nanoparticles in rats with adjuvant induced arthritis. AB - 50 kDa chitosan was conjugated with folate, a specific tissue-targeting ligand. Nanoparticles such as chitosan-DNA and folate-chitosan-DNA were prepared by coacervation process. The hydrodynamic intravenous injection of nanoparticles was performed in the right posterior paw in normal and arthritic rats. Our results demonstrated that the fluorescence intensity of DsRed detected was 5 to 12 times more in the right soleus muscle and in the right gastro muscle than other tissue sections. beta-galactosidase gene expression with X-gal substrate and folate chitosan-plasmid nanoparticles showed best coloration in the soleus muscle. Treated arthritic animals also showed a significant decrease in paw swelling and IL-1beta and PGE2 concentration in serum compared to untreated rats. This study demonstrated that a nonviral gene therapeutic approach using hydrodynamic delivery could help transfect more efficiently folate-chitosan-DNA nanoparticles in vitro/in vivo and could decrease inflammation in arthritic rats. PMID- 21274260 TI - Mammalian models of Duchenne Muscular Dystrophy: pathological characteristics and therapeutic applications. AB - Duchenne muscular dystrophy (DMD) is a devastating X-linked muscle disorder characterized by muscle wasting which is caused by mutations in the DMD gene. The DMD gene encodes the sarcolemmal protein dystrophin, and loss of dystrophin causes muscle degeneration and necrosis. Thus far, therapies for this disorder are unavailable. However, various therapeutic trials based on gene therapy, exon skipping, cell therapy, read through therapy, or pharmaceutical agents have been conducted extensively. In the development of therapy as well as elucidation of pathogenesis in DMD, appropriate animal models are needed. Various animal models of DMD have been identified, and mammalian (murine, canine, and feline) models are indispensable for the examination of the mechanisms of pathogenesis and the development of therapies. Here, we review the pathological features of DMD and therapeutic applications, especially of exon skipping using antisense oligonucleotides and gene therapies using viral vectors in murine and canine models of DMD. PMID- 21274261 TI - Multiphoton microscopy for ophthalmic imaging. AB - We review multiphoton microscopy (MPM) including two-photon autofluorescence (2PAF), second harmonic generation (SHG), third harmonic generation (THG), fluorescence lifetime (FLIM), and coherent anti-Stokes Raman Scattering (CARS) with relevance to clinical applications in ophthalmology. The different imaging modalities are discussed highlighting the particular strength that each has for functional tissue imaging. MPM is compared with current clinical ophthalmological imaging techniques such as reflectance confocal microscopy, optical coherence tomography, and fluorescence imaging. In addition, we discuss the future prospects for MPM in disease detection and clinical monitoring of disease progression, understanding fundamental disease mechanisms, and real-time monitoring of drug delivery. PMID- 21274262 TI - Antinociceptive activity of Melicope ptelefolia ethanolic extract in experimental animals. AB - Melicope ptelefolia is a medicinal herb commonly used in Malaysia to treat fever, pain, wounds, and itches. The present study was conducted to evaluate the antinociceptive activity of the Melicope ptelefolia ethanolic extract (MPEE) using animal models of nociception. The antinociceptive activity of the extract was assessed using acetic acid-induced abdominal writhing, hot-plate, and formalin-induced paw licking tests. Oral administration of MPEE produced significant dose-dependent antinociceptive effects when tested in mice and rats using acetic acid-induced abdominal constriction test and on the second phase of the formalin-induced paw licking test, respectively. It was also demonstrated that MPEE had no effect on the response latency time to the heat stimulus in the thermal model of the hot-plate test. In addition, the antinociception produced by MPEE was not blocked by naloxone. Furthermore, oral administration of MPEE did not produce any effect in motor performance of the rota-rod test and in acute toxicity study no abnormal behaviors as well as mortality were observed up to a dose level of the extract of 5 g/kg. These results indicated that MPEE at all doses investigated which did not produce any sedative and toxic effects exerted pronounce antinociceptive activity that acts peripherally in experimental animals. PMID- 21274263 TI - Role of bone marrow-derived monocytes/macrophages in the repair of mucosal damage caused by irradiation and/or anticancer drugs in colitis model. AB - Mucosal damage is a common side effect of many cancer treatments, especially radiotherapy and intensive chemotherapy, which often induce bone marrow (BM) suppression. We observed that acetic acid- (AA-) induced mucosal damage in the colon of mice was worsened by simultaneous treatment with irradiation or 5-FU. However, irradiation 14 days prior to the AA treatment augmented the recovery from mucosal damage, suggesting that the recovery from BM suppression had an advantageous effect on the mucosal repair. In addition, BM transplantation also augmented the recovery from AA-induced mucosal damage. We further confirmed that transplanted BM-derived cells, particularly F4/80+Gr1+ "inflammatory" monocytes (Subset 1), accumulated in the damaged mucosal area in the early healing phase, and both of Subset 1 and F4/80+Gr1- "resident" monocytes (Subset 2) accumulated in this area in later phases. Our results suggest that monocytes/macrophages contribute to the mucosal recovery and regeneration following mucosal damage by anticancer drug therapy. PMID- 21274265 TI - Intravenous sphingosylphosphorylcholine protects ischemic and postischemic myocardial tissue in a mouse model of myocardial ischemia/reperfusion injury. AB - HDL, through sphingosine-1-phosphate (S1P), exerts direct cardioprotective effects on ischemic myocardium. It remains unclear whether other HDL-associated sphingophospholipids have similar effects. We therefore examined if HDL associated sphingosylphosphorylcholine (SPC) reduces infarct size in a mouse model of transient myocardial ischemia/reperfusion. Intravenously administered SPC dose-dependently reduced infarct size after 30 minutes of myocardial ischemia and 24 hours reperfusion compared to controls. Infarct size was also reduced by postischemic, therapeutical administration of SPC. Immunohistochemistry revealed reduced polymorphonuclear neutrophil recruitment to the infarcted area after SPC treatment, and apoptosis was attenuated as measured by TUNEL. In vitro, SPC inhibited leukocyte adhesion to TNFalpha-activated endothelial cells and protected rat neonatal cardiomyocytes from apoptosis. S1P3 was identified as the lysophospholipid receptor mediating the cardioprotection by SPC, since its effect was completely absent in S1P3-deficient mice. We conclude that HDL-associated SPC directly protects against myocardial reperfusion injury in vivo via the S1P3 receptor. PMID- 21274264 TI - Biology of obesity: lessons from animal models of obesity. AB - Obesity is an epidemic problem in the world and is associated with several health problems, including diabetes, cardiovascular disease, respiratory failure, muscle weakness, and cancer. The precise molecular mechanisms by which obesity induces these health problems are not yet clear. To better understand the pathomechanisms of human disease, good animal models are essential. In this paper, we will analyze animal models of obesity and their use in the research of obesity associated human health conditions and diseases such as diabetes, cancer, and obstructive sleep apnea syndrome. PMID- 21274266 TI - Modulation of toll-like receptor signalling as a new therapeutic principle. PMID- 21274268 TI - Genetic rodent models of amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the selective death of motor neurons in the motor cortex, brainstem, and spinal cord. A large number of rodent models are available that show motor neuron death and a progressive motor phenotype that is more or less reminiscent of what occurs in patients. These rodent models contain genes with spontaneous or induced mutations or (over) express different (mutant) genes. Some of these models have been of great value to delineate potential pathogenic mechanisms that cause and/or modulate selective motor neuron degeneration. In addition, these genetic rodent models play a crucial role in testing and selecting potential therapeutics that can be used to treat ALS and/or other motor neuron disorders. In this paper, we give a systematic overview of the most important genetic rodent models that show motor neuron degeneration and/or develop a motor phenotype. In addition, we discuss the value and limitations of the different models and conclude that it remains a challenge to find more and better rodent models based on mutations in new genes causing ALS. PMID- 21274267 TI - Mouse models of Escherichia coli O157:H7 infection and shiga toxin injection. AB - Escherichia coli O157:H7 has been responsible for multiple food- and waterborne outbreaks of diarrhea and/or hemorrhagic colitis (HC) worldwide. More importantly, a portion of E. coli O157:H7-infected individuals, particularly young children, develop a life-threatening sequela of infection called hemolytic uremic syndrome (HUS). Shiga toxin (Stx), a potent cytotoxin, is the major virulence factor linked to the presentation of both HC and HUS. Currently, treatment of E. coli O157:H7 and other Stx-producing E. coli (STEC) infections is limited to supportive care. To facilitate development of therapeutic strategies and vaccines for humans against these agents, animal models that mimic one or more aspect of STEC infection and disease are needed. In this paper, we focus on the characteristics of various mouse models that have been developed and that can be used to monitor STEC colonization, disease, pathology, or combinations of these features as well as the impact of Stx alone. PMID- 21274269 TI - Effect of combination therapy with sodium ozagrel and panax ginseng on transient cerebral ischemia model in rats. AB - Sodium ozagrel (SO) prevents platelet aggregation and vasoconstriction in the cerebral ischemia. It plays an important role in the prevention of brain damage induced by cerebral ischemia/reperfusion. Recently, many animal studies have suggested that the Panax ginseng (PG) has neuroprotective effects in the ischemic brain. In this study, we assessed the neuroprotective effects that come from a combination therapy of SO and PG in rat models with middle cerebral artery occlusion (MCAO). Animals with MCAO were assigned randomly to one of the following four groups: (1) control (Con) group, (2) SO group (3 mg/kg, intravenously), (3) PG group (200 mg/kg, oral feeding), and (4) SO + PG group. The rats were subjected to a neurobehavior test including adhesive removal test and rotarod test at 1, 3, 7, 10, and 15 days after MCAO. The cerebral ischemic volume was quantified by Metamorph imaging software after 2-3-5 triphenyltetrazolium (TTC) staining. The neuronal cell survival and astrocytes expansion were assessed by immunohistofluorescence staining. In the adhesive removal test, the rats of PG or SO + PG group showed significantly better performance than those of the control group (Con: 88.1 +/- 24.8, PG: 43.6 +/- 11, SO + PG: 11.8 +/- 7, P < .05). Notably, the combination therapy group (SO + PG) showed better performance than the SO group alone (SO: 56 +/- 12, SO + PG: 11.8 +/- 7, P < .05). In TTC staining for infarct volume, cerebral ischemic areas were also significantly reduced in the PG group and SO + PG group (Con: 219 +/- 32, PG: 117 +/- 8, SO + PG: 99 +/- 11, P < .05). Immunohistofluorescence staining results showed that the group which received SO + PG group therapy had neuron cells in the normal range. They also had a low number of astrocytes and apoptotic cells compared with the control or SO group in the peri-infarction area. During astrocytes staining, compared to the SO + PG group, the PG group showed only minor differences in the number of NeuN-positive cells and quantitative analysis of infarct volume. In conclusion, these studies showed that in MCAO rat models, the combination therapy with SO and PG may provide better neuroprotective effects such as higher neuronal cell survival and inhibition of astrocytes expansion than monotherapy with SO alone. PMID- 21274271 TI - Experimental model of zymosan-induced arthritis in the rat temporomandibular joint: role of nitric oxide and neutrophils. AB - AIMS: To establish a new model of zymosan-induced temporomandibular joint (TMJ) arthritis in the rat and to investigate the role of nitric oxide. METHODS: Inflammation was induced by an intra-articular injection of zymosan into the left TMJ. Mechanical hypernociception, cell influx, vascular permeability, myeloperoxidase activity, nitrite levels, and histological changes were measured in TMJ lavages or tissues at selected time points. These parameters were also evaluated after treatment with the nitric oxide synthase (NOS) inhibitors L-NAME or 1400 W. RESULTS: Zymosan-induced TMJ arthritis caused a time-dependent leucocyte migration, plasma extravasation, mechanical hypernociception, and neutrophil accumulation between 4 and 24 h. TMJ immunohistochemical analyses showed increased inducible NOS expression. Treatment with L-NAME or 1400 W inhibited these parameters. CONCLUSION: Zymosan-induced TMJ arthritis is a reproducible model that may be used to assess both the mechanisms underlying TMJ inflammation and the potential tools for therapies. Nitric oxide may participate in the inflammatory temporomandibular dysfunction mechanisms. PMID- 21274272 TI - Metabolomic profiling for identification of novel potential biomarkers in cardiovascular diseases. AB - Metabolomics involves the identification and quantification of metabolites present in a biological system. Three different approaches can be used: metabolomic fingerprinting, metabolic profiling, and metabolic footprinting, in order to evaluate the clinical course of a disease, patient recovery, changes in response to surgical intervention or pharmacological treatment, as well as other associated features. Characteristic patterns of metabolites can be revealed that broaden our understanding of a particular disorder. In the present paper, common strategies and analytical techniques used in metabolomic studies are reviewed, particularly with reference to the cardiovascular field. PMID- 21274270 TI - Animal models of bacterial keratitis. AB - Bacterial keratitis is a disease of the cornea characterized by pain, redness, inflammation, and opacity. Common causes of this disease are Pseudomonas aeruginosa and Staphylococcus aureus. Animal models of keratitis have been used to elucidate both the bacterial factors and the host inflammatory response involved in the disease. Reviewed herein are animal models of bacterial keratitis and some of the key findings in the last several decades. PMID- 21274273 TI - Androgen receptor signalling in prostate cancer: the functional consequences of acetylation. AB - The androgen receptor (AR) is a ligand activated transcription factor and member of the steroid hormone receptor (SHR) subfamily of nuclear receptors. In the early stages of prostate carcinogenesis, tumour growth is dependent on androgens, and AR directly mediates these effects by modulating gene expression. During transcriptional regulation, the AR recruits numerous cofactors with acetylation modifying enzymatic activity, the best studied include p300/CBP and the p160/SRC family of coactivators. It is known that recruitment of histone acetyltransferases (HATs) and histone deacetylases (HDACs) is key in fine-tuning responses to androgens and is thus likely to play a role in prostate cancer progression. Further, these proteins can also modify the AR itself. The functional consequences of AR acetylation, the role of modifying enzymes in relation to AR transcriptional response, and prostate cancer will be discussed. PMID- 21274274 TI - Metabolic bone disease in the bariatric surgery patient. AB - Bariatric surgery has proven to be a life-saving measure for some, but for others it has precipitated a plethora of metabolic complications ranging from mild to life-threatening, sometimes to the point of requiring surgical revision. Obesity was previously thought to be bone protective, but this is indeed not the case. Morbidly obese individuals are at risk for metabolic bone disease (MBD) due to chronic vitamin D deficiency, inadequate calcium intake, sedentary lifestyle, chronic dieting, underlying chronic diseases, and the use of certain medications used to treat those diseases. After bariatric surgery, the risk for bone-related problems is even greater, owing to severely restricted intake, malabsorption, poor compliance with prescribed supplements, and dramatic weight loss. Patients presenting for bariatric surgery should be evaluated for MBD and receive appropriate presurgical interventions. Furthermore, every patient who has undergone bariatric surgery should receive meticulous lifetime monitoring, as the risk for developing MBD remains ever present. PMID- 21274275 TI - Maintenance of weight loss in adolescents: current status and future directions. AB - There is a dearth of research on the long-term efficacy and safety of treatments for adolescent obesity. This narrative review examined several approaches to treatment, focusing on long-term effectiveness data in adolescents, as well as relevant findings from studies of adults. The available research suggests that lifestyle modification has promise in obese adolescents, although it is not clear that any particular dietary or physical activity approach is more effective than another. Meal replacements are quite effective in adults and deserve further research in adolescents. Extending the length of treatment to teach weight loss maintenance skills is likely to improve long-term outcomes in adolescents, and delivering treatment via the Internet or telephone is a novel way of doing so. Treatment that combines lifestyle modification with the medication orlistat generally appears to be safe but only marginally superior to lifestyle modification alone. More research is needed on the management of adolescent obesity, which has been overlooked when compared with research on the treatment of obesity in children and adults. PMID- 21274276 TI - How children move: activity pattern characteristics in lean and obese chinese children. AB - Physical activity and sedentary behavior are central components of lifetime weight control; however, our understanding of dimensions of these behaviors in childhood is limited. This study investigated free-living activity pattern characteristics and the individual variability of these characteristics in 84 lean and obese Chinese children (7-9 y) during the school day and over the weekend. Activity pattern characteristics were established from triaxial accelerometry (StayHealthy RT3). Results indicated that children's free-living activity is characterized by many short-duration, low-intensity bouts of movement. Obese children take longer rest intervals between bouts and engage in fewer activity bouts both at school and at home. Intraindividual variability in activity patterns was low during school days but high for the rest intervals between bouts and number of activity bouts per day at the weekend. Finding ways to reduce the rest time between bouts of movement and increase the number of movement bouts a child experiences each day is an important next step. PMID- 21274277 TI - Influence of Sleeve Gastrectomy on NASH and Type 2 Diabetes Mellitus. AB - Background. Nonalcoholic fatty liver disease is present in up to 85% of adipose patients and may proceed to nonalcoholic steatohepatitis (NASH). With insulin resistance and obesity being the main risk factors for NASH, the effect of isolated sleeve gastrectomy (ISG) on these parameters was examined. Methods. 236 patients underwent ISG with intraoperative liver biopsy from December 2002 to September 2009. Besides demographic data, pre-operative weight/BMI, HbA1c, AST, ALT, triglycerides, HDL and LDL levels were determined. Results. A significant correlation of NASH with higher HbA1c, AST and ALT and lower levels for HDL was observed (P < .05, <.0001, <.0001, <.01, resp.). Overall BMI decreased from 45.0 +/- 6.8 to 29.7 +/- 6.5 and 31.6 +/- 4.4 kg/m(2) at 1 and 3 years. An impaired weight loss was demonstrated for patients with NASH and patients with elevated HbA1c (plateau 28.08 kg/m(2) versus 29.79 kg/m(2) and 32.30 kg/m(2) versus 28.79 kg/m(2), resp.). Regarding NASH, a significant improvement of AST, ALT, triglyceride and HDL levels was shown (P < .0001 for all). A resolution of elevated HbA1c was observed in 21 of 23 patients. Summary. NASH patients showed a significant loss of body weight and amelioration of NASH status. ISG can be successfully performed in these patients and should be recommended for this subgroup. PMID- 21274278 TI - Tissue-specific effects of bariatric surgery including mitochondrial function. AB - A better understanding of the molecular links between obesity and disease is potentially of great benefit for society. In this paper we discuss proposed mechanisms whereby bariatric surgery improves metabolic health, including acute effects on glucose metabolism and long-term effects on metabolic tissues (adipose tissue, skeletal muscle, and liver) and mitochondrial function. More short-term randomized controlled trials should be performed that include simultaneous measurement of metabolic parameters in different tissues, such as tissue gene expression, protein profile, and lipid content. By directly comparing different surgical procedures using a wider array of metabolic parameters, one may further unravel the mechanisms of aberrant metabolic regulation in obesity and related disorders. PMID- 21274279 TI - Serum neopterin is not increased in obese juveniles. AB - Objective. Cardiovascular disease is associated with inflammation and immune activation, concentrations of immune activation markers like neopterin predict outcome in adults. Methods. Serum neopterin concentrations and early metabolic and pre-atherosclerotic symptoms were analyzed in 295 obese juveniles and 101 normal weight controls of similar age. Additionally, the influence of a 12 months weight reduction program on neopterin levels was investigated in 31 obese juveniles. Results. Intima-media thickness of common carotid arteries (IMT) and the concentrations of C-reactive protein (CRP) were increased in the obese juveniles (P < .001). Also triglycerides, oxidized LDL, fasted insulin levels, HOMA-index, leptin, liver transaminases and uric acid were increased compared to the controls. However, serum neopterin was decreased in the obese versus non obese juveniles (P < .03). The intervention consisting of regular sports, nutritional devices, and a psychologic attendance led after 12 months to an increase of neopterin concentration (P < .05; paired test). Conclusions. Neopterin concentrations in juvenile obesity behaved considerably different from what was demonstrated in adults, levels did not correlate with metabolic and pre atherosclerotic symptoms found in early phases although early vascular burden and chronic low grade inflammation was indicated by increased IMT and CRP. Neopterin concentrations increased after a 12 months intervention program. PMID- 21274280 TI - Attenuation of Diabetic Nephropathy in Otsuka Long-Evans Tokushima Fatty (OLETF) Rats with a Combination of Chinese Herbs (Tangshen Formula). AB - Diabetic nephropathy is one of the most significant microvascular complications in patients with type 2 diabetics. The concise mechanism of diabetic nephropathy is unknown and there is no successful treatment. The objective of study was to investigate effects of Chinese herbs (Tangshen Formula) on diabetic nephropathy in Otsuka Long-Evans Tokushima Fatty (OLETF) rats. OLETF rats and LETO rats were divided into four groups: LETO control, OLETF diabetics, OLETF diabetics treated with Tangshen Formula, and OLETF diabetics treated with Monopril. Body weight, blood glucose, and 24 h urinary proteins were measured once every four weeks. Blood samples and kidney tissues were obtained for analyses of total cholesterol, triglyceride, whole blood viscosity, plasma viscosity, and pathohistological examination at 36 and 56 weeksrespectively. Untreated OLETF rats displayed diabetic nephropathy over the study period. Treatment of OLETF rats with Tangshen Formula attenuated the increases in blood glucose, body weight, 24 h urinary protein content, serum total cholesterol, whole blood viscosity and plasma viscosity at certain time. Treatment with Tangshen Formula also reduced glomerulosclerotic index and interstitial fibrotic index seen in OLETF rats. In conclusion, Tangshen Formula could attenuate the development of diabetic nephropathy in OLETF rat diabetic model. PMID- 21274281 TI - Cystic Dilation of the Aqueductus Sylvii in Case of Trisomy 17p11.2-pter with the Deletion of the Terminal Portion of the Chromosome 6. AB - Since the 1970s, about 30 cases of partial or complete trisomy 17p have been presented in the literature. Partial trisomies of the short arm of chromosome 17 are somewhat more common, but complete trisomy is quite rare. Most of these cases were described in infants and newborns; and to our knowledge only 3 cases of trisomy 17p have been detected intrauterine. Phenotypic features of trisomy 17p in fetuses are intrauterine growth retardation, ventriculomegaly, cleft lip and cleft palate, micrognathia, horseshoe kidneys, single umbilical artery, and congenital heart defects. The sonographic and foetopathologic findings of a pregnancy trisomy 17p11.2-pter with the deletion of the terminal portion of the chromosome 6 due to paternal balanced translocation are described in this case report. PMID- 21274282 TI - Successful control of acute myelofibrosis with lenalidomide. AB - Acute panmyelosis with myelofibrosis (APMF) is a rare, fatal hematological neoplasm that is characterized by the acute onset of cytopenias and fibrosis in the bone marrow in the absence of splenomegaly or fibrosis-related morphological changes in the RBCs. We present the case of a 59-year-old female who presented with a two-month history of anemia, leucopenia and a normal platelet count. The marrow was heavily fibrotic, and no aspirate material could be obtained; the biopsy showed extensive infiltration with small to medium size megakaryocytes, dysplastic changes in the erythroid compartment, and left shift in the myeloid cells. The patient was treated for four months with anabolic steroids (Danazol), growth factors and received regular blood transfusions. At 4 months after diagnosis, the patient was started on Lenalidomide, 10 mg/day for a 21-d-course along with growth factor support. At 6 months after treatment, the patient was transfusion-independent, had normalized blood counts, and, at 32 months on continuous lenalidomide treatment, her needs for growth factor support have been minimized. Repeat bone marrow biopsies showed a patchy distribution of fibrosis with areas of normal cellularity and morphology. To our knowledge, this is the first case for a medication that could reverse the fatal outcome of APMF. PMID- 21274283 TI - Laser capture microdissection in dentistry. AB - Laser capture microdissection (LCM) allows for the microscopic procurement of specific cell types from tissue sections that can then be used for gene expression analysis. According to the recent development of the LCM technologies and methodologies, the LCM has been used in various kinds of tissue specimens in dental research. For example, the real-time polymerase-chain reaction (PCR) can be performed from the formaldehyde-fixed, paraffin-embedded, and immunostained sections. Thus, the advance of immuno-LCM method allows us to improve the validity of molecular biological analysis and to get more accurate diagnosis in pathological field in contrast to conventional LCM. This paper is focused on the presentation and discussion of the existing literature that covers the fields of RNA analysis following LCM in dentistry. PMID- 21274284 TI - Hepatitis C Virus Evasion from RIG-I-Dependent Hepatic Innate Immunity. AB - Exposure to hepatitis C virus (HCV) usually results in persistent infection that often develops into chronic liver disease. Interferon-alpha (IFN) treatment comprises the foundation of current approved therapy for chronic HCV infection but is limited in overall efficacy. IFN is a major effector of innate antiviral immunity and is naturally produced in response to viral infection when viral pathogen-associated molecular patterns (PAMPs) are recognized as nonself and are bound by cellular pathogen recognition receptors (PRRs), including Toll-like receptors (TLRs) and the RIG-I-like receptors (RLRs). Within hepatocytes, RIG-I is a major PRR of HCV infection wherein PAMP interactions serve to trigger intracellular signaling cascades in the infected hepatocyte to drive IFN production and the expression of interferon-stimulated genes (ISGs). ISGs function to limit virus replication, modulate the immune system, and to suppress virus spread. However, studies of HCV-host interactions have revealed several mechanisms of innate immune regulation and evasion that feature virus control of PRR signaling and regulation of hepatic innate immune programs that may provide a molecular basis for viral persistence. PMID- 21274285 TI - 15,16-Dihydrotanshinone I, a Compound of Salvia miltiorrhiza Bunge, Induces Apoptosis through Inducing Endoplasmic Reticular Stress in Human Prostate Carcinoma Cells. AB - 5,16-dihydrotanshinone I (DHTS) is extracted from Salvia miltiorrhiza Bunge (tanshen root) and was found to be the most effective compound of tanshen extracts against breast cancer cells in our previous studies. However, whether DHTS can induce apoptosis through an endoplasmic reticular (ER) stress pathway was examined herein. In this study, we found that DHTS significantly inhibited the proliferation of human prostate DU145 carcinoma cells and induced apoptosis. DHTS was able to induce ER stress as evidenced by the upregulation of glucose regulation protein 78 (GRP78/Bip) and CAAT/enhancer binding protein homologous protein/growth arrest- and DNA damage-inducible gene 153 (CHOP/GADD153), as well as increases in phosphorylated eukaryotic initiation factor 2alpha (eIF2alpha), c jun N-terminal kinase (JNK), and X-box-binding protein 1 (XBP1) mRNA splicing forms. DHTS treatment also caused significant accumulation of polyubiquitinated proteins and hypoxia-inducible factor (HIF)-1alpha, indicating that DHTS might be a proteasome inhibitor that is known to induce ER stress or enhance apoptosis caused by the classic ER stress-dependent mechanism. Moreover, DHTS-induced apoptosis was reversed by salubrinal, an ER stress inhibitor. Results suggest that DHTS can induce apoptosis of prostate carcinoma cells via induction of ER stress and/or inhibition of proteasome activity, and may have therapeutic potential for prostate cancer patients. PMID- 21274286 TI - Hepatic and renal failure after anterior myocardial infarction induced apical ventricular septal defect. AB - We report the case of a 68-year-old man suffering from incremental hepatic and renal failure one month after anterior myocardial infarction. Cardiac MRI showed a pronounced apical post-AMI aneurysm, a moderate to severe mitral and tricuspid regurgitation as well as a hemodynamically highly significant 12 mm apical ventricular septal defect with a left-to-right ventricular shunt of almost 63% as the underlying cause. Heart X-ray revealed a severe LAD in-stent restenosis. CAPD catheter drainage of hydroperitoneum due to congestive liver and renal failure was provided in combination with intensified CAPD hemodialysis. Heart surgery was performed where the apical aneurysm was excised, the mitral valve was reconstructed, the IVSD was closed and the subtotally in-stent occluded LAD was bypassed. Post-surgery, the ascites were significantly reduced, and CAPD hemodialysis therapy could be terminated since the renal function gradually improved (MDRD = 25 mL/min). To our knowledge, for the first time we report successful CAPD catheter drainage of hydroperitoneum in combination with CAPD hemodialysis. PMID- 21274287 TI - A Case of Treatment Resistant Depression and Alcohol Abuse in a Person with Mental Retardation: Response to Aripiprazole and Fluvoxamine Therapy upon Consideration of a Bipolar Diathesis after Repetitive Failure to Respond to Multiple Antidepressant Trials. AB - Mental Retardation (MR) is a developmental disability characterized by impairments in adaptive daily life skills and difficulties in social and interpersonal functioning. Since multiple causes may contribute to MR, associated clinical pictures may vary accordingly. Nevertheless, when psychiatric disorders as Treatment Resistant Depression (TRD) and/or alcohol abuse co-exist, their proper detection and management is often troublesome, essentially due to a limited vocabulary MR people could use to describe their symptoms, feelings and concerns, and the lack of reliable screening tools. Furthermore, MR people are among the most medicated subjects, with (over) prescription of antidepressants and/or typical antipsychotics being the rule rather than exception. Thus, treatment resistance or even worsening of depression, constitute frequent occurrences. This report describes the case of a person with MR who failed to respond to repetitive trials of antidepressant monotherapies, finally recovering using aripiprazole to fluvoxamine augmentation upon consideration of a putative bipolar diathesis for "agitated" TRD. Although further controlled investigations are needed to assess a putative bipolar diathesis in some cases of MR associated to TRD, prudence is advised in the long-term prescription of antidepressant monotherapies in such conditions. PMID- 21274288 TI - Yoga for persistent fatigue in breast cancer survivors: results of a pilot study. AB - Approximately one-third of breast cancer survivors experiences persistent fatigue for months or years after successful treatment completion. There is a lack of evidence-based treatments for cancer-related fatigue, particularly among cancer survivors. This single-arm pilot study evaluated the feasibility and preliminary efficacy of a yoga intervention for fatigued breast cancer survivors based on the Iyengar tradition. Iyengar yoga prescribes specific poses for individuals with specific medical problems and conditions; this trial emphasized postures believed to be effective for reducing fatigue among breast cancer survivors, including inversions and backbends performed with the support of props. Twelve women were enrolled in the trial, and 11 completed the full 12-week course of treatment. There was a significant improvement in fatigue scores from pre- to post intervention that was maintained at the 3-month post-intervention followup. Significant improvements were also observed in measures of physical function, depressed mood, and quality of life. These results support the acceptability of this intervention and suggest that it may have beneficial effects on persistent post-treatment fatigue. However, results require replication in a larger randomized controlled trial. PMID- 21274289 TI - Poorly differentiated squamous cell carcinoma arising in tattooed skin. AB - Introduction. Tattoos have increasingly become accepted by mainstream Western society. As a result, the incidence of tattoo-associated dermatoses is on the rise. The presence of a poorly differentiated squamous cell carcinoma in an old tattooed skin is of interest as it has not been previously documented. Case Presentation. A 79-year-old white homeless man of European descent presented to the dermatology clinic with a painless raised nodule on his left forearm arising in a tattooed area. A biopsy of the lesion revealed a poorly differentiated squamous cell carcinoma infiltrating into a tattoo. The lesion was completely excised and the patient remains disease-free one year later. Conclusion. All previous reports of squamous cell carcinomas arising in tattoos have been well differentiated low-grade type or keratoacanthoma-type and are considered to be coincidental rather than related to any carcinogenic effect of the tattoo pigments. Tattoo-associated poorly differentiated invasive carcinoma appears to be extremely rare. PMID- 21274290 TI - Nutrition and growth. AB - Nutrition plays a fundamental role in determining the growth of individuals. An appropriate growth progression is considered a harbinger of adequate nutrient intake and good health. On the other hand growth deceleration with or without short stature may indicate inadequate nutrition, even when there is no body weight deficit for height. Nutritional growth retardation (NGR) is most prevalent in populations at risk of poverty. However in affluent communities patients with NGR are often referred to the specialist because of short stature and delayed sexual development. The diagnosis may be overlooked and/or be established after exhaustive evaluations, if the pattern of weight progression over time is not considered. Patients with so-called idiopathic short stature may present diminished nutrient intake and decreased IGF-I levels, however their nutritional status and body weight progression patterns are usually not addressed by pediatric endocrinologists. NGR patients may cease to gain appropriate weight and fail to grow in height, even without exhibiting body weight deficits for height. They adapt to decreased nutrient intake by decreasing growth progression and thereby achieve equilibrium by decreasing the nutrient demands. This occurs by diminishing their metabolic rates and erythrocyte Na+, K+- ATPase activity, however they may not present alterations in other clinical biochemical markers of malnutrition. Therefore accurate weights and heights plotted on the growth chart over time are necessary to detect NGR. Nutritional rehabilitation is accompanied with catch up growth, though it may be difficult to change the dietary habits of adolescents who exhibit NGR. PMID- 21274291 TI - Precocious puberty and normal variant puberty: definition, etiology, diagnosis and current management. AB - This review describes several aspects of the management of precocious puberty (PP) and variants in girls and boys. PP is characterized by early pubertal changes, acceleration of growth velocity and rapid bone maturation that often result in reduced adult height. Onset of pubertal signs before the age of 8 years in girls and 9 years in boys should always be evaluated carefully. The main principles of therapy are to stop the progression of secondary sex characteristics and menses (in girls), to increase final adult height, to promote psychosocial well-being, and to treat the underlying cause if known. PMID- 21274292 TI - The relationship between leptin and norepinephrine levels during OGTT in normotensive and hypertensive obese adolescents. AB - BACKGROUND/AIMS: Studies in adult population have suggested that leptin might play a role in inducing obesity related hypertension mediated by the sympathetic nervous system. This association has not been established for adolescents. Our study is designed to explore the relationship between leptin and norepinephrine levels in pediatric patients and to identify any contributors to hypertension for this population. METHODS: Thirty-nine obese adolescents, divided into four groups by gender and hypertension status were included in the study. Leptin and norepinephrine levels were measured during oral glucose tolerance tests (OGTT) to optimize hormonal secretion. T tests were used to compare baseline levels of glucose, insulin, leptin and norepinephrine at 0 hour point of OGTT between the hypertensive and normotensive patients for both genders. Analysis of covariance (ANCOVA) was used for comparison of subsequent levels between the hypertensive and normotensive groups for in both genders, with the corresponding baseline level as the covariance. Models with and without BMI adjustment were created and their results were found to be consistent. Correlation between leptin and norepinephrine was examined at each time point and through analysis of area under the curve (AUC). RESULTS: Contrary to the previous findings obtained in adult patients, our results did not show any direct relationships between levels of leptin and norepinephrine. A slight decrease in norepinephrine level at 1 hour in the normotensive male group and a significant increase in leptin level at 1 hour in the hypertensive female group was observed. CONCLUSION: Our preliminary data suggest that norepinephrine and leptin levels at 0 and 1 hour during routine OGTT, for males and females, respectively, may help identify a subgroup of obese adolescents who have higher risk for hypertension and cardiovascular complications. PMID- 21274293 TI - Comparison of the efficacy and safety of insulin glargine and insulin detemir with NPH insulin in children and adolescents with type 1 diabetes mellitus receiving intensive insulin therapy. AB - OBJECTIVE: The purpose of this study was to compare the efficacy and safety of insulin glargine and detemir with NPH insulin in children and adolescents with type 1 diabetes mellitus (DM). METHODS: Thirty four children and adolescents with type 1 DM (mean age 12.7 +/- 3.4 years, diabetes duration 5.4 +/- 3.0 years) were included in the study. All patients had been receiving intensive insulin therapy with insulin aspart and NPH for at least 6 months before switching from NPH to insulin glargine (Group 1, n=19) or detemir (Group 2, n=15). The medical records obtained within 6 months before and after treatment with insulin glargine and detemir were retrospectively reviewed and the data were compared in each group. RESULTS: The mean age and duration of DM were similar in two groups (p>0.05). In both groups, switching from NPH to insulin glargine or detemir, resulted in a reduction in HbA(1c) (p0.05, for both). Patients in the detemir treated group had less increment in body mass index (BMI) SDS at the end of 6 months of therapy compared to NPH and glargine treated patients (p>0.05, for both). No side effects were noted throughout the study. CONCLUSION: Both insulin glargine and detemir improved HbA(1c) at short-term and proved to be safe and well tolerated in children and adolescents with type 1 DM. PMID- 21274294 TI - Evaluation of adolescents for polycystic ovary syndrome in an urban population. AB - OBJECTIVE: To assess the quality of diagnostic work-up received by patients with "possible" polycystic ovary syndrome (PCOS). DESIGN: A retrospective chart review. SETTING: A hospital based Pediatric Clinic in New York City. PATIENTS: Sixty female patients aged 13-19 years, with a primary ICD-9 diagnosis of ovarian dysfunction (256), menstrual irregularity (626), or hirsutism (704.1) were randomly selected for evaluation. In addition, 18 patients who were assigned the same ICD-9 codes at the Pediatric Endocrine Clinic were assessed. MAIN OUTCOME: Rates of assessment for diagnostic criteria of PCOS and selected co-morbidities. RESULTS: Twenty-five percent (15/60) of the patients were evaluated for PCOS according to the Rotterdam Criteria, and only 2 were evaluated for common co morbidities associated with PCOS. Of the 28 patients who presented with two or more signs of PCOS (menstrual irregularity plus either obesity, hirsutism and/or acne), 15 were evaluated for PCOS (54%), but only 7% were assessed for common co morbidities. All patients referred to the Pediatric Endocrine Clinic received appropriate evaluation for PCOS. In addition, 89% of the study group underwent further assessment for selected complications of PCOS. CONCLUSIONS: Patients presenting to an inner-city pediatric clinic with "possible" PCOS often do not receive a complete diagnostic evaluation. In addition, those evaluated for PCOS are often not adequately screened for the known health consequences associated with this condition. These findings suggest that PCOS is under evaluated and possibly under diagnosed in this pediatric population, which raises serious concerns regarding the potential for major longterm public health consequences. PMID- 21274295 TI - Weismann-Netter-Stuhl syndrome: a family report. AB - Weismann-Netter-Stuhl (WNS) syndrome is a rare skeletal anomaly that affects the diaphyseal part of both the tibiae and fibulae with posterior cortical thickening and anteroposterior bowing. This anomaly is usually bilateral and symmetrical. The patients are generally of short stature. In some cases, a family history suggesting genetic transmission of a mutation with an unknown locus has been reported. In this paper we present an infant with WNS syndrome with bilateral involvement of the femur. Similar clinical findings were defined in three other family members. PMID- 21274296 TI - Neonatal sludge: a finding of congenital hypothyroidism. AB - Congenital hypothyroidism is one of the most urgent diseases of the neonate. When diagnosed and treated at an early stage, its most important complication, mental retardation, is preventable. The signs of congenital hypothyroidism are nonspecific in neonates. Only 5% of the cases have characteristic clinical findings. One of the most important and earliest signs is prolonged jaundice during the neonatal period. We report herein a case of congenital hypothyroidism, who presented with icterus accompanied with sludge formation into the gallbladder, which disappeared after treatment with L-thyroxine. PMID- 21274297 TI - Growth hormone replacement therapy: transition from adolescence to adulthood. AB - Consideration of GH re-testing should be performed in all adolescents reaching the transition period (if not at start of puberty) who had been previously diagnosed with idiopathic, isolated GH deficiency. In the presence of multiple hormone deficiencies and/or clear-cut evidence of organic disease, persistence of severe GH deficiency is much more likely. Thus, GH deficiency may be "confirmed" by a low serum IGF-I concentration. During the transition period, the optimal time to reassess the integrity of the GH-IGF-I axis after prior GH treatment, the specific testing protocol to use, and the definition of GH deficiency all remain unknown. During the transition period, patients should have their GH dose lowered with (upward) adjustments made on the basis of age-and gender-adjusted serum IGF I concentrations. GH treatment during the transition period has been shown in most, but not all, studies to be beneficial in preventing development of the features of the adult GH deficiency syndrome. It is important to remember that, during the transition period in teenagers with GH deficiency, there must be initiation of a careful plan for transfer of care to an intermist-endocrinologist with expertise in management of hypothalamic-pituitary disease in young adults. PMID- 21274299 TI - Patient age, race and the type of diabetes have an impact on the presenting symptoms, latency before diagnosis and laboratory abnormalities at time of diagnosis of diabetes mellitus in children. AB - OBJECTIVE: To correlate the presence and duration of the symptoms with laboratory data in children with new onset diabetes mellitus (DM) and to determine the impact of gender, race, age, and type of diabetes on these relationships. METHODS: This was a single institution prospective study in which we asked the families of 112 children with new-onset DM a standard set of questions concerning the presence and duration of symptoms. We then reviewed selected laboratory data and explored the relationships between the symptoms, laboratory findings, gender, age, race, type of diabetes (T1DM or T2DM), and presence or absence of a history of diabetes in a close relative. RESULTS: Over 90% of patients had polyuria and polydipsia (mean duration 17 and 19 days), but only 50% of the families sought medical attention for this complaint. Children less than 5 years of age and African American children with T1DM were more dehydrated at presentation. More profound acidosis was seen in patients of younger age (<5 years), those with greater weight loss (9% or higher), and those with higher initial serum glucose (p<0.01). Mean hemoglobin A1c (HbA1c) was close to 11% for each subgroup and strongly correlated with the proportion of weight loss (p=0.0015), but not with the initial blood glucose, corrected serum sodium, or BUN levels. CONCLUSIONS: Parents of children with new onset DM might not report polyuria or polydypsia as their main concern when they seek medical attention, so primary care physicians must be alert to the diagnosis of diabetes in any child with significant weight loss. Young children (<5 years old) and African American children with new onset T1DM are more dehydrated and young children (<5 years old) are more acidotic. PMID- 21274298 TI - Diagnosis of diseases of steroid hormone production, metabolism and action. AB - Biochemical tests have been the basis for investigations of disorders affecting steroid hormones. In recent years it has been possible however to study the genes that determine functional enzymes, cofactors, receptors, transcription factors and signaling systems that are involved in the process. Analyses of mutations are available as a diagnostic service for only a few of these genes although research laboratories may be able to provide a service. Both biochemical and genetic research have brought to light new disorders. Some genes for transcription factors involved in the development of the endocrine organs have also been identified and patients with defects in these processes have been found. This paper will review general aspects of adrenal disorders with emphasis on clinical and laboratory findings. As with all endocrine investigations there are few single measurements that provide a definitive answer to a diagnosis. Timing of samples in relation to age, gender and time of day needs to be considered. PMID- 21274301 TI - Combined evaluation of IGF-1 and IGFBP-3 as an index of efficacy and safety in growth hormone treated patients. AB - OBJECTIVE: Measurement of serum insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3) levels has been recommended as a useful index for monitoring of growth hormone (GH) therapy in GH deficient children. In this study we aimed to evaluate IGF-1/IGFBP-3 molar ratio during GH treatment as an index of safety and efficacy. METHODS: Serum IGF-1 and IGFBP-3 levels and molar ratio of IGF-1/IGFBP-3 were evaluated in 50 GH deficienct children, during 3 years of GH therapy and these parameters were compared with the growth response. RESULTS: All patients completed the first year, 38 the second year and 26 the third year of therapy. Although 15 patients in the first year, 5 patients in the second year, and 5 patients in the third year had high IGF-1 SDS values, height increments were similar in the low IGF-1 group and in the normal or high IGF-1 level groups. Molar ratios were also not statistically different between the groups. Molar ratio of IGF-1/IGFBP-3 seemed to be more reliable in evaluating the efficacy than basal IGF-1 level. CONCLUSIONS: Evaluation of the molar ratio of IGF-1/IGFBP-3 may be recommended as a tool to monitor GH treatment and it may be possible to individualize GH treatment accordingly. PMID- 21274300 TI - The relationship between serum adiponectin, tumor necrosis factor-alpha, leptin levels and insulin sensitivity in childhood and adolescent obesity: adiponectin is a marker of metabolic syndrome. AB - OBJECTIVE: This study aimed (a) to investigate the relationship between the degree of obesity and serum adiponectin, tumor necrosis factor (TNF)-alpha, leptin, insulin levels and the lipid profile; (b) to clarify the relationship between insulin resistance/glucose tolerance and adipocytokine levels; and (c) to investigate the value of adipocytokine levels as a marker of metabolic syndrome (MS). METHODS: We studied 151 obese children and adolescents (86 boys and 65 girls; mean age was 12.3+/-2.4 years). We defined obesity as a body-mass index (BMI) z-score more than 2 SD above the mean for age and sex. The control group consisted of 100 children (48 boys, 52 girls, mean age 12.4+/-2.5 years). Fasting glucose, insulin levels and lipid profiles were measured in all cases and controls after a 12-hour fast. Adiponectin, TNF-alpha, and leptin levels were measured in the subjects who participated in the adipocytokine branch of the study. An oral glucose tolerance test (OGTT) was also performed in all obese patients. Obese patients were grouped into three subgroups according to their glucose tolerance and insulin sensitivity assessment, and also according to whether they were grouped as MS or not. RESULTS: Serum levels of total cholesterol, LDL and VLDL cholesterol, log triglyceride, insulin, leptin and TNF alpha were higher, whereas HDL and square root adiponectin levels were lower in the obese group when compared with controls. Multiple regression analysis among BMI-z score, LDL, triglyceride, HOMA-IR, leptin and TNF-alpha as determinants of adiponectin revealed that BMI-z score was the only determinant for adiponectin (r:-0.45, p<0.0001). Adiponectin levels in hyperinsulinemic and impaired glucose tolerance groups (IGT) tended to be lower than in normoinsulinemic obese children, however, the difference was not significant. There was a weak negative correlation between adiponectin levels and increasing severity of insulin resistance (r=-0.23, p=0.005) in the groups of obese subjects. Mean serum adiponectin level in subjects with MS was lower than in subjects without MS (p=0.008). CONCLUSIONS: Evaluation of serum adiponectin levels might contribute to an early intervention in obese children with MS. PMID- 21274302 TI - A novel mutation causing pseudohypoparathyroidism 1A with congenital hypothyroidism and osteoma cutis. AB - Various inactivating mutations in guanine nucleotide-binding protein, alpha stimulating activity polypeptide1 (GNAS1) gene have been described with poor phenotype correlation. Pseudohypoparathyroidism type 1a (PHP1a) results from an inactivating mutation in the GNAS1 gene. Hormone resistance occurs not only to parathyroid hormone (PTH), but typically also to other hormones which signal via G protein coupled receptors including thyroid stimulating hormone (TSH), gonadotropins, and growth hormone releasing hormone. In addition, the phenotype of Albright hereditary osteodystrophy (AHO) is observed, which may include short stature, round facies, brachydactyly, obesity, ectopic soft tissue or dermal ossification (osteoma cutis) and psychomotor retardation with variable expression. We present a 2-year-old boy with PHP 1A who initially presented at age 3 weeks with congenital hypothyroidism. By 17 months of age, he manifested osteoma cutis, psychomotor retardation, obesity, brachydactyly and resistance to PTH with normocalcemia and mild hyperphosphatemia. Genetic analysis revealed a novel mutation in exon 13 of GNAS1 in our patient. This mutation, c.1100_1101insA, resulted in a frameshift and premature truncation of bases downstream. This mutation was also found in the mother of this patient who was also noted to have short stature, obesity, brachydactyly and non progressive osteoma cutis, but no hormone resistance.We report a novel heterozygous mutation causing PHP1A with PTH and TSH resistance and AHO which has not been described previously. PHP1A is also a rare presentation of congenital hypothyroidism. PMID- 21274303 TI - Melnick-Needles syndrome associated with growth hormone deficiency: a case report. AB - Melnick-Needles syndrome is an X-linked dominant bone dysplasia characterized by a typical facies (exophthalmos, full cheeks, micrognathia, and malalignment of teeth), flaring of the metaphyses of long bones, s-like curvature of the lower extremities, irregular constriction in the ribs, and sclerosis of base of the skull. The phenotype of affected individuals varies, even within families. About fifty cases of Melnick-Needles syndrome have been reported to date. Short stature is not a well-known component of the disorder. There is only one reported case of Melnick-Needles syndrome associated with growth hormone deficiency. A six-year old girl who presented to our clinic with short stature was diagnosed as Melnick Needles syndrome based upon characteristic clinical and radiological findings. Two different stimulation tests demonstrated growth hormone deficiency. Presenting this second case of Melnick-Needles syndrome associated with growth hormone deficiency, we suggest that this association may be coincidental, but that it may also be a consequence of craniofacial abnormalities or an independent component of the disorder. PMID- 21274304 TI - Hypothalamo-pituitary insufficiency associated with ectrodactyly-ectodermal dysplasia-clefting syndrome. AB - Ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome is characterized by ectodermal dysplasia, ectrodactyly and facial clefting with multiple congenital anomalies such as urinary tract anomaly, lacrimal duct obstruction, and hearing loss. This syndrome is a rare disease transmitted by autosomal dominant inheritance with variable penetrance. Clinical expression is variable. In EEC syndrome with midline defect hypothalamo-pituitary endocrinopathy is expected, however hormonal disorders in EEC syndrome have rarely been reported. We present two patients with EEC syndrome associated with hypothalamo-pituitary insufficiency. PMID- 21274305 TI - Aromatase inhibitors to augment height: continued caution and study required. AB - Aromatase inhibitors (AIs) are a class of drugs that prevent conversion of androgens to estrogens, and that are approved in the United States as adjunctive treatment of estrogen receptor-positive breast cancer. Because ultimate fusion of the growth plates is estrogen-dependent in both boys and girls, AI administration may help to slow down epiphysial maturation and allow for greater height potential. Research trials in children with short stature have predominantly been done in Finland and Florida. Despite the apparent efficacy described by these groups, only ~110 children worldwide have been treated with AIs in research protocols (and usually concomitant with other growth-promoting agents) as of the end of 2008 (and none to final height). That said, many children are being treated with AI's in the United States outside of research protocols. Furthermore, little is known about the short- and long-term safety of AIs in children. Thus, it is imperative that there be well-designed, long-term studies of efficacy and safety of AI use in pediatric populations. PMID- 21274306 TI - The effect of vitamin D treatment on serum adiponectin levels in children with vitamin D deficiency rickets. AB - OBJECTIVE: Adiponectin and its receptors are known to be expressed in osteoblasts and may have important functions in normal bone cells. The aim of this study was to investigate the effect of vitamin D therapy on serum adiponectin levels in children with vitamin D deficiency rickets (VDDR). METHODS: 21 patients with VDDR were included in the study. Patients were treated with 300,000 U D3 (IM) and calcium lactate (50mg/kg/ day, PO, for 10 days). Anthropometric parameters and serum biochemical markers including calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), intact parathormone (iPTH), 25-hydroxyvitamin D (25(OH)D), and adiponectin levels were measured before and after one month of therapy. RESULTS: Weight and length, but not BMI, increased significantly after treatment. Serum 25(OH)D level increased significantly after treatment, while serum adiponectin level decreased (4.21+/-1.84 vs 52.73+/-17.63 ng/ml, p<0.000; 150.1+/-66.14 vs 84.29+/-9.06 mg/ml, p<0.000, respectively). No significant correlations were found between serum adiponectin and 25(OH)D levels before and after treatment or between delta adiponectin concentrations and delta 25(OH)D levels. CONCLUSION: Serum adiponectin levels are increased in patients with VDDR, a finding which is probably related to increased osteoblastic activity. PMID- 21274307 TI - Vitamin D deficiency in Turkish mothers and their neonates and in women of reproductive age. AB - OBJECTIVE: Materno-fetal vitamin D deficiency (VDD) may occur in the early neonatal period. We aimed to evaluate the vitamin D (vitD) status and risk factors for VDD in healthy newborns and their mothers, and also in fertile women. METHODS: Serum 25 hydroxyvitamin D3 (25(OH)D), calcium (Ca), phosphorus (P) and alkaline phosphatase (ALP) levels were measured in 70 mothers (study group) and their newborns, and in umbilical cord samples. 104 nonpregnant fertile women comprised the control group. Demographic factors such as education and clothing habits of the mother, number of pregnancies and month of delivery were recorded. A serum 25(OH)D level below 11 ng/ml was accepted as severe, 11-25 ng/ml as moderate VDD, and a value over 25 ng/ml as normal. RESULTS: Severe VDD was found in 27% of the mothers, and moderate deficiency in 54.3%. Severe VDD was detected in 64.3% of the neonates, and moderate deficiency in 32.9%. Only 18.6% of the mothers and 2.9% of the neonates had normal vitD levels. In the control group, severe VDD was observed in 26.9%, and moderate deficiency in 45.2%. Only 27.8% of the controls had normal vitD levels. In the control group, the 25(OH)D levels of the women dressed in modern clothes were significantly higher than those of the women wearing traditional clothes. This difference was not observed in the study group because 75% of these 70 mothers wore modern clothes. Mothers giving birth during the summer months and their neonates had significantly higher serum 25(OH)D levels than those of the mothers giving birth during the winter months and their neonates. CONCLUSION: The study has shown that in Turkey VDD is an important problem in women of reproductive age, in mothers and their neonates. The 25(OH)D levels obtained from the cord may serve as a guide in the determination of the high risk groups. PMID- 21274308 TI - Diagnostic use of skeletal survey in suspected skeletal dysplasia. AB - OBJECTIVE: To review the practice of skeletal surveys in cases of suspected skeletal dysplasia. METHODS: Retrospective review of records of patients with suspected skeletal dysplasia between December 1997 and December 2005. RESULTS: A diagnosis of a specific skeletal dysplasia was reached in 155 out of a total of 285 suspected cases (54%). In 260 (91%), a record of radiological examination was available and out of these cases, 91 (35%) had a full skeletal survey. A diagnosis was reached in 79% of cases that had a full skeletal survey and in 44% of cases that had a limited survey. A possible skeletal dysplasia was excluded in 44 out of 260 (17%) cases. In 79 out of 260 (30%) cases, skeletal abnormalities were present but a clear diagnosis could not be reached. Over the period of study, there was no clear change in the practice of performing x-rays and the rate of reaching a diagnosis. CONCLUSION: A clear diagnosis of skeletal dysplasia is not possible in a third of cases and there is a need for greater access to multidisciplinary input. PMID- 21274309 TI - Iodine overload and severe hypothyroidism in two neonates. AB - Iodine overload frequently leads to transient hyperthyrotropinemia or hypothyroidism, and rarely to hyperthyroidism in neonates. Iodine exposure can be prenatal, perinatal or postnatal. Herein we report two newborn infants who developed severe hypothyroidism due to iodine overload. The overloading was caused by excessive use of an iodinated antiseptic for umbilical care in the first case, and as a result of maternal exposure and through breast milk with a high iodine level in the second case. Presenting the two cases, we wanted to draw attention to these preventable causes of hypothyroidism in infants. PMID- 21274310 TI - Metabolic syndrome features presenting in early childhood in Alstrom syndrome: a case report. AB - Alstrom syndrome is a rare autosomal recessive disorder characterized by retinal degeneration, sensorineural hearing loss, early-onset obesity, and non-insulin dependent diabetes mellitus. Affected individuals have normal birth weight, but growth deceleration starts at about 8-10 years of age. In patients with the disorder linked to chromosome 2, the increase in body mass index is very high in childhood and continues high thereafter. In this paper, we report a patient who had the proposed diagnostic criteria for Alstrom syndrome associated with metabolic syndrome starting at age 7, a relatively early age. PMID- 21274311 TI - A rare cause of precocious puberty: hepatoblastoma. AB - Hepatoblastoma, an embryonal tumor, is one of the most common primary liver tumors in childhood. It secretes human chorionic gonadotropin (hCG), which can cause precocious puberty (PP). Herein, we present a case with PP who had enlarged penile size noticed during a diagnosis of hepatoblastoma. Laboratory examination revealed increased testosterone, alpha-fetoprotein (AFP), and hCG levels. Serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were within prepubertal ranges. The diagnosis of hepatoblastoma was made by liver biopsy. Chemotherapy was administered, and the patient was referred to surgery. Ten months later, testis volumes were below 4 ml bilaterally, and penile length was 5.5 cm. Serum testosterone, AFP, and hCG levels decreased. Resection of the tumor and chemotherapy are essential for the treatment of hepatoblastoma and they can eliminate the symptoms of PP. PMID- 21274312 TI - Nutritional rickets. AB - Nutritional rickets (NR) is still the most common form of growing bone disease despite the efforts of health care providers to reduce the incidence of the disease. Today, it is well known that the etiology of NR ranges from isolated vitamin D deficiency (VDD) to isolated calcium deficiency. In Turkey, almost all NR cases result from VDD. Recent evidence suggests that in addition to its short- or long-term effects on skeletal development, VDD during infancy may predispose the patient to diseases such as diabetes mellitus, cancer and multiple sclerosis. Among the factors responsible for the high prevalence of VDD in developing countries and its resurgence in developed countries is limited sunshine exposure due to individuals' spending more time indoors (watching television and working on computer) or avoiding sun exposure intentionally for fear of skin cancer. Traditional clothing (covering the entire body except the face and hands) further limits the exposure time to sunlight and, thus, decreases the endogenous synthesis of vitamin D. In Turkey, maternal VDD and exclusive breastfeeding without supplementation were reported to be the most prominent reasons leading to NR. The diagnosis of NR is established by a thorough history and physical examination and confirmed by laboratory evaluation. Recent reports draw attention to the supplemental doses of vitamin D required to achieve a serum 25 hydroxyvitamin D level of at least 20 ng/ml (50 nmol/l) - the serum concentration that is needed to optimize absorption of dietary calcium and to suppress excessive secretion of parathyroid hormone. This type of prevention will also reduce fracture risk as well as prevent long-term negative effect of vitamin D insufficiency. PMID- 21274313 TI - Waist circumference and mid-upper arm circumference in evaluation of obesity in children aged between 6 and 17 years. AB - OBJECTIVE: The purpose of this study was to determine the cut-off values for waist circumference (WC) and mid-upper arm circumference (MUAC) and to assess their use in screening for obesity in children. METHODS: Anthropometric measurements of a total of 2621 boys and 2737 girls aged 6-17 years were analyzed. WC and MUAC values were compared with ROC analysis using body mass index (BMI) cut-off values of the International Obesity Task Force (IOTF) and using WC>= 90th percentile.for MUAC. RESULTS: In both genders, except for boys and girls in the 6-year age group and post-pubertal boys, the differences between area under curve (AUC) values for WC and MUAC were not significant, indicating that both indices performed equally well in predicting obesity. Sensitivity was suboptimal through age groups 6-9 years in the boys and sensitivity was suboptimal at 6, 7,14 and 17 years both in boys and girls. CONCLUSIONS: We conclude that MUAC can be a useful parameter in screening obesity and body fat distribution in children and, can be applied in epidemiological studies and in clinical practice. PMID- 21274314 TI - Celiac disease and autoimmune thyroid disease in children with type 1 diabetes mellitus: clinical and HLA-genotyping results. AB - OBJECTIVE: Increased prevalence of celiac disease (CD) and autoimmune thyroid disorders (ATD) in patients with Type 1 diabetes mellitus (T1D) has been widely reported. Such an association may lead to adverse effects on the growth, bone metabolism and fertility, and response to therapy may become difficult. The aim of this study was to evaluate the clinical findings and HLA typing results in patients with T1D associated with CD or ATD. METHODS: The association of CD and ATD was evaluated in 38 children with T1D aged 1.5-16.8 years who had been followed for 48.3+/-28 months. Diagnosis of CD was based on positivity for serum endomysial IgA antibody and histopathological findings of intestinal biopsy specimens. Thyroid autoimmunity was assessed by antithyroglobulin and antithyroid peroxidase antibodies and with diagnostic ultrasonographic findings. RESULTS: ATD was detected in 31.5%, and CD-in 7.8% of T1D patients. Subjects with CD showed either no symptoms or suggestive problems such as short stature, hepatosteatosis, pubertal delay and difficulties in the control of diabetes. Patients with ATD had no clinical symptoms. DQ8 was the most prominent finding in CD. CONCLUSIONS: It is essential that patients with T1D, regardless of presence or absence of symptoms, should be investigated for CD and ATD. PMID- 21274315 TI - Effect of hypo-and euthyroid status on serum cystatin C levels. AB - OBJECTIVE: The aim of this study was to investigate the effect of hypo- and euthyroid status on serum cystatin C (CysC) levels in children and to explore whether CysC can be used as a marker of the thyroid status. METHODS: Twenty five patients with hypothyroidism (10M, 15F; mean age:8.7+/-4.9 years) and 21 healhty age-matched controls (9M, 12F; mean age: 9.7+/-5.0 years) were included in this study. Serum thyrotropin (TSH), free thyroxine (fT4), serum CysC and creatinine levels were studied in patients with hypothyroidism twice, i.e. in the euthyroid (on L-T4) and hypothyroid state, and in controls. RESULTS: No significant differences in creatinine, glomerular filtration rate (GFR) and CysC levels were observed between the study group in the euthyroid status and the control group. CysC (mg/dL) level was found to be lower in the hypothyroid status(0.6+/-0.1) than in the euthyroid status (0.66+/-0.1) (p=0.01). In hypothyroid status, CysC levels showed a positive correlation with GFR (r=0.463, p=0.02) and GFR had positivecorrelation with fT4 (r=0.563, p=0.012). CONCLUSIONS: We demonstrated a significant effect of thyroid dysfunction on CysC levels, but the changes in serum CysC levels in hypo- and euthyroid status did not exceed the reference interval. It may be concluded that serum CysC levels have limited use in evaluating the peripheral effects of thyroid hormones. PMID- 21274316 TI - Prevalence of overweight and obesity in children and adolescents in eastern Turkey. AB - OBJECTIVE: The aim of this study was to estimate the prevalence of overweight and obesity in school children in Eastern Turkey. METHODS: This study included 9048 school children aged 6-18 years. The subjects were classified as overweight and obese, according to the International Obesity Task Force. RESULTS: We found prevalence of overweight of 11.1% in the studied population. It was detected that 2.2% of the population in the study was obese; 2.1% of males and 2.3% of females. While the prevalence of obesity was extremely low before 9 ages and after 15, it reached to high values at puberty and just before pubertal period in boys. The prevalence of overweight was higher in girls and reached to peak point at pubertal ages. Generally, the prevalence of obesity and overweight was slightly higher in girls than in boys, although the boys were more obese in prepubertal ages. CONCLUSION: Overweight and obesity are concerns for children and adolescents in low socio-economic status regions as well. PMID- 21274317 TI - Two siblings with isolated GH deficiency due to loss-of-function mutation in the GHRHR gene: successful treatment with growth hormone despite late admission and severe growth retardation. AB - Patients with growth hormone releasing hormone receptor (GHRHR) mutations exhibit pronounced dwarfism and are phenotypically and biochemically indistinguishable from other forms of isolated growth hormone deficiency (IGHD). We presented here two siblings with clinical findings of IGHD due to a nonsense mutation in the GHRHR gene who reached their target height in spite of late GH treatment. Two female siblings were admitted to our clinic with severe short stature at the age of 13.8 (patient 1) and 14.8 years (patient 2). On admission, height in patient 1 was 107 cm (-8.6 SD) and 117 cm (-6.7 SD) in patient 2. Bone age was delayed in both patients (6 years and 9 years). Clinical and biochemical analyses revealed a diagnosis of complete IGHD (peak GH levels on stimulation test was 0.06 ng/mL in patient 1 and 0.16 ng/mL in patient 2). Patients were given recombinant human GH treatment. Genetic analysis of the GH and GHRHR genes revealed that both patientscarried the GHRHR gene mutation p.Glu72X (c.214 G>T) in exon 3 in homozygous (or hemizygous) state. After seven years of GH treatment, the patients reached a final height appropriate for their target height. Final height was 151 cm (-1.5 SD) in patient 1 and 153 cm (-1.2 SD) in patient 2. In conclusion, genetic analysis is indicated in IGHD patients with severe growth failure and a positive family history. In spite of the very late diagnosis in these two patients who presented with severe growth deficit due to homozygous loss-of function mutations in GHRHR, their final heights reached the target height. PMID- 21274318 TI - Sporadic nonautoimmune neonatal hyperthyroidism due to A623V germline mutation in the thyrotropin receptor gene. AB - Neonatal hyperthyroidism is a rare disorder and occurs in two forms. An autoimmune form is associated with maternal Graves' disease, resulting from transplacental passage of maternal thyroid-stimulating antibodies and a nonautoimmune form is caused by gain of function mutations in the thyrotropin receptor (TSHR) gene. Thyrotoxicosis caused by germline mutations in the TSHR gene may lead to a variety of clinical consequences. To date, 55 activating mutations of the TSHR gene have been documented. Fourteen cases with sporadic activating TSHR germline mutations have been described. Here we report a male infant with nonautoimmune hyperthyroidism due to an activating germline TSHR mutation (A623V), whose clinical picture started in the newborn period with severe hyperthyroidism. His parents did not have the same mutation. This mutation had been previously detected as a somatic mutation in patients with toxic adenomas. This is the first report of a sporadic case of nonautoimmune congenital hyperthyroidism associated with A623V mutation. PMID- 21274319 TI - Vitamin D deficiency rickets mimicking pseudohypoparathyroidism. AB - Vitamin D deficiency rickets (VDDR) is a disorder biochemically characterized by elevated serum alkaline phosphatase (ALP) activity, normal or decreased serum calcium (Ca) and inorganic phosphate concentrations, secondary hyperparathyroidism and decreased serum 25-hydroxyvitamin D (25(OH)D) levels. In stage 1 VDDR, urinary amino acid and phosphate excretion are normal with minimal or no findings of rickets on radiographs. Pseudohypoparathyroidism (PHP) is an inherited disorder characterized by end-organ resistance to parathormone (PTH). VDDR occasionally resembles PHP type 2 in clinical presentation and biochemical features, creating difficulties in the differential diagnosis of these two entities. Here we report an infant diagnosed with VDDR. In addition to inadequate vitamin D intake, usage of antiepileptic drugs (AED) may have led to the worsening of the vitamin D deficiency. The patient presented with a history of febrile convulsions, for which he received phenobarbital treatment. The initial findings of hypocalcemia, hyperphosphatemia and normal tubular reabsorption of phosphate, mimicking PHP 2, responded well to vitamin D and oral Ca treatment with normalization of serum Ca, phosphorus (P), ALP and PTH levels. PMID- 21274320 TI - Monogenic diabetes secondary to congenital lipodystrophy in a 14-year-old Yemeni girl. AB - A 14-year-old female from Yemen presented with intense abdominal pain and headache. She was born at term to distant cousins, developmentally delayed and significantly dysmorphic. Four years ago, she was diagnosed with diabetes mellitus and undiagnosed hepatic, cardiac, genetic, neurologic, endocrine, musculoskeletal, and gastrointestinal disorders. No therapy was prescribed. Admission laboratory data showed blood glucose = 391 mg/dl, hemoglobin A1c= 12.2%, C-peptide = 3.5 ng/ml, insulin = 6.8 uIU/ml, triglyceride =385 mg/dl, and serum leptin <0.5 ng/ml, (1.1-27.5). Chromosome analysis (46, XX) was normal and serology for Glutamic acid Decarboxylase (GAD), hepatitis and HIV were negative. Clinical examination and laboratory data suggested congenital generalized lipodystrophy (CGL, type BSCL-2). This case illustrates that CGL should be in the differential diagnosis for non-obese patients with diabetes and insulin resistance. PMID- 21274321 TI - Update on some aspects of neonatal thyroid disease. AB - This article explores the basic development and pathophysiology of the thyroid gland. New factors in the normal development of the thyroid in the neonate are mentioned. The incidence of congenital hypothyroidism continues to increase. We describe congenital hypothyroidism, its possible etiologies, treatment and outcomes. We explore hypothyroxinanemia in pre-term neonates and the risk/benefit of prophylactic thyroid hormone replacement. We discuss the late rise of thyrotropin (TSH) in ill infants and those with very low birth weight. Ill infants or those born premature should have their thyroid function tests routinely monitored. On the occasion of borderline thyroid function test results, TRH testing can be useful in identifying those infants with either persistent or transient hypothyroidism. TRH testing is also helpful in identifying those patients with secondary hypothyroidism. With the early identification and prompt and proper treatment, neonates with congenital hypothyroidism, transient or persistent, should have positive long-term outcomes. PMID- 21274322 TI - Insulin resistance in obese children and adolescents: HOMA-IR cut-off levels in the prepubertal and pubertal periods. AB - OBJECTIVE: Childhood obesity is associated with an increased risk for insulin resistance. The underlying mechanism for the physiological increase in insulin levels in puberty is not clearly understood. The aim of the present study was to determine the cut-off values for homeostasis model assessment for insulin resistance (HOMA-IR) in obese children and adolescents according to gender and pubertal status. METHODS: Two hundred and eight obese children and adolescents (141 girls, 127 boys) aged between 5 and 18 years were included in the study. The children were divided into prepubertal and pubertal groups. A standard oral glucose tolerance test (OGTT) was carried out in all children. A total insulin level exceeding 300 MUU/mL in the blood samples, collected during the test period, was taken as the insulin resistance criterion. Cut-off values for HOMA-IR were calculated by receiver operating characteristic (ROC) analysis. RESULTS: In the prepubertal period, the rate of insulin resistance was found to be 37% in boys and 27.8% in girls,while in the pubertal period, this rate was 61.7% in boys and 66.7% in girls. HOMA-IR cut-off values for insulin resistance in the prepubertal period were calculated to be 2.67 (sensitivity 88.2%, specificity 65.5%) in boys and 2.22 (sensitivity 100%, specificity 42.3%) in girls, and in the pubertal period, they were 5.22 (sensitivity 56%, specificity 93.3%) in boys and 3.82 (sensitivity 77.1%, specificity 71.4%) in girls. CONCLUSIONS: Since gender, obesity and pubertal status are factors affecting insulin resistance, cut off values which depend on gender and pubertal status, should be used in evaluation of insulin resistance. PMID- 21274323 TI - Normative data for penile length in Turkish newborns. AB - BACKGROUND: Local normative data for penile size will aid physicians in clinical practice. There are no studies on stretched penile length (SPL) in newborn Turkish boys. OBJECTIVE: To establish normative data for SPL of newborn Turkish boys and compare these with data from different countries. METHODS: 514 newborn Turkish boys, who were not small for gestational age (SGA) or premature, were included in this cross-sectional study. SPLs of the newborns were measured by the same investigator. The correlations between SPL and gestational age, weight, length, and head circumference were evaluated. RESULTS: The 3(rd) percentile value for SPL was found as 3.00 cm in these Turkish newborns. Positive correlations were shown between SPL and height (r=0.240, p<0.001), weight (r=0.251, p<0.001), and head circumference (r=0.235, p<0.001). Multiple linear regression analysis showed that SPL positively correlated with height and head circumference (p=0.021 and p= 0.042, respectively). CONCLUSIONS: This is the largest study on SPL in newborns from our country. This normative data can be used in clinical practice for defining micropenis. PMID- 21274324 TI - Evaluation of nutritional status in Turkish adolescents as related to gender and socioeconomic status. AB - OBJECTIVE: To evaluate the nutritional status of Turkish high school adolescents using anthropometric indicators and to determine the relationship of nutritional status with gender and socioeconomic status (SES) in adolescents. METHODS: Six hundred eighty adolescent students (n=284 males, 396 females) aged 14-18 years were selected from 6 high schools of different regions. Nutritional status was evaluated according to the anthropometric indicators, which were based on the WHO criteria. Adolescents were grouped into three SES categories. RESULTS: The rates of being stunted, underweight, and overweight/obesity were 4.4%, 5.0% and 16.8%, respectively. Height and weight standard deviation scores (SDS) were significantly lower in adolescents with low SES (p<0.05). The frequency of stunting was significantly higher in adolescents with low SES (p=0.012). Frequency of underweight, overweight and obesity did not differ significantly between socioeconomic groups and genders (p>0.05). CONCLUSION: Adolescents of low SES were shorter and thinner than those of other SES categories. Undernutrition needs to be addressed in low SES. Among all Turkish adolescents, the major nutritional problems were overweight and obesity. There were no SES and gender differences in prevalence of overweight and obesity among the Turkish school adolescents living in urban areas. Prevalence of obesity is rising, regardless of differences in SES and gender, in developing countries too. PMID- 21274325 TI - Ghrelin levels in children with constitutional delay of growth and puberty. AB - OBJECTIVE: In this study, we aimed to show the role of ghrelin in growth delay in children with constitutional delay of growth and puberty (CDGP). METHODS: Thirty male children with CDGP constituted the study group and fifteen healthy children with normal growth of similar ages-the control group. In both groups, fasting and postprandial plasma ghrelin levels, serum insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) levels were determined. RESULTS: There were no differences in fasting and postprandial ghrelin levels (824.23+/-523.46 pg/mL and 447.26+/-259.92 pg/mL, respectively) in children with CDGP compared to the levels in the control group (687.38+/-481.43 pg/mL and 365.59+/-260.43 pg/mL, respectively; p>0.05). Differences in fasting and postprandial ghrelin levels were also similar in the two groups (394.44+/-369.10 pg/mL and 346.55+/-338.67 pg/mL, respectively; p>0.05). Serum IGF-1 levels were significantly depressed in children with CDGP compared to those in the control group (239.5+/-83.95 ng/mL and 339.20+/-63.08 ng/mL, respectively; p<0.05). CONCLUSION: Decreased appetite and feeding problems in children with CDGP were not related to depressed ghrelin levels. In addition, ghrelin levels did not increase to compensate for the decreased appetite and feeding problems in CDGP. PMID- 21274326 TI - Familial glucocorticoid deficiency type 2: a case report. AB - Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease resulting from resistance to the action of adrenocorticotropic hormone (ACTH) on the adrenal cortex, which leads to isolated glucocorticoid deficiency with normal mineralocorticoid secretion. It may present in infancy or early childhood with hyperpigmentation, failure to thrive, recurrent infections, hypoglycemic attacks and convulsions that may result in coma or death. Laboratory investigations reveal low cortisol and androgen levels with high ACTH associated with normal reninaldosterone axis. The disorder may be caused by mutations in the gene of ACTH receptor (MC2R), or mutations in the newly described melanocortin- 2 receptor accessory protein (MRAP) namely, FGD type 1 and FGD type 2, respectively. Twenty five percent of FGD cases are due to the mutations of the ACTH receptor, while FGD type 2 accounts for approximately 15-20% of FGD cases. Here, we report a six-month-old male infant, who presented with recurrent hypoglycemic convulsions. Serum hormone analysis showed low cortisol and androgen levels associated with a high ACTH concentration. No mutation was found in the NR0B1 and MC2R genes excluding congenital adrenal hypoplasia and FGD type 1. We found a homozygous deletion (c. 106+1delG) in intron 3 of MRAP gene. To our knowledge, this is the first Turkish patient reported with FGD type 2 due to a known MRAP mutation. PMID- 21274327 TI - Hypothyroidism due to hepatic hemangioendothelioma: a case report. AB - Although hemangioendothelioma (HHE) is a commonly encountered hepatic tumor during infancy, HHE-related hypothyroidism is rare. We present a patient who developed HHE-related hypothyroidism during the neonatal period and showed marked improvement in hypothyroidism by regression of HHE. A 28-day-old boy with TSH level of 77 mIU/mL on neonatal screening and diagnosed as congenital hypothyroidism was started on L-thyroxine (L-T4) (11 MUg/kg/day) therapy on the 21(th) day of life. On physical examination, the liver was palpable 5 cm below the right costal margin, and the thyroid gland was nonpalpable. Thyroid ultrasonography was normal. Although L-T4 dose was increased to 15 MUg/kg/day, TSH was not suppressed and free T3 level remained low. HHE in both lobes of the liver was detected by abdominal ultrasonography and magnetic resonance imaging. Treatment was started with prednisolone 2 mg/kg/day and alpha-interferon 3 million U/m(2)/3 times per week. Thyroid dysfunction was thought to be due to type 3 iodothyronine deiodinase activity expressed by HHE. L-T4 therapy was changed to Bitiron(r) tablet, which includes both T4 and T3, and euthyroidism was attained within 1 month. Thyroid hormone requirement was reduced and treatment was discontinued after regression of the HHE. At the most recent visit, the patient was 21 months old and off treatment. His growth and neurological development were normal for age and he was euthyroid. HHE should be considered in cases with severe hypothyroidism resistant to high-dose thyroid hormone replacement. The treatment of HHE in combination with T4 and T3 therapy results in euthyroidism. PMID- 21274328 TI - Neonatal diabetes mellitus accompanied by diabetic ketoacidosis and mimicking neonatal sepsis: a case report. AB - Neonatal diabetes mellitus (DM) develops within the first six weeks of life with basic findings including dehydration, hyperglycaemia, and mild or no ketonemia/ketonuria. It can be either transient or permanent. Here, we report a case of a one-month-old infant with permanent neonatal diabetes, due to pancreatic hypoplasia, accompanied by diabetic ketoacidosis (DKA). The hyperglycaemia and ketoacidosis resolved by the 14(th) hour of treatment, consisting of IV insulin and rehydration. Subsequently, insulin treatment was continued with neutral protamine hagedorn (NPH) insulin. Breastfeeding was started and was continued at intervals of three hours. Following initiation of breastfeeding, the stools became watery, loose, yellow-green in color, and frequent (8-10 times a day). They contained no blood or mucus. Replacement of pancreatic enzymes resulted in decreased stool frequency. Neonatal DM due to pancreatic hypoplasia and associated with DKA may mimic sepsis and should be kept in mind in all newborns who present with fever, dehydration, and weight loss. PMID- 21274329 TI - Cleidocranial dysplasia: a case report. AB - Cleidocranial dysplasia (CCD) is a rare autosomal dominant skeletal disease. CCD is caused by mutation in the gene on 6p21 encoding transcription factor CBFA1, i.e. runt-related transcription factor 2(RUNX2). The disease is characterized by a persistently open anterior fontanelle and skull sutures, hypoplastic or aplastic clavicles, dental abnormalities, short stature, a wide pubic symphysis, and a variety of other skeletal changes. A major finding of CCD is hypoplasia or aplasia of clavicular bones resulting in the ability of the patient to approximate the shoulders. Delayed closure of the anterior fontanelle and of metopic sutures causes frontal bossing. We report a case of CCD in a 3.5-year-old boy who referred to our clinic because of an unclosed anterior fontanelle and emphasize the importance of clinical findings in CCD. PMID- 21274331 TI - Circulating insulin-like growth factor binding protein-4 (IGFBP-4) is not regulated by parathyroid hormone and vitamin D in vivo: evidence from children with rickets. AB - OBJECTIVE: Insulin-like growth factor binding protein-4 (IGFBP-4), inhibits IGF actions under a variety of experimental conditions. Parathyroid hormone (PTH), 1.25-hydroxy(OH)vitamin D, IGF-I, IGF-II and transforming growth factor (TGF)-b are the major regulators of IGFBP-4 production in vitro. However, little is known about the in vivo regulation of circulating IGFBP-4 in humans. METHODS: We measured serum concentrations of calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), PTH, vitamin D, IGF-I, IGFBP-3, and IGFBP-4 in infants (n=22) with nutritional rickets before and after treatment of rickets with vitamin D (300 000 U single dose po). RESULTS: The mean+/-SD age of the patients was 1.3+/ 1.6 years (range 0.2-3). Serum Ca and P increased, whereas ALP and PTH decreased after treatment (Ca from 6.6+/-1.4 to 9.5+/-1.6 mg/dL, P from 3.9+/-1.4 to 5.4+/ 0.8 mg/dL, ALP from 2590+/-2630 to 1072+/-776 IU/mL and PTH from 407+/-248 to 27.4+/-20.8 ng/dL, respectively). Vitamin D levels were low (7.8+/-2.5 ng/mL) and increased after treatment (18.1+/-4.0 ng/mL, p<0.001). Serum IGF-I and IGFBP-3 levels both increased after treatment (IGF-I: 13.5+/-12.2 vs. 23.7+/-14.2 ng/mL, p<0.001 and IGFBP-3: 1108+/-544 vs. 1652+/-424 ng/mL, p<0.001). However, serum IGFBP-4 levels did not change significantly after treatment (18.8+/-8.0 vs. 21.5+/-4.8 ng/mL). No correlation between PTH and IGF-I, IGFBP-3 or IGFBP-4 was detected. Significant correlations were observed between PTH and ALP (r=0.53, p<0.05), and between IGF-I and IGFBP-3 (r=0.46, p<0.05). CONCLUSION: The results demonstrate that contrary to in vivo studies, circulating IGFBP-4 levels are not influenced by secondary hyperparathyroidism in vitamin D deficiency rickets since IGFBP-4 levels did not change after normalization of PTH with vitamin D treatment. PMID- 21274332 TI - Association between the corrected QT interval and carotid artery intima-media thickness in obese children. AB - OBJECTIVE: Sudden death has been reported in asymptomatic obese adults and the mechanism is unclear. In recent years, obesity has shown a dramatic increase in children and this enhances the risk factors for the development of cardiovascular disease. The aim of this study was to investigate whether there is repolarization abnormality and any potential risk factor such as increase in intima-media thickness (IMT) of carotid artery for corrected QT (QTc) prolongation among obese children. METHODS: A total of 60 obese children, 30 of which had features of metabolic syndrome (MS), and 23 age-matched controls were included in the study. QTc interval was calculated at rest. The IMT of both common carotid arteries (CCA) was measured. The relationship between QTc, IMT of right and left CCA and insulin sensitivity indices were evaluated in the study group. RESULTS: The QTc interval of the children with simple exogenous obesity (SEO) were longer than in the controls (p=0.024). The IMT of both carotid arteries of the obese girls and boys with and without MS were higher than the controls (p=<0.001). The QTc was significantly affected by the parameters pertaining to the right carotid artery IMT, to chronologic age and HDL-C. CONCLUSION: Since obesity may cause subclinical atherosclerotic disease regardless of sex, obese children must be followed closely for early cardiovascular problems. PMID- 21274330 TI - Steroid assays in paediatric endocrinology. AB - Most steroid disorders of the adrenal cortex come to clinical attention in childhood and in order to investigate these problems, there are many challenges to the laboratory which need to be appreciated to a certain extent by clinicians. The analysis of sex steroids in biological fluids from neonates, over adrenarche and puberty present challenges of specificities and concentrations often in small sample sizes. Different reference ranges are also needed for interpretations. For around 40 years, quantitative assays for the steroids and their regulatory peptide hormones have been possible using immunoassay techniques. Problems are recognised and this review aims to summarise the benefits and failings of immunoassays and introduce where tandem mass spectrometry is anticipated to meet the clinical needs for steroid analysis in paediatric endocrine investigations. It is important to keep a dialogue between clinicians and the laboratory, especially when any laboratory result does not make sense in the clinical investigation. PMID- 21274333 TI - Fetal-neonatal ovarian cysts--their monitoring and management: retrospective evaluation of 20 cases and review of the literature. AB - OBJECTIVE: Neonatal ovarian cysts (NOC) are usually self-limiting structures. However, large or complex cysts may lead to severe complications. A standard guide to management, treatment and follow-up of NOC is not yet available. The aim of this study was to evaluate retrospectively the records of NOC patients from two medical centers. METHODS: A total of 20 newborns with NOC were included in the study. The size and localization of the cyst, the age, the signs and symptoms at presentation, and the possible maternal and fetal-neonatal etiologic factors were recorded. Follow-up procedures and treatment modalities were evaluated. RESULTS: The mean age at diagnosis was 34 gestational weeks. The cysts (mean size 53+/-15 mm) were predominantly in the right ovary (75%) and were evaluated as large cysts in 16 (80%) of the patients. In 5 of the patients with large cysts and in 1 of the 4 patients with small cysts, the cysts were evaluated as complex cysts. Torsion of the ovary was detected in five (25%) cases and these cases were treated surgically. Patients with simple cysts were closely followed by ultrasonography until the cysts disappeared. CONCLUSION: To date, there is no precise guide for the monitoring and treatment of NOCs. Surgical treatment should always be performed in a way to protect the ovaries and to ensure future fertility. In our NOC series, it has been possible to apply a non-invasive follow up program and minimally invasive surgical procedures. PMID- 21274334 TI - Ghrelin levels and postnatal growth in healthy infants 0-3 months of age. AB - OBJECTIVE: The effect of ghrelin on growth of the newborn has long been argued, but not fully clarified. In this study, we aimed to investigate the relationship between ghrelin levels and growth parameters in the first 3 months of life. METHODS: The study included 60 babies (27 girls and 33 boys) born at gestational ages between 38-42 weeks. The newborns were divided into three groups according to the Lubchenco curves as: small for gestational age (SGA), appropriate for gestational age (AGA) and large for gestational age (LGA). The relationship between ghrelin levels and growth parameters in the third month was investigated. RESULTS: Ghrelin concentrations were significantly higher in SGA (2.4+/-2.6 ng/dL) babies than in AGA (1.3+/-0.9 ng/dL) and LGA (1.0+/-0.8 ng/dL) babies. The lowest ghrelin levels were in the LGA group. In SGA infants, ghrelin concentrations were inversely correlated with change in weight (r=-0.577; p=0.001), change in length (r=-0.361; p=0.005), and change in head circumference (r=-0.387; p=0.002). CONCLUSION: The results show that at age 3 months, SGA infants had higher ghrelin levels than AGA and LGA infants. Our findings indicate that ghrelin may be involved in the process of catch-up growth in these infants. PMID- 21274335 TI - Acquired generalized lipodystrophy associated with autoimmune hepatitis and low serum C4 level. AB - Lipodystrophies are a group of diseases characterized by loss of fat tissue and are associated with insulin resistance. A six-year-old girl followed with the diagnosis of autoimmune hepatitis showed a severe loss of fat tissue, hyperinsulinemia, impaired glucose tolerance, hypertriglyceridemia and low serum complement 4 (C4) levels. She had coarse facial features with generalized loss of subcutaneous fat and prominent muscularity. Remarkable acanthosis nigricans was present over the neck, axilla, and umbilicus. Two hours after glucose loading, the glucose tolerance test revealed a glucose level of 258 mg/dL, a HbA1c value of 6.8%, and an insulin level of 642.9 mIU/mL, documenting a state of insulin resistance and type 2 diabetes mellitus. Acquired generalized lipodystrophy was diagnosed and metformin with dietary intervention was initiated. Low serum complement levels proved the autoimmune nature of the process. We conclude that the serum complement levels must be investigated in patients with acquired lipodystrophy, particularly when it is associated with autoimmune hepatitis. PMID- 21274336 TI - Neonatal hyperthyroidism associated with isolated submandibular sialadenitis: is it just a coincidence? AB - Isolated submandibular sialadenitis is extremely rare in the neonatal period. All reported cases had predisposing factors such as prematurity, dehydration, anatomic deformities, calculi, and long-term oro-gastric tube feeding. Here, we present a case of neonatal isolated submandibular sialadenitis without any known risk factors and who was diagnosed later with hyperthyroidism secondary to maternal Graves' disease. Both sialadenitis and hyperthyroidism resolved with appropriate treatment. While both conditions are rare and important in neonatal emergency care, the possibility of neonatal hyperthyroidism should be explored in cases with isolated sialadenitis if there is no other risk factor. Possible mechanisms for this uncommon association are discussed. PMID- 21274337 TI - Insulin oedema in newly diagnosed type 1 diabetes mellitus. AB - Despite the essential role of insulin in the management of patients with insulin deficiency, insulin use can lead to adverse effects such as hypoglycaemia and weight gain. Rarely, crucial fluid retention can occur with insulin therapy, resulting in an oedematous condition. Peripheral or generalised oedema is an extremely rare complication of insulin therapy in the absence of heart, liver or renal involvement. It has been reported in newly diagnosed type 1 diabetes, in poorly controlled type 2 diabetes following the initiation of insulin therapy, and in underweight patients on large doses of insulin. The oedema occurs shortly after the initiation of intensive insulin therapy. We describe two adolescent girls with newly diagnosed type 1 diabetes, who presented with oedema of the lower extremities approximately one week after the initiation of insulin treatment; other causes of oedema were excluded. Spontaneous recovery was observed in both patients. PMID- 21274338 TI - Al-Awadi/Raas-Rothschild syndrome in a newborn with additional anomalies. AB - Al-Awadi/Raas-Rothschild (AARR) syndrome is a rare phocomelia syndrome characterized by limb/pelvic hypoplasia/aplasia, renal anomalies such as horseshoe and polycystic kidney, and abnormal facial features including cleft palate, hypertelorism and micro-retrognatia. Autosomal recessive inheritance has been proposed for AARR syndrome. In this report a boy affected with AARR syndrome is presented. The previous pregnancy of the mother was terminated because of lower limb agenesis detected at 14th week of gestation. This report emphasizes the importance of recognizing severe pelvic and limb deficiencies in newborns with AARR syndrome and differentiating the syndrome from other multiple malformation syndromes. Fetal ultrasonography at 15th week of gestation is helpful in diagnosing the major extremity anomalies in the fetus. PMID- 21274340 TI - The effect of insulin resistance and obesity on low-density lipoprotein particle size in children. AB - OBJECTIVE: In adults, it was shown that obesity and insulin resistance affect low density lipoprotein (LDL) particle size and small dense (sd) LDL is associated with cardiovascular diseases. In this study, we investigated the effect of obesity and insulin resistance on LDL particle size. METHODS: Twenty-six obese children (13 girls, 13 boys) with a median age of 10.5 years and 27 healthy control subjects (17 girls, 10 boys) with a median age of 11.5 were enrolled in the study. RESULTS: The number of patients with insulin resistance in the obese group was 15 out of 26. In the control group, there was no subject with insulin resistance. Serum triglyceride and very LDL (VLDL) levels were higher and serum high-density lipoprotein levels (HDL) were lower in the obese patients than in the controls. There was no statistical difference in the LDL particle size between the two groups (medians: 26.6 vs. 26.7 nm (p=0.575)). The size of LDL particle was not correlated with body mass index (BMI) standard deviation score (SDS), homeostasis model assessment of insulin resistance (HOMA-IR), or serum lipids. CONCLUSION: Measurement of LDL particle size as a routine procedure is not necessary in childhood obesity. PMID- 21274341 TI - Gender differences in cardiovascular risks of obese adolescents in the Bronx. AB - OBJECTIVE: The associations between the degree of obesity and cardiovascular disease (CVD) risks and the impact of gender differences with regard to these risk factors are not well understood. The aim of our study was to examine the gender-specific differences in CVD risk factors in inner-city minority youths. METHODS: A total of 269 adolescents (109 males and 160 females) were included in this retrospective study. Data on multiple metabolic variables were collected. Evaluation of abnormalities in these parameters was based on standard criteria. Pearson correlations were calculated to examine the relationship between body mass index (BMI) z-score and obesity-related parameters. Chi-square and Fisher's tests were used to compare the frequencies of single or multiple cardiovascular risks in the two gender groups. RESULTS: In the male group, BMI z-scores showed significant positive correlations with insulin resistance and diastolic blood pressure. In the female group, BMI z-scores showed significant positive correlations with insulin resistance and systolic blood pressure. In both genders, the prevalence of CVD risks was high, but a similar risk pattern was established in both sexes, with dyslipidemia being the highest, hypertension the second, and impaired glucose tolerance (IGT) being the least outstanding. The most important finding in this study was that the male group had a significantly higher prevalence of systolic hypertension. CONCLUSION: Male inner-city minority adolescents show a high prevalence of CVD risks associated with obesity. Appropriate risk stratification is critical to developing and implementing both therapeutic and preventive interventions. PMID- 21274339 TI - Genetics of isolated growth hormone deficiency. AB - When a child is not following the normal, predicted growth curve, an evaluation for underlying illnesses and central nervous system abnormalities is required, and appropriate consideration should be given to genetic defects causing growth hormone (GH) deficiency (GHD). Because Insulin-like Growth Factor-I (IGF-I) plays a pivotal role, GHD could also be considered as a form of IGF-I deficiency (IGFD). Although IGFD can develop at any level of the GH-releasing hormone (GHRH) GH-IGF axis, a differentiation should be made between GHD (absent to low GH in circulation) and IGFD (normal to high GH in circulation). The main focus of this review is on the GH gene, the various gene alterations and their possible impact on the pituitary gland. However, although transcription factors regulating the pituitary gland development may cause multiple pituitary hormone deficiency, they may present initially as GHD. PMID- 21274342 TI - Growth of children with type 1 diabetes mellitus. AB - OBJECTIVE: To retrospectively evaluate the effect of type 1 diabetes on growth. METHODS: Patients with Type 1 diabetes mellitus (T1DM) followed for at least one year after diagnosis, and without coexisting disorder that could affect growth, were included in this retrospective analysis. Height and body mass index (BMI) values were recorded. According to the data obtained at the end of each year of disease, the patients were divided into two groups: Group 1 (patients whose height standard deviation score (SDS) did not change or showed improvement) and Group 2 (patients whose height SDS showed a decline). The two groups were compared with respect to clinical and laboratory variables. RESULTS: Among the 248 patients followed, 101 (M/F:55/46) fulfilled the inclusion criteria. Overall, the mean height SDS of the patients did not change significantly during the follow-up period. BMI SDS showed no change during the course of the disease, except for a significant rise observed at the end of the first year compared to the value at diagnosis. Height SDS of the patients in Group 1 was higher compared to those in Group 2 from the 2nd year of disease onwards (2nd year, p=0.03; 3rd year, p=0.02; 4th year, p=0.01; 5th year, p=0.03). The ratio of patients presenting with diabetic ketoacidosis at onset was significantly higher in Group 1 at the 4th year of diagnosis (p=0.03). Additionally, the mean HbA1c level showed a modest negative correlation with Delta height SDS at the 3rd year of diagnosis (r=-0.3, p=0.03). CONCLUSIONS: No significant deteriorative effect of T1DM on auxological parameters was observed at short term. Some clinical and laboratory variables related with metabolic control were found to correlate with growth. PMID- 21274343 TI - Fine-needle aspiration biopsy in the diagnosis and follow-up of thyroid nodules in childhood. AB - OBJECTIVE: To assess the role of fine-needle aspiration biopsy (FNAB) in the management of pediatric thyroid nodules. METHODS: Results of 30 FNABs performed in our clinic were retrospectively reviewed. Clinical and surgical follow-up data were obtained from the patient files, and clinical correlation and accuracy of FNAB were evaluated. RESULTS: The results of 30 FNABs were reported as benign in 24 (80%), insufficient in 4 (13.3%) patients, malignant in 1 (3.3%), and suspicious in 1 (3.3%) patient. One patient with a FNAB result of malignancy underwent surgery and the histological diagnosis was papillary carcinoma. FNAB was repeated in two of the insufficient biopsies, and reported as benign; in one of these patients, the thyroid nodule disappeared and in one, remained stable at clinical follow-up. Four of the patients with benign FNAB results underwent surgery at clinical follow-up because of an increase in the size of the nodules and one patient was found to have papillary carcinoma. The remaining patients were clinically followed. In this study, the malignancy prevalence was 6.6% in patients with thyroid nodules. There was only one false-negative case. CONCLUSION: FNAB is a reliable diagnostic tool in the management of pediatric thyroid nodules. PMID- 21274345 TI - Long-term follow-up of a pseudohypoparathyroidism type 1A patient with missense mutation (Pro115Ser) in exon 5. AB - Pseudohypoparathyroidism (PHP) refers to end-organ resistance that primarily impairs the renal actions of parathyroid hormone (PTH). The patients with PHP type Ia (PHP-Ia), one of the 4 types of PHP, show resistance to other peptide hormones as well as clinical features of Albright hereditary osteodystrophy (AHO), a constellation of short stature, obesity, brachydactyly, ectopic ossifications, and/or mental retardation. Here we report clinical follow-up for a long-term period in a PHP-Ia case who had a missense mutation leading to the substitution of proline by serine (Prol115Ser) in exon 5 which has been reported previously in only two patients. An 11-year-old boy applied for hand spasm to our hospital. On physical examination, he had short stature, round-shaped face and brachydactly. Laboratory evaluation revealed PTH and TSH resistance. Molecular genetic analysis of the GNAS gene revealed a P115S substitution. The patient was followed up for 13 years. Normocalcaemia was achieved with reduced doses of calcitriol (0.25 MUg/day) and calcium supplements (40 mg/kg/day). Daily requirement for levothyroxine supplementation was still high (2.3 MUg/kg) to achieve euthyroidism. His pubertal development was Tanner stage V and he has no gonadotropin resistance. To our knowledge, this is the first report concerning long-term follow-up of this rare mutation. We believe that despite the genetic heterogeneity of AHO, phenotype/genotype correlations of this kind of rare mutations may help to understand progress of the disease. PMID- 21274344 TI - Congenital goitrous hypothyroidism, deafness and iodide organification defect in four siblings: Pendred or pseudo-Pendred syndrome? AB - Pendred syndrome (PDS) is an autosomal recessive disorder characterized by congenital deafness, goiter and iodide organification defect. Presence of inner ear malformations is essential for the clinical diagnosis. Most individuals with PDS are clinically and biochemically euthyroid. Mutations in the PDS gene encoding pendrin protein have been shown to be associated with PDS. It has been recently demonstrated that some families with features of PDS do not have the inner ear malformations and mutations in the PDS gene. This condition has been named as "pseudo-Pendred syndrome" (pseudo-PDS), and has been hypothesized to be of autoimmune origin. Here we report four siblings who have goiter, severe hypothyroidism, a positive perchlorate discharge test and sensorineural deafness, but not the inner ear abnormality which is diagnostic for PDS. We suggest that thyroid peroxidase (TPO) gene should be analyzed in pseudo-PDS patients with congenital goitrous hypothyroidism and deafness. PMID- 21274346 TI - Genoa syndrome and central diabetes insipidus: a case report. AB - Genoa syndrome was first described by Camera et al in 1993 in two patients with semilobar holoprosencephaly (HPE), craniosynostosis and abnormal small hands with cone-shaped epiphyses and hypoplastic terminal phalanges of fingers (OMIM: 601370). In 2001, Lapunzina et al reported a case of craniosynostosis and HPE associated with several other malformations and suggested that these findings could be attributed to a severe form of Genoa syndrome or to a newly recognized syndrome. Endocrinopathies in association with HPE are frequently reported in the literature. Diabetes insipidus, hypothyroidism, hypocortisolism, and growth hormone deficiency are frequently associated with HPE. We here report a case of semilobar HPE, craniosynostosis and cleft lip/palate, possibly a case of Genoa syndrome, associated with central diabetes insipidus. PMID- 21274347 TI - Neonatal episodic hypoglycemia: a finding of valproic acid withdrawal. AB - The treatment of epilepsy during pregnancy is a worldwide problem. Drugs need to be used to control seizures in the mothers. In utero, exposure to valproic acid (VPA) and phenytoin (PH) may cause congenital malformations and also withdrawal symptoms such as irritability, jitteriness and symptoms of hypoglycemia. We present here a newborn with episodic hypoglycemia due to in utero exposure to VPA and PH. The mother was diagnosed as having complex partial epilepsy and was treated with PH (200 mg/day) and VPA (600 mg/day). The offspring developed jitteriness on the second day of life. The infant was hypoglycemic (32 mg/dl). These findings were accepted as withdrawal symptoms, since serum levels of VPA and PH were 37.8 MUg/ml (50-100 MUg/ml) and 6.37 MUg/dl (10-20 MUg/ml), respectively. Measurement of blood glucose is important and should be carefully monitored in infants exposed to antiepileptics in utero. PMID- 21274348 TI - An atypical cutaneous reaction to rivastigmine transdermal patch. AB - Rivastigmine is a cholinesterase inhibitor which improves cognitive function and is currently being used in patients with mild to moderate Parkinson's and Alzheimer's dementia. This drug can be given orally or topically, as transdermal patch. The latter form is currently used for most excellent compliance and few side effects. The most common cutaneous side effects are irritative dermatitis. We report the second case of active sensitization by the rivastigmine-patch in a patient suffering from Alzheimer's dementia. PMID- 21274349 TI - Apical ballooning syndrome: the "broken heart" syndrome. PMID- 21274350 TI - Neuroleptic malignant syndrome after exposure to asenapine: a case report. PMID- 21274351 TI - Symptoms and course of psychosis after methamphetamine abuse: one-year follow-up of a case. PMID- 21274352 TI - Psychiatric presentation of a child with Crohn's disease. PMID- 21274353 TI - Are advanced paternal age and point mutation at chromosome 4 associated with schizophrenia? PMID- 21274354 TI - Roles and goals of a palliative care psychiatrist. PMID- 21274355 TI - Preventive medical services use among community mental health patients with severe mental illness:the influence of gender and insurance coverage. AB - INTRODUCTION: This study examines predictors of reduced preventive health service use in patients with severe mental illness by examining psychiatric diagnoses and demographic factors. METHOD: Of 387 patients approached in 4 community mental health clinics regarding their preventive health services use from January 2005 to May 2007, 234 (60.5%) were interviewed. Of those participants interviewed, 221 had a DSM-IV-TR diagnosis of (1) primary psychotic disorder (schizophrenia or schizoaffective disorder), (2) bipolar disorder, or (3) recurrent major depressive disorder. Psychiatric disorders and demographic factors that predicted high service utilization were analyzed using analysis of variance and chi2 tests. RESULTS: In the linear predictive model, use of preventive services was not statistically different among the 3 diagnostic groups. Participants with primary psychotic disorder used a similar number of preventive services compared to those with bipolar disorder and major depression. Women used more services than men (P < .01), and individuals with health insurance used more than uninsured participants (P < .001). CONCLUSION: Male gender and not having medical insurance were predictive of lower preventive health service use in this sample of patients with severe mental illness. Further research is needed to replicate these findings and to improve use of preventive health services in people with severe mental illness. PMID- 21274356 TI - Perceived reasons for and consequences of substance abuse among patients with psychosis. AB - BACKGROUND: Substance use is a common comorbidity with psychotic illnesses. Although several theories exist to explain this link, individual reasons for use may differ. The aim of this study was to evaluate patient perceptions of the reasons for and consequences of their substance use in patients with psychosis and compare them with those of an age-, sex-, and tobacco use-matched control sample without psychosis. METHOD: Consecutively admitted patients were divided into 2 groups, those who had substance dependence without psychosis (n = 32), admitted in our addiction unit, and those who had psychotic illness with substance dependence, admitted in our inpatient psychosis unit and referred to as the dual-diagnosis group (n = 62). Patients were administered the Schedules for Clinical Assessment in Neuropsychiatry for ICD-10 Diagnostic Criteria for Research to confirm schizophrenia, bipolar affective disorder, and substance dependence diagnoses and were asked open-ended questions to evaluate the perceived reasons for and consequences of their substance use. The study was conducted from July to September 2006. RESULTS: There were significant differences between the 2 groups in reasons for maintenance and relapse of both cannabis use and alcohol use, the 2 most common substances. While the substance dependence without psychosis group attributed both maintenance and relapse to external factors such as nature of work, social milieu, or peer pressure, the dual-diagnosis group attributed them to internal factors such as enhancement of positive mood and alleviation of withdrawal effects. CONCLUSIONS: Individuals with psychosis have greater vulnerability to internal factors, which may maintain substance use. Targeting perceived internal factors may play a useful role in management and possibly identification and prevention of psychosis in vulnerable individuals in the future. PMID- 21274357 TI - Sleep quality in borderline personality disorder: a cross-sectional study. AB - OBJECTIVE: In this study, relationships between sleep quality and borderline personality disorder were examined using 2 self-report measures. METHOD: Using a cross-sectional design in a sample of convenience of internal medicine outpatients, we surveyed men and women (N=76), aged 18 years or older, who were seeking nonemergent medical care during the period January 2009 to September 2009. Sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI) and borderline personality was assessed with 2 measures: the borderline personality scale of the Personality Diagnostic Questionnaire-4 (PDQ-4) and the Self-Harm Inventory (SHI). RESULTS: The global PSQI score was statistically significantly associated with scores on the PDQ-4 (P < .01), the SHI (P < .01), and the combination PDQ-4 and SHI (P < .01). With regard to the components of the PSQI, subjective sleep quality (P < .05), sleep duration (P < .05), and daytime dysfunction (P < .01) were all statistically significantly associated with scores on the PDQ-4, and sleep latency was statistically significantly associated with the combined PDQ-4 and SHI (P < .05). CONCLUSIONS: Individuals with borderline personality symptomatology demonstrate a poorer overall quality of sleep than those without these symptoms. PMID- 21274358 TI - Variations in the probability of depression screening at community-based physician practice visits. AB - BACKGROUND: Despite depression screening being a US Preventive Services Task Force-recommended practice in primary care, little is known about the degree to which it is performed and the factors associated with its conduct. METHOD: Using a nationally representative sample (National Ambulatory Medical Care Survey) of adult, community-based physician practice visits during the survey years 2005 to 2007 (total = 55,143; representing approximately 1.7 billion visits nationally), we estimated the probability of depression screening and variation by visit characteristics. RESULTS: Depression screening occurred at 2.29% of adult, community-based physician practice visits. Visits with primary care physicians were more likely to include depression screening (AOR = 2.19; 95% CI, 1.31-3.65), as were visits for preventive (AOR = 4.09; 95% CI, 2.55-6.57) and chronic care (AOR = 2.00; 95% CI, 1.44-2.80) compared to visits for acute care. Compared to the Northeast, visits in the West were less likely to include depression screening (AOR = 0.27; 95% CI, 0.13-0.57), as were visits for patients having >= 6 visits within the past 12 months (AOR = 0.65; 95% CI, 0.42-1.00) when compared to visits for new patients. Depression screening was more common at visits for patients with ICD-9-diagnosed depression (AOR = 7.51; 95% CI, 5.38-10.50) and for females (AOR = 1.26; 95% CI, 1.00-1.57). Bivariate analyses revealed that depression screening was more common at visits for patients with hyperlipidemia (3.21% vs 2.09%, P = .0086), obesity (4.59% vs 2.08%, P < .0001), and osteoporosis (4.46% vs 2.21%, P = .0002) and less common at visits for patients with diabetes (1.58% vs 2.39%, P = .0102). CONCLUSIONS: Depression screening at community-based physician practice visits in the United States appears to be low (2.29%) and may reflect an undefined optimal screening interval or strategy in published guidelines, lack of reimbursement incentives, or incomplete documentation in the medical record. Opportunities exist to improve depression screening in males, patients with chronic disease (especially diabetes), and the western region of the United States. PMID- 21274359 TI - Effects of a multimodal lifestyle intervention on body mass index in patients with bipolar disorder: a randomized controlled trial. AB - OBJECTIVE: Patients with bipolar disorder are at increased risk of weight gain, which in turn increases the risk for somatic disease and nonadherence to maintenance therapy. Therefore, interventions addressing weight gain are expedient for the management of this disorder. We set out to evaluate the effects of a lifestyle intervention on body mass index (BMI) and cardiovascular and metabolic parameters in patients with bipolar disorder undergoing mood stabilizing pharmacologic treatment. METHOD: Fifty outpatients with bipolar disorder undergoing mood-stabilizing treatment participated in a randomized controlled trial (waiting control group: n = 24 and multimodal lifestyle intervention group: n = 26). Groups consisted of 2 cohorts (cohort 1: March 2005 February 2006; cohort 2: September 2005-August 2006). The intervention lasted 5 months and consisted of 11 group sessions and weekly fitness training. BMI and body weight as well as cardiovascular and metabolic parameters were determined at 3 assessment points: at pretreatment baseline, at 5 months (end of treatment), and at 11 months (6-month follow-up). RESULTS: Intention-to-treat analyses showed that the intervention significantly reduced BMI over time (P = .03), with significant and stable mean differences in BMI change between groups of 0.7 kg/m2 (95% CI, 0.2-1.3) at 5 months and 0.8 kg/m2 (95% CI, 0.1-1.6) at 11 months' follow-up assessment. The lifestyle intervention had no significant effect on cardiovascular and metabolic parameters (all nonsignificant). The BMI reduction was only seen in female patients (P = .003). CONCLUSIONS: BMI in patients with bipolar disorder can be reduced with a long-lasting effect by a multimodal lifestyle intervention. However, this effect was only seen in female participants, indicating the need for gender-specific interventions. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00980863. PMID- 21274360 TI - Subjective versus objective: an exploratory analysis of latino primary care patients with self-perceived depression who do not fulfill primary care evaluation of mental disorders patient health questionnaire criteria for depression. AB - OBJECTIVE: Identification and treatment of depression may be difficult for primary care providers when there is a mismatch between the patient's subjective experiences of illness and objective criteria. Cultural differences in presentation of symptoms among Latino immigrants may hinder access to care for treatment of depression. This article seeks to describe the self-perceptions and symptoms of Latino primary care patients who identify themselves as depressed but do not meet screening criteria for depression. METHOD: A convenience sample of Latino immigrants (N = 177) in Corona, Queens, New York, was obtained from a primary care practice from August 2008 to December 2008. The sample was divided into 3 groups according to whether participants met Patient Health Questionnaire diagnostic criteria for depression and whether or not participants had a self perceived mental health problem and self-identified their problem as "depression" from a checklist of cultural idioms of distress. Psychosocial, demographic, and treatment variables were compared between the 3 groups. RESULTS: Participants' descriptions of symptoms had a predominantly somatic component. The most common complaints were animo bajo (low energy) and decaimiento (weakness). Participants with "subjective" depression had mean scores of somatic symptoms and depression severity that were significantly lower than the participants with "objective" depression and significantly higher than the group with no depression (P < .0001). CONCLUSIONS: Latino immigrants who perceive that they need help with depression, but do not meet screening criteria for depression, still have significant distress and impairment. To avoid having these patients "fall through the cracks," it is important to take into account culturally accepted expressions of distress and the meaning of illness for the individual. PMID- 21274361 TI - Meta-analysis of suicidality in placebo-controlled clinical trials of adults taking bupropion. AB - OBJECTIVE: To assess a possible relationship between treatment with bupropion (vs placebo) and expressed suicidal ideation and behavior. DATA SOURCES: This analysis, based on the US Food and Drug Administration's (FDA's) analysis of antidepressant suicidality data, included 8,953 adult subjects receiving bupropion and 6,520 adult subjects receiving placebo from randomized, placebo controlled trials with bupropion conducted between 1976 and 2006 across multiple indications, including major depressive disorder (MDD). A text string search of the adverse event database and case report form comments was performed to identify potential suicidal events. FDA search criteria included the following text strings: accident-, injur-, suic-, or overdos-, including all events coded as accidental overdose, attempt, cut, gas, hang, hung, jump, mutilat-, self damag , self harm, self inflict-, shoot, slash, poison, asphyxiation, suffocation, firearm, burn, drown, gun, immolat-, and monoxide, and the following terms were added by GlaxoSmithKline to the search criteria: accident, lacerat-, MVA, and hospital. The database search included data beginning from the first dose of study medication through 1 day following the last dose. DATA EXTRACTION: Suicidal event narratives were classified using the Columbia Classification Algorithm for Suicide Assessment. Additionally, changes on rating scale items for depressed mood and suicidality were analyzed. DATA SYNTHESIS: In the MDD population, the incidence of suicidal behavior or ideation was 17/3,179 (0.53%) versus 11/2,310 (0.48%) for the bupropion and placebo groups, respectively (OR = 1.28; 95% CI, 0.59-2.86). For suicidal behavior, the incidence was 8/3,179 (0.25%) versus 2/2,310 (0.09%), respectively (OR = 3.52; 95% CI, 0.81-24.48). No suicidal behavior event was noted in the other indications, and no completed suicides were reported during treatment. No significant worsening was observed for bupropion relative to placebo on the rating scale items. No differential treatment effects were observed by gender or age; regardless of treatment, however, the 18- to 24 year-old group had the greatest odds of having a suicide event. CONCLUSIONS: Although no statistically significant differences were observed between bupropion and placebo in expressed suicidal ideation or behavior, we believe that all patients treated with antidepressants should receive careful monitoring for clinical worsening, suicidality, or unusual changes in behavior. PMID- 21274362 TI - Impairment and functioning in a sample of primary care patients with generalized anxiety disorder: results from the primary care anxiety project. AB - OBJECTIVE: To examine the extent of functional impairment associated with generalized anxiety disorder (GAD) in a sample of primary care patients. METHOD: Participants (N = 128) were part of the Primary Care Anxiety Project (PCAP), a study conducted in 15 primary care practices in the northeastern United States. Patients were recruited in primary care practice waiting rooms from July 1997 to May 2001. Participants screening positive for anxiety symptoms received a diagnostic interview and an assessment of health-related functioning (Medical Outcomes Study 36-item Short-Form Health Survey [SF-36]). Effect sizes are reported for comparisons of SF-36 scores between patients with a DSM-IV diagnosis of GAD and general population and medical sample norms. RESULTS: Relative to general population normative SF-36 scores, primary care patients with GAD evidenced impaired functioning on both the physical and mental component summary scales. Patients with GAD also evidenced greater impairment in psychosocial functioning than that previously reported for samples of patients with major medical illnesses, including type II diabetes, hypertension, recent myocardial infarction, and congestive heart failure. This finding held true even when GAD patients with comorbid medical illnesses and comorbid Axis I mental disorders were excluded from the comparison. CONCLUSIONS: Primary care patients with GAD experience substantial impairment that cannot be accounted for by concurrent medical illnesses or comorbid Axis I mental disorders. PMID- 21274363 TI - Correlates of medication adherence among patients with bipolar disorder: results of the bipolar evaluation of satisfaction and tolerability (BEST) study: a nationwide cross-sectional survey. AB - OBJECTIVE: To identify and describe correlates of medication adherence in a large, national sample of outpatients with bipolar disorder. METHOD: Data were collected via a self-report, Web-based survey in January and February of 2008 from US patients aged 18-65 years who reported a diagnosis of bipolar disorder and current use of psychotropic medication. Patients with a Composite International Diagnostic Interview-bipolar disorder (CIDI-bipolar disorder) score >= 7, indicating a high risk of bipolar disorder, were included in the analyses. Medication adherence was assessed via the Morisky Medication Adherence Scale, with scores >= 2 being considered nonadherent. The primary analysis was a multivariate binomial logistic regression with adherence as the dependent variable. Covariates included patient demographics, physical health measures including Medical Outcomes Study 8-item Short-Form Health Survey physical summary score, number of manic and depressive episodes, 24-item Behavior and Symptom Identification Scale (BASIS-24), Liverpool University Neuroleptic Side-Effect Rating Scale (LUNSERS), Satisfaction With Antipsychotic Medication scale (SWAM), and current psychiatric medication use. RESULTS: Nearly half (49.5%) of the 1,052 bipolar patients in the analysis were classified as being nonadherent. Adherence was positively associated with college degree, higher SWAM total score, and monotherapy treatment. Adherence was negatively associated with female sex, alcohol use, BASIS-24 total score, and LUNSERS total score. CONCLUSIONS: Nonadherence is common among patients with bipolar disorder. By addressing tolerability issues and treatment satisfaction, which are both significant correlates of adherence, health care providers may be able to improve adherence and, ultimately, treatment outcomes. PMID- 21274364 TI - Switching from oral donepezil to rivastigmine transdermal patch in Alzheimer's disease: 20-week extension phase results. AB - OBJECTIVE: To evaluate the long-term safety, tolerability, and efficacy of 2 strategies for switching from donepezil to rivastigmine transdermal patches in patients with mild to moderate Alzheimer's disease. METHOD: This was a prospective, 25-week, randomized, open-label, parallel-group study to evaluate an immediate or delayed switch (7-day withdrawal) from donepezil (5 to 10 mg/d) to rivastigmine transdermal patches (4.6 mg/24 h). Participants included male and female patients, aged >= 50 years, with a DSM-IV-TR diagnosis of mild to moderate dementia of the Alzheimer's type, defined as a Mini-Mental State Examination score of 10-24, inclusive. Patients were enrolled between February 2007 and February 2008. The study was split into a 5-week core phase and a 20-week extension phase. Safety and efficacy results from the extension phase are presented. RESULTS: Both switching strategies were well tolerated. Rates of discontinuation for any reason were similar between the groups. Discontinuations due to adverse events were also similar, and the incidence of gastrointestinal adverse events was low. Apart from Alzheimer's Disease Cooperative Study Activities of Daily Living Scale scores, at the end of the study, there was no statistically significant change from baseline in cognitive, behavioral, or global outcomes. Over half of the patients preferred rivastigmine transdermal patches to a tablet. CONCLUSIONS: This study suggests that the majority of patients receiving donepezil tablets can be safely switched to rivastigmine transdermal patches without significant deterioration in cognition, behavior, and global functioning. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00305903. PMID- 21274365 TI - Sodium valproate-induced hyponatremia: a case report. PMID- 21274366 TI - Non-HDL Cholesterol: A New Endpoint in Cardio-Metabolic Health Monitoring. PMID- 21274367 TI - Priapism during treatment with olanzapine, quetiapine, and risperidone in a patient with schizophrenia: a case report. PMID- 21274368 TI - The relationship between self-reported pain and borderline personality symptomatology among internal medicine outpatients. PMID- 21274369 TI - Delayed psychosis induced by bupropion in a former cocaine abuser: a case report. PMID- 21274370 TI - Nestin in gastrointestinal and other cancers: effects on cells and tumor angiogenesis. AB - Nestin is a class VI intermediate filament protein that was originally described as a neuronal stem cell marker during central nervous system (CNS) development, and is currently widely used in that capacity. Nestin is also expressed in non neuronal immature or progenitor cells in normal tissues. Under pathological conditions, nestin is expressed in repair processes in the CNS, muscle, liver, and infarcted myocardium. Furthermore, increased nestin expression has been reported in various tumor cells, including CNS tumors, gastrointestinal stromal tumors, pancreatic cancer, prostate cancer, breast cancer, malignant melanoma, dermatofibrosarcoma protuberances, and thyroid tumors. Nestin is reported to correlate with aggressive growth, metastasis, and poor prognosis in some tumors; however, the roles of nestin in cancer cells have not been well characterized. Furthermore, nestin is more specifically expressed in proliferating small-sized tumor vessels in glioblastoma and gastric, colorectal, and prostate cancers than are other tumor vessel markers. These findings indicate that nestin may be a marker for newly synthesized tumor vessels and a therapeutic target for tumor angiogenesis. It has received a lot of attention recently as a cancer stem cell marker in various cancer cells including brain tumors, malignant rhabdoid tumors, and uterine, cervical, prostate, bladder, head and neck, ovarian, testicular, and pancreatic cancers. The purpose of this review is to clarify the roles of nestin in cancer cells and in tumor angiogenesis, and to examine the association between nestin and cancer stem cells. Nestin has the potential to serve as a molecular target for cancers with nestin-positive cancer cells and nestin-positive tumor vasculature. PMID- 21274372 TI - Differentiation of Crohn's disease from intestinal tuberculosis in India in 2010. AB - Differentiating intestinal tuberculosis from Crohn's disease (CD) is an important clinical challenge of considerable therapeutic significance. The problem is of greatest magnitude in countries where tuberculosis continues to be highly prevalent, and where the incidence of CD is increasing. The final clinical diagnosis is based on a combination of the clinical history with endoscopic studies, culture and polymerase chain reaction for Mycobacterium tuberculosis, biopsy pathology, radiological investigations and response to therapy. In a subset of patients, surgery is required and intraoperative findings with pathological study of the resected bowel provide a definitive diagnosis. Awareness of the parameters useful in distinguishing these two disorders in each of the different diagnostic modalities is crucial to accurate decision making. Newer techniques, such as capsule endoscopy, small bowel enteroscopy and immunological assays for Mycobacterium tuberculosis, have a role to play in the differentiation of intestinal tuberculosis and CD. This review presents currently available evidence regarding the usefulness and limitations of all these different modalities available for the evaluation of these two disorders. PMID- 21274371 TI - Peginterferon and ribavirin treatment for hepatitis C virus infection. AB - Pegylated interferon alpha (IFNalpha) in combination with ribavirin is currently recommended as a standard-of-care treatment for chronic hepatitis C virus (HCV) infection. This combination therapy has drastically improved the rate of sustained virological response, specifically in difficult-to-treat patients. Recently, individualized treatment, such as response-guided therapy, is being developed based on host-, HCV- and treatment-related factors. Furthermore, modified regimens with currently available medications, novel modified IFNalpha and ribavirin or combinations with specifically targeted antiviral therapy for HCV agents, are currently being investigated. The purpose of this review is to address some issues and epoch-making topics in the treatment of chronic HCV infection, and to discuss more optimal and highly individualized therapeutic strategies for HCV-infected patients. PMID- 21274373 TI - Is diabetes a causal agent for colorectal cancer? Pathophysiological and molecular mechanisms. AB - The possible relationship between diabetes mellitus (DM) and colorectal cancer (CRC), concerning pathophysiological and molecular mechanisms is highlighted in this review. The most recent and complete articles and developments in this particular field were thoroughly reviewed. Common risk factors, such as obesity, sedentary lifestyle, and Western diet between DM and CRC, led to the theory that DM might be a causal agent for CRC development. Various studies have connected type 2 DM and CRC, either proximal or distal, in both sexes. Additionally, chronic insulin treatment has been linked with increased colorectal tumor risk among type 2 diabetic patients. Interestingly, elevated hemoglobin A1c has been proven to be an independent predictor of aggressive clinical behavior in CRC patients. These mechanisms include the insulin-like growth factor hyperinsulinemia theory and the participation of oncogenic intracellular signaling pathways. Furthermore, it has been proposed that Cox-2 inhibitors might have a role in decreasing the incidence of CRC. Finally, the use of statins to reduce the risk for colon cancer in patients with diabetes has remained controversial. Diabetic patients over 50 should receive counseling regarding their elevated risk for CRC, and screening colonoscopy should be recommended before initiating insulin therapy. However, there are no current guidelines, and this strategy is not yet applicable to some countries, as the corresponding risk would not allow screening colonoscopy to be adopted. There is strong evidence to indicate that DM is a causal agent for CRC development. This conclusion provides new impetus for re-evaluating CRC screening worldwide. PMID- 21274374 TI - Ghrelin and gastrin in advanced gastric cancer before and after gastrectomy. AB - AIM: To investigate plasma ghrelin, gastrin and growth hormone secretagogue receptor (GHS-R) expression in advanced gastric cancer (GC) before and after resection. METHODS: Seventy subjects in whom endoscopy of the upper gastrointestinal tract was performed in the Department of General Surgery at Cracow University during the past decade: (1) 25 patients with GC associated with Helicobacter pylori (H. pylori) infection; (2) 10 patients with GC 4-5 years after (total or subtotal) gastrectomy; (3) 25 healthy H. pylori-negative controls, matched by age and BMI to the above two groups; and (4) 10 GC patients 4-5 years after total gastrectomy. Ghrelin and gastrin plasma concentrations were measured by specific radioimmunoassay under fasting conditions and postprandially at 60 and 90 min after ingestion of a mixed meal. GHS-R expression was examined in biopsy samples from intact healthy mucosa and GC tissue using semi quantitative reverse transcription-polymerase chain reaction. RESULTS: In healthy controls, fasting plasma ghrelin levels were significantly elevated and declined markedly at 60 and 90 min after a mixed meal. The concomitant enhanced ghrelin, GHS-R and gastrin expression in GC tissue over that recorded in intact mucosa, and the marked rise in plasma gastrin in these subjects under fasting conditions indicate the role of these hormonal factors in GC formation. Fasting plasma levels and postprandial response of ghrelin and gastrin appear to be inversely correlated in healthy subjects. Feeding in the controls resulted in a significant fall in plasma ghrelin with a subsequent rise in plasma gastrin, but in H. pylori positive GC patients submitted to total or distal gastrectomy, feeding failed to affect significantly the fall in plasma ghrelin that was recorded in these patients before surgery. Fasting ghrelin concentrations were significantly lower in patients 4-5 years after total gastrectomy compared to those in healthy controls and to these in GC patients before surgery. CONCLUSION: Elevated plasma gastrin and suppression of fasting ghrelin in patients with GC suggest the existence of a close relationship between these two hormones in gastric carcinogenesis. PMID- 21274376 TI - A potential oncogenic role of the commonly observed E2F5 overexpression in hepatocellular carcinoma. AB - AIM: To explore the expression pattern of E2F5 in primary hepatocellular carcinomas (HCCs) and elucidate the roles of E2F5 in hepatocarcinogenesis. METHODS: E2F5 expression was analyzed in 120 primary HCCs and 29 normal liver tissues by immunohistochemistry analysis. E2F5-small interfering RNA was transfected into HepG2, an E2F5-overexpressed HCC cell line. After E2F5 knockdown, cell growth capacity and migrating potential were examined. RESULTS: E2F5 was significantly overexpressed in primary HCCs compared with normal liver tissues (P = 0.008). The E2F5-silenced cells showed significantly reduced proliferation (P = 0.004). On the colony formation and soft agar assays, the number of colonies was significantly reduced in E2F5-silenced cells (P = 0.004 and P = 0.009, respectively). E2F5 knockdown resulted in the accumulation of G0/G1 phase cells and a reduction of S phase cells. The number of migrating/invading cells was also reduced after E2F5 knockdown (P = 0.021). CONCLUSION: To our knowledge, this is the first evidence that E2F5 is commonly overexpressed in primary HCC and that E2F5 knockdown significantly repressed the growth of HCC cells. PMID- 21274375 TI - Bifidobacterium lactis attenuates onset of inflammation in a murine model of colitis. AB - AIM: To assess the anti-inflammatory effect of the probiotic Bifidobacterium lactis (B. lactis) in an adoptive transfer model of colitis. METHODS: Donor and recipient mice received either B. lactis or bacterial culture medium as control (deMan Rogosa Sharpe) in drinking water for one week prior to transfer of a mix of naive and regulatory T cells until sacrifice. RESULTS: All recipient mice developed signs of colonic inflammation, but a significant reduction of weight loss was observed in B. lactis-fed recipient mice compared to control mice. Moreover, a trend toward a diminution of mucosal thickness and attenuated epithelial damage was revealed. Colonic expression of pro-inflammatory and T cell markers was significantly reduced in B. lactis-fed recipient mice compared to controls. Concomitantly, forkhead box protein 3, a marker of regulatory T cells, was significantly up-regulated by B. lactis. CONCLUSION: Daily oral administration of B. lactis was able to reduce inflammatory and T cells mediators and to promote regulatory T cells specific markers in a mouse model of colitis. PMID- 21274377 TI - Blocking NF-kappaB nuclear translocation leads to p53-related autophagy activation and cell apoptosis. AB - AIM: To investigate the anti-tumor effects of nuclear factor-kappaB (NF-kappaB) inhibitor SN50 and related mechanisms of SGC7901 human gastric carcinoma cells. METHODS: MTT assay was used to determine the cytotoxic effects of SN50 in gastric cancer cell line SGC7901. Hoechst 33258 staining was used to detect apoptosis morphological changes after SN50 treatment. Activation of autophagy was monitored with monodansylcadaverine (MDC) staining after SN50 treatment. Immunofluorescence staining was used to detect the expression of light chain 3 (LC3). Mitochondrial membrane potential was measured using the fluorescent probe JC-1. Western blotting analysis were used to determine the expression of proteins involved in apoptosis and autophagy including p53, p53 upregulated modulator of apoptosis (PUMA), damage-regulated autophagy modulator (DRAM), LC3 and Beclin 1. We detected the effects of p53-mediated autophagy activation on the apoptosis of SGC7901 cells with the p53 inhibitor pifithrin-alpha. RESULTS: The viability of SGC7901 cells was inhibited after SN50 treatment. Inductions in the expression of apoptotic protein p53 and PUMA as well as autophagic protein DRAM, LC3 and Beclin 1 were detected with Western blotting analysis. SN50-treated cells exhibited punctuate microtubule-associated protein 1 LC3 in immunoreactivity and MDC labeled vesicles increased after treatment of SN50 by MDC staining. Collapse of mitochondrial membrane potential Deltapsi were detected for 6 to 24 h after SN50 treatment. SN50-induced increases in PUMA, DRAM, LC3 and Beclin 1 and cell death were blocked by the p53 specific inhibitor pifithrin-alpha. CONCLUSION: The anti tumor activity of NF-kappaB inhibitors is associated with p53-mediated activation of autophagy. PMID- 21274378 TI - Association between EGF +61A/G polymorphism and gastric cancer in Caucasians. AB - AIM: To investigate the association between epidermal growth factor (EGF) +61A/G polymorphism and susceptibility to gastric cancer, through a cross-sectional study. METHODS: Polymerase chain reaction restriction fragment length polymorphism analyses were used to genotype EGF +61 in 207 patients with gastric lesions (162 patients with gastric adenocarcinomas, 45 with atrophy or intestinal metaplasia) and 984 controls. All subjects were Caucasian. RESULTS: Genotype distribution was 23.5% for GG and 76.5% for GA/AA in the control group, 18.4% for GG and 68.6% for GA/AA in the entire group with gastric lesions and 17.9% for GG and 82.1% for GA/AA in the group with gastric adenocarcinoma. No statistically significant associations were found between EGF +61 variants and risk for developing gastric cancer [odds ratios (OR) = 1.41, 95% confidence intervals (CI): 0.90-2.21, P = 0.116]. However, the stratification of individuals by gender revealed that males carrying A alleles (EGF +61A/G or AA) had an increased risk for developing gastric cancer as compared to GG homozygous males (OR = 1.55, 95% CI: 1.05-2.28, P = 0.021). CONCLUSION: In summary, we found that males who were A carriers for EGF +61 had an increased risk for developing gastric cancer. This result may be explained by the suggestion that women secrete less gastric acid than men. PMID- 21274379 TI - Long-term outcome of chronic hepatitis C patients with sustained virological response to peginterferon plus ribavirin. AB - AIM: To assess the clinical, biochemical and virological long-term outcome in chronic hepatitis C (CHC) patients with a sustained virological response (SVR) after peginterferon (PEG-IFN) plus ribavirin combination therapy. METHODS: One hundred and fifty three patients with a SVR after treatment with PEG-IFN plus ribavirin were included in a 5-year follow-up study in a single Spanish center, based on standard clinical practice. Clinical anamnesis, biochemical analysis, hepatitis C virus RNA and alpha-fetoprotein measurement, ultrasonography and transient elastography were performed annually. RESULTS: The mean follow-up period of the 153 patients was 76 +/- 13 mo after they obtained a SVR. Five patients (3.26%) presented with cirrhosis before treatment and 116 (75.8%) had genotype 1. No patient showed evidence of hepatic decompensation. One patient (0.65%) developed a hepatocellular carcinoma at month 30 after achieving SVR. There were no virological relapses during this follow-up period. Persistently elevated alanine aminotransferase was found in only one patient (0.65%). At the end of the 5-year follow-up, the mean value of transient elastography was 7 +/- 4.3 kPa (F1). There were no deaths and no other tumors. CONCLUSION: The long-term outcome of 153 CHC patients with SVR to PEG-IFN plus ribavirin was good. No evidence of a virological relapse was seen. One patient (0.65%) developed a hepatocellular carcinoma. PMID- 21274380 TI - EUS-guided drainage is more successful in pancreatic pseudocysts compared with abscesses. AB - AIM: To compare the results for endoscopic ultrasound (EUS)-guided drainage of clear fluid pancreatic pseudocysts with the results for abscess drainage. METHODS: All patients referred for endoscopic drainage of a fluid collection were prospectively included. The outcome was recorded. RESULTS: Altogether 26 pseudocysts or abscesses were treated in 25 (6 female) patients. One endoscopist performed the procedures. Non-infected pseudocysts were present in 15 patients and 10 patients had infected fluid collections. The cyst size ranged between 28 cm * 13 cm and 5 cm * 5 cm. The EUS drainage was successful in 94% of the pseudocysts and in 80% of the abscesses (P = 0.04). The complication rate in pseudocysts was 6% and in abscesses was 30% (P = 0.02). Recurrence of a pseudocyst occurred in one patient (4%) after 6 mo; the patient was successfully retreated. CONCLUSION: EUS-guided drainage of pseudocysts is associated with a higher success rate and a lower complication rate compared with abscess drainage. PMID- 21274381 TI - Evaluation of Cladribine treatment in refractory celiac disease type II. AB - AIM: To evaluate cladribine [2-chlorodeoxyadenosine (2-CdA)] therapy in refractory celiac disease (RCD) II. METHODS: An open-label cohort-study of RCD II patients treated with 2-CdA was performed between 2000 and 2010. Survival rate, enteropathy associated T-cell lymphoma (EATL) occurrence, clinical course, and histological and immunological response rates were evaluated. RESULTS: Overall, 32 patients were included with a median follow-up of 31 mo. Eighteen patients responded well to 2-CdA. Patients responsive to 2-CdA had a statistically significant increased survival compared to those who were unresponsive. The overall 3- and 5-year survival was 83% in the responder and 63% and 22% in the non-responder group, respectively. The overall 2-year clinical, histological and immunological response rates were 81%, 47% and 41%, respectively. Progression into EATL was reported in 16%, all of these patients died. CONCLUSION: Treatment of RCD II with 2-CdA holds promise, showing excellent clinical and histological response rates, and probably less frequent transition into EATL. PMID- 21274382 TI - Proximal and distal esophageal sensitivity is decreased in patients with Barrett's esophagus. AB - AIM: To investigate sensations to multimodal pain stimulation in the metaplastic and normal parts of the esophagus in patients with Barrett's esophagus (BE). METHODS: Fifteen patients with BE and 15 age-matched healthy volunteers were subjected to mechanical, thermal and electrical pain stimuli of the esophagus. Both the metaplastic part and the normal part (4 and 14 cm, respectively, above the esophago-gastric junction) were examined. At sensory thresholds the stimulation intensity, referred pain areas, and evoked brain potentials were recorded. RESULTS: Patients were hyposensitive to heat stimulation both in the metaplastic part [median stimulation time to reach the pain detection threshold: 15 (12-34) s vs 14 (6-23) s in controls; F = 4.5, P = 0.04] and the normal part of the esophagus [median 17 (6-32) s vs 13 (8-20) s in controls; F = 6.2, P = 0.02]. Furthermore, patients were hyposensitive in the metaplastic part of the esophagus to mechanical distension [median volume at moderate pain: 50 (20-50) mL vs 33 (13-50) mL in controls; F = 5.7, P = 0.02]. No indication of central nervous system abnormalities was present, as responses were comparable between groups to electrical pain stimuli in the metaplastic part [median current evoking moderate pain: 13 (6-26) mA vs 12 (9-24) mA in controls; F = 0.1, P = 0.7], and in the normal part of the esophagus [median current evoking moderate pain: 9 (6 16) mA, vs 11 (5-11) mA in controls; F = 3.4, P = 0.07]. Furthermore, no differences were seen for the referred pain areas (P-values all > 0.3) or latencies and amplitudes for the evoked brain potentials (P-values all > 0.1). CONCLUSION: Patients with BE are hyposensitive both in the metaplastic and normal part of esophagus likely as a result of abnormalities affecting peripheral nerve pathways. PMID- 21274383 TI - T2* magnetic resonance imaging of the liver in thalassemic patients in Iran. AB - AIM: To investigate the accuracy of T2*-weighted magnetic resonance imaging (MRI T2*) in the evaluation of iron overload in beta-thalassemia major patients. METHODS: In this cross-sectional study, 210 patients with beta-thalassemia major having regular blood transfusions were consecutively enrolled. Serum ferritin levels were measured, and all patients underwent MRI T2* of the liver. Liver biopsy was performed in 53 patients at an interval of no longer than 3 mo after the MRI T2* in each patient. The amount of iron was assessed in both MRI T2* and liver biopsy specimens of each patient. RESULTS: Patients' ages ranged from 8 to 54 years with a mean of 24.59 +/- 8.5 years. Mean serum ferritin level was 1906 +/- 1644 ng/mL. Liver biopsy showed a moderate negative correlation with liver MRI T2* (r = -0.573, P = 0.000) and a low positive correlation with ferritin level (r = 0.350, P = 0.001). Serum ferritin levels showed a moderate negative correlation with liver MRI T2* values (r = -0.586, P = 0.000). CONCLUSION: Our study suggests that MRI T2* is a non-invasive, safe and reliable method for detecting iron load in patients with iron overload. PMID- 21274384 TI - Silence of HIN-1 expression through methylation of its gene promoter in gastric cancer. AB - AIM: To clarify the role of high in normal-1 (HIN-1) gene promoter methylation during gastric cancer development. METHODS: Gastric cancer cell lines and tissue specimens were analyzed for expression of HIN-1 mRNA and protein using the semi quantitative reverse transcription polymerase chain reaction and immunohistochemistry. The methylation of the HIN-1 gene promoter was detected in gastric carcinoma cells and tissues using methylation-specific polymerase chain reaction. The 3-(4,5-dimethylthiazol-2yl)-5-(3-carboxymethoxyphenyl)-2-(4 sulfophenyl)-2H-tetrazolium cell viability assay and flow cytometry were used to assess the changes in behaviors of gastric cancer cells with or without 5-aza-2' deoxycytidine treatment. RESULTS: HIN-1 was not expressed in 4 of 5 gastric cancer cell lines. The demethylation reagent 5-aza-2'-deoxycytidine was able to induce or upregulate HIN-1 expression in gastric cancer cell lines, which is associated with reduction of tumor cell viability. Furthermore, methylation of the HIN-1 gene promoter was shown in 57.8% (26/45) of the primary gastric cancer and 42.1% (17/38) of adjacent tissue samples, but was not shown in normal gastric mucosa (0/10). From the clinicopathological data of the patients, methylation of the HIN-1 gene promoter was found to be associated with tumor differentiation (P = 0.000). CONCLUSION: High methylation of HIN-1 gene promoter results in silence of HIN-1 expression in gastric cancer. 5-aza-2'-deoxycytidine reverses HIN-1 methylation and reduces viability of gastric cancer cells. PMID- 21274385 TI - Anorectal malignant melanomas: retrospective experience with surgical management. AB - AIM: To present the experience and outcomes of the surgical treatment for the patients with anorectal melanoma from the Cancer Hospital, Chinese Academy of Medical Sciences. METHODS: Medical records of the diagnosis, surgery, and follow up of 56 patients with anorectal melanoma who underwent surgery between 1975 and 2008 were retrospectively reviewed. The factors predictive for the survival rate of these patients were identified using multivariate analysis. RESULTS: The 5 year survival rate of the 56 patients with anorectal melanoma was 20%, 36 patients underwent abdominoperineal resection (APR) and 20 patients underwent wide local excision (WLE). The rates of local recurrence of the APR and WLE groups were 16.13% (5/36) and 68.75% (13/20), (P = 0.001), and the median survival time was 22 mo and 21 mo, respectively (P = 0.481). Univariate survival analysis demonstrated that the number of tumor and the depth of invasion had significant effects on the survival (P < 0.05). Multivariate analysis showed that the number of tumor [P = 0.017, 95% confidence interval (CI) = 1.273-11.075] and the depth of invasion (P = 0.015, 95% CI = 1.249-7.591) were independent prognostic factors influencing the survival rate. CONCLUSION: Complete or R0 resection is the first choice of treatment for anorectal melanoma, prognosis is poor regardless of surgical approach, and early diagnosis is the key to improved survival rate for patients with anorectal melanoma. PMID- 21274386 TI - Isolated pancreatic granulocytic sarcoma: a case report and review of the literature. AB - Granulocytic sarcoma (GS) is an extramedullary tumor mass consisting of immature myeloid cells. Isolated pancreatic granulocyte sarcoma is extremely rare. We report a very unusual pancreatic granulocytic sarcoma in a patient without acute myeloid leukemia. The patient presented with acute epigastric pain because of splenic infarction due to a mass consisting of myeloblasts in the pancreatic tail. The patients underwent splenectomy and distal pancreatectomy. Pathology and immunohistochemistry suggested a GS. Despite local surgery, an isolated tumor recurred 2 mo after operation and the patient died 3 mo after removal of the tumor. Only 7 reported cases of pancreatic GS were identified in the literature and the mass was located in the pancreatic head. This is the first report of GS in the pancreatic tail with splenic infarction. PMID- 21274387 TI - Pernicious anemia: what are the actual diagnosis criteria? AB - A gastric intrinsic factor output under 200 U/h after pentagastrin stimulation (N > 2000 U/h) is specific for pernicious anemia. The other findings are either variable or non specific. Serum intrinsic factor antibodies, considered as specific in general practice, are present only in half of the patients with pernicious anemia. In their absence, since the disappearance of the Schilling tests, the gastric tubage currently used for the study of gastric acid secretion, is obligatory for the simultaneous study of intrinsic factor output. This study is important to eliminate another disease much more frequent than pernicious anemia, the protein bound to cobalamin malabsorption was observed in achlorhydric simple atrophic gastritis in the presence of intrinsic factor secretion. PMID- 21274388 TI - Meow meow or miaow miaow: a new drug of concern. PMID- 21274389 TI - Medical disability and pain medication prescription among internal medicine outpatients. PMID- 21274390 TI - A review of new atypical antipsychotic launches in the United States. AB - In this article we investigate the post-launch retail prescription trends of asenapine (Saphris((r)), Merck and Co.) and iloperidone (Fanapt((r)), Vanda Pharmaceuticals Inc./Novartis), two new atypical antipsychotics to launch in the United States market in October 2009 and January 2010, respectively. In the first 12 months following the asenapine launch, and in the nine months since the iloperidone launch, asenapine and iloperidone have secured 0.22 and 0.10 percent of the total prescription market; however, both products nearly double those respective shares when total prescriptions are isolated to new patient prescriptions (0.44% for asenapine and 0.17% for iloperidone). Since launch, asenapine has shown stronger signs of growth, largely attributed to its approval in multiple indications as compared to iloperidone's single indication. PMID- 21274391 TI - Psychiatric disorders: a global look at facts and figures. AB - According to data from Western countries, psychiatric disorders are relatively prevalent. For example, in the United States general population, data from the National Comorbidity Survey Replication study indicate that about one-quarter of individuals experience a psychiatric disorder in a given year, with lifetime rates at about 50 percent. For both prevalence designations, anxiety disorders are most common. According to data from the European Study of the Epidemiology of Mental Disorders, the 12-month and lifetime-prevalence rates for psychiatric disorders among European general populations are 11.5 and 25.9 percent, respectively, with mood and anxiety disorders evidencing approximately equal rates. As expected, in primary care settings, the prevalence of psychiatric disorders in the United States and Europe is high, with point-prevalence rates varying, but affecting approximately 25 to 30 percent of patients. In primary care settings, the most common psychiatric diagnoses are mood and anxiety disorders as well as somatoform disorders. While no global summary of cost of care is available, the high prevalence rates of psychiatric disorders correspond with high expenditures for mental healthcare, as evidenced by a number of sources. Given these latter findings, prevention becomes all the more relevant in terms of cost management. PMID- 21274392 TI - The blood brain barrier and the role of ratiometric molecular analysis in schizophrenia. AB - The etiology of schizophrenia and other chronic psychotic disorders is complicated considering the multifactorial contribution of developmental, biological, and environmental factors. The role of the blood brain barrier has not yet been established as part of schizophrenia etiology; however, in previous blood brain barrier articles, we discussed potential consequences of various biological abnormalities due to dysregulation of molecular components, such as cofactors,(1) signaling molecules,(2) enzymes,(3) cytokines,(4) and antibodies.(5) In this review, we will discuss the potential use of peripheral ratiometric molecular analysis relevant to the central nervous system for the evaluation of the development of schizophrenia. PMID- 21274393 TI - Recommendation for DSM-V: A Proposal for Adding Causal Specifiers to Axis I Diagnoses. AB - Causal specifiers are certain and possible causes of mental disorders and can be biological, genetic, environmental, developmental, social, psychodynamic, behavioral, cognitive, or personality characteristics. Depending upon the clinical judgment of the degree of certainty, a causal specifier can be a definite etiopathogenesis or a factor contributing to manifestations of mental disorders. The author recommends adding causal specifiers to Axis I diagnoses in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition to improve communication among clinicians. PMID- 21274394 TI - Neurobehavioral problems associated with phenylketonuria. PMID- 21274395 TI - Controversies in the definition and treatment of idiopathic short stature (ISS). AB - The term idiopathic short stature (ISS) refers to short children with no identifiable disorder of the growth hormone (GH)/insulin like growth factor (IGF) axis and no other endocrine, genetic or organ system disorder. This heterogeneous group of short children without GH deficiency (GHD) includes children with constitutional delay of growth and puberty, familial short stature, or both, as well as those with subtle cartilage and bone dysplasias. In rare cases, ISS is due to IGF molecular abnormalities. In this review we tackle the major challenges in the definition and treatment of ISS. PMID- 21274397 TI - The weight and height percentiles in 6-18 year old children in Kayseri and comparison with Istanbul data. AB - BACKGROUND: One of the mostly used and preferred method in following the growth of children is to plot weight and height values of the children on standard percentile charts. It is essential for each country to use its own populations' updated percentile curves. However, data on the growth of children living in different regions are also needed for comparison with the national standards. METHODS: This study was conducted in Kayseri with a trained team in order to obtain anthropometrical measurements in children and adolescents. Weight and height measurements from 5727 (2785 boys, 2942 girls) healthy school children (aged between 6 to 18 years) from all socioeconomic levels were randomly selected. Smoothed percentile curves were produced by LMS method. RESULTS: Smoothed percentile curves including the percentile values for 3rd, 5th, 10th, 25th, 50th, 75th, 85th, 90th, 95th and 97th and standard deviation scores were calculated for boys and girls. The 3rd, 50th and 97th centiles of weight and height of these children were compared with the respective values of the established national standards obtained from Istanbul children. CONCLUSIONS: This study presents data and smoothed percentile curves for weight and height measurement of healthy central Anatolia children aged 6 to 18 years. Nationwide studies are needed to bring out the regional differences in our country. PMID- 21274396 TI - CYP21A2 gene mutations in congenital adrenal hyperplasia: genotype-phenotype correlation in Turkish children. AB - BACKGROUND: Congenital adrenal hyperplasia (CAH) due 21-hydroxylase deficiency (21-OHD) is a common autosomal recessive disorder. It is caused by defects in the CYP21A2 gene. OBJECTIVE: Our aim was to determine the frequency of common gene mutations and to evaluate genotype-phenotype correlations in Turkish 21-OHD patients. METHODS: Molecular analysis of the CYP21A2 gene was performed for the detection of the eight most common point mutations [p.P30L, IVS2-13C>G (IVS-2), p.I172N, exon 6 mutation cluster (p.I236N, p.V237E, p.M239K), p.V281L, p.Q318X, p.R356W, 8-bp-deletion], of large deletion and conversion by southern blotting, allele specific semi-quantitative PCR/enzyme restriction method and sequencing, in 56 patients with 21-OHD, from 52 families. RESULTS: Disease-causing mutations were identified in 77 out of 91 alleles (84.6%) of the patients. Mutations were found in 34 of 43 alleles (79.1%) in salt wasting (SW; n=26), 32 of 36 alleles (88.8%) in simple virilizing (SV; n=24) and 11 of 12 alleles (91.6%) in non classical (NC; n=6) form of CAH. The most frequent mutations were IVS-2 (22.0%), large conversion (14.3%), p.I172N (9.9%) p.R356W (8.8%), and large deletion (6.6%). In the SW form, the most frequent genotypes were homozygous for IVS-2 (11.5%) and homozygous for large conversion of the gene (11.5%). In the SV form, the most frequent genotype was homozygous for IVS-2 (20%), followed by compound heterozygous for p.I172N/8-bp del (10%). Homozygous for p.V281L (16.7%) was most common in NC. In most cases there was good correlation between genotype and phenotype. In the SW and NC forms, genotypes of all the patients correlated with their phenotypes. CONCLUSIONS: This is the first comprehensive study on the molecular basis of CAH patients in the Turkish population. Based on these results, we propose a modified screening strategy to facilitate molecular testing of CAH patients in our population. PMID- 21274398 TI - Audit of microalbumin excretion in children with type I diabetes. AB - OBJECTIVE: To investigate prevalence, persistence and clinical correlates of increased microalbumin excretion in random urine samples collected in a paediatric diabetes clinic. METHOD: Random urine samples were collected annually in patients >10 years attending the diabetes clinic in the Royal Hospital for Sick Children, Edinburgh. Albumin excretion is expressed as albumin:creatinine ratio (ACR) and classified as normal (10 mg/mmol), or macroalbuminuria (>47 mg/mmol in females, >35 mg/mmol in males). We analyzed retrospectively results on 421 urine samples collected from 217 patients (109 males), of a median age of 12.3 years (94% 10-16 years) over 3 years. For each sample, the corresponding mean HbA1c over the previous year was calculated. RESULTS: Prevalence of micro- and macro-albuminuria in individual samples was 1% and 0.5% respectively. ACR was equivocal in 10.1% and 4.7% in samples from females and males respectively (p=0.03). HbA1c showed borderline significant differences across ACR groups (p=0.06). Equivocal ACR excretion was associated with slightly higher mean HbA1c (9.5+/-1.3%) compared to normal albuminuria (9.0+/-1.1%, p3.5 mg/mmol. The 14-16 years age group patients were most likely to have ACR >3.5 mg/mmol (p=0.05). CONCLUSIONS: Female sex and increasing age, but not HbA1c, were independently associated with increased ACR. A robust mechanism for collection of repeat early morning urine samples from patients with increased ACR in random urine samples, and follow-up of those patients who have persistently high microalbumin excretion are important. It is also important to confirm the usefulness of ACR measurements in random urine samples as a marker of incipent nephropathy. PMID- 21274399 TI - Glucagon-like peptide-1 and-2 levels in children with diabetic ketoacidosis. AB - OBJECTIVE: The aim of this study was to investigate whether insulin deficiency and increased catabolism may have a role in the regulation of plasma glucagon like peptide (GLP)-1 and GLP-2 levels in children with diabetic ketoacidosis (DKA) and whether insulin treatment may affect the levels of these polypeptides. METHODS: Plasma GLP-1 and -2 levels were measured in 24 patients with DKA aged 8 to 14 years before insulin infusion (time 0), when ketonemia and acidosis disappeared (time 1), and when weight gain started (time 2). Eighteen healthy children aged 8 to 14 years constituted the control group. RESULTS: At time 0, mean plasma GLP-1 and GLP-2 levels were significantly elevated in the patients compared with the control group (p<0.05 and p<0.01, respectively). At time 1 when ketonemia and acidosis disappeared, GLP-1 and GLP-2 levels decreased significantly from the initial levels (p<0.05 and p<0.01, respectively). At this time, while GLP-1 level was not different from that of the controls, GLP-2 level was higher than that of the controls (p<0.05). GLP-1 and-2 levels did not show any significant differences between the patients and controls when weight gain started (time 2). CONCLUSION: Our results show that DKA is associated with increased plasma GLP-1 and -2 concentrations. Effective fluid and insulin treatment resulted in a significant decrease in plasma GLP-1 and -2 levels. This may be due to the negative feedback effect of insulin on the production of these polypeptides. PMID- 21274400 TI - A patient with 22q11.2 deletion syndrome: case report. AB - 22q11 deletion is one of the most frequently encountered genetic syndromes. The phenotypic spectrum shows a wide variability. We report a boy who presented at age 11.9 years with seizures due to hypocalcemia as a result of hypoparathyroidism. FISH analysis revealed a heterozygote deletion at 22q11.2. Positive findings for the syndrome were delayed speech development due to velofacial dysfunction, recurrent croup attacks in early childhood due to latent hypocalcemia and mild dysmorphic features. The findings of this patient indicate that 22q11 deletion syndrome may present with a wide spectrum of clinical findings and that this diagnosis needs to be considered even in patients of older ages presenting with hypocalcemia. PMID- 21274401 TI - Interactions between Natural Health Products and Oral Anticoagulants: Spontaneous Reports in the Italian Surveillance System of Natural Health Products. AB - Introduction. The safety of vitamin K antagonists (VKA) use can be compromised by many popular herbal supplements taken by individuals. The literature reports that 30% of warfarin-treated patients self-medicates with herbs. Possible interactions represent an health risk. We aimed to identify all herbs-oral anticoagulants interactions collected in the Italian database of suspected adverse reactions to "natural health" products. Methods. The Italian database of spontaneous reports of suspected adverse reactions to natural products was analyzed to address herb VKAs interactions. Results. From 2002 to 2009, we identified 12 reports with 7 cases of INR reduction in patients treated with warfarin (n = 3) and acenocoumarol (n = 4), and 5 cases of INR increase (all warfarin associated). It was reported 8 different herbal products as possibly interacting. Discussion. Our study confirms the risk of interactions, highlighting the difficulty to characterize them and their mechanisms and, finally, prevent their onset. The reported data underline the urgent need of healthcare providers being aware of the possible interaction between natural products and VKA, also because of the critical clinical conditions affecting patients. This is the first step to have the best approach to understand possible INR alterations linked to herb-VKA interaction and to rightly educate patients in treatment with VKA. PMID- 21274402 TI - Contributions of cytogenetics and molecular cytogenetics to the diagnosis of adipocytic tumors. AB - Over the last 20 years, a number of tumor-specific chromosomal translocations and associated fusion genes have been identified for mesenchymal neoplasms including adipocytic tumors. The addition of molecular cytogenetic techniques, especially fluorescence in situ hybridization (FISH), has further enhanced the sensitivity and accuracy of detecting nonrandom chromosomal translocations and/or other rearrangements in adipocytic tumors. Indeed, most resent molecular cytogenetic analysis has demonstrated a translocation t(11;16)(q13;p13) that produces a C11orf95-MKL2 fusion gene in chondroid lipoma. Additionally, it is well recognized that supernumerary ring and/or giant rod chromosomes are characteristic for atypical lipomatous tumor/well-differentiated liposarcoma and dedifferentiated liposarcoma, and amplification of 12q13-15 involving the MDM2, CDK4, and CPM genes is shown by FISH in these tumors. Moreover, myxoid/round cell liposarcoma is characterized by a translocation t(12;16)(q13;p11) that fuses the DDIT3 and FUS genes. This paper provides an overview of the role of conventional cytogenetics and molecular cytogenetics in the diagnosis of adipocytic tumors. PMID- 21274403 TI - Aortocaval fistula in rat: a unique model of volume-overload congestive heart failure and cardiac hypertrophy. AB - Despite continuous progress in our understanding of the pathogenesis of congestive heart failure (CHF) and its management, mortality remains high. Therefore, development of reliable experimental models of CHF and cardiac hypertrophy is essential to better understand disease progression and allow new therapy development. The aortocaval fistula (ACF) model, first described in dogs almost a century ago, has been adopted in rodents by several groups including ours. Although considered to be a model of high-output heart failure, its long term renal and cardiac manifestations are similar to those seen in patients with low-output CHF. These include Na+-retention, cardiac hypertrophy and increased activity of both vasoconstrictor/antinatriureticneurohormonal systems and compensatory vasodilating/natriuretic systems. Previous data from our group and others suggest that progression of cardiorenal pathophysiology in this model is largely determined by balance between opposing hormonal forces, as reflected in states of CHF decompensation that are characterized by overactivation of vasoconstrictive/Na+-retaining systems. Thus, ACF serves as a simple, cheap, and reproducible platform to investigate the pathogenesis of CHF and to examine efficacy of new therapeutic approaches. Hereby, we will focus on the neurohormonal, renal, and cardiac manifestations of the ACF model in rats, with special emphasis on our own experience. PMID- 21274404 TI - Collagen-based films containing liposome-loaded usnic acid as dressing for dermal burn healing. AB - The aim of this study was assess the effect of collagen-based films containing usnic acid as a wound dressing for dermal burn healing. Second-degree burn wounds were performed in forty-five Wistar rats, assigned into nine groups: COL-animals treated with collagen-based films; PHO-animals treated with collagen films containing empty liposomes; UAL-animals treated with collagen-based films containing usnic acid incorporated into liposomes. After 7, 14, and 21 days the animals were euthanized. On 7th day there was a moderate infiltration of neutrophils, in UAL, distributed throughout the burn wounds, whereas in COL and PHO, the severity of the reaction was slighter and still limited to the margins of the burn wounds. On the 14th day, the inflammatory reaction was less intense in UAL, with remarkable plasma cells infiltration. On the 21st day, there was reduction of the inflammation, which was predominantly composed of plasma cells in all groups, particularly in UAL. The use of the usnic acid provided more rapid substitution of type-III for type-I collagen on the 14th day, and improved the collagenization density on the 21st day. It was concluded that the use of reconstituted bovine type-I collagen-based films containing usnic acid improved burn healing process in rats. PMID- 21274405 TI - Elongator: an ancestral complex driving transcription and migration through protein acetylation. AB - Elongator is an evolutionary highly conserved complex. At least two of its cellular functions rely on the intrinsic lysine acetyl-transferase activity of the elongator complex. Its two known substrates--histone H3 and alpha-tubulin- reflect the different roles of elongator in the cytosol and the nucleus. A picture seems to emerge in which nuclear elongator could regulate the transcriptional elongation of a subset of stress-inducible genes through acetylation of histone H3 in the promoter-distal gene body. In the cytosol, elongator-mediated acetylation of alpha-tubulin contributes to intracellular trafficking and cell migration. Defects in both functions of elongator have been implicated in neurodegenerative disorders. PMID- 21274406 TI - Development and validation of the Arizona Cognitive Test Battery for Down syndrome. AB - Neurocognitive assessment in individuals with intellectual disabilities requires a well-validated test battery. To meet this need, the Arizona Cognitive Test Battery (ACTB) has been developed specifically to assess the cognitive phenotype in Down syndrome (DS). The ACTB includes neuropsychological assessments chosen to 1) assess a range of skills, 2) be non-verbal so as to not confound the neuropsychological assessment with language demands, 3) have distributional properties appropriate for research studies to identify genetic modifiers of variation, 4) show sensitivity to within and between sample differences, 5) have specific correlates with brain function, and 6) be applicable to a wide age range and across contexts. The ACTB includes tests of general cognitive ability and prefrontal, hippocampal and cerebellar function. These tasks were drawn from the Cambridge Neuropsychological Testing Automated Battery (CANTAB) and other established paradigms. Alongside the cognitive testing battery we administered benchmark and parent-report assessments of cognition and behavior. Individuals with DS (n=74, ages 7-38 years) and mental age (MA) matched controls (n=50, ages 3-8 years) were tested across 3 sites. A subsample of these groups were used for between-group comparisons, including 55 individuals with DS and 36 mental age matched controls. The ACTB allows for low floor performance levels and participant loss. Floor effects were greater in younger children. Individuals with DS were impaired on a number ACTB tests in comparison to a MA-matched sample, with some areas of spared ability, particularly on tests requiring extensive motor coordination. Battery measures correlated with parent report of behavior and development. The ACTB provided consistent results across contexts, including home vs. lab visits, cross-site, and among individuals with a wide range of socio-economic backgrounds and differences in ethnicity. The ACTB will be useful in a range of outcome studies, including clinical trials and the identification of important genetic components of cognitive disability. PMID- 21274407 TI - DEPRESSION STIGMA, RACE, AND TREATMENT SEEKING BEHAVIOR AND ATTITUDES. AB - This study examined the relationship between internalized and public stigma on treatment-related attitudes and behaviors in a community sample of 449 African American and white adults aged 18 years and older. Telephone surveys were administered to assess level of depressive symptoms, demographic characteristics, stigma, and treatment-related attitudes and behaviors. Multiple regression analysis indicated that internalized stigma mediated the relationship between public stigma and attitudes toward mental health treatment. Within group analyses indicated that the mediating effect of internalized stigma was significant for whites only. Among African Americans, internalized stigma did not mediate public stigma; it was directly related to attitudes toward mental health treatment. The internalization of stigma is key in the development of negative attitudes toward mental health treatment, and future research should focus on this aspect of stigma in both individual and community-based efforts to reduce stigma. PMID- 21274408 TI - Exercise, sleep quality, and mediators of sleep in breast and prostate cancer patients receiving radiation therapy. AB - Cancer patients often report impaired sleep quality. Impaired sleep quality may be due to increased levels of sleep-mediating cytokines resulting from cancer treatment. Exercise may have a positive influence on sleep-mediating cytokines, such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and soluble tumor necrosis factor-alpha receptor (sTNF-R), which may improve sleep quality. This two-arm pilot study compared the influence of a home-based exercise intervention with standard care/control on sleep quality and mediators of sleep. Breast and prostate cancer patients (n = 38) beginning radiation therapy were randomized to a 4-week exercise program or no exercise arm. Global sleep quality, subjective sleep quality, sleep latency, sleep duration, sleep efficiency, sleep disturbances, use of sleep medication, and daytime dysfunction were assessed with the Pittsburgh Sleep Quality Index. IL-6, TNF-alpha, and sTNF-R were measured before and after intervention. There was a greater improvement in sleep quality in the exercise group from pre- to postintervention, although the difference was not significant. Additionally, there were associations between IL-6 and sleep efficiency and duration, suggesting that regulation of sleep-mediating cytokines by exercise may mediate improvements in sleep-quality components. PMID- 21274410 TI - Unaccusative verb production in agrammatic aphasia: the argument structure complexity hypothesis. AB - This study examined patterns of verb production in narrative samples of eight individuals with agrammatic aphasia and seven education- and age-matched normal subjects. Comprehension and constrained production of two types of intransitive verbs-unaccusatives whose argument structure triggers a complex syntactic derivation and unergatives that are considered syntactically simple- was also tested. Results showed that in narrative tasks a hierarchy of verb production difficulty as seen in previous studies [Aphasiology 11 (1997) 473; Brain and Language 74 (2000) 1] emerged for the aphasic participants, with a preference noted for production of verbs with a fewer number of arguments. Both normal and agrammatic subjects also showed fewer productions of unaccusative intransitive verbs in their narrative samples as compared to other verb types (supporting findings reported by Kegl [Brain and Language 50 (1995) 151]. In contrast to relatively spared comprehension of both unaccusative and unergative intransitives, the aphasic participants showed significantly greater difficulty producing unaccusatives as compared to unergatives in the constrained task. These findings suggest that deficits in accessing verbs for production are influenced by the verb's argument structure entry and led to what is referred to as the 'argument structure complexity hypothesis'. When verbs become more complex in terms of the number of associated arguments or when the argument structure entry of the verb does not directly map to its s-structure representation, production difficulty increases. PMID- 21274411 TI - Selective impairment of morphosyntactic production in a neurological patient. AB - In this paper we describe the impaired morphosyntactic production of a neurological patient (R.B.). The patient's production of almost all freestanding morphological material (e.g. subjects, verbs, and function words) is unimpaired, while production of bound inflectional morphology is impaired. We show that this impairment involves featural information on both verbs and nouns and discuss it in the context of the Distributed Morphology model of morphosyntactic processing. We conclude that her error pattern is consistent with impaired ability to convert featural information to morphological material after sentence formation is complete. PMID- 21274409 TI - Mouse mammary tumor virus molecular biology and oncogenesis. AB - Mouse mammary tumor virus (MMTV), which was discovered as a milk-transmitted, infectious cancer-inducing agent in the 1930s, has been used since that time as an animal model for the study of human breast cancer. Like other complex retroviruses, MMTV encodes a number of accessory proteins that both facilitate infection and affect host immune response. In vivo, the virus predominantly infects lymphocytes and mammary epithelial cells. High level infection of mammary epithelial cells ensures efficient passage of virus to the next generation. It also results in mammary tumor induction, since the MMTV provirus integrates into the mammary epithelial cell genome during viral replication and activates cellular oncogene expression. Thus, mammary tumor induction is a by-product of the infection cycle. A number of important oncogenes have been discovered by carrying out MMTV integration site analysis, some of which may play a role in human breast cancer. PMID- 21274412 TI - Semantic anomaly judgement in individuals with probable Alzheimer's disease. AB - BACKGROUND: Research has shown that individuals with probable Alzheimer's disease (PrAD) show impaired semantic knowledge of nouns. More specifically, while they demonstrate preserved superordinate category information, information regarding specific semantic attributes associated with subordinates appears to be disrupted. Results of some recent studies suggest that PrAD participants may also be impaired in processing semantic information associated with verbs. AIMS: Provided that a parallel exists between PrAD participants' noun and verb impairment, it is plausible that the semantic deficits observed in the breakdown of their noun lexicon may also exist in their knowledge of verb-related information. This experiment examined PrAD participants' knowledge of the semantic restrictions associated with the complements of verbs. METHODS #ENTITYSTARTX00026; PROCEDURES: Fourteen PrAD participants were asked to judge the semantic plausibility of 44 auditorily presented sentences. To examine their knowledge of the selection restriction of verbs, each verb was paired with two plausible complements that fully met the restriction, an implausible complement that violated the specific attributes required but belonged to the correct semantic category, and an implausible complement that violated the semantic category requirement. OUTCOMES #ENTITYSTARTX00026; RESULTS: Results showed that PrAD participants' errors were primarily on anomalous sentences that contained implausible complements that belonged to the correct semantic category. CONCLUSIONS: This finding confirms our hypothesis and suggests that a parallel pattern exists in PrAD participants' breakdown in noun and verb knowledge. PMID- 21274413 TI - Verbs: some properties and their consequences for agrammatic Broca's aphasia. AB - It has repeatedly been shown that agrammatic Broca's aphasics have serious problems with the retrieval of verbs on action naming tests (Miceli, Silveri, Villa & Caramazza, 1984; Kohn, Lorch & Pearson, 1989; Basso, Razzano, Faglioni & Zanobio, 1990; Jonkers, 1998; Kim & Thompson, 2000). Less attention has been paid to the production of verbs at the sentence level (but see Miceli, Mazzuchi, Menn & Goodglass, 1983; Thompson, Shapiro, Li & Schendel, 1995; Thompson, Lange, Schneider & Shapiro, 1997; Bastiaanse & Van Zonneveld, 1998; Bastiaanse, Rispens & Van Zonneveld, 2000; Friedmann, 2000), although it has been mentioned that in agrammatic spontaneous speech verbs are lacking (Saffran, Berndt & Schwartz, 1989; Thompson et al., 1995, but see Bastiaanse & Jonkers, 1998).In this paper, three cross-linguistic studies are discussed to show that these problems with verbs have consequences for other grammatical morphemes and structures that have been mentioned to be impaired in agrammatic speech and that these consequences are different per language, depending on linguistic characteristics. The first study focuses on finiteness and compares the production of finite verbs in matrix and embedded clauses in Dutch and English, showing that a linguistic rule in Dutch (Verb Second), which does not exist in English, can explain the different performance of Dutch and English agrammatic Broca's aphasics. The second study focuses on determiners and (finite) verbs in German and shows that poor determiner production is directly related to poor verb production. The last study demonstrates that the ability to construct negative sentences is dependent on the language specific relation between verb movement and negation: Dutch and Norwegian agrammatics perform equally well on affirmative and negative sentences, whereas English and Spanish agrammatics are more impaired on negative sentences.Overall, these studies show that the problems agrammatics encounter with verbs and their properties have a spin-off on the production of other word classes and that the characterization 'problems with grammatical morphemes' is too general for telegraphic speech. PMID- 21274414 TI - Neutron reflectometry of supported hybrid bilayers with inserted peptide. AB - The insertion of a synthetic amphiphilic, alpha-helical peptide into a supported hybrid bilayer membrane (HBM) was studied by neutron reflectometry to elucidate the resulting nanostructure. The HBM consisted of a self-assembled monolayer of perdeuterated octadecanethiol on gold and an overlying leaflet of acyl-deuterated phosphatidylcholine (d-DMPC). Using contrast variation, several reflectivity spectra were recorded for each step of film fabrication, and simultaneously modeled. This analysis indicated that peptide insertion into the DMPC lipid leaflet is the likeliest mode of incorporation. PMID- 21274415 TI - It Takes a Village to Deliver and Test Child and Family-Focused Services. AB - OBJECTIVES: The purpose of this article is to highlight the benefits of collaboration in child focused mental health services research. METHOD: Three unique research projects are described. These projects address the mental health needs of vulnerable, urban, minority children and their families. In each one, service delivery was codesigned, interventions were co-delivered and a team of stakeholders collaboratively tested the impact of each one. RESULTS: The results indicate that the three interventions designed, delivered, and tested are associated with reductions in youth mental health symptoms. CONCLUSION: These interventions are feasible alternatives to traditional individualized outpatient treatment. PMID- 21274416 TI - Soluble Neuregulin and Schwann Cell Myelination: a Therapeutic Potential for Improving Remyelination of Adult Axons. AB - Myelination in the peripheral nervous system (PNS) is induced by close contact signaling between axons and Schwann cells. Previous studies have identified membrane-bound neuregulin-1 (Nrg1) type III, expressed on the axons, as the key instructive signal that regulates Schwann cell myelination. In our recent study, we show that recombinant soluble Nrg1 elicits a similar pro-myelinating effect on Schwann cells, albeit in a dosage-dependent manner: Nrg1 promotes myelination at low concentrations but inhibits it at high concentrations. The inhibitory effect of Nrg1 is mediated through its activation of the Ras/Raf/Erk pathway in Schwann cells, and inhibition of the pathway using a pharmacologic inhibitor restores myelination. We also show that soluble Nrg1 enhances myelination on axons that do not express sufficient amount of Nrg1 type III needed for robust myelination. These findings are significant as they suggest that combined therapies aimed at enhancing Nrg1 signaling and blocking the Ras/Raf/Erk activation may be an effective strategy for improving remyelination on adult axons, which, as shown in our recent data, express low levels of Nrg1 type III. In this report we provide an overview of our recent findings and discuss the therapeutic potential of soluble Nrg1. PMID- 21274417 TI - mTOR Signaling and Entrainment of the Mammalian Circadian Clock. AB - The biochemistry, physiology and behavior of nearly all organisms are influenced by an inherent circadian (24 hr) clock timing mechanism. For mammals, the linchpin of this biological timing process is located in the suprachiasmatic nuclei (SCN) of the hypothalamus. One key feature of the SCN clock is that it is tightly entrained to lighting cues, thus ensuring that the clock is synchronized to the ever-changing seasonal light cycle. Within the field of circadian biology, there has been intense interest in understanding the intracellular signaling events that drive this process. To this end, our recent studies have revealed a role for an evolutionarily conserved translational control kinase, the mammalian target of rapamycin (mTOR), in the SCN clock entrainment process. Here we provide an overview of mechanisms of inducible mTOR activation in the SCN, and describe the effects of mTOR on clock protein synthesis and behavioral rhythmicity. Given that dysregulation of SCN timing has been associated with an array of clinical conditions (e.g., hypertension, obesity, diabetes, depression), new insights into the molecular mechanisms that regulate clock timing may provide new therapeutic treatments for circadian rhythm-associated disorders. PMID- 21274418 TI - Intracellular Distribution-based Anticancer Drug Targeting: Exploiting a Lysosomal Acidification Defect Associated with Cancer Cells. AB - The therapeutic usefulness of anticancer agents relies on their ability to exert maximal toxicity to cancer cells and minimal toxicity to normal cells. The difference between these two parameters defines the therapeutic index of the agent. Towards this end, much research has focused on the design of anticancer agents that have optimized potency against a variety of cancer cell types; however, much less effort is spent on the design of drugs that are minimally toxic to normal cells. We have previously described a concept for a novel drug delivery platform that relies on the propensity of drugs with optimal physicochemical properties to distribute differently in normal versus cancer cells due to differences in intracellular pH gradients. Specifically, we demonstrated in vitro that certain weakly basic anticancer agents had the propensity to distribute to intracellular locations in normal cells that prevent interaction with the drug target, and to intracellular locations in cancer cells that promote drug-target interactions. We refer to this concept broadly as intracellular distribution-based drug targeting. Here we will discuss current in vivo work from our laboratory that examined the role of lysosome pH on the intracellular distribution and toxicity of inhibitors of the Hsp90 molecular chaperone in mice. PMID- 21274419 TI - Fibroblast Growth Factor 2 Mediates Isoproterenol-induced Cardiac Hypertrophy through Activation of the Extracellular Regulated Kinase. AB - Fibroblast growth factor 2 (basic FGF or FGF2) has been shown to affect growth and differentiation in some tissues and to be required for cardiac hypertrophy in vivo. FGF2 has been shown in vitro to signal through the mitogen-activated protein kinase (MAPK) to affect cell survival and growth. To ascertain the role of FGF2 in cardiac hypertrophy, wildtype, Fgf2 knockout, non-transgenic, and FGF2 transgenic mice were treated with isoproterenol or saline via subcutaneous mini osmotic pump implants to induce a hypertrophic response to beta-adrenergic stimulation. Fgf2 knockout hearts are protected from isoproterenol-induced cardiac hypertrophy; whereas, FGF2 transgenic hearts show exacerbated cardiac hypertrophy as assessed by heart weight-to-body weight ratios and myocyte cross sectional area. Echocardiography reveals significantly decreased fractional shortening in isoproterenol-treated FGF2 transgenic mice but not in Fgf2 knockout mice suggesting that FGF2 mediates the maladaptive cardiac dysfunction seen in cardiac hypertrophy induced by isoproterenol. Western blot analysis also reveals alterations in MAPK signaling in Fgf2 knockout and FGF2 transgenic hearts subjected to isoproterenol treatment, suggesting that this cascade mediates FGF2's pro-hypertrophic effect. Pharmacologic inhibition of extracellular signal regulated kinase (ERK) signaling results in an attenuated hypertrophic response in isoproterenol-treated FGF2 transgenic mice, but this response is not seen with p38 mitogen-activated protein kinase (p38) pathway inhibition, suggesting that FGF2 activation of ERK but not p38 is necessary for FGF2's role in the mediation of cardiac hypertrophy. PMID- 21274420 TI - The Evidence Base for Improving School Outcomes by Addressing the Whole Child and by Addressing Skills and Attitudes, Not Just Content. AB - If we want the best academic outcomes, the most efficient and cost-effective route to achieve that is, counterintuitively, not to narrowly focus on academics, but to also address children's social, emotional, and physical development. Similarly, the best and most efficient route to physical health is through also addressing emotional, social, and cognitive wellness. Emotional wellness, similarly, depends critically on social, cognitive, and physical wellness. PMID- 21274421 TI - End-functionalized glycopolymers as mimetics of chondroitin sulfate proteoglycans. AB - Glycosaminoglycans are sulfated polysaccharides that play important roles in fundamental biological processes, such as cell division, viral invasion, cancer and neuroregeneration. The multivalent presentation of multiple glycosaminoglycan chains on proteoglycan scaffolds may profoundly influence their interactions with proteins and subsequent biological activity. However, the importance of this multivalent architecture remains largely unexplored, and few synthetic mimics exist for probing and manipulating glycosaminoglycan activity. Here, we describe a new class of end-functionalized ring-opening metathesis polymerization (ROMP) polymers that mimic the native-like, multivalent architecture found on chondroitin sulfate (CS) proteoglycans. We demonstrate that these glycopolymers can be readily integrated with microarray and surface plasmon resonance technology platforms, where they retain the ability to interact selectively with proteins. ROMP-based glycopolymers are part of a growing arsenal of chemical tools for probing the functions of glycosaminoglycans and for studying their interactions with proteins. PMID- 21274422 TI - Sustained Release of a Monoclonal Antibody from Electrochemically Prepared Mesoporous Silicon Oxide. AB - Nanostructured mesoporous silica (SiO(2)) films are used to load and release the monoclonal antibody bevacizumab (Avastin) in vitro. A biocompatible and biodegradable form of mesoporous SiO(2) is prepared by electrochemical etching of single crystalline Si, followed by thermal oxidation in air at 800 degrees C. Porous SiO(2) exhibits a negative surface charge at physiological pH (7.4), allowing it to spontaneously adsorb the positively charged antibody from an aqueous phosphate buffered saline solution. This electrostatic adsorption allows bevacizumab to be concentrated by >100* (300 mg bevacziumab per gram of porous SiO(2) when loaded from a 1 mg mL(-1) solution of bevacziumab). Drug loading is monitored by optical interferometric measurements of the thin porous film. A two component Bruggeman effective medium model is employed to calculate percent porosity and film thickness, and is further used to determine the extent of drug loading into the porous SiO(2) film. In vitro drug release profiles are characterized by an enzyme-linked immunosorbent assay (ELISA), which confirms that the antibody is released in its active, VEGF-binding form. The nanostructured delivery system described here provides a sustained release of the monoclonal antibody where approximately 98% of drug is released over a period of one month. PMID- 21274423 TI - Adaptive Hotelling Discriminant Functions. AB - Any observer performing a detection task on an image produces a single number that represents the observer's confidence that a signal (e.g., a tumor) is present. A linear observer produces this test statistic using a linear template or a linear discriminant. The optimal linear discriminant is well-known to be the Hotelling observer and uses both first- and second-order statistics of the image data. There are many situations where it is advantageous to consider discriminant functions that adapt themselves to some characteristics of the data. In these situations, the linear template is itself a function of the data and, thus, the observer is nonlinear. In this paper, we present an example adaptive Hotelling discriminant and compare the performance of this observer to that of the Hotelling observer and the Bayesian ideal observer. The task is to detect a signal that is imbedded in one of a finite number of possible random backgrounds. Each random background is Gaussian but has different covariance properties. The observer uses the image data to determine which background type is present and then uses the template appropriate for that background. We show that the performance of this particular observer falls between that of Hotelling and ideal observers. PMID- 21274424 TI - Prediction based classification for longitudinal biomarkers. AB - Assessment of circulating CD4 count change over time in HIV-infected subjects on antiretroviral therapy (ART) is a central component of disease monitoring. The increasing number of HIV-infected subjects starting therapy and the limited capacity to support CD4 count testing within resource-limited settings have fueled interest in identifying correlates of CD4 count change such as total lymphocyte count, among others. The application of modeling techniques will be essential to this endeavor due to the typically non-linear CD4 trajectory over time and the multiple input variables necessary for capturing CD4 variability. We propose a prediction based classification approach that involves first stage modeling and subsequent classification based on clinically meaningful thresholds. This approach draws on existing analytical methods described in the receiver operating characteristic curve literature while presenting an extension for handling a continuous outcome. Application of this method to an independent test sample results in greater than 98% positive predictive value for CD4 count change. The prediction algorithm is derived based on a cohort of n = 270 HIV-1 infected individuals from the Royal Free Hospital, London who were followed for up to three years from initiation of ART. A test sample comprised of n = 72 individuals from Philadelphia and followed for a similar length of time is used for validation. Results suggest that this approach may be a useful tool for prioritizing limited laboratory resources for CD4 testing after subjects start antiretroviral therapy. PMID- 21274425 TI - Diabetic Cardiomyopathy: Mechanisms and Therapeutic Targets. AB - The incidence and prevalence of diabetes mellitus are each increasing rapidly in our society. The majority of patients with diabetes succumb ultimately to heart disease, much of which stems from atherosclerotic disease and hypertension. However, cardiomyopathy can develop independent of elevated blood pressure or coronary artery disease, a process termed diabetic cardiomyopathy. This disorder is a complex diabetes-associated process characterized by significant changes in the physiology, structure, and mechanical function of the heart. Here, we review recently derived insights into mechanisms and molecular events involved in the pathogenesis of diabetic cardiomyopathy. PMID- 21274426 TI - Procalcitonin: a key marker in children with urinary tract infection. AB - Urinary tract infections (UTIs) are the most common source of bacterial infections among young febrile children. Accurate diagnosis of acute pyelonephritis (APN) and vesicoureteral reflux (VUR) is important because of their association with renal scarring, leading in the cases to long-term complications. However, the gold standard examinations for both are either DMSA scan (for APN and scar) or cystography (for VUR) and present limitations (feasibility, pain, cost, etc.). Procalcitonin, a reliable marker of bacterial infections, was demonstrated to be a good predictor of both renal parenchymal involvement in the acute phase and late renal scars. Furthermore, it was also found to be associated with high-grade VUR and was the key tool of a clinical decision rule to predict high-grade VUR in children with a first UTI. Therefore, procalcitonin may certainly be found playing a role in the complex and still debated picture of which examination should be performed after UTI in children. PMID- 21274427 TI - Interferonbeta-1b Induces the Expression of RGS1 a Negative Regulator of G Protein Signaling. AB - We present evidence of a link between interferonbeta-1b (IFN-beta) and G-protein signaling by demonstrating that IFN-beta can induce the expression of the negative regulator of G-protein signaling 1 (RGS1). RGS1 reduces G-protein activation and immune cell migration by interacting with heterotrimeric G proteins and enhancing their intrinsic GTPase activity. In this study, IFN-beta treatment resulted in the induction of RGS1 in peripheral blood mononuclear cells (PBMCs), monocytes, T cells, and B cells. Induction of RGS1 by IFN-beta was concentration dependent and observed at both the RNA and protein level. Other members of the RGS family were not induced by IFN-beta, and induction of RGS1 required the activation of the IFN receptor. In addition, RGS1 induction was observed in PBMCs obtained from IFN-beta-treated multiple sclerosis patients suggesting a possible, as yet unexplored, involvement of G-protein regulation in disease treatment. The upregulation of RGS1 by IFN-beta has not been previously reported. PMID- 21274428 TI - Protein kinase C-regulated abeta production and clearance. AB - Alzheimer's disease (AD) is the most common form of dementia among the elderly population. AD, which is characterized as a disease of cognitive deficits, is mainly associated with an increase of amyloid beta-peptide (Abeta) in the brain. A growing body of recent studies suggests that protein kinase C (PKC) promotes the production of the secretory form of amyloid precursor protein (sAPPalpha) via the activation of alpha-secretase activity, which reduces the accumulation of pathogenic Abeta levels in the brain. Moreover, activation of PKCalpha and mitogen-activated protein kinase (MAPK) is known to increase sAPPalpha. A novel type of PKC, PKCepsilon, activates the Abeta degrading activity of endothelin converting enzyme type 1 (ECE-1), which might be mediated via the MAPK pathway as well. Furthermore, dysregulation of PKC-MAPK signaling is known to increase Abeta levels in the brain, which results in AD phenotypes. Here, we discuss roles of PKC in Abeta production and clearance and its implication in AD. PMID- 21274429 TI - Absorption of nickel, chromium, and iron by the root surface of primary molars covered with stainless steel crowns. AB - Objective. The purpose of this study was to analyze the absorption of metal ions released from stainless steel crowns by root surface of primary molars. Study Design. Laboratory research: The study included 34 primary molars, exfoliated or extracted during routine dental treatment. 17 molars were covered with stainless steel crowns for more than two years and compared to 17 intact primary molars. Chemical content of the mesial or distal root surface, 1 mm apically to the crown or the cemento-enamel junction (CEJ), was analyzed. An energy dispersive X-ray spectrometer (EDS) was used for chemical analysis. Results. Higher amounts of nickel, chromium, and iron (5-6 times) were found in the cementum of molars covered with stainless-steel crowns compared to intact molars. The differences between groups were highly significant (P < .001). Significance. Stainless-steel crowns release nickel, chromium, and iron in oral environment, and the ions are absorbed by the primary molars roots. The additional burden of allergenic metals should be reduced if possible. PMID- 21274430 TI - Role of toll-like receptors and their downstream molecules in the development of nonalcoholic Fatty liver disease. AB - Activation of innate immunity is associated with the development of liver disease, including non-alcoholic fatty liver disease (NAFLD). In the innate immune system, Toll-like receptors (TLRs) are sensors that recognize bacterial and viral components such as lipopolysaccharide, bacterial DNA, and peptidoglycan. Recent data have demonstrated that the liver is exposed to a high load of TLR ligands due to bacterial overgrowth and increased intestinal permeability in NAFLD. Upon stimulation by these TLR ligands, hepatic immune cells produce various mediators that are involved in host defense. On the other hand, these mediators alter lipid metabolism, insulin signaling, and cell survival. Indeed, some TLR-deficient mice demonstrate lesser degrees of NAFLD even though TLR ligands are increased. This paper will highlight the recent progress on the study of TLR signaling and their downstream molecules in the development of NAFLD. PMID- 21274431 TI - Atherosclerosis and thrombosis: insights from large animal models. AB - Atherosclerosis and its thrombotic complications are responsible for remarkably high numbers of deaths. The combination of in vitro, ex vivo, and in vivo experimental approaches has largely contributed to a better understanding of the mechanisms underlying the atherothrombotic process. Indeed, different animal models have been implemented in atherosclerosis and thrombosis research in order to provide new insights into the mechanisms that have already been outlined in isolated cells and protein studies. Yet, although no model completely mimics the human pathology, large animal models have demonstrated better suitability for translation to humans. Indeed, direct translation from mice to humans should be taken with caution because of the well-reported species-related differences. This paper provides an overview of the available atherothrombotic-like animal models, with a particular focus on large animal models of thrombosis and atherosclerosis, and examines their applicability for translational research purposes as well as highlights species-related differences with humans. PMID- 21274432 TI - Biomethane production as an alternative bioenergy source from codigesters treating municipal sludge and organic fraction of municipal solid wastes. AB - Energy recovery potential of a mesophilic co-digester treating OFMSW and primary sludge at an integrated biomethanization plant was investigated based on feasibility study results. Since landfilling is still the main solid waste disposal method in Turkey, land scarcity will become one of the most important obstacles. Restrictions for biodegradable waste disposal to sanitary landfills in EU Landfill Directive and uncontrolled long-term contamination with gas emissions and leachate necessitate alternative management strategies due to rapid increase in MSW production. Moreover, since energy contribution from renewable resources will be required more in the future with increasing oil prices and dwindling supplies of conventional energy sources, the significance of biogas as a renewable fuel has been increased in the last decade. Results indicated that almost 93% of annual total cost can be recovered if 100% renewable energy subsidy is implemented. Besides, considering the potential revenue when replacing transport fuels, about 26 heavy good vehicles or 549 cars may be powered per year by the biogas produced from the proposed biomethanization plant (PE = 100,000; X(PS) = 61 g TS/PE.day; X(SS-OFMSW) = 50 g TS/PE.day). PMID- 21274434 TI - Resistant hypertension and obstructive sleep apnea: the sparring partners. AB - Enhanced target organ damage and cardiovascular morbidity represent common issues observed in both resistant hypertension and obstructive sleep apnea. Common pathophysiological features and risk factors justify their coexistence, especially in individuals with increased upper-body adiposity. Impaired sodium handling, sympathetic activation, accelerated arterial stiffening, and impaired cardiorenal hemodynamics contribute to drug-resistant hypertension development in obstructive sleep apnea. Effective CPAP therapy qualifies as an effective "add on" to the underlying antihypertensive pharmacological therapy, and emerging evidence underlines the favorable effect of mineralocorticoid antagonists on both resistant hypertension and obstructive sleep apnea treatment. PMID- 21274433 TI - The role of Syk/CARD9-coupled C-type lectin receptors in immunity to Mycobacterium tuberculosis infections. AB - There is increasing interest in understanding the mechanisms underlying the interactions that occur between Mycobacterium tuberculosis and host innate immune cells. These cells express pattern recognition receptors (PRRs) which recognise mycobacterial pathogen-associated molecular patterns (PAMPs) and which can influence the host immune response to the infection. Although many of the PRRs appear to be redundant in the control of M. tuberculosis infection in vivo, recent discoveries have revealed a key, nonredundant, role of the Syk/CARD9 signalling pathway in antimycobacterial immunity. Here we review these discoveries, as well as recent data investigating the role of the Syk/CARD9 coupled PRRs that have been implicated in mycobacterial recognition, including Dectin-1 and Mincle. PMID- 21274435 TI - Surgical Reimplantation for the Correction of Vesicoureteral Reflux following Failed Endoscopic Injection. AB - Purpose. In recent years, endoscopic injection became the procedure of choice for the correction of vesicoureteral reflux in the majority of the centers. Unfortunately, endoscopic treatment is not always successful and sometimes requires more than one trial to achieve similar results to that of an open reimplantation surgery. Our aim of this study is to evaluate the feasibility and success rate of open ureteral reimplantation following failed endoscopic procedure. Patients and Methods. During 2004-2010, we evaluated 16 patients with persistent vesicoureteral reflux (grades II-IV) following failed endoscopic treatment. All patients underwent open ureteral reimplantation. All patients were followed with an ultrasound 6 weeks following surgery and every 6 months thereafter for an average of 22 months. Voiding cystography was performed at 3 months after surgery. Results. During unilateral open ureteral reimplantation, the implanted deposit from previous procedures was either excised, drained, or incorporated into the neotunnel with the ureter. Vesicoureteral reflux was resolved in all patients with 100% success rate. No new hydronephrosis or signs of obstruction developed in any of the patients. qDMSA renal scan was available in 8 patients showing improvement of function in 5 and stable function in 3, and no new scars were identified. Conclusions. Open ureteral reimplantation is an excellent choice for the correction of failed endoscopic treatment in children with vesicoureteral reflux. PMID- 21274436 TI - Regulation of Cisplatin cytotoxicity by cu influx transporters. AB - Platinum drugs are an important class of cancer chemotherapeutics. However, the use of these drugs is limited by the development of resistance during treatment with decreased accumulation being a common mechanism. Both Cu transporters CTR1 and CTR2 influence the uptake and cytotoxicity of cisplatin. Although it is structurally similar to CTR1, CTR2 functions in a manner opposite to that of CTR1 with respect to Pt drug uptake. Whereas knockout of CTR1 reduces Pt drug uptake, knockdown of CTR2 enhances cisplatin uptake and cytotoxicity. CTR2 is subject to transcriptional and posttranscriptional regulation by both Cu and cisplatin; this regulation is partly dependent on the Cu chaperone ATOX1. Insight into the mechanisms by which CTR1 and CTR2 regulate sensitivity to the Pt-containing drugs has served as the basis for novel pharmacologic strategies for improving their efficacy. PMID- 21274437 TI - Nonsurgical treatment options for Basal cell carcinoma. AB - Basal cell carcinoma (BCC) remains the most common form of nonmelanoma skin cancer (NMSC) in Caucasians, with perhaps as many as 2 million new cases expected to occur in the United States in 2010. Many treatment options, including surgical interventions and nonsurgical alternatives, have been utilized to treat BCC. In this paper, two non-surgical options, imiquimod therapy and photodynamic therapy (PDT), will be discussed. Both modalities have demonstrated acceptable disease control rates, cosmetically superior outcomes, and short-term cost-effectiveness. Further studies evaluating long-term cure rates and long-term cost effectiveness of imiquimod therapy and PDT are needed. PMID- 21274439 TI - Using bacterial artificial chromosomes in leukemia research: the experience at the university cytogenetics laboratory in Brest, France. AB - The development of the bacterial artificial chromosome (BAC) system was driven in part by the human genome project in order to construct genomic DNA libraries and physical maps for genomic sequencing. The availability of BAC clones has become a valuable tool for identifying cancer genes. We report here our experience in identifying genes located at breakpoints of chromosomal rearrangements and in defining the size and boundaries of deletions in hematological diseases. The methodology used in our laboratory consists of a three-step approach using conventional cytogenetics followed by FISH with commercial probes, then BAC clones. One limitation to the BAC system is that it can only accommodate inserts of up to 300 kb. As a consequence, analyzing the extent of deletions requires a large amount of material. Array comparative genomic hybridization (array-CGH) using a BAC/PAC system can be an alternative. However, this technique has limitations also, and it cannot be used to identify candidate genes at breakpoints of chromosomal rearrangements such as translocations, insertions, and inversions. PMID- 21274438 TI - The pathological roles of ganglioside metabolism in Alzheimer's disease: effects of gangliosides on neurogenesis. AB - Conversion of the soluble, nontoxic amyloid beta-protein (Abeta) into an aggregated, toxic form rich in beta-sheets is a key step in the onset of Alzheimer's disease (AD). It has been suggested that Abeta induces changes in neuronal membrane fluidity as a result of its interactions with membrane components such as cholesterol, phospholipids, and gangliosides. Gangliosides are known to bind Abeta. A complex of GM1 and Abeta, termed "GAbeta", has been identified in AD brains. Abnormal ganglioside metabolism also may occur in AD brains. We have reported an increase of Chol-1alpha antigens, GQ1balpha and GT1aalpha, in the brain of transgenic mouse AD model. GQ1balpha and GT1aalpha exhibit high affinities to Abetas. The presence of Chol-1alpha gangliosides represents evidence for genesis of cholinergic neurons in AD brains. We evaluated the effects of GM1 and Abeta1-40 on mouse neuroepithelial cells. Treatment of these cells simultaneously with GM1 and Abeta1-40 caused a significant reduction of cell number, suggesting that Abeta1-40 and GM1 cooperatively exert a cytotoxic effect on neuroepithelial cells. An understanding of the mechanism on the interaction of GM1 and Abetas in AD may contribute to the development of new neuroregenerative therapies for this disorder. PMID- 21274441 TI - Comparative analysis on applicability of satellite and meteorological data for prediction of malaria in endemic area in bangladesh. AB - Relationships between yearly malaria incidence and (1) climate data from weather station and (2) satellite-based vegetation health (VH) indices were investigated for prediction of malaria vector activities in Bangladesh. Correlation analysis of percent of malaria cases with Advanced Very High Resolution Radiometer- (AVHRR ) based VH indices represented by the vegetation condition index (VCI-moisture condition) and the temperature condition index (TCI-estimates thermal condition) and with rainfall, relative humidity, and temperature from ground-based meteorological stations. Results show that climate data from weather stations are poorly correlated and are not applicable to estimate prevalence in Bangladesh. The study also has shown that AVHRR-based vegetation health (VH) indices are highly applicable for malaria trend assessment and also for the estimation of the total number of malaria cases in Bangladesh for the period of 1992-2001. PMID- 21274440 TI - Increased nitric oxide and attenuated diastolic blood pressure variability in african americans with mildly impaired renal function. AB - We investigated the relationship between renal function, blood pressure variability (BPV), and nitric oxide (NO) in a group of African Americans with normal or mildly impaired renal function. 24-hour ambulatory blood pressure monitoring was performed, NO measured, and glomerular filtration rate (GFR) calculated in 38 African Americans. Participants were categorized as having normal (GFR > 90 mL/min per 1.73 m(2)) or mildly impaired (GFR 60-89 mL/min per 1.73 m(2)) renal function. Diastolic BPV was significantly lower in the mildly impaired renal function group. Regression analyses revealed a significant positive association between GFR and diastolic BPV for the entire study group. Plasma NO levels were significantly higher in the mildly impaired renal function group and negatively correlated with diastolic BPV. In conclusion, diastolic BPV was reduced in African Americans with mildly impaired renal function, which may be the result of increased NO production. These results conflict with previous findings in diseased and nonblack populations and could provide rationale for studying BPV early in the disease state when BP-buffering mechanisms are still preserved. PMID- 21274442 TI - Large intra-articular anterior cruciate ligament ganglion cyst, presenting with inability to flex the knee. AB - A 41-year-old female presented with a 3-month history of gradually worsening anterior knee pain, swelling and inability to flex the knee. Magnetic resonance imaging (MRI) revealed a large intra-articular cystic swelling anterior to the anterior cruciate ligament (ACL), extending into the Hoffa's infrapatellar fat pad. Following manipulation under anaesthesia and arthroscopic debridement of the cyst, the patient's symptoms were relieved with restoration of normal knee motion. ACL ganglion cysts are uncommon intra-articular pathological entities, which are usually asymptomatic and diagnosed incidentally by MRI. This is the first reported case of an ACL cyst being so large as to cause a mechanical block to knee flexion. PMID- 21274443 TI - Cell adhesion signaling and its impact on tumorigenesis. PMID- 21274444 TI - Successful long-term use of infliximab in refractory pouchitis in an adolescent. AB - Pouchitis is a common complication that develops after an ileal pouch-anal anastomosis after colectomy for ulcerative colitis. In some cases, pouchitis becomes chronic and refractory to conventional therapies including antibiotics, corticosteroids, immunomodulators, probiotics, and anti-inflammatory drugs. We report a case of an adolescent with chronic pouchitis who not only improved with infliximab therapy but remains in long-term remission with maintenance therapy without any adverse effects. Infliximab is a safe and effective therapy for refractory pouchitis and may obviate the need for pouch removal and a permanent ileostomy. PMID- 21274445 TI - Role of vitamin d in the prevention of pancreatic cancer. AB - Pancreatic cancer is a malignancy of poor prognosis which is mostly diagnosed at advanced stages. Current treatment modalities are very limited creating great interest for novel preventive and therapeutic options. Vitamin D seems to have a protective effect against pancreatic cancer by participating in numerous proapoptotic, antiangiogenic, anti-inflammatory, prodifferentiating, and immunomodulating mechanisms. 25-hydroxyvitamin D [25(OH)D] serum concentrations are currently the best indicator of vitamin D status. There are three main sources of vitamin D: sun exposure, diet,and dietary supplements. Sun exposure has been associated with lower incidence of pancreatic cancer in ecological studies. Increased vitamin D levels seem to protect against pancreatic cancer, but caution is needed as excessive dietary intake may have opposite results. Future studies will verify the role of vitamin D in the prevention and therapy of pancreatic cancer and will lead to guidelines on adequate sun exposure and vitamin D dietary intake. PMID- 21274446 TI - Clinical Interaction between Brain and Kidney in Small Vessel Disease. AB - Patients with chronic kidney disease (CKD) are well known to have a higher prevalence of cardiovascular disease from epidemiological studies. Recently, CKD has also been shown to be related to neurological disorders, not only ischemic brain injury but also cognitive impairment. This cerebrorenal connection is considered to involve small vessel disease in both the kidney and brain, based on their hemodynamic similarities. Clinical studies suggest that markers for CKD such as estimated glomerular filtration rate (eGFR), proteinuria, and albuminuria may be helpful to predict brain small vessel disease, white matter lesions (WMLs), silent brain ischemia (SBI), and microhemorrhages. Recently, changes in the vascular system of the brain have been shown to contribute to the onset and progression of cognitive impairment, not only vascular dementia but also Alzheimer's disease. Patients with CKD are also reported to have higher risk of impaired cognitive function in the future compared with non-CKD subjects. These results indicate that CKD markers may be helpful to predict the future risk of neuronal disease. PMID- 21274447 TI - Genetic polymorphisms and posttraumatic complications. AB - Major trauma is the leading cause of death in young adults. Despite advances in prehospital system and treatment in hospital, mortality rates have not improved significantly over the past decades. Victims of severe injuries who survive the initial hours have great risk for additional life-threatening complicaitons, including uncontrollable infection (sepsis) and multiple organ dysfunction syndrome (MODS). Single nucleotide polymorphisms (SNPs) have been shown to affect susceptibility to the course of numerous diseases. Accumulating evidence suggests that genetic backgrounds also play important roles in posttraumatic complications. Genetic polymorphisms may become powerful biomarkers for diagnosis and prognosis of trauma-induced complications. Recent advances in studies on associations between genetic polymorphisms and sepsis or MODS have led to better understanding of posttraumatic complications. Here we summarise recent findings on genetic variations in molecules of the innate immune system and other systems as well as their connection with susceptibility to posttraumatic complications. PMID- 21274448 TI - Guidelines for the Development of Comprehensive Care Centers for Congenital Adrenal Hyperplasia: Guidance from the CARES Foundation Initiative. AB - Patients with rare and complex diseases such as congenital adrenal hyperplasia (CAH) often receive fragmented and inadequate care unless efforts are coordinated among providers. Translating the concepts of the medical home and comprehensive health care for individuals with CAH offers many benefits for the affected individuals and their families. This manuscript represents the recommendations of a 1.5 day meeting held in September 2009 to discuss the ideal goals for comprehensive care centers for newborns, infants, children, adolescents, and adults with CAH. Participants included pediatric endocrinologists, internal medicine and reproductive endocrinologists, pediatric urologists, pediatric surgeons, psychologists, and pediatric endocrine nurse educators. One unique aspect of this meeting was the active participation of individuals personally affected by CAH as patients or parents of patients. Representatives of Health Research and Services Administration (HRSA), New York-Mid-Atlantic Consortium for Genetics and Newborn Screening Services (NYMAC), and National Newborn Screening and Genetics Resource Center (NNSGRC) also participated. Thus, this document should serve as a "roadmap" for the development phases of comprehensive care centers (CCC) for individuals and families affected by CAH. PMID- 21274449 TI - Innate immune effectors in mycobacterial infection. AB - Tuberculosis, which is caused by infection with Mycobacterium tuberculosis (Mtb), remains one of the major bacterial infections worldwide. Host defense against Mtb is mediated by a combination of innate and adaptive immune responses. In the last 15 years, the mechanisms for activation of innate immunity have been elucidated. Toll-like receptors (TLRs) have been revealed to be critical for the recognition of pathogenic microorganisms including mycobacteria. Subsequent studies further revealed that NOD-like receptors and C-type lectin receptors are responsible for the TLR-independent recognition of mycobacteria. Several molecules, such as active vitamin D(3), secretary leukocyte protease inhibitor, and lipocalin 2, all of which are induced by TLR stimulation, have been shown to direct innate immune responses to mycobacteria. In addition, Irgm1-dependent autophagy has recently been demonstrated to eliminate intracellular mycobacteria. Thus, our understanding of the mechanisms for the innate immune response to mycobacteria is developing. PMID- 21274450 TI - Insulin sensitivity, serum lipids, and systemic inflammatory markers in school aged obese and nonobese children. AB - The impact of obesity as a systemic low-grade inflammatory process has only partially been explored. To this effect, 704 community-based school-aged children (354 obese children and 350 age-, gender-, and ethnicity-matched controls) were recruited and underwent assessment of plasma levels of fasting insulin and glucose, lipids, and a variety of proinflammatory mediators that are associated with cardiometabolic dysfunction. Obese children were at higher risk for abnormal HOMA and cholesterol levels. Furthermore, BMI z score, HOMA, and LDL/HDL ratio strongly correlated with levels of certain inflammatory mediators. Taken together, obesity in children is not only associated with insulin resistance and hyperlipidemia, but is accompanied by increased, yet variable, expression of markers of systemic inflammation. Future community-based intervention and phenotype correlational studies on childhood obesity will require inclusion of expanded panels of inflammatory biomarkers to provide a comprehensive assessment of risk on specific obesity-related morbidities. PMID- 21274451 TI - Administration of a decoction of sucrose- and polysaccharide-rich radix astragali (huang qi) ameliorated insulin resistance and Fatty liver but affected Beta-cell function in type 2 diabetic rats. AB - The current investigation attempted to confirm the beneficial actions of a chemically characterized Radix Astragali decoction (AM-W) against type 2 diabetic (T2D) Sprague-Dawley (SD) rats. Using a case/control design, after 2 months of treatment with AM-W (500 mg/kg, daily i.p.) in T2D rats therapeutic outcomes were compared. Sucrose and Astragalus polysaccharides (ASPs) were shown to exist in nearly equal proportions in AM-W. Body weight loss, an improvement in insulin sensitivity, and an attenuation of fatty liver after AM-W administration in T2D rats were evident. Surprisingly, blood sugar, beta-cell function, and glucose tolerance in T2D rats did not improve with AM-W treatment. Further investigation indicated the deleterious effects of the addition of sucrose (100 and 500 MUg/mL) and APSs (500 MUg/mL) on glucose-stimulated insulin secretion and viability, respectively. In conclusion, a proper administration dosage and a reduction in the sucrose content are keys to maximizing the merits of this herb. PMID- 21274452 TI - An emerging pulmonary haemorrhagic syndrome in dogs: similar to the human leptospiral pulmonary haemorrhagic syndrome? AB - Severe pulmonary haemorrhage is a rare necropsy finding in dogs but the leptospiral pulmonary haemorrhagic syndrome (LPHS) is a well recognized disease in humans. Here we report a pulmonary haemorrhagic syndrome in dogs that closely resembles the human disease. All 15 dogs had massive, pulmonary haemorrhage affecting all lung lobes while haemorrhage in other organs was minimal. Histologically, pulmonary lesions were characterized by acute, alveolar haemorrhage without identifiable vascular lesions. Seven dogs had mild alveolar wall necrosis with hyaline membranes and minimal intraalveolar fibrin. In addition, eight dogs had acute renal tubular necrosis. Six dogs had a clinical diagnosis of leptospirosis based on renal and hepatic failure, positive microscopic agglutination test (MAT) and/or positive blood/urine Leptospira specific PCR. Leptospira could not be cultured post mortem from the lungs or kidneys. However, Leptospira-specific PCR was positive in lung, liver or kidneys of three dogs. In summary, a novel pulmonary haemorrhagic syndrome was identified in dogs but the mechanism of the massive pulmonary erythrocyte extravasation remains elusive. The lack of a consistent post mortem identification of Leptospira spp. in dogs with pulmonary haemorrhage raise questions as to whether additional factors besides Leptospira may cause this as yet unrecognized entity in dogs. PMID- 21274453 TI - Basal-like phenotype in a breast carcinoma case series from Sudan: prevalence and clinical/pathological correlations. AB - Basal-like breast cancer, an aggressive subtype associated with high grade, poor prognosis, and younger age, is reported frequently in Africa. We analyzed the expression of the basal cytokeratins (CKs) 5/6 and 17 in a case series from Central Sudan and investigated correlations among basal CK status, ER, PgR, and Her-2/neu, and individual/clinicopathological data. Of 113 primary breast cancers 26 (23%), 38 (34%), and 46 (41%) were, respectively, positive for CK5/6, CK17, and combined basal CKs (CK5/6 and/or CK17). Combined basal CK+ status was associated with higher grade (P < .03) and inversely correlated with ER (P < .002), PgR (P = .004) and combined ER and/or PgR (P < .0002). Two clusters based on all tested markers were generated by hierarchical cluster analysis and k-mean clustering: I: designated "hormone receptors positive/luminal-like" and II: designated "hormone receptors negative", including both basal-like and Her-2/neu+ tumors. The most important factors for dataset variance were ER status, followed by PgR, CK17, and CK5/6 statuses. Overall basal CKs were expressed in a fraction of cases comparable to that reported for East and West African case series. Lack of associations with age and tumor size may represent a special feature of basal like breast cancer in Sudan. PMID- 21274456 TI - Lifestyle practices and cardiovascular disease mortality in the elderly: the leisure world cohort study. AB - Modifiable behavioral risk factors are major contributing causes of death, but whether the effects are maintained in older adults is uncertain. We explored the association of smoking, alcohol consumption, caffeine intake, physical activity, and body mass index on cardiovascular disease (CVD) mortality in 13,296 older adults and calculated risk estimates using Cox regression analysis in four age groups (<70, 70-74, 75-79, and 80+ years). The most important factor was current smoking, which increased risk in all age-sex groups. In women, alcohol consumption (<=3 drinks/day) was related to decreased (15-30%) risk in those <80 years old; in men, 4+ drinks/day was associated with reduced (15-30%) risk. Active 70+ year olds had 20-40% lower risk. Both underweight and obese women were at increased risk. Lifestyle practices impact CVD death rates in older adults, even those aged 80+ years. Not smoking, moderate alcohol consumption, physical activity, and normal weight are important health promoters in our aging population. PMID- 21274455 TI - Effects of tert-butylhydroquinone on intestinal inflammatory response and apoptosis following traumatic brain injury in mice. AB - Traumatic brain injury (TBI) can induce intestinal inflammatory response and mucosal injury. Antioxidant transcription factor nuclear factor erythroid 2 related factor 2 (Nrf2) has been shown in our previous studies to prevent oxidative stress and inflammatory response in gut after TBI. The objective of this study was to test whether tert-butylhydroquinone (tBHQ), an Nrf2 inducer, can protect against TBI-induced intestinal inflammatory response and mucosal injury in mice. Adult male ICR mice were randomly divided into three groups: (1) sham + vehicle group, (2) TBI + vehicle group, and (3) TBI + tBHQ group (n = 12 per group). Closed head injury was adopted using Hall's weight-dropping method. Intestinal mucosa apoptosis and inflammatory-related factors, such as nuclear factor kappa B (NF-kappaB), tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL-1beta), interleukin-6 (IL-6) and intercellular adhesion molecule-1 (ICAM-1), were investigated at 24 h after TBI. As a result, we found that oral treatment with 1% tBHQ prior to TBI for one week markedly decreased NF-kappaB activation, inflammatory cytokines production, and ICAM-1 expression in the gut. Administration of tBHQ also significantly attenuated TBI-induced intestinal mucosal apoptosis. The results of the present study suggest that tBHQ administration could suppress the intestinal inflammation and reduce the mucosal damage following TBI. PMID- 21274454 TI - Animal models of colitis-associated carcinogenesis. AB - Inflammatory bowel disease (IBD) is a group of chronic inflammatory disorders that affect individuals throughout life. Although the etiology and pathogenesis of IBD are largely unknown, studies with animal models of colitis indicate that dysregulation of host/microbial interactions are requisite for the development of IBD. Patients with long-standing IBD have an increased risk for developing colitis-associated cancer (CAC), especially 10 years after the initial diagnosis of colitis, although the absolute number of CAC cases is relatively small. The cancer risk seems to be not directly related to disease activity, but is related to disease duration/extent, complication of primary sclerosing cholangitis, and family history of colon cancer. In particular, high levels and continuous production of inflammatory mediators, including cytokines and chemokines, by colonic epithelial cells (CECs) and immune cells in lamina propria may be strongly associated with the pathogenesis of CAC. In this article, we have summarized animal models of CAC and have reviewed the cellular and molecular mechanisms underlining the development of carcinogenic changes in CECs secondary to the chronic inflammatory conditions in the intestine. It may provide us some clues in developing a new class of therapeutic agents for the treatment of IBD and CAC in the near future. PMID- 21274457 TI - Fibrous tumor of the breast: case report of an underrecognized entity. AB - Fibrous tumor of the breast is an underappreciated, distinctive, benign, nonrecurrent lesion of the breast. The cytological features of this condition are not well characterized. We present a case report of a 30-year-old female presenting with a hard mass in her right breast. Fine needle aspiration showed smears of low cellularity showing a few clusters and sheets of mostly uniform benign epithelial cells, some of which were lined by myoepithelial cells. Scattered bipolar bare nuclei or stromal fragments were not seen. Excision with subsequent histopathological examination revealed a well-circumscribed, heavily collagenous tumor with atrophy and replacement of the epithelial and ductal elements of the breast, and diagnosed as fibrous tumor. Being nonrecurrent, it is important to distinguish this lesion from fibromatosis of the breast. PMID- 21274458 TI - Improving blood pressure control in patients with diabetes mellitus and high cardiovascular risk. AB - Patients with diabetes mellitus and symptomatic coronary artery disease are also likely to be hypertensive and, overall, are at very high cardiovascular (CV) risk. This paper reports the findings of a posthoc analysis of the 1113 patients with diabetes mellitus in the ACTION trial: ACTION itself showed that outcomes in patients with stable angina and hypertension were significantly improved when a long-acting calcium channel blocking drug (nifedipine GITS) was added to their treatment regimens. This further analysis of the ACTION database in those patients with diabetes has identified a number of practical therapeutic issues which are still relevant because of potential outcome benefits, particularly in relation to BP control. For example, despite background CV treatment and, specifically, despite the widespread use of ACE Inhibitor drugs, the addition of nifedipine GITS was associated with significant benefits: improvement in BP control by an average of 6/3 mmHg and significant improvements in outcome. In summary, this retrospective analysis has identified that the addition of nifedipine GITS resulted in improved BP control and significant outcome benefits in patients with diabetes who were at high CV risk. There is evidence to suggest that these findings are of direct relevance to current therapeutic practice. PMID- 21274459 TI - Antimetastatic Potentials of Dioscorea nipponica on Melanoma In Vitro and In Vivo. AB - Recent studies have revealed pleiotropic anticancer and antiproliferative capabilities of Dioscorea nipponica Makino whereas the effect of this plant on metastasis of cancer cells has not been clearly clarified. In the present study, we extracted Dioscorea nipponica Makino with methanol (DNE1), chloroform (DNE2), ethyl acetate (DNE3), n-butanol (DNE4), and water (DNE5). We first demonstrate that DNE3 was found to be effective in reducing the lung metastases formation by about 99.5% as compared to vehicle-treated control animals. When a nontoxic concentration of the extract was treated directly to highly metastatic murin melanoma cells (B16F10) and human melanoma cells (A2058) in vitro, it exerted a dose-dependent inhibitory effect on the invasion (P < .001), motility (P < .001), secretion of MMPs (P < .001), and u-PA (P < .001) of both cell lines. To investigate the possible mechanisms involved in these events, we performed western blot analysis to find that DNE inhibited phosphorylation of Akt. A treatment with DNE3 to B16F10 cells also inhibited the activation of NF-kappaB and increased the expression of IkappaB. Taken together, these findings suggested that DNE3 could reduce the metastasis of melanoma cells, thereby constituting an adjuvant treatment for metastasis control. PMID- 21274460 TI - Loss of the NHE2 Na+/H+ exchanger in mice results in dilation of folliculo stellate cell canaliculi. AB - Genetic ablation of the NHE2 Na+/H+ exchanger causes gastric achlorhydria, absorptive defects in kidney and colon, and low fertility. Here we show that NHE2 is expressed in the pituitary, with the highest mRNA expression in pars distalis and lower expression in pars intermedia. In pars distalis of NHE2-null mice, prominent cyst-like dilatations of folliculo-stellate (FS) cell canaliculi developed with age, and there were increased FS cell area, accumulation of lipid in FS cell cytoplasm, redundancies in FS cell basement membrane, and other changes. The expansion of the canaliculi indicates that NHE2 is a major absorptive Na+/H+ exchanger in the luminal membranes lining the extensive network of channels formed by FS cells, which may provide a means of intrapituitary communication. The results suggest that NHE2 contributes to homeostatic regulation of the volume and composition of the canalicular fluid and may counter the secretory activity of the CFTR Cl- channel, which is known to be expressed in pituitary. PMID- 21274462 TI - Seasonal evaluation of outdoor/indoor air quality in primary schools in Lisbon. AB - The aim of this study was to evaluate the indoor (I) and outdoor (O) levels of NO2, speciated volatile organic compounds (VOCs) and carbonyls at fourteen primary schools in Lisbon (Portugal) during spring, autumn and winter. Three of these schools were also selected to be monitored for comfort parameters, such as temperature and relative humidity, carbon dioxide (CO2), carbon monoxide (CO), total VOCs, and both bacterial and fungal colony-forming units per cubic metre. The concentration of CO2 and bioaerosols greatly exceeded the acceptable maximum values of 1800 mg m-3 and 500 CFU m-3, respectively, in all seasons. Most of the assessed VOCs and carbonyls occurred at I/O ratios above unity in all seasons, thus showing the importance of indoor sources and building conditions in indoor air quality. However, it has been observed that higher indoor VOC concentrations occurred more often in the colder months, while carbonyl concentrations were higher in the warm months. In general, the I/O NO2 ratios ranged between 0.35 and 1, never exceeding the unity. Some actions are suggested to improve the indoor air quality in Lisbon primary schools. PMID- 21274463 TI - Continuous glucose monitoring by means of mid-infrared transmission laser spectroscopy in vitro. AB - The continuous surveillance of glucose concentration reduces short-term risks and long-term complications for people with diabetes mellitus, a disorder of glucose metabolism. As a first step towards the continuous monitoring of glucose, reagent free transmission spectroscopy in the mid-infrared region has been carried out in vitro using a quantum cascade laser and an optical silver halide fiber. A 30 MUm gap in the fiber allowed for transmission spectroscopy of aqueous glucose solutions at a wavelength of 9.69 MUm, which is specific to a molecular vibration of glucose. A noise-equivalent concentration as low as 4 mg/dL was achieved at an average power of 1.8 mW and an integration time of 50 s. This is among the most precise of glucose measurements using mid-infrared spectroscopy. Even with the very low average laser power of 0.07 mW the sensitivity of previous results (using a fiber optical evanescent field analysis) has been improved upon by almost one order of magnitude. Finally, the impact of potentially interfering substances such as other carbohydrates was analyzed. PMID- 21274464 TI - Dissociation kinetics of Mn2+ complexes of NOTA and DOTA. AB - The kinetics of transmetallation of [Mn(nota)](-) and [Mn(dota)](2-) was investigated in the presence of Zn(2+) (5-50-fold excess) at variable pH (3.5 5.6) by (1)H relaxometry. The dissociation is much faster for [Mn(nota)](-) than for [Mn(dota)](2-) under both experimental and physiologically relevant conditions (t(1/2) = 74 h and 1037 h for [Mn(nota)](-) and [Mn(dota)](2-), respectively, at pH 7.4, c(Zn(2+)) = 10(-5) M, 25 degrees C). The dissociation of the complexes proceeds mainly via spontaneous ([Mn(nota)](-)k(0) = (2.6 +/- 0.5) * 10(-6) s(-1); [Mn(dota)](2-)k(0) = (1.8 +/- 0.6) * 10(-7) s(-1)) and proton-assisted pathways ([Mn(nota)](-)k(1) = (7.8 +/- 0.1) * 10(-1) M(-1) s(-1); [Mn(dota)](2-)k(1) = (4.0 +/- 0.6) * 10(-2) M(-1) s(-1), k(2) = (1.6 +/- 0.1) * 10(3) M(-2) s(-1)). The observed suppression of the reaction rates with increasing Zn(2+) concentration is explained by the formation of a dinuclear Mn(2+)-L-Zn(2+) complex which is about 20-times more stable for [Mn(dota)](2-) than for [Mn(nota)](-) (K(MnLZn) = 68 and 3.6, respectively), and which dissociates very slowly (k(3)~10(-5) M(-1) s(-1)). These data provide the first experimental proof that not all Mn(2+) complexes are kinetically labile. The absence of coordinated water makes both [Mn(nota)](-) and [Mn(dota)](2-) complexes inefficient for MRI applications. Nevertheless, the higher kinetic inertness of [Mn(dota)](2-) indicates a promising direction in designing ligands for Mn(2+) complexation. PMID- 21274468 TI - Simultaneous molecular imaging based on electron paramagnetic resonance of 14N- and 15N-labelled nitroxyl radicals. AB - The major advancement outlined in this communication is the simultaneous visualisation of two kinds of nitroxyl radicals using electron paramagnetic resonance (EPR) spectroscopy and imaging. PMID- 21274469 TI - The study of the interaction of (cytosine-5)-DNA methyltransferase SsoII with DNA by acoustic method. AB - The interaction of (cytosine-5)-DNA methyltransferase SsoII (M.SsoII) with double stranded DNA was studied by means of thickness shear mode acoustic method (TSM) and gel electrophoresis. M.SsoII recognizes in double-stranded DNA the methylation site 5'-CCNGG-3' (N=A, C, G, T) and methylates the inner cytosine residue. M.SsoII also acts as a transcription factor via binding to the regulatory site 5'-AGGACAAATTGTCCT-3' in the promoter region of SsoII restriction modification system. We designed three 60-mer biotinylated DNA duplexes: with the methylation site (60met), with the regulatory site (60reg), and without a specific binding site (60oct). A strong binding of M.SsoII with each one of the studied DNA immobilized on the TSM transducer has been shown. The equilibrium dissociation constants, K(D), of the M.SsoII-DNA complexes decreased in the order 60oct>60reg>60met, suggesting a higher stability of M.SsoII-60met complex in comparison with the others. The association rate constant, k(a), was also higher for 60met, while similar values were obtained for 60reg and 60oct. The difference in the kinetic parameters for 60met and 60reg suggested a possible way of coordination between the two M.SsoII functions in a cell. PMID- 21274470 TI - Si-H and Si-Cl bond activation reactions of titanium hydrazides with silanes and subsequent Ti-H/E-H (E = Si or H) sigma-bond metathesis. AB - The Ti=NNMe(2) group of Cp*Ti{MeC(N(i)Pr)(2)}(NNMe(2)) undergoes 1,2-addition with Si-Cl and reversible addition with Si-H bonds of RSiH(2)X (R = Ph or Bu; X = Cl or H). Labeling studies show that the so-formed silylhydrazide-hydride products react with primary silanes or H(2)via sigma-bond metathesis between Ti-H and either Si-H or H-H. PMID- 21274471 TI - All-numerical noise filtering of fluorescence signals for achieving ultra-low limit of detection in biomedical applications. AB - We present an all-numerical method for post-processing of the fluorescent signal as obtained from labeled molecules by capillary electrophoresis (CE) in an optofluidic chip, on the basis of data filtering in the Fourier domain. It is shown that the method outperforms the well-known lock-in amplification during experiments in the reduction of noise by a factor of (square root)2. The method is illustrated using experimental data obtained during CE separation of molecules from a commercial DNA ladder with 17 fluorescently labeled molecules having different base-pair sizes. An improvement in signal-to-noise ratio by a factor of ~10 is achieved, resulting in a record-low limit of detection of 210 fM. PMID- 21274472 TI - NMR evidence of the kinetic and thermodynamic products in the NIS promoted cyclization of 1-phenyl-4-pentenylamines. Synthesis and reactivity of trans-2 phenyl-5-iodopiperidines. AB - The intramolecular reaction of secondary amines with tethered alkenes using NIS was studied, which gave insight into the kinetic vs. thermodynamic control of the iodoaminocyclization and the regioselectivity of the aziridinium ring-opening reactions, and led to functionalized piperidines. PMID- 21274473 TI - Resonance scattering detection of trace melamine using aptamer-modified nanosilver probe as catalyst without separation of its aggregations. AB - Nanosilver was modified by aptamer (ssDNA) to obtain a resonance scattering (RS) probe (AgssDNA) for melamine (MA). Based on the catalytic effect of the probe on the Fehling particle reaction, a nanocatalytic RS assay is proposed for the determination of 0.02-1.06 MUg L(-1) MA. PMID- 21274474 TI - One-step synthesis of mesoporous two-line ferrihydrite for effective elimination of arsenic contaminants from natural water. AB - Mesoporous two-line (2-lines) ferrihydrite is successfully synthesized by a facile one-step method. The ferrihydrite is characterized by X-ray diffraction (XRD), Raman spectrum, N(2) adsorption, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The 2-lines ferrihydrite with mesoporous structure possesses excellent adsorption performance for arsenic (As(III)) contamination. Experimental results show that As(III) contamination can be effectively removed within 2 h by this 2-lines ferrihydrite, which is attributed to the special mesoporous structure and large surface area (133 m(2) g(-1)). The As(III) loading capacity of our obtained mesoporous 2-lines ferrihydrite is up to 128 mg(As) g(-1)(Fe). In addition, As(III) can be easily desorbed from 2-lines ferrihydrite by simple heat treatment in alkali solution. After reusage for 10 times, it still presents good adsorption performance, indicating the excellent stability of the 2-lines ferrihydrite. Furthermore, the mesoporous 2-lines ferrihydrite is also effective for As(III) removal when some natural water constituents are present. Therefore, the high adsorption capability of the mesoporous 2-lines ferrihydrite makes it a potentially attractive adsorbent for the removal of As(III) contamination from natural water. PMID- 21274475 TI - Recovery of a freshwater wetland from chemical contamination after an oil spill. AB - In March 2009, a cargo ship spilled 250 tons of heavy fuel oil off the Queensland coast of Australia. The pristine National Park Moreton Island, seven nautical miles to the east of the spill site, was most affected by the oil slick. Contamination of the island's shoreline was widespread, with freshwater wetlands particularly slow to recover as clean-up needed to be carefully managed to avoid damage to this sensitive ecosystem. During the clean-up process on Moreton Island a monitoring program was initiated using traditional chemical analysis in combination with bioanalytical techniques to assess the extent and variability in contamination at sites on the shoreline and freshwater wetlands. Water accommodated fractions (WAF) of oil residues from samples taken directly after the spill on the shoreline showed the same level of toxic potency as samples from the wetland while baseline-toxicity equivalent concentrations (baseline-TEQ) and 2,3,7,8-tetrachlorodibenzodioxin equivalent concentrations (TCDDEQ) were much lower in oil collected from the sandy beach. The umuC assay for genotoxicity and the E-SCREEN assay for estrogenic effects indicated the extracts were not genotoxic or estrogenic. PAH concentrations and toxicity in grab water samples were below detectable levels, however, extracts from time integrated silicone passive samplers deployed for several weeks at the contaminated sites gave measurable responses in the bioassays with TCDDEQ levels increased relative to the control site. The low levels of baseline-TEQ and TCDDEQ present after 8 months had further decreased 6 months later indicating satisfactory recovery of this pristine ecosystem after an oil spill. PMID- 21274476 TI - Assessing the risk to firefighters from chemical vapors and gases during vehicle fire suppression. AB - Despite the frequent occurrence of vehicle fires, very few studies investigating firefighters' potential inhalation exposures during vehicle fire suppression have been conducted. In this paper, we present an assessment of firefighters' health risk from vehicle fire suppression that accounts for the mixture of gases and vapors likely to be found in these fires. Summa canisters were used to collect emissions from the engine and cabin fires of a single vehicle and were analyzed for 75 volatile organic compounds (VOCs). Firefighters' breathing zone concentrations (BZCs) of aromatic hydrocarbons, aldehydes, isocyanates, and carbon monoxide were measured during the suppression of three vehicle fires. The Summa canister and BZC data were used to develop a simple model for predicting BZCs for the compounds that were not measured in the firefighters' breathing zones. Hazard quotients (HQs) were calculated by dividing the predicted and measured BZCs by the most conservative short-term exposure limits (STELs) or ceiling limits. Hazard indices (HIs) were determined by adding HQs for compounds grouped by the target organ for acute health effects. Any HIs above unity represented unacceptable risks. According to this mixture analysis, the estimated 95(th) percentile of the exposure distribution for the study population represents >= 9.2 times the acceptable level of risk to the respiratory tract and eyes. Furthermore, chemicals known or reasonably anticipated to be human carcinogens contributed to > 45% of these HIs. While STELs are not usually based on carcinogenicity, maintaining exposures below STELs may protect individuals from the biological stress that could result from short-term exposures to carcinogens over time. Although vehicle fires are suppressed quickly (<10 min), this assessment suggests that firefighters have the potential to be overexposed to acute toxins during vehicle fire suppression and should therefore wear self contained breathing apparatus at all times during vehicle fire response. PMID- 21274477 TI - A polyacrylamide microbead-integrated chip for the large-scale manufacture of ready-to-use esiRNA. AB - Endoribonuclease-prepared siRNAs (esiRNAs) have the advantages of cost effectiveness and lower off-target effects than chemically synthesized siRNA. However, the current manufacture of esiRNA is a complex process, requiring an expensive instrument and demanding skills to accomplish the transfer, purification, quantification and normalization of liquid samples. These performances significantly hamper the application of esiRNAs on a large-scale level. In this study, we present a polymer microbead-integrated chip capable of the large-scale manufacture of esiRNA in a convenient and robust manner. This chip is able to perform the amplification, transcription and enzymatic digestion of targets on polymer scaffold, thus simplifying the transfer and purification manipulation process. What is also noted, this chip can readily tailor and normalize the amount of esiRNA product by controlling the number of DNA probes and the cycle of the amplification reaction. Thus the esiRNA, also referred to as gel-esiRNA, can be immediately applied to loss-of-function study without any further treatment. The silencing specificity and efficiency of gel-esiRNAs were assessed on transcriptional, translational or cell functional levels. All data of real-time PCR, Western blot assay, or FACS clearly supported that the gel-esiRNA produced specific gene silencing as effectively as the one generated following the conventional approach. We believe that this approach would provide a more robust and cost-effective choice to manufacture esiRNAs, thus promising both more intensive and extensive applications of these heterogeneous RNA strands. PMID- 21274483 TI - Expanding the scope of antiretroviral therapy for HIV infection. PMID- 21274478 TI - Thermoplastic microfluidic devices and their applications in protein and DNA analysis. AB - Microfluidics is a platform technology that has been used for genomics, proteomics, chemical synthesis, environment monitoring, cellular studies, and other applications. The fabrication materials of microfluidic devices have traditionally included silicon and glass, but plastics have gained increasing attention in the past few years. We focus this review on thermoplastic microfluidic devices and their applications in protein and DNA analysis. We outline the device design and fabrication methods, followed by discussion on the strategies of surface treatment. We then concentrate on several significant advancements in applying thermoplastic microfluidic devices to protein separation, immunoassays, and DNA analysis. Comparison among numerous efforts, as well as the discussion on the challenges and innovation associated with detection, is presented. PMID- 21274484 TI - Changing epidemiology of enteric fevers in Singapore. AB - INTRODUCTION: We studied the epidemiological trends of enteric fevers (typhoid and paratyphoid fever) in Singapore from 1990 to 2009 and carried out a review of the current prevention and control measures. MATERIALS AND METHODS: Epidemiological records of all reported enteric fevers maintained by the Communicable Diseases Division, Ministry of Health from 1990 to 2009 were analysed. RESULTS: A total of 2464 laboratory confirmed cases of enteric fevers (1699 cases of typhoid and 765 cases of paratyphoid) were reported. Of these, 75% were imported, mainly from India and Indonesia. There had been a significant fall in the mean annual incidence rate of indigenous enteric fevers from 4.3 per 100,000 population in 1990 to 0.26 per 100,000 population in 2009 (P <0.005) with a corresponding increase in the proportion of imported cases from 71% between 1990 and 1993 to 92% between 2006 and 2009 (P <0.0005). Imported cases involving foreign contract workers increased significantly from 12.8% between 1990 and 1993 to 40.4% between 2006 and 2009 (P <0.0005). CONCLUSION: Singapore has experienced a marked decline in the incidence of enteric fevers that is now comparable to that of other developed countries. Continued vigilance and proactive measures that address the changing epidemiology of enteric fevers in Singapore are necessary to sustain the milestone achieved in the past 2 decades. PMID- 21274485 TI - Outcomes of oral tongue cancer: does age matter? AB - INTRODUCTION: This is a retrospective study aimed to analyse the outcomes of oral tongue cancer with emphasis on young people. MATERIALS AND METHODS: Patients treated radically between 1998 and 2006 were included and categorised according to treatment modalities (Group A: Surgery, Group B: Surgery and adjuvant therapy, Group C: Definitive radiotherapy) and age groups (<= 40 and > 40 years). Overall survival (OS), disease-free survival (DFS), locoregional relapse-free survival (LRS) and metastasis-free survival (MFS) were estimated using Kaplan-Meier method. RESULTS: There were 123 patients with 32%, 53% and 15% in Group A, B and C, respectively. Of these, 17 patients (14%) were <=40 years with 6 (15%), 8 (12%) and 3 (16%) young oral tongues in Group A, B and C, respectively. Five-year OS and DFS were 69%/72%, 41%/47% and 16%/9.5% for Group A, B and C, respectively. Young patients had similar survival as the older population with 5-year OS of 83%, 75% and 33% in Group A, B and C, as compared to the older patients (66%, 36% and 13%, respectively). CONCLUSION: Young oral tongue patients did not have worse outcomes. PMID- 21274486 TI - Epidemiology of skin diseases in renal transplant recipients in a tertiary hospital. AB - INTRODUCTION: There is no published epidemiological data on skin diseases in kidney transplant recipients in this tropical country, which has multi-ethnic groups with the Chinese as the predominant ethnic group. MATERIALS AND METHODS: Skin diseases of 143 renal transplant recipients were studied in a skin clinic of a tertiary institution during annual surveillance visits from June 2006 to March 2009. RESULTS: Our study showed that except the common drug specific skin manifestations, sebaceous hyperplasia (56.6%), seborrheic keratosis (60.8%), melanocytic naevi (76.9%), skin tags (37.1%) and viral (29.4%) and fungal (20.3%) infections were the most prevalent skin diseases among renal transplant recipients living in Singapore. The prevalence of pre-malignant and malignant tumours was very low (11.2% actinic keratosis, 1.4% Bowen's disease, 1.4% squamous cell carcinoma, 0.7% basal cell carcinoma, 0.7% keratoacanthoma). Male predominance was seen in sebaceous hyperplasia (72.4% vs 32.1%), actinic keratosis (17.2% vs 1.8%), viral (36.8% vs 19.6%) and fungal (27.6% vs 8.9%) infections. Our study also showed increased prevalence of sebaceous hyperplasia with increased age but its prevalence was significantly higher than that reported in the age matched general population. The prevalence of seborrheic keratosis, actinic keratosis and viral infection correlated positively with post-transplant duration. CONCLUSIONS: Our study provides epidemiological data for the prevalence of skin diseases in renal transplant recipients. It emphasises the importance of dermatologic follow-up for renal transplant patients in order to obtain a diagnosis and manage treatable skin diseases. PMID- 21274487 TI - Elevated level of carbonyl compounds correlates with insulin resistance in type 2 diabetes. AB - INTRODUCTION: Recent periodicals direct that reactive carbonyl compounds are formed due to existing oxidative stress in type 2 diabetes mellitus, which further nonenzymatically react with proteins and lipids to form irreversible advanced glycation end products (AGE) and advanced lipoxidation end products (ALE). In type 2 diabetes mellitus, insulin resistance plays a pivotal role in hyperglycaemia. In this study, we tried to fi nd the relation between insulin resistance and carbonyl stress. MATERIALS AND METHODS: Forty-seven patients of type 2 diabetes mellitus (age 51 +/- 5.06 years) were selected and fasting plasma glucose, serum insulin, total carbonyl compounds, HbA1c, thiobarbituric acid reacting substances (TBARS) and Trolox equivalent antioxidant capacity (TEAC) were estimated using standard protocols. Homeostatic model assessement of insulin resistance (HOMA-IR) was evaluated from fasting plasma glucose and serum insulin levels. RESULTS: We found highly significant correlations of carbonyl compounds with HOMA-IR, fasting plasma glucose and glycated haemoglobin (HbA1c). Correlations of lipid peroxidation end product, TBARS were not so significant. CONCLUSION: Findings from this study indicate that the level of carbonyl compounds can be a biomarker of insulin resistance in type 2 diabetes mellitus. PMID- 21274488 TI - Impact of depression on health related quality of life in patients with diabetes. AB - INTRODUCTION: Diabetes mellitus (DM) is a serious chronic illness that has a major impact on the quality of life of the individuals. Our aim was to examine the determinants of health-related quality of life (HRQOL) in patients with DM. MATERIALS AND METHODS: Adult outpatients attending a Diabetes Centre were recruited on consecutive basis between August 2006 and February 2007. Clinical data were collected from interviews with the subjects and from medical records. Assessment of depressive symptoms was done using the Center for Epidemiologic Studies Depression Scale (CES-D) and HRQOL using the Short Form 36 Health Survey (SF-36). A two-step regression analysis was conducted for identifying factors affecting patients' quality of life. RESULTS: Five hundred and thirty-seven patients participated in the study. The mean (SD) age of the participants was 54.7 (13.3) years and 315 (58.7%) were males. The prevalence of depressive symptoms was 31.1% (n = 167). After adjusting for other variables, the effects of depressive symptoms persisted for all the 8 domains of SF-36 (P <0.001 for all). The medical factors that were negatively associated with HRQOL were a diagnosis of Type 1 DM, duration of the illness of more than 10 years, HbA1c levels of >=7%, and comorbidity of stroke and retinopathy. Being male and a regular exerciser had a positive effect on HRQOL. CONCLUSION: These findings highlight the importance of detecting and treating comorbid depression in DM. PMID- 21274489 TI - Major workplace related accidents in Singapore: A major trauma centre's experience. AB - INTRODUCTION: Major workplace related accidents pose a significant healthcare resource challenge in Singapore. MATERIALS AND METHODS: Our study looks at the epidemiology of patients who were admitted for workplace related accidents, in a single institution, with an Injury Severity Score of >9. RESULTS: There were 196 cases of major workplace related accidents admitted between January 2006 and December 2007. The median age of patients admitted was 37 years with a large percentage being males (95.4%) and non-residents (57.1%). The most common ethnic group was Chinese (53.1%) followed by Indians (23.5%). The most common mechanism of injury was fall from height (66.3%) followed by injuries as a result of falling objects at work (21.9%). The percentage of patients who required surgical intervention was 69.9%. Patients admitted for major workplace related accidents had a median length of stay of 5 days in the hospital, a median length of 24 days of medical leave (ML), certifying them unfit for duty and the average cost of stay for each patient was S$11,000. CONCLUSIONS: We have a better understanding of the epidemiology and socio-economic impact of workplace related accidents through this study. Workplace related accidents result in significant number of man-days lost from work and monetary cost to employers, medical insurance and the hospital. With an improved understanding, we propose methods to prevent and reduce such accidents in future. A direct consequence of which will be the possible reduction of hospitalisation costs and better allocation of healthcare resources in the future. PMID- 21274490 TI - Management of acute ST-elevation myocardial infarction: Reperfusion options. AB - Primary percutaneous coronary intervention and thrombolysis remain therapies of choice for patients presenting with ST-segment elevation myocardial infarction (STEMI). Clinical outcome in the management of acute STEMI is dependent on myocardial reperfusion time and reperfusion strategies. Optimisation of these strategies should take into consideration logistical limitations of the local medical systems and the various patient profiles. We review the reperfusion strategies and its history in Singapore, comparing its clinical application with that in some developed Western countries. PMID- 21274491 TI - Human rights as a cornerstone of AIDS prevention, treatment and public health measures. PMID- 21274492 TI - Recurrent group B streptococcal septicemia in a very low birth weight infant with infective endocarditis and submandibular cellulitis. PMID- 21274493 TI - Cysticercosis of the levator palpebrae superioris. PMID- 21274494 TI - Cutaneous angiosarcoma associated with the Kasabach-Merritt syndrome. PMID- 21274495 TI - Forestier's disease presenting as a retropharyngeal mass in an elderly with dysphagia. PMID- 21274496 TI - Development of ceftazidime resistance in Burkhoderia pseudomallei in a patient experiencing melioidosis with mediastinal lymphadenitis. PMID- 21274497 TI - A tiny stone induced ureteral rupture. Urolithiasis. PMID- 21274498 TI - An unusual cause of lymphadenopathy and rash. Kikuchi-Fujimoto disease. PMID- 21274499 TI - Bone and joint decade extended. PMID- 21274500 TI - Excision arthroplasty of the hip joint in dogs and cats. PMID- 21274501 TI - Median sternotomy and ventral stabilisation using pins and polymethylmethacrylate for a comminuted T5 vertebral fracture in a Miniature Schnauzer. AB - A 2.9 kg Miniature Schnauzer was referred to our clinic, the Emergency & Critical Care Medicine Service at the Michigan State University Veterinary Teaching Hospital, following a dog fight. Physical examination findings upon admission included multiple thoracic wounds, absence of hindlimb deep pain, and marked Schiff-Sherrington syndrome. Computed tomography imaging revealed thoracic wall penetration and a comminuted T5 vertebral fracture. Thoracic exploration and thoracic wall repair were performed through a median sternotomy. The vertebral fracture was exposed and stabilised intra-thoracically through the same approach using pins and polymethylmethacrylate. The pins were placed percutaneously into the vertebral bodies of the adjacent vertebrae. Recovery was uncomplicated and fracture healing was documented eight weeks postoperatively. Spinal trauma secondary to dog fights is relatively common. The presence of concurrent penetrating thoracic injury negatively affects prognosis and necessitates thoracic exploration as soon as feasible. The approach should allow complete thoracic exploration to repair parietal and visceral damage, thus indicating the need for median sternotomy rather than an intercostal approach. The present case report suggested that median sternotomy can be used to safely apply stabilisation devices for the treatment of concurrent spinal trauma. Direct visualisation of the vertebral bodies permitted optimal implant anchorage as compared to potentially more hazardous techniques such as dorsal pinning. PMID- 21274502 TI - Effects of the histone deacetylase inhibitor ITF2357 in autoinflammatory syndromes. AB - We explored the effects of the oral histone deacetylase (HDAC) inhibitor ITF2357 in patients with autoinflammatory syndrome. In this prospective open-label pilot study, eight patients were enrolled; one patient with tumor necrosis factor receptor-associated periodic syndrome (TRAPS), three patients with hyper-IgD and periodic fever syndrome (HIDS) and four patients with Schnitzler syndrome were closely followed during 90 d of ITF2357 treatment. Three patients with Schnitzler syndrome and one TRAPS patient experienced a partial remission. In four patients, there was no effect. In HIDS patients, there was a tendency toward a higher attack frequency and increasing attack severity. In two patients (one TRAPS and one HIDS), we observed a decrease of acute-phase response without signs of clinical improvement. One patient with Schnitzler syndrome showed a partial response despite an ongoing acute-phase response. In conclusion, ITF2357 monotherapy was able to induce partial response only in patients with Schnitzler syndrome and no response in patients with HIDS. PMID- 21274503 TI - Histone deacetylase inhibitors as therapeutic agents for acute central nervous system injuries. AB - Histone deacetylase (HDAC) inhibitors are emerging as a novel class of potentially therapeutic agents for treating acute injuries of the central nervous system (CNS). In this review, we summarize data regarding the effects of HDAC inhibitor administration in models of acute CNS injury and discuss issues warranting clinical trials. We have previously shown that the pan-HDAC inhibitor ITF2357, a compound shown to be safe and effective in humans, improves functional recovery and attenuates tissue damage when administered as late as 24 h after injury. Using a well-characterized, clinically relevant mouse model of closed head injury, we demonstrated that a single dose of ITF2357 administered 24 h after injury improves neurobehavioral recovery and reduces tissue damage. ITF2357 induced functional improvement was found to be sustained up to 14 d after trauma and was associated with augmented histone acetylation. Single postinjury administration of ITF2357 also attenuated injury-induced inflammatory responses, as indicated by reduced glial accumulation and activation as well as enhanced caspase-3 expression within microglia/macrophages after treatment. Because no specific therapeutic intervention is currently available for treating brain trauma patients, the ability to affect functional outcome by postinjury administration of HDAC inhibitors within a clinically feasible timeframe may be of great importance. Furthermore, a growing body of evidence indicates that HDAC inhibitors are beneficial for treating various forms of acute CNS injury including ischemic and hemorrhagic stroke. Because HDAC inhibitors are currently approved for other use, they represent a promising new avenue of treatment, and their use in the setting of CNS injury warrants clinical evaluation. PMID- 21274505 TI - Autophagy inhibition enhances etoposide-induced cell death in human hepatoma G2 cells. AB - Induction of autophagy usually acts as a survival mechanism of cancer cells in response to chemotherapy. However, the function and molecular mechanism of autophagy in human hepatoma cells under drug treatment is still not clear. To address this issue, we established an experimental model in which HepG2 cells were treated with etoposide, a widely used anticancer agent. We demonstrate the etoposide-induced accumulation of GFP-LC3 dots by fluorescent microscopy, the up regulation of LC3-II protein expression by Western blotting and the increased number of autophagic vacuoles by electron microscopy, confirming the activation of autophagy by etoposide in HepG2 cells. Inhibition of autophagy by either 3 methyladenine (3MA) or beclin-1 small interfering RNA enhanced etoposide-induced cell death. Furthermore, activation of p53 and AMPK was detected in etoposide treated cells and inhibition of AMPK triggered apoptosis through suppression of autophagy. On the other hand, inactivation of p53 promoted cell survival through augmentation of autophagy. Collectively, these findings indicate that etoposide induced autophagy promotes hepatoma cell adaptation and survival, and that autophagy inhibition improves the chemotherapeutic effect of etoposide. Moreover, AMPK activation is clearly associated with etoposide-induced autophagy. We conclude that manipulation of AMPK may be a promising approach of adjuvant chemotherapy for hepatocellular carcinoma. PMID- 21274504 TI - Histone deacetylase (HDAC) inhibition as a novel treatment for diabetes mellitus. AB - Both common forms of diabetes have an inflammatory pathogenesis in which immune and metabolic factors converge on interleukin-1beta as a key mediator of insulin resistance and beta-cell failure. In addition to improving insulin resistance and preventing beta-cell inflammatory damage, there is evidence of genetic association between diabetes and histone deacetylases (HDACs); and HDAC inhibitors (HDACi) promote beta-cell development, proliferation, differentiation and function and positively affect late diabetic microvascular complications. Here we review this evidence and propose that there is a strong rationale for preclinical studies and clinical trials with the aim of testing the utility of HDACi as a novel therapy for diabetes. PMID- 21274506 TI - SP100 reduces malignancy of human glioma cells. AB - The nuclear autoantigen SP100 (speckled protein 100) is reported to control cellular gene expression, cell growth and differentiation. To investigate its relevance in brain tumors, we investigated SP100 expression and function in human glioblastomas and meningiomas. SP100 was expressed in both tumors at the mRNA and protein levels in situ and in vitro, however, expression in meningioma samples and meningioma cells exceeded that in glioblastoma samples and cultivated cells significantly. Moreover, whereas nearly all meningioma cells were SP100 immunopositive, only part of the glioblastoma cells were SP100 stainable. In vitro, SP100 was upregulated by interferon-alpha and -gamma in both malignant cell types. To study its functional role, SP100 was overexpressed in glioblastoma cells. This SP100 overexpression reduced considerably the glioblastoma cell proliferation and migration to fetal calf serum. We conclude that SP100 expression reduces malignancy of brain tumors. Since meningiomas show a generally higher SP100 expression, this may be one of the factors explaining their lower malignancy compared to glioblastomas. PMID- 21274507 TI - Combining magnetic resonance spectroscopy and molecular genomics offers better accuracy in brain tumor typing and prediction of survival than either methodology alone. AB - Recent advents in magnetic resonance spectroscopy (MRS) techniques permit subsequent microarray analysis over the entire human transcriptome in the same tissue biopsies. However, extracting information from such immense quantities of data is limited by difficulties in recognizing and evaluating the relevant patterns of apparent gene expression in the context of the existing knowledge of phenotypes by histopathology. Using a quantitative approach derived from a knowledge base of pathology findings, we present a novel methodology used to process genome-wide transcription and MRS data. This methodology was tested to examine metabolite and genome-wide profiles in MRS and RNA in 55 biopsies from human subjects with brain tumors with ~100% certainty. With the guidance of histopathology and clinical outcome, 15 genes with the assistance of 15 MRS metabolites were able to be distinguished by tumor categories and the prediction of survival was better than when either method was used alone. This new method, combining MRS, genomics, statistics and biological content, improves the typing and understanding of the complexity of human brain tumors, and assists in the search for novel tumor biomarkers. It is an important step for novel drug development, it generates testable hypotheses regarding neoplasia and promises to guide human brain tumor therapy provided improved in vivo methods for monitoring response to therapy are developed. PMID- 21274508 TI - SALL4 is essential for cancer cell proliferation and is overexpressed at early clinical stages in breast cancer. AB - Few target molecules have been identified that enable the diagnosis of breast cancer with a high sensitivity and specificity, especially in the early clinical stages of cancer. Here, we present the first evidence for diagnostic performance of gene expression for SALL4, a transcription factor that plays an essential role in the embryonic development and self-renewal of embryonic stem (ES) cells, in breast cancer. The sensitivity and specificity of SALL4 was 80.4 and 80.0%, respectively, as estimated using the cut-off value obtained from the analysis of the receiver operating characteristic curve. Furthermore, comparison of paired cancer and non-cancer tissues from the same breast cancer patient revealed elevated SALL4 mRNA levels in 86.1% (31/36) of the specimens. No obvious correlations were detected between clinicopathological factors and SALL4 mRNA expression; however, SALL4 mRNA was expressed at a high level even in the early clinical stages of the cancer. An siRNA experiment to determine the significance of SALL4 expression showed complete inhibition of proliferation in breast cancer MCF7 cells. This inhibitory effect of siRNA was induced by cell cycle arrest mainly at the G1 phase, leading to increased cell volume. These results suggest that SALL4 mRNA may be a new tool to support the diagnosis of breast cancer, and it may also represent a novel therapeutic target. PMID- 21274509 TI - Expression of the sperm fibrous sheath protein CABYR in human cancers and identification of alpha-enolase as an interacting partner of CABYR-a. AB - Calcium-binding tyrosine phosphorylation regulated protein (CABYR), a family of isoforms resulting from alternative splicing, has been identified as a cancer/testis antigen (CT88) in lung cancer and hypothesized to be a promising target for immunotherapy. Here, we report the expression of CABYR in various cancer tissues/cell lines. Expression profiles of individual isoforms were different among cancers. Furthermore, protein and mRNA levels did not correlate for individual isoforms. While CABYR-c/d were the most abundant splicing variants, CABYR-a was the predominant protein isoform. Finally, CABYR-a, but not CABYR-c, was found to interact with alpha-enolase in vivo. Collectively, the data indicate that CABYR is a CT antigen widely expressed in diverse cancer cells. However, individual protein isoforms may be differentially regulated by post transcriptional and post-translational mechanisms and may have a unique role in carcinogenesis. The protein expression pattern of various CABYR isoforms is important with regard to the consideration of using CABYR as a target antigen for the development of vaccines for cancer therapy. PMID- 21274510 TI - [Epidemiology, clinical picture and management of atrial fibrillation]. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia, affects approximately 1% of adults and prevalence increases with age. Nine per cent of those aged 80 years and older have AF. AF is associated with increased cardiovascular mortality and morbidity, including stroke.Stroke in patients with AF is more severe and more likely to be fatal. Prevention of thromboembolism with oral anticoagulants and rate or rhythm control are the main therapeutic strategies for patients with AF. Vitamin K antagonists reduce the risk of stroke in patients with AF, however are underutilized. Dronedarone is the first antiarrhythmic drug that reduces the stroke rate. PMID- 21274511 TI - Genetic analysis and molecular mapping of a novel recessive gene xa34(t) for resistance against Xanthomonas oryzae pv. oryzae. AB - A new bacterial blight recessive resistance gene xa34(t) was identified from the descendant of somatic hybridization between an aus rice cultivar (cv.) BG1222 and susceptible cv. IR24 against Chinese race V (isolate 5226). The isolate was used to test the resistance or susceptibility of F(1) progenies and reciprocal crosses of the parents. The results showed that F(1) progenies appeared susceptibility there were 128R (resistant):378S (susceptible) and 119R:375S plants in F(2) populations derived from two crosses of BG1222/IR24 and IR24/BG1222, respectively, which both calculates into a 1R:3S ratio. 320 pairs of stochastically selected SSR primers were used for genes' initial mapping. The screened results showed that two SSR markers, RM493 and RM446, found on rice chromosome 1 linked to xa34(t). Linkage analysis showed that these two markers were on both sides of xa34(t) with the genetic distances 4.29 and 3.05 cM, respectively. The other 50 SSR markers in this region were used for genes' fine mapping. The further results indicated that xa34(t) was mapped to a 1.42 cM genetic region between RM10927 and RM10591. In order to further narrow down the genomic region of xa34(t), 43 of insertion/deletion (Indel) markers (BGID1-43) were designed according to the sequences comparison between japonica and indica rice. Parents' polymorphic detection and linkage assay showed that the Indel marker BGID25 came closer to the target gene with a 0.4 cM genetic distance. A contig map corresponding to the locus was constructed based on the reference sequences aligned by the xa34(t) linked markers. Consequently, the locus of xa34(t) was defined to a 204 kb interval flanked by markers RM10929 and BGID25. PMID- 21274512 TI - Diabetes mellitus and incidence of kidney cancer: a meta-analysis of cohort studies. AB - AIMS/HYPOTHESIS: Diabetes is associated with increased risk of cancer at several sites, but its association with cancer of the kidney is unclear. We performed a systematic review with meta-analysis to examine the association between diabetes and incidence of kidney cancer. METHODS: Pertinent studies were identified by searching PubMed (from January 1966 to December 2010) and reviewing the reference lists of relevant articles. We included cohort studies reporting RR estimates and 95% CI (or data to calculate them) of the association between diabetes and kidney cancer incidence. Summary RRs were calculated using a random-effects model. RESULTS: Nine cohort studies met the inclusion criteria. Analysis of all studies showed that compared with individuals without diabetes, patients with diabetes had a statistically significant increased risk of kidney cancer (RR 1.42, 95% CI 1.06-1.91). There was heterogeneity among studies (p < 0.001 for heterogeneity). The association was stronger in women (RR 1.70, 95% CI 1.47-1.97) than in men (RR 1.26, 95% CI 1.06-1.49). When restricting the analysis to studies that had adjusted for body mass index (n = 3) or cigarette smoking (n = 3), the RRs were 1.12 (95% CI 0.99-1.27) and 1.29 (95% CI 1.05-1.58), respectively. CONCLUSIONS/INTERPRETATION: This meta-analysis indicates a positive association between diabetes and risk of kidney cancer. Future research should attempt to establish whether this association is causal. PMID- 21274514 TI - Validation, reliability, and responsiveness of Prolapse Quality of Life Questionnaire (P-QOL) in a Brazilian population. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study was to translate and validate a Brazilian version of the "Prolapse Quality of Life Questionnaire" (P-QOL) an instrument to assess quality of life of women with genital prolapse. METHODS: Sixty-five patients answered the P-QOL twice. The reliability was assessed using Cronbach's alpha coefficient and validity was assessed comparing symptom scores between affected and asymptomatic women and comparing symptom scores with prolapse stages. Responsiveness was obtained with patients who underwent to genital prolapse surgical corrections. RESULTS: The results have showed that the Brazilian Portuguese version of P-QOL has had very good psychometric properties. All items achieved a Cronbach's alpha greater than 0.70. The test-retest reliability confirmed that the questionnaire was able to detect changes in quality-of-life after treatment. CONCLUSIONS: We concluded that the Portuguese version of the P-QOL is a very good instrument to assess quality-of-life in women with genital Prolapse. PMID- 21274515 TI - The effect of prior bisphosphonate therapy on the subsequent therapeutic effects of strontium ranelate over 2 years. AB - Many osteoporotic women prescribed strontium ranelate have previously received bisphosphonates. Prior bisphosphonate use blunted the spinal bone mineral density (BMD) response for 6 months. Hip BMD was blunted to a degree for 2 years, although there was an overall increase in hip BMD in contrast to the heel where BMD did not increase. INTRODUCTION: Many osteoporotic women commenced on strontium ranelate have already received treatment with bisphosphonates. This study investigates whether prior bisphosphonate use impairs the subsequent therapeutic response to strontium ranelate. METHODS: Women were recruited who were either bisphosphonate naive or currently receiving a bisphosphonate. All women received strontium ranelate and were followed up for 2 years. RESULTS: One hundred and twenty women were recruited. After 2 years, the bisphosphonate-naive group had significant BMD increases of 8.9%, 6.0% and 6.4% at the spine, hip and heel, respectively. In the prior bisphosphonate group, BMD increased significantly at the spine (4.0%) and hip (2.5%) but not at the heel. At all time points at all sites, the BMD increase was greater in the bisphosphonate-naive group. BMD at the spine did not increase during the first 6 months in the prior bisphosphonate group but then increased in parallel with the bisphosphonate-naive group. In contrast, the difference between the two groups in hip BMD continued to increase throughout the 2 years. P1NP was suppressed in the prior bisphosphonate group for the first 6 months. CONCLUSIONS: After bisphosphonate exposure, the BMD response to strontium ranelate is blunted for only 6 months at the spine. At the hip, a degree of blunting was observed over 2 years, although there was an overall increase in hip BMD in contrast to the heel where no increase in BMD was observed. PMID- 21274516 TI - Development of a fluorophore-ribosomal DNA restriction typing method for monitoring structural shifts of microbial communities. AB - DNA restriction fragment polymorphism technologies such as amplified ribosomal DNA restriction analysis (ARDRA) and terminal restriction fragment length polymorphism (T-RFLP) have been widely used in investigating microbial community structures. However, these methods are limited due to either the low resolution or sensitivity. In this study, a fluorophore-ribosomal DNA restriction typing (f DRT) approach is developed for structural profiling of microbial communities. 16S rRNA genes are amplified from the community DNA and digested by a single restriction enzyme Msp I. All restriction fragments are end-labeled with a fluorescent nucleotide Cy5-dCTP via a one-step extension reaction and detected with an automated DNA sequencer. All 50 predicted restriction fragments between 100 and 600 bp were detected when twelve single 16S rRNA gene sequences were analyzed using f-DRT approach; 92% of these fragments were determined with accuracy of +/-2 bp. In the defined model communities containing five components with different ratios, relative abundance of each component was correctly revealed by this method. The f-DRT analysis also showed structural shifts of intestinal microbiota in carcinogen-treated rats during the formation of precancerous lesions in the colon, as sensitive as multiple digestion-based T RFLP analysis. This study provides a labor and cost-saving new method for monitoring structural shifts of microbial communities. PMID- 21274517 TI - Degradation product emission from historic and modern books by headspace SPME/GC MS: evaluation of lipid oxidation and cellulose hydrolysis. AB - Volatile organic compounds emitted from a several decade series of bound periodicals (1859-1939) printed on ground wood paper, as well as historical books dating from the 1500s to early 1800s made from cotton/linen rag, were studied using an improved headspace SPME/GC-MS method. The headspace over the naturally aging books, stored upright in glass chambers, was monitored over a 24-h period, enabling the identification of a wide range of organic compounds emanating from the whole of the book. The detection of particular straight chain aldehydes, as well as characteristic alcohols, alkenes and ketones is correlated with oxidative degradation of the C(18) fatty acid constituency of paper. The relative importance of hydrolytic and oxidative chemistry involved in paper aging in books published between 1560 and 1939 was examined by comparing the relative abundances of furfural (FUR) a known cellulose hydrolysis product, and straight chain aldehydes (SCA) produced from the oxidation of fatty acids in paper. The relative abundance of furfural is shown to increase across the 379-year publication time span. A comparison of relative SCA peak areas across the series of books examined reveals that SCA emission is more important in the cotton/linen rag books than in the ground wood books. PMID- 21274518 TI - Glycation and oxidation of histones H2B and H1: in vitro study and characterization by mass spectrometry. AB - Among the post-translational modifications, oxidation and glycation are of special interest, especially in diseases such as diabetes, and in aging. The synergistic interaction between glycation and oxidation, also known as "glycoxidation" is highly relevant due to its involvement in the production of deleterious changes at the molecular level. Non-enzymatic damage to nuclear proteins has potentially severe consequences for the maintenance of genomic integrity [54]. In this report, we study glycated histones and its in vitro oxidation. Data concerning the modifications that occurred in the histones were obtained by analysis of enzymatic digests (Glu-C and Arg-C) of unmodified and glycated histones, obtained before and after oxidation. Analysis was then performed using a MALDI-MS/MS-based approach combined with nano liquid chromatography. This approach allowed us to identify histone H2B and H1 specific sites of oxidation and to distinguish the most affected residues for each histone. The results showed the occurrence of a cumulative effect of oxidative damage in the glycated histones when subjected to in vitro oxidation, suggesting that structural changes caused by glycation induces histones to a pro-oxidant state. Comparing the data of oxidized glycated histones with data from unmodified oxidized histones, using the same model of oxidation, the results clearly show that these oxidative modifications occur earlier and more extensively in glycated histones. Furthermore, the results pointed to an increased oxidative damage in the vicinity of the glycated residues. PMID- 21274519 TI - Comparison of different types of stationary phases for the analysis of soy isoflavones by HPLC. AB - Nowadays, there are new technologies in high-performance liquid chromatography columns available enabling faster and more efficient separations. In this work, we compared three different types of columns for the analysis of main soy isoflavones. The evaluated columns were a conventional reverse phase particle column, a fused-core particle column, and a monolithic column. The comparison was in terms of chromatographic parameters such as resolution, asymmetry, number of theoretical plates, variability of retention time, and peak width. The lower column pressure was provided by the monolithic column, although lower chromatographic performance was achieved. Conventional and fused-core particle columns presented similar pressure. Results also indicate that direct transfer between particle and monolithic columns is not possible requiring adjustment of conditions and a different method optimization strategy. The best chromatographic performance and separation speed were observed for the fused-core particle column. Also, the effect of sample solvent on the separation and peak shape was evaluated and indicated that monolithic column is the most affected especially when using higher concentrations of acetonitrile or ethanol. Sample solvent that showed the lowest effect on the chromatographic performance of the columns was methanol. Overall evaluation of methanol and acetonitrile as mobile phase for the separation of isoflavones indicated higher chromatographic performance of acetonitrile, although methanol may be an attractive alternative. Using acetonitrile as mobile phase resulted in faster, higher resolution, narrower, and more symmetric peaks than methanol with all columns. It also generated the lower column pressure and flatter pressure profile due to mobile phase changes, and therefore, it presents a higher potential to be explored for the development of faster separation methods. PMID- 21274520 TI - An evaluation method for determination of non-polar pesticide residues in animal fat samples by using dispersive solid-phase extraction clean-up and GC-MS. AB - A rapid and easy method has been proposed, optimized and evaluated for quantitative determination at trace level of a representative group of non-polar pesticides in fat samples. The method includes n-hexane-saturated acetonitrile extraction, fat precipitation by cooling pre clean-up followed by dispersive solid-phase extraction (d-SPE) based on QuEChERS procedure clean-up. Determination was performed by gas chromatography-mass spectrometry (GC-MS) in selected ion monitoring (SIM) mode. Efficiency of the d-SPE clean-up step was evaluated by comparison with fat oxidation treatment and gel permeation chromatography. Different combinations of d-SPE extraction reagents and sample amounts were tested in order to minimize matrix co-extractives and interferences. Best recoveries were obtained with 1200 mg of MgSO(4), 400 mg of end-capped C(18), 400 mg of PSA and 1 g of sample amount. SIM method, matrix effect, precision, and accuracy were evaluated with spiked pork fat samples for 38 representative pesticides. Results of this study showed that this technique is applicable in routine analysis for its application into monitoring programs. It simplifies time-consuming clean-up steps and allows a satisfactory long-term chromatographic performance. PMID- 21274521 TI - Short and medium latency muscle responses evoked by electrical vestibular stimulation are a composite of all stimulus frequencies. AB - Electrical vestibular stimulation produces biphasic responses in muscles maintaining balance. The two components of these muscle responses (termed the short latency and medium latency components) are believed to be independent and elicited by vestibular stimuli of different frequencies. We tested these hypotheses by determining (a) if frequency-specific stimulation protocols could evoke independently the short and medium latency responses and (b) whether these two components are triggered by distinct brain regions with a fixed time delay, interacting around 10 Hz. First, subjects were provided 10-25 Hz, 0-10 Hz, and 0 25 Hz vestibular stimuli to selectively modulate the short latency, medium latency, or both components of the response; and second, they were provided twenty sinusoidal stimuli from 1 to 20 Hz with a 0-20 Hz control trial, designed to determine whether an interaction between the short and medium latency responses occurs at a specific stimulation frequency. Both the 0-10 Hz and 10-25 Hz vestibular stimuli elicited multiphasic waveforms, suggesting the short and medium latency components were not modulated independently by the frequency specific stimuli. Sinusoidal vestibular stimuli evoked responses at the stimulated frequency but no evidence of a reflex component interaction was observed. Instead, summation of the responses evoked by each of the sinusoidal stimuli resembled the biphasic response to broad bandwidth stimuli. Due to the lack of interaction and linear contribution of all stimulus frequencies to both the short and medium latency responses, the present results support the use of broad bandwidth electrical vestibular signal for physiological or clinical testing. PMID- 21274522 TI - Ca2+-dependent phosphorylation of RyR2 can uncouple channel gating from direct cytosolic Ca2+ regulation. AB - Phosphorylation of the cardiac ryanodine receptor (RyR2) is thought to be important not only for normal cardiac excitation-contraction coupling but also in exacerbating abnormalities in Ca2+ homeostasis in heart failure. Linking phosphorylation to specific changes in the single-channel function of RyR2 has proved very difficult, yielding much controversy within the field. We therefore investigated the mechanistic changes that take place at the single-channel level after phosphorylating RyR2 and, in particular, the idea that PKA-dependent phosphorylation increases RyR2 sensitivity to cytosolic Ca2+. We show that hyperphosphorylation by exogenous PKA increases open probability (P(o)) but, crucially, RyR2 becomes uncoupled from the influence of cytosolic Ca2+; lowering [Ca2+] to subactivating levels no longer closes the channels. Phosphatase (PP1) treatment reverses these gating changes, returning the channels to a Ca2+ sensitive mode of gating. We additionally found that cytosolic incubation with Mg2+/ATP in the absence of exogenously added kinase could phosphorylate RyR2 in approximately 50% of channels, thereby indicating that an endogenous kinase incorporates into the bilayer together with RyR2. Channels activated by the endogenous kinase exhibited identical changes in gating behavior to those activated by exogenous PKA, including uncoupling from the influence of cytosolic Ca2+. We show that the endogenous kinase is both Ca2+-dependent and sensitive to inhibitors of PKC. Moreover, the Ca2+-dependent, endogenous kinase-induced changes in RyR2 gating do not appear to be related to phosphorylation of serine 2809. Further work is required to investigate the identity and physiological role of this Ca2+-dependent endogenous kinase that can uncouple RyR2 gating from direct cytosolic Ca2+ regulation. PMID- 21274523 TI - Calcium inhibits dihydropyridine-stimulated increases in opening and unitary conductance of a plant Ca2+ channel. AB - We have previously characterized the "RCA" channel (root Ca2+ channel), a voltage dependent, Ca2+-permeable channel found in plasma membrane-enriched vesicles from wheat roots incorporated into artificial planar lipid bilayers. Earlier work indicated that this channel was insensitive to 1,4-dihydropyridines (DHPs, such as nifedipine and 202-791). However, the present study shows that this channel is sensitive to DHPs, but only with submillimolar Ca2+, when the probability of channel opening is reduced, with flickery closures becoming increasingly evident as Ca2+ activity decreases. Under these ionic conditions, addition of nanomolar concentrations of (+) 202-791 or nifedipine caused an increase in both the probability of channel opening and the unitary conductance. It is proposed that there is a competitive interaction between Ca2+ and DHPs at one of the Ca2+ binding sites involved in Ca2+ permeation and that binding of a DHP to one of the Ca2+-permeation sites facilitates movement of other calcium ions through the channel. The present study shows that higher plant Ca2+-permeable channels can be greatly affected by very low concentrations of DHPs and that channel sensitivity may vary with the ionic conditions of the experiment. The results also indicate interesting structural and functional differences between plant and animal Ca2+ permeable channels. PMID- 21274524 TI - Isolated unilateral agenesis of the pulmonary artery: surgical repair with an artificial graft. AB - This report describes a 3-month-old Japanese boy with a diagnosis of isolated unilateral agenesis of the proximal right pulmonary artery with severe pulmonary hypertension. One-stage reconstruction of the right pulmonary artery was performed without cardiopulmonary bypass. The hilar right pulmonary artery and the distal main pulmonary artery were joined by anastomosis to an artificial ring graft. The boy's postoperative course was uneventful, and the pressure in the pulmonary artery was within the normal range. Although mild right pulmonary artery stenosis remained, the authors' therapeutic strategy may provide a clinically important option for isolated unilateral agenesis of the pulmonary artery. PMID- 21274525 TI - Geographical and temporal dissemination of salmonellae isolated from domestic animal hosts in the Culiacan Valley, Mexico. AB - The prevalence and diversity of salmonellae from domestic animal hosts were investigated in the Culiacan Valley, Mexico. A total of 240 farm animal feces (cows, chicken, and sheep) were evaluated for Salmonella spp. presence from July 2008 to June 2009. Salmonella enterica subsp. enterica strains were isolated from 76 samples (31.7%), and 20 serotypes were identified being Salmonella Oranienburg (25%), Salmonella Give (14%), Salmonella Saintpaul (12%), and Salmonella Minnesota (11%) the most frequent isolates. Twenty-four percent (18/76) of the isolates were resistant to ampicillin. Salmonella Oranienburg, Salmonella Minnesota, Salmonella Give, Salmonella Agona, Salmonella Weltevreden, and Salmonella Newport serotypes showed multiple pulsed-field electrophoresis patterns. Salmonella Oranienburg was the dominant serotype in the Culiacan Valley; however, no specific distribution patterns were detected in animal sources or sampling sites. The genetic diversity of salmonellae could be an evidence of the continuous animal exposition to the bacteria. Also, Salmonella adaptation in asymptomatic animals could be justified by the development of natural host immunity. This study provides novel information about Salmonella population distribution in domestic animals living at tropical areas. The presence of asymptomatic carriers may be critical to understand the routes of transmission of Salmonella in areas of high disease prevalence. PMID- 21274526 TI - Structural gene variants in the porcine mannose-binding lectin 1 (MBL1) gene are associated with low serum MBL-A concentrations. AB - Mannose-binding lectin (MBL) is a collagenous lectin that kills a wide range of pathogenic microbes through complement activation. The MBL1 and MBL2 genes encode MBL-A and MBL-C, respectively. MBL deficiency in humans is associated with higher susceptibility to viral as well as bacterial infections. A number of single nucleotide polymorphisms (SNP) have been identified in the collagen-like domain of the human MBL gene, of which several are strongly associated with decreased concentrations of MBL in serum. In this study, we have identified a number of SNPs in the porcine MBL-A gene. Sequence comparisons identified a total of 14 SNPs, eight of which were found in exons and six in introns. Four of the eight exon-located SNPs were non-synonymous. Sequence data from several Duroc and Landrace pigs identified four different haplotypes. One haplotype was found in Duroc pigs only, and three haplotypes were found in the Landrace pigs. One of the identified haplotypes was associated with low concentration of MBL-A in serum. The concentration of MBL-A in serum was further assessed in a large number of Duroc and Landrace boars to address its correlation with disease frequency. The MBL-A concentration in Duroc boars showed one single population, whereas Landrace boars showed four distinct populations for MBL-A concentration. The Landrace boars were finally assessed for disease incidence, and the association with the concentration of MBL-A in serum was investigated. No association between MBL and disease incidence was found in this study. PMID- 21274528 TI - Biochemical characterization of a new type of intracellular PHB depolymerase from Rhodospirillum rubrum with high hydrolytic activity on native PHB granules. AB - A Rhodospirillum rubrum gene that is predicted to code for an extracellular poly(3-hydroxybutyrate) (PHB) depolymerase by the recently published polyhydroxyalkanoates (PHA) depolymerase engineering database was cloned. The gene product (PhaZ3( Rru )) was expressed in recombinant E. coli, purified and biochemically characterized. PhaZ3( Rru ) turned out, however, to share characteristics of intracellular PHB depolymerases and revealed a combination of properties that have not yet been described for other PHB depolymerases. A fusion of PhaZ3( Rru )with the enhanced cyan fluorescent protein was able to bind to PHB granules in vivo and supported the function as an intracellular PHB depolymerase. Purified PhaZ3( Rru ) was specific for short-chain-length polyhydroxyalkanoates (PHA(SCL)) and hydrolysed both untreated native PHB granules as well as trypsin activated native PHB granules to a mixture of mono- and dimeric 3 hydroxybutyrate. Crystalline (denatured) PHB granules were not hydrolysed by PhayZ3( Rru ). Low concentrations of calcium or magnesium ions (1-5 mM) reversibly (EDTA) inhibited the enzyme. Our data suggest that PhaZ3( Rru ) is the representative of a new type of the growing number of intracellular PHB depolymerases. PMID- 21274527 TI - Functional analysis of frequently expressed Chinese rhesus macaque MHC class I molecules Mamu-A1*02601 and Mamu-B*08301 reveals HLA-A2 and HLA-A3 supertypic specificities. AB - The Simian immunodeficiency virus (SIV)-infected Indian rhesus macaque (Macaca mulatta) is the most established model of HIV infection and AIDS-related research, despite the potential that macaques of Chinese origin is a more relevant model. Ongoing efforts to further characterize the Chinese rhesus macaques' major histocompatibility complex (MHC) for composition and function should facilitate greater utilization of the species. Previous studies have demonstrated that Chinese-origin M. mulatta (Mamu) class I alleles are more polymorphic than their Indian counterparts, perhaps inferring a model more representative of human MHC, human leukocyte antigen (HLA). Furthermore, the Chinese rhesus macaque class I allele Mamu-A1*02201, the most frequent allele thus far identified, has recently been characterized and shown to be an HLA-B7 supertype analog, the most frequent supertype in human populations. In this study, we have characterized two additional alleles expressed with high frequency in Chinese rhesus macaques, Mamu-A1*02601 and Mamu-B*08301. Upon the development of MHC-peptide-binding assays and definition of their associated motifs, we reveal that these Mamu alleles share peptide-binding characteristics with the HLA A2 and HLA-A3 supertypes, respectively, the next most frequent human supertypes after HLA-B7. These data suggest that Chinese rhesus macaques may indeed be a more representative model of HLA gene diversity and function as compared to the species of Indian origin and therefore a better model for investigating human immune responses. PMID- 21274529 TI - Thyroid protection before 123I-ioflupane (DaTSCAN) imaging. PMID- 21274530 TI - Spatial rule-based assessment of habitat potential to predict impact of land use changes on biodiversity at municipal scale. AB - In human dominated landscapes, ecosystems are under increasing pressures caused by urbanization and infrastructure development. In Alpine valleys remnant natural areas are increasingly affected by habitat fragmentation and loss. In these contexts, there is a growing risk of local extinction for wildlife populations; hence assessing the consequences on biodiversity of proposed land use changes is extremely important. The article presents a methodology to assess the impacts of land use changes on target species at a local scale. The approach relies on the application of ecological profiles of target species for habitat potential (HP) assessment, using high resolution GIS-data within a multiple level framework. The HP, in this framework, is based on a species-specific assessment of the suitability of a site, as well of surrounding areas. This assessment is performed through spatial rules, structured as sets of queries on landscape objects. We show that by considering spatial dependencies in habitat assessment it is possible to perform better quantification of impacts of local-level land use changes on habitats. PMID- 21274531 TI - Long-term benthic macroinvertebrate community monitoring to assess pollution abatement effectiveness. AB - The benthic macroinvertebrate community of East Fork Poplar Creek (EFPC) in East Tennessee was monitored for 18 years to evaluate the effectiveness of a water pollution control program implemented at a major United States (U.S.) Department of Energy facility. Several actions were implemented to reduce and control releases of pollutants into the headwaters of the stream. Four of the most significant actions were implemented during different time periods, which allowed assessment of each action. Macroinvertebrate samples were collected annually in April from three locations in EFPC (EFK24, EFK23, and EFK14) and two nearby reference streams from 1986 through 2003. Significant improvements occurred in the macroinvertebrate community at the headwater sites (EFK24 and EFK23) after implementation of each action, while changes detected 9 km further downstream (EFK14) could not be clearly attributed to any of the actions. Because the stream was impacted at its origin, invertebrate recolonization was primarily limited to aerial immigration, thus, recovery has been slow. As recovery progressed, abundances of small pollution-tolerant taxa (e.g., Orthocladiinae chironomids) decreased and longer lived taxa colonized (e.g., hydropsychid caddisflies, riffle beetles, Baetis). While assessments lasting three to four years may be long enough to detect a response to new pollution controls at highly impacted locations, more time may be needed to understand the full effects. Studies on the effectiveness of pollution controls can be improved if impacted and reference sites are selected to maximize spatial and temporal trending, and if a multidisciplinary approach is used to broadly assess environmental responses (e.g., water quality trends, invertebrate and fish community assessments, toxicity testing, etc.). PMID- 21274532 TI - Mucosal advancement flap anoplasty for chronic anal fissure resistant to conservative therapy. AB - BACKGROUND: Sphincter-sparing procedures are increasingly advocated in the treatment of chronic anal fissures (CAF) resistant to conservative management. Herein, we report about our results with sphincter-sparing transanal mucosal advancement flap anoplasty (MAAP) to treat CAF. PATIENTS AND METHODS: The present study was a retrospective single-center analysis of patients in whom conservative management of CAF failed and who subsequently underwent MAAP between January 2003 and December 2008. RESULTS: A total of 26 patients with a median age of 46.5 years (range: 17-79 years) had undergone MAAP after suffering with CAF for a median period of 9 months (range: 4-36 months). Surgery was well tolerated in all patients. One patient developed a perianal abscess at the operative site 3 weeks after MAAP, which required excision. At 2, 12, and 24 months follow-up, all patients were free of pain with no fissure recurrence or any worsening of incontinence. CONCLUSIONS: Mucosal advancement flap anoplasty might be another sphincter-sparing treatment option in patients suffering from CAF. To draw final conclusions about the value of MAAP in the treatment of CAF, more solid data are required. PMID- 21274533 TI - Erlotinib efficacy and cerebrospinal fluid concentration in patients with lung adenocarcinoma developing leptomeningeal metastases during gefitinib therapy. AB - PURPOSE: We have treated patients with non-small-cell lung cancer (NSCLC) who developed leptomeningeal metastases (LM) during gefitinib therapy, and then found symptomatic improvement following treatment change to erlotinib. Based on this experience, we wondered whether erlotinib could be detected in cerebrospinal fluid (CSF) when it was used for NSCLC patients with LM. This study was conducted to determine erlotinib concentrations in CSF and assess responses to erlotinib in patients with NSCLC developing LM during gefitinib therapy. METHODS: Three advanced NSCLC patients with LM that developed during gefitinib therapy were treated with erlotinib. On day 28 after the initiation of erlotinib treatment, plasma and CSF were obtained and the concentrations of erlotinib in these samples were measured. Eastern Cooperative Oncology Group (ECOG) performance status (PS) and neurologic symptoms were determined. RESULTS: Erlotinib CSF penetration was 6.3% +/- 6.1% (mean +/- SD). In cases 1 and 2, we observed improvements in ECOG PS and neurologic symptoms. In case 3, cytological improvement was seen in the CSF. In each patient, deletion of exon 19 or exon 21 L858R mutation of the epidermal growth factor receptor (EGFR) gene was detected in carcinoma cells from the CSF. CONCLUSIONS: We report on 3 patients with NSCLC who had developed LM during gefitinib treatment and showed clinical improvements following change to erlotinib therapy. In all cases, small but measurable penetration of erlotinib into CSF was observed. Because EGFR mutations were detected in all cases, we suggest that erlotinib is a therapeutic option for LM carcinoma cells with EGFR mutations. PMID- 21274534 TI - Assessment of kidney organ quality and prediction of outcome at time of transplantation. AB - The critical importance of donor organ quality, i.e., number of surviving nephrons, ability to withstand injury, and capacity for repair in determining short- and long-term outcomes is becoming increasingly clear. This review provides an overview of studies to assess donor kidney quality and subsequent transplant outcomes based on clinical pathology and transcriptome-based variables available at time of transplantation. Prediction scores using clinical variables function when applied to large data sets but perform poorly for the individual patient. Histopathology findings in pre-implantation or post-reperfusion biopsies help to assess structural integrity of the donor kidney, provide information on pre-existing donor disease, and can serve as a baseline for tracking changes over time. However, more validated approaches of analysis and prospective studies are needed to reduce the number of discarded organs, improve allocation, and allow prediction of outcomes. Molecular profiling detects changes not seen by morphology or captured by clinical markers. In particular, molecular profiles provide a quantitative measurement of inflammatory burden or immune activation and reflect coordinated changes in pathways associated with injury and repair. However, description of transcriptome patterns is not an end in itself. The identification of predictive gene sets and the application to an individualized patient management needs the integration of clinical and pathology-based variables, as well as more objective reference markers of transplant function, post-transplant events, and long-term outcomes. PMID- 21274536 TI - The surface finite element method for pattern formation on evolving biological surfaces. AB - In this article we propose models and a numerical method for pattern formation on evolving curved surfaces. We formulate reaction-diffusion equations on evolving surfaces using the material transport formula, surface gradients and diffusive conservation laws. The evolution of the surface is defined by a material surface velocity. The numerical method is based on the evolving surface finite element method. The key idea is based on the approximation of Gamma by a triangulated surface Gamma(h) consisting of a union of triangles with vertices on Gamma. A finite element space of functions is then defined by taking the continuous functions on Gamma(h) which are linear affine on each simplex of the polygonal surface. To demonstrate the capability, flexibility, versatility and generality of our methodology we present results for uniform isotropic growth as well as anisotropic growth of the evolution surfaces and growth coupled to the solution of the reaction-diffusion system. The surface finite element method provides a robust numerical method for solving partial differential systems on continuously evolving domains and surfaces with numerous applications in developmental biology, tumour growth and cell movement and deformation. PMID- 21274535 TI - Contribution of the immune system to the chemotherapeutic response. AB - The immune system plays an important role in the surveillance of neoplastic cells by eliminating them before they manifest as full-blown cancer. Despite this, tumors do develop in the presence of a functioning immune system. Conventional chemotherapy and its ability to directly kill tumor cells is one of the most effective weapons in the fight against cancer, however, increasing evidence suggests that the therapeutic efficacy of some cytotoxic drugs relies on their capacity to interact with the immune system. Killing of tumor cells in a manner that favors their capture by immune cells or selective targeting of immunosuppressive pathways by specific chemotherapies promotes the generation of an effective anti-cancer response; however, this alone is rarely sufficient to cause elimination of advanced disease. An understanding of the immunological events occurring in both animal models and patients undergoing chemotherapy will guide decisions for the development of appropriate combinations and scheduling for the integration of chemotherapy with immunotherapy. PMID- 21274537 TI - The variability of male quality and female mate choice decisions: second-order stochastic dominance and the behavior of searchers under a sequential search strategy. AB - The strategy employed by a female to sample prospective mates determines the likelihood that a high-quality male is encountered in the search process. In general, the choosiness of females is expected to depend on the variability of quality amongst the males that are sampled. The sequential search strategy is a prominent model of search behavior that involves the use of a threshold criterion to evaluate encountered individuals. In this paper, we show that the stochastic dominance of one distribution of male quality over another at the second order is necessary and sufficient for the optimal threshold criterion to differ under two distributions of male quality when the cost to sample males is held constant and the mean quality of males under each of the distributions is identical. A difference of the variance of male quality between two distributions does not imply that one distribution stochastically dominates the other at the second order and, hence, should not, in general, be used to assess the relative variability of quality amongst prospective mates. The adjustment of the threshold criterion in response to experimental manipulations of the distribution of male quality has been inferred from induced differences of the duration of search or the number of males sampled in the search process. Here we show that such inferences are unjustified. In particular, the difference of the threshold criterion imposed by second-order stochastic dominance does not determine the distribution under which females are expected to sample a larger number of males in the search process. PMID- 21274538 TI - Therapeutic responses and prognosis in adult-onset Still's disease. AB - To date, the treatment of adult-onset Still's disease (AOSD) has been largely empirical; therefore, this study was conducted to investigate the response to therapy and prognostic factors of AOSD. Fifty-four Korean patients with AOSD were enrolled based on Yamaguchi's criteria. We retrospectively analyzed the treatments and prognosis. Thirty-nine patients (72.2%) were female, and the average age at disease onset was 37.3 years. Twenty-nine patients had a monocyclic disease (53.7%), five had a polycyclic (9.3%) and fifteen had a chronic articular disease (27.7%) and five died (9.3%). The elevated ESR and corticosteroids refractoriness were associated with poor prognosis (P = 0.023 and P = 0.009, respectively). The patients that died were older than those survived (49.2 +/- 11.8 vs. 42.2 +/- 14 year old, P = 0.024). Forty-two patients were treated with non-steroidal anti-inflammatory drugs; however, they also needed corticosteroids and intravenous immunoglobulin (IVIG). Among 50 patients treated with high-dose corticosteroids, 21 patients (42%) were resistant to corticosteroids and treated with IVIG or anti-tumor necrosis factor (TNF) agents. Of the 23 patients medicated with IVIG, the prognosis was better in IVIG responsive patients, indicating a therapeutic effect. Methotrexate was the most commonly used disease modifying anti-rheumatic drugs (27 patients, 50%), and the corticosteroid requirements were lower in the methotrexate-responsive patients. Approximately half of AOSD patients had a poor prognosis and were corticosteroids resistance. An elevated ESR and non-response to corticosteroids were associated with poor prognosis. Patients who died were older than those survived. PMID- 21274539 TI - The effect of local corticosteroid injection on F-wave conduction velocity and sympathetic skin response in carpal tunnel syndrome. AB - The aim of this study was to evaluate the efficacy of steroid injection for the treatment of the carpal tunnel syndrome (CTS), with F-wave parameters and sympathetic skin response (SSR). Seventeen hands of 10 women patients were treated with local steroid injection with 2-month follow-up. All patients underwent single injection into the carpal tunnel. Response to injection was measured nerve conduction studies (NCSs), median nerve F waves, and SSR before and after treatment. To determine the normal values, 42 hands of 21 healthy women were also studied. There was a significant improvement of sensory and motor nerve conduction values when compared to baseline values (P < 0.01). At the end of follow-up period, the median sensory distal latency and the sensory latency differences between the median and the ulnar nerve were improved 35 and 65%, respectively. The maximum, mean F-wave amplitudes and chronodispersion showed a slight improvement with respect to baseline values and controls, but statistical significance was not achieved after treatment. Although no statistically significant improvements were observed in SSR parameters, slightly decreased amplitudes and increased habituation of SSR were noted at the end of the treatment. The present study shows that the local steroid injection results in improvement in NCSs values, but the F-wave parameters were not effectual in short term outcome of CTS treatment. These findings suggest that the sensory latency differences between the median and the ulnar wrist-to-digit 4 are better parameters in the median nerve recovery after treatment than the median sensory distal latency. Furthermore, the SSR does not seem to be a sensitive method in follow-up of CTS treatment. PMID- 21274540 TI - Downregulation of putative UDP-glucose: flavonoid 3-O-glucosyltransferase gene alters flower coloring in Phalaenopsis. AB - Anthocyanin is the primary pigment contributing to red, violet, and blue flower color formation. The solubility of anthocyanins is enhanced by UDP glucose: flavonoid 3-O-glucosyltransferase (UFGT) through transfer of the glucosyl moiety from UDP-glucose to 3-hydroxyl group to produce the first stable pigments. To assess the possibility that UFGT is involved in the flower color formation in Phalaenopsis, the transcriptional activities of PeUFGT3, and other flower color related genes in developing red or white flower buds were examined using RT-PCR analysis. In contrast with chalcone synthase, chalcone isomerase, and anthocyanidin synthase genes, PeUFGT3 transcriptional activity was higher expressed in the red color of Phalaenopsis cultivars. In the red labellum of Phalaenopsis 'Luchia Lady', PeUFGT3 also showed higher expression levels than that in the white perianth. PeUFGT3 was predominantly expressed in the red region of flower among various Phalaenopsis cultivars. To investigate the role of PeUFGT3 in red flower color formation, PeUFGT3 was specifically knocked down using RNA interference technology via virus inducing gene silencing in Phalaenopsis. The PeUFGT3-suppressed Phalaenopsis exhibited various levels of flower color fading that was well correlated with the extent of reduced level of PeUFGT3 transcriptional activity. Furthermore, there was a significant decrease in anthocyanin content in the PeUFGT3-suppressed Phalaenopsis flowers. The decrease of anthocyanin content due to PeUFGT3 gene silencing possibly caused the faded flower color in PeUFGT3-suppressed Phalaenopsis. Consequently, these results suggested that the glycosylation-related gene PeUFGT3 plays a critical role in red color formation in Phalaenopsis. PMID- 21274541 TI - Robotic partial nephrectomy versus laparoscopic partial nephrectomy: a single laparoscopic trained surgeon's experience in the development of a robotic partial nephrectomy program. AB - OBJECTIVES: We evaluated whether the surgical approach during the implementation of a robotic kidney surgery program influenced perioperative and oncologic outcomes. METHODS: We prospectively evaluated a single institution experience with minimally invasive partial nephrectomy between 2006 and 2010. The study cohort comprised 86 consecutively treated patients who underwent laparoscopic partial nephrectomy (LPN, N = 59) or robotic-assisted (RPN, N = 27) partial nephrectomy by a single surgeon. RESULTS: There was no difference between the LPN and RPN cohort in terms of gender, age, operative side, American Society of Anesthesiology score, or preoperative estimated glomerular filtration rate (eGFR). An early unclamping technique was used for 22 (82%) patients in the RPN cohort and 6 (10%) patients in the LPN cohort. (P < 0.001). Warm ischemia time was lower in the RPN cohort (mean 18.5 vs. 28.0 min, P = <0.001) as result of majority undergoing early unclamping. There was no difference in operative time, estimated blood loss, length of stay, transfusion rate, positive surgical margin, or postoperative decrease in eGFR. There was no difference in mean eGFR decrease after early unclamping (16%) versus traditional clamping (22%); however, 11 (29%) patients had greater than 50% decrease in eGFR after traditional clamping versus 0 patients after early unclamping (P = 0.014). CONCLUSION: Patients undergoing RPN during implementation of a robotic kidney surgery program when compared with LPN appear to have equivalent perioperative outcomes and oncologic efficacy. RPN patients had surgery later in our minimally invasive partial nephrectomy experience, and these results may not be generalizable to laparoscopic and/or robotic naive surgeons. PMID- 21274543 TI - Postoperative outcome following pyeloplasty in children using miniflank incision and transanastomotic stent: a prospective observational study. AB - PURPOSE: To assess the postoperative outcome in children undergoing pyeloplasty, using a single transanastomotic indigenized stent. METHODS: 329 pyeloplasties were performed by small miniflank incision (3-5 cm) with lateral position for unilateral cases and prone position for bilateral cases during 1993-2009. The procedure involved decompression of the hydronephrotic sac, single layer anastomosis at the PUJ using 5/6-0 suture (reduction of the pelvis if required). An indigenized # 6, Teflon transanastomotic stent (TAS) with multiple holes (modified recently to a self-retaining loop in pelvis) was placed and taken out through the renal pelvis and the main skin incision. The stent served both as a nephrostomy and a stent. The kidney was not mobilized during the procedure. Postoperative results were assessed for early complications. RESULTS: The mean age of the patients was 3.4 years (1 month-14 years). Bilateral simultaneous pyeloplasties were done in 16 cases with a mean age of 5.6 months (2-12). The stent was removed after 4-5 days in most cases after confirming distal flow on clamping. The post-operative complications included slippage of stent (11), blockage/nondrainage (7), difficult retrieval (4), urine leak (4), urinoma (3) and post-operative infection (1). DTPA scan at 3 months follow-up depicted improved drainage in 271 units, preserved renal function in 58 units and improved renal function more than 5% in 246 units. CONCLUSION: Pyeloplasty using a single Teflon TAS is helpful not only in achieving effective drainage in children undergoing pyeloplasty, but also avoids the complications usually encountered with the use of nephrostomies, or double J stents. PMID- 21274542 TI - Assimilation of water and dietary ions by the gastrointestinal tract during digestion in seawater-acclimated rainbow trout. AB - Recent studies focusing on the consequences of feeding for ion and water balance in freshwater fish have revealed the need for similar comparative studies in seawater fish. A detailed time course sampling of gastrointestinal (GI) tract contents following the ingestion of a single meal of a commercial diet revealed the assimilation of both water and dietary ions (Na(+), Cl(-), K(+), Ca(2+), Mg(2+)) along the GI tract of seawater-acclimated rainbow trout (Oncorhynchus mykiss) which had been fasted for 1 week. Consumption of the meal did not change the drinking rate. There was a large secretion of fluid into the anterior intestine and caecae (presumably bile and/or pancreatic secretions). As a result, net assimilation (63%) of the ingested water along the GI tract was lower than generally reported for fasted trout. Mg(2+) was neither secreted into nor absorbed from the GI tract on a net basis. Only K(+) (93% assimilated) and Ca(2+) (43% assimilated) were absorbed in amounts in excess of those provided by ingested seawater, suggesting that dietary sources of K(+) and Ca(2+) may be important to seawater teleosts. The oesophagus-stomach served as a major site of absorption for Na(+), Cl(-), K(+), Ca(2+), and Mg(2+), and the anterior intestine and caecae as a major site of net secretion for all of these ions, except Cl(-). Despite large absorptive fluxes of these ions, the ionic composition of the plasma was maintained during the digestion of the meal. The results of the present study were compared with previous work on freshwater-acclimated rainbow trout, highlighting some important differences, but also several similarities on the assimilation of water and ions along the gastrointestinal tract during digestion. This study highlights the complicated array of ion and water transport that occurs in the intestine during digestion while revealing the importance of dietary K(+) and Ca(2+) to seawater-acclimated rainbow trout. Additionally, this study reveals that digestion in seawater-acclimated rainbow trout appears to compromise intestinal water absorption. PMID- 21274545 TI - Intestinal spirochetosis as a causative factor for colocolic intussusception. PMID- 21274544 TI - NOD2 exonic variations in Iranian Crohn's disease patients. AB - PURPOSE: The NOD2 gene is known to have a strong association with Crohn's disease, but different trends were reported in occurrence of NOD2 variants in distinct ethnicities. The aim of this study was to assess all exonic sequences of the NOD2 gene in Iranian Crohn's disease patients and healthy controls to identify any existing variation and evaluate their association with Crohn's disease. METHODS: A total of 90 non-related Crohn's disease patients and 120 sex- and age-matched healthy controls of Iranian origin were enrolled in this study. The participants were referred to a tertiary center in a 2-year period (2006 2008). The exonic regions of the NOD2 gene were amplified by polymerase chain reaction and evaluated by direct sequencing. RESULTS: A total of 21 sequence variations were identified among all exonic regions of the NOD2 gene, of which eight had an allele frequency of more than 5%. Eight new mutations (one in exon 2 and seven in exon 4) were observed. The three main variants (R702W, G908R, and 1007fs) showed allele frequencies of 13.3%, 2.2%, and 1.7%, respectively. Three new variations (P371T, A794P, and Q908H) and R702W mutation were significantly more frequent in Crohn's disease patients compared to controls. CONCLUSIONS: Eight novel mutations were identified in the NOD2 exons, but the pathophysiological importance of these variants remains unclear. Iranian patients with their different genetic reservoirs may demonstrate some novel characteristics for disease susceptibility. PMID- 21274546 TI - [Hospital financing for 2011: relevant changes in rheumatology]. AB - The following article presents the major general and specific changes for rheumatology in the financing of inpatient care in Germany for 2011. In addition to relevant changes in the G-DRG classification system and coding, the new legislation and insurance company auditing procedures are covered. The impact these changes will have on hospitals specialized in rheumatology is discussed. PMID- 21274547 TI - Are venotonic drugs effective for decreasing acute posttraumatic oedema following ankle sprain? A prospective randomized clinical trial. AB - OBJECTIVE: Lower leg oedema after trauma may cause various degrees of pain, disability and delay in patient recovery. In this prospective randomized study, we hypothesized that venotonic drugs had no effect in clinical outcome of patients with ankle sprain. PATIENTS AND METHODS: Eighty-one patients with type II and III ankle sprain were screened and randomly assigned for receiving standard conservative treatment alone (control group, 39 patients) or with oral intake of a venotonic drug (micronized purified flavonoid fraction, Daflon 1,000 mg * 3) for 20 days (study group, 42 patients). Measurement of the circumference of ankle region in two different locations and assessment of pain intensity with the Visual Analogue Score were performed at the time of patients' admission and during the 7th and 20th posttraumatic day. RESULTS: Patients demographics were comparable in both groups. There were no significant differences between the two groups regarding the values of perimeter of ankle joint or pain intensity at all the examined time points. CONCLUSIONS: Venotonic drugs seem not to decrease the posttraumatic oedema or pain in patients who suffer from moderate or severe ankle sprain. PMID- 21274548 TI - Relation between alignments of upper and subaxial cervical spine: a radiological study. AB - OBJECTIVE: To reveal the relation between alignments of upper and subaxial cervical spine and deduce the optimal atlantoaxial fusion angle by a radiological study. METHODS: 414 asymptomatic volunteers (213 males, 201 females) underwent cervical lateral radiographs in neutral position. The Oc-C2 angle, C1-C2 angle and C2-C7 angle were measured. Relations among these three angles and relations between angles and age were analyzed. RESULTS: The mean Oc-C2 angle was 16.3 degrees +/- 7.0 degrees in females, significantly larger than 14.9 degrees +/- 6.5 degrees in males. The mean C1-C2 angles were 28.2 degrees +/- 4.0 degrees in females and 26.4 degrees +/- 4.6 degrees in males, and C2-C7 angles were 12.7 degrees +/- 6.6 degrees and 16.3 degrees +/- 7.3 degrees , correspondingly. The mean C1-C2 angle in females was significantly larger than that in males, while C2-C7 angle smaller than that in males. The C2-C7 angle correlated significantly not only with C1-C2 angle but also with Oc-C2 angle. And correlation between C1-C2 angle and C2-C7 angle was stronger than that between Oc C2 angle and C2-C7 angle. There were also significant positive correlations between C1-C2 and Oc-C2 angles. Oc-C2 angle, C1-C2 angle, and C2-C7 angle correlated significantly with age in both sexes. CONCLUSIONS: There were negative correlations between C1-C2 angle and C2-C7 angle as well as between Oc-C2 angle and C2-C7 angle, and the former correlation was stronger. C1-C2 fixation angle was the key to regulate postoperative subaxial alignment in atlantoaxial arthrodesis. The optimal atlantoaxial fusion angle may be between 25 degrees and 30 degrees . PMID- 21274549 TI - Mast cell chymase is present in uterine cervical carcinoma and it detaches viable and growing cervical squamous carcinoma cells from substratum in vitro. AB - Increased numbers of mast cells is a typical feature of a variety of human cancers. The major mediators in the secretory granules of the MC(TC) type of mast cells, serine proteinases tryptase and chymase, may be involved in squamous cell carcinoma (SCC) lesions by inducing matrix remodeling and epithelial cell detachment. The objective of this study was to analyze immunohistochemically whether MC(TC) mast cells as well as protease inhibitors, squamous cell carcinoma antigens (SCCAs), are present in the uterine cervical SCC. In addition, the effect of tryptase and chymase on uterine cervical SCC cell lines was studied in vitro. Here we report that tryptase- and chymase-positive mast cells are present in significant numbers in the peritumoral stroma of SCC lesions. Also, weak SCCA 2 immunoreactivity is observed in the SCC lesions, but only SCCA-1 in uterine cervical specimens with nonspecific inflammation. In cell cultures, especially chymase, but not tryptase, was shown to induce effective detachment of viable, growing and non-apoptotic SiHa SCC cells from substratum. Chymase also detached viable ME-180 SCC cells from substratum as well as degraded fibronectin. In contrast, normal keratinocytes underwent apoptotic cell death after similar prolonged chymase treatment. No inhibition of chymase was detected by SiHa cell sonicates nor did these cells express marked SCCA immunopositivity. MC(TC) mast cells containing tryptase and chymase are present in the peritumoral stroma of uterine cervical SCC and the malignant cells are only weakly immunoreactive for the chymase inhibitor SCCA-2. It is chymase that appears to be capable of inducing effective detachment of viable and growing SCC cells and therefore, it may release SCC cells from a tumor leading to spreading of malignant cells. PMID- 21274550 TI - Airway management in critically ill patients. AB - In critically ill patients, endotracheal intubation is associated with a high risk of complications, including severe hypoxemia and hypotension. The purpose of this review is to discuss the definitions, complications, airway assessment, and patient optimization with respect to these patients. In addition, we present different approaches and techniques to help secure the airway in critically ill patients. We also discuss strategies to help minimize the risk of a difficult or failed airway and to mitigate the severe life-threatening complications associated with this high-risk procedure. PMID- 21274551 TI - H3.5 is a novel hominid-specific histone H3 variant that is specifically expressed in the seminiferous tubules of human testes. AB - The incorporation of histone variants into chromatin plays an important role for the establishment of particular chromatin states. Six human histone H3 variants are known to date, not counting CenH3 variants: H3.1, H3.2, H3.3 and the testis specific H3.1t as well as the recently described variants H3.X and H3.Y. We report the discovery of H3.5, a novel non-CenH3 histone H3 variant. H3.5 is encoded on human chromosome 12p11.21 and probably evolved in a common ancestor of all recent great apes (Hominidae) as a consequence of H3F3B gene duplication by retrotransposition. H3.5 mRNA is specifically expressed in seminiferous tubules of human testis. Interestingly, H3.5 has two exact copies of ARKST motifs adjacent to lysine-9 or lysine-27, and lysine-79 is replaced by asparagine. In the Hek293 cell line, ectopically expressed H3.5 is assembled into chromatin and targeted by PTM. H3.5 preferentially colocalizes with euchromatin, and it is associated with actively transcribed genes and can replace an essential function of RNAi-depleted H3.3 in cell growth. PMID- 21274553 TI - Reconstruction of devastating head injuries: a useful method in forensic pathology. AB - Crushing head injuries usually do not allow direct visual identification of individuals, and above all, it constitutes an obstacle to comprehensive evaluation of discrete traumatic changes of the skin and soft tissues. We present our experience with the plastic adaptation of devastating head injuries in the two exemplary cases. The principal of the reconstruction is manual repositioning of bone fragments of the cranial and facial parts of the skull and careful approximation of the wound edges and their gradual suture using suture material. The reconstruction method can be recommended as an auxiliary technique in the identification of unknown victims with crushing head injuries and in the evaluation of devastating gunshot wound of the head. PMID- 21274552 TI - Chromatin configuration and epigenetic landscape at the sex chromosome bivalent during equine spermatogenesis. AB - Pairing of the sex chromosomes during mammalian meiosis is characterized by the formation of a unique heterochromatin structure at the XY body. The mechanisms underlying the formation of this nuclear domain are reportedly highly conserved from marsupials to mammals. In this study, we demonstrate that in contrast to all eutherian species studied to date, partial synapsis of the heterologous sex chromosomes during pachytene stage in the horse is not associated with the formation of a typical macrochromatin domain at the XY body. While phosphorylated histone H2AX (gammaH2AX) and macroH2A1.2 are present as a diffuse signal over the entire macrochromatin domain in mouse pachytene spermatocytes, gammaH2AX, macroH2A1.2, and the cohesin subunit SMC3 are preferentially enriched at meiotic sex chromosome cores in equine spermatocytes. Moreover, although several histone modifications associated with this nuclear domain in the mouse such as H3K4me2 and ubH2A are conspicuously absent in the equine XY body, prominent RNA polymerase II foci persist at the sex chromosomes. Thus, the localization of key marker proteins and histone modifications associated with the XY body in the horse differs significantly from all other mammalian systems described. These results demonstrate that the epigenetic landscape and heterochromatinization of the equine XY body might be regulated by alternative mechanisms and that some features of XY body formation may be evolutionary divergent in the domestic horse. We propose equine spermatogenesis as a unique model system for the study of the regulatory networks leading to the epigenetic control of gene expression during XY body formation. PMID- 21274555 TI - Subfoveal choroidal thickness in typical age-related macular degeneration and polypoidal choroidal vasculopathy. AB - PURPOSE: To investigate the subfoveal choroidal thickness in eyes with typical age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV), using enhanced depth imaging optical coherence tomography. METHODS: Retrospective observational case series of 44 eyes of 44 patients (12 females and 32 males) with typical AMD or PCV located in the subfoveal region. Cross sectional images of the choroid of each of the involved eyes were obtained by a spectral-domain OCT. The choroidal thickness under the fovea was retrospectively studied. RESULTS: Of the 44 eyes involved in this study, 21 eyes were diagnosed as typical AMD and the other 23 eyes were diagnosed as PCV. The difference in subfoveal choroidal thickness between the eyes with typical AMD (245 MUm) and those with PCV (293 MUm) was statistically significant, even after adjusting for age, spherical equivalent, and gender distribution (P = 0.045). When compared to eyes with subfoveal choroidal thickness less than 300 MUm, those with subfoveal choroidal thickness of 300 MUm or more were 5.6 times more likely to have PCV (adjusted odds ratio 5.60, 95% confidence interval 1.30-24.0, P = 0.021). CONCLUSIONS: The choroid under the fovea was thicker in eyes with PCV than those with typical AMD. This result suggests that the choroidal vascular lesion seen in PCV may not be just the choroidal neovascularization accompanied by saccular capillary dilations at the border, but may have a significant structural difference in the choroid compared to typical AMD. PMID- 21274556 TI - Comparative expression of hexose transporters (SGLT1, GLUT1, GLUT2 and GLUT5) throughout the mouse gastrointestinal tract. AB - Hexose transporters play a pivotal role in the absorption of food-derived monosaccharides in the gastrointestinal tract. Although a basic knowledge of the hexose transporters has already been gained, their detailed distribution and comparative intensities of expression throughout the gastrointestinal tract have not been fully elucidated. In this study, we quantitatively evaluated the expression of SGLT1, GLUT1, GLUT2, and GLUT5 by in situ hybridization and real time PCR techniques using a total of 28 segments from the gastrointestinal tract of 9-week-old mice. GLUT2 and GLUT5 mRNA expressions were detected predominantly from the proximal to middle parts of the small intestine, showing identical expression profiles, while SGLT1 mRNA was expressed not only in the small intestine but also in the large intestine. Notably, GLUT1 mRNA was expressed at a considerable level in both the stomach and large intestine but was negligible in the small intestine. Immunohistochemistry demonstrated the polarized localization of hexose transporters in the large intestine: SGLT1 on the luminal surface and GLUT1 on the basal side of epithelial cells. The present study provided more elaborate information concerning the localization of hexose transporters in the small intestine. Furthermore, this study revealed the significant expression of glucose transporters in the large intestine, suggesting the existence of the physiological uptake of glucose in that location in mice. PMID- 21274557 TI - No protective role for hypoxic pulmonary vasoconstriction in severe hypergravity induced arterial hypoxemia. AB - Supine subjects exposed to hypergravity show a marked arterial desaturation. Previous work from our laboratory has also shown a paradoxical reduction of lung perfusion in dependent lung regions in supine subjects exposed to hypergravity. We reasoned that the increased lung weight during hypergravity caused either direct compression of the blood vessels in the dependent lung tissue or that poor regional ventilation caused reduced perfusion through hypoxic pulmonary vasoconstriction (HPV). The objective of this study was to evaluate the importance of HPV through measurements of arterial oxygenation during exposure to hypergravity with normal and attenuated HPV. A further increased arterial desaturation during hypergravity with attenuated HPV would support the hypothesis that HPV contributes to the paradoxical redistribution of regional perfusion. In a two-phased randomized study we first exposed 12 healthy subjects to 5 G while supine during two single-blinded conditions; control and after 50 mg sildenafil p.o.. In a second phase, 12 supine subjects were exposed to 5 G during three single-blinded conditions; control, after 100 mg sildenafil p.o. and after inhalation of 10 MUg iloprost. There was a substantial arterial desaturation by 5 30% units in all subjects with no or only minor differences between conditions. The results speak against HPV as a principal mechanism for the hypergravity induced reduction of lung perfusion in dependent lung regions in supine humans. PMID- 21274558 TI - Sonographic findings predictive of the need for surgical management in pediatric patients with small bowel intussusceptions. AB - PURPOSE: This study aims to evaluate ultrasound findings that are predictive of the need for surgical management in pediatric patients with small bowel intussusceptions (SBIs). METHODS: A retrospective review of pediatric patients with SBIs treated from 2004 to 2009 was conducted. Patients were divided into surgical and non-surgical groups. Demographic data, ultrasound findings, treatments, and outcomes were collected and analyzed. RESULTS: There were 56 cases of SBIs in 31 males and 25 females ranging in age from 4 months to 9 years; 39 patients were managed conservatively and 17 patients underwent surgery. The mean length and diameter of the intussusception in the surgical group were 6.53 and 2.78 cm, respectively, and 3.21 and 1.81 cm, respectively in the non-surgical group (both, P < 0.001). Multivariate logistic regression analysis indicated that diameter, length, and thickness of the outer rim were independent predictors of surgery. Receiver operating characteristic curve analysis indicated an intussusception diameter >=2.1 cm, length >=4.2 cm, and thickness of the outer rim >=0.40 cm were optimal cutoff values for predicting the need for surgery. CONCLUSIONS: A diameter >=2.1 cm, length >=4.2 cm, and thickness of the outer rim >=0.40 cm predict the need for surgical management in pediatric patients with SBIs. PMID- 21274560 TI - Ectopic expression of a novel peach (Prunus persica) CBF transcription factor in apple (Malus * domestica) results in short-day induced dormancy and increased cold hardiness. AB - Low, non-freezing temperatures and/or short daylength (SD) regulates cold acclimation and dormancy in fruit trees. Regarding cold acclimation, C-repeat binding factor (CBF/DREB) transcriptional activator genes have the well documented ability to induce the expression of a suite of genes associated with increased cold tolerance. We isolated a full-length cDNA of a peach CBF gene, designated PpCBF1 (GenBank Accession HM992943), and constitutively expressed it using an enhanced 35S promoter in apple. Unexpectedly, constitutive overexpression of the PpCBF1 in apple resulted in strong sensitivity to short daylength. Growth cessation and leaf senescence were induced in transgenic lines exposed to SD and optimal growth temperatures of 25 degrees C over a 4-week period. Following 1-4 weeks of SD and 25 degrees C trees were returned to LD and 25 degrees C in the greenhouse. Control (untransformed) plants continued to grow while transgenic lines receiving two or more weeks of SD remained dormant and began to drop leaves. Constitutive overexpression of the PpCBF1 in apple resulted in a 4-6 degrees C increase in freezing tolerance in both the non-acclimated and acclimated states, respectively, compared with untransformed M.26 trees. This is the first instance that constitutive overexpression of a CBF gene has resulted in SD-induction of dormancy and to our knowledge the first time apple has been shown to strongly respond to short daylength as a result of the insertion of a transgene. PMID- 21274559 TI - The diversity and commonalities of gastroenteropancreatic neuroendocrine tumors. AB - BACKGROUND: Recent data demonstrate that the incidence of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) has increased exponentially (overall ~500%) over the last three decades, thus refuting the erroneous concept of rarity. GEP-NETs comprise 2% of all malignancies and in terms of prevalence, are the second commonest gastrointestinal malignancy after colorectal cancer. Diagnosis is usually late since there is no biochemical screening test and symptoms are protean and overlooked. As a consequence, 60-80% exhibit metastases with a consequent suboptimal outcome. DISCUSSION: The gastrointestinal tract and pancreas exhibit ~17 different neuroendocrine cell types, but neither the cell of origin nor the biological basis of GEP-NETs is understood. This review examines GEP-NETs from the cellular and molecular perspective and addresses the distinct patterns of functional tumor biology pertinent to clinicians. Although grouped as a neoplastic entity (NETs), each lesion is derived from distinct cell precursors, produces specific bioactive products, exhibits distinct chromosomal abnormalities and somatic mutation events and has uniquely dissimilar clinical presentations. GEP-NETs demonstrate very different survival rates reflecting the intrinsic differences in malignant potential and variations in proliferative regulation. Apart from the identification of the inhibitory role of the somatostatin receptors, there is limited biological knowledge of the key regulators of proliferation and hence a paucity of successful targeted therapeutic agents. IGF I, TGFbeta and a variety of tyrosine kinases have been postulated as key regulatory elements; rigorous data is still required to define predictably effective and rational therapeutic strategy in an individual tumor. A critical issue in the clinical management of GEP-NETs is the need to appreciate both the neuroendocrine commonalities of the disease as well as the unique characteristics of each tumor. The further acquisition of a detailed biological and molecular appreciation of GEP-NETs is vital to the development of effective management strategy. PMID- 21274561 TI - Visualisation of stromules in transgenic wheat expressing a plastid-targeted yellow fluorescent protein. AB - Stromules are stroma-filled tubules that extend from the plastids in all multicellular plants examined to date. To facilitate the visualisation of stromules on different plastid types in various tissues of bread wheat (Triticum aestivum L.), a chimeric gene construct encoding enhanced yellow fluorescent protein (EYFP) targeted to plastids with the transit peptide of wheat granule bound starch synthase I was introduced by Agrobacterium-mediated transformation. The gene construct was under the control of the rice Actin1 promoter, and EYFP fluorescence was detected in plastids in all cell types throughout the transgenic plants. Stromules were observed on all plastid types, although the stromule length and abundance varied markedly in different tissues. The longest stromules (up to 40 MUm) were observed in epidermal cells of leaves, whereas only short beak-like stromules were observed on chloroplasts in mesophyll cells. Epidermal cells in leaves and roots contained the highest proportion of plastids with stromules, and stromules were also abundant on amyloplasts in the endosperm tissue of developing seeds. The general features of stromule morphology and distribution were similar to those shown previously for tobacco (Nicotiana tabacum L.) and arabidopsis (Arabidopsis thaliana (L.) Heynh.). PMID- 21274562 TI - Study of patients with Hyper-IgM type IV phenotype who recovered spontaneously during late childhood and review of the literature. AB - Hyper-IgM syndromes are characterized by normal or elevated serum IgM levels with the absence or reduced levels of other immunoglobulins. There are some patients with defective class-switch recombination (CSR) who do not have CD40L, CD40, AID, and UNG defects. The aim of this study is to determine the B-cell functions of patients with Hyper-IgM type 4 phenotype. Ten patients (seven males and three females) 84.2 +/- 16.5 months of age with initial low serum IgG and IgA and high or normal IgM levels were included. Clinically, 50% had recurrent upper respiratory tract, 10% urinary tract, 10% lower respiratory tract infections, and 30% had mixed type infections. Lymphoid hyperplasia, overt autoimmune manifestations, or malignancy was not noted. Seven of 10 patients were studied twice; at the age of 34.2 +/- 13.7 and at 86.6 +/- 12.3 months. Absolute lymphocyte counts and lymphocyte subsets were normal in all cases. All of them had normal expression of CD40 on B cells and CD40L on activated T cells for males. At first examination, all patients had normal in vitro sCD40L+rIL-4 induced B cell proliferation response and somatic hypermutation but CSR towards IgE was absent. AID and UNG genes did not show any abnormalities. All showed improvement in both clinical findings and Ig levels during the follow-up period of 55.8 +/- 14.8 months. Ages for normalization of IgG and IgA were 68.2 +/- 8.7 and 70.2 +/- 21.6 months, respectively. During the second evaluation: In vitro sCD40L+rIL-4-induced B-cell proliferation was normal in all cases, whereas CSR was still abnormal in five of eight patients. Two of the patients had an increase in in vitro CSR response but still low IgG2 subclass levels. Three patients with initially absent in vitro CSR response also normalized. CONCLUSION: Clinical manifestations and immunoglobulin levels of the patients with Hyper-IgM type 4 phenotype recovered in late childhood at about 6 years of age. There was a transient CSR defect which was not observed in cases with transient hypogammaglobulinemia of infancy. Detection of a non-AID or non-UNG associated CSR defect in infancy should be confirmed later on since spontaneous recovery may occur. PMID- 21274563 TI - Clinical and epidemiological characteristics of patients with influenza A (H1N1) 2009 attended to at the emergency room of a children's hospital. AB - In June 2009, the first influenza pandemic of the twenty-first century, due to the swine origin influenza A (H1N1) 2009 virus, was declared. This study aimed to describe the epidemiological and clinical features, complications, lethality and risk factors for hospital admission of microbiologically confirmed cases of influenza A (H1N1) 2009 infection seen at the emergency department of a children's hospital. All cases of children with influenza A (H1N1) 2009 viral infection, confirmed microbiologically by real-time reverse transcription polymerase chain reactions and treated in the emergency room between July and December 2009, were prospectively included. Patients were compared according to admission requirement to study variables associated with the risk of hospitalisation. Oseltamivir was the antiviral used for the treatment and its safety was analysed. Four hundred and twelve patients with influenza A (H1N1) 2009 infection were included. The most frequent symptoms were: fever (96%), cough (95%) and coryza (90%). Eighty-five patients (20.6%) were admitted: three to the paediatric intensive care unit and two died. Hospitalised children were younger than those not admitted (median age 5 vs 8 years; p = 0.001). Age under 1 year (OR 6.01; CI 95% 2.77-13.05), pneumonia (OR 7.99; CI 95% 3.50-18.22) and haemoglobinopathy or underlying blood disorders (OR 5.99; CI 95% 1.32-27.30) were statistically significant risk factors for admission. No differences were observed regarding onset of antiviral treatment among admitted and non-admitted patients. Treatment with oseltamivir was well tolerated. In conclusion, the incidence of severe cases and lethality of influenza A (H1N1) 2009 infection were low in our setting, even in a population with risk factors for developing complications. PMID- 21274564 TI - Palliative care for children and adolescents in Switzerland: a needs analysis across three diagnostic groups. AB - The objective of this qualitative study was to explore the perceptions and needs of families who care for a child with a life-limiting disease. Considering the heterogeneity of life-limiting diseases in childhood, three diagnostic groups were defined: (a) cancer, (b) neurological disorders, and (c) non-cancer/non neurological conditions. Fifteen parents whose child had been treated in one of four children's hospitals and received palliative care or had died within the previous 2 years were interviewed. The main interview topics were: communication with professionals, need for support in care (at home or hospital), and bereavement support. Irrespective of the center of care, parents of children with diagnoses other than cancer reported a lack of support concerning practical issues of care and psychosocial aspects. Parents of children with cancer expressed difficulties related to coordination of care especially when care was provided at home. Bereaved parents emphasized their wish for bereavement support. Our findings demonstrate shortcomings in pediatric palliative care in Switzerland and outline basic needs of affected families including psychosocial support, coordination of care and bereavement support. Based on these findings we formulate some suggestions on how to initiate pediatric palliative care in a most efficient way and tailored to the needs of families in Switzerland. PMID- 21274565 TI - A case report of hyperthyroid-associated thymic hypertrophy in a child, presenting as an anterior mediastinal mass. AB - We present the case of an 8-year-old boy with an anterior mediastinal mass and signs of hyperthyroidism. The anterior mediastinal mass had radiologic characteristics suggestive of thymic hypertrophy and regressed with antithyroid therapy. Though thymic hypertrophy is a known manifestation of hyperthyroidism, this is the youngest reported case. In selected cases, the diagnosis may be made based on the clinical picture, radiologic appearance, and response to antithyroid therapy without the need of a thymic biopsy or thymectomy. PMID- 21274567 TI - Origin and hierarchy of basal lamina-forming and -non-forming myogenic cells in mouse skeletal muscle in relation to adhesive capacity and Pax7 expression in vitro. AB - As a novel approach to distinguish skeletal myogenic cell populations, basal lamina (BL) formation of myogenic cells was examined in the mouse compensatory enlarged plantaris muscles in vivo and in fiber-bundle cultures in vitro. MyoD(+) myogenic cells located inside the regenerative muscle fiber BL were laminin(-) but interstitial MyoD(+) cells were laminin(+). This was also confirmed by electron microscopy as structural BL formation. Similar trends were observed in the fiber-bundle cultures including satellite cells and interstitial myogenic cells and laminin(+) myogenic cells predominantly showed non-adhesive (non-Ad) behavior with Pax7(-), whereas laminin(-) cells were adhesive (Ad) with Pax7(+). Moreover, non-Ad/laminin(+) and Ad/laminin(-) myotubes were also observed and the former type showed spontaneous contractions, while the latter type did not. The origin and hierarchy of Ad/Pax7(+)/laminin(-) and non-Ad/Pax7(-)/laminin(+) myogenic cells were also examined using skeletal muscle interstitium-derived CD34(+)/45(-) (Sk-34) and CD34(-)/45(-) (Sk-DN) multipotent stem cells, which were composed of non-committed myogenic cells with a few (<1%) Pax7(+) cells in the Sk-DN cells at fresh isolation. Both cell types were separated by Ad/non-Ad capacity in repetitive culture. As expected, both Ad/Pax7(+)/laminin(-) and non Ad/Pax7(-)/laminin(+) myogenic cells consistently appeared in the Ad and non-Ad cell culture. However, Ad/Pax7(+)/laminin(-) cells were repeatedly detected in the non-Ad cell culture, while the opposite phenomenon did not occur. This indicates that the source of non-Ad/ Pax7(-)/laminin(+) myogenic cells was present in the Sk-34 and Sk-DN stem cells and they were able to produce Ad/ Pax7(+)/ laminin(-) myogenic cells during myogenesis as primary myoblasts and situated hierarchically upstream of the latter cells. PMID- 21274566 TI - Inhibition of SAH-hydrolase activity during seed germination leads to deregulation of flowering genes and altered flower morphology in tobacco. AB - Developmental processes are closely connected to certain states of epigenetic information which, among others, rely on methylation of chromatin. S adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) are key cofactors of enzymes catalyzing DNA and histone methylation. To study the consequences of altered SAH/SAM levels on plant development we applied 9-(S)-(2,3 dihydroxypropyl)-adenine (DHPA), an inhibitor of SAH-hydrolase, on tobacco seeds during a short phase of germination period (6 days). The transient drug treatment induced: (1) dosage-dependent global DNA hypomethylation mitotically transmitted to adult plants; (2) pleiotropic developmental defects including decreased apical dominance, altered leaf and flower symmetry, flower whorl malformations and reduced fertility; (3) dramatic upregulation of floral organ identity genes NTDEF, NTGLO and NAG1 in leaves. We conclude that temporal SAH-hydrolase inhibition deregulated floral genes expression probably via chromatin methylation changes. The data further show that plants might be particularly sensitive to accurate setting of SAH/SAM levels during critical developmental periods. PMID- 21274568 TI - Apoptosis in the developing human heart resembles apoptosis in epithelial tissues. AB - It is widely accepted that apoptosis plays an important role in the development of the heart as well as in different heart diseases. Despite extensive research efforts, many issues regarding apoptosis in the heart remain unsolved, including the detection of apoptotic cardiomyocytes, their morphological features, the mechanisms of their removal and the clinical significance of apoptosis in the heart. It has been suggested that fetal cardiomyocytes resemble epithelial tissues. To test this hypothesis, we analyzed the expression of an epithelial marker cytokeratin 18 (CK18) and caspase-cleaved-CK18, recognized by antibody M30, as well as the expression of cleaved caspase-3 and desmosomal and classical cadherins, major components of desmosomes and adherens junctions in fetal hearts in comparison to infant and adult human hearts. We found that, in fetal hearts, cardiomyocytes expressed CK18 and that apoptotic cardiomyocytes expressed caspase cleaved CK18, being recognized by antibody M30. Furthermore, desmosomal and classical cadherins exhibited a membraneous reaction similar to epithelial tissues. In adults and children after the age of 6 months, cadherins were localized in the intercalated disks, cardiomyocytes lost CK18 expression and apoptotic cardiomyocytes were no longer recognized by M30. We conclude that apoptosis in the developing human heart resembles apoptosis in epithelial tissues, exhibiting different characteristics than in the adult human heart. PMID- 21274569 TI - Molecular evolution and functional characterization of the orexigenic peptide 26RFa and its receptor in vertebrates. AB - Several neuropeptides possessing the RFamide motif at their C-termini (designated RFamide peptides) have been characterized in the hypothalamus of a variety of vertebrates. To date, five groups of the RFamide peptide family have been shown to exert several important neuroendocrine, behavioral, sensory, and autonomic functions. Since the discovery of the 26-amino acid RFamide peptide (termed 26RFa) from the frog brain, 26RFa has been shown to exert orexigenic activity in mammals and to be a ligand of the previously identified orphan G-protein-coupled receptor GPR103. Recently, 26RFa and its cognate receptor GPR103 have been identified in the brain of birds. This mini-review summarizes the advances in the identification, localization, and functions of 26RFa and its cognate receptor GPR103 in vertebrates and highlights recent progress made in birds. PMID- 21274570 TI - Quantitative analysis of denatured collagen by collagenase digestion and subsequent MALDI-TOF mass spectrometry. AB - Collagens are the most abundant proteins in vertebrate tissues and constitute significant moieties of the extracellular matrix (ECM). The determination of the collagen content is of relevance not only in the field of native tissue research, but also regarding the quality assessment of bioengineered tissues. Here, we describe a quantitative method to assess small amounts of collagen based on MALDI TOF (matrix-assisted laser desorption/ionization time-of-flight) mass spectrometry (MS) subsequent to digestion of collagen with clostridial collagenase (clostridiopeptidase A) in order to obtain characteristic oligopeptides. Among the resulting peptides, Gly-Pro-Hyp, which is highly indicative of collagen, has been used to assess the amount of collagen by comparing the Gly-Pro-Hyp peak intensities with the intensities of a spiked tripeptide (Arg-Gly-Asp). The approach presented herein is both simple and convenient and allows the determination of collagen in microgram quantities. In tissue samples such as cartilage, the actual collagen content has additionally been determined for comparative purposes by nuclear magnetic resonance spectroscopy subsequent to acidic hydrolysis. Both methods give consistent data within an experimental error of +/-10%. Although the differentiation of the different collagen types cannot be achieved by this approach, the overall collagen contents of tissues can be easily determined. PMID- 21274571 TI - A landscape perspective on bat foraging ecology along rivers: does channel confinement and insect availability influence the response of bats to aquatic resources in riverine landscapes? AB - River and riparian areas provide an important foraging habitat for insectivorous bats owing to high insect availability along waterways. However, structural characteristics of the riverine landscape may also influence the location of foraging bats. We used bat detectors to compare bat activity longitudinally along river reaches with contrasting channel confinement, ratio of valley floor width to active channel width, and riparian vegetation, and laterally with distance from the river along three different reach types. We measured rates of insect emergence from the river and aerial insect availability above the river and laterally up to 50-m into the riparian habitat in order to assess the relationship between food resources and insectivorous bat activity. Longitudinally, bat activity was concentrated along confined reaches in comparison to unconfined reaches but was not related to insect availability. Laterally, bats tracked exponential declines in aquatic insects with distance from the river. These data suggest that along the lateral dimension bats track food resources, but that along the longitudinal dimension channel shape and landscape structure determine bat distributions more than food resources. PMID- 21274572 TI - Indirect effects of species interactions on habitat provisioning. AB - Species that shelter in a biogenic habitat can influence their refugia and, in turn, play an essential role in shaping local patterns of biodiversity. Here we explore a positive feedback loop between the provisioning rate of habitat-forming branching corals and their associated fishes and show how interactions between two groups of fish--the planktivorous damselfish and predatory hawkfish--altered the feedback. A field experiment confirmed that skeletal growth of branching coral (genus Pocillopora) increased substantially with increasing numbers (biomass) of resident fishes, likely because they greatly increased the interstitial concentrations of nutrients. Because there is a positive relationship between colony size and number (biomass) of associated fishes (primarily damselfishes in the Family Pomacentridae), a structure-function feedback loop exists in which increasing numbers of damselfish enhance coral growth and larger corals host greater abundances (and species richness) of fish. However, interactions between damselfishes and arc-eye hawkfish, Paracirrhites arcatus, a largely solitary resident, can disrupt this positive feedback loop. Field surveys revealed a marked pattern of fish occupancy related to coral size: Pocillopora colonies of sufficient size to host fish (>40 cm circumference) had either groups of damselfish or an arc-eye hawkfish; only larger colonies (>75 cm) were occupied by both the damselfish and hawkfish. Subsequent short- and long term experiments revealed that on intermediate-sized Pocillopora colonies, arc eye hawkfish prevented the establishment of damselfish by suppressing their recruitment. The demographic consequences to the host coral were substantial; in a 1-year-long experiment, intermediate-size Pocillopora occupied by hawkfish grew at half the rate of corals that hosted groups of damselfish. These findings indicate that: (1) species which occupy a biogenic habitat can enhance the provisioning rate of their habitat; (2) such positive feedbacks between community structure and ecosystem function can be disrupted by a strong interactor; (3) even substantial consequences on ecosystem processes that arise can be difficult to discern. PMID- 21274573 TI - A meta-analysis of responses of soil biota to global change. AB - Global environmental changes are expected to impact the abundance of plants and animals aboveground, but comparably little is known about the responses of belowground organisms. Using meta-analysis, we synthesized results from over 75 manipulative experiments in order to test for patterns in the effects of elevated CO(2), warming, and altered precipitation on the abundance of soil biota related to taxonomy, body size, feeding habits, ecosystem type, local climate, treatment magnitude and duration, and greenhouse CO(2) enrichment. We found that the positive effect size of elevated CO(2) on the abundance of soil biota diminished with time, whereas the negative effect size of warming and positive effect size of precipitation intensified with time. Trophic group, body size, and experimental approaches best explained the responses of soil biota to elevated CO(2), whereas local climate and ecosystem type best explained responses to warming and altered precipitation. The abundance of microflora and microfauna, and particularly detritivores, increased with elevated CO(2), indicative of microbial C limitation under ambient CO(2). However, the effects of CO(2) were smaller in field studies than in greenhouse studies and were not significant for higher trophic levels. Effects of warming did not depend on taxon or body size, but reduced abundances were more likely to occur at the colder and drier sites. Precipitation limited all taxa and trophic groups, particularly in forest ecosystems. Our meta-analysis suggests that the responses of soil biota to global change are predictable and unique for each global change factor. PMID- 21274574 TI - Additive effects of herbivory, nectar robbing and seed predation on male and female fitness estimates of the host plant Ipomopsis aggregata. AB - Many antagonistic species attack plants and consume specific plant parts. Understanding how these antagonists affect plant fitness individually and in combination is an important research focus in ecology and evolution. We examined the individual and combined effects of herbivory, nectar robbing, and pre dispersal seed predation on male and female estimates of fitness in the host plant Ipomopsis aggregata. By examining the effects of antagonists on plant traits, we were able to tease apart the direct consumptive effects of antagonists versus the indirect effects mediated through changes in traits important to pollination. In a three-way factorial field experiment, we manipulated herbivory, nectar robbing, and seed predation. Herbivory and seed predation reduced some male and female fitness estimates, whereas plants tolerated the effects of robbing. The effects of herbivory, robbing, and seed predation were primarily additive, and we found little evidence for non-additive effects of multiple antagonists on plant reproduction. Herbivory affected plant reproduction through both direct consumptive effects and indirectly through changes in traits important to pollination (i.e., nectar and phenological traits). Conversely, seed predators primarily had direct consumptive effects on plants. Our results suggest that the effects of multiple antagonists on estimates of plant fitness can be additive, and investigating which traits respond to damage can provide insight into how antagonists shape plant performance. PMID- 21274575 TI - Cancer control--a global challenge requiring collaborative solutions. PMID- 21274576 TI - Complementary and alternative medicine use and assessment of quality of life in Korean breast cancer patients: a descriptive study. AB - PURPOSE: The worldwide use of complementary and alternative medicine (CAM) among cancer patients has increased, with breast cancer patients being more likely to use CAM compared with any other cancer patients. However, few surveys have systematically described CAM use among Korean breast cancer patients. This study investigated the use of CAM among patients who were diagnosed with breast cancer, along with the relevant demographic and clinical factors related to CAM use. We also compared the difference in quality of life between CAM users and nonusers. METHODS: A total of 661 patients were invited to participate in this study during routine clinic visits, with 425 patients ultimately participating. Three hundred ninety-nine questionnaires were completed and used in the final analysis. Quality of life was evaluated based on the Korean versions of the EORTC QLQ-C30 and EORTC QLQ-BR23. RESULTS: Previous or current CAM usage was reported by 229 patients (57.4%). Independent factors related to CAM use were marital status, cancer stage, and coexisting illness. The common types of CAM use included exercise therapy (43.2%) and ingestion of vitamins and minerals (41.9%). The reasons for CAM use were to boost the immune system (53.2%), promote health (46.8%) and prevent recurrence (37.7%). Large proportions (70.4%) of CAM users did not discuss their CAM use with their physicians. Only a small number of CAM users (2.5%) answered that they were unsatisfied with their CAM use, with most CAM users reporting that they would continue their CAM use. Quality of life was not significantly different between CAM users and nonusers. CONCLUSIONS: A significant number of patients with breast cancer have used CAM, and health care providers should be aware of the variety of CAM methods and their patients' CAM uses for the proper management of breast cancer. PMID- 21274577 TI - Antibiotics in palliative medicine--results from a prospective epidemiological investigation from the HOPE survey. AB - BACKGROUND: Patients with advanced cancer are highly susceptible to infections. The decision whether to treat an active or suspected infection or to withhold or withdraw an antibiotic treatment in end-of-life care may be difficult. In order to quantify the antimicrobial prescribing practices and decision-making processes in palliative care units in Germany, a survey was performed as part of the Hospice and Palliative Evaluation in 2006. METHOD: With a specifically designed questionnaire, 448 patients for whom an active or suspected infection and antibiotic treatment was discussed were documented. Data on the use of and indication for antibiotic treatment and the decision-making on withdrawal or withholding of antibiotic therapy were collected. RESULTS: 286 (63.8%) received an antibiotic therapy. In 88 cases, withdrawal of an ongoing treatment was documented. The most frequent reasons for withdrawal were: deterioration of general status (41.4%), inefficiency of therapy (25.7%), and explicit wish of patient (14.3%; multiple answers possible). Outcome of antimicrobial therapy was rated poor or very poor for a fifth of the cases and accordingly, antibiotics were more likely to be withdrawn if the clinical success was considered to be poor. The initiation of therapy was often decided by physicians solely, whereas withdrawing and withholding therapy demanded more often involvement of other team members in the decision-making process. CONCLUSION: The initiation of therapy seems to be easier than withdrawing and withholding, as involvement of other team members in the decision-making process was then sought more often. When antibiotics were given until death, the indication should be reconsidered because of a possibly undesirable prolongation of the dying process. Clinical practice may benefit from clear definitions of treatment goals and outcome criteria to better evaluate the necessity for and success of antimicrobial treatment. PMID- 21274578 TI - Advanced craniofacial juvenile nasopharyngeal angiofibroma. Description of surgical series, case report, and review of literature. AB - BACKGROUND: Juvenile nasopharyngeal angiofibroma (JNA) is a rare benign tumor occurring almost exclusively in adolescent and young adult males. The tumor is characterized by slow progression, aggressive growth, high vascularization, and increased rate of persistence and recurrence. The aim of this study was to describe a case of giant JNA from our practice and discuss the controversies of surgical treatment of advanced JNA. MATERIAL AND METHODS: A series of 29 consecutive male patients with JNA Fisch grade III and IV was surgically treated in Burdenko Neurosurgical Institute from 2000 until 2008. In the vast majority of cases, endovascular embolization and surgical removal via orbitozygomatic approach were applied. RESULTS: Gross total resection was achieved in 24 cases (83%). Complications were encountered in eight cases. No mortality was observed. In three patients, the diseases recurred. An illustrative case is described. CONCLUSION: Surgical treatment is the basic tactics in management of extensive JNA including endovascular embolization and resection of the tumor. We recommend using orbitozygomatic approach or its modifications in JNA. Radiation therapy may be recommended for patients with small residual tumor. PMID- 21274579 TI - Flibanserin attenuates L: -DOPA-sensitized contraversive circling in the unilaterally 6-hydroxydopamine-lesioned rat model of Parkinson's disease. AB - A central problem in the treatment of Parkinson's disease (PD) is the development of motor disturbances like L: -DOPA-induced dyskinesia (LID) after long-term treatment. Preclinical and clinical studies demonstrated that serotonin 5-HT(1A) receptor agonists attenuate this disabling motor side effect. The aim of this study was to investigate the ability of flibanserin compared to buspirone to attenuate L: -DOPA-sensitized contraversive circling in hemiparkinsonian rats, which is an animal model of LID. Both drugs have a preferential affinity for the serotonin 5-HT(1A) receptors. Buspirone was in comparison because it was expected to have an effect in this model. Unilaterally 6-hydroxydopamine lesioned rats were treated twice daily intraperitoneally (ip) with L: -DOPA methylester (12.5 mg/kg) and benserazide (3.25 mg/kg) for 21 days (on days 1, 3, 5, 8, 11, 14, 17 and 21). On day 24, L: -DOPA-sensitized rats were treated ip 5 min prior to administration of L: -DOPA methyl ester and benserazide with either saline (controls), 2.5, 5 and 10 mg/kg buspirone or flibanserin. Acute administration of both flibanserin and buspirone, dose dependently, attenuated the increased contraversive circling. An almost complete inhibition of the turning response was observed at 5 mg/kg buspirone and 10 mg/kg flibanserin. The current preclinical findings further implicate the 5-HT(1A) receptor as a promising therapeutic target for the reduction of LID and predict a potential efficacy of flibanserin in the treatment of LID in PD. PMID- 21274580 TI - "Bouquet arrest", monopolar chromosomes segregation, and correction of the abnormal spindle. AB - According to our data, the arrest of univalents in bouquet arrangement is a widespread meiotic feature in cereal haploids and allohaploids (wide hybrids F(1)). We have analyzed 83 different genotypes of cereal haploids and allohaploids with visualization of the cytoskeleton and found a bouquet arrest in 45 of them (in 30% to 100% pollen mother cells (PMCs)). The meiotic plant cell division in 26 various genotypes with a zygotene bouquet arrest was analyzed in detail. In three of them in PMCs, a very specific monopolar conic-shaped figure at early prometaphase is formed. This monopolar figure consists of mono-oriented univalents and their kinetochore fibers converging in pointed pole. Such figures are never observed at wild-type prometaphase or in asynaptic meiosis in the variants without a bouquet arrest. Later at prometaphase, the bipolar central spindle fibers join in this monopolar figure, and a bipolar spindle with all univalents connected to one pole is formed. As a result of monopolar chromosome segregation at anaphase and normal cytokinesis at telophase, a dyad with one member carrying a restitution nucleus and the other enucleated is formed. However, such phenotype has only three genotypes among 26 analyzed with a bouquet arrest. In the remaining 23 haploids and allohaploids, the course of prometaphase was altered after the conic monopolar figure formation. In these variants, the completely formed conic monopolar figure was disintegrated into a chaotic network of spindle fibers and univalents acquired a random orientation. This arrangement looks like a mid-prometaphase in the wild-type meiosis. At late prometaphase, a bipolar spindle is formed with the univalents distributed more or less equally between two poles, similar to the phenotypes without a bouquet arrest. The product of cell division is a dyad with aneuploid members. Thus, the spindle abnormality-monopolar chromosome orientation-is corrected. In some cells the correction of the prometaphase monopolus occurs by means of its splitting into two half-spindles and their rotation along the future division axis. PMID- 21274581 TI - Survival of atraumatic restorative treatment (ART) sealants and restorations: a meta-analysis. AB - The purpose of this study is to perform a systematic investigation plus meta analysis into survival of atraumatic restorative treatment (ART) sealants and restorations using high-viscosity glass ionomers and to compare the results with those from the 2005 ART meta-analysis. Until February 2010, four databases were searched. Two hundred four publications were found, and 66 reported on ART restorations or sealant survival. Based on five exclusion criteria, two independent reviewers selected the 29 publications that accounted for the meta analysis. Confidence intervals (CI) and or standard errors were calculated and the heterogeneity variance of the survival rates was estimated. Location (school/clinic) was an independent variable. The survival rates of single-surface and multiple-surface ART restorations in primary teeth over the first 2 years were 93% (CI, 91-94%) and 62% (CI, 51-73%), respectively; for single-surface ART restorations in permanent teeth over the first 3 and 5 years it was 85% (CI, 77 91%) and 80% (CI, 76-83%), respectively and for multiple-surface ART restorations in permanent teeth over 1 year it was 86% (CI, 59-98%). The mean annual dentine lesion incidence rate, in pits and fissures previously sealed using ART, over the first 3 years was 1%. No location effect and no differences between the 2005 and 2010 survival rates of ART restorations and sealants were observed. The short term survival rates of single-surface ART restorations in primary and permanent teeth, and the caries-preventive effect of ART sealants were high. CLINICAL RELEVANCE: ART can safely be used in single-surface cavities in both primary and permanent teeth. ART sealants have a high caries preventive effect. PMID- 21274582 TI - Mutational analysis of conserved aspartic acid residues in the Methanothermobacter thermautotrophicus MCM helicase. AB - Minichromosome maintenance (MCM) helicases are thought to function as the replicative helicases in archaea and eukarya, unwinding the duplex DNA in the front of the replication fork. The archaeal MCM helicase can be divided into three parts, the N-terminal, catalytic, and C-terminal regions. The N-terminal part of the protein is divided into three domains, A, B, and C, and was shown to be involved in protein multimerization and binding to single- and double-stranded DNA. Two Asp residues found in domain C are conserved among MCM proteins from different archaea. These residues are located in a loop at the interface with domain A. Mutations of these residues in the Methanothermobacter thermautotrophicus MCM protein, Asp202 and Asp203, to Asn result in a significant reduction in the ability of the enzyme to bind DNA and in lower thermal stability. However, the mutant proteins retained helicase and ATPase activities. Further investigation of the DNA binding revealed that the presence of ATP rescues the DNA binding deficiencies by these mutant proteins. Possible roles of these conserved residues in MCM function are discussed. PMID- 21274584 TI - Urotensin-II in systemic sclerosis: a new peptide in pathogenesis. AB - Systemic sclerosis (SSc) is a rare multisystem chronic disease and its etiology is still unknown. To obtain and generate reasonable treatment methods, new mediators or targets are needed. Urotensin-II (U-II) is predominantly a vasoactive peptide with fibrotic and prothrombotic features. Like endothelin-1 (ET-1), U-II could play an important role in SSc pathogenesis given its properties of convenient one-to-one SSc pathogenetic pathways. A consecutive group of 55 patients diagnosed with SSc and 30 healthy controls were included in the study. Patients and healthy controls were evaluated for clinical and laboratory manifestations, specific organ involvement, autoantibodies, and activity scores specific for SSc. In addition, plasma ET-1 and plasma levels of U II-like immunoreactivity of both groups were compared. ET-1 level significantly increased in the SSc group in contrast to the healthy controls (6.38 +/- 1.39 and 0.99 +/- 0.27 pg/ml; p = 0.006). U-II was also significantly elevated in patients, and the plasma levels of U-II-like immunoreactivity were positively correlated with ET-1 (8.19 +/- 1.74 and 1.02 +/- 0.19 pg/ml; p = 0.003 and p = 0.0001; r = 0.887). For reasonable treatment of SSc, we need to focus on new targets such as ET-1 and U-II. This study hypothesized that these mediators could have a role in SSc pathogenesis, and U-II antagonist might be a potential alternative therapy for these patients. PMID- 21274586 TI - Hepatitis C and B prevalence in Spanish prisons. AB - Purpose The Prevalhep study seeks to determine the prevalence of factors associated with the hepatitis C (HCV) and B (HBV) virus in Spanish prisoners. Methods This was an observational, cross-sectional study which randomly selected 18 Spanish prisons to participate, with 21 prisoners per centre. Results There were 378 prisoners selected, 370 of whom had serological HCV and 342 had HBV data. The HCV population was predominantly male (91.6%), middle age (66.7% <= 40 years of age), of Spanish origin (60.5%), with a history of injection drug use (IDU; 23.2%), in prison <5 years (71.2%) and having entered prison after 2006 (51.9%). The prevalence of HCV was 22.7% (n = 84; 95% CI, 18.3-27.1) and HBV was 2.6% (n = 9; 95% CI, 0.2-4.9%). Of the patients with HCV, 40.5% were co-infected with HIV, 0.3% co-infected with HBV, and 1.5% with triple virus co-infection (HBV + HCV + HIV). The three markers of HB had been measured in 99 inmates: 32.1% had post-vaccination immunity (antiHBS+) and 30.4% contact status with HBV (HBcAb + and/or HBsAg+), while 37.5% were susceptible to HB. Conclusions The prevalence of HBV and HCV has decreased in the Spanish prison population, probably as a result of decrease in IDU transmission, and an increase in immigrant prisoner population that does not have this risk behaviour. PMID- 21274587 TI - Concentrations of procalcitonin and C-reactive protein, white blood cell count, and the immature-to-total neutrophil ratio in the blood of neonates with nosocomial infections: Gram-negative bacilli vs coagulase-negative staphylococci. AB - This study was undertaken to determine whether concentrations of procalcitonin in the blood of neonates with nosocomial infections depend on the type of pathogen. Qualification for the study group was based on the clinical signs of infection. We found that infections with Gram-positive (chiefly coagulase-negative staphylococci) and Gram-negative bacteria are accompanied by elevated concentrations of procalcitonin. In the case of Gram-positive bacteria, other laboratory signs of infection studied by us (concentration of C-reactive protein, white blood cell count, immature-to-total neutrophil ratio) were not discriminatory, confirming the diagnostic usefulness of procalcitonin measurements in nosocomial infections of the neonate with Gram-negative or Gram positive bacteria. PMID- 21274588 TI - Carbohydrate metabolism and cell protection mechanisms differentiate drought tolerance and sensitivity in advanced potato clones (Solanum tuberosum L.). AB - In potatoes and many other crops, drought is one of the most important environmental constraints leading to yield loss. Development of drought-tolerant cultivars is therefore required for maintaining yields under climate change conditions and for the extension of agriculture to sub-optimal cropping areas. Drought tolerance mechanisms have been well described for many crop plants including Native Andean potato. However, knowledge on tolerance traits suitable for commercial potato varieties is scarce. In order to describe drought tolerance mechanisms that sustain potato yield under water stress, we have designed a growth-chamber experiment with two Solanum tuberosum L. cultivars, the more drought tolerant accession 397077.16, and the sensitive variety Canchan. After 21 days of drought exposure, gene expression was studied in leaves using cDNA microarrays. The results showed that the tolerant clone presented more differentially expressed genes than the sensitive one, suggesting greater stress response and adaptation. Moreover, it exhibited a large pool of upregulated genes belonging to cell rescue and detoxication such as LEAs, dehydrins, HSPs, and metallothioneins. Transcription factors related to abiotic stresses and genes belonging to raffinose family oligosaccharide synthesis, involved in desiccation tolerance, were upregulated to a greater extent in the tolerant clone. This latter result was corroborated by biochemical analyses performed at 32 and 49 days after drought that showed an increase in galactinol and raffinose especially in clone 397077.16. The results depict key components for the drought tolerance of this advanced potato clone. PMID- 21274589 TI - Improving healthcare delivery through patient informatics and quality centric data. PMID- 21274590 TI - NIRViz: 3D visualization software for multimodality optical imaging using visualization toolkit (VTK) and insight segmentation toolkit (ITK). AB - Optical imaging using near-infrared light is used for noninvasive probing of tissues to recover vascular and molecular status of healthy and diseased tissues using hemoglobin contrast arising due to absorption of light. While multimodality optical techniques exist, visualization techniques in this area are limited. Addressing this issue, we present a simple framework for image overlay of optical and magnetic resonance (MRI) or computerized tomographic images which is intuitive and easily usable, called NIRViz. NIRViz is a multimodality software platform for the display and navigation of Digital Imaging and Communications in Medicine (DICOM) MRI datasets and 3D optical image solutions geared toward visualization and coregistration of optical contrast in diseased tissues such as cancer. We present the design decisions undertaken during the design of the software, the libraries used in the implementation, and other implementation details as well as preliminary results from the software package. Our implementation uses the Visualization Toolkit library to do most of the work, with a Qt graphical user interface for the front end. Challenges encountered include reslicing DICOM image data and coregistration of image space and mesh space. The resulting software provides a simple and customized platform to display surface and volume meshes with optical parameters such as hemoglobin concentration, overlay them on magnetic resonance images, allow the user to interactively change transparency of different image sets, rotate geometries, clip through the resulting datasets, obtain mesh and optical solution information, and successfully interact with both functional and structural medical image information. PMID- 21274591 TI - Fully automatic region of interest selection in glomerular filtration rate estimation from 99mTc-DTPA renogram. AB - Glomerular filtration rate (GFR) is a common accepted standard estimation of renal function. Gamma camera-based methods for estimating renal uptake of (99m)Tc diethylenetriaminepentaacetic acid (DTPA) without blood or urine sampling have been widely used. Of these, the method introduced by Gates has been the most common method. Currently, most of gamma cameras are equipped with a commercial program for GFR determination, a semi-quantitative analysis by manually drawing region of interest (ROI) over each kidney. Then, the GFR value can be computed from the scintigraphic determination of (99m)Tc-DTPA uptake within the kidney automatically. Delineating the kidney area is difficult when applying a fixed threshold value. Moreover, hand-drawn ROIs are tedious, time consuming, and dependent highly on operator skill. Thus, we developed a fully automatic renal ROI estimation system based on the temporal changes in intensity counts, intensity-pair distribution image contrast enhancement method, adaptive thresholding, and morphological operations that can locate the kidney area and obtain the GFR value from a (99m)Tc-DTPA renogram. To evaluate the performance of the proposed approach, 30 clinical dynamic renograms were introduced. The fully automatic approach failed in one patient with very poor renal function. Four patients had a unilateral kidney, and the others had bilateral kidneys. The automatic contours from the remaining 54 kidneys were compared with the contours of manual drawing. The 54 kidneys were included for area error and boundary error analyses. There was high correlation between two physicians' manual contours and the contours obtained by our approach. For area error analysis, the mean true positive area overlap is 91%, the mean false negative is 13.4%, and the mean false positive is 9.3%. The boundary error is 1.6 pixels. The GFR calculated using this automatic computer-aided approach is reproducible and may be applied to help nuclear medicine physicians in clinical practice. PMID- 21274592 TI - Ventriculoperitoneal shunt for hydrocephalus caused by central nervous system metastasis. AB - The development of better diagnostic tools and therapeutic modalities has increased the incidence of central nervous system (CNS) metastasis in malignant tumor patients. Hydrocephalus can result from CNS metastasis and frustrate cancer treatment. The authors sought to investigate the outcomes and the roles of ventriculoperitoneal shunts (VPS) in patients with CNS metastasis. The medical records of 50 consecutive patients who underwent VPS for hydrocephalus related to CNS metastasis were analyzed retrospectively. Data included features of primary malignancies, CNS involvement, clinical course and surgical outcome. Median patient age was 55.0 years (range 25-77), and 30 female and 20 male patients were included in the study. At the time of VPS, 10 patients had parenchymal metastases only and 40 patients had leptomeningeal seeding (LMS). Symptom improvement was observed postoperatively in 40 patients (80%), mean Karnofsky performance status (KPS) scale change was from 37.8 to 46.0, and median survival from VPS was 3.0 months (2 days to 54 months). A ventricular opening pressure of >30 cmH(2)O (HR 6.44, 95% CI 1.26-32.9, P = 0.02) and further cancer treatment after VPS (HR 0.17, 95% CI 0.07-0.42, P < 0.0001) were found to be independent risk factors of poorer and better survival, respectively. Hydrocephalus in CNS metastasis requiring VPS is commonly associated with LMS. VPS is an effective palliative measure and an adequate cancer treatment after VPS may provide the best means of improving survival. PMID- 21274593 TI - Diabetic retinopathy screening using single-field digital fundus photography at a district level in Costa Rica: a pilot study. AB - To report on our initial experience screening for diabetic retinopathy (DR) using digital fundus photography and standarized criteria. Cross-sectional prospective study of all 1327 diabetic patients referred to the Ophthalmology Department of the Clorito Picado Clinic in San Jose, Costa Rica between April 2008 and March 2009. Patients were screened with a single-field 45-degree digital color retinal image centered on the fovea. The main outcome measures were prevalence of DR, waiting time for a fundus photograph appointment and the number of patients that needed to be evaluated by an ophthalmologist. In this population of 1327 patients, 85% did not have any retinopathy. The prevalence of DR was 15%. Mild non-proliferative DR (NPDR) was seen in 5.8% (70/1215), moderate NPDR in 3.9% (47/1215), severe NPDR in 4.7% (57/1215) and proliferative DR in 0.6% (8/1215). Macular edema was present in 2.6% (32) patients. 13.8% of patients required pupillary dilation for an adequate image to be taken and 8.8% of the images were unreadable. The average waiting time for a fundus photograph appointment was 49.1 days. A total of 13.8% (183/1327) patients were referred to the ophthalmologist. Of these referrals, 61.2% (112/183) were because of unreadable images and 38.8% (71/183) were referred for further ophthalmic treatment. Digital fundus photographic screening for DR appears to be a viable option for the improvement of screening for DR in Costa Rica. PMID- 21274594 TI - Practical issues with vitamin K antagonists: elevated INRs, low time-in therapeutic range, and warfarin failure. AB - Millions of patients worldwide are prescribed vitamin K antagonists for a variety of medical conditions annually. Despite widespread and long-standing experience with these medications, medical care providers are often confronted with challenging clinical situations. Vitamin K antagonists have a narrow therapeutic index secondary to intrinsic patient characteristics and extrinsic factors including a propensity for drug-drug interactions. Clinicians are required to titrate doses according to the measured international normalized ratio for each individual, balancing the risk of bleeding with preventing thrombosis. The risk of major bleeding associated with vitamin K antagonists has been reported to range from 1 to 3% per year. This narrative review will provide an overview of the most commonly used vitamin K antagonists and discuss the importance of assessing quality of anticoagulation with respect to clinical outcomes. Practical approaches to managing excessive anticoagulation, variable anticoagulation, and anticoagulation failure will be provided, drawing on evidence where applicable and expert opinion where evidence is limited. PMID- 21274595 TI - The triglyceride:high-density lipoprotein-cholesterol ratio and steno-occlusive disease in the intracranial arteries. AB - The extent of carotid artery atherosclerosis correlates with increased plasma concentrations of total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) and with a decreased plasma concentration of high-density lipoprotein cholesterol (HDL-C). However, emerging data suggest that a triglyceride (TG):HDL C ratio may be a better predictor of vascular risk than the traditional lipid measures such as TC and LDL-C. The purpose of this study was to evaluate the association between TC, LDL-C, TG, HDL-C, and the TG:HDL-C ratio with steno occlusive disease in the intracranial cerebral arteries. We analyzed the records of 361 stroke-free subjects who underwent brain magnetic resonance angiography as part of their voluntary health checks. The presence of a steno-occlusive lesion in the basilar artery (BA) and in the horizontal portion of the middle cerebral artery (MCA) was assessed using brain 3D time of flight magnetic resonance angiography. All patients had fasting lipid panels drawn. We categorized serum lipid indices into quartiles and logistic regression analyses were performed. No serum lipid index was associated with the prevalence of MCA disease; TC, LDL-C, and HDL-C concentrations were not correlated with the prevalence of BA disease. A TG concentration in the third quartile compared with the lowest quartile was associated with increased prevalence of BA disease. The TG:HDL-C ratios in the upper three quartiles compared with the lowest quartile were associated with increased prevalence of BA disease. In conclusion, the TG:HDL-C ratio is more highly associated with the intracranial steno-occlusive disease than any standard lipid measure. PMID- 21274596 TI - Effects of linoleic acid and eicosapentaenoic acid on cell proliferation and lipid-metabolism gene expression in primary duck hepatocytes. AB - Several studies have investigated that linoleic acid (LA) and eicosapentaenoic acid (EPA) affect cell proliferation and lipid catabolic gene expression in mammals. To determine if LA and EPA increase duck cell proliferation and lipid catabolic gene expression, the authors exposed duck primary hepatocyte cultures to LA or EPA. The results showed that both LA and EPA increased cell proliferation in a dose-dependent manner (100 MUM). The effect on specific cell cycle phases was also studied; LA and EPA (100 MUM) deceased the proportion of cells in the G0/G1 phase from 83 to 80.8 and 80.3%, respectively, concomitant with an increase in the proportion of S-phase cells (11.5 and 10.5 vs. 8%, respectively). The expression of PPAR-alpha and PPAR-alpha target genes, such as acyl-CoA oxidase (ACOX), lipoprotein lipase (LPL), liver fatty acid-binding protein (L-FABP), was examined by quantitative real-time PCR. The results showed that the expression of the PPAR-alpha, ACOX, and LPL genes increased significantly following LA and EPA exposure, but that the expression of L-FABP remained unchanged. This study provides the first characterization of LA- and EPA induced cell proliferation and PPAR-alpha and PPAR-alpha target gene transcriptional responses in duck primary hepatocyte cultures. PMID- 21274597 TI - cis-Vaccenyl acetate, a female-produced sex pheromone component of Ortholeptura valida, a longhorned beetle in the subfamily Lepturinae. AB - We report the identification, synthesis, and field bioassays of a female-produced sex attractant pheromone component of the cerambycid beetle Ortholeptura valida (LeConte). Headspace volatiles from females contained a female-specific compound, (Z)-11-octadecen-1-yl acetate, which elicited a strong response from antennae of adult males in coupled gas chromatography-electroantennogram analyses. In field bioassays, significant numbers of males were collected by traps baited with this compound. The pheromone represents a new structural class of cerambycid pheromones, and is the first pheromone identified for a cerambycid species in the subfamily Lepturinae. PMID- 21274598 TI - A multi-component species identifying pheromone in the goldfish. AB - Although it has been established that sexually-immature goldfish and their relatives recognize members of their own species by using chemicals that they release, the identity of this cue(s) and whether it might be produced and used by other life stages is not yet known. To address this question, this study tested the behavioral responses of sexually immature and mature goldfish to each other's body washings, their sensitivity to this cue, the role of the olfactory sense in detecting it, and whether it is comprised of either polar and/or non-polar compounds. Tests that used two-choice mazes discovered that juvenile, immature, mature male, and mature female goldfish all release and respond to a common chemical cue(s). Dilution studies next demonstrated that this cue is active when diluted over 10 times and thus capable of functioning as a short range attractant/identifier. Olfactory occlusion demonstrated that it is detected by the olfactory sense. Finally, chemical fractionation demonstrated that it is comprised of both polar and non-polar components but likely does not include bile acids. Together, these results suggest that all life stages of goldfish use a complex multicomponent pheromonal odor to discern species identity, and that this odor has the potential to function with hormonal metabolites to identify sexual condition in behaviorally active fish of many species. PMID- 21274599 TI - Directly oxidized chemiluminescence of 2-substituted-4,5-di(2-furyl)-1H imidazole by acidic potassium permanganate and its analytical application for determination of albumin. AB - In the paper, 2,4,5-tri(2-furyl)-1H-imidazole (TFI) and 2-phenyl-4,5-di(2-furyl) 1H-imidazole (PDFI), were chosen to investigate chemiluminescence (CL) properties of 2-substituted-4,5-di(2-furyl)-1H-imidazoles. The directly oxidized CL of analytes by potassium permanganate (KMnO(4)) was in detail studied. The KMnO(4) could directly oxidize TFI/PDFI to produce strong CL emission in acidic solution. The effects of experimental conditions were investigated. Under the optimal conditions, the effect of albumin on the TFI/PDFI-KMnO(4) system was investigated. It was found that the addition of albumin into the system could induce enhancement of CL signal, and the enhanced CL intensity is linearly related to the logarithm of concentration of albumin. Based on this study, a novel CL method has been developed for the determination of albumin with high sensitivity and good selectivity. The method was applied to the determination of albumin in human serum samples, and the results were in agreement with those obtained by the bromcresol green (BCG) method. The relative errors for the analytical results were from -5.8% to 4.2%. These new phenomena would further enable people to exploit more CL analytical application of the heterocyclic imidazole derivatives. PMID- 21274600 TI - An NBD-based sensitive and selective fluorescent sensor for copper(II) ion. AB - A new 7-nitrobenz-2-oxa-1,3-diazole (NBD) derived fluorescent probe (1) exhibiting high selectivity for Cu(2+) detection, produced significant fluorescence quenching in the presence of Cu(2+) ion, while the metal ions Ca(2+), Cd(2+), Co(2+), Fe(2+), Hg(2+), Mg(2+), Mn(2+), Ni(2+) and Zn(2+) produced only minor changes in fluorescence. The apparent association constant (K (a)) for Cu(2+) binding in chemosensor 1 was found to be 1.22 * 10(3) M(-1). The maximum fluorescence quenching activity caused by Cu(2+) binding to 1 was observed over the pH range 6-10. PMID- 21274601 TI - Evidence for strong mixing between the LC and MLCT excited states in some heteroleptic iridium(III) complexes. AB - The synthesis, structure and photophysical properties of series of new luminescent cyclometalated Iridium (III) complexes are reported. The cyclometalated ligand used here is 2-aryl imidazole and the auxiliary ligand is acetyl acetone (acac). The crystal structure of the complex (dmdpi)(2)Ir(acac) (5) show that the Iridium(III) ion resides in a distorted octahedral environment. All complexes exhibit bright photoluminescence (PL) at room temperature and (fpdmdmpi)(2)Ir(acac) 4 has a high solution PL quantum efficiency of 0.56. The role played by electron releasing and electron withdrawing substituents of the 2 arylimidazole ligands towards the stability of HOMO and how the substituent influences the luminescent behaviour are discussed. Furthermore those substituents have effect on the contribution to mixing between (3)(pi-pi*) and (3)(MLCT) for the lowest excited states. PMID- 21274602 TI - Synthesis and study of the photophysical properties of a new Eu3+ complex with 3 hydroxypicolinamide. AB - This work reports on the synthesis and characterization of a new complex of Eu(3+) with the 3-hydroxypicolinamide ligand (Hhpa). Here we present an approach for obtaining bis[2-carbamoyl(kappaO)pyridin-3-olato(kappaO')] lanthanide complexes, which were characterized through elemental analysis, thermal analysis, infrared and photoluminescence spectroscopies (emission, excitation, luminescence lifetimes, quantum efficiencies, Judd-Ofelt parameters and quantum yields). Although hpa can act as a bidentate ligand in different conformations, the results attest for the occurrence of a unique coordination site of low symmetry for the Eu(3+) ions, in which two anionic hpa ligands coordinate the cations through an O/O chelating system. The phosphorescence of the synthesized gadolinium complex provides the energy of the triplet state, which is determined to be at 20,830 cm(-1) over the ground state. This makes the Hhpa ligand very adequate for sensitizing the Eu(3+) luminescence, which leads to a very efficient antenna effect and opens a wide range of applications for the complex in light emitting organic-inorganic devices. PMID- 21274603 TI - Detection of Staphylococcus aureus carrying the gene for toxic shock syndrome toxin 1 by quantum-dot-probe complexes. AB - In this study, a high-sensitive and high-specific method to detect the toxic shock syndrome toxin-1 (TSST-1)-producing Staphylococcus aureus was developed based on quantum dot (QD) and oligonucleotide probe complexes. S. aureus carrying tst gene which is responsible for the production of TSST-1 were detected based on fluorescence resonance energy transfer (FRET) occurring between CdSe/ZnS QD donors and black hole quencher (BHQ) acceptors. QD-DNA probe was prepared by conjugating the carboxyl-modified QD and the amino-modified DNA with the EDC. Photoluminescence (PL) quenching was achieved through FRET after the addition of BHQ-DNA which was attached to tst gene probe by match sequence hybridization. The PL recovery was detected in the presence of target DNA by BHQ-DNA detached from QD-DNA probe because of the different affinities. In contrast, mismatch oligonucleotides and DNAs of other bacteria did not contribute to fluorescence intensity recovery, which exhibits the higher selectivity of the biosensor. The experimental results showed clearly that the intensity of recovered QD PL is linear to the concentration of target DNA within the range of 0.2-1.2 MUM and the detection limit was 0.2 MUM. PMID- 21274604 TI - Synthesis and optoelectronic properties of symmetrical thiophene based 2,5 disubstiuted 1,3,4-oxadiazoles: highly fluorescent materials for OLED applications. AB - Symmetrical 2,5-disubstituted thiophene derivatives containing 1,3,4-oxadiazole moiety bearing different aromatic substitutions were synthesized by employing convenient and simple synthetic protocols using thiophene-2,5,dicarboxylic acid as a starting material. The structures of these target molecules were established by their analytical and spectral data. The photophysical and electrochemical studies were carried out on these compounds and found that they exhibit good fluorescent properties with high quantum yield. PMID- 21274605 TI - Cucurbit[7]uril disrupts aggregate formation between rhodamine B dyes covalently attached to glass substrates. AB - Dye aggregation is detrimental to the performance of high optical density dye doped photonic materials. To overcome this challenge, the ability of cucurbit[7]uril (CB7) as a molecular host to disrupt aggregate formation on glass substrates was examined. Rhodamine B was covalently attached to glass slides by initially coating the surface with azidohexylsiloxane followed by copper catalyzed "click" triazole formation with rhodamine B propargyl ester. The absorption and emission spectra of rhodamine B coated slides in water indicated diverse heterogeneous properties as surface dye density varied. Fluorescence quenching due to dye aggregation was evident at high surface dye density. Addition of aqueous cucurbit[7]uril (CB7) to the surface-tethered dyes perturbed the spectra to reveal a considerable reduction in heterogeneity, which suggested that the presence of a surface in close proximity does not significantly impair CB7's ability to complex with tethered rhodamine B. PMID- 21274606 TI - Actinomycins like anti-cancer photo-sensitizers. AB - Spectroscopic and microscopic study on application of actinomycins as anti-tumor photo-sensitizing drugs was carried out in this work. It has been shown that 7 aminoactinomycin (7AAMD) and actinomycin D (AMD) inside cells of line HeLa bind not only with DNA, but also with proteins. Fluorescence of 7AAMD in HeLa cells and destruction of these cells by photosensitizing with actinomycin D were detected. When photo-destruction occurs, the antibiotic is released out from destroyed cells. PMID- 21274607 TI - Dimensions of adolescent psychopathology and relationships to suicide risk indicators. AB - Youth suicide represents an area of important public and mental health concern. Although diagnostic correlates (e.g., depression) of suicidality have been identified, very few studies of youth have analyzed relationships between empirically-derived dimensions of psychopathology, representing broader dimensions of risk, and different suicidality indicators. We recruited 223 adolescents (57% female; 32% ethnic minority) from mental health agencies and the community to assess psychopathology, substance use, and suicidality relying on multiple measures and reporters (youth, parent, and clinician). Using a 3-factor model of psychopathology, we found that the Internalizing factor (including depression and generalized anxiety) was associated with both suicidal thinking and behaviors (threats/attempts), the Externalizing factor (conduct, oppositional, and attention deficit disorders) was negatively related only to suicidal thinking, and the Substance Use factor (alcohol and cannabis use) related to suicidal behaviors of threats/attempts but not suicidal thinking. The results show the utility of a dimensional conceptualization for clarifying distinct vulnerabilities to suicidal thinking versus overt behaviors and have implications for the construct validity of distinct dimensions of psychopathology. PMID- 21274608 TI - Adolescent sexuality and positive well-being: a group-norms approach. AB - The link between adolescent sexual activity and psychological well-being is a controversial issue in developmental psychology. This cross-sectional study investigated the association between three aspects of teenage sexuality (genital sexual experience, age of sexual onset, and number of sex partners) and positive well-being (hedonic, eudaimonic, and overall) in a sample of 475 high school seniors (48% female; 89% White) from a single school district in a rural upstate New York community. Based on a group-norms perspective, we expected higher well being in adolescents whose sexual behaviors followed group-normative patterns. As expected, sexually experienced and on-time (at age 16) students reported higher well-being than sexually inexperienced or late-onset (17 or older) students. Contrary to expectations, a high number of sex partners and an early sexual onset (15 or younger) were not related to lower well-being. Early-onset girls reported higher levels of well-being than normative-onset peers. Findings are discussed in relationship to theoretical perspectives and past empirical findings of teenage sexuality as a developmental asset versus risk. PMID- 21274609 TI - Juggling work and motherhood: the impact of employment and maternity leave on breastfeeding duration: a survival analysis on Growing Up in Scotland data. AB - In 2005, Scotland became the first nation to make breastfeeding in public a legal right, but current breastfeeding targets and maternity leave allowance do not acknowledge the conflicting demands women face when juggling employment and motherhood. This paper explores how employment and maternity leave relate to breastfeeding duration among mothers in Scotland. The Growing Up in Scotland national longitudinal cohort study of 5,217 babies born in 2004-2005 was used. Multivariate proportional hazards regression models were specified using one cross-sectional wave of data to predict breastfeeding duration. Mothers working as employees, full-time (Hazard Ratio 1.6) or part-time (HR1.3), had a higher risk of earlier breastfeeding cessation than non-working mothers. However, self employed mothers did not differ significantly from non-working mothers in their breastfeeding patterns. Mothers who took longer maternity leave breastfed for longer. The relationships between employment, maternity leave and breastfeeding duration were significant when controlling for known predictors of breastfeeding. Younger mothers, those with less formal education, single mothers, those of white ethnic background, and first-time mothers were more likely to stop breastfeeding sooner, as has been noted in previous research. Employment and early return to work are both factors associated with a shorter duration of breastfeeding. More flexible working conditions and more generous employment leave could help to prolong breastfeeding among working mothers. Current health and employment policy in Scotland and the UK could be better coordinated so that working mothers have the adequate support to meet the conflicting demands of employment and motherhood. PMID- 21274610 TI - Long term memory profile of disorders associated with dysregulation of the RAS MAPK signaling cascade. AB - In the present study we evaluated long term memory in twenty individuals with molecularly confirmed diagnosis of Noonan syndrome and LEOPARD syndrome, two disorders caused by mutations in genes coding transducers participating in the RAS-MAPK signaling cascade. The profile of explicit long term memory abilities was investigated using PROMEA, which includes a battery of tests specifically developed to assess memory and learning in verbal, visual and spatial domains. Ten individuals (50%) had impaired (<=5th percentile) or below average (<=15th percentile) performance on a delayed verbal free recall memory task, four (20%) on a delayed visual recognition memory task, and only one (5%) on a delayed spatial recognition memory task. Our data suggest that dysregulation of the RAS MAPK cascade may be associated with a pattern of reduced verbal recall memory performance but relative sparing of visual and spatial recognition memory. PMID- 21274611 TI - HIV risk behavior among HIV-infected men who have sex with men in Bangkok, Thailand. AB - We assessed prevalence of sexually transmitted infection (STIs), sexual risk behaviors, and factors associated with risk behaviors among HIV-infected MSM attending a public STI clinic serving MSM in Bangkok, Thailand. Between October 2005-October 2007, 154 HIV-infected MSM attending the clinic were interviewed about sexual risk behaviors and evaluated for STIs. Patients were examined for genital ulcers and had serologic testing for syphilis and PCR testing for chlamydia and gonorrhea. Results showed that sexual intercourse in the last 3 months was reported by 131 men. Of these, 32% reported anal sex without a condom. STIs were diagnosed in 41%. Factors associated with having sex without a condom were having a steady male partner, having a female partner and awareness of HIV status <1 month. Sexual risk behaviors and STIs were common among HIV-infected MSM in this study. This highlights the need for increased HIV prevention strategies for HIV-infected MSM. PMID- 21274612 TI - The impact of stressful life events on unprotected anal intercourse among gay and bisexual men. AB - We investigated the hypothesis that gay and bisexual men experiencing stressful life events are more likely to engage in risky sexual behavior. Data were from a cohort study of 155 HIV-positive and 207 HIV-negative men in Ontario, Canada (1998-2007). We quantified the relation between stressful life events and unprotected anal intercourse with a non-regular partner. In the past 6 months, 19% reported unprotected intercourse (HIV+: 28%; HIV-: 13%) and 58% reported one or more stressful life events (HIV+: 64%; HIV-: 55%). Among HIV-negative men, the odds of unprotected intercourse increased by 1.15 for each additional event (95%CI 1.06, 1.24). Among HIV-positive men, those who reported the event "problems due to alcohol or drugs" were 1.80 (95%CI 1.27, 2.56) times more likely to report unprotected intercourse. Interventions to assist men to cope with stress may help to prevent population spread of HIV and improve overall health. PMID- 21274613 TI - Evolutionary features and intracellular behavior of the PRTB protein. AB - Human PRTB encodes a proline-rich protein of 168 amino acids (PRTB). We analyzed the evolutionary patterns of PRTB from various vertebrate species. Maximum likelihood analyses indicated that while mammalian PRTB has been very well conserved and underwent a significantly slower rate of evolution, only the branch leading to fish PRTB has undergone adaptive evolution. We generated several mutant PRTBs fused to the GFP variant, Venus, and found that the degradation of PRTB was enhanced by the transfection of an E2, UbcH5. Since mutation of the K153 site in PRTB was refractory to its degradation, proteolysis was suggested to be mediated by ubiquitination of K153. The subcellular localization of PRTB was also investigated, which showed that mutation of the K4 site completely prevented the nuclear localization of this protein. Together, these results suggest that Lys residues might play important roles in regulating the intracellular dynamics of the PRTB protein. PMID- 21274614 TI - Genomic structure of the immigrant Siddis of East Africa to southern India: a study of 20 autosomal DNA markers. AB - The Siddis are a tribal group of African origin living in Karnataka, India. They have undergone considerable cultural change due to their proximity to neighboring population groups. To understand the biological consequences of these changes, we describe the genomic structure of the Siddis and the contribution from putative ancestral populations using 20 autosomal DNA markers. The distribution of Alu indel markers and a genetic distance analysis reveals their closer affinities with Africans. The levels of genomic diversity and heterozygosity are high in all the populations of southern India. Genetic admixture analysis reveals a predominant contribution from Africans, a lesser contribution from south Indians, and a slight one from Europeans. There is no evidence of gametic disequilibrium in the Siddis. The genetic homogeneity of the Siddis, in spite of its admixed origin, suggests the utility of this population for genetic epidemiological studies. PMID- 21274616 TI - The fractal globule as a model of chromatin architecture in the cell. AB - The fractal globule is a compact polymer state that emerges during polymer condensation as a result of topological constraints which prevent one region of the chain from passing across another one. This long-lived intermediate state was introduced in 1988 (Grosberg et al. 1988) and has not been observed in experiments or simulations until recently (Lieberman-Aiden et al. 2009). Recent characterization of human chromatin using a novel chromosome conformational capture technique brought the fractal globule into the spotlight as a structural model of human chromosome on the scale of up to 10 Mb (Lieberman-Aiden et al. 2009). Here, we present the concept of the fractal globule, comparing it to other states of a polymer and focusing on its properties relevant for the biophysics of chromatin. We then discuss properties of the fractal globule that make it an attractive model for chromatin organization inside a cell. Next, we connect the fractal globule to recent studies that emphasize topological constraints as a primary factor driving formation of chromosomal territories. We discuss how theoretical predictions, made on the basis of the fractal globule model, can be tested experimentally. Finally, we discuss whether fractal globule architecture can be relevant for chromatin packing in other organisms such as yeast and bacteria. PMID- 21274615 TI - Do nuclear envelope and intranuclear proteins reorganize during mitosis to form an elastic, hydrogel-like spindle matrix? AB - The idea of a spindle matrix has long been proposed in order to account for poorly understood features of mitosis. However, its molecular nature and structural composition have remained elusive. Here, we propose that the spindle matrix may be constituted by mainly nuclear-derived proteins that reorganize during the cell cycle to form an elastic gel-like matrix. We discuss this hypothesis in the context of recent observations from phylogenetically diverse organisms that nuclear envelope and intranuclear proteins form a highly dynamic and malleable structure that contributes to mitotic spindle function. We suggest that the viscoelastic properties of such a matrix may constrain spindle length while at the same time facilitating microtubule growth and dynamics as well as chromosome movement. A corollary to this hypothesis is that a key determinant of spindle size may be the amount of nuclear proteins available to form the spindle matrix. Such a matrix could also serve as a spatial regulator of spindle assembly checkpoint proteins during open and semi-open mitosis. PMID- 21274617 TI - IGF-1 participates differently in regulation of severing activity of katanin and spastin. AB - Spastin and p60-katanin are AAA family proteins that participate in microtubule severing, while lipotransin, another AAA family protein is a hormone sensitive lipase interacting protein. Sequence alignment analysis suggests that lipotransin and human p60-katanin are the orthologs of each other. Studies identified that insulin may negatively regulate ATPase activity of lipotransin. To reveal the effects of insulin on regulation of severing activity of p60-katanin and spastin, hippocampal neurons over-expressing spastin and p60-katanin were treated with IGF 1. Changes in neuronal branching by considering the total process lengths and average process numbers were quantitatively analyzed. According to the results of this study, total process lengths of hippocampal neurons and average process numbers remained similar in control and p60-katanin over-expressing neurons upon IGF-1 treatment, while significant decrease was observed in spastin over expressing neurons. This study indicated that IGF-1 participates differently in the regulation of spastin and p60-katanin in terms of neuronal branching. PMID- 21274618 TI - Baclofen and adenosine inhibition of synaptic transmission at CA3-CA1 synapses display differential sensitivity to K+ channel blockade. AB - The metabotropic GABA(B) and adenosine A(1) receptors mediate presynaptic inhibition through regulation of voltage-dependent Ca(2+) channels, whereas K(+) channel regulation is believed to have no role at the CA3-CA1 synapse. We show here that the inhibitory effect of baclofen (20 MUM) and adenosine (300 MUM) on field EPSPs are differentially sensitive to Cs(+) (3.5 mM) and Ba(2+) (200 MUM), but not 4-aminopyridine (100 MUM). Barium had no effect on paired-pulse facilitation (PPF) in itself, but gave significant reduction (14 +/- 5%) when applied in the presence of baclofen, but not adenosine, suggesting that the effect is presynaptic and selective on the GABA(B) receptor-mediated response. The effect of Ba(2+) on PPF was not mimicked by tertiapin (30 nM), indicating that the underlying mechanism does not involve GIRK channels. Barium did not affect PPF in slices from young rats (P7-P8), suggesting developmental regulation. The above effects of Ba(2+) on adult tissue were reproduced when measuring evoked whole-cell EPSCs from CA1 pyramidal neurons: PPF was reduced by 22 +/- 3% in the presence of baclofen and unaltered in adenosine. In contrast, Ba(2+) caused no significant change in frequency or amplitude of miniature EPSCs. The Ba(2+)-induced reduction of PPF was antagonized by LY341495, suggesting metabotropic glutamate receptor involvement. We propose that these novel effects of Ba(2+) and Cs(+) are exerted through blockade of inwardly rectifying K(+) channels in glial cells, which are functionally interacting with the GABA(B) receptor-dependent glutamate release that generates heterosynaptic depression. PMID- 21274619 TI - Reliability and validity evidence of scores on the Slovene version of the questionnaire about interpersonal difficulties for adolescents. AB - This study analyzed the psychometric properties of scores on the Slovene version of the Questionnaire about Interpersonal Difficulties for Adolescents (QIDA) in a sample of 1,334 adolescents (44% boys), ranging in age from 12 to 18 years (M = 15.61). Confirmatory factor analyses replicated the correlated five-factor structure of the QIDA: Assertiveness, Heterosexual Relationships, Public Speaking, Family Relationships, and Close Friendships. Internal consistency and test-retest reliability were reasonable. Correlations of scores on the QIDA with scores of neuroticism, low extraversion, and low openness, as measured by the Inventory of Child/Adolescent Individual Differences, and scores of fear of negative evaluation, and tension and inhibition in social contacts, as measured by the Social Anxiety Scale for Adolescents were found, revealing differential links with QIDA subscale scores. Girls reported more difficulties than boys. Age differences showed a small but significant decrease in QIDA total score over adolescence. PMID- 21274620 TI - Parental and peer predictors of social anxiety in youth. AB - The aim of the current study was to extend etiological models of social anxiety in youth by examining the relative importance of parental (i.e., parental anxiety, rejection, and overcontrol) and peer factors (i.e., social acceptance, social support, and friendship quality). Sixty-three youth (ages 7-12; 52% male) and their parents participated in the study. Using multiple informants of these factors, results generally indicated that higher levels of parental anxiety, rejection, and overcontrol were related to higher levels of social anxiety. Higher levels of social support, acceptance, and validation were associated with lower levels social anxiety. The strongest predictors of social anxiety symptoms (as rated by an independent evaluator) were parental anxiety and friendship quality (i.e., validation from a peer). The strongest predictors of child rated social anxiety symptoms were parental overcontrol and perceived social acceptance. Findings are discussed in the context of current etiological models and suggest that interventions aimed at lowering social anxiety in youth address both parental anxiety and peer relationships. PMID- 21274621 TI - Elimination of the chemotherapy resistant subpopulation of 4T1 mouse breast cancer by haploidentical NK cells cures the vast majority of mice. AB - Metastatic breast cancer is currently incurable despite initial responsiveness, assumingly due to the presence of chemoresistant subpopulations that can be characterized as label retaining cells (LRC). In the 4T1 mouse breast cancer model, we previously achieved cure after Cyclophosphamide and Total Body Irradiation (CY + TBI) followed by haploidentical bone marrow and spleen transplantation (BMSPLT). CY + TBI without transplantation induced only transient impaired tumor growth indicating a critical role of donor immune cells. As it remained unknown if the 4T1 model resembles human disease with respect to the presence of subpopulations of chemoresistant LRC, we now demonstrate this is indeed the case. Chemoresistance of 4T1 LRC was demonstrated by in vitro co incubation of fluorescently labeled 4T1 cells in limiting dilution with cyclophosphamide, doxorubicin or cisplatinum, after which only LRC containing colonies remained. LRC also remain in vivo after treatment with CY + TBI. Succeeding experiments set up to identify the haploidentical effector cell responsible for cure and, therefore, for the elimination of chemoresistant LRC designate donor NK cells crucial for the anti-tumor effect. NK cell depletion of the haploidentical graft fully abrogated the anti-tumor effect. Increased disease free survival retained after transplantation of haploidentical bone marrow and NK cell-enriched spleen cell grafts, even in the absence of donor T-cells or of donor bone marrow. Tumor growth analysis indicates the anti-tumor effect being immediate (days). Based on these data, it is worthwhile to explore alloreactive adoptive NK cell therapy as consolidation for patients with metastasized breast cancer. PMID- 21274622 TI - The conceptual model and guiding principles of a supported-education program for Orthodox Jewish persons with severe mental illness. AB - An innovative culturally-oriented supported-education program has been established in Israel to address the needs of religious Jewish persons with severe mental illness. This program is utilizing a highly regarded institution in the Orthodox communities, a Beit Midrash, a study hall for religious studies, as a context for rehabilitation. Based on open-ended interviews conducted with the staff members of this program, its conceptual framework and guiding principles have been identified and analyzed. In this program common principles of psychiatric rehabilitation have been adapted and incorporated into a context which has not been known so far as a context for psychiatric rehabilitation. In addition, innovative supported-education methods of work which are compatible with the cultural context of Orthodox Jewish persons have been implemented, such as opportunities provided to the participants to reconstruct their views of their daily struggles and enhance their sense of spirituality via the discussion of socially-oriented religious texts. The culturally-oriented context of the Beit Midrash enables outreach to a population which might otherwise not receive any services. This is a promising model for addressing the unique needs of religious persons with severe mental illness and for filling a gap in the resources available for the rehabilitation of this population in the community. PMID- 21274623 TI - Housing satisfaction among chronically homeless adults: identification of its major domains, changes over time, and relation to subjective well-being and functional outcomes. AB - There is limited consensus on the critical domains of housing satisfaction among chronically homeless adults and little information on changes in housing satisfaction over time or whether housing satisfaction at initial entry into housing is correlated with subsequent subjective well-being or other outcomes. The current study tracked housing satisfaction over a 2-year period in a multi site supported housing initiative and examined the predictive value of clients' housing satisfaction when they were first housed on various subjective and functional outcomes. A total of 756 participants from 11 sites were enrolled in the study. Six domains of housing satisfaction were identified: good environment, control and consumer choice, physical quality, geographic proximity to desirable resources, positive case manager contact, and frequency of landlord interaction. Over 2 years, there were slight declines in housing satisfaction on physical quality of housing and satisfaction with case manager contact, and an increase in satisfaction with landlord interaction. Consistent with some previous research, housing satisfaction was not predictive of housing tenure, clinical outcomes, or duration of program participation. While becoming housed is a significant gain for chronically homeless people, their satisfaction with housing did not predict functional outcomes. PMID- 21274624 TI - Transient stasis of pancreatic fluid flow together with mild injury of the pancreatic duct cause chronic pancreatitis. AB - BACKGROUND: Little is known about the etiopathogenesis of chronic pancreatitis, due mainly to the lack of simple animal models suitable to study inflammatory and fibrogenetic processes in the pancreas. AIMS: The purpose of this study was to examine whether transient congestion of pancreatic fluid flow alone or slight ductal injury alone is sufficient, or where both are required, to induce chronic pancreatic injury. METHODS: Three different models of pancreatitis were tested in rats induced by retrograde intraductal infusion of 40 MUl/100 g body weight of 0.01% agarose (group A), 40 MUl/100 g body weight of 0.1% sodium taurocholate (group T), or a mixture of the two solutions (group M). Histological alterations of the pancreas were examined by hematoxylin-eosin staining, changes in type IV collagen structure were studied by immunostaining, and the gelatinolytic activity of latent and active matrix metalloproteinase-2 (MMP-2) was analyzed by zymography. RESULTS: In group A and T rats, histological alterations of the pancreas and the gelatinolytic activity of MMP-2 returned to baseline levels by day 14, and immunoreactivity for type IV collagen appeared as continuous lines along the basement membrane. In group M rats, however, acinar damage, fibrosis and fatty degeneration were observed even on day 56, and type IV collagen was detected as discontinuous lines until day 56. MMP-2 was significantly elevated from day 5 to day 42. CONCLUSIONS: Co-existence of transient stasis of pancreatic fluid flow, together with mild damage to the pancreatic duct and acinar cells, exert synergistic effects on the development of persistent pancreatic injury with continuous disorganization of type IV collagen in the basement membrane of the ducts. PMID- 21274625 TI - Does anesthesiologist-directed sedation for ERCP improve deep cannulation and complication rates? AB - OBJECTIVES: While some gastroenterologists provide their own sedation for endoscopic retrograde cholangiopancreatography (ERCP), others utilize anesthesiologists. There is limited information comparing cannulation success and complication rates between these two approaches. Theoretically, anesthesiologist directed sedation (ADS) may lead to an improved deep cannulation rate by virtue of using deeper and more constant levels of sedation and by removing the minute by-minute medication management and physiologic monitoring responsibilities from the endoscopy team. AIMS: To compare ERCP deep cannulation success and complications between gastroenterologist-directed sedation (GDS) and ADS. METHODS: All ERCPs completed by senior advanced endoscopists at a tertiary referral center over a 2-year period were reviewed. During the first year, all ERCP sedation was performed with GDS utilizing a narcotic and a benzodiazepine. Due to a change in division policy and practice, during the second year, all ERCP sedation was provided by ADS. Patients with prior papillary interventions were excluded. Demographics, procedure indications, deep cannulation success, sedation provider, and procedural complications were recorded. RESULTS: A total of 367 patients were studied: 178 (48.5%) GDS and 189 (51.5%) ADS. There was no difference in the groups with respect to race, age, and gender. Four patients (2.3%) in the GDS group could not be sedated. There were two deaths, one in each group; one death was due to cholangitis/sepsis and the other was due to post-ERCP pancreatitis. The overall cannulation success rates were similar between the two groups (94.4% vs. 95.2%, P = 0.36). CONCLUSIONS: Deep ductal cannulation rates between GDS and ADS are similar. PMID- 21274627 TI - Methodological challenges examining subgroup differences: examples from universal school-based youth violence prevention trials. AB - This article reviews the literature on school-based universal violence prevention programs to illustrate key methodological challenges for investigating subgroup differences in prevention effects. The variety of potential moderating factors examined within this literature is discussed within the context of a social ecological model. Our review of this literature identified the following methodological issues: the need for a clear a priori theoretical basis for selecting potential moderators, inflated Type I error rates that result from large numbers of comparisons, the absence of explicit tests of moderation, interpretive issues arising from a restricted range on moderator variables, the failure to report effect size estimates, the presence of potential confounding factors, and the importance of examining factors that might operate at multiple ecological levels. These points are illustrated using examples of studies, primarily within youth violence prevention research, that have identified factors within the individual, school, and community that moderate the outcomes of preventive interventions. We conclude with general recommendations for future work. These include the benefits of using the social-ecological model to provide a basis for moving from exploratory to more theory-driven confirmatory models of subgroup differences, the potential merits of qualitative research designed to identify factors that may influence the effectiveness of intervention efforts for specific subgroups of individuals, and the provision of effect size estimates and confidence intervals for effect sizes in prevention reports. PMID- 21274628 TI - Individual, social, and environmental factors associated with initiating methamphetamine injection: implications for drug use and HIV prevention strategies. AB - The purpose of this study was to determine the incidence and predictors of initiating methamphetamine injection among a cohort of injection drug users (IDU). We conducted a longitudinal analysis of IDU participating in a prospective study between June 2001 and May 2008 in Vancouver, Canada. IDU who had never reported injecting methamphetamine at the study's commencement were eligible. We used Cox proportional hazards models to identify the predictors of initiating methamphetamine injection. The outcome was time to first report of methamphetamine injection. Time-updated independent variables of interest included sociodemographic characteristics, drug use patterns, and social, economic and environmental factors. Of 1317 eligible individuals, the median age was 39.9 and 522 (39.6%) were female. At the study's conclusion, 200 (15.2%) participants had initiated injecting methamphetamine (incidence density: 4.3 per 100 person-years). In multivariate analysis, age (adjusted hazard ratio [aHR]: 0.96 per year older, 95%CI: 0.95-0.98), female sex (aHR: 0.58, 95%CI: 0.41-0.82), sexual abuse (aHR: 1.63, 95%CI: 1.18-2.23), using drugs in Vancouver's drug scene epicentre (aHR: 2.15 95%CI: 1.49-3.10), homelessness (aHR: 1.43, 95%CI: 1.01 2.04), non-injection crack cocaine use (aHR: 2.06, 95%CI: 1.36-3.14), and non injection methamphetamine use (aHR: 3.69, 95%CI: 2.03-6.70) were associated with initiating methamphetamine injection. We observed a high incidence of methamphetamine initiation, particularly among young IDU, stimulant users, homeless individuals, and those involved in the city's open drug scene. These data should be useful for the development of a broad set of interventions aimed at reducing initiation into methamphetamine injection among IDU. PMID- 21274629 TI - A novel membrane based process to isolate photosystem-I membrane complex from spinach. AB - The isolation of photosystem-I (PS-I) from spinach has been conducted using ultrafiltration with 300 kDa molecular weight cut-off polyethersulfone membranes. The effects of ultrafiltration operating conditions on PS-I activity were optimized using parameter scanning ultrafiltration. These conditions included solution pH, ionic strength, stirring speed, and permeate flux. The effects of detergent (Triton X-100 and n-dodecyl-beta-D-maltoside) concentration on time dependent activity of PS-I were also studied using an O(2) electrode. Under optimized conditions, the PS-I purity obtained in the retentate was about 84% and the activity recovery was greater than 94% after ultrafiltration. To our knowledge, this is the first report of the isolation of a membrane protein using ultrafiltration alone. PMID- 21274630 TI - Global contexts, social capital, and acculturative stress: experiences of Indian immigrant men in New York City. AB - Immigrants depend on within-group social networks for social support during the acculturation process. Within-group social networks are linked to higher mutual concern and reciprocity, lower acculturative stress, and lower depression among immigrants Studies are limited, however, about immigrants' social support in the contexts of global connectedness and transnational connectivity. Grounded in social capital approach and immigrant health framework, this qualitative, community-based study examined the social networks of immigrant men from India to New York City. Drawing upon the participants' narratives, the author illustrates the ways that social capital influences social networking and acculturative stress in post-immigration sociocultural contexts along with its implications for community-based interventions. PMID- 21274631 TI - Latino residential isolation and the risk of obesity in Utah: the role of neighborhood socioeconomic, built-environmental, and subcultural context. AB - The prevalence rate of obesity in the United States has been persistently high in recent decades, and disparities in obesity risks are routinely observed. Both individual and contextual factors should be considered when addressing health disparities. This study examines how Latino-white spatial segregation is associated with the risk of obesity for Latinos and whites, whether neighborhood socioeconomic resources, the built environment, and subcultural orientation serve as the underlying mechanisms, and whether neighborhood context helps explain obesity disparities across ethnic and immigrant groups. The study was based on an extensive database containing self-reported BMI measures obtained from driver license records in Utah merged with census data and several GIS-based data. Multilevel analyses were performed to examine the research questions. For both men and women, Latino residential isolation is significantly and positively linked to the risk of obesity; after controlling for immigrant concentration, this effect gets amplified. Moreover, for men and women, the segregation effect is partly attributable to neighborhood SES and the built environment; and only for women is it partly attributable to obesity prevalence in the neighborhood. Place matters for individual risk of obesity for both men and women and there are multifarious pathways linking residence to obesity. Among the demographic, socioeconomic, physical, and cultural aspects of neighborhood context examined in this study, perhaps the most modifiable environment features that could prevent weight gain and its associated problems would be the built environmental factors such as greenness, park access, and mixed land use. PMID- 21274632 TI - True love waits: do Southern Baptists? Premarital sexual behavior among newly married Southern Baptist Sunday school students. AB - This study measures premarital sex prevalence, sources of sex education, and support for secular sex education among 151 newly married young adults surveyed at 9 Texas Southern Baptist churches. More than 70% of respondents reported having had premarital vaginal or oral sex, but more than 80% regretted premarital sex. The proportion of premarital sex exceeded 80% in 6 of 9 churches, among men and women married after age 25 and women married before age 21. School sex education was the only source of information about sexually transmitted infections for 57% of respondents, and 65% supported secular sex education despite church opposition. PMID- 21274633 TI - CHOP deletion does not impact the development of diabetes but suppresses the early production of insulin autoantibody in the NOD mouse. AB - C/EBP homologous protein (CHOP) has been proposed as a key transcription factor for endoplasmic reticulum (ER) stress-mediated beta-cell death induced by inflammatory cytokines in vitro. However, the contribution of CHOP induction to the pathogenesis of type 1 diabetes is not yet clear. To evaluate the relevance of CHOP in the pathogenesis of type 1 diabetes in vivo, we generated CHOP deficient non-obese diabetic (NOD.Chop (-/-)) mice. CHOP deficiency did not affect the development of insulitis and diabetes and apoptosis in beta-cells. Interestingly, NOD.Chop (-/-) mice exhibited a delayed appearance of insulin autoantibodies compared to wild-type (wt) mice. Adoptive transfer with the diabetogenic, whole or CD8(+)-depleted splenocytes induced beta-cell apoptosis and the rapid onset of diabetes in the irradiated NOD.Chop (-/-) recipients with similar kinetics as in wt mice. Expression of ER stress-associated genes was not significantly up-regulated in the islets from NOD.Chop (-/-) compared to those from wt mice or NOD-scid mice. These findings suggest that CHOP expression is independent of the development of insulitis and diabetes but might affect the early production of insulin autoantibodies in the NOD mouse. PMID- 21274635 TI - Ethics of care and responsibility: normative fragments. PMID- 21274634 TI - The role of IAP antagonist proteins in the core apoptosis pathway of the mosquito disease vector Aedes aegypti. AB - While apoptosis regulation has been studied extensively in Drosophila melanogaster, similar studies in other insects, including disease vectors, lag far behind. In D. melanogaster, the inhibitor of apoptosis (IAP) protein DIAP1 is the major negative regulator of caspases, while IAP antagonists induce apoptosis, in part, by binding to DIAP1 and inhibiting its ability to regulate caspases. In this study, we characterized the roles of two IAP antagonists, Michelob_x (Mx) and IMP, in apoptosis in the yellow fever mosquito Aedes aegypti. Overexpression of Mx or IMP caused apoptosis in A. aegypti Aag2 cells, while silencing expression of mx or imp attenuated apoptosis. Addition of recombinant Mx or IMP, but not cytochrome c, to Aag2 cytosolic extract caused caspase activation. Consistent with this finding, AeIAP1 bound and inhibited both initiator and effector caspases from A. aegypti, and Mx and IMP competed with caspases for binding to AeIAP1. However, a difference was observed in the BIR domains responsible for Dronc binding by AeIAP1 versus DIAP1. These findings demonstrate that the mechanisms by which IAP antagonists regulate apoptosis are largely conserved between A. aegypti and D. melanogaster, although subtle differences exist. PMID- 21274636 TI - Are mitochondrial haplogroups associated with extreme longevity? A study on a Spanish cohort. AB - Mitochondrial haplogroups could influence individual susceptibility to mitochondrial DNA (mtDNA) damage, and human longevity, as indicated by previous studies with Caucasian (European) or Asian cohorts. Here, we compared the frequency of mtDNA haplogroups in a group of Spanish (Caucasian) centenarians (n = 65, aged 100-108 years, 58 women, most from the central part of Spain) and a group of healthy young adults (n = 138, 62 women, aged 20-40 years) of the same ethnic origin. We did not find significant differences between centenarians and the control group (P > 0.2). Only two centenarians (both women) had the haplogroup J, which hampered comparison with the control group (n = 15, five women). Our data confirm that the potential effects of mitochondrial haplogroups on human longevity might be population/geographic specific, with important differences between studies (notably, with regard to the previously reported potential benefit brought about by the haplogroup J) arising from the different living environment and ethnic background of the study cohorts. PMID- 21274637 TI - Relationship between cytomegalovirus (CMV) IgG serology, detectable CMV DNA in peripheral monocytes, and CMV pp65(495-503)-specific CD8+ T cells in older adults. AB - In immunocompetent individuals, cytomegalovirus (CMV) is thought to persist in a latent state in monocytes and myeloid progenitor cells, establishing a lifelong infection. In CMV-seropositive older adults, aging has been associated with both expansion of CMV pp65(495-503)-specific CD8(+) T cell clones and shrinkage of the T cell repertoire that characterize T cell immunosenescence. In fact it has been suggested that chronic CMV infection is a driving force in age-related T cell immunosenescence. In older adults, chronic CMV infection is conventionally diagnosed by positive IgG serology which does not distinguish between past and persistent infections. To better define the relationship between chronic CMV infection and expansion of CMV pp65(495-503)-specific CD8(+) T cells, we directly assessed CMV viral DNA in monocyte-enriched peripheral blood mononuclear cells in 16 HLA-A2-positive elderly volunteers (mean age = 83 years). While all participants had positive CMV IgG serology by enzyme-linked immunosorbent assays, only nine (56%) had detectable CMV DNA by nested polymerase chain reaction. These nine individuals had significantly higher percentages of CMV pp65(495-503) tetramer-positive CD8(+) T cells (median = 1.3%) than those without detectable CMV DNA (median = 0.1%; p < 0.001). Absolute CMV IgG antibody titers did not differ between these two groups (median = 54.6 vs 44.2 EU/ml, respectively, p = 0.4). CMV IgM titers were negative for all 16 participants, suggesting that recent primary CMV infection was unlikely. These results demonstrate a strong association between the presence of CMV DNA in peripheral monocytes and the expansion of CD8(+) T cells specific for the CMV immunodominant epitope pp65(495 503). Although the sample size in this study is relatively small, these findings provide initial evidence suggesting the heterogeneity of CMV IgG-seropositive older adult population and CMV viral DNA detection in peripheral monocytes as an informative tool to better understand the relationship between chronic CMV infection and T cell immunosenescence. PMID- 21274638 TI - Photochemical transformation of the thyroid hormone levothyroxine in aqueous solution. AB - PURPOSE: The direct aqueous photolysis of the thyroid hormone levothyroxine (T(4)) has been studied. METHODS AND RESULT: One of the major photoproducts, i.e., 4-[4-(2-amino-2-carboxy-ethyl)-2,6-diiodo-phenoxy]-penta-2,4-dienoic acid (P1), was isolated by liquid chromatography and structurally assigned by mass spectrometric (MS) and nuclear magnetic resonance spectroscopic methods. The identity of a second major product, i.e., 3,5-diiodo-L: -thyrosine (P3), was confirmed through access to a commercially available standard. Furthermore, the structures of three additional transformation products are proposed on the basis of data obtained by high-resolution MS analyses. UV absorption spectra were determined for T(4) and the two photoproducts P1 and P3. Disappearance quantum yields were calculated for T(4) (phi = 0.014 at pH 12) and P3 (phi = 0.024 at pH 12 and phi = 0.010 at pH 8.5), whereas the compound P1 was found to be stable under the studied conditions (T(1/2) = 600 min). CONCLUSION: The results indicate that solar UV light may have a significant impact on the fate of T(4) in the aquatic environment. PMID- 21274639 TI - Concentration-dependent RDX uptake and remediation by crop plants. AB - The potential RDX contamination of food chain from polluted soil is a significant concern in regards to both human health and environment. Using a hydroponic system and selected soils spiked with RDX, this study disclosed that four crop plant species maize (Zea mays), sorghum (Sorghum sudanese), wheat (Triticum aestivum), and soybean (Glycine max) were capable of RDX uptake with more in aerial parts than roots. The accumulation of RDX in the plant tissue is concentration-dependent up to 21 mg RDX/L solution or 100 mg RDX/kg soil but not proportionally at higher RDX levels from 220 to 903 mg/kg soil. While wheat plant tissue harbored the highest RDX concentration of 2,800 MUg per gram dry biomass, maize was able to remove a maximum of 3,267 MUg RDX from soil per pot by five 4 week plants at 100 mg/kg of soil. Although RDX is toxic to plants, maize, sorghum, and wheat showed reasonable growth in the presence of the chemical, whereas soybeans were more sensitive to RDX. Results of this study facilitate assessment of the potential invasion of food chain by RDX-contaminated soils. PMID- 21274640 TI - Assessing the potential exposure risk and control for airborne titanium dioxide and carbon black nanoparticles in the workplace. AB - PURPOSE: This study assessed the potential exposure risks for workers in the workplace exposed to airborne titanium dioxide nanoparticles (TiO(2)-NPs) and carbon black nanoparticles (CB-NPs). The risk management control strategies were also developed for the NP engineering workplace. METHODS: The method used in this study was based on the integrated multiple-path particle dosimetry model to estimate the cumulative dose of nanoparticles (NPs) in the human lung. The study then analyzed toxicological effects such as pulmonary cytotoxicity and inflammation and evaluated the health risk associated with exposure to NPs in the workplace. Risk control measures such as the use of ventilating systems and N95 respirator protection are also discussed. RESULTS AND DISCUSSION: This study found that: (1) the cumulative dose of CB-NPs was greater than that of TiO(2)-NPs in human lungs; (2) there is a potential health risk to workers exposed to TiO(2) NPs and CB-NPs in the absence of control measures in the workplace, with higher health risks associated with CB-NPs than TiO(2)-NPs; and (3) the use of a ventilating system and an N95 respirator offers greater protection in the workplace and significantly reduces the health risks associated with NP exposure. CONCLUSION: The present risk management control strategy suggests that the most effective way to reduce airborne NPs is to incorporate the use of a ventilating system combined with N95 respirator protection. This will enable the concentrations of TiO(2)-NPs and CB-NPs to be reduced to acceptable exposure levels. PMID- 21274641 TI - The bioaccumulation and translocation of Fe, Zn, and Cu in species of mushrooms from Russula genus. AB - INTRODUCTION: Many previous studies revealed a high ability of mushrooms to accumulate heavy metals from environment. This paper concerns the capacity of some wild macromycetes belonging to Russula genus to accumulate heavy metals in natural condition of pH (between 6.5 and 6.8) and the pattern of metal translocation in the fruiting body. MATERIALS AND METHODS: The studied Russula species are Russula virescens, Russula cyanoxantha, Russula foetens, and Russula nigrescens, which were harvested from forestry ecosystem from South Romania. The metal concentration in mushrooms and their substrate was established by EDXRF method. RESULTS AND DISCUSSION: The concentrations of iron (Fe), zinc (Zn), and copper (Cu) in the fruiting body depends on species and vary between 58.83 340.34, 19.70-99.62, and 5.03-9.37 mg/kg for Fe, Zn, and Cu, respectively. The bioaccumulation factor has subunit values for the three studied trace metals, which show the low capacity of these species of mushrooms to accumulate metals if the concentrations in soil increase over the normal threshold for these elements. The high values of translocation factor demonstrate the mobility of Fe, Zn, and Cu in the studied mushrooms. PMID- 21274642 TI - Inventory of heavy metal content in organic waste applied as fertilizer in agriculture: evaluating the risk of transfer into the food chain. AB - BACKGROUND, AIM, AND SCOPE: In this work, an environmental risk assessment of reusing organic waste of differing origins and raw materials as agricultural fertilizers was carried out. An inventory of the heavy metal content in different organic wastes (i.e., compost, sludge, or manure) from more than 80 studies at different locations worldwide is presented. MATERIALS AND METHODS: The risk analysis was developed by considering the heavy metal (primarily Cd, Cu, Ni, Pb, and Zn) concentrations in different organic residues to assess their potential environmental accumulation and biotransfer to the food chain and humans. A multi compartment model was used to estimate the fate and distribution of metals in different environmental compartments, and a multi-pathway model was used to predict human exposure. RESULTS: The obtained hazard index for each waste was concerning in many cases, especially in the sludge samples that yielded an average value of 0.64. Among the metals, Zn was the main contributor to total risk in all organic wastes due to its high concentration in the residues and high biotransfer potential. Other more toxic metals, like Cd or Pb, represented a negligible contribution. CONCLUSIONS: These results suggest that the Zn content in organic waste should be reduced or more heavily regulated to guarantee the safe management and reuse of waste residues according to the current policies promoted by the European Union. PMID- 21274643 TI - Distribution of mono- through hexa-chlorobenzenes in floodplain soils and sediments of the Tittabawassee and Saginaw Rivers, Michigan. AB - INTRODUCTION: Chlorobenzenes are used as solvents or as feedstocks in the production of pesticide formulations, dyes, room deodorizers, moth-proofing agents, and de-inking solvents. Chlorobenzenes were produced by the Dow Chemical Company in Midland, Michigan, for several decades. In this study, concentrations of 12 chlorobenzene (CBz) congeners, from mono- to hexachlorobenzenes, were measured in more than 150 floodplain soil (FPS), surface sediment, and sediment core (SC) samples collected during 2002-2004 from the Pine River, Tittabawassee River, Shiawassee River, Saginaw River, and Saginaw Bay, Michigan. METHODS: Five grams of wet sediment were homogenized with anhydrous sodium sulfate and extracted with 20% dichloromethane/hexane. The extracts were purified by silica gel column chromatography and analyzed by a gas chromatograph interfaced with a mass spectrometer (GC/MS). RESULTS: Mean concentrations of SigmaCBz in FPS and surface sediment were seven to 30 times higher in the Tittabawassee River (80 and 60 ng/g dry weight (dw), respectively) than in the Saginaw River (2.4 and 8.1 ng/g dw, respectively) and Saginaw Bay (5.5 and 8.0 ng/g dw, respectively). Concentrations of SigmaCBz were low in surface sediment and FPS from locations upstream of Midland, Michigan, on the Tittabawassee River. Concentrations of SigmaCBz were higher in FPS than in surface sediment of the Tittabawassee River; on the contrary, surface sediment contained higher concentrations of CBz than FPS from the other rivers studied. High concentrations of hexachlorobenzene were found in FPS of the Tittabawassee River. All CBz congeners, except for dichlorobenzenes (DCBz), showed a trend of spatial decrease with downstream of the Dow Chemical Company in Midland. The CBz congener composition of the samples showed multiple patterns that reflected differences in historical emissions and environmental partitioning, arising from variations in physico-chemical properties of CBz. 1,4-Dichlorobenzene (1,4-DCBz) was found in all of the samples and accounted for a high proportion of total CBz. The relationship between concentrations of CBz and previously reported concentrations of PCDD/Fs for the same set of samples (Kannan et al. 2008) was significant, indicating similarities in sources and depositions of these two classes of compounds in the watershed. PMID- 21274644 TI - Urban-rural differences in physical activity in Belgian adults and the importance of psychosocial factors. AB - Recent research in urban planning and public health has drawn attention to the associations between urban form and physical activity in adults. Because little is known on the urban-rural differences in physical activity, the main aims of the present study were to examine differences in physical activity between urban and rural adults and to investigate the moderating effects of the physical environment on the relationship between psychosocial factors and physical activity. In Flanders, Belgium, five rural and five urban neighborhoods were selected. A sample of 350 adults (20-65 years of age; 35 adults per neighborhood) participated in the study. Participants wore a pedometer for 7 days, and self reported physical activity and psychosocial data were also collected. Results showed that urban adults took more steps/day and reported more walking and cycling for transport in the neighborhood, more recreational walking in the neighborhood, and more walking for transportation outside the neighborhood than rural adults. Rural adults reported more recreational cycling in the neighborhoods. The physical environment was a significant moderator of the associations between several psychosocial factors (modeling from family, self efficacy, and perceived barriers) and physical activity. In rural participants, adults with psychosocial scores above average were more physically active, whereas there were no differences in physical activity according to psychosocial factors in urban participants. These results are promising and plead for the development of multidimensional interventions, targeting specific population subgroups. In rural environments, where changing the environment would be a very challenging task, interventions focusing on modifiable psychosocial constructs could possibly be effective. PMID- 21274645 TI - Prevalence and predictors of physical inactivity in a slum in Brazil. AB - The aim of this study was to ascertain the prevalence of physical inactivity and examine the role of potential predictors in a very low-income adult population in a slum located in Recife city, northeast of Brazil. A cross-sectional study was conducted with 1,176 subjects aged 20-60 years residing in a slum. Using the short version of the International Physical Activity Questionnaire, 307 (26.1%) study participants-97 (23.8%) men and 210 (27.3%) women-have a low physical activity score (MET-minutes per week). Increased age was associated with physical inactivity only in people without overweight/obesity. Low physical activity was less common (i.e., respondents were more active) than in other Brazilian population-based studies. These results suggest that the relationship between physical activity and socioeconomic level is more complex and depends on the internal characteristics of the community. PMID- 21274646 TI - Are building-level characteristics associated with indoor allergens in the household? AB - Building-level characteristics are structural factors largely beyond the control of those who live in them. We explored whether building-level characteristics and indoor allergens in the household are related. We examined the relationship between building-level characteristics and indoor allergens: dust mite, cat, cockroach, and mouse. Building-level characteristics measured were presence of pests (seeing cockroaches and rodents), building type (public housing, buildings zoned commercially and residentially, and building size), and building condition (building age and violations). Allergen cutpoints were used for categorical analyses and defined as follows: dust mite: >0.25 MUg/g; cat: >1 MUg/g; cockroach: >1 U/g; mouse: >1.6 MUg/g. In fully adjusted linear analyses, neither dust mite nor cat allergen were statistically significantly associated with any building-level characteristics. Cockroach allergen was associated with the presence of cockroaches (2.07; 95% CI, 1.23, 3.49) and living in public housing (2.14; 95% CI, 1.07, 4.31). Mouse allergen was associated with the presence of rodents (1.70; 95% CI, 1.29, 2.23), and building size: living in a low-rise (<8 floors; 0.60; 95% CI, 0.42, 0.87) or high-rise (8 + floors; 0.50; 95% CI, 0.29, 0.88; compared with house/duplex). In fully adjusted logistic analyses, cat allergen was statistically significantly associated with living in a high-rise (6.29; 95% CI, 1.51, 26.21; compared with a house/duplex). Mouse allergen was associated with living in public housing (6.20; 95% CI, 1.01, 37.95) and building size: living in a low-rise (0.16; 95% CI, 0.05, 0.52) or high-rise (0.06; 95% CI, 0.01, 0.50; compared with a house/duplex). Issues concerning building size and public housing may be particularly critical factors in reducing asthma morbidity. We suggest that future research explore the possible improvement of these factors through changes to building code and violations adherence, design standards, and incentives for landlords. PMID- 21274647 TI - HIV-1 Tat-mediated neurotoxicity in retinal cells. AB - The current study was aimed at investigating the effect of HIV-1 protein Tat on the retinal neurosensory cell line R28. Exposure of Tat resulted in induction of pro-inflammatory mediators such as CXCL10 and TNF-alpha in addition to the activation marker GFAP in these cells. Conditioned media from Tat-treated R28 cells was able to induce monocyte migration, an effect that was blocked by CXCR3 antagonist. Complementary studies in the HIV-1 Tat-transgenic mice, showed a complete absence of the nuclear layer and the outer photoreceptor segments of the retina with a concomitant increase in glial activation. These findings lend support to the observation in post-HAART era of increased incidence of immune response-mediated retinal degeneration. These findings have direct relevance to diseases such as immune response uveitis and patients recovering from CMV retinitis. PMID- 21274648 TI - Recruitment and follow-up of adolescent and young adult cancer survivors: the AYA HOPE Study. AB - INTRODUCTION: Cancer is rare in adolescents and young adults (AYA), but these patients have seen little improvement in survival in contrast to most other age groups. Furthermore, participation in research by AYAs is typically low. We conducted a study to examine the feasibility of recruiting a population-based sample of AYA survivors to examine issues of treatment and health outcomes. METHODS: Individuals diagnosed in 2007-08 and age 15-39 at the time of diagnosis with acute lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, germ cell cancer or sarcoma were identified by 7 Surveillance, Epidemiology, and End Results (SEER) cancer registries, mailed surveys within 14 months after diagnosis and again a year later, and had medical records reviewed. RESULTS: 525 (43%) of the eligible patients responded, 39% refused and 17% were lost to follow-up. Extensive efforts were required for most potential respondents (87%). 76% of respondents completed the paper rather than online survey version. In a multivariate model, age, cancer site, education and months from diagnosis to the first mailing of the survey were not associated with participation, although males (p < 0.01), Hispanics and non-Hispanic blacks (p < 0.001) were less likely to participate. 91% of survivors completing the initial survey completed the subsequent survey. DISCUSSION: Despite the response rate, those who participated adequately reflected the population of AYA cancer survivors. The study demonstrates that cancer registries are valuable foundations for conducting observational, longitudinal population-based research on AYA cancer survivors. IMPLICATIONS FOR CANCER SURVIVORS: Achieving a reasonable response rate in this population is possible, but requires extensive resources. PMID- 21274650 TI - Racial differences in well-being and cancer concerns in prostate cancer patients. AB - BACKGROUND: We analyzed the racial differences in physical well-being, social/family well-being, functional well-being, emotional well-being, and prostate cancer specific worry among men with clinically localized prostate cancer. METHODS: In this prospective cohort study, we recruited 121 Caucasian and 77 African American men with newly diagnosed prostate cancer. Participants completed the Functional Assessment of Cancer Therapy-Prostate (FACT-P) instrument at baseline and at 3, 6, 12 and 24 months follow-up. To determine the between and within group differences on all functional measures (physical well being, social/family well-being, functional well-being, emotional well-being, and prostate cancer specific concerns), we used repeated measures ANOVA. RESULTS: Except for education, income and hospital type, the two racial groups had comparable socio-demographic and clinical attributes. At 3 months post-treatment, both groups experienced a decline in physical well-being and increase in prostate cancer specific concerns. Baseline values of these measures were not recovered by 24-month follow-up. In particular, lack of energy was the most prominent contributor to declining physical well-being. The ability to have and maintain an erection was the most severe prostate cancer specific concern. Lack of energy and concern regarding erection ability varied between the two groups over the follow up period. CONCLUSIONS: Our findings provide an insight into not only the overall racial variation in physical health and prostate cancer specific concern, but also the temporal differences in these measures that can occur over a 24-month follow-up. This has important implications for effective management of localized prostate cancer patients from different racial groups and merits further research. PMID- 21274649 TI - Quality of life among Latina breast cancer patients: a systematic review of the literature. AB - INTRODUCTION: The Latino population is the most rapidly growing ethnic minority in the United States and Latinas have higher rates of advanced breast cancer and more rigorous treatments than White women. However, the literature lacks reviews on quality of life among this population of breast cancer patients. METHODS: A systematic review of the breast cancer quality of life (QOL) literature was conducted among studies that provided a comparison of mental, physical, social, or sexual QOL between Latinas and other racial/ethnic groups. Of the 375 studies reviewed, 20 quantitative studies and two qualitative studies met criteria for inclusion. RESULTS: Latinas were more likely to report poor mental, physical, and social QOL, relative to non-Latinas. Only four studies assessed sexual QOL, making it difficult to draw any conclusions. Of these four QOL domains, the largest disparity was found in the area of mental health in which Latinas reported poorer QOL compared to non-Latina Whites and Blacks. DISCUSSION/CONCLUSIONS: Most quantitative studies revealed either that Latinas consistently evidenced significantly lower QOL than non-Latinas on all measures (6 studies) or reported mixed findings in which Latinas generally demonstrated significantly worse QOL on most, but not all, measures (12 studies) included in the study. Explanatory mechanisms including socio-demographic, treatment-related, and culturally-relevant factors are discussed. Implications for research design, measurement, and clinical work are also included. IMPLICATIONS FOR CANCER SURVIVORS: Although not entirely consistent, data suggest that Latina breast cancer survivors on average experience worse QOL than non-Latina Whites. Understanding ethnic differences in QOL among breast cancer survivors can inform interventions targeted at improving health status for Latinas. PMID- 21274651 TI - Tuberculosis abscess causing spinal cord compression: a rare presentation. PMID- 21274652 TI - A comparison of antibiotic point prevalence survey data from four Irish regional/general hospitals. AB - INTRODUCTION: Point prevalence surveys (PPS) are increasingly used to examining and compare hospital antibiotic consumption. The aim of this study was to identify the (1) point prevalence of antibiotic use in one regional hospital and (2) compare PPS data from similar regional/general hospitals. METHODS: Data were collected on all inpatients with an active antibiotic prescription and on all prescriptions issued in the emergency department over a 24-h period. Point prevalence data were obtained from three other regional/general hospitals. RESULTS: The frequency of antibiotic use was hospital A = 29%, B = 38%, C = 34% and D = 37%. Overall, the most commonly prescribed antibiotic was co-amoxiclav (30%), followed by macrolides (12%). However, new generation broad-spectrum antibiotics, such as piperacillin/tazobactam or ciprofloxacin, were also commonly used. Prescribing for common conditions such as respiratory infection or cellulites showed diverse antibiotic selection. CONCLUSION: Point prevalence survey data using a standardised methodology could facilitate both local audit and national benchmarking to monitor antibiotic use. PMID- 21274653 TI - Calcium fructoborate--potential anti-inflammatory agent. AB - Calcium fructoborate is a boron-based nutritional supplement. Its chemical structure is similar to one of the natural forms of boron such as bis-manitol, bis-sorbitol, bis-fructose, and bis-sucrose borate complexes found in edible plants. In vitro studies revealed that calcium fructoborate is a superoxide ion scavenger and anti-inflammatory agent. It may influence macrophage production of inflammatory mediators, can be beneficial for the suppression of cytokine production, and inhibits progression of endotoxin-associated diseases, as well as the boric acid and other boron sources. The mechanisms by which calcium fructoborate exerts its beneficial anti-inflammatory effects are not entirely clear, but some of its molecular biological in vitro activities are understood: inhibition of the superoxide within the cell; inhibition of the interleukin 1beta, interleukin-6, and nitric oxide release in the culture media; and increase of the tumor necrosis factor-alpha production. Also, calcium fructoborate has no effects on lipopolysaccharide-induced cyclooxygenase-2 protein express. The studies on animals and humans with a dose range of 1-7 mg calcium fructoborate (0.025-0.175 mg elemental boron)/kg body weight/day exhibited a good anti inflammatory activity, and it also seemed to have negligible adverse effect on humans. PMID- 21274654 TI - Hepcidin treatment modulates the expression of divalent metal transporter-1, ceruloplasmin, and ferroportin-1 in the rat cerebral cortex and hippocampus. AB - Elevated iron levels are considered to play a role in the neurodegenerative mechanisms that underlie Alzheimer's and Parkinson's disease. The linkage between hepcidin (Hepc) and ferroportin-1 (FPN1), the divalent metal transporter 1 (DMT1), and ceruloplasmin (CP) in the brain is unknown. To discern the role of Hepc in regulating the expression of these proteins, we investigated FPN1, DMT1, and CP protein and mRNA expression in the brain after the intracerebroventricular injection of Hepc. Our results show that after Hepc injection, expression of FPN1 mRNA and FPN1 protein was inhibited in the cerebral cortex and hippocampus. Furthermore, we showed a clear change of DMT1 and CP protein and mRNA levels in the brain. The immunohistochemical analysis revealed an increase of DMT1 and a decrease of CP levels. Semi-quantitative analysis using PCR methods showed an increase of DMT1(+IRE) mRNA, and a decrease of DMT1(-IRE) mRNA and CP mRNA levels. Since alterations in iron levels in the brain are causally linked to degenerative conditions such as Alzheimer's disease, an improved understanding of the regulation of iron transport protein expression such as FPN1, DMT1, and CP could lead to novel strategies for treatments. PMID- 21274655 TI - Two-stage fractionation of corn stover using aqueous ammonia and hot water. AB - Hot water and aqueous ammonia fractionation of corn stover were used to separate hemicellulose and lignin and improve enzymatic digestibility of cellulose. A two stage approach was used: The first stage was designed to recover soluble lignin using aqueous ammonia at low temperature, while the second stage was designed to recover xylan using hot water at high temperature. Specifically, the first stage employed a batch reaction using 15 wt.% ammonia at 60 degrees C, in a 1:10 solid:liquid ratio for 8 h, while the second stage employed a percolation reaction using hot water, 190-210 degrees C, at a 20 ml/min flow rate for 10 min. After fractionation, the remaining solids were nearly pure cellulose. The two-stage fractionation process achieved 68% lignin purity with 47% lignin recovery in the first stage, and 78% xylan purity, with 65% xylan recovery in the second stage. Two-stage treatment enhanced the enzymatic hydrolysis of remaining cellulose to 96% with 15 FPU/g of glucan using commercial cellulase enzymes. Enzyme hydrolyses were nearly completed within 12-24 h with the remaining solids fraction. PMID- 21274656 TI - Cellulase production by pink pigmented facultative methylotrophic strains (PPFMs). AB - Pink pigmented facultative methylotrophs (PPFM) isolated from water samples of Cooum and Adyar rivers in Chennai and soil samples of forests located in various districts of Tamil Nadu, India were screened for cellulase production using carboxymethylcellulose agar (CMC agar) medium. The strains showed wide variations in the production of clearing zones around the colonies on CMC agar medium flooded with Congo red. CMCase and filter paper assays were used to quantitatively measure the cellulase activity of 13 PPFM strains. Among the strains, Methylobacterium gregans, MNW 60, MHW 109, MSF 34, and MSF 40 showed cellulolytic activity ranging from 0.73 to 1.16 U mL(-1) with wide temperature (35-65 degrees C) and pH (5 to 8) tolerance. SDS-PAGE analysis of the crude enzyme of PPFM strain MNW 60 exhibited several protein bands, and zymogram analysis revealed two dimeric cellulase bands with molecular mass of ~92 and 42 kDa. Scanning electron microscopic studies revealed significant morphological differences between the cells grown in normal and CMC amended medium. The strain MNW 60 was identified as Methylobacterium sp. based on biochemical, physiological, and morphological analyses, and the methylotrophic nature was authenticated by the presence of mxaF gene, encoding methanol dehydrogenase as a key indicator enzyme of methylotrophs, with 99% similarity to Methylobacterium lusitanum. With the 16S ribosomal RNA sequence showing 97% similarity to M. lusitanum strain MP2, this can be proposed as a novel taxon of the genus Methylobacterium. The study forms the first detailed report on the extracellular cellulase production by pink pigmented Methylobacterium sp., and it is expected that this might be the basis for further studies on cellulase production by PPFMs to explore the molecular mechanism, strain improvement, and large-scale cellulase production for its application. PMID- 21274657 TI - Production of astaxanthin from cellulosic biomass sugars by mutants of the yeast Phaffia rhodozyma. AB - Astaxanthin is a potential high-value coproduct in an ethanol biorefinery. Three mutant strains of the astaxanthin-producing yeast Phaffia rhodozyma, which were derived from the parent strain ATCC 24202 (UCD 67-210) and designated JTM166, JTM185, and SSM19, were tested for their capability of utilizing the major sugars that can be generated from cellulosic biomass, including glucose, xylose, and arabinose, for astaxanthin production. While all three strains were capable of metabolizing these sugars, individually and in mixtures, JTM185 demonstrated the greatest sugar utilization and astaxanthin production. Astaxanthin yield by this strain (milligrams astaxanthin per gram of sugar consumed) was highest for xylose, followed by arabinose and then glucose. The kinetics of sugar utilization by strain JTM185 was studied in fermenters using mixtures of glucose, xylose, and arabinose at varied concentrations. It was found that glucose was utilized preferentially, followed by xylose, and lastly, arabinose. Astaxanthin yield was significantly affected by sugar concentrations. Highest yields were observed with sugar mixtures containing the highest concentrations of xylose and arabinose. Hydrolysates produced from sugarcane bagasse and barley straw pretreated by the soaking in aqueous ammonia method and hydrolyzed with the commercial cellulase preparation, AccelleraseTM 1000, were used for astaxanthin production by the mutant strain JTM185. The organism was capable of metabolizing all of the sugars present in the hydrolysates from both biomass sources and produced similar amounts of astaxanthin from both hydrolysates, although these amounts were lower when compared to yields obtained with reagent grade sugars. PMID- 21274658 TI - Development and characterization of an environmentally friendly process sequence (autohydrolysis and organosolv) for wheat straw delignification. AB - The present work describes the delignification of wheat straw through an environmentally friendly process resulting from sequential application of autohydrolysis and organosolv processes. Wheat straw autohydrolysis was performed at 180 degrees C during 30 min with a liquid-solid ratio of 10 (v/w); under these conditions, a solubilization of 44% of the original xylan, with 78% of sugars as xylooligosaccharides of the sum of sugars solubilized in the autohydrolysis liquors generated by the hemicellulose fraction hydrolysis. The corresponding solid fraction enrichment with 63.7% of glucan and 7.55% of residual xylan was treated with a 40% ethanol and 0.1% NaOH aqueous solution at a liquid-solid ratio of 10 (v/w), with the best results obtained at 180 degrees C during 20 min. The highest lignin recovery, measured by acid precipitation of the extracted lignin, was 3.25 g/100 ml. The lignin obtained by precipitation was characterized by FTIR, and the crystallinity indexes from the native cellulose, the cellulose recovered after autohydrolysis, and the cellulose obtained after applying the organosolv process were obtained by X-ray diffraction, returning values of 21.32%, 55.17%, and 53.59%, respectively. Visualization of the fibers was done for all the processing steps using scanning electron microscopy. PMID- 21274659 TI - Improved FLP recombinase, FLPe, efficiently removes marker gene from transgene locus developed by Cre-lox mediated site-specific gene integration in rice. AB - Site-specific recombination systems, such as FLP-FRT and Cre-lox, carry out precise recombination reactions on their respective targets in plant cells. This has led to the development of two important applications in plant biotechnology: marker-gene deletion and site-specific gene integration. To draw benefits of both applications, it is necessary to implement them in a single transformation process. In order to develop this new process, the present study evaluated the efficiency of FLP-FRT system for excising marker gene from the transgene locus developed by Cre-lox mediated site-specific integration in rice. Two different FLP recombinases, the wild-type FLP (FLPwt) and its thermostable derivative, FLPe, were used for the excision of marker gene flanked by FLP recombination targets (FRT). While marker excision mediated by FLPwt was undetectable, use of FLPe resulted in efficient marker excision in a number of transgenic lines, with the relative efficiency reaching up to ~100%. Thus, thermo-stability of FLP recombinase in rice cells is critical for efficient site-specific recombination, and use of FLPe offers practical solutions to FLP-FRT-based biotechnology applications in plants. PMID- 21274660 TI - Imaging of coronary inflammation with FDG-PET: feasibility and clinical hurdles. AB - Conventional algorithms and noninvasive imaging tests for the identification of stable, hemodynamically significant coronary artery disease offer little insight into the detection of potentially vulnerable and inflamed coronary plaques, those most likely to rupture and cause acute coronary syndromes. Positron emission tomography (PET) with fluorodeoxyglucose (FDG) serves as a potential novel modality for the identification of plaque inflammation, as initial studies in animal and human studies have demonstrated that FDG uptake correlates with macrophage accumulation and inflammation. Therapy with anti-inflammatory agents has also been demonstrated in the arterial vasculature to reduce plaque FDG uptake. Although imaging of coronary inflammation with FDG-PET holds tremendous promise, several hurdles remain to be surmounted prior to widespread clinical application. PMID- 21274661 TI - Maladaptive opioid use behaviors and psychiatric illness: what should we do with what we know? AB - It is well established that opioids are broadly effective for chronic pain. Although there is some agreement that stable, moderate dosing is desirable; longer-term management of patients with chronic pain often confronts clinicians with difficult decisions regarding when to intensify opioid treatment and when to declare failure. Under these circumstances the concern for addiction arises with uncomfortable frequency in specialty settings. An emerging literature has defined a number of plausible markers of risk for aberrant opioid use behaviors in clinical chronic pain populations. Some of these risk factors involve the presence of comorbid psychiatric illnesses, which puts clinicians in the difficult position of deciding whether or not to limit treatment to patients who are more complex. The authors discuss the issues of bad behavioral outcomes in opioid therapy, the implications of this emerging literature for clinicians, and suggest broad areas in which researchers can improve the knowledge base with which clinicians operate. PMID- 21274662 TI - Assessment of behavioral disorders in preschool-aged children. AB - The preschool-aged clinical practice of child and adolescent psychiatrists is increasing as the awareness of very young children with social/emotional and/or behavioral problems continues to grow. As the referrals grow, so do the ways in which we assess these disturbances of behavior and regulation. This review attempts to highlight the most often used measures and to investigate developing tools and their current status. PMID- 21274663 TI - Are aerobics trophic for cognition in late life? PMID- 21274664 TI - First automatic radiosynthesis of 11C labeled Telmisartan using a multipurpose synthesizer for clinical research use. AB - OBJECTIVE: Telmisartan, a nonpeptide angiotensin II AT1 receptor antagonist, is an antihypertensive drug. Positron emission tomography (PET) imaging with [(11)C]Telmisartan is expected to provide information about the whole body pharmacokinetics of telmisartan as well as the transport function of hepatic OATP1B3. We developed a first automatic preparation system of [(11)C]Telmisartan to applicable clinical research using a new (11)C and (18)F multipurpose synthesizer. METHODS: Two milligrams of precursor (1) in 5 MUl of 1 M KOH in 0.5 ml of dimethyl sulfoxide was reacted with [(11)C]CH(3)I for 5 min at 120 degrees C. The resultant solution was hydrolyzed with 1 M NaOH at 100 degrees C for 3 min. The neutralization was carried out with acetic acid, followed by purification with high-performance liquid chromatography. The desired radioactive fraction was collected and solvent was replaced by 10 ml saline containing 0.3 ml of EtOH and 0.5 ml of PEG400, and then passed through a sterile 0.22 MUm filter (Millex-GV, Millipore) to a pyrogen-free vial as the final product. RESULTS: The yield of [(11)C]Telmisartan for clinical research use was 16.8 +/- 2.9% EOB as decay corrected (n = 8, mean +/- SD) in 32-36 min. The radiochemical purity of [(11)C]Telmisartan was >97%, and specific activity was higher than 86.3 MBq/nmol. CONCLUSIONS: We succeeded in the first synthesis of [(11)C]Telmisartan for clinical research use by appropriate quality tests. PMID- 21274665 TI - Actual concepts in rhinosinusitis: a review of clinical presentations, inflammatory pathways, cytokine profiles, remodeling, and management. AB - Rhinosinusitis (RS) is a heterogeneous group of diseases. It is a significant and increasing health problem that affects about 15% of the population in Western countries. It has a substantial impact on patients' health-related quality of life and daily functioning and represents a huge financial burden to society and the health care system as a result of the direct and indirect costs. In addition, RS is not well-understood, and little is known about the etiology and pathophysiology. In the past decade, many papers have been published that have changed our understanding of RS. RS is commonly classified into acute and chronic RS based on symptom duration. In acute RS, an inflammatory reaction initiated by a viral infection characterizes most uncomplicated, mild to moderate cases. Therefore, the first line of treatment for these cases are intranasal steroids and not antibiotics. In severe and complicated cases, antibiotics combined with topical steroids remain the treatment of choice. On the other hand, chronic RS is actually subdivided into two distinct entities (chronic rhinosinusitis with and without polyps), as growing evidence indicates that these entities have specific inflammatory pathways and cytokine profiles. The authors review recent data regarding the clinical presentations, cytokine profiles, tissue remodeling, and modalities of treatment for each form of RS. PMID- 21274666 TI - Gastric cancer surgery: an American perspective on the current options and standards. AB - Gastric cancer is prevalent globally, particularly in Asian countries such as Japan and Korea. While the prevalence of gastric cancer is not nearly as high in the United States (U.S.) as in Asia, the treatment armamentarium differs widely between regions. The role of surgery for gastric cancer in the U.S. has changed drastically over the last decade. While the natural history of gastric cancer seen in the U.S. markedly differs from that seen in Asia, the U.S. experience with endoscopic and minimally invasive techniques is beginning to parallel those seen in Japan and Korea. Minimally invasive surgery has truly come into the forefront of our surgical armamentarium, and its role, along with robotic and endoscopic approaches, remains to be defined as standard of care. At present, minimally invasive approaches appear to offer oncologically equivalent outcomes compared with standard open gastrectomy when performed by experienced surgeons. Extended lymphadenectomy does not appear to offer benefit with improved survival in our patient population, although sufficient lymph node sampling is imperative for adequate staging. Despite aggressive approaches to surgical resection for cure, the U.S. population tends to present with more advanced disease and have a worse prognosis than our Asian counterparts. Palliation with resection and possibly stent placement should be offered for improved quality of life in late stage disease. PMID- 21274667 TI - Chemotherapy in the treatment of metastatic gastric cancer: is there a global standard? AB - Gastric cancer remains one of the leading causes of cancer mortality worldwide even though its incidence has been decreasing in recent years. Despite remarkable advancements in chemotherapy, advanced gastric cancer has remained a therapeutic challenge for physicians as well as for patients. While early chemotherapeutic regimens succeeded in showing a modest but definite improvement over best supportive care, no single regimen stood out as superior. Most early trials failed to show survival benefit of combination regimens over single agent fluorouracil, but combination regimens were shown to have better response rates. Based on these data, the Japanese adopted single agent fluorouracil as a reference standard for further investigations, while the rest of the world used a doublet containing fluorouracil and platinum. As more clinical trials were conducted, the Japanese standard evolved into a doublet, while the Western countries adopted triplet combinations. There is no established global standard as yet, but with the introduction of newer targeted agents based on molecular assays and personalized approaches combined with conventional chemotherapy, multiple regimens are likely to emerge as global standards rather than one standard treatment for all. PMID- 21274668 TI - Clip placement after an 11-gauge vacuum-assisted stereotactic breast biopsy: correlation between breast thickness and clip movement. AB - PURPOSE: To retrospectively evaluate the accuracy of clip placement on the basis of measurements obtained on pre- and post-vacuum-assisted 11-gauge stereotactic biopsy mammograms and to analyze the factors that can predict which patients will experience a significant movement of the clip. MATERIALS AND METHODS: The pre- and post-vacuum-assisted 11-guage stereotactic biopsy mammographic findings in 204 cases undergoing clip placement were reviewed. The clip-to-lesion distance was measured. The correlations between the clinical-mammographic findings and the likelihood of clip movement were evaluated. RESULTS: Target mammographic lesion types of the 204 cases were characterized as calcification in all but one case, which was a distortion lesion. The clip-to-lesion distance was within 5 mm on both the craniocaudal and mediolateral oblique projections in 119 (58%) cases, within 6-10 mm in 28 (14%), within 11-19 mm in 25 (12%), and was > 20 mm in 32 (16%). The variability of the clip-to-lesion distance was greatest in the plane orthogonal to the compression plane used for stereotactic biopsy. Breast thickness was the only factor that was predictive of a significant movement of the clip, and thin breasts tended to exhibit greater clip movement. CONCLUSION: Breast thickness may be a useful factor for predicting the degree of clip movement after 11-gauge vacuum-assisted stereotactic biopsy. PMID- 21274669 TI - Cellular thermotolerance is associated with heat shock protein 70.1 genetic polymorphisms in Holstein lactating cows. AB - Heat shock proteins (Hsp) are known to protect cells from several stressors. Nucleotide changes in the flanking regions [5'- and 3'-untranslated region (UTR)] of Hsp gene might affect inducibility, degree of expression, or stability of Hsp70 mRNA. The present study aimed to investigate the association between inducible Hsp70.1 single nucleotide polymorphisms (SNPs) and heat shock (HS) response of peripheral blood mononuclear cells (PBMC) in dairy cows. Four hundred forty-six Italian Holstein cows were genotyped for four Hsp70.1 SNPs: g895 C/- and g1128 G/T in 5'-UTR, and g2154 G/A and g64 G/T in 3'-UTR. Genetic polymorphisms in 3'-UTR of bovine Hsp70.1 gene resulted monomorphic. Distribution of alleles of the nucleotide sequence polymorphism within the 5'-UTR of the bovine Hsp70.1 gene were 81.2% and 18.8% for C and -, respectively, and 77.8% and 22.2% for G and T, respectively. Among the 446 genotyped animals, a group of cows balanced for days in milk and parity was selected to be representative of the following genotypes: CC (n = 8), C- (n = 7), and -- (n = 7) and GG (n = 8), GT (n = 11), and TT (n = 3) in 5'-UTR. PBMC were isolated from blood samples and heated at 43 degrees C in thermal bath for 1 h and then incubated at 39 degrees C in atmosphere of 5% CO(2) for 1, 2, 4, 8, 16, and 24 h (recovery times). Cell viability was determined by XTT assay. Gene and protein expression of Hsp70.1 was determined by real-time reverse transcription-polymerase chain reaction and by ELISA assay, respectively. For the two SNPs detected, one allele was the most frequent (C, 66.8% and G, 56.8%). Genotypes -- and TG showed higher (P < 0.05) viability compared with CC and GG, respectively. Genotypes C- and TT had intermediate viability. Gene expression of Hsp70.1 showed higher (P < 0.001) levels in -- and TG genotype compared with their counterparts. Genotypes -- and TG showed the higher level of inducible Hsp70.1 protein in respect to C-, TT and CC, GG. In conclusion, exposure to HS differently affected cell viability and gene and protein expression of Hsp70.1 in the selected genotypes. These results indicate that the presence of SNPs (C/- and G/T) in the 5'-UTR region of inducible Hsp70.1 ameliorates HS response and tolerance to heat of bovine PBMC. These mutation sites may be useful as molecular genetic markers to assist selection for heat tolerance. PMID- 21274670 TI - Heat-shock protein 90 alpha (HSP90alpha) modulates signaling pathways towards tolerance of oxidative stress and enhanced survival of hepatocytes of Mugil cephalus. AB - Oxidative stress causes damage at the cellular level and activates a number of signaling pathways. Earlier, we have demonstrated that pollutant-related oxidative stress upregulates heat-shock protein 90 alpha (HSP90alpha) against stress insult in hepatocytes of Mugil cephalus living in a polluted estuary. However, the impact of pollution-induced HSP90alpha upregulation on stress tolerance is not clear. Here we propose that the effect of stress resistance depends on the ability of HSP90alpha to modulate the signaling pathways involving proteins such as apoptosis signal-regulating kinase 1, c-Jun NH(2)-terminal protein kinase 1/2, signal transducers and activators of transcription, extracellular signal-regulated kinase 1/2, protein kinase B, nuclear factor-kappa binding, Ets-like protein 1, and B cell lymphoma-2. In order to investigate this, the activation of HSP90alpha-associated signaling molecules was examined by Western blotting and immunohistochemistry. The relationship between the protein expression patterns was identified by Spearman's rank correlation analysis. The signaling proteins exhibited differential modulation as revealed from their expression patterns in pollutant-exposed fish hepatocytes, in comparison with the control fish hepatocytes. The results suggested that in spite of the prevalence of oxidative stress in pollutant-exposed fish hepatocytes, the stress-mediated induction of HSP90alpha enabled the hepatocytes to become stress tolerant and to survive by modulating the actions of key proteins and kinases in the signal transduction pathways. PMID- 21274671 TI - B-Raf mutations, microsatellite instability and p53 protein expression in sporadic basal cell carcinomas. AB - Basal Cell Carcinoma (BCC) is the most common skin malignancy. Genes related to the Ras/Raf signalling pathway have been implicated in the pathogenesis of skin cancer. The objective of this study was to investigate the presence of B-Raf mutations in sporadic BCCs as well as its correlation with the phenotype of microsatellite instability (MSI), the clinicopathological parameters of the tumours and p53 protein expression. 83 BCC specimens were screened for B-Raf mutations, applying polymerase chain reaction, single-stranded conformation polymorphism (PCR-SSCP) and DNA sequencing. MSI status was examined using mononucleotide microsatellite markers and p53 protein expression was demonstrated by immunohistochemical staining. A C to T transition at 1790 nucleotide leading to a silent mutation L597L; and a T to A transversion causing an amino acid change (F610I) have been found. MSI was detected in 5% of the cases and p53 accumulation was present in 37/83 samples studied. Although rare B-Raf alterations have been observed in BCC, none of them harboured the hot-spot mutation T1799A commonly present in melanomas and colon carcinomas. Consequently, no correlation could be determined between B-Raf alterations, MSI status, the clinicopathological features and p53 protein expression. Our results are in favour of a secondary importance for Ras signalling cascade genes in BCC pathogenesis. PMID- 21274672 TI - Primary uterine NK-cell lymphoma, nasal-type: a unique malignancy of a prominent cell type of the endometrium. AB - Natural killer (NK) cells host in the human endometrium with dedicated role in reproductive physiology. Interestingly, malignant transformation of these specialized cells has not been presented thus far. Here we report a primary endometrial NK-cell lymphoma of a 48 year-old patient presenting with irregular bleeding. The endometrial curetting showed a dense lymphomatous infiltrate demonstrating highly infiltrative aggressive features with characteristic angiocentric, partially angiodestructive growth pattern and accompanying focal necroses. The lymphoma cells displayed a CD3epsilon/CD56/TIA-1/granzyme-B positive and CD5/CD4/CD8/TCRgammadelta-negative immunophenotype, proved to be positive for Epstein-Barr virus by EBER in situ hybridization, and revealed no clonal T-cell receptor gene rearrangement. The diagnosis of uterine extranodal NK cell lymphoma, nasal-type was made. Clinically, the disease was limited to the uterus at diagnosis, but progressed rapidly, and the patient died within 5 months due disseminated lymphoma, irrespective of intensive chemotherapy. Genuine NK cell lymphomas occurring in the uterus as primary site seem to be rare making the therapeutic decisions extremely complicated. PMID- 21274673 TI - Clinical and prognostic value of the presence of irregular giant nuclear cells in pT1 ovarian clear cell carcinoma. AB - In the early stages of epithelial ovarian cancer, histopathological grading is important. However, the grading of ovarian clear cell carcinoma (OCCC) remains controversial. We aimed to identify irregular giant nuclear cells (IGNCs) by a simple method in clinical practice, and to evaluate the prognostic value of IGNCs in pT1 OCCC. Eighty-seven pT1 OCCC patients who underwent initial surgery at Jikei University Kashiwa Hospital, Chiba, Japan, were retrospectively assessed. Paraffin-embedded tissue sections (PTSs) stained with hematoxylin and eosin were reviewed. Giant nuclear cells (GNCs) were defined as cells with a nuclear length of more than twice the median nuclear length. GNCs with irregular nuclear circumferences were defined as IGNCs. Cases where one or more GNCs existed and where IGNCs accounted for >10% of the GNCs were classified as IGNC-positive. We also attempted to identify IGNCs on touch imprint cytology smears (TICSs). Among the 87 cases, 68 were IGNC-negative and 19 were IGNC-positive. The 5-year disease free and overall survival rates were 88.9% and 90.3% in the total patients, 98.3% and 100% in the IGNC-negative group, and 59.7% and 62.0% in the IGNC-positive group, respectively. These survival rates were significantly lower in the IGNC positive group than in the IGNC-negative group (adjusted hazard ratio = 14, 95% confidence interval = 2.7-124 and adjusted hazard ratio = 25, 95% confidence interval = 2.9-768, respectively). Prognostic differences were not identified for other factors. IGNC identification on 28 available TICSs predicted IGNC identification on PTSs (sensitivity = 50.0%, specificity = 100%, P = 0.007). The presence of IGNCs has clinical and prognostic value for pT1 OCCC. PMID- 21274674 TI - Promoter hypermethylation of RASSF1A, MGMT, and HIC-1 genes in benign and malignant colorectal tumors. AB - Hypermethylation at the promoter region is an important epigenetic mechanism underlying the inactivation of tumor suppressor genes and frequently occurs as an early event in the development of different types of cancer including colorectal carcinoma (CRC). The aim of the present study is the detection of methylation status for some tumor suppressor genes including RASSF1A, MGMT, and HIC-1 in both cancerous and precancerous lesions of colorectal mucosa to evaluate the possibility of developing epigenetic biomarker for early detection of Egyptian CRC. Tissue biopsy was collected from 72 patients (36 CRC, 17 adenomatous polyps, and 19 ulcerative colitis), and in addition, adjacent normal-appearing tissues were collected as control. Promoter hypermethylation status for RSSAF1A, MGMT, and HIC-1 genes was detected after isolation of genomic DNA from the tissues samples using methylation-specific PCR technique. High frequency of methylation at MGMT, RASSFA, and HIC-1 was detected in CRC patients (25%, 47.2%, and 41.7% respectively). The highest methylation detected in adenomatous polyps patients was in MGMT gene (47.1%) followed by 35.3% for HIC-1 and only 5.9% for RASSF1A gene. HIC-1 gene exhibited highest frequency of methylation in ulcerative colitis patients (57.8%) whereas it was 26.3% for both RASSF1A and MGMT genes. A nonsignificant association was recorded between the methylation status in different genes examined with the clinicopathological factors except the association between methylation at RASSF1A gene with gender (p=0.005), and it was significant. In conclusion, aberrant hypermethylation at promoter region of RASSFA, MGMT, and HIC-1 genes is involved in Egyptian CRCs. Hypermethylation of MGMT and HIC-1 genes plays an important role in the initiation of disease especially ulcerative colitis-carcinoma pathway. PMID- 21274675 TI - Investigation of miR-21, miR-141, and miR-221 in blood circulation of patients with prostate cancer. AB - In addition to their potential as tissue-based markers for cancer classification and prognostication, the study of microRNAs (miRNAs) in blood circulation is also of interest. In the present study, we investigated the amounts of three cancer related miRNAs, miR-21, -141, and -221 in blood plasma of prostate cancer (PCa) patients. A cohort of 51 patients with PCa was enrolled into the study, and miRNAs were measured in two subgroups, with localized/local advanced or metastatic PCa. A group of 20 healthy individuals served as the control group. miRNAs were quantified from the total RNA fraction using 200 MUl plasma and the small RNA molecule RNU1A as a control for normalizing the miRNA amounts in circulation. We found similar levels of three miRNAs in healthy subjects with median values of 0.039, 0.033 and 0.04, respectively; (p = n.s.). In the patients, the miRNA levels were higher, with miR-21 being the highest (median, 1.51). The miR-221 levels were intermediate (median, 0.71) while the miR-141 displayed the lowest levels (median, 0.051). The differences between the control group and the patients were highly significant for the miR-21 (p < 0.001; area under the curve (AUC), 88%) and -221 (p < 0.001; AUC, 83%) but not for the miR 141 (p = 0.2). In patients diagnosed with metastatic PCa, levels of all three miRNAs were significantly higher than in patients with localized/local advanced disease where the difference for the miR-141 was most pronounced (p< 0.001; AUC, 75.5%). In conclusion, analysis of miR-21, -141, and -221 in blood of PCa patients reveals varying patterns of these molecules in clinical subgroups of PCa. PMID- 21274676 TI - Free-standing urethane/urea elastomer films undoped and doped with ferro-nano particles. AB - We report on an experimental study of the structures presented by urethane/urea elastomeric films without and with ferromagnetic nanoparticles incorporated. The study is made by using the X-ray diffraction, nuclear magnetic resonance (NMR), optical, atomic and magnetic force (MFM) microscopy techniques, and mechanical assays. The structure of the elastomeric matrix is characterized by a distance of 0.46 nm between neighboring molecular segments, almost independent on the stretching applied. The shear casting performed in order to obtain the elastomeric films tends to orient the molecules parallel to the flow direction thus introducing anisotropy in the molecular network which is reflected on the values obtained for the orientational order parameter and its increase for the stretched films. In the case of nanoparticles-doped samples, the structure remains nearly unchanged although the local order parameter is clearly larger for the undoped films. NMR experiments evidence modifications in the molecular network local ordering. Micrometer size clusters were observed by MFM for even small concentration of magnetic particles. PMID- 21274677 TI - Effective line tension and contact angles between membrane domains in biphasic vesicles. AB - Inhomogeneities in membranes give rise to localized interactions at the interface between domains in two-component vesicles. The corresponding energy is expressed as a line tension between the two phases. In this paper we study the implications of the thickness mismatch between domains which has been experimentally reported to be of order 20-30% and the conditions under which the induced line tension can destabilize the domains in inhomogeneous vesicles. For asymmetric lipidic membranes we prove an increase of the line tension and the existence of a contact angle. Adsorption of impurities is also examined, our scope being the extension of the Canham-Helfrich model to describe elastic deformations and chemical interactions arising at microscopic scales. This mismatch effect may have important consequences for the stability of very small domains. PMID- 21274678 TI - Case of Japanese patient with x-linked ocular albinism associated with GPR143 gene mutation. PMID- 21274679 TI - Transitions and transformations. PMID- 21274680 TI - Update in neuroimaging. PMID- 21274682 TI - Neuroimaging of cerebral ischemia and infarction. AB - The imaging workup for patients with suspected acute ischemic stroke has advanced significantly over the past few years. Evaluation is no longer limited to noncontrast computed tomography, but now frequently also includes vascular and perfusion imaging. Although acute stroke imaging has made significant progress in the last few decades with the development of multimodal approaches, there are still many unanswered questions regarding their appropriate use in the setting of daily patient care. It is important for all physicians taking care of stroke patients to be familiar with current multimodal computed tomography and magnetic resonance imaging techniques, including their strengths, limitations, and their role in guiding therapy. PMID- 21274681 TI - MRI in rodent models of brain disorders. AB - Magnetic resonance imaging (MRI) is a well-established tool in clinical practice and research on human neurological disorders. Translational MRI research utilizing rodent models of central nervous system (CNS) diseases is becoming popular with the increased availability of dedicated small animal MRI systems. Projects utilizing this technology typically fall into one of two categories: 1) true "pre-clinical" studies involving the use of MRI as a noninvasive disease monitoring tool which serves as a biomarker for selected aspects of the disease and 2) studies investigating the pathomechanism of known human MRI findings in CNS disease models. Most small animal MRI systems operate at 4.7-11.7 Tesla field strengths. Although the higher field strength clearly results in a higher signal to-noise ratio, which enables higher resolution acquisition, a variety of artifacts and limitations related to the specific absorption rate represent significant challenges in these experiments. In addition to standard T1-, T2-, and T2*-weighted MRI methods, all of the currently available advanced MRI techniques have been utilized in experimental animals, including diffusion, perfusion, and susceptibility weighted imaging, functional magnetic resonance imaging, chemical shift imaging, heteronuclear imaging, and (1)H or (31)P MR spectroscopy. Selected MRI techniques are also exclusively utilized in experimental research, including manganese-enhanced MRI, and cell specific/molecular imaging techniques utilizing negative contrast materials. In this review, we describe technical and practical aspects of small animal MRI and provide examples of different MRI techniques in anatomical imaging and tract tracing as well as several models of neurological disorders, including inflammatory, neurodegenerative, vascular, and traumatic brain and spinal cord injury models, and neoplastic diseases. PMID- 21274683 TI - Neuroimaging of hemorrhage and vascular defects. AB - Intracranial hemorrhage is the third most common cause of stroke and involves the accumulation of blood within brain parenchyma or the surrounding meningeal spaces. Accurate identification of acute hemorrhage and correct characterization of the underlying pathology, such as tumor, vascular malformation, or infarction, is a critical step in planning appropriate therapy. Neuroimaging studies are required not only for diagnosis, but they also provide important information on the type of hemorrhage, etiology, and the pathophysiological process. Historically, computed tomography (CT) scan has been the diagnostic imaging study of choice; however, there is growing evidence suggesting that magnetic resonance imaging (MRI) is at least as sensitive as CT to detect intraparenchymal hemorrhages in the hyperacute setting, and actually superior to CT in the subacute and chronic settings. Unique MRI and CT characteristics differentiate secondary causes of hemorrhage from the more common hypertensive hemorrhage. Baseline and serial studies can be used to identify patients who might benefit from acute interventions. In addition, new imaging modalities, (such as magnetic resonance spectroscopy, diffusion tensor imaging, and 320-row CT) are promising research techniques that have the potential to enhance our understanding of the tissue injury and recovery after intracranial hemorrhages. PMID- 21274684 TI - Imaging for the diagnosis and management of traumatic brain injury. AB - To understand the role of imaging in traumatic brain injury (TBI), it is important to appreciate that TBI encompasses a heterogeneous group of intracranial injuries and includes both insults at the time of impact and a deleterious secondary cascade of insults that require optimal medical and surgical management. Initial imaging identifies the acute primary insult that is essential to diagnosing TBI, but serial imaging surveillance is also critical to identifying secondary injuries such as cerebral herniation and swelling that guide neurocritical management. Computed tomography (CT) is the mainstay of TBI imaging in the acute setting, but magnetic resonance tomography (MRI) has better diagnostic sensitivity for nonhemorrhagic contusions and shear-strain injuries. Both CT and MRI can be used to prognosticate clinical outcome, and there is particular interest in advanced applications of both techniques that may greatly improve the sensitivity of conventional CT and MRI for both the diagnosis and prognosis of TBI. PMID- 21274685 TI - Neuroimaging in multiple sclerosis: neurotherapeutic implications. AB - Imaging techniques, in particular magnetic resonance imaging (MRI), play an important role in the diagnosis and management of multiple sclerosis (MS) and related demyelinating diseases. Findings on MRI studies of the brain and spinal cord are critical for MS diagnosis, are used to monitor treatment response and may aid in predicting disease progression in individual patients. In addition, results of imaging studies serve as essential biomarkers in clinical trials of putative MS therapies and have led to important insights into disease pathophysiology. Although they are useful tools and provide in vivo measures of disease-related activity, there are some important limitations of MRI findings in MS, including the non-specific nature of detectable white matter changes, the poor correlation with clinical disability, the limited sensitivity and ability of standard measures of gadolinium enhancing lesions and T2 lesions to predict future clinical course, and the lack of validated biomarkers of long term outcomes. Advancements that hold promise for the future include new techniques that are sensitive to diffuse changes, the increased use of higher field scanners, measures that capture disease related changes in gray matter, and the use of combined structural and functional imaging approaches to assess the complex and evolving disease process that occurs during the course of MS. PMID- 21274686 TI - Neuroimaging in amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by progressive degeneration of upper motor neurons (UMN) and lower motor neurons (LMN). While LMN dysfunction can be confirmed by electromyography (EMG) and muscle biopsy, UMN involvement is more difficult to detect, particularly in the early phase. Objective and sensitive measures of UMN dysfunction are needed for early diagnosis and monitoring of disease progression and therapeutic efficacy. Advanced magnetic resonance imaging (MRI) techniques, such as diffusion, perfusion, magnetization transfer imaging, functional MRI, and MR spectroscopy, provide insight into the pathophysiological processes of ALS and may have a role in the identification and monitoring of UMN pathology. This article provides an overview of these neuroimaging techniques and their potential roles in ALS. PMID- 21274687 TI - Neuroimaging in Parkinson's disease. AB - Parkinson's disease (PD) is a common disorder in which the primary features can be related to dopamine deficiency. Changes on structural imaging are limited, but a wealth of abnormalities can be detected using positron emission tomography, single photon emission computed tomography, or functional magnetic resonance imaging to detect changes in neurochemical pathology or functional connectivity. The changes detected on these studies may reflect the disease process itself and/or compensatory responses to the disease, or they may arise in association with disease- and/or treatment-related complications. This review will focus mainly on neurochemical and metabolic studies and reviews various approaches to the assessment of dopaminergic function as well as the function of other neurotransmitters that may be affected in PD. A number of clinical applications are highlighted, including diagnostic utility, identification of preclinical disease, changes associated with motor and nonmotor complications of PD, and the effects of various therapeutic interventions. PMID- 21274689 TI - Neuroimaging in psychiatric disorders. AB - In psychiatry, neuroimaging facilitates the diagnosis of psychiatric disorders and the development of new medications. It is used to detect structural lesions causing psychosis and to differentiate depression from neurodegenerative disorders or brain tumors. Functional neuroimaging, mostly in the form of molecular neuroimaging with positron emission tomography or single photon emission tomography, facilitates the identification of therapeutic targets, the determination of the dose of a new drug needed to occupy its target in the brain, and the selection of patients for clinical trials. PMID- 21274688 TI - Neuroimaging in dementia. AB - Dementia is a common illness with an incidence that is rising as the aged population increases. There are a number of neurodegenerative diseases that cause dementia, including Alzheimer's disease, dementia with Lewy bodies, and frontotemporal dementia, which is subdivided into the behavioral variant, the semantic variant, and nonfluent variant. Numerous other neurodegenerative illnesses have an associated dementia, including corticobasal degeneration, Creutzfeldt-Jakob disease, Huntington's disease, progressive supranuclear palsy, multiple system atrophy, Parkinson's disease dementia, and amyotrophic lateral sclerosis. Vascular dementia and AIDS dementia are secondary dementias. Diagnostic criteria have relied on a constellation of symptoms, but the definite diagnosis remains a pathologic one. As treatments become available and target specific molecular abnormalities, differentiating amongst the various primary dementias early on becomes essential. The role of imaging in dementia has traditionally been directed at ruling out treatable and reversible etiologies and not to use imaging to better understand the pathophysiology of the different dementias. Different brain imaging techniques allow the examination of the structure, biochemistry, metabolic state, and functional capacity of the brain. All of the major neurodegenerative disorders have relatively specific imaging findings that can be identified. New imaging techniques carry the hope of revolutionizing the diagnosis of neurodegenerative disease so as to obtain a complete molecular, structural, and metabolic characterization, which could be used to improve diagnosis and to stage each patient and follow disease progression and response to treatment. Structural and functional imaging modalities contribute to the diagnosis and understanding of the different dementias. PMID- 21274695 TI - ["My disease is one of the mind and difficult to define": Robert Walser (1879 1956) and his mental illness]. AB - Robert Walser (1878-1956) is among the most prominent German-speaking writers born in Switzerland. His early writings are fascinating due to his intensive affectivity and oneiric experiences; his late work impresses through his idiosyncratic use of language and his micrographs. Due to a psychotic disease he stayed in Swiss Mental State Hospitals (Waldau and Herisau) throughout the final 27 years of his life. According to his case records Robert Walser suffered from a schizophrenic disorder (ICD-10) and from a combined sluggish/manneristic catatonia according to K. Leonhard. Walser's psychotic disorder was characterized by a chronic course with sharp-cut symptomatology with stiff postures, repetitive behaviour, movement mannerisms and omissions (manneristic component) complemented by loss of incentive, severe autism and persistent verbal hallucinations (speech sluggish component). In the late stages his psychopathology affected the process of thinking and writing in a specific manner: his handwriting became illegibly small, and his train of thoughts did not get to the point. At age 54 he stopped writing when transferred from Waldau to Herisau, and subsequently, due to manneristic omission, he was never again able to restart literary writing. The analysis of Robert Walser's psychotic disease may contribute to a deeper understanding of his literary production, which influenced such classical German authors like Franz Kafka, Hermann Hesse and Robert Musil. PMID- 21274691 TI - Optical coherence tomography (OCT): imaging the visual pathway as a model for neurodegeneration. AB - Axonal and neuronal degeneration are important features of multiple sclerosis (MS) and other neurologic disorders that affect the anterior visual pathway. Optical coherence tomography (OCT) is a non-invasive technique that allows imaging of the retinal nerve fiber layer (RNFL), a structure which is principally composed of ganglion cell axons that form the optic nerves, chiasm, and optic tracts. Since retinal axons are nonmyelinated until they penetrate the lamina cribrosa, the RNFL is an ideal structure (no other central nervous system tract has this unique arrangement) for visualizing the processes of neurodegeneration, neuroprotection and, potentially, even neuro-repair. OCT is capable of providing high-resolution reconstructions of retinal anatomy in a rapid and reproducible fashion and permits objective analysis of the RNFL (axons) as well as ganglion cells and other neurons in the macula. In a systematic OCT examination of multiple sclerosis (MS) patients, RNFL thickness and macular volumes are reduced when compared to disease-free controls. Conspicuously, these changes, which signify disorganization of retinal structural architecture, occur over time even in the absence of a history of acute demyelinating optic neuritis. RNFL axonal loss in MS is most severe in those eyes with a corresponding reduction in low contrast letter acuity (a sensitive vision test involving the perception of gray letters on a white background) and in those patients who exhibit the greatest magnitude of brain atrophy, as measured by validated magnetic resonance imaging techniques. These unique structure-function correlations make the anterior visual pathway an ideal model for investigating the effects of standard and novel therapies that target axonal and neuronal degeneration. We provide an overview of the physics of OCT, its unique properties as a non-invasive imaging technique, and its potential applications toward understanding mechanisms of brain tissue injury in MS, other optic neuropathies, and neurologic disorders. PMID- 21274690 TI - The role of medical imaging in defining CNS abnormalities associated with HIV infection and opportunistic infections. AB - In this review of the current literature, we examine the role of medical imaging in providing new and relevant information on central nervous system (CNS) injury associated with human immunodeficiency virus (HIV) infection and various clinical manifestations of this injury. Common imaging modalities used to examine CNS injury in HIV infection include structural magnetic resonance imaging, magnetic resonance spectroscopy, diffusion tensor imaging, functional MRI, and positron emissions tomography. Clinical implications for the findings are discussed for each of these modalities individually and collectively. In addition, the direction for future studies is suggested in an attempt to provide possible methods that might answer the many questions that remain to be answered on the evolution and progression of CNS injury in the context of HIV infection. PMID- 21274696 TI - [Treatment of Alzheimer's disease according to the S3 guidelines on dementia. Choline esterase inhibitors for all and for ever?]. PMID- 21274698 TI - [Indications for deformity correction with minimally invasive spondylodesis]. AB - The indications for surgical treatment of thoracic, lumbar, combined and thoracolumbar scoliosis are given for a curvature of the thoracic spine with a Cobb angle more than 50 degrees and more than 45 degrees in the lumbar spine. The maximum Cobb angle is 90 degrees . The aim is the correction of more than 50% in the frontal plane and correction of scoliosis is possible in flexible curvatures up to 90%. By the minimally invasive surgical technique the muscular damage is completely avoided on the convex side but on the concave side this is only partly possible. This is the first report of a muscle preserving minimally invasive surgical technique for the convex side of scoliosis. PMID- 21274699 TI - Exploring the relationship between vitamin D and basic personality traits. AB - RATIONALE: Several studies suggest an association between hypovitaminosis D and basic and executive cognitive functions, depression, bipolar disorder, and schizophrenia. A recent study confirms neophobic responses in vitamin D receptor mutant mice. We explored whether the plasma levels of 1,25-dihydroxyvitamin D (1,25(OH)(2)D(3)), the active form of vitamin D, are correlated with basic personality traits. METHODS: A total of 206 healthy unrelated volunteers (108 male, 98 female, age 31 +/- 13 years) completed the German version of the NEO Five-Factor Inventory (NEO-FFI), which allows reliable and valid assessment of personality along the dimensions neuroticism, extraversion, openness to new experiences, agreeableness and conscientiousness. RESULTS: We found a significant correlation between 1,25(OH)(2)D(3) concentration and the factor extraversion (n = 206, r = 0.202, p = 0.004) and the factor openness (n = 206, r = 0.148, p = 0.034). CONCLUSION: The possible mechanisms by which 1,25(OH)(2)D(3) acts on the brain might include Ca(2+) signaling, buffering antioxidant, and anti inflammatory defenses against vascular injury, stimulating neurotrophins and improving metabolic and cardiovascular function. In conclusion, we suggest that 1,25(OH)(2)D(3) might influence personality traits, promoting extrovert and open behavior. PMID- 21274700 TI - CD-1 and Balb/cJ mice do not show enduring antidepressant-like effects of ketamine in tests of acute antidepressant efficacy. AB - RATIONALE: In patients, ketamine is a fast-acting antidepressant that can induce long-lasting symptom relief. Similar rapid effects have been reported in rodents, but reports of lasting effects are limited. OBJECTIVES: We sought to extend past findings by examining dose-response curves that overlap with the individual doses previously reported to induce lasting effects in rodents and determining whether effects generalize to the tail suspension test (TST) and Balb/cJ mice. METHODS: Using common tests of antidepressant efficacy we first confirmed our ability to detect the effects of desipramine, a well-characterized antidepressant drug. Next, we sought to determine whether two non-competitive NMDA antagonists, ketamine and MK-801, had long-lasting antidepressant-like effects in CD-1 mice, a strain that has often been used to demonstrate the short-term antidepressant-like effects of ketamine. Finally, we examined the short- and long-term effects of ketamine in a mouse strain that is more sensitive to antidepressant-like effects, Balb/cJ mice. RESULTS: In CD-1 mice, desipramine treatment yielded significant short-term antidepressant-like effects in the TST and the forced swimming test (FST). However, no significant enduring effects of ketamine or MK-801 were observed 1 week later. Short-term effects of ketamine in the TST were observed in Balb/cJ mice, but lasting effects were absent 1 week later. CONCLUSIONS: Although the TST and FST have been widely used to detect antidepressant-like effects in mice, they do not appear to be sensitive to long-lasting antidepressant-like effects of ketamine in mice and, therefore, do not model the therapeutic effects of ketamine that have been reported in humans with major depression. PMID- 21274701 TI - S 18986 reverses spatial working memory impairments in aged mice: comparison with memantine. AB - RATIONALE: Normal or pathological ageing is characterized by working-memory dysfunction paired with a marked reduction in several neurotransmitters activity. The development of therapeutic strategy centered on the glutamatergic system known to bear a critical role in cognitive functions, is therefore of major importance in the treatment of mild forms of AD or age-related memory dysfunctions. OBJECTIVES: In Experiment 1, we investigated the effects of ageing on spatial working memory measured by sequential alternation (SA). Thus, the decay of alternation rates over a series of trials separated by varying intertrial temporal intervals (ITI, from 5 sec to 180 sec) was studied in mice of different age groups. In Experiment 2, we investigated the memory-enhancing potential of S 18986--a modulator of AMPA receptors--on age-related SA impairments, in comparison with memantine--an antagonist of NMDA receptors--. RESULTS: In Experiment 1, aged mice responded at chance with shorter ITI's and exhibited greater levels of interference in the SA task as compared to young adult mice. In Experiment 2, (1) S 18986 at 0.03 and 0.1 mg/kg reversed the memory deficit in aged mice but did not modify performance in young adult mice; (2) memantine at 10 mg/kg also increased SA rates in aged mice but did not improve performance in young adult mice. CONCLUSION: The SA task is a useful tool to reveal age-induced time-dependent working memory impairments. As compared to memantine, S 18986--a compound targeting AMPA receptors--contributes a valuable therapy in the treatment of age-related cognitive dysfunctions or mild forms of AD. PMID- 21274702 TI - High impulsivity predicting vulnerability to cocaine addiction in rats: some relationship with novelty preference but not novelty reactivity, anxiety or stress. AB - RATIONALE: Impulsivity is a vulnerability marker for drug addiction in which other behavioural traits such as anxiety and novelty seeking ('sensation seeking') are also widely present. However, inter-relationships between impulsivity, novelty seeking and anxiety traits are poorly understood. OBJECTIVE: The objective of this paper was to investigate the contribution of novelty seeking and anxiety traits to the expression of behavioural impulsivity in rats. METHODS: Rats were screened on the five-choice serial reaction time task (5 CSRTT) for spontaneously high impulsivity (SHI) and low impulsivity (SLI) and subsequently tested for novelty reactivity and preference, assessed by open-field locomotor activity (OF), novelty place preference (NPP), and novel object recognition (OR). Anxiety was assessed on the elevated plus maze (EPM) both prior to and following the administration of the anxiolytic drug diazepam, and by blood corticosterone levels following forced novelty exposure. Finally, the effects of diazepam on impulsivity and visual attention were assessed in SHI and SLI rats. RESULTS: SHI rats were significantly faster to enter an open arm on the EPM and exhibited preference for novelty in the OR and NPP tests, unlike SLI rats. However, there was no dimensional relationship between impulsivity and either novelty-seeking behaviour, anxiety levels, OF activity or novelty-induced changes in blood corticosterone levels. By contrast, diazepam (0.3-3 mg/kg), whilst not significantly increasing or decreasing impulsivity in SHI and SLI rats, did reduce the contrast in impulsivity between these two groups of animals. CONCLUSIONS: This investigation indicates that behavioural impulsivity in rats on the 5-CSRTT, which predicts vulnerability for cocaine addiction, is distinct from anxiety, novelty reactivity and novelty-induced stress responses, and thus has relevance for the aetiology of drug addiction. PMID- 21274703 TI - An acute psychosocial stressor increases drinking in non-treatment-seeking alcoholics. AB - RATIONALE: Although studies suggest that stress is an important reason for relapse in alcoholics, few controlled studies have been conducted to examine this assumption. Evidence of stress-potentiated drinking would substantiate this clinical observation and would contribute to the development of a model that would be valuable to alcohol treatment research. OBJECTIVES: The hypothesis was tested that an acute psychosocial stressor, the Trier Social Stress Test (TSST), increases alcohol consumption in non-treatment-seeking alcoholics. METHODS: Seventy-nine alcohol-dependent participants (40 women) were randomly assigned to receive the TSST or a no-stress condition. Immediately afterward, all participants received an initial dose of their preferred alcoholic beverage to achieve a target blood alcohol concentration of 0.03 g/dl (to prime subsequent drinking in the laboratory). Participants then participated in a mock taste test of two glasses of beer. Primary dependent measures were whether s/he drank all of the beer available (yes/no) and total amount of beer consumed (milliliters). RESULTS: Stressed participants were twice as likely as non-stressed participants to drink all of the beer available, a significant effect. Although the stressed group drank more milliliters than the non-stressed group, this effect failed to reach significance, likely due to ceiling effects. There were no significant stress group * gender effects on either outcome. CONCLUSIONS: This study supports that stress-potentiated drinking is valid and can be modeled in a clinical laboratory setting. PMID- 21274705 TI - Minerals form a continuum phase in mature cancellous bone. AB - Bone is a hierarchically structured composite consisting of a protein phase (type I collagen) and a mineral phase (carbonated apatite). The objective of this study was to investigate the hierarchical structure of mineral in mature bone. A method to completely deproteinize bone without altering the original structure is developed, and the completion is confirmed by protein analysis techniques. Stereoscopy and field emission electron microscopy are used to examine the structural features from submillimeter- to micrometer- to nanometer-length scales of bovine femur cancellous bone. Stereoscopic images of fully deproteinized and demineralized bovine femur cancellous bone samples show that fine trabecular architecture is unaltered and the microstructural features are preserved, indicating the structural integrity of mineral and protein constituents. SEM revealed that bone minerals are fused together and form a sheet-like structure in a coherent manner with collagen fibrils. Well-organized pore systems are observed at varying hierarchical levels. Mineral sheets are peeled off and folded after compressive deformation, implying strong connection between individual crystallites. Results were compared with commercially available heat deproteinized bone (Bio-Oss((r))), and evidence showed consistency in bone mineral structure. A two-phase interpenetrating composite model of mature bone is proposed and discussed. PMID- 21274704 TI - Sazetidine-A, a selective alpha4beta2 nicotinic acetylcholine receptor ligand: effects on dizocilpine and scopolamine-induced attentional impairments in female Sprague-Dawley rats. AB - BACKGROUND: Neuronal nicotinic receptor systems have been shown to play key roles in cognition. Nicotine and nicotinic analogs improve attention and nicotinic antagonists impair it. This study was conducted to investigate the role of alpha4beta2 nicotinic receptors in sustained attention using a novel selective alpha4beta2 nicotinic receptor ligand, sazetidine-A. METHODS: Female rats were trained to perform the signal detection task to a stable baseline of accuracy. The rats were injected with saline, sazetidine-A (0.01, 0.03, and 0.1 mg/kg), dizocilpine (0.05 mg/kg), or their combination; or, in another experiment, the rats were injected with the same doses of sazetidine-A, scopolamine (0.02 mg/kg), or their combination. RESULTS: Percent hit and percent correct rejection showed that dizocilpine caused significant (p < 0.025) impairments in performance, which were significantly reversed by each of the sazetidine-A doses. Response omissions were significantly (p < 0.05) increased by dizocilpine, and this was also significantly reversed by each of the sazetidine-A doses. None of the sazetidine A doses had significant effects on hit, correct rejection, or response omissions when given alone. Scopolamine also caused significant (p < 0.0005) impairments in percent hit and percent correct rejection and increased response omissions, which were significantly attenuated by all the sazetidine-A doses for percent hit and response omissions and by the highest dose of sazetidine-A for percent correct rejection. Both scopolamine and dizocilpine significantly (p < 0.0005) increased response latency, an effect which was significantly attenuated by sazetidine-A coadministration. CONCLUSIONS: These studies imply an important role for alpha4beta2 nicotinic receptors in improving sustained attention under conditions that disrupt it. Very low doses of sazetidine-A or drugs with a similar profile may provide therapeutic benefit for reversing attentional impairment in patients suffering from mental disorders and/or cognitive impairment. PMID- 21274706 TI - Bone mass and bone size in pre- or early pubertal 10-year-old black and white South African children and their parents. AB - Genetic factors are thought to maintain bone mass in socioeconomically disadvantaged black South Africans. We compared bone mass between environmentally disadvantaged black and advantaged white children and their parents, after determining the most appropriate method by which to correct bone mineral content (BMC) for size. We collected data from 419 healthy black and white children of mean age 10.6 years (range 10.0-10.9), 406 biological mothers, and 100 biological fathers. Whole-body, femoral neck, lumbar spine, and mid- and distal one-third of radius bone area (BA) and BMC were measured by dual-energy X-ray absorptiometry. Power coefficients (PCs) were calculated from the linear-regression analyses of ln(BMC) on ln(BA) and used to correct site-specific BMC for bone size differences. Heritability (1/2h(2), %) by maternal and paternal descent was estimated by regressing children's Z scores on parents' Z scores. Correcting BMC for height, weight, and BA(PC) accounted for the greatest variance of BMC at all skeletal sites. In so doing, BMC in blacks was up to 2.6 times greater at the femoral neck and lumbar spine. Maternal and paternal heritability was estimated to be ~30% in both black and white subjects. These results may in part explain the lower prevalence of fragility fractures at the hip in black South African children when compared to whites. Heritability was comparable between environmentally disadvantaged black and advantaged white South African children and similar to that reported for Caucasians in other parts of the world. PMID- 21274707 TI - Irregular structure of the HIV fusion peptide in membranes demonstrated by solid state NMR and MD simulations. AB - To better understand peptide-induced membrane fusion at a molecular level, we set out to determine the structure of the fusogenic peptide FP23 from the HIV-1 protein gp41 when bound to a lipid bilayer. An established solid-state (19)F nuclear magnetic resonance (NMR) approach was used to collect local orientational constraints from a series of CF(3)-phenylglycine-labeled peptide analogues in macroscopically aligned membranes. Fusion assays showed that these (19)F-labels did not significantly affect peptide function. The NMR spectra were characteristic of well-behaved samples, without any signs of heterogeneity or peptide aggregation at 1:300 in 1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine (DMPC). We can conclude from these NMR data that FP23 has a well-defined (time averaged) conformation and undergoes lateral diffusion in the bilayer plane, presumably as a monomer or small oligomer. Attempts to evaluate its conformation in terms of various secondary structures, however, showed that FP23 does not form any type of regular helix or beta-strand. Therefore, all-atom molecular dynamics (MD) simulations were carried out using the orientational NMR constraints as pseudo-forces to drive the peptide into a stable alignment and structure. The resulting picture suggests that FP23 can adopt multiple beta-turns and insert obliquely into the membrane. Such irregular conformation explains why the structure of the fusion peptide could not be reliably determined by any biophysical method so far. PMID- 21274710 TI - Efficacy of ultrasound-guided steroid injections for pain management of midfoot joint degenerative disease. AB - OBJECTIVE: To examine the efficacy of ultrasound (US)-guided injections for midfoot joint degenerative changes. MATERIALS AND METHODS: The US images and radiographs of 63 patients with midfoot joint degenerative changes were retrospectively reviewed. In those patients who had US-guided intra-articular steroid injection, the response to the injection was recorded by reviewing the 2 week pain diaries and clinical notes. Partial or complete pain relief was defined as a positive response and the same or increased level of pain as a negative response to the injection. RESULTS: Fifty-nine (59/63, 93.6%) patients with midfoot joint degenerative changes received US-guided injection. The majority of patients had a positive response up to 3 months post-injection (78.4% still experiencing pain relief at 2 weeks, 57.5% at 3 months and fewer than 15% of patients further than 3 months post-injection). The number of positive therapeutic responses did not differ significantly between patients with diagnostic and non-diagnostic response (p = 0.2636). CONCLUSIONS: US-guided intra articular injections for midfoot degenerative changes can have a good therapeutic result in the majority of patients up to 3 months post-injection. Therapeutic response cannot be predicted by a positive diagnostic response. PMID- 21274709 TI - Stability and folding dynamics of polyglutamic acid. AB - The thermal stability and folding dynamics of polyglutamic acid were studied by equilibrium circular dichroism (CD), Fourier-transform infrared (FTIR), and time resolved temperature-jump infrared (IR) spectroscopy. Polyglutamic acid (PGA) forms alpha-helical peptides in aqueous solution and is an ideal model system to study the helix-coil transition. Melting curves were monitored with CD and FTIR as a function of pD. At low pD, PGA aggregates at temperatures above 323 K, whereas at pD >5, unfolding and refolding are reversible. At pD 5.4, a helix-coil transition occurs with a transition temperature T(m) of 307 K. At slightly higher pD of 6.2, the peptide conformation is already in a coil structure and only small conformational changes occur upon heating. We determined the equilibrium constant for the reversible helix-coil transition at pD 5.4. The dynamics of this transition was measured at single IR wavelengths after a nanosecond laser-excited temperature jump of ?T ~ 10 K. Relaxation constants decreased with increasing peptide temperature. Folding and unfolding rates as well as activation energies were extracted based on a two-state model. Our study shows how equilibrium and time-resolved infrared spectroscopic data can be combined to characterize a structural transition and to analyze folding mechanisms. PMID- 21274708 TI - Knowledge-based computational methods for identifying or designing novel, non homologous antimicrobial peptides. AB - We describe computational approaches for identifying promising lead candidates for the development of peptide antibiotics, in the context of quantitative structure-activity relationships (QSAR) studies for this type of molecule. A first approach deals with predicting the selectivity properties of generated antimicrobial peptide sequences in terms of measured therapeutic indices (TI) for known antimicrobial peptides (AMPs). Based on a training set of anuran AMPs, the concept of sequence moments was used to construct algorithms that could predict TIs for a second test set of natural AMPs and could also predict the effect of point mutations on TI values. This approach was then used to design peptide antibiotics (adepantins) not homologous to known natural or synthetic AMPs. In a second approach, many novel putative AMPs were identified from DNA sequences in EST databases, using the observation that, as a rule, specific subclasses of highly conserved signal peptides are associated exclusively with AMPs. Both anuran and teleost sequences were used to elucidate this observation and its implications. The predicted therapeutic indices of identified sequences could then be used to identify new types of selective putative AMPs for future experimental verification. PMID- 21274711 TI - Role of dynamic MRI in the follow-up of acute Charcot foot in patients with diabetes mellitus. AB - PURPOSE: To evaluate the usefulness of magnetic resonance imaging (MRI) in assessing the level of activity of acute Charcot foot, monitoring treatment response and predicting healing time. MATERIALS AND METHODS: Forty diabetic patients with acute Charcot foot were prospectively enrolled. Patients underwent limb immobilization and were followed every 3 months by clinical examination (skin temperature and circumferences) and MRI. MR protocol included T1-weighted and fast spin echo inversion recovery (FSE-IR) sequences, and a dynamic study (fast spoiled gradient echo), after gadolinium administration (0.1 ml/kg). The contrast medium uptake rate at D-MRI and the signal intensity (SI) ratio on the FSE-IR sequence were measured. RESULTS: At baseline, mean contrast medium uptake rate was 136 +/- 49.7% and the mean SI ratio was 5 +/- 3. A high intra- and inter observer agreement was found for the contrast medium uptake rate, whereas a low agreement was observed for the SI ratio. At 3 months' follow-up, reduction of the contrast medium uptake rate was observed in all patients with improved clinical findings (n = 34), whereas the SI ratio was reduced in 15/34 (44.1%) patients. Mean healing time was significantly related to the baseline contrast medium uptake rate (P=0.005); it was 5.3 +/- 2.7 months in patients with contrast medium uptake rate <= 100%, compared with 9.1 +/- 2.5 months in the remaining patients (P=0.0003). CONCLUSIONS: Contrast medium uptake rate obtained at D-MRI represents a reproducible parameter that is reliable for predicting and monitoring treatment outcome in acute Charcot foot. PMID- 21274712 TI - In situ RHAMM protein expression in acute myeloid leukemia blasts suggests poor overall survival. AB - Treatment options for patients with high-risk acute myeloid leukemia (AML) include high-dose chemotherapy regimens in combination with allogeneic hematopoietic stem cell transplantation, which takes advantage of the donor T cell-mediated graft-versus-leukemia effect. Together with beneficial responses observed in assays targeted at leukemia-associated antigens (LAA), this encouraged research on cancer vaccines and adoptive cellular therapies in AML. The receptor for hyaluronic acid-mediated motility (RHAMM, CD168) was identified as one of the most promising LAA in AML. Thus far, little is known about in situ expression in leukemic bone marrow blasts or the prognostic role of RHAMM and its interaction partners in AML. We immunohistochemically analyzed the expression and prognostic significance of RHAMM on trephine bone marrow biopsies from 71 AML cases that had been evaluated for cytogenetics and presence of FLT3-internal tandem duplications and NPM1 mutations. Fifty-five patients (77%) were treated with curative intent, while 16 (23%) received the most appropriate supportive care. Twenty of 71 (28%) AML cases were considered RHAMM+. Receiver operating characteristic curves showed significant discriminatory power considering overall survival (OS) in AML patients treated curatively for RHAMM (p = 0.015). Multivariable analysis revealed that expression of RHAMM in >5% of leukemic blasts identifies a subgroup of curatively treated cases with adverse OS independent of failures to achieve complete remission. RHAMM not only represents a promising LAA with specific T-cell responses in AML but, if assessed in situ on blasts, also a probable prognostic factor. PMID- 21274713 TI - Sensitive and rapid detection of the insect pathogenic fungus Metarhizium anisopliae var. anisopliae by loop-mediated isothermal amplification. AB - A set of six specific primers was designed by targeting intergenic spacer region (IGS) sequences. With Bst DNA polymerase, the products could be clearly amplified for 60 min at 62 degrees C in a simple water bath. The sensitivity of the loop mediated isothermal amplification (LAMP) for detecting Metarhizium anisopliae var. anisopliae was about 0.01 pg fungal DNA per reaction (equivalent to 27 conidia). LAMP products could be judged with agar gel or naked eye after addition of SYBR Green I. There were no cross reactions with other fungal isolates indicating high specificity of the LAMP. The LAMP could detect the presence of M. anisopliae var. anisopliae from soil. The detection limits for M. anisopliae var. anisopliae of LAMP reaction was 50 conidia per reaction in soil. PMID- 21274714 TI - Cardiac MRI assessed left ventricular hypertrophy in differentiating hypertensive heart disease from hypertrophic cardiomyopathy attributable to a sarcomeric gene mutation. AB - OBJECTIVE: To evaluate the value of cardiac magnetic resonance imaging (CMRI) assessed left ventricular hypertrophy (LVH) in differentiating between hypertensive heart disease and hypertrophic cardiomyopathy (HCM). METHODS: 95 unselected subjects with mild-to-moderate hypertension, 24 patients with HCM attributable to the D175N mutation of the alpha-tropomyosin gene and 17 control subjects were studied by cine CMRI. Left ventricular (LV) quantitative and qualitative characteristics were evaluated. RESULTS: LV maximal end-diastolic wall thickness, wall thickness-to-LV volume ratio, end-diastolic septum thickness and septum-to-lateral wall thickness ratio were useful measures for differentiating between LVH due to hypertension and HCM. The most accurate measure for identifying patients with HCM was the LV maximal wall thickness >= 17 mm, with a sensitivity, specificity, negative predictive value, positive predictive value, and accuracy of 90%, 93%, 86%, 95% and 91%, respectively. LV maximal wall thickness in the anterior wall, or regional bulging in left ventricular wall was found only in patients with HCM. LV mass index was not discriminant between patients with HCM and those with LVH due to hypertension. CONCLUSION: LV maximal thickness measured by CMRI is the best anatomical parameter in differentiating between LVH due to mild-to-moderate hypertension and HCM attributable to a sarcomeric mutation. CMRI assessment of location and quality of LVH is also of value in differential diagnosis. PMID- 21274715 TI - Magnetic resonance angiography (MRA) of the calf station at 3.0 T: intraindividual comparison of non-enhanced ECG-gated flow-dependent MRA, continuous table movement MRA and time-resolved MRA. AB - OBJECTIVES: To compare 3D non-enhanced ECG-gated inflow-dependent MRA (NE-MRA) vs. continuous table movement (CTM) MR-angiography and time-resolved TWIST-MRA in the calf station at 3.0 T in a clinical patient collective. METHODS: 36 patients (27 male/9 female, 66.1 +/- 14.4 years) with PAOD (stage II-IV) underwent during a single MRI: NE-MRA, contrast-enhanced CTM-MRA and TWIST-MRA with a single dose of a gadolinium-based contrast agent. The image quality (IQ) and the degree of stenoses were rated on a four-point scale. Positive (PPV) and negative predictive values (NPV), sensitivity (SS) and specificity (SP) for stenoses detection were calculated for NE-MRA vs. CTM-MRA and vs. TWIST-MRA. Values were obtained for overall graduation of wall changes and for severe stenoses (>70%). RESULTS: With NE-MRA 122/288 segments were not assessable. Compared with CTM-MRA and TWIST-MRA the IQ was significantly inferior (p < 0.0001 to p = 0.0426). CTM-MRA/TWIST-MRA detected stenoses in 44.9%/46.1% of the segments, NE-MRA in 53.5%. SS/NPV of the NE-MRA ranged from 97.8 to 100%. The SP and PPV ranged from 72.7 to 85.5% and 66.7 to 78.2%. CONCLUSION: Contrast-enhanced MRA techniques are superior to NE MRA regarding IQ and correct identification of stenoses. If technically successful, NE-MRA is characterised by high NPV and overestimation of the degree of stenoses. PMID- 21274716 TI - US-guided diffuse optical tomography for breast lesions: the reliability of clinical experience. AB - PURPOSE: To prospectively assess the reliability of US-guided diffuse optical tomography (US-DOT) using interobserver agreement for the diagnosis of breast lesions with individual real-time imaging and to assess the interobserver agreement of conventional sonography (US) combined with US-DOT for differentiation between benignity and malignancy breast lesions. MATERIALS AND METHODS: An Institutional Review Board approved this study, and all subjects provided written informed consent. 122 breast lesions in 111 patients evaluated with US-guided core biopsy were included. Assessments with US and US-DOT for cases subjected to biopsy were obtained by two radiologists using individual real time imaging prior to biopsy and were prospectively recorded by each performer. With DOT, the total haemoglobin concentration (THC) for each breast lesion was measured. Histopathological results from US-guided biopsies were used as a reference standard. To assess measurement interobserver agreement, the intraclass correlation coefficient (ICC) and the Bland-Altman plot were used for THC in US DOT and the kappa values and ROC analysis were used to evaluate the diagnostic performances of the US BI-RADS final assessment in US and combined US and US-DOT. RESULTS: Of 122 US-guided core biopsied lesions, 83 (68.0%) were diagnosed as benign, and 39 (32.0%) as malignant. Excellent correlation was seen in the THC in US-DOT (ICC score 0.796; 95% confidence interval, 0.708-0.857). The interobserver agreement in BI-RADS final assessment with US and US-DOT (almost perfect; kappa = 0.8618) was improved compared with that of US (substantial agreement, kappa = 0.6574). However, the overall areas under the ROC curve did not show significant differences between US and combined US and US-DOT, 0.8894 and 0.8975, respectively (P = 0.981). CONCLUSIONS: The reliability of THC in US-DOT showed excellent correlation in overall real-time performance. Although the inter observer agreement for BI-RADS final assessment of US was improved by using US DOT, the performances of radiologists with respect to the characterization of breast masses as benign or malignant were not significantly improved with US-DOT. PMID- 21274717 TI - PET/CT without capacity limitations: a Danish experience from a European perspective. AB - OBJECTIVES: We report the 3-year clinical experience of a large new Danish PET/CT centre without capacity limitations in relation to national and European developments. METHODS: The use of PET/CT in cancer was registered from early 2006 to early 2009 to judge the impact on patient management and to compare it with national and European trends. RESULTS: 6056 PET/CT examinations were performed in 4327 patients. Activity increased by 86 examinations per month compared with the same month the year before. Referrals came primarily from oncology (23.0%), haematology (21.6%), surgery (12.6%), internal medicine (12.7%) and gynaecology (5.5%). Referral indications were diagnosis (31.3%), staging (22.3%), recurrence detection (21.2%), response evaluation (17.0%) and other (8.2%). Response from nearly 60% of users showed that PET/CT caused a change in diagnosis and/or staging and/or treatment plan in 36.0% of cases. During the study period, there was a steep increase in the national use of FDG and in the European use of PET/CT. CONCLUSIONS: We recorded a constantly increasing use of PET/CT that caused a change in diagnosis and/or staging and/or treatment plan in 36.0% of cases. In line with national and European trends this may suggest a shift in favour of functional rather than anatomical imaging. PMID- 21274718 TI - Different strategies for performing pulmonary vein isolation in patients with pulmonary vein rhythm. AB - Pulmonary vein (PV) isolation was performed in atrial fibrillation (AF) patients whose cardiac rhythm was dominated by the ectopic beats originating from the PV. We herein report two cases with dominant PV ectopic rhythm that underwent catheter ablation for the treatment of paroxysmal AF. In one case, a permanent pacemaker implantation was required to treat a symptomatic long sinus pause after the isolation of all four PVs, while no AF was documented during the 5-year period after ablation. However, the isolation of all four PVs except for a PV with a dominant ectopic rhythm was performed in the other case. The latter case was free from both AF and symptomatic bradycardia following the procedure without the implantation of a pacemaker. Selective PV isolation therefore appears to be an effective therapy to both achieve the successful treatment of AF and to prevent the manifestation of sick sinus syndrome. PMID- 21274719 TI - Electrical storm originating from a left ventricular epicardial scar in a patient with completely normal endocardial voltage. AB - We report a patient with non-ischemic dilated cardiomyopathy presenting with an electrical storm because of a poorly tolerated monomorphic ventricular tachycardia. Electroanatomical mapping revealed a scar restricted to the epicardium, whereas the endocardial voltage map was completely normal. Epicardial catheter ablation based on substrate mapping and limited pace and entrainment mapping eliminated the tachycardia. PMID- 21274720 TI - Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra cerebellar pilocytic astrocytoma. AB - Missense mutations of the V600E type constitute the vast majority of tumor associated somatic alterations in the v-RAF murine sarcoma viral oncogene homolog B1 (BRAF) gene. Initially described in melanoma, colon and papillary thyroid carcinoma, these alterations have also been observed in primary nervous system tumors albeit at a low frequency. We analyzed exon 15 of BRAF spanning the V600 locus by direct sequencing in 1,320 adult and pediatric tumors of the nervous system including various types of glial, embryonal, neuronal and glioneuronal, meningeal, adenohypophyseal/sellar, and peripheral nervous system tumors. A total of 96 BRAF mutations were detected; 93 of the V600E type and 3 cases with a three base pair insertion between codons 599 and 600. The highest frequencies of BRAF (V600E) mutations were found in WHO grade II pleomorphic xanthoastrocytomas (42/64; 66%) and pleomorphic xanthoastrocytomas with anaplasia (15/23; 65%), as well as WHO grade I gangliogliomas (14/77; 18%), WHO grade III anaplastic gangliogliomas (3/6) and pilocytic astrocytomas (9/97; 9%). In pilocytic astrocytomas BRAF (V600E) mutation was strongly associated with extra-cerebellar location (p = 0.009) and was most frequent in diencephalic tumors (4/12; 33%). Glioblastomas and other gliomas were characterized by a low frequency or absence of mutations. No mutations were detected in non-glial tumors, including embryonal tumors, meningiomas, nerve sheath tumors and pituitary adenomas. The high mutation frequencies in pleomorphic xanthoastrocytomas, gangliogliomas and extra cerebellar pilocytic astrocytomas implicate BRAF (V600E) mutation as a valuable diagnostic marker for these rare tumor entities. Future clinical trials should address whether BRAF (V600E) mutant brain tumor patients will benefit from BRAF (V600E)-directed targeted therapies. PMID- 21274721 TI - Biochemical markers predicting pre-term delivery in symptomatic patients: phosphorylated insulin-like growth factor binding protein-1 and fetal fibronectin. AB - PURPOSE: The aim of this study was to evaluate the efficacy of the phosphorylated insulin-like growth factor-binding protein (phIGFBP-1) and of the fetal fibronectin test (fFN) in predicting pre-term delivery in symptomatic women. METHODS: We included 210 symptomatic women at 24-34 weeks' gestation, who underwent the phIGFBP-1 and fFN test. We analyzed the prevalence of pre-term delivery in these patients within 7 days upon admission, before the 34th and the 37th weeks' gestation. RESULTS: The 3.8% of women delivered within 7 days upon the admission, the 7.6% before 34 weeks and the 16.2% before 37 weeks' gestation. The phIGFBP-1 and fFN test had a high specificity and a high negative predictive value in predicting pre-term delivery within 7 days, before 34 and before 37 weeks' gestation. The logistic regression of phIGFBP-1 was statistically significant in predicting pre-term delivery with an odds ratio of 10.08 <34 weeks' gestation. The multivariate analysis showed that the phIGFBP test had a higher OR <34 weeks' gestation (p < 0.001) and that the two variables were independent and useful in combination to predict pre-term delivery (<37 weeks' gestation). CONCLUSION: The phIGFBP-1 test may be better that the fFN test in predicting pre-term delivery before 34 weeks' gestation. PMID- 21274722 TI - Ultrasound diagnosis and comprehensive surgical treatment of complete non puerperal uterine inversion. AB - INTRODUCTION: Ultrasonographic diagnosis of very rare case of complete non puerperal uterine inversion secondary to a large sub-mucous fibroid. CASE REPORT: A 50-year-old woman was admitted with heavy vaginal bleeding. Detailed vaginal and abdominal ultrasound, using color Doppler flow, raised the suspicion of complete uterine inversion. The distal ends of the fallopian tubes and part of the ovaries were demonstrated adherent to the uterine fundus. Laparoscopy showed there was no uterus inside the abdomen because of complete uterine inversion. Only a dimple with a constriction ring was found at the site of the uterus. A sub mucous 6 cm fibroid was attached to the fundus, and vaginal myomectomy was performed to reduce uterine size in order to restore the uterus to its abdominal position. However, the uterus was impacted and only cutting longitudinally the anterior and posterior fornices helped to restore the uterus and facilitate an abdominal hysterectomy. Histological examination of the uterus and fibroid following hysterectomy confirmed their benign nature. CONCLUSION: Ultrasonographic diagnosis of complete uterine inversion is feasible. However, high index of suspicion is necessary. PMID- 21274724 TI - Work-related upper extremity disorders: one-year follow-up in an occupational diseases registry. AB - PURPOSE: To study the course and consequences of work-related upper extremity disorders in the registry of the Netherlands Centre for Occupational Diseases (NCvB). METHODS: A follow-up study was performed in a sample of consecutive cases of work-related upper extremity disorders notified to the NCvB. Perceived severity was measured with VAS (0-100), quality of life with VAS (0-100) and SF 36, functional impairment with DASH and sickness absence with a questionnaire. Measurements took place directly after notification (T0) and after 3, 6 and 12 months (T1-T3). A linear mixed model was used to compare scores over time. RESULTS: Average age of the 48 consecutive patients (89% response) was 42 years; 48% were men. Perceived severity, functional impairment and sickness absence decreased statistically significant during the follow-up period, and quality of life scores improved. Patients older than 45 years scored worse on perceived severity of the disease, functional impairment and quality of life than did younger patients. CONCLUSIONS: The role of registries of occupational diseases for preventive policy can be extended by creating longitudinal data in sample projects. In the sample from our registry, work-related upper extremity disorders had a favourable course. PMID- 21274725 TI - The E2 protein of human papillomavirus type 8 increases the expression of matrix metalloproteinase-9 in human keratinocytes and organotypic skin cultures. AB - Non-melanoma skin cancer (NMSC) is the most frequent human cancer of Caucasian populations. Although the ultraviolet irradiation is a key contributor to the establishment of this keratinocyte malignancy, the infection by some types of human papillomavirus (HPV) has also been implicated in NMSC development. Cancers occur as a result of a complex series of interactions between the cancer cell and its surrounding matrix. The matrix metalloproteinases (MMPs) play a role in degrading the extracellular matrix. MMP9 is an important gelatinase involved in processes such as cell migration, invasion and metastasis. In this report, we demonstrated by EMSA experiments that the MMP9 promoter contains a binding site for the transcriptional regulator E2 of HPV8. Transient reporter gene assays showed that HPV8-E2 activated the MMP9 promoter in a dose-dependent manner in human epidermal keratinocytes. An E2 transactivation-defective mutant (I73L) as well as a DNA-binding deficient mutant (R433K) demonstrated no activation of the MMP9 promoter, suggesting that both an intact transactivation and DNA-binding domain are required for E2 activation of the MMP9-promoter. The functional role of the E2 binding site within the MMP9 promoter was also confirmed by mutating the E2 binding site. In organotypic cultures of human skin, an overexpression of MMP9 was observed in suprabasal layers of the HPV8 E2-expressing epidermis thus confirming the results of the monolayer cultures. These results demonstrate that the early gene E2 of HPV8 is able to increase the expression of MMP9 by direct activation of the MMP9-promoter. PMID- 21274726 TI - Common genetic variation in the 3'-untranslated region of gonadotropin-releasing hormone receptor regulates gene expression in cella and is associated with thyroid function, insulin secretion as well as insulin sensitivity in polycystic ovary syndrome patients. AB - Gonadotropin-releasing hormone receptor (GNRHR) is a member of the G protein coupled Ca(2+)-dependent family of receptors. It interacts with GnRH, whose signaling plays an important role in thyroid-stimulating hormone (TSH) secretion and insulin activity. There has been no study on the genetic effect of GNRHR on TSH secretion and insulin action in polycystic ovary syndrome (PCOS). We decided to investigate whether naturally occurring genetic variation at the human GNRHR locus is associated with thyroid function, insulin secretion and insulin sensitivity in PCOS. We undertook a systematic search for polymorphisms in GNRHR by resequencing the gene and then genotyped common single-nucleotide polymorphisms across the locus in 261 PCOS patients well-phenotyped for several metabolic traits to determine associations. A test for association of common genetic variants with susceptibility to PCOS was carried out in a large cohort of 948 subjects. Finally, we experimentally validated the marker-on-trait associations using GNRHR 3'-UTR region/reporter analysis in 293T cells. The 3' UTR variant rs1038426 was associated with serum thyroid concentration (P = 0.007), change of insulin levels during oral glucose tolerance test (P = 0.004) and insulin sensitivity index (P = 0.014). In a functional study, 3'-UTR variant T allele increased reporter expression by a transfected luciferase reporter/GNRHR 3'-UTR expression plasmid. In conclusion, our results strongly suggest that common genetic variant in GNRHR contributes to the phenotypic expression of PCOS. The findings suggest novel pathophysiological links between the GNRHR locus and thyroid function and insulin secretion in PCOS. PMID- 21274727 TI - Germline PKHD1 mutations are protective against colorectal cancer. AB - The autosomal recessive polycystic kidney disease (ARPKD) gene, PKHD1, has been implicated in the genesis or growth of colorectal adenocarcinoma, as a high level of somatic mutations was found in colorectal tumor tissue. To determine whether carriers of a single PKHD1 mutation are at increased risk of colorectal carcinoma, we assessed the prevalence of the commonest European mutation, T36M. First, we assayed a European cohort of ARPKD patients and found T36M was responsible for 13.1% of mutations. We then investigated two European cohorts with colorectal adenocarcinoma versus two control cohorts of similar age and gender. Screening for the most common PKHD1 mutation, T36M, we detected 15:3,603 (0.42%) controls versus 1:3,767 (0.027%) colorectal cancer individuals, indicating that heterozygous PKHD1 mutations are not a risk factor and are protective (p=0.0002). We also show that the carriage rate for PKHD1 mutations in the European population is higher than previous accepted at 3.2% (1:31 genomes). PMID- 21274728 TI - Thoracic spine fractures: injury profile and outcomes of a surgically treated cohort. AB - There are only few reports in literature about the treatment of traumatic lesions of the thoracic spine. They have been grouped together with thoracolumbar fractures, ignoring the particular biomechanics of the thoracic segment. The objective of this retrospective cohort is to describe the clinical presentation and outcomes of surgically treated patients with these injuries. Data were obtained from the institutional database of medical registries, identifying all the patients who had been treated for thoracic spine fractures, from January 1, 1995 through December 31, 2005 in our institution. The study group included the 51 surgically treated patients. General and surgery-related complications were considered as clinical outcomes and injury-related disability was also assessed. Statistical analysis evaluating possible associations with timing and type of surgery, neurological impairment and associated injuries was carried out. Motor vehicle accident was the most frequent mechanism of injury. Six patients had an incomplete neurological deficit, whereas 22 had a complete lesion. Thirty-two patients presented at least one complication. Five of the neurologically intact patients, while 20 of those with neurological impairment presented general complications (p = 0.0001). None of the patients' neurological status deteriorated after surgery. All patients with complete spinal cord injury and those with incomplete cord injury with partial functional recovery received disability compensation. Short pedicle instrumentations should be used whenever possible, but also long instrumentations and mixed constructs may be necessary for the management of such unique fractures. PMID- 21274729 TI - Idiopathic scoliosis in Korean schoolchildren: a prospective screening study of over 1 million children. AB - Cross-sectional epidemiologic scoliosis screening was carried out to determine the current prevalence of scoliosis in the Korean population and to compare with the results of previous studies. Between 2000 and 2008, 1,134,890 schoolchildren underwent scoliosis screening. The children were divided into two age groups, 10 12-year-olds (elementary school) and 13-14-year-olds (middle school), to calculate age- and sex-specific prevalence rates. Children with a scoliometer reading >=5 degrees were referred for radiograms. Two surgeons independently measured curve types, magnitudes, and Risser scores (inter-observer r = 0.964, intra-observer r = 0.978). Yearly and overall prevalence rates of scoliosis were calculated. There were 584,554 boys and 550,336 girls in the sample, with a male to female ratio of 1.1:1. There were 77,910 (6.2%) children (26,824 boys and 51,086 girls) with scoliometer readings >5 degrees , and 37,339 of them had positive results with Cobb angles >=10 degrees (positive predictive value, 46.4%). The overall scoliosis prevalence rate was 3.26%; girls had a higher prevalence (4.65%) than boys (1.97%). Prevalence rates increased progressively from 1.66 to 6.17% between 2000 and 2008, with the exception of 2002. According to age and gender, 10-12-year-old girls had the highest scoliosis prevalence rates (5.57%), followed by 13-14-year-old girls (3.90%), 10-12-year-old boys (2.37%), and 13-14-year-old boys (1.42%). In girls and boys, prevalence rates dropped by 64.53 and 60.65% among 10-12-year-olds and 13-14-year-olds, respectively (P = 0.00). The proportion of 10 degrees -19 degrees curves was 95.25 and 84.45% in boys and girls, respectively; and the proportion of 20 degrees -29 degrees curves was 3.91 and 11.28%, which was a significant difference (P = 0.00). Thoracic curves were the most common (47.59%) followed by thoracolumbar/lumbar (40.10%), double (9.09%), and double thoracic (3.22%) curves. A comparison of the curve patterns revealed significant differences between genders (P = 0.00). We present this report as a guide for studying the prevalence of idiopathic scoliosis in a large population, and the increasing trend in the prevalence of idiopathic scoliosis emphasizes the need for awareness. PMID- 21274730 TI - CRPS I following artificial disc surgery: case report and review of the literature. AB - We report a case of type 1 complex regional pain syndrome (CRPS I) of the left leg following the implantation of an artificial disc type in the L4/5 segment of the lumbar spine using a midline left-sided retroperitoneal approach. This approach included the mobilisation of the sympathetic trunk with incision and resection of the intervertebral disc. The perioperative and immediate postoperative periods were uneventful, but on the second postoperative day the patient complained of a progressive allodynia of the whole left leg in combination with weakness of the limb. Neurological examination did not reveal any radicular deficit or paresis. A sympathetic reaction following the mobilisation of the sympathetic trunk during the ventral preparation of the spine was suspected and investigated further. A diagnosis of CRPS I was proposed, and the patient was treated with analgesia, co-analgesics for pain alienation, and systemic corticosteroid therapy. A computed tomography-guided sympathetic block and lymphatic drainage were performed. Following conservative orthopaedic rehabilitation therapy, the degree of pain, allodynia, weakness, and swelling were reduced and the condition of the patient was ameliorated. The cost-benefit ratio of spinal arthroplasty is still controversial. The utility of this paper is to debate a possible cause of a painful complication, which can invalidate the results of a successful operation. PMID- 21274731 TI - Analysis and characterization of the complete genome of a member of a new species of kobuvirus associated with swine. AB - A virus belonging to a new species in the genus Kobuvirus, family Picornaviridae, was first isolated in 2008 from apparently healthy pigs in Hungary and China. We report the complete genome sequence and the genetic organization of the novel porcine kobuvirus strain Y-1-CHI, which was identified in China. The RNA genome of strain Y-1-CHI contains 8210 nucleotides (nt) and has an organization similar to that of other picornaviruses. The full-length nucleotide sequence of Y-1-CHI was 88.62%, 58.66%, and 48.86% identical to those of S-1-HUN, U-1, and Aichi virus, respectively. No positive results were found in 454 stool samples from children with acute gastroenteritis. Dendrograms indicated that Y-1-CHI and S-1 HUN are most closely related to each other and belong to the same species. Our results suggest that members of this novel species have the typical genome characteristics of members of the genus Kobuvirus and may be distributed globally in swine. PMID- 21274732 TI - Mass retraction movement of the anterior upper teeth using orthodontic mini implants as anchorage. AB - BACKGROUND: Several studies have demonstrated the application of mini-implants in the orthodontic treatment as anchorage during the retraction movement of the anterior teeth. PURPOSE: This study was designed to evaluate the mass retraction movement of the anterior upper teeth using orthodontic mini-implants as anchorage. MATERIALS AND METHODS: Nine patients with class I malocclusion and Angle's class II, needing extractions of the upper first premolars, were enrolled in this case series. The retraction was performed using sliding mechanics and orthodontic anchorage on mini-implants. Measures were taken by initial and final cephalometric X-rays of the retraction movement to evaluate whether the mini implants remained stationary and displacements of the incisors and the upper first premolars. RESULTS: Out of 18 mini-implants, 8 mesialized (0.45 mm, average) and 3 extruded (0.14 mm, average). The upper incisors were retracted on the average of 4.21 mm, extruded 0.33 mm, and tipped 10.3 degrees . There were no statistical significant modifications in the placement of the posterior teeth. CONCLUSIONS: Although there was a very small displacement of the mini-implants, they still provided an adequate anchorage for the retraction of the anterior teeth, and there was no loss in the anchorage of the posterior teeth. PMID- 21274734 TI - Temperature change during non-contact diode laser irradiation of implant surfaces. AB - A temperature increase of more than 10 degrees C can compromise bone vitality. Laser radiation with different wavelengths has been used for the treatment of peri-implantitis, but little is known about the effect of laser irradiation on temperature rise on the implant surface. In this study, the temperature gradient (?T) generated by laser irradiation of implant surface using two diode lasers (810 nm and a 980 nm) with 2 W of power has been recorded by two thermocouples (one in the cervical area and one in the apical area) and studied. The 810-nm diode laser showed the following results: after 60 s of irradiation with 2 W of continuous mode the temperature gradient in the cervical area of the implant (?Tc) was 37.2 degrees C, while in the apical area (?Ta) was 27.2 degrees C. The 980-nm diode laser showed the following results: after 60 s of irradiation with 2 W continuous mode ?Tc was 41.1 degrees C, and ?Ta was 30.6 degrees C. The 810-nm diode laser with 2 W continuous mode generated a temperature increase of 10 degrees C after only 14 s. The 980-nm diode lasers groups produced a much more rapid temperature increase. In only 12 s, the continuous wave of 980 nm reached the 10 degrees C temperature rise. From the present in vitro study it was concluded that the irradiation of implant surfaces with diode lasers may produce a temperature increase above the critical threshold (10 degrees C ) after only 10 s. PMID- 21274733 TI - Low-level laser therapy: a useful technique for enhancing the proliferation of various cultured cells. AB - The aim of this work is to review the available literature on the details of low level laser therapy (LLLT) use for the enhancement of the proliferation of various cultured cell lines including stem cells. A cell culture is one of the most useful techniques in science, particularly in the production of viral vaccines and hybrid cell lines. However, the growth rate of some of the much needed mammalian cells is slow. LLLT can enhance the proliferation rate of various cell lines. Literature review from 1923 to 2010. By investigating the outcome of LLLT on cell cultures, many articles report that it produces higher rates of ATP, RNA, and DNA synthesis in stem cells and other cell lines. Thus, LLLT improves the proliferation of the cells without causing any cytotoxic effects. Mainly, helium neon and gallium-aluminum-arsenide (Ga-Al-As) lasers are used for LLLT on cultured cells. The results of LLLT also vary according to the applied energy density and wavelengths to which the target cells are subjected. This review suggests that an energy density value of 0.5 to 4.0 J/cm(2) and a visible spectrum ranging from 600 to 700 nm of LLLT are very helpful in enhancing the proliferation rate of various cell lines. With the appropriate use of LLLT, the proliferation rate of cultured cells, including stem cells, can be increased, which would be very useful in tissue engineering and regenerative medicine. PMID- 21274735 TI - Increased Slug and decreased E-cadherin expression is related to poor prognosis in patients with gastric cancer. AB - BACKGROUND: The expression of E-cadherin correlates with the progression and metastasis of gastric cancer. Slug, a member of the snail family of transcriptional factors, is a newly identified factor that represses transcription of the E-cadherin gene. The purpose of the present study was to evaluate the clinical significance of E-cadherin and Slug expression in gastric cancer. METHODS: Immunohistochemistry was used to investigate the expression of E cadherin and Slug proteins in 164 patients with gastric cancer. The relationships between the expression of these proteins and clinicopathological factors, including prognosis, were analyzed. RESULTS: Positive expression of E-cadherin and Slug was observed in 43.9 and 29.9% of cases, respectively. Tumors with reduced E-cadherin or positive Slug expression had greater extent of lymph node metastasis, lymphatic invasion, and venous invasion, and were at a worse stage than the tumors with preserved E-cadherin or negative Slug expression. Slug expression was significantly correlated with reduced E-cadherin expression; 37 of the 49 (75.5%) tumors with positive Slug expression had reduced E-cadherin expression (P = 0.0008). Patients with reduced E-cadherin expression or positive Slug expression had poor clinical outcomes. In the group with preserved E cadherin expression, the 5-year survival rate was better for patients who were negative for Slug expression than for those who were positive for Slug expression (P = 0.0001). However, multivariate analysis indicated that E-cadherin expression and Slug expression were not independent prognostic factors. CONCLUSIONS: Evaluation of not only the expression of E-cadherin, but also the coexpression of E-cadherin and Slug in patients with preserved E-cadherin expression would be useful for predicting malignant properties of gastric cancer. PMID- 21274736 TI - Correlation between endoscopic macroscopic type and invasion depth for early esophagogastric junction adenocarcinomas. AB - BACKGROUND: Although correlations between endoscopic macroscopic type and tumor depth have been reported for superficial esophageal squamous cell carcinoma and early gastric and early colorectal adenocarcinomas, there is no published study investigating the correlation between endoscopic macroscopic type and invasion depth for mucosal (M) and submucosal (SM) adenocarcinomas located at the esophagogastric junction (EGJ). We decided to analyze, therefore, the relationship between endoscopic macroscopic type and tumor depth for such cancers. METHODS: We retrospectively reviewed 73 early EGJ adenocarcinomas (M/SM = 33/40; differentiated/undifferentiated type = 70/3) in 73 consecutive patients treated endoscopically and/or surgically between January 2000 and December 2008. The mean age of the patients was 63.9 years (range 37-85 years) and the male/female ratio was 62:11. EGJ adenocarcinoma was defined as junctional carcinoma (type II) according to the Siewert classification. RESULTS: We found polypoid type lesions (0-I) in 14 patients, non-polypoid type without mixed type (0-IIa, 0-IIb, or 0-IIc) in 39, and mixed type (0-IIa + IIc or 0-IIc + IIa) in 20 patients. Non-polypoid type without mixed type (31%; 12/39) lesions had a significantly lower risk for SM invasion compared to polypoid type (79%; 11/14; p < 0.01) and mixed type (85%; 17/20; p < 0.01) lesions. In polypoid type lesions, the risk of SM invasion was significantly lower for the pedunculated subtype (0 Ip) than for the sessile subtype (0-Is) lesions (0%; 0/2 vs. 92%; 11/12; p < 0.05). M lesions (mean size 14.5 +/- 7.5 mm) were significantly smaller than SM lesions (24.5 +/- 7.7 mm; p < 0.01). CONCLUSIONS: Determination of endoscopic macroscopic type may be useful in accurately diagnosing early EGJ adenocarcinoma invasion depth. PMID- 21274737 TI - Human thymic stromal lymphopoietin enhances expression of CD80 in human CD14+ monocytes/macrophages. AB - OBJECTIVE: Human thymic stromal lymphopoietin (TSLP), an epithelial cell-derived cytokine, promotes inflammatory T helper type 2 cell (Th2) differentiation of naive CD4(+) T cells. TSLP is highly produced in keratinocytes of patients with atopic dermatitis and bronchial epithelia of patients with asthma and was thought to be a master switch for allergic inflammation. We sought to examine the effect of TSLP in human monocytes/macrophages. METHODS: The effect of TSLP on the expression of cell surface antigens (CD11c, CD16, CD54, CD80, CD86, and HLA-DR) in peripheral blood CD14(+) monocytes/macrophages was examined. RESULTS: TSLP enhanced the expression of CD80 in peripheral blood CD14(+) monocytes/macrophages but not that of other cell surface antigens. It was associated with an increased percentage of CD14(dim/-), CD80(+), CD11c(+), and HLA-DR(+) cells, which was consistent with the increased differentiation of myeloid dendritic cells. CONCLUSIONS: TSLP induces CD80 expression in human peripheral blood CD14(+) monocytes/macrophages; this indicates monocyte/macrophage activation. This may be associated with their differentiation into myeloid dendritic cells. PMID- 21274738 TI - Antileukemic activity and cellular effects of rhodium(III) crown thiaether complexes. AB - The cytostatic properties of novel rhodium(III) thiacrown ether complexes [RhCl(LL)([9]aneS(3))](n+) with either aromatic kappa(2)N ligands (n = 2) or anionic chelate ligands (n = 1) have been investigated for the human cancer cell lines HT-29 and MCF-7 and for immortalized HEK-293 cells. Taken together with literature IC(50) values for analogous complexes with polypyridyl ligands or 1,4 dithiane, the in vitro assays indicate that dicationic complexes with soft kappa(2)N (imino) or kappa(2)S (thiaether) ligands exhibit significantly higher antiproliferative effects than those with hard kappa(2)N (amino) ligands. Dicationic complexes are more active than monocationic complexes with similar ligands. Pronounced apoptosis-inducing properties towards Jurkat cells were established for complexes with LL = bpm, dpq, and 1,4-dithiane. The order of activity (bpm > 1,4-dithiane > dpq > bpy) contrasts to that observed for adhesive cancer cells (bpm > bpy, 1,4-dithiane > dpq). Necrosis is insignificant in all cases. The percentage of Jurkat cells exhibiting apoptosis after 24 or 48 h incubation periods is directly correlated to the percentage of cells exhibiting high levels of reactive oxygen species. As established by online monitoring with a sensor chip system, treatment of MCF-7 cells with the bpm and 1,4-dithiane complexes leads to a significant and permanent concentration-dependent decrease in oxygen consumption and cellular adhesion. PMID- 21274739 TI - Occupational rehabilitation in Hong Kong: current status and future needs. AB - INTRODUCTION: This paper reviews the development of occupational rehabilitation in Hong Kong, both in terms of the science as well as the service for injured workers. Besides, it also reviews the existing Employees' Compensation Ordinance for work injury to illustrate how the policy could influence the success and development of the discipline. METHODS: Five experienced occupational rehabilitation providers, including 1 occupational medicine specialist, 3 occupational therapists, and 1 physiotherapist critically reviewed the past and current development of occupational rehabilitation in Hong Kong as well as the local contextual factors, which could influence its future development. RESULTS: Since the enactment of the Employees' Compensation Ordinance in the 1950s, there have been progressive improvements in the field of occupational rehabilitation in Hong Kong. Services in the early years were mostly based on the biomedical model, where doctors and patients tended to focus on clinical symptoms and physical pathology when making clinical decisions. Since then, remarkable academic achievements have been made in the field locally, from the validation of clinical instruments for assessment of work capacity, assessment of employment readiness to the evaluation of efficacy of interventional programs for injured workers focusing on work related outcomes. However, there has been a relatively lack of progress in the development of related policies and implementation of related programs for occupational rehabilitation. There is no built in linkage between rehabilitation, compensation and prevention in the current system in Hong Kong, and there is no rehabilitation policy specific to those workers with occupational diseases and injuries. CONCLUSIONS: There are still deficiencies in the development and provision of occupational rehabilitation services in Hong Kong. Incorporation of requirements for occupational rehabilitation at the legislation and policy levels should be seriously considered in the future. Besides, the development of the Occupational Medicine subspecialty in the public hospital system in Hong Kong is considered a facilitator to the future development of occupational rehabilitation in Hong Kong. PMID- 21274740 TI - From cooperation to conflict? Swedish rehabilitation professionals' experiences of interorganizational cooperation. AB - PURPOSE: This article analyses Swedish rehabilitation professionals' experiences of interorganizational cooperation in return-to-work and labour market reintegration. METHOD: Two groups (n = 15) from different organizations met on a regular basis to discuss their practice from a cooperation perspective. The participants had experience of cooperation in the organizational setting of Coordination Associations. The groups worked with a tutor according to a problem based methodology, to discuss how their practice is influenced by new structures for cooperation. The material was analysed inductively using qualitative content analysis. RESULTS: Interorganizational cooperation in rehabilitation is generally perceived as promoting coherence and communication. Nevertheless, there are several contradictory factors in the implementation of such work forms, primarily inflexible sickness insurance regulations and inability of managers to implement cooperation in regular practice. CONCLUSIONS: While interorganizational cooperation promotes professional discretion and tailored solutions, the insurance system contradicts such ambitions through increased governance. Ultimately, the contradictory tendencies of cooperative initiatives and the stricter governance of sickness insurance regulations are political matters. If political attempts to promote interorganizational cooperation are to succeed, the increasing sectorization that results from strict governance of sickness insurance regulations needs to be targeted on a system level. PMID- 21274741 TI - Effects of TGF-beta and b-FGF on the potential of peripheral blood-borne stem cells and bone marrow-derived stem cells in wound healing in a murine model. AB - Peripheral blood fibrocytes make up a newly identified leukocyte subpopulation that displays fibroblast-like properties. These blood-borne cells can rapidly enter the site of injury at the same time as circulating inflammatory cells. Marrow stroma includes a subpopulation of undifferentiated cells that are capable of becoming one of a number of phenotypes, including chondrocytes, osteoblasts, adipocytes, and fibroblasts. Adult human bone marrow contains a minority population of bone marrow mesenchymal stem cells (BMSCs) that contribute to the regeneration of tissues such as bone, cartilage, muscle, ligaments, tendons, fat, and stroma. Evidence that these BMSCs are pluripotent, rather than being a mixture of committed progenitor cells each with a restricted potential, includes their rapid proliferation in culture. We hypothesized that peripheral blood mesenchymal stem cells (PBMSCs) and BMSCs have an effective role in wound healing. In this study, we identified and quantified the marrow stem cells (MSCs) derived from blood and bone marrow recruited and migrated to the wound site. Our results show that the synergistic effects of transforming growth factor-beta (TGF beta) and basic fibroblast growth factor (b-FGF) lead to a significant increase in migration and recruitment of both PBMSCs and BMSCs to the wound site, with more potent effects on PBMSCs as compared with BMSCs. Reverse transcription polymerase chain reaction of collagen type I (COL1A1) transcripts (348 bp) confirmed that TGF-beta and b-FGF activate collagen I (production in marrow stem cells at higher transcription levels), with more vigorous effects of TGF-beta on PBMSCs as compared with the same condition on BMSCs. PMID- 21274742 TI - Beneficial effect of a CXCR4 agonist in murine models of systemic inflammation. AB - The chemokine CXC receptor 4 (CXCR4) is activated by stromal cell-derived factor (SDF-1alpha). CXCR4 may be part of a lipopolysaccharide (LPS) sensing co clustering complex that modulates TLR4 activation and evidence suggest that SDF 1alpha can activate anti-inflammatory signaling pathways and suppress inflammation. In the present study we examined the hypothesis that the SDF-1alpha peptide analog and CXCR4 agonist CTCE-0214 is anti-inflammatory in three distinct models of murine systemic inflammation. Our findings demonstrate that CTCE-0214 in vivo significantly suppressed plasma tumor necrosis factor alpha (TNF-alpha) increases in acute endotoxemia and following zymosan-induced multiple organ dysfunction syndrome (MODS). In both models, CTCE-0214 did not suppress plasma increases in the anti-inflammatory cytokine interleukin (IL)-10. CTCE-0214 improved survival without antibiotics in a model of severe sepsis induced by cecal ligation and puncture (CLP). CTCE-0214 also decreased plasma increases in IL-6 but not TNF-alpha and IL-10 in response to CLP-induced inflammation. We demonstrated in a moderately severe model of CLP (one puncture) that IL-6 levels at 24 h were similar to sham controls. However in severe CLP (two punctures) plasma IL-6 levels were markedly elevated. Plasma SDF-1alpha levels varied inversely with the plasma IL-6. In addition to the beneficial effect of CTCE-0214 in these models of systemic inflammation in vivo, we also demonstrated that the analog dose dependently suppressed LPS-induced IL-6 production in bone marrow derived macrophages. CTCE-0214 therefore may be beneficial in controlling inflammation sepsis and systemic inflammatory syndromes. PMID- 21274743 TI - Effect of donor JNK signal transduction inhibition on transplant outcome in brain dead rat model. AB - Renal grafts from brain-dead donors compared to living donors have a significantly shortened survival time due to heightened renal immunogenicity. The influence of pretreatment with a JNK signal transduction inhibitor on ischemia reperfusion injury was examined in a renal transplant model using donors from a standardized rat model of brain death. Donors were treated immediately after induction of brain death with a JNK signal transduction inhibitor or saline. Kidney grafts from experimental group and control groups (saline-treated brain dead or living donor grafts) were examined serially up to 7 days post transplantation by morphology, immunohistology, and real-time PCR. JNK inhibition reduced the intensity of ischemia-reperfusion injury and acute rejection compared to saline treated donors. Likewise, cellular infiltration, mRNA transcription of some representative proinflammatory mediators and MHC-II molecules in the grafts were diminished in the JNK-inhibited donors compared to saline controls. Lewis rats transplanted with kidneys from JNK inhibited, brain-dead BN donors survived significantly longer than rats transplanted with saline treated brain-dead donors. The JNK inhibitor pretreatment of brain dead rats improved donor kidney quality, and improved graft survival. PMID- 21274744 TI - Impact of selenium on the leukotriene B4 synthesis pathway during isoproterenol induced myocardial infarction in experimental rats. AB - Selenium (Se), an essential micronutrient, exerts its biological functions through selenoproteins. There are evidences that show Se to have an impact on the course and outcome of a number of etiologically inflammatory diseases. Leukotriene B(4) (LTB(4)) is an inflammatory mediator, and its production is mediated through two specific enzymes--lipooxygenase (LOX) and leukotriene A(4) hydrolase (LTA(4)H). We examined the effect of Se on LTB(4) synthesis during isoproterenol (ISP)-induced myocardial infarction (MI) in rats. Rats were divided as: control, ISP, Se, and Se + ISP. Sodium selenite was administered at dose of 8 MUg/100 g/day. ISP was injected subcutaneously twice (10 mg/100 g body weight). The rats pretreated with Se had increased concentration of phospholipids and enhanced biosynthetic enzymes compared with that of ISP. The activities of phospholipases decreased on Se treatment. The level of calcium was increased in ISP group whereas, on Se treatment, it was near normal levels. Activities of LOX and expression of LTA(4)H were down-regulated in the case of Se-pretreated rats. Our study shows the anti-inflammatory mechanism of selenium during MI. PMID- 21274746 TI - Postural control during visual and kinesthetic motor imagery. AB - Despite the accumulating evidence supporting an interaction between cognitive functions and postural control, little is known about the selective impact of the mental representation of an action, i.e., motor imagery (MI) on postural control. As postural oscillations are reduced during a cognitive task of backward silent counting, a greater stability is also expected during MI compared to a no-task condition (standing). Twenty participants took part in this experiment, which aimed at providing evidence that MI may improve postural stability. They were requested to mentally imagine a movement while standing on a force-plate. Results showed a decrease in both path length and postural sway variability on the anterior-posterior and lateral axes during all dual-task sessions, as compared to the motionless condition. These postural adjustments might result from both central and peripheral processes, and/or increased muscle stiffness. Conversely, postural oscillation amplitude increased on the vertical axis during MI of three vertical jumps, hence suggesting that postural regulations remain task-related during MI. Finally, our data showed that kinesthetic and visual imagery differentially impacted the postural regulation. PMID- 21274745 TI - Variation in folate pathway genes and distal colorectal adenoma risk: a sigmoidoscopy-based case-control study. AB - BACKGROUND: Folate-associated one-carbon metabolism (FOCM) is an important pathway in colorectal neoplasia risk but data on genetic variation in this pathway are largely limited to studies of single SNPs in selected genes. METHODS: We used a comprehensive tagSNP approach to study the association between genetic variation in 11 genes in the FOCM pathway and risk of incident distal colorectal adenomas in a sigmoidoscopy-based case-control study. We included 655 cases (one or more adenomas) and 695 controls (no adenomas) recruited from one of two Kaiser Permanente clinics between 1991 and 1995. We assessed a total of 159 tagSNPs selected using Haploview Tagger as well as selected non-synonymous SNPs. We used unconditional logistic regression to model the association between SNPs and risk of distal adenomas, assuming a log-additive model. RESULTS: Five SNPs in the SLC19A1 (RFC1) gene: rs1051266 (G80A), rs283895, rs2236484, rs12482346, and rs2838958 were associated with adenoma risk after correction for multiple testing (all corrected p values <= 0.043). The non-synonymous SLC19A1 SNP G80A interacted significantly with the MTHFR C677T genotype (interaction p value = 0.018). CONCLUSION: Our data suggest that genetic variation in SLC19A1 may modify the risk of distal colorectal adenoma. PMID- 21274747 TI - Determination of aluminium in groundwater samples by GF-AAS, ICP-AES, ICP-MS and modelling of inorganic aluminium complexes. AB - The paper presents the results of aluminium determinations in ground water samples of the Miocene aquifer from the area of the city of Poznan (Poland). The determined aluminium content amounted from <0.0001 to 752.7 MUg L(-1). The aluminium determinations were performed using three analytical techniques: graphite furnace atomic absorption spectrometry (GF-AAS), inductively coupled plasma atomic emission spectrometry (ICP-AES) and inductively coupled plasma mass spectrometry (ICP-MS). The results of aluminium determinations in groundwater samples for particular analytical techniques were compared. The results were used to identify the ascent of ground water from the Mesozoic aquifer to the Miocene aquifer in the area of the fault graben. Using the Mineql+ program, the modelling of the occurrence of aluminium and the following aluminium complexes: hydroxy, with fluorides and sulphates was performed. The paper presents the results of aluminium determinations in ground water using different analytical techniques as well as the chemical modelling in the Mineql+ program, which was performed for the first time and which enabled the identification of aluminium complexes in the investigated samples. The study confirms the occurrence of aluminium hydroxy complexes and aluminium fluoride complexes in the analysed groundwater samples. Despite the dominance of sulphates and organic matter in the sample, major participation of the complexes with these ligands was not stated based on the modelling. PMID- 21274748 TI - Insurance and prevention: ethical aspects. AB - In recent decades, prevention policies--i.e., insurance policies constructed to give incentives to investments in prevention and thereby reduce reliance on insurance--have been much discussed both with regard to different kinds of market insurance and, albeit primarily within a European context and in relation to an ongoing discussion about the need for a shift towards an "active" welfare state, with regard to social insurance. The present contribution identifies normative issues that deserve attention in relation to a general introduction of prevention policies in market insurance and social insurance. It is argued that the importance of these normative issues suggests that arguments and distinctions drawn from moral and political philosophy should play a more prominent role both in the debate on the shift towards an active welfare state and the use of prevention policies in market insurance. PMID- 21274749 TI - Abstracts of the Society of Surgical Oncology 64th Annual Cancer Symposium. March 2-5, 2011. San Antonio, Texas, USA. PMID- 21274751 TI - Prognostic markers and staging systems for patients with colorectal liver metastases. PMID- 21274750 TI - Glioma-initiating cells and molecular pathology: implications for therapy. AB - There is now compelling evidence that gliomas harbor a small population of cells, termed glioma-initiating cells (GICs), characterized by their ability to undergo self-renewal and initiate tumorigenesis. The development of therapeutic strategies targeted toward GIC signaling may improve the treatment of malignant gliomas. The characterization of GICs provides a clue to elucidating histological heterogeneity and treatment failure. The role of the stem cell marker CD133 in the initiation and progression of brain tumors is still uncertain. Here, we review some of the signaling mechanisms involved in GIC biology, such as phosphatase and tensin homolog (PTEN), sonic hedgehog, Notch, and WNT signaling pathways, maternal embryonic leucine-zipper kinase (MELK), BMI1, and Janus kinase signal transducer and activator of transcription (JAK-STAT) signaling. In addition, we discuss the role of microRNAs in GICs by focusing on microRNA-21 regulation by type I interferon. PMID- 21274753 TI - Gene mutations and prognostic factors analysis in extragastrointestinal stromal tumor of a Chinese three-center study. AB - BACKGROUND: Most gastrointestinal stromal tumors (GISTs) have gain-of-function mutation of the c-kit gene, and some have mutation of the platelet-derived growth factor receptor-alpha (PDGFR-alpha) gene. Extragastrointestinal stromal tumors (EGISTs) are mesenchymal tumors that occur outside the digestive tract. But the clinicopathologic characteristics of EGISTs are still poorly understood. METHODS: Paraffin-embedded tissues from 25 cases of EGIST were analyzed for CD117, CD34, Ki-67, S-100, smooth muscle actin, and desmin expression by immunohistochemical method. These cases of EGISTs were also evaluated for the presence of c-kit exons 9, 11, 13, and 17 mutations and PDGFR-alpha exons 12 and 18 mutations. Survival analysis was used to evaluate the prognostic factors. RESULTS: c-kit mutations were detected in 44% of EGIST patients and all were exon 11 mutations. PDGFR alpha mutations were found in 12% of the 25 cases and all were exon 18 mutations. Survival analysis indicated that mitotic count and Ki-67 labeling index (Ki-67 LI) were significant predictors of survival. CONCLUSION: The pattern of c-kit and PDGFR-alpha mutation in EGISTs was essentially similar to that in GISTs. From the molecular genetics aspect, EGISTs may be a special subtype of GISTs. The results also show that the combination of mitotic counts and Ki-67 LI may be useful for predicting the prognosis of EGISTs. PMID- 21274754 TI - Activation of AMP-activated protein kinase contributes to doxorubicin-induced cell death and apoptosis in cultured myocardial H9c2 cells. AB - Despite its potent antitumor effect, clinical use of Doxorubicin is limited because of serious side effects including myocardial toxicity. Understanding the cellular mechanism involved in this process in a better manner is beneficial for optimizing Doxorubicin treatment. In the current study, the authors focus on the AMP-activated protein kinase (AMPK) in the said process. In this study, the authors discovered for the first time that Doxorubicin induces AMPK activation in cultured rat embryonic ventricular myocardial H9c2 cells. Reactive oxygen species (ROS)-dependent LKB1 activation serves as the upstream signal for AMPK activation by Doxorubicin. Evidence in support of the activation of AMPK contributing to Doxorubicin-induced H9c2 cell death/apoptosis--probably by modulating multiple downstream signal targets, including regulating JNK, p53, and inhibiting mTORC1- is provided in this article. PMID- 21274755 TI - Cell signaling of angiotensin II on vascular tone: novel mechanisms. AB - Angiotensin II (Ang II) is a pleiotropic hormone that influences the function of many cell types and regulates many organ systems. In the cardiovascular system, it is a potent vasoconstrictor that increases peripheral vascular resistance and elevates arterial pressure. It also promotes inflammation, hypertrophy, and fibrosis, which are important in vascular remodeling in cardiovascular diseases. The diverse actions of Ang II are mediated via AT(1) and AT(2) receptors, which couple to many signaling molecules, including small G proteins, phospholipases, mitogen-activated protein (MAP) kinases, phosphatases, tyrosine kinases, NADPH oxidase, and transcription factors. In general, acute Ang II stimulation induces vasoconstriction through changes in the intracellular free calcium concentration [Ca(2+)](i), whereas long-term stimulation leads to cell proliferation and proinflammatory responses. This review focuses on signaling processes of vasoconstriction and highlights some new mechanisms regulating the contractile machinery in controlling vasomotor tone by Ang II, including RhoA/Rho kinase, transient receptor potential (TRP) channels, reactive oxygen species, and arachidonic acid metabolites. PMID- 21274756 TI - Metabolic syndrome, androgens, and hypertension. AB - Obesity is one of the constellation of factors that make up the definition of the metabolic syndrome. Metabolic syndrome is also associated with insulin resistance, dyslipidemia, hypertriglyceridemia, and type 2 diabetes mellitus. The presence of obesity and metabolic syndrome in men and women is also associated with increased risk of cardiovascular disease and hypertension. In men, obesity and metabolic syndrome are associated with reductions in testosterone levels. In women, obesity and metabolic syndrome are associated with increases in androgen levels. In men, reductions in androgen levels are associated with inflammation, and androgen supplements reduce inflammation. In women, increases in androgens are associated with increases in inflammatory cytokines, and reducing androgens reduces inflammation. This review discusses the possibility that the effects of androgens on metabolic syndrome and its sequelae may differ between males and females. PMID- 21274757 TI - The role of C-reactive protein as a risk predictor of coronary atherosclerosis: implications from the JUPITER trial. AB - Much controversy surrounds the use of high-sensitivity C-reactive protein (hs CRP) as a marker of cardiovascular (CV) risk. Although data regarding the association of hs-CRP with CV disease is extensive and consistent, its role in clinical practice remains unclear. The American Heart Association (AHA) recently published a scientific statement regarding criteria for evaluation of novel markers of CV risk. This article provides a comprehensive review of data regarding hs-CRP as a risk marker for CV disease in the context of these AHA criteria. The impact of the JUPITER trial on the utility of hs-CRP as a risk marker is emphasized. The review concludes with an evidence-based statement regarding the current role of hs-CRP in CV risk prediction. PMID- 21274758 TI - Treatment of diabetic sensory polyneuropathy. AB - OPINION STATEMENT: No current disease-modifying treatments have been shown definitively in randomized clinical trials to reduce or reverse diabetic sensory polyneuropathy (DSP). It is increasingly recognized that individuals with "prediabetes" or impaired glucose regulation can already have a "small-fiber" neuropathy, or mild DSP, in which sensory axons of both small and larger diameter are damaged. Small-fiber neuropathy is frequently associated with pain, and these patients may present to a neurologist for evaluation before the underlying glucose dysregulation has been diagnosed. It is important to identify these individuals, because aggressive diabetic control and lifestyle interventions can delay the onset of diabetes and may reverse small-fiber neuropathy associated with early diabetes mellitus. Although treatment currently focuses on pain associated with DSP, attention should be paid to potential risk factors for neuropathy. For example, glycemic control and hyperlipidemia should be improved with diet, exercise, and medications. Hypertension that is a risk marker for more severe neuropathy should be treated. Angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers not only treat hypertension but also may directly reduce the progression of neuropathy. Class I or II clinical studies support the use of sodium valproate, pregabalin, duloxetine, amitriptyline, gabapentin, venlafaxine, opioids, and topical capsaicin in treating diabetic neuropathic pain. Pregabalin and gabapentin are relatively well tolerated and have few medication interactions. Sodium valproate has been shown to be effective but is not recommended for use in women of childbearing potential, and patients must be monitored for hepatotoxicity and thrombocytopenia. Tricyclic antidepressants such as amitriptyline are often used for nocturnal pain but require caution in the elderly or anyone with cardiac disease. Venlafaxine and duloxetine successfully treat neuropathic pain independently of their effect on depression. Opioid medications are associated with a high rate of adverse effects but with careful monitoring, they can be effective in treating resistant neuropathic pain. Capsaicin is an effective topical treatment that lacks systemic side effects. The lidocaine patch is effective in relieving pain associated with postherpetic neuralgia, but only class III evidence supports its use for diabetic neuropathic pain. No current Class I or II studies support other treatment modalities. PMID- 21274759 TI - Can computed tomography predict hip stability in posterior wall acetabular fractures? AB - BACKGROUND: In a pilot study, two-dimensional (2-D) CT assessment of posterior wall fracture fragments predicted hip stability with small fracture fragments and instability for large fracture fragments. QUESTIONS/PURPOSES: To confirm the previous findings, we determined whether there is sufficient observer consistency and accuracy to predict hip stability in posterior wall acetabular fractures for this CT assessment method and assessed its ease of clinical use. METHODS: We selected 10 fractures having variable characteristics with known clinical outcome and created three study participant groups, based on level of training, for evaluation. Each observer reviewed the CT scans from the 10 fractures and applied the method in two separate sessions, the second after at least a 1-month washout period. RESULTS: Participants reported subjective ease in using the method, averaging 5 minutes (range, 3-11 minutes) for each assessment. Intraobserver and interobserver reliability were both greater than 0.80 regardless of the level of experience. Although sensitivity was 90%, specificity was only 61% after comparison with examination under anesthesia (EUA). Inappropriate nonoperative treatment would have occurred in 6% of cases and inappropriate operative treatment in 16%. CONCLUSIONS: This method for assessing hip instability is reliable, reproducible, and easy to learn and use. However, as a diagnostic tool in the clinical setting, it is useful only for fractures involving greater than 50% of the posterior wall owing to limited accuracy. For fractures less than 50%, EUA should be performed to determine hip stability. PMID- 21274761 TI - Surgical technique: modern Luque trolley, a self-growing rod technique. AB - BACKGROUND: The challenge when managing early-onset scoliosis (EOS) is to prevent curve progression while maintaining spinal growth. Current surgical treatments (growing rods, VEPTR) require repetitive interventions to lengthen the implants. QUESTIONS/PURPOSES: We asked whether a modern Luque trolley construct could achieve and maintain scoliosis correction in EOS during spinal growth without the need for repetitive surgeries, thus decreasing the morbidity of the surgical treatment. METHODS: We retrospectively reviewed five patients who underwent a modern Luque trolley construct between 2003 and 2008. This construct consists of inserting apical gliding spinal anchors using muscle-sparing techniques to the proximal and distal fixed anchors found in the dual growing rod construct. We documented age at surgery, correction and maintenance of deformity, spinal growth, number of procedures, and complications. RESULTS: The primary curve was corrected from 60 degrees to 21 degrees and was maintained at 21 degrees at a minimum followup of 2 years (mean, 4 years; range, 2-5.5 years). An average of 10 vertebrae was spanned allowing the spine to grow a mean of 3 cm over 4 years, representing a mean of 77% of the expected growth. Two of the five cases outgrew the construct requiring lengthening of rods. One patient had gradual recurrence of deformity without substantial axial growth that required revision surgery after 4 years. CONCLUSION: Modifications of the Luque trolley may be useful for managing EOS without the morbidity of repetitive surgery. However, questions such as the effect of wear debris and the risk of spontaneous fusions still remain. PMID- 21274760 TI - Whole bone mechanics and bone quality. AB - BACKGROUND: The skeleton plays a critical structural role in bearing functional loads, and failure to do so results in fracture. As we evaluate new therapeutics and consider treatments to prevent skeletal fractures, understanding the basic mechanics underlying whole bone testing and the key principles and characteristics contributing to the structural strength of a bone is critical. QUESTIONS/PURPOSES: We therefore asked: (1) How are whole bone mechanical tests performed and what are the key outcomes measured? (2) How do the intrinsic characteristics of bone tissue contribute to the mechanical properties of a whole bone? (3) What are the effects of extrinsic characteristics on whole bone mechanical behavior? (4) Do environmental factors affect whole bone mechanical properties? METHODS: We conducted a PubMed search using specific search terms and limiting our included articles to those related to in vitro testing of whole bones. Basic solid mechanics concepts are summarized in the context of whole bone testing and the determinants of whole bone behavior. RESULTS: Whole bone mechanical tests measure structural stiffness and strength from load-deformation data. Whole bone stiffness and strength are a function of total bone mass and the tissue geometric distribution and material properties. Age, sex, genetics, diet, and activity contribute to bone structural performance and affect the incidence of skeletal fractures. CONCLUSIONS: Understanding and preventing skeletal fractures is clinically important. Laboratory tests of whole bone strength are currently the only measures for in vivo fracture prediction. In the future, combined imaging and engineering models may be able to predict whole bone strength noninvasively. PMID- 21274763 TI - Nonaccidental trauma in children: editorial comment. PMID- 21274762 TI - A squeaky reputation: the problem may be design-dependent. AB - BACKGROUND: Squeaking is reportedly a complication in patients having ceramic-on ceramic total hip implants. The etiology remains unknown and multifactorial with recent studies suggesting a relationship between the audible squeak and implant design. When we evaluated our ceramic-on-ceramic cohort, we noticed squeaking primarily in patients receiving an acetabular system designed with an elevated titanium rim. OBJECTIVES/PURPOSES: We therefore (1) determined the incidence of squeaking among four different ceramic-on-ceramic bearing surfaces used for THA at our institution; (2) evaluated the association between different acetabular designs and the incidence of squeaking; and (3) assessed other potential variables associated with squeaking. METHODS: We retrospectively reviewed 1507 patients having a ceramic-on-ceramic THA between 2002 and 2009; we separately analyzed those receiving an acetabular system with and without an elevated titanium rim. Data were collected through phone-administered questionnaires and retrospective reviews of patient charts for intraoperative findings, followup reports, demographic information, and radiographic findings. RESULTS: Squeaking occurred in 92 of the 1507 patients (6%). All 92 patients with squeaking received an elevated rim design (1291 patients) or an incidence of 7% with that design. We found no association between squeaking and any other examined factors. CONCLUSION: Our findings complement the theory from in vitro studies suggesting that neck impingement on the elevated titanium rim is the probable cause of the increased frequency of squeaking with this design. PMID- 21274764 TI - The effects of dimensional naming upon children's performance in a modified optional shift problem. AB - In a modified optional shift paradigm, shift and test tasks were administered concurrently to 120 second-grade children. Ss required, during shift learning, to verbalize the values of the previously relevant dimension showed an increase in reversal responding in the test task, whereas those required to verbalize the values of the previously irrelevant dimension showed an increase in nonreversal responding. The results are in good agreement with predictions made from an extension of Hull-Spence discrimination learning theory. PMID- 21274765 TI - A propositional theory of recognition memory. AB - This paper modifies the Anderson and Bower (1972) theory of recognition memory for words. A propositional representation is outlined for the contextual information underlying word recognition. Logical arguments are offered for preferring this representation over the undifferentiated associative representation used earlier. The propositional representation is used to interpret effects of verbal context upon recognition memory. The implications of these context effects are considered for two-process models of recall and recognition. PMID- 21274766 TI - Semantic memory: Searching for attributes vs searching for names. AB - The purpose of this experiment was to determine whether searching for a word that has a particular attribute (a fruit that is yellow) involves a different process than searching for a word whose name has a particular form (a fruit whose name begins with "p"). Ss saw category nouns paired with adjectives or letter restrictors presented on a series of blocked trials and a series of mixed trials. The Ss had to produce a word that fell in the space defined by the noun and the restricting adjective or letter. RT was fastest when trials were blocked and when a letter followed the presentation of the noun. This finding suggested the existence of two retrieval plans that can be executed when S has knowledge of the forthcoming type of item. PMID- 21274767 TI - Central processing uncertainty as a determinant of choice reaction time. AB - It was demonstrated that central processing uncertainty (Hc) can be derived to provide a single valued statement of the information hypothesis RT=a+b (Hc) across test stimulus sets and across several levels of test stimulus probability in an information reduction task. The derivation procedure assumes successive tests of stimulus hypotheses with Bayesian revision of stimulus probabilities after failure of an initial test. It was shown that the procedure can be generalized to data from single test stimuli in an information conservation task. Stimulus and response repetition effects were estimated for the information reduction task data. PMID- 21274768 TI - Presentation modality, rehearsal-prevention conditions, and auditory confusions in tests of short-term memory. AB - Ss were presented four-letter sequences either auditorily or visually and asked for ordered recall after 0, 2.1, 4.2, 8.4, or 12.6 sec of digit categorization. Three different rehearsal-prevention conditions were required during presentation of the memory set: categorizing, suppressing (saying "dah"), or pronouncing each letter. Recall was worst after categorizing, best after pronouncing. Auditory presentation led to better recall after no delay but more rapid forgetting than visual presentation, regardless of the rehearsal-prevention condition. These results, and analyses of auditory confusions, are inconsistent with a view of memory which asserts that sensory information is encoded auditorily regardless of presentation modality or vocalization behavior during presentation. PMID- 21274769 TI - Visual signal detection and the locus of foreperiod effects. AB - The effect of alertness on S's sensitivity to external signals was determined by varying the foreperiod in a visual signal detection task. Discriminability increased with increasing foreperiods up to an optimal foreperiod, beyond which it decreased slightly. This pattern of results parallels closely that of many foreperiod studies in which reaction time was the dependent variable. Because no speeded response was required in this signal detection task, it was concluded that alertness must be affecting an information processing stage prior to those associated with responding. Other evidence indicates that alertness does not affect sensory stages either. Alertness, by elimination, must be affecting the operation of a central stage, Posner's view of alertness which implicates the central stages is discussed. PMID- 21274770 TI - The effect ofsome andall on reaction time for semantic decisions. AB - Two experiments tested a model proposed by Meyer (1970) to account for the times required to verify semantic-memory statements quantified byall orsome. Each S was presented with bothall andsome statements in a mixed list, and the discriminability of false statements of the two quantifier types was controlled. In Experiment I positive subset statements ("horses are animals") were verified more quickly when quantified byall rather thansome; the reverse ordering occurred for negative subset statements ("horses are not animals"). Sentences with pseudowords in subject or predicate position took longer to reject than false real-word sentences. These findings contradict :Meyer's theoretical predictions and suggest that his earlier results were artifactual. Experiment II replicated the faster verification of positive subset statements quantified byall. This result was further shown to be predictable from the frequency with which Ss gave the predicate as a completion ofAll/Some S are _. The production frequency of predicates which form subset statements was lower when the quantifier wassome rather thanall. However, holding predicate production frequency constant, sentences with different quantifiers were verified equally quickly. PMID- 21274771 TI - Scanning temporally structured lists: Evidence for dual retrieval processes. AB - Ss were presented with lists of memory items containing one temporal pause. After each list, Ss were asked to classify a test item as positive or negative based on the memory information. In Experiments I and II, the test item was to be classified as positive if it occurred in the memory set at all, and mean reaction times for the decision were longer than for a no-pause control. In Experiment III, a positive response was required provided that the test item was in a relevant portion of the list as defined by a postlist cue. Reaction times were longer and showed a somewhat different pattern than for a no-pause control. An interpretation was offered based on the hypothetical existence of two simultaneously executed serial scans, one "exhaustive" and the other "self terminating," as defined by S. Sternberg. PMID- 21274772 TI - The function of one-word mediators in the recall of word pairs. AB - The problem of demonstrating that natural language mediators play a role in learning and are not epiphenomena resulting from learning is an important problem in cognitive learning theories. Using a cued-recall and a free-recall learning task, Ss were requested to add a one-word mediator to some of the pairs of concrete nouns presented, The mediated pairs were learned better than the control pairs in both tasks. Both words were recalled only when the mediator was also recalled. Also, one-word mediators were the most effective recall cues and were the best recalled words in free recall. A two-stage learning model adequately described the data. However, a counterargument can be made which considers the mediator to be a high associate of one of the words presented and actually has no direct link to the other presented word. A possible experimental resolution of the problem is discussed. PMID- 21274773 TI - Relative frequency of attribute relevance and response times in visual search. AB - Two experiments, one using a between-Ss and one a within-Ss design, showed that response latencies to single attribute probe stimuli were longer when the target stimulus embodied two attributes (form and color) rather than a single attribute. The magnitude of this "mixed attribute effect" was influenced by the probability of attribute relevance, but the "probability effect" was mostly due to a "repetition effect," such that latencies on trials involving repetitions of the same attribute were shorter than when the relevant attribute was shifted. Implications of these results are drawn for the issues of holistic vs attributized representation of the target stimulus and serial vs parallel search of a set of attributes. Although no class of models can be ruled out on the basis of these experiments, constraints can be imposed on the versions of each that are compatible with the data presented. PMID- 21274774 TI - Stimulus selection and the number of stimulus components. AB - The number of word components in the compound stimuli of paired-associate lists were varied, and the words within a compound were presented either in a constant or in a variable order from trial to trial. The number of components, above one, had no appreciable effect on the difficulty of learning, and the variable order lists were more difficult than the constant order. Recall with the word components as cues showed that the amount of selection decreased with the variable order lists as the number of components increased. With the constant order lists, selection tended to remain constant as number of components increased. This was interpreted as the result of the availability of a rule for selection in the constant order conditions. PMID- 21274775 TI - The influence of one memory retrieval on a subsequent memory retrieval. AB - Ss produced an instance of a category and following zero or two intervening items produced a second instance of the same category. The second instance was produced more quickly than the initial instance. This finding, in conjunction with other data reported in the paper, indicate that the reduction in latency for the second instance is due mostly to a reduction in the rate with which the category is searched. PMID- 21274776 TI - The assessment of discriminative encoding in memory for paired associates. AB - A technique for providing for the measurement of encoding stability and intralist stimulus discrimination is presented and applied to the analysis of some paired associate data. Essentially, the measure involves a recall test for all stimuli in the list except one, then presenting either a previously tested stimulus or the missing stimulus. Recognition of repeated stimuli reflects code stability, and recognition of the missing stimulus reflects stimulus discrimination. PMID- 21274777 TI - Using semantic memory to find vs create a mood. AB - Ss produced words from semantic memory which satisfied certain constraints. In Experiment I, a noun category plus a number and a letter were presented (e.g., ANIMAL-I-D, FRUIT-P-3), and S produced an instance of the category which had the given letter in the position designated by the given number. Faster responses occurred when the position cue occurred before the letter rather than after it. In Experiments II and III, Ss saw only a number and a letter (e.g., l-D, P-3) and were required to produce any word that had the given letter in the position designated by the given number. Order of the position and letter cues did not influence response times. The effect of order in one case and not the other strongly suggests that producing a word that satisfies certain semantic constraints involves a different process from producing a word that satisfies only certain orthographic restrictions. PMID- 21274778 TI - The anatomy of free recall. AB - The relative importance of various covert cues used in free recall is inferred on the basis of conditional probabilities of free recall given success vs failure of cued recall of the same material. Thirty-six names associated with pictures arranged in a 6 by 6 matrix were learned. A free recall test of names was followed by cued recall of names, with pictures, positions, or joint pictures and positions used as cues. Matching tests based on these cues were also administered. The tests were given at one of two stages of training, immediately or after 2 days. Pictorial and position cues are equally well encoded, but pictorial cues are less accessible and, therefore, relatively more useful in cued recall than in free recall. Position and pictorial information related to the names appears to be encoded and forgotten independently, and there is no evidence for summation of subthreshold encoding effect. PMID- 21274779 TI - Cognition of the relation between an event and a circumstance understood to explain the event. AB - A model is advanced for the process of explanation, according to which (a) an event to be explained is understood to be a value on a particular dimension of variation; (b) a circumstance believed to explain the event is understood to be a value on another dimension of variation; (c) the two dimensions are understood to be related such that the dimension whose value is to be explained is more likely to take that value when the dimension of circumstance takes its obtaining value than when the dimension of circumstance takes an alternative value. Evidence for the model is reported from a study in which Ss made two judgments about a human action-wchich of two statements of circumstance specifying alternative values for a certain dimension was the better explanation for the action, and which of the same two statements described the case in which the action, or for certain items the opposite action, was more likely to occur. For each of five different actions, the judgments were significantly related as required by the model. PMID- 21274780 TI - The cross-situational validity of risk as a value. AB - Demand characteristics and risk are confounded on the choice dilemma items. Thus, it is difficult using that instrument to determine if individuals view themselves as more risky than others because of a cultural value of risk or instructional demand characteristics. The present study asked Ss to make judgments for themselves and for others on either the choice dilemmas (with risk-oriented or risk-neutral instructions) or on one of three other measures of risk taking (behavior prediction scale, risk of aversive consequences, zero expected value bets) which have exhibited the risky shift but do not have the instructional problems of the choice dilemmas. Only on the choice dilemmas did Ss view themselves as being more risky. On all other measures, Ss viewed themselves as either equal to or more conservative than others. These findings cast doubt on the validity of value type theories as general explanations for the risky shift. PMID- 21274781 TI - Response set effects in recognition memory. AB - In three experiments, Ss responded to individual digits or letters according to whether or not each was in some prememorized list. There were either two possible responses (yes-no condition) or a single response (yes-only and no-only conditions). With memory sets of one, two, or four digits, RT was a linear function of memory set size. The slope of the function was least under the yes only condition and greatest under the yes-no condition. Nonspecific practice had little effect on any of the slopes. With memory sets of 4, 8, or 12 letters, the slopes under the yes-only and yes-no conditions did not seem to differ, and practice with specific sets flattened the function considerably in both cases. Overall, the errors under the yes-no condition were mostly false alarms, those under the no-only condition mostly misses, and those under the yes-no condition were divided about equally. The results are interpreted partially in terms of a multiple-observations model of decision time. PMID- 21274782 TI - Interference in memory for multiple contexts. AB - Remembering that an item occurred in several different lists is formulated here in terms of retrieval of corresponding list tags associated to the item. Therefore, associative interference should operate upon remembering the several list contexts in which an item appeared. Experimental Ss studied four (or five) overlapping lists of 16 words, sampled from a master set of 32 words, with a given word exemplifying one of the 2 4 (or 2s 5 ) possible sequences of appearances and nonappearances over the four (or five) lists. Later Ss rated from memory for each word and for each list whether that word had occurred in that list. After correcting for interlist generalization effects, indices of discriminative memory revealed strong proactive interference and weaker retroactive interference. Discriminative memory that an item occurred in a given list was poorer the more prior or more subsequent lists in which that item had also occurred. Thus, list differentiation appears explicable in terms of item specific associative interference. PMID- 21274783 TI - Pictures and words in visual search. AB - Ss in three experiments searched through an array of pictures or words for a target item that had been presented as a picture or a word. In Experiments I and II, the pictures were line drawings of familiar objects and the words were their printed labels; in Experiment III, the stimuli were photographs of the faces of famous people and their corresponding printed names. Search times in Experiments I and II were consistently faster when the array items were pictures than when they were words, regardless of the mode of the target items. Search was also faster with pictures than with words as targets when the search array also consisted of pictures, but target mode had no consistent effect with words as array items. Experiment III yielded a completely different pattern of results: Search time with names as targets and faces as search array items was significantly slower than in the other three conditions, which did not differ from each other. Considered in relation to several theories, the results are most consistent with a dual-coding interpretation. That is, items that are cognitively represented both verbally and as nonverbal images can be searched and compared in either mode, depending on the demands of the task. The mode actually used depends on whether the search must be conducted through an array of pictures or words. PMID- 21274784 TI - Speed-accuracy tradeoff in double stimulation: Effects on the first response. AB - A single-stimulation and two double-stimulation response conditions were compared using explicit payoff matrices to vary speed-accuracy tradeoff. Under accuracy payoff, response latency (RT(1)) to the first stimulus increased as ISI dropped but accuracy remained high and relatively constant. Under speed payoff, RT(1) was only slightly affected by ISI but accuracy dropped as ISI decreased. Transmitted information rates consistently reflected detrimental effects of short ISI. In double stimulation, but not in single stimulation, error response latency exceeded correct response latency. Furthermore, error response latencies were found to be far more variable and more sensitive to changes in speed-accuracy condition than were correct response latencies. Finally, under both speed and accuracy conditions, response latency to the first of two successive stimuli was faster if a response was also required to the second stimulus. Implications of the data for possible models of double-stimulation speed-accuracy tradeoff are considered. PMID- 21274785 TI - Incorporating quantitative information into a linear ordering. AB - Ss were required to learn linear orderings of four terms (A > B > C > D). Each pair of terms was described as being either "just barely," "moderately," or "very much" different on some meaningful dimension. Two distinct strategies for coding this information were observed. Some Ss varied the spacing of the terms along some continuum (e.g., A_B___C_____D), while others spaced the terms evenly along a continuum and inserted verbal tags to represent the quantitative information (e.g., A just barely B moderately C very much D). The former strategy was consistently found to be superior. Performance did not vary as a function of the quantitative difference between the terms. PMID- 21274786 TI - Determinants of perceived choice, number of options, and perceived time in making a selection. AB - An experiment was conducted to investigate the effects of number of choice options and perceived time taken to make a selection upon perceived choice. College students were asked to make a selection from a set of options which varied in numerosity; after making their selection, they were given information which varied their perception of time in making the selection. As predicted, perceived choice was found to be greater (1) the greater the number of options when a person perceived that he had taken a relatively short time; (2) if the selection involved a moderately large number of options than if it involved either a small or a very large number when a person perceived that he had taken a relatively long time; (3) the longer the time a person thought he had taken, except when the selection involved a very large number of options-in which case, perceived choice was greater the shorter the perceived time. The experiment also provided evidence about the relationship between perceived choice and perceived competence. PMID- 21274787 TI - Acquisition of information from rapidly presented verbal and nonverbal stimuli. AB - Two experiments tested recognition memory for rapidly presented stimuli. In Experiment I 16 words were presented at exposure times ranging from 25 to 500 msec followed by a yes-no recognition test. The results showed a strong dependence of memory performance on both exposure time and serial position. In Experiment II 16 random forms were presented at exposure times ranging from 125 to 2000 msec followed by a yes-no recognition test. Results for random forms showed that memory performance was strongly dependent on exposure time but not on serial position. Taken together, the results of Experiments I and II suggest qualitative encoding differences between verbal vs nonverbal stimuli. PMID- 21274788 TI - Learning conceptual rules: III. Processes contributing to rule difficulty. AB - Eight unique bidimensional conceptual rule forms were compared in a rule learning paradigm. It was predicted that rule difficulty order and error distributions across stimulus class defined by a truth table would be a function of Ss' preexperimental experience predominantly with conjunctive concepts. The hypothesis stated specifically that loci of difficulty with rules derive from: (a) assignment of TT stimuli (those with both relevant attributes) to the negative category; (b) assignment of FF stimuli (those with neither relevant attributes) to the positive category; (c) assignment of TT and FF stimuli to the same category. The main effects of rule and truth table class and the interaction of rule and truth table class were statistically significant. The results confirm all predictions about rule order and error distributions. PMID- 21274789 TI - Processing strategies in picture-sentence verification tasks. AB - The encoding and comparison strategies used by observers in matching pictures and sentences were investigated. The location of the mismatch or difference between a sentence and a picture was varied, and the latencies of "same"-"different" responses were compared as a function of whether the mismatch occurred in the sentence subject, verb, or object. Sentences were presented auditorily and varied in both voice and reversibility. Pictures either preceded or were presented simultaneously with the sentences. In all cases, Ss adopted a serial self terminating comparison strategy and a surface structure encoding strategy: The comparison was terminated as soon as a mismatch was encountered, and actives were processed in the order subject-verb-object, whereas passives were processed in the order object-verb-subject. PMID- 21274790 TI - Impression order effects as a function of the personal relevance of the object of description. AB - The influence of different target stimuli on impression order effects was tested. Sixty Ss evaluated bivalent sets of personality trait adjectives which purportedly described a hypothetical stranger, the E, or the Ss themselves. Under unwarned recall conditions, variations in the object of description significantly influenced impression order effects (p < .01). It was suggested that this effect may have been a function of attention decrements and implicit evaluations associated with various levels of personal relevance of the impression formation task. Analyses of adjective recall supported the verbal memory hypothesis of impression formation for only the LH sets in the forewarned recall condition. Recall analyses, however, suggested the importance of recall measurement criteria used in tests of the verbal memory hypothesis. PMID- 21274791 TI - The solution of anagrams: A reexamination of the effects of transition letter probabilities, letter moves, and word frequency on anagram difficulty. AB - Word frequency (WF), number of letter moves, and solution word transition letter probabilities (TP) were related to anagram solution. The solution word TP measure was based on the relative frequencies of correct to incorrect bigrams within the pool of bigrams defined by the letters of the anagram rather than on the absolute frequencies of the correct bigrams. This bigram rank measure, which also took word length and letter position into account, was a powerful predictor of anagram difficulty (p < .001). Likewise, number of letter moves predicted anagram solution strongly (p < .001), but WF was only a marginal predictor (.05 < p < .10). In addition, there were no significant interactions among the three variables, nor wasanagram TP consistently related to anagram difficulty. The results were interpreted in terms of an approach which combined elements of an hypothesis and an S-R mediational theory. PMID- 21274792 TI - On the predictor variable for choice reaction time. AB - A survey of published research using the Sternberg task was made for the period 1966 to early 1973. A majority of the data are better described by a linear equation involving log positive set size than by one involving set size per se as the scale of the predictor variable. PMID- 21274793 TI - The effects of formal and acoustic repetition in the Brown-Peterson paradigm. AB - On a given trial in the Peterson and Peterson paradigm, the trigram B, K, T was presented. For one group this same trigram had been presented three trials earlier (exact repetition). For another group the critical item which had preceded the consonant trigram was BEE, KAY, TEA (homophonic repetition). Both groups showed a repetition facilitation significant beyond that of the appropriate control groups. The exact repetition group excelled the homophonic repetition group. Postexperimental questionnaires on awareness of the experimental manipulation did not precisely clarify the results obtained. The data support the view of multiple encoding. PMID- 21274794 TI - Recognition and recall by children and adults as a function of variations in memory encoding instructions. AB - In four experiments Ss were instructed to learn a set of 40 words by producing implicit associative responses to each item (association instructions), by repeating items over and over (repetition instruction), or by using their own devices (neutral instructions). Experiment I showed that recognition memory (RM) accuracy was greatest under association instructions for adults and children and least under repetition instructions for children. The implications of these results for a frequency theory analysis for RM were discussed. Experiments II, III, and IV examined free recall (FR) as a function of encoding instructions at short (1 min) and long (either 90 min or 24 h) retention intervals. FR was worst under repetition instructions, with little overall difference between the association and neutral conditions. However, in Experiments III and IV, using school children, the neutral condition exceeded the others in FR after 90 min but not after 1 min. PMID- 21274795 TI - Mental operations on number symbols by children. AB - Children 4 to 6 years of age made choices among colors that had been associated with numbers. Prior to learning four number-color associations, pretraining on counting and ordering objects was given to half of the Ss. Associations were established by either absolute (paired associate) or relative (choice discrimination) methods, and then tests involving "more or less" questions on each of the possible six color pairs were given. Numerical associations were acquired best with absolute training or counting-ordering pretraining. Using the children's justifications for their responses, the test data were fit by Estes's (1966) scanning model; a response strength model based on Luce's (1959) axiom failed. Young children apparently possess an ordered numerical scale, can map this scale onto other nonquantitative symbols, and can generate, compare, and make ordinal decisions using these symbols. PMID- 21274796 TI - Mechanisms of aural encoding: VIII. Phonetic interference and context-sensitive coding in short-term memory. AB - In previous experiments Ss were presented for ordered recall with sequences of five consonant phonemes paired with /a/ in which the middle three consonant phonemes shared the same manner of articulation (voiced, unvoiced, nasal), the same place of articulation (front, middle, back), or neither the same manner nor place of articulation (control sequences). Compared to performance in control sequences, the middle consonant phoneme was always more difficult to recall in manner of articulation sequences but not in place of articulation sequences. The results suggested that for these sequences consonant phonemes were not remembered in terms of their place of articulation. In the present experiment, sequences of consonant-vowel (CV) or vowel-consonant (VC) syllables were presented for recall in which each consonant phoneme was paired with a different vowel. When consonant phonemes in the different sequence types were presented for recall with different vowels, phonetic interference was observed for the middle consonant in place of articulation sequences as well as manner of articulation sequences, and the effect was observed in both CV and VC groups. It was suggested that vowels are encoded in short-term memory in terms of their place of articulation and that presenting consonant phonemes for recall with different vowels caused Ss to use this dimension to code consonant phonemes in short-term memory. PMID- 21274798 TI - Naive misconceptions of Cooke and Breedin's research: response to Ranney. AB - In this paper, we respond to Ranney's (1994) comment on our paper on naive physics (Cooke & Breedin, 1994). In his comment, Ranney criticizes our methods and analyses, as well as our claims of theoretical inconsistency. In response to Ranney, we show that mast of his criticisms can be traced to several misconceptions. Some of these misconceptions seem to stem from his drawing of inappropriate similarities between his own research and ours. Specifically, ftanney seems to hall faun' misconceptions about our research: (1) the belief that trajectory responses in our study were relevant to our claims about theoretical consistency, (2) tie belief that aggregation of theoretical variations weakens claims of inconsistency, (3) the belief that the method of written reports is inferior to the method of structured interviews, and (4) the belief that our proposal of on-the-fly theorizing is at odds with temporal consistency and nonimpetus beliefs. PMID- 21274799 TI - Editor's comments. PMID- 21274806 TI - Residential satisfaction as an intervening variable in residential mobility. AB - The stress-threshold model (Wolpert, 1965; Brown and Moore, 1970) assumes that people do not consider moving unless they experience residential stress. This paper develops a similar model of residential mobility in which residential satisfaction acts as an intervening variable between individual and residence variables and mobility. The model is tested with data from a panel study of Rhode Island residents. The results indicate that residential satisfaction at the first interview is related to the wish to move and to mobility in the year following the interview. Individual and residence characteristics such as age of head duration of residence, home ownership, and room crowding are shown to affect mobility through their effect on residential satisfaction. PMID- 21274807 TI - Effect on unwanted fertility of extending physician-administered birth control in the United States. AB - A goal of publicly subsidized family planning programs in the United States is to prevent unwanted births, and the primary means being used to achieve this goal is to increase coverage with physician-administered contraception, with priority being given to persons from low-income families. We analyzed data from families living in low-income neighborhoods to determine whether that means would contribute to that goal, and if so, how much unwanted fertility might be decreased through increased coverage with physician-administered methods.The results indicate that increased coverage with those methods would decrease unwanted fertility by 80 percent (79 percent among blacks, 83 percent among whites). Increasing the ratio of sterilization to pill and IUD makes the effect of the increased coverage even more dramatic. PMID- 21274808 TI - The bogue-palmore technique for estimating direct fertility measures from indirect indicators as applied to Tennessee counties, 1960 and 1970. AB - Bogue and Palmore's technique for estimating direct fertility measures from indirect indicators IS applied to the 95 counties of Tennessee 1960 and 1970. Findings based on these data tentatively suggest that this technique may be better suited for cross-national research than for analysis of small population units. It is recommended that the "own child" method is more appropriate for estimating fertility when utilizing data on counties. PMID- 21274809 TI - Pregnancy termination intervals in a rural area of Bangladesh. AB - Pregnancy termination intervals, i.e., live birth to live birth (LB-LB), live birth to fetal loss (LB-FL), and fetal loss to live birth (FL-LB), are analyzed prospectively between 1966 and 1970 in a rural population (117,000) of Bangladesh. Results indicate that the mean LB-LB interval was almost 30 months, the LB-FL interval 27 months, and the FL-LB interval 18 months. In addition, postpartum amenorrhea was estimated to be about 13-14 months, and the time added by a fetal loss toa LB-LB interval about 15 months. No relationship was found between LB-LB intervals and the number of living or dead children. PMID- 21274810 TI - Demographic transition: A forcing model. AB - Transition Theory provides the theoretical underpinning for many explanations for past population changes and, more importantly, for many population projections. Our paper proves, through the use of symbolic logic, that Transition Theory does not contain principles strong enough to support population projections. Such projections, consequently, must be based upon their author's intuition rather than a reasoned application of Transition Theory. We follow our proofs with a brief discussion of various ways in which the Theory may be modified. Our emphasis is upon and only upon the logical characters of these modifications. PMID- 21274811 TI - The life-cycle squeeze: The interaction of men's occupational and family life cycles. AB - This paper is concerned with analyzing one structural source of pressure for wives to contribute to family income. This is the "life-cycle squeeze"-the situation where a man's resources are inadequate to meet the needs engendered by the number and ages of his children. Studies of how economic needs vary by family life-cycle stage indicate that one high point of need occurs when men are in their forties and early fifties. However, 1960 Census data on earnings patterns by age indicate that in only relatively high-level professional, managerial and sales occupations do average earnings peak at the same time family income needs are peaking. For most blue-collar and many medium- and low-level white collar occupations, median earnings are highest for younger men, and men at an age when family costs are at their maximum are earning somewhat less, on the average. As a consequence, the families of such men run the risk of a deterioration in their level of living unless an additional income is brought into the household. PMID- 21274812 TI - White-nonwhite differentials in occupational mobility among men in the United States, 1962-1972. AB - Intercohort shifts between 1962 and 1972 in the occupation distributions of white and nonwhite men are analyzed and compared at ages 35-44, 45-54, and 55-64. Both white and nonwhite occupation distributions were upgraded over the decade, but among nonwhites the shifts away from the lowest-status occupations were expressed partly in increasing rates of absence from the labor force. There are indications of especially rapid shifts in the occupation distributions of nonwhite men at ages 35-44. Among whites and nonwhites intercohort shifts in the occupation distribution can be attributed primarily to changing patterns of movement from first full-time civilian jobs to current occupations, rather than to changing occupational origin distributions or patterns of movement to first jobs. The white and nonwhite occupation distributions did not show a clear pattern of convergence over the decade. They became less similar at ages 35-44 and more similar at older ages. White and nonwhite distributions were most likely to converge in those occupation groups where the share of whites was stable or declining, rather than in groups whose share of the occupation distribution was increasing. Later cohorts of nonwhites would have a much more favorable occupational distribution if they had enjoyed the mobility patterns of whites in earlier cohorts. In 1972, as in 1962, the inferior occupational chances of nonwhites are due primarily to their disadvantageous patterns of occupational mobility, rather than to impoverished social origins. PMID- 21274813 TI - Marriage, divorce, and mortality: A life table analysis. AB - The life status table, an analytical model which follows a birth cohort through life and through the never-married, presently married, widowed and divorced statuses, is developed and applied to data from four Western populations. Particular attention is given to recent marriage, remarriage, and divorce trends in California. California data for 1969 imply that 40 percent of all marriages will end in divorce, that each marrying male will marry an average of 12/3 times, and that every woman born can expect to spend 61/2 years in the divorced state. Rising divorce rates may be seen as signaling fundamental changes in both the nature of the American family and the structure of American society. PMID- 21274814 TI - The marriage squeeze. AB - If the sex-age structure of the population is equilibrated, observed marriage patterns are assumed to reflect preferred mate selections. With regard to age, these preferences can be expressed in terms of the probabilities of unmarried persons of given ages marrying persons of various ages. To study the situation of unequilibrated sexes, these probabilities can be used to compute, for each combination of ages of groom and bride, the expected number of grooms and the expected number of brides. If either of these numbers exceeds the other, the corresponding sex is in a "marriage squeeze." The comparison among the expected number of grooms, that of brides, and the observed number of marriages supplies information on the effects of the squeeze.In Australia, marriage statistics of 1949 were considered to reflect preferred selections. In 1958, men of most ages were in a squeeze. As a consequence, some relatively younger and older men did not get married, and some relatively younger and older women improved their chances of marriage in the year under consideration. 291-299. PMID- 21274815 TI - New estimates of the vital rates of the United States black population during the nineteenth century. AB - The difficulties of obtaining credible estimates of vital rates for the black population throughout the entire nineteenth century are overcome in this study. The methodology employed the notion of deviating networks of mortality rates for each general mortality level, which was taken from the United Nations studyThe Concept of a Stable Population. Period life tables and vital rates for intercensal periods were generated from the new estimates of the black population at each census date. The results of this study are highly compatible both with the life tables for the death-registration states in the twentieth century and the recent Coale and Rives reconstruction for the period from 1880 to 1970 and with several estimates of vital rates previously made for the mid-nineteenth century. This study places the mean life expectancy at birth for the black population during the nineteenth century at about 33.7 years for both sexes. The infant death rate (1000m (0)) is shown to have varied between 222 and 237 for females and between 266 and 278 for males. The intrinsic crude death rate centered on 30.4 per thousand during the century, while the birth rate declined from 53.2 early in the century to about 43.8 at the end. PMID- 21274816 TI - Mapping of population density. AB - The Bureau of the Census listing of geographical coordinates of centroids of all enumeration districts together with population counts from the U. S. 1970 Census of Population was used to contruct via computer five nationwide geographical grids of population density with sector dimensions of 0.01, 0.02, 0.04, 0.1, and 0.25 degrees of latitude and longitude. The entire population of a district was assigned to a grid sector if the coordinates of the district centroid fell within the boundaries of the sector. The sectors were then rank-ordered according to population density, and listings were made of sector population, population density, geographical location, cumulative population, area of sector, and cumulative area. The five sets of data were synthesized into single equations describing population as a function of density in one case and of area in another. From these data it was found, for example, that about 800,000 people live in 19 sectors of 0.01-degree dimensions with a population density of 100,000 people per square mile or greater (nearly all in Manhattan); about 10 million live in 183 sectors of 0.02-degree dimensions with a population density of 23,000 per square mile or greater; and about half of the total U. S. population, that is, about 100 million people, reside within about 0.6 percent of the area of the United States, that is, within 20,000 square miles.Four representative displays of population density are shown for the Northeast Corridor, including isometric views and a contour map. PMID- 21274817 TI - New criteria for personality disorders in DSM-V. AB - Diagnosing disorders in the current edition of the DSMIV involves two aspects. The first is the concept of a personality disorder, which currently is defined as a pervasive, stable and presents at least from adolescence pattern of "inner experience and behavior" that is deviant from a person's cultural norms. The second aspect involves defining what type of personality disorder is present among a list of ten, with a catch-all "not otherwise specified category". There are many problems with the existing system: the different personality types are poorly defined and the diagnostic criteria overlap heavily. The proposed revision on the DSM-V website appears quite complicated and has three major facets: a new definition for personality disorder, focused on "adaptive failure" involving "impaired sense of self-identity" or "failure to develop effective interpersonal functioning"; five personality types (Antisocial/Psychopathic, Avoidant, Borderline, Obsessive-Compulsive, and Schizotypal); and a series of six personality "trait domains", each of them with a subset of facets. This new proposed system for personality disorder diagnosis may be controversial. Finally challenges for the next future are discussed. PMID- 21274818 TI - Study of the clinical profiles of patients with eating disorders in specific units. AB - OBJECTIVE: The purpose of this study is to describe the clinical profiles of patients diagnosed of a specific Eating Behavior Disorder (EBD) who come to a specialized outpatient unit for patients over 18 years old with this disorder. METHOD: This is an observational, cross-sectional and descriptive study in which 101 medical records of patients with an eating disorder diagnosis have been analyzed retrospectively. RESULTS: The clinical profiles observed showed 93.9% women, medium age 29.9%, in which 33% of the patients had an illness course of 2 to 5 years. Purgative forms were more frequently observed. A total of 19.8% had substance abuse disorders and 54.4% anxiety disorders. CONCLUSIONS: Specific units for Eating Disorders should be included in the combined resources that not only allow for treatment of the eating behavior disorders but also for their psychopathological comorbidities, the prognosis and evolution of the disease depending on the latter. PMID- 21274819 TI - Consensus of the SEPG on depression in the elderly. AB - BACKGROUND: The limitation of clinical-epidemiological know-how and evidence regarding therapeutic efficiency in depression among the elderly and extremely elderly patients has given rise to an excessive variety of practices in clinical care of these patients in the Spanish health system. The Spanish Society of Psychogeriatrics (SEPG) has raised the question of the need to unify criteria through a structured approach based on professional consensus. OBJECTIVES: To develop an expert consensus of clinical recommendations to improve the clinical treatment of depression in elderly patients in Spain, sponsored by the Spanish Society of Psychogeriatrics (SEPG). METHODS: Modified Delphi Consensus, in two rounds. The study was conducted in four phases: 1) constitution of a Scientific Committee, project promoter and responsible for bibliographic review and formulation of recommendations for discussion 2) constitution of a multicenter Panel of Experts with representatives from this specialist field 3) postal survey comprised of two rounds, with interim processing of opinions and a report for the experts and 4) discussion of results during an on-site meeting of the Scientific Committee. RESULTS: The survey evaluation was completed by 61 experts consulted, in two rounds. In the first round, consensus was reached in 39 of the 54 questions analyzed. Following interaction by the panel, this consensus was increased to a total of 46 survey items (85% of the proposed contents). It was impossible to obtain a sufficiently unanimous consensus on the remaining 8 questions, either due to differences of opinion among the professionals or a lack of established criterion in most of the experts. CONCLUSIONS: A full list of criteria and clinical recommendations for the purpose of rationalizing the treatment of depression in elderly patients and reducing excessive variability in clinical practice is presented. The recommendations are qualified in accordance with the degree of consensus of the professionals endorsing them and can be considered valid until new scientific information becomes available that justifies their review. PMID- 21274820 TI - Attentional network task in schizophrenic patients and theirs unaffected first degree relatives: a potential endofenotype. AB - INTRODUCTION: In recent years, reports of attentional deficits in schizophrenic patients and in their biological relatives have rapidly increased, including an important effort to search for the endophenotypes in order to link specific genes to this illness. Posner et al. developed a test, the Attention Network Test (ANT), to study the neural networks. This test provides a separate measure for each one of the three anatomically-defined attention networks (alerting, orienting and executive control). METHODOLOGY: In this paper, we investigate the attentional performance in 32 schizophrenic patients, 29 unaffected first degree relatives and 29 healthy controls using the ANT through a study of family association. We have studied the efficiency of the segregated executive control, alerting and orienting networks by measuring how response latencies (reaction time) were modified by the cue position and the flanking stimuli. We also studied the familial association of these attentional alterations. RESULTS: The ANOVA revealed main effects of flanker and cue condition and a significant interaction effect between flanker and groups studied. The schizophrenic patients and their relatives had a longer median reaction time than the control group. The probands and their relatives significantly differed from the healthy controls in terms of their conflict resolution; however, the alerting network appeared to be conserved. CONCLUSIONS: Our results support the thesis of a specific attentional deficit in schizophrenia and show the segregation of the three attentional networks. The family association of these reported alterations supports the idea of a potential endophenotype in schizophrenia. PMID- 21274821 TI - A brief and rapid procedure to measure the intensity of depressive symptoms in Primary Care. AB - INTRODUCTION: Depression occupies a substantial part of medical visit attendance. However, medical practitioners have very little time so that a brief, quick and reliable procedure to evaluate the intensity of symptoms and their changes could be useful. Our objective has been to analyze the reliability of a self-applied Visual Analogue Scale (VAS) to measure symptom intensity in depressed patients within this context. MATERIAL AND METHODS: One hundred depressed outpatients (ICD 10) stated their clinical situation on a VAS. The psychiatrist evaluated them using a Global Clinical Impression (GGI) and Hamilton Depression Rating Scale (HDRS-17). RESULTS AND CONCLUSIONS: The patient's VAS showed high correlation with the HDRS-17 and with the GCI used by the psychiatrist (r = 0.63 and r=0.58; p=0.000). This suggests that the use of a VAS in Primary Care could be useful and reliable for these purposes within the medical contexts of those having little time availability. Key-words: Depression, primary care, medical patients, assessment, evaluation. PMID- 21274822 TI - Validation and psychometric properties of the State Impulsivity Scale (SIS). AB - INTRODUCTION: Impulsivity is a complex phenomenon that can be evaluated from a trait or state perspective. Impulsive trait is a predisposition relatively stable over time, but not always perceptible by behavior. However, the impulsivity state covers transient variations on impulsivity levels that are dependent on environmental or biologic conditions. OBJECTIVE: This study has aimed to validate a scale to assess impulsivity as a state in a Spanish sample. METHOD: State Impulsivity Scale (SIS) was designed based on three experimental models: Reward, Automatism and Attentional. All the items in the SIS explore the presence and frequency of impulsive behaviors. Statistical analyses of reliability and validity were done. Convergent validity was examined by means of correlations among SIS and Barratt Impulsiveness Scale (BIS-11), Sensitivity to the punishment and sensitivity to the reward questionnaire (SPSRQ) and Sensations Seeking Scale type V (SSS). RESULTS: We used a Spanish sample of 70 patients who had at least one diagnosis of Impulse Control Disorder (IP), 73 psychiatric patients without impulsive disorders (NIP) and 150 control subjects (CS). The values obtained reveal the high reliability of the SIS (Cronbach's alpha coefficients 0.884), factor analysis confirmed the theoretical three-dimensional structure and convergent validity was excellent. SIS also demonstrated its capacity for discrimination among IP group and NIP and CS groups. CONCLUSIONS: SIS is a new impulsive behavior assessment instrument validated in Spanish population. The results obtained indicate adequate psychometric properties for its use in the clinical and research fields. Key Words: State Impulsivity, Trait, Evaluation, Scale. PMID- 21274823 TI - Endophenotypes and suicide behaviour. AB - BACKGROUND: Recent studies have suggested that genetic predisposition to suicidal behavior may be independent of the risk of suicide associated to mental disorders, such as affective disorders, schizophrenia or alcohol dependence. Given the suicidal behavior heterogeneity and its hereditary complexity, the need to find demonstrable intermediate phenotypes that may make it possible to establish links between genes and suicide behaviors (endophenotypes) seems to be necessary. The main objective is to review which are the candidate endophenotypes of suicidal behaviors. METHODS: We carried out a non-systematic review of all published literature in English, French and Spanish in MEDLINE. The search terms were endophenotypes and suicide behaviors. CONCLUSIONS: The main candidate endophenotypes of suicidal behaviors are neuropsychological (decision-making, executive functions), personality traits (impulsivity, aggressiveness, and neuroticism), neurochemistry (5-HIAA in CNS) and neuroimaging (fMRI of cerebral amygdala or PET of prefrontal cortex metabolism). PMID- 21274824 TI - Overvalued ideas: psychopathologic issues. AB - The position attributed in recent years to overvalued ideas between delusion and obsession and that are derived from the reduction of the construct per se to one of its characteristics, that is, insight, has undergone a critical review. Using a case with dysmorphophobic ideas, the difficulties to define it and differentiate it from delusion are proposed and different psychopathological approaches are outlined that make it possible to reconstruct the case differently. PMID- 21274825 TI - Methylphenidate in depersonalization disorder: a case report. AB - The symptom of depersonalization is frequently associated with other mental disorders, physiological effects of substances or medical diseases. However, it is rare that, as in the case presented, the experiences of depersonalization form an isolated entity, a primary depersonalization disorder. Among the many psychoactive drugs studied, none of them has been shown to be the treatment of choice. Among those with which the best results are obtained are opioid receptor antagonists (naloxone and naltrexone), the combination of selective serotonin reuptake inhibitors with lamotrigine and clorimipramine. Although with virtually no evidence, we are presenting a case that responded spectacularly to methylphenidate. PMID- 21274826 TI - Neuroleptic-induced toxic hepatitis. PMID- 21274828 TI - Plasma levels following application of paclitaxel-coated balloon catheters in patients with stenotic or occluded femoropopliteal arteries. AB - PURPOSE: Paclitaxel-coated balloon catheters inhibit restenosis after coronary and peripheral angioplasty (PCI,PTA). The aim of this study was to investigate paclitaxel plasma levels and laboratory parameters following PTA with paclitaxel coated balloons (PCB) in peripheral arteries. MATERIALS AND METHODS: This single treatment arm, multicenter study included 14 patients with Rutherford stage 1 - 5 with occlusions of up to 5 cm or >= 70 % diameter stenosis of the superficial femoral or popliteal arteries (SFA, PA). PTA was performed using up to three PCB catheters. The paclitaxel plasma levels and safety laboratory parameters were determined by collecting blood samples pre-intervention, immediately post intervention, at 0.5, 1, 2, 4, 8, 24 hours and 1 and 4 weeks post-intervention (p. i.). Vital signs were monitored to assess clinical safety. RESULTS: PTA was performed successfully in all patients. Paclitaxel plasma levels were always below a level and duration known to cause systemic side effects. A mean peak paclitaxel plasma level (40 ng/ml) was reached immediately p. i. and decreased rapidly below detectable levels in more than half of the patients already 2 hours p. i. The paclitaxel plasma concentrations returned to values below detectable levels at 24 hours p. i. in all patients. Laboratory parameters and vital signs did not give any reason for safety concerns. No adverse events associated with balloon coating were observed. CONCLUSION: The results of 14 patients with peripheral arterial occlusive disease show no systemic bioavailability of paclitaxel > 24 hours after PTA with one or more PCB catheters, indicating that the PCB catheter is safe with regard to possible systemic effects. PMID- 21274829 TI - [Colloid cyst in the cavernous sinus]. PMID- 21274830 TI - [IgG food allergies - a subject of controversy]. PMID- 21274831 TI - Cloning of farm animals: impact on animal health and welfare and implications in trade. AB - The commercial use of animal cloning for breeding food producing animals has been limited so far by biological and technical constraints such as adverse effects on the health and welfare of animals, especially high perinatal and postnatal disease and mortality of clones. However, the improvement of the technique may overcome those problems in future and contribute to the spread of cloning in agricultural production, which raises concern not only on health and welfare aspects but also on food safety and ethics. This may cause conflict in international trade. The present article reviews these topics on the basis of up to-date scientific opinions. PMID- 21274832 TI - [Antimicrobial resistance of Staphylococcus aureus and coagulase negative staphylococci isolated from mastitis milk samples from sheep and goats]. AB - Staphylococcus aureus and coagulase negative staphylococci (CNS) were isolated from ovine and caprine mastitis milk samples originating from more than 40 Swiss farms. CNS dominated as causal microorganisms of mastitis in small ruminants. By restriction fragment length polymorphism (RFLP) analysis of the groEL gene and sequencing of 16S rDNA, various CNS species were identified, albeit certain of them predominated. For susceptibility testing of mastitis pathogens to selected antibiotics, minimal inhibitory concentrations were determined. Of the 67 S. aureus and 208 CNS strains, 31.3 % and 8.2 % were resistant to penicillin, 29.9 % and 1.0 % to ampicillin, 1.5 % and 10.6 % to erythromycin, and 3.0 % and 7.7 % to tetracycline, respectively. Moreover, 10 CNS strains (4.8 %) were resistant to oxacillin and one CNS strain to sulfamethoxazole/trimethoprim. The results obtained describe for the first time the resistance situation of mastitis pathogens from sheep and goats in Switzerland. However, accompanying and preventing measures are also of importance in mastitis control of small ruminants. PMID- 21274833 TI - Ultrasonography of the abdominal wall before and after laparotomy in cows. AB - The ultrasonographic appearance of the normal abdominal wall in the flank region was investigated before and after exploratory laparotomy in five cows (group A). The results were compared with those after surgical correction of left displaced abomasum in 10 cows (group B) and of caecal dilatation in another 10 cows (group C). We hypothesized that in group C and group B, wound healing would be impaired because of the higher risk of complications compared to group A. A 10.0 MHz linear transducer was used to examine the abdominal wall immediately before exploratory laparotomy and for 10 days (groups B, C) or 30 days (group A) postoperatively. The thickness of the individual layers of the abdominal wall was determined. The skin and the individual muscle layers could be well differentiated via ultrasonography in all the cows preoperatively. In group A, the total thickness of the abdominal wall ranged from 2.80 to 3.40 cm; the skin and the subcutaneous tissues were 0.60 to 0.80 cm, the external abdominal oblique muscle 0.50 to 0.70 cm, the internal abdominal oblique muscle 0.50 to 0.70 cm, the transverse abdominal muscle 0.50 to 0.75 cm, and the transverse fascia and peritoneum were 0.20 to 0.30 cm. Groups B and C had similar findings. There was no significant difference in the course of healing, the thickness of the abdominal wall or thickness of the individual layers during healing among the three groups of cows. Features of healing included subcutaneous emphysema in 19 cows, seroma in 19 and haematoma in 2 cows. However, the occurrence of these events did not differ significantly among the three groups. Ultrasonographic examination of the wound on day 10 postoperatively was unremarkable in 24 cows. A seroma was still present on day 15 postoperatively in one cow of group B. PMID- 21274834 TI - [Cumulation of Ornithonyssus bacoti (tropical rat mite) infestations of pet rodents and their owners in the Canton of Zurich and Graubunden]. AB - In spring 2009 several cases of infestation with Ornithonyssus bacoti ("tropical rat mite") in pet rodents have been diagnosed at the Institute of Parasitology, University of Zurich. Although adequate animal hosts were present, owners also became victims of mite infestation. The owners presented cutaneous lesions such as pruritic red papules partly with a central vesicle, predominantly disposed in groups. Particularly children with close body contact to their pet rodents were strongly affected. Because the definite diagnosis was usually yielded at a late time-point, the medical treatment remained unsatisfactory in some cases. The mite infestation of the pets was mostly detected after the owners also became affected. The owners noticed merely non-specific signs such as increased restlessness, itching and shaggy coat on their animals. Efficient healing was achieved only if the parasites were completely eliminated, i.e. also the pets were treated, the cages cleaned and the apartments professionally disinfested. A definite diagnosis of "Infestation with Ornithonyssus bacoti" is only possible by means of morphological identification on an isolated mite, which is most likely to be found in the environment of the animals. Pet owners should be informed about the zoonotic potential of O. bacoti. PMID- 21274836 TI - [Not Available]. PMID- 21274835 TI - Acute pulmonary edema and airway hemorrhage in a goat during sevoflurane anesthesia. AB - A goat was scheduled for experimental surgery under general anesthesia. The first attempt of performing endotracheal intubation failed and provoked laryngeal spasm. After repeated succesful intubation of inhalation anesthesia was delivered in high concentrations of sevoflurane. Suddenly hypertension and tachycardia were observed, followed by foamy airway secretion and then severe airway hemorrhage. The authors hypothesize that laryngeal spasm provoked respiratory distress and pulmonary edema. The delivered high concentrations of sevoflurane probably enhanced a hyperadrenergic response, predisposing to the development of airway hemorrhage. PMID- 21274838 TI - [Not Available]. PMID- 21274837 TI - [Not Available]. PMID- 21274839 TI - [Not Available]. PMID- 21274840 TI - [Not Available]. PMID- 21274841 TI - [Nursing development at the Solothurn hospitals. Towards clinically oriented nursing expertise and practice development]. AB - At the Solothurn Hospitals (soH), 13 academically educated nurses are responsible for the development of nursing care with the goal to improve patient-oriented, effective, appropriate, and economic care. The strategy contains three priorities: a) expert care of single patients in demanding situations, b) sustained application of organisational methods such as primary nursing, nursing process, and skill/grade mix, and c) design and management of practice development projects related to specific patient groups. A first evaluation with qualitative and quantitative methods showed that the exemplary care of single patients by expert nurses was evaluated as positive for the patients as well as for the teams on two wards by nurses who were interviewed. After the introduction of primary nursing, the application rate was 81 to 90 % and the introduction of fall prevention methods in geriatric rehabilitation decreased the fall rate from 8.2 to 5.5 per 1000 patient days. A comparision with the literature shows that the expert nurses of soH perform both, working at the bedside and being responsible for practice development projects, as specialised Advanced Practice Nurses (APNs). APNs at the Solothurn Hospitals work also as generalists when organisational methods need to be consolidated. Their successes depend from their integration into the hierarchy and both, into the nursing as well as into the interprofessional teams. Competencies in Transformational Leadership also are essential at all management levels. PMID- 21274842 TI - [Quality needs competence and responsibility - challenges and perspectives of Advanced Nursing Practice for the health care system from a nursing science perspective]. AB - Advanced Nursing Practice seems to be an answer to the complex challenges of the health system. However, the quality of Advanced Nursing Practice is researched by comparison to medical care. These attempts to legitimise Advanced Nursing Practice decrease the potentials of nursing care. In contrast to this, a prospect for Advanced Nursing Practice should be derived from the core of nursing, namely the relation to the life-world of the clients, the closeness to the clients and their families, and the opportunity for consistency in health care. This vision has to be realised by means of autonomy and responsibility in nursing care. The competence to autonomous and responsible decision-making is based on an educational process, where the ability to perceive the situation of client as changeable is developed. PMID- 21274843 TI - [The first steps of an ANP-team - challenges and chances of ANP-teams at the Children's University Hospital Zurich]. AB - In the past, various individual ANP-roles such as Clinical Nurse Specialist and Nurse Practitioner were developed in the USA and in several countries of Northern Europe. In Switzerland, the number of university-educated nurse specialists is still very limited. In order to promote sustainable progress in nursing practice despite of this background, Advanced Nursing Practice teams (ANP-teams) have continuously been established at Kinderspital Zurich for the last eight years. This approach has proven to be an excellent option especially in highly complex situations where targeted and adequate solutions for patients are a major issue. In this article, the structure of the ANP-teams is discussed, with the personnel mix as a key factor. Important supportive elements are a clear definition of tasks as well as an allocation of individual tasks to either clinical or conceptual groups. The ANP teams are highly motivated and goal-oriented, they integrate nurses with various backgrounds of experience or training whereby mutual learning is being encouraged. PMID- 21274844 TI - [Development and implementation of a multidisciplinary nurse-led educational programme for inpatients with heart failure: the Basel-HF-Programme]. AB - Individuals with chronic heart failure are a vulnerable group of patients, with a poor prognosis and frequent hospitalisations. Research shows that multidisciplinary education outpatient programmes for heart failure (HF) increases the quality of life of these patients and decreases mortality and rehospitalisation respectively. As a result of this research, the University Hospital Basel has developed and implemented a multidisciplinary, nurse-led inpatient programme. The article describes the development and difficulties of the programme from its beginning until the verification of its effectiveness. Based on a systematic review of the literature and principles of action research the programme was developed by a group of nurses specialised in HF and two physicians under the guidance of an Advanced Practice Nurse student. The group developed a patient pathway and guidelines describing education, skills training sessions for patients, as well as descriptions of responsibilities and tasks of the different members of the multidisciplinary team. To date, an individualised programme with information material and specific documentation is offered to patients who receive personalised recommendations before their discharge. For the nurses the implementation of the programme was a new challenge of structured counselling in their normal "busy" routine because of this challenge the nurses needed continuing coaching. PMID- 21274845 TI - [SpitexPlus: assessment of and specialised nursing care for elderly and their families living in the community]. AB - Current demographic developments and the high prevalence of chronic conditions require new approaches to nursing care of the elderly population in Switzerland. New care models need to be developed that go beyond traditional nursing practice with its focus on the individual. Existing preventive home visit and case management programmes have mostly focussed on the young old with the goal to maintain functional health and prevent institutionalisation. Families, who play a crucial role in the care of the elderly at home, were not included. The purpose of this article is to describe the development of the SpitexPlus Project, which is directed at people 80 years and older and their families, irrespective of their health status and social situation. It aims to improve self-care capabilities and quality of life in people 80+ and their families and to enable them to manage the challenges of daily life at home. Evidence based nursing interventions, based on the principles of health promotion, empowerment, family centeredness, and partnership were developed. The development of the programme phases, interventions, and the role of the advanced practice nurses are described in detail. Potential benefits for nursing practice are delineated. PMID- 21274846 TI - Hydrogel embedding of precision-cut liver slices in a microfluidic device improves drug metabolic activity. AB - A microfluidic-based biochip made of poly-(dimethylsiloxane) was recently reported for the first time by us for the incubation of precision-cut liver slices (PCLS). In this system, PCLS are continuously exposed to flow, to keep the incubation environment stable over time. Slice behavior in the biochip was compared with that of slices incubated in well plates, and verified for 24 h. The goal of the present study was to extend this incubation time. The viability and metabolic activity of precision-cut rat liver slices cultured in our novel microflow system was examined for 72 h. Slices were incubated for 1, 24, 48, and 72 h, and tested for viability (enzyme leakage (lactate dehydrogenase)) and metabolic activity (7-hydroxycoumarin (phase II) and 7-ethoxycoumarin (phase I and II)). Results show that liver slices retained a higher viability in the biochip when embedded in a hydrogel (Matrigel) over 72 h. This embedding prevented the slices from attaching to the upper polycarbonate surface in the microchamber, which occurred during prolonged (>24 h) incubation in the absence of hydrogel. Phase II metabolism was completely retained in hydrogel-embedded slices when medium supplemented with dexamethasone, insulin, and calf serum was used. However, phase I metabolism was significantly decreased with respect to the initial values in gel-embedded slices with medium supplements. Slices were still able to produce phase I metabolites after 72 h, but at only about ~10% of the initial value. The same decrease in metabolic rate was observed in slices incubated in well plates, indicating that this decrease is due to the slices and medium rather than the incubation system. In conclusion, the biochip model was significantly improved by embedding slices in Matrigel and using proper medium supplements. This is important for in vitro testing of drug metabolism, drug-drug interactions, and (chronic) toxicity. PMID- 21274847 TI - Effect of a mechanical stimulation bioreactor on tissue engineered, scaffold-free cartilage. AB - Achieving sufficient functional properties prior to implantation remains a significant challenge for the development of tissue engineered cartilage. Many studies have shown chondrocytes respond well to various mechanical stimuli, resulting in the development of bioreactors capable of transmitting forces to articular cartilage in vitro. In this study, we describe the production of sizeable, tissue engineered cartilage using a novel scaffold-free approach, and determine the effect of perfusion and mechanical stimulation from a C9-x Cartigen bioreactor on the properties of the tissue engineered cartilage. We created sizable tissue engineered cartilage from porcine chondrocytes using a scaffold free approach by centrifuging a high-density chondrocyte cell-suspension onto an agarose layer in a 50 mL tube. The gross and histological appearances, biochemical content, and mechanical properties of constructs cultured in the bioreactor for 4 weeks were compared to constructs cultured statically. Mechanical properties were determined from unconfined uniaxial compression tests. Constructs cultured in the bioreactor exhibited an increase in total GAG content, equilibrium compressive modulus, and dynamic modulus versus static constructs. Our study demonstrates the C9-x CartiGen bioreactor is able to enhance the biomechanical and biochemical properties of scaffold-free tissue engineered cartilage; however, no additional enhancement was seen between loaded and perfused groups. PMID- 21274848 TI - Accumulation and photodynamic activity of chlorin e6 in cisplatin-resistant human lung cancer cells. AB - Cisplatin or cis-diamminedichloroplatinum (II) (CDDP) is one of the most potent anticancer drugs, but the emergence of acquired resistance to CDDP is a major problem in clinical settings. The purpose of this study was to investigate and compare the cellular accumulation and photodynamic activity of chlorin e6, a photosensitizer, in human lung cancer A549 cell line and its CDDP-resistant subline. First, we established the CDDP-resistant (A549/CDDP) cell subline with fourfold greater half-maximal inhibitory concentration value of CDDP on cell growth than that of the parent A549 cells. The cellular accumulation of chlorin e6 was temperature sensitive, and there were no significant differences in chlorin e6 accumulation between the two cell lines. The mRNA expression levels of ABCC1, ABCC2, and ABCG2 in A549/CDDP cells were comparable to those in A549 cells, whereas ABCB1 mRNA level was significantly higher in A549/CDDP cells than in A549 cells. In consistent with chlorin e6 accumulation, chlorin e6-mediated photodynamic activity on A549/CDDP cells was similar to that on A549 cells, whereas no cytotoxicity was observed when these cell lines were kept in dark. Our observations suggest that CDDP resistance has no significant influence on accumulation and photodynamic activity of chlorin e6 in A549 cells. PMID- 21274849 TI - Individual and collective social cognitive influences on peer aggression: exploring the contribution of aggression efficacy, moral disengagement, and collective efficacy. AB - This follow-up study with 1,167 primarily White adolescents (aged 13.45 years at T1, 613 females) examined the impact of self-efficacy for aggression, moral disengagement, and collective efficacy beliefs on peer aggression in schools. Students completed questionnaire measures at the beginning and end of the school year (8 months apart). High aggression efficacy and moral disengagement scores predicted higher frequency of peer aggression over time. Low collective efficacy beliefs regarding the ability of students and teachers to collaboratively act to inhibit peer aggression were also associated with more frequent aggression, although this association was stronger at higher levels of moral disengagement. The findings of this study highlight the need to consider collective efficacy beliefs in conjunction with individual social cognitive processes when seeking to explain aggressive behavior. PMID- 21274850 TI - Support for religio-political aggression among teenaged boys in Gaza: part II: neuroendocrinological findings. AB - Hormones seem to play important roles in the regulation of human aggression. Multiple studies have confirmed that testosterone (T) levels exhibit complex relationships with aggression, dominance, and/or risk-taking behavior. Some evidence suggests that cortisol (CORT) interacts with T and may also be associated with aspects of mood and aggression. However, almost no research to date has investigated the possibility that these neuroendocrine factors are associated with variations in political attitudes or with political aggression. During the second intifada, we tested the hypothesis that morning salivary T and/or salivary CORT levels might be associated with self-rated aggression or with support for religio-political aggression (RPA) among 14-year-old Palestinian boys living in Gaza. We obtained and averaged weekly 09:00 hr salivary measures of T and CORT for more than 1 month. Averaged morning T levels did not correlate with self-rated aggression, but were positively associated with agreement with the statement "religious ends justify any means," (r = .355, P = .014) and marginally associated with a composite measure of support for RPA (r = .247, P = .094). Average CORT levels were inversely correlated with self-rated aggression (r = -.328, P = .037) and with anger (r = -.373, P = .016), but CORT levels were not associated with support for RPA or with the statement "religious ends justify any means." Acknowledging that a modest sample size and methodological issues necessarily limit confidence in our conclusions, these results may represent the first findings regarding neurobiological correlates of support for political aggression. PMID- 21274851 TI - Moral disengagement in self-reported and peer-nominated school bullying. AB - This study examined the relation between moral disengagement and different self reported and peer-nominated positions in school bullying. The aims of this study were to (1) investigate moral disengagement among children for whom self-reported and peer-nominated bully status diverged and (2) compare levels of disengagement among self-reported and peer-nominated pure bullies, pure victims, bully-victims, and children not involved in bullying. A sample of 739 Danish sixth grade and seventh grade children (mean age 12.6) was included in the study. Moral disengagement was measured using a Danish version of the Moral Disengagement Scale and bullying was measured using both self-reports and peer nominations. Results revealed that both self-reported and peer-nominated bullying were related to moral disengagement, and that both pure bullies and bully-victims displayed higher moral disengagement than outsiders. Discrepancies between self-reported and peer-nominated bullying involvement indicates that a person's social reputation has a stronger association with moral disengagement than so far expected. Implications are discussed, highlighting the importance of further research and theory development. PMID- 21274852 TI - Criminal thinking patterns, aggression styles, and the psychopathic traits of late high school bullies and bully-victims. AB - This study explored the current psychological characteristics and criminal behavior history of individuals who retrospectively reported being bullies, bully victims, victims, or controls (i.e. neither victims nor bullies) during their last 2 years of high school. College students (n = 960) completed measures of criminal thinking, aggression, psychopathy, and criminal behavior online. We predicted bullies and bully-victims would demonstrate the highest scores for criminal thinking, proactive aggression, psychopathy, and have the most criminal infractions. Bullies and bully-victims had significantly higher scores on criminal thinking, aggression, psychopathy, and criminal behaviors than victims or controls. Additionally, men were significantly higher in criminal thinking, aggression, psychopathy, and had more criminal acts than women. There were no gender by bully group interactions. Logistic regression analyses differentiated bully-victims from bullies. Bully-victims tended to be male, higher in criminal thinking, and higher in reactive aggression. In addition, bully-victims were distinct from victims, showing higher criminal thinking and higher proactive aggression. PMID- 21274853 TI - Trajectories of aggression, delinquency, and substance use across middle school among urban, minority adolescents. AB - This study evaluated bidirectional associations between substance use, aggression, and delinquency across sixth, seventh, and eighth grades using data available from a large study of urban minority youth (n = 2,931). Group-based trajectory analysis revealed trajectories of aggression, delinquency, and substance use which support the existence of both adolescent-limited and life course persistent offenders. In addition, a pattern of decreasing aggression was observed during middle school. Clear temporal associations were observed between developmental changes in aggression, delinquency, and substance use. Notably, the decreasing aggression trajectory was as likely to be associated with high trajectories of substance initiation as was the high aggression trajectory. Furthermore, trajectories of delinquency were differentially associated with future substance use; however, substance use trajectories did not predict trajectories of delinquency. There were few gender differences in the developmental progression of these problem behaviors during middle school with only two exceptions, males were more likely to follow a trajectory of decreasing aggression and a trajectory of high stable delinquency. Evaluations of ethnic/racial differences in the trajectory group membership also revealed few differences. The results of this study provide important information regarding interconnections between developmental changes in problem behavior that occur during the middle school years, highlighting groups that may be missed via traditional analytic approaches that predict mean changes. PMID- 21274854 TI - The development of the Social Bullying Involvement Scales. AB - This study reports findings of a newly developed measure of social bullying based on Underwood's [2003] framework of social aggression. The Social Bullying Involvement Scales (SBIS) consist of four scales measuring the extent to which children experience social victimization, engage in social bullying, witness social bullying, and intervene in social bullying. The sample consisted of 636 participants (311 females and 325 males, age range 11-16 years; 71% White). Confirmatory factor analysis supported a revised version of Underwood's framework for each of the four participant role scales. Internal consistencies for each scale ranged from .93 to .97. Results revealed that social victimization was related to an increase in anxiety, depressive, and externalizing behaviors. Social bullying was associated with an increase in general externalizing behaviors only. Social witnessing was moderately correlated with depression scores. Intervening in social bullying was not linked with psychological maladjustment or externalizing behaviors. The SBIS provides a comprehensive measure of social victimization, social bullying, social witnessing, and social intervening. PMID- 21274855 TI - Media violence, physical aggression, and relational aggression in school age children: a short-term longitudinal study. AB - Many studies have shown that media violence has an effect on children's subsequent aggression. This study expands upon previous research in three directions: (1) by examining several subtypes of aggression (verbal, relational, and physical), (2) by measuring media violence exposure (MVE) across three types of media, and (3) by measuring MVE and aggressive/prosocial behaviors at two points in time during the school year. In this study, 430 3rd-5th grade children, their peers, and their teachers were surveyed. Children's consumption of media violence early in the school year predicted higher verbally aggressive behavior, higher relationally aggressive behavior, higher physically aggressive behavior, and less prosocial behavior later in the school year. Additionally, these effects were mediated by hostile attribution bias. The findings are interpreted within the theoretical framework of the General Aggression Model. PMID- 21274856 TI - Psychopathic personality traits in relational aggression among young adults. AB - Psychopathy is a robust predictor of overt physical aggression that may also be relevant to relational aggression (RA). This study was conducted to investigate the utility of psychopathic personality traits in the prediction of RA in a sample of 291 college students. Hierarchical multiple regression analyses indicated that both primary and secondary psychopathic traits explained additional variance in general/peer and romantic RA beyond physical aggressiveness. Consistent with previous research, no gender differences were found on either form of RA, challenging the popular stereotype of RA as a female behavior. Moreover, psychopathic traits were not differentially predictive of RA by gender or level of physical aggressiveness. Implications of these findings for research and clinical practice are discussed. PMID- 21274857 TI - Cyclooctatetraene dianion--an artifact? AB - Cyclooctatetraene in its dianionic form (COT(2-)) is considered to be partially or fully aromatic due to the fact that, unlike its neutral counterpart, it adopts planar structure with CC bonds equalized. However, some authors report that this dianion is neither planar nor aromatic. Thus, we performed a detailed analysis of the COT(2-) case. The influence of several technical parameters on the result of calculations on COT(2-) was investigated. It appears from our analysis that the use of some specific level of approximation may lead to very misleading results in which the COT ring occurs in its neutral structure, in fact being neither planar nor aromatic. Additionally, our results may suggest that COT(2-) dianion is rather an artificial structure (being the result of specific basis set description) and should not occur in experimental conditions. PMID- 21274858 TI - Health care reform: how personalized medicine could help bundling of care for liver diseases. PMID- 21274859 TI - Osteopontin: a missing link between hedgehog signaling and fibrosis in nonalcoholic steatohepatitis. PMID- 21274860 TI - Autoimmune hepatitis and antigen-specific T regulatory cells: when can we send in the regulators? PMID- 21274861 TI - Inosine triphosphatase genetic variants are protective against anemia during antiviral therapy for HCV2/3 but do not decrease dose reductions of RBV or increase SVR. AB - Two functional variants in the inosine triphosphatase (ITPA) gene causing inosine triphosphatase (ITPase) deficiency protect against ribavirin (RBV)-induced hemolytic anemia and the need for RBV dose reduction in patients with genotype 1 hepatitis C virus (HCV). No data are available for genotype 2/3 HCV. We evaluated the association between the casual ITPA variants and on-treatment anemia in a well-characterized cohort of genotype 2/3 patients treated with variable-duration pegylated interferon alfa-2b (PEG-IFN-alpha2b) and RBV. Two hundred thirty-eight Caucasian patients were included in this retrospective study [185 (78%) with genotype 2 and 53 (22%) with genotype 3]. Patients were treated with PEG-IFN alpha2b plus weight-based RBV (1000/1200 mg) for 12 (n = 109) or 24 weeks (n = 129). The ITPA polymorphisms rs1127354 and rs7270101 were genotyped, and an ITPase deficiency variable was defined that combined both ITPA variants according to their effect on ITPase activity. The primary endpoint was hemoglobin (Hb) reduction in week 4. We also considered Hb reduction over the course of therapy, the need for RBV dose modification, and the rate of sustained virological response (SVR). The ITPA variants were strongly and independently associated with protection from week 4 anemia (P = 10(-6) for rs1127354 and P = 10(-7) for rs7270101). Combining the variants into the ITPase deficiency variable increased the strength of association (P = 10(-11) ). ITPase deficiency protected against anemia throughout treatment. ITPase deficiency was associated with a delayed time to an Hb level < 10 g/dL (hazard ratio = 0.25, 95% confidence interval = 0.08 0.84, P = 0.025) but not with the rate of RBV dose modification (required per protocol at Hb < 9.5 g/dL). There was no association between the ITPA variants and SVR. CONCLUSION: Two ITPA variants were strongly associated with protection against treatment-related anemia in patients with genotype 2/3 HCV, but they did not decrease the need for RBV dose reduction or increase the rate of SVR. PMID- 21274862 TI - Knockdown of autophagy enhances the innate immune response in hepatitis C virus infected hepatocytes. AB - The role of autophagy in disease pathogenesis following viral infection is beginning to be elucidated. We have previously reported that hepatitis C virus (HCV) infection in hepatocytes induces autophagy. However, the biological significance of HCV-induced autophagy has not been clarified. Autophagy has recently been identified as a novel component of the innate immune system against viral infection. In this study, we found that knockdown of autophagy-related protein beclin 1 (BCN1) or autophagy-related protein 7 (ATG7) in immortalized human hepatocytes (IHHs) inhibited HCV growth. BCN1- or ATG7-knockdown IHHs, when they were infected with HCV, exhibited increased expression of interferon-beta, 2',5'-oligoadenylate synthetase 1, interferon-alpha, and interferon-alpha inducible protein 27 messenger RNAs of the interferon signaling pathways in comparison with infected control IHHs. A subsequent study demonstrated that HCV infection in autophagy-impaired IHHs displayed caspase activation, poly(adenosine diphosphate ribose) polymerase cleavage, and apoptotic cell death. CONCLUSION: The disruption of autophagy machinery in HCV-infected hepatocytes activates the interferon signaling pathway and induces apoptosis. Together, these results suggest that HCV-induced autophagy impairs the innate immune response. PMID- 21274863 TI - Strong influence of human leukocyte antigen (HLA)-DP gene variants on development of persistent chronic hepatitis B virus carriers in the Han Chinese population. AB - Chronic hepatitis B virus (HBV) infection is a major health issue, especially in Asia. A recent genome-wide association study (GWAS) implicated genetic variants in the human leukocyte antigen (HLA)-DP locus associated with chronic hepatitis B in Japanese and Thai populations. To confirm whether the polymorphisms at the HLA DP genes are associated with persistent chronic HBV infection in Han Chinese, we conducted an independent case-control study using 521 persistent chronic HBV carriers and 819 controls that included 571 persons with HBV natural clearance and 248 never HBV-infected (healthy) individuals. Eleven single nucleotide polymorphisms (SNPs) in a region including HLA-DPA and HLA-DPB and an adjacent SNP in strong linkage disequilibrium (LD) with a neighboring HLA-DR13 locus were genotyped using the TaqMan SNP genotyping assay. Eleven variants at HLA-DP showed a strong association with persistent chronic HBV carrier status (P = 1.82 * 10( 12) to 0.01). We also stratified the analysis by HBV clearance status to test the association between these polymorphisms and HBV natural clearance; similar results were obtained (P = 2.70 * 10(-11) to 0.003). Included SNPs define highly structured haplotypes that were also strongly associated with HBV chronic infection (block 1: odds ratio [OR] = 0.54, P = 8.73 * 10(-7) ; block 2: OR = 1.98, P = 1.37 * 10(-10) ). These results further confirm that genetic variants in the HLA-DP locus are strongly associated with persistent HBV infection in the Han Chinese population. PMID- 21274864 TI - Secular trend of the viral genotype distribution in children with chronic hepatitis B virus infection after universal infant immunization. AB - Genotypes B and C are the major hepatitis B virus (HBV) genotypes in Taiwan, and genotype C is associated with more severe liver disease than genotype B. Whether the implementation of the hepatitis B immunization program has affected the secular trend of the HBV genotype distribution remains unknown. We thus investigated the HBV genotypes in hepatitis B surface antigen (HBsAg)-carrier children born before the implementation of the universal infant immunization program and in those born afterward. One hundred seven children who were infected with HBV despite appropriate immunization were enrolled as immunized cases with HBV breakthrough infection. Each case was matched with two unimmunized HBsAg carriers according to the age at enrollment. HBV genotypes were determined with molecular methods. Compared with unimmunized HBsAg carriers, more immunized children had HBsAg-positive mothers (65.9% versus 100%, P < 0.001) and were infected with genotype C (16.4% versus 42.1%, P < 0.001). Among the children born to HBsAg-positive mothers, the mothers' and children's HBV genotypes were highly concordant in both unimmunized [kappa = 0.97, 95% confidence interval (CI) = 0.90 1.00] and immunized children (kappa = 0.97, 95% CI = 0.92-1.00). After adjustments for gender, maternal age, and delivery mode, immunized HBsAg-carrier children born to HBsAg-positive mothers had a higher likelihood of genotype C infection than unimmunized children (odds ratio = 3.03, 95% CI = 1.62-5.65, P = 0.001). However, the increased genotype C to genotype B ratio was not seen in the HBsAg-carrier mother pool in the postimmunization era. CONCLUSION: In the postimmunization era, most HBV breakthrough infections are due to maternal transmission, and immunized children born to genotype C mothers may have a higher rate of breakthrough infection than those born to genotype B mothers. PMID- 21274865 TI - The GRACILE mutation introduced into Bcs1l causes postnatal complex III deficiency: a viable mouse model for mitochondrial hepatopathy. AB - Mitochondrial dysfunction is an important cause for neonatal liver disease. Disruption of genes encoding oxidative phosphorylation (OXPHOS) components usually causes embryonic lethality, and thus few disease models are available. We developed a mouse model for GRACILE syndrome, a neonatal mitochondrial disease with liver and kidney involvement, caused by a homozygous BCS1L mutation (232A>G). This gene encodes a chaperone required for incorporation of Rieske iron sulfur protein (RISP) into complex III of respiratory chain. Homozygous mutant mice after 3 weeks of age developed striking similarities to the human disease: growth failure, hepatic glycogen depletion, steatosis, fibrosis, and cirrhosis, as well as tubulopathy, complex III deficiency, lactacidosis, and short lifespan. BCS1L was decreased in whole liver cells and isolated mitochondria of mutants at all ages. RISP incorporation into complex III was diminished in symptomatic animals; however, in young animals complex III was correctly assembled. Complex III activity in liver, heart, and kidney of symptomatic mutants was decreased to 20%, 40%, and 40% of controls, respectively, as demonstrated with electron flux kinetics through complex III. In high-resolution respirometry, CIII dysfunction resulted in decreased electron transport capacity through the respiratory chain under maximum substrate input. Complex I function, suggested to be dependent on a functional complex III, was, however, unaffected. CONCLUSION: We present the first viable model of complex III deficiency mimicking a human mitochondrial disorder. Incorporation of RISP into complex III in young homozygotes suggests another complex III assembly factor during early ontogenesis. The development of symptoms from about 3 weeks of age provides a convenient time window for studying the pathophysiology and treatment of mitochondrial hepatopathy and OXPHOS dysfunction in general. PMID- 21274866 TI - Relationship between the pattern of hepatic iron deposition and histological severity in nonalcoholic fatty liver disease. AB - Previous studies examining the relationship between hepatic iron deposition and histological severity in nonalcoholic fatty liver disease (NAFLD) have been inconclusive. The goal of this study was to examine the relationship between hepatic iron deposition and liver histology in 849 patients enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network. Hepatic iron staining was performed in a central laboratory, and the stains were scored for grade and cellular and parenchymal localization by a central pathology committee; the relationship between the grade and pattern of iron deposition and the clinical, laboratory, and histological variables was examined with univariate and multivariate analyses. Stainable hepatic iron was present in 293 of 849 patients (34.5%) in one of three histological patterns: a hepatocellular (HC) pattern [63/849 (7.4%)], a reticuloendothelial system (RES) cell pattern [91/849 (10.7%)], or a mixed RES/HC pattern [139/849 (16.4%)]. Patients with the RES iron staining pattern were more likely to have advanced fibrosis compared to those with those with HC iron (P = 0.01). Patients with RES iron were also more likely to have advanced histological features such as fibrosis (P = 0.049), portal inflammation (P = 0.002), HC ballooning (P = 0.006), and definite nonalcoholic steatohepatitis (P = 0.007) compared to those with patients with HC or mixed iron patterns. The presence of RES iron (odds ratio = 1.60, 95% confidence interval = 1.10-2.33, P = 0.015) was independently associated with advanced hepatic fibrosis on multiple regression analysis after adjustments for age, gender, diabetes status, and body mass index. CONCLUSION: The presence and pattern of hepatic iron deposition are associated with distinct histological features in patients with NAFLD and may have implications for pathophysiology and therapy. PMID- 21274867 TI - Hepatocyte nuclear factor-4 alpha regulates liver triglyceride metabolism in part through secreted phospholipase A2 GXIIB. AB - Hepatocyte nuclear factor-4 alpha (HNF-4alpha) is an important transcription factor governing the expression of genes involved in multiple metabolic pathways. Secreted phospholipase A(2) GXIIB (PLA(2) GXIIB) is an atypical member of a class of secreted phospholipases A(2) . We establish in this study that PLA(2) GXIIB is an HNF-4alpha target gene. We demonstrate that HNF-4alpha binds to a response element on the PLA(2) GXIIB promoter. Moreover, HNF-4alpha agonists induce PLA(2) GXIIB expression in human hepatocarcinoma cells. Importantly, PLA(2) GXIIB-null mice accumulate triglyceride, cholesterol, and fatty acids in the liver and develop severe hepatosteatosis resembling some of the phenotypes of liver specific HNF-4alpha-null mice. These defects are in part due to compromised hepatic very low-density lipoprotein secretion. Finally, adenovirus-mediated overexpression of HNF-4alpha elevates serum triglyceride level in wild-type but not PLA(2) GXIIB-null mice. CONCLUSION: Collectively, these evidences suggest that HNF-4alpha is a key physiological PLA(2) GXIIB transcriptional regulator and that PLA(2) GXIIB is a novel mediator of triglyceride metabolism in the liver. PMID- 21274868 TI - Dissociation between APOC3 variants, hepatic triglyceride content and insulin resistance. AB - Nonalcoholic fatty liver disease (NAFLD) is an escalating health problem that is frequently associated with obesity and insulin resistance. The mechanistic relationship between NAFLD, obesity, and insulin resistance is not well understood. A nonsynonymous variant in patatin-like phospholipase domain containing 3 (rs738409, I148M) has been reproducibly associated with increased hepatic triglyceride content (HTGC) but has not been associated with either the body mass index (BMI) or indices of insulin resistance. Conversely, two sequence variants in apolipoprotein C3 (APOC3) that have been linked to hypertriglyceridemia (rs2854117 C > T and rs2854116 T > C) have recently been reported to be associated with both hepatic fat content and insulin resistance. Here we genotyped two APOC3 variants in 1228 African Americans, 843 European Americans and 426 Hispanics from a multiethnic population based study, the Dallas Heart Study and test for association with HTGC and homeostatic model of insulin resistance (HOMA-IR). We also examined the relationship between these two variants and HOMA-IR in the Atherosclerosis Risk in Communities (ARIC) study. No significant difference in hepatic fat content was found between carriers and noncarriers in the Dallas Heart Study. Neither APOC3 variant was associated with HOMA-IR in the Dallas Heart Study; this lack of association was confirmed in the ARIC study, even after the analysis was restricted to lean (BMI < 25 kg/m(2) ) individuals (n = 4399). CONCLUSION: Our data do not support a causal relationship between these two variants in APOC3 and either HTGC or insulin resistance in middle-aged men and women. PMID- 21274869 TI - Liver transplantation for hepatocellular carcinoma: the impact of human immunodeficiency virus infection. AB - Liver transplantation (LT) has become an accepted therapy for end-stage liver disease in human immunodeficiency virus-positive (HIV+) patients, but the specific results of LT for hepatocellular carcinoma (HCC) are unknown. Between 2003 and 2008, 21 HIV+ patients and 65 HIV- patients with HCC were listed for LT at a single institution. Patient characteristics and pathological features were analyzed. Univariate analysis for overall survival (OS) and recurrence-free survival (RFS) after LT was applied to identify the impact of HIV infection. HIV+ patients were younger than HIV- patients [median age: 48 (range = 41-63 years) versus 57 years (range = 37-72 years), P < 0.001] and had a higher alpha fetoprotein (AFP) level [median AFP level: 16 (range = 3-7154 MUg/L] versus 13 MUg/L (range = 1-552 MUg/L), P = 0.04]. There was a trend toward a higher dropout rate among HIV+ patients (5/21, 23%) versus HIV- patients (7/65, 10%, P = 0.08). Sixteen HIV+ patients and 58 HIV- patients underwent transplantation after median waiting times of 3.5 (range = 0.5-26 months) and 2.0 months (range = 0.5-24 months, P = 0.18), respectively. No significant difference was observed in the pathological features of HCC. With median follow-up times of 27 (range = 5-74 months) and 36 months (range = 3-82 months, P = 0.40), OS after LT at 1 and 3 years reached 81% and 74% in HIV+ patients and 93% and 85% in HIV- patients, respectively (P = 0.08). RFS rates at 1 and 3 years were 69% and 69% in HIV+ patients and 89% and 84% in HIV- patients, respectively (P = 0.09). In univariate analysis, HIV status did not emerge as a prognostic factor for OS or RFS. CONCLUSION: Because of a higher dropout rate among HIV+ patients, HIV infection impaired the results of LT for HCC on an intent-to-treat basis but had no significant impact on OS and RFS after LT. PMID- 21274870 TI - Sorafenib suppresses postsurgical recurrence and metastasis of hepatocellular carcinoma in an orthotopic mouse model. AB - Surgical resection is the first-line treatment for hepatocellular carcinoma (HCC) patients with well-preserved liver function. Nevertheless, the rate of postoperative recurrence at 5 years is as high as 70%, and this gravely jeopardizes the therapeutic outcome. Clearly, new approaches are needed for preventing the relapse of this deadly disease. Taking advantage of a luciferase labeled orthotopic xenograft model of HCC, we examined the role of sorafenib, the first systemic drug approved for advanced HCC patients, in the prevention of HCC recurrence. We found that sorafenib suppressed the development of postsurgical intrahepatic recurrence and abdominal metastasis and consequently led to prolonged postoperative survival of mice in this model. Furthermore, hyperactivity of extracellular signal-regulated kinase signaling caused by elevated levels of growth factors associated with postoperative liver regeneration enhanced the sensitivity of HCC cells to sorafenib; this provides a plausible explanation for the observation that recurrent tumors are more responsive to growth inhibition by sorafenib. CONCLUSION: Our results strongly suggest that by effectively reducing postoperative recurrence, sorafenib has a potential application in early-stage HCC patients who have undergone hepatectomy with curative intention. PMID- 21274871 TI - Acetylcholinesterase, a key prognostic predictor for hepatocellular carcinoma, suppresses cell growth and induces chemosensitization. AB - Acetylcholinesterase (ACHE) plays important roles in the cholinergic system, and its dysregulation is involved in a variety of human diseases. However, the roles and implications of ACHE in hepatocellular carcinoma (HCC) remain elusive. Here we demonstrate that ACHE was significantly down-regulated in the cancerous tissues of 69.2% of HCC patients, and the low ACHE expression in HCC was correlated with tumor aggressiveness, an elevated risk of postoperative recurrence, and a low survival rate. Both the recombinant ACHE protein and the enhanced expression of ACHE significantly inhibited HCC cell growth in vitro and tumorigenicity in vivo. Further study showed that ACHE suppressed cell proliferation via its enzymatic activity of acetylcholine catalysis and degradation. Moreover, ACHE could inactivate mitogen-activated protein kinase and phosphatidyl inositol-3'-phosphate kinase/protein kinase B pathways in HCC cells and thereby increase the activation of glycogen synthase kinase 3beta and lead to beta-catenin degradation and cyclin D1 suppression. In addition, increased ACHE expression could remarkably sensitize HCC cells to chemotherapeutic drugs (i.e., adriamycin and etoposide). CONCLUSION: For the first time, we describe the function of ACHE as a tumor growth suppressor in regulating cell proliferation, the relevant signaling pathways, and the drug sensitivity of HCC cells. ACHE is a promising independent prognostic predictor for HCC recurrence and the survival of HCC patients. These findings provide new insights into potential strategies for drug discovery and improved HCC treatment. PMID- 21274872 TI - Autoimmune acute liver failure: proposed clinical and histological criteria. AB - Identifying autoimmune hepatitis as the etiology of acute liver failure (ALF) is potentially important, because administering corticosteroids might avoid the need for liver transplantation. However, clinical and histological criteria of autoimmune ALF (AI-ALF) have not been defined. Liver sections (biopsies and explants) from a 72-patient subset of the ALF Study Group Registry with indeterminate ALF were reviewed by a pathologist blinded to all clinical data and were diagnosed with probable AI-ALF based on four features suggestive of an autoimmune pathogenesis: distinctive patterns of massive hepatic necrosis (present in 42% of sections), presence of lymphoid follicles (32%), a plasma cell enriched inflammatory infiltrate (63%), and central perivenulitis (65%). Forty two sections (58%) were considered probable for AI-ALF; this group demonstrated higher serum globulins (3.7 +/- 0.2 g/dL versus 3.0 +/- 0.2 g/dL; P = 0.037) and a higher prevalence of antinuclear and/or anti-smooth muscle antibodies (73% versus 48%; P = 0.034) compared to those without histology suggestive of probable AI-ALF. Thirty patients concordant for autoantibodies and probable AI-ALF upon histological analysis were more likely to have the classical autoimmune hepatitis phenotype (female predominance [72% versus 48%; P < 0.05], higher globulins [3.9 +/- 0.2 g/dL versus 3.0 +/- 0.2 g/dL; P < 0.005], and higher incidence of chronic hepatitis in long-term follow-up [67% versus 17%, P = 0.019]) compared to the population without concordant AI-ALF histology and autoantibodies. CONCLUSION: Patients with indeterminate ALF often have features of autoimmune disease by histological analysis, serological testing, and clinical recurrence during follow up. In contrast to classical autoimmune hepatitis, histological features of AI ALF predominate in the centrilobular zone. PMID- 21274873 TI - B cell depletion therapy exacerbates murine primary biliary cirrhosis. AB - Primary biliary cirrhosis (PBC) is considered a model autoimmune disease due to the clinical homogeneity of patients and the classic hallmark of antimitochondrial antibodies (AMAs). Indeed, the presence of AMAs represents the most highly directed and specific autoantibody in autoimmune diseases. However, the contribution of B cells to the pathogenesis of PBC is unclear. Therefore, although AMAs appear to interact with the biliary cell apotope and contribute to biliary pathology, there is no correlation of disease severity and titer of AMAs. The recent development of well-characterized monoclonal antibodies specific for the B cell populations, anti-CD20 and anti-CD79, and the development of a well defined xenobiotic-induced model of autoimmune cholangitis prompted us to use these reagents and the model to address the contribution of B cells in the pathogenesis of murine PBC. Prior to the induction of autoimmune cholangitis, mice were treated with either anti-CD20, anti-CD79, or isotype-matched control monoclonal antibody and followed for B cell development, the appearance of AMAs, liver pathology, and cytokine production. Results of the studies reported herein show that the in vivo depletion of B cells using either anti-CD20 or anti-CD79 led to the development of a more severe form of cholangitis than observed in control mice, which is in contrast with results from several other autoimmune models that have documented an important therapeutic role of B cell-specific depletion. Anti-CD20/CD79-treated mice had increased liver T cell infiltrates and higher levels of proinflammatory cytokines. CONCLUSION: Our results reflect a novel disease-protective role of B cells in PBC and suggest that B cell depletion therapy in humans with PBC should be approached with caution. PMID- 21274874 TI - Autoantigen-specific regulatory T cells, a potential tool for immune-tolerance reconstitution in type-2 autoimmune hepatitis. AB - Effector CD4 and CD8 T cell immune responses to cytochrome P450IID6 (CYP2D6), the autoantigen of autoimmune hepatitis type 2 (AIH-2), are permitted by a numerical and functional impairment of CD4(pos) CD25(high) regulatory T cells (T-regs). We aimed to investigate whether T-regs specific for CYP2D6 immunodominant regions and restricted by the appropriate human leukocyte antigen (HLA)-DR molecule can be generated in patients with AIH-2 and can control CD4 and CD8 T cell effectors targeting identical or overlapping CYP2D6 regions. CYP2D6-specific regulatory T cells (CYP2D6 T-regs) were obtained from peptide-pulsed monocyte-depleted peripheral blood mononuclear cells of 17 patients with AIH-2, who were positive for the predisposing HLA-DR7 and/or HLA-DR3 alleles. Their antigen specificity was assessed by cytofluorimetry using HLA class II tetramers and their cytokine profile by intracellular staining. T-reg ability to suppress was ascertained by measuring reduction of CD4(pos) CD25(neg) cell proliferation/effector cytokine secretion and of CD8 T cell cytotoxicity. The most efficient suppression of effector T cell proliferation, inflammatory cytokine release, and cytotoxicity was obtained by coculturing T-regs with CYP2D6-peptide-loaded semimature dendritic cells (smDCs), and smDC-CYP2D6 T-regs also expressed high levels of FOXP3 (forkhead box P3). Possession of the appropriate HLA-DR molecule and recognition of the CYP2D6 autoantigenic sequence were critical to the synergistic smDC-CYP2D6 T-reg immunoregulatory functions, and lack of either element led to poor control of responder cell proliferation and cytokine secretion. Moreover, interferon-gamma neutralization significantly boosted the suppressive ability of CYP2D6 T-regs. CONCLUSION: T-regs generated under CYP2D6-specific conditions and cocultured with smDCs are highly effective at controlling autoreactive T cells, thus providing the basis for a powerful and tailored form of immunotherapy for AIH-2. PMID- 21274875 TI - Combination of retinoic acid and ursodeoxycholic acid attenuates liver injury in bile duct-ligated rats and human hepatic cells. AB - Cholestasis leads to liver cell death, fibrosis, cirrhosis, and eventually liver failure. Despite limited benefits, ursodeoxycholic acid (UDCA) is the only Food and Drug Administration-approved treatment for cholestatic disorders. Retinoic acid (RA) is a ligand for nuclear receptors that modulate bile salt homeostasis. RA also possesses immunomodulatory effects and is used to treat acute promyelocytic leukemia and inflammatory disorders such as psoriasis, acne, and rheumatoid arthritis. To test whether the supplementation of RA with UDCA is superior to UDCA alone for treating cholestasis, male Sprague-Dawley rats underwent common bile duct ligation (BDL) for 14 days and were treated with phosphate-buffered saline (PBS), UDCA, all-trans retinoic acid (atRA), or UDCA and atRA by gavage. Treatment with UDCA and atRA substantially improved animal growth rates, significantly reduced liver fibrosis and bile duct proliferation, and nearly eliminated liver necrosis after BDL. Reductions in the bile salt pool size and liver hydroxyproline content were also seen with treatment with atRA or atRA and UDCA versus PBS and UDCA. Furthermore, atRA and UDCA significantly reduced liver messenger RNA and/or protein expression of transforming growth factor beta1 (Tgf-beta1), collagen 1a1 (Col1A1), matrix metalloproteinase 2 (Mmp2), cytokeratin 19, alpha-smooth muscle actin (alpha-SMA), cytochrome P450 7A1 (Cyp7a1), tumor necrosis factor alpha, and interleukin-beta1. The molecular mechanisms of this treatment were also assessed in human hepatocytes, hepatic stellate cells, and LX-2 cells. atRA alone or in combination with UDCA greatly repressed CYP7A1 expression in human hepatocytes and significantly inhibited COL1A1, MMP2, and alpha-SMA expression and/or activity in primary human hepatic stellate cells and LX-2 cells. Furthermore, atRA reduced TGF-beta1-induced Smad2 phosphorylation in LX-2 cells. CONCLUSION: Our findings indicate that the addition of RA to UDCA reduces the bile salt pool size and liver fibrosis and might be an effective supplemental therapy with UDCA for cholestatic diseases. PMID- 21274876 TI - Different biochemical correlates for different neuropsychiatric abnormalities in patients with cirrhosis. AB - The diagnosis of hepatic encephalopathy (HE) relies on clinical, neurophysiological, psychometric and laboratory variables. The relationships between such tests remain debated. The aim of this study was to determine the laboratory correlates/prognostic value of neurophysiological/psychometric abnormalities in patients with cirrhosis. Seventy-two patients and 14 healthy volunteers underwent EEG and paper-and-pencil psychometry (PHES). Blood was obtained for C reactive protein (CRP), interleukin 6 (IL6), tumor necrosis factor (TNF)alpha, ammonia and indole/oxindole. Patients were followed prospectively for a median of 22 months in relation to the occurrence of death, transplantation and HE-related hospitalizations. Thirty-three patients had normal PHES and EEG, 6 had abnormal PHES, 18 abnormal EEG and 13 abnormal PHES and EEG. Patients with abnormal PHES had higher CRP (17 +/- 22 vs 7 +/- 6, P < 0.01), IL6 (32 +/- 54 vs 12 +/- 13, P < 0.05) and TNFalpha (17 +/- 8 vs 11 +/- 7, P < 0.001) levels than those with normal PHES. Patients with abnormal EEG had higher indole (430 +/- 270 vs 258 +/- 255, P < 0.01) and ammonia (66 +/- 35 vs 45 +/- 27, P < 0.05) levels than those with normal EEG. Psychometric test scores showed significant correlations with CRP, TNFalpha and IL6; EEG indices with ammonia and IL6. CRP and TNFalpha concentrations were independent predictors of abnormal PHES, ammonia and indole of abnormal EEG on multivariate analysis. Seven patients were lost to follow-up; of the remaining 65, 20 died and 14 underwent transplantation; 15 developed HE requiring hospitalization. PHES and EEG performance were independent predictors of HE and death (P < 0.05). CONCLUSION: PHES and EEG abnormalities in patients with cirrhosis have partially different biochemical correlates and independently predict outcome. PMID- 21274877 TI - Unrecognized acetaminophen toxicity as a cause of indeterminate acute liver failure. AB - Despite extensive investigations, the cause of liver injury in 14% of patients with acute liver failure remains unknown (indeterminate). In a pilot study using a novel assay, highly specific acetaminophen-cysteine adducts were detected in 7 of 36 indeterminate patients (19%). To extend these observations, sera from 110 subjects enrolled in the Acute Liver Failure Study Group registry with indeterminate acute liver failure were analyzed with a similar but more efficient and sensitive adduct assay. As positive controls, another 199 patients with known or presumed acetaminophen-induced liver failure were assessed for the presence and quantity of adducts. Clinical, laboratory, and outcome data were compared for the two groups. On the basis of previous data for known therapeutic exposures and acetaminophen overdoses, an adduct concentration >=1.0 nmol/mL of serum indicated a definite acetaminophen overdose. Among the 110 indeterminate cases, 18% had assay values >=1.0 with a median level of 9.2 nmol/mL; 94.5% of the positive controls (known acetaminophen cases) had values >=1.0 nmol/mL. Regardless of the initial diagnosis, subjects with elevated adduct levels demonstrated the clinical profile and hyperacute biochemical injury pattern associated with acetaminophen overdose: a predominance of female gender, very high aminotransferase levels, and low bilirubin levels. CONCLUSION: These data confirm and extend previous observations regarding the high (18%) prevalence of unrecognized or uncertain acetaminophen toxicity among subjects with indeterminate acute liver failure. N Acetylcysteine use was limited in this group, presumably because of the lack of a specific diagnosis of acetaminophen toxicity. PMID- 21274878 TI - Effect of sorafenib on murine liver regeneration. AB - Hepatocellular carcinoma (HCC) is a common cause of cancer-related death. Sorafenib prolongs survival of patients with advanced disease and is approved for the systemic treatment of unresectable HCC. It possesses antiangiogenic and antiproliferative properties by way of inhibition of the receptor tyrosine kinases vascular endothelial growth factor receptor 2 (VEGFR-2) and platelet derived growth factor receptor-beta 1/2 (PDGFR-beta) and the kinase RAF. Sorafenib represents a candidate compound for adjuvant therapy in HCC patients. The aim of our study was to investigate whether sorafenib affects liver regeneration. C57BL6 mice received sorafenib orally at 30 mg/kg/day or its vehicle either for 14 days until the day before hepatectomy or starting the day after surgery or both. Animals were sacrificed 24, 72, and 120 hours after hepatectomy. Liver regeneration was calculated as a percent of initial liver weight. Bromodeoxyuridine (BrdU) incorporation and phospho-extracellular signal regulated kinase (pERK1/2) were determined by immunohistochemistry on liver sections. VEGF-A, PDGF-BB, and hepatocyte growth factor (HGF) levels were measured in liver tissue homogenates. Histological analysis of scar tissue was performed. Treatment stopped 1 day before surgery had no impact on liver regeneration. Continuous sorafenib treatment and treatment started 1 day after surgery had statistically significant effects on liver regeneration at 120 hours compared to vehicle-treated control animals (72% +/- 12 versus control 88% +/- 15 and 70% +/- 13 versus control 86% +/- 5 at 120 hours, both P <= 0.02). BrdU incorporation showed decreased numbers of positive nuclei in both groups receiving sorafenib after surgery. Phospho-ERK levels were reduced in sorafenib treated animals. An increase of VEGF-A levels was observed in mice receiving sorafenib. Wound-healing complications were observed in animals receiving sorafenib after surgery and confirmed on histological sections. CONCLUSION: This preclinical study shows that sorafenib did not impact on liver regeneration when ceased before surgery; however, administration after hepatectomy affected late liver regeneration. PMID- 21274879 TI - Excessive hepatomegaly of mice with hepatocyte-targeted elimination of integrin linked kinase following treatment with 1,4-bis [2-(3,5-dichaloropyridyloxy)] benzene. AB - TCBOPOP (1,4-bis [2-(3,5-dichaloropyridyloxy)] benzene) an agonist of the constitutive androstane receptor (CAR), produces rapid hepatocyte hyperplasia and hepatomegaly in the absence of hepatic injury. In this study we demonstrate that integrin-linked kinase (ILK), which is involved in transmission of the extracellular matrix (ECM) signaling by way of integrin receptors, plays an important role in regulating TCPOBOP-induced proliferation of hepatocytes and hepatomegaly. Hepatocyte-specific ILK knockout mice (ILK/liver-/- mice) and wildtype mice (WT) were given a single dose of TCPOBOP (3 mg/kg) by oral gavage. Mice were sacrificed at days 1, 2, 5, and 7 after TCPOBOP administration. WT mice showed maximum proliferation on days 1 and 2, which came back to baseline levels by days 5 and 7 after TCPOBOP administration. The ILK/liver-/- mice, on the other hand, showed a prolonged and a sustained proliferative response as evident by an increased number of proliferative cell nuclear antigen assay (PCNA)-positive cells even at days 5 and 7 after TCPOBOP administration. At day 7 the WT mice showed close to a 2.5-fold increase in liver weight, whereas the ILK/liver-/- mice showed a 3.7-fold increase in liver weight. The prolonged proliferative response in the ILK/liver-/- mice seems to be due to sustained induction of CAR leading to sustained induction of c-Myc, which is known to be a key mediator of TCPOPOP-CAR induced direct liver hyperplasia. CONCLUSION: The data indicate that ECM-mediated signaling by way of ILK is essential for adjustment of final liver size and proper termination of TCPOBOP-induced proliferation of hepatocytes. PMID- 21274880 TI - Serum chemokine CXC ligand 10 (CXCL10) predicts fibrosis progression after liver transplantation for hepatitis C infection. AB - The recurrence of liver fibrosis after liver transplantation (LT) for hepatitis C virus (HCV) infection is responsible for graft loss and patient mortality. Although the contribution of the immune system to fibrosis recurrence is anticipated, systematic studies evaluating immune parameters as predictive markers of allograft fibrosis are lacking. The infiltration of immune cells into the graft is governed by chemokines. Here we assessed the predictive value of serum levels of chemokines [chemokine (C-X-C motif) ligand 9 (CXCL9), CXCL10, CXCL11, and chemokine (C-C motif) ligand 2 (CCL2)] with respect to fibrosis recurrence after LT in 90 HCV-infected organ recipients. Chemokines were determined within the first and third years after LT and were correlated with histological fibrosis progression in protocol biopsy samples at 1, 3, 5, and 7 years (median follow-up = 3 years). The association of chemokines with fibrosis progression was assessed by univariate and multivariate analyses and by Cox regression analysis. The results for the analyzed chemokines showed that CXCL10 levels in the first year after LT were strongly associated with early fibrosis recurrence (P = 0.005) independently of risk confounders (including the donor age, HCV viral load, HCV genotype, acute rejection, and inflammatory activity). As assessed by Cox regression analysis, a CXCL10 serum level <= 140 pg/mL was significantly predictive of the absence of F2 fibrosis (P = 0.001), whereas a level <= 220 pg/mL early after LT predicted the absence of F3 fibrosis during follow-up (P = 0.035). CONCLUSION: CXCL10 is an independent biomarker of the recurrence of significant fibrosis after LT for HCV infection. These results might guide patients' care after transplantation and help us to select optimal candidates for antiviral therapy post-LT. PMID- 21274881 TI - The use of whole organ decellularization for the generation of a vascularized liver organoid. AB - A major roadblock to successful organ bioengineering is the need for a functional vascular network within the engineered tissue. Here, we describe the fabrication of three-dimensional, naturally derived scaffolds with an intact vascular tree. Livers from different species were perfused with detergent to selectively remove the cellular components of the tissue while preserving the extracellular matrix components and the intact vascular network. The decellularized vascular network was able to withstand fluid flow that entered through a central inlet vessel, branched into an extensive capillary bed, and coalesced into a single outlet vessel. The vascular network was used to reseed the scaffolds with human fetal liver and endothelial cells. These cells engrafted in their putative native locations within the decellularized organ and displayed typical endothelial, hepatic, and biliary epithelial markers, thus creating a liver-like tissue in vitro. CONCLUSION: These results represent a significant advancement in the bioengineering of whole organs. This technology may provide the necessary tools to produce the first fully functional bioengineered livers for organ transplantation and drug discovery. PMID- 21274882 TI - Human hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein cures fas-induced acute liver failure in mice by attenuating free-radical damage in injured livers. AB - Acute liver failure (ALF) is a rare syndrome with a difficult clinical management and a high mortality rate. During ALF, several molecular pathways governing oxidative stress and apoptosis are activated to induce massive tissue injury and suppress cell proliferation. There are few anti-ALF drug candidates, among which is the C-type lectin Reg3alpha, or human hepatocarcinoma-intestine pancreas/pancreatitis-associated protein (HIP/PAP), which displayed promising properties for tissue regeneration and protection against cellular stress in transgenic mice. We report on substantial preclinical and clinical advances in the development of a recombinant (rc) full-length human HIP/PAP protein as an anti-ALF drug. The curative effects and mechanisms of action of rcHIP/PAP were investigated in murine Fas-induced ALF. Primary hepatocytes were cultured with cytotoxic doses of tumor necrosis factor alpha/actinomycin-D, transforming growth factor beta, agonistic Fas antibody or hydrogen peroxide, and various concentrations of rcHIP/PAP. Cell viability, proliferation index, apoptosis, and oxidation were monitored. We found that rcHIP/PAP significantly improved survival in Fas-intoxicated mice in a dose-dependent and time-dependent manner, with optimum effects when it was injected at advanced stages of ALF. Primary hepatocytes were efficiently protected against multiple cell death signals by rcHIP/PAP. This survival benefit was linked to a depletion of oxidized biomolecules in injured liver cells due to a strong reactive oxygen species scavenging activity of rcHIP/PAP. Clinically, an escalating dose phase 1 trial demonstrated a good tolerability and pharmacokinetic profile of rcHIP/PAP in healthy subjects. CONCLUSION: The rcHIP/PAP protein exhibited significant curative properties against ALF in mice. It is a free-radical scavenger that targets a broad spectrum of death effectors and favors liver regeneration. The good safety profile of rcHIP/PAP during a phase 1 trial encourages evaluation of its efficacy in patients with ALF. PMID- 21274883 TI - Activation of alpha(1) -adrenergic receptors stimulate the growth of small mouse cholangiocytes via calcium-dependent activation of nuclear factor of activated T cells 2 and specificity protein 1. AB - Small cholangiocytes proliferate via activation of calcium (Ca(2+) )-dependent signaling in response to pathological conditions that trigger the damage of large cyclic adenosine monophosphate-dependent cholangiocytes. Although our previous studies suggest that small cholangiocyte proliferation is regulated by the activation of Ca(2+) -dependent signaling, the intracellular mechanisms regulating small cholangiocyte proliferation are undefined. Therefore, we sought to address the role and mechanisms of action by which phenylephrine, an alpha(1) adrenergic agonist stimulating intracellular D-myo-inositol-1,4,5-triphosphate (IP(3) )/Ca(2+) levels, regulates small cholangiocyte proliferation. Small and large bile ducts and cholangiocytes expressed all AR receptor subtypes. Small (but not large) cholangiocytes respond to phenylephrine with increased proliferation via the activation of IP(3) /Ca(2+) -dependent signaling. Phenylephrine stimulated the production of intracellular IP(3) . The Ca(2+) dependent transcription factors, nuclear factor of activated T cells 2 (NFAT2) and NFAT4, were predominantly expressed by small bile ducts and small cholangiocytes. Phenylephrine stimulated the Ca(2+) -dependent DNA-binding activities of NFAT2, NFAT4, and Sp1 (but not Sp3) and the nuclear translocation of NFAT2 and NFAT4 in small cholangiocytes. To determine the relative roles of NFAT2, NFAT4, or Sp1, we knocked down the expression of these transcription factors with small hairpin RNA. We observed an inhibition of phenylephrine induced proliferation in small cholangiocytes lacking the expression of NFAT2 or Sp1. Phenylephrine stimulated small cholangiocyte proliferation is regulated by Ca(2+) -dependent activation of NFAT2 and Sp1. CONCLUSION: Selective stimulation of Ca(2+) -dependent small cholangiocyte proliferation may be key to promote the repopulation of the biliary epithelium when large bile ducts are damaged during cholestasis or by toxins. PMID- 21274884 TI - Sterol transporter adenosine triphosphate-binding cassette transporter G8, gallstones, and biliary cancer in 62,000 individuals from the general population. AB - Gallstone disease, a risk factor for biliary cancer, has a strong heritable component, but the underlying genes are largely unknown. To test the hypothesis that ABCG8 (adenosine triphosphate-binding cassette transporter G8) Asp19His (D19H) genotype predicted risk of gallstones and biliary cancer in the general population, we studied 62,279 white individuals from The Copenhagen City Heart Study and The Copenhagen General Population Study, randomly selected to reflect the adult Danish population aged 20 to 80+ years. Endpoints were recorded from January 1976 through May 2009. During a mean follow-up of, respectively, 31 and 4.4 years, 3124 participants developed symptomatic gallstone disease and 30 developed biliary cancer. The multifactorially adjusted hazard ratio for symptomatic gallstone disease was 1.9 (95% confidence interval, 1.7-2.1) in DH heterozygotes (prevalence, 12%), and 3.3 (2.3-4.6) in HH homozygotes (0.4%) versus noncarriers (P for trend <0.001). Mean age at onset of symptomatic gallstone disease was 56 years for noncarriers, 54 for DH heterozygotes, and 52 for HH homozygotes (P for trend <0.001). The fraction of all gallstones attributed to D19H was 11%. The multifactorially adjusted hazard ratio for biliary cancer was 4.0 (1.9-8.4) in DH heterozygotes and HH homozygotes combined versus noncarriers (P < 0.001). The fraction of all biliary cancers attributed to the D19H genotype was 27%. Finally, D19H genotype associated with stepwise increases in plasma levels of alanine aminotransferase and gamma glutamyltransferase of up to 14% and 25% in HH homozygotes, and with corresponding stepwise reductions in plasma levels of total and low-density lipoprotein cholesterol of up to 5% versus noncarriers (all comparisons, P for trend <0.001). CONCLUSION: In this general population cohort, ABCG8 D19H genotype was an important predictor of both symptomatic gallstone disease and biliary cancer. PMID- 21274887 TI - From the bedside to the community: comparative effectiveness, health services, and implementation research. PMID- 21274885 TI - Interferon regulatory factor 3 and type I interferons are protective in alcoholic liver injury in mice by way of crosstalk of parenchymal and myeloid cells. AB - Alcoholic liver disease (ALD) features increased hepatic exposure to bacterial lipopolysaccharide (LPS). Toll-like receptor-4 (TLR4) recognizes LPS and activates signaling pathways depending on MyD88 or TRIF adaptors. We previously showed that MyD88 is dispensable in ALD. TLR4 induces Type I interferons (IFNs) in an MyD88-independent manner that involves interferon regulatory factor-3 (IRF3). We fed alcohol or control diets to wild-type (WT) and IRF3 knock-out (KO) mice, and to mice with selective IRF3 deficiency in liver parenchymal and bone marrow-derived cells. Whole-body IRF3-KO mice were protected from alcohol-induced liver injury, steatosis, and inflammation. In contrast to WT or bone marrow specific IRF3-KO mice, deficiency of IRF3 only in parenchymal cells aggravated alcohol-induced liver injury, associated with increased proinflammatory cytokines, lower antiinflammatory cytokine interleukin 10 (IL-10), and lower Type I IFNs compared to WT mice. Coculture of WT primary murine hepatocytes with liver mononuclear cells (LMNC) resulted in higher LPS-induced IL-10 and IFN-beta, and lower tumor necrosis factor alpha (TNF-alpha) levels compared to LMNC alone. Type I IFN was important because cocultures of hepatocytes with LMNC from Type I IFN receptor KO mice showed attenuated IL-10 levels compared to control cocultures from WT mice. We further identified that Type I IFNs potentiated LPS-induced IL 10 and inhibited inflammatory cytokine production in both murine macrophages and human leukocytes, indicating preserved cross-species effects. These findings suggest that liver parenchymal cells are the dominant source of Type I IFN in a TLR4/IRF3-dependent manner. Further, parenchymal cell-derived Type I IFNs increase antiinflammatory and suppress proinflammatory cytokines production by LMNC in paracrine manner. CONCLUSION: Our results indicate that IRF3 activation in parenchymal cells and resulting type I IFNs have protective effects in ALD by way of modulation of inflammatory functions in macrophages. These results suggest potential therapeutic targets in ALD. PMID- 21274888 TI - Hepatocyte-specific magnetic resonance imaging contrast agents. PMID- 21274889 TI - Noninvasive assessment of portal hypertension in patients with cirrhosis. AB - Severe portal hypertension is responsible for complications and death. Although measurement of the hepatic venous pressure gradient is the most accurate method for evaluating the presence and severity of portal hypertension, this technique is considered invasive and is not routinely performed in all centers. Several noninvasive techniques have been proposed to measure portal hypertension. Certain methods evaluate elements related to the pathogenesis of portal hypertension through the measurement of hyperkinetic syndrome, for example, or they investigate the development of hepatic fibrosis through the measurement of increased intrahepatic vascular resistance. Other methods evaluate the clinical consequences of portal hypertension, such as the presence of esophageal varices or the development of portosystemic shunts. Methods evaluating increased hepatic vascular resistance are fairly accurate and mainly involve the detection of hepatic fibrosis by serum markers and transient elastography. The radiological assessment of hyperkinetic syndrome probably has value but is still under investigation. The assessment of severe portal hypertension by the presence of varices may be performed with simple tools such as biological assays, computed tomography, and esophageal capsules. More sophisticated procedures seem promising but are still under development. Screening tools for large populations must be simple, whereas more complicated procedures could help in the follow-up of already diagnosed patients. Although most of these noninvasive methods effectively identify severe portal hypertension, methods for diagnosing moderate portal hypertension need to be developed; this shows that further investigation is needed in this field. PMID- 21274891 TI - Survival of the fittest: selection of hepatitis C virus variants during liver graft reinfection. PMID- 21274890 TI - Development of molecularly targeted therapies in biliary tract cancers: reassessing the challenges and opportunities. AB - Biliary tract cancers (BTCs), which encompass intra- and extrahepatic cholangiocarcinomas as well as gallbladder carcinomas, are a genetically diverse collection of cancers. Most patients with BTC will present with unresectable or metastatic disease. Although the standard systemic chemotherapy approaches are emerging, the prognosis remains poor. Development of molecularly targeted therapies in advanced BTC remains challenging. Recent early-stage clinical trials with targeted therapies appear promising, although the relationships between subsets of patients with positive responses to therapy and tumor genetics remain unexplored. Here we summarize the relevant molecular pathogenesis, recent and ongoing clinical trials with targeted agents, and the key issues in clinical trial design in BTC. PMID- 21274892 TI - Modeling and therapy of human liver diseases using induced pluripotent stem cells: how far have we come? PMID- 21274893 TI - Hyponatremia in patients with acute variceal bleeding treated with terlipressin. PMID- 21274895 TI - No evidence for caspase-dependent apoptosis in acetaminophen hepatotoxicity. PMID- 21274896 TI - Tribute to Ymke Warren. PMID- 21274897 TI - Introduction to the special section: "the effects of bonds between human and nonhuman primates on primatological research and practice". AB - This commentary introduces this special section on ''the Effects of Bonds Between Human and Nonhuman Primates on Primatological Research and Practice.'' The aim is to explore the different causes and consequences of bonding experiences between observers and observed in different primatological contexts. In the first contribution, Vitale asks what are the possible consequences of such bonding in behavioral primatology. Examples of beneficial consequences of this kind of relationship come fromstudies on cognitive abilities of great apes. Furthermore, an empathic attitude with the experimental animals leads to better care and attention toward individual welfare needs. Coleman discusses the particular case of nonhuman primates housed in research laboratories. Care-giving practices arediscussed in relation to scientific, ethical and emotional issues. Morimura et al. present the case of the first Japanese sanctuary for retiring chimpanzees from research where, in order to facilitate the social living of re-located chimpanzees, face-to-face interactions between caregivers and chimpanzees areessential. Asquith discusses the role of an thropomorphism, and proposes that this attitude can help to better understand the lives of primates, in more contextualized scenarios. In relation to this view, sheemphasizes how the term ''primate culture'' accords with some definition of the term ''human culture.''Fuentes, in his article asks whether national, class and ethnic characteristics can influence bonding between human and nonhuman primates, and calls for focused quantitative studies. Finally, Rose calls for the application of the concept of biosynergy, explained as promoting the formation of healthy and sustainable bonding relationships among living creatures. One of the most important aspects emerging from these papers is the need to better understand whether the issue of bonding in primatological studiescan be generalized to other areas of research such as conservation, behavior, captive care, or whether each of these disciplines needs to develop their own understanding of the effects of bonding in ''producing science.'' PMID- 21274898 TI - Being human and doing primatology: national, socioeconomic, and ethnic influences on primatological practice. AB - The emerging manifesto, center of the essay collection this commentary is part of, points out that primatology is a primate's science and field of endeavor. It is about primates, and constructed and carried out by primates. But the relationships between different primates involved in primatology cannot be described merely as scientific, zoological, or conservatory. A main point emerging from this perspective is that the relationships amongst primates (as scientists and as subjects) are affected by primatologists' experiences outside of academic science and within the cultural schema that we acquire as members of human societies. My contribution focuses on the primatologists and their sometimes discussed, but too often ignored, cultural and ethnic contexts as influences on how they study, think about, and interact with other primates. In our views and bonds with other primates, do national, class, and ethnic factors count? PMID- 21274899 TI - Of bonds and boundaries: what is the modern role of anthropomorphism in primatological studies? AB - Anthropomorphism (and its obverse, zoomorphism) continues to shift and propel us toward changing perspectives on ourselves and other animals. Discussions of anthropomorphism in primate behavior are ostensibly about our use and definition of terms, but ultimately reflect our views of what is unique to humans or unknowable in other animals. Primatologists doing long-term fieldwork report on the bonds that are inevitably formed through familiarity with their study subjects and how anecdotes and anthropomorphism help them to gain a contextualized view of animal lives. This fuller view of animal society serves as an aid to understanding different rationalities and provides a more effective modern role for anthropomorphism than does seeking to demonstrate isomorphic capacities in alloprimates. Although most ordinary language terms are accepted among primatologists, "primate culture" serves as an example of a term and a concept that overreached acceptable anthropomorphic limits when defined to accord with definitions of modern human culture. Comparing similar behavioral forms as the product of similar selective pressures acting on specific early traits, producing homoplasies through convergent evolution, provides a nonanthropomorphic basis for seeking similarities in human and alloprimate behavior. PMID- 21274900 TI - Kinda baboons (Papio kindae) and grayfoot chacma baboons (P. ursinus griseipes) hybridize in the Kafue river valley, Zambia. AB - The ranges of small kinda (Papio kindae) and much larger grayfooted chacma (P. ursinus griseipes) baboons adjoin in the Kafue National Park, Zambia. In a visual survey of baboons at 48 sites in the Kafue River drainage we found that, contrary to previous reports, groups at the species interface near the town of Ngoma are phenotypically diverse and presumably formed by multigenerational hybridization. Mitochondrial and/or Y-chromosome genetic markers from fecal samples (N=164) collected at 29 sites support this conclusion. Groups with phenotypic signs of a history of hybridization also had taxon-specific mitochondria and Y-haplotypes from both parental species. Although the distribution of mitochondrial haplotypes largely mirrored that of external phenotypes, a significant proportion of male specimens from grayfoot as well as hybrid groups carried kinda Y-chromosomes, and kinda Y-chromosomes were involved in all observed cases of mitochondrial/Y chromosome discordance. These observations are consistent with, though they do not prove, a population history in which the range of chacmas and the hybrid zone have advanced at the expense of the kinda range. They also suggest that, unexpectedly, kinda male*chacma female matings are much more common than the reciprocal cross in the ancestry of hybrids. We suggest that distinctive male kinda behavior and the "juvenile" appearance of kinda baboons of both sexes, perhaps combined with obstetric difficulties of a small kinda female carrying the large offspring of a chacma male, may account for this bias. PMID- 21274901 TI - Key questions to consider in stalking cases. AB - Stalkers can inflict severe injury upon and have been known to kill their victims. Based on the detailed responses of 1,565 stalking victims, a set of key questions was produced with the aim of increasing the opportunities of police officers to identify potentially dangerous stalkers. Despite marked methodological differences and the inclusion of a large number of variables, regression analyses for significant correlates for physical assault per se and for severe violence largely reflected the results of earlier works. For severe violence (n=136), the most important correlate was a high level of victim fear, suggesting that victims are adept at assessing their own risk of stalker violence. The set of 11 questions performed well on preliminary tests and is presented here. PMID- 21274902 TI - 2D correlation spectra edited by the sign of relative coupling constant. AB - Modifications (CSEc and CSEh) of recently published SQSQc and SQSQh pulse sequences are proposed and tested on detection of small (~2 Hz) signed silicon carbon coupling constants. The new sequences increase signal intensity by simplifying the spectra. The signals are about four times stronger than in SQSQc or SQSQh spectra, achieving the sensitivity of E.COSY-type experiment. The information about sign and magnitude of the coupling is preserved. CSEc and CSEh spectra for two silicon compounds are presented and compared. The two new sequences allow editing of heteronuclear correlation spectra according to the sign of the selected heteronuclear coupling constants. PMID- 21274903 TI - NMR analysis of conformationally dependent (n)J(C, H) and (n)J(C, C) in the trisaccharide alpha-L-Rhap-(1 -> 2)[alpha-L-Rhap-(1 -> 3)]-alpha-L-Rhap-OMe and a site-specifically labeled isotopologue thereof. AB - An array of NMR spectroscopy experiments have been carried out to obtain conformationally dependent (1)H,(13)C- and (13)C,(13)C-spin-spin coupling constants in the trisaccharide alpha-L-Rhap-(1 -> 2)[alpha-L-Rhap-(1 -> 3)]-alpha L-Rhap-OMe. The trisaccharide was synthesized with (13)C site-specific labeling at C2' and C2", i.e. in the rhamnosyl groups in order to alleviate (1)H spectral overlap. This facilitated the measurement of a key trans-glycosidic proton-proton cross-relaxation rate using 1D (1)H,(1)H-T-ROESY experiments as well as a (3)J(C, H) coupling employing 1D (1)H,(13)C-long-range experiments, devoid of potential interference from additional J coupling. By means of both the natural abundance compound and the (13)C-labeled sample 2D (1)H,(13)C-J-HMBC and (1)H,(13)C-HSQC HECADE NMR experiments, total line-shape analysis of (1)H NMR spectra and 1D (13)C NMR experiments were employed to extract (3)J(C, H) , (2)J(C, H), (3)J(C, C), and (1)J(C, C) coupling constants. The (13)C site-specific labeling facilitates straightforward determination of (n)J(C, C) as the splitting of the (13)C natural abundance resonances. This study resulted in eight conformationally dependent coupling constants for the trisaccharide and illustrates the use of (13)C site-specific labeling as a valuable approach that extends the 1D and 2D NMR methods in current use to attain both hetero- and homonuclear spin-spin coupling constants that subsequently can be utilized for conformational analysis. PMID- 21274904 TI - Prevalence and incidence of delirium in long-term care. AB - OBJECTIVES: (1) To describe the prevalence and 6-month incidence of delirium in long-term care facility (LTCF) residents age 65 and over; (2) To describe differences in these measures by resident baseline characteristics. METHODS: A multisite, prospective observational study was conducted in seven LTCFs in the province of Quebec, Canada. Residents of age 65 and over were recruited into two cohorts: Cohort A with a Mini-Mental State Examination (MMSE) score of 10 or more and Cohort B with an MMSE score of less than 10. Baseline resident measurements were obtained from research resident assessments, nurse interviews, and chart review. Weekly resident assessments for up to 24 weeks included the Confusion Assessment Method (CAM). RESULTS: Two hundred seventy-nine residents were recruited and completed baseline delirium assessments: 204 in Cohort A and 75 in Cohort B. The prevalence of delirium at baseline was 3.4% in Cohort A and 33.3% in Cohort B. The incidence of delirium among those without delirium at baseline (per 100 person-weeks of follow-up) was 1.6 in Cohort A and 6.9 in Cohort B. In multivariate analyses, a diagnosis of dementia, moderate to severe cognitive impairment, and depressive symptoms at baseline were associated with a greater prevalence and incidence of delirium. CONCLUSION: Delirium is an important clinical problem in LTCF residents, particularly among those with moderate to severe cognitive impairment at baseline. PMID- 21274905 TI - Loneliness among the rural older people in Anhui, China: prevalence and associated factors. AB - OBJECTIVES: To clarify the prevalence of loneliness and evaluate the impact of social support, family function and socio-demographic factors on loneliness and their correlation among the rural older people in Anhui, China. METHODS: A sample of 5652 older people were surveyed using the UCLA (University of California at Los Angeles)-Loneliness Scale, the FAD (family assessment device), and the SSRS (Social Support Rating Scale). RESULTS: 78.1% of the older people had moderate to severe levels of loneliness. There was a great difference between loneliness level and subjects' age, marital status and income, family size and education level. Social support and family function were negatively associated with loneliness. Multiple regressions indicated that more social support and better family function offered protection against loneliness. CONCLUSIONS: The high rate of loneliness among rural older people in Anhui deserves attention. Family function and social support have played an important role in the development and course of loneliness. The strategy and intervention to alleviate loneliness among rural older people should be designed to enhance family function and social support. PMID- 21274907 TI - Ordered materials for organic electronics and photonics. AB - We present a critical review of semiconducting/light emitting, liquid crystalline materials and their use in electronic and photonic devices such as transistors, photovoltaics, OLEDs and lasers. We report that annealing from the mesophase improves the order and packing of organic semiconductors to produce state-of-the art transistors. We discuss theoretical models which predict how charge transport and light emission is affected by the liquid crystalline phase. Organic photovoltaics and OLEDs require optimization of both charge transport and optical properties and we identify the various trade-offs involved for ordered materials. We report the crosslinking of reactive mesogens to give pixellated full-colour OLEDs and distributed bi-layer photovoltaics. We show how the molecular organization inherent to the mesophase can control the polarization of light emitting devices and the gain in organic, thin-film lasers and can also provide distributed feedback in chiral nematic mirrorless lasers. We update progress on the surface alignment of liquid crystalline semiconductors to obtain monodomain devices without defects or devices with spatially varying properties. Finally the significance of all of these developments is assessed. PMID- 21274908 TI - ZnS nanostructure arrays: a developing material star. AB - Semiconductor nanostructure arrays are of great scientific and technical interest because of the strong non-linear and electro-optic effects that occur due to carrier confinement in three dimensions. The use of such nanostructure arrays with tailored geometry, array density, and length-diameter-ratio as building blocks are expected to play a crucial role in future nanoscale devices. With the unique properties of a direct wide-bandgap semiconductor, such as the presence of polar surfaces, excellent transport properties, good thermal stability, and high electronic mobility, ZnS nanostructure arrays has been a developing material star. The research on ZnS nanostructure arrays has seen remarkable progress over the last five years due to the unique properties and important potential applications of nanostructure arrays, which are summarized here. Firstly, a survey of various methods to the synthesis of ZnS nanostructure arrays will be introduced. Next recent efforts on exploiting the unique properties and applications of ZnS nanostructure arrays are discussed. Potential future directions of this research field are also highlighted. PMID- 21274909 TI - Spectroscopic characterization of charged defects in polycrystalline pentacene by time- and wavelength-resolved electric force microscopy. AB - Spatial maps of topography and trapped charge are acquired for polycrystalline pentacene thin-film transistors using electric and atomic force microscopy. In regions of trapped charge, the rate of trap clearing is studied as a function of the wavelength of incident radiation. PMID- 21274910 TI - Selective electron- or hole-transport enhancement in bulk-heterojunction organic solar cells with N- or B-doped carbon nanotubes. AB - Doping improves performance. N- or B-doped carbon nanotubes (CNTs) uniformly dispersed in the active layer of P3HT/PCMB (poly (3-hexylthiophene/[6,6]-phenyl C61-butyric acid methyl ester) bulk-heterojunction solar cells selectively enhance electron or hole transport and eventually help carrier collection. Specifically, the incorporation of 1.0 wt% B-doped CNTs results in balanced electron and hole transport and accomplishes a power conversion efficiency improvement from 3.0% (without CNTs) to 4.1%. PMID- 21274911 TI - Hierarchical nanostructures by sequential self-assembly of styrene dimethylsiloxane block copolymers of different periods. AB - Poly(styrene-block-dimethylsiloxane) (PS-b-PDMS) block copolymers with a period as low as 13 nm have been self-assembled on a template formed from PS-b-PDMS of a 34-40 nm period, which is itself templated by micron-scale substrate features prepared using conventional lithography. This hierarchical process provides a simple method for directing the self-assembly of sub-10 nm features and registering them on the substrate. PMID- 21274912 TI - Rechargeable Mg batteries with graphene-like MoS2 cathode and ultrasmall Mg nanoparticle anode. AB - The combination of a highly exfoliated, graphene-like MoS2 cathode and ultrasmall Mg nanoparticle anode is proposed, for the first time, for rechargeable Mg batteries. Such a configuration exhibits an operating voltage of 1.8 V and a well reversible discharge capacity of ca. 170 mA h g-1, emphasizing the necessity of rational morphological control of electrode materials and opening up new opportunities for rechargeable Mg batteries. PMID- 21274913 TI - Towards gigahertz operation: ultrafast low turn-on organic diodes and rectifiers based on C60 and tungsten oxide. AB - Ultrafast organic diodes with low turn-on voltage based on a junction between C60 and WO3 are proposed. The high electron mobility of C60 layers and the optimal work function of hexamethyldisilazane (HMDS)-treated WO3 layers together provide ideal diode characteristics including high rectification ratio and low turn-on voltage. Ultrahigh frequency (UHF) compatible rectifiers with a low voltage drop are demonstrated with the C60/WO3 diodes. PMID- 21274914 TI - Self-powered, ultrafast, visible-blind UV detection and optical logical operation based on ZnO/GaN nanoscale p-n junctions. AB - Ultrafast-response (20 MUs) UV detectors, which are visible-blind and self powered, in devices where an n-type ZnO nanowire partially lies on a p-type GaN film, are demonstrated. Moreover, a CdSe-nanowire red-light detector powered by a nanoscale ZnO/GaN photovoltaic cell is also demonstrated, which extends the device function to a selective multiwavelength photodetector and shows the function of an optical logical AND gate. PMID- 21274915 TI - Organic electronics on banknotes. AB - Organic transistors and circuits are fabricated directly on the surface of banknotes. The transistors operate with voltages of 3 V and have a field-effect mobility of about 0.2 cm2 V-1s-1. For an array of 100 transistors a yield of 92% is obtained. PMID- 21274916 TI - Directed 2D-to-3D pattern transfer method for controlled fabrication of topologically complex 3D features in silicon. AB - A process that allows control over the 3D motion of catalyst nanostructures during metal-assisted chemical etching by their local pinning prior to etching is demonstrated. The pinning material acts as a fulcrum for rotation of the catalyst structures resulting in etching of silicon features with rotational geometry. PMID- 21274917 TI - Highly flexible silver nanowire electrodes for shape-memory polymer light emitting diodes. AB - Shape-memory polymer light-emitting diodes (PLEDs) using a new silver nanowire/polymer electrode are reported. The electrode can be stretched by up to 16% with only a small increase in sheet resistance. Large deformation shape change and recovery of the PLEDs to various bistable curvatures result in minimal loss of electroluminescence performance. PMID- 21274918 TI - Reduced coercive field in BiFeO3 thin films through domain engineering. PMID- 21274919 TI - Mechanically durable superhydrophobic surfaces. AB - Development of durable non-wetting surfaces is hindered by the fragility of the microscopic roughness features that are necessary for superhydrophobicity. Mechanical wear on superhydrophobic surfaces usually shows as increased sticking of water, leading to loss of non-wettability. Increased wear resistance has been demonstrated by exploiting hierarchical roughness where nanoscale roughness is protected to some degree by large scale features, and avoiding the use of hydrophilic bulk materials is shown to help prevent the formation of hydrophilic defects as a result of wear. Additionally, self-healing hydrophobic layers and roughness patterns have been suggested and demonstrated. Nevertheless, mechanical contact not only causes damage to roughness patterns but also surface contamination, which shortens the lifetime of superhydrophobic surfaces in spite of the self-cleaning effect. The use of photocatalytic effect and reduced electric resistance have been suggested to prevent the accumulation of surface contaminants. Resistance to organic contaminants is more challenging, however, oleophobic surface patterns which are non-wetting to organic liquids have been demonstrated. While the fragility of superhydrophobic surfaces currently limits their applicability, development of mechanically durable surfaces will enable a wide range of new applications in the future. PMID- 21274921 TI - Activation of "inert" alkenyl/aryl C-O bond and its application in cross-coupling reactions. AB - Enol and phenol functionalities are very common in organic molecules. Utilization of these materials is very appealing in organic synthesis because they are important alternatives to organohalides in cross-coupling reactions. In this review, we summarize the transition-metal-catalyzed cross-coupling of enol- and phenol-based electrophiles, including phosphates, sulfonates, ethers, carboxylates, and phenolates. PMID- 21274922 TI - Highly stereoselective [4+2] cycloaddition of azlactones to beta,gamma unsaturated alpha-ketoesters catalyzed by an axially chiral guanidine base. PMID- 21274923 TI - Gold-catalyzed synthesis of 3-pyrrolidinones and nitrones from N-sulfonyl hydroxylamines via oxygen-transfer redox and 1,3-sulfonyl migration. PMID- 21274924 TI - Highly efficient gold nanoparticle catalyzed deoxygenation of amides, sulfoxides, and pyridine N-oxides. PMID- 21274925 TI - Aminotroponiminatozinc(I) complexes: syntheses and spectroscopic analyses. PMID- 21274926 TI - Helical chirality of azobenzenes induced by an intramolecular chiral axis and potential as chiroptical switches. PMID- 21274927 TI - Directed, remote gas-phase C-H and C-C bond activations by metal oxide cations anchored to a nitrile group. PMID- 21274928 TI - Regiodivergent addition of carbon units to dual-activated alkynes for stereoselective construction of tetrasubstituted alkenes. PMID- 21274929 TI - Alternating arrays of different conjugated polymers utilizing a synthetic cross linker. PMID- 21274930 TI - Synthesis and structure analysis of (K[DB18 C6])4(C60)5.12THF containing C60 in three different bonding states. AB - A new fulleride, (K[DB18C6])(4)(C(60))(5).12THF, was prepared in solution using the "break-and-seal" approach by reacting potassium, fullerene, and dibenzo[18]crown-6 in tetrahydrofuran. Single crystals were grown from solution by the modified "temperature difference method". X-ray analysis was performed revealing a reversible phase transition occurring on cooling. Three different crystal structures of the title compound at different temperatures of data acquisition are addressed in detail: the "high-temperature phase" at 225 K (C2, Z=2, a=49.055(1), b=15.075(3), c=18.312(4) A, beta=97.89(3) degrees ), the "transitional phase" at 175 K (C2 m, Z=2, a=48.436(5), b=15.128(1), c=18.280(2) A, beta=97.90(1) degrees ), and the "low-temperature phase" at 125 K (Cc, Z=4, a=56.239(1), b=15.112(3), c=36.425(7) A, beta=121.99(1) degrees ). On cooling, partial radical recombination of C(60)(.-) into the (C(60))(2)(2-) dimeric dianion occurs; this is first time that the fully ordered dimer has been observed. Further cooling leads to formation of a superstructure with doubled cell volume in a different space group. Below 125 K, C(60) exists in the structure in three different bonding states: in the form of C(60)(.-) radical ions, (C(60))(2)(2-) dianions, and neutral C(60), this being without precedent in the fullerene chemistry, as well. Experimental observations of one conformation exclusively of the fullerene dimer in the crystal structure are further explained on the basis of DFT calculations considering charge distribution patterns. Temperature-dependent measurements of magnetic susceptibility at different magnetic fields confirm the phase transition occurring at about 220 K as observed crystallographically, and enable for unambiguous charge assignment to the different C(60) species in the title fulleride. PMID- 21274931 TI - Direct determination of bioavailable molybdenum in carbon nanotubes. AB - Bioavailable residual metallic impurities within carbon nanotubes (CNTs) are responsible for the toxicity of CNTs. Herein we present a method for fast, sensitive determination of bioavailable molybdenum residual catalyst impurities within CNTs by using electrochemical oxidation in neutral pH buffers at low potentials. This method is unique because no other method can rapidly distinguish between bioavailable/mobilizable impurities from defects in CNTs and between the total amounts of impurities. This method will be indispensable for future toxicological studies of CNTs. PMID- 21274932 TI - Bijvoet in solution reveals unexpected stereoselectivity in a Michael addition. AB - The absolute configuration of small crystallizable molecules can be determined with anomalous X-ray diffraction as shown by Bijvoet in 1951. For the majority of compounds that can neither be crystallized nor easily be converted into crystallizable derivatives, stereocontrolled organic synthesis is still required to establish their absolute configuration. In this contribution, a new fundamental methodology for resolving the absolute configuration will be presented that does not require crystallization. With residual dipolar coupling enhanced NMR spectroscopy, ensembles of a limited number of structures are created reflecting the correct conformations and relative configuration. Subsequently, from these ensembles, optical rotation dispersion (ORD) spectra are predicted by DFT calculations and compared to experimental results. The combination of these two steps reveals the absolute configuration of a flexible molecule in solution, which is a big challenge to chiroptical methods and DFT in the absence of NMR spectroscopy. Here the absolute stereochemistry of the product of a new Michael addition, synthesized via a niobium(V) chiral enolate, will be elucidated by using the new methodology. PMID- 21274933 TI - The influence of linker geometry in bis(3-hydroxy-N-methyl-pyridin-2-one) ligands on solution phase uranyl affinity. AB - Seven water-soluble, tetradentate bis(3-hydroxy-N-methyl-pyridin-2-one) (bis-Me 3,2-HOPO) ligands were synthesized that vary only in linker geometry and rigidity. Solution-phase thermodynamic measurements were conducted between pH 1.6 and pH 9.0 to determine the effects of these variations on proton and uranyl cation affinity. Proton affinity decreases by introduction of the solubilizing triethylene glycol group as compared to unsubstituted reference ligands. Uranyl affinity was found to follow no discernable trends with incremental geometric modification. The butyl-linked 4 li-Me-3,2-HOPO ligand exhibited the highest uranyl affinity, consistent with prior in vivo decorporation results. Of the rigidly-linked ligands, the o-phenylene linker imparted the best uranyl affinity to the bis-Me-3,2-HOPO ligand platform. PMID- 21274934 TI - Copper-catalyzed azide-alkyne cycloaddition in the synthesis of polydiacetylene: "click glycoliposome" as biosensors for the specific detection of lectins. AB - Supramolecular self-assembly of conjugated diacetylenic amphiphile-tethered ligands photopolymerize to afford polydiacetylene (PDA) functional liposomes. Upon specific interaction with a variety of biological analytes in aqueous solution, PDA exhibits rapid colorimetric transitions. The PDA nanoassemblies, which are excellent membrane mimics, include an ene-yne polymeric reporter responsible for the chromatic transitions and the molecular recognition elements that are responsible for selective and specific binding to the biological target. A bottleneck in the fabrication of these colorimetric biosensors is the preparation of the diacetylenic monomer embedded with the recognition element of choice. In the present work, we make use of copper-catalyzed azide-alkyne cycloaddition (CuAAC) as key step in the preparation of sugar-coated liposome biosensors. The regioselective click ligation of the triacetylenic N-(2 propynyl)pentacosa-10,12-diynamide (NPPCDAM) with a variety of mannose- and lactose-tethered azides afforded chemo- and regioselectively the corresponding 1,2,3-triazole. The obtained diacetylenic monomers were incorporated efficiently into vesicles to afford functional mannose- and lactose-coated glycoliposomes. The obtained PDA-based click glycoliposomes have been characterized by using transmission electronic microscopy (TEM), dynamic light scattering (DLS), and UV/Vis spectroscopy. The efficiency of the reported approach was demonstrated by the rapid optimization of the hydrophilic spacer between the lipidic matrix and the mannose head group for the colorimetric detection of Concavalin A. PMID- 21274935 TI - Elucidating gating effects for hydrogen sorption in MFU-4-type triazolate-based metal-organic frameworks featuring different pore sizes. AB - A highly porous member of isoreticular MFU-4-type frameworks, [Zn(5)Cl(4)(BTDD)(3)] (MFU-4l(arge)) (H(2)-BTDD=bis(1H-1,2,3-triazolo[4,5 b],[4',5'-i])dibenzo[1,4]dioxin), has been synthesized using ZnCl(2) and H(2) BTDD in N,N-dimethylformamide as a solvent. MFU-4l represents the first example of MFU-4-type frameworks featuring large pore apertures of 9.1 A. Here, MFU-4l serves as a reference compound to evaluate the origin of unique and specific gas sorption properties of MFU-4, reported previously. The latter framework features narrow-sized pores of 2.5 A that allow passage of sufficiently small molecules only (such as hydrogen or water), whereas molecules with larger kinetic diameters (e.g., argon or nitrogen) are excluded from uptake. The crystal structure of MFU 4l has been solved ab initio by direct methods from 3D electron-diffraction data acquired from a single nanosized crystal through automated electron diffraction tomography (ADT) in combination with electron-beam precession. Independently, it has been solved using powder X-ray diffraction. Thermogravimetric analysis (TGA) and variable-temperature X-ray powder diffraction (XRPD) experiments carried out on MFU-4l indicate that it is stable up to 500 degrees C (N(2) atmosphere) and up to 350 degrees C in air. The framework adsorbs 4 wt % hydrogen at 20 bar and 77 K, which is twice the amount compared to MFU-4. The isosteric heat of adsorption starts for low surface coverage at 5 kJ mol(-1) and decreases to 3.5 kJ mol(-1) at higher H(2) uptake. In contrast, MFU-4 possesses a nearly constant isosteric heat of adsorption of ca. 7 kJ mol(-1) over a wide range of surface coverage. Moreover, MFU-4 exhibits a H(2) desorption maximum at 71 K, which is the highest temperature ever measured for hydrogen physisorbed on metal-organic frameworks (MOFs). PMID- 21274936 TI - Protein nanotubes with an enzyme interior surface. AB - This report describes the synthesis and enzyme activities of multilayered protein nanotubes with an alpha-glucosidase (alphaGluD) interior surface. The nanotubes were prepared by using an alternating layer-by-layer (LbL) assembly of human serum albumin (HSA) and oppositely charged poly-L-arginine (PLA) into a track etched polycarbonate (PC) membrane (pore size=400 nm) followed by addition of alphaGluD as the last layer of the wall. Subsequent dissolution of the PC template yielded (PLA/HSA)(2)PLA/alphaGluD nanotubes. SEM measurements revealed the formation of uniform hollow cylinders with (413+/-17) nm outer diameter and (52+/-3) nm wall thickness. In aqueous media, the nanotubes captured a fluorogenic glucopyranoside, 4-methyl-umbelliferyl-alpha-D-glucopyranoside (MUGlc), into their one-dimensional pore space and hydrolyzed the substrate efficiently to form alpha-D-glucose. We determined the enzyme parameters (Michaelis constant, K(M), and catalytic constant, k(cat), values) of the protein nanotubes. The several-micrometers-long cylinders were of sufficient length to be spun down by centrifugation at 4000 g, so the product could therefore be easily separated. Similar biocatalysts were prepared by complexation of biotinylated alphaGluD into HSA-based nanotubes bearing a single avidin layer as an internal surface. The obtained hybrid nanotubes also exhibited the same enzyme activity for the MUGlc hydrolysis. PMID- 21274937 TI - On the significance of the anchoring group in the design of antenna materials based on phthalocyanine stopcocks and zeolite L. AB - The synthesis of stopcocks based on zinc phthalocyanine for selective adsorption at the channel entrances of zeolite L is reported. The introduction of either an inert SiMe3 moiety, an imidazolium cation or a reactive isothiocyanate (NCS) group allows attachment to the channel entrances of zeolite L through van der Waals interactions, electrostatic interactions, or covalent binding, respectively. Stopcocks that rely on van-der-Waals-driven adsorption require careful selection of the solvent used for the deposition onto the zeolite surface to avoid a nonspecific distribution of the molecules. Regarding the design of photonic antenna systems, a stopcock with a cationic tail was found to be the most convenient, based on the observation that efficient energy transfer from molecules located in the zeolite nanochannels is more readily obtained than in the other cases. PMID- 21274938 TI - Exploring electronic versus steric effects in stereoselective ring-opening polymerization of lactide and beta-butyrolactone with amino-alkoxy-bis(phenolate) yttrium complexes. AB - A series of methoxy-amino-bis(phenol)s (ONOO(R(1),R(2)))H(2) possessing on the phenol rings R(1) ortho substituents with variable steric and electronic properties (R(1)=CMe(2)Ph, 1; CMe(2)tBu, 3; CMe(2)(4-CF(3)C(6)H(4)), 5; CPh(3), 9; Cl, 10) has been synthesized and further reacted with [Y{N(SiHMe(2))(2)}(3)](THF)(2) to give cleanly the corresponding yttrium compounds [Y(ONOO(R(1),R(2))){N(SiHMe(2))(2)}(thf)(n)] (Y-x); the solid-state structures of Y-3 and Y-10 have been determined. These amido complexes have been used as initiators for the ring-opening polymerization (ROP) of rac-lactide (LA) and rac-beta-butyrolactone (BBL) to provide heterotactically enriched poly(lactic acid)s (PLAs) and syndiotactically enriched poly(3-hydroxybutyrate)s (PHBs), respectively, by means of a chain-end control mechanism. Most of these polymerizations proceeded in a controlled fashion, giving polymers with narrow polydispersities and experimental molecular weights in good agreement with calculated values. The nature of the R(1) ortho substituents has a profound impact on the rates and, more spectacularly, on the stereocontrol of the polymerizations. The heterotactic stereocontrol in the ROP of rac-LA appears to be governed essentially by steric considerations; the larger the substituent, the higher the heterotacticity: R(1)=Cl (P(r)=0.56)?CMe(3) (P(r)=0.80)?CMe(2)Ph (P(r)=0.90) 0.05 for all but the upper portion of the right lung. The distribution of regional ventilation was evaluated by calculating ventilation gradients in the superior/inferior (S/I) direction. The average S/I gradient obtained using the (3)He MRI method was found to be 0.17 +/- 0.04 cm(-1) , whereas the average S/I gradient obtained using the Xe-CT method was found to be 0.016 +/- 0.005 cm(-1) . In general, S/I ventilation gradients obtained from both methods were significantly different from each other (p = 0.0019 by two-tailed paired t-test). These regional differences in ventilation measurements may be caused by the manner in which the gas contrast agents distribute physiologically and/or by the imaging modality. PMID- 21274967 TI - MRI of the prostate: clinical relevance and emerging applications. AB - MRI of the prostate can aid in many aspects of prostate cancer management, from initial detection to treatment planning and follow-up. This review describes the current strengths and limitations of conventional anatomic and molecular MR imaging techniques (including MR spectroscopic imaging and dynamic contrast enhanced imaging) for aiding prostate cancer management. It also describes promising emerging approaches for acquiring, analyzing, and applying MR imaging data, and the major research and educational efforts that will be required to realize the potential of prostate MR imaging in routine clinical practice. PMID- 21274965 TI - Aurora kinase-A regulates microtubule organizing center (MTOC) localization, chromosome dynamics, and histone-H3 phosphorylation in mouse oocytes. AB - Aurora kinases (AURKs) are conserved serine/threonine kinases, crucial in regulating cell cycle events. Mammalian oocytes express all three Aurk isoforms throughout meiosis, with AurkA being the predominant isoform. Inhibition of all AURK isoforms by pharmacological means disrupts oocyte meiosis. Therefore, AurkA short interfering RNA (siRNA) was performed to silence AurkA gene expression in mouse oocytes and to further assess the function of AurkA during meiosis by analyzing subsequent loss-of-function oocyte phenotypes. Results indicated that AurkA siRNA applied in our experiments specifically knocked down both AurkA gene and protein expression without influencing transcript levels of AurkB/AurkC and other endogenous protein expression, such as GAPDH and ERK-2. AURKA was not essential for resumption of meiosis, but it potentiated oocyte meiotic progression. Knockdown of AurkA led to a significant reduction in the number of oocytes proceeding to metaphase II (MII). AurkA siRNA resulted in abnormal spindle assembly, improper localization of microtubule organizing centers (MTOCs) and misalignment of chromosomes in metaphase I (MI) oocytes. Co immunoprecipitations demonstrated that AURKA was physically associated with phospho-Histone H3 ser10 in meiotic oocytes. AurkA siRNA dramatically reduced Histone H3 ser10 phosphorylation, but not ser28, and resulted in a significant increase of abnormal chromosome segregation in MII oocytes. In conclusion, as a predominant isoform among Aurks in oocytes, AurkA plays critical roles in mouse oocyte meiosis by regulating spindle and chromosome dynamics. PMID- 21274968 TI - Cardiovascular MRI for the assessment of heart failure: focus on clinical management and prognosis. AB - Cardiovascular MR (CMR) has an emerging role in the noninvasive diagnostic assessment of heart failure (HF). Different imaging sequences allow for a detailed assessment of cardiac morphology, function, myocardial perfusion, tissue characterization, and blood flow measurement. This article reviews the key applications of CMR in HF, with special focus on how CMR may influence the diagnostic and therapeutic approach of HF patients. PMID- 21274969 TI - Whole-brain cerebral blood flow mapping using 3D echo planar imaging and pulsed arterial tagging. AB - PURPOSE: To quantitate cerebral blood flow (CBF) in the entire brain using the 3D echo planar imaging (EPI) PULSAR (pulsed star labeling) technique. MATERIALS AND METHODS: The PULSAR technique was modified to 1) incorporate a nonselective inversion pulse to suppress background signal; 2) to use 3D EPI acquisition; and 3) to modulate flip angle in such a manner as to minimize the blurring resulting from T1 modulation along the slice encoding direction. Computation of CBF was performed using the general kinetic model (GKM). In a series of healthy volunteers (n = 12), we first investigated the effects of introducing an inversion pulse on the measured value of CBF and on the temporal stability of the perfusion signal. Next we investigated the effect of flip angle modulation on the spatial blurring of the perfusion signal. Finally, we evaluated the repeatability of the CBF measurements, including the influence of the measurement of arterial blood magnetization (a calibration factor for the GKM). RESULTS: The sequence provides sufficient perfusion signal to achieve whole brain coverage in ~ 5 minutes. Introduction of the inversion pulse for background suppression did not significantly affect computed CBF values, but did reduce the fluctuation in the perfusion signal. Flip angle modulation reduced blurring, resulting in higher estimates of gray matter (GM) CBF and lower estimates of white matter (WM) CBF. The repeatability study showed that measurement of arterial blood signal did not result in significantly higher error in the perfusion measurement. CONCLUSION: Improvements in acquisition and sequence preparation presented here allow for better quantification and localization of perfusion signal, allowing for accurate whole-brain CBF measurements in 5 minutes. PMID- 21274970 TI - Support vector machine multiparametric MRI identification of pseudoprogression from tumor recurrence in patients with resected glioblastoma. AB - PURPOSE: To automatically differentiate radiation necrosis from recurrent tumor at high spatial resolution using multiparametric MRI features. MATERIALS AND METHODS: MRI data retrieved from 31 patients (15 recurrent tumor and 16 radiation necrosis) who underwent chemoradiation therapy after surgical resection included post-gadolinium T1, T2, fluid-attenuated inversion recovery, proton density, apparent diffusion coefficient (ADC), and perfusion-weighted imaging (PWI) derived relative cerebral blood volume (rCBV), relative cerebral blood flow (rCBF), and mean transit time maps. After alignment to post contrast T1WI, an eight-dimensional feature vector was constructed. An one-class-support vector machine classifier was trained using a radiation necrosis training set. Classifier parameters were optimized based on the area under receiver operating characteristic (ROC) curve. The classifier was then tested on the full dataset. RESULTS: The sensitivity and specificity of optimized classifier for pseudoprogression was 89.91% and 93.72%, respectively. The area under ROC curve was 0.9439. The distribution of voxels classified as radiation necrosis was supported by the clinical interpretation of follow-up scans for both nonprogressing and progressing test cases. The ADC map derived from diffusion weighted imaging and rCBV, rCBF derived from PWI were found to make a greater contribution to the discrimination than the conventional images. CONCLUSION: Machine learning using multiparametric MRI features may be a promising approach to identify the distribution of radiation necrosis tissue in resected glioblastoma multiforme patients undergoing chemoradiation. PMID- 21274971 TI - MR spectroscopy of normative premature newborns. AB - PURPOSE: To establish normative metabolite ratios throughout the newborn brain using three-dimensional (3D) MR spectroscopic imaging (MRSI). MATERIALS AND METHODS: MRI and MRSI have been valuable tools for assessing normal and abnormal neuronal maturation for newborns. In this study, we performed whole brain 3D MRSI in addition to comprehensive anatomic and other functional imaging methods to examine maturation. Fifty-five newborn subjects (28.4 +/- 2.6 weeks postconception age at birth, 34.1 +/- 3.1 weeks postconception age at scan, 32 males and 23 females) had high quality MRSI studies (104 exams) and normal neurodevelopmental outcome (neuromotor score = 0, mental development index score > 85) at age 12 months. RESULTS: The NAA to Cho ratio increased significantly with age for all regions. Lac to NAA ratio decreased significantly with age in the regions of thalamus, basal ganglia, cortical spinal tract, and parietal white matter, and showed a decreasing trend in the other regions. CONCLUSION: Brain metabolites can be obtained through in vivo 3D MRSI and used to monitor newborn brain maturation. PMID- 21274972 TI - Left ventricular diastolic function assessment from three-dimensional three directional velocity-encoded MRI with retrospective valve tracking. AB - PURPOSE: To compare parameters describing left ventricular (LV) diastolic function obtained with three-dimensional (3D) three-directional velocity-encoded (VE) MRI with retrospective valve tracking and two-dimensional (2D) one directional VE MRI in patients with ischemic heart failure. Second, to compare classification of LV diastolic function, and in particular for discriminating restrictive filling patterns, with both MRI techniques versus Doppler echocardiography. MATERIALS AND METHODS: The 3D and 2D VE MRI early (E) and atrial (A) peak flow rate indices, determined from transmitral waveform analyses, were compared. Also, net forward flow volume per cycle and transmitral regurgitation fraction were determined. Agreement in classifying diastolic filling patterns between 3D and 2D VE MRI versus Doppler echocardiography was evaluated using kappa statistics. RESULTS: The 3D three-directional VE MRI with retrospective valve tracking was statistically significantly different from 2D one-directional VE MRI for net forward flow volume and regurgitation fraction through the mitral valve and all parameters describing the diastolic waveform filling pattern, except for the E deceleration time and E/A filling ratio. Kappa agreement between 3D three-directional VE MRI with retrospective valve tracking and echocardiography for classifying diastolic filling patterns was superior to 2D one-directional VE MRI and echocardiography (i.e., kappa = 0.91 versus kappa = 0.79, respectively). CONCLUSION: The 3D three-directional VE MRI with retrospective valve tracking better describes LV diastolic function as compared to 2D one-directional VE MRI in patients with ischemic heart failure. PMID- 21274973 TI - T(2) preparation method for measuring hyperemic myocardial O(2) consumption: in vivo validation by positron emission tomography. AB - PURPOSE: To validate a new T(2) -prepared method for the quantification of regional myocardial O(2) consumption during pharmacologic stress with positron emission tomography (PET). MATERIALS AND METHODS: A T(2) prepared gradient-echo sequence was modified to measure myocardial T(2) within a single breath-hold. Six beagle dogs were randomly selected for the induction of coronary artery stenosis. Magnetic resonance imaging (MRI) experiments were performed with the T(2) imaging and first-pass perfusion imaging at rest and during either dobutamine- or dipyridamole-induced hyperemia. Myocardial blood flow (MBF) was quantified using a previously developed model-free algorithm. Hyperemic myocardial O(2) extraction fraction (OEF) and consumption (MVO(2) ) were calculated using a two-compartment model developed previously. PET imaging using (11) C-acetate and (15) O-water was performed in the same day to validate OEF, MBF, and MVO(2) measurements. RESULTS: The T(2) -prepared mapping sequence measured regional myocardial T(2) with a repeatability of 2.3%. By myocardial segment-basis analysis, MBF measured by MRI is closely correlated with that measured by PET (R(2) = 0.85, n = 22). Similar correlation coefficients were observed for hyperemic OEF (R(2) = 0.90, n = 9, mean difference of PET - MRI = -2.4%) and MVO(2) (R(2) = 0.83, n = 7, mean difference = 4.2%). CONCLUSION: The T(2) -prepared imaging method may allow quantitative estimation of regional myocardial oxygenation with relatively good accuracy. The precision of the method remains to be improved. PMID- 21274974 TI - Optimized density-weighted imaging for dynamic contrast-enhanced 3D-MR mammography. AB - PURPOSE: To increase the spatial coverage and to reduce slice crosstalk combined with an optimal signal-to-noise ratio (SNR) in 3D dynamic contrast-enhanced (DCE) magnetic resonance (MR) mammography. MATERIALS AND METHODS: Asymmetric sampling schemes and a new reconstruction strategy based on virtual coils are presented for density-weighted (DW) 3D imaging. Additionally, for MR mammography an alternating DW (ADW) sampling along the k(y) direction shifts the undersampling artifacts out of the signal reception region. Virtual coils for effective DW (VIDED) imaging suppresses the aliasing in undersampled DW imaging. VIDED and ADW were compared to the conventional Cartesian imaging in phantom and in vivo MR mammography studies. RESULTS: The slice crosstalk was significantly reduced by VIDED and compared to Cartesian imaging the SNR increased by 16%. Additionally, VIDED and ADW provided a substantially increased field of view (FOV) in the slice direction and allowed the spatial resolution to be improved (up to 60% for ADW and 30% for VIDED) without lengthening the scan time. CONCLUSION: VIDED and ADW improve the image quality in 3D DCE MR mammography by enhancing the spatial resolution, reducing the slice crosstalk at nearly optimal SNR, and increasing the FOV in the slice direction. For VIDED no lengthening of the scan time or usage of multichannel receiver coils is necessary. PMID- 21274975 TI - Dynamic contrast-enhanced MRI of primary rectal cancer: quantitative correlation with positron emission tomography/computed tomography. AB - PURPOSE: To assess the correlations between parameters measured on dynamic contrast-enhanced magnetic resonance imaging and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in rectal cancer. MATERIALS AND METHODS: To assess the correlations between parameters measured on dynamic contrast-enhanced MRI and FDG-PET in rectal cancer. RESULTS: Significant correlations were only demonstrated between k(ep) and SUVmax (r = 0.587, P = 0.001), and k(ep) and SUVmean (r = 0.562, P = 0.002). No significant differences were found in imaging parameters between well, moderately and poorly differentiated adenocarcinoma groups. However, there was a trend that higher imaging values were found in poorly differentiated adenocarcinomas. CONCLUSION: Positive correlations were found between k(ep) and SUV values in primary rectal adenocarcinomas suggesting an association between angiogenesis and metabolic activity and further reflecting that angiogenic activity in washout phase is better associated with tumor metabolism than the uptake phase. PMID- 21274976 TI - Single region of interest versus multislice T2* MRI approach for the quantification of hepatic iron overload. AB - PURPOSE: To evaluate the effectiveness of the single ROI approach for the detection of hepatic iron burden in thalassemia major (TM) patients in respect to a whole liver measurement. MATERIALS AND METHODS: Five transverse hepatic slices were acquired by a T2* gradient-echo sequence in 101 TM patients and 20 healthy subjects. The T2* value was calculated in a single region of interest (ROI) defined in the medium-hepatic slice. Moreover, the T2* value was extracted on each of the eight ROIs defined in the functionally independent segments. The mean hepatic T2* value was calculated. RESULTS: For patients, the mean T2* values over segments VII and VIII were significantly lower. This pattern was substantially preserved in the two groups identified considering the T2* normal cutoff. All segmental T2* values were correlated with the single ROI T2* value. After the application of a correction map based on T2* fluctuations in the healthy subjects, no significant differences were found in the segmental T2* values. CONCLUSION: Hepatic T2* variations are low and due to artifacts and measurement variability. The single ROI approach can be adopted in the clinical arena, taking care to avoid the susceptibility artifacts, occurring mainly in segments VII and VIII. PMID- 21274977 TI - Diffusion MRI predicts transrectal ultrasound biopsy results in prostate cancer detection. AB - PURPOSE: To evaluate the ability of diffusion tensor imaging (DTI) to predict the transrectal ultrasound (TRUS) biopsy outcomes in persons who have no history of previous TRUS biopsy and present with elevated prostate-specific antigen (PSA) levels. MATERIALS AND METHODS: Thirty-seven participants underwent DTI, followed by 12-core TRUS-guided needle biopsy within 2 weeks. DTI was performed using endorectal coils on a 1.5 Tesla scanner at 1-mm(3) spatial resolution. By comparing with the TRUS biopsy results, the optimum thresholds of the trace apparent diffusion coefficient (tADC) and of the nodular size were investigated. The diagnostic performance of both criteria, the tADC threshold (Criteria A) and the tADC threshold combined with nodular size threshold (Criteria B), were evaluated. RESULTS: The optimum tADC threshold was 1.0 MUm(2)/ms. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of prostate cancer (PCA) detection for Criteria A were 98%, 89%, 73%, 99%, and 91%, respectively, and were 97%, 98%, 92%, 99% and 98% for Criteria B. CONCLUSION: Owing to high negative predictive value, the tADC threshold could be used to exclude subjects with clinically undetectable PCA. Adding the nodular size threshold, the combined threshold could identify the tADC-positive segments that are likely to yield positive biopsy results. PMID- 21274978 TI - Measuring bone erosion and edema in rheumatoid arthritis: a comparison of manual segmentation and RAMRIS methods. AB - PURPOSE: To investigate the reliability, feasibility, and validity of a computer assisted manual segmentation (outlining) technique for measuring magnetic resonance imaging (MRI) bone erosion and edema at the wrist in rheumatoid arthritis (RA). MATERIALS AND METHODS: The 3T MRI scans were obtained in 22 RA patients (<2 years). Bone erosion and edema volumes were scored by two readers using outlining and were compared with RAMRIS scores. RESULTS: Using outlining, intraobserver reliability for erosions and edema was high: intraclass correlation coefficients (ICCs) = 0.994 (0.991, 0.997) and 0.996 (0.994, 0.998), respectively (Reader 1). Interobserver reliability was high for bone erosion (ICC [90% confidence interval, CI] = 0.80 [0.64, 0.92]) and comparable to RAMRIS scoring (ICC 0.78 [0.64, 0.92]), but was only moderate for bone edema (0.46 [0.00, 0.96]), compared with RAMRIS (ICC = 0.84 [0.73, 0.94]). The methods were highly correlated for erosion scores, r = 0.90, 0.82 (Readers 1 and 2) and moderately correlated for edema, r = 0.57, 0.87. CONCLUSION: Segmentation (outlining) can be used to measure the volume of MRI bone erosion and edema at the wrist in RA patients. When compared with RAMRIS scoring, outlining had similar reliability for quantifying erosions but reliability was lower for bone edema, possibly reflecting difficulty delineating the borders of affected bone. PMID- 21274979 TI - Performance of MUMRI-Based virtual bone biopsy for structural and mechanical analysis at the distal tibia at 7T field strength. AB - PURPOSE: To assess the performance of a 3D fast spin echo (FSE) pulse sequence utilizing out-of-slab cancellation through phase alternation and micro-magnetic resonance imaging (MUMRI)-based virtual bone biopsy processing methods to probe the serial reproducibility and sensitivity of structural and mechanical parameters of the distal tibia at 7.0T. MATERIALS AND METHODS: The distal tibia of five healthy subjects was imaged at three timepoints with a 3D FSE sequence at 137 * 137 * 410 MUm(3) voxel size. Follow-up images were retrospectively 3D registered to baseline images. Coefficients of variation (CV) and intraclass correlation coefficients (ICCs) for measures of scale and topology of the whole tibial trabecular bone (TB) cross-section as well as finite-element-derived Young's and shear moduli of central cuboidal TB subvolumes (8 * 8 * 5 mm(3) ) were evaluated as measures of reproducibility and reliability. Four additional cubic TB subregions (anterior, medial, lateral, and posterior) of similar dimensions were extracted and analyzed to determine associations between whole cross-section and subregional structural parameters. RESULTS: The mean signal-to noise ratio (SNR) over the 15 image acquisitions was 27.5 +/- 2.1. Retrospective registration yielded an average common analysis volume of 67% across the three exams per subject. Reproducibility (mean CV = 3.6%; range, 1.5%-5%) and reliability (ICCs, 0.95-0.99) of all parameters permitted parameter-based discrimination of the five subjects in spite of the narrow age range (26-36 years) covered. Parameters characterizing topology were better able to distinguish two individuals who demonstrated similar values for scalar measurements (~ 34% difference, P < 0.001). Whole-section axial stiffness encompassing the cortex was superior at distinguishing two individuals relative to its central subregional TB counterpart (~ 8% difference; P < 0.05). Interregion comparisons showed that although all parameters were correlated (mean R(2) = 0.78; range 0.57-0.99), the strongest associations observed were those for the erosion index (mean R(2) = 0.95, P <= 0.01). CONCLUSION: The reproducibility and structural and mechanical parameter-based discriminative ability achieved in five healthy subjects suggests that 7T-derived MUMRI of TB can be applied towards serial patient studies of osteoporosis and may enable earlier detection of disease or treatment-based effects. PMID- 21274980 TI - Degenerative endplate changes of the lumbosacral spine: dynamic contrast-enhanced MRI profiles related to age, sex, and spinal level. AB - PURPOSE: To investigate differences in perfusion profiles between degenerative endplate marrow changes and normal vertebral marrow in relation to spinal level, age, and sex with dynamic contrast-enhanced magnetic resonance imaging (DCE MRI). MATERIALS AND METHODS: Ninety-two consecutive patients referred for evaluation of low back pain or sciatica, without history of malignant or chronic disease, underwent conventional and DCE MRI of the lumbosacral spine. Fifty-two of them demonstrated degenerative endplate marrow changes. Regions of interest were placed on sites of normal marrow (group A) and degenerative changes (group B) on subtracted images. Fitted time-intensity curves (fTICs) were generated and evaluated for curve pattern. Both groups were stratified into upper (L1-L2) and lower (L3-I1) levels, males and females younger or older than 50 years. Perfusion parameters were calculated and statistically compared for both groups and subgroups. Receiver operator curve (ROC) analysis was also performed. RESULTS: Two fTIC patterns were identified. Perfusion parameters of degenerative changes and normal marrow differed significantly, even when groups were stratified for spinal level, age, and sex (P < 0.05). A time to peak value >108 seconds was characteristic for degenerative changes with sensitivity 69.5% and specificity 84.6%. CONCLUSION: DCE MRI profiles of degenerative endplate marrow changes of the lumbosacral spine differ significantly from normal marrow regardless of spinal level, age, or sex. PMID- 21274981 TI - Fast spin-echo triple echo dixon: Initial clinical experience with a novel pulse sequence for simultaneous fat-suppressed and nonfat-suppressed T2-weighted spine magnetic resonance imaging. AB - PURPOSE: To evaluate a prototype fast spin-echo (FSE) triple-echo Dixon (FTED) technique for T2-weighted spine imaging with and without fat suppression compared to conventional T2-weighted fast recovery (FR) FSE and short-tau inversion recovery (STIR) imaging. MATERIALS AND METHODS: Sixty-one patients were referred for spine magnetic resonance imaging (MRI) including sagittal FTED (time 2:26), STIR (time 2:42), and T2 FRFSE (time 2:55). Two observers compared STIR and FTED water images and T2 FRFSE and FTED T2 images for overall image quality, fat suppression, anatomic sharpness, motion, cerebrospinal fluid (CSF) flow artifact, susceptibility, and disease depiction. RESULTS: On FTED images water and fat separation was perfect in 58 (.95) patients. Compared to STIR, the FTED water images demonstrated less motion in 57 (.93) of 61 patients (P < 0.05), better anatomic sharpness in 51 (.84) and patients (P < 0.05), and less CSF flow artifact in 7 (.11) P < 0.05) patients. There was no difference in fat suppression or chemical shift artifact. T2 FRFSE and FTED T2 images showed equivalent motion, CSF flow, and chemical shift artifact. Lesion depiction was equivalent on FTED water and STIR images and FTED T2 and T2 FRFSE images. CONCLUSION: FTED efficiently provides both fat-suppressed and nonfat-suppressed T2-weighted spine images with excellent image quality, equal disease depiction, and 56% reduction in scan time compared to conventional STIR and T2 FRFSE. PMID- 21274982 TI - Nonenhanced methods for lower-extremity MRA: a phantom study examining the effects of stenosis and pathologic flow waveforms at 1.5T. AB - PURPOSE: To evaluate the signal properties of 2D time of flight (TOF), quiescent interval single-shot (QISS), ECG-gated 3D fast spin-echo (FBI), and ungated 3D fast spin-echo ghost (Ghost) magnetic resonance angiography (MRA) over a range of flow velocities in a pulsatile flow phantom with a 50% diameter stenosis at 1.5T. MATERIALS AND METHODS: Blood-mimicking fluid was pumped at eight peak flow velocities through a stenotic region in triphasic and monophasic waveforms. Vascular signal proximal, within, and distal to the stenosis was measured from the source images of the four MRA methods. Coronal maximum intensity projection images were used to compare image quality. RESULTS: TOF and QISS signal trends were similar, but QISS exhibited the most consistent signal across velocities. At high velocities (>= 42.4 cm/s), TOF showed poststenotic signal loss that was not observed with QISS. FBI and Ghost signals peaked at low velocities (3.9-9.7 cm/s) without flow compensation and at high velocities (>= 64.6 cm/s) with flow compensation. CONCLUSION: FBI and Ghost demonstrated dependence on blood flow velocity and flow compensation. TOF was sensitive to flow artifacts at high velocities. QISS proved most robust for accurately depicting the normal lumen and stenosis under a wide range of flow conditions. Monophasic and triphasic flow did not appreciably affect the signal performance of any method. PMID- 21274984 TI - Susceptibility-related MR signal dephasing under nonstatic conditions: experimental verification and consequences for qBOLD measurements. AB - PURPOSE: To experimentally verify a theoretical model describing the MR signal dephasing under nonstatic conditions in a voxel containing a vascular network, and to estimate the stability of the model for qBOLD measurements. MATERIALS AND METHODS: Measurement phantoms reflecting the properties of the theoretical model, i.e., statistically distributed and randomly oriented cylinders in a homogeneous medium were constructed by randomly coiled polyamide fibers immersed in a NiSO(4) solution. The resemblance between measured and theoretical signal curves was investigated by calculation of root mean squared error maps. Simulated nonstatic dephasing data were evaluated using the static dephasing model to estimate the stability of the model and the influence of input parameters. RESULTS: The theoretical model describing the MR signal dephasing under nonstatic conditions was experimentally verified in phantom measurements. In simulations, it was found that, by neglecting the effect of diffusion when predicting the MR signal-time course expected in an in vivo measurement of the tissue oxygenation, errors of 10 30% would be introduced into the parameter estimation. The simulations indicate unpredictable results for simultaneous evaluation of blood oxygenation level and blood volume fraction. CONCLUSION: Neglecting the effects of diffusion in quantitative BOLD measurements could give rise to substantial errors in the parameter estimation. PMID- 21274983 TI - Evaluation of possible drug-drug interaction between gadoxetic acid and erythromycin as an inhibitor of organic anion transporting peptides (OATP). AB - PURPOSE: To evaluate if erythromycin compromises liver-specific enhancement of gadoxetic acid; both compounds competing in organic anion transporting peptides (OATP) -mediated hepatocytic uptake. MATERIALS AND METHODS: The study was approved by institutional review board. Twelve healthy subjects (nine men, three woman; mean age, 38.7 years) were examined twice by MR imaging with prior administration of NaCl solution (placebo) or 1000 mg of erythromycin following a randomized sequence. Gadoxetic acid (0.025 mmol/kg body weight) was administered 15 min after the end of infusions. Pre- and 20 min postcontrast two-dimensional gradient-recalled-echo sequences were acquired. Relative enhancements of liver parenchyma and ratio of means were calculated from signal intensity measurements. Plasma levels of gadoxetic acid and erythromycin were determined and given in geometric means and coefficients of variation (CV). RESULTS: Concentration of erythromycin directly after end of infusion was 13.9 mg/L (CV 14.9%). Gadolinium plasma concentrations 5 min after gadoxetic acid administration were 138.7 MUmol/L (CV 20.4%) after erythromycin infusion and 129.6 MUmol/L (CV 22.8%) after placebo. Mean relative enhancements of liver parenchyma were 88.1 (SD 24.9%) after erythromycin infusion and 92.6 (SD 17.9%) after placebo. Ratio of relative enhancements was 0.951 (95% confidence interval, 0.833; 1.061; statistically not significant). CONCLUSION: Coadministration of erythromycin has no effect on gadoxetic acid enhanced liver MR imaging. PMID- 21274985 TI - Pacemaker lead tip heating in abandoned and pacemaker-attached leads at 1.5 Tesla MRI. AB - PURPOSE: To assess the risk of RF-induced heating in pacemaker-attached and abandoned leads using in vitro temperature measurements at 1.5 Tesla as a function of lead length. MATERIALS AND METHODS: Five custom lead lengths, 20-60 cm, were exposed to a uniform magnitude and phase radiofrequency electric field to examine the effect of lead length on pacemaker lead tip heating for pacemaker attached and abandoned pacemaker leads. RESULTS: Abandoned and pacemaker-attached leads show resonant heating behavior and maximum heating occurs at different lead lengths due to the differences in termination conditions. For clinical lead lengths (40-60 cm) abandoned leads exhibited greater lead tip heating compared with pacemaker-attached leads. CONCLUSION: Current recommendations for MRI pacemaker safety should highlight the possible increased risk for patients with abandoned leads as compared to pacemaker-attached leads. PMID- 21274986 TI - Aliasing artifacts with the BLADE technique: causes and effective suppression. AB - PURPOSE: To elucidate the causes of aliasing artifacts with the BLADE technique and clarify the effective suppression methods. MATERIALS AND METHODS: We separately observed the aliasing artifacts of BLADE from features inside and then outside the defined field-of-view (FOV) using phantom studies. The effectiveness of suppressing them with phase oversampling (POS) and presaturation pulses (SAT) was evaluated. Finally, our observations were confirmed for a healthy volunteer. RESULTS: Characteristic aliasing artifacts were observed from both inside and outside the FOV. Those from inside the FOV were sufficiently suppressed by using a POS of 25%, considering the acquisition time prolongation. Those from outside the FOV were nearly suppressed using SAT outside the FOV without selecting needless receiver coils. Aliasing artifacts on the coronal images of the head and neck with a healthy volunteer were completely suppressed by a combination of using a POS of 25% and using SAT on all four sides outside the FOV. CONCLUSION: The characteristic aliasing artifacts of BLADE are caused from both inside and outside the defined FOV. They can be effectively suppressed by a combination of using a POS of 25% and using SAT on all four sides outside the FOV. PMID- 21274987 TI - Development of a wide-view visual presentation system for visual retinotopic mapping during functional MRI. AB - PURPOSE: To develop and validate the functionality of a novel wide-view visual presentation system with a horizontal and vertical eccentricity angle of 60 degrees for retinotopic mapping by functional MRI (fMRI). MATERIALS AND METHODS: The wide-view presentation system consisted of a 52-mm diameter optical fiber, an entrance apparatus and a presentation apparatus. The terminal edge of the optical fiber at the entrance is flat, while the terminal edge on the presentation apparatus is a sphere of 60 mm in diameter. The subjects wore contact lenses with +20, +22, or +25 magnification to focus on the stimulus, and the visual field eccentricity angle could reach 60 degrees . The signal to noise ratio valuation experiment was performed to evaluate the clarity and quality of the MRI picture image. Checkerboard and random dot stimuli were used to prove that this system could be applied to retinotopic mapping by fMRI. RESULTS: The results of the experiment demonstrated that the system is safe in the MRI environment with minimal distortion and can be used for visual retinotopic mapping studies. Wide field mapping areas (V6, MST) were found in the human visual cortex. Compared with previous studies, the V1 and MT+ surface area approaches but does not fully cover the anatomical area. Nonetheless, the area achieved using the new system is larger than those achievable in previous fMRI studies. CONCLUSION: We developed a versatile, low-cost system for presenting wide-view visual stimuli in the MRI environment. The fMRI retinotopic mapping results proved the viability of this system. PMID- 21274988 TI - Detailed assessment of the hemodynamic response to psychosocial stress using real time MRI. AB - PURPOSE: To demonstrate that combining the Montreal Imaging Stress Task (MIST) with real-time cardiac magnetic resonance imaging (MRI) allows detailed assessment of the cardiovascular mental stress response. MATERIALS AND METHODS: 22 healthy volunteers (1:1 M:F, 26-64 years) underwent MRI during rest and the MIST. Real-time spiral phase contrast MR, accelerated with sensitivity encoding (SENSE) was used to assess stroke volume (SV), and radial k-t SENSE was used to assess ventricular volumes. Simultaneous heart rate (HR) and blood pressure (BP) measures allowed calculation of cardiac output (CO), systemic vascular resistance (SVR), and arterial compliance (TAC). Endocrine responses were assessed using salivary cortisol. RESULTS: In response to stress, BP increased due to increased CO and reduced TAC but not increased SVR, which fell. HR, not SV, determined CO increases. Greater BP responses occurred in men due to greater CO increases and relatively higher SVR. Older participants had greater BP responses due to greater falls in TAC. Greater cortisol response was correlated with greater falls in TAC but resting cortisol and TAC were not related. CONCLUSION: This new approach allows detailed, accurate assessment of stress physiology. Preliminary findings suggest stress exposes relationships, not seen at rest, of cardiovascular function with age, sex, and endocrine function. PMID- 21274989 TI - Cardiovascular magnetic resonance imaging for accurate sizing of the left atrium: predictability of pulmonary vein isolation success in patients with atrial fibrillation. AB - PURPOSE: To prospectively determine the most reproducible approach for left atrial size assessment using cardiovascular magnetic resonance (CMR) imaging in patients with atrial fibrillation and its value for prediction of pulmonary vein isolation (PVI) treatment success. MATERIALS AND METHODS: Eighty patients underwent CMR imaging prior to PVI; the CMR examination included standard cine sequences, a multislice cine sequence in 4-chamber orientation with full left atrial coverage, and a contrast-enhanced MR angiography of the left atrium. Left atrial size was determined as: diameter, area, volume segmented from angiography, and diastolic/systolic volumes from cine imaging (Simpson's rule). All measurements were carried out by two independent observers and repeated by one observer to assess inter- and intrareader variability. Treatment success was defined as persisting sinus rhythm after PVI (follow-up period 12.6 +/- 6.6 months). RESULTS: All left-atrial measurements showed substantial intrareader agreement. Interreader agreement was substantial for diastolic/systolic left atrial volumes only. Calculated bias was found to be minimal (0.1%-4.9%). Predictability of PVI treatment success was best using cine volumetric measurements (cutoff value for diastolic volume, 112 mL) yielding a sensitivity and specificity of 80% and 70%, respectively. CONCLUSION: Left-atrial volumetry based on cine imaging represented the most reproducible approach to determine left-atrial size. PVI success was predicted best using cine volumetry. PMID- 21274990 TI - Correction of left ventricular wall thickening from short-axis cine MRI for basal descent through-plane motion. AB - PURPOSE: To solve the problem of the basal descent movement in quantification of the regional left ventricular (LV) myocardial wall thickness (WTh) and wall thickening (%WT) in short-axis (SA) cine MRI for effectively assessing the regional wall motion of LV myocardium. MATERIALS AND METHODS: LV long-axis tagged MRI and SA cine MRI were performed to calculate the longitudinal translation and circumferential WTh of LV myocardium in eight normal volunteers. The new SA end systolic thickness (EST) data were reconstructed from the original EST data, based on the quantified longitudinal translation of LV myocardium. RESULTS: The mean %WT of six segments in the basal section after correction was significantly different from that before correction in both intra- and inter-operator experiments. The polar map also showed the significant improvement of the variability of regional %WT and lack of quantification of %WT in the most basal SA slices after correction. CONCLUSION: The proposed technique demonstrated an important advantage to calculate the %WT in the most basal SA myocardial tissue, which was considered difficult to be achieved using cine MRI. PMID- 21274991 TI - Prostate T(1) quantification using a magnetization-prepared spiral technique. AB - PURPOSE: To adapt a magnetization-prepared spiral imaging technique, termed T1prep, for time-efficient radiofrequency (RF)-insensitive prostate T(1) quantification at 1.5 T and evaluate signal-to-noise ratio (SNR) limits to voxel based versus subregion analysis. MATERIALS AND METHODS: A magnetization-prepared spiral imaging technique was adapted for robust T(1) contrast development, multislice imaging within 5 minutes, and data regression to a monoexponential decay. In vitro testing evaluated RF insensitivity of the multislice acquisition plus method accuracy. A pilot study was performed in 15 patients with low or intermediate risk localized prostate cancer. RESULTS: The multislice design displayed excellent RF insensitivity (<1% error for RF mistunings to +/- 20%) and accuracy (within 3% of gold standard for T(1) values between 140 and 2100 msec). A clinical pilot study reported significantly reduced T(1) from PZ to CG to tumor subregions (PZ: 1421 +/- 168 msec, n = 11; CG: 1314 +/- 49 msec, n = 13; 1246 +/- 68 msec, n = 8). SNR measurements identified an inappropriateness of voxel-based analysis. CONCLUSION: T1prep can quantify prostate T(1) as an adjunct measure for quantitative perfusion measurements and longitudinal treatment response monitoring. Intrapatient heterogeneities support T(1) assessment within individual patients. SNR calculations will support a transition to voxel-based analysis in future trials. PMID- 21274992 TI - Scan-Rescan reproducibility of carotid bifurcation geometry from routine contrast enhanced MR angiography. AB - PURPOSE: To demonstrate the feasibility of rapid and reliable geometric characterization of normal carotid bifurcation geometry from routine 3D contrast enhanced magnetic resonance (MR) angiograms. MATERIALS AND METHODS: Repeat scans of 61 participants, acquired as part of the Atherosclerosis Risk in Communities (ARIC) Carotid MRI substudy, were digitally segmented using automated 3D level set methods, relying on an operator only to select the branch endpoints and thresholds for the 3D lumen surface initialization. Geometric factors characterizing the 3D lumen geometry were then extracted automatically. RESULTS: Of 122 scans, 117 could be segmented within 5 minutes each, with 40% being of sufficiently high quality to require less than 2 minutes each. Irrespective of scan quality, geometric factors were found to be highly reproducible, with intraclass correlation coefficients (ICCs) typically above 0.9. The reconstructed lumen surfaces were reproducible to <0.3 mm on average, comparable to previous MRI-based reproducibility studies. Owing to the automated nature of the analysis, operator reliability was near-perfect (ICC >0.99), with lumen surface differences <0.1 mm. CONCLUSION: The 3D geometry of the carotid bifurcation can be characterized rapidly and with a high degree of consistency, even for suboptimal image qualities. This bodes well for large-scale retrospective or prospective studies aimed at teasing out the influence of local vs. systemic risk factors for early atherosclerosis. PMID- 21274993 TI - Interstitial MR lymphography in mice with gadopentetate dimeglumine and gadoxetate disodium. AB - PURPOSE: To investigate the utility of interstitial MR lymphography with gadopentetate dimeglumine (Gd-DTPA) or gadoxetate disodium (Gd-EOB-DTPA) in mice. MATERIALS AND METHODS: We performed MR lymphography after the subcutaneous injection of Gd-DTPA or Gd-EOB-DTPA (0.1, 0.5, or 2.0 MUmol per mouse) into the right footpad in six healthy mice, and the time courses of contrast enhancement were assessed. Additionally, the lymphatic pathways from two distinct sites were assessed in tandem by interstitial MR lymphography studies. RESULTS: Subcutaneous injection of Gd-DTPA or Gd-EOB-DTPA caused lymph node enhancement immediately after injection, followed by a rapid decline. Dose dependency was shown for the lymph node enhancement, and a high-dose injection caused prominent visualization of the veins. Lymph node enhancement did not differ significantly between Gd-DTPA and Gd-EOB-DTPA or between Gd-EOB-DTPA premixed and not premixed with bovine serum albumin. The tandem assessment of two lymphatic pathways was feasible, and image fusion aided detailed comparison. CONCLUSION: Interstitial MR lymphography with Gd-DTPA or Gd-EOB-DTPA allowed clear visualization of the lymphatic pathway in healthy mice, and no significant difference was found between the two agents. Their rapid kinetics limits the imaging timing window, however, facilitates repeated assessment in a single imaging session. PMID- 21274994 TI - Prospective motion correction for magnetic resonance spectroscopy using single camera Retro-Grate reflector optical tracking. AB - PURPOSE: To introduce and evaluate a method of prospective motion correction for localized proton magnetic resonance spectroscopy (1H-MRS) using a single-camera optical tracking system. MATERIALS AND METHODS: Five healthy participants were scanned at 3T using a point-resolved spectroscopic sequence (PRESS) with a motion tracking module and phase navigator. Head motion in six degrees was tracked with a Retro-Grate Reflector (RGR) tracking system and target via a mirror mounted inside the bore. Participants performed a series of three predetermined motion patterns during scanning. RESULTS: Left-right rotation (Rz) (average 12 degrees ) resulted in an increase in the total choline to total creatine ratio (Cho/Cr) of +14.6 +/- 1.5% (P = 0.0009) for scans without correction, but no change for scans with correction (+1.1 +/- 1.5%; P = 0.76). Spectra with uncorrected Z translations showed large lipid peaks (skull) with changes in Cho/Cr of -13.2 +/- 1.6% (P = 0.02, no motion correction) and -2.2 +/- 2.4% (P = 0.51) with correction enabled. There were no significant changes in the ratios of N acetylaspartate, glutamate+glutamine, or myo-inositol to creatine compared to baseline scans for all experiments. CONCLUSION: Prospective motion correction for 1H-MRS, using single-camera RGR tracking, can reduce spectral artifacts and quantitation errors in Cho/Cr ratios due to head motion and promises improved spectral quality and reproducibility. PMID- 21274995 TI - Standardizing predictive values in diagnostic imaging research. PMID- 21274997 TI - Intergenerational cohabitation in modern Indonesia: filial support and dependence. AB - Informal filial care plays an important role for elderly parents facing health challenges. Ageing, however, exacerbates the burden of filial care because the ratio of older to younger individuals is higher and disabled parents live longer. The well-being of elderly parents is even more insecure in Asian developing countries that are undergoing unprecedented ageing and drastic changes in social norms and values, whereas old-age support systems have yet to be developed. In this paper, we investigate factors that influence cohabitation decision by elderly parents and their adult children using the longitudinal Indonesian Family Life Survey (IFLS). Focusing on new cohabitation in which a parent who lives independently starts to cohabitate with a child, we conduct transition analysis to make a more convincing causal interpretation than the standard cross-sectional approach. We find that, while parental needs are important, cohabitation is influenced to a larger extent by the costs and gains of children. The elderly facing health and economic challenges are at higher risk of not receiving filial support than other elderly individuals. PMID- 21274998 TI - Ultrastructural observations on antennal sensilla of Cnaphalocrocis medinalis (Lepidoptera: Pyralidae). AB - The morphology and ultrastructure of the antennal sensilla of Cnaphalocrocis medinalis (Lepidoptera: Pyralidae) was studied by scanning and transmission electron microscopic techniques. Eight morphological types of sensillum were recorded in both sexes: sensilla trichodea (S. trichodea), sensilla basiconc (S. basiconc), sensilla coeloconica (S. coeloconica), sensilla styloconica (S. styloconica), sensilla squamous (S. squamous), sensilla auricillica (S. auricillica), Bohm bristles (B. bristles), and sensilla cavity (S. cavity). S. trichodea were the most abundant sensilla and were distributed over the entire antennal surface. Four different types of S. trichodea and S. basiconc were observed. The number of S. basiconc and S. coeloconica of males were greater than those of females of C. medinalis. S. squamous formed on the dorsal part of the antenna, as a cluster in females and as in a line in males. Higher magnification revealed that S. basiconc had an olfactory function, while the character of longer length of these sensilla suggested that they also played a rolein sensing mechanical or other chemical stimuli. Transmission electron microscopy (TEM) of S. squamous revealed nonporous walls suggesting a non-olfactory function. S. coeloconica, S. styloconica, and S. cavity may be involved in the perception of humidity, temperature, heat, and CO2. Because of their particular location, we infer that B. bristles may function in sensing the position and movements of the antennae, while the function of S. auricillica is as yet unknown. The results obtained provide direct morphological evidence that antennae possess structures that can play a role in finding mates and locating host plants. PMID- 21274999 TI - Depth-dependent anisotropies of amides and sugar in perpendicular and parallel sections of articular cartilage by Fourier transform infrared imaging. AB - Full thickness blocks of canine humeral cartilage were microtomed into both perpendicular sections and a series of 100 parallel sections, each 6 MUm thick. Fourier transform infrared (IR) imaging was used to image each tissue section eleven times under different IR polarizations (from 0 degrees to 180 degrees polarization states in 20 degrees increments and with an additional 90 degrees polarization), at a spatial resolution of 6.25 MUm and a wavenumber step of 8 cm 1. With increasing depth from the articular surface, amide anisotropies increased in the perpendicular sections and decreased in the parallel sections. Both types of tissue sectioning identified a 90 degrees difference between amide I and amide II in the superficial zone (SZ) of cartilage. The fibrillar distribution in the parallel sections from the SZ was shown to not be random. Sugar had a weak but recognizable anisotropy in the upper part of the radial zone (RZ) in the perpendicular sections. The depth-dependent anisotropic data were fitted with a theoretical equation that contained three signature parameters, which illustrate the arcade structure of collagens with the aid of a fibril model. Fourier transform IR imaging of both perpendicular and parallel sections provides the possibility of determining the three-dimensional macromolecular structures in articular cartilage. Being sensitive to the orientation of the macromolecular structure in healthy articular cartilage aids the prospect of detecting the early onset of the tissue degradation that may lead to pathological conditions such as osteoarthritis. PMID- 21275000 TI - Combination of normal light and fluorescence microscopy for authentication of five Lonicera species flower buds. AB - The flower buds of five Lonicera species, Lonicera japonica Thunb., L. macranthoides Hand.-Mazz., L. hypoglauca Miq., L. confusa DC. and L. fulvotomentosa Hsu et S.C. Cheng are confusable and usually utilized under the same name "Jinyinhua" in different areas for morphological similarity. Studies found that these five species possess extreme differences in chemical compounds, correspondingly showing different pharmacological activities and clinical applications. To ensure efficacy and safety of these herbal medicines and prevent unknown adverse effect, in this work, a simple, rapid and effective method combining normal light and fluorescence microscopy was developed for authentication. Surface slides and transverse sections of these buds were investigated to reveal their differences. As a routine technique, normal light microscopy which gives detailed microscopic features such as glandular hairs and nonglandular hairs, can easily distinguish four species except L. confusa. Fluorescence technique, which could present different distribution of fluorescence materials, is further employed to identify three species including L. confusa successfully. It is the first report to identify these five Lonicera species by combining normal light and fluorescence microscopy. This work indicated combining normal light and fluorescence microscopy could be a powerful method in authentication of confused species. PMID- 21275001 TI - Disclosure in 3D of slit-membrane as well as -strands, and en-face basal lamina in situ of renal glomerulus of normal rats in embedment-free section transmission electron microscopy. AB - With higher contrast and transparency due to the absence of epon and stereo viewing effect due to thicker sections than conventional electron microscopy as methodological advantages, the renal glomerular slits were re-examined in embedment-free section electron microscopy. In addition to clear demonstration of strands bridging the slits in forms of ladders with highly irregular intervals and various extension-directions and length, this study disclosed clearly for the first time in the "section" TEM thin sheets which partially spanned the slit together with the strand-ladders. No strands were found to align in forms of typical zippers in normal kidney. Furthermore, en-face ultrastructure of the basal lamina in situ was clearly demonstrated in superimposed sites of the endothelial fenestrae with the slits. PMID- 21275002 TI - Distribution of nestin protein: immunohistochemical study in enteric plexus of rat duodenum. AB - The intermediate nestin filament is expressed in neural stem cells, neuroectodermal tumors and various adult tissues under situations that reproduce developmental phases, e.g., physiological renewal of certain cell types, tissue regeneration, and healing or revascularization. In the human gastrointestinal tract, nestin has been reported in glial cells and interstitial cells of Cajal. We examined by immunohistochemistry the appearance and distribution of nestin protein in enteric ganglia of rat duodenum. Through the myenteric and submucosal plexuses, a high number of nestin-positive cells were visualized in this specie. The nestin-positive cells were smaller and more numerous than enteric neurons. They were present both within and around ganglia. The results of this study suggest that the rat enteric glial cells (EGCs) are rich in nestin, a protein usually associated with dividing or migrating cells and the dynamic reorganization of nestin filaments during the cell cycle. EGCs could function as enteric stem cells. PMID- 21275004 TI - Spatial and functional relationships between air conduits and blood capillaries in the pulmonary gas exchange tissue of adult and developing chickens. AB - The documented data regarding the three-dimensional structure of the air capillaries (ACs), the ultimate sites of gas exchange in the avian lung is contradictory. Further, the mode of gas exchange, described as cross-current has not been clearly elucidated. We studied the temporal and spatial arrangement of the terminal air conduits of the chicken lung and their relationship with the blood capillaries (BCs) in embryos as well as the definitive architecture in adults. Several visualization techniques that included corrosion casting, light microscopy as well as scanning and transmission electron microscopy were used. Two to six infundibulae extend from each atrium and give rise to numerous ACs that spread centrifugally. Majority of the ACs are tubular structures that give off branches, which anastomose with their neighboring cognates. Some ACs have globular shapes and a few are blind-ending tapering tubes. During inauguration, the luminal aspects of the ACs are characterized by numerous microvillus-like microplicae, which are formed during the complex processes of cell attenuation and canalization of the ACs. The parabronchial exchange BCs, initially inaugurated as disorganized meshworks, are reoriented via pillar formation to lie predominantly orthogonal to the long axes of the ACs. The remodeling of the retiform meshworks by intussusceptive angiogenesis essentially accomplishes a cross-current system at the gas exchange interface in the adults, where BCs form ring-like patterns around the ACs, thus establishing a cross-current system. Our findings clarify the mode of gas exchange in the parabronchial mantle and illuminate the basis for the functional efficiency of the avian lung. PMID- 21275003 TI - Expression of caspase-8 and caspase-9 in rat hippocampus during postnatal development. AB - The role of caspases in the regulation of apoptosis of neurons during development is well established. An emerging body of evidence indicates that caspases may also play significant roles which are nonapoptotic. We have demonstrated previously that the executor caspase-3 exhibited a unique pattern of spatiotemporal expression in the postnatal rat hippocampal subregions, and the activation of caspase-3 in different hippocampal neurons appeared to have distinct roles during postnatal development. In the present study, we examined the expressions of initiator caspases in the hippocampus, using immunofluorescent staining for caspase-8 and caspase-9, and Hoechst 33342 staining for nuclear chromatin to assess caspase-8 and -9 expression in the CA1, CA3, and the dentate gyrus (DG) on postnatal days (P) 0, P2, P4, P7, P14, P21, P28, P56. The results indicate that caspase-8 and caspase-9 were expressed in pyramidal neurons of CA1 and CA3 fields, and granular neurons of the DG during development. Caspase-8 was expressed in a general upward trend while caspase-9 showed a slight downward pattern, but still remained at high levels in the adult hippocampus. The expression profiles of caspases-8 and -9 are distinct from that of the apoptotic cells. These data indicate that caspase-8 may be involved not only in the classical apoptotic function, but also in the cell death of necrosis, and in response to different insults and other nonapoptotic functions. Caspase-9 plays a role in apoptosis during postnatal development, but it may have other functions as well. PMID- 21275005 TI - Force spectroscopy of an elastic peptide: effect of D2O and temperature on persistence length. AB - This study explores the mechanical unfolding of elastic protein analogues as a function of temperature, in both H2O and D2O, using atomic force microscopy (AFM) force spectroscopy in a specially constructed AFM liquid cell. This represents the first time that the effect of D2O on protein flexibility has been investigated at the single molecule level by this technique. Model elastic peptides, R6, were encoded from synthetic genes expressed in Escherichia coli. The peptides possess short N- and C-terminal domains with central repetitive domains containing 13 repeats of the motif PGQGQQ-plus-GYYPTSLQQ. These sequences mimic those in native high molecular weight subunit glutenin proteins which confer elasticity to bread dough. Fitting single molecule stretching events to the worm-like chain model, allows determination of the molecular persistence length under various experimental conditions. The effect of increasing the temperature is to increase the persistence length of the peptide in both H2O and D2O, consistent with the expected "thermal softening" effect. However, the effect is significantly enhanced in D2O, in which the persistence length at 45 degrees C is ~25% greater than the value measured in H2O at the same temperature. Stronger intrapeptide H-bonding due to isotopic substitution of hydrogen for deuterium is the most likely cause of the enhanced backbone rigidity. PMID- 21275006 TI - The emotional regulatory features of bulimic episodes and compulsive exercise in muscle dysmorphia: a case report. AB - Muscle dysmorphia is a recently identified psychiatric condition, whose relationship to the eating disorders remains unclear. This case describes an adolescent male who met diagnostic criteria for both an eating disorder not otherwise specified and muscle dysmorphia, allowing the first examination of read muscle dysmorphia presentations. This case suggests that muscle dysmorphia may present inclusive of episodes of binge eating and purging in addition to compulsive exercise, which may serve an emotional regulation function. We suggest that the assessment of muscle dysmorphia include a comprehensive assessment of all eating disorder features including bulimic symptoms, and that treatment address these features. Clinical implications for the conceptualization of muscle dysmorphia are discussed. PMID- 21275007 TI - Perfectionism and learning experiences in dance class as risk factors for eating disorders in dancers. AB - There is strong evidence that perfectionism is a risk factor for eating disorders. Women who engage in dance training have been reported to be at risk for eating disorders, and it has been hypothesised that expectancies about thinness and restricting food intake are formed partly as a result of exposure to thinness related learning (TRL) experiences in this environment, which may increase their risk. To clarify the relative contribution of perfectionism and learning in accounting for eating disorder symptoms in this group, 142 female ballet dancers completed an online survey. Through structural equation modelling it was found that the association between perfectionism and eating disorder symptoms was partially mediated by learning about thinness and restriction. The results suggest that eating disorder symptoms in dancers are significantly influenced by the interaction of perfectionism and learning, and future research should investigate the efficacy of prevention programs to target these risk factors in female dancers. PMID- 21275008 TI - Eating in eating disorders. AB - The aim of this paper is to bring eating back into the centre of the eating disorder discourse. The ability to interrogate and understand the central processes of appetite has increased considerably since the discovery of leptin and the ability to observe brain function with scanning methodologies. This has led to substantial progress in understanding the biological causative and maintaining factors in eating disorders, opening up the possibility of translating the latest findings into new forms of treatment. The biological mechanisms underpinning symptoms evolution and course of illness will first be described, follows by a discussion on integrating the research evidence in fear and feeding into patient care. PMID- 21275009 TI - Affect consciousness and eating disorders. Short term stability and subgroup characteristics. AB - The aim of the study was to analyse differences in observer rated affect consciousness (AC) between subgroups of patients diagnosed with eating disorders (N = 44; 30 with anorexia nervosa and 14 with bulimia nervosa), and a non clinical group (N = 40). Another aim was to study the short-term stability of AC over 10-11 weeks of treatment and its relation to self-reported eating pathology and general psychopathology. A moderate short-term stability of AC was found but the levels were not correlated with eating pathology or psychopathology. No differences between the two diagnostic categories were found, but the eating disorder group as whole had significantly lower AC compared with a non-eating disorder reference group. AC seems to be a moderately stable ability that differentiates patients diagnosed with eating disorders from a non-clinical population. However, AC is not related to symptoms of eating disorder or general psychiatric symptoms in this group of patients. PMID- 21275010 TI - Orthographic context and the acquisition of orthographic knowledge in normal and dyslexic readers. AB - We tested the hypothesis that the acquisition of orthographic knowledge of novel words that are presented in an indistinct context, that is a context with many orthographically similar words, would be more difficult for dyslexic than for normal readers. Participants were 19 Dutch dyslexic children (mean age 10;9 years), 20 age-matched and 20 reading-age-matched normal readers. During training the children repeatedly read a series of nonwords in a distinct (KWOG with KWES and SNAR) and an indistinct (KWOG with KWOS and KROG) orthographic context. At posttest, the dyslexic children were slower but more accurate in the reading of nonwords if these had been acquired in an indistinct than in a distinct training context. In normal readers context did not have an effect. We argue that dyslexic children's sensitivity to orthographic context is due to their problems in the acquisition of fully specified orthographic representations causing interference by similar words. PMID- 21275011 TI - PEGylated inorganic nanoparticles. AB - Application of inorganic nanoparticles in diagnosis and therapy has become a critical component in the targeted treatment of diseases. The surface modification of inorganic oxides is important for providing diversity in size, shape, solubility, long-term stability, and attachment of selective functional groups. This Minireview describes the role of polyethylene glycol (PEG) in the surface modification of oxides and focuses on their biomedical applications. Such a PEGylation of surfaces provides "stealth" characteristics to nanomaterials otherwise identified as foreign materials by human body. The role of PEG as structure-directing agent in synthesis of oxides is also presented. PMID- 21275013 TI - Thermodynamic methods and models to study flexible metal-organic frameworks. AB - Much attention has recently been focused on a fascinating subclass of metal organic frameworks that behave in a remarkable stimuli-responsive fashion. These soft porous crystals feature dynamic crystalline frameworks displaying reversible, large-amplitude structural deformations under external physical constraints such as temperature, electric field or gas exposure. The number of reported syntheses of such materials is rapidly growing and they are promising for practical applications, such as gas capture, purification and fluid separation. Herein, we summarize the recently developed thermodynamic tools that can help understand the process of fluid adsorption and fluid mixture coadsorption in these flexible nanoporous materials. These tools, which include both molecular simulation methods and analytical models, can help rationalize experimental results and predict adsorption properties over a wide range of thermodynamic conditions. A particular focus is given on how these methods can guide the experimental exploration of a large number of materials and working conditions (temperature, pressure, composition) to help design efficient processes relying on fluid adsorption in soft porous crystals. PMID- 21275014 TI - Light gives molecules the chills. PMID- 21275015 TI - Monodisperse water-in-water-in-oil emulsion droplets. PMID- 21275016 TI - Direct evidence of coexisting horseshoe and extended helix conformations of membrane-bound alpha-synuclein. PMID- 21275017 TI - Exploring the drug-binding site Sudlow I of human serum albumin: the role of water and Trp214 in molecular recognition and ligand binding. PMID- 21275018 TI - DNA molecular solvation in neat ionic liquids. PMID- 21275019 TI - A facile one-step solvothermal synthesis of SnO2/graphene nanocomposite and its application as an anode material for lithium-ion batteries. PMID- 21275020 TI - The role of the ethynyl substituent on the pi-pi stacking affinity of benzene: a theoretical study. AB - Herein, we report a high-level theoretical study (SCS-RI-MP2(full)/aug-cc-pVTZ) examining the stacking affinity of 1,3,5-triethynylbenzene. The stacking properties of this compound are compared to those of benzene and 1,3,5 trifluorobenzene. The results indicate that the ethynyl substituent improves the stacking affinity of the arene, since the binding energies for the stacked ethynyl-substituted arene dimers are higher than those of both benzene and the fluoro-substituted arene. This interesting behaviour has been studied by examining the energetics, geometries and electron charge density features of the complexes. A query in the Cambridge Structural Database returned several X-ray crystal structures containing pi-pi stacking interactions of 1,3,5 triethynylaryls that strongly agree with the theoretical results. PMID- 21275021 TI - Stability and dynamics of cyclic diguanylic acid in solution. AB - Cyclic diguanylic acid (CDG) is a ubiquitous messenger involved in bacterial signaling networks. Despite its central role in motility, biofilm formation, virulence, and flagellum development, fundamental properties such as its aggregation state are still poorly understood. Here the dynamics and stability of metal-free and Mg(2+)-bound CDG are characterized. Atomistic simulations establish that the CDG dimer is slightly favored (by -5 kcal mol(-1)) over its dissociated form (2 CDG), while the Mg(2+) ion coordinated in the X-ray structure readily dissociates from (CDG)(2) in solution and prefers water coordination. As a ligand in a protein, CDG binds both as a U-shaped and a quasilinear monomer. The current results indicate that the energy difference between these two conformations is only a few kilocalories per mole, which explains the facile adaptation to different protein environments. This, together with the slight preference of (CDG)(2) over 2 CDG suggests that (CDG)(2) binding to a protein does probably not occur via sequential binding of two individual monomers. PMID- 21275022 TI - Spectral diffusion of single molecules in a hierarchical energy landscape. AB - Spectral diffusion as a result of both the transitions between different molecular conformers and the ''molecular softness'' of quasi-free perylene diimides on a SiO(2) surface is investigated by means of single-molecule spectroscopy, which reveals the time dependence of both the fluorescence spectra and the three-dimensional orientation. Spectral wavelengths of all single emitters cover a wide energy range of about 0.27 eV, which is due to different types of conformers with large differences in optical transition energy. Time dependent spectral trajectories of single emitters within this wavelength manifold are evaluated with a model transcribed from the analysis of spatial diffusion. Spectral diffusion processes are closely correlated with fluorescence emission and excitation power. The overall analysis of spectral diffusion reveals, similar to proteins, a hierarchy of energy barriers in a broad energy landscape. PMID- 21275023 TI - DFT/TDDFT investigation of the modulation of photochromic properties in an organoboron-based diarylethene by fluoride ions. AB - The diarylethene derivative 1,2-bis-(5'-dimesitylboryl-2'-methylthieny-3'-yl) cyclopentene (1) containing dimesitylboryl groups is an interesting photochromic material. The dimesitylboryl groups can bind to F(-), which tunes the optical and electronic properties of the diarylethene compound. Hence, the diarylethene derivative 1 containing dimesitylboryl groups is sensitive to both light and F( ), and its photochromic properties can be tuned by a fluoride ion. Herein, we studied the substituent effect of dimesitylboron groups on the optical properties of both the closed-ring and open-ring isomers of the diarylethene molecule by DFT/TDDFT calculations and found that these methods are reliable for the determination of the lowest singlet excitation energies of diarylethene compounds. The introduction of dimesitylboron groups to the diarylethene compound can elongate its conjugation length and change the excited-state properties from pi->pi* transition to a charge-transfer state. This explains the modulation of photochromic properties through the introduction of dimesitylboron groups. Furthermore, the photochromic properties can be tuned through the binding of F(-) to a boron center and the excited state of the diarylethene compound is changed from a charge-transfer state to a pi->pi* transition. Hence, a subtle control of the photochromic spectroscopic properties was realized. In addition, the changes of electronic characteristics by the isomerization reaction of diarylethene compounds were also investigated with theoretical calculations. For the model compound 2 without dimesitylboryl groups, the closed-ring isomer has better hole- and electron-injection abilities, as well as higher charge-transport rates, than the open-ring isomer. The introduction of dimesitylboron groups to diarylethene can dramatically improve the charge-injection and -transport abilities. The closed isomer of compound 1 (1 C) has the best hole- and electron-injection abilities, whereas the charge-transport rates of the open isomer of compound 1 (1 O) are higher than those of 1 C. Importantly, 1 O is an electron-accepting and transport material. These results show that the diarylethene compound containing dimesitylboryl groups has promising potential to be applied in optoelectronic devices and thus is worth to be further investigated. PMID- 21275024 TI - Influence of hydrogen bonds and nonspecific interactions on the spectral and photophysical properties of the excited singlet states of 4-aminophthalimide in amine solution. AB - The hydrogen-bond and nonspecific interaction energies for 4-aminophthalimide (4 AP), often used as a probe, in the ground electronic and excited singlet states are determined using ab initio computational methods. It is shown that the 4-AP molecule can form three relatively strong hydrogen bonds with trimethylamine (TMA) and triethylamine (TEA), which leads to the formation of S(0)-complexes between the solute and solvent molecules. Only two of the hydrogen bonds with the amine group of 4-AP change significantly their energies upon excitation and deactivation. The theoretical results are necessary to explain the spectral and unusual photophysical properties of 4-AP in amine solutions. PMID- 21275025 TI - Control of cross relaxation of multiple-quantum coherences induced by fast chemical exchange under heteronuclear double-resonance irradiation. AB - A fully analytical description of the control of the cross-correlated cross relaxation of multiple-quantum coherences in the presence of local dynamics under heteronuclear double-resonance radio-frequency (RF) irradiation is presented. The contribution of chemical exchange to relaxation can be partly or fully quenched by RF fields. We assume a correlated two-site chemical exchange model with arbitrary populations, and show that in the limit of fast exchange the dependence of the effective multiple-quantum cross-relaxation rate on the applied RF amplitude can be described by a compact analytical expression. Numerical simulations and preliminary experiments support our theoretical results. The relaxation dispersion as a function of RF amplitude can provide accurate information on the kinetics of correlated processes. PMID- 21275026 TI - Surface-directed spinodal decomposition of solvent-quenched organic transistor blends. AB - This paper describes the first example of the application of a combination of the Flory-Huggins and Cahn-Hilliard theories to model and simulate microstructure evolution in solution-processed functional blend layers of organic semiconductors, as used in organic electronics devices. Specifically, the work considers phase separation of the active blend components of organic transistors based on triisopropylsilylpentacene (TIPS-pentacene) and poly(alpha methylstyrene) (PalphaMS). By calculation and estimation of relevant physical parameters, it is shown that the vertically phase-separated structure observed in as-cast blend layers containing PalphaMS of a sufficiently high molecular weight (of the order of 10(2) kDa) evolves via surface-directed spinodal decomposition. The surface-directed effect can already be triggered by small differences in substrate- and/or air-interface interaction energies of the separating phases. During phase separation, which commences at the interfaces, bulk features of the TIPS-enriched phase formed by thermal noise collapse to give the experimentally observed trilayer structure of TIPS-PalphaMS-TIPS. The reported near absence of solution-state phase separation of as-cast blend layers containing a low molecular weight PalphaMS (of the order of 1 kDa) is also reproduced. PMID- 21275027 TI - High-performance oxygen sensors based on Eu(III) complex/polystyrene composite nanofibrous membranes prepared by electrospinning. AB - An optical oxygen sensor based on an Eu(III) complex/polystyrene (PS) composite nanofibrous membrane is prepared by electrospinning. The emission intensity of [Eu(TTA)(3) (phencarz)] (TTA=2-thenoyltrifluoroacetonate, phencarz=2-(N ethylcarbazolyl-4)imidazo[4,5-f]1,10-phenanthroline) decreases with increasing oxygen concentration, and thus the [Eu(TTA)(3) (phencarz)]/PS composite nanofibrous membranes can be used as an optical oxygen-sensing material based on emission quenching caused by oxygen. Elemental analysis, UV/Vis absorption spectra, scanning electron microscopy (SEM), fluorescence microscopy, luminescence-intensity quenching Stern-Volmer plots, and excited-state decay analysis are used to characterize the obtained oxygen-sensing materials. A high sensitivity (I(N2) /I(O2)) of 3.38 and short response and recovery times (t(?) =5.0, t(?) =8.0 s) are obtained. These results are the best values reported for oxygen sensors based on Eu(III) complexes. The high surface area-to-volume ratio and porous structure of the electrospun nanofibrous membranes are taken to be responsible for the outstanding performance. PMID- 21275028 TI - Thermomorphic behavior of the ionic liquids [C4mim][FeCl4] and [C12mim][FeCl4]. AB - The iron-containing ionic liquids 1-butyl-3-methylimidazolium tetrachloroferrate(III) [C(4)mim][FeCl(4)] and 1-dodecyl-3-methylimidazolium tetrachloroferrate(III) [C(12)mim][FeCl(4)] exhibit a thermally induced demixing with water (thermomorphism). The phase separation temperature varies with IL weight fraction in water and can be tuned between 100 degrees C and room temperature. The reversible lower critical solution temperature (LCST) is only observed at IL weight fractions below ca. 35 % in water. UV/Vis, IR, and Raman spectroscopy along with elemental analysis prove that the yellow-brown liquid phase recovered after phase separation is the starting IL [C(4)mim][FeCl(4)] and [C(12)mim][FeCl(4)], respectively. Photometry and ICP-OES show that about 40 % of iron remains in the water phase upon phase separation. Although the process is thus not very efficient at the moment, the current approach is the first example of an LCST behavior of a metal-containing IL and therefore, although still inefficient, a prototype for catalyst removal or metal extraction. PMID- 21275029 TI - Spontaneous formation of biocompatible vesicles in aqueous mixtures of amino acid based cationic surfactants and SDS/SDBS. AB - The spontaneous formation of vesicles by six amino acid-based cationic surfactants and two anionic surfactants (sodium dodecylbenzene sulfonate (SDBS) and sodium dodecyl sulfate (SDS)) is reported. The head-group structure of the cationic surfactants is minutely altered to understand their effect on vesicle formation. To establish the regulatory role of the aromatic group in self aggregation, both aliphatic and aromatic side-chain-substituted amino acid-based cationic surfactants are used. The presence of aromaticity in any one of the constituents favors the formation of vesicles by cationic/anionic surfactant mixtures. The formation of vesicles is primarily dependent on the balance between the hydrophobicity and hydrophilicity of both cationic and anionic surfactants. Vesicle formation is characterized by surface tension, fluorescence anisotropy, transmission electron microscopy, dynamic light scattering, and phase diagrams. These vesicles are thermally stable up to 65 degrees C, determined by temperature-dependent fluorescence anisotropy. According to the MTT assay, these catanionic vesicles are nontoxic to NIH3T3 cells, thus indicating their wider applicability as delivery vehicles to cells. Among the six cationic surfactants examined, tryptophan- and tyrosine-based surfactants have the ability to reduce HAuCl(4) to gold nanoparticles (GNPs), which is utilized to obtain in-situ synthesized GNPs entrapped in vesicles without the need for any external reducing agent. PMID- 21275030 TI - Chemical shift tensors in isomers of adenine: relation to aromaticity of purine rings? AB - The (13)C and (15)N chemical shift tensors are measured, calculated, and compared for three N-benzyladenine isomers with an attempt to characterize differences in electron distribution in the purine ring related to the position of the substituent. Furthermore, the aromaticity of the purine rings is evaluated on the basis of nucleus-independent chemical shifts, and variations among the isomers are discussed. Both parameters indicate significant differences between the electronic properties of the N3-substituted compound and the N7/N9 pair of structures, which can be viewed more generally as the reason for the different stabilities of the individual tautomers. PMID- 21275031 TI - Restriction of photoinduced twisted intramolecular charge transfer. AB - An intensive investigation of structure-property relationships in the aggregation induced enhanced emission (AIEE) of luminescent compounds is essential for the rational design of highly emissive solid-state materials. In the AIEE-active compounds N,N'-bis[3-hydroxy-4-(2'-benzothiazolyl)phenyl]isophthalamide and N,N' bis[3-hydroxy-4-(2'-benzothiazolyl)phenyl]-5-tert-butylisophthalamide, fast photoinduced twisted intramolecular charge transfer (TICT) of the enol excited state is found to be mainly responsible for the weak emission of their dilute solutions. The photoinduced TICT enol excited state is formed with a greatly distorted configuration, due to the large rotation about the C-N single bond. This facilitates nonradiative TICT decay from the normal enol excited state to the highly twisted enol excited state, rather than proton-transfer decay to the keto excited state. In aggregates, photoinduced nonradiative deactivation of TICT is strongly prohibited, so that excited-state intramolecular proton transfer (ESIPT) becomes the dominant decay, and hence contributes greatly to the subsequent emission enhancement of the keto form. Molecular design and investigation of analogous single-armed compounds further verifies this kind of AIEE mechanism. PMID- 21275032 TI - X-ray near-edge absorption study of temperature-induced low-spin-to-high-spin change in metallo-supramolecular assemblies. AB - X-ray absorption near the iron K edge (XANES) was used to investigate the characteristics of temperature-induced low-spin-to-high-spin change (SC) in metallo-supramolecular polyelectrolyte amphiphile complexes (PAC) containing FeN(6) octahedra attached to two or six amphiphilic molecules. Compared to the typical spin-crossover material Fe(phen)(2) (NCS)(2) XANES spectra of PAC show fingerprint features restricted to the near-edge region which mainly measures multiple scattering (MS) events. The changes of the XANES profiles during SC are thus attributed to the structure changes due to different MS path lengths. Our results can be interpreted by a uniaxial deformation of FeN(6) octahedra in PAC. This is in agreement with the prediction that SC is originated by a structural phase transition in the amphiphilic matrix of PAC, but in contrast to Fe(phen)(2) (NCS)(2), showing the typical spin crossover being associated with shortening of all the metal-ligand distances. PMID- 21275034 TI - Davydov splitting of excitons in cyclic bacteriochlorophyll a nanoaggregates of bacterial light-harvesting complexes between 4.5 and 263 K. AB - The nature of electronic excitations created by photon absorption in the cyclic B850 aggregates of 18 bacteriochlorophyll molecules of LH2 antenna complexes of photosynthetic bacteria is studied over a broad temperature range using absorption, fluorescence, and fluorescence anisotropy spectra. The latter technique has been proved to be suitable for revealing the hidden structure of excitons in inhomogeneously broadened spectra of cyclic aggregates. A theoretical model that accounts for differences of absorbing excitons in undeformed and emitting exciton polarons in deformed antenna lattices is also developed. Only a slight decrease of the exciton bandwidth and exciton coupling energy with temperature is observed. Survival of excitons in the whole temperature span from cryogenic to nearly ambient temperatures strongly suggests that collective, coherent electronic excitations might play a role in the functional light harvesting process taking place at physiological temperatures. PMID- 21275036 TI - Making available information from studies sponsored by the pharmaceutical industry: some current practices. AB - Since the web-based registry ClinicalTrials.gov was launched on 29 February 2000, the pharmaceutical industry has made available an increasing amount of information about the clinical trials that it sponsors. The process has been spurred on by a number of factors including a wish by the industry to provide greater transparency regarding clinical trial data; and has been both aided and complicated by the number of institutions that have a legitimate interest in guiding and defining what should be made available. This article reviews the history of this process of making information about clinical trials publicly available. It provides a reader's guide to the study registries and the databases of results; and looks at some indicators of consistency in the posting of study information. PMID- 21275037 TI - The potential for bias in reporting of industry-sponsored clinical trials. AB - Concerns about potentially misleading reporting of pharmaceutical industry research have surfaced many times. The potential for duality (and thereby conflict) of interest is only too clear when you consider the sums of money required for the discovery, development and commercialization of new medicines. As the ability of major, mid-size and small pharmaceutical companies to innovate has waned, as evidenced by the seemingly relentless decline in the numbers of new medicines approved by Food and Drug Administration and European Medicines Agency year-on-year, not only has the cost per new approved medicine risen: so too has the public and media concern about the extent to which the pharmaceutical industry is open and honest about the efficacy, safety and quality of the drugs we manufacture and sell. In 2005 an Editorial in Journal of the American Medical Association made clear that, so great was their concern about misleading reporting of industry-sponsored studies, henceforth no article would be published that was not also guaranteed by independent statistical analysis. We examine the precursors to this Editorial, as well as its immediate and lasting effects for statisticians, for the manner in which statistical analysis is carried out, and for the industry more generally. PMID- 21275038 TI - Comments on 'The potential for bias in the reporting of industry sponsored clinical trials' by Stephen Pyke et al. and 'Proposed best practice for statisticians in the reporting and publication of pharmaceutical industry sponsored clinical trials' by James Matcham et al. Pharmaceutical Statistics. PMID- 21275039 TI - Commentary: Professional responsibilities. PMID- 21275040 TI - Commentary. PMID- 21275041 TI - Bactericidal block copolymer micelles. AB - Block copolymer micelles with bactericidal properties were designed to deactivate pathogens such as E. coli bacteria. The micelles of PS-b-PAA and PS-b-P4VP block copolymers were loaded with biocides TCMTB or TCN up to 20 or 30 wt.-%, depending on the type of antibacterial agent. Bacteria were exposed to loaded micelles and bacterial deactivation was evaluated. The micelles loaded with TCN are bactericidal; bacteria are killed in less than two minutes of exposure. The most likely interpretation of the data is that the biocide is transferred to the bacteria by repeated micelle/bacteria contacts, and not via the solution. PMID- 21275042 TI - Location, location, location. PMID- 21275046 TI - Combating cystic fibrosis: in search for CF transmembrane conductance regulator (CFTR) modulators. PMID- 21275045 TI - Allosteric inhibitor development targeting HIV-1 integrase. AB - HIV-1 integrase (IN) is one of three essential enzymes for viral replication, and is a focus of ardent antiretroviral drug discovery and development efforts. Diligent research has led to the development of the strand-transfer-specific chemical class of IN inhibitors, with two compounds from this group, raltegravir and elvitegravir, advancing the farthest in the US Food and Drug Administration (FDA) approval process for any IN inhibitor discovered thus far. Raltegravir, developed by Merck & Co., has been approved by the FDA for HIV-1 therapy, whereas elvitegravir, developed by Gilead Sciences and Japan Tobacco, has reached phase III clinical trials. Although this is an undoubted success for the HIV-1 IN drug discovery field, the emergence of HIV-1 IN strand-transfer-specific drug resistant viral strains upon clinical use of these compounds is expected. Furthermore, the problem of strand-transfer-specific IN drug resistance will be exacerbated by the development of cross-resistant viral strains due to an overlapping binding orientation at the IN active site and an equivalent inhibitory mechanism for the two compounds. This inevitability will result in no available IN-targeted therapeutic options for HIV-1 treatment-experienced patients. The development of allosterically targeted IN inhibitors presents an extremely advantageous approach for the discovery of compounds effective against IN strand-transfer drug-resistant viral strains, and would likely show synergy with all available FDA-approved antiretroviral HIV-1 therapeutics, including the IN strand-transfer-specific compounds. Herein we review the concept of allosteric IN inhibition, and the small molecules that have been investigated to bind non active-site regions to inhibit IN function. PMID- 21275047 TI - Strategies towards improving the pharmacokinetic profile of epsilon-substituted lysinol-derived HIV protease inhibitors. PMID- 21275048 TI - Fragment-based design of ligands targeting a novel site on the integrase enzyme of human immunodeficiency virus 1. PMID- 21275049 TI - Synthesis and evaluation of potent ene-yne inhibitors of type II dehydroquinases as tuberculosis drug leads. PMID- 21275050 TI - Tetrahydrobenzothiophene derivatives: conformationally restricted inhibitors of type II dehydroquinase. PMID- 21275051 TI - Potent and selective inhibition of cysteine proteases from Plasmodium falciparum and Trypanosoma brucei. PMID- 21275052 TI - Reactions of antimalarial peroxides with each of leucomethylene blue and dihydroflavins: flavin reductase and the cofactor model exemplified. AB - Flavin adenine dinucleotide (FAD) is reduced by NADPH-E. coli flavin reductase (Fre) to FADH(2) in aqueous buffer at pH 7.4 under argon. Under the same conditions, FADH(2) in turn cleanly reduces the antimalarial drug methylene blue (MB) to leucomethylene blue. The latter is rapidly re-oxidized by artemisinins, thus supporting the proposal that MB exerts its antimalarial activity, and synergizes the antimalarial action of artemisinins, by interfering with redox cycling involving NADPH reduction of flavin cofactors in parasite flavin disulfide reductases. Direct treatment of the FADH(2) generated from NADPH-Fre FAD by artemisinins and antimalaria-active tetraoxane and trioxolane structural analogues under physiological conditions at pH 7.4 results in rapid reduction of the artemisinins, and efficient conversion of the peroxide structural analogues into ketone products. Comparison of the relative rates of FADH(2) oxidation indicate optimal activity for the trioxolane. Therefore, the rate of intraparastic redox perturbation will be greatest for the trioxolane, and this may be significant in relation to its enhanced in vitro antimalarial activities. (1)H NMR spectroscopic studies using the BNAH-riboflavin (RF) model system indicate that the tetraoxane is capable of using both peroxide units in oxidizing the RFH(2) generated in situ. Use of the NADPH-Fre-FAD catalytic system in the presence of artemisinin or tetraoxane confirms that the latter, in contrast to artemisinin, consumes two reducing equivalents of NADPH. None of the processes described herein requires the presence of ferrous iron. Ferric iron, given its propensity to oxidize reduced flavin cofactors, may play a role in enhancing oxidative stress within the malaria parasite, without requiring interaction with artemisinins or peroxide analogues. The NADPH-Fre-FAD system serves as a convenient mimic of flavin disulfide reductases that maintain redox homeostasis in the malaria parasite. PMID- 21275053 TI - Improved inhibitors of trypanothione reductase by combination of motifs: synthesis, inhibitory potency, binding mode, and antiprotozoal activities. AB - Trypanothione reductase (TR) is an essential enzyme in the trypanothione-based redox metabolism of trypanosomatid parasites. This system is absent in humans and, therefore, offers a promising target for the development of selective new drugs against African sleeping sickness and Chagas' disease. Over the past two decades, a variety of nonpeptidic small-molecule ligands of the parasitic enzyme were discovered. A current goal is to decipher the binding mode of these known inhibitors in order to optimize their structures. We analyzed the binding mode of recently reported 1-(1-(benzo[b]thiophen-2-yl)cyclohexyl)piperidine (BTCP) analogues using computer modeling methods. This led us to conclude that the analogues occupy a different region of the active site than the diaryl sulfide based class of inhibitors. A combination of the two motifs significantly increased affinity for the enzyme compared to the respective parent compounds. The newly synthesized conjugates exhibit K(ic) values for TR as low as 0.51+/-0.1 MUM and high selectivity for the parasitic enzyme over the related human glutathione reductase (hGR), as was predicted by our molecular modeling studies. In vitro studies showed IC(50) values in the low micromolar to submicromolar range against Trypanosoma brucei rhodesiense, often in combination with low cytotoxicity against mammalian cells. Interestingly, even stronger activities were found against Plasmodium falciparum. PMID- 21275054 TI - Design, synthesis and biological evaluation of novel inhibitors of Trypanosoma brucei pteridine reductase 1. AB - Genetic studies indicate that the enzyme pteridine reductase 1 (PTR1) is essential for the survival of the protozoan parasite Trypanosoma brucei. Herein, we describe the development and optimisation of a novel series of PTR1 inhibitors, based on benzo[d]imidazol-2-amine derivatives. Data are reported on 33 compounds. This series was initially discovered by a virtual screening campaign (J. Med. Chem., 2009, 52, 4454). The inhibitors adopted an alternative binding mode to those of the natural ligands, biopterin and dihydrobiopterin, and classical inhibitors, such as methotrexate. Using both rational medicinal chemistry and structure-based approaches, we were able to derive compounds with potent activity against T. brucei PTR1 (K(i)(app)=7 nM), which had high selectivity over both human and T. brucei dihydrofolate reductase. Unfortunately, these compounds displayed weak activity against the parasites. Kinetic studies and analysis indicate that the main reason for the lack of cell potency is due to the compounds having insufficient potency against the enzyme, which can be seen from the low K(m) to K(i) ratio (K(m)=25 nM and K(i)=2.3 nM, respectively). PMID- 21275055 TI - Synthesis and evaluation of indatraline-based inhibitors for trypanothione reductase. AB - The search for novel compounds of relevance to the treatment of diseases caused by trypanosomatid protozoan parasites continues. Screening of a large library of known bioactive compounds has led to several drug-like starting points for further optimisation. In this study, novel analogues of the monoamine uptake inhibitor indatraline were prepared and assessed both as inhibitors of trypanothione reductase (TryR) and against the parasite Trypanosoma brucei. Although it proved difficult to significantly increase the potency of the original compound as an inhibitor of TryR, some insight into the preferred substituent on the amine group and in the two aromatic rings of the parent indatraline was deduced. In addition, detailed mode of action studies indicated that two of the inhibitors exhibit a mixed mode of inhibition. PMID- 21275056 TI - Synthesis and in vitro/in vivo evaluation of the antitrypanosomal activity of 3 bromoacivicin, a potent CTP synthetase inhibitor. AB - The first convenient synthesis of enantiomerically pure (alphaS,5S)-alpha-amino-3 bromo-4,5-dihydroisoxazol-5-yl acetic acid (3-bromoacivicin) is described. We demonstrate that 3-bromoacivicin is a CTP synthetase inhibitor three times as potent as its 3-chloro analogue, the natural antibiotic acivicin. Because CTP synthetase was suggested to be a potential drug target in African trypanosomes, the in vitro/in vivo antitrypanosomal activity of 3-bromoacivicin was assessed in comparison with acivicin. Beyond expectation, we observed a 12-fold enhancement in the in vitro antitrypanosomal activity, while toxicity against mammalian cells remained unaffected. Despite its good in vitro activity and selectivity, 3 bromoacivicin proved to be trypanostatic and failed to completely eradicate the infection when tested in vivo at its maximum tolerable dose. PMID- 21275057 TI - Second-generation iminoxylitol-based pharmacological chaperones for the treatment of Gaucher disease. AB - A series of O-alkyl iminoxylitol derivatives was synthesized and evaluated as beta-glucocerebrosidase (GCase) inhibitors. This structure-activity study shows a dramatic influence of the position of the alkyl chain (alpha-C1, O2, O3, or O4) on human GCase inhibition. Remarkably, 1,2-shift of the alkyl chain from C1 to O2 was found to maintain high inhibitory potency toward GCase as well as chaperone activity at sub-inhibitory concentration (10 nM). Removal of the stereogenic center at the pseudo-anomeric position led to shorter and more practical synthetic sequences. 2-O-Alkyl iminoxylitol derivatives constitute a new promising class of leads for the treatment of Gaucher disease by means of pharmacological chaperone therapy. PMID- 21275060 TI - Leveraging gigawatt potentials by smart heat-pump technologies using ionic liquids. AB - One of the greatest challenges to science in the 21 st century is the development of efficient energy production, storage, and transformation systems with minimal ecological footprints. Due to the lack of efficient heat-transformation technologies, industries around the world currently waste energy in the gigawatt range at low temperatures (40-80 degrees C). These energy potentials can be unlocked or used more efficiently through a new generation of smart heat pumps operating with novel ionic liquid (IL)-based working pairs. The new technology is expected to allow revolutionary technical progress in heat-transformation devices, for example, significantly higher potential efficiencies, lower specific investments, and broader possibilities to incorporate waste energy from renewable sources. Furthermore, due to drastically reduced corrosion rates and excellent thermal stabilities of the new, IL-based working pairs, the high driving temperatures necessary for multi-effect cycles such as double- or triple-effect absorption chillers, can also be realized. The details of this novel and innovative heat-transformation technology are described. PMID- 21275058 TI - Synthesis and antimicrobial evaluation of nitazoxanide-based analogues: identification of selective and broad spectrum activity. AB - A library composed of nitazoxanide-based analogues was synthesized and assayed for increased antibacterial efficacy against the pyruvate-ferredoxin oxidoreductase (PFOR) using microorganisms Helicobacter pylori, Campylobacter jejuni and Clostridium difficile. Derivatives were found to recapitulate and improve activity against these organisms and select analogues were tested for their ability to disrupt the PFOR enzyme directly. The library was also screened for activity against staphylococci and resulted in the identification of analogues capable of inhibiting both staphylococci and all PFOR organisms at low micromolar minimum inhibitory concentrations with low toxicity to human foreskin cells. PMID- 21275061 TI - Efficient acid-base bifunctional catalysts for the fixation of CO(2) with epoxides under metal- and solvent-free conditions. AB - A series of acid-base bifunctional catalysts (ABBCs) that contain one or two Bronsted acidic sites in the cationic part and a Lewis-basic site in the anionic part are used as efficient catalysts for the synthesis of cyclic carbonates by cycloaddition of CO(2) to epoxides, without the use of additional co-catalyst or co-solvent. The effects of the catalyst structures and various reaction parameters on the catalytic performance are investigated in detail. Almost complete conversion can be achieved in 1 h for propylene oxide using [{(CH(2))(3)COOH}(2) im]Br under mild reaction conditions (398 K and 2 MPa). Furthermore, the catalyst can be recycled over five times without substantial loss of catalytic activity. This protocol is found to be applicable to a variety of terminal epoxides, producing the corresponding cyclic carbonates in good yields and high selectivities. A synergistic effect of the acidic and the basic sites as well as suitable hydrogen-bonding strength of ABBCs are considered crucial for the reaction to proceed smoothly. The activities of the ABBCs increase remarkably with increasing carboxylic-acid chain length of the cation. This metal- and solvent-free process thus represents an environmentally friendly process for BTC-catalyzed conversion of CO(2) into value-added chemicals. PMID- 21275062 TI - Overall water splitting under visible light through a two-step photoexcitation between TaON and WO3 in the presence of an iodate-iodide shuttle redox mediator. AB - A two-step, photocatalytic water splitting system consisting of Pt-loaded TaON (a H(2) evolution photocatalyst), Pt-loaded WO(3) (an O(2) evolution photocatalyst), and an iodate-iodide (IO(3)(-)/I(-)) shuttle redox mediator is investigated under visible light irradiation. Photocatalytic oxidation of water to O(2) and reduction of IO(3)(-) to I(-) proceeded with good selectivity over the Pt-WO(3) photocatalyst, even in the presence of a considerable amount of I(-) anions in the solution. The key difference between the adsorption properties of IO(3)(-) and I(-) anions on WO(3) strongly suggested that the photoexcited electrons could react efficiently with IO(3)(-) adsorbed on WO(3), whereas the photogenerated holes selectively reacted with water molecules owing to the low adsorptivity of I(-) on WO(3). Photocatalytic H(2) evolution on Pt-TaON proceeded efficiently, accompanied by I(-) oxidation to IO(3)(-) due to a substantial amount of adsorption of I(-) anions on the surface, whereas H(2) evolution was significantly inhibited by the competitive adsorption of IO(3)(-), which consumes photoexcited electrons. It was also found that WO(3) photocatalysts loaded with platinum oxide (PtO) showed a much higher activity for O(2) evolution in the presence of the electron acceptor IO(3)(-), compared to those loaded with Pt metal. Overall water splitting at a steady rate was demonstrated using a combination of Pt-TaON and Pt(PtO)-WO(3) in an aqueous NaI solution with neutral or weakly acidic pH values, where the concentration of NaI significantly affected the efficiency. PMID- 21275063 TI - Chemical, electrochemical, and photochemical catalytic oxidation of water to dioxygen with mononuclear ruthenium complexes. AB - Four new Ru(II)-Cl and Ru(II)-H(2)O complexes containing the meridional 2,2':6',2"-terpyridine (trpy) ligand and the chelating 2-(5-phenyl-1H-pyrazol-3 yl)pyridine (H3p) ligand of general formula in- and out-[Ru(II) (trpy)(H3p)(X)](n+) (X=Cl, n=1; X=H(2)O, n=2) have been prepared, isolated and thoroughly characterized both in solution and in the solid state. In solution, all the complexes are characterized spectroscopically by UV/Vis and NMR, and their redox properties investigated by means of cyclic voltammetry, square wave voltammetry, and coulometry. In the solid state, monocrystal X-ray diffraction analysis was carried out for the in and out Ru-Cl complexes. The capacity of the Ru-aqua complexes to act as water oxidation catalysts (WOCs) was also investigated chemically, electrochemically, and photochemically. The performance of these complexes has also been compared to two previously described complexes of general formula in- and out-[Ru(II)(trpy)(Hbpp)(H(2)O)](2+) (Hbpp is 2,2'-(1H pyrazole-3,5-diyl)dipyridine)), the capacity of which as WOCs had not been previously described. PMID- 21275064 TI - Hydrothermal decarboxylation and hydrogenation of fatty acids over Pt/C. AB - We report herein on the conversion of saturated and unsaturated fatty acids to alkanes over Pt/C in high-temperature water. The reactions were done with no added H(2) . The saturated fatty acids (stearic, palmitic, and lauric acid) gave the corresponding decarboxylation products (n-alkanes) with greater than 90 % selectivity, and the formation rates were independent of the fatty acid carbon number. The unsaturated fatty acids (oleic and linoleic acid) exhibited low selectivities to the decarboxylation product. Rather, the main pathway was hydrogenation to from stearic acid, the corresponding saturated fatty acid. This compound then underwent decarboxylation to form heptadecane. On the basis of these results, it appears that this reaction system promotes in situ H(2) formation. This hydrothermal decarboxylation route represents a new path for using renewable resources to make molecules with value as liquid transportation fuels. PMID- 21275065 TI - Synthesis of 5-(hydroxymethyl)furfural in ionic liquids: paving the way to renewable chemicals. AB - The synthesis of 5-(hydroxymethyl)furfural (HMF) in ionic liquids is a field that has grown rapidly in recent years. Unique dissolving properties for crude biomass in combination with a high selectivity for HMF formation from hexose sugars make ionic liquids attractive reaction media for the production of chemicals from renewable resources. A wide range of new catalytic systems that are unique for the transformation of glucose and fructose to HMF in ionic liquids has been found. However, literature examples of scale-up and process development are still scarce, and future research needs to complement the new chemistry with studies on larger scales in order to find economically and environmentally feasible processes for HMF production in ionic liquids. This Minireview surveys important progress made in catalyst development for the synthesis of HMF in ionic liquids, and proposes future research directions in process technology. PMID- 21275067 TI - Enantio- and regioselective iridium-catalyzed allylic hydroxylation. AB - The first enantioselective allylic hydroxylation to prepare branched allylic alcohols directly is described. Bicarbonate was used as nucleophile in conjunction with new single component Ir-catalysts, which are stable to air and water. Excellent regio- and enantioselectivities have been achieved with a representative set of substrates. PMID- 21275069 TI - Tuning hyperfine fields in conjugated polymers for coherent organic spintronics. AB - An appealing avenue for organic spintronics lies in direct coherent control of the spin population by means of pulsed electron spin resonance techniques. Whereas previous work has focused on the electrical detection of coherent spin dynamics, we demonstrate here the equivalence of an all-optical approach, allowing us to explore the influence of materials chemistry on the spin dynamics. We show that deuteration of the conjugated polymer side groups weakens the local hyperfine fields experienced by electron-hole pairs, thereby lowering the threshold for the resonant radiation intensity at which coherent coupling and spin beating occur. The technique is exquisitively sensitive to previously obscured material properties and offers a route to quantifying and tuning hyperfine fields in organic semiconductors. PMID- 21275070 TI - Direct imaging and probing of the p-n junction in a planar polymer light-emitting electrochemical cell. AB - A vast array of semiconductor applications relies on the ability to dope the materials by the controlled introduction of impurities in order to achieve desired charge carrier concentration and conduction type. In this way, various functional metal/semiconductor or semiconductor/semiconductor junctions can be constructed for device applications. Conjugated polymers are organic semiconductors that can be electrochemically doped to form a dynamic p-n junction. The electronic structure and even the existence of such a polymer p-n junction had been the subject of intense scrutiny and debate. In this work, the formation of the world's largest frozen polymer p-n junction and its light emission are visualized. With a pair of micromanipulated probes, we mapped the potential distribution of the p-n junction under bias across the entire interelectrode gap of over 10 mm. Site-selective current-voltage measurements reveal that the polymer junction is a graded p-n junction, with a much more conductive p region than n region. PMID- 21275071 TI - The association between low-grade inflammation, iron status and nucleic acid oxidation in the elderly. AB - This study applied a case-control approach to investigate the association between low-grade inflammation, defined by high values within the normal range of C reactive protein (CRP) and interleukin-6 (IL-6), and urinary markers of nucleic acid oxidation. No differences in excretion of urinary markers of nucleic acid oxidation between cases and controls were found and multivariable linear regression analysis showed no association between urinary markers of nucleic acid oxidation and inflammatory markers. Post-hoc multivariable linear regression analysis showed significant associations between nucleic acid oxidation and various iron status markers and especially a close relationship between nucleic acid oxidation and ferritin. This study shows no association between low-grade inflammation and urinary markers of nucleic acid oxidation in a population of elderly Italian people. The results suggest that low-grade inflammation only has a negligible impact on whole body nucleic acid oxidation, whereas iron status seems to be of great importance. PMID- 21275079 TI - MicroRNA expression in rat brain exposed to repeated inescapable shock: differential alterations in learned helplessness vs. non-learned helplessness. AB - MicroRNA (miRNA) expression was measured within frontal cortex of male Holtzman rats subjected to repeated inescapable shocks at days 1 and 7, tested for learned helplessness (LH) at days 2 and 8, and sacrificed at day 15. We compared rats that did vs. did not exhibit LH, as well as rats that were placed in the apparatus and tested for avoidance but not given shocks (tested controls, TC). Non-learned helpless (NLH) rats showed a robust adaptive miRNA response to inescapable shock whereas LH rats showed a markedly blunted response. One set of 12 miRNAs showed particularly large, significant down-regulation in NLH rats relative to tested controls (mir-96, 141, 182, 183, 183*, 298, 200a, 200a*, 200b, 200b*, 200c, 429). These were encoded at a few shared polycistronic loci, suggesting that the down-regulation was coordinately controlled at the level of transcription. Most of these miRNAs are enriched in synaptic fractions. Moreover, almost all of these share 5'-seed motifs with other members of the same set, suggesting that they will hit similar or overlapping sets of target mRNAs. Finally, half of this set is predicted to hit Creb1 as a target. We also identified a core miRNA co-expression module consisting of 36 miRNAs that are highly correlated with each other across individuals of the LH group (but not in the NLH or TC groups). Thus, miRNAs participate in the alterations of gene expression networks that underlie the normal (NLH) as well as aberrant (LH) response to repeated shocks. PMID- 21275081 TI - Satiety: have we neglected dietary non-nutrients? AB - Satiety, which is the inhibition of eating following the end of a meal, is influenced by a number of food characteristics, including compositional and structural factors. An increased understanding of these factors and the mechanisms whereby they exert their effects on satiety may offer a food-based approach to weight management. Water and gas, which are often neglected in nutrition, are major components of many foods and contribute to volume, and to sensory and other characteristics. A review of previous short-term studies that evaluated the effects of water or gas in foods on satiety showed that while satiety was generally increased, effects on subsequent intakes were not always apparent. These studies were diverse in terms of design, timings and food matrices, which precludes definitive conclusions. However, the results indicate that solids may be more effective at increasing satiety than liquids, but gas may be as effective as water. Although increased gastric distension may be the main mechanism underlying these effects, pre-ingestive and ingestive impacts on cognitive, anticipatory and sensory responses also appear to be involved. Furthermore, there is limited evidence that water on its own may be effective at increasing satiety and decreasing intakes when drunk before, but not with, a meal. Longer-term extrapolation suggests that increasing food volumes with water or gas may offer weight-management strategies. However, from a practical viewpoint, the effects of water and gas on satiety may be best exploited by using these non-nutrients to manipulate perceived portion sizes, without increasing energy contents. PMID- 21275080 TI - 3-Hydroxykynurenine and clinical symptoms in first-episode neuroleptic-naive patients with schizophrenia. AB - One branch of the tryptophan catabolic cascade is the kynurenine pathway, which produces neurotoxic [3-hydroxykynurenine (3-OHKY), quinolinic acid] and neuroinhibitory (kynurenic acid) compounds. Kynurenic acid acts as a competitive antagonist at the glycine site of N-methyl-d-asparate receptors at high concentrations and as a non-competitive antagonist on the alpha7-nicotinic acetylcholine receptor at low concentrations. Kynurenine compounds also influence cognitive functions known to be disrupted in schizophrenia. Alterations in tryptophan metabolism are therefore of potential significance for the pathophysiology of this disorder. In this paper, tryptophan metabolites were measured from plasma using high-pressure liquid chromatography coupled with electrochemical coulometric array detection, and relationships were tested between these metabolic signatures and clinical symptoms for 25 first-episode neuroleptic-naive schizophrenia patients. Blood samples were collected and clinical and neurological symptoms were rated at baseline and again at 4 wk following initiation of treatment. Level of 3-OHKY and total clinical symptom scores were correlated when patients were unmedicated and neuroleptic-naive, and this relationship differed significantly from the correlation observed for patients 4 wk after beginning treatment. Baseline psychosis symptoms were predicted only by neurological symptoms. Moreover, baseline 3-OHKY predicted clinical change at 4 wk, with the lowest concentrations of 3-OHKY being associated with the greatest improvement in symptoms. Taken together, our findings suggest a neurotoxic product of tryptophan metabolism, 3-OHKY, predicts severity of clinical symptoms during the early phase of illness and before exposure to antipsychotic drugs. Baseline level of 3-OHKY may also predict the degree of clinical improvement following brief treatment with antipsychotics. PMID- 21275082 TI - The control of meal size in human subjects: a role for expected satiety, expected satiation and premeal planning. AB - Unlike energy expenditure, energy intake occurs during discrete events: snacks and meals. The prevailing view is that meal size is governed by physiological and psychological events that promote satiation towards the end of a meal. This review explores an alternative and perhaps controversial proposition. Specifically that satiation plays a secondary role, and that meal size (kJ) is controlled by decisions about portion size, before a meal begins. Recently, techniques have been developed that enable us to quantify 'expected satiation' and 'expected satiety' (respectively, the fullness and the respite from hunger that foods are expected to confer). When compared on a kJ-for-kJ basis, these expectations differ markedly across foods. Moreover, in self-selected meals, these measures are remarkably good predictors of the energy content of food that ends up on our plate, even more important than palatability. Expected satiation and expected satiety are influenced by the physical characteristics of a food (e.g. perceived volume). However, they are also learned. Indeed, there is now mounting evidence for 'expected-satiation drift', a general tendency for a food to have higher expected satiation as it increases in familiarity. Together, these findings show that important elements of control (discrimination and learning/adaptation) are clearly evident in plans around portion size. Since most meals are eaten in their entirety, understanding the nature of these controls should be given high priority. PMID- 21275083 TI - Antipsychotic treatment beyond antipsychotics: metacognitive intervention for schizophrenia patients improves delusional symptoms. AB - BACKGROUND: Although antipsychotic medication still represents the treatment of choice for schizophrenia, its objective impact on symptoms is only in the medium effect size range and at least 50% of patients discontinue medication in the course of treatment. Hence, clinical researchers are intensively looking for complementary therapeutic options. Metacognitive training for schizophrenia patients (MCT) is a group intervention that seeks to sharpen the awareness of schizophrenia patients on cognitive biases (e.g. jumping to conclusions) that seem to underlie delusion formation and maintenance. The present trial combined group MCT with an individualized cognitive-behavioural therapy-oriented approach entitled individualized metacognitive therapy for psychosis (MCT+) and compared it against an active control. METHOD: A total of 48 patients fulfilling criteria of schizophrenia were randomly allocated to either MCT+ or cognitive remediation (clinical trial NCT01029067). Blind to intervention, both groups were assessed at baseline and 4 weeks later. Psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) and the Psychotic Symptom Rating Scales (PSYRATS). Jumping to conclusions was measured using a variant of the beads task. RESULTS: PANSS delusion severity declined significantly in the combined MCT treatment compared with the control condition. PSYRATS delusion conviction as well as jumping to conclusions showed significantly greater improvement in the MCT group. In line with prior studies, treatment adherence and subjective efficacy was excellent for the MCT. CONCLUSIONS: The results suggest that the combination of a cognition-oriented and a symptom-oriented approach ameliorate psychotic symptoms and cognitive biases and represents a promising complementary treatment for schizophrenia. PMID- 21275084 TI - Mental disorders as mechanistic property clusters. PMID- 21275085 TI - Are bipolar II patients cognitively impaired? A systematic review. AB - BACKGROUND: There is evidence that bipolar disorder (BD) is associated with significant neurocognitive deficits and this occurs in individuals with BD type I (BD I) and with BD type II (BD II). Only a few studies have focused on cognitive impairment in BD II. The aim of this study was to describe the pattern of cognitive impairment in patients with BD II, in order to identify specific cognitive deficits that distinguish BD II from BD I patients as well as from healthy subjects. METHOD: We performed a systematic review of the literature of neuropsychological studies of BD II published between 1980 and July 2009. Fourteen articles fulfilled the inclusion criteria and were included in this review. RESULTS: Main cognitive deficits found in BD II include working memory and some measures of executive functions (inhibitory control) and approximately half of the studies also detected verbal memory impairment. CONCLUSIONS: There are subtle differences between the two subtypes regarding cognition. This may suggest neurobiological differences between the two subgroups which will be helpful in order to determine cognitive endophenotypes in BD subtypes. PMID- 21275086 TI - Teenage motherhood and risk of premature death: long-term follow-up in the ONS Longitudinal Study. AB - BACKGROUND: Teenage motherhood is relatively common in the UK, but little is known about related health inequalities in this population. We estimated cause specific mortality risks over three decades in a nationally representative cohort. METHOD: We examined premature mortality in a 1.1% sample of all women who were teenagers in England and Wales during the 1970s, 1980s and 1990s using data from the Office for National Statistics Longitudinal Study (ONS LS). Our primary outcome was suicide. Long-term follow-up to 31 December 2006, to a potential maximum age of 49 years, was achieved through near-complete routine linkage to national mortality records. We created a time-dependent exposure variable, with relative risks estimated according to age when women first experienced motherhood versus a reference group of those currently without children. RESULTS: Women who were teenage mothers were around 30% more likely to die prematurely by any cause and almost 60% more likely to die unnaturally, whereas first-time motherhood at mature age conferred lower risk compared to women without children. Teenage motherhood was associated with a more than doubled risk of suicide [mortality rate ratio (MRR) 2.23, 95% confidence interval (CI) 1.30-3.83], and elevated risks of fatal cancer of the cervix and lung were also found. Changing the reference category to first-time mothers at 20 years and above also revealed a significant elevation in risk of accidental death. CONCLUSIONS: The complex psychosocial needs of these women require greater attention from clinicians, public health professionals, social services and policymakers. Their elevated risk of poor health outcomes may persist well beyond the actual teenage motherhood years. PMID- 21275087 TI - Incidence and risk factors for late-life depression in the Ibadan Study of Ageing. AB - BACKGROUND: We present the incidence and risk factors for major depressive disorder (MDD) among community-dwelling elderly Nigerians. METHOD: A cohort study of persons aged >= 65 years residing in eight contiguous Yoruba-speaking states in south-west and north-central Nigeria was conducted between November 2003 and December 2007. Of the 2149 baseline sample, 1408 (66%) were successfully followed up after approximately 39 months. Face-to-face in-home assessments were conducted with the World Health Organization (WHO) Composite International Diagnostic Interview, version 3 (CIDI.3) and diagnosis was based on the DSM-IV. Incident MDD was determined in the group with no prior lifetime history of MDD at baseline and who were free of dementia at follow-up (n=892). RESULTS: During the follow-up period, 308 persons had developed incident MDD, representing a rate of 104.3 [95% confidence interval (CI) 93.3-116.6] per 1000 person-years. Compared to males, the age-adjusted hazard for females was 1.63 (95% CI 1.30-2.06). Lifetime or current subsyndromal symptoms of depression at baseline did not increase the risk of incident MDD. Among females, but not males, rural residence and poor social network were risk factors for incident MDD. Physical health status at baseline did not predict new onset of MDD. CONCLUSIONS: The finding of a high incidence of MDD among elderly Nigerians complements earlier reports of a high prevalence of the disorder in this understudied population. Social factors, in particular those relating to social isolation, constitute a risk for incident MDD. PMID- 21275088 TI - By the way, doctor. I've been diagnosed as having chilblains in the fingers on both hands. What causes chilblains? Is there a cure? PMID- 21275089 TI - [The role of tricuspid valve insufficiency in a progress of chronic heart insufficiency. Modern view concerning the problem solution]. PMID- 21275090 TI - [Clinical toxicology--a new field of using fat emulsions]. PMID- 21275091 TI - [Inguinal hernia alloplasty preserving the cremaster muscle using anterior access]. PMID- 21275092 TI - [Activation of reconstructive processes in rat tissues under the action of radiofrequency current with a periodic impulse mode of modulation]. AB - The action of a current in the radio frequency range with a periodic impulse mode of modulation on the activation of recovery processes in the skin and skeletal muscles has been studied. The action of a radio frequency current with a power of 1 W, as opposed to that of the weaker action (0.1 W) and stronger (4 W) action, leads to the activation of recovery processes in the skin and skeletal muscles. Recovery processes are manifested in the increase in proliferation and activation of angiogenesis in the skin, and also in formation of new muscle fibers. Recovery processes in muscles are accompanied by activation and migration of satellite cells of muscle tissue in the zone of action of the radio frequency current. PMID- 21275093 TI - [Energetic metabolism during individual development of Lymnaea stagnalis (Lymnaeidae, Gastropoda): III. Late postlarval ontogeny]. AB - Changes in the rate and intensity of oxygen consumption during individual ontogeny of 14 specimens of Lymnaea stagnalis in the period from the 10th week after emergence until death was investigated in aquaculture. It was demonstrated that the rate of oxygen consumption increased and the intensity of this process decreased during the whole period of observations. Alterations of these parameters were accompanied with permanent oscillations of their meanings. The correlation between intensity of oxygen consumption (q) and age (t) can be described with the equation q = q(st)(1-exp(-k(g)(t+t0))). The values of coefficients of this equation do not differ significantly between individuals and, on average, comprise k(g) = 0.0696 +/- 0.0072 weeks(-1); q(st) = 60.42 +/- 2.6 mcl O2/(hour(g)); t0 = -3.0 +/- 0.7 weeks. The dependence of the rate of oxygen consumption (Q, microl O2/h) on body weight (M, g) for all data is significantly described with the allometric equation Q = 0.369M(0.779). PMID- 21275094 TI - [Zoobenthos communities and their seasonal dynamics in nonfreezing springs of Baikal region]. AB - The faunal composition, structure of the zoobenthos communities, and seasonal changes in two springs in the south of Irkutsk area are investigated. Both springs have the water temperature 4-5 degrees C all year round. The fauna consists of widely distributed hydrobionts, crenobionts, stygobionts, and near water organisms. Arctic relicts and elements of the Lake Baikal fauna are found. In macroinvertebrate communities, chironomid larvae dominate (by abundance and biomass), as do oligochaetes (by abundance). The lowest quantitative parameters are recorded in autumn-winter, and the highest parameters, in spring (March April). Then they abruptly decline owing to emergence of amphibiotic insects. The structure of spring communities has regional specificity. By biomass of macrozoobenthos, the springs are comparable with mesotrophic and even eutrophic lakes. PMID- 21275095 TI - [Tendencies of nematodes communities to recover after soil cover degradation]. AB - The way nematodes form communities on a new substrate after complete soil and plant cover degradation is studied on a model of industrial dumping. It is revealed that recovery of soil cover after degradation begins with invasion of mainly the upper soil horizon by nematodes. At the early stages, species that are resistant to unfavorable environmental conditions dominate (bacteriophages), next the abundances of carnivores and nematodes that are connected with plants increase, which indicates the process of biocenosis regeneration. PMID- 21275096 TI - Proceedings of the Water Research Conference. Lisbon, Portugal. April 11-14, 2010. PMID- 21275098 TI - Evolution today and tomorrow, Darwin evaluated by contemporary evolutionary and philosophical theories. Proceedings of an international conference. April 23-24, 2009. Lisbon, Portugal. PMID- 21275097 TI - Special issue on polyamines dedicated to the memory of Nello Bagni. PMID- 21275099 TI - Proceedings of the 19th International Symposium on Shiftwork and Working Time. August 2-6, 2009. Venice, Italy. PMID- 21275100 TI - The puzzle posed by COMMD1, a newly discovered protein binding Cu(II). AB - Copper is critically important for cellular metabolism. It plays essential roles in developmental processes, including angiogenesis. The liver is central to mammalian copper homeostasis: biliary excretion is the major route of excretion for ingested copper and serves to regulate the total amount of copper in the organism. An extensive network of proteins manipulates copper disposition in hepatocytes, but comparatively little is known about this protein system. Copper exists in two oxidation states: most extracellular copper is Cu(II) and most, if not all, intracellular copper is Cu(I). Typical intracellular copper-binding proteins, such as the Cu-transporting P-type ATPases ATP7B (Wilson ATPase) and ATP7A (Menkes ATPase), bind copper as Cu(I). Accordingly, the recent discovery that the ubiquitous protein COMMD1 binds Cu(II) exclusively raises the question as to what role Cu(II) may play in intracellular processes. This issue is particularly important in the liver and brain. In humans, Wilson's disease, due to mutations in ATP7B, exhibits progressive liver damage from copper accumulation; in some Bedlington terriers, mutations in COMMD1 are associated with chronic copper-overloaded liver disease, clinically distinct from Wilson's disease. It seems unlikely that Cu(II), which generates reactive oxygen species through the Fenton reaction, has a physiological role intracellularly; however, Cu(II) might be the preferred state of copper for elimination from the cell, such as by biliary excretion. We argue that COMMD1 participates in the normal disposition of copper within the hepatocyte and we speculate about that role. COMMD1 may contribute to the mechanism of biliary excretion of copper by virtue of binding Cu(II). Additionally, or alternatively, COMMD1 may be an important component of an intracellular system for utilizing Cu(II), or for detecting and detoxifying it. PMID- 21275101 TI - Intraoperative carcinoid hypertensive crisis precipitated by yttrium 90 microsphere radioembolotherapy. PMID- 21275102 TI - Radioiodine therapy and latex allergy. PMID- 21275103 TI - Proceedings of the 12th Symposium on Cochlear Implants in Children. June 17-20, 2009. Seattle, Washington, USA. PMID- 21275104 TI - Comments on continuous glucose monitoring consensus statement. PMID- 21275105 TI - Nello Bagni: A life in science. PMID- 21275106 TI - Compression therapy. Proceedings of a meeting organized by the International Compression Club. September 2008. Lucca, Italy. PMID- 21275107 TI - Mitochondrial fatty acid oxidation disorders. Proceedings of an international symposium. October 2008. Fulda, Germany. PMID- 21275108 TI - Proceedings of the International Symposium on Neglected Influenza Viruses. February 3-5, 2010. Amelia Island, Florida, USA. PMID- 21275109 TI - Proceedings of the 10th International Symposium on Sjogren's Syndrome. October 1 3, 2009. Brest, France. PMID- 21275110 TI - Proceedings of the 4th International Workshop on Surface Modification for Chemical and Biochemical Sensing (SMCBS 2009). November 6-10, 2009. Cracow, Poland. PMID- 21275111 TI - Proceedings of the 35th Annual Meeting of JSOPMB (Japan Society for Organ Preservation and Medical Biology). November 22-23, 2008. Tokyo, Japan. PMID- 21275113 TI - Haiti: lessons learnt. PMID- 21275112 TI - Proceedings of a conference of the Arts and Humanities Research Council (AHRC) Center for the Evolution of Cultural Diversity. London, United Kingdom. PMID- 21275114 TI - The hypothesis of an effective safe and novel radioprotective agent: hydrogen rich solution. AB - Most ionizing radiation-induced damage is caused by radical oxygen species (ROS). Some radioprotectors, such as amifostine, exert radioprotective effects by scavenging radical oxygen species. Recent studies show that hydrogen (H) has antioxidant activities that protect the brain and intestine against ischaemia reperfusion injury and stroke by selectively reducing hydroxyl and peroxynitrite radicals. However it is seldom regarded as a radioprotective agent. In like manner we hypothesize that hydrogen may be an effective, specific and novel radioprotective agent. But H2 is explosive, while hydrogen-rich solution (solution such as physiological saline saturated with molecular hydrogen) is safer. PMID- 21275115 TI - Association between anthropometric hormonal measurements and bone mineral density in puberty and constitutional delay of growth and puberty. AB - The aim of this study is to evaluate the acquisition of bone mineral in healthy children throughout puberty and in children with constitutional delay of growth and puberty (CDGP), and to relate changes in bone mass to age, weight, height, sitting height, body mass index and sex hormones in healthy boys. A total of 90 boys: 15 boys with CDGP and 75 healthy boys in different pubertal stages were examined. The number of children assigned to each Tanner stages was 15. Although bone age, weight and Body Mass Index (BMI) were significantly higher in stages II, III, IV V compared to stage I and CDGI mean height and sitting height values were higher in stages III, IV V compared to stage I and CDGP Also, serum FSH, LH, oestradiol, total and free testosterone levels progressively increased, although serum sex hormone binding globulin (SHBG) levels decreased, in healthy children with progression of sexual development. Significant increase was observed for serum oestradiol levels at stage II and above (p < 0.001), for serum total and free testosterone levels at stage III and above (p < 0.001), for serum FSH and LH levels at stage IV and above (p < 0.01 and p < 0.001) respectively. Also, it was shown that bone mineral content (BMC) and bone mineral density (BMD) measurements were significantly higher for pubertal stage III and above groups according to both the CDGP group and stage I group. When BMD and BMC measurements of children with CDGP (0.62 +/- 0.05 gr/cm2 and 23.4 +/- 2.8 gr) were compared with bone age, age, BMI and height-matched controls, there was no significant difference between children with CDGP and controls, except for age. Bone mineral density and BMC measurements in children with CDGP were significantly lower than those of age matched controls (for pubertal stage III: p < 0.05, for pubertal stage IV: p < 0.01). The strongest correlation coefficients were found between BMD and height among auxological parameters (r = 0.63, p < 0.001) and serum oestradiol levels among hormones (r = 0.55, p < 0.001). The most important findings of this investigation was the determination of body composition and hormonal measurement changes during puberty in boys; oestradiol was the most potent determinant of BMD among pubertal boys. We suggested that there is a critical age period for accumulation of bone mass according to the results. Longitudinal studies will elucidate why sufficient mineralization does take place after puberty starts in CDGP PMID- 21275116 TI - Clinical and laboratory features of youth onset type 2 diabetes in Jamaica. AB - OBJECTIVES: To assess the frequency of youth onset Type 2 diabetes mellitus (T2D) in Jamaica and the characteristics of youth with this form of diabetes. METHODS: Patients from two major referral hospitals, diagnosed with diabetes before age 25 years and < 6 years prior to the study, were evaluated. Classification was based on the presence of GAD-65 and IA-2 diabetes autoantibodies (AB), fasting (FCP) and stimulated C-peptide (SCP) measurements, serum leptin and clinical phenotype as follows: (i) Type IA diabetes--AB+, (ii) Type lB diabetes--AB- and FCP < 230 pmol/l and/or SCP < 660pmol/l, (iii) Type 2 diabetes - AB- and FCP > 500 pmol/L and or SCP 2 1160 pmol/l (iv) Untypeable diabetes--AB- and FCP 230-500 pmol/l and or SCP 660-1160 pmol/l and (v) Lipoatrophic diabetes--clinical phenotype and serum leptin. RESULTS: Fifty-eight participants (21M, 37F, age 20-8 years, duration of diabetes 2.6-2 years) were enrolled in the study. Using the classification criteria, Type 1 diabetes was the most common form of diabetes: 18 (31%) Type 1A, 18 (31%) Type IB. Overall 22% (13 patients) had T2D. Patients with T2D were more likely to be female, older at diagnosis, obese and have a higher blood pressure when compared to those with Type 1 diabetes. In logistic regression analysis, age of diabetes onset, gender BMI, systolic and diastolic blood pressure were significantly associated with T2D. Obesity measured by BMI was the strongest predictor of T2D. CONCLUSIONS: While Type 1 diabetes was the predominant form of diabetes in this study, a significant proportion of Jamaicans with youth onset diabetes may have T2D. Obesity is the strongest clinical predictor of Type 2 diabetes in the young diabetic patient. PMID- 21275117 TI - Knowledge and practice of occupational infection control among healthcare workers in Jamaica. AB - OBJECTIVE: To assess the knowledge, compliance and practice among healthcare workers of occupational infection control at two hospitals in Jamaica. METHODS: Employing a cross-sectional study design, medical personnel (physicians and nurses) at two hospitals in Jamaica, were studied, utilizing a structured questionnaire consisting of 14 items to collect the data. RESULTS: Participants considered the following fluids, not blood stained, high risk for HIV transmission: breast milk (79%), saliva (14%), urine (27%), pleural fluid (53%), CSF (55%), synovial fluid (37%), faeces (27%), peritoneal fluid (53%) and vomitus (21%). The respondents estimated the risk of transmission of infection after a needlestick injury from a patient with: HIV, mean 22.5%, HB, 34% and HCV, 26%. Needles for drawing blood were identified as having the highest risk for transmission of infections in 63%. The following precautions were adhered to all the time: wearing gloves (38%), not re-sheathing needles (22%), not passing needles directly to others (70%), properly disposing of sharps (86%) and regarding patients' blood and other high risk fluid as potentially infected (62%). Post exposure, 43% indicated bleeding/squeezing the NSI site as the initial first-aid procedure, washing with soap and water (29%) and irrigating the area with water (20%). CONCLUSIONS: Healthcare workers are aware of the risk of transmission of infection, however compliance with universal precautions was inadequate. An improvement in knowledge and practice with clear guidelines are needed and a comprehensive programme to educate HCWs regarding compliance with universal precautions is urgently required. PMID- 21275118 TI - Prevalence of needlestick injuries and other high risk exposures among healthcare workers in Jamaica. AB - OBJECTIVE: To assess the prevalence of needlestick injuries (NSIs) and other high risk exposures among healthcare workers at two hospitals in Jamaica. METHODS: Employing a cross-sectional study design, medical personnel (physicians, nurses) at two hospitals in Jamaica, were studied, utilizing a structured questionnaire consisting of 14 items to collect data on needle stick injuries and other injuries. RESULTS: There were 67 needlestick injuries in 47 persons. Of those sustaining an injury, 52% of physicians and 40% of nurses had NSIs. Re-capping needles accounted for 21% of injuries, various minor procedures, 21%, injury during surgery, 19.4% and taking blood, 12%. In those sustaining NSIs, 47% were reported and 26% of reported cases received counselling. Appropriate blood tests were performed on 34% and post-exposure prophylaxis (PEP) for HIV was administered to 30%. Hollow bore needles caused 47.8% of injuries, 25.4% occurred with suture needles and 19.4% with intravenous branulas. Other occupational exposure was reported by 31%, including blood on hands and other body parts 39%, blood to face and eyes, 18%, splashed with liquor, 18%, splashed with bloody fluid, 11% and contact with vomitus and urine in eye, 4%. CONCLUSION: Needlestick injuries and other high risk exposures were high; incident reporting and post exposure management were inadequate. A comprehensive programme to address factors that contribute to the occurrence of NSIs and other occupational exposures is urgently needed. PMID- 21275119 TI - Dynamics of antibiotic usage in the intensive care unit at the University Hospital of the West Indies. AB - OBJECTIVE: To determine antibiotic usage patterns in the Intensive Care Unit (ICU) at the University Hospital of the West Indies (UHWI). METHOD: A cross sectional, analytical study of consecutive patients admitted to the ICU was conducted between July and December 2007. Exclusion criteria were HIV-positive patients, patients < 12 years and those discharged or who died within 48 hours of admission. Data were collected from medical records, stored and analysed using the SPSS Version 12. RESULTS: Of the 150 eligible patients, 109 had complete data (73%). Mean age was 50.8 +/- 20.7 years, with mean APACHE II score of 15.6 +/- 6.7. Forty-five patients (41.3%) received prophylactic antibiotics, most commonly ceftriaxone (31.7%) and metronidazole (19.0%). Appropriate discontinuation within 24 hours occurred in only 11.1%. Two-thirds of patients (67.9%) were treated with empiric antibiotics, most commonly piperacillin/tazobactam (32.1%), ceftazidime (27.5%) or metronidazole (27.5%). Reasons for empiric choice were primarily coverage of organisms based on presumed source of sepsis (45.6%), and broad spectrum, high-powered coverage (23.5%). Courses ranged from 1 - 42 days and were adequate based on subsequent cultures in 71% of cases. Culture reports took between 2 - 8 days with a mean of 3.7 days to become available. De-escalation was practised in only 2 of 26 (7.7%) cases and intravenous to oral switch therapy in only 3.3%. Thirty-two (29.4%) patients died, with sepsis being a cause in 12 (37.5%). CONCLUSIONS: Improved attention to discontinuation of prophylactic antibiotics, appropriate duration of antibiotic courses and de-escalation are essential if the antibiotic practices in the ICU at the UHWI are to compare favourably with international recommendations. PMID- 21275120 TI - A survey of physicians' knowledge and attitudes regarding antimicrobial resistance and antibiotic prescribing practices at the University Hospital of the West Indies. AB - OBJECTIVE: To identify physicians' knowledge and attitudes regarding antimicrobial resistance and antibiotic prescribing practices at the University Hospital of the West Indies (UHWI). METHODS: A cross-sectional survey of physicians at the UHWI was conducted between September 2008 and April 2009 using a 28-item, self-administered questionnaire. Eligible physicians from several specialities were identified from departmental rotas. RESULTS: A total of 174 physicians completed the questionnaire, a response rate of 73%. Most physicians considered antibiotic resistance to be an extremely important global problem (55%) but less significant nationally (35%). Factors identified as important in producing resistance included widespread use of antibiotics (91%), inappropriate empiric choices (79%) and use of broad-spectrum agents (70%). Hand-washing was not considered to be important in reducing resistance. Useful interventions included access to current information on local resistance patterns (90%), institutional specific antibiotic guidelines (89%) and educational programmes (89%). Antibiotic cycling (40%) and restriction (35%) were regarded as less helpful. Knowledge of resistance-prone antibiotics and specific resistant organisms at the UHWI was poor, except for methicillin-resistant Staphylococcus aureus (MRSA). Empiric therapy for common infections was appropriate in most cases, and antibiotic choices were guided by availability of drugs (89%) and patient factors such as renal disease or allergy (80%). Only 45% of physicians would de-escalate to a narrow-spectrum antibiotic guided by a microbiology report, and consultants were more likely to de-escalate therapy than junior staff (p = 0.002). CONCLUSIONS: Although physicians were aware of the problem of resistance to antibiotics and the contributory factors, their practice did not reflect measures to reduce it. Continuing educational programmes and institution specific antibiotic prescribing guidelines are needed. PMID- 21275121 TI - Knowledge and attitudes of students at a Caribbean offshore medical school towards sexually transmitted infections and use of condoms. AB - BACKGROUND: Sexually transmitted infections remain one of the predominant health issues that affect young adults. The aim of this study is to assess the level of knowledge, the attitudes and misconceptions of medical students at a Caribbean University towards STIs and condom use. METHOD: A cross-sectional descriptive study was carried out among medical students by employing semi-structured questionnaires. RESULTS: Out of 150 questionnaires, 130 were completed, showing a response rate of 87%. The ages of the respondents ranged from 19 to 45 years with a mean age of 26 (SD 5.2) years. The findings indicated that the knowledge of students concerning STIs is high (95.4%). Twenty-four (18.5%) of the respondents had experienced vaginal/penile discharge following sexual intercourse over the last 6 months. The correlation of beliefs in condom usage and risky behaviour gives an odds ratio of 0.19 indicating a lower use of condoms among the students. A negative attitude towards condom usage was seen in 3.8% of the respondents. The main reason for condom usage was to prevent unwanted pregnancy and not to prevent contracting sexually transmitted infections. CONCLUSION: The knowledge of students about STIs in this study was found to be high, however risky behaviour such as having sexual intercourse with commercial sex-workers and regular unprotected sexual activities were identified although the prevalence of such behaviour was found to be low. We therefore recommend that behaviour modification programmes with regard to sex education and condom usage be implemented for the medical students as they are to be the future educators of the public on these matters. PMID- 21275122 TI - The pathology of breast cancer in Jamaica: the National Public Health Laboratory study. AB - OBJECTIVE: To document the pathologic features of breast cancer in Jamaica. METHODS: The pathology reports and slides of all patients diagnosed with breast cancer at the National Public Health Laboratory between January 1999 and December 2002 were reviewed. Patient age and gender side involved, number of tumours identified, tumour size, histologic type, histologic grade, degree of lymph node involvement and parish of origin of the specimens were documented. RESULTS: There were 772 patients, 762 females and 10 males; age range 21 to 96 (mean 57.9 +/- 15.9) years. There were 778 specimens (6 bilateral cases), the majority of whom originated from Kingston and St Andrew (34.7%). Manchester (22.9%), St Catherine (13.9%) and St Ann (7.3%) were the next most common sources. The left breast was involved in 50.5% of cases. Gross tumour was identified in 641 (82.4%) specimens, the number of tumours ranging from 1 - 6 (mean 1.1 +/- 0.6). The maximum gross tumour dimension ranged from 0.3 to 15 cm (mean 4.1 +/- 2.7 cm). Infiltrating duct carcinoma was the predominant histologic type (69.3 %); 13.3%, 49.5% and 37.2 % of all infiltrating tumours were well, moderately and poorly differentiated respectively. In-situ lesions (7.1% of tumours) were all of the ductal phenotype. Axillary lymph nodes were submitted in 296 (38.1%) cases; metastatic disease was identified in 224 (75.7%) of these. The total number of nodes submitted ranged from 1 - 34 (mean 10.8 +/- 6.7) with an average of 6.1 (+/ 5.8) being positive for metastases (range 1 - 29). CONCLUSIONS: The pathologic features of breast cancer documented in this series including average tumour size, histologic types and grade and the degree of lymph node involvement are consistent with patient presentation at relatively advanced stages of disease and highlight the urgent need for public health intervention including a national screening programme. PMID- 21275123 TI - Plyometric training improves power and agility in Jamaica's national netball team. AB - OBJECTIVE: Plyometric training is widely used in conditioning, power training and in prevention and rehabilitation of injuries in some sports. This study sought to investigate the effect of a three-week plyometric training programme on jump performance and agility in Jamaican national netball players. METHOD: Eighteen national netballers participated in a Plyometric training programme. Subjects were evaluated using the Vertical Jump Test, the Broad Jump Test and the Illinois Agility Test prior to the start of the programme and at week 3. DATA ANALYSIS: The data were analysed using SPSS version 12 for Windows. A One-Sample Kolmogorov Smirnov Test showed normal distribution of data and a paired samples t-test was used to determine whether the mean change in jump performance and agility was significant. RESULTS: All eighteen subjects completed the three weeks of training. Three subjects were shown to be outliers at week 3 and this resulted in data from 15 subjects being analysed. At the end of the three weeks, there were significant improvements in Vertical Jump Scores (p = 0.023), Broad Jump Scores (p = 0.002) and Agility scores (p = 0.045). CONCLUSION: Three weeks of Plyometric training can lead to significant improvements in jump performance and agility and should be integrated into the national training programme at intervals yet to be determined. PMID- 21275124 TI - The evidence-based management of bilateral ethmoid osteomas: diagnosis, endoscopic resection and review of the literature. AB - A 56-year old woman presented with headaches and nasal congestion secondary to bilateral ethmoid osteomas and she made a full recovery following endoscopic resection. Paranasal osteomas are common, benign, encapsulated tumours that are often asymptomatic, but may present similarly to rhinosinusitis and occasionally cause complications depending on their anatomical location. Bilateral ethmoidal osteomas, however are a rare occurrence and have not been previously reported in the English literature as far as the authors are aware. Ethmoidal and fronto ethmoidal osteomas, like other paranasal osteomas, are easily diagnosed using computed tomography and are increasingly amenable to endoscopic resection. An evidence-based management plan is presented. PMID- 21275125 TI - Degenerative disc disease of the lumbar spine on MRI. AB - A retrospective analysis was done of all patients referred for MRI of the lumbar spine at the University Hospital of the West Indies, Kingston, Jamaica, during the three-year period January 1, 2005 and December 31, 2007. Data were collected to determine patients 'age, gender, weight and the presence or absence of degenerative disc disease (DDD). The patients' presenting symptoms were not evaluated. There were 362 patients examined: 154 males, 204 females and four uncharacterized, aged between 8 and 87 (mean age = 50.45) years. Degenerative Disc Disease (DDD), was found in 283 (78.2%) patients: 121 males, 159 females and three unidentified, with a total of 669 degenerate discs. L 4/5 and L 5/S 1 were most frequently affected accounting for 31.2% and 30.6% of degenerate discs respectively. Patients with DDD were significantly heavier and significantly older than patients without disc disease. Gender was not predictive of DDD in general nor of involvement of any particular disc though a marginally significant tendency was found for males to more frequently have DDD at L1/2 and L5/S1. CONCLUSION: Degenerative disc disease of the lumbar spine occurred more frequently in older and heavier patients. Gender did not affect the presence or the extent of the disease; compared to females, males showed a marginally increased tendency to have DDD at L1/2 and L5/S1. PMID- 21275126 TI - Anxiety and depression in medical students related to desire for and expectations from a medical career. AB - OBJECTIVE: In this article, we aimed to analyse the anxiety and depression levels of medical student's related to their desire for a career in medicine and expectations from that career. METHODS: In a cross-sectional design, students from the first two years of medical school filled-out a questionnaire consisting of demographics, Hospital Anxiety and Depression Scales (HADS) and questions about their medical career decision. RESULTS: The mean anxiety score was 7.66 +/- 3.21 and the mean depression score was 5.77 +/- 3.45. According to cut-off levels, 20.3% of medical students had anxiety, 29.3% had depressive symptoms. Males and second year students had significantly high levels of depression (p < 0.05). Students who were pressured to become doctors and who expected to gain much money were both more anxious and more depressed (p < 0.05). CONCLUSION: External pressures, desire to become a medical doctor and expectations from a medical education have significant effects on anxiety and depression levels of medical students. Guidance for affected students is important and this is the responsibility of medical educators and faculties. PMID- 21275127 TI - Factors associated with academic performance of physical therapy students. AB - Understanding the pre-matriculation factors that influence academic success facilitates the recruitment and retention of students who are more likely to graduate on time. OBJECTIVE: To determine the factors associated with the academic performance of students enrolled in the physical therapy diploma programme. METHODS: Records of 250 students enrolled over a twenty-year period at the School of Physical Therapy were reviewed. Data were collected and organized using a data collection sheet. Data were analysed using the Statistical Package for the Social Sciences (SPSS). Relationships between the independent variables: age, gender marital status, work history and entry qualifications, and the dependent variables: academic performance (percentage of subjects passed at the first sitting of examinations and success in the Final Qualifying Examination), withdrawal and delayed graduation were examined using correlation coefficient, t test, ANOVA and chi-square as appropriate. RESULTS: Results revealed that students gaining the minimum entry qualifications at one sitting of GCE O' Level/CXC examinations (p < 0.01) and who had GCE A' Level passes (p < 0.05) were less likely to withdraw from the programme. Students without prior work experience performed better during the course of study (p < 0.05) but the older and married students were more likely to withdraw (p < 0.01). Older students performed better on the Final Qualifying Practical and Theory Examinations taken at the end of the academic programme (p < 0.05) but had a lower percentage of subjects passed at the first sitting of course examinations (p < 0.05). CONCLUSION: Students with better academic preparation demonstrated better academic performance. These findings were consistent with prior studies in the field. PMID- 21275128 TI - Febrile neutropaenia in cancer patients. AB - BACKGROUNDS: Febrile neutropaenia is a common complication of chemotherapy in cancer patients. Empirical antibiotic regimes are based on the epidemiological characteristics of bacterial isolates globally and locally. METHOD: This study retrospectively reviewed all cases of febrile neutropaenia in patients with confirmed cancer admitted at the University Hospital of the West Indies in the four-year period between, January 1, 2003 and December 31, 2006 and who received chemotherapy. Cases were identified from blood culture records and hospital charts which were reviewed to determine the aetiological agents causing bacteraemia, their antimicrobial susceptibilities and clinicalfeatures. These cases were compared with non-neutropaenic cancer patients admitted with fever. RESULTS: A total of 197 febrile episodes in cancer patients were reviewed. Thirty seven per cent had febrile neutropaenia while 62% were non-neutropaenic. Acute myeloid leukaemia was the most common haematological malignancy and the most common solid tumour was breast cancer. Twenty-six per cent of patients had a positive blood culture. In febrile neutropaenic patients, Escherichia coli was the most common organism isolated followed by coagulase-negative staphylococci while in non-neutropaenic patients, coagulase-negative staphylococci was most common. Acinetobacter infections was prominent in non-neutropaenic patients but absent in neutropaenic patients. More than one organism was cultured in 9 neutropaenic and 18 non-neutropaenic patients. Mortality was 10.8% in neutropaenic and 24.4% in non-neutropaenic patients. CONCLUSION: Gram-negative organisms are the predominant isolates in febrile neutropaenic episodes in this cohort of patients. Non-neutropaenic patients had an increased mortality with an increase in Acinetobacter infections and multiple isolates. PMID- 21275129 TI - A limited and useful approach to determine proximal periodontal health. AB - Previous researchers have shown that there exists an interaction between gingival blood flow and gingival health. The purpose of this study was to compare the papillary blood flow at sites treated by a bridge with the blood flow at untreated sites. Twenty persons with resin-bonded fixed partial dentures were included in the study. The contralateral natural teeth of the site symmetrical to that of the restorations were used as controls. Blood flow was measured from the middle point of the papillae from both test and control sites by Laser Doppler Flowmetry (LDF). The plaque index, papillary bleeding index and probing depth measurements were recorded. There was a statistically significant difference between the test and control sites in papillary blood flow measurements and clinical indices (p < 0.05). Moreover there was statistical significance between gingival blood flow measurements and papillary bleeding index in the experimental group (p < 0.05). In short, there exists an important relationship between resin bonded fixed partial dentures and papillary blood flow. Although there were no correlations between LDF values and clinical parameters, it can be emphasized, within the limits of the study, that LDF readings have limited diagnostic value, at least when it comes to clinical performance of fixed prosthesis. PMID- 21275130 TI - Immunoglobulin light chain amyloidosis associated with multiple myeloma in a young patient: a case report. AB - The authors present an uncommon case of systemic amyloidosis associated with multiple myeloma in a 35-year old woman. Systemic amyloidosis commonly presents in association with clonal plasma cell proliferative disorders, and less frequently as secondary or of a hereditary origin. Amyloidosis is usually associated with multiple myeloma in older patients and frequently has an unfavourable prognosis. PMID- 21275131 TI - Supraventricular tachyarrhythmia and Brugada syndrome: a case of atrial fibrillation and Brugada syndrome in a young patient without structural heart disease. AB - We report a case of a 29-year old man who initially presented with a single episode of syncope. The initial electrocardiogram (ECG) showed atrial fibrillation and an ST segment elevation on lead V1. A flecainide test unmasked the Brugada syndrome. The pathophysiology of Brugada syndrome and atrial fibrillation in this patient could be connected by sodium channel dysfunction throughout the heart. In addition, we reviewed the possible connection between Brugada syndrome and atrial fibrillation. PMID- 21275132 TI - A cystic hepatic lesion: when to worry? AB - A 16-year old female presented to hospital with abdominal pain. Features on computed tomography raised the possibility of biliary cystadenoma or cystadenocarcinoma. She underwent a liver resection, and histopathology confirmed a serous biliary cystadenoma. This case is presented to highlight the radiological features of this uncommon pre-malignant condition as well as to summarize a management algorithm for cystic liver lesions. PMID- 21275133 TI - Mathematical models in medical sciences: a balance in knowledge. PMID- 21275134 TI - Ruptured sinus of Valsalva complicated by right and left sided endocarditis, R - > L--shunt and congestive cardiac failure. PMID- 21275135 TI - Necessity of comprehensive suicide prevention measures among women in Japan: a comparison between Japan and France in age-classified suicide rates. PMID- 21275136 TI - Apical balloon syndrome (Takotsubo stress cardiomyopathy) or aborted myocardial infarction. PMID- 21275137 TI - Mental health trusts would be better off focusing on service improvement. PMID- 21275138 TI - Big boys don't cry. PMID- 21275139 TI - Spaghetti junction. PMID- 21275140 TI - Beyond bricks and mortar. PMID- 21275141 TI - Self-harm. PMID- 21275142 TI - Growing concern at the impact of benefit cuts on people's mental health. PMID- 21275143 TI - Reduction in disability living allowance. PMID- 21275144 TI - Eating disorders. Your guide to today's mental health issues. PMID- 21275145 TI - Social understanding of lesbian and gay people's mental health. PMID- 21275146 TI - Doctor's orders. PMID- 21275147 TI - Patients are often told to reduce their stress levels. PMID- 21275148 TI - Let's get spiritual. PMID- 21275149 TI - A gender for change. PMID- 21275150 TI - Looking at ordinary people's tales of living with their mental illness. Interviewed by Alita Howe. PMID- 21275151 TI - Climate change adaptation in New York City: building a risk management response. The New York City Panel on Climate Change 2010 Report. PMID- 21275152 TI - Proceedings of the First International Conference on Thymic Malignancies. August 20-21, 2009. Bethesda, Maryland, USA. PMID- 21275153 TI - Interplay between manganese and zinc homeostasis in the human pathogen Streptococcus pneumoniae. AB - ICP-MS analysis of Streptococcus pneumoniae reveals a high cell-associated Mn(II) concentration that is comparable to that of Zn(II). Stressing these cells with 100-200 MUM Zn(II) leads to a slow-growth phenotype and a total Mn(II) concentration that is reduced, with no decrease of other metal ions. Supplementation of the growth media with as little as 10 MUM Mn(II) fully restores the growth defect and cell-associated Mn(II) to normal levels. DNA microarray analysis reveals that zinc stress induces the expected upregulation of czcD (encoding a zinc effluxer), but also a pleiotropic transcriptional response suggestive of mild cell wall stress. Genes encoding a nitric oxide (NO) detoxification system (nmlR) and the Mn(II) uptake system (psaBCA) are also induced. We conclude that Zn(II) toxicity results in a cytoplasmic Mn(II) deficiency, possibly caused by competition at the Mn(II) uptake transporter protein PsaA. PMID- 21275154 TI - Proceedings of the 11th International Symposium on Hyphenated Techniques in Chromatography and Hyphenated Chromatographic Analyzers. Bruges, Belgium. January 27-29, 2010. PMID- 21275156 TI - 6th international conference on conservative management of spinal deformities lyon, france. 21-23 may 2009. Abstracts. PMID- 21275155 TI - Global trends in emerging zoonotic diseases. Proceedings of the International Conference on Emerging Zoonotic Diseases. Cairo, Egypt. October 15-17, 2009. PMID- 21275157 TI - [Progress of study on Chinese medicine treatment of amenorrhea caused by antipsychotic drug]. PMID- 21275158 TI - [Progress of treatment for antipsychotics induced tardive dyskinesia and its integrative medical therapy]. PMID- 21275159 TI - [Thinking and clinical practice on the acupunctural therapy of schizophrenic]. PMID- 21275160 TI - [Analysis on the depression related factors in elderly patients after stroke and the effect of Chinese medicine on them]. AB - OBJECTIVE: To study the depression related factors in elderly patients after stroke and to explore the effect of Chinese medicine anti-depression treatment for improving neurological function in patients with after-stroke depression. METHODS: Three hundred and seventy-seven after-stroke elderly patients were sorted, according to their Hamilton Depression Scale-17 (HAMD17) scores, to the non-depression group (NDG, 116 patients) and the depression group (DG, 261 patients). The depression related factors in them were analysed. Moreover, patients in DG were randomly subassigned to two groups, the 135 patients in the treated group were treated with Chinese medicine and general stroke-treatment, and the 126 patients in the control group were treated only with general stroke treatment for 4 weeks. HAMD17 scores of neurological deficit (NDS), scores of sleep dysfunction rating scale (SDRS), Hamilton anxiety rating scale (HAMA), and treatment emergent symptom scale (TESS) in them were observed before and after treatment. RESULTS: Prevalence rate of depression in patients with cerebral hemorrhage was 79.78% (71/89), significantly higher than that in patients with cerebral infarction, 65.97% (190/288, P < 0.05). Patients of stroke with lesion occurred at cerebellum, brain stem, or cerebral hemisphere (frontal lobe) and those with moderate/severe neurological deficit were more liable to suffer from depression. The HAMD17, HAMA, SDRS, and NDS scores in the treated group after treatment were all improved more significantly than in the control group (P < 0.05). NDS score reduced in the treated group significantly from 19.1 +/- 16.3 before treatment to 31.3 +/- 14.8 after treatment, showing the evident recovery of nerve function. CONCLUSION: The occurrence of depression after stroke is closely related with the nature and position of the lesion, as well as the degree of neurological deficit in patients. Chinese medicine could improve the depressive manner effectively and thus to make for recovery of neurological function. PMID- 21275161 TI - [Effect of three-step acupuncture combined with small dosage antipsychotic in treating incipient schizophrenia]. AB - OBJECTIVE: To explore the clinical efficacy and safety of three-step acupuncture (TSA) combined with small dosage antipsychotic in treating incipient schizophrenia (IS). METHODS: Sixty IS patients were randomly assigned to the test group and the control group equally. Patients in the test group received the combined therapy of TSA and antipsychotic, while patients in the control group were treated by full-dose antipsychotic, all for 8 weeks. The clinical efficacy was assessed by the positive and negative syndrome scale (PANSS), and the adverse reaction was evaluated by treatment emergent symptom scale (TESS). RESULTS: The clinical efficacy in the two groups showed insignificant difference at the end of the 8-week treatment (P > 0.05), but the total scores of PANSS evaluated at the end of the 2nd and 4th week in the test group (74.26 +/- 9.54, 56.33 +/- 10.12) were significantly higher than those in the control group (85.56 +/- 9.73, 70.57 +/- 9.62), respectively (P < 0.05), furthermore, TESS analysis showed that the incidence of adverse reactions in nervous system and autonomic nervous system in the test group were also lesser than in the control group (P < 0.05). CONCLUSION: The combined therapy of TSA and small dose antipsychotic shows an efficacy equivalent to that of full-dose antipsychotic, but with shorter initiation time and less side effects. PMID- 21275162 TI - [Effects of Huatan Tongluo Granule on SOCS-3 and TNF-alpha expressions in patients with acute cerebral infarction]. AB - OBJECTIVE: To observe the effect of Huatan Tongluo Granule (HTG) on the expression of suppressors of cytokine signaling-3 (SOCS-3) and tumor necrosis factor-alpha (TNF-alpha) in patients with acute cerebral infarction (ACI) of phlegm-wind-stasis obstruction (PWSO) syndrome type. METHODS: Sixty-six ACI patients of PWSO type admitted within 72 h were randomized into the treatment group (34 cases) and the control group (32 cases), they were treated with foundational therapeutics, but HTG was given additionally to patients in the treatment group. SOCS-3 expression was detected by ELISA before treatment (d0) and on the 3rd (d3) and 7th day (d7) of treatment; TNF-alpha expression was detected by chemiluminescence at dO and d7. Data were compared with the respective parameters obtained from 20 healthy persons as normal control. Meantime, the degree of neuro-deficit in the two groups was evaluated by NIH Stroke scale and Barthel index on d0, d7, d14 and d21. RESULTS: SOCS-3 expression at d0, d3, d7; and TNF-alpha expression at d0, d7 were higher in the two patients' groups significantly than in normal controls (P < 0.05). As compared with the control group, on d7, SOCS-3 expression was higher (360.98 +/- 123.31 ng/L vs. 281.87 +/- 133.66 ng/L) and TNF-alpha expression was lower (35.72 +/- 19.94 ng/L vs. 49.86 +/- 34.79 ng/L), while the NIHSS score on d7 and d14, as well as the Barthel index on d14 and d21 were lower in the treatment group (all P < 0.05). CONCLUSIONS: The acting mechanism of HTG for promoting nerve function recovery of ACI patients is possibly and closely related with the up-regulation of the inflammation suppressive factor SOCS-3, the down-regulation of the inflammation promoting factor TNF-alpha, and the elimination of secondary inflammatory injury after cerebral ischemia. PMID- 21275163 TI - [Relationship between tongue presentations and serum level of C-reactive protein in patients with acute cerebral infarction]. AB - OBJECTIVE: To investigate the relationship between tongue presentations and the serum level of C-reactive protein (CRP) in patients with acute cerebral infarction (ACI). METHODS: Tongue presentations of 200 incipient unilateral ACI patients were observed, their serum CRP level was determined, and the relationship between the two entries was analyzed. RESULTS: Serum level of CRP in patients with thick tongue coating were significantly more than those with thin coating (117 cases vs. 73 cases); tongue coating was greasy in 149 patients and un-greasy in 51 patients. Spearman correlation analysis showed that the serum level of CRP was positively correlated with the thickness of tongue coating (r = 0.186, P = 0.008); also with the greasy degree. The difference of CRP levels in patients with different color and dryness of tongue was insignificant statistically (P > 0.05). CONCLUSION: Correlation between tongue presentations and serum CRP level is possibly existed in patients with ACI. PMID- 21275164 TI - [Study on the relation between Pi-deficiency pattern and metabolic syndrome in patients with polycystic ovarian syndrome]. AB - OBJECTIVE: To evaluate the relation between Pi-deficiency syndrome (PDS) pattern and metabolic syndrome (MS) in patients with polycystic ovarian syndrome (PCOS), for exploring their internal pathologic mechanism. METHODS: Among the 102 PCOS patients, 22 complicated with MS (PCOS-MS) and 80 not complicated with MS (PCOS NMS), the Chinese medicine syndrome pattern was differentiated as PDS in 50 patients and non-PDS in 52. The clinical data, in terms of fasting blood glucose (FBG), fasting insulin (FINS), waistline, body weight (BW), stature, blood pressure (BP), etc. was collected and compared and the relation between data was analyzed. RESULTS: Levels of FINS and homeostasis model of assessment for insulin resistence index (HOMA-IR), in PCOS-MS patients were significantly higher than those in PCOS-NMS patients, also higher in patients of PDS pattern than those of non-PDS pattern (P < 0.01); the occurrences of MS and PDS were highly positively correlated with levels of FINS and HOMA-IR (P < 0.01); incidence of MS in patients of PDS pattern was significantly higher than those in patients of non PDS pattern (P < 0.05); presenting of PDS was positively related with the existence of MS (P < 0.05), but in case of the FINS or HOMA-IR factor being controlled, statistical meaning of the relativity between them turned to insignificant (P > 0.05). CONCLUSIONS: PCOS patients of PDS pattern are the high risk population of MS, which might be related with the insulin resistance. So, early treatment of PCOS, especially on patients of PDS pattern, is of important significance for preventing the complication, as MS, of the disease. PMID- 21275165 TI - [Relation of serum estradiol and progesterone levels with abortive anticipation in pregnant women with fetal irritability and vaginal bleeding]. AB - OBJECTIVE: To investigate the serum levels of estradiol (E2) and progesterone (P) in patients with the auras of threatened abortion (ATA), i.e., fetal irritability and vaginal bleeding, and the relation with prognosis. METHODS: Chinese medicine syndrome of 598 pregnant women with ATA consulted in authors' hospital were differentiated into 5 types, 151 patients of Shen-deficiency type; 151 of Pi-Shen deficiency type; 36 of qi-blood insufficiency type, 235 of blood-heat type, and 25 of traumatic injured type. Their serum levels of E2 and P at the 5th to 13th gestation week were monitored by competitive chemiluminescnet enzyme immunoassay. And the outcome of pregnancy, continued or defeated, was observed. RESULTS: (1) From the 7th gestation week on, serum E2 level in women with continued pregnancy (CP) increased continuously, showed a higher value than that at the previous week (P < 0.05), and was higher than that in women with defeated pregnancy (DP) of same gestation age (P < 0.05). (2) Serum P level was not different in CP women at various gestation age (P > 0.05), but from the 7th week on, it was higher in CP women than in DP women of same gestation age (P < 0.05). (3) The comparison of serum E2 in CP versus DP of women with Shen-deficiency type or Pi-Shen deficiency type was identical to that in CP versus DP of all women enrolled. CONCLUSIONS: Serum levels of E2 and P in women with ATA at 5th to 13th gestation weeks were obtained. The 7th week of pregnancy is the critical period of pregnancy development, a comparative high E2 levels and its sustained and steady elevation indicates the good-ending of pregnancy with fetal irritability and vaginal bleeding. The Chinese medicine syndrome presented in women with ATA is dominantly the Shen-deficiency type. The variation of serum E2 is one of the important material foundation in pregnancy with fetal irritability and vaginal bleeding of Shen-deficiency type. PMID- 21275166 TI - [Regulatory effect of astragalus injection on Th1/Th2 cell function in patients with cervical cancer]. AB - OBJECTIVE: To investigate the effect of Astragalus in regulating the imbalance between naive helper T cells (Th1/Th2) cytokines expression in patients with cervical cancer. METHODS: Thirty patients with cervical cancer received intravenous dripping with 20 mL of Astragalus Injection (AI, contained extract from 40 g of crude drug) per day for 1 week, peripheral blood sample was collected from patients separately before and after treatment for extract mononuclear cells by density gradient centrifugation. The positive percentages of CD4+ interferon-gamma (IFN-gamma ) cell and CD4+ interleukin-4 (IL-4) cell in total CD4+ cells were measured by flow cytometry; the contents of IFN-gamma, IL-4 in culture supernate were detected with ELISA; and the expressions of T-cell transcription factor T-cells (T-bet) and GATA-binding protein-3 (GATA-3) were determined by RT-PCR. The data were controlled by those get from 10 healthy persons. RESULTS: CD4+ IFN-gamma positive cell percentage, T-bet mRNA expression level and concentration of IFN-gamma in supernate were significantly lower in patients than those in healthy control respectively, while CD4+ IL-4 positive percentage, level of GATA3 mRNA expression and IL-4 concentration in supernate were insignificantly different between the two groups. After AI treatment, the lowered parameters were up-regulated (P < 0.05), and no obvious change was observed in the CD4+ IL-4 positive cell associated parameters. CONCLUSION: Th1/Th2 cell function imbalance existed in patients with cervical cancer, showing a Th2 predominant reaction mode; AI can regulate the imbalance, offset to Th1, thus to display its anti-tumor effect. PMID- 21275168 TI - [Survey on status of intervention therapy for heart diseases in Chinese medical hospital in China]. AB - OBJECTIVE: To investigate the nationwide status of intervention therapy for heart diseases (hIT) in Chinese medicine and integrated medical hospitals in China, and to push forward the development of intervention technique. METHODS: Hospitals met the inclusion criteria were screened out by searching the "database of hospitals and medical institutions in China" from the Chinese Medical Network; and related materials from them were gathered with questionnaires by mail. RESULTS: Reply was gathered from 239 of the 250 questionnaires mailed, by which, it was known that hIT has been carried out in 37 hospitals, until May 2009, a total of 34 327 cases of coronary angiography was completed, percutaneous coronary intervention (PCI) was performed in 12 670 patients with coronary heart disease, 3 631 patients received pacemaker implantation, 2 187 cases of radiofrequency catheter ablation, and 652 cases of congenital heart disease related interventional therapy were accomplished. Additional, 13 hospitals (35.1%) had annually completed more than 200 cases of coronary angiography or 100 cases of PCI. CONCLUSIONS: hLT technique has been developed to a definite extent in Chinese medicine/integrated medical hospitals, which plays an important role in promoting the integrative medical research on cardiovascular diseases. However, related policy, support and normalization are necessary for its healthy and well-ordered development. PMID- 21275167 TI - [Effect of Bizhongxiao decoction on proteomics of peripheral blood mononuclear cells in patients with rheumatoid arthritis]. AB - OBJECTIVE: To probe in the possible acting mechanism of Bizhongxiao Decoction (BZXD) for treatment of early active rheumatoid arthritis (RA) by way of observing the two-dimensional gel electrophoresis map of proteins in peripheral blood mononuclear cells (PBMCs) of healthy persons and RA patients (intervened or un-intervened with BZXD), analyzing the differential proteins and seeking out the RA associated proteins. METHODS: Eighteen patients with early active RA were randomized into the BZXD group and the methotrexate (MTX) group, nine in each group, they were treated with BZXD (contained 15 Chinese herbs, as Herba Hedyotis diffusae, Herba Sarcandrae glabrae, Radix Salviae miltiorrhizae, Caulis Trachelosperi, Rhizoma Drynariae, Semen Coicis, etc.) and MTX combined with nimesulide Tablets respectively, three months as a treatment course, and their blood samples were collected for observation. Besides, blood samples from 9 healthy persons were taken as normal controls. PBMCs were isolated from blood using lymphozytes separation medium, and total protein in the cells was extracted through immobilized pH gradient two-dimensional gel electrophoresis. After Coomassie brilliant blue G250 staining, gel-image analysis was performed using PDQuest software. The differentially expressed proteins were identified by matrix assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS). Then partial proteins were validated by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: The 2-DE protein profile of PBMCs from healthy persons and RA patients before and 3 months after treatment were obtained, and 23 differential protein spots were found, 14 from 18 differential protein spots were successfully identified, of which 8 proteins were up-regulated and 6 proteins were down-regulated in RA patients as compared with control. After 3-month treatment, 5 differentially expressed proteins showed more obvious in the BZXD group than in the MTX group. RT-PCR verified that the expression of ApoA-I in all the three groups was consistent with the outcomes of 2-DE. CONCLUSIONS: Some differentially expressed proteins exist in the PBMCs of RA patients, which may play a potential role in the pathogenesis of RA; BZXD may treat RA by way of regulating the expression of some differential proteins in patients. PMID- 21275169 TI - [Factor analysis on the distribution of Chinese medicine syndromes in patients with hyperlipidemia in Xinjiang region]. AB - OBJECTIVE: To investigate the distributive rule of Chinese medicine syndromes in patients with hyperlipidemia (HLE) in Xinjiang region. METHODS: Chinese medicine syndrome of HLE patients were differentiated. The common factors of diagnostic information for dominating HLE were extracted by factor analysis and the syndrome type was determined based on Chinese medicine theory and experiences of experts. RESULTS: The syndromes in HLE patients of Xinjiang region were mainly the Pi-Shen deficiency with insufficient Jin syndrome (I), the qi-blood deficiency syndrome (II), the Fei-Wei dryness syndrome (III), the phlegm-dampness obstructing Fei syndrome (IV), the dampness-heat accumulation syndrome (V), and the Gan-Shen yin deficiency with blood-stasis syndrome (VI). Syndrome II was the most commonly encountered one (35.09%), the next were syndrome III (29.82%) and I (13.45%). Scores of the 6 syndromes, which embodied the severity of disease, were different significantly (F = 32.746, P < 0.01), the highest presented in syndrome I and the second in Syndrome VI. CONCLUSIONS: Syndrome in hyperlipidemia patients of Xinjiang region is dominantly the deficiency syndrome, combined with qi-stagnancy and blood-stasis, showing a complex state involving multiple organs and all the qi, blood and Jin-Ye in body. PMID- 21275170 TI - [Protective effect of astragalosides on anoxia/reoxygenation injury of hippocampal neuron]. AB - OBJECTIVE: To study the effect of astragalosides (AST) on the anoxia/reoxygenation (A/R) injured neuron in rat. METHODS: Primary cultured rat's hippocampal neurons were made into A/R model cells. The cell viability was detected by MTT assay and lactate dehydrogenase releasing methods; the activity of superoxide dismutase (SOD), and contents of malondialdehyde (MDA) and nitride oxide (NO) in culture supernate were detected; the apoptosis rate of hippocampal neurons after A/R was measured by flow cytometry with double-staining of Hoechst33258 and AnnexinV-PI; and intracellular calcium ion [Ca2+]i was observed with a cofocal laser-scanning microscope and determined by fluorescent probe Fluo 3/AM. RESULTS: AST enhanced the cell viability of neurons after A/R injury, increased SOD activity and decreased the MDA and NO contents in supernate, reduced the A/R-induced apoptosis and decreased the calcium overload in neurons. CONCLUSION: AST has the protective effects on A/R injured neurons, the mechanism is possibly related with its anti-oxidation and calcium overload reducing actions. PMID- 21275171 TI - [Effect of Qindan Capsule on expression of vascular adventitial collagen I and III in old spontaneous hypertensive rats]. AB - OBJECTIVE: To investigate the effect of Qindan Capsule (QDC) on gene and protein expression of vascular adventitial collagen I and III (VAC1 and VAC3) in spontaneously hypertensive rats (SHR), for further research the possible mechanism of vascular adventitial fibroblasts remodeling. METHODS: Thirty-two SHR, 40 weeks old, were equally randomized into the model group and the three treated groups treated respectively with high (750 mg/Kg x d) and low dosage QDC (150 mg/Kg x d), and losartan (30 mg/Kg x d), once a day for 12 weeks. Besides, a normal blank control group and a normal QDC (750 mg/Kg x d) medicated group were set up with same aged Wistar-Kyoto rats. Systolic blood pressures of rats were monitored, gene and protein expressions of VAC1 and VAC3 in rats' thoracic aortic adventitia were detected at the end of experiment using immune-histochemical staining and real-time quantitative fluorescent PCR respectively. RESULTS: Compared with the model group, blood pressure as well as the gene and protein expressions of VAC1 and VAC3 were all lower in the two QDC (high and low dosage) treated groups (P < 0.05). CONCLUSION: QDC could not only effectively reduce the blood pressure in SHR, but also suppress and even reverse their thoracic aorta adventitial vascular remodeling, which is displayed by the obvious lowering of VAC1 and VAC2 expression levels. PMID- 21275172 TI - [Effect of cinobufotalin on growth of xenograft of endometrial carcinoma cell line ishikawa in nude mouse and its impact on RRM2 expression]. AB - OBJECTIVE: To investigate the inhibitory effect of cinobufotalin (CBT) on the growth of xenograft endometrial carcinoma cell line ishikawa in nude mice, and its impact on the expression of ribonucleotide reductase subunit M2 (RRM2). METHODS: Eleven nude mice with xenograft were randomly divided into two groups, the CBT group and the control group, which received intra-tumor injection of CBT and saline respectively for one week. The sizes of xenografts were measured before and after the treatment to calculate the inhibition ratio of tumor proliferation; the RRM2-mRNA and protein expressions in tumor tissue were measured by RT-PCR and Western blot respectively. RESULTS: After treatment, the size of xenografts in the CBT group was (0.1314 +/- 0.0304) cm3, which was significantly lower than that in the control group (0.360 0 +/- 0.1145) cm3, (P < 0.05), the tumor proliferation inhibition ratio being 43.46%. The differences of RRM2 mRNA and protein expression levels between the two group were significant (P = 0.019 and P = 0.001). CONCLUSION: CBT significantly inhibits the growth of the xenografts of endometrial carcinoma Ishikawa in nude mice, and the action mechanism is possibly associated with the inhibition on RRM2 expression. PMID- 21275173 TI - [Effect of Guanxinkang on ATP-sensitive potassium channel in myocardial cells of rat with ischemic/ reperfusion injury]. AB - OBJECTIVE To investigate the effect of Guanxinkang (GXK) on ATP-sensitive potassium channel in myocardial cells of rat with ischemic/reperfusion injury and its possible mechanism for cardiac vascular protection and anti-myocardial ischemia. METHODS: Wistar rats were established into I/R injured models by 10 min perfusion--30 min no-flow ischemia--45 min reperfusion, and divided into 5 groups: the I/R model group and 4 treatment groups treated respectively with glibenclamide, pinacidil, GXK and GXK+glibenclamide. Rats' heart were isolated for detecting Ca(2+)-Mg(2+)-ATPase, Na(+)-K(+)-ATPase activity in myocardial cells, and the changes of current in ATP-sensive potassium channel (K(ATP)) was recorded by whole patch clamp technique. Data were controlled by those taken from normal rats in a control group. RESULTS: K(ATP) in the GXK treated group were higher than that in the I/R model group; and similar to that in the pinacidil treated group (P > 0.05). As compared with the model group, activities of Ca(2+) Mg(2+)-ATPase and Na(+)-K(+)-ATPase in the GXK treated group were increased significantly (P < 0.05). CONCLUSION: GXK shows definite intervention effect on myocardial I/R injury; which is possibly by way of furthering the opening of K(ATP) channel, decreasing Ca2+ influx, and inhibiting Ca2+ overload. PMID- 21275174 TI - [Effect of combined use of rehmannia and rhodiola on hemopoietic function in mice with bone marrow depression]. AB - OBJECTIVE To explore the effect of combined use of rehmannia (RM) and rhodiola (RD) on peripheral leukopenia and bone marrow hematopoietic function suppression induced by cyclophosphamide (CTX) in mice. METHODS: ICR mice were established into bone marrow inhibition models by intraperitoneal injection of CTX, and were administered with RM, RD or its extract (RDE), singly or in mixture, via gastrogavage for 10 days. The changes of peripheral hemogram, bone marrow nucleated cell proliferation, CFU-GM colony formation, GM-CSF and erythropoietin (EPO) secretion were observed. RESULTS: Compared with the un-treated model mice, the peripheral white blood cell count was significantly higher in model mice treated with RDE and RM mixture; the bone marrow nucleated cells count, CFU-GM formation, and GM-CSF production were significant higher in model mice treated with RD and RM mixture, showing statistical significance (P < 0.01); while EPO production in the RD and RM mixture treated group was slightly elevated, but the difference showed no statistical significance. CONCLUSION: RD and RM mixture could regulate hematopoietic system by promoting the production of bone marrow cells and colonies, as well as enhancing the synthesis of related cytokines, such as GM-CSF, so as to increase the amount of peripheral white blood cells and restore the hematopoietic function of organism. PMID- 21275175 TI - [Effect of atractylodes macrocephalaon polysaccharides for reducing liver ischemia/reperfusion injury in rats after orthotopic liver autotransplantation]. AB - OBJECTIVE: To explore the effect of atractylodes macrocephalaon polysaccharides (AMP) intervention for reducing liver ischemia/reperfusion (I/R) injury in rats after orthotopic liver autotransplantation. METHODS: SD rat I/R injured model was established by liver autotransplantation. SD rats were randomly divided into three groups: the model group, the AMP group and the sham-operated group. They were infused with saline, AMP and saline respectively after operation, and killed in batches at different time points (1, 6 and 24 h after operation), for determining blood levels of alanine aminotransferase (ALT), total bilirubin (TBIL), direct bilirubin (DBIL), aspartate aminotransferase (AST), superoxide dismutase (SOD) and malondialdehyde (MDA), and detecting the expression of nuclear factor kappa-B (NF-kappaB) in liver tissue by immunohistochemical method. The pathological examination of liver was performed as well. RESULTS: Compared with the model group, in the AMP group at any time points after operation, the serum levels of ALT, AST, DBIL, TBIL and MDA were lower and of SOD were higher (P < 0.05); the elevated expression of NF-kappaB was weakened (P < 0.05), and the pathologic changes (liver congestion, swelling, hepatocyte necrosis and portal area inflammation cell infiltration) were lessened. CONCLUSION: AMP could reduce the post-transplantation liver I/R injury in rats, which might be associated with its effects on inhibiting NF-kappaB expression, intervening membrane destruction of liver cells by free oxygen radicals, suppressing enzyme, and alleviating morphological damages of liver. PMID- 21275176 TI - [Effect of Bushen Huoxue recipe on the state of extracellular matrix in glomerulosclerosis rats model]. AB - OBJECTIVE: To investigate the effect and acting mechanism of Bushen Huoxue Recipe (BHR) on the state of extracellular matrix in glomerulosclerosis (GS) rats model. METHODS: GS rat model was established by unilateral nephrectomy and adriamycin injection. Model rats were randomly divided into 4 groups: the normal control group, the model group, the test group treated by BHR, and the positive control group treated with fosinopril sodium, with 11 rats in each group. The 24 h urinary protein and renal function of rats were observed, the contents of matrix metalloproteinase 1 (MMP-1), tissue inhibitor of metalloproteinase 1 (TIMP-1) in renal tissue and transforming growth factor-beta1 (TGF-beta1) in blood plasma, and renal tissue were detected. RESULTS: Compared with those in the normal control group, 24 h urinary protein was increased and renal function was deprived in the model group; TIMP-1 expression increased, MMP1 expression decreased in renal tissue of rats in the model group, showing statistical difference between groups (P < 0.05). As compared with the model group, the abnormal changes of TIMP 1 and MMP1 expressions were ameliorated in the two groups treated either by BHR or fosinopril (P < 0.05). The content of TGF-beta1 in the model group, either in blood or in renal tissue, was significantly higher than those in the normal control group respectively (P < 0.01), showing no significant change after BHR treatment. CONCLUSION: The protective effect of BHR on renal function in rats with GS is possibly by way of influencing expressions of TGF-beta1, TIMP-1 and MMP1 to regulate the state of extracellular matrix and lessen the matrix aggregation. PMID- 21275177 TI - [Effect of ginsenoside Rg1 on the microenvironment dependent differentiation of human bone marrow mesenchymal stem cell to vaso-endothelioid formative cells in vitro]. AB - OBJECTIVE: To investigate the effect of ginsenoside Rg1 on the microenvironment dependent differentiation of human mesenchymal stem cells (hMSCs) to vaso endothelioid cells (VECs) in vitro. METHODS: The in vitro differentiation of hMSCs to VECs were established adopting the in vivo environment simulated semi permeable membrane separated non-contact co-culturing method. The mRNA expressions of endothelial markers, such as platelet endothelial adhesive factor 1 (CD31), vascular hemophillia factor (vWF) and vascular endothelial cadherin (VE cadherin) were analyzed by RT-PCR; the protein expressions of CD31 and vascular endothelial adhesive factor-1 (VCAM1) were detected by fluorescence immunohistochemistry; structural identification for the endothelial characteristics of differentiated hMSCs were made under electron microscopy; and the percentage of CD31 expression in differentiated hMSCs was determined by flow cytometry to explore the effect of ginsenoside Rg1 on the differentiation. RESULTS: The bone marrow mesenchymal stem cells co-cultured with mature endothelial membrane showed a microenvironment dependent capacity for differentiating to endothelium, with the morphological changes revealed starting from the 2nd week, showing cell body contraction, polygonal-shaped change; and at the 3rd week, the markedly speedily cell proliferation with elliptic or slabstone like change of cells. High levels of classic endothelial cell markers, such as mRNA expressions of CD31, vWF, VE-cadherin, and protein expressions of CD31 and VCAM1, were shown; the typical weibel-palade body of endothelial cell was found in the differentiated cells. Moreover, percentage of CD31 expression in the differentiated hMSCs was increased after Rg1 treatment dose-dependently. CONCLUSION: Under the microenvironment of co-culture, hMSCs could differentiate into cells presenting the characteristics of endothelial cell in aspects of the morphology and ultrastructure of cells, as well as the gene and protein expressions of cell markers; ginsenoside Rg1 can promote the microenvironment dependent differentiation of hMSCs to VECs system in vitro. PMID- 21275178 TI - [Key issues on the clinical pathway development: a view from Chinese medicine and integrative medicine]. AB - Comparing with the Western medicine, the clinical pathway development of Chinese medicine (CM)/integrative medicine (IM), on one hand, should follow the basic principles of general clinical pathway; on the other and prior hand, it ought to coordinate with the rule of CM, and display sufficiently the advantages of CM based upon the evidences. Several key issues which may be encountered in the development and the relevant strategies were introduced in this paper. PMID- 21275179 TI - [Retrospection and reflection on the integrated Chinese and Western medicine]. AB - Integration of Chinese medicine and Western medicine is the necessary outcome in the reality of co-existence of the two medicines nowadays, also an inevitable tendency of cross-comprehensive, systematization, internationalization and diversification in the progress of science development and research. Experienced over half a century's self-innovation, lots of achievements in clinical and experimental studies have been achieved by the integrated Chinese and Western medicine (ICWM), but it still remains in the primary period of developing, and some deficiencies existed yet. So, we should have the foresight and mind of "Harmony in Diversity" and make effort to establish a series of independent and perfect theoretical system, for making more breakthrough development of ICWM. PMID- 21275180 TI - [A randomized double-blinded controlled study on treatment of schizophrenia by in vitro fostered bezoar combined with haloperidol]. PMID- 21275181 TI - [Clinical effectiveness of internal taking and external washing with Chinese drugs for treatment of flat wart and its correlation with IL-18 and IL-10]. PMID- 21275182 TI - [Clinical observation on treatment of insomnia mainly by needling at frontal sideline no.1]. PMID- 21275183 TI - [Report of a patient with SAPHO syndrome treated by integrative Chinese and Western medicine]. PMID- 21275184 TI - ["Zhi bai dihuang" or "zhi bo dihuang"?--a discussion on English translation of Chinese medicine prescriptions]. PMID- 21275186 TI - [ADHD--the need of moving focus]. PMID- 21275185 TI - [Progress on pharmacological researches of salvia miltiorrhiza and its chief components in coronary heart disease and pancreatitis]. PMID- 21275187 TI - [The milk report lacks certain "good epidemiologic practice"]. PMID- 21275188 TI - Learning and memory mutations impair acoustic priming of mating behaviour in Drosophila. AB - The courtship song in Drosophila melanogaster has two components, a low-frequency hum and a train of pulses with a species-specific interpulse interval (IPI) of 30 40 ms(1,2). The IPIs oscillate rhythmically, with periods between 50 and 60 s in wild-type males(3). When females are stimulated with artificial songs in the presence of courting but silent (wingless) males, the 'pulse song' and its oscillation can enhance mating success(4-6). If separated males and females are first simultaneously primed with invariant 34-ms IPIs, their subsequent mating success is improved(7). However, exclusive prestimulation of females leads to faster mating only when the hum component of the song is applied, not constant 34 ms IPIs(5). We have re-examined these findings by testing whether prior exposure of females to a rhythmic pulse song speeds up subsequent mating performance. We report here that it does. Furthermore, learning and memory mutations(8), expressed in the females to whom songs are being played, either 'block' or attenuate the effectiveness of acoustical priming. PMID- 21275189 TI - Relation of age, sex, and infection to reflux: Data indicating high spontaneous cure rate in pediatric patients. PMID- 21275190 TI - Herbicide exposure and veterans with covered service in Korea. Final rule. AB - This document adopts as a final rule the Department of Veterans Affairs' (VA) proposal to amend VA adjudication, medical, and vocational rehabilitation and employment regulations to incorporate relevant provisions of the Veterans Benefits Act of 2003. Specifically, this document amends VA regulations regarding herbicide exposure of certain veterans who served in or near the Korean demilitarized zone and regulations regarding spina bifida in their children. It also amends VA's medical regulations by correcting the Health Administration Center's hand-delivery address. PMID- 21275191 TI - Ironic inversion in Eliza Haywood's fiction: fantomina and "The History of the Invisible Mistress". AB - This article contends that Fantomina can best be understood as an ironic inversion of "The History of the Invisible Mistress", a Spanish nouvelle published as an interpolated tale in Paul Scarron's Le Roman Comique. Both works revolve around the efforts of a heroine to capture and hold the attention of a young man upon whom she has set her heart. The plot of both works concerns the successive disguises by which the heroines seek to test their heroes. But where Don Carlos, the hero of "The History of the Invisible Mistress", remains chaste and faithful to his initial pledge, Beauplaisir, with whom Fantomina becomes sexually involved, displays the inconstancy of a roving libertine. Hence, where "The History of the Invisible Mistress" ends happily in marriage, Fantomina concludes with its heroine's pregnancy and exile in disgrace by her mother to a monastery in France. A comparison of the two texts affords a fascinating glimpse into Haywood's aims and strategies in Fantomina. PMID- 21275192 TI - "[N]ot subject to our sense" : Margaret Cavendish's fusion of Renaissance science, magic and fairy lore. AB - This article explores Margaret Cavendish's depictions of alchemy, witchcraft and fairy lore in her scientific treatise Philosophical Letters and in fictional texts from Natures Pictures and Poems and Fancies. Though Cavendish was a dedicated materialist, she appropriates theories of magic from early modern science and folklore into her materialist epistemology. As Cavendish draws upon a fusion of early modern conceptions of magic, she creates a radical theory of matter which not only challenges patriarchy and binary oppositions, but also explores the plurality and mystery that can exist within an infinitely complex material world. PMID- 21275194 TI - "Dear mother England": motherhood and nineteenth-century criticism of Shakespeare. AB - This article examines a selection of nineteenth-century appraisals of the mothers in Shakespeare's plays. Nineteenth-century interest in motherhood is hardly surprising, since society at this time regarded the family as the foundation stone of social order, with the mother figure at its ideological centre. The royal family itself set the standard with Queen Victoria, mother of nine, representing the ideal. The significance of motherhood at this time coincided with a rising wave of enthusiasm for Shakespeare's plays and the characters he created, characters that subsequently became role models for real women to emulate. Moreover, where the plays appeared to be wanting in respect of ideal mothers, nineteenth-century critics supplied the void with speculative adaptations and interpretations. In reality, however, notions of the ideal mother were fraught with difficulties and the evidence presented here suggests that whilst many nineteenth-century appraisals of Shakespearean mothers helped to perpetuate notions of the ideal and thereby uphold this significant part of the dominant ideology, others were clearly an attempt to negotiate a place between the real and the ideal. PMID- 21275195 TI - "A hint of it, with initials": adultery, textuality and publicity in Jane Austen's Lady Susan. AB - In spite of Jane Austen's professed "eye" for an adulteress, comparatively little attention has been paid to adultery and divorce as themes and contexts of her fiction. Her unpublished epistolary novel Lady Susan has a distinctive status in Austen's oeuvre, recognized as being exemplary of her "style" and yet atypical of her later achievement. A neglected context for the novel is the extensive reporting of adultery trials in contemporary print culture and the moral panic concerning adultery in the 1780s and 1790s, focusing initially on the adulteress as the brazen woman of fashion and later as a figure of sentimentalized abjection. A particularly notorious case, that involving Lady Henrietta Grosvenor and George III's brother, the Duke of Cumberland, is directly alluded to in Lady Susan. The textual strategies of adultery trial literature, particularly its emphasis on indirection through the use of detail or "hint", had a long-term influence on the development of Austen's fiction and her positioning of herself as a professional writer after the 1790s. PMID- 21275196 TI - Silver bullet or trojan horse? The effects of inclusionary zoning on local housing markets in the United States. AB - Many local governments are adopting inclusionary zoning (IZ) as a means of producing affordable housing without direct public subsidies. In this paper, panel data on IZ in the San Francisco metropolitan area and suburban Boston are used to analyse how much affordable housing the programmes produce and how IZ affects the prices and production of market-rate housing. The amount of affordable housing produced under IZ has been modest and depends primarily on how long IZ has been in place. Results from suburban Boston suggest that IZ has contributed to increased housing prices and lower rates of production during periods of regional house price appreciation. In the San Francisco area, IZ also appears to increase housing prices in times of regional price appreciation, but to decrease prices during cooler regional markets. There is no evidence of a statistically significant effect of IZ on new housing development in the Bay Area. PMID- 21275197 TI - Housing and location choices of retiring households: evidence from France. AB - In this paper, a study is made of the mobility and housing choices of the elderly when retiring, using household data collected in France. From a theoretical viewpoint, individuals are likely to decrease their housing quantity because of an income loss when retiring, but they may also increase it to benefit from more housing comfort for leisure. Using the 1992 Trois Generations survey, it is first shown that housing mobility at retirement is substantial in France, with a variety of self-reported motives. Then, using the 1994-2001 French Europanel survey, evidence is found of both upsizing and downsizing for mobile recent retirees. In many cases, housing adjustments lead to a correction of the initial disequilibrium between the number of rooms and the number of occupants. However, a significant proportion of mobile recent retirees improve the quality of their dwelling. PMID- 21275198 TI - Planning delay and the responsiveness of English housing supply. AB - There is growing international interest in the impact of regulatory controls on the supply of housing. Most research focuses on the supply impacts of prescribed limits on land use but housing supply may also be affected by the process of planning monitoring and approval but this is hard to measure in detail. The UK has a particularly restrictive planning regime and a detailed and uncertain process of development control linked to it, but does offer the opportunity of detailed site-based investigation of planning delay. This paper presents the findings of empirical research on the time taken to gain planning permission for selected recent major housing projects in southern England. The scale of delay found was far greater than is indicated by average official data measuring the extent to which local authorities meet planning delay targets. Hedonic modelling indicated that there is considerable variation in the time it takes local authorities to process planning applications. Housing association developments are processed more quickly than those of large developers and small sites appear to be particularly time-intensive. These results suggest that delays in development control may be a significant contributory factor to the low responsiveness of UK housing supply to upturns in market activity. PMID- 21275199 TI - Estimation and analysis of preference heterogeneity in residential choice behaviour. AB - Effective and efficient planning and development of residential environments require clarifying the nature of residential preferences. In reality, residential preferences are heterogeneous, so the standard econometric models that assume only one type of preference are not optimal. In this study, conjoint choice experiment methods are employed with a mixed logit approach. The findings reveal significant heterogeneity with regard to some residential attributes. The determinants of preference heterogeneity were also investigated by conducting regression analyses on the attributes that were valued heterogeneously. Overall, the relationships observed between the explanatory variables and the heterogeneity in the valuations were understandable. However, coefficient of determination values for each model were low, indicating that the bulk of preference heterogeneity results from unobservable factors. PMID- 21275200 TI - Gentrification and community fabric in Chicago. AB - Critical authors of gentrification point to its deleterious impacts on displaced residents. Research on the nature or actual forms of impacts has not advanced much, however. This paper attempts to specify impacts on low-income racial/ethnic groups (Latinos in particular) in five Chicago neighbourhoods, with a particular focus on neighbourhood-based fabrics of support and advancement. Limited in their mobility and exchange value resources, lower-income groups depend on such fabrics far more than do the higher income. In fact, they have fewer choices and are most vulnerable to place-based shifts. The case seems especially challenging for minorities who, like European immigrants before them, depend largely on place based platforms/social fabrics but, unlike them, confront the added factors of race and urban restructuring. PMID- 21275201 TI - Ethnic diversity and employment growth in English cities. AB - There are many reasons why cities with diverse populations may grow faster. Ethnic diversity might attract human capital, tourists or firms, increase productivity through diverse approaches to problem-solving or ethnic minority entrepreneurship. Yet there are also reasons to believe that diversity could be harmful, by leading to sub-optimal provision of public goods or reducing trust or social capital. Or it may be irrelevant, being merely a proxy for class. A number of studies have shown both positive and negative relationships between diversity and growth, using a range of different measures for "diversity." This paper asks two questions: have more diverse English cities grown faster? And does measurement matter: is it important to have a multinational population or an ethnically diverse one? To answer these questions, in this paper a range of models are estimated for employment growth for 53 English cities between 1981 and 2001. The evidence suggests that cities with a high proportion of their populations born abroad in 1981 grew faster in the subsequent 10 years. Neither diversity by country of birth nor ethnic diversity is significant in the period 1991-2001. However, when variables accounting for both are included together, it appears that cities with a large number of migrants saw higher employment growth in the 1990s, but that ethnically diverse cities were less successful. The results presented here suggest that considerable attention needs to be paid to the variable used to indicate "diversity" in these studies and that the impact of diversity varies according to nature of the groups any indicator for "diversity" is representing. PMID- 21275202 TI - Bicycle use in Germany: explaining differences between municipalities with social network effects. AB - This paper aims to account for important factors influencing bicycle use and focuses in particular on differences between 20 selected German municipalities with considerable variation in their bicycle mode share. Using data from the nation-wide survey Mobility in Germany 2002, a mode choice model for bicycling is developed. In an extension to previous research, social network or spillover effects as a measure of the city's bicycling culture are also taken into account. These effects are modelled using an instrumental variable approach. It is shown that social network effects increase the probability of cycling for shopping and recreational trip purposes, but not for school, work or errands. Furthermore, it is found that cycling infrastructure matters only for shopping and errand trips. Finally, commuting trips by bicycle seem to be largely independent of any policy variables. PMID- 21275203 TI - Child-cribs for the poor and kindergartens for the rich: two directions for early childhood institutions in Sweden, 1854-1930. PMID- 21275204 TI - The 1944 Education Act and outdoor education: from policy to practice. PMID- 21275205 TI - Solving "the retardation problem" in primary education: the case of South Australia. PMID- 21275206 TI - Cheers and jeers for alcohol. PMID- 21275207 TI - Taking the keys from an older driver. PMID- 21275208 TI - Mercury in canned tuna still a concern: new tests reinforce a need for some people to limit consumption. PMID- 21275209 TI - Xena, warrior princess, or Judith, sexual warrior? The search for a liberating image of women's power in popular culture. PMID- 21275210 TI - Birth control: the political-economic rationale behind Jean Bodin's "Demonomanie". PMID- 21275211 TI - Sympathy with the poor: theories of punishment in Hugo Grotius and Adam Smith. PMID- 21275212 TI - Uttered from the heart: guilty rhetoric among the Aztecs. PMID- 21275213 TI - Naming for kin and the development of modern family structures: an analysis of a rural region in the Netherlands in the nineteenth and early twentieth centuries. PMID- 21275217 TI - Household, family, and economy among wine-growing peasants: the case of lower Austria in the first half of the nineteenth century. PMID- 21275218 TI - The impact of demographic and socio-economic change on the living arrangements of the elderly in Sundsvall, Sweden, during the nineteenth century. PMID- 21275219 TI - Land, labor, and love: household arrangements in nineteenth century eastern Finland - cultural heritage or socio-economic structure? PMID- 21275220 TI - Legal restrictions on marriage: marriage and inequality in the Austrian Tyrol during the nineteenth century. PMID- 21275221 TI - Age structuring and the lives of abandoned children. PMID- 21275222 TI - The age of war orphans: construction and realities of a group of state wards between education and assistance (1917-1935). PMID- 21275223 TI - Blood vessels and lymphatics in calcific aortic stenosis--in support of its inflammatory pathogenesis. AB - In developed countries, calcific aortic stenosis (CAS) has become the most common acquired valvular disease. It is considered a for of atherosclerosis and, like the latter, of inflammatory origin. Majority of cases of CAS are classified etiologically as either senile ("degenerative")--developing on previously normal aortic valve with three cusps, or based on congenitally malformed--bicuspid aortic valve. Twenty-eight cases of CAS (18 of the senile type, 7 of the bicuspid valve type, and 3 of indeterminable type) were examined by means of histology and immunohistochemistry (CD31 for blood vessels; D2-40 for lymphatics). In the calcified cusps, blood vessels were present in all 28 cases, and lymphatics in 14 of them. Vascularization was associated with lymphocytic infiltrates in 24 cases. There was no difference in the pattern between the two types of CAS. The origin of the cusp vessels is discussed. Our finding in the calcified cusps of both blood and lymphatic vessels together with lymphocytic infiltrates supports the inflammatory theory of the CAS pathogenesis. PMID- 21275224 TI - Histologic findings after sodium phosphate bowel preparation for colonoscopy. Diagnostic pitfalls of colonoscopic biopsies. AB - Oral sodium phosphate (NaP) has been increasingly used for bowel preparation before the colonoscopy because it shows good patients tolerance and effective bowel cleansing ability. However, new studies describe that NaP can induce colonic mucosal damage. For better characterization of these changes, we examined histologically segmental colonic biopsies from 42 patients receiving NaP bowel solution before the colonoscopy. The series includes 25 male and 17 female patients in age from 19 to 81 years (average age 46.7 ys). Clinical symptoms in 37 patients included diarrhea, constipation, bleeding and abdominal cramps. The most frequent reason for colonoscopy was suspicion of microscopic colitis. Five patients underwent endoscopy to rule out the presence of neoplasia. None of the patients took drugs before the colonoscopy. Histologically, all specimens showed mild focal edema, hyperemia and hemorrhages. In addition to edema and hemorrhage, in 26 patients (61.9%), patchy mononuclear infiltration in the upper part of lamina propria and increased epithelial cell proliferation of individual crypts were seen. Mucosal structure was normal, with partial sloughing of normal or flattened surface epithelium. In 5 patients (11.9%), some biopsy samples contained scattered neutrophilic leucocytes in the lamina propria/superficial epithelium, isolated basal cryptitis, increased proliferation and apoptosis of the crypt epithelium. In two patients with focal cryptitis (4.8%), small erosions were found. Mild basal cryptitis, increased proliferation and striking apoptosis were present in two inflammatory pseudopolyps (in two patients). In 4 patients, solitary tubular adenomas with low-grade dysplasia without any reactive changes were found. In addition, 300 hyperplastic polyps removed endoscopically after the NaP application, were examined. Two polyps (0.75%) showed cryptitis and isolated multinucleated epithelial cells in the superficial part of the crypts. Our results are similar to those previously described in other studies of colonic changes after the NaP application. It reflects probably a similarity in composition of used NaP solutions. PMID- 21275225 TI - Guidelines for autopsy investigation of sudden cardiac death. AB - Although sudden cardiac death is one of the most important mode of death in Western Countries, pathologists and public health physicians have not given this problem the attention it deserves. New methods of preventing potentially fatal arrhythmias have been developed, and the accurate diagnosis of the causes of sudden cardiac death is now of particular importance. Pathologists are responsible for determining the precise cause of sudden death but there is considerable variation in the way in which they approach this increasingly complex task. The Association for European Cardiovascular Pathology developed guidelines, which represent the minimum standard that is required in the routine autopsy practice for the adequate assessment of sudden cardiac death, including not only a protocol for heart examination and histological sampling, but also for toxicology and molecular investigation. Our recommendations apply to university medical centres, regional and district hospitals and all types of forensic medicine institutes. If a uniform method of investigation is adopted throughout the European Union, this will lead to improvements in standards of practice, allow meaningful comparisons between different communities and regions and, most importantly, permit future trends in the patterns of disease causing sudden death to be monitored. PMID- 21275226 TI - An autopsy case of carbamazepine poisoning. AB - We present a case of fatal carbamazepine poisoning. Quantitative analysis of carbamazepine using high performance liquid chromatography, revealed that the concentrations of carbamazepine were 50.2 microg/ml in the femoral venous blood and 60.3 microg/ml in the heart blood, respectively, and many unabsorbed tablets were also observed in the stomach contents. We concluded that the cause of death was due to carbamazepine overdose. PMID- 21275227 TI - An autopsy case of poisoning with selective serotonin reuptake inhibitor, paroxetine. AB - A female in her twenties was found dead in her room. She had received medications for depression and panic disorder, and had attemped suicide several times. Many packets of prescribed drugs, including paroxetine, were found near the corpse. At autopsy, the lungs were edematous. The organs were slightly congested with putrefactive change. Autolytic rupture, considered as gastromalasia, was observed in the anterior cardiac portion of stomach wall. Toxicological examination revealed 0.78, 3.20 and 17.63 microg/ml of paroxetine in the heart blood, femoral blood and urine, respectively. Acetaminophen and phenobarbital were also identified within therapeutic or sub-lethal levels. Taking into consideration postmortem diffusion of drugs, we evaluated postmortem data and concluded that the death was mainly due to toxicity of paroxetine with serotonin syndrome. PMID- 21275228 TI - Vomitus as a cause of fatal diving accident of a commercial diver. AB - The forensic expertise of the victim of fatal diving accident (commercial diver), who died in depth of 41 mts due of unknown reasons, had been realised by the authors. One of the authors of the paper was present on site of the diving accident as a diving medicine specialist. The autopsy revealed, that the cause of death of the diver was suffocation due to vomitus and massive aspiration of gastric content to the airways. The commercial diving technology (full-face diving mask with oro-nasal inner mask) was used. The authors point out some peculiarities in interpretation of such a fatal diving accident. PMID- 21275229 TI - Cardio-respiratory responses of the 6-minute walk test in patients with refractory heart failure during the preoperative period for heart transplant surgery. AB - BACKGROUND: The six-minute walk test (6MWT) has been used to assess functional capacity, clinical status and prognosis. There are a very few descriptions in the literature on the safety and metabolic impact of the test, especially in patients with severe heart failure, awaiting cardiac transplantation. OBJECTIVE: The aim of the present study was to assess the cardiovascular responses and correlate the performance on the 6MWT with clinical status. METHOD: From 15 initial candidates, twelve patients (10 males) aged 52 +/- 8 years were submitted to a comprehensive clinical evaluation. The patients performed the 6MWT with electrocardiographic and perceived exertion monitoring in addition to determination of blood lactate concentration. Patients were followed up for 12 months. RESULTS: The patients walked 399.4 +/- 122.5 meters, reaching a perceived exertion (PE) of 14.3 +/- 1.5 and an increase of 34% in resting heart rate. Two patients exhibited a greater severity of arrhythmia prior to the 6MWT, which did not increase during exertion. Four patients exhibited a significant increase in blood lactate levels (>5 mmol/dL) and three interrupted the test prematurely. The distance walked (D) revealed a correlation with the ejection fraction (%) and functional classification (NYHA). After 12 months of follow up, three patients died and seven were re-hospitalized due to heart failure decompensation. CONCLUSION: Clinical and electrocardiographic behavior suggests that the 6MWT is safe, but may be considered of high intensity for some patients with severe heart failure. Variables related to the performance on the 6MWT may be associated to worsening clinical status in this population. PMID- 21275230 TI - AngioJet rheolytic thrombectomy for acute superficial femoral artery stent or femoropopliteal by-pass thrombosis. AB - Thrombosis of superficial femoral artery (SFA) nitinol stents or polytetrafluoroethylene (PTFE) femoropopliteal bypass grafts after discontinuation of antiplatelet therapy is an emergent clinical challenge of acute limb ischemia (ALI), requiring immediate percutaneous intervention. Currently, there is no evidence-based approach for the management of such complications. We describe the cases of two patients presenting with ALI due to nitinol stent thrombosis after discontinuation of antiplatelet therapy and the case of a patient presenting with ALI due to PTFE femoropopliteal graft thrombosis in which limb salvage was obtained by AngioJet rheolytic thrombectomy and re-stenting. In both cases, the thrombus was successfully removed using the Possis AngioJet mechanical thrombectomy catheter and percutaneous transluminal angioplasty (PTA) was performed to recanalize two femoropopliteal nitinol stents and a femoropopliteal PTFE graft. In both cases, optimal angiographic result was obtained. To the best of our knowledge, these are the first three cases reporting the use of the AngioJet rheolytic thrombectomy in ALI due to stent or graft thrombosis. Taken together, these cases suggest that AngioJet rheolytic thrombectomy might represent a novel effective strategy in the percutaneous treatment of stent or graft thrombosis determining ALI. PMID- 21275231 TI - Comparative analysis of remote results of transluminal balloon angioplasty in treatment of lower limb critical ischaemia in groups of patients with and without diabetes mellitus. AB - All the hitherto conducted studies aimed at determining the efficacy of transluminal balloon angioplasty (TLBAP) in patients presenting with lower limb critical ischaemia (LLCI) have either dealt with the whole population of the patients involved, including a large proportion therein of patients with simultaneously present diabetes mellitus (DM), or solely investigated a group of patients suffering exclusively from diabetic foot syndrome. There has virtually been no information about non-diabetic patients, thus casting reasonable doubts upon feasibility of subjecting them to TLBAP, especially in the situation wherein there does exist a surgical alternative. In order to elucidate the problem concerned, we performed a comparative analysis of the incidence rate of freedom from LLCI relapses following TLBAP in diabetic versus non-diabetic patients. Based on the findings obtained from this analysis, a conclusion was made that the remote results of TLBAP were statistically not considered to be different in the groups of diabetic patients and non-diabetic subjects within the time frame of a 12-month follow up period. For the joint group, the cumulative probability of freedom from LLCI relapses during one year amounted to 65%, which is comparable with the outcomes of distal bypass grafting operations. PMID- 21275232 TI - Open repair of complex abdominal aortic aneurysms. PMID- 21275233 TI - Bioinformatic strategies to provide functional clues to the unknown genes in Plasmodium falciparum genome. AB - The fight against Plasmodium falciparum, the species responsible for 90% of the lethal forms of human malaria, took a new direction with the publication of its genome in 2002. However, the hopes that the genome should help bringing to the foreground the expected new "vaccines candidates" or "targets of new medicines" were disappointed by the low number of genes that could be functionally annotated -less than 40% upon the genome publication, just over 50% eight years later. This 10% gain of knowledge was made possible by the efforts of the entire scientific community in many directions which include: the production of transcriptomic and proteomic profiles at various stages of the parasite development and in response to drug or stress treatments; the proteomic study of subcellular compartments; the sequencing of numerous Plasmodium related species (allowing whole genome comparisons) and the sequencing of numerous P. falciparum strains (allowing investigations of gene polymorphism). In parallel with this production of experimental biological data, the development of original mining tools adapted to the P falciparum specificities quickly appeared as a priority, as the performances of "classical" bioinformatic tools, used successfully for other genomes, had limited efficacy. This was the aim of the PlasmoExplore project launched in 2007. This brief review does not cover all efforts made by the international community to decipher the P falciparum genome but focuses on improvements and novel mining methods investigated by the PlasmoExplore consortium, and some of the lessons we could learn from these efforts. PMID- 21275234 TI - Biochemical research elucidating metabolic pathways in Pneumocystis. AB - Advances in sequencing the Pneumocystis carinii genome have helped identify potential metabolic pathways operative in the organism. Also, data from characterizing the biochemical and physiological nature of these organisms now allow elucidation of metabolic pathways as well as pose new challenges and questions that require additional experiments. These experiments are being performed despite the difficulty in doing experiments directly on this pathogen that has yet to be subcultured indefinitely and produce mass numbers of cells in vitro. This article reviews biochemical approaches that have provided insights into several Pneumocystis metabolic pathways. It focuses on 1) S-adenosyl-L methionine (AdoMet; SAM), which is a ubiquitous participant in numerous cellular reactions; 2) sterols: focusing on oxidosqualene cyclase that forms lanosterol in P carinii; SAM:sterol C-24 methyltransferase that adds methyl groups at the C-24 position of the sterol side chain; and sterol 14alpha-demethylase that removes a methyl group at the C-14 position of the sterol nucleus; and 3) synthesis of ubiquinone homologs, which play a pivotal role in mitochondrial inner membrane and other cellular membrane electron transport. PMID- 21275235 TI - Comparison of efficiency of various DNA extraction methods from cysts of Giardia intestinalis measured by PCR and TaqMan real time PCR. AB - The aim of the presented study was to work out an effective method of extraction of DNA from Giardia intestinalis cysts as well as a sensitive and specific method for detection of DNA of this protozoan using a polymerase chain reaction (PCR). Twelve protocols for DNA extraction have been compared. Purification and extraction of DNA were preceded by additional actions in order to destroy the cysts' wall. The highest effectiveness of DNA extraction was obtained in case of alternating application of freezing the samples in liquid nitrogen and their incubation in water bath in the temperature of 100 degrees C, and then the extraction with the QIAamp DNA Tissue Mini Kit (QIAGEN)--T kit--with an all night long incubation with proteinase K in 56 degrees C. Effectiveness of DNA extraction with the use of each kit after extraction with each treatment was measured by nested PCR product of beta-giardin gene fragment and C(T) values of real time PCR of the SSU rRNA gene of G. intestinalis. The detection limit, defined as the lowest number detected in 100% cases, was 100 cysts per 200 microl when effectiveness was evaluated with nested PCR and 50 oocysts with real time PCR after extraction DNA with T kit. Results of our comparative studies have shown that all stages preceding the molecular detection of G. intestinalis DNA are equally important, and materially influence on the final effect and this version of method seems to be very useful for the sensitive detection of DNA of G. intestinalis. PMID- 21275236 TI - Oswaldofiaria chabaudi n. sp. (Nematoda: Onchocercidae) from a South American tropidurid lizard (Squamata: Iguania) with an update on Oswaldofilariinae. AB - A new species of Oswaldofilaria is described from Tropidurus torquatus (Tropiduridae: Iguania); its prevalence at the rocky study area at Juiz de Fora, Minas Gerais, Brazil, was approximately 30% and its mean intensity 3.13 +/- 2.51. Oswaldofilaria chaboudi n. sp. is distinct from the thirteen Oswaldofilaria species known in Australia, Africa and South-America in having the following characteristics: oesophagus medium-sized, left spicule 1 mm long and high spicular ratio (about 5), tail extremity ornated in both sexes with a bifurcated projection, and tooth-like structures near phasmids in the female. A long left spicule and high spicular ratio are convergent derived characters also found in a parasite of Australian crocodilians, O. kanbaya, and in several species of the closely related genus Befilaria, such as the Central American B. puertoricensis from polychrotids. Oswaldofilaria in South America is represented by eight species. Within these, a primitive group that is parasitic in Iguanidae, Polychrotidae (Iguania) and Crocodylidae and that possesses a long oesophagus is recognised, together with two distinct derived lines: three species with numerous, aligned precloacal papillae, parasitic in Teiidae (Laterato) and Scincidae (Scincomorpha), and O. chabaudi n. sp., in which this character is absent. Tropidurids (Tropiduris and Plica) had previously been reported in the host range of two oswaldofilarine genera, Oswaldofilaria and Piratuba, and their parasites assigned to known species described from other groups of lizards. PMID- 21275237 TI - Yelirella nomen novum for Rileyella Spratt, 2003 (Pentastomida: Cephalobaenida), a junior homonym of Rileyella Townsend, 1909 (Diptera: Tachinidae). AB - Yelirella nomen novum is proposed as a replacement name for Rileyella Spratt, 2003 (Pentastomida: Cephalobaenida), which is a junior homonym of Rileyella Townsend, 1909 (Diptera: Tachinidae), resulting in the new combination Yelirella petauri (Spratt, 2003) n. comb. PMID- 21275238 TI - Intestinal parasites infections in hospitalized AIDS patients in Kinshasa, Democratic Republic of Congo. AB - To determine the prevalence and the species spectrum of intestinal parasites (IP) involved in hospitalized AIDS patients, a prospective observational and cross sectional study was carried out in the four main hospitals in Kinshasa, Democratic Republic of the Congo. From November 2006 through September 2007, a single stool sample was collected from 175 hospitalized AIDS patients older than 15 years. Parasites were detected by light microscopy, including Ziehl-Neelsen, Fungi-Fluor, modified trichrome stains, and by immunofluorescence antibody tests and PCR for species diagnosis of microsporidia. At baseline, 19 patients (10.8%) were under antiretroviral therapy and 156 (89.2%) were eligible for ART. The main diagnosis for justifying hospitalization was intestinal infection associated with diarrhea in 87 out of 175 (49.7%). 47 out of 175 (26.9%) were found to harbor an IP, and 27 out of 175 (15.4%) were infected with at least one opportunistic IP (OIP). Prevalence rate for OIP were 9.7%, 5.1%, 1.7% and 0.6% for Cryptosporidium sp., Enterocytozoon bieneusi, Isospora belli and Encephalitozoon intestinalis respectively. Considering patients with diarrhea only, prevalence rate were 12.6%, 4.6%, 3.4% and 1.1% respectively. The other IP observed were Entamoeba histolytica/Entamoeba dispar in nine cases (5.1%), Ascoris lumbricoides in seven cases (4.0%), Giardia intestinalis in three cases (1.7%), hookworm in two cases (1.1%) and Trichiuris trichiura, Enterobius vermicularis, Schistosoma mansoni in one patient each (0.6%). No significant relationship was established between any individual IP and diarrhea. These results underline the importance of OIP in symptomatic AIDS patients regardless of diarrhea at the time of the hospitalisation, and showed that routine microscopic examination using stains designed for Cryptosporidium spp. or the microsporidia should be considered due to the absence of clinical markers. PMID- 21275239 TI - Clinical efficacy and safety in head lice infection by Pediculus humanis capitis De Geer (Anoplura: Pediculidae) of a capillary spray containing a silicon-oil complex. AB - Head lice are endemic worldwide. Resistance to permethrin and doubts about the safety of pesticides promoted the use of physical therapies (wet-combing, dry-on suffocation). The aim of our study was to test the pediculicidal and ovicidal effects of one application of a silicon-oil complex composed of dimethiconol and castor oil. The study was a prospective cohort of 108 infested patients (11 males, 97 females; 58 children, 50 adults), in Sri-Lanka. Pediculicidal efficacy was evaluated as the percentage of patients free of live lice one hour after the application of the treatment and at day 1 (wet combing). Ovicidal efficacy was calculated as the proportion of subjects without larval stages at days 1 and 7 among subjects followed up all over the study. In normal conditions of use, in this open cohort, a pediculicidal effect of a dimethiconol-castor-oil lotion was.shown one hour after application in 99/108 (91.7%) treated subjects and at day 1 in 86/99 (87%) subjects and an ovicidal effect at day 7 in 79/108 (73.2%) treated subjects. A second application of the same product was necessary to increase the cure rate to 79.6% (86/108) at day 8. In our study, the second application of the same product was performed seven days later, but the best time for additional applications should be defined in further studies. However, the efficacy of this safe physical treatment was similar to that of chemical pediculicides (malathion, permethrin). PMID- 21275240 TI - Results of a European multicentric field efficacy study of fipronil-(S) methoprene combination on flea infestation of dogs and cats during 2009 summer. AB - Despite the increasing number of ectoparasiticides for pets and their use, flea infestations of cats and dogs are still widespread in Europe. It is therefore important to assess the maintenance of efficacy of the ectoparasiticides for cats and dogs. The present studies aimed to evaluate the efficacy of monthly treatments using a fipronil/(S)-methoprene combination spot-on (Frontline Combo) on dogs and cats from private veterinary clinics located in seven European countries. The survey was conducted for three months during the flea season 2009. A total of 233 dogs and 180 cats were included. Each animal was treated at Days 0 (Day 0), 30 (D30) and 60 (D60) at the vet clinics. For each animal, at least three flea counts were performed at D0, D30 and/or D60 and/or day 90 (Day 90) in order to evaluate the prevalence of flea infestation and the efficacy of control. At the beginning of the study the prevalence of infested animals was 41.63% (97/233) in dogs and 47.22% (85/180) in cats. At D90, the number of dogs remaining infested fell to 8/211 therefore 91.75% became flea-free. The number of infested cats fell from 85 to 9/173 at D90 therefore 89.41% were cured. All animals still infested at Day 90 were living under epidemiological conditions that favour heavy flea burdens. These results are similar or better to previous studies, indicating the continuous high level of efficacy for fipronil 10 years after launch. PMID- 21275241 TI - Comparative acaricidal efficacy of the topically applied combinations fipronil/(S)-methoprene, permethrin/imidacloprid and metaflumizone/ amitraz against Dermacentor reticulatus, the European dog tick (ornate dog tick, Fabricius, 1794) in dogs. AB - The acaricidal efficacy against Dermacentor reticulatus in dogs of the commercial topical combinations fipronil/(S)-methoprene (FRONTLINE Combo spot-on dog), imidacloprid/permethrin (Advantix) and metaflumizone/amitraz (ProMeris Duo) was evaluated and compared. Three treatment groups and one untreated control group of six adult Beagle dogs each were randomly formed. Each treatment was administered topically once on Day-0, according to the recommended label dose and instructions for use. All dogs were infested weekly with approximately 50 adult unfed D. reticulatus over a period of seven weeks. Ticks were removed and counted approximately 48 hours after each infestation. The percent reduction in numbers of ticks for fipronil/(S)-methoprene was > or = 97% compared to untreated controls for all seven weekly infestations. The percent reductions for imidacloprid/permethrin and metaflumizone/amitraz were satisfactory initially but fell and stayed below 90 % after three weeks. From the third week onwards, fipronil/(S)-methoprene treated dogs had significantly fewer ticks than imidacloprid/permethrin or metaflumizone/amitraz treated dogs (p < 0.05). PMID- 21275242 TI - Argas (Persicargas) persicus (Oken, 1818) (Ixodida: Argasidae) in Sicily with considerations about its Italian and West-Mediterranean distribution. AB - Recently, in the province of Trapani (Western Sicily), some overwintering specimens of the argasid tick Argos (Persicargas) persicus (Oken, 1818) were observed and collected. Morphological and genetic analysis were utilized in order to reach a definitive identification. The species was found in two semi-natural sites where, having been found repeatedly, its presence does not appear accidental. Moreover the characteristics of the Sicilian findings seem to exclude a human-induced spread. This record, the first regarding Sicily and South Italy, is discussed together with the previous doubtful citations for Italy. These findings revalue not only all the old citations for Italy but also the hypothesis that the Mediterranean distribution of this argasid is of a natural origin. PMID- 21275243 TI - Borrelia burgdorferi in ticks and dogs in the province of Vojvodina, Serbia. AB - Lyme disease is a tick borne zoonotic infection, caused by Borrelia burgdorferi s.l. bacteria. For the transmission of the disease, the presence of ticks is a prerequisite. Lyme borreliosis mostly occurs in people and dogs, but it may occur in other animals. Ticks which carry B. burgdorferi s.l. in Serbia are of the Ixodes ricinus specis. In Serbia, Lyme disease was detected for the first time in the late '80-es. In dogs, clinical symptoms may occur even months after a tick bite, and include weakness, lymphadenopathy, fever, lameness, arthritis, etc. In our survey, we have observed tick and dog populations in the province of Vojvodina (northern part of Serbia). I. ricinus ticks were collected and examined for the presence of B. burgdorferi s.l. in several chosen locations. In addition, blood samples were collected from house dogs and pets from the same locations, and analyzed for the presence of antibodies specific for B. burgdorferi s.l. The results showed a mean infection of ticks of 22.12%, and a mean seroprevalence of Lyme disease in dogs of 25.81%. We conclude that in Vojvodina there is an actual risk of Lyme borreliosis for other animals and humans, because of the persistence of B. burgdorferi s.l. in both tick and dog populations. PMID- 21275244 TI - Exon variability of gene encoding glycerol-3-phosphate dehydrogenase of Ixodes ricinus ticks. AB - We have previously found apparent differences in Gpdh allele frequences between borrelia infected and uninfected Ixodes ricinus as revealed by native gel electrophoresis of allozyme polymorphisms. The present study deals with the genetic basis of the observed allozyme polymorphism. Multiple sequence alignment of 36 Gpdh open reading frames identified a total of 40 polymorphic nucleotide sites. Of the 40 polymorphic nucleotide sites, 34 were silent (did not result in amino acid residue change), while six were active causing a change in the amino acid chain. All polymorphic amino acid sites were situated within the N-terminal NAD-binding domain, whereas the C-terminal substrate-binding domain was highly conserved. Analysis of the obtained Gpdh sequences and GPDH allozyme polymorphisms for individual ticks pointed to amino acid changes at positions 61 (glycine-to-glutamic acid), 64 (serine-to-cysteine) and 102 (glycine-to-arginine) as a key for differential mobility of GPDH allozymes in an electric field. Our findings are discussed in the context of the molecular basis of I. ricinus host finding behavior. PMID- 21275245 TI - Application of GIS in epizootiological surveillance of swine trichinellosis in one endemic district in Serbia. AB - Application of new tools for epizootiological investigations in veterinary medicine, such as Geographical Information Systems (GIS), offers a new approach and possibilities for the eradication or control of infectious diseases. GIS is particularly useful for research conducted in small areas strongly impacted by man. Trichinellosis is a world-wide zoonosis, which is endemic in some European countries, Balkan district and Serbia in particular. There are very few data on GIS application in the field of trichinellosis. We here present the application of GIS for mapping Trichinella spp. occurrence and spatial and temporal patterns of Trichinello infection in one endemic district in Serbia. Settlements with trichinellosis were marked and particular points of interest were designated. Data on prevalence of Trichinella infection in domestic swine accompanied by location of foci indicated the existence of disease geographical stationarity. This first report on GIS application in Serbia will facilitate trichinellosis surveillance and monitoring of Trichinella spp. circulation among domestic pigs, and populations of synanthropic and sylvatic animals. PMID- 21275246 TI - Physical insight into the sonochemical degradation of 2,4-dichlorophenol. AB - In this study, we have attempted to reveal the physical or mechanistic features of the sonochemical degradation of 2,4-dichlorophenol (2,4-DCP). The principal physical phenomenon underlying sonochemical effects is radial motion of cavitation bubbles and production of radicals from transient collapse of these bubbles. We reveal some important physical facets of sonochemical degradation of 2,4-DCP by adopting dual approach of coupling experimental results with simulations of radial motion of cavitation bubble. First, the location of the degradation is predominantly the interfacial region between bubble and bulk medium, and secondly, the extent of degradation is controlled by conservation- and not the production--of oxidizing radicals that affects the probability of radical-pollutant interaction. PMID- 21275247 TI - Adsorption of hexa-valent chromium using treated wood charcoal--elucidation of rate-limiting process. AB - In the present study, locally available wood charcoal was used as an adsorbent to remove Cr (VI) from water. It was found to be giving poor removal efficiency whereby only 19% of Cr (VI) was removed. Considering the fact that wood charcoal possesses a honeycomb structure, an acid treatment was tried with HCl, H2SO4 and HNO3. Treatment with concentrated hydrochloric acid has improved the removal efficiency of wood charcoal to 94%. Kinetic studies were carried out with various systemic parameters, namely initial Cr (VI) concentration (0.5, 1, 2 mg/L), adsorbent size (0.11, 0.18, 0.25, 0.36, 0.51 mm) and agitation speed (130 to 180 rpm) to understand and determine the equilibrium time, order of reaction, rate constants, diffusion coefficients, and to determine the maximum adsorption capacity and also the rate limiting process. It was found that the uptake of Cr (VI) onto wood charcoal reached equilibrium within the first 6 h of contact time. Isothermal studies explained by using the Freundlich model revealed that the maximum adsorptive capacity (Q(max)) of the treated wood charcoal is 677 microg/g, which is well within the standard/feasible value for a wood-based charcoal. The process limiting the rate of adsorption (rate limiting step) was analyzed using the kinetic data as well as using various systemic parameters such as initial Cr (VI) concentration, adsorbent size, and agitation speed was finally confirmed by the multiple interruption test. It was concluded that the adsorption process was controlled by film diffusion. PMID- 21275248 TI - Hidden flows and waste processing--an analysis of illustrative futures. AB - An existing materials flow model is adapted (using Excel and AMBER model platforms) to account for waste and hidden material flows within a domestic environment. Supported by national waste data, the implications of legislative change, domestic resource depletion and waste technology advances are explored. The revised methodology offers additional functionality for economic parameters that influence waste generation and disposal. We explore this accounting system under hypothetical future waste and resource management scenarios, illustrating the utility of the model. A sensitivity analysis confirms that imports, domestic extraction and their associated hidden flows impact mostly on waste generation. The model offers enhanced utility for policy and decision makers with regard to economic mass balance and strategic waste flows, and may promote further discussion about waste technology choice in the context of reducing carbon budgets. PMID- 21275249 TI - The synergy of permeable pavements and geothermal heat pumps for stormwater treatment and reuse. AB - The use of permeable pavement systems with integrated geothermal heat pumps for the treatment and recycling of urban runoff is novel and timely. This study assesses the efficiency of the combined technology for controlled indoor and uncontrolled outdoor experimental rigs. Water quality parameters such as biochemical oxygen demand, nutrients, total viable heterotrophic bacteria and total coliforms were tested before and after treatment in both rigs. The water borne bacterial community genomic deoxyribonucleic acid (DNA) was analyzed by polymerase chain reaction (PCR) amplification followed by denaturing gradient gel electrophoresis (DGGE) and was further confirmed by DNA sequencing techniques. Despite the relatively high temperatures in the indirectly heated sub-base of the pavement, potentially pathogenic organisms such as Salmonella spp., Escherichia coli, faecal Streptococci and Legionella were not detected. Moreover, mean removal rates of 99% for biochemical oxygen demand, 97% for ammonia-nitrogen and 95% for orthophosphate-phosphates were recorded. This research also supports decision-makers in assessing public health risks based on qualitative molecular microbiological data associated with the recycling of treated urban runoff. PMID- 21275250 TI - Heavy metals removal from mine runoff using compost bioreactors. AB - Permeable bioreactors have gained both research and management attention as viable methods for treating mine runoff waters. We examined the operation of a field-scale bioreactor (containing mixed compost, straw and gravel) for treatment of runoff from the Mother Load (ML) mine in northern Idaho, U.S. and compared it to an experimental laboratory-scale reactor, containing a similar matrix and treating similar mine runoff water. In general both reactors were efficient in removing most of the metals assayed, Al, As, Cd, Fe, Ni, Pb and Zn, with the exception of Mn. Both systems showed evidence of bacterial-mediated sulphate reduction and concomitant metal sulphide complexes. However, the experimental laboratory bioreactor showed greater proportions of immobile metals reductions than did the ML bioreactor, presumably due to the greater action of sulphate reducing bacteria. The major metal removal mechanism in the ML bioreactor was surmised to be adsorption. Differences in metal removal mechanisms between the reactors were hypothesized to be due to fluctuating hydraulic residence times at the ML site, in turn, due to unregulated runoff flow. PMID- 21275251 TI - Aqueous photocatalytic oxidation of sulfamethizole. AB - Aqueous photocatalytic oxidation (PCO) of a non-biodegradable sulphonamide antibiotic sulfamethizole was studied. The impacts of photocatalyst dose, initial pH, and substrate concentration in the range from 1 to 100 mg L(-1) were examined with a number of organic and inorganic by-products determined, suggesting the initial break-up of the SMZ molecule at the sulphonamide bond. The experiments were carried out under artificial near-UV and visible light, and solar radiation using Degussa P25 and less efficient visible light-sensitive C-doped titanium dioxide as photocatalysts. PMID- 21275252 TI - Kinetic parameters and inhibition response of ammonia- and nitrite-oxidizing bacteria in membrane bioreactors and conventional activated sludge processes. AB - Ammonium and nitrite oxidizing biomasses (AOB and NOB) were investigated in parallel pilot plants: a membrane bioreactor (MBR) and a conventional activated sludge process (CASP) fed with domestic wastewater. The kinetics of AOB and NOB were monitored through titrimetric tests. The maximum specific growth rate of the AOB (micro(max,AOB)) was affected by the solids' retention time (SRT) maintained during the start up: by varying the start up SRT from 20 d to 8 d, micro(max,AOB) in the CASP varied from 0.45 d(-1) +/- 0.04 to 0.72 d(-1) +/- 0.2 respectively; the mean value of micro(max,AOB) in the MBR samples (always maintained at SRT = 20 d) was in the range 0.45-0.49 d(-1). The endogenous decay coefficients of the NOB and AOB and the maximum specific growth rates of the NOB were similar in both MBR and CASP. Inhibition tests with different concentrations of allylthiourea (ATU) were carried out on samples from both activated sludge systems: the MBR sludge exhibited higher sensitivity to a low ATU concentration; however, the maximum nitrification activity recovered more rapidly than the CASP sludge. PMID- 21275253 TI - Leaching properties of Mn-slag from the pyrometallurgical recycling of alkaline batteries: standardized leaching tests and influence of operational parameters. AB - In the present study, different complementary leaching tests were applied to a Mn rich slag sample that was not thoroughly studied until now, in order to understand the potential mobility of the elements (Mn, Si, Fe, Ca, K, Mg, Al) within it. Several standard leaching tests (EN 12457-1 and -2, and TCLP) were carried out in order to compare results to regulatory values: the Mn-rich slag studied could be considered as 'inert' waste with respect to the release of the main trace metallic elements (Cu, Ni and Zn). In order to have a better understanding of the environmental behaviour of the Mn-rich slag constituents, other tests were performed. These experiments revealed that the dissolution of the Mn-rich slag was favoured for pH < or = 6. The mobility of the major elements was governed by the solubility of the primary solid phases and the precipitation of secondary minerals. The Visual MINTEQ modelling allowed the leaching results to be completed. From an environmental point of view, the reuse of this slag in acidic conditions has to be rejected due to the dissolution of the main solid phase. PMID- 21275254 TI - Zinc and lead leaching from contaminated industrial waste sludges using coupled processes. AB - Metal pollution of solid matrices, like soils, sediments and sludge, is widespread across the globe, and the clean-up of these matrices presents many difficulties. The aim of this study was to develop an efficient leaching technique for metal removal from an industrial carbon sludge contaminated with Zn (8600 mg kg(-1)) and Pb (389 mg kg(-1)). To this end, the possibility of coupling processes, such as extraction with mineral acids, EDTA addition, ultrasound and bioleaching, was investigated. Lead, but not zinc, was totally removed by EDTA treatment (1200 mg L(-1), pH 6.0). Ultrasound treatment was ineffective in metal leaching at all tested pH values, either with or without EDTA addition, probably because of the reduction in size of the carbon particles and the concomitant increase in surface area available for metal binding. A ferrous-iron-oxidizing, endogenous microflora lixiviated 90% of Zn at pH 2.5 in seven days, whereas, after the addition of Acidithiobacillus ferrooxidans, 100% of Zn was removed within four days. These results indicated that the clean-up process for the metal contaminated sludge should combine an initial chelation step with Na-EDTA (pH 6.0) for complete removal of Pb, followed by a second bioleaching step with A. ferrooxidans for total removal of Zn. PMID- 21275255 TI - Sorption of 226Ra from waste effluents using Syrian bentonite. AB - In view of environmental concern, sorption of radium on natural bentonite mineral (Aleppo, Syria) was investigated using a batch-type method. Data were expressed in terms of distribution coefficients. An attempt to increase the selectivity of bentonite for radium was made by preparing M-derivatives. Loss of mineral crystallinity in acidic media and the formation of a new phase, such as BaCO3, in Ba-derivative were evidenced by XRD characterizations. Of the cationic forms, Na bentonite showed the highest affinity. Mechanisms of radium uptake were studied using M-derivatives and simulated radium solutions. The obtained results indicated that surface sorption/surface ion exchange were the predominant processes. The distinct sorption behaviour observed with the Ba-form was, possibly, a reflection of radium coprecipitation with barium carbonate. The competing order of macro components, likely present in waste streams, was investigated by studying different concentrations of the corresponding salt media. Sodium was found to be the weakest inhibitor. The performance of natural bentonite and the most selective forms, i.e. Ba- and Na-derivatives, to sorb radium from actual oil co-produced waters, collected form Der Ezzor Petroleum Company (DEZPC), was studied. This showed the influential effect ofpH compared with other parameters. PMID- 21275256 TI - Impact of extracellular polymeric substances on the settlement ability of aerobic granular sludge. AB - Instability of aerobic granular sludge (AGS), which is mainly caused by filamentous outgrowth, is a bottleneck in applying this technology to treat wastewater. In order to reduce the effect of filamentous outgrowth on settlement ability of AGS, the role of the distribution of extracellular polymeric substances (EPS) in settlement ability was investigated in this study. Chemical oxygen demand (COD) of influent increased gradually from 1000 mg L(-1) to 2000 mg L(-1) to 4000 mg L(-1) as organic loading rate (OLR) changed from 2 to 4 to 8 kg COD m(-3) d(-1) in the synthetic influent. The relationship between settlement ability and EPS was investigated. The sharp increase in loosely bound EPS (LB EPS) content reduced the settlement ability, whereas the highest content of tightly bound EPS (TB-EPS) was observed in the sludge with best settlement ability. The TB-EPS plays an important role in maintaining the matrix structure of AGS. Abundance of LB-EPS did not favour the settlement ability of AGS. These results would provide useful information for improvement of stability of AGS. PMID- 21275257 TI - Electrochemical oxidation of tannic acid contaminated wastewater by RuO2/IrO2/TaO2-coated titanium and graphite anodes. AB - The electrochemical oxidation of tannic acid contaminated wastewater by RuO2/IrO2/TaO2-coated titanium and graphite anodes has been investigated. The effect of the process variables, such as initial pH, current density, processing time, concentration of the electrolyte and anode materials, on the degradation of tannic acid was studied. During the various stages of electrolysis, parameters such as COD, chloride ion concentration and UV-Vis spectra were examined and discussed. The maximum chemical oxygen demand (COD) removal efficiency of 94% was achieved at pH 5, operated at the current density of 8.10 mA/cm2, electrolyte (NaCl) concentration of 0.1 M and at 60 min of electrolysis using graphite anodes. The experimental results showed that the electrochemical oxidation process could effectively reduce the COD from the tannic acid contaminated wastewater. An acidic pH showed the maximum reduction of COD compared with neutral and alkaline pH. Increase in current density, process time and electrolyte (NaCl) concentration with the increase in COD removal. Graphite anodes showed maximum removal of COD and better tannic acid degradation when compared with RuO2/IrO2/TaO2-coated titanium anodes. PMID- 21275258 TI - Retention of nickel from aqueous solutions using iron oxide and manganese oxide coated sand: kinetic and thermodynamic studies. AB - In this study, the removal of nickel ions from aqueous solutions using iron oxide and manganese oxide coated sand (ICS and MCS) under different experimental conditions was investigated. The effect of metal concentration, contact time, solution pH and temperature on the amount of Ni(II) sorbed was studied and discussed. Langmuir and Freundlich isotherm constants and correlation coefficients for the present systems at different temperatures were calculated and compared. The equilibrium process was well described by the Langmuir isotherm model: the maximum sorption capacities (at 29 K) were 2.73 mg Ni/g and 3.33 mg Ni/g of sorbent for ICS and MCS, respectively. Isotherms were also used to evaluate the thermodynamic parameters (deltaG degrees, deltaH degrees, deltaS degrees) of adsorption. The sorption kinetics were tested for the pseudo-first order, pseudo-second-order and intra-particle diffusion models. Good correlation coefficients were obtained for the pseudo-second-order kinetic model, showing that the nickel uptake process followed the pseudo-second-order rate expression. PMID- 21275259 TI - Removal of COD and colour from young municipal landfill leachate by Fenton process. AB - Landfill is a common solution for the final disposal of municipal solid waste in Turkey. In recent years, studies of landfill leachate treatment by Fenton process have indicated that these methods can effectively reduce concentrations of organic contaminants and colour. The aim of this study is to investigate the removal efficiencies of colour and organic matter as COD from young municipal landfill leachate and the effect of operating conditions such as initial pH and Fenton's reagent dosage. Leachate was collected from municipal sanitary landfill located in city of Konya, Turkey. The main characteristics of the leachate were: pH = 7.25, colour = 3510 ptCo, COD = 38200 mgL(-1), BOD5 = 22000 mgL(-1), ratio of BOD5/COD was 0.58 and alkalinity as CaCO3 = 10250 mgL(-1). It is observed that presenting a high value of COD and BOD5 and the rate of BOD5/COD values indicate that the leachate can be defined as young. The treatment of the leachate by Fenton process was carried out in a batch reactor. Under the optimal operation conditions (initial pH = 3, 2000 mgL(-1) Fe2+ and 5000 mgL(-1) H2O2), 55.9% of the initial COD and 89.4% colour were removed. PMID- 21275260 TI - Targeting inflammatory cell signaling mechanisms: a promising road to new therapeutic agents in chemoprevention and cancer therapy. PMID- 21275261 TI - Triazoloacridone C-1305 abrogates the restriction checkpoint in cells lacking functional p53 and promotes their accumulation in the G2/M phase of the cell cycle. AB - Triazoloacridone C-1305, a new topoisomerase II inhibitor, exhibits potent cytostatic activity toward various tumours under in vitro and in vivo conditions. Interestingly, mouse cells lacking poly(ADP-ribose) polymerase-1 are much more sensitive to C-1305 than their normal counterparts. In the present study we tested the hypothesis that the functional status of p53 in tumour cells might have an impact on the efficiency of C-1305 in experiments with both p53-deficient human HL-60 promyelocytic leukemia cells and human MCF-7 breast cancer cells harboring a functional p53 pathway. Exposure of both cancer cell lines to C-1305 reduced the number of viable cells in a time- and concentration-dependent manner. Remarkably, however, HL-60 cells were much more strongly affected than MCF-7 cells. Measurements of DNA concentrations in single cells revealed that C-1305 arrested the tested cancer cells at the G/M transition. Analysis of the cell cycle and apoptosis regulators revealed that C-1305 strongly elevated phosphorylation of CDK1 at the inhibitory sites (Thr14/Tyr15) in HL-60 cells. Furthermore, C-1305 increased phosphorylation of pRb protein and CDK2 at Thr160 in HL60 cells, but not in MCF-7 cells. These observations suggest that C-1305 abrogates the restriction checkpoint and promotes G1/S transition in cells lacking functional p53. PMID- 21275262 TI - Effect of anti-estrogen combined with roscovitine, a selective CDK inhibitor, on human breast cancer cells differing in expression of ER. AB - Roscovitine (ROSC), a selective inhibitor of cyclin-dependent kinases (CDKs) reduces numbers of cancer cells in a concentration-dependent manner. At low doses ROSC arrests cell cycle progression and at higher doses it induces apoptosis. ROSC efficiently inhibits proliferation of human ER-alpha positive MCF-7 breast cancer cells by inducing G/M arrest and concomitantly initiates apoptosis by a p53-dependent pathway. However, the effect of ROSC is much weaker on MCF-7 cells maintained in the presence of estrogen-mimicking compounds. Therefore, we have examined the action of ROSC on other breast cancer cell lines differing in ER status and confirmed that tamoxifen (TAM) affects the efficacy of this CDK inhibitor. ROSC was effective against all tested breast cancer cell lines, arresting them at G1/S or G2/M transition and inducing apoptosis in SKBR-3 cells. Interestingly, TAM affected all tested cell lines, irrespective of their ER-a status, and in combination with ROSC it enhanced G1 or G2 arrest. Our results provide evidence that ROSC can be combined with antiestrogen therapy and that the mode of ROSC action strongly depends on the cellular context. The effect of TAM on ER-negative cancer cells indicates that TAM also crosstalks with other steroid hormone receptors. PMID- 21275263 TI - Roscovitine, a small molecule CDK inhibitor induces apoptosis in multidrug resistant human multiple myeloma cells. AB - Small molecule inhibitors of cyclin-dependent kinases (CDKs) show high therapeutic potential against rapidly dividing cancers and malignancies, characterized by the accumulation of transformed cells due to deregulation of apoptosis, such as multiple myeloma. In the present study we addressed the possibility that pharmacological CDK inhibitors like Roscovitine (ROSC) may be effective against human multiple myeloma cells that have acquired resistance to doxorubicin (DOX). For this purpose we selected an experimental model of human multiple myeloma-sensitive (RPMI-8226s) and doxorubicin-resistant (RPMI 8226(DOX40)) cell lines. Exposure of RPMI-8826 cells to ROSC markedly increased the proportion of hypoploid cells, representing cells undergoing apoptosis, in both sensitive and resistant cells. Unlike ROSC, DOX at high dosage did not elevate the apoptosis rate in the RPMI-8226(DOX40) cell line. Our results show that ROSC has the capacity to induce apoptosis in the RPMI-8226(DOX40) cells overexpressing the P-gp glycoprotein. Since ROSC not only inhibits cell cycle related CDKs but also negatively regulates kinases involved in the regulation of transcription, its administration to quiescent multidrug-resistant cells might be advantageous. Inhibition of transcription of pro-survival genes such as BCL2 and MCL-1 as well as destabilization of survivin seems to improve its therapeutic efficacy. PMID- 21275264 TI - Tamoxifen enhances the anti-proliferative effect of roscovitine, a selective cyclin-dependent kinase inhibitor, on human ER-positive human breast cancer cells. AB - We reported recently that roscovitine (ROSC), a selective cyclin-dependent kinase (CDK) inhibitor, can arrest human ER-positive MCF-7 breast cancer cells in the G2 phase of the cell cycle and concomitantly induce apoptosis. The observed effects of ROSC were diminished in MCF-7 cells maintained in the presence of estrogen mimicking compounds. Therefore, we decided to test whether combining ROSC with anti-estrogen therapy would modulate the efficacy of ROSC action. Exposure of MCF 7 cells to tamoxifen (TAM) for 24 h decreased the number of living cells by approximately 10%. This was associated with a ca. 25% increase in the G1 cell population and reduction in the proportion of S-phase cells. Unlike TAM, estrogen had very weak effects on the cell cycle progression of MCF-7 cells within 24 h. The proliferation-promoting effect of estrogen did not become evident until cultivation of cells for 48 h. Addition of estrogen to MCF-7 cells 1 h prior to TAM administration abolished the anti-estrogen-induced G1 arrest. Simultaneous treatment of MCF-7 cells with ROSC and TAM strongly enhanced the anti proliferative effect of ROSC. This was potentiated after co-treatment with estrogen. These results clearly indicate that the efficacy of treating ER positive breast cancers by ROSC can be enhanced by combined application of antiestrogens. PMID- 21275265 TI - Cerium oxide nanoparticles: a promise for applications in therapy. AB - In the last years, increasing biological interest is emerging for nanotechnology that can improve pharmacological treatments, by using nanomaterials. In particular, cerium oxide nanoparticles, considered one of the most interesting nanomaterials for their catalytic properties, show a promise for application in therapy. Due to the presence of oxygen vacancies on its surface and autoregenerative cycle of its two oxidation states, Ce3+ and Ce4+, nanoceria can be used as an antioxidant agent. Because many disorders are associated with oxidative stress and inflammation, cerium oxide nanoparticles may be a tool for the treatment of these pathologies. In this review we analyze the opinions, sometimes conflicting, of the scientific community about nanoceria, together with its capability to protect from various damages that induce cells to death, and to reduce oxidative stress, associated with a consequent reduction of inflammation. PMID- 21275266 TI - Combining an FPTase inhibitor with cisplatin facilitates induction of apoptosis in human A549 lung cancer cells. AB - Despite great efforts to develop efficacious curative treatments, the prognosis for lung cancer patients is poor. In the present study we compared the effects of cisplatin (CP), a strong DNA damaging compound, with those of roscovitine (ROSC), a selective inhibitor of cyclin-dependent kinases (CDKs), on wt p53-positive human A549 lung adenocarcinoma cells harboring a mutated K-RAS gene. Asynchronously growing A549 cells were relatively resistant to CP treatment for 24 h, but after exposure to CP at sufficiently high doses (> or = 20 microM) an accumulation of S-arrested cells was observed. However, after post-incubation of CP-treated cells in a drug-free medium for a further 48 h the number of living cells was markedly reduced. Combining CP with L-744,832, a small molecule FPTase inhibitor (FTI), slightly enhanced its anti-proliferative effect. Interestingly, FTI sensitized A549 cells to CP-induced apoptosis. ROSC inhibited A549 cells at the G/M transition, resulting in a marked decrease in the number of viable cells within 24 h, and prolonged treatment with ROSC for 48 h reduced the frequency of living cells by inducing apoptosis. The effects of ROSC (unlike those of CP) were more strongly enhanced by inhibition of the Ras protein processing pathway. Our preliminary results indicate that functional p53 contributes to the outcome of the therapy in human A549 cells by certain anti-cancer drugs. PMID- 21275267 TI - Urodynamic evaluation after abdominal hysterectomies for gynecological malignancies. AB - The aim of this study was to evaluate the effect of abdominal hysterectomy made for gynecological malign diseases on lower urinary tract functions in asymptomatic patients by preoperative and postoperative urodynamic measurements. Thirty four asymptomatic women, who were operated for gynecological malignancies by abdominal hysterectomy from September 2008 to June 2009, in Dicle University Hospital Department of Obstetrics and Gynecology, were included in this study. Urodynamic measurements were performed before the operation and in the sixth week of surgery. No statistically significant changes were detected in first urge, normal urge, and strong urge, bladder capacity before and after surgery. The evaluation of functional urethral length showed a significant difference by UPP between pre and postoperative values (p = 0.003). The decreases in values of the maximum urethral pressure and the maximum urethral closing pressure were significant (p = 0.004 and p = 0.048). The voiding time was found to be statistically increased (p = 0.002), voided volume and residual urine volume were remained unchanged. There were no significant differences in other measurements. Preoperative and postoperative urodynamic studies are necessary to determine and cure urinary dysfunctions caused by abdominal hysterectomy. PMID- 21275268 TI - Micronucleus index of rats treated with sodium nitrite can be amplified by sodium chloride. AB - OBJECTIVE: The possible effect of sodium chloride as an amplifier of sodium nitrite co-carcinogenicity was assayed by in vivo experiments. RESEARCH METHODS & PROCEDURES: 18 male rats who matched for age and weight were tested for this experiment. They were at age of 8 weeks and weight of them was around 190 grams. They were exposed to the same environmental conditions, and they were divided into 3 groups: 1--The unexposed rats who were not under any special treatment (C group) 2--Rats who were treated twice with sodium nitrite in a dose of 5.18 mg/kg body weight, with an interval of 24 hours (N group). 3--Rats who were given sodium nitrite the same as second group, 24 hours after a single application of 1 ml of saturated sodium chloride solution (29 percent) (SN group). The bone marrow samplings were performed and the micronuclei index was evaluated in all three groups. RESULTS: Sodium chloride combined with nitrite induced the significant elevation of micronuclei count in the SN group (p < 0.001). But sodium nitrite without sodium chloride did not have the same effect. CONCLUSIONS: The data offers a possible amplification of sodium nitrite's co-carcinogenicity by sodium chloride in rats. PMID- 21275269 TI - Risk factors for persistent gestational trophoblastic neoplasia. AB - This retrospective study evaluated the risk factors for persistent gestational trophoblastic disease (GTN) and determined their odds ratios. This study included 100 cases with GTN admitted to our clinic. Possible risk factors recorded were age, gravidity, parity, size of the neoplasia, and beta-human chorionic gonadotropin levels (beta-hCG) before and after the procedure. Statistical analyses consisted of the independent sample t-test and logistic regression using the statistical package SPSS ver. 15.0 for Windows (SPSS, Chicago, IL, USA). Twenty of the cases had persistent GTN, and the differences between these and the others cases were evaluated. The size of the neoplasia and histopathological type of GTN had no statistical relationship with persistence, whereas age, gravidity, and beta-hCG levels were significant risk factors for persistent GTN (p < 0.05). The odds ratios (95% confidence interval (CI)) for age, gravidity, and pre- and post-evacuation beta-hCG levels determined using logistic regression were 4.678 (0.97-22.44), 7.315 (1.16-46.16), 2.637 (1.41-4.94), and 2.339 (1.52-3.60), respectively. Patient age, gravidity, and beta-hCG levels were risk factors for persistent GTN, whereas the size of the neoplasia and histopathological type of GTN were not significant risk factors. PMID- 21275270 TI - Euthanasia. PMID- 21275271 TI - Dentistry--the way it was. PMID- 21275272 TI - Mandibular guidance partial denture for cancer patients--case report. PMID- 21275273 TI - Oral pathology quiz. Case number 1. Peripheral odontogenic neoplasm. PMID- 21275274 TI - Oral pathology quiz. Case number 2. Verruciform xanthoma. PMID- 21275275 TI - Practice merger: questions & answers. PMID- 21275276 TI - Attitudes of pediatric dentists toward parental presence during dental treatment of children. AB - BACKGROUND: This study was performed to examine the current attitudes of pediatric dentists in the United States toward the presence of parents in the dental operatory during dental treatment for their children. METHODS: E-mail letters were sent to the 1516 American pediatric dentists listed in the directory of the American Academy of Pediatric Dentistry. Respondents were directed to follow a hyperlink provided in the e-mail letter to a website containing survey questions. Answers were directly submitted via the internet into a database supported by the New Jersey Dental School. RESULTS: 905 acceptable surveys were received (60% response rate). Most practitioners (74%) generally allowed parental presence, although a majority (58%) felt that children would be less cooperative in the presence of parents. Initial examination had the highest frequency of parental presence allowed, whereas sedation had the lowest. When practitioners considered whether to allow parental presence, age and behavior were the two most important factors reported. Some demographic factors that had an effect on parental presence policy were region of the country (more parental presence was allowed in the Northeast and West), area of practice (more parental presence was allowed in suburban or urban areas), and type of practice (solo practitioners were more likely to exclude parents). Most practitioners reported a recent change to allow more parental presence because of changes in the expectation of parents (67%), and legal issues (66%). CONCLUSIONS: Most American pediatric dentists allow parents in the dental operatory most of the time that children receive dental treatment. CLINICAL IMPLICATIONS: Practitioners might wish to follow the findings of this study and allow parents into the treatment operatory whenever children receive dental treatment. PMID- 21275277 TI - Patient's page. Why doesn't my insurance pay for this? PMID- 21275278 TI - State opposition to federal health care. PMID- 21275279 TI - Health care reform bill changes--effective 2010. PMID- 21275280 TI - Mapping dental establishments in Oklahoma just before the recession. AB - Census Bureau data indicate a continuing increase in the number and size of dental establishments in the period just prior to the recent recession. During this same period, the combination of a limited increase of the population in Oklahoma and limited proportional increase in the numbers of dentists and dental establishments resulted in decreases in population-to-dental facility ratios. The usual favorable expectations of an economic upswing after a recession for dental establishments may need to be tempered given these developments. PMID- 21275281 TI - The 2009 Oklahoma youth risk behavior survey. PMID- 21275282 TI - Three quick fixes for broken appointments. PMID- 21275283 TI - Are family physicians the answer to ED doctor shortage, or 'blasphemy'? AB - Some organizations maintain that family physicians have the skills and training necessary to practice in the ED and help combat the current physician shortage, while others maintain their training is inadequate. Here are some issues to take into consideration with such candidates: Have they obtained thorough experience the necessary skills to practice in the ED? Have they received a significant amount of clinical training in an ED? Has their training progress been monitored by a teaching attending? PMID- 21275284 TI - Alert addresses patient suicides. AB - The Joint Commission has issued a Sentinel Event Alert about patient suicides in the ED and med/surg units because they represent environments that are distinct from that of the psych unit.The ED faces special challenges because of its fast paced environment. Recognize and look for psychiatric issues that might be the result of the patient's reaction to their physical problems. Schedule an inservice following a near miss or a successful suicide. It will be much more impactful if staff can relate to an incident. Be on the alert for signs of psychological problems in your patients, i.e., agitation manifested by pacing the floor. PMID- 21275285 TI - ED targets end-of-life patients. AB - The new Life-Sustaining Management and Alternative (LSMA) services program in the ED at St. Joseph's Regional Medical Center in Paterson, NJ, is designed to offer patients with life-limiting disease greater control over their care choices and also help them contact services such as hospice if they are needed. Two ED physicians and one nurse are on call 24/7 for consulting referrals from ED physicians. The consultants meet with the patient and their family to review the case and present alternatives. The program shifts the traditional ED focus of curing to one of caring. PMID- 21275286 TI - Elderly women get unnecessary UCs. AB - In a recent study, it was found that more than half of the female ED patients who were 80 or older received unnecessary urinary catheters (UCs). The authors note the following proposed actions to limit these errors: Have clear-cut indications and non-indications for the placement of urinary catheters. Require that all such procedures have orders from an ED physician. Make sure that newer or rotating staff are made aware of your department's guidelines. PMID- 21275287 TI - Improved flow aids patient safety. AB - The ED at Enumclaw (WA) Regional Hospital has reduced its rate of patients who left without being seen from 5% to between .8% and 1.1% and cut its door-to-doc time from an average of 52 minutes to an average of 16 minutes with the institution of a new triage and treatment process. At the same time, it has improved patient safety and received an award from the Washington State Medical Association. When patients present, one of two registration clerks takes down the chief complaint and quickly registers the patient to give them an account number. After initial registration,"team intake" staff takes them to a patient room or a triage room. A five-tier triage system is used to determine placement of patients. PMID- 21275288 TI - Transradial interventions. PMID- 21275289 TI - A quarter century & change of directions: femoral to radial approach? PMID- 21275290 TI - Transradial PCI: is it safe? Is it feasible? Is it better and to what extent? PMID- 21275291 TI - Transradial peripheral vascular interventions. AB - Recently the importance of post procedure bleeding contributing to both short term and long-term mortality has lead to a renewed interest in transradial coronary interventions in the United States. It has been long known that the incidence of access site bleeding is dramatically decreased by transradial access but the procedure is only used in 1% of coronary interventions in the United States, far below the rest of the world. In India, Japan and some European centers 50% of interventions are transradial. To extend this benefit of lower incidence of access site complications, we started using a transradial approach for peripheral interventions for the lower extremities, renal and subclavian arteries. By experience, we realized that in many cases the radial approach makes the procedure actually simpler. Also, in many instances, the transradial approach allows discharge of the patient on the same day. In this paper, we describe our approach to lower extremity, renal and subclavian interventional procedures. PMID- 21275292 TI - Gentleman, rebel and believer: the radial way. AB - The manuscript highlights some historic milestones of the universal trans-radial approach (TRA) and describes some characteristics that "radialists" share (at least in the author's opinion). The author argues against common misconceptions about the TRA, like the use of more iodine contrast, more X-ray exposition, a lower rate of successful angioplasty. Data illustrating the conversion from a trans-femoral approach catheterization laboratory to a complete TRA laboratory are presented, showing the speed of the switch and the rapid clinical benefit observed. The author concludes with possible future directions for TRA supporters, on how to optimize the material for the puncture step, how to reduce the radial occlusion rate and how to promote the TRA as the first access for acute coronary syndromes managed invasively. PMID- 21275293 TI - Fundamental issues to be addressed before and during a transradial procedure. AB - The transradial approach (TRA) is being increasingly adopted in Europe, and is currently implemented in 60% of angioplasty procedures in France. This vascular route improves the comfort of the patient as well as that of the paramedical staff whilst allowing a reduction in hospitalization duration and cost. Most importantly, it reduces the risk of vascular and bleeding complications with a potential impact on mid-term mortality. With the classical transfemoral approach, certain patients are more prone to access site complications (elderly patients, women, severely obese patients). These population is also the same in which the TRA is the most difficult to perform. For this reason, operators are advised to start their learning period with the easiest cases: a palpable radial artery in a young patient in a non-emergency setting. Though the radial artery is a small vessel, slightly less than 3 mm in diameter, it is large enough to accommodate devices for simple and complex angioplasties such as bifurcations with kissing balloons, rotablator procedures and saphenous venous graft angioplasty with distal protection devices. A negative Allen test used to be considered an absolute contraindication to the TRA. In fact, assessment of the palmar arches using pulse oxymetry examination is now recommended. It is more sensible and less frequently negative. However, given the low risk of radial occlusion and the extremely low morbidity rate, the patency of the palmar arch is less frequently tested in "radial" centres. The TRA is already the gold standard approach in some countries in Europe. It requires specific practice in order to avoid a number of pitfalls such as spasm, which can be almost completely avoided by a good prevention, anatomic difficulties, which can be easily solved by a good knowledge of anatomic variations. PMID- 21275294 TI - Anatomical considerations in transradial intervention. AB - The radial artery is currently regarded as a useful vascular access site for coronary procedures. The transradial approach for percutaneous coronary procedures has the advantage of reduced access site complications but is associated with specific technical challenges in comparison with the transfemoral approach. Transradial procedure failures can sometimes be due to failure to puncture the artery, radial artery spasm and anatomic variations of radial brachial-axillary-subclavian artery axis or arch of aorta. Therefore, adequate anatomical information of the radial artery should be helpful in performing the transradial coronary procedure. In short proper patient selection and pre procedure preparation; gentle and patient approach; liberal use of dye injection (check shoots) when in doubt; asking patient to breathe deeply when needed and thoughtful problem solving approach are the key factors to achieve high transradial success rate. PMID- 21275295 TI - Transradial percutaneous coronary interventions: technique, materials & procedure in the light of anatomical and technical considerations. AB - Transradial access is associated with enhanced patients' comfort, significant lower complication rates in diagnostic coronary angiography and better immediate and long-term outcomes after transradial percutaneous coronary interventions. Access failure has been reported to occur in less than 3-7% of cases due to anatomical circumstances (e.g., anomalous radial branching patterns, tortuosity e.g. radial loops, and small radial artery diameters). Radial coronary angiography and angioplasty entail a secondary learning curve of at least 150 cases in order to become familiar and comfortable with this technique. In contrast to previous established techniques (e.g. Sones-arteriotomy), the patient should be positioned in a comfortable supine position with his right arm next to his hip and the interventionist next to the right side of the patient. 19 gauge needles and 0.018 inch wires enhance the chance of successful cannulation the radial artery. A spasmolytic cocktail (3 mg Dinitrate, 3 mg verapamil, at least 3.000 U Heparine) should always be given intraarterially. Longer sheaths (> 13 cm) are not necessary. Essential for easy passage of the vertebralian artery and the common brachio-cephalic trunc (as the most dangerous part of the procedure) in order to reach the ascending aorta, the patient should be asked for a deep inspiration and/or dorsoflexion of his head An Amplatz-II catheter can be used for LCA, RCA and in some cases for LV-angiogram. The sheath should always be removed immediately and hemostasis achieved by radial compression (e.g. clamp). There is a close relationship between access failure respective radial spasm or occlusions and anatomical circumstances (i.e., hypoplastic radial artery, radioulnar loop, or small radial diameters: radial diameter-to-catheter ration < 1.0; assessment by Duplex). Although the radial access can be used in the majority of patients, the use is limited in patients with very small radial diameters and/or with complex lesions (e.g kissing balloon, etc). PMID- 21275296 TI - Transradial percutaneous coronary interventions: indications, success rates & clinical outcome. AB - Before ten years, radial artery was discovered as a useful vascular access site for percutaneous coronary procedures. It has the advantage of reduced access site complications but is associated with specific technical challenges in comparison with the transfemoral approach. Although earlier data from a meta-analysis indicated higher procedure failure rates with radial--as compared to femoral access (7.2 vs. 2.4%), more recent data from prospective multicenter studies and large meta analysis showed significantly better outcomes with radial access versus femoral access in contemporary, real-world clinical settings of percutaneous cardiovascular procedures (e.g. PREVAIL-, PRESTO-ACS-studies). This includes also challenging coronary procedures in acute coronary syndromes (NSTEMI and STEMI) where the radial access was associated with fewer bleeding complications leading to better long-term outcomes. Transradial procedure failures can sometimes be due to variation in radial artery anatomy (e.g. vessel diameter, anomalous branching patterns, tortuosity) or risk factors for radial spasms (e.g. smoking, anxiety, vessel diameter, age, gender). Postprocedural radial occlusions (0.6-1.2%) seems strongly be related to these anatomical variances, which possibly may be reduced by the use of smaller catheter, however 5 French lumen diameter guiding catheter include limitations regarding treating options in complex coronary lesion. In conclusion, the transradial access for coronary angiography and interventions is not only to enhance patients comfort, but shows significant better long-term results due to less bleeding complications as compared to the femoral access. PMID- 21275297 TI - Brewing the right cocktail for radial intervention. AB - Radial access angioplasty has increased in popularity worldwide due to its decrease of access site complications, early patient mobility, patient comfort and lower costs. In a minority of patients, radial artery occlusion and radial artery spasm occurs. Because of the dual blood supply to the hand, radial artery occlusion is not associated with major clinical sequelae but prevention is important. Radial artery spasm rarely leads to serious vascular complications but can cause patient discomfort and can result in prolonging or failure of the procedure. Pharmacological and non-pharmacological strategies have been evaluated to prevent radial artery occlusion and radial artery spasm. A number of pharmacological 'cocktails' have been successfully tested but there is currently no agreement on the optimal combination of agents. In order to evaluate the best strategy to prevent radial artery occlusion and radial artery spasm we reviewed the relevant studies to date. From these studies it is clear that a 'cocktail' of agents should be given before transradial coronary angiography or angioplasty. A combination of heparin, nitroglycerin and verapamil is associated with the best preventive outcome. PMID- 21275298 TI - Radial artery: how many times? AB - BACKGROUND AND PURPOSE: Transradial approach for diagnostic and interventional procedures is becoming common practice. It has not been well determined how many times the same radial artery can be cannulated without complications. Aim of the study was to evaluate safety, feasibility and efficacy of repeat transradial procedures. METHODS: From May 1998 to March 2009 we studied 4818 consecutive patients (75.44% male; age 64.02 +/- 11.6 Years) via radial artery by a single experienced operator. RESULTS: A repeat transradial procedure through the same radial artery was performed in 670 patients: twice in 514 cases, three times in 119, four times in 25 patients, five times in 7 patients, six times in 3 patients and seven times in one patient. Repeat PCI was performed in 412 patients. 6F catheters were used in 98.11%. There was no significant difference in radial puncture success rate and vascular access time: puncture success rate was 99.23% in the initial procedure and 98.11% (5 puncture failure) in repeated transradial artery procedures, and vascular access time was 1.5 +/- 2.1 min at the initial procedure and 2.2 +/- 3.1 min at repeat (p = ns). CONCLUSIONS: Failure of repeat puncture may be due to thickening of the tunica intima resulting from sheath insertion injuries or because of periarterial fibrosis at the prior radial puncture site. We believe that repeated use of the same radial artery is effective in considering its high procedural success and low complication rates in majority of patients in the hands of experienced operators. PMID- 21275299 TI - How to prevent & to manage radial artery spasm during coronary interventions? PMID- 21275300 TI - Transradial vs femoral percutaneous coronary intervention for left main disease in octogenarians. AB - BACKGROUND: Little data is available on the immediate and late results of transradial percutaneous coronary intervention (PCI) compared to standard femoral approach in high-risk patients. Our objective was to compare our experience in > 80 years old patients undergoing left main PCI with transradial and femoral approach. METHODS: This was a retrospective analysis of octogenarians patients treated for left main PCI in our center. In-hospital and late results were assessed RESULTS: From 2002 to 2008, one hundred and three octogenarians underwent PCI for left main disease. Ninety (87%) patients were treated by transradial approach and 13 (13%) by femoral approach. Patients were older in the radial group (85 +/- 3 years vs 82 + 3 years, p = 0.0067). All patients were pretreated with aspirin and clopidogrel. Patients received heparin-only in 90% of transradial cases and 85% of femoral cases (p = 0.63), bivalirudin in 0% vs 15% (p = 0.63) and platelets glycoprotein IIb/IIIa inhibitors in 33% vs 23% (p = 0.54), respectively. Patients received 3 +/- 2 stents in both groups with no difference in the rate of drug eluting stents (44% vs 69%, p = 0.14). Angiographic success was obtained in 98% vs 92% (p = 0.34) respectively with similar fluoroscopic time, procedure duration and contrast volume. Procedures were performed in 5-6Fr in 93% of transradial cases and 85% of femoral cases (p = 0.14). At 30 days, deaths (6% vs 15%, p = 0.21), myocardial infarction (12% vs 15%, p = 0.67) and revascularization (1% vs 0%, p = 1.00) were similar in transradial and femoral cases, respectively. Bleeding requiring transfusion occurred in 14% of radial cases compared to 23% in femoral cases (p = 0.42). Access site complications, mostly hematoma occurred less frequently after transradial than femoral approach (6% vs 31%, p = 0.014). At follow-up, cardiac death (17% vs 150%, p = 1.00), MI (23% vs 23%, p = 1.00) and revascularization (11% vs 0%, p = 0.35) remained similar in both groups. CONCLUSIONS: The majority of octogenarians with left main disease can be treated by transradial approach with similar acute and long-term results as with femoral approach but with less risk of bleeding and access site complications. PMID- 21275301 TI - How to manage difficult anatomic conditions affecting transradial approach coronary procedures? AB - The adoption of transradial approach for percutaneous coronary diagnostic and interventional procedures is known to reduce access-site complications. However, anatomic variants of brachial-radial axis, axillary-subclavian-anonymous axis and aortic arch may obstacle successful completion of transradial procedures. In the present paper, we discuss how to diagnose and manage the possible obstacles occurring at the different steps of transradial diagnostic and interventional procedures. PMID- 21275302 TI - Radial approach to right heart catheterization and intervention. AB - Transradial cardiac procedures have many advantages over the femoral approach, but forgotten is a similarly eloquent approach to venous access. Central venous access can actually be easily obtained using the forearm veins without risking the femoral or neck approaches. Whether it is needed for right heart hemodynamic monitoring or diagnosis with a cardiac catheter, as a site for temporary pacing during periods of iatrogenic bradycardia from interventional techniques, or as a sit for a transvencus interventional procedure, forearm venous access can provide a reliable and safe entry site to compliment or complete the transradial procedure. Venous access from the forearm can be accomplished efficiently and without compromise by avoiding an otherwise riskier anatomical approach. Understanding venous techniques and recognizing this important adjunct to transradial interventions completes the operator's radial skills and further enhance the potential of transradial interventions. PMID- 21275303 TI - Transulnar approach: the rationale from the radialist's view. AB - BACKGROUND: Radial access, besides providing greater comfort to the patient and reduction of hospital costs, promotes unequivocal reduction of vascular complications, with possible prognosis implication. A series of cases has shown that when its use is not suitable, ulnar access presents itself as a viable and effective alternative. OBJECTIVE: To evaluate the safety and effectiveness of ulnar approach in the performance of coronary procedures after failed attempt in obtaining radial access. METHODS AND RESULTS: From May 2007 to February 2009, 115 patients underwent 122 coronary procedures via ulnar access and were included in a prospective registry. The average age was 61.3 +/- 11.1 years, 67 (58%) were female and 36 (31%) were diabetic. Procedure success was achieved in 116 (95%) cases. There were no cases of major bleeding, transfusions or vascular repair surgery among the complications. There were hematomas in 4.9% of the cases, though mostly superficial, light to moderate spasms in 4% and asymptomatic ulnar artery occlusion, with no evidence of ischemia in 1.6%. CONCLUSIONS: The ulnar artery is a feasible and effective alternative approach to perform coronary procedures. When radial access is not available, it presents a similar safety profile with virtually no occurrence of hemorrhagic complications. PMID- 21275304 TI - Safety and feasibility of selective angiography of left internal mammary artery grafts via right transradial approach. AB - BACKGROUND AND PURPOSE: Right transradial approach (TRA) for cardiovascular procedures is becoming common practice, but angiography and PCI of left mammary artery by-pass graft (LIMA) via the right radial artery is still technically challenging. Aim of the study was to evaluate the possibility to put a stable catheter in left mammary from right radial approach. METHODS: From June 2002 to March 2009, 246 consecutive patients (88% male; age 67.7 +/- 7.8 years) with previous CABG underwent LIMA graft angiography via right TRA by a single experienced operator. RESULTS: An adequate radial access was obtained in all patients. Selective angiography of LIMA was successfully performed in 218 patients (89.1%). In the remaining 28 (10.9%) the LIMA approach from right radial failed because of severe tortuosity of brachiocephalic trunk or severe calcified and tortuous left subclavian artery. 13 patients underwent PCI and stentingon mid distal native LAD trough LIMA using 6FIM4 guiding catheter. No periprocedural cerebro-vascular complications, no vascular injury at the LIMA takeoff as a result of selective canulation, no injury of the left subclavian artery were observed CONCLUSIONS: In patients with previous CABG, the presence of LIMA grafts is not a limitation to successfully perform diagnostic and interventional procedures via the right radial approach with experienced operators. PMID- 21275305 TI - Our technique for transradial coronary angiography and interventions. AB - The transradial approach for coronary angiography was introduced twenty years ago. Since then, considerable advancements have been made in this technique that proved to be effective in many interventional procedures and in several, even high-risk patient subsets (acute coronary syndromes, elderly, fully anticoagulated and obese patients). The main advantage of transradial approach over transfemoral approach is represented by the striking reduction in the rate of access-related vascular complications and bleedings. In recent years, bleeding prevention has become an issue of paramount importance, since recent large trials and registries clearly showed that bleedings are associated with major adverse events at follow up. Nevertheless, the prevalence of transradial approach for coronary procedures worldwide is still quite low and nowadays, in the United States, the favourite strategy for bleeding prevention is mostly based on the adoption of new antithrombotic drugs (such as bivalirudin and fondaparinux) rather than on the selection of an alternative, safer vascular access route. In this review we deal with several clinical and technical issues about transradial approach, including: 1) patient selection; 2) cath lab set-up, access technique and dedicated hardware; 3) reaching the coronary ostia: how to deal with anomalous anatomy; 4) selection and manipulation of catheters; 5) haemostasis and post-procedural issues. PMID- 21275306 TI - How to perform selective angiography and percutaneous coronary intervention through a left mammary artery from the right radial artery? PMID- 21275307 TI - Transradial interventions: our experience. AB - Traditional coronary angiography and angioplasty are usually performed via femoral approach. Though this route provides an easier vascular access, it is associated with a smaller but potentially serious incidence of vascular complications at the puncture site that may result in significant groin haematoma, blood transfusion or require surgical repair. A useful and safe alternative approach is through the transradial access. This route has a very low rate of vascular complications and also allows early mobilization of patients. Though this approach is less commonly used all over the world, recently the usage of this technique has improved. Currently we as a team of Heart Care Clinic are performing more than 90% of the procedure via transradial route. We have performed thousands of angiographies and angioplasties by this route in past several years. Here we performed an analysis of our experience with transradial angiography and angioplasty, demonstrating this to be a safe and effective technique suitable for most of the patients. PMID- 21275308 TI - Selection of hardware and cathlab preparation for transradial approach. AB - The percutaneous transradial approach for cardiac catheterization has been shown to be a safe alternative to femoral artery approach, owing to the favorable anatomical relation of the radial artery to surrounding structures and the dual blood supply to the hand. Selection of guide catheter is elementary but an issue of extreme importance in performance of percutaneous coronary interventions (PCI) and depends on the size of aorta, location of ostia on the aorta, the kind of back-up required and whether the artery arises from a normal origin or anomalously. Currently a variety of guiding catheters are available, each with a unique design and construction, which has vastly improved the technique of transradial PCI. However, much of the cause for procedural failure of the radial approach is associated with the need for higher technical skills and the difficulty in using femoral catheters in the smaller radial artery. There is a learning curve, and many interventionists are uncomfortable attempting a more technically challenging procedure. Nevertheless, it is a procedure that can be taught, and with the innovation of new catheters and devices made specifically for radial approach, it may become easier to adopt for interventionists with a sound knowledge of the anatomical considerations and skill on guiding catheters and hardwares. The current article provides a vivid insight on the various aspects of the learning curve for Transradial approach including proper patient selection, radial access assessment, troubleshooting arm vessel anomalies, guide catheter selection and engagement, augmentation of guide support, and adjunctive device selection. PMID- 21275309 TI - Angiotensin-converting enzyme inhibitors and beta-blockers in cardiac asymptomatic patients with Duchenne muscular dystrophy. AB - Duchenne muscular dystrophy (DMD) is an X-linkedrecessive disorder caused by the absence of dystrophin. Cardiac dysfunction is a classical complication in this disease. Most DMD patients remain asymptomatic for years in spite of the progression of cardiac dysfunction because of their limited daily activities. Angiotensin-converting enzyme inhibitors and beta-blockers may delay the onset and the progression of cardiac dysfunction and have to be recommended earlier in this disease. PMID- 21275310 TI - Pi--from the Greeks to the cardiologists: the pi sign- aberrant OM from LAD. PMID- 21275311 TI - Tips and tricks for radial interventions. PMID- 21275312 TI - The symphony of interdisciplinary care. PMID- 21275313 TI - Multidisciplinary treatment of a patient with craniofacial disorders. PMID- 21275314 TI - Computerized skeletal age assessment. PMID- 21275315 TI - Reverse Twin Block appliance for early dental Class III correction. PMID- 21275316 TI - Long-term results of permanent bonded retention. PMID- 21275317 TI - The bi-helix opening spring for lingual orthodontics. PMID- 21275318 TI - Low-friction space closure with a hybrid bracket-tube system. PMID- 21275319 TI - We've come a long way... and we're still moving forward. PMID- 21275320 TI - When cancer pain breaks through, what can you do? AB - Breakthrough pain in cancer patients can be very difficult to manage, primarily because of its heterogeneous and fleeting nature, so careful assessment is imperative to finding an adequate treatment regimen. Only a paucity of good research exists to support current interventions, and additional viable options need to be discovered. Oncology nurses must play an integral role in improving the treatment of breakthrough pain-one patient, one in-service for colleagues, and one clinical research study at a time. PMID- 21275321 TI - Thorough pain assessment: a nursing imperative. PMID- 21275322 TI - Facing forward: meeting the rehabilitation needs of cancer survivors. AB - Decreased physical functioning, either transient or enduring, is encountered by many individuals at various points in the cancer trajectory. Oncology nurses are well positioned to promote functional recovery, as they have intensive contact with cancer patients in multiple settings and throughout all phases of the disease continuum. This article reviews effective screening tools that nurses can use to identify the rehabilitation needs of individual patients and initiate appropriate interventions or referrals for additional rehabilitation services. It also outlines realistic rehabilitation protocols that can help oncology nurses to reduce and prevent impairments that may occur during cancer and its treatment. As will be discussed, patients' functional performance can also be directly improved by enhanced incorporation of rehabilitation principles into oncology nursing practice. PMID- 21275323 TI - Framing the challenges of cancer rehabilitation. PMID- 21275324 TI - Mindfulness meditation. PMID- 21275325 TI - Triple-negative breast cancer. PMID- 21275326 TI - Sexual function of the gynecologic cancer survivor. PMID- 21275327 TI - Cabazitaxel, a taxane for men with hormone-refractory metastatic prostate cancer. PMID- 21275328 TI - Pt. deteriorates-nurses fail to call dr.-death results. Doctors Hospital, Doctors Hospital, 1997, L.P.[sic] v. Hernandez, 01-10-00270-CV TXCA1 (10/21/2010)-TX. PMID- 21275329 TI - Defendant dr. files cross claim v. hospital & nurses. Case on point: Bulsara v. Watkins, 210 Ark. 453 (11/18/2010) -KY. PMID- 21275330 TI - NY: RN's report used to deny pay't for MRI: summary judgment for MRI provider granted. Rockaway Med. & Diagnostic, P.C v. Country-Wide Ins. Co., 2010-52012 (11/19/2010)-NY. PMID- 21275331 TI - Benefits awarded employee who resigned for 'unsafe worksite'. Case on point: Shelton v. Board of Review, A-4534-0831 (10/14/2010)-NJ. PMID- 21275332 TI - Music therapy as an adjunctive treatment in the management of stress for patients being weaned from mechanical ventilation. AB - This project investigated music therapy (MT) in managing anxiety associated with weaning from mechanical ventilation. The use of sedation to treat anxiety during weaning is problematic because side effects (e.g., respiratory depression) are precisely the symptoms that cause the weaning process to be interrupted and consequently prolonged. Study goals were to determine the feasibility of incorporating MT into the weaning process and to evaluate the efficacy of the intervention, based on levels of anxiety, Days to Wean (DTW), and patient/nurse satisfaction. Adult patients received multiple MT sessions per week while undergoing weaning trials from mechanical ventilation. Feasibility was determined by successful enrollment in the study and nurse survey. Efficacy was evaluated through anxiety, as measured by heart rate, respiratory rate, and patient/nurse survey; DTW; and patient/nurse satisfaction. Nurse surveys reported that MT was successfully incorporated into the milieu and 61 subjects were enrolled. Significant differences in heart rate and respiratory rate were found from the beginning to the end of MT sessions (p < .05 and p < .0001, respectively), indicating a more relaxed state. No significant difference in mean DTW was found between study and control subjects. Patient/nurse satisfaction was high. Music therapy can be used successfully to treat anxiety associated with weaning from mechanical ventilation. Limitations and suggestions for further research are discussed. PMID- 21275333 TI - The effect of music therapy on relaxation, anxiety, pain perception, and nausea in adult solid organ transplant patients. AB - Organ transplant recipients characteristically experience low levels of relaxation and high levels of anxiety, pain, and nausea. Although music therapy has demonstrated effectiveness in ameliorating these types of conditions with patients in other areas of medical hospitals, no studies have evaluated the effects of music therapy on solid organ transplant patients. The purpose of this study was to assess the impact of music therapy on anxiety, relaxation, pain, and nausea levels in recovering patients on the adult transplant unit of the hospital utilizing a pre-posttest design. Participants (N = 58) received an individual 15 35 minute music therapy session consisting of live patient-preferred music and therapeutic social interaction. To remain consistent with the hospital's evaluative instruments during this pilot study, participants' self-reported levels of anxiety, relaxation, pain, and nausea, were based on separate 10-point Likert-type scales. The principal investigator observed affect and verbalizations at pre and posttest. Results indicated there were significant improvements in self-reported levels of relaxation, anxiety (both p < .001), pain (p < .01), and nausea (p < .05). Although there was no reliability measure, there were significant increases in positive verbalizations and positive affect (p < .001). All participants reported that they would desire music therapy again during a future long-term hospital stay. From the results of this exploratory study, it seems that music therapy can be a viable psychosocial intervention for hospitalized postoperative solid transplant patients. Implications for clinical practice and suggestions for future research are provided. PMID- 21275334 TI - Music therapy CD creation for initial pediatric radiation therapy: a mixed methods analysis. AB - A mixed methods research design was used to investigate the effects of a music therapy CD (MTCD) creation intervention on pediatric oncology patients' distress and coping during their first radiation therapy treatment. The music therapy method involved children creating a music CD using interactive computer-based music software, which was "remixed" by the music therapist-researcher to extend the musical material. Eleven pediatric radiation therapy outpatients aged 6 to 13 years were randomly assigned to either an experimental group, in which they could create a music CD prior to their initial treatment to listen to during radiation therapy, or to a standard care group. Quantitative and qualitative analyses generated multiple perceptions from the pediatric patients, parents, radiation therapy staff, and music therapist-researcher. Ratings of distress during initial radiation therapy treatment were low for all children. The comparison between the two groups found that 67% of the children in the standard care group used social withdrawal as a coping strategy, compared to 0% of the children in the music therapy group; this trend approached significance (p = 0.076). MTCD creation was a fun, engaging, and developmentally appropriate intervention for pediatric patients, which offered a positive experience and aided their use of effective coping strategies to meet the demands of their initial radiation therapy treatment. PMID- 21275335 TI - Contributions of music to aging adults' quality of life. AB - The purpose of this study was: (a) To evaluate and to compare the impact of three music programs (choir, music appreciation and preventive music therapy sessions) on the quality of life of healthy older adults, and (b) to identify the motivations and the difficulties that seniors encounter when participating in activities of this type, in order to come up with recommendations and strategies for the design of appropriate programs for older adults. A pre-posttest quasi experimental design without equivalent control group was used in this project. The sample included 83 persons over 65 years of age. The data collection was carried out through an ad hoc questionnaire that included the four aspects of the construct of quality of life (physical health, subjective health, psychological well-being and interpersonal relations), a questionnaire on motivation and another on satisfaction about the program. This questionnaire on quality of life was administered twice: at the beginning of the programs (pretest) and at the end (posttest). The results of this study indicate that the participants perceived improvements in some aspects of their quality of life. In addition, the main reasons which motivate participation in these musical activities are to broaden the social network and to acquire new knowledge. The results are discussed in the light of the challenges of active and satisfactory aging. PMID- 21275336 TI - Effects of the therapist's nonverbal behavior on participation and affect of individuals with Alzheimer's disease during group music therapy sessions. AB - In healthcare settings, medical professionals' nonverbal behavior impacts patients' satisfaction and long-term physical, cognitive, and emotional well being. The purpose of this research was to determine the effects of a music therapist's nonverbal behavior, affect and proximity, on participation and affect of 38 individuals with Alzheimer's disease and other related dementia (ADRD) during movement-to-music, singing, and instrument playing. Data indicated 62% of the individuals evinced positive affect when the therapist utilized affect and proximity combined, followed by the affect only condition (53%), proximity only condition (30%), and no affect or proximity condition (28%). A Friedman analysis indicated a significant difference in individuals' affect according to treatment conditions, chi(r)2 (3, 4) = 34.05, p = .001. Nonverbal behavior also impacted individuals' accuracy of participation, with participation at 79% for both affect and proximity combined, 75% for affect only, 71% for no affect or proximity, and 70% for proximity only. A significant difference occurred for participation by treatment conditions, F (3, 111) = 4.05, p = .009, eta2 = .10. Clinical implications are discussed. PMID- 21275337 TI - Microarrays for personalized genomic medicine. AB - The combination of single nucleotide polymorphisms (SNPs) database and high density SNP array allows the use of SNPs as informative polymorphic markers for Mendelian diseases with complex traits efficiently. With the high-density and high-resolution SNP arrays, we can detect even the smallest structural changes that would have been missed with conventional low-density cytogenetic techniques for prognostic and diagnostic utilities. Accurate mapping may be useful for genotype-phenotype correlation in individual basis and for prenatal investigations. Here, we review some applications of genome-wide SNP genotyping on detecting homozygous candidate region in consanguineous family priors to mutation analysis. In addition to personalized genomic medicine, studying the genetic heterogeneity in diverse ancestral population helps to implementing effective clinical management. PMID- 21275338 TI - Molecular staging estimates occult tumor burden in colorectal cancer. AB - Tumor cells in regional lymph nodes are a key prognostic marker of survival and predictive marker of response to adjuvant chemotherapy in colorectal cancer. However, clinicopathologic techniques to detect lymph node metastases remain imperfect, and approximately 30% of patients with lymph nodes negative by histology (pN0) develop recurrent disease, reflecting occult metastases that escape detection. These observations underscore an unmet clinical need for accurate approaches to identify occult nodal metastases in colorectal cancer patients. GUCY2C is a receptor whose expression normally is restricted to intestinal epithelial cells, but is universally overexpressed by colorectal cancer cells. A prospective, multicenter, blinded clinical trial established the prognostic utility of GUCY2C qRT-PCR to detect occult nodal metastases in pN0 colorectal cancer patients. Molecular staging revealed that approximately 13% of pN0 patients were free of cancer cells, while approximately 87% had GUCY2C results that suggested occult metastases. The presence of occult nodal metastases was the most powerful independent predictor of time to recurrence and disease free survival. These observations establish the utility of molecular detection of occult nodal metastases for assessing prognostic risk in pN0 colorectal cancer patients. Advancing GUCY2C into staging paradigms in clinical laboratories will require validation in independent patient populations, definition of the relationship between the quantity of occult tumor metastases and risk, and determination of the utility of GUCY2C qRT-PCR to identify pN0 patients who might benefit from adjuvant chemotherapy. PMID- 21275339 TI - Cardiotrophin-1 in cardiovascular regulation. AB - Cardiotrophin (CT)-1 was discovered by coupling expression cloning with an embryonic stem cell-based model of cardiogenesis. Comparison of similarity in amino acid sequence and conformational structure indicates that CT-1 is a member of the interleukin (IL)-6 type cytokine family that shares the transmembrane signaling protein, glycoprotein (gp) 130 as a receptor. These cytokines mediate overlapping pleiotropic actions on a variety of cell types including cardiac myocytes, hepatocytes, megakaryocytes, osteoclasts, and neuronal cells. CT lmediates its hypertrophic and cytoprotective properties through the Janus kinase/signal transducers and activators of transcription (JAK/STAT), mitogen activated protein (MAP) kinase, phosphatidylinositol (PI) 3 kinase, and nuclear factor kappa B (NFkappaB) pathways. CT-1 gene and protein are distributed not only in the heart, but also in the pulmonary, renal, gastrointestinal, cerebral, and muscular tissues. CT-1 could also be synthesized and secreted from vascular endothelial cells and adipocytes. CT-1 has hypertrophic actions on the cardiac myocytes, skeletal muscle cells, and smooth muscle cells as well as cytoprotective actions on the cardiac myocytes, neuronal cells, and hepatocytes. CT-1 is circulating in the body, and its plasma concentration is increased in various cardiovascular and renal diseases such as hypertension, congestive heart failure, myocardial infarction, valvular heart disease, metabolic syndrome, and chronic kidney disease. Treatment with CT-1 is beneficial in experimental animal models of cardiovascular diseases. CT-1 specifically protects the cardiac myocytes from ischemic damage when CT-1 is given not only prior to the ischemia, but also given at the time of reoxygenation. Current evidence suggests that CT-1 plays an important role in the regulation of the cardiovascular system. PMID- 21275340 TI - Metabolic rate depression: the biochemistry of mammalian hibernation. AB - During winter hibernation, small mammals fall into long periods of deep cold torpor where metabolic rate is suppressed by > 90% and core body temperature can fall to near 0 degrees C. Studies with hibernators illustrate the molecular regulatory mechanisms that coordinate the suppression of metabolic functions during torpor, reprioritize energy use, and preserve/stabilize macromolecules to support long-term viability during cold torpor. This review explores mechanisms including posttranslational modification of proteins, differential regulation of enzymes, global suppression of transcription and translation including a role for microRNA, torpor-responsive gene expression, signal transduction, and regulation of transcription factors. The molecular basis of natural torpor in hibernating mammals offers models and applications that are relevant to issues in clinical science including hypothermia and ischemia resistance, inducible torpor, organ preservation, and atrophy resistance. PMID- 21275341 TI - Endothelial cell biology: role in the inflammatory response. AB - Human endothelial cells are multifunctional cells that line blood vessels and are capable of secreting a variety of biologically active mediators. They normally maintain vascular hemostasis and prevent thrombotic complications. When affected by infection, stress, hypertension, dyslipidemia, or high homocysteine levels, endothelial cells undergo changes resulting in "dysfunction," characterized typically by decreased endothelial expression of nitric oxide, enhanced expression of cell adhesion molecules, and associated increased binding of circulating leukocytes to these cells. There is accompanying cytokine and chemokine elaboration, resulting in cellular recruitment and the orchestration of an acute inflammatory response that can culminate in chronic inflammation if reparative mechanisms are not operative. This review will address the basic biology of endothelial cells; the expression and regulation of endothelial derived cytokines, chemokines, and growth factors; the transcriptional regulation of these genes in endothelial cells; and the role played by these fascinating cells in human disease. PMID- 21275342 TI - Pathogenesis, laboratory, and clinical characteristics of Helicobacter pylori associated immune thrombocytopenic purpura. AB - Idiopathic thrombocytopenic purpura (ITP) is a common autoimmune disease mediated by autoantibodies against platelet glycoproteins. This hemorrhagic disorder may be primary or secondary to various illnesses, including lymphoproliferative, autoimmune, or infectious diseases. Among the latter causes, there is increasing laboratory and clinical evidence that documents a pathogenic role of Helicobacter pylori infection in ITP. The aim of this review is to analyze the current knowledge on the pathogenic, diagnostic, clinical, and therapeutic characteristics of H. pylori-associated ITP. PMID- 21275343 TI - Methylation of DNA in cancer. AB - Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Global changes in the epigenetic landscape are a hallmark of cancer. Methylation of cytosine bases in DNA provides a layer of epigenetic control in many eukaryotes that has important implications for normal biology and disease. DNA methylation is a crucial epigenetic modification of the genome that is involved in regulating many cellular processes. These include embryonic development, transcription, chromatin structure, X-chromosome inactivation, genomic imprinting, and chromosome stability. Consistent with these important roles, a growing number of human diseases including cancer have been found to be associated with aberrant DNA methylation. Recent advancements in the rapidly evolving field of cancer epigenetics have described extensive reprogramming of every component of the epigenetic machinery in cancer, such as DNA demethylation. Hypomethylation of the genome largely affects the intergenic and intronic regions of the DNA, particularly repeat sequences and transposable elements, and it is believed to result in chromosomal instability and increased mutation events. Therefore, we propose that R/G-chromosome band boundaries, which correspond with the early/late-switch regions of replication timing and a transition in relative GC content, correspond to "unstable" genomic regions in which concentrated occurrences of repetitive sequences and transposable elements including LINE and Alu elements are hypomethylated during tumorigenesis. In this review, we discuss the current understanding of alterations in DNA methylation composing the epigenetic landscape that occurs in cancer compared with normal cells, the roles of these changes in cancer initiation and progression, and the potential use of this knowledge in designing more effective treatment strategies. PMID- 21275345 TI - Indiana AG sues WellPoint for breach. PMID- 21275344 TI - MGMA: keep stage 2 MU criteria workable. PMID- 21275346 TI - It's showtime for meaningful use. PMID- 21275347 TI - The long shadow of meaningful use. PMID- 21275348 TI - Game changers pushing EHRs forward. PMID- 21275349 TI - Moving target. New mobile devices offer opportunities and headaches for health care CIOs. PMID- 21275350 TI - Convergence factor. Disney facility consolidates I.T. to focus on boosting its patient-friendly atmosphere. PMID- 21275351 TI - Managing meds. PMID- 21275352 TI - Military Medical Academia--the strategic intent. PMID- 21275353 TI - Cold steel and warm hearts: the professional ethics and strategic planning of expeditionary warfare. PMID- 21275354 TI - The management of pancreatic trauma. AB - Pancreatic trauma is an uncommon occurrence and so a consensus about optimal management is not readily available. Isolated pancreatic injury occurs only occasionally, as in the majority of cases there is concurrent visceral or vascular injury. Morbidity and mortality are related to delay in diagnosis, concurrent organ injury or the presence and extent of pancreatic duct injury. PMID- 21275355 TI - Managing pain on the battlefield: an introduction to continuous peripheral nerve blocks. AB - OBJECTIVE: To determine the strength of evidence supporting the battlefield use of Continual Peripheral Nerve Blocks (CPNBs). METHODS: Publication review identifying 380 potentially relevant papers. RESULTS: CPNBs have been well trialled and are used routinely in civilian hospitals. The procedure is not without acute and chronic complications related to agents used, catheters themselves and infection risks. These techniques are being used increasingly in military field hospitals to manage pain, however research concerning their use on the battlefield is limited and further trials are required to confidently conclude efficacy. CONCLUSION: CPNBs are just one component within military medicine of a rapidly evolving polymodal system of pain management. Common combat wounds, namely traumatic amputations, are compatible with this technique, however current evidence concerning their battlefield use is limited. Extensive UK military trials are ongoing and the results of which are expected to clarify questions regarding complication rate and efficacy. PMID- 21275356 TI - The effectiveness of an informal teaching programme for junior doctors identifying pleural effusions using ultrasound at the bedside. AB - OBJECTIVES: The use of bedside ultrasound to localise pleural effusions has gained in popularity in recent years. We investigated whether or not junior doctors could accurately identify thoracic anatomical structures and localise pleural effusions using bedside ultrasound. METHODS: Junior doctors were instructed by a consultant chest physician in the theory and practice of using ultrasound to localise pleural effusions, and then instructed in the method of inserting a Seldinger chest drain. Juniors were instructed to record a scan picture, including labelling of relevant structures. We then conducted a review of 52 images, noting indications, complications and the grade of doctor performing the scan. A consultant radiologist reviewed the scan pictures to confirm that the anatomy was correctly identified. RESULTS: Fifty out of 52 images (96%) were of diagnostic quality, with the anatomy correctly identified. The complication rate from chest drain insertion was 3.85%. CONCLUSIONS: With instruction, junior doctors can competently utilise basic chest ultrasound, obtain useful images, identify relevant thoracic anatomy and insert chest drains by the Seldinger technique with a low rate of complications. We suggest thoracic ultrasound should be more widely taught to junior doctors. PMID- 21275357 TI - The additional value of a pneumatic leg brace in the treatment of recruits with medial tibial stress syndrome; a randomized study. AB - OBJECTIVE: To study the additional effect of a pneumatic leg brace with standard rehabilitation for the treatment of medial tibial stress syndrome (MTSS) in recruits. METHODS: In a single blinded randomized study, 15 recruits (age 17-22) followed a rehabilitation programme consisting of leg exercises and a graded running programme. Recruits performed daily exercises and ran three times a week. The running programme consisted of 6 consecutive phases. One group was, after randomization, additionally provided with a pneumatic leg brace. Follow-up was provided every other week. Days to completing the running programme was the primary outcome measure, the Sports Activity Rating Scale (SARS) score and satisfaction with the treatment were secondary outcome measures. RESULTS: In total 14 recruits completed the rehabilitation programme. No differences were found in the number of days until phase six of the running schedule was finished between the brace and the control group (Brace 58.8 +/- 27.7 (mean +/- SD) vs Non Brace 57.9 +/- 26.2 (mean +/- SD, p = 0.57). Also no differences were found in the SARS scores between the groups. Overall satisfaction with the treatment was 6.4 +/- 1.1 (mean +/- SD) on a 1-10 scale for the brace group and 7.1 +/- 0.7 (mean +/- SD) for the control group (p = 0.06). Comfort of the brace was assessed as 4.8 +/- 1.3 (mean +/- SD) on a 1-10 scale. CONCLUSIONS: No additional large effect of the pneumatic leg brace could be found in recruits and wearing of the brace was not feasible, since the wearing comfort was low. PMID- 21275358 TI - Compartment syndrome of the foot--implications for military surgeons. AB - INTRODUCTION: Compartment syndrome of the foot is a rare complication of injury to the foot. Treatment by decompression of the compartments is debatable. The debate surrounding decompression stems from the rarity of the condition, the lack of consensus regarding the anatomy of the foot compartments and whether to accept the inevitable contractures by not decompressing. The aim of this paper is two fold; firstly to sample current military orthopaedic experience and secondly establish if there exists a consensus of opinion in how and if to perform fasciotomy of the foot thereby providing guidance to other clinicians. METHOD: A questionnaire was sent to 10 DMS orthopaedic consultants to identify their experience with foot compartment syndrome and performing foot fasciotomies. RESULTS: Five had performed a foot fasciotomy (average 2, range 1-6) over an average of 6.2 years as consultant and an average of 7.3 months deployed. Most commonly two dorsal and a medial incision were used to decompress the foot. One surgeon advocated not decompressing the foot and accepting the subsequent contractures, CONCLUSION: DMS clinicians need to remain vigilant to compartment syndrome of the foot and especially in cases of crush or blast injury or of multiple fractures. If diagnosed or even if an impending compartment syndrome is suspected then, in line with the current weight of expert opinion, the foot should be decompressed and the deployed orthopaedic surgeon should be capable of performing it. Evidence concerning their battlefield use is limited. Extensive UK military trials are ongoing and the results of which are expected to clarify questions regarding complication rate and efficacy. PMID- 21275359 TI - Furosemide in the treatment of phosgene induced acute lung injury. AB - METHOD: Using previously validated methods, 16 anaesthetised large white pigs were exposed to phosgene (target inhaled dose 0.3 mg kg(-1)), established on mechanical ventilation and randomised to treatment with either nebulised furosemide (4 ml of 10 mg x ml(-1) solution) or saline control. Treatments were given at 1, 3, 5, 7, 9, 12, 16 and 20 hours post phosgene exposure; the animals were monitored to 24 hours following phosgene exposure. RESULTS: Furosemide treatment had no effect on survival, and had a deleterious effect on PaO2: FiO2 ratio between 19 and 24 hours. All other measures investigated were unaffected by treatment. CONCLUSION: Nebulised furosemide treatment following phosgene induced acute lung injury does not improve survival and worsens PaO2: FiO2 ratio. Nebulised furosemide should be avoided following phosgene exposure. PMID- 21275360 TI - Noroviruses: a challenge for military forces. AB - For military forces, the control of infectious acute gastroenteritis constitutes an old, constant and unsolved concern. Recent epidemiological studies suggest that the common bacterial causes are being overtaken by viruses. Norviruses are the most alarming group and norovirus outbreaks in military forces are regularly reported. Illness is generally mild and characterised by acute vomiting and diarrhoea, which lasts for a few days on average, but may be severe and potentially life-threatening in subjects who are already dehydrated due to daily activity. Moreover, outbreaks may diminish operational effectiveness. Prevention of norovirus infection currently relies on strict application of personal and collective hygiene rules including isolation of the cases, to the greatest possible extent. Although noroviruses are frequently mentioned as the cause of gastroenteritis outbreaks in troops deployed overseas, laboratory diagnosis is rarely done. So their real burden in military forces remains unclear and further epidemiological studies are required to determine the full impact of norovirus gastroenteritis on troops. PMID- 21275361 TI - Acute spinal epidural haematoma causing cord compression after chiropractic neck manipulation: an under-recognised serious hazard? AB - Spinal manipulative therapy performed by chiropractors is increasingly common in the United Kingdom. Spinal epidural haematoma is a rare complication of such physical therapy but when identified represents a neurological emergency. We describe the case of a 64 year-old man who presented with a dense hemiplegia due to a spinal epidural haematoma following cervical spine manipulation performed for acute neck pain. The clinical features and surgical management of the case are discussed and we stress the importance of recognition of chiropractic manipulation as a potential cause of neurological sequelae and discuss the potential pitfalls of such therapy as it becomes more widespread. PMID- 21275362 TI - Swimming-induced pulmonary oedema--a hazard in intensive military training? AB - Swimming-Induced Pulmonary Oedema (SIPE) has been described in military combat swimmers in both the US and Israeli Navies. The pathophysiology is explained by the immersion in cold water, and its effects on central vascular volume. SIPE has been hypothesized to be caused by pulmonary capillary stress failure (PCSF) due to elevations in pulmonary capillary transmural pressure. This leads to mechanical impairment and leakage of blood cells and proteins from capillaries. Patients with SIPE can present with pronounced dyspnoea, cough, hypoxemia and profuse frothy haemoptysis. Physical examination and chest X-rays usually show evidence of pulmonary oedema. The treatment of choice is to recognize the symptoms, get the patient out of the water and follow with close observation for emergent problems. Soldiers prone to acquire SIPE should be identified as this medical condition has a high degree of recurrence. The awareness of the symptoms of SIPE will increase appropriate diagnosis and therefore inform treatment. PMID- 21275363 TI - The Indian mutiny--Part 3. PMID- 21275364 TI - The challenges of military medical decision making. PMID- 21275365 TI - Liked it or loathed it, we all served: the conscript doctors. PMID- 21275366 TI - A national service psychiatrist's story. PMID- 21275367 TI - Development and evaluation of endothelin-A receptor (radio)ligands for positron emission tomography. AB - The expression and function of endothelin (ET) receptors are abnormal in cardiovascular diseases, tumor progression, and tumor metastasis. A previously reported promising radioligand for positron emission tomography (PET) based on the non-peptide ET(A) receptor antagonist PD 156707 showed specific binding to target receptors in the myocardium but high accumulation in bile and intestine, probably because of its high lipophilicity. In this study we describe the synthesis of a series of fluorinated derivatives with hydrophilic building blocks. All compounds were evaluated as high affinity ET(A) receptor ligands (16, 17, 23-26, K(i) = 1.4-7.9 nM) with high subtype selectivity over the ET(B) receptor. [(18)F]3-Benzo[1,3]dioxol-5-yl-4-{3-[1-(2-{2-[2-(2 fluoroethoxy)ethoxy]ethoxy}ethyl)-1H-[1,2,3]triazol-4-ylmethoxy]-4,5 dimethoxybenzyl}-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one ([(18)F]17) was synthesized as one of the radioligands of this series that possesses a higher hydrophilicity and an excellent stability in human serum. Improved clearance properties and specific uptake in target organs have been confirmed by biodistribution studies and small animal PET imaging. PMID- 21275368 TI - Reaction of the molybdenum- and copper-containing carbon monoxide dehydrogenase from Oligotropha carboxydovorans with quinones. AB - Carbon monoxide dehydrogenase (CODH) from Oligotropha carboxydovorans catalyzes the oxidation of carbon monoxide to carbon dioxide, providing the organism both a carbon source and energy for growth. In the oxidative half of the catalytic cycle, electrons gained from CO are ultimately passed to the electron transport chain of the Gram-negative organism, but the proximal acceptor of reducing equivalents from the enzyme has not been established. Here we investigate the reaction of the reduced enzyme with various quinones and find them to be catalytically competent. Benzoquinone has a k(ox) of 125.1 s(-1) and a K(d) of 48 MUM. Ubiquinone-1 has a k(ox)/K(d) value of 2.88 * 10(5) M(-1) s(-1). 1,4 Naphthoquinone has a k(ox) of 38 s(-1) and a K(d) of 140 MUM. 1,2-Naphthoquinone 4-sulfonic acid has a k(ox)/K(d) of 1.31 * 10(5) M(-1) s(-1). An extensive effort to identify a cytochrome that could be reduced by CO/CODH was unsuccessful. Steady-state studies with benzoquinone indicate that the rate-limiting step is in the reductive half of the reaction (that is, the reaction of oxidized enzyme with CO). On the basis of the inhibition of CODH by diphenyliodonium chloride, we conclude that quinone substrates interact with CODH at the enzyme's flavin site. Our results strongly suggest that CODH donates reducing equivalents directly to the quinone pool without using a cytochrome as an intermediary. PMID- 21275369 TI - Sequence-specific B-DNA flexibility modulates Z-DNA formation. AB - Conversion of right-handed B-DNA into left-handed Z-DNA is one of the largest structural transitions in biology that plays fundamental roles in gene expression and regulation. Z-DNA segments must form within genomes surrounded by a sea of B DNA and require creation of energetically costly B/Z junctions. Here, we show using a combination of natural abundance NMR R(1rho) carbon relaxation measurements and CD spectroscopy that sequence-specific B-DNA flexibility modulates the thermodynamic propensity to form Z-DNA and the location of B/Z junctions. We observe sequence-specific flexibility in B-DNA spanning fast (ps ns) and slow (MUs-ms) time scales localized at the site of B/Z junction formation. Further, our studies show that CG-repeats play an active role tuning this intrinsic B-DNA flexibility. Taken together, our results suggest that sequence-specific B-DNA flexibility may provide a mechanism for defining the length and location of Z-DNA in genomes. PMID- 21275370 TI - Gated channels in a honeycomb-like zinc-dicarboxylate-bipyridine framework with flexible alkyl ether side chains. AB - Covalent functionalization of 1,4-benzenedicarboxylate (bdc) with methoxyethoxy groups induces conformational freedom in this molecule. Applying these 2,5 disubstituted bdc derivatives in metal-organic framework synthesis together with 4,4'-bipyridine as coligand yields novel honeycomb-like structures. The cylindrical channels of these materials are populated with flexible groups, which act as molecular gates for guest molecules. This allows highly selective sorption of CO(2) over N(2) and CH(4). PMID- 21275371 TI - Arsenic--an old story with big stakes. PMID- 21275372 TI - To the nth degree. PMID- 21275373 TI - A comparative analysis of odour treatment technologies in wastewater treatment plants. AB - Biofiltration, activated sludge diffusion, biotrickling filtration, chemical scrubbing, activated carbon adsorption, regenerative incineration, and a hybrid technology (biotrickling filtration coupled with carbon adsorption) are comparatively evaluated in terms of environmental performance, process economics, and social impact by using the IChemE Sustainability Metrics in the context of odor treatment from wastewater treatment plants (WWTP). This comparative analysis showed that physical/chemical technologies presented higher environmental impacts than their biological counterparts in terms of energy, material and reagents consumption, and hazardous-waste production. Among biological techniques, the main impact was caused by the high water consumption to maintain biological activity (although the use of secondary effluent water can reduce both this environmental impact and operating costs), biofiltration additionally exhibiting high land and material requirements. From a process economics viewpoint, technologies with the highest investments presented the lowest operating costs (biofiltration and biotrickling filtration), which suggested that the Net Present Value should be used as selection criterion. In addition, a significant effect of the economy of scale on the investment costs and odorant concentration on operating cost was observed. The social benefits derived from odor abatement were linked to nuisance reductions in the nearby population and improvements in occupational health within the WWTP, with the hybrid technology exhibiting the highest benefits. On the basis of their low environmental impact, high deodorization performance, and low Net Present Value, biotrickling filtration and AS diffusion emerged as the most promising technologies for odor treatment in WWTP. PMID- 21275374 TI - Design, synthesis, and study of a mycobactin-artemisinin conjugate that has selective and potent activity against tuberculosis and malaria. AB - Although the antimalarial agent artemisinin itself is not active against tuberculosis, conjugation to a mycobacterial-specific siderophore (microbial iron chelator) analogue induces significant and selective antituberculosis activity, including activity against multi- and extensively drug-resistant strains of Mycobacterium tuberculosis. The conjugate also retains potent antimalarial activity. Physicochemical and whole-cell studies indicated that ferric-to-ferrous reduction of the iron complex of the conjugate initiates the expected bactericidal Fenton-type radical chemistry on the artemisinin component. Thus, this "Trojan horse" approach demonstrates that new pathogen-selective therapeutic agents in which the iron component of the delivery vehicle also participates in triggering the antibiotic activity can be generated. The result is that one appropriate conjugate has potent and selective activity against two of the most deadly diseases in the world. PMID- 21275375 TI - Enzymatic deamination of the epigenetic base N-6-methyladenine. AB - Two enzymes of unknown function from the amidohydrolase superfamily were discovered to catalyze the deamination of N-6-methyladenine to hypoxanthine and methyl amine. The methylation of adenine in bacterial DNA is a common modification for the protection of host DNA against restriction endonucleases. The enzyme from Bacillus halodurans, Bh0637, catalyzes the deamination of N-6 methyladenine with a k(cat) of 185 s(-1) and a k(cat)/K(m) of 2.5 * 10(6) M(-1) s(-1). Bh0637 catalyzes the deamination of N-6-methyladenine 2 orders of magnitude faster than adenine. A comparative model of Bh0637 was computed using the three-dimensional structure of Atu4426 (PDB code: 3NQB) as a structural template and computational docking was used to rationalize the preferential utilization of N-6-methyladenine over adenine. This is the first identification of an N-6-methyladenine deaminase (6-MAD). PMID- 21275376 TI - An asymmetric synthesis of (2S,5S)-5-substituted azepane-2-carboxylate derivatives. AB - To facilitate a drug discovery project, we needed to develop a robust asymmetric synthesis of (2S,5S)-5-substituted-azepane-2-carboxylate derivatives. Two key requirements for the synthesis were flexibility for elaboration at C5 and suitability for large scale preparation. To this end we have successfully developed a scalable asymmetric synthesis of these derivatives that starts with known hydroxy-ketone 8. The key step features an oxidative cleavage of aza bicyclo[3.2.2]nonene 14, which simultaneously generates the C2 and C5 substituents in a stereoselective manner. PMID- 21275377 TI - Time-course changes in potential biomarkers detected using a metabonomic approach in Walker 256 tumor-bearing rats. AB - A metabonomic approach based on complementary hydrophilic interaction chromatography and reversed-phase liquid chromatography combined with tandem mass spectrometry and time-course analysis of metabolites was implemented to find more reliable potential biomarkers in urine of Walker 256 tumor-bearing rats. A major challenge in metabonomics is distinguishing reliable biomarkers that are closely associated with the genesis and progression of diseases from those that are unrelated but altered significantly. In this study, these biomarkers were selected according to the change trends of discriminating metabolites during the genesis and progression of cancer. Seven consecutive batches of urine samples from preinoculation to 16 days after were collected and analyzed. Multivariate analysis revealed 87 discriminating metabolites. Time-course analysis of discriminating metabolites was used to select more reliable biomarkers with regular and reasonable change trends. Finally, 47 were found and 15 were identified including 12 carnitine derivatives, 2 amino acid derivatives, 1 nucleoside. On the basis of time-course behaviors of these potential biomarkers, we hypothesize such disruption might result from elevated cell proliferation, reduced beta-oxidation of fatty acids, and poor renal tubular reabsorption. These studies demonstrate that this method can help to find more reliable potential biomarkers and provide valuable biochemical insights into metabolic alterations in tumor-bearing biosystems. PMID- 21275379 TI - Complexation between pentiptycene derived bis(crown ether)s and CBPQT4+ salt: ion controlled switchable processes and changeable role of the CBPQT4+ in host-guest systems. AB - The pentiptycene derived bis(crown ether)s with two 24-crown-8 moieties in the cis position could include the CBPQT(4+) ring inside their cavities to form 1:1 complexes, and the naphthalene groups connected in the crown ether moieties showed less effective complexation ability toward the CBPQT(4+) ring than the host containing two terminal benzene rings. This result was probably due to the stereohindrance effect of the naphthalene groups, and it was obviously different from that of the pentiptycene derived mono(crown ether)s. For the pentiptycene derived bis(crown ether) with two 24-crown-8 moieties in the trans position, it formed a 1:2 stable complex with the CBPQT(4+) salt in solution and in the solid state, in which the pentiptycene moiety played an important role in stabilizing the complex. Moreover, binding and release of the CBPQT(4+) ring in the complexes based on the pentiptycene-derived crown ethers could be chemically controlled by adding and removing potassium ions, in which the complexation modes played the key role. Interestingly, it was further found that switching the role of the CBPQT(4+) ring in host and guest systems based on the pentiptycene derived bis(crown ether)s was easily achieved, which represents a new kind of supramolecular system. PMID- 21275378 TI - Improved precision of iTRAQ and TMT quantification by an axial extraction field in an Orbitrap HCD cell. AB - Improving analytical precision is a major goal in quantitative differential proteomics as high precision ensures low numbers of outliers, a source of false positives with regard to quantification. In addition, higher precision increases statistical power, i.e., the probability to detect significant differences. With chemical labeling using isobaric tags for relative and absolute quantitation (iTRAQ) or tandem mass tag (TMT) reagents, quantification is based on the extraction of reporter ions from tandem mass spectrometry (MS/MS) spectra. We compared the performance of two versions of the LTQ Orbitrap higher energy collisional dissociation (HCD) cell with and without an axial electric field with regard to reporter ion quantification. The HCD cell with the axial electric field was designed to push fragment ions into the C-trap and this version is mounted in current Orbitrap XL ETD and Orbitrap Velos instruments. Our goal was to evaluate whether the purported improvement in ion transmission had a measurable impact on the precision of MS/MS based quantification using peptide labeling with isobaric tags. We show that the axial electric field led to an increased percentage of HCD spectra in which the complete set of reporter ions was detected and, even more important, to a reduction in overall variance, i.e., improved analytical precision of the acquired data. Notably, adequate precision of HCD-based quantification was maintained even for low precursor ion intensities of a complex biological sample. These findings may help researchers in their design of quantitative proteomics studies using isobaric tags and establish HCD-based quantification on the LTQ Orbitrap as a highly precise approach in quantitative proteomics. PMID- 21275380 TI - Real-time monitoring of plasmonic evolution in thick Ag:SiO(2) films: nanocomposite optical tuning. AB - An in situ optical microspectroscopy study of the surface plasmon resonance (SPR) evolution of Ag nanoparticles (NPs) embedded in thick SiO(2) films deposited on soda-lime glass has been conducted during thermal processing in air. The temperature and time dependences of the SPR were analyzed in the context of Mie extinction and crystal growth theories and were discussed along with consideration of oxidation processes and film/substrate physicochemical interactions. At relatively high temperatures, Ag NPs were indicated to grow first through a diffusion-based process and subsequently via Ostwald ripening. At lower temperatures, an initial decrease in Ag particle size was indicated due to oxidation, followed by NP diffusion-based growth. The growth and oxidation stages appeared temperature and time dependent, allowing for the tuning of material properties. The product of Ag NP oxidation was revealed by photoluminescence spectroscopy performed ex situ as single Ag(+) ions. The oxidative effect of the air atmosphere on Ag NPs was shown to be ultimately circumvented by the thick nanocomposite film. The phenomenon was explained on the basis of the displacement of the Ag/Ag(+) redox equilibrium toward Ag NP stability after ion migration toward the substrate being self-constrained. In addition, the current spectroscopic approach has been proposed for estimating the activation energy for silver diffusion in the SiO(2) matrix. PMID- 21275381 TI - Optical nanosensor platform operating in near-physiological pH range via polymer brush-mediated plasmon coupling. AB - The nanosensors' platform made of a stimuli-responsive polymer/noble metal nanoparticle composite thin film exploits the combination of the swelling shrinking transition in a poly(N,N'-dimethylaminoethyl methacrylate) brush and the localized surface plasmon resonance in metal nanoparticles to enable the transduction of changes in the solution pH in the near-physiological range into a pronounced optical signal. PMID- 21275382 TI - Controlled hydrogenation of graphene sheets and nanoribbons. AB - The electronic properties of graphene sheets and nanoribbons with different degrees of hydrogenation have been investigated using a combination of charge transport and Raman spectroscopy experiments. The field-effect transistor mobility of graphene is shown to be highly sensitive to the treatment time during atomic hydrogen dose and follows an exponential decrease with time. Raman spectroscopy demonstrates linearly increasing defect-band intensity, and when considered together with transport data, the relationship between graphene mobility and the crystalline size of intact sp(2) carbon regions can be derived. Further, the increase in width of the voltage plateau for monolayer and bilayer graphene points to the formation of midgap states. For partially hydrogenated graphene, the temperature-dependent transport in these states shows a weak insulating behavior. A comparison of Raman spectrum and conductivity data of partially hydrogenated monolayer and bilayer graphene suggests that the latter is also quite susceptible to adsorption of hydrogen atoms, despite a stiffer lattice structure. PMID- 21275383 TI - Magnesium(II) complexes of 2,4-N,N'-disubstituted 1,3,5-triazapentadienyl ligands: synthesis and characterization of [N(Dipp)C(NMe2)NC(NMe(2))N(SiMe3)MgBr]2 and [N(R)C(R')NC(R')N(SiMe3)]2Mg (Dipp = 2,6-iPr2-C6H3, R = Ph, SiMe(3); R' = NMe2, 1-piperidino). AB - Treatment of the appropriate lithium or sodium 2,4-N,N'-disubstituted 1,3,5 triazapentadienate [RNC(R')NC(R')N(SiMe(3))M](2) (R = Ph, 2,6-(i)Pr(2) C(6)H(3)(Dipp) or SiMe(3); R' = NMe(2) or 1-piperidino; M = Li or Na) with one or half equivalent portion of MgBr(2)(THF)(2) in Et(2)O under mild conditions furnishes in good yield the first structurally characterized molecular magnesium 2,4-N,N'-disubstituted 1,3,5-triazapentadienates [DippNC(NMe(2))NC(NMe(2))N(SiMe(3))MgBr](2) (1), [{RNC(R')NC(R')N(SiMe(3))}(2)Mg] (R = Ph, R' = NMe(2) 2; R = Ph, R' = 1-piperidino 3; R = SiMe(3), R' = 1 piperidino 4). The solid-state structure of 1 is dimeric and those of 2, 3, and 4 are monomeric. The ligand backbone NCNCN in 1 adopts a W-shaped configuration, while in 2, 3 and 4 adopts a U-shaped configuration. PMID- 21275384 TI - Oxidation resistance of graphene-coated Cu and Cu/Ni alloy. AB - The ability to protect refined metals from reactive environments is vital to many industrial and academic applications. Current solutions, however, typically introduce several negative effects, including increased thickness and changes in the metal physical properties. In this paper, we demonstrate for the first time the ability of graphene films grown by chemical vapor deposition to protect the surface of the metallic growth substrates of Cu and Cu/Ni alloy from air oxidation. In particular, graphene prevents the formation of any oxide on the protected metal surfaces, thus allowing pure metal surfaces only one atom away from reactive environments. SEM, Raman spectroscopy, and XPS studies show that the metal surface is well protected from oxidation even after heating at 200 degrees C in air for up to 4 h. Our work further shows that graphene provides effective resistance against hydrogen peroxide. This protection method offers significant advantages and can be used on any metal that catalyzes graphene growth. PMID- 21275385 TI - Cholesteric and nematic liquid crystalline phase behavior of double-stranded DNA stabilized single-walled carbon nanotube dispersions. AB - The first lyotropic cholesteric single-walled carbon nanotube (SWNT) liquid crystal phase was obtained by dispersing SWNTs in an aqueous solution of double stranded DNA (dsDNA). Depending on the dispersion methodology, the polydomain nematic phase previously reported for other lyotropic carbon nanotube dispersions could also be obtained. The phase behavior and dispersion microstructure were affected by the relative concentrations of dsDNA and SWNT and whether small bundles were removed prior to concentrating the dispersions. This readily controlled phase behavior opens new routes for producing SWNT films with controlled morphology. PMID- 21275386 TI - Flavonoids from eight tropical plant species that inhibit the multidrug resistance transporter ABCG2. AB - Overexpression of ABCG2, a membrane-bound multi-drug transporter, can make tumor cells resistant to treatment with conventional chemotherapeutic agents. A high throughput screening effort with the NCI repository of natural product extracts revealed that eight tropical plant extracts significantly inhibited the function of ABCG2. This activity was tracked throughout the extract fractionation process to a series of ABCG2 inhibitory flavonoids (1-13). Their structures were identified by a combination of NMR, mass spectrometry, and circular dichroism studies, and this resulted in the elucidation of (2S)-5,7,3'-trihydroxy-4' methoxy-8-(3''-methylbut-2''-enyl)-flavonone (1), (2S)-5,7,3',5'-tetrahydroxy-8 [3'',8''-dimethylocta-2''(E),7''-dienyl]flavonone (3), and 5,7,3'-trihydroxy-3,5' dimethoxy-2'-(3'-methylbut-2-enyl)flavone (12) as new compounds. PMID- 21275387 TI - Quercetin reduces neutrophil recruitment induced by CXCL8, LTB4, and fMLP: inhibition of actin polymerization. AB - Recent in vitro data have suggested that the flavonoid quercetin (1) does not affect the functioning of neutrophils. Therefore, we evaluated in vivo and in vitro whether or not 1 affects neutrophil function, focusing on recruitment. The in vivo treatment with 1 inhibited in a dose-dependent manner the recruitment of neutrophils to the peritoneal cavity of mice induced by known chemotatic factors such as CXCL1, CXCL5, LTB(4), and fMLP. Furthermore, 1 also inhibited in a concentration-dependent manner the chemoattraction of human neutrophils induced by CXCL8, LTB(4), and fMLP in a Boyden chamber. In vitro treatment with 1 did not affect human neutrophil surface expression of CXCR1, CXCR2, BLT1, or FLPR1, but rather reduced actin polymerization. These results suggest that 1 inhibits actin polymerization, hence, explaining the inhibition of neutrophil recruitment in vivo and in vitro and highlighting its possible usefulness to diminish excessive neutrophil migration during inflammation. PMID- 21275388 TI - 7Li NMR studies on complexation reactions of lithium ion with cryptand C211 in ionic liquids: comparison with corresponding reactions in nonaqueous solvents. AB - (7)Li NMR spectra of DEME-TFSA [DEME=N,N-diethyl-N-methyl-N-(2 methoxyethyl)ammonium; TFSA=bis(trifluoromethanesulfonyl)amide], EMI-TFSA (EMI=1 ethyl-3-methylimidazolium), MPP-TFSA (MPP = N-methyl-N-propylpyridinium), DEME PFSA [PFSA=bis(pentafluoroethanesulfonyl)amide], and DEME-HFSA [HFSA=bis(heptafluoropropanesulfonyl)amide] ionic liquid (IL) solutions containing LiX (X=TFSA, PFSA, or HFSA) and C211 (4,7,13,18-tetraoxa-1,10 diazabicyclo[8.5.5]eicosane) were measured at various temperatures. As a result, it was found that the uncomplexed Li(I) species existing as [Li(X)(2)](-) in the present ILs exchange with the complexed Li(I) ([Li.C211](+)) and that the exchange reactions proceed through the bimolecular mechanism, [Li.C211](+) + [*Li(X)(2)](-)=[*Li.C211](+) + [Li(X)(2)](-). Kinetic parameters [k(s)/(kg m(-1) s(-1)) at 25 degrees C, DeltaH(++)/(kJ mol(-1)), DeltaS(++)/(J K(-1) mol(-1))] are as follows: 5.57*10(-2), 69.8 +/- 0.4, and -34.9 +/- 1.0 for the DEME-TFSA system; 5.77*10(-2), 70.6 +/- 0.2, and -31.9 +/- 0.6 for the EMI-TFSA system, 6.13*10(-2), 69.0 +/- 0.3, and -36.7 +/- 0.7 for the MPP-TFSA system; 1.35 * 10( 1), 65.2 +/- 0.5, and -43.1 +/- 1.4 for the DEME-PFSA system; 1.14*10(-1), 64.4 +/- 0.3, and -47.1 +/- 0.6 for the DEME-HFSA system. To compare these kinetic data with those in conventional nonaqueous solvents, the exchange reactions of Li(I) between [Li.C211](+) and solvated Li(I) in N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO) were also examined. These Li(I) exchange reactions were found to be independent of the concentrations of the solvated Li(I) and hence proposed to proceed through the dissociative mechanism. Kinetic parameters [k(s)/s(-1) at 25 degrees C, DeltaH(++)/(kJ mol(-1)), DeltaS(++)/(J K(-1) mol( 1))] are as follows: 1.10 * 10(-2), 68.9 +/- 0.2, and -51.3 +/- 0.4 for the DMF system; 1.13*10(-2), 76.3 +/- 0.3, and -26.3 +/- 0.8 for the DMSO system. The differences in reactivities between ILs and nonaqueous solvents were proposed to be attributed to those in the chemical forms of the uncomplexed Li(I) species, i.e., the negatively charged species ([Li(X)(2)](-)) in ILs, and the positively charged ones ([Li(solvent)(n)](+)) in nonaqueous solvents. PMID- 21275389 TI - Irradiation stability of folic Acid in powder and aqueous solution. AB - This study attempts to examine the folic acid stability after irradiation treatment, under different physical states, pH values, and atmosphere conditions. Aqueous folic acid samples, folic acid in powder, and wheat flour fortified with folic acid were irradiated by an electron beam (E-beam) between 0 (control) and 10.0 kGy. It was realized that the physical state of folic acid plays an important role on its stability toward E-beam processing, being largely unstable in solution, no matter the pH and atmosphere conditions assayed. Otherwise, folic acid in powder showed huge irradiation stability, even when mixed in a dry food matrix, such as fortified wheat flour samples. PMID- 21275390 TI - Integrated catalytic C-H transformations for one-pot synthesis of 1 arylisoindoles from isoindolines via palladium-catalyzed dehydrogenation followed by C-H arylation. AB - A one-pot conversion of isoindolines to 1-arylisoindoles was established from palladium-catalyzed cascade C-H transformations, that is, the dehydrogenation of isoindolines to give isoindoles, with subsequent C-H arylation of the isoindoles. PMID- 21275391 TI - A new trick (hydroxyl radical generation) for an old vitamin (B12). AB - Photolysis of hydroxocobalamin in the presence of plasmid DNA (pBR322) results in DNA cleavage. Temporal control of hydroxyl radical production and DNA strand scission by hydroxocobalamin was demonstrated using a 2-deoxyribose assay and a plasmid relaxation assay, respectively. The light-driven hydroxocobalamin mediated catalytic formation of hydroxyl radicals was demonstrated using radical scavenging studies of DNA cleavage and via recycling of a hydroxocobalamin-resin conjugate several times without loss of efficacy. PMID- 21275392 TI - Predicting myelosuppression of drugs from in silico models. AB - Anticancer agents targeting proliferating cell populations in tumor as well as in normal tissues can lead to a number of side effects including hematotoxicity, a common dose-limiting toxicity associated with oncology drugs. Myelosuppression, regarded as unacceptable for other therapeutic indications, is considered a clinical risk also for new targeted anticancer drugs acting specifically on tumor cells. Thus, it becomes important not only to evaluate the potential toxicity of such new therapeutics to human hematopoietic tissue during preclinical development but also to anticipate this liability in early drug discovery. This could be achieved by using in silico models to guide the design of new lead compounds and the selection of analogs with reduced myelosuppressive potential. Hence, the purpose of this study was to develop computational models able to predict the potential myelotoxicity of drugs from their chemical structure. The data set analyzed included 38 drugs. The structural diversity and the drug-like space covered by these molecules were investigated using the ChemGPS methodology. Two sets of potentially relevant descriptors for modeling myelotoxicity (i.e., 3D Volsurf+ and 2D structural and electrotopological E-states descriptors) were selected and a Principal Component Analysis was carried out on the entire set of data. The first two PCs were able to discriminate the highest from the least myelotoxic compounds with a total accuracy of 95%. Then, a quantitative PLS model was developed by correlating a selected subset of in vitro hematotoxicity data with Volsurf+ descriptors. After variable selection, the PLS analysis resulted in a one-latent-variable model with r(2) of 0.79 and q(2) of 0.72. The inclusion of 2D descriptors in the PLS analysis improved only slightly the robustness and quality of the model that predicted the pIC(50) values of 21 drugs not included in the model with a RMSEP of 0.67 and a squared correlation coefficient (r(0)(2)) of 0.70. Furthermore, in order to investigate whether the highly myelotoxic compounds are characterized by common structural features, which should be taken into consideration in the design of new candidate drugs, the entire data set was analyzed using GRIND toxicophore-based descriptors. One toxicophore emerged from the interpretation of the model. The toxicophore elements, at least determined by the molecules used in this study, are a pattern of H-bond acceptor groups, presence of a H-bond donor and H-bond acceptor regions at ~15 A distance and a hydrophobic and H-bond acceptor interacting regions separated by a distance of ~12.4 A. Moreover, the dimensions of the molecule play a role in its recognition as a myelotoxic compound. PMID- 21275393 TI - Design of multitarget activity landscapes that capture hierarchical activity cliff distributions. AB - An activity landscape model of a compound data set can be rationalized as a graphical representation that integrates molecular similarity and potency relationships. Activity landscape representations of different design are utilized to aid in the analysis of structure-activity relationships and the selection of informative compounds. Activity landscape models reported thus far focus on a single target (i.e., a single biological activity) or at most two targets, giving rise to selectivity landscapes. For compounds active against more than two targets, landscapes representing multitarget activities are difficult to conceptualize and have not yet been reported. Herein, we present a first activity landscape design that integrates compound potency relationships across multiple targets in a formally consistent manner. These multitarget activity landscapes are based on a general activity cliff classification scheme and are visualized in graph representations, where activity cliffs are represented as edges. Furthermore, the contributions of individual compounds to structure-activity relationship discontinuity across multiple targets are monitored. The methodology has been applied to derive multitarget activity landscapes for compound data sets active against different target families. The resulting landscapes identify single-, dual-, and triple-target activity cliffs and reveal the presence of hierarchical cliff distributions. From these multitarget activity landscapes, compounds forming complex activity cliffs can be readily selected. PMID- 21275394 TI - Fluorinated amphiphiles control the insertion of alpha-hemolysin pores into lipid bilayers. AB - The insertion of fully folded and assembled ion channels and pores into planar lipid bilayers for electrical recording has been facilitated by the use of conventional detergents at a final concentration below the critical micelle concentration (CMC). After the desired number of channels or pores (often one) has been incorporated into a bilayer, it is important to prevent further insertion events, which is often done by awkward techniques such as perfusion. Here, we show that the addition of single-chain fluorinated amphiphiles (F amphiphiles) with zwitterionic, simple neutral, and neutral oligomeric headgroups at a concentration above the CMC prevents the further insertion of staphylococcal alpha-hemolysin pores, MspA pores, and Kcv potassium channels into lipid bilayers. We found the commercially available F(6)FC (fluorinated fos-choline with a C(6)F(13)C(2)H(4) chain) to be the least perturbing and most effective agent for this purpose. Bilayers are known to be resistant to F-amphiphiles, which in this case we suppose sequester the pores and channels within amphiphile aggregates. We suggest that F-amphiphiles might be useful in the fabrication of bilayer arrays for nanopore sensor devices and the rapid screening of membrane proteins. PMID- 21275395 TI - Bidirectional fluorescence resonance energy transfer (FRET) in mutated and chemically modified yellow fluorescent protein (YFP). AB - Fluorescence resonance energy transfer (FRET) using fluorescent protein variants are used for studying the associations and biomolecular motions of macromolecules inside the cell. Intramolecular FRET utilizing fluorescent chemical labels has been applied in nucleic acid chemistry for detection of specific sequence. However, the biotechnological applications of intramolecular FRET in fluorescent proteins have not been exploited. This study demonstrates the intramolecular FRET between fluorescent protein and conjugated chemical label whereby FRET occurs from inside to outside and vice versa for fluorescent protein. The fluorescent protein is modified for the attachment of chemical fluorophores and the novel FRET pairs created by conjugation are MDCC (435/475)-Citrine (516/529) and Citrine-Alexa fluor (568/603). These protein-label pairs exhibited strong intramolecular FRET and the energy transfer efficiency was determined based on the time evolution of the ratio of emission intensities of labeled and unlabeled proteins. The efficiency was found to be 0.79 and 0.89 for MDCC-Citrine and 0.24 and 0.65 for Citrine-Alexa Fluor pairs when the label is conjugated at different sites in the protein. Forster distance and the average distance between the fluorophores were also determined. The bidirectional approach described here can provide new insights into designing FRET-based sensors. PMID- 21275396 TI - Reactive compatibilization of polycarbonate and poly(methyl methacrylate) in the presence of a novel transesterification catalyst SnCl2.2H2O. AB - We compare the effectiveness of various known organometallic transesterification catalysts with a novel SnCl(2).2H(2)O transesterification catalyst in the formation of homogeneous PC/PMMA blends with single T(g). It is shown that SnCl(2).2H(2)O works more efficiently than the other organometallic transesterification catalysts. Even 0.1% (wt/wt) of SnCl(2).2H(2)O is enough to establish an interaction between PC and PMMA phases, leading to the formation of a homogeneous PC/PMMA blend with single T(g) and single degradation temperature. FTIR, (1)H NMR, and XRD studies provide evidence of the formation of PC-g-PMMA graft copolymer, which acts as a compatibilizer between the PC and PMMA phases. A significant improvement in the optical transparency of the PC/10PMMA blend prepared using SnCl(2).2H(2)O catalyst as compared with PC/10PMMA without any catalyst is observed. There is also a change in the morphology from granular in uncompatibilized blends to lamellar in the compatibilized blends. PMID- 21275397 TI - Virtual screening for ligands of the insect molting hormone receptor. AB - Insect growth is regulated by the orchestrated event of ecdysteroids and their receptor proteins. Agonists/antagonists of ecdysteroid receptor are predicted to disrupt normal growth, providing good candidates of new insecticides. A database of over 2 million compounds was subjected to a shape-based virtual screening cascade to identify novel nonsteroidal hits similar to the known EcR ligand ponasterone A. Testing revealed micromolar hits against two strains of insect cells. Docking experiments against EcR were used to support the predicted binding mode of these ligands based on their overlay to ponasterone A. PMID- 21275398 TI - Nuclear energy in Europe: uranium flow modeling and fuel cycle scenario trade offs from a sustainability perspective. AB - The European nuclear fuel cycle (covering the EU-27, Switzerland and Ukraine) was modeled using material flow analysis (MFA).The analysis was based on publicly available data from nuclear energy agencies and industries, national trade offices, and nongovernmental organizations. Military uranium was not considered due to lack of accessible data. Nuclear fuel cycle scenarios varying spent fuel reprocessing, depleted uranium re-enrichment, enrichment assays, and use of fast neutron reactors, were established. They were then assessed according to environmental, economic and social criteria such as resource depletion, waste production, chemical and radiation emissions, costs, and proliferation risks. The most preferable scenario in the short term is a combination of reduced tails assay and enrichment grade, allowing a 17.9% reduction of uranium demand without significantly increasing environmental, economic, or social risks. In the long term, fast reactors could theoretically achieve a 99.4% decrease in uranium demand and nuclear waste production. However, this involves important costs and proliferation risks. Increasing material efficiency is not systematically correlated with the reduction of other risks. This suggests that an overall optimization of the nuclear fuel cycle is difficult to obtain. Therefore, criteria must be weighted according to stakeholder interests in order to determine the most sustainable solution. This paper models the flows of uranium and associated materials in Europe, and provides a decision support tool for identifying the trade-offs of the alternative nuclear fuel cycles considered. PMID- 21275399 TI - Total synthesis of lathyranoic acid A. AB - The first total synthesis of lathyranoic acid A (1) was accomplished stereoselectively in a linear sequence of 20 steps and an overall yield of 1.4%. This modular synthesis featured a cyclic, stereocontrolled Cu-catalyzed intramolecular cyclopropanation to construct the cis-cyclopropane unit, a Grubbs metathesis to construct the gamma-substituted cyclopentenone moiety, and an anion mediated conjugate addition. PMID- 21275400 TI - Differential effects of dissolved organic carbon upon re-entrainment and surface properties of groundwater bacteria and bacteria-sized microspheres during transport through a contaminated, sandy aquifer. AB - Injection-and-recovery studies involving a contaminated, sandy aquifer (Cape Cod, Massachusetts) were conducted to assess the relative susceptibility for in situ re-entrainment of attached groundwater bacteria (Pseudomonas stuzeri ML2, and uncultured, native bacteria) and carboxylate-modified microspheres (0.2 and 1.0 MUm diameters). Different patterns of re-entrainment were evident for the two colloids in response to subsequent injections of groundwater (hydrodynamic perturbation), deionized water (ionic strength alteration), 77 MUM linear alkylbenzene sulfonates (LAS, anionic surfactant), and 76 MUM Tween 80 (polyoxyethylene sorbitan monooleate, a very hydrophobic nonionic surfactant). An injection of deionized water was more effective in causing detachment of micrsopheres than were either of the surfactants, consistent with the more electrostatic nature of microsphere's attachment, their extreme hydrophilicity (hydrophilicity index, HI, of 0.99), and negative charge (zeta potentials, zeta, of -44 to -49 mv). In contrast, Tween 80 was considerably more effective in re entraining the more-hydrophobic native bacteria. Both the hydrophilicities and zeta potentials of the native bacteria were highly sensitive to and linearly correlated with levels of groundwater dissolved organic carbon (DOC), which varied modestly from 0.6 to 1.3 mg L(-1). The most hydrophilic (0.52 HI) and negatively charged (zeta -38.1 mv) indigenous bacteria were associated with the lowest DOC. FTIR spectra indicated the latter community had the highest average density of surface carboxyl groups. In contrast, differences in groundwater (DOC) had no measurable effect on hydrophilicity of the bacteria-sized microspheres and only a minor effect on their zeta. These findings suggest that microspheres may not be very good surrogates for bacteria in field-scale transport studies and that adaptive (biological) changes in bacterial surface characteristics may need to be considered where there is longer-term exposure to contaminant DOC. PMID- 21275401 TI - Design, synthesis, and insecticidal activities of novel monohalovinylated pyrethroids. AB - A series of novel monohalovinylated pyrethroids are designed and synthesized to replace one halo atom with a hydrogen atom on the double bond of dihalopyrethroids. Bioassays indicate that some of the synthesized compounds, such as 3j and 1j, exhibit high insecticidal activities against mosquitoes ( Culex pipiens pallens ), oriental armyworms ( Mythimna separata ), alfalfa aphids ( Aphis medicagini ), and carmine spider mites ( Tetranychus cinnabarinus ). Photolytic results of E-cis-1j suggest that monohalovinylated pyrethroids are photodegraded more easily than compound 12. PMID- 21275402 TI - Stapling of a 3(10)-helix with click chemistry. AB - Short peptides are important as lead compounds and molecular probes in drug discovery and chemical biology, but their well-known drawbacks, such as high conformational flexibility, protease lability, poor bioavailability and short half-lives in vivo, have prevented their potential from being fully realized. Side chain-to-side chain cyclization, e.g., by ring-closing olefin metathesis, known as stapling, is one approach to increase the biological activity of short peptides that has shown promise when applied to 3(10)- and alpha-helical peptides. However, atomic resolution structural information on the effect of side chain-to-side chain cyclization in 3(10)-helical peptides is scarce, and reported data suggest that there is significant potential for improvement of existing methodologies. Here, we report a novel stapling methodology for 3(10)-helical peptides using the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction in a model aminoisobutyric acid (Aib) rich peptide and examine the structural effect of side chain-to-side chain cyclization by NMR, X-ray diffraction, linear IR and femtosecond 2D IR spectroscopy. Our data show that the resulting cyclic peptide represents a more ideal 3(10)-helix than its acyclic precursor and other stapled 3(10)-helical peptides reported to date. Side chain to-side chain stapling by CuAAC should prove useful when applied to 3(10)-helical peptides and protein segments of interest in biomedicine. PMID- 21275403 TI - Synthesis and evaluation of 11C-labeled imidazo[2,1-b]benzothiazoles (IBTs) as PET tracers for imaging beta-amyloid plaques in Alzheimer's disease. AB - We report a novel series of (11)C-labeled imidazo[2,1-b]benzothiazoles (IBTs) as tracers for imaging of cerebral beta-amyloid (Abeta) deposits in patients with Alzheimer's disease (AD) by means of positron emission tomography (PET). From a series of 11 compounds, candidates were identified to have a high binding affinity for Abeta. Selected compounds were prepared as O- or N-[(11)C]methyl derivatives and shown to have a high initial brain uptake in wild-type mice (range 1.9-9.2% I.D./g at 5 min). 2-(p-[(11)C]Methylaminophenyl)-7 methoxyimidazo[2,1-b] benzothiazole ([(11)C]5) was identified as a lead based on the combined favorable properties of high initial brain uptake, rapid clearance from normal brain, and high in vitro affinity for Abeta(1-40) (K(i) = 3.5 nM) and Abeta(1-42) (5.8 nM), which were superior to the Pittsburgh compound B (1a). In an APP/PS1 mouse model of AD (Tg), we demonstrate a specific uptake of [(11)C]5 in Abeta-containing telencephalic brain regions by means of small-animal PET that was confirmed by regional brain biodistribution, ex vivo autoradiography, and immunohistochemistry. Analysis of brain sections of Tg mice receiving a single bolus injection of [(11)C]5 and [(3)H]1a together revealed that the tracers bind to Abeta plaques in the brain of Tg mice in a comparable pattern. Taken together, these data suggest that IBTs represent useful PET imaging agents for high sensitivity detection of Abeta plaques. PMID- 21275404 TI - A programmable molecular robot. AB - We have developed a programmable and auton-omous molecular robot whose motion is fueled by DNA hybridization. Instructions determining the path to be followed are programmed into the fuel molecules, allowing precise control of cargo motion on a branched track. PMID- 21275405 TI - In situ observation of water dissociation with lattice incorporation at FeO particle edges using scanning tunneling microscopy and X-ray photoelectron spectroscopy. AB - The dissociation of H2O and formation of adsorbed hydroxyl groups on FeO particles grown on Au(111) were identified with in situ X-ray photoelectron spectroscopy (XPS) at water pressures ranging from 3 * 10(-8) to 0.1 Torr. The facile dissociation of H2O takes place at FeO particle edges, and it was successfully observed in situ with atomically resolved scanning tunneling microscopy (STM). The in situ STM studies show that adsorbed hydroxyl groups were formed exclusively along the edges of the FeO particles with the O atom becoming directly incorporated into the oxide crystalline lattice. The STM results are consistent with coordinatively unsaturated ferrous (CUF) sites along the FeO particle edge causing the observed reactivity with H2O. Our results also directly illustrate how structural defects and under-coordinated sites participate in chemical reactions. PMID- 21275406 TI - Polydiacetylene incorporated with peptide receptors for the detection of trinitrotoluene explosives. AB - Because of their unique optical and stimuli-response properties, polydiacetylene based platforms have been explored as an alternative to complex mechanical and electrical sensing systems. We linked chromic responsive polydiacetylene (PDA) onto a peptide-based molecular recognition element for trinitrotoluene (TNT) molecules in order to provide a system capable of responding to the presence of a TNT target. We first identified the trimer peptide receptor that could induce chromic changes on a PDA backbone. We then investigated the multivalent interactions between TNT and our peptide-based receptor by nuclear magnetic resonance (NMR) spectroscopy. We further characterized various parameters that affected the conjugated PDA system and hence the chromic response, including the size of end-group motifs, the surface density of receptors, and the length of alkane side chains. Taking these necessary design parameters into account, we demonstrated a modular system capable of transducing small-molecule TNT binding into a detectable signal. Our conjugated PDA-based sensor coupled with molecular recognition elements has already proven useful recently in the development of another sensitive and selective electronic sensor, though we expect that our results will also be valuable in the design of colorimetric sensors for small molecule detection. PMID- 21275407 TI - Tripeptide motifs in biology: targets for peptidomimetic design. PMID- 21275408 TI - Squalene based nanocomposites: a new platform for the design of multifunctional pharmaceutical theragnostics. AB - This study reports the design of a novel theragnostic nanomedicine which combines (i) the ability to target a prodrug of gemcitabine to an experimental solid tumor under the influence of a magnetic field with (ii) the imaging of the targeted tumoral nodule. This concept is based on the inclusion of magnetite nanocrystals into nanoparticles (NPs) constructed by self-assembling molecules of the squalenoyl gemcitabine (SQgem) bioconjugate. The nanocomposites are characterized by an unusually high drug loading, a significant magnetic susceptibility, and a low burst release. When injected to the L1210 subcutaneous mice tumor model, these magnetite/SQgem NPs were magnetically guided, and they displayed considerably greater anticancer activity than the other anticancer treatments (magnetite/SQgem NPs nonmagnetically guided, SQgem NPs, or gemcitabine free in solution). The histology and immunohistochemistry investigation of the tumor biopsies clearly evidenced the therapeutic superiority of the magnetically guided nanocomposites, while Prussian blue staining confirmed their accumulation at the tumor periphery. The superior therapeutic activity and enhanced tumor accumulation has been successfully visualized using T(2)-weighted imaging in magnetic resonance imaging (MRI). This concept was further enlarged by (i) the design of squalene-based NPs containing the T(1) Gd(3+) contrast agent instead of magnetite and (ii) the application to other anticancer squalenoyls, such as, cisplatin, doxorubicin, and paclitaxel. Thus, by combining different anticancer medicines as well as contrast imaging agents in NPs, we open the door toward generic conceptual framework for cancer treatment and diagnosis. This new theragnostic nanotechnology platform is expected to have important applications in cancer therapy. PMID- 21275409 TI - Electrochemical crystallization of plasmonic nanostructures. AB - We show how gold recrystallizes when under the influence of electrochemical potentials. This "cold annealing" occurs without charge transfer reactions and preserves nanoscale structural features. By performing the process on plasmonic nanostructures, grain growth is monitored noninvasively by optical spectroscopy. In this way, the influence from crystal structure on plasmon resonances can be investigated independently. Observed spectral changes are in excellent agreement with analytical models and changes in electron relaxation time and plasma frequency are calculated. PMID- 21275410 TI - Frictionless sliding of single-stranded DNA in a carbon nanotube pore observed by single molecule force spectroscopy. AB - Smooth inner pores of carbon nanotubes (CNT) provide a fascinating model for studying biological transport. We used an atomic force microscope to pull a single-stranded DNA oligomer from a carbon nanotube pore. DNA extraction from CNT pores occurs at a nearly constant force, which is drastically different from the elastic profile commonly observed during polymer stretching with atomic force microscopy. We show that a combination of the frictionless nanotube pore walls and an unfavorable DNA solvation energy produces this constant force profiles. PMID- 21275411 TI - Pd-catalyzed carbonylative reactions of aryl iodides and alkynyl carboxylic acids via decarboxylative couplings. AB - Alkynyl carboxylic acids reacted with aryl iodides under a CO atmosphere in the presence of a palladium catalyst to produce alpha,beta-alkynyl aryl ketones in good yields. The maximum turnover number was 16 800. The desired carbonylative coupling was formed from phenyl propiolic acid without any formation of a noncarbonylative coupling product in the absence of CuI. However, the reaction with alkyl-substituted alkynyl carboxylic acids required CuI as a cocatalyst for high yield. PMID- 21275412 TI - Effect of chemical substituents on the structure of glassy diphenyl polycarbonates. AB - Polycarbonates offer a wide variety of physical property behavior that is difficult to predict due to complexities at the molecular scale. Here, the physical structure of amorphous glassy polycarbonates having aliphatic and cycloaliphatic chemical groups is explored through atomistic simulations. The influence of chemical structure on solubility parameter, torsion distributions, radial distribution function, scattering structure factor, orientation distributions of phenylene rings and carbonate groups, and free volume distributions, leading to interchain packing effects, are shown. The effect of the cyclohexyl ring at the isopropylidene carbon as compared to the effect of the methyl groups positioned on the phenylene rings results in a larger reduction in the solubility parameter (delta). The interchain distance estimated for polycarbonates in this work is in the range of 5-5.8 A. The o-methyl groups on the phenylene rings, as compared to a cyclohexyl ring, lead to higher interchain distances. The highest interchain distance is observed with a trimethylcyclohexylidene group at the isopropylidene carbon. Atomistic simulations reveal two different types of packing arrangement of nearest-neighbor chains in the glassy state, one type of which agrees with the NMR experimental data. The fundamental insights provided here can be utilized for design of chemical structures for tailored macroscopic properties. PMID- 21275413 TI - Highly stable and porous cross-linked polymers for efficient photocatalysis. AB - Porous cross-linked polymers (PCPs) with phosphorescent [Ru(bpy)(3)](2+) and [Ir(ppy)(2)(bpy)](+) building blocks were obtained via octacarbonyldicobalt (Co(2)(CO)(8))-catalyzed alkyne trimerization reactions. The resultant Ru- and Ir PCPs exhibited high porosity with specific surface areas of 1348 and 1547 m(2)/g, respectively. They are thermally stable at up to 350 degrees C in air and do not dissolve or decompose in all solvents tested, including concentrated hydrochloric acid. The photoactive PCPs were shown to be highly effective, recyclable, and reusable heterogeneous photocatalysts for aza-Henry reactions, alpha-arylation of bromomalonate, and oxyamination of an aldehyde, with catalytic activities comparable to those of the homogeneous [Ru(bpy)(3)](2+) and [Ir(ppy)(2)(bpy)](+) photocatalysts. This work highlights the potential of developing photoactive PCPs as highly stable, molecularly tunable, and recyclable and reusable heterogeneous photocatalysts for a variety of important organic transformations. PMID- 21275415 TI - Enantioselective synthesis of alpha-alkyl,alpha-vinyl amino acids via [2,3] sigmatropic rearrangement of selenimides. AB - Chiral alpha-alkyl,alpha-vinyl amino acids (quaternary vinyl glycine derivatives) are prepared with high levels of enantiomeric purity by [2,3]-sigmatropic rearrangement of allylic selenimides. The required trisubstituted allylic selenides are prepared by an organocatalytic alpha-selenenylation of aldehydes followed by Horner-Wadsworth-Emmons (HWE) olefination. Both (E)-and (Z) geometrical isomers are available giving access to both enantiomers of the desired products. PMID- 21275414 TI - Evaluation of multivalent, functional polymeric nanoparticles for imaging applications. AB - A series of multivalent, functional polymer nanoparticles with diagnostic/imaging units and targeting ligands for molecular targeting were synthesized with the loading of the chain-end-functionalized GRGDS peptide targeting sequence (model system based on integrin alpha(v)beta(3)) ranging from 0 to 50%. Accurate structural and functional group control in these systems was achieved through a modular approach involving the use of multiple functionalized macromonomer/monomer units combined with living free radical polymerization. In cellulo results show an increase in uptake in alpha(v)beta(3) integrin-positive U87MG glioblastoma cells with increasing RGD loading and a possible upper limit on the effectiveness of the number of RGD peptides for targeting alpha(v)beta(3) integrin. Significantly, this increased targeting efficiency is coupled with in vivo biodistribution results, which show decreased blood circulation and increased liver uptake with increasing RGD loading. The results demonstrate the importance of controlling ligand loading in order to achieve optimal performance for therapeutic and imaging applications for multivalent nanoparticle-based systems. PMID- 21275416 TI - Copper-catalyzed carboxylation of alkylboranes with carbon dioxide: formal reductive carboxylation of terminal alkenes. AB - Carboxylation of alkylboron compounds (alkyl-9-BBN) with CO(2) proceeded in the presence of catalytic amounts of CuOAc/1,10-phenanthroline and a stoichiometric amount of KO(t)Bu. The alkylboranes are easily and widely available through the alkene hydroboration, and thus the overall process represents a reductive carboxylation of alkenes with CO(2). The broad functional group compatibility and the inexpensiveness of the Cu/1,10-phenathoroline catalyst system are attractive features of this protocol. PMID- 21275417 TI - Parts-per-billion Fourier transform ion cyclotron resonance mass measurement accuracy with a "walking" calibration equation. AB - Ion cyclotron resonance frequency, f, is conventionally converted to ion mass-to charge ratio, m/z (mass "calibration") by fitting experimental data spanning the entire detected m/z range to the relation, m/z = A/f + B/f(2), to yield rms mass error as low as ~200 ppb for ~10,000 resolved components of a petroleum crude oil. Analysis of residual error versus m/z and peak abundance reveals that systematic errors limit mass accuracy and thus the confidence in elemental composition assignments. Here, we present a calibration procedure in which the spectrum is divided into dozens of adjoining segments, and a separate calibration is applied to each, thereby eliminating systematic error with respect to m/z. Further, incorporation of a third term in the calibration equation that is proportional to the magnitude of each detected peak minimizes systematic error with respect to ion abundance. Finally, absorption-mode data analysis increases mass measurement accuracy only after minimization of systematic errors. We are able to increase the number of assigned peaks by as much as 25%, while reducing the rms mass error by as much as 3-fold, for significantly improved confidence in elemental composition assignment. PMID- 21275418 TI - Synthesis, photophysical characterization, and enzymatic incorporation of a microenvironment-sensitive fluorescent uridine analog. AB - The synthesis of a microenvironment-sensitive base-modified fluorescent ribonucleoside analog based on a 5-(benzo[b]thiophen-2-yl)pyrimidine core, enzymatic incorporation of its corresponding triphosphate into RNA oligonucleotides, and photophysical characterization of fluorescently modified oligoribonucleotides are described. PMID- 21275419 TI - Metabotyping of Caenorhabditis elegans and their culture media revealed unique metabolic phenotypes associated to amino acid deficiency and insulin-like signaling. AB - Insulin/IGF-like signaling (IIS) and nutrient sensing are among the most potent regulators of health status and aging. Here, a global view of the metabolic changes in C. elegans with impaired function of IIS represented by daf-2 and daf 16 and the intestinal di- and tripeptide transport pept-1 was generated using (1)H nuclear magnetic resonance spectroscopic analysis of worm extracts and spent culture media. We showed that specific metabolic profiles were significantly associated with each type of mutant. On the basis of the metabonomics data, selected underlying processes were further investigated using proteomic and transcriptomic approaches. The observed changes suggest a decreased activity of the one carbon metabolism in pept-1(lg601) mutants. Higher concentration of branched-chain amino acids (BCAA) and altered transcript levels of genes involved in BCAA metabolism were observed in long-living strains daf-2(e1370) and daf 2(e1370);pept-1(lg601) when compared to wild types and daf-16(m26);daf 2(e1370);pept-1(lg601) C. elegans, suggesting a DAF-16-dependent mechanism. PMID- 21275420 TI - Direct observation of macrostructure formation of hierarchically structured meso macroporous aluminosilicates with 3D interconnectivity by optical microscope. AB - Hierarchically structured spongy meso-macroporous aluminosilicates with high tetrahedral aluminum content were synthesized from a mixture of single molecular alkoxide precursor, (sec-BuO)2-Al-O-Si(OEt)3, already containing Si-O-Al bonds, and a silica coreactant, tetramethoxysilane (TMOS). The spontaneous byproduct templated macroporous structure formation has been directly visualized using in situ high-resolution optical microscopy (OM), allowing the crucial observation of a microbubble dispersion which is directly correlated to the macrostructure observed by electronic microscopies (SEM and TEM). This discovery leads to a comparative study with meso-macroporous pure metal oxide and to a proposal of the formation mechanism of meso-macroporous aluminosilicates with 3D interconnectivity. The aluminosilicate phase/microbubbles emulsion is produced by a phase separation process occurring between the aluminosilicate nanoparticles and the liquid hydrolysis-condensation reaction byproducts (water, methanol, ethanol, and butanol). The use of alkoxysilane improves the heterocondensation rates between the highly reactive aluminum alkoxide part of the single precursor and added silica species but, above all, leads to the spontaneous generation of an unusual meso-macroporosity in alkaline media. The particles obtained at pH = 13.0 featured regular micrometer-sized macrospheres separated by very thin mesoporous walls and connected by submicrometric openings, providing a 3D interconnectivity. The slight increase in pH value to 13.5 induced significant modifications in morphology and textural properties due to the slower gelification process of the aluminosilicate phase, resulting in the formation of an aluminosilicate material constituted of 1-2 um large independent hollow mesoporous spheres. PMID- 21275421 TI - Rh(III)-catalyzed directed C-H olefination using an oxidizing directing group: mild, efficient, and versatile. AB - An efficient Rh(III)-catalyzed oxidative olefination by directed C-H bond activation of N-methoxybenzamides is reported. In this mild, practical, selective, and high-yielding process, the N-O bond acts as an internal oxidant. In addition, simply changing the substituent of the directing/oxidizing group results in the selective formation of valuable tetrahydroisoquinolinone products. PMID- 21275423 TI - Enantioselective/anion-selective incorporation of tris(ethylenediamine) complexes into 2D coordination spaces between tripalladium(II) supramolecular layers with D penicillaminate. AB - The formation of a cocrystallized coordination compound, [Pd(3)(D pen)(3)](2).[M(en)(3)](ClO(4))(3) (D-H(2)pen = D-penicillamine; M = Co(III) or Rh(III)), from [Pd(3)(D-pen)(3)] and [M(en)(3)](ClO(4))(3) is reported. In this compound, only the Delta-configurational [M(en)(3)](3+) cations were incorporated when its racemic (Delta/Lambda) isomer was employed. Besides this enantioselective incorporation of complex cations, this compound was found to show the selective incorporation of ClO(4)(-) as the anion species. PMID- 21275424 TI - Tunable band gaps in bilayer graphene-BN heterostructures. AB - We investigate band gap tuning of bilayer graphene between hexagonal boron nitride sheets, by external electric fields. Using density functional theory, we show that the gap is continuously tunable from 0 to 0.2 eV and is robust to stacking disorder. Moreover, boron nitride sheets do not alter the fundamental response from that of free-standing bilayer graphene, apart from additional screening. The calculations suggest that graphene-boron nitride heterostructures could provide a viable route to graphene-based electronic devices. PMID- 21275425 TI - The isomerization of methoxy radical: intramolecular hydrogen atom transfer mediated through acid catalysis. AB - The catalytic ability of water, formic acid, and sulfuric acid to facilitate the isomerization of the CH(3)O radical to CH(2)OH has been studied. It is shown that the activation energies for isomerization are 30.2, 25.7, 4.2, and 2.3 kcal mol( 1), respectively, when the reaction is carried out in isolation and with water, formic acid, or sulfuric acid as a catalyst. The formation of a doubly hydrogen bonded transition state is central to lowering the activation energy and facilitating the intramolecular hydrogen atom transfer that is required for isomerization. The changes in the rate constant for the CH(3)O-to-CH(2)OH isomerization with acid catalysis have also been calculated at 298 K. The largest enhancement in the rate, by over 12 orders of magnitude, is with sulfuric acid. The results of the present study demonstrate the feasibility of acid catalysis of a gas-phase radical isomerization reaction that would otherwise be forbidden. PMID- 21275426 TI - Synthesis and diversification of 1,2,3-triazole-fused 1,4-benzodiazepine scaffolds. AB - A substituted heterocyclic scaffold comprising a 1,4-benzodiazepine fused with a 1,2,3-triazole ring has been synthesized and diversified via a variety of refunctionalizations. The strategy features the rapid assembly of the scaffold by combining 3-4 reactants in an efficient multicomponent assembly process, followed by an intramolecular Huisgen cycloaddition. PMID- 21275427 TI - Facial selectivity and stereospecificity in the (4 + 3) cycloaddition of epoxy enol silanes. AB - The scope of the (4 + 3) cycloaddition using epoxy enol silanes has been examined. Unhindered and nucleophilic dienes react to give the highest yields, but hindered dienes give rise to higher diastereoselectivities. Notably, the cycloaddition shows facial selectivity and stereospecificity for the stereochemistry of the epoxy enol silane. PMID- 21275428 TI - Solid-state combinatorial screening of (Sr,Ca,Ba, Mg)2Si5N8:Eu(2+) phosphors. AB - We employed a solid-state combinatorial chemistry technique to screen 4 ternary phosphor systems: (Sr,Ca,Ba)(2)Si(5)N(8):Eu(2+), (Sr,Ca,Mg)(2)Si(5)N(8):Eu(2+), (Sr,Mg,Ba)(2)Si(5)N(8):Eu(2+), and (Ca,Ba,Mg)(2)Si(5)N(8):Eu(2+). The current pure nitride-based system did not allow for the use of conventional liquid solution-based high-throughput experimentation, so that a specially designed solid-state high-throughput powder-dispensing synthesis technique was employed. As a result, four well-defined ternary combinatorial libraries were developed in terms of photoluminescent (PL) intensity and color chromaticity with no skipped compositions, which provided a quantitative relationship between PL properties and the composition of AE(2)Si(5)N(8):Eu(2+) (AE = alkaline earth elements) phosphors. PMID- 21275429 TI - Polymorphism of the epidermal growth factor receptor extracellular ligand binding domain: the dimer interface depends on domain stabilization. AB - Epidermal growth factor receptors (EGFRs) and their cytoplasmic tyrosine kinases play important roles in cell proliferation and signaling. The EGFR extracellular domain (sEGFR) forms a dimer upon the binding of ligands, such as epidermal growth factor (EGF) and transforming growth factor alpha (TGFalpha). In this study, multiple molecular dynamics (MD) simulations of the 2:2 EGF.sEGFR3-512 dimer and the 2:2 TGFalpha.sEGFR3-512 dimer were performed in solvent and crystal environments. The simulations of systems comprising up to half a million atoms reveal part of the structural dynamics of which sEGFR dimers are capable. The solvent simulations consistently exhibited a prominent conformational relaxation from the initial crystal structures on the nanosecond time scale, leading to symmetry breaking and more extensive contacts between the two sEGFR monomers. In the crystal control simulation, this symmetry breaking and compaction was largely suppressed by crystal packing contacts. The simulations also provided evidence that the disordered domain IV of sEGFR may act as a stabilizing spacer in the dimer. Thus, the simulations suggest that the sEGFR dimer can take diverse configurations in solvent environments. These biologically relevant conformations of the EGFR signal transduction network can be controlled by contacts among the structural domains of sEGFR and its ligands. PMID- 21275430 TI - Cu(II) mediated generation and spectroscopic study of the tris(4-anisyl)amine radical cation and dication. Unusually shielded chemical shifts in the dication. AB - The reaction of tris(4-anisyl)amine (TAA) with Cu(2+) ion leading to formation of the TAA radical cation and dication is described. Spectroscopic studies confirm the formation of the radical cation and dication. (1)H and (13)C NMR spectral studies reveal interesting structural features of the dication. PMID- 21275431 TI - Improved understanding of atmospheric organic aerosols via innovations in soft ionization aerosol mass spectrometry. AB - Organic molecules are a significant and highly varied component of atmospheric aerosols. Measurement of aerosol composition and improvements in our understanding of the complex chemistry involved in their formation and aging are being aided by innovations in soft ionization aerosol MS. (To listen to a podcast about this feature, please go to the Analytical Chemistry multimedia page at pubs.acs.org/page/ancham/audio/index.html.). PMID- 21275432 TI - Oligonucleotide array-in-well platform for detection and genotyping human adenoviruses by utilizing upconverting phosphor label technology. AB - We have developed a robust array-in-well test platform based on an oligonucleotide array, combining advantages of simple instrumentation and new upconverting phosphor reporter technology. Upconverting inorganic lanthanide phosphors have a unique property of photoluminescence emission at visible wavelengths under near-infrared excitation. No autofluorescence is produced from the sample or support material, enabling a highly sensitive assay. In this study, the assay is performed in standard 96-well microtiter plates, making the technique easily adaptable to high-throughput analysis. The oligonucleotide array in-well assay is employed to detect a selection of ten common adenovirus genotypes causing human infections. The study provides a demonstration of the advantages and potential of the upconverting phosphor-based reporter technology in multianalyte assays and anti-Stokes photoluminescence detection with an anti Stokes photoluminescence imaging device. PMID- 21275433 TI - Bioaccessibility of carotenoids and vitamin e from pasta: evaluation of an in vitro digestion model. AB - The present investigation aimed to expand the knowledge of bioaccessibility of carotenoids, tocopherols, and tocotrienols from cereal products such as pasta. Because most of the published approaches assessing the bioaccessibility of lipophilic micronutrients dealt with fruits and vegetables, a prevalent in vitro digestion procedure was modified. Additionally, several digestion parameters were evaluated with regard to their impact on the bioaccessibility of carotenoids and vitamin E from pasta. Overall, the estimated values were highly dependent on the amount of bile extract present in the digestive medium and to a lesser extent on the simulated gastric pH and the incubation time with digestive enzymes. The bioaccessibility of carotenoids and vitamin E from durum wheat pasta was quite high (71 +/- 5 and 70 +/- 4%, respectively), whereas these micronutrients were considerably less accessible from pasta containing 10% eggs (57 +/- 1 and 49 +/- 5%, respectively). PMID- 21275434 TI - Urinary metabolic biomarkers of hepatocellular carcinoma in an Egyptian population: a validation study. AB - The advent of metabonomics has seen a proliferation of biofluid profiling studies of patients with hepatocellular carcinoma. The majority of these studies have been conducted in single indigenous populations making the widespread applicability of candidate metabolite biomarkers difficult. Presented here is a urinary proton nuclear magnetic resonance spectroscopy study of mainly hepatitis C virus infected Egyptian patients with hepatocellular carcinoma, which corroborates findings of a previous study from our group of mainly hepatitis B infected Nigerian patients with hepatocellular carcinoma. Using multivariate statistical analysis, in the form of orthogonal signal-corrected partial least squared discriminant analysis, the sensitivity and specificity of the technique for distinguishing patients with tumors from healthy controls and patients with cirrhosis was 100%/94% and 81%/71%, respectively. Discriminatory metabolites included glycine, trimethylamine-N-oxide, hippurate, citrate, creatinine, creatine, and carnitine. This metabolic profile bears similarity to profiles identified in the Nigerian cohort of subjects indicative of tumor effects on physiology, energy production, and aberrant chromosomal methylation. This is the first study to identify similarly altered urine metabolic profiles of hepatocellular carcinoma in two etiologically and ethnically distinct populations, suggesting that altered metabolism as a result of tumorogenesis is independent of these two factors. PMID- 21275435 TI - Inactivated influenza vaccines: recent progress and implications for the elderly. AB - The current public health strategy for the containment of influenza is annual vaccination, which is recommended for the elderly and for those in risk factor categories that present the highest morbidity and mortality. However, because the immune response in the elderly is known to be less vigorous than in younger adults, research in the last decade has focused on improving the immune response to vaccination and increasing the protection of aged populations. The decreased efficacy of vaccines in the elderly is due to several factors, such as a decrease in the number of Langerhans cells, the limited capacity of dendritic cells to present antigen, defects in the expression of Toll-like receptors and the reduced expression of MHC class I and II molecules. Also, production of mature naive T cells by the thymus decreases with age. Among several approaches proposed to address the need for more immunogenic vaccines compared with conventional agents, the most well proven is the use of adjuvants. The first licensed adjuvant, aluminium-based mineral salts (alum), introduced in the 1920s, remains the standard worldwide adjuvant for human use and it has been widely used for almost a century. However, the addition of alum adjuvant to a split or subunit influenza vaccine has induced only marginal improvements. Other adjuvants have been developed and approved for human use since 1997; in particular, MF59, an oil-in water adjuvant emulsion of squalene, which is able to increase immunogenicity of seasonal, pre-pandemic and pandemic subunit vaccines while maintaining acceptable safety and tolerability profiles. More recently, another oil-in-water emulsion, AS03, has been approved as a component of pre-pandemic H5N1 and pandemic H1N1 2009 vaccines. Besides adjuvants, several other strategies have been assessed to enhance antibody response in the elderly and other less responsive subjects, such as high-dose antigen vaccines, carrier systems (liposomes/virosomes) and the intradermal route of immunization. In particular, the potential of intradermal vaccination is well documented and the recent availability of an appropriate injection system, which combines simplicity, safety and ease of use, has allowed evaluation of the tolerability, safety and immunogenicity of the intradermal influenza vaccine in large numbers of subjects. Data that emerged from large clinical trials showed an improved immunogenicity compared with that of standard vaccine. Observational studies or comparisons between adjuvanted, intradermal or high-dose versus conventional vaccines are needed to evaluate whether the greater immunogenicity observed in a number of recent studies is correlated with greater protection against influenza and influenza-related complications and death. PMID- 21275436 TI - Epidemiology, pathophysiology and medical management of postoperative ileus in the elderly. AB - As the population of the Western world ages, the number of major surgical procedures performed in the elderly population will by necessity increase. Within virtually every surgical specialty, studies have shown that patients should not be denied surgery on the basis of chronological age alone. It has recently been recognized that physiological age is far more important within the decision making algorithm as to whether or not to proceed with major surgery in the septuagenarian and octogenarian populations and beyond. Not unexpectedly, not only the results of these operations, but also the associated morbidities, are similar in older and younger populations. Therefore, it is not surprising that postoperative ileus (POI) affects patients of all ages. POI is a multifactorial condition that is exacerbated by opioid analgesics, bed rest and other conditions that may be rather prevalent in the postoperative elderly patient. Therefore, as major surgical interventions are considered in this population, appropriate assessment and, ideally, correction of any physiological disturbances should be undertaken along with implementation of standardized enhanced recovery protocols. Ideally, through this combined approach, an appreciable impact can be made on reducing POI while controlling postoperative pain and limiting postoperative thromboembolic, cardiopulmonary, cerebral and infectious complications. This article reviews the potential impact of pharmacological agents, laparoscopy and other manoeuvres on POI in the elderly. PMID- 21275437 TI - Safety of clopidogrel in older patients: a nonrandomized, parallel-group, controlled, two-centre study. AB - BACKGROUND: The safety and efficacy of clopidogrel therapy in patients with stable coronary artery disease or acute coronary syndromes undergoing percutaneous coronary intervention (PCI) have been demonstrated. OBJECTIVES: To evaluate the safety (primary outcome, defined as any bleeding complication or thrombocytopenia) and adverse outcomes (secondary outcomes, defined as death from cardiovascular causes, myocardial infarction or stroke) of clopidogrel therapy in patients aged >=75 years with stable or unstable coronary artery disease undergoing PCI, and to compare these outcomes with those in younger controls. METHODS: Patients with both stable coronary heart disease and acute coronary syndromes undergoing PCI were included in the study. Two groups were formed according to age at the time of admission. Patients aged >=75 years (the study group, n = 149) formed one group; the other group included patients aged <75 years (the control group, n = 298). During an ad hoc PCI procedure, a 600 mg loading and 75 mg/day maintenance dose of clopidogrel in addition to aspirin (acetylsalicylic acid) therapy (300 mg/day) were administrated to both treatment groups. In-hospital outcomes were investigated during a mean +/- SD follow-up period of 5.3 +/- 3.9 days. RESULTS: The first safety (primary) outcome of any bleeding event occurred in 16.1% of the patients in the study (older) group and 6.0% of the patients in the control (younger) group (odds ratio [OR] 2.987; 95% CI 1.565, 5.701; p = 0.001). The second safety outcome of TIMI (Thrombolysis in Myocardial Infarction) major bleeding occurred in 4.0% of the patients in the study group and 0.7% of the patients in the control group (OR 6.210; 95% CI 1.238, 31.151; p = 0.012). Other safety outcomes of TIMI minor/minimal bleeding and thrombocytopenia were not different between the two groups. The rate of the first adverse (secondary) outcome of the composite of death from cardiovascular causes, myocardial infarction or stroke was higher in older patients (12.1% vs 5.4%) [OR 2.422; 95% CI 1.197, 4.899; p = 0.012], primarily driven by stroke events (2.0% vs 0%; p = 0.014). CONCLUSIONS: Any bleeding and TIMI major bleeding complications increase in patients aged >=75 years treated with clopidogrel in addition to aspirin. PMID- 21275438 TI - Association of anticholinergic drugs with hospitalization and mortality among older cardiovascular patients: A prospective study. AB - BACKGROUND: Many potentially inappropriate drugs prescribed to older people have anticholinergic properties as adverse effects and are therefore potentially harmful. These effects typically include constipation, dry mouth, blurred vision, dizziness and slowing of urination. It has been shown that drugs with anticholinergic properties (DAPs) are associated with cognitive decline and dementia, may contribute to events such as falls, delirium and impulsive behaviour, are associated with self-reported adverse effects and physical impairment, and may even be associated with mortality. However, studies of the prognostic implications of DAPs remain scarce. OBJECTIVE: To evaluate the impact of DAPs on hospitalization and mortality in older patients with stable cardiovascular disease (CVD). METHODS: This was a prospective study with a mean follow-up of 3.3 years involving two study groups: users (n = 295) and non-users (n = 105) of DAPs. The participants were 400 community-dwelling older people (aged 75-90 years) with stable CVD participating in a secondary prevention study of CVD (DEBATE) in Helsinki, Finland. The use of DAPs was estimated using definitions from the previous scientific literature. The Charlson Comorbidity Index (CCI) was used to estimate the burden of co-morbidity and the Mini-Mental State Examination test was used to assess cognitive function. The risks in the two study groups for hospital visits, number of days spent in hospital care and mortality were measured from 2000 to the end of 2003. RESULTS: The unadjusted follow-up mortality was 20.7% and 9.5% among the users and non-users of DAPs, respectively (p = 0.010). However, the use of DAPs was not a significant predictor of mortality in multivariate analysis after adjustment for age, sex and CCI score (hazard ratio 1.57; 95% CI 0.78, 3.15). The mean +/- SD number of hospital days per person-year was higher in the DAP user group (14.9 +/- 32.5) than in the non-user group (5.2 +/- 12.3) [p < 0.001]. In a bootstrap-type analysis of covariance adjusted for age, sex and CCI score, the use of DAPs predicted the number of days spent in hospital (p = 0.011). CONCLUSIONS: The use of DAPs in older patients with stable CVD was associated with an increased number of hospital days but not with mortality. PMID- 21275439 TI - Systemic exposure to armodafinil and its tolerability in healthy elderly versus young men: an open-label, multiple-dose, parallel-group study. AB - BACKGROUND: Armodafinil (Nuvigil((r)), Cephalon, Inc., Frazer, PA, USA), the longer-lasting isomer of racemic modafinil, is a nonamphetamine, wakefulness promoting medication. In patients with excessive sleepiness associated with shift work disorder, treated obstructive sleep apnoea, or narcolepsy, armodafinil has been found to improve wakefulness throughout the shift or day. In addition, while not approved for this indication, armodafinil has been found to improve excessive sleepiness associated with jet-lag disorder. OBJECTIVE: This study evaluated systemic exposure to armodafinil and its two major circulating metabolites, R modafinil acid and modafinil sulfone, and assessed the tolerability profile of armodafinil in elderly and young subjects. METHODS: The pharmacokinetics and tolerability of armodafinil were assessed in an open-label, multiple-dose, parallel-group study in two groups (n = 25 in each group) of healthy men (elderly group aged >=65 years and young group aged 18-45 years) who received armodafinil 50 mg on day 1, 100 mg on day 2 and 150 mg once daily on days 3 through 7. Plasma concentrations of armodafinil and its metabolites were quantified over 72 hours following the last dose on day 7. Pharmacokinetic parameters, including area under the plasma drug concentration-versus-time curve during a dosing interval (AUC(tau)) and maximum observed plasma drug concentration (C(max)), and tolerability were assessed. RESULTS: All 50 subjects enrolled in the study were evaluable for tolerability and 49 were included in the pharmacokinetic analysis. One elderly subject was excluded from the pharmacokinetic analyses because of apparent noncompliance with armodafinil dosing. Systemic exposure following administration of armodafinil, as measured by steady-state AUC(tau) and C(max) values, was approximately 15% greater in elderly subjects compared with young subjects. Geometric mean ratios for AUC(tau) and C(max) in the two groups were 1.14 (95% CI 1.03, 1.25; p = 0.0086) and 1.15 (95% CI 1.08, 1.24; p = 0.0002), respectively. When data were analysed for elderly subgroups, systemic exposure in the old-elderly group (age >=75 years; n = 7) was 27% greater than in young subjects, as compared with 10% greater in the young-elderly group (age 65-74 years; n = 17). Although steady-state exposure to the metabolite R-modafinil acid was also higher in elderly than in young subjects (geometric mean ratios for AUC(tau) and C(max) were 1.73 and 1.61, respectively; p < 0.0001), there were no significant differences in systemic exposure to modafinil sulfone. Armodafinil was generally well tolerated by both groups. Headache (four subjects in each group), nausea (one in the elderly group and four in the young group), insomnia (two in the elderly group and one in the young group), and dizziness (two in the young group) were the most common adverse events. CONCLUSIONS: Systemic exposure following administration of armodafinil is increased in the elderly in comparison with younger subjects, particularly in those aged >=75 years. Although the increase in plasma armodafinil concentration in elderly subjects does not appear to result in more adverse events compared with young subjects, consideration should be given to the use of lower dosages of armodafinil for the management of excessive sleepiness in older patients, particularly the very elderly. PMID- 21275440 TI - Once-daily trospium chloride 60 mg extended release in subjects with overactive bladder syndrome who use multiple concomitant medications: Post hoc analysis of pooled data from two randomized, placebo-controlled trials. AB - BACKGROUND: Overactive bladder syndrome (OAB) is associated with various co morbidities; treatment of these frequently results in multiple medication use (MMU) and the potential for drug-drug interactions, which may lead to adverse events and altered efficacy. With the aging population, the prevalence of MMU is likely to increase in the overall population, an increase due in part to treatment of co-morbidities that are more common in the elderly. OBJECTIVE: To assess safety and efficacy outcomes with once-daily trospium chloride 60 mg extended release (XR) in subjects with OAB who were taking multiple concomitant medications. STUDY DESIGN: Post hoc analysis of pooled data from two 12-week randomized, placebo-controlled studies. SETTING: Urology, urogynaecology, and primary care offices/clinics. PATIENTS: Subjects aged >=18 years with OAB for >=6 months who had baseline urinary frequency of >=30 toilet voids/3 days; >=1 'severe' urgency severity rating/3 days (on the Indevus Urgency Severity Scale); and pure urge urinary incontinence (UUI) or mixed incontinence with predominant UUI, with >=3 UUI episodes/3 days. This analysis utilized data from subjects taking concomitant medications, focusing on those taking seven or more. INTERVENTION: Once-daily trospium chloride 60 mg XR or placebo. MAIN OUTCOME MEASURE: Predictors of treatment-emergent adverse events (TEAEs) identified by multivariate logistic regression analysis. RESULTS: Concomitant medications were being taken by 1135 subjects (placebo, n = 576; trospium chloride XR, n = 559); 427 were taking seven or more (placebo, n = 199; trospium XR, n = 228). Among subjects taking seven or more concomitant medications, there was no significant difference between trospium chloride XR and placebo in the proportion of subjects experiencing one or more TEAEs (64.5% vs 58.3%). Logistic regression analysis indicated that the odds of experiencing a TEAE were influenced by concomitant medication use, but not by randomization assignment to trospium chloride XR or to placebo, suggesting that concomitant drugs contribute more to TEAEs than trospium chloride XR. Compared with subjects taking one to two concomitant medications, the adjusted odds ratio (OR) for experiencing any TEAE was 3.39 (95% CI 2.39, 4.80; p < 0.0001) for subjects taking seven or more concomitant medications. The adjusted OR for experiencing any TEAE for subjects randomized to active treatment compared with placebo was 1.19 (95% CI 0.85, 1.67; p = 0.31). Efficacy in subjects taking seven or more concomitant medications was similar to that in the overall pooled study population. CONCLUSIONS: Trospium chloride XR does not increase the likelihood of a TEAE compared with placebo. The probability of experiencing a TEAE was significantly influenced by use of multiple concomitant medications. Trospium chloride XR was as effective in subjects with OAB taking seven or more concomitant medications as in the overall pooled study population. The data support the conclusion that trospium chloride XR is safe and effective in patients with OAB taking multiple concomitant medications. PMID- 21275441 TI - Cost effectiveness of rasagiline and pramipexole as treatment strategies in early Parkinson's disease in the UK setting: An economic Markov model evaluation. PMID- 21275442 TI - Rosiglitazone: trials, tribulations and termination. PMID- 21275443 TI - Bacteraemic pneumococcal pneumonia: current therapeutic options. AB - Streptococcus pneumoniae is the major bacterial cause of pneumonia, meningitis and otitis media, and continues to be associated with significant morbidity and mortality in individuals both in the developed and developing world. Management of these infections is potentially complicated by the emergence of resistance of this pathogen to many of the commonly used first-line antimicrobial agents. A number of significant risk factors exist that predispose to the occurrence of pneumococcal pneumonia, including lifestyle factors, such as exposure to cigarette smoke, as well as underlying medical conditions, such as HIV infection. Several of these predisposing factors also enhance the risk of bacteraemia. The initial step in the pathogenesis of pneumococcal infections is the occurrence of nasopharyngeal colonization, which may be followed by invasive disease. The pneumococcus has a myriad of virulence factors that contribute to these processes, including a polysaccharide capsule, various cell surface structures, toxins and adhesins, and the microorganism is also an effective producer of biofilm. Antibacterial resistance is emerging in this microorganism and affects all the various classes of drugs, including the beta-lactams, the macrolides and the fluoroquinolones. Even multidrug resistance is occurring. Pharmacokinetic/pharmacodynamic parameters allow us to understand the relationship between the presence of antibacterial resistance in the pneumococcus and the outcome of pneumococcal infections treated with the different antibacterial classes. Furthermore, these parameters also allow us to predict which antibacterials are most likely to be effective in the management of pneumococcal infections and the correct dosages to use. Most guidelines for the management of community-acquired pneumonia recommend the use of either a beta lactam/macrolide combination or fluoroquinolone monotherapy for the empirical therapy of more severe hospitalized cases with pneumonia, including the subset of cases with pneumococcal bacteraemia. There are a number of adjunctive therapies that have been studied for use in combination with standard antibacterial therapy, in an attempt to decrease the high mortality, of which macrolides in particular, corticosteroids and cyclic adenosine monophosphate-elevating agents appear potentially most useful. PMID- 21275444 TI - Optimizing therapy for iron overload in the myelodysplastic syndromes: recent developments. AB - The myelodysplastic syndromes (MDS) are characterized by cytopenias and risk of progression to acute myeloid leukaemia (AML). Most MDS patients eventually require transfusion of red blood cells for anaemia, placing them at risk of transfusional iron overload. In beta-thalassaemia major, transfusional iron overload leads to organ dysfunction and death; however, with iron chelation therapy, organ function is improved, and survival improved to near normal and correlated with the degree of compliance with chelation. In lower-risk MDS, several nonrandomized studies suggest an adverse effect of iron overload on survival and that lowering iron with chelation may minimize this impact. Emerging data indicate that chelation may improve organ function, particularly hepatic function, and a minority of patients may have improvement in cell counts and decreased transfusion requirements. While guidelines for MDS generally recommend chelation in selected lower-risk patients, data from nonrandomized trials suggest iron overload may impact adversely on the outcome of higher-risk MDS and stem cell transplantation (SCT). This effect may be due to increased transplant related mortality, infection and AML progression, and preliminary data suggest that lowering iron may be beneficial in this patient group. Other areas of active and future investigation include optimizing the monitoring of iron overload using imaging such as T2* MRI and measures of labile iron and oxidative stress; correlating new methods of measuring iron to clinical outcomes; clarifying the contribution of different cellular and extracellular iron pools to iron toxicity; optimizing chelation by using agents that access the appropriate iron pools to minimize the relevant clinical consequences in individual patients; and incorporating measures of quality of life and co-morbidities into clinical trials of chelation in MDS. It should be noted that chelation is costly and potentially toxic, and in MDS should be initiated after weighing potential risks and benefits for each patient until more definitive data are available. In this review, data on the impact of iron overload in MDS and SCT are discussed; for example, several noncontrolled studies show inferior survival in patients with iron overload in these clinical settings, including an increase in transplant-related mortality and infection risk. Possible mechanisms of iron toxicity include oxidative stress, which can damage cellular components, and the documented impact of lowering iron on organ function with measures such as iron chelation therapy includes an improvement in elevated liver transaminases. Lowering iron also appears to improve survival in both lower-risk MDS and SCT in nonrandomized studies. Selected aspects of iron metabolism, transport, storage and distribution that may be amenable to future intervention and improved removal of iron from important cellular sites are discussed, as are attempts to quantify quality of life and the importance of co-morbidities in measures to treat MDS, including chelation therapy. PMID- 21275446 TI - Olmesartan medoxomil/amlodipine/hydrochlorothiazide: fixed-dose combination in hypertension. AB - The antihypertensive agents olmesartan medoxomil, amlodipine and hydrochlorothiazide (HCTZ) are now available as a fixed-dose combination tablet (olmesartan medoxomil/amlodipine/HCTZ). In a 12-week, randomized, double-blind, multicentre trial (TRINITY) in adults with moderate to severe hypertension, olmesartan medoxomil + amlodipine + HCTZ triple combination therapy produced significantly greater least squares mean reductions from baseline in seated diastolic blood pressure (BP) [primary endpoint] and seated systolic BP than olmesartan medoxomil/amlodipine, olmesartan medoxomil/HCTZ or amlodipine + HCTZ. Furthermore, significantly more patients achieved BP goals and targets with the triple combination regimen than with any of the dual combination regimens at week 12, with olmesartan medoxomil + amlodipine + HCTZ also demonstrating benefit over the dual regimens in terms of ambulatory BP control. According to subgroup analyses of the TRINITY trial, olmesartan medoxomil + amlodipine + HCTZ was more effective in reducing BP and achieving BP goals than each of the dual therapies, irrespective of hypertension severity, age, sex, race or diabetes mellitus status. Data from a number of smaller clinical studies indicated that olmesartan medoxomil + amlodipine + HCTZ triple combination therapy provides antihypertensive efficacy in patients whose BP is not adequately controlled with olmesartan medoxomil + amlodipine. Olmesartan medoxomil + amlodipine + HCTZ was generally well tolerated in the TRINITY study, with adverse events usually being mild or moderate in severity. PMID- 21275445 TI - Management of schizophrenia in children and adolescents: focus on pharmacotherapy. AB - Schizophrenia in subjects younger than 13 years is defined as very-early-onset schizophrenia, and its prevalence is estimated at 1 in 10 000, while early-onset schizophrenia occurs between 13 and 17 years, and its prevalence is about 0.5%. Only a minority of youths show a complete recovery, and the majority of patients present a moderate to severe impairment at the outset. Treatment of schizophrenia always needs both pharmacological and nonpharmacological interventions. Nonpharmacological interventions include counselling for the patients and the family, psychological support, behavioural treatments, social and cognitive rehabilitation, assistance in social and scholastic activities, enhancement of social skills and family support. Pharmacological treatment is necessary for remission and control of positive and negative symptoms. Furthermore, proper pharmacotherapy can greatly increase the efficacy of psychosocial interventions. Available literature on pharmacotherapy in children and adolescents with schizophrenia is critically reviewed, including both first- and second-generation antipsychotics. Data on efficacy and safety are reported for all the marketed atypical antipsychotics (clozapine, risperidone, olanzapine, quetiapine, ziprasidone and aripiprazole), based on randomized, placebo-controlled studies and the most relevant open-label or naturalistic studies. Adverse effects of concern are closely analysed, such as extrapyramidal side effects and tardive dyskinesia, metabolic syndrome (including hyperglycaemia and hyperlipidaemia), weight gain, hyperprolactinaemia, hepatotoxicity, seizures, and cardiovascular and haematological adverse effects. Finally, practical guidelines for the management of specific clinical situations are provided: the first phases and the long-term approach to pharmacotherapy, the treatment refractoriness and the use of clozapine in youths, the agitated adolescent and the treatment of negative symptoms and of affective co-morbidity. Current experience indicates that, based on low rates of remission, low effect size of medications and frequent adverse effects, mainly metabolic syndrome, further research is warranted, with both randomized, placebo-controlled studies and long-term, naturalistic follow-up of large samples of patients with different age ranges. PMID- 21275447 TI - MMX(r) Mesalazine: a review of its use in the management of mild to moderate ulcerative colitis. AB - The Multi MatriX system (MMX(r)) formulation of mesalazine (Lialda(r); Mesavancol(r); Mezavant(r)) [henceforth referred to as MMX mesalazine] is an oral, high-dose, once-daily, gastro-resistant, prolonged-release formulation indicated for use in patients with mild to moderate ulcerative colitis. Mesalazine has numerous anti-inflammatory effects on the mucosa of the colon, parts of which are frequently inflamed in ulcerative colitis. MMX mesalazine is believed to act topically. Therapy with MMX mesalazine 2.4 or 4.8 g once daily for 8 weeks was superior to placebo in inducing clinical and endoscopic remission in patients with mild to moderate ulcerative colitis. In 12-month maintenance trials, MMX mesalazine 2.4 g/day maintained remission in about two-thirds of patients and was as effective as Asacol(r) 2.4 g/day (another oral formulation of mesalazine) as maintenance therapy. In general, MMX mesalazine was well tolerated in both short- and long-term clinical trials; its tolerability profile did not differ clinically to that of placebo or Asacol(r). The majority of adverse events reported in clinical trials were gastrointestinal in nature. Therefore, MMX mesalazine appears to be a valuable option in the management of patients with mild to moderate ulcerative colitis. PMID- 21275448 TI - Intravenous vernakalant: a review of its use in the management of recent-onset atrial fibrillation. AB - Intravenous vernakalant (Brinavess(r)) is an atrial-repolarization-delaying agent that is currently approved in the EU for the rapid conversion of recent-onset atrial fibrillation to sinus rhythm. Vernakalant blocks atrial-specific potassium and sodium ion channels, prolonging atrial refractory periods and rate dependently slowing atrial conduction, without promoting ventricular arrhythmia. In pivotal randomized, phase III trials, intravenous vernakalant 3 mg/kg administered as a 10-minute infusion, followed by a 2 mg/kg 10-minute infusion after 15 minutes if atrial fibrillation persisted, was effective in the rapid termination of recent-onset atrial fibrillation in nonsurgical patients (>=3 hours' to <=7 days' duration) and in those with postoperative atrial fibrillation (3-72 hours' duration) following cardiac surgery. Conversion to sinus rhythm occurred rapidly following infusion of vernakalant, with the majority of patients converting after the first dose, and conversion to sinus rhythm was generally associated with a rapid resolution of symptoms. These antiarrhythmic effects of vernakalant were durable, with most responders remaining in sinus rhythm 24 hours after treatment initiation. In nonsurgical patients with recent-onset atrial fibrillation of 3-48 hours' duration, vernakalant was more effective than intravenous amiodarone, with a significantly higher proportion of patients converting to sinus rhythm within the first 90 minutes of treatment. Vernakalant was generally well tolerated in clinical trials, with most adverse events being of mild or moderate severity and not treatment limiting. Increases in QRS or QT intervals were transient, and there was no increased incidence of ventricular arrhythmia observed with vernakalant compared with placebo. Therefore, intravenous vernakalant provides an effective option for the management of recent onset atrial fibrillation. PMID- 21275451 TI - MicroRNA binding-site polymorphisms as potential biomarkers of cancer risk. AB - Identification of people or populations at risk for developing cancer is a key to improved screening programs and earlier detection, with the hope of a commensurate reduction in cancer mortalities. Genetic alterations that change gene expression levels have long been investigated for association with development of cancer. Misregulation of genes through altered interactions is another potential mechanism of oncogenesis. Gene regulation by microRNAs (miRNAs) is a relatively new area of study, and a growing body of evidence suggests that alterations in this process may be associated with increased cancer risk. This can occur through alterations in miRNA levels, interactions with targets, or perhaps more complicated combinations of the two. Here we review the current data for association between single nucleotide polymorphisms (SNPs) in miRNA binding sites and specific cancers. This growing body of literature suggests that these SNPs have a potential role as biomarkers for cancer risk. PMID- 21275452 TI - Next-generation sequencing in the analysis of human microbiota: essential considerations for clinical application. AB - The development of next-generation sequencing (NGS) presents an unprecedented opportunity to investigate the complex microbial communities that are associated with the human body. It offers for the first time a basis for detailed temporal and spatial analysis, with the potential to revolutionize our understanding of many clinically important systems. However, while advances continue to be made in areas such as PCR amplification for NGS, sequencing protocols, and data analysis, in many cases the quality of the data generated is undermined by a failure to address fundamental aspects of experimental design. While little is added in terms of time or cost by the analysis of repeat samples, the exclusion of DNA from dead bacterial cells and the extracellular matrix, the use of efficient nucleic acid extraction methodologies, and the implementation of safeguards to minimize the introduction of contaminating nucleic acids, such considerations are essential in achieving an accurate representation of the system being studied. In this review, the chronic bacterial infections that characterize lower respiratory tract infections in cystic fibrosis patients are used as an example system to examine the implications of a failure to address these issues when designing NGS based analysis of human-associated microbiota. Further, ways in which the impact of these factors can be minimized are discussed. PMID- 21275453 TI - A new cyclo-oxygenase-2 gene variant in the Han Chinese population is associated with an increased risk of gastric carcinoma. AB - BACKGROUND AND OBJECTIVE: Cyclo-oxygenase-2 (COX-2, also known as prostaglandin synthase 2) influences carcinogenesis through regulation of angiogenesis, apoptosis, and cytokine expression. COX-2 is encoded by the gene PTGS2. Several studies have suggested that PTGS2 single-nucleotide polymorphisms (SNPs) are involved in gastrointestinal carcinogenesis. In this study, we observed the PTGS2 Val511Ala (5939T/C) polymorphism in the Chinese population for the first time, and investigated whether this polymorphism might contribute to gastric cancer in a case-control study conducted in the Gansu province of China, a high-risk area for gastric cancer. METHODS: We determined the genotypes of 110 gastric cancer patients and 138 controls using polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) analysis. Data were statistically analyzed using a chi-squared test and a logistic regression model. RESULTS AND CONCLUSION: In our analysis, PTGS2 5939C allele carriers were at increased risk of gastric cancer (odds ratio [OR] 1.742; 95% confidence interval [CI] 1.009, 3.005; p = 0.045). We also found an interaction between Helicobacter pylori infection, a family history of gastric cancer, and presence of the 5939C allele. This study further indicated that H. pylori-positive status and family history jointly contribute to a higher risk of gastric cancer. PMID- 21275454 TI - Cost effectiveness of interferon-gamma release assay for tuberculosis screening of rheumatoid arthritis patients prior to initiation of tumor necrosis factor alpha antagonist therapy. AB - BACKGROUND: The prevalence of tuberculosis (TB) in rheumatoid arthritis (RA) patients is higher than that in the general population, and RA patients are considered a high-risk group. Currently, TB screening of RA patients receiving immunosuppressive therapy such as tumor necrosis factor-alpha (TNFalpha) antagonists is performed by the tuberculin skin test (TST) in Japan. Interferon gamma release assays (QuantiFERON(r)-TB Gold In-Tube [QFT] and T-SPOT.TB(r)) are new alternatives to the TST to diagnose latent TB infection (LTBI) and active TB, and offer higher specificity and no cross-reactivity with Bacillus Calmette Guerin (BCG) vaccine. We evaluated the cost effectiveness of QFT versus TST in non-BCG-vaccinated and BCG-vaccinated RA patients. METHODS: We constructed a Markov model to evaluate the cost effectiveness of QFT and TST. The target population is a hypothetical cohort of 1000 RA patients, using a societal perspective and the lifetime horizon. All costs and clinical benefits were discounted at a fixed annual rate of 3%. RESULTS: In base-case analysis, the QFT strategy was the most cost effective ($US1044.52; 23.03499 quality-adjusted life years [QALYs]) compared with the TST strategy for non-BCG-vaccinated RA patients ($US1824.61; 22.98153 QALYs) and for BCG-vaccinated RA patients ($US2096.34; 22.98153 QALYs) [year 2009 values]. The incidence of TB in RA patients with TNFalpha antagonist therapy influenced the cost effectiveness. When the incidence of TB in RA patients with TNFalpha antagonist therapy is under 0.00066, the TST strategy is more cost effective than the QFT strategy. CONCLUSIONS: QFT screening is more effective and less costly than the TST for both BCG-vaccinated and non BCG-vaccinated RA patients prior to TNFalpha antagonist therapy in Japan. These findings may be applicable to other countries when choosing optimal LTBI screening of RA patients. PMID- 21275455 TI - Cost-effectiveness analysis of KRAS testing and cetuximab as last-line therapy for colorectal cancer. AB - BACKGROUND: Cetuximab, a monoclonal antibody directed against the epidermal growth factor receptor, improves progression-free survival and overall survival in patients with metastatic colorectal cancer (mCRC). However, patients with a KRAS gene mutation do not benefit from cetuximab therapy. METHODS: We performed a cost-effectiveness analysis of KRAS testing and cetuximab treatment as last-line therapy for patients with mCRC in Japan. In our analysis, we considered three treatment strategies. In the 'KRAS-testing strategy' (strategy A), KRAS testing was performed to guide treatment: patients with wild-type KRAS received cetuximab, and those with mutant KRAS received best supportive care (BSC). In the 'no-KRAS-testing strategy' (strategy B), genetic testing was not conducted and all patients received cetuximab. In the 'no-cetuximab strategy' (strategy C), genetic testing was not conducted and all patients received BSC. To evaluate the cost effectiveness of KRAS testing, the KRAS-testing strategy was compared with the no-KRAS-testing strategy; to evaluate the cost effectiveness of KRAS testing and cetuximab, the KRAS-testing strategy was compared with the no-cetuximab strategy; and to evaluate the cost effectiveness of cetuximab treatment without KRAS testing, the no-KRAS-testing strategy was compared with the no-cetuximab strategy. A three-state Markov model was used to predict expected costs and outcomes for each group. Outcomes in the model were based on those reported in a retrospective analysis of data from the National Cancer Institute of Canada Clinical Trials Group CO.17 study. We included only direct medical costs from the perspective of the Japanese healthcare payer. A 3% discount rate was used for both costs and outcome. Two outcomes, life-years (LYs) gained and quality adjusted life-years (QALYs) gained, were used to calculate the incremental cost effectiveness ratio (ICER). RESULTS: Our cost-effectiveness analysis revealed that the KRAS-testing strategy was dominant compared with the no-KRAS-testing strategy, with an expected cost reduction of Y0.5 million per patient and an estimated budget impact of Y3-5 billion ($US42-59 million; July 2010 values) per year. The ICER of the KRAS-testing strategy compared with the no-cetuximab strategy was Y11 million ($US120 000) per LY gained and Y16 million ($US160 000) per QALY gained, whereas the ICER of the KRAS-testing strategy compared with the no-KRAS-testing strategy was Y14 million ($US180 000) per LY gained and Y21 million ($US230 000) per QALY gained. These results were supported by the sensitivity analysis. CONCLUSIONS: KRAS testing is recommended before administering cetuximab as last-line therapy for patients with mCRC. However, our analysis suggests that the ICER of cetuximab treatment (with or without KRAS testing) is too high, even if treatment is limited to patients with wild-type KRAS. PMID- 21275457 TI - Genomic changes in salivary gland pleomorphic adenomas detected by comparative genomic hybridization. AB - The aim of this study was to investigate whether so far unknown chromosomal alterations in pleomorphic adenoma (PA) exist. To this end, tissue samples from 18 patients with parotid gland PA were studied by comparative genomic hybridization (CGH) using Phi-29-DNA-polymerase for DNA amplification. The most common aberrations were losses of chromosomal material of 19p (6/18), 9q, 16p, and 19q (in 3 out of 18 patients each). Additional losses were observed on 4p, 5q, and 17q (2 / 18 each). Gains involved chromosomes 2p, 4p, 6p, 17q, and 21q (2 / 18 each). Losses of 19p have been associated with inactivation of tumor suppressor genes in carcinomas previously. As a result, pleomorphic adenomas show a considerable diversity of chromosomal gains and losses detected by CGH. The 19p arm, and particularly its 19p13 region, need be further studied to elucidate the potential impact of associated lost tumor suppressor genes on PA development. PMID- 21275458 TI - Prohibitin as a novel target protein of luteinizing hormone in ovarian epithelial carcinogenesis. AB - The exact role of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in ovarian epithelial carcinoma (OEC) development has not been yet characterized. This prompted us to identify particular proteins to better understand the underlying mechanism. Total proteins from ovarian epithelial tumor (OET) cells treated with gonadotropins were analyzed by proteomics. Western blot and immunohistochemistry were used to validate the target protein (prohibitin) and to detect its expression in human ovarian tissue of serous tumors. As the results, prohibitin was found to be significantly up-regulated by LH, with a maximum of 2.5-fold increase at the concentration of 200 mIU/mL. The expression of prohibitin was steadily decreased from benign serous cystadenomas to borderline tumors and serous carcinomas (P < 0.0001). The difference between any two groups was significant (P < 0.001). Collectively, data from this study indicate that prohibitin is one LH-associated protein and it may be protective of ovarian cancer development and progression, supporting that LH may play an inhibitory role in ovarian tumorigenesis. PMID- 21275459 TI - Hypermethylation and aberrant expression of Wnt-antagonist family genes in gastric cardia adenocarcinoma. AB - The canonical Wnt signalling pathway plays a key role during embryogenesis and pathogenesis of various types of tumors. Recently, several studies have shown that the promoter hypermethylation of Wnt-antagonist genes, including sFRP-1, sFRP-2, sFRP-4, sFRP-5, Wif-1 and Dkk-3, have been certified to contribute to the tumorigenesis of several cancers. The aim of this study was to investigate the promoter methylation of Wnt-antagonist genes in gastric cardia adenocarcinoma (GCA) and corresponding adjacent non-cancerous tissues, and to establish the possible relationship between DNA methylation status and the pathogenesis of GCA. MSP, RT-PCR methods were applied respectively to examine the CpG methylation of the Wnt-antagonist genes and its mRNA expression in tumors and corresponding non cancerous tissues, and immunohistochemistry method was used to determine protein expression of beta-catenin(the key factor of the Wnt signalling pathway) and cyclin D1(the target gene of this pathway). The frequency of promoter methylation of sFRP-1, sFRP-2, sFRP-4, sFRP-5, Wif-1 and Dkk-3 genes in GCA tumor tissues were 78.7%(74/94), 76.6%(72/94), 70.2%(66/94), 77.1%(73/94), 61.7%(58/94) and 21.3%(20/94), respectively, which were significantly higher than those in adjacent non-cancerous tissues. Furthermore, the frequencies of silenced mRNA expression of these six genes in GCA tumor tissues were significantly higher than those in adjacent non-cancerous tissues. Methylation levels of these six genes were all correlated with loss of mRNA expression. The ectopic expression of beta catenin and cyclin D1 was significantly more frequent in GCA tumor tissues than that in adjacent non-cancerous tissues and correlated with each Wnt-antagonist genes hypermethylation status. Epigenetic silencing of Wnt-antagonist genes expression by promoter hypermethylation may play an important role in gastric cardia adenocarcinoma. PMID- 21275460 TI - Synergistic apoptotic effect of arabinoxylan rice bran (MGN-3/Biobran) and curcumin (turmeric) on human multiple myeloma cell line U266 in vitro. AB - The present study was carried out to investigate the synergistic apoptotic potential of arabinoxylan rice bran (MGN-3/Biobran) and curcumin (turmeric) on human multiple myeloma (MM) cell line U266 , in vitro. U266 cells were cultured with MGN-3 (50 or 100MUg/ml) and curcumin (2.5-10MUM) for 3 days. The effects of MGN-3 and curcumin on the growth and survival of the U266 cells were determined by trypan blue, MTT assay, flow cytometry analysis of cancer cell cycle, and apoptosis. Expression of proapoptotic Bax, and antiapoptotic Bcl2 was determined by Western blot analysis. Treatment with MGN-3 alone or curcumin alone caused a dose-dependent inhibition in the proliferation of U266 cells. However, a synergistic effect was noticed post-treatment with both agents that maximized at 100MUg/ml MGN-3 plus 10MUM curcumin. This synergy was characterized by an 87% decrease in cell number and a 2.6 fold increase in the percentage of apoptotic U266 cells. Cell cycle analysis showed a 53% decrease in the percentage of cells in the G0-G1 phase treated with MGN-3 and curcumin (from 36% to 17%). Analysis of the expression of the pro and antiapoptotic molecules Bax and Bcl-2 revealed synergistic effects of these agents, as the expression of Bcl-2 was decreased and Bax was increased. This resulted in a cellular microenvironment favorable for apoptosis. We conclude that MGN-3 and curcumin synergize in the induction of U266 cell apoptosis. This data may establish the foundation for in vivo studies that could have therapeutic implications. PMID- 21275461 TI - Relationship of resistin levels with endometrial cancer risk. AB - Cancer of endometrium (CAE) is the most common gynecologic malignancy in industrialized nations. Increased resistin levels, an adipocytokine produced by adipose tissue and macrophages, have been considered as a risk factor in gastric, colon and breast cancer, recently. No studies associating resistin levels with endometrial cancer have been done so far. The purpose of this case-control study was to determine the relationship between serum circulating resistin levels and resistin gene -420C>G (rs3219175) variant in endometrial cancer patients. 37 Caucasian female patients and 39 healthy controls were enrolled in this study. Difference in resistin levels between age and BMI matched patients group (mean 24.2 ng/ml) and control subjects (mean 10.1 ng/ml) were statistically significant (p <001). We also determined single nucleotide polymorphism -420C>G (rs3219175) within resistin gene and no significant association between resistin levels and investigated polymorphism was found. Furthermore, no significant association between higher resistin levels and diabetes mellitus 2, body mass index, smoking or age have been observed within studied groups. To our knowledge, this is the first study examining the relationship between serum resistin levels and endometrial cancer and our results show, that patients with endometrial cancer have significantly increased circulating levels of resistin compared to control subjects. PMID- 21275462 TI - Coagulation disorders in patients with locally advanced head and neck cancer - should they really be disregarded? AB - The aim of the study was to analyse coagulation disorders in patients with locally advanced cancer of the head and neck (CHN)and with no other clinical cause for coagulation disorders treated with radiation therapy alone or concurrent chemoradiotherapy. We also assessed the duration of disorders in the course of therapy. The analysed group consisted of 33 patients with locally advanced CHN documented as stage T3 or T4 acc. to the TNM classification. Coagulology tests (activated partial thromboplastic time /APTT/, prothrombin time, fibrinogen concentration, euglobulin lysis time, C - reactive protein and anti-thrombin III concentration, d-dimer level, PAI-1, plasminogen level and plasmin-anti-plasmin assays) were performed before, during and after the completion of treatment. In all cases pre-tratment abnormal fibrinolysis was observed. We observed elevated PAI-1 levels in all blood tests regardless of the treatment stage, while elevated plasminogen concentration and euglobulin lysis time was observed in a majority of tests. Increased PAI-1 level persisted independently of tumor regression during treatment. Half of our patients also presented with a tendency towards shortened APTT. One patient had a significantly higher d-dimer level at the end of the treatment. Decreased APTT was the sole factor influencing overall survial (OS) confirmed in multivariate analysis (Cox's proportinal hazard model). Despite the occurence of abnormal fibrinolysis and decreased APTT, we did not observe an increased risk of coagulation disorders. We conclude that among caogulation tests only a decrease in APTT is, at present, a stasistically confirmed predective factor of shorter OS in CHN patients. Autothrombotic prophylactic treatment may be an effective option in this clinical setting. There is need for further studies on large patient groups. PMID- 21275463 TI - Clinical implication of (18)F-FDG PET/CT in carcinoma of unknown primary. AB - The value of (18)F-Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) in the detection of carcinoma of unknown primary (CUP) differs among the studies. This study aimed to evaluate the role of (18)F-FDG PET/CT in CUP. Fifty-one patients (19 women, 32 men) with metastasis confirmed by histopathology from an unknown primary tumor were included in this study. Patients received 370 MBq of (18)F-FDG intravenously, and PET/CT was performed at 60 minutes after injection. Primary tumor sites were detected in 5 of 51 patients (9.6%): in 2 patients with carcinoma of the lung, in 1 patient with carcinoma of the gallbladder, in 1 patient with carcinoma of the esophagus, and in 1 patient with carcinoma of the stomach. No primary tumor was discovered in the remaining 46 patients (90.4%) during the follow-up. The sensitivity, specificity, and accuracy of (18)F-FDG PET/CT were 100%, 80.4%, and 82.4%. The positive and negative predictive values were 35.7 and 100%, respectively. Based on the data presented, (18)F-FDG PET/CT has a clinical implicative value in detecting the primary tumor of CUP. PET/CT can be useful to rule out the possibility of detecting the primary tumor during the follow-up. PMID- 21275464 TI - Quantification of ZAP-70 expression in chronic lymphocytic leukemia: T/B-cell ratio of mean fluorescence intensity provides stronger prognostic value than percentage of positive cells. AB - Expression of ZAP-70 measured by flow cytometry belongs to the most powerful prognostic parameters in chronic lymphocytic leukemia (CLL). However, many technical factors such as setting of the positivity threshold may significantly influence results.. Quantification using mean fluorescent intensity (MFI) may eliminate the subjective error which is inevitable in the isotype control method. The aim of the present project was therefore to assess the prognostic significance of ZAP-70 using three different methods. Between 2005 and 2010 we measured ZAP-70 expression in 157 patients with CLL (108 males, 49 females, median age 60 years [range, 31-82]; low/intermediate/high Rai risk in 41/48/11%). Expression of ZAP-70 was determined by flow cytometry using phycoerythrin (PE) conjugated monoclonal antibody, clone 1E7.2. Evaluation was performed by 1) percentage of positive cells compared to isotype control (cut-off 20%), 2) MFI ratio of T-cells/CLL cells (cut-off 3.0); 3) MFI ratio of ZAP-70/isotype control on CLL cells (cut-off 2.5). MFI method with T-cells/CLL cells ratio was the best in the identification of patients with unfavourable outcome: ZAP-70 positive patients had significantly shorter time to treatment (TTT, median 24 vs. 55 months, p=0.0001) and overall survival (OS, median 97 vs 174 months, p=0.0074). The differences in TTT a OS were not significant with the use of isotype percentage and MFI isotype methods. Combined analysis of ZAP-70 with CD38 expression or IgVH mutation status lead to identification of a subgroup with the longest TTT and OS (ZAP-70 and CD38 negative, p<0.0001 and p=0.012; ZAP-70 negative and mutated IgVH genes, p<0.0001 and p=0.0019). In conclusion, our results suggest that measurement of ZAP-70 expression in CLL by MFI using T cells/CLL cells ratio might be the optimal method for accurate prediction of clinical course. Combined analysis of ZAP-70 with CD38 or IgVH mutation status further refined individual patient's prognosis. PMID- 21275465 TI - Percutaneous US-guided needle biopsies of solid renal masses. AB - Our objective was to examine the variables affecting diagnostic yield and complications in percutaneous ultrasonography-guided needle biopsies of solid renal masses. Percutaneous ultrasonography-guided needle biopsy of solid renal masses was performed in 172 patients with either large size (18G) cutting needles or small size (20G) aspiration needles. Retrospectively, 120 patients with diagnosis by percutaneous biopsy and follow-up data were included in this series. Age, gender, side, locations in kidneys, necrosis, calcification, maximum size, needle groups due to needle size and type (either 18G cutting needles or 20G aspiration needles), and needle pass were selected as variables. Their role was investigated in diagnostic yield. Two needle groups were divided and compared for diagnostic yield and safety. Also, change in treatment was evaluated. The mean maximum size of the masses was 8.8+/-4.9 cm. The only predictor affecting accuracy was side of kidney (p=0.002). Among patients, 15 (12.5%) and 105 (87.5%) had benign and malignant solid masses, respectively. Small and large needle groups did not differ in accuracy, 80.3% vs. 87.1% (p=1.000). Technical success was detected as 100%. No major complications neither tumor seeding was seen. Percutaneous ultrasonography-guided needle biopsy of solid renal masses is effective and safe method with large size cutting needles and small aspiration needles. Change in clinical management was significant at 63.3% rate. Diagnostic yield was low in left kidney relating to right kidney, 69.4 vs. 93.1, while upper lobe location did not lead to significant false result. Repeat biopsies can be taken under CT guidance after nondiagnostic diagnosis in solid tumors of left kidney. All the needles including large cutting type were found safe. PMID- 21275466 TI - The expression of histone demethylase JMJD1A in renal cell carcinoma. AB - BACKGROUND: Hypoxia-inducible factor 1alpha has been shown to play a central role in RCC tumorigenesis by acting as a transcription factor. Histone demethylase JMJD1A is an iron- and 2-oxoglutarate-dependent dioxygenase which catalyze the demethylation of mono- and dimethylated H3K9. JMJD1A can be upregulated by hypoxia via HIF-1 and associated with cancer. The expression of JMJD1A was determined in 10 kidney cancer tissue and adjacent tissue by quantitative polymerase chain reaction, western blotting and immunohistochemistry. Furthermore, the expression of JMJD1A was investigated in cell line 786-0 through adding nickle or cobalt ion to mimic hypoxic environment. The expression of JMJD1A was higher in cancer tissue than adjacent tissue, and in hypoxic environment than normal environment. In cancer tissue, the JMJD1A mainly located around blood vessels which indicated that JMJD1A is involved tumor angiogenesis. CONCLUSION: the increased expression of JMJD1A might be associated with the progression of kidney cancer. KEYWORDS: renal cell carcinoma, histone demethylase, JMJD1A, hypoxia-inducible factor, iron. PMID- 21275467 TI - Silencing STAT3 may inhibit cell growth through regulating signaling pathway, telomerase, cell cycle, apoptosis and angiogenesis in hepatocellular carcinoma: potential uses for gene therapy. AB - The genesis and development of hepatocellular carcinoma (HCC) is related to the abnormity of signaling pathway, telomerase, cell cycle, apoptosis, angiogenesis, and others, in which STAT3 signaling pathway plays a key role. The HCC cell line HepG2 was transfected with small interfering RNA (siRNA) directed against STAT3. After 72 h, cell growth and cycle were analysed by MTT and Flow cytometry. Then, the protein was extracted and the protein expression of STAT3, Smad3, p44/42, TERT, caspase-3, XIAP, Grp-78, HSP-27, MMP-2, MMP-9, VEGF-A, cyclin A, and cyclin E was detected by Western blot. After the transfection, HCC cell growth was inhibited during the 24-72 h time period and the cell cycle was arrested in G0/G1. STAT3 protein expression was inhibited at 72 h after the transfection. Interestingly, Smad3, p-caspase-3, p-p44/42, Grp78, cyclin A, and cyclin E protein expression was increased at 72 h, while TERT, caspase-3, XIAP, MMP-2, MMP 9, and VEGF-A protein expression decreased at 72 h. However, P44/42, and HSP27 protein expression showed no change following transfection. The results demonstrated that STAT3 signaling pathway may participate in HCC genesis and development through regulating the protein expression of other signaling pathway, telomerase, apoptosis, cell cycle and angiogenesis; thereby, blockade of the Stat3 pathway represents a potential strategy for future treatment. KEYWORDS: STAT3, signaling pathway, telomerase, cell cycle, apoptosis, angiogenesis. PMID- 21275468 TI - Combination of capecitabine and mitomycin C as first-line treatment in patients with metastatic breast cancer. AB - Optimal first-line chemotherapy for metastatic breast cancer (MBC) is challenging, particularly in patients previously treated with (neo) adjuvant anthracyclines/taxanes. Based on preclinical synergy with mitomycin C (MMC) and capecitabine in human tumor xenografts, we conducted a phase II study of first line capecitabine and MMC in MBC. Patients received 3-weekly chemotherapy comprising MMC 8 mg/m2 day 1 and capecitabine 1000 mg/m2 twice daily, days 1-14. Combination chemotherapy was administered for a maximum six cycles, single-agent capecitabine could be continued until progressive disease or unacceptable toxicity. Thirty patients were included, objective response rate was 65.5%. After a median follow-up of 18.5 months, median time to progression was 8.5 months and median overall survival was 29.8 months. The main adverse events were thrombocytopenia, pneumonitis and hemolytic uremic syndrome. Our data suggest that first-line capecitabine and MMC has good antitumor activity in MBC, but is associated with MMC-specific toxicity. PMID- 21275469 TI - ATLA (Alternatives to Laboratory Animals): past, present and future. PMID- 21275470 TI - The development and evaluation of in vitro alternative assays: a personal perspective. AB - Over the past 30 years, FRAME has actively participated in the development, evaluation and validation of in vitro alternative methods through the FRAME Alternatives Laboratory (FAL) in the University of Nottingham Medical School. Much has been learned through collaboration with industry (especially the cosmetics industry), other organisations (especially ECVAM), and certain individuals (notably Dr Bjorn Ekwall), particularly in relation to the need to use human cell cultures and to obtain, wherever possible, high-quality human data for use in in vivo/in vitro comparisons. Reference is made to the author's experience as Director of the FAL, notably in the development of in vitro assays for basal cytotoxicity, phototoxicity and the effects of repeated dosage. PMID- 21275471 TI - An assessment of the use of chimpanzees in hepatitis C research past, present and future: 2. Alternative replacement methods. AB - The use of chimpanzees in hepatitis C virus (HCV) research was examined in the report associated with this paper (1: Validity of the chimpanzee model), in which it was concluded that claims of past necessity of chimpanzee use were exaggerated, and that claims of current and future indispensability were unjustifiable. Furthermore, given the serious scientific and ethical issues surrounding chimpanzee experimentation, it was proposed that it must now be considered redundant--particularly in light of the demonstrable contribution of alternative methods to past and current scientific progress, and the future promise that these methods hold. This paper builds on this evidence, by examining the development of alternative approaches to the investigation of HCV, and by reviewing examples of how these methods have contributed, and are continuing to contribute substantially, to progress in this field. It augments the argument against chimpanzee use by demonstrating the comprehensive nature of these methods and the valuable data they deliver. The entire life-cycle of HCV can now be investigated in a human (and much more relevant) context, without recourse to chimpanzee use. This also includes the testing of new therapies and vaccines. Consequently, there is no sound argument against the changes in public policy that propose a move away from chimpanzee use in US laboratories. PMID- 21275472 TI - Reporting the implementation of the Three Rs in European primate and mouse research papers: are we making progress? AB - It is now more than 20 years since both Council of Europe Convention ETS123 and EU Directive 86/609/EEC were introduced, to promote the implementation of the Three Rs in animal experimentation and to provide guidance on animal housing and care. It might therefore be expected that reports of the implementation of the Three Rs in animal research papers would have increased during this period. In order to test this hypothesis, a literature survey of animal-based research was conducted. A randomly-selected sample from 16 high-profile medical journals, of original research papers arising from European institutions that featured experiments which involved either mice or primates, were identified for the years 1986 and 2006 (Total sample = 250 papers). Each paper was scored out of 10 for the incidence of reporting on the implementation of Three Rs-related factors corresponding to Replacement (justification of non-use of non-animal methods), Reduction (statistical analysis of the number of animals needed) and Refinement (housing aspects, i.e. increased cage size, social housing, enrichment of cage environment and food; and procedural aspects, i.e. the use of anaesthesia, analgesia, humane endpoints, and training for procedures with positive reinforcement). There was no significant increase in overall reporting score over time, for either mouse or primate research. By 2006, mouse research papers scored an average of 0 out of a possible 10, and primate research papers scored an average of 1.5. This review provides systematic evidence that animal research is still not properly reported, and supports the call within the scientific community for action to be taken by journals to update their policies. PMID- 21275473 TI - Development of in vitro models for a better understanding of the early pathogenesis of Batrachochytrium dendrobatidis infections in amphibians. AB - Batrachochytrium dendrobatidis, the causal agent of chytridiomycosis, is implicated in the global decline of amphibians. This chytrid fungus invades keratinised epithelial cells, and infection is mainly associated with epidermal hyperplasia and hyperkeratosis. Since little is known about the pathogenesis of chytridiomycosis, this study was designed to optimise the conditions under which primary keratinocytes and epidermal explants of amphibian skin could be maintained ex vivo for several days. The usefulness of the following set-ups for pathogenesis studies was investigated: a) cultures of primary keratinocytes; b) stripped epidermal (SE) explants; c) full-thickness epidermal (FTE) explants on MatrigelTM; d) FTE explants in cell culture inserts; and e) FTE explants in Ussing chambers. SE explants proved most suitable for short-term studies, since adherence of fluorescently-labelled zoospores to the superficial epidermis could be observed within one hour of infection. FTE explants in an Ussing chamber set up are most suitable for the study of the later developmental stages of B. dendrobatidis in amphibian skin up to five days post-infection. These models provide a good alternative for in vivo experiments, and reduce the number of experimental animals needed. PMID- 21275474 TI - European experimental animal use declines ever so slightly. AB - The latest report on experimental animal use in the EU indicates a slight decrease. However, the figures, which are for 2008, show that around 12 million animals are still used in laboratories throughout Europe. To date, only a summary of the data has been published, and so this report is limited to giving a comparison of trends and significant changes. The impact on the figures of the revision of Directive 86/609/EEC and the 7th Amendment to the Cosmetics Directive 76/768/EEC is discussed. In addition, consideration is given to which areas of research and regulation will need to be closely monitored, and the importance of continuing to push for the implementation of Three Rs initiatives is highlighted. PMID- 21275475 TI - Mind the gap. AB - The unmet needs of biomedical and clinical research are highlighted by reference to drug -induced liver injury(DILI), non-alcoholic fatty liver disease (NAFLD) and its severe form, non-alcoholic steatohepatitis (NASH). Examples in these areas highlight the major limitations of animal models with respect to predicting, examining and managing these clinically significant forms of liver injury. The way in which these knowledge gaps are being bridged by studies involving the use of human tissues and primary cells are described. PMID- 21275476 TI - The use of human tissues and cells in biomedical research: the unusual suspects. AB - There are compelling reasons to search for alternatives to the use of animals in medical and pharmaceutical research. Aside from the obvious animal welfare issues, both the well-established differences between animal models and humans, and the inherent inter-individual variability in human biological responses, indicate that human-based alternatives are urgently required. However, any such alternative must out-perform the animal-based alternative, otherwise there will be little or no uptake and adoption by end-users. Data obtained from inbred animal models is often highly reproducible, and is therefore attractive to researchers in the fields of biomedical and pharmaceutical research. The inter individual variability observed during human volunteer and human tissue-based studies is often considered to be problematic, and has been highlighted further with the advent of the 'omics' technologies, which generate large biological datasets. However, the variability in both baseline data and response to pharmacological or toxicological challenge observed in human tissues potentially contains a veritable gold mine of information, which may be critical for the advancement of drug discovery. PMID- 21275477 TI - The development of cell line models of childhood brain tumours. AB - Childhood brain cancers have a significant impact on society. Currently, it is possible to make sophisticated diagnoses, but the treatments do not reflect patient differences and are out-dated. In order to develop better therapies and improve the outcome, we must first understand the underlying biology of brain cancer and how cells influence the disease process. For that purpose, several lines of brain cancer stem cells have been isolated, which have retained the characteristics of their original tissues. These in vitro human cell models are a much-needed addition to research on childhood brain cancers. PMID- 21275478 TI - Accelerating clinical insights: how to use accelerator mass spectrometry to make better early development decisions. AB - This paper is an overview of the applications of the technique of Accelerator Mass Spectrometry (AMS) in the biomedical drug development field. The work described here has been carried out at Xceleron (York, UK and Germantown, MD, USA), and it aims to apply AMS to provide better information about the human pharmacokinetic/metabolic behaviour of drugs or drug candidates as early as possible. It is hoped that the use of this technique will contribute to the delivery of better, more effective drugs onto the market sooner, which will be good news for all concerned. PMID- 21275479 TI - A human approach to drug development: opportunities and limitations. AB - The pharmaceutical industry is failing in its primary function, with increasing expenditure and decreased output in terms of new medicines brought to market. It cannot carry on as it is, without sliding into a terminal decline. It must, therefore, take some positive steps toward addressing its problems. We do not have to look far to see one very obvious problem, namely, the industry's continuing reliance on nonhuman biology as the basis of its evaluation of potential safety and efficacy. The time has come to focus on the relevant, and to realise that more human-based testing is essential, if the industry is to survive as a source of innovation in drug therapy. This can incorporate earlier clinical testing, in the form of microdosing, and promotion of the development of more powerful computational approaches based on human information. Fortunately, headway is being made in both approaches. However, a problem remains in the lack of functional evaluation of human tissues, where the lack of commitment, and the inadequacy of the tissue resource itself, are hampering any serious developments. An outline of a collaborative scheme is proposed, that will address this issue, central to which is improved access to research tissues from heart-beating organ donors. PMID- 21275480 TI - The use of functional human tissues in drug development. AB - Drug development currently depends on animal models to provide an accurate prediction of human physiology and pathophysiology. However, as is clear from clinical trial failures during phases II and III, such in vivo models do not always predict the effects that a drug can elicit in humans. Tests with human tissues, which are obviously considered to be the closest model of human in vivo function, could fill the gap between animal-based tests and trials in patients. Despite clear advantages, logistical and ethical barriers prevent fresh human tissues from being widely used during drug development. Biopta is aiming to make human tissue testing a regular element of drug development, and works to lower the barriers surrounding the availability of tissue and practicalities of experimental work. PMID- 21275481 TI - Cell- and tissue-based approaches for cartilage repair. AB - Damage and degeneration of articular joints is a major healthcare concern, due to the association of joint disease with ageing, the current strong demographic changes in the proportion of elderly in the population, and the increased incidence of trauma in a sports-active younger population. These joints are biomechanical organs that transmit load between bones in our skeleton, and the articular cartilage forms a load-bearing surface that covers the bone within the joints. All the forces across the joints are thus transmitted through the cartilage, and it therefore makes an important biomechanical contribution to joint function. The cartilage is particularly prone to damage, and has limited capacity for natural repair. Although joint replacement is successful, it is less so in younger patients. For these patients, there is currently great interest in developing cell-based treatments for the biological repair of articular cartilage. PMID- 21275482 TI - A three-dimensional in vitro model of breast cancer: Toward replacing the need for animal experiments. AB - While the events leading to breast cancer development are not fully understood, a pre-invasive lesion, ductal carcinoma in situ (DCIS), is recognised as the main precursor of invasive disease. Understanding how pre-invasive lesions develop into invasive breast cancer is critical, since currently there is no way of predicting which tumours are likely to progress, leading to unnecessary surgical intervention or chemotherapy. With a lack of good animal models able to mimic DCIS progression in a laboratory setting, there has been a shift toward developing in vitro human models which more accurately represent human disease. By manipulating individual cell populations in these models, we can recapitulate the complex cellular interactions involved in disease progression, an essential step in understanding breast cancer behaviour. PMID- 21275483 TI - Development of a cell-based diabetic wound assay. AB - Chronic wounds require prolonged healthcare and adversely affect the quality of life of patients. They are particularly prominent in patients with diabetes, and their relative numbers are set to increase with the rise of diabetes within our population. Research is still needed to understand the factors leading to such wounds, to understand why they persist for such long periods of time, and also to develop new and efficacious treatment strategies. One problem facing this research is a lack of adequate animal models, as the current models do not truly reflect the human condition and often lead to much animal suffering. Hence, over the past four years, our group has been trying to develop a human-based in vitro diabetic wound model, which could be used as a high-throughput screening system to pre-screen potential chronic diabetic wound healing agents and to reduce unnecessary animal pain and suffering. To this end, we have isolated healthy and diseased skin fibroblasts from patient tissue biopsies. Crucially, to create a cell reporter system that can be widely used in the future, the cells were immortalised in order to escape senescence. By using microarray analysis, gene expression pattern differences have been identified between healthy and diseased cells, and disease-specific 'reporter' genes have been selected for further studies. The promoters of these reporter genes have been coupled to fluorescent reporter constructs and inserted back into the diseased fibroblasts, so that we now have proof-of-concept for a real-time diabetic reporter system for future exploitation. PMID- 21275484 TI - Filter-well technology for advanced three-dimensional cell culture: perspectives for respiratory research. AB - Cell culture has long been a valuable tool for studying cell behaviour. Classical plastic substrates are two-dimensional, and usually promote cellular proliferation and inhibit differentiation. Understanding cell behaviour within complex multicellular tissues requires the systematic study of cells within the context of specific model microenvironments. A model system must mimic, to a certain degree, the in vivo situation, but, at the same time, can significantly reduce its complexity. There is increasing agreement that moving up to the third dimension provides a more physiologically-relevant and predictive model system. Moreover, many cellular processes (morphogenesis, organogenesis and pathogenesis) have been confirmed to occur exclusively when cells are ordered in a three dimensional (3-D) manner. In order to achieve the desired in vivo phenotype, researchers can use microporous membranes for improved in vitro cell culture experiments. In the present review, we discuss the applications of filter-well technology for the advanced 3-D cell culture of human pulmonary cells. PMID- 21275485 TI - Biomimetic design of artificial micro-vasculatures for tissue engineering. AB - Over the last decade, highly innovative micro-fabrication techniques have been developed that are set to revolutionise the biomedical industry. Fabrication processes, such as photolithography, wet and dry etching, moulding, embossing and lamination, have been developed for a range of biocompatible and biodegradable polymeric materials. One area where these fabrication techniques could play a significant role is in the development of artificial micro-vasculatures for the creation of tissue samples for drug screening and clinical applications. Despite the enormous technological advances in the field of tissue engineering, one of the major challenges is the creation of miniaturised fluid distribution networks to transport nutrients and waste products, in order to sustain the viability of the culture. In recent years, there has been considerable interest in the development of microfluidic manifolds that mimic the hierarchical vascular and parenchymal networks found in nature. This article provides an overview of microfluidic tissue constructs, and also reviews the hydrodynamic scaling laws that underpin the fluid mechanics of vascular systems. It shows how Murray's law, which governs the optimum ratio between the diameters of the parent and daughter branches in biological networks, can be used to design the microfluidic channels in artificial vasculatures. It is shown that it is possible to introduce precise control over the shear stress or residence time in a hierarchical network, in order to aid cell adhesion and enhance the diffusion of nutrients and waste products. Finally, the paper describes the hydrodynamic extensions that are necessary in order to apply Murray's law to the rectangular channels that are often employed in artificial micro-vasculatures. PMID- 21275486 TI - Physiologically-based pharmacokinetic modelling for the reduction of animal use in the discovery of novel pharmaceuticals. AB - The challenges of physiologically-based pharmacokinetic (PBPK) modelling and approaches to replacing the use of animals, in order to determine drug pharmacokinetics, are discussed. Reference is made to the limitations of in vivo animal studies in drug discovery. In particular, the ways in which animal studies contribute to drug attrition during the post-preclinical phase of testing are considered. PMID- 21275487 TI - Development and application of human virtual excitable tissues and organs: from premature birth to sudden cardiac death. AB - The electrical activity of cardiac and uterine tissues has been reconstructed by detailed computer models in the form of virtual tissues. Virtual tissues are biophysically and anatomically detailed, and represent quantitatively predictive models of the physiological and pathophysiological behaviours of tissue within an isolated organ. The cell excitation properties are quantitatively reproduced by equations that describe the kinetics of a few dozen proteins. These equations are derived from experimental measurements of membrane potentials, ionic currents, fluxes, and concentrations. Some of the measurements were taken from human cells and human ion channel proteins expressed in non-human cells, but they were mostly taken from cells of other animal species. Data on tissue geometry and architecture are obtained from the diffusion tensor magnetic resonance imaging of ex vivo or post mortem tissue, and are used to compute the spread of current in the tissue. Cardiac virtual tissues are well established and reproduce normal and pathological patterns of cardiac excitation within the atria or ventricles of the human heart. They have been applied to increase the understanding of normal cardiac electrophysiology, to evaluate the candidate mechanisms for re-entrant arrhythmias that lead to sudden cardiac death, and to predict the tissue level effects of mutant or pharmacologically-modified ion channels. The human full-term virtual uterus is still in development. This virtual tissue reproduces the in vitro behaviour of uterine tissue biopsies, and provides possible mechanisms for premature labour. PMID- 21275488 TI - A social science view on the FRAME symposium: identities and networks. AB - This paper, written by two social scientists, presents a social science perspective on the issues raised at the FRAME symposium on Human Alternatives to Animal Studies. Drawing upon the authors' experience of conducting research with stem cell scientists, issues around access to human tissue for in vitro uses are considered. The paper concludes by raising questions pertinent to both interested social scientists and the Three Rs agenda. PMID- 21275490 TI - Principles of drug literature evaluation for observational study designs. AB - Clinical pharmacists must often interpret and use data derived from observational studies when making clinical decisions and recommendations, answering drug information questions, and educating patients about drug therapy. This is the third article in a three-part series intended to enhance clinical pharmacists' understanding of methods frequently used in such research and their application to patient care. Principles for critical evaluation of published observational studies are presented. Issues of bias and confounding that must be taken into account when assessing the data derived from observational studies are explained. Finally, examples of applications in pharmacy practice are presented. PMID- 21275491 TI - Interdisciplinary patient care in the intensive care unit: focus on the pharmacist. AB - The field of critical care medicine began to flourish only within the last 40 years, yet it provides some of the best examples of collaborative pharmacy practice models and evidence for the value of pharmacist involvement in interdisciplinary practice. This collaborative approach is fostered by critical care organizations that have elected pharmacists into leadership positions and recognized pharmacists through various honors. There is substantial literature to support the value of the critical care pharmacist as a member of an interdisciplinary intensive care unit (ICU) team, particularly in terms of patient safety. Furthermore, a number of economic investigations have demonstrated cost savings or cost avoidance with pharmacist involvement. As the published evidence supporting pharmacist involvement in patient care activities in the ICU setting has increased, surveys have demonstrated an increase in the percentage of pharmacists performing clinical activities. In addition, substantial support of pharmacists has been provided by other clinicians, safety officers, and administrative personnel who have been involved with the initiation and expansion of critical care pharmacy services in their own institutions. Although there is still room for improvement in the range of pharmacist involvement, particularly with respect to interdisciplinary activities related to education and scholarship, pharmacists have become essential members of interdisciplinary care teams in ICU settings. PMID- 21275492 TI - Assessment of the 4Ts pretest clinical scoring system as a predictor of heparin induced thrombocytopenia. AB - STUDY OBJECTIVE: To evaluate the utility of the 4Ts clinical scoring system as a pretest probability method for the detection of heparin-induced thrombocytopenia (HIT). DESIGN: Prospective observational study. SETTING: Medical and surgical inpatients at a tertiary care medical center. PATIENTS: Eighty consecutive patients with suspicion of HIT who had a polyspecific enzyme-linked immunosorbent assay (ELISA) performed between December 1, 2008, and April 1, 2009, for detection of platelet factor 4 (PF4)-heparin antibodies. MEASUREMENTS AND MAIN RESULTS: The predictive value of the 4Ts scoring system as determined by using a standard laboratory marker of HIT--the ELISA--and the interrater reliability of the scoring system were assessed. Sixty-seven (84%) of the 80 patients had low clinical probability of HIT based on the calculated 4Ts score. The ELISA result was negative for PF4-heparin antibodies in 74 patients (93%). Based on the results of the ELISA, the negative predictive value of the 4Ts score was 91%. Each 4Ts score was calculated by two independent investigators and adjudicated by a third investigator when necessary. The interrater reliability of the scoring system was fair (Cohen kappa coefficient 0.362, 95% confidence interval [CI] 0.222-0.502; weighted kappa coefficient 0.554 (95% CI 0.441-0.667). Determination of the timing of HIT was associated with the largest number of discrepancies (16) between evaluators, followed by other causes of thrombocytopenia (15), degree of decline in platelet count (14), and the presence of thrombosis or other sequelae (2). CONCLUSION: A low 4Ts score supports a low probability of HIT based on the results of the polyspecific ELISA. Overall, the interrater reliability of the scoring system was fair. Components of the 4Ts scoring system need to be further clarified or modified in order to improve interrater reliability and thereby increase the clinical utility of this pretest probability model. PMID- 21275493 TI - Outpatient treatment of Pseudomonas aeruginosa bronchial colonization with long term inhaled colistin, tobramycin, or both in adults without cystic fibrosis. AB - STUDY OBJECTIVE: To compare clinical and microbiologic outcomes in adults without cystic fibrosis who had Pseudomonas aeruginosa bronchial colonization and were receiving inhaled colistin or colistin plus tobramycin with those who were receiving inhaled tobramycin as outpatient treatment. DESIGN: Prospective, observational cohort study. SETTING: Referral pneumology service at a tertiary university care hospital. PATIENTS: Eighty-one Caucasian adults without cystic fibrosis who received 97 courses of inhaled colistin alone, colistin plus tobramycin, or inhaled tobramycin alone as outpatient treatment of P. aeruginosa bronchial colonization between January 2004 and December 2008. MEASUREMENTS AND MAIN RESULTS: The frequency and duration of hospitalizations for respiratory exacerbations were the primary outcomes compared among treatment groups. Secondary outcomes were emergence of bacterial resistance, antibiotic use during admission, emergence of other opportunistic microorganisms, achievement of sustained P. aeruginosa eradication in the airways, and mortality, as well as safety and changes in respiratory function. No significant differences between colistin and tobramycin were found in the mean number of hospital admissions, duration of hospitalizations, duration of antibiotic treatment, adverse events, mortality, or emergence of other opportunistic microorganisms. Emergence of resistance to colistin was lower than resistance to tobramycin (hazard ratio 0.09, 95% confidence interval [CI] 0.03-0.32). Patients treated with both inhaled antibiotics had fewer days of hospitalization and fewer days of antibiotic use than those treated with tobramycin alone (relative risk [RR] 0.33, 95% CI 0.10 1.12, and RR 0.27, 95% CI 0.08-0.93, respectively). CONCLUSION: Results with colistin were similar to those with tobramycin for inhaled treatment of P. aeruginosa colonization in this population; however, combined use of colistin and tobramycin appeared to be associated with fewer days of hospitalization and shorter duration of antibiotic treatment. Prospective, double-blind, placebo controlled trials of outpatient nebulized antibiotics, especially colistin plus tobramycin, should be performed to ascertain the efficacy of this therapy for treatment of P. aeruginosa colonization in patients without cystic fibrosis. PMID- 21275494 TI - Lack of effect from a previous single dose of nevirapine on virologic and immunologic responses after 6 months of antiretroviral regimens containing either efavirenz or lopinavir-ritonavir. AB - STUDY OBJECTIVE: To evaluate the effect of a previous single dose of nevirapine given to prevent mother-to-child transmission of human immunodeficiency virus (HIV) on virologic and immunologic measures after months of an antiretroviral regimen containing either efavirenz or lopinavir-ritonavir. DESIGN: Retrospective subgroup analysis of data from the Phidisa II trial. SETTING: Six South African research clinics. Patients. A total of 394 women with HIV who completed 6 months of combination antiretroviral regimen containing either efavirenz or lopinavirritonavir as part of the Phidisa II trial. MEASUREMENTS AND MAIN RESULTS: During the screening process for the Phidisa II study, 478 women were asked about previous nevirapine use: 392 women (82%) were nevirapine naive, and 86 (18%) had received nevirapine. During the study, patients received either an efavirenz-based or lopinavir-ritonavir- based antiretroviral regimen. After 6 months of treatment, virologic (HIV RNA levels) and immunologic (CD4(+) cell count) responses were measured. These data were compared between women with or without previous nevirapine exposure, and between women who received efavirenz versus lopinavirritonavir. After 6 months of treatment, 394 women (324 nevirapine naive, 70 exposed to nevirapine) had follow-up HIV RNA results. Two hundred twenty-seven (70.1%) of the nevirapine-naive patients and 48 (68.6%) of the nevirapine-exposed patients achieved HIV RNA levels lower than 400 copies/ml (p=0.89), with CD4(+) cell count increases of 115.5 and 120.4 cells/mm(3), respectively (p=0. 7). Among the nevirapine-exposed women, 27 (75%) of 36 efavirenz-treated and 21 (61.8%) of 34 lopinavir-ritonavir-treated patients had HIV RNA levels lower than 400 copies/ml at months (p=0.31). CONCLUSION: In this retrospective analysis of a small cohort, previous exposure to a single dose of nevirapine did not affect virologic outcomes after 6 months of either an efavirenz-based or lopinavir-ritonavir-based antiretroviral regimen. As efavirenz is one of the first-line combination antiretroviral therapies administered in Africa, it remains an option for women who received single-dose nevirapine. PMID- 21275495 TI - Extemporaneous compounding of oral liquid dosage formulations and alternative drug delivery methods for anticancer drugs. AB - Oncology pharmacists face a constant challenge with patients who cannot swallow oral anticancer drugs, making extemporaneous oral liquid preparation a requirement. Improper extemporaneous preparation of these agents, especially with the traditional chemotherapy with a narrow therapeutic index, may increase the risk of over- or underdosing. In community pharmacies, multiple barriers exist that prevent these pharmacies from preparing extemporaneous oral anticancer drug formulations for a patient's use at home. In a home setting, patients or caregivers without proper counseling and education on how to safely handle chemotherapy are at increased risk for exposure to these drugs. Based on a review of the literature, compounding recipes are available for 46% of oral anticancer agents. A paucity of data exists on dose uniformity, bioequivalence, and stability of extemporaneous oral liquid formulations of anticancer drugs. Pharmacists must have an understanding of the basic scientific principles that are an essential foundation for the proper preparation of extemporaneous oral anticancer liquid formulations. The collaborative effort of a multidisciplinary team can also help identify different barriers in the community setting, especially in areas where community pharmacies may lack resources for the extemporaneous compounding of oral chemotherapy, and to find ways to coordinate better pharmaceutical care. There are great opportunities for oncology pharmacists, as well as community pharmacists, as a resource for educating and monitoring patients receiving oral chemotherapy to ensure dosing accuracy, safe administration, and proper disposal of hazardous drugs. Development of national guidelines to promote standards of practice in the community and/or home setting is urgently needed to help improve the safety of dispensing and handling oral chemotherapeutic agents, including extemporaneously compounded oral liquid formulations of these drugs. PMID- 21275496 TI - Contemporary management of transient ischemic attack: role of the pharmacist. AB - Transient ischemic attacks (TIAs) have been redefined recently. The new tissue based definition of TIA abandons the 24-hour restriction on symptom duration previously used to differentiate TIA from acute ischemic stroke and requires neuroimaging studies to identify the cause of the ischemia and to determine the presence and extent of brain injury. This new definition brings to light the need for urgent diagnostic testing and timely initiation of treatment, as well as secondary prevention measures to reduce the increased risk of stroke, cardiovascular complications, and death in the days and weeks after a TIA. Pharmacists play a key role in identifying patients at risk for a first or recurrent TIA or stroke, educating high-risk patients on the signs and symptoms of TIA or stroke and the need for urgent evaluation and treatment, overcoming barriers to timely diagnosis and treatment, and ensuring that appropriate primary or secondary prevention strategies are in place. Furthermore, studies have shown that pharmacist-led interventions can lead to significant improvements in modifiable risk factors, such as blood pressure and cholesterol levels, as well as drug adherence, and may reduce the occurrence of strokes. These interventions may also help maintain patients' health-related quality of life and improve patients' satisfaction with care. PMID- 21275497 TI - Therapeutic drug monitoring of voriconazole and posaconazole. AB - Despite the availability of newer antifungal agents, invasive fungal diseases remain a leading cause of morbidity and mortality in immunocompromised patients. Voriconazole and posaconazole are two extended-spectrum triazoles indicated for treatment and prophylaxis of invasive fungal diseases. Recently, there has been increased interest in the utility of therapeutic drug monitoring to optimize safety and efficacy of antifungals in an attempt to improve patient outcomes. We reviewed the pharmacokinetic and pharmacodynamic characteristics of voriconazole and posaconazole in the context of clinical indications for therapeutic drug monitoring. In addition, the most recent evidence examining the relationship between serum concentrations of voriconazole and posaconazole and their efficacy or toxicities was evaluated. This information was then integrated to formulate recommendations for use of therapeutic drug monitoring in clinical settings. PMID- 21275498 TI - 5-Fluorouracil-induced Tako-Tsubo-like syndrome. AB - Tako-Tsubo cardiomyopathy (also known as apical ballooning syndrome) is a relatively new clinical entity characterized by reversible left ventricular dysfunction. Its clinical presentation and electrocardiographic findings are similar to acute myocardial infarction but without significant coronary artery disease. Cardiotoxicity is a major complication of various anticancer drugs; however, only a few cases of Tako-Tsubo cardiomyopathy associated with anticancer drugs, including 5-fluorouracil, have been reported. We describe a 48-year-old man who developed acute coronary syndrome, thought to be similar to Tako-Tsubo syndrome, after receiving a chemotherapy regimen consisting of 5-fluorouracil, oxaliplatin, and calcium folinate (FOLFOX protocol) for colic adenocarcinoma. Approximately 24 hours after receiving his first cycle of chemotherapy, the patient, who did not have a history of cardiovascular disease, developed chest pain, with abnormal electrocardiographic results and a mildly increased troponin T level. Coronary angiography did not show any significant coronary lesions. Echocardiography revealed marked left ventricular dysfunction (left ventricular ejection fraction [LVEF] 15%) with severe hypokinesia in all apical and median segments. The patient was stabilized with the introduction of an intraaortic balloon pump and pressor therapy. One month later, myocardial magnetic resonance imaging confirmed total recovery of left ventricular systolic function. Thus, the second chemotherapy cycle was administered at half the dose-intensity, along with ramipril and diltiazem. The chemotherapy regimen was well tolerated. Two weeks later, at the end of the third chemotherapy cycle, administered using the full dose regimen, the patient experienced cardiac arrest, necessitating cardiopulmonary resuscitation. After transfer to the cardiology intensive care unit, acute heart failure recurred (LVEF 35%). Normal recovery of left ventricular function occurred a few days later. Chemotherapy was discontinued, and treatment with bisoprolol was started. Four months later, the patient remained completely asymptomatic of any cardiac manifestations. Use of the Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 8) between the patient's development of acute coronary Tako-Tsubo-like syndrome and 5-fluorouracil. Clinicians should be aware of this potential adverse effect when monitoring patients receiving chemotherapy with 5-fluorouracil. PMID- 21275499 TI - Own voice qualities (OVQ) in hearing-aid users: there is more than just occlusion. AB - OBJECTIVE: Hearing-aid users' problems with their own voice caused by occlusion are well known. Conversely, it remains essentially undocumented whether hearing aid users expected not to have occlusion-related problems experience own-voice issues. DESIGN: To investigate this topic, a dedicated Own Voice Qualities (OVQ) questionnaire was developed and used in two experiments with stratified samples. STUDY SAMPLE: In the main experiment, the OVQ was administered to 169 hearing-aid users (most of whom were expected not to have occlusion-related problems) and to a control group of 56 normally-hearing people. In the follow-up experiment, the OVQ was used in a cross-over study where 43 hearing-aid users rated own voice for an open fitting and a small-vent earmould fitting. RESULTS: The results from the main experiment show that hearing-aid users (without occlusion) have more problems than the normal-hearing controls on several dimensions of own voice. The magnitude of these differences was found to be generally larger than the differences observed between the open fitting and the small-vent fitting in the follow-up experiment. CONCLUSIONS: This suggests that own voice is a potentially important concern, even for hearing-aid users who are not expected to have occlusion-related problems. PMID- 21275500 TI - Optimizing the perception of soft speech and speech in noise with the Advanced Bionics cochlear implant system. AB - OBJECTIVE: This study aimed to provide guidelines to optimize perception of soft speech and speech in noise for Advanced Bionics cochlear implant (CI) users. DESIGN: Three programs differing in T-levels were created for ten subjects. Using the T-level setting that provided the lowest FM-tone, sound-field threshold levels for each subject, three additional programs were created with input dynamic range (IDR) settings of 50, 65 and 80 dB. STUDY SAMPLE: Subjects were postlinguistically deaf adults implanted with either the Clarion CII or 90K CI devices. RESULTS: Sound-field threshold levels were lowest with T-levels set higher than 10% of M-levels and with the two widest IDRs. Group data revealed significantly higher scores for CNC words presented at a soft level with an IDR of 80 dB and 65 dB compared to 50 dB. Although no significant group differences were seen between the three IDRs for sentences in noise, significant individual differences were present. CONCLUSIONS: Setting Ts higher than the manufacturer's recommendation of 10% of M-levels and providing IDR options can improve overall speech perception; however, for some users, higher Ts and wider IDRs may not be appropriate. Based on the results of the study, clinical programming recommendations are provided. PMID- 21275501 TI - Altered biliary epithelial cell and monocyte responses to lipopolysaccharide as a TLR ligand in patients with primary biliary cirrhosis. AB - OBJECTIVE: Lipopolysaccharide (LPS) is suspected to trigger primary biliary cirrhosis (PBC) in susceptible individuals, yet the precise mechanism of its effect in PBC remains largely unknown. The aim of this study was to investigate altered responses to LPS ligand for Toll-like receptors (TLRs) in pathogenesis of PBC in vivo and in vitro. MATERIAL AND METHODS: In vivo, we investigated levels of LPS and pro-inflammatory cytokines in sera and expression of LPS receptors in liver tissues from 162 patients with PBC, 325 patients with other liver diseases and 80 healthy controls. In vitro, altered responses to LPS on monocytes and cultured human biliary epithelial cells (BECs) from patients with PBC were determined. RESULTS: Significantly higher levels of LPS in patients with PBC were detected, compared with patients with other liver diseases and healthy controls. Immunohistochemically, expression of TLR4, CD14, CD68 and NF-kappaB was significantly enhanced in liver tissues from patients with PBC. Before LPS stimulation, we found significantly higher serum levels of tumor necrosis factor alpha, interleukin (IL)-1beta, IL-6 and IL-8 in patients with PBC than those in healthy controls. After LPS stimulation, TLR4 expression and pro-inflammatory cytokine production in CD14-positive monocytes and cultured BEC from patients with PBC increased significantly. CONCLUSIONS: These results indicated that patients with PBC were prone to exhibit higher serum LPS level, hypersensitivity of monocytes and BEC to LPS, and enhanced production of pro-inflammatory cytokines. LPS altered expression of TLR4, CD14 and NF-kappaB on monocytes and BEC, which may be implicated in the pathogenesis and progression of PBC. PMID- 21275504 TI - Review of literature on the mental health of doctors: are specialist services needed? AB - BACKGROUND: Mental ill health is common among doctors. Fast, efficient diagnosis and treatment are needed as mentally ill doctors pose a safety risk to the public, yet they are often reluctant to seek help. AIMS: To review literature regarding risk factors and potential barriers to help-seeking unique to doctors; to consider the success of interventions by specialist services for doctors. METHOD: Key phrases regarding the 'mental health of doctors' were entered into internet searches and journal databases to identify relevant research. When key authors were identified, author-specific searches were carried out. FINDINGS: There are contradictory reports about the prevalence of mental ill health in doctors but it is generally agreed that doctors face a large number of risk factors, both occupational and individual; and help-seeking is difficult due to complexities surrounding a doctor becoming a patient. Specialist services developed specifically for interventions for doctors with mental health problems tend to show promising results but further research is needed. CONCLUSIONS: The unique and complex situation of a doctor becoming a patient benefits from specialist services; such services should focus on early intervention and raising awareness. PMID- 21275507 TI - Self-rated Health in Middle-aged Women: Associations with Sense of Coherence and Socioeconomic and Health-related Factors. AB - This study aimed to describe and analyse self-rated health in relation to sense of coherence and socioeconomic and health-related factors and to explore the associations between self-rated health and these factors in order to identify health resources and health limitations in a group of healthy middle-aged women. Healthy middle-aged women from a defined geographical area in Southern Sweden ( n =577) answered a postal survey with the sense of coherence scale and questions about socioeconomic and health-related conditions. The results showed that very good/rather good self-rated health was associated with high sense of coherence and good economic situation, and these factors can be seen as a health resource. Poor self-rated health was most strongly associated with perceived symptoms of tension, weak sense of coherence, treatment for depression, treatment for chronic disease, and difficult economic situation, and these factors can be seen as health limitations. In conclusion, only 29% of the women rated their health as very good and 41% of the women had symptoms of tension but they were not sick listed. It is of major public health interest to improve the understanding of self-rated health and to develop health promotion for women and methods to prevent symptoms of tension and sick-listing. PMID- 21275508 TI - Geriatric Rehabilitation: Elderly Clients' Experiences of a Pre-discharge Occupational Therapy Group Programme. AB - This study describes how elderly people, temporarily living in a pre-discharge community rehabilitation centre, may experience participation in an in-patient occupational therapy programme built around group activities. The group activity programme was comprised of five sessions, each focusing on a theme chosen to encourage reflection and mutual sharing of experiences and support. Data were collected through interviews with each of the three participants immediately after each of the five group sessions. The resultant 15 interviews were analysed by adopting a Grounded Theory approach. The results show that the ways in which the participants experienced participating in the group activity programme can be described from two distinct core categories: experiences of activation and experiences of transformation . The category of activation emerged from their experiences of a creative force whilst engaged in performing the activities and from their discovery that the group was a good place for learning . Engagement in the group activities also seemed to bring about a transformation in the participants in that their experiences triggered reflection and adaptation , which contributed to a change in attitude and a personal synthesis where their new discoveries were internalized. The study shows the potential a group activity programme in occupational therapy has in triggering an adaptational and reflective process within elderly people facing discharge from hospital. Hence, group activity interventions in occupational therapy are suggested as one possible way to support the elderly person in the discharge process from hospital to the home. PMID- 21275509 TI - Applicability of pediatric evaluation of disability inventory in norway. AB - The Pediatric Evaluation of Disability Inventory (PEDI) is an instrument for evaluating functional performance in disabled children aged 6 months to 7.5 years. PEDI measures both performance and caregiver assistance in three domains: self-care, mobility and social function. The purpose of this study was to investigate the applicability of the American normative reference values of PEDI, to describe ability among Norwegian children. This was investigated in a sample of 52 non-disabled Norwegian children in the age range 1.0-5.9 years. The Norwegian sample scored significantly lower than the American reference values for Functional Skills; self-care (mean 39; p <0.001), Care-giver Assistance; self care (mean 43; p <0.001), and Functional Skills; mobility (mean 43, p <0.001). For caregiver assistance, mobility, and for functional skills and caregiver assistance, social function, there was good agreement between observations in the Norwegian sample and PEDI reference values. The result calls for a larger study, from which Norwegian reference values for PEDI can be derived. PMID- 21275510 TI - Integrated health human resource options: the impact on occupational therapy professional practice. AB - Healthcare systems in many countries have gone through numerous changes over the last two decades. Funding bodies and employers have tried to find cost-effective, innovative ways to deliver quality healthcare including methods to reduce labour expenses. Three approaches to cost-savings have been proposed for healthcare professionals: multiskilling, cross-training, and personnel substitution. The advantages and disadvantages associated with each approach are outlined. Issues related to professional practice roles are then reviewed and discussed. Implications for occupational therapy practice are presented and recommendations for the future are made. PMID- 21275511 TI - Experienced health, life satisfaction, sense of coherence, and coping resources in individuals living with heart failure. AB - The purpose of this study was to explore relationships between experienced health, sense of coherence, coping resources, and life satisfaction in individuals living with heart failure. Twenty-two patients--12 men and 10 women- were included in the study. All subjects were admitted to a eight-week programme of aerobic training. Four questionnaires were used: the Minnesota Living with Heart Failure Questionnaire (MHLF), the Sense of Coherence scale (SOC), the Coping Resources Inventory (CRI), and the Life Satisfaction Checklist of Fugl Meyer et al. After the exercise programme the mean score of MLHF was significantly lower as compared with the start of the programme. The majority of the individuals reported that they were satisfied with life as a whole, family life, partnership relation contact with friends, and their psychological state of health. Only one-third were satisfied with their sexual life. A high sense of coherence and coping resources characterized the subjects. There was a slight tendency for those who reported satisfaction with life as whole to report a stronger sense of coherence, a higher degree of coping resources, and a lower degree of symptoms of heart failure. A conclusion was that clinicians should emphasize that patients can continue to remain active and enjoy a reasonable quality of life. PMID- 21275512 TI - Pharmacological preconditioning by low dose cobalt protoporphyrin induces heme oxygenase-1 overexpression and alleviates retinal ischemia-reperfusion injury in rats. AB - PURPOSE: Retinal ischemia-induced neuronal death plays a crucial role in certain severe visual impairment diseases. The aims of this study were to investigate the effects of low dose cobalt protoporphyrin IX (CoPP), an inducer of heme oxygenase 1 (HO-1), on the retina of rats against ischemia-reperfusion (IR) injury. METHODS: Retinal IR was achieved in rats by raising intraocular pressure for 60 min. CoPP (1 mg/ kg) was injected intraperitoneally 24 hr before IR. Retinal injury was assessed by the number of retinal ganglion cells (RGCs) seven days after reperfusion. TUNEL assay was used to detect the appearance of apoptotic cells 24 hr after reperfusion. The expressions of the HO-1 and Bax proteins were evaluated by Western blot. RESULTS: Both HO-1 expression, examined by Western blot, and enzyme activity were increased strongly after CoPP administration. Rats treated with CoPP before IR had more RGCs (p = 0.034) and less apoptotic cells (p = 0.04) together with downregulated Bax protein levels (p = 0.03) compared to ischemic rats without CoPP. The protective effects of CoPP were HO-1 dependent because the upregulation of HO-1 and the RGC protection were both abolished by the HO-1 inhibitor tin protoporphyrin (SnPP). CONCLUSIONS: In this study, we demonstrated that induction of HO-1 expression by low dose CoPP ameliorated retinal damage from IR injury. The favorable effect appears to be related with modulations of the apoptotic pathway. PMID- 21275513 TI - Immediate break-down of blood retinal barrier by infusion of triolein emulsion observed by fluorescein angiography. AB - PURPOSE: The purpose of this study is to investigate immediate changes in the blood retinal barrier (BRB) after the infusion of triolein emulsion. MATERIALS AND METHODS: Triolein emulsion was infused into the carotid artery of 12 cats to induce experimental fat embolism. The injection of fluorescein dye into the carotid artery followed immediately. Early retinal vascular flow was recorded by a fluorescein angiography (FA) video, and then a FA photograph was obtained up to 30 min after the injection. Leakage of the dye in the choroidal or retinal vessels was evaluated. RESULTS: In the early phase, multifocal non-perfuse areas were noted in all cats due to embolism by triolein emulsion, which was released by blood perfusion in the late phase. Perfusion defects persisted in the retina of five cats and in the choroid of four cats. Leakage of the dye through the retinal vessels was seen in five cats (42%) in the early phase and in nine cats (75%) in the late phase. In the choroid, leakage of the dye was seen in seven cats (58%) in the early phase and in all cats (100%) in the late phase. CONCLUSIONS: The inner and outer BRB was opened immediately after infusion of triolein emulsion into the carotid artery. Embolism by triolein emulsion was readily resolved due to the liquid nature of triolein. PMID- 21275514 TI - Vitreous levels of pigment epithelium-derived factor and vascular endothelial growth factor in macular edema with central retinal vein occlusion. AB - PURPOSE: To investigate whether pigment epithelium-derived factor (PEDF) or vascular endothelial growth factor (VEGF) influences macular edema in patients with central retinal vein occlusion (CRVO). MATERIALS AND METHODS: In 27 patients who had CRVO with macular edema and 21 patients with nonischemic ocular diseases (control group), retinal ischemia was evaluated by measuring the area of capillary nonperfusion on fluorescein angiography and macular edema was examined by optical coherence tomography. Vitreous fluid samples were obtained during pars plana vitrectomy. RESULTS: The vitreous level of VEGF was significantly higher in the CRVO patients than in the controls (median: 366 vs. 15.6 pg/ml, P < 0.0001), while the vitreous level of PEDF was significantly lower in the patients than in the controls (median: 17.5 vs. 28.4 ng/ml, P = 0.0298). Vitreous levels of VEGF were significantly higher in CRVO patients with retinal ischemia than in those without ischemia (P < 0.0001), while PEDF levels did not show a significant difference. Vitreous levels of VEGF and PEDF were related to the retinal thickness at the central fovea (P = 0.0059 and P = 0.0308, respectively). CONCLUSIONS: VEGF and PEDF may independently influence retinal vascular permeability in CRVO patients with macular edema. PMID- 21275515 TI - Formulation of indomethacin eye drops via complexation with cyclodextrins. AB - PURPOSE: Topically administered indomethacin is used in the management and prevention of ocular inflammation and cystoid macular edema related to cataract surgery and in the maintenance of mydriasis during cataract surgery. Pharmaceutically, the main obstacle in formulating indomethacin as eye drops is its low solubility and aqueous instability. Inclusion complexation of indomethacin with cyclodextrins (CDs) was our interest in this research to obtain stable and effective aqueous indomethacin eye drops. MATERIALS AND METHODS: The influence of beta-CD, hydroxypropyl-beta-CD (HP-beta-CD), and sulfobutyl ether beta-CD (SBE-beta-CD) on indomethacin solubility was investigated. Indomethacin HP-beta-CD complex was prepared and characterized by infrared spectroscopy, differential scanning calorimetry, and X-ray diffractometry and was subjected to in vitro release and stability studies. The anti-inflammatory effect of formulated indomethacin-HP-beta-CD eye drops on chemically burned albino rabbit eyes was compared to those of Indocollyre((r)) and Voltaren((r)) eye drops. RESULTS: HP-beta-CD was found to have a high solubilizing effect towards indomethacin and was thus selected for its formulation. Formulated indomethacin HP-beta-CD eye drops exhibited delayed release and high drug stability compared to the drug solution. Draize rabbit eye irritation test and histological examination on albino rabbit eyes treated with indomethacin-HP-beta-CD eye drops revealed that these eye drops were non-irritant. The anti-inflammatory studies indicated that formulating indomethacin eye drops via complexation with HP-beta CD significantly improves the therapeutic efficacy of the indomethacin compared to the investigated eye drops. CONCLUSION: An aqueous ocular delivery system for the poor water soluble anti-inflammatory indomethacin was prepared using HP-beta CD as a complexing agent. Besides a sufficient solubility for the drug, many factors were studied in the development of this system, such as stability and safety. In addition, indomethacin-HP-beta-CD eye drops showed promising management to corneal inflammation. PMID- 21275516 TI - Blink rate, blink amplitude, and tear film integrity during dynamic visual display terminal tasks. AB - PURPOSE: The present study aimed at investigating the influence of the level of dynamism of two different visual display terminal tasks on spontaneous eyeblink rate, blink amplitude, and tear film integrity. MATERIAL AND METHODS: A total of 25 healthy, young volunteers participated in the study. Blink rate and blink amplitude were recorded in silent primary gaze conditions and while subjects were playing two computer games of similar cognitive demands but different rate of visual information presentation. For each experimental condition, tear volume was evaluated by measuring meniscus height and with the red phenol thread test. Fluorescein and non-invasive break-up time tests, as well as the observation of interference patterns and the estimation of the dry area extension, were employed to assess tear stability. RESULTS: Statistically significant differences were revealed in blink rate (F = 595.85, p < 0.001) and blink amplitude (chi(2) = 34.00, p < 0.001), with blink rate during fast- and slow-paced game play decreasing to almost 1/3 and 1/2 of baseline levels, respectively, and with a larger percentage of incomplete blinks during dynamic tasks. Fluorescein and non invasive break-up time tests and dry area extension were able to differentiate between experimental conditions in general (F = 408.42, p < 0.001; F = 163.49, p < 0.001; chi(2) = 20.74, p < 0.001), as well as between fast- and slow-paced games, thus suggesting that tear quality was more affected than tear volume. CONCLUSIONS: Blink rate, blink amplitude, and tear film stability were compromised during the most dynamic visual display terminal task, suggesting a negative influence of not only the cognitive aspects of the task, but also of the rate at which new visual information is presented. Frequent breaks and blinking awareness training are recommended for visual display terminal users requiring prolonged periods of visually demanding dynamic computer play or work. PMID- 21275517 TI - The effect of long-term storage on the biological and histological properties of cryopreserved amniotic membrane. AB - PURPOSE: Cryopreserved amniotic membrane (AM) is widely used in ophthalmology because of its anti-angiogenic, anti-inflammatory, and wound healing promoting capabilities. A common method to conserve the tissue is the storage in cryo medium containing 50% glycerol at -80 degrees C. The aim of this study was to examine the influence of storage time on the sterility as well as the histological and biological properties of cryopreserved AM. METHODS: Amniotic membrane from different donors was stored in cell culture media containing 50% glycerol for different time periods, on average 4 months (group 1), 15 months (group 2), and 24 months (group 3), at -80 degrees C. Samples of the tissue and cryo-medium were examined for bacterial and fungal contamination. Tissue samples were incubated in 0.5 ml/cm(2) serum-free medium at 37 degrees C. The medium was changed after 1, 2, and 3 days. The proteins released by AM were TCA-precipitated and the presence of the proteins TIMP-1 and IL-1ra was analyzed using Western blotting and semi quantified by means of image analysis. Integrity of the amniotic epithelium and the basement membrane components collagen IV, collagen VII, laminin, laminin 5, and fibronectin were examined by haematoxylin eosin stain and immunohistochemistry in cryosections of AM. RESULTS: None of the examined samples showed bacterial or fungal contamination. The soluble proteins TIMP-1 and IL-1ra were found in all samples of medium incubated for all time periods. The examined proteins were detectable after one-day incubation but the staining signal diminished significantly in the second and third wash after 48 hr and 72 hr. Differences in the intensity of the Western blot signal between the three particular groups were statistically not significant. The epithelia of all samples were intact. The basement membranes of all samples showed a similar distribution of collagen IV, collagen VII, laminin, laminin 5, and fibronectin. CONCLUSIONS: Long-term storage of amniotic membrane in cell culture media with 50% glycerol does not significantly impair sterility, histology, or biological properties of AM. PMID- 21275518 TI - Time course of cold cataract development in anesthetized mice. AB - PURPOSE: The aim of the present study was to study the time-course development of cold cataract in mice under general anesthesia. METHODS: We anesthetized five groups of 10 mice (12 weeks old) with 400 mg/Kg intraperitoneal injections of chloral hydrate and exposed them to 0, 7, 15, 23, and 37 degrees C for 1 hr. Cataract development was assessed and graded as no cataract, mild, medium, or severe at 10, 20, 30, 45, and 60 min after the exposure started. For quantification purposes, a value from 0 to 3 was assigned to each cataract grade, and the median value was calculated for each group and time point (cataract index, CI). RESULTS: The CI for each temperature fitted a negative exponential equation. We found that four mice of the 37 degrees C group, nine of the 23 degrees C group, and all animals of the 15, 7, and 0 degrees C groups developed cataract. The cataract started at 10 min after exposure to 0 degrees C and at 20 min when exposed to 7, 15, and 23 degrees C. The speed of development and CI significantly increased with lower temperatures. Similar results were observed when the procedure was repeated 48 hr later in the 15, 23, and 37 degrees C groups. In all instances the cataract was reversible. CONCLUSION: Our findings show that cold cataract development is temperature dependent and that cataract formation starts between 10 and 20 min after exposure to low temperature. This finding is relevant for those experimental settings in which clear ocular media are required. PMID- 21275519 TI - Retinal degeneration and rd1 mutation in NC/Tnd mice-a human atopic dermatitis model. AB - PURPOSE: NC/Tnd mice, a spontaneous model for human atopic dermatitis, are also useful animal models for various corneal disorders accompanying allergic diseases. The purposes of the current study were to investigate the development of retinal degeneration in NC/Tnd mice. MATERIALS AND METHODS: Histological examination was performed to determine time-dependent alterations of the retina in NC/Tnd from 8 to 28 days of age. Apoptotic cells were determined by TUNEL assay. Retinal function was examined by electroretinography. Fundoscopy was performed in NC/Tnd mice at 8 weeks of age. Melanin contents in whole-eye extracts were measured by spectrophotometry. Since the retinal degeneration 1 (rd1) mutation in the rod photoreceptor cyclic guanosine monophosphate phosphodiesterase 6 beta-subunit (Pde6b(rd1)) has been identified in laboratory mice, the possible existence of the rd1 mutation was analyzed with PCR genotyping and gene sequencing. C57BL/6, WB, and C3H/HeN mice were used as controls. RESULTS: Histological examination revealed rapid postnatal retinal degeneration in NC/Tnd mice. The number of apoptotic cells in the outer nuclear layer (ONL) increased with aging, and finally the ONL disappeared. Histological abnormality was not obvious in the inner nuclear layer or the ganglion cell layer. Electroretinography shows no response in adult NC/Tnd mice. Fundoscopic observation revealed hypopigmentation in the retina, and melanin contents in the eye were significantly reduced when compared with other inbred strains. Insertion in the rd1 allele was confirmed and a nonsense mutation of Pde6b(rd1) gene was determined in NC/Tnd mice. CONCLUSIONS: NC/Tnd mice also preserve the Pde6b(rd1) gene mutation resulting in the rapid postnatal retinal degeneration similar to that in C3H/HeN mice. Unlike C3H/HeN mice, since melanin contents of the retina in NC/Tnd mice was decreased, unknown defects may be present in the process of melanin composition in retinal pigment epithelial cells during fetal development of NC/Tnd mice. PMID- 21275520 TI - Validation of the flush method as an alternative to basal or reflex tear collection. AB - PURPOSE: To validate the more easily applicable "flush" tear collection technique as a viable alternative to basal and reflex tear collection. MATERIALS AND METHODS: Total protein content (TPC) and immunoglobulin A (IgA) concentrations were determined in the basal, reflex, and flush tears of 16 healthy non-contact lens wearers. The overall protein profile was established using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and mass spectrometry (MS). RESULTS: Collection-rates were 4.6 +/- 6.7 MUl/min, 13.9 +/- 11.1 MUl/min, and 25.7 +/- 12.4 MUl/min for the basal, reflex, and flush tears, respectively. TPC was 7.14 +/- 2.22 mg/mL, 6.01 +/- 2.11 mg/mL, and 3.79 +/- 1.51 mg/ mL for basal, reflex, and flush tears, respectively, with flush tears being significantly less concentrated than basal (p = 0.001) and reflex (p = 0.008). IgA concentration was 1.04 +/- 0.29 mg/ mL, 0.64 +/- 0.26 mg/mL, and 0.65 +/- 0.23 mg/mL for basal, reflex, and flush tears, respectively, with basal tears being significantly more concentrated (p < 0.001). As a percentage of TPC, IgA represented 19.8 +/- 14.9%, 11.4 +/- 3.9%, and 19.8 +/- 8.7% for basal, reflex, and flush, respectively. The flush was not significantly different to basal (p = 1.00) but significantly greater than reflex (p = 0.02). SDS-PAGE showed the same tear profiles for basal and flush tears. MS identified the most abundant proteins in all tear types. CONCLUSIONS: The flush method allows much faster collection than basal secretion sampling but returns essentially the same spectrum of proteins in similar proportions. This behavior is confirmation that the flush technique has utility as a more convenient alternative to basal tear sampling in studies involving composition analysis. PMID- 21275521 TI - Use of the anterior chamber maintainer in trabeculectomy following vitrectomy. AB - PURPOSE: To retrospectively observe the effects of anterior chamber maintainer (ACM) placement in glaucoma patients undergoing trabeculectomy following vitrectomy. METHODS: Trabeculectomy was performed on 51 secondary glaucoma patients (51 eyes), all of whom had undergone vitrectomy. During trabeculectomy, an ACM was placed in 27 eyes (group A), but not in the remaining 24 (group B). Intra- and post-operative complications were recorded. Intraocular pressure (IOP) measurements were recorded pre-operatively and repeated post-operatively on follow up days 1, 3, and 7, and months 1, 3, 6, 12, 18, and 24. Surgical success rates were recorded. RESULTS: Mean pre-operative IOPs of groups A and B were 32.74 +/- 11.25 and 34.29 +/- 9.68 mmHg, respectively. In group A, anterior chamber bleeding (two cases), and choroidal detachment and/or ciliary detachment (four cases) occurred. In group B, anterior chamber bleeding (five cases), and choroidal detachment and/or ciliary detachment (11 cases) occurred. There was a statistically significant difference between the two groups. There also was statistically significant difference in post-operative IOPs between the two groups at 12 and 24 months. The surgical success rate of group A was higher than that of group B. CONCLUSION: ACM is effective in maintaining IOP and reducing complications during trabeculectomy following vitrectomy, thereby increasing surgical success rates. PMID- 21275522 TI - Self-reported driving difficulty by persons with hemianopia and quadrantanopia. AB - PURPOSE: To compare self-reported driving difficulty by persons with hemianopic or quadrantanopic field loss with that reported by age-matched drivers with normal visual fields; and to examine how their self- reported driving difficulty compares to ratings of driving performance provided by a certified driving rehabilitation specialist (CDRS). METHOD: Participants were 17 persons with hemianopic field loss, 7 with quadrantanopic loss, and 24 age-matched controls with normal visual fields, all of whom had current driver's licenses. Information was collected via questionnaire regarding driving difficulties experienced in 21 typical driving situations grouped into three categories (involvement of peripheral vision, low visibility conditions, and independent mobility). On-road driving performance was evaluated by a CDRS using a standard assessment scale. RESULTS: Drivers with hemianopic and quadrantanopic field loss expressed significantly more difficulty with driving maneuvers involving peripheral vision and independent mobility, compared to those with normal visual fields. Drivers with hemianopia and quadrantanopia who were rated as unsafe to drive based upon an on-road assessment by the CDRS were no more likely to report driving difficulty than those rated as safe. CONCLUSION: This study highlights aspects of driving that hemianopic or quadrantanopic persons find particularly problematic, thus suggesting areas that could be focused on driving rehabilitation. Some drivers with hemianopia or quadrantanopia may inappropriately view themselves as good drivers when in fact their driving performance is unsafe as judged by a driving professional. PMID- 21275523 TI - The scientific surgeon. AB - The scientific surgeon begins with Joseph Lister and his seminal work on the development of antiseptic surgery published in 1867 in Lancet. No other significant works of the times compare to Lister's contributions in this particular field of surgery. Lister utilized pristine scientific principles, learned in part from Pasteur, to understand and apply the germ theory of disease to practical surgery. In this regard, in previous publications, we have considered Lister as the "Father of Scientific Surgery." The scientific surgeon as a well-defined professional did not exist until the first residency in surgery was developed. Halsted of Hopkins introduced the first systematic and scientific surgical residency in 1901. This is the time, then, in which the scientific surgeon was formed and educated. Other programs followed Halsted's residency guidelines in surgery. The scientific surgeon is now well integrated and fully based on the science applied to surgery. Halsted's surgery was reproduced by other programs; and with time uniformity was established by all programs offering surgical residencies in the United States and many other parts of the world. The scientific surgeon is a firm reality at this point. PMID- 21275524 TI - Surgical innovator. AB - To be a surgical innovator is to be someone who has the capacity to modify established concepts in surgery. The surgeon innovator is able to change old ideas and ways of practicing the specialty. The life of the surgical innovator is in constant flux, always looking for avenues of improvement within the discipline. C. Walton Lillehei, Owen H. Wangensteen, William S. Halsted, and Alfred Blalock are a few of many good examples of American surgeon innovators whose contributions can help us to discern how they thought about innovation within the surgical sciences. Lillehei, Wangensteen, Halsted, and Blalock had several things in common, such as recognition of the idea, persistence in developing the strategy, commitment to the project, and final completion of a response to the problem or problems in question. These four innovators readily contemplated the essence of innovation but mostly dedicated themselves to search for the appropriate answers to serious and difficult clinical tasks. PMID- 21275525 TI - Minimal invasive technique for gene delivery in porcine liver lobe segment. AB - INTRODUCTION: The feasibility and outcome of large volume injection of gene solution in a segment of a liver lobe, without backflow, were studied in a porcine model, using a custom-designed balloon catheter. METHOD: Eight anesthetized pigs underwent successful injection of 200 ml of gene solution at a rate of 20 ml/s via a minimally invasive technique without backflow. A custom made balloon catheter was introduced under fluoroscopy guidance into the right lateral liver lobe via the right external jugular vein. The vein of the liver lobe was occluded with the balloon catheter and contrast material was injected to check if total occlusion was achieved. Since there was no backflow an angiographic pump injected the solution. The catheter was left in place for 10 min. Then contrast material was injected to check whether the vein remained occluded. RESULTS: All animals tolerated the procedure without obvious adverse effects. Ultrasound scan showed no gross changes within liver three days following the infusion. A transient rise in platelet count was observed which returned to normal after 13 days and remained stable; all other biochemistry values were normal. CONCLUSIONS: Injecting large volume of gene solution in a liver lobe segment using this minimally invasive technique in a porcine model is possible, making the development of a successful gene transfer protocol in humans feasible. PMID- 21275526 TI - Role of endothelial chemokines and their receptors during inflammation. AB - Chemokines are a large group of small cytokines known for their chemotactic ability to regulate the recruitment of leukocytes to sites of inflammation. This occurs through the binding of chemokines to their receptors located on the leukocyte that results in cellular changes such as actin rearrangement and cell shape, which allow for the migration of the leukocyte. In addition to regulating leukocyte function, it is now becoming apparent that other nonhematopoetic cells, such as smooth muscle cells and endothelial cells, can also be regulated by chemokines. Studies within the past 10 years has demonstrated the presence of various chemokine receptors on endothelial cells as well as the ability of chemokines to activate these receptors resulting in various cellular responses including migration, proliferation, and cellular activation. The purpose of this review is to highlight the research that has been done to date demonstrating the important role for chemokines in regulating endothelial function during various inflammatory conditions associated with angiogenesis, homeostasis, and leukocyte transmigration. This review will focus specifically on the role of the endothelium in mediating chemokine effects associated with wound healing, atherosclerosis, and autoimmune diseases, conditions where leukocyte recruitment and angiogenesis play a major role. Recent progress in the development and implementation of therapeutics agents against these small molecules, or their receptors, will also be addressed. PMID- 21275527 TI - Chondrocytes within osteochondral grafts are more resistant than osteoblasts to tissue culture at 37 degrees C. AB - It is proposed that an ideal osteochondral allograft for cartilage repair consists of a devitalized bone but functional cartilage. The different modes of nutrient supply in vivo for bone (vascular support) and cartilage (diffusion) suggest that a modulation of storage conditions could differentially affect the respective cells, resulting in the proposed allograft. For this purpose, osteochondral tissues from porcine humeral heads were either cultured at 37 degrees C for up to 24 hr or stored at 4 degrees C for 24 hr, the temperature at which osteochondral allografts are routinely stored. Functionality of the cells was assessed by in situ hybridization for transcripts encoding collagen types I and II. At 37 degrees C, a time-dependent significant reduction of the bone surface covered with functional cells was observed with only 5% +/- 5% coverage left at 24 hr compared with 41% +/- 10% at 0 hr. Similarly, cartilage area containing functional cells was significantly reduced from 84% +/- 7% at 0 hr to 70% +/- 3% after 24 hr. After 24 hr at 4 degrees C, a significantly reduced amount of functional cells covering bone surfaces was observed (27% +/- 5%) but not of cells within the cartilage (79% +/- 8%). In the applied experimental setup, bone cells were more affected by tissue culture at 37 degrees C than cartilage cells. Even though chondrocytes appear to be more sensitive to 37 degrees C than to 4 degrees C, the substantially reduced amount of functional bone cells at 37 degrees C warrants further investigation of whether a preincubation of osteochondral allografts at 37 degrees C--prior to regular storage at 4 degrees C--might result in an optimized osteochondral allograft with devitalized bone but viable cartilage. PMID- 21275528 TI - Cardiovascular assessment in radiotelemetry-implanted pregnant rats. AB - OBJECTIVE: The aim of this study was to assess the potential adverse effects of the chronic use of surgically implanted radiotelemetry transmitters and femoral catheters on embryo-fetal development in rats. METHODS: Two groups of 10 female rats were implanted with femoral catheters and radiotelemetry transmitters. Ten additional rats were implanted with femoral catheters alone. The females were then time mated with male rats and pregnancy confirmed. Saline was continuously infused from gestation days 6-17. Saline infusion was replaced with 0.8 MUg/ml angiotensin II in one group of animals, on gestation days 6, 9, 12, and 15 in order to demonstrate the validity of the system to detect changes in hemodynamic function by a pharmacologically active agent. Embryo-fetal development was assessed by examination of the number and location of the fetuses, early and late resorptions, and number of implantation sites. Parameters evaluated included postimplantation loss, live litter size, mean fetal body weights, and fetal sex ratios. RESULTS: Intrauterine survival was unaffected in all groups. Mean numbers of corpora lutea and implantation sites and the mean litter proportions of preimplantation loss were similar across all groups. Infusion of angiotensin II elicited the expected hemodynamic response, i.e., increased arterial blood pressure with a concomitant decrease in heart rate. CONCLUSION: Radiotelemetry can be used in combination with continuous intravenous infusion as a viable methodology for detecting test article induced changes in cardiovascular function in pregnant rats, with no effects on intrauterine growth and survival or fetal morphology. PMID- 21275529 TI - Tunica albuginea reefing: a novel technique for the treatment of erectile dysfunction. AB - BACKGROUND: "Tunica albuginea (TA) reefing" is a modification of Shafik's "TA overlapping" operation. Both techniques are based on the fact that in venogenic erectile dysfunction patients, the TA exhibits degenerative and atrophic collagen and elastic fibers causing its subluxation and flabbiness. This had led to loss of the veno-occlusive mechanism of the TA and venous leakage during erection. AIM: Reefing of the redundant tissue by bilateral excision of an ellipse of the TA provides a more effective correction of the TA and achieves a good support of the corpora cavernosa during tumescence. MATERIAL AND METHODS: The study included 24 patients with a mean age of 33.5 +/- 1.7 SD years. Intracorporal pressure was measured preoperatively and postoperatively. After penile degloving, an ellipse was excised from both lateral aspects of the penile shaft, extending from the glans penis to its root, and the two edges of each wound were reefed by continuous Dexon suture. RESULTS: The TA ellipses were taken as biopsies and revealed degenerative changes when stained with hematoxylin and eosin and Masson's trichrome stain. Postoperatively, there was an intracorporal pressure increase (p < .01) in 20 out of 24 patients of the study and a decrease in 4 out of 24. Six months after operation, the patients showed significantly (p < .01) improved scores for the domain of erectile function over the preoperative scores. CONCLUSION: The reefing operation corrects the TA flabbiness to a greater extent, lends more support to corporal tissue, and improves the veno-occlusive mechanism. PMID- 21275531 TI - Reduction in thigh circumference and improvement in the appearance of cellulite with dual-wavelength, low-level laser energy and massage. AB - OBJECTIVES: This study evaluated the efficacy and safety of a low-level, dual wavelength laser energy and massage device for improving the appearance of cellulite and reducing thigh circumference. METHODS: Subjects (n = 83) with mild to moderate cellulite enrolled in this IRB-approved, open-label, multicenter study. Their right or left thighs received eight treatments with a low-level, dual-wavelength laser and massage device. The untreated contralateral thigh served as a control. Circumferences of the upper, middle, and lower thighs (treated and untreated) were measured before the fifth and eighth treatments and 1 month after the final treatment. RESULTS: Reduction in thigh circumference of the treated areas exceeded those of the control areas for the upper, middle, and lower thigh in most subjects. The maximum reduction (-0.82 cm) occurred in the upper thigh at 1 month. The mean reduction of the upper, middle, and lower thigh circumferences was -0.64 cm for the treated thighs compared to -0.20 cm for untreated thighs. The difference was significant (p < 0.0001). Fifty-nine (71.1%) treatment thighs lost circumference compared to 44 (53.0%) control thighs. Resolution of adverse effects including erythema, swelling, and increased urination was seen within 30 minutes after treatment. All were resolved without sequelae and within the expected duration. CONCLUSION: The low-level, dual wavelength laser energy and massage device safely improves the appearance of cellulite while reducing thigh circumference. PMID- 21275532 TI - Peer feedback as an aid to learning--what do we want? Feedback. When do we want it? Now! AB - BACKGROUND: With 360 degrees appraisals integral to professional life, learning how to give constructive feedback is an essential generic skill. AIM: To use a formative objective structured clinical examination (OSCE) for skills acquisition and development in giving feedback, whilst facilitating awareness of the importance of communication skills in clinical practice. METHODS: Medical and nursing students took part in a formative OSCE. Using actors as simulated patients, a three-station OSCE circuit was repeated three times so that students could rotate through the roles as 'candidate', 'examiner' and 'observer'. As 'candidates', they received immediate feedback on their consultation from the 'examiner'/'observer'. The events were evaluated using a questionnaire and focus groups. RESULTS: Students immensely valued this learning event for considering expectations for a performance (91-100%). Concerns around giving peers feedback were acknowledged, and they were divided on preference for feedback from peers or tutors (48% versus 52%). But training in providing feedback and criteria for assessment were considered helpful, as was instruction by faculty to give corrective feedback to peers. CONCLUSIONS: Peer observation and professional accountability for giving constructive feedback enhanced awareness of their skills education and training needs. It also opened the dialogue for identifying opportunities for peer assessment and feedback to support work-based education and skills development. PMID- 21275533 TI - Feedback data sources that inform physician self-assessment. AB - BACKGROUND: Self-assessment is a process of interpreting data about one's performance and comparing it to explicit or implicit standards. AIM: To examine the external data sources physicians used to monitor themselves. METHODS: Focus groups were conducted with physicians who participated in three practice improvement activities: a multisource feedback program; a program providing patient and chart audit data; and practice-based learning groups. We used grounded theory strategies to understand the external sources that stimulated self-assessment and how they worked. RESULTS: Data from seven focus groups (49 physicians) were analyzed. Physicians used information from structured programs, other educational activities, professional colleagues, and patients. Data were of varying quality, often from non-formal sources with implicit (not explicit) standards. Mandatory programs elicited variable responses, whereas data and activities the physicians selected themselves were more likely to be accepted. Physicians used the information to create a reference point against which they could weigh their performance using it variably depending on their personal interpretation of its accuracy, application, and utility. CONCLUSIONS: Physicians use and interpret data and standards of varying quality to inform self assessment. Physicians may benefit from regular and routine feedback and guidance on how to seek out data for self-assessment. PMID- 21275534 TI - Cross-cultural adaptation of an innovative approach to learning about difficult conversations in healthcare. AB - BACKGROUND: The Program to Enhance Relational and Communication Skills (PERCS) was developed at a large hospital in the United States to enhance clinicians' preparedness to engage in difficult conversations. AIM: To describe the implementation of PERCS in an Italian hospital and assess the program's efficacy. METHODS: The Italian PERCS program featured 4-h experiential workshops enrolling 10-15 interdisciplinary participants. The workshops were organized around the enactment and debriefing of realistic case scenarios portrayed by actors and volunteer clinicians. Before and after the workshop, participants rated their perceived preparation, communication and relational skills, confidence, and anxiety on 5-point Likert scales. Open-ended questions explored their reflections on the learning. T-tests and content analysis were used to analyze the quantitative and qualitative data, respectively. RESULTS: 146 clinicians attended 13 workshops. Participants reported better preparation, confidence, and communication skills (p < 0.001) after the workshops. The program had a different impact depending on the discipline. Participants valued the emphasis on group feedback, experiential and interdisciplinary learning, and the patient's perspective, and acquired: new communication skills, self-reflective attitude, reframed perspective, and interdisciplinary teamwork. CONCLUSION: PERCS proved culturally adaptable to the Italian context and effective in improving participants' sense of preparation, communication skills, and confidence. PMID- 21275535 TI - Neurology for internal medicine residents: working towards a national Canadian curriculum consensus. AB - BACKGROUND: Partly due to the absence of a standardized neurology curriculum, internal medicine residents often perceive neurology lowest in terms of the level of knowledge and clinical confidence. AIMS: To compare the learning needs of internal medicine residents with the perceived learning needs of neurology and internal medicine program directors and to integrate these needs by developing a focused nationwide neurology curriculum for internal medicine residents rotating through neurology. METHODS: Medical residents and neurology and internal medicine program directors from programs across the Canada were asked to complete an online survey and to rank an exhaustive list of neurology topics. A modified Delphi approach was used to obtain consensus on the top 20 topics to include in the curriculum. RESULTS: Over 80% of residents felt their competency in neurology was average or below after completing their neurology rotation. There was very high correlation between the topics ranked by residents and staff. We were able to achieve consensus on 20 topics to be included in a neurology curriculum for internal medicine residents. CONCLUSION: Through a modified Delphi approach we were able to produce a neurology curriculum for internal medicine residents rotating through neurology based on the input of program directors across the country. PMID- 21275536 TI - Can Japanese students embrace learner-centered methods for teaching medical interviewing skills? Focus groups. AB - BACKGROUND: Students' perceptions of learner-centered methods for teaching medical interviewing skills have not been fully explored. AIM: To explore Japanese students' perceptions of learner-centered methods for teaching medical interviewing skills such as role play with student-created scenarios, peer assisted video reviews, and student-led small group debriefing. METHODS: We conducted three focus groups with a total of 15 students who participated in the learner-centered seminars on medical interviewing skills at the Nagoya University School of Medicine. The transcripts were analyzed by two authors independently. Keywords and concepts were identified and a thematic framework was developed. RESULTS: Overall, students valued the experience of writing their own scenarios for role play, but some questioned their realism. Many students commented that peer-assisted video reviews provided them with more objective perspectives on their performance. However, some students expressed concerns about competitiveness during the video reviews. While students appreciated teachers' minimum involvement in the group debriefing, some criticized that teachers did not explain the objectives of the seminar clearly. Many students had difficulties in exchanging constructive feedback. CONCLUSION: We were able to gain new insights into positive and negative perceptions of students about learner centered methods for teaching medical interviewing skills at one medical school in Japan. PMID- 21275537 TI - A single generic multi-source feedback tool for revalidation of all UK career grade doctors: does one size fit all? AB - BACKGROUND: The UK Department of Health is considering a single, generic multi source feedback (MSF) questionnaire to inform revalidation. METHOD: Evaluation of an implementation pilot, reporting: response rates, assessor mix, question redundancy and participants' perceptions. Reliability was estimated using Generalisability theory. RESULTS: A total of 12,540 responses were received on 977 doctors. The mean time taken to complete an MSF exercise was 68.2 days. The mean number of responses received per doctor was 12.0 (range 1-17) with no significant difference between specialties. Individual question response rates and participants' comments about questions indicate that some questions are less appropriate for some specialities. There was a significant difference in the mean score between specialities. Despite guidance, there were significant differences in the mix of assessors across specialties. More favourable scores were given by progressively more junior doctors. Nurses gave the most reliable scores. CONCLUSIONS: It is feasible to electronically administer a generic questionnaire to a large population of doctors. Generic content is appropriate for most but not all specialties. The differences in mean scores and the reliability of the MSF between specialties may be in part due to the specialty differences in assessor mix. Therefore the number and assessor mix should be standardised at specialty level and scores should not be compared across specialties. PMID- 21275538 TI - Exploring the validity and reliability of a questionnaire for evaluating veterinary clinical teachers' supervisory skills during clinical rotations. AB - BACKGROUND: Feedback to aid teachers in improving their teaching requires validated evaluation instruments. When implementing an evaluation instrument in a different context, it is important to collect validity evidence from multiple sources. AIM: We examined the validity and reliability of the Maastricht Clinical Teaching Questionnaire (MCTQ) as an instrument to evaluate individual clinical teachers during short clinical rotations in veterinary education. METHODS: We examined four sources of validity evidence: (1) Content was examined based on theory of effective learning. (2) Response process was explored in a pilot study. (3) Internal structure was assessed by confirmatory factor analysis using 1086 student evaluations and reliability was examined utilizing generalizability analysis. (4) Relations with other relevant variables were examined by comparing factor scores with other outcomes. RESULTS: Content validity was supported by theory underlying the cognitive apprenticeship model on which the instrument is based. The pilot study resulted in an additional question about supervision time. A five-factor model showed a good fit with the data. Acceptable reliability was achievable with 10-12 questionnaires per teacher. Correlations between the factors and overall teacher judgement were strong. CONCLUSIONS: The MCTQ appears to be a valid and reliable instrument to evaluate clinical teachers' performance during short rotations. PMID- 21275539 TI - Mixing it but not mixed-up: mixed methods research in medical education (a critical narrative review). AB - BACKGROUND: Some important research questions in medical education and health services research need 'mixed methods research' (particularly synthesizing quantitative and qualitative findings). The approach is not new, but should be more explicitly reported. AIM: The broad search question here, of a disjointed literature, was thus: What is mixed methods research - how should it relate to medical education research?, focused on explicit acknowledgement of 'mixing'. METHODS: Literature searching focused on Web of Knowledge supplemented by other databases across disciplines. FINDINGS: Five main messages emerged: - Thinking quantitative and qualitative, not quantitative versus qualitative - Appreciating that mixed methods research blends different knowledge claims, enquiry strategies, and methods - Using a 'horses for courses' [whatever works] approach to the question, and clarifying the mix - Appreciating how medical education research competes with the 'evidence-based' movement, health services research, and the 'RCT' - Being more explicit about the role of mixed methods in medical education research, and the required expertise CONCLUSION: Mixed methods research is valuable, yet the literature relevant to medical education is fragmented and poorly indexed. The required time, effort, expertise, and techniques deserve better recognition. More write-ups should explicitly discuss the 'mixing' (particularly of findings), rather than report separate components. PMID- 21275540 TI - Excellence in teaching and learning in medical schools. PMID- 21275541 TI - Implementation science: Addressing complexity in medical education. PMID- 21275542 TI - Implementation of simulation in surgical practice: minimally invasive surgery has taken the lead: the Dutch experience. AB - Minimal invasive techniques are rapidly becoming standard surgical techniques for many surgical procedures. To develop the skills necessary to apply these techniques, box trainers and/or inanimate models may be used, but these trainers lack the possibility of inherent objective classification of results. In the past decade, virtual reality (VR) trainers were introduced for training minimal invasive techniques. Minimally invasive surgery (MIS) is, by nature, very suitable for this type of training. The specific psychomotor skills and eye-hand coordination needed for MIS can be mastered largely using VR simulation techniques. It is also possible to transfer skills learned on a simulator to real operations, resulting in error reduction and shortening of procedural operating time. The authors aim to enlighten the process of gaining acceptance in the Netherlands for novel training techniques. The Dutch Societies of Surgery, Obstetrics and Gynecology, and Urology each developed individual training curricula for MIS using simulation techniques, to be implemented in daily practice. The ultimate goal is to improve patient safety. The authors outline the opinions of actors involved, such as different simulators, surgical trainees, surgeons, surgical societies, hospital boards, government, and the public. The actual implementation of nationwide training curricula for MIS is, however, a challenging step. PMID- 21275543 TI - Medical students as teachers: how preclinical teaching opportunities can create an early awareness of the role of physician as teacher. AB - BACKGROUND: As future physicians, questions about when medical students realize they will have to teach remain under-explored. AIM: To understand when students serving in pre-clinical teaching roles make the connection between teaching and being a physician. METHODS: Medical students involved in a peer instruction program included: (1) archived first-year student interview candidate data (n = 60/150); (2) focus groups of first-year students selected as instructors (n = 16/60); and (3) focus groups of second-year students (n = 16/24) who taught for the program. A modified extended-term mixed-method research design involved data from the pre-hire interviews and post-hire focus group. RESULTS: Prior to teaching, none of the first year interviewees made an explicit connection between teaching and being a physician. The new instructors selected to teach minimally made a connection and only after prompting. The majority of the experienced instructors did make the connection; however, and did so spontaneously. CONCLUSION: It was only after they taught medicine-related material that students saw the benefits of teaching as a way of preparing for becoming a physician and not merely as a way to review or help their peers. PMID- 21275544 TI - How to become a better clinical teacher: a collaborative peer observation process. AB - BACKGROUND: Peer observation of teaching (PoT) is most commonly done as a way of evaluating educators in lecture or small group teaching. Teaching in the clinical environment is a complex and hectic endeavor that requires nimble and innovative teaching on a daily basis. Most junior faculty start their careers with little formal training in education and with limited opportunity to be observed or to observe more experienced faculty. AIM: Formal PoT would potentially ameliorate these challenges. METHODS: This article describes a collaborative peer observation process that a group of 11 clinician educators is using as a longitudinal faculty development program. RESULTS: The process described in this article provides detailed and specific teaching feedback for the observed teaching attending while prompting the observing faculty to reflect on their own teaching style and to borrow effective teaching techniques from the observation. CONCLUSION: This article provides detailed examples from written feedback obtained during collaborative peer observation to emphasize the richness of this combined experience. PMID- 21275545 TI - Problems presented by medical students seeking support: a possible intervention framework. AB - BACKGROUND: Academically bright and ambitious medical students must cope with a combination of curriculum, assessment, career choice, personal, family and social pressures. Many seek support, and some present complex problems that consume substantial resources. A few continue unresolved into postgraduate life and may affect future professional performance. Early intervention may be helpful in minimising the impact on both individual students and school resources. AIM: To develop a broad classification framework for personal problems presented by medical students to student support services. METHODS: We report a study of more complex student problems presenting to student support services. A three stage iterative process, involving student support faculty from several international medical schools, discussed case scenarios based on pooled experience and developed a framework for categorising and considering management. RESULTS: Seven profiles of student problems were developed, based on composites of unidentified cases drawn from participants' experiences, reflecting: immaturity; learning skills; organisational skills; health or personal issues and poor insight. Broad characteristics and brief prognostic comments are provided for each profile. DISCUSSION: While profiles may overlap and each student may have a unique set of issues, there appears to be similarities that allow some categorisation for management strategies and prognostic features in both undergraduate and postgraduate medical education. Further work is needed to develop 'diagnostic' assessments that might guide intervention. CONCLUSION: This classification may assist early intervention into personal problems presented by medical students to student support services. PMID- 21275546 TI - Impact of High School Certificate scores on the selection process of medical students. PMID- 21275547 TI - eMedical Teacher. PMID- 21275549 TI - Does alendronate disturb the healing process of posterior lumbar interbody fusion? A prospective randomized trial. AB - OBJECT: Bisphosphonate medications are widely used for the treatment of osteoporosis, but they might disturb the healing process of spinal fusion. The object of this prospective randomized controlled study was to evaluate the effect of bisphosphonate medication on spinal fusion through radiographic, clinical, and biological assessments. METHODS: A total of 40 patients with osteoporosis who were candidates for single-level posterior lumbar interbody fusion were randomly assigned to the alendronate group (alendronate sodium 35 mg/week) or the control group (vitamin D, alfacalcidol 1 MUg/day). Pedicle screw fixation and carbon polyetheretherketone cages were used for all the patients. Bone graft material was prepared as a mixture of local bone and beta-tricalcium phosphate in a ratio of 2:1. Functional radiography and CT scans were used to evaluate fusion status and cage subsidence. The incidence of vertebral compression fractures (VCFs) occurring after surgery (subsequent VCFs) was assessed by means of MR imaging. Bridging bone formation was graded into 3 categories: Grade A (bridging bone through bilateral cages), Grade B (bridging bone through a unilateral cage), or Grade C (incomplete bony bridging). A solid fusion was defined as less than 5 degrees of angular motion in flexion-extension radiographs and the presence of bridging bone through the cage (Grade A or B). Clinical outcome was evaluated by means of the Oswestry Disability Index. Bone metabolic markers (serum bone alkaline phosphatase, serum and urine Type I collagen cross-linked N telopeptides) were measured to investigate the biological effects of alendronate on spinal fusion. RESULTS: Bridging bone formation (Grade A or B) was more frequently observed in the alendronate group at all postoperative assessment periods. At 1-year postoperative follow-up, a solid fusion was achieved in 95% of the patients in the alendronate group and 65% of those in the control group. Cage subsidence (> 2 mm) was observed in 5% of the alendronate group and 29% of the control group. No vertebral fractures were observed in the alendronate group, whereas 24% of patients in the control group showed subsequent VCFs. There was no statistically significant between-groups difference in clinical outcomes, but poor clinical results in the control group were associated with pseudarthrosis and subsequent VCFs. Biochemical analysis of bone turnover demonstrated that alendronate inhibited bone resorption from the early phase of the fusion process and also suppressed bone formation after 6 months postoperatively. CONCLUSIONS: Favorable mechanical circumstances provided by alendronate overcame its detrimental biological effect on the healing process of spinal fusion. The authors recommend that osteoporosis patients undergoing spinal fusion take bisphosphonates throughout the postoperative period. PMID- 21275551 TI - Arteriovenous malformation of the conus supplied by the artery of Desproges Gotteron. AB - The artery of Desproges-Gotteron is rarely mentioned in the literature and is unfamiliar to most neurosurgeons. The authors report a unique case of an arteriovenous malformation (AVM) of the conus in an adult woman, which received blood supply from an artery of Desproges-Gotteron. The patient presented with intermittent pain radiating down the right posterior thigh and foot and transient bladder incontinence. On examination, there was weakness of the right lower limb with hypalgesia of the plantar aspect of the right foot. Magnetic resonance imaging revealed a mass near the anterior aspect of the conus medullaris and angiography confirmed a spinal AVM at the L-1 level and a shunt located at the inferior L-3 level. The patient underwent transarterial embolization, and at 2 year follow-up, repeat angiography demonstrated no evidence of residual or recurrent spinal AVM, intermittent and tolerable pain without treatment interventions, and a normal neurological examination. The artery of Desproges Gotteron appears to be a rare arterial variation. Moreover, the authors believe this to be the first case of a conal AVM supplied by such an artery. The anatomy and implications of such an arterial variant are discussed. PMID- 21275550 TI - Long-term stability after multilevel cervical laminectomy for spinal cord tumor resection in von Hippel-Lindau disease. AB - OBJECT: Despite the frequent multiplicity and development of new spinal cord hemangioblastomas that require multiple resections in patients with von Hippel Lindau (VHL) disease, the long-term effects of spinal surgery on spinal column stability in this neoplasia disorder are not known. To determine the effect of multilevel cervical laminectomy for spinal cord tumor resection in VHL, the authors analyzed long-term clinical and radiographic outcomes. METHODS: The authors included consecutive patients enrolled in a prospective VHL disease natural history study who underwent cervical laminectomy(s) for spinal cord hemangioblastoma resection. Serial clinical examinations, neck disability indices, and radiographs (static and dynamic), as well as operative records, were analyzed. RESULTS: Twenty-five adult patients (16 female, 9 male) with VHL disease underwent 34 operations (mean 1.4 +/- 0.7 [+/- SD]/patient) for the resection of cervical spinal cord hemangioblastomas (mean number of lamina removed/surgery 3.0 +/- 1.3). The mean age at surgery was 33.9 +/- 11.9 years (range 18-61 years), and the mean follow-up duration was 9.1 +/- 5.6 years. At last follow-up, radiographic criteria indicated that 9 patients (36%) had spinal column instability, 13 patients (52%) developed a cervical spinal deformity, 4 patients (16%) developed moderate to severe neck disability, and 3 patients (12%) met the criteria for clinical instability. Removal of the C-2 lamina was associated with the development of clinical instability (p = 0.02, Fisher exact test); older age at surgery was associated with the development of cervical deformity (p = 0.05, logistic regression); and a greater number of operations (suboccipital-T4) were associated with increased neck disability indices (p = 0.01, linear regression). CONCLUSIONS: Whereas patients with VHL disease will often require multiple laminectomies for cervical spinal cord hemangioblastoma resection, a limited number of patients (12%) will develop clinical instability. Because prophylactic cervical instrumentation confers limited benefit at the time of spinal cord tumor resection for most patients, and because these patients need life-long MR imaging of the spinal cord, the quality of which may be affected by instrumentation, longitudinal clinical and radiological evaluation may be used to determine which patients will require stabilization. PMID- 21275552 TI - Traumatic lateral expulsion of the L-4 vertebral body from the spinal column. AB - Traumatic lateral spondyloptosis is mostly a lateral shearing injury that must be tremendous enough to completely disrupt the strong musculoligamentous and bony structures. This injury has only been described at single levels in the lumbar spine. Lateral expulsion of a vertebral body from the spinal column due to 2 level adjacent spondyloptosis has not been previously reported. This 16-year-old girl was referred to our center for the management of an extremely unusual L2-5 fracture-dislocation. Motor deficits were incomplete and sacral sensation was spared. Three-dimensional reconstructed CT scans revealed a fracture involving the superior L-4 vertebral body and endplate. There was also complete disruption of the L4-5 disc space. The majority of the L-4 vertebral body was expelled to the right of the spinal column, with the collapse of L-3 and a small remnant of the L-4 superior endplate onto L-5. Surgical management involved decompression, reduction, reconstruction of L-4 with a cage, and L1-ilium stabilization and fusion. Only a few attachments of the psoas muscles had to be divided to roll the L-4 vertebral body out posterolaterally, similar to the method of complete en bloc spondylectomy used in oncology. Neurological recovery has thus far included the resumption of normal bladder and bowel function, as well as ambulation with the use of a right leg brace. Perhaps this type of fracture has not been previously described because many patients would be expected to succumb to vascular or visceral injury. The authors believe this is the first case report of double lateral spondyloptosis at adjacent levels, resulting in expulsion of the vertebral body from the spinal column. PMID- 21275553 TI - Magnetic resonance imaging findings in treated spinal dural arteriovenous fistulas: lack of correlation with clinical outcomes. AB - OBJECT: Little information is available on follow-up MR imaging after treatment of spinal dural arteriovenous fistulas (DAVFs). The authors studied MR imaging findings in treated spinal DAVFs in relation to clinical outcomes. METHODS: A retrospective review of patients with spinal DAVFs who had undergone both pre- and postoperative spinal MR imaging was conducted. Postoperative MR images were obtained as routine follow-up studies or because of subjective or objective clinical deterioration. Several pre- and posttreatment MR imaging characteristics were evaluated by 2 neuroradiologists blinded to the clinical outcome. Clinical outcomes of motor, sensory, and urinary function (in relation to the patient's preoperative status) at the time of the postoperative MR imaging were obtained from the clinical record. The chi-square, Fisher exact, and rank-sum tests were performed to correlate imaging findings and changes with clinical outcomes. RESULTS: Thirty-four patients met inclusion criteria. Treatment was surgical in 33 patients and endovascular in 1 patient. Follow-up MR imaging was performed at a mean 168 +/- 107 days after treatment. Twenty-seven patients (79.4%) were either clinically stable or improved, and 7 (20.6%) experienced worsening in one or more clinical outcomes. Most patients were found to have improvement of MR imaging changes. However, some degree of persistent spinal cord signal abnormality, enhancement, and swelling was observed in 31 (91.2%), 29 (85.3%), and 18 (52.3%) patients, respectively. Changes in these MR imaging characteristics compared with preoperative MR imaging did not correlate with clinical outcomes (p > 0.05), with the one exception of a significant correlation between change in urinary function and extent of spinal cord contrast enhancement (p = 0.026), a correlation of uncertain importance. Ten of the 34 patients underwent posttreatment digital subtraction angiography, and 3 of these patients had recurrent/residual DAVFs. Worsening of motor function significantly correlated with recurrent/residual DAVF (p = 0.053). CONCLUSIONS: Spinal cord abnormalities persist on postoperative MR imaging studies in patients with treated spinal DAVFs, and although they tend to mildly improve with time, these changes may not correlate with clinical outcomes. However, regardless of imaging findings, worsening motor function may correlate with a recurrent or residual DAVF. PMID- 21275554 TI - Ossification of the ligamentum flavum of the thoracic spine in the Korean population. AB - OBJECT: Thoracic ossification of the ligamentum flavum (OLF), a main cause of thoracic myelopathy, is an uncommon disease entity. It is seen mostly in East Asia, although the majority of reports have issued from Japan. In the present study, the clinical features and prognostic factors of thoracic OLF were examined in a large number of Korean patients. METHODS: Data from 51 consecutive patients who underwent decompressive laminectomy with or without fusion for thoracic OLF between 1998 and 2008 were retrospectively analyzed. Patients were evaluated pre- and postoperatively using the modified Japanese Orthopedic Association (JOA) scale (maximum total score of 11). Patient age, sex, preoperative symptoms, duration of initial symptoms, number of involved segments, duration of follow-up, presence of dural adhesion (dural tearing), intramedullary high signal intensity, morphological classification of OLF (axial or sagittal), coexisting disease, and fusion or no fusion were also evaluated. Surgical outcomes were assessed using JOA recovery rate/outcome scores, and patient satisfaction grades and prognostic factors were analyzed. RESULTS: There were 18 men and 33 women with a mean age of 60.9 years (range 38-80 years). A mean preoperative JOA score of 5.5 improved to a mean score of 7.4 at the last follow-up (mean 52 months after surgery). The mean duration of the initial symptoms was 34.5 months (range 0.1-240 months) prior to surgery. The most common symptoms were motor dysfunction (80%); sensory deficit (67%); and pain, numbness, and claudication (59%) in the lower extremities. Knee hyperreflexia appeared in 69% of the patients. There were a total of 130 ossified segments, and the mean number of segments per patient was 2.6. Ninety-two (71%) of 130 segments were located below T-8. Recovery outcomes were good (18 patients), fair (16 patients), unchanged (11 patients), or worse (6 patients). Thirty-one patients (61%) were satisfied with their operations. Patients with a beak type of OLF on sagittal MR images experienced a higher recovery rate and a better satisfaction grade than did those with a round OLF. The patients with higher preoperative JOA scores demonstrated significantly higher JOA scores postoperatively (p < 0.001), and the preoperative JOA score had a significant correlation with the recovery rate in patients exhibiting mainly motor dysfunction (p = 0.040, r = 0.330). CONCLUSIONS: Of the thoracic OLF studies published to date, the present analysis involves the largest Korean population. The most common symptoms of thoracic OLF were motor dysfunction and sensory deficit in the lower extremities, although pain, numbness, and claudication were observed in some patients and were notably accompanied by knee hyperreflexia. At a minimum of 2 years after surgery for thoracic OLF, operative outcomes were generally good, and the prognostic factors affecting good surgical outcomes included a beak type of OLF and a preoperative JOA score > 6. PMID- 21275555 TI - Clinical and methodological precision of spinal navigation assisted by 3D intraoperative O-arm radiographic imaging. AB - OBJECT: In recent years, the importance of intraoperative navigation in neurosurgery has been increasing. Multiple studies have proven the advantages and safety of computer-assisted spinal neurosurgery. The use of intraoperative 3D radiographic imaging to acquire image information for navigational purposes has several advantages and should increase the accuracy and safety of screw guidance with navigation. The aim of this study was to evaluate the clinical and methodological precision of navigated spine surgery in combination with the O-arm multidimensional imaging system. METHODS: Thoracic, lumbar, and sacral pedicle screws that were placed with the help of the combination of the O-arm and StealthStation TREON plus navigation systems were analyzed. To evaluate clinical precision, 278 polyaxial pedicle screws in 139 vertebrae were reviewed for medial or caudal perforations on coronal projection. For the evaluation of the methodological accuracy, virtual and intraoperative images were compared, and the angulation of the pedicle screw to the midsagittal line was measured. RESULTS: Pedicle perforations were recorded in 3.2% of pedicle screws. None of the perforated pedicle screws damaged a nerve root. The difference in angulation between the actual and virtual pedicle screws was 2.8 degrees +/- 1.9 degrees . CONCLUSIONS: The use of the StealthStation TREON plus navigation system in combination with the O-arm system showed the highest accuracy for spinal navigation compared with other studies that used traditional image acquisition and registration for navigation. PMID- 21275556 TI - Alendronate and fusion. PMID- 21275557 TI - Oncogenic osteomalacia of the cervical spine: a rare case of curative resection and reconstruction. AB - Oncogenic osteomalacia (OO) is a rare paraneoplastic syndrome, with only 100 reported cases in the literature. The majority of OO-associated mesenchymal tumors are due to a lesion called phosphaturic mesenchymal tumor, mixed connective tissue (PMTMCT) variant. There have been only 6 reported cases of OO of the spine. With this paper the authors present a case of OO of the cervical spine in a patient who initially presented with multiple pathological fractures of unknown cause, and who eventually underwent staged C-5 spondylectomy followed by circumferential stabilization. Resection of the cervical lesion led to resolution of his hypophosphatemia and prevention of any further pathological fractures. The authors describe a rare cervical neoplasm, its treatment, and review the literature on this rare bony pathological entity. PMID- 21275558 TI - Delayed postoperative hemorrhage in 21 patients with intracranial epidermoid cysts. AB - OBJECT: Intracranial epidermoid cysts are rare, potentially curable, benign lesions that are sometimes associated with severe postoperative complications, including hemorrhage. Delayed hemorrhage, defined as one that occurred after an initial unremarkable postoperative CT scan, contributed to most cases of postoperative hemorrhage in patients with epidermoid cyst. In this study, the authors focus on delayed hemorrhage as one of the severe postoperative complications in epidermoid cyst, report its incidence and its clinical features, and analyze related clinical parameters. METHODS: There were 428 cases of intracranial epidermoid cysts that were surgically treated between 2002 and 2008 in Beijing Tiantan Hospital, and these were retrospectively reviewed. Among them, the cases with delayed postoperative hemorrhage were chosen for analysis. Clinical parameters were recorded, including the patient's age and sex, the chief surgeon's experience in neurosurgery, the year in which the operation was performed, tumor size, adhesion to neurovascular structures, and degree of resection. These parameters were compared in patients with and without delayed postoperative hemorrhage to identify risk factors associated with this entity. RESULTS: The incidences of postoperative hemorrhage and delayed postoperative hemorrhage in patients with epidermoid cyst were 5.61% (24 of 428) and 4.91% (21 of 428), respectively, both of which were significantly higher than that of postoperative hemorrhage in all concurrently treated intracranial tumors, which was 0.91% (122 of 13,479). The onset of delayed postoperative hemorrhage ranged from the 5th to 23rd day after the operation; the median time of onset was the 8th day. The onset manifestation included signs of intracranial hypertension and/or meningeal irritation (71.4%), brain herniation (14.3%), seizures (9.5%), and syncope (4.8%). Neuroimages revealed hematoma in 11 cases and subarachnoid hemorrhage in 10 cases. The rehemorrhage rate was 38.1% (8 of 21). The mortality rate for delayed postoperative hemorrhage was 28.6% (6 of 21). None of the clinical parameters was correlated with delayed postoperative hemorrhage (p > 0.05), despite a relatively lower p value for adhesion to neurovascular structures (p = 0.096). CONCLUSIONS: Delayed postoperative hemorrhage contributed to most of the postoperative hemorrhages in patients with intracranial epidermoid cysts and was a unique postoperative complication with unfavorable outcomes. Adhesion to neurovascular structures was possibly related to delayed postoperative hemorrhage (p = 0.096). PMID- 21275559 TI - Hemangioblastoma. PMID- 21275560 TI - The epidemiological trends of head injury in the largest Canadian adult trauma center from 1986 to 2007. AB - OBJECT: This study documents the epidemiology of head injury over the course of 22 years in the largest Level I adult trauma center in Canada. This information defines the current state, changing pattern, and relative distribution of demographic factors in a defined group of trauma patients. It will aid in hypothesis generation to direct etiological research, administrative resource allocation, and preventative strategies. METHODS: Data on all the trauma patients treated at Sunnybrook Health Sciences Centre (SHSC) from 1986 to 2007 were collected in a consecutive, prospective fashion. The authors reviewed these data from the Sunnybrook Trauma Registry Database in a retrospective fashion. The aggregate data on head injury included demographic data, cause of injury, and Injury Severity Score (ISS). The collected data were analyzed using univariate techniques to depict the trend of variables over years. The authors used the length of stay (LOS) and number of deaths per year (case fatality rate) as crude measures of outcome. RESULTS: A total of 16,678 patients were treated through the Level I trauma center at SHSC from January 1986 to December 2007. Of these, 9315 patients met the inclusion criteria (ISS > 12, head Abbreviated Injury Scale score > 0). The median age of all trauma patients was 36 years, and 69.6% were male. The median ISS of the head-injury patients was 27. The median age of this group of patients increased by 12 years over the study period. Motorized vehicle accidents accounted for the greatest number of head injuries (60.3%) although the relative percentage decreased over the study period. The median transfer time of patients sustaining a head injury was 2.58 hours, and there was an approximately 45 minute improvement over the 22-year study period. The median LOS in our center decreased from 19 to 10 days over the study period. The average case fatality rate was 17.4% over the study period. In multivariate analysis, more severe injuries were associated with increased LOS as was increasing time from injury to hospital presentation. Age and injury severity were independently predictive of mortality. CONCLUSIONS: These data will provide useful information to guide future studies on the changing patterns of head injury, possible mechanisms of injury, and efficient resource allocation for management of this condition. PMID- 21275561 TI - Vertebral artery pexy for microvascular decompression of the facial nerve in the treatment of hemifacial spasm. AB - OBJECT: Hemifacial spasm (HFS) is caused by arterial or venous compression of cranial nerve VII at its root exit zone. Traditionally, microvascular decompression of the facial nerve has been an effective treatment for posterior inferior and anterior inferior cerebellar artery as well as venous compression. The traditional technique involves Teflon felt or another construct to cushion the offending vessel from the facial nerve, or cautery and division of the offending vein. However, using this technique for severe vertebral artery (VA) compression can be ineffective and fraught with complications. The authors report the use of a new technique of VA pexy to the petrous or clival dura mater in patients with HFS attributed to a severely ectatic and tortuous VA, and detail the results in a series of patients. METHODS: Six patients with HFS due to VA compression underwent a retrosigmoid craniotomy, combined with a far-lateral approach in some patients. On identification of the site of VA compression, the vessel was mobilized adequately for the decompression. Great care was taken to avoid kinking the perforating vessels arising from the VA. Two 8-0 nylon sutures were passed through to the wall of the VA and then through the clival or petrous dura, and then tied to alleviate compression on cranial nerve VII. RESULTS: Patients were followed for at least 1 year postoperatively (mean 2.7 years, range 1-4 years). All 6 patients had complete resolution of their HFS. Facial function was tested postoperatively, and was stable when compared with the preoperative baseline. Two of the 3 patients with preoperative tinnitus had resolution of this symptom after the procedure. Postoperative imaging demonstrated VA decompression of the facial nerve and no evidence of stroke in all patients. One patient suffered from hearing loss, another developed a postoperative transient unilateral vocal cord paralysis, and a third patient developed a pseudomeningocele that resolved with the placement of a lumbar drain. CONCLUSIONS: Hemifacial spasm and other neurovascular syndromes are effectively treated by repositioning the compressing artery. Careful study of the preoperative MR images may identify a select group of patients with HFS due to an ectatic VA. Rather than traditional decompression with only pledget placement, these patients may benefit from a VA pexy to provide an effective, safe, and durable resolution of their symptoms while minimizing surgical complications. PMID- 21275562 TI - Chronic subdural hematoma. PMID- 21275563 TI - Ventricle wall movements and cerebrospinal fluid flow in hydrocephalus. AB - OBJECT: The dynamics of fluid flow in normal pressure hydrocephalus (NPH) are poorly understood. Normally, CSF flows out of the brain through the ventricles. However, ventricular enlargement during NPH may be caused by CSF backflow into the brain through the ventricles. A previous study showed this reversal of flow; in the present study, the authors provide additional clinical data obtained in patients with NPH and supplement these data with computer simulations to better understand the CSF flow and ventricular wall displacement and emphasize its clinical implications. METHODS: Three NPH patients and 1 patient with aqueductal stenosis underwent cine phase-contrast MR imaging (cine MR imaging) for measurement of CSF flow and ventricle wall movement during the cardiac cycle. These data were compared to data previously obtained in 8 healthy volunteers. The CSF flow measurements were obtained at the outlet of the aqueduct of Sylvius. Calculation of the ventricular wall movement was determined from the complete set of cine MR images obtained axially at the middle of the lateral ventricle. The data were obtained before and after CSF removal with a ventriculoperitoneal shunt with an adjustable valve. To supplement the clinical data, a computational model was used to predict the transmural pressure and flow. RESULTS: In healthy volunteers, net CSF aqueductal flow was 1.2 ml/minute in the craniocaudal direction. In patients with NPH, the net CSF flow was in the opposite direction- the caudocranial direction--before shunt placement. After shunting, the magnitude of the abnormal fluid flow decreased or reversed, with the flow resembling the normal flow patterns observed in healthy volunteers. CONCLUSIONS: The authors' MR imaging-based measurements of the CSF flow direction and lateral ventricle volume size change and the results of computer modeling of fluid dynamics lead them to conclude that the directional pattern and magnitude of CSF flow in patients with NPH may be an indication of the disease state. This has practical implications for shunt design and understanding the mechanisms that produce hydrocephalus. PMID- 21275564 TI - Chronic spontaneous diploic hematoma. AB - The authors report the case of a 23-year-old woman with cafe-au-lait spots and axillary and inguinal freckling who presented with a diploic chronic spontaneous hematoma of the left parietal bone. To the authors' knowledge, this case represents the first description of a diploic hematoma in a patient with stigmata of neurofibromatosis Type 1 unrelated to head trauma. Plain skull radiography showed an osteolytic lesion with well-circumscribed margins, corresponding to the hematoma, together with exuberant perilesional vascular markings. Angiography demonstrated an incidental aneurysm of the left supraclinoidal internal carotid artery and an unusual cortical venous drainage toward the diploic vessels. The blood flow of these vessels on the right hemicranium was sluggish and exhibited enlarged diploic venous lacunas. The authors hypothesize that the hematoma was formed by both an abnormal venous drainage toward the diploic vascular net, together with a vasculopathy that caused stenosis and obstruction of the normal drainage pathways from these vessels. PMID- 21275565 TI - Anacardic acid induces caspase-independent apoptosis and radiosensitizes pituitary adenoma cells. AB - OBJECT: Pituitary adenomas, which are common intracranial tumors, are associated with significant patient morbidity due to hormone secretion or mass effect or as a complication of therapy. Epigenetic regulation has emerged as an important component of malignant tumor pathogenesis, although the contribution in the progression of benign pituitary tumors remains largely unexplored. The present study evaluates the effect of anacardic acid (6-pentadecyl salicylic acid), a natural histone acetyltransferase inhibitor, on pituitary adenoma cells. METHODS: The concentration- and time-dependent effects of anacardic acid on the viability of GH3 and MMQ pituitary adenoma cells were determined by 3-(4,5-dimethylthiazoyl 2-yl)-2,5-diphenyltetrazolium bromide assay. Cell cycle phase distribution, protein expression, and percentage of apoptotic cells were assessed by flow cytometry and Western blotting. Colony forming assays were used to study the radiosensitizing effect of anacardic acid. RESULTS: The present study identifies a novel antiproliferative and cytotoxic effect of anacardic acid on pituitary adenoma cells. These effects were associated with an increase in poly([adenosine diphosphate]-ribose) polymerase cleavage, sub-G1 arrest, and annexin V staining, consistent with apoptotic cell death; however, the pancaspase inhibitor carbobenzoxy-valyl-alanyl-aspartyl-(O-methyl)-fluoromethylketone failed to reverse anacardic acid-induced cell death, suggesting a possible nonclassical apoptotic mechanism. Anacardic acid also reduced the expression of survivin and X linked inhibitor of apoptosis protein, antiapoptotic proteins associated with cellular survival and radioresistance, and radiosensitized pituitary adenoma cells. CONCLUSIONS: These findings warrant further exploration of anacardic acid as a single agent or as an adjunct to radiation therapy for the treatment of pituitary tumors. PMID- 21275566 TI - Patterns of sound change in children with phonological disorders. AB - This paper presents longitudinal data that provide insight into the phonological learning of five children. These children were superficially similar in that all presented with errors affecting production of [s]; however, it will be argued that each child possessed a phonological system that was unique in certain ways. Production of [s]was established with each participant using a motoric training approach, and generalization was assessed over a 3-4-month period using a 50-item probe. Once treatment was initiated, changes in the production of [s]and in other properties of the phonological systems were observed. Some of these changes illustrated apparent learning strategies that were child-specific, whereas other changes were common to all of these children and may, in fact, be universal in nature. PMID- 21275567 TI - The substitution of [s] for aspirated targets: perceptual and acoustic evidence from Cantonese. AB - The substitution of [s] for word-initial aspirated targets was examined in a Cantonese-speaking pre-school child. Perceptual analysis showed that the child produced [ph] accurately, but substituted [s] for /t(h)/, /ts(h)/ and /k(h)/. Acoustic analysis revealed no subphonemic contrast between the target /s/, and the substituted [s] for /t(h)/, /ts(h)/ and /k(h)/. The unusual substitution of [s] for aspirated lingual targets, and the lack of a subphonemic contrast among [s] productions were described in terms of feature geometry. The target feature patterns of [-continuant, +spread] were produced as [+continuant, +spread], with maintenance of the default place feature (coronal). It is proposed that the child had immature motor control of the coordination of supralaryngeal and laryngeal movements. Examination of the child's productions of aspirated lingual targets at pre-, mid- and post-therapy revealed that compensatory articulation changed over time as the child learned to coordinate laryngeal and oral movements. PMID- 21275568 TI - The effects of semantic predictability in non-pathological older adults' production of a phonemic contrast. AB - The present study examined the effects of semantic predictability in non pathological older adults' production of the /t/-/d/ phonemic voice contrast. Experiment 1 examined young and older adults' production of /t/ and /d/ words embedded in semantically biasing and neutral passages and when produced in the clear or in noise. Experiment 2 assessed the perceptual intelligibility of subjects' production by examining listeners' identification of the /t/-/d/ words produced in Experiment 1. The results replicate previous findings demonstrating that duration lengthens in neutral vs. biasing contexts. However, the results also show agerelated differences. Older adults preserved the /t/-/d/ contrast in all the experimental manipulations; young adults were more variable. In addition, listeners were better able to identify the words produced by the older adults. We suggest that older adults compensate pragmatically for their cognitive inability to integrate and process the semantic information in the neutral contexts. Consequently, they adopt a strategy for all passages and hyperarticulate the /t/ /d/ contrast in an attempt to ensure successful communication. It is believed that these results contribute to the understanding of the normal ageing process in speech production, and may help identify differences between normal life-span developments and pathological deviations during communication. PMID- 21275569 TI - Lexical characteristics of sound change. AB - The purpose of this study was to determine the relationship between sound change and lexical structure in two children with functional phonological disorders. Specifically, the question of how sound change infuses through the developing lexicon was addressed. A chronology of phonemic acquisition for the children who participated has previously been documented. These archival data were now extended to evaluate lexical change relative to sounds acquired. Lexical change was examined through the parameters of neighbourhood density and word frequency. Results of this study revealed two converging patterns across children: (a) for each child there was one parameter (neighbourhood density or word frequency) of lexical change which held across all sounds acquired, and (b) for each child the alternative parameter patterned differentially by sound. This variability in lexical change was hypothesized to be associated with the relative degree of feature specification of the sounds acquired. This has theoretical implications for the overlay of phonological and lexical structure, and clinical potential for remediation of phonological disorders. PMID- 21275571 TI - The biatrial cryo-maze procedure for treatment of atrial fibrillation: a single center experience. AB - OBJECTIVES: The Cox-maze III procedure is the benchmark for atrial fibrillation (AF) surgery but has been replaced by surgical ablation. We evaluated our experience with biatrial cryoablation using the full Cox-maze III lesion pattern, and adhering follow-up to current guidelines. DESIGN: Forty-three patients underwent the biatrial cryo-maze procedure as a concomitant (n = 37) or stand alone procedure (n = 6). Mean age was 64.8 +/- 9.5 years. Overall, AF was paroxysmal/persistent/permanent in 28/14/58%. Mean AF duration was 5.2 +/- 6.5 years. Follow-up included prospective evaluation at 1, 3 and 12 months, long-term monitoring and transthoracic echocardiography. RESULTS: No mortality and no complications related to the ablation procedure occurred. One patient suffered a stroke at 12 months. In the concomitant group, rhythm was sinus/pacing without AF/AF in 65/16/19% at three months, and 59/22/19% at 12 months. Five patients received new pacemakers (12%). In the stand-alone group, 5/6 (83%) patients had sinus rhythm with no AF at three and 12 months. Overall, 35/43 patients (81%) had sinus/paced rhythm at 12 months with no AF and no anti-arrhythmic drugs. Echocardiography showed satisfactory results in all patients. CONCLUSIONS: The biatrial cryo-maze procedure is safe and effective in surgical patients with concomitant AF, and could be considered for selected patients with lone AF. PMID- 21275572 TI - Assessing air medical crew real-time readiness to perform critical tasks. AB - BACKGROUND: Air medical transport has had problems with its safety record, attributed in part to human error. Flight crew members (FCMs) must be able to focus on critical safety tasks in the context of a stressful environment. Flight crew members' cognitive readiness (CR) to perform their jobs may be affected by sleep deprivation, personal problems, high workload, and use of alcohol and drugs. OBJECTIVE: The current study investigated the feasibility of using a computer-based cognitive task to assess FCMs' readiness to perform their job. METHODS: The FCMs completed a short questionnaire to evaluate their physiologic and psychological state at the beginning and end of each shift. The FCMs then performed 3 minutes of a computer-based cognitive task called synthetic work environment (SYNWIN test battery). Task performance was compared with the questionnaire variables using correlation and regression analysis. Differences between the beginning and end of each shift were matched and compared using a paired Students t test. RESULTS: SYNWIN performance was significantly worse at the end of a shift compared with the beginning of the shift (p = 0.028) primarily because of decrement in the memory component. The SYNWIN composite scores were negatively correlated to degree of irritability felt by the participant, both before (r = -0.25) and after (r = -0.34) a shift and were significantly correlated with amount of sleep (0.22), rest (0.30), and life satisfaction (0.30). CONCLUSIONS: Performance by FCMs on a simple, rapid, computer-based psychological test correlates well with self-reported sleep, rest, life satisfaction, and irritability. Although further studies are warranted, these findings suggest that assessment of the performance of FCMs on a simple, rapid, computer-based, multitasking battery is feasible as an approach to determine their readiness to perform critical safety tasks through the SYNWIN task battery. PMID- 21275573 TI - Comparison of first-attempt success between tibial and humeral intraosseous insertions during out-of-hospital cardiac arrest. AB - BACKGROUND: Intraosseous (IO) needle insertion is often utilized in the adult population for critical resuscitation purposes. Standard insertion sites include the proximal humerus and proximal tibia, for which limited comparison data are available. OBJECTIVE: This study compared the frequencies of IO first-attempt success between humeral and tibial sites in out-of-hospital cardiac arrest. METHODS: This observational study was conducted in an urban setting between August 28, 2009, and October 31, 2009, and included all medical cardiac arrest patients for whom resuscitative efforts were performed. Cardiac arrest protocols stipulate that paramedics insert an IO line for initial vascular access. During the first month of the study, the proximal humerus was the preferred primary insertion site, whereas the tibia was preferred throughout the second month. The primary outcome was first-attempt success, defined as secure IO needle position in the marrow cavity and normal fluid flow. Any needle dislodgment during resuscitation was also recorded. The association between first-attempt IO success and initial IO insertion location was analyzed using a test of independent proportions and 95% confidence intervals (CIs) for the difference in proportions. RESULTS: There were 88 cardiac arrest patients receiving IO placement, with 58 (65.9%) patients receiving their initial IO attempt in the tibia. The rate of first-time IO success at the tibia was significantly higher than that observed at the humerus (89.7% vs. 60.0%; p < 0.01). There were 18 initial successes at the humerus; for six (33.3%) of these, the needle became dislodged during resuscitation, compared with 52 initial successes at the tibia, with three (5.8%) dislodgments. The rate of total success for initial IO placements was significantly lower for the humerus (40.0%) compared with that for the tibia (84.5%; p < 0.01) during resuscitation efforts. CONCLUSIONS: In this subset of patients, tibial IO needle placement appeared to be a more effective insertion site than the proximal humerus. Success rates were higher with a lower incidence of needle dislodgments. Further randomized studies are required in order to validate these results. PMID- 21275574 TI - Submersion and early-onset acute respiratory distress syndrome: a case report. AB - Drowning is a common cause of accidental death, particularly in younger people, and acute respiratory failure is common in these patients. This case report describes a healthy 18-year-old man who suffered a cardiorespiratory arrest due to submersion while swimming in a freshwater lake. First-responder cardiopulmonary resuscitation and defibrillation using an automated external defibrillator resulted in a return of spontaneous circulation. The patient was evacuated to a tertiary care center by a rotor-wing air medical crew. The crew experienced difficulties in oxygenating and ventilating the patient because of early-onset acute respiratory distress syndrome (ARDS). This case report describes the pathophysiology and prehospital management of a patient with suspected early-onset ARDS secondary to drowning. This case report is unique because it describes the oxygenation and ventilation difficulties encountered in managing this patient in the transport setting, and possible strategies to deal with these difficulties. Finally, this case report highlights the prehospital bypass decision-making process for patients requiring specialized medical care. PMID- 21275581 TI - Perception of foreign accent syndrome speech and its relation to segmental characteristics. AB - Foreign accent syndrome (FAS) is an acquired neurogenic disorder characterized by altered speech that sounds foreign-accented. This study presents a British subject perceived to speak with an Italian (or Greek) accent after a brainstem (pontine) stroke. Native English listeners rated the strength of foreign accent and impairment they perceived in speech of the FAS subject, alongside that of two native English speakers and Italian, Greek, and French L2 speakers acting as controls. The FAS subject was perceived to be as foreign-sounding as the L2 control speakers, but was also perceived as mildly impaired. The FAS subject's own perception of accents was also explored and it was found that his ability to distinguish presence and absence of accent does not seem to be affected. The relationship between listeners' perceptions and features of the FAS speech is explored via correlational statistics and qualitative analysis. Impressionistic phonetic analysis, supplemented by acoustic analysis, confirmed a number of features consistent with a typical Italian (and also Greek) accent and the Italian and Greek L2 speakers. A pre-stroke and a post-stroke sample from the FAS subject were compared and the nature of post-stroke changes in segmental realizations is discussed. PMID- 21275582 TI - Comparative speaking, shouting and singing voice range profile measurement: physiological and pathological aspects. AB - The Voice Range Profile (VRP) measurement offers a method for the investigation of voice modalities i.e. speaking voice, shouting voice and singing voice in their mutual pitch and intensity relations. The parameters FO and SPL are evaluated by means of automatic pitch and SPL measurements from (1) sustained phonation /a:/ in the speaker's natural pitch and intensity range, (2) the continuous speaking voice beginning with Pianissimo up to Fortissimo, (3) the shouting voice. Vocal intensity is plotted vertically, vocal pitch horizontally. The displays of the vocal intensity versus fundamental frequency are defined as singing voice range profile (VRP), speaking VRP and shouting VRP. The VRPs are superimposed on the same plot. Their form, their shape and their position to each other are analysed. The physiological relationships between the VRPs of the different voice modalities to each other are defined. The pathological relationships between the VRPs (i.e. reduction, shifting) give information about etiology and pathomechanism of voice disorders. PMID- 21275583 TI - Anxiety associated with botox injections for adductor spasmodic dysphonia. AB - This study investigated the relationship between anxiety and Botox injections in a group of patients with adductor spasmodic dysphonia. The aim of the study was to record the course of anxiety using both self report as well as Speech and Language Therapists' evaluation of anxiety. The study confirmed that most patients within the group showed increased anxiety prior to intervention with a gradual decline in the post intervention period. The decline of anxiety seems to reflect the outcome of the procedure rather than the procedure itself. Individual variations and their implications are discussed. PMID- 21275584 TI - Occupational risk factors and voice disorders. AB - From the point of view of occupational health, the field of voice disorders is very poorly developed as compared, for instance, to the prevention and diagnostics of occupational hearing disorders. In fact, voice disorders have not even been recognized in the field of occupational medicine. Hence, it is obviously very rare in most countries that the voice disorder of a professional voice user, e.g. a teacher, a singer or an actor, is accepted as an occupational disease by insurance companies. However, occupational voice problems do not lack significance from the point of view of the patient. We also know from questionnaires and clinical studies that voice complaints are very common. Another example of job-related health problems, which has proved more successful in terms of its occupational health status, is the repetition strain injury of the elbow, i.e. the "tennis elbow". Its textbook definition could be used as such to describe an occupational voice disorder ("dysphonia professional is"). In the present paper the effects of such risk factors as vocal loading itself, background noise and room acoustics and low relative humidity of the air are discussed. Due to individual factors underlying the development of professional voice disorders, recommendations rather than regulations are called for. There are many simple and even relatively low-cost methods available for the prevention of vocal problems as well as for supporting rehabilitation. PMID- 21275585 TI - Substitute laryngeal voice sources after partial laryngectomies. AB - The larynx is a highly adjustable organ, preserving at least some of its functions even when severely damaged. Partial surgical excision (trauma) of the larynx creates new anatomical and functional conditions for the production of voice. Depending on the type and extent of the excision, functional closure of the glottis is compromised, usually resulting in a hyperkinetic pattern of voice production. The glottal voice source is jeopardized, which can result in the creation of substitute laryngeal voice sources. Their capacity for voice production is limited, and therefore these mechanisms have considerable clinical significance. In this paper, the incidence of substitute laryngeal voice sources after partial laryngectomies and its clinical implications are analyzed. PMID- 21275586 TI - Figures of speech and context awareness following right hemisphere infarcts. AB - The ability to interpret figures of speech was tested in nineteen patients with right hemisphere damage (RDH) and in seventeen controls. All subjects were presented fifteen expressions with metaphoric meanings and asked to select one of three pictures; one illustrating the literal meaning of the expression, one the metaphoric meaning and one a noun in the expression. RHD patients were expected to have problems in interpreting the metaphoric expressions but the hypothesis that the RHD group would select the literal picture more often than the controls was rejected. The groups differed, however, in the distribution of non-metaphoric answers, and in the way the tasks were solved. The performance by the RHD patients may reflect deficient awareness of the context. PMID- 21275587 TI - Learning disabilities and language pathology in patients with galactosemia. AB - In spite of adequate dietary regimen, many patients with galactosemia have developmental abnormalities. We studied 8 patients with galactosemia, aged 9 months to 19 years who had all been treated with a galactose-free diet from an early stage. Neurological functioning, general developmental, and language and speech development were assessed in all cases. The results show that even medically well treated children and young adults with galactosemia are at risk to develop disabilities, including mental retardation, speech and language disabilities. Verbal dyspraxia was diagnosed in 3 of 6 patients, who had acquired verbal language, all with IQ 70 or below. This may indicate that verbal dyspraxia is just one symptom among others in patients with galactosemia and mental retardation. PMID- 21275588 TI - The acquisition of Swedish as second language in a group of Arabic-speaking pre school children: word order patterns and phrasal morphology. AB - Children with Swedish as a second language (L2) and Swedish children with specific language impairment (SLI) have displayed interesting similarities in their linguistic development. A group of 18 normally developed Arabic-speaking children, five and six years old, were tested with respect to their development of word order patterns and phrasal morphology in the noun phrase. The results were in accordance with Pienemann's processability theory, that predicts the order of acquisition of both morphological and syntactical structures. The results on word order patterns showed similarities between L2 and SLI children. Processability theory could be a powerful tool in analyzing the grammar in children with SLI. PMID- 21275589 TI - The parameters of care for cleft lip and palate patients in Aarhus, Denmark. AB - Aarhus Cleft Palate Institute receives approximately 75 new cleft patients a year. Due to statuary notification of all newborn cleft patients to the Institute, the treatment protocol can be offered to the family from right after birth, and a coordinated team approach can be established. The individually planned primary surgery, speech and growth of the maxillo-facial skeleton is followed by regular team examinations. Speech development is followed from the child is one year old in order to be able to provide speech assessment as soon as problems of hypernasality and articulation disorders or language delay is evident. One of the goals of speech assessment is to achieve acceptable speech as early as possible and at best before school start. Orthodontic treatment is usually started at 8 years of age, in UCLP and BCLP patients in combination with bonegrafting at 9-11 years of age. In patients with impaired growth of the maxilla, attention is paid to identify candidates for orthognathic surgical treatment as early as possible. All secondary surgical treatment on jaws, lips and nose are coordinated and usually the treatment can be finished by the late teens. The described team approach towards the parameters of care for cleft lip and palate patients has basically been used for more than 50 years. A systematic follow-up and data collection on all patients provide a scientific base for evaluation of treatment results. Based on long-term investigations the protocol has gradually been modified during time to improve the quality of patient care. PMID- 21275590 TI - A short history of laryngoscopy. AB - Visual examination of the larynx has a history rich in personalities and anecdotes. Beginning with early experiments, and continuing with the work of the eminent Spanish voice teacher Manuel Garcia, the history of indirect and direct laryngoscopy is presented, complete with contemporary illustrations. As with most medical advances, laryngoscopy is the result of advancing technology, leavened by human ingenuity. Despite the contemporary sophistication of videostroboscopy and laryngeal microsurgery. Garcia's original technique of mirror examination remains part of every laryngologist's armamentarium. PMID- 21275592 TI - Understanding Rasch and item response theory models: applications to the estimation and validation of interval latent trait measures from responses to rating scale questionnaires. AB - BACKGROUND: Modern psychometric theory is now routinely used in clinical vision research, as well as other areas of health research, to measure latent health states on continuous interval scales from responses to self-report rating scale questionnaires. Two competing theories are commonly employed: Rasch theory and item response theory. METHODS: Because the field is currently in transition from using traditional scoring algorithms based on classical test theory to using the more modern approaches, this article offers a tutorial review of Rasch theory and item response theory and of the analytical methods employed by the two theories to estimate and validate measures. PMID- 21275593 TI - Design and baseline data of a randomized trial to evaluate coverage and frequency of mass treatment with azithromycin: the Partnership for Rapid Elimination of Trachoma (PRET) in Tanzania and The Gambia. AB - OBJECTIVES: Trachoma is the principal cause of infectious blindness. As part of its strategy to eliminate trachoma, the World Health Organization recommends annual mass antibiotic treatment for at least 3 years with an 80% population coverage target. However, to date, ideal population coverage and mass treatment duration have not been determined and further evaluation of treatment recommendations in areas of varying endemicity is warranted. The studies presented here evaluate the impact of coverage level and frequency of mass treatment with single dose azithromycin on trachoma and ocular C. trachomatis infection. METHODS: The Partnership for the Rapid Elimination of Trachoma supervises 2 randomized, community-based clinical trials in Tanzania and The Gambia. Although each trial is a stand-alone effort, protocols, data collection, and analytic approaches have been harmonized to permit generalizations. Communities in each site were randomized using a 2X2 factorial design to standard (80%-90.0%) versus high (over 90.0%) treatment coverage; communities were further randomized to annual treatment for 3 years versus a "graduation" rule where evidence indicates an absence of follicular trachoma or infection and annual treatment is halted. RESULTS: Average prevalence of follicular trachoma in children age less than 5 years was 32.2% in Tanzania and 5.96% in The Gambia. Randomization appeared to be effective, as prevalence was not statistically different between the arms within each country. CONCLUSIONS: There are challenges in harmonizing 2, large trials in Africa. Study outcomes will provide critical data to national trachoma control programs on treatment methodology and resource allocation toward elimination of the disease. PMID- 21275594 TI - A survey of severe visual impairment and blindness in children attending thirteen schools for the blind in sri lanka. AB - PURPOSE: To identify the causes of blindness and severe visual impairment (BL/SVI) in children attending schools for the blind in Sri Lanka, and to provide optical devices and ophthalmic treatment where indicated. METHODS: Two hundred and six children under 16 years from 13 schools for the blind in Sri Lanka were examined by a team of ophthalmologists and optometrists. Data were entered in the World Health Organization Prevention of Blindness Eye Examination Record for Childhood Blindness (WHO/PBL ERCB). RESULTS: Of the 206 children, 83.5% were blind (BL = Visual acuity [VA] <3/60), and 9.2% had severe visual impairment (SVI = VA <6/60 to 3/60 in the better eye). The major anatomical site of BL/SVI was the retina in 35.9% of cases, followed by the whole globe in 22.4% of cases. The major underlying aetiologies of BL/SVI were unknown in 43.8% of cases and hereditary in 37.5%. Avoidable causes of BL/SVI accounted for 34.9% of cases; retinopathy of prematurity made up the largest proportion of this subgroup. One third of the children required an optical device to improve their vision. CONCLUSION: Just over one third of the children in schools for the blind in Sri Lanka had potentially avoidable causes of BL/SVI. Vision could also be improved in a third of children. The data support the need to develop specialized pediatric ophthalmic services, particularly in the face of advancing neonatal life support in Sri Lanka, and the need for increased provision of optical support. PMID- 21275595 TI - Prevalence of age-related macular degeneration in Thailand. AB - PURPOSE: To determine the prevalence of age-related macular degeneration (AMD) in Thailand. METHODS: In this population-based study, data of participants in the Thailand National Survey of Visual Impairment in 2006-2007 were analyzed. Participants selected for this study were more than 50 years old, and were recruited from 42 districts of 21 provinces. They were interviewed, tested for visual acuity, examined for eye screening, and measured for intraocular pressure. They had digital fundus photographs taken using a nonmydriatic fundus camera through dilated pupils. The diagnosis of AMD, according to the standard international grading system, was made from the interpretation of the digital images by at least 2 retinal specialists. The observed data were used for predicting estimates of the prevalence of AMD in Thailand. RESULTS: Data from 10,788 participants were analyzed. There were 321/10,788 (3%, 95% CI: 2.7-3.3%) participants diagnosed as having AMD. The mean age was 62.1 (range 50-98, SD 8.8) years old. There were 294 (2.7%) and 27 (0.3%) participants with early AMD (38.4% male) and late AMD (74.1% male) respectively. Of the late AMD, 20 (74.1%) were wet AMD and 7 (25.9%) were geographic atrophy. Based on the population census of Thailand, this could be translated into 351,000 and 39,000 patients with early and late AMD respectively. CONCLUSIONS: Based on these data, it is projected that Thailand will have a large number of late AMD sufferers. This makes it imperative to develop new strategies for the national public health system, aiming to incorporate already available late AMD treatment. PMID- 21275596 TI - Resolution of choroidal neovascularization secondary to punctate inner choroidopathy (PIC) with intravitreal anti-VEGF agents: a case series. AB - Case series of four patients with CNVM secondary to PIC treated solely with anti VEGF in three cases and in combination with PDT in the other. This series reveals long term follow up (3 months to 28 months) which is currently not described in the literature. PMID- 21275597 TI - Unusual toxoplasmic chorioretinitis in advanced age: a diagnostic problem. AB - PURPOSE: To raise awareness regarding presentation of toxoplasmic chorioretinitis late in life, and to discuss the invasive diagnostic options. PATIENTS/METHODS: Case report. RESULTS: A 62-year-old patient presenting with posterior vitritis and a focus of retinitis was misdiagnosed and treated with antivirals and corticosteroids. Relapse after initial stabilization justified a vitreous tap for culture and DNA detection of a number of infectious agents, leading to the correct diagnosis of T.gondii infection. CONCLUSIONS: Ocular sampling may be necessary to secure timely diagnosis and treatment of atypical retinitis. Acquired ocular toxoplasmosis may be under-recognized as a cause of infectious posterior uveitis and caution should be applied when administering steroids without a definite diagnosis. PMID- 21275598 TI - Leber's hereditary optic neuropathy precipitated by tadalafil use for erectile dysfunction. AB - Leber's hereditary optic neuropathy (LHON) is an inherited condition leading to bilateral centrocaecal scotoma. Phosphodiesterase type-5 (PDE5) inhibitors such as tadalafil are widely used for male erectile dysfunction. We present a case of a middle-aged male whose LHON presented acutely following tadalafil use. It is postulated that this is due to alteration in the optic nerve head perfusion. PMID- 21275599 TI - Iris cysts: a review. AB - Iris cysts though uncommon, present diagnostic and therapeutic challenges. With the advent of better investigational modalities it is not so difficult to characterize iris cysts and differentiate them from uveal tumors. Management strategies however, are still not clearly defined and long term course especially of inclusion cysts of the iris remains dismal. In this review we present the classification, pathogenesis, differential diagnosis and management options along with long term clinical course of eyes with iris cysts. PMID- 21275600 TI - Horner's syndrome and sixth nerve paresis secondary to a petrous internal carotid artery aneurysm. AB - We describe a report of a child with a horner's syndrome and sixth nerve paresis secondary to a petrous internal carotid artery (ICA) aneurysm. Management of this condition involved coiling of the aneurysm and the use of botulinum toxin to manage his strabismus and associated symptoms. PMID- 21275601 TI - Vitreous web after pars plana vitrectomy and bevacizumab with fluid-air exchange. AB - BACKGROUND: Intravitreal bevacizumab may result in intraocular inflammation of infectious and non-infectious etiology. Appropriate recognition of a sterile process can circumvent unnecessary treatment for endophthalmitis. DESIGN: Observational case report. METHODS: A marked web-like inflammatory response within the vitreous following intraoperative intravitreal bevacizumab is described in a patient with pre-proliferative diabetic retinopathy, macular edema, and epiretinal membrane who underwent pars plana vitrectomy, membrane peel, endolaser, and fluid-air exchange. Wide-field fundus photography captured the full extent of this reaction. RESULTS: On post-operative day one, the patient presented with vitreous opacities in the form of a web of multiple white strands inferior to an air bubble, with minimal anterior or vitreous cell. At one week, the inflammatory reaction had completely resolved. CONCLUSION: Existing reports of intraocular inflammation following intravitreal bevacizumab range from uveitis to infectious endophthalmitis. With wide-field fundus imaging, we report an acute, marked web-like inflammatory response following intraoperative intravitreal bevacizumab that resolved spontaneously. PMID- 21275602 TI - Central corneal thickness as a predictor of visual field loss in primary open angle glaucoma for a Hispanic population. AB - BACKGROUND: Primary Open Angle Glaucoma is a multi-factorial disease with a devastating impact on the quality of life of the patient in the moderate and severe stages of the disease. Identifying risk factors for the development of moderate to severe visual field loss may decrease the proportion of patients that experience the severe forms of this disease. PURPOSE: To evaluate whether the central corneal thickness correlates inversely with the severity of visual field loss in Primary Open Angle Glaucoma. METHODS: Retrospective review of 308 charts of patients seen during a six-week period by a glaucoma specialist in his community practice in a large Hispanic area. Patients were classified as normal, ocular hypertensive, and those with Primary Open Angle Glaucoma. Odds ratios and 95% confidence interval were calculated to evaluate risk factors associated to ocular hypertension and Primary Open Angle Glaucoma. Finally, a multivariate polytomous regression model was used to evaluate central corneal thickness as an independent predictor of outcome after adjustment for age and hypertension. Statistical significance was set at p<0.05. RESULTS: Patients with Primary Open Angle Glaucoma show a statistically significant inverse correlation between central corneal thickness and the severity of the visual field damage. CONCLUSION: Thinner corneas could be considered a risk factor for the severity of visual field loss in Primary Open Angle Glaucoma. PMID- 21275603 TI - Fungal keratitis following deep lamellar keratoplasty. AB - A young man affected from keratoconus was submitted to deep lamellar keratoplasty (DLK). The day after, the presence of pseudochamber between the donor and the recipient cornea was observed by the slit-lamp and the patient was submitted to the injection of an air bubble into the anterior chamber. Approximately six days later, multiple, whitish patches mostly located in the centre of the lamellar interface were noticed. Medical treatment was started immediately but no improvement was observed and penetrating keratoplasty was performed. Although this organism has been described as a microbial pathogen in blepharitis, conjunctivitis, keratitis, canaliculitis, dacryocystitis, and endophthalmitis, to the best of our knowledge, this is the first case report of keratitis after DLK caused by Actinomyces species. PMID- 21275604 TI - Interleukin-13 induces mucin 5AC production involving STAT6/SPDEF in human airway epithelial cells. AB - Mucus hypersecretion is commonly observed in many chronic airway inflammatory diseases. Mucin 5AC (MUC5AC) is a major airway mucin because of its high expression in goblet cells. Here, the authors identified a gene called SAM domain containing prostate-derived Ets factor (SPDEF) that was induced by interleukin (IL)-13. Their results showed that specific knockdown of SPDEF reduced IL-13 induced MUC5AC expression in human airway epithelial cells. This finding was associated with decreased expression of anterior gradient 2 (AGR2) and Ca(2+) activated Cl(-) channel (CLCA1), which regulate IL-13-mediated MUC5AC overproduction. Furthermore, transfection with SPDEF siRNA enhanced expression of forkhead box a2 (Foxa2), a key transcription factor that is known to prevent mucus production. The authors also demonstrated that the repression of STAT6 inhibited expression of SPDEF and MUC5AC induced by IL-13. These results show that SPDEF plays a critical role in regulating a transcriptional network mediating IL-13-induced MUC5AC synthesis dependent on STAT6. PMID- 21275605 TI - The role of CCR1 expression in the retinal degeneration in rd mice. AB - PURPOSE: Chemokine receptors are reported to be involved in neuronal cell death and CNS neurodegenerative diseases. The aim of the current study was to investigate the expression of CCR1, a major chemokine receptor for CC chemokines in retinal dystrophy in rd (retinal degeneration) mice and further explore its role in photoreceptor degeneration. MATERIALS AND METHODS: The expression levels of CCR1 mRNA in the whole control and rd retinas at postnatal days (P) 8, 10, 12, 14, 16, and 18 were determined by RT-PCR assay. Location of CCR1 in the retina of rd mice at each age group was studied by immunohistochemical analysis. Expression of CCR1 in the photoreceptor cells and apoptotic cells was determined by double labeling. RESULTS: Expression of CCR1 mRNA was noted in both control and rd retinas at each age group. CCR1-positive cells started to emerge in the outer nuclear layer (ONL) in rd retinas at P8 and reached a peak at P12 and P14. Double labeling of CCR1 with rhodopsin, CD11b, or TUNEL staining showed expression of CCR1 in the photoreceptor cells, rather than in the microglial cells. Partial CCR1 expression was observed in some of the apoptotic photoreceptor cells. CONCLUSIONS: Expression of CCR1 in the photoreceptor cells was increased with the progress of retinal degeneration in rd mice. Activation of CCR1 may play a role in the photoreceptor apoptosis. PMID- 21275606 TI - Pulmonary injury after combined exposures to low-dose low-LET radiation and fungal spores. AB - Exposure to infectious microbes is a likely confounder after a nuclear terrorism event. In combination with radiation, morbidity and mortality from an infection may increase significantly. Pulmonary damage after low-dose low-LET irradiation is characterized by an initial diffuse alveolar inflammation. By contrast, inhaled fungal spores produce localized damage around pulmonary bronchioles. In the present study, we assessed lung injury in C57BL/6 mice after combined exposures to whole-body X radiation and inhaled fungal spores. Either animals were exposed to Aspergillus spores and immediately irradiated with 2 Gy, or the inoculation and irradiation were separated by 8 weeks. Pulmonary injury was assessed at 24 and 48 h and 1, 2, 4, 8, and 24 weeks later using standard H&E stained sections and compared with sham-treated age-matched controls. Immunohistochemistry for invasive inflammatory cells (macrophages, neutrophils and B and T lymphocytes) was performed. A semi-quantitative assessment of pulmonary injury was made using three distinct parameters: local infiltration of inflammatory cells, diffuse inflammation, and thickening and distortion of alveolar architecture. Radiation-induced changes in lung architecture were most evident during the first 2 weeks postexposure. Fungal changes were seen over the first 4 weeks. Simultaneous combined exposures significantly increased the duration of acute pulmonary damage up to 24 weeks (P < 0.01). In contrast, administration of the fungus 8 weeks after irradiation did not produce enhanced levels of acute pulmonary damage. These data imply that the inhalation of fungal spores at the time of a radiation exposure alters the susceptibility of the lungs to radiation-induced injury. PMID- 21275607 TI - A model for assessing cognitive impairment after fractionated whole-brain irradiation in nonhuman primates. AB - To investigate the effect of fractionated whole-brain irradiation on nonhuman primates, 6-9-year-old male rhesus monkeys were irradiated with 40 Gy delivered as two 5-Gy fractions/week for 4 weeks. Cognitive function was assessed 5 days/week for 4 months prior to fractionated whole-brain irradiation and for 11 months after irradiation using a Delayed-Match-to-Sample (DMS) task at both low and high cognitive loads. Local rates of cerebral glucose metabolism were measured prior to and 9 months after irradiation using [(18)F]-2-deoxy-2-fluoro-d glucose positron emission tomography. Low cognitive load trials did not reveal a significant reduction in performance until 7 months after irradiation; performance then declined progressively. In high cognitive load trials, the initial impairment was observed ~1 month after irradiation. This was followed by a transient recovery period over the next 1-2 months, after which performance declined progressively through 11 months after irradiation. Nine months after irradiation, glucose uptake during the DMS task was decreased in the cuneate and prefrontal cortex and was increased in the cerebellum and thalamus compared with the levels prior to irradiation. Results from this pilot study suggest that the radiation-induced changes in cognition and brain metabolism observed in rhesus monkeys may be similar to those observed in brain tumor patients receiving brain irradiation. PMID- 21275608 TI - Examining the suitability of riboflavin/UVA treatment for strengthening the stromal bioequivalent of a human cornea construct. AB - PURPOSE: To improve the mechanical stability of a tissue-engineered human cornea construct, which is used as an in vitro model for drug absorption studies, the collagen matrix of this construct is to be strengthened by collagen cross linking. A suitable method to induce photooxidative cross-linking of collagen fibrils is UVA irradiation combined with riboflavin as a photosensitizer. MATERIALS AND METHODS: After riboflavin/UVA treatment, the viscoelastic properties of the collagen matrix and the molecular weight of its proteins, as well as cell viability of the human corneal keratocytes (HCK) incorporated in the stromal matrix, were analyzed depending on the dose of irradiation. In addition, the cell damage to the HCKs after riboflavin/UVA treatment was also analyzed in monolayer cultures. Various luminescent cell assays were performed to clarify whether the decrease of cell viability was a consequence of apoptosis or necrosis. Furthermore, fluorescent double staining was carried out using an apoptotic/necrotic cells detection kit. RESULTS: The improvement of mechanical properties was low, whereas resultant cell damage was considerable and enduring. When lower doses of irradiation were used, the reduction of cell viability was triggered by apoptosis while necrosis supervened for increased doses of irradiation. CONCLUSION: We conclude that in contrast to clinical applications, the riboflavin/UVA treatment does not seem to be a suitable method to obtain a sufficiently firm stromal matrix including vital keratocytes to build a tissue engineered human cornea construct to be used as an in vitro model for drug absorption studies. PMID- 21275621 TI - Therapeutic horseback riding:. AB - This paper reviews the literature on the benefits of therapeutic horseback riding and the outcomes of eleven data-based studies purpoting to validate the claims that horseback riding offers therapeutic benefits. These studies have focused on physical and psychosocial variables. The literature on the benefits of riding reported obvious beneficial effects, while the outcome studies were able to document only some of these claims. The studies generally reported some significant effects from the therapeutic intervention. An examination of the outcome studies revealed weak scientific rigor, small sample sizes, and a lack of homogeneous populations. Furthermore, use of standardized measures was limited as authors frequently relied on nonstandardized observational techniques to evaluate change. This review indicates a need for further research into both the physical and psychosocial areas with both children and adults. In addition, there is a need for research which would improve the methodological rigor, homogeneity of populations, sample size, and use of standardized measurement instruments. PMID- 21275622 TI - A study of therapeutic effects of horseback riding for children with cerebral palsy. AB - This article describes major findings from a study of the therapeutic benefits of horseback riding for children with cerebral palsy. Nineteen children (aged 4-12 years) with mild or moderate degrees of cerebral palsy were recruited from a children's treatment centre. Prior to randomization, the children were stratified according to their degree of disability. Ten children were allocated to a riding (experimental) group, and participated in one-hour weekly riding classes for six months. The remaining nine children were put on a waiting list for riding. The results of the study were inconclusive as so often in the case with children with cerebral palsy. Qualitative results gleaned from the weekly progress recordings of the riding instructor, reports of the on-site physical therapist, and reports from parents showed clear progressions in physical and psychosocial functioning. Results of standardized quantitative assessments showed few statistically significant changes in the children. The study clearly indicates a need for further research and for finding or developing instruments that are able to capture and reveal meaningful changes in physical and psychosocial status. PMID- 21275623 TI - Reliability of the peabody developmental gross motor scale in children with cerebral palsy. AB - The test/retest, intrarater, and interrater reliability of the Peabody Development Gross Motor Scale (PDGMS) was assessed in 12 children with mild or moderate cerebral palsy. A baseline test was administered, scored, and videotaped by one rater and rescored from the videotape by a second independent rater. In order to minimize the effect of developmental maturation, test/retest correlation coefficients of the tests were performed two weeks apart. The intraclass correlation coefficients ranged from 0.82 to 0.98. For interrater reliability, testing following the same protocol was repeated at 2 weeks, 3 and 6 months. Interrater correlation coefficients (r) ranged from 0.89 to 0.98. Interrater correlation coefficients (ICC) from scoring and later rescoring ten videotapes with the closest and furthest interrater agreement ranged from 0.88 to 0.99. The balance and locomotor skill categories were most responsive for assessing gross motor function in this population. These data support the use of the PDGMS as an assessment tool for children with cerebral palsy and the reliability of videotaping assessments. PMID- 21275624 TI - Development and preliminary validation of an instrument to assess quality of sitting of children with neuromotor dysfunction. AB - The development of a clinical instrument to assess static and dynamic postural control in sitting in children with neuromotor dysfunction is described. A review of the literature has supported the need for objective assessment tools for measuring various aspects of functioning with this population. In this paper the conceptual basis and preliminary validation study results of a new instrument, the Sitting Assessment for Children with Neuromotor Dysfunction (SACND) are presented. Initial results show the SACND to have good inter-rater reliability, and discriminant validity. Construct validity testing suggest the SACND shows promise for use by clinicians and researchers. Further research is needed to assess the SACND's test-retest reliability, the major underlying test constructs, and the effects of intervention on test scores. PMID- 21275625 TI - Nutritional needs of children with developmental disabilities and the school lunch program. PMID- 21275627 TI - Item of interest. PMID- 21275630 TI - A phase III study of anti-B4-blocked ricin as adjuvant therapy post-autologous bone marrow transplant: CALGB 9254. AB - Anti-B4-blocked ricin (anti-B4-bR) is a potent immunotoxin directed against the CD19 antigen. Previous phase I and II studies suggested a possible role for anti B4-bR as consolidation after high-dose chemotherapy and autologous stem cell transplant. Cancer and Leukemia Group B (CALGB) 9254 is a phase III study which randomized 157 patients with B-cell lymphoma in complete remission following autologous transplant to treatment with anti-B4-bR or observation. With a median follow-up time for patients of 5.8 years, the median event-free survival for protocol treatment and observation are 2.1 and 2.9 years, respectively (p = 0.275). The median overall survival for treatment and observation are 6.1 years and not reached, respectively (p = 0.063). Therefore, no differences were found in event-free survival and overall survival between protocol treatment and observation, although there was a trend toward improved survival with observation. These data fail to support a role for anti-B4-bR as consolidative therapy after bone marrow transplant in patients with B-cell lymphoma. PMID- 21275631 TI - Prognostication of diffuse large B-cell lymphoma in the rituximab era. AB - Predicting the prognosis of patients diagnosed with diffuse large B-cell lymphoma (DLBCL) has been a moving target over the last several years. While earlier prognostic models relied mainly on such clinical variables as age, stage of disease, and performance status, it has become evident from gene-expression microarray studies that DLBCL is a heterogeneous disease in terms of molecular pathogenesis and cell of origin. Despite providing considerable insight into disease biology, these techniques are not widely available and are, at least at present, not applicable to routine clinical practice. Furthermore, older prognostic models need to be revalidated and modified as improved therapeutic options become available. In this review, we discuss pertinent studies on individual biomarkers and pattern-based biomarker models, with an emphasis on markers evaluated in patients treated with rituximab-containing chemotherapy. We also discuss recent and ongoing therapeutic trials using drugs that target molecular markers and pathways involved in the pathogenesis of DLBCL or those that adversely influence prognosis. The ultimate goal of these efforts is to refine prognostication of DLBCL using widely available, reproducible, and consistently predictive biomarker models applicable to currently used chemoimmunotherapy, and to create a pathophysiologically based framework for the rational design of individually tailored therapy. PMID- 21275632 TI - Successful control of steroid-intolerant Evans' syndrome associated with allogeneic peripheral blood hematopoietic stem cell transplant by rituximab. PMID- 21275633 TI - Frontline treatment of follicular lymphoma with fludarabine, cyclophosphamide, and rituximab followed by rituximab maintenance: toxicities overcome its high antilymphoma effect. Results from a Spanish Cooperative Trial (LNHF-03). AB - We assessed the efficacy of fludarabine, cyclophosphamide, and rituximab in combination (FCR) as frontline treatment in patients with follicular lymphoma (FL) followed by rituximab maintenance. Seventy-five untreated patients with FL received FCR followed by maintenance with rituximab 375 mg/m(2) weekly during 4 weeks and every 6 months for 2 years. The overall response rate was 100%, with 89% complete remission (CR) and 11% partial remission (PR). Molecular remission was observed in all but one patient. Only eight patients completed all therapy planned. With a median follow-up of 47 months, the 5-year overall survival (OS), progression-free survival (PFS), and event-free survival (EFS) were 77%, 93%, and 72%, respectively. Age below 60 and low Follicular Lymphoma International Prognostic Index (FLIPI) correlated with a better EFS. Ten patients died due to toxic complications. The FCR regimen is highly effective in untreated patients with FL, with 89% CR, including molecular responses, and a low progression rate. However, the high incidence of treatment-related mortality makes this regimen unsafe and it cannot be recommended as an upfront therapy in FL. PMID- 21275634 TI - Mantle cell lymphoma in a mother and her daughter. PMID- 21275639 TI - High-pressure protein crystallography and NMR to explore protein conformations. AB - High-pressure methods for solving protein structures by X-ray crystallography and NMR are maturing. These techniques are beginning to impact our understanding of thermodynamic and structural features that define not only the protein's native conformation, but also the higher free energy conformations. The ability of high pressure methods to visualize these mostly unexplored conformations provides new insight into protein function and dynamics. In this review, we begin with a historical discussion of high-pressure structural studies, with an eye toward early results that paved the way to mapping the multiple conformations of proteins. This is followed by an examination of several recent studies that emphasize different strengths and uses of high-pressure structural studies, ranging from basic thermodynamics to the suggestion of high-pressure structural methods as a tool for protein engineering. PMID- 21275640 TI - Assembly of bacterial inner membrane proteins. AB - Numerous membrane proteins form multisubunit protein complexes, which contain both integral and peripheral subunits, in addition to prosthetic groups. Bacterial membrane proteins are inserted into the inner membrane by the Sec translocase and YidC insertase. Their folding can be facilitated by YidC and the phospholipid phosphatidylethanolamine (PE). Glycine zippers and other motifs promote transmembrane-transmembrane (TM-TM) helix interactions that may lead to the formation of alpha-helical bundles of membrane proteins. During or after membrane insertion, the subunits of oligomeric membrane proteins must find each other to build the homo-oligomeric and the hetero-oligomeric membrane complexes. Although chaperones may function as assembly factors in the formation of the oligomer, many protein oligomers appear to fold and oligomerize spontaneously. Current studies show that most subunits of hetero-oligomers follow a sequential and ordered pathway to form the membrane protein complex. If the inserted protein is misfolded or the membrane protein is misassembled, quality control mechanisms exist that can degrade the proteins. PMID- 21275642 TI - The origins and current status of behavioral activation treatments for depression. AB - The past decade has witnessed a resurgence of interest in behavioral interventions for depression. This contemporary work is grounded in the work of Lewinsohn and colleagues, which laid a foundation for future clinical practice and science. This review thus summarizes the origins of a behavioral model of depression and the behavioral activation (BA) approach to the treatment and prevention of depression. We highlight the formative initial work by Lewinsohn and colleagues, the evolution of this work, and related contemporary research initiatives, such as that led by Jacobson and colleagues. We examine the diverse ways in which BA has been investigated over time and its emerging application to a broad range of populations and problems. We close with reflections on important directions for future inquiry. PMID- 21275643 TI - Acute stress disorder revisited. AB - Acute stress disorder (ASD) was introduced into the Diagnostic and Statistical Manual (DSM) taxonomy in 1994 to address the lack of a specific diagnosis for acute pathological reactions to trauma and the role that dissociative phenomena play both in the short- and long-term reactions to trauma. In this review, we discuss the history and goals of the diagnosis and compare it with the diagnoses of acute stress reaction, combat stress reaction, and posttraumatic stress disorder (PTSD). We also evaluate the research on the validity and limitations of ASD as a diagnosis, the relationship between peritraumatic dissociation and other symptomatology, the extent to which PTSD is predicted by previous ASD or peritraumatic dissociation, and other important issues such as impairment and risk factors related to ASD. We conclude with our recommendations for changes in DSM-5 criteria and the development of more sophisticated research that considers ASD as but one of two or possibly three common acute posttraumatic syndromes. PMID- 21275644 TI - Genetic regulation of sporopollenin synthesis and pollen exine development. AB - Pollen acts as a biological protector of male sperm and is covered by an outer cell wall polymer called the exine, which consists of durable sporopollenin. Despite the astonishingly divergent structure of the exine across taxa, the developmental processes of its formation surprisingly do not vary, which suggests the preservation of a common molecular mechanism. The precise molecular mechanisms underlying pollen exine patterning remain highly elusive, but they appear to be dependent on at least three major developmental processes: primexine formation, callose wall formation, and sporopollenin synthesis. Several lines of evidence suggest that the sporopollenin is built up via catalytic enzyme reactions in the tapetum, and both the primexine and callose wall provide an efficient substructure for sporopollenin deposition. Herein, we review the currently accepted understanding of the molecular regulation of sporopollenin biosynthesis and examine unanswered questions regarding the requirements underpinning proper exine pattern formation, as based on genetic evidence. PMID- 21275641 TI - Regulation of phospholipid synthesis in the yeast Saccharomyces cerevisiae. AB - The yeast Saccharomyces cerevisiae, with its full complement of organelles, synthesizes membrane phospholipids by pathways that are generally common to those found in higher eukaryotes. Phospholipid synthesis in yeast is regulated in response to a variety of growth conditions (e.g., inositol supplementation, zinc depletion, and growth stage) by a coordination of genetic (e.g., transcriptional activation and repression) and biochemical (e.g., activity modulation and localization) mechanisms. Phosphatidate (PA), whose cellular levels are controlled by the activities of key phospholipid synthesis enzymes, plays a central role in the transcriptional regulation of phospholipid synthesis genes. In addition to the regulation of gene expression, phosphorylation of key phospholipid synthesis catalytic and regulatory proteins controls the metabolism of phospholipid precursors and products. PMID- 21275645 TI - Anion channels/transporters in plants: from molecular bases to regulatory networks. AB - Anion channels/transporters are key to a wide spectrum of physiological functions in plants, such as osmoregulation, cell signaling, plant nutrition and compartmentalization of metabolites, and metal tolerance. The recent identification of gene families encoding some of these transport systems opened the way for gene expression studies, structure-function analyses of the corresponding proteins, and functional genomics approaches toward further understanding of their integrated roles in planta. This review, based on a few selected examples, illustrates that the members of a given gene family exhibit a diversity of substrate specificity, regulation, and intracellular localization, and are involved in a wide range of physiological functions. It also shows that post-translational modifications of transport proteins play a key role in the regulation of anion transport activity. Key questions arising from the increasing complexity of networks controlling anion transport in plant cells (the existence of redundancy, cross talk, and coordination between various pathways and compartments) are also addressed. PMID- 21275646 TI - Folate biosynthesis, turnover, and transport in plants. AB - Folates are essential cofactors for one-carbon transfer reactions and are needed in the diets of humans and animals. Because plants are major sources of dietary folate, plant folate biochemistry has long been of interest but progressed slowly until the genome era. Since then, genome-enabled approaches have brought rapid advances: We now know (a) all the plant folate synthesis genes and some genes of folate turnover and transport, (b) certain mechanisms governing folate synthesis, and (c) the subcellular locations of folate synthesis enzymes and of folates themselves. Some of this knowledge has been applied, simply and successfully, to engineer folate-enriched food crops (i.e., biofortification). Much remains to be discovered about folates, however, particularly in relation to homeostasis, catabolism, membrane transport, and vacuolar storage. Understanding these processes, which will require both biochemical and -omics research, should lead to improved biofortification strategies based on transgenic or conventional approaches. PMID- 21275647 TI - Convergent evolution in plant specialized metabolism. AB - Plants synthesize a multitude of compounds that contribute to adaptation to their ecological niches. Such compounds serve as attractants of other living organisms beneficial to the plants or as defense against other biotic as well as abiotic agents. Selection for increased fitness, a never-ending process, has resulted in each plant lineage synthesizing a distinct set of specialized metabolites appropriate for its environment. The total number of specialized metabolites found in the plant kingdom far exceeds the capacity of any one plant genome to encode the necessary enzymes, and just as a plant lineage acquires the ability to make new specialized compounds during evolution, it also loses the ability to make others. Although the ability of plants to make novel, specialized metabolites continues to evolve, there are also many examples in which different plants have independently evolved the ability to make compounds already present in other plant lineages or to make different compounds that fulfill the same role both are examples of convergent evolution. Here, we discuss many examples of convergent evolution in specialized metabolism. There are many genetic and biochemical mechanisms that can give rise to convergent evolution, and we conclude that, overall, convergent evolution in plant specialized metabolism is surprisingly common. PMID- 21275649 TI - Patient Barriers to Mammography Identified During a Reminder Program. AB - Abstract Background: Patient mammogram reminders are effective at increasing screening, but patient barriers remain. We evaluated patient characteristics and reported barriers for their association with mammogram completion after a reminder program. Methods: This retrospective cohort study used data from electronic records and a subgroup survey. Participants were female Kaiser Permanente Northwest health maintenance organization (HMO) members aged 50-69 who were 20 months past their last mammogram (index date) and had received a reminder intervention (n = 4708). A mailed survey was completed by 340 of 667 (50.2%) women who received it. The intervention was a "mammogram due soon" postcard 20 months after the last mammogram, followed by up to two automated phone calls and one live call for nonresponders. The outcome was mammogram completion at 10 months after index date. Results: Characteristics associated with lower mammogram completion rates were aged <60 (odds ratio [OR] 0.69, p < 0.0001), health plan membership <5 years (OR 0.81, p = 0.019), family income <$40,000/year (OR 0.77, p = 0.018), and obesity (OR 0.67, p < 0.0001). Obese women were more likely than nonobese women to report "too much pain" from mammograms (31.3% vs.18.8%, p < 0.01). Younger women were more likely to endorse that they were "too busy" (19.1% vs. 6.4%, p < 0.001) and had more worries about mammogram accuracy (2.5 vs. 2.3 on a 5-point scale, p < 0.05). Pain mediated the relationship between obesity and mammogram completion rates (indirect effect = -0.111, p = 0.008). Conclusions: Important barriers to mammogram completion remain even after an effective mammogram reminder system among insured patients. Tailored interventions are necessary to overcome these barriers. PMID- 21275651 TI - Answering the hard questions: the Genetic Testing Registry and its request for information. PMID- 21275652 TI - Genetic tests need the Human Variome Project. PMID- 21275653 TI - Association of heme oxygenase-1 gene polymorphisms with essential hypertension and blood pressure in the Chinese Han population. AB - Many studies have suggested that heme oxygenase-1 (HMOX1) might be implicated in blood pressure (BP) regulation. We hypothesized that this gene might be responsible for the variation of susceptibility to essential hypertension (EH) and BP and investigated three polymorphisms in HMOX1 (i.e., the (GT)n repeat in the HMOX1 promoter and single-nucleotide polymorphisms (SNPs) rs2071746 and rs2071749) in population-based samples of 789 Han Chinese from Xinjiang, China. The GT repeat numbers >=33, 27-32, and <27 in the HMOX1 promoter were defined as long (L), middle (M), and short (S) alleles, respectively. The participants carrying SS or SM genotype were sorted into one group, and the participants carrying SL, MM, ML, or LL genotype were sorted into another group. The (GT)n repeat in the HMOX1 promoter showed significant association with EH and BP, whereas SNPs rs2071746 and rs2071749 did not. Compared with the SS+SM (GT)n group, the MM+SL+ML+LL (GT)n group had a lower risk of EH (adjusted odds ratio, 0.58; 95% confidence interval, 0.41-0.82; p = 0.002) and lower systolic (128.3 +/ 1.3 vs. 132.2 +/- 1.0 mm Hg, adjusted p = 0.014) and diastolic BPs (81.7 +/- 0.8 vs. 84.5 +/- 0.7 mm Hg, adjusted p = 0.009). These findings provide the first genetic evidence for the role of the (GT)n repeat in the HMOX1 promoter in the susceptibility to human EH and the variation of BP. PMID- 21275654 TI - Development of a brochure for increasing awareness of inherited breast cancer in black women. AB - Low levels of awareness about hereditary breast cancer and ovarian cancer and underutilization of genetic services combined with the high incidence of early onset breast cancer in the black community underscore the urgent need to provide information about hereditary breast and ovarian cancer to black women. The primary goal of the present study was to develop a culturally targeted brochure designed to increase awareness about inherited breast cancer among black women using the principles of Learner Verification. Three focus groups were conducted with black women, including those with or without a history of breast cancer (n = 46), to evaluate the brochure. Data were analyzed through hand coding using a simple classification system placing participants' responses in the predetermined Learner Verification categories. On the basis of the feedback obtained, the brochure has been modified to improve cultural-targeting, relevance, and clarity and has been made available for dissemination. Our study illustrates the importance of obtaining feedback from the target audience when developing a culturally targeted informational brochure for black women. Further, the complexity of our subject matter (i.e., inherited breast and ovarian cancer) underscores the importance of using inviting visuals and personal vignettes, while maintaining a simple and clear message. PMID- 21275655 TI - Prevalence of UGT1A1 gene polymorphism in patients with hemolytic anemia in southern Brazil. AB - The aim of the work was to determine the variation of UGT1A1 genotypes in patients with hemolytic anemia in the southern Brazil. Three hundred twenty-three patients with hemolytic anemia were genotyped for UGT1A1 along with 232 controls. Allelic and genotypic distribution did not differ among studied groups. The TA7/TA7 genotype presented a frequency that ranged from 3.2% to 18.0% (nonsignificant). Alleles TA5 and TA8 were also found in the sample, even though southern Brazil is a major Caucasoid region. Genotype prevalence was very similar to those of African origins, reflecting the diversity of ethnic origins and the high degree of admixture in southern Brazil. Further studies should be conducted to correlate the modulating role of UGT1A1 polymorphism with the clinical conditions of each patient with hemolytic anemia. PMID- 21275687 TI - CanMEDS 2000: Extract from the CanMEDS 2000 Project Societal Needs Working Group Report. PMID- 21275686 TI - EDITORIAL International standards of medical education: a global responsibility. PMID- 21275688 TI - Minimum essential requirements and standards in medical education. AB - Increasing globalization of medicine and worldwide migration of physicians call for urgent definition of a set of global standards and requirements to guide medical education curricula. This article reviews the definition of standards in general, and proposes a definition of standards and global minimum essential requirements for use in medical education. They may serve as a tool for the improvement of quality and international comparisons of basic medical programs. Reviewing the use of medical standards worldwide, the China Medical Board established the Institute for International Medical Education (IIME). The IIME project is aimed at defining 'global minimum essential requirements' comprising sciences basic to medicine, clinical knowledge and skills, professional values, behavior and ethics of universal value. They represent only a portion of requirements since the curriculum of each country and medical school has to address its unique health and social needs. Finally, existing impediments and hesitation in use of international standards in medical education are presented. PMID- 21275689 TI - The concept and practicability of a core curriculum in basic medical education. AB - The core curriculum is defined as that which is common rather than essential. It is considered at different levels: institutional, national and global. As its size is inversely proportional to variability in healthcare needs, the core becomes smaller as the geographical unit becomes larger. A rationale for identifying the core is established at all three levels. The risk of stereotypy among curricula and dampening of innovation can be avoided if a significant part of the curriculum is elective, and if schools are free to determine how the core should be achieved. Focusing exclusively on the minimum discourages excellence. Many of the potential disadvantages of a core curriculum can be avoided if the core is combined with options. The core should emphasize higher-order cognitive and process skills and should be reviewed intermittently in the light of trends in healthcare and education. It should be developed in consultation with curriculum implementers using a competency-based approach. In developing international standards, societal relevance of the curriculum should not be sacrificed at the altar of standardization. The scientific bases of medicine, process skills and desirable practices in educating the basic doctor are fertile areas in which to look for international standards. PMID- 21275690 TI - The content of undergraduate health professional courses: a topic largely ignored? AB - Considerable debate has occurred about educational processes within undergraduate courses for healthcare professionals. Less attention appears to have been directed to issues of curriculum content.This paper examines the potential influence of curriculum content on a number of outcomes, and examines the methods that can be used determine curriculum content. The balance between different content areas in a curriculum has the potential to affect allocation of human resources, research capacity and output, and hence the power base of discipline groups. Changes to the balance of content will therefore be sensitive, and threatening to some groups. While the optimal way to determine curriculum content would be on the basis of evidence from experimental studies, such studies have not been conducted. Opinion-based approaches have been commonly used. While such processes demonstrate increasing commitment to determining content that is most relevant to producing good clinicians, the results depend on the stakeholders involved. Despite the considerable difficulties in conducting rigorous research concerning curriculum content, there is a need to develop a research agenda in this area. PMID- 21275691 TI - Making videos for medical undergraduate teaching in child psychiatry: the development, use and perceived effectiveness of structured videotapes of clinical material for use by medical students in child psychiatry. AB - The rationale for using videotapes in medical student teaching is presented with some examples of their use. The process of producing videotapes for use in the undergraduate child psychiatry course at the University of Leicester Medical School is then described, based on eight videos made so far. This includes planning, patient recruitment, and the technical issues associated with video production. The use of the videotapes is then contextualized. Feedback from medical students on the usefulness and quality of the videos is presented. There is finally a brief discussion of some of the issues that arise for both patients and clinicians when videos are made and used for medical student teaching. PMID- 21275692 TI - Data and metadata: development of a digital curriculum. AB - The teaching potential of a problem-based learning (PBL-)oriented curriculum sparks a lot of enthusiasm, but the matrix-type organization of the curriculum elements calls for more powerful organizational tools than the block-oriented structure of previous curricula. Also, the multitude of digital elements available for teaching purposes present a fascinating development, but again the task of putting this offering into order is considerable. The aim of the present project was to set up a database-driven curriculum, organizing the administrative information in a way that allows the multiaxial access required by the new curriculum. Also, we wished to catalogue existing and upcoming digital teaching resources in a way that allowed a logical connection to the curricular activities. The database has a relational structure containing all the administrative information on lessons, as well as topic keywords and abstracts. An index table of the teaching resources forms a link to the curriculum database, and allows the resources to be searched based on curriculum information (topic, term, lecturer etc). Upcoming challenges include acquisition and quality assurance of teaching resources and teaching, as well as motivating the teachers and students. Automated data acquisition mechanisms and curricular activities available only online may be valuable elements in this ongoing process. PMID- 21275693 TI - Can nurses teach tomorrow's doctors? A nursing perspective on involvement in community-based medical education. AB - The increasing importance of primary care suggests an important role for the whole primary healthcare team in the education of 'tomorrow's doctors'. Few studies have evaluated the contribution and views of staff other than general practitioners. We used a questionnaire survey to elicit the perspective of 65 community-based nurses involved in a new undergraduate medical course. Some 67% of the cohort had already undertaken training to teach others, and were confident of their teaching skills but were overly reliant on the general practitioners for information, and on the goodwill of colleagues for time to teach. The findings suggest a need for structural changes in the process of multidisciplinary medical education, supporting the need for teaching commitments to be coordinated at practice rather than individual tutor level. The high level of professional development for teaching among community nurses suggests that there is a sound basis for encouraging such valuable professional input into medical education in the future. PMID- 21275694 TI - Acquiring and demonstrating attitudes in medical education: attitudes to homosexuality as a case study. AB - The main features of a learning programme for medical students that addresses attitudinal issues, using as an example attitudes to homosexuality, are described. Essential and useful features and strategies of the exercise are outlined, together with potential problems. PMID- 21275695 TI - Clerkship assessment assessed. AB - This article reviews consistent research findings concerning the assessment of clinical competence during the clerkship phase of the undergraduate medical training programme on issues of reliability, validity, effect on training programme and learning behaviour, acceptability and costs. Subsequently, research findings on the clinical clerkship as a learning environment are discussed demonstrating that the clinical attachment provides a rather unstructured educational framework. Five fundamental questions (why, what, when, how, who) are addressed to generate general suggestions for improving assessment on the basis of the evidence on assessment and clinical training. Good assessment requires a thoughtful compromise between what is achievable and what is ideal. It is argued that educational effects are eminently important in this compromise, particularly in the unstructured clinical setting. Maximizing educational effects can be achieved in combination with improvements of other measurement qualities of the assessment. Two concrete examples are provided to illustrate the recommended assessment strategies. PMID- 21275696 TI - Impact of different scoring methods on the clinical skills assessment of internal medicine students. AB - The aim of this study was to determine how different scoring methods could influence the results achieved in clinical competence assessment examinations at the end of the medical school curriculum. Fifty-six final-year medical school students were examined using a programme of multimedia computer-based simulated cases (Procuste programme). For generating results, the following scoring methods were applied: (1) the method used for the Internal Medicine official certification examination which includes both weighted and unweighted items; (2) a method with only unweighted items;(3) a method which includes single-item analysis. Each time an absolute pass/fail cut-off standard ( S 60/100) and a relative pass/fail cut-off (mean minus 1 standard deviation) were applied.Taking as a reference the first method, the effect of using different scoring methods on the percentage of student failure was evaluated. Furthermore, correlation studies between the results obtained with these scoring methods and the grades reported by the examinees during the medical school curriculum were performed. It was found that the first method generated a more realistic pass/fail rate compared with the two other methods. Furthermore this method, which has been used for the last 10 years for administering internal medicine examinations, showed better correlation coefficients with the curriculum scores. PMID- 21275698 TI - Do you know? PMID- 21275697 TI - Supervised teaching practice: a system for teacher support and quality assurance. AB - Supervised teaching practice is practical supervision of teaching under the tutelage of an established teacher. It is proposed as a cost-effective integrated approach to linking the support and development of teachers with quality assurance. In modern undergraduate medical curricula increasing value is placed on teaching and teacher-training. The response to the General Medical Council's demand for a new style of undergraduate medical education requires a system of practical and continuous training which will ensure the highest standard among teachers. Supervised teaching practice offers such a system. PMID- 21275700 TI - What's new in medical education: items of interest to medical educators. PMID- 21275701 TI - Jottings. PMID- 21275724 TI - Outcomes in medical education must be wide, long and deep. PMID- 21275725 TI - A curriculum should meet future demands. PMID- 21275727 TI - What is a spiral curriculum? PMID- 21275726 TI - AMEE Medical Education Guide No. 15: Problem-based learning: a practical guide. AB - This practical guide for health professions teachers provides a perspective of one of the most important educational developments in the past 30 years.Problem based learning (PBL) is a continuum of approaches rather than one immutable process. It is a teaching method that can be included in the teacher's tool-kit along with other teaching methods rather than used as the sole educational strategy.PBL reverses the traditional approach to teaching and learning. It starts with individual examples or problem scenarios which stimulate student learning. In so doing, students arrive at general principles and concepts which they then generalize to other situations. PBL has many advantages. It facilitates the acquisition of generic competences, encourages a deep approach to learning and prepares students for the adult learning approach they need for a lifetime of learning in the health care professions. It is also fun. PBL helps in curriculum planning by defining core, ensuring relevance of content, integrating student learning and providing prototype cases. There are also drawbacks associated with PBL. Students may fail to develop an organized framework for their knowledge. The PBL process may inhibit good teachers sharing their enthusiasm for their topic with students and student identification with good teachers.Teachers may not have the skills to facilitate PBL.The problem scenario is of crucial significance. It should engage the students' interest and be skilfully written. While the medium selected for presentation of the scenario is usually print, other media may be used.The clinical tasks carried out by the student may replace the problem scenario as the focus for learning.Students are supported during the PBL process by tutors and/or study guides.The amount of support required is inversely related to the students' prior learning and understanding of the PBL process. A range of additional learning resources and opportunities may be made available to the students, including textbooks, videotapes, computer-based material, lectures and clinical sessions. Tutors require group facilitation skills, an understanding of the PBL process and knowledge of the course and of the curriculum in general.They need special personal qualities and it is preferable if they have expertise in the content area.While special assessment processes have been developed to assess students learning by the PBL method, the general principles of assessment apply to PBL courses and a mixed menu of assessment methods needs to be employed. Curriculum design involves a skilful blend of educational strategies designed to help students achieve the curriculum outcomes. PBL may make a valuable contribution to this blend but attention needs to be paid to how it is implemented. PMID- 21275728 TI - How to write short cases for assessing problem-solving skills. AB - In assessment of problem solving the use of short case-based testing is a promising development. In this approach an examination consists of large numbers of short cases each of which contain a small number of questions. These questions are aimed at essential decisions.Writing such cases, however, is not easy. In this article a description of this type of examination is provided.Also strategies and pitfalls are described in writing these cases. These strategies pertain to the selection of essential decisions, the careful writing of cases and questions and the selection of question formats. PMID- 21275729 TI - Seven years' experience of continuous assessment for degree examination in general practice. AB - The GMC in Tomorrow's Doctors recommends innovation in both the medical curriculum and its assessment. However, few models of assessment adequately reflect the innovative teaching approaches and higher level function required of students by many undergraduate modules currently taught in the UK.This article presents a unique example of continuous assessment for summative purposes of a well-established module in general practice, having equal status in medical finals with medicine and surgery. The methods of assessment are described, together with modifications and results over a period of 7 years. This may provide a useful model for assessment of other new curricula. PMID- 21275730 TI - Educational Commission for Foreign Medical Graduates: clinical skills assessment prototype. AB - The Clinical Skills Assessment is an OSCE-based performance examination that is now the final test requirement for Educational Commission for Foreign Medical Graduates certification of graduates of foreign medical schools. Its design, test development and scoring methodologies are presented, as are the processes used for validation, standard setting, calibration and equating. Some of the logistical challenges of implementing a high-stakes examination for a population of uncertain size and potentially high heterogeneity are considered. Finally, the unique aspects of Clinical Skills Assessment in comparison with other OSCE instruments are highlighted. PMID- 21275731 TI - Giving effective feedback to medical students: a workshop for faculty and house staff. AB - Medical school faculty members and house officers often feel uncomfortable giving direct, behaviorally based feedback on performance to medical students. This paper describes a structured approach to teaching faculty members to give effective feedback to medical students, using an interactive workshop format. Starting with six key principles for effective feedback, participants practise giving feedback to 'standardized students' and develop strategies for framing the feedback in terms which are useful for students.This paper also describes the development of the workshop scenarios and provides the authors'specific strategies for giving effective feedback in various situations. PMID- 21275732 TI - Rhetoric and reality: two perspectives on community trust involvement in undergraduate medical education. AB - The GMC report Tomorrow's Doctors recommended that medical teaching should reflect the shift in health care provision towards primary care. A project was initiated at King's College School of Medicine and Dentistry (merged in August 1998 with United Medical and Dental Schools of Guy's and St Thomas') in 1995 to extend existing general practicebased teaching into other primary care settings, particularly community trusts.To inform this project, two postal surveys were undertaken to assess the extent and content of current teaching by community trust staff, and attitudes towards such teaching. Questionnaires were analysed from 19 medical schools and 167 community trusts. Eighteen (94.7%) medical schools and 120 (71.9%) community trusts reported involvement in teaching by community trust staff.There were substantial differences between the information given by the two groups of respondents. Such discrepancies suggested that teaching was uncoordinated, although respondents were committed to developing the role of community trusts in teaching. Medical schools highlighted valuable learning experiences for students available in primary care, and community trusts emphasized the positive impact of teaching on their staff and status. PMID- 21275733 TI - Educational implications of multiskilled healthcarers. AB - Two years ago the multiskilling debate was extended by introducing a framework for challenging and changing NHS workforce policy and planning along multiskilling lines. In this article, the main educational issues surrounding multiskilling are examined in the light of broader evidence. PMID- 21275734 TI - The establishment of student needs: an important internal factor affecting course outcome. AB - Ensuring effectiveness in teaching and learning requires that those features of a programme threatening maximal student achievement be identified. Learner involvement in establishing these features is important in ensuring programme success and student motivation.This study aimed to identify these features through assessment of self-perceived needs and concerns, and to establish strategies for their resolution. A survey instrument, developed from a pilot study, was administered to secondand third-year medical students. Students were asked to identify and rank the 10 needs or concerns that caused most distress for them and suggest solutions.Both groups identified content overload as their most serious concern followed by learning problems and time management. Other problems for junior students were failure to cope with work and fear of failure. Senior students identified financial matters, time constraints on recreation and sport and the general medical school atmosphere as problems.The commonest solutions offered were: introduction of a study skills course; curriculum rearrangement; provision of transport; and improvement in lecturing skills. Many of the data are transferable and useful for the general understanding of student needs and concerns in teaching institutions. PMID- 21275735 TI - Hospital doctors and health promotion: support for teaching behaviour change. AB - This article describes the development in the West Midlands Region of an educational pack for junior hospital doctors on the principles and practice of health promotion. It has been designed to encourage young doctors to apply research-based strategies for behaviour change within their own work and to provide informed support to the work of other professionals who have more time to spend with patients. The process of development was informed by a research study of cardiologists' understanding of health promotion and by pilot work with a variety of hospital specialties. The educational pack focuses on those aspects of health promotion work of most relevance to junior doctors.It uses the'Cycle of Change'model developed by Prochaska & DiClemente, to help patients (and doctors) change their behaviour. It can be used either independently, or as material to support interactive teaching and learning sessions. It is thus designed to integrate with the new learner-centred, interactive learning movement in medical education. PMID- 21275736 TI - The development of an undergraduate course in child psychiatry. AB - This paper begins with a brief review of child psychiatry teaching to undergraduate medical students.Teaching methods are also considered.The development of the current child psychiatry course at the University of Leicester is then described. This falls naturally into three stages from the beginning of the project to improve on the previous course. For clarity, the results are presented separately for each stage. The changes from one stage to the next and the rationale for these changes are presented in the overall discussion. The final section considers the present position and how we can further develop the clinical child psychiatry teaching programme. PMID- 21275737 TI - Development and implementation of a cardiovascular system course at the International Medical College: a new innovation in medical education. AB - The International Medical College (IMC) was established in Kuala Lumpur in 1993 in partnership with several established medical schools, to provide a preclinical curriculum for students before they complete their clinical training in the partner schools.The curriculum is system based and multidisciplinary with an emphasis on problem-based learning. This paper describes the planning and implementation of the cardiovascular system course at the IMC.The development of the course matrix was defined in terms of the weekly themes and course content with the Study Guide providing an interface between the curriculum planners and the students.The timetable of learning experiences included the plenary sessions, practicals, small-group learning, clinical skills and hospital experiences. The strengths and weaknesses of the first iteration of this course at the IMC are discussed and reviewed in relation to the performance of students on their final examinations and their evaluation of the presentation of the course. PMID- 21275738 TI - Towards reform: the medical curriculum of the medical school of the Westfalische Wilhelms-Universitat, Munster, FRG. AB - The medical curriculum in Germany is based on the licensing regulations 'Approbationsordung fur Arzte' (Approbationsordnung, 1970) resulting in a uniform curriculum in all of the country's 36 medical schools. However, the Medizinische Fakultat of the Westfalische Wilhelms-Universitat, Munster, Germany has implemented a modified medical curriculum. It aims to increase practical clinical training. The structure of the curriculum and results of this approach at Munster medical school are presented. PMID- 21275739 TI - Evolution of the second medical school in Nepal: a case study. AB - Nepal is located between China and India in the Asian subcontinent, with one of the lowest doctor:population ratios in the world, 1:30,000. A systematic approach was undertaken in the development of academic programmes at B. P. Koirala Institute of Health Sciences, Dharan.This paper presents the expectations and perceptions of health care professionals, medical graduates, teachers and employers regarding criteria for student selection, entrance examination pattern, curriculum, qualification of teachers and nature of graduates. It also elaborates on perceptions of non-medical people about the types of doctors and the desired attitude of doctors to their patients. This paper also discusses briefly the curriculum implementation carried out by the Institute in the 5 years of its existence, the important feature of the curriculum being incorporation of early patient contact and exposure in the community.These are achieved with problem based learning through the student-centred integrated curriculum. PMID- 21275741 TI - Abstracts of presentations at the AMEE Prague Conference, 30 August-2 September 1998, part 2. PMID- 21275740 TI - Can we teach a gentler rectal examination? AB - A total of 201 first-year medical students were trained in a standard method of rectal examination; half of the year were additionally instructed to mimic a rectal examination using a clenched left fist (Group 2, n = 103). Competence in rectal examination was assessed during an objective structured clinical skills examination.Technique was assessed using a standardized marking scheme alongside global examiner assessments of gentleness and adequacy (on scales of 1, very poor to 5, very good). Students demonstrated a high standard for the technique (mean 85.1%), with no difference between groups for this score or for adequacy, though group 2 scored significantly better for gentleness. The addition of a simple, practical teaching technique of using the fist to mimic the anus and rectum resulted in an appropriately gentle examination.This approach should help students to develop the confidence to perform the examination when required and whilst ensuring patient comfort. PMID- 21275743 TI - What's new in medical education: items of interest to medical educators. PMID- 21275742 TI - Do you know? PMID- 21275745 TI - News for AMEE members. PMID- 21275746 TI - Jottings. PMID- 21275757 TI - Reduced 13C-D-xylose absorption in alcoholics is more likely caused by alterations in small intestinal mucosa than delayed gastric emptying. AB - OBJECTIVE: Alterations of the small intestinal absorptive surface are a probable cause of D-xylose malabsorption in chronic alcoholism. Delayed gastric emptying, however, may influence the (13)C-D-xylose breath test, which is used to study intestinal function in alcoholics. The aim of this study was to measure gastric emptying in alcoholics to elucidate whether retention of the test meal could explain the malabsorptive pattern of the (13)C-D-xylose breath test observed in alcoholics. MATERIAL AND METHODS: Fifteen alcoholics performed the (13)C-octanoic acid and the (13)C-D-xylose breath tests on consecutive days in a random order. The (13)CO(2) expired was measured every 30 or 15 min for 4 h in the (13)C-D xylose and the (13)C-octanoic acid breath tests, respectively, using a mass spectrometer equipped with a gas chromatograph. Test meals consisted of 100 mg of (13)C-D-xylose and 5 g of unmarked D-xylose dissolved in 250 ml water and 91 mg (13)C-octanoic acid embedded in a one-egg omelette served with white bread with margarine, respectively. RESULTS: The alcoholic patients had a lower (13)C-D xylose breath index compared with healthy controls (p < 0.0001). None of the (13)C-octanoic acid breath test variables, T(50%), T(max), T(lag), or GEC revealed any significant differences between the groups. CONCLUSION: The pathological (13)C-D-xylose breath test in this group of alcoholics is unlikely to be caused by delayed gastric emptying. Malabsorption is the probable cause of the pathological (13)C-D-xylose breath test results in alcoholics. PMID- 21275758 TI - Gene therapy for canine leukocyte adhesion deficiency with lentiviral vectors using the murine stem cell virus and human phosphoglycerate kinase promoters. AB - Children with leukocyte adhesion deficiency type 1 (LAD-1) and dogs with canine LAD (CLAD) develop life-threatening bacterial infections due to mutations in the leukocyte integrin CD18. Here, we compared the human phosphoglycerate kinase (hPGK) promoter to the murine stem cell virus (MSCV) promoter/enhancer in a self inactivating HIV-1-derived lentiviral vector to treat animals with CLAD. Four CLAD dogs were infused with CD34(+) cells transduced with the hPGK vector, and two CLAD dogs received MSCV vector-transduced CD34(+) cells. Infusions were preceded by a nonmyeloablative dose of 200 cGy total body irradiation. Comparable numbers of transduced cells were infused in each group of animals. Only one of four CLAD animals treated with the hPGK-cCD18 vector had reversal of CLAD, whereas both MSCV-cCD18 vector-treated dogs had reversal of the phenotype. Correction of CLAD depends both upon the percentage of CD18(+) myeloid cells and the level of expression of CD18 on individual myeloid cells. In this regard, the hPGK promoter directed low levels of expression of CD18 on neutrophils compared to the MSCV promoter, likely contributing to the suboptimal clinical outcome with the hPGK vector. PMID- 21275762 TI - Survey of radioiodine therapy safety practices highlights the need for user friendly recommendations. PMID- 21275763 TI - Thyroid hormone analogues: ready for prime time. PMID- 21275764 TI - Development of a microRNA-based molecular assay for the detection of papillary thyroid carcinoma in aspiration biopsy samples. AB - BACKGROUND: Although thyroid nodules are common and diagnosed in over 5% of the adult population, only 5% harbor malignancy. Patients with clinically suspicious thyroid nodules need to undergo fine-needle aspiration biopsy (FNAB). The main limitation of FNAB remains indeterminate cytopathology. Only 20%-30% of the indeterminate nodules harbor malignancy, and therefore up to 80% of patients undergo unnecessary thyroidectomy. The aim of this study was to identify and validate a panel of microRNAs (miRNAs) that could serve as a platform for an FNAB based diagnostic for thyroid neoplasms. METHODS: The study population included 27 consecutive patients undergoing total thyroidectomy for FNAB-based papillary thyroid cancer (n = 20) and benign disorders (n = 7). Aspiration biopsy was performed from the index lesion and from the opposite lobe normal tissue in all study patients at the time of operation. RNA was extracted from all aspiration biopsy samples. Quantitative polymerase chain reaction on a panel of previously selected miRNAs was performed. Polymerase chain reaction results were compared with final histopathology. miRNA from tumor tissues was amplified using the highest value of each miRNA expression in normal tissue as a threshold for malignancy detection. RESULTS: Diagnostic characteristics were most favorable for mir-221 in differentiating benign from malignant thyroid pathology. mir-221 was overexpressed in 19 patients (p < 0.0001) with a sensitive yield of 95%. Specificity, negative and positive predictive value, and accuracy of the miRNA panel were 100%, 96%, 100%, and 98%, respectively. CONCLUSIONS: miRNA quantification for differential diagnosis of thyroid neoplasms within aspiration biopsy samples is feasible and may improve the accuracy of FNAB cytology. PMID- 21275765 TI - Current safety practices relating to I-131 administration for diseases of the thyroid: a survey of physicians and allied practitioners. AB - BACKGROUND: There is little information about the individual safety instructions provided by healthcare professionals to patients receiving radioactive iodine (I 131) therapy for the treatment of benign and malignant thyroid disorders or about whether these instructions are consistent across medical specialties. Currently, no national guidelines exist to standardize safety instructions related to I-131 administration. Here, we examine the spectrum of I-131 safety practices in contemporary use. METHODS: Members of major societies of physicians and allied specialists who treat patients with thyroid disorders were invited to complete a 27-question online survey about safety practices related to I-131 administration. Data from questionnaires were analyzed by type of safety recommendation and grouped according to provider specialty and geographic location. RESULTS: A total of 311 endocrinologists, surgeons, nuclear medicine radiologists, and allied health professionals completed questionnaires. They indicated that patients often receive instruction from more than one treating specialist. The decision to hospitalize a patient for treatment and the length of stay were determined by the patient's social situation and the dose of I-131 administered. Starting at I-131 doses between 259 and 1073 MBq (7 and 29 mCi), over 60% of respondents advised avoiding contact with children, sexual activity, and breastfeeding, with the latter recommendation continuing beyond 48 hours after treatment. Personal hygiene, laundry, and meal preparation precautions varied across respondents. Over 90% of respondents used serum or urine testing to screen for pregnancy status. Precautions to delay parenthood were given more often to female than male patients (90% vs. 60%), with a minimum recommended delay of 6 months. About 20% of respondents considered insurance coverage as a factor in selecting outpatient versus inpatient I-131 therapy, and this consideration varied geographically. CONCLUSION: A wide variety of safety recommendations are given to patients who receive I-131. To our knowledge, this survey represents the first organized inquiry into safety practices related to I-131 administration. The diversity of responses suggests an opportunity for multispecialty collaboration in defining more uniform recommendations for patient safety instructions during and after I 131 treatment. PMID- 21275766 TI - Calcitonin-negative neuroendocrine tumor of the thyroid: a distinct clinical entity. AB - BACKGROUND: Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor (NET) that arises from the parafollicular cells (C-cells) of the thyroid gland which produces calcitonin (CT) and is, therefore, a serum and immunohistochemical biomarker of MTC. Here, we describe a patient with another form of NET arising with the thyroid gland. PATIENT FINDINGS: This is a forty-year-old woman who underwent total thyroidectomy for a thyroid nodule that had features of an NET on fine needle aspiration. Her serum CT and carcinoembryonic antigen were normal. Surgical pathology showed a well-differentiated NET with immunohistochemical stains positive for markers of follicular cells (thyroglobulin and synaptophysin), positive for neuroendocrine markers (neuron specific enolase and chromogranin A), but negative for CT, the defining marker of MTC. CONCLUSIONS: We describe a rare case of a nonmedullary NET of the thyroid gland arising from thyroid follicular cells, not parafollicular cells. We suggest that calcitonin negative neuroendocrine tumor of the thyroid gland (CNNETT) may be an entity that has not been recognized in the literature. This distinction between MTC and CNNETT may be important, as the treatment and prognosis may differ. PMID- 21275767 TI - Sorafenib induced thyroiditis in two patients with hepatocellular carcinoma. AB - BACKGROUND: Sorafenib is a multi-targeted tyrosine kinase inhibitor licensed for the treatment of hepatocellular carcinoma and renal cell carcinoma. Thyroid function test abnormalities have been reported for different tyrosine kinase inhibitors, but only limited data on thyroid function test abnormalities related to sorafenib are available, demonstrating the occurrence of hypothyroidism in patients treated with sorafenib. SUMMARY: We describe two patients who developed temporary hyperthyroidism during the course of sorafenib treatment, which was followed by overt and subclinical hypothyroidism, respectively. Thyroid ultrasonography showed an atrophic thyroid gland in patient 1 , and signs of thyroiditis in patient 2 . Detailed reassessment of thyroid volumes on routinely performed computerized tomography scans showed a gradual decrease in thyroid volume during sorafenib treatment in one patient, suggesting progressive thyroid destruction. CONCLUSION: This case report describes in detail and for the first time two cases of sorafenib-induced thyroiditis. We assume that this sorafenib induced destructive thyroiditis is an important cause of sorafenib-induced hypothyroidism. PMID- 21275768 TI - Resolution of Cushing's syndrome and exacerbation of autoimmune thyroiditis. PMID- 21275771 TI - Immunological status of the progeny of breeder hens kept on ochratoxin A (OTA) contaminated feed. AB - This study aimed to evaluate the immunological status of the progeny of breeder hens kept on ochratoxin A (OTA)-contaminated feed. For this purpose, 84 White Leghorn (WL) layer breeder hens (40-weeks-of-age) were divided into seven groups (A-G). Hens in the Group A were fed a commercial layer ration while those in Groups B-G were kept on a diet amended with 0.1, 0.5, 1.0, 3.0, 5.0, or 10.0 mg OTA/kg, respectively, for 3 weeks. Fertile eggs were set for hatching on the weekly basis to get the progeny of each week separately. Hatched chicks (n = 10 from each group) were euthanized at Day 14 of age, and their immunological organs weighed and fixed in neutral buffered formalin. An indirect immunoperoxidase method was applied to study the frequency of immunoglobulin(s)-bearing cells in the spleen and bursa of Fabricius from these progeny. From other chicks within each set, at Day 16 of age, lymphoblastogenic responses against an intradermal administration of phytohemagglutinin (PHA-P) were determined. Relative weights of the bursa of Fabricius and of the thymus were significantly lower in the progeny of hens fed OTA-contaminated diet for 14 and 21 days. The frequencies of IgA-, IgG-, and IgM-bearing cells were also significantly (P <= 0.05) lower in the bursa of Fabricius and spleen of the progeny chicks obtained from dams fed the OTA-mixed diet. Progeny chicks obtained from the breeder hens fed higher doses of OTA showed significantly lower responses to PHA-P than did counterpart chicks from control hens. The findings of this study suggested that there were immunosuppressive effects from OTA in the progeny obtained from breeder hens kept on OTA-contaminated diets. PMID- 21275776 TI - Emodin-induced microglial apoptosis is associated with TRB3 induction. AB - Emodin (1,3,8-trihydroxy-6-methylanthraquinone), a natural anthraquinone compound isolated from the rhizome of rhubarb, has been reported to treat brain injury after intracerebral hemorrhage. Treatment of neurons with emodin is able to decrease glutamate excitotoxicity, modulate calcium homeostasis, and induce Bcl-2 expression. However, the effects of emodin on the brain-resident innate immune cells are unclear. In the present study, the mouse microglial cell line, BV-2, was selected to investigate the effects of emodin on microglial activation and apoptosis. Cell viability and apoptosis were sequentially measured with the CellTiter-Glo Luminescent Cell Viability Assay, YOPRO-1 and Caspase-Glo 3/7 Assay Systems. The degree of microglial activation was evaluated using quantitative RT PCR to measure expression of inflammatory markers. Treatment of BV-2 cells with emodin caused caspase-mediated apoptosis in a dose-dependent manner, and emodin augmented LPS-induced microglial apoptosis to repress inflammatory activation. In response to emodin treatment, reactive oxygen species (ROS) production was increased, and TRB3 was markedly activated. siRNA knockdown of TRB3 attenuated emodin-induced microglial apoptosis. Ectopic overexpression of TRB3 decreased cell viability and was associated with dysregulation of the prosurvival Akt/FOXO3 pathway. These results demonstrate that emodin induces BV-2 cell apoptosis through TRB3 and consequently eliminates inflammatory microglia. Our findings provide a novel molecular basis through which emodin exerts neuroprotective effects, treating brain injury after intracerebral hemorrhage. PMID- 21275777 TI - Quality by design approach in the optimization of the spray-drying process. AB - CONTEXT/OBJECTIVE: The aim of this study was to illustrate the influence of the processing parameters, inlet temperature, atomization air flow rate and feed flow rate, on critical quality attributes of spray-dried powders using design of experiments (DoE). METHODS: Spray-dried powders were characterized by laser diffraction, X-ray powder diffraction (XRPD) and near-infrared spectroscopy (NIR). Multivariate analysis of two different experimental designs was performed to elucidate the optimal process conditions. RESULTS AND DISCUSSION: XRPD revealed that the spray-dried powders consisted of crystalline beta-mannitol and amorphous trehalose. Non-invasive NIR measurement was successfully used for correlating the critical quality attribute particle size with size determined by laser diffraction. The full factorial design proved to be unsuitable due to the non-linear influence of factors. The composite face-centered design improved the quality of the models and showed both linear and non-linear influence of the parameters on the outcomes. A model explaining the influence of the factors on all quality attributes showed similar results as the models optimized for a single response. CONCLUSION: This study showed the applicability of DoE for the investigation of spray-dried powders. The knowledge of the interplay between process parameters and quality attributes will enable rational process design to achieve a desired outcome. PMID- 21275778 TI - Update on anesthesia and the immune response in newborns delivered by cesarian section. AB - In infants delivered by cesarian section, the immune system could be influenced by anesthetic drugs that may cross the placenta and reach the fetal circulation. Factors that determine placental transfer of anesthetics and their distribution into and ultimate removal from fetal tissue include physiochemical properties of the compound; the anatomic features of the maternal circulation, placenta, and fetus; and the hemodynamic and pharmacokinetic events that occur within them. Because the anesthetic agents can interfere with many neonatal function, the aim of this manuscript is to review the interference of regional or general anesthesia on neonatal immune response. PMID- 21275772 TI - Anticancer activity of metal complexes: involvement of redox processes. AB - Cells require tight regulation of the intracellular redox balance and consequently of reactive oxygen species for proper redox signaling and maintenance of metal (e.g., of iron and copper) homeostasis. In several diseases, including cancer, this balance is disturbed. Therefore, anticancer drugs targeting the redox systems, for example, glutathione and thioredoxin, have entered focus of interest. Anticancer metal complexes (platinum, gold, arsenic, ruthenium, rhodium, copper, vanadium, cobalt, manganese, gadolinium, and molybdenum) have been shown to strongly interact with or even disturb cellular redox homeostasis. In this context, especially the hypothesis of "activation by reduction" as well as the "hard and soft acids and bases" theory with respect to coordination of metal ions to cellular ligands represent important concepts to understand the molecular modes of action of anticancer metal drugs. The aim of this review is to highlight specific interactions of metal-based anticancer drugs with the cellular redox homeostasis and to explain this behavior by considering chemical properties of the respective anticancer metal complexes currently either in (pre)clinical development or in daily clinical routine in oncology. PMID- 21275787 TI - Electric field-guided neuron migration: a novel approach in neurogenesis. AB - Effective directional neuron migration is crucial in development of the central nervous system and for neurogenesis. Endogenous electrical signals are present in many developing systems and crucial cellular behaviors such as neuronal cell division, cell migration, and cell differentiation are all under the influence of such endogenous electrical cues. Preclinical in vivo studies have used electric fields (EFs) to attempt to enhance regrowth of damaged spinal cord axons with some success. Recent evidence shows that small EFs not only guide axonal growth, but also direct the earlier events of neuronal migration and neuronal cell division. This raises the possibility that applied or endogenous EFs, perhaps in combination, may direct transplanted neural stem cells, or regenerating neurons, to the desired site after brain injury or neuron degeneration. The high complexity of both structure and function of the nervous system, however, poses significant challenges to techniques for applying EFs to promote neurogenesis. The evolution of functional biomaterials and nanotechnology may provide promising solutions for the application of EFs in guiding neuron migration and neurogenesis within the central nervous system. PMID- 21275791 TI - Claudins: control of barrier function and regulation in response to oxidant stress. AB - Claudins are a family of nearly two dozen transmembrane proteins that are a key part of the tight junction barrier that regulates solute movement across polarized epithelia. Claudin family members interact with each other, as well as with other transmembrane tight junction proteins (such as occludin) and cytosolic scaffolding proteins (such as zonula occludens-1 (ZO-1)). Although the interplay between all of these different classes of proteins is critical for tight junction formation and function, claudin family proteins are directly responsible for forming the equivalent of paracellular ion selective channels (or pores) with specific permeability and thus are essential for barrier function. In this review, we summarize current progress in identifying structural elements of claudins that regulate their transport, assembly, and function. The effects of oxidant stress on claudins are also examined, with particular emphasis on lung epithelial barrier function and oxidant stress induced by chronic alcohol abuse. PMID- 21275795 TI - Anti-scratching behavioral effect of Lactobacillus plantarum PM008 isolated from kimchi in mice. AB - To isolate antipruritic lactic acid bacteria (LAB) from kimchi, a traditional Korean food, we investigated the interleukin (IL)-4 production-inhibitory effect in the colon of mice for previously isolated LAB. Orally administered Lactobacillus plantarum PM008 potently inhibited the expression of IgE-switching cytokine, IL-4, and of proinflammatory cytokines, IL-1beta and TNF-alpha, in the colon of mice. Its inhibitory effect was dependent on the dosage and administration period. When PM008 was orally administered to mice, the number of PM008 detected in the intestine and feces by polymerase chain reaction (PCR) and fluorescence in situ hybridization (FISH) methods was dependent on the administration dosage and period. The number of PM008 attached in the intestine was gradually decreased with increasing time after completion of its oral administration. PM008 dose-dependently inhibited the scratching behavior induced by histamine or compound 48/80. PM008 treated at a dose of 1 * 10(10) CFU for 14 days inhibited the histamine- and compound 48/80-induced scratching behaviors by 32.8% and 48.6%, respectively. This inhibitory effect continued, although reduced, at 7 days after stopping the oral administration of PM008 attached in the intestine. Based on these findings, L. plantarum PM008 may improve pruritus by inhibiting IL-4 expression. PMID- 21275797 TI - Neurogenesis in adult human brain after traumatic brain injury. AB - While much work has been conducted regarding the neurogenesis response to traumatic brain injury (TBI) in rodents, it remains largely unknown whether neurogenesis in adult human brain also responds to TBI in a similar manner. Here, we performed immunocytochemistry on 11 brain specimens from patients with traumatic brain injury, who underwent surgical intervention. We found that expression of neural stem/progenitor cell (NSC) protein markers, including DCX, TUC4, PSA-NCAM, SOX2 and NeuroD, was increased in the perilesional cortex of human brain after TBI compared to that of normal brain. Confocal images showed that these NSC proteins were expressed in one single cell. We also found that proliferative markers were expressed in NSC protein-positive cells after TBI, and the number of proliferative NSCs was significantly increased after TBI. Our data suggest that TBI may also induce neurogenesis in human brain. PMID- 21275807 TI - Quality indicators and specifications for key analytical-extranalytical processes in the clinical laboratory. Five years' experience using the Six Sigma concept. AB - BACKGROUND: The results of 5 years of experience (2004-2008) with process-based quality management using quality indicators for key laboratory processes (analytic and extra-analytic) in a group of clinical laboratories affiliated with the Catalan Health Institute are presented. Our purpose was to analyze the evolution of the indicators, identify processes that require corrective measures, and obtain specifications that are more robust than the preliminary ones proposed in a previous study by the same group. METHODS: The yearly average was recorded for each indicator in each laboratory, the yearly interlaboratory median was calculated, and the changes occurring were studied to determine their continuity in the 5-year period. For each indicator, the average of the yearly medians was calculated and the results transformed to the Six Sigma scale to estimate the degree of control over the related process. It was suggested to establish the yearly interlaboratory median as the desirable specification for each indicator. RESULTS: The medians for most indicators were stable during the period studied. Thus, the specifications proposed in the first study were considered robust in these cases. The Six Sigma statistic provided added value in this study because it enabled detection of processes that should be improved, in which case the specifications proposed were considered provisional despite their stability. After identifying processes that have the greatest impact on patient safety, the group set a specification of 0%, regardless of the actual specification obtained, although the members are conscious of the difficulty in attaining this level of quality. Certain processes that are in a period of change obtained specifications that are considered in a phase of consolidation. CONCLUSIONS: The results for indicators related with sample collection indicate that the process is stable and well controlled. However, based on the results for Hemolyzed serum sample, the group saw the need for installing centrifuges in all phlebotomy centers and established a recommendation to unify the system for measuring hemolysis. The indicator External control exceeds acceptance limit clearly highlighted the need to rigorously monitor the analytic phase of the clinical laboratory. The values obtained for the indicator Reports from referred tests exceed delivery time show that there is considerable deviation regarding the expected report delivery time, whereas for in-house laboratory reports, delivery time is satisfactory. PMID- 21275806 TI - Transplantation of marrow stromal cells restores cerebral blood flow and reduces cerebral atrophy in rats with traumatic brain injury: in vivo MRI study. AB - Cell therapy promotes brain remodeling and improves functional recovery after various central nervous system disorders, including traumatic brain injury (TBI). We tested the hypothesis that treatment of TBI with intravenous administration of human marrow stromal cells (hMSCs) provides therapeutic benefit in modifying hemodynamic and structural abnormalities, which are detectable by in vivo MRI. hMSCs were labeled with superparamagnetic iron oxide (SPIO) nanoparticles. Male Wistar rats (300-350 g, n=18) subjected to controlled cortical impact TBI were intravenously injected with 1 mL of saline (n=9) or hMSCs in suspension (n=9, approximately 3 * 10(6) SPIO-labeled hMSCs) 5 days post-TBI. In vivo MRI measurements consisting of cerebral blood flow (CBF), T2-weighted imaging, and 3D gradient echo imaging were performed for all animals 2 days post-TBI and weekly for 6 weeks. Functional outcome was evaluated with modified neurological severity score and Morris water maze test. Cell engraftment was detected in vivo by 3D MRI and confirmed by double staining. Ventricle and lesion volumetric alterations were measured using T2 maps, and hemodynamic abnormality was tracked by MRI CBF measurements. Our data demonstrate that treatment with hMSCs following TBI diminishes hemodynamic abnormalities by early restoration and preservation of CBF in the brain regions adjacent to and remote from the impact site, and reduces generalized cerebral atrophy, all of which may contribute to the observed improvement of functional outcome. PMID- 21275808 TI - Laboratory testing for the antiphospholipid syndrome: making sense of antiphospholipid antibody assays. AB - The antiphospholipid syndrome (APS) is an autoimmune condition characterised by a wide range of clinical features (primarily thrombosis and/or obstetric related), associated with the presence of antiphospholipid antibodies (aPL) as detected by a diverse range of laboratory tests. APS remains a significant diagnostic challenge for clinicians across a wide range of specialities, largely due to issues related to laboratory testing as well as the expanding range of reported clinical manifestations of APS. The laboratory issues include limitations in detailed knowledge by both clinical and laboratory personnel regarding the 'complete' range of available aPL tests, as well as ongoing problems with assay reproducibility and standardisation. aPL are identified using diverse laboratory procedures based on one of two distinct test processes, namely solid phase and liquid phase assays. The former includes anticardiolipin antibodies (aCL) and anti-beta(2)-glycoprotein I antibodies (abeta(2)GPI). The latter are centred on clot-based tests that are used to identify the so-called lupus anticoagulant (LA). This article will discuss: (i) issues related to laboratory testing for APS in terms of the currently available solid-phase and liquid-phase assays, and identifiable biases resulting from these tests usually being performed in different laboratories; (ii) current problems with calibration, standardisation and reproducibility of these assays; (iii) pre-analytical, analytical and post analytical considerations and ongoing initiatives for improvement; (iv) issues related to potential combinations/panels of available aPL tests; and (v) the entities of seropositive APS, seronegative APS and non-APS aPL-positivity. In doing so, this review will hopefully help bridge the two disciplines of haematology and immunology ('representing' liquid-phase and solid-phase aPL testing, respectively), by improving the understanding of those working in each of these disciplines of the merits and limitations of the assays performed in the other discipline, and encouraging inter-discipline cooperation in the reporting of aPL test results. PMID- 21275809 TI - Trefoil factor family peptides in human saliva and cyclical cervical mucus. Method evaluation and results on healthy individuals. AB - BACKGROUND: Trefoil peptides are 7-12 kDa molecules, se-creted by a variety of mucin-producing epithelial cells from different tissues and believed to be essential for protection and maintenance of gastrointestinal mucosa. Data on concentrations of trefoil peptides in secretions are limited. METHODS: We validated in-house ELISA assays, developed for measurement of trefoil peptide concentrations (TFF1, TFF2 and TFF3) in serum, for use with saliva and cervical mucus. Saliva from healthy individuals (n=30), and cervical mucus as well as blood collected three times during the menstrual cycle from healthy women (n=18) were analyzed. RESULTS: Recovery of all trefoil peptides in the initial supernatants of saliva and (cervical mucus) were 86 and (92)% or more. Recovery of exogenously added trefoil peptides was 93 and (95)% or more. Western blotting showed that antibodies used in the TFF3-ELISA assay recognised one molecule of the same size as TFF3 in both saliva and cervical mucus. Median concentrations of TFF1, TFF2 and TFF3 in saliva and (cervical mucus) were 2.7 (2.7), 0.08 (0.58) and 14 (430) nmol/g protein, with a significant decrease in concentrations in cervical mucus after ovulation. Serum concentrations resembled previously measured values in blood donors and showed no cyclic change. CONCLUSIONS: Previously established ELISA assays can be employed for measurement of trefoil peptides in saliva and cervical mucus. TFF3 was the predominant trefoil peptide in both saliva and cervical mucus, and TFF3 in cervical mucus represents the highest concentration measured in a biological fluid to date. PMID- 21275810 TI - More on preanalytical variables affecting platelet function testing using light transmittance aggregometry. PMID- 21275811 TI - Laboratory testing and/or monitoring of the new oral anticoagulants/antithrombotics: for and against? PMID- 21275812 TI - Evaluation of multiplex PCR using dual-priming oligonucleotide for the detection of vanA and vanB in vancomycin-resistant enterococci. PMID- 21275813 TI - The plodding diagnosis of monogenic autoinflammatory diseases in childhood: from the clinical scenery to laboratory investigation. AB - Autoinflammatory diseases (AID) are inherited errors of innate immunity which, although individually uncommon, collectively set up an emerging chapter of medicine. Careful analysis and identification of AID is essential to prompt effective treatment and improve survival and quality of life in these patients. Research into pediatric AID is lagging behind studies in adults, though a better understanding of AID in infancy could lead to improved diagnostic protocols and reduce long-term disability. This review provides a detailed summary of monogenic AID in childhood to help pediatricians correctly recognize these conditions and also highlight recent developments in the laboratory diagnostic work-up. PMID- 21275814 TI - B-type natriuretic peptide measurement in primary care; magnitude of associations with cardiovascular risk factors and their therapies. Observations from the STOP HF (St. Vincent's Screening TO Prevent Heart Failure) study. AB - BACKGROUND: An effective prevention strategy for heart failure in primary care requires a reliable screening tool for asymptomatic ventricular dysfunction. Preliminary data indicate that B-type natriuretic peptide (BNP) may be suitable for this task. However, for the most effective use of this peptide, the interrelationships between associated risk factors and their therapies on BNP, and in particular their magnitude of effect, needs to be established in a large primary care population. Therefore, the objective of the study was to establish the extent of the association between BNP, cardiovascular risk factors and their therapies. METHODS: BNP measurement and clinical review was preformed on 1122 primary care patients with cardiovascular risk factors. Multivariate analyses identified significant associates of BNP concentrations which were further explored to establish the magnitude of their association. RESULTS: Associates of BNP were age (1.36-fold increase in BNP/decade), female (1.28), beta-blockers (1.90), myocardial infarction (1.36), arrhythmia (1.98), diastolic blood pressure; all p<0.01. A novel method was devised that plotted median BNP per sliding decade of age for the various combinations of these principal associates. CONCLUSIONS: The data presented underline the importance of considering several clinical and therapeutic factors when interpreting BNP concentrations. Most of these variables were associated with increased concentrations, which may in part explain the observed false-positive rates for detecting ventricular dysfunction using this peptide. Furthermore, the design of studies or protocols using BNP as an endpoint or a clinical tool should take particular account of these associations. This analysis provides the foundation for age, risk factor and therapy adjusted reference ranges for BNP in this setting. PMID- 21275815 TI - Elevated concentrations of NE-homocysteinyl-lysine isopeptide in acute myocardial infarction: links with ADMA formation. AB - BACKGROUND: A homocysteine (Hcy) metabolite, thioester Hcy-thiolactone, whose reaction with protein lysine residues affords N-homocysteinylated proteins, has been implicated in cardiovascular disease. Proteolytic turnover of N homocysteinylated proteins generates the isopeptide NE-homocysteinyl-lysine (N Hcy-Lys). METHODS: We determined N-Hcy-Lys in serum and a NO syntase inhibitor asymmetric dimethylarginine (ADMA), as well as symmetric dimethylarginine (SDMA) and glutathione in plasma by high performance liquid chromatography in 52 consecutive patients with acute myocardial infarction (AMI) recruited within the first 12 h following onset of chest pain. Associations of N-Hcy-Lys with markers of thrombin generation, oxidative stress, enhanced inflammation, fibrinolysis, and autoantibodies against homocysteinylated proteins were also analyzed. RESULTS: N-Hcy-Lys concentrations, detectable in 45 (86.5%) patients (>0.1 MUmol/L), were 127.3% higher compared with healthy controls. N-Hcy-Lys correlated with ADMA (r=0.50; p<0.001), SDMA (r=0.43; p<0.01), glutathione (r=0.37; p<0.05), fibrinogen (r=0.39; p<0.01) and plasminogen activator inhibitor-1 (r=0.32; p<0.05), but not with plasma total Hcy, anti-N-Hcy-protein autoantibodies, vitamin B(12), folate, interleukin-6, plasma thrombin-antithrombin (TAT) complexes, prothrombin fragments F1+2 or 8-isoprostaglandin F(2alpha) a marker of oxidative stress. CONCLUSIONS: N-Hcy-Lys is increased in AMI patients and its formation is linked with the nitric oxide synthase inhibitor ADMA. PMID- 21275816 TI - Advanced glycation endproducts as gerontotoxins and biomarkers for carbonyl-based degenerative processes in Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common dementia disorder of later life. Although there might be various different triggering events in the early stages of the disease, they appear to converge on a few characteristic final pathways in the late stages, characterized by inflammation and neurodegeneration. Here, we review the hypothesis that advanced glycation end products (AGEs), which reflect carbonyl stress, an imbalance between the production of reactive carbonyl compounds and their detoxification, can serve as biomarkers for the progression of disorder. AGE modification may explain many of the neuropathological and biochemical features of AD, such as extensive protein cross-linking shown as amyloid plaques and neurofibrillary tangles, inflammation, oxidative stress and neuronal cell death. Although accumulation of AGEs is a normal feature of aging, it appears to be significantly accelerated in AD. We suggest that higher AGE concentrations in brain tissue and in cerebrospinal fluid might be able to distinguish between normal aging and AD. PMID- 21275817 TI - Evaluation of hematological parameters on admission for the prediction of 7-day in-hospital mortality in a large trauma cohort. AB - BACKGROUND: We evaluated the complete blood count (CBC) for the prediction of 7 day in-hospital mortality in a large adult trauma cohort. METHODS: We conducted an analysis of two prospectively collected databases on 1673 patients aged >=18 years admitted to a level I trauma center (2005-2007). Comparisons between survivors and non-survivors within 7 days after admission and between single and multiple trauma patients were made. Discriminative performance for 7-day in hospital mortality was assessed using the area under the receiver operating characteristic curve (ROC). Logistic regression was used to identify independent prognostic factors for 7-day in-hospital mortality. RESULTS: Comparison between survivors and non-survivors showed significant differences in white blood cell (WBC) count, absolute neutrophil count, segmented neutrophil count and most red blood cell (RBC) and platelet indices. Comparison between single and multiple trauma patients showed significant differences for WBC count and differential count and most RBC and platelet indices. Among the CBC parameters, RBC count (ROC=0.748), hemoglobin concentration (Hb) (ROC=0.734), hematocrit (Ht) (ROC=0.726), platelet count (PLT) (ROC=0.684) and plateletcrit (PCT) (ROC=0.696) showed the highest ROC. Using logistic regression we showed that RBC count, Hb, Ht, PLT and PCT were predictors of 7-day in-hospital mortality independently of patient's age, injury severity and initial physiological state. CONCLUSIONS: Significant differences in CBC parameters were found between survivors and non survivors and between patients with single and multiple trauma, but most of the CBC parameters demonstrated poor to moderate predictive ability for 7-day in hospital mortality in adult trauma patients. Routine laboratory workup of trauma patients should be performed as treatment guidance. However, prognostic value of initial hematological parameters remains limited. PMID- 21275820 TI - Repair of peripheral nerve defects in rabbits using keratin hydrogel scaffolds. AB - Entubulation of transected nerves using bioabsorbable conduits is a promising alternative to sural nerve autografting, but full functional recovery is rarely achieved. Numerous studies have suggested that scaffold-based conduit fillers may promote axon regeneration, but no neuroinductive biomaterial filler has been identified. We previously showed that a nerve guide filled with keratin hydrogel actively stimulates regeneration in a mouse model, and results in functional outcomes superior to empty conduits at early time points. The goal of the present study was to develop a peripheral nerve defect model in a rabbit and assess the effectiveness of a keratin hydrogel filler. Although repairs with keratin-filled conduits were not as consistently successful as autograft overall, the use of keratin resulted in a significant improvement in conduction delay compared to both empty conduits and autograft, as well as a significant improvement in amplitude recovery compared to empty conduits when measurable regeneration did occur. Taking into account all study animals (i.e., regenerated and nonregenerated), histological assessment showed that keratin-treated nerves had significantly greater myelin thickness than empty conduits. These data support the findings of our earlier study and suggest that keratin hydrogel fillers have the potential to be used clinically to improve conduit repair. PMID- 21275821 TI - Hypoxia-inducible factor-1alpha is essential for hypoxia-induced mesenchymal stem cell mobilization into the peripheral blood. AB - Mobilization of mesenchymal stem cells (MSCs) is a promising strategy for tissue repair and regenerative medicine. The establishment of an appropriate animal model and clarification of the underlying mechanisms are beneficial to develop the mobilization regimens for therapeutic use. In this study, we therefore established a rat MSC mobilization model and investigated the related mechanisms, using continuous hypoxia as the mobilizing stimulus. We found that MSCs could be mobilized into peripheral blood of rats exposed to short-term hypoxia (2 days) and the mobilization efficiency increased in a time-dependent manner (2-14 days). Hypoxia-inducible factor-1alpha (HIF-1alpha) was upregulated during hypoxic exposure and was expressed continuously in bone marrow. Inhibition of HIF-1alpha expression by YC-1 remarkably reduced the number of mobilized MSCs, suggesting that HIF-1alpha is essential for hypoxia-induced MSC mobilization. Further, we investigated the potential role of HIF-1alpha target genes, vascular endothelial growth factor (VEGF), and stromal cell-derived factor-1alpha (SDF-1alpha). VEGF expression was elevated from day 2 to day 7 of hypoxia, stimulating an increase in bone marrow sinusoidal vessels and possibly facilitating the egress of MSCs. SDF-1alpha protein levels were increased in the peripheral blood of rats during MSC mobilization and promoted the migration of MSCs under hypoxic conditions in vitro. These results suggest that HIF-1alpha plays a pivotal role in hypoxia induced MSC mobilization, possibly acting via its downstream genes VEGF and SDF 1alpha. These data provide a novel insight into the mechanisms responsible for MSC mobilization and may help in the development of clinically useful therapeutic agents. PMID- 21275825 TI - Association between acid suppressive therapy and spontaneous bacterial peritonitis in cirrhotic patients with ascites. AB - OBJECTIVE: Proton pump inhibitor (PPI) or histamine-2 receptor antagonist (H2RA) therapy may cause intestinal bacterial overgrowth and translocation. Therefore, acid suppressive therapy may increase the risk of spontaneous bacterial peritonitis (SBP) in cirrhotic patients with ascites. MATERIAL AND METHODS: A total of 176 cirrhotic patients with ascites who underwent diagnostic paracentesis between September 2004 and April 2009 were included in the analysis. Patients with gastrointestinal hemorrhage and/or antibiotic therapy within 2 weeks prior to hospital admission were excluded. SBP was defined as >=250/mm(3) polymorphonuclear white blood cells with or without a positive culture from the ascitic fluid. Eighty-three patients (mean age 56.1 years, 63 males) had SBP and 93 (mean age 54.7 years, 75 males) did not. RESULTS: On the multivariate analysis, a Child-Pugh class C (OR = 2.890, 95% CI 1.443-5.786; p = 0.003), high MELD scores (>= 20, OR = 3.540, 95% CI 1.155-10.849; p = 0.027), and PPI use (OR = 3.443, 95% CI 1.164-10.188; p = 0.025) were risk factors for SBP. H2RA was not associated with SBP. CONCLUSIONS: PPI use, as well as Child-Pugh class C and high MELD scores, was an independent risk factor for the development of SBP in cirrhotic patients with ascites. Further prospective studies are warranted to clarify this issue. PMID- 21275826 TI - In vitro optimization of liposomal nanocarriers prepared from breast tumor cell specific phage fusion protein. AB - Fusion proteins created by phage display peptides with tumor cell specificity and the pVIII major coat protein of filamentous phages have been explored recently as a simple and cost-effective means for preparing tumor-targeted liposomes that improve the cytotoxicity of anticancer drugs in vitro. The next step in the development of this approach is the optimization of the liposome composition for the maximum targeting activity and subsequent testing in vivo. This study aimed to investigate the impact of preparation protocols, lipid composition and phage protein content on the targeting efficiency of phage protein-modified liposomes. Analysis of size, zeta potential and morphology was used to investigate the effect of preparation protocols on the stability and homogeneity of the phage liposomes. A previously developed coculture targeting assay and a factorial design approach were used to determine the role of lipid composition of the liposomal membrane on the target cell specificity of the phage liposomes. Western blot combined with proteinase K treatment detected the orientation of targeted phage protein in liposomal membrane. Phage protein, DPPG and PEG(2k)-PE showed positive effects on target specificity of phage liposomes. The results served to identify optimal formulation that offer an improved liposomal affinity for target tumor cells over the non-optimized formulation. PMID- 21275828 TI - Targeting of lysosomes by liposomes modified with octadecyl-rhodamine B. AB - The use of lysosome-targeted liposomes may significantly improve a delivery of therapeutic enzymes into lysosomes for the treatment of lysosome-associated diseases. The aim of this research was to achieve a specific intracellular targeting of lysosomes, by using liposomes modified with the lysosomotropic octadecyl-rhodamine B (RhB) and loaded with a model compound, fluorescein isothiocyanate (FITC)-dextran (FD). Plain and RhB-modified liposomes were prepared by hydration of lipid films and loaded with FD or with 5 dodecanoylaminofluorescein di-beta-d-galactopyranoside (C(12)FDG), a specific substrate for the intralysosomal beta-galactosidase. The delivery of these liposomes and their content to lysosomes in HeLa cells was investigated by confocal microscopy, flow cytometry, and subcellular fractionation. Confocal microscopy demonstrated that RhB-liposomes co-localize well with the specific lysosomal markers, unlike plain liposomes. The comparison of the FITC fluorescence of the lysosomes isolated by subcellular fractionation also showed that the efficiency of FD delivery into lysosomes by RhB-modified liposomes was significantly higher compared with plain liposomes. These results were additionally confirmed by the flow cytometry of the intact cells treated with C(12)FDG-loaded liposomes that also demonstrated increased lysosomal targeting by RhB-modified liposomes. The modification of the liposomal surface with a lysosomotropic ligand, such as octadecyl-RhB, can significantly increase the delivery of liposomal loads to lysosomes. PMID- 21275829 TI - Hydrogen sulfide: redox metabolism and signaling. AB - The recognition of hydrogen sulfide (H(2)S) as an endogenously produced gas with signaling potential has stimulated research on a multitude of physiological effects mediated in the cardiovascular, immune, gastrointestinal, genitourinary, endocrine, and central nervous systems. The heightened activity in the area of H(2)S biology led to convening of the first international conference on H(2)S in Shanghai in the summer of 2009 and to two Forum issues published in 2010 by Antioxidants & Redox Signaling on the physiological effects of H(2)S. Yet, fundamental questions regarding the biogenesis and regulation of H(2)S, the bioenergetics of its catabolism, its tissue concentrations, and elucidation of its molecular targets remain. Some of these issues are the subject of the current Forum on H(2)S. PMID- 21275830 TI - Characterization and in vivo testing of mesenchymal stem cells derived from human embryonic stem cells. AB - Mesenchymal stem cells (MSCs) have been shown to contribute to the recovery of tissues through homing to injured areas, especially to hypoxic, apoptotic, or inflamed areas and releasing factors that hasten endogenous repair. In some cases genetic engineering of the MSC is desired, since they are excellent delivery vehicles. We have derived MSCs from the human embryonic stem cell (hESC) line H9 (H9-MSCs). They expressed CD105, CD90, CD73, and CD146, and lacked expression of CD45, CD34, CD14, CD31, and HLA-DR, the hESC pluripotency markers SSEA-4 and Tra 1-81, and the hESC early differentiation marker SSEA-1. Marrow-derived MSCs showed a similar phenotype. H9-MSCs did not form teratoma in our initial studies, whereas the parent H9 line did so robustly. H9-MSCs differentiated into bone, cartilage, and adipocytes in vitro, and displayed increased migration under hypoxic conditions. Finally, using a hindlimb ischemia model, H9-MSCs were shown to home to the hypoxic muscle, but not the contralateral limb, by 48 h after IV injection. In summary, we have defined methods for differentiation of hESCs into MSCs and have defined their characteristics and in vivo migratory properties. PMID- 21275832 TI - Development of osteogenic cell sheets for bone tissue engineering applications. AB - The use of scaffolds in combination with osteogenic cells has been the gold standard in bone tissue engineering strategies. These strategies have, however, in many cases failed to produce the desired results due to issues such as the immunogenicity of the biomaterials used and cell necrosis at the bulk of the scaffold related to deficient oxygen and nutrients diffusion. Here, we originally propose the use of cell sheet (CS) engineering as a possible way to overcome some of these obstacles. Osteogenic CSs were fabricated by culturing rat bone marrow stromal cells in thermoresponsive culture dishes. The CSs were recovered from the dishes using a low-temperature treatment and then were implanted subcutaneously in nude mice. New bone formation was verified from day 7 post-transplantation using X-ray, microcomputed tomography, and histological analysis. The presence of a vascularized marrow was also verified in the newly formed bone after 6 weeks of transplantation. Further, osteocytes were found in this newly formed tissue, supporting the conclusion that mature bone was formed after ectopically transplanting osteogenic CSs. These results therefore confirm the great potentiality of CS engineering to be used in bone tissue engineering applications. PMID- 21275843 TI - The effect of cell seeding density on the cellular and mechanical properties of a mechanostimulated tissue-engineered tendon. AB - The initial seeding density is a critical variable in functional tissue engineering. A sufficient number of cells uniformly distributed throughout the scaffold is a key requirement to achieve homogeneous extracellular matrix deposition in vitro. However, high initial seeding densities might have negative repercussions on nutrient availability, cellular metabolism, and cell viability. In the current study, our aim was to understand the implications of using high seeding densities (3, 5, and 10 million cells/mL) in a human umbilical vein (HUV) tendon model subjected to 1 h of cyclic stretching per day at 2% strain and a frequency of 0.0167 Hz in a mechanostimulating bioreactor, on nutrient availability, cell viability and metabolism, and construct properties. Mechanostimulated constructs seeded with 3 million cells/mL had significantly higher cell number than the static controls and resulted in a 20-fold increase in proliferation rates and a 3-fold increase in tensile strength values after 1 week of culture in the bioreactor. However, higher seeding densities resulted in cell death, degraded extracellular matrix, and poorer mechanical properties. Nutrient and growth factor mass transport limitations are implicated in the inability of the decellularized HUV to support high cell numbers. The effective diffusion coefficient for glucose was measured to be 0.21+/-0.04 cm(2)/day. In the absence of convective flow, proteins and growth factors with a molecular radius larger than 4.9 nm could not diffuse through the HUV. Cells seeded in the HUV consumed 10.5+/-0.5 ng/cell/day of glucose. Glucose diffusion coefficient and glucose consumption rates in the HUV indicated the presence of glucose mass transport limitations when cell seeding densities exceed 3 million cells/mL. PMID- 21275831 TI - Bone marrow-targeted liposomal carriers. AB - INTRODUCTION: Bone marrow-targeted drug delivery systems appear to offer a promising strategy for advancing diagnostic, protective and/or therapeutic medicine for the hematopoietic system. Liposome technology can provide a drug delivery system with high bone marrow targeting that is mediated by specific phagocytosis in bone marrow. AREA COVERED: This review focuses on a bone marrow specific liposome formulation labeled with technetium-99 m. Interspecies differences in bone marrow distribution of the bone marrow-targeted formulation are emphasized. This review provides a liposome technology to target bone marrow. In addition, the selection of proper species for the investigation of bone marrow targeting is suggested. EXPERT OPINION: It can be speculated that the bone marrow macrophages have a role in the delivery of lipids to the bone marrow as a source of energy and for membrane biosynthesis or in the delivery of fat-soluble vitamins for hematopoiesis. This homeostatic system offers a potent pathway to deliver drugs selectively into bone marrow tissues from blood. High selectivity of the present bone marrow-targeted liposome formulation for bone marrow suggests the presence of an active and specific mechanism, but specific factors affecting the uptake of the bone marrow mononuclear phagocyte system are still unknown. Further investigation of this mechanism will increase our understanding of factors required for effective transport of agents to the bone marrow, and may provide an efficient system for bone marrow delivery for therapeutic purposes. PMID- 21275844 TI - The disulfide proteome and other reactive cysteine proteomes: analysis and functional significance. AB - Ten years ago, proteomics techniques designed for large-scale investigations of redox-sensitive proteins started to emerge. The proteomes, defined as sets of proteins containing reactive cysteines that undergo oxidative post-translational modifications, have had a particular impact on research concerning the redox regulation of cellular processes. These proteomes, which are hereafter termed "disulfide proteomes," have been studied in nearly all kingdoms of life, including animals, plants, fungi, and bacteria. Disulfide proteomics has been applied to the identification of proteins modified by reactive oxygen and nitrogen species under stress conditions. Other studies involving disulfide proteomics have addressed the functions of thioredoxins and glutaredoxins. Hence, there is a steadily growing number of proteins containing reactive cysteines, which are probable targets for redox regulation. The disulfide proteomes have provided evidence that entire pathways, such as glycolysis, the tricarboxylic acid cycle, and the Calvin-Benson cycle, are controlled by mechanisms involving changes in the cysteine redox state of each enzyme implicated. Synthesis and degradation of proteins are processes highly represented in disulfide proteomes and additional biochemical data have established some mechanisms for their redox regulation. Thus, combined with biochemistry and genetics, disulfide proteomics has a significant potential to contribute to new discoveries on redox regulation and signaling. PMID- 21275845 TI - Positioning of a polymorphic quantitative trait nucleotide in the Ncf1 gene controlling oxidative burst response and arthritis severity in rats. AB - The Ncf1 gene, encoding the P47(PHOX) protein that regulates production of reactive oxygen species (ROS) by the phagocyte NADPH oxidase (NOX2) complex, is associated with autoimmunity and arthritis severity in rats. We have now identified that the single-nucleotide polymorphism (SNP) resulting in an M153T amino acid substitution mediates arthritis resistance and thus explains the molecular polymorphism underlying the earlier identified Ncf1 gene effect. We identified the SNP in position 153 to regulate ROS production using COS(PHOX) cells transfected with mutated Ncf1. To determine the role of this SNP for control of arthritis, we used the Wistar strain, identified to carry only the postulated arthritis resistant SNP in position 153. When this Ncf1 allele was backcrossed to the arthritis susceptible DA strain, both granulocyte ROS production and arthritis resistance were restored. Position 153 is located in the hinge region between the PX and SH3 domains of P47(PHOX). Mutational analysis of this position revealed a need for an -OH group in the side chain but we found no evidence for phosphorylation. The polymorphism did not affect assembly of the P47(PHOX)/P67(PHOX) complex in the cytosol or membrane localization, but is likely to operate downstream of assembly, affecting activity of the membrane NOX2 complex. PMID- 21275847 TI - Bioactive porous beads as an injectable urethral bulking agent: in vivo animal study for the treatment of urinary incontinence. AB - In our previous study, growth factor (basic fibroblast growth factor [bFGF] or vascular endothelial growth factor)-immobilized polycaprolactone (PCL)/Pluronic F127 porous beads were fabricated by an isolated particle-melting/melt-molding particulate-leaching method. The growth factors were easily immobilized onto the pore surfaces of the PCL/F127 beads via heparin binding, and were continuously released for up to 28 days. In this study, the growth factor-immobilized porous beads were investigated for their potential use as an injectable urethral bulking agent for the treatment of stress urinary incontinence (SUI). From the in vivo study using Sprague-Dawley rats as an urinary incontinent animal model, it was observed that the growth factor (bFGF or vascular endothelial growth factor) immobilized porous beads had effective cure behaviors for SUI as follows: the narrowed urethral lumen and the regeneration of smooth muscle around the urethra. In particular, the bFGF-immobilized PCL/F127 porous beads showed desirable smooth muscle regeneration and electrical contractility, which indicates it can be a good candidate as an injectable bioactive bulking agent for the treatment of SUI. PMID- 21275848 TI - Ezetimibe and low density lipoprotein subfractions: an ongoing debate. AB - There is evidence that small dense low density lipoprotein (sdLDL) subfractions are more atherogenic than buoyant LDL. Therefore, it is relevant to assess the effect of lipid lowering drugs on LDL subfractions. In this editorial we discuss the effect of ezetimibe (EZE; a cholesterol transport inhibitor) alone or in combination with a statin, on sdLDL levels. We conclude that, based on currently available evidence, more studies are needed before a definitive answer can be provided regarding the effect of EZE on sdLDL levels. PMID- 21275849 TI - The molecular pathogenesis and management of bronchial carcinoids. AB - INTRODUCTION: In terms of well-differentiated neuroendocrine tumors (NETs), the lung is the second most common site of occurrence, after the gastro-entero pancreatic axis, and comprises ~ 25% of all NETs which may occur in various parts of the body. Pulmonary NETs are classified into four groups including typical carcinoid tumors, atypical carcinoid tumors, small cell lung carcinoma and large cell neuroendocrine carcinomas. Among pulmonary NETs, typical and atypical carcinoid tumors of the lung are generally indolent, but do have a (albeit low) potential to metastasize. AREAS COVERED: The molecular biology and novel molecular pathways and drug targets in bronchial carcinoids are reviewed in this paper. A full data search is performed through PubMed over the years 2000 - 2010 with key words 'neuroendocrine tumors of the lung, bronchial carcinoid, lung carcinoid, foregut carcinoid, pulmonary carcinoid, pulmonary NETs, lung NETs, molecular biology, autoradiography, nuclear medicine, treatment'; all relevant publications are included, together with selected publications prior to that date. EXPERT OPINION: Although lying at the benign end of the spectrum of pulmonary NETs, bronchial carcinoids can metastasize, and the pathogenesis of these tumors is poorly understood. Several intracellular signaling pathways are under investigation to define new targets for the successful treatment of these tumors. In terms of treatment, further research should additionally focus on the already known but promising drug options. PMID- 21275850 TI - Efficacy of racemic albuterol versus levalbuterol used as a continuous nebulization for the treatment of acute asthma exacerbations: a randomized, double-blind, clinical trial. AB - OBJECTIVE: To compare racemic albuterol (RAC) with levalbuterol (LEV) in continuous form for the treatment of acute pediatric asthma exacerbations in the emergency department. STUDY DESIGN: Children between the ages of 6 and 17 inclusive were enrolled if they had a history of asthma, presented to the emergency department with an acute asthma exacerbation, and had an initial forced expiratory volume in 1 second (FEV1) <70% predicted. Patients were then randomized to receive either 7.5 mg of RAC or 3.75 mg of LEV over 1 hour, in addition to standard asthma therapies. Spirometry and asthma scoring were performed at the end of the first hour, and a second hour-long nebulization with the same drug was administered if deemed necessary. Spirometry and asthma scoring were again performed and the final disposition was recorded. As a second, optional part of the study, baseline serum albuterol levels were collected on some patients before treatment. RESULTS: A total of 99 patients completed the study (44 RAC and 55 LEV). Baseline characteristics were similar except that the RAC group had a higher baseline asthma score. Children in the RAC group had a greater improvement in their FEV1 (p = .043) as well as in their asthma scores (p = .01) after 1 hour of continuous treatment compared to the LEV group. The greater improvement in asthma scores was maintained after the second hour of continuous therapy in the RAC group (p = .008) but not for FEV1 measurements (p = .57). There were no differences between groups for changes in heart rate, respiratory rate, oxygen saturation, or rates of admission. CONCLUSIONS: At the doses used, RAC appears to be superior to LEV with respect to changes in FEV1 and asthma score. There was no significant difference between the drugs with respect to admission rates or side-effect profile. PMID- 21275851 TI - Obesity and poor asthma control in patients with severe asthma. AB - BACKGROUND: Asthma is a public health problem as it leads to hospitalization and eventual death, particularly in its severe forms. Many studies have demonstrated an association between obesity and asthma. OBJECTIVE: The aim of this study was to investigate the relationship between obesity and asthma control in a group of patients at a reference center for severe asthma in Brazil. METHODS: This cross sectional study was conducted in the outpatient central reference clinic of the Program for Control of Asthma in the State of Bahia. It included 508 subjects with severe asthma of both genders and above 18 years of age. All the participants answered a sociodemographic and a clinical questionnaire to collect information on their asthma and comorbidities, such as rhinitis and gastro esophageal reflux disease (GERD). Participants also completed the Asthma Control Questionnaire, performed a spirometry test, and had their weight, height, and waist and hip circumferences registered. RESULTS: Logistic regression analysis demonstrated a positive association between body mass index (BMI) and uncontrolled asthma [odds ratio (OR) 1.5; 95% confidence interval (CI) 1.02 2.20]. Symptoms of chronic rhinitis and GERD were also significantly associated with uncontrolled asthma (OR 3.68, 95% CI 1.50-9.01; and OR 2.78, 95% CI 1.91 4.03, respectively). There was no correlation between waist-to-hip ratios and asthma control. CONCLUSION: In our sample of patients with severe asthma, those who were obese were more likely to have uncontrolled asthma than patients with a normal BMI. Nevertheless, this is not conclusive evidence for a direct causal association between obesity and poor asthma control. Future studies are necessary to dissect the relationship between obesity and asthma outcomes. PMID- 21275855 TI - Editorial. PMID- 21275856 TI - President's Letter. PMID- 21275857 TI - The first 20 years of the RANZCP Examination: 1970-1990. PMID- 21275858 TI - The components of the fellowship examination: 1970-1990. PMID- 21275859 TI - Reflections on schizophrenia. PMID- 21275860 TI - Neil conaghy: an appreciation. PMID- 21275861 TI - Early psychosis prevention and intervention centre. PMID- 21275863 TI - Guidelines for informed consent. PMID- 21275862 TI - I have seen the future and it works. PMID- 21275864 TI - Medifraud and excessive servicing. PMID- 21275865 TI - Vale most common fee. PMID- 21275866 TI - The changing face of psychiatry and the role of the board of research. PMID- 21275867 TI - Senate inquiry into psychotheraputic medication. PMID- 21275869 TI - 1993 agm. PMID- 21275868 TI - A Medicare no-claim. PMID- 21275870 TI - Australia Day honour. PMID- 21275872 TI - More managerese. PMID- 21275871 TI - Vale. PMID- 21275873 TI - Correspondence. PMID- 21275874 TI - Prizes and awards. PMID- 21275875 TI - Conferences. PMID- 21275877 TI - Evaluation of auricular lymph node cell lymphocyte proliferation and cytokine production as non-radioactive endpoints during murine contact allergy. AB - The murine local lymph node assay (LLNA) has been developed as a test method to assess allergic contact dermatitis. In spite of the validity of the LLNA, attention was drawn to the two disadvantages: use of radioactivity for in vivo measurement of lymph node cell proliferation ([(3)H]-thymidine labeling) and the possibility of false positive results caused by non-specific cell activation as a result of inflammatory processes in the skin (irritation). We aimed to investigate the following non-radioactive endpoints of LLNA: 5-bromo-2' deoxyuridine (BrdU) incorporation ex vivo and in vivo, in vivo and ex vivo cytokine production with or without phytohemagglutinin (PHA) stimulation. Here, 8 12-week-old female BALB/c mice were treated topically with the strong sensitizer 2,4-dinitrochlorobenzene (DNCB) in acetone:olive oil (AOO, 4:1 [v/v]) at levels of 0.025, 0.05, 0.01, or 0.25% (w/v). Ear thickness was also measured to determine the differentiation index (DI) indicating the proportion of non specific activation due to irritating properties of test compound. At the concentration of 0.05%, stimulation index (SI) value was found to be 3 for DNCB based on in vivo and ex vivo BrdU incorporation. The results of the in vivo and ex vivo non-radioactive LLNA assays were compatible both with each other and with previous radioactive LLNA data. Our results indicate that non-radioactive endpoints may be used as an alternative to the [(3)H]-thymidine LLNA. The levels of T(H)1 cytokines (IL-2 and IFNgamma) and T(H)2 cytokines (IL-4 and IL-5) in lymph node cell cultures were significantly (P < 0.01) increased when DNCB was applied at the concentrations of 0.05 and 0.1%, respectively. As the DI was > 1, the applied concentrations of DNCB caused only allergic effect but not any irritant effect. This study reports that the use of these non-radioactive endpoints can assess allergic contact dermatitis caused by chemicals. PMID- 21275878 TI - Function of the phosphatidylinositol transfer protein gene family: is phosphatidylinositol transfer the mechanism of action? AB - Phosphatidylinositol transfer proteins (PITPs) bind and facilitate the transport of phosphatidylinositol (PI) and phosphatidylcholine between membrane compartments. They are highly conserved proteins, are found in both unicellular and multicellular organisms, and can be present as a single domain or as part of a larger, multi-domain protein. The hallmark of PITP proteins is their ability to sequester PI in their hydrophobic pocket. Ablation or knockdown of specific isoforms in vivo has wide ranging effects such as defects in signal transduction via phospholipase C and phosphoinositide 3-kinase, membrane trafficking, stem cell viability, Drosophila phototransduction, neurite outgrowth, and cytokinesis. In this review, we identify the common mechanism underlying each of these phenotypes as the cooperation between PITP proteins and lipid kinases through the provision of PI for phosphorylation. We propose that recruitment and concentration of PITP proteins at specific membrane sites are required for PITP proteins to execute their function rather than lipid transfer. PMID- 21275879 TI - Systematic chromosomal analysis of cultured mouse neural stem cell lines. AB - The potential use of neural stem cells (NSCs) in basic research, drug testing, and for the development of therapeutic strategies is dependent on their large scale in vitro amplification which, however, introduces considerable risks of genetic instability and transformation. NSCs have been derived from different sources, but the occurrence of chromosomal instability has been monitored only to a limited extent in relationship to the source of derivation, growth procedure, long-term culture, and genetic manipulation. Here we have systematically investigated the effect of these parameters on the chromosomal stability of pure populations of mouse NSCs obtained after neuralization from embryonic stem cells (ESCs) or directly from fetal or adult mouse brain. We found that the procedure of NSCs establishment is not accompanied by genetic instability and chromosomal aberration. On the contrary, we observed that a composite karyotype appears in NSCs above extensive passaging. This phenomenon is more evident in ESC- and adult sub-ventricular zone-derived NSCs and further deteriorates after genetic engineering of the cells. Fetal-derived NSCs showed the greatest euploidy state with negligible clonal structural aberrations, but persistent clonal numerical abnormalities. It was previously published that long-term passaged ESC- and adult sub-ventricular zone-derived NSCs did not show any defects in the cells' proliferative and differentiative capacity nor induced in vivo tumour formation, although we here report on the chromosomal abnormalities of these cells. Although chromosomal aberrations are known to occur less frequently in human cells, studies performed on murine stem cells provide an important complement to understand the biological events occurring in human lines. PMID- 21275880 TI - Natural disaster and crisis: lessons learned about cleft and craniofacial care from Hurricane Katrina and the West Bank. AB - Cleft care is generally characterized by staged, carefully timed surgeries and long-term, team-centered follow-up. Acute and chronic crises can wreak havoc on the comprehensive team care required by children with craniofacial anomalies. In addition, there is evidence that crises, including natural disasters and chronic disruptions, such as political turmoil and poverty, can lead to an increased incidence of craniofacial anomalies. The purpose of this article is to delineate the impact of acute and chronic crises on cleft care. Hurricane Katrina in New Orleans, Louisiana, in 2005, resulted in an acute crisis that temporarily disrupted the infrastructure necessary to deliver cleft care; chronic turmoil in the West Bank/Palestine has resulted in an absence of infrastructure to deliver cleft care. Through these central examples, this article will illustrate-through the prism of cleft care-the need for (1) disaster preparedness for acute crises, (2) changing needs following acute crises that may lead to persistent chronic disruption, and (3) baseline and long-term monitoring of population changes after a disaster has disrupted a health care delivery system. PMID- 21275885 TI - Mild mitochondrial uncoupling as a therapeutic strategy. AB - Mild mitochondrial uncoupling, or the reduction of the efficiency of energy conversion without compromising intracellular high energy phosphate levels, is a protective therapeutic strategy under many laboratory conditions. Here we discuss these conditions, which include both cell and animal models of ischemia reperfusion and complications associated with the metabolic syndrome. We also discuss drugs that promote mild mitochondrial uncoupling and naturally occurring mild mitochondrial uncoupling pathways involving free fatty acid cycling and K(+) transport. PMID- 21275886 TI - Investigating mitochondrial dysfunction to increase drug safety in the pharmaceutical industry. AB - Drug-induced mitochondrial dysfunction is a contributor to both late-stage compound attrition and post-market drug withdrawals. This review outlines the mechanisms which lead to drug-induced mitochondrial dysfunction and discusses the tremendous advances that have been made in the development of in vitro methods to identify mitochondrial impairment. Potentially useful animal models and in vivo methods to detect drug-induced mitochondrial impairment are also discussed. PMID- 21275887 TI - Techniques to investigate neuronal mitochondrial function and its pharmacological modulation. AB - Mitochondria are central regulators of neuronal homeostasis and survival, and increasingly viewed as a drug target in several acute and chronic neurological disorders, e.g. stroke, Alzheimer's, Parkinson's, and Huntington's diseases. Frequent working hypotheses aim to establish whether and how chemical or genetic lesions affect mitochondrial function in neurons, and whether this can be rescued by pharmacological treatments. However, the generic designation 'mitochondrial function' actually encompasses a wide spectrum of individual activities, too numerous to be fully quantified by any single available technique. This review aims to provide a broad perspective on the roles played by neuronal mitochondria, and addresses multiple techniques that can be used to derive instructive functional indicators. These include measurements of mitochondrial respiration, ATP production, membrane potential, calcium handling, biogenesis, dynamic movement as well as fusion and fission. Technique descriptions are preceded by a summary of mitochondrial physiology and pharmacological tools required for functional modulation and parameter determination. Hopefully, these will assist researchers interested in testing mitochondria as a drug target in neurological disease models. PMID- 21275888 TI - Mitochondria as a drug target in health and disease. PMID- 21275889 TI - Exploring quantitative nanostructure-activity relationships (QNAR) modeling as a tool for predicting biological effects of manufactured nanoparticles. AB - Evaluation of desired and undesired, biological effects of Manufactured NanoParticles (MNPs) is of critical importance for the future of nanotechnology. Experimental studies, especially toxicological, are time-consuming and costly, calling for the development of efficient computational tools capable of predicting biological events caused by MNPs from their structure and physical chemical properties. This mini-review assesses the potential of modern cheminformatics methods such as Quantitative Structure - Activity Relationship modeling to develop statistically significant and externally predictive models that can accurately forecast biological effects of MNPs from the knowledge of their physical, chemical, and geometrical properties. We discuss major approaches for model building and validation using both experimental and computed properties of nanomaterials. We consider two different categories of MNP datasets: (i) those comprising MNPs with diverse metal cores and organic decorations, for which experimentally measured properties can be used as particle's descriptors, and (ii) those involving MNPs possessing the same core (e.g., carbon nanotubes), but different surface-modifying organic molecules, for which computational descriptors can be calculated for a single representative of the decorative molecule. We illustrate those concepts with three case studies for which we successfully built and validated predictive models. In summary, this mini-review demonstrates that, analogous to conventional applications of QSAR modeling for the analysis of datasets of bioactive organic molecules, its application to modeling MNPs that we term Quantitative Nanostructure Activity Relationship (QNAR) modeling can be useful for (i) predicting activity profiles of novel MNPs solely from their representative descriptors and (ii) designing and manufacturing safer nanomaterials with desired properties. PMID- 21275890 TI - High-throughput tools for the study of protein-nanostructured surface interaction. AB - The aim of this review is to describe and to analyze the ingredients that are necessary in order to develop a robust and effective experimental approach for the high-throughput characterization of protein-nanostructured surface interaction. In the first part of this paper we review the nanostructured surface synthesis methods that are potentially able to create nanostructured inorganic surface libraries. In the second part, we address another fundamental aspect consisting in the availability of high-throughput proteins detection methods. We describe in details new emerging analytical tools compatible with nanostructured surfaces, analyzing different possible strategies, depending on the objective of the experiment and on the library format. PMID- 21275891 TI - Engineered nucleases for targeted genome modification. PMID- 21275892 TI - Adverse effects, adverse events and side-effects: does the terminology matter? PMID- 21275893 TI - Hydrogen sulphide in heart and systemic circulation. AB - In the mammalian cardiovascular system, H(2)S joins carbon monoxide (CO) and endothelial derived relaxing factors, (EDRFs)-nitric oxide (NO), as the third gasotransmitter. In the vasculature, cystathionine-gamma-lyase (CSE) is the main enzyme responsible for H(2)S biosynthesis starting from the substrate e.g. L cysteine. There is a growing body of evidence that supports a role for H(2)S in regulating the vascular homeostasis. H(2)S (NaHS) is known to induce a concentration-dependent relaxation of large conduit arteries. Interestingly, H(2)S also relaxes peripheral resistance vessels such as mesenteric arteries suggesting a role for H(2)S also in the regulation of vascular resistance and systemic blood pressure. This vasodilatory effect is dependent on the activation of K(ATP) channels. However, a cross-talk exists between the L-Argine/NO and L cysteine/H(2)S pathways. Furthermore, it has been shown that H(2)S acts as an endogenous non-selective inhibitor of phosphodiesterase activity. Compelling evidence links H(2)S to regulation of erectile function while it remains unclear whether the L-cysteine/H(2)S pathway plays a pathogenetic role in erectile dysfunction. Despite the rapid growth of the field, it should be noted that several aspects of H(2)S physiology in the cardiovascular system remain unsolved and the lack of reliable inhibitors and donors remains a major limitation. PMID- 21275894 TI - The neurophysiology of hydrogen sulfide. AB - Hydrogen sulfide (H(2)S) has emerged as the third endogenous gaseous mediator in the central and peripheral nervous system. H(2)S is generated by three enzymes, cystathionine beta-synthase (CBS), cystathionine gamma-lyase (CSE) and 3 mercaptopyruvate sulfurtransferase (3MST). In the CNS, H(2)S, generated mainly by CBS in astrocytes and 3MST in neurons, appears to participate in cognition, memory, regulation of the cardiopulmonary functions and neuroprotection. In the peripheral nervous system, evidence suggests that H(2)S may be involved in autonomic control of the cardiopulmonary and gastrointestinal functions as well pain and inflammation. PMID- 21275895 TI - Hydrogen sulfide: from physiology to pharmacology. AB - Gaseous neutroasmitters are a growing family of enzimatically generated gaseous mediators that exert regulatory functions in mammals. It is now widely recognized that hydrogen sulfide (H(2)S), along with nitric oxide (NO) and carbon monoxide (CO), is an important signaling molecule in cardiovascular, nervous, gastrointestinal, liver and lung physiology and pharmacology. The production of H(2)S from L-cysteine is catalysed primarily by two enzymes, cystathionine gamma lyase and cystathionine beta-synthase. Evidence is accumulating to demonstrate that H(2)S delivered exogenously exerts beneficial effects in animal models of inflammation and pain highlighting the potential for the therapeutic exploitation of H(2)S. Several hybrids have been developed coupling an H(2)S-releasing moiety to conventional drugs. These molecular hybrids are currently evaluated for efficacy in animal models of gastrointestinal, cardiovascular and neurogical disorders and erectile dysfunction. The anti-inflammatory activity of H(2)S has also been exploited for generating anti-platelets and anti-inflammatory agents that inhibit cyclo-oxygenases while sparing the gastrointestinal and cardiovascular tract. PMID- 21275896 TI - Hydrogen sulfide-based therapies: focus on H2S releasing NSAIDs. AB - Nonsteroidal anti-inflammatory pain medications, commonly referred to as NSAIDs, are effective treatment for pain, fever and inflammation. However their use associates with a 4-6 fold increase in the risk of gastrointestinal bleeding. The basic mode of action of NSAIDs lies in the inhibition of cyclooxygenases (COXs), a family of enzymes involved in the generation of prostaglandins (PGs). The COX exists at least in two isoforms, COX-1 and COX-2, with PGs mediating inflammation at site of injury generated by the COX-2, while COX-1 produces PGs that are essential in maintaining integrity in the gastrointestinal tract. Selective inhibitors of COX-2, the coxibs, spare the gastrointestinal tract while exerting anti-inflammatory and analgesic effects. However, their use has been linked to an increased risk of thrombo-embolic events. Nitric oxide (NO) and hydrogen sulfide (H(2)S), are potent vasodilatory agents that maintain mucosal integrity in the gastrointestinal tract. In the last decade hybrid molecules that release NO or H(2)S have been coupled with non-selective NSAIDs to generate new classes of anti inflammatory and analgesic agents with the potential to spare the gastrointestinal and cardiovascular system. These agents, the NO-releasing NSAIDs, or CINOD, and the H(2)S-releasing NSAIDs are currently investigated as a potential alternative to NSAIDs and coxibs. Naproxcinod has been the first, and so far the only, CINOD extensively investigated in clinical trials. Despite its promising profile, the approval of this drug was recently rejected by the Food and Drug Administration because the lack of long-term controlled studies. NSAIDs that release H(2)S as a mechanism to support an enhanced gastrointestinal and cardiovascular safety are being investigated in preclinical studies. Either naproxen or diclofenac coupled to an H(2)S releasing moiety has been reported to cause less gastrointestinal and cardiovascular injury than parent NSAIDs in preclinical models. PMID- 21275897 TI - Hydrogen sulfide in gastrointestinal and liver physiopathology. AB - Hydrogen sulfide (H(2)S) is a gas that can be formed by the action of two enzymes, cystathionine gamma lyase (CSE) and cystathionine beta synthase (CBS). H(2)S has been known for hundreds of years for its poisoning effect, however the idea that H(2)S is not only a poison, but can exert a physiological role in mammalian organisms, originates from the evidence that this gaseous mediator is produced endogenously. In addition to H(2)S synthesis by gastrointestinal tissue, the intestinal mucosa, particularly in the large intestine, is regularly exposed to high concentrations of H(2)S that are generated by some species of bacteria and through the reduction of unabsorbed intestinal inorganic sulphate. This review reports on the effects of H(2)S in the gastrointestinal tract and liver and provides information on the therapeutic applications of H(2)S-donating drugs. PMID- 21275898 TI - Hydrogen sulphide and pain. AB - Physiopathological mechanisms and treatment of pain remain a significant challenge. In the last decade, the gasotransmitter hydrogen sulphide (H(2)S) has received wide attention for its ability to act as a multilevel regulatory molecule in a variety of biologic functions in mammals including modulation of pain processing. Results from preclinical models of pain, including experimentally-induced somatic, neurophatic and visceral pain have provided non univocal finding and, depending on the model, H(2)S has been reported to exert either pronociceptive and antinociceptive effects. Several biochemical explanations might account for these differences: thus, H(2)S-induced pronociception appears linked to activation of T-type Ca(2+) channels while analgesia is due to K(ATP) channels opening. Moreover, local administration of H(2)S causes pain and, in contrast, systemic H(2)S administration results into antinociception. In the view of possibility to use H(2)S-realising drugs or compounds that block H(2)S synthesis for pain treatment, additional studies are needed to exploit the therapeutic potential of H(2)S in pain signalling. PMID- 21275899 TI - Hydrogen sulfide in inflammation: friend or foe? AB - Hydrogen sulfide (H(2)S), the gaseous mediator produced by various cells in our body, was recently discovered to play a major role in human physiology despite its toxic nature known for centuries. In addition to its pathophysiological relevance in cardiovascular and neuronal disorders, there is considerable interest in the significance of H(2)S in inflammation. A number of preclinical studies in our laboratory as well as by others, using H(2)S donors and inhibitors of its endogenous synthesis, have provided evidence for both pro- and anti inflammatory character of H(2)S. But so far, there is a significant lack of support from relevant clinical studies. One of the major contentious issues being variable dose and sampling time, controversies exist on the precise friend or foe nature of this gaseous transmitter. However, it is well accepted that once a clearer picture of the whole story of H(2)S in inflammation emerges, potential for therapeutic manipulations in this field are immense. This review focuses on the intriguing effects of H(2)S in some of the inflammatory conditions such as acute pancreatitis, sepsis, burn injuries and local inflammation of the joints. Active research projects have been undertaken to elucidate the mechanisms of action of H(2)S in inflammation, including neurogenic inflammation and interaction with other biological mediators and pathways. The early and fragmentary evidence obtained holds promise for a successful drug intervention for these inflammatory diseases. PMID- 21275900 TI - Hydrogen sulfide generation in mammals: the molecular biology of cystathionine beta- synthase (CBS) and cystathionine-gamma-lyase (CSE). AB - Cystathionine-beta-synthase (CBS) and cystathionine-gamma-lyase (CSE) are two key enzymes involved in the synthesis of hydrogen sulphide (H(2)S). CBS catalyzes the pyridoxal 5'-phosphate (PLP)-dependent conversion of homocysteine in Cystathionine whilst CSE the pyridoxal 5'-phosphate (PLP)-dependent synthesis of L-cysteine from Cystathionine. In mammals, CBS gene transcription is poorly investigated and the activity of the enzyme is highly regulated. In fact, the CBS enzyme contains a heme cofactor that functions as a redox sensor and utilizes S adenosylmethionine (SAM) as an allosteric activator. Impaired CBS activity causes hyperhomocystinuria and hyperhomocysteinemia, both risk factors for cardiovascular diseases. Murine CSE gene regulation is well characterized but little is known about the human counterpart and there is no information regarding the enzyme activity regulation. Recently it has been demonstrated that CSE transcription is regulated by the nuclear receptor Farnesoid X Receptor (FXR). Mutations that decrease the activity of CSE cause cystathioninuria, hypercystathioninemia and increase the risk of developing atherosclerosis and bladder cancer. This review focuses on the recent aspects of the molecular regulation of both CBS and CSE and highlights the possibility that members of the nuclear receptors superfamily might be involved in the regulation of hydrogen sulphide metabolism. PMID- 21275901 TI - An update in H(2)S in physiology, pathophysiology and pharmacology. PMID- 21275902 TI - Responses of hypertrophied myocytes to reactive species: implications for glycolysis and electrophile metabolism. AB - During cardiac remodelling, the heart generates higher levels of reactive species; yet an intermediate 'compensatory' stage of hypertrophy is associated with a greater ability to withstand oxidative stress. The mechanisms underlying this protected myocardial phenotype are poorly understood. We examined how a cellular model of hypertrophy deals with electrophilic insults, such as would occur upon ischaemia or in the failing heart. For this, we measured energetics in control and PE (phenylephrine)-treated NRCMs (neonatal rat cardiomyocytes) under basal conditions and when stressed with HNE (4-hydroxynonenal). PE treatment caused hypertrophy as indicated by augmented atrial natriuretic peptide and increased cellular protein content. Hypertrophied myocytes demonstrated a 2.5 fold increase in ATP-linked oxygen consumption and a robust augmentation of oligomycin-stimulated glycolytic flux and lactate production. Hypertrophied myocytes displayed a protected phenotype that was resistant to HNE-induced cell death and a unique bioenergetic response characterized by a delayed and abrogated rate of oxygen consumption and a 2-fold increase in glycolysis upon HNE exposure. This augmentation of glycolytic flux was not due to increased glucose uptake, suggesting that electrophile stress results in utilization of intracellular glycogen stores to support the increased energy demand. Hypertrophied myocytes also had an increased propensity to oxidize HNE to 4-hydroxynonenoic acid and sustained less protein damage due to acute HNE insults. Inhibition of aldehyde dehydrogenase resulted in bioenergetic collapse when myocytes were challenged with HNE. The integration of electrophile metabolism with glycolytic and mitochondrial energy production appears to be important for maintaining myocyte homoeostasis under conditions of increased oxidative stress. PMID- 21275904 TI - 1001 model organisms to study cilia and flagella. AB - Most mammalian cell types have the potential to assemble at least one cilium. Immotile cilia participate in numerous sensing processes, while motile cilia are involved in cell motility and movement of extracellular fluid. The functional importance of cilia and flagella is highlighted by the growing list of diseases due to cilia defects. These ciliopathies are marked by an amazing diversity of clinical manifestations and an often complex genetic aetiology. To understand these pathologies, a precise comprehension of the biology of cilia and flagella is required. These organelles are remarkably well conserved throughout eukaryotic evolution. In this review, we describe the strengths of various model organisms to decipher diverse aspects of cilia and flagella biology: molecular composition, mode of assembly, sensing and motility mechanisms and functions. Pioneering studies carried out in the green alga Chlamydomonas established the link between cilia and several genetic diseases. Moreover, multicellular organisms such as mouse, zebrafish, Xenopus, Caenorhabditis elegans or Drosophila, and protists such as Paramecium, Tetrahymena and Trypanosoma or Leishmania each bring specific advantages to the study of cilium biology. For example, the function of genes involved in primary ciliary dyskinesia (due to defects in ciliary motility) can be efficiently assessed in trypanosomes. PMID- 21275903 TI - ARAP1 association with CIN85 affects epidermal growth factor receptor endocytic trafficking. AB - BACKGROUND INFORMATION: ARAP1 is an Arf (ADP-ribosylation factor)-directed GAP (GTPase-activating protein) that inhibits the trafficking of EGFR (epidermal growth factor receptor) to the early endosome. To further understand the function of ARAP1, we sought to identify proteins that interact with ARAP1. RESULTS: Here we report that ARAP1 associates with the CIN85 (Cbl-interacting protein of 85 kDa). Arg86 and Arg90 of ARAP1 and the SH3 (Src homology 3) domains of CIN85 are necessary for the interaction. We found that a mutant of ARAP1 with reduced affinity for CIN85 does not efficiently rescue the effect of reduced ARAP1 expression on EGFR trafficking to the early endosome. Reduced expression of CIN85 has a similar effect as reduced expression of ARAP1 on traffic of the EGFR. Cbl proteins regulate the endocytic trafficking of the EGFR by mediating ubiquitination of the EGFR. Overexpression of ARAP1 reduced ubiquitination of the EGFR by Cbl and slowed Cbl-dependent degradation of the EGFR. Reduced expression of ARAP1 accelerated degradation of EGFR but did not affect the level of ubiquitination of the receptor that was detected. CONCLUSION: ARAP1 interaction with CIN85 regulates endocytic trafficking of the EGFR and affects ubiquitination of EGFR. We propose a model in which the ARAP1-CIN85 complex drives exit of EGF EGFR-Cbl complex from a pre-early endosome into a pathway distinct from the early endosome/lysosome pathway. PMID- 21275905 TI - The ciliary pocket: a once-forgotten membrane domain at the base of cilia. AB - The PC (primary cilium) is present on most cell types in both developing and adult tissues in vertebrates. Despite multiple reports in the 1960s, the PC was almost forgotten for decades by most of the cell biology community, mainly because its function appeared enigmatic. This situation changed 10 years ago with the key discovery that this fascinating structure is the missing link between complex genetic diseases and key signalling pathways during development and tissue homoeostasis. A similar misfortune might have happened to an original membrane domain found at the base of PC in most cell types and recently termed the 'ciliary pocket'. A morphologically related structure has also been described at the connecting cilium of photoreceptors and at the flagellum in spermatids. Its organization is also reminiscent of the flagellar pocket, a plasma membrane invagination specialized in uptake and secretion encountered in kinetoplastid protozoa. The exact function of the ciliary pocket remains to be established, but the recent observation of endocytic activity coupled to the fact that vesicular trafficking plays important roles during ciliogenesis brought excitement in the ciliary community. Here, we have tried to decipher what this highly conserved membrane domain could tell us about the function and/or biogenesis of the associated cilium. PMID- 21275906 TI - Effect of metformin therapy on cardiac function and survival in a volume-overload model of heart failure in rats. AB - Advanced HF (heart failure) is associated with altered substrate metabolism. Whether modification of substrate use improves the course of HF remains unknown. The antihyperglycaemic drug MET (metformin) affects substrate metabolism, and its use might be associated with improved outcome in diabetic HF. The aim of the present study was to examine whether MET would improve cardiac function and survival also in non-diabetic HF. Volume-overload HF was induced in male Wistar rats by creating ACF (aortocaval fistula). Animals were randomized to placebo/MET (300 mg.kg(-1) of body weight.day(-1), 0.5% in food) groups and underwent assessment of metabolism, cardiovascular and mitochondrial functions (n=6 12/group) in advanced HF stage (week 21). A separate cohort served for survival analysis (n=10-90/group). The ACF group had marked cardiac hypertrophy, increased LVEDP (left ventricular end-diastolic pressure) and lung weight confirming decompensated HF, increased circulating NEFAs (non-esterified 'free' fatty acids), intra-abdominal fat depletion, lower glycogen synthesis in the skeletal muscle (diaphragm), lower myocardial triacylglycerol (triglyceride) content and attenuated myocardial (14)C-glucose and (14)C-palmitate oxidation, but preserved mitochondrial respiratory function, glucose tolerance and insulin sensitivity. MET therapy normalized serum NEFAs, decreased myocardial glucose oxidation, increased myocardial palmitate oxidation, but it had no effect on myocardial gene expression, AMPK (AMP-activated protein kinase) signalling, ATP level, mitochondrial respiration, cardiac morphology, function and long-term survival, despite reaching therapeutic serum levels (2.2+/-0.7 MUg/ml). In conclusion, MET induced enhancement of myocardial fatty acid oxidation had a neutral effect on cardiac function and survival. Recently reported cardioprotective effects of MET may not be universal to all forms of HF and may require AMPK activation or ATP depletion. No increase in mortality on MET supports its safe use in diabetic HF. PMID- 21275907 TI - Ninety years of AOGS. PMID- 21275908 TI - Guest editorial. PMID- 21275909 TI - Cerebral palsy and induction of labor. PMID- 21275910 TI - Effects of the September 11, 2001 disaster on pregnancy outcomes: a systematic review. AB - BACKGROUND: The terrorist explosions of the World Trade Center in New York City and the other events on the Pentagon and in Pennsylvania on 11 September 2001 were stressful events that affected people around the world. Pregnant women and their offspring are especially vulnerable during and after such a terrorist attack. The objective was to systematically review the risks of adverse pregnancy outcomes after the terrorist attacks on Sept 11, 2001. METHODS: The Meta-analysis of Observational Studies in Epidemiology (MOOSE) criteria were used for reporting of this review. Statistical analyses were performed using RevMan 5.0. RESULTS: Ten reports of low-to-moderate risk of methodological bias were included. There was increased risks of infants with birthweight of 1,500 g-1,999 g (adjusted odds ratio [AOR] 1.67 [95%CI 1.11-2.52]) and small-for-gestational age births (AOR 1.90; 95%CI 1.05-3.46) in New York. There was increased risks of low birthweight (relative risk 2.25; 95%CI 1.29-3.90) and preterm births (relative risk 1.50; 95%CI 1.06-2.14) among ethnically Arabic women living in California There was a reduction in birthweight by 276 g and in head circumference by 1 cm when DNA adducts, a marker for environmental toxin exposure, were doubled in maternal blood. In Holland, a 48-g reduction in birthweight was reported. CONCLUSIONS: The World Trade Center disaster influenced pregnancy outcomes in New York, among ethnically Arab women living in California and among Dutch women. The adverse outcomes are likely due to environmental pollution and stress in New York, ethnic harassment in California and communal bereavement and stress in Holland. PMID- 21275911 TI - The severity of clinical manifestations in preeclampsia correlates with the amount of placental infarction. AB - OBJECTIVE: To correlate placental histopathology, in particular ischemic changes, with the clinical severity of preeclampsia. DESIGN: A blinded retrospective study. SETTING: One Swedish hospital. SAMPLE: One hundred and fifty-seven women with severe (n= 116) or mild (n= 41) preeclampsia and 157 normotensive women matched according to gestational-age. METHODS: One senior pathologist, blinded to clinical data and group, examined all histological slides. In the statistical analyses, adjustment for gestational week was done when appropriate. MAIN OUTCOME MEASURES: Placental histopathological findings. RESULTS: Amount of infarction increased with the severity of preeclampsia (p < 0.001). Infarction involving >=5% of the placental tissue was seen in 39.7% of severe preeclampsia, 17.1% of mild preeclampsia and 5.1% of non-preeclampsia. When comparing placentas in severe preeclampsia, mild preeclampsia and non-preeclampsia, there was an increase in the presence of any infarction (80.2%, 61.0%, vs. 20.4%). Also, there was a difference in the presence of decidual arteriopathy (35.3%, 22.0%, vs. 3.8%) and accelerated villous maturation (71.6%, 53.3%, vs. 12.6%). We found no difference in intervillous thrombosis, abruption placenta or placental weight in relation to gestational week. CONCLUSIONS: In pregnancies with mild or severe preeclampsia, a large proportion of the placentas had histological signs of pathology, in particular signs of ischemia. The pathology was similar, but more pronounced in severe compared to mild preeclampsia, suggesting mild and severe preeclampsia to have similar underlying etiology. PMID- 21275912 TI - Significant effects on neonatal morbidity and mortality after regional change in management of post-term pregnancy. AB - OBJECTIVE: To evaluate the effects on neonatal morbidity of a regional change in induction policy for post-term pregnancy from 43(+0) to 42(+0) gestational weeks (GWs). DESIGN AND SETTING: Nationwide retrospective register study between 2000 and 2007. POPULATION: All singleton pregnancies with a gestational age of >41(+2) GW (n= 119,198). METHODS: All Swedish counties were divided into three groups where study group allocation was designated by the proportion of pregnancies >42(+2) GW among all pregnancies of >41(+2) GW. Stockholm county formed a separate group. MAIN OUTCOME MEASURES: Perinatal morbidity. RESULTS: In counties with the most active management, 19% of pregnancies >41(+2) GW were delivered at >42(+2) GW during 2000-2004 compared to 7.1% in 2005-2007. In the least active counties, corresponding figures were 21.0% compared to 19.4%. During 2005-2007, the odds ratios for meconium aspiration and 5-minute Apgar score of <=6 in the least compared to most active counties, were 1.55 (95% CI: 1.03-2.33) and 1.26 (95% CI: 1.06-1.51). In Stockholm >42(+2) GW seen among pregnancies of >41(+2) decreased from 21.0% in 2000-2004 to 5.9% in 2005-2007. Reduced perinatal death risks by 48%, meconium aspiration of 51% and low Apgar scores by 31% in 2005-2007 compared with 2000-2004 were observed. Rates of operative deliveries at >41(+2) GW in Stockholm were unaltered. CONCLUSION: A significant reduction in perinatal morbidity was found, with no influence on operative delivery rates for post-term pregnancy in Stockholm. We advocate a nationwide change toward more active management of post-term pregnancies. PMID- 21275913 TI - Fear of childbirth, women's preference for cesarean section and childhood abuse: a longitudinal study. AB - OBJECTIVE: To examine the association between childhood abuse and fear of childbirth and the wish for cesarean section during second pregnancy. DESIGN: A longitudinal cohort study using data from the Norwegian Mother and Child Cohort Study (MoBa) conducted by the Norwegian Institute of Public Health. SETTING: Fifty maternity units in Norway, 1999-2006. SAMPLE: We included 4,876 women who participated in the MoBa study during their first and second pregnancy. METHODS: Postal questionnaires at 18 and 30 weeks' gestation and 6 months postpartum linked to the Medical Birth Registry of Norway. MAIN OUTCOME MEASURES: Associations between childhood abuse and women's fear of childbirth and preference for cesarean section during second pregnancy were assessed using regression analyses, adjusting for confounding factors such as mode of delivery and birth experience of first pregnancy. RESULTS: Of 4,876 women, 1,023 (21%) reported some form of childhood abuse. Compared to women without a history of childhood abuse, childhood-abused women more frequently reported fear of childbirth (23% vs. 15%, p < 0.001) and the wish for cesarean section (6.4% vs. 4.0%, p < 0.002) during second pregnancy. The association between childhood abuse and fear of childbirth and preference for cesarean section remained significant after adjusting for mode of first delivery and experience of first birth (adjusted odds ratio [OR] 1.53, 95%CI 1.24-1.90 and 1.57, 1.09-2.27, respectively). CONCLUSION: Childhood abuse is associated with fear of childbirth and preference for cesarean section during second pregnancy. Mode of delivery and postpartum self-reported birth experience of the first pregnancy did not alter this association significantly. PMID- 21275914 TI - Factors related to elevated vaginal pH in the first trimester of pregnancy. AB - OBJECTIVE: To assess different bacterial and epidemiological factors associations with increased vaginal pH in the pregnant women population during the first trimester. DESIGN: A cross-sectional, observational study. SETTING: Three outpatient clinics in Riga. POPULATION: From July 2009 until January 2010, 139 unselected consecutive pregnant women at the first prenatal visit. METHODS: Pregnant women were submitted to an interview, vaginal examination and vaginal specimen collection for pH measurement and native microscopy. MAIN OUTCOME MEASURES: Vaginal pH >=4.5 was considered as elevated. Abnormal bacterial microflora was classified according to Donders. RESULTS: Elevated vaginal pH was significantly associated with bacterial vaginosis (p < 0.001), aerobic vaginitis (p < 0.001) and mixed aerobic vaginitis and bacterial vaginosis flora (p < 0.001) and presence of sperm cells in the smears (p= 0.024). Most cases with sperm were associated with abnormal vaginal flora. Normal lactobacillary morphotypes were more often found in the pH <=4.4 group (p < 0.001), while leptosomic and short types were found more frequently with increased pH. CONCLUSIONS: Elevated vaginal pH is associated with different types of abnormal vaginal flora and the presence of sperm cells. PMID- 21275915 TI - Prevalence of anemia and micronutrient deficiencies in early pregnancy in rural Bangladesh, the MINIMat trial. AB - OBJECTIVE: To describe the prevalence of anemia and micronutrient deficiencies as well as their determinants in early pregnancy. DESIGN: Baseline data from a population-based randomized intervention trial. SETTING: The study was conducted in Matlab, a sub-district in rural Bangladesh from 1 January to 31 December 2002. POPULATION: Pregnant women (n= 740) were enrolled in approximately week 14 in pregnancy. METHODS: Data were collected using questionnaires, physical examinations and laboratory analyses of blood samples for concentrations of hemoglobin, ferritin, zinc, folate and vitamin B-12. MAIN OUTCOME MEASURES: Covariates associated with anemia and micronutrient deficiencies in bivariate analyses were evaluated in multivariate logistic regression models adjusting for potential confounders. RESULTS: Anemia was present in 28% of the women, 55% were zinc deficient, 46% were vitamin B-12 deficient and 18% were folate deficient. Anemia was not associated with iron deficiency but rather with vitamin B-12 deficiency. Infestation with Ascaris was highly prevalent (67%) and associated with both folate and vitamin B-12 deficiency. Anemia and micronutrient deficiencies all varied significantly with season. CONCLUSIONS: The high prevalences of zinc and vitamin B-12 deficiencies in early pregnancy are a concern, as it could lead to adverse pregnancy outcomes and increased health risks for both mother and child. The prevalence of iron deficiency was low, but as this was during early pregnancy, the women might develop iron deficiency and consequently iron deficiency anemia as the pregnancy progresses. PMID- 21275916 TI - Cervical insulin-like growth factor binding protein-1 (IGFBP-1) to predict spontaneous onset of labor and induction to delivery interval in post-term pregnancy. AB - OBJECTIVE: To evaluate whether insulin-like growth factor binding protein-1 (IGFBP-1) assessed in cervical secretion can predict successful induction and spontaneous onset of labor in post-term pregnancy, compared to ultrasound measurement of cervical length and Bishop score. DESIGN: Cohort study, originating from a randomized controlled trial. SETTING: Obstetric department of a university and tertiary referral hospital, Norway. POPULATION: Five hundred and eight post-term women who had been randomized to induction of labor or expectant management 1 week beyond estimated day of delivery (289 [+/-2] days of gestation). METHODS: Time to delivery was related to presence of IGFBP-1 in cervical secretion, Bishop score and ultrasound measurement of cervical length recorded at inclusion. MAIN OUTCOME MEASURES: Spontaneous onset of labor and delivery within 3 days in the expectant management, and delivery within 24 hours of induction in the induction group. Test characteristics (sensitivity, specificity and negative and positive values and likelihood ratios) for IGFBP-1, Bishop score and cervical length were calculated. Logistic regression and Cox regression were used to account for parity and body mass index. RESULTS: With expectant management, IGFBP-1 predicted spontaneous labor onset and delivery within 72 hours with low sensitivity and high specificity (0.45 and 0.80, respectively), as did Bishop score (0.24, 0.92). Cervical length was more sensitive (0.67, 0.58). IGFBP-1 predicted successful induction within 24 hours with low sensitivity and high specificity (0.30, 0.85), such as Bishop score (0.06, 1.00) and cervical length (0.45, 0.76). Parity enhanced successful induction. CONCLUSION: IGFBP-1 predicts both spontaneous labor onset and successful induction in post-term pregnancy. Bishop score and cervical length performed equally well. PMID- 21275917 TI - Vaginal cleansing and postoperative infectious morbidity in vaginal hysterectomy. A register study from the Swedish National Register for Gynecological Surgery. AB - OBJECTIVE: To evaluate whether preoperative vaginal preparation routines influence postoperative infectious morbidity in vaginal hysterectomy and to analyze risk factors for postoperative infectious morbidity. DESIGN: Retrospective, longitudinal cohort study. SETTING: Forty -three hospitals in Sweden, participating in the Swedish National Register for Gynecological Surgery. POPULATION: All 6,496 women who were enrolled in the Register and underwent vaginal or laparoscopically assisted vaginal hysterectomy between 1 January 2000 and 1 February 2008. METHODS: Register data were collected prospectively using doctors' forms and patient questionnaires. Information about vaginal preparation routines in the clinics were achieved retrospectively by an e-mail survey. Multiple logistic regression analyses models were used to determine associations and risk factors. MAIN OUTCOME MEASURES: Infectious morbidity within 6-8 weeks postoperatively. RESULTS: No significant differences were seen in postoperative infectious morbidity in long term between vaginal preparation using saline or chlorhexidine solution or no cleansing. At discharge from hospital, those who had had vaginal cleansing using saline solution had a significantly higher risk of postoperative infections. Risk factors for infectious morbidity were young age, obesity, peroperative injury of the urinary bladder, operative time and duration of hospital stay. Protective were prophylactic antibiotics and concomitant prolapse surgery. CONCLUSIONS: Saline solution should not be used for vaginal cleansing due to a higher risk of infectious morbidity in the immediate postoperative period. Infectious morbidity may be reduced further by employing preventive measures such as meticulous surgical technique, preoperative weight reduction in obese women and minimizing time in hospital. PMID- 21275918 TI - Surgical-site infections and postoperative complications: agreement between the Danish Gynecological Cancer Database and a randomized clinical trial. AB - OBJECTIVE: Surgical-site infections are serious complications and thorough follow up is important for accurate surveillance. We aimed to compare the frequency of complications recorded in a clinical quality database with those noted in a randomized clinical trial with follow-up visits. DESIGN: Evaluation study. SETTING: Danish Gynecological Cancer Database (DGCD) and the Danish multicenter trial on perioperative oxygen and surgical-site infections (PROXI). SAMPLE: Paired data from 222 patients who participated in the PROXI trial taking place at Copenhagen University Hospital, Rigshospitalet between November 2006 and October 2008 and data from the DGCD. METHODS: Outcomes within 30 days from the trial and the database were compared and levels of agreements were calculated with kappa statistics. MAIN OUTCOME MEASURES: Primary outcome was surgical-site infection. Other outcomes included re-operation, urinary tract infection, pneumonia and sepsis. RESULTS: Surgical-site infection was found in 21 of 222 patients (9.5%) in the PROXI trial versus 6 of 222 patients (2.7%) in the DGCD (p < 0.01, kappa 0.42). Twelve of 15 superficial and three of six deep or organ-space surgical site infections were registered in the PROXI trial, but not in the DGCD. Agreements between secondary outcomes were very varying (kappa-value 0.77 for re operation, 0.37 for urinary tract infections, 0.19 for sepsis and 0.18 for pneumonia). CONCLUSIONS: The randomized trial reported significantly more surgical-site infections than the clinical database. The DGCD reported only 50% of the deep and organ-space infections, and hence, the low-overall agreement indicates a need for more careful database registration. PMID- 21275919 TI - Incompleteness of Swedish local clinical guidelines for acupuncture treatment during childbirth. AB - OBJECTIVE: To investigate the presence and content of local clinical guidelines for acupuncture treatment in Swedish labor and postnatal wards. DESIGN: A Swedish national survey. MAIN OUTCOME MEASURES: Presence and content of clinical guidelines for acupuncture. Setting. All Swedish labor and postnatal wards at the time of data collection (April 2007-March 2008). MATERIAL AND METHODS: Enquiry was made on local clinical guidelines for acupuncture treatment at 50 labor and 50 postnatal wards. The standards for reporting interventions in controlled trials of acupuncture document was used to identify core aspects of acupuncture treatment and the proportion of wards with guidelines on these aspects was evaluated. RESULTS: Guidelines were obtained from 27 labor wards and 22 postnatal wards. Descriptions of the core aspects of acupuncture treatment, such as acupuncture rationale, needling details and treatment regimens, were limited in most. All local guidelines included indications for treatment, but these were not based on scientific evidence of effect, and only two mentioned the importance of achieving de-qi - a feeling of soreness reflecting an effective treatment. Few clinical guidelines required that the practitioners' acupuncture education should be on an academic level and relevant references based on clinical trials were lacking in all guidelines. CONCLUSION: Swedish local clinical guidelines on acupuncture for childbirth-related symptoms lack sufficient information to support midwives and obstetricians in administering acupuncture treatment. The content of the guidelines was unclear, inconclusive and, in some cases, irrelevant, and a majority lacked important information on indications and technique. PMID- 21275920 TI - Induction of labor and cerebral palsy: a population-based study in Norway. AB - OBJECTIVE: To investigate the association between labor induction and later development of cerebral palsy (CP). DESIGN: Registry-based cohort study. SETTING: Perinatal data on all children born in Norway 1996-1998 were obtained from the Medical Birth Registry of Norway (MBRN). Neurodevelopmental data were collected from the Norwegian Cerebral Palsy Registry (CPRN). POPULATION: A total of 176,591 children surviving the neonatal period. Of 373 children with CP, detailed data were available on 241. METHODS: Unadjusted and adjusted odds ratios (OR) with 95% confidence intervals (CI) were calculated as estimates of the relative risk that a child with CP was born after labor induction. MAIN OUTCOME MEASURES: Total CP and spastic CP subtypes. RESULTS: Bilateral cerebral palsy was more frequently observed after induced labor (OR: 3.1; 95% CI 2.1-4.5). For children born at term the association between bilateral CP and labor induction was stronger (OR: 4.4; 95% CI 2.3-8.6). The association persisted after adjustment for maternal disease, gestational age, standard deviation score for birthweight (z-score) and prelabor rupture of membranes (PROM) (adjusted OR: 3.7; 95%CI 1.8-7.5). Among children with CP born at term, four-limb involvement (quadriplegia) was significantly more frequent after induced (45.5%) compared with non-induced labor (8.0%). There was no significant association between labor induction and unilateral CP subtype or CP in preterm born children. CONCLUSIONS: In this study population, we found that labor induction at term was associated with excess risk of bilateral spastic CP and in particular CP with four-limb involvement. PMID- 21275921 TI - Low serum interleukin-17 is associated with preterm delivery. AB - OBJECTIVE: To study maternal serum interleukin-17 (IL-17) during normal pregnancy and evaluate the association with preterm delivery. DESIGN: Prospective study. SETTING: Aarhus University Hospital, Denmark. POPULATION: Three cohorts: (a) low risk cohort of 1,069 women who had serum drawn in weeks 12 and 19, (b) subgroup of the low-risk cohort, consisting of 40 women, who had serum drawn at 12, 19, 26, 33 and 39 weeks of gestation and (c) a symptomatic cohort of 93 women admitted with symptoms of preterm delivery at a gestational age of 24(+ 0) weeks to 33(+ 6) weeks. METHODS: Serum IL-17 determined by an in-house developed multiplex sandwich immunoassay. MAIN OUTCOME MEASURES: Preterm delivery <37(+0) weeks gestation. RESULTS: Serum IL-17 did not change during normal pregnancy. At admission to hospital, women with preterm contractions had significantly decreased serum IL-17 as compared with normal pregnancies (median <4 [interquartile ranges, IQR, <4-10 pg/ml] vs. 174 pg/ml [IQR, 92 - 485 pg/ml]); this difference was enhanced and highly significant for women delivering preterm versus term (median <4 [IQR, <4-7.9 pg/ml] vs. median 6.0 [IQR, <4-221 pg/ml]; p value 0.03). Serum IL-17 was also lower in women with preterm prelabor rupture of membranes. A slightly, but not statistically significant decrease was found in weeks 12 and 19 in low-risk women who subsequently delivered preterm. CONCLUSION: Maternal serum IL-17 may be involved in preterm delivery. PMID- 21275922 TI - Postural control in women with premenstrual symptoms during oral contraceptive treatment. AB - OBJECTIVE: This study investigates postural control among women with and without premenstrual symptoms (PMS) on oral contraceptive (OC) treatment. DESIGN: Prospective repeated measures design. SETTING: Women's health clinical research unit at a university hospital. POPULATION: Fifteen women using low-dose monophasic oral contraceptives participated in the study. Depending on premenstrual symptoms, the women were divided into one PMS group and one non-PMS group. METHODS: Postural control (displacement area) was measured using an AMTI((r)) force platform during the active hormone phase (OC phase) and the hormone-free phase (non-OC phase) of the pill chart. Premenstrual symptoms were evaluated prospectively using the Cyclicity Diagnoser. MAIN OUTCOME MEASURES: Displacement area as a measure of postural control. RESULTS: Six of 15 women showed premenstrual symptoms (primarily negative mood symptoms) between the phases and were considered having premenstrual symptoms. When analyzing postural control, the PMS group displayed a significantly greater displacement area in the OC-phase compared to the non-OC phase. In contrast, the non-PMS group did not show any significant difference between the phases. Furthermore, the PMS group had significantly greater displacement area during the OC phase compared to the non-PMS group. CONCLUSIONS: The present study shows that women with premenstrual symptoms have greater displacement area than those without premenstrual symptoms during the active phase of oral contraceptive treatment. Negative mood symptoms may affect the maintenance of postural control by central interactions. Further studies are needed to clarify the precise mechanism for altered postural control in women with premenstrual symptoms. PMID- 21275923 TI - Weight after childbirth: a 2-year follow-up of obese women in a weight-gain restriction program. AB - OBJECTIVE: To investigate the effects of a weight-gain restriction program on weight development or weight maintenance 2 years after childbirth. DESIGN: A case control intervention study. SETTING: Antenatal care clinics in the southeast of Sweden. SAMPLE: One hundred and fifty-five obese pregnant women who participated in a weight-gain restriction program with weekly support during pregnancy and every 6 months during the two first years after childbirth. The control group consisted of 193 obese pregnant women. METHODS: Follow-up weight measurements were done at 12 and 24 months after childbirth. MAIN OUTCOME MEASURES: Weight change in kilogram at 12 and 24 months postpartum. RESULTS: A greater percentage of women in the intervention group showed a weight loss 24 months after delivery than did women in the control group at that same time (p= 0.034). Women in the intervention group who gained less than 7 kg during pregnancy had a significantly lower weight than the controls at the 24 months follow-up (p= 0.018). The mean value of weight change in the intervention group was -2.2 kg compared to +0.4 kg in the control group from early pregnancy to the follow-up 12 months after childbirth (p= 0.046). CONCLUSIONS: An intervention program with weekly motivational support visits during pregnancy and every 6 months after childbirth seems to have an impact on weight gain up to 24 months after childbirth for those women in the intervention group who succeeded in restricting their gestational weight gain to less than 7 kg. PMID- 21275924 TI - Repeat cerclage prolongs pregnancy in women with prolapsed membranes. AB - We evaluated repeat cerclage in women with prolapsed membranes. Twenty-two women with bulging membranes after primary cerclage were offered repeat cerclage; 11 chose a repeat cerclage and 11 chose bed rest. The median gestational age at delivery, birthweight and survival rates were significantly higher in the repeat cerclage group compared to the bed rest group (mean 26.8 weeks vs. 21.7 weeks, p= 0.04, mean birthweight 1180 g vs. 491 g, p= 0.01 odds ratio for survival 22.0, 95% CI, 2.1-236). Early repeat cerclage under antibiotic cover may be beneficial in women with bulging membranes after a prior failing cerclage attempt. PMID- 21275925 TI - Eclampsia is more prevalent during the winter season in Sweden. AB - Hypertensive pregnancy conditions have shown seasonal variations and have been related to low levels of vitamin D. In Sweden, the hours of sunlight per day are few in winter. We hypothesized that eclampsia would be more common in the winter season. We performed a population-based cross-sectional study of all singleton deliveries in Sweden during a 5-year period (n= 482,759 women). All parturients with eclampsia were included as cases and those without formed control group. The incidence of eclampsia was nearly doubled during winter season (odds ratio 1.9, 95% confidence interval 1.4-2.6) as compared to other seasons. The incidence of eclampsia during the period studied (1990-1994) was four in 10,000 pregnancies. We found that eclampsia was twice as common in winter and we introduce the alternative hypothesis that lack of sunlight exposure increases women's susceptibility to eclampsia, possibly due to vitamin D insufficiency. PMID- 21275926 TI - Postpartum maternal pneumococcal meningitis complicated by endocarditis. AB - Bacterial meningitis is associated with high morbidity and mortality. Few cases of pneumococcal meningitis during pregnancy and the postpartum period have been reported. We describe a case of postpartum pneumococcal meningitis complicated by endocarditis. A 26-year-old para-2 woman who had had a normal vaginal delivery at 38 weeks at a maternity home was transported to our hospital with a 39.5 degrees C fever 11 days postpartum. Eight hours after her arrival, her state of consciousness deteriorated rapidly. Lumbar puncture revealed Gram-positive cocci consistent with Streptococcus pneumoniae. She was immediately treated with antibiotics and subsequently diagnosed with endocarditis. Final culture results from the blood and cerebrospinal fluid confirmed the presence of S. pneumoniae. She recovered completely with no evidence of neurological damage. Maintaining a high clinical suspicion and initiating appropriate diagnostic testing and therapeutic interventions promptly are essential to reducing the morbidity and mortality associated with bacterial meningitis. PMID- 21275927 TI - Addison's disease presenting as hyperemesis, hyponatremia and pancytopenia in early pregnancy. PMID- 21275928 TI - Three-dimensional ultrasound of deep infiltrating endometriosis involving the rectosigmoid colon. PMID- 21275929 TI - End-stage renal disease: a new trajectory of functional decline in the last year of life. AB - OBJECTIVES: To determine the functional trajectory in the last year of life in end-stage renal disease managed without dialysis. DESIGN: Longitudinal cohort study of functional status over time and toward death. SETTING: Three renal units in the United Kingdom. PARTICIPANTS: Patients with Stage 5 chronic kidney disease managed conservatively (without dialysis). MEASUREMENTS: The main outcome measure was functional status, measured using the Karnofsky Performance Scale. RESULTS: Seventy-five participants (mean age 80.7, 62% response rate) recruited and followed up monthly for up to 2 years (median 8-month follow-up, range 1-23 months). Forty-nine (66%) died during follow-up. Those who died had similar distribution of age, ethnicity, primary renal pathology, and comorbidity as those still alive at study end. Analysis according to time before death revealed that functional status remained stable during the last year of life but declined steeply in the last month of life. CONCLUSION: This distinctive renal trajectory, reported here for the first time, contrasts with that previously described in other conditions. This has important clinical implications-the steep functional decline indicates that healthcare services need to be rapidly responsive to changing needs in this population as function declines in the last months and weeks of life. PMID- 21275930 TI - Patterns of change in depression after stroke. AB - OBJECTIVES: To provide estimates of change in depressive symptoms and determine how changes in depressive symptom influence recovery of functional status. DESIGN: Prospective cohort study. SETTING: Eleven inpatient medical rehabilitation facilities located across the United States. PARTICIPANTS: Five hundred forty-four persons with a first-time stroke. MEASUREMENTS: General linear regression model estimates assessed associations between depressive symptom change and functional status 3 and 12 months after discharge. RESULTS: The majority of persons with stroke were aged 75 and older, white, female, and married. The most prevalent stroke type was ischemic. For participants without depression at discharge, those who reported fewer depressive symptoms 12 months after stroke than before had an adjusted functional status score of 108.2, whereas those with more symptoms had an adjusted functional status score of 104.6. For participants who were depressed at discharge, those who reported fewer depressive symptoms 12 months after stroke than before had an adjusted functional status score of 100.3, whereas those with more symptoms had an adjusted functional status score of 88.0. CONCLUSION: Tracking depressive symptom change in the hospital and after discharge is clinically relevant and is an important component of patient care and recovery of functional status. PMID- 21275931 TI - Depression and cognitive impairment in older adult emergency department patients: changes over 2 weeks. AB - OBJECTIVES: To evaluate older adult emergency department (ED) patients for depression and cognitive impairment and to re-evaluate those findings 2 weeks later. DESIGN: Prospective cohort study. SETTING: ED. PARTICIPANTS: One thousand two hundred six older community-dwelling ED patients consented to participate; 811 (67%) completed the 2-week follow-up. MEASUREMENTS: Screening for depression (9-item Patient Health Questionnaire) and cognitive impairment (Six-Item Screener) was performed. Changes were evaluated through paired comparisons. RESULTS: At 2-week follow-up, for depression, 27 of 97 (28%) with baseline positive tests remained positive, and 22 of 706 (3%) with baseline negative tests were positive. At 2-week follow-up, for cognitive impairment, five of 43 (12%) with baseline positive tests remained positive, and 11 of 765 (1%) with baseline negative tests were positive. CONCLUSION: Significant variability exists for depression and cognitive impairment testing completed during and after the ED visit, with markedly fewer subjects testing positive at follow-up. The variability may reflect changes in clinical state, confounding from other conditions, or poor validity of the instruments in the ED setting. Further studies are needed to explain these findings before case-finding for these conditions is implemented in the ED setting. PMID- 21275932 TI - Influenza vaccination in young children reduces influenza-associated hospitalizations in older adults, 2002-2006. AB - OBJECTIVES: To assess how influenza vaccination coverage in children is related to pneumonia and influenza (P&I) in older adults and whether sociodemographic factors modify these associations. DESIGN: Approximately 5 million hospitalization records from the Centers for Medicare and Medicaid Services for four influenza years (2002-2006) were abstracted. A single-year age distribution of rates of P&I hospitalization was estimated according to state for each influenza season; an exponential acceleration in the P&I rates with age was observed for each influenza season. State- and season-specific P&I rate accelerations were regressed against the percentage of vaccinated children, older adults, or both using mixed effects models. SETTING: U.S. population, 2002 to 2006. PARTICIPANTS: U.S. population aged 65 and older. MEASUREMENTS: State-level influenza annual vaccination coverage data in children and older adults were obtained from the National Immunization Survey and the Behavioral Risk Factor Surveillance System, respectively. RESULTS: Child influenza vaccination coverage was negatively associated with age acceleration in P&I, whereas influenza vaccination in the older adults themselves was not significantly associated with P&I in older adults. CONCLUSION: Vaccination of children against influenza may induce herd immunity against influenza for older adults and has the potential to be more beneficial to older adults than the existing policy of preventing influenza by vaccinating older adults themselves. PMID- 21275933 TI - Healthy behaviors and onset of functional disability in older adults: results of a national longitudinal study. AB - OBJECTIVES: To examine the combined effect of healthy behaviors on the development of functional disability in an elderly cohort. DESIGN: Prospective cohort study. SETTING: Taiwan Longitudinal Study in Aging from 1989, 1993, 1996, 1999, and 2003. PARTICIPANTS: A national sample of 1,940 men and 1,247 women aged 60 and older without functional disability at baseline. MEASUREMENTS: Functional disability was defined as difficulty with activities of daily living: taking a bath or walking 200 to 300 m. Time to functional disability was the age at midpoint between the first occurrence of disability onset in the survey year and prior survey year. Considering that the onset of disability is probably a precursor of death, for those who died without disability, time to disability onset was set at the midpoint between the last follow-up and death year. Four healthy behaviors were measured: not smoking, moderate alcohol consumption, regular exercise, and sleeping 6 to 8 hours per day. A Cox proportional hazards model with time-dependent covariates was used to analyze the association between age at the first functional disability and prior healthy behavior, after controlling for sex, time-varying disease status, marital status, and education. RESULTS: Healthy behaviors were linked to the onset of functional disability. Participants who performed one or more healthy behaviors were 15% to 75% less likely to be disabled than those who performed none. CONCLUSION: In the population studied, healthy behaviors were associated with lower incidence of functional disability. As the number of healthy behaviors increased, the likelihood of disability decreased. PMID- 21275934 TI - Hepatocellular carcinoma in older adults: clinical features, treatments, and survival. AB - OBJECTIVES: To evaluate the clinical features, treatments, stages, and survival in older adults with hepatocellular carcinoma (HCC). DESIGN: A consecutive case study with retrospective medical record review. SETTING: University hospital (tertiary referral center) in Korea. PARTICIPANTS: Two hundred sixty-two participants with HCC diagnosed between May 1, 2003, and December 31, 2006. MEASUREMENTS: Clinical characteristics, treatments, four staging systems for HCC, and survival in older (>=65, n=113) and younger (<65, n=149) people with HCC. RESULTS: The older HCC group were less likely to have hepatitis B virus infection and diffuse tumors and had more comorbidities, poorer performance status, smaller tumor area, and multinodular disease. There were no significant differences between the two groups with regard to Child-Pugh-Turcotte score, Model for End Stage Liver Disease (MELD) score, Child class, alpha-fetoprotein levels, and tumor stage at diagnosis. Approximately 88% of subjects were treated regardless of age, but resection was performed less frequently in the older participants. Older participants with HCC had overall survival and liver-related mortality similar to those of the younger participants, although they had poorer performance, greater comorbidity, and less likelihood of receiving surgery than the younger patients. CONCLUSION: This study supports the effectiveness and safety of nonsurgical treatment for older adults with HCC. Further study is needed to elucidate the reasons for similar prognoses in the older adults in spite of the greater burdens of comorbidities and poorer performance status. PMID- 21275935 TI - Generalized cowpox infection in a patient with Darier disease. PMID- 21275936 TI - Incidence of cancer in the context of atopic dermatitis. PMID- 21275938 TI - Mutations in two genes on chromosome 13 resulting in a complex hair and skin phenotype due to two rare genodermatoses: KLICK and autosomal recessive woolly hair/hypotrichosis simplex. PMID- 21275939 TI - Late-onset inversa recessive dystrophic epidermolysis bullosa caused by glycine substitutions in collagen type VII. AB - Dystrophic epidermolysis bullosa (DEB) is a rare hereditary skin disorder caused by mutations in COL7A1, encoding collagen type VII.1 Clinical manifestations of COL7A1 mutations range from generalized skin blistering to mild localized blistering or nail dystrophy.2 The investigation of the molecular basis of DEB has revealed more than 540 different mutations that cannot entirely explain phenotypic variations (HGMD Professional 2010.3, https://portal.biobase international. com/hgmd/). Inversa recessive DEB (RDEB-I) is a subtype characterized by generalized blistering in the neonatal period. The condition improves with age, and in adults blistering is restricted to intertriginous areas, and severe lesions of the oral and genital mucosa and nail changes occur in the majority of described patients.2 Recent data suggested that amino-acid substitutions affecting arginines or glycines at borders of collagenic subdomains might cause this phenotype.3 We report a German patient with an unusually mild RDEB-I harbouring compound heterozygous mutations in COL7A1. PMID- 21275940 TI - Rhodotorula mucilaginosa infection in Li-Fraumeni-like syndrome: a new pathogen in folliculitis. PMID- 21275941 TI - Effectiveness of antimicrobial photodynamic therapy with a single treatment of RLP068/Cl in an experimental model of Staphylococcus aureus wound infection. AB - BACKGROUND: Chronic leg ulceration is a common health problem. It is well known that a clinically relevant bacterial load in chronic cutaneous wounds interferes significantly with the normal process of healing. Staphylococcus aureus is the most important representative of the staphylococcal group which causes clinically relevant infections within immunocompetent patients. OBJECTIVES: To investigate the efficacy of a single treatment of antimicrobial photodynamic therapy (APDT) with RLP068/Cl in a mouse model of a surgical wound infection induced with a methicillin-resistant strain of S. aureus (MRSA). METHODS: Wounds, established through the panniculus carnosus of BALB/c and CD1 mice, were inoculated with 5 x 10(7) c.f.u. of MRSA. Mice were randomized into four groups respectively receiving no treatment, APDT with placebo, APDT with a new phthalocyanine derivative (RLP068/Cl) and intraperitoneal teicoplanin. RESULTS: On day 2 from infection, a strong reduction of bacterial counts (~ 3 logs) was observed in mice treated with RLP068/Cl in comparison with infected untreated mice. On day 9 from infection, a comparable and significant (~ 2 logs) reduction of bacterial counts was found in mice treated with RLP068/Cl or with teicoplanin. At this time, histological examinations revealed that wounds treated with RLP068/Cl showed a complete re-epithelialization with a continuous epithelial lining. CONCLUSIONS: The results of the in vivo study demonstrated that APDT with RLP068/Cl may be useful in the management of chronic infected wounds, accelerating the repair process through a significant bacterial inhibition. PMID- 21275942 TI - Management of palmoplantar pustulosis: do we need to change? AB - Palmoplantar pustulosis (PPP) is difficult to treat. There is little hard evidence for the efficacy of any treatment and no published guidelines for its management. A number of exacerbating factors are well documented and there is some evidence for the importance of others. Smoking is the most recognized environmental trigger and recent research has concentrated on the role of eccrine sweat glands in this regard. Other factors, including tonsillar streptococcal infection and gluten sensitivity, may be important in selected cases. The aim of this review is to challenge dermatologists to consider alternative management strategies for PPP and design clinical trials that will enable the development of useful therapeutic guidelines. PMID- 21275943 TI - Noncultured extracted hair follicle outer root sheath cell suspension for transplantation in vitiligo. AB - BACKGROUND: Current noncultured cell-based transplantation therapies for vitiligo largely involve shave skin biopsy for preparation of noncultured melanocyte suspension. As the overall proportion of melanocytes is low in the epidermis, these techniques require basal cell layer enrichment, which adds additional steps. We tried follicular unit extraction (FUE) to harvest hair follicles as a source of melanocytes. OBJECTIVES: To evaluate the efficacy of a novel surgical method for vitiligo: noncultured extracted hair follicular outer root sheath (ORS) cell suspension transplantation. METHODS: Fourteen patients with vitiligo, stable for at least 3 months, were included in this prospective study. Fifteen to 25 hair follicles were extracted from occipital scalp using the FUE method. Hair follicles were incubated with trypsin-ethylenediamine tetraacetic acid solution at 37 degrees C for 90 min to separate ORS cells. The cell suspension was filtered through a 70-MUm cell strainer, then centrifuged for 5 min at 1000 r.p.m. to obtain a cell pellet. The pellet was resuspended and applied to the dermabraded recipient area and dressed. RESULTS: The mean +/- SD repigmentation was 65.7 +/- 36.7%. Overall, nine of 14 patients achieved > 75% repigmentation. Mean percentage repigmentation was significantly higher in patients with >= 1 year stability than those with < 1 year stability (P = 0.02). CONCLUSIONS: Extracted hair follicular ORS cell suspension can be a useful simplified transplantation method for vitiligo. The transplantation procedure should be reserved for patients with vitiligo stable for at least 1 year. A larger study is needed for further evaluation. PMID- 21275944 TI - Efficacy of high doses of botulinum toxin A for treating provoked vestibulodynia. AB - BACKGROUND: Provoked vestibulodynia is difficult to treat. The beneficial effects of botulinum toxin A are being considered because of the muscular anomalies observed in this pathology. OBJECTIVE: To evaluate the efficacy of botulinum toxin A in the treatment of provoked vestibulodynia. METHODS: Patients aged between 18 and 60 years presenting with provoked vestibulodynia (according to the 2003 International Society for the Study of Vulvar Disease classification) received 50 U of botulinum toxin A bilaterally in the bulbospongiosus muscle under electromyographic monitoring. Pain was evaluated by a visual analogue scale (VAS), quality of life was evaluated by the Dermatology Life Quality Index and sexual function by the Female Sexual Function Index. RESULTS: Twenty patients received the injections. Sixteen patients presented with a muscular hyperactivity on electromyography. After 3 months, 80% of the patients improved in terms of pain. Mean +/- SD VAS values significantly decreased from 8.37 +/- 1.22 (range 4.5-10) to 2.57 +/- 2.67 (0-9; P < 0.0001) at month 3 and to 3.90 +/- 2.92 (0-9; P < 0.001) at month 6. Quality of life and sexual function improved significantly during the first 6 months (P < 0.0001). After 3 months, 13 patients (out of 18 for whom intercourse was not possible before the injections; 72%) were able to have sexual intercourse. CONCLUSION: Botulinum toxin A seems to be an effective and safe treatment for provoked vestibulodynia; 100 U botulinum toxin A significantly reduced pain 3 and 6 months after injections without side-effects. The treatment also improved quality of life and sexual function of patients. Botulinum toxin A appears to be a promising option for managing sexual pain disorder. PMID- 21275945 TI - A study of the efficacy of carbon dioxide and pigment-specific lasers in the treatment of medium-sized congenital melanocytic naevi. AB - BACKGROUND: Treatment of medium-sized congenital melanocytic naevi (CMN) can be challenging. OBJECTIVES: To present the results of treatment of 55 CMN with the carbon dioxide (CO(2) ) and pigment-specific lasers. METHOD: CO(2) and Q-switched lasers (frequency-doubled Nd:YAG, Nd:YAG and alexandrite) were used to treat 55 CMN. Patients were treated at 3-month intervals until maximum clearance. Clinical response at 3-6 months after final treatment was graded as poor (< 50%), good (50 75%) or excellent (> 75%). Outcomes were evaluated on case note review and questionnaire. RESULTS: Thirty-six of the 55 CMN were macular and 19 were mammillated. Twenty-seven CMN were present on the head and neck. For macular CMN, outcomes were better for truncal CMN. Scarring and pallor were seen in three lower limb macular CMN treated with a CO(2) laser. Mammillated CMN on the head and neck showed most improvement. Pigment-specific lasers were of no additional benefit. Repigmentation occurred in 6% of macular and 21% of mammillated CMN. Partial or complete regimentation of CMN was reported by 46% of patients. CONCLUSIONS: Compared with macular CMN, mammillated CMN show a marginally better response to laser treatment. CMN on the limbs respond poorly. Pigment-specific lasers do not lighten mammillated CMN. Adverse effects can occur with CO(2) laser treatment of macular CMN on lower limbs. PMID- 21275946 TI - Evaluation of platelet transfusion clinical trials. PMID- 21275947 TI - Comparison of intravenous immunoglobulin and high dose anti-D immunoglobulin as initial therapy for childhood immune thrombocytopenic purpura. PMID- 21275948 TI - A retrospective case control study of recombinant factor VIIa in patients with intracranial haemorrhage caused by trauma. PMID- 21275949 TI - Mutations of CD79A, CD79B and EZH2 genes in immunodeficiency-related non-Hodgkin lymphomas. PMID- 21275950 TI - CD20 expression predicts survival in paediatric post-transplant lymphoproliferative disease (PTLD) following solid organ transplantation. AB - The prognostic role of CD20 expression and Epstein-Barr virus (EBV) positivity in post-transplant lymphoproliferative disease (PTLD) after solid organ transplantation (SOT) in paediatric patients is poorly understood. We retrospectively examined the relationship of CD20 and EBV with the time interval from SOT to PTLD diagnosis, and PTLD-related event-free (EFS) and overall survival (OS) in 45 consecutive PTLD patients (<=25 years) following SOT. These 45 paediatric SOT patients (28 heart, 11 liver, six kidney) were diagnosed with PTLD 45 months (mean; SD 43; range 4-153; median 24.5) after SOT, with PTLD diagnosis at 118 months (mean) (SD 77; range 14-287) of age. Of 40 evaluable tumours (11 monomorphic, 19 polymorphic, five early lesions, five rare subtypes), 32 (80%) had detectable EBV and 28 (70%) were classified as CD20(+) . Patients whose PTLD expressed CD20 or EBV had shorter intervals between SOT and PTLD onset (28 vs. 64 or 77 months for CD20 and EBV respectively) (P < 0.02), even after adjusting for age at SOT. Patients with CD20(+) tumours had higher 5-year PTLD related EFS (83.7% vs. 28.6%, P < 0.001) and OS (95.8% vs. 56.3%, P = 0.01). EBV expression was unrelated to PTLD-related EFS or OS. CD20 expression is associated with timing of development of PTLD and predicts survival in PTLD diagnosed following paediatric SOT. PMID- 21275951 TI - Blood transfusion usage among adults with sickle cell disease - a single institution experience over ten years. AB - Transfusion of red blood cells is a major therapeutic option in sickle cell disease (SCD). There is strong evidence for its efficacy, particularly in primary and secondary stroke prevention in children, however, its use in other areas remains controversial. This study assessed the patterns of transfusion in the adult cohort attending King's College Hospital over a 10-year period, from 2000 to 2009. Total blood usage has increased significantly (P = 0.006) during this time, with 78% of the blood received by only 6% of the patients. The increase is explained by increased automated red cell exchange and increased usage for planned and acute transfusions for sickle-related complications. PMID- 21275952 TI - Quantitative and functional analyses of CD4(+) CD25(+) FoxP3(+) regulatory T cells in chronic phase chronic myeloid leukaemia patients at diagnosis and on imatinib mesylate. PMID- 21275953 TI - Vitamin D deficiency and chronic pain in sickle cell disease. PMID- 21275954 TI - Subclones with the t(9;22)/BCR-ABL1 rearrangement occur in AML and seem to cooperate with distinct genetic alterations. AB - In AML, cooperation of mutations suppressing differentiation ('class-II mutations') with 'class-I-mutations' increasing cell proliferation is frequent. In rare cases of myeloid malignancies, the BCR-ABL1 fusion was reported to cooperate as class-I-mutation with class-II-mutations, but most cases had to be classified as blast phase of chronic myeloid leukaemia (CML). We identified five cases of Philadelphia positive subclones in AML occurring in coincidence with other genetic lesions: 1:220 patients with inv(16)/CBFB-MYH11 (0.5%), 2:272 AML cases with t(8;21)/RUNX1-RUNX1T1 (0.7%), 1:1029 NPM1-mutated AML (0.1%), and one patient with s-AML following MDS with a 5q-deletion. Four patients had m-BCR (e1a2) BCR-ABL1 transcripts; one case only had an M-BCR (b3a2) breakpoint. These cases allow some interesting conclusions: The BCR-ABL1 rearrangement apparently can cooperate with the NPM1 mutation similar to other class-I-mutations. The identification of Philadelphia positive subclones in <1% of patients with CBF leukaemias fits well with previous observations that most CBF-AML are accompanied by activating mutations in genes enhancing proliferation. Since we observed the occurrence of the Philadelphia positive subclones at diagnosis, at relapse, or throughout the disease, the time point of the emergence of Philadelphia subclones seems variable in AML. Clinical research should further concentrate on Philadelphia positive subclones in AML to assess the clinical impact. PMID- 21275955 TI - Response to the letter by Nicolas et al, BJH-2010-01422. PMID- 21275956 TI - Gene expression profiling: a possible tool in the prediction of outcome in paediatric acute lymphoblastic leukaemia? PMID- 21275957 TI - Regression of gastroduodenal amyloid deposition in systemic AL amyloidosis after intensive chemotherapies. PMID- 21275958 TI - Compound heterozygosity for two novel mutations in the erythrocyte protein 4.2 gene causing spherocytosis in a Caucasian patient. PMID- 21275959 TI - Thrombin generation in patients with acquired haemophilia and clinical bleeding risk. PMID- 21275960 TI - Re-transplantation after bortezomib-based therapy. PMID- 21275961 TI - The effects of hydroxycarbamide and magnesium on haemoglobin SC disease: results of the multi-centre CHAMPS trial. AB - In a phase-II multi-centre double-blinded trial, we evaluated haematological effects of oral hydroxycarbamide (HC) and magnesium (Mg) in patients with HbSC, aged 5-53 years old. Subjects were randomized to HC + placebo, Mg + placebo, HC + Mg, or placebo + placebo. The primary endpoint was the proportion of hyperdense red blood cells after 8 weeks. Thirty-six subjects were evaluable, but the study was terminated early because of slow enrollment. In the combined HC groups, mean cell volume and HbF were increased, but differences were not seen in hyperdense red cells or vaso-occlusive events. Mg had no effects. Further investigation of hydroxycarbamide as monotherapy in HbSC disease is warranted. PMID- 21275962 TI - Risk of cardiovascular disease in double heterozygous carriers and homozygous carriers of F5 R506Q (factor V Leiden) and F2 (prothrombin) G20210A: a retrospective family cohort study. PMID- 21275963 TI - No association of HLA-A supertype with outcome in childhood acute lymphoblastic leukaemia: results of the UKALL XI trial. PMID- 21275964 TI - High usual dietary vitamin K intake is associated with low relative variability in vitamin K intake: implications for anticoagulant therapy. PMID- 21275965 TI - Higher risk of primary cancers after polycythaemia vera and vice versa. PMID- 21275966 TI - Haemophagocytic lymphohistiocytosis is a recurrent and specific complication of acute erythroid leukaemia. PMID- 21275967 TI - Analysis of the oxygen sensing pathway genes in familial chronic myeloproliferative neoplasms and identification of a novel EGLN1 germ-line mutation. PMID- 21275968 TI - CD200 expression in plasma cell myeloma. PMID- 21275969 TI - TET2 and TP53 mutations are frequently observed in blastic plasmacytoid dendritic cell neoplasm. PMID- 21275970 TI - The autoimmune manifestations associated with myelodysplastic syndrome respond to 5-azacytidine: a report on three cases. PMID- 21275971 TI - ADAMTS13 activity and the risk of thrombotic thrombocytopenic purpura relapse in pregnancy. PMID- 21275972 TI - Is rituximab-induced late-onset neutropenia a good prognostic indicator in lymphoproliferatve disorders? PMID- 21275973 TI - Influence of 6q22-23 on overall survival in primary central nervous system lymphoma. Analysis of North Central Cancer Treatment Group trials 86 72 52, 93 73 51 and 96 73 51. PMID- 21275974 TI - Feasibility and efficacy of administration of bortezomib-containing regimens to patients over the age of 70 years. PMID- 21275975 TI - Reduction in rate of epilepsy from neurocysticercosis by community interventions: the Salama, Honduras study. AB - PURPOSE: Epilepsy is highly prevalent in developing countries like Honduras, with few studies evaluating this finding. This population-based study evaluated the impact of an 8-year public health and educational intervention program in reducing symptomatic epilepsies in rural Salama, Honduras. METHODS: We used the capture and recapture method including review of charts, previous databases, key informants from the community, and a second house-to-house survey for epilepsy. Epilepsy incidence and prevalence day after the interventions was May 5, 2005. Residents with active epilepsy with onset after May 1997 were offered neurologic evaluation, electroencephalography, and brain tomography. New data over 8 years were compared to preintervention data from the initial baseline 1997 study utilizing prevalence ratios and confidence intervals. Other calculations utilized chi square or Fisher's exact tests. KEY FINDINGS: Thirty-three of 36 patients with onset of active epilepsy after 1997 accepted evaluations to determine etiology. Symptomatic etiology was found in 58.3%. Neurocysticercosis (NCC) was again the most frequent cause (13.9%), followed by perinatal insults (11.1%). Epilepsy secondary to NCC was significantly reduced from 36.9% in 1997 (p = 0.02). The incidence (35.7/100,000) and prevalence (11.8/1,000) of active epilepsy were not significantly reduced when compared to the incidence (92.7/100,000) and prevalence (15.4/1,000) of active epilepsy in 1997. SIGNIFICANCE: Our cohort appears to indicate that health and educational community interventions can reduce preventable epilepsy from NCC in a hyperendemic population in a low-resource, developing country. Plans are underway for the Honduran Government to institute this rural model countrywide. PMID- 21275976 TI - The social and economic consequences of epilepsy: a controlled national study. AB - PURPOSE: Epilepsy causes a significant burden to patients and to society. We aimed to calculate the factual excess in direct and indirect costs associated with epilepsy. METHODS: Using records from the Danish National Patient Registry (1998-2006), we identified 64,587 Danish patients with a diagnosis of epilepsy. Using a ratio of one patient record to four control subject records, we identified 258,345 age- and gender-matched randomly chosen citizens from the Danish Civil Registration System Statistics. Direct costs included frequencies and costs of hospitalizations and weighted outpatient use, according to diagnosis related group, and specific outpatient costs based on data from the Danish Ministry of Health. The use and costs of drugs were based on data from the Danish Medicines Agency. The frequencies of visits and hospitalizations and costs from primary sectors were based on data from the National Health Security. Indirect costs included labor supply-based income data, and all social transfer payments obtained from the Coherent Social Statistics. KEY FINDINGS: Patients with epilepsy had significantly higher rates of health-related contacts and medication use and a higher socioeconomic cost, lower employment rates, and income compared with control subjects. These effects were identified up to 8 years before diagnosis, and worsened thereafter. The direct net annual health care and indirect costs were ?14,575 for patients and ?1,163 for controls, giving a consequent excess cost of ?13,412. In addition, patients with epilepsy received an annual mean excess social transfer income of ?4,194. SIGNIFICANCE: Epilepsy has major socioeconomic consequences for the individual patient and for society. PMID- 21275977 TI - Adenosine kinase as a target for therapeutic antisense strategies in epilepsy. AB - PURPOSE: Given the high incidence of refractory epilepsy, novel therapeutic approaches and concepts are urgently needed. To date, viral-mediated delivery and endogenous expression of antisense sequences as a strategy to prevent seizures have received little attention in epilepsy therapy development efforts. Here we validate adenosine kinase (ADK), the astrocyte-based key negative regulator of the brain's endogenous anticonvulsant adenosine, as a potential therapeutic target for antisense-mediated seizure suppression. METHODS: We developed adenoassociated virus 8 (AAV8)-based gene therapy vectors to selectively modulate ADK expression in astrocytes. Cell type selectivity was achieved by expressing an Adk-cDNA in sense or antisense orientation under the control of an astrocyte specific gfaABC1D promoter. Viral vectors where injected into the CA3 of wild type mice or spontaneously epileptic Adk-tg transgenic mice that overexpress ADK in brain. After virus injection, ADK expression was assessed histologically and biochemically. In addition, intracranial electroencephalography (EEG) recordings were obtained. KEY FINDINGS: We demonstrate in wild-type mice that viral overexpression of ADK within astrocytes is sufficient to trigger spontaneous recurrent seizures in the absence of any other epileptogenic event, whereas ADK downregulation via AAV8-mediated RNA interference almost completely abolished spontaneous recurrent seizures in Adk-tg mice. SIGNIFICANCE: Our data demonstrate that modulation of astrocytic ADK expression can trigger or prevent seizures, respectively. This is the first study to use an antisense approach to validate ADK as a rational therapeutic target for the treatment of epilepsy and suggests that gene therapies based on the knock down of ADK might be a feasible approach to control seizures in refractory epilepsy. PMID- 21275978 TI - EEG-fMRI reveals activation of brainstem and thalamus in patients with Lennox Gastaut syndrome. AB - PURPOSE: Even if etiologies of Lennox-Gastaut syndrome (LGS) are diverse, the multiple causes converge into a final common pathway that results in this specific epilepsy phenotype. There is little knowledge, however, about neuronal networks that may be a part of this pathway. METHODS: To investigate these networks, 11 children with LGS and 9 control children with multifocal epileptic activity were investigated using simultaneous recordings of EEG and functional MRI (EEG-fMRI) in a 3 Tesla scanner. KEY FINDINGS: Individual and group analyses revealed significant activation of brainstem and thalamus (especially centromedian and anterior thalamus) associated with epileptiform discharges in patients with LGS. None of the patients with multifocal epileptic activity presented with the same hemodynamic activation pattern. SIGNIFICANCE: Because brainstem activation has been associated with infantile spasms, which often evolve into LGS, and thalamus activation has been observed in patients with primary (idiopathic generalized syndromes) and secondary (focal epilepsies) bilateral synchrony, the described network in LGS may represent the common pathogenetic pathway of these different conditions. PMID- 21275979 TI - Intranasal versus intravenous lorazepam for control of acute seizures in children: a randomized open-label study. AB - PURPOSE: Intravenous lorazepam is considered the drug of first choice for control of acute convulsive seizures. However, resource or personnel constraints necessitate the study of alternative routes and medications. This study compared the efficacy and adverse effects of intranasal versus intravenous lorazepam in children aged 6-14 years who presented with acute seizures. METHODS: This was a randomized open-label study conducted at an Indian hospital from August 2008 to April 2009. One hundred forty-one consecutive children aged 6-14 years who presented convulsing to the emergency room were included. After stabilization, the children were randomized to receive either intravenous or intranasal lorazepam (0.1 mg/kg, maximum 4 mg). The primary outcome measure was clinical seizure remission within 10 min of drug administration. The study was registered with clinicaltrials.gov (NCT00735527). KEY FINDINGS: Seventy patients were randomized to receive intravenous and 71 to receive intranasal lorazepam. The patients in the two groups were comparable at baseline. Clinical seizure remission within 10 min of drug administration was found in 80% of the intravenous group as compared to 83.1% of intranasal group. The lower limit of 95% confidence interval for effect size was approximately -9.7%, with an a priori cutoff for noninferiority of -10%. SIGNIFICANCE: Intranasal administration of lorazepam is not found to be inferior to intravenous administration for termination of acute convulsive seizures in children. PMID- 21275980 TI - Neuroimaging in identifying focal cortical dysplasia and prognostic factors in pediatric and adolescent epilepsy surgery. AB - PURPOSE: The purpose of this study is to determine the sensibility of each imaging tool in identifying focal cortical dysplasia (FCD) in children and adolescents with epilepsy and to define the prognostic factors of pediatric and adolescent epilepsy surgery. METHODS: We identified 48 children with FCD who underwent resective surgery and analyzed their preoperative data. The results of various anatomic and functional neuroimaging studies were compared for accuracy in locating the lesion. We also investigated clinical factors that affected the outcome of surgical treatment. KEY FINDINGS: Brain magnetic resonance imaging (MRI) was able to localize FCD in 30 patients and fluorodeoxyglucose positron emission tomography (FDG-PET) and/or subtraction ictal single photon emission computed tomography (SPECT) coregistered with MRI provided additional information that helped to define the lesion in 13 patients. When comparing the pathologic results between a mild malformation of cortical development (MCD) and FCD type I and II, we noted a strong tendency for patients with FCD to have MRI abnormalities (p = 0.005). In addition, severe pathologic features (Palmini's classification, FCD type II) (p = 0.025) showed significant correlation with a better surgical outcome. To define the primary epileptogenic area, various interictal epileptiform discharges and the results of multimodal neuroimaging studies were helpful, and younger age at the time of operation could aid in more favorable surgical outcomes (p = 0.048). SIGNIFICANCE: Our study showed a significant relationship between pathologic grade and the detectability of FCD by brain MRI. In addition, early surgery can be justified by showing that advanced neuroimaging studies in children with FCD and even with extensive epileptiform discharges have a higher rate of success. PMID- 21275981 TI - Presurgical functional transcranial Doppler sonography (fTCD) with intravenous echo enhancing agent SonoVue enables determination of language lateralization in epilepsy patients with poor temporal bone windows. AB - Presurgical determination of language lateralization is important for planning and outcome estimation of neurosurgical interventions in patients with drug refractory epilepsy. Functional transcranial Doppler sonography (fTCD) provides an established measure for language lateralization using the temporal bone windows for continuous recording of the cerebral blood flow velocity (CBFV) in both middle cerebral arteries (MCAs). However, because of insufficient temporal bone windows, fTCD cannot be applied properly in every patient. Here, we established stable and sufficient CBFV signals in both MCAs using continuous intravenous application of echo-enhancing agent SonoVue in 7 of 10 patients with poor temporal bone windows and were thus able to determine language lateralization. We conclude that the application of SonoVue can solve one principal disadvantage of fTCD and improves the applicability of the technique as a presurgical functional language lateralization procedure. PMID- 21275983 TI - Error control of iterative linear solvers for integrated groundwater models. AB - An open problem that arises when using modern iterative linear solvers, such as the preconditioned conjugate gradient method or Generalized Minimum RESidual (GMRES) method, is how to choose the residual tolerance in the linear solver to be consistent with the tolerance on the solution error. This problem is especially acute for integrated groundwater models, which are implicitly coupled to another model, such as surface water models, and resolve both multiple scales of flow and temporal interaction terms, giving rise to linear systems with variable scaling. This article uses the theory of "forward error bound estimation" to explain the correspondence between the residual error in the preconditioned linear system and the solution error. Using examples of linear systems from models developed by the US Geological Survey and the California State Department of Water Resources, we observe that this error bound guides the choice of a practical measure for controlling the error in linear systems. We implemented a preconditioned GMRES algorithm and benchmarked it against the Successive Over-Relaxation (SOR) method, the most widely known iterative solver for nonsymmetric coefficient matrices. With forward error control, GMRES can easily replace the SOR method in legacy groundwater modeling packages, resulting in the overall simulation speedups as large as 7.74*. This research is expected to broadly impact groundwater modelers through the demonstration of a practical and general approach for setting the residual tolerance in line with the solution error tolerance and presentation of GMRES performance benchmarking results. PMID- 21275984 TI - Tidal boundary conditions in SEAWAT. AB - SEAWAT, a U.S. Geological Survey groundwater flow and transport code, is increasingly used to model the effects of tidal motion on coastal aquifers. Different options are available to simulate tidal boundaries but no guidelines exist nor have comparisons been made to identify the most effective approach. We test seven methods to simulate a sloping beach and a tidal flat. The ocean is represented in one of the three ways: directly using a high hydraulic conductivity (high-K) zone and indirect simulation via specified head boundaries using either the General Head Boundary (GHB) or the new Periodic Boundary Condition (PBC) package. All beach models simulate similar water fluxes across the upland boundary and across the sediment-water interface although the ratio of intertidal to subtidal flow is different at low tide. Simulating a seepage face results in larger intertidal fluxes and influences near-shore heads and salinity. Major differences in flow occur in the tidal flat simulations. Because SEAWAT does not simulate unsaturated flow the water table only rises via flow through the saturated zone. This results in delayed propagation of the rising tidal signal inland. Inundation of the tidal flat is delayed as is flow into the aquifer across the flat. This is severe in the high-K and PBC models but mild in the GHB models. Results indicate that any of the tidal boundary options are fine if the ocean-aquifer interface is steep. However, as the slope of that interface decreases, the high-K and PBC approaches perform poorly and the GHB boundary is preferable. PMID- 21275985 TI - Monitoring regional groundwater extraction: the problem. AB - As hydraulic disturbances (signals) are propagated through a groundwater system two things happen: (1) the higher frequencies in the disturbance are filtered out by the physics of the system and (2) the disturbance takes time to propagate through the system. The filtering and time delays depend on the aquifer diffusivity. This means, for example, if one is observing a water table aquifer at some distance from where annual recharge is occurring, only the long-term average effect of the recharge will be transmitted to the observation point--the system filters out annual variations. These facts have profound impacts on what is feasible to monitor. For example, if one is concerned about the impact of pumping on a spring in a water table aquifer, where the pumping is more than 20 miles or so from the spring, there will be a long delay before the pumping impacts the spring and there will be an equally long delay before a long-term reduction in the pumping regime will restore the spring. The filtering by lower diffusivity groundwater systems makes it impossible to discriminate between the impacts of several major pumpers in the system and/or long-term climate changes. PMID- 21275986 TI - Public attitudes about health information technology, and its relationship to health care quality, costs, and privacy. AB - OBJECTIVE: To understand Americans' attitudes concerning health information technology's (IT's) potential to improve health care and differences in those attitudes based on demographics and technological affinity. DATA SOURCES/STUDY SETTING: A random-digit-dial sample with known probability of selection for every household in the United States with a telephone, plus a supplemental sample of cell phone users. Telephone interviews were conducted from August 2009 through November 2009. STUDY DESIGN: Data were analyzed to present univariate estimates of Americans' opinions of health IT, as well as multivariate logistic regressions to assess hypotheses relating individuals' characteristics to their opinions. Characteristics used in our model include age, race, ethnicity, gender, income, and affinity to technology. FINDINGS: A large majority (78 percent) favor use of electronic medical records (EMRs); believe EMRs could improve care and reduce costs (78 percent and 59 percent, respectively); believe benefits of EMR use outweigh privacy risks (64 percent); and support health care information sharing among providers (72 percent). Regression analyses show more positive attitudes among those with higher incomes and greater comfort using electronic technologies. CONCLUSION: The findings suggest that Americans believe that health IT adoption is an effective means to improve the quality and safety of health care. PMID- 21275987 TI - The association between care experiences and parent ratings of care for different racial, ethnic, and language groups in a Medicaid population. AB - OBJECTIVE: To examine the association between care experiences and parent ratings of care within racial/ethnic/language subgroups. DATA SOURCE: National Consumer Assessment of Healthcare Providers and Systems Benchmarking Database 3.0 (2003 2006). Sample Characteristics. 111,139 parents of minor Medicaid managed care enrollees. STUDY DESIGN: Cross-sectional observational study predicting "poor" (0 5 on 0-10 scale) parent ratings of personal doctor, specialist, health care, and health plan from care experiences for different parent race/ethnicity/language subgroups (Latino/Spanish, Latino/English, white, and black). PRINCIPAL FINDINGS: Care experiences had similar associations with the probability of poor parent ratings of care across the four racial/ethnic/language subgroups (p>.20). A one standard deviation improvement in the doctor communication care experience was associated with about half the frequency of poor ratings of care for personal doctor and health care in all subgroups (p<.05). Sensitivity analysis of individual communication items found that failure to provide explanations to children predicted poor ratings of care only among whites, who also weighed the length of physician interaction more heavily than other subgroups. CONCLUSIONS: Communication-based interventions may improve experiences and ratings of care for all subgroups, although implementation of these interventions may need to consider preferences associated with race, ethnicity, and language. PMID- 21275988 TI - Development and validation of a predictive algorithm to identify adult asthmatics from medical services and pharmacy claims databases. AB - OBJECTIVE: To develop and validate the accuracy of a predictive model to identify adult asthmatics from administrative health care databases. STUDY SETTING: An existing electronic medical record project in Montreal, Quebec. STUDY DESIGN: One thousand four hundred and thirty-one patients with confirmed asthma status were identified from primary care physician's electronic medical record. DATA COLLECTION/EXTRACTION METHODS: Therapeutic indication of asthma in an electronic prescription and/or confirmed asthma from an automated problem list were used as the gold standard. Five groups of asthma-specific markers were identified from administrative health care databases to estimate the probability of the presence of asthma. Cross-validation evaluated the diagnostic ability of each predictive model using 50 percent of sample. PRINCIPAL FINDINGS: The best performance in discriminating between the patients with asthma and those without it included indicators from medical service and prescription claims databases. The best fitting algorithm had a sensitivity of 70 percent, a specificity of 94 percent, and positive predictive value of 65 percent. The prescriptions claims-specific algorithm demonstrated a nearly equal performance to the model with medical services and prescription claims combined. CONCLUSIONS: Our algorithm using asthma-specific markers from administrative claims databases provided moderate sensitivity and high specificity. PMID- 21275989 TI - Comparison of telephone with World Wide Web-based responses by parents and teens to a follow-up survey after injury. AB - OBJECTIVE: To identify sociodemographic factors associated with completing a follow-up survey about health status on the web versus by telephone, and to examine differences in reported health-related quality of life by method of response. DATA SOURCES/STUDY SETTINGS: Survey about child health status of 896 parents of children aged 0-17 years treated in a hospital emergency department or admitted for a traumatic brain injury or arm injury, and 227 injured adolescents aged 14-17 years. STUDY DESIGN: The main outcomes were characteristics of those who completed a follow-up survey on the web versus by telephone and health related quality of life by method of response. PRINCIPAL FINDINGS: Email addresses were provided by 76.9 percent of parents and 56.5 percent of adolescents at baseline. The survey was completed on the web by 64.9 percent of parents and 40.2 percent of adolescents through email. Parents with email access who were Blacks, Hispanics, had lower incomes, and those who were not working were less likely to choose the web mode for completing the survey. Unlike adolescents, the amount of time for parents to complete the survey online was significantly shorter than completion by telephone. Differences by survey mode were small but statistically significant in some of the six functional outcome measures examined. CONCLUSIONS: Survey mode was associated with several sociodemographic characteristics. Sole use of web surveys could provide biased data. PMID- 21275990 TI - Dynamics of neuron-glia interplay upon exposure to unconjugated bilirubin. AB - Microglia are the main players of the brain immune response. They act as active sensors that rapidly respond to injurious insults by shifting into different activated states. Elevated levels of unconjugated bilirubin (UCB) induce cell death, immunostimulation and oxidative stress in both neurons and astrocytes. We recently reported that microglial phagocytic phenotype precedes the release of pro-inflammatory cytokines upon UCB exposure. We investigated whether and how microglia microenvironment influences the response to UCB. Our findings revealed that conditioned media derived from UCB-treated astrocytes reduce microglial inflammatory reaction and cell death, suggesting an attempt to curtail microglial over activation. Conditioned medium from UCB-challenged neurons, although down regulating tumor necrosis factor-alpha and interleukin-1beta promoted the release of interleukin-6 and nitric oxide, the activation of matrix metalloproteinase-9, and cell death, as compared with UCB-direct effects on microglia. Moreover, soluble factors released by UCB-treated neurons intensified the phagocytic properties manifested by microglia under direct exposure to UCB. Results from neuron-microglia mixed cultures incubated with UCB evidenced that sensitized microglia were able to prevent neurite outgrowth impairment and cell death. In conclusion, our data indicate that stressed neurons signal microglial clearance functions, but also overstimulate its inflammatory potential ultimately leading to microglia demise. PMID- 21275991 TI - The ALS8-associated mutant VAPB(P56S) is resistant to proteolysis in neurons. AB - VAMP/synaptobrevin associated proteins A and B (VAPA and VAPB), are type IV membrane proteins enriched on ER and Golgi membranes. Both VAPA and B interact with cytoplasmic lipid transport proteins and cytoskeletal elements to maintain the structure and composition of ER and Golgi membranes. Truncated forms of both proteins are present in some tissues but the functional significance of this is not clear. In rodents processing of VAPA occurs in most tissues, however, truncated forms of VAPB have only been reported in brain tissue. It is demonstrated here that the extent of VAPB processing in rat increases during postnatal development and that it is restricted to neurons. The C-terminal polypeptide generated by this cleavage reaction remains associated with cell membranes, but its subcellular distribution is distinct from the full-length protein. A mutant form of VAPB is associated with a familial form of neurodegenerative disease, amyotrophic lateral sclerosis type 8. The mutant protein, VAPB(P56S) , is resistant to truncation in primary neuronal cultures, although remains sensitive to some form of proteolysis when over-expressed in HEK293 cells. These data suggest that neuronal cells have a particular requirement for VAPB proteolysis and that reduced levels of processed polypeptides may contribute to the neurodegeneration associated with amyotrophic lateral sclerosis type 8. PMID- 21275992 TI - ABA signalling modulates the detection of the LM6 arabinan cell wall epitope at the surface of Arabidopsis thaliana seedling root apices. AB - * The hormonal and physiological regulations underpinning the cell contexts of structural features of the heterogeneous cell wall pectic polysaccharide rhamnogalacturonan-I are far from being understood. * The effect of the modulation of abscisic acid (ABA) concentrations and sensitivity on the detection of the LM6 1,5-arabinan epitope at the surface of Arabidopsis thaliana seedling root apices was assessed by means of fluorescence imaging. * Treatment with 50 nM ABA resulted in an increase in the detection of the LM6 epitope at the root surface in the region of the meristem. An inhibitor of ABA biosynthesis and introduction of the ABA synthesis mutation aba3-2 resulted in reduced epitope detection. The same ABA application resulted in an increase in the number of epidermal root meristem cells and both this and LM6 epitope detection were specifically disrupted in the abi4 ABA-insensitive mutant. These two effects were uncoupled with the application of higher ABA concentrations, which resulted in a reduction in the number of epidermal root meristem cells but increased LM6 epitope detection. * This work demonstrates a role for ABI4-mediated ABA signalling in the modulation of pectic arabinan occurrence at the A. thaliana root meristem. PMID- 21275993 TI - Extensive metabolic cross-talk in melon fruit revealed by spatial and developmental combinatorial metabolomics. AB - * Variations in tissue development and spatial composition have a major impact on the nutritional and organoleptic qualities of ripe fleshy fruit, including melon (Cucumis melo). To gain a deeper insight into the mechanisms involved in these changes, we identified key metabolites for rational food quality design. * The metabolome, volatiles and mineral elements were profiled employing an unprecedented range of complementary analytical technologies. Fruits were followed at a number of time points during the final ripening process and tissues were collected across the fruit flesh from rind to seed cavity. Approximately 2000 metabolite signatures and 15 mineral elements were determined in an assessment of temporal and spatial melon fruit development. * This study design enabled the identification of: coregulated hubs (including aspartic acid, 2 isopropylmalic acid, beta-carotene, phytoene and dihydropseudoionone) in metabolic association networks; global patterns of coordinated compositional changes; and links of primary and secondary metabolism to key mineral and volatile fruit complements. * The results reveal the extent of metabolic interactions relevant to ripe fruit quality and thus have enabled the identification of essential candidate metabolites for the high-throughput screening of melon breeding populations for targeted breeding programmes aimed at nutrition and flavour improvement. PMID- 21275994 TI - Using log-log scaling slope analysis for determining the contributions to variability in biological variables such as leaf mass per area: why it works, when it works and how it can be extended. PMID- 21275995 TI - Arabidopsis VILLIN4 is involved in root hair growth through regulating actin organization in a Ca2+-dependent manner. AB - * Villin is one of the major actin filament bundling proteins in plants. The function of Arabidopsis VILLINs (AtVLNs) is still poorly understood in living cells. In this report, the biochemical activity and cellular function of AtVLN4 were examined. * The biochemical property of AtVLN4 was characterized by co sedimentation assays, fluorescence microscopy and spectroscopy of pyrene fluorescence. The in vivo function of AtVLN4 was analysed by ectopically expressing it in tobacco pollen and examining the phenotypes of its T-DNA insertional plants. * Recombinant AtVLN4 protein exhibited multiple activities on actin, including actin filament bundling, calcium (Ca(2+))-dependent filament severing and barbed end capping. Expression of AtVLN4 in tobacco pollen induced the formation of supernumerary actin cables and reduced pollen tube growth. Loss of function of AtVLN4 resulted in slowing of root hair growth, alteration in cytoplasmic streaming routes and rate, and reduction of both axial and apical actin bundles. * Our results demonstrated that AtVLN4 is involved in root hair growth through regulating actin organization in a Ca(2+)-dependent manner. PMID- 21275996 TI - Effects of UV-B on secondary metabolites of St. John's Wort (Hypericum perforatum L.) grown in controlled environments. AB - The medicinal plant industry is under increasing scrutiny due to wide variance in active ingredient (AI) concentration from values claimed on labels. Reasons for this disparity include environmental and genotypic variation which influence AI concentration. St. John's wort (Hypericum perforatum) is a popular herbal remedy which also exhibits marked variance in AI concentration among products. This study evaluated concentration changes of three biologically active metabolites of H. perforatum after exposure to UV light while plants were still vegetative. Treatments were performed with 55-day-old plants grown under 400 MUmol m(-2) s( 1) PAR for 16 h a day. Three UV light treatments were evaluated: a single dose, a daily dose and an increasing daily dose. Concentrations of hyperforin, pseudohypericin and hypericin were monitored for 7 days after each treatment. A daily dose and an increasing daily dose did not produce significantly greater increases in secondary metabolites compared to single dose treatments. These results suggest the small but significant transient metabolite concentration increases in H. perforatum can be induced by UV light exposure. Information from this study can be useful in optimizing total biomass and metabolite production in controlled environments. PMID- 21275997 TI - Effects of supplemental UV-A on the development, anatomy and metabolite production of Phyllanthus tenellus cultured in vitro. AB - Phyllanthus tenellus is widely used for its antiviral, analgesic and hepatoprotective properties. Although the production of several chemical classes of secondary metabolites is influenced by UV radiation, particularly phenolic compounds, we also know that UV radiation can result in anatomical and developmental damage. However, the morphological, anatomical and phytochemical changes in response to UV-A exposure are generally understudied in the Phyllanthaceae. Therefore, we evaluated the effects of UV-A radiation on plant development and leaf anatomy, as well as the production of secondary metabolites and the contents of carotenoids and chlorophylls a and b, in P. tenellus. To accomplish this, in vitro cultures of P. tenellus were maintained for 60 days under white light (WL) and WL plus UV-A radiation. Results showed different phenotypic responses under additional UV-A, such as high phenolic metabolite production, increasing dimensions of abaxial epidermis and thickness of palisade parenchyma. Compared to plants cultured under WL, UV-A radiation caused damage to plant morphogenesis, including a reduced number of branches and shoots, consequently reducing the rate of proliferation. On the other hand, geraniin, ellagic acid and carotenoid contents increased after UV-A exposure, indicating that this light source is an important resource for inducing phenolic compounds. PMID- 21275998 TI - In vivo viability of stored red blood cells derived from riboflavin plus ultraviolet light-treated whole blood. AB - BACKGROUND: A novel system using ultraviolet (UV) light and riboflavin (Mirasol System, CaridianBCT Biotechnologies) to fragment nucleic acids has been developed to treat whole blood (WB), aiming at the reduction of potential pathogen load and white blood cell inactivation. We evaluated stored red blood cell (RBC) metabolic status and viability, in vitro and in vivo, of riboflavin/UV light-treated WB (IMPROVE study). STUDY DESIGN AND METHODS: The study compared recovery and survival of RBCs obtained from nonleukoreduced WB treated using three different UV light energies (22, 33, or 44 J/mL(RBC)). After treatment, WB from 12 subjects was separated into components and tested at the beginning and end of component storage. After 42 days of storage, an aliquot of RBCs was radiolabeled and autologously reinfused into subjects for analysis of 24-hour recovery and survival of RBCs. RESULTS: Eleven subjects completed the in vivo study. No device related adverse events were observed. By Day 42 of storage, a significant change in the concentrations of sodium and potassium was observed. Five subjects had a 24-hour RBC recovery of 75% or more with no significant differences among the energy groups. RBC t(1/2) was 24 +/- 9 days for the combined three groups. Significant correlations between 24-hour RBC recovery and survival, hemolysis, adenosine triphosphate (ATP), and CO(2) levels were observed. CONCLUSIONS: This study shows that key RBC quality variables, hemolysis, and ATP concentration may be predictive of their 24-hour recovery and t(1/2) survival. These variables will now be used to assess modifications to the system including storage duration, storage temperature, and appropriate energy dose for treatment. PMID- 21275999 TI - The influence of maintaining the correct whole blood-to-anticoagulant ratio during donation on the quality of leukoreduced whole blood. AB - BACKGROUND: It is unclear whether maintaining the correct whole blood-to anticoagulant (WB : AC) ratio during collection can improve the quality of red blood cell (RBC)-containing blood products to a clinically relevant degree. STUDY DESIGN AND METHODS: A total of 2 * 20 CPDA-1 leukoreduced whole blood (WB) units suspended in CPDA-1 were investigated. In one group, AC was continuously added to the donated blood, maintaining the correct WB : AC ratio during collection, using a new drawing device (MacoPharma ABC). In the other group, WB units were produced conventionally. Adenosine triphosphate (ATP), 2,3-diphosphoglycerate, free hemoglobin (Hb), potassium, glucose, lactate, pH, and variables of coagulation were determined on Days 1, 7, 21, 35, 42, and 49 of storage. Variables of RBC deformability and aggregability were determined using a laser-assisted optical rotational cell analyzer. RESULTS: The ABC and conventional group showed comparable unit volumes of 525 (SD, 5.3) mL versus 524 (SD, 10.2) mL and Hb content of 65.9 (SD, 5.1) g/unit versus 67.5 (SD, 7.8) g/unit, but higher variation after conventional blood drawing (p = 0.006 and p = 0.07, respectively) was observed. During storage, none of the measured quality variables were significantly different between the groups. Mean (SD) ATP was 2.33 (0.41) umol/g Hb versus 2.24 (0.39) umol/g Hb after 42-day storage. Deformability was not different (p = 0.44), whereas the extent of the aggregability was higher in the conventional group (p = 0.04). CONCLUSION: The ABC device provided a better standardized blood product but did not improve RBC storage variables or plasma quality. It slightly reduced RBC aggregability during storage. Excess AC at the beginning of a donation appears not to significantly affect RBC storage in conventional blood drawing. PMID- 21276000 TI - Evaluation of algorithms for the diagnostic assessment and the reentry of blood donors who tested reactive for antibodies against hepatitis B core antigen. AB - BACKGROUND: Screening of blood donations for antibodies against hepatitis B core antigen (anti-HBc) is an accepted method to prevent some transfusion-transmitted hepatitis B virus (HBV) infections. However, anti-HBc testing may result in donor loss due to unspecific results in the currently available anti-HBc tests. Algorithms to distinguish true-positive from false-positive results and for reentry of those donors who tested false anti-HBc positive were evaluated retrospectively. STUDY DESIGN AND METHODS: Samples that tested reactive for anti HBc by chemiluminescent microparticle immunoassay (CMIA) were investigated for anti-HBc by microparticle immunoassay, for anti-HBs and hepatitis B surface antigen (HBsAg) by CMIA, and for HBV DNA by individual-donor nucleic acid testing. Results were classified true positive, indeterminate, and false positive for anti-HBc. Donors who tested indeterminate and false positive were admitted for reentry if follow-up testing for anti-HBc became negative and no further evidence for an HBV infection was apparent. RESULTS: A total of 554 of 148,000 samples, taken from 30,000 individuals within 3 years tested reactive for anti HBc by CMIA. Of those, 553 could be further classified: 142 (26%) true positive, 76 (14%) indeterminate, and 335 (60%) false positive. A total of 214 of 411 (52%) samples termed indeterminate or false positive were admitted for reentry and able to provide further donations. In one donor, anti-HBc-positive/HBsAg- and HBV DNA negative HBV DNA was detectable during follow-up. CONCLUSION: According to our proposed algorithm, 26% of anti-HBc-reactive results tested by CMIA were true positive. Many donors tested indeterminate or false positive can provide future donations if our proposed algorithm for reentry is applied. One donor at risk for transmitting HBV was identified solely by anti-HBc testing. PMID- 21276001 TI - Peroxiredoxin-2 as a candidate biomarker to test oxidative stress levels of stored red blood cells under blood bank conditions. AB - BACKGROUND: Several researches on aging red blood cells (RBCs)--performed both in vivo and under blood bank conditions--revealed that RBC membrane proteins undergo a number of irreversible alterations, mainly due to oxidative stress. The individuation of proteins to be used as indicators of irreversible RBC injury and to be proposed as candidate biomarkers of oxidative damage or aging status during blood storage is therefore of great interest. STUDY DESIGN AND METHODS: Based on this purpose we performed proteomic analysis of the membranes of RBCs during various storage periods under blood bank conditions. Changes in protein composition of RBC membranes were monitored as a function of the storage period by means of polyacrylamide gel electrophoresis coupled with immunoblotting and mass spectrometry analyses. RESULTS: During storage, a progressive linkage of typical cytosolic proteins to the membrane was detected, including both antioxidant and metabolic enzymes (such as catalase, peroxiredoxin-2 [Prx2], and 2,3-bisphosphoglycerate-mutase), as well as nonreducible cross-linkings of probably oxidized or denatured hemoglobin. This phenomenon was unequivocally related to oxidative stress, since storage of RBCs under anaerobic conditions showed a suppression of these protein recruitments to the membrane. CONCLUSION: The detailed analysis of these protein associations to the membrane of aged RBCs allowed Prx2 to be suggested as a potential RBC oxidative stress marker for the sake of developing new approaches in quality assurance of blood components. PMID- 21276003 TI - The year in immunology. Preface. PMID- 21276002 TI - Adipokines as novel biomarkers and regulators of the metabolic syndrome. AB - Over the past two decades our view of adipose tissue has undergone a dramatic change from an inert energy storage tissue to an active endocrine organ. Adipose tissue communicates with other central and peripheral organs by synthesis and secretion of a host of molecules that we generally refer to as adipokines. The levels of some adipokines correlate with specific metabolic states and have the potential to impact directly upon the metabolic homeostasis of the system. A dysregulation of adipokines has been implicated in obesity, type 2 diabetes, hypertension, cardiovascular disease, and an ever-growing larger list of pathological changes in a number of organs. Here, we review the recent progress regarding the synthesis, secretion, and physiological function of adipokines with perspectives on future directions and potential therapeutic goals. PMID- 21276004 TI - The role of STAT5 in the development, function, and transformation of B and T lymphocytes. AB - The transcription factor signal transducer and activator of transcription 5 (STAT5) is activated by a number of cytokine and growth hormone receptors and plays a key role in the development and function of many organ systems. In this review, we focus on recent discoveries about the role of STAT5 in the development and function of B and T lymphocytes. Of particular interest is the growing appreciation for the function of STAT5 as a transcriptional repressor. Finally, we discuss recent discoveries about the role of STAT5 in transformation of B and T lymphocytes. PMID- 21276005 TI - The role of the PD-1 pathway in autoimmunity and peripheral tolerance. AB - Programmed death-1 (PD-1) is a surface receptor critical for the regulation of T cell function during immunity and tolerance. PD-1 interactions with its ligands PD-L1 and PD-L2 inhibit T cell effector functions in an antigen-specific manner. This paper examines the role of PD-1 in limiting autoreactivity and establishing self-tolerance and discusses the hypothesis that PD-1 ligand (PD-L) expression both spatially and temporally dictates the fate of self-reactive T cells during the breakdown of peripheral tolerance and development of autoimmunity. We focus our discussion on the role of PD-1/PD-L interactions during peripheral tolerance, the differential role for PD-L1 and PD-L2 in response to environmental or self antigens, and the impact of PD-1 signaling on dynamic T cell motility and the T cell receptor (TCR) stop signal. Finally, we discuss the potential to selectively target the PD-1 pathway therapeutically to alter T cell function during autoimmunity. PMID- 21276006 TI - New insights into basophil biology: initiators, regulators, and effectors of type 2 inflammation. AB - Recent studies indicate that basophils perform essential functions in multiple models of Th2 cytokine-dependent immunity and inflammation. In addition to their role as late phase effector cells, basophil populations can express MHC class II and costimulatory molecules, migrate into draining lymph nodes, present antigen to naive CD4(+) T cells, and promote Th2 cell differentiation. In this context, basophils have been shown to contribute to the induction and propagation of Th2 cytokine responses following exposure to some helminth parasites or allergens. In this review, we discuss recent studies that provide new insights into basophil development, regulation, and effector function. In addition, we discuss the ability of basophils to act both independently and cooperatively with dendritic cells to support Th2 cytokine-mediated inflammation. PMID- 21276009 TI - Complexation of Hg with phytochelatins is important for plant Hg tolerance. AB - Three-week-old alfalfa (Medicago sativa), barley (Hordeum vulgare) and maize (Zea mays) were exposed for 7 d to 30 um of mercury (HgCl(2) ) to characterize the Hg speciation in root, with no symptoms of being poisoned. The largest pool (99%) was associated with the particulate fraction, whereas the soluble fraction (SF) accounted for a minor proportion (<1%). Liquid chromatography coupled with electro-spray/time of flight mass spectrometry showed that Hg was bound to an array of phytochelatins (PCs) in root SF, which was particularly varied in alfalfa (eight ligands and five stoichiometries), a species that also accumulated homophytochelatins. Spatial localization of Hg in alfalfa roots by microprobe synchrotron X-ray fluorescence spectroscopy showed that most of the Hg co localized with sulphur in the vascular cylinder. Extended X-ray Absorption Fine Structure (EXAFS) fingerprint fitting revealed that Hg was bound in vivo to organic-S compounds, i.e. biomolecules containing cysteine. Albeit a minor proportion of total Hg, Hg-PCs complexes in the SF might be important for tolerance to Hg, as was found with Arabidopsis thaliana mutants cad2-1 (with low glutathione content) and cad1-3 (unable to synthesize PCs) in comparison with wild type plants. Interestingly, high-performance liquid chromatography electrospray ionization-time of flight analysis showed that none of these mutants accumulated Hg-biothiol complexes. PMID- 21276008 TI - PARP-1 deficiency blocks IL-5 expression through calpain-dependent degradation of STAT-6 in a murine asthma model. AB - BACKGROUND: We recently showed that poly(ADP-ribose)polymerase-1 (PARP-1) may play a role in allergen (ovalbumin)-induced airway eosinophilia, potentially through a specific effect on IL-5 production. We also reported that while IL-5 replenishment promotes reversal of eosinophilia in lungs of PARP-1(-/-) mice, IL 4 or Immunoglobulin E replenishment do not, suggesting a potentially significant regulatory relationship between PARP-1 and IL-5. OBJECTIVE: To explore the mechanism by which PARP-1 regulates IL-5 production and to determine how PARP-1 inhibition blocks allergen-induced eosinophilia. METHODS: This study was conducted using a murine model of allergic airway inflammation and primary splenocytes. RESULTS: PARP-1 knockout-associated reduction in IL-5 upon allergen exposure occurs at the mRNA level. Such an effect appears to take place after IL 4 receptor activation as PARP-1 inhibition exerted no effect on JAK1/JAK3 activation. Signal transducer and activator of transcription-6 (STAT-6) protein was severely downregulated in spleens of PARP-1(-/-) mice without any effect on mRNA levels, suggesting an effect on protein integrity rather than gene transcription. Interestingly, the degradation of STAT-6 in PARP-1(-/-) mice required allergen stimulation. Additionally, PARP-1 enzymatic activity appears to be required for STAT-6 integrity. The downregulation of STAT-6 coincided with mRNA and protein reduction of GATA-binding protein-3 and occupancy of its binding site on the IL-5 gene promoter. IL-4 was sufficient to induce STAT-6 downregulation in both PARP-1(-/-) mice and isolated splenocytes. Such degradation may be mediated by calpain, but not by proteasomes. CONCLUSION: These results demonstrate a novel function of PARP-1 in regulating IL-5 expression during allergen-induced inflammation and explain the underlying mechanism by which PARP-1 inhibition results in IL-5 reduction. PMID- 21276007 TI - Role of TLR2-dependent inflammation in metastatic progression. AB - Inflammation is a part of the host defense system, which provides protection against invading pathogens. However, it has become increasingly clear that inflammation can be evoked by endogenous mediators through Toll-like receptors (TLRs) to enhance tumor progression and metastasis. Here, we discuss the roles of TLR-mediated inflammation in tumor progression and the mechanisms through which it accomplishes this pathogenic function. PMID- 21276010 TI - delta(13) C of leaf-respired CO(2) reflects intrinsic water-use efficiency in barley. AB - Leaf intrinsic water-use efficiency (WUE), the ratio of photosynthetic rate to stomatal conductance (A/g(s) ), is a key plant trait linking terrestrial carbon and water cycles. A rapid, integrative proxy for A/g(s) is of benefit to crop breeding programmes aiming to improve WUE, but also for ecologists interested in plant carbon-water balance in natural systems. We hypothesize that the carbon isotope composition of leaf-respired CO(2) (delta(13) C(Rl) ), two hours after leaves are transferred to the dark, records photosynthetic carbon isotope discrimination and so provides a proxy for A/g(s) . To test this hypothesis, delta(13) C(Rl) was measured in four barley cultivars grown in the field at two levels of water availability and compared to leaf-level gas exchange (the ratio of leaf intercellular to ambient CO(2) partial pressure, C(i) /C(a) , and A/g(s) ). Leaf-respired CO(2) was more (13) C-depleted in plants grown at higher water availability, varied between days as environmental conditions changed, and was significantly different between cultivars. A strong relationship between delta(13) C(Rl) and delta(13) C of sucrose was observed. delta(13) C(Rl) was converted into apparent photosynthetic discrimination (Delta(13) C(Rl) ) revealing strong relationships between Delta(13) C(Rl) and C(i) /C(a) and A/g(s) during the vegetative stage of growth. We therefore conclude that delta(13) C(Rl) may provide a rapid, integrative proxy for A/g(s) in barley. PMID- 21276011 TI - Temporal matching among diurnal photosynthetic patterns within the crown of the evergreen sclerophyll Olea europaea L. AB - Trees are modular organisms that adjust their within-crown morphology and physiology in response to within-crown light gradients. However, whether within plant variation represents a strategy for optimizing light absorption has not been formally tested. We investigated the arrangement of the photosynthetic surface throughout one day and its effects on the photosynthetic process, at the most exposed and most sheltered crown layers of a wild olive tree (Olea europaea L.). Similar measurements were made for cuttings taken from this individual and grown in a greenhouse at contrasted irradiance-levels (100 and 20% full sunlight). Diurnal variations in light interception, carbon fixation and carbohydrate accumulation in sun leaves were negatively correlated with those in shade leaves under field conditions when light intensity was not limiting. Despite genetic identity, these complementary patterns were not found in plants grown in the greenhouse. The temporal disparity among crown positions derived from specialization of the photosynthetic behaviour at different functional and spatial scales: architectural structure (crown level) and carbon budget (leaf level). Our results suggest that the profitability of producing a new module may not only respond to construction costs or light availability, but also rely on its spatio-temporal integration within the productive processes at the whole crown level. PMID- 21276012 TI - Ultra-small TiO(2) nanoparticles disrupt microtubular networks in Arabidopsis thaliana. AB - In spite of the mounting concerns, current understanding of the extent and mechanisms of phytotoxicity of manufactured nanomaterials remains limited. Here we show that in Arabidopsis thaliana, ultra-small anatase TiO(2) nanoparticles cause reorganization and elimination of microtubules followed by the accelerated and 26S proteasome-dependent degradation of tubulin monomers. Similar to other microtubule-disrupting agents, TiO(2) nanoparticles induce isotropic growth of root cells. Because microtubules are essential for the normal function of all eukaryotic cells, these results reveal a potentially important consequence of environmental pollution by this widely used nanomaterial. PMID- 21276013 TI - Changes to the proteome and targeted metabolites of xylem sap in Brassica oleracea in response to salt stress. AB - Root-to-shoot signalling via xylem sap is an important mechanism by which plants respond to stress. This signalling could be mediated by alteration in the concentrations of inorganic and/or organic molecules. The effect of salt stress on the contents of xylem sap in Brassica olarecea has been analysed by mass spectrometry in order to quantify these changes. Subcellular location of arabinogalactan proteins (AGPs) by immunogold labelling and peroxidase isozymes was also analysed by isoelectrofocusing. The xylem sap metabolome analysis demonstrated the presence of many organic compounds such as sugars, organic acids and amino acids. Of these, amino acid concentrations, particularly that of glutamine, the major amino acid in the sap, were substantially reduced by salt stress. The xylem sap proteome analysis demonstrated the accumulation of enzymes involved in xylem differentiation and lignification, such as cystein proteinases, acid peroxidases, and a putative hydroxycinnamoyl-CoA:shikimate hydroxycinnamoyl transferase under salt stress. The peroxidase isozyme pattern showed that salt stress induced a high accumulation of an acid isoform. These results suggest that xylem differentiation and lignification is induced by salt stress. The combination of different methods to analyse the xylem sap composition provides new insights into mechanisms in plant development and signalling under salt stress. PMID- 21276014 TI - Shaping ability and cleaning effectiveness of Mtwo versus coated and uncoated EasyShape instruments in severely curved root canals of extracted teeth. AB - AIM: To compare the cleaning effectiveness and shaping ability of Mtwo, PVD coated and uncoated EasyShape nickel-titanium rotary instruments during the preparation of curved root canals in extracted human teeth. METHODOLOGY: A total of 60 root canals of mandibular and maxillary molars with curvatures ranging between 25 degrees and 35 degrees were divided into three groups of 20 canals. Based on radiographs taken prior to instrumentation with the initial instrument inserted into the canal, the groups were balanced with respect to the angle and the radius of canal curvature. Canals were prepared using a low-torque control motor according the single-length technique. Using pre- and post-instrumentation radiographs, straightening of the canal curvatures was determined with a computer image analysis program. Preparation time, changes of working length and instrument failures were also recorded. These data were analysed statistically using ANOVA and Student-Newman-Keuls test. The amounts of debris and smear layer were quantified on the basis of a numerical evaluation scale. The data established for scoring the debris and the smear layer were recorded separately and analysed statistically using the Kruskal-Wallis test. RESULTS: During preparation, one coated and two uncoated EasyShape files fractured. Completely clean root canals were never observed. All instruments maintained the original canal curvature well with no significant differences between the different instruments (P > 0.05). Instrumentation with Mtwo files was significantly faster than with the two other instruments (P < 0.05). For debris removal Mtwo instruments achieved significantly better results (P < 0.001) than the two EasyShape instruments. The use of coated EasyShape files resulted in significantly less debris compared to instrumentation with uncoated EasyShape instruments (P < 0.05). The results for remaining smear layer were similar and not significantly different for the coronal, middle and apical third of the canals (P > 0.05) but in summary significantly less smear layer was observed following instrumentation with Mtwo (P < 0.01). CONCLUSIONS: Under the conditions of this study, all instruments maintained the original canal curvature well. The use of Mtwo instruments resulted in good canal cleanliness. PVD-coating of EasyShape instruments had no impact on their shaping ability but improved their cleaning effectiveness. PMID- 21276015 TI - The effect of the elastic modulus of endodontic posts on static load failure. AB - AIM: To compare posts of different flexibility using static load testing. Hypotheses tested were (1) the flexural modulus of endodontic posts does not show a linear relationship with failure load and (2) the flexural modulus of endodontic posts does not show an association with failure mode. METHODOLOGY: Thirty 2 mm diameter rods of a glass fibre material Aesthetiplus (A), a carbon fibre Composipost (C) and stainless steel (S) were cemented into 90 roots of extracted human teeth using resin cement. Composite resin cores were added and the roots embedded in self-curing acrylic resin. Samples were loaded at 90 degrees in a universal testing machine until failure. Failure loads and fracture levels were compared using one-way anova and post-hoc Scheffe tests. Proportions of different failure modes were compared with Chi square tests (alpha = 0.05). RESULTS: Mean failure loads - MPa (SD) were A - 278.69 (85.79), C - 258.86 (82.05), S - 347.37 (74.50). There was no significant difference in the mean failure load of roots containing the FRC posts (P = 0.639), but it was significantly greater for steel post samples (P < 0.01). The mean level of fracture among the groups was not significantly different (P = 0.879). No root fractures were 'favourable'. Significantly more root fractures and fewer core fractures occurred for group A than for groups C or S (P < 0.01). CONCLUSION: The elastic modulus of an endodontic post does not appear to be a principal factor influencing load at failure or mode of failure of post-restored teeth. PMID- 21276016 TI - Bacterial leakage in root canals filled with conventional and MTA-based sealers. AB - AIM: To evaluate bacterial leakage after filling root canals with several endodontic sealers, including MTA-based materials. METHODOLOGY: One hundred and thirty single-rooted extracted human teeth were randomly divided into experimental groups (n = 15) and two control groups (n = 5). Six root canal sealers were namely: AH Plus (AHP), Sealer 26 (S26), Epiphany SE (ESE), Sealapex (SEL), Active GP (AGP), Endofill (EDF), and two MTA-based sealers were namely: Endo CPM Sealer (CPM) and MTA-based sealer (MTAS, MTA Sealer). Teeth in the control groups were either filled with no sealer or made completely impermeable. Root canals were prepared and filled with either gutta-percha and one of the sealers or with Resilon and Epiphany SE. Teeth were sterilized by ethylene oxide prior to the bacterial leakage experiments using Enterococcus faecalis. Leakage was evaluated every 24 h for 16 weeks. Data were analysed by the Kaplan-Meier, Kruskal-Wallis and Dunn tests at 5% significance. RESULTS: Control groups had either immediate leakage or no leakage. During 120 days, significantly more leaking samples were detected for AGP, CPM and MTAS (P < 0.05). The best sealing ability was observed for AH Plus and Sealapex (P < 0.05). CONCLUSIONS: All sealers evaluated allowed bacterial leakage. The MTA-based sealers had the most leakage. PMID- 21276017 TI - Temporal expression pattern of sodium channel Nav 1.8 messenger RNA in pulpitis. AB - AIM: To determine mRNA expression levels of Nav 1.8 in inflamed pulps of rats. METHODOLOGY: Inflammation was induced by creating pulp exposures in rat incisors. Histopathological changes in the induced pulpitis were evaluated 1, 3, 7 and 10 days after exposure. Using real-time PCR, the relative mRNA expression levels of Nav 1.8 in the inflamed rat dental pulp was determined. RESULTS: At day 1, no inflammation was evident in the pulp tissue, whereas increased levels of inflammatory responses were identified at day 3 and day 7. No pulpal inflammation was evident in day 10 or in the control group. Nav 1.8 was expressed in the rat dental pulp and increased at day 3 and day 7. Time course study of dental pulp inflammation indicated that differences in relative mRNA expression levels of Nav 1.8 were correlated with the severity of inflammation. CONCLUSIONS: Nav 1.8 channels seem to be expressed significantly more under a temporal control so as to be associated with a severity of inflammation during pulpitis. As Nav 1.8 has been considered to have a role in neuropathic pain, its expression within dental pulp may contribute to the pathophysiology of tooth pain. PMID- 21276018 TI - Efficacy of several techniques for the removal of calcium hydroxide medicament from root canals. AB - AIM: To compare the efficacy of several techniques for the removal of calcium hydroxide (Ca(OH)(2)) from root canals. METHODOLOGY: The root canals of 24 freshly extracted human mandibular premolars were prepared with ProTaper rotary instruments. The teeth were sectioned longitudinally along the length of the instrumented canals. The roots were subsequently reassembled with wires. After Ca(OH)(2) was placed into the canals, four techniques were used for its removal. In Group I, the teeth were irrigated with 5 mL of 2.5% NaOCl. Group II was treated in the same manner as Group I, but 5 mL of 17% EDTA was used in addition to NaOCl. In Group III, the teeth were irrigated with 5 mL of 2.5% NaOCl and agitated by an ultrasonic unit. In Group IV, the teeth were irrigated with 5 mL of 2.5% NaOCl and a CanalBrush was used to remove the Ca(OH)(2) . The roots were disassembled and digital photographs were taken. Measurements of residual Ca(OH)(2) were performed as percentages of the overall canal surface area. The data was analysed with one-way ANOVA with post hoc Tukey test. RESULTS: Significantly less residual material was obtained with a CanalBrush and passive ultrasonic agitation of NaOCl than the other groups (P < 0.05). There was no significant difference between syringe delivery of NaOCl and NaOCl+EDTA (P > 0.05). CONCLUSIONS: None of the techniques removed the Ca(OH)(2) dressing completely. CanalBrush and ultrasonic agitation of NaOCl were significantly more effective than irrigant-only techniques. PMID- 21276019 TI - Three-point bending testing of fibre posts: critical analysis by finite element analysis. AB - AIM: To evaluate the effect of taper, specimen supports and the isotropic and orthotropic properties of the posts on flexure and stress response during three point bending using finite element analysis. METHODOLOGY: A three-dimensional finite element model of a fibre post was created. The occlusal portion was cylindrical whilst the apical portion was tapered. Five different support positions were evaluated during a simulated three-point bending test: M1 - support distance of 10 mm centralized and no tilt; M2 - 10 mm centralized with tilt; M3 - 10 mm not centralized and no tilt; M4 - 10 mm not centralized with tilt; M5 - 6 mm not centralized with no tilt. A sixth post model (M6) was a centralized post without tapered section. The applied properties were elastic and orthotropic. RESULTS: Tilting the tapered posts to level them in the test setup had little effect on the outcome. Flexure increased when 50% of the bent portion involved taper (M1, M2). If only 20% of the bent post involved taper (M3, M4), the flexure values were close to M6 (no taper). The orthotropic properties also caused increased flexure compared to an isotropic post. Maximum stresses were only a little higher when 50% of the bend structure involved taper, whilst the orthotropic properties had little effect. CONCLUSIONS: Regardless of levelling, the flexural stress determination with tapered fibre posts in the three-point bending test was valid as long as the tapered portion was limited in length. PMID- 21276020 TI - Influence of cusp coverage on the fracture resistance of premolars with endodontic access cavities. AB - AIM: To assess the influence of cusp reduction and coverage with composite resin on the fracture resistance of premolars with prepared access cavities. METHODOLOGY: Endodontic access cavities were prepared in 60 premolar teeth that were divided into four test groups: R1, R2, R3 and NR (n=15). In all test groups, MOD cavities were prepared and extended towards one of the cusps. The remaining cusp-wall thickness was: 1-1.5 mm in R1, 1.5-2 mm in R2 and 2-3 mm in both R3 and NR groups. In addition, in group R1, R2 and R3 the same cusp was reduced in height to 3.5 mm. Cuspal coverage and MOD restorations were performed using composite resin. Ten intact premolars served as positive controls and another ten MOD-prepared unrestored premolars as negative controls. Teeth were submitted to cyclic fatigue of 1.2 million cycles. A compressive load was applied 30 degrees to the long axis of the teeth until fracture. Fracture loads were recorded and the means and the Confidence Intervals were compared. RESULTS: The mean fracture resistance of each of the cusp-reduced groups R1, R2 and R3 (603, 712 and 697 N, respectively) was significantly higher than the non-reduced cusp group (305 N) and was comparable to the intact-premolar group (653 N). CONCLUSIONS: Cusp reduction and coverage with composite resin significantly increased the fracture resistance of premolar teeth with MOD and endodontic access cavities. PMID- 21276021 TI - Efficacy of several digital radiographic imaging systems for laboratory determination of endodontic file length. AB - AIM: To compare the efficacy of different digital radiographic imaging systems for determining the length of endodontic files. METHODOLOGY: K-type endodontic files were introduced into the canals of 40 extracted human permanent single rooted teeth and fixed in place at random lengths. The teeth were radiographed using Digora Optime, CygnusRay MPS and CDR Wireless digital imaging systems. Six observers measured every file length in all the images and repeated this procedure in 50% of the image samples, and assigned a score to the level of difficulty found. Analysis of variance for differences between digital systems and Tukey's test were performed. The level of intraobserver agreement was measured by intraclass correlation. The assigned scores were evaluated by Kruskal Wallis and Dunn's tests. RESULTS: The CDR Wireless values did not differ significantly from the actual lengths and the CygnusRay MPS values. The Digora Optime system was significantly different from the others and overestimated the values (P <= 0.05). The Digora Optime was significantly easier to use for taking measurements and the CygnusRay MPS the most difficult (P <= 0.05). All digital radiographic imaging systems showed excellent agreement with the Intraclass Correlation Coefficient >0.95. CONCLUSIONS: The three digital radiographic imaging systems were precise. The CDR Wireless system was significantly more accurate in determining endodontic file lengths, and similarly to Digora Optime, was considered the least difficult to use when assessing endodontic file lengths. PMID- 21276022 TI - Balloon-facilitated delivery of a left ventricular pacing lead. AB - While modern implant tools have contributed greatly to the success of cardiac resynchronization therapy, technical challenges remain. A common problem is the inability to advance left ventricular pacing leads into branch veins that are tortuous or arise at steep angles. In these cases, advancement of the lead causes it to buckle and prolapse into the coronary sinus or great cardiac vein. Lead prolapsed can be avoided by employing a balloon to temporarily obstruct the coronary sinus or great cardiac vein just upstream from the branch vein. The balloon redirects the force of advancement laterally into the branch vein, facilitating delivery. PMID- 21276023 TI - The QRS narrowing index predicts reverse left ventricular remodeling following cardiac resynchronization therapy. AB - BACKGROUND: The relationship between QRS narrowing and response to cardiac resynchronization therapy (CRT) has been controversial. OBJECTIVE: We sought to analyze the relationship between QRS narrowing and reverse remodeling in patients undergoing CRT, taking into account potential confounders including pre-CRT QRS duration and underlying QRS morphology. METHODS: We reviewed pre- and postimplant electrocardiograms and echocardiograms in a cohort of 233 patients undergoing the new implantation of a CRT device between December 2001 and September 2006. For inclusion in the final cohort, patients had New York Heart Association classes II IV heart failure, left ventricular ejection fraction (LVEF) <= 40%, and QRS duration >=120 ms. Response to CRT was defined as a reduction in left ventricular end-systolic volume (LVESV) of >=10%. A multivariate model was constructed to determine the relationship between QRS change and response to CRT. RESULTS: Patients with QRS narrowing had significantly greater reductions in left ventricular end-diastolic volume (LVEDV) (mL) (-26.5 +/- 52.5 vs -4.8 +/- 44.0, P = 0.002) and LVESV (mL) (-34.0 +/- 55.5 vs -9.9 +/- 45.8, P = 0.002) and improvement in LVEF (%) (8.9 +/- 12.8 vs 4.5 +/- 9.0, P = 0.007) than patients without narrowing. In univariate analysis, female gender (P = 0.0002), percent QRS narrowing from baseline (P = 0.008), lack of nitrate (P<=0.0001) and antiarrhythmic medication use (P = 0.01), lack of a nonspecific intraventricular conduction delay (=0.02), nonischemic cardiomyopathy (P = 0.003), and lower pre CRT LVEDV (P = 0.006) and LVESV [P = 0.01]) were associated with responders. In a multivariate model, QRS narrowing, indexed to the baseline QRS duration, remained strongly associated with response (odds ratio 0.08 [0.01-0.56], P = 0.01). CONCLUSIONS: After adjusting for potential confounders, QRS narrowing, indexed to baseline QRS duration, is associated with enhanced reverse ventricular remodeling following CRT. PMID- 21276024 TI - The relationship between heart rate variability and serum cytokines in chronic chagasic patients with persistent parasitemia. AB - BACKGROUND: Persistent parasitemia, immunological, and autonomic nervous system impairments may play an important role in the evolution and clinical outcome of the chronic phase of Chagas' disease by triggering functional cardiovascular changes. METHODS: Three groups were evaluated: 17 chronic chagasic patients with the indeterminate form (IChD), 12 chronic chagasic patients with cardiac forms (ChHD), and 29 individuals as a healthy control group. Parasitemia was assessed by polymerase chain reaction; hemoculture, heart rate variability by linear and nonlinear methods, and interleukin (IL)-1beta, IL-4, IL-6, IL-10, IL-12, IL-13, IL-17, and tumor necrosis factor-alpha, and interferon (IFN)-gamma serum cytokines were assessed by enzyme-linked immune assay. RESULTS: Twenty-nine chronic chagasic patients were positive for parasitemia (17 IChD and 12 ChHD). Heart rate variability parameters in baseline condition and after cold face test were significantly decreased in chagasic patients compared to controls. Tilt tests showed no alteration. However, using nonlinear indices, ChHD patients presented lower values compared to IChD and controls. Differences in the expression of serum cytokines were observed between chagasic patients and controls. However, among the groups, ChHD presented higher median values of IL-10 and lower of IFN-gamma compared to IChD. CONCLUSION: Both chagasic groups present an autonomic impairment using linear methods. The nonlinear methods revealed that the ChHD group had a higher cardiovascular risk. Serum cytokine concentrations between chagasic patients were similar. However, ChHD showed higher concentrations of IL-10 and lower of IFN-gamma, suggesting some established process of immune regulation. PMID- 21276025 TI - Fungi in freshwaters: ecology, physiology and biochemical potential. AB - Research on freshwater fungi has concentrated on their role in plant litter decomposition in streams. Higher fungi dominate over bacteria in terms of biomass, production and enzymatic substrate degradation. Microscopy-based studies suggest the prevalence of aquatic hyphomycetes, characterized by tetraradiate or sigmoid spores. Molecular studies have consistently demonstrated the presence of other fungal groups, whose contributions to decomposition are largely unknown. Molecular methods will allow quantification of these and other microorganisms. The ability of aquatic hyphomycetes to withstand or mitigate anthropogenic stresses is becoming increasingly important. Metal avoidance and tolerance in freshwater fungi implicate a sophisticated network of mechanisms involving external and intracellular detoxification. Examining adaptive responses under metal stress will unravel the dynamics of biochemical processes and their ecological consequences. Freshwater fungi can metabolize organic xenobiotics. For many such compounds, terrestrial fungal activity is characterized by cometabolic biotransformations involving initial attack by intracellular and extracellular oxidative enzymes, further metabolization of the primary oxidation products via conjugate formation and a considerable versatility as to the range of metabolized pollutants. The same capabilities occur in freshwater fungi. This suggests a largely ignored role of these organisms in attenuating pollutant loads in freshwaters and their potential use in environmental biotechnology. PMID- 21276026 TI - When a habitat freezes solid: microorganisms over-winter within the ice column of a coastal Antarctic lake. AB - A major impediment to understanding the biology of microorganisms inhabiting Antarctic environments is the logistical constraint of conducting field work primarily during the summer season. However, organisms that persist throughout the year encounter severe environmental changes between seasons. In an attempt to bridge this gap, we collected ice core samples from Pony Lake in early November 2004 when the lake was frozen solid to its base, providing an archive for the biological and chemical processes that occurred during winter freezeup. The ice contained bacteria and virus-like particles, while flagellated algae and ciliates over-wintered in the form of inactive cysts and spores. Both bacteria and algae were metabolically active in the ice core melt water. Bacterial production ranged from 1.8 to 37.9 MUg CL(-1) day(-1). Upon encountering favorable growth conditions in the melt water, primary production ranged from 51 to 931 MUg CL(-1) day(-1). Because of the strong H(2) S odor and the presence of closely related anaerobic organisms assigned to Pony Lake bacterial 16S rRNA gene clones, we hypothesize that the microbial assemblage was strongly affected by oxygen gradients, which ultimately restricted the majority of phylotypes to distinct strata within the ice column. This study provides evidence that the microbial community over-winters in the ice column of Pony Lake and returns to a highly active metabolic state when spring melt is initiated. PMID- 21276027 TI - Shoo fly, don't bother me! Efficacy of traditional methods of protecting cattle from tsetse. AB - Studies were made of the efficacy of using smoke and housing to protect cattle from tsetse (Diptera: Glossinidae) in Zimbabwe. The efficacy of smoke was assessed by its effect on catches in Epsilon traps baited with a blend of acetone, 1-octen-3-ol, 4-methylphenol and 3-n-propylphenol. The efficacies of different types of kraal (enclosure) were gauged according to the catches of electrocuting targets (E-targets), baited with natural ox odour, placed within various designs of kraal. Smoke from burning wood (Colophospermum mopane) or dried cow dung reduced the catch of traps by approximately 50-90%. Kraals with a continuous wooden or netting wall, 1.5 m high, reduced catches of E-targets by approximately 75%. Arrangements of electric nets were used to assess the numbers of tsetse attacking live cattle within kraals and/or near sources of smoke. The results confirmed findings with traps and E-targets: kraals reduced the numbers of tsetse that fed by approximately 80% and smoke reduced the numbers attracted by approximately 70%; the use of both reduced overall attack rates by approximately 90%. The inclusion of 4-methylguaiacol, a known repellent for tsetse and a natural component of wood smoke, halved the catches of traps and E targets and the numbers of tsetse attacking cattle. The practical benefits and difficulties of using repellents and/or housing to manage trypanosomiases are discussed. PMID- 21276028 TI - Rapid and validated fluorometric HPLC method for determination of gabapentin in human plasma and urine for clinical application. AB - WHAT IS KNOWN AND OBJECTIVE: A rapid derivatization and validated HPLC method for gabapentin in human plasma and urine is needed for clinical use. The objective of this study was to establish a rapid and validated analytical method for the determination of gabapentin in human plasma and urine using isocratic fluorometric HPLC for clinical application. METHODS: This analytical method is based on precolumn fluorescent derivatization using 4-fluoro-7-nitro benzofurazan. The derivatization was coupled to fast HPLC separation using a 2.3 MUm-particle size ODS column (100 * 4.6 mm i.d.). RESULTS AND DISCUSSION: The derivatization of gabapentin was optimized and HPLC separation was achieved over an ODS column with a run time of 3.5 min. Calibration curves in human plasma and urine were linear over the concentration ranges of 0.05-10 and 10-1000 MUg/mL, respectively. Intra- and inter-assay precision and accuracy values of plasma were within 8.0% and 101-109% and within 8.3% and 94-108%, respectively. Those of urine were within 8.5% and 97-106% and within 9.5% and 97-105%, respectively. This validated method was applied to a pharmacokinetic study in healthy subjects. Interindividual variations in plasma disposition and urinary excretion of gabapentin were observed. WHAT IS NEW AND CONCLUSION: A rapid and validated isocratic fluorometric HPLC method for the determination of gabapentin in human plasma and urine for clinical application has been established. This method can be utilized to evaluate the pharmacokinetic disposition of gabapentin in humans. PMID- 21276030 TI - Children's views on attending a remedial class - because of concentration difficulties. AB - BACKGROUND: An increasing number of segregating solutions (e.g. remedial classes) can be seen in Swedish schools. The aim of this article is to stress how children describe why they attend a remedial class and what it means to be a pupil in that setting. METHODS: The data collection consists of semi-structured interviews with 10 pupils between 10 and 12 years old attending 10 different remedial classes because they had been attributed with having concentration difficulties or diagnosed with attention deficit/hyperactivity disorder. The content of the interviews was described and analysed in relation to the classroom context. The socio-cultural perspective is used as a screen to describe and understand the children's comments about attending remedial class. RESULTS AND CONCLUSIONS: All interviews with the children indicate that they are carriers of their schools' compensatory perspective. This means that they are fully aware of the fact that they are regarded as difficult, with annoying and problematic behaviour, deviating from pupils' in general. The remedial class creates social difficulties for the children; they see themselves as deviant, they lose old friends and there are limited possibilities of establishing new friendship in remedial classes. PMID- 21276029 TI - Intravenous administration of human embryonic stem cell-derived neural precursor cells attenuates cuprizone-induced central nervous system (CNS) demyelination. AB - AIMS: Previous studies have demonstrated the therapeutic potential for human embryonic stem cell-derived neural precursor cells (hES-NPCs) in autoimmune and genetic animal models of demyelinating diseases. Herein, we tested whether intravenous (i.v.) administration of hES-NPCs would impact central nervous system (CNS) demyelination in a cuprizone model of demyelination. METHODS: C57Bl/6 mice were fed cuprizone (0.2%) for 2 weeks and then separated into two groups that either received an i.v. injection of hES-NPCs or i.v. administration of media without these cells. After an additional 2 weeks of dietary cuprizone treatment, CNS tissues were analysed for detection of transplanted cells and differences in myelination in the region of the corpus callosum (CC). RESULTS: Cuprizone-induced demyelination in the CC was significantly reduced in mice treated with hES-NPCs compared with cuprizone-treated controls that did not receive stem cells. hES NPCs were identified within the brain tissues of treated mice and revealed migration of transplanted cells into the CNS. A limited number of human cells were found to express the mature oligodendrocyte marker, O1, or the astrocyte marker, glial fibrillary acidic protein. Reduced apoptosis and attenuated microglial and astrocytic responses were also observed in the CC of hES-NPC treated mice. CONCLUSIONS: These findings indicated that systemically administered hES-NPCs migrated from circulation into a demyelinated lesion within the CNS and effectively reduced demyelination. Observed reductions in astrocyte and microglial responses, and the benefit of hES-NPC treatment in this model of myelin injury was not obviously accountable to tissue replacement by exogenously administered cells. PMID- 21276031 TI - Association of leisure time physical activity and sports competition activities with high blood pressure levels: study carried out in a sample of Portuguese children and adolescents. AB - BACKGROUND: A better understanding of the different domains and characteristics of children's and adolescent's physical activity (PA) could be a strategy to clarify the association of this behaviour with the early development of cardiovascular risk factors. OBJECTIVES: To examine the relationship between leisure time physical activity (LTPA) and sports competition activities (SCA) with high blood pressure (HBP) levels in a sample of children and adolescents from Porto, Portugal. STUDY DESIGN: This is a cross-sectional study, which comprised 503 boys and 572 girls, aged 8-17 years old. LTPA and SCA were assed by self-reported. Students were assigned as active and non-active in SCA or LTPA according to their self-reported participation. Participants were classified as HBP when they are above of the last quartile for systolic and/or diastolic BP adjusted for gender and age. RESULTS: Do not be engaged in LTPA (OR: 1.47; 95% CI: 1.12; 1.93) and SCA (OR: 1.36; 95% CI: 1.02; 1.81) was significantly associated with the likelihood of being HBP. However, when cardiorespiratory fitness (CRF) (OR: 1.23; 95% CI: 0.91; 1.67) and body mass index (BMI) (OR: 1.31; 95% CI: 0.98; 1.75) were included on SCA model, the association between SCA with HBP did not showed significant results. CONCLUSION: Children and adolescents who are not engaged in SCA or LTPA are more likely to be classified as having HBP; however, the relationship between SCA and HBP was dependent of CRF and BMI. Further, PA strategies should take these differences on the relationship between HBP, SCA and LTPA. PMID- 21276032 TI - The substance and sources of young children's healthy eating and physical activity knowledge: implications for obesity prevention efforts. AB - BACKGROUND: The prevalence of overweight among young children is increasing at an alarming rate. Global efforts to address the issue can benefit from understanding how young children's experiences across multiple contexts shape their perspectives of healthy weight. METHODS: This qualitative study examines the substance and sources of young American children's knowledge related to healthy eating, physical activity and media practices. Role play and semi-structured interviews were conducted in child-care settings with 81 children aged 3-5 who represented diverse socio-economic statuses and ethnic backgrounds. RESULTS: Children demonstrated better understanding of the benefits of healthy eating compared with physical activity. Snacks and beverages consumed outside mealtime were less likely to be healthy even among the 40% of children who demonstrated an understanding of healthy nutrition. The majority of children's leisure activity selections involved media and minimally active pursuits. Three quarters of the children were unable to articulate reasons for healthy choices or identify the sources of their health understandings. The media was listed as source of health information more frequently than adults. CONCLUSION: Obesity prevention efforts targeting young children need to use consistent messaging across all contexts in which children develop in order to increase their understanding that physical activity and eating choices support health. Efforts need to counter inaccurate information and address the rationale for health practices. Key gaps in young children's understanding include: the importance of drinking water, that snacks are part of nutritional intake and the benefits of engaging in physical activities. PMID- 21276033 TI - Social competence of elementary-school children: relationships to maternal authoritativeness, supportive maternal responses and children's coping strategies. AB - BACKGROUND: Although the influences of parenting on children's development of social competence have been well established, research on the underlying mechanisms of this link is relatively limited. The present study examined children's coping strategies as a mediator of the effects of maternal authoritativeness and maternal inductive responses on their social competence. METHOD: The mothers of 183 Hong Kong Chinese children aged 6 to 8 years (89 girls and 94 boys) reported on their adoption of authoritative parenting and their responses to their children's expressions of emotion, and rated their children's adoption of constructive coping strategies. The children's teachers reported on the children's prosocial behaviour, and rated their level of peer acceptance at school. RESULTS: A model of maternal authoritativeness and supportive maternal responses affecting children's social competence is presented. The study results show that the effects of authoritative parenting on children's adoption of constructive coping strategies were mediated by supportive maternal responses to children's expression of emotion, and that the effects of maternal authoritativeness and maternal responses on children's social competence were mediated by children's coping strategies. These results suggest that school personnel should organize training programmes on emotion-coping strategies for both parents and children. CONCLUSION: The findings imply that positive parenting facilitates children's acquisition of constructive emotion-coping strategies. Programmes on emotion-coping strategies should be introduced for both parents and school children. PMID- 21276034 TI - Services for children with developmental co-ordination disorder: the experiences of parents. AB - BACKGROUND: Parents provide valuable information on their experiences of engaging with therapy services for their children, which can inform the future development of these services. The aim of this study was to explore the views and experiences of parents who had accessed therapy services for their child with developmental co-ordination disorder (DCD). METHODS: Seven focus groups were conducted incorporating 52 parents who had a child diagnosed with, or fitting the diagnostic criteria for DCD. Focus groups were audiotaped, transcribed and analysed thematically. FINDINGS: Parents reported struggling to gain access to therapy services. When they gained access, they found the services beneficial for their child but continued to experience difficulties regarding the quality of service delivery. CONCLUSIONS/IMPLICATIONS: The study suggests that parents thought some health-care professionals lacked knowledge and understanding of DCD, which they believed impacted upon early recognition and access to services. They perceived that therapy at an early age was vital for children's development, and indicated that a clearer path for accessing these services was necessary in addition to improved service quality. They called for an increase in awareness of DCD by all therapy service professionals to aid early recognition and improved treatment. PMID- 21276035 TI - Expectations of and reactions to disability and normality experienced by parents of children with intellectual disability in Sweden. AB - BACKGROUND: Much research has been devoted to the emotional burdens of having a child with intellectual disability (ID), but very little of this has focused on the burdens imposed by negative public attitudes towards disability. Adjustment has primarily been thought of as adjustment to the actual disability rather than adjustment to attitudes or prejudices towards disability. AIM: The aim of the present study was to study expectations of and reactions to disability and normality experienced by parents of children with ID in their everyday life in Sweden. RESEARCH QUESTIONS: Do the parents relate to the tragedy discourse and, if so, how? Do parents relate to other expectations and disability discourses and, if so, how? What subject positions do the discourses offer? METHOD: The analysis was based on 17 semi-structured interviews with nine fathers and eight mothers of nine children with different IDs. The children were newly diagnosed and were from 6 months to 5 years of age. RESULTS: Four discourses (tragedy and the lived experience, tragedy and the outsider perspective, the clinical gaze and the super-parent ideal) and subject positions relating to these discourses are discussed. DISCUSSION: The results of this study show that parents of young children with disabilities relate to a wide range of social processes and practices, which could be thought to affect their emotional well-being and parental identity negatively. PMID- 21276036 TI - Utilization of mental health services by survivors of severe paediatric traumatic brain injury: a population-based study. AB - A study of general and specialist mental health and psychology service provider records confirms very high rates of utilization by a population of survivors of severe paediatric traumatic brain injury. PMID- 21276037 TI - An hour less sleep is a risk factor for childhood conduct problems. AB - BACKGROUND: There is emerging evidence that sleep problems in childhood may have enduring consequences. Studies using parental and objective sleep measurement suggest that sleep difficulties in children may be associated with behavioural problems. However, the findings using objective sleep measures are inconsistent and it is not clear what aspects of sleep quality are associated with daytime behavioural difficulties. The aim of this paper is to identify which behavioural symptoms are best predicted by actigraphic sleep measures in a general population sample of school-aged children aged 6-11 years. METHODS: Actigraphy was used to measure sleep in 91 typically developing children aged 6-11 years for 6 days. Parents completed the Strengths and Difficulties Questionnaire (SDQ). A series of multivariate linear regression models were computed to analyse the effects of sleep on SDQ subscales. RESULTS: Sleep did not predict emotional symptoms or hyperactivity. After controlling for age and gender, sleep accounted for 18% of the variance in conduct problems. Only actual sleep time in minutes made a significant contribution to the model. CONCLUSIONS: A child who sleeps 1 h less than the average child may be at risk of conduct problems. Clinicians should consider routinely screening for sleep difficulties when assessing children with conduct problems. PMID- 21276038 TI - The impact of school-day variation in weight and height on National Child Measurement Programme body mass index-determined weight category in Year 6 children. AB - BACKGROUND: In England, the National Child Measurement Programme (NCMP) annually measures the weight and height of Year 6 schoolchildren (age 10-11 years). While measurement protocols are defined, the time of measurement within the school day is not. This study examined the impact of school-day variation in weight and height on NCMP body mass index (BMI)-determined weight category in Year 6 children. METHODS: Standing height and weight were measured in morning and afternoon sessions in 74 children, boys (n= 34; height: 141.16 +/- 7.45 cm; weight: 36.48 +/- 9.46 kg, BMI: 18.19 +/- 3.98 kg/m(2) ) and girls (n= 40; height: 144.58 +/- 7.66 cm; weight: 42.25 +/- 11.29 kg; BMI: 19.97 +/- 3.98 kg/m(2) ) aged 11 +/- 0.3 years. RESULTS: In the whole sample, height decreased (Mean =-0.51 cm, 95% CI: -0.39 to -0.64 cm, P= 0.01), weight did not change (Mdn = 36.40 to 36.35, P= 0.09) and BMI increased (Mdn = 18.04 to 18.13, P= 0.01). In girls weight increased (Mdn = 41.40 to 41.60, P= 0.01). BMI percentile increased (Mdn = 57th to 59.5th centile, P= 0.01). One girl increased in BMI category from morning to afternoon according to the clinical cut-offs (<=2nd, >91st and >98th) and three girls increased BMI category according to the population monitoring cut offs (<=2nd, >=85th, >=95th). CONCLUSIONS: School-day variation in height (and in girls alone, weight) impact upon increased BMI and BMI percentile in afternoon versus morning measurements in Year 6 children. Although not reaching statistical significance, resultant variation in categorization at the individual level may lead to unwarranted follow-up procedures being initiated. Further research with larger samples is required to further explore the impact of daily variability in height and weight upon both clinical and population monitoring BMI-determined weight status categorization in the NCMP. PMID- 21276039 TI - Obesity prevention in the family day care setting: impact of the Romp & Chomp intervention on opportunities for children's physical activity and healthy eating. AB - BACKGROUND: The Romp & Chomp intervention reduced the prevalence of overweight/obesity in pre-school children in Geelong, Victoria, Australia through an intervention promoting healthy eating and active play in early childhood settings. This study aims to determine if the intervention successfully created more health promoting family day care (FDC) environments. METHODS: The evaluation had a cross-sectional, quasi-experimental design with the intervention FDC service in Geelong and a comparison sample from 17 FDC services across Victoria. A 45-item questionnaire capturing nutrition- and physical activity-related aspects of the policy, socio-cultural and physical environments of the FDC service was completed by FDC care providers (in 2008) in the intervention (n= 28) and comparison (n= 223) samples. RESULTS: Select results showed intervention children spent less time in screen-based activities (P= 0.03), organized active play (P < 0.001) and free inside play (P= 0.03) than comparison children. There were more rules related to healthy eating (P < 0.001), more care provider practices that supported children's positive meal experiences (P < 0.001), fewer unhealthy food items allowed (P= 0.05), higher odds of staff being trained in nutrition (P= 0.04) and physical activity (P < 0.001), lower odds of having set minimum times for outside (P < 0.001) and organized (P= 0.01) active play, and of rewarding children with food (P < 0.001). CONCLUSIONS: Romp & Chomp improved the FDC service to one that discourages sedentary behaviours and promotes opportunities for children to eat nutritious foods. Ongoing investment to increase children's physical activity within the setting and improving the capacity and health literacy of care providers is required to extend and sustain the improvements. PMID- 21276040 TI - Chronic kidney disease growth factors in renal fibrosis. AB - 1. The common pathological alteration in virtually every progressive chronic kidney disease (CKD) is renal fibrosis. 2. This review focuses on some growth factors, which are particularly well-established in contributing to fibrosis, such as the profibrotic, transforming growth factor-beta, and connective tissue growth factor (CTGF), as well as the antifibrotic, bone morphogenic protein 7. The role of other growth factors is only starting to emerge (e.g. platelet derived growth factor), and the role of yet others remains unclear (e.g. vascular endothelial growth factor). 3. Whether circulating or excreted, growth factors might serve as biomarkers of renal fibrosis and CKD remains largely unanswered. 4. Animal studies suggest that manipulation of growth factors might be an effective treatment option for patients with renal fibrosis and CKD. So far, only inhibition of CTGF is being tested in patients with diabetic nephropathy. PMID- 21276041 TI - All-cause mortality of elderly Australian veterans using COX-2 selective or non selective NSAIDs: a longitudinal study. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Previous studies have found varying impact of exposure to COX-2 selective and non-selective NSAIDs. WHAT THIS STUDY ADDS: * Individuals receiving a COX-2 selective NSAID had an increased risk of all-cause mortality after correction for age, sex and cardiovascular risk as measured by co-prescription. * Despite differences in the pharmacokinetic properties of the COX-2 selective inhibitor drugs, our study lends no support to clinicians preferring any one COX-2 selective inhibitor drug, or substituting one for another on the grounds of mortality risk alone. * The Australian Department of Veterans' Affairs data sets make it possible to conduct timely record linkage studies of all-cause mortality from use of medicines in a large and clinically relevant population. AIM: To determine hazard ratios for all-cause mortality in elderly Australian veterans taking COX-2 selective and non-selective NSAIDs. METHODS: Patient cohorts were constructed from claims databases (1997 to 2007) for veterans and dependants with full treatment entitlement irrespective of military service. Patients were grouped by initial exposure: celecoxib, rofecoxib, meloxicam, diclofenac, non-selective NSAID. A reference group was constructed of patients receiving glaucoma/hypothyroid medications and none of the study medications. Univariate and multivariate analyses were performed using Cox proportional hazards regression models. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated for each exposure group against each of the reference group. The final model was adjusted for age, gender and co-prescription as a surrogate for cardiovascular risk. Patients were censored if the gap in supply of study prescription exceeded 30 days or if another study medication was initiated. The outcome measure in all analyses was death. RESULTS: Hazard ratios and 95% CIs, adjusted for age, gender and cardiovascular risk, for each group relative to the reference group were: celecoxib 1.39 (1.25, 1.55), diclofenac 1.44 (1.28, 1.62), meloxicam 1.49 (1.25, 1.78), rofecoxib 1.58 (1.39, 1.79), non selective NSAIDs 1.76 (1.59, 1.94). CONCLUSIONS: In this large cohort of Australian veterans exposed to COX-2 selective and non-selective NSAIDs, there was a significant increased mortality risk for those exposed to either COX-2 selective or non-selective NSAIDs relative to those exposed to unrelated (glaucoma/hypothyroid) medications. PMID- 21276042 TI - A pharmacokinetic and safety study of single dose intravenous combretastatin A4 phosphate in Chinese patients with refractory solid tumours. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Three pharmacokinetic and safety studies for combretastatin A4 phosphate (CA4P), the first vascular disrupting agent, have been conducted in Western countries. * The maximum tolerated dose (MTD) was approximately 60-68 mg m(-2). * CA4P-related grade 3 or 4 adverse events were tumour pain, dyspnoea, hypoxia and syncope in patients who received doses >= 50 mg m(-2). WHAT THIS STUDY ADDS: * This is the first pharmacokinetic and safety study conducted in East Asian patients. * There appeared to be a trend that Chinese patients metabolized CA4 more rapidly and had greater neurotoxicity than patients in Western countries. * We observed favourable clinical responses in patients with refractory nasopharyngeal carcinoma. * CA4P-induced acute renal failure was seen in one dehydrated Chinese patient. AIMS: This trial was conducted to evaluate the safety and pharmacokinetics of combretastatin A4 phosphate (CA4P) given intravenously as a single dose to Chinese patients with refractory solid tumours. METHODS Twenty-five patients were treated with single doses of CA4P according to a dose escalation scheme: 5, 10, 20, 33, 50, 65 and 85 mg m(-2) infused intravenously over 30 min. RESULTS: CA4P was generally well tolerated at <= 65 mg m(-2). Transient, moderate increases in the heart rate corrected QT interval occurred at all doses. CA4P produced a transient dose dependent increase in neural and gastrointestinal toxicities. Acute renal failure occurred in one dehydrated patient who had also taken paracetamol. There were seven episodes of dose-limiting toxicity at doses >=65 mg m(-2), including two episodes of reversible ataxia at 85 mg m(-2).For CA4, at 50 mg m(-2),mean (SD) peak plasma concentration (C(max) was 0.99 (0.33) mM, area under the curve from time zero to time of last quantifiable concentration (AUC(0,t)) was 1.42 (0.30) mM h and terminal elimination half-life (t(1/2)was 1.81 (0.61) h. At 65 mg m 2,C(max) was 1.73 (0.62) mM,AUC(0,t) was 3.19 (1.47) mM h and t (1/2) was 1.90 (0.61) h [corrected]One patient with nasopharyngeal carcinoma had an obvious clinical response with central necrosis in the metastatic lung mass. CONCLUSION Doses <= 65 mg m(-2) given as 30 min infusions define the maximum tolerated dose in East Asian patients, and doses in the range of 50-65 mg m(-2) have been selected for further studies. PMID- 21276043 TI - Preventing the aortic complications of Marfan syndrome: a case-example of translational genomic medicine. AB - The translational path from pharmacological insight to effective therapy can be a long one. We aim to describe the management of Marfan syndrome as a case-example of how pharmacological and genomic insights can contribute to improved therapy. We undertook a literature search for studies of Marfan syndrome, to identify milestones in description, understanding and therapy of the syndrome. From the studies retrieved we then weaved an evidence-based description of progress. Marfan syndrome shows considerable heterogeneity in clinical presentation. It relies on defined clinical criteria with confirmation based on FBN1 mutation testing. Surgical advances have prolonged life in Marfan syndrome. First-line prophylaxis of complications with beta-adrenoceptor blockers became established on the basis that reduction of aortic pressure and heart rate would help. Over activity of proteinases, first suggested in 1980, has since been confirmed by evidence of over-expression of matrix metalloproteinases (MMP), notably MMP-2 and MMP-9. The search for MMP inhibitors led to the evaluation of doxycycline, and both animal studies and small trials, provided early evidence that this widely used antimicrobial agent was useful. Identification of the importance of TGF-beta led to evaluation of angiotensin II type I receptor (AT(1) R) blockers with highly promising results. Combination prophylactic therapy would appear rational. Pharmacological and genomic research has provided good evidence that therapy with losartan and doxycycline would prevent the aortic complications of Marfan syndrome. If on-going well designed trials confirm their efficacy, the outlook for Marfan syndrome patients would be improved considerably. PMID- 21276044 TI - Cra negatively regulates acid survival in Yersinia pseudotuberculosis. AB - Survival in acidic environments is important for successful infection of gastrointestinal pathogens. Many bacteria have evolved elaborate mechanisms by inducing or repressing gene expression, which subsequently provide pH homeostasis and enable acid survival. In this study, we employed comparative proteomic analysis to identify the acid-responsive proteins of a food-borne enteric bacterium, Yersinia pseudotuberculosis. The expression level of eight proteins involved in carbohydrate metabolism was up- or downregulated over twofold at pH 4.5 compared with pH 7.0. The role of a global transcriptional regulator catabolite repressor/activator Cra was further studied in this acid survival process. lacZ-fusion analysis showed that expression of cra was repressed under acidic pH. Deletion of the cra gene increased acid survival by 10-fold, whereas complementation restored the wild-type phenotype. These results lead us to propose that, in response to acidic pH, the expression of cra gene is downregulated to increase acid survival. This is the first study to demonstrate the regulatory role of Cra in acid survival in an enteric bacterium. PMID- 21276045 TI - Maintaining network security: how macromolecular structures cross the peptidoglycan layer. AB - Peptidoglycan plays a vital role in bacterial physiology, maintaining cell shape and resisting cellular lysis from high internal turgor pressures. Its integrity is carefully maintained by controlled remodeling during growth and division by the coordinated activities of penicillin-binding proteins, lytic transglycosylases, and N-acetylmuramyl-l-alanine amidases. However, its small pore size (~2 nm) and covalently closed structure make it a formidable barrier to the assembly of large macromolecular cell-envelope-spanning complexes involved in motility and secretion. Here, we review the strategies used by Gram-negative bacteria to assemble such macromolecular complexes across the peptidoglycan layer, while preserving its essential structural role. In addition, we discuss evidence that suggests that peptidoglycan can be integrated into cell-envelope spanning complexes as a structural and functional extension of their architecture. PMID- 21276046 TI - Using an insect model to assess correlation between temperature and virulence in Bacillus weihenstephanensis and Bacillus cereus. AB - The closely related bacterial species Bacillus cereus and Bacillus weihenstephanensis are adapted to the mesophilic and the psychrotrophic temperature range, respectively. While B. cereus strains are associated with foodborne diseases, B. weihenstephanensis strains are so far not, although similar virulence genes are found in both species. Our investigations show that both species were virulent in the insect model, Galleria mellonella, following infection via oral and haemocoel routes. However, virulence of B. weihenstephanensis was much higher at 15 degrees C than at 37 degrees C. Furthermore, a temperature-dependent difference between the species was seen in a cell culture cytotoxicity assay. In summary, our results demonstrate for the first time virulence of B. weihenstephanensis strains in an in vivo model. In addition, we found that G. mellonella is a useful model for studies of the psychrotolerant species of the B. cereus group, suggesting that insects might be an ecological growth niche for several members of this bacterial group. PMID- 21276047 TI - The role of DNA binding with the Cry8Ea1 toxin of Bacillus thuringiensis. AB - The Cry8Ea1 protoxin is a DNA-protein complex. Both forms of the Cry8Ea1 toxin (with or without DNA binding) were obtained separately, and their stability and ability to insert into a phospholipid monolayer in vitro were compared. The presence of DNA can prevent the toxin from aggregation. Data regarding the penetration of the Cry8Ea1 toxin and Cry8Ea1 toxin-DNA complex into the air/water interface without a phospholipid monolayer show that the Cry8Ea1 toxin-DNA complex is more likely to move towards the air/water interface and is more hydrophobic. Experiments examining the protein interaction with the phospholipid monolayer show that the ability of the Cry8Ea1 toxin-DNA complex to insert into the lipid bilayer is much greater than that of the Cry8Ea1 toxin without DNA. PMID- 21276048 TI - UV-resistant Acinetobacter sp. isolates from Andean wetlands display high catalase activity. AB - Andean wetlands are characterized by their extreme environmental conditions such as high UV radiation, elevated heavy metal content and salinity. We present here the first study on UV tolerance and antioxidant defense of four Acinetobacter strains: Ver3, Ver5 and Ver7, isolated from Lake Verde, and N40 from Lake Negra, both lakes located 4400 m above sea level. All four isolates displayed higher UV resistance compared with collection strains, with Ver3 and Ver7 being the most tolerant strains not only to UV radiation but also to hydrogen peroxide (H(2)O(2)) and methyl viologen (MV) challenges. A single superoxide dismutase band with similar activity was detected in all studied strains, whereas different electrophoretic pattern and activity levels were observed for catalase. Ver3 and Ver7 displayed 5-15 times higher catalase activity levels than the control strains. Analysis of the response of antioxidant enzymes to UV and oxidative challenges revealed a significant increase in Ver7 catalase activity after H(2)O(2) and MV exposure. Incubation of Ver7 cultures with a catalase inhibitor resulted in a significant decrease of tolerance against UV radiation. We conclude that the high catalase activity displayed by Ver7 isolate could play an important role in UV tolerance. PMID- 21276049 TI - A case of erythema multiforme associated with primary Epstein-Barr virus infection. AB - We present a case of primary Epstein-Barr virus (EBV) infection with erythema multiforme. A 1-year-old Japanese boy presented with skin eruptions, including typical target lesions and a low-grade fever. Just before the skin biopsy, 95 copies/MUg DNA of EBV genome was detected in peripheral blood mononuclear cells, which subsequently increased to 6,834 copies/MUg DNA. Skin tissue collected from the skin lesion showed the typical pathologic findings of erythema multiforme. EBV-encoded small nuclear RNA signals were not detected in the skin tissue by in situ hybridization. PMID- 21276050 TI - Epidermolysis bullosa nevus-like lesions in a pediatric patient with pyoderma gangrenosum. AB - Epidermolysis bullosa-associated nevi are recently described dysplastic nevi found in patients with epidermolysis bullosa. These lesions display clinical features of unusual nevi suggestive of malignancy but thus far cases with malignant transformation have not been reported. We describe a case of epidermolysis bullosa-type nevi developing in a child with pyoderma gangrenosum. The nevi in our patient were found in areas previously affected by pyoderma gangrenosum and were clinically concerning for malignancy. However, they were only moderately atypical on light and confocal microscopy. This case demonstrates that pediatric patients with cutaneous inflammation, bullae formation, or both, are at risk for developing unusual nevi at previous sites of skin involvement. Considering the absence of malignant change in these nevi, we suggest that close observation can be employed in cases where this diagnosis can be confirmed both clinically and microscopically. PMID- 21276051 TI - Microcystic adnexal carcinoma: the first reported congenital case. AB - Microcystic adenexal carcinoma is a rare, locally aggressive, malignant appendage tumor also known as sclerosing sweat duct carcinoma. Since widespread recognition of microcystic adenexal carcinoma as a distinct clinicopathologic entity, approximately 300 total cases have been reported in the literature, with only eight previous cases reported in children under the age of 18, with no reported cases in patients younger than 6 years old. Our patient is unique in that the lesion was present at birth, making this the youngest case of microcystic adenexal carcinoma reported. PMID- 21276052 TI - Acute onset of generalized pruritic rash in a toddler. Diagnosis: systemic allergic (contact) dermatitis to nickel from ingestion of metal coins. PMID- 21276053 TI - Hyperkeratotic papules in a child with Down syndrome. Diagnosis: acquired reactive perforating collagenosis in Down syndrome. PMID- 21276054 TI - Multiple translucent papules on the nose of a 5-year-old boy. Diagnosis: multiple eccrine hidrocystomas. PMID- 21276055 TI - Ectopic cilia in a 14-year-old boy. AB - Ectopic cilia is a very rare condition in human beings, usually presented as a tuft of densely grouped hair on the lateral quadrant of the upper eyelid or conjunctival surface of the eyelid. The embryologic origin of this anomaly is unknown, and few cases have been recorded in literature. In most cases, it causes no apparent medical morbidity but is treated by surgical excision because of its cosmetic aspect. We report a 14-year-old boy with ectopic cilia with approximately 20 hairs occurring as single and grouped hairs pattern emerging from anterior surface of eyelid. Positive history of the same anomaly in his paternal grandfather demonstrates evidence of an inherited genetic disorder. PMID- 21276056 TI - Familial annular erythema--a rare dermatology diagnosis. AB - We report the second case of autosomal dominant familial annular erythema since its original description in 1966 by Beare et al. A three and a half-year-old boy presented at five days of age with a widespread annular urticated erythematous rash which has persisted despite treatment with various antihistamines and mast cell stabilizers. His mother reports an identical eruption with an absence of systemic symptoms. PMID- 21276057 TI - Disseminated congenital comedones. AB - A 3-month-old boy with congenital and extensive skin comedones without any other extracutaneous manifestations is reported. This patient does not fit with other reported disorders of congenital or childhood extensive comedones, such as nevus comedonicus, familial dyskeratotic comedones, idiopathic disseminated comedones, childhood flexural comedones, and acne neonatorum. PMID- 21276058 TI - Poroid hidradenoma in a child: an unusual presentation. AB - Poroid neoplasm is a benign sweat gland neoplasm that accounts for 10% of sudoriferous tumors. Poroid hidradenoma is an uncommon variant that usually affects adults, with a peak of incidence in the seventh decade. It is rare in children. We report the first case of poroid hidradenoma presenting in a 13-year old boy. PMID- 21276059 TI - Linear syringocystadenoma papilliferum: an unusual location. AB - Syringocystadenoma papilliferum is a rare benign adnexal skin tumor of apocrine or eccrine glands. We report here an 18-year-old girl who had linear syringocystadenoma papilliferum in the pubic region, which is very rare. PMID- 21276060 TI - Familial progressive hypermelanosis in Indian monozygotic twins. AB - Familial hyperpigmentation, or melanosis universalis hereditaria, is a rare hyperpigmentary disorder with onset in infancy. Here, we describe monozygotic twins with similar pattern of progressive hyperpigmentation with onset in early neonatal period without any family history. Histopathological examination showed increased melanin throughout the epidermis. Although hereditary defects may influence melanogenesis resulting in a pigmentary anomaly, the pathogenesis of hyperpigmentation in this case remains unclear. PMID- 21276061 TI - Diffuse normolipemic plane xanthoma in a child with common variable immunodeficiency. AB - Diffuse plane xanthoma is extremely rare in children. Although it may be associated with systemic disorders, its etiology remains obscure in a number of patients. The case of a boy with common variable immunodeficiency and normal serum lipid levels, who developed diffuse plane xanthoma during treatment with intravenous immunoglobulins, is reported. PMID- 21276062 TI - Clinical, dermoscopic, and histopathologic features in a case of infantile hemangioma without proliferation. AB - Infantile hemangioma precursors or those without a proliferative phase may mimic a port-wine stain. We describe a case of infantile hemangioma precursor, which proved to be Glut-1 positive in biopsy, with the dermoscopic features of red round globular vessels, red comma-like vessels, and red linear vessels. These dermoscopic features should help to distinguish infantile hemangioma precursors or those with an absent or minimal growth phase from a port-wine stain. PMID- 21276063 TI - Improvement of nonbullous congenital ichthyosiform erythroderma following functional endoscopic sinus surgery. AB - We report the case of a child with congenital nonbullous ichthyosiform erythroderma on long-term isotretinoin who developed progressively worsening ichthyosis along with recurrent bouts of sinusitis. Endoscopic sinus surgery revealed osteophytes, most likely an isotretinoin-related adverse event, and post operatively the patient's sinus disease and skin disease both dramatically improved. This case represents the first report, to our knowledge, of ichthyosis improving after endoscopic sinus surgery. PMID- 21276064 TI - Case report: Congenital dacryocystocele and dacryocystitis. AB - Congenital dacryocystocele is a uncommon type of nasolacrimal duct obstruction. Differential diagnosis for masses in the medial canthal region of a newborn include encephalocele, hemangioma, nasal glioma, and dermoid cyst. Because of the risk of becoming infected (acute dacryocystitis) and potentially lethal due to septicemia, aggressive management, including admission for intravenous antibiotics and surgical removal, is now advocated by many pediatric ophthalmologists if the cyst cannot be decompressed. Because of the commonly associated nasal cyst, infants with nasolacrimal dacryocyctocele may also experience respiratory distress especially when breast-feeding. The following case of dacryocystocele, which had progressed to dacryocystitis, was misdiagnosed as an infantile hemangioma. It is important to diagnose this entity quickly and refer for appropriate antibiotic and surgical management to avoid more serious sequelae of sepsis and possible death. PMID- 21276065 TI - Polyomavirus BK: possibly associated skin eruption in a patient with hemorrhagic cystitis. AB - A 14-year-old girl with Fanconi anemia was submitted to allogeneic hematopoietic stem cell transplantation. After 17 days she developed hemorrhagic cystitis due to polyoma BK virus (BKV), confirmed by PCR (polymerase chain reaction). Two weeks after the appearance of the urinary symptoms the patient presented numerous papules and vesicles on both hands and feet. PCR of the skin lesions and plasma was positive for BKV. The relationship of BKV with frequent infections in immunocompromised patients is well established. The positive PCR of vesicular fluid suggests that this was the causative agent of the skin lesion in this case. There are no reports of skin lesions with positive PCR for BKV. PMID- 21276066 TI - Cellular neurothekeomas arising on a cafe-au-lait macule. AB - Neurothekeoma is a tumor probably derived from the nerve sheath, which usually appears during the first 2 decades of life as a solitary papule or nodule; multiple neurothekeomas are very unusual. We present a case of multiple cellular neurothekeomas arising on a cafe-au-lait macule in a child, a situation that has not been reported to our knowledge. PMID- 21276067 TI - Re: Management of nevus sebaceous and the risk of basal cell carcinoma: an 18 year review. By Rosen et al: Pediatric Dermatology v26, n6, 676-681, Nov/Dec 2009. PMID- 21276069 TI - Sock-line bands: presentation of additional follow-up and eight new cases. PMID- 21276070 TI - Obesity in adolescence is associated with left ventricular hypertrophy and hypertension. AB - BACKGROUND: Obesity is a risk factor for hypertension (HTN) and left ventricular hypertrophy (LVH). However, the association between obesity, HTN or LVH in adolescents has not been studied in a large population. METHOD: Utilizing a database of screening echocardiograms, we assessed for the presence of LVH and HTN (defined as systolic blood pressure (SBP) > 140 mmHg or diastolic blood pressure (DBP) > 90 mmHg) in obese adolescents (BMI > 30) using univariate and multivariate analysis. RESULTS: A total of 2072 subjects were identified between the ages of 13-19 years. LVH was significantly more prevalent in obese subjects (47/166 [28.3%] vs. nonobese subjects (99/1612 [6.1%]) with a P-value of <0.001. Using multivariate analysis adjusting for age, gender and blood pressure, obesity remained strongly associated with the presence of LVH (OR 4.51, CI: 2.83-7.19, P < 0.001). Elevated SBP and DBP were also strongly associated with obesity. SBP > 140 was present in 38% of obese subjects (54/142) versus 12.7% of nonobese subjects (172/1, 353). DBP > 90 was present in 10.6% of obese subjects (15/141) of versus 3.1% of nonobese subjects (42/1352). After adjustment for age, gender and LVH, obesity remained independently associated with HTN (for SBP > 140, OR 2.24, CI: 1.46-3.45, P < 0.001, and for DBP > 90, OR 2.10, CI: 1.063-4.17, P = 0.03). CONCLUSION: Obese adolescents have a significantly higher prevalence of HTN and LVH. Our analysis suggests a direct negative effect of obesity on cardiovascular function starting early in teenage years. (Echocardiography 2011;28:150-153). PMID- 21276071 TI - Recurrent mitral regurgitation late after annuloplasty for ischemic mitral regurgitation. AB - In 106 patients who had mitral annuloplasty for ischemic mitral regurgitation (MR), 71 patients (67%) had satisfactory outcomes with <2+ MR (grade 0-4) throughout the follow-up period (44 +/- 31 months), while 35 patients (33%) had significant recurrent MR (>=2+) late after annuloplasty (>=6 months) during the follow-up period (45 +/- 30 months). Compared to those with recurrent MR, the success group had a significantly higher proportion of patients whose left ventricular (LV) ejection fraction (EF) stayed stable or increased over the follow-up period postoperatively (47/70 = 67% vs. 14/35 = 40%, P < 0.01). The success group had a higher proportion of patients whose LV end-systolic volume stayed stable or decreased (37/63 = 59% vs. 6/35 = 17%, P < 0.01) and lower LV sphericity in systole (0.46 +/- 0.096 vs. 0.60 +/- 0.10, P < 0.01). In conclusion, recurrent ischemic MR after annuloplasty is associated with increasing LV size, decreasing LVEF, and increasing sphericity of the LV. PMID- 21276073 TI - Reduced atrial emptying after orthotopic heart transplantation masquerading as restrictive transmitral Doppler flow pattern?*. AB - BACKGROUND: An elevated early (E) to late (A) diastolic filling velocities ratio, typically seen in advanced diastolic dysfunction, has also been observed after cardioversion of atrial fibrillation as a consequence of the depressed left atrial (LA) contractility. We hypothesized that the impaired LA contractile function demonstrated after orthotopic cardiac transplantation (OCT) could also lead to this "pseudorestrictive" pattern. METHOD: E/A ratio related to the tissue Doppler early mitral annular velocity (Ea) as preload-independent index of LV relaxation was evaluated in all consecutive OCT patients between 2005 and 2007. RESULTS: The study population comprised 48 patients 97 +/- 77 months after OCT. Thirty-two patients (67%) had an E/A ratio > 2. LV systolic function and myocardial relaxation assessed by the Ea velocity were similar compared to patients with normal ratio (61 +/- 6% vs. 60 +/- 12%, P = 0.854 and 15 +/- 4 cm/s vs. 14 +/- 3 cm/s, r = 0.15, P = 0.323, respectively). On the other hand, the proportion of the recipient and donor LA cuffs as estimated by the recipient/global LA area ratio and the LA emptying fraction significantly correlated with the E/A ratio (r = 0.40, P = 0.005 and r =-0.33, P = 0.022, respectively). CONCLUSION: Our study shows that there is a high prevalence of elevated E/A ratio after standard OCT which seems mainly related to reduced LA contractility. Recognition of this "pseudorestrictive" pattern may avoid misdiagnosis of diastolic dysfunction. PMID- 21276074 TI - Transmural myocardial strain gradient: a new and robust quantitative index of left ventricular wall motion based on myocardial strain imaging. AB - BACKGROUND: Peak strain has been promising as an index of wall motion but it is sometimes susceptible to the image quality. OBJECTIVE: We investigated the feasibility of a novel index, transmural myocardial strain gradient (TMSG), derived from myocardial strain M-mode imaging (TDI-Q, Toshiba) for quantifying regional systolic wall motion. METHOD: We measured transmural myocardial strain distribution at the left ventricular lateral, posterior, inferior, septal, anteroseptal and anterior walls in the basal and midventricular short-axis images using TDI-Q. Twenty normals (35 +/- 3 years) and 35 consecutive patients (63 +/- 9 years) with coronary artery disease (CAD, 19 patients with old myocardial infarction, 4 patients with acute myocardial infarction, 12 patients with angina pectoris) were studied. Peak strain, endocardial- and epicardial-half strain and TMSG ((peak strain, - epicardial strain)/distance between peak and epicardial points) were obtained. Coefficient of variation (CV) of each index was calculated. RESULTS: In control subjects, the best reproducibility of the variables was obtained for TMSG with the smallest CV (11.6%) (27.8%, 28.1%, and 35.5%, respectively for CV of peak strain, endocardial- and epicardial-half strain). All segments in control subjects and normal segments in CAD patients showed no significant difference in TMSG (15.1 +/- 1.8 vs. 15.1 +/- 1.6%/mm, P = ns). TMSG was the lowest for akinetic segments and highest for the normal segments (P < 0.001). CONCLUSION: TMSG was more robust than simple strain values to quantitatively assess wall motion. This could successfully identify subtle regional differences in wall function. PMID- 21276075 TI - A patient selection score for cardiac resynchronization therapy. AB - BACKGROUND: We hypothesized a patient selection score (PSS) may improve patient selection for cardiac resynchronization therapy (CRT). METHODS: Of 136 patients who received CRT, group A included 100 study patients and group B 36 patients for validation. A positive response to CRT was a left ventricular (LV) end-systolic volume decrease of >=15% and survival from heart failure at end of follow-up. RESULTS: Of 100 group A patients, 37 (37%) were CRT responders during 14-month follow-up. A 7-point PSS was generated based on six variables. The cutoff point for PSS to predict a positive response to CRT was >4 by receiver operating characteristic (ROC) analysis. The area under the ROC curve (AUC) for PSS to predict CRT response was 0.94 (P = 0.0001). CRT responders in patients with a PSS > 4 and <=4 were 33/40 (83%), and 4/60 (7%), respectively (P < 0.001). Multivariate Cox proportional regression analysis showed that PSS was related to CRT response (hazard ratio = 10.3, P < 0.0001). The CRT response rate in patients with a PSS > 4 in Group B was also significantly higher compared to a PSS <= 4 (88% vs. 16%, P < 0.001). The AUC for PSS to predict a CRT response in Group B was 0.91 (P = 0.0001). CONCLUSIONS: Patients with a PSS >4 are the most likely to respond to CRT. Using this score system, a PSS score >4 can predict the probability of a CRT response up to 88% in patients with heart failure and a wide QRS duration. PMID- 21276076 TI - Increased intima-media thickness in carriers of the ldl-receptor defective gene versus noncarriers with newly detected asymptomatic severe hypercholesterolemia. AB - BACKGROUND: The data on the examination of early vascular alterations in carriers of molecular defects of the low-density lipoprotein-receptor (LDL-R) in comparison to noncarriers with severe hypercholesterolemia are controversial. AIMS: To examine the difference between patients with severe hypercholesterolemia, who are carriers and noncarriers of LDL-R defective gene, with respect to their functional (flow-mediated vasodilation) and structural (intima-media thickness of carotid artery) characteristics of arterial wall. A total of 250 hypercholesterolemic patients were enrolled. Biochemistry parameters were examined by routine methods. The molecular biological analysis included R3500Q-mutation in the Apolipoprotein-B (Apo-B) gene, LDL-R gene mutation and polymorphism (and the promoter region), as large rearrangements. Determination of flow-mediated vasodilation and intima-media thickness of common carotid artery was performed with Hewlett Packard Sonos 5500, using automated computer software MedicaSoft. IMT.lab. RESULTS: There was no significant difference between the groups with respect to total cholesterol, LDL, HDL, Apo-B, Apolipoprotein A(1) (Apo-A(1) ), asymmetric dimethylarginine (ADMA), homocysteine, and cellular adhesion molecules. The Apo-B/Apo A(1) index differed significantly (t = 11.23, P < 0.001) between the two groups and this difference was found even after adjustment for age and gender. There was no significant difference with respect to the endothelial dependent and independent vasodilatation between the examined groups (P > 0.05). We were founded a significantly higher carotid IMT in the carriers versus noncarriers. This significant difference was confirmed after adjustment for age and gender. Statistically significant correlations we were founded between IMT mean and age (log) (r(xy) = 0.45; P < 0.01), cholesterol * years score (log) (r(xy) = 0.53; P < 0.01), Apo-B/A(1) (log) (r(xy) = 0.66; P < 0.001) in the group of the carriers. Backward selection process selected Apo B/A(1) as the most important statistically significant factor related to IMT mean of common carotid artery (F = 105.22; P = 0.001; R(2) = 0.72). CONCLUSION: Our data demonstrate that carriers of the LDL-R defective gene have a higher carotid IMT and Apo B/Apo A(1) index than noncarriers, whereas no difference between the groups was found with respect to the level of lipid parameters, ADMA, total homocysteine, cell adhesion molecules and %FMD. Apo-B/A(1) is a predictor of IMT mean in the group of the carriers of the LDL-receptor gene. PMID- 21276077 TI - Effect of performing real time three-dimensional transesophageal echocardiography in addition to two-dimensional transesophageal echocardiography on operator diagnostic confidence. AB - BACKGROUND: This study evaluates the effects of performing real time three dimensional transesophageal echocardiography in addition to conventional two dimensional transesophageal echocardiography on diagnostic confidence. METHODS: Operator diagnostic confidence in addressing clinical questions posed by the referral was scored using a five-point scale for two-dimensional transesophageal echocardiography alone and the combination of two-dimensional and real time three dimensional transesophageal echocardiography in 136 consecutive patients undergoing examination in an academic hospital. RESULTS: Mean diagnostic confidence score was higher for the combined studies compared to two-dimensional transesophageal echocardiography alone (4.5 vs. 4.1, P < 0.001)). The addition of real time three-dimensional transesophageal echocardiography increased diagnostic confidence score in 45 (33.1%) patients, and the percentage of studies with total diagnostic confidence rose from 40.4% with two-dimensional transesophageal echocardiography alone to 65.4% after performing real time three-dimensional transesophageal echocardiography. Type of clinical indication was associated with improved score by the combined exams (P < 0.004). The addition of real time three dimensional transesophageal echocardiography was most likely to improve diagnostic confidence score in studies performed to assess valve disease (56.1%) and least likely in examinations performed for intracardiac infection (14.9%). The location (anterior or posterior) of the primary cardiac pathology was not associated with improved score by the combined studies (P = 0.498). CONCLUSIONS: The addition of real time three-dimensional transesophageal echocardiography to two-dimensional transesophageal echocardiography increases diagnostic confidence in examinations routinely performed in an academic practice. Further studies of the impact of real time three-dimensional transesophageal echocardiography on patient management, outcomes and displacement of or need for downstream testing are warranted. PMID- 21276078 TI - Diagnosis and percutaneous closure of a large coronary fistula. PMID- 21276079 TI - Coexistence of TDP-43 and tau pathology in neurodegeneration with brain iron accumulation type 1 (NBIA-1, formerly Hallervorden-Spatz syndrome). AB - We report here an autopsy case of sporadic adult-onset Hallervorden-Spatz syndrome, also known as neurodegeneration with brain iron accumulation type 1 (NBIA1), without hereditary burden. A 49-year-old woman died after a 27-year disease course. At the age of 22, she suffered from akinesia, resting tremor, and rigidity. At the age of 28, she was admitted to our hospital because of worsening parkinsonism and dementia. Within several years, she developed akinetic mutism. At the age of 49, she died of bleeding from a tracheostomy. Autopsy revealed a severely atrophic brain weighing 460 g. Histologically, there were iron deposits in the globus pallidus and substantia nigra pars reticulata, and numerous axonal spheroids in the subthalamic nuclei. Neurofibrillary tangles were abundant in the hippocampus, cerebral neocortex, basal ganglia, and brain stem. Neuritic plaques and amyloid deposits were absent. Lewy bodies and Lewy neurites, which are immunolabeled by anti-alpha-synuclein, were absent. We also observed the presence of TDP-43-positive neuronal perinuclear cytoplasmic inclusions, with variable frequency in the dentate gyrus granular cells, frontal and temporal cortices, and basal ganglia. TDP-43-positive glial cytoplasmic inclusions were also found with variable frequency in the frontal and temporal lobes and basal ganglia. The present case was diagnosed with adult-onset NBIA-1 with typical histological findings in the basal ganglia and brainstem. However, in this case, tau and TDP 43 pathology was exceedingly more abundant than alpha-synuclein pathology. This case contributes to the increasing evidence for the heterogeneity of NBIA-1. PMID- 21276080 TI - An immunohistochemical finding in glioneuronal lesions associated with epilepsy: the appearance of nestin-positive, CD34-positive and tau-accumulating cells. AB - Several kinds of unusual cells have been pathologically identified in epileptic patients. CD34-positive, nestin-positive and tau-positive cells are some of them. However, no reports have investigated the significance of these cells. We examined 14 cases of seizure-associated glioneuronal lesions to investigate the incidences and distributions of these cells and the association between their incidence and clinical parameters. CD34-positive and nestin-positive cells were seen in 43% and 50% of cases, respectively. In the regions with structural anomalies, there were increased numbers of CD34-positive cells and nestin positive cells, but they were identified as different cells. Both examinations showed many abnormal processes in oligodendroglial-like cells with round nuclei. In contrast, few reactive astrocytes that demonstrated immunoreactivity for glial fibrillary acidic protein were found in this area. Tau accumulation was present in 37% of cases. There was no correspondence with the regions showing increasing numbers of nestin or CD34-positive cells. There were no significant associations between epileptic clinical parameters and the incidences of the abovementioned immunopositive cells. CD34-positive cells and nestin-positive cells are found as frequently as balloon cells and are associated with abnormal reconstitution of the cortex. These findings support the assertion that increases in the numbers of these cells might contribute to promoting epilepsy. In addition, these immunopositive cells are valuable findings for the pathological identification of epileptogenic lesions. PMID- 21276081 TI - Atypical teratoid/rhabdoid tumors may show morphological and immunohistochemical features seen in choroid plexus tumors. AB - Atypical teratoid/rhabdoid tumors (AT/RT) are aggressive embryonal tumors having a poor prognosis and are associated with mutations in the tumor suppressor gene hSNF5/SMARCB1/INI1. Differential diagnosis includes choroid plexus carcinoma which has occasionally been attributed as showing an inactivation of INI1/SMARCB1 nuclear staining in immunohistochemistry. However, these findings have been challenged by others. We therefore examined eight AT/RTs from six patients by immunohistochemistry for membranous expression of the inward rectifier potassium channel Kir7.1, which was in the central nervous system so far considered specific for choroid plexus tumors and normal choroid plexus epithelium. Two AT/RT cases exhibited membranous staining of Kir7.1, indicating a plexus epithelial differentiation of these tumors. The implications of these results on tumor diagnosis are discussed. PMID- 21276082 TI - Developmental alterations of the spinal trigeminal nucleus disclosed by substance P immunohistochemistry in fetal and infant sudden unexplained deaths. AB - We investigated the immunohistochemical expression of substance P (SP) in the brainstems of 56 subjects aged from 17 gestational weeks to 10 post natal months, who died of unknown (sudden unexplained fetal deaths and SIDS) and known causes (controls). The goals of this study were: (i) to obtain basic information about the expression of SP during the first phases of human nervous system development; (ii) to evaluate whether there are alterations of this neuromodulator in victims of sudden death; and (iii) to verify any correlation with maternal cigarette smoking. Immunohistochemistry demonstrated SP immunoreactivity in the caudal trigeminal nucleus area, with a progressive increase in the density of SP positive fibers of the corresponding tract during normal development from fetal life to the first post natal months. Delineation of the structure of the human trigeminal nucleus, little investigated so far, provided essential data on its morphologic and functional development. Instead, a negative or low SP expression was detectable in the fibers of this tract in a wide subset of SIDS victims and, conversely, a high SP-expression in a wide subset of sudden fetal deaths. We postulate, on the basis of these results, that SP has a functional importance in the early phases of central nervous system development and in the regulation of autonomic functions. In addition, the observation of a significant correlation between sudden unexplained death, altered SP staining and maternal smoking leads us to suggest a close relation between the absorption of cigarette smoke in utero and a decreased functional activity of the trigeminal nucleus, that can trigger sudden death of the fetus during pregnancy or of the infant in the first months of life. PMID- 21276083 TI - Hypertrophy of hippocampal end folium neurons in patients with mesial temporal lobe epilepsy. AB - Hypertrophic and dysmorphic neurons have been identified in the hippocampal end folium of patients with mesial temporal lobe epilepsy (mTLE). No data are available regarding the correlation between these cellular alterations and the severity of hippocampal sclerosis (HS), and the significance of this phenomenon has been unclear. We evaluated both the perikaryon and nuclear areas of residual neurons in the hippocampal end folium of 47 patients with mTLE, seven with lesional neocortical temporal lobe epilepsy (LTLE), and 10 controls without seizure episodes. According to the severity of neuron loss in the end folium, we defined mTLE cases showing slight (<10%) or no, moderate (10-50%) and severe (>50%) loss as groups A, B and C, respectively. We also performed immunohistochemistry with antibodies against heat shock protein 70 and the phosphorylated epitope of neurofilament. In both mTLE and LTLE cases, the perikaryon and nuclear areas of the end folium neurons were significantly greater than those in the controls (P < 0.0001), and those in mTLE were significantly greater than those in LTLE. There were no differences in areas between groups A and B, but the areas in group C were significantly greater than those of both groups A and B. Neurons with large, bizarre morphology were labeled with both antibodies. Neuronal hypertrophy is evident in patients with epilepsy, and appears to advance gradually as the hippocampal sclerosis becomes more severe. This alteration may be a consequence of cellular stress incurred by neurons. PMID- 21276084 TI - Perioperative management of transurethral surgery for benign prostatic hyperplasia: a nationwide survey in Japan. AB - OBJECTIVES: Various types of minimally invasive surgical treatments, including transurethral resection of prostate (TURP), are being carried out in Japan for patients with benign prostatic hyperplasia (BPH). The aim of the present study was to elucidate the current status of perioperative care for these treatments by carrying out a nationwide survey. METHODS: Assisted by the Japanese Endourology and ESWL Association, perioperative data from 157 institutions participating in this survey were collected and analyzed. RESULTS: This survey included 3918 patients undergoing TURP, 242 TUR in saline (TURis), 638 holmium laser enucleation of the prostate (HoLEP), 90 holmium laser ablation (HoLAP) and 241 photoselective vaporization (PVP). Mean operative time was shorter in TURP (71 min) and longer in HoLEP (127). Although no transfusions were required in cases undergoing HoLAP or PVP, blood was frequently transfused in those undergoing TURis (25.6%), TURP (10.2%) and HoLEP (7.8%), and the difference was significant. During the hospital stay, the incidence of TUR-syndrome, postoperative bleeding requiring bladder irrigation, acute urinary retention/difficulty on micturition and pad use at discharge was highest in TURP (2.3%), TURis (7.9%), HoLAP (16.7%) and HoLEP (15.1%), respectively. Two patients undergoing TURP died (0.05%). The shortest mean postoperative hospital stay was for PVP (1.6 days, even if the readmission rate within 90 days was the highest in this same group; 6.2%). Perioperative care during hospital stay varied among the five types of procedures. CONCLUSIONS: This survey provides useful documentation on the current status of minimally invasive treatments for BPH in Japan. Complication rates for TURP are not significantly higher as compared with other procedures. Thus, TURP can still be considered as the gold standard for BPH treatment. PMID- 21276085 TI - Robustness of a loop-mediated isothermal amplification reaction for diagnostic applications. AB - We evaluated the robustness of loop-mediated isothermal amplification (LAMP) of DNA for bacterial diagnostic applications. Salmonella enterica serovar Typhi was used as the target organism and compared with a real-time quantitative PCR (qPCR) for testing assay performance and reproducibly, as well as the impact of pH and temperature stability. This isothermal amplification method appeared to be particularly robust across 2 pH units (7.3-9.3) and temperature values (57-67 degrees C). The detection limit was comparable to that observed using optimized home-brew qPCR assays. The specificity of the amplification reaction remained high even at temperatures markedly different from the optimal one. Exposing reagents to the ambient temperature during the preparation of the reaction mixture as well as prolonging times for preparing the amplification reaction did not yield false-positive results. LAMP remained sensitive and specific despite the addition of untreated biological fluids such as stool or urine that commonly inhibit PCR amplification. Whereas the detection of microorganisms from whole blood or a blood-culture medium typically requires extensive sample purification and removal of inhibitors, LAMP amplification remained more sensitive than conventional qPCR when omitting such preparatory steps. Our results demonstrate that LAMP is not only easy to use, but is also a very robust, innovative and powerful molecular diagnostic method for both industrialized and developing countries. PMID- 21276086 TI - Porphyromonas gingivalis stimulates monocyte adhesion to human umbilical vein endothelial cells. AB - Monocyte recruitment to the endothelium is a crucial step in the inflammatory response that precedes the development of atherosclerosis. We assessed the effect of Porphyromonas gingivalis on monocyte adhesion to endothelial cells, cytokine production during monocyte/endothelial cell co-culture, and the expression of cell adhesion molecules on human umbilical vein endothelial cells (HUVEC) and their ligands on monocytes. Porphyromonas gingivalis challenge significantly increased the adhesion of THP-1 monocytes to HUVEC, the production of interleukin (IL)-6, IL-8, and monocyte chemoattractant protein 1 (MCP-1) in co-cultures of HUVEC and THP-1 cells, and the transcription and translation of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E selectin in HUVEC. The transcription of tumor necrosis factor receptor-associated factor 1 was also increased in HUVEC and THP-1 cells by P. gingivalis infection. Moreover, the stimulation of monocyte adhesion to HUVEC by P. gingivalis infection was partially inhibited by pretreatment with a mixture of anti-ICAM-1, VCAM, and -E-selectin monoclonal antibodies. These data suggest that adherence between HUVEC and THP-1 cells, followed by the production of cytokines and chemokines, was enhanced by increased expression of cell adhesion molecules on P. gingivalis-sensitized HUVEC, which in turn led to inflammatory atherogenesis. PMID- 21276087 TI - Effects of an aqueous alfalfa extract on production performance, egg quality and lipid metabolism of laying hens. AB - The present study was conducted to evaluate the effect of an aqueous alfalfa extract (AAE) on production performance, egg quality and lipid metabolism of laying hens between 28 and 36 weeks of age. Four groups of commercial hens (Hy Line Brown) were fed with diets containing 0, 0.05%, 0.1% and 0.15% AAE. Dietary AAE had no effect on egg production parameters (p > 0.05). Shell strength was increased (linear and quadratic effects; p < 0.05) with gradient addition of AAE. Furthermore, shell strength was notably higher (p < 0.05) in 0.1% and 0.15% AAE groups than the control group. With an exception of serum low and high density lipoprotein cholesterol, serum total triglycerides and liver cholesterol concentration (day 42), lipid indices in yolk, serum and liver were lowered (linear and quadratic effects; p < 0.05) at day 42 and day 56 as AAE in diets increased, as well as the enzyme activities of acetyl-CoA carboxylase (ACC) and beta-hydroxy-beta-methylglutaryl-CoA (HMG-CoA) reductase. In relation to the control group, cholesterol and triglycerides in yolk, liver and serum and serum very low density lipoprotein cholesterol were lower in 0.15% AAE-treated birds at day 42 and day 56. It also significantly decreased activities of ACC, HMG-CoA reductase and fatty acid synthetase (FAS) at day 56. The 0.1% AAE decreased triglycerides in yolk, liver and serum, as well as the activities of ACC and FAS at day 56. These data suggest that dietary AAE could be applied to improve egg shell quality and modify the lipid status of laying hens and eggs. PMID- 21276088 TI - High brain-natriuretic peptide level predicts cirrhotic cardiomyopathy in liver transplant patients. AB - Cirrhotic cardiomyopathy may appear following liver transplantation. Brain natriuretic peptide (BNP) values exceeding 391 pg/ml or 567 pg/ml may partially reflect ventricular stress because of cardiac dysfunction or indicate cirrhotic cardiomyopathy, respectively. The aim of the study was to assess cardiac dysfunction in liver transplant patients and its correlation with BNP as a biomarker. From 1/2008 to 7/2009, 157 adult liver transplant recipients with proven cirrhosis were recruited for the study. BNP and liver enzymes were recorded upon admission, on the first postoperative day (POD) and 1 week after transplantation. Patients with ischemic heart attacks were excluded from the study. We identified two groups of patients. Group 1 was characterized by a BNP <391 pg/ml and Group 2 by a BNP >391 pg/ml. Group 2 had a significantly higher model of end-stage liver disease score than Group 1 (median 30, range 10-40 versus median 22, range 10-40, respectively; P = 0.003), required significantly more dialysis treatments and had a significantly higher mortality rate. Postoperative echocardiography in patients with a BNP >391 pg/ml indicated diastolic dysfunction in all of the patients and systolic dysfunction in 10 of the patients. Increased serum-BNP was associated with an overall higher mortality rate. PMID- 21276089 TI - Flt3L-mobilized dendritic cells bearing H2-Kbm1 apoptotic cells do not induce cross-tolerance to CD8+ T cells across a class I MHC mismatched barrier. AB - Tolerization of allogeneic CD8(+) T cells is still a pending issue in the field of transplantation research to achieve long-term survival. To test whether dendritic cells (DC) bearing allogeneic major histocompatibility complex (MHC) class I mismatched apoptotic cells could induce cross-tolerance to alloreactive CD8(+) T cells, the following experimental strategy was devised. Rag2/gamma(c) KO B6 mice were treated with Fms-like tyrosine kinase 3 ligand (Flt3L)-transduced B16 melanoma cells to drive a rapid expansion and mobilization of DC in vivo. Of all DC populations expanded, splenic CD11c(+) CD103(+) CD8alpha(+) DC were selectively involved in the process of antigen clearance of X-ray irradiated apoptotic thymocytes in vivo. Considering that CD11c(+) CD103(+) CD8alpha(+) DC selectively take up apoptotic cells and that they are highly specialized in cross presenting antigen to CD8(+) T cells, we investigated whether B6 mice adoptively transferred with Flt3L-derived DC loaded with donor-derived apoptotic thymocytes could induce tolerance to bm1 skin allografts. Our findings on host anti-donor alloresponse, as revealed by skin allograft survival and cytotoxic T lymphocyte assays, indicated that the administration of syngeneic DC presenting K(bm1) donor derived allopeptides through the indirect pathway of antigen presentation was not sufficient to induce cross-tolerance to alloreactive CD8(+) T cells responding to bm1 alloantigens in a murine model of skin allograft transplantation across an MHC class I mismatched barrier. PMID- 21276090 TI - The principles of gift law and the regulation of organ donation. AB - The principles of gift law establish a consistent international legal understanding of consent to donation under a range of regulatory systems. Gift law as the primary legal principle is important to both the foundation of systems that prevent organ sales and the consideration of strategies to increase organ donation for transplantation. PMID- 21276091 TI - Striving to achieve a national self-sufficiency. PMID- 21276092 TI - A MADS-box transcription factor MoMcm1 is required for male fertility, microconidium production and virulence in Magnaporthe oryzae. AB - Appressorium formation is a key step in the infection cycle of Magnaporthe oryzae. Mst12 is a transcription factor essential for appressorium penetration and invasive growth. In this study we used the affinity purification approach to identify proteins that physically associate with Mst12. One of the Mst12 interacting genes identified was MoMCM1, which encodes a MADS-box protein orthologous to yeast Mcm1. MoMcm1 interacted with both Mst12 and Mata-1 in yeast two-hybrid assays. Deletion of MoMCM1 resulted in the loss of male fertility and microconidium production. The Momcm1 mutant was defective in appressorium penetration and formed narrower invasive hyphae, which may be responsible for its reduced virulence. In transformants expressing MoMCM1-eGFP fusion, GFP signals were observed in the nucleus. We also generated the Momcm1 mst12 double mutant, which was defective in penetration and non-pathogenic. On hydrophilic surfaces, germ tubes produced by the double mutant were severely curved, and 20% of them formed appressoria. In contrast, the Momcm1 or mst12 mutant did not form appressoria on hydrophilic surfaces. These results suggest that MoMCM1 and MST12 have overlapping functions to suppress appressorium formation under non-conducive conditions. MoMcm1 may interact with Mst12 and MatA-1 to regulate germ tube identity and male fertility respectively. PMID- 21276094 TI - Multiple effects of benzamide antibiotics on FtsZ function. AB - Cell division in almost all bacteria is orchestrated by the essential tubulin homologue FtsZ, which assembles into a ring-like structure and acts as a scaffold for the division machinery. Division was recently validated as an important target for antibiotics by the demonstration that low-molecular-weight inhibitors of FtsZ, called benzamides, can cure mice infected with Staphylococcus aureus. In treated cells of Bacillus subtilis we show that FtsZ assembles into foci throughout the cell, including abnormal locations at the cell poles and over the nucleoid. These foci are not inactive aggregates because they remain dynamic, turning over almost as rapidly as untreated polymers. Remarkably, although division is completely blocked, the foci efficiently recruit division proteins that normally co-assemble with FtsZ. However, they show no affinity for components of the Min or Nucleoid occlusion systems. In vitro, the benzamides strongly promote the polymerization of FtsZ, into hyperstable polymers, which are highly curved. Importantly, even at low concentrations, benzamides transform the structure of the Z ring, resulting in abnormal helical cell division events. We propose that benzamides act principally by promoting an FtsZ protomer conformation that is incompatible with a higher-order level of assembly needed to make a division ring. PMID- 21276093 TI - CaMtw1, a member of the evolutionarily conserved Mis12 kinetochore protein family, is required for efficient inner kinetochore assembly in the pathogenic yeast Candida albicans. AB - Proper assembly of the kinetochore, a multi-protein complex that mediates attachment of centromere DNA to spindle microtubules on each chromosome, is required for faithful chromosome segregation. Each previously characterized member of the Mis12/Mtw1 protein family is part of an essential subcomplex in the kinetochore. In this work, we identify and characterize CaMTW1, which encodes the homologue of the human Mis12 protein in the pathogenic budding yeast Candida albicans. Subcellular localization and chromatin immunoprecipitation assays confirmed CaMtw1 is a kinetochore protein. CaMtw1 is essential for viability. CaMtw1-depleted cells and cells in which CaMtw1 was inactivated with a temperature-sensitive mutation had reduced viability, accumulated at the G2/M stage of the cell cycle, and exhibited increased chromosome missegregation. CaMtw1 depletion also affected spindle length and alignment. Interestingly, in C. albicans, CaMtw1 and the centromeric histone, CaCse4, influence each other for kinetochore localization. In addition, CaMtw1 is required for efficient kinetochore recruitment of another inner kinetochore protein, the CENP-C homologue, CaMif2. Mis12/Mtw1 proteins have well-established roles in the recruitment and maintenance of outer kinetochore proteins. We propose that Mis12/Mtw1 proteins also have important co-dependent interactions with inner kinetochore proteins and that these interactions may increase the fidelity of kinetochore formation. PMID- 21276095 TI - DNA supercoiling is differentially regulated by environmental factors and FIS in Escherichia coli and Salmonella enterica. AB - Although Escherichia coli and Salmonella enterica inhabit similar niches and employ similar genetic regulatory programmes, we find that they differ significantly in their DNA supercoiling responses to environmental and antibiotic challenges. Whereas E. coli demonstrates large dynamic transitions in supercoiling in response to growth phase, osmotic pressure and novobiocin treatment, supercoiling levels are much less variable in S. enterica. The FIS protein is a global regulator of supercoiling in E. coli, but it was found to have less influence over supercoiling control in S. enterica. These inter-species differences fine-tune gene promoters to endogenous supercoiling and FIS levels. Transferring a Salmonella virulence gene promoter (P(ssrA) ) into a new enteric host (E. coli) caused aberrant expression in response to stimulatory signals. Reciprocal horizontal transfer of topA promoters, which control expression of topoisomerase I, between E. coli and S. enterica revealed how these orthologous promoters have evolved to respond differentially to FIS and supercoiling levels in their cognate species. This also identified a previously unrecognized osmoregulation of topA expression that is independent of FIS and supercoiling in both E. coli and S. enterica. These findings suggest that E. coli and S. enterica may be unexpectedly divergent in their global regulation of cellular physiology. PMID- 21276096 TI - Lactococcal phage p2 ORF35-Sak3 is an ATPase involved in DNA recombination and AbiK mechanism. AB - Virulent phages of the Siphoviridae family are responsible for milk fermentation failures worldwide. Here, we report the characterization of the product of the early expressed gene orf35 from Lactococcus lactis phage p2 (936 group). ORF35(p2), also named Sak3, is involved in the sensitivity of phage p2 to the antiviral abortive infection mechanism AbiK. The localization of its gene upstream of a gene coding for a single-strand binding protein as well as its membership to a superfamily of single-strand annealing proteins (SSAPs) suggested a possible role in homologous recombination. Electron microscopy showed that purified ORF35(p2) form a hexameric ring-like structure that is often found in proteins with a conserved RecA nucleotide-binding core. Gel shift assays and surface plasmon resonance data demonstrated that ORF35(p2) interacts preferentially with single-stranded DNA with nanomolar affinity. Atomic force microscopy showed also that it preferentially binds to sticky DNA substrates over blunt ends. In addition, in vitro assays demonstrated that ORF35(p2) is able to anneal complementary strands. Sak3 also stimulates Escherichia coli RecA-mediated homologous recombination. Remarkably, Sak3 was shown to possess an ATPase activity that is required for RecA stimulation. Collectively, our results demonstrate that ORF35(p2) is a novel SSAP stimulating homologous recombination. PMID- 21276097 TI - Haem release from haemopexin by HxuA allows Haemophilus influenzae to escape host nutritional immunity. AB - Haemophilus influenzae is an obligate human commensal/pathogen. This haem auxotroph must acquire haem from its host to sustain aerobic growth. Haem haemopexin complexes are one of the potential sources of haem for this microorganism. Haemopexin is a glycoprotein that binds haem with high affinity (subpicomolar Kd) and involved in haem recycling. HxuA, a cell surface protein, is the key to haem acquisition from haemopexin. In this study, we reconstituted a functional Hxu system from H. influenzae in Escherichia coli K-12 that mediated active haem transport across the outer membrane from haem-haemopexin, in the presence of the inner membrane energy-transducing TonB-ExbB-ExbD complex from H. influenzae. A secreted variant of HxuA, HxuA(dm), was produced in E. coli. HxuA(dm) functionally complemented an hxuA mutant of H. influenzae for haem haemopexin acquisition. HxuA(dm) interacted with haemopexin and haem-haemopexin, with which it formed high-affinity, stoichiometric complexes. Following the interaction between haem-haemopexin and HxuA(dm), haem was no longer bound to its initial high-affinity site and became accessible to its cognate haem receptor, HxuC. HxuA(dm) and the HxuA(dm)-haemopexin complex do not appear to bind haem at detectable levels (affinities below 10(6) M(-1)). HxuA thus appears to 'release' haem from haem-haemopexin complexes and to prevent haem sequestering by haemopexin. PMID- 21276098 TI - Complex binding of the FabR repressor of bacterial unsaturated fatty acid biosynthesis to its cognate promoters. AB - Two transcriptional regulators, the FadR activator and the FabR repressor, control biosynthesis of unsaturated fatty acids in Escherichia coli. FabR represses expression of the two genes, fabA and fabB, required for unsaturated fatty acid synthesis and has been reported to require the presence of an unsaturated thioester (of either acyl carrier protein or CoA) in order to bind the fabA and fabB promoters in vitro. We report in vivo experiments in which unsaturated fatty acid synthesis was blocked in the absence of exogenous unsaturated fatty acids in a DeltafadR strain and found that the rates of transcription of fabA and fabB were unaffected by the lack of unsaturated thioesters. To examine the discrepancy between our in vivo results and the prior in vitro results we obtained active, natively folded forms of the E. coli and Vibrio cholerae FabRs by use of an in vitro transcription-translation system. We report that FabR bound the intact promoter regions of both fabA and fabB in the absence of unsaturated acyl thioesters, but bound the two promoters differently. Native FabR bound the fabA promoter region provided that the canonical FabR binding site is extended by inclusion of flanking sequences that overlap the neighbouring FadR binding site. In contrast, although binding to the fabB operator also required a flanking sequence, a non-specific sequence could suffice. However, unsaturated thioesters did allow FabR binding to the minimal FabR operator sites of both promoters which otherwise were not bound. Thus unsaturated thioester ligands were not essential for FabR/target DNA interaction, but acted to enhance binding. The gel mobility shift data plus in vivo expression data indicate that despite the remarkably similar arrangements of promoter elements, FadR predominately regulates fabA expression whereas FabR is the dominant regulator of fabB expression. We also report that E. coli fabR expression is not autoregulated. Complementation, qRT-PCR and fatty acid composition analyses demonstrated that V. cholerae FabR was a functional repressor of unsaturated fatty acid synthesis. However, in contrast to E. coli, gel mobility shift assays indicated that neither E. coli nor V. cholerae FabRs bound the V. cholerae fabB promoter, although both proteins efficiently bound the V. cholerae fabA promoter. This asymmetry was shown to be due to the lack of a FabR binding site within the V. cholerae fabB promoter region. PMID- 21276099 TI - Mutation of GOGAT prevents pea bacteroid formation and N2 fixation by globally downregulating transport of organic nitrogen sources. AB - Mutation of gltB (encoding glutamate oxoglutarate amidotransferase or GOGAT) in RU2307 increased the intracellular Gln:Glu ratio and inhibited amino acid transport via Aap and Bra. The mechanism probably involves global post translational inhibition independent of Ntr. Transport was separately restored by increased gene expression of Aap or heterologous transporters. Likewise, second site suppressor mutations in the RNA chaperone Hfq elevated transport by Aap and Bra by increasing mRNA levels. Microarrays showed Hfq regulates 34 ABC transporter genes, including aap, bra and opp. The genes coding for integral membrane proteins and ABC subunits aapQMP braDEFGC were more strongly elevated in the hfq mutants than solute-binding proteins (aapJ braC). aapQMP and braDEFG are immediately downstream of stem-loops, indicating Hfq attenuates downstream translation and stability of mRNA, explaining differential expression of ABC genes. RU2307 nodulated peas and bacteria grew down infection threads, but bacteroid development was arrested and N(2) was not fixed. This probably results from an inability to synthesize or transport amino acids. However, GOGAT and GOGAT/AldA double mutants carrying suppressor mutations that increased amino acid uptake fixed N(2) on pea plants. Thus de novo ammonium assimilation into amino acids is unnecessary in bacteroids demonstrating sufficient amino acids are supplied by plants. PMID- 21276100 TI - Rhythms of sleep: orchestrating memory consolidation (Commentary on Clemens et al.). PMID- 21276101 TI - Oestrogen-independent, experience-induced maternal behaviour in female mice. AB - Nulliparous female mice that have not experienced mating, pregnancy or parturition show near immediate spontaneous maternal behaviour when presented with foster pups. The fact that virgin mice display spontaneous maternal behaviour indicates that the hormonal events of pregnancy and parturition are not necessary to produce a rapid onset of maternal behaviour in mice. However, it is not known how similar maternal behaviour is between virgin and lactating mice. In the present study, we show that naturally postpartum females are faster to retrieve pups and spend more time crouching over pups than spontaneously maternal virgin females, and that these differences diminish with increased maternal experience. Moreover, 4 days of experience with pups induced pup retrieval on a novel T-maze. Furthermore, the effects of experience on subsequent maternal responsiveness are not dependent on gonadal hormones because ovariectomised females with 4 days of pup experience show pup retrieval on a novel T-maze similar to that of postpartum mice. Four days of maternal experience also induced T-maze pup retrieval in ovariectomised aromatase knockout female mice that was not significantly different from the maternal responsiveness of ovariectomised wild-type littermates. These data suggest that maternal experience can induce maternal behaviour in females that have never been exposed to oestradiol at any time in development or adulthood. Finally, ovariectomised pup-experienced females continue to retrieve pups on a novel T-maze 1 month after the initial experience, suggesting that, even in the absence of oestradiol, maternal experience produces long-lasting modifications in maternal responsiveness. PMID- 21276102 TI - Dopamine D1 receptor blockage potentiates AMPA-stimulated luteinising hormone release in the goldfish. AB - Previous microarray analyses of the goldfish hypothalamus led us to hypothesise that dopamine could potentially inhibit the excitatory effects of glutamate on luteinising hormone (LH). Post-spawning female goldfish were pre-treated (-4.5 h) with either saline (C; control), SCH 23390 (S; D(1) -receptor antagonist) or sulpiride (L; D(2) -receptor antagonist), followed by an i.p. injection, at -0.5 h, of saline or the glutamate agonist AMPA (A, SA or LA). Blood, hypothalamus and telencephalon tissues were collected. Serum LH was not affected in the S, L, A, or LA groups relative to control as determined by radioimmunoassay. The SA group, however, showed a 289% (P<0.0005) increase in serum LH compared to either treatment alone or control. Real-time reverse transcriptase-polymerase chain reaction identified the mRNAs for ionotropic (Gria2a, Gria4) glutamate receptor subunits, activin betaa, isotocin, and cGnRH-II as being significantly affected by some of the treatments. The same experiment conducted with sexually-regressed female fish showed a very different LH profile, indicating that this mechanism is seasonally-dependent. We also show that i.p. injection of 1 MUg/g isotocin was able to increase LH levels by 167% in sexually regressed female fish relative to controls. Taken together, these results demonstrate that blockage of the D(1) receptor primes post-spawning goldfish for AMPA-stimulated LH release, and provides further insights into the central regulation of reproduction. PMID- 21276103 TI - Transcription-dependence of histone H3 lysine 27 trimethylation at the Arabidopsis polycomb target gene FLC. AB - The FLC gene encodes a MADS box repressor of flowering that is the main cause of the late-flowering phenotype of many Arabidopsis ecotypes. Expression of FLC is repressed by vernalization; maintenance of this repression is associated with the deposition of histone 3 K27 trimethylation (H3K27me3) at the FLC locus. However, whether this increased H3K27me3 is a consequence of reduced FLC transcription or the cause of transcriptional repression is not well defined. In this study we investigate the effect of changes in transcription rate on the abundance of H3K27me3 in the FLC gene body, a chromatin region that includes sequences required to maintain FLC repression following vernalization. We show that H3K27me3 is inversely correlated with transcription across the FLC gene body in a range of ecotypes and mutants with different flowering times. We demonstrate that the FLC gene body becomes marked with H3K27me3 in the absence of transcription. When transcription of the gene body is directed by an inducible promoter, H3K27me3 is removed following activation of transcription and H3K27me3 is added after transcription is decreased. The rate of addition of H3K27me3 to the FLC transgene following inactivation of transcription is similar to that observed in the FLC gene body following vernalization. Our data suggest that reduction of FLC transcription during vernalization leads to an increase of H3K27me3 levels in the FLC gene body that in turn maintains FLC repression. PMID- 21276104 TI - The Clavata2 genes of pea and Lotus japonicus affect autoregulation of nodulation. AB - The number of root nodules developing on legume roots after rhizobial infection is controlled by the plant shoot through autoregulation and mutational inactivation of this mechanism leads to hypernodulation. We have characterised the Pisum sativum (pea) Sym28 locus involved in autoregulation and shown that it encodes a protein similar to the Arabidopsis CLAVATA2 (CLV2) protein. Inactivation of the PsClv2 gene in four independent sym28 mutant alleles, carrying premature stop codons, results in hypernodulation of the root and changes to the shoot architecture. In the reproductive phase sym28 shoots develops additional flowers, the stem fasciates, and the normal phyllotaxis is perturbed. Mutational substitution of an amino acid in one leucine rich repeat of the corresponding Lotus japonicus LjCLV2 protein results in increased nodulation. Similarly, down-regulation of the Lotus Clv2 gene by RNAi mediated reduction of the transcript level also resulted in increased nodulation. Gene expression analysis of LjClv2 and Lotus hypernodulation aberrant root formation Har1 (previously shown to regulate nodule numbers) indicated they have overlapping organ expression patterns. However, we were unable to demonstrate a direct protein-protein interaction between LjCLV2 and LjHAR1 proteins in contrast to the situation between equivalent proteins in Arabidopsis. LjHAR1 was localised to the plasma membrane using a YFP fusion whereas LjCLV2-YFP localised to the endoplasmic reticulum when transiently expressed in Nicotiana benthamiana leaves. This finding is the most likely explanation for the lack of interaction between these two proteins. PMID- 21276105 TI - Cost of diabetes and its complications in Thailand: a complete picture of economic burden. AB - Diabetes is a common metabolic disorder with increasing burden in Thailand. The chronic nature along with associated complications makes the disease very costly. In Thailand, there exist some studies on cost of diabetes; however, those studies estimated the cost either from provider or from patient perspective. In order to capture the complete picture of economic burden caused by diabetes, using prevalence-based approach; the present study estimated the cost of illness of diabetes from societal perspective, the broadest viewpoint covering all costs irrespective of who incur them. Data were collected from 475 randomly selected diabetic patients who received treatment from Waritchaphum hospital in Sakhon Nakhon province of Thailand during 2007-2008 with a response rate of 98%. A micro costing approach was used to calculate the cost. The direct medical cost was calculated by multiplying the quantity of medical services consumed by their unit costs while indirect cost was calculated by using human capital approach. The total cost of illness of diabetes for 475 study participants was estimated as USD 418,696 for the financial year 2008 (1 USD = 32 THB). Of this, 23% was direct medical cost, 40% was direct non-medical cost and 37% was indirect cost. The average cost of illness per diabetic patient was USD 881.47 in 2008 which was 21% of per capita gross domestic product of Thailand. Existence of complications increased the cost substantially. Cost of informal care contributed 28% of total cost of illness of diabetes. Therefore, the disease not only affected the individual but also the family members, friends and neighbours. The economic and social burden of the disease therefore emphasises the need for initiatives to prevent the disease prevalence and counselling to the diabetic patients to prevent the progression of the disease and its devastating complications. PMID- 21276106 TI - Thriving, not just surviving, in emotionally demanding fields of practice. AB - Research within the disciplines of Social Work and Education has for sometime acknowledged the tragedy, trauma, conflict and misery that can be experienced by workers in their associated professions. More recently, there has been an aligned interest in the role of passion, emotion and energy in sustaining these professionals through such experiences. This paper contributes to the growing literature in this area by reporting on a study conducted with five social workers and six teachers who work in Australian lower socioeconomic, urban-fringe and communities. It also engages the concept of the 'personal domain' to explore how these social workers and teachers cannot only survive, but can actually thrive in demanding work contexts. The methodology adopted for the study was an appreciative enquiry approach, where these professionals, each with over a decade of experience in urban-fringe communities, were recruited via non-probability, purposive, snowballing techniques and interviewed about what sustained them in their work during November 2008-February 2009. Thematic analysis of the interviews found that participants not only identified specific survival strategies, but could also articulate how their life experiences, ideologies, beliefs, values and other life resources informed their work in ways that aided their flourishing as professionals. The paper concludes by calling for further research into the work of social work and teaching professionals from a 'personal domain' perspective and considering the potential implications of such research for these professions, particularly in terms of promoting professional trajectories characterised first by endurance, and then by development and triumph. PMID- 21276107 TI - Providing the family-nurse partnership programme through interpreters in England. AB - This study looks at the delivery of the Family-Nurse Partnership (FNP) in England with interpreters. This home-visiting programme for vulnerable, young first-time mothers is known in the USA as the Nurse-Family Partnership (NFP). FNP is manualised with a number of fidelity targets and stretch objectives. This study covers the first two phases, pregnancy and infancy (up to 12 months). The programme relies on the development of a close nurse-client relationship. Interpreters can be a barrier for therapeutic work with vulnerable groups. The aims are to determine from quantitative and qualitative data whether the FNP programme can be delivered with fidelity in the presence of an interpreter and to explore issues concerned with the impact of interpreters on relationships. Statistical comparisons were made of delivery objectives over 2 years, from April 2007 to February 2009, in the 10 sites in England, spread across all nine Government Office Regions providing FNP. Forty-three clients had an interpreter at some point and 1261 did not. Qualitative interviews were conducted between April and May 2009 with 30 stakeholders (nurses, clients, interpreters). In relation to quantitative indicators, the percentage of planned content covered in visits was lower with interpreters (pregnancy 90% vs. 94%; infancy 88% vs. 93%) and both understanding and involvement of clients, as judged by nurses on 5-point scales, were lower (understanding, pregnancy 4.3 vs. 4.6, infancy 3.8 vs. 4.5; involvement, pregnancy 4.4 vs. 4.7, infancy 3.7 vs. 4.5). The interpreter was not thought by nurses to impede the development of a collaborative client-nurse relationship unless the interpreter and client became too close, but some nurses and clients reported that they would rather manage without an interpreter. Some stress was noted for nurses delivering the programme with an interpreter. More research is needed to determine the extent to which interpreters accurately convey the programme's strength-based approach. PMID- 21276108 TI - Rapid shifts in multiple life history traits in a population of threespine stickleback. AB - Measurement of the rate of phenotypic or genetic change provides data bearing on many questions of fundamental interest to biologists, including how fast changes can proceed, whether shifts occur gradually or in bursts and how long high rates of change can be sustained. Because traits exist in functionally and genetically correlated suites, studies tracking many traits are likely to be the most informative. We quantify very rapid phenotypic changes in egg size (now smaller), clutch size (larger) and the age/size of both breeding females and males (younger, smaller) in an Alaskan population, with these traits shifting at rates from 0.13 to 0.30 haldanes over a 10-year period. In contrast, female reproductive effort and the allometric relationship of clutch size to body size changed little. These shifts appear to be caused by an altered selective landscape, with the presumed selective agent being increasing lake productivity. Some of the traits undoubtedly have at heritable component and thus represent genetic evolution as well as phenotypic. PMID- 21276109 TI - Direct and correlated responses to artificial selection on sexual size dimorphism in the flour beetle, Tribolium castaneum. AB - Sexual size dimorphism (SSD) is a conspicuous yet poorly understood pattern across many organisms. Although artificial selection is an important tool for studying the evolution of SSD, previous studies have applied selection to only a single sex or to both sexes in the same direction. In nature, however, SSD likely arises through sex-specific selection on body size. Here, we use Tribolium castaneum flour beetles to investigate the evolution of SSD by subjecting males and females to sexually antagonistic selection on body size (sexes selected in opposite directions). Additionally, we examined correlated responses to body size selection in larval growth rates and development time. After seven generations, SSD remained unchanged in all selected lines; this observed lack of response to short-term selection may be attributed to evolutionary constraints arising from between-sex body size correlations. Developmental traits showed complex correlated responses under different selection treatments. These results suggest that sex-specific larval development patterns may facilitate the evolution of SSD. PMID- 21276110 TI - A comparative analysis of senescence in adult damselflies and dragonflies (Odonata). AB - Any population whose members are subject to extrinsic mortality should exhibit an increase in mortality with age. Nevertheless, the prevailing opinion is that populations of adult damselflies and dragonflies do not exhibit such senescence. Here, we challenge this contention by fitting a range of demographic models to the data on which these earlier conclusions were based. We show that a model with an exponential increase in age-related mortality (Gompertz) generally provides a more parsimonious fit than alternative models including age-independent mortality, indicating that many odonates do indeed senesce. Controlling for phylogeny, a comparison of the daily mortality of 35 odonate species indicates that although male and female mortalities are positively correlated, mortality tends to be higher in males of those species that exhibit territoriality. Hence, we show for the first time that territoriality may impose a survivorship cost on males, once the underlying phylogenetic relationships are accounted for. PMID- 21276111 TI - Temporal change in inbreeding depression in life-history traits in captive populations of guppy (Poecilia reticulata): evidence for purging? AB - Inbreeding depression, which generally affects the fitness of small populations, may be diminished by purging recessive deleterious alleles when inbreeding persists over several generations. Evidence of purging remains rare, especially because of the difficulties of separating the effects of various factors affecting fitness in small populations. We compared the expression of life history traits in inbred populations of guppy (Poecilia reticulata) with contemporary control populations over 10 generations in captivity. We estimated inbreeding depression as the difference between the two types of populations at each generation. After 10 generations, the inbreeding coefficient reached a maximum value of 0.56 and 0.16 in the inbred and control populations, respectively. Analysing changes in the life-history traits across generations showed that inbreeding depression in clutch size and offspring survival increased during the first four to six generations in the populations from the inbred treatment and subsequently decreased as expected if purging occurred. Inbreeding depression in two other traits was weaker but showed similar changes across generations. The loss of six populations in the inbred treatment indicates that removal of deleterious alleles also occurred by extinction of populations that presumably harboured high genetic load. PMID- 21276112 TI - Plastic and evolutionary responses of cell size and number to larval malnutrition in Drosophila melanogaster. AB - Both development and evolution under chronic malnutrition lead to reduced adult size in Drosophila. We studied the contribution of changes in size vs. number of epidermal cells to plastic and evolutionary reduction of wing size in response to poor larval food. We used flies from six populations selected for tolerance to larval malnutrition and from six unselected control populations, raised either under standard conditions or under larval malnutrition. In the control populations, phenotypic plasticity of wing size was mediated by both cell size and cell number. In contrast, evolutionary change in wing size, which was only observed as a correlated response expressed on standard food, was mediated entirely by reduction in cell number. Plasticity of cell number had been lost in the selected populations, and cell number did not differ between the sexes despite males having smaller wings. Results of this and other experimental evolution studies are consistent with the hypothesis that alleles which increase body size through prolonged growth affect wing size mostly via cell number, whereas alleles which increase size through higher growth rate do so via cell size. PMID- 21276113 TI - Neurocysticercosis: an unusual cause of seizure in the New Zealand setting. AB - Neurocysticercosis is an unusual cause of seizure in the New Zealand setting. We report on the presentation of a 12-year-old Indian boy, who was found to have neurocysticercosis after presenting with a generalized seizure. Treatmeant of neurocysticercosis is controversial, and the evidence from the literature regarding treatment with anthelmintic (or cysticydal) medication is reviewed. Other treatment measures including anticonvulsant therapy and corticosteroids is also discussed. PMID- 21276114 TI - Iodine-induced neonatal hypothyroidism secondary to maternal seaweed consumption: a common practice in some Asian cultures to promote breast milk supply. AB - Mild iodine deficiency is a recognised problem in Australia and New Zealand. However, iodine excess can cause hypothyroidism in some infants. We highlight two cases which illustrate the risks of excess dietary iodine intake during pregnancy and breastfeeding. They also describe a cultural practice of consuming seaweed soup to promote breast milk supply. Although most attention recently has been on the inadequacy of iodine in Australian diets, the reverse situation should not be overlooked. Neither feast nor famine is desirable. PMID- 21276115 TI - Brucellosis acquired by eating imported cheese. AB - Pyrexia of unknown origin is an important clinical presentation in both paediatric and adult medicine. We present a case of pyrexia of unknown origin in a 14 year-old boy which turned out to be due to infection with Brucella melitensis, despite the patient not having left Great Britain - an officially brucellosis-free country - in six years. Repeated history-taking provided a clue to the diagnosis. PMID- 21276116 TI - Basilar artery occlusion in a 14-year old female successfully treated with acute intravascular intervention: case report and review of the literature. AB - Basilar artery occlusion (BAO) is a rare cause of paediatric stroke that may result in severe neurological disability including a 'locked-in' state. Acute interventional therapy for paediatric BAO is limited to a small number of published case reports. Of 13 previously published cases that have undergone acute intravascular therapy, six made a full neurological recovery, six had residual deficits ranging from mild dysarthria and ataxia to vegetative state and one patient died. The time from symptom onset to intervention was >= 12 h in 77% (10/13). We reported a 14-year-old female patient presenting with altered sensorium that progressed to a 'locked-in' state due to idiopathic BAO who made a full clinical recovery after successful mechanical thrombectomy at 24 h following symptom onset. Acute neuro-interventional therapy for paediatric BAO can result in complete neurological recovery despite the presence of severe neurological deficits and a prolonged period of time from symptom onset to clinical diagnosis. PMID- 21276117 TI - Trimethylaminuria: an under-recognised and socially debilitating metabolic disorder. AB - Primary flavin mono-oxygenase 3 deficiency, an inborn error of choline metabolism, leads to an accumulation of trimethylamine, which because of its associated pungent odour of rotting fish, is a socially crippling disorder. Although it often has its onset in early childhood, it may take years or even decades before the diagnosis is established. In this review the clinical biochemical and genetic features of the disorder are reported. The principles of therapy will also be covered, including dietary, pharmacological approaches, as well as techniques used to manipulate the gastrointestinal environment as a strategy to reduce the gastrointestinal load of trimethylamine. PMID- 21276118 TI - Circulating cell-derived microparticles in women with pregnancy loss. AB - PROBLEM: To analyze cell-derived microparticles (cMP) in pregnancy loss (PL), both recurrent miscarriages (RM) and unexplained fetal loss (UFL). METHOD OF STUDY: Non-matched case-control study was performed at Vall d'Hebron Hospital. Cell-derived microparticles of 53 PL cases, 30 with RM, 16 with UFL, and 7 (RM + UFL), were compared to 38 healthy pregnant women. Twenty healthy non-pregnant women act as controls. Cell-derived microparticles were analyzed through flow cytometry. Results are given as total annexin (A5+), endothelial-(CD144+/CD31+ CD41-), platelet-(CD41+), leukocyte-(CD45+) and CD41- c-MP/MUL of plasma. Antiphospholipid antibodies (aPLA) were analyzed according to established methods. RESULTS: Comparing PL versus healthy pregnant, we observed a significant endothelial cMP decrease in PL. When comparing RM subgroup with controls, we observed significant decreases in endothelial cMP. When comparing the PL positive for aPLA versus PL-aPLA-negative, no cMP numbering differences were seen. CONCLUSION: Pregnancy loss seems to be related to endothelial cell activation and/or consumption. A relationship between aPLA and cMP could not be demonstrated. PMID- 21276119 TI - Modulation of cytokine and chemokine secretions in rhesus monkey trophoblast co culture with decidual but not peripheral blood monocyte-derived macrophages. AB - PROBLEM: Decidual macrophages are thought to promote pregnancy success, in part through interactions with invading trophoblast cells in hemochorial placentation. However, the factors that constitute this regulatory cross talk are not well understood. METHOD OF STUDY: Rhesus monkey decidual and peripheral blood-derived macrophages were co-cultured with primary Rhesus trophoblasts. Macrophage functions including cell-surface marker expression, antigen uptake and processing, in vitro migration, and cytokine and chemokine secretions were evaluated. RESULTS: While most macrophage functions were unchanged by trophoblast co-culture, changes in the secretion of selected cytokines and the migration of trophoblasts were noted when decidual (but generally, not peripheral blood monocyte-derived) macrophages were cultured with trophoblasts. In addition, basal secretion differed significantly between peripheral blood-derived and decidual macrophages for a broad spectrum of cytokines. When trophoblasts were pre-treated with an anti-Mamu-AG antibody, 25D3, there was no change in cytokine or chemokine secretion. CONCLUSION: Macrophage cytokine expression can be modulated by trophoblast co-culture, but it remains unclear how Mamu-AG is involved. PMID- 21276120 TI - Regulation of costimulatory signal in maternal-fetal immune tolerance. AB - A pregnancy is associated with modifications in the immune status of the mother, but the mechanisms are not well understood. Several observations have indicated that CD28/CTLA-4 and B7-1/B7-2 are involved in the maternal-fetal immune regulation. This review aims to recapitulate our current knowledge concerning the role of CD28/CTLA-4 and B7-1/B7-2 in maternal-fetal immune regulation. Several studies suggest that up-regulation of B7-2 and/or CD28 and/or down-regulation of CTLA-4 are correlated with the occurrence of pregnancy loss. Therefore, an accurate expression of costimulatory molecules at the maternal-fetal interface may ensure that the decidual cells do not elicit a 'danger' signal to the maternal immune system, perhaps instead contributing to the establishment of immune tolerance in vivo. It is showed that costimulation blockade with anti-B7 mAbs results in altered allogeneic T-cell response and overcomes increased maternal rejection to the fetus, which improves fetus growth in the abortion prone system. These findings suggest that the anti-B7-treated T cells not only function as potent suppresser cells but also exert immunoregulatory effect on the maternal T cells. This procedure might be potentially useful to immunotherapy for human recurrent spontaneous abortion. PMID- 21276121 TI - Expression profiles of peripheral CD160+ lymphocytes during the course of healthy human pregnancy. AB - PROBLEM: CD160 receptor is expressed by natural killer (NK) and T-cell subsets, and after activation, it could enhance cytotoxicity or pro-inflammatory cytokine production on NK cells. Here, we investigated the phenotype of peripheral CD160+ cells during healthy pregnancy. METHOD OF STUDY: We analyzed the expression of CD69 activation marker, gamma/delta TCR, and NKG2A or NKG2D NK cell receptors on CD160+ lymphocytes of non-pregnant and healthy pregnant women at four different stages of pregnancy by flow cytometry. RESULTS: In our hands, CD160 receptor positive lymphocytes were present during pregnancy; however, they had different characteristics depending on gestational age. During implantation, CD160+ cells showed low activation rate, decreased NK receptor expression while 40% of Vdelta2 + T cells expressed CD160 receptor. In turn, all the above parameters increased as pregnancy proceeds. CONCLUSION: Our results indicate that CD160+ lymphocytes could be able to play a role in the maintenance of healthy pregnancy. PMID- 21276122 TI - A randomized controlled trial of lycopene treatment on soluble receptor for advanced glycation end products in seminal and blood plasma of normospermic men. AB - PROBLEM: The aim of present study was to investigate the effects of antioxidant lycopene on soluble receptor for advanced glycation end products (sRAGE) levels in blood and seminal plasma in normospermic males. METHODS: Study included 15 fertile volunteers and 13 normospermic male partners from infertile relationships. The treatment was 12-week administration of 20 mg of lycopene or placebo followed by crossover and treatment for a further 12 weeks. The ELISA kit Quantikine((r)) was used to determine sRAGE levels. RESULTS: Lycopene administration decreased sRAGE levels in seminal plasma in fertile volunteers (controls) as well as in male partners in the infertile relationships group (P=0.008 and P=0.012, respectively). No significant effect of lycopene on sRAGE in blood plasma was found in either group, but seminal plasma sRAGE was significantly suppressed. CONCLUSION: Lycopene decreased sRAGE in seminal, but not in blood plasma. This may be because of selective local uptake of lycopene in the male reproductive tract, namely in prostate. Decreased sRAGE may be caused by lycopene suppression of oxidative stressors and explain in part the putative improvement in fertility reported after lycopene treatment. PMID- 21276123 TI - Facilitative debriefing techniques for simulation-based learning. PMID- 21276124 TI - Procalcitonin as a biomarker for bacterial infections in patients with liver cirrhosis in the emergency department. AB - OBJECTIVES: The objective was to determine the diagnostic accuracy of procalcitonin measurement for bacterial infections in patients with all causes of liver cirrhosis. METHODS: The authors conducted a cross-sectional study of 98 patients with cirrhosis treated in the emergency department (ED) of Chang-Gung Memorial Hospital, Taiwan. Serum procalcitonin levels and other clinical information were obtained concurrently. Patients were assigned to a sepsis or nonsepsis group after the medical records were reviewed by two emergency physicians blinded to the study. Receiver operating characteristic (ROC) curve analysis was conducted to determine the sensitivity, specificity, likelihood ratio, and suggested cutoff values. The diagnostic accuracy of the C-reactive protein (CRP) level was also determined for comparison. RESULTS: A total of 98 patients were enrolled for analysis in 1 year. Twenty-seven patients (27.6%) were assigned to the sepsis group. Eleven patients (11.2%) had positive blood cultures. The areas under the ROC curves for procalcitonin and CRP in predicting sepsis were 0.89 (95% confidence interval [CI] = 0.77 to 0.92) and 0.81 (95% CI = 0.72 to 0.89), respectively (p = 0.11). The cutoff that maximized Youden's index was 0.49 ng/mL for procalcitonin and 24.7 mg/L for CRP. At these cutoffs, the sensitivity and specificity were 81.5 and 87.3% for procalcitonin and 80.0 and 80.3% for CRP. These results suggest that procalcitonin measurement shows at least an equivalent diagnostic accuracy to CRP measurement. CONCLUSIONS: Procalcitonin provided satisfactory diagnostic accuracy in differentiating bacterial infections in patients with all causes of liver cirrhosis in the ED. A cutoff value of 0.5 ng/mL is suggested for clinical use. PMID- 21276125 TI - Physician narrative belongs among the scholarly tracks. PMID- 21276128 TI - PET-guided breast biopsy. AB - Molecular imaging, using positron emission tomography (PET), has become an integral step in the evaluation of many patients with malignancy. However, its use in patients with breast cancer has been limited by the lower levels of (18) F fluorodeoxyglucose (FDG) uptake in some breast malignancies compared to other cancers, the small size of many breast cancers, and the need for biopsy under PET guidance. High-resolution breast PET, or positron emission mammography (PEM), with biopsy guidance software, now addresses these issues. We report a prospective, multicenter study designed to test the efficacy and safety of PEM biopsy guidance software in women with FDG-avid breast lesions worrisome for malignancy. The intervention chosen was vacuum-assisted core biopsy. Nineteen subjects underwent a total of 24 PEM-guided biopsies. All lesions were successfully targeted and sampled as determined by post-biopsy image scan evaluation, specimen imaging, and pathologic concordance. Invasive cancer was identified in 13 of 24 lesions (54%), while four (17%) were high-risk lesions and three of these were upgraded to malignancy at excision. No serious adverse events occurred and all patients found the procedure to cause only minimal to mild discomfort. High-resolution PEM-guided breast biopsy is both safe and effective for the sampling of PET-depicted breast lesions. PMID- 21276129 TI - Tracing human papilloma virus in breast tumors of Iranian breast cancer patients. PMID- 21276130 TI - Retinoids for chemoprophylaxis of nonmelanoma skin cancer. PMID- 21276131 TI - Diclofenac pharmacokinetic meta-analysis and dose recommendations for surgical pain in children aged 1-12 years. AB - BACKGROUND: Diclofenac is an effective, opiate-sparing analgesic for acute pain in children, which is commonly used in pediatric surgical units. Recently, a Cochrane review concluded the major knowledge gap in diclofenac use is dosing information. A pharmacokinetic meta-analysis has been undertaken with the aim of recommending a dose for children aged 1-12 years. METHODS: Studies containing diclofenac pharmacokinetic data were identified during a Cochrane systematic review, and authors were asked to provide raw data. A pooled population analysis was undertaken in NONMEM to define the pharmacokinetics of intravenous, oral, and rectal diclofenac in children. Simulations were performed to recommend a dose yielding an equivalent area under diclofenac concentration-time curve (AUC) to a 50-mg dispersible tablet in adults. RESULTS: Data from 111 children aged 1-14 years consisting of 375 samples following intravenous, oral suspension, and suppositories were used. Adult dispersible tablet and suspension data were added to provide a reference AUC and support the absorption modeling, respectively. A three-compartment model described disposition, a dual-absorption compartment model was used for suspension and dispersible tablet data, and single-absorption compartment model for suppositories. The estimate of clearance was 16.5 l.h(-1) .70 kg(-1) and bioavailabilities were 0.36, 0.63, and 0.35 for suspension, suppository, and dispersible tablets, respectively. CONCLUSIONS: Single doses of 0.3 mg.kg(-1) for intravenous, 0.5 mg.kg(-1) for suppositories, and 1 mg.kg(-1) for oral diclofenac in children aged 1-12 years are recommended as they yield a similar AUC to 50 mg in adults. PMID- 21276132 TI - Genome-wide association studies for discovery of genes involved in asthma. AB - Asthma is the result of a complex interaction between environmental factors and genetic variants that confer susceptibility. Studies of the genetics of asthma have previously been conducted using linkage designs and candidate gene association studies. Recently, the association study design has been extended from specific candidate genes to an unbiased genome-wide approach: the genome wide association study (GWAS). To date, there have been 12 GWAS to look for susceptibility loci for asthma and related traits. The first GWAS for asthma discovered a novel associated locus on chromosome 17q21 encompassing the genes ORMDL3, GSDMB and ZPBP2. None of these genes would have been selected in a candidate association study based on current knowledge of the functions of these genes. Nevertheless, this finding has been consistently replicated in independent populations of European ancestry and also in other ethnic groups. Thus, chromosome 17q21 seems to be a true asthma susceptibility locus. Other genes that were identified in more than one GWAS are IL33, RAD50, IL1RL1 and HLA-DQB1. Additional novel susceptibility genes identified in a single study include DENND1BI and IL2RB. Discovering the causal mechanism behind these associations is likely to yield great insights into the development of asthma. It is likely that further meta-analyses of asthma GWAS data from existing international consortia will uncover more novel susceptibility genes and further increase our understanding of this disease. PMID- 21276133 TI - Year in review 2010: tuberculosis, pleural diseases, respiratory infections. PMID- 21276134 TI - Loss of E-cadherin in mouse gastric epithelial cells induces signet ring-like cells, a possible precursor lesion of diffuse gastric cancer. AB - Alterations in the E-cadherin gene are associated with sporadic and hereditary diffuse-type gastric cancer. To determine how the loss of function of E-cadherin affects gastric epithelial cell phenotypes, we generated transgenic mice using the Cre-loxP system in which the E-cadherin gene is specifically knocked out in the parietal cell lineage. In the transgenic mice, expression of E-cadherin was lost or reduced in proton pump-expressing parietal cells, which became round in shape and were pushed out of the glands to accumulate in the stromal area. Additionally, gastric mucosa exhibited hyperplasia from 3 months in the mice, some cells of which later became positive for trefoil factor 2, a marker of spasmolytic polypeptide-expressing metaplasia. From 6 months, E-cadherin negative/proton pump-negative cells appeared from the parietal cell lineage, which increased in number to form cell clusters. Moreover, signet ring-like cells, which are morphologically similar to signet ring carcinoma cells, were found in the cell clusters from 12 months. However, no invasive gastric adenocarcinomas were found in the E-cadherin-deficient mice, even at 24 months or later. These data indicate that the loss of E-cadherin induces possible pre cancerous lesions in the gastric mucosa but may not be sufficient for its malignant conversion. PMID- 21276135 TI - Bmi1 regulates cell fate via tumor suppressor WWOX repression in small-cell lung cancer cells. AB - Mortality from lung cancer is important worldwide. Recently, epigenetic aberration of lung cancer, not only genomic DNA methylation but also chromatin modification, has become an important target for lung cancer research, although previous research has demonstrated that lung cancer develops as a result of both environmental and genetic factors. Here, we demonstrated that an epigenetic regulator/polycomb group protein Bmi1 is more highly expressed in small-cell lung cancer (SCLC) than in non-small-cell lung cancer by immunohistochemical analysis. In vitro experiments indicated that Bmi1 reduction by lentivirus-derived shRNA significantly suppressed proliferation, colony formation and in vivo tumor formation. Importantly, apoptosis was induced by Bmi1 depletion in small-cell lung cancer cells. Furthermore, a tumor suppressor WWOX was identified as a Bmi1 target in the cells by a chromatin immunoprecipitation assay and a quantitative real-time PCR assay; WWOX had a role as a tumor suppressor in SCLC cells; therefore, the Bmi1/WWOX pathway could be a new candidate for a new therapeutic approach for SCLC. PMID- 21276136 TI - Downregulation of a newly identified laminin, laminin-3B11, in vascular basement membranes of invasive human breast cancers. AB - Laminins present in the basement membranes (BM) of blood vessels are involved in angiogenesis and other vascular functions that are critical for tumor growth and metastasis. Two major vascular laminins, the alpha4 (laminin-411/421) and alpha5 (laminin-511/521) types, have been well characterized. We recently found a third type of vascular laminin, laminin-3B11, consisting of the alpha3B, beta1 and gamma1 chains, and revealed its biological activity. Laminin-3B11 potently stimulates vascular endothelial cells to extend lamellipodial protrusions. To understand the roles of laminin-3B11 in blood vessel functions and tumor growth, we examined localization of the laminin alpha3B chain in normal mammary glands and breast cancers, in comparison with the alpha4 and alpha5 laminins. In the immunohistochemical analysis, the alpha3B laminin was co-localized with the alpha4 and alpha5 laminins in the BM of venules and capillaries of normal breast tissues, but alpha3B was scarcely detected in vessels near invasive breast carcinoma cells. In contrast, the alpha4 laminin was overexpressed in capillaries of invasive carcinomas, where a large number of macrophages were found. The alpha5 laminin appeared to be weakly downregulated in cancer tissues, especially in capillary vessels. Furthermore, our in vitro analysis indicated that TNF-alpha significantly suppressed the laminin alpha3B expression in vascular endothelial cells, while it, as well as IL-1beta and TGF-alpha, upregulated the alpha4 expression. These results suggest that Lm3B11/3B21 may be required for normal mature vessels and interfere with tumor angiogenesis. PMID- 21276139 TI - Assessment of gastrointestinal motor functions by MRI: a comprehensive review. AB - BACKGROUND: Magnetic resonance imaging (MRI) is a useful technique for evaluating gastrointestinal (GI) motor functions because it provides multi-planar imaging capability, high imaging speed, good spatial resolution and excellent soft tissue contrast. Moreover, multiple parameters of GI function can be assessed non invasively during a single study. PURPOSE: This critical review of the literature discusses the strengths and limitations of MRI for evaluating GI motor functions. PMID- 21276137 TI - Resveratrol as an adjunct therapy in cyclophosphamide-treated MCF-7 cells and breast tumor explants. AB - Cyclophosphamide (CPA) has efficacy as a breast cancer therapy. However, toxicity to CPA limits its clinical applications. Hence there is a need to develop compounds that may be combined with it to improve the efficacy and overcome toxicity. We showed previously that Resveratrol (RES), a chemopreventive agent, increased the growth inhibitory effect of CPA-treated MCF-7 cells. Here we have explored the molecular basis of 5 mM CPA and 50 MUM RES as a combination on cell cycle progression, apoptosis and oxidative stress in MCF-7 breast cancer cells. Efficacy of the combination was also evaluated in a serum-free tumor explant culture model. The combination elicited enhanced anti-proliferative action coupled with differential expression of cell-cycle, apoptosis and stress factors. Furthermore, co-treatment superiority in histologically validated ER positive breast cancer explants suggests that this combination may be a worthy future clinical anti-neoplastic regimen. PMID- 21276138 TI - Clinicopathological significance and prognostic value of CD133 expression in triple-negative breast carcinoma. AB - Currently, CD133 is one of the best markers to characterize cancer stem cells and Her-1 is reported as an important marker for the prognosis of triple-negative breast cancer. To investigate the relationship between the expression of CD133 and Her-1 and clinicopathology as well as prognosis in triple-negative breast cancer, 67 cases of triple-negative invasive ductal breast carcinoma taken from 422 patients with breast cancer were analyzed by immunohistochemistry and clinicopathology with follow-up. The CD133 and Her-1 were expressed as positive in 43.3% (29/67) and 53.7% (36/67) of patients, respectively. The expression of CD133 corresponded to tumor size (P = 0.022), clinical stage (P = 0.001) and lymphatic metastasis (P = 0.001), but not to age and histological grade. By Kaplan-Meier analysis the expression of CD133 was correlative with overall survival (OS) (log rank = 9.346, P = 0.002) and disease free survival (DFS) (log rank = 38.840, P = 0.0001) time of breast cancer patients. The expression of Her 1 was corresponding to tumor size (P = 0.031), clinical stage (P = 0.005) and lymphatic metastasis (P = 0.002), but not to age and histological grade. By Kaplan-Meier analysis the expression of Her-1 was correlative with overall survival (OS) (log rank = 7.998, P = 0.005) and DFS (log rank = 4.227, P = 0.040) time of patients with cancer. It is concluded that the expression of CD133 and Her-1 may be correlative with prognosis in triple-negative breast cancer. PMID- 21276141 TI - Implementation of a simple age-based strategy in the prevention of cardiovascular disease: the Polypill approach. AB - BACKGROUND: A combination of medications that simultaneously reduce several cardiovascular risk factors in people above a specified age, without selection based on risk factor measurement, has been proposed as a simple strategy for reducing the risk of cardiovascular disease and shown to be effective in randomized trials (the Polypill approach). AIMS: To assess acceptance of the Polypill approach and adherence to preventive treatment among individuals taking part in a cardiovascular disease prevention service. METHODS: Daily treatment with simvastatin (40 mg), amlodipine (2.5 mg), bendroflumethiazide (1.25 mg), lisinopril (5 mg) [or candesartan (4 mg) if cough was reported] and folic acid (0.8 mg) was offered, as separate components, to people >= 55 years with no history of cardiovascular, renal or liver disease. An audit of adverse effects, adherence and requests for blood pressure and cholesterol measurement was determined by telephone consultation. RESULTS: Between 2006 and 2010, 269 participants started treatment with the Polypill components. Follow-up ranged from 3 to 48 months (mean 20). A total of 222 participants (83%) adhered to treatment, including 30 (11%) who switched from the angiotensin-converting enzyme inhibitor (lisinopril) to the angiotensin receptor blocker (candesartan) because of cough. Ten participants (4%) continued to take treatment but stopped taking one or more drugs because of other symptoms, and 37 (14%) stopped all treatment, eight because of adverse effects and 29 for non-medical reasons. No one requested a blood pressure or cholesterol measurement. CONCLUSION: This is the first demonstration of the application of the Polypill approach in practice. The method was accepted and the Polypill components were well tolerated, with good adherence and no demand for information about risk factors. PMID- 21276143 TI - Evidence-based medical practice in developing countries: the case study of Iran. AB - RATIONALE, AIMS AND OBJECTIVES: Attitude towards and knowledge of various groups of health care providers regarding evidence-based medicine (EBM) have been assessed worldwide. Also, barriers to practising EBM have been found to be different in different countries. However, there is little evidence on the place of EBM among some developing countries, like Iran. The aim of this study was to explore the current status of EBM among different medical specialists in Iran. METHODS: This cross-sectional study was conducted from August 2007 until March 2009 on a sample of 181 doctors in different medical specialties practising in Isfahan, Iran, not including faculty members. Attitude towards EBM and the barriers in practice and awareness of technical terms were investigated through a self-administered questionnaire. RESULTS: Less than half (41%) of the doctors reported they use EBM in their practice. They believed EBM improves the quality of health care services (70%); however, their understanding of the technical terms used in EBM was poor. The barrier to practising EBM identified by most respondents (74.3%) was the lack of EBM training courses in their academic curriculum. CONCLUSION: Despite the general welcoming attitude of all groups of specialists, they had insufficient knowledge and inadequate use of EBM in their practice. Designing and conducting EBM training courses and its integration into the general practitioners' training curriculum should be considered. PMID- 21276142 TI - Evaluation of the agreement between guidelines and initial antihypertensive drug treatment using a national health care reimbursement database. AB - RATIONALE, AIMS AND OBJECTIVES: To test the agreement between guidelines for the management of hypertension and medical practices while avoiding frequent limitations such as the use of non-representative samples of practitioners and self-reporting of their practices over a short period of time. METHODS: The characteristics of initial antihypertensive drug treatment in a large representative sample of the French population aged 50-80 (n = 17 855) were collected from a national health care reimbursement database and compared with national guidelines over a 5-year period. RESULTS: Major discrepancies are observed including the use of non-recommended drug classes such as loop and potassium sparing diuretics alone or in association and the absence of distinction between patients according to their age. More minor discrepancies are the preferential use of mono-therapies over drug combinations and of some bi therapies among those recommended. Some degree of concordance with the guidelines is also observed including the specific characteristics of the treatment of diabetics compared with other categories of patients and the preferential use of long-acting dihydropyridine calcium antagonists and of low-dose thiazide diuretics when these drug classes are chosen. Several of these discrepancies or concordances, which mainly reflect general practitioner (GP) activity, show time trends over the entire follow-up period with no significant effect of the guideline released during this period. CONCLUSIONS: At the French national level, the agreement between initial antihypertensive drug treatment and guidelines varies considerably depending on the characteristics of the treatment that are considered. The GPs who delivered the treatment do not seem to have been influenced by the guidelines released over the last decade. PMID- 21276144 TI - Monitoring and evaluation of infectious rotaviruses in various wastewater effluents and receiving waters revealed correlation and seasonal pattern of occurrences. AB - AIMS: Sewage systems are important nodes to monitor enteric pathogens transmitted via water. The aim of this study was to assess the presence of rotaviruses in effluents from wastewater treatment plants (WWTPs) and receiving streams in Beijing, China, to evaluate the reductions of rotaviruses in WWTPs and to provide viral fate and transport data for further epidemiological studies. METHODS AND RESULTS: Two PCR-based methods, including an RT-qPCR and another quantitative RT PCR (ICC-RT-qPCR), which was integrated with cell culturing, were applied to conduct a 1-year monitoring of infectious rotaviruses and viral genes in effluents from three WWTPs and the receiving waters in Beijing, China. The ICC-RT qPCR was able to detect more positive samples than RT-qPCR, showing positive results for 67% of primary effluents, 47% of secondary effluents and 14% of tertiary effluents, in comparison with 44, 22 and 6% by RT-qPCR, respectively. Seasonal variations of rotaviruses were observed in all effluents with higher occurrences in winter than in summer, which correlated well with the seasonal pattern of rotaviruses in the river receiving wastewater effluents. The reduction efficiencies by different treatment processes were assessed. Secondary treatments can remove most of infectious rotaviruses in primary sewage, with annual average reduction values of 2.08 +/- 0.63, 2.83 +/- 0.49 and 2.00 +/- 1.10 log(10) for the three WWTPs, respectively. Tertiary treatments were able to further remove infectious rotaviruses. CONCLUSIONS: The results showed a year-round distribution of rotaviruses in three WWTPs in Beijing and provided important information regarding the transport and susceptibility of rotaviruses to different levels of wastewater treatment processes. SIGNIFICANCE AND IMPACT OF THE STUDY: This study, for the first time, revealed the whole year prevalence and reductions of rotaviruses in WWTPs and the corresponding receiving waters in China, and demonstrated the impact of wastewater discharge on the potential spreading of infectious rotaviruses and public health. PMID- 21276140 TI - Evidence-based medicine training in a resource-poor country, the importance of leveraging personal and institutional relationships. AB - RATIONALE, AIMS AND OBJECTIVES: Efforts to implement evidence-based medicine (EBM) training in developing countries are limited. We describe the results of an international effort to improve research capacity in a developing country; we conducted a course aimed at improving basic EBM attitudes and identified challenges. METHOD: Between 2005 and 2009, we conducted an annual 3-day course in Peru consisting of interactive lectures and case-based workshops. We assessed self-reported competence and importance in EBM using a Likert scale (1 = low, 5 = high). RESULTS: Totally 220 clinicians participated. For phase I (2005-2007), self-reported EBM competence increased from a median of 2 to 3 (P < 0.001) and the perceived importance of EBM did not change (median = 5). For phase II (2008 2009), before the course, 8-72% graded their competence very low (score of 1-2). After the course, 67-92% of subjects graded their increase in knowledge very high (score of 4-5). The challenges included limited availability of studies relevant to the local reality written in Spanish, participants' limited time and lack of long-term follow-up on practice change. Informal discussion and written evaluation from participants were universally in agreement that more training in EBM is needed. CONCLUSIONS: In an EBM course in a resource-poor country, the baseline self-reported competence and experience on EBM were low, and the course had measurable improvements of self-reported competence, perceived utility and readiness to incorporate EBM into their practices. Similar to developed countries, translational research and building the research capacity in developing countries is critical for translating best available evidence into practice. PMID- 21276145 TI - Evaluation of an immunomagnetic separation assay in combination with cultivation to improve Legionella pneumophila serogroup 1 recovery from environmental samples. AB - AIMS: Legionella isolation from environmental samples is often difficult because of the presence of heterotrophic-associated bacteria that frequently overgrow when using standard culture (ISO 11731, 1998; NF T90-431, 2003) methods. To improve Legionella pneumophila recovery from complex water samples (water from cooling towers, biofilms), we evaluated an immunomagnetic separation (IMS) assay using a monoclonal antibody raised against the lipopolysaccharide of Leg. pneumophila sg1 in combination with culture. METHODS AND RESULTS: This study was conducted on 51 environmental specimens. The comparison between IMS-culture and standard culture (ISO 11731, 1998; NF T90-431, 2003) methods was made using ISO 17994, 2004 criteria for establishing equivalence between microbiological methods based on the upper and lower (XH and XL) values of the relative difference (95% confidence limit) and D as maximum acceptable deviation (value of the confidence limit). CONCLUSIONS: We found that the average performance of IMS culture was higher than the reference method. PMID- 21276147 TI - An international trial of quantitative PCR for monitoring Legionella in artificial water systems. AB - AIMS: To perform an international trial to derive alert and action levels for the use of quantitative PCR (qPCR) in the monitoring of Legionella to determine the effectiveness of control measures against legionellae. METHODS AND RESULTS: Laboratories (7) participated from six countries. Legionellae were determined by culture and qPCR methods with comparable detection limits. Systems were monitored over >=10 weeks. For cooling towers (232 samples), there was a significant difference between the log mean difference between qPCR (GU l(-1) ) and culture (CFU l(-1) ) for Legionella pneumophila (0.71) and for Legionella spp. (2.03). In hot and cold water (506 samples), the differences were less, 0.62 for Leg. pneumophila and 1.05 for Legionella spp. Results for individual systems depended on the nature of the system and its treatment. In cooling towers, Legionella spp. GU l(-1) always exceeded CFU l(-1) , and usually Legionella spp. were detected by qPCR when absent by culture. The pattern of results by qPCR for Leg. pneumophila followed the culture trend. In hot and cold water, culture and qPCR gave similar results, particularly for Leg. pneumophila. There were some marked exceptions with temperatures >=50 degrees C, or in the presence of supplementary biocides. Action and alert levels for qPCR were derived that gave results comparable to the application of the European Guidelines based on culture. Algorithms are proposed for the use of qPCR for routine monitoring. CONCLUSIONS: Action and alert levels for qPCR can be adjusted to ensure public health is protected with the benefit that remedial actions can be validated earlier with only a small increase in the frequency of action being required. SIGNIFICANCE AND IMPACT OF THE STUDY: This study confirms it is possible to derive guidelines on the use of qPCR for monitoring the control of legionellae with consequent improvement to response and public health protection. PMID- 21276146 TI - Survival of Escherichia coli O157:H7 and Salmonella enterica serovar Typhimurium in manure and manure-amended soil under tropical climatic conditions in Sub Saharan Africa. AB - AIMS: To establish the fate of Escherichia coli O157:H7 and Salmonella Typhimurium in manure and manure-amended agricultural soils under tropical conditions in Sub-Saharan Africa. METHODS AND RESULTS: Survival of nonvirulent E. coli O157:H7 and Salm. Typhimurium at 4 and 7 log CFU g(-1) in manure and manure-amended soil maintained at >=80% r.h. or exposed to exclusive field or screen house conditions was determined in the Central Agro-Ecological Zone of Uganda. Maintaining the matrices at high moisture level promoted the persistence of high-density inocula and enhanced the decline of low-density inocula in the screen house, but moisture condition did not affect survival in the field. The large majority of the survival kinetics displayed complex patterns corresponding to the Double Weibull model. The two enteric bacteria survived longer in manure amended soil than in manure. The 7 log CFU g(-1) E. coli O157:H7 and Salm. Typhimurium survived for 49-84 and 63-98 days, while at 4 log CFU g(-1) , persistence was 21-28 and 35-42 days, respectively. CONCLUSIONS: Under tropical conditions, E. coli O157:H7 and Salm. Typhimurium persisted for 4 and 6 weeks at low inoculum density and for 12 and 14 weeks at high inoculum density, respectively. SIGNIFICANCE AND IMPACT OF THE STUDY: Persistence in the tropics was (i) mostly shorter than previously observed in temperate regions thus suggesting that biophysical conditions in the tropics might be more detrimental to enteric bacteria than in temperate environments; (ii) inconsistent with published data isothermally determined previously hence indicating the irrelevance of single point isothermal data to estimate survival under dynamic temperature conditions. PMID- 21276148 TI - Kinetic model-based prediction of the persistence of Salmonella enterica serovar Typhimurium under tropical agricultural field conditions. AB - AIM: Present a kinetic model-based approach for using isothermal data to predict the survival of manure-borne enteric bacteria under dynamic conditions in an agricultural environment. METHODS AND RESULTS: A model to predict the survival of Salmonella enterica serovar Typhimurium under dynamic temperature conditions in soil in the field was developed. The working hypothesis was that the inactivation phenomena associated with the survival kinetics of an organism in an agricultural matrix under dynamic temperature conditions is for a large part due to the cumulative effect of inactivation at various temperatures within the continuum registered in the matrix in the field. The modelling approach followed included (i) the recording of the temperature profile that the organism experiences in the field matrix, (ii) modelling the survival kinetics under isothermal conditions at a range of temperatures that were registered in the matrix in the field; and (iii) using the isothermal-based kinetic models to develop models for predicting survival under dynamic conditions. The time needed for 7 log CFU g(-1) Salmonella Typhimurium in manure and manure-amended soil to reach the detection limit of the enumeration method (2 log CFU g(-1) ) under tropical conditions in the Central Agro-Ecological Zone of Uganda was predicted to be 61-68 days and corresponded with observed CFU of about 2.2-3.0 log CFU g( 1) , respectively. The Bias and Accuracy factor of the prediction was 0.71-0.84 and 1.2-1.4, respectively. CONCLUSIONS: Survival of Salm. Typhimurium under dynamic field conditions could be for 71-84% determined by the developed modelling approach, hence substantiating the working hypothesis. SIGNIFICANCE AND IMPACT OF THE STUDY: Survival kinetic models obtained under isothermal conditions can be used to develop models for predicting the persistence of manure borne enteric bacteria under dynamic field conditions in an agricultural environment. PMID- 21276149 TI - Enrichment, isolation and characterization of fungi tolerant to 1-ethyl-3 methylimidazolium acetate. AB - AIMS: This work aimed to characterize microbial tolerance to 1-ethyl-3 methylimidazolium acetate ([C2mim][OAc]), an ionic liquid that has emerged as a novel biomass pretreatment for lignocellulosic biomass. METHODS AND RESULTS: Enrichment experiments performed using inocula treated with [C2mim][OAc] under solid and liquid cultivation yielded fungal populations dominated by Aspergilli. Ionic liquid-tolerant Aspergillus isolates from these enrichments were capable of growing in a radial plate growth assay in the presence of 10% [C2mim][OAc]. When a [C2mim][OAc]-tolerant Aspergillus fumigatus strain was grown in the presence of switchgrass, endoglucanases and xylanases were secreted that retained residual enzymatic activity in the presence of 20% [C2mim][OAc]. CONCLUSIONS: The results of the study suggest that tolerance to ionic liquids is a general property of the Aspergilli. SIGNIFICANCE AND IMPACT OF THE STUDY: Tolerance to an industrially important ionic liquid was discovered in a fungal genera that is widely used in biotechnology, including biomass deconstruction. PMID- 21276150 TI - Pitavastatin inhibits hepatic steatosis and fibrosis in non-alcoholic steatohepatitis model rats. AB - AIM: Non-alcoholic steatohepatitis (NASH) may progress to liver cirrhosis, and NASH patients with liver cirrhosis are at risk of developing hepatocellular carcinoma. Statins, 3-hydroxy-3-methyglutaryl-coenzyme A reductase inhibitors, are well known to reduce low-density lipoprotein cholesterol and reduce the incidence of coronary heart disease and other major vascular events by anti inflammatory and antifibrotic effects, and antiproliferative properties in colorectal cancers have also been reported. Recently, statins have been reported to improve hepatic steatosis; however, the effect on fibrosis is controversial. METHODS: The effects of pitavastatin (one of the strongest statins) were examined using a choline-deficient L-amino acid-defined (CDAA) diet liver fibrosis model. RESULTS: Pitavastatin significantly attenuated increases in serum aspartate aminotransferase, alanine aminotransferase, hepatic steatosis, oxidative stress, pre-neoplastic lesions (glutathione S-transferase placental form-positive lesions), expression of cytokines, such as tumor necrosis factor alpha and transforming growth factor-beta1, and the expression of tissue inhibitor of metalloproteinase-1, tissue inhibitor of metalloproteinase-2 and type I procollagen genes followed by attenuating fibrosis of the liver of CDAA fed rats. CONCLUSION: These results indicate that pitavastatin may inhibit steatosis, hepatic fibrosis and carcinogenesis in rat model of NASH. PMID- 21276151 TI - Comparative study of cisplatin and epirubicin in transcatheter arterial chemoembolization for hepatocellular carcinoma. AB - AIM: Transcatheter arterial chemoembolization (TACE) is an established treatment for unresectable hepatocellular carcinoma (HCC). However, it is unclear which chemotherapeutic agent should be selected for TACE. The aim of this study was to compare the efficacy of cisplatin (CDDP) with that of epirubicin (EPI) in TACE for patients with unresectable or relapsed HCC. METHODS: We performed a historical cohort study involving 131 patients treated with a first TACE, defined as either an initial treatment for previously untreated HCC or a first treatment for relapsed HCC after curative resections or ablations. Efficacy was estimated as the response rate (RR) and it was adjusted for the confounding factors that were defined in this study. RESULTS: The RR were 62.5% (20/32) for the first TACE with CDDP and 51.5% (51/99) for that with EPI. In the adjusted analysis for a history of hepatectomy, percutaneous treatment combined with TACE and tumor factors, the odds ratio was 1.72 (95% confidence interval [CI] = 0.70-4.48). However, a test for interaction between the number of tumors and the chemotherapeutic agent was statistically significant (P = 0.016). In multiple HCC, the RR were 66.7% (10/17) for CDDP and 39.6% (30/46) for EPI. The odds ratio was 4.11 (95% CI = 1.14-17.2). CONCLUSION: CDDP may be more effective than EPI in TACE for multiple HCC. A randomized controlled study is needed to clarify the efficacy of CDDP in TACE in patients with multiple HCC. PMID- 21276152 TI - Studies on virus kinetics using infectious fluorescence-tagged hepatitis C virus cell culture. AB - AIM: Studies of the complete hepatitis C virus (HCV) life cycle have become possible with the development of a HCV-JFH1 cell culture system. METHODS: In this study, we constructed two fluorescence protein-tagged recombinant JFH1 virus clones, JFH1-EYFP and JFH1-AsRed, as well as two corresponding clones with adaptive mutations, JFH1-EYFP mutant and JFH1-AsRed mutant, that and were as effective as JFH1 in producing infectious virus particles, and investigated their viral infection life cycles. RESULTS: After infection of the fluorescence tagged mutant viruses, infected cells increased exponentially. In cells, EYFP or AsRed and NS5A were expressed as a fusion protein and co-localized in core proteins. The rate of the cell-cell spread was dependent on the cell densities with a maximum of 10(2.5) /day. Treatment of cells with interferon or a protease inhibitor suppressed expansion of virus-positive cells. CONCLUSION: Taken together, these results indicate that fluorescence-tagged HCV is a useful tool to study virus infection life cycles and to assist in the search for novel antiviral compounds. PMID- 21276153 TI - No associations of polymorphisms in ADPRT with hepatitis B virus clearance and hepatocellular carcinoma occurrence in a Korean population. AB - AIM: The human adenosine diphosphate ribosyl transferase (ADPRT) gene might significantly affect cancer by encoding poly(ADP-ribose) polymerase 1 enzyme (PARP-1) and promoting an important role in cellular responses to DNA damage, genomic stabilization and regulation of tumor suppressor genes. We explored whether polymorphisms of ADPRT affect clearance of hepatitis B virus (HBV) infection or risk of hepatocellular carcinoma (HCC) occurrence in a Korean HBV cohort. METHODS: Genotyping was performed in a total of 1066 subjects composed of 434 spontaneously recovered (SR) subjects as normal controls and 632 chronic carriers (CC) of HBV who were further classified into 325 patients with liver cirrhosis (LC)/chronic hepatitis (CH) and 307 patients with HCC. RESULTS: Logistic analyses of six common single nucleotide polymorphisms (SNP) and their haplotypes revealed that none of the polymorphisms were significantly associated with clearance of HBV infection and HCC occurrence, except for nominal evidence of association between haplotype 2 (ht2) with HBV clearance (P = 0.05). In the analysis of age of HCC occurrence which is an important factor in disease progression to HCC, results from Cox proportional hazards showed that none of the variants were significantly associated with onset age of HCC occurrence, although a nominal signal in ht4 (P = 0.03, but P(corr) > 0.05) was initially detected. CONCLUSION: Although ADPRT is an important gene for cellular responses and tumor regulations, our study provides evidence that ADPRT variations do not affect HBV clearance and HCC occurrence. PMID- 21276154 TI - In-office cosmetic procedures. PMID- 21276155 TI - Facial volume restoration of the aging face with poly-l-lactic acid. AB - The purpose of this article is to discuss current techniques used with poly-l lactic acid to safely and effectively address changes observed in the aging face. Several important points deserve mention. First, this unique agent is not a filler but a stimulator of the host's own collagen, which then acts to volumize tissue in a gradual, progressive, and predictable manner. The technical differences between the use of biostimulatory agents and replacement fillers are simple and straightforward, but are critically important to the safe and successful use of these products and will be reviewed in detail. Second, in addition to gains in technical insights that have improved our understanding of how to use the product to best advantage, where to use the product to best advantage in facial filling has also improved with ever-evolving insights into the changes observed in the aging face. Finally, it is important to recognize that a patient's final outcome, and the amount of product and work it will take to get there, is a reflection of the quality of tissues with which they start. This is, of course, an issue of patient selection and not product selection. PMID- 21276156 TI - Rejuvenation of the neck with liposuction and ancillary techniques. AB - An aesthetically pleasing neck is an important component of physical appearance and a frequently targeted area for a variety of rejuvenative procedures. In appropriately selected patients, liposuction of the neck using tumescent local anesthesia can effectively render a more youthful appearance to the anterior and lateral neck by removing superficial adipose tissue and redraping the skin. This article will review all aspects of neck liposuction, including neck and lower face anatomy, proper patient selection and evaluation, necessary equipment, as well as all peri-procedural management. An in-depth discussion of administration of tumescent local anesthesia and proper liposuction technique is also included. Lastly, a number of ancillary techniques to further enhance the appearance of the neck including laser lipolysis, fractional ablative CO(2) resurfacing, and treatment of platysmal banding will be briefly discussed. PMID- 21276157 TI - Fractionated CO2 laser skin rejuvenation. AB - Fractional photothermolysis has been reported in the literature to improve both the pigmentary and textural changes associated with photoaging. The objective of the study was to review the literature of non-ablative fractional laser (NAFL) and ablative fractional laser (AFL) resurfacing for the treatment of photoaging. This is a review of the Medline literature evaluating NAFL and AFL for photoaging. Review of the literature supports the use of NAFL and AFL as safe and effective treatments for photoaging. It is likely that the controlled, limited dermal heating of fractional resurfacing initiates a cascade of events in which normalization of the collagenesis/collagenolysis cycle occurs. The advent of fractionated resurfacing for the treatment of photoaging is a significant advance over ablative laser resurfacing treatments, which were complicated by prolonged erythema, delayed onset hypopigmentation, and scarring. PMID- 21276158 TI - Botulinum toxin type A for aging face and aesthetic uses. AB - Botulinum neurotoxin type A injection to correct and/or reverse the physical effects of aging process has become one of the most frequently requested cosmetic procedures at an outpatient setting. Careful clinical evaluation together with proper use of the techniques, including pre- and post-procedures recommendations, reconstitution of the products, techniques, and doses, are described in this article. This article also covers the main indications of botulinum neurotoxin type A for aging face and other aesthetic uses, as well as some possible adverse reactions and their management. PMID- 21276159 TI - Ablative fractional CO2 resurfacing for photoaging of the hands: pilot study of 10 patients. AB - Extrinsic aging of the hands involves alterations in pigmentation, wrinkling, and texture as a result of chronic ultraviolet and environmental exposures. Inherent tissue properties of the skin of the dorsal hand have made it challenging to safely and effectively improve all three parameters of photoaging with a single device. Recent successes with non-ablative fractional lasers on the hands, as well as success of ablative fractional lasers on the neck and chest, raise the question of potential efficacy of ablative lasers for photorejuvenation of the hands. This was a prospective pilot study of ablative fractional CO(2) laser in 10 participants, each receiving three treatments to one hand at 4-6-week intervals. Subjective assessments by investigator and participants were performed 1 month after each treatment. At 1-month follow-up after final treatment, investigators rated mean improvement of 26-50% for wrinkles, 51-75% for pigment, and 26-50% for texture. Participants rated mean improvement after final treatment as 26-50% for wrinkles, 51-75% for pigment, and 51-75% for texture. Other than significant edema noted in one participant after the first treatment, side effects were limited to transient erythema and edema, with no long-term scarring or pigmentary alteration. In this pilot study, ablative fractional resurfacing was safe and effective for the treatment of all markers of extrinsic aging of the hands. A high degree of improvement was achieved in two to three treatments with no long-term sequelae. PMID- 21276160 TI - Soft-tissue augmentation with hyaluronic acid and calcium hydroxyl apatite fillers. AB - Soft-tissue augmentation with hyaluronic acid and calcium hydroxyl apatite are among the most widely used minimally invasive cosmetic treatments for the correction of contour deficiencies and wrinkles of the face without the risk, recovery time, and expense of a major surgery. Training and experience in the art and science of fillers is essential for the successful creation of a more youthful and natural appearance. An understanding of the different products, the injection techniques, the indications, and the potential complications of each filler are paramount to success. PMID- 21276161 TI - MAL-PDT for difficult to treat nonmelanoma skin cancer. AB - With an incidence of over 3.5 million nonmelanoma skin cancers (NMSCs) per year in the United States, there is an increasing need for effective, cost-effective treatments for NMSC. When surgical excision is impractical or not feasible, methyl aminolevulinate photodynamic therapy (MAL-PDT) has demonstrated consistently high long-term cure rates ranging from 70-90%, with superior cosmetic outcomes compared with other treatment modalities. With the exception of invasive squamous cell carcinoma, MAL-PDT has been successful in treating all types of NMSC, especially in patients with multiple comorbidities, field cancerization, and lesions in cosmetically sensitive locations. Herein, a step-by step description of the procedure for MAL-PDT is provided, followed by a review of outcomes from large clinical trials performed over the past 15 years for each variant of NMSC. After reading this review, clinicians should have a thorough understanding of the benefits and limits of MAL-PDT, and should be able to add this valuable procedure to their armamentarium of therapies for NMSC. PMID- 21276162 TI - Laser hair removal. AB - The extended theory of selective photothermolysis enables the laser surgeon to target and destroy hair follicles, thereby leading to hair removal. Today, laser hair removal (LHR) is the most commonly requested cosmetic procedure in the world and is routinely performed by dermatologists, other physicians, and non-physician personnel with variable efficacy. The ideal candidate for LHR is fair skinned with dark terminal hair; however, LHR can today be successfully performed in all skin types. Knowledge of hair follicle anatomy and physiology, proper patient selection and preoperative preparation, principles of laser safety, familiarity with the various laser/light devices, and a thorough understanding of laser tissue interactions are vital to optimizing treatment efficacy while minimizing complications and side effects. PMID- 21276163 TI - Vertical vector face lift. AB - Facial rejuvenation using local anesthesia has evolved in the past decade as a safer option for patients seeking fewer complications and minimal downtime. Mini- and short-scar face lifts using more conservative incision lengths and extent of undermining can be effective in the younger patient with lower face laxity and minimal loose, elastotic neck skin. By incorporating both an anterior and posterior approach and using an incision length between the mini and more traditional face lift, the Vertical Vector Face Lift can achieve longer-lasting and natural results with lesser cost and risk. Submentoplasty and liposuction of the neck and jawline, fundamental components of the vertical vector face lift, act synergistically with superficial musculoaponeurotic system plication to reestablish a more youthful, sculpted cervicomental angle, even in patients with prominent jowls. Dramatic results can be achieved in the right patient by combining with other procedures such as injectable fillers, chin implants, laser resurfacing, or upper and lower blepharoplasties. PMID- 21276164 TI - Ultrasound-guided drainage of a seroma following tumescent liposuction. AB - Of the complications that can occur following tumescent liposuction, seroma formation is unusual. It is a common practice for seromas to be aspirated blindly with a needle and syringe. We present a case of seroma formation following liposuction, with a subsequent step-by-step technical description of ultrasound guided drainage of the seroma. Utilization of ultrasound provides a safe, effective method for aspirating seromas, allowing for accurate visualization and delineation of the seroma margins, proper needle placement, and monitoring of progress. It is a simple and useful tool in postprocedural management of patients undergoing liposuction. PMID- 21276165 TI - Novel method of minimally invasive removal of large lipoma after laser lipolysis with 980 nm diode laser. AB - Lipomas are the most common benign tumor of the soft tissue, often presenting as soft, mobile subcutaneous masses. These lesions are often removed for cosmetic reasons, although they may be removed secondary to considerable discomfort or paresthesias. The large majority of lipomas appear as small, solitary lesions that are best removed by surgical excision. However, surgical removal of large (>10 cm) or multiple lesions may result in significant scarring. Tumescent local anesthesia and liposuction of larger lesions has been successful in a number of cases although this technique can be hindered by overly fibrous lesions. Laser lipolysis, performed alone or before liposuction, can further facilitate removal of these lesions. This technique is a minimally invasive and effective method of lipoma removal, resulting in an excellent cosmetic outcome. This report describes step-by-step removal of a large lipoma located on the back, as well as a review of currently employed techniques for minimally invasive treatment of lipomas. PMID- 21276166 TI - Candida parapsilosis infection following the electrosurgery procedure. AB - Subcutaneous mycoses are fungal infections that predominantly affect the dermis and subcutaneous tissue. The most common pathogen responsible for these infections is Candida albicans; however, another yeast from this group, Candida parapsilosis, becomes the cause of increasing numbers of mycotic infections. Recent reports suggested that this microorganism may be particularly resistant to disinfectants, which can facilitate its spread through the medical staff, instruments, and biomaterial. We report a case of a patient in whom a C. parapsilosis infection occurred as a complication following a minor electrocoagulation procedure. Because all obtained laboratory findings were nonspecific, the infection could be properly diagnosed only through cultures from the skin lesion. PMID- 21276167 TI - Improvement of ulcerative pyoderma gangrenosum with hyperbaric oxygen therapy. AB - Pyoderma gangrenosum (PG) is a rare noninfectious destructive neutrophilic dermatosis of unknown origin affecting the skin and occasionally the subcutaneous fat. In this report, we present the results of intensive hyperbaric oxygen (HBO) therapy in a 62-year-old Greek woman who had been diagnosed with ulcerative PG two years ago, but had been resistant to other therapies. PMID- 21276168 TI - Intradermal injection of PPD as a novel approach of immunotherapy in anogenital warts in pregnant women. AB - Immunotherapy for treatment of recalcitrant warts was used through different modalities including intralesional injection of purified protein derivative (PPD), which is an extract of Mycobacterium tuberculosis, used for testing exposure to tuberculin protein, either from a previous vaccination or from the environment. This method is used to evaluate the efficacy of a new approach of intradermal injection of PPD in the treatment of anogenital warts in pregnant women. A total of 40 pregnant women, aged 20-35 years, and presented with anogenital warts were enrolled in this study. Human papillomavirus (HPV) typing was done using the GP5+/GP6+ PCR assay. The patients were treated with weekly injections of PPD given intradermally in the forearms, and evaluated for the response regularly. HPV type-6 was the predominant genotype (67.5%). Overall, the improvement in this study was 85% and was related to the extent of tuberculin reactivity. Nineteen (47.5%) patients demonstrated complete clearance, 15 (37.5%) had partial response, and three (7.5%) had minimal response. Three (7.5%) cases did not respond to treatment. Side effects were minimal and insignificant. Treatment of anogenital warts in pregnant women with intradermal injection of PPD was found to be a unique, safe, and effective modality of immunotherapy. PMID- 21276169 TI - Chondrodermatitis nodularis chronica helicis and photodynamic therapy: a new therapeutic option? AB - Chondrodermatitis nodularis chronica helicis (CNCH) is a fairly frequent disorder of unknown etiology. Although the elective therapy is surgery, local application of topical steroids, antibiotic ointments, intralesional injection of collagen, cryotherapy, curettage followed by diathermy, and CO(2) laser treatment have also been proposed. The aim of the study was to test the utility of photodynamic therapy (PDT) for CNCH. Two patients with painful CNCH underwent PDT with a 635 nm light source for 20 minutes (70 J/cm(2) ) after application of cream containing 20% 5-aminolevulinic acid (5-ALA) and occlusion for 3 hours. The lesions decreased considerably in size and pain ceased within a few weeks. The results suggest that this method can be useful for treating CNCH, especially in patients with contraindications for surgery. PMID- 21276170 TI - Genetic and molecular analysis of nematode-microbe interactions. AB - Symbiosis, the living together of unlike organisms, such as between microbes and their multicellular eukaryotic hosts, can be categorized as parasitic, commensal or mutualistic. The establishment of symbiosis and the outcome of microbe-host interactions are dictated largely by both microbe- and host-derived factors. Over the last decade, the nematode Caenorhabditis elegans has provided a facile experimental system to study such interactions, with parasitic interactions being the primary focus. The myriad of genetic and molecular tools available has made C. elegans a powerful model system to interrogate the interactions between a host and its pathogens, and has provided a greater understanding of the molecular underpinnings of these interactions, many of which were found to be conserved across other taxa. Commensal and mutualistic interactions between worms and their microbes, although less studied, have the potential to enhance our understanding of genetic and molecular features underlying host-microbe interactions. Here, we highlight new insights obtained in delineating the signalling pathways that function within and between host cells in combating assaults from extracellular and intracellular pathogens. We also discuss potential new insights that could be gained from further studies into commensal and mutualistic relationships between nematodes and microbes. PMID- 21276171 TI - Evidence of direct cell-cell fusion in Borrelia by cryogenic electron tomography. AB - Some Borrelia species are the causative agents of tick-borne Lyme disease responsible for different disabilities depending on species and hosts. Borrelia are highly motile bacterial cells, and light microscopy shows that these spirochetes can associate with each other during movement. Using cryo-electron tomography, we observed closely associated Borrelia cells. Some of these showed a single outer membrane surrounding two longitudinally arranged cytoplasmic cylinders. We also observed fusion of two cytoplasmic cylinders and differences in the surface layer density of fused spirochetes. These processes could play a role in the interaction of Borrelia species with the host's immune system. PMID- 21276175 TI - Reducing the time to continence after radical prostatectomy. PMID- 21276176 TI - The successful, sustainable elimination of a waiting list for urology outpatients. PMID- 21276177 TI - Long-term follow-up of T1 high-grade bladder cancer after intravesical bacille Calmette-Guerin treatment. AB - OBJECTIVE: To report the long-term results of bacille Calmette-Guerin (BCG) intravesical therapy in relation to disease progression and recurrence in primary T1 high-grade (HG) bladder cancer (BC) confirmed by central pathological review. PATIENTS AND METHODS: In all, 136 patients from two university centres (Rotterdam, n = 49; Toronto, n = 87) were diagnosed with primary T1HG BC. One experienced uro-pathologist reviewed all slides, ensuring all cases were indeed HG and that muscle was present in all specimens. Patients were treated with BCG induction (six instillations) after transurethral resection (TUR) of the tumour and followed with cystoscopy and urinary cytology. Predictors for recurrence, progression and survival were assessed with multivariable Cox regression models. RESULTS: Mean (range) follow-up was 6.5 (0.3-21.6) years. There were no significant differences for recurrence (P = 0.52), progression (P = 0.35) and disease-specific survival (DSS) (P = 0.69) between the two centres. Among the cohort, 47 patients (35%) recurred and 42 (30.9%) progressed with a median time to progression of 2.1 years; 16 (38%) of these progressions occurred >= 3 years after the initial BCG course; 22 (16%) patients who progressed died from BC. Overall, 96 (71%) patients had no evidence of disease at the last follow-up. Carcinoma in situ was the only independent predictor for recurrence in multivariate analysis (P = 0.011). No independent predictors were found for progression. CONCLUSIONS: Conservative treatment with BCG is a valid option in primary T1HG BC. Nevertheless, the aggressive nature of T1HG BC is evident in the fact that 30% progressed, with a high proportion of these progression events occurring >= 3 years after BCG. Caution should be exercised when relying on the long-term effects of BCG, and close follow-up of these patients should not be neglected. PMID- 21276178 TI - Hepcidin, anaemia, and prostate cancer. PMID- 21276179 TI - A modification of the embedding of tapered ileum in a continence mechanism as described previously: a self-critical analysis. PMID- 21276185 TI - Decreasing phantom limb pain through observation of action and imagery: a case series. AB - BACKGROUND: Phantom limb pain is often resistant to treatment. Techniques based on visual-kinesthetic feedback could help reduce it. OBJECTIVE: The objective of the current study was to test if a novel intervention combining observation and imagination of movements can reduce phantom limb pain. METHODS: This single-case multiple baseline study included six persons with upper or lower limb phantom pain. Participants' pain and imagery abilities were assessed by questionnaires. After a 3-5-week baseline, participants received a two-step intervention of 8 weeks. Intervention 1 was conducted at the laboratory with a therapist (two sessions/week) and at home (three sessions/week); and Intervention 2 was conducted at home only (five times/week). Interventions combined observation and imagination of missing limb movements. Participants rated their pain level and their ease to imagine daily throughout the study. RESULTS: Time series analyses showed that three participants rated their pain gradually and significantly lower during Intervention 1. During Intervention 2, additional changes in pain slopes were not significant. Four participants reported a reduction of pain greater than 30% from baseline to the end of Intervention 2, and only one maintained his gains after 6 months. Group analyses confirmed that average pain levels were lower after intervention than at baseline and had returned to baseline after 6 months. Social support, degree of functionality, and perception of control about their lives prior to the intervention correlated significantly with pain reduction. CONCLUSIONS: Persons with phantom limb pain may benefit from this novel intervention combining observation and motor imagery. Additional studies are needed to confirm our findings, elucidate mechanisms, and identify patients likely to respond. PMID- 21276183 TI - Preservation of femoral bone thickness in middle age predicts survival in genetically heterogeneous mice. AB - To see whether age-related changes in bone could predict subsequent lifespan, we measured multiple aspects of femur size and shape at 4, 15, and 24 months of age in genetically heterogeneous mice. Mice whose cortical bone became thicker from 4 to 15 months, associated with preservation of the endosteal perimeter, survived longer than mice whose endosteal cavity expanded, at the expense of cortical bone, over this age range. Femur size at age 4 months was also associated with a difference in life expectancy: mice with larger bones (measured by length, cortical thickness, or periosteal perimeter) had shorter lifespans. Femur length, midlife change in cortical bone thickness, and midlife values of CD8 T memory cells each added significant power for longevity prediction. Mice in the upper half of the population for each of these three endpoints lived, on average, 103 days (12%) longer than mice with the opposite characteristics. Thus, measures of young adult bone dimensions, changes as a result of bone remodeling in middle age, and immunological maturation provide partially independent indices of aging processes that together help to determine lifespan in genetically heterogeneous mice. PMID- 21276184 TI - Nitrite supplementation reverses vascular endothelial dysfunction and large elastic artery stiffness with aging. AB - We tested the hypothesis that short-term nitrite therapy reverses vascular endothelial dysfunction and large elastic artery stiffening with aging, and reduces arterial oxidative stress and inflammation. Nitrite concentrations were lower (P < 0.05) in arteries, heart, and plasma of old (26-28 month) male C57BL6 control mice, and 3 weeks of sodium nitrite (50 mg L(-1) in drinking water) restored nitrite levels to or above young (4-6 month) controls. Isolated carotid arteries of old control mice had lower acetylcholine (ACh)-induced endothelium dependent dilation (EDD) (71.7 +/- 6.1% vs. 93.0 +/- 2.0%) mediated by reduced nitric oxide (NO) bioavailability (P < 0.05 vs. young), and sodium nitrite restored EDD (95.5 +/- 1.6%) by increasing NO bioavailability. 4-Hydroxy-2,2,6,6 tetramethylpiperidine 1-oxyl (TEMPOL), a superoxide dismutase (SOD) mimetic, apocynin, a nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) inhibitor, and sepiapterin (exogenous tetrahydrobiopterin) each restored EDD to ACh in old control, but had no effect in old nitrite-supplemented mice. Old control mice had increased aortic pulse wave velocity (478 +/- 16 vs. 332 +/- 12 AU, P < 0.05 vs. young), which nitrite supplementation lowered (384 +/- 27 AU). Nitrotyrosine, superoxide production, and expression of NADPH oxidase were ~100 300% greater and SOD activity was ~50% lower in old control mice (all P < 0.05 vs. young), but were ameliorated by sodium nitrite treatment. Inflammatory cytokines were markedly increased in old control mice (P < 0.05), but reduced to levels of young controls with nitrite supplementation. Short-term nitrite therapy reverses age-associated vascular endothelial dysfunction, large elastic artery stiffness, oxidative stress, and inflammation. Sodium nitrite may be a novel therapy for treating arterial aging in humans. PMID- 21276186 TI - Reliability of a preliminary 3-D pain mapping program. AB - OBJECTIVE: The objective of this preliminary investigation was to evaluate the test-retest reliability of a new pain assessment method referred to as 3-D pain mapping. METHODS: In Study 1, 101 chronic noncancer pain patients from four sites reported their pain using the method on two occasions (separated by approximately 10 days). The patients marked intensity, surface location, and depth of pain on a 3-D computer display of a male or female body. The model body could be rotated in order to mark multiple pain locations. In Study 2, 25 patients from a single site were tested with a revised version of the mapping program used in Study 1. Each patient gave ratings on two occasions separated by approximately 1 week. RESULTS: In Study 1, the intra-class correlations of the 3-D pain mapping measures were moderate to high for maximum pain intensity (0.73), vertical location of the point of maximum pain (0.94), and the number of pain marks (0.84). Correlations were low for the horizontal location of the point of maximum pain (0.56) and for the depth of pain (0.50). In Study 2, using the revised program, intra-class correlations were moderate for pain intensity (0.76), and high for the vertical (0.99) and horizontal (0.98) locations of the point of maximum pain, number of pain marks (0.89), and the depth of pain (0.84). CONCLUSION: Three-dimensional pain mapping enables patients to report the location and intensity of their pain on all parts of the body, and such ratings are highly reliable. Future studies are needed to determine whether the clinical value of this method can improve the accuracy of pain diagnoses and the quality of pain management. PMID- 21276187 TI - A new program in pain medicine for medical students: integrating core curriculum knowledge with emotional and reflective development. AB - OBJECTIVE: Improvements in clinical pain care have not matched advances in scientific knowledge, and innovations in medical education are needed. Several streams of evidence indicate that pain education needs to address both the affective and cognitive dimensions of pain. Our aim was to design and deliver a new course in pain establishing foundation-level knowledge while comprehensively addressing the emotional development needs in this area. SETTING: One hundred eighteen first-year medical students at Johns Hopkins School of Medicine. OUTCOME MEASURES: Performance was measured by multiple-choice tests of pain knowledge, attendance, reflective pain portfolios, and satisfaction measures. RESULTS: Domains of competence in pain knowledge included central and peripheral pain signalling, pharmacological management of pain with standard analgesic medications, neuromodulating agents, and opioids; cancer pain, musculoskeletal pain, nociceptive, inflammatory, neuropathic, geriatric, and pediatric pain. Socio-emotional development (portfolio) work focused on increasing awareness of pain affect in self and others, and on enhancing the commitment to excellence in pain care. Reflections included observations on a brief pain experience (cold pressor test), the multidimensionality of pain, the role of empathy and compassion in medical care, the positive characteristics of pain-care role models, the complex feelings engendered by pain and addiction including frustration and disappointment, and aspirations and commitments in clinical medicine. The students completing feedback expressed high levels of interest in pain medicine as a result of the course. DISCUSSION: We conclude that a 4-day pain course incorporating sessions with pain specialists, pain medicine knowledge, and design-built elements to strengthen emotional skills is an effective educational approach. SUMMARY: Innovations in medical education about pain are needed. Our aim was to design and deliver a new course for medical students addressing both the affective and cognitive dimensions of pain. Combining small-group sessions with pain specialists, active-learning approaches to pain knowledge, and design-built elements to strengthen emotional skills was highly effective. PMID- 21276188 TI - The effect of brief electrical and manual acupuncture stimulation on mechanical experimental pain. AB - OBJECTIVE: Although manual and electrical stimulation are frequently used in acupuncture analgesia, studies comparing both stimulation modalities are contradictory. This blinded, placebo-controlled cross-over study investigates effects of brief manual and electrical acupuncture stimulation on pressure pain detection thresholds (PPDT) compared with nonpenetrating sham acupuncture (NPSA). INTERVENTIONS: Forty-five healthy volunteers received electrically and manually stimulated acupuncture and NPSA at large intestine 4 and 11 in randomized order. PPDT was assessed using pressure algometry at the second toe before; during; and 0, 2, and 5 minutes after each intervention. Stimulus intensity during stimulation was rated on a 0-10 numeric rating scale (NRS). RESULTS: PPDT rose from 316 kPa (standard deviation [SD] 149) to 398 kPa (SD 157) and 405 kPa (SD 184) immediately after acupuncture with manual and electrical stimulation, respectively, and to 380 kPa (SD 175) and 367 kPa (SD 168) after NPSA with simulated manual and electrical stimulation, respectively. During the intervention, electroacupuncture produced a higher PPDT increase than any other procedure (P<0.001). Immediately after, both acupuncture procedures were significantly more effective than NPSA (P<0.001) but did not mutually differ (P=0.082). NRS ratings differed significantly: manual acupuncture 4.1, electroacupuncture 2.7, manual NPSA 2.5, electro-NPSA 1.2 (P<0.001 except for electroacupuncture vs manual NPSA, P=0.271). CONCLUSION: Electroacupuncture produced higher PPDT elevation than manual acupuncture, and acupuncture in general showed significantly greater analgesic effect than NPSA. These effects seem to be short lasting (<5 minutes) in the context of only brief acupuncture. The superiority of acupuncture to NPSA provides further evidence for acupuncture specific analgesic effects. PMID- 21276189 TI - Ecological or recalled assessments in chronic musculoskeletal pain? A comparative study of prospective and recalled pain assessments in low back pain and lower limb painful osteoarthritis. AB - OBJECTIVES: The objective of this study was to compare ecological and recalled pain intensity assessments over 29 days in hip and knee osteoarthritis (O) and chronic low back pain (L). PATIENTS AND METHODS: Rheumatologists were asked to enroll patients with O and L, with pain intensity above 40 mm, in a prospective study for 29 days. Pain intensity was assessed with physicians on Days 1 and 29, and ecologically, over the intervening 28-day period, by random phone calls. RESULTS: We carried out correlation analyses for 353 (159 O, 194 L) patients: Overall recalled daily pain was strongly correlated with calculated 3-day mean pain assessments (r=0.96 [O]; 0.93 [L]) and evening pain (r=0.96 [O], 0.90 [L]). Correlations between ecological and recalled measures were stronger for recall over the last 7 days than for recall over the last 28 days in osteoarthritis patients (r=0.78, r=0.63), but were similar for both recall periods in low back pain patients (r=0.70, r=0.72). Correlations between assessments for the last 7 and 28 days were stronger for ecological (r=0.88 [O], 0.91 [L]) than for clinical (r=0.77 [O]; 0.86 [L]) assessments. After adjustment for current pain intensity, correlations remained significant for ecological assessments, but not for clinical assessments. Recalled pain assessments were more accurate when made after 24 hours (r=0.71 [O]; 0.70 [L]) than when made after 48 hours (r=0.63 [O]; 0.61 [L]). CONCLUSIONS: For both low back pain and osteoarthritis, overall daily pain recall is a reliable measurement correlated with daily ecological measurements, whereas a rapid decrease in recall occurs after 48 hours. The most reliable period for pain recall was 7 days, but the results obtained were influenced by current pain. PMID- 21276190 TI - Effectiveness of traditional Chinese "gua sha" therapy in patients with chronic neck pain: a randomized controlled trial. AB - OBJECTIVE: Gua sha is a traditional East Asian healing technique where the body surface is press-stroked with a smooth-edged instrument to intentionally raise therapeutic petechiae. A traditional indication of Gua sha is neck pain; no data from controlled trials exist to support this claim. The researchers aimed to investigate the effectiveness of Gua sha in the symptomatic treatment of chronic neck pain. DESIGN: The study was designed as an open randomized controlled clinical trial. SETTING: The study was set in Kliniken Essen-Mitte, Academic Teaching Hospital of the University Duisburg-Essen, Germany. SUBJECTS: Forty eight outpatients (58.5+/-8.0 years; 41 female) with chronic mechanical neck pain were the subjects of the study. INTERVENTION: Patients were randomized into Gua sha (N=24) or control groups (N=24) and followed up for 7 days. Gua sha patients were treated once with Gua sha, while control patients were treated with a local thermal heat pad. OUTCOME MEASURES: Primary outcome was change of neck pain severity after 1 week as assessed by visual analog scale. Secondary outcomes included pain at motion, the neck disability index (NDI) and quality-of-life (Short-Form [36] Health Survey). RESULTS: Neck pain severity after 1 week improved significantly better in the Gua sha group compared with the control group (group difference -29.9 mm, 95% confidence interval: -43.3; -16.6 mm; P<0.001). Significant treatment effects were also found for pain at motion, scores on the NDI, and dimensions of quality-of-life. The treatment was safe and well tolerated. CONCLUSION: Gua sha has beneficial short-term effects on pain and functional status in patients with chronic neck pain. The value of Gua sha in the long-term management of neck pain and related mechanisms remains to be clarified. PMID- 21276191 TI - [Do we need the European specialist in dermatology and venereology]. PMID- 21276197 TI - [Perimamillar located ulcerous skin lesion in a 75-year old patient]. PMID- 21276198 TI - The putative diabetic plasma marker, soluble CD36, is non-cleaved, non-soluble and entirely associated with microparticles. AB - BACKGROUND: CD36 is a widely expressed cell surface receptor that binds lipoproteins, and its function has been implicated in many complications of the metabolic syndrome. A cell-free form of CD36, soluble CD36 (sCD36), has been reported in human plasma, found to be elevated in obesity and diabetes, and claimed as a marker of insulin resistance. OBJECTIVE: To determine the nature of sCD36; in particular, whether sCD36 is truly soluble or, as hypothesized, is found as a component of circulating microparticles (MPs). METHODS: Lipoproteins were fractionated by density gradient centrifugation, and plasma MPs were isolated by ultracentrifugation, size exclusion, and immunoprecipitation with CD36 detected by immunoblotting. MPs from plasma and activated platelets were analyzed by multicolor flow cytometry, with a DyLight-488 anti-CD36 conjugate in combination with antibodies against different cellular markers. RESULTS: Cell free plasma CD36 was not observed associated with lipoproteins and was not a proteolytic fragment; rather, it was associated with the plasma MP fraction, suggesting that sCD36 in the plasma of normal subjects is a product of circulating MPs. Cytometric and immunoblotting analyses of plasma from normal donors showed that these MPs were derived mainly from platelets. Analysis of in vitro activated platelets also showed that CD36 to be secreted in the form of MPs. CONCLUSIONS: sCD36 is not a proteolytic product, but rather is associated with a specific subset of circulating MPs that can readily be analysed. This finding will enable more specific investigations into the cellular source of the increased levels of plasma CD36 found in subjects with diabetes. PMID- 21276199 TI - Using evidence to improve patient safety and the quality of health care. PMID- 21276200 TI - Microbial alcohol-conferred hemolysis is a late response to alcohol stress. AB - We have reported previously that growth on alcohol vapors confers hemolytic properties on certain yeast species and strains ['microbial alcohol-conferred hemolysis' (MACH)]. In a recent study, we analyzed the genetic basis of MACH in Saccharomyces cerevisiae using the EUROSCARF mutant collection. The data suggested that intact mitochondrial and respiratory chain functions are critical for the observed alcohol-mediated hemolysis. We proposed that the uncontrolled cellular uptake of alcohol results in yeast 'hyper-respiration', leading to elaboration of hemolytic molecules such as hydrogen peroxide and lytic lipids. In the current study, we have further analyzed the molecular mechanisms involved in the MACH phenomenon in S. cerevisiae, using DNA microarrays. The patterns of regulation were confirmed by quantitative reverse transcriptase PCR. The results presented here lend further support to this hypothesis, based on upregulation of the genes responsible for coping with vast amounts of hydrogen peroxide produced as a byproduct of excessive oxidation of alcohol. These results, taken together, show that alcohol-mediated hemolysis in yeast appears to be related to the overproduction of hemolytic byproducts, particularly hydrogen peroxide, which accumulates during long-term exposure of S. cerevisiae to both ethanol and n butanol. PMID- 21276201 TI - Bipolar disorder risk alleles in adult ADHD patients. AB - Attention-deficit/hyperactivity disorder (ADHD) has an estimated prevalence of 3 5% in adults. Genome-wide association (GWA) studies have not been performed in adults with ADHD and studies in children have so far been inconclusive, possibly because of the small sample sizes. Larger GWA studies have been performed on bipolar disorder (BD) and BD symptoms, and several potential risk genes have been reported. ADHD and BD share many clinical features and comorbidity between these two disorders is common. We therefore wanted to examine whether the reported BD genetic variants in CACNA1C, ANK3, MYO5B, TSPAN8 and ZNF804A loci are associated with ADHD or with scores on the Mood Disorder Questionnaire (MDQ), a commonly used screening instrument for bipolar spectrum disorders. We studied 561 adult Norwegian ADHD patients and 711 controls from the general population. No significant associations or trends were found between any of the single nucleotide polymorphisms (SNPs) studied and ADHD [odds ratios (ORs) <= 1.05]. However, a weak association was found between rs1344706 in ZNF804A (OR = 1.25; P = 0.05) and MDQ. In conclusion, it seems unlikely that these six SNPs with strong evidence of association in BD GWA studies are shared risk variants between ADHD and BD. PMID- 21276202 TI - Clinical appearance, differential diagnoses and therapeutical options of chondrodermatitis nodularis chronica helicis Winkler. AB - The article on chondrodermatitis nodularis chronica helicis summarizes various clinical pictures and differential diagnoses of this entity. This lesion is usually characterized by a solid or cystic nodule but ulcerations or crusts may also occur. The most common differential diagnoses include benign or malignant tumours, which are often confused with chondrodermatitis nodularis chronica helicis. The characteristic pain associated with this condition may serve as an important diagnostic clue in order to rule out other differential diagnoses. The therapy of chondrodermatitis nodularis chronica helices encompasses several conservative as well as surgical treatment options. PMID- 21276203 TI - The Arabidopsis protein kinase Pto-interacting 1-4 is a common target of the oxidative signal-inducible 1 and mitogen-activated protein kinases. AB - In Arabidopsis thaliana, the serine/threonine protein kinase oxidative signal inducible 1 (OXI1), mediates oxidative stress signalling. Its activity is required for full activation of the mitogen-activated protein kinases (MAPKs), MPK3 and MPK6, in response to oxidative stress. In addition, the serine/threonine protein kinase Pto-interacting 1-2 (PTI1-2) has been positioned downstream from OXI1, but whether PTI1-2 signals through MAPK cascades is unclear. Using a yeast two-hybrid screen we show that OXI1 also interacts with PTI1-4. OXI1 and PTI1-4 are stress-responsive genes and are expressed in the same tissues. Therefore, studies were undertaken to determine whether PTI1-4 is positioned in the OXI1/MAPK signalling pathway. The interaction between OXI1 and PTI1-4 was confirmed by using in vivo co-immunoprecipitation experiments. OXI1 and PTI1-4 were substrates of MPK3 and MPK6 in vitro. Although no direct interaction was detected between OXI1 and MPK3 or MPK6, in vitro binding studies showed interactions between MPK3 or MPK6 with PTI1-4. In addition, PTI1-4 and MPK6 were found in vivo in the same protein complex. These results demonstrate that PTI1-4 signals via OXI1 and MPK6 signalling cascades. PMID- 21276204 TI - Structural requirements of isoquinolones as novel selective c-Jun N-terminal kinase 1 inhibitors: 2D and 3D QSAR analyses. AB - The c-Jun N-terminal kinases are attractive targets because of their involvement in several diseases. In this work, a combined molecular modeling study for a set of isoquinolones as inhibitors of JNK1 was performed by molecular docking, genetic algorithm-multiple linear regression and comparative molecular field analysis to rationalize the structural requirements responsible for the inhibitory activity of these compounds. Molecular docking study was employed to explore the binding mode of the active compound at the active site of JNK1. Based on the docked conformations, highly predictive 2D, 3D quantitative structure activity relationship models were developed. The best 2D quantitative structure activity relationship model was established using genetic algorithm-multiple linear regression method containing four molecular descriptors. The best comparative molecular field analysis model was obtained with a cross-validated coefficient q(2) of 0.562, non-cross-validated r(2) values of 0.994. The information from quantitative structure-activity relationship models and molecular docking is useful for the design of novel JNK1 inhibitors with improved activities. PMID- 21276205 TI - Vascular endothelial growth factor protects post-ganglionic sympathetic neurones from the detrimental effects of hydrogen peroxide by increasing catalase. AB - AIM: Vascular production of hydrogen peroxide (H(2)O(2)) is implicated in the development and progression of vascular disease. Hydrogen peroxide also promotes neuronal degeneration, which suggests that vascular H(2)O(2) would promote degeneration of perivascular sympathetic nerves. Vascular cells also produce vascular endothelial growth factor (VEGF), which could protect perivascular nerves from the detrimental effects of H(2)O(2) . The aim of this study was to test these hypotheses. METHODS: The effects of H(2)O(2) and VEGF on neuronal survival and noradrenaline uptake were studied in cultures of rat post-ganglionic sympathetic neurones. Western analyses of catalase and growth associated protein 43 were performed and reactive oxygen species (ROS) were measured using the fluorescent indicator 5-(and-6)-chloromethyl-2'7'-dichlorodihydrofluorescein diacetate, acetyl ester. RESULTS: Hydrogen peroxide (30 MUm) decreased the survival of post-ganglionic sympathetic neurones (57.8 +/- 4.8% of control) and decreased noradrenaline uptake into the neurones (14 +/- 6% of control). Hyperglycaemia, which is known to increase H(2)O(2), also decreased survival (31.4 +/- 12% of control) and noradrenaline uptake (42 +/- 18.4% of control). VEGF reduced the effects of H(2)O(2) (94.3 +/- 12% of control) and hyperglycaemia (83.5 +/- 23.6% of control) on survival. VEGF increased catalase, a primary determinant of intracellular concentrations of H(2)O(2) , and decreased H(2)O(2) induced increases in ROS. CONCLUSION: These results indicate that VEGF protects post-ganglionic sympathetic neurones from the detrimental effects of H(2)O(2). Our data suggest that an increase in catalase is the mechanisms underlying this neuroprotection. PMID- 21276206 TI - Granulocyte colony-stimulating factor stabilizes cardiac electrophysiology and decreases infarct size during cardiac ischaemic/reperfusion in swine. AB - AIM: Effects of granulocyte colony-stimulating factor (G-CSF) on cardiac electrophysiology during ischaemic/reperfusion (I/R) period are unclear. We hypothesized that G-CSF stabilizes cardiac electrophysiology during I/R injury by prolonging the effective refractory period (ERP), increasing the ventricular fibrillation threshold (VFT) and decreasing the defibrillation threshold (DFT), and that the cardioprotection of G-CSF is via preventing cardiac mitochondrial dysfunction. METHODS: In intact-heart protocol, pigs were infused with either G CSF or vehicle (n = 7 each group) without I/R induction. In I/R protocol, pigs were infused with G-CSF (0.33 MUg kg(-1 ) min(-1) ) or vehicle (n = 8 each group) for 30 min prior to a 45-min left anterior descending artery occlusion and at reperfusion. Diastolic pacing threshold (DPT), ERP, VFT and DFT were determined in all pigs before and during I/R period. Rat's isolated cardiac mitochondria were used to test the protective effect of G-CSF (100 nm) in H(2) O(2) -induced mitochondrial oxidative damage. RESULTS: Neither G-CSF nor vehicle altered any parameter in intact-heart pigs. During ischaemic period, G-CSF significantly increased the DPT, ERP and VFT without altering the DFT. During reperfusion, G CSF continued to increase the DPT without altering other parameters. The infarct size was significantly decreased in the G-CSF group, compared to the vehicle. G CSF could also prevent cardiac mitochondrial swelling, decrease ROS production, and prevent mitochondrial membrane depolarization. CONCLUSION: G-CSF increases the DPT, ERP and VFT and reduces the infarct size, thus stabilizing the myocardial electrophysiology, and preventing fatal arrhythmia during I/R. The protective mechanism could be via its effect in preventing cardiac mitochondrial dysfunction. PMID- 21276207 TI - Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010: (published in Chinese on Chinese Journal of Hepatology 2010; 18:163 166). PMID- 21276208 TI - Guidelines for the diagnosis and management of alcoholic liver disease: update 2010: (published in Chinese on Chinese Journal of Hepatology 2010; 18: 167-170). PMID- 21276209 TI - Production and diagnostic application of a purified, E. coli-expressed, serological-specific chicken anaemia virus antigen VP3. AB - The aim of this study was to evaluate the production of chicken anaemia virus VP3 protein in different Escherichia coli strains and to address the diagnostic application of purified E. coli-expressed VP3 protein for the detection of chicken anaemia virus (CAV) infection and the development of an ELISA kit. Three E. coli strains, BL21, BL21 codonplus RP and BL21 pLysS, each harbouring a VP3 protein expressing plasmid, were investigated after induction to produce recombinant VP3 protein. After isopropyl-beta-D-thiogalactoside (IPTG) induction, VP3 protein was successfully expressed in all three E. coli strains. The BL21 pLysS strain gave the best performance in terms of protein productivity and growth profile. In addition, the optimal culture temperature and IPTG concentration were found to be 0.25 mM and 20 degrees C, respectively. Using Ni NTA-purified VP3 protein as an ELISA coating antigen, the purified VP3 was shown to be highly antigenic and able to discriminate sera from chickens infected with CAV from those that were uninfected during an evaluation of CAV infection serodiagnosis. A VP3-based ELISA demonstrated 100% (6/6 x 100%) specificity and sensitivities of 91.3% (21/23 x 100%) and 82.6% (19/23 x 100%) using cut-off values of the mean plus 2 SD and the mean plus 3 SD, respectively. PMID- 21276210 TI - Improving yeast strains using recyclable integration cassettes, for the production of plant terpenoids. AB - BACKGROUND: Terpenoids constitute a large family of natural products, attracting commercial interest for a variety of uses as flavours, fragrances, drugs and alternative fuels. Saccharomyces cerevisiae offers a versatile cell factory, as the precursors of terpenoid biosynthesis are naturally synthesized by the sterol biosynthetic pathway. RESULTS: S. cerevisiae wild type yeast cells, selected for their capacity to produce high sterol levels were targeted for improvement aiming to increase production. Recyclable integration cassettes were developed which enable the unlimited sequential integration of desirable genetic elements (promoters, genes, termination sequence) at any desired locus in the yeast genome. The approach was applied on the yeast sterol biosynthetic pathway genes HMG2, ERG20 and IDI1 resulting in several-fold increase in plant monoterpene and sesquiterpene production. The improved strains were robust and could sustain high terpenoid production levels for an extended period. Simultaneous plasmid-driven co-expression of IDI1 and the HMG2 (K6R) variant, in the improved strain background, maximized monoterpene production levels. Expression of two terpene synthase enzymes from the sage species Salvia fruticosa and S. pomifera (SfCinS1, SpP330) in the modified yeast cells identified a range of terpenoids which are also present in the plant essential oils. Co-expression of the putative interacting protein HSP90 with cineole synthase 1 (SfCinS1) also improved production levels, pointing to an additional means to improve production. CONCLUSIONS: Using the developed molecular tools, new yeast strains were generated with increased capacity to produce plant terpenoids. The approach taken and the durability of the strains allow successive rounds of improvement to maximize yields. PMID- 21276211 TI - Dialectical Behavioral Therapy for Adolescents (DBT-A): a clinical Trial for Patients with suicidal and self-injurious Behavior and Borderline Symptoms with a one-year Follow-up. AB - BACKGROUND: To date, there are no empirically validated treatments of good quality for adolescents showing suicidality and non-suicidal self-injurious behavior. Risk factors for suicide are impulsive and non-suicidal self-injurious behavior, depression, conduct disorders and child abuse. Behind this background, we tested the main hypothesis of our study; that Dialectical Behavioral Therapy for Adolescents is an effective treatment for these patients. METHODS: Dialectical Behavioral Therapy (DBT) has been developed by Marsha Linehan - especially for the outpatient treatment of chronically non-suicidal patients diagnosed with borderline personality disorder. The modified version of DBT for Adolescents (DBT-A) from Rathus & Miller has been adapted for a 16-24 week outpatient treatment in the German-speaking area by our group. The efficacy of treatment was measured by a pre-/post- comparison and a one-year follow-up with the aid of standardized instruments (SCL-90-R, CBCL, YSR, ILC, CGI). RESULTS: In the pilot study, 12 adolescents were treated. At the beginning of therapy, 83% of patients fulfilled five or more DSM-IV criteria for borderline personality disorder. From the beginning of therapy to one year after its end, the mean value of these diagnostic criteria decreased significantly from 5.8 to 2.75. 75% of patients were kept in therapy. For the behavioral domains according to the SCL-90 R and YSR, we have found effect sizes between 0.54 and 2.14.During treatment, non suicidal self-injurious behavior reduced significantly. Before the start of therapy, 8 of 12 patients had attempted suicide at least once. There were neither suicidal attempts during treatment with DBT-A nor at the one-year follow-up. CONCLUSIONS: The promising results suggest that the interventions were well accepted by the patients and their families, and were associated with improvement in multiple domains including suicidality, non-suicidal self-injurious behavior, emotion dysregulation and depression from the beginning of therapy to the one year follow-up. PMID- 21276212 TI - Regular physical exercise training assists in preventing type 2 diabetes development: focus on its antioxidant and anti-inflammatory properties. AB - Diabetes mellitus has emerged as one of the main alarms to human health in the 21st century. Pronounced changes in the human environment, behavior and lifestyle have accompanied globalization, which resulted in escalating rates of both obesity and diabetes, already described as diabesity. This pandemic causes deterioration of life quality with high socio-economic costs, particularly due to premature morbidity and mortality. To avoid late complications of type 2 diabetes and related costs, primary prevention and early treatment are therefore necessary. In this context, effective non-pharmacological measures, such as regular physical activity, are imperative to avoid complications, as well as polymedication, which is associated with serious side-effects and drug-to-drug interactions. Our previous work showed, in an animal model of obese type 2 diabetes, the Zucker Diabetic Fatty (ZDF) rat, that regular and moderate intensity physical exercise (training) is able, per se, to attenuate insulin resistance and control glycaemia, dyslipidaemia and blood pressure, thus reducing cardiovascular risk, by interfering with the pathophysiological mechanisms at different levels, including oxidative stress and low-grade inflammation, which are key features of diabesity. This paper briefly reviews the wide pathophysiological pathways associated with Type 2 diabetes and then discusses in detail the benefits of training therapy on glycaemic control and on cardiovascular risk profile in Type 2 diabetes, focusing particularly on antioxidant and anti-inflammatory properties. Based on the current knowledge, including our own findings using an animal model, it is concluded that regular and moderate intensity physical exercise (training), due to its pleiotropic effects, could replace, or at least reduce, the use of anti-diabetic drugs, as well as of other drugs given for the control of cardiovascular risk factors in obese type 2 diabetic patients, working as a physiological "polypill". PMID- 21276213 TI - Removing noise from pyrosequenced amplicons. AB - BACKGROUND: In many environmental genomics applications a homologous region of DNA from a diverse sample is first amplified by PCR and then sequenced. The next generation sequencing technology, 454 pyrosequencing, has allowed much larger read numbers from PCR amplicons than ever before. This has revolutionised the study of microbial diversity as it is now possible to sequence a substantial fraction of the 16S rRNA genes in a community. However, there is a growing realisation that because of the large read numbers and the lack of consensus sequences it is vital to distinguish noise from true sequence diversity in this data. Otherwise this leads to inflated estimates of the number of types or operational taxonomic units (OTUs) present. Three sources of error are important: sequencing error, PCR single base substitutions and PCR chimeras. We present AmpliconNoise, a development of the PyroNoise algorithm that is capable of separately removing 454 sequencing errors and PCR single base errors. We also introduce a novel chimera removal program, Perseus, that exploits the sequence abundances associated with pyrosequencing data. We use data sets where samples of known diversity have been amplified and sequenced to quantify the effect of each of the sources of error on OTU inflation and to validate these algorithms. RESULTS: AmpliconNoise outperforms alternative algorithms substantially reducing per base error rates for both the GS FLX and latest Titanium protocol. All three sources of error lead to inflation of diversity estimates. In particular, chimera formation has a hitherto unrealised importance which varies according to amplification protocol. We show that AmpliconNoise allows accurate estimates of OTU number. Just as importantly AmpliconNoise generates the right OTUs even at low sequence differences. We demonstrate that Perseus has very high sensitivity, able to find 99% of chimeras, which is critical when these are present at high frequencies. CONCLUSIONS: AmpliconNoise followed by Perseus is a very effective pipeline for the removal of noise. In addition the principles behind the algorithms, the inference of true sequences using Expectation-Maximization (EM), and the treatment of chimera detection as a classification or 'supervised learning' problem, will be equally applicable to new sequencing technologies as they appear. PMID- 21276215 TI - Caries-preventive effect of glass ionomer and resin-based fissure sealants on permanent teeth: An update of systematic review evidence. AB - BACKGROUND: This article constitutes a partial update of the original systematic review evidence by Yengopal et al. from 15 January 2008 (published in the Journal of Oral Science in 2009) with primary focus on research quality in regard to bias risk in trials. Its aim is to update the existing systematic review evidence from the English literature as to whether caries occurrence on pits and fissures of teeth sealed with either GIC or resin is the same. METHODS: In addition to the 12 trials included during the original systematic review, 5 new trials were identified during the database search (up to 26 August 2010) and 2 further trials were included from a hand search and reference check. Of these, 3 trials were excluded and 16 were accepted for data extraction and quality assessment. The quality of accepted trials was assessed, using updated quality criteria, and the risk of bias was investigated in more depth than previously reported. In addition, the focus of quantitative synthesis was shifted to single datasets that were extracted from the accepted trials. RESULTS: Twenty-six dichotomous and 4 continuous datasets were extracted. Meta-analysis and cumulative meta-analysis were used in combining clinically homogenous datasets. The overall outcome of the computed datasets suggest no difference between the caries-preventive effects of GIC- and resin-based fissure sealants. CONCLUSIONS: This overall outcome is in agreement with the conclusions of the original systematic review. Although the findings of the trials identified in this update may be considered to be less affected by attrition- and publication bias, their risk of selection- and detection-/performance bias is high. Thus, verification of the currently available results requires further high quality randomised control trials. PMID- 21276217 TI - Impact on the Quality of Life of an Educational Program for the Prevention of Work-Related Musculoskeletal Disorders: a randomized controlled trial. AB - BACKGROUND: Work-related musculoskeletal disorders (WMSD) are a major cause for concern in public health and the main causes of sick leave. Treatments for WMSD have given disappointing results; prevention is the best strategy, but results of preventive measures have not been consistent. To the best of our knowledge there are few studies in literature that evaluated the impact of a specific program aimed at preventing WMSD on the quality of life of employed persons. METHODS: One hundred and one clerical and production workers in a steel trading company were enrolled in an open-label randomized controlled clinical trial (parallel groups) to compare the efficacy of an educational program for primary prevention of WMSD with control intervention. The primary outcome was a change in the physical functioning domain of the quality of life (QL) measured by Medical Outcomes Study Short Form 36 Health Survey (SF-36). The intervention group underwent six consecutive weekly sessions concerning specific orientations for the prevention of WMSD, while the control group received general health education in an identical schedule. The SF-36 and theses Work Limitation Questionnaire (WLQ) were evaluated at weeks zero, five and 26. RESULTS: Baseline characteristics of the interventions groups were comparable, and both groups comprised predominantly young healthy individuals. No significant differences in the variation of the SF 36 and WLQ between the groups were observed at weeks five and 26. However, both groups demonstrated improvement in some aspects of SF-36, suggesting that both educational interventions have beneficial impacts on QL. CONCLUSIONS: A specific educational program aimed at the preventing of WMSD was comparable with general health orientation for the improvement of QL and work capacity in a sample of healthy workers during a six month period. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00874718 PMID- 21276216 TI - The involvement of interleukin-1 and interleukin-4 in the response of human annulus fibrosus cells to cyclic tensile strain: an altered mechanotransduction pathway with degeneration. AB - INTRODUCTION: Recent evidence suggests that intervertebral disc (IVD) cells derived from degenerative tissue are unable to respond to physiologically relevant mechanical stimuli in the 'normal' anabolic manner, but instead respond by increasing matrix catabolism. Understanding the nature of the biological processes which allow disc cells to sense and respond to mechanical stimuli (a process termed 'mechanotransduction') is important to ascertain whether these signalling pathways differ with disease. The aim here was to investigate the involvement of interleukin (IL)-1 and IL-4 in the response of annulus fibrosus (AF) cells derived from nondegenerative and degenerative tissue to cyclic tensile strain to determine whether cytokine involvement differed with IVD degeneration. METHODS: AF cells were isolated from nondegenerative and degenerative human IVDs, expanded in monolayers and cyclically strained in the presence or absence of the cytokine inhibitors IL-1 receptor antagonist (IL-1Ra) or IL-4 receptor antibody (IL-4RAb) with 10% strain at 1.0 Hz for 20 minutes using a Flexcell strain device. Total RNA was extracted from the cells at time points of baseline control and 1 or 24 hours poststimulation. Quantitative real-time polymerase chain reaction was used to analyse the gene expression of matrix proteins (aggrecan and type I collagen) and enzymes (matrix metalloproteinase 3 (MMP3) and a disintegrin and metalloproteinase with a thrombospondin type 1 motif 4 (ADAMTS4)). RESULTS: Expression of catabolic genes (MMP3 and ADAMTS4) decreased in AF cells derived from nondegenerative tissue in response to 1.0-Hz stimulation, and this decrease in gene expression was inhibited or increased following pretreatment of cells with IL-1Ra or IL-4RAb respectively. Treatment of AF cells derived from degenerative tissue with an identical stimulus (1.0-Hz) resulted in reduced anabolic gene expression (aggrecan and type I collagen), with IL-1Ra or IL-4RAb pretreatment having no effect. CONCLUSIONS: Both IL-1 and IL-4 are involved in the response of AF cells derived from nondegenerative tissue to 1.0-Hz cyclic tensile strain. Interestingly, the altered response observed at 1.0-Hz in AF cells from degenerative tissue appears to be independent of either cytokine, suggesting an alternative mechanotransduction pathway in operation. PMID- 21276218 TI - Food compensation: do exercise ads change food intake? AB - BACKGROUND: Past research has shown that promotional messages such as food advertising influence food consumption. However, what has gone largely unexplored is the effect of exercise advertising on food intake. This study experimentally tested the effects of exposure to exercise commercials on food intake at a lunch meal as compared to the effects of control commercials. METHODS: Prior to eating lunch, 125 participants (71 women, 54 men) watched 8 commercials, either all related to exercise or fitness (n=67) or neutral products (i.e. car insurance) (n=58). The meal consisted of a pasta dish with tomato sauce, salad and chocolate pudding. The post-lunch questionnaire included questions about body mass index, exercise habits, motivation and dietary restraint. RESULTS: Participants exposed to exercise commercials reduced their caloric intake by 21.7% relative to the control condition. Additionally, watching exercise messages increased the perceived healthiness and liking of the meal. Although exercise habits and intentions did not moderate the effect of commercial condition on food intake, we also found that this intake reduction was driven by participants with higher body mass index levels. CONCLUSIONS: These results imply that exercise messages may serve as a reminder of the link between food and physical activity and affect food consumption. It also highlights the need for increased awareness that these messages have powerful influences not only on exercise behavior, but also on closely related behaviors such as eating. PMID- 21276219 TI - Production of lentiviral vectors with enhanced efficiency to target dendritic cells by attenuating mannosidase activity of mammalian cells. AB - BACKGROUND: Dendritic cells (DCs) are antigen-presenting immune cells that interact with T cells and have been widely studied for vaccine applications. To achieve this, DCs can be manipulated by lentiviral vectors (LVs) to express antigens to stimulate the desired antigen-specific T cell response, which gives this approach great potential to fight diseases such as cancers, HIV, and autoimmune diseases. Previously we showed that LVs enveloped with an engineered Sindbis virus glycoprotein (SVGmu) could target DCs through a specific interaction with DC-SIGN, a surface molecule predominantly expressed by DCs. We hypothesized that SVGmu interacts with DC-SIGN in a mannose-dependent manner, and that an increase in high-mannose structures on the glycoprotein surface could result in higher targeting efficiencies of LVs towards DCs. It is known that 1 deoxymannojirimycin (DMJ) can inhibit mannosidase, which is an enzyme that removes high-mannose structures during the glycosylation process. Thus, we investigated the possibility of generating LVs with enhanced capability to modify DCs by supplying DMJ during vector production. RESULTS: Through western blot analysis and binding tests, we were able to infer that binding of SVGmu to DC SIGN is directly related to amount of high-mannose structures on SVGmu. We also found that the titer for the LV (FUGW/SVGmu) produced with DMJ against 293T.DCSIGN, a human cell line expressing the human DC-SIGN atnibody, was over four times higher than that of vector produced without DMJ. In addition, transduction of a human DC cell line, MUTZ-3, yielded a higher transduction efficiency for the LV produced with DMJ. CONCLUSION: We conclude that LVs produced under conditions with inhibited mannosidase activity can effectively modify cells displaying the DC-specific marker DC-SIGN. This study offers evidence to support the utilization of DMJ in producing LVs that are enhanced carriers for the development of DC-directed vaccines. PMID- 21276220 TI - Properties of contextual memory formed in the absence of alphaCaMKII autophosphorylation. AB - The alpha-isoform of calcium/calmodulin-dependent kinase II (alphaCaMKII) is a major synaptic kinase that undergoes autophosphorylation after NMDA receptor activation, switching the kinase into a calcium-independent activity state. This alphaCaMKII autophosphorylation is essential for NMDA receptor-dependent long term potentiation (LTP), induced by a single tetanus, in hippocampal area CA1 and in neocortex. Furthermore, the alphaCaMKII autophosphorylation is essential for contextual long-term memory (LTM) formation after a single training trial but not after a massed training session. Here, we show that in the absence of alphaCaMKII autophosphorylation contextual fear conditioning is hippocampus dependent and that multi-tetanus-dependent late-LTP cannot be induced in hippocampal area CA1. Furthermore, we show that in the absence of alphaCaMKII autophosphorylation contextual LTM persists for 30 days, the latest time point tested. Additionally, contextual, but not cued, LTM formation in the absence of alphaCaMKII autophosphorylation appears to be impaired in 18 month-old mice. Taken together, our findings suggest that alphaCaMKII autophosphorylation-independent plasticity in the hippocampus is sufficient for contextual LTM formation and that alphaCaMKII autophosphorylation may be important for delaying age-related impairments in hippocampal memory formation. Furthermore, they propose that NMDA receptor-dependent LTP in hippocampal area CA1 is essential for contextual LTM formation after a single trial but not after massed training. Finally, our results challenge the proposal that NMDA receptor-dependent LTP in neocortex is required for remote contextual LTM. PMID- 21276221 TI - Bmi-1 promotes invasion and metastasis, and its elevated expression is correlated with an advanced stage of breast cancer. AB - BACKGROUND: B-lymphoma Moloney murine leukemia virus insertion region-1 (Bmi-1) acts as an oncogene in various tumors, and its overexpression correlates with a poor outcome in several human cancers. Ectopic expression of Bmi-1 can induce epithelial-mesenchymal transition (EMT) and enhance the motility and invasiveness of human nasopharyngeal epithelial cells (NPECs), whereas silencing endogenous Bmi-1 expression can reverse EMT and reduce the metastatic potential of nasopharyngeal cancer cells (NPCs). Mouse xenograft studies indicate that coexpression of Bmi-1 and H-Ras in breast cancer cells can induce an aggressive and metastatic phenotype with an unusual occurrence of brain metastasis; although, Bmi-1 overexpression did not result in oncogenic transformation of MCF 10A cells. However, the underlying molecular mechanism of Bmi-1-mediated progression and the metastasis of breast cancer are not fully elucidated at this time. RESULTS: Bmi-1 expression is more pronouncedly increased in primary cancer tissues compared to matched adjacent non-cancerous tissues. High Bmi-1 expression is correlated with advanced clinicopathologic classifications (T, N, and M) and clinical stages. Furthermore, a high level of Bmi-1 indicates an unfavorable overall survival and serves as a high risk marker for breast cancer. In addition, inverse transcriptional expression levels of Bmi-1 and E-cadherin are detected between the primary cancer tissues and the matched adjacent non-cancerous tissues. Higher Bmi-1 levels are found in the cancer tissue, whereas the paired adjacent non-cancer tissue shows higher E-cadherin levels. Overexpression of Bmi 1 increases the motility and invasive properties of immortalized human mammary epithelial cells, which is concurrent with the increased expression of mesenchymal markers, the decreased expression of epithelial markers, the stabilization of Snail and the dysregulation of the Akt/GSK3beta pathway. Consistent with these observations, the repression of Bmi-1 in highly metastatic breast cancer cells remarkably reduces cellular motility, invasion and transformation, as well as tumorigenesis and lung metastases in nude mice. In addition, the repression of Bmi-1 reverses the expression of EMT markers and inhibits the Akt/GSK3beta/Snail pathway. CONCLUSIONS: This study demonstrates that Bmi-1 promotes the invasion and metastasis of human breast cancer and predicts poor survival. PMID- 21276222 TI - Low-intensity blue-enriched white light (750 lux) and standard bright light (10,000 lux) are equally effective in treating SAD. A randomized controlled study. AB - BACKGROUND: Photoreceptor cells containing melanopsin play a role in the phase shifting effects of short-wavelength light. In a previous study, we compared the standard light treatment (SLT) of SAD with treatment using short-wavelength blue enriched white light (BLT). Both treatments used the same illuminance (10,000 lux) and were equally highly effective. It is still possible, however, that neither the newly-discovered photoreceptor cells, nor the biological clock play a major role in the therapeutic effects of light on SAD. Alternatively, these effects may at least be partly mediated by these receptor cells, which may have become saturated as a result of the high illuminances used in the therapy. This randomized controlled study compares the effects of low-intensity BLT to those of high-intensity SLT. METHOD: In a 22-day design, 22 patients suffering from a major depression with a seasonal pattern (SAD) were given light treatment (10,000 lux) for two weeks on workdays. Subjects were randomly assigned to either of the two conditions, with gender and age evenly distributed over the groups. Light treatment either consisted of 30 minutes SLT (5000 degrees K) with the EnergyLight(r) (Philips, Consumer Lifestyle) with a vertical illuminance of 10,000 lux at eye position or BLT (17,000 degrees K) with a vertical illuminance of 750 lux using a prototype of the EnergyLight(r) which emitted a higher proportion of short-wavelengths. All participants completed questionnaires concerning mood, activation and sleep quality on a daily basis. Mood and energy levels were also assessed on a weekly basis by means of the SIGH-SAD and other assessment tools. RESULTS: On day 22, SIGH-SAD ratings were significantly lower than on day 1 (SLT 65.2% and BLT 76.4%). On the basis of all assessments no statistically significant differences were found between the two conditions. CONCLUSION: With sample size being small, conclusions can only be preliminary. Both treatment conditions were found to be highly effective. The therapeutic effects of low-intensity blue-enriched light were comparable to those of the standard light treatment. Saturation effects may play a role, even with a light intensity of 750 lux. The therapeutic effects of blue-enriched white light in the treatment of SAD at illuminances as low as 750 lux help bring light treatment for SAD within reach of standard workplace and educational lighting systems. PMID- 21276224 TI - Evolution of major milk proteins in Mus musculus and Mus spretus mouse species: a genoproteomic analysis. AB - BACKGROUND: Due to their high level of genotypic and phenotypic variability, Mus spretus strains were introduced in laboratories to investigate the genetic determinism of complex phenotypes including quantitative trait loci. Mus spretus diverged from Mus musculus around 2.5 million years ago and exhibits on average a single nucleotide polymorphism (SNP) in every 100 base pairs when compared with any of the classical laboratory strains. A genoproteomic approach was used to assess polymorphism of the major milk proteins between SEG/Pas and C57BL/6J, two inbred strains of mice representative of Mus spretus and Mus musculus species, respectively. RESULTS: The milk protein concentration was dramatically reduced in the SEG/Pas strain by comparison with the C57BL/6J strain (34 +/- 9 g/L vs. 125 +/- 12 g/L, respectively). Nine major proteins were identified in both milks using RP-HPLC, bi-dimensional electrophoresis and MALDI-Tof mass spectrometry. Two caseins (beta and alphas1) and the whey acidic protein (WAP), showed distinct chromatographic and electrophoresis behaviours. These differences were partly explained by the occurrence of amino acid substitutions and splicing variants revealed by cDNA sequencing. A total of 34 SNPs were identified in the coding and 3'untranslated regions of the SEG/Pas Csn1s1 (11), Csn2 (7) and Wap (8) genes. In addition, a 3 nucleotide deletion leading to the loss of a serine residue at position 93 was found in the SEG/Pas Wap gene. CONCLUSION: SNP frequencies found in three milk protein-encoding genes between Mus spretus and Mus musculus is twice the values previously reported at the whole genome level. However, the protein structure and post-translational modifications seem not to be affected by SNPs characterized in our study. Splicing mechanisms (cryptic splice site usage, exon skipping, error-prone junction sequence), already identified in casein genes from other species, likely explain the existence of multiple alphas1-casein isoforms both in SEG/Pas and C57BL/6J strains. Finally, we propose a possible mechanism by which the hallmark tandem duplication of a 18-nt exon (14 copies) may have occurred in the mouse genome. PMID- 21276223 TI - Pharmacological and non-pharmacological interventions to influence adipose tissue function. AB - Obesity is associated with metabolic derangements such as insulin resistance, inflammation and hypercoagulobility which can all be understood as consequences of adipose tissue dysfunction. The potential role for adipose tissue derived cytokines and adipokines in the development of vascular disease and diabetes may produce a clinical need to influence adipose tissue function. Various pharmacological and non-pharmacological interventions affect plasma cytokine and adipokine levels. The effects of these interventions depend on weight loss per se, changes in fat distribution without weight loss and/or direct effects on adipose tissue inflammation.Weight loss, as a result of diet, pharmacology and surgery, positively influences plasma adipokines and systemic inflammation. Several classes of drugs influence systemic inflammation directly through their anti-inflammatory actions. PPAR-gamma agonism positively influences adipose tissue inflammation in several classes of intervention such as the thiazolidinediones and perhaps salicylates, CB1-antagonists and angiotensin II receptor blockers. Furthermore, within drug classes there are differential effects of individual pharmacologic agents on adipose tissue function.It can be concluded that several commonly used pharmacological and non-pharmacological interventions have unintended influences on adipose tissue function. Improving adipose tissue function may contribute to reducing the risk of vascular diseases and the development of type 2 diabetes. PMID- 21276225 TI - Manual muscle strength testing of critically ill patients: feasibility and interobserver agreement. AB - INTRODUCTION: It has been proposed that intensive care unit (ICU)-acquired weakness (ICUAW) should be assessed using the sum of manual muscle strength test scores in 12 muscle groups (the sum score). This approach has been tested in patients with Guillain-Barre syndrome, yet little is known about the feasibility or test characteristics in other critically ill patients. We studied the feasibility and interobserver agreement of this sum score in a mixed cohort of critically ill and injured patients. METHODS: We enrolled patients requiring more than 3 days of mechanical ventilation. Two observers performed systematic strength assessments of each patient. The primary outcome measure was interobserver agreement of weakness as a binary outcome (ICUAW is sum score less than 48; "no ICUAW" is a sum score greater than or equal to 48) using the Cohen's kappa statistic. RESULTS: We identified 135 patients who met the inclusion criteria. Most were precluded from study participation by altered mental status or polytrauma. Thirty-four participants were enrolled, and 30 of these individuals completed assessments conducted by both observers. Six met the criteria for ICUAW recorded by at least one observer. The observers agreed on the diagnosis of ICUAW for 93% of participants (Cohen's kappa = 0.76; 95% confidence interval (CI), 0.44 to 1.0). Observer agreement was fair in the ICU (Cohen's kappa = 0.38), and agreement was perfect after ICU discharge (Cohen's kappa = 1.0). Absolute values of sum scores were similar between observers (intraclass correlation coefficient 0.83; 95% CI, 0.67 to 0.91), but they differed between observers by six points or more for 23% of the participants. CONCLUSIONS: Manual muscle testing (MMT) during critical illness was not possible for most patients because of coma, delirium and/or injury. Among patients who were able to participate in testing, we found that interobserver agreement regarding ICUAW was good, particularly when evaluated after ICU discharge. MMT is insufficient for early detection of ICU-acquired neuromuscular dysfunction in most patients and may be unreliable during critical illness. PMID- 21276226 TI - Acute and second-meal effects of almond form in impaired glucose tolerant adults: a randomized crossover trial. AB - BACKGROUND: Nut consumption may reduce the risk of developing type 2 diabetes. The aim of the current study was to measure the acute and second-meal effects of morning almond consumption and determine the contribution of different nut fractions. METHODS: Fourteen impaired glucose tolerant (IGT) adults participated in a randomized, 5-arm, crossover design study where whole almonds (WA), almond butter (AB), defatted almond flour (AF), almond oil (AO) or no almonds (vehicle - V) were incorporated into a 75 g available carbohydrate-matched breakfast meal. Postprandial concentrations of blood glucose, insulin, non-esterified free fatty acids (NEFA), glucagon-like peptide-1 (GLP-1) and appetitive sensations were assessed after treatment breakfasts and a standard lunch. RESULTS: WA significantly attenuated second-meal and daylong blood glucose incremental area under the curve (AUCI) and provided the greatest daylong feeling of fullness. AB and AO decreased blood glucose AUCI in the morning period and daylong blood glucose AUCI was attenuated with AO. WA and AO elicited a greater second-meal insulin response, particularly in the early postprandial phase, and concurrently suppressed the second-meal NEFA response. GLP-1 concentrations did not vary significantly between treatments. CONCLUSIONS: Inclusion of almonds in the breakfast meal decreased blood glucose concentrations and increased satiety both acutely and after a second-meal in adults with IGT. The lipid component of almonds is likely responsible for the immediate post-ingestive response, although it cannot explain the differential second-meal response to AB versus WA and AO. PMID- 21276227 TI - Flavonoid engineering of flax potentiate its biotechnological application. AB - BACKGROUND: Flavonoids are a group of secondary plant metabolites important for plant growth and development. They show also a protective effect against colon and breast cancer, diabetes, hypercholesterolemic atherosclerosis, lupus nephritis, and immune and inflammatory reactions. Thus, overproduction of these compounds in flax by genetic engineering method might potentiate biotechnological application of these plant products. RESULTS: Flax plants of third generation overexpressing key genes of flavonoid pathway cultivated in field were used as plant material throughout this study. The biochemical properties of seed, oil and seedcake extracts and fibre from natural and transgenic flax plants were compared. The data obtained suggests that the introduced genes were stably inherited and expressed through plant generations. Overproduction of flavonoid compounds resulted in increase of fatty acids accumulation in oil from transgenic seeds due to protection from oxidation offered during synthesis and seed maturation. The biochemical analysis of seedcake extracts from seeds of transgenic flax revealed significant increase in flavonoids (kaempferol), phenolic acids (coumaric, ferulic, synapic acids) and lignan content. Fibres, another product of flax plant showed increase in the level of catechine and acetylvanillone and decrease in phenolic acids upon flax modification.Biochemical analysis results were confirmed using IR spectroscopy. The integral intensities of IR bands have been used for identification of the component of phenylpropanoid pathway in oil, seedcake extract and fibre from control and transgenic flax. It was shown that levels of flavonoids, phenolic acids and lignans in oil and seedcake extract was higher in transgenic flax products compared to control. An FT-IR study of fibres confirmed the biochemical data and revealed that the arrangement of the cellulose polymer in the transgenic fibres differs from the control; in particular a significant decrease in the number of hydrogen bonds was detected. CONCLUSIONS: All analysed products from generated transgenic plants were enriched with antioxidant compounds derived from phenylopropanoid pathway Thus the products provide valuable source of flavonoids, phenolic acids and lignan for biomedical application. The compounds composition and quantity from transgenic plants was confirmed by IR spectroscopy. Thus the infrared spectroscopy appeared to be suitable method for characterization of flax products. PMID- 21276228 TI - Paget's disease of the breast in a male with lymphomatoid papulosis: a case report. AB - INTRODUCTION: Paget's disease is an eczematous skin change of the nipple that is usually associated with an underlying breast malignancy. Male breast cancer represents only 1-3% of all breast malignancies and Paget's disease remains very rare. CASE PRESENTATION: We present the case of a 67-year-old Caucasian man with lymphomatoid papulosis who was diagnosed with Paget's disease of the nipple and who was treated successfully with surgery alone. We discuss the presentation, investigations, management and pathogenesis of Paget's disease of the nipple. CONCLUSION: The case highlights the need to be vigilant when new skin lesions arise in the context of an underlying chronic skin disorder. PMID- 21276229 TI - In vivo imaging of pancreatic tumours and liver metastases using 7 Tesla MRI in a murine orthotopic pancreatic cancer model and a liver metastases model. AB - BACKGROUND: Pancreatic cancer is the fourth leading cause of tumour death in the western world. However, appropriate tumour models are scarce. Here we present a syngeneic murine pancreatic cancer model using 7 Tesla MRI and evaluate its clinical relevance and applicability. METHODS: 6606PDA murine pancreatic cancer cells were orthotopically injected into the pancreatic head. Liver metastases were induced through splenic injection. Animals were analyzed by MRI three and five weeks following injection. Tumours were detected using T2-weighted high resolution sequences. Tumour volumes were determined by callipers and MRI. Liver metastases were analyzed using gadolinium-EOB-DTPA and T1-weighted 3D-Flash sequences. Tumour blood flow was measured using low molecular gadobutrol and high molecular gadolinium-DTPA. RESULTS: MRI handling and applicability was similar to human systems, resolution as low as 0.1 mm. After 5 weeks tumour volumes differed significantly (p < 0.01) when comparing calliper measurments (n = 5, mean 1065 mm3+/-243 mm3) with MRI (mean 918 mm3+/-193 mm3) with MRI being more precise. Histology (n = 5) confirmed MRI tumour measurements (mean size MRI 38.5 mm2+/ 22.8 mm2 versus 32.6 mm2+/-22.6 mm2 (histology), p < 0,0004) with differences due to fixation and processing of specimens. After splenic injection all mice developed liver metastases with a mean of 8 metastases and a mean volume of 173.8 mm3+/-56.7 mm3 after 5 weeks. Lymphnodes were also easily identified. Tumour accumulation of gadobutrol was significantly (p < 0.05) higher than gadolinium DTPA. All imaging experiments could be done repeatedly to comply with the 3R principle thus reducing the number of experimental animals. CONCLUSIONS: This model permits monitoring of tumour growth and metastasis formation in longitudinal non-invasive high-resolution MR studies including using contrast agents comparable to human pancreatic cancer. This multidisciplinary environment enables radiologists, surgeons and physicians to further improve translational research and therapies of pancreatic cancer. PMID- 21276230 TI - Smallest detectable change in volume differs between mass flow sensor and pneumotachograph. AB - BACKGROUND: To assess a pulmonary function change over time the mass flow sensor and the pneumotachograph are widely used in commercially available instruments. However, the smallest detectable change for both devices has never been compared. Therefore, the aim of this study is to determine the smallest detectable change in vital capacity (VC) and single-breath diffusion parameters measured by mass flow sensor and or pneumotachograph. METHOD: In 28 healthy pulmonary function technicians VC, transfer factor for carbon monoxide (DLCO) and alveolar volume (VA) was repeatedly (10*) measured. The smallest detectable change was calculated by 1.96 x Standard Error of Measurement *?2. FINDINGS: The mean (range) of the smallest detectable change measured by mass flow sensor and pneumotachograph respectively, were for VC (in Liter): 0.53 (0.46-0.65); 0.25 (0.17-0.36) (p = 0.04), DLCO (in mmol*kPa-1*min-1): 1.53 (1.26-1.7); 1.18 (0.84-1.39) (p = 0.07), VA (in Liter): 0.66. (0.53-0.82); 0.43 (0.34-0.53) (p = 0.04) and DLCO/VA (in mmol*kPa-1*min-1*L-1): 0.22 (0.19-0.28); 0.19 (0.14-0.22) (p = 0.79). CONCLUSIONS: Smallest detectable significant change in VC and VA as measured by pneumotachograph are smaller than by mass flow sensor. Therefore, the pneumotachograph is the preferred instrument to estimate lung volume change over time in individual patients. PMID- 21276231 TI - Immediate latissimus dorsi pedicle flap reconstruction following the removal of an eight kilogram giant phyllodes tumour of the breast: a case report. AB - INTRODUCTION: Phyllodes tumors account for less than 1% of breast tumors in women, and giant phyllodes tumors are those that are larger than 10 cm in diameter. Removal of such large tumors places a huge burden on the surgeon to reconstruct a breast that is aesthetically acceptable by the patient. We report what may be the largest giant phyllodes tumor and, most likely, the first latissimus dorsi flap used to cover such a large defect caused by the resection. CASE PRESENTATION: We report the case of a 36-year-old Malaysian woman who presented with a three-year history of gradually increasing swelling of the left breast, with skin changes. Examination revealed a huge, globular, lobulated mass measuring 400 mm by 350 mm. The patient had a mastectomy with an immediate latissimus dorsi pedicled myocutaneous flap reconstruction. The breast weighed 8.27 kg, and ex vivo, the tumor measured 280 mm by 250 mm by 180 mm. Histopathologic analysis confirmed the diagnosis as a giant phyllodes tumor. At 12-month follow-up, the patient reports no complications and is satisfied with the aesthetic outcome. CONCLUSION: Giant phyllodes tumors are very rare tumors that can reach up to 40 cm in diameter. Reconstruction of such a defect is a great challenge, and we report what we believe is the first latissimus dorsi flap to cover successfully a defect of approximately 400 mm by 350 mm. PMID- 21276232 TI - High-density lipoprotein cholesterol, cognitive function and mortality in a U.S. national cohort. AB - Low levels of both high density lipoprotein cholesterol (HDL) and cognitive function are associated with increased mortality risk. HDL plays an important role in brain metabolism. We test the hypotheses that the relative protective effect of high HDL level as related to mortality is greater in persons with impaired cognitive function than in others. Data were analyzed from a longitudinal mortality follow-up study of 4911 American men and women aged 60 years and over examined in 1988-1994 followed an average 8.5 yr. Measurements at baseline included HDL, a short index of cognitive function (SICF), socio demographics, health status, and self-reported leisure-time physical activity. In proportional hazards regression analysis, no significant interaction of HDL with cognitive function was found (p = 0.08); there was a significant age-SICF interaction. After stratifying by age and adjusting for confounding by multiple variables, independent associations of HDL and SICF score with survival were strongest among the oldest persons. Consistent with its association with HDL, cognitive function and survival, controlling in addition for physical activity reduced the associations. In a nationwide cohort of older Americans, analyses demonstrated a lower risk of death independent of confounders among those high HDL and SICF scores, strongest among the oldest persons. PMID- 21276233 TI - A new mapping method for quantitative trait loci of silkworm. AB - BACKGROUND: Silkworm is the basis of sericultural industry and the model organism in insect genetics study. Mapping quantitative trait loci (QTLs) underlying economically important traits of silkworm is of high significance for promoting the silkworm molecular breeding and advancing our knowledge on genetic architecture of the Lepidoptera. Yet, the currently used mapping methods are not well suitable for silkworm, because of ignoring the recombination difference in meiosis between two sexes. RESULTS: A mixed linear model including QTL main effects, epistatic effects, and QTL * sex interaction effects was proposed for mapping QTLs in an F2 population of silkworm. The number and positions of QTLs were determined by F-test and model selection. The Markov chain Monte Carlo (MCMC) algorithm was employed to estimate and test genetic effects of QTLs and QTL * sex interaction effects. The effectiveness of the model and statistical method was validated by a series of simulations. The results indicate that when markers are distributed sparsely on chromosomes, our method will substantially improve estimation accuracy as compared to the normal chiasmate F2 model. We also found that a sample size of hundreds was sufficiently large to unbiasedly estimate all the four types of epistases (i.e., additive-additive, additive dominance, dominance-additive, and dominance-dominance) when the paired QTLs reside on different chromosomes in silkworm. CONCLUSION: The proposed method could accurately estimate not only the additive, dominance and digenic epistatic effects but also their interaction effects with sex, correcting the potential bias and precision loss in the current QTL mapping practice of silkworm and thus representing an important addition to the arsenal of QTL mapping tools. PMID- 21276234 TI - Phase II study evaluating consolidation whole abdominal intensity-modulated radiotherapy (IMRT) in patients with advanced ovarian cancer stage FIGO III--the OVAR-IMRT-02 Study. AB - BACKGROUND: The prognosis for patients with advanced FIGO stage III epithelial ovarian cancer remains poor despite the aggressive standard treatment, consisting of maximal cytoreductive surgery and platinum-based chemotherapy. The median time to recurrence is less than 2 years, with a 5-years survival rate of -20-25%. Recurrences of the disease occur mostly intraperitoneally.Ovarian cancer is a radiosensitive tumor, so that the use of whole abdominal radiotherapy (WAR) as a consolidation therapy would appear to be a logical strategy. WAR used to be the standard treatment after surgery before the chemotherapy era; however, it has been almost totally excluded from the treatment of ovarian cancer during the past decade because of its high toxicity. Modern intensity-modulated radiation therapy (IMRT) has the potential of sparing organs at risk like kidneys, liver, and bone marrow while still adequately covering the peritoneal cavity with a homogenous dose.Our previous phase I study showed for the first time the clinical feasibility of intensity-modulated WAR and pointed out promising results concerning treatment tolerance. The current phase-II study succeeds to the phase I study to further evaluate the toxicity of this new treatment. METHODS/DESIGN: The OVAR-IMRT-02 study is a single-center one arm phase-II trial. Thirty seven patients with optimally debulked ovarian cancer stage FIGO III having a complete remission after chemotherapy will be treated with intensity-modulated WAR as a consolidation therapy.A total dose of 30 Gy in 20 fractions of 1.5 Gy will be applied to the entire peritoneal cavity including the liver surface and the pelvic and para-aortic node regions. Organ at risk are kidneys, liver (except the 1 cm-outer border), heart, vertebral bodies and pelvic bones.Primary endpoint is tolerability; secondary objectives are toxicity, quality of life, progression free and overall survival. DISCUSSION: Intensity-modulated WAR provides a new promising option in the consolidation treatment of ovarian carcinoma in patients with a complete pathologic remission after adjuvant chemotherapy. Further consequent studies will be needed to enable firm conclusions regarding the value of consolidation radiotherapy within the multimodal treatment of advanced ovarian cancer. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01180504. PMID- 21276235 TI - A cross-sectional investigation of regional patterns of diet and cardio-metabolic risk in India. AB - BACKGROUND: The role of diet in India's rapidly progressing chronic disease epidemic is unclear; moreover, diet may vary considerably across North-South regions. METHODS: The India Health Study was a multicenter study of men and women aged 35-69, who provided diet, lifestyle, and medical histories, as well as blood pressure, fasting blood, urine, and anthropometric measurements. In each region (Delhi, n=824; Mumbai, n=743; Trivandrum, n=2,247), we identified two dietary patterns with factor analysis. In multiple logistic regression models adjusted for age, gender, education, income, marital status, religion, physical activity, tobacco, alcohol, and total energy intake, we investigated associations between regional dietary patterns and abdominal adiposity, hypertension, diabetes, and dyslipidemia. RESULTS: Across the regions, more than 80% of the participants met the criteria for abdominal adiposity and 10 to 28% of participants were considered diabetic. In Delhi, the "fruit and dairy" dietary pattern was positively associated with abdominal adiposity [highest versus lowest tertile, multivariate-adjusted OR and 95% CI: 2.32 (1.03-5.23); Ptrend=0.008] and hypertension [2.20 (1.47-3.31); Ptrend<0.0001]. In Trivandrum, the "pulses and rice" pattern was inversely related to diabetes [0.70 (0.51-0.95); Ptrend=0.03] and the "snacks and sweets" pattern was positively associated with abdominal adiposity [2.05 (1.34-3.14); Ptrend=0.03]. In Mumbai, the "fruit and vegetable" pattern was inversely associated with hypertension [0.63 (0.40-0.99); Ptrend=0.05] and the "snack and meat" pattern appeared to be positively associated with abdominal adiposity. CONCLUSIONS: Cardio-metabolic risk factors were highly prevalent in this population. Across all regions, we found little evidence of a Westernized diet; however, dietary patterns characterized by animal products, fried snacks, or sweets appeared to be positively associated with abdominal adiposity. Conversely, more traditional diets in the Southern regions were inversely related to diabetes and hypertension. Continued investigation of diet, as well as other environmental and biological factors, will be needed to better understand the risk profile in this population and potential means of prevention. PMID- 21276236 TI - Dietary intake in the Personalized Medicine Research Project: a resource for studies of gene-diet interaction. AB - BACKGROUND: To describe the dietary intake of participants in the Personalized Medicine Research Project (PMRP), and to quantify differences in nutrient intake by smoking status and APOE4-a genetic marker that has been shown to modify the association between risk factors and outcomes. METHODS: The PMRP is a population based DNA, plasma and serum biobank of more than 20,000 adults aged 18 years and older in central Wisconsin. A questionnaire at enrollment captures demographic information as well as self-reported smoking and alcohol intake. The protocol was amended to include the collection of dietary intake and physical activity via self-reported questionnaires: the National Cancer Institute 124-item Diet History Questionnaire and the Baecke Physical Activity Questionnaire. These questionnaires were mailed out to previously enrolled participants. APOE was genotyped in all subjects. RESULTS: The response rate to the mailed questionnaires was 68.2% for subjects who could still be contacted (alive with known address). Participants ranged in age from 18 to 98 years (mean 54.7) and 61% were female. Dietary intake is variable when comparing gender, age, smoking, and APOE4. Over 50% of females are dietary supplement users; females have higher supplement intake than males, but both have increasing supplement use as age increases. Food energy, total fat, cholesterol, protein, and alcohol intake decreases as both males and females age. Female smokers had higher macronutrient intake, whereas male nonsmokers had higher macronutrient intake. Nonsmokers in both genders use more supplements. In females, nonsmokers and smokers with APOE4 had higher supplement use. In males, nonsmokers with APOE4 had higher supplement use between ages 18-39 only, and lower supplement use at ages above 39. Male smokers with APOE4 had lower supplement use. CONCLUSION: Dietary intake in PMRP subjects is relatively consistent with data from the National Health and Nutrition Examination Survey (NHANES). Findings suggest a possible correlation between the use of supplements and APOE4. The PMRP dietary data can benefit studies of gene-environment interactions and the development of common diseases. PMID- 21276237 TI - One statistical test is sufficient for assessing new predictive markers. AB - BACKGROUND: We have observed that the area under the receiver operating characteristic curve (AUC) is increasingly being used to evaluate whether a novel predictor should be incorporated in a multivariable model to predict risk of disease. Frequently, investigators will approach the issue in two distinct stages: first, by testing whether the new predictor variable is significant in a multivariable regression model; second, by testing differences between the AUC of models with and without the predictor using the same data from which the predictive models were derived. These two steps often lead to discordant conclusions. DISCUSSION: We conducted a simulation study in which two predictors, X and X*, were generated as standard normal variables with varying levels of predictive strength, represented by means that differed depending on the binary outcome Y. The data sets were analyzed using logistic regression, and likelihood ratio and Wald tests for the incremental contribution of X* were performed. The patient-specific predictors for each of the models were then used as data for a test comparing the two AUCs. Under the null, the size of the likelihood ratio and Wald tests were close to nominal, but the area test was extremely conservative, with test sizes less than 0.006 for all configurations studied. Where X* was associated with outcome, the area test had much lower power than the likelihood ratio and Wald tests. SUMMARY: Evaluation of the statistical significance of a new predictor when there are existing clinical predictors is most appropriately accomplished in the context of a regression model. Although comparison of AUCs is a conceptually equivalent approach to the likelihood ratio and Wald test, it has vastly inferior statistical properties. Use of both approaches will frequently lead to inconsistent conclusions. Nonetheless, comparison of receiver operating characteristic curves remains a useful descriptive tool for initial evaluation of whether a new predictor might be of clinical relevance. PMID- 21276238 TI - Population transcriptomics of Drosophila melanogaster females. AB - BACKGROUND: Variation at the level of gene expression is abundant in natural populations and is thought to contribute to the adaptive divergence of populations and species. Gene expression also differs considerably between males and females. Here we report a microarray analysis of gene expression variation among females of 16 Drosophila melanogaster strains derived from natural populations, including eight strains from the putative ancestral range in sub Saharan Africa and eight strains from Europe. Gene expression variation among males of the same strains was reported previously. RESULTS: We detected relatively low levels of expression polymorphism within populations, but much higher expression divergence between populations. A total of 569 genes showed a significant expression difference between the African and European populations at a false discovery rate of 5%. Genes with significant over-expression in Europe included the insecticide resistance gene Cyp6g1, as well as genes involved in proteolysis and olfaction. Genes with functions in carbohydrate metabolism and vision were significantly over-expressed in the African population. There was little overlap between genes expressed differently between populations in females and males. CONCLUSIONS: Our results suggest that adaptive changes in gene expression have accompanied the out-of-Africa migration of D. melanogaster. Comparison of female and male expression data indicates that the vast majority of genes differing in expression between populations do so in only one sex and suggests that most regulatory adaptation has been sex-specific. PMID- 21276239 TI - Expression of the embryonic stem cell marker SOX2 in early-stage breast carcinoma. AB - BACKGROUND: The SRY-related HMG-box family of transcription factors member SOX2 has been mainly studied in embryonic stem cells as well as early foregut and neural development. More recently, SOX2 was shown to participate in reprogramming of adult somatic cells to a pluripotent stem cell state and implicated in tumorigenesis in various organs. In breast cancer, SOX2 expression was reported as a feature of basal-like tumors. In this study, we assessed SOX2 expression in 95 primary tumors of postmenopausal breast cancer patients. METHODS: Samples from 95 patients diagnosed and treated at the University of Tuebingen Institute of Pathology and Women's Hospital were analyzed by immunohistochemistry for SOX2 expression in the primary tumor samples and in corresponding lymph node metastasis, where present. Furthermore, SOX2 amplification status was assessed by FISH in representative samples. In addition, eighteen fresh frozen samples were analyzed for SOX2, NANOG and OCT4 gene expression by real-time PCR. RESULTS: SOX2 expression was detected in 28% of invasive breast carcinoma as well as in 44% of ductal carcinoma in situ (DCIS) lesions. A score of SOX2 expression (score 0 to 3) was defined in order to distinguish SOX2 negative (score 0) from SOX2 positive samples (score 1-3) and among latter the subgroup of SOX2 high expressors (score 3 > 50% positive cells). Overall, the incidence of SOX2 expression (score 1-3) was higher than previously reported in a cohort of lymph node negative patients (28% versus 16.7%). SOX2 expression was detected across different breast cancer subtypes and did not correlate with tumor grading. However, high SOX2 expression (score 3) was associated with larger tumor size (p = 0.047) and positive lymph node status (0.018). Corresponding metastatic lymph nodes showed higher SOX2 expression and were significantly more often SOX2 positive than primary tumors (p = 0.0432). CONCLUSIONS: In this report, we show that the embryonic stem cell factor SOX2 is expressed in a variety of early stage postmenopausal breast carcinomas and metastatic lymph nodes. Our data suggest that SOX2 plays an early role in breast carcinogenesis and high expression may promote metastatic potential. Further studies are needed to explore whether SOX2 can predict metastatic potential at an early tumor stage. PMID- 21276240 TI - A validation of the first genome-wide association study of calcaneus ultrasound parameters in the European Male Ageing Study. AB - BACKGROUND: A number of single nucleotide polymorphisms (SNPs) have been associated with broadband ultrasound attenuation (BUA) and speed of sound (SOS) as measured by quantitative ultrasound (QUS) at the calcaneus in the Framingham 100K genome-wide association study (GWAS) but have not been validated in independent studies. The aim of this analysis was to determine if these SNPs are associated with QUS measurements assessed in a large independent population of European middle-aged and elderly men. The association between these SNPs and bone mineral density (BMD) measured using dual-energy X-ray absorptiometry (DXA) was also tested. METHODS: Men aged 40-79 years (N = 2960) were recruited from population registers in seven European centres for participation in an observational study of male ageing, the European Male Ageing Study (EMAS). QUS at the calcaneus was measured in all subjects and blood was taken for genetic analysis. Lumbar spine (LS), femoral neck (FN) and total hip (TH) BMD were measured by DXA in a subsample of 620 men in two centres. SNPs associated with BUA or SOS in the Framingham study with p < 10-4 were selected and genotyped using SEQUENOM technology. Linear regression was used to test for the association between SNPs and standardised (SD) bone outcomes under an additive genetic model adjusting for centre. The same direction of effect and p < 0.05 indicated replication. RESULTS: Thirty-four of 38 selected SNPs were successfully genotyped in 2377 men. Suggestive evidence of replication was observed for a single SNP, rs3754032, which was associated with a higher SOS (beta(SD) = 0.07, p = 0.032) but not BUA (beta(SD) = 0.02, p = 0.505) and is located in the 3'UTR of WDR77 (WD repeat domain 77) also known as androgen receptor cofactor p44. A single SNP, rs238358, was associated with BMD at the LS (beta(SD) = -0.22, p = 0.014), FN (beta(SD) = -0.31,p = 0.001) and TH (beta(SD) = -0.36, p = 0.002) in a locus previously associated with LS BMD in large-scale GWAS, incorporating AKAP11 and RANKL. CONCLUSIONS: We found suggestive evidence of association between a single SNP located in the 3'UTR of WDR77 with calcaneal ultrasound parameters. The majority of SNPs, associated with QUS parameters in the Framingham Study, were not replicated in an independent population sample of European men. PMID- 21276241 TI - Visualization of protein interactions in living Drosophila embryos by the bimolecular fluorescence complementation assay. AB - BACKGROUND: Protein interactions control the regulatory networks underlying developmental processes. The understanding of developmental complexity will, therefore, require the characterization of protein interactions within their proper environment. The bimolecular fluorescence complementation (BiFC) technology offers this possibility as it enables the direct visualization of protein interactions in living cells. However, its potential has rarely been applied in embryos of animal model organisms and was only performed under transient protein expression levels. RESULTS: Using a Hox protein partnership as a test case, we investigated the suitability of BiFC for the study of protein interactions in the living Drosophila embryo. Importantly, all BiFC parameters were established with constructs that were stably expressed under the control of endogenous promoters. Under these physiological conditions, we showed that BiFC is specific and sensitive enough to analyse dynamic protein interactions. We next used BiFC in a candidate interaction screen, which led to the identification of several Hox protein partners. CONCLUSION: Our results establish the general suitability of BiFC for revealing and studying protein interactions in their physiological context during the rapid course of Drosophila embryonic development. PMID- 21276242 TI - Pattern of neural responses to verbal fluency shows diagnostic specificity for schizophrenia and bipolar disorder. AB - BACKGROUND: Impairments in executive function and language processing are characteristic of both schizophrenia and bipolar disorder. Their functional neuroanatomy demonstrate features that are shared as well as specific to each disorder. Determining the distinct pattern of neural responses in schizophrenia and bipolar disorder may provide biomarkers for their diagnoses. METHODS: 104 participants underwent functional magnetic resonance imaging (fMRI) scans while performing a phonological verbal fluency task. Subjects were 32 patients with schizophrenia in remission, 32 patients with bipolar disorder in an euthymic state, and 40 healthy volunteers. Neural responses to verbal fluency were examined in each group, and the diagnostic potential of the pattern of the neural responses was assessed with machine learning analysis. RESULTS: During the verbal fluency task, both patient groups showed increased activation in the anterior cingulate, left dorsolateral prefrontal cortex and right putamen as compared to healthy controls, as well as reduced deactivation of precuneus and posterior cingulate. The magnitude of activation was greatest in patients with schizophrenia, followed by patients with bipolar disorder and then healthy individuals. Additional recruitment in the right inferior frontal and right dorsolateral prefrontal cortices was observed in schizophrenia relative to both bipolar disorder and healthy subjects. The pattern of neural responses correctly identified individual patients with schizophrenia with an accuracy of 92%, and those with bipolar disorder with an accuracy of 79% in which mis-classification was typically of bipolar subjects as healthy controls. CONCLUSIONS: In summary, both schizophrenia and bipolar disorder are associated with altered function in prefrontal, striatal and default mode networks, but the magnitude of this dysfunction is particularly marked in schizophrenia. The pattern of response to verbal fluency is highly diagnostic for schizophrenia and distinct from bipolar disorder. Pattern classification of functional MRI measurements of language processing is a potential diagnostic marker of schizophrenia. PMID- 21276243 TI - Adherence to treatment guidelines for acute diarrhoea in children up to 12 years in Ujjain, India--a cross-sectional prescription analysis. AB - BACKGROUND: Diarrhoea accounts for 20% of all paediatric deaths in India. Despite WHO recommendations and IAP (Indian Academy of Paediatrics) and Government of India treatment guidelines, few children suffering from acute diarrhoea in India receive low osmolarity oral rehydration solution (ORS) and zinc from health care providers. The aim of this study was to analyse practitioners' prescriptions for acute diarrhoea for adherence to treatment guidelines and further to determine the factors affecting prescribing for diarrhoea in Ujjain, India. METHODS: This cross-sectional study was conducted in pharmacies and major hospitals of Ujjain, India. We included prescriptions from all practitioners, including those from modern medicine, Ayurveda, Homeopathy as well as informal health-care providers (IHPs). The data collection instrument was designed to include all the possible medications that are given for an episode of acute diarrhoea to children up to 12 years of age. Pharmacy assistants and resident medical officers transferred the information regarding the current diarrhoeal episode and the treatment given from the prescriptions and inpatient case sheets, respectively, to the data collection instrument. RESULTS: Information was collected from 843 diarrhoea prescriptions. We found only 6 prescriptions having the recommended treatment that is ORS along with Zinc, with no additional probiotics, antibiotics, racecadotril or antiemetics (except Domperidone for vomiting). ORS alone was prescribed in 58% of the prescriptions; while ORS with zinc was prescribed in 22% of prescriptions, however these also contained other drugs not included in the guidelines. Antibiotics were prescribed in 71% of prescriptions. Broad-spectrum antibiotics were prescribed and often in illogical fixed-dose combinations. One such illogical combination, ofloxacin with ornidazole, was the most frequent oral antibiotic prescribed (22% of antibiotics prescribed). Practitioners from alternate system of medicine and IHPs are significantly less likely (OR 0.13, 95% CI 0.04-0.46, P = 0.003) to prescribe ORS and zinc than pediatricians. Practitioners from 'free' hospitals are more likely to prescribe ORS and zinc (OR 4.94, 95% CI 2.45-9.96, P < 0.001) and less likely to prescribe antibiotics (OR 0.01, 95% CI 0.01-0-04, P < 0.001) compared to practitioners from 'charitable' hospitals. Accompanying symptoms like the presence of fever, pain, blood in the stool and vomiting significantly increased antibiotic prescribing. CONCLUSION: This study demonstrated low adherence to standard treatment guidelines for management of acute diarrhoea in children under 12 years in Ujjain, India. Key public health concerns were the low use of zinc and the high use of antibiotics, found in prescriptions from both specialist paediatricians as well as practitioners from alternate systems of medicine and informal health-care providers. To improve case management of acute diarrhoea, continuing professional development programme targeting the practitioners of all systems of medicine is necessary. PMID- 21276244 TI - Methylphenidate for treating tobacco dependence in non-attention deficit hyperactivity disorder smokers: a pilot randomized placebo-controlled trial. AB - BACKGROUND: Methylphenidate blocks the re-uptake of dopamine by binding to the dopamine transporter in the presynaptic cell membrane and increases extracellular dopamine levels. Similarities in neuropsychologic effects between nicotine and methylphenidate make it an intriguing potential therapeutic option. Previous research of methylphenidate in smokers has suggested a possible beneficial effect for the relief of nicotine withdrawal symptoms, but showed no efficacy in helping smokers with attention deficit hyperactivity disorder (ADHD) to stop smoking. METHODS: To investigate potential efficacy for relieving nicotine withdrawal symptoms and promoting smoking abstinence, we conducted a randomized, double blind, placebo-controlled, phase II study of once-a-day osmotic-release oral system methylphenidate (OROS-MPH, Concerta(r)) at a target dose of 54-mg/day for 8 weeks compared with placebo in 80 adult cigarette smokers. RESULTS: Of the 80 randomized subjects and median smoking rate was 20 cigarettes per day. At the end of the medication phase, the biochemically confirmed 7-day point prevalence smoking abstinence was 10% (4/40) for the placebo group and 2.5% (1/40) for the OROS-MPH group. Nicotine withdrawal was not found to differ significantly between treatment groups during the first 14 days following the start of medication prior to the target quit date (p = 0.464) or during the first 14 days following the target quit date (p = 0.786). CONCLUSION: We observed no evidence of efficacy of OROS-MPH to aid smokers to stop smoking. Although there are biologically plausible hypotheses that support the use of OROS-MPH for treating tobacco dependence, we found no evidence to support such hypotheses. In addition to no increase in smoking abstinence, we saw no effect of OROS-MPH for tobacco withdrawal symptom relief and no change in smoking rates was observed in the OROS MPH group compared to the placebo group. PMID- 21276245 TI - RNA-seq analyses of blood-induced changes in gene expression in the mosquito vector species, Aedes aegypti. AB - BACKGROUND: Hematophagy is a common trait of insect vectors of disease. Extensive genome-wide transcriptional changes occur in mosquitoes after blood meals, and these are related to digestive and reproductive processes, among others. Studies of these changes are expected to reveal molecular targets for novel vector control and pathogen transmission-blocking strategies. The mosquito Aedes aegypti (Diptera, Culicidae), a vector of Dengue viruses, Yellow Fever Virus (YFV) and Chikungunya virus (CV), is the subject of this study to look at genome-wide changes in gene expression following a blood meal. RESULTS: Transcriptional changes that follow a blood meal in Ae. aegypti females were explored using RNA seq technology. Over 30% of more than 18,000 investigated transcripts accumulate differentially in mosquitoes at five hours after a blood meal when compared to those fed only on sugar. Forty transcripts accumulate only in blood-fed mosquitoes. The list of regulated transcripts correlates with an enhancement of digestive activity and a suppression of environmental stimuli perception and innate immunity. The alignment of more than 65 million high-quality short reads to the Ae. aegypti reference genome permitted the refinement of the current annotation of transcript boundaries, as well as the discovery of novel transcripts, exons and splicing variants. Cis-regulatory elements (CRE) and cis regulatory modules (CRM) enriched significantly at the 5'end flanking sequences of blood meal-regulated genes were identified. CONCLUSIONS: This study provides the first global view of the changes in transcript accumulation elicited by a blood meal in Ae. aegypti females. This information permitted the identification of classes of potentially co-regulated genes and a description of biochemical and physiological events that occur immediately after blood feeding. The data presented here serve as a basis for novel vector control and pathogen transmission-blocking strategies including those in which the vectors are modified genetically to express anti-pathogen effector molecules. PMID- 21276246 TI - Oncolytic targeting of androgen-sensitive prostate tumor by the respiratory syncytial virus (RSV): consequences of deficient interferon-dependent antiviral defense. AB - BACKGROUND: Oncolytic virotherapy for cancer treatment utilizes viruses for selective infection and death of cancer cells without any adverse effect on normal cells. We previously reported that the human respiratory syncytial virus (RSV) is a novel oncolytic virus against androgen-independent PC-3 human prostate cancer cells. The present study extends the result to androgen-dependent prostate cancer, and explores the underlying mechanism that triggers RSV-induced oncolysis of prostate cancer cells. METHODS: The oncolytic effect of RSV on androgen sensitive LNCaP human prostate cancer cells and on androgen-independent RM1 murine prostate cancer cells was studied in vitro in culture and in vivo in a xenograft or allograft tumor model. In vitro, cell viability, infectivity and apoptosis were monitored by MTT assay, viral plaque assay and annexin V staining, respectively. In vivo studies involved virus administration to prostate tumors grown in immune compromised nude mice and in syngeneic immune competent C57BL/6J mice. Anti-tumorogenic oncolytic activity was monitored by measuring tumor volume, imaging bioluminescent tumors in live animals and performing histopathological analysis and TUNEL assay with tumors RESULTS: We show that RSV imposes a potent oncolytic effect on LNCaP prostate cancer cells. RSV infectivity was markedly higher in LNCaP cells compared to the non-tumorigenic RWPE-1 human prostate cells. The enhanced viral burden led to LNCaP cell apoptosis and growth inhibition of LNCaP xenograft tumors in nude mice. A functional host immune response did not interfere with RSV-induced oncolysis, since growth of xenograft tumors in syngeneic C57BL/6J mice from murine RM1 cells was inhibited upon RSV administration. LNCaP cells failed to activate the type-I interferon (IFNalpha/beta)-induced transcription factor STAT-1, which is required for antiviral gene expression, although these cells could produce IFN in response to RSV infection. The essential role of IFN in restricting infection was further borne out by our finding that neutralizing IFN activity resulted in enhanced RSV infection in non-tumorigenic RWPE-1 prostate cells. CONCLUSIONS: We demonstrated that RSV is potentially a useful therapeutic tool in the treatment of androgen sensitive and androgen-independent prostate cancer. Moreover, impaired IFN mediated antiviral response is the likely cause of higher viral burden and resulting oncolysis of androgen-sensitive prostate cancer cells. PMID- 21276247 TI - Effects of immunomodulatory drugs on TNF-alpha and IL-12 production by purified epidermal langerhans cells and peritoneal macrophages. AB - BACKGROUND: Langerhans cells constitute a special subset of immature dendritic cells localized in the epidermis that play a key role in the skin's immune response. The production of cytokines is a key event in both the initiation and the regulation of immune responses, and different drugs can be used to remove or modify their production by DC and, therefore, alter immune responses in a broad spectrum of diseases, mainly in human inflammatory and autoimmune diseases. In the present study, we examined the effects of prednisone, thalidomide, cyclosporine A, and amitriptyline, drugs used in a variety of clinical conditions, on the production of TNF-alpha, IL-10, and IL-12 by purified epidermal Langerhans cells and peritoneal macrophages in BALB/c mice. FINDINGS: All drugs inhibited TNF-alpha production by Langerhans cells after 36 hours of treatment at two different concentrations, while prednisone and thalidomide decreased IL-12 secretion significantly, amitriptyline caused a less pronounced reduction and cyclosporine A had no effect. Additionally, TNF-alpha and IL-12 production by macrophages decreased, but IL-10 levels were unchanged after all treatments. CONCLUSIONS: Our results demonstrate that these drugs modulate the immune response by regulating pro-inflammatory cytokine production by purified epidermal Langerhans cells and peritoneal macrophages, indicating that these cells are important targets for immunosuppression in various clinical settings. PMID- 21276248 TI - ZFNGenome: a comprehensive resource for locating zinc finger nuclease target sites in model organisms. AB - BACKGROUND: Zinc Finger Nucleases (ZFNs) have tremendous potential as tools to facilitate genomic modifications, such as precise gene knockouts or gene replacements by homologous recombination. ZFNs can be used to advance both basic research and clinical applications, including gene therapy. Recently, the ability to engineer ZFNs that target any desired genomic DNA sequence with high fidelity has improved significantly with the introduction of rapid, robust, and publicly available techniques for ZFN design such as the Oligomerized Pool ENgineering (OPEN) method. The motivation for this study is to make resources for genome modifications using OPEN-generated ZFNs more accessible to researchers by creating a user-friendly interface that identifies and provides quality scores for all potential ZFN target sites in the complete genomes of several model organisms. DESCRIPTION: ZFNGenome is a GBrowse-based tool for identifying and visualizing potential target sites for OPEN-generated ZFNs. ZFNGenome currently includes a total of more than 11.6 million potential ZFN target sites, mapped within the fully sequenced genomes of seven model organisms; S. cerevisiae, C. reinhardtii, A. thaliana, D. melanogaster, D. rerio, C. elegans, and H. sapiens and can be visualized within the flexible GBrowse environment. Additional model organisms will be included in future updates. ZFNGenome provides information about each potential ZFN target site, including its chromosomal location and position relative to transcription initiation site(s). Users can query ZFNGenome using several different criteria (e.g., gene ID, transcript ID, target site sequence). Tracks in ZFNGenome also provide "uniqueness" and ZiFOpT (Zinc Finger OPEN Targeter) "confidence" scores that estimate the likelihood that a chosen ZFN target site will function in vivo. ZFNGenome is dynamically linked to ZiFDB, allowing users access to all available information about zinc finger reagents, such as the effectiveness of a given ZFN in creating double-stranded breaks. CONCLUSIONS: ZFNGenome provides a user-friendly interface that allows researchers to access resources and information regarding genomic target sites for engineered ZFNs in seven model organisms. This genome-wide database of potential ZFN target sites should greatly facilitate the utilization of ZFNs in both basic and clinical research.ZFNGenome is freely available at: http://bindr.gdcb.iastate.edu/ZFNGenome or at the Zinc Finger Consortium website: http://www.zincfingers.org/. PMID- 21276250 TI - Prevalence of Acanthosis Nigricans in an urban population in Sri Lanka and its utility to detect metabolic syndrome. AB - BACKGROUND: Insulin resistance (IR) plays a major role in the pathogenesis of metabolic syndrome. Acanthosis nigricans (AN) is an easily detectable skin condition that is strongly associated with IR. The aims of this study were, firstly, to investigate the prevalence of AN among adults in an urban Sri Lankan community and secondly, to describe its utility to detect metabolic syndrome. FINDINGS: In a community based investigation, 35-64 year adults who were selected using stratified random sampling, underwent interview, clinical examination, liver ultrasound scanning, and biochemical and serological tests. Metabolic syndrome was diagnosed on revised ATP III criteria for Asian populations. AN was identified by the presence of dark, thick, velvety skin in the neck.2957 subjects were included in this analysis. The prevalence of AN, metabolic syndrome and type 2 diabetes mellitus were 17.4%, 34.8% and 19.6%, respectively. There was a strong association between AN and metabolic syndrome. The sensitivity, specificity, positive predictive value and negative predictive value of AN to detect metabolic syndrome were 28.2%, 89.0%, 45.9% and 79.0% for males, and 29.2%, 88.4%, 65.6% and 62.3% for females, respectively. CONCLUSIONS: AN was common in our study population, and although it did not have a high enough sensitivity to be utilized as a screening test for metabolic syndrome, the presence of AN strongly predicts metabolic syndrome. PMID- 21276249 TI - Prolactin-induced mouse mammary carcinomas model estrogen resistant luminal breast cancer. AB - INTRODUCTION: Tumors that express estrogen receptor alpha (ERalpha+) comprise 75% of breast cancers in women. While treatments directed against this receptor have successfully lowered mortality rates, many primary tumors initially or later exhibit resistance. The paucity of murine models of this "luminal" tumor subtype has hindered studies of factors that promote their pathogenesis and modulate responsiveness to estrogen-directed therapeutics. Since epidemiologic studies closely link prolactin and the development of ERalpha+ tumors in women, we examined characteristics of the aggressive ERalpha+ and ERalpha- carcinomas which develop in response to mammary prolactin in a murine transgenic model (neu related lipocalin- prolactin (NRL-PRL)). To evaluate their relationship to clinical tumors, we determined phenotypic relationships among these carcinomas, other murine models of breast cancer, and features of luminal tumors in women. METHODS: We examined a panel of prolactin-induced tumors for characteristics relevant to clinical tumors: histotype, ERalpha/progesterone receptor (PR) expression and estrogen responsiveness, Activating Protein 1 (AP-1) components, and phosphorylation of signal transducer and activator of transcription 5 (Stat5), extracellular signal regulated kinase (ERK) 1/2 and AKT. We compared levels of transcripts in the ERalpha-associated "luminal" signature that defines this subtype of tumors in women and transcripts enriched in various mammary epithelial lineages to other well-studied genetically modified murine models of breast cancer. Finally, we used microarray analyses to compare prolactin-induced ERalpha+ and ERalpha- tumors, and examined responsiveness to estrogen and the anti-estrogen, Faslodex, in vivo. RESULTS: Prolactin-induced carcinomas were markedly diverse with respect to histotype, ERalpha/PR expression, and activated signaling cascades. They constituted a heterogeneous, but distinct group of murine mammary tumors, with molecular features of the luminal subtype of human breast cancer. In contrast to morphologically normal and hyperplastic structures in NRL-PRL females, carcinomas were insensitive to ERalpha-mediated signals. These tumors were distinct from mouse mammary tumor virus (MMTV)-neu tumors, and contained elevated transcripts for factors associated with luminal/alveolar expansion and differentiation, suggesting that they arose from physiologic targets of prolactin. These features were shared by ERalpha+ and ERalpha- tumors, suggesting a common origin, although the former exhibited transcript profiles reflecting greater differentiation. CONCLUSIONS: Our studies demonstrate that prolactin can promote diverse carcinomas in mice, many of which resemble luminal breast cancers, providing a novel experimental model to examine the pathogenesis, progression and treatment responsiveness of this tumor subtype. PMID- 21276251 TI - The activation mechanism of Irga6, an interferon-inducible GTPase contributing to mouse resistance against Toxoplasma gondii. AB - BACKGROUND: The interferon-inducible immunity-related GTPases (IRG proteins/p47 GTPases) are a distinctive family of GTPases that function as powerful cell autonomous resistance factors. The IRG protein, Irga6 (IIGP1), participates in the disruption of the vacuolar membrane surrounding the intracellular parasite, Toxoplasma gondii, through which it communicates with its cellular hosts. Some aspects of the protein's behaviour have suggested a dynamin-like molecular mode of action, in that the energy released by GTP hydrolysis is transduced into mechanical work that results in deformation and ultimately rupture of the vacuolar membrane. RESULTS: Irga6 forms GTP-dependent oligomers in vitro and thereby activates hydrolysis of the GTP substrate. In this study we define the catalytic G-domain interface by mutagenesis and present a structural model, of how GTP hydrolysis is activated in Irga6 complexes, based on the substrate twinning reaction mechanism of the signal recognition particle (SRP) and its receptor (SRalpha). In conformity with this model, we show that the bound nucleotide is part of the catalytic interface and that the 3'hydroxyl of the GTP ribose bound to each subunit is essential for trans-activation of hydrolysis of the GTP bound to the other subunit. We show that both positive and negative regulatory interactions between IRG proteins occur via the catalytic interface. Furthermore, mutations that disrupt the catalytic interface also prevent Irga6 from accumulating on the parasitophorous vacuole membrane of T. gondii, showing that GTP-dependent Irga6 activation is an essential component of the resistance mechanism. CONCLUSIONS: The catalytic interface of Irga6 defined in the present experiments can probably be used as a paradigm for the nucleotide-dependent interactions of all members of the large family of IRG GTPases, both activating and regulatory. Understanding the activation mechanism of Irga6 will help to explain the mechanism by which IRG proteins exercise their resistance function. We find no support from sequence or G-domain structure for the idea that IRG proteins and the SRP GTPases have a common phylogenetic origin. It therefore seems probable, if surprising, that the substrate-assisted catalytic mechanism has been independently evolved in the two protein families. PMID- 21276252 TI - Women's perceptions of homebirths in two rural medical districts in Burkina Faso: a qualitative study. AB - BACKGROUND: In developing countries, most childbirth occurs at home and is not assisted by skilled attendants. The situation increases the risk of death for both mother and child and has severe maternal complications. The purpose of this study was to describe women's perceptions of homebirths in the medical districts of Ouargaye and Diapaga. METHODS: A qualitative approach was used to gather information. This information was collected by using focus group discussions and individual interviews with 30 women. All the interviews were tape recorded and managed by using QSR NVIVO 2.0, qualitative data management software. RESULTS: The findings show that homebirths are frequent because of prohibitive distance to health facilities, fast labour and easy labour, financial constraints, lack of decision making power to reach health facilities. CONCLUSION: The study echoes the need for policy makers to make health facilities easily available to rural inhabitants to forestall maternal and child deaths in the two districts. PMID- 21276253 TI - Potential efficacy of mitochondrial genes for animal DNA barcoding: a case study using eutherian mammals. AB - BACKGROUND: A well-informed choice of genetic locus is central to the efficacy of DNA barcoding. Current DNA barcoding in animals involves the use of the 5' half of the mitochondrial cytochrome oxidase 1 gene (CO1) to diagnose and delimit species. However, there is no compelling a priori reason for the exclusive focus on this region, and it has been shown that it performs poorly for certain animal groups. To explore alternative mitochondrial barcoding regions, we compared the efficacy of the universal CO1 barcoding region with the other mitochondrial protein-coding genes in eutherian mammals. Four criteria were used for this comparison: the number of recovered species, sequence variability within and between species, resolution to taxonomic levels above that of species, and the degree of mutational saturation. RESULTS: Based on 1,179 mitochondrial genomes of eutherians, we found that the universal CO1 barcoding region is a good representative of mitochondrial genes as a whole because the high species recovery rate (> 90%) was similar to that of other mitochondrial genes, and there were no significant differences in intra- or interspecific variability among genes. However, an overlap between intra- and interspecific variability was still problematic for all mitochondrial genes. Our results also demonstrated that any choice of mitochondrial gene for DNA barcoding failed to offer significant resolution at higher taxonomic levels. CONCLUSIONS: We suggest that the CO1 barcoding region, the universal DNA barcode, is preferred among the mitochondrial protein-coding genes as a molecular diagnostic at least for eutherian species identification. Nevertheless, DNA barcoding with this marker may still be problematic for certain eutherian taxa and our approach can be used to test potential barcoding loci for such groups. PMID- 21276255 TI - Successful treatment of a child with vascular pythiosis. AB - BACKGROUND: Human pythiosis is an emerging and life-threatening infectious disease caused by Pythium insidiosum. It occurs primarily in tropical, subtropical and temperate areas of the world, including Thailand. The aim of this report is to present the first pediatric case of typical vascular pythiosis. CASE PRESENTATION: A 10-year-old boy with underlying beta-thalassemia presented with gangrenous ulcers and claudication of the right leg which were unresponsive to antibiotic therapy for 6 weeks. Computerized tomography angiography indicated chronic arterial occlusion involving the right distal external iliac artery and its branches. High-above-knee amputation was urgently done to remove infected arteries and tissues, and to stop disease progression. Antibody to P. insidiosum was detected in a serum sample by the immunoblot and the immunochromatography tests. Fungal culture followed by nucleic sequence analysis was positive for P. insidiosum in the resected iliac arterial tissue. Immunotherapeutic vaccine and antifungal agents were administered. The patient remained well and was discharged after 2 months hospitalization without recurrence of the disease. At the time of this communication he has been symptom-free for 2 years. CONCLUSIONS: The child presented with the classical manifestations of vascular pythiosis as seen in adult cases. However, because pediatricians were unfamiliar with the disease, diagnosis and surgical treatment were delayed. Both early diagnosis and appropriate surgical and medical treatments are crucial for good prognosis. PMID- 21276254 TI - Intervention, integration and translation in obesity research: Genetic, developmental and metaorganismal approaches. AB - Obesity is the focus of multiple lines of inquiry that have -- together and separately -- produced many deep insights into the physiology of weight gain and maintenance. We examine three such streams of research and show how they are oriented to obesity intervention through multilevel integrated approaches. The first research programme is concerned with the genetics and biochemistry of fat production, and it links metabolism, physiology, endocrinology and neurochemistry. The second account of obesity is developmental and draws together epigenetic and environmental explanations that can be embedded in an evolutionary framework. The third line of research focuses on the role of gut microbes in the production of obesity, and how microbial activities interact with host genetics, development and metabolism. These interwoven explanatory strategies are driven by an orientation to intervention, both for experimental and therapeutic outcomes. We connect the integrative and intervention-oriented aspects of obesity research through a discussion of translation, broadening the concept to capture the dynamic, iterative processes of scientific practice and therapy development. This system-oriented analysis of obesity research expands the philosophical scrutiny of contemporary developments in the biosciences and biomedicine, and has the potential to enrich philosophy of science and medicine. PMID- 21276256 TI - Comparative analysis of pepper and tomato reveals euchromatin expansion of pepper genome caused by differential accumulation of Ty3/Gypsy-like elements. AB - BACKGROUND: Among the Solanaceae plants, the pepper genome is three times larger than that of tomato. Although the gene repertoire and gene order of both species are well conserved, the cause of the genome-size difference is not known. To determine the causes for the expansion of pepper euchromatic regions, we compared the pepper genome to that of tomato. RESULTS: For sequence-level analysis, we generated 35.6 Mb of pepper genomic sequences from euchromatin enriched 1,245 pepper BAC clones. The comparative analysis of orthologous gene-rich regions between both species revealed insertion of transposons exclusively in the pepper sequences, maintaining the gene order and content. The most common type of the transposon found was the LTR retrotransposon. Phylogenetic comparison of the LTR retrotransposons revealed that two groups of Ty3/Gypsy-like elements (Tat and Athila) were overly accumulated in the pepper genome. The FISH analysis of the pepper Tat elements showed a random distribution in heterochromatic and euchromatic regions, whereas the tomato Tat elements showed heterochromatin preferential accumulation. CONCLUSIONS: Compared to tomato pepper euchromatin doubled its size by differential accumulation of a specific group of Ty3/Gypsy like elements. Our results could provide an insight on the mechanism of genome evolution in the Solanaceae family. PMID- 21276257 TI - Ultrasonography and color Doppler in juvenile idiopathic arthritis: diagnosis and follow-up of ultrasound-guided steroid injection in the ankle region. A descriptive interventional study. AB - BACKGROUND: The ankle region is frequently involved in juvenile idiopathic arthritis (JIA) but difficult to examine clinically due to its anatomical complexity. The aim of the study was to evaluate the role of ultrasonography (US) of the ankle and midfoot (ankle region) in JIA. Doppler-US detected synovial hypertrophy, effusion and hyperemia and US was used for guidance of steroid injection and to assess treatment efficacy. METHODS: Forty swollen ankles regions were studied in 30 patients (median age 6.5 years, range 1-16 years) with JIA. All patients were assessed clinically, by US (synovial hypertrophy, effusion) and by color Doppler (synovial hyperemia) before and 4 weeks after US-guided steroid injection. RESULTS: US detected 121 compartments with active disease (joints, tendon sheaths and 1 ganglion cyst). Multiple compartments were involved in 80% of the ankle regions. The talo-crural joint, posterior subtalar joint, midfoot joints and tendon sheaths were affected in 78%, 65%, 30% and 55% respectively. Fifty active tendon sheaths were detected, and multiple tendons were involved in 12 of the ankles. US-guidance allowed accurate placement of the corticosteroid in all 85 injected compartments, with a low rate of subcutaneous atrophy (4,7%). Normalization or regression of synovial hypertrophy was obtained in 89%, and normalization of synovial hyperemia in 89%. Clinical resolution of active arthritis was noted in 72% of the ankles. CONCLUSIONS: US enabled exact anatomical location of synovial inflammation in the ankle region of JIA patients. The talo-crural joint was not always involved. Disease was frequently found in compartments difficult to evaluate clinically. US enabled exact guidance of steroid injections, gave a low rate of subcutaneous atrophy and was proved valuable for follow-up examinations. Normalization or regression of synovial hypertrophy and hyperemia was achieved in most cases, which supports the notion that US is an important tool in the management of ankle involvement in JIA. PMID- 21276258 TI - Babassu aqueous extract (BAE) as an adjuvant for T helper (Th)1-dependent immune responses in mice of a Th2 immune response-prone strain. AB - BACKGROUND: The aqueous extract of a Brazilian palm-tree fruit - the babassu - (BAE) exerts a clear immunostimulative activity in vivo. In the present work, the possibility that BAE can promote Th1 immune responses in mice of a Th2 immune response-prone strain - the BALB/c was investigated. BAE itself, and preparations consisting of Leishmania amazonensis promastigote extract (LE), adsorbed or not to Al(OH)3, and in the presence or not of BAE, were used as immunogens. LE and Al(OH)3 have been shown to preferentially elicit Th2 immune responses. RESULTS: The addition of BAE to LE-containing immunogenic preparations, adsorbed or not to Al(OH)3, clearly promoted the in vitro production of interferon gamma (IFN gamma), a major Th1-dependent cytokine, and not of interleukin (IL-)4 (a Th2 dependent cytokine), by LE-stimulated splenocytes of immunized BALB/c mice. It also promoted the in vivo formation of IgG2a anti-LE antibodies. However, immunization with LE by itself led to an increased production of IL-4 by LE stimulated splenocytes, and this production, albeit not enhanced, was not reduced by the addition of BAE to the immunogen. On the other hand, the IL-4 production by LE-stimulated splenocytes was significantly lower in mice immunized with a preparation containing Al(OH)3-adsorbed LE and BAE than in mice immunized with the control preparation of Al(OH)3-adsorbed LE without BAE. Moreover, an increased production of IFN-gamma, and not of IL-4, was observed in the culture supernatants of splenocytes, from BAE-immunized mice, which were in vitro stimulated with BAE or which received no specific in vitro stimulus. No differences in IL-10 (an immunoregulatory cytokine) levels in the supernatants of splenocytes from mice that were injected with BAE, in relation to splenocytes from control mice, were observed. The spontaneous ex vivo production of NO by splenocytes of mice that had been injected with BAE was significantly higher than the production of NO by splenocytes of control mice. CONCLUSIONS: Based on the results described above, BAE, or biologically active molecules purified from it, should be further investigated as a possible adjuvant, in association or not with aluminium compounds, for the preferential induction of Th1-dependent immune responses against different antigens in distinct murine strains and animal species. PMID- 21276259 TI - Coexistence of diploid, triploid and tetraploid crucian carp (Carassius auratus) in natural waters. AB - BACKGROUND: Crucian carp (abbreviated CC) belongs to the genus of Carassius within the family of Cyprinidae. It has been one of the most important freshwater species for Chinese aquaculture and is especially abundant in the Dongting water system of Hunan province. CC used to be considered as all diploid forms. However, coexistence of diploid (abbreviated 2nCC), triploid (abbreviated 3nCC) and tetraploid crucian carp (abbreviated 4nCC) population of the Dongting water system was first found by our recently researches. RESULTS: We examined the ploidy level and compared biological characteristics in different ploidy CC. In reproductive mode, 2nCC was bisexual generative and 4nCC generated all-female offspring by gynogenesis. However, 3nCC generated progenies in two different ways. 3nCC produced bisexual triploid offspring fertilized with 3nCC spermatozoa, while it produced all-female triploid offspring by gynogenesis when its ova were activated by heterogenous spermatozoa. The complete mitochondrial DNA of three different ploidy fishes was sequenced and analyzed, suggesting no significant differences. Interestingly, microchromosomes were found only in 3nCC, which were concluded to be the result of hybridization. Allogenetic DNA fragments of Sox genes were obtained in 3nCC and 4nCC, which were absent in 2nCC. Phylogenetics analysis based on Sox4 gene indicated 3nCC and 4nCC formed a separate group from 2nCC. CONCLUSIONS: In summary, this is the first report of the co-existence of three types of different ploidy crucian carps in natural waters in China. It was proved that the coexistence of different ploidy CC was reproductively maintained. We further hypothesized that 3nCC and 4nCC were allopolyploids that resulted from hybridization. The different ploidy CC population we obtained in this study possesses great significance for the study of polyploidization and the evolution of vertebrates. PMID- 21276260 TI - Drug suicide: a sex-equal cause of death in 16 European countries. AB - BACKGROUND: There is a lack of international research on suicide by drug overdose as a preventable suicide method. Sex- and age-specific rates of suicide by drug self-poisoning (ICD-10, X60-64) and the distribution of drug types used in 16 European countries were studied, and compared with other self-poisoning methods (X65-69) and intentional self-injury (X70-84). METHODS: Data for 2000-04/05 were collected from national statistical offices. Age-adjusted suicide rates, and age and sex distributions, were calculated. RESULTS: No pronounced sex differences in drug self-poisoning rates were found, either in the aggregate data (males 1.6 and females 1.5 per 100,000) or within individual countries. Among the 16 countries, the range (from some 0.3 in Portugal to 5.0 in Finland) was wide. 'Other and unspecified drugs' (X64) were recorded most frequently, with a range of 0.2-1.9, and accounted for more than 70% of deaths by drug overdose in France, Luxembourg, Portugal and Spain. Psychotropic drugs (X61) ranked second. The X63 category ('other drugs acting on the autonomic nervous system') was least frequently used. Finland showed low X64 and high X61 figures, Scotland had high levels of X62 ('narcotics and hallucinogens, not elsewhere classified') for both sexes, while England exceeded other countries in category X60. Risk was highest among the middle-aged everywhere except in Switzerland, where the elderly were most at risk. CONCLUSIONS: Suicide by drug overdose is preventable. Intentional self poisoning with drugs kills as many males as females. The considerable differences in patterns of self-poisoning found in the various European countries are relevant to national efforts to improve diagnostics of suicide and appropriate specific prevention. The fact that vast majority of drug-overdose suicides came under the category X64 refers to the need of more detailed ICD coding system for overdose suicides is needed to permit better design of suicide-prevention strategies at national level. PMID- 21276261 TI - An Expressed Sequence Tag collection from the male antennae of the Noctuid moth Spodoptera littoralis: a resource for olfactory and pheromone detection research. AB - BACKGROUND: Nocturnal insects such as moths are ideal models to study the molecular bases of olfaction that they use, among examples, for the detection of mating partners and host plants. Knowing how an odour generates a neuronal signal in insect antennae is crucial for understanding the physiological bases of olfaction, and also could lead to the identification of original targets for the development of olfactory-based control strategies against herbivorous moth pests. Here, we describe an Expressed Sequence Tag (EST) project to characterize the antennal transcriptome of the noctuid pest model, Spodoptera littoralis, and to identify candidate genes involved in odour/pheromone detection. RESULTS: By targeting cDNAs from male antennae, we biased gene discovery towards genes potentially involved in male olfaction, including pheromone reception. A total of 20760 ESTs were obtained from a normalized library and were assembled in 9033 unigenes. 6530 were annotated based on BLAST analyses and gene prediction software identified 6738 ORFs. The unigenes were compared to the Bombyx mori proteome and to ESTs derived from Lepidoptera transcriptome projects. We identified a large number of candidate genes involved in odour and pheromone detection and turnover, including 31 candidate chemosensory receptor genes, but also genes potentially involved in olfactory modulation. CONCLUSIONS: Our project has generated a large collection of antennal transcripts from a Lepidoptera. The normalization process, allowing enrichment in low abundant genes, proved to be particularly relevant to identify chemosensory receptors in a species for which no genomic data are available. Our results also suggest that olfactory modulation can take place at the level of the antennae itself. These EST resources will be invaluable for exploring the mechanisms of olfaction and pheromone detection in S. littoralis, and for ultimately identifying original targets to fight against moth herbivorous pests. PMID- 21276262 TI - Identification and functional characterization of small non-coding RNAs in Xanthomonas oryzae pathovar oryzae. AB - BACKGROUND: Small non-coding RNAs (sRNAs) are regarded as important regulators in prokaryotes and play essential roles in diverse cellular processes. Xanthomonas oryzae pathovar oryzae (Xoo) is an important plant pathogenic bacterium which causes serious bacterial blight of rice. However, little is known about the number, genomic distribution and biological functions of sRNAs in Xoo. RESULTS: Here, we performed a systematic screen to identify sRNAs in the Xoo strain PXO99. A total of 850 putative non-coding RNA sequences originated from intergenic and gene antisense regions were identified by cloning, of which 63 were also identified as sRNA candidates by computational prediction, thus were considered as Xoo sRNA candidates. Northern blot hybridization confirmed the size and expression of 6 sRNA candidates and other 2 cloned small RNA sequences, which were then added to the sRNA candidate list. We further examined the expression profiles of the eight sRNAs in an hfq deletion mutant and found that two of them showed drastically decreased expression levels, and another exhibited an Hfq dependent transcript processing pattern. Deletion mutants were obtained for seven of the Northern confirmed sRNAs, but none of them exhibited obvious phenotypes. Comparison of the proteomic differences between three of the DeltasRNA mutants and the wild-type strain by two-dimensional gel electrophoresis (2-DE) analysis showed that these sRNAs are involved in multiple physiological and biochemical processes. CONCLUSIONS: We experimentally verified eight sRNAs in a genome-wide screen and uncovered three Hfq-dependent sRNAs in Xoo. Proteomics analysis revealed Xoo sRNAs may take part in various metabolic processes. Taken together, this work represents the first comprehensive screen and functional analysis of sRNAs in rice pathogenic bacteria and facilitates future studies on sRNA-mediated regulatory networks in this important phytopathogen. PMID- 21276263 TI - Women-focused development intervention reduces delays in accessing emergency obstetric care in urban slums in Bangladesh: a cross-sectional study. AB - BACKGROUND: Recognizing the burden of maternal mortality in urban slums, in 2007 BRAC (formally known as Bangladesh Rural Advancement Committee) has established a woman-focused development intervention, Manoshi (the Bangla abbreviation of mother, neonate and child), in urban slums of Bangladesh. The intervention emphasizes strengthening the continuum of maternal, newborn and child care through community, delivery centre (DC) and timely referral of the obstetric complications to the emergency obstetric care (EmOC) facilities. This study aimed to assess whether Manoshi DCs reduces delays in accessing EmOC. METHODS: This cross-sectional study was conducted during October 2008 to January 2009 in the slums of Dhaka city among 450 obstetric complicated cases referred either from DCs of Manoshi or from their home to the EmOC facilities. Trained female interviewers interviewed at their homestead with structured questionnaire. Pearson's chi-square test, t-test and Mann-Whitney test were performed. RESULTS: The median time for making the decision to seek care was significantly longer among women who were referred from home than referred from DCs (9.7 hours vs. 5.0 hours, p < 0.001). The median time to reach a facility and to receive treatment was found to be similar in both groups. Time taken to decide to seek care was significantly shorter in the case of life-threatening complications among those who were referred from DC than home (0.9 hours vs.2.3 hours, p = 0.002). Financial assistance from Manoshi significantly reduced the first delay in accessing EmOC services for life-threatening complications referred from DC (p = 0.006). Reasons for first delay include fear of medical intervention, inability to judge maternal condition, traditional beliefs and financial constraints. Role of gender was found to be an important issue in decision making. First delay was significantly higher among elderly women, multiparity, non life-threatening complications and who were not involved in income-generating activities. CONCLUSIONS: Manoshi program reduces the first delay for life-threatening conditions but not non-life-threatening complications even though providing financial assistance. Programme should give more emphasis on raising awareness through couple/family-based education about maternal complications and dispel fear of clinical care to accelerate seeking EmOC. PMID- 21276264 TI - Current management of intracerebral haemorrhage in China: a national, multi centre, hospital register study. AB - BACKGROUND: We aimed to examine current practice of the management and secondary prevention of intracerebral haemorrhage (ICH) in China where the disease is more common than in Western populations. METHODS: Data on baseline characteristics, management in-hospital and post-stroke, and outcome of ICH patients are from the ChinaQUEST (QUality Evaluation of Stroke Care and Treatment) study, a multi centre, prospective, 62 hospital registry in China during 2006-07. RESULTS: Nearly all ICH patients (n = 1572) received an intravenous haemodiluting agent such as mannitol (96%) or a neuroprotectant (72%), and there was high use of intravenous traditional Chinese medicine (TCM) (42%). Neurosurgery was undertaken in 137 (9%) patients; being overweight, having a low Glasgow Coma Scale (GCS) score on admission, and Total Anterior Circulation Syndrome (TACS) clinical pattern on admission, were the only baseline factors associated with this intervention in multivariate analyses. Neurosurgery was associated with nearly three times higher risk of death/disability at 3 months post-stroke (odd ratio [OR] 2.60, p < 0.001). Continuation of antihypertensives in-hospital and at 3 and 12 months post-stroke was reported in 732/935 (78%), 775/935 (83%), and 752/935 (80%) living patients with hypertension, respectively. CONCLUSIONS: The management of ICH in China is characterised by high rates of use of intravenous haemodiluting agents, neuroprotectants, and TCM, and of antihypertensives for secondary prevention. The controversial efficacy of these therapies, coupled with the current lack of treatments of proven benefit, is a call for action for more outcomes based research in ICH. PMID- 21276265 TI - A rapid equity focused health impact assessment of a policy implementation plan: An Australian case study and impact evaluation. AB - BACKGROUND: Equity focused health impact assessments (EFHIAs), or health equity impact assessments, are being increasingly promoted internationally as a mechanism for enhancing the consideration of health equity in the development of policies, programs and projects. Despite this there are relatively few examples of examples of completed EFHIAs available. This paper presents a case study of a rapid EFHIA that was conducted in Australia on a health promotion policy implementation plan. It briefly describes the process and findings of the EFHIA and evaluates the impact on decision-making and implementation. METHODS: The rapid EFHIA was undertaken in four days, drawing on an expert panel and limited review of the literature. A process evaluation was undertaken by email one month after the EFHIA was completed. An impact evaluation was undertaken two years later based on five semi-structured interviews with members of the EFHIA working group and policy officers and managers responsible for implementing the plan. A cost estimation was conducted by the EFHIA working group. FINDINGS: The EFHIA made both general and specific recommendations about how the health equity impacts of the policy implementation plan could be improved. The impact evaluation identified changes to development and implementation that occurred as a result of the EFHIA, though there was disagreement about the extent to which changes could be attributed solely to the EFHIA. Those responsible considered the recommendations of the EFHIA in the next versions of their ABHI implementation plans. Factors that influenced the impact of the EFHIA included consolidating understandings of equity, enabling discussion of alternatives, and differing understandings of the purpose of the EFHIA. The EFHIA cost US$4,036 to undertake. CONCLUSIONS: This EFHIA was conducted in a short timeframe using relatively few resources. It had some reported impacts on the development of the implementation plan and enhanced overall consideration of health equity. This case highlights some of the factors and preconditions that may maximise the impact of future EFHIAs on decision-making and implementation. PMID- 21276266 TI - Nationwide shifts in the double burden of overweight and underweight in Vietnamese adults in 2000 and 2005: two national nutrition surveys. AB - BACKGROUND: In developing countries, overweight prevalence is increasing while underweight prevalence is still high. This situation is known as the double nutrition burden. Both underweight and overweight are related to increased risk of chronic non-communicable diseases, reduced well-being and quality of life. This study aims to compare the prevalence of overweight and underweight among Vietnamese adults in 2000 and 2005. METHODS: The study was based on two nationally representative surveys, the National Nutrition Survey 2000 (14,452 subjects) and the National Adult Obesity Survey 2005 (17,213 subjects). Adults aged 25-64 years were sampled to be nationally representative. Multiple multinomial logistic regression analysis was used to investigate the association of underweight and overweight with socio-economic indicators. RESULTS: The distribution of BMI across the population and population groups indicated a shift towards higher BMI levels in 2005 as compared to 2000. The nationwide prevalence of overweight (BMI >= 25 kg/m2) and obesity (BMI >= 30 kg/m2) was 6.6% and 0.4% respectively in 2005, almost twice the rates of 2000 (3.5% and 0.2%). Using the Asian BMI cut-off of 23 kg/m2 the overweight prevalence was 16.3% in 2005 and 11.7% in 2000. In contrast, the underweight prevalence (BMI < 18.5 kg/m2) of 20.9% in 2005 was lower than the rate of 25.0% in 2000. Women were more likely to be both underweight and overweight as compared to men in both 2000 and 2005. Urban residents were more likely to be overweight and less likely to be underweight as compared to rural residents in both years. The shifts from underweight to overweight were clearer among the higher food expenditure levels. CONCLUSIONS: The double nutrition burden was clearly present in Vietnam. The distribution of BMI across the population groups generally indicated a shift towards higher BMI levels in 2005 as compared to 2000. The prevalence of overweight was increased while the declined level of undernutrition was still high in 2005. The shifts of underweight to overweight were most obvious among population groups with higher food expenditure levels. PMID- 21276267 TI - Interplay between HIV entry and transportin-SR2 dependency. AB - BACKGROUND: Transportin-SR2 (TRN-SR2, TNPO3, transportin 3) was previously identified as an interaction partner of human immunodeficiency virus type 1 (HIV 1) integrase and functions as a nuclear import factor of HIV-1. A possible role of capsid in transportin-SR2-mediated nuclear import was recently suggested by the findings that a chimeric HIV virus, carrying the murine leukemia virus (MLV) capsid and matrix proteins, displayed a transportin-SR2 independent phenotype, and that the HIV-1 N74D capsid mutant proved insensitive to transportin-SR2 knockdown. RESULTS: Our present analysis of viral specificity reveals that TRN SR2 is not used to the same extent by all lentiviruses. The DNA flap does not determine the TRN-SR2 requirement of HIV-1. We corroborate the TRN-SR2 independent phenotype of the chimeric HIV virus carrying the MLV capsid and matrix proteins. We reanalyzed the HIV-1 N74D capsid mutant in cells transiently or stably depleted of transportin-SR2 and confirm that the N74D capsid mutant is independent of TRN-SR2 when pseudotyped with the vesicular stomatitis virus glycoprotein (VSV-G). Remarkably, although somewhat less dependent on TRN-SR2 than wild type virus, the N74D capsid mutant carrying the wild type HIV-1 envelope required TRN-SR2 for efficient replication. By pseudotyping with envelopes that mediate pH-independent viral uptake including HIV-1, measles virus and amphotropic MLV envelopes, we demonstrate that HIV-1 N74D capsid mutant viruses retain partial dependency on TRN-SR2. However, this dependency on TRN-SR2 is lost when the HIV N74D capsid mutant is pseudotyped with envelopes mediating pH-dependent endocytosis, such as the VSV-G and Ebola virus envelopes. CONCLUSION: Here we discover a link between the viral entry of HIV and its interaction with TRN-SR2. Our data confirm the importance of TRN-SR2 in HIV-1 replication and argue for careful interpretation of experiments performed with VSV-G pseudotyped viruses in studies on early steps of HIV replication including the role of capsid therein. PMID- 21276268 TI - Focus on the research utility of intravascular ultrasound - comparison with other invasive modalities. AB - Intravascular ultrasound (IVUS) is an invasive modality which provides cross sectional images of a coronary artery. In these images both the lumen and outer vessel wall can be identified and accurate estimations of their dimensions and of the plaque burden can be obtained. In addition, further processing of the IVUS backscatter signal helps in the characterization of the type of the plaque and thus it has been used to study the natural history of the atherosclerotic evolution. On the other hand its indigenous limitations do not allow IVUS to assess accurately stent struts coverage, existence of thrombus or exact site of plaque rupture and to identify some of the features associated with increased plaque vulnerability. In order this information to be obtained, other modalities such as optical coherence tomography, angioscopy, near infrared spectroscopy and intravascular magnetic resonance imaging have either been utilized or are under evaluation. The aim of this review article is to present the current utilities of IVUS in research and to discuss its advantages and disadvantages over the other imaging techniques. PMID- 21276269 TI - Krill oil significantly decreases 2-arachidonoylglycerol plasma levels in obese subjects. AB - We have previously shown that krill oil (KO), more efficiently than fish oil, was able to downregulate the endocannabinoid system in different tissues of obese zucker rats.We therefore aimed at investigating whether an intake of 2 g/d of either KO or menhaden oil (MO), which provides 309 mg/d of EPA/DHA 2:1 and 390 mg/d of EPA/DHA 1:1 respectively, or olive oil (OO) for four weeks, is able to modify plasma endocannabinoids in overweight and obese subjects.The results confirmed data in the literature describing increased levels of endocannabinoids in overweight and obese with respect to normo-weight subjects. KO, but not MO or OO, was able to significantly decrease 2-arachidonoylglycerol (2-AG), although only in obese subjects. In addition, the decrease of 2-AG was correlated to the plasma n-6/n-3 phospholipid long chain polyunsaturated fatty acid (LCPUFA) ratio. These data show for the first time in humans that relatively low doses of LCPUFA n-3 as KO can significantly decrease plasma 2-AG levels in obese subjects in relation to decrease of plasma phospholipid n-6/n-3 LCPUFA ratio. This effect is not linked to changes of metabolic syndrome parameters but is most likely due to a decrease of 2-AG biosynthesis caused by the replacement of 2-AG ultimate precursor, arachidonic acid, with n-3 PUFAs, as previously described in obese Zucker rats. PMID- 21276271 TI - Primary placement technique of jejunostomy using the entristarTM skin-level gastrostomy tube in patients with esophageal cancer. AB - BACKGROUND: We developed a skin-level jejunostomy tube (SLJT) procedure for patients undergoing esophagectomy using a skin-level gastrostomy tube (G-tube) (EntristarTM; Tyco Healthcare, Mansfield, Mass), in order to improve their nutrition status and quality of life (QOL). We describe the procedure and the adverse effects of SLJT in patients with esophageal cancer (EC). METHODS: Over a 24-month period (March 2008 to March 2010), there were 16 patients (mean age: 61.8 years; age range: 49-75 years; 15 men, 1 woman) who had Stage II or III EC. Primary jejunostomy was performed under general anesthesia during esophagectomy. The technical success and the immediate and delayed complications of the procedure were recorded. JEJUNOSTOMY TECHNIQUES: SLJT placement using the G-tube (20Fr) was performed 20 cm from the Treitz ligament on the side opposing the jejunal mesenterium. The internal retention bolster was exteriorized through an incision in the abdominal wall. A single purse string suture using a 4-0 absorbable suture was performed. The internal retention bolster was then inserted into the jejunal lumen via the small incision. The intestine adjacent to the tube was anchored to the peritoneum using a single stitch. RESULTS: The SLJT was successfully inserted in all 16 patients. No early complications were documented. Follow-up for a median of 107 days (range, 26-320 days) revealed leakage to the skin in four patients, including superficial wound infections in two patients. There were no cases of obstruction of the tube or procedure-related death. CONCLUSIONS: This SLJT placement technique using the G-tube is a safe procedure in patients with EC and allows the creation of a long-term feeding jejunostomy. PMID- 21276270 TI - Identification of potential target genes for the tomato fruit-ripening regulator RIN by chromatin immunoprecipitation. AB - BACKGROUND: During ripening, climacteric fruits increase their ethylene level and subsequently undergo various physiological changes, such as softening, pigmentation and development of aroma and flavor. These changes occur simultaneously and are caused by the highly synchronized expression of numerous genes at the onset of ripening. In tomatoes, the MADS-box transcription factor RIN has been regarded as a key regulator responsible for the onset of ripening by acting upstream of both ethylene- and non-ethylene-mediated controls. However, except for LeACS2, direct targets of RIN have not been clarified, and little is known about the transcriptional cascade for ripening. RESULTS: Using immunoprecipitated (IPed) DNA fragments recovered by chromatin immunoprecipitation (ChIP) with anti-RIN antibody from ripening tomato fruit, we analyzed potential binding sites for RIN (CArG-box sites) in the promoters of representative ripening-induced genes by quantitative PCR. Results revealed nearly a 5- to 20-fold enrichment of CArG boxes in the promoters of LeACS2, LeACS4, PG, TBG4, LeEXP1, and LeMAN4 and of RIN itself, indicating direct interaction of RIN with their promoters in vivo. Moreover, sequence analysis and genome mapping of 51 cloned IPed DNAs revealed potential RIN binding sites. Quantitative PCR revealed that four of the potential binding sites were enriched 4- to 17-fold in the IPed DNA pools compared with the controls, indicating direct interaction of RIN with these sites in vivo. Near one of the four CArG boxes we found a gene encoding a protein similar to thioredoxin y1. An increase in the transcript level of this gene was observed with ripening in normal fruit but not in the rin mutant, suggesting that RIN possibly induces its expression. CONCLUSIONS: The presented results suggest that RIN controls fruit softening and ethylene production by the direct transcriptional regulation of cell-wall modifying genes and ethylene biosynthesis genes during ripening. Moreover, the binding of RIN to its own promoter suggests the presence of autoregulation for RIN expression. ChIP-based analyses identified a novel RIN-binding CArG-box site that harbors a gene associated with RIN expression in its flanking region. These findings clarify the crucial role of RIN in the transcriptional regulation of ripening initiation and progression. PMID- 21276272 TI - Modular Chemical Descriptor Language (MCDL): Stereochemical modules. AB - BACKGROUND: In our previous papers we introduced the Modular Chemical Descriptor Language (MCDL) for providing a linear representation of chemical information. A subsequent development was the MCDL Java Chemical Structure Editor which is capable of drawing chemical structures from linear representations and generating MCDL descriptors from structures. RESULTS: In this paper we present MCDL modules and accompanying software that incorporate unique representation of molecular stereochemistry based on Cahn-Ingold-Prelog and Fischer ideas in constructing stereoisomer descriptors. The paper also contains additional discussions regarding canonical representation of stereochemical isomers, and brief algorithm descriptions of the open source LINDES, Java applet, and Open Babel MCDL processing module software packages. CONCLUSIONS: Testing of the upgraded MCDL Java Chemical Structure Editor on compounds taken from several large and diverse chemical databases demonstrated satisfactory performance for storage and processing of stereochemical information in MCDL format. PMID- 21276273 TI - Pathophysiological aspects of hyperglycemia in children with meningococcal sepsis and septic shock: a prospective, observational cohort study. AB - INTRODUCTION: The objective of this study was to investigate the occurrence of hyperglycemia and insulin response in critically ill children with meningococcal disease in the intensive care unit of an academic children's hospital. METHODS: Seventy-eight children with meningococcal disease were included. The group was classified into shock non-survivors, shock survivors and sepsis survivors. There were no sepsis-only non-survivors. The course of laboratory parameters during 48 hours was assessed. Insulin sensitivity and beta-cell function on admission were investigated by relating blood glucose level to insulin level and C-peptide level and by homeostasis model assessment (HOMA) [beta-cell function (HOMA-%B) and insulin sensitivity (HOMA-%S)]. RESULTS: On admission, hyperglycemia (glucose >8.3 mmol/l) was present in 33% of the children. Shock and sepsis survivors had higher blood glucose levels compared with shock non-survivors. Blood glucose level on admission correlated positively with plasma insulin, C-peptide, cortisol, age and glucose intake. Multiple regression analysis revealed that both age and plasma insulin on admission were significantly related to blood glucose. On admission, 62% of the hyperglycemic children had overt insulin resistance (glucose >8.3 mmol/l and HOMA-%S <50%); 17% had beta-cell dysfunction (glucose >8.3 mmol/l and HOMA-%B <50%) and 21% had both insulin resistance and beta-cell dysfunction. Hyperglycemia was present in 11% and 8% of the children at 24 and 48 hours after admission, respectively. CONCLUSIONS: Children with meningococcal disease often show hyperglycemia on admission. Both insulin resistance and beta cell dysfunction play a role in the occurrence of hyperglycemia. Normalization of blood glucose levels occurs within 48 hours, typically with normal glucose intake and without insulin treatment. PMID- 21276274 TI - Patient satisfaction, feasibility and reliability of satisfaction questionnaire among patients with pulmonary tuberculosis in urban Uganda: a cross-sectional study. AB - BACKGROUND: A comprehensive understanding of the barriers to and facilitators of poor tuberculosis (TB) treatment outcome is still lacking; posing a major obstacle to finding effective solutions. Assessment of patient satisfaction in TB programs would contribute to the understanding of gaps in healthcare delivery and the specific needs of individual patients. However, tools for assessing patient satisfaction are lacking. OBJECTIVE: To establish patient satisfaction, the feasibility and reliability of a questionnaire for healthcare service satisfaction and a questionnaire for satisfaction with information received about TB medicines among adult TB patients attending public and private program clinics in Kampala, Uganda. METHODS: In a cross-sectional study, we recruited 133 patients of known HIV status and confirmed pulmonary TB receiving care at the public and private hospitals in Kampala, Uganda. Participants were enrolled based on length of TB treatment as follows: starting therapy, completed two months of therapy, and completed eight months of therapy. A translated and standardized 13 item patient healthcare service satisfaction questionnaire (PS-13) and the Satisfaction with Information about Medicines Scale (SIMS) tool were administered by trained interviewers. Factor analysis was used to systematically group the PS 13 questionnaire into three factors of technical quality of care, responsiveness to patient preference, and management of patient preference satisfaction subscales. The SIMS tool was analyzed with two subscales of information about the action and usage of medication and the potential problems with medication. RESULTS: Of the 133 participants, 35% (46/133) were starting, 33% (44/133) had completed two months, and 32% (43/133) had completed eight months of TB therapy. The male to female and public to private hospital ratios in the study population were 1:1. The PS-13 and the SIMS tools were highly acceptable and easily administered. Both scales and the subscales demonstrated acceptable internal consistency with Cronbach's alpha above 0.70. Patients that were enrolled at the public hospital had relatively lower PS-13 satisfaction scores (0.48 (95% confidence interval (CI), 0.42 - 0.52)), (0.86 (95% CI, 0.81 - 0.90)) for technical quality of care and responsiveness to patient preferences, respectively compared to patients that were enrolled at the private hospital. For potential problems SIMS subscale, male patients that were recruited at the public hospital had relatively lower satisfaction scores (0.58 (95% CI, 0.40 - 0.86)) compared to female patients after adjusting for other factors. Similarly, patients that had completed eight months of TB treatment had relatively higher satisfaction scores (1.23 (95% CI, 1.06 - 1.44)) for action and usage SIMS subscale, and higher satisfaction scores (1.09 (95% CI, 1.03 - 1.16)) for management of patient preference (PS-13 satisfaction subscale) compared to patients that were starting treatment, respectively. CONCLUSION: The study provides preliminary evidence that the PS-13 service satisfaction and the SIMS tools are reliable measures of patient satisfaction in TB programs. Satisfaction score findings suggest differences in patient satisfaction levels between public and private hospitals; between patients starting and those completing TB therapy. PMID- 21276275 TI - MEMOSys: Bioinformatics platform for genome-scale metabolic models. AB - BACKGROUND: Recent advances in genomic sequencing have enabled the use of genome sequencing in standard biological and biotechnological research projects. The challenge is how to integrate the large amount of data in order to gain novel biological insights. One way to leverage sequence data is to use genome-scale metabolic models. We have therefore designed and implemented a bioinformatics platform which supports the development of such metabolic models. RESULTS: MEMOSys (MEtabolic MOdel research and development System) is a versatile platform for the management, storage, and development of genome-scale metabolic models. It supports the development of new models by providing a built-in version control system which offers access to the complete developmental history. Moreover, the integrated web board, the authorization system, and the definition of user roles allow collaborations across departments and institutions. Research on existing models is facilitated by a search system, references to external databases, and a feature-rich comparison mechanism. MEMOSys provides customizable data exchange mechanisms using the SBML format to enable analysis in external tools. The web application is based on the Java EE framework and offers an intuitive user interface. It currently contains six annotated microbial metabolic models. CONCLUSIONS: We have developed a web-based system designed to provide researchers a novel application facilitating the management and development of metabolic models. The system is freely available at http://www.icbi.at/MEMOSys. PMID- 21276276 TI - Who is really at risk? Identifying risk factors for subthreshold and full syndrome eating disorders in a high-risk sample. AB - BACKGROUND: Numerous longitudinal studies have identified risk factors for the onset of most eating disorders (EDs). Identifying women at highest risk within a high-risk sample would allow for focusing of preventive resources and also suggests different etiologies. METHOD: A longitudinal cohort study over 3 years in a high-risk sample of 236 college-age women randomized to the control group of a prevention trial for EDs. Potential risk factors and interactions between risk factors were assessed using the methods developed previously. Main outcome measures were time to onset of a subthreshold or full ED. RESULTS: At the 3-year follow-up, 11.2% of participants had developed a full or partial ED. Seven of 88 potential risk factors could be classified as independent risk factors, seven as proxies, and two as overlapping factors. Critical comments about eating from teacher/coach/siblings and a history of depression were the most potent risk factors. The incidence for participants with either or both of these risk factors was 34.8% (16/46) compared to 4.2% (6/144) for participants without these risk factors, with a sensitivity of 0.75 and a specificity of 0.82. CONCLUSIONS: Targeting preventive interventions at women with high weight and shape concerns, a history of critical comments about eating weight and shape, and a history of depression may reduce the risk for EDs. PMID- 21276278 TI - Healthy lifestyle factors associated with reduced cardiometabolic risk. AB - Minimal data are available regarding the cumulative effects of healthy lifestyle behaviours on cardiometabolic risk. The objective of the present study was to examine a combination of healthy lifestyle behaviours associated with cardiometabolic risk reduction. The analysis was based on a cross-sectional study of 1454 participants from the population-based Lipid Research Clinic's Princeton Follow-up Study. The healthy lifestyle factors included fruit and vegetable intake >= 5 servings/d, meat intake <= 2 servings/d, never smoking, consuming 2-6 alcoholic drinks/week, television (TV) viewing time <= 2 h/d and moderate to vigorous physical activity >= 4 h/week. The combination of healthy lifestyle behaviours was strongly and negatively associated with the presence of cardiometabolic risk, as well as with a composite cardiometabolic risk score after adjustment for race, age, generation and sex. With each additional healthy lifestyle factor, cardiometabolic risk decreased by 31 % (OR 0.69; 95 % CI 0.61, 0.78). A higher healthy lifestyle score was associated with a lower prevalence of cardiometabolic risk (P for trend < 0.001). Compared with individuals having 0-1 healthy lifestyle behaviours, those with 5 or 6 healthy lifestyle behaviours had a 70 % lower prevalence of cardiometabolic risk (OR 0.30; 95 % CI 0.13, 0.67). Healthy lifestyle behaviours including sufficient fruit and vegetable intake, less meat intake, less TV viewing time, abstinence from smoking, modest alcohol intake and regular exercise are associated with reduced cardiometabolic risk. PMID- 21276277 TI - Molecular and cellular pathobiology of Ehrlichia infection: targets for new therapeutics and immunomodulation strategies. AB - Ehrlichia are small obligately intracellular bacteria in the order Rickettsiales that are transmitted by ticks and associated with emerging life-threatening human zoonoses. Vaccines are not available for human ehrlichiosis, and therapeutic options are limited to a single antibiotic class. New technologies for exploring host-pathogen interactions have yielded recent advances in understanding the molecular interactions between Ehrlichia and the eukaryotic host cell and identified new targets for therapeutic and vaccine development, including those that target pathogen virulence mechanisms or disrupt the processes associated with ehrlichial effector proteins. Animal models have also provided insight into immunopathological mechanisms that contribute significantly to understanding severe disease manifestations, which should lead to the development of immunomodulatory approaches for treating patients nearing or experiencing severe disease states. In this review, we discuss the recent advances in our understanding of molecular and cellular pathobiology and the immunobiology of Ehrlichia infection. We identify new molecular host-pathogen interactions that can be targets of new therapeutics, and discuss prospects for treating the immunological dysregulation during acute infection that leads to life-threatening complications. PMID- 21276279 TI - Breast-feeding and growth in children until the age of 3 years: the Generation R Study. AB - Breast-feeding has been suggested to be associated with lower risks of obesity in older children and adults. We assessed whether the duration and exclusiveness of breast-feeding are associated with early postnatal growth rates and the risks of overweight and obesity in preschool children. The present study was embedded in a population-based prospective cohort study from early fetal life onwards, among 5047 children and their mothers in The Netherlands. Compared with children who were breast-fed, those who were never breast-fed had a lower weight at birth (difference 134 (95 % CI - 190, - 77) g). No associations between breast-feeding duration and exclusivity with growth rates before the age of 3 months were observed. Shorter breast-feeding duration was associated with an increased gain in age- and sex-adjusted standard deviation scores for length, weight and BMI (P for trend < 0.05) between 3 and 6 months of age. Similar tendencies were observed for the associations of breast-feeding exclusivity with change in length, weight and BMI. Breast-feeding duration and exclusivity were not consistently associated with the risks of overweight and obesity at the ages of 1, 2 and 3 years. In conclusion, shorter breast-feeding duration and exclusivity during the first 6 months tended to be associated with increased growth rates for length, weight and BMI between the age of 3 and 6 months but not with the risks of overweight and obesity until the age of 3 years. PMID- 21276280 TI - Antioxidant effect of astaxanthin on phospholipid peroxidation in human erythrocytes. AB - Phospholipid hydroperoxides (PLOOH) accumulate abnormally in the erythrocytes of dementia patients, and dietary xanthophylls (polar carotenoids such as astaxanthin) are hypothesised to prevent the accumulation. In the present study, we conducted a randomised, double-blind, placebo-controlled human trial to assess the efficacy of 12-week astaxanthin supplementation (6 or 12 mg/d) on both astaxanthin and PLOOH levels in the erythrocytes of thirty middle-aged and senior subjects. After 12 weeks of treatment, erythrocyte astaxanthin concentrations were higher in both the 6 and 12 mg astaxanthin groups than in the placebo group. In contrast, erythrocyte PLOOH concentrations were lower in the astaxanthin groups than in the placebo group. In the plasma, somewhat lower PLOOH levels were found after astaxanthin treatment. These results suggest that astaxanthin supplementation results in improved erythrocyte antioxidant status and decreased PLOOH levels, which may contribute to the prevention of dementia. PMID- 21276281 TI - Chronic dietary n-3 PUFA intervention improves dyslipidaemia and subsequent cardiovascular complications in the JCR:LA- cp rat model of the metabolic syndrome. AB - There is increasing interest in the potential chronic beneficial effects of dietary n-3 PUFA on the metabolic syndrome (MetS) and associated cardiovascular complications. We have recently established that increased dietary n-3 PUFA has a profound acute benefit on fasting lipids and the postprandial pro-inflammatory response in the JCR:LA-cp rat, a model of the MetS. However, it is unclear to what extent chronic dietary n-3 PUFA intervention can modulate the progression of end-stage metabolic and vascular complications. The present study aimed to determine the chronic effects of dietary n-3 PUFA supplementation on fasting and non-fasting dyslipidaemia, insulin resistance and vascular complications in the JCR:LA-cp rodent model. JCR:LA-cp rats were fed an isoenergetic lipid-balanced diet supplemented with 5 % n-3 PUFA (w/w) of the total fat (fish oil-derived EPA/DHA) for 16 weeks. Fasting and non-fasting (postprandial) plasma lipid profile was assessed. Hepatic and adipose tissue was probed for the expression of lipogenic proteins (acyl-CoA carboxylase (ACC), fatty acid synthase (FAS) and sterol regulatory element-binding protein-1 (SREBP-1)), while the activity of Jun N-terminal kinase (JNK) was assessed via Western blot to target phosphorylated JNK protein in primary enterocytes. The frequency of myocardial lesions was assessed by haematoxylin and eosin staining. Increased dietary n-3 PUFA improved both the fasting and postprandial lipid profiles (TAG, cholesterol and apoB48) in the JCR:LA-cp rat, potentially via the down-regulation of the hepatic or adipose tissue expression of lipogenic enzymes (ACC, FAS and SREBP-1). Rats fed the 5 % n 3 PUFA diet had lower (58.2 %; P < 0.01) enterocytic phosphorylated JNK protein and secreted less cholesterol (30 %; P < 0.05) into mesenteric lymph compared with the control. The chronic metabolic benefits of dietary n-3 PUFA may underlie the potential to reduce vascular complications during the MetS, including the observed reduction in the frequency (approximately 80 %) of late-stage 3 myocardial lesions. PMID- 21276282 TI - Population-based study on the prevalence of spirometric obstructive pattern in Porto, Portugal. AB - BACKGROUND: The diagnosis of obstructive lung disease (OLD) based on clinical grounds is challenging. There have been no population-based COPD studies that collected pulmonary function data in Portugal, a country in transition between phases 2 and 3 of the smoking epidemic. OBJECTIVE: To estimate the prevalence of obstructive pattern on spirometry in a representative sample of adults from Porto, Portugal. METHODS: We conducted a health survey between 2001 and 2003, and 758 participants >= 40 years old had reliable spirometry. We used a structured questionnaire to collect demographic, clinical, social, and behavioral data. Obstructive pattern was defined as FEV(1)/FVC < 70%. Logistic regression was performed to quantify the association between socio-demographic and clinical factors and outcome. RESULTS: The participants' mean +/- SD age was 58.5 +/- 11.5 years, and 62% were women. The prevalence of spirometric obstructive pattern was 10.7%, 95% CI 8.6-13.1%; 13.4% in men, and 9.1% in women (P = .08). The age adjusted odds ratios for cumulative smoking exposure of less than and more than 20 pack years, in comparison with never smokers, were 3.49 (95% CI 1.02-11.92) and 3.91 (95% CI 1.29-11.89) among men, and 1.47 (95% CI 0.53-4.08) and 2.68 (95% CI 1.07-6.68) among women, respectively. Previously diagnosed OLD was reported by 30.9% (95% CI 21.1-42.1%) of the participants with spirometric obstructive pattern. Spirometry confirmed the OLD diagnosis in 20.5% (95% CI 13.7-28.7%) of subjects who self-reported OLD (kappa = 0.14, 95% CI 0.07-0.20). CONCLUSIONS: The prevalence of spirometric obstructive pattern was high. Considering Portugal's position in the smoking epidemic, together with the aging of the population, we can expect an increase in the prevalence of OLD in older people and in women. Our results confirm the limited validity of self-reported OLD in epidemiological studies. PMID- 21276283 TI - Retrospective monitoring in the management of persistent asthma. AB - BACKGROUND: There is still considerable disagreement on several aspects of monitoring asthma with symptom score and peak expiratory flow (PEF). OBJECTIVE: To investigate patient adherence to a retrospective diary-card monitoring method in patients with poorly controlled persistent asthma, in a clinical management setting; to develop improved methods for fast manual entry data into a computer; and to generate real-time informative graphs of the data. METHODS: In 115 consecutive adult patients we applied a diary-card monitoring method in which the patient records symptom score and PEF. We analyzed the diary cards of 84 patients. We used SigmaPlot software to graph the data, and linear regression to analyze the relationship between days of expected diary-card completion and days of actual correct diary-card completion (completed entries). RESULTS: Linear regression gave an overall correlation coefficient (r(2)) of 0.65. Surprisingly, the r(2) values in the patients with mild, moderate, and severe asthma were 0.24, 0.44, and 0.99, respectively, revealing a striking correlation between adherence and severity. Moreover, when we arbitrarily set 75% as the minimum acceptable rate of days of completed diary-card entries, 68% of the patients were in the over-75% category. Remarkably, 100% of the patients with severe asthma were above the 75% cut-off. The graphing method we tested proved user-friendly, flexible, and quick, allowing computerized processing of 30 days of data sets in 5 min, and generation of high-quality self-explanatory graphs that facilitate rapid management decision making via visual pattern recognition. CONCLUSIONS: In a clinical setting, retrospective monitoring of patients with moderate and severe persistent asthma by symptom score and PEF is feasible, and patient adherence appears to be good, particularly in patients with severe asthma. We recommend a lower priority on retrospective monitoring in patients with mild persistent asthma. Monitoring should be carried out according to a definite follow-up protocol. Improving the quality and standardization of the monitoring graph is a priority. PMID- 21276284 TI - A new heat and moisture exchanger for laryngectomized patients: endotracheal temperature and humidity. AB - OBJECTIVE: To assess the endotracheal temperature and humidity and clinical effects of 2 models of a new heat and moisture exchanger (HME): Rplus, which has regular breathing resistance, and Lplus, which has lower breathing resistance. METHODS: We measured endotracheal temperature and humidity in 10 laryngectomized patients, for 10 min each, with and without the HMEs. We sequentially tested 4 HME models (all Atos Medical, Horby, Sweden), in randomized order: Rplus, Lplus, Provox Normal (the HME we regularly use and which we considered the reference HME), and Stomvent (an older HME model). We also assessed the short-term clinical and practical effects of the Rplus and Lplus in a prospective 3-week trial with 13 laryngectomized patients. RESULTS: Rplus and Lplus had better humidification than Provox Normal (6.8 mg H(2)O/L, 4.3 mg H(2)O/L, and 3.7 mg H(2)O/L, respectively, P < .001), and no significant temperature difference. During the 3 week study period, 7 of the 13 patients reported noticeably lower mucus production with Rplus and Lplus. CONCLUSIONS: Rplus and Lplus had better heating and humidification than Provox Normal. Although Stomvent also performed well, its design is less convenient for laryngectomized patients. Further HME improvement is still warranted and should focus on improving the HME's heating capacity. PMID- 21276285 TI - Bilateral Bochdalek hernias presenting as respiratory failure in an elderly patient. AB - Bochdalek hernia occurs from a congenital defect of the diaphragm, allowing the passage of abdominal structures into the thoracic cavity, limiting lung expansion and ventilatory function. Bochdalek hernia is common in neonates but rarely occur in adults; there are only 4 documented cases in the elderly population. We present a case of an 88-year-old woman with severe hypoxia and respiratory failure that required ventilatory support, in whom bilateral Bochdalek hernias progressed over the years and severely invaded the thoracic cavity, causing acute decompensation. This is a rare condition in adults but can cause substantial morbidity when the involvement of the thoracic cavity is severe. PMID- 21276286 TI - Infected cavitating pulmonary infarction. PMID- 21276288 TI - Operational research, a State of the Art series in the Journal. PMID- 21276289 TI - Treatment of multidrug-resistant tuberculosis: definition of the outcome 'failure'. PMID- 21276290 TI - Operational research for improved tuberculosis control: the scope, the needs and the way forward. AB - The promotion of research is one of the main components of the World Health Organizations Stop TB Strategy, which includes 'programme-based operational research (OR)' and 'research on introducing new tools into practice'. The importance of OR in improving tuberculosis (TB) control was recognised a long time ago, and historical OR studies have been instrumental in the development of major strategies for TB control. Although a growing number of OR projects are being conducted in the world today, little is known about their results or their likely impact on TB control programmes. As funding organisations increasingly recognise the need for OR, we propose a rational framework to conduct OR, which covers a spectrum from local setting-oriented to international policy guiding research, and determines the relevance, replicability and generalisability of the results. OR in TB control is aimed at 1) improving programme performance; 2) assessing the feasibility, effectiveness and impact of new strategies or interventions on TB control; and 3) collecting evidence to guide policy recommendations on specific interventions. This requires strengthened capacity to plan and conduct OR in low-income countries and appropriate support to conduct both nationally and internationally led OR projects. Suggestions are made for potential steps for improved purpose-driven OR, which may help to improve TB control locally and inform policy recommendations internationally. PMID- 21276291 TI - Tuberculin skin test and isoniazid prophylaxis among health care workers in high tuberculosis prevalence areas. AB - The tuberculin skin test (TST) is an important tool for the detection of latent tuberculosis (TB) and the identification of health care workers (HCWs) who require chemoprophylaxis. Although TST is inexpensive, easily available and the preferred test in most TB-prevalent settings, it has recognised limitations, including subjective interpretation, false positivity, cross reactivity with non tuberculous mycobacteria, administration errors and the requirement for two visits. Given these limitations and the unavailability of better screening tests in resource-limited settings, the acceptance rate for chemoprophylaxis among HCWs has remained low. Furthermore, chemoprophylaxis in these settings is complicated by the high rate of drug-resistant TB, potential adverse reactions, prescription of chemoprophylaxis in undiagnosed active TB patients and the unavailability of follow-up systems provided by occupational health programmes. In the present article, we provide our viewpoint and a practical approach along with existing evidence supporting or discouraging the use of TST and isoniazid chemoprophylaxis for TB screening and management among HCWs in TB-prevalent settings. PMID- 21276292 TI - Human immunodeficiency virus associated tuberculosis more often due to recent infection than reactivation of latent infection. AB - BACKGROUND: It is unclear whether human immunodeficiency virus (HIV) increases the risk of tuberculosis (TB) mainly through reactivation or following recent Mycobacterium tuberculosis (re)infection. Within a DNA fingerprint-defined cluster of TB cases, reactivation cases are assumed to be the source of infection for subsequent secondary cases. As HIV-positive TB cases are less likely to be source cases, equal or higher clustering in HIV-positives would suggest that HIV mainly increases the risk of TB following recent infection. METHODS: A systematic review was conducted to identify all studies on TB clustering and HIV infection in HIV-endemic populations. Available individual patient data from eligible studies were pooled to analyse the association between clustering and HIV. RESULTS: Of seven eligible studies, six contributed individual patient data on 2116 patients. Clustering was as, or more, likely in the HIV-positive population, both overall (summary OR 1.26, 95%CI 1.0-1.5), and within age groups (OR 1.50, 95%CI 0.9-2.3; OR 1.00, 95%CI 0.8-1.3 and OR 2.57, 95%CI 1.4-5.7) for ages 15-25, 26-50 and >50 years, respectively. CONCLUSIONS: Our results suggest that HIV infection mainly increases the risk of TB following recent M. tuberculosis transmission, and that TB control measures in HIV-endemic settings should therefore focus on controlling M. tuberculosis transmission rather than treating individuals with latent M. tuberculosis infection. PMID- 21276293 TI - Household expenditure and tuberculosis prevalence in VietNam: prediction by a set of household indicators. AB - OBJECTIVE: To study the association between TB and household expenditure in a nationwide TB prevalence survey in Viet Nam using nine household characteristics. METHOD: To assess the prevalence of TB in Viet Nam, a nationwide stratified cluster sample survey was conducted from 2006 to 2007. Nine household characteristics used in the second Viet Nam Living Standards Survey (VLSS) were scored per household. In the VLSS dataset, we regressed these nine characteristics against household expenditure per capita, and used the coefficients to predict household expenditure level (in quintiles) in our survey and assess its relation with TB prevalence. RESULTS: The prevalence of bacteriologically confirmed TB was 307 per 100,000 population in persons aged >= 15 years (95%CI 249-366). After adjustment for confounders, prevalence was found to be associated with household expenditure level: the rate was 2.5 times higher for those in the lowest household expenditure quintile (95%CI 1.6-3.9) than those in the highest quintile. CONCLUSION: With a set of nine household characteristics, we were able to predict household expenditure level fairly accurately. There was a significant association between TB prevalence rates and estimated household expenditure level, showing that TB is related to poverty in Viet Nam. PMID- 21276294 TI - Risk of travelling to the country of origin for tuberculosis among immigrants living in a low-incidence country. AB - SETTING: Two thirds of tuberculosis (TB) patients in the Netherlands are foreign born. OBJECTIVE: To determine if travelling to the country of origin is a risk factor for TB among two different immigrant groups that have lived in the Netherlands for at least 2 years. DESIGN: In this unmatched case-control study, the frequency and duration of travel to the country of origin in the preceding 12 months were compared between adult Moroccan and Turkish TB patients and community controls. RESULTS: Moroccan patients had travelled more often (26/32 = 81%) in the preceding year than Moroccan controls (472/816 = 58%). The travel-associated odds ratio (OR) for TB among Moroccans was 3.2 (95%CI 1.3-7.7), and increased to 17.2 (95%CI 3.7-79) when the cumulative duration of travel exceeded 3 months. The corresponding population fraction of Moroccan TB cases attributable to recent travel was 56% (95%CI 19-71). Among Turkish immigrants TB was not associated with travel (OR 0.9, 95%CI 0.3-2.4). CONCLUSION: Travel to the country of origin was a risk factor for TB among Moroccans, but not among Turkish people living in the Netherlands. The difference in travel-associated OR between these two immigrant groups is probably related to differences in TB incidence in these countries. PMID- 21276295 TI - Risk factors for tuberculosis in Greenland: case-control study. AB - SETTING AND OBJECTIVE: Despite several efforts aiming at disease control, the incidence of tuberculosis (TB) remains high in Greenland, averaging 131 per 100,000 population during the period 1998-2007. The purpose of the present study was to disclose risk factors for TB. METHODS: A case-control study was performed among 146 patients diagnosed with TB in the period 2004-2006. For each patient, four healthy age- and sex-matched control persons living in the same district were included. All participants completed a questionnaire regarding socio demographic and lifestyle factors. Risk factor analyses were carried out using logistic regression models. RESULTS: Factors associated with TB were Inuit ethnicity, living in a small settlement, unemployment, no access to tap water, no bathroom or flushing toilet, underweight, smoking, frequent intake of alcohol and immunosuppressive treatment. The multivariate model showed that Inuit ethnicity (OR 15.3), living in a settlement (OR 5.1), being unemployed (OR 4.1) and frequent alcohol use (OR 3.1) were independent determinants of risk. Unemployment was associated with the highest population-attributable risk (29%). CONCLUSION: Risk factors associated with living in a settlement should be further explored and an investigation of genetic susceptibility is warranted. PMID- 21276296 TI - Contact investigation for tuberculosis in Taiwan contacts aged under 20 years in 2005. AB - OBJECTIVE: To measure the tuberculosis (TB) incidence rate and assess the relative risk of TB disease in contacts based on the tuberculin skin test (TST) and sputum status of index cases. DESIGN: All contacts aged <20 years who were exposed to a TB case in 2005 were cross-matched using an electronic surveillance system to estimate TB incidence over a 24-month follow-up period. RESULTS: Among 6959 contacts there were 67 secondary cases (1%). The incidence was highest in the first year after exposure and decreased by half in the second year (P = 0.001). The relative risks of developing TB in contacts aged 0-4, 5-9, 10-14 and 15-19 years were respectively 325, 209, 337 and 53 times greater than for the general population. The hazard ratio of developing TB among contacts with a TST >= 15 mm induration was 12 times higher than for those with a TST < 5 mm (P = 0.003). CONCLUSIONS: The relative risk of developing TB disease within 24 months of exposure was approximately 200-300 times greater for contacts aged <15 years. The majority developed TB within 12 months of exposure. PMID- 21276297 TI - The use of light-emitting diode fluorescence to diagnose mycobacterial lymphadenitis in fine-needle aspirates from children. AB - BACKGROUND: Fine-needle aspiration biopsy (FNAB) is a simple, safe and effective method for investigating suspected mycobacterial lymphadenitis in children. Fluorescence microscopy can provide rapid mycobacterial confirmation. Light emitting diodes (LEDs) provide a cheap and robust excitation light source, making fluorescence microscopy feasible in resource-limited settings. OBJECTIVE: To compare the diagnostic performance of LED fluorescence microscopy on Papanicolaou (PAP) stained smears with the conventional mercury vapour lamp (MVL). METHODS: FNAB smears routinely collected from palpable lymph nodes in children with suspected mycobacterial disease were PAP-stained and evaluated by two independent microscopists using different excitatory light sources (MVL and LED). Mycobacterial culture results provided the reference standard. A manually rechargeable battery-powered LED power source was evaluated in a random subset. RESULTS: We evaluated 182 FNAB smears from 121 children (median age 31 months, interquartile range 10-67). Mycobacterial cultures were positive in 84 of 121 (69%) children. The mean sensitivity with LED (mains-powered), LED (rechargeable battery-powered) and MVL was respectively 48.2%, 50.0% and 51.8% (specificity 78.4%, 86.7% and 78.4%). Inter-observer variation was similar for LED and MVL (kappa = 0.5). CONCLUSION: LED fluorescence microscopy provides a reliable alternative to conventional methods and has many favourable attributes that would facilitate improved, decentralised diagnostic services. PMID- 21276298 TI - Epidemiology of tuberculosis in Benin. AB - SETTING: Benin, West Africa. OBJECTIVE: To describe the epidemiology of tuberculosis (TB) in Benin. DESIGN: Analysis of two tuberculin surveys initiated in 1987 and 1994 and of the quarterly reports of the Basic Management Units to the National Tuberculosis Programme from 1995 to 2007. RESULTS: The average annual risk for a child in Benin of becoming infected with Mycobacterium tuberculosis was around 0.5% in the mid 1980s. The notification rate increased by approximately 1% each year over the observation period and was on average 35 per 100,000 population, with a male-to-female sex ratio of 1.8 and no shift in the age structure of the cases over the observation period. Human immunodeficiency virus prevalence was 14% (97% of the patients were tested). There is a strong gradient of incident notification rates from the north to the south of the country that seems to be related to the population density. CONCLUSION: Both the tuberculin skin test survey results and the notification data suggest that the TB problem in Benin is much smaller than in eastern and southern African countries. PMID- 21276299 TI - Smear-negative, culture-positive pulmonary tuberculosis among patients with chronic cough in Cotonou, Benin. AB - SETTING: The main tuberculosis (TB) centre in Benin, West Africa, where only 2% of adult pulmonary TB cases are sputum smear-negative, all other pulmonary cases being smear-positive. OBJECTIVES: To assess the burden of smear-negative, culture positive pulmonary TB among TB suspects in Cotonou, and to estimate the total number of non-smear-positive TB cases at country level. DESIGN: For 1 year, one morning sputum culture was performed for every TB suspect (cough lasting >3 weeks, as defined in Benin's national guidelines) with three negative sputum smears (fluorescence technique). RESULTS: Of 214 TB suspects for whom culture was performed, only 22 smear-negative, culture-positive cases were identified. During the same period, 831 sputum smear-positive cases were diagnosed. Culture therefore contributed only 2.6% of the total number of bacteriologically proven cases. CONCLUSION: These results show the relatively low input of culture in TB diagnosis among chronic coughers in Cotonou, Benin, and demonstrates that the expected number of non-smear-positive TB cases in Benin is probably much lower than the World Health Organization's current annual estimates. PMID- 21276300 TI - The FIDELIS initiative: innovative strategies for increased case finding. AB - SETTING: Low-income, high tuberculosis (TB) burden countries. OBJECTIVE: To compare case finding of new smear-positive pulmonary TB patients in projects funded to apply innovative approaches. DESIGN: Prospective application of innovative approaches to case finding within routine services to determine the numbers of additional cases detected and the cost per additional case detected, according to the type of approach applied. RESULTS: Between 2003 and 2007, 51 FIDELIS projects were implemented in 18 countries; 273,239 cases were reported, of which 85,267 were additional to the number reported in the previous year. The median cost per additional case was US$103. The interventions employed were: 1) social mobilisation and information, education and communication; 2) engagement of the private sector; 3) innovative approaches for microscopy services; 4) enhanced or semi-active case finding; 5) health systems strengthening; and 6) use of incentives. None of these was significantly more likely to detect additional cases or to have a lower cost per additional case than any of the others. CONCLUSION: While there was a substantial increase in cases detected, at a moderate cost per additional case, we were unable to show that any single intervention had an advantage over the others. PMID- 21276301 TI - Use of fluoroquinolone antibiotics leads to tuberculosis treatment delay in a South African gold mining community. AB - BACKGROUND: Empiric use of fluoroquinolone (FQ) antibiotics could delay tuberculosis (TB) treatment and lead to FQ-resistant TB. METHODS: We examined the impact of FQ use on TB outcomes, including smear status, treatment delay and FQ resistance, through a retrospective cohort study of 440 FQ-exposed and 511 non exposed patients in a gold mining community in South Africa. We considered both recent (<= 100 days before sputum collection) and distant exposure (<= 1 year). We examined 201 and 180 isolates from FQ-exposed and non-exposed individuals for the presence of gyrA mutations. RESULTS: Patients recently exposed to >= 5 days of FQ were less likely to be smear-positive (OR 0.27, 95%CI 0.11-0.63), with an increased time to treatment (time ratio 2.02, 95%CI 1.19-3.44). The strength of association decreased when we considered distant exposure. Adjusting for smear status nullified the effect of FQ exposure on treatment delay. We detected a gyrA mutation in one isolate (0.5%) taken from an individual exposed to FQ for 8 days. CONCLUSION: FQ exposure is associated with treatment delay, mediated by negative smear status. Short exposures to FQ do not routinely lead to resistance encoded by gyrA mutations. We recommend prudent use of FQ in settings with a high burden of human immunodeficiency virus and TB. PMID- 21276302 TI - Lay health worker-supported tuberculosis treatment adherence in South Africa: an interrupted time-series study. AB - SETTING: Better integration of treatment support for people living with tuberculosis (TB) and human immuno-deficiency virus/acquired immune-deficiency syndrome (HIV/AIDS) is a challenge in many settings, and has been identified as a service priority. OBJECTIVE: To determine the impact, compared to directly observed therapy, of a TB treatment intervention modelled on the community antiretroviral treatment (ART) support programme in South Africa. DESIGN: An interrupted time-series design was used, including five intervention clinics and five comparison clinics. Data were collected from January 2005 to March 2008 and analysed using Poisson regression. RESULTS: Between April 2007 and March 2008, a total of 71% of all new TB patients starting treatment at the intervention clinics were placed on the intervention. There were no significant differences in cure or treatment success rates for new TB patients between intervention and comparison clinics. There was a small improvement in smear conversion rates in intervention clinics when compared to comparison clinics. CONCLUSION: The new model does not result in significantly different TB cure and treatment success rates, but does result in small improvements in smear conversion rates for smear positive TB patients. The model holds potential for the better integration of TB and ART support. PMID- 21276303 TI - Cohort analysis of directly observed treatment outcomes for tuberculosis patients in urban Pakistan. AB - BACKGROUND: This quasi-experimental cohort study aimed to evaluate World Health Organization (WHO) defined tuberculosis (TB) treatment outcomes for patients under directly observed treatment at a health facility (clinic DOT) or at home (family DOT) in urban Pakistan. METHODS: We enrolled 582 sputum smear-positive TB patients being treated by either clinic DOT (n = 295) or family DOT (n = 287) in 11 treatment centres. Patients and/or family members were interviewed for baseline measurements. WHO-defined treatment outcomes were evaluated at the end of treatment. Proportions of 'cured' patients were computed. A log-binomial model was used to evaluate the associations of various factors with 'cured' status. RESULTS: The proportion of 'cured' patients was respectively 66% and 34% in the clinic DOT and family DOT groups (risk difference 0.32; 95%CI 0.24-0.39). Patients on clinic DOT were more likely to achieve cure (adjusted relative risk [RR(adj)] 1.85; 95%CI 1.43-2.39) than those on family DOT, as were patients satisfied with their health care worker's attitude (RR(adj) 5.73; 95%CI 2.54 12.96). CONCLUSION: Clinic DOT nearly doubled the proportion of cured patients compared to family DOT. Efforts to improve care-provider attitudes to enhance patient satisfaction, and effective implementation of the WHO's public-private mix approach, may enhance TB control in this and similar settings. PMID- 21276304 TI - Intensified scale-up of public-private mix: a systems approach to tuberculosis care and control in India. AB - SETTING: India's Revised National Tuberculosis Control Programme (RNTCP) implemented an intensified scale-up of public-private mix (PPM) DOTS covering 50 million population in 14 major cities. OBJECTIVES: To describe the processes and outcomes of the systems approach adopted. METHODS: National schemes for engagement with different providers were applied. Additional human resources were provided to assist with implementation. All health care providers were mapped, a concise training module and advocacy kit were developed, and sensitisation and training activities were conducted. National advocacy efforts complemented local initiatives. Data were captured in a PPM-focused surveillance system. RESULTS: Intensified PPM resulted in a 12% increase in notification of new smear-positive pulmonary TB cases. Contribution to case notification by providers varied widely: health department 67%, medical colleges 16%, private practitioners 6%, non government organisations 7%, and the rest 4%. Treatment success was above the 85% target for all sectors combined. Strong public sector implementation and differentiation of roles and responsibilities among providers played major roles. The lessons learnt have been used by the RNTCP to inform future policy development. CONCLUSION: The systems approach to the intensified PPM scale-up used in the 14 cities was productive. However, many challenges and barriers to scale-up of PPM DOTS in India remain. PMID- 21276305 TI - Tuberculosis 'retreatment others': profile and treatment outcomes in the state of Andhra Pradesh, India. AB - SETTING: The Government of India's Revised National Tuberculosis Control Programme (RNTCP), Andhra Pradesh, South India. OBJECTIVES: To study the basic characteristics and treatment outcomes of tuberculosis (TB) patients classified as 'retreatment others' and compare their treatment outcomes with smear-positive retreatment TB cases (relapse, failure, and treatment after default [TAD]). DESIGN: Retrospective record and report review of a patient cohort (n = 1237) registered as 'retreatment others' under the RNTCP from July to September 2008. RESULTS: Of 1009 patient records of 'retreatment others' reviewed, 674 (67%) were males, 892 (88%) were aged 15-64 years, 847 (84%) were pulmonary sputum smear negative, 843 (84%) had unknown human immunodeficiency virus (HIV) status and 55 (5.5%) were HIV-positive. All patients were treated with the RNTCP intermittent (thrice weekly) retreatment regimen. Eighty per cent were successfully treated (cured plus treatment completed). Successful outcomes were higher in females (84%), in patients with extra-pulmonary TB (87%) and in HIV-negative patients (87%). The treatment outcomes were significantly better for 'retreatment others' (P < 0.05) than among the sputum smear-positive retreatment cases (78% for relapses, 59% for failures and 73% for TAD). CONCLUSIONS: 'Retreatment others' were predominantly sputum smear-negative TB, with significantly better treatment outcomes than among smear-positive retreatment patients. Future studies may assess the accuracy of the diagnoses and factors contributing to the occurrence of 'retreatment others'. PMID- 21276306 TI - Performance comparison of four methods for detecting multidrug-resistant Mycobacterium tuberculosis strains. AB - SETTING: National Tuberculosis Reference Laboratory, Kuwait. OBJECTIVE: To compare Genotype MTBDRplus (gMTBDR(+)), INNO-LiPA Rif.TB (INNO-LiPA), polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing for detecting rifampicin (RMP) and/or isoniazid (INH) resistance associated mutations in the rpoB hot-spot region (HSR-rpoB), the katG codon 315 (katG315) and the inhA regulatory region (inhA-RR) among multidrug-resistant Mycobacterium tuberculosis (MDR-TB) isolates. DESIGN: A total of 82 MDR-TB and 43 pansusceptible M.tuberculosis BACTEC 460-characterised isolates were processed using molecular techniques and the Mycobacterial Growth Indicator Tube (MGIT) 960 system. RESULTS: All susceptible strains contained wild-type sequences in target genes. RMP resistance was detected in respectively 78, 77 and 79 MDR-TB strains by gMTBDR(+), INNO-LiPA and HSR-rpoB sequencing. Two isolates with Ins514TTC mutation were detected as RMP-resistant by gMTBDR(+) but as RMP-susceptible by INNO-LiPA. One isolate with L533P mutation, detected as RMP-susceptible by gMTBDR(+), was detected as RMP-resistant by INNO-LiPA. Two of three isolates detected as RMP-susceptible by gMTBDR(+), INNO-LiPA, HSR-rpoB sequencing and the MGIT 960 system contained a I572F mutation that is outside HSR-rpoB. INH resistance was detected in respectively 76, 60, 60 and 22 MDR-TB strains by gMTBDR(+), katG315 PCR-RFLP, katG315 sequencing and inhA-RR sequencing. CONCLUSIONS: Although gMTBDR(+) accurately detected ~ 88% of MDR-TB strains, some rpoB mutations were either missed or were outside the region of analysis of the gMTBDR(+) assay. PMID- 21276307 TI - Drug susceptibility testing proficiency in the network of supranational tuberculosis reference laboratories. AB - SETTING: The network of supranational tuberculosis reference laboratories (SRLs). OBJECTIVE: To evaluate the annual SRL Rounds 6-14 of proficiency testing for first-line drug susceptibility testing (DST). DESIGN: Panels consisted of 20-30 cultures (including 10 pairs of duplicate strains), aiming at 50% resistance prevalence with a variety of profiles. The 27 SRLs participating in at least one of these rounds were free to use their preferred DST method. A judicial gold standard of at least 80% concordant 'susceptible' or 'resistant' was used to determine sensitivity, specificity and efficiency; otherwise the strain was excluded. RESULTS: Of 600 strains, 10% were excluded from evaluation. The average SRL sensitivity and specificity varied between rounds, without attaining significance or trends. Both sensitivity and specificity remained at >95% for isoniazid (INH), rifampicin (RMP) and streptomycin and at >80% for ethambutol. The 16 SRLs participating in all rounds performed consistently better. CONCLUSION: The rounds succeeded in comparing the proficiency of laboratories, and should be further promoted for DST quality assessment. However, to function with greater precision and to ultimately improve the clinical relevance of DST, the INH and RMP judicial result gold standard also needs to take into account genotypic and treatment outcome information. PMID- 21276308 TI - Aerodigestive tract, lung and haematological cancers are risk factors for tuberculosis: an 8-year population-based study. AB - SETTING: The deterioration of immunity in cancer patients may be associated with a higher incidence of tuberculosis (TB). OBJECTIVE: Despite several previous studies on cancer and TB, no population-based investigation has been published. We performed a nationwide population-based study to investigate the incidence of active TB among cancer patients, and the cancer-type specific risk factors related to TB. DESIGNS: This nationwide population-based retrospective cohort study was based on data obtained from the Taiwan National Health Insurance Database. A total of 16,487 cancer patients and 65,948 controls matched for age and sex were recruited. RESULTS: The incidence of TB per 100,000 person-years was 339 in the cancer patients and 202 in the controls, which gives a crude incidence rate ratio of 1.68 (95%CI 1.42-1.98). The hazard ratio (HR) was 1.67 (95%CI 1.42 1.96) after adjusting for age, sex and comorbidity. Cox regression showed that cancers of the aerodigestive tract, including oral, nasopharyngeal and oesophageal and lung cancer (HR 3.09, 95%CI 2.42-3.94) and haematological cancers, including non-Hodgkin's lymphoma and leukaemia (HR 3.22, 95%CI 1.98 5.22), were significant risk factors for TB. CONCLUSION: Cancer patients have a higher incidence of TB than controls. Patients with aerodigestive tract, lung and haematological cancers are especially vulnerable to TB. PMID- 21276309 TI - Strain classification of Mycobacterium tuberculosis: congruence between large sequence polymorphisms and spoligotypes. AB - Spoligotyping is used in molecular epidemiological studies, and signature patterns have identified strain families. However, homoplasy occurs in the markers used for spoligotyping, which could lead to identical spoligotypes in phylogenetically unrelated strains. We determined the accuracy of strain classification based on spoligotyping using the six large sequence and single nucleotide polymorphisms-defined lineages as a gold standard. Of 919 Mycobacterium tuberculosis isolates, 870 (95%) were classified into a spoligotype family. Strains from a particular spoligotype family belonged to the same lineage. We did not find convergence to the same spoligotype. Spoligotype families appear to be sub-lineages within the main lineages. PMID- 21276310 TI - Low agreement between the T-SPOT(r).TB assay and the tuberculin skin test among college students in China. AB - T-SPOT(r).TB and the tuberculin skin test (TST) were used to screen for latent tuberculosis infection among 899 Chinese college students. The positivity rates for T-SPOT(r).TB and TST were respectively 13.0% (95% confidence interval [CI] 10.4-15.9) and 24.9% (95%CI 21.5-28.6) among students with a bacille Calmette Guerin (BCG) scar (agreement of both tests 72.3%; 95%CI 68.6-75.8; kappa = 0.118), and respectively 17.3% (95%CI 11.7-24.2) and 23.7% (95%CI 17.3-31.2) among those without a BCG scar (agreement 73.1%; 95%CI 65.4-79.9; kappa = 0.179). These results demonstrate low agreement between the TST and T-SPOT.TB in the Chinese population studied. PMID- 21276311 TI - Performance of culture and drug susceptibility testing in pulmonary tuberculosis patients in northern China. AB - Multidrug-resistant tuberculosis (MDR-TB) is a growing problem in China. In 2008, all smear-positive pulmonary TB patients in a city in northern China were expected to undergo routine culture and drug susceptibility testing (DST). We assessed the performance of this system. There were 915 patients, of whom 356 (39%) had culture performed; 275 (30%) had positive cultures and 236 (26%) had DST. Of the 236 patients with DST, 6% of new and 32% of previously treated patients had MDR-TB. Culture and DST is an important service for the correct management of patients, and solutions to improve the current system need to be considered. PMID- 21276312 TI - Intention to quit smoking among human immunodeficiency virus infected adults in Johannesburg, South Africa. AB - Although smoking is common in human immunodeficiency virus (HIV) infected individuals, in resource-constrained, high HIV prevalence settings, information on smoking cessation intent and acceptability is limited. Of 150 self-reported current smokers surveyed in two South African HIV clinics, 62 (42%) reported intent to quit smoking in the next year, while 86 (58%) were not interested in quitting or had no plan to quit; 132 (82%) had attempted to quit at least once in the past. Respondents' preferred cessation strategies were counseling and nicotine replacement. A high proportion of HIV-infected smokers want to quit, and interventions should be provided as part of HIV care. PMID- 21276313 TI - Clinical relevance of classification according to weaning difficulty. AB - OBJECTIVE: To evaluate the clinical relevance of the weaning from mechanical ventilation classification system derived from the 2005 international consensus conference, in patients who receive mechanical ventilation for more than 48 hours, and evaluate its correlation with prognosis. METHODS: We conducted a retrospective cohort study in a 12-bed intensive care unit (ICU) in a teaching hospital. We included patients who required > 48 hours of mechanical ventilation and who passed a spontaneous breathing trial (SBT). Weaning and sedation were monitored according to standardized protocol-directed procedures. We collected data on physiological characteristics, mechanical ventilation duration, ICU and hospital stay, and mortality from the medical records database. We assessed one year mortality with a prospective, standardized method. Multivariate logistic regression was performed to evaluate the association between weaning categories and outcome. RESULTS: We included 329 ventilation episodes, in which 115 patients passed at least one SBT. Thirty-four patients (30%) succeeded in their first SBT (simple weaning group), 47 patients (40%) succeeded in their 2nd or 3rd SBT or in less than 7 days of weaning (the difficult weaning group), and 34 patients (30%) required more than 3 SBTs or more than 7 days of weaning (the prolonged weaning group). There were significant differences in ICU and hospital mortality between the simple, difficult, and prolonged-weaning groups. Prolonged weaning was an independent risk factor for longer ICU stay (odds ratio 15.11, 95% CI 1.61 141.91, P = .01) and hospital mortality (odds ratio 3.66, 95% CI 0.99-13.51). However, the weaning process did not impact one-year mortality (odds ratio 2.61, 95% CI 0.82-8.35). CONCLUSIONS: The new weaning classification system is clinically relevant and correlates to ICU and hospital mortality, but not to one year mortality. PMID- 21276314 TI - Hypoxemia adds to the CURB-65 pneumonia severity score in hospitalized patients with mild pneumonia. AB - BACKGROUND: Hypoxemia may influence the prognosis of patients with mild pneumonia, regardless of the initial CURB-65 score (confusion, blood urea nitrogen > 20 mg/dL, respiratory rate > 30 breaths/min, blood pressure < 90/60 mm Hg, and age >= 65 y). OBJECTIVE: To determine the risk factors associated with hypoxemia and the influence of hypoxemia on clinical outcomes in hospitalized patients with mild pneumonia. METHODS: We performed a multicenter prospective cohort study of 585 consecutive hospitalized patients with mild pneumonia (CURB 65 groups 0 and 1). We stratified the patients according to the presence of hypoxemia, defined as a P(aO(2))/F(IO(2)) < 300 mm Hg on admission. We assessed the risk factors associated with hypoxemia, hypoxemia's influence on the course of pneumonia, and clinical outcomes (mortality, hospital stay, and need for intensive care unit admission), with multivariable regression. RESULTS: Fifty percent of the patients (294 cases) had hypoxemia on admission. The risk factors independently associated with hypoxemia were: bilateral radiological involvement (odds ratio 2.8, 95% CI 1.1-7.5), history of COPD (odds ratio 2.5, 95% CI 1.4 4.3), and hypoalbuminemia (odds ratio 2.0, 95% CI 1.1-3.5). The hypoxemic patients had longer hospital stay, higher intensive care unit admission rate, higher rate of severe sepsis, and higher mortality than the non-hypoxemic patients. CONCLUSIONS: Hypoxemia in patients with mild pneumonia is independently associated with several adverse clinical and radiological variables, and the hypoxemic patients had worse clinical outcomes than the non-hypoxemic patients. Therefore, additional attention should be paid to the presence of hypoxemia, regardless of a low CURB-65 score. PMID- 21276315 TI - Timing of the onset of acute respiratory distress syndrome: a population-based study. AB - BACKGROUND: Many patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) have had recent healthcare interventions prior to developing ALI/ARDS. OBJECTIVE: To determine the timing of ALI/ARDS onset in relation to hospital admission and other healthcare interventions. METHODS: We conducted a population-based observational cohort study with a validated electronic surveillance tool, and identified patients with possible ALI/ARDS among critically ill adults at Mayo Clinic hospitals that provide critical care services for Olmsted County, Minnesota, in 2006. Trained investigators independently reviewed electronic medical records and confirmed the presence and timing of ALI/ARDS based on the American-European consensus definition. RESULTS: Of 124 episodes of ALI in 118 patients, only 5 did not fulfill the ARDS criteria. The syndrome developed a median 30 hours (IQR 10-82 h) after hospital admission in 79 patients (67%). ARDS was present on admission in 39 patients (33%), of whom 14 had recent hospitalization, 6 were transferred from nursing homes, and 3 had recent out-patient contact (1 antibiotic prescription, 1 surgical intervention, and 1 chemotherapy). Only 16 ARDS patients (14%) did not have known recent contact with a healthcare system. Compared to ARDS on admission, hospital acquired ARDS was more likely to occur in surgery patients (54% vs 15%, P < .001), and had longer adjusted hospital stay (mean difference 8.9 d, 95% CI 0.3 17.4, P = .04). CONCLUSIONS: ARDS in the community most often develops either during hospitalization or in patients who recently had contact with a healthcare system. These findings have important implications for potential preventive strategies. PMID- 21276316 TI - Tracheal secretion management in the mechanically ventilated patient: comparison of standard assessment and an acoustic secretion detector. AB - BACKGROUND: Standard indications for endotracheal suctioning are often based on clinical judgment on the deterioration of the patient's condition, and/or routine suctioning. TBA Care is a secretion detector that analyses airway sounds and indicates the need for suctioning. OBJECTIVE: To determine the efficacy of TBA Care in detecting retained secretions, compared to standard indications. METHODS: We conducted a prospective randomized trial with 72 general intensive care unit patients randomized at intubation into 2 groups, differing only in suctioning indications. The control group indications were at least 3 scheduled suctionings per day or were clinically driven. The secretion-detector group indications were device signal or clinically driven. At each suctioning session we recorded the indication for suctioning and the amount of secretions removed. Patients were followed until intensive care unit discharge or extubation. Diagnosis of ventilator-associated pneumonia was confirmed via microbiological analysis of suctioned secretions. RESULTS: We analyzed 1,705 suctionings in the control group and 1,354 in the secretion-detector group. The secretion-detector group had fewer suctionings per day (3.9 +/- 2.3 vs 4.8 +/- 1.2, P = .002) and a lower rate of unnecessary suctionings (4% vs 12%, P < .001). In the secretion-detector group, 97% of the suctionings were performed following the signal from the TBA Care device. In the control group, clinical deterioration (65%) was the most frequent indication for suctioning. The incidence of ventilator-associated pneumonia was similar in the groups. CONCLUSIONS: TBA Care seems to give valid and timely indications for suctioning, anticipating clinical deterioration due to secretion retention and reducing unnecessary suctionings. (ClinicalTrials.gov registration NCT00932776.). PMID- 21276317 TI - Uvular necrosis as an unusual complication of bronchoscopy via the nasal approach. AB - Bronchoscopy can cause post-procedural throat discomfort due to oropharyngeal irritation. We report a rare complication of bronchoscopy that resulted in similar symptoms. A 30-year-old man complained of severe throat discomfort a day after bronchoscopy. Examination revealed a swollen, elongated uvula. The lower half of the uvula was completely white, consistent with uvular necrosis. He was managed conservatively with topical lidocaine and antihistamines. At a follow-up examination 2 weeks later his symptoms had substantially improved and the necrosed uvula had separated, leaving a shortened uvula with an irregular border. Simple precautions taken during bronchoscopy can avoid this rare complication that causes persistent symptoms. PMID- 21276318 TI - Superior vena cava syndrome in thoracic malignancies. AB - The superior vena cava syndrome (SVCS) comprises various symptoms due to occlusion of the SVC, which can be easily obstructed by pathological conditions (eg, lung cancer, due to the low internal venous pressure within rigid structures of the thorax [trachea, right bronchus, aorta]). The resulting increased venous pressure in the upper body may cause edema of the head, neck, and upper extremities, often associated with cyanosis, plethora, and distended subcutaneous vessels. Despite the often striking clinical presentation, SVCS itself is usually not a life-threatening condition. Currently, randomized controlled trials on many clinically important aspects of SVCS are lacking. This review gives an interdisciplinary overview of the pathophysiology, etiology, clinical manifestations, diagnosis, and treatment of malignant SVCS. PMID- 21276319 TI - Leak profile inspection during nasal continuous positive airway pressure. AB - BACKGROUND: Patients treated with nasal continuous positive airway pressure (nasal CPAP) for obstructive sleep apnea (OSA) often have adverse effects from and poor adherence to CPAP. OBJECTIVE: To describe abnormal CPAP leak profiles and assess inter-observer reliability in identifying leak profiles and the correlation of leak profiles with leak rate and clinical outcomes. METHODS: In a sleep-disorders clinic we prospectively studied 35 consecutive patients newly diagnosed with moderate or severe OSA, and who had undergone polysomnographic diagnosis and nasal CPAP titration. We analyzed the data recorded by their CPAP machines during their first week of CPAP. Two independent clinical sleep specialists inspected each night's leak profiles. We defined a "continuous" leak profile segment as a leak increase of >= 20 L/min for > 5 min. We defined a "serrated" leak profile segment as a leak that oscillated up to >= 20 L/min in <= 5 min. With a validated questionnaire, we surveyed the patients about adverse effects. RESULTS: Overall inter-observer agreement was 88% for continuous leak and 92% for serrated leaks. The kappa values were 0.76 and 0.85, respectively. Deviance (+/- 2 SD) between scorers was -14% to 11% for continuous leaks, and 15% to 9% for serrated leaks. The duration of manually scored profiles correlated modestly but significantly with the machine-recorded leaks. The mean +/- SD adherence to CPAP was lower in the patients with the highest quartile of continuous leak (5.28 +/- 2.24 h/night versus 6.66 +/- 1.72 h/night). Adverse effects increased with increasing serrated leak (P = .01). CONCLUSIONS: Manually scored leak profiles in patients treated with nasal CPAP can guide clinicians with respect to short-term adherence to nasal CPAP and adverse effects. PMID- 21276320 TI - Effect of albuterol on expiratory resistance in mechanically ventilated patients. AB - BACKGROUND: In mechanically ventilated patients with COPD, the response of the expiratory resistance of the respiratory system (expiratory R(RS)) to bronchodilators is virtually unknown. OBJECTIVE: To examine the effect of inhaled albuterol on expiratory R(RS), and the correlation of albuterol-induced changes in expiratory R(RS) with end-inspiratory resistance and the expiratory flow volume relationship. METHODS: We studied 10 mechanically ventilated patients with COPD exacerbation, before and 30 min after administration of albuterol. We obtained flow-volume curves during passive expiration, divided the expired volume into 5 equal volume slices, and then calculated the time constant and dynamic effective deflation compliance of the respiratory system (effective deflation C(RS)) of each slice via regression analysis of the volume-flow and post occlusion volume-tracheal pressure relationships, respectively. For each slice we calculated expiratory R(RS) as the time constant divided by the effective deflation C(RS). RESULTS: Albuterol significantly decreased the expiratory R(RS) (mean expiratory R(RS) 42.68 +/- 17.8 cm H(2)O/L/s vs 38.08 +/- 16.1 cm H(2)O/L/s) and increased the rate of lung emptying toward the end of expiration (mean time constant 2.51 +/- 1.2 s vs 2.21 +/- 1.2 s). No correlation was found between the albuterol-induced changes in expiratory R(RS) and that of end inspiratory resistance. Only at the end of expiration did albuterol-induced changes in the expiratory flow-volume relationship correlate with changes in expiratory R(RS) in all patients. CONCLUSIONS: In patients with COPD, albuterol significantly decreases expiratory resistance at the end of expiration. In mechanically ventilated patients, neither inspiratory resistance nor the whole expiratory flow-volume curve may be used to evaluate the bronchodilator response of expiratory resistance. PMID- 21276321 TI - Anemia in COPD: a systematic review of the prevalence, quality of life, and mortality. AB - Anemia is common in patients with chronic diseases. However, little is known regarding the prevalence of comorbid anemia and its impact on quality of life, healthcare utilization, and mortality in patients with COPD. We conducted a systematic review and synthesis of the literature (1966 to March 2010). The prevalence of comorbid anemia in patients with COPD ranges from 7.5% to 34%, depending upon the populations selected and diagnostic tools employed to determine the level of hemoglobin. Comorbid anemia in patients with COPD was associated with greater healthcare resource utilization, impaired quality of life, older age, and male gender. Moreover, anemia in patients with COPD is an independent prognostic predictor of premature mortality and a greater likelihood of hospitalization. The true prevalence of anemia in patients with COPD is unknown. There is a lack of consensus agreement regarding this hematological abnormality's true frequency. Based on the findings from the existing literature, more work is necessary to establish the true prevalence of anemia in COPD. Robust and prospective clinical studies are needed to improve the management of COPD patients with comorbid anemia. PMID- 21276322 TI - Higher PEEP in patients with acute lung injury: a systematic review and meta analysis. AB - BACKGROUND: Studies of ventilation strategies that included higher PEEP in patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) have yielded conflicting results. OBJECTIVE: To determine whether higher PEEP during volume-limited and pressure-limited ventilation is associated with 28 day mortality or barotrauma rates in patients with ALI/ARDS. METHODS: We searched MEDLINE, CENTRAL, EMBASE, CINAHL, Web of Science, and the bibliographies of retrieved papers to identify randomized controlled trials that compared higher and lower PEEP in adult patients with ALI/ARDS who were already receiving volume limited or pressure-limited ventilation. Two of us independently abstracted study level data, including study design, patient characteristics, study methods, intervention, and main results. We pooled the study-level data with a random effects model, unless heterogeneity was low (I(2) < 50%), in which case we used a fixed-effects model. The primary outcome was 28-day mortality. RESULTS: Four randomized trials (2,360 participants) were evaluated. Higher PEEP had a nonsignificant trend toward lower 28-day mortality (pooled relative risk 0.90, 95% CI 0.79-1.02). There was no difference in barotrauma between the 2 groups (pooled relative risk 1.17, 95% CI 0.90-1.52). Two studies reported an adjusted hospital death rate, and the pooled results of sensitivity analysis with those adjusted rates were identical to those of the unadjusted analysis. CONCLUSIONS: In 4 recent studies that used volume-limited or pressure-limited ventilation in ALI/ARDS patients, higher PEEP was not associated with significantly different short-term mortality or barotrauma. This study does not support the routine use of higher PEEP in patients with ALI/ARDS. PMID- 21276323 TI - Bronchodilator responsiveness following a negative methacholine challenge test. PMID- 21276324 TI - Transitioning the respiratory therapy workforce for 2015 and beyond. AB - The American Association for Respiratory Care established a task force in late 2007 to identify likely new roles and responsibilities of respiratory therapists (RTs) in the year 2015 and beyond. A series of 3 conferences was held between 2008 and 2010. The first task force conference affirmed that the healthcare system is in the process of dramatic change, driven by the need to improve health while decreasing costs and improving quality. This will be facilitated by application of evidence-based care, prevention and management of disease, and closely integrated interdisciplinary care teams. The second task force conference identified specific competencies needed to assure safe and effective execution of RT roles and responsibilities in the future. The third task force conference was charged with creating plans to change the professional education process so that RTs are able to achieve the needed skills, attitudes, and competencies identified in the previous conferences. Transition plans were developed by participants after review and discussion of the outcomes of the first two conferences and 1,011 survey responses from RT department managers and RT education program directors. This is a report of the recommendations of the third task force conference held July 12-14, 2010, on Marco Island, Florida. The participants, who represented groups concerned with RT education, licensure, and practice, proposed, discussed, and accepted that to be successful in the future a baccalaureate degree must be the minimum entry level for respiratory care practice. Also accepted was the recommendation that the Certified Respiratory Therapist examination be retired, and instead, passing of the Registered Respiratory Therapist examination will be required for beginning clinical practice. A date of 2020 for achieving these changes was proposed, debated, and accepted. Recommendations were approved requesting resources be provided to help RT education programs, existing RT workforce, and state societies work through the issues raised by these changes. PMID- 21276325 TI - Guidelines for conducting tuberculin skin test surveys in high-prevalence countries. AB - This Supplement provides an update on guidelines first published in 1996 on conducting a tuberculin skin test survey and analyzing the resulting data. The updated guidelines add experiences gained from community surveys, revisit the proposed sampling strategies, and provide additional information on ethical considerations. PMID- 21276326 TI - 'I didn't want her to panic': unvoiced patient agendas in primary care consultations when consulting about antidepressants. AB - BACKGROUND: Patient participation in primary care treatment decisions has been much debated. There has been little attention to patients' contributions to primary care consultations over a period of time, when consulting about depression and its treatment with antidepressants. AIM: To explore: (1) what issues remain unsaid during a primary care consultation for depression but are later raised by the patient as important during a research interview; (2) patients' reasons for non-disclosure; (3) whether unvoiced agendas are later voiced; and (4) the nature of the GP-patient relationship in which unvoiced agendas occur. DESIGN OF STUDY: Qualitative interview study. SETTING: Primary health care. METHOD: Patients were recruited through six general practices in the south west of England. Qualitative interviews were carried out with 10 'pairs' of GPs and patients who presented with a new or first episode of moderate to severe depression and were prescribed antidepressants. Follow-up patient interviews were conducted at 3 and 6 months. Throughout the 6-month period, patients were invited to record subsequent consultations (with GPs' consent), using a patient-held tape recorder. RESULTS: Twenty-three unvoiced agendas were revealed, often within decision-making relationships that were viewed in positive terms by patients. Unvoiced agendas included: a preference for immediate treatment, a preference to increase dosage, and the return or worsening of suicidal thoughts. In some cases, patients were concerned that they were 'letting the GP down' by not being able to report feeling better. CONCLUSION: Unvoiced agendas are not necessarily an indication that 'shared decision making' is absent but may in some cases represent patients' attempts to 'protect' their GPs. PMID- 21276327 TI - International comparison of clinicians' ability to identify depression in primary care: meta-analysis and meta-regression of predictors. AB - BACKGROUND: There are international differences in the epidemiology of depression and the performance of primary care physicians but the factors underlying these national differences are uncertain. AIM: To examine the international variability in diagnostic performance of primary care physicians when diagnosing depression in primary care. DESIGN OF STUDY: A meta-analysis of unassisted clinical diagnoses against semi-structured interviews. METHOD: A systematic literature search, critical appraisal, and pooled analysis were conducted and 25 international studies were identified involving 8917 individuals. A minimum of three independent studies per country were required to aid extrapolation. RESULTS: Clinicians in the Netherlands performed best at case finding (the ability to rule in cases of depression with minimal false positives) (AUC+ 0.735) and this was statistically significantly better than the ability of clinicians in Australia (AUC+ 0.622) and the US (AUC+ 0.653), who were the worst performers. Clinicians from Italy had intermediate case-finding abilities. Regarding screening (the ability to rule out cases of no depression with minimal false negatives) there were no strong differences. Looking at overall accuracy, primary care physicians in Italy and the Netherlands were most successful in their diagnoses and physicians from the US and Australia least successful (83.5%, 81.9%, 74.3%, and 67.0%, respectively). GPs in the UK appeared to have the lowest ability to detect depression, as a proportion of all cases of depression (45.6%; 95% CI = 27.7% to 64.2%). Several factors influenced detection accuracy including: collecting data on clinical outcomes; routinely comparing the clinical performance of staff; working in small practices; and having long waits to see a specialist. CONCLUSION: Assuming these differences are representative, there appear to be international variations in the ability of primary care physicians to diagnose depression, but little differences in screening success. These might be explained by organisational factors. PMID- 21276328 TI - The rise of cholesterol testing: how much is unnecessary. AB - BACKGROUND: Laboratory testing has increased dramatically over recent decades, which is a consequence particularly of repeat testing or monitoring, as either a response to treatment or follow-up. AIM: To assess rates of measurement of lipid levels (total cholesterol, high-density lipoprotein, triglyceride) for diagnosis and monitoring over the last 20 years. DESIGN OF STUDY: Audit of electronic database. SETTING: A single region in the UK (Oxfordshire). METHOD: Specimens from individual patients were matched over time. All tests that were the third or more in a 3-year period were considered to be for monitoring, while the first and second were considered to be for diagnosis. As recent evidence-based recommendations suggest that frequent monitoring of cholesterol may reflect measurement error rather than true changes, between one and three tests in each 3 year period were considered to be 'necessary'. RESULTS: Over the 20 years from 1987 there has been a more than 15-fold rise in the overall number of lipid tests requested. After a small decline in the early 1990s, testing rose steadily after publication of several large statin trials, particularly tests requested in primary rather than secondary care. Repeat testing (likely to be for monitoring) rose from 24% of tests (1993-1995) to 61% (2005-2007), with between 42% and 79% of tests in 2005-2007 possibly being unnecessary. Mean cholesterol values declined over time from 1996 onwards. CONCLUSION: In the last decade, the number of cholesterol tests performed in Oxfordshire has risen dramatically. Much of this appears to be for monitoring purposes rather than case finding or risk assessment. The majority of cholesterol tests requested may be unnecessary. PMID- 21276330 TI - Polypharmacy: one of the greatest prescribing challenges in general practice. PMID- 21276331 TI - Working with non-medical prescribers. PMID- 21276332 TI - To excise or not to excise? Should GPs remove possible melanomas? PMID- 21276334 TI - Dermatology research in primary care: why, what, and how? PMID- 21276333 TI - Integrated medicine in the management of chronic illness: a qualitative study. AB - BACKGROUND: Complementary and alternative medicine (CAM) is popular with patients, yet how patients use CAM in relation to orthodox medicine (OM) is poorly understood. AIM: To explore how patients integrate CAM and OM when self managing chronic illness. DESIGN OF STUDY: Qualitative analysis of interviews. METHOD: Semi-structured interviews were conducted with individuals attending private CAM practices in the UK, who had had a chronic benign condition for 12 months and were using CAM alongside OM for more than 3 months. Patients were selected to create a maximum variation sample. The interviews were analysed using framework analysis. RESULTS: Thirty five patient interviews were conducted and seven categories of use were identified: using CAM to facilitate OM use; using OM to support long-term CAM use; using CAM to reduce OM; using CAM to avoid OM; using CAM to replace OM; maximising relief using both CAM and OM; and returning to OM. Participants described initiating CAM use following a perceived lack of suitable orthodox treatment. Participants rejecting OM for a specific condition never totally rejected OM in favour of CAM. CONCLUSION: Patients utilise CAM and OM in identifiably different ways, individualising and integrating both approaches to manage their chronic conditions. To support patients and prevent potential adverse interactions, open dialogue between patients, OM practitioners, and CAM practitioners must be improved. PMID- 21276335 TI - NICE guidelines for chronic obstructive pulmonary disease: implications for primary care. PMID- 21276336 TI - Medication compliance aids: a qualitative study of users' views. AB - BACKGROUND: Despite the rapid rise in the use of multicompartmental compliance aids (MCAs), little is known about the role they play in self-management of medication. AIM: To explore the perceived benefits of MCAs for people using them to manage their own or a relative's medication. DESIGN OF STUDY: Qualitative study using in-depth interviews. SETTING: West Northumberland. METHOD: Recruitment was via posters and leaflets in general practices and community pharmacies. In-depth interviews were conducted using a topic guide. RESULTS: Nineteen people were interviewed. Three overarching themes emerged in relation to medicine taking: disruption, organisation, and adherence, which impacted on control. The medication regime had caused disruption to their lives and this had led to the purchase of an MCA. The MCA enabled them to organise their medication, which they believed had improved the efficiency of medicine taking and saved time. Although the MCA did not prompt them to take their medication, they could see whether they had actually taken it or not, which alleviated their anxiety. To meet their individual needs and lifestyles, some had developed broader systems of medication management, incorporating the MCA. For a small cost--the initial outlay for the MCA and time spent loading it--they gained control over the management of their medication and their condition. CONCLUSION: This group found the use of an MCA to be beneficial, but advice and support regarding how best to manage their medication and on the most appropriate design to suit their needs would be helpful. PMID- 21276337 TI - Placebo interventions in practice: a questionnaire survey on the attitudes of patients and physicians. AB - BACKGROUND: Few studies have investigated whether patients and physicians differ in their attitudes regarding placebo interventions in medical practice. AIM: To compare the proportions of patients and physicians who would accept therapies that do not work through specific pharmacological or physiological action but by enhancing self-healing capacities and by exploiting contextual factors. DESIGN OF STUDY: Survey of a random sample of GPs and patients consecutively attending in primary care practices. SETTING: Four hundred and seventy-seven patients and 300 GPs from primary care practices of the Canton Zurich of Switzerland were approached. METHOD: Two questionnaires on responders' attitudes regarding non specific therapies. RESULTS: The response rates were 87% for patients and 79% for GPs. Eighty-seven per cent of patients and 97% of GPs thought that physical complaints can get better by believing in the effectiveness of the therapy. Overall there was more support for placebo interventions among patients than among GPs, yet 90% of the physicians admitted to actively proposing treatments intended to take advantage of non-specific effects. Seventy per cent of the patients wanted to be explicitly informed when receiving a non-specific intervention, whereas physicians thought this was the case for only 33% of their patients. Fifty-four per cent of patients would be disappointed when learning they had unknowingly been treated with pure placebo ('sugar pill'), while only 44% would feel that way after treatment with impure placebo (for example, herbal medicine). CONCLUSION: GPs rather underestimate the openness of their patients to non-specific therapies. However, patients want to be appropriately informed. Developing specific professional standards could help physicians to harness the 'power of the placebo', while remaining authentic and credible. PMID- 21276338 TI - Questionnaire severity measures for depression: a threat to the doctor-patient relationship? AB - BACKGROUND: Since 2006 the Quality Outcomes Framework (QOF) has rewarded GPs for carrying out standardised assessments of the severity of symptoms of depression in newly diagnosed patients. AIM: To gain understanding of GPs' opinions and perceived impact on practice of the routine introduction of standardised questionnaire measures of severity of depression through the UK general practice contract QOF. DESIGN OF STUDY: Semi-structured qualitative interview study, with purposive sampling and constant comparative analysis. SETTING: Thirty-four GPs from among 38 study general practices in three sites in England, UK: Southampton, Liverpool, and Norfolk. METHOD: GPs were interviewed at a time convenient to them by trained interviewers. Interviews were audiorecorded and transcribed verbatim in preparation for thematic analysis, to identify key views. RESULTS: Analysis of the interviews suggested that the use of severity questionnaires posed an intrusion into the consultation. GPs discursively polarised two technologies: formal assessment versus personal enquiry, emphasising the need to ensure the scores are used sensitively and as an aid to clinical judgement rather than as a substitute. Importantly, these challenges implicitly served a function of preserving GPs' identities as professionals with expertise, constructed as integral to the process of diagnosis. CONCLUSION: GP accounts indicated concern about threats to patient care. Contention between using severity questionnaires and delivering individualised patient care is significantly motivated by GP concerns to preserve professional expertise and identity. It is important to learn from GP concerns to help establish how best to optimise the use of severity questionnaires in depression. PMID- 21276339 TI - Potential health impacts of multiple drug prescribing for older people: a case control study. AB - Using a prescription-survey linkage dataset for 4506 people aged >=50 years from six general practices, the null hypothesis that multiple drug prescribing was not associated with changes in health over a 3-year time-period was investigated. There was a significant trend in the adjusted association between higher levels of multidrug therapy and deterioration in both physical and psychological health over a 3-year time period. The study highlights the potential need for assessing drug prescribing in terms of overall health. PMID- 21276340 TI - Primary excision of cutaneous melanoma: does the location of excision matter. AB - Melanoma is diagnosed more quickly if primarily excised in primary care, but current guidelines discourage this. The reports of all melanomas excised in north east Scotland between 1991 and 2007 were analysed for adequacy of excision. Reports were analysed blinded as to source. Of primary biopsies performed in primary care, 72.5% were reported as completely excised, compared with 69.7% of those performed in secondary care (P<0.612). The difference remained non significant following adjustment for important confounders. PMID- 21276341 TI - Depression indicators in a national sample of older community and care home patients: applying the Quality and Outcomes Framework. AB - In a national primary care database sample of older people (>=65 years), 81% (83 588/103 821) of community and 58% (1702/2940) of care home residents with diabetes or heart disease had depression case finding recently recorded; 66% (1418/2145) of community and 22% (26/118) of care home residents with a new depression episode had a depression-severity assessment recorded. Age, sex, and higher care home dementia prevalence did not explain these differences. Case finding and assessment of depression need to be improved in older people, particularly care home residents. PMID- 21276342 TI - Primary care diagnostic technology update: point-of-care testing for glycosylated haemoglobin. AB - CLINICAL QUESTION: In the monitoring of patients with type 1 and type 2 diabetes, what advantages does point-of-care HbA(1c) testing provide over current practice? PMID- 21276343 TI - Deep venous thrombosis. PMID- 21276344 TI - Self-monitored blood pressure measurements. PMID- 21276345 TI - Junior response to the global health editorial. PMID- 21276346 TI - Chronic daily headache. PMID- 21276347 TI - Experiences of academic GP specialty trainees. PMID- 21276348 TI - Managing respiratory tract infections. PMID- 21276349 TI - Work, fit notes, and occupational health. PMID- 21276351 TI - Patient encounters in very deprived areas. PMID- 21276352 TI - Wellbeing and support. PMID- 21276353 TI - Tips for GP trainees working in psychiatry. PMID- 21276356 TI - The primary care electronic health record: who's righting the software? PMID- 21276360 TI - Paraspinal approach for thoracolumbar fracture. AB - OBJECTIVE: To explore the advantages and indications of the paraspinal approach by anatomical study and clinical application. METHODS: The anatomical data and clinical practice of 27 cases were analyzed to explore the accurate approach between the paraspinal muscles and the structure of ambient tissues, as well as the results of clinical application of paraspinal approach. The operation time, blood loss, incision length, radiographic result (Cobb angle, height of anterior edge of the vertebrae) were compared with those in 24 cases treated by traditional approach. RESULTS: Complete exposure of the facets could be easily performed by identifying natural cleavage plane between the multifidus and longissimus muscles. The natural muscular cleavage was (1.47+/-0.23) cm lateral to the midline for females, and (1.64+/-0.35) cm for males at T(12) level. The distance was (3.3+/-0.6) cm lateral to the midline for females, and (3.7+/-1.0) cm for males at L(4) level. In paraspinal approach group, the operation time was (76.2+/-15.7) min, blood loss was (91.6+/-16.9) ml and incision length was (7.6+/ 0.8) cm. In traditional approach group, the operation time was (121.4+/-19.6) min, blood loss was (218.7+/-32.3) ml and incision length was (17.4+/-2.1) cm. To compare paraspinal approach with traditional approach, the operation time, blood loss and incision length had statistical difference (P less than 0.05) and the radiographic result (Cobb angle, height of anterior edge of the vertebrae) had no statistical difference (P larger than 0.05). CONCLUSIONS: When the paraspinal approach is performed through natural cleavage plane between the multifidus and longissimus muscles, there are no wide muscular disinsertions, leaving the supraspinous and interspinous ligaments intact. The distance of natural cleavage to the midline is different at T(12) and L(4) planes. By this approach, the facet joints can be explored easily and completely, and a clear surgical field will be available for the placement of pedicle screws. As a minimally invasive approach, it can be widely used in thoracolumbar spine surgery. PMID- 21276361 TI - Effect of leptin on bone metabolism in rat model of traumatic brain injury and femoral fracture. AB - OBJECTIVE: To observe serum and callus leptin expression within the setting of fracture and traumatic brain injury (TBI). METHODS: A total of 64 male SD rats were randomized equally into 4 groups: nonoperated group, TBI group, fracture group, and fracture+TBI group. Rats were sacrificed at 2, 4, 8 and 12 weeks after fracture+TBI. Serum leptin was detected using radioimmunoassay, and callus formation was measured radiologically. Callus leptin was analyzed by immunohistochemistry. RESULTS: Serum leptin levels in the fracture group, TBI group and combined fracture+TBI group were all significantly increased compared with control group at the 2 week time-point (P less than 0.05). Serum leptin in the combined fracture +TBI group was significantly higher than that in the fracture and TBI groups at 4 and 8 weeks after injury (P less than 0.05). The percentage of leptin-positive cells in the fracture+TBI callus and callus volume were significantly higher than those in the fracture-only group (P less than 0.01). CONCLUSIONS: We demonstrated elevated leptin expression within healing bone especially in the first 8 weeks in a rat model of fracture and TBI. A close association exists between leptin levels and the degree of callus formation in fractures. PMID- 21276362 TI - Closed reduction and percutaneous pinning of displaced supracondylar fractures of humerus in children with delayed presentation. AB - OBJECTIVE: Supracondylar fractures of the humerus account for 60% of all the fractures around the pediatric elbow and even in developed countries 18% of patients undergo surgery 48 hours or longer following presentation in the hospital. Management guidelines are not clear yet for these patients who present late. The aim of this prospective study was to evaluate the clinical, radiological and functional outcome following closed reduction and percutaneous pinning of widely displaced supracondylar fractures of the humerus presenting 12 hours or more after injury. METHODS: We reviewed the functional and radiological results of closed reduction and percutaneous pinning using crossed K-wires in 40 patients with displaced extension type supracondylar fracture of the humerus (Gartland type III) with a delay of more than 12 hours in presentation. The average age of patients was 4.5 years and the mean delay in presentation was 17.55 hours. RESULTS: Closed reduction and percutaneous pinning was successful in 90% of patients. The mean follow up period was 15 months. The Baumann's angle was restored within 4 degrees of the unaffected side in all patients. Use of a small medial incision in patients with severe swelling helped us avoid ulnar nerve injury. Using Flynn's criteria, 38 patients (95%) had an excellent result. Two patients had mild myositis and both had a poor result. None of the patients developed cubitus varus. CONCLUSION: Closed reduction and crossed pinning of displaced supracondylar fractures of humerus in children is a safe and effective method even with delayed presentation. PMID- 21276363 TI - Analysis of misdiagnosis in patients with multiple trauma. AB - OBJECTIVE: To explore the features, treatment outcomes and reasons for misdiagnosis in patients with multiple trauma, so as to decrease the incidence of misdiagnosis. METHODS: A total of 3 163 patients with multiple trauma who were admitted in our department from August 1997 to August 2008, were retrospectively studied to compare the features of diagnosis and treatment. There were 2 117 males (66.93%) and 1 046 females (33.07%) with the mean age of 36.46 years (range, 14-80 years). Parameters such as general status, traumatic condition, diagnosis and treatment situation, prognosis and mortality were analyzed. The differences between misdiagnosis group and correct diagnosis group were compared in terms of severity of injury, complications and treatment outcomes to elucidate the cause and prevention of misdiagnosis. RESULTS: The misdiagnosis rate of multiple trauma in this study was 16.19%. The major anatomic sites misdiagnosed were limbs and pelvis (299 positions, 39.50%), abdominal region and pelvic organ (148 positions, 19.55%), and thoracic region (109 positions, 14.40%). In misdiagnosis group, ISS, length of hospital stay, rates of disturbance of consciousness, critical cases and shock cases were 33.78+/-19.64, (23.59+/-7.26) days, 49.22%, 33.01% and 47.46%, respectively, which were significantly higher than those of the correct diagnosis group (P less than 0.01). And the data showed that the more serious the injury was, the higher the rate of misdiagnosis would be. The rate of primary diagnosis by trauma surgeons in correct diagnosis group was 75.78%, significantly higher than that of the misdiagnosis group (X(2) equal to 382.01, P less than 0.01). The mortality rate of the misdiagnosis group was 2.93%, which was significantly higher than that for all patients (X(2) equal to 5.22, P less than 0.05). CONCLUSIONS: The results indicated that patients with severe multiple trauma are at high risk of misdiagnosis in early treatment. The mortality rate of misdiagnosed patients is higher than the correctly-diagnosed patients. To prevent misdiagnosis, physicians need to take great care to conduct thorough clinical examinations and repeated evaluation. PMID- 21276364 TI - Coccygectomy for stubborn coccydynia. AB - OBJECTIVE: To evaluate the preliminary clinical outcomes of coccygectomy in patients with coccydynia after a failure of conservative treatment. METHODS: From May 2002 to January 2010, 31 patients with coccydynia were treated by coccygectomy in our department after conservative measures had failed to produce significant relief. A questionnaire, which included the extent of relief in the painful area, improvement in quality of life, intensity of pain in the sitting position, and pain score during daily activities, was used to evaluate the results. RESULTS: All patients were followed up for 1 to 6 years (mean 3.3 years). The results were excellent in 20 patients (64.5%), good in 7 patients (22.6%), moderate in 3 patients (9.7%) and poor in 1 patient (3.2%). The excellent and good rates amounted to 87.1%. All patients except one had complete resolution of their symptoms and were subjectively highly satisfied with the outcomes of the surgery. Only 2 cases of superficial infection were observed postoperatively. CONCLUSION: Coccygectomy is a feasible management option for patients with coccygodynia that has no response to conservative treatments. PMID- 21276365 TI - Anatomical and biomechanical analysis of sacral pedicle and lateral mass. AB - OBJECTIVE: To study the anatomical and biomechanical features of sacral pedicle and lateral mass so as to provide reference for clinical screw fixation technology of sacral pedicle and lateral mass. METHODS: A total of 60 adult patients'spiral CT images of the sacrum and coccyx were selected randomly. The entry points of sacral pedicle and lateral mass screws were determined, and the screw trajectory was measured using the three dimensional reconstruction method. Meanwhile, the gross anatomy was scrutinized in 15 adult cadaver specimens to determine the sacral pedicle and lateral mass screw entry points. The length, width and angle of sacral pedicle and lateral mass screw trajectory were measured. Eight of 15 cadaver specimens were selected to test the maximal extraction force of sacral pedicle and lateral mass screws. The clinical data of 15 cases treated by pedicle and lateral mass screw technology were collected and analyzed. RESULTS: The diameter and length of S(1)-S(5) sacral pedicle and lateral mass screw trajectory were regular, with about 20 degree inclination angle. The S(1) pedicle screw entry point was located at the intersection point of the basal lateral part of articular process and median line of transverse process, and no significant difference was found for the maximal extraction force between pedicle and lateral mass screws (P larger than 0.05). The entry points of S(2)-S(5) pedicle screws were located at the intersection point of the line connecting adjacent posterior sacral foramina and median line of the transverse process. The lateral mass screw entry point of S(2)-S(5) was on the median side of intersection point between median line of the transverse process and lateral sacral crest. The maximal extraction force of pedicle screws was significantly greater than that of lateral mass screws (P less than 0.05). CONCLUSION: Both the sacral pedicle and the lateral mass screw fixation techniques can offer effective fixation and reconstruction for fracture of the sacrum and coccyx, but pedicle screw fixation may be more convenient, safe and reliable than lateral mass screw fixation. PMID- 21276366 TI - Influence of hinge position on the effectiveness of open-door expansive laminoplasty for cervical spondylotic myelopathy. AB - OBJECTIVE: To assess the influence of different hinge positions on clinical results of expansive open-door laminoplasty (EOLP) for cervical spondylotic myelopathy (CSM). METHODS: A total of 102 CSM patients who underwent EOLP from February 2006 to February 2007 were enrolled in this randomized controlled trial. Using a random digits table, 57 patients with the hinge located at the inner margin of the lateral mass were classified as wide-open group, while 45 patients with the hinge positioned at the lamina margin served as narrow-open group. All patients were observed over 24 months, and the clinical and radiological results were analyzed statistically. RESULTS: There were no significant differences in operation duration, intraoperative bleeding volume, Japanese Orthopaedic Association (JOA) scores, cervical curvature index, range of motion and neural function recovery rate. The neural functions were satisfactorily improved after surgery in both groups, while the severity of axial symptoms was significantly lower in the narrow-open group than in the wide-open group (P equal to 0.003). The incidence of C(5) palsy in the wide-open group was higher than that in the narrow-open group (5.3% vs 0), even though the difference did not reach statistical significance (one tailed Fisher's exact test, P equal to 0.17). CONCLUSIONS: Proper inward shift of the hinge can ensure effectiveness of surgical decompression, avoid an excessive backward shift of the spinal cord, decrease the incidence of C(5) palsy and alleviate the severity of axial symptoms. PMID- 21276367 TI - Surgical treatment strategy for multiple injury patients in ICU. AB - OBJECTIVE: To investigate the surgical treatment for patients with multiple injuries in ICU. METHODS: Clinical data of 163 multiple injury patients admitted to ICU of our hospital from January 2006 to January 2009 were retrospectively studied, including 118 males and 45 females, with the mean age of 36.2 years (range, 5-67 years). The injury regions included head and neck (29 cases), face (32 cases), chest (89 cases), abdomen (77 cases), pelvis and limbs (91 cases) and body surface (83 cases). There were 57 cases combined with shock. ISS values varied from 10 to 54, 18.42 on average. Patients received surgical treatments in ICU within respectively 24 hours (10 cases), 24-48 hours (8 cases), 3-7 days (7 cases) and 8-14 days (23 cases). RESULTS: For the 163 patients, the duration of ICU stay ranged from 2 to 29 days, with the average value of 7.56 days. Among them, 143 were cured (87.73%), 11 died in the hospital (6.75%) due to severe hemorrhagic shock (6 cases), craniocerebral injury (3 cases) and multiple organ failure (2 cases), and 9 died after voluntarily discharging from hospital (5.52%). The total mortality rate was 12.27%. CONCLUSIONS: The damage control principle should be followed when multiple injury patients are resuscitated in ICU. Surgical treatment strategies include actively controlling hemorrhage, treating the previously missed injuries and related wounds or surgical complications and performing planned staging operations. PMID- 21276368 TI - Functional recovery of sciatic nerve through inside-out vein graft in rats. AB - OBJECTIVE: Present study aimed at further comprehensive functional, histomorphometrical and immunohistochemical assessment of peripheral nerve regeneration using rat sciatic nerve transection model. METHODS: The 10-mm rat sciatic nerve gap was created in rats. In control group nerve stumps were sutured to adjacent muscle and in treatment group the gap was bridged using an inside-out vein graft. In sham-operated group the nerve was manipulated and left intact. All animals underwent walking track analysis test 4, 8, and 12 weeks after surgery. Subsequently, muscle mass measurement was performed to assess reenervation, histological examination to observe the sciatic nerve regeneration morphologically and immunohistochemistry to detect Schwann cells using anti S 100. Results were analyzed using a factorial ANOVA with two between-subjects factors. Bonferroni test for pairwise comparisons was used to examine the effect of treatments. RESULTS: Functional analysis of myelinated nerve fibers showed that nerve function improved significantly in the time course in treatment group. However, quantitative morphometrical analysis of myelinated nerve fibers showed that there was no significant difference between 8 and 12 weeks in treatment group. Muscle weight ratio was bigger and weight loss of the gastrocnemius muscle was ameliorated by inside-out vein grafting. The position of positive immunohistochemical reactions further implied that regenerated axons and Schwann cell-like cells existed after vein grafting was performed, and was accompanied by the process of myelination and structural recovery of regenerated nerves. CONCLUSION: Functional analysis of peripheral nerve repair is far more reliable than quantitative morphometrical analysis. PMID- 21276369 TI - K-wire and tension band wire fixation in treating sternoclavicular joint dislocation. AB - OBJECTIVE: To evaluate the feasibility and therapeutic effect of treating sternoclavicular joint dislocation by K-wire and tension band wire fixation, and to improve the safety and stability of this technique. METHODS: This study consisted of 9 cases, 6 males and 3 females with the mean age of 25 years (range, 9-62 years). The causes were traffic accident in 7 cases, falling in 1 case and fight in 1 case. The duration from injury to operation was 2 hours to 7 days. There were 5 left dislocations and 4 right dislocations; 8 anterior dislocations and 1 posterior dislocation, including one combined with left scapular fracture and one with left olecranon fracture. Open reduction and internal fixation using K-wires and tension band wires were performed to treat dislocations. RESULTS: All patients were followed up for 6 to 24 months, 10 months on average. According to Rockwood's rating scale on postoperative sternoclavicular joint, 8 cases achieved excellent outcomes with an average score of 13.88, and the rest case achieved a good outcome with the score of 12. Anatomical reduction was obtained in all cases. There were no such postoperative complications as severe infection, injury to blood vessel and nerve, failure of fixation, etc. Patients were all satisfied with the anatomical reduction and functional recovery. CONCLUSIONS: The technique of K-wire and tension band wire fixation is safe, simple, effective, less invasive and has been successfully used in orthopedic surgery. It is effective in treating sternoclavicular joint dislocation though it has some disadvantages. PMID- 21276370 TI - Coupled external fixator and skin flap transposition for treatment of exposed and nonunion bone. AB - OBJECTIVE: To discuss the effect of coupled external fixator and skin flap transposition on exposed and nonunion bones. METHODS: The data of 12 cases of infected nonunion and exposed bone following open fracture treated in our hospital during the period of March 1998 to June 2008 were analysed. There were 10 male patients, 2 female patients, whose age were between 19-52 years and averaged 28 years. There were 10 tibial fractures and 2 femoral fractures. The course of diseases lasted for 12-39 months with the mean period of 19 months. All the cases were treated by the coupled external fixator and skin flap transposition. RESULTS: Primary healing were achieved in 10 cases and delayed healing in 2 cases in whom the tibia was exposed due to soft tissue defect and hence local flap transposition was performed. All the 12 cases had bony union within 6-12 months after operation with the average time of 8 months. They were followed up for 1-3 years and all fractures healed up with good function and no infection recurrence. CONCLUSION: The coupled external fixator and skin flap transposition therapy have shown optimal effects on treating infected, exposed and nonunion bones. PMID- 21276371 TI - Management of duodenal trauma. AB - Duodenal trauma is uncommon but nowadays seen more and more frequently due to the increased automobile accidents and violent events. The management of duodenal trauma can be complicated, especially when massive injury to the pancreatic duodenal-biliary complex occurs simultaneously. Even the patients receive surgeries in time, multiple postoperative complications and high mortality are common. To know and manage duodenal trauma better, we searched the recent related literature in PubMed by the keywords of duodenal trauma, therapy, diagnosis and abdomen. It shows that because the diagnosis and management are complicated and the mortality is high, duodenal trauma should be treated in time and tactfully. And application of new technology can help improve the management. In this review, we discussed the incidence, diagnosis, management, and complications as well as mortality of duodenal trauma. PMID- 21276372 TI - Positron emission tomography (PET) and magnetic resonance imaging (MRI) for the assessment of axillary lymph node metastases in early breast cancer: systematic review and economic evaluation. AB - BACKGROUND: Breast cancer is the most common type of cancer in women. Evaluation of axillary lymph node metastases is important for breast cancer staging and treatment planning. OBJECTIVES: To evaluate the diagnostic accuracy, cost effectiveness and effect on patient outcomes of positron emission tomography (PET), with or without computed tomography (CT), and magnetic resonance imaging (MRI) in the evaluation of axillary lymph node metastases in patients with newly diagnosed early-stage breast cancer. DATA SOURCES: A systematic review of literature and an economic evaluation were carried out. Key databases (including MEDLINE, EMBASE and nine others) plus research registers and conference proceedings were searched for relevant studies up to April 2009. A decision analytical model was developed to determine cost-effectiveness in the UK. REVIEW METHODS: One reviewer assessed titles and abstracts of studies identified by the search strategy, obtained the full text of relevant papers and screened them against inclusion criteria. Data from included studies were extracted by one reviewer using a standardised data extraction form and checked by a second reviewer. Discrepancies were resolved by discussion. Quality of included studies was assessed using the quality assessment of diagnostic accuracy studies (QUADAS) checklist, applied by one reviewer and checked by a second. RESULTS: Forty-five citations relating to 35 studies were included in the clinical effectiveness review: 26 studies of PET and nine studies of MRI. Two studies were included in the cost-effectiveness review: one of PET and one of MRI. Of the seven studies evaluating PET/CT (n = 862), the mean sensitivity was 56% [95% confidence interval (CI) 44% to 67%] and mean specificity 96% (95% CI 90% to 99%). Of the 19 studies evaluating PET only (n = 1729), the mean sensitivity was 66% (95% CI 50% to 79%) and mean specificity 93% (95% CI 89% to 96%). PET performed less well for small metastases; the mean sensitivity was 11% (95% CI 5% to 22%) for micrometastases (<= 2 mm; five studies; n = 63), and 57% (95% CI 47% to 66%) for macrometastases (> 2 mm; four studies; n = 111). The smallest metastatic nodes detected by PET measured 3 mm, while PET failed to detect some nodes measuring > 15 mm. Studies in which all patients were clinically node negative showed a trend towards lower sensitivity of PET compared with studies with a mixed population. Across five studies evaluating ultrasmall super-paramagnetic iron oxide (USPIO) enhanced MRI (n = 93), the mean sensitivity was 98% (95% CI 61% to 100%) and mean specificity 96% (95% CI 72% to 100%). Across three studies of gadolinium-enhanced MRI (n = 187), the mean sensitivity was 88% (95% CI 78% to 94%) and mean specificity 73% (95% CI 63% to 81%). In the single study of in vivo proton magnetic resonance spectroscopy (n = 27), the sensitivity was 65% (95% CI 38% to 86%) and specificity 100% (95% CI 69% to 100%). USPIO-enhanced MRI showed a trend towards higher sensitivity and specificity than gadolinium-enhanced MRI. Results of the decision modelling suggest that the MRI replacement strategy is the most cost-effective strategy and dominates the baseline 4-node sampling (4-NS) and sentinel lymph node biopsy (SLNB) strategies in most sensitivity analyses undertaken. The PET replacement strategy is not as robust as the MRI replacement strategy, as its cost-effectiveness is significantly affected by the utility decrement for lymphoedema and the probability of relapse for false-negative (FN) patients. LIMITATIONS: No included studies directly compared PET and MRI. CONCLUSIONS: Studies demonstrated that PET and MRI have lower sensitivity and specificity than SLNB and 4-NS but are associated with fewer adverse events. Included studies indicated a significantly higher mean sensitivity for MRI than for PET, with USPIO-enhanced MRI providing the highest sensitivity. However, sensitivity and specificity of PET and MRI varied widely between studies, and MRI studies were relatively small and varied in their methods; therefore, results should be interpreted with caution. Decision modelling based on these results suggests that the most cost-effective strategy may be MRI rather than SLNB or 4 NS. This strategy reduces costs and increases quality-adjusted life-years (QALYs) because there are fewer adverse events for the majority of patients. However, this strategy leads to more FN cases at higher risk of cancer recurrence and more false- positive (FP) cases who would undergo unnecessary axillary lymph node dissection. Adding MRI prior to SLNB or 4-NS has little effect on QALYs, though this analysis is limited by lack of available data. Future research should include large, well-conducted studies of MRI, particularly using USPIO; data on the long-term impacts of lymphoedema on cost and patient utility; studies of the comparative effectiveness and cost-effectiveness of SLNB and 4-NS; and more robust UK cost data for 4-NS and SLNB as well as the cost of MRI and PET techniques. FUNDING: This study was funded by the Health Technology Assessment programme of the National Institute of Health Research. PMID- 21276375 TI - Trends and future challenges in medical editing. PMID- 21276376 TI - APACHE-II score correlation with mortality and length of stay in an intensive care unit. AB - OBJECTIVE: To correlate the APACHE-II score system with mortality and length of stay in ICU. STUDY DESIGN: Cohort study. PLACE AND DURATION OF STUDY: The Intensive Care Unit (ICU) of the Aga Khan University Hospital, Karachi, from May 2005 to May 2006. METHODOLOGY: All adult patients who were admitted in the ICU were included. APACHE-II score was calculated at the second and seventh days of admission in the ICU. Patients who were discharged alive from the ICU or died after first APACHE-II Score (at 2nd day) were noted as the primary outcome measurement. Second APACHE-II score (at 7th day) was used to predict the length of stay in the ICU. Pearson's correlation coefficient (r) was determined with significance at p < 0.05. RESULTS: In the lowest score category 3-10, 27 out of 30 patients (90%) were discharged and only 3 (10%) died. Out of those 39 patients whose APACHE-II score was found in high category 31-40, 33 (84.6%) deaths were observed. This revealed that there might be more chances of death in case of high APACHE-II score (p=0.001). Insignificant but an inverse correlation (r = -0.084, p < 0.183) was observed between APACHE-II score and length of ICU stay. CONCLUSION: The APACHE-II scoring system was found useful for classifying patients according to their disease severity. There was an inverse relationship between the high score and the length of stay as well higher chances of mortality. PMID- 21276377 TI - Outcome of double vs. single valve replacement for rheumatic heart disease. AB - OBJECTIVE: To compare the follow-up results of double valve replacement (DVR) i.e. mitral valve replacement (MVR) and aortic valve replacement (AVR) vs. isolated MVR or AVR for rheumatic heart disease. STUDY DESIGN: An interventional qausi-experimental study. PLACE AND DURATION OF STUDY: Department of Cardiac Surgery, Punjab Institute of Cardiology, Lahore, from September 1994 till December 2007. METHODOLOGY: Prospective follow-up of 493 patients with mechanical heart valves was carried out using clinical assessment, international normalized ratio and echocardiography. Patients were divided into three groups: group I having MVR, group II having AVR and group III having DVR. Survival, time and causes of mortality, and frequency of valve thrombosis, haemorrhage and cerebrovascular haemorrhage was noted in the three groups and described as proportions. Actuarial survival was analyzed by Kaplan-Meier method. RESULTS: There were 493 with 287 (58.3%) in group I, 87 (17.6%) in group II and 119 (24.1%) in group III. Total follow-up was 2429.2 patient (pt)-years. Of 77 (15.6%) deaths, 19 (3.8%) were in-hospital and 58 (11.8%) were late. In-hospital mortality was highest 4 (4.6%) in group II followed by 5 (4.2%) group III and 10 (3.5%) group I. Late deaths were 39 (13.4%) in group I, 9 (10.2%) in group II and 10 (8.3%) in group III. The total actuarial survival was 84.4% with survival of 83%, 85.1%, 87.4% in groups I, II and III respectively. On follow-up valve thrombosis occurred in 12 (0.49%/pt-years) patients; 9 (0.67%/pt-years) group I, 1 (0.22%/pt-years) in group II and 2 (0.31%/pt-years) in group III. Severe haemorrhage occurred in 19 (0.78%/pt-years); 14 in (1.04%/pt-years) in group I, 3 (0.66%/pt-years) group II and 2 (0.31%/pt-years) in group III. Cerebrovascular accidents occurred in 34 (1.3%/pt-years); 26 (1.95%/pt-years) in group I and 4 in groups II (0.89%/pt-years) and III (0.62%/pt-years) each. CONCLUSION: In patients with rheumatic heart disease having combined mitral and aortic valve disease DVR should be performed whenever indicated as it has similar in-hospital mortality and better late survival as compared to isolated aortic or mitral valve replacement. PMID- 21276378 TI - Comparison of convergence angle of prepared teeth for full veneer metal ceramic crowns. AB - OBJECTIVE: To compare clinically practiced convergence angle values of tooth preparation with recommended values, and also the effect of tooth position and operator experience on convergence angle. STUDY DESIGN: Analytical study. PLACE AND DURATION OF STUDY: The study was carried out at the Dental clinic, The Aga Khan University Hospital, Karachi, from January to June 2007. METHODOLOGY: A minimum of 75 crown preparation dies including 25 dies in each group of teeth (anterior, premolars and molars) were collected retrospectively which were prepared by residents and specialists of operative dentistry. AutoCAD 2007 software was used for measurement of convergence angle. One sample t-test was applied to compare the mean practiced convergence angle values with its recommended values. Two way ANOVA was applied to measure difference in convergence angle values with respect to operator experience and tooth type with the level of significance being alpha=0.050. RESULTS: Mean reported convergence angle value was 22.72 degrees , which was significantly greater (p < 0.001) than the recommended values. Statistically significant difference in convergence angle was found between anterior vs. molar teeth and between premolars vs. molar teeth (p=0.0001 and p=0.002, respectively). CONCLUSION: There was a considerable disparity between the convergent angles values recorded in this study and the recommended guidelines. Measured convergence angle values were greater for posterior teeth as compared to the anterior teeth. PMID- 21276379 TI - Chromosomal study for prognostic grouping in chronic lymphocytic leukemia. AB - OBJECTIVE: To determine the frequency of various cytogenetic aberrations in newly diagnosed chronic lymphocytic leukemia (CLL) patients, and their detection rate by cytogenetic and fluorescent In situ hybridization (FISH) technique separately. STUDY DESIGN: A case series. PLACE AND DURATION OF STUDY: Clinical and Molecular Cytogenetics Laboratories, University of California, Los Angeles, USA, from November 2007 to July 2008. METHODOLOGY: Analysis was made on 100 diagnosed chronic lymphocytic leukemia patients. Cytogenetics and FISH technique were performed on blood or bone marrow samples. RESULTS: Nineteen out of 100 cases (19%) showed karyotype abnormalities; whereas 55 showed abnormalities using the CLL-specific FISH probes. The most frequent abnormality detected by standard cytogenetics was trisomy 12. The most common abnormality detected by FISH was a deletion of 13q14 (40 out of 55 cases; 72% of the abnormal). CONCLUSION: For prognostic grouping of CLL patients, FISH must always be requested which may even replace standard karyotyping. These chromosomal markers help in choosing the therapeutic options. PMID- 21276380 TI - Frequency of hepatitis D virus infection in hepatitis B surface antigen-positive liver diseases. AB - OBJECTIVE: To determine the frequency of HDV among hepatitis B surface antigen (HBsAg)-positive liver disorders. STUDY DESIGN: An observational cross-sectional study. PLACE AND DURATION OF STUDY: Medical Unit I, Chandka Medical College Hospital, Larkana, from July 2003 to June 2008. METHODOLOGY: Adult patients with HBs liver related disorders were evaluated for the presence of delta antibodies using commercially available ELISA kits. Descriptive statistics were used for describing data. Proportions of anti D antibodies between gender and age were compared using chi-square test with significance at p < 0.05. RESULTS: Of the 774 cases, 438 were males (60.4%) and 336 were females (39.6%). The mean age was 36.5 +/- 14.39 for males and 34.03 +/- 13.16 years for females ranging from 15 to 60 years. Anti-HDV was positive in 183 patients (23.6%).The frequency of HDV was not significantly different between the gender groups (p=0.718). HDV infection was markedly higher in chronic than acute liver disorders. CONCLUSION: The HBV/HDV co infection is frequent in the studied area. Therefore, practitioners and health care managers should be made aware of the risk of dual infection with HBV and HDV. PMID- 21276381 TI - Human leukocyte antigen class II susceptibility conferring alleles among non insulin dependent diabetes mellitus patients. AB - OBJECTIVE: To determine the frequency of Human Leukocyte Antigen (HLA) class II susceptibility conferring alleles among type 2 Diabetes mellitus patients, in comparison with healthy controls. STUDY DESIGN: Cross-sectional comparative study. PLACE AND DURATION OF STUDY: Department of Immunology, Armed Forces Institute of Pathology, Rawalpindi, from January 2009 to April 2010. METHODOLOGY: Patients with non-insulin dependent Diabetes mellitus meeting World Health Organization criteria were studied. These were compared with age and gender matched healthy control subjects. For each subject (patients as well as controls), DNA was extracted from ethylene diamine tetra-acetate sample and HLA class II DRB1 typing was carried out at allele group level (DRB1*01-DRB1*16) by sequence specific primers. Human leukocyte antigen DRB1 type was determined by agarose gel electrophoresis and results were recorded. Frequencies were determined as number of an allele divided by total number of alleles per group; p value was computed using Pearson's chi-square test. RESULTS: Among the 100 patients, there were 63 males and 37 females with 68 controls. A total of 13 different HLA DRB1 alleles were detected, with DRB1*15 being the commonest in both the groups. The allele DRB1*13 had statistically significant higher frequency in patient group as compared to controls (p = 0.005). CONCLUSION: HLA DRB1*13 was found with a significantly increased frequency in non-insulin dependent Diabetes mellitus. PMID- 21276382 TI - Carotid intima-media thickness correlation with lipid profile in patients with familial hypercholesterolemia versus controls. AB - OBJECTIVE: To determine the variations in carotid intima-media thickness (CIMT) in familial hypercholesterolemia (FH) patients and its use as predictive marker for premature cardiovascular diseases. STUDY DESIGN: Comparative study. PLACE AND DURATION OF STUDY: National Institute of Cardiovascular Diseases and Dr. Ziauddin Hospital, Karachi, from June 2008 to October 2009. METHODOLOGY: Familial hypercholesterolemia was clinically diagnosed by premature coronary diseases, xanthomas, arcus cornealis and family history of premature coronary heart diseases. Controls were age matched normal individuals without hypercholesterolemia. Their lipid profile was tested after overnight fasting. CIMT was measured in mm using B-mode ultrasonography using linear probe. Student t-test was applied to compare mean CIMT of cases and the control. The mean CIMT values of the FH cases were correlated with LDL using Pearson's correlation test. RESULTS: Forty cases with hypercholesterolemia gave consent to participate in the study. These patients had total cholesterol >=200 mg/dL and LDL >=160 mg/dL as compared to twenty controls of similar age with total cholesterol <=200 mg/dL and LDL <=130 mg/dL. Mean CIMT for the cases was 0.77 +/- 0.18 mm while mean CIMT for control was 0.59 +/- 0.08 mm. The mean CIMT for the cases ranged from 0.7-1.83 mm and 0.48-0.73 mm for controls. Among the FH cases, 25% (n=11) had arterial plaques. Mean CIMT was significantly correlated to LDL-cholesterol (r = 0.725**, p < 0.001). CONCLUSION: In this study, CIMT was found to be significantly increased in familial hypercholesterolemia and it correlated with raised LDL cholesterol. Both are predictive of premature cardiovascular diseases. PMID- 21276383 TI - Urological complications in ureteric stenting live related renal transplantation. AB - OBJECTIVE: To determine the frequency and types of post-transplant urological complications in live-related kidney transplantation with reference to the impact of JJ ureteric stent. STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: Shaikh Zayed Postgraduate Medical Institute and National Institute of Kidney Diseases, Lahore, from June 2006 to July 2010. METHODOLOGY: Consecutive renal transplantations, donors being alive were relatives, reterospectively reviewed. All patients underwent extravesical ureteroneocystostomy and all, except one were stented. From the retrieved clinical records, the frequency and types of various minor and major urological complications and their management was studied. All the complications were managed according to standard guidelines. RESULTS: The overall incidence of urological complications among transplant recipients was 11.9%, observed in 12 patients. The complications were urinary leakage in 2 (2%) and clot retention, ureterovesical junction obstruction and wound infection in one (1%) patient each. Urinary tract infection was observed in 7 (6.9%) patients. CONCLUSION: Urinary tract infection was the most common urologic complication in the studied cases. The technique of stented extravesical ureteronecystostomy had a low rate of urological complications in this series. Other factors which may reduce the urological complications are preserving adventitia, fat and blood supply of ureter by delicate dissection during donor nephrectomy and prevent kinking and twisting of ureter are important factors in reducing the post transplant urological complications. PMID- 21276384 TI - Post-dural puncture posterior reversible encephalopathy syndrome. AB - We report the case of a young patient with 36 weeks pregnancy, and an acute respiratory infection with severe bronchospasm, who developed an occipital headache and neck pain on the third day of inadvertent dural puncture during placement of combined epidural spinal anaesthesia for caesarian section. It was diagnosed as post-dural puncture headache until generalised tonic clonic seizures occurred the next day raising the suspicion of postpartum eclampsia or meningitis. Posterior reversible encephalopathy syndrome was diagnosed on MRI of the brain which showed features of reversible ischemia in the posterior region of the brain. With anticonvulsant therapy and antibiotics there was complete resolution of neurological symptoms. We highlight the importance of high index of suspicion of this reversible encephalopathy in obstetric cases with intentional or inadvertent dural puncture, with headache similar to post-dural punctural headache, and the essential role of neuroradiology in confirmation of the diagnosis, as placement of an epidural blood patch would be highly detrimental in these cases. PMID- 21276385 TI - Paraneoplastic Addisonian pigmentation and acquired ichthyosis as presenting features of multiple myeloma. AB - Black brown hyperpigmentation of the mucosae, sunexposed skin, palmar creases and frictional sites (Addisonian pigmentation) is characteristic of Addison disease. However, it can also occur as a paraneoplastic manifestation of tumours like bronchogenic carcinoma. Acquired ichthyosis starts later in life and can also be a paraneoplastic presentation. We report a unique combination of paraneoplastic Addisonian pigmentation and acquired ichthyosis as presenting features in a patient with undiagnosed multiple myeloma. To the best of our knowledge this combination of paraneoplastic dermatosis has not been documented before in multiple myeloma. It is concluded that the presence of more than one suspicious dermatosis may be an indicator of being paraneoplastic requiring necessary work up. PMID- 21276386 TI - Wilkie's syndrome. AB - Wilkie's syndrome is a rare variant of small intestinal obstruction resulting from compression of third part of the duodenum by the superior mesenteric artery. A girl 15 years of age, presented with postprandial abdominal pain, bilious vomiting and weight loss. Radiological imaging revealed vascular duodenal compression which was relieved by timely surgical intervention. PMID- 21276387 TI - Familial adenomatous polyposis. AB - Familial adenomatous polyposis represents approximately 1% of all colorectal tumours and is caused by germline mutations in the adenomatous polyposis coli (APC) gene. A 38-year-old lady presented with abdominal pain, diarrhoea and iron deficiency anemia. There was no history of colorectal cancer in the family. Colonoscopy showed hundreds of polyps throughout the colon sparing the rectum, and an ulcerative tumour of the sigmoid colon. The diagnosis was familial adenomatous polyposis (FAP) and adenocarcinoma of the sigmoid colon. Colectomy with ileorectal anastomosis was performed and later on she was given chemotherapy and advice life long surveillance. The patient had one brother and one sister, without clinical symptoms. The brother had a single hyperplastic rectal polyp, while the sister refused colonoscopy. The patient has 2 sons, the elder son had normal colonoscopic findings, and the younger son was also diagnosed as a patient of FAP and referred for colectomy. PMID- 21276388 TI - Multiple carpometacarpal volar dislocation. AB - A case of multiple carpometacarpal joints volar dislocation in a young man of 25 years of age is reported. He presented with pain and deformity of his left hand immediately after road traffic accident. He was unable to move his left hand. X rays of the affected hand showed volar dislocation of all four medial carpometacarpal joints. Dislocated joints were reduced, fixed with K-wires and immobilized in slab. K-wires were removed after 8 weeks. Hand function is satisfactory on the follow-up. PMID- 21276389 TI - Maxillofacial rehabilitation of a large cleft palate using fixed-removable prosthesis. AB - Maxillofacial defects either congenital or acquired, lead to a marked loss of both the functional efficiency and aesthetic profile of the affected individuals. Plastic surgery and tissue reconstruction is the treatment of choice. However, in certain clinical scenarios, removable and/or fixed obturator prosthesis can be the only option available. The management of these critical cases should be planned after a detailed investigation and diagnosis, evaluation of the subject's expectations and demands, socioeconomic status, available technical facilities and utilization of a multi-disciplinary team approach. This report discusses the intra oral rehabilitation of a complete, unilateral cleft palate along with dento alveolar rehabilitation. A fixed-removable prosthesis was provided to gain functional as well as aesthetic results without extensive surgical correction. PMID- 21276390 TI - Cervical lymph node metastases in squamous cell carcinoma of tongue and floor of mouth. AB - Oral squamous cell carcinoma has high chances of cervical lymph node metastasis. This case series describes the distribution of cervical lymph nodes in 50 cases of squamous cell carcinoma of tongue and floor of mouth. The mean age was 47.28+/ 10.5 years. Thirty positive metastatic lymph nodes were found; 90% occurring at level I-II mostly in T4 size but also in T1 and T2 cases. The distribution of involved lymph nodes in oral cancer affects the neck dissection extent and is, therefore, an important pre-operative feature. PMID- 21276391 TI - Immunoproliferative small intestinal disease (IPSID). AB - This study describes the frequency, demographics, clinical presentation, endoscopic findings, histopathological features, treatment and outcome of 'Immunoproliferative small intestinal disease' (IPSID). Archives contained a total of 27 cases of IPSID diagnosed and treated over an 18-year period. A M: F ratio of 2.4:1 was seen with a mean and median ages of 28.7 and 25 years. Most patients (68.8%) presented with abdominal pain and diarrhoea. In the majority (62.5%), duodenum was the primary site of involvement. Endoscopy showed polypoidal, raised or flat lesions. Biopsy findings included blunting or flattening of villi with dense plasma cell infiltrate and lymphoepithelial lesions. Twenty-four cases were categorized as stage A and B (benign and intermediate) and three were categorized as stage C (malignant, diffuse large B cell lymphoma with plasmacytoid features). Stage A and B patients responded well to antibiotic treatment (tetracycline) with regression of the lesions while for stage C patients standard CHOP chemotherapy was administered. PMID- 21276392 TI - A new working classification proposed for forensic odontology. PMID- 21276393 TI - Overuse of antibiotics in children for upper respiratory infections (URIs): a dilemma. PMID- 21276394 TI - [Optimization of colon cancer surgery]. PMID- 21276395 TI - [Molecular biological aspects of Marfan syndromes]. AB - Marfan syndrome (MFS) is a hereditary connective tissue disorder. Studies of MFS have established the critical contribution of fibrillin-1 deficiency to disease progression through altered cell-matrix interactions and dysregulated TGF-beta signalling. It is now known that the disease is caused by altered regulation of TGF-beta. As a result, the definition of MFS- and MFS-related diseases as the prototypical structural disorder of the connective tissue has changed to that of a developmental abnormality with broad and complex effects on the morphogenesis and tissue remodelling. PMID- 21276396 TI - [Clinical aspects of Marfan syndrome]. AB - Marfan syndrome (MFS) and MFS-related diseases are inherited connective tissue disorders involving several organ systems. The diagnosis of MFS is difficult as the many symptoms overlap with those of other systemic connective tissue diseases. The phenotype is progressive. Effective surgical therapy and standardized follow-up programs have led to an improved lifespan for the affected individuals. Selective angiotensin II, type 1 (AT1) blockers may improve several manifestations of MFS, but the outcome of clinical trials is presently unknown. This review describes the importance of a coordinated strategy for diagnosis, treatment and follow-up. PMID- 21276397 TI - [Excess mortality from cardiovascular disease in patients with rheumatoid arthritis]. AB - The cardiovascular morbidity and mortality are increased in rheumatoid arthritis and probably equal those of patients with type 2 diabetes mellitus. The European League Against Rheumatism has recently provided evidence-based guidelines for cardiovascular risk management in patients with rheumatoid arthritis and we here briefly summarise these guidelines and other recent data in this area of research. PMID- 21276398 TI - [Denosumab--a new efficient osteoporosis therapy]. AB - Denosumab is a new biological (monoclonal antibody) antiresorptive treatment of osteoporosis which is administrated as a subcutaneous 60 mg injection twice a year. Compared with placebo, three years of treatment increases bone mineral density by 6-9% and decreases the risk of vertebral and hip fractures by 68% and 40%, respectively, in postmenopausal women with osteoporosis. In men with iatrogenic hypogonadism due to prostate cancer, the risk of vertebral fractures is decreased by 62%. Side effects are few, but the treatment may increase risk of infections. PMID- 21276399 TI - [Regional anaesthesia may be used in selected acute compartment syndrome patients]. AB - Acute compartment syndrome (ACS) is a serious condition which, if not treated promptly, can cause severe disability or even death. Regional anaesthesia (epidural analgesia or peripheral nerve blocks) is increasingly used in postoperative pain management in orthopaedic surgery, but has been presumed to mask the symptoms of ACS. We present a short review of the current literature relating regional anaesthesia to a delayed diagnosis of ACS and find no convincing evidence that regional anaesthesia is unsafe in patients with a high risk of ACS. PMID- 21276400 TI - [Zygomycosis (mucormycosis) in patients with haematologic malignancy]. AB - Zygomycosis is an invasive and increasingly emerging life-threatening infection. Diabetes is the most common risk factor; however, zygomycosis has increased among patients with haematologic malignancy, which is now the second most common risk factor with an incidence of 16%. Rapid diagnosis and treatment are essential for patient survival. In the Danish literature, only a few cases have been reported. We present two cases of zygomycosis, both with a fatal outcome, and we discuss the pathogenesis and treatment of invasive zygomycosis. PMID- 21276401 TI - [Indication for iodine-123 in scintigraphy of the thyroid gland]. AB - Diagnostic work-up of a coincidental finding of a mediastinal tumour in asymptomatic patients should initially be done by non-invasive imaging modalities. We present a case in which traditional use of 99mTc pertechnetate scintigraphy was insufficient in a male with an enlarged thyroid gland. Application of iodine-123 can show diagnostic superiority owing to ideal tracer properties for scintigraphic imaging of the thyroid gland, such as pure gamma emission, organic binding and slow wash-out. The cons are a high radiation burden, price and lack of availability, as iodine-123 is a cyclotron product. PMID- 21276402 TI - [Peroneal nerve palsy in patient with Ehlers-Danlos syndrome]. AB - Ehlers-Danlos syndrome (EDS) is a hereditary generalized connective tissue disorder characterized by skin hyperextensibility, joint hypermobility and tissue fragility. Peripheral neuropathy is described sporadically. Although the exact mechanism of the neuropathy is not well-known, excessive stretch and abnormal connective tissue support are the suggested causative agents. To our knowledge, total peroneal nerve palsy occurring in conjunction with a growth spurt has not previously been described. We describe the case of a young male patient, who developed a total unilateral peroneal palsy during a growth spurt. PMID- 21276403 TI - [HELLP in the second trimester in a patient with antiphospholipid syndrome]. AB - The syndrome of haemolysis, elevated liver enzymes and low platelets (HELLP) is estimated to occur in 0.01-0.2% of pregnancies and is considered a severe form of preeclampsia. It is associated with considerable risk of maternal and foetal mortality. HELLP syndrome associated with antiphospholipid syndrome is known to occur early in the pregnancy. We report a case of severe HELLP syndrome complicated by multiple hepatic infarctions and portal vein thrombosis in the second trimester in a patient with antiphospholipid syndrome. PMID- 21276404 TI - [Pathognomonic presentation of Kingella kingae infection]. AB - Kingella kingae is an important and probably under-recognized pathogen in children. It has a predilection for bones, joints and vascular endothelium, but can also cause bacteraemia alone. We present a case of Kingella kingae that manifested itself by presternal soft tissue infection, and suggest that infection of the lower sternum and the junction between the manubrium and the xyphoid process are typical, if not pathognomonic for the organism. PMID- 21276405 TI - [Intraosseous cavernous haemangioma of the bony orbit]. AB - Primary orbital intraosseous haemangioma represents a rare, histopathologically benign, vascular tumour of the bony orbit. Only 46 cases have been documented to date. The most frequent presentation is a painless mass on the orbital rim. This condition often affects patients in their fourth and fifth decades of life. More women than men are affected. Histopathologically, the lesions are cavernous, capillary or mixed. The cavernous subtype is the most common one. Surgery can be complicated by life-threatening haemorrhage. The authors present a new case. PMID- 21276406 TI - The vitamin D receptor: a tumor suppressor in skin. AB - Epidemiologic evidence supporting a major chemopreventive role for vitamin D in various malignancies is strong. Likewise the use of the active metabolite of vitamin D, 1,25(OH)(2)D(3), and its analogs to prevent and/or treat a wide variety of malignancies in animals is well established. The evidence has been less compelling for epidermal carcinogenesis perhaps because the same agent that produces vitamin D in the skin, UVB radiation (UVR), is also the same agent that results in most epidermal malignancies. However, recent studies indicate that the role of vitamin D and its receptor (VDR) in protecting against the development of epidermal tumors deserves a closer look. One such study found mice lacking the VDR were quite sensitive to epidermal tumor formation following the administration of the carcinogen DMBA. A more recent study showed that these mice were similarly more sensitive to tumor formation following UVR, results we have confirmed. The epidermis of the VDR null mouse is hyperproliferative with gross distortion of hair follicles, structures that may provide the origin for the tumors found in the skin following such treatment. Two interacting pathways critical for epidermal and hair follicle function, beta-catenin and hedgehog (Hh), result in epidermal tumors when they are activated abnormally. Thus, we considered the possibility that loss of VDR predisposes to epidermal tumor formation by activation of either or both beta-catenin and Hh signaling. We determined that all elements of the Hh signaling pathway are upregulated in the epidermis and utricles of the VDR null mouse, and that 1,25(OH)(2)D(3) suppresses the expression of these elements in normal mouse skin. In addition we observed that the transcriptional activity of beta-catenin was increased in keratinocytes lacking the VDR. These results lead us to the hypothesis that the VDR with its ligand 1,25(OH)(2)D(3) functions as a tumor suppressor with respect to epidermal tumor formation in response to UVR by regulating Hh and beta-catenin signaling. PMID- 21276407 TI - Dynamic contrast-enhanced ultrasonography (DCE-US) and anti-angiogenic treatments. AB - Dynamic contrast-enhanced ultrasonography (DCE-US) is a current functional imaging technique enabling a quantitative assessment of tumor perfusion using raw linear data. DCE-US allows calculating several parameters as slope of wash-in or area under the curve representing, respectively, blood flow or blood volume. Decrease of vascularization can easily be detected in responders after 1 or 2 weeks of anti-angiogenic treatment for gastrointestinal stromal tumors (GIST), renal cell carcinoma (RCC), and hepatocellular carcinoma (HCC) and is correlated with progression-free survival and overall survival in RCC or HCC. DCE-US is supported by the French National Cancer Institute (INCa), which is currently studying the technique in metastatic breast cancer, melanoma, colon cancer, gastrointestinal stromal tumors and renal cell carcinoma, as well as in primary hepatocellular carcinoma, to establish the optimal perfusion parameters and timing for quantitative anticancer efficacy assessments. Currently 479 patients are included in 19 centers and the preliminary results on 400 patients with 1096 DCE-US demonstrated that the area under the curve (AUC) quantified at 1 month could be a robust parameter to predict response at 6 months. PMID- 21276408 TI - Regulatory T cells and the quest for transplant tolerance. AB - Many regulatory cell types exist in the immune system; they contribute to immune tolerance and immune homeostasis via different mechanisms. Therapeutic manipulation of such cell types for the induction of transplant tolerance has attracted tremendous attention. However, studies in this area have uncovered unexpected challenges, and translation of regulatory T cells toward clinical utilities is fraught with difficulties. In this review, we provide a broad overview on recent progresses in the study of regulatory T cells, highlighting the complexities of regulatory cell types and the unanticipated challenges. We also discuss the opportunities and emerging approaches in harnessing the potency of regulatory T cells in clinical transplantation. PMID- 21276409 TI - The genetics of asthma and allergic disorders. AB - Asthma and allergic diseases are complex conditions caused by a combination of genetic and environmental factors. More than 100 genes have been associated with asthma and related conditions through candidate gene approaches, but issues of insufficient replication have made conclusions difficult to draw. Despite this, several overarching themes in the biology and pathogenesis of asthma have been revealed as a result of this work. In mid-2007, the first genome wide association study (GWAS) targeting asthma was published, and in the intervening years more than a dozen such studies have been reported examining asthma, allergic diseases, and related intermediate phenotypes and quantitative traits. A few previously suspected genetic variants have been confirmed in these studies as asthma susceptibility loci, or as loci contributing to disease severity or response to treatment. Additionally, unexpected and largely uncharacterized genes have been identified as new susceptibility loci for asthma, altering lung function or perturbing immune function. In this review, we summarize these GWAS, as well as the functional themes and characteristics underlying asthma that have been revealed through decades of genetic and genomic research. PMID- 21276411 TI - Emerging techniques to treat limbal epithelial stem cell deficiency. AB - Visual performance, to a large extent, depends on the optical and refractive properties of the eye. The cornea is of great importance to this system. However, it requires a healthy epithelium for protection and optimal functioning. A sophisticated apparatus which relies on unipotent stem cells ensures the homeostasis of the corneal epithelium. A number of pathologic conditions can damage this mechanism, thereby compromising the ocular surface. This article will examine the concepts underlying a healthy or diseased corneal surface. Subsequently, current therapeutic approaches to regenerate a healthy epithelium and potential future developments will be discussed. PMID- 21276410 TI - Developing an effective gene therapy for prostate cancer: New technologies with potential to translate from the laboratory into the clinic. AB - Prostate cancer is the second leading cause of cancer-related deaths in men in the U.S. At present, no single or combination therapy has shown efficacy in decreasing disease progression in patients with metastatic disease. A potentially viable approach for treating late-stage prostate cancer is gene therapy. Adenoviruses (Ad) are the most commonly used mode of gene delivery, but progress using this vector has been hampered by concerns over the safety and practicality of viruses including conditionally replicating Ads (CRAds), particularly for intravenous delivery, and the inefficiency of non-viral transfection techniques. Major challenges for effective gene therapy using Ads are the limited infectivity of regular Ad serotype 5 (Ad5) and the inability to specifically deliver the therapeutic directly into diseased tissue without trapping in the liver or elimination by the immune system. The shortcoming in using Ad5 is mostly attributed to a reduction in Coxsackie-adenovirus receptors (CAR) on the surface of cancer cells, which can be mitigated by generating tropism-modified Ads permitting CAR-independent infection of tumor cells. The limitations of systemic gene delivery can now be overcome by using a novel targeted-delivery approach such as ultrasound (US) contrast agents (microbubbles) to deliver effective therapeutic reagents, Ads, or recombinant proteins, combined with ultrasound targeted microbubble destruction (UTMD), to develop a site-specific therapy in immune competent transgenic mouse models. These unique strategies for enhancing the efficacy of gene therapy provide a direct path to translation from the laboratory into the clinic for developing an effective gene therapy of prostate cancer. PMID- 21276412 TI - Replicative senescence in kidney aging, renal disease, and renal transplantation. AB - Cellular or replicative senescence is classically seen as the key element of aging. In renal disease and after kidney transplantation, there is increasing evidence that replicative senescence pathways (p53 and p16) play a central role in disease progression and graft outcome, independent of chronological age. In this review, we summarize the current concepts in the molecular mechanisms of cellular senescence, and correlate these theories with the available literature on aging of native kidneys, kidney diseases, and outcome of renal allografts. Recent data illustrate the complex biology of senescence in vivo, and disprove the concept that senescence is an intrinsic injury process with immanent deleterious consequences. Senescence acts as a homeostatic mechanism that can even limit renal fibrosis, at least in animal studies. In a human setting, it remains to be investigated whether cellular senescence plays an active or a bystander role in fibrogenesis and atrophy of renal tissue. PMID- 21276413 TI - Cytokine regulation of B-cell migratory behavior favors formation of germinal centers in autoimmune disease. AB - Chemotaxis is essential for shaping immune responses and chemokine-receptor antagonists are now being evaluated as therapies for various inflammatory and autoimmune diseases. However, the dysregulation of chemotaxis in autoimmune disease may involve both promotion and inhibition of B-cell migration. This review focuses on the disparate mechanisms by which two inflammatory cytokines that have been associated with autoimmune disease, namely interferon-alpha (IFN alpha) and interleukin-17 (IL-17), may regulate B-cell migratory responses. Chemotactic responses play a key role in orchestrating the cell-cell interactions in the germinal centers (GCs). This process involves active shuttling of the antigen-carrying B cells between the marginal zone and the GCs. We have shown that in autoimmune BXD2 mice, the migration of marginal zone precursor B cells is promoted by high levels of IFN-alpha produced by plasmacytoid dendritic cells in the marginal sinus that antagonize the activity of the S1P(1) chemokine receptor. In contrast, within the GCs, interleukin-17A (IL-17A) upregulates the expression of regulators of G protein signaling (RGS) in B cells to desensitize the G protein-coupled receptor (GPCR) signaling pathway of CXCL12 and CXCL13 chemokines. This promotes a prolonged stable interaction of B and T cells in the GC that induces high levels of activation-induced cytidine deaminase (AICDA) thereby enabling development of pathogenic autoantibody-producing B cells. PMID- 21276414 TI - El condor pasa: reflections on the condor trial. PMID- 21276415 TI - Hepatic steatosis in HIV/HCV-coinfected patients: time to reevaluate! PMID- 21276417 TI - Improved detection of botulinum neurotoxin type A in stool by mass spectrometry. AB - Botulinum neurotoxins (BoNTs) are the most toxic substances known to humankind. Rapid and sensitive detection of BoNTs is necessary for timely clinical confirmation of the disease state in botulism. BoNTs cleave proteins and peptide mimics at specific sites. A mass spectrometry (MS)-based method, Endopep-MS, can detect these cleavages and has detection limits of 0.05-0.5 mouse LD(50) (U) in serum, depending on the BoNT serotypes. In this method, the products generated from cleavage of peptide substrates using antibody affinity-purified toxins are detected by MS. Nonspecific bound endogenous proteases or peptidases in stool can coextract with the toxin, cleaving the peptide substrates and reducing the sensitivity of the method. Here we report a method to reduce nonspecific substrate cleavage by reducing stool protease coextraction in the Endopep-MS assay. PMID- 21276418 TI - Aquaporin-3 in keratinocytes and skin: its role and interaction with phospholipase D2. AB - Aquaporin 3 (AQP3) is an aquaglyceroporin that transports water and glycerol and is expressed in the epidermis, among other epithelial tissues. We have recently shown that there is an association between this glycerol channel and phospholipase D2 (PLD2) in caveolin-rich membrane microdomains. While PLD2 is able to hydrolyze membrane phospholipids to generate phosphatidic acid, this enzyme also catalyzes, in the presence of primary alcohols, a transphosphatidylation reaction to produce a phosphatidylalcohol. We have proposed that AQP3 associated with PLD2 provides the physiological primary alcohol glycerol to PLD2 for use in the transphosphatidylation reaction to generate phosphatidylglycerol (PG). Further, we have proposed that PG functions as a signaling molecule to mediate early epidermal keratinocyte differentiation, and manipulation of this signaling module inhibits keratinocyte proliferation and enhances differentiation. In contrast, other investigators have suggested a proliferative role for AQP3 in keratinocytes. In addition, AQP3 knockout mice exhibit an epidermal phenotype, characterized by dry skin, decreased elasticity and delayed barrier repair and wound healing, which can be corrected by glycerol but not other humectants. AQP3 levels have also been found to be altered in human skin diseases. In this article the evidence supporting a role for AQP3 in the epidermis will be discussed. PMID- 21276419 TI - First solid-state NMR analysis of uniformly 13C-enriched major light-harvesting complexes from Chlamydomonas reinhardtii and identification of protein and cofactor spin clusters. AB - The light-harvesting complex II (LHCII) is the main component of the antenna system of plants and green algae and plays a major role in the capture of sun light for photosynthesis. The LHCII complexes have also been proposed to play a key role in the optimization of photosynthetic efficiency through the process of state 1-state 2 transitions and are involved in down-regulation of photosynthesis under excess light by energy dissipation through non-photochemical quenching (NPQ). We present here the first solid-state magic-angle spinning (MAS) NMR data of the major light-harvesting complex (LHCII) of Chlamydomonas reinhardtii, a eukaryotic green alga. We are able to identify nuclear spin clusters of the protein and of its associated chlorophyll pigments in 13C-13C dipolar homonuclear correlation spectra on a uniformly 13C-labeled sample. In particular, we were able to resolve several chlorophyll 131 carbon resonances that are sensitive to hydrogen bonding to the 131-keto carbonyl group. The data show that 13C NMR signals of the pigments and protein sites are well resolved, thus paving the way to study possible structural reorganization processes involved in light harvesting regulation through MAS solid-state NMR. PMID- 21276420 TI - Smad3 contributes to positioning of proliferating cells in colonic crypts by inducing EphB receptor protein expression. AB - Deficiency of Smad3, an intracellular mediator of TGF-beta, was shown to significantly accelerate re-epithelialization of the colonic mucosa. This study was performed to investigate the molecular mechanisms by which Smad3 controls colonic epithelial cell proliferation and crypt formation. Smad3(ex8/ex8) C57BL/6 mice were used in this study and wild-type littermates served as controls. The number of proliferating cells in the isolated colonic epithelium of Smad3(-/-) mice was significantly increased compared to that in wild-type littermates. Protein levels of the cell cycle inhibitors p21 and p27 were significantly decreased, while that of c-Myc was increased in the isolated colonic epithelium from Smad3(-/-) mice. In the colonic tissue of wild-type mice, cell proliferation was restricted to the bottom of the crypts in accordance with nuclear beta catenin staining, whereas proliferating cells were located throughout the crypts in Smad3(-/-) mice in accordance with nuclear beta-catenin staining, suggesting that Smad3 is essential for locating proliferating cells at the bottom of the colonic crypts. Notably, in Smad3(-/-) mice, there was loss of EphB2 and EphB3 receptor protein expression, critical regulators of proliferating cell positioning, while EphB receptor protein expression was confirmed at the bottom of the colonic crypts in wild-type mice. These observations indicated that disturbance of the EphB/ephrin B system brings about mispositioning of proliferating cells in the colonic crypts of Smad3(-/-) mice. In conclusion, Smad3 is essential for controlling number and positioning of proliferating cells in the colonic crypts and contributes to formation of a "proliferative zone" at the bottom of colonic crypts in the normal colon. PMID- 21276421 TI - 7-Chloro-6-piperidin-1-yl-quinoline-5,8-dione (PT-262), a novel ROCK inhibitor blocks cytoskeleton function and cell migration. AB - The 5,8-quinolinediones are precursors for producing multiple types of bioactive products. In this study, we investigated a new compound derived from 5,8 quinolinediones, 7-chloro-6-piperidin-1-yl-quinoline-5,8-dione (designated as PT 262), which markedly induced cytoskeleton remodeling and migration inhibition in lung carcinoma cells. Comparison with various cytoskeleton inhibitors, including paclitaxel, colchicine and phallacidin, the cell morphology following treatment with PT-262 was similar to phallacidin on the cell elongation and abnormal actin polymerization. However, PT-262 did not directly bind to actin filaments. ROCK (Rho-associated coiled-coil forming protein kinase) is a downstream effector of RhoA to mediate the phosphorylation of myosin light chain (MLC) and cytoskeleton reorganization. The RhoA-ROCK-MLC pathway has been shown to promote cancer cell migration and metastasis. Interestingly, PT-262 was more effective on inhibiting ROCK kinase activities than specific ROCK inhibitors Y-27632 and H-1152. PT-262 induced cytoskeleton remodeling and migration inhibition in A549 lung carcinoma cells. The total MLC and phosphorylated MLC proteins and stress fibers were blocked after treatment with PT-262. Nonetheless, the RhoA protein and GTPase activity were not altered by PT-262. A computational model suggests that PT-262 interacts with the ATP-binding site of ROCK protein. Together, these findings demonstrate that PT-262 is a new ROCK inhibitor. PMID- 21276422 TI - The NADPH oxidase inhibitor VAS2870 impairs cell growth and enhances TGF-beta induced apoptosis of liver tumor cells. AB - Liver tumor cells show several molecular alterations which favor pro-survival signaling. Among those, we have proposed the NADPH oxidase NOX1 as a prosurvival signal for liver tumor cells. On the one side, we have described that FaO rat hepatoma cells show NOX1-dependent partial resistance to apoptosis induced by Transforming Growth Factor beta (TGF-beta). On the other side, we have shown that FaO cells, as well as different human hepatocellular carcinoma (HCC) cell lines, are able to proliferate in the absence of serum through the activation of a NOX1 dependent signaling pathway. The aim of this work was to analyze the effects of NADPH oxidase pharmacological inhibition in liver tumor cells using the inhibitor VAS2870. This compound inhibits dose-dependently autocrine increase of cell number in FaO rat hepatoma cells, and almost completely blocked ROS production and thymidine incorporation when used at 25MUM. Such inhibitory effect on autocrine growth is coincident with lower mRNA levels of EGFR (Epidermal Growth Factor Receptor) and its ligand TGF-alpha (Transforming Growth Factor-alpha), and decreased phosphorylation of the EGFR itself and other downstream targets, such as SRC or AKT. Moreover, NADPH oxidase pharmacological inhibition also effectively attenuates serum-dependent growth and phosphorylation of AKT and ERK. Importantly, these inhibitory effects on either autocrine or serum-dependent cell growth are observed in several human HCC cell lines. Finally, we have observed that VAS2870 is also effective in enhancing apoptosis induced by a physiological stimulus, such as TGF-beta. In summary, NADPH oxidase pharmacological inhibition could be considered a promising tool in the treatment of liver cancer. PMID- 21276423 TI - Arf nucleotide binding site opener [ARNO] promotes sequential activation of Arf6, Cdc42 and Rac1 and insulin secretion in INS 832/13 beta-cells and rat islets. AB - Glucose-stimulated insulin secretion [GSIS] involves interplay between small G proteins and their regulatory factors. Herein, we tested the hypothesis that Arf nucleotide binding site opener [ARNO], a guanine nucleotide-exchange factor [GEF] for the small G-protein Arf6, mediates the functional activation of Arf6, and that ARNO/Arf6 signaling axis, in turn, controls the activation of Cdc42 and Rac1, which have been implicated in GSIS. Molecular biological [i.e., expression of inactive mutants or siRNA] and pharmacological approaches were employed to assess the roles for ARNO/Arf6 signaling pathway in insulin secretion in normal rat islets and INS 832/13 cells. Degrees of activation of Arf6 and Cdc42/Rac1 were quantitated by GST-GGA3 and PAK-1 kinase pull-down assays, respectively. ARNO is expressed in INS 832/13 cells, rat islets and human islets. Expression of inactive mutants of Arf6 [Arf6-T27N] or ARNO [ARNO-E156K] or siRNA-ARNO markedly reduced GSIS in isolated beta-cells. SecinH3, a selective inhibitor of ARNO/Arf6 signaling axis, also inhibited GSIS in INS 832/13 cells and rat islets. Stimulatory concentrations of glucose promoted Arf6 activation, which was inhibited by secinH3 or siRNA-ARNO, suggesting that ARNO/Arf6 signaling cascade is necessary for GSIS. SecinH3 or siRNA-ARNO also inhibited glucose-induced activation of Cdc42 and Rac1 suggesting that ARNO/Arf6 might be upstream to Cdc42 and Rac1 activation steps, which are necessary for GSIS. Lastly, co immunoprecipitation and confocal microscopic studies suggested increased association between Arf6 and ARNO in glucose-stimulated beta-cells. These findings provide the first evidence to implicate ARNO in the sequential activation of Arf6, Cdc42 and Rac1 culminating in GSIS. PMID- 21276424 TI - Protection against ischemic stroke damage by synergistic treatment with amlodipine plus atorvastatin in Zucker metabolic rat. AB - Ischemic stroke is a major neurologic disorder and a leading cause of disability and death in the world. We compared neuroprotective effects of single or combination therapy of amlodipine (AM) and atorvastatin (AT) in such a metabolic syndrome model Zucker rat. The animals were pretreated with vehicle, AM, AT, or the combination of AM plus AT for 28days, and physical and serum parameters were analyzed, then 90min of transient middle cerebral artery occlusion (tMCAO), was performed followed by immunohistochemical analyses at 24h. Without affecting serum levels of lipids, adiponectin, and leptin, the combination therapy of AM plus AT ameliorated the post-ischemic brain weight increase. The single treatment with AM or AT itself exerted neuroprotective effects with reducing inductions of MMP-9 and AT2R, as well as with preserving collagen IV, and the combination therapy of AM plus AT showed a further synergistic benefit against acute ischemic neural damages. Single AT was more protective on these 3 molecules than single AM at this time point of 24h after tMCAO. Thus, the combination therapy with AM plus AT extended the neuroprotectives effect of single treatment with AM or AT on a part of neurovascular unit and a hypertension-related receptor. PMID- 21276425 TI - The trunk as a part of the kinematic chain for reaching movements in healthy subjects and hemiparetic patients. AB - The aims of this study were first to further assess the role of the 3D trunk angular rotations as part of the kinematic chain for seated-reaching movements within arm's length in a large 3D workspace in healthy subjects and second, to assess if these degrees of freedom participate in the compensatory strategy in hemiparetic patients. Ten healthy subjects, eight patients with right, and eight patients with left hemiparesis following stroke were included. They performed seated reaching movements at a comfortable speed to nine targets positioned in a large 3D workspace within arm's length. An electromagnetic system was used to record kinematics of the trunk and hand. Trunk flexion, lateral flexion and torsion were analyzed as a function of target direction, distance and height. In both healthy subjects and patients, all three trunk rotations participated in the reaching movement (except for near targets in healthy subjects). Trunk flexion was greater in patients but followed a similar pattern to healthy subjects. Trunk torsion was more influenced by target distance in healthy subjects while in patients it was greatly influenced by direction. Trunk lateral flexion was similar between groups. Comparing the two patient groups, there was greater flexion to the external targets in the RHD group and different strategies in the use of torsion between groups. 3D trunk rotations thus seem to be tuned to the distance and direction of the target in the workspace in both healthy subjects and stroke patients for reaching movements within arm's length. PMID- 21276426 TI - Ginsenoside Rb1 improves spatial learning and memory by regulation of cell genesis in the hippocampal subregions of rats. AB - Ginsenoside Rb1 (Rb1) is known to improve learning and memory in hippocampus dependent tasks. However, the cellular mechanism remains unknown. Cell genesis in hippocampus is involved in spatial learning and memory. In the present study, Rb1 was orally administrated to adult rats for 30days. The behavioral training tests indicated that Rb1 improved spatial cognitive performance of rats in Morris water maze (MWM). Furthermore, we investigated the effects of Rb1 on cell genesis in adult rats' hippocampus, using thymidine analog bromodeoxyuridine (BrdU) as a marker for dividing cells. It has been shown that hippocampal cell genesis can be influenced by several factors such as learning and exercise. In order to avoid the effects of the interfering factors, only the rats treated with Rb1 without training in MWM were used to investigate cell genesis in hippocampus. When BrdU was given to the rats 30days prior to being killed, it was shown that oral administration of Rb1 significantly increased cell survival in dentate gyrus and hippocampal subregion CA3. However, when BrdU was injected 2h prior to sacrifice, the results indicated that Rb1 had no significant influence on cell proliferation in the hippocampal subregions. Thus, an increase of cell survival in hippocampus stimulated by Rb1 may be one of the mechanisms by which ginseng facilitates spatial learning and memory. Our study also indicates that Rb1 may be developed as a therapeutic agent for patients with memory impairment. PMID- 21276427 TI - Feasibility study for functional test battery of SOD transgenic rat (H46R) and evaluation of edaravone, a free radical scavenger. AB - We evaluated a battery of functional tests for investigating the effects of edaravone, a free radical scavenger, in SOD1 transgenic (H46R) rat model of amyotrophic lateral sclerosis. Edaravone (1.5 or 3.0mg/kg/h) or saline was administered intravenously to rats by continuous infusion (1h per day) for 2days, followed by a 2-day holiday. Lifetime and duration of illness were evaluated, and motor function was assessed using the hind-foot reflex test, landing foot-splay test, rota rod test and inclined plate test at a predetermined time point at which half of the control animals had died. Statistical comparison of motor functions of edaravone-treated and control SOD1 transgenic rats at an objectively determined time point was confirmed to be feasible. Edaravone-treated male rats showed significantly better performance in the landing foot-splay test. The present model seems suitable for evaluating motor function of H46R SOD1 transgenic rats, and be useful for examining the therapeutic potential of edaravone to treat amyotrophic lateral sclerosis. PMID- 21276428 TI - Decreased reuptake of dopamine in the dorsal striatum in the absence of alpha synuclein. AB - The presynaptic protein alpha-synuclein (alpha-syn) plays a role in dopaminergic neurotransmission in the nigrostriatal dopaminergic system. Mutations in this protein have been linked to pathogenesis of Parkinson's disease. However, the details of regulation of dopamine homeostasis by alpha-syn and its molecular targets are generally unknown. We investigated the effect of alpha-syn deletion on striatal dopaminergic homeostasis. Two alpha-syn deficient mouse lines, one carrying a spontaneous deletion of alpha-syn locus and the other a transgenic alpha-syn knockout, were used in the study. Stimulated and basal extracellular dopamine levels were determined in the dorsal striatum by in vivo voltammetry and in vivo microdialysis, respectively. Dopamine transporter expression was studied by immunohistochemistry. Stimulated dopamine overflow and basal extracellular dopamine levels were higher in mice lacking alpha-syn with a concomitant decrease in dopamine transporter expression and reuptake in the dorsal striatum. We show that alpha-syn deletion produces significant adaptive changes in the striatal dopaminergic system via modulation of reuptake. PMID- 21276429 TI - Treadmill training improves motor skills and increases tyrosine hydroxylase immunoreactivity in the substantia nigra pars compacta in diabetic rats. AB - The aim of this study was to evaluate the effects of treadmill training on motor skills and immunoreactivity to tyrosine hydroxylase in the substantia nigra pars compacta and ventral tegmental area from diabetic rats induced by streptozotocin. Male Wistar rats were divided into three groups: control, diabetic and trained diabetic. Treadmill training was performed for 8weeks. Blood glucose concentrations and body weight were evaluated 48h after diabetes induction and every 30days thereafter. Motor skills were evaluated on the rotarod and open field tests. Then, animals were transcardially perfused and the brains were post fixed, cryoprotected and sectioned in a cryostat. Immunohistochemistry for tyrosine hydroxylase analyses was done in the ventral tegmental area and in the substantia nigra. Motor skills showed that diabetic animals had a decrease in the latency to fall and enhanced number of falls in the rotarod test compared to control and trained diabetic animals. In the open field, diabetic animals had a decrease in the number of crossed squares, rearings and spent a less time moving compared to control and trained diabetic animals. In diabetic animals, optical densitometry of immunohistochemistry showed that tyrosine hydroxylase reaction decreased in the ventral tegmental area and in the neurons and process in the substantia nigra. In the later region, that decrease was reversed by treadmill training. In conclusion, we demonstrated that treadmill training can reverse the loss of the motor skills, which was correlated to tyrosine hydroxylase immunoreactivity in the substantia nigra of diabetic animals without pharmacological treatment. PMID- 21276430 TI - Brain penetrating IgG-erythropoietin fusion protein is neuroprotective following intravenous treatment in Parkinson's disease in the mouse. AB - Parkinson's disease (PD) is caused by oxidative stress, and erythropoietin (EPO) reduces oxidative stress in the brain. However, EPO cannot be developed as a treatment for PD, because EPO does not cross the blood-brain barrier (BBB). A brain penetrating form of human EPO has been developed wherein EPO is fused to a chimeric monoclonal antibody (MAb) against the mouse transferrin receptor (TfR), which is designated as the cTfRMAb-EPO fusion protein. The TfRMAb acts as a molecular Trojan horse to transport the fused EPO into brain via transport on the BBB TfR. Experimental PD was induced in adult mice by the intra-striatal injection of 6-hydroxydopamine, and PD mice were treated with 1mg/kg of the cTfRMAb-EPO fusion protein intravenously (IV) every other day starting 1 h after toxin injection. Following 3weeks of treatment mice were euthanized for measurement of striatal tyrosine hydroxylase (TH) enzyme activity. Mice treated with the cTfRMAb-EPO fusion protein showed a 306% increase in striatal TH enzyme activity, which correlated with improvement in three assays of neurobehavior. The blood hematocrit increased 10% at 2weeks, with no further changes at 3weeks of treatment. A sandwich ELISA showed the immune reaction against the cTfRMAb-EPO fusion protein was variable and low titer. In conclusion, the present study demonstrates that a brain penetrating form of EPO is neuroprotective in PD following IV administration with minimal effects on erythropoiesis. PMID- 21276431 TI - A pronociceptive role for the 5-HT2 receptor on spinal nociceptive transmission: an in vivo electrophysiological study in the rat. AB - Serotonin (5-HT) plays a major yet complex role in modulating spinal nociceptive transmission as a consequence of the number of 5-HT receptor subtypes. These include the 5-HT2 receptor, which is further sub classified into 5-HT2A, B and C. Studies have described both a pro- and antinociceptive action following 5-HT2A receptor activation; therefore, to shed light on the directional nature of spinal 5-HT2A receptor activity, we investigated the effects of spinal administration of the 5-HT2A receptor antagonist, ketanserin, on the evoked responses of dorsal horn neurones to electrical, mechanical and thermal stimulation. We also assessed the effects of systemic administration of ritanserin, a 5-HT2A/2C receptor antagonist and spinal application of (+/-)-2,5-Dimethoxy-4-iodoamphetamine hydrochloride (DOI) (3.6 and 17.8MUg/50MUl), a 5-HT2A/2C agonist, on the same evoked neuronal responses. Ketanserin (1, 10 and 100MUg/50MUl) produced a dose related inhibition of the evoked responses to noxious mechanical punctate and thermal stimuli only. Ritanserin (2mg/kg) replicated the inhibitory effects seen with ketanserin on the natural evoked neuronal responses and also potently inhibited the C-fibre, post discharge, input and wind-up evoked responses. DOI increased the mechanical and thermal evoked responses, an effect reversed by ketanserin. Thus, our findings show that spinal ketanserin (1-100MUg/50MUl) and systemic ritanserin (2mg/kg), at these doses, have similar antinociceptive effects, whereas the agonist, DOI, produced excitatory effects, on spinal neuronal activity. Our data, therefore, supports a pronociceptive role for 5-HT2 receptors, most likely through modulation of 5-HT2A receptor activity, on spinal nociceptive transmission under normal conditions. PMID- 21276432 TI - fMRI correlates of working memory: specific posterior representation sites for motion and position information. AB - We assume that working memory is provided by a network comprising domain-general anterior and different domain-specific posterior brain areas depending on the type of stimulus and the task demands. Based on imaging studies from perception, we hypothesized that dynamic spatial (motion) and static spatial (position) information can be dissociated during retention in working memory. Participants were presented with a moving dot. About one second after stimulus presentation, a cue indicated whether its motion or end position should be held in memory. Six seconds later, a second stimulus was shown which was to be compared with the first one with respect to identity on the cued dimension. In the baseline condition, the cue indicated that no memory task would follow. We contrasted activity during maintenance of the different features. Differential activations in regions related to motion perception (area hMT/V5+, superior temporal sulcus) were observed in the motion working memory task. For position working memory, enhanced activations in a right brain region at the temporo-parieto-occipital junction emerged. The results are discussed with respect to domain-specific regions active in perception and how they can be also involved in short term retention for those very features. It is suggested that two types of spatial information categories can be dissociated: dynamic spatial (motion) and static spatial (position) information seem to be processed by different working memory structures. PMID- 21276433 TI - Impairment of synaptic plasticity in hippocampus is exacerbated by methylprednisolone in a rat model of traumatic brain injury. AB - Patients with traumatic brain injury (TBI) exhibit impaired cognitive capability that is exacerbated with methylprednisolone (MP). Since long-term potentiation (LTP) is a leading cellular model underlying learning, we hypothesize that MP disturbs the electrophysiological character in the hippocampus by decreasing the number of interneurons post-traumatically in the dentate gyrus (DG) and cornu ammonis3 (CA3) regions, resulting in learning deficits. To test this hypothesis, we investigated the alterations of learning abilities and correlated the alternation with hippocampal synaptic plasticity in rats receiving lateral fluid percussion injury (FPI) and being treated with MP. We found that MP aggravates the spatial learning deficiency and changes in the excitability of the DG and cornu ammonis1 (CA1) areas in rats subjected to FPI. The functional and electrophysiological deficits are associated with a decrease in the number of parvalbumin-immunoreactive (PV-IR) and cholecystokinin-immunoreactive (CCK-IR) GABAergic cells. The data suggest that MP therapy may decrease the number of DG interneurons in post-traumatic hippocampus, resulting in the aggravated deficits of learning ability induced by TBI. PMID- 21276434 TI - Tumor necrosis factor-alpha (TNF-alpha) augments AMPA-induced Purkinje neuron toxicity. AB - It is well recognized that exposure of neurons to excessive levels of the excitatory neurotransmitter glutamate, termed glutamate excitotoxicity, contributes to the damage and degeneration seen in many acute and chronic neurological diseases. However, it is becoming increasingly evident that inflammation also can play a role in certain neurodegenerative diseases and inflammatory mediators, such as tumor necrosis factor-alpha (TNF-alpha), may directly interact with excitotoxic processes. In a postnatal rat cerebellar slice model, we found that TNF-alpha exacerbated AMPA-induced excitotoxicity in Purkinje neurons in a dose-dependent manner beyond the toxicity caused by AMPA alone. It also was shown that combinations of TNF-alpha and AMPA increased the mean intracellular activity of calpains, calcium-activated cysteine proteases that are known to contribute to cell death in Purkinje neurons. Additionally, these combinations augmented colbalt influx, a marker for calcium entry that selectively occurs through calcium permeable AMPA receptors only. Pharmacologic blockade of calcium permeable AMPA receptors with a specific antagonist, 1 naphthyl acetyl spermine (NASPM), reversed the apparent increase in AMPA receptor calcium permeability caused by TNF-alpha as measured by cobalt influx; caused a reduction in the Purkinje neuron calpain activity; and reversed the enhanced neurodegeneration induced by the combination of TNF-alpha and AMPA. From these studies we concluded that TNF-alpha augmented AMPA-induced toxicity in Purkinje neurons by increasing intracellular calcium flux through calcium permeable AMPA receptors, and this increase in calcium was directly involved in enhanced activation of calpains and a greater percentage of Purkinje neuron loss. PMID- 21276435 TI - The role of aldehyde reductase AKR1A1 in the metabolism of gamma-hydroxybutyrate in 1321N1 human astrocytoma cells. AB - The role of the aldehyde reductase AKR1A1 in the biosynthesis of gamma hydroxybutyrate (GHB) has been investigated in cell lines using a specific double stranded siRNA designed to knock down expression of the enzyme. This enzyme, along with the aldo-keto reductase AKR7A2, has been proposed previously to be one of the major succinic semialdehyde reductases in brain. The AKR1A1 siRNA was introduced into the human astrocytoma cell line (1321N1) and AKR1A1 expression was monitored using quantitative reverse-transcriptase PCR and Western blots. Results show an 88% reduction in mRNA levels and a 94% reduction in AKR1A1 protein expression 72 h after transfection with the siRNA. Aldehyde reductase activity was examined in silenced cells by following the aldehyde-dependent conversion of NADPH to NADP at 340 nm. This revealed a 30% decrease in pNBA reductase activity in cell extracts after AKR1A1 silencing. Succinic semialdehyde reductase activity was significantly lower in silenced cells when measured using high concentrations (1mM) of succinic semialdehyde, but not with low concentrations (10 MUM). The effect of silencing on intracellular and extracellular GHB levels was measured using gas chromatography-mass spectrometry. Results show that AKR1A1 has little effect on the production of GHB, indicating that in this cell line alternative enzymes such as the AKR7A2 are likely to play a more significant role in GHB biosynthesis. PMID- 21276436 TI - Metabolic mechanisms of methanol/formaldehyde in isolated rat hepatocytes: carbonyl-metabolizing enzymes versus oxidative stress. AB - Methanol (CH(3)OH), a common industrial solvent, is metabolized to toxic compounds by several enzymatic as well as free radical pathways. Identifying which process best enhances or prevents CH(3)OH-induced cytotoxicity could provide insight into the molecular basis for acute CH(3)OH-induced hepatoxicity. Metabolic pathways studied include those found in 1) an isolated hepatocyte system and 2) cell-free systems. Accelerated Cytotoxicity Mechanism Screening (ACMS) techniques demonstrated that CH(3)OH had little toxicity towards rat hepatocytes in 95% O(2), even at 2M concentration, whereas 50 mM was the estimated LC(50) (2h) in 1% O(2), estimated to be the physiological concentration in the centrilobular region of the liver and also the target region for ethanol toxicity. Cytotoxicity was attributed to increased NADH levels caused by CH(3)OH metabolism, catalyzed by ADH1, resulting in reductive stress, which reduced and released ferrous iron from Ferritin causing oxygen activation. A similar cytotoxic mechanism at 1% O(2) was previous found for ethanol. With 95% O(2), the addition of Fe(II)/H(2)O(2), at non-toxic concentrations were the most effective agents for increasing hepatocyte toxicity induced by 1M CH(3)OH, with a 3-fold increase in cytotoxicity and ROS formation. Iron chelators, desferoxamine, and NADH oxidizers and ATP generators, e.g. fructose, also protected hepatocytes and decreased ROS formation and cytotoxicity. Hepatocyte protein carbonylation induced by formaldehyde (HCHO) formation was also increased about 4-fold, when CH(3)OH was oxidized by the Fenton-like system, Fe(II)/H(2)O(2), and correlated with increased cytotoxicity. In a cell-free bovine serum albumin system, Fe(II)/H(2)O(2) also increased CH(3)OH oxidation as well as HCHO protein carbonylation. Nontoxic ferrous iron and a H(2)O(2) generating system increased HCHO-induced cytotoxicity and hepatocyte protein carbonylation. In addition, HCHO cytotoxicity was markedly increased by ADH1 and ALDH2 inhibitors or GSH-depleted hepatocytes. Increased HCHO concentration levels correlated with increased HCHO induced protein carbonylation in hepatocytes. These results suggest that CH(3)OH at 1% O(2) involves activation of the Fenton system to form HCHO. However, at higher O(2) levels, radicals generated through Fe(II)/H(2)O(2) can oxidize CH(3)OH/HCHO to form pro-oxidant radicals and lead to increased oxidative stress through protein carbonylation and ROS formation which ultimately causes cell death. PMID- 21276437 TI - Increased levels of 4HNE-protein plasma adducts in Rett syndrome. AB - OBJECTIVE: Rett syndrome (RTT) is a neurological disorder and a leading cause of mental retardation in females. It is caused by mutations in methyl-CpG-binding protein 2 (MeCP2) gene and more rarely in cyclin-dependent kinase-like 5 (CDKL5) and forkhead box protein G1 (FOXG1) genes. Increased oxidative stress (OS) has been documented in MeCP2-RTT patients. Here, we evaluated the levels of 4 hydroxynonenal plasma protein adducts (4HNE-PAs) in MeCP2-, CDKL5-, and FOXG1-RTT and in their clinical variants. DESIGN AND METHODS: 4HNE-PAs were determined by Western blot in plasma from healthy subjects and RTT patients. RESULTS: 4HNE-PAs levels were increased in MeCP2- and CDKL5-related RTT but not in FOXG1-related RTT. CONCLUSION: These results showed that OS is present in RTT clinical variants and could play a key role in RTT pathogenesis. Under the OS point of view FOXG1 related RTT appears to be distinct from the MeCP2/CDKL5, suggesting a distinct mechanism involved in its pathogenesis. PMID- 21276438 TI - Addition of oligosaccharide decreases the freezing lesions on human red blood cell membrane in the presence of dextran and glucose. AB - Although incubation with glucose before freezing can increase the recovery of human red blood cells frozen with polymer, this method can also result in membrane lesions. This study will evaluate whether addition of oligosaccharide (trehalose, sucrose, maltose, or raffinose) can improve the quality of red blood cell membrane after freezing in the presence of glucose and dextran. Following incubation with glucose or the combinations of glucose and oligosaccharides for 3h in a 37 degrees C water bath, red blood cells were frozen in liquid nitrogen for 24h using 40% dextran (W/V) as the extracellular protective solution. The postthaw quality was assessed by percent hemolysis, osmotic fragility, mean corpuscle volume (MCV), distribution of phosphatidylserine, the postthaw 4 degrees C stability, and the integrity of membrane. The results indicated the loading efficiency of glucose or oligosaccharide was dependent on their concentrations. Moreover, addition of trehalose or sucrose could efficiently decrease osmotic fragility of red blood cells caused by incubation with glucose before freezing. The percentage of damaged cell following incubation with glucose was 38.04+/-21.68% and significantly more than that of the unfrozen cells (0.95+/ 0.28%, P<0.01). However, with the increase of the concentrations of trehalose, the percentages of damaged cells were decreased steadily. When the concentration of trehalose was 400mM, the percentage of damaged cells was 1.97+/-0.73% and similar to that of the unfrozen cells (P>0.05). Moreover, similar to trehalose, raffinose can also efficiently prevent the osmotic injury caused by incubation with glucose. The microscopy results also indicated addition of trehalose could efficiently decrease the formation of ghosts caused by incubation with glucose. In addition, the gradient hemolysis study showed addition of oligosaccharide could significantly decrease the osmotic fragility of red blood cells caused by incubation with glucose. After freezing and thawing, when both glucose and trehalose, sucrose, or maltose were on the both sides of membrane, with increase of the concentrations of sugar, the percent hemolysis of frozen red blood cells was firstly decreased and then increased. When the total concentration of sugars was 400mM, the percent hemolysis was significantly less than that of cells frozen in the presence of dextran and in the absence of glucose and various oligosaccharides (P<0.01). However, when both glucose and trehalose were only on the outer side of membrane, with increase of the concentrations of sugars, the percent hemolysis was increased steadily. Furthermore, addition of oligosaccharides can efficiently decrease the osmotic fragility and exposure of phosphatidylserine of red blood cells frozen with glucose and dextran. In addition, trehalose or raffinose can also efficiently mitigate the malignant effect of glucose on the postthaw 4 degrees C stability of red blood cells frozen in the presence of dextran. Finally, addition of trehalose can efficiently protect the integrity of red blood cell membrane following freezing with dextran and glucose. In conclusion, addition of oligosaccharide can efficiently reduce lesions of freezing on red blood cell membrane in the presence of glucose and dextran. PMID- 21276439 TI - S-adenosylmethionine prevents the up regulation of Toll-like receptor (TLR) signaling caused by chronic ethanol feeding in rats. AB - Toll-like receptors (TLR) play a role in mediating the proinflammatory response, fibrogenesis and carcinogenesis in chronic liver diseases such as alcoholic liver disease, non-alcoholic liver disease, hepatitis C and hepatocellular carcinoma. This is true in experimental models of these diseases. For this reason, we investigated the TLR proinflammatory response in the chronic intragastric tube feeding rat model of alcohol liver disease. The methyl donor S-adenosylmethionine was also fed to prevent the gene expression changes induced by ethanol. Ethanol feeding tended to increase the up regulation of the gene expression of TLR2 and TLR4. SAMe feeding prevented this. TLR4 and MyD88 protein levels were significantly increased by ethanol and this was prevented by SAMe. This is the first report where ethanol feeding induced TLR2 and SAMe prevented the induction by ethanol. CD34, FOS, interferon responsive factor 1 (IRF-1), Jun, TLR 1,2,3,4,6 and 7 and Traf-6 were found to be up regulated as seen by microarray analysis where rats were sacrificed at high blood alcohol levels compared to pair fed controls. Il-6, IL-10 and IFNgamma were also up regulated by high blood levels of ethanol. The gene expression of CD14, MyD88 and TNFR1SF1 were not up regulated by ethanol but were down regulated by SAMe. The gene expression of IL-1R1 and IRF1 tended to be up regulated by ethanol and this was prevented by feeding SAMe. The results suggest that SAMe, fed chronically prevents the activation of TLR pathways caused by ethanol. In this way the proinflammatory response, fibrogenesis, cirrhosis and hepatocellular carcinoma formation due to alcohol liver disease could be prevented by SAMe. PMID- 21276440 TI - Dendritic cells stimulated with outer membrane protein A (OmpA) of Salmonella typhimurium generate effective anti-tumor immunity. AB - Gram-negative bacterial outer membrane proteins (Omps) have an important role in pathogenesis and signal reception. We previously reported that Acinetobacter OmpA (AbOmpA) induced maturation of bone marrow-derived dendritic cells (BMDCs) and that AbOmpA-primed DCs produced IL-12 which generated Th1 CD4(+) T-cells. We analyzed the effects of Salmonella typhimurium OmpA (OmpA-Sal) on dendritic cell (DC) maturation in the present study, and determined that tumor antigen-pulsed DCs stimulated with OmpA-Sal induced anti-tumor responses in a mouse model. OmpA Sal activated BMDCs by augmenting expression of MHC class II and of the co stimulatory molecules CD80 and CD86. RT-PCR revealed that IL-12(p40) gene expression is highly augmented in OmpA-Sal-stimulated BMDCs. DNA (CRT/E7) vaccination combined with OmpA-Sal stimulation generated more antigen-specific CD8(+) T-cells in the present study. Certain antigen-pulsed BMDCs stimulated with OmpA-Sal induced strong PADRE-specific CD4(+) and E7-specific CD8(+) T-cell responses. In addition, BMDCs stimulated with OmpA-Sal (OmpA-Sal-BMDCs) and pulsed with both E7 and PADRE peptide generated greater numbers of E7-specific CD8(+) effector and memory T-cells than those pulsed with E7 peptide alone. E7- and PADRE-expressing OmpA-Sal-BMDC vaccines resulted in significant long-term protective anti-tumor effects in vaccinated mice. Our data suggested that E7- and PADRE-expressing BMDCs that were matured in the presence of OmpA-Sal might enhance anti-tumor immunity and support the therapeutic use of OmpA-Sal in DC based immunotherapy. PMID- 21276441 TI - Pneumococcal serotype distribution and antimicrobial resistance in Chinese children hospitalized for pneumonia. AB - A prospective study was performed to determine serotype distribution and antimicrobial resistance in Streptococcus pneumoniae (S. pneumoniae) from Chinese children <5 years old meeting pneumonia criteria. A total of 3865 children were enrolled and 338 S. pneumoniae isolates were obtained. The most frequent serotypes were 19F (55.6%), 19A (13.9%), 23F (10.1%), 6B (4.7%), and 14 (3.6%). The 7-, 10- and 13-valent conjugate vaccines, respectively, covered 76.3%, 76.9%, and 92.3% of isolates. Out of the isolates, six (1.8%) were penicillin resistant. All except 1 of the isolates were resistant to erythromycin. Serotype 19A showed the highest drug resistance. The use of PCV7 has the potential to prevent a substantial number of pneumococcal infections. However, PCV13 is likely to prevent more episodes of pneumococcal disease in China because of the high rates of 19A. PMID- 21276442 TI - Induction of protection in mice against a respiratory challenge by a vaccine formulated with the Chlamydia major outer membrane protein adjuvanted with IC31(r). AB - IC31((r)), a novel adjuvant, has been shown to be effective by increasing the levels of IFN-gamma in animal models when delivered with several antigens. Here, we tested the ability of IC31((r)), to enhance the protective ability of the Chlamydia trachomatis native major outer membrane protein (nMOMP). BALB/c mice were immunized by the intramuscular (i.m.) and subcutaneous (s.c.) routes with nMOMP+IC31((r)). Another group of animals was immunized with nMOMP+Alum and as a negative control mice were immunized with ovalbumin (Ova)+IC31((r)). Animals immunized with nMOMP+IC31((r)) developed high Chlamydia-specific IgG titers. The serum levels of IgG1 were higher than those of the IgG2a. T cells, from the spleens of mice immunized with IC31((r))-adjuvanted nMOMP demonstrated a strong lymphoproliferative reaction to Chlamydia elementary bodies (EB) compared with the groups immunized with nMOMP+Alum or Ova+IC31((r)). A similar comparison between these groups of mice revealed that the levels of IFN-gamma in the supernatants from stimulated T-cells were significantly higher in animals immunized with nMOMP+IC31((r)). Following an intranasal challenge with C. trachomatis, the mice immunized with IC31((r))-adjuvanted nMOMP showed significant protection. The change in body weight, an indication of the severity of the infection, was significantly less reduced in mice immunized with nMOMP+IC31((r)). Furthermore, the weight of the lungs, as well as the pulmonary Chlamydia burden, was significantly lower in the animals immunized with nMOMP+IC31((r)) when compared with the groups immunized with nMOMP+Alum or with Ova+IC31((r)). In conclusion, these results provide the rationale for further preclinical testing of IC31((r)) using other chlamydial antigens, and support the potential evaluation of this adjuvant in human vaccines against Chlamydia. PMID- 21276443 TI - Cardiac-specific NRAP overexpression causes right ventricular dysfunction in mice. AB - The muscle-specific protein NRAP is concentrated at cardiac intercalated disks, plays a role in myofibril assembly, and is upregulated early in mouse models of dilated cardiomyopathy. Using a tet-off system, we developed novel transgenic lines exhibiting cardiac-specific NRAP overexpression ~2.5 times greater than normal. At 40-50 weeks, NRAP overexpression resulted in dilation and decreased ejection fraction in the right ventricle, with little effect on the left ventricle. Expression of transcripts encoding brain natriuretic peptide and skeletal alpha-actin was increased by cardiac-specific NRAP overexpression, indicative of a cardiomyopathic response. NRAP overexpression did not alter the levels or organization of N-cadherin and connexin-43. The results show that chronic NRAP overexpression in the mouse leads to right ventricular cardiomyopathy by 10 months, but that the early NRAP upregulation previously observed in some mouse models of dilated cardiomyopathy is unlikely to account for the remodeling of intercalated disks and left ventricular dysfunction observed in those cases. PMID- 21276444 TI - Leishmania major: Protective capacity of DNA vaccine using amastin fused to HSV-1 VP22 and EGFP in BALB/c mice model. AB - An intercellular spreading strategy using herpes simplex virus type 1 (HSV-1) VP22 protein is employed to enhance DNA vaccine potency of Leishmania major amastin antigen in BALB/c mice model. We evaluated the immunogenicity and protective efficacy of plasmid DNA vaccines encoding amastin-enhanced green fluorescent protein (EGFP) and VP22-amastin-EGFP. Optimal cell-mediated immune responses were observed in BALB/c mice immunized with VP22-amastin-EGFP as assessed by cytokine gene expression analysis using real time RT-PCR. Vaccination with the VP22-amastin-EGFP fusion construct elicited significantly higher IFN gamma response upon antigen stimulation of splenocytes from immunized mice compared to amastin as a sole antigen. Mice immunized by VP22-amastin-EGFP showed partial protection following infectious challenge with L. major, as measured by parasite load in spleens. These results suggest that the development of DNA vaccines encoding VP22 fused to a target Leishmania antigen would be a promising strategy to improve immunogenicity and DNA vaccine potency. PMID- 21276445 TI - Elongation factor 1-alpha is released into the culture medium during growth of Giardia intestinalis trophozoites. AB - The molecular pathogenesis of the intestinal parasite Giardia intestinalis is still not fully understood but excretory-secretory products have been suggested to be important during host-parasite interactions. Here we used SDS-PAGE gels and MALDI-TOF analysis to identify proteins released by Giardia trophozoites during in vitro growth. Serum proteins (mainly bovine serum albumin) in the growth medium, bind to the parasite surface and they are continuously released, which interfere with parasite secretome characterization. However, we identified two released Giardia proteins: elongation factor-1 alpha (EF-1alpha) and a 58 kDa protein, identified as arginine deiminase (ADI). This is the first description of EF-1alpha as a released/secreted Giardia protein, whereas ADI has been identified in an earlier secretome study. Two genes encoding EF-1alpha were detected in the Giardia WB genome 35 kbp apart with almost identical coding sequences but with different promoter and 3' regions. Promoter luciferase-fusions showed that both genes are transcribed in trophozoites. The EF-1alpha protein localizes to the nuclear region in trophozoites but it relocalizes to the cytoplasm during host cell interaction. Recombinant EF-1alpha is recognized by serum from giardiasis patients. Our results suggest that released EF-1alpha protein can be important during Giardia infections. PMID- 21276446 TI - Expression levels of encystation mediating factors in fresh strain of Acanthamoeba castellanii cyst ESTs. AB - The life cycle of Acanthamoeba consists of two stages, trophozoite and cyst. The cyst form is resistant to almost all antibiotics. By long term cultivation, Acanthamoeba severely attenuated the encysting ability. To determine the changing of gene expression by the long term cultivation, especially focusing an encystation mediating factors, this study compared the ESTs of the fresh strain and the old strain, and trophozoite. Comparison of the KOG (euKaryotic Orthologous Groups) analysis relative to trophozoite revealed higher percentages of cyst ESTs related to G (Carbohydrate transport and metabolism), H (Coenzyme transport and metabolism), I (Lipid transport and metabolism), D (Cell cycle control, cell division, chromosome partitioning), T (signal transduction mechanisms), and O (Posttranslational modification, protein turnover, chaperones). In addition to this result, KOG analysis of fresh strain relative to old strain showed higher percentage of cyst ESTs related to metabolism category and T (signal transduction mechanisms) article. ESTs of the fresh strain revealed more various gene profiles compared to the old strain including encystation mediating factors like autophagy related proteins (Z article) and signal transduction proteins (T article). Twenty seven kinds of protein kinase C (PKC) like genes were detected in cyst or trophozoite ESTs and twenty one of them were highly expressed during encystation. The information of the expressed genes during encystation in only the fresh strain will provide new clues to understanding the encystation mechanism of encysting protozoa including Acanthamoeba. PMID- 21276447 TI - MicroRNA-29a regulates pro-inflammatory cytokine secretion and scavenger receptor expression by targeting LPL in oxLDL-stimulated dendritic cells. AB - There is increasing evidence that microRNAs (miRNAs) play important roles in cell proliferation, apoptosis and differentiation that accompany inflammatory responses. However, whether microRNAs are associated with DC immuno-inflammatory responses with oxidized low density lipoprotein (oxLDL) stimulation is not yet known. Our study aims to explore the link of miRNAs with lipid-overload and immuno-inflammatory mechanism for atherosclerosis. In DCs transfected with microRNA-29a mimics or inhibitors, we showed that microRNA-29a plays an important role in proinflammatory cytokine secretion and scavenger receptor expression upon oxLDL-treatment. Furthermore, we suggest an additional explanation for the mechanism of microRNA-29a regulation of its functional target, lipoprotein lipase. We conclude that microRNA-29a could regulate pro-inflammatory cytokine secretion and scavenger receptor expression by targeting lipoprotein lipase in oxLDL-stimulated dendritic cells. PMID- 21276448 TI - Predicted expansion of the claudin multigene family. AB - Claudins (Cldn) are essential membrane proteins of tight junctions (TJs), which form the paracellular permselective barrier. They are produced by a multi-gene family of 24 reported members in mouse and human. Based on a comprehensive search combined with phylogenetic analyses, we identified three novel claudins (claudin 25, -26, and -27). Quantitative RT-PCR revealed that the three novel claudins were expressed in a tissue- and/or developmental stage-dependent manner. Claudins 25 and -26, but not claudin-27, were immunofluorescently localized to TJs when exogenously expressed in cultured MDCK and Eph epithelial cell lines. These findings expand the claudin family to include at least 27 members. PMID- 21276449 TI - The Evi1, microRNA-143, K-Ras axis in colon cancer. AB - MicroRNA profiling of diseased/non-diseased tissue has identified expression signatures associated with a wide range of pathogenic conditions including malignancy. For example, colon cancer is associated with the under expression of miRNA-143 yet the molecular etiology of under expression is unknown. The K-Ras oncogene is a target of miRNA-143. Here, we show that the ecotropic viral integration site 1 oncoprotein (Evi1) is a transcriptional suppressor of the miRNA-143 gene. We find an indirect relationship between miRNA-143 and Evi1 expression. A complex molecular axis linking Evi1, miRNA-143 is operational in human colon cancer. PMID- 21276450 TI - AP-site cleavage activity of tyrosyl-DNA phosphodiesterase 1. AB - APE-independent base excision repair (BER) pathway plays an important role in the regulation of DNA repair mechanisms. In this study it has been found that recently discovered tyrosyl-DNA phosphodiesterase 1 (Tdp1) catalyzes the AP site cleavage reaction to generate breaks with the 3'- and 5'-phosphate termini. The removal of the 3'-phosphate is performed by polynucleotide kinase phosphatase (PNKP). Tdp1 is known to interact stably with BER proteins: DNA polymerase beta (Pol beta), XRCC1, PARP1 and DNA ligase III. The data suggest a role of Tdp1 in the new APE-independent BER pathway in mammals. PMID- 21276451 TI - The ribonuclease/angiogenin inhibitor is also present in mitochondria and nuclei. AB - The data presented here show for the first time that the protein known as "ribonuclease (RNase) inhibitor" (RI or RNH1) is present not only in the cell cytosol, but also in mitochondria, the central organelles in cell redox homeostasis. This finding directly correlates with the reported ability of RI to protect the cell from oxidative stress, with its sensitivity to oxidation and reactivity as a reactive oxygen species scavenger. While this study was carried out we also surprisingly discovered the presence of RI in the cell nucleus. We deem that these data open new views in the investigation on the cellular role(s) of the RI. PMID- 21276452 TI - [Best wishes for 2011]. PMID- 21276453 TI - [Chronic urticaria and corticodependence: corticosteroids have no role in the treatment of urticaria]. PMID- 21276454 TI - [CO2 fractional resurfacing: side effects and immediate complications]. AB - BACKGROUND: Fractional resurfacing is a new concept in laser treatment designed to divide radiation into multiple evenly spaced microspots. The aim of our study was to analyze side effects and complications following fractional CO2 laser therapy. PATIENTS AND METHODS: This retrospective study involved the analysis of records of patients treated with ablative fractional CO2 laser. Pain, type and duration of usual side effects, and immediate complications were analysed. RESULTS: Forty-six treatments were studied. The average duration of erythema was 5.2 (+/-2) days while that of scabs was 4.1 (+/-1.9) days. Average pain was 3.3/10 (+/-2.5) for nine patients premedicated with Emla(r) and 4.1/10 (+/-2) for the other 14 non-premedicated patients. Complications were reported for 21.7% of the 46 treatments, as follows: 10.6% facial herpes, some of which occurred despite antiviral prophylaxis (valacyclovir 500 mg/day p.o.), 8.7% inflammatory reactions, including severe facial swelling, and 2.2% acne. All complications resolved quickly. DISCUSSION: Our study specifically examined the safety of CO2 fractional lasers and showed an acceptable per interventional pain and simple follow-ups. The frequency of complications was high compared to that described with the Fraxel(r), but no severe complications were reported. Given the extent of herpes complications, our study encourages the prescription of valacyclovir prophylaxis 500 mg twice a day for all patients. Patients should also be informed of the high risk of severe inflammatory reaction. PMID- 21276455 TI - [Diagnosis of skin cancer by dermatologists in the French West Indies: a prospective study]. AB - BACKGROUND: The incidence of skin cancer is not well established in the French West Indies, aside from old data concerning cutaneous melanoma. METHOD: A prospective study was performed over a 3-month period in late 2007 in the French West Indies. The number of new cases of histologically confirmed skin cancer was determined using a questionnaire. RESULTS: The rate of participation of dermatologists was 82 %. During the study period, 166 skin cancers were diagnosed in 134 patients (66 women and 68 men: mean age=63.3 years, SD=2.5), including 137 basal cell carcinomas, 12 melanomas, seven squamous cell carcinomas, six Bowen's disease, one B lymphoma and one Paget's disease. The raw incidence of skin cancers detected by dermatologists was calculated as 64.6 cases/100 000 inhabitants/year for basal cell carcinoma, 5.7 cases/100 000 inhabitants/year for melanoma, 3.3 cases/100 000 inhabitants/year for squamous cell carcinoma, and 2.8 cases/100 000 inhabitants/year for Bowen's disease. Seven melanomas (almost exclusively of plantar topography) and seven basal cell carcinomas were diagnosed in patients of phototype V or VI. DISCUSSION: Although lower than in metropolitan France, the number of skin cancers diagnosed by dermatologists in the French West Indies is fairly high. In addition, this study indicates the significant incidence of basal cell carcinomas and melanomas in subjects with phototype V or VI, underreported in the literature. These findings highlight the need to begin longer-term studies and to include skin carcinomas in the cancer registry of the French West Indies in order to better identify their characteristics among the Caribbean population. PMID- 21276456 TI - [Histopathological study of Mycobacterium marinum infection]. AB - INTRODUCTION: Skin infection by Mycobacterium marinum induces the classic granuloma of aquariums and swimming pools. The histopathological signs have been described primarily in small series of typical cases, generally with no bacteriological evidence. In a national survey of proven infection with M. marinum detailed data was collected for 63 patients. The aim of this new study was to describe microscopic signs of the infection based upon biopsies taken from these patients. PATIENTS AND METHODS: Unstained slides from 32 biopsies of the skin (n=24) or synovial biopsies (n=8) were prepared; they originated from 27 patients. They were examined after standard staining and after Ziehl-Neelsen staining, without knowledge of the clinical data. RESULTS: All biopsies were taken from the upper limb of 18 men and nine women of mean age 48 years. Tubercular granulomas were observed in only 60% of cases. The largest and most numerous were seen in the synovial samples. Due to their palisade appearance, they were occasionally impossible to distinguish from rheumatoid nodules. In 20% of cases, neutrophil collections were seen without granulomas and in remaining 20% of cases, relatively non-specific infiltrate was observed. Epidermal changes consisted in psoriasiform or pseudocarcinomatous hyperplasia, particularly at the edges of ulcerated areas; invasion of the dermo-epidermal junction was seen in five cases. Follicular necrosis was observed in four cases with lymphoplasmacytic infiltrates remote from the granulomas being seen in 22 biopsies. Ziehl-Neelsen staining revealed no bacilli. DISCUSSION: The originality of this series consists of bacteriological proof of M. marinum infection and the absence of biopsy selection based on clinical criteria. It shows that the typical granulomas are in fact present in less than two third of cases, and that these may be confused with rheumatoid nodules. The chief characteristic of these lesions is the very low concentration of microorganisms present, in contrast with other forms of mycobacterium, making them difficult to see; routine confirmation cannot thus be expected from specific staining procedures. In one case out of five, the infiltrate suggested no infectious origin, although deep skin biopsies and synovial biopsies provided more information. For all forms of necrotic granuloma, whether or not accompanied by collections of neutrophils, a culture should be carried out in a specific medium, even in the absence of microscopic evidence of bacilli. PMID- 21276457 TI - [Algorithm for treatment of juvenile facial acne]. PMID- 21276458 TI - [Rosacea-like demodicidosis and chronic blepharitis]. AB - Demodicidosis is a parasitic skin disease caused by the follicle mites Demodex sp. In this article, we present a case of rosacea-like demodicidosis, discuss the clinical features of Demodex infestation in man and review their diagnosis and therapeutic modalities. A 37-year-old woman presented in our department with chronic blepharitis present for one year. On physical examination, the patient presented blepharitis and papulovesicles with fine scaling limited to the face. There was no telangectasia. The patient did not report flushing episodes or any kind of photosensitivity. A diagnosis of rosacea-like demodicidosis and Demodex blepharitis was based on the presence of numerous Demodex folliculorum in the eyelashes and scrapings of skin lesions. The patient was put on topic and oral metronidazole for 2 months and on yellow mercury ointment for 15 days. The course involved disappearance of the facial mites and complete remission without recurrence. Screening for Demodex sp is essential to establish the correct diagnosis and ensure suitable treatment. PMID- 21276459 TI - [Granulomas induced by injections of leuprorelin acetate (Enantone(r))]. AB - BACKGROUND: Gonadorelin analogues (LHRH) are used for the endocrine treatment of prostatic cancer, central early puberty and various gynaecological conditions. Cutaneous adverse events seldom occur. We report a case of injection-site granulomas induced by leuprorelin acetate (Enantone(r)). CASE REPORT: A 76-year old man presented with several subcutaneous nodules on his left arm. The nodules were hard but painless. He had received subcutaneous injections of Enantone(r) for prostatic cancer. Histological examination of a skin biopsy specimen demonstrated granulomatous inflammation with a necrotic centre; screening for an infectious aetiology was negative. Serial sections showed giant cells containing translucent round microspheres in the subcutaneous tissue. Limitation to the leuprorelin acetate injection sites in the arm and detection at histological analysis of microspheres probably bound to an injected product militated in favour of granulomas caused by injections of Enantone(r). DISCUSSION: Injection site granulomas caused by Enantone(r) are rare. Their formation may depend on the mode of administration: the more superficial the injection, the higher the risk of developing granulomas. The formation of these lesions is probably a foreign body reaction to the excipient. PMID- 21276460 TI - [Granulomatous skin disease in an immunocompromised child]. AB - BACKGROUND: The development of systemic and/or cutaneous granulomas associated with immunodeficiency is well established, particularly with common variable immunodeficiency (CVID). We report the case of an immunocompromised child presenting with cutaneous granulomas, predominantly on the face. PATIENTS AND METHODS: A boy aged 6 years and 9 months presenting complex and incompletely defined immunodeficiency presented with gradually worsening cutaneous lesions of granulomatous aspect on his face and right foot. Extensive laboratory tests showed no infectious or neoplastic processes. Biopsies of the lesions confirmed the presence of granulomas. Systemic corticosteroids produced no satisfying improvement and were changed to anti-TNFalpha. The lesions had completely disappeared after 6 months. Treatment was continued for 6 months, with no relapse 6 months after discontinuation. CONCLUSION: The originality of our case lies in the presentation of cutaneous granulomas, appearing in the context of an undefined immunodeficiency other than CVID, as well as in the therapeutic aspect, with the successful use of biotherapies in such a clinical setting. PMID- 21276461 TI - [Familial histoid leprosy]. AB - BACKGROUND: Histoid leprosy is a very particular and rare anatomoclinical form of lepromatous leprosy. Familial cases are extremely rare. We report two new cases of histoid leprosy in a sister and brother born of a non-consanguineous marriage. PATIENTS AND METHODS: We report the case of a sister and brother, aged 21 and 25 years respectively, who were admitted to the National Leprology Centre for multibacillary leprosy. Questioning revealed the existence of family contact with an uncle and two maternal cousins, all of whom had histoid leprosy. On clinical examination, multiple erythematous papules and nodules were noted, some of which were umbilicated while others were ulcerated. Palpation also revealed subcutaneous nodules on the thighs and forearms. No neurological disorders were found in the two patients. Histopathological analysis of cutaneous biopsy samples of nodular lesions for the two patients showed dermal-hypodermic nodular infiltrates comprising spindle cells with a few macrophages. Ziehl-Neelsen staining showed numerous alcohol-acid resistant bacilli (BAAR) without globi. Both patients were placed on the multi-drug regimen recommended by the WHO for multibacillary leprosy. An extremely favourable therapeutic response was obtained after 3 months of treatment. The patients had presented no relapse of erythema nodosum leprosum after two years of follow-up. CONCLUSION: Histoid leprosy is a clinical entity that must be clearly differentiated through its clinical and histopathological features, which distinguish it from polar lepromatous leprosy. There may be a genetic predisposition to this clinical leprosy form, but this requires confirmation by genetic studies. PMID- 21276462 TI - [Membranous glomerulonephritis as a paraneoplastic manifestation of melanoma]. AB - BACKGROUND: Membranous glomerulonephritis (MG) is generally idiopathic. Causes of secondary MG (15 % of cases), namely solid or haematological cancers, are common, with parallel development between the two diseases suggesting paraneoplastic syndrome. However, paraneoplastic syndrome is rare in melanoma. We report a case of a patient with stage III melanoma presenting MG developing in parallel to the melanoma. PATIENTS AND METHODS: A 61-year-old man was referred for melanoma on the right side with a Breslow index of 3mm, and without ulceration. While the patient had no adenopathy, he was presenting severe hypertension diagnosed two months earlier as well as diffuse pitting oedema, with weight gain of 15kg in one month. Additional treatment of the patient's melanoma included extended excision, examination of the two right axillary sentinel nodes (positive), and axillary lymph node dissection revealing four more metastatic nodes. A thoracic-abdominal pelvic CAT scan showed no further metastasis. Investigation of the oedema revealed nephrotic syndrome with hypoalbuminaemia of 14g/L and proteinuria of 5g/24h. Renal biopsy resulted in the diagnosis of MG. Histological and immunohistochemical examination (HMB-45, Melan A, S100 protein) showed no tumour cells in the kidney, and urinary cytology was negative. Non-tumoral causes of MG were thus ruled out. The oedema regressed rapidly following surgical treatment of the melanoma, with no specific renal or oncological treatment being given. Two years after axillary lymph node dissection, the patient was in complete remission of his melanoma and renal tests showed spontaneous regression of nephrotic syndrome, with disappearance of the oedema, normalisation of blood pressure and gradual correction of serum albumin (40g/L) and proteinuria (1g/24h). DISCUSSION: Paraneoplastic MG has been described particularly in patients with gastrointestinal and pulmonary cancer. To our knowledge, this is only the second case associated with melanoma. Our report suggests the need for routine cutaneous examination as part of the initial investigations for MG. PMID- 21276463 TI - [Autochthonous filaria in south-west France caused by Dirofilaria repens]. AB - BACKGROUND: Dirofilariasis is an autochthonous disease caused by Dirofilaria (Nochtiella) repens, a subcutaneous parasite of dogs and other carnivorous animals. Human infection leads to a self-limiting disease that generally presents clinically as a subcutaneous nodule. We describe a case occurring outside the classical endemic Mediterranean region. PATIENTS AND METHODS: A 38-year-old woman presented with a scalp nodule present for six months. Surgery revealed a thread like parasite identified as a female Dirofilaria repens without microfilariae. DISCUSSION: This case points to the spread of this disease to temperate areas beyond the regions classically affected. PMID- 21276464 TI - [Anaemia and photosensitization might point to erythropoietic protoporphyria]. PMID- 21276465 TI - [Pruritic pretibial hypopigmentation in West Indian patients]. PMID- 21276466 TI - [Plantar tumor]. PMID- 21276467 TI - [Erythropoietic protoporphyria]. PMID- 21276468 TI - [Lupus erythematosus]. PMID- 21276469 TI - [Pigmented lesion on the left breast]. PMID- 21276470 TI - [Onychomatricoma]. PMID- 21276471 TI - [A new "rasopathy": mutation in the CBL tumour-suppressor gene in neuro-cardio facio-cutaneous syndrome similar to Noonan syndrome]. PMID- 21276472 TI - [Nevus lipomatosus cutaneous superficialis]. PMID- 21276473 TI - [Genital lichen nitidus]. PMID- 21276475 TI - Effects of titanium dioxide nano-particles on growth and some histological parameters of zebrafish (Danio rerio) after a long-term exposure. AB - According to some previous studies, titanium dioxide (TiO(2)) nanoparticles (NPs) would be of low to medium ecological toxicity in short-term tests. But the long term risks of TiO(2) NPs that is currently unknown. In this study, we used the zebrafish (Danio rerio) as in vivo model to assess the chronic toxicity of TiO(2) NPs. Our results revealed that there are obvious adverse effect to zebrafish, including concentration-dependent and time-dependent inhibition of growth and decrease the liver weight ratio of zebrafish. Meanwhile, only the gills displayed histopathologic change including thickening of oedema and the gill lamellae. ICP MS examination showed that TiO(2) NPs were accumulated and distributed in gill, liver, heart as well as brain. Our present study suggested that the TiO(2) NPs could translocate among organs and pass through the blood-brain and the blood heart barrier after long-term exposure. Given the widespread use of TiO(2) NPs, a systematic, coherent, and tested foundation for managing the uncertain health and environmental aspects of TiO(2) NPs is necessary. PMID- 21276474 TI - Methoxychlor affects multiple hormone signaling pathways in the largemouth bass (Micropterus salmoides) liver. AB - Methoxychlor (MXC) is an organochlorine pesticide that has been shown to have estrogenic activity by activating estrogen receptors and inducing vitellogenin production in male fish. Previous studies report that exposure to MXC induces changes in mRNA abundance of reproductive genes in the liver and testes of largemouth bass (Micropterus salmoides). The objective of the present study was to better characterize the mode of action of MXC by measuring the global transcriptomic response in the male largemouth liver using an oligonucleotide microarray. Microarray analysis identified highly significant changes in the expression of 37 transcripts (p<0.001) (20 induced and 17 decreased) in the liver after MXC injection and a total of 900 expression changes (p<0.05) in transcripts with high homology to known genes. Largemouth bass estrogen receptor alpha (esr1) and androgen receptor (ar) were among the transcripts that were increased in the liver after MXC treatment. Functional enrichment analysis identified the molecular functions of steroid binding and androgen receptor activity as well as steroid hormone receptor activity as being significantly over-represented gene ontology terms. Pathway analysis identified c-fos signaling as being putatively affected through both estrogen and androgen signaling. This study provides evidence that MXC elicits transcriptional effects through the estrogen receptor as well as androgen receptor-mediated pathways in the liver. PMID- 21276476 TI - Development of an ex vivo brown trout (Salmo trutta fario) gonad culture for assessing chemical effects on steroidogenesis. AB - A variety of natural and synthetic environmental substances have been shown to disrupt vertebrate reproduction through mimicking or modifying the regulation of the endocrine system. Tests to screen for any such chemicals that directly interact with the steroid hormone receptors are widely available; however, few tests have been developed to identify chemicals that affect endocrine function through non-receptor mediated mechanisms. The aim of this study was, therefore, to develop an assay for the identification of substances that disrupt the activity of enzymes involved in the sex steroid biosynthesis cascade, in particular the aromatase enzyme, CYP19, that catalyses the final conversion of androgens to estrogens. A gonad ex vivo assay was developed using gonad explants harvested from juvenile brown trout and cultured in a modified Leibovitz medium. Effects on sex steroid biosynthesis were quantified through measurement of 17beta estradiol (E2) and testosterone (T) concentrations in the medium after 2 days incubation. Exposure of ovary explants to 100 ng/mL 1,4,6-androstatriene-3,17 dione (ATD), a potent pharmaceutical aromatase inhibitor, reduced E2 concentrations and elevated T concentrations confirming that CYP19 activity could be inhibited in the assay. Exposure of ovary explants to 250 ng/mL prochloraz, an imidazole fungicide, also reduced E2 concentrations but did not affect T levels, consistent with reports that in addition to inhibiting CYP19 activity, prochloraz also inhibits enzymes in the steroidogenic pathway upstream of the CYP19 enzyme. Exposure to a third chemical, tributyltin (TBT), did not affect T or E2 concentrations, further supporting previous evidence that the CYP19 modulating effects of this chemical are not mediated through direct inhibition of CYP19 activity. These results demonstrate that the gonad ex vivo assay developed here can be successfully used to identify substances that disrupt sex steroid biosynthesis and further that it has the potential to inform on their specific mode of action. PMID- 21276477 TI - Evaluation of oxidative stress biomarkers in Zosterisessor ophiocephalus from the Venice Lagoon, Italy. AB - Several studies carried out in the last years have demonstrated the presence of a wide range of contaminants in some areas of the Venice Lagoon. Many of these contaminants are able to drive free radical reactions, which lead to oxidative stress and can potentially affect fish health. In the present study, oxidative stress biomarkers were examined in three different sites (Porto Marghera, Val di Brenta and Caroman) of the Venice Lagoon and their levels monitored in Zosterisessor ophiocephalus, one of the most common fish species present in the lagoon. Schmorl's staining revealed the presence of melanomacrophage centres in spleen and head kidney, and the highest number of melanomacrophage centres was observed in the animals sampled at the Porto Marghera (Porto Marghera vs Val di brenta and Caroman: p<0.01). The cellular localization of HNE and NT, investigated through an immunohistochemical approach, showed that immunopositivity was mainly localized in melanomacrophage centres of spleen and kidney. It is relevant that the animals of the detoxified control group did not exhibit any immunoreactivity. By Western blot, the antibodies against HNE and NT recognized in the liver polypeptides damaged by oxidative stress with molecular weights under 66kDa. Comparing the relative densities, animals from the Val di Brenta site exhibited the lowest levels of HNE adducts (p<0.05), whereas animals from the Porto Marghera site exhibited the highest levels of NT adducts (p<0.05). MDA levels, measured spectrophotometrically by TBARS assay did not exhibit any statistical difference among sites. PMID- 21276478 TI - Behavioral responses of adult male and female fathead minnows to a model estrogenic effluent and its effects on exposure regime and reproductive success. AB - Laboratory studies of adult male fathead minnows have shown that when they are exposed to estrogens, they lose their ability to compete for access to females and sire young, suggesting that estrogenic effluents may reduce the genetic fitness of populations of wild fishes. However, it is unknown whether wild fish which are exposed to effluent actually compete with unexposed fishes, how long effects of estrogen exposure last, and whether females are affected by estrogens. This study addressed these issues using the fathead minnow (FHM) and effluent from the Metropolitan Wastewater Treatment Plant (MWTP) a well-studied source of environmental estrogens (EEs) in the Mississippi River. Maze tests found that adult FHMs are neither attracted nor repelled by MWTP effluent while previous studies have shown that minnows are attracted to the warmer waters which characterize effluents; it is realistic that previously unexposed fish enter MWTP effluent in the spring and then compete with exposed individuals. Competitive spawning experiments showed that male FHMs exposed to 44ng E2/l (a high but realistic level) for three weeks failed to compete with unexposed males while males exposed to 4ng E2/l outcompeted and sired more young than unexposed males (p<0.05). The effects of estrogen exposure disappeared within a week of moving fish into uncontaminated water. Female FHM reproductive output and behavior were unaffected by exposure to estrogen. Taken together, these experiments suggest that the behavior of wild fishes likely determines their exposure to EEs and that while the effects of this exposure are likely significant to populations of wild fish, they will be location specific because of factors which determine the duration and intensity of male exposure. We conclude that the role of fish behavior in endocrine disruption strongly warrants additional consideration. PMID- 21276479 TI - Ultraviolet B retards growth, induces oxidative stress, and modulates DNA repair related gene and heat shock protein gene expression in the monogonont rotifer, Brachionus sp. AB - Ultraviolet B (UV-B) radiation causes direct cellular damage by breakage of DNA strands and oxidative stress induction in aquatic organisms. To understand the effect of UV-B radiation on the rotifer, Brachionus sp., several parameters including 24-h survival rate, population growth rate, and ROS level were measured after exposure to a wide range of UV-B doses. To check the expression of other important inducible genes such as replication protein A (RPA), DNA-dependent protein kinase (DNA-PK), Ku70, Ku80, and heat shock proteins (hsps) after UV-B radiation, we observed dose- and time-dependency at 2kJ/m(2). We also examined 13 hsp genes for their roles in the UV-B damaged rotifer. Results showed that UV-B remarkably inhibited the population growth of Brachionus sp. The level of intracellular reactive oxygen species (ROS) was high at 2kJ/m(2), suggesting that 2kJ/m(2) would already be toxic. This result was supported by other enzymatic activities, such as GSH levels, glutathione peroxidase, glutathione S transferase, and glutathione reductase. For dose dependency, low doses of UV-B radiation (2, 4, and 6kJ/m(2)) significantly up-regulated the examined genes (e.g. RPA, DNA-PK, Ku70, and Ku80). For the time course study, RPA genes showed immediate up-regulation but returned to basal or lower expression levels compared to the control 3h after UV-B exposure. The DNA-PK and Ku70/80 genes significantly increased, indicating that they may be involved in repairing processes against a low dose of UV-B exposure (2kJ/m(2)). At the basal level, the hsp90alpha1 gene showed the highest expression, and followed by hsp10, hsp30, hsp60, and hsc70, and hsp90beta in adults (w/o egg). In eggs, the hsp10 gene was expressed the highest, and followed by hsp30, hsp27, hsp90alpha1, and hsp60 genes. In real-time RT-PCR array on rotifer hsp genes, low doses of UV-B radiation (2 and 4kJ/m(2)) showed up-regulation of several hsp genes but most of the hsp genes showed down regulation at 8kJ/m(2) and higher, indicating that significant Hsp-mediated cellular damage already occurred at low doses. For the time course study of four hsp genes (hsp20, hsp27, hsp70, hsp90alpha1), they showed a significant correlation for UV-B radiation (2kJ/m(2)). In this paper, we demonstrated that UV B radiation would affect growth retardation with up- or down-regulation of some important genes in DNA replication, repair process, and chaperoning. This finding provides a better understanding of molecular mechanisms involved in UV-B-mediated cellular damage in the rotifer, Brachionus sp. PMID- 21276480 TI - Biochemical responses of Mytilus galloprovincialis as biomarkers of acute environmental pollution caused by the Don Pedro oil spill (Eivissa Island, Spain). AB - In the present work, the potential use of several antioxidant and detoxification biomarkers in the digestive gland of wild mussels (Mytilus galloprovincialis) for biomonitoring the marine pollution induced by the Don Pedro oil spill has been investigated. Two locations from the East to South-East of Eivissa (Ibiza) and Formentera islands were selected, one extensively affected by the oil spill and the other one not affected and considered as the control area. Mussels were sampled one, two and six months after the Don Pedro accident. Polycyclic aromatic hydrocarbon (PAH) levels were significantly increased in the soft tissues of mussels in the affected area one month after the disaster, returning to normal values after six months. Markers of oxidative damage in lipids--malondialdehyde, and in proteins--carbonyl derivates, and antioxidant enzyme--catalase, superoxide dismutase and glutathione peroxidase, activities significantly increased as result of the spill oil after one month, returning to basal values at two month sampling time. Glutathione/glutathione disulfide ratio (GSH/GSSG), as a marker of the redox status, was reduced after one and two months indicating a more oxidized situation. Markers of detoxification--glutathione-S-transferase and cytochrome P4501A activities and metallothionein gene expression--were significantly increased by the oil spill one month after the accident, returning to the basal values at two month sampling time. In conclusion, the Don Pedro accident induced a transient situation of PAHs pollution resulting in enhanced antioxidant and detoxification defense systems in the wild mussel M. galloprovincialis returning to normal levels six months from the spill. The selected biomarkers are a useful tool for biomonitoring the response to acute exposure to pollutants in marine mussels. PMID- 21276481 TI - Identification, characterization and expression profiles of Chironomus riparius glutathione S-transferase (GST) genes in response to cadmium and silver nanoparticles exposure. AB - In this study, we report the identification and characterization of 13 cytosolic GST genes in Chironomus riparius from Expressed Sequence Tags (ESTs) database generated using pyrosequencing. Comparative and phylogenetic analyses were undertaken with Drosophila melanogaster and Anopheles gambiae GSTs and 3 Delta, 4 Sigma, 1 each in Omega, Epsilon, Theta, Zeta and 2 unclassified classes of GSTs were identified and characterized. The relative mRNA expression levels of all of the C. riparius GSTs (CrGSTs) genes under different developmental stages were varied with low expression in the larval stage. The antioxidant role of CrGSTs was studied by exposing fourth instar larvae to a known oxidative stress inducer Paraquat and the relative mRNA expression to different concentrations of cadmium (Cd) and silver nanoparticles (AgNPs) for various time intervals were also studied. All the CrGSTs showed up- or down regulation to varying levels based upon the concentration, and duration of exposure. The highest mRNA expression was noticed in Delta3, Sigma4 and Epsilon1 GST class in all treatments. These results show the role of CrGST genes in defense against oxidative stress and its potential as a biomarker to Cd and AgNPs exposure. PMID- 21276482 TI - The contribution of 'Midwifery' to support for breast feeding: announcing our first virtual issue. PMID- 21276483 TI - Twenty-five years of breast-feeding research in Midwifery. AB - This paper explores some of the significant changes that have taken place with regard to the protection, promotion and support of breast feeding during the past three decades. The period covered since the first issue of Midwifery in 1985, has been marked by some dramatic reversals of harmful discourses and detrimental practices with regard to infant and young child feeding and more specifically breast feeding. Midwifery has spanned this period with the publication of 80 papers on breast feeding. This collection of papers has both influenced and reflected upon changes in international and national breast-feeding strategies and practices. Six papers have been selected for a special virtual edition of Midwifery to reflect the diversity of breast-feeding research in terms of issues explored, methodology and country of origin (www.midwiferyjournal.com). Considerable progress is reflected in these papers. However, there are still enormous challenges ahead in working towards the optimisation of infant and young child feeding. In addition to continuing to conduct and collate robust scientific and epidemiological research we need further studies that explore the political, economic, socio-cultural and psychological factors influencing women's infant feeding practices. Our professional practice needs to continue to improve in order to provide women and families with appropriate support, encouragement and resources to enable them to breastfeed effectively. Finally, we need to continue to challenge the systems and approaches at organisational and community levels that impede women in their endeavours to feed their infants in optimum ways. PMID- 21276484 TI - [Current topics in cardiology 2010. Introduction]. PMID- 21276485 TI - [Update on geriatric cardiology]. AB - This article contains a review of the main developments in the field of geriatric cardiology reported during 2010. The focus is on research into the specific characteristics of elderly patients with heart failure, ischemic heart disease, valvular heart disease and arrhythmias. PMID- 21276486 TI - [Update in interventional cardiology]. AB - This article contains a detailed review of the most important studies on interventional cardiology reported in either publications or presentations. With regard to coronary interventions, ST-elevation myocardial infarction is highlighted because of the ongoing substantial expansion in primary angioplasty programs. Drug-eluting stents, especially new-generation stents, continue to be the focus of numerous studies. Clinical outcomes in diabetic patients with left main coronary artery or multivessel disease are also dealt with by much research. In addition, intracoronary diagnostic techniques, particularly optical coherence tomography, is reviewed. Finally, there is increasing interest in the percutaneous treatment of structural heart disease, particularly percutaneous aortic valve implantation. PMID- 21276487 TI - [Progress in hypertension and diabetes in 2010]. AB - New developments in hypertension and diabetes mellitus in 2010 have been dominated by the search for a consensus on the aims of blood pressure control and on diagnostic criteria for diabetes mellitus, both of which have featured in the clinical studies and guidelines published throughout the year. These two risk factors continue to provoke debate about the seriousness of their implications for cardiovascular disease, and knowledge about them is increasing. The year 2010 was notable for the publication of new diagnostic criteria for diabetes mellitus by the American Diabetes Association, of revised guidelines on hypertension from the European Society of Hypertension, and of the results of a number of clinical trials and meta-analyses that have deepened our knowledge of the treatment of hypertension and diabetes. PMID- 21276488 TI - [Progress on cardiac imaging techniques]. AB - The development of a noninvasive diagnostic test follows a typical timeline: description, enthusiasm, clinical assessment and application, and epidemiological study. However, for techniques such as echocardiography that are widely available, have no harmful effects and are inexpensive, clinical applications may become widespread before they have been evaluated. Real progress is being made with the use of new methodologies, such as myocardial deformation echocardiography and three-dimensional echocardiography. Three-dimensional transesophageal echocardiography has returned echocardiography to its place at the center of modern cardiac diagnosis after it had been displaced in recent years by cardiac multislice CT and cardiac magnetic resonance. However, the new radiological techniques that have helped to reduce radiation exposure to patients and that have improved image acquisition could restore CT to the heart of general cardiac diagnosis. At the moment, it is not possible to displace the echocardiography from its central role in cardiac imaging. This article contains a review of the most important publications on echocardiography, magnetic resonance imaging and cardiac CT that have appeared recently in cardiology journals, mainly during 2010. PMID- 21276489 TI - [Heart failure and heart transplant]. AB - The mission of the Heart Failure and Transplantation Section of the Spanish Society of Cardiology is to study, to promote interest in, and to disseminate information about all aspects of myocardial dysfunction and heart transplantation. Heart failure is a highly prevalent condition that consumes a substantial proportion of healthcare resources. Consequently, there is considerable interest in the disorder. Numerous lines of clinical and preclinical research are actively being pursued and new ways of increasing knowledge about the disease are constantly being explored. The aim of this article was to describe the most recent developments concerning heart failure and its treatment. Firstly, the latest publications on chronic heart failure are analyzed. Then, there is a review of the most recent studies on resynchronization therapy and of clinical trials on acute heart failure. Thirdly, new developments in right heart dysfunction and pulmonary hypertension, and the findings of the Spanish Pulmonary Hypertension Registry are discussed. Finally, the latest information on ventricular assist devices and heart transplantation is presented. In addition, the most important data obtained from official transplantation registries (i.e. the Spanish Heart Transplantation Registry and the Spanish Post-Heart Transplantation Tumor Registry) are reviewed. PMID- 21276490 TI - [Update in ischemic heart disease]. AB - This article contains a review of the main developments reported in 2010 concerning the pathophysiology, prevention, prognosis and treatment of ST-segment elevation and non-ST-segment elevation acute coronary syndromes, and of recommendations made by the most recent clinical practice guidelines. PMID- 21276491 TI - [Update on pediatric cardiology and congenital heart disease: imaging techniques, pulmonary arterial hypertension, hybrid treatment, and surgical treatment]. AB - This article contains a review of the most significant contributions to pediatric cardiology and congenital heart disease reported in publications between September 2009 and August 2010. The review focuses on imaging techniques, new treatment for pulmonary arterial hypertension in pediatric patients, and therapy in general (e.g. hybrid treatment and surgical treatment). With regard to imaging techniques, the review highlights the increasing application of congenital heart disease diagnosis during fetal life, the introduction of new echocardiographic techniques (e.g. tissue Doppler imaging, two-dimensional speckle-tracking imaging and three-dimensional echocardiography) into routine clinical practice, and the growing use of cardiac CT and magnetic resonance imaging in diagnosis and the assessment of cardiac function, respectively. The role played by cardiac interventions continues to increase and cardiac surgery is becoming more advanced and has, in some cases, been combined with hybrid techniques. However, there are still a number of controversial issues in cardiac surgery that have not yet been resolved, such as whether or not fenestration should be used with Fontan surgery, the optimum type of correction for hypoplastic left heart syndrome, and the best conduit for pulmonary artery replacement. PMID- 21276492 TI - [Preventive cardiology and cardiac rehabilitation]. AB - The Preventive Cardiology and Rehabilitation Section of the Spanish Society of Cardiology provides the principal national reference point for scientific knowledge about cardiovascular risk factors in the Spanish population, about the incidence and prevalence of cardiovascular disease in Spain, and about disease prevention and the use of cardiac rehabilitation to improve the quality of life and prolong the survival of individuals already affected by the disease. By necessity, research into cardiovascular prevention involves sponsoring the implementation of studies into cardiovascular risk factors and disease occurrence. The MESYAS study is a good example. It is the fruit of the combined efforts of members of the metabolic syndrome working group belonging to our Section of the Spanish Society of Cardiology and its aim was to answer a number of unresolved questions that had arisen about the incidence, prevalence and consequences of cardiovascular disease in the Spanish population. Today, after this cohort has been followed up for more than 5 years, the first analysis of the cardiovascular events that occurred in the cohort and their relationship with individual risk factors observed many years previously has become available. Here, the metabolic syndrome working group reports some interesting findings. With the aim of communicating up-to-date information that has undergone expert review, the coordinator of the cardiac rehabilitation working group has the responsibility of summarizing, evaluating and updating the scientific data available on the important subject of the secondary prevention of cardiovascular disease. PMID- 21276493 TI - [Progress in clinical cardiology. The clinical cardiologist's response to new cardiovascular drugs]. AB - This article contains a review of major new developments in drug treatment and the impact they could have for the general cardiologist. New treatments for arrhythmias, chronic ischemic heart disease, and secondary prevention are changing the practice of clinical cardiology. In addition, recent publications on treatment adherence and therapeutic inertia are discussed. Finally, the work of the Clinical Cardiology and Outpatient Section of the Spanish Society of Cardiology during the last year is described. PMID- 21276494 TI - [Progress in cardiac electrophysiology and arrhythmias]. AB - This article provides a commentary on some of the most significant research on cardiac arrhythmias published during the last year. Publications were selected for their clinical importance or because they report on improvements in the invasive techniques used in cardiac electrophysiology. PMID- 21276495 TI - [Progress in cardiac pacing]. AB - This article contains a discussion of the most recent developments in cardiac resynchronization therapy, of the feasibility of performing magnetic resonance imaging in patients with cardiac pacemakers, and of the current and future status of leadless pacing. Finally, the most significant scientific articles published in the last year are reviewed. PMID- 21276496 TI - Invited commentary. PMID- 21276497 TI - Invited commentary. PMID- 21276498 TI - The Society for Vascular Surgery: built to last. PMID- 21276499 TI - Invited commentary. PMID- 21276500 TI - Are intrasac pressure measurements useful after endovascular repair of abdominal aortic aneurysms? AB - Few would argue with the need for long-term follow-up after endovascular repair of abdominal aortic aneurysms. A small risk of reintervention persists and the challenge remains to identify those patients that will require additional procedures to prevent subsequent complications. The ideal follow-up regimen remains elusive. Up until this point, most regimens have consisted of radiologic imaging, with either computed tomography (CT) scans or ultrasonography to identify continued aneurysm perfusion (endoleaks) and document sac dynamics, either shrinkage, growth, or stability. However, aneurysm sac growth or shrinkage serves only as a surrogate measurement for pressurization, and although it is uniformly believed that attachment site endoleaks require treatment, it remains controversial as to how to determine which type II endoleaks pressurize an aneurysm sufficiently to require therapy. In response to these difficulties, several manufacturers have developed pressure sensors that can be implanted at the time of the initial repair. They have been shown capable of measuring intrasac pressures that have appropriately responded to reinterventions for endoleaks. However, are they the answer we are looking for? Are they ready for widespread use? Do they offer a reliable and consistent measure of intrasac pressure that can be trusted to determine the need, or lack of need, for further therapy? Our debaters will try to convince us one way or another. PMID- 21276501 TI - Editors' commentary. PMID- 21276502 TI - Development of femoro-femoral and axillo-femoral bypass procedures. PMID- 21276505 TI - Regarding "Stent fractures in the Hemobahn/Viabahn stent graft after endovascular popliteal aneurysm repair". PMID- 21276506 TI - Regarding "Inherent problems with randomized clinical trials with observational/no treatment arms". PMID- 21276508 TI - Regarding "Causes of late mortality after endovascular and open surgical repair of infrarenal abdominal aortic aneurysms". PMID- 21276509 TI - Regarding "Endovenectomy of the common femoral vein and intraoperative iliac vein recanalization for chronic iliofemoral venous occlusion". PMID- 21276511 TI - Promoting high-quality breast imaging. PMID- 21276512 TI - Establishing a comprehensive breast magnetic resonance imaging service in a community hospital. AB - Advances made since the first application of breast magnetic resonance imaging (MRI) in the late 1980s have made it an integral complement to a comprehensive breast assessment centre. Incorporating breast MRI into an existing practice can appear daunting, but a structured and organized approach allows for a smoother transition. With a well thought out plan that engages all team members and experience in interpretation and performing of interventional procedures, breast MRI will serve to add valuable information in patient management. PMID- 21276513 TI - Foreword: athletic foot and ankle injuries. PMID- 21276514 TI - Preface: athletic injuries of the foot and ankle. PMID- 21276515 TI - Etiology, pathophysiology, and most common injuries of the lower extremity in the athlete. AB - The majority of injuries during sport are to the lower extremity (more than 50%), most of which occur in children and young adults younger than 25 years and involve fractures, ligament injuries, or tendon injuries. This article discusses the etiology of some of the most common foot and ankle sports-related injuries. The authors focus on clinical findings, associated injuries, pathophysiology, and current trends. Many of these factors are discussed in detail elsewhere in this issue. PMID- 21276516 TI - New technology and techniques in the treatment of foot and ankle injuries. AB - The advancement of new technologies in the treatment of foot and ankle injuries seems exponential over the last several years. As surgeons expand their knowledge of the pathology and improve their treatment techniques, they come upon new and different ways to treat the same pathologic conditions. Foot and ankle injuries are commonplace in competitive sports. This article provides an overview of the diagnosis and treatment, including surgical techniques, of common foot and ankle injuries. PMID- 21276517 TI - Hallux, sesamoid, and first metatarsal injuries. AB - Hallux, sesamoid, and first metatarsal injuries are common foot injuries and have implications in the biomechanical functionality of the first ray and foot. They are essential for propulsion in normal gait. As part of the first ray, it is an important contributor to normal locomotion. Any structure disruption or injury can create angular changes or arthritis, which can have biomechanical implications, including pain, disability, compensation, swelling, and reduced range of motion. PMID- 21276518 TI - Plantar plate tears: a review of the modified flexor tendon transfer repair for stabilization. AB - Forefoot pain is one of the most common presenting problems in a foot and ankle practice. One of the most common presenting problems, yet most commonly missed problems, is a plantar plate tear. Often the problem is considered to be potential neuroma, fat pad atrophy, or a generalized diagnosis of metatarsalgia or metatarsal head overload. Unfortunately, not enough attention is placed on the plantar and medial/lateral ligamentous structures of the metatarsal-phalangeal joints. This lack of attention results in poor diagnosis, lack of care, treatment for the wrong condition, and ultimate frustration for the patients and doctor. PMID- 21276519 TI - Lisfranc injury and Jones fracture in sports. AB - This article provides an update and overview of Lisfranc injury and Jones fracture in the athletic population. Sports-related Lisfranc sprains or fractures are subtle injuries that can be easily missed. Now, there is greater understanding of midfoot sprains that represent a spectrum of injury to the Lisfranc ligament complex. Most types of fifth metatarsal fractures have a favorable prognosis and can be treated conservatively. The treatment options for Jones fractures in athletes have been much debated. This article discusses issues related to anatomy, mechanism of injury, clinical presentation, imaging, and diagnosis, which are necessary to appropriately treat these injuries. PMID- 21276520 TI - Chronic ankle and subtalar joint instability in the athlete. AB - Chronic ankle and subtalar joint (STJ) instability is a common clinical entity and the physician must be able to determine the exact pathologic condition for proper treatment. There are many diagnostic techniques that can be used to evaluate the ankle joint and STJ. These diagnostic techniques do not take the place of a proper patient history taking. Appropriate and aggressive rehabilitation should be attempted in all cases of chronic ankle and subtalar instability before electing surgical reconstruction. PMID- 21276521 TI - Lateral ankle triad: the triple injury of ankle synovitis, lateral ankle instability, and peroneal tendon tear. AB - Many articles have been published that discuss various lateral ankle injuries and specific lateral ankle pathology. The purpose of this article is to explore and present a specific combination of findings that the author's multiphysician practice has noticed on a frequently recurring basis. The triple injury of ankle synovitis, ankle instability, and peroneal tendon tear can be termed the Lateral Ankle Triad. While it is common to find each of these specific injuries individually, they are often found in combination. PMID- 21276522 TI - Acute and chronic Achilles tendon ruptures in athletes. AB - The Achilles tendon is the most injured tendon of athletes in the lower extremities and is the most common tendon to rupture spontaneously. Operative repair provides earlier return to sporting activities and lesser rate of rerupture. The general goal is to attempt anastomosis of the acute ruptured ends; however, delayed ruptures may require more extensive procedures. New surgical approaches, including percutaneous and mini-open techniques, are being introduced to potentially diminish perioperative complications. Advent of early protective range of motion and rehabilitation has shown a potential for earlier return to sporting activities for Achilles ruptures. PMID- 21276523 TI - Dance medicine of the foot and ankle: a review. AB - All forms of dance are highly demanding activities, with a lifetime injury incidence of up to 90%. Most dance types are stressful, particularly on the dancer's forefoot, but certainly there is no area of the foot or ankle that is exempt from potential injury. Dancers often have unusual difficulties related to the dynamic biomechanical forces required by their individual dance form. A thorough understanding of these movements guides the physician to the cause of the injury, particularly in understanding specific overuse injuries. This article discusses biomechanics of the foot and the imaging and treatment of dance-related injuries. PMID- 21276524 TI - Current concepts for the use of platelet-rich plasma in the foot and ankle. AB - Platelet-rich plasma (PRP) injections have been used and studied since the 1970s. Its use has become more popularized over the last several years in the treatment of foot and ankle injuries. Platelets are a normal product found in the clotting cascade and inflammatory process of healing. They produce granules that release growth factors that promote healing. PRP works by increasing the concentration of platelets, thereby increasing the concentration of growth factors and increasing healing potential. PRP has an advantage over many tissue engineering products in that it is autologous. It has been studied and used for the treatment of tendon injuries, chronic wounds, ligamentous injuries, cartilage injuries, muscle injuries, and bone augmentation. The results from in vitro and in vivo studies in foot and ankle injuries are promising. The applications for treatment in the foot and ankle may be broader than once thought. PMID- 21276525 TI - Pathology-designed custom molded foot orthoses. AB - Treating patients with custom foot orthoses for common pathologies is a rewarding experience when the proper steps are taken during foot casting and custom orthosis prescription writing. This article describes successful methods for orthoses casting and prescription writing for custom-molded orthoses for Achilles tendonitis, pes planus, hallux limitus, plantar fasciitis/heel spurs, lateral ankle instability, metatarsalgia, and pes cavus. In addition, a summary of orthotic laboratory instructions for each pathology-designed custom orthosis is provided, which should be considered by orthotic laboratories. PMID- 21276526 TI - Physical therapy and rehabilitation of the foot and ankle in the athlete. AB - Foot and ankle injuries in athletes are common. Physical therapy plays a fundamental role in the management of sports injuries. The purpose of this article is to (1) raise awareness for using physical therapy for treatment of foot and ankle injuries in athletes, (2) discuss considerations specific to athletes during the rehabilitation process, and (3) increase the reader's knowledge about the in-depth role of physical therapy in the management of foot and ankle injuries in athletes. PMID- 21276527 TI - Primary subtalar joint arthrodesis with internal and external fixation for the repair of a diabetic comminuted calcaneal fracture. AB - Comminuted, intra-articular calcaneal fractures can cause severe lower extremity impairment and have devastating effects on a patient's well being. Diabetes is a multisystem process that may cause neuropathy and loss of protective sensation further complicating the prognosis. Not all calcaneal fractures are created equal and when considering the patient's overall presentation and extent of injury, the combined approach of internal and external fixation for fracture reduction may be beneficial for restoration of anatomic alignment and function. PMID- 21276528 TI - External fixation for surgical off-loading of diabetic soft tissue reconstruction. AB - Early and aggressive treatment of diabetic foot wounds is imperative for the reduction of amputation risk. Whereas sound local wound care is important for successful management; chronic wounds often reach a stagnant point in healing because of diabetic vasculopathy, immunopathy, or neuropathy. The type, size, shape, and location of wound may not always allow primary closure or grafting. In patients with adequate perfusion and in the absence of infection, local advancement flaps are suitable for durable closure. A review and case report demonstrating the use of these flaps with external fixation as an adjunctive therapy for surgical off-loading is presented. PMID- 21276529 TI - The American College of Surgeons: a legacy of leadership. PMID- 21276530 TI - Invited commentary. PMID- 21276531 TI - Is laparoscopic repeat hepatectomy feasible? A tri-institutional analysis. AB - BACKGROUND: A laparoscopic approach has not been advocated for repeat hepatectomy on a large scale. This report analyzes the experience of 3 institutions pioneering laparoscopic repeat liver resection (LRLR). The aim of this study was to evaluate the feasibility, safety, oncologic integrity, and outcomes of LRLR. STUDY DESIGN: All patients undergoing LRLR were identified. Since 1997, 76 LRLRs have been attempted. Operative indications were metastasis (n = 63), hepatocellular carcinoma (n = 3), and benign tumors (n = 10). All patients had 1 or more earlier liver resections (28 open, 44 laparoscopic), including 16 major resections (en bloc removal of 3 or more Couinaud segments). RESULTS: Eight conversions (11%) to open resections (n = 7) or radiofrequency ablation (n = 1) were required due to technical difficulties or hemorrhage. LRLRs included 49 wedge or segmental resections and 19 major hepatectomies. Median blood loss and operative time were 300 mL and 180 minutes. Patients with previous open liver resection (group B) experienced more intraoperative blood loss and transfusion requirements than those with earlier laparoscopic resections (group A) (p = 0.02; p = 0.01, respectively). R0 resection was achieved in 58 of 64 (91%) patients with malignant tumor. The incidence of postoperative complications and duration of hospital stay were not statistically different between the 2 groups. Bile leakages developed in 5 (6.6%) patients, including 1 requiring reoperation. There was no perioperative death. Median tumor size was 25 mm (range 5 to 125 mm) and the median number of tumors was 2 (range 1 to 7). Median follow-up was 23.5 months (range 0 to 86 months). There was no port-site metastasis. The 3- and 5 year actuarial survivals for patients with colorectal metastases were 83% and 55%, respectively. CONCLUSIONS: Laparoscopic repeat hepatic resections can be performed safely and with good results, particularly in patients with earlier laparoscopic resections. PMID- 21276532 TI - Does preoperative anemia adversely affect colon and rectal surgery outcomes? AB - BACKGROUND: Complications associated with blood transfusions have resulted in widespread acceptance of low hematocrit levels in surgical patients. However, preoperative anemia seems to be a risk factor for adverse postoperative outcomes in certain surgical patients. This study investigated the National Surgical Quality Improvement Program (NSQIP) database to determine if preoperative anemia in patients undergoing open and laparoscopic colectomies is an independent predictor for an adverse composite outcome (CO) consisting of myocardial infarction, stroke, progressive renal insufficiency or death within 30 days of operation, or for an increased hospital length of stay (LOS). STUDY DESIGN: Hematocrit levels were categorized into 4 classes: severe, moderate, mild, and no anemia. From 2005 to 2008, the NSQIP database recorded 23,348 elective open and laparoscopic colectomies that met inclusion criteria. Analyses using multivariable models, controlling for potential confounders and stratifying on propensity score, were performed. RESULTS: Compared with nonanemic patients, those with severe, moderate, and mild anemia were more likely to have the adverse CO with odds ratios of 1.83 (95% CI 1.05 to 3.19), 2.19 (95 % CI 1.63 to 2.94), and 1.49 (95% CI 1.20 to 1.86), respectively. Patients with a normal hematocrit had a reduced hospital LOS, compared with those with severe, moderate, and mild anemia (p < 0.01). A history of cardiovascular disease did not significantly influence these findings. CONCLUSIONS: This large multicenter database analysis suggests that the presence of severe and moderate and even mild preoperative anemia is an independent risk factor for complications and a longer hospital stay after colon surgery. PMID- 21276533 TI - Three-step method for lymphadenectomy in gastric cancer surgery: a single institution experience of 120 patients. AB - BACKGROUND: Gastric cancer is one of the most common malignancies and a leading cause of cancer death. Complete resection is still the only treatment to offer a cure for patients with gastric cancer. Lymphadenectomy is the most important part of curative resection, but lymphadenectomy is also very difficult in gastric cancer surgery. The aim of this study was to report our 3-step method for lymphadenectomy and clarify its safety and value in gastric cancer. STUDY DESIGN: A total of 120 consecutive patients underwent our 3-step method for lymphadenectomy at the Second Affiliated Hospital Zhejiang University College of Medicine between February 2006 and July 2007. The main surgical procedure was performed from right to left and from caudal to cranial. Clinical factors, surgical variables, postoperative morbidity, and hospital (30-day) mortality were analyzed retrospectively. RESULTS: Total gastrectomy was performed in 41 patients; combined adjacent organ resection was performed in 9 patients. The mean operation time was 201.8 minutes, and the mean blood loss was 376.7 mL. The median postoperative hospital stay was 14.9 +/- 4.3 days. A total of 3,569 lymph nodes (LNs) were removed and examined, and 2,879 were negative. More than 15 LNs were examined in all 120 patients. The median number of examined LNs was 29 (range 17 to 64; mean 29.7 +/- SD 9.6) per patient, and the median number of positive LNs was 5 (range 0 to 37; mean 5.8 +/- SD 7.1) per patient. The overall incidence of postoperative complications was 10.8%, and the rate of hospital death was 0%. The median follow-up period for those patients was 34.3 months (range 10 to 53 months), and the overall 3-year survival rate was 40.6%. CONCLUSIONS: The 3-step method for lymphadenectomy is easy to perform and is a safe and useful procedure for gastric cancer surgery. PMID- 21276534 TI - Mental practice: effective stress management training for novice surgeons. AB - BACKGROUND: Surgeons are often subject to excessive levels of acute stress that can impair their performance. Mental practice (MP) is a strategy used in other high-performance industries to alleviate anxiety. This study investigated if MP reduces stress in novice surgeons. STUDY DESIGN: A prospective, randomized controlled design was used with 20 novice surgeons recruited by random sampling. After baseline testing, participants underwent training on an evidence-based virtual reality (VR) curriculum. They then performed 5 VR laparoscopic cholecystectomies (LC) after being randomized to MP or control groups. The MP group performed 30 minutes of MP using a validated MP training protocol before each LC; control participants conducted an unrelated activity. Stress was assessed subjectively using the validated State-Trait Anxiety-Inventory (STAI) questionnaire and objectively with a continuous heart rate (HR) monitor and salivary cortisol. Mental imagery was assessed using the validated mental imagery questionnaire. RESULTS: Eighteen participants completed the study. There were no intergroup differences in baseline stress, imagery, or technical ability. Comparing the MP group with controls, subjective stress (STAI) was lower for the MP group (median 8.40 vs 11.31, p < 0.01). Objective stress was also significantly reduced for the MP group in terms of the average HR (median 72 vs 88 beats/minute, p < 0.0001), maximum HR (median 102 vs 119 beats/minute, p < 0.01), and cortisol (median 2.26 vs 3.85 nmol/L, p < 0.05). Significant negative correlations were obtained between stress and imagery, indicating that improved imagery was associated with lower stress (p < 0.05). CONCLUSIONS: A short period of MP reduces the subjective, cardiovascular, and neuroendocrine response to stress on a VR simulator. Additional research should determine whether this effect extends beyond novice surgeons and transfers to the operating room. PMID- 21276535 TI - Observational teamwork assessment for surgery: content validation and tool refinement. AB - BACKGROUND: Effective teamwork is crucial for safe surgery. Failures in nontechnical and teamwork skills are frequently implicated in adverse events. The Observational Teamwork Assessment for Surgery (OTAS) tool assesses teamwork of the entire team in the operating room. Empirical testing of OTAS has yet to explore the content validity of the tool. STUDY DESIGN: This was a cross sectional observational study. Data were collected in 30 procedures by 2 trained researchers. Five teamwork behaviors were scored (ie, communication, leadership, cooperation, coordination, and monitoring) and behavior exemplar completion was recorded (phase 1). Expert operating room personnel (5 surgeons, 5 anesthesiologists, and 5 scrub nurses) assessed the content validity of the OTAS exemplar behaviors. Finally, a panel of operating room patient-safety experts refined the exemplars (phase 2). RESULTS: In total, the observability (presence/absence) of 130 exemplars was assessed by 2 blinded observers in 30 general surgical cases. Observer agreement was high (Cohen's kappa >= 0.41) for 83.85% (109 of 130) of exemplar behaviors; 60.77% (79 of 130) of exemplar behaviors were observed frequently with high observer agreement. The majority of the exemplars were rated by expert operating room practitioners and an expert panel as substantial contributors to teamwork and patient safety. Based on expert consensus, 21 behavior exemplars were removed from OTAS and an additional 23 were modified. CONCLUSIONS: The exemplars of OTAS demonstrated very good content validity. Taken together with recent evidence on the construct validity of the tool, these findings demonstrate that OTAS is psychometrically robust for capturing teamwork in the operating room. PMID- 21276536 TI - Levels of evidence for laparoscopic surgery for colorectal cancer. PMID- 21276538 TI - Electronic synoptic operation report. PMID- 21276540 TI - Snow day revisited. PMID- 21276541 TI - Editorial comment on plagiarism. PMID- 21276542 TI - Plagiarism: Are there practical ways to avoid it? PMID- 21276543 TI - Cardiac arrest in the PACU: an analysis of evolving challenges for perianesthesia nursing. AB - Cardiac arrest in the PACU is a rare and poorly described event, with attendant limitations to experiential learning for the perianesthesia nurse. Good outcome from in-hospital cardiac arrest events differs partly because of variability in direct causes and clinical responses. Development of in-house training programs tailored to retain basic and advanced life support skills and enhance perianesthesia nurse responses to PACU arrests are essential to improving outcomes. PMID- 21276544 TI - Preprocedure warming maintains normothermia throughout the perioperative period: a quality improvement project. AB - Research supports the practice of preprocedure warming as a method to prevent the development of unplanned perioperative hypothermia. ASPAN defines hypothermia as a core temperature lower than 36 degrees C. The purpose of this quality improvement project was to explore the idea that preprocedure warming maintains perioperative normothermia. Information was obtained through retrospective chart reviews (n = 148). Temperatures were compared for patients who received standard preprocedure care versus patients who were warmed with a warming gown for one hour preprocedure. Before the institution of warming, about 50% of the patients received in the PACU were hypothermic. After the warming was instituted, only 12% of patients were received in a hypothermic state in the PACU. Concepts discussed in this paper include preprocedure warming, postprocedure hypothermia, and complications associated with hypothermia. PMID- 21276545 TI - Creating a safer perioperative environment with an obstructive sleep apnea screening tool. AB - Obstructive sleep apnea (OSA) is a common condition that increases the risk of complications for patients undergoing sedation and/or general anesthesia. The purpose of this quality improvement project was to promote evidence-based practice for nurses to screen patients with OSA in the perioperative setting. A step-by-step team process was implemented using the Iowa Model of Evidence-Based Practice in a shared leadership environment at an acute care facility to educate staff and evaluate the practice change. A pilot project reviewed patient data pre and post-implementation of an OSA screening tool, which revealed evidence of safer patient care. As a result of incorporating an OSA assessment, patient advocacy and a safer perioperative environment was created. PMID- 21276547 TI - EBP: Evidence to practice implementation. PMID- 21276546 TI - Effect of infused norepinephrine dosage on pressure ulcers in perianesthesia care unit patients: a pilot study. AB - To determine whether treatment with moderate-high dose norepinephrine is a contributory cause increasing the risk of pressure ulcer development in critical postoperative, mechanically ventilated, hyperglycemic patients. A pilot clinical cohort study was conducted in a PACU in a tertiary hospital. A convenience sample of 16 hyperglycemic patients undergoing mechanical ventilation with at least 24 hours' stay in the PACU were divided into two groups of eight according to dosage of norepinephrine infusion at any moment during the days monitored. One group received >= 2.5 mg/hour, and the other received <2.5 mg/hour. The dose of norepinephrine administered by continuous venous infusion and the occurrence of stage II pressure ulcers were recorded. The proportion of patients with pressure ulcers in the group receiving moderate-high dose of norepinephrine was 50% compared with 0% in the low-dose group (P = .038). The odds ratio for daily average norepinephrine administered (mg/hour) was 2.21 (95% CI = 1.27 to +infinite); exact P = .0049. The odds ratio for daily average norepinephrine administered adjusting for weight (mg/kg/hour) was 3.05 (95% CI = 1.299 to +infinite); exact P = .0016. Moderate-high dose norepinephrine is a contributory cause that significantly increases the risk of pressure ulcer development in certain short-stay PACU patients. PMID- 21276548 TI - Persistent postsurgical and posttrauma pain. PMID- 21276549 TI - Research: an influential force in transforming health policy. PMID- 21276550 TI - Research news: Perioperative normothermia. PMID- 21276551 TI - The review process: What is it? PMID- 21276552 TI - What does the patient protection and affordable care act mean to you and your patients? PMID- 21276553 TI - Extensor tendoscopy of the ankle. AB - The extensor digitorum longus muscle (EDL) arises from the upper three-quarters of the extensor surface of the fibula, the interosseous septum and from a small area of the tibia across the superior tibiofibular joint. It forms its four tendons which are restrained by the superior and inferior extensor retinacula. The two retinacula prevent the EDL and extensor hallucis longus (EHL) tendons from bow stringing. The inferior extensor retinaculum also contributes to the stability of the subtalar joint. Extensor tendoscopy has been performed in 3 patients and no neural injury was noted. PMID- 21276554 TI - Avulsion fracture of the peroneus longus tendon insertion at the base of the first metatarsal: report of a case. AB - Isolated avulsion fracture of the peroneus longus tendon insertion at the base of the first metatarsal is very rare. Similar to most avulsion fractures that result from excessive strain at a tendon or ligament insertion, this type of injury is caused by the strong tension exerted by the peroneus longus tendon. The mechanisms leading to this lesion and treatment options are not clearly defined. We present the case of an isolated minimally displaced intra-articular avulsion fracture at the plantar lateral base of the first metatarsal. Faced with a painful non-union following conservative treatment we considered excision of the bony fragment and first tarsometatarsal arthrodesis. This leads to a favourable functional outcome. PMID- 21276555 TI - Island lateral plantar artery perforator flap for reconstruction of weight bearing plantar areas. AB - Reconstruction of the foot often presents difficulties, particularly in weight bearing areas (WBA). The peculiarities of WBA tissues are rarely found in other regions of the body. The case examined, presents a 72-year-old diabetic patient, with lower-limb arteriopathy, and sensitive and motor neuropathy, with an ulcer in the weight-bearing area of the foot, close to the V metatarsal bone. The plantar defect was reconstructed by using an island V-Y 6cm*3cm flap, based on the lateral plantar artery perforators. The postoperative course was smooth and the flap survived completely. The lateral plantar artery perforator flap is minimally invasive and provides a valid alternative for the repair of glabrous plantar defects. PMID- 21276556 TI - Hindfoot endoscopy for accessory flexor digitorum longus and flexor hallucis longus tenosynovitis. AB - We present a case report involving the flexor digitorum accessorius longus (FDAL) tendon which travels through a fibro-osseous tunnel together with the flexor hallucis longus (FHL) tendon, causing a stenosing tenosynovitis. The patient was admitted with posteromedial ankle pain and diagnosed clinically as FHL tenosynovitis. We found two tendons in the tunnel during hindfoot endoscopy. The stenosis was relieved by endoscopic debridement. After the operation, we checked the MRI images and observed two tendons. We concluded that the accessory tendon was the FDAL. Two years later the patient was admitted with the same symptoms. We excised the FDAL muscle and the patient's symptoms resolved. The FDAL muscle is a cause of FHL tenosynovitis. Because of its variability and mostly asymptomatic nature, it may not be noticed it on an MRI scan. Hindfoot endoscopy is a safe tool for the diagnosis of this condition and curative treatment is afforded by excision of the FDAL muscle. PMID- 21276557 TI - Opening wedge low tibial osteotomy: a minimally invasive approach. AB - Valgus osteotomy of the distal tibia may decrease the symptoms of ankle osteoarthritis and halt the progression of degeneration by redistributing or decreasing joint contact stress. Classically, opening wedge low tibial osteotomy was performed as an open procedure and the osteotomy site was stabilised by K wires or medial plates. Potential complication of the medial wound can be disastrous. Wound breakdown can lead to exposure of the implant. We present a minimally invasive approach with osteotomy and bone grafting through a small posteromedial wounds and the osteotomy site is stabilized with MIPO (minimally invasive plate osteosynthesis) technique. This approach can minimize the soft tissue dissection and the potential wound complication. PMID- 21276558 TI - Functional outcomes following ceramic total joint replacement for hallux rigidus. AB - INTRODUCTION: The aim of this study was to evaluate functional outcomes following ceramic arthroplasty used in the treatment of osteoarthritis of the hallux metatarsophalangeal (MTP) joint. MATERIALS AND METHODS: Thirty-seven consecutive patients who underwent press-fit ceramic joint arthroplasty were identified. Joint movement, gait pressure studies, radiographs, patient's outcome based on the American Orthopaedic Foot and Ankle Society (AOFAS) scale, hallux metatarsal phalangeal-interphalangeal index (HMPI) and visual analogue pain scales were assessed. RESULTS: Mean follow-up was 33 (12-60) months. Ninety-two percent of patients were satisfied with the surgery. AOFAS and HMPI scores were good to excellent in more than 90%. Six implants had lucent lines of greater than 2mm at 18 months. Three of these joints also had subsidence of both components. There was no correlation between implant loosening and patient outcomes. Mean hallux pressure at toe-off decreased from 7.1 to 3.5 N cm-2 (p<0.01) equalising with normal contralateral toe pressure. Three patients required revision surgery and one patient had a transient wound infection. CONCLUSIONS: Good to excellent results have been achieved following ceramic total MTP joint arthroplasty. The clinical relevance of progressive lucencies around the implant is uncertain and longer follow-up may identify subsidence and ultimate failure. PMID- 21276559 TI - A reliable surgical approach for the two-staged amputation in unsalvageable limb and life threatening acute progressive diabetic foot infections: tibiotalar disarticulation with vertical crural incisions and secondary transtibial amputation. AB - BACKGROUND: If all efforts to treat acute progressive diabetic foot infection remain insufficient, the decision of major amputation should be undertaken. For this purpose, guillotine amputation is usually performed first. However, guillotine amputation below the knee level may cause the corresponding infection to spread to preserved anatomical spaces. METHOD: First stage of our procedure consists of tibiotalar disarticulation and vertical incisions performed throughout the lower leg to remove the septic foot and drain the compartments. During the interval period, appropriate antibiotherapy and wound care are applied. After the interval period, definitive transtibial amputation is performed in the second stage. RESULTS: Fifty-nine percent of the 62 transtibial amputations were healed completely. Failure developed in 3 cases which required opening of the amputation stump. In one patient, revision amputation at a higher transtibial level was done. Infection and necrosis reached to the knee joint in the other two patients and transfemoral amputation became the only treatment option for these 2 cases. CONCLUSION: Tibiotalar disarticulation with vertical lower leg incisions as a first stage of two-stage transtibial amputation is a safe and reliable method. It reduces the risk of unnecessary tissue sacrifice and failure rate of the secondary transtibial amputation. PMID- 21276560 TI - Case series of 17 modified Weil's osteotomies for Freiberg's and Kohler's II AVN, with AOFAS scoring pre- and post-operatively. AB - BACKGROUND: Treatment for metatarsal head avascular necrosis is largely conservative. For severe or refractory cases there are various surgical options. METHODS: We have performed a 'modified Weil's osteotomy' of the distal metatarsal in order to manage this problem. We present the largest case series, to our knowledge, with 17 such cases. The patients were scored pre- and post-operatively using the AOFAS Forefoot scoring system. RESULTS: We found that this procedure provided a mean score improvement of 36 points, with a complication rate of 5.9%. CONCLUSION: We would advocate this modified osteotomy as an effective, reliable and safe treatment option. PMID- 21276561 TI - The arthroscopic Lapidus procedure. AB - BACKGROUND: Hypermobility of the first metatarsocuneiform (MC) joint is one of the causes believed to contribute to symptomatic hallux valgus. An arthrodesis of the first MC joint offers definitive correction of the intermetatarsal angle. This procedure can be associated with pseudoarthrosis and shortening of the first ray. This study presents our experience and results with an arthroscopic technique for performing this arthrodesis. MATERIALS AND METHODS: Five patients with severe hallux valgus associated with hypermobility of the first MC joint were treated with this operation. RESULTS: The functional assessment scales revealed very good results. Radiographic evaluation confirmed fusion in all the patients. The hallux valgus angle improved by 25.6 degrees , the intermetatarsal angle improved by 10.6 degrees . The shortening of the first ray was limited to 2.7 mm. CONCLUSION: This new technique is a valid option for performing an arthrodesis of the MC joint. PMID- 21276562 TI - Functional outcome after percutaneous tendo-Achilles lengthening. AB - BACKGROUND: Percutaneous tendo-Achilles lengthening (PTAL) is a common procedure performed as an adjunct to other procedures that are used to treat a variety of foot and ankle disorders. Despite the widespread use of PTAL, the only literature to substantiate its efficacy comes from the treatment of forefoot ulceration in diabetics. The complications of the procedure include pain along the Achilles tendon, difficulty using stairs, weakness with toe-off, inadvertent complete tenotomy, and cosmetic appearance. We sought to investigate the functional outcomes specific to PTAL when performed in tandem with triple arthrodesis and subtalar fusion. MATERIALS AND METHODS: A retrospective review of 107 patients who underwent 117 procedures was performed. Outcomes were assessed by telephone interview using a standard questionnaire. The most common procedure in the study population was triple arthrodesis (91%). RESULTS: Fifty-eight percent of the patients reported moderate improvement in motion postoperatively, but 80% reported some degree of persistent stiffness. Despite 38% of patients reporting postoperative weakness, 66% and 61% stated that ascending and descending stairs, respectively, was easier. CONCLUSION: Overall, 81% of the study population had a positive opinion regarding their surgery. In this heterogeneous population, we showed modest improvement in Achilles tendon-related outcomes when PTAL was performed in tandem with other surgeries. PMID- 21276563 TI - A comparative study of radiation dose and screening time between mini C-arm and standard fluoroscopy in elective foot and ankle surgery. AB - BACKGROUND: Mini C-arm devices have gained popularity in extremity surgery. There is little evidence of the benefits of this technique in the clinical setting of foot and ankle surgery. We used dose area product (DAP) to compare radiation usage between mini C-arm and standard fluoroscopy. METHODS: We prospectively reviewed 127 cases requiring intra-operative screening during elective foot and ankle surgery. RESULTS: Mini C-arm was used in 55 patients and standard fluoroscopy in 72 patients. There was a statistically significant reduction in mean DAP using the mini C-arm, 3.46 Gy cm2 vs 7.43 Gy cm2 (P=0.0013). There was no difference in screening time. The annual saving from using the mini C-arm could be L9391, saving the total cost of the device over 5 years. CONCLUSION: The mini C-arm reduces radiation risk and costs when compared to standard fluoroscopy. We recommend its regular use in foot and ankle surgery. PMID- 21276564 TI - Dysplasia epiphysealis hemimelica: a report of four cases. AB - Dysplasia epiphysealis hemimelica (DEH), also known as Trevor's disease, is a rare congenital skeletal developmental disorder in childhood. It is characterized by an asymmetric osteocartilaginous overgrowth arising from epiphyses or epiphyseal equivalents. Lesions have hemimelic topography, usually occur in the lower limbs, most commonly in the ankle and the knee and affect either the medial or lateral part of one epiphysis. OBJECTIVE: The purpose of this study is to describe the imaging features of DEH by reporting four cases. MATERIALS AND METHODS: We present four cases of DEH in one female and three males aged between 7 and 15 years. Lower limb is involved in all cases and patients suffer from pain, limited function and deformity. Radiographs and CT findings were reviewed. All patients were treated by surgical excision. RESULTS: Plain X-ray revealed in all cases an irregular ossification arising from the affected epiphysis. The CT scan revealed an irregular fragmented osteocartilaginous mass involved from the epiphysis, with enlargement of epiphyses and intra-articular extension. CONCLUSION: The early diagnosis and treatment of DEH is necessary in preventing articular function, CT assists in defining the anatomic relationship between the mass and its parent epiphysis and in evaluating the condition of the articular cartilage and soft tissue. The distinct clinical and radiographic features should enable to differentiate the osteochondroma and the DHE. PMID- 21276565 TI - Special report: highlights of the twenty-fifth annual summer meeting of the American Orthopaedic Foot and Ankle Society, Vancouver, Canada, July 16-18, 2009. AB - The Twenty-fifth Annual Summer Meeting of the American Orthopaedic Foot and Ankle Society (AOFAS) was held 16-18 July 2009 at the Westin Bayshore Hotel in Vancouver, British Columbia, Canada. There were 521 registered attendees, including 339 (65%) individuals from 42 of the United States and 182 (35%) attendees from 32 countries outside the United States. PMID- 21276566 TI - If I were the coach. PMID- 21276567 TI - Oculomotor diagnostic protocol for the mTBI population. PMID- 21276569 TI - Implants suggested for glaucoma case. PMID- 21276570 TI - Rosacea and its ocular manifestations. AB - BACKGROUND: Rosacea is a chronic condition affecting the facial and ocular surface tissues. It is historically underdiagnosed and affects people of all ethnicities. The exact pathophysiology of rosacea is poorly understood. A variety of medical therapies are available to treat the various signs and symptoms of rosacea. Currently, there is no cure for the condition. METHODS: This report is a literature review. RESULTS: The clinical manifestations of rosacea are diverse, with periods of exacerbation and remission. Many short- and long-term treatments are available to alleviate the symptoms and effects of rosacea. Variations are common in the medications used, dosages, and durations of treatment. Current topical, oral, and surgical treatment options are presented and reviewed. As a chronic condition, rosacea treatment should be tailored toward individuals and adjusted over time. CONCLUSIONS: Subtle presentations of rosacea may be overlooked by health care providers. When treating the condition, certain individuals may require both systemic and topical therapy to effectively control rosacea outbreaks. Eye care professionals need to be aware of the presence of rosacea to appropriately treat ocular surface disease that is not responding as expected to standard topical therapy. Severe facial and ocular surface damage caused by rosacea may need surgical intervention. Specific treatment protocols are elusive because of the diversity of the disease. Additional research is needed to find the exact cause of rosacea to more effectively manage the dermatologic and ocular manifestations of the disease and to find a cure. PMID- 21276571 TI - Percutaneous treatment of mitral regurgitation: from feasibility to clinical application? PMID- 21276572 TI - Combination of copeptin and high-sensitivity cardiac troponin T assay in unstable angina and non-ST-segment elevation myocardial infarction: a pilot study. AB - BACKGROUND: High-sensitivity cardiac troponin assays have improved the detection of acute coronary syndrome. AIM: To examine the possible incremental value of copeptin in the detection of acute coronary syndrome. METHODS: We designed a prospective cohort study to compare the performance of high-sensitivity cardiac troponin T (hs-cTnT) measured at admission in combination with copeptin, and the performance of hs-cTnT alone, measured at admission, 3 hours and 6 hours, in patients with suspected acute coronary syndrome of < 6 hours' duration after onset of symptoms (exclusion of patients with ST-segment elevation myocardial infarction). RESULTS: Fifty-eight consecutive patients fulfilled our criteria and were included. After detailed investigations, the final adjudicated diagnosis was acute coronary syndrome in 30 patients (including acute myocardial infarction in 13 and unstable angina in 17) and non-acute coronary syndrome in 28 patients. Measured on admission, hs-cTnT concentration was > 14 ng/mL (99 th percentile) in 22 patients with acute coronary syndrome; repetition of the measurement at 3 hours and 6 hours identified three and four additional patients, respectively. The combination of copeptin with hs-cTnT determined on admission identified 26 patients with acute coronary syndrome, with a negative predicted value of 82.6%. The area under the receiver operating characteristic curve was 0.90 for hs-cTnT measured on admission, and 0.94 if repeated at 3 hours and 6 hours or combined with copeptin measurement at admission (non-significant difference). CONCLUSIONS: This prospective study demonstrated that a dual marker strategy that combines hs cTnT with copeptin increased slightly the detection of acute coronary syndrome at admission. PMID- 21276573 TI - Initial clinical experience with implantation of left ventricular lead guided by Overlay Ref for the treatment of congestive heart failure. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) improves clinical outcome in selected patients with advanced congestive heart failure. The Overlay Ref technique may facilitate the procedure for implanting left ventricular (LV) pacing leads to deliver CRT. AIM: To assess the feasibility of deploying a LV pacing lead into a coronary sinus side branch guided by Overlay Ref. METHODS: Data from 88 consecutive patients who met the CRT implantation criteria in our hospital between 28 November 2007 and 30 December 2009 were randomly assigned to two groups. Forty-four patients underwent CRT device implantation using Overlay Ref to guide target vein selection and advance a specifically designed pacing lead into the target vein (Overlay Ref group); 44 patients were conventionally implanted (control group). RESULTS: LV lead implantation was successful in all patients. Mean CRT total procedure times (skin-to-skin) were: Overlay Ref group, 80.7 +/- 18.0 min; control group, 98.5 +/- 32.2 min; p = 0.029. Mean placement of LV pacing lead into target vein times were: Overlay Ref group, 16.2 +/- 7.7 min; control group, 36.4 +/- 23.4 min; p=0.004. Mean total fluoroscopy times were: Overlay Ref group, 13.6 +/- 4.3 min; control group, 23.8 +/- 15.7 min; p=0.007. Mean LV lead fluoroscopy times were: Overlay Ref group, 5.7 +/- 2.9 min; control group, 14.4 +/- 4.6 min; p=0.003. No major complications occurred. CONCLUSIONS: Overlay Ref facilitates location of and entry into the coronary sinus, and shortens the duration of LV pacing lead implantation into the target vein. PMID- 21276574 TI - Therapeutic effects of continuous infusion of brain natriuretic peptides on postmyocardial infarction ventricular remodelling in rats. AB - BACKGROUND: Previous studies have shown protective effects of brain natriuretic peptide (BNP) against the postmyocardial infarction (MI) remodelling process. The transcription factor NF-kappaB is known to play an important role after MI. AIMS: To investigate if NF-kappaB is involved in the protective effects of BNP against adverse post-MI remodelling. METHODS: Rats were randomly assigned to five groups: sham-operation; MI by coronary ligation; MI treated with chronic BNP infusion; MI treated with enalapril; MI treated with BNP+enalapril. Rats were closely monitored for survival rate analysis. Rats from each group were sacrificed on days 3, 7 and 28 postoperation. RESULTS: The results showed that chronic continuous BNP infusion achieved similar effects to enalapril therapy, as evidenced by improved survival rate within the 28-day observation period compared with MI group rats; this effect was closely associated with preserved cardiac geometry and performance. The treatment combination did not offer extra benefits in terms of survival rate. Both BNP and enalapril therapy produced higher heart tissue concentrations of cyclic guanosine monophosphate and lower expression levels of inflammatory cytokines, including tumour necrosis factor-alpha, interleukin-1 and interleukin-6. These benefits were associated with lower phosphorylation levels of NF-kappaB subunits IkappaBalpha, p50 and p65. While enalapril significantly inhibited extracellular matrix remodelling via regulation of the protein expression ratio of matrix metalloproteinase/tissue inhibitor of metalloproteinase and the activity of matrix metalloproteinase, these variables were not affected by BNP, indicating that the two therapies involve different mechanisms. CONCLUSION: Chronic BNP infusion can provide beneficial effects against adverse post-MI remodelling. PMID- 21276575 TI - Routine use of coronary computed tomography as initial diagnostic test for angina pectoris. AB - BACKGROUND: Coronary computed tomography (CCT) detects coronary obstruction with high sensitivity and might be useful for diagnosis of angina pectoris. AIM: In this pilot study, we sought to prospectively evaluate the performance of CCT as initial work up and determine the significance of this strategy according to the pretest likelihood of having coronary artery disease (CAD). METHODS: One hundred and eighty patients with chest discomfort and suspected angina were prospectively referred for CCT with a 64-slice CT scan. Invasive coronary angiography (ICA) was performed on the basis of CCT findings (stenosis>50%). Patients were classified into tertiles according to estimated pretest probability of obstructive CAD using the Duke Clinical Score (low, intermediate and high). Strategy failure was defined as unnecessary ICA or major adverse cardiac event (MACE) within 6 months in patients without significant stenosis by CCT. RESULTS: Pretest probability for CAD was 53 +/- 29%. Significant stenosis was detected by CCT in 51 patients; 47 (26%) underwent ICA. Sixteen strategy failures were reported: 15 patients (10%) were referred for ICA that did not confirm significant coronary stenosis and one MACE occurred in a patient without significant stenosis by CCT. Strategy failures were 8% in low-probability, 1.7% in intermediate-probability and 15% in high probability patients (P=0.03). CONCLUSIONS: CCT as an initial step for angina diagnosis is most effective in patients with an intermediate probability of CAD. In patients with low or high likelihood, it is associated with a high rate of unnecessary ICA but not with adverse events. PMID- 21276576 TI - Is early surgery beneficial in infective endocarditis? A systematic review. AB - We do not know whether surgery during the active phase of infective endocarditis improves prognosis, as no randomized trial data exist. Several observational studies published recently have examined the influence of surgery on prognosis by performing a propensity score analysis. The aim of the present paper is to review these studies, in order to determine whether or not early surgery decreases mortality in adult patients with infective endocarditis. Among nine published studies, 4199 patients were included overall. The rate of surgery during the active phase of infective endocarditis ranged from 23 to 53%. Surgery was significantly beneficial in six studies (adjusted hazard ratios or odds ratios ranging from 0.27 to 0.47), neutral in two studies and without benefit in one study (hazard ratio 1.9; 95% confidence interval 1.1-3.2). Conflicting results appear to be related to differences in statistical methods. When using appropriate models, surgery is significantly associated with reduced long-term mortality. Results from these observational studies suggest that current surgical practices in infective endocarditis are beneficial in terms of long-term survival. However, we cannot conclude that surgery is beneficial and must be performed in all patients with infective endocarditis. Surgery was associated with a favourable outcome in those patients in whom infective endocarditis presentation and patient characteristics led the physicians to perform surgery. Patients who seem to benefit most from surgery are those who fulfil management guidelines (embolic event, heart failure and/or intracardiac abscess). PMID- 21276577 TI - Three-dimensional echocardiography in congenital heart disease. AB - Three-dimensional (3D) echocardiography has improved dramatically due to technical advances in probe design and computer processing. Congenital heart disease demands a detailed understanding of the spatial relationships of cardiac structures to plan treatment, making 3D echocardiography highly attractive. Novel projections of cardiac structures can be achieved that are impossible by two dimensional methods, and high frequency probes are now available to allow better 3D imaging in small children. The introduction of a 3D transoesophageal echo probe has extended the applications to real-time guidance of catheter procedures. All of these developments mean that 3D echocardiography is now an accepted complementary imaging technique to conventional cross-sectional echocardiography in congenital heart disease. In addition to morphology, 3D echocardiography can analyse ventricular volumes and function with fewer geometric assumptions than cross-sectional techniques. Analysis of myocardial motion, including 3D tracking of wall motion, is an emerging technique that may become important, particularly in long-term follow-up of operated congenital heart disease. Normal ranges of ventricular volumes and synchrony remain to be established in children. Further improvements in image processing, including automation of analyses and tailoring of software to ventricles of abnormal shape, may move such techniques from a research setting into more mainstream clinical practice. PMID- 21276578 TI - Cardiac computed tomography in right-sided carcinoid heart disease. PMID- 21276579 TI - Asymptomatic intracardiac migration of a sharp foreign body. PMID- 21276580 TI - Segmental analysis of a complex congenital heart disease using cardiac MDCT. Analyse of congenital heart disease: use of MDCT. PMID- 21276581 TI - Drug-eluting stent fracture and intramyocardial coronary course. PMID- 21276582 TI - Content-context binding in verbal working memory updating: on-line and off-line effects. AB - The role of content-context binding in working memory updating has received only marginal interest, despite its undoubted relevance for the updating process. In the classical updating paradigm, the main focus has been on the process of discarding information when new information is presented. Its efficacy has been determined by measurement of the accuracy of recalled, updated information. In the current study we measured the working memory updating process directly, employing a dynamic memory task composed of alternating sequences of learning, active maintenance and updating phases. Binding was manipulated by changing the type of updating (total or partial) and the strength of the perceptual connection between items. The on-line updating process and the off-line efficacy were separately analysed. Both on-line and off-line measures indicated that partial updating conditions, where the operation of updating content-context binding was required, were more demanding than both total updating conditions and memory and maintenance phases. Our results suggest that working memory updating can be identified not only as a process of substitution of information, but also as inhibition of no longer relevant information and, above all, as a binding updating. PMID- 21276583 TI - "Time flies in the presence of angry faces"... depending on the temporal task used! AB - A number of studies have reported that the perception of an arousing emotional stimulus, such as an angry face, results in temporal overestimations which are probably due to the speeding up of a clock-like system. The aim of the present study was to examine whether this emotional effect can be generalized to all temporal tasks irrespective of the underlying cognitive processes involved in each task. Five different temporal tasks involving the presentation of neutral and angry faces were therefore tested: bisection, generalization, verbal estimation, production and reproduction. Our results showed an overestimation of time for the angry compared to the neutral faces in the temporal bisection, verbal estimation and production tasks but not in the temporal generalization and reproduction tasks. Moreover, the results obtained in the temporal verbal estimation and production tasks suggest that this temporal overestimation of the angry faces was associated with relatively more accurate estimates. The involvement of both arousal and attention mechanisms in the effect of emotional facial expressions on time perception is discussed in the light of the differences in the impact of the same emotional stimulus as a function of the temporal task considered. PMID- 21276584 TI - The influence of quiet eye training and pressure on attention and visuo-motor control. AB - The aim of this study was to examine the efficacy of an intervention designed to train effective visual attentional control (quiet eye-training) for a far aiming skill, and determine whether such training protected against attentional disruptions associated with performing under pressure. Sixteen novice participants wore a mobile eye-tracker to assess their visual attentional control (quiet eye) during the completion of 520 basketball free throws carried out over 8 days. They first performed 40 pre-test free throws and were randomly allocated into a quiet eye (QE) training or Control group (technical instruction only). Participants then performed 360 free throws during a training period and a further 120 test free throws under conditions designed to manipulate the level of anxiety experienced. The QE trained group maintained more effective visual attentional control and performed significantly better in the pressure test compared to the Control group, providing support for the efficacy of attentional training for visuo-motor skills. PMID- 21276585 TI - Sex, clinical symptoms, and angiographic findings in patients with diabetes mellitus and coronary artery disease (from the Bypass Angioplasty Revascularization Investigation [BARI] 2 Diabetes trial). AB - Previous studies have reported differences in presenting symptoms and angiographic characteristics between women and men undergoing evaluation for suspected coronary artery disease (CAD). We examined the relation between symptoms and extent of CAD in patients with type 2 diabetes mellitus and known CAD enrolled in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. Of 1,775 patients (533 women, 30%, and 1,242 men, 70%), women were more likely than men to have angina (65% vs 56%, p <0.001) or an atypical angina/anginal equivalent (71% vs 58%, p <0.001). More women reported unstable angina (17% vs 13%, p = 0.047) or were in a higher Canadian Cardiology Society class compared to men (Canadian Cardiology Society classes II to IV 78% vs 68%, p = 0.002). Fewer women than men had no symptoms (14% vs 22%, p <0.001). Women had a lower mean myocardial jeopardy index (42.5 +/- 24.3 vs 47.9 +/- 24.3, p <0.001), smaller number of total significant lesions (2.3 +/- 1.7 vs 2.7 +/- 1.8, p <0.001), and fewer jeopardized left ventricular regions (p <0.001 for distribution) or long-term occlusions (29% vs 42%, p <0.001). After adjustment for relevant covariates, the odds of having CAD symptoms were still higher in women than men (odds ratio for angina 1.31, 95% confidence interval 1.02 to 1.69; odds ratio for atypical angina 1.52, 95% confidence interval 1.17 to 1.96). In conclusion, in a high-risk group of patients with known CAD and diabetes mellitus, women were more symptomatic than men but had less obstructive CAD. These data suggest that factors other than epicardial CAD severity influence symptom presentation in women in this population. PMID- 21276586 TI - Effect of simvastatin and fenofibrate on cytokine release and systemic inflammation in type 2 diabetes mellitus with mixed dyslipidemia. AB - The aim of our study was to compare the effect of simvastatin and fenofibrate treatment on the secretory function of human monocytes and lymphocytes and on systemic inflammation in type 2 diabetes and to assess whether their coadministration is superior to treatment with only 1 of these drugs. One hundred ninety-six adult patients with recently diagnosed and previously untreated type 2 diabetes and mixed dyslipidemia, complying throughout the study with lifestyle intervention and treated with metformin, were randomized in a double-blind fashion to receive simvastatin (40 mg), fenofibrate (200 mg), simvastatin plus fenofibrate, or placebo for 90 days. Main outcome measurements were monocyte and lymphocyte release of proinflammatory cytokines and plasma levels of C-reactive protein. One hundred ninety patients completed the study. Simvastatin and fenofibrate decreased monocyte release of tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, and monocyte chemoattractant protein-1 and lymphocyte release of interleukin-2, interferon-gamma, and tumor necrosis factor alpha, which was accompanied by a decrease in plasma C-reactive protein levels. Anti-inflammatory effects of fenofibrate partly correlated with the improvement in insulin sensitivity. Lymphocyte-suppressing, but not monocyte-suppressing, effect was stronger if these 2 agents were administered together. In conclusion, simvastatin and fenofibrate exhibit a similar effect on the secretory function of human monocytes and lymphocytes and on systemic inflammation in type 2 diabetic subjects with mixed dyslipidemia. This effect may be clinically relevant in the prevention of vascular complications in metformin- and diet-treated subjects with newly diagnosed diabetic dyslipidemia. PMID- 21276587 TI - [Management of cardiac arrhythmias during pregnancy]. AB - INTRODUCTION: Pregnancy can precipitate or exacerbate cardiac arrhythmias. Management of those arrhythmias is not very different from that in non-pregnant women. OBJECTIVE: In this review we tried to specify factors which favour arrhythmias in pregnant women and to show their specific management. METHODS: We carried out a search through PubMed using as keywords: pregnancy, cardiac arrhythmias, antiarrhythmics. RESULTS: Hemodynamic perturbations, direct electrophysiological effects of hormones and underlying heart disease are potential factors that can promote arrhythmias in pregnancy. Usually, no drug therapy is needed for the management of supraventricular or ventricular premature beats but potential promoting factors should be eliminated. In paroxysmal supraventricular tachycardia, vagal maneuvers should be tried firstly. Adenosine could be used if vagal maneuvers are ineffective. In pregnant women with atrial fibrillation, the goal of treatment is the conversion to sinus rhythm or the control of ventricular rate. Ventricular arrhythmias are usually uncommon during pregnancy and often occur in the absence of structural heart disease and are responsive to drug therapy. Symptomatic bradycardia rarely complicates pregnancy and its management does not differ from that in non-pregnant women. PMID- 21276588 TI - Preparation and optical properties of silver nanowires and silver-nanowire thin films. AB - Silver nanowires and silver-nanowire thin films have attracted much attention due to their extensive applications in Surface-Enhanced Raman Scattering (SERS) and Surface-Enhanced Fluorescence (SEF). Thin films of silver nanowires within polyelectrolyte layers of poly(allylamine hydrochloride) (PAH) and poly(sodium 4 styrenesulfonate) (PSS) were fabricated by the Spin-Assisted Layer-by-Layer (SA LbL) method. The surface coverage, thickness, and absorbance properties of the silver-nanowire films were controlled by the number of layers deposited. Both transverse and longitudinal surface plasmon (SP) modes of the silver-nanowires were observed in the absorbance spectra, as was evidence for nanowire interaction. Two-dimensional finite difference time-domain (2D FDTD) simulations predict that the maximum field enhancement occurs at the ends and cross-sectional edges of the wires for the longitudinal and transverse modes, respectively. Silver nanowires were synthesized by a facile, high-yield solvothermal approach, which can be easily manipulated to control the aspect ratio of the nanowires. The effects of polyvinylpyrrolidone (PVP) concentration and molecular weight on the growth of the silver nanowires, which are not documented in the original procedure, are discussed. It is shown that the growth mechanism for silver nanowires in the solvothermal synthesis is similar to that reported for the polyol synthesis. PMID- 21276589 TI - Quantitative electrocardiography for predicting postoperative atrial fibrillation after cardiac surgery. AB - BACKGROUND: Atrial fibrillation (AF) after cardiac surgery is a common marker of poor outcomes. Quantitative electrocardiographic (ECG) measurements may be valuable predictors of postoperative AF. METHODS: We evaluated clinical and ECG predictors of postoperative AF in 13,356 patients who underwent cardiac surgery in sinus rhythm. RESULTS: A total of 4724 patients (35%) developed postoperative AF. P-wave amplitude in leads aVR and V(1) were the strongest ECG predictors. A less negative P-wave amplitude in lead aVR was associated with increased risk for postoperative AF (odds ratio, 1.46; 95% confidence interval, 1.32-1.61), as was a more positive or a more negative P-wave amplitude in lead V(1) (odds ratio, 1.25; 95% confidence interval, 1.16-1.36) after adjusting for clinical and procedural predictors of postoperative AF. Reclassification analysis showed a 7% discrimination improvement (P < .0001). CONCLUSIONS: P-wave amplitude in lead aVR and lead V(1) are powerful predictors of postoperative AF and, in combination with other clinical predictors, can guide application of prophylactic interventions. PMID- 21276590 TI - Prolonged QT and cardiac arrest after heart transplantation: inherited or acquired? AB - The long QT syndrome is an inherited arrhythmogenic disease characterized by prolongation of QT interval, syncope, and sudden cardiac death because of ventricular tachycardia, mainly in the form of Torsades de Pointes. We present an unusual case of prolonged QT interval and cardiac arrest caused by Torsades de Pointes in the early phase after orthotopic heart transplant. PMID- 21276591 TI - A multidifferentiator-based approach to the reliable determination of T-wave offset in electrocardiograms. AB - The determination of T-wave offset is still a very difficult task in the measurement of the QT interval. Several methods of determining the T-wave offset can be categorized into slope methods, threshold methods, or differential methods. The threshold- and slope-based methods are sensitive to low-frequency noise. The differential methods, in which a single differential operation is usually used for feature extraction, are susceptible to morphological variations in the range of the T-wave offset. In this study, a multidifferential filter comprising a series of simple multiscale differentiators with multiorders is proposed as a feature selector and extractor for T-wave offset in electrocardiograms (ECGs). This newly proposed approach was tested on artificial ECGs (the Conformance Testing Services for Computerized Electrocardiography Test data set: 1919 ECGs were generated with signal-to-noise ratios ranging from 10 to 60 dB, in increments of 0.5 dB, with 172,306 T waves with specified references) simulated at various noise levels and a set of clinical ECGs (3415 ECGs with 14,099 T waves, annotated by 3 cardiologists) and compared with existing detection methods. The accuracies achieved with the proposed approach were -0.269 +/- 5.53 and 0.400 +/- 9.89 milliseconds for the artificial and clinical ECGs, respectively. These test results indicate that the proposed method outperforms the other methods evaluated on both the artificial and clinical ECGs. The proposed approach is also more suitable for clinical applications in accordance with the performance requirements of the International Electrotechnical Commission. PMID- 21276592 TI - Genetics of the coenzyme Q10 pathway and rosuvastatin-induced muscle effects. PMID- 21276594 TI - Patient satisfaction with outpatient neurology services: a momentum for improvement. AB - BACKGROUND: Outcome measures of patient satisfaction are increasingly accepted as an integral component of the overall healthcare quality assessment. AIMS OF STUDY: A survey of the outpatient neurology services in Addis Ababa, Ethiopia was performed to determine the overall patient satisfaction, provide an assessment of current services and form the foundation for improved expansion of neurological care. METHODS: 233 patients were recruited from the Addis Ababa University Teaching Hospital outpatient general neurology clinic by a cross-sectional sample survey design. Data from structured interview and abstraction of medical records were analyzed by SPSS for Windows version 15.0 computer software. Visual analysis of mean satisfaction scores and Spearman's rho correlation coefficients generated priority indices serving to guide expansion of neurology services. RESULTS: 212 patients with mean age of 40.1 and a 1:1M: F ratio completed the survey. The variation of overall patient satisfaction (mean, 70.4; SD, 12.4) was independently predicted by patient clinical outcome expectations and satisfaction on waiting area, overall service of doctor and card room [R(2)=0.305; F (8,195)=10.685, p=0.000]. Mean satisfaction scores for specific dimensions of the outpatient general neurology clinic ranged from 57.2 for waiting time at the clinic to 74.0 for overall service of the guards. Waiting time at the clinic stood first among the top five priority indices. CONCLUSION: This survey demonstrates predictors of overall patient satisfaction with the outpatient neurology services, and delineates priority areas warranting further improvement. It is the first African study on patient satisfaction with neurology services, and provides a guide for neurological or other specialty clinics seeking to improve and expand medical services. PMID- 21276593 TI - Childhood trauma history differentiates amygdala response to sad faces within MDD. AB - OBJECTIVE: Heightened amygdala reactivity to aversive stimuli in major depression is regarded as a core feature of the underlying physiology but individual differences in amygdala response may also arise secondary to persistent changes in limbic function during early neurodevelopment relative to stressors such as childhood trauma. We sought to determine whether heightened amygdala response is a core feature of depression or a general risk factor for psychopathology secondary to early life stress. METHOD: Twenty unipolar depressed patients with and without a history of significant early life trauma and 16 healthy comparison subjects underwent functional MRI in a cross-sectional study comparing neural response to sad and neutral faces. RESULTS: We observed a robust positive correlation between physical abuse and right amygdala response. A much weaker relationship with other forms of abuse and neglect was also found, suggesting differences between abuse subtypes and amygdala response. Group differences in amygdala response suggest heightened reactivity was not characteristic of persons with depression in general but was true primarily in those with a significant history of abuse. CONCLUSION: These findings suggest the relationship between childhood trauma and risk for depression is mediated by heightened amygdala response but varies by abuse type. Preliminary evidence for two distinct depression phenotypes based on trauma history was also supported, consistent with differential etiology. PMID- 21276595 TI - Association between divalent metal transport 1 encoding gene (SLC11A2) and disease duration in amyotrophic lateral sclerosis. AB - BACKGROUND: Dysregulation of iron homeostasis is one possible pathophysiological mechanism involved in motor neuron degeneration in amyotrophic lateral sclerosis (ALS). SLC11A2 gene encodes the divalent metal transport 1 (DMT1) mediating iron transport in cerebral endosomal compartments. The objective of the study was to analyze DMT1 as a possible risk or modulating factor in sporadic ALS (SALS). METHODS: We performed a case-control association study on an intronic polymorphism (rs407135) previously analyzed in another neurodegenerative disease, Alzheimer's disease. This polymorphism was studied by DNA sequencing in 579 French patients with SALS and 517 healthy matched individuals. The clinical characteristics of patients were analyzed in relation to their genotypes. RESULTS: We observed that the C allele of rs407135 in SLC11A2 was associated with a shorter disease duration in SALS patients with onset in the legs [Hazard ratio: 1.5 [1.1-2.1] (p=0.02)]. These results are in line with previous observations suggesting that bulbar and spinal motor neurons have different metabolic regulation and gene expression profiles. CONCLUSIONS: Our findings support an implication for iron metabolism in ALS and suggest that the genotype of the SLC11A2 gene could modulate the duration of the disease in French SALS patients. PMID- 21276596 TI - Carotid stenosis as predictor of stroke after transient ischemic attacks. AB - ABCD2 score identifies high-risk TIAs but its validity in different countries and hospitals is unknown. Doubts remain also about the role of diagnostic work up for patients with TIAs in the emergency department. The present study was undertaken to confirm the usefulness of ABCD2 score in the emergency department of Trento Hospital and to evaluate if other exams (carotid ultrasound or CT scan) commonly performed in TIA patients are helpful. We retrospectively analysed discharge diagnosis of around 120,000 patients seen at the first aid of Trento Hospital over a 28 month period. ABCD2 score, carotid ultrasound and CT scan were recorded and were correlated with recurrence of stroke at different time points (mean follow-up period of 11.4 months) in all patients with TIA. We identified 965 patients with focal neurologic deficit and 502 could be classified as TIA. An ischemic stroke recurred in 30 patients at the end of the follow-up (30% in the first two days). ABCD2 score confirmed its value. A significant carotid stenosis (>70%) was an independent risk factor for stroke at any time point. Our study confirms the role of ABCD2 in a large Italian cohort of TIA patients but also suggests the importance of performing a carotid ultrasound as soon as possible. PMID- 21276597 TI - Predictors of non-invasive ventilation tolerance in amyotrophic lateral sclerosis. AB - BACKGROUND: The most frequent cause of death in patients with Amyotrophic Lateral Sclerosis (ALS) is respiratory failure. Recently, it has been shown that non invasive ventilation improves survival and quality of life in ALS patients with respiratory failure, but little is known about predictors of non-invasive ventilation adaptation and tolerance. In this study we evaluated the effect of a comprehensive information about non-invasive ventilation use and a prolonged and intensive monitoring on tolerance to this palliative care. METHODS: We prospectively monitored all consecutive ALS patients with chronic respiratory failure and indication to non-invasive ventilation between January 2005 and December 2007. Non-invasive ventilation adaptation was always performed in a hospital setting. RESULTS: Forty-four patients were considered eligible: six declined the non-invasive ventilation proposal and one was excluded due to severe fronto-temporal dementia. Non-invasive ventilation was offered to thirty-seven inpatients in our ALS Centre, thirty-two of whom presented with severe (n=9) or mild-moderate (n=23) bulbar impairment at non-invasive ventilation initiation. The mean time interval for adaptation to ventilation was 5+/-2 days, but patients remained in hospital for an average extended period of one week. Thirty-five of the 37 patients who started non-invasive ventilation, including those with severe bulbar impairment, remained tolerant at twelve months follow-up. CONCLUSIONS: Our study shows that an intensive educational training and adaptation on non-invasive ventilation, when performed in a hospital multidisciplinary setting, increases compliance and tolerance over time, even in those patients with severe bulbar impairment. However, the design of our study, mainly based on a continuous monitoring and educational training of the patients, might not make it fully applicable to an outpatients setting. PMID- 21276598 TI - Disappearance of some human African trypanosomiasis transmission foci in Zambia in the absence of a tsetse fly and trypanosomiasis control program over a period of forty years. AB - We conducted a situation analysis of human African trypanosomiasis (HAT) in Zambia from January 2000 to April 2007. The aim of this survey was to identify districts in Zambia that were still recording cases of HAT. Three districts namely, Mpika, Chama, and Chipata were found to be still reporting cases of HAT and thus lay in HAT transmission foci in North Eastern Zambia. During the period under review, 24 cases of HAT were reported from these three districts. We thereafter reviewed literature on the occurrence of HAT in Zambia from the early 1960s to mid 1990s. This revealed that HAT transmission foci were widespread in Western, North Western, Lusaka, Eastern, Luapula, and Northern Provinces of Zambia during this period. In this article we have tried to give possible reasons as to why the distribution of HAT transmission foci is so different between before and after 2000 when there has been no active national tsetse fly and trypanosomiasis control program in Zambia. PMID- 21276599 TI - Identification and functional characterization of the Varicella zoster virus ORF11 gene product. AB - The deletion of ORF11 severely impaired VZV infection of human skin xenografts. Here, we investigate the characteristics and functions of the ORF11 gene product. ORF11 is expressed as a 118kDa polypeptide in VZV-infected cells; the protein is present in the nucleus and cytoplasm and is incorporated into VZ virions. Although ORF11 had little effect in transactivating VZV gene promoters in transfection assays, deleting ORF11 from the virus was associated with reduced expression of immediate early proteins IE4, IE62 and IE63, and the major glycoprotein, gE. ORF11 was identified as an RNA binding protein and its RNA binding domain was defined. However, disrupting the ORF11 RNA binding domain did not affect skin infection, indicating that RNA binding capacity, conserved among the alphaherpesviruses homologues, is not essential while the contribution of ORF11 to the expression of the IE proteins and gE may be required for VZV pathogenesis in skin in vivo. PMID- 21276600 TI - Regulation of human papillomavirus type 16 early gene expression in trophoblastic and cervical cells. AB - We compared the outcome of different cellular and viral factors on the regulation of the HPV-16 early viral gene expression in trophoblastic and cervical cancer cells. A high variability of the long control (LCR) activity was observed, prompting us to evaluate the role of secreted factors in the control of the early gene expression in trophoblastic cell lines. Endogenous progesterone and exogenous dexamethasone were found to activate LCR driven transcriptional activity. Since host cells express HPV early proteins to regulate LCR activity, we investigated the effect of the combined HPV-16 early proteins on the LCR driven transcription and the possible involvement of E2. A physiological level of HPV-16 early proteins expression strongly induced the LCR driven reporter activity. According to mutational analysis, E1 and E2 proteins, indispensable for viral replication, were not involved in LCR extrachromosomal transcriptional regulation. This suggests that E5 and/or E6 and/or E7, consequently, activated viral transcription. PMID- 21276601 TI - Taxonomic and nontaxonomic responses to ecological changes in an urban lowland stream through the use of Chironomidae (Diptera) larvae. AB - Biotic descriptors--both taxonomic (diversity indices, species richness, and indicator species) and nontaxonomic (biomass, oxygen consumption/production, and anatomical deformities)--are useful tools for measuring a stream's ecological condition. Nontaxonomic parameters detect critical effects not reflected taxonomically. We analyzed changes in Chironomidae populations as taxonomic parameters and mentum deformities as a nontaxonomic parameter for evaluating a South-American-plains stream (Argentina). We performed samplings seasonally (March, June, September, and December; 2005) and physical and chemical measurements at three sampling sites of the stream (DC1 at river source, through DC3 downstream). The specimens collected in sediment and vegetation were analyzed to investigate mouth deformities in Chironomidae larvae. We identified a total of 9 taxa from Chironomidae and Orthocladiinae subfamilies. Shannon's diversity index for Chironomidae decreased from 1.6 bits ind-1 (DC1) to 0.3 bits ind-1 (DC3). The total density of the Chironomidae exhibited a great increase in abundance at site DC3, especially that of Chironomus calligraphus. Chironomidae taxonomic composition also changed among the three sites despite their spatial proximity: C. calligraphus, Goeldichironomus holoprasinus, Parachironomus longistilus, and Polypedilum were present at all three; Corynoneura and Paratanytarsu at DC1 only; Cricotopus at DC1 and DC3; Apedilum elachistus notably at DC2 and DC3; and Parametriocnemus only at DC2. C. calligraphus individuals from DC1 showed no mentum deformities; only 2 from DC2 exhibited mouth-structure alterations; while specimens from DC3 presented the most abnormalities, especially during autumn and late winter. Type-II deformities (supernumerary teeth and gaps) were the most common. Anatomical deformities are sublethal effects representing an early alert to chemically caused environmental degradation. Mentum deformities in benthic-Chironomidae larvae constitute an effective biological-surveillance tool for detecting adverse conditions in sediments and evaluating sediment-quality-criteria compliance. Taxonomic (community composition) and nontaxonomic (condition of larval mouth parts) descriptors, used together, can indicate a stream's ecological state. PMID- 21276602 TI - Ecological factors differentially affect mercury levels in two species of sympatric marine birds of the North Pacific. AB - In 2003 and 2004, we measured mercury concentrations and delta15N and delta13C values in the whole blood of adults of two species of seabirds, Cassin's auklet (Ptychoramphus aleuticus) and rhinoceros auklet (Cerorhinca monocerata), during their prelaying, incubation, and provisioning periods. We also collected whole blood from the offspring of both seabirds. Among prey items, delta15N values were higher in fish than in crustaceans, while delta13C did not vary systematically between prey types. Mercury concentrations in prey showed little relationship with either stable isotope. In the zooplanktivorous Cassin's auklet, year, reproductive stage, and delta15N and delta13C stable isotope values explained only 14% of the variation in mercury concentrations in adult blood, and none of these variables had a statistically significant effect. In contrast, these same variables explained 41% of the variation in mercury levels in the more piscivorous rhinoceros auklet, and all but delta15N values had statistically significant effects. Mercury concentrations in adult rhinoceros auklets were higher in 2003 than in 2004; higher prior to laying than during the incubation or provisioning periods; and increased with delta13C values--but in just one of two years. In both species, mercury concentrations were substantially higher in adults than in nestlings. Our results accord with previous studies in showing that mercury concentrations can vary among years, species and age classes, while the marked variation with reproductive stage is noteworthy because it is so rarely considered. Our results may help to explain the disparate conclusions of previous studies: while many factors influence mercury concentrations in marine predators, they apparently do so in a manner that defies easy characterization. We believe that there is a need for more studies that consider a range of physiological, ecological and behavioral factors that might affect mercury burdens in marine predators. PMID- 21276603 TI - Intercomparison of air quality data using principal component analysis, and forecasting of PM10 and PM2.5 concentrations using artificial neural networks, in Thessaloniki and Helsinki. AB - In this paper we propose a methodology consisting of specific computational intelligence methods, i.e. principal component analysis and artificial neural networks, in order to inter-compare air quality and meteorological data, and to forecast the concentration levels for environmental parameters of interest (air pollutants). We demonstrate these methods to data monitored in the urban areas of Thessaloniki and Helsinki in Greece and Finland, respectively. For this purpose, we applied the principal component analysis method in order to inter-compare the patterns of air pollution in the two selected cities. Then, we proceeded with the development of air quality forecasting models for both studied areas. On this basis, we formulated and employed a novel hybrid scheme in the selection process of input variables for the forecasting models, involving a combination of linear regression and artificial neural networks (multi-layer perceptron) models. The latter ones were used for the forecasting of the daily mean concentrations of PM10 and PM2.5 for the next day. Results demonstrated an index of agreement between measured and modelled daily averaged PM10 concentrations, between 0.80 and 0.85, while the kappa index for the forecasting of the daily averaged PM10 concentrations reached 60% for both cities. Compared with previous corresponding studies, these statistical parameters indicate an improved performance of air quality parameters forecasting. It was also found that the performance of the models for the forecasting of the daily mean concentrations of PM10 was not substantially different for both cities, despite the major differences of the two urban environments under consideration. PMID- 21276604 TI - Improved survival in non-Ashkenazi Jewish ovarian cancer patients with BRCA1 and BRCA2 gene mutations. AB - OBJECTIVES: Previous studies report a survival advantage in ovarian cancer patients with Ashkenazi Jewish (AJ) breast cancer gene (BRCA) founder mutations. The purpose of this study was to determine if this association exists in patients with non-Ashkenazi Jewish (non-AJ) BRCA mutations. We also sought to account for "survival bias" by minimizing lead time that may exist between diagnosis and genetic testing. METHODS: Patients with stage III/IV ovarian cancer and a non-AJ BRCA mutation, seen between January 1996 and July 2007, were identified from eight institutions. Patients with sporadic ovarian cancer were compared to similar cases, matched by age, stage, year of diagnosis, and vital status at time interval to BRCA testing. Progression-free (PFS) and overall survival (OS) were calculated by the Kaplan-Meier method. Multivariate Cox proportional hazards models were calculated for variables of interest. Fisher's exact test and chi square were also used for analysis. RESULTS: Ninety-five advanced stage ovarian cancer patients with non-AJ BRCA mutations and 183 sporadic controls were analyzed. Compared to sporadic ovarian cancer patients, non-AJ BRCA patients had longer PFS (27.9 months vs. 17.9 months, HR 0.61 [95% CI 0.43-0.86]) and OS (101.7 months vs. 54.3 months, HR 0.43 [95% CI 0.27-0.68]). BRCA status was an independent predictor of PFS and OS. CONCLUSIONS: This multicenter study demonstrates a significant survival advantage in advanced stage ovarian cancer patients with non-AJ BRCA mutations, confirming the previous studies in the Jewish population. This improved survival was evident when accounting for the "survival bias" that coincides with genetic testing. PMID- 21276605 TI - Characteristics of 44 cervical cancers diagnosed following Pap-negative, high risk HPV-positive screening in routine clinical practice. AB - OBJECTIVE: To characterize the cervical cancers diagnosed following a Pap negative, high risk human papillomavirus (HPV)-positive (Pap-/HPV+) screen in routine clinical practice. METHODS: Using data from Kaiser Permanente Northern California, we investigated the cases of cervical cancer diagnosed between January, 2003 and January, 2009 following Pap-/HPV+ screen. Two cervical specimens were routinely collected for cervical cancer screening, one for conventional cytology and the other for high risk HPV testing using Hybrid Capture 2 (Qiagen). RESULTS: Forty-four women (median age at diagnosis=44years) were diagnosed with primary invasive cervical cancer with a recent history of one or more Pap-/HPV+ screens. Twenty-six women had one Pap-/HPV+ screen preceding the diagnosis of cancer, 15 had two, and three had three. There were 16 squamous cancers, one small cell cancer, 24 adenocarcinomas, 2 adenosquamous carcinomas, and one case with separate invasive squamous and adenocarcinoma. FIGO Stage was IA in 11 women, IB in 31 women and IIA in 2 women. Treatment included a pelvic node dissection in 30, 2 (6.7%) of whom had positive nodes. CONCLUSIONS: HPV testing contributes to early cervical cancer diagnosis detection in women with negative Pap tests. Most women in this cohort have early stage, node negative, treatable and potentially curable disease. Adenocarcinoma predominated as might be expected because cytology misses these cancers and their precursors. The majority of cancers were diagnosed following a single Pap-/HPV+ screen, suggesting that effective triage to colposcopy of women with a Pap-/HPV+ screen would be preferable to retesting in one year as currently recommended. PMID- 21276606 TI - Inferior vena cava filter placement in the gynecologic oncology patient: A 15 year institutional experience. AB - OBJECTIVE: Venous thrombosis is a frequent complication of gynecologic cancer. Data regarding the use of inferior vena cava (IVC) filters in this population is limited. The aim of this study was to review our experience with gynecologic oncology patients who received an IVC filter, specifically to evaluate indications for filter placement and survival outcomes. METHODS: This was a retrospective, single-institution study of patients who had an IVC filter placed after a histologically confirmed gynecologic malignancy. Patients were identified from a prospectively collected interventional radiology (IR) database. Clinicopathologic characteristics, procedure details, and outcome data were obtained from outpatient and inpatient medical records. Survival after IVC filter placement was analyzed using the Kaplan-Meier product limit method and compared by log-rank test. RESULTS: A total of 128 patients were identified and 103 were found to be eligible for analysis. Most patients had ovarian cancer (52%), followed by cervical cancer (25%) and endometrial cancer (21%). Two-thirds had advanced stage disease (III/IV). The procedure complication rate was 2%. Median survival after IVC filter placement was 7.8months (95% CI, 4.1-13.6). The most common indication for IVC filter placement was contraindication to anticoagulation secondary to hemorrhage (44%), followed by perioperative indications (30%) and failed anticoagulation (14%). There was no difference in survival by IVC filter placement indication (p=0.18). The majority of the IVC filters placed were permanent (90.5%) and in an infrarenal position (95.8%). There was no difference in survival according to specific thromboembolic event (DVT vs. PE vs. both). Patients able to receive anticoagulation after IVC filter placement had improved survival (HR 0.45, 95%CI 0.45-0.27, p=0.003). CONCLUSIONS: We present the largest series of gynecologic oncology patients treated with IVC filters. Long-term survival after IVC filter placement is uncommon. Patients who receive anticoagulation after IVC filter placement have an improved survival over those who do not receive anticoagulation; this difference in survival may be secondary to worsening disease causing contraindications to anticoagulation. PMID- 21276607 TI - Activation of mTOR signaling pathway associated with adverse prognostic factors of epithelial ovarian cancer. AB - OBJECTIVE: Activation of the mammalian target of rapamycin (mTOR) pathway enhances cell survival and growth by regulating the efficiency of protein translation. This study was conducted to evaluate the association of activated mTOR signaling molecules with the clinicopathologic characteristics in epithelial ovarian cancer. METHODS: Immunohistochemical staining with antibodies against p 4EBP1, p-mTOR, and p-p70S6K were performed on specimens of 103 patients with ovarian cancer. Tumors were classified as chemoresistant in cases where time to recurrence after the end of chemotherapy was shorter than 6months. RESULTS: Expressions of p-mTOR, p-4EBP1, and p-p70S6K were detected in 47.6%, 85.4%, and 64.1% of all patients, respectively. p-4EBP1 overexpression was associated with advanced stage (p=0.04), histologic grade (p<0.01), residual mass (p<0.01), shorter disease-free survival rate (p=0.01) and chemoresistance (p=0.02). p p70S6K was associated with residual mass with marginal significance (p=0.06). p 4EBP1 expression was correlated with p-p70S6K expression (r=0.42, p<0.01), whereas p-mTOR was not associated with expression of its downstream effectors or prognostic factors. CONCLUSIONS: Our findings suggest that p-4EBP1 expression was associated with poor prognostic factors of ovarian cancer and that p-4EBP1 overexpression may be a prognostic biomarker of ovarian cancer. PMID- 21276608 TI - A phase II, single-arm study of the anti-alpha5beta1 integrin antibody volociximab as monotherapy in patients with platinum-resistant advanced epithelial ovarian or primary peritoneal cancer. AB - OBJECTIVE: This phase II, multicenter, single-arm, two-stage study in platinum resistant, advanced epithelial ovarian or primary peritoneal cancer evaluated the efficacy, safety, and tolerability of weekly single-agent volociximab. Pharmacokinetic/pharmacodynamic (PK/PD) studies were also performed. METHODS: Sixteen patients were enrolled in Stage 1. Volociximab was administered at 15mg/kg IV qwk until progression of disease or drug intolerability. Tumor response was assessed every 8weeks. Serum samples for PK or whole blood for the evaluation of circulating tumor cells, endothelial cells, and endothelial progenitor cells were obtained on Days 1, 8, 15, 29, and 50. Ascites from one patient was collected for volociximab concentration analysis. Archived tumor tissue was analyzed by immunohistochemistry (IHC) for alpha5 integrin expression. RESULTS: Safety data are available on all 16 patients; 14 were evaluable for efficacy. One patient had stable disease at 8weeks. The remaining 13 progressed on treatment. Twelve patients (75%) experienced study-related adverse events (AEs); the most common (>=20%) were headache and fatigue. Three patients experienced possible study-related serious AEs (SAEs): reversible posterior leukoencephalopathy syndrome, pulmonary embolism, and hyponatremia. Peak serum concentrations of volociximab increased 2-3 fold from Day 1 to Day 50. Clinically relevant trough levels were achieved (>150MUg/mL). IHC analysis of archived tumor sections showed low-to-moderate expression of alpha5 integrin on all ovarian cancer tissue evaluated. CONCLUSION: Despite insufficient clinical activity in this refractory patient population to continue the study, weekly volociximab was well tolerated, and the gained understanding of the mechanism of action of volociximab will inform future development efforts. PMID- 21276609 TI - Incidence of lymph node and adnexal metastasis in endometrial stromal sarcoma. AB - OBJECTIVE: To determine the incidence of adnexal and lymph node (LN) metastasis in newly diagnosed endometrial stromal sarcoma (ESS). METHODS: We identified all cases with a diagnosis of ESS evaluated at our institution from January 1, 1980 to October 31, 2009. All uterine pathology was reviewed at our center. High-grade or undifferentiated tumors and ESS arising in extrauterine sites were excluded. Pertinent clinical data were abstracted from electronic medical records. Appropriate statistical tests were performed using SPSS16.0. RESULTS: We identified 94 cases of ESS. LN metastasis was identified in 7 (19%) of 36 patients who underwent LN evaluation. Six of the 7 cases with LN metastasis had lymphovascular invasion (LVI). LVI status was not reported in the other case. Five of the 7 patients with LN metastasis had grossly positive LNs with or without other gross extrauterine disease. Of 20 patients with disease grossly limited to the uterus and grossly normal LNs, 2 (10%) had LN metastasis. Both of these cases had LVI and extensive myoinvasion. Eighty-seven cases (93%) underwent salpingo-oophorectomy. Adnexal metastasis was identified in 11 (13%) of 87 cases, all manifested by gross adnexal tumor and occurring in patients with other gross pelvic extrauterine disease. CONCLUSION: The incidence of LN metastasis in ESS is commonly associated with gross extrauterine disease, extensive myoinvasion, and LVI. Since myoinvasion and LVI status often are not assessable at the time of hysterectomy, LN dissection remains a reasonable option at primary surgery. The rate of adnexal metastasis appears to be negligible in the absence of gross adnexal and extrauterine tumor. PMID- 21276610 TI - Clear cell carcinoma of the ovary: a report from the first Ovarian Clear Cell Symposium, June 24th, 2010. AB - OBJECTIVES: Recent literature has highlighted histological types of ovarian carcinoma as distinct diseases, each with unique clinical and molecular features. Historically, the diagnosis of ovarian clear cell carcinoma (CCC) has been of concern to both patients and physicians due to reports that CCC is associated with a worse prognosis than the more common serous type of ovarian carcinoma (HGSC). This review discusses the unique features of ovarian CCC. METHODS: In June of 2010, a group of researchers and clinicians convened in Vancouver to review and discuss the clinical, pathological, molecular, and treatment-related features of CCC. RESULTS: CCC is the second most common type of ovarian epithelial cancer, representing 5-25% of ovarian carcinomas. It is characterised by its association with endometriosis, and frequent mutations of ARID1A and PIK3CA. Low-stage CCC appears to have a better outcome than stage matched HGSC, while the opposite is true for high-stage disease, suggesting that the current standard treatments applied to HGSC are ineffective for CCC. CONCLUSIONS: Ovarian CCC is highly distinct from HGSC, and a clearer understanding of the basic biology of this disease is needed. Alternative therapies should be explored: irradiation and targeting disease-specific molecular markers should be examined in greater detail. Finally, novel approaches to clinical trial design are needed due to the smaller numbers of patients affected. PMID- 21276611 TI - Elasticity boundary conditions required for cell mechanotaxis on microelastically patterned gels. AB - Directional cell migration induced by a mechanical gradient on a substrate surface toward a harder region, so-called mechanotaxis or durotaxis, has recently drawn attention not only in the field of mechanobiology but also for possible cell manipulation in biomedical engineering. Before we can use mechanotaxis to control cell migration on a biomaterial surface, quantitative design criteria for a microelasticity gradient should be established. To clarify the conditions required to induce mechanotaxis, the effects of a microelasticity boundary on cell culture hydrogels have been systematically assessed with regard to fibroblast migration based on a custom-built reduction projection-type photolithographic microelasticity patterning system with elasticity-tunable photocurable styrenated gelatins, which is a thoroughly-improved system of our previous simple photomasking method [41]. As a result, the conditions required to induce mechanotaxis were found to include a certain threshold jump in elasticity (30-40 kPa) and a sufficiently narrow width of the elasticity boundary (50 MUm) comparable to a single cell's adhered area, i.e., a sufficiently high gradient strength (30-40 kPa/50 MUm in our gelatinous gel system). A significant asymmetric distribution of the number and size of focal adhesions across the elasticity boundary was confirmed to be one of the driving factors of mechanotaxis by indirect immunofluorescence microscopy, and mechanistic considerations in the design criteria are discussed. PMID- 21276612 TI - An injectable vehicle for nucleus pulposus cell-based therapy. AB - An injectable hydrogel, acting as a reservoir for cell delivery and mimicking the native environment, offers promise for nucleus pulposus (NP) repair and regeneration. Herein, the potential of a stabilised type II collagen hydrogel using poly(ethylene glycol) ether tetrasuccinimidyl glutarate (4S-StarPEG) cross linker, enriched with hyaluronic acid (HA) was investigated. The optimally stabilised type II collagen hydrogel was determined by assessing free amine groups, resistance to enzymatic degradation, gel point. The potential toxicity of the cross-linker was initially assessed against adipose-derived stem cells (ADSCs). After addition of HA (molar ratio type II collagen:HA 9:0, 9:1, 9:4.5, 9:9) within the hydrogel, the behaviour of the encapsulated NP cells was evaluated using cell proliferation assay, gene expression analysis, cell distribution and cell morphology. A significant decrease (p < 0.05) in the free amine groups of collagen was observed, confirming successful cross-linking. Gelation was independent of the concentration of 4S-StarPEG (8 min at 37 degrees C). The 1 mm cross-linked hydrogel yielded the most stable after enzymatic degradation (p < 0.05). No toxicity of the 4S-StarPEG was noted for the ADSCs. NP cell viability was high regardless of the concentration of HA (>80%). A cell proliferation was not seen after 14 days in its presence. At a gene expression level, HA did not influence NP cells phenotype after seven days in culture. After seven days in culture, the type I collagen mRNA expression was maintained (p > 0.05). The optimally stabilised and functionalised type II collagen/HA hydrogel system developed in this study shows promise as an injectable reservoir system for intervertebral disc regeneration. PMID- 21276613 TI - Plerixafor and G-CSF for PBSC mobilization in patients with lymphoma who failed previous attempts with G-CSF and chemotherapy: a REL (Rete Ematologica Lombarda) experience. AB - Plerixafor has been previously reported to improve PBSC collection in pts undergoing PBSC mobilization. Aim of the study was to assess the efficacy of plerixafor and G-CSF in pts with lymphoma who failed previous attempts of PBSC mobilization with conventional schemes of chemotherapy+G-CSF. 35 heavily pre treated lymphoma pts (29 NHL, 6 HL) classified as "poor mobilizers" were enrolled in a program of compassionate use of plerixafor in 7 Italian centres of REL (Rete Ematologica Lombarda). Median number of previous lines of therapy was 3 and median number of previous attempts of mobilizations was 2. The median number of circulating CD34+ cells/MUL following plerixafor was 11/MUL. It was >=10/MUL in 17 pts and >=20/MUL in 10 pts; 13 were able to collect >=2*10(6) CD34+ cells/kg with a median of 1 apheresis procedure; 4 pts collected >=4*10(6) CD34+ cells/kg. A total of 6 pts had proceeded to transplant at the time of analysis. The median dose of PBSCs infused was 4*10(6)/kg and hematopoietic recovery was regular. In conclusion, plerixafor combined with G-CSF allows a collection of adequate number of PBSC in approximately 40% of cases of poor mobilizer, heavily pre-treated pts with lymphoma, who need consolidation with ASCT. PMID- 21276614 TI - Long-term follow-up of acquired nonaccommodative esotropia in a population-based cohort. AB - PURPOSE: To describe the clinical characteristics and long-term outcomes of children diagnosed over a 30-year period with acquired nonaccommodative esotropia (ANAET). DESIGN: Retrospective chart review of a population-based cohort. PARTICIPANTS: All pediatric (<19 years of age) residents of Olmsted County, Minnesota, who were diagnosed with ANAET from January 1, 1965, to December 31, 1994. METHODS: The medical records of all potential patients identified by the resources of the Rochester Epidemiology Project were reviewed. MAIN OUTCOME MEASURES: Incidence, clinical characteristics, and long-term motor and sensory outcomes of children with ANAET. RESULTS: A total of 174 children were diagnosed during the 30-year period, yielding an incidence of 1 in 287 live births. The median age at diagnosis for the 174 patients was 4.0 years (range, 10 months to 18.2 years), and 61% (107) were male (P = 0.009). Although 11% (8/75) of those queried were diplopic, none of the 174 was subsequently diagnosed with an intracranial lesion. During a mean follow-up of 10.9 years (range, 0 days to 37 years), 127 patients (73%) underwent strabismus surgery (mean, 1 surgery; range, 0-3 surgeries). Among the 127 patients who underwent surgery, the median final stereoacuity was 3000 seconds of arc, including 8 patients (6.3%) with >= 50 seconds of arc. Patients who were older (>44 months) at ANAET diagnosis (P = 0.005) and without amblyopia at their initial examination (P < 0.001) were more likely to achieve excellent final stereopsis. CONCLUSIONS: In this population based cohort, ANAET occurred in 1 in 287 children and was more prevalent among male children. Although diplopia was relatively common, none of the children were found to have an intracranial malignancy. Most patients achieved good motor and sensory outcomes, with the best results among those with a later onset of their deviation and no amblyopia. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 21276615 TI - Optimizing diagnosis and management of nocardia keratitis, scleritis, and endophthalmitis: 11-year microbial and clinical overview. AB - OBJECTIVE: To identify clinical factors and microbiological assays that facilitate a rapid diagnosis of Nocardia keratitis, scleritis, and endophthalmitis, and to determine optimal medical and surgical management strategies. DESIGN: Retrospective, consecutive case series. PARTICIPANTS: A total of 111 cases of keratitis, 11 cases of scleritis, and 16 cases of endophthalmitis, all culture-proven Nocardia infections, were identified between January 1999 and January 2010. INTERVENTION: The keratitis cases underwent intensive medical management, and the scleritis and endophthalmitis cases required concurrent surgical intervention for disease control. Corneal and scleral scrapings, as well as undiluted vitreous sample, were submitted for microbiologic evaluation (direct smear and culture). MAIN OUTCOME MEASURES: Historical points, clinical findings, and microbiologic assays that facilitated a prompt Nocardia diagnosis were identified, and management choices were examined for correlation with final acuity. RESULTS: Ocular exposure to soil or plant matter was a common historical point in cases of Nocardia keratitis (48%) and scleritis (45%), respectively. Nocardia keratitis often (38.7%) presented with "wreath"-shaped anterior stromal infiltrate or infiltrate interspersed with elevated, pinhead-sized, chalky lesions. Most patients with scleritis (63.4%) presented with nodular lesions demonstrating pointed abscesses. Nocardia endophthalmitis typically (75%) presented with endoexudates or nodular exudates surrounding the pupillary border. Gram stain and 1% acid-fast stain enabled prompt diagnosis of Nocardia in 64% and 63% of keratitis cases and 45% and 63% of scleritis cases, respectively. Direct smear was usually not revealing in cases of Nocardia endophthalmitis. Isolates from Nocardia keratitis, scleritis, and endophthalmitis demonstrated 97%, 100%, and 90% susceptibility to amikacin, respectively. Nocardia keratitis resolved with medical therapy alone in 82% of cases. Younger age and better initial acuity correlated with improved final acuity in keratitis cases. Outcomes were poor after Nocardia scleritis and endophthalmitis. CONCLUSIONS: Early appropriate treatment often results in visual recovery in eyes with Nocardia keratitis. Despite aggressive and prompt surgical intervention, the prognosis for Nocardia scleritis and endophthalmitis is more guarded. Nocardia isolated from ocular infections demonstrate high levels of susceptibility to amikacin. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 21276616 TI - Effect of dual-focus soft contact lens wear on axial myopia progression in children. AB - PURPOSE: To test the efficacy of an experimental Dual-Focus (DF) soft contact lens in reducing myopia progression. DESIGN: Prospective, randomized, paired-eye control, investigator-masked trial with cross-over. PARTICIPANTS: Forty children, 11-14 years old, with mean spherical equivalent refraction (SER) of -2.71 +/- 1.10 diopters (D). METHODS: Dual-Focus lenses had a central zone that corrected refractive error and concentric treatment zones that created 2.00 D of simultaneous myopic retinal defocus during distance and near viewing. Control was a single vision distance (SVD) lens with the same parameters but without treatment zones. Children wore a DF lens in 1 randomly assigned eye and an SVD lens in the fellow eye for 10 months (period 1). Lens assignment was then swapped between eyes, and lenses were worn for a further 10 months (period 2). MAIN OUTCOME MEASURES: Primary outcome was change in SER measured by cycloplegic autorefraction over 10 months. Secondary outcome was a change in axial eye length (AXL) measured by partial coherence interferometry over 10 months. Accommodation wearing DF lenses was assessed using an open-field autorefractor. RESULTS: In period 1, the mean change in SER with DF lenses (-0.44 +/- 0.33 D) was less than with SVD lenses (-0.69 +/- 0.38 D; P < 0.001); mean increase in AXL was also less with DF lenses (0.11 +/- 0.09 mm) than with SVD lenses (0.22 +/- 0.10 mm; P < 0.001). In 70% of the children, myopia progression was reduced by 30% or more in the eye wearing the DF lens relative to that wearing the SVD lens. Similar reductions in myopia progression and axial eye elongation were also observed with DF lens wear during period 2. Visual acuity and contrast sensitivity with DF lenses were not significantly different than with SVD lenses. Accommodation to a target at 40 cm was driven through the central distance-correction zone of the DF lens. CONCLUSIONS: Dual-Focus lenses provided normal acuity and contrast sensitivity and allowed accommodation to near targets. Myopia progression and eye elongation were reduced significantly in eyes wearing DF lenses. The data suggest that sustained myopic defocus, even when presented to the retina simultaneously with a clear image, can act to slow myopia progression without compromising visual function. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 21276617 TI - Associated morbidity of blepharitis. AB - OBJECTIVE: To evaluate the prevalence of systemic medical conditions in patients with blepharitis. DESIGN: A retrospective observational case-control study. PARTICIPANTS AND CONTROLS: All the members who were diagnosed with blepharitis in the Central District of Clalit Health Services in Israel (years 2000-2009; n=16706) and 16706 age- and gender-matched controls randomly selected from the district members. METHODS: Analysis of the prevalence of various ocular and systemic conditions, risk factors, age, gender, marriage status, country of origin, place of residency, and socioeconomic status. MAIN OUTCOME MEASURES: The prevalence of any associated morbidity. RESULTS: Demographically, a significantly higher tendency to develop blepharitis was found in populations of lower socioeconomic class, populations living in urban areas, and Ashkenazi Jews. A significant association of P<0.001 was found with some inflammatory diseases (gastritis, peptic ulcer, asthma, arthropathy, and ulcerative colitis), psychologic conditions (anxiety, irritable bowel syndrome, neuroses, and depression), hormonal conditions (hypothyroidism and prostatic hypertrophy), cardiovascular diseases (carotid artery disease, hyperlipidemia, hypertension, and ischemic heart disease), and other eye conditions (chalazion, pterygium). The strongest associations found were between blepharitis and chalazia (odds ratio [OR] 4.7; confidence interval [CI], 3.8-5.7), rosacea (OR 3; CI, 2.1-4.3), pterygia (OR 2.0; CI, 1.5-2.6), ulcerative colitis (OR 2.3; CI, 1.2-4.2), irritable bowel syndrome (OR 1.8; CI, 1.3-2.5), anxiety (OR 1.6; CI, 1.4-1.9), and gastritis (OR 1.6; CI, 1.4-1.7). CONCLUSIONS: Some ocular and systemic conditions are more prevalent among patients with blepharitis. Better understanding of the pathophysiologic association between those diseases and blepharitis may help in its treatment and prevention. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 21276618 TI - Primary undifferentiated large cell carcinoma of the lacrimal gland. AB - PURPOSE: To report a unique case of primary undifferentiated large cell carcinoma (LCCA) of the lacrimal gland, a tumor not previously described in the ophthalmic literature. DESIGN: Single interventional case report. PARTICIPANTS: A patient affected by undifferentiated LCCA of the lacrimal gland. METHODS: A 65-year-old white man with a 3-month history of a painful mass in the left lacrimal gland fossa underwent an incisional biopsy that revealed a "high-grade" epithelial malignancy. Systemic workup revealed enlargement of the regional lymph nodes, and subsequently the patient underwent extended exenteration with clear histologic margins and radical neck lymphadenectomy followed by adjunctive radiotherapy. Fifteen months postoperatively, the patient is alive and well without evidence of local recurrence or metastatic disease. MAIN OUTCOME MEASURES: Treatment result, evidence of local recurrences or distant metastasis, and follow-up. RESULTS: Histologic examination revealed a poorly circumscribed tumor composed of large cells invading orbital fat, lateral rectus muscle, and peripheral nerves. The surrounding orbital bone was infiltrated, but the surgical margins were clear. The cell population was composed of large cells (>30 MUm) with eosinophilic cytoplasm and ovoid and irregular nuclei containing a prominent nucleoli and coarse chromatin. The cell borders were well defined. Mitosis figures were abundant, and Ki-67 was positive in more than 60% of the cells. The cells were arranged in cords and trabeculae or irregular sheets of discohesive cells. The immunophenotype analysis showed positivity for cytokeratin but negative cytokeratin 20 stains, which is considered a distinctive feature of LCCA. CONCLUSIONS: Undifferentiated LCCAs are rare tumors of the major salivary glands, especially the parotid gland. Primary undifferentiated LCCA of the lacrimal gland has never been reported in the literature. Differential diagnosis must include a primary source in another organ. Given the aggressive nature of the tumor, radical surgery followed by radiotherapy is recommended, but evidence-based indications regarding the preferred line of treatment are lacking and the prognosis remains guarded. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 21276619 TI - Reliability of the Hamilton Rating Scale for Depression: a meta-analysis over a period of 49 years. AB - The aim of this study was to provide a comprehensive meta-analytic review of the reliability of the Hamilton Rating Scale for Depression (HRSD) for the period 1960-2008, taking into consideration all three types of reliability: internal consistency, inter-rater, and test-retest reliability. This is the first such meta-analytic study of a clinician-administered psychiatric scale. A thorough literature search was conducted using MEDLINE and PsycINFO. The total number of collected articles was 5548, of which 409 reported one or more reliability coefficients. The effect size was obtained by the z-transformation of reliability coefficients. The meta-analysis was performed separately for internal consistency, inter-rater and test-retest reliability. A pooled mean for alpha coefficient in random effects model was 0.789 (95%CI 0.766-0.810). The meta regression analysis revealed that higher alpha coefficients were associated with higher variability of the HRSD total scores. With regard to inter-rater reliability, pooled means in random effects model were 0.937 (95%CI 0.914-0.954) for the intraclass correlation coefficient, 0.81 (95%CI 0.72-0.88) for the kappa coefficient, 0.94 (95%CI 0.90-0.97) for the Pearson correlation coefficient, and 0.91 (95%CI 0.78-0.96) for the Spearman rank correlation coefficient. A meta regression analysis showed positive association between inter-rater reliability and publication year. Test-retest reliability of HRSD ranged between 0.65 and 0.98 and generally decreased with extending the interval between two measurements (Spearman r between the duration of interval and test-retest reliability figures= 0.74). Results suggest that HRSD provides a reliable assessment of depression. Figures indicate good overall levels of internal consistency, inter-rater and test-retest reliability, but some HRSD items (e.g., "loss of insight") do not appear to possess a satisfactory reliability. PMID- 21276620 TI - Chronotropic incompetence or tachycardiomyopathy as trigger of myocardial dysfunction in critically ill patients? PMID- 21276621 TI - Trends in inflammatory biomarkers during atrial fibrillation ablation across different catheter ablation strategies. AB - INTRODUCTION: Chest pain after atrial fibrillation (AF) ablations is a common complaint with a wide differential diagnosis including coronary events. Elevation of troponins (Trop I) has been shown with radio-frequency (RF) ablation for atrial fibrillation. New devices including cryoballoon and multipolar ablation catheters have been introduced as alternative methods. We aim to compare cardiac injury following AF ablations according to different ablation technologies. METHODS: In consecutive patients undergoing AF ablations with RF ablation, cryoballoon or multipolar ablation catheter (PVAC), Trop I, creatine kinase (CK) and CRP were analyzed immediately prior to and 24h following completion of ablation. Coronary events and symptoms and serial ECGs post procedure were evaluated. RESULTS: A total of 243 patients were included, 18.5% of them females. The mean age was 63 +/- 11 years old. Baseline Trop I, CK and CRP levels were within normal range in all patients. After RF ablation Trop I, CK and CRP levels were elevated in 100%, 20% and 91% of patients respectively (Trop I 3.55 pg/ml [range: 0.60-24.01 pg/ml], CK 147 U/l [range: 56-380 U/l] and CRP 2.15 mg/dl [range: 0.28-20.98 mg/dl]). All post-procedure Trop I levels were above the range of myocardial infarction (>0.15 ng/ml). After cryoballoon ablation, Trop I and CK levels were significantly higher than after RF or PVAC ablation (p<0.001). No ischemic ECG changes were documented. CONCLUSIONS: Trop I elevations are not specific for ischemia in the setting of chest pain after AF ablation. Cryoballoon ablation resulted in a higher amount of cardiac injury. PMID- 21276622 TI - The development of the pulmonary vein revisited. PMID- 21276623 TI - Weight loss in women with metabolic syndrome. PMID- 21276624 TI - Migraine from microembolism of noncompaction? PMID- 21276625 TI - Plasma active matrix metalloproteinase 9 associated to diastolic dysfunction in patients with coronary artery disease. PMID- 21276626 TI - Genomics and ecological overview of the genus Bifidobacterium. AB - Members of the genus Bifidobacterium are high G+C Gram positive bacteria belonging to the phylum Actinobacteria, and represent common inhabitants of the gastro-intestinal tract (GIT) of mammals, birds and certain cold-blooded animals. The overall microbial population that resides in the GIT, referred to as the "gut microbiota", is an extremely complex community of microorganisms whose functions are believed to have a significant impact on human physiology. Different ecological relationships between bifidobacteria and their host can be developed, ranging from opportunistic pathogenic interactions (e.g. in the case of Bifidobacterium dentium) to a commensal or even health-promoting relationship (e.g. in the case of Bifidobacterium bifidum and Bifidobacterium breve species). Among the known health-promoting or probiotic microorganisms, bifidobacteria represent one of the most dominant group and some bifidobacterial species are frequently used as the probiotic ingredient in many functional foods. However, despite the generally accepted importance of bifidobacteria as constituents of the human microbiota, there is only limited information available on their phylogeny, physiology and genetics. Moreover, host-microbiota interactions and cross-talk between different members of the gut microbiota are far from completely understood although they represent a crucial factor in the development and maintenance of human physiology and immune system. The aim of this review is to highlight the genetic and functional features of bifidobacteria residing in the human GIT using genomic and ecology-based information. PMID- 21276627 TI - Survivability of probiotics encapsulated in alginate gel microbeads using a novel impinging aerosols method. AB - Encapsulation of probiotic bacteria in cross-linked alginate beads is of major interest for improving the survivability in harsh acid and bile environment and also in food matrices. Alginate micro beads (10-40 MUm) containing the probiotics Lactobacillus rhamnosus GG and Lactobacillus acidophilus NCFM were produced by a novel technique based on dual aerosols of alginate solution and CaCl(2) cross linking solution. Extruded macro beads (approximately 2mm diameter) produced by the conventional method and micro beads produced by novel aerosols technique offered comparable protection to L. rhamnosus in high acid and bile environment. Chitosan coating of micro beads resulted in a significant increase in survival time of L. rhamnosus from 40 to 120 min in acid condition and the reduction in cell numbers was confined to 0.94 log over this time. Alginate macro beads are more effective than micro beads in protecting L. acidophilus against high acid and bile. Chitosan coating of micro beads resulted in similar protection to L. acidophilus in macro beads in acid and extended the survival time from 90 to at least 120 min. Viability of this organism in micro beads was 3.5 log after 120 min. The continuous processing capability and scale-up potential of the dual aerosol technique offers potential for an efficient encapsulation of probiotics in very small alginate micro beads below sensorial detection limits while still being able to confer effective protection in acid and bile environment. PMID- 21276628 TI - Development of monoclonal antibody based sandwich ELISA for the rapid detection of pathogenic Vibrio parahaemolyticus in seafood. AB - Thermostable direct hemolysin (TDH) and TDH-related hemolysin (TRH) are considered important virulence factors of Vibrio parahaemolyticus and strains producing either of these or both are considered pathogenic. In this study, we generated monoclonal antibodies (mAbs) against purified TRH recombinant protein of pathogenic V. parahaemolyticus. Sandwich enzyme-linked immunosorbent assays (ELISA) using the hybridoma clone 4B10 showed higher sensitivity of detection compared to other clones. Using mAb 4B10 based sandwich ELISA, we could detect pathogenic V. parahaemolyticus in 41.18% (14 out of 34) of the seafood samples analyzed. PCR targeting the toxR gene showed the presence of V. parahaemolyticus in 64.7% (22 out of 34) seafood samples. Further, PCR targeting the virulence genes showed that 6 seafood samples harboured the tdh gene while 9 harboured the trh gene indicating the presence of pathogenic V. parahaemolyticus. Our results show that mAb 4B10 sandwich ELISA developed in this study could be used as a rapid method for screening seafood samples for the presence of pathogenic V. parahaemolyticus. PMID- 21276629 TI - Development of a DNA microarray for detection and identification of Legionella pneumophila and ten other pathogens in drinking water. AB - The safety and accessibility of drinking water are major concerns throughout the world. Consumption of water contaminated with infectious agents, toxic chemicals or radiological hazards represents a significant health risk and is strongly associated with mortality. Therefore, we have developed an oligonucleotide-based microarray using the sequences of 16S-23S rDNA internal transcribed spacer regions (ITS) and the gyrase subunit B gene (gyrB) found in the most prevalent and devastating waterborne pathogenic agents. This new diagnostic contains 26 specific probes and can simultaneously detect Aeromonas hydrophila, Klebsiella pneumoniae, Legionella pneumophila, Pseudomonas aeruginosa, Salmonella spp., Shigella spp., Staphylococcus aureus, Vibrio choleraeo, Vibrio parahaemolyticus, Yersinia enterocolitica and Leptospira interrogans. Testing was carried out against a total of 218 bacterial strains, including 53 representative strains, 103 clinical isolates and 62 strains of other bacterial species belonging to 10 genera and 48 species. The results were specific and reproducible, with a detection sensitivity of 0.1 ng DNA or 10(4)CFU/ml achieved for pure cultures of each target organism. The diluted cultures and real drinking water samples were tested by the microarray with 100% accuracy. This novel diagnostic method is superior in time- and labor-efficiency to conventional bacterial culture and antiserum agglutination, and can be readily applied to epidemiological surveillance and other food safety applications. PMID- 21276630 TI - Rapid enumeration of low numbers of moulds in tea based drinks using an automated system. AB - Aseptically prepared cold drinks based on tea have become popular worldwide. Contamination of these drinks with harmful microbes is a potential health problem because such drinks are kept free from preservatives to maximize aroma and flavour. Heat-tolerant conidia and ascospores of fungi can survive pasteurization, and need to be detected as quickly as possible. We were able to rapidly and accurately detect low numbers of conidia and ascospores in tea-based drinks using fluorescent staining followed by an automated counting system. Conidia or ascospores were inoculated into green tea and oolong tea, and samples were immediately filtered through nitrocellulose membranes (pore size: 0.8 MUm) to concentrate fungal propagules. These were transferred onto potato dextrose agar and incubated for 23 h at 28 degrees C. Fungi germinating on the membranes were fluorescently stained for 30 min. The stained mycelia were counted selectively within 90s using an automated counting system (MGS-10LD; Chuo Electric Works, Osaka, Japan). Very low numbers (1 CFU/100ml) of conidia or ascospores could be rapidly counted, in contrast to traditional labour intensive techniques. All tested mould strains were detected within 24h while conventional plate counting required 72 h for colony enumeration. Counts of slow-growing fungi (Cladosporium cladosporioides) obtained by automated counting and by conventional plate counting were close (r(2) = 0.986). Our combination of methods enables counting of both fast- and slow-growing fungi, and should be useful for microbiological quality control of tea-based and also other drinks. PMID- 21276631 TI - The study on the impact of glycated pea proteins on human intestinal bacteria. AB - The traditionally perceived function of nutrition includes supplying the consumer with the appropriate quantity and quality of substrates. As nutritional substrates, proteins are prone to spontaneously occurring non-enzymatic glycosylation (glycation) which can alter their molecular structure, making them highly bioactive. Glycated food proteins are able to modify the bacterial intestinal ecosystem, which is of great importance for the optimal usage of nutrients and maintenance of both intestinal homeostasis and balanced health status of the consumer. This study aimed to determine the impact of glycated pea proteins on the intestinal bacteria from a healthy human. The analyses were conducted with the use of experimental batch-type simulator models imitating human intestinal conditions. The glycated pea proteins affected the growth of gut commensal bacteria, particularly lactobacilli and bifidobacteria, whose levels increased significantly. There was a corresponding shift in the bacterial metabolites with increased levels of the short chain fatty acids (SCFAs); acetate, propionate lactate and butyrate. Intestinal bacteria were able to utilize these pea proteins thus indicating that the energy encrypted in glycated pea proteins, partially inaccessible for gastric enzymes, may be salvaged by gut microbiota. Such changes in microbial composition may beneficially impact the intestinal environment and exert a health-promoting effect in humans. PMID- 21276632 TI - Detection and characterization of Salmonella in lairage, on pig carcasses and intestines in five slaughterhouses. AB - In this study, conducted at five slaughterhouses, individual pigs were sampled and followed up from stunning to cooling down of the carcasses. In this way, Salmonella prevalence and possible risk points were described. At the lairage area, pens were sampled using overshoes. At stunning and bleeding, pigs were individually identified and subsequently swabs were taken of the oral cavity and the carcass after polishing, splitting and forced chilling. Additionally, duodenum, ileum, rectum and mesenteric lymph nodes were extracted and samples were taken of the scalding water. All samples were submitted to Salmonella isolation and Salmonella isolates were serotyped and genotyped by pulsed-field gel electrophoresis (PFGE). Of all samples taken (n = 1953), 14.1% were Salmonella positive. The prevalence of S. in the lairage area varied widely (from 0 to 100%) between the slaughterhouses. Of the sampled pigs (n = 226), 48.2% were positive in at least one sample. Statistical analysis revealed that the contamination of the lairage area was related to a higher amount of positive carcasses after polishing. Furthermore, the contamination of the carcasses after splitting and forced chilling was related to the contamination level of the carcass after polishing. A relation between the outer (carcass) contamination and the inner (gut content and lymph nodes) contamination of a pig could not be established. The predominant serotypes were S. Typhimurium (58.7%) and S. Derby (17.4%). Genotyping revealed 46 different PFGE profiles among the 276 Salmonella isolates. The same genotype at the lairage area as in the oral cavity of the pigs was found in 95%. The results indicate that the lairage area is a primary source of Salmonella in slaughter pigs and that carcass contamination originates from the environment rather than from the pig (inner contamination) itself. It further shows that slaughterhouses vary in their capability of dealing with Salmonella positive pigs. A slaughterhouse specific approach is needed, however, general guidelines should be provided to decrease the contamination level of the lairage area and the slaughter environment. PMID- 21276633 TI - Combined effect of ultrasound and organic acids to reduce Escherichia coli O157:H7, Salmonella Typhimurium, and Listeria monocytogenes on organic fresh lettuce. AB - This study was performed to compare the effectiveness of individual treatments (ultrasound and organic acids) and their combination on reducing foodborne pathogens on organic fresh lettuce. Lettuce leaves were inoculated with a cocktail of three strains each of Escherichia coli O157:H7, Salmonella Typhimurium, and Listeria monocytogenes and treated with ultrasound (40 kHz) alone, organic acids (0.3, 0.5, 0.7, 1.0, and 2.0%--malic acid, lactic acid, and citric acid) alone and combined with ultrasound and organic acids for 5 min. For all 3 pathogens, the combined treatment of ultrasound and organic acids resulted in additional 0.8 to 1.0 log reduction compared to individual treatments, without causing significant quality change (color and texture) on lettuce during 7 day storage. The maximum reductions of E. coli O157:H7, S. Typhimurium, and L. monocytogenes were 2.75, 3.18, and 2.87 log CFU/g observed after combined treatment with ultrasound and 2% organic acid for 5 min, respectively. Our results suggest that the combined treatment of ultrasound with organic acids was effective at increasing pathogen reduction compared to individual treatments without significantly affecting quality, and demonstrates its potential as a novel method to increase the microbial safety on organic fresh lettuce. PMID- 21276634 TI - Review--Persistence of Listeria monocytogenes in food industry equipment and premises. AB - To understand why Listeria monocytogenes may persist in food industry equipment and premises, notably at low temperature, scientific studies have so far focused on adhesion potential, biofilm forming ability, resistance to desiccation, acid and heat, tolerance to increased sublethal concentration of disinfectants or resistance to lethal concentrations. Evidence from studies in processing plants shows that the factors associated with the presence of L. monocytogenes are those that favor growth. Interestingly, most conditions promoting bacterial growth were shown, in laboratory assays, to decrease adhesion of L. monocytogenes cells. Good growth conditions can be found in so-called harborage sites, i.e. shelters due to unhygienic design of equipment and premises or unhygienic or damaged materials. These sites are hard to eliminate. A conceptual model of persistence/no persistence based on the relative weight of growth vs. outcome of cleaning and disinfection is suggested. It shows that a minimum initial bacterial load is necessary for bacteria to persist in a harborage site and that when a low initial bacterial charge is applied, early cleaning and disinfection is the only way to avoid persistence. We conclude by proposing that there are no strains of L. monocytogenes with unique properties that lead to persistence, but harborage sites in food industry premises and equipment where L. monocytogenes can persist. PMID- 21276635 TI - Fluorescence in situ hybridization for detection of classical propionibacteria with specific 16S rRNA-targeted probes and its application to enumeration in Gruyere cheese. AB - The classical or dairy propionibacteria have well-documented industrial applications and have been proposed for probiotic applications. Given their industrial importance it is necessary to employ fast and reliable techniques to monitor the growth during products elaboration, industrial fermentations or the intestinal transit. Therefore, the aim of this investigation was to design oligonucleotide probes targeting the 16S rRNA of dairy propionibacteria and optimise the fluorescence in situ hybridization (FISH) protocol to detect these bacteria. Two specific probes were in silico designed to detect Propionibacterium freudenreichii and P. jensenii, named Pfr435 and Pj446 respectively. The FISH protocol was optimised for the hybridisation of propionibacteria cells with the universal probe Eub338 and the designed probes. These probes were assayed in situ for their specificity to hybridise species of propionibacteria by observation using fluorescence microscopy and results were compared with the probe Pap446 previously designed for P. acidipropionici. Probes Pap446, Pfr435 and Pj446 were also evaluated by fluorescence spectrophotometry to assess the influence of cells physiological state during growth in batch culture in the fluorescence intensity. The maximum fluorescence intensity was observed at the onset of the stationary phase of growth and was then reduced. However, changes on the cells permeability did not reduce the efficiency of 16S rRNA hybridisation with the fluorescence labelled probes. Propionibacteria counts obtained by FISH and plate count methods were compared in a commercial Gruyere cheese. The results showed that this method can be used as a rapid technique for the enumeration of these bacteria in cheese samples. PMID- 21276636 TI - [Ocular complications of HIV infection: experience of the Northern Excellence Pole of Morocco]. AB - INTRODUCTION: HIV infection is associated with a wide variety of ophthalmic manifestations. The objective of this study was to identify the ocular complications of HIV/AIDS in Morocco. MATERIAL AND METHODS: A retrospective study conducted in the internal medicine department of the Rabat Teaching Hospital between 1998 and 2008. All HIV-positive patients were retained for the study. Each patient had an exhaustive ocular examination. RESULTS: Of 115 ophthalmologic examinations, 28 were abnormal. Twenty-seven patients had stage C HIV infection and one patient was in stage A. The ocular manifestations were: 21 cases of ocular HIV-related anomalies (microangiopathies), four cases of cytomegalovirus (CMV) retinitis, one case of toxoplasmosis chorioretinitis, one case of CMV retinitis associated with toxoplasmosis chorioretinitis, two cases of Cryptococcus neoformans infection, two cases of varicella-zoster virus (VZV) retinitis, and one case of conjunctival Kaposi sarcoma. The CD4 count average was of 86+/-91/mm(3). Twenty-six patients had a CD4 count lower than 200/mm(3). Progression was favorable in 85 % of the cases, with three cases of blindness: bilateral in a case of VZV retinitis and unilateral in two cases of CMV retinitis and toxoplasmosis chorioretinitis. CONCLUSION: CMV infection is the main ocular opportunistic infection in our series. However, Highly Active Antiretroviral Treatment (HAART) may be the cause for the decline in the prevalence of ocular diseases and visual impairment in HIV/AIDS. PMID- 21276637 TI - [Giant apocrine hydrocystoma of the internal canthus]. AB - Hydrocystoma is a benign tumor whose development involves the sudoriferous eccrine or apocrine glands. We report the case of a giant apocrine hydrocystoma in a 70-year-old female diabetic patient. The tumor's natural progression over 10 years and its volume caused significant functional and aesthetic damage. This article discusses the radiological, clinical, anatomopathological, and therapeutic aspects of this tumor. The case is original in the tumor's location, size, and its double visual and lachrymal functional involvement as well as its aesthetic damage. PMID- 21276638 TI - Trends in mupirocin resistance in meticillin-resistant Staphylococcus aureus and mupirocin consumption at a tertiary care hospital. PMID- 21276639 TI - Intention to comply with post-exposure management among nurses exposed to blood and body fluids in Taiwan: application of the theory of planned behaviour. AB - Nurses are at significant risk from occupationally acquired bloodborne virus infections following a needlestick and sharps injury. This study aimed to apply the theory of planned behaviour (TPB) to predict nurses' intention to comply with occupational post-exposure management. A cross-sectional survey was applied to select registered nurses who worked in human immunodeficiency virus (HIV) designated hospitals. An anonymous, self-administered questionnaire based on the TPB was distributed to 1630 nurses and 1134 (69.5%) questionnaires were returned. From these, a total of 802 nurses (71%) reported blood and body fluid exposure incidents during 2003-2005 and this group was used for analysis. Only 44.6% of the 121 exposed nurses who were prescribed post-exposure prophylaxis (PEP) by infectious disease doctors returned to the clinic for interim monitoring, and only 56.6% of exposed nurses confirmed their final serology status. Structural equation modelling was used to test the TPB indicating perceived behavioural control (the perception of the difficulty or ease of PEP management, beta=0.58), subjective norm (the perception of social pressure to adhere to PEP, beta=0.15), and attitudes (beta=0.12) were significant direct effects on nurses' intention to comply with post-exposure management. The hypothesised model test indicated that the model fitted with the expected relationships and directions of theoretical constructs [chi(2) (14, N=802)=23.14, P=0.057, GFI=0.987, RMSEA=0.039]. The TPB model constructs accounted for 54% of the variance in nurses' intention to comply with post-exposure management. The TPB is an appropriate model for predicting nurses' intention to comply with post-exposure management. Healthcare facilities should have policies to decrease the inconvenience of follow-up to encourage nurses to comply with post-exposure management. PMID- 21276640 TI - Differences in surveillance definitions for neonatal healthcare-associated laboratory-confirmed bloodstream infection and clinical sepsis. PMID- 21276641 TI - Disinfection and sterilisation practices in laboratories of a research institution in Uganda. PMID- 21276642 TI - A task analysis of emergency physician activities in academic and community settings. AB - STUDY OBJECTIVE: We characterize and compare the work activities, including peak patient loads, associated with the workplace in the academic and community emergency department (ED) settings. This allows assessment of the effect of future ED system operational changes and identifies potential sources contributing to medical error. METHODS: This was an observational, time-motion study. Trained observers shadowed physicians, recording activities. Data included total interactions, distances walked, time sitting, patients concurrently treated, interruptions, break in tasks, physical contact with patients, hand washing, diagnostic tests ordered, and therapies rendered. Activities were classified as direct patient care, indirect patient care, or personal time with a priori definitions. RESULTS: There were 203 2-hour observation periods of 85 physicians at 2 academic EDs with 100,000 visits per year at each (N=160) and 2 community EDs with annual visits of 19,000 and 21,000 (N=43). Reported data present the median and minimum-maximum values per 2-hour period. Emergency physicians spent the majority of time on indirect care activities (academic 64 minutes, 29 to 91 minutes; community 55 min, 25 to 95 minutes), followed by direct care activities (academic 36 minutes, 6 to 79 minutes; community 41 minutes, 5 to 60 minutes). Personal time differed by location type (academic 6 minutes, 0 to 66 minutes; community 13 minutes, 0 to 69 minutes). All physicians simultaneously cared for multiple patients, with a median number of patients greater than 5 (academic 7 patients, 2 to 16 patients; community 6 patients, 2 to 12 patients). CONCLUSION: Emergency physicians spend the majority of their time involved in indirect patient care activities. They are frequently interrupted and interact with a large number of individuals. They care for a wide range of patients simultaneously, with surges in multiple patient care responsibilities. Physicians working in academic settings are interrupted at twice the rate of their community counterparts. PMID- 21276643 TI - Synthesis and biological evaluation of substituted (thieno[2,3-d]pyrimidin-4 ylthio)carboxylic acids as inhibitors of human protein kinase CK2. AB - A novel series of substituted (thieno[2,3-d]pyrimidin-4-ylthio)carboxylic acids has been synthesized and tested in vitro towards human protein kinase CK2. It was revealed that the most active compounds inhibiting CK2 are 3-{[5-(4 methylphenyl)thieno[2,3-d]pyrimidin-4-yl]thio}propanoic acid and 3-{[5-(4 ethoxyphenyl)thieno[2,3-d]pyrimidin-4-yl]thio}propanoic acid (IC(50) values are 0.1 MUM and 0.125 MUM, respectively). Structure-activity relationships of 28 tested thienopyrimidine derivatives have been studied and binding mode of this chemical class has been predicted. Evaluation of the inhibitors on seven protein kinases revealed considerable selectivity towards CK2. PMID- 21276644 TI - Diet induced thermogenesis, fat oxidation and food intake following sequential meals: influence of calcium and vitamin D. AB - BACKGROUND & AIMS: The mechanisms linking dietary calcium and vitamin D to body weight regulation require confirmation. METHODS: Eleven subjects, aged (mean +/- SEM) 54 +/- 1.2 y and BMI 31 +/- 2.4 kg/m(2), participated in a randomised within subject, sequential meal protocol comparing a low calcium trial (LCT) to an isoenergetic high calcium trial (HCT). Diet induced thermogenesis (DIT), fat oxidation rates (FOR), serum leptin, subjective feelings of hunger/satiety were measured at fasting and hourly over 8 h. Spontaneous food intake at a buffet and over the following 30 h was recorded. Postprandial responses, calculated as change (Delta) from baseline for each meal, were analysed by paired t-tests and 2 * 2 repeated measures ANOVA. RESULTS: HCT resulted in lesser suppression of DeltaFOR (p = 0.02) and a significantly greater DIT (p = 0.01). Further, the buffet to dinner interval was prolonged (p = 0. 083) and reported 24 h energy intake following this trial was significantly reduced (p = 0.017). ?leptin following HCT but not LCT was negatively related to 24 h fat intake (r = -0.81, p = 0.016). CONCLUSIONS: Higher calcium and vitamin D intake at a breakfast meal acutely increased postprandial FOR and DIT over two successive meals, and reduced spontaneous energy intake in the subsequent 24 h period. Australian New Zealand Clinical Trials Registry (ANZCTR) number: ACTRN12609000418279. PMID- 21276645 TI - Low-level maternal methylmercury exposure through rice ingestion and potential implications for offspring health. AB - Fish consumption is considered the primary pathway for MeHg (MeHg) exposure; however, MeHg exposure also occurs through rice ingestion. Rice is grown in an aquatic environment and although documented MeHg concentrations in rice are lower compared to fish tissue, human exposures exceed international guidelines in some regions where rice is a staple food and rice MeHg levels are elevated. Studies concerning human health exposure to MeHg should also include populations where maternal MeHg exposure occurs through ingestion of rice. Rice does not contain long-chain polyunsaturated fatty acids, which are associated with confounding developmental outcomes in offspring. Rice is also a staple food for more than half the world's population; therefore, it is critical to investigate the potential health risks of maternal ingestion of rice to the developing fetus, the most susceptible population to the deleterious effects of MeHg. Data concerning MeHg in rice are reviewed and micronutrients in rice are discussed. PMID- 21276646 TI - Resilience to suicidality: the buffering hypothesis. AB - Recent years have seen a growing interest into resilience to suicidality, which has been described as a perception or set of beliefs which buffer individuals from suicidality in the face of stressors. The current review extends this research by introducing the buffering hypothesis, a framework for the investigation of resilience to suicidality. The key proposal of this is that psychological resilience factors should be viewed as existing on a separate dimension to risk which acts to moderate the impact of risk on suicidality. Furthermore, like risk factors, resilience factors are bipolar, with their positive pole conferring resilience and their negative pole acting to amplify suicidality. Seventy-seven studies were identified which investigated (a) whether psychological moderators of risk exist and (b) the particular psychological constructs which may act as moderators. The review found strong support for the existence of psychological moderators and indicated a moderating impact of attributional style, perfectionism, agency and hopelessness. These findings support the buffering hypothesis and suggest that a range of psychological factors may confer resilience to suicidality. These results suggest that the identification of moderators may improve estimates of suicide risk and that the development of buffering factors could be a key focus of suicide interventions. PMID- 21276647 TI - Development of a data dictionary for the Strategies for Post Arrest Resuscitation Care (SPARC) network for post cardiac arrest research. AB - BACKGROUND: The widely accepted Utstein style has standardized data collection and analysis in resuscitation and post resuscitation research. However, collection of many of these variables poses significant practical challenges. In addition, several important variables in post resuscitation research are missing. OBJECTIVE: Our aim was to develop a comprehensive data dictionary and web-based data collection tool as part of the Strategies for Post Arrest Resuscitation Care (SPARC) Network project, which implemented a knowledge translation program for post cardiac arrest therapeutic hypothermia in 37 Ontario hospitals. METHODS: A list of data variables was generated based on the current Utstein style, previous studies and expert opinion within our group of investigators. We developed a data dictionary by creating clear definitions and establishing abstraction instructions for each variable. The data dictionary was integrated into a web based collection form allowing for interactive data entry. Two blinded investigators piloted the data collection tool, by performing a retrospective chart review. RESULTS: A total of 454 variables were included of which 400 were Utstein, 2 were adapted from existing studies and 52 were added to address missing elements. Kappa statistics for two outcome variables, survival to discharge and induction of therapeutic hypothermia were 0.86 and 0.64, respectively. CONCLUSION: This is the first attempt in the literature to develop a data dictionary as part of a standardized, pragmatic data collection tool for post cardiac arrest research patients. In addition, our dataset defined important variables that were previously missing. This data collection tool can serve as a reference for future trials in post cardiac arrest care. PMID- 21276648 TI - A molecular and cytogenetic investigation of FMR1 gene premutations in Polish patients with primary ovarian insufficiency. AB - OBJECTIVE: The aim of this study was to determine the prevalence of premutations in the FMR1 gene that cause primary ovarian insufficiency (POI) in a group of affected women. STUDY DESIGN: Forty DNA samples were purified from peripheral blood collected from women with ovarian failure who were under 40 years of age. A routine cytogenetic test was performed to eliminate chromosomal aberrations as the cause of POI. The DNA was analysed by polymerase chain reaction (PCR) with primers specific to the FMR1 gene region. The PCR products were then separated in denaturing polyacrylamide gels using an ABI Prism 377 sequencer. RESULTS: Cytogenetic analysis of the samples revealed two X/autosome translocations. DNA analysis identified FMR1 gene premutations in three patients. The frequency of X/autosome translocations in the studied group was 2/40 (5.0%), and the frequency of FMR1 gene premutations was 3/38 cases (7.9%). Thus, genetic tests allowed for the identification of POI in five (12.5%) out of 40 women. CONCLUSION: FMR1 gene premutation is a common genetic cause of POI. PMID- 21276649 TI - Pregnancy in women with a systemic right ventricle after surgically and congenitally corrected transposition of the great arteries. AB - OBJECTIVE: To determine maternal and neonatal outcomes in women with a systemic right ventricle (RV). STUDY DESIGN: A retrospective (historical) cohort study of maternal and neonatal outcomes at a tertiary referral academic obstetric unit (Chelsea and Westminster Hospital, London). RESULTS: Nineteen pregnancies in 14 women with a systemic RV were compared with 76 controls. There were no maternal deaths. In the study group cardiac complications occurred in six (32%) pregnancies. Obstetric complications occurred in four (21%) case pregnancies, not significantly higher than in the control group. The rate of neonatal complication was significantly higher in the study population with neonatal complications in 12 (63%) case pregnancies compared with 13 (17%) control pregnancies. The median birthweight centile was 9 in the study population, significantly lower than the control population. CONCLUSIONS: Our cohort study demonstrates high maternal and neonatal morbidity and low birthweight in the presence of a systemic RV. Cardiac complications were more common in women with RV dysfunction and arrhythmias prior to pregnancy. Preconception counselling and tertiary care during pregnancy for these patients is highly advisable. PMID- 21276650 TI - Hydrogen yield from a hydrogenase in Frankia R43 at different levels of the carbon source propionate. AB - Fermentative hydrogen yield was investigated in the Frankia strain R43, which was grown in different amounts of the carbon source propionate. In relation to hydrogen yield, the hydrogenase enzyme was characterized by use of Western blot. A bioreactor study revealed a 10-fold increase in growth within 50 h. The study showed that there is an active anaerobic hydrogen production in Frankia R43 and that this hydrogenase is immunologically related to the subunit HoxU of Ralstonia eutropha. PMID- 21276651 TI - Evaluation of severe subclavian artery stenosis by color Doppler flow imaging. AB - This study evaluates the diagnostic value of the hemodynamic parameters of color Doppler flow imaging (CDFI) for severe (70 to 99%) subclavian artery stenosis (SAS) using digital subtraction angiography (DSA) as the reference standard. Two hundred fifty-two patients with suspected SAS were recruited into the study and examined from June 2005 to December 2009. The degree of stenosis was classified as moderate (50 to 69%) or severe (70 to 99%) stenosis. By using CDFI, the residual diameter (Dr), peak systolic velocity (PSV1) and end diastolic velocity (EDV) at the stenotic vessel segments, as well as the original diameter (Do) and PSV2 of the relative normal segments distal to the stenosis (the segment distal to the poststenotic dilation) were recorded. The diameter stenosis rate (1-Dr/Do) and PSV ratio (PSV1/PSV2) were calculated. Using DSA as the reference standard, the diagnostic values and optimal cutoff values for each parameter for the evaluation of severe (70%-99%) were determined using receiving operating characteristic curve analysis. Among the 252 patients, 109 patients were diagnosed as having severe (70 to 99%) SAS and 143 patients had moderate (50 to 69%) SAS. The optimal cutoff values for PSV1, EDV and the PSV1/PSV2 ratio for evaluating severe (70 to 99%) SAS were PSV1 >=343 cm/s, EDV >=60 cm/s and PSV1/PSV2 >=4.0, respectively. The accuracy for diagnosing SAS with PSV1 (86.1%) was higher than that of EDV (85.7%), PSV1/PSV2 (84.9%) and 1-Dr/Do (80.2%). In addition, when PSV1 was used in combination with EDV and 1-Dr/Do, the accuracy for diagnosing SAS increased from 86.1% to 87.3%. When PSV1 was used in combination with EDV and PSV1/PSV2, the accuracy for diagnosing SAS reached 95.8%. In conclusion, the CDFI hemodynamic parameters of PSV1, EDV and PSV1/PSV2 show good consistency with DSA for diagnosing severe (70 to 99%) SAS, and a combination of these three parameters can ensure even greater accuracy for diagnosing SAS. PMID- 21276652 TI - A new method for the acquisition of ultrasonic strain image volumes. AB - This article presents a new method for acquiring three-dimensional (3-D) volumes of ultrasonic axial strain data. The method uses a mechanically-swept probe to sweep out a single volume while applying a continuously varying axial compression. Acquisition of a volume takes 15-20 s. A strain volume is then calculated by comparing frame pairs throughout the sequence. The method uses strain quality estimates to automatically pick out high quality frame pairs, and so does not require careful control of the axial compression. In a series of in vitro and in vivo experiments, we quantify the image quality of the new method and also assess its ease of use. Results are compared with those for the current best alternative, which calculates strain between two complete volumes. The volume pair approach can produce high quality data, but skillful scanning is required to acquire two volumes with appropriate relative strain. In the new method, the automatic quality-weighted selection of image pairs overcomes this difficulty and the method produces superior quality images with a relatively relaxed scanning technique. PMID- 21276653 TI - Photoacoustic imaging with a commercial ultrasound system and a custom probe. AB - Building photoacoustic imaging (PAI) systems by using stand-alone ultrasound (US) units makes it convenient to take advantage of the state-of-the-art ultrasonic technologies. However, the sometimes limited receiving sensitivity and the comparatively narrow bandwidth of commercial US probes may not be sufficient to acquire high quality photoacoustic images. In this work, a high-speed PAI system has been developed using a commercial US unit and a custom built 128-element piezoelectric-polymer array (PPA) probe using a P(VDF-TrFE) film and flexible circuit to define the elements. Since the US unit supports simultaneous signal acquisition from 64 parallel receive channels, PAI data for synthetic image formation from a 64- or 128-element array aperture can be acquired after a single or dual laser firing, respectively. Therefore, two-dimensional (2-D) B-scan imaging can be achieved with a maximum frame rate up to 10 Hz, limited only by the laser repetition rate. The uniquely properties of P(VDF-TrFE) facilitated a wide -6 dB receiving bandwidth of over 120% for the array. A specially designed 128-channel preamplifier board made the connection between the array and the system cable, which not only enabled element electrical impedance matching but also further elevated the signal-to-noise ratio (SNR) to further enhance the detection of weak photoacoustic signals. Through the experiments on phantoms and rabbit ears, the good performance of this PAI system was demonstrated. PMID- 21276654 TI - Effects of near-field ultrasound stimulation on new bone formation and osseointegration of dental titanium implants in vitro and in vivo. AB - A near-field ultrasound stimulation system was designed for use in in vitro and in vivo trials. The intensity of ultrasound was studied to optimize the osseointegration of the dental titanium implant into the adjacent bone. MG63 osteoblast-like cells were seeded on commercial purity titanium (CP-Ti) plate, and then sonicated for 3 min/day at a frequency of 1 MHz and intensities of 0.05, 0.15 and 0.30 W/cm(2), using either pulsed or continuous ultrasound. Cells were analyzed to determine viability (inhibition of (3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) reduction) and alkaline phosphatase (ALP). Tissue culture was performed in vitro by placing a CP-Ti plate in a cultured rat neonatal calvarial defect in response to ultrasound stimulation. In the in vivo trial, screw-shaped CP-Ti implants were inserted into the metaphysis of rabbit tibia, and then stimulated by ultrasound for 10 min daily for 30 d. All samples were processed for histomorphometric evaluation and analyzed by image system. Color Doppler ultrasonography was inspected to evaluate the supply of blood flow. Pulsed ultrasound groups had higher MTT and ALP than control. Tissue culture indicated that pulsed ultrasound groups promoted cell migration and new bone regeneration more effectively than in the control. In animal study, blood flow and mature type I collagen fibers were more prevalent around titanium implants, and bone formation was accelerated in pulsed ultrasound groups. In conclusion, low-intensity pulsed ultrasound at 0.05-0.3 W/cm(2) may accelerate cell proliferation and promote the maturation of collagen fibers and support osteointegration. PMID- 21276655 TI - Placental 3-D power Doppler angiography--regional variation and reliability of two ultrasonic sphere biopsy techniques. AB - Three-dimensional power Doppler angiography and 4D View allows quantification of placental "vascularity" using sonobiopsy or manual tracing. We used two vascular "biopsy" techniques: nontargeted sphere placement and systematic uniform random sphere placement (SURS). We hypothesised that random application of spheres would result in less reliability and the basal zone would display higher values than the chorionic zone. Forty women between 18+6 to 21+6 weeks gestation were recruited. A single volume of the placenta was acquired. Data was analysed twice by a single observer. Significantly higher values were seen for all vascular indices in the basal zone. Reliability was greatest for the whole placental technique with intraclass correlation coefficients of 0.9 and limits of agreement for flow index (FI) of -3.81 to 2.50 (equivalent to -7.8% to 5.1%) compared with 0.6 and -13.2 to 18.3 (-64.6% to 78.2%) for the nontargeted sphere technique. Whole placental values are more reliable than biopsy techniques with significantly different results seen with each technique. PMID- 21276656 TI - Visualization of HIFU-induced lesion boundaries by axial-shear strain elastography: a feasibility study. AB - In this paper, we report on a study that investigated the feasibility of reliably visualizing high-intensity focused ultrasound (HIFU) lesion boundaries using axial-shear strain elastograms (ASSE). The HIFU-induced lesion cases used in the present work were selected from data acquired in a previous study. The samples consisted of excised canine livers with thermal lesions produced by a magnetic resonance-compatible HIFU system (GE Medical System, Milwaukee, WI, USA) and were cast in a gelatin block for the elastographic experiment. Both single and multiple HIFU-lesion samples were investigated. For each of the single-lesion samples, the lesion boundaries were determined independently from the axial strain elastogram (ASE) and ASSE at various iso-intensity contour thresholds (from -2 dB to -6 dB), and the area of the enclosed lesion was computed. For samples with multiple lesions, the corresponding ASSE was analyzed for identifying any unique axial-shear strain zones of interest. We further performed finite element modeling (FEM) of simple two-inclusion cases to verify whether the in vitro ASSE obtained were reasonable. The results show that the estimation of the lesion area using ASSE is less sensitive to iso-intensity threshold selection, making this method more robust compared with the ASE-based method. For multiple lesion cases, it was shown that ASSE enables high-contrast visualization of a "thin" untreated region in between multiple fully-treated HIFU-lesions. This contrast visualization was also noticed in the FEM predictions. In summary, the results demonstrate that it is feasible to reliably visualize HIFU lesion boundaries using ASSE. PMID- 21276657 TI - Lord of the rings: a promising novel treatment for renal cell carcinoma? PMID- 21276658 TI - Ammonia vapor sensing properties of polyaniline-titanium(IV)phosphate cation exchange nanocomposite. AB - In this study, the electrically conducting polyaniline-titanium(IV)phosphate (PANI-TiP) cation exchange nanocomposite was synthesized by sol-gel method. The cation exchange nanocomposite based sensor for detection of ammonia vapors was developed at room temperature. It was revealed that the sensor showed good reversible response towards ammonia vapors ranging from 3 to 6%. It was found that the sensor with p-toluene sulphonic acid (p-TSA) doped exhibited higher sensing response than hydrochloric acid doped. This sensor has detection limit <=1% ammonia. The response of resistivity changes of the cation exchange nanocomposite on exposure to different concentrations of ammonia vapors shows its utility as a sensing material. These studies suggest that the cation exchange nanocomposite could be a good material for ammonia sensor at room temperature. PMID- 21276659 TI - MnOx-CeO2-Al2O3 mixed oxides for soot oxidation: activity and thermal stability. AB - MnO(x)-CeO(2)-Al(2)O(3) mixed oxides were prepared by impregnating manganese acetate and cerium nitrate on alumina powders using the sol-gel method. The thermal stabilities of MnO(x)-CeO(2) and Al(2)O(3)-modified mixed oxides were evaluated by treating at 800 degrees C in dry air flow for 20h. The introduction of Al(2)O(3) markedly increases the textural stability of the catalyst with a relatively high dispersion of MnO(x) and CeO(2), remaining a strong synergistic effect between these two oxides. The NO oxidation activity of the ternary oxides experiences a smaller loss after high-temperature calcination, and a low soot oxidation temperature is attained in the presence of NO. PMID- 21276660 TI - Evaluation of hand function after early excision and skin grafting of burns versus delayed skin grafting: a randomized clinical trial. AB - INTRODUCTION: Thermal injury of the hand is characterized by disfigurement and deformity with marked problems because the patient is no longer able to perform the daily living activities and function at school or work. Early excision and grafting (E&G) were introduced to decrease hospital stay, hospital cost, and septic complications and to eliminate burn toxins. In this study, E&G was compared with delayed skin grafting in deep hand burns. MATERIALS AND METHOD: 40 patients with deep second- and third- degree hand burns with average burn size less than 30% total body surface area (TBSA) were randomly divided into E&G group and delayed grafting group. All hands in both groups were subjected to pre and post operative program of physiotherapy. Measurement of total active motion (TAM) of each digit and grip strength was recorded pre and post operative. Hand function using Jebsen-Taylor hand function test (JTHFT) was recorded three months after operation in both groups. RESULTS: There were statistically significant differences in both groups regarding to TAM, hand grip strength and Jebsen-Taylor hand function test favoring the E&G group. CONCLUSION: The study concluded that early excision and skin grafting with physiotherapy gave better results than delayed grafting in terms of preservation of hand function and shortened hospital stay. PMID- 21276661 TI - Sociodemographic correlates of energy drink consumption with and without alcohol: results of a community survey. AB - OBJECTIVE: We examined the sociodemographic correlates of energy drink use and the differences between those who use them with and without alcohol in a representative community sample. METHODS: A random-digit-dial landline telephone survey of adults in the Milwaukee, Wisconsin area responded to questions about energy drink and alcohol plus energy drink use. RESULTS: Almost one-third of respondents consumed at least one energy drink in their lifetime, while slightly over 25% used energy drinks in the past year and 6% were past-year alcohol plus energy drink users. There were important racial/ethnic differences in consumption patterns. Compared to non-users, past-year energy drink users were more likely to be non-Black minorities; and past-year alcohol plus energy drink users when compared to energy drink users only were more likely to be White and younger. Alcohol plus energy drink users also were more likely to be hazardous drinkers. CONCLUSIONS: Our results which are among the first from a community sample suggest a bifurcated pattern of energy drink use highlighting important population consumption differences between users of energy drinks only and those who use alcohol and energy drinks together. PMID- 21276662 TI - One-time or repeat offenders? An examination of the patterns of alcohol-related consequences experienced by college students across the freshman year. AB - Recent studies have examined alcohol-related consequences in college students as an independent outcome variable, rather than as a result of heavy drinking. The present study examined the patterns of consequences experienced by first-year college students (n=169). Specifically, the number of distinct consequences and the frequency of repeated consequences were evaluated as well as the combination of the two. Results revealed that 80% of participants reported experiencing multiple consequences, with over 34% of students reporting 6 or more unique consequences over the course of their freshmen year. In addition, nearly 50% of the sample reported experiencing 3 or more consequences repeatedly. Further, 23% of the sample reported experiencing 5 or more repeated consequences and 6 or more multiple consequences. These individuals experienced 38% of the multiple consequences and 54% of the repeated consequences reported by the entire sample, suggesting individuals who endorsed experiencing multiple consequences repeatedly also experienced a disproportionate number of the total consequences reported by the sample. The findings suggest there are specific high-risk patterns of alcohol related consequences and demonstrate a need for further examination of additional variables that predict consequences. PMID- 21276663 TI - Predictors of alcohol-related outcomes in college athletes: the roles of trait urgency and drinking motives. AB - Research has shown that college students participating in athletics drink more than other students, yet relatively few studies have examined variables that are associated with alcohol-related outcomes among this population. The purpose of this study was to examine the relationships among trait urgency, general drinking motives and sport-related drinking motives, and both alcohol use and alcohol related problems. Data were collected from 198 college students participating in either intercollegiate or recreational athletics at three U.S. universities. Structural equation modeling was used to examine a series of theoretically derived explanatory models. All variables included in the model were directly associated with alcohol use and/or alcohol-related problems. The specific patterns of relationships differed across the motives and trait urgency variables. Sport-related coping motives, sport-related positive reinforcement motives, and general enhancement motives had direct relationships with alcohol use, while trait urgency, general coping motives, and sport-related positive reinforcement motives had direct relationships with alcohol-related problems. Several indirect effects on alcohol use and alcohol-related problems were also found. This study suggests that general drinking motives, sport-related drinking motives, and trait urgency all serve as important predictors of alcohol-related outcomes in college athletes. PMID- 21276664 TI - Consumer and treatment provider perspectives on reducing barriers to opioid substitution treatment and improving treatment attractiveness. AB - In New Zealand approximately 4600 people receive opioid substitution treatment (OST) for opioid dependence, primarily methadone maintenance treatment. This study explored ways in which OST could be improved, given the significant waiting times for treatment. Two parallel surveys were conducted: 1) peer interviews with 85 regular daily or almost daily opioid drug users (51.8% receiving OST, 18.8% not currently receiving OST, and 29.4% never received OST) and; 2) a census of all 18 specialist OST service providers. When asked how OST might be improved, the four categories most commonly cited by the opioid users were 'better treatment by staff', 'more flexibility', 'better takeaway arrangements', and 'decreased waiting time'. Both opioid users and specialist services rated 'restricted takeaways' and 'having to go on a waiting list' in the top three perceived barriers to OST. Almost all services reported significant resource issues and barriers to the transfer of stable clients from specialist services to continuing treatment in primary care. The findings from this study indicate how OST can be made more accessible and attractive and thus achieve better uptake and retention. PMID- 21276665 TI - Detection and molecular analysis of West Nile virus infections in birds of prey in the eastern part of Austria in 2008 and 2009. AB - The emergence of West Nile virus (WNV) was expected in Austria since the initial discovery of the infection in neighbouring Hungary in 2003/2004. In 2008 six cases of West Nile disease were diagnosed at the Institute for Veterinary Disease Control Modling, Austrian Agency for Health and Food Safety (AGES), involving five goshawks (Accipiter gentilis) and one gyrfalcon (Falco rusticolus), which were found dead in the eastern Austrian federal states of Lower Austria, Vienna and Styria, respectively. Pathomorphological and immunohistochemical findings suggested a WNV infection. Virus was isolated in embryonated specific pathogen free chicken eggs and propagated in mouse neuroblastoma cells (NA), in which a cytopathic effect occurred. The virus was identified and characterised by electron microscopic examination and molecular detection using RT-PCR, sequencing, and phylogenetic analysis. The Austrian WNV sequences exhibited nucleotide identities of 99.9% to the lineage 2 WNV sequences described in Hungary since 2004. In addition, 71 sera of 14 different bird species were screened for the presence of WNV antibodies using a commercial ELISA: 43.7% of the tested samples showed antibody titers. Selected positive sera were also subjected to WNV neutralisation tests, in which the ELISA results were verified in 66%. The results of this study confirm unambiguously the presence of a lineage 2 WNV infection in birds of prey in the eastern part of Austria. PMID- 21276666 TI - IncN plasmids carrying bla CTX-M-1 in Escherichia coli isolates on a dairy farm. AB - The aim of the study was to compare the prevalence of extended-spectrum beta lactamase (ESBL)-producing Escherichia coli bovine isolates on a conventional dairy cattle farm with high consumption of parenteral and intramammary cephalosporins (farm A) and on an organic dairy farm with no cephalosporin use (farm B). ESBL-producing E. coli were isolated from rectal swabs and milk filters by selective cultivation on MacConkey agar with cefotaxime (2mg/l). ESBL genes were identified by polymerase chain reaction (PCR) and sequencing, and the genetic diversity of the isolates was determined by XbaI pulsed field gel electrophoresis (PFGE). Conjugative transfer, incompatibility group, and restriction fragment length polymorphism (RFLP) profiles of the ESBL-carrying plasmids were studied. Higher prevalence (39%, n(rectal samples in cows)=309) of CTX-M-1-producing E. coli isolates was found on farm A compared to farm B (<1%, n(rectal samples in cows)=154; 0%, n(rectal samples in calves)=46). Using PFGE, the isolates from farm A were divided into nine pulsotypes. In all ESBL-positive isolates, the bla(CTX-M-1) gene was carried on 40 kb IncN conjugative plasmids of three related HincII restriction profiles. Horizontal gene transfer through transmission of IncN plasmids harboring bla(CTX-M-1) as well as clonal dissemination of a particular clone seems to be involved in dissemination of CTX M-1-producing E. coli isolates in cows on the farm using cephalosporins in treating bacterial infections. The study demonstrates a possible role of cephalosporin use in the widespread occurrence of CTX-M-1-producing E. coli on the conventional dairy cattle farm compared to the organic farm. PMID- 21276667 TI - From the lab to the bedside: the present of research, i.e. the future of neonatology. PMID- 21276668 TI - 2nd International Conference on Clinical Neonatology-Torino, Italy, March 10-12, 2011. Foreword. PMID- 21276669 TI - Fructose in fetal cord blood and its relationship with maternal and 48-hour newborn blood concentrations. AB - BACKGROUND: Studies have suggested that different non-glucose sugars and sugar alcohols play a role in placental and fetal metabolism. However, the role of fructose in the fetal and newborn metabolism is unclear and studies are scarce. AIM: Our objective was to investigate the presence of fructose in umbilical cord blood in full-term gestation and its relationship with maternal and 48-hour-old- newborn blood concentrations, to evaluate fructose production by the fetus and newborn infant. METHODS: Blood fructose and glucose concentrations were determined by HPLC in 26 paired samples of maternal blood, umbilical cord vein, and peripheral newborn blood at 48 h after birth. ANOVA, the Friedman Analysis of Variance on Ranks and the Pearson correlation with p<0.05 were used. RESULTS: Fructose concentration in umbilical cord blood was higher than maternal blood (p=0.024), suggesting endogenous fructose production by the fetal-placental unit via the sorbitol pathway. Fructose concentrations were higher in newborns at 48 h after birth than in the fetal umbilical cord blood (p=0.004), suggesting that fructose production is a continuous process from fetus to newborn. CONCLUSIONS: Fructose production by the sorbitol pathway, present in the fetus and newborn, is an alternative pathway in glucose metabolism probably used to maintain redox balance in the fetus. We suggest that endogenous fructose, similar to dietary ingested fructose, under physiological conditions produces the backbone for triacylglycerol and lipid synthesis in the fetus and newborn. Therefore the route for metabolizing fructose is already present in the early steps of human development. PMID- 21276670 TI - Hyperglycaemia in preterm neonates: what to know, what to do. AB - Neonatal hyperglycaemia is a frequent complication in VLBW infants during the first week of life. The more common causes include high glucose intake, stress situations such as sepsis, NEC, and surgical treatments, as well as the administration of vasoactive drugs and methylxanthines. The appropriate definition is unclear. Hyperglycaemia has been associated with increased mortality and major morbidities. There have been insufficient randomized clinical trials to help in clarifying which infants should be treated, and there are insufficient data on the pharmacokinetics of insulin in these vulnerable patients. PMID- 21276671 TI - Early weaning from CPAP to high flow nasal cannula in preterm infants is associated with prolonged oxygen requirement: a randomized controlled trial. AB - OBJECTIVE: To determine the better approach for weaning preterm infants from nasal continuous positive airway pressure (NCPAP) with or without transitioning to nasal cannula (NC). DESIGN/METHODS: This is a randomized, open label, controlled trial. Preterm infants born at >=28 weeks gestation who were clinically stable on NCPAP of 5 cm H(2)O with FiO(2)<0.30 for at least 24 h were randomly assigned to one of 2 groups. The no-NC group were kept on NCPAP until they were on FiO(2)=0.21 for 24 h, and then were weaned off NCPAP completely without any exposure to NC. If they met failing criteria, NCPAP was re instituted. The NC-group was weaned off NCPAP when FiO(2) was <=0.30 to NC (2 L/min) followed by gradual weaning from oxygen. Infants who failed NC were supported back with NCPAP for 24 h before making a second attempt of NC. RESULTS: Sixty neonates were enrolled; 30 in each group. The two groups were similar in birthweight, gestational age, sex, antenatal steroids, mode of delivery, use of surfactant and xanthines, and duration of mechanical ventilation. After randomization, the no-NC group had fewer days on oxygen [median (interquartile range): 5 (1-8) vs 14 (7.5-19.25) days, p<0.001] and shorter duration of respiratory support [10.5 (4-21) vs 18 (11.5-29) days, p=0.03]. There were no differences between groups regarding success of weaning from NCPAP. CONCLUSIONS: Weaning preterm infants from NCPAP to NC is associated with increased exposure to oxygen and longer duration of respiratory support. PMID- 21276672 TI - Are late preterm infants as susceptible to RSV infection as full term infants? AB - Preterm infants are at increased risk of being rehospitalised during the first few months of life with severe respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) that usually manifests as apnea and hypoxemia. This occurs more commonly in preterm infants < 33 weeks gestational age (GA), but recent studies demonstrate that late preterm infants (those born between 34 weeks and 0 days to 36 weeks and 6 days GA) are equally susceptible to RSV LRTI as those with lower GA. Factors associated with severe LRTI include immaturity of both the humoral and cell-mediated immune system and interrupted lung development prior to 36 weeks GA which results in lower functional residual capacity, reduced compliance, diminished forced expiratory air flow and impaired gas exchange. Morbidity and mortality are significantly increased in late preterms compared to their term counterparts. Prophylaxis with palivizumab against RSV infection seems to be crucial. Due to the large number of infants in this age group, additional risk factors have been identified in order to tailor palivizumab prophylaxis effectively to those at highest risk for severe RSV LRTI. PMID- 21276673 TI - Nutrition in centenarians. AB - The oldest old are among the fastest growing segment of the population and it is important to understand not only the influence of modifiable lifestyle factors such as diet and nutrition on the achievement of exceptional longevity but also the role, if any, of these factors on maintaining optimal cognitive, mental and physical health into advanced age. This review summarizes studies of dietary intake and patterns of long-lived peoples and presents current knowledge of nutritional status of centenarians as determined with nutritionally relevant biomarkers, providing information on comparative levels of the various biomarkers between centenarians and older adult controls and on the prevalence and predictors of nutritional deficiencies in centenarians. The studies indicate that BMI and nutritional status as indicated by circulating levels of antioxidant vitamins, vitamin B12, folate, homocysteine and 25(OH) vitamin D of centenarians are quite heterogeneous and influenced by region of residency and many of the demographic, dietary and lifestyle factors that influence nutritional status in other older adults. While many of the studies have been small, convenience samples of relatively healthy community-dwelling centenarians, a few have population-based or included participants of varying cognitive functioning. These and future studies examining associations between nutritional status and cognitive, mental and physical function should be instrumental in determining the role of nutrition in promoting longevity and improving the quality of life in these exceptional survivors. PMID- 21276674 TI - [Anticoagulant (AVK) and antibiotic drug interactions in community practice]. AB - AIM: Anticoagulants (AVK) are frequently responsible for iatrogenic accidents leading to hospitalisation. Antibiotics (ATB) are likely to interact with AVK. The aim of this study was to assess if Loire region practitioners complied with the French agency for the safety of health products (AFSSAPS) recommendations for AVK/ATB association. METHOD: Two strategies were implemented: a retrospective study of the 2007 Loire region general health insurance data on a population exposed to a single AVK split in two groups, exposed or not to antibiotics; a focus-group of practitioners from the Maine et Loire subdivision. RESULTS: Blood tests were not always performed. The proportion of blood tests per month was significantly more frequent in the AVK/ATB group than in the group "not exposed" to antibiotics. GPs did not implement this recommendation, which doesn't correspond to their behaviour, as analysed by a focus-group, and to the low incidence of hospitalisations due to AVK/ATB interaction. CONCLUSION: Loire region practitioners do not follow AFSSAPS recommendations. AVK/ATB interaction must be a GP's constant concern whether responsible or not for initiating AVK. PMID- 21276675 TI - [Pathological humeral fracture revealing bone hydatic cyst]. PMID- 21276676 TI - Management of true aneurysms of hemodialysis access fistulas. AB - OBJECTIVES: This study was designed to determine the clinical presentation, characteristics, and management of true aneurysms in dialysis access fistulas. METHODS: Patients presenting with symptoms or functional arteriovenous fistula (AVF) problems and aneurysmal enlargement of the outflow vein were evaluated with duplex ultrasound scans. Dilatation to more than three times the native vessel diameter was considered aneurysmal. Pseudoaneurysms were excluded from the study. Patients' demographics, aneurysm characteristics (diameter, location, thrombus, association with stenosis, and outflow obstruction), symptoms, type of treatment, and follow-up were recorded. RESULTS: Twenty-three patients with a mean age of 55 years were found to have 29 upper extremity aneurysms of the outflow vein on duplex ultrasound scan. Nine patients (39%) had radiocephalic, 11 patients (48%) had brachiocephalic, 2 patients (9%) had brachiobasilic, and 1 patient (4%) had radiobasilic arteriovenous fistula. The average aneurysm size was 3.3 cm and the mean time from fistula placement to treatment was 47.1 months. Four patients (17%) were asymptomatic and were repaired due to technical and mechanical problems with AVFs, including stenosis and lack of normal vein for cannulation, compromising continued use. Nineteen patients (83%) presented with symptoms, including pain (48%), skin changes (30%), venous hypertension (22%), steal syndrome (22%), and high output failure (9%). Four patients (17%) were found to have outflow vein stenosis, 2 patients (9%) had central venous stenosis, and 2 patients (9%) had central venous occlusion. In 13 patients (56%) who had a functioning kidney transplant, the fistula was ligated with or without aneurysm excision. Three of the 13 patients developed superficial phlebitis with 1 patient requiring surgical evacuation of a clot; the other 2 patients were managed conservatively. Two of the 13 patients required creation of new access due to renal transplant failure. In the remaining 10 patients, the aneurysm was treated and the fistula salvaged due to a persistent need for hemodialysis. The median follow-up of these patients was 19 months ranging from 8 to 25 months. Seven patients (30%) underwent excision and repair with the great saphenous vein and 3 patients (13%) had excision and repair with prosthetic material, 2 of which underwent central venous angioplasty and stenting. Two patients developed thrombosis of their repair requiring new access in the contralateral arm. Three patients needed secondary percutaneous interventions for anastomotic stenosis. CONCLUSION: Although true aneurysms in patients with dialysis access are uncommon, significant complications may occur as a consequence of their presence. These complications can be treated and the fistulas can usually be salvaged. PMID- 21276677 TI - Placement of wrist ulnar-basilic autogenous arteriovenous access for hemodialysis in adults and children using microsurgery. AB - OBJECTIVES: The distal basilic forearm vein is frequently preserved and might be used more frequently for placement of an ulnar-basilic autogenous arteriovenous access (UB-AAVA) in the wrist despite the small size of the two vessels. The scarcity of publications led us to initiate a prospective study regarding the placement and outcomes of UB-AAVAs. METHODS: Seventy patients (63 adults, seven children) with no usable cephalic vein in either forearm were selected consecutively over 4 years for placement of a UB-AAVA. The prerequisite was a clinically visible or palpable forearm basilic vein after placing a tourniquet. Regional anesthesia, prophylactic hemostasis, and a surgical microscope were used systematically. Secondary superficialization was performed in two patients. Most non-matured accesses were abandoned in favor of the placement of a more proximal autogenous access. Mean follow-up was 20 months (SD =15). RESULTS: Immediate patency was obtained in 94% of adults and 100% of children. Success (in-use access) was achieved in 60% of patients (38/63 adults and 6/7 children) after a mean postoperative interval of 80 days (SD = 64; range, 31-277). Failures included four immediate thromboses, one postoperative death, and 21 never-matured accesses. No steal syndrome was observed. Initial failures included, primary patency rates in adults at 1 and 2 years were 42% +/- 6% and 30% +/- 7%, respectively; secondary patency rates at 1 year and 2 years were 60% +/- 6% and 53% +/- 7%, respectively. CONCLUSIONS: Although patency rates are not as good as those achieved with radial cephalic-AAVA, the UB-AAVA is an alternative autogenous forearm access before the placement of any other access involving the basilic vein. The use of the surgical microscope is mandatory, and more than usual time is required to achieve maturation. PMID- 21276678 TI - Spontaneous dissection with rupture of the superior mesenteric artery from segmental arterial mediolysis. AB - Spontaneous dissection of the superior mesenteric artery (SMA) is rare. We report a case of rupture of the SMA after spontaneous dissection in a 51-year-old male who presented with acute onset of abdominal pain and hypotension. The patient was initially treated with intravenous fluid resuscitation and endovascular intervention followed by open surgery. No identifiable cause for dissection was found. The patient was diagnosed as having segmental arterial mediolysis (SAM). The patients' presentation, treatment, outcome, and all relevant imaging, pathologic, and laboratory studies were reviewed. The relevant features of the case and SAM are presented herein. In addition, a review of all available published literature on SAM to date is presented. PMID- 21276679 TI - Long-term sac behavior after endovascular abdominal aortic aneurysm repair with the Excluder low-permeability endoprosthesis. AB - PURPOSE: Sac regression is a surrogate marker for clinical success in endovascular aneurysm repair (EVAR) and has been shown to be device-specific. The low porosity Excluder endograft (Excluder low-permeability endoprosthesis [ELPE]; W. L. Gore & Associates Inc, Flagstaff, Ariz) introduced in 2004 was reported in early follow-up to be associated with sac regression rates similar to other endografts, unlike the original Excluder which suffered from sac growth secondary to fluid accumulation in the sac. The purpose of this study was to determine whether this behavior is durable in mid-term to long-term follow-up. METHODS: Between July 2004 and December 2007, 301 patients underwent EVAR of an abdominal aortic aneurysm (AAA) with the ELPE at two institutions. Baseline sac size was measured by computed tomography (CT) scan at 1 month after repair. Follow-up beyond 1 year was either with a CT or ultrasound scan. Changes in sac size >=5 mm from baseline were determined to be significant. Endoleak history was assessed with respect to sac behavior using chi(2) and logistic regression analysis. RESULTS: Two hundred sixteen patients (mean age 73.6 years and 76% men) had at least 1-year follow-up imaging available for analysis. Mean follow-up was 2.6 years (range, 1-5 years). The average minor-axis diameter was 52 mm at baseline. The proportion of patients with sac regression was similar during the study period: 58%, 66%, 60%, 59%, and 63% at 1 to 5 years, respectively. The proportion of patients with sac growth increased over time to 14.8% at 4-year follow-up. The probability of freedom from sac growth at 4 years was 82.4%. Eighty patients (37.7%) had an endoleak detected at some time during follow-up with 29.6% (16 of 54) residual endoleak rate at 4 years; 13 of the residual 16 endoleaks were type II. All patients with sac growth had endoleaks at some time during the study compared with only 18% of patients with sac regression (P < .0001). CONCLUSION: A sustained sac regression after AAA exclusion with ELPE is noted up to 5-year follow-up. Sac enlargement was observed only in the setting of a current or previous endoleak, with no cases of suspected hygroma formation noted. PMID- 21276680 TI - The effect of eversion and conventional-patch technique in carotid surgery on postoperative hypertension. AB - OBJECTIVE: Postcarotid endarterectomy hypertension (HTN) is associated with neurological and cardiac complications. The purpose of this study was to assess the influence of eversion carotid endarterectomy (E-CEA) and conventional carotid endarterectomy (C-CEA) on postoperative blood pressure in the first 4 days after surgery. METHODS: Two hundred seventy-six consecutive CEAs that were performed between February 2008 and September 2009 were reviewed retrospectively with a computerized registry. After exclusion of patients with severe stroke (modified Rankin Scale of 3-5), prior contralateral and ipsilateral carotid surgery and more than 70% stenosis of the contralateral carotid artery, 201 cases remained (E CEA group: n = 100 vs C-CEA group: n = 101) for analysis. Results in terms of systolic blood pressure, use of intravenous and oral vasodilators, alterations of the existing antihypertensive medications, and perioperative complications (neck hematoma, myocardial infarction, stroke, and death) were compared. RESULTS: Groups were similar with regard to age, sex, and cardiovascular risk factors except for a higher incidence of nicotine use (59% vs 43%; P = .02) in the C-CEA group. Patients in the C-CEA group had a significantly higher percentage of symptomatic carotid artery stenosis (54% vs 23%, respectively; P < .0001). Despite a lower preoperative (baseline) mean systolic blood pressure (130 mm Hg vs 135 mm Hg; P = .02) patients in the E-CEA group had a significantly higher mean systolic blood pressure in the postoperative course up to the day 4 after surgery (134 mm Hg vs 126 mm Hg; P < .0001) and required more frequent intravenous (28% vs 9.9%; P = .001) and oral vasodilators (54% vs 27.7%; P = .0002) compared to those in the C-CEA group. Two-thirds (14 of 21 = 66%) of patients in the E-CEA group with preoperative high blood pressure (systolic blood pressure >=140 mm Hg and diastolic pressure >=90 mm Hg) required vasodilators and only one-third (11 of 33 = 33%) in the C-CEA group (P = .03). Atropine use due to bradycardia was necessary after 8 cases (8%) in the C-CEA group and only after 1 case (1%) in the E-CEA group (P = .03). Furthermore, the dosage of existing antihypertensive medications was increased and/or additional medications were prescribed twofold more in the E-CEA group (33% vs 17%; P = .009). No statistically significant difference was noted in the perioperative complication rate. CONCLUSION: It is concluded that E-CEA is associated with significantly higher postoperative blood pressure that persists for at least 4 days after surgery. Patients with inadequate preoperative high blood pressure control are particularly at risk after E-CEA. PMID- 21276682 TI - Differential expression of elastin assembly genes in patients with Stanford Type A aortic dissection using microarray analysis. AB - OBJECTIVE: Pathologic studies have demonstrated that aortic dissection is initiated by an intimal tear, followed by the rapid growth of an intramural hematoma that dissects the media and is characterized by elastin degradation. Genetic extracellular matrix abnormalities and proteinases may be the predisposing factors in aortic dissection, but little is known about the role of elastic fiber assembly. Fibulin-1 is an extracellular protein that is expressed in the vascular basement membrane. It regulates elastic fiber assembly and hence provides integrity in aortic structure. This study investigates the expression profiles of genes responsible for the elastolysis in the dissected human aorta, especially those coding fibulin-1, matrix metalloproteinase-9 (MMP-9), and elastin. METHODS: Intraoperative aortic samples were obtained from Chinese patients with Stanford Type A aortic dissection. Both the ascending dissected aortas (primary tear) and the adjacent intact aortas were collected for comparison. Control aortic tissues were obtained from healthy organ donors. The gene profile study was determined by the Affymetrix HG-U133A GeneChip (Affymetrix, Santa Clara, Calif) and analyzed by GeneSpring GX11.0 (Agilent Technologies Inc, Palo Alto, Calif). Only the genes displaying a net signal intensity two-fold higher than the mean background were used for analysis. To evaluate elastin expression, aortic sections were stained with Movat pentachrome stain. Fibulin-1, MMP-9, and elastin mRNA and protein expression were further confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) and immunoblotting, respectively. RESULTS: Eight male Chinese aortic dissection patients (mean age, 45.8 years) and eight gender- and age-matched organ donors were recruited for the study. On the Affymetrix platform, 2,250 of 22,283 genes (10.1%) were detectable. The dissected and adjacent macroscopically intact aorta displayed similar gene expression patterns. In contrast, 11.2% (252) of the detectable genes were differentially expressed in the dissected and control aortas. Of these, 102 genes were upregulated, and 150 genes were downregulated. Based on the gene ontology, genes that code for extracellular matrix protein components and regulating elastic fiber assembly, like fibulin-1 and elastin, were downregulated, while enzymes like MMP-9 and MMP-11 that degrade matrix proteins were upregulated in dissected aortas. RT-PCR and Western blot results further validated the results. CONCLUSIONS: Our gender- and age-matched study demonstrated that the alternated genes in the elastin assembly of dissected aortas may predispose structural failure in the aorta leading to dissection. However, no significant gene alterations in the adjacent intact and dissected aortas of the same patient can be found. Therefore, the genetic changes found in the dissected aortas most likely developed before the dissection starts. The inhibition of the aberrant expression of the fibulin-1 gene and that of the related matrix proteinase may open a new avenue for preventing aortic dissection. PMID- 21276681 TI - A randomized controlled trial of endovascular aneurysm repair versus open surgery for abdominal aortic aneurysms in low- to moderate-risk patients. AB - BACKGROUND: Several studies, including three randomized controlled trials (RCTs), have shown that endovascular repair (EVAR) of abdominal aortic aneurysms (AAA) offered better early results than open surgical repair (OSR) but a similar medium term to long-term mortality and a higher incidence of reinterventions. Thus, the role of EVAR, most notably in low-risk patients, remains debated. METHODS: The ACE (Anevrysme de l'aorte abdominale: Chirurgie versus Endoprothese) trial compared mortality and major adverse events after EVAR and OSR in patients with AAA anatomically suitable for EVAR and at low-risk or intermediate-risk for open surgery. A total of 316 patients with >5 cm aneurysms were randomized in institutions with proven expertise for both treatments: 299 patients were available for analysis, and 149 were assigned to OSR and 150 to EVAR. Patients were monitored for 5 years after treatment. Statistical analysis was by intention to treat. RESULTS: With a median follow-up of 3 years (range, 0-4.8 years), there was no difference in the cumulative survival free of death or major events rates between OSR and EVAR: 95.9% +/- 1.6% vs 93.2% +/- 2.1% at 1 year and 85.1% +/- 4.5% vs 82.4% +/- 3.7% at 3 years, respectively (P = .09). In-hospital mortality (0.6% vs 1.3%; P = 1.0), survival, and the percentage of minor complications were not statistically different. In the EVAR group, however, the crude percentage of reintervention was higher (2.4% vs 16%, P < .0001), with a trend toward a higher aneurysm-related mortality (0.7% vs 4%; P = .12). CONCLUSIONS: In patients with low to intermediate risk factors, open repair of AAA is as safe as EVAR and remains a more durable option. PMID- 21276683 TI - Surgical versus endovascular repair by iliac branch device of aneurysms involving the iliac bifurcation. AB - OBJECTIVE: To evaluate early and late results of open (OR) and endovascular aneurysm repair by iliac side branch device (EVRISB) for aneurysms involving the iliac bifurcation (AIB). METHODS: Between January 2004 and March 2010, 118 patients were diagnosed with AIBs and underwent OR or EVRISB at two European vascular centers. Particularly, 64 (54.2%) patients were treated by EVRISB and 54 (45.8%) by OR. In one center, 24 consecutive patients were treated by surgery because this was the standard therapeutic approach until January 2005. For the rest of the study period until March 2010, 64 consecutive patients with AIB suitable for EVRISB underwent placement of branched devices. In the other center, 30 consecutive patients with AIBs were treated by OR because advanced endovascular imaging was not available during the study period. RESULTS: No significant differences in demographics, anatomical characteristics, or comorbidities of the patients were recorded between the two groups. Early (30 day) mortality was 0% for EVRISB versus 5.5% for the OR group (P < .001). Major morbidity occurred in 4.6% versus 9.3% of the patient subgroups, respectively (P < .001). Buttock claudication and colonic ischemia were recorded in 5.9% and 2% of OR patients compared with 3.1% and 0% of EVRISB cases (P > .05). Primary patency rates were 98.4% for EVRISB and 100% for OR patients. Primary and secondary endoleak rates of the EVRISB group were 12.5% and 6.3%, respectively. CONCLUSIONS: Endovascular repair by iliac branch device of aneurysms involving the iliac bifurcation can be accomplished with very low morbidity and mortality rates. Especially for young active patients or in cases of contralateral occlusion, the preservation of hypogastric artery seems to be a strong argument for use of EVRISB as a preferable therapy option. PMID- 21276684 TI - The chimney procedure is an emergently available endovascular solution for visceral aortic aneurysm rupture. AB - A 79-year-old woman presented with a ruptured saccular thoracoabdominal aortic aneurysm involving the celiac and mesenteric artery. The patient was unfit for open surgical repair. A "chimney" procedure was performed, which involved placement of stents in the aortic side branches alongside the endograft. The patient underwent another chimney procedure 2 weeks later for a type I endoleak. Computed tomography angiography (CTA) at 1 and 6 months showed a good result with no endoleaks or graft migration. The chimney procedure provides an alternative for emergency patients unfit for open repair and has the advantage that stents can be used that are already available in most institutions. PMID- 21276685 TI - Endovascular management of ascending aortic pathology. AB - BACKGROUND: Endovascular treatment of the ascending aorta is particularly challenging because of the anatomic features of this aortic segment. Only patients without connective tissue disorders, clinically relevant aortic regurgitation or stenosis, or concomitant coronary artery disease can be considered for an endovascular procedure. We report our results in a series of patients with aneurysms or intramural hematoma, penetrating ulcers, or floating thrombus who were scheduled for stent grafting. METHODS: Only patients with ascending aortic pathology who were unfit for open surgery were treated with an endograft. When preoperative computed tomography imaging showed severe calcification of the aortic arch or thrombus lining, temporary clamping of the carotid arteries before wire and catheter introduction was performed. An extracorporeal bypass from the right groin to both carotid arteries with a roller pump was established and maintained during the procedure. The endograft was placed across the aortic valve into the left ventricle and deployed in a retrograde fashion. At the end of the procedure, ventriculography and, if necessary, coronary angiography was performed to rule out any damage to the left ventricle or the valve apparatus. RESULT: Eleven patients were scheduled for stent graft exclusion of ascending aortic pathology. In five cases because of discrepancies in length measurements and sizing, the thoracic endograft was cut to length intraoperatively after partial deployment on the operating table and reloaded to avoid covering of the innominate artery. The mean length of the ascending aorta covered was longer in aneurysm patients than in those with dissection. An 81-year-old patient presented with a type Ia leak. The distal landing zone in one patient was enlarged by debranching. One patient died after wire perforation of the left ventricle, and one patient sustained a cerebral stroke. Combined morbidity and mortality was 18%, and the technical success rate was 91%. CONCLUSIONS: Stent grafting of the ascending aorta is technically feasible but should be reserved for selected high-risk patients only, preferably in centers where vascular specialists cooperate closely with interventional cardiologists. Cardiac surgery with cardiopulmonary bypass is still the gold standard to treat ascending aortic aneurysms. Stent graft exclusion of more advanced and complex ascending aortic pathology should be performed only in centers with the necessary experience in transvalvular cardiac procedures. PMID- 21276686 TI - Intimal sarcoma of the superficial femoral artery with osteosarcomatous differentiation. AB - Sarcomas of the large vessels usually present centrally in the aorta, pulmonary artery, and inferior vena cava. Peripheral arterial sarcomas are exceptionally rare. They have been reported in the iliac and common or profunda femoral arteries, and are frequently undifferentiated. In this study, we describe a differentiated intimal sarcoma of the superficial femoral artery with abundant osteosarcoma within the specimen. Before knowing the diagnosis, treatment was for a presumed pseudoaneurysm using excision and bypass. Postoperatively, the patient received palliative radiation therapy. The tumor's location and histopathology are unique. A differentiated intimal sarcoma has never been reported in the superficial femoral artery, and it represents the second peripheral arterial intimal sarcoma reported with osteosarcomatous differentiation. PMID- 21276687 TI - Positional compression of the axillary artery causing upper extremity thrombosis and embolism in the elite overhead throwing athlete. AB - OBJECTIVES: To describe the spectrum of axillary artery pathology seen in high performance overhead athletes and the outcomes of current treatment. METHODS: A retrospective review of patients that had undergone management of axillary artery lesions in a specialized center for thoracic outlet syndrome (TOS). Treatment outcomes were assessed with respect to arterial pathology and operative management. RESULTS: Nine male athletes were referred for arterial insufficiency in the dominant arm between January 2000 and August 2010, representing 1.6% of 572 patients treated for TOS (19% of 47 patients treated for arterial TOS). Seven were elite baseball pitchers (six professional, one collegiate), and two were professional baseball coaches with practice pitching responsibilities, with a mean age of 30.9 +/- 2.9 years. Presenting symptoms included arm fatigue (five), finger numbness (four), cold hypersensitivity/Raynaud's (two), rest pain (one), and cutaneous fingertip embolism (one). Three patients underwent transcatheter thrombolysis prior to referral, including one with angioplasty and stenting. At angiography and surgical exploration 2.5 +/- 0.8 weeks after symptom presentation (range, 1-8 weeks), six patients had occlusion of the distal axillary artery opposite the humeral head either at rest (three) or with arm elevation (three), one had axillary artery dissection with positional occlusion, and two had thrombosis of circumflex humeral artery aneurysms. Five patients had embolic arterial occlusions distal to the elbow. Treatment included segmental axillary artery repair with saphenous vein (n = 7; five interposition bypass grafts and two patch angioplasties), ligation/excision of circumflex humeral artery aneurysms (n = 2), and distal artery thrombectomy/thrombolysis (n = 2). Mean postoperative hospital stay was 3.8 +/- 0.5 days, and the time until resumption of unrestricted overhead throwing was 10.8 +/- 2.7 weeks. At a median follow-up of 15 months (range, 3-123 months), primary-assisted patency was 89%, and secondary patency was 100%. All nine patients had continued careers in professional baseball, although one retired during long-term follow-up. CONCLUSIONS: Repetitive positional compression of the axillary artery can cause a spectrum of pathology in the overhead athlete, including focal intimal hyperplasia, aneurysm formation, segmental dissection, and branch vessel aneurysms. Prompt recognition of these rare lesions is crucial given their propensity toward thrombosis and distal embolism, with positional arteriography necessary for diagnosis. Full functional recovery can usually be anticipated within several months of surgical treatment, consisting of mobilization and segmental reconstruction of the diseased axillary artery or ligation/excision of branch aneurysms, as well as concomitant management of distal thromboembolism. PMID- 21276688 TI - Transient cortical blindness after thoracic endovascular aneurysm repair. AB - We report a patient who presented with transient cortical blindness 12 hours after completion of a thoracic endovascular aneurysm repair. Computed tomography of the brain demonstrated no acute findings. The patient's symptoms resolved spontaneously after 72 hours. To our knowledge, this is the first report of transient cortical blindness after endovascular aortic aneurysm repair. This is an uncommon diagnosis that is important to recognize in a modern vascular surgery practice. PMID- 21276689 TI - Q fever (Coxiella burnetii) causing an infected thoracoabdominal aortic aneurysm. AB - We report a patient, which we believe is the first, with a thoracoabdominal aortic aneurysm, Crawford type IV, caused by Q fever (Coxiella burnetii). Treatment consisted of antibiotic therapy started preoperatively and continued postoperatively and an open repair, including resection of the infected aneurysm, replacement with a rifampin-soaked polyester graft, and an omental wrap covering the grafts. After 13 months of follow-up, the patient had no signs of infection, and results of laboratory findings were normal. PMID- 21276690 TI - Repairing immediate proximal endoleaks during abdominal aortic aneurysm repair. AB - INTRODUCTION: Successful endovascular exclusion of abdominal aortic aneurysms is largely dependent on adequate apposition of the stent graft to the aortic wall. Proximal endoleaks at the time of stent graft placement are uncommon but are more prevalent in patients with challenging neck anatomy. If these initial leaks do not respond to simple balloon angioplasty, Palmaz stents (Cordis Endovascular, Warren, NJ) and covered stent graft cuffs both have been used to seal the endoleak. Long-term data regarding the efficacy of one method over the other, however, is lacking. METHODS: We retrospectively reviewed a database of all infrarenal aortic aneurysm repairs with an intraoperatively diagnosed type Ia endoleak requiring Palmaz stent or covered stent graft cuff placement. Fenestrated and branch grafts were excluded. All records and appropriate imaging studies were reviewed. The primary end points were technical success of aneurysm exclusion, recurrence of a type Ia leak, and need for reintervention. RESULTS: At the time of the initial aneurysm repair, 72 patients required an adjunctive covered extension or Palmaz stent; of these, 24 (33%) underwent sole placement of a Palmaz stent, 45 (62.5%) underwent placement of a covered stent graft cuff, and 3 required both a cuff and a Palmaz stent. Aneurysmal exclusion was successful in all patients before leaving the operating room. No recurrent type Ia endoleak developed in patients who underwent Palmaz stent placement. Of the 45 patients who underwent cuff placement, proximal leaks developed in 3 that required reintervention: 1 was managed with a Palmaz stent and the other 2 required open surgical revision. CONCLUSIONS: Palmaz stent placement and stent graft cuff placement are frequently used to seal immediate proximal endoleaks that do not resolve with balloon angioplasty. Both methods appear to be durable long-term options to facilitate endovascular exclusion of abdominal aortic aneurysms. PMID- 21276691 TI - Treatment strategies of arterial steal after arteriovenous access. AB - INTRODUCTION: Ischemic steal syndrome (ISS) associated with arteriovenous (AV) access is rare but can result in severe complications. Multiple techniques have been described to treat ISS with varying degrees of success. This study compares the management and success associated with these techniques. METHODS: Patients with ISS between June 2003 and June of 2008 at the University of Pittsburgh Medical Center were retrospectively reviewed. Demographics, type of AV access, management technique, and success of intervention were recorded. Success was defined as resolution of ISS symptoms while preserving access function. One hundred consecutive AV access procedures were reviewed for comparison. Data were analyzed using chi(2) test, Fisher's exact test, and Student's t test. The study was approved by our institutional review board. RESULTS: A total of 114 patients with ISS had a mean age of 65 years (range, 20-90 years), were predominantly female (66%), diabetic (61%), and with a brachial origin fistula (69%). Risk factors for ISS included coronary artery disease (CAD; P < .001), hypertension (P < .001), and tobacco use (P = .048). Women were noted to have a brachial origin access more frequently than men (odds ratio [OR], 3.1; P = .009). Forty-four patients with mild steal were observed. Seventy patients underwent 87 procedures. Procedures performed included ligation (n = 27), banding (n = 22), distal revascularization and interval ligation (DRIL; n = 21), improvement of proximal inflow (n = 9), revision using distal inflow (RUDI; n = 4), and proximalization of arterial inflow (PAI; n = 3). Early procedures (<30 days from the index fistula) were mostly ligation (50%) or banding (38%), while DRIL was the most frequent choice for late interventions (41%). Banding had a high failure rate (62%) and was the most common reason for reintervention (8 of 11, 73%) and DRIL had a better success rate than banding (P <= .05). In our current practice, 18% of patients had an AV fistula with the proximal radial artery (PRA) as the inflow source, while this type of fistula accounted for only 2% of all ISS patients. Ligation resolved symptoms in all patients, but the AV access was lost. CONCLUSIONS: Risk factors for development of ISS include CAD, diabetes, female gender, hypertension, and tobacco use. Among various options to treat ISS, banding has a low success rate and high likelihood for reintervention, while DRIL is particularly effective although not uniformly. Less invasive treatment options such as RUDI and PAI may be quite effective in treating ISS. Use of the PRA as the inflow source may decrease the incidence of ISS. PMID- 21276692 TI - Low molecular weight (LMW) heparin inhibits injury-induced femoral artery remodeling in mouse via upregulating CD44 expression. AB - OBJECTIVE: The mechanism of postangioplasty restenosis remains poorly understood. Low molecular weight (LMW) heparin has been shown to inhibit the proliferation of vascular smooth muscle cells (VSMCs), which is the principal characteristic of restenosis. Studies have shown that LMW heparin could bind to CD44. We hypothesized that LMW heparin might modulate CD44 expression thereby decreasing vascular remodeling. METHODS: Vascular remodeling was induced in CD44(+/+) and CD44(-/-) mice and treated with LMW heparin. The arteries were harvested for histologic assessment and determination of CD44 expression. Bone marrow transplantation was introduced to further explore the role and functional sites of CD44. Effects of LMW heparin on growth capacity, CD44 expression were further studied using the cultured mouse VSMCs. RESULTS: Transluminal injury induced remarkable remodeling in mouse femoral artery (sham wall thickness percentage [WT%]: 3.4 +/- 1.2% vs injury WT%: 31.8 +/- 4.7%; P < .001). LMW heparin reduced the remodeling significantly (WT%: 17.8 +/- 3.5%, P < .005). CD44(-/-) mice demonstrated considerably thicker arterial wall remodeling (WT%: 46.2 +/- 7.6%, P = .0035), and CD44-chimeric mice exhibited equal contributions of the local and circulating CD44 signal to the neointima formation. LMW heparin markedly upregulated CD44 expression in the injured femoral arteries. In vitro, LMW heparin decreased mouse VSMC growth capacity and upregulated its CD44 expression simultaneously in a dose-dependent and time-dependent manner, which could be partially blocked by CD44 inhibitor. CONCLUSIONS: LMW heparin inhibits injury induced femoral artery remodeling, at least partially, by upregulating CD44 expression. PMID- 21276693 TI - Assessment of mouse hind limb endothelial function by measuring femoral artery blood flow responses. AB - OBJECTIVE: Substantial progress has been made in cell therapy strategies and in gene- and cytokine-introduced angiogenesis using a variety of mouse models, such as hind limb ischemia models. Endothelial function is an important target in evaluating the effects and outcomes of these potential therapies. Although animal models have been established for estimating endothelium-dependent function by measuring the blood flow responses in carotid and renal arteries and the abdominal aorta, a model specific for an indicated hind limb by measuring femoral artery blood flow (FABF) has not yet been established. METHODS: A 2-day protocol was designed, including exploration of the segmental femoral artery on the first day, and evaluation of endothelium-dependent vasodilatation function the next day. By placing a transonic flow probe around the left femoral artery, the FABF in response to endothelium-dependent and endothelium-independent vasodilatory stimulations was reproducibly measured. Hemodynamic measurements, including the left FABF and mean arterial pressure, were recorded. RESULTS: In normal controls, the baseline left FABF averaged 0.12 +/- 0.01 mL/min. Acetylcholine increased the FABF up to 0.41 +/- 0.02 mL/min. Rose bengal-associated photochemical injury was titrated to cause endothelial dysfunction but without disturbing the integrity of the endothelial layer. The response to acetylcholine significantly decreased 10 minutes after photochemical injury and was further impaired after 1 and 24 hours. However, the response to nitroprusside was preserved. A femoral and iliac artery wire-injury model was also introduced to cause endothelial and smooth muscle cell injury. One day after the wire injury, the responses to acetylcholine and nitroprusside injections were both remarkably attenuated. CONCLUSIONS: This model can be widely used to analyze the in vivo endothelium-dependent vasodilatation function before and after a variety of therapeutic interventions on a mouse hind limb. PMID- 21276694 TI - Endovascular treatment of axillosubclavian arterial transection in patients with blunt traumatic injury. AB - Axillosubclavian arterial transection due to blunt traumatic injury poses a treatment challenge in the multiply injured patient. Endovascular repair can be technically successful if the injury is focal. We describe an endovascular technique utilizing combined brachial and femoral access to create a through-and through brachial-femoral wire and repair the arterial injury with a covered stent. PMID- 21276695 TI - Safety in the preparation of cytotoxic drugs: How to integrate gravimetric control in the quality assurance policy? AB - PURPOSE: We present the way to integrate gravimetric control (GC) in a centralized preparation of cytotoxic drugs unit. Two different modalities are described. In the first strategy, the balance is located inside the isolator, whereas in the second, it is located outside in order to remove many technical and ergonomic constraints. These two modalities are compared in terms of benefits and limits. METHODS: GC consists in comparing the observed weight variation with the expected weight variation using a precision balance. According to the B-in strategy, this variation is directly attributable to the weight of the cytotoxic solution injected, whereas with the B-out strategy, the weight of various additional components must be taken into account. RESULTS: Five hundred and seventy-seven preparations have been weighed. For "B-in" strategy, the 95% confidence interval is [1.02-1.14%] and every preparation is below the threshold of 5%. For "B-out" strategy, the 95% confidence interval is [2.34-2.63%] and 94% of preparations are below the threshold of 5%. B-in strategy is distinctly more precise than B-out strategy and can be applied to all preparations. However, B out strategy is a feasible option in practice and enables the detection of an important mistake. All in all, results obtained from B-out strategy can be considered as a quality indicator in the production line. CONCLUSION: Results of GC are helpful in the final step of release, which the pharmacist is responsible for. Many contributions in the quality assurance policy could justify using of GC in every unit. PMID- 21276696 TI - [Rare primary localization of hydatidosis]. PMID- 21276697 TI - Exploring generalizability in a study of costs for community-based palliative care. AB - CONTEXT: Palliative care researchers face challenges recruiting and retaining study subjects. OBJECTIVES: This article investigates selection, study site, and participation biases to assess generalizability of a cost analysis of palliative care program (PCP) clients receiving care at home. METHODS: Study subjects' sociodemographic, geographic, survival, disease, and treatment characteristics were compared for the same year and region with those of three populations. Comparison I was with nonstudy subjects enrolled in the PCP to assess selection bias. Comparison II was with adults who died of cancer to assess study site bias. Comparison III was with study-eligible persons who declined to participate in order to assess participation bias. RESULTS: Comparison I: When compared with the other 1010 PCP clients, the 50 study subjects were on average 3.6 years younger (P=0.03), enrolled 70 days longer in the PCP (P<0.001), lived 6.7 km closer to the PCP (P<0.0001), and were more likely to have cancer (96.0% vs. 86.4%, P=0.05). Comparison II: Compared with all cancer decedents, the 45 study subjects who died of cancer were on average 7.0 years younger (P<0.001), lived 2.7 km closer to the PCP (P<0.001), and were more likely to have had radiotherapy (62.2% vs. 33.8%, P<0.0001) and medical oncology (28.9% vs. 14.8%, P=0.01) consultations. Comparison III: The 50 study subjects lived on average 42 days longer after their diagnosis (P=0.03) and 2.6 km closer to the PCP (P=0.01) than the 110 eligible persons who declined to participate. CONCLUSION: If the study findings are applied to populations that differ from the study subjects, inaccurate conclusions are possible. PMID- 21276698 TI - Terminal hospitalizations of nursing home residents: does facility increasing the rate of do not resuscitate orders reduce them? AB - CONTEXT: Terminal hospitalizations are costly and often avoidable with appropriate advance care planning. OBJECTIVES: This study examined the association between advance care planning, as measured by facility rate of do not resuscitate (DNR) orders in U.S. nursing homes (NHs) and changes in terminal hospitalization rates. METHODS: Retrospective cohort study of the changing prevalence of DNR orders in U.S. NHs. Using a fixed effect multivariate model, we examined whether increasing facility rate of DNR orders correlates with reductions in terminal hospitalizations in the last week of life, controlling for changes in facility characteristics (staffing, use of NP/PA, case mix of nursing residents, admission volume, racial composition, payer mix). RESULTS: The average facility rate of terminal hospitalizations was 15.5%, fluctuating between 1999 (15.0%) and 2007 (14.8%). NHs starting with low rates of DNR orders that increased their rates had fewer terminal hospital admissions in 2007 (11.2%) than facilities with continuously low DNR usage. Even after applying a multivariate fixed effect model, the effect of changes in facility DNR order rate on terminal hospitalization was -0.056 (95% confidence interval: -0.061, -0.050), indicating that for every 10% increase in DNR orders there was 0.56% decrease in terminal hospitalizations. This rate can be compared with the increase of 0.70% in the terminal hospitalization rate when an NH became disproportionately dependent on Medicaid funding or the 0.40% decrease in terminal hospitalization rate associated with adding a nurse practitioner to the clinical staff complement. CONCLUSION: NHs that changed their culture of decision making by increasing their facility rate of DNR orders decreased their rate of terminal hospitalizations. PMID- 21276699 TI - Association between serum cortisol and testosterone levels, opioid therapy, and symptom distress in patients with advanced cancer. AB - CONTEXT: Patients with advanced cancer often experience symptoms such as pain, anorexia, and fatigue. Opioid therapy for the management of cancer pain may result in neurohormonal dysfunction that may contribute to a patient's symptom burden. OBJECTIVES: To examine the association between serum cortisol and testosterone levels, opioid therapy, and symptom distress in patients with cancer. METHODS: A retrospective chart review was performed on 77 consecutive patients with advanced cancer referred for symptoms of fatigue or cachexia. We collected information regarding cortisol levels (am or random), testosterone levels (men only), morphine equivalent daily dose (MEDD), and symptom severity measured by the Edmonton Symptom Assessment Scale. Nonparametric correlation analysis was performed. RESULTS: The median age was 63 years (range 24-79), and 62% were men (n=48). Most patients had gastrointestinal (n=33, 43%) or thoracic (n=21, 27%) malignancies and were Caucasian (n=46, 60%). The median random cortisol level was 19.1 MUg/dL (Q1-Q3, 13.4-23.8 [normal, 4.3-22.4]), which correlated with MEDD (Spearman coefficient, 0.25, P=0.032) and symptoms including pain (0.50, P<0.001), fatigue (0.29, P=0.012), nausea (0.34, P=0.003), depression (0.24, P=0.032), and anxiety (0.25, P=0.031). Pain and nausea remained significant after Bonferroni correction. Median morning cortisol level (n=28) was 20.6 MUg/dL (Q1-Q3, 16.6-25.4) and significantly correlated with pain (0.55, P=0.003) after Bonferroni correction. Patients with a MEDD <30 mg/day had a mean random cortisol level of 16.6 MUg/dL, whereas patients with a MEDD >= 30 mg/day had a mean random cortisol level of 20.6 MUg/dL (P=0.01). In 44 male patients with cancer, MEDD was inversely correlated with the total testosterone level ( 0.52, P=0.001). CONCLUSION: In patients with advanced cancer, elevated random cortisol levels were associated with pain and opioid use, although abnormally low levels of cortisol were found to be infrequent. Patients on higher opioid therapy (MEDD >30) had increased cortisol levels, and male patients had lower testosterone levels. Our study suggests that opioid therapy in patients with advanced cancer may inhibit gonadal function while sparing the adrenal axis. Future studies are needed. PMID- 21276700 TI - "It depends": viewpoints of patients, physicians, and nurses on patient practitioner prayer in the setting of advanced cancer. AB - CONTEXT: Although prayer potentially serves as an important practice in offering religious/spiritual support, its role in the clinical setting remains disputed. Few data exist to guide the role of patient-practitioner prayer in the setting of advanced illness. OBJECTIVES: To inform the role of prayer in the setting of life threatening illness, this study used mixed quantitative-qualitative methods to describe the viewpoints expressed by patients with advanced cancer, oncology nurses, and oncology physicians concerning the appropriateness of clinician prayer. METHODS: This is a cross-sectional, multisite, mixed-methods study of advanced cancer patients (n=70), oncology physicians (n=206), and oncology nurses (n=115). Semistructured interviews were used to assess respondents' attitudes toward the appropriate role of prayer in the context of advanced cancer. Theme extraction was performed based on interdisciplinary input using grounded theory. RESULTS: Most advanced cancer patients (71%), nurses (83%), and physicians (65%) reported that patient-initiated patient-practitioner prayer was at least occasionally appropriate. Furthermore, clinician prayer was viewed as at least occasionally appropriate by the majority of patients (64%), nurses (76%), and physicians (59%). Of those patients who could envision themselves asking their physician or nurse for prayer (61%), 86% would find this form of prayer spiritually supportive. Most patients (80%) viewed practitioner-initiated prayer as spiritually supportive. Open-ended responses regarding the appropriateness of patient-practitioner prayer in the advanced cancer setting revealed six themes shaping respondents' viewpoints: necessary conditions for prayer, potential benefits of prayer, critical attitudes toward prayer, positive attitudes toward prayer, potential negative consequences of prayer, and prayer alternatives. CONCLUSION: Most patients and practitioners view patient-practitioner prayer as at least occasionally appropriate in the advanced cancer setting, and most patients view prayer as spiritually supportive. However, the appropriateness of patient-practitioner prayer is case specific, requiring consideration of multiple factors. PMID- 21276701 TI - Characterization of chemosensory alterations in advanced cancer reveals specific chemosensory phenotypes impacting dietary intake and quality of life. AB - CONTEXT: Taste and smell (chemosensory) alterations are common and distressing among advanced cancer patients, but their specific nature is poorly described and seldom linked to dietary intake. Details of altered chemosensory perception may help to explain food intake behaviors. OBJECTIVES: Our goal was to characterize chemosensory alterations and their relationship with dietary intake and quality of life (QOL). METHODS: Adult advanced cancer patients (n=192) completed a chemosensory self-assessment questionnaire to characterize changes in their sense of smell and four basic tastes (sweet, sour, salty, and bitter) since the onset of cancer, three-day food record, and QOL questionnaire. RESULTS: Patients experienced either no alteration in any basic tastes and sense of smell sensations (26% of patients) or one of three altered chemosensory phenotypes: 1) stronger sensations overall (42%), 2) weaker sensations overall (18%), or 3) mixed (some sensations stronger and others weaker, 14%). For individual sensations (sweet, sour, salty, bitter, and smell), stronger sensation was twice more prevalent than weaker sensation (P=0.035). Patients reporting chemosensory alteration consumed 20%-25% fewer calories per day (P=0.0018), experienced greater weight loss (P=0.0036), and had poorer QOL scores (P=0.0176) compared with patients with no alterations, but results did not vary by chemosensory phenotype. Chemosensory alterations were not related to tumor type (P=0.884), gender (P=0.286), or nausea (P=0.278). CONCLUSION: Chemosensory alterations predict dietary intake and QOL; the identification of chemosensory phenotypes provides a rationale to adjust the properties of foods and dietary recommendations in function of the specific nature of these changes. PMID- 21276702 TI - Death, time and the theory of relativity. AB - Many people believe that spending large amounts of money on end-of-life care is unjustified and even irrational. This fails to recognize that the value of time, particularly quality time, appears to increase as death draws near. Paying for treatment that merely allows patients and families to avoid confronting the inevitability of death is wrong. However, palliative care, which can bolster the quality of a patient's remaining days, provides benefits that extend to the family and beyond. How can the notion of time gaining value toward the end of life be incorporated into conventional cost-benefit analyses? A standard QALY (Quality Adjusted Life Years) is the product of quality of life and time, without adjusting for any change in the value of time. An additional variable--a Valuation Index (Palliative) (or VIP)--needs to be factored into the equation, providing a rational explanation for what otherwise might be deemed irrational spending. When one recognizes the multitude of important things that happen as people approach the very end of life, the numbers start to add up. PMID- 21276703 TI - Healing: the power of presence. A reflection. AB - The focus of my work as a teacher and Episcopal priest has been pastoral. In my work of chaplaincy, spiritual director, and trainer of spiritual directors, I have been powerfully aware of the importance of presence. Furthermore, I have concentrated on the significance of healing-physical, emotional, and spiritual-as distinguished from curing. This article is a reflection, based on my decades of experience, as contrasted with an academic exploration of the history, various traditions, or the methodology of healing. PMID- 21276704 TI - Comparing three life-limiting diseases: does diagnosis matter or is sick, sick? AB - CONTEXT: At advanced stages, cancer, congestive heart failure (CHF), and chronic obstructive pulmonary disease (COPD) produce high rates of hospitalization, disability, and annual mortality. Despite similar prognoses, patients with cancer often are treated differently than those with other illnesses, the former being seen as terminal vs. chronic. OBJECTIVES: The purpose of this study was to compare the functional capacity, emotional well-being, and quality of life of patients in three disease groups to assess whether diagnosis distinguishes differences in patient experience, and compare patients with cancer and noncancer diagnoses. METHODS: Baseline data from a cohort study of 210 patients who had an estimated 50% two-year mortality were analyzed. The patients had Stage IV breast, prostate, or colon cancer; Stage IIIb or IV lung cancer; New York Heart Association Stage III or IV CHF with a left ventricular ejection fraction of <40%; or COPD with hypercapnea (pC02>46) and at least one hospitalization or Emergency Department visit during the past year. Measures included the Rosow Breslau Activities of Daily Living/Instrumental Activities of Daily Living tool, Profile of Mood States anxiety subscale, brief Centers for Epidemiologic Studies Depression Scale, and the Functional Assessment of Cancer Therapy-General quality of-life instrument. Analyses included descriptive statistics, analysis of variance, and adjusted linear regression models. RESULTS: A majority of illness outcomes did not differ by diagnostic category. Functional status was associated with diagnosis, with CHF and COPD patients faring worse than those with cancer. Overall, illness experience was most significantly related to disease severity, demographics, and emotional and social well-being. CONCLUSION: Comparing patients with advanced cancer, CHF, and COPD, illness experience was more similar than different. Patients living with life-limiting illnesses other than cancer may benefit from whole-person services often extended to cancer patients. PMID- 21276705 TI - The Diabetes Symptom Self-Care Inventory: development and psychometric testing with Mexican Americans. AB - CONTEXT: Type 2 diabetes is prevalent throughout the world. In previous studies of Mexican Americans with type 2 diabetes, 95%-97% of those sampled reported having symptoms they believe were caused by diabetes and most self-treated their symptoms. To more accurately capture Mexican Americans' symptom prevalence and their self-treatments, the Diabetes Symptom Self-Care Inventory (DSSCI) was adapted from the Diabetes Self-Care Instrument. OBJECTIVES: This article describes the modification process used to perfect the DSSCI for use in improving self-care among people with type 2 diabetes. METHODS: This instrumentation study used qualitative and quantitative methods. The study was completed in four phases that used focus groups, cognitive interviews, and survey administration. Four convenience samples were drawn from community-dwelling Mexican American adults, aged 25-75 years, with type 2 diabetes in an urban area and a rural location in Texas. RESULTS: Phase I: Seven focus groups (n=45) generated data for revising items. Phase II: Cognitive interviews with 16 participants were used to evaluate four revisions of the questionnaire. Phase III: Surveys were administered to 81 participants. Total number of symptoms on the DSSCI correlated with scores on the Centers for Epidemiological Studies-Depression scale (r=0.65, P<0.001), Illness Perception Questionnaire-Revised Diabetes Symptom subscale (r=0.57, P<0.001), and Audit of Diabetes-Dependent Quality of Life scale (r=-0.42, P<0.001). Minor revisions followed. Phase IV: Test-retest stability was demonstrated (n=44). CONCLUSION: The DSSCI is a culturally relevant, sound measure of Mexican Americans' diabetes symptoms and the actions they take to address them. PMID- 21276706 TI - Urgent endovascular treatment of a ruptured tibioperoneal pseudoaneurysm in Behcet's disease. AB - BACKGROUND: Behcet's disease is an autoimmune, systemic vasculitis disease that is characterized by oral aphthous and genital ulcerations and ocular lesions. Vascular manifestations in the form of aneurysms are the main predictors of mortality and morbidity in such cases. Normally, these aneurysms are located in the pulmonary arteries, the aorta, carotid, subclavia, and the femoropopliteal sector. Open surgery presents a maximum complication rate of 50%, principally in the form of anastomotic pseudoaneurysms. METHODS: We report the case of a 41-year old man who was diagnosed with Behcet's disease 3 years before, and attended the emergency department after a 10-day history of pain and an infragenicular swelling edema in the right limb, without any previous record of trauma. RESULTS: An initial vascular exploration revealed a pusatile mass in the infrapopliteal region and absence of the posterior tibial pulse in the right limb. The rest of the exploration did not reveal any alterations. A Doppler ultrasound scan showed a ruptured infrapopliteal pseudoaneurysm. An emergency, selective arteriography of the popliteal artery was performed by using a contralateral femoral access approach, and a ruptured tibioperoneal pseudoaneurysm was embolized with three 5 mm metallic coils (Cook). The patient was discharged after 4 days and in the 2 years since then has remained asymptomatic. CONCLUSIONS: Aneurysms of the distal vessels in Behcet's disease are very infrequent and each case should be evaluated on an individual basis. Endovascular treatment is a good therapeutic alternative. PMID- 21276707 TI - Thoracic aortic stent-grafting for acute, complicated, type B aortic dissections. AB - BACKGROUND: To report a single-center experience of aortic stent-grafting for the treatment of acute, complicated, type B aortic dissections. METHODS: A retrospective review was conducted of the data obtained from all patients who underwent endovascular stent-grafting for acute, type B aortic dissection between 2006 and 2009. The primary and secondary endpoints were 30-day mortality and morbidity rates, respectively. RESULTS: In all, 104 thoracic endovascular aortic aneurysm repairs were performed during the study period. Nine (8.6%) patients (six men; mean age: 65 years) underwent thoracic endovascular aortic aneurysm repair for acute, complicated, type B aortic dissections. Seven (78%) patients had uncontrolled hypertension on presentation. Visceral branch vessel involvement of the dissection was limited to the celiac axis origin in one patient with no evidence of visceral malperfusion. The indication for repair was aortic rupture in five patients, renal malperfusion in two, and persistent pain in the remaining two. Average time taken from presentation to surgery was 5.5 days. Two patients presenting with aortic ruptures had retrograde extension of the dissection that required replacement of the aortic valve and ascending aorta. The mean length of thoracic aorta covered was 21 cm. Complete coverage of the left subclavian artery was required in three patients and partial coverage in two. On completion angiogram, two type I endoleaks were detected, one of which was resolved by postoperative day 5. The 30-day mortality rate was 22%. One mortality was secondary to aortic rupture. The other mortality was due to multiorgan system failure. Seven patients (78%) had one or more major complications. There were no strokes or paraplegia. CONCLUSION: The association of morbidity and mortality with endovascular stent-grafting for acute, complicated, type B aortic dissections is significant, which most likely reflects the lethal nature of the disease. The precise role of endovascular treatment in these patients remains to be defined. PMID- 21276708 TI - Technical modifications for endovascular infrarenal AAA repair for the angulated and dumbbell-shaped neck: the precuff Kilt technique. AB - BACKGROUND: High risk surgical patients with abdominal aortic aneurysms and difficult infrarenal necks continue to be challenged when performing endovascular repair. Although fenestrated and branched endografts may ultimately be the main method of repair for these patients, their current limited availability has prompted the use of alternative endovascular techniques to enhance success of endovascular aortic aneurysm repair in patients with "dumbbell" shaped and angulated necks. METHODS: A retrospective review of all patients who underwent endovascular abdominal aneurysm repair with a predeployed aortic cuff (Kilt) at University of California, Los Angeles between January 2009 and April 2010 was performed. RESULTS: Four patients underwent initial Kilt placement before endovascular abdominal aortic aneurysm (AAA) repair. The mean age of these patients was 78.0 + 7.0 years. All were American Society of Anesthesiologists class 3 patients with multiple medical comorbidities. All of them had angulated and dumbbell-shaped necks. Median follow-up period was 11 months (8-18 months). All patients had postoperative computed tomography at 1 and 6 months because of their high-risk neck anatomy. One patient was found to have a large type I endoleak on computed tomography 1 month postoperatively. He required placement of an additional aortic cuff and Palmaz stent, after which the endoleak was found to have resolved. There were no open conversions, aneurysm sac enlargement, or perioperative deaths. CONCLUSION: Short-term follow-up suggests that the Kilt technique may be useful in certain high-risk patients with traditionally unfavorable anatomy for endovascular abdominal aortic aneurysm repair. It can be performed with minimal patient morbidity, even in high-risk patients. Anatomic features most amenable to this technique include dumbbell-shaped and angulated infrarenal necks. PMID- 21276710 TI - Retroperitoneal versus direct femoral artery approach for thoracic endovascular aortic repair access: a case-control study. AB - BACKGROUND: Many individuals who are candidates for thoracic endovascular aortic repair (TEVAR) are found to have iliac artery anatomy and/or disease that preclude transfemoral endovascular access and require retroperitoneal surgical approach through more proximal arteries. This relatively more invasive technique could potentially affect the procedural outcomes. This study compares the retroperitoneal with transfemoral access used for TEVAR in a single center. METHOD: In this study, 133 consecutive patients (96 men; mean age +/- SD: 69.5 +/ 14.7 years) who underwent TEVAR between 1994 and 2009 in a single center were retrospectively evaluated. The type of endovascular access was identified in all the patients. The basic demographics, access method, endograft type, 30-day morbidity and mortality rates, as well as procedure recordings including fluoroscopic and procedure duration, estimated blood loss, and duration of hospitalization were compared between the TEVAR procedures performed using a surgical retroperitoneal approach and those using the standard femoral access. RESULTS: Retroperitoneal access was used in 19 (14.3%; 13 women; mean age +/- SD: 71 +/- 12.2 years) and direct femoral access in 114 (85.7%; 24 women; mean age +/ SD: 69 +/- 15.4 years) patients. Two of the retroperitoneal accesses were obtained after failure of femoral approach. Techniques that were used included iliac artery conduit (seven patients), aortic artery conduit (eight patients), aortobifemoral artery graft conduit (one patient), and direct sheath introduction through the distal aorta (two patients) or common iliac artery (one patient). Retroperitoneal approach was used more frequently in women (35%) as compared with men (6%) (p = 0.0001). In all, 79% of the retroperitoneal approaches were associated with use of delivery sheath sizes larger than 24F (p = 0.049). TEVAR technical success was 100% with retroperitoneal and 97.3% with femoral access (p > 0.05). Thirty-day mortality rates were 0% and 8.8% and the rates of access artery injury were 5.3% and 4.4% in retroperitoneal and femoral access groups, respectively (p > 0.05). The incidence of retroperitoneal hematoma was significantly higher with retroperitoneal access (21% vs. 2.6%, p = 0.008). Additionally, retroperitoneal access was associated with significant increase in estimated blood loss and duration of hospitalization (p < 0.05). CONCLUSIONS: Type of access does not affect TEVAR success and the early mortality rate. Retroperitoneal approach is a valuable alternative technique in cases involving failed or impossible femoral access. However, this approach is associated with higher chances of retroperitoneal bleeding and longer procedural time and duration of hospitalization. Thoracic endografts with smaller delivery systems could minimize the need for this approach in the future. PMID- 21276709 TI - Current usage and future directions for the bovine pericardial patch. AB - Bovine pericardium (BP) is widely used in surgery and is commonly used as a patch after arteriotomy in cardiovascular surgery. BP patches have several advantages compared with prosthetic patches, including superior biocompatability, easy handling, less suture line bleeding, and possibly reduced rates of infection. These advantages of BP have led to its common use during carotid endarterectomy (CEA). However, long-term clinical results reported after CEA have suggested several issues that may be related to the patch, including restenosis, pseudoaneurysm formation, infection, fibrosis, calcification, and thrombosis. These complications may diminish the long-term efficacy of CEA and suggest potential areas for improvement of surgical patches. Understanding the mechanisms by which BP heals after patch angioplasty may lead to next generation tissue engineered patches. PMID- 21276711 TI - Robot-assisted treatment of splenic artery aneurysms. AB - BACKGROUND: Although splenic artery aneurysms (SAAs) are relatively uncommon, they are clinically relevant because of the risk of rupture. Optimal management is a matter of debate and involves the use of percutaneous endovascular stenting, which has limitations, versus the open surgical approach which can lead to significant morbidity. The present study reports the outcomes of robot-assisted surgery for SAA and its role in overcoming many of the limitations of laparoscopy. METHODS: A total of nine patients with incidentally detected SAAs underwent a surgery between September 2001 and November 2007. Six of these nine patients underwent a robot-assisted splenic aneurysm resection with vascular reconstruction. The remaining three cases included one robotic arterial ligation, one robotic partial splenectomy, and one laparoscopic splenectomy. RESULTS: The mean operating time was 212 +/- 61 minutes (range: 90-300), mean intraoperative blood loss was 186.6 +/- 202.4 mL (range: 0-500), and mean hospital stay was 7.1 +/- 3.7 days (range: 3-14). The morbidity rate was 11.1% and no mortality was reported. Doppler-ultrasonography surveillance showed regular organ perfusion in all patients with vascular reconstruction. CONCLUSION: Robot-assisted surgery for SAA represents one of the most advanced developments among minimally invasive procedures and can become an important option for the treatment of this disease. PMID- 21276712 TI - Low P-values exclude nothing, and P-values are no substitute for measures of effect. PMID- 21276713 TI - Omega-3 fatty acid deficiency: a preventable risk factor for schizophrenia? PMID- 21276714 TI - Immunoglobulin treatment in primary antibody deficiency. AB - The primary antibody deficiency syndromes are characterised by recurrent respiratory tract infections and the inability to produce effective immunoglobulin (Ig) responses. The best-known primary antibody deficiencies are common variable immunodeficiency (CVID), X-linked agammaglobulinaemia (XLA), immunoglobulin G (IgG) subclass deficiency, and selective antibody deficiency with normal immunoglobulins (SADNI). Therapy in these patients consists of prophylactic antibiotics and/or Ig replacement therapy. Diagnostic delay remains common owing to limited awareness of the presenting features and may result in increased morbidity and mortality. Replacement therapy with immunoglobulins increases life expectancy and reduces the frequency and severity of infections, but the effect on end-organ damage is still unknown. Both intravenous immunoglobulin (IVIg) and subcutaneous immunoglobulin (SCIg) treatment appear to be safe, with comparable efficacy. A starting dose of 300-400 mg/kg/month in IVIg and 100 mg/week for SCIg is recommended. IgG trough levels should be >5 g/L for patients with agammaglobulinaemia and 3 g/L greater than the initial IgG level for patients with CVID; however, the clinical response should be foremost in choosing the dose and trough level. Infusion-related adverse reactions are generally mild owing to improved manufacturing processes. In this paper, aspects of Ig replacement therapy in primary antibody-deficient patients will be addressed. PMID- 21276715 TI - Strategies to overcome extended-spectrum beta-lactamases (ESBLs) and AmpC beta lactamases in shigellae. AB - Oral cephalosporins and mecillinam are used to treat Shigella infections, but are compromised by extended-spectrum beta-lactamases (ESBLs) and plasmid AmpC beta lactamases. Potential solutions include combining an oral or intravenous cephalosporin with a beta-lactamase inhibitor (BLI) or using an oral penem. These strategies were examined using Escherichia coli transconjugants and clinical isolates with ESBLs or AmpC, as a proxy for shigellae. The Clinical and Laboratory Standards Institute agar dilution method was used with inocula of 10(4) and 10(6) colony-forming units/spot. ESBLs conferred resistance to the cephalosporins and mecillinam, at least at high inoculum, although: (i) ceftibuten was significantly compromised only by SHV and CTX-M-15 ESBLs, but not by TEM or CTX-M-9 and -14; (ii) cefdinir was little affected by TEM-type ESBLs, and mecillinam was little affected by CTX-M-9 group enzymes. The BLI clavulanic acid reduced the minimum inhibitory concentrations (MICs) of cephalosporins and mecillinam to <=2 mg/L for ESBL-producers, even at high inocula; sulbactam in particular and tazobactam were less effective, especially against SHV types. Strains with AmpC were resistant to all cephalosporins+/-inhibitors, but mecillinam remained active (MIC=1 mg/L) against a strain with AmpC alone, whereas strains with TEM-1+AmpC were susceptible to mecillinam+clavulanic acid at <=2 mg/L. Faropenem was active against all ESBL- and AmpC-producers at 4 mg/L, with little inoculum effect or inhibitor potentiation. In conclusion, cephalosporin+clavulanic acid combinations overcame ESBLs, with ceftibuten+clavulanic acid being particularly promising. Mecillinam+clavulanic acid and faropenem overcame both ESBLs and AmpC enzymes. Clinical utility will depend also on a drug's ability to reach intracellular shigellae in the intestinal epithelium and this deserves exploration for clavulanic acid and faropenem. PMID- 21276716 TI - Trends in prescribing of psychotropic medications for inpatient adolescents in Israel: a 10 years retrospective analysis. AB - We examined the trends in prescribing psychotropic drugs to children and adolescents within an inpatients adolescent psychiatric ward in Israel. Data of 414 subjects, ranging from 12- to 22-year-old, covering the years 1997, 2002 and 2007, was examined retrospectively. Analyzed variables included the number and type of drug prescriptions per patient at discharge, the subjects' age at discharge and the number of diagnoses per patient at discharge. Analysis of variance (ANOVA) with repeated measures was used to evaluate changes between the three calendar years, along the 10-year study period, while Pearson chi(2) test was performed for categorical variables. Over the study period the mean age at discharge decreased significantly, by about a year and a half, the mean number of diagnoses increased significantly, from 1.6 to 2.4 diagnoses per patient and the total number of drugs prescribed at discharge increased significantly from 1.48 to 1.93 per patient. Overall, the number of patients who were prescribed mood stabilizers increased by 14%, those who were prescribed antidepressants increased by almost 24%, almost 16% in antipsychotics prescriptions and 51.5% in prescriptions of atypical antipsychotics. Typical antipsychotic prescriptions decreased by 35.5% and accordingly, the number of patients who were prescribed agents for the treatment of extra-pyramidal side effects decreased by almost 24%. Due to a low number of inpatients with attention deficit and hyperactivity disorder (ADHD), no significant statistical conclusion could be drawn regarding trends in psychostimulant prescriptions. Our findings agree with other published studies from the last two decades. The growing use of psychotropic agents in children and adolescents merit a continuous concern with regard to their effects on the developing brain and impact on quality of life and to authorizing these drugs for use in specific young age subgroups. PMID- 21276717 TI - Sodium oxybate in maintaining alcohol abstinence in alcoholic patients with and without psychiatric comorbidity. AB - Sodium oxybate (SMO) is a GABA-ergic drug currently used for the treatment of alcohol-dependence in some European countries. In particular, clinical studies have shown a role of SMO in promoting alcohol abstinence, as well as in relieving withdrawal symptoms. The aim of this study was to describe alcohol abstinence and the onset of craving for and abuse of SMO in alcohol-dependent subjects with and without psychiatric co-morbidity. Forty-eight patients were enrolled and classified into two groups: group A (20 alcoholics without any psychiatric co morbidity) and group B (28 alcoholics with a psychiatric co-morbidity). All patients were treated with oral SMO (50 mg/kg of body weight t.i.d.) for 12 weeks. Alcohol abstinence as well as alcohol drinking during the 12 weeks of treatment did not differ between the two groups at the end of treatment (p=0.9). In addition, a reduction of alcohol intake in both groups has been observed (p<0.0001). On the other hand, craving for SMO was significantly more frequent in group B than group A (p=0.001). Cases of SMO abuse were observed in almost 10% of group B patients. In conclusion, alcohol abstinence achieved through SMO administration does not differ in patients with and without psychiatric co morbidity. However, alcoholics with co-morbid borderline disorders appear to be at high risk of developing craving for and abuse of the drug; therefore, SMO may not be indicated in these patients. PMID- 21276718 TI - [Usefulness of serum procalcitonin in the early diagnosis of maternal-fetal bacterial infection. A prospective study]. AB - Early diagnosis avoiding unnecessary treatment of maternal-fetal bacterial infection remains one of the greatest challenges for obstetricians and pediatricians. To meet these objectives, many inflammatory mediators were used, including procalcitonin (PCT). The aim of our study was to determine the usefulness of PCT in early diagnosis and management of neonatal infection. SUBJECTS AND METHODS: Over a period of 8 months, all living newborns with highly suspected maternal-fetal bacterial infection who were to receive antibiotic treatment according to our neonatal unit protocol were included in this prospective study. Serum PCT concentrations were determined at birth and after 12h of life using a specific immunoluminometric assay. Two distinct populations were defined based on clinical, biological, and bacteriological criteria: group 1: infected neonates, and group 2: noninfected neonates. STATISTICAL METHODS: We compared PCT means in different groups and determined the cut-off value correlated with maternal-fetal bacterial infection by analyzing the receiver operating characteristics curve (ROC). RESULTS: A total of 130 neonates were included in the study: 38 (29%) were classified in group 1 with 29 possible infections and 9 defined infections, including 5 cases of septicemia. The average PCT at birth in group 1 was significantly higher than in group 2 (3.52 +/- 8.19 ng/ml vs 0.43 +/- 0.73 ng/ml; P<0.001). The PCT threshold value at birth found by the ROC curve with the highest sensitivity (71.1%) and highest specificity (62%) was 0.215 ng/ml. The negative predictive value (NPV) was 83.8%, making it possible to avoid unnecessary treatment in the majority of the cases. The PCT threshold value within 12h of birth was 3.78 ng/ml, for a sensitivity of 89.5% and 1 NPV of 94.4%. CONCLUSION: PCT is a valuable biological examination because it can be administered early, it is sensitive, and it has a NPV. These characteristics make PCT a biological argument that can be used in the initial decision on whether to administer antibiotics. Another study will be conducted to establish the cut-off value. PMID- 21276719 TI - Protist-like inclusions in amber, as evidenced by Charentes amber. AB - The mid-Cretaceous amber of France contains thousands of protist-like inclusions similar in shape to some ciliates, flagellates and amoebae. The sheer abundance of these inclusions and their size variation within a single amber piece are not concordant with true fossil protists. French amber is coniferous in origin, which generally does not preserve well protists without cell walls. Thus, it would be surprising if French Cretaceous amber had preserved millions of protists. Here, we present a survey of the protist-like inclusions from French amber and attempt to elucidate their origins. Diverse Cretaceous ambers (from Spain, Germany and Lebanon), also derived from conifer resins, contain thousands of protist-like inclusions. In contrast, Tertiary ambers and modern resins are poor in protist like fossils. This suggests these inclusions originated from early Cretaceous plant resins, probably secreted with the resin by trees that did not survive after the Cretaceous (such as the Cheirolepidiaceae). A review of the recent literature on amber microfossils indicates several protist-like inclusions that are unlikely to have a biological origin have already been described as real fossil protists. This is problematic in that it will bias our understanding of protist evolution. PMID- 21276720 TI - Energy expenditure during daily activities as measured by two motion sensors in patients with COPD. AB - BACKGROUND: In patients with chronic obstructive pulmonary disease (COPD), energy expenditure (EE) assessment during the performance of daily activities is not yet studied in depth. The aim of this study was to determine which daily activities are more demanding to patients with COPD and to compare the accuracy of EE estimation given by the pedometer Digiwalker SW701 (DW) and the multisensor SenseWear Armband (SAB). METHODS: Thirty-six patients with COPD (20 men; FEV1 48 +/- 15%predicted; BMI 25.7 +/- 8 kg/m(2)) were submitted to a modified version of the Glittre ADL-test, which included five activities performed for 1 min each: walking on the level, walking on the level carrying a backpack, walking up/downstairs, rising/sitting in chairs and moving objects in and out of a shelf. During the protocol subjects wore both devices concomitantly, and indirect calorimetry (IC) was simultaneously performed as the criterion method to assess EE. RESULTS: The most demanding daily activity for individuals with COPD was walking up/downstairs (4.9 +/- 1.7 kcal versus 3.7 +/- 1.4 to 4.2 +/- 1.8 kcal for the other tasks; p < 0.05). EE estimation by the SAB did not show difference in comparison to IC for the sum of the five activities (SAB = 22.7 +/- 7 kcal versus IC = 21 +/- 8 kcal; p > 0.05), although overestimation was found in activities involving walking. DW showed significant EE underestimation in the sum of the activities (9.6 +/- 4.3 kcal; p < 0.05 versus IC) and for each activity. CONCLUSION: Walking up/downstairs was the most energy-demanding daily activity for patients with COPD. Furthermore, during daily activities, the multisensor showed adequate overall estimation of energy expenditure, as opposed to the pedometer. PMID- 21276721 TI - Association between lung function, hypertension and blood pressure medication. AB - BACKGROUND: Several studies showed an association between lung function and hypertension. However, it must be considered that antihypertensive treatment might have an effect on lung function, too. So far, this potential effect of antihypertensive medication on lung function has been investigated mainly in patients with already existing pulmonary diseases. Thus, the aim of this analysis was to determine whether hypertension and its medical treatment are associated with lung function impairment in a general adult population. METHODS: Within the cross-sectional study ECRHS-I Erfurt 1158 adults aged between 20 and 65 years performed lung function tests and blood pressure measurements. Additionally, information on anthropometric measurements, sociodemographic characteristics and medical history was available. Multivariate regression models were applied to study the association between lung function, blood pressure and antihypertensive treatment. RESULTS: The combination of high blood pressure and the use of antihypertensive medication had the strongest negative effect on lung function. Thus, it was associated with a deterioration in FEV(1) of -150 ml (p=0.01) and in FVC of -190 ml (p<0.01). When using both high blood pressure and antihypertensive medication as individual variables in one regression model, only medication decreased FEV(1) and FVC significantly (each p<0.01). CONCLUSIONS: We speculate that high blood pressure in combination with antihypertensive treatment and not HBP itself might be associated with reduced lung function in a general adult population. Nevertheless, it must be considered that antihypertensive medication might just be an indicator for very high blood pressure. PMID- 21276722 TI - Conclusiveness of fine needle aspiration in 2419 histologically confirmed benign and malignant breast lesions. AB - We aimed to retrospectively assess (1) the conclusiveness of breast fine needle aspiration (FNA) in a histologically confirmed population and (2) the clinical and radiologic determinants of a conclusive diagnosis. Aspirates were diagnosed as inadequate, benign, atypical, suspicious or malignant. We defined a conclusive FNA diagnosis as 'benign' in histologically benign lesions and as 'malignant' in histologically malignant lesions. In 2419 breast lesions, the proportion of conclusive diagnoses was 46.1% (95% confidence interval, 42.0-50.2%) in histologically benign lesions (n = 571) and 81.6% (95% confidence interval, 79.8% 83.4%) in histologically malignant lesions (n = 1848). On multivariate analysis, factors associated with a conclusive preoperative diagnosis included tumour diameter of 2-2.9 cm (P < 0.001), malignant histology (P < 0.001) and the pathologist examining the aspirate (P = 0.02). Breast FNA has to be utilised selectively in the routine work-up of breast lesions. In suspicious lesions of large size, FNA may still be used to obtain a quick confirmation of malignancy. PMID- 21276723 TI - PAR-4/LKB1 mobilizes nonmuscle myosin through anillin to regulate C. elegans embryonic polarization and cytokinesis. AB - BACKGROUND: The serine/threonine kinase LKB1 regulates cell growth and polarity in metazoans, and loss of LKB1 function is implicated in the development of some epithelial cancers. Despite its fundamental role, the mechanism by which LKB1 regulates polarity establishment and/or maintenance is unclear. In the present study, we use the nematode C. elegans to investigate the role of the LKB1 ortholog PAR-4 in actomyosin contractility, a cellular process essential for polarity establishment and cell division in the early embryo. RESULTS: Using high resolution time-lapse imaging of GFP-tagged nonmuscle myosin II (NMY-2), we found that par-4 mutations reduce actomyosin contractility during polarity establishment, leading to the mispositioning of anterior PAR proteins and to defects in contractile ring ingression during cytokinesis. Fluorescence recovery after photobleaching analysis revealed that the mobility of a cortical population of NMY-2 was reduced in par-4 mutants. Interestingly, the contractility defects of par-4 mutants depend on the reciprocal activity of ANI-1 and ANI-2, two C. elegans homologs of the actin cytoskeletal scaffold protein anillin. CONCLUSION: Because loss of PAR-4 promoted inappropriate accumulation of ANI-2 at the cell cortex, we propose that PAR-4 controls C. elegans embryonic polarity by regulating the activity of anillin family scaffold proteins, thus enabling turnover of cortical myosin and efficient actomyosin contractility. This work provides the first description of a cellular mechanism by which PAR-4/LKB1 mediates cell polarization. PMID- 21276724 TI - Visual influences on echo suppression. AB - Locating sounds in realistic scenes is challenging because of distracting echoes and coarse spatial acoustic estimates. Fortunately, listeners can improve performance through several compensatory mechanisms. For instance, their brains perceptually suppress short latency (1-10 ms) echoes by constructing a representation of the acoustic environment in a process called the precedence effect. This remarkable ability depends on the spatial and spectral relationship between the first or precedent sound wave and subsequent echoes. In addition to using acoustics alone, the brain also improves sound localization by incorporating spatially precise visual information. Specifically, vision refines auditory spatial receptive fields and can capture auditory perception such that sound is localized toward a coincident visual stimulus. Although visual cues and the precedence effect are each known to improve performance independently, it is not clear whether these mechanisms can cooperate or interfere with each other. Here we demonstrate that echo suppression is enhanced when visual information spatially and temporally coincides with the precedent wave. Conversely, echo suppression is inhibited when vision coincides with the echo. These data show that echo suppression is a fundamentally multisensory process in everyday environments, where vision modulates even this largely automatic auditory mechanism to organize a coherent spatial experience. PMID- 21276725 TI - Apoptosis ensures spacing pattern formation of Drosophila sensory organs. AB - BACKGROUND: In both vertebrates and invertebrates, developing organs and tissues must be precisely patterned. One patterning mechanism is Notch/Delta-mediated lateral inhibition. Through the process of lateral inhibition, Drosophila sensory organ precursors (SOPs) are selected and sensory bristles form into a regular pattern. SOP cell fate is determined by high Delta expression and following expression of neurogenic genes like neuralized. SOP selection is spatially and temporally regulated; however, the dynamic process of precise pattern formation is not clearly understood. RESULTS: In this study, using live-imaging analysis, we show that the appearance of neuralized-positive cells is random in both timing and position. Excess neuralized-positive cells are produced by developmental errors at several steps preceding and accompanying lateral inhibition. About 20% of the neuralized-positive cells show aberrant cell characteristics and high Notch activation, which not only suppress neural differentiation but also induce caspase-dependent cell death. These cells never develop into sensory organs, nor do they disturb bristle patterning. CONCLUSIONS: Our study reveals the incidence of developmental errors that produce excess neuralized-positive cells during sensory organ development. Notch activation in neuralized-positive cells determines aberrant cell fate and typically induces caspase-dependent cell death. Apoptosis is utilized as a mechanism to remove cells that start neural differentiation at aberrant positions and timing and to ensure robust spacing pattern formation. PMID- 21276726 TI - Intertissue mechanical stress affects Frizzled-mediated planar cell polarity in the Drosophila notum epidermis. AB - Frizzled/planar cell polarity (Fz/PCP) signaling controls the orientation of sensory bristles and cellular hairs (trichomes) along the anteroposterior axis of the Drosophila thorax (notum). A subset of the trichome-producing notum cells differentiate as "tendon cells," serving as attachment sites for the indirect flight muscles (IFMs) to the exoskeleton. Through the analysis of chascon (chas), a gene identified by its ability to disrupt Fz/PCP signaling under overexpression conditions, and jitterbug (jbug)/filamin, we show that maintenance of anteroposterior planar polarization requires the notum epithelia to balance mechanical stress generated by the attachment of the IFMs. chas is expressed in notum tendon cells, and its loss of function disturbs cellular orientation at and near the regions where IFMs attach to the epidermis. This effect is independent of the Fz/PCP and fat/dachsous systems. The chas phenotype arises during normal shortening of the IFMs and is suppressed by genetic ablation of the IFMs. chas acts through jbug/filamin and cooperates with MyosinII to modulate the mechanoresponse of notum tendon cells. These observations support the notion that the ability of epithelia to respond to mechanical stress generated by one or more interactions with other tissues during development and organogenesis influences the maintenance of its shape and PCP features. PMID- 21276727 TI - A kinetic comparison of asparagine synthetase isozymes from higher plants. AB - Four previously identified maize asparagine synthetase (AsnS) genes and a soy AsnS gene have been cloned and expressed in Escherichia coli. The enzymes have been purified and kinetically characterized. The plant AsnS proteins were expressed mainly in the inclusion bodies although small amounts of one form (ZmAsnS2) were recovered in the soluble fraction. In order to measure the kinetic properties of these enzymes a sensitive assay based on the detection of Asn by HPLC has been developed. In addition a method to refold the recombinant plant AsnS to produce active enzyme has been developed. The plant AsnS enzymes are kinetically distinct with substantial differences in K(m) (Gln) and V(max) values when compared to each other. These differences may be important factors for transgenic studies using AsnS genes for crop improvement. PMID- 21276728 TI - A model for morbidity after lung resection in octogenarians. AB - OBJECTIVE: Age is an important risk factor for morbidity after lung resection. This study was performed to identify specific risk factors for complications after lung resection in octogenarians. METHODS: A prospective database containing patients aged 80 years or older, who underwent lung resection at a single institution between January 2000 and June 2009, was reviewed. Preoperative, histopathologic, perioperative, and outcome variables were assessed. Morbidity was measured as a patient having any perioperative event as defined by the Society of Thoracic Surgeons General Thoracic Surgery Database. A multivariable risk model for morbidity was developed using a panel of established preoperative and operative variables. Survival was calculated using the Kaplan-Meier method. RESULTS: During the study period, 193 patients aged 80 years or older (median age 82 years) underwent lung resection: wedge resection in 77, segmentectomy in 13, lobectomy in 96, bilobectomy in four, and pneumonectomy in three. Resection was accomplished via thoracoscopy in 149 patients (77%). Operative mortality was 3.6% (seven patients) and morbidity was 46% (89 patients). A total of 181 (94%) patients were discharged directly home. Postoperative events included atrial arrhythmia in 38 patients (20%), prolonged air leak in 24 patients (12%), postoperative transfusion in 22 patients (11%), delirium in 16 patients (8%), need for bronchoscopy in 14 patients (7%), and pneumonia in 10 patients (5%). Significant predictors of morbidity by multivariable analysis included resection greater than wedge (odds ratio 2.98, p=0.006), thoracotomy as operative approach (odds ratio 2.6, p=0.03), and % predicted forced expiratory volume in 1s (odds ratio 1.28 for each 10% decrement, p=0.01). CONCLUSIONS: Octogenarians can undergo lung resection with low mortality. Extent of resection, use of a thoracotomy, and impaired lung function increase the risk of complications. Careful evaluation is necessary to select the most appropriate approach in octogenarians being considered for lung resection. PMID- 21276729 TI - Type 1 congenital pulmonary airway malformation with a partial anomalous pulmonary venous connection. PMID- 21276730 TI - Left ventriculoplasty for dilated cardiomyopathy in Fukuyama-type muscular dystrophy. AB - A 29-year-old man was hospitalized because of heart failure causing dilated cardiomyopathy (DCM). On admission, he had elevated creatinine kinase levels (hyper CKemia) (4283IUl-) and false enlargement of bilateral calves. By a muscular biopsy, he was diagnosed as Fukuyama-type muscular dystrophy. Although neuromuscular diseases are often related to cardiomyopathy, reports showing a relation between cardiomyopathy and Fukuyama-type muscular dystrophy have been rare. Our group performed the partial left venticulectomy of the posterior wall and approximation of the papillary muscle, mitral valve annuloplasty, and tricuspid valve annuloplasty for DCM in the patient with Fukuyama-type muscular dystrophy, after obtaining informed consent from the patient and his family. At the 1-year follow-up examination, the neuromuscular symptoms had not progressed, and the left ventricular function was improved (left ventricular end-diastolic dimension (LVDd) 77-66 mm, left ventricular end-systolic dimension (LVDs) 73-59 mm, and ejection fraction (EF) 26-30%). This is the first case report of a left ventriculoplasty in a patient with Fukuyama-type muscular dystrophy. PMID- 21276731 TI - Transabdominal subcostal approach in surgical management of Morgagni hernia. AB - OBJECTIVE: Morgagni hernia is an uncommon type of diaphragmatic hernias whose pathophysiology is not clear. We aimed to retrospectively evaluate morbidity, mortality, and treatment outcomes in 13 cases of Morgagni hernia treated with the subcostal approach. MATERIAL AND METHODS: Between 1993 and 2009, 13 patients with Morgagni hernia were operated in our department. Of the 13 patients with a median age of 65 years (range: 13-78), 12 were female. Chest roentgenograms, thorax computed tomography (CT), and barium enema roentgenographic studies were used as diagnostic utilities. The contents of the hernia, as diagnosed with CT and confirmed at surgery, were omentum and colon in all patients. RESULTS: All the patients were operated electively except one patient on ventilation treatment. Transabdominal repair with the subcostal approach was performed in all patients. There was no operative morbidity and mortality. The median hospital stay was 8 days (range: 6-14 days). There was no recurrence during the follow-up of 48.8 months (1-132 months). CONCLUSION: We recommend the transabdominal subcostal approach in patients with Morgagni hernia for surgical exposure, easy repair of the hernia sac, and low morbidity. PMID- 21276732 TI - Biomedical and psychological risk in cardiac surgery: is EuroSCORE a more comprehensive risk measure than Stroke Index? AB - OBJECTIVE: Several composite risk score indices, the most common being the Stroke Index and the European System for Cardiac Operative Risk Evaluation (EuroSCORE), have been developed to predict perioperative events such as cerebrovascular accidents or death. The main aim of the present study was to compare the preoperative associations between the Stroke Index or the EuroSCORE with anxiety, depression, memory, attention, and executive functions scores in patients undergoing cardiac surgery. METHODS: Ninety-one patients were required to perform a preoperative psychological evaluation. Trail Making Test A and B (TMT A/B), Memory with 10 and 30s interference, Digit Span Test, Phonemic Fluency, State and Trait Anxiety Inventory (STAI Y1/Y2), and Center for Epidemiological Study of Depression Scale (CES-D) were administered. The Stroke Index and the EuroSCORE were also considered for each patient. Correlations between the Stroke Index or the EuroSCORE, mood, and neuropsychological scores were performed. RESULTS: Seventy-seven patients completed the psychological evaluation. The Stroke Index was significantly correlated with TMT A (rho=0.40, p=0.001), TMT B (rho=0.38, p=0.001), Memory with 10s (rho=-0.34, p=0.003) and 30s (rho=-0.40, p=0.001) interference, and Phonemic Fluency (rho=-0.29, p=0.01), but not with Digit Span Test (rho=-0.18, p=0.13), STAI Y1 (rho=0.08, p=0.44), STAI Y2 (rho=0.06, p=0.56), and CES-D (rho=0.11, p=0.31) scores. The EuroSCORE was significantly correlated not only with TMT A (rho=0.49, p=0.001), TMT B (rho=0.42, p=0.001), Memory with 10s (rho=-0.23, p=0.04) and 30s (rho=-0.35, p=0.002) interference, Phonemic Fluency (rho=-0.28, p=0.01), and Digit Span Test (rho=-0.28, p=0.01) but also with STAI Y1 (rho=0.27, p=0.02), STAI Y2 (rho=0.23, p=0.04), and CES-D (rho=0.26, p=0.02). CONCLUSIONS: While both the Stroke Index and the EuroSCORE account for the relationship between biomedical and cognitive risk factors in predicting perioperative risk, only the EuroSCORE also accounts for affective dysfunctions, which, in turn, have been proved to represent risk factors for perioperative adverse events. Therefore, compared with the Stroke Index, the EuroSCORE can be considered a more complete risk index in predicting perioperative risk. Data also suggest that a comprehensive preoperative evaluation of biomedical, mood, and cognitive performances might provide a more accurate mirror of the actual risk in patients undergoing cardiac surgery. PMID- 21276733 TI - Editorial comment: Back to the future: chest physiotherapy comes full circle. PMID- 21276734 TI - Alternative paratracheal lymph node dissection in left-sided hilar lung cancer patients: comparing the number of lymph nodes dissected to the number of lymph nodes dissected in right-sided mediastinal dissections. AB - OBJECTIVE: Removing or sampling lymph nodes from the bilateral paratracheal area through a left thoracotomy is not a standard procedure in patients with lung cancer. The aim of this study was to evaluate the feasibility of a technique without ductus arteriosus division and mobilization of the aortic arch and to compare the number of lymph nodes resected in left-sided dissections to the number of lymph nodes removed in right-sided mediastinal dissections that are routinely performed in clinical practice. METHODS: A total of 93 patients with hilar lung cancer were evaluated. A prospective study was conducted on 51 patients with primary left-sided hilar lung cancer, who underwent left thoracotomy and paratracheal lymphadenectomy between January 2008 and January 2010. The number of nodes dissected in these patients was compared with the number of nodes dissected in 42 patients with right-sided hilar lung cancer by right-sided mediastinal dissection within the same period. RESULTS: The mean number of resected nodes in the bilateral paratracheal area via left thoracotomy was 8.4 (2-18 nodes). The distribution from 4R-4L-2L-2R was as follows: 3.3-2.5 0.5-2.1, respectively. Six patients (11.7%) were diagnosed with occult N2, and two (3.9%) of these patients also had N3 disease concomitantly. The number of dissected nodes from the ipsilateral station 2 via right-sided versus left-sided thoracotomy was 1.6 versus 0.5 (p=0.000), whereas the number of dissected nodes from ipsilateral station 4 via right-sided versus left-sided thoracotomy was 3.3 versus 2.5, respectively (p=0.1). The number of dissected nodes from the contralateral station 2 via right-sided versus left-sided thoracotomy was 0.2 versus 2.1 (p=0.000), whereas those numbers from the contralateral station 4 via right-sided versus left-sided thoracotomy were 1.0 versus 3.3, respectively (p=0.000). CONCLUSIONS: Lymphadenectomy of the paratracheal area via left thoracotomy without ductus arteriosus division and mobilization of the aortic arch is technically feasible. From these data, regardless of approach, more lymph nodes are obtained from the right paratracheal space; this appears to be due to the fact that there are more right-sided paratracheal lymph nodes. PMID- 21276735 TI - Perceptions of male knowledge and support among U.S. women obtaining abortions. AB - PURPOSE: At least one national study has shown that most women having abortions have consulted with male partners before terminating a pregnancy. However, little is known about the extent to which women perceive men to be supportive of their abortion decisions or which relationship characteristics are associated with male knowledge of and support for the abortion. METHODS: We used data from a nationally representative sample of 9,493 women obtaining abortions to examine perceptions of male knowledge and support for the abortion according to three relationship characteristics: Union status, length of relationship, and exposure to intimate partner violence (IPV). MAIN FINDINGS: The overwhelming majority of women reported that the men with whom they got pregnant knew about the abortion, and most perceived these men to be supportive. Cohabiting and, to a lesser extent, married women as well as those in longer relationships were more likely to report both of these outcomes, even after controlling for demographic characteristics. Exposure to IPV by the man involved in the pregnancy, reported by 7% of abortion patients, substantially reduced the likelihood that women perceived the men to know about or to be supportive of the abortion. CONCLUSION: Our results suggest that most women obtaining abortions are able to rely on male partners for social support. Education and counseling efforts that incorporate or reach out to male partners may increase support for women obtaining abortions. However, this strategy may not be appropriate for all women, especially those exposed to IPV. PMID- 21276736 TI - Alcohol use as a marker for risky sexual behaviors and biologically confirmed sexually transmitted infections among young adult African-American women. AB - INTRODUCTION: Previous research has primarily focused on the relationship between illicit drug use and HIV/sexually transmitted infection (STI) risk behavior among African-American women. Very few studies have solely reviewed the role of alcohol use on risky sexual behavior. The present study examined the relationship between alcohol use at non-abuse levels and risky sexual behaviors and STIs among young adult African-American women. METHODS: Eight hundred forty-eight African American women, ages 18 to 29, participated at baseline, with 669 and 673 women at 6 and 12 months follow-up, respectively. Participants completed an Audio Computer Assisted Survey Interview assessing sociodemographics, alcohol use, and risky sexual behaviors. Subsequently, participants provided two vaginal swab specimens for STIs. RESULTS: Multivariate logistic regression analyses were conducted for cross-sectional analyses, with illicit drug use as a covariate. Women who consumed alcohol were more likely to have multiple partners and risky partners. Binary generalized estimating equation models assessed the impact of alcohol use at baseline on risky sexual behavior and STIs over a 12-month period. Illicit drug use, intervention group, and baseline outcome measures were entered as covariates. Alcohol consumption predicted positive results for chlamydia, positive results for any STI, and never using a condom with a casual partner over a 12-month follow-up period. DISCUSSION: Frequency of alcohol use at non-abuse levels was correlated with and predicted risky sexual behaviors and STIs. Prevention programs for African-American women should incorporate education regarding the link between alcohol and HIV/STI risk behaviors and the potential negative health consequences. PMID- 21276737 TI - Heterogeneity of chronic lung allograft dysfunction: insights from protein expression in broncho alveolar lavage. AB - BACKGROUND: Chronic lung allograft dysfunction (CLAD) remains a major risk factor for death after lung transplantation. Previous data suggested that within CLAD at least 2 phenotypes are present: a neutrophilic type (nCLAD or neutrophilic reversible allograft dysfunction [NRAD]), reversible with azithromycin therapy, vs a low neutrophilic type, non-responsive to azithromycin (fibrotic bronchiolitis obliterans syndrome [fBOS]). We aimed to further characterize this dichotomy by measuring multiple proteins in the bronchoalveolar lavage (BAL) fluid of 28 lung recipients. METHODS: Patients were retrospectively subdivided by the absence or presence of CLAD and subsequently by their response to azithromycin, resulting in 3 groups: 10 stable, 9 responsive (nCLAD/NRAD), and 9 non-responsive (fBOS). Enzyme-linked immunosorbent assay was used to measure 32 different proteins. RESULTS: Protein variations were predominantly present in the nCLAD/NRAD group, whereas no differences were observed in the fBOS group compared with control. MCP-1 (p < 0.01), RANTES (p < 0.05), IL-1beta (p < 0.01), IL-8 (p < 0.01), TIMP-1 (p < 0.01), MMP-8 (p < 0.01), MMP-9 (p < 0.01), HGF (p < 0.001), MPO (p < 0.01), and bile acid (p < 0.05) concentrations were upregulated in nCLAD/NRAD compared with fBOS, whereas PDGF-AA (p < 0.05) was downregulated. CONCLUSIONS: These data provide further evidence that within CLAD there is a heterogeneity of phenotypes with different mechanisms involved. Further investigation is warranted to unravel the pathophysiology of both phenotypes. PMID- 21276738 TI - Patient-specific endovascular simulation influences interventionalists performing carotid artery stenting procedures. AB - OBJECTIVE: The ability to perform patient-specific simulated rehearsal of complex endovascular interventions is a technological advance with potential benefits to patient outcomes. This study aimed to evaluate whether patient-specific rehearsal of a carotid artery stenting (CAS) procedure has an influence on tool selection and the use of fluoroscopy. METHODS: Following case note and computed tomography (CT) angiographic review of a real patient case, subjects performed the CAS procedure on a virtual reality simulator. Endovascular tool requirements and fluoroscopic angles were evaluated with a pre- and post-case questionnaire. Participants also rated the simulation from 1 (poor) to 5 (excellent). RESULTS: Thirty-three endovascular physicians with varying degrees of CAS experience were recruited: inexperienced (5-20 CAS procedures) n = 11, moderately (21-50 CAS procedures) n = 7 or highly experienced (>50 CAS procedures) n = 15. For all participants, 96 of a possible 363 changes (26%) were observed from pre- to post case questionnaires. This was most notable for optimal fluoroscopy C-arm position 15/33 (46%), choice of selective catheter 13/33 (39%), choice of sheath or guiding catheter 11/33 (33%) and balloon dilatation strategy 10/33 (30%). Experience with the CAS procedure did not influence the degree of change significantly (p > 0.05), and all groups exhibited a considerable modification in tool and fluoroscopy preference. The model was considered realistic and useful as a tool to practice a real case (median score 4/5). CONCLUSION: Patient-specific simulated rehearsal of a complex endovascular procedure strongly influences tool selection and fluoroscopy preferences for the real case. Further research has to evaluate how this technology may transfer from in vitro to in vivo and if it can reduce the radiation dose and the number of endovascular tools used and improve outcomes for patients in the clinical setting. PMID- 21276739 TI - Prevalence of echocardiographic evidence of cardiac disease in apparently healthy cats with murmurs. AB - The objective of this prospective study was to determine the prevalence of echocardiographic evidence of heart disease in apparently healthy cats with heart murmurs. Thirty-two privately owned domestic cats were examined. All cats were considered healthy on the basis of history and physical examination, except for the finding of a heart murmur on auscultation. Cats on any medications (besides regular flea, tick and heartworm preventative) or that were pregnant or lactating were excluded from this study. The prevalence of echocardiographic evidence of heart disease in this population of cats was 53%. Therefore, identification of a heart murmur on routine physical examination in apparently healthy cats warrants further investigation. PMID- 21276740 TI - Ultrasonographic study of the feline sciatic nerve. AB - This study was conducted to describe the ultrasonographic appearance and technique for the evaluation of sciatic nerve (ScN) in cats. An anatomical study was carried out using six feline cadavers to determine anatomic landmarks. An ultrasonographic 'in vitro' study was performed using eight pelvic limbs from four fresh feline cadavers to assess the ScN in three regions (glutea, femoralis and popliteal) using a 4-13MHz linear transducer. Five healthy adult experimental cats were employed for an 'in vivo' ultrasonographic study of the ScN using the same protocol described for the 'in vitro' study. The ultrasonographic images of the ScN were well correlated with those obtained in the anatomical study. The ScN was easily identified in all the approaches. The ScN was observed as a hypoechoic structure with internal echoes, outlined by hyperechoic lines. This study shows the usefulness of ultrasound to evaluate the entire pathology of the ScN in the cat. PMID- 21276741 TI - Ultrasound-guided percutaneous surgery for carpal tunnel syndrome: a cadaver study. AB - OBJECTIVE: To assess the feasibility of ultrasound-guided surgery for carpal tunnel syndrome. METHOD: We first studied the ultrasound and anatomic findings in 30 cadaver wrists to determine the best surgical approach and the best plane for releasing the flexor retinaculum. We then used 104 cadaver wrists to assess the feasibility of our technique by performing the surgical procedure then extensively dissecting each wrist and hand. Our evaluation criteria were full release of the transverse carpal ligament and absence of injury to the vessels, nerves, and tendons. RESULTS: The transverse carpal ligament was fully released in all 104 forearms. Full release required a single pass in 61 forearms, two passes in 27 forearms, and three passes in 16 forearms. No injuries to adjacent structures were identified. CONCLUSIONS: Our cadaver study supports the feasibility of percutaneous surgery under ultrasound-guidance for carpal tunnel syndrome. PMID- 21276742 TI - Actuality of juvenile dermatomyositis. AB - Juvenile dermatomyositis is a rare disorder, but remains the most commonly occurring chronic inflammatory myopathy among children. Other than the proximal muscles and skin, which are routinely affected, vasculopathy may affect other viscera and can be multisystemic. A redefinition of the diagnostic criteria is currently underway and is likely to lead to other clinical signs and to sensitive and non-invasive examinations such as MRI. The impact of juvenile dermatomyositis on health and quality of life remains significant despite systemic corticosteroid therapy and immunosuppressor treatment, which have considerably improved the prognosis. Numerous predictors for favourable and pejorative evolution have been identified. The standardisation and the generalisation of clinical assessment tools will make it possible to carry out the clinical trials required to determine the relevance of the new therapeutic options available for children. PMID- 21276743 TI - Infantile digital fibromatosis: our experience and long-term results. AB - Infantile fibromatosis is an uncommon benign proliferation of myofibroblasts in the dermal tissue on the digits and toes with a marked tendency for recurrence. Inclusion bodies in the cytoplasm of neoplastic fibroblasts are a characteristic histologic feature of this condition. The tumor may often resolve spontaneously. There is very little written in the literature on this subject, with only a few or isolated cases having been described. We report our experience of seven cases of recurrent infantile fibromatosis that underwent surgical treatment. PMID- 21276744 TI - High-dimensional time irreversibility analysis of human interbeat intervals. AB - Time irreversibility is a subject of increasing interest in biomedicine. However, measurements of this property have been limited to a two-dimensional state space and few effective methods for high-dimensional time irreversibility testing have been reported. Using a strategy based on multiple bidimensional tests, we propose an extension of the traditional low-dimensional method for the estimation of time irreversibility in a high-dimensional state space. The method is applied to both physiological and synthetic interbeat (RR) intervals and the results indicate that time irreversibility should be an intrinsic characteristic of human RR intervals and is complementary to the conventional properties that can be measured in the time and frequency domain. Furthermore, a loss of time irreversibility is detected when the method is applied to patients with congestive heart failure (CHF). Compared with the traditional time irreversibility test, the proposed method is not only capable of quantifying time irreversibility in a more reliable manner, but is also effective for analysis of short records of only a few minutes' length, which would be more useful clinically. PMID- 21276745 TI - Acute effects of bilateral subthalamic stimulation on decision-making in Parkinson's disease. AB - BACKGROUND: Pathological gambling can develop in Parkinson's disease (PD), and impairment of decision-making may play an important role in the mechanism. To assess acute effects of bilateral subthalamic nucleus deep brain stimulation (STN DBS) on decision-making, patients with PD who were eligible for STN-DBS were evaluated using the Iowa Gambling Task (IGT). METHODS: The study participants were 16 patients with PD who underwent bilateral STN-DBS, and 16 age-matched control patients with PD. The participants performed the IGT pre-operatively and 2-4 weeks post-operatively with on- and off-stimulation. Participants' one hundred card selections were divided into five blocks of 20 cards each. RESULTS: The total IGT score was not significantly different before surgery, on stimulation or off-stimulation, but DBS patients tended to perform worse in the on-DBS session compared to off-DBS session (P = 0.019) only in the last block of the task. The IGT score did not correlate with levodopa equivalent dose or performance on the measures of executive function, but did correlate with self reported depression symptoms, and active contact of stimulation. CONCLUSION: Bilateral STN-DBS may affect decision-making in acute post-operative stage. PMID- 21276746 TI - Chemical modification in the creation of novel biocatalysts. AB - Enzymes are able to perform a multitude of chemical and biochemical transformations with efficiencies that are typically unrivalled by chemical catalysts. However, these evolved systems may lack breadth or utility in other non-natural applications. Altering enzyme and protein scaffolds through covalent modification can expand the usefulness of native biocatalysts not only for synthetic application but also for therapeutic use. This review summarizes recent developments in the field of chemical modification of enzymes and how they can be applied to synthesis and biological research. PMID- 21276747 TI - Comment on "Effect of CC chemokine ligand 5 and CC chemokine receptor 5 genes polymorphisms on the risk and clinicopathological development of oral cancer" by Weng et al., Oral Oncol 46 (2010) 767-772. PMID- 21276748 TI - Myelin sheath: a new possible role in sleep mechanism. PMID- 21276749 TI - ICEVchInd5 is prevalent in epidemic Vibrio cholerae O1 El Tor strains isolated in India. AB - Integrative conjugative elements (ICEs) of the SXT/R391 family are self transmissible mobile elements mainly involved in antibiotic resistance spread among gamma-Proteobacteria, including Vibrio cholerae. We demonstrated that the recently described ICEVchInd5 is prevailing in V. cholerae O1 clinical strains isolated in Wardha province (Maharashtra, India) from 1994 to 2005. Genetic characterization by ribotyping and multiple-locus SSR analysis proved the same clonal origin for V. cholerae O1 isolates in Wardha province over an 11-year period and was used to assess the correlation between strain and ICE content among ours and different Indian reference strains. In silico analysis showed the existence of at least 3 sibling ICEs of ICEVchInd5 in V. cholerae O1 El Tor reference strains, isolated in the Indian subcontinent after 1992. PMID- 21276750 TI - Detection of bacterial pathogens in Mongolia meningitis surveillance with a new real-time PCR assay to detect Haemophilus influenzae. AB - Since the implementation of Haemophilus influenzae (Hi) serotype b vaccine, other serotypes and non-typeable strains have taken on greater importance as a cause of Hi diseases. A rapid and accurate method is needed to detect all Hi regardless of the encapsulation status. We developed 2 real-time PCR (rt-PCR) assays to detect specific regions of the protein D gene (hpd). Both hpd assays are very specific and sensitive for detection of Hi. Of the 63 non-Hi isolates representing 21 bacterial species, none was detected by the hpd #1 assay, and only one of 2 H. aphrophilus isolates was detected by the hpd #3 assay. The hpd #1 and #3 assays detected 97% (229/237) and 99% (234/237) of Hi isolates, respectively, and were superior for detection of both typeable and non-typeable Hi isolates, as compared to previously developed rt-PCR targeting ompP2 or bexA. The diagnostic sensitivity and specificity of these rt-PCR assays were assessed on cerebrospinal fluid specimens collected as part of meningitis surveillance in Ulaanbaatar, Mongolia. The etiology (Neisseria meningitidis, Hi, and Streptococcus pneumoniae) of 111 suspected meningitis cases was determined by conventional methods (culture and latex agglutination), previously developed rt-PCR assays, and the new hpd assays. The rt-PCR assays were more sensitive for detection of meningitis pathogens than other classical methods and improved detection from 50% (56/111) to 75% (83/111). The hpd #3 assay identified a non-b Hi that was missed by the bexA assay and other methods. A sensitive rt-PCR assay to detect both typeable and non-typeable Hi is a useful tool for improving Hi disease surveillance especially after Hib vaccine introduction. PMID- 21276751 TI - Gender and age affect balance performance in primary school-aged children. AB - OBJECTIVES: Compromised stability may hinder a child's ability to master fundamental movement skills and, in turn, the capacity to participate in sporting activities. Therefore, the aim of this study was to investigate postural stability of primary school-aged children and to determine how this was moderated by age and gender. DESIGN: Cross-sectional. METHOD: Static posturography of primary school-aged boys (n=37) and girls (n=47) was assessed while the children were standing feet apart, feet together and in single limb stances for 30s. RESULTS: The boys displayed greater sway than the girls for all conditions, although only the single limb stance scores were significantly different between the two groups (boys: 632+/-323 mm; girls: 456+/-338 mm; p=0.04). Eight-year-old children displayed significantly greater sway than the older children during the two dual limb stance conditions, whereas the 8-year-old children performed significantly poorer during the single limb condition than the 10-year-old children. CONCLUSIONS: This study shows that when postural stability was challenged, boys displayed greater postural sway than girls and, although proficiency in performing dual limb balance tasks appeared achievable by the time children are 9-years of age; the more difficult single limb balance task required a further 12 months to develop. As balance is important for movement skill development and injury prevention, care should be taken to ensure movement tasks are appropriately designed for boys and girls of different ages. PMID- 21276752 TI - Are Active Australia physical activity questions valid for older adults? AB - OBJECTIVE: The Active Australia Survey (AAS) is used for physical activity (PA) surveillance in the general Australian adult population, but its validity in older adults has not been evaluated. Our aim was to examine the convergent validity of the AAS questions in older adults. DESIGN: The AAS was validated against pedometer step counts as an objective measure of PA, self-reported physical function, and a step-test to assess cardiorespiratory fitness. METHOD: Participants were community-dwelling adults, aged 65-89 y, with the ability to walk 100 m. They completed a self-administered AAS and the step-test in one interview. One week earlier, they completed the Short Form-36 physical function subscale. Between these two interviews, they each wore a YAMAX Digiwalker SW200 pedometer and recorded daily steps. Using the AAS data, daily walking minutes and total PA minutes (walking, moderate-intensity PA and vigorous-intensity PA) were compared with the validity measures using Spearman rank-order correlations. Fifty three adults completed the study. RESULTS: Median daily walking minutes were 34.2 (interquartile range [IQR] 17.1, 60.0), and median daily total PA minutes were 68.6 (IQR 31.4, 113.6). Walking and total PA minutes were both moderately correlated with pedometer steps (Spearman correlation r=0.42, p=0.003, for each) but not with step-test seconds to completion (r=-0.11, p=0.44; r=-0.25, p=0.08, respectively). Total PA minutes were significantly correlated with physical function scores (r=0.39, p=0.004), but walking minutes were not (r=0.15, p=0.29). CONCLUSIONS: This initial examination of the psychometric properties of the AAS for older adults suggests that this surveillance tool has acceptable convergent validity for ambulatory, community-dwelling older adults. PMID- 21276753 TI - Virtual histology: a window to the heart of atherosclerosis. AB - Intravascular ultrasound has done much to improve our understanding of atherosclerosis and the impact of percutaneous intervention on the coronary artery. However, subjectivity in interpreting the acoustic reflection of the ultrasound signal has spawned the development of other progressive technologies. Virtual histology intravascular ultrasound (VHIVUS) utilises the ultrasound backscatter signal in order to colour code plaque into four pre-specified subtypes based on their histological composition. We review the background behind traditional grey scale intravascular ultrasound (IVUS) and examine the current evidence for VHIVUS and its potential for use in clinical interventional practice. PMID- 21276754 TI - Management of uncommon chemotherapy-induced emergencies. AB - Chemotherapy can induce various clinical emergencies. Prompt recognition and management of these adverse events are important for avoiding further morbidity and mortality. Some events such as hypersensitivity and extravasation are quite common, whereas emergencies such as neutropenic typhlitis, pancreatitis, and acute haemolysis are very rare. Little information exists on the management of rare chemotherapy-induced emergencies that affect fewer than 1% of patients. We review these uncommon chemotherapy-induced life-threatening emergencies, their pathogenesis and management, and recommendations for rechallenge with the offending chemotherapy. PMID- 21276755 TI - Correlates of dietary intake in youth with diabetes: results from the SEARCH for diabetes in youth study. AB - OBJECTIVE: To explore demographic, socioeconomic, diabetes-related, and behavioral correlates of dietary intake of dairy, fruit, vegetables, sweetened soda, fiber, calcium, and saturated fat in youth with diabetes. METHODS: Cross sectional study of youth 10-22 years old with type 1 (T1DM, n = 2,176) and type 2 diabetes (T2DM, n = 365). Association of dietary intake, demographics, socioeconomic status, behavioral, and diabetes-related measures was explored with quantile regression. RESULTS: T1DM males had lower consumption of vegetables, fruit, and fiber, and higher consumption of soda and saturated fat than females (P < .01). African Americans had lower dairy and higher soda intake than non Hispanic T1DM whites (P < .01). Soda consumption was higher in older T2DM youth than in younger participants (P < .01). Lifestyle and physical activity patterns were also significantly associated with dietary intake. CONCLUSIONS AND IMPLICATIONS: Identified demographic and behavioral correlates may help dietitians to focus on groups of youth with diabetes who have lower adherence to a healthful diet. Diet counseling groups may be tailored according to these major determinants. PMID- 21276756 TI - B lymphocytes are resistant to death receptor 5-induced apoptosis. AB - Death Receptor 5 (DR5) induces apoptosis in various types of cells and is a potential therapeutic target. We have investigated whether targeting DR5 could be used to eliminate pathogenic B lymphocytes from systemic lupus erythematosus (SLE) patients. We examined DR5 expression and function on B lymphocytes from healthy controls subjects, SLE patients, and human tonsil. DR5 was expressed similarly on all B cell subpopulations, including resting and activated B cells. Expression of DR5 was equivalent on B cells from SLE patients and healthy subjects. Additionally, DR5 expression was unchanged after B lymphocyte stimulation. However, B cells were resistant to DR5-induced apoptosis, including after in vitro activation. No changes in subsets of B cells were observed in subjects of a trial of CS-1008, an agonist anti-DR5. While DR5 shows promise as a way to selectively eliminate tumor cells and activated synoviocytes, these data suggest DR5 alone cannot be used as a target to remove pathogenic SLE B cells. PMID- 21276757 TI - Intermittent rhythmic delta activity patterns. AB - Intermittent rhythmic delta activity is a typical EEG pattern that was originally described by W.A. Cobb in 1945 (J Neurol Neurosurg Psychiatr 1945;8:65-78). It may be classified into three distinct forms according to the main cortical region involved on the EEG: frontal (FIRDA), temporal (TIRDA), and occipital (OIRDA) intermittent delta activity. This article is a review of the main aspects of these patterns, with a special focus on EEG features and problems that may be encountered during interpretation of these patterns. In contrast to FIRDA and OIRDA, TIRDA is highly indicative of ipsilateral pathology. OIRDA and TIRDA are highly correlated with epilepsy, whereas FIRDA is a rather nonspecific EEG pattern. PMID- 21276758 TI - An analysis of global research funding for the frontotemporal dementias: 1998 2008. AB - BACKGROUND: To better understand the status of frontotemporal dementia (FTD) research, and identify opportunities to accelerate translational research, we analyzed international funding for FTD and related dementias between 1998 and 2008. METHODS: Search terms were compiled to define the clinical spectrum of FTD and all known mechanisms. Funders were asked to return grants that contained these search terms in the title or abstract. Grants were classified according to the most reasonably achieved stated aim using a classification scheme of research activities that was developed to map grants along the continuum from basic research to clinical trials of treatments. RESULTS: This analysis captured 613 grants ($432,167,275), from 19 private and public funders from 7 countries and the European Union. National Institutes of Health contributed $360 million (MM), 53% of grants and 83% of total funding. Foundations contributed $43 MM, 35% of grants and 10% of total funding, an increase in recent years. A total of $319 MM (74%, funding) went toward basic research, of which 10% was dedicated to preclinical treatment development, clinical treatment evaluation, and developing detection, diagnostic, and imaging technologies and reagents. CONCLUSIONS: FTD received moderate funding over the past decade, which has decreased almost five fold during this period. A sizable proportion of FTD funding supported mechanisms shared with Alzheimer's disease. Few programs advanced past validating target models and into drug discovery and preclinical development, indicating that the knowledge gained from recent research has still not advanced into treatment development. Quantitative analysis of funding highlighted under-resourced areas as well as redundant efforts, enabling a more strategic approach toward advancing FTD drug discovery and development. PMID- 21276759 TI - Height of female Americans in the 19th century and the antebellum puzzle. AB - Using 19th century state prison records, this study contrasts the biological standard of living of comparable US African-American and white females during a period of relatively rapid economic development. White females were consistently taller than black females by about 1.5 cm (0.6 in.). Whites from Great Lakes and Plains states and black Southwestern females were the tallest. US females were tall compared to their European counterparts. The height of females began to decline in the antebellum period, possibly before that of males. The recovery of physical stature was also earlier among females than among males. This implies that the biological standard of lower-class men and women did not move in parallel during the onset of modern economic growth. It also implies that the antebellum puzzle was most likely rooted in the endogenous forces of socio economic change rather than the exogenous changes in the disease environment. PMID- 21276760 TI - Treatment of chronic hepatitis B: update of the recommendations from the 2007 Italian Workshop. AB - The Italian recommendations for the therapy of hepatitis B virus (HBV)-related disease were issued in 2008. Subsequently in 2008 the nucleotide analogue (NA) Tenofovir was approved for antiviral treatment. The introduction of this important new drug has called for the current guidelines update, which includes some additional revisions: (a) the indication for therapy is extended to mild liver fibrosis and the indication for treatment is graded as "possible", "optional" or "mandatory" according to the fibrosis stage; (b) two different treatment strategies are described: first line definite duration treatment with interferon, long-term treatment of indefinite duration with NA; (c) the indication to follow either strategy is also based on the stage of liver fibrosis; (d) virological monitoring is modified to include the definitions of failure and of sustained virological response to interferon therapy; (e) the recommendation to use HBV DNA assays with high sensitivity and wide linear ranges is underlined (f) guidelines on post-treatment follow-up after finite treatment with NA, potential side effects of therapy and non-virological monitoring are defined; (g) definitions and treatment of patients without optimal response to NA are reported; (f) treatment and monitoring of compensated or decompensated cirrhosis and hepatocellular carcinoma are updated. PMID- 21276761 TI - Meta-analysis of the heterogeneity of X chromosome inactivation in human pluripotent stem cells. AB - In mammals, X chromosome inactivation (XCI) is a process in which one of the two X chromosomes is silenced, following XIST expression. Mouse female pluripotent stem cells do not express Xist, and harbor two active X chromosomes. However, analysis of XCI in human embryonic stem cells (hESCs), mainly based on XIST expression, was not conclusive. Here, we studied XCI in hESCs by meta-analysis of the expression of the entire set of genes on the X chromosome in 21 female hESC lines. Thus, we could divide the ES cell lines into three categories: lines with no XCI, lines with full XCI, and lines with partial XCI. The partial inactivation of the X chromosome always involved the middle of the chromosome, surrounding the XIST transcription site. The status of XCI in some of the cell lines was validated by either allelic-specific expression or DNA methylation analysis. Interestingly, analysis of 10 female human-induced pluripotent stem cell (hiPSC) lines demonstrated similar heterogeneity in the inactivation of X chromosome and could also be classified into the same three categories detected in hESCs. Thus, we could show that in some hiPSC lines, the X chromosome was activated on reprogramming. Based on our analysis, we propose a model of the dynamics of XCI in pluripotent stem cells. PMID- 21276762 TI - Outcome of day-case laparoscopic fundoplication for gastro-esophageal reflux disease. AB - AIM: To assess the acceptability, feasibility and results of day-case laparoscopic fundoplication for gastro-esophageal reflux disease (GERD) in an university tertiary care center. METHODS: Day-case surgery for GERD was proposed routinely to all patients with proven asymptomatic, uncomplicated GERD fulfilling predetermined inclusion criteria from September 2003 and January 2007. All patients underwent standard anesthetic, surgical, analgesic and antiemetic protocols. Patients had a 360 degrees Nissen-Rosetti laparoscopic fundoplication. Evaluation, according to intent-to-treat analysis, included inclusion criteria, admission to conventional hospital facilities, unplanned post operative consultation or readmission, complication and reoperation rates as well as patient satisfaction at 12 months, using the validated Visick score and Gastro Intestinal Quality of Life Index (GIQLI) questionnaire. RESULTS: Of 152 patients undergoing laparoscopic fundoplication for GERD during the study period, 49 (32.2%) had day-case procedures. Forty patients (81.6%) were discharged 6 to 8h after operation. Nine patients were converted to in-patient hospitalization because of nausea (n=5), inadequate pain control (n=3) or anxiety (n=1), seven (77.8%) of these were discharged within 23h. Unplanned consultation or hospitalization was necessary in 14.3% and 4.1% of cases respectively, mainly for dysphagia. The postoperative complication rate was 6.1%. At 12 months, 89.6% of patients were Visick 1 to 3 (excellent to satisfactory results). Reoperation was needed in three cases. Patient quality of life, evaluated by GIQLI, was significantly enhanced by surgery (88.9+/-27.3 preoperatively versus 111.2+/-24.0 postoperatively, P<0.001). CONCLUSIONS: Day-case laparoscopic fundoplication for GERD is feasible and well tolerated in selected patients. PMID- 21276763 TI - Unusual cause should be kept in mind of abdominal pain in female patient. Fitz Hugh-Curtis syndrome. PMID- 21276764 TI - A pancreatic mass in a patient with nausea and vomiting. Extrapulmonary small cell carcinoma of the pancreas. PMID- 21276765 TI - A patient with Crohn's disease and portal hypertension. Nodular regenerative hyperplasia. PMID- 21276766 TI - NEMO catches the FOX. PMID- 21276767 TI - Stretching the limits in Crohn's disease. PMID- 21276768 TI - Release on demand: Artificial insemination by ovulation-triggered release of implanted sperms. PMID- 21276769 TI - Molecular imaging of c-Met tyrosine kinase activity. AB - The receptor tyrosine kinase c-Met and its ligand, hepatocyte growth factor/scatter factor (HGF/SF), modulate signaling cascades implicated in cellular proliferation, survival, migration, invasion, and angiogenesis. Therefore, dysregulation of HGF/c-Met signaling can compromise the cellular capacity to moderate these activities and can lead to tumorigenesis, metastasis, and therapeutic resistance in various human malignancies. To facilitate studies investigating HGF/c-Met receptor coupling or c-Met signaling events in real time and in living cells and animals, here we describe a genetically engineered reporter where bioluminescence can be used as a surrogate for c-Met tyrosine kinase activity. c-Met kinase activity in cultured cells and tumor xenografts was monitored quantitatively and dynamically in response to the activation or inhibition of the HGF/c-Met signaling pathway. Treatment of tumor-bearing animals with a c-Met inhibitor and the HGF neutralizing antibody stimulated the reporter's bioluminescence activity in a dose-dependent manner and led to a regression of U-87 MG tumor xenografts. Results obtained from these studies provide unique insights into the pharmacokinetics and pharmacodynamics of agents that modulate c-Met activity and validate c-Met as a target for human glioblastoma therapy. PMID- 21276770 TI - Induction of integrin beta3 in PGE2-stimulated adhesion of mastocytoma P-815 cells to the Arg-Gly-Asp-enriched fragment of fibronectin. AB - We previously demonstrated that prostaglandin (PG) E2 stimulates adhesion of mastocytoma P-815 cells (P-815 cells) to the Arg-Gly-Asp (RGD)-enriched matrix via the PGE2 receptor subtype EP4 [Hatae N, Kita A, Tanaka S, Sugimoto Y, Ichikawa A. Induction of adherent activity in mastocytoma P-815 cells by the cooperation of two prostaglandin E2 receptor subtypes, EP3 and EP4. J Biol Chem 2003;278:17977-81]. Here we investigated the role of various integrin subtypes in the induction of adherent activity in PGE(2)-stimulated P-815 cells. FACS analysis showed that P-815 cells express high levels of integrin alpha4, alpha5, beta1 and beta2 subunits and moderate levels of integrin alphaIIb, alphav, beta3 and beta7 subunits. When treated with PGE2, the EP4 agonist ONO-AE1-329 or the cell permeable cAMP analogue, 8-Br-cAMP, P-815 cells showed markedly increased cell surface expression of integrin alphaIIb, alphav and beta3 subunits, and these expressions were significantly reduced by addition of the protein synthesis inhibitor cycloheximide. Along with increased cell surface expression, mRNA and protein levels of the integrin beta3 subunit, but not of integrin alphaIIb and alphav subunits, were simultaneously elevated. On the other hand, adhesion of P 815 cells in response to PGE2 or 8-Br-cAMP was abolished by antibodies specific for integrin alphav and beta3 subunits, but not by antibodies for integrin alpha4, alpha5, beta1, beta2 and beta7 subunits. Moreover, treatment with tirofiban, an integrin alphaIIbbeta3 antagonist, or eptifibatide, an integrin alphavbeta3/alphaIIbbeta3 antagonist resulted in a decrease in adhesion of P-815 cells in response to PGE2 or 8-Br-cAMP. These results suggest that de novo synthesis of the integrin beta3 subunit plays a pivotal role in PGE2-induced adhesion of P-815 cells to the RGD-enriched matrix through EP4-mediated cAMP signaling. PMID- 21276771 TI - Lack of association between protocadherin 11-X/Y (PCDH11X and PCDH11Y) polymorphisms and late onset Alzheimer's disease. AB - A recent genome-wide association study (GWA) reported a significant association between single nucleotide polymorphisms (SNPs) at the PCDH11X gene and late-onset Alzheimer's disease (LOAD). Our research was designated to replicate this association, including non previously analyzed PCDH11X and PCDH11Y SNPs. We genotyped four PCDH11X and one PCDH11Y SNPs in a total of 420 LOAD patients and 350 healthy controls from Spain. Allele and genotype frequencies did not differ between patients and controls for the five SNPs, even after correcting by gender, age, and APOE-epsilon4 status. Our data were in agreement with recent reports that failed to confirm the association between PCDH11X polymorphisms and LOAD, and extended the lack of association to common PCDH11Y variants. PMID- 21276772 TI - Chronic stress-induced changes in REM sleep on theta oscillations in the rat hippocampus and amygdala. AB - The present study investigated the effect of Chronic Immobilization Stress (CIS) on theta oscillations in the hippocampus and amygdala during Rapid Eye Movement (REM) sleep. Adult male Wistar rats were subjected to 2h of CIS daily for 10days. Polysomnographic recordings with electroencephalogram (EEG) from hippocampus (CA3 and CA1 subregion) and lateral nucleus of amygdala (LA) were carried out after termination of CIS protocol on the 7th, 14th and 21st day. The results showed a bimodal distribution on the total REM sleep duration in CIS rats: group of rats exhibited increased REM sleep duration considered as a stress-enhanced REM (SER) and rats with reduced REM sleep as stress-reduced REM sleep (SRR) group. The bimodal distribution in REM sleep was continued to exhibit even after 21 days of termination of stress, showing increased REM sleep in SER and reversible REM sleep in SRR rats. In addition to changes in sleep, increased REM sleep in SER rats was associated with attenuated theta activity in the hippocampus and amygdala, while the SRR rats did not show attenuated theta activities during the stress recovery period. Thus, the study demonstrates the dependence of synchronized amygdalo-hippocampal theta activity with the CIS-induced enhanced REM sleep duration. This raises the possibility that CIS-induced manifestations of the anxiety may be associated with synchronized theta oscillations in the hippocampus and amygdala. PMID- 21276773 TI - Degeneration of mesencephalic dopaminergic neurons in klotho mouse related to vitamin D exposure. AB - Parkinson's disease (PD), which is characterized by degeneration of mesencephalic dopaminergic neurons of unclear etiology, is primarily an age-related neurodegenerative disorder, while the normal process of aging is also known to decrease the number of dopaminergic neurons in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA). However, no consensus exists regarding how advancing age may predispose the dopaminergic system to PD. The Klotho-insufficient (klotho) mouse exhibits a syndrome that resembles human aging. Recent studies have revealed that abnormal activation of vitamin D is the major cause of this phenotype. In this study, we examined mesencephalic dopaminergic neurons of klotho mice and identified tyrosine hydroxylase-positive neurons in the SNc and VTA, and found that levels of striatal dopamine were significantly decreased with aging in klotho mice. Notably, these phenotypes were rescued by vitamin D restriction, suggesting that abnormal activation of vitamin D due to Klotho insufficiency leads to degeneration of the dopaminergic system. The present study provides new insights into the pathology of age-related degeneration of dopaminergic neurons possibly related to Klotho-mediated regulation of vitamin D. PMID- 21276774 TI - Sensory experience selectively regulates transmitter synthesis enzymes in interglomerular circuits. AB - Sensory experience influences brain organization and function. A particularly striking example is in the olfactory bulb where reduction of odorant sensory signals profoundly down-regulates dopamine in glomerular neurons. There are two large populations of glomerular inhibitory interneurons: (1) GABAergic periglomerular (PG) cells, whose processes are limited to a single glomerulus, regulate intraglomerular processing and (2) DAergic-GABAergic short axon (SA) cells, whose processes contact multiple glomeruli, regulate interglomerular processing. The inhibitory neurotransmitter GABA is synthesized from L-glutamic acid by the enzyme glutamic acid decarboxylase (GAD) of which there are two major isoforms: GAD65 and GAD67. GAD65 is expressed in uniglomerular PG cells. GAD67 is expressed by SA cells, which also co-express the rate-limiting enzyme for dopamine synthesis, tyrosine hydroxylase (TH). Deafferentation or sensory deprivation decreases TH expression but it is not known if sensory input alters GAD isoforms. Here we report that either deafferentation or reduction of sensory input by nares occlusion significantly reduced GAD67 protein and the number of SA cells expressing GAD67. However, neither manipulation altered GAD65 protein or the number of GAD65 PG cells. These findings show that sensory experience strongly impacts transmitter regulation in the circuit that controls neural processing across glomeruli but not in the circuit that regulates intraglomerular processing. PMID- 21276775 TI - MicroRNAs 144, 145, and 214 are down-regulated in primary neurons responding to sciatic nerve transection. AB - MicroRNAs (miRNAs) play an important role in the development, differentiation, proliferation, survival, and oncogenesis of cells and organisms including nervous system. However, the role of miRNAs in primary neurons of dorsal root ganglion (DRG) after injury was not clear. In this study, a miRNA microarray analysis was performed, and a total of 21 miRNAs were found to be down-regulated following unilateral sciatic nerve transection. The miR-144, miR-145, and miR-214 were further validated using quantitative reverse transcriptase PCR (qRT-PCR). Moreover, in situ hybridization (ISH) experiments using locked nucleic acid (LNA) modified DNA oligonucleotide probes verified that miR-144, miR-145, and miR-214 were expressed in primary neurons of DRG and down-regulated following sciatic nerve transection. Predictions of potential miRNA targets involved were identified by performing a bioinformatics analysis. These predictions were tested using miRNA luciferase reporter vectors, with Robo2 and srGAP2 evaluated as the potential targets of miR-145 and miR-214, respectively. The role of miR-145 in cultured primary neurons was also investigated, and the result found that miR-145 miR-145 inhibited neurite growth and down-regulated Robo2 expression. Finding from this study suggested that miRNAs of DRG can mediated the course of regeneration including through Slit-Robo-srGAP signaling pathway after injury. PMID- 21276776 TI - Combined contribution of tactile and proprioceptive feedback to hand movement perception. AB - Here we investigated how the tactile modality is used along with muscle proprioception in hand movement perception, whether these two sensory inputs are centrally integrated and whether they work complementarily or concurrently. The illusory right hand rotations induced in eleven volunteers by a textured disk scrolling under their hand in two directions at three velocities and/or by mechanical vibration applied to their wrist muscles at three frequencies were compared. The kinesthetic illusions were copied by the subjects on-line with their left hand. RESULTS: 1) in all the subjects, tactile stimulation alone induced an illusory hand rotation in the opposite direction to that of the disk, and the velocity of the illusion increased non-linearly with the disk velocity: the highest gain (the illusion velocity to disk velocity ratio) occurred at the slowest disk rotation; 2) adding a consistent proprioceptive stimulus increased the perceptual effects, whereas adding a conflicting proprioceptive stimulus of increasing frequency gradually decreased the tactile illusions and reversed their initial direction; 3) under both consistent and conflicting conditions, only strong proprioceptive stimulation significantly affected the gain of the resulting illusions, whereas the largest gain always occurred at low tactile stimulation levels when the illusory movements were in the same direction as the tactile-induced illusion. Tactile information may equal or even override muscle proprioceptive information in the perception of relatively small, slow hand movements. These two somatosensory inputs may be integrated complementarily, depending on their respective relevance to the task of accurately perceiving one's own hand movements. PMID- 21276777 TI - Aldose reductase (AKR1B3) regulates the accumulation of advanced glycosylation end products (AGEs) and the expression of AGE receptor (RAGE). AB - Diabetes results in enhanced chemical modification of proteins by advanced lipoxidation end products (ALEs) and advanced glycation end products (AGEs) precursors. These modifications have been linked to the development of several secondary diabetic complications. Our previous studies showed that aldose reductase (AR; AKR1B3) catalyzes the reduction of ALEs and AGEs precursors; however, the in vivo significance of this metabolic pathway during diabetes and obesity has not been fully assessed. Therefore we examined the role of AR in regulating ALEs and AGEs formation in murine models of diet-induced obesity and streptozotocin-induced diabetes. In comparison with wild-type (WT) and AR-null mice fed normal chow, mice fed a high-fat (HF) diet (42% kcal fat) showed increased accumulation of AGEs and protein-acrolein adducts in the plasma. AGEs and acrolein adducts were also increased in the epididymal fat of WT and AR-null mice fed a HF diet. Deletion of AR increased the accumulation of 4-hydroxy-trans 2-nonenal (HNE) protein adduct in the plasma and increased the expression of the AGE receptor (RAGE) in HF fed mice. No change in AGEs formation was observed in the kidneys of HF-fed mice. In comparison, renal tissue from AR-null mice treated with streptozotocin showed greater AGE accumulation than streptozotocin-treated WT mice. These data indicated that AR regulated the accumulation of lipid peroxidation derived aldehydes and AGEs under conditions of severe, but not mild, hyperglycemia and that deletion of AR increased RAGE-induction via mechanisms that were independent of AGEs accumulation. PMID- 21276778 TI - Novel alkenal/one reductase activity of yeast NADPH:quinone reductase Zta1p. Prospect of the functional role for the zeta-crystallin family. AB - zeta-Crystallins are a Zn(2+)-lacking enzyme group with quinone reductase activity, which belongs to the medium-chain dehydrogenase/reductase superfamily. It has been recently observed that human zeta-crystallin is capable of reducing the alpha,beta-double bond of alkenals and alkenones. Here we report that this activity is also shared by the homologous Zta1p enzyme from Saccharomyces cerevisiae. While the two enzymes show similar substrate specificity, human zeta crystallin exhibits higher activity with lipid peroxidation products and Zta1p is more active with cinnamaldehyde. The presence of Zta1p has an in vivo protective effect on yeast strains exposed to the toxic substrate 3-penten-2-one. Analysis of ZTA1 gene expression indicates an induction under different types of cellular stress, including ethanol and dimethylsulfoxide exposure and by reaching the stationary growth phase. The role of Zta1p in the yeast adaptation to some stress types and the general functional significance of zeta-crystallins are discussed. PMID- 21276779 TI - Water-restraint stress enhances methamphetamine-induced cardiotoxicity. AB - Methamphetamine (MAP) and stress both cause a variety of cardiovascular problems. Stress also increases stimulant drug-seeking or drug-taking behavior by both humans and animals. In addition to the physiological effects on circulation, metabolism, and excretion, stress affects subject's responses to stimulant drugs such as MAP. However, the mechanisms underlying the drug-stress interactions remain unknown. In the present study, we assessed the effects of stress on myocardial responses to MAP in mice. Mice were injected with MAP (30mg/kg) immediately before exposure to water-restraint stress (WRS), which has often been used as a stressor in animal experiments. The combination of MAP with WRS produced a significant increase (p<0.01) in the leakage of proteins specific to myocardial damage and the levels of cytokines IL-6, TNF-alpha, and IL-10. The histological findings indicated the possibility that a combination of MAP with WRS induced cardiac myocytolysis. We also examined the expression of heat shock proteins (Hsps), which have cardioprotective effects. Administration of MAP alone significantly stimulated the RNA expressions of Hsp32, 60, 70, and 90 and the protein Hsp70 in cardiac muscles, whereas the expressions due to WRS or MAP plus WRS were not increased. These results reveal the fact that exposure to WRS depresses the induction of Hsps, in particular Hsp70, due to MAP injection, following to enhance MAP-induced myocardial damage. We believe that interactions between MAP and severe stress, including environmental temperature, affect the induction of Hsps, following to susceptibility of hosts to cardiotoxicity due to the stimulant drug. PMID- 21276780 TI - NADH fluorescence lifetime analysis of the effect of magnesium ions on ALDH2. AB - Aldehyde dehydrogenase 2 (ALDH2) catalyzes oxidation of toxic aldehydes to carboxylic acids. Physiologic levels of Mg(2+) ions influence ALDH2 activity in part by increasing NADH binding affinity. Traditional fluorescence measurements monitor the blue shift of the NADH fluorescence spectrum to study ALDH2-NADH interactions. By using time-resolved fluorescence spectroscopy, we have resolved the fluorescent lifetimes (tau) of free NADH (tau=0.4 ns) and bound NADH (tau=6.0 ns). We used this technique to investigate the effects of Mg(2+) on the ALDH2 NADH binding characteristics and enzyme catalysis. From the resolved free and bound NADH fluorescence signatures, the K(D) for NADH with ALDH2 ranged from 468 MUM to 12 MUM for Mg(2+) ion concentrations of 20 to 6000 MUM, respectively. The rate constant for dissociation of the enzyme-NADH complex ranged from 0.4s(-1) (6000 MUM Mg(2+)) to 8.3s(-1) (0 MUM Mg(2+)) as determined by addition of excess NAD(+) to prevent re-association of NADH and resolving the real-time NADH fluorescence signal. The apparent NADH association/re-association rate constants were approximately 0.04 MUM(-1)s(-1) over the entire Mg(2+) ion concentration range and demonstrate that Mg(2+) ions slow the release of NADH from the enzyme rather than promoting its re-association. We applied NADH fluorescence lifetime analysis to the study of NADH binding during enzyme catalysis. Our fluorescence lifetime analysis confirmed complex behavior of the enzyme activity as a function of Mg(2+) concentration. Importantly, we observed no pre-steady state burst of NADH formation. Furthermore, we observed distinct fluorescence signatures from multiple ALDH2-NADH complexes corresponding to free NADH, enzyme-bound NADH, and, potentially, an abortive NADH-enzyme-propanal complex (tau=11.2 ns). PMID- 21276781 TI - In vitro effects of active constituents and extracts of Orthosiphon stamineus on the activities of three major human cDNA-expressed cytochrome P450 enzymes. AB - Orthosiphon stamineus (OS) has been traditionally used to treat diabetes, kidney and urinary disorders, high blood pressure and bone or muscular pain. To assess the possibility of drug-herb interaction via interference of metabolism, effects of four OS extracts of different polarity and three active constituents (sinensetin, eupatorin and rosmarinic acid) on major human cDNA-expressed cytochrome P450 (CYP) enzymes were investigated. Three substrate-probe based high performance liquid chromatography (HPLC) assays were established to serve as activity markers for CYP2C9, CYP2D6 and CYP3A4. Our results indicate that OS extracts and constituents exhibited differential modulatory effects on different CYPs. While none of the OS components showed significant inhibition on CYP2C9, eupatorin strongly and uncompetitively inhibited CYP2D6 activity with a K(i) value of 10.2MUM. CYP3A4 appeared to be the most susceptible enzyme to OS inhibitory effects. It was moderately inhibited by OS dichloromethane and petroleum ether extract with mixed-type and noncompetitive inhibitions (K(i)=93.7 and 44.9MUg/mL), respectively. Correlation study indicated that the inhibition was accounted for by the presence of eupatorin in the extracts. When IC(50) values of these extracts were expressed in volume per dose unit to reflect inhibitory effect at recommended human doses from commercially available products, moderate inhibition was also observed. In addition, CYP3A4 was strongly and noncompetitively inhibited by eupatorin alone, with a K(i) value of 9.3MUM. These findings suggest that co-administration of OS products, especially those with high eupatorin content, with conventional drugs may have the potential to cause drug-herb interactions involving inhibition of major CYP enzymes. PMID- 21276782 TI - Functional expression of novel human and murine AKR1B genes. AB - The Aldo Keto Reductases (AKRs) are a superfamily of enzymes that catalyze the reduction of biogenic and xenobiotic aldehydes and ketones. AKR1B family has 2 known members in humans and 3 in rodents. Two novel gene loci, hereafter referred to as AKR1B15 in human and Akr1b16 in mouse have been predicted to exist within the AKR1B clusters. AKR1B15 displays 91% and 67% sequence identity with human genes AKR1B10 and AKR1B1, respectively while Akr1b16 shares 82-84% identity with murine Akr1b8 and Akr1b7. We tested the hypothesis that AKR1B15 and Akr1b16 genes are expressed as functional proteins in human and murine tissues, respectively. Using whole tissue mRNA, we were able to clone the full-length open reading frames for AKR1B15 from human eye and testes, and Akr1b16 from murine spleen, demonstrating that these genes are transcriptionally active. The corresponding cDNAs were cloned into pET28a and pIRES-hrGFP-1alpha vectors for bacterial and mammalian expression, respectively. Both genes were expressed as 36kDa proteins found in the insoluble fraction of bacterial cell lysate. These proteins, expressed in bacteria showed no enzymatic activity. However, lysates from COS-7 cells transfected with AKR1B15 showed a 4.8-fold (with p-nitrobenzaldehyde) and 3.3-fold (with dl-glyceraldehyde) increase in enzyme activity compared with untransfected COS-7 cells. The Akr1b16 transcript was shown to be ubiquitously expressed in murine tissues. Highest levels of transcript were found in heart, spleen, and lung. From these observations we conclude that the predicted AKR1B15 and 1b16 genes are expressed in several murine and human tissues. Further studies are required to elucidate their physiological roles. PMID- 21276783 TI - Activities of aldo-keto reductase 1 enzymes on two inhaled corticosteroids: implications for the pharmacological effects of inhaled corticosteroids. AB - Inhaled corticosteroids (ICS) are a mainstay anti-inflammatory therapy for the management of asthma. ICS are synthetic glucocorticoids that are structurally similar to the natural active human glucocorticoid cortisol. Steroid transforming enzymes of the aldo-keto reductase (AKR) family, namely AKR1D1 (5beta-steroid reductase) and AKR1C1-4 (ketosteroid reductases) are implicated in the systemic metabolism of cortisol in liver. In this study, the activities of these AKR1 enzymes on cortisol and two ICS compounds budesonide (BUD) and flunisolide (FLU) were investigated. It was found that the catalytic efficiency of AKR1D1 for the reduction of the double bond in cortisol was 4- and 10-fold higher than the catalytic efficiencies of AKR1D1 with FLU and BUD, respectively. This suggests that compared to cortisol, for which the 5beta-reduction is a major metabolic pathway, a lower degree of systemic (hepatic) metabolism of BUD and FLU via AKR1D1 takes place. In addition, BUD potently inhibited AKR1D1 and AKR1C4, the key steroid metabolizing enzymes in liver, which may disrupt endogenous steroid hormone metabolism and thus contribute to BUD-induced systemic effects. Activities of AKR1C1-3 on cortisol and the two ICS compounds (targeting the 20 keto group) suggest these enzymes may be involved in the local (lung) metabolism of these glucocorticoids. PMID- 21276784 TI - Correlations of six related pyrimidine metabolites and diabetic retinopathy in Chinese type 2 diabetic patients. AB - BACKGROUND: Diabetic retinopathy (DR), a kind of diabetic microvascular complication, is the leading cause of visual impairment in adults aged 30 to 65 years. Despite rapid research progress, robust predictors to assess prospectively with high precision the risk for DR in individuals with diabetes are still lacking. We investigated the relationship between pyrimidine metabolites and disease, and find out the potential biomarkers for diagnosis. METHODS: The study group consisted of 116 subjects who were divided to 3 groups: control (n=41), type 2 diabetes without retinopathy (DM, n=37), and with retinopathy (DR, n=38). Biochemical and clinical parameters, concentrations of related metabolites, including of cytosine, cytidine, uridine, thymine, thymidine and 2'-deoxyuridine were measured in plasma of all participants. RESULTS: There was a significant increase of concentrations of cytosine (p=0.010), cytidine (p<0.001) and thynidine (p<0.001) with DR compared to DM. The concentration of uridine, thymine and 2'-deoxyuridine did not change. CONCLUSIONS: The concentrations of cytosine, cytidine and thynidine may be useful for monitoring the progression of DR and evaluating the treatment. And cytidine has good sensitivity and specificity for diagnosis. PMID- 21276785 TI - Detection of macro-creatine kinase and macroamylase by polyethylene glycol precipitation and ultrafiltration methods. AB - BACKGROUND: Macroenzymes may cause elevations in serum enzyme activity. Macroenzymes are not common; however their detection is important because they cause diagnostic confusion and therapeutic errors. METHODS: We analyzed 2 of the most prevalent macroenzymes in the literature, macro-creatine kinase (macro-CK) and macroamylase, using 2 methods for detection, polyethylene glycol (PEG) precipitation and ultrafiltration (UF). Enzyme measurements were made using a Roche Modular Analytics P analyzer. Imprecision was assessed using quality control material. We evaluated 125 samples from apparently healthy subjects to establish reference intervals. For macro-CK comparison, 94 samples with activities >200 U/l were analyzed with both PEG precipitation and UF and compared to electrophoresis. PEG precipitation and UF were compared for macroamylase detection using 130 samples with amylase activities >110 U/l. RESULTS: UF was more precise and demonstrated narrower reference intervals for both analytes. PEG precipitation and UF were able to detect true cases of macro-CK with overall agreement with electrophoresis of 79.8% and 80.9%, respectively. Both methods detected the same number of 'positive' macroamylase samples; however PEG precipitation resulted in a greater number of 'indeterminate' cases. CONCLUSION: This is the first report where UF has been shown useful for the detection of both macro-CK and macroamylase. PMID- 21276786 TI - Altered differentiation and paracrine stimulation of mammary epithelial cell proliferation by conditionally activated Smoothened. AB - The Hedgehog (Hh) signaling network is critical for patterning and organogenesis in mammals, and has been implicated in a variety of cancers. Smoothened (Smo), the gene encoding the principal signal transducer, is overexpressed frequently in breast cancer, and constitutive activation in MMTV-SmoM2 transgenic mice caused alterations in mammary gland morphology, increased proliferation, and changes in stem/progenitor cell number. Both in transgenic mice and in clinical specimens, proliferative cells did not usually express detectable Smo, suggesting the hypothesis that Smo functioned in a non-cell autonomous manner to stimulate proliferation. Here, we employed a genetically tagged mouse model carrying a Cre recombinase-dependent conditional allele of constitutively active Smo (SmoM2) to test this hypothesis. MMTV-Cre- or adenoviral-Cre-mediated SmoM2 expression in the luminal epithelium, but not in the myoepithelium, was required for the hyper proliferative phenotypes. High levels of proliferation were observed in cells adjacent or in close-proximity to Smo expressing cells demonstrating that SmoM2 expressing cells were stimulating proliferation via a paracrine or juxtacrine mechanism. In contrast, Smo expression altered luminal cell differentiation in a cell-autonomous manner. SmoM2 expressing cells, purified by fluorescence activated cell sorting (FACS) via the genetic fluorescent tag, expressed high levels of Ptch2, Gli1, Gli2, Jag2 and Dll-1, and lower levels of Notch4 and Hes6, in comparison to wildtype cells. These studies provide insight into the mechanism of Smo activation in the mammary gland and its possible roles in breast tumorigenesis. In addition, these results also have potential implications for the interpretation of proliferative phenotypes commonly observed in other organs as a consequence of hedgehog signaling activation. PMID- 21276787 TI - Zebrafish retinoic acid receptors function as context-dependent transcriptional activators. AB - RA receptors (RARs) have been thought to function through a binary repressor activator mechanism: in the absence of ligand, they function as transcriptional repressors, and, in the presence of ligand, they function as transcriptional activators. This prevailing model of RAR mechanism has been derived mostly from in vitro studies and has not been widely tested in developmental contexts. Here, we investigate whether zebrafish RARs function as transcriptional activators or repressors during early embryonic anterior-posterior patterning. Ectopic expression of wild-type zebrafish RARs does not disrupt embryonic patterning and does not sensitize embryos to RA treatment, indicating that RAR availability is not limiting in the embryo. In contrast, ectopic expression of hyperactive zebrafish RARs induces expression of a RA-responsive reporter transgene as well as ectopic expression of endogenous RA-responsive target genes. However, ectopic expression of dominant negative zebrafish RARs fails to induce embryonic phenotypes that are consistent with loss of RA signaling, despite their ability to function as transcriptional repressors in heterologous cell culture assays. Together, our studies suggest that zebrafish RAR function is context-dependent and that, during early patterning, zebrafish RARs function primarily as transcriptional activators and may only have minimal ability to act as transcriptional repressors. Thus, it seems that the binary model for RAR function does not apply to all in vivo scenarios. Taking into account studies of RA signaling in tunicates and tetrapods, we propose a parsimonious model of the evolution of RAR function during chordate anterior-posterior patterning. PMID- 21276788 TI - Evolutionary uniformitarianism. AB - I present a new compilation of the distribution of the temporal distribution of new morphologies of marine invertebrates associated with the Ediacaran-Cambrian (578-510 Ma) diversification of Metazoa. Combining this data with previous work on the hierarchical structure of gene regulatory networks, I argue that the distribution of morphologies may be, in part, a record of the time-asymmetric generation of variation. Evolution has been implicitly viewed as a uniformitarian process where the rates may vary but the underlying processes, including the types of variation, are essentially invariant through time. Recent studies demonstrate that this uniformitarian assumption is false, suggesting that the types of variation may vary through time. PMID- 21276789 TI - A revised model of Xenopus dorsal midline development: differential and separable requirements for Notch and Shh signaling. AB - The development of the vertebrate dorsal midline (floor plate, notochord, and hypochord) has been an area of classical research and debate. Previous studies in vertebrates have led to contrasting models for the roles of Shh and Notch signaling in specification of the floor plate, by late inductive or early allocation mechanisms, respectively. Here, we show that Notch signaling plays an integral role in cell fate decisions in the dorsal midline of Xenopus laevis, similar to that observed in zebrafish and chick. Notch signaling promotes floor plate and hypochord fates over notochord, but has variable effects on Shh expression in the midline. In contrast to previous reports in frog, we find that Shh signaling is not required for floor plate vs. notochord decisions and plays a minor role in floor plate specification, where it acts in parallel to Notch signaling. As in zebrafish, Shh signaling is required for specification of the lateral floor plate in the frog. We also find that the medial floor plate in Xenopus comprises two distinct populations of cells, each dependent upon different signals for its specification. Using expression analysis of several midline markers, and dissection of functional relationships, we propose a revised allocation mechanism of dorsal midline specification in Xenopus. Our model is distinct from those proposed to date, and may serve as a guide for future studies in frog and other vertebrate organisms. PMID- 21276790 TI - Identification of a dopaminergic enhancer indicates complexity in vertebrate dopamine neuron phenotype specification. AB - The dopaminergic neurons of the basal ganglia play critical roles in CNS function and human disease, but specification of dopamine neuron phenotype is poorly understood in vertebrates. We performed an in vivo screen in zebrafish to identify dopaminergic neuron enhancers, in order to facilitate studies on the specification of neuronal identity, connectivity, and function in the basal ganglia. Based primarily on identification of conserved non-coding elements, we tested 54 DNA elements from four species (zebrafish, pufferfish, mouse, and rat), that included 21 genes with known or putative roles in dopaminergic neuron specification or function. Most elements failed to drive CNS expression or did not express specifically in dopaminergic neurons. However, we did isolate a discrete enhancer from the otpb gene that drove specific expression in diencephalic dopaminergic neurons, although it did not share sequence conservation with regulatory regions of otpa or other dopamine-specific genes. For the otpb enhancer, regulation of expression in dopamine neurons requires multiple elements spread across a large genomic area. In addition, we compared our in vivo testing with in silico analysis of genomic regions for genes involved in dopamine neuron function, but failed to find conserved regions that functioned as enhancers. We conclude that regulation of dopaminergic neuron phenotype in vertebrates is regulated by dispersed regulatory elements. PMID- 21276791 TI - Homologous recombination proteins are associated with centrosomes and are required for mitotic stability. AB - In response to DNA damage, cells need robust repair mechanisms to complete the cell cycle successfully. Severe forms of DNA damage are repaired by homologous recombination (HR), in which the XRCC2 protein plays a vital role. Cells deficient in XRCC2 also show disruption of the centrosome, a key component of the mitotic apparatus. We find that this centrosome disruption is dynamic and when it occurs during mitosis it is linked directly to the onset of mitotic catastrophe in a significant fraction of the XRCC2-deficient cells. However, we also show for the first time that XRCC2 and other HR proteins, including the key recombinase RAD51, co-localize with the centrosome. Co-localization is maintained throughout the cell cycle, except when cells are finishing mitosis when RAD51 accumulates in the midbody between the separating cells. Taken together, these data suggest a tight functional linkage between the centrosome and HR proteins, potentially to coordinate the deployment of a DNA damage response at vulnerable phases of the cell cycle. PMID- 21276792 TI - Morphologic and proteomic characterization of exosomes released by cultured extravillous trophoblast cells. AB - Exosomes represent an important intercellular communication vehicle, mediating events essential for the decidual microenvironment. While we have demonstrated exosome induction of pro-inflammatory cytokines, to date, no extensive characterization of trophoblast-derived exosomes has been provided. Our objective was to provide a morphologic and proteomic characterization of these exosomes. Exosomes were isolated from the conditioned media of Swan71 human trophoblast cells by ultrafiltration and ultracentrifugation. These were analyzed for density (sucrose density gradient centrifugation), morphology (electron microscopy), size (dynamic light scattering) and protein composition (Ion Trap mass spectrometry and western immunoblotting). Based on density gradient centrifugation, microvesicles from Sw71 cells exhibit a density between 1.134 and 1.173g/ml. Electron microscopy demonstrated that microvesicles from Sw71 cells exhibit the characteristic cup-shaped morphology of exosomes. Dynamic light scattering showed a bell-shaped curve, indicating a homogeneous population with a mean size of 165nm +/- 0.5nm. Ion Trap mass spectrometry demonstrated the presence of exosome marker proteins (including CD81, Alix, cytoskeleton related proteins, and Rab family). The MS results were confirmed by western immunoblotting. Based on morphology, density, size and protein composition, we defined the release of exosomes from extravillous trophoblast cells and provide their first extensive characterization. This characterization is essential in furthering our understanding of "normal" early pregnancy. PMID- 21276793 TI - Comparative effects of TGF-beta2/Smad2 and TGF-beta2/Smad3 signaling pathways on proliferation, migration, and extracellular matrix production in a human lens cell line. AB - The signaling pathway of transforming growth factor beta2 (TGF-beta2)/Smad plays an important role in the pathological process in posterior capsule opacification (PCO) after cataract surgery. Smad2 and Smad3 are both receptor-regulated Smads (R-Smads) of the TGF-beta2 signaling pathway. We aim to find which among Smad2, Smad3, and Smad2&3 plays a key role in PCO pathology. The signal characteristics of TGF-beta2 and Smad proteins in the human lens cell line HLE-B3 were investigated. Smad2, Smad3, or Smad2&3 were silenced using small interfering RNA. We then tested cell proliferation by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and cell growth curve assays, migration by transwell and wound-healing assays, and extracellular matrix production including alpha smooth muscle actin (alphaSMA), fibronectin, and type I collagen by real-time PCR assay, with and without TGF-beta2 exposure. Silencing Smad3 blocked the effect of TGF-beta2 on cell proliferation and production of fibronectin and type I collagen. Silencing Smad2 blocked the effect of TGF-beta2 on cell migration and production of alphaSMA. Smad2 depletion enhanced Smad3 activity in cell proliferation and ECM production, whereas Smad3 depletion enhanced Smad2 activity in migration and alphaSMA expression. Silencing Smad2 and Smad3 efficiently blocked the effect of TGF-beta2on cell proliferation, migration, and extracellular matrix production. Smad2 and Smad3 are both key in the TGF-beta2 signaling pathway. We can prevent the development of PCO following cataract surgery by blocking the TGF-beta2/Smad2&3 signaling pathway. PMID- 21276794 TI - Cyclophilin D deficiency prevents diet-induced obesity in mice. AB - Mitochondrial coupling efficiency is pivotal in thermogenesis and energy homeostasis. Here we show that deletion of cyclophilin D (CypD), a key modulator of the mitochondrial permeability transition pore, demonstrated resistance to diet-induced obesity (DIO) in both male and female mice, due to increased basal metabolic rate, heat production, total energy expenditure and expenditure of fat energy, despite increased food consumption. Absorption of fatty acids is not altered between CypD(-/-) and wild-type mice. Adult CypD(-/-) developed hyperglycemia, insulin resistance and glucose intolerance albeit resistant to DIO. These data demonstrate that inhibition of CypD function could protect from HFD-IO by increasing energy expenditure in both male and female mice. Inhibition of CypD may offer a novel target to modulate metabolism. PMID- 21276795 TI - Isolation of novel Bacillus species showing high mosquitocidal activity against several mosquito species. AB - Two novel mosquitocidal bacteria, VB17 and VB24, identified as new Bacillus species were isolated from dead mosquito larvae obtained in Florida aquatic habitats. Gas chromatographic analysis of fatty acid methyl esters (GC-FAME) and 16S rRNA sequencing indicated that VB24 is closely related to Bacillus sphaericus whereas VB17 does not have a close relationship with either Bacillus thuringiensis or B. sphaericus. Both isolates were significantly more active than B. sphaericus 2362 against Aedes taeniorhynchus, Anopheles quadrimaculatus, Culex quinquefasciatus larvae, and as active as B. sphaericus 2362 against Anopheles gambiae. Interestingly, however, both were not active against Aedes aegypti larvae, indicating some level of insecticidal specificity. PMID- 21276796 TI - CaMKII in myocardial hypertrophy and heart failure. AB - Many signals have risen and fallen in the tide of investigation into mechanisms of myocardial hypertrophy and heart failure (HF). In our opinion, the multifunctional Ca and calmodulin-dependent protein kinase II (CaMKII) has emerged as a molecule to watch, in part because a solid body of accumulated data essentially satisfy Koch's postulates, showing that the CaMKII pathway is a core mechanism for promoting myocardial hypertrophy and heart failure. Multiple groups have now confirmed the following: (1) that CaMKII activity is increased in hypertrophied and failing myocardium from animal models and patients; (2) CaMKII overexpression causes myocardial hypertrophy and HF and (3) CaMKII inhibition (by drugs, inhibitory peptides and gene deletion) improves myocardial hypertrophy and HF. Patients with myocardial disease die in equal proportion from HF and arrhythmias, and a major therapeutic obstacle is that drugs designed to enhance myocardial contraction promote arrhythmias. In contrast, inhibiting the CaMKII pathway appears to reduce arrhythmias and improve myocardial responses to pathological stimuli. This brief paper will introduce the molecular physiology of CaMKII and discuss the impact of CaMKII on ion channels, Ca handling proteins and transcription in myocardium. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure". PMID- 21276797 TI - Ischemia/reperfusion injury: the benefit of having STAT3 in the heart. PMID- 21276798 TI - Association of genetic variation in the natriuretic peptide system with cardiovascular outcomes. AB - Polymorphisms within individual natriuretic peptide genes have been associated with risk factors for cardiovascular disease, but their association with clinical outcomes was previously unknown. This study aimed to investigate the association between genetic variants in key genes of the natriuretic peptide system with cardiovascular outcomes in patients with coronary artery disease. Coronary disease patients (n=1810) were genotyped for polymorphisms within NPPA, NPPB, NPPC, NPR1 and NPR2. Clinical history, natriuretic peptide concentrations, echocardiography, all-cause mortality and cardiovascular hospital readmissions were recorded over a median 2.8 years. Minor alleles of NPPA rs5068, rs5065 and rs198358 were associated with less history of hypertension; minor alleles of NPPA rs5068 and rs198358 was also associated with higher circulating natriuretic peptide levels (p=0.003 to p=0.04). Minor alleles of NPPB rs198388, rs198389, and rs632793 were associated with higher circulating BNP and NT-proBNP (p=0.001 to p=0.03), and reduced E/E(1) (p=0.011), or LVESVI (p=0.001) and LVEDVI (p=0.004). Within NPPC, both rs11079028 and rs479651 were associated with higher NT-proBNP and CNP (p=0.01 to p=0.03), and rs479651 was associated with lower LVESVI (p=0.008) and LVEDVI (p=0.018). NPR2 rs10758325 was associated with smaller LVMI (p<0.02). A reduced rate of cardiovascular readmission was observed for minor alleles of NPPA rs5065 (p<0.0001), NPPB rs632793 (p<0.0001), rs198388 (p<0.0001), rs198389 (p<0.0001), and NPR2 rs10758325 (p<0.0001). There were no associations with all-cause mortality. In established cardiovascular disease, natriuretic peptide system polymorphisms were associated with natriuretic peptide levels, hypertension, echocardiographic indices and the incidence of hospital readmission for cardiovascular events. PMID- 21276799 TI - Uncoupling between enhanced excitation-contraction coupling and the response to heart disease: lessons from the PI3Kgamma knockout murine model. AB - The heart is a mechanosensitive organ that adapts its morphology to changing hemodynamic conditions via a process named mechanotransduction, which is the primary means of detecting mechanical stress in the extracellular environment. In the heart, mechanical signals are propagated into the intracellular space primarily via cell adhesion complexes and are subsequently transmitted from cell to cell via paracrine signaling. Enhanced excitation-contraction coupling increases myocardial contractility in various experimental models. However, these animal models routinely show increased susceptibility to biomechanical stress with the development of early ventricular dilation and reduced systolic function in the setting of adverse myocardial remodeling. The enhanced susceptibility of the PI3Kgamma knockout mice to biomechanical stress is linked to a cAMP-dependent up-regulation of matrix metalloproteinase with a loss of N-cadherin mediated cell adhesion. Enhancing cell-cell adhesion and cell-ECM interaction will promote the salutary effects of enhanced intracellular Ca(2+) cycling on whole heart function and booster the therapeutic potential of normalizing intracellular Ca(2+) cycling in patients with heart failure. PMID- 21276800 TI - Emerging roles of SIRT1 deacetylase in regulating cardiomyocyte survival and hypertrophy. AB - Calorie restriction is considered to be the best environmental intervention providing health benefits to mammals. The underlying mechanism of this intervention seems to be controlled by a group of NAD-dependent deacetylases, collectively called sirtuins. In mammals, there are seven sirtuin analogs, SIRT1 SIRT7. The founding member of this family, SIRT1, is shown to protect cardiomyocytes from apoptosis and age-dependent degeneration in a dose dependent manner-protecting cells at low doses but showing detrimental effects at high doses. Studies performed with overexpression or knockdown of SIRT1 indicated that, although it protects cells from oxidative stress and ischemia-reperfusion injury, it promotes hypertrophy of cardiomyocytes. Activation of endogenous SIRT1 by resveratrol also displayed pro-survival and pro-hypertrophic activity of SIRT1. In this article, we review recent findings documenting the role of SIRT1 in regulating cardiac myocyte growth and survival under stress, and the proposed mechanism behind its cardioprotective effects. We also briefly discuss two other sirtuin analogs which have been shown to have cardioprotective effects. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure". PMID- 21276801 TI - The Prohead-I structure of bacteriophage HK97: implications for scaffold-mediated control of particle assembly and maturation. AB - Virus capsid assembly requires recruiting and organizing multiple copies of protein subunits to form a closed shell for genome packaging that leads to infectivity. Many viruses encode scaffolding proteins to shift the equilibrium toward particle formation by promoting intersubunit interactions and stabilizing assembly intermediates. Bacteriophage HK97 lacks an explicit scaffolding protein, but the capsid protein (gp5) contains a scaffold-like N-terminal segment termed the delta domain. When gp5 is expressed in Escherichia coli, the delta domain guides 420 copies of the subunit into a procapsid with T=7 laevo icosahedral symmetry named Prohead-I. Prohead-I can be disassembled and reassembled under mild conditions and it cannot mature further. When the virally encoded protease (gp4) is coexpressed with gp5, it is incorporated into the capsid and digests the delta domain followed by autoproteolysis to produce the metastable Prohead-II. Prohead-I(+P) was isolated by coexpressing gp5 and an inactive mutant of gp4. Prohead-I and Prohead-I(+P) were compared by biochemical methods, revealing that the inactive protease stabilized the capsid against disassembly by chemical or physical stress. The crystal structure of Prohead-I(+P) was determined at 5.2 A resolution, and distortions were observed in the subunit tertiary structures similar to those observed previously in Prohead-II. Prohead-I(+P) differed from Prohead-II due to the presence of the delta domain and the resulting repositioning of the N-arms, explaining why Prohead-I can be reversibly dissociated and cannot mature. Low-resolution X-ray data enhanced the density of the relatively dynamic delta domains, revealing their quaternary arrangement and suggesting how they drive proper assembly. PMID- 21276802 TI - Divide and conquer? Persistence of infectious agents in spatial metapopulations of hosts. AB - Persistence of an infectious agent in a population is an important issue in epidemiology. It is assumed that spatially fragmenting a population of hosts increases the probability of persistence of an infectious agent and that movement of hosts between the patches is vital for that. The influence of migration on persistence is however often studied in mean-field models, whereas in reality the actual distance travelled can be limited and influence the movement dynamics. We use a stochastic model, where within- and between-patch dynamics are coupled and movement is modelled explicitly, to show that explicit consideration of movement distance makes the relation between persistence of infectious agents and the metapopulation structure of its hosts less straightforward than previously thought. We show that the probability of persistence is largest at an intermediate movement distance of the host and that spatially fragmenting a population of hosts is not necessarily beneficial for persistence. PMID- 21276803 TI - T cell state transition produces an emergent change detector. AB - We model the stages of a T cell response from initial activation to T cell expansion and contraction using a system of ordinary differential equations. Results of this modeling suggest that state transitions enable the T cell population to detect change and respond effectively to changes in antigen stimulation levels, rather than simply the presence or absence of antigen. A key component of the system that gives rise to this emergent change detector is initial activation of naive T cells. The activation step creates a barrier that separates the long-term, slow dynamics of naive T cells from the short-term, fast dynamics of effector T cells. This separation allows the T cell population to compare current, up-to-date changes in antigen levels to long-term, steady state levels. As a result, the T cell population responds very effectively to sudden shifts in antigen levels, even if the antigen were already present prior to the change. This feature provides a mechanism for T cells to react to rapidly expanding sources of antigen stimulation, such as viruses, while maintaining tolerance to constant or slowly fluctuating sources of stimulation, such as healthy tissue during growth. In addition to modeling T cell activation, we also formulate a model of the proliferation of effector T cells in response to the consumption of positive growth signal, secreted throughout the T cell response. We discuss how the interaction between T cells and growth signal generates an emergent threshold detector that responds preferentially to large changes in antigen stimulation while ignoring small ones. As a final step, we discuss how the de novo generation of adaptive regulatory T cells during the latter phase of the T cell response creates a negative feedback loop that controls the duration and magnitude of the T cell response. Hence, the immune network continually adjusts to a shifting baseline of (self and non-self) antigens, and responds primarily to abrupt changes in these antigens rather than merely their presence or absence. PMID- 21276804 TI - Skeletal muscle arteriolar function following myocardial infarction: Analysis of branch-order effects. AB - Diminished bioavailability of nitric oxide (NO) may impair skeletal muscle arteriolar function after myocardial infarction (MI). We tested the hypotheses that chronic MI induced would diminish 1) endothelial function in large (resting diameter ~75MUm) feed arterioles, and 2) functional dilation in feed arterioles, but not smaller arcade (~25MUm) or transverse (~15MUm) arterioles, in the spinotrapezius muscle of female Sprague-Dawley rats. Additionally, we hypothesized that blockade of NO production with N(G)-nitro-l-arginine methyl ester (l-NAME; 30mg/kg i.v.) would have a greater blunting effect on control rats than MI rats. Endothelial function of the feed arterioles was assessed with an infusion of acetylcholine (1.5MUg i.v.) after pretreatment with indomethacin (5mg/kgi.p.). MI blunted the response to acetylcholine in feed arterioles (p=0.037), but did not affect resting or post-contraction diameter at any branching order. l-NAME had similar effects on MI and SHAM rats; the response to acetylcholine was blunted in feed arterioles (p=0.003), resting diameter was diminished in arcade arterioles (p=0.003), and post-contraction diameter was diminished in both arcade arterioles (p=0.03) and transverse arterioles (p=0.05). In conclusion, despite endothelial dysfunction in feed arterioles, functional dilation was not affected by MI in any branching order studied. l-NAME had similar effects on MI and SHAM rats that were branch order-dependent. These branch-order effects should be considered in future studies of the control of blood flow. PMID- 21276805 TI - Signaling pathways mediating phosphorylation and inactivation of glycogen synthase kinase-3beta by the recombinant human delta-opioid receptor stably expressed in Chinese hamster ovary cells. AB - Besides being involved in analgesia, delta-opioid receptors have recently been shown to exert antidepressant-like and neuroprotective effects. Glycogen synthase kinase-3beta (GSK-3beta), a key enzyme involved in cellular apoptosis and in mood disorders, may constitute a molecular target of delta-opioid receptors. However, relatively little is known on how delta-opioid receptors affect the multiple signaling pathways regulating GSK-3beta. In the present study, we show that activation of human delta-opioid receptors stably expressed in Chinese hamster ovary (CHO) cells induced a rapid GSK-3beta phosphorylation on Ser9 and a significant inhibition of the kinase activity. This effect was dependent on G proteins Gi/Go, unaffected by cell transfection with the Gbetagamma scavenger transducin, required the Src non-receptor tyrosine kinase and the specific involvement of the alpha isoform of phosphatidylinositol 3-kinase. delta-Opioid agonists activated the protein kinase Akt in a Src-dependent manner and chemical inhibition of Akt or stable expression of a dominant negative Akt1 mutant reduced the stimulation of GSK-3beta phosphorylation. Moreover, delta-opioid receptor regulation of Akt and GSK-3beta was dependent on transphosphorylation and transactivation of platelet-derived growth factor and insulin-like growth factor 1 receptor tyrosine kinases. AMP-activated protein kinase (AMPK) activity was also required, as delta-opioid effects on Akt and GSK-3beta were mimicked by the AMPK activator A-769662 and reduced by the AMPK inhibitor Compound C. Conversely, inhibition of protein kinase C isoforms, extracellular signal-regulated protein kinases 1/2 and mammalian target of rapamycin was without effect, although the latter two kinases were activated by delta-opioid agonists. The results identify Src-dependent transactivation of receptor tyrosine kinases as a key process in delta-opioid receptor inhibitory control of GSK-3beta and reveal a novel delta opioid regulatory mechanism mediated by AMPK. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'. PMID- 21276807 TI - Serotonin transporter and memory. AB - The serotonin transporter (SERT) has been associated to diverse functions and diseases, though seldom to memory. Therefore, we made an attempt to summarize and discuss the available publications implicating the involvement of the SERT in memory, amnesia and anti-amnesic effects. Evidence indicates that Alzheimer's disease and drugs of abuse like d-methamphetamine (METH) and (+/-)3,4 methylenedioxymethamphetamine (MDMA, "ecstasy") have been associated to decrements in the SERT expression and memory deficits. Several reports have indicated that memory formation and amnesia affected the SERT expression. The SERT expression seems to be a reliable neural marker related to memory mechanisms, its alterations and potential treatment. The pharmacological, neural and molecular mechanisms associated to these changes are of great importance for investigation. PMID- 21276806 TI - Neuroimaging insights into the role of cortical GABA systems and the influence of nicotine on the recovery from alcohol dependence. AB - This paper reviews evidence suggesting that nicotine and tobacco smoke profoundly modulate the effects of alcohol on gamma-aminobutyric acid (GABA) neuronal function, specifically at the GABA(A)-benzodiazepine receptor (GABA(A)-BZR). The focus of this paper is on recent neuroimaging evidence in preclinical models as well as clinical experiments. First, we review findings implicating the role of alcohol at the GABA(A)-BZR and discuss the changes in GABA(A)-BZR availability during acute and prolonged alcohol withdrawal. Second, we discuss preclinical evidence that suggests nicotine affects GABA neuronal function indirectly by a primary action at neuronal nicotinic acetylcholine receptors. Third, we show how this evidence converges in studies that examine GABA levels and GABA(A)-BZRs in alcohol-dependent smokers and nonsmokers, suggesting that tobacco smoking attenuates the chemical changes that occur during alcohol withdrawal. Based on a comprehensive review of literature, we hypothesize that tobacco smoking minimizes the changes in GABA levels that typically occur during the acute cycles of drinking in alcohol-dependent individuals. Thus, during alcohol withdrawal, the continued tobacco smoking decreases the severity of the withdrawal-related changes in GABA chemistry. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'. PMID- 21276809 TI - Involvement of histaminergic receptor mechanisms in the stimulation of NT-3 synthesis in astrocytes. AB - Neurotrophin-3 (NT-3) is produced by astrocytes, in addition to neurons, and monoamine neurotransmitters play a role in controlling NT-3 synthesis. The impact of histamine (HA) on the regulation of NT-3 synthesis in cultured astrocytes has not been studied. We evaluated the involvement of histamine receptors and intracellular mechanisms in the regulation of NT-3 production by HA. Real-time PCR was performed to examine the expression of all known histamine receptor subtypes in cultured rat cortical astrocytes. Pharmacological tools, selective for the H1, H2 and H3 receptors and intracellular systems, were utilized to confirm functional properties of HA receptors in histaminergic up-regulation of astrocytic NT-3 synthesis. HA potently and transiently elevated NT-3 expression and protein levels by more than twofold. In addition to H1 and H2 receptors, cultured astrocytes also express H3 receptors, which activate G(i/o) proteins to inhibit adenylyl cyclase and modulate MAP kinase activity. Histaminergic stimulation was partly inhibited by selective H1, H2, and H3 antagonists whereas selective H1, H2, and H3 agonists or mediators of the intracellular histaminergic pathways increased NT-3 levels. Inhibitors of PKA, PKC, and CaMK II significantly reduced the HA-induced increase in NT-3 cellular levels whereas the MAP kinase cascade inhibitor completely blocked the stimulatory action of HA and all selective agonists. In conclusion, the synthesis of astrocytic NT-3 stimulated by HA is a receptor-mediated process, which is fine-tuned via subtle modulation of parallel histaminergic H1, H2, and H3 pathways that converge at the level of MAP kinase activity. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'. PMID- 21276808 TI - Alterations in AMPA receptor subunits and TARPs in the rat nucleus accumbens related to the formation of Ca2+-permeable AMPA receptors during the incubation of cocaine craving. AB - Cue-induced cocaine seeking intensifies or incubates after withdrawal from extended access cocaine self-administration, a phenomenon termed incubation of cocaine craving. The expression of incubated craving is mediated by Ca2+ permeable AMPA receptors (CP-AMPARs) in the nucleus accumbens (NAc). Thus, CP AMPARs are a potential target for therapeutic intervention, making it important to understand mechanisms that govern their accumulation. Here we used subcellular fractionation and biotinylation of NAc tissue to examine the abundance and distribution of AMPAR subunits, and GluA1 phosphorylation, in the incubation model. We also studied two transmembrane AMPA receptor regulatory proteins (TARPs), gamma-2 and gamma-4. Our results, together with earlier findings, suggest that some of the new CP-AMPARs are synaptic. These are probably associated with gamma-2, but they are loosely tethered to the PSD. Levels of GluA1 phosphorylated at serine 845 (pS845 GluA1) were significantly increased in biotinylated tissue and in an extrasynaptic membrane-enriched fraction. These results suggest that increased synaptic levels of CP-AMPARs may result in part from an increase in pS845 GluA1 in extrasynaptic membranes, given that S845 phosphorylation primes GluA1-containing AMPARs for synaptic insertion and extrasynaptic AMPARs supply the synapse. Some of the new extrasynaptic CP-AMPARs are likely associated with gamma-4, rather than gamma-2. The maintenance of CP AMPARs in NAc synapses during withdrawal is accompanied by activation of CaMKII and ERK2 but not CaMKI. Overall, AMPAR plasticity in the incubation model shares some features with better described forms of synaptic plasticity, although the timing of the phenomenon and the persistence of related neuroadaptations are significantly different. PMID- 21276810 TI - Modulation of methylmercury uptake by methionine: prevention of mitochondrial dysfunction in rat liver slices by a mimicry mechanism. AB - Methylmercury (MeHg) is an ubiquitous environmental pollutant which is transported into the mammalian cells when present as the methylmercury-cysteine conjugate (MeHg-Cys). With special emphasis on hepatic cells, due to their particular propensity to accumulate an appreciable amount of Hg after exposure to MeHg, this study was performed to evaluate the effects of methionine (Met) on Hg uptake, reactive species (RS) formation, oxygen consumption and mitochondrial function/cellular viability in both liver slices and mitochondria isolated from these slices, after exposure to MeHg or the MeHg-Cys complex. The liver slices were pre-treated with Met (250 MUM) 15 min before being exposed to MeHg (25 MUM) or MeHg-Cys (25 MUM each) for 30 min at 37 degrees C. The treatment with MeHg caused a significant increase in the Hg concentration in both liver slices and mitochondria isolated from liver slices. Moreover, the Hg uptake was higher in the group exposed to the MeHg-Cys complex. In the DCF (dichlorofluorescein) assay, the exposure to MeHg and MeHg-Cys produced a significant increase in DFC reactive species (DFC-RS) formation only in the mitochondria isolated from liver slices. As observed with Hg uptake, DFC-RS levels were significantly higher in the mitochondria treated with the MeHg-Cys complex compared to MeHg alone. MeHg exposure also caused a marked decrease in the oxygen consumption of liver slices when compared to the control group, and this effect was more pronounced in the liver slices treated with the MeHg-Cys complex. Similarly, the loss of mitochondrial activity/cell viability was greater in liver slices exposed to the MeHg-Cys complex when compared to slices treated only with MeHg. In all studied parameters, Met pre-treatment was effective in preventing the MeHg- and/or MeHg Cys-induced toxicity in both liver slices and mitochondria. Part of the protection afforded by Met against MeHg may be related to a direct interaction with MeHg or to the competition of Met with the complex formed between MeHg and endogenous cysteine. In summary, our results show that Met pre-treatment produces pronounced protection against the toxic effects induced by MeHg and/or the MeHg Cys complex on mitochondrial function and cell viability. Consequently, this amino acid offers considerable promise as a potential agent for treating acute MeHg exposure. PMID- 21276811 TI - FluAlert: a qualitative evaluation of providers' desired characteristics and concerns regarding computerized influenza vaccination alerts. AB - OBJECTIVE: To explore pediatric providers' perceived barriers to influenza vaccine delivery, and desired characteristics and potential concerns regarding an influenza vaccine alert integrated into the electronic health record (EHR). METHODS: Four focus groups with providers (n=21) and five individual interviews with practice leaders in an urban, pediatric primary care network affiliated with an academic medical center in New York City were conducted. Data were collected during the 2009-10 influenza season and analyzed using thematic analysis. RESULTS: Participants identified several barriers to influenza vaccine delivery, including remembering to vaccinate during sick visits, need to review multiple sources of immunization information, time shortages and inadequate staffing. They felt that an alert could help many of these challenges. They desired the following alert characteristics: 1) alerting providers early in the visit, 2) accurately determining patients' vaccine status by merging multiple sources of immunization information, 3) facilitating vaccine ordering, and 4) generating appropriate documentation in the EHR when vaccines were refused or otherwise not given. Potential concerns regarding the alert included reliability and accuracy of alert, workflow interruptions and forced actions. CONCLUSIONS: This study highlights providers' interest in a well-integrated, accurate alert that streamlines assessment of vaccination eligibility, ordering and documentation without impeding work-flow. PMID- 21276812 TI - Randomized controlled trial of the Physical Activity Leaders (PALs) program for adolescent boys from disadvantaged secondary schools. AB - OBJECTIVE: The aim of this study was to evaluate the efficacy and feasibility of the Physical Activity Leaders (PALs) program. PALs is an obesity prevention program for low-active adolescent boys from disadvantaged schools. METHODS: The study was conducted in the Hunter Region, New South Wales (NSW), Australia from June to December 2009. Four disadvantaged secondary schools were randomized to treatment conditions for the 6-month study period. Participants were 100 adolescent boys [mean (SD) age=14.3(0.6) years; BMI=22.1 kg/m(-2) (4.6); BMI z score=0.6 (1.2)]. The primary outcome was change in BMI and secondary outcomes were body fat (bioelectrical impedance analysis), waist circumference, muscular fitness (leg dynamometer, 90o push-up test and 7-stage sit-up test), physical activity (5-days of pedometry) and selected dietary behaviors. RESULTS: Significant group-by-time interaction effects were found for BMI (mean difference=-0.8 kg/m(-2), p<0.001, d =0.7), BMI z-score (mean difference=-0.2, p<0.001, d=0.7), and body fat (mean difference=-1.8%, p<0.05, d=0.5), but not for waist circumference, muscular fitness or physical activity. Participants in the intervention group reduced their consumption of sugar-containing beverages. CONCLUSIONS: The PALs program was a feasible and efficacious approach to induce healthy weight loss in adolescent boys from disadvantaged secondary schools. PMID- 21276813 TI - Depressive symptoms and self-reported fast-food intake in midlife women. AB - OBJECTIVE: To examine the association between depressive symptoms and fast-food intake in midlife women. METHODS: Data were analyzed from a cross-sectional study of 626 women aged 45-54 years conducted from 2000 to 2004 in Baltimore, Maryland. The presence of depressive symptoms was measured using the Center for Epidemiologic Studies-Depression scale and defined as a score of 16 or greater. The frequency of fast-food intake was assessed using self-reported questionnaire data, and was categorized as "at least weekly", "at least monthly, but less than weekly" and "less than monthly". RESULTS: Approximately 25% of the study sample reported depressive symptoms; 14% consumed fast-food "at least weekly," and 27% "at least monthly, but less than weekly". Compared to their counterparts, women with depressive symptoms had significantly greater odds of reporting higher fast food intake (confounder-adjusted odds ratio: 1.54; 95% confidence interval: 1.06 2.25). Other covariates associated with a higher frequency of fast-food intake included black race and body mass index >=30 kg/m(2). CONCLUSIONS: Findings from this study indicate that the presence of depressive symptoms is positively associated with fast-food intake in midlife women. These results may have important health implications given that both depression and dietary consumption patterns are risk factors for a number of diseases. PMID- 21276814 TI - Moxifloxacin monotherapy versus beta-lactam mono- or combination therapy in hospitalized patients with community-acquired pneumonia. AB - OBJECTIVE: In this observational study, we compared the outcomes of moxifloxacin monotherapy as compared to beta-lactam monotherapy as well as beta-lactam combination therapy in patients with community-acquired pneumonia (CAP). METHODS: Patients recruited within the German Competence Network for CAP (CAPNETZ) were evaluated for treatment regimen. Primary outcome variables were six months overall mortality, pneumonia-related mortality according to clinical judgment and treatment failures (necessity for treatment change and death). RESULTS: Overall, 4091 patients (mean age 64.4+/-17.8 (range 18-101) years, 2433 male (59.5%)) were included. 2068 patients received moxifloxacin (n=365) or beta-lactam monotherapy (n=1703). 330 patients died within six months. After controlling for confounders in multivariate analysis, moxifloxacin monotherapy had higher survival as compared to beta-lactam monotherapy (hazard ratio for moxifloxacin 0.57, 95% CI 0.35-0.92). Multivariate analysis including interaction terms showed that the protective effect of moxifloxacin was not present for CRB-65 class 0 but increased with higher CRB-65 scores (HR 0.69, 95% CI 0.50-0.96). Regarding pneumonia-related death, moxifloxacin monotherapy was also protective in multivariate analysis (HR 0.36, 95% CI 0.13-0.99). Moxifloxacin was also significantly associated with less treatment failures (p<0.001). In addition, it was not inferior to combination beta-lactam treatment (p=0.062). CONCLUSIONS: In CRB-65 class 0 moxifloxacin was equivalent to beta-lactams. Our observations are in support of a use of moxifloxacin monotherapy in hospitalized patients with moderate CAP (CRB-65 classes 1 and 2). PMID- 21276815 TI - The use of long acting beta2-agonists, alone or in combination with inhaled corticosteroids, in chronic obstructive pulmonary disease (COPD): a risk-benefit analysis. AB - Chronic obstructive pulmonary disease (COPD) is a slowly progressive, largely non reversible pulmonary disease which is characterised by airflow limitation. It is one of the few diseases with an increasing mortality rate and by 2020 it is predicted to be the third leading cause of death. The mainstays of current treatment are long acting beta2 agonists (LABAs) coupled with an increasing reliance on inhaled corticosteroids (ICS). Two LABAs (salmeterol and formoterol) are currently licensed for COPD both as monotherapy and in combination with ICS (fluticasone propionate (FP) and budesonide respectively). A comprehensive review of the risk-benefit of these medicines in COPD is provided here which concludes that there is limited efficacy for LABAs in COPD either alone or in combination with ICS and no overall modification of the disease process. However, where directly compared, combination therapy usually provides an advantage over monotherapy. Importantly the apparent effectiveness of treatment may significantly depend upon the outcome measure chosen with some measures possibly underestimating the extent of benefit. ICS benefit may also be greater in those patients who respond to treatment. Set against this benefit are recent concerns that a number of issues related to the clinical trial design such as prior use of ICS and different withdrawal rates between groups may be significantly influencing results. Furthermore there is no evidence of a dose response relationship with regard to ICS dose. A key issue with combination therapy is the excess risk of pneumonia conferred by the use of an ICS in this patient population. This risk does not appear to be proportional to the ICS dose but may differ between FP and budesonide. We conclude that further studies are required to identify the optimal dose of ICS, in terms of both risk and benefit, and to confirm their benefit in steroid naive patients. Furthermore it will be important to determine whether the risk of pneumonia is apparent with both FP and budesonide and to identify factors which may predict steroid responsiveness in COPD. PMID- 21276817 TI - Impaired regulation of synaptic actin cytoskeleton in Alzheimer's disease. AB - Representing the most common cause of dementia, Alzheimer's disease (AD) has dramatically impacted the neurological and economic health of our society. AD is a debilitating neurodegenerative disease that produces marked cognitive decline. Much evidence has accumulated over the past decade to suggest soluble oligomers of beta-amyloid (Abeta) have a critical role in mediating AD pathology early in the disease process by perturbing synaptic efficacy. Here we critically review recent research that implicates synapses as key sites of early pathogenesis in AD. Most excitatory synapses in the brain rely on dendritic spines as the sites for excitatory neurotransmission. The structure and function of dendritic spines are dynamically regulated by cellular pathways acting on the actin cytoskeleton. Numerous studies analyzing human postmortem tissue, animal models and cellular paradigms indicate that AD pathology has a deleterious effect on the pathways governing actin cytoskeleton stability. Based on the available evidence, we propose the idea that a contributing factor to synaptic pathology in early AD is an Abeta oligomer-initiated collapse of a "synaptic safety net" in spines, leading to dendritic spine degeneration and synaptic dysfunction. Spine stabilizing pathways may thus represent efficacious therapeutic targets for combating AD pathology. PMID- 21276818 TI - Utility of transcranial Doppler ultrasound for the integrative assessment of cerebrovascular function. AB - There is considerable utility in the use of transcranial Doppler ultrasound (TCD) to assess cerebrovascular function. The brain is unique in its high energy and oxygen demand but limited capacity for energy storage that necessitates an effective means of regional blood delivery. The relative low cost, ease-of-use, non-invasiveness, and excellent temporal resolution of TCD make it an ideal tool for the examination of cerebrovascular function in both research and clinical settings. TCD is an efficient tool to access blood velocities within the cerebral vessels, cerebral autoregulation, cerebrovascular reactivity to CO(2), and neurovascular coupling, in both physiological states and in pathological conditions such as stroke and head trauma. In this review, we provide: (1) an overview of TCD methodology with respect to other techniques; (2) a methodological synopsis of the cerebrovascular exam using TCD; (3) an overview of the physiological mechanisms involved in regulation of the cerebral blood flow; (4) the utility of TCD for assessment of cerebrovascular pathology; and (5) recommendations for the assessment of four critical and complimentary aspects of cerebrovascular function: intra-cranial blood flow velocity, cerebral autoregulation, cerebral reactivity, and neurovascular coupling. The integration of these regulatory mechanisms from an integrated systems perspective is discussed, and future research directions are explored. PMID- 21276816 TI - Glutamate pharmacology and metabolism in peripheral primary afferents: physiological and pathophysiological mechanisms. AB - In addition to using glutamate as a neurotransmitter at central synapses, many primary sensory neurons release glutamate from peripheral terminals. Primary sensory neurons with cell bodies in dorsal root or trigeminal ganglia produce glutaminase, the synthetic enzyme for glutamate, and transport the enzyme in mitochondria to peripheral terminals. Vesicular glutamate transporters fill neurotransmitter vesicles with glutamate and they are shipped to peripheral terminals. Intense noxious stimuli or tissue damage causes glutamate to be released from peripheral afferent nerve terminals and augmented release occurs during acute and chronic inflammation. The site of action for glutamate can be at the autologous or nearby nerve terminals. Peripheral nerve terminals contain both ionotropic and metabotropic excitatory amino acid receptors (EAARs) and activation of these receptors can lower the activation threshold and increase the excitability of primary afferents. Antagonism of EAARs can reduce excitability of activated afferents and produce antinociception in many animal models of acute and chronic pain. Glutamate injected into human skin and muscle causes acute pain. Trauma in humans, such as arthritis, myalgia, and tendonitis, elevates glutamate levels in affected tissues. There is evidence that EAAR antagonism at peripheral sites can provide relief in some chronic pain sufferers. PMID- 21276819 TI - Separated interface nerve electrode prevents direct current induced nerve damage. AB - Direct current, DC, can be used to quickly and reversibly block activity in excitable tissue, or to quickly and reversibly increase or decrease the natural excitability of a neuronal population. However, the practical use of DC to control neuronal activity has been extremely limited due to the rapid tissue damage caused by its use. We show that a separated interface nerve electrode, SINE, is a much safer method to deliver DC to excitable tissue and may be valuable as a laboratory research tool or potentially for clinical treatment of disease. PMID- 21276820 TI - Combined fluorescent in situ hybridization and immunofluorescence: limiting factors and a substitution strategy for slide-mounted tissue sections. AB - The simultaneous localization of several anatomical markers is often required to understand and analyze the organization of complex brain nuclei or identify neuronal networks recruited during a specific biological stimulus. Gathering such information is usually achieved by the combined detection of both mRNA and proteins. Staining techniques using fluorescence have progressively overtaken the use of radioactive tissue labeling and immunostaining based on the avidin-biotin peroxidase complex. Despite the promise offered by the combination of fluorescent in situ hybridization (FISH) and immunofluorescence (IF), in terms of reduced bench time and easy visualization of multiple labels at once, some technical hurdles have to be overcome to produce reliable data from these state-of-the-art neuroanatomy techniques. Here, we have adapted a combination of FISH and IF for slices mounted on a microscope slide, using mRNA (GAD65 mRNA) and proteins (NeuN, FosB or TH) widely studied in neuroanatomy, to validate this method. Proteinase K (PK), which is often used to optimize riboprobe penetration, is a major limiting factor in obtaining successful IF labeling. This study demonstrates the inaccuracy of PK and provides appropriate tools to improve the efficiency of the combined FISH-IF procedure to obtain high quality fluorescent multi-labeling. PMID- 21276821 TI - CANTAB delayed matching to sample task performance in juvenile baboons. AB - This study reports the administration of the Cambridge Neuropsychological Test Automated Battery system's delayed matching to sample (DMTS) task to juvenile baboons. Nine subjects (female=5, male=4) were trained with delay intervals ranging from 0 to 80s. Trial unique stimuli were utilized in combination with matching to sample, in contrast to non-matching to sample, to more accurately assess components of medial temporal lobe (hippocampal formation) mediated working memory. These parameters force subjects to rely on recognition for matching stimuli and overcome their innate tendency to choose novel stimuli (non matching), thus increasing task difficulty. Testing with delays intervals of 0-2, 4, 8, and 16s revealed decreased percent correct responding as delay intervals increased. An effect of 1 vs. 3 distractor stimuli on accuracy was also noted. Increasing the number of distractors resulted in decreased observing response latencies. The increase in choice response latency seen with increasing delay interval was independent of number of distractor stimuli presented. There were no sex differences in task performance. Our laboratory is focused on understanding the functional consequences of suboptimal conditions during pregnancy and early postnatal life in offspring. The ability of juvenile baboons to perform the DMTS task demonstrates the utility of this non-human primate model in examining pre- and post-natal conditions that impact the development of working memory. Evaluation of causes and consequences of impaired working memory in a variety of human diseases will be assisted by the use of this task in nonhuman primate models of human health and disease. PMID- 21276822 TI - ESeroS-GS modulates lipopolysaccharide-induced macrophage activation by impairing the assembly of TLR-4 complexes in lipid rafts. AB - The binding of lipopolysaccharides (LPS) to macrophages results in inflammatory responses. In extreme cases it can lead to endotoxic shock, often resulting in death. A broad range of antioxidants, including tocopherols, can reduce LPS activity in vitro and in vivo. To elucidate the underlying mechanisms of their action, we investigated the effect of the sodium salt of gamma-L-glutamyl-S-[2 [[[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6 yl]oxy]carbonyl]-3-[[2-(1H-indol-3-yl)ethyl]amino]-3-oxopropyl]-L cysteinylglycine (ESeroS-GS), a novel alpha-tocopherol derivative, on LPS-induced inflammation in vitro and in vivo. ESeroS-GS reduced the transcription of TNF alpha, IL-1beta, IL-6 and iNOS genes in a dose-dependent manner in RAW264.7 macrophages, and inhibited the release of these inflammatory factors. In addition, ESeroS-GS inhibited LPS-induced mortality in a mouse sepsis model. Electrophoretic mobility shift assays (EMSA) and reporter gene assays revealed that ESeroS-GS down-regulated the transcriptional activity of NF-kappaB. By analyzing the partitioning of CD14 and Toll-like receptor 4 (TLR-4) in cell membrane microdomains, we found that ESeroS-GS attenuates the binding of LPS to RAW264.7 cells via interfering with the relocation of CD14 and TLR-4 to lipid rafts, blocking the activation of interleukin-1 receptor-associated kinase 1 (IRAK-1), and inhibiting the consequent phosphorylation of TAK1 and IKKalpha/beta, which together account for the suppression of NF-kappaB activation. Taken together, our data suggest that ESeroS-GS can modulate LPS signaling in macrophages by impairing TLR-4 complex assembly via a lipid raft dependent mechanism. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. PMID- 21276823 TI - Downregulation of Akt and FAK phosphorylation reduces invasion of glioblastoma cells by impairment of MT1-MMP shuttling to lamellipodia and downregulates MMPs expression. AB - Human malignant glioblastomas are highly invasive tumors. Increased cell motility and degradation of the surrounding extracellular matrix are essential for tumor invasion. PI3K/Akt signaling pathway emerges as a common pathway regulating cellular proliferation, migration and invasion; however, its contribution to particular process and downstream cascades remain poorly defined. We have previously demonstrated that Cyclosporin A (CsA) affects glioblastoma invasion in organotypic brain slices and tumorigenicity in mice. Here we show that CsA impairs migration and invasion of human glioblastoma cells by downregulation of Akt phosphorylation. Interference with PI-3K/Akt signaling was crucial for CsA effect on invasion, because overexpression of constitutively active myr-Akt antagonized drug action. Furthermore, the drug was not effective in T98G glioblastoma cells with constitutively high level of phosphorylated Akt. CsA, comparably to pharmacological inhibitors of PI3K/Akt signaling (LY294002, A443654), reduced motility of glioblastoma cells, diminished MMP-2 gelatinolytic activity and MMP-2 and MT1-MMP expression. The latter effect was mimicked by overexpression of dominant negative Akt mutants. We demonstrate that CsA and LY294002 reduced MMP transcription partly via modulation of IkappaB phosphorylation and NFkappaB transcriptional activity. Those effects were not mediated by inhibition of calcineurin, a classical CsA target. Additionally, CsA reduced phosphorylation and activity of focal adhesion kinase that was associated with rapid morphological alterations, rearrangement of lamellipodia and impairment of MT1-MMP translocation to membrane protrusions. Our results document novel, Akt-dependent mechanisms of interference with motility/invasion of human glioblastoma cells: through a rapid modulation of cell adhesion and MT1-MMP translocation to membrane protrusions and delayed, partly NFkappaB-dependent, downregulation of MMP-2 and MT1-MMP expression. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. PMID- 21276824 TI - Trinucleotide repeat sequence-based PCR as a potential approach for genotyping Mycobacterium gordonae strains. AB - Diseases that are caused by non-tuberculous mycobacteria (NTM) continue to pose difficult clinical problems, and the epidemiological aspect of NTM-caused diseases is of great importance. In the case of Mycobacterium gordonae there is no adequate genotyping scheme. Here we present a potential rapid and reproducible genetic assay that uses trinucleotide repeat sequence-based PCR (TRS-PCR) for genotyping M. gordonae. The proposed method constitutes a useful single-primer PCR screen for genotyping this species. Among 10 TRS-containing primers, after applying (CAC)4-based PCR to 36 strains of M. gordonae, we found a discriminatory index of 0.975. The accuracy of this analysis was supported by a reasonable reproducibility of 92%. These results were compared with the Enterobacterial Repetitive Intergenic Consensus Sequences (ERIC)-PCR typing scheme which had lower discriminatory index of 0.93 and its reproducibility was only 86.3%. PMID- 21276825 TI - Effects of sex differences and regulation of the sleep-wake cycle on aversive memory encoding. AB - Formation of aversive memories sometimes involves a pathogenic cognitive process that could lead to the development of posttraumatic stress disorder (PTSD). Here, we explore chronobiological aspects of shifts in aversive memory encoding abilities around habitual sleep onset periods (SOPs). Thirty university students, who were randomly assigned to one of two groups, watched a suspenseful movie for 2 h, beginning either 3h prior to their habitual sleep onset periods (pre-SOP group) or 1h after their habitual sleep onset periods (post-SOP group). Recognition accuracy was tested 15 min after the movie finished and again 10h after the movie finished, after a sleep period. Overall recognition accuracy was higher in the post-SOP women than in the pre-SOP women, while that in the pre-SOP men was higher than that in the post-SOP men. The recognition accuracy gap (aversive-neutral) was significantly greater in the post-SOP women than in the pre-SOP women throughout both recognition sessions, while there was a non significant group difference for men. These findings suggest that habitual SOP is a watershed in women's ability to learn to identify aversive events. Women more correctly encode aversive episodes post-SOP than pre-SOP, which could contribute to high PTSD prevalence in women. PMID- 21276826 TI - Spinal motor actions of the MU-opioid receptor agonist DAMGO in the cat. AB - For further evaluation of opioidergic spinal motor functions the action of the MU opioid receptor agonist DAMGO was tested on transmission in different non nociceptive and nociceptive spinal reflex pathways from flexor reflex afferents (FRA), and in non-FRA reflex pathways in spinal cats. The action of DAMGO was complex, not following a simple pattern with selective depression of nociceptive pathways compared to non-nociceptive ones. Monosynaptic reflexes of the flexor posterior biceps semitendinosus (PBSt) and transmission in nociceptive as well as non-nociceptive excitatory FRA pathways to PBSt were depressed, while the specific excitatory nociceptive non-FRA pathway from the central foot pad to foot extensors was mainly not depressed but rather facilitated by DAMGO. DAMGO caused a facilitation of monosynaptic reflexes to the extensor gastrocnemius soleus (GS) and partly a reversal of inhibitory to excitatory conditioning effects from cutaneous afferents to GS. FRA interneurones could show either an increase or a cessation of their spontaneous activity, but responsiveness to nociceptive and non-nociceptive afferent activation was blocked by DAMGO. The main DAMGO action is generated via interneuronal systems rather than on motoneurones themselves. The results indicate that opioidergic spinal functions are extensively involved in spinal motor control exceeding a mere suppression of nociceptive motor withdrawal reactions. PMID- 21276827 TI - Physiological correlates and emotional specificity of human piloerection. AB - Piloerection is known as an indicator of strong emotional experiences. However, little is known about the physiological and emotional specificity of this psychophysiological response. In the presented study, piloerection was elicited by audio stimuli taken from music and film episodes. The physiological response accompanying the incidence of piloerection was recorded with respect to electrodermal, cardiovascular and respiratory measures and compared to a matched control condition. The employment of an optical recording system allowed for a direct and objective assessment of visible piloerection. The occurrence of piloerection was primarily accompanied by an increase of phasic electrodermal activity and increased respiration depth as compared to a matched control condition. This physiological response pattern is discussed in the context of dominant theories of human piloerection. Consideration of all available evidence suggests that emotional piloerection represents a valuable indicator of the state of being moved or touched. PMID- 21276828 TI - Metabotropic glutamate mGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT2A receptor agonists. AB - Hallucinogenic drugs, including mescaline, psilocybin and lysergic acid diethylamide (LSD), act at serotonin 5-HT2A receptors (5-HT2ARs). Metabotropic glutamate receptor 2/3 (mGluR2/3) ligands show efficacy in modulating the responses induced by activation of 5-HT2ARs. The formation of a 5-HT2AR-mGluR2 complex suggests a functional interaction that affects the hallucinogen-regulated cellular signaling pathways. Here, we tested the cellular and behavioral effects of hallucinogenic 5-HT2AR agonists in mGluR2 knockout (mGluR2-KO) mice. Mice were intraperitoneally injected with the hallucinogens DOI (2 mg/kg) and LSD (0.24 mg/kg), or vehicle. Head-twitch behavioral response, expression of c-fos, which is induced by all 5-HT2AR agonists, and expression of egr-2, which is hallucinogen-specific, were determined in wild type and mGluR2-KO mice. [(3)H]Ketanserin binding displacement curves by DOI were performed in mouse frontal cortex membrane preparations. Head twitch behavior was abolished in mGluR2-KO mice. The high-affinity binding site of DOI was undetected in mGluR2-KO mice. The hallucinogen DOI induced c-fos in both wild type and mGluR2-KO mice. However, the induction of egr-2 by DOI was eliminated in mGlu2-KO mice. These findings suggest that the 5-HT2AR-mGluR2 complex is necessary for the neuropsychological responses induced by hallucinogens. PMID- 21276829 TI - Influence of gymnastics training on the development of postural control. AB - This study investigated the influence of gymnastics training on the postural control of children with and without the use of visual information. Two age groups, aged 5-7 and 9-11 years old, of gymnasts and nongymnasts were asked to maintain an upright and quiet stance on a force platform with eyes open (EO) and eyes closed (EC) for 30s. Area of the stabilogram (AOS) and mean velocity of the center of pressure (COP) in anterior-posterior (AP) and medial-lateral (ML) directions were calculated and used to investigate the effects of gymnastics training, age, and visual information. Younger gymnasts presented greater postural control compared to younger nongymnasts while visual information did not improve postural control in younger nongymnasts. Younger gymnasts displayed improved postural control with EO compared to EC. The mean velocity of the COP in the ML direction was: less for younger gymnasts than younger nongymnasts with EO. These results suggest that gymnastics training promotes improvements in postural control of younger children only, which results from their use of visual information when available. PMID- 21276830 TI - The effect of static and dynamic visual gestures on stuttering inhibition. AB - The aim of the study was to evaluate the role of steady-state and dynamic visual gestures of vowels in stuttering inhibition. Eight adults who stuttered recited sentences from memory while watching video presentations of the following visual speech gestures: (a) a steady-state /u/, (b) dynamic production of /a-i-u/, (c) steady-state /u/ with an accompanying audible 1 kHz pure tone, and (d) dynamic production of /a-i-u/ with an accompanying audible 1 kHz pure tone. A 1 kHz pure tone and a no-external signal condition served as control conditions. Results revealed a significant main effect of auditory condition on stuttering frequency. Relative to the no-external signal condition, the combined visual plus pure tone conditions resulted in a statistically significant reduction in stuttering frequency. In addition, a significant difference in stuttering frequency was also observed when the visual plus pure tone conditions were compared to the visual only conditions. However, no significant differences were observed between the no external signal condition and visual only conditions, or the no-external signal condition and pure tone condition. These findings are in contrast to previous findings demonstrated by similar vowel gestures presented via the auditory modality that resulted in high levels of stuttering inhibition. The differential role of sensory modalities in speech perception and production as well as their individual capacities to transfer gestural information for the purposes of stuttering inhibition is discussed. PMID- 21276831 TI - In vitro effects of neuropeptide Y in rat neocortical and hippocampal tissue. AB - Neuropeptide Y (NPY) network effects in hippocampus and frontal cortex and its impact on epileptiform neocortical discharges were investigated in rat juvenile brain slices. NPY (1 MUM) reduced amplitudes of paired pulse stimulation in hippocampal brain tissue (p<0.05) whereas NPY (1 nM-2 MUM) had no effect in neocortex. Late stage epileptiform activity in the neocortex was unaffected by NPY (1 MUM). Our results point to a region dependent effect of NPY with a high impact on hippocampal and minimal impact on neocortical networks. PMID- 21276832 TI - Adaptation of gaze anchoring through practice in young and older adults. AB - During visually guided manual movements, gaze is usually fixated to a target until a pointing movement is completed to that target, showing gaze anchoring. We previously examined gaze anchoring during a two-segment eye-hand task under a low accuracy constraint. Eye movements were made to predetermined first and second targets, while hand movements were varied across two conditions: (1) stop at the first target and discontinue (HS1) and (2) stop at both the first and the second targets (HS1S2). Young adults previously broke gaze anchoring at the first target only when the second pointing was excluded (HS1). However, older adults did not break gaze anchoring for either condition. The present study further investigated whether young and older adults break gaze anchoring through short-term practice under the same conditions. An HS1 practice proceeded to an HS1S2 practice. The results showed that the timing of terminating gaze anchoring relative to pointing completion oscillated considerably during the HS1 practice until it was stabilized. Conversely, that timing was stable during the HS1S2 practice. Nevertheless, the young adults benefited from the HS1 practice and broke gaze anchoring even when the second pointing was included in HS1S2. This indicates that gaze anchoring to pointing completion is not a prerequisite for the production of subsequent pointing. By contrast, older adults did not improve the timing of gaze anchoring termination for either practice condition, thereby failing to break gaze anchoring. Thus, aging compromises a predictive control of terminating gaze anchoring relative to pointing completion, which is difficult to overcome through short-term practice. PMID- 21276833 TI - Tin chloride enhances parvalbumin-positive interneuron survival by modulating heme metabolism in a model of cerebral ischemia. AB - SnCl(2) has been reported to increase the expression of heme-oxygenase 1 (HO-1), a major antioxidant enzyme, and to decrease ischemic injury, in non-nervous tissues. This study examined the neuroprotective effect of SnCl(2) in the hippocampus of rats submitted to cerebral ischemia. SnCl(2) was administered 18 h before bilateral carotids obstruction. Changes in HO-1 expression and activity, heme content, inducible nitric oxide synthase (iNOS) expression and parvalbumin positive interneuron survival were studied. Thereafter both behavior and memory recovery were tested. The administration of SnCl(2) increased the expression of HO-1 protein and HO activity in the hippocampus and concomitantly decreased heme content at both mitochondrial and nuclear level. Furthermore, ischemized animals showed a strong increase in iNOS expression in the hippocampus, where a loss of parvalbumin positive interneurons also occurred. Pre-treatment with SnCl(2), decreased both iNOS expression in ischemized rats and increased cell survival. The beneficial effects of SnCl(2) were prevented by concomitant treatment with SnMP, a strong inhibitor of HO activity. SnCl(2) also caused an improvement in short term memory recovery. Our results showed that following SnCl(2) administration, HO-1 is strongly induced in the hippocampus and modulate iNOS expression, resulting in a strong neuroprotective effect. PMID- 21276834 TI - Baicalin prevents the production of hydrogen peroxide and oxidative stress induced by Abeta aggregation in SH-SY5Y cells. AB - Alzheimer's disease (AD) is a common form of neurodegenerative disease. Mounting evidence suggests that metal ions play a key role in the aggregation of amyloid beta peptide (Abeta), which acts as a factor or cofactor in the etiopathogenesis of AD. Therefore, inhibition of Abeta aggregation emerges as a potential approach for the treatment of AD. We have found that baicalin can interact with copper directly and inhibits Abeta1-42 aggregation. In addition, baicalin protects SH SY5Y cells from oxidative injuries induced by Abeta1-42 aggregation through decreasing H(2)O(2) production that is normally formed as a deleterious by product of beta amyloid aggregation and the formation of plaques. Taken together, these data indicate that baicalin may be a potential agent to inhibit Abeta aggregation and thereby delay, mitigate or modify the progression of neurodegenerative diseases such as AD. PMID- 21276835 TI - Kisspeptin-10 elicits triphasic cytosolic calcium responses in immortalized GT1-7 GnRH neurones. AB - Kisspeptins, which are alternatively called as metastin since they were originally identified as products of metastasis suppressor gene KiSS-1, are the natural ligands for the G protein-coupled receptor 54 (GPR54). Kisspeptins are the most potent activators of hypothalamic-pituitary-gonadal (HPG) axis reported to date. The pulsatile pattern of GnRH release, which results in the intermittent release of gonadotropic hormones from the pituitary, has a critical importance for reproductive function but the factors responsible from this release pattern are not known. Therefore, the pattern of kisspeptin-induced intracellular signaling and the role of PKC in the intracellular signaling cascade were investigated by fluorescence calcium imaging using the immortalized GnRH secreting GT1-7 hypothalamic neurons. Kisspeptin-10 caused a triphasic change characterized by an initial small increase followed by a significant decrease and increase in intracellular free calcium concentrations ([Ca(2+)](i)). The changes in [Ca(2+)](i) were significantly attenuated by pre-treatment with protein kinase C inhibitor. The compatibility of appeared mirrored-patterns of kisspeptin-10 induced changes in [Ca(2+)](i) concentrations in these neurons and GnRH secretion confirm the importance of intracellular calcium flux downstream from GPR54 through PKC signaling pathway. PMID- 21276836 TI - Seasonal variations of Substance P in the striatum of the female rat are affected by maternal and offspring pinealectomy. AB - The effect of pinealectomy (PIN-X) and PIN-X+melatonin treatment during pregnancy (PIN-X+MEL) 100MUg/100g body weight on Substance P (SP) in the striatum was investigated in offspring female rats. Female offspring were divided into control and PIN-X at the neonatal period, and studied at days 31 and 60. PIN-X mother/control offspring showed a positive influence on striatal SP values in winter, at both ages and in spring at day 31. However, this effect of maternal PIN-X was not observed in summer or fall. The effect of PIN-X on the offspring showed a positive effect in spring at day 31 and summer at the two ages studied. This effect was not observed in fall or winter. Two generations, PIN-X mother/PIN X offspring, altered the effect of mother or offspring PIN-X and decreased the SP values in winter, spring and summer. Only striatal SP at day 60 in fall was increased. In two generations PIN-X, the striatal SP values were similar to those observed in control mother/control offspring. The effect of PIN-X+MEL treatment on mothers during pregnancy was inhibitory for the intact offspring and stimulatory for PIN-X offspring. In conclusion, the results indicate that maternal and offspring PIN-X seem to exert a rotative and positive seasonal influence from winter to spring to summer. Two generations PIN-X disrupted this rotative circuit and in fall a compensatory discharge of SP was observed. PMID- 21276838 TI - Structure-activity relationship of acridine derivatives to amyloid aggregation of lysozyme. AB - BACKGROUND: Amyloid-related diseases (such as Alzheimer's disease or diabetes type II) are associated with self-assembly of protein into amyloid aggregates. METHODS: Spectroscopic and atomic force microscopy were used to determine the ability of acridines to affect amyloid aggregation of lysozyme. RESULTS: We have studied the effect of acridine derivatives on the amyloid aggregation of lysozyme to investigate the acridine structure-activity relationship. The activity of the effective planar acridines was characterized by the half-maximum depolymerization concentration DC(50) and half-maximal inhibition concentration IC(50). For the most effective acridine derivatives we examined their interaction with DNA and their effect on cell viability in order to investigate their eventual influence on cells. We thus identified planar acridine derivatives with intensive anti amyloid activity (IC(50) and DC(50) values in micromolar range), low cytotoxicity and weak ability to interfere with the processes in the cell. CONCLUSIONS: Our findings indicate that both the planarity and the tautomerism of the 9 aminoacridine core together with the reactive nucleophilic thiosemicarbazide substitution play an important role in the anti-amyloid activities of studied derivatives. GENERAL SIGNIFICANCE: The present findings favor the application of the selected active planar acridines in the treatment of amyloid-related diseases. PMID- 21276837 TI - Biochemical effects of ozone on asthma during postnatal development. AB - BACKGROUND: Ozone exposure during early life has the potential to contribute to the development of asthma as well as to exacerbate underlying allergic asthma. SCOPE OF REVIEW: Developmentally regulated aspects of sensitivity to ozone exposure and downstream biochemical and cellular responses. MAJOR CONCLUSIONS: Developmental differences in antioxidant defense responses, respiratory physiology, and vulnerabilities to cellular injury during particular developmental stages all contribute to disparities in the health effects of ozone exposure between children and adults. GENERAL SIGNIFICANCE: Ozone exposure has the capacity to affect multiple aspects of the "effector arc" of airway hyperresponsiveness, ranging from initial epithelial damage and neural excitation to neural reprogramming during infancy. This article is part of a Special Issue entitled: Biochemistry of Asthma. PMID- 21276839 TI - Dynamics of choice during estimation of subjective value. AB - This study characterized preferential choice in binary trials and investigated intra-session variations in response time (RT). In Experiment 1, participants (N=77) were asked to choose the preferred of two images of body wash; all unique combinations of 19 images were presented. The results showed: (a) marked and consistent individual preferences for specific stimuli; (b) RT decreased monotonically with increasing exposure to each stimulus; (c) RT decreased exponentially as a function of relative preference ranking of the 2 images in a trial; and (d) a regression model efficiently predicted trial RT as a function of exposure and relative preference. Experiment 2 (N=112) explored the effect of amount of exposure on RT, and relative preference as a function of the type of choice task (a previously completed vs. a new choice task). The results showed that: (a) within a single choice task, amount of exposure and relative preference between the stimuli predicted the systematic changes in RT observed in Exp. 1; and (b) when the choice task changed, the effects of previous amount of exposure, and relative stimulus preference did not transfer to the new task. PMID- 21276840 TI - Transcriptional regulation of bone sialoprotein gene by interleukin-11. AB - Interleukin-11 (IL-11) is a stromal cell-derived cytokine that belongs to the interleukin-6 family of cytokines. IL-11 has many biological activities and has roles in hematopoiesis, immune responses, the nervous system and bone metabolism. Bone sialoprotein (BSP) is a mineralized tissue-specific protein expressed in differentiated osteoblasts that appears to function in the initial mineralization of bone. IL-11 (20 ng/ml) increased BSP mRNA and protein levels at 12h in osteoblast-like ROS 17/2.8 cells. In a transient transfection assay, IL-11 (20 ng/ml) increased luciferase activity of the construct (-116 to +60) in ROS 17/2.8 cells and rat bone marrow stromal cells. Introduction of 2 bp mutations to the luciferase constructs showed that the effects of IL-11 were mediated by a cAMP response element (CRE), a fibroblast growth factor 2 response element (FRE) and a homeodomain protein-binding site (HOX). Luciferase activities induced by IL-11 were blocked by protein kinase A inhibitor, tyrosine kinase inhibitor and ERK1/2 inhibitor. Gel shift analyses showed that IL-11 (20 ng/ml) increased nuclear protein binding to CRE, FRE and HOX. CREB1, phospho-CREB1, c-Fos, c-Jun, JunD and Fra2 antibodies disrupted the formation of CRE-protein complexes. Dlx5, Msx2, Runx2 and Smad1 antibodies disrupted FRE- and HOX-protein complex formations. These studies demonstrate that IL-11 stimulates BSP transcription by targeting CRE, FRE and HOX sites in the proximal promoter of the rat BSP gene. Moreover, phospho-CREB1, c-Fos, c-Jun, JunD, Fra2, Dlx5, Msx2, Runx2 and Smadl transcription factors appear to be key regulators of IL-11 effects on BSP transcription. PMID- 21276841 TI - Development of tonotopy in the auditory periphery. AB - Acoustic frequency analysis plays an essential role in sound perception, communication and behavior. The auditory systems of most vertebrates that perceive sounds in air are organized based on the separation of complex sounds into component frequencies. This process begins at the level of the auditory sensory epithelium where specific frequencies are distributed along the tonotopic axis of the mammalian cochlea or the avian/reptilian basilar papilla (BP). Mechanical and electrical mechanisms mediate this process, but the relative contribution of each mechanism differs between species. Developmentally, structural and physiological specializations related to the formation of a tonotopic axis form gradually over an extended period of time. While some aspects of tonotopy are evident at early stages of auditory development, mature frequency discrimination is typically not achieved until after the onset of hearing. Despite the importance of tonotopic organization, the factors that specify unique positional identities along the cochlea or basilar papilla are unknown. However, recent studies of developing systems, including the inner ear provide some clues regarding the signalling pathways that may be instructive for the formation of a tonotopic axis. PMID- 21276842 TI - Lateral superior olive function in congenital deafness. AB - The development of cochlear implants for the treatment of patients with profound hearing loss has advanced considerably in the last few decades, particularly in the field of speech comprehension. However, attempts to provide not only sound decoding but also spatial hearing are limited by our understanding of circuit adaptations in the absence of auditory input. Here we investigate the lateral superior olive (LSO), a nucleus involved in interaural level difference (ILD) processing in the auditory brainstem using a mouse model of congenital deafness (the dn/dn mouse). An electrophysiological investigation of principal neurons of the LSO from the dn/dn mouse reveals a higher than normal proportion of single spiking (SS) neurons, and an increase in the hyperpolarisation-activated I(h) current. However, inhibitory glycinergic input to the LSO appears to develop normally both pre and postsynaptically in dn/dn mice despite the absence of auditory nerve activity. In combination with previous electrophysiological findings from the dn/dn mouse, we also compile a simple Hodgkin and Huxley circuit model in order to investigate possible computational deficits in ILD processing resulting from congenital hearing loss. We find that the predominance of SS neurons in the dn/dn LSO may compensate for upstream modifications and help to maintain a functioning ILD circuit in the dn/dn mouse. This could have clinical repercussions on the development of stimulation paradigms for spatial hearing with cochlear implants. PMID- 21276843 TI - Complex primary afferents: What the distribution of electrophysiologically relevant phenotypes within the spiral ganglion tells us about peripheral neural coding. AB - Spiral ganglion neurons are the first neural element of the auditory system. They receive precise synaptic signals which represent features of sound stimuli encoded by hair cell receptors and they deliver a digital representation of this information to the central nervous system. It is well known that spiral ganglion neurons are selectively responsive to specific sound frequencies, and that numerous structural and physiological specializations in the inner ear increase the quality of this tuning, beyond what could be accomplished by the passive properties of the basilar membrane. Further, consistent with what we know about other sensory systems, it is becoming clear that the parallel divergent innervation pattern of type I spiral ganglion neurons has the potential to encode additional features of sound stimuli. To date, we understand the most about the sub-modalities of frequency and intensity coding in the peripheral auditory system. Work reviewed herein will address the issue of how intrinsic electrophysiological features of the neurons themselves have the potential to contribute to the precision of coding and transmitting information about these two parameters to higher auditory centers for further processing. PMID- 21276844 TI - Recalibration of the auditory continuity illusion: sensory and decisional effects. AB - An interrupted sound can be perceived as continuous when noise masks the interruption, creating an illusion of continuity. Recent findings have shown that adaptor sounds preceding an ambiguous target sound can influence listeners' rating of target continuity. However, it remains unclear whether these aftereffects on perceived continuity influence sensory processes, decisional processes (i.e., criterion shifts), or both. The present study addressed this question. Results show that the target sound was more likely to be rated as 'continuous' when preceded by adaptors that were perceived as clearly discontinuous than when it was preceded by adaptors that were heard (illusorily or veridically) as continuous. Detection-theory analyses indicated that these contrastive aftereffects reflect a combination of sensory and decisional processes. The contrastive sensory aftereffect persisted even when adaptors and targets were presented to opposite ears, suggesting a neural origin in structures that receive binaural inputs. Finally, physically identical but perceptually ambiguous adaptors that were rated as 'continuous' induced more reports of target continuity than adaptors that were rated as 'discontinuous'. This assimilative aftereffect was purely decisional. These findings confirm that judgments of auditory continuity can be influenced by preceding events, and reveal that these aftereffects have both sensory and decisional components. PMID- 21276845 TI - A critical analysis of single-frequency LCR databridge impedance measurements of human skin. AB - Testing whether the barrier of skin samples has sufficient integrity for meaningful measurements of in-vitro chemical permeability is usually required when data are generated for regulatory purposes. Recently, skin integrity has been assessed using LCR databridge measurements, which are reported as resistances determined in either series (SER) or parallel (PAR) modes at a single frequency, typically 100 or 1000Hz. Measurements made at different combinations of mode and frequency are known to differ, although the skin literature reveals confusion over the meaning of these differences and the impact on the interpretation of integrity test results. Here, the theoretical meanings of resistance and capacitance measurements in PAR and SER mode are described and confirmed experimentally. SER-mode resistances are equal to the real part of the complex impedance; whereas, PAR-mode resistances are the inverse of the real part of the admittance. Capacitance measurements reported in SER and PAR modes are similar manipulations of the imaginary parts of the complex impedance and admittance. A large body of data from human cadaver skin is used to show that the PAR-mode resistance and SER-mode capacitance measured at 100Hz are sensitive to skin resistivity, which is the electrical measurement most closely related to skin integrity. PMID- 21276846 TI - Ethylacetate fraction from Korean seaside starfish, Asterias amurensis, has an inhibitory effect on MMP-9 activity and expression and on migration behavior of TNF-alpha induced human aortic smooth muscle cells. AB - Atherosclerosis is accompanied by the proliferation of human aortic smooth muscle cells (HASMC) and their movement into the intima. Many reports have indicated the involvement of gelatinases (MMP-9 and MMP-2) in this pathogenesis. The ethylacetate fraction from starfish, Asterias amurensis (EFA), harvested from the Korean seaside has an inhibitory effect on MMP-9 and MMP-2 activities, as well as on the expression of MMP-9 in TNF-alpha induced HASMC in a dose-dependent manner. Also, EFA inhibits the migration of TNF-alpha induced HASMC in transwells containing gelatin coated plugs. EFA was not cytotoxic to HASMC over the range 0 1mg/ml. By Western-blot analysis, it was revealed that the phosphorylation of extracellular signal regulated kinase (ERK) in TNF-alpha induced cells was inhibited and nuclear factor kappa B (NF-kappaB) p65 levels in nuclear extracts were decreased by EFA treatment. In addition, ERK inhibitor (U0126) treated cells exhibited decreased MMP-9 activity in the zymographic assay. From these results, it was found that the gelatinolytic activity was regulated (1) by enzymatic inhibition of both MMP-9 and MMP-2, as well as (2) by the decreased production of MMP-9 via ERK pathways in EFA treated HASMCs. Taken together, it has been shown that EFA has a putative anti-atherosclerotic effect. PMID- 21276847 TI - Chronic blockade of glucocorticoid receptors by RU486 enhances lipopolysaccharide induced depressive-like behaviour and cytokine production in rats. AB - Although accumulating evidence supports a role for cytokines in the pathophysiology of depression, the cytokine hypothesis of depression is debatable. It has been suggested that neuroendocrine and immune systems acting in concert may have roles in the development and the maintenance of the disease. Glucocorticoid receptor (GR) is the key element which exerts both anti inflammatory and cytokine-inhibiting effects. Whether functional changes of GR are involved in the pathophysiology of cytokine-induced depression remains elusive. In the present study, the effects of both acute and chronic GR blockade on depressive-like behaviour and cytokine production induced by lipopolysaccharides (LPS), cytokine inducer, were investigated in rats. Acute or chronic blockade of GR was achieved by a single administration or repeated administrations, respectively, of the GR antagonist RU486 (RU). Behavioural measurements, including saccharin preference, locomotor activity, and immobility time, were assessed. The serum levels of proinflammatory cytokines (TNFalpha, IL 1beta, and IFNgamma) were determined by ELISA. The results showed that LPS induced significant but transient depressive-like behaviour. Repeated, but not single, administration of RU significantly enhanced and prolonged LPS-induced depressive-like behaviour and an increase in the serum production of TNFalpha and IFNgamma. These results indicate that the effective blockade of GR enhanced the depressive-like behaviour induced by cytokines. Findings from this study suggest that GR dysfunction may be an important contributing factor to the development of cytokine-related depression. These findings add to the growing evidence of mechanisms by which cytokines influence depression. PMID- 21276848 TI - Attenuation of microglial and IL-1 signaling protects mice from acute alcohol induced sedation and/or motor impairment. AB - Alcohol-induced proinflammatory central immune signaling has been implicated in the chronic neurotoxic actions of alcohol, although little work has examined if these non-neuronal actions contribute to the acute behavioral responses elicited by alcohol administration. The present study examined if acute alcohol-induced sedation (loss of righting reflex, sleep time test) and motor impairment (rotarod test) were influenced by acute alcohol-induced microglial-dependent central immune signaling. Inhibition of acute alcohol-induced central immune signaling, through the reduction of proinflammatory microglial activation with minocycline, or by blocking interleukin-1 (IL-1) receptor signaling using IL-1 receptor antagonist (IL-1ra), reduced acute alcohol-induced sedation in mice. Mice treated with IL-1ra recovered faster from acute alcohol-induced motor impairment than control animals. However, minocycline led to greater motor impairment induced by alcohol, implicating different mechanisms in alcohol-induced sedation and motor impairment. At a cellular level, IkappaBalpha protein levels in mixed hippocampal cells responded rapidly to alcohol in a time-dependent manner, and both minocycline and IL-1ra attenuated the elevated levels of IkappaBalpha protein by alcohol. Collectively these data suggest that alcohol is capable of rapid modification of proinflammatory immune signaling in the brain and this contributes significantly to the pharmacology of alcohol. PMID- 21276849 TI - Measurement of plasma hydrogen sulfide in vivo and in vitro. AB - The gasotransmitter hydrogen sulfide is known to regulate multiple cellular functions during normal and pathophysiological states. However, a paucity of concise information exists regarding quantitative amounts of hydrogen sulfide involved in physiological and pathological responses. This is primarily due to disagreement among various methods employed to measure free hydrogen sulfide. In this article, we describe a very sensitive method of measuring the presence of H2S in plasma down to nanomolar levels, using monobromobimane (MBB). The current standard assay using methylene blue provides erroneous results that do not actually measure H2S. The method presented herein involves derivatization of sulfide with excess MBB in 100 mM Tris-HCl buffer (pH 9.5, 0.1 mM DTPA) for 30 min in 1% oxygen at room temperature. The fluorescent product sulfide-dibimane (SDB) is analyzed by RP-HPLC using an eclipse XDB-C18 (4.6 * 250 mm) column with gradient elution by 0.1% (v/v) trifluoroacetic acid in acetonitrile. The limit of detection for sulfide-dibimane is 2 nM and the SDB product is very stable over time, allowing batch storage and analysis. In summary, our MBB method is suitable for sensitive quantitative measurement of free hydrogen sulfide in multiple biological samples such as plasma, tissue and cell culture lysates, or media. PMID- 21276850 TI - Proteasome inhibitor-I enhances tunicamycin-induced chemosensitization of prostate cancer cells through regulation of NF-kappaB and CHOP expression. AB - Although endoplasmic reticulum (ER) stress induction by some anticancer drugs can lead to apoptotic death of cancer cells, combination therapy with other chemicals would be much more efficient. It has been reported that proteasome inhibitors could induce cancer cell death through ER-stress. Our study, however, showed a differential mechanism of proteasome inhibitor-I (Pro-I)-induced cell death. Pro I significantly enhanced apoptotic death of PC3 prostate cancer cells pretreated with tunicamycin (TM) while other signaling inhibitors against p38, mitogen activated kinase (MEK) and phosphatidyl-inositol 3-kinase (PI3K) did not, as evidenced by cell proliferation and cell cycle analyses. NF-kappaB inhibition by Pro-I, without direct effect on ER-stress, was found to be responsible for the TM induced chemosensitization of PC3 cells. Moreover, TM-induced/enhancer-binding protein (C/EBP) homologous protein (CHOP) expression was enhanced by Pro-I without change in GRP78 expression. CHOP knockdown by siRNA also showed a significant decrease in Pro-I chemosensitization. All these data suggest that although TM could induce both NF-kappaB activation and CHOP expression through ER stress, both NF-kappaB inhibition and increased CHOP level by Pro-I are required for enhanced chemosensitization of PC3 prostate cancer cells. Thus, our study might contribute to the identification of anticancer targets against prostate cancer cells. PMID- 21276851 TI - Extended Fujita approach to the molecular weight distribution of polysaccharides and other polymeric systems. AB - In 1962 H. Fujita (H. Fujita, Mathematical Theory of Sedimentation Analysis, Academic Press, New York, 1962) examined the possibility of transforming a quasi continuous distribution g(s) of sedimentation coefficient s into a distribution f(M) of molecular weight M for linear polymers using the relation f(M)=g(s).(ds/dM) and showed that this could be done if information about the relation between s and M is available from other sources. Fujita provided the transformation based on the scaling relation s=kappa(s)M(0.5), where kappa(s) is taken as a constant for that particular polymer and the exponent 0.5 essentially corresponds to a randomly coiled polymer under ideal conditions. This method has been successfully applied to mucus glycoproteins (S.E. Harding, Adv. Carbohyd. Chem. Biochem. 47 (1989) 345-381). We now describe an extension of the method to general conformation types via the scaling relation s=kappaM(b), where b=0.4-0.5 for a coil, ~0.15-0.2 for a rod and ~0.67 for a sphere. We give examples of distributions f(M) versus M obtained for polysaccharides from SEDFIT derived least squares g(s) versus s profiles (P. Schuck, Biophys. J. 78 (2000) 1606-1619) and the analytical derivative for ds/dM performed with Microcal ORIGIN. We also describe a more direct route from a direct numerical solution of the integral equation describing the molecular weight distribution problem. Both routes give identical distributions although the latter offers the advantage of being incorporated completely within SEDFIT. The method currently assumes that solutions behave ideally: sedimentation velocity has the major advantage over sedimentation equilibrium in that concentrations less than 0.2mg/ml can be employed, and for many systems non-ideality effects can be reasonably ignored. For large, non-globular polymer systems, diffusive contributions are also likely to be small. PMID- 21276852 TI - Crystal structure of YdaL, a stand-alone small MutS-related protein from Escherichia coli. AB - Sequence homologs of the small MutS-related (Smr) domain, the C-terminal endonuclease domain of MutS2, also exist as stand-alone proteins. In this study, we report the crystal structure of a proteolyzed fragment of YdaL (YdaL39-175), a stand-alone Smr protein from Escherichia coli. In this structure, residues 86-170 assemble into a classical Smr core domain and are embraced by an N-terminal extension (residues 40-85) with an alpha/beta/alpha fold. Sequence alignment indicates that the N-terminal extension is conserved among a number of stand alone Smr proteins, suggesting structural diversity among Smr domains. We also discovered that the DNA binding affinity and endonuclease activity of the truncated YdaL39-175 protein were slightly lower than those of full-length YdaL1 187, suggesting that residues 1-38 may be involved in DNA binding. PMID- 21276853 TI - Crystal structure of Sa240: a ribose pyranase homolog with partial active site from Staphylococcus aureus. AB - Ribose is transported into cells in its pyranose form and must be rearranged to its furanose form for further utilization. Ribose pyranase RbsD catalyzes the conversion of ribose from the pyranose to furanose form. This is the key step for substrate supply to ribokinase RbsK, which converts ribose to ribose-5-phosphate for further metabolism. Sequence analysis indicated Sa240 from Staphylococcus aureus was a ribose pyranase homolog. Here we showed that Sa240 formed dimeric structure both in solution and in crystal. S240-ribose complex structure showed a ribose binding site formed by an incomplete active site compared with RbsD. Because the catalytic activity of ribose pyranase depends on its oligomeric state, we propose Sa240 is catalytically inactive in its dimeric structure. PMID- 21276854 TI - Dynamic properties of extremophilic subtilisin-like serine-proteases. AB - The investigation of the structural determinants of enzymatic temperature adaptation is a crucial pre-requisite both in terms of fundamental research and industrial applications to develop new biocatalysts active at different temperature ranges. In several cases, the differences related to cold- or warm adaptation are related to subtle structural and aminoacidic differences at the molecular level, often hard to detect. In this context, we present a comparative study of psychrophilic, mesophilic and thermophilic subtilisin-like serine proteases by all-atom molecular dynamics (MD) simulations in explicit solvent using a multiple-replica approach. Our results strongly enforce the current view on localized flexibility in crucial functional regions for cold-adapted serine proteases and point out a different optimization and usage of salt-bridge interactions and networks in cold- and warm-adapted enzymes. The analyses allow to identify a subset of structural and dynamic features strictly associated to cold adaptation and which change from cold- to heat-active subtilisins. In particular, the thermophilic subtilisin presents a high affinity calcium binding site which is not structurally conserved in the mesophilic and psychrophilic counterparts, which, as it turns out from the MD analyses, at the same position show a stable salt bridge network and no stabilizing intra-molecular interactions, respectively. These aspects, along with differential flexibility in regions close to the active site or substrate binding pocket, can be an indication of evolution at this protein site toward a lower stability moving from high to low temperature conditions. PMID- 21276855 TI - Molecular cloning and characterization of Foxp3 in Atlantic salmon (Salmo salar). AB - Foxp3 is a T cell-specific transcription factor and plays a key role in the development of Treg cells and in the immune regulatory process during inflammation. Here we report cloning and characterization of the full-length cDNA of Atlantic salmon Foxp3, which possesses a Forkhead domain, a zinc finger domain and a leucine-zipper domain as its counterpart in mammals. Foxp3 is highly expressed in thymus. Furthermore, regulated expression was observed in head kidney cells in response to beta-glucan and mitogens (LPS and ConA), and in the head kidney, spleen and liver after intraperitoneal injection of live Aeromonas salmonicida. In addition, transfection of CHSE-214 cells with salmon Foxp3 fused with a C-termial RFP tag, resulted in the expression of the transgene in and close to the nuclei upon stimulation. Taken together, these results suggest the presence of a Foxp3 gene in Atlantic salmon that may be an important transcription factor in immune regulation, and further research may reveal the existence of Treg-like T cells in this species. PMID- 21276857 TI - An improved index of phase-synchronization for electrophysiological data in the presence of volume-conduction, noise and sample-size bias. AB - Phase-synchronization is a manifestation of interaction between neuronal groups measurable from LFP, EEG or MEG signals, however, volume conduction can cause the coherence and the phase locking value to spuriously increase. It has been shown that the imaginary component of the coherency (ImC) cannot be spuriously increased by volume-conduction of independent sources. Recently, it was proposed that the phase lag index (PLI), which estimates to what extent the phase leads and lags between signals from two sensors are nonequiprobable, improves on the ImC. Compared to ImC, PLI has the advantage of being less influenced by phase delays. However, sensitivity to volume-conduction and noise, and capacity to detect changes in phase-synchronization, is hindered by the discontinuity of the PLI, as small perturbations turn phase lags into leads and vice versa. To solve this problem, we introduce a related index, namely the weighted phase lag index (WPLI). Differently from PLI, in WPLI the contribution of the observed phase leads and lags is weighted by the magnitude of the imaginary component of the cross-spectrum. We demonstrate two advantages of the WPLI over the PLI, in terms of reduced sensitivity to additional, uncorrelated noise sources and increased statistical power to detect changes in phase-synchronization. Another factor that can affect phase-synchronization indices is sample-size bias. We show that, when directly estimated, both PLI and the magnitude of the ImC have typically positively biased estimators. To solve this problem, we develop an unbiased estimator of the squared PLI, and a debiased estimator of the squared WPLI. PMID- 21276856 TI - Characterizing Alzheimer's disease using a hypometabolic convergence index. AB - This article introduces a hypometabolic convergence index (HCI) for the assessment of Alzheimer's disease (AD); compares it to other biological, cognitive and clinical measures; and demonstrates its promise to predict clinical decline in mild cognitive impairment (MCI) patients using data from the AD Neuroimaging Initiative (ADNI). The HCI is intended to reflect in a single measurement the extent to which the pattern and magnitude of cerebral hypometabolism in an individual's fluorodeoxyglucose positron emission tomography (FDG-PET) image correspond to that in probable AD patients, and is generated using a fully automated voxel-based image-analysis algorithm. HCIs, magnetic resonance imaging (MRI) hippocampal volume measurements, cerebrospinal fluid (CSF) assays, memory test scores, and clinical ratings were compared in 47 probable AD patients, 21 MCI patients who converted to probable AD within the next 18months, 76 MCI patients who did not, and 47 normal controls (NCs) in terms of their ability to characterize clinical disease severity and predict conversion rates from MCI to probable AD. HCIs were significantly different in the probable AD, MCI converter, MCI stable and NC groups (p=9e-17) and correlated with clinical disease severity. Using retrospectively characterized threshold criteria, MCI patients with either higher HCIs or smaller hippocampal volumes had the highest hazard ratios (HRs) for 18-month progression to probable AD (7.38 and 6.34, respectively), and those with both had an even higher HR (36.72). In conclusion, the HCI, alone or in combination with certain other biomarker measurements, has the potential to help characterize AD and predict subsequent rates of clinical decline. More generally, our conversion index strategy could be applied to a range of imaging modalities and voxel-based image-analysis algorithms. PMID- 21276858 TI - A novel method for reliable and fast extraction of neuronal EEG/MEG oscillations on the basis of spatio-spectral decomposition. AB - Neuronal oscillations have been shown to underlie various cognitive, perceptual and motor functions in the brain. However, studying these oscillations is notoriously difficult with EEG/MEG recordings due to a massive overlap of activity from multiple sources and also due to the strong background noise. Here we present a novel method for the reliable and fast extraction of neuronal oscillations from multi-channel EEG/MEG/LFP recordings. The method is based on a linear decomposition of recordings: it maximizes the signal power at a peak frequency while simultaneously minimizing it at the neighboring, surrounding frequency bins. Such procedure leads to the optimization of signal-to-noise ratio and allows extraction of components with a characteristic "peaky" spectral profile, which is typical for oscillatory processes. We refer to this method as spatio-spectral decomposition (SSD). Our simulations demonstrate that the method allows extraction of oscillatory signals even with a signal-to-noise ratio as low as 1:10. The SSD also outperformed conventional approaches based on independent component analysis. Using real EEG data we also show that SSD allows extraction of neuronal oscillations (e.g., in alpha frequency range) with high signal-to noise ratio and with the spatial patterns corresponding to central and occipito parietal sources. Importantly, running time for SSD is only a few milliseconds, which clearly distinguishes it from other extraction techniques usually requiring minutes or even hours of computational time. Due to the high accuracy and speed, we suggest that SSD can be used as a reliable method for the extraction of neuronal oscillations from multi-channel electrophysiological recordings. PMID- 21276859 TI - Improving quantification of functional networks with EEG inverse problem: evidence from a decoding point of view. AB - Decoding experimental conditions from single trial Electroencephalographic (EEG) signals is becoming a major challenge for the study of brain function and real time applications such as Brain Computer Interface. EEG source reconstruction offers principled ways to estimate the cortical activities from EEG signals. But to what extent it can enhance informative brain signals in single trial has not been addressed in a general setting. We tested this using the minimum norm estimate solution (MNE) to estimate spectral power and coherence features at the cortical level. With a fast implementation, we computed a support vector machine (SVM) classifier output from these quantities in real-time, without prior on the relevant functional networks. We applied this approach to single trial decoding of ongoing mental imagery tasks using EEG data recorded in 5 subjects. Our results show that reconstructing the underlying cortical network dynamics significantly outperforms a usual electrode level approach in terms of information transfer and also reduces redundancy between coherence and power features, supporting a decrease of volume conduction effects. Additionally, the classifier coefficients reflect the most informative features of network activity, showing an important contribution of localized motor and sensory brain areas, and of coherence between areas up to 6cm distance. This study provides a computationally efficient and interpretable strategy to extract information from functional networks at the cortical level in single trial. Moreover, this sets a general framework to evaluate the performance of EEG source reconstruction methods by their decoding abilities. PMID- 21276860 TI - Localization of extended brain sources from EEG/MEG: the ExSo-MUSIC approach. AB - We propose a new MUSIC-like method, called 2q-ExSo-MUSIC (q >= 1). This method is an extension of the 2q-MUSIC (q >= 1) approach for solving the EEG/MEG inverse problem, when spatially-extended neocortical sources ("ExSo") are considered. It introduces a novel ExSo-MUSIC principle. The novelty is two-fold: i) the parameterization of the spatial source distribution that leads to an appropriate metric in the context of distributed brain sources and ii) the introduction of an original, efficient and low-cost way of optimizing this metric. In 2q-ExSo-MUSIC, the possible use of higher order statistics (q >= 2) offers a better robustness with respect to Gaussian noise of unknown spatial coherence and modeling errors. As a result we reduced the penalizing effects of both the background cerebral activity that can be seen as a Gaussian and spatially correlated noise, and the modeling errors induced by the non-exact resolution of the forward problem. Computer results on simulated EEG signals obtained with physiologically-relevant models of both the sources and the volume conductor show a highly increased performance of our 2q-ExSo-MUSIC method as compared to the classical 2q-MUSIC algorithms. PMID- 21276862 TI - The neurophysiology of human biological motion processing: a high-density electrical mapping study. AB - The neural processing of biological motion (BM) is of profound experimental interest since it is often through the movement of another that we interpret their immediate intentions. Neuroimaging points to a specialized cortical network for processing biological motion. Here, high-density electrical mapping and source-analysis techniques were employed to interrogate the timing of information processing across this network. Participants viewed point-light-displays depicting standard body movements (e.g. jumping), while event-related potentials (ERPs) were recorded and compared to ERPs to scrambled motion control stimuli. In a pair of experiments, three major phases of BM-specific processing were identified: 1) The earliest phase of BM-sensitive modulation was characterized by a positive shift of the ERP between 100 and 200 ms after stimulus onset. This modulation was observed exclusively over the right hemisphere and source-analysis suggested a likely generator in close proximity to regions associated with general motion processing (KO/hMT). 2) The second phase of BM-sensitivity occurred from 200 to 350 ms, characterized by a robust negative-going ERP modulation over posterior middle temporal regions bilaterally. Source-analysis pointed to bilateral generators at or near the posterior superior temporal sulcus (STS). 3) A third phase of processing was evident only in our second experiment, where participants actively attended the BM aspect of the stimuli, and was manifest as a centro-parietal positive ERP deflection, likely related to later cognitive processes. These results point to very early sensory registration of biological motion, and highlight the interactive role of the posterior STS in analyzing the movements of other living organisms. PMID- 21276861 TI - Multi-contrast human neonatal brain atlas: application to normal neonate development analysis. AB - MRI is a sensitive method for detecting subtle anatomic abnormalities in the neonatal brain. To optimize the usefulness for neonatal and pediatric care, systematic research, based on quantitative image analysis and functional correlation, is required. Normalization-based image analysis is one of the most effective methods for image quantification and statistical comparison. However, the application of this methodology to neonatal brain MRI scans is rare. Some of the difficulties are the rapid changes in T1 and T2 contrasts and the lack of contrast between brain structures, which prohibits accurate cross-subject image registration. Diffusion tensor imaging (DTI), which provides rich and quantitative anatomical contrast in neonate brains, is an ideal technology for normalization-based neonatal brain analysis. In this paper, we report the development of neonatal brain atlases with detailed anatomic information derived from DTI and co-registered anatomical MRI. Combined with a diffeomorphic transformation, we were able to normalize neonatal brain images to the atlas space and three-dimensionally parcellate images into 122 regions. The accuracy of the normalization was comparable to the reliability of human raters. This method was then applied to babies of 37-53 post-conceptional weeks to characterize developmental changes of the white matter, which indicated a posterior-to anterior and a central-to-peripheral direction of maturation. We expect that future applications of this atlas will include investigations of the effect of prenatal events and the effects of preterm birth or low birth weights, as well as clinical applications, such as determining imaging biomarkers for various neurological disorders. PMID- 21276863 TI - Impact of EEG-vigilance on brain glucose uptake measured with [(18)F]FDG and PET in patients with depressive episode or mild cognitive impairment. AB - INTRODUCTION: [(18)F]fluorodeoxyglucose positron emission tomography ([(18)F]FDG PET) is a well-established method for the examination of the cerebral glucose metabolism of patients with affective disorder or memory impairment. An understudied question is how far results are influenced by interindividual differences in central nervous arousal as assessed with electroencephalogram (EEG vigilance) during the PET recording. Building upon previous neuroimaging studies, we supposed an association between EEG-vigilance and normalized brain [(18)F]FDG uptake (nFDGu) as measured by [(18)F]FDG-PET. For the first time, the present study exploratively investigated this association in a routine diagnostic work up. MATERIALS AND METHODS: Simultaneous 31-channel EEG and [(18)F]FDG-PET under resting conditions were acquired from 14 patients with depressive episode or mild cognitive impairment (MCI). EEG-vigilance was automatically classified by using the VIGALL algorithm (Vigilance Algorithm Leipzig). A nonparametric voxelwise simple linear regression with vigilance measure as predictor and nFDGu as criterion was performed using the Statistical nonParametric Mapping toolbox. RESULTS: The main finding was a significant negative correlation between vigilance measure and nFDGu in bilateral frontal and temporal regions, bilateral cingulate gyrus and right thalamus with vigilance-related changes of nFDGu between 17.1 and 44.4%. DISCUSSION: Simultaneous EEG and [(18)F]FDG-PET under resting conditions revealed that brain regions associated with EEG-vigilance partly overlapped with regions of impaired nFDGu in depression and MCI, as reported by previous studies. Vigilance-related changes of nFDGu were about the same magnitude as disease-related metabolic changes in patients with affective disorder or memory impairment as reported in previous studies. Therefore, our data suggest that differences in EEG-vigilance might influence alterations of nFDGu in disorders such as depression or MCI. Whether this possible impact of vigilance on nFDGu should be taken into account during the routine diagnostic application of [(18)F]FDG-PET has to be explored in future studies with larger patient groups. PMID- 21276864 TI - A novel alkaline serine protease with fibrinolytic activity from the polychaete, Neanthes japonica. AB - A new protease named NJP with fibrinolytic activity was isolated from Neanthes japonica (Izuka), by a combination of ammonium sulfate fractionation, hydrophobic chromatography, ion-exchange chromatography and gel filtration. The molecular mass of NJP was approximately 28.6-33.5kDa as estimated by MALDI-TOF mass spectrometry and SDS-PAGE, which revealed a monomeric form of the protease. The isoelectric point of NJP determined by 2-DE was 9.2. NJP was stable in the range of pH 7.0-11.0 with a maximum enzymatic activity at 40 degrees C and pH 9.0. The hydrolyzing activity of NJP on fibrinogen started from the Aalpha-chain, followed by the Bbeta-chain, and the gamma-chain at last. NJP had also a higher specificity for the chromogenic substrate S-2238 for thrombin. NJP activity was completely inhibited by PMSF. Analysis of partial amino acid sequences showed that NJP had very low homology with other known fibrinolytic enzymes. These results indicate that NJP is a novel alkaline thrombin-like serine protease. Thus NJP may have potential applications in the prevention and treatment of thrombosis. PMID- 21276865 TI - Identification of a puromycin-sensitive aminopeptidase from zebrafish (Danio rerio). AB - An aminopeptidase from zebrafish (Danio rerio) was purified 1247-fold to homogeneity with 35.4% recovery by column chromatography successively on DEAE sephacel, hydroxyapatite, and phenyl-sepharose. The molecular mass of the enzyme was estimated at 98 kDa by SDS-PAGE and gel filtration. Optimum temperature and pH of the enzyme were 45 degrees C and 7.5, respectively. The enzyme preferentially hydrolyzed substrate Leu-MCA with k(cat)/K(m) of 4.2*10(6)M(-1)s( 1) and an activation energy of 68.9 kJ M(-1) [corrected], respectively. It was specifically inhibited by bestatin, puromycin and metal-chelating agents, and Zn(2+) seemed to be its metal cofactor(s). Some l-amino acids significantly inhibited its activity, and l-cysteine was a non-competitive inhibitor with a K(i) of 0.27 mM. According to the peptide mass fingerprint analysis, the enzyme was highly matched with the predicted D. rerio aminopeptidase puromycin sensitive (gi: 255683530) (EC 3.4.11.14), suggesting that the present enzyme is a puromycin sensitive aminopeptidase of zebrafish. PMID- 21276866 TI - A selenium-dependent glutathione peroxidase in the Japanese scallop, Mizuhopecten yessoensis: cDNA cloning, promoter sequence analysis and mRNA expression. AB - Glutathione peroxidase (GPx) is an antioxidant enzyme that protects cells from oxidative damage in the innate immune responses against bacterial infections. GPx is also involved in immune defenses. In this study, we report cloning and characterization of a GPx (designated as MyGPx) coding sequences and promoter from Japanese scallop, Mizuhopecten yessoensis. The full-length 1081 nt MyGPx mRNA contained a 28 nt 5' untranslated region (UTR), a 603 nt open reading frame and a 450 nt 3' UTR containing a polyadenylation signal (AATAAA). Multiple sequence alignment revealed that amino acids essential to enzymatic function of MyGPx proteins were highly conserved. A 1628 nt 5'-flanking sequence of MyGPx was identified by genome walking. Here, several potential transcription factor binding sites were detected in the putative promoter region, and nine single nucleotide polymorphisms (SNPs) were found in the 5' sequence flanking the promoter region. Quantitative Real time PCR (qRT-PCR) was employed to measure GPx mRNA expression in adult tissues and monitor mRNA expression patterns during embryonic development and following stimulation by the bacteria Vibrillo anguillarum. Collectively, the results suggest that MyGPx fulfills an important function during M. yessoensis development and may be an important immune effector in adult molluscs. PMID- 21276867 TI - Engineering a non-native hydrogen production pathway into Escherichia coli via a cyanobacterial [NiFe] hydrogenase. AB - Biotechnology is a promising approach for the generation of hydrogen, but is not yet commercially viable. Metabolic engineering is a potential solution, but has largely been limited to native pathway optimisation. To widen opportunities for use of non-native [NiFe] hydrogenases for improved hydrogen production, we introduced a cyanobacterial hydrogen production pathway and associated maturation factors into Escherichia coli. Hydrogen production is observed in vivo in a hydrogenase null host, demonstrating coupling to host electron transfer systems. Hydrogenase activity is also detected in vitro. Hydrogen output is increased when formate production is abolished, showing that the new pathway is distinct from the native formate dependent pathway and supporting the conclusion that it couples cellular NADH and NADPH pools to molecular hydrogen. This work demonstrates non-native hydrogen production in E. coli, showing the wide portability of [NiFe] hydrogenase pathways and the potential for metabolic engineering to improve hydrogen yields. PMID- 21276868 TI - Computation of metabolic fluxes and efficiencies for biological carbon dioxide fixation. AB - With rising energy prices and concern over the environmental impact of fossil fuel consumption, the push to develop biomass derived fuels has increased significantly. Although most global carbon fixation occurs via the Calvin Benson Bassham cycle, there are currently five other known pathways for carbon fixation; the goal of this study was to determine the thermodynamic efficiencies of all six carbon fixation pathways for the production of biomass using flux balance analysis. The three chemotrophic pathways, the reductive acetyl-CoA pathway, the 3-hydroxypropionate/4-hydroxybutyrate cycle and the dicarboxylate/4 hydroxybutyrate cycle, were found to be more efficient than photoautotrophic carbon fixation pathways. However, as hydrogen is not freely available, the energetic cost of hydrogen production from sunlight was calculated and included in the overall energy demand, which results in a 5 fold increase in the energy demand of chemoautotrophic carbon fixation. Therefore, when the cost of hydrogen production is included, photoautotrophic pathways are more efficient. However, the energetic cost for the production of 12 metabolic precursors was found to vary widely across the different carbon fixation pathways; therefore, different pathways may be more efficient at producing products from a single precursor than others. The results of this study have significant impact on the selection or design of autotrophic organisms for biofuel or biochemical production. Overall biomass production from solar energy is most efficient in organisms using the reductive TCA cycle, however, products derived from one metabolic precursor may be more efficiently produced using other carbon fixation pathways. PMID- 21276869 TI - The contribution of animal models to the understanding of the host range and virulence of influenza A viruses. AB - Since ferrets were first used in 1933 during the initial isolation of influenza A viruses, animal models have been critical for influenza research. The following review discusses the contribution of mice, ferrets, and non-human primates to the study of influenza virus host range and pathogenicity. PMID- 21276870 TI - Influenza genome diversity and evolution. AB - The influenza viruses contain highly variable genomes and are able to infect a wide range of host species. Large-scale sequencing projects have collected abundant influenza sequence data for assessing influenza genome diversity and evolution. This work reviews current influenza sequence databases characteristics and statistics, as well as recent studies utilizing these databases to unravel influenza virus diversity and evolution. Also discussed are the newest deep sequencing methods and their applications to influenza virus research. PMID- 21276871 TI - Confronting influenza virus: a common but ever-changing pathogen. PMID- 21276872 TI - Uncovering the global host cell requirements for influenza virus replication via RNAi screening. AB - Influenza virus is reliant on numerous host cell functions during its replication cycle. RNA interference technology, applied on a genome-wide level, has identified human host factors that are necessary for efficient virus replication and provides new insight into how influenza virus interacts with its host at the molecular level. PMID- 21276873 TI - Overview/reflections on the 2009 H1N1 pandemic. AB - The Influenza A H1N1 2009 pandemic was a test of the global public health response. Strategies that worked included mass vaccine production and antivirals while quarantine and isolation proved futile. Among the lessons learned was the importance of severity in the definition of a pandemic. PMID- 21276874 TI - Electrocardiographic imaging: back to the drawing board? PMID- 21276875 TI - Community events as viable sites for recruiting minority volunteers who agree to be contacted for future research. AB - Reaching out to medically underserved racial/ethnic groups is a key challenge in population research. To increase their participation opportunities, we asked adults attending community events to complete a survey about their health concerns and invited them to join a registry of individuals agreeing to future study invitation. Approximately 66% of the 2298 survey responders joined the registry. Multivariate analysis showed that Hispanics were more likely to agree to contact than Whites. Agreers endorsed a wider range of health concerns than non-agreers. PMID- 21276876 TI - Recruitment and retention strategies in longitudinal clinical studies with low income populations. AB - BACKGROUND: Conducting longitudinal research studies with low-income and/or minority participants present a unique set of challenges and opportunities. PURPOSE: To outline the specific strategies employed to successfully recruit and retain participants in a longitudinal study of nutritional anticipatory guidance during early childhood, conducted with a low-income, ethnically diverse, urban population of mothers. METHODS: We describe recruitment and retention efforts made by the research team for the 'MOMS' Study (Making Our Mealtimes Special). The 'multilayered' approach for recruitment and retention included commitment of research leadership, piloting procedures, frequent team reporting, emphasis on participant convenience, incentives, frequent contact with participants, expanded budget, clinical staff buy-in, a dedicated phone line, and the use of research project branding and logos. RESULTS: Barriers to enrollment were not encountered in this project, despite recruiting from a low-income population with a large proportion of African-American families. Process evaluation with clinic staff demonstrated the perception of the MOMS staff was very positive. Participant retention rate was 75% and 64% at 6 months and 12 months post-recruitment, respectively. We attribute retention success largely to a coordinated effort between the research team and the infrastructure support at the clinical sites, as well as project branding and a dedicated phone line. CONCLUSIONS: Successful participant recruitment and retention approaches need to be specific and consistent with clinical staff buy in throughout the project. PMID- 21276877 TI - TRPV1 channels in the nucleus of the solitary tract mediate thermal prolongation of the LCR in decerebrate piglets. AB - Elevating body temperature or just the temperature of the dorsal medulla by approximately 2 degrees C prolongs the laryngeal chemoreflex (LCR) in decerebrate neonatal piglets. We tested the hypothesis that transient receptor potential vanilloid 1 (TRPV1) receptors in the nucleus of the solitary tract (NTS) mediate thermal prolongation of the LCR. We studied the effect of a selective TRPV1 receptor antagonist on thermal prolongation of the LCR, and we tested the effect of a TRPV1 agonist on the duration of the LCR under normothermic conditions. We studied 37 decerebrate neonatal piglets between the ages of post-natal days 4 and 7. The TRPV1 receptor antagonist, 5'-iodoresiniferatoxin (65MUM/L in 100nL), blocked thermal prolongation of the LCR when injected bilaterally into the region of the NTS. The TRPV1 agonist, resiniferatoxin (0.65-1.0mM/L in 100nL), prolonged the LCR after bilateral injection into the NTS even when the body temperature of each piglet was normal. The effect of the TRPV1 agonists could be blocked by treatment with the GABA(A) receptor antagonist, bicuculline, whether given intravenously (0.3mg/kg) or focally injected bilaterally into the NTS (10mM in 100nL). We conclude that TRPV1 receptors in the NTS mediate thermal prolongation of the LCR. PMID- 21276878 TI - Mathematical model to predict risk for lymphoedema after treatment of cutaneous melanoma. AB - AIM: To evaluate risk factors for lymphoedema development in the upper and lower limbs and to propose a model that predicts risk of lymphoedema after lymphadenectomy. PATIENTS: We studied 84 patients who had undergone radical lymphadenectomies for cutaneous melanoma from 1990 to 2008. METHODS: The patients included underwent an evaluation that consisted of measurement of limb volume using perimetry, application of the manually acquired perimetric data to the truncated-cone formula, and data from medical records. RESULTS: Using multivariate analysis, we obtained the following risk factors for the development of lymphoedema: reconstruction with graft (p = 0.013), Breslow depth >4mm (p = 0.029), ilioinguinal lymphadenectomy (p = 0.037) and wound infection (p = 0.036). We assigned points to each factor as dictated by the value of the regression coefficient, as follows: infection (1 point), ilioinguinal lymphadenectomy and Breslow >4mm (2 points each) and reconstruction with graft (3 points). The mathematical model for predicting lymphoedema risk in the limb ipsilateral to the lymphadenectomy was based on risk groups, defined by score: low risk = 0 point (for which we calculated an 8.3% chance of developing lymphoedema), intermediate risk = 1-2 points (26.8%), high risk = 3 points (52.9%) and very high risk = 4 or more points (88.9%). CONCLUSIONS: This study identified a melanoma thickness >4mm, graft reconstruction, ilioinguinal lymphadenectomy and infection as risk factors for lymphoedema. From these factors, we constructed a mathematical model that successfully predicted risk of post-lymphadenectomy lymphoedema. The combined presence of these risk factors increased the chance of developing lymphoedema. PMID- 21276879 TI - Clinical applications of Telerobotic ENT-Head and Neck surgery. AB - OBJECTIVE: To review the published clinical data in Telerobotic ENT-Head and Neck surgery, evaluate the benefit of existing clinical applications and identify areas for potential development. METHODS: A qualitative review was performed of publications in PubMed, Medline and the Cochrane Database identified from the following keyword searches: Telerobotic/Robotic ENT, Otorhinolaryngology, Head and Neck surgery, Thyroid and Parathyroid surgery. Preclinical studies and non clinical review articles were excluded. RESULTS: Forty-five publications were identified including 7 review articles. Transoral robotic surgery (TORS) was reported in 20 clinical studies, robotic-assisted thyroidectomy in 13 studies, parathyroidectomy in 4 studies and skull base surgery in 1 study. The majority of TORS publications relate to oropharyngeal malignancy which were Stage III and IV. Clinical benefits include avoidance or dose reduction of adjuvant chemoradiotherapy and improved swallow function. The primary clinical advantage of robotic-assisted neck surgery is the avoidance of a neck scar. The learning curve for robotic thyroidectomy is 50 cases. Body habitus is an important factor for assessment of robotic feasibility in transoral and neck surgery. CONCLUSION: The application of robotic-assisted parathyroidectomy, thyroidectomy and TORS suggests promising improvements in patient care. Randomised control trials are needed to assess clinical outcome, cost effectiveness and patient benefit in the existing applications. Continued development of robotic technology will expand the viable clinical applications in this specialty. PMID- 21276880 TI - A 10 Mb duplication in chromosome band 5q31.3-5q33.1 associated with late-onset lipodystrophy, ichthyosis, epilepsy and glomerulonephritis. AB - We report here a 44 years-old patient with late-onset partial lipodystrophy, mental retardation, epilepsy, ichtyosis and glomerulonephritis, carrying a 10 Mb duplication of the chromosome 5q31.3-5q32.1 region detected by array-CGH. PMID- 21276881 TI - Search of somatic GATA4 and NKX2.5 gene mutations in sporadic septal heart defects. AB - High prevalence of somatic mutations in the cardiac transcription factor genes NKX2.5 and GATA4 have been reported in the affected cardiovascular tissue of patients with isolated cardiac septal defects, suggesting a role of somatic mutations in the pathogenesis of these congenital heart defects (CHDs). However, all somatic mutations have been identified in DNA extracted from an archive of formalin-fixed cardiac tissues. In the present study, to address the hypothesis that somatic mutations are important in isolated CHDs, we analyzed the GATA4 and NKX2.5 genes in the fresh-frozen pathologic cardiac tissue specimen and corresponding non-diseased tissue obtained from a series of 62 CHD patients, including 35 patients with cardiac septal defects and 27 with other cardiac anomalies. We identified one variant and two common polymorphisms in the NKX2.5 gene, and six variants and two common polymorphisms in the GATA4 gene. All identified variants were seen in both the fresh-frozen pathologic cardiac tissue and the corresponding non-diseased tissue, which indicates that they all were constitutional variants. The present study has identified NKX2.5 and GATA4 constitutional variants in our CHD cohort, but was unable to replicate the previously published findings of high prevalence of somatically derived sequence mutations in patients with cardiac septal defects using fresh-frozen cardiac tissues rather than formalin-fixed tissues. PMID- 21276882 TI - Increased bone strength is associated with improved bone microarchitecture in intact female rats treated with strontium ranelate: a finite element analysis study. AB - Strontium ranelate has been previously shown to act on bone metabolism and to be effective in postmenopausal osteoporosis treatment by preventing vertebral and non-vertebral fractures. Animal studies explicitly demonstrated that bone strength was improved with strontium ranelate treatment, but the contribution of either improved bone microarchitecture or intrinsic quality of the bone tissue is not clear. Therefore, the purpose of this research was to address this issue by using the unique capability of finite element (FE) analysis to integrate both intrinsic bone quality properties from nano-indentation and microarchitecture measured by micro-computed tomography (MUCT). The two groups included intact female Fischer rats fed a normal diet (controls, N=12) or a diet containing strontium ranelate (900mg/kg/day; N=12) for a period of 104weeks. The L(5) vertebra was scanned by MUCT and a morphological analysis of the vertebral body was performed. Subsequently, those MUCT data were the basis of FE models with added virtual endcaps that simulated axial compression tests. The FE models were solved with the vertebral bodies only and repeated with the vertebral processes intact. In the initial stages, the intrinsic bone properties were kept constant between the control and the treated animals in order to independently study the impact of microarchitectural changes on bone strength. Morphological data indicated a significant improvement in bone microarchitecture associated with strontium ranelate compared to controls, including a 40% (p<0.01) higher trabecular thickness, a 28% (p<0.01) higher cortical thickness, and no significant change in the number of trabeculae (p=0.56). The poor correlation of bone strontium content against bone volume fraction (BV/TV) (R(2)=0.013, p=0.74) and BMD (R(2)=0.153, p=0.23) indicated that the morphological data were not biased by the presence of strontium in bone. The FE simulations demonstrated a 22% (p<0.01) increase of stiffness and 29% (p<0.01) increase in strength compared to controls. The magnitudes were greater, but the relative differences were similar when the entire intact vertebra was modeled compared to the vertebral body alone. Adjusting the FE models to account for differences in intrinsic bone tissue quality between control and treated animals resulted in an even higher bone strength with strontium ranelate. Furthermore, load transfer in strontium ranelate treated animals shifted from an equal distribution between cortical and trabecular compartments to more load being supported by the trabecular bone (a shift of 8%, p<0.02). Tissue-level stresses were reduced on average (-7%, p<0.01) and more homogeneously distributed. Together, these findings indicated that, independently from bone strontium content, microarchitectural adaptations played a major role in the increased bone strength associated with strontium ranelate exposure and that the changes in load distribution resulted in patterns that were more favorable to resisting fracture. PMID- 21276883 TI - Prospective one-year bone loss in treatment-naive HIV+ men and women on single or multiple drug HIV therapies. AB - Antiretroviral therapy has decreased the rate of HIV-related mortality and extended the life span of HIV patients. Current guidelines recommend the use of a 3-drug regimen, such as two nucleoside reverse transcriptase inhibitors and a protease inhibitor, boosted by ritonavir. Osteoporosis can be associated with the HIV disease itself or with antiretroviral therapy. Many trials have been conducted employing a single drug regimen to simplify antiretroviral therapy but few studies assessed the effect of the single drug regimen on bone mineral density (BMD). The objectives of the study were to assess and compare the relative (%) changes in lumbar spine and hip BMD over 48 weeks in HIV patients treated with mono or triple antiretroviral regimens The study was conducted using data from a randomized trial (MONARK) conducted in 136 antiretroviral-naive HIV patients (89 men and 47 women) comparing the antiviral efficacy of a single-drug protease inhibitor regimen of lopinavir/ritonavir (LPV/r) versus LPV/r in combination with zidovudine (ZDV) and lamivudine (3TC). Lumbar spine and total hip BMD were assessed in 100 patients by dual-energy X-ray absorptiometry at baseline and 48 weeks. 48 week-BMD data were available for 43 patients (mean age 37years) with a mean baseline lumbar spine Z-score of -0.1 in the LPV/r monotherapy group and for 25 patients (mean age 35.8years) with a mean baseline lumbar spine Z-score of -0.2 in the LPV/r+ZDV+3TC group. After 48weeks, lumbar spine BMD significantly decreased by 4.4% (-5.1% to -2.1%, P<=0.001) in the LPV/r group and by 4.0% (-5.0% to -1.7%, P<=0.0001) in the LPV/r+ZDV+3TC group. There was no significant difference in BMD changes between the two groups. These results suggest that bone loss is observed 48 weeks after the initiation of antiretroviral therapy, whether the patients receive a single- or triple-drug antiretroviral regimen. PMID- 21276884 TI - Association between the elbow flexion test and extraneural pressure inside the cubital tunnel. AB - PURPOSE: The elbow flexion test is a standard, provocative diagnostic test for cubital tunnel syndrome (CubTS). The purpose of this study was to investigate the association between the elbow flexion test and the degree of extraneural pressure in the cubital tunnel of CubTS patients. METHODS: Extraneural pressure on the ulnar nerve in the cubital tunnel was evaluated using 0.7-mm thickness catheter during surgery of 25 CubTS cases and compared with the results of preoperative elbow flexion testing. Statistic analysis was performed using Student's t-test with a confidence level of 95% (p < .05). RESULTS: Forty-eight percent of the patients were positive for the elbow flexion test. Mean extraneural pressure was significantly higher in maximum elbow flexion than in maximum elbow extension (p < .001). No significant association was seen between the result of 45 seconds of the elbow flexion test and the extraneural pressure in the cubital tunnel induced by maximum elbow flexion (p = .45). CONCLUSIONS: Our results suggested that the mechanism of provocation of symptoms of CubTS by the elbow flexion could not be explained simply by dynamic pressure in the cubital tunnel, and other pathophysiological factors could also be contributing. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic III. PMID- 21276885 TI - Chemical denervation with botulinum neurotoxin a improves the surgical manipulation of the muscle-tendon unit: an experimental study in an animal model. AB - PURPOSE: The chemical denervation that results from botulinum neurotoxin A (BoNT A) causes a temporary, reversible paresis that can result in easier surgical manipulation of the muscle-tendon unit in the context of tendon rupture and repair. The purpose of the study was to determine whether BoNT-A injections can be used to temporarily and reversibly modulate active and passive skeletal muscle properties. METHODS: Male CD1 mice weighing 40-50 g were divided into a 1-week postinjection group (n = 13: n = 5 saline and n = 8 BoNT-A) and a 2-week postinjection group (n = 17: n = 7 saline and n = 10 BoNT-A). The animals had in vivo muscle force testing and in vivo biomechanical evaluation. RESULTS: There was a substantial decline in the maximal single twitch amplitude (p < .05) and tetanic amplitude (p < .05) at one week and at 2 weeks after BoNT-A injection, when compared to saline-injected controls. BoNT-A injection significantly reduced the peak passive properties of the muscle-tendon unit as a function of displacement at one week (p < .05). Specifically, the stiffness of the BoNT-A injected muscle-tendon unit was 0.417 N/mm compared to the control saline injected group, which was 0.634 N/mm, a 35% reduction in stiffness (p < .05). CONCLUSIONS: Presurgical treatment with BoNT-A might improve the surgical manipulation of the muscle-tendon unit, thus improving surgical outcomes. The results implicate neural tone as a substantial contributor to the passive repair tension of the muscle-tendon unit. The modulation of neural tone through temporary, reversible paresis is a novel approach that might improve intraoperative and postoperative passive muscle properties, allowing for progressive rehabilitation while protecting the surgical repair site. PMID- 21276886 TI - Quantitative measurements of the coronoid in healthy adult patients. AB - PURPOSE: We investigated the hypothesis that a quantitative 3-dimensional computed tomography (CT) modeling technique that can measure size, shape, and proximal articular surface area can be used to develop formulas that could predict the volume and proximal surface area of the intact coronoid based on anatomical and demographic data available in patients with fracture of the coronoid process. METHODS: We used a consecutive series of 50 CT scans with a slice thickness of 1.25 mm or less obtained in patients with fracture of the distal humerus, but no injury to the coronoid, to create 3-dimensional models. The volume and articular surface area of the coronoid were measured, and predictive formulas were based on anatomical measurements. We calculated gender using multiple linear regression. RESULTS: There were significant correlations between total coronoid volume and coronoid articular surface area for coronoid width, radial neck diameter, radial head diameter, height, weight, and gender. Multiple linear regression modeling with the factors radial head diameter, radial neck diameter, coronoid width, height, weight, and gender resulted in formulas that could account for 71.8% of the variation in coronoid volume and 66.2% of the variation in coronoid articular surface area. The average relative percent difference was 1.32% for the coronoid volume and 0.68% for the coronoid articular surface area. CONCLUSIONS: The volume and articular surface area of the coronoid can be estimated based on anatomical measurements and gender. This may lead to better estimates of lost fragments when modeling the fractured coronoid and CT scan of the opposite limb is not available. PMID- 21276887 TI - The comparative stability of screw versus plate versus screw and plate coronoid fixation. AB - PURPOSE: To compare the biomechanical characteristics of screw versus plate versus both screw and plate fixation for large, type 3 O'Driscoll coronoid fractures. METHODS: Synthetic ulnas had 70% of their coronoids cut. Fixation was performed with either a cannulated screw, a plate, or both a screw and a plate. Energy to failure, force at failure, first cycle stiffness, and stiffness at failure were measured on a servohydraulic testing machine under cyclic posterior axial loading. RESULTS: The combination of a plate and screw had significantly greater energy to failure (83 Nm), force required to cause failure (634 N), and stiffness at failure (387 N/mm) compared to either an isolated plate (38 Nm, 474 N, 237 N/mm, respectively) or a screw (10 Nm, 279 N, 149 N/mm, respectively). For energy to failure and force required to cause failure, the plate group significantly outperformed the screw group. There was no significant difference in stiffness at the time of failure between the plate and screw groups. CONCLUSIONS: For type 3 O'Driscoll coronoid fractures or nonunions when both a screw and a plate can be placed, the combination of these 2 fixation devices appears to produce significantly greater biomechanical stability than either fixation device alone. PMID- 21276888 TI - Vascular perfusion of a flexor carpi ulnaris muscle turnover pedicle flap for posterior elbow soft tissue reconstruction: a cadaveric study. AB - PURPOSE: The use of a pedicled flexor carpi ulnaris (FCU) muscle proximal turnover flap has been described previously for soft tissue reconstruction at the posterior elbow. Whereas consistent arterial supply to the FCU has been reported, the reliability of distal flap perfusion has not been confirmed. This study evaluated the vascular perfusion of an FCU turnover flap, based on the most proximal primary vascular pedicle that would permit a proximal turnover flap reconstruction to include the olecranon tip. METHODS: In 12 fresh-frozen, proximal humeral human amputation specimens, the FCU flap was elevated from distal to proximal, preserving the most proximal primary vascular pedicle to the muscle belly that would permit flap coverage of the olecranon tip. The axillary artery was injected with India ink after ligation of radial and ulnar arteries at the wrist. After injection, each specimen was sectioned transversely at 0.5-cm increments to assess vascular perfusion of the muscle using loupe magnification. RESULTS: The distance from the olecranon tip to the distal FCU muscle belly was 25.9 cm. The primary vascular pedicle that would facilitate creation of a proximal turnover flap was, on average, 5.9 cm distal to the olecranon tip. Perfusion of FCU muscle as measured distal to this primary pedicle was present in 50% to 100% of the muscle belly at an average of 8.9 cm beyond the pedicle. Perfusion of 25% to 50% of the FCU muscle belly was present at an average of 11.1 cm beyond the pedicle. Perfusion became less consistent (<25%) within the muscle belly at an average distance of 11.6 cm. CONCLUSIONS: Use of a proximally based, pedicled FCU muscle turnover flap provides a reliable option for soft tissue reconstruction at the posterior elbow. We observed consistent arterial perfusion of the muscle flap when preserving a proximal vascular pedicle 5.9 cm distal to the olecranon tip. PMID- 21276889 TI - Biomechanics of the volar plate of the proximal interphalangeal joint: a dynamic ultrasonographic study. AB - PURPOSE: To study the biomechanics of the volar plate of the proximal interphalangeal (PIP) joint using ultrasonography. METHODS: The subjects were 20 normal and 5 pathological digits. We included as normal subjects 20 digits (10 index and 10 middle fingers) of 10 hands of 10 volunteers who had no history of trauma or any other hand-related pathological conditions. To clarify the biomechanical effect of the A3 pulley for the volar plate motion, we included a total of 5 digits (1 index, 2 middle, and 2 ring) of 4 hands of 4 consecutive patients who had flexor tendon repair surgeries in zone II with the A3 pulley left open as pathological subjects. Transducers were applied volarly to the PIP joint and the ultrasonographic plane was kept in the central axis of the digits to display the volar plate and the flexor tendons in the same image. We recorded cine videos during active joint motion. We also obtained sequential static images for morphological analysis. RESULTS: The motion of the volar plate of the normal PIP joint was as follows: when joint flexion started, the volar plate slid proximally to lie parallel to the condylar slope of the proximal phalanx. In 30 degrees of flexion, the flexor tendons tightened and the distal portion of the volar plate moved volarward. In 45 degrees or more of flexion, the distal portion protruded over the lip of the middle phalanx. The lip rolled dorsalward in the recess in return. In the flexor tendon repair cases, the distal portion of the volar plate did not move volarward at all, even when the joint flexed 45 degrees or more. The main body of the volar plate showed a marked wavelike or sigmoid deformity. CONCLUSIONS: To characterize the biomechanics of the volar plate of the PIP joint, we propose the following 3 sequential phases: sliding, elevating, and rolling in the recess. The A3 pulley may serve as an elevator of the volar plate, triggering the next phase of rolling in the recess. The recess can provide some articulation which the lip of the middle phalanx can roll in. PMID- 21276890 TI - Defining ulnar variance in the adolescent wrist: measurement technique and interobserver reliability. AB - PURPOSE: The measurement technique for ulnar variance in the adolescent population has not been well established. The purpose of this study was to assess the reliability of a standard ulnar variance assessment in the adolescent population. METHODS: Four orthopedic surgeons measured 138 adolescent wrist radiographs for ulnar variance using a standard technique. There were 62 male and 76 female radiographs obtained in a standardized fashion for subjects aged 12 to 18 years. Skeletal age was used for analysis. We determined mean variance and assessed for differences related to age and gender. We also determined the interrater reliability. RESULTS: The mean variance was -0.7 mm for boys and -0.4 mm for girls; there was no significant difference between the 2 groups overall. When subdivided by age and gender, the younger group (<= 15 y of age) was significantly less negative for girls (boys, -0.8 mm and girls, -0.3 mm, p < .05). There was no significant difference between boys and girls in the older group. The greatest difference between any 2 raters was 1 mm; exact agreement was obtained in 72 subjects. Correlations between raters were high (r(p) 0.87-0.97 in boys and 0.82-0.96 for girls). Interrater reliability was excellent (Cronbach's alpha, 0.97-0.98). CONCLUSIONS: Standard assessment techniques for ulnar variance are reliable in the adolescent population. Open growth plates did not interfere with this assessment. Young adolescent boys demonstrated a greater degree of negative ulnar variance compared with young adolescent girls. PMID- 21276891 TI - Prevalence of carpal fracture in Singapore. AB - PURPOSE: To determine the prevalence of carpal fracture in Singapore, to compare demographic differences between isolated scaphoid and other carpal fractures, and to identify parameters associated with multiple carpal fractures. METHODS: A total of 149 patients with 162 carpal fractures seen at the National University Hospital in 2009 were enrolled into the study. We retrospectively reviewed their case records and radiographic studies. Pertinent demographic data including patient age, gender, occupation, injured wrist, dominant hand, mechanism of injury, and type of carpal fracture were then recorded and statistically analyzed. We also performed a separate analysis of isolated scaphoid versus other carpal fractures and single versus multiple carpal fractures. RESULTS: Patients with carpal fracture were predominantly male (132), below 40 years of age (116), and usually right hand dominant (136). The more common occupations were students (30), full-time military national servicemen (24), and construction workers (14). Most presented after a fall on an outstretched hand from standing height (81). The scaphoid was the most common single carpal fracture (99). This was followed by triquetrum (27), hamate (5), pisiform (4), lunate (2), capitate (1), and trapezium (1). No fracture of the trapezoid was encountered. Ten patients had multiple carpal fractures, of which 4 were perilunate fracture dislocations. The mean age and male/female ratio for isolated scaphoid and other carpal fractures was 26 years versus 41 years (p<.001) and 13:1 versus 4:1 (p=.036), respectively. A high-energy mechanism of injury was the only parameter associated with multiple carpal fractures (p=.009). CONCLUSIONS: The prevalence of carpal fracture in our population was consistent with studies performed in other countries. Military conscription was identified as an at-risk activity predisposing to carpal fracture. Isolated scaphoid and other carpal fractures exhibit different demographics in terms of age and gender, which may be related to differences in the mechanism of injury. A high-energy mechanism of injury was associated with multiple carpal fractures. PMID- 21276892 TI - In vivo length changes of carpal ligaments of the wrist during dart-throwing motion. AB - PURPOSE: The dart-throwing motion is an important movement pattern during most wrist actions. The aim of this study was to investigate length changes in the wrist ligaments in different positions of the dart-throw motion in vivo. METHODS: We obtained computed tomography scans of the wrists of 6 volunteers at 5 positions of the wrist during the dart-throw motion: 20 degrees of radial deviation with 60 degrees of extension; 10 degrees of radial deviation with 30 degrees of extension; the neutral position of the carpus; 20 degrees of ulnar deviation with 30 degrees of flexion; and 40 degrees of ulnar deviation with 60 degrees of flexion. We reconstructed the 3-dimensional carpal and distal radioulnar joint structures with customized software and computed changes in length of 8 palmar and dorsal wrist ligaments. RESULTS: From wrist radial deviation with extension to ulnar deviation with flexion, the radioscaphocapitate, long radiolunate, ulnocapitate, and ulnotriquetral ligaments decreased significantly in length but the dorsal radiocarpal ligament and the dorsal intercarpal (DIC) ligament inserting on the trapezoid lengthened significantly; the ulnolunate ligament and the DIC ligament inserting on the scaphoid were shortest in neutral position. CONCLUSIONS: At wrist radial extension, the radioscaphocapitate, long radiolunate, ulnocapitate, and ulnotriquetral ligaments are lengthened and under increased tension. At wrist ulnar flexion, the dorsal radiocarpal ligament and the DIC ligament inserting on the trapezoid are lengthened and under increased tension. The ulnolunate ligament and the DIC ligament inserting on the scaphoid are the shortest and under the least tension in neutral position. These findings will help us understand the biomechanics of the carpus during the dart-throwing motion. PMID- 21276893 TI - Scaphoid and lunate translation in the intact wrist and following ligament resection: a cadaver study. AB - PURPOSE: To determine the amount of scaphoid and lunate translation that occurs in normal cadaver wrists during wrist motion, and to quantify the change in ulnar translation when specific dorsal and volar wrist ligaments were sectioned. METHODS: We measured the scaphoid and lunate motion of 37 cadaver wrists during wrist radioulnar deviation and flexion-extension motions using a wrist joint motion simulator. We quantified the location of the centroids of the bones during each motion in the intact wrists and after sectioning either 2 dorsal ligaments along with the scapholunate interosseous ligament or 2 volar ligaments and the scapholunate interosseous ligament. RESULTS: In the intact wrist, the scaphoid and lunate statistically translated radially with wrist ulnar deviation. With wrist flexion, the scaphoid moved volarly and the lunate dorsally. After sectioning either the dorsal or volar ligaments, the scaphoid moved radially. After sectioning the dorsal or volar ligaments, the lunate statistically moved ulnarly and volarly. CONCLUSIONS: Measurable changes in the scaphoid and lunate translation occur with wrist motion and change with ligament sectioning. However, for the ligaments that were sectioned, these changes are small and an attempt to clinically measure these translations of the scaphoid and lunate radiographically may be limited. The results support the conclusion that ulnar translocation does not occur unless multiple ligaments are sectioned. Injury of more than the scapholunate interosseous ligament along with either the dorsal intercarpal and dorsal radiocarpal or the radioscaphocapitate and scaphotrapezial ligaments is needed to have large amounts of volar and ulnar translation. PMID- 21276894 TI - The ethics of clinical research. AB - The purpose of this article is to discuss the ethical concepts involved in the conception, design, execution, analysis, publication, and reporting of clinical research. Although it might seem burdensome to comply with these ethical necessities, they can assist in the organization of a well-run clinical trial, if considered at the onset of a study, while also protecting the valuable human subjects who volunteer for these trials. PMID- 21276895 TI - Astley Cooper: his life and surgical contributions. AB - Sir Astley Paston Cooper (1768-1841) was a successful and influential British surgeon during the early decades of the 19th century. He was a dedicated anatomist, an accomplished researcher, an inspiring teacher, and a skillful surgeon. Cooper published about the cause and treatment of Dupuytren's disease 10 years before Dupuytren. His contributions were widespread and substantially advanced the understanding and treatment of breast disease, vascular aneurysms, and abdominal wall hernias, along with orthopedic, otologic, and hand surgery. His contributions to surgical science have endured and are being used today. PMID- 21276896 TI - Septic flexor tenosynovitis. PMID- 21276897 TI - Management of the septic wrist. PMID- 21276898 TI - Reconstruction for ulnar artery aneurysm at the wrist. AB - Arterial aneurysms of the upper limb most commonly involve the ulnar artery at the wrist. Hypothenar hammer syndrome is the usual cause of arterial trauma that forms the aneurysm. After excision of the aneurysm, vein or arterial conduits bridge the arterial gap. Digital ischemia is relieved by arterial reconstruction; however, many patients continue to experience cold-related symptoms. PMID- 21276899 TI - Index finger pollicization. AB - The thumb is a specialized organ with unique functions that cannot be replicated by any other digit. The most powerful technique for construction of a missing thumb is index finger pollicization. In this article, we outline our technique for index finger pollicization. Over a 30-year period, certain technical refinements have improved the function and appearance of these transposed digits. PMID- 21276900 TI - Cutaneous warts. PMID- 21276901 TI - Metacarpophalangeal joint arthritis. AB - Arthritis of the metacarpophalangeal joint can result in considerable disability and pain. Inflammatory, posttraumatic, crystalline, and osteoarthritis are common etiologies of joint disease. A variety of nonsurgical treatment options have been shown to be effective, including activity modification, anti-inflammatory medications, splinting, and cortisone injections. In addition, newer generation disease-modifying antirheumatic drugs geared toward the treatment of rheumatoid arthritis have shown promise in retarding the inflammatory process. Another, relatively newer, conservative treatment option includes topical anti inflammatories such as diclofenac sodium that are now approved by the Federal Drug Administration. Surgical treatment options most commonly include arthroplasty and arthrodesis. In the treatment of thumb metacarpophalangeal arthritis, arthrodesis is a popular and generally reliable surgical solution. In the fingers, arthroplasty remains the most common treatment option. Traditional constrained silicone joint replacements remain the most commonly used. Newer generation, unconstrained, surface replacement arthroplasties have shown promise in the treatment of osteoarthritis and select cases of inflammatory arthritis in which there is good bone stock, no or minimal deformity, adequate supporting soft tissues, and good disease control. PMID- 21276902 TI - Carpometacarpal and scaphotrapeziotrapezoid arthritis: arthroscopy, arthroplasty, and arthrodesis. AB - Osteoarthritis of the first carpometacarpal joint is the second most common site of osteoarthritis in humans. Symptomatic isolated scaphotrapeziotrapezoid joint arthritis, though less common overall, is also frequently observed by the hand surgeon. Investigations on the etiology, pathophysiology, natural history, outcomes of traditional treatments, and new forms of surgical techniques have been attracting more interest in the field of hand surgery. The goal of this article is to sort through the current prevailing ideas using recently available literature and to offer a concise, updated guide to further enhance the understanding of thumb carpometacarpal and scaphotrapeziotrapezoid arthritis. PMID- 21276904 TI - Social networking among upper extremity patients. PMID- 21276905 TI - Extensor tendon injuries. PMID- 21276906 TI - Evaluation of function and appearance of adults with untreated triphalangeal thumbs. PMID- 21276909 TI - Treatment of vascular anomalies of the upper extremity. PMID- 21276911 TI - Common iliac vein stenosis and risk of symptomatic pulmonary embolism: an inverse correlation. AB - PURPOSE: To test the hypothesis that a common iliac vein (CIV) stenosis may impair embolization of a large deep venous thrombosis (DVT) to the lungs, decreasing the incidence of a symptomatic pulmonary embolism (PE). MATERIALS AND METHODS: Between January 2002 and August 2007, 75 patients diagnosed with unilateral DVT were included in a single-institution case-control study. Minimum CIV diameters were measured 1 cm below the inferior vena cava (IVC) bifurcation on computed tomography (CT) images. A significant stenosis in the CIV ipsilateral to the DVT was defined as having either a diameter 4 mm or less or a greater than 70% reduction in lumen diameter. A symptomatic PE was defined as having symptoms and imaging findings consistent with a PE. The odds of symptomatic PE versus CIV stenosis were assessed using logistic regression models. The associations between thrombus location, stenosis, and symptomatic PE were assessed using a stratified analysis. RESULTS: Of 75 subjects, 49 (65%) presented with symptomatic PE. There were 17 (23%) subjects with a venous lumen 4 mm or less and 12 (16%) subjects with a greater than 70% stenosis. CIV stenosis of 4 mm or less resulted in a decreased odds of a symptomatic PE compared with a lumen greater than 4 mm (odds ratio [OR] 0.17, P = .011), whereas a greater than 70% stenosis increased the odds of DVT involving the CIV (OR 7.1, P = .047). CONCLUSIONS: Among patients with unilateral DVT, those with an ipsilateral CIV lumen of 4 mm or less have an 83% lower risk of developing symptomatic PE compared with patients with a CIV lumen greater than 4 mm. PMID- 21276912 TI - Hybrid procedure with antegrade stent-graft placement for aortic arch aneurysms: preliminary experience in eight patients. AB - PURPOSE: To report one-stage hybrid procedures combining debranching surgery and antegrade stent-graft placement in eight patients with aortic arch aneurysms. MATERIALS AND METHODS: Eight patients with atherosclerotic aneurysms (n = 7) or traumatic pseudoaneurysm (n = 1) were enrolled. Proximal landing zones were in zones 1 (n = 2), 2 (n = 5), and 3 (n = 1). In one zone 3 landing (distal to left subclavian artery), hybrid surgery was chosen in view of irregularity of the proximal landing zone. RESULTS: In six patients with zone 2 and 3 landings, stent grafts were successfully placed through the surgical conduit made near the aortic root without cardiopulmonary bypass or deep hypothermic circulatory arrest. As the two patients with zone 1 involvement had an ascending aorta with a large diameter that would have required a stent graft with an oversized proximal end for safe anchoring, the proximal ascending aorta was transected, after which the stent graft was successfully placed into the transected aortic lumen; the proximal end of the stent graft was then sutured to the ascending aorta under cardiopulmonary bypass and selective cerebral perfusion. One patient died after the procedure of acute myocardial infarction. Neurologic complications occurred in three patients: one showed complete recovery and the other two showed substantial improvement. Minimal endoleak was observed at the proximal site of the stent graft in one patient. CONCLUSIONS: The hybrid procedure with antegrade stent-graft placement is feasible for the treatment of aortic arch aneurysms. Although cardiopulmonary bypass and deep hypothermic cardiopulmonary arrest were avoided in most patients, the rate of neurologic complications suggests the need for further refinement to improve the safety of the technique. PMID- 21276913 TI - Ischemic skin ulceration complicating glue embolization of type II endoleak after endovascular aneurysm repair. AB - The optimal treatment for type II endoleaks remains unclear. The present report describes a case of ischemic skin ulceration after glue embolization of a type II endoleak with challenging access in a multiply comorbid 82-year-old woman with an expanding aneurysm sac 3 years after endovascular aneurysm repair. Embolization was performed from a proximal position with an n-butyl cyanoacrylate/Ethiodol mixture to allow flow into the endoleak because direct sac puncture was hazardous. One week after intervention, an eschar, which progressed to superficial necrosis as a result of partial nontarget delivery of sclerosant, developed over the left iliac crest. The eschar was self-limiting, with complete resolution by 6 months. PMID- 21276914 TI - Transhepatic hemodialysis catheters: functional outcome and comparison between early and late failure. AB - PURPOSE: To describe the authors' experience with transhepatic placement of catheters, highlighting early and late complications, and to determine if this procedure is a viable option in patients in whom central venous occlusions present a significant challenge. MATERIALS AND METHODS: The records of all the patients who underwent placement of transhepatic hemodialysis from January 2003 to October 2008 were retrospectively reviewed. Selected patients were dialysis dependent, having undergone multiple access procedures and revisions. Kaplan Meier analysis was used to estimate primary and secondary patency. RESULTS: Twenty-two patients (mean age 42 years, range 22-70 years, 59% women) underwent a total of 127 transhepatic catheter placements at 24 transhepatic access sites; technical success was achieved in all cases. There were no hepatic injuries (bleeding or fistula formation). There were 105 exchanges in 14 patients, with a mean of 7.5 exchanges, a median of 5 exchanges (range 1-18 exchanges), and a catheter migration rate of 0.39 per 100 catheter-days. The sepsis rate was 0.22 per 100 catheter-days, and the catheter thrombosis rate was 0.18 per 100 catheter days. The mean cumulative catheter duration in situ was 506.2 days, and the mean time catheter in situ was 87.7 days. The mean total access site interval was 1,046 catheter-days (range of 423-1,413 catheter-days). CONCLUSIONS: Transhepatic hemodialysis catheter placement is associated with low rates of morbidity. In this series, transhepatic catheters provided the possibility of long-term functionality, despite associated high rates of catheter-related maintenance, provides a potentially viable access for patients with exhausted access options. PMID- 21276915 TI - The arterial distribution of Embozene and Embosphere microspheres in sheep kidney and uterus embolization models. AB - PURPOSE: To compare the in vivo distribution of the new embolic Embozene versus Embosphere as a control in the sheep renal and uterine vasculature. MATERIALS AND METHODS: Twelve sheep (three per group of product and size) were selectively embolized with Embozene 700 MUm, Embozene 900 MUm, Embosphere 500-700 MUm, or Embosphere 700-900 MUm, in one renal artery (0.5 mL microspheres) and in the two uterine arteries (0.25 mL each) and sacrificed 72 hours later for pathologic examination of kidney and uterus. Partition of microspheres in the vasculature was determined according to a classification of the renal and the uterine vasculatures into several zones. Vascular diameters and microsphere deformation were measured. RESULTS: Embozene 700 MUm and Embozene 900 MUm occluded significantly more distally than Embosphere 500-700 MUm and Embosphere 700-900 MUm in renal and uterine vasculature. For Embozene, the vessel diameter was not significantly different between the two sizes, for each organ, whereas it was significantly larger for Embosphere 700-900 MUm than for Embosphere 500-700 MUm in each organ. Embozene deformation was significantly higher than that of Embosphere in renal and uterine vasculature, increased from proximal to distal in location for both organs and correlated negatively with vessel diameter (Rho = 0.623; P < .0001). Embosphere deformation did not vary according to the zone. CONCLUSIONS: Embozene microspheres have a higher in vivo deformation, which results in a more distal occlusion within the vascular network compared with reference Embosphere microspheres. The diameter of occluded vessels varied for the tested size range for Embosphere but was independent of the tested microsphere size range used for Embozene. The deformation of Embozene appears to determine the size of the vessels occluded as opposed to the granulometric particle size, which makes level of occlusion unpredictable. PMID- 21276916 TI - In-vitro imaging of femoral artery nitinol stents for deformation analysis. AB - PURPOSE: Femoral artery stents are prone to fracture, and studying their deformations could lead to a better understanding of the cause of breakage. The present study sought to develop a method of imaging and analyzing stent deformation in vitro with use of a calibrated test device. MATERIALS AND METHODS: High-resolution (approximately 200 MUm) volumetric data were obtained with a flat panel detector-based C-arm computed tomography system. A nitinol stent placed in a testing device was imaged with various loads that caused bending, axial tension, and torsion. Semiautomatic software was developed to calculate the bending, extension, and torsion from the stent images by measuring the changes in the radius of curvature, eccentricity, and angular distortions. RESULTS: For the axial tension case, there was generally good agreement between the physical measurements and the image-based measurements. The bending measurements had better agreement at bend angles lower than 30 degrees . For stent torsion, the hysteresis between the loading and unloading curves were larger for the image based results compared with physical measurements. CONCLUSIONS: An imaging and analysis framework has been set up for the analysis of stent deformations that shows fairly good agreement between physical and image-based measurements. PMID- 21276917 TI - In-vivo imaging of femoral artery nitinol stents for deformation analysis. AB - PURPOSE: The authors have developed a direct method to study femoral artery stent deformations in vivo. A previously described imaging and analysis approach based on a calibrated phantom was used to examine stents in human volunteers treated for atherosclerotic disease. In this pilot study, forces on stents were evaluated under different in-vivo flexion conditions. MATERIALS AND METHODS: The optimized imaging protocol for imaging with a C-arm computed tomography system was first verified in an in-vivo porcine stent model. Human data were obtained by imaging 13 consenting volunteers with stents in femoral vessels. The affected leg was imaged in straight and bent positions to observe stent deformations. Semiautomatic software was used to calculate the changes in bending, extension, and torsion on the stents for the two positions. RESULTS: For the human studies, tension and bending calculation were successful. Bending was found to compress stent lengths by 4% +/- 3% (-14.2 to 1.5 mm), increase their average eccentricity by 10% +/- 9% (0.12 to -0.16), and change their mean curvature by 27% +/- 22% (0 to -0.005 mm(-1)). Stents with the greatest change in eccentricity and curvature were located behind the knee or in the pelvis. Torsion calculations were difficult because the stents were untethered and are symmetric. In addition, multiple locations in each stent underwent torsional deformations. CONCLUSIONS: The imaging and analysis approach developed based on calibrated in vitro measurements was extended to in-vivo data. Bending and tension forces were successfully evaluated in this pilot study. PMID- 21276918 TI - Re: Noninvasive repair of broken tunneled pleural catheters. PMID- 21276919 TI - Particle embolization as primary endovascular management of a patient with massive hemoptysis and isolated unilateral absence of the left pulmonary artery. PMID- 21276920 TI - Interpreting arterial wall inflammation around stents in the porcine coronary artery model. PMID- 21276921 TI - Fracture of Navilyst Exodus biliary catheters. PMID- 21276923 TI - Management of anterior shoulder instability: ask the experts. PMID- 21276924 TI - Expanding the frontiers of shoulder arthroscopy. PMID- 21276925 TI - Custom triflange outrigger ulnar component in revision total elbow arthroplasty. AB - HYPOTHESIS: This study describes the rationale for, and tests the hypothesis that, a custom outrigger triflange ulnar component for revision total elbow arthroplasty would decrease the contact stresses at the bushings and overcome excessive bushing wear in active patients who have bone and ligamentous deficiency. MATERIALS AND METHODS: Five consecutive revisions for failed Coonrad Morrey total elbow arthroplasties were performed with the custom outrigger triflange ulnar component for patients with accelerated bushing wear, ulnar component loosening, and deficient humeral condyles. The mean age at the time of surgery was 48 years (range, 32-64 years). Follow-up averaged 81 months (range, 65-124 months). The average number of previous operations was 2.4 (range, 2-3). RESULTS: The Mayo Elbow Performance Score improved from 40 (range, 15-65) preoperatively to 91 (range, 80-100) at the latest follow-up. There were two excellent and three good results. There was no radiographic or clinical evidence of bushing wear at 6.8 years of follow-up (range, 5.5-10.3 years). One patient required further revision of the humeral component due to mechanical loosening, which had not been revised at the time of the index surgery. DISCUSSION: A custom outrigger triflange ulnar component is an effective alternative for revising loose Coonrad-Morrey ulnar components in active patients with absent humeral epicondyles and accelerated bushing wear. CONCLUSION: It may be an alternative to revision with standard components until improved surgical designs addressing this problem become commercially available. PMID- 21276926 TI - Radiocapitellar stability: the effect of soft tissue integrity on bipolar versus monopolar radial head prostheses. AB - INTRODUCTION: Radiocapitellar stability depends, in part, on concavity compression mechanics. This study was conducted to examine the effects of the soft tissues on radiocapitellar stability with radial head prostheses. HYPOTHESIS: Monopolar radial head implants are more effective in stabilizing the radiocapitellar joint than bipolar radial head prostheses, with the soft tissues intact or repaired. MATERIALS AND METHODS: Twelve fresh frozen elbow specimens were used to evaluate radiocapitellar stability with monopolar and bipolar radial heads. The study variables focused on varying soft tissue conditions and examined the mean peak subluxation forces put forth by each prosthesis design. RESULTS: With the soft tissues intact, the mean peak force resisting posterior subluxation depended significantly on the radial head used (P = .03). Peak force was greatest for the native radial head (32 +/- 7 N) and least with the bipolar prosthesis (12 +/- 3 N), with the monopolar prosthesis falling in between (21 +/- 4 N). The presence of soft tissues significantly affected the bipolar implant's ability to resist subluxation, though it did not significantly impact the native or monopolar radial heads. DISCUSSION: This study reveals the dependence of radiocapitellar stability on soft tissue integrity, particularly for bipolar prostheses. Overall, monopolar prostheses have a better capacity to resist radiocapitellar subluxation. CONCLUSION: From a biomechanical perspective, the enhancement of elbow stability with a monopolar radial head prosthesis is superior to that with a bipolar design. This is especially true when the integrity of the soft tissues has been compromised, such as in trauma. PMID- 21276927 TI - The impact of ulnar collateral ligament tear and reconstruction on contact pressures in the lateral compartment of the elbow. AB - HYPOTHESIS: Complete ulnar collateral ligament (UCL) injury increases articular pressure and reduces contact area compared with the normal intact UCL. UCL reconstruction restores the contact area and contact pressure observed in the native joint. MATERIALS AND METHODS: Six male cadaveric elbows were mounted on a custom jig capable of simulating the 2 critical phases of the throwing motion during pitching. A contact sensor was placed through an anterior arthrotomy into the radiocapitellar joint. Each specimen then underwent valgus loading at 1.75 and 5.25 Nm of torque with the biceps, brachialis, and triceps under axial load in each testing condition. RESULTS: The average valgus laxity in the intact elbow at 90 degrees was 3.7 degrees +/- 0.6 degrees at the 5.25 Nm level of torque, which doubled after transection. The reconstruction group demonstrated less laxity (2.4 degrees +/- 0.4 degrees ) and reduced valgus angulation of the ulna at 5.25 Nm of torque. The transected UCL condition showed peak contact pressure 67% higher compared with the native ligament group at 5.25 Nm of torque. The reconstructed group increased peak articular cartilage pressures by 33% from the native ligament. At 5.25 Nm of torque for the 90 degrees flexion phase, the transected UCL condition showed an average contact pressure of 84% greater than that of the native ligament group. Reconstruction of the UCL restored average articular pressures to within 20% of intact values at 90 degrees . CONCLUSION: UCL injury increases radiocapitellar contact pressures and reduces resistance of the elbow to valgus loading. Contact pressures and valgus laxity can be improved with UCL reconstruction. DISCUSSION: Taken as a whole, the peak pressure data indicate that the reconstruction restores valgus stability and lateral contact pressures to nearly normal levels under the conditions tested. Because the 90 position is the clinically significant position, these laboratory data support the clinical success of the docking procedure. PMID- 21276928 TI - A predictive model of shoulder instability after a first-time anterior shoulder dislocation. AB - INTRODUCTION: Management of a first-time anterior shoulder dislocation (FTASD) involves important clinical and policy decisions. Predictive disease modeling can improve the quality of information disseminated in treatment discussions. In this paper, we describe a general-purpose, publicly available model and illustrate its potential as a tool for management of a FTASD. METHODS: A Markov decision model of the natural history of a FTASD was constructed. Outcome probabilities and effectiveness were derived from the literature or estimated by expert opinion where necessary. Outcomes were the Western Ontario Shoulder Instability index (WOSI) and the probability of a patient experiencing recurrent instability, undergoing surgical stabilization, and having a stable shoulder at 10 years. The model was both internally and externally validated. Outcomes were examined for specific cases. RESULTS: The model was effectively externally validated against two studies, a Swedish prospective cohort of Hovelius et al and Botonni et al's military cohort. It can produce detailed outcome predictions for individuals; eg, an 18-year-old man has a 77% risk of dislocation in year 1 and a 32% chance of having a stable shoulder in 10 years. CONCLUSION: Detailed and specific information about prognosis is critical in the management of a FTASD. Disease modeling lends itself well to these needs and allows improved shared decision making. Our model was externally validated and can predict specific outcomes. As a publically available resource, it will allow physicians to accurately predict the expected outcome of treatment based on covariates, patient demographics, and their own surgical success rates. PMID- 21276929 TI - Outcome measures in the management of proximal humeral fractures: a systematic review of their use and psychometric properties. PMID- 21276930 TI - Genetically modified salmon vying for a spot at the dinner table. PMID- 21276931 TI - Kinase inhibition that hinges on halogen bonds. AB - A major challenge for the discovery of protein kinase inhibitors is to identify potent, selective, and novel pharmacophores. In this issue, Fedorov et al. (2011) describes KH-CB19, an ATP-competitive inhibitor of cdc2-like kinase that interacts with the ATP hinge region through a halogen-bonding motif. PMID- 21276932 TI - A jump-start for planarian head regeneration. AB - Planaria are simple flatworms with an extraordinary ability to regenerate missing body parts. This makes them a unique model system for the study of regeneration. Extending an earlier chemical screen, Beane et al. (2011) now reveal a role for H+/K+ ATPase and membrane depolarization in anterior regeneration in planaria. PMID- 21276933 TI - Protein modification by arginylation. AB - The modification of protein by arginine catalyzed by arginyltransferases (ATE1) described by the Kashina group in this issue shows that arginylation of protein occurs widely in biology and is being recognized as a key regulatory reaction such as phosphorylation of proteins (Wang et al., 2011). PMID- 21276934 TI - Prohibitin(g) cancer: aurilide and killing by Opa1-dependent cristae remodeling. AB - Proapoptotic drugs targeting the mitochondrial Bcl-2 rheostat of apoptosis are tools to selectively kill cancer cells. Sato et al. (2011) expand the available toolkit by identifying the target of the cytotoxic natural product aurilide in the prohibitin Opa1-dependent apoptotic cristae remodeling. PMID- 21276936 TI - How the local geometry of the Cu-binding site determines the thermal stability of blue copper proteins. AB - Identifying the factors that govern the thermal resistance of cupredoxins is essential for understanding their folding and stability, and for improving our ability to design highly stable enzymes with potential biotechnological applications. Here, we show that the thermal unfolding of plastocyanins from two cyanobacteria--the mesophilic Synechocystis and the thermophilic Phormidium--is closely related to the short-range structure around the copper center. Cu K-edge X-ray absorption spectroscopy shows that the bond length between Cu and the S atom from the cysteine ligand is a key structural factor that correlates with the thermal stability of the cupredoxins in both oxidized and reduced states. These findings were confirmed by an additional study of a site-directed mutant of Phormidium plastocyanin showing a reverse effect of the redox state on the thermal stability of the protein. PMID- 21276935 TI - Biocompatible quantum dots for biological applications. AB - Semiconductor quantum dots are quickly becoming a critical diagnostic tool for discerning cellular function at the molecular level. Their high brightness, long lasting, size-tunable, and narrow luminescence set them apart from conventional fluorescence dyes. Quantum dots are being developed for a variety of biologically oriented applications, including fluorescent assays for drug discovery, disease detection, single protein tracking, and intracellular reporting. This review introduces the science behind quantum dots and describes how they are made biologically compatible. Several applications are also included, illustrating strategies toward target specificity, and are followed by a discussion on the limitations of quantum dot approaches. The article is concluded with a look at the future direction of quantum dots. PMID- 21276937 TI - Genome mining in Streptomyces clavuligerus: expression and biochemical characterization of two new cryptic sesquiterpene synthases. AB - Two presumptive terpene synthases of unknown biochemical function encoded by the sscg_02150 and sscg_03688 genes of Streptomyces clavuligerus ATCC 27074 were individually expressed in Escherichia coli as N-terminal-His6-tag proteins, using codon-optimized synthetic genes. Incubation of recombinant SSCG_02150 with farnesyl diphosphate (1, FPP) gave (-)-delta-cadinene (2) while recombinant SSCG_03688 converted FPP to (+)-T-muurolol (3). Individual incubations of (-) delta-cadinene synthase with [1,1-2H2]FPP (1a), (1S)-[1-2H]-FPP (1b), and (1R)-[1 2H]-FPP (1c) and NMR analysis of the resulting samples of deuterated (-)-delta cadinene supported a cyclization mechanism involving the intermediacy of nerolidyl diphosphate (4) leading to a helminthogermacradienyl cation 5. Following a 1,3-hydride shift of the original H-1(si) of FPP, cyclization and deprotonation will give (-)-delta-cadinene. Similar incubations with recombinant SSCG_03688 supported an analogous mechanism for the formation of (+)-T-muurolol (3), also involving a 1,3-hydride shift of the original H-1(si) of FPP. PMID- 21276938 TI - Peptide length and leaving-group sterics influence potency of peptide phosphonate protease inhibitors. AB - The ability to follow enzyme activity in a cellular context represents a challenging technological frontier that impacts fields ranging from disease pathogenesis to epigenetics. Activity-based probes (ABPs) label the active form of an enzyme via covalent modification of catalytic residues. Here we present an analysis of parameters influencing potency of peptide phosphonate ABPs for trypsin-fold S1A proteases, an abundant and important class of enzymes with similar substrate specificities. We find that peptide length and stability influence potency more than sequence composition and present structural evidence that steric interactions at the prime-side of the substrate-binding cleft affect potency in a protease-dependent manner. We introduce guidelines for the design of peptide phosphonate ABPs and demonstrate their utility in a live-cell labeling application that specifically targets active S1A proteases at the cell surface of cancer cells. PMID- 21276939 TI - Dihydroisoxazole analogs for labeling and visualization of catalytically active transglutaminase 2. AB - We report the synthesis and preliminary characterization of "clickable" inhibitors of human transglutaminase 2 (TG2). These inhibitors possess the 3-halo 4,5-dihydroisoxazole warhead along with bioorthogonal groups such as azide or alkyne moieties that enable subsequent covalent modification with fluorophores. Their mechanism for inhibition of TG2 is based on halide displacement, resulting in the formation of a stable imino thioether. Inhibition assays against recombinant human TG2 revealed that some of the clickable inhibitors prepared in this study have comparable specificity as benchmark dihydroisoxazole inhibitors reported earlier. At low micromolar concentrations they completely inhibited transiently activated TG2 in a WI-38 fibroblast scratch assay and could subsequently be used to visualize the active enzyme in situ. The potential use of these inhibitors to probe the role of TG2 in celiac sprue as well as other diseases is discussed. PMID- 21276940 TI - Specific CLK inhibitors from a novel chemotype for regulation of alternative splicing. AB - There is a growing recognition of the importance of protein kinases in the control of alternative splicing. To define the underlying regulatory mechanisms, highly selective inhibitors are needed. Here, we report the discovery and characterization of the dichloroindolyl enaminonitrile KH-CB19, a potent and highly specific inhibitor of the CDC2-like kinase isoforms 1 and 4 (CLK1/CLK4). Cocrystal structures of KH-CB19 with CLK1 and CLK3 revealed a non-ATP mimetic binding mode, conformational changes in helix alphaC and the phosphate binding loop and halogen bonding to the kinase hinge region. KH-CB19 effectively suppressed phosphorylation of SR (serine/arginine) proteins in cells, consistent with its expected mechanism of action. Chemical inhibition of CLK1/CLK4 generated a unique pattern of splicing factor dephosphorylation and had at low nM concentration a profound effect on splicing of the two tissue factor isoforms flTF (full-length TF) and asHTF (alternatively spliced human TF). PMID- 21276941 TI - A chemical genetics approach reveals H,K-ATPase-mediated membrane voltage is required for planarian head regeneration. AB - Biophysical signaling is required for both embryonic polarity and regenerative outgrowth. Exploiting endogenous ion transport for regenerative therapies will require direct regulation of membrane voltage. Here, we develop a pharmacological method to target ion transporters, uncovering a role for membrane voltage as a key regulator of anterior polarity in regenerating planaria. Utilizing the highly specific inhibitor, SCH-28080, our data reveal that H(+),K(+)-ATPase-mediated membrane depolarization is essential for anterior gene expression and brain induction. H(+),K(+)-ATPase-independent manipulation of membrane potential with ivermectin confirms that depolarization drives head formation, even at posterior facing wounds. Using this chemical genetics approach, we demonstrate that membrane voltage controls head-versus-tail identity during planarian regeneration. Our data suggest well-characterized drugs (already approved for human use) might be exploited to control adult stem cell-driven pattern formation during the regeneration of complex structures. PMID- 21276942 TI - Heterologous expression, biosynthesis, and mutagenesis of type II lantibiotics from Bacillus licheniformis in Escherichia coli. AB - Lichenicidin is a class II two-component lantibiotic produced by Bacillus licheniformis. It is composed of the two peptides Blialpha and Blibeta, which act synergistically against various Gram-positive bacteria. The lichenicidin gene cluster was successfully expressed in Escherichia coli, thus constituting the first report to our knowledge of a full reconstitution of a lantibiotic biosynthetic pathway in vivo by a Gram-negative host. This system was further exploited to characterize and assign the function of proteins encoded in the biosynthetic gene cluster in the maturation of lichenicidin peptides. Moreover, a trans complementation system was developed for expression of Blialpha and Blibeta variants in vivo. This contribution will spur future studies in the heterologous expression and engineering of lantibiotics. PMID- 21276943 TI - SHP2 is a target of the immunosuppressant tautomycetin. AB - SHP2 phosphatase is a positive transducer of growth factor and cytokine signaling. SHP2 is also a bona fide oncogene; gain-of-function SHP2 mutations leading to increased phosphatase activity cause Noonan syndrome, as well as multiple forms of leukemia and solid tumors. We report that tautomycetin (TTN), an immunosuppressor in organ transplantation, and its engineered analog TTN D-1 are potent SHP2 inhibitors. TTN and TTN D-1 block T cell receptor-mediated tyrosine phosphorylation and ERK activation and gain-of-function mutant SHP2 induced hematopoietic progenitor hyperproliferation and monocytic differentiation. Crystal structure of the SHP2?TTN D-1 complex reveals that TTN D 1 occupies the SHP2 active site in a manner similar to that of a peptide substrate. Collectively, the data support the notion that SHP2 is a cellular target for TTN and provide a potential mechanism for the immunosuppressive activity of TTN. Moreover, the structure furnishes molecular insights upon which therapeutics targeting SHP2 can be developed on the basis of the TTN scaffold. PMID- 21276944 TI - Specificity analysis-based identification of new methylation targets of the SET7/9 protein lysine methyltransferase. AB - We applied peptide array methylation to determine an optimized target sequence for the SET7/9 (KMT7) protein lysine methyltransferase. Based on this, we identified 91 new peptide substrates from human proteins, many of them better than known substrates. We confirmed methylation of corresponding protein domains in vitro and in vivo with a high success rate for strongly methylated peptides and showed methylation of nine nonhistone proteins (AKA6, CENPC1, MeCP2, MINT, PPARBP, ZDH8, Cullin1, IRF1, and [weakly] TTK) and of H2A and H2B, which more than doubles the number of known SET7/9 targets. SET7/9 is inhibited by phosphorylation of histone and nonhistone substrate proteins. One lysine in the MINT protein is dimethylated in vitro and in vivo demonstrating that the product pattern created by SET7/9 depends on the amino acid sequence context of the target site. PMID- 21276945 TI - Arginyltransferase is an ATP-independent self-regulating enzyme that forms distinct functional complexes in vivo. AB - Posttranslational arginylation mediated by arginyl transferase (ATE1) plays an important role in cardiovascular development, cell motility, and regulation of cytoskeleton and metabolic enzymes. This protein modification was discovered decades ago, however, the arginylation reaction and the functioning of ATE1 remained poorly understood because of the lack of good biochemical models. Here, we report the development of an in vitro arginylation system, in which ATE1 function and molecular requirements can be tested using purified recombinant ATE1 isoforms supplemented with a controlled number of components. Our results show that arginylation reaction is a self-sufficient, ATP-independent process that can affect different sites in a polypeptide and that arginyl transferases form different molecular complexes in vivo, associate with components of the translation machinery, and have distinct, partially overlapping subsets of substrates, suggesting that these enzymes play different physiological functions. PMID- 21276946 TI - Marine natural product aurilide activates the OPA1-mediated apoptosis by binding to prohibitin. AB - Aurilide is a potent cytotoxic marine natural product that induces apoptosis in cultured human cells at the picomolar to nanomolar range; however, its mechanism of action has been unknown. Results of the present study showed that aurilide selectively binds to prohibitin 1 (PHB1) in the mitochondria, activating the proteolytic processing of optic atrophy 1 (OPA1) and resulting in mitochondria induced apoptosis. The mechanism of aurilide cytotoxicity suggests that PHB1 is an apoptosis-regulating protein amenable to modulation by small molecules. Aurilide may serve as a small-molecule tool for studies of mitochondria-induced apoptosis. PMID- 21276949 TI - 17-hydroxyprogesterone caproate, progesterone, preterm birth prevention, and safety: who decides? Someone should. PMID- 21276947 TI - Mutations in prickle orthologs cause seizures in flies, mice, and humans. AB - Epilepsy is heritable, yet few causative gene mutations have been identified, and thus far no human epilepsy gene mutations have been found to produce seizures in invertebrates. Here we show that mutations in prickle genes are associated with seizures in humans, mice, and flies. We identified human epilepsy patients with heterozygous mutations in either PRICKLE1 or PRICKLE2. In overexpression assays in zebrafish, prickle mutations resulted in aberrant prickle function. A seizure phenotype was present in the Prickle1-null mutant mouse, two Prickle1 point mutant (missense and nonsense) mice, and a Prickle2-null mutant mouse. Drosophila with prickle mutations displayed seizures that were responsive to anti-epileptic medication, and homozygous mutant embryos showed neuronal defects. These results suggest that prickle mutations have caused seizures throughout evolution. PMID- 21276950 TI - Endoscopic treatment of a transmigrated intrauterine device to colonic wall: a case report. AB - We report an asymptomatic 23-year-old female patient who was diagnosed to have a transmigrated intrauterine device (IUD) during a routine gynecological examination. After the IUD had been located within the colonic wall by further investigation, the IUD was successfully extracted via transanal route by colonoscopic intervention. PMID- 21276951 TI - [Cavernous haemangioma of the right atrium]. AB - Cardiac haemangiomas are rare benign primitive tumors. We are reporting the case of a 67-year-old woman presenting with a haemangioma of the right atrium. This tumor was discovered by echocardiography because of cerebral strokes. The magnetic resonance imaging determined the characteristics of the tumor. It was completely resected through a right atrial approach. This was a round mobile mass, pediculed and implanted at the inferior area of the interatrial septum. The histopathological analysis revealed a cavernous haemangioma. PMID- 21276952 TI - [Convulsives crisis revealing left-ventricular non-compaction with apical myocardial infarction]. AB - Left-ventricular non-compaction is a rare congenital disorder and its association with myocardial infarction is rarely described in literature. We report the case of a patient in whom the diagnosis was established after multiple convulsive crisis. The resemblance of certain consequences of these two pathologies reports the difficulty of the diagnosis of imputability and all the specificity of this observation. PMID- 21276953 TI - [Usefulness of tricuspid annular displacement (TAD) to identify right ventricular dysfunction in normotensive patients with acute pulmonary embolism]. AB - BACKGROUND: Echocardiographic criteria of right ventricular dysfunction (RVD) in acute pulmonary embolism (PE) differ among published studies. Assessment of RV systolic function remains difficult because of the RV's complex shape. We aimed to evaluate RV systolic function with TAD in patients (pts) with acute PE. TAD (QLAB, Philips Medical Imaging) was based on a tissue-tracking algorithm that is ultrasound beam angle independent for automated detection of tricuspid annular displacement. DESIGN: Prospective and observational study. METHODS: All adults' pts who were diagnosed with PE from December 2008 to December 2009 at Princess Grace Hospital, Monaco were eligible for this study after exclusion of history of heart failure. We evaluated 36 consecutive pts with PE (18 male, mean age 62.7 years), which underwent echocardiography, plasma BNP titration during the first day after admission, and a second echocardiography obtained within 48 hours before discharge. RESULTS: TAD value were significantly lower in pts with abnormal RV function by echocardiogram (15.9 +/- 0.3 vs. 12.7 +/- 0.2 ; P = 0.026). Pts with a normal BNP (<80 pg/ml) had an elevated TAD (16.4 +/- 0.2 vs. 11.2 +/- 0.3 mm ; P < 0.0001). At discharge, echocardiographic data were obtained from 33 pts (mean: 8.3 +/- 3.5 days). RV end diastolic diameter, RV to LV diameter, pulmonary arterial systolic pressure, mean pulmonic valve acceleration time, RV FAC, Sa and TAD were significantly improved. There was no difference between TAD among pts with echocardiographic RVD at baseline vs. pts without RVD (14.9 +/- 3.7 vs. 16.1 +/- 2.9 mm ; P = 0.3). Four pts who deteriorated during short-term observation had substantially lower TAD values than those with uncomplicated courses (7.7 +/- 0.4mm vs. 14.6 +/- 0.2 mm ; P = 0.001). In conclusion, impaired TAD was associated with decreased RV systolic function in pts with acute PE. To identify the clinical meaning of decreased TAD, larger trials with longer follow-up periods are needed. PMID- 21276954 TI - [Correlation of TIMI risk score with angiographic extent and severity of coronary artery disease in non-ST-elevation acute coronary syndromes]. AB - AIM OF STUDY: To determine whether the TIMI risk score correlates with the angiographic extent and severity of coronary artery disease in patients with non ST-elevation acute coronary syndrome undergoing cardiac catheterization. PATIENTS AND METHOD: We conducted a retrospective review of 239 medical records of patients who underwent coronary angiography secondary to non-ST-elevation acute coronary syndrome between 2002 and 2006. Patients were classified into three groups according to TIMI risk score: TIMI scores 0 to 2 (group 1: n=121), 3 to 4 (group 2: n=100), and 5 to 7 (group 3: n=18). We compared the coronary angiography findings of the three groups. RESULTS: Patients of group 1 had a greater likelihood of normal or non significant CAD than patients of group 2 (36.3 % vs 13 %, P<0.001) and than patients of group 3 (36.3 % vs 0 %, P=0.002). One-vessel disease was found more often in patients with TIMI score 0 to 2 than in patients with TIMI score 5 to 7 (28.9 % vs 0 %; P=0.01), and in patients with TIMI score 3 to 4 than in those with score 5 to 7 (35 % vs 0 %, P=0.006). However, 1-vessel disease was found in patients of group 1 as often as in patients of group 2. The frequency of two-vessel disease was similar whatever the level of TIMI score was low, intermediate or high. Three-vessel or left main disease was more likely found in patients of group 3 than in patients of group 2 (66.7 % vs 26 %; P=0.01), and than patients of group 1 (66.7 % vs 13.2 %; P<0.001). Chronic coronary occlusions and coronary calcifications were also more likely found in patients with TIMI score 5 to 7. CONCLUSION: In patients with non ST-elevation acute coronary syndrome undergoing cardiac catheterization, the TIMI risk score correlated with the extent and severity of coronary artery disease. PMID- 21276955 TI - [Influence of diabetes mellitus on the prognosis of non-ST-elevation acute coronary syndromes]. AB - AIM OF STUDY: Analyze the influence of diabetes mellitus on the prognosis, at short and middle term of patients with non-ST-segment-elevation acute coronary syndrome. PATIENTS AND METHOD: We conducted a retrospective review of 308 consecutive medical records of patients admitted to the care unit of our department with a non-ST-segment-elevation acute coronary syndrome. One hundred and fifty-six patients were diabetics (group 1) and 152 were not (group 2). We compared the demographic, clinical, angiographic and therapeutic characteristics of the two groups and we analyzed the prognosis of diabetic and non-diabetic patients at short term (30 days) and at middle term (average: 28 months; extreme: 12 months, 72 months). RESULTS: The mean age was similar into both groups (60.8 years). Diabetic patients were more often women (42.1% vs 23.1%) and presented a higher prevalence of systemic hypertension, dyslipidemia and family history of coronary artery disease. Smoking was more frequent in group 2. The rates of coronary angiography, percutaneous transluminal coronary angioplasty, and coronary bypass surgery were similar in the two groups. At 30 days, diabetic patients were at increased risk for acute heart failure (19.1% vs 6.4%) and for major cardiac events (12.5% vs 6.4%). A pejorative prognosis was also observed at middle term among diabetic patients. They were at greater risk for readmissions for non-ST-segment-elevation acute coronary syndrome (42% vs 25%), for major cardiac events (49.3% vs 31.6%) and for new revascularizations (17.3% vs 7.2%). In a Cox multivariate analysis, diabetes mellitus remains an independent risk factor for major cardiac events at middle term. CONCLUSION: Our study confirms the pejorative prognosis of acute coronary syndromes without ST elevation at short and middle term in diabetic patients. PMID- 21276956 TI - Redo aortic valve surgery: early and late outcomes. AB - BACKGROUND: Repeat aortic valve surgery (rAVS) is usually associated with an increased risk profile due to advanced patient age and comorbidities. We analyzed the current early and late results for isolated rAVS. METHODS: One hundred fifty five patients underwent isolated rAVS from November 1994 to April 2008, of which, 86 received isolated redo aortic valve surgery (rAVS without root) and 69 received aortic root replacement (rAVS with root) as the second operation. RESULTS: Patient age was 58 +/- 16 years; 23% were female. The indications for redo surgery were infective endocarditis (27.1%, n = 42), bioprosthetic structural valve dysfunction and degeneration (23.8%, n = 37), mechanical valve nonstructural dysfunction (7.2%, n = 11), paravalvular leak (18.1%, n = 28), aortic dissection (2.6%, n = 4), and aortic aneurysm (7.1%, n = 11). Early mortality was 4.5% (n = 7) for all patients (3.5% for rAVS without root and 5.8% for rAVS with root, p = 0.5). Left ventricular ejection fraction less than 0.30 (odds ratio 9.2, 95% confidence interval [CI] 1.1 to 80.3) and preoperative neurologic dysfunction (odds ratio 22.1, 95% CI 2.3 to 197.4) were found to be the independent predictors for in-hospital mortality according to multivariate analysis. Follow-up was 100% complete with a mean duration of 2.7 +/- 2.8 years for all patients. Five-year and eight-year survival was 66% +/- 5% and 61% +/- 6% for all patients and did not significantly differ between surgical groups. Cox regression analysis revealed the following independent predictors of long-term survival: preoperative New York Heart Association functional class IV (hazard ratio 2.2, 95% CI 1.5 to 3.2, p < 0.01) and infective endocarditis (hazard ratio 2.2, 95% CI 1.4 to 3.1, p < 0.01). CONCLUSIONS: Repeat isolated aortic valve surgery is associated with respectable outcomes. Follow-up results reveal good long-term survival for this group. PMID- 21276957 TI - Reliability and validity analysis of the transfer assessment instrument. AB - OBJECTIVES: To describe the development and evaluate the reliability and validity of a newly created outcome measure, the Transfer Assessment Instrument (TAI), to assess the quality of transfers performed by full-time wheelchair users. DESIGN: Repeated measures. SETTING: 2009 National Veterans Wheelchair Games in Spokane, WA. PARTICIPANTS: A convenience sample of full-time wheelchair users (N=40) who perform sitting pivot or standing pivot transfers. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Intraclass correlation coefficients (ICCs) for reliability and Spearman correlation coefficients for concurrent validity between the TAI and a global assessment scale (0-100 visual analog scale [VAS]). RESULTS: No adverse events occurred during testing. Intrarater ICCs for 3 raters ranged between .35 and .89, and the interrater ICC was .642. Correlations between the TAI and a global assessment VAS ranged between .19 (P=.285) and .69 (P>.000). Item analyses of the tool found a wide range of results, from weak to good reliability. Evaluators found the TAI to be safe and able to be completed in a short time. CONCLUSIONS: The TAI is a safe, quick outcome measure that uses equipment typically found in a clinical setting and does not ask participants to perform new skills. Reliability and validity testing found the TAI to have acceptable interrater and a wide range of intrarater reliability. Future work indicates the need for continued refinement including removal or modification of items found to have low reliability, improved education for clinicians, and further reliability and validity analysis with a more diverse subject population. The TAI has the potential to fill a void in assessment of transfers. PMID- 21276958 TI - Medical and psychosocial complications associated with method of bladder management after traumatic spinal cord injury. AB - OBJECTIVES: To determine the relationships between bladder management method and medical complications (renal calculi or decubitus ulcers), number of hospital days, and psychosocial factors. We hypothesized that indwelling catheterization would be associated with more complications, more hospitalizations, and worse psychosocial outcomes compared with other bladder management methods. DESIGN: Inception cohort study. SETTING: Model spinal cord injury (SCI) centers funded by the National Institute on Disability and Rehabilitation Research from 1973 to 2005. PARTICIPANTS: Persons with new traumatic SCI (N=24,762) enrolled in the National SCI Database entire data set forms I and II. Patients were stratified according to the bladder management method recorded at each time of data collection into 1 of 4 groups as follows: indwelling catheterization, spontaneous voiding, condom catheterization, and intermittent catheterization. Those who reported no management method or errors in reporting were excluded (n=1564). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Medical complications, including pressure ulcer number and grade of worst ulcer, kidney stones, and hospitalizations, as well as psychosocial factors (satisfaction with life, perceived health status, societal participation), were stratified by bladder management method. Results were adjusted for level and completeness of neurologic injury and other confounding and modifying factors. RESULTS: Compared with other forms of bladder management, use of an indwelling catheter was associated with more pressure ulcers and longer and more hospitalizations for all causes and urology-specific causes. Indwelling catheter use was associated with the lowest levels of participation, but similar satisfaction with life and perceived health status. CONCLUSIONS: Indwelling catheterization was associated with more medical complications and lower levels of participation than other bladder management methods, but more research is required to ascertain the causality of these complications. PMID- 21276959 TI - Marital status, marital transitions, well-being, and spinal cord injury: an examination of the effects of sex and time. AB - OBJECTIVE: To examine the applicability of marital resource (marriage has substantial benefits for well-being over not being married) or marital crisis (marital dissolution leads to poorer well-being) models to the spinal cord injury (SCI) population by studying the effects of sex, marital status, and marital transitions on well-being. DESIGN: Prospective cohort study from the SCI Model Systems National Database. SETTING: Community. PARTICIPANTS: Men (n=4864) and women (n=1277) who sustained traumatic SCI and completed a minimum of 1 follow-up interview beginning at 1 year through 15 years postinjury. INTERVENTIONS: None. MAIN OUTCOMES MEASURES: Life satisfaction, depressive symptoms, and self perceived health status by using linear mixed models for longitudinal data. RESULTS: In general, well-being improved over time since injury. Hypothesis testing supported the marital crisis model, as marital loss through being or becoming separated or divorced and being or becoming widowed, had the most consistent and negative impact across well-being outcomes, whereas being or becoming married had an advantage for only lower depression symptoms over time. However, marital dissolution or loss did not have a uniformly adverse impact on well-being outcomes, and this effect often was moderated by sex, such that widows had higher depressive symptoms and poorer self-perceived health than widowers, but separated or divorced women had higher life satisfaction and self-perceived health than men. Irrespective of sex, being separated or divorced versus being single was associated with higher depressive symptoms over time. CONCLUSIONS: Results support the marital crisis model and that women and men can experience marital dissolution differently. All marital loss does not result in compromised well-being and all marriage does not enhance well-being, highlighting complex dynamics worthy of further investigation in this population. PMID- 21276960 TI - Obesity and inpatient rehabilitation outcomes for patients with a traumatic spinal cord injury. AB - OBJECTIVE: To examine the effect of obesity on change in FIM self-care and mobility ratings and community discharge for patients with traumatic spinal cord injury (SCI). DESIGN: Retrospective cohort study analyzing National Model Systems SCI Database data. SETTING: Fourteen Model Systems SCI programs. PARTICIPANTS: Patients (N=1524) with a new traumatic SCI discharged from Model Systems rehabilitation centers between October 2006 and October 2009. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Change in FIM self-care and mobility ratings, discharge destination. Separate analyses were conducted by neurologic category: paraplegia incomplete, paraplegia complete, tetraplegia incomplete, and tetraplegia complete. RESULTS: Of all patients with traumatic SCI, approximately 25% were obese at admission. Patients who were obese were more likely to be married and slightly older than nonobese patients. In patients with paraplegia incomplete, obese patients had lower FIM self-care (-1.9; 95% confidence interval [CI], -3.4 to -.4) and mobility score gains (-1.5; 95% CI, -2.9 to -.1) than normal-weight patients. For patients with paraplegia complete, obese patients had significantly lower self-care (-2.2; 95% CI, -3.5 to -.8) and mobility score gains (-2.7; 95% CI, -3.9 to -1.5). For patients with tetraplegia incomplete and tetraplegia complete, FIM self-care and mobility ratings for obese patients were not significantly different from ratings for normal-weight patients. Within each neurologic category, the percentage of patients discharged to the community was not significantly different for nonobese and obese patients. CONCLUSIONS: Obesity appears to be a barrier to meeting self-care and mobility functional goals for patients with paraplegia in inpatient SCI rehabilitation. PMID- 21276961 TI - Safety, tolerance, and efficacy of extended-release niacin monotherapy for treating dyslipidemia risks in persons with chronic tetraplegia: a randomized multicenter controlled trial. AB - OBJECTIVE: To test the safety, tolerance, and efficacy of extended-release niacin monotherapy on dyslipidemia in persons with chronic tetraplegia. DESIGN: Placebo controlled, blinded, multicenter, randomized controlled trial. SETTING: Three spinal cord injury research/rehabilitation centers. PARTICIPANTS: Persons with chronic tetraplegia (N=54) and low plasma high-density lipoprotein cholesterol (HDL-C) levels. INTERVENTION: Extended-release niacin monotherapy (48 weeks; n=31) on a dose-titration schedule versus matched placebo (n=23). MAIN OUTCOME MEASURES: Safety was assessed by using percentages of treatment-emergent adverse events and increased levels of hepatic transaminases, uric acid, glycosylated hemoglobin, and fasting glucose. Tolerance was assessed by using participant reports for frequency and intensity of adverse effects of extended-release niacin. Primary effectiveness outcomes were fasting HDL-C level and plasma total cholesterol (TC)/HDL-C ratio. Secondary outcomes included plasma low-density lipoprotein cholesterol (LDL-C) and TC levels and LDL-C/HDL-C ratio. RESULTS: Significant increases in fasting HDL-C levels (24.5%) were accompanied by decreases in TC/HDL-C and LDL-C/HDL-C ratios, LDL-C levels, and TC levels (all P<.05). No evidence of sustained hepatotoxicity or hyperglycemia was observed. Treatment-emergent withdrawals (12.9%) accompanied flushing (n=1), hypotension/presyncope (n=1), and diarrhea (n=2). One subject experienced transient hyperuricemia. Other drug-reported symptoms did not differ from those for placebo. CONCLUSIONS: Extended-release niacin monotherapy is safe, tolerated, and effective for most persons with chronic tetraplegia. Special precautions for changes in bowel habits and postadministration hypotension should be observed. PMID- 21276962 TI - Further evidence for the efficacy of a metacognitive group training in schizophrenia. AB - Metacognitive training (MCT) for patients with schizophrenia is a novel psychological group treatment targeting cognitive biases putatively involved in the pathogenesis of schizophrenia (e.g. jumping to conclusions, overconfidence in errors). Its eight modules are available cost-free online in many languages. In the present study, 36 subacute or remitted patients were randomly allocated to either the MCT or a wait-list group who received treatment-as-usual (TAU). Baseline and post assessments were 8 weeks apart and were performed blind to group status. MCT showed significantly greater improvement on the following parameters relative to the TAU group: delusion distress (PSYRATS), memory and social quality of life. In the MCT group, the rate of jumping to conclusions bias was reduced after training. No differences occurred on the PANSS. The present study confirms prior reports that MCT exerts beneficial effects on some cognitive and symptomatic parameters. PMID- 21276963 TI - Is our self nothing but reward? AB - Neuroscience has increasingly explored the neural mechanisms underlying our sense of self. Recent studies have demonstrated the recruitment of regions like the ventral tegmental area, ventromedial prefrontal cortex, and the ventral striatum to self-specific stimuli-regions typically associated with reward-related processing. This raises the question of whether there is a relationship between self and reward and, if so, how these different fields can be linked. Three relationship models that aim to explore the relationship between self and reward are discussed here: integration, segregation, and parallel processing. Their pros and cons are reviewed in light of the most recent findings. The conclusion is that both the fields of self and reward may benefit from increased interaction. This interaction may help to fill in some of the missing pieces regarding reward related processing, as well as illuminate how brain function can bring forward the philosophical concept and psychological reality of self. PMID- 21276964 TI - Activation of nuclear PPARgamma receptors by the antidiabetic agent pioglitazone suppresses alcohol drinking and relapse to alcohol seeking. AB - BACKGROUND: Pioglitazone and rosiglitazone belong to the class of thiazolidinediones (TZDs). They were first developed as antioxidants and then approved for the clinical treatment of insulin resistance and Type 2 diabetes. TZDs bind with high affinity and activate peroxisome proliferator-activated receptor-gamma (PPARgamma) receptors, which in the brain are expressed both in neurons and in glia. METHODS: We evaluated the effect of PPARgamma activation by TZDs on alcohol drinking, relapse-like behavior, and withdrawal in the rat. We also tested the effect of TZDs on alcohol and saccharin self-administration. RESULTS: We showed that activation of PPARgamma receptors by pioglitazone (0, 10, and 30 mg/kg) and rosiglitazone (0, 10 and 30 mg/kg) given orally selectively reduced alcohol drinking. The effect was blocked by pretreatment with the selective PPARgamma antagonist GW9662 (5 MUg/rat) given into the lateral cerebroventricle, suggesting that this TZD's effect is mediated by PPARgamma receptors in the central nervous system. Pioglitazone abolished reinstatement of alcohol seeking, a relapse-like behavior, induced by yohimbine, a pharmacologic stressor, but did not affect cue-induced relapse. In the self-administration experiments, pioglitazone reduced lever pressing for alcohol but not for saccharin. Finally, pioglitazone prevented the expression of somatic signs of alcohol withdrawal. CONCLUSIONS: These findings provide new information about the role of brain PPARgamma receptors and identify pioglitazone as candidate treatments for alcoholism and possibly other addictions. PMID- 21276965 TI - Mapping repetition suppression of the N100 evoked response to the human cerebral cortex. AB - BACKGROUND: Repetition suppression (RS) phenomena, such as those observed using paired-identical-stimulus (S1-S2) paradigms, likely reflect adaptive functions such as habituation and, more specifically, sensory gating. METHODS: To better characterize the neural networks underlying RS, we analyzed auditory S1-S2 data from electrodes placed on the cortices of 64 epilepsy patients who were being evaluated for surgical therapy. We identified regions with maximal amplitude responses to S1 (i.e., stimulus registration regions), regions with maximal suppression of responses to S2 relative to S1 (i.e., RS), and regions with no or minimal RS. RESULTS: Auditory perceptual regions, such as the superior temporal gyri, were shown to have significant initial registration activity (i.e., strong response to S1). Several prefrontal, cingulate, and parietal lobe regions were found to exhibit stronger RS than those recorded from the auditory perceptual areas. CONCLUSIONS: The data strongly suggest that the neural network underlying repetition suppression may include regions not previously thought to be involved, such as the parietal and cingulate cortexes. In addition, the data also support the notion that the initial response to stimuli and the ability to suppress the stimuli if repeated are two separate, but likely related, functions. PMID- 21276966 TI - Chemometric analysis of lipase-catalyzed synthesis of xylitol esters in a solvent free system. AB - Immobilized Candida antarctica lipase B-catalyzed esterification of xylitol and two fatty acids (capric and caproic acid) were studied in a solvent-free system. The Taguchi orthogonal array method based on three-level-four-variables with nine experiments was applied for the analysis and optimization of the reaction parameters including time, substrate molar ratio, amount of enzyme, and amount of molecular sieve. The obtained conversion was higher in the esterification of xylitol and capric acid with longer chain length. The optimum conditions derived via the Taguchi approach for the synthesis of xylitol caprate and xylitol caproate were reaction time, 29 and 18h; substrate molar ratio, 0.3 and 1.0; enzyme amount, 0.20 and 0.05g, and molecular sieve amount of 0.03g, respectively. The good correlation between the predicted conversions (74.18% and 61.23%) and the actual values (74.05% and 60.5%) shows that the model derived from the Taguchi orthogonal array can be used for optimization and better understanding of the effect of reaction parameters on the enzymatic synthesis of xylitol esters in a solvent-free system. PMID- 21276967 TI - Catalytic conversion of xylose to furfural over the solid acid SO4 2--/ZrO2 Al2O3/SBA-15 catalysts. AB - Al-promoted SO4 2--/ZrO2SBA-15 catalysts were prepared and characterized by XRD, BET, ICP and NH3-TPD techniques. The influence of introducing aluminum on the structure and surface properties of the catalyst and the catalytic activity for dehydration of xylose to furfural has been investigated. The introduction of the Al stabilizes the tetragonal phase of the ZrO2 and thus increases the number and intensity of acid sites. Based on the characterization of the deactivated catalyst, the accumulation of byproducts is the main reason for the deactivation of the catalyst. Regeneration with H2O2 can completely recover the catalytic activity of the deactivated catalyst. PMID- 21276968 TI - Strain measurement from 3D micro-CT images of a breast-mimicking phantom. AB - Strain distribution in compressed tissues gives information about elasticity of the tissues. We have measured strain from two sets of 3D micro-CT images of a breast-mimicking phantom; one obtained without compressing the phantom and the other with compressing it. To measure strain, we first calculated compression induced displacements of high-intensity feature patterns in the image. In measuring displacement of a pixel of interest, we searched the pixel in the compressed-phantom image, whose surrounding resembles the uncompressed-phantom image most closely, using the image correlation technique. From the displacement data, we calculated average strain at a region of interest. With the calculated average strains, we could distinguish the hard inclusion in the phantom which was not distinguishable from the background body of the phantom in the ordinary micro CT images. The calculated strains account for stiffness of the tissue of interest, one of the important parameters for diagnosing malignant tissues. We present experimental results of the displacement and strain measurement along with FEM analysis results. PMID- 21276969 TI - Seven roads traveled well and seven to be traveled more. AB - Over the past 30 years, controlled ovarian hyperstimulation, cryopreservation, intracytoplasmic sperm injection, improved embryologic technology, vaginal egg retrieval, donor gametes, and surrogacy have gotten us where we are. For future progress, we must have group thinking, widely available assisted reproductive technologies, the ability to identify fertilized eggs with newborn potential, an understanding of oligospermia, better preimplantation genetic diagnosis, somatic reproduction, and exogenesis. PMID- 21276970 TI - Effects of different temperatures, velocities and loads on the gliding resistance of flexor digitorum profundus tendons in a human cadaver model. AB - The purpose of this study was to investigate the effects of temperature, velocity and load on the gliding resistance (GR) of flexor digitorum profundus (FDP) tendons in a human cadaver model. A total of 40 FDP tendons from the index through small digits of ten human cadavers were tested to assess the effect of temperature (4, 23 or 36 degrees C), velocity (2, 4, 6, 8, 10 or 12 mm/s) and load (250, 500, 750, 1000, 1250 and 1500 g) on GR. The mean GR at 4 degrees C was significantly higher than the mean GR at 36 degrees C (p<0.0066). There was no significant difference in the mean GR of the tested velocities. The mean GR was proportional to load, with each successive load having significantly higher GR than the loads before it (all p<0.001). There was no significant difference in the mean GR by digit. In this in vitro model, we have demonstrated that tendon gliding resistance is proportional to load, independent of velocity and somewhat affected by temperature. We conclude that it is important to specify these conditions when reporting gliding resistance, especially load and temperature. PMID- 21276971 TI - Study of the abnormal late co-elution phenomenon of low density polyethylene in size exclusion chromatography using high temperature size exclusion chromatography and high temperature asymmetrical flow field-flow fractionation. AB - The elution behaviour of linear and branched polyethylene samples in SEC was studied. For the branched samples an abnormal late co-elution of large and small macromolecules manifests itself as an abnormal re-increase of the molar mass and the radius of gyration values detected with multi angle light scattering at high elution volumes in SEC. The late co-elution of small and large macromolecules cannot be explained by the SEC mechanism alone. The influence of several experimental parameters on the late co-elution was studied. It was found that the type of SEC column and the flow rate have a significant influence. The late eluting part of the sample was fractionated and separated by HT-SEC- and HT-AF4 MALS. The different results of both methods have been discussed with the aim to find possible explanations for the late elution. The experiments indicate that especially large branched structures show an increased tendency for the phenomenon. PMID- 21276972 TI - Di-n-amyl L-tartrate-boric acid complex chiral selector in situ synthesis and its application in chiral nonaqueous capillary electrophoresis. AB - A chiral selector, di-n-amyl L-tartrate-boric acid complex, was in situ synthesized by the reaction of di-n-amyl L-tartrate with boric acid in a nonaqueous background electrolyte (BGE) using methanol as the medium. And a new method of chiral nonaqueous capillary electrophoresis (NACE) was developed with the complex as the chiral selector. It has been demonstrated that the chiral selector is suitable for the enantioseparation of some beta-blockers and beta agonists in NACE. Some chiral analytes that could not be resolved in aqueous microemulsion electrokinetic chromatography (MEEKC) with the same chiral selector obtained baseline resolutions in the NACE system. The enantioseparation mechanism was considered to be ion-pair principle and the nonaqueous system was more favorable for the ion-pair formation which is quite useful for the chiral recognition. The addition of a proper concentration of triethylamine into the BGE to control the apparent pH (pH*) enhanced the enantiomeric discrimination. In order to achieve a good enantioseparation, the effects of di-n-amyl L-tartrate and boric acid concentration, triethylamine concentration, applied voltage, as well as capillary length were investigated. Under the optimum conditions, all of the tested chiral analytes including six beta-blockers and five beta-agonists were baseline resolved. PMID- 21276973 TI - Wormlike micelles formed by mixed cationic and anionic gemini surfactants in aqueous solution. AB - The formation and the properties of wormlike micelles in aqueous solutions of mixed cationic and anionic gemini surfactants, 2-hydroxyl-propanediyl-alpha,omega bis(dimethyldodecylammonium bromide) (12-3(OH)-12) and O,O'-bis(sodium 2 dodecylcarboxylate)-p-benzenediol (C(12)phiC(12)), have been studied by steady state and dynamic rheological measurements at 25 degrees C. With the addition of a small amount of C(12)phiC(12) into the solution of 12-3(OH)-12, the total surfactant concentration of which was always kept at 80 mmol L(-1), the solution viscosity was strongly enhanced and its maximum was much larger than that of the mixed system of propanediyl-alpha,omega-bis(dimethyldodecylammonium bromide) (12 3-12) and C(12)phiC(12). The results of dynamic rheology measurements showed that 12-3(OH)-12/C(12)phiC(12) formed longer wormlike micelles in comparison with 12-3 12/C(12)phiC(12). This was attributed to the effect of hydrogen bonding occurring between 12-3(OH)-12 molecules, which was an effective driving force promoting micellar growth. As few C(12)phiC(12) participated in the micelles, the electrostatic attraction between the oppositely charged head groups of 12-3(OH) 12 and C(12)phiC(12) made the molecules in the aggregates pack more tightly. This reinforced the hydrogen-bonding interactions and greatly promoted the micellar growth. PMID- 21276974 TI - Microspectroscopic analysis of green fluorescent proteins infiltrated into mesoporous silica nanochannels. AB - The infiltration of enhanced green fluorescent protein (EGFP) into nanochannels of different diameters in mesoporous silica particles was studied in detail by fluorescence microspectroscopy at room temperature. Silica particles from the MCM 41, ASNCs and SBA-15 families possessing nanometer-sized (3-8 nm in diameter) channels, comparable to the dimensions of the infiltrated guest protein EGFP (barrel structure with dimensions of 2.4 nm * 4.2 nm), were used as hosts. We found that it is necessary to first functionalize the surfaces of the silica particles with an amino-silane for effective encapsulation of EGFP. We demonstrated successful infiltration of the protein into the nanochannels based on fluorescence microspectroscopy and loading capacity calculations, even for nanochannel diameters approaching the protein dimensions. We studied the spatial distributions of the EGFPs within the silica particles by confocal laser scanning microscopy (CLSM) and multimode microscopy. Upon infiltration, the fluorescence lifetime drops as expected for an emitter embedded in a high refractive index medium. Further, the spectral properties of EGFP are preserved, confirming the structural integrity of the infiltrated protein. This inorganic-protein host guest system is an example of a nanobiophotonic hybrid system that may lead to composite materials with novel optical properties. PMID- 21276975 TI - Effects of sodium laurylsulfate on crystal structure of calcite formed from mixed solutions. AB - Sodium laurylsulfate (SLS), an anionic surfactant, was used for tailoring calcite via a solution route. SLS was dissolved in calcium and carbonate source solutions at various concentrations and critical micelle concentrations (CMCs). The crystallized particles were characterized using X-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM), laser-scattering particle size measurements, and thermogravimetric analysis (TGA). Energy dispersive spectroscopy (EDS) analysis was carried out to measure sulfur profiles on the surface of the particles. SLS tended to produce small calcite particles in the carbonate source solution, whereas this effect was not obvious in the calcium source solution. It is believed that the electrostatic repulsion force in the carbonate source solution contributes to the different particle refining effects of SLS seen in the two solutions. PMID- 21276976 TI - pH sensitive swelling and releasing behavior of nano-gels based on polyaspartamide graft copolymers. AB - pH sensitive nano-gels based on polyaspartamide graft copolymers are prepared by UV crosslinking the self-assembled nano-aggregates in the presence of a series of hydrophobic and hydrophilic grafting segments. While the physical nano-aggregates dissociate via ionization of the pH sensitive moiety, the nano-gels synthesized in this study swell instead. The chemical structure and morphology of the resulting nano-gels were analyzed using FTIR, (1)H FTNMR, and TEM. The pH dependence of the particle size, 120-250 nm, was investigated using a light scattering analyzer. The swelling behavior of the nano-cores under acidic conditions triggered abrupt release of the drug; this pH dependence occurs reversibly and quickly. The nano-gels prepared may have endosomal rupturing characteristics, as their buffering capacity is as strong as that of uncrosslinked nano-aggregates. The nano-gels synthesized as such possess potential application as sustained releasing drug carriers for intracellular delivery. PMID- 21276977 TI - Emotional reactivity, regulation and childhood stuttering: a behavioral and electrophysiological study. AB - The purpose of this preliminary study was to assess whether behavioral and psychophysiological correlates of emotional reactivity and regulation are associated with developmental stuttering, as well as determine the feasibility of these methods in preschool-age children. Nine preschool-age children who stutter (CWS) and nine preschool-age children who do not stutter (CWNS) listened to brief background conversations conveying happy, neutral, and angry emotions (a resolution conversation followed the angry conversation), then produced narratives based on a text-free storybook. Electroencephalograms (EEG) recorded during listening examined cortical correlates of emotional reactivity and regulation. Speech disfluencies and observed emotion regulation were measured during a narrative immediately after each background conversation. Results indicated that decreased use of regulatory strategies is related to more stuttering in children who stutter. However, no significant differences were found in EEG measurements of emotional reactivity and regulation between CWS and CWNS or between emotion elicitation conditions. Findings were taken to suggest that use of regulatory strategies may relate to the fluency of preschool-age children's speech-language output. LEARNING OUTCOMES: The reader will be able to (1) describe emotional reactivity and regulation processes, (2) discuss evidence for or against the relations of emotional reactivity, regulation and stuttering, (3) understand how multiple measures can be used to measure emotional reactivity and regulation. PMID- 21276978 TI - High-quality lung fixation by controlled closed loop perfusion for stereological analysis in a large animal model. AB - BACKGROUND: Stereology is an essential method for quantitative analysis of lung structure. Adequate fixation is a prerequisite for stereological analysis to avoid bias in pulmonary tissue, dimensions and structural details. We present a technique for in situ fixation of large animal lungs for stereological analysis, based on closed loop perfusion fixation. MATERIALS AND METHODS: Twenty anesthetized ventilated pigs (30 +/- 3 kg) underwent cannulation of the pulmonary artery and ligation of the right hilus. Following circulatory arrest a continuous positive pressure of 12 mbar was applied to the airways and lung perfusion started with the fixative solution (1.5% paraformaldehyde; 1.5% glutaraldehyde in 0.15 M HEPES). In five animals, a single-pass perfusion technique was performed, in 15 subsequent animals, the closed-loop technique was applied. Afterwards, lungs were removed, externally postfixed in the recycled fixative solution, and stored at 4 degrees C. Fifteen lung specimens underwent stereological analysis with volume estimation and subsequent systematic uniform random sampling for light and electron microscopic analysis. RESULTS: Singlepass perfusion did not result in satisfactory fixation. Left lung closed loop perfusion rate was 0.5-0.7 L/min with total median [min-max] perfusion time of 15 min (11-19). Perfusion pressure was 15 mm Hg (9-33). Subsequent lung analysis revealed well-preserved cell and tissue ultrastructure. CONCLUSION: The closed loop perfusion technique represents a valuable and reproducible fixation method in large animal models. Pressure controlled fixation perfusion results in high-quality preservation of in situ parenchymal architecture of lungs with or without injury, which is ideally suited for quantitative assessment of lung structure by stereology. PMID- 21276979 TI - Recombinant factor XIII mitigates hemorrhagic shock-induced organ dysfunction. AB - BACKGROUND: Plasma factor XIII (FXIII) is responsible for stabilization of fibrin clot at the final stage of blood coagulation. Since FXIII has also been shown to modulate inflammation, endothelial permeability, as well as diminish multiple organ dysfunction (MOD) after gut ischemia-reperfusion injury, we hypothesized that FXIII would reduce MOD caused by trauma-hemorrhagic shock (THS). MATERIALS AND METHODS: Rats were subjected to a 90 min THS or trauma sham shock (TSS) and treated with either recombinant human FXIII A(2) subunit (rFXIII) or placebo immediately after resuscitation with shed blood or at the end of the TSS period. Lung permeability, lung and gut myeloperoxidase (MPO) activity, gut histology, neutrophil respiratory burst, microvascular blood flow in the liver and muscles, and cytokine levels were measured 3 h after the THS or TSS. FXIII levels were measured before THS or TSS and after the 3-h post-shock period. RESULTS: THS induced lung permeability as well as lung and gut MPO activity was significantly lower in rFXIII-treated than in placebo-treated animals. Similarly, rFXIII treated rats had lower neutrophil respiratory burst activity and less ileal mucosal injury. rFXIII-treated rats also had a higher liver microvascular blood flow compared with the placebo group. Cytokine response was more favorable in rFXIII-treated animals. Trauma-hemorrhagic shock did not cause a drop in FXIII activity during the study period. CONCLUSIONS: Administration of rFXIII diminishes THS-induced MOD in rats, presumably by preservation of the gut barrier function, limitation of polymorphonuclear leukocyte (PMN) activation, and modulation of the cytokine response. PMID- 21276980 TI - Minimally invasive surgery improves short-term outcomes in elderly colorectal cancer patients. AB - BACKGROUND: Minimally invasive surgery (MIS) for colorectal resection has been shown to improve short-term outcomes compared with open surgery in patients with colorectal cancer. Currently, there is a paucity of data demonstrating similar efficacy between MIS and open colorectal resection in the elderly population. We hypothesized that minimally invasive surgery provides improved short-term outcomes in elderly patients with colorectal cancer. METHODS: A review of 242 consecutive elderly (>= 65 y of age) patients who underwent either open or MIS colorectal resection for adenocarcinoma at one institution was conducted. Short term and oncologic outcomes were analyzed. Continuous variables were analyzed by the Mann-Whitney U test. Categorical variables were compared by chi(2) tests. Survival was compared by the Kaplan-Meier method using the log rank test for comparison. RESULTS: Of the 242 elderly patients with colorectal cancer (median American Society of Anesthesiology score (ASA) scores of 3), 80% (n = 195) of patients underwent open and 20% (n = 47) had MIS colorectal cancer resections. Patients undergoing MIS had a faster return of bowel function, decreased days to nasogastric tube removal, decreased days to flatus and bowel movement, and quicker advancement to clear liquid and regular diets. The overall length of hospital stay in the MIS group was decreased by 40% as well as a trend towards a 50% decrease in SICU stay. Additionally, there was 66% decrease in cardiac complications in the MIS group. When evaluating for oncologic adequacy as measured by number of lymph nodes and surgical resection margins, MIS surgery offered equivalent results as open resection. Furthermore, there was no significant difference in overall survival for MIS versus open colorectal surgery. CONCLUSION: Minimally invasive colorectal cancer resection leads to improved short-term outcomes as demonstrated by decreased length of hospital stay and faster return of bowel function. Additionally, there appears to be no difference in oncologic outcomes in the elderly. On the basis of our data, age alone should not be a contra-indication to laparoscopic colorectal cancer resection. PMID- 21276981 TI - Sentinel node mapping with thermoresponsive magnetic nanoparticles in rats. AB - BACKGROUND: In this study, we investigated the ability of magnetic resonance imaging (MRI) after interstitial administration of thermoresponsive magnetic nanoparticles to detect the sentinel lymph node (SLN). MATERIALS AND METHODS: Postcontrast MRI scans were acquired following subcutaneous injection of thermoresponsive magnetic nanoparticles into the thoracic wall of rats. The signal-to-noise ratio of axillary lymph nodes was calculated to assess whether the SLN could be detected by MRI. In a second experiment, after injecting thermoresponsive magnetic nanoparticles, i.e., Therma-Max 36, Therma-Max 42, Therma-Max 55, and Ferridex, into the subserosa of the cecum of rats, the injection sites, the SLNs, and the distant lymph nodes were resected and examined histologically in order to determine which nanoparticles, if any, were specifically retained in the SLN. RESULTS: MRI showed that the signal-to-noise ratio of axillary SLNs was significantly lower 24 h after injection of Therma-Max 42 than on the precontrast images (P < 0.05). Histologic evaluation revealed that Therma-Max 36 aggregated at body temperature and did not migrate to the SLN. Therma-Max 42, on the other hand, aggregated, and the particles became large enough to be retained in the SLNs. Therma-Max 55 and Ferridex did not aggregate, and they both migrated to the SLNs and the distant lymph nodes. CONCLUSIONS: The results of this study showed that thermoresponsive magnetic nanoparticles could be targeted to the SLN by adjusting the temperature at which they aggregate, and that they could be used as a contrast agent for SLN mapping by MRI. PMID- 21276982 TI - Models of lower extremity damage in mice: time course of organ damage and immune response. AB - BACKGROUND: Post-traumatic inflammatory changes have been identified as major causes of altered organ function and failure. Both hemorrhage and soft tissue damage induce these inflammatory changes. Exposure to heterologous bone in animal models has recently been shown to mimic this inflammatory response in a stable and reproducible fashion. This follow-up study tests the hypothesis that inflammatory responses are comparable between a novel trauma model ("pseudofracture", PFx) and a bilateral femur fracture (BFF) model. MATERIALS AND METHODS: In C57BL/6 mice, markers for remote organ dysfunction and inflammatory responses were compared in four groups (control/sham/BFF/PFx) at the time points 2, 4, and 6 h. RESULTS: Hepatocellular damage in BFF and PFx was highly comparable in extent and evolution, as shown by similar levels of NFkappaB activation and plasma ALT. Pulmonary inflammatory responses were also comparably elevated in both trauma models as early as 2 h after trauma as measured by myeloperoxidase activity (MPO). Muscle damage was provoked in both BFF and PFx mice over the time course, although BFF induced significantly higher AST and CK levels. IL-6 levels were also similar with early and sustained increases over time in both trauma models. CONCLUSIONS: Both BFF and PFx create similar reproducible inflammatory and remote organ responses. PFx will be a useful model to study longer term inflammatory effects that cannot be studied using BFF. PMID- 21276983 TI - Effects of resveratrol on ileal smooth muscle reactivity in polymicrobial sepsis model. AB - OBJECTIVE: To determine the effects of resveratrol on the ileal smooth muscle reactivity in polymicrobial sepsis. MATERIAL AND METHODS: Polimicrobial sepsis was induced by the cecal ligation and perforation (CLP) procedure. Sprague Dawley rats were divided into three groups. Rats in resveratrol group received resveratrol after CLP (100 mg/kg, i.p.). Rats received saline immediately after CLP in the sepsis group. Control group rats underwent sham operation. The rats were sacrificed and the ileum was excised 24 h after the operation. Contractile and relaxant responses in isolated smooth muscle strips (SMS) were determined using an in vitro muscle technique. TNFalpha and IL-6 levels were measured in blood samples. RESULTS: Contractile responses to carbachol and KCl and relaxant responses to transmural electrical field stimulation (EFS) were significantly decreased in the sepsis group compared with control and resveratrol groups. No significant changes were observed for smooth muscle reactivity in the resveratrol and control groups. Sodium nitroprusside (SNP) or papaverine-induced relaxations were similar in the all groups. Resveratrol treatment supressed increased TNFalpha and IL-6 levels in blood seen in sepsis group. CONCLUSION: Ileal smooth muscle reactivity was improved after resveratrol treatment in rats with sepsis. The results of the present study indicate that the beneficial effects of resveratrol might be, at least in part, attributed to its effects on non adrenergic non-cholinergic pathway and/or anti-inflammatory and antioxidant activity. PMID- 21276984 TI - CC Chemokine receptor 5 deficiency does not prevent local immune responses to adenovirus vector in islet transplant recipients. AB - BACKGROUND: CC chemokine receptor 5 (CCR5) plays an important role in mediating inflammation. We examined the effect of CCR5 on the immune response to adenovirus vectors and graft function in islet transplant model. MATERIALS AND METHODS: Syngeneic wild-type (WT) or CCR5-deficient (KO) mouse islets transduced with adenovirus encoding beta-gal were transplanted under the renal capsule. After transplant, blood glucose, glucose tolerance, graft cellular infiltration, transgene and chemokine/receptor expression, and systemic anti-adenoviral/-beta gal immune response were evaluated. RESULTS: Diabetes was reversed in 1 d in both WT and KO untransduced recipients, while islets transduced with adenovirus failed to reverse diabetes until 10 d post-transplant in WT recipients or even longer (>15 d) in KO recipients (P < 0.05). A profound infiltration of CD4(+), CD8(+) cells and macrophages was observed in both WT and KO transduced grafts at 25 d. Though transgene expression was significantly reduced, insulin and beta-gal expression persisted over 3 mo. Glucose tolerance was impaired in all grafts in KO recipients compared with untransduced grafts in WT recipients at 25 d post transplant, but was equivalent at 3 mo. Early expression of CCR2 mRNA was increased in transduced grafts in both WT and KO recipients. No systemic antivector immunity was demonstrated in any recipient group. CONCLUSIONS: Transduction of islets with adenovirus causes significant local inflammation in islet grafts and impairs early graft function in CCR5-deficient recipients, but long-term graft function is preserved. Thus, CCR5 absence does not prevent the local immune response to adenovirus transduction, and vector-associated graft dysfunction is not mediated by CCR5. PMID- 21276985 TI - Interleukin-7 treatment reverses parenteral nutrition-induced impairment of resistance to bacterial pneumonia with increased secretory immunoglobulin A levels. AB - BACKGROUND: Absence of enteral delivery of nutrients causes gut associated lymphoid tissue (GALT) atrophy and an imbalance between immunoglobulin A (IgA) inhibiting Th1 and IgA-stimulating Th2 cytokine levels in the gut, leading to impaired mucosal immunity. We previously demonstrated exogenous IL-7 to reverse parenteral nutrition (PN)-induced GALT cell loss but not to normalize the gut cytokine imbalance or reduce secretory IgA levels, in uninjured mice. Herein, we examined effects of exogenous IL-7 during PN on survival and IgA levels after intra-tracheal bacterial challenge. METHODS: Sixty-five male Institute of Cancer Research (ICR) mice were randomized to chow, PN or PN+IL-7 (1 MUg/kg, administered i.v. twice a day), and jugular vein catheters were inserted. The chow and PN mice received normal saline i.v. infusions instead of IL-7. After 5 d of feeding (chow or PN) and treatment, 8 * 10(7)Pseudomonas aeruginosa were instilled intra-tracheally. Survival was observed in 41 mice, while 24 were killed at 6 h after challenge and small intestinal, nasal and bronchoalveolar washings were obtained for IgA measurement. RESULTS: PN significantly reduced survival time and IgA levels in small intestine and bronchoalveolar washings compared with chow feeding. IL-7 treatment restored these parameters. Therefore, no significant differences in survival or secretory IgA levels were found between the chow and PN+IL-7 groups. CONCLUSIONS: Exogenous IL-7 reverses PN-induced impairment of resistance to respiratory tract infections associated with increased secretory IgA levels. PMID- 21276986 TI - Occurrence of Pyrodinium bahamense var. compressum along the southern coast of the Baja California Peninsula. AB - As part of a continuing toxic microalgae monitoring program, 22 phytoplankton samples were collected from July to November 2010 at several sampling stations along the southern coast of the Baja California Peninsula. For the first time, the toxic dinoflagellate Pyrodinium bahamense var. compressum was found along the southeastern and southwestern coasts of the peninsula. P. bahamense var. bahamense was first observed off San Jose del Cabo, which is an extension of the range of this variety. Both varieties occur as solitary cells. P. bahamense var. compressum occurred at temperatures ranging between 24.5 degrees C and 31 degrees C, whereas var. P.bahamense occurred at 28.5 degrees C to 29 degrees C, indicating its tropical and subtropical nature. Occurrence of P. bahamense var. compressum along this coastline may be related to El Nino 2009-2010. PMID- 21276987 TI - Estimation of southern resident killer whale exposure to exhaust emissions from whale-watching vessels and potential adverse health effects and toxicity thresholds. AB - Southern resident killer whales in British Columbia and Washington are exposed to heavy vessel traffic. This study investigates their exposure to exhaust gases from whale-watching vessels by using a simple dispersion model incorporating data on whale and vessel behavior, atmospheric conditions, and output of airborne pollutants from the whale-watching fleet based on emissions data from regulatory agencies. Our findings suggest that current whale-watching guidelines are usually effective in limiting pollutant exposure to levels at or just below those at which measurable adverse health effects would be expected in killer whales. However, safe pollutant levels are exceeded under worst-case conditions and certain average-case conditions. To reduce killer whale exposure to exhaust we recommend: vessels position on the downwind side of whales, a maximum of 20 whale watching vessels should be within 800 m at any given time, viewing periods should be limited, and current whale-watch guidelines and laws should be enforced. PMID- 21276988 TI - Hepatic biotransformation genes and enzymes and PAH metabolites in bile of common sole (Solea solea, Linnaeus, 1758) from an oil-contaminated site in the Mediterranean Sea: a field study. AB - The aim of the present field study was to evaluate the response of hepatic biotransformation genes and enzymes of the common sole collected from an area characterized by the presence of an oil-refinery. Based on ?PAHs levels detected in sediments, three sites were identified: an high-impact site in front of the refinery, a moderate impact site and a reference site at increasing distances from the refinery. Transcription of cyp1a, udpgt and gst genes and related enzyme activities, such as EROD, BROD, MROD, B(a)PMO, UDPGT and GST, were assessed in sole liver. PAHs bile metabolites were measured. The link between phases I and II is discussed with regard to levels of PAHs measured in sediments and fillets. Results provide sequencing data on biotransformation genes essential for further studies on transcriptional responses in common sole and confirm phase I enzyme activities as useful tools for future biomonitoring studies in marine coastal areas. PMID- 21276989 TI - A biomonitoring study: Heavy metals in macroalgae from eastern Aegean coastal areas. AB - The concentrations of metals were measured in macroalgae species seasonally at eight coastal stations along the eastern Aegean coast. Sediment and seawater samples were also collected to detect their metal contents in order to gain more information on the environmental conditions of the area and possible bioaccumulation patterns. The aim of this study is, to gather more information on the use of selected species as cosmopolitan biomonitors for the eastern Aegean; to provide information on the marine environmental quality by the use of macroalgae and to determine which algae species are suitable as biomonitoring species for the study area. The relative abundance of metals in macroalgae decreases in the order: Fe-Zn-Cu-Cr-Cd-Hg-Pb and seawater: Fe-Zn-Pb-Cu-Cr-Cd-Hg. In sediment the distribution order from higher to lower was Fe-Cr-Zn-Pb-Cu-Hg-Cd. The brown algae Cystoseira sp., the green algae Ulva sp. and Enteromorpha sp. possess high potential as cosmopolitan biomonitors for trace metals in the Aegean Sea. PMID- 21276990 TI - Contemporary 14C radiocarbon levels of oxygenated polybrominated diphenyl ethers (O-PBDEs) isolated in sponge-cyanobacteria associations. AB - Considerable debate surrounds the sources of oxygenated polybrominated diphenyl ethers (O-PBDEs) in wildlife as to whether they are naturally produced or result from anthropogenic industrial activities. Natural radiocarbon ((14)C) abundance has proven to be a powerful tool to address this problem as recently biosynthesized compounds contain contemporary (i.e. modern) amounts of atmospheric radiocarbon; whereas industrial chemicals, mostly produced from fossil fuels, contain no detectable (14)C. However, few compounds isolated from organisms have been analyzed for their radiocarbon content. To provide a baseline, we analyzed the (14)C content of four O-PBDEs. These compounds, 6-OH BDE47, 2'-OH-BDE68, 2',6-diOH-BDE159, and a recently identified compound, 2'-MeO 6-OH-BDE120, were isolated from the tropical marine sponges Dysidea granulosa and Lendenfeldia dendyi. The modern radiocarbon content of their chemical structures (i.e. diphenyl ethers, C(12)H(22)O) indicates that they are naturally produced. This adds to a growing baseline on, at least, the sources of these unusual compounds. PMID- 21276991 TI - Cytochrome P450 isozyme protein verified in the skin of southern hemisphere humpback whales (Megaptera novaeangliae): implications for biochemical biomarker assessment. AB - Large mysticete whales represent a unique challenge for chemical risk assessment. Few epidemiological investigations are possible due to the low incidence of adult stranding events. Similarly their often extreme life-history adaptations of prolonged migration and fasting challenge exposure assumptions. Molecular biomarkers offer the potential to complement information yielded through tissue chemical analysis, as well as providing evidence of a molecular response to chemical exposure. In this study we confirm the presence of cytochrome P450 reductase (CPR) and cytochrome P450 isoenzyme 1A1 (CYP1A1) in epidermal tissue of southern hemisphere humpback whales (Megaptera novaeangliae). The detection of CYP1A1 in the integument of the humpback whale affords the opportunity for further quantitative non-destructive investigations of enzyme activity as a function of chemical stress. PMID- 21276992 TI - Differential proteome analysis of mature and germinated embryos of Araucaria angustifolia. AB - Araucaria angustifolia is an endangered Brazilian native conifer tree. The aim of the present work was to identify differentially expressed proteins between mature and germinated embryos of A. angustifolia, using one and two dimensional gel electrophoresis approaches followed by protein identification by tandem mass spectrometry. The identities of 32 differentially expressed protein spots from two dimensional gel maps were successfully determined, including proteins and enzymes involved in storage mobilization such as the vicilin-like storage protein and proteases. A label free approach, based on spectral counts, resulted in detection of 10 and 14 mature and germinated enriched proteins, respectively. Identified proteins were mainly related to energetic metabolism pathways, translational processes, oxidative stress regulation and cellular signaling. The integrated use of both strategies permitted a comprehensive protein expression overview of changes in germinated embryos in relation to matures, providing insights into the this process in a recalcitrant seed species. Applications of the data generated on the monitoring and control of in vitro somatic embryos were discussed. PMID- 21276993 TI - Does adherence to the Mediterranean diet have a protective effect against active and passive smoking? AB - OBJECTIVE: To investigate the existing evidence about whether adherence to the Mediterranean diet may have a role as an effect modifier of active and passive smoking on human health. STUDY DESIGN: Review. METHODS: An overview of emerging evidence and published studies that cover the interaction between the Mediterranean diet and smoking. RESULTS: Both epidemiological and laboratory studies have shown that the Mediterranean diet has a protective effect against biochemical and molecular processes that lead to cancer, cardiovascular disease and respiratory illness. Based on the high daily intake of vitamins and antioxidants, the Mediterranean diet is comprised of a number of compounds that could alter certain outcomes related to smoking. Studies have indicated that certain diseases attributable to smoking, such as lung cancer, asthma and cardiovascular disease, are inversely associated with certain antioxidants and lipids. CONCLUSIONS: The literature indicates that the existence of a partial interaction between adherence to the Mediterranean diet and the health effects of smoking is possible. Further research is needed to lead to a conclusive statement on this hypothesis. PMID- 21276994 TI - Mapping of sexual health promotion in North West England, 2008. AB - OBJECTIVE: To map sexual health promotion activity and resources across North West England. STUDY DESIGN: Survey. METHODS: A survey of all sexual health promotion activity commissioned by primary care trusts (PCTs) was carried out using a self-completion questionnaire for PCT sexual health commissioners in North West England. RESULTS: Sixteen out of 24 PCTs responded. Some PCTs had difficulty in identifying the relevant commissioner. Most activity was focused on young people, especially around the National Chlamydia Screening Programme (NCSP) and teenage pregnancy, and on particular high-risk groups such as lesbian, gay and bisexual people, those living with human immunodeficiency virus and commercial sex workers. All PCTs commissioned education/training and a condom distribution service. Other common activities included outreach work, and producing and disseminating materials. Most services were confined to one PCT. Most PCTs were unable to identify the resources committed to sexual health promotion. The emergent themes in the analysis of service development ideas and comments were all linked to commissioning: commissioning and strategy; funding; needs assessment; service development and provision; contracting and monitoring; evaluation and evidence; and regional perspective. CONCLUSIONS: A simple tool to map sexual health promotion activities commissioned by PCTs was developed. Many PCTs could not identify a commissioner for sexual health or the resources committed to sexual health promotion. Sexual health promotion activity focused on young people (linked to the NCSP and teenage pregnancy) and particular high-risk groups, with resultant gaps and a mismatch with the epidemiology. The most frequently commissioned activities were education/training and condom provision (despite the limited evidence base). A series of recommendations to PCTs, sexual health networks and providers are made. PMID- 21276995 TI - Dogs mean arterial pressure and heart rate responses during high propofol plasma concentrations estimated by a pharmacokinetic model. AB - Propofol total intravenous anesthesia should provide stability of the cardiovascular system. In this study, mean arterial pressure and heart rate were evaluated in eight healthy dogs anesthetized with increasing rates of propofol. The cerebral state index (CSI) was studied as an additional parameter. Although the estimated propofol plasma concentration reached a maximal value of 15.3 MUg ml(-1), no hypotension or bradycardia were observed. Exploration of each animal's data revealed high inter-individual variability regarding mean arterial pressure and heart rate. Considering the logarithmic of the concentration, a moderate depressant effect of propofol on mean arterial pressure was revealed in five dogs but the effect was not followed on heart rate. PMID- 21276996 TI - [Surgical devices]. AB - Surgical devices mean the whole surgical department i.e., working space, useful tools for its good process and respect of its rules for the users. That working space obeys to strict rules relating to its conception, its building or the behaviour of people in that space. Working tools (furniture, material and surgical tools) have to respect requirements of the surgical team and the patients. The local rules respect will warrant optimal quality and efficiency. We will successively present architectural imperative rules and will detail arrangement of the surgeons preparing room and the real surgical space. PMID- 21276997 TI - Peritoneal tuberculosis. PMID- 21276998 TI - Comprehensive analysis of host gene expression in Autographa californica nucleopolyhedrovirus-infected Spodoptera frugiperda cells. AB - Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV) is the best studied baculovirus and most commonly used virus vector for baculovirus expression vector systems. The effect of AcMNPV infection on host cells is incompletely understood. A microarray based on Spodoptera frugiperda ESTs was used to investigate the impact of AcMNPV on host gene expression in cultured S. frugiperda, Sf21 cells. Most host genes were down-regulated over the time course of infection, although a small number were up-regulated. The most highly up regulated genes encoded heat shock protein 70s and several poorly characterized proteins. Regulated genes with the highest score identified by functional annotation clustering included primarily products required for protein expression and trafficking in the ER and golgi. All were significantly down-regulated by approximately 12h post-infection. Microarray data were validated by qRT-PCR. This study provides the first comprehensive host transcriptome overview of Sf21 cells during AcMNPV infection. PMID- 21276999 TI - A cyclin-binding motif in human papillomavirus type 18 (HPV18) E1^E4 is necessary for association with CDK-cyclin complexes and G2/M cell cycle arrest of keratinocytes, but is not required for differentiation-dependent viral genome amplification or L1 capsid protein expression. AB - The G2/M arrest function of human papillomavirus (HPV) E4 proteins is hypothesized to be necessary for viral genome amplification. Full-length HPV18 E1^E4 protein is essential for efficient viral genome amplification. Here we identify key determinants within a CDK-bipartite consensus recognition motif in HPV18 E1^E4 that are critical for association with active CDK-cyclin complexes and in vitro phosphorylation at the predicted CDK phosphorylation site (threonine 23). The optimal cyclin-binding sequence ((43)RRLL(46)) within this E4 motif is required for G2/M arrest of primary keratinocytes and correlates with cytoplasmic retention of cyclin B1, but not cyclin A. Disruption of this motif in the E4 ORF of HPV18 genomes, and the subsequent generation of stable cell lines in primary keratinocytes revealed that this motif was not essential for viral genome amplification or L1 capsid protein induction. We conclude that the HPV18 E4 G2/M arrest function does not play a role in early vegetative events. PMID- 21277000 TI - Physico-chemical changes in metal-spiked sediments deployed in the field: implications for the interpretation of in situ studies. AB - Manipulative field studies are useful for investigating cause-effect relationships between contamination and benthic community health. However, there are many challenges for creating environmentally relevant exposures and determining what measurements are necessary to correctly interpret the results. This study describes the physical and chemical changes in the properties of metal spiked marine sediments deployed in four different locations for up to 11 months. The test sediments lost between 20% and 75% of their volume during the deployment period, with the greatest losses occurring at sites affected by strong hydrodynamic activity. More sediment was lost from clean treatments than those spiked with high metal concentrations and corresponded with differential recruitment of infauna to these treatments. In general, a greater proportion of spiked-metals remained at lower energy sites (48-85%) than at higher energy sites (15-48%). The decreased metal concentrations were attributed mostly to the loss of the metal-spiked sediments (through resuspension) and their dilution with sediments depositing from the surrounding environment. A range of recommendations are made for optimising the information gained from field-based studies using metal-spiked sediments. These include the careful documentation of physico chemical sediment properties pre- and post-deployment, the use of co-located sediment traps and knowledge of site-specific hydrodynamic processes. PMID- 21277001 TI - The evaluation of stability during the composting of different starting materials: comparison of chemical and biological parameters. AB - Three blends formed by: (i) food processing waste (CP(FP)), (ii) waste water sewage sludge (CP(WW)), and (iii) their mixture (CP(FP+WW)), blended with tree pruning as bulking agent, were composted over 3 months. During composting the blends were monitored for the main physical-chemical characteristics: temperature, oxygen saturation level (O(2)%), pH, total and volatile solids, total organic carbon, and organic nitrogen (N(org)). In addition to the main parameters, the dissolved organic carbon (DOC), the inorganic nitrogen and the Oxygen Uptake Rate (OUR) were monitored. All the mixtures easily reached a peak temperature around 70 degrees C, related to the lowest O(2)%. After 90 d, CP(FP), CP(FP+WW), and CP(WW) showed an organic matter mineralization of 43%, 35% and 33%, respectively; CP(FP) fitted an exponential model while both CP(FP+WW), and CP(WW) fitted a logistic model. During composting an OUR reduction of 79%, 78% and 73% was registered in CP(FP), CP(FP+WW), and CP(WW), respectively; the OUR successfully fitted the adopted exponential model and well reflected the stabilization process in time. The N(org) recovery at the end of the process was positive only in CP(WW) (11.6%). The DOC significantly decreased during the composting process but did not successfully fit any model. The mineral nitrogen did not follow the typical pattern with NH(4)(+) disappearance and NO(3)(-) accumulation. Strong NO(3)(-) losses were evident in all blends, while NH(4)(+) accumulations were detectable only in CP(FP), and CP(FP+WW). The NH(4)(+)/NO(3)( ) ratio did not satisfactorily reflect the composting process over time. The comparison of the first order (exponential) and logistic (sigmoidal) models applied to the OUR and OM course highlights the role of mineral nitrogen as limiting factor during composting of the more stabilized sludge. PMID- 21277002 TI - Hominin occupations at the Dmanisi site, Georgia, Southern Caucasus: raw materials and technical behaviours of Europe's first hominins. AB - Dmanisi is the oldest site outside of Africa that records unquestioned hominin occupations as well as the dispersal of hominins in Europe and Asia. The site has yielded large numbers of artefacts from several periods of hominin occupation. This analysis of Dmanisi stone tool technology includes a review of all the pieces recovered during the last 15 years of excavations. This lithic assemblage gives insights into the hominin behaviour at 1.7-1.8 Ma in Eurasia. Dmanisi hominins exploited local rocks derived from either nearby riverbeds or outcrops, and petrographic study provides data on patterns of stone procurement. Recent geological surveys and technological studies of the artefacts illustrate the roles of hominins in composing the assemblage. Dmanisi hominins selected two types of blanks, including cobbles and angular blocks, of basalt, andesite, and tuffs. Many complete cobbles, pebbles, and rolled blocks in basalt were unmodified, and geological analyses and surveys indicate that hominins brought manuports back to the site, suggesting a complex procurement strategy. Cores, flakes and debris show that all stages of flaking activity took place at the site. Numerous unifacial cores suggest that knapping was not very elaborate. Centripetal knapping is observed on some flake-cores. Knapping was influenced by the blank shape and natural angles. Most flaked objects were either cores or chopper-cores. Flakes predominate while flake tools are rare. The Dmanisi lithic assemblage is comparable to Oldowan sites in Africa in terms of reduction sequence, organisation of the removals, platform types, and the lack of retouched flakes. Dmanisi artefacts and may have been produced by the original hominins in Europe and Asia. PMID- 21277003 TI - Importance of monsoon rainfall in mass fluxes of filtered and unfiltered mercury in Gwangyang Bay, Korea. AB - We investigated the effects of the East Asian Summer Monsoon (EASM), which brings approximately half of Korea's annual rainfall in July, on the concentration and particle-water partitioning, and sources of Hg in coastal waters. Surface seawater samples were collected from eight sites in Gwangyang Bay, Korea, during the monsoon (July, 2009) and non-monsoon dry (April and November, 2009) seasons and the concentrations of suspended particulate matter, chlorophyll-a, and unfiltered and filtered Hg were determined. We found significant (p<0.05) increases in filtered Hg in the monsoon season (1.8 +/- 0.019 pM) compared to the dry season (0.62 +/- 0.047 pM). In contrast, the Hg concentrations associated with particles showed no significant differences (p>0.05) between the monsoon (459 +/- 141 pmol g(-1)) and the dry season (346 +/- 30 pmol g(-1)), which resulted in decreased particle-water partition coefficients of Hg in the monsoon season compared to the values in the dry season: 5.7 +/- 0.1 in April, 5.3 +/- 0.1 in July, and 5.8 +/- 0.1 in November. The annual Hg input to Gwangyang Bay was estimated at 64 +/- 6.6 mol yr(-1) and 27 +/- 1.9 mol yr(-1) for unfiltered and filtered Hg, respectively. The Hg discharged from rivers was a major source of Hg in Gwangyang Bay: the river input contributed 83 +/- 13% of total input of unfiltered and 73 +/- 6.0% of filtered Hg. On a monthly basis, unfiltered Hg input was 17 +/- 11 mol month(-1) in the monsoon season and 3.2 +/- 0.70 mol month(-1) in the dry season, while filtered Hg input was 7.1 +/- 4.1 mol month( 1) in the monsoon and 1.3 +/- 0.26 mol month(-1) in the dry. Consequently, the EASM resulted in an unfiltered Hg input 5.3 times greater than the mean dry month input and a filtered Hg input 5.5 times greater than the mean dry month input, which is mainly attributable to enhanced river water discharge during the monsoon season. PMID- 21277004 TI - Evaluation of a multiple regression model for the forecasting of the concentrations of NOx and PM10 in Athens and Helsinki. AB - Forecasting models based on stepwise multiple linear regression (MLR) have been developed for Athens and Helsinki. The predictor variables were the hourly concentrations of pollutants (NO, NO(2), NO(x), CO, O(3), PM(2.5) and PM(10)) and the meteorological variables (ambient temperature, wind speed/direction, and relative humidity) and in case of Helsinki also Monin-Obukhov length and mixing height of the present day. The variables to be forecasted are the maximum hourly concentrations of PM(10) and NO(x), and the daily average PM(10) concentrations of the next day. The meteorological pre-processing model MPP-FMI was used for computing the Monin-Obukhov length and the mixing height. The limitations of such statistical models include the persistence of both the meteorological and air quality situation; the model cannot account for rapid changes (on a temporal scale of hours or less than a day) that are commonly associated, e.g., with meteorological fronts, or episodes of a long-range transport origin. We have selected the input data for the model from one urban background and one urban traffic station both in Athens and Helsinki, in 2005. We have used various statistical evaluation parameters to analyze the performance of the models, and inter-compared the performance of the predictions for both cities. Forecasts from the MLR model were also compared to those from an Artificial Neural Network model (ANN) to investigate, if there are substantial gains that might justify the additional computational effort. The best predictor variables for both cities were the concentrations of NO(x) and PM(10) during the evening hours as well as wind speed, and the Monin-Obukhov length. In Athens, the index of agreement (IA) for NO(x) ranged from 0.77 to 0.84 and from 0.69 to 0.72, in the warm and cold periods of the year. In Helsinki, the corresponding values of IA ranged from 0.32 to 0.82 and from 0.67 to 0.86 for the warm and cold periods. In case of Helsinki the model accuracy was expectedly better on the average, when Monin-Obukhov length and mixing height were included as predictor variables. The models provide better forecasts of the daily average concentration, compared with the maximum hourly concentration for PM(10). The results derived by the ANN model where only slightly better than the ones derived by the MLR methodology. The results therefore suggest that the MLR methodology is a useful and fairly accurate tool for regulatory purposes. PMID- 21277005 TI - Cadmium solubility in paddy soils: effects of soil oxidation, metal sulfides and competitive ions. AB - Cadmium (Cd) is a non-essential element for human nutrition and is an agricultural soil contaminant. Cadmium solubility in paddy soils affects Cd accumulation in the grain of rice. This is a human health risk, exacerbated by the fact that rice grains are deficient in iron (Fe) and zinc (Zn) for human nutrition. To find ways of limiting this potential risk, we investigated factors influencing Cd solubility relative to Fe and Zn during pre-harvest drainage of paddy soils, in which soil oxidation is accompanied by the grain-filling stage of rice growth. This was simulated in temperature-controlled "reaction cell" experiments by first excluding oxygen to incubate soil suspensions anaerobically, then inducing aerobic conditions. In treatments without sulfur addition, the ratios of Cd:Fe and Cd:Zn in solution increased during the aerobic phase while Cd concentrations were unaffected and the Fe and Zn concentrations decreased. However, in treatments with added sulfur (as sulfate), up to 34 % of sulfur (S) was precipitated as sulfide minerals during the anaerobic phase and the Cd:Fe and Cd:Zn ratios in solution during the aerobic phase were lower than for treatments without S addition. When S was added, Cd solubility decreased whereas Fe and Zn were unaffected. When soil was spiked with Zn the Cd:Zn ratio was lower in solution during the aerobic phase, due to higher Zn concentrations. Decreased Cd:Fe and Cd:Zn ratios during the grain filling stage could potentially limit Cd enrichment in paddy rice grain due to competitive ion effects for root uptake. PMID- 21277006 TI - Why and how to combine evidence in environmental assessments: weighing evidence and building cases. AB - All types of environmental decisions benefit from assessments that assemble and analyze diverse evidence. The diversity of that evidence creates complexities that can be managed using an explicit, well-designed process. We suggest two adaptations from the legal lexicon, weight of evidence and building a case. When weighing evidence, weights are assigned to each piece of evidence, and then the body of evidence is weighed in favor of each hypothesis by amassing the weights. Finally, the total weights of evidence for the alternative hypotheses are compared to determine which alternative has the preponderance of evidence in its favor. When building a case, pieces of evidence are organized to show relationships among multiple hypotheses or complex interactions among agents, events, or processes. We provide processes for weighing evidence and building a case and illustrate both approaches in a case study involving the decline of a kit fox population. The general approach presented here is flexible, transparent, and defensible. During its development, it has been applied to risk assessments for contaminated sites and to causal assessments in aquatic and terrestrial systems. It is intended to balance the need for rigor and discipline with the need for sufficient flexibility to accept all relevant evidence and generate creative solutions to difficult environmental problems. PMID- 21277007 TI - Statin use in patients with nephrotic syndrome is associated with a lower risk of venous thromboembolism. AB - BACKGROUND: Nephrotic syndrome (NS) is a well-known risk factor for venous thromboembolism (VTE), however preventive measures are not routinely taken. In non-renal populations, statins are associated with lower risk of VTE. Hence, we set up this single-center retrospective cohort study to assess whether statin use influenced VTE risk in NS subjects. METHODS: We analyzed 289 consecutive patients with NS (defined by proteinuria >= 3.5 g/day) who were aged >18 years at the study entry and followed for at least 6 months. Use of statins and concomitant medication were determined. RESULTS: Of patients with NS (59% men; mean age, 42 years), 48% used statins for at least 1 month during NS. Using univariate and time-dependent Cox regression analyses, hazard ratio for VTE in statin users versus non-users was 0.2 (95%CI, 0.1-0.7) and 0.6 (95% CI, 0.2 -2.0), respectively. Adjustments for potential confounders did not change outcomes. Three VTE events occurred in a total of 812 statin-years, corresponding to an annual incidence of 0.37% (95%CI, 0.12-1.15). In contrast, 17 VTE occurred in a total of 2106 patient-years without statin exposure, annual incidence 0.81% (95%CI, 0.50-1.30). CONCLUSIONS: Although statistically significant, the hazard ratio of 0.2 for VTE risk in statin users versus non-users could have been biased, but the time-dependent hazard ratio of 0.6 was probably not. As the association was in the same direction for both analyses, we conclude that statin use is associated with a lower risk of VTE in patients with NS. PMID- 21277008 TI - Prognostic significance of Bcl-xL gene expression in human colorectal cancer. AB - Bcl-xL is a pro-survival member of the Bcl-2 family that plays indispensable roles in regulating cell survival and apoptosis. It is overexpressed in many malignant tumors including colorectal cancer (CRC). However, it is still unclear if Bcl-xL can be used as an independent molecular marker for predicting the prognosis of CRC patients. In this study, reverse transcription-PCR assay was performed to detect the expression of Bcl-xL mRNA in CRC and corresponding non tumor colon tissues. Immunohistochemistry was performed to detect the immunolocalization of Bcl-xL protein in sixty-eight primary CRC tissue samples. The association between Bcl-xL protein expression and clinicopathological factors of CRC patients was analyzed and the survival was assessed by the Kaplan-Meier method and proportional hazards model. The averaged level of Bcl-xL mRNA expression in CRC tissues (0.85+/-0.13) was significantly higher than that in non tumor colon tissues (0.08+/-0.02). Immunohistochemical staining showed that the Bcl-xL protein was mainly located in the cytoplasm of tumor cells. The level of Bcl-xL protein expression was closely correlated with tumor differentiation (P=0.002), lymph node metastasis (P=0.010), venous permeation (P=0.004), and Duke's classification (P=0.021). Furthermore, patients with high Bcl-xL expression showed poorer overall survival than those with low Bcl-xL expression (P=0.016). Univariate and multivariate analysis indicated that the status of Bcl xL protein expression might be an independent prognostic marker for CRC patients (P=0.032). Taken together, immunohistochemical assessment of status of Bcl-xL protein may offer a valuable approach for predicting survival after curative surgery for colorectal cancer. PMID- 21277009 TI - Extended cytoreduction of tumor at the porta hepatis by an interdisciplinary team approach in patients with epithelial ovarian cancer. AB - OBJECTIVE: The objective of this study was to describe the development and experience in resection of tumor at the porta hepatis in patients with ovarian cancer by an interdisciplinary team approach. METHODS: From August 2007 to June 2009, 11 women (2 primary and 9 recurrent ovarian cancers) underwent extended cytoreductive surgery including resection of tumor at the porta hepatis by hepatobiliary surgeons. RESULTS: Tumor resection at the porta hepatis was required in 7.1% of the patients (11/155) during the study period. The median tumor size of the porta hepatis was 2.0cm (range, 0.7-4cm). All visible tumors at the porta hepatis were completely resected with co-operation of hepatobiliary surgeons. Optimal cytoreduction was achieved in all patients. There was no significant morbidity related to tumor resection of the porta hepatis and mortality associated with surgery. Five of 11 patients had recurrent disease at median 8months (range, 1-13) after the surgery with a median follow-up of 8months (range, 3-21months). CONCLUSION: Tumor resection at the porta hepatis is feasible with acceptable morbidities in patients with ovarian cancer by an interdisciplinary team approach with hepatobiliary surgeons. Long term follow up is needed to know the impact on survival. PMID- 21277010 TI - Is surgical restaging indicated in apparent stage IA pure ovarian dysgerminoma? The MITO group retrospective experience. AB - OBJECTIVE: Conservative surgery followed by platinum-based chemotherapy is considered the standard approach for pure ovarian dysgerminoma (POD), except for correctly staged IA patients. The aim of study was to evaluate the outcome of IA POD patients with incomplete surgical staging in order to define the proper management. METHODS: Data concerning primary treatment and recurrence were reviewed for 26 patients with stage IA POD treated in MITO (Multicenter Italian Trials in Ovarian Cancer) centers. RESULTS: Median age was 22.5years. Primary surgery was fertility sparing for 17 patients (65.4%) and radical surgery was performed in 9 patients due to older age or gonadal dysgenesis. Only five patients (19.2%) had complete surgical staging; 38.5% had lymph node dissection, 46.2% had peritoneal biopsies and/or omentectomy and 65.4% had peritoneal washing. Seven patients received adjuvant chemotherapy. Overall recurrence rate was 11.5%: all recurrences occurred in the group submitted to incomplete staging procedure. No patients treated with adjuvant chemotherapy relapsed. One patient had pelvic recurrence, one patient relapsed in the abdomino-pelvic peritoneum and lymph nodes and the third patient showed a peritoneum, lymph nodal and residual ovary relapse. All patients with recurrence were cured by salvage therapy: 2 patients were treated with surgery plus chemotherapy and one only with chemotherapy. After a median follow-up of 100months all patients are alive without evidence of disease. Six patients opted for conception and delivered healthy infants, two with IVF with donor oocyte. CONCLUSIONS: IA POD prognosis is excellent. Conservative surgery with a complete surgical staging is the gold standard. Patients with incomplete staging could undergo surgical restaging or surveillance. Chemotherapy should be reserved to relapse with excellent chances of therapeutic success. PMID- 21277011 TI - Recurrence patterns and prognosis of endometrial stromal sarcoma and the potential of tyrosine kinase-inhibiting therapy. AB - OBJECTIVE: Endometrial stromal sarcoma (ESS) is a rare uterine malignancy. The current treatment approaches yield unsatisfactory results, and potential therapeutic targets need exploration. METHODS: We reviewed the electronic medical records of 74 patients with low-grade ESS who had been evaluated at the University of Texas MD Anderson Cancer Center between 1995 and 2006. Using immunohistochemistry, we tested the expression of targets in paraffin-embedded tissue samples taken from 13 of the patients. RESULTS: Forty-seven patients (64%) had a recurrence, and 16 (22%) had died of their disease at last follow-up. The 10-year progression-free survival (PFS) rate was 43% (median PFS duration, 108months), and the overall survival (OS) rate was 85% (median OS, 288months). Patients who received hormonal therapy had an overall response rate of 27%; another 53% had stable disease, with a median time to progression of 24months. No complete response or partial response was observed among patients who received radiotherapy or chemotherapy. In the paraffin-embedded specimens we tested, c-abl was expressed universally. Expression of PDGF-alpha, PDGF-beta, VEGF, and c-Kit was detected in 33%, 36%, 54%, and 8%, of specimens, respectively. EGFR and HER-2 were not detectable in any specimens. CONCLUSIONS: Our study suggests that ESS is a hormone-dependent malignancy, with hormonal therapy having activity in recurrent disease. Targeted therapy, specifically targeting c-abl may be a potential treatment for this disease. PMID- 21277012 TI - Overexpression of miR-429 induces mesenchymal-to-epithelial transition (MET) in metastatic ovarian cancer cells. AB - OBJECTIVE: Ovarian cancer (OC) is the most lethal of all gynecological malignancies primarily due to the sloughing-off of highly metastatic cells from primary tumors and their subsequent spread throughout the peritoneal cavity. Since the epithelial-to-mesenchymal transition (EMT) of OC cells located at the periphery of primary tumors is essential to this process, molecular interventions that can block EMT are of potential clinical significance. Members of the miR200 family of microRNAs have been implicated in EMT in other cancers. Our purpose was to determine if miR200 family microRNAs may be involved in EMT in OC and of potential therapeutic value in reducing OC metastasis. METHODS: Gene expression profiles of two OC cell lines with different metastatic potentials were monitored using qRT-PCR (quantitative reverse transcription polymerase chain reaction). The effect of over-expression of a miR-200 family microRNA (miR-429) in metastatic OC cells was monitored on molecular (qRT-PCR and microarray) and functional (morphology, migration, invasiveness and anchorage independence assays) levels. RESULTS: Molecular profiling of two OC cell lines with differing metastatic potentials identified significant differences in previously established epithelial and mesenchymal cell biomarkers including E-cadherin, ZEB1, ZEB2, miR 205 and miR-200 family microRNAs. Ectopic overexpression of miR-429, a member of the miR-200 family of microRNAs, in mesenchymal-like OC cells resulted in reversal of the mesenchymal phenotype (mesenchymal-epithelial transition, MET). CONCLUSIONS: Our results indicate that miR-429 may not only be a useful biomarker of EMT in ovarian cancer, but also of potential therapeutic value in abating OC metastasis. PMID- 21277013 TI - Structural basis of the 9-fold symmetry of centrioles. AB - The centriole, and the related basal body, is an ancient organelle characterized by a universal 9-fold radial symmetry and is critical for generating cilia, flagella, and centrosomes. The mechanisms directing centriole formation are incompletely understood and represent a fundamental open question in biology. Here, we demonstrate that the centriolar protein SAS-6 forms rod-shaped homodimers that interact through their N-terminal domains to form oligomers. We establish that such oligomerization is essential for centriole formation in C. elegans and human cells. We further generate a structural model of the related protein Bld12p from C. reinhardtii, in which nine homodimers assemble into a ring from which nine coiled-coil rods radiate outward. Moreover, we demonstrate that recombinant Bld12p self-assembles into structures akin to the central hub of the cartwheel, which serves as a scaffold for centriole formation. Overall, our findings establish a structural basis for the universal 9-fold symmetry of centrioles. PMID- 21277014 TI - Preverbal error-monitoring in stutterers and fluent speakers. AB - This study was designed to characterize the brain system that monitors speech in people who stutter and matched controls. We measured two electrophysiological peaks associated with action-monitoring: the error-related negativity (ERN) and the error positivity (Pe). Both the ERN and Pe were reliably observed after errors in a rhyming task and a nonverbal flanker task, replicating previous reports of a language-monitoring ERN and demonstrating that the Pe can also be elicited by phonological errors. In the rhyming task, stutterers showed a heightened ERN peak regardless of whether they actually committed an error. Similar results, though only marginally significant, were obtained from the flanker task. These results support the vicious cycle hypothesis, which posits that stuttering results from over-monitoring the speech plan. The elevation of the ERN in stutterers and the similarity of the results between the flanker and rhyming tasks implies that speech-monitoring may rely on the same neural substrate as action-monitoring. PMID- 21277015 TI - CRP: star trekking the galaxy of risk markers. PMID- 21277016 TI - C-reactive protein concentration and the vascular benefits of statin therapy: an analysis of 20,536 patients in the Heart Protection Study. AB - BACKGROUND: It has been suggested that inflammation status, as assessed by C reactive protein (CRP) concentration, modifies the vascular protective effects of statin therapy. In particular, there have been claims that statins might be more beneficial in people with raised CRP concentrations, and might even be ineffective in people with low concentrations of both CRP and LDL cholesterol. This study aimed to test this hypothesis. METHODS: In 69 UK hospitals, 20,536 men and women aged 40-80 years at high risk of vascular events were randomly assigned to simvastatin 40 mg daily versus matching placebo for a mean of 5.0 years. Patients were categorised into six baseline CRP groups (<1.25, 1.25-1.99, 2.00 2.99, 3.00-4.99, 5.00-7.99, and >=8.00 mg/L). The primary endpoint for subgroup analyses was major vascular events, defined as the composite of coronary death, myocardial infarction, stroke, or revascularisation. Analysis was by intention to treat. This study is registered, number ISRCTN48489393. FINDINGS: Overall, allocation to simvastatin resulted in a significant 24% (95% CI 19-28) proportional reduction in the incidence of first major vascular event after randomisation (2033 [19.8%] allocated simvastatin vs 2585 [25.2%] allocated placebo). There was no evidence that the proportional reduction in this endpoint, or its components, varied with baseline CRP concentration (trend p=0.41). Even in participants with baseline CRP concentration less than 1.25 mg/L, major vascular events were significantly reduced by 29% (99% CI 12-43, p<0.0001; 239 [14.1%] vs 329 [19.4%]). No significant heterogeneity in the relative risk reduction was recorded between the four subgroups defined by the combination of low or high baseline concentrations of LDL cholesterol and CRP (p=0.72). In particular, there was clear evidence of benefit in those with both low LDL cholesterol and low CRP (27% reduction, 99% CI 11-40, p<0.0001; 295 [15.6%] vs 400 [20.9%]). INTERPRETATION: Evidence from this large-scale randomised trial does not lend support to the hypothesis that baseline CRP concentration modifies the vascular benefits of statin therapy materially. FUNDING: UK Medical Research Council, British Heart Foundation, Merck, Roche Vitamins, and GlaxoSmithKline. PMID- 21277017 TI - Peptide-conjugated polyamidoamine dendrimer as a nanoscale tumor-targeted T1 magnetic resonance imaging contrast agent. AB - A tumor-targeting carrier, peptide HAIYPRH (T7)-conjugated polyethylene glycol modified polyamidoamine dendrimer (PAMAM-PEG-T7) was explored to deliver magnetic resonance imaging (MRI) contrast agents targeting to the tumor cells specifically. Two different types of tumors, liver cancer and early brain glioma model (involved with the blood-brain barrier), were chosen to evaluate the imaging capacity of this contrast agent. PAMAM-PEG-T7 was synthesized, conjugated with diethylene triamine pentaacetic acid (DTPA) and further chelated gadolinium (Gd), yielding GdDTPA-PAMAM-PEG-T7. The result of ICP-AES showed that about 92 Gd ions could be loaded per PAMAM molecule. The calculated longitudinal relaxivity R1 of the GdDTPA-PAMAM-PEG-T7 was 10.7 mm(-1) S(-1) per Gd (984.4 mm(-1) S(-1) per PAMAM), while that of GdDTPA was only 4.8 mm(-1) S(-1). PAMAM-PEG-T7 had better targeting capacity to the liver cancer cells in vitro and in vivo, compared with PAMAM-PEG. The accumulation of PAMAM-PEG-T7 was 162.5% times that of PAMAM-PEG. But for glioma cells, PAMAM-PEG-T7 did not show its specificity. Furthermore, GdDTPA-PAMAM-PEG-T7 could improve the diagnostic efficiency of liver cancer with the enhanced signal (187%), compared to 130% for PAMAM-PEG and 121% for GdDTPA. GdDTPA-PAMAM-PEG-T7 could selectively identify liver cancer but not early glioma. This nanoscaled MRI contrast agent GdDTPA-PAMAM-PEG-T7 might allow for selective and efficient diagnosis of tumors without the natural barrier including liver cancer. PMID- 21277018 TI - A biodegradable amphiphilic and cationic triblock copolymer for the delivery of siRNA targeting the acid ceramidase gene for cancer therapy. AB - One of the key challenges in the development of RNA interference-based cancer therapy is the lack of an efficient delivery system for synthetic small interfering RNAs (siRNAs) that would enable efficient uptake by tumor cells and allow for significant knockdown of a target transcript in vivo. Here, we describe a micelleplex system based on an amphiphilic and cationic triblock copolymer, which can systemically deliver siRNA targeting the acid ceramidase (AC) gene for cancer therapy. This triblock copolymer, consisting of monomethoxy poly(ethylene glycol), poly(epsilon-caprolactone) and poly(2-aminoethyl ethylene phosphate), self-assembles into micellar nanoparticles (MNPs) in aqueous solution with an average diameter of 60 nm and a zeta potential of approximately 48 mV. The resulting micelleplex, formed by the interaction of MNPs and siRNA, was effectively internalized by BT474 breast cancer cells and siRNA was subsequently released, resulting in significant gene knockdown. This effect was demonstrated by significant down-regulation of luciferase expression in BT474-luciferase cells which stably express luciferase, and suppression of AC expression in BT474 cells at both the transcriptional and protein level, following delivery of specific siRNAs by the micelleplex. Furthermore, a micelleplex carrying siRNA targeting the AC (micelleplex(siAC)) gene was found to induce remarkable apoptosis and reduce the proliferation of cancer cells. Systemic delivery of micelleplex(siAC) significantly inhibited tumor growth in a BT474 xenograft murine model, with depressed expression of AC and no positive activation of the innate immune response, suggesting therapeutic promise for micelleplex siRNA delivery in cancer therapy. PMID- 21277019 TI - Computed tomography imaging of cancer cells using acetylated dendrimer-entrapped gold nanoparticles. AB - We report a new use of acetylated dendrimer-entrapped gold nanoparticles (Au DENPs) for in vitro and in vivo computed tomography (CT) imaging of cancer cells. In this study, Au DENPs prepared using amine-terminated generation 5 poly(amidoamine) dendrimers were subjected to an acetylation reaction to neutralize the positive surface potential. The acetylated Au DENPs were used for both in vitro and in vivo CT imaging of a human lung adencarcinoma cell line (SPC A1 cells). Micro-CT images show that SPC-A1 cells can be detected under X-ray after incubation with the acetylated Au DENPs in vitro and the xenograft tumor model can be imaged after both intratumoral and intraperitoneal administration of the particles. Transmission electron microscopy data further confirm that the acetylated Au DENPs are able to be uptaken dominantly in the lysosomes of the cells. Combined morphological observation of cells after hematoxylin and eosin staining, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay of cell viability, and flow cytometric analysis of cell cycle show that the acetylated Au DENPs do not appreciably affect the cell morphology, viability, and cell cycle, indicating their good biocompatibility at the given concentration range. Findings from this study suggest that the developed acetylated Au DENPs have a great potential to be used for CT imaging of cancer cells. PMID- 21277020 TI - Anti-Flt1 peptide - hyaluronate conjugate for the treatment of retinal neovascularization and diabetic retinopathy. AB - Anti-angiogenic therapeutics has been investigated extensively for the treatment of retinal and choroidal vascular diseases, and diabetic retinopathy. Anti-Flt1 peptide of GNQWFI is an antagonistic peptide for vascular endothelial growth factor receptor 1 (VEGFR1 or Flt1) inhibiting VEGFR1-mediated endothelial cell migration and tube formation. In this work, anti-Flt1 peptide (GGNQWFI) was chemically conjugated to tetra-n-butyl ammonium modified hyaluronate (HA-TBA) via amide bond formation in dimethyl sulfoxide (DMSO) using benzotriazol-1-yloxy tris(dimethylamino)phosphonium hexafluorophosphate (BOP). The resulting HA - GGNQWFI conjugate self-assembled to form micelle-like nanoparticles in aqueous solution, as confirmed and characterized by transmission electron microscopy (TEM). According to in vitro biological activity tests, HA - GGNQWFI conjugate exhibited a dose-dependent inhibition effect on the binding of Flt1-Fc to VEGF(165) coated on the well. Furthermore, anti-Flt1 peptide - HA conjugate effectively inhibited retinal choroidal neovascularization (CNV) in laser induced CNV model rats. The retinal vascular permeability and the deformation of retinal vascular structure were also significantly reduced in diabetic retinopathy model rats after treatment with anti-Flt1 peptide - HA conjugate. Pharmacokinetic analysis confirmed the increased mean residence time of anti-Flt1 peptide after conjugation to HA longer than 2 weeks. PMID- 21277021 TI - Authors' comments: t(4;11) leukemias display addiction to MLL-AF4 but not to AF4 MLL. PMID- 21277022 TI - Metallo-salen complexes show promise towards treatment of leukemia. PMID- 21277023 TI - Risk of suicide and mixed episode in men in the postpartum period. AB - OBJECTIVES: To assess suicide risk in men with mood disorders at the postpartum period. METHODS: We conduct a longitudinal study with 650 men whose child has born from April 2007 to May 2008 at maternity hospital. The first assessment was in the antenatal period and the second within 30 to 60days postpartum. Suicide risk, anxiety disorders, hypomanic, manic and mixed episodes were assessed by the Mini International Neuropsychiatric Interview (MINI). RESULTS: The prevalence of suicide risk in fathers in postpartum was of 4.8%. Fathers with postpartum depression were 20.97 (CI: 5.74; 76.53) more likely to present suicide risk and those with mixed episodes showed a chance of 46.50 (CI: 10.52; 205.53) times higher than those who did not suffer from any mood disorder. CONCLUSION: Mixed episodes are common in fathers at postpartum, posing a higher suicide risk than depressive and manic/hypomanic episodes. Therefore, in order to reduce the suicide risk, clinicians should address and treat adequately mixed affective states in this specific population. PMID- 21277024 TI - The role of the Nod-like receptor family in trophoblast innate immune responses. AB - There is a strong clinical association between intrauterine infections and pregnancy complications, such as preterm labor. The placenta functions as an active barrier whereby the trophoblast recognizes microbes through pattern recognition receptors, such as the well characterized Toll-like receptors, in order to respond to pathogens at the maternal-fetal interface. Consequently, either an inefficient or overactive placental response to an infectious trigger, may have a significant impact on pregnancy outcome. Recently the placenta has been shown to express a newly identified family of pattern recognition receptors, the cytoplasmic-based Nod-like receptors (NLRs). As a result of their restricted localization, NLRs function as intracellular receptors that respond to infectious components, which have gained access to the cytoplasmic compartment. Thus, NLRs may provide the trophoblast with a recognition system that may be critical in placental responses to microorganisms or their cell wall components that have gained access to the cell's intracellular space, or that have evaded recognition by the TLRs. This review will discuss what is currently known about the role of NOD proteins, NALP proteins, and the inflammasome at the maternal-fetal interface, and their potential role in infection-associated pregnancy complications, like preterm labor. As we learn more about their function at the maternal-fetal interface, we will have a better understanding of their function in normal pregnancy and their potential to contribute to the pathogenesis of infection- and inflammation-associated pregnancy complications. PMID- 21277025 TI - The human decidual NK-cell response to virus infection: what can we learn from circulating NK lymphocytes? AB - NK cells present in the peripheral blood respond rapidly to pathogens or pathogen infected cells by various means including cytotoxicity and production of cytokines. Whether decidual NK (dNK) cells are able to play a similar role when the pregnant uterus is infected by viruses is still largely unknown. Decidual NK cells are generally considered as poorly cytotoxic when compared to their peripheral blood counterparts. However, we have recently demonstrated that freshly isolated dNK cells from healthy early pregnant uterus do have a cytotoxic potential mediated by the specific engagement of NKp46 activating receptor. We further found that the co-engagement of CD94/NKG2A inhibiting receptor drastically inhibits the cytolytic function of dNK. This latter observation suggests that in situ the CD94/NKG2A receptor interaction with its HLA-E specific ligand is a dominant negative regulatory mechanism that prevents unwanted dNK cell cytotoxicity in non-infected pregnant uterus. How do dNK cells behave when they are activated by virus-infected cells present at the maternal-fetal interface? Largely based on data obtained from circulating NK cells, this review briefly discusses the following questions: Does uterine viral infection promote decidual NK cell proliferative capacity in situ? Are dNK cells able to kill virus infected autologous decidual target cells and thus limit the virus spreading to the fetus? Which viral-mediated signal(s) and molecular interactions may subvert inhibition of dNK cytotoxic potential? Does uterine viral infection promote decidual NK cell secretion of cytokines and chemokines that boost the anti-viral immune response? PMID- 21277026 TI - Movement disorders in nonpsychotic siblings of patients with nonaffective psychosis. AB - Movement disorders such as dyskinesia and Parkinsonism have frequently been reported in (drug-naive) patients with nonaffective psychosis. Therefore movement disorders may be related to schizophrenia. Siblings of patients with nonaffective psychosis also appear to have subtle forms of movement disorders. This suggests that motor abnormalities may also be related to the risk of developing the disease. Subtle forms are not always detected with the use of the standard observation-based clinical rating scales, which are less sensitive than mechanical instrument measurement. This study compared the presence and severity of dyskinesia and Parkinsonism in 42 non-psychotic siblings of patients with nonaffective psychosis and in 38 controls as measured by mechanical instruments and clinical rating scales. There were no significant differences in movement disorders between siblings and controls on the basis of clinical assessments. However, mechanical measurements indicated that siblings compared to controls displayed significantly more dyskinesia and Parkinsonism signs. These results suggest that motor signs could be markers of vulnerability for psychosis or schizophrenia. In addition this study shows that mechanical instrument measurement of movement disorders is more sensitive than assessment with clinical rating scales. Therefore, it may be used in screening programs for populations at risk for psychosis. PMID- 21277027 TI - Evaluation of the immunogenicity of a transgenic tobacco plant expressing the recombinant fusion protein of GP5 of porcine reproductive and respiratory syndrome virus and B subunit of Escherichia coli heat-labile enterotoxin in pigs. AB - Escherichia coli heat-labile enterotoxin B subunit (LTB) can be used as an adjuvant for co-administered antigens. Our previous study showed that the expression of neutralizing epitope GP5 of porcine reproductive and respiratory syndrome virus (PRRSV) in transgenic tobacco plant (GP5-T) could induce PRRSV specific immune responses in pigs. A transgenic tobacco plant co-expressing LTB and PRRSV GP5 as a fusion protein (LTB-GP5-T) was further constructed and its immunogenicity was evaluated. Pigs were given orally three consecutive doses of equal concentration of recombinant GP5 protein expressed in leaves of LTB-GP5-T or GP5-T at a 2-week interval and challenged with PRRSV at 7 weeks post-initial immunization. Pigs receiving LTB-GP5-T or GP5-T developed PRRSV-specific antibody and cell-mediated immunity and showed significantly lower viremia and tissue viral load and milder lung lesions than wild type tobacco plant (W-T). The LTB GP5-T-treated group had relatively higher immune responses than the GP5-T-treated group, although the differences were not statistically significant. PMID- 21277028 TI - Identification of astrocyte-derived immune suppressor factor that induces apoptosis of autoreactive T cells. AB - In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, apoptosis of T cells is mainly seen at inflammation sites of the central nervous system (CNS). Cumulative data suggests that astrocytes might render T cells susceptible to induction of apoptotic cell death. We observed that apoptotic cell death of proteolipid protein (PLP)-reactive T cells was induced by an interferon (IFN)-gamma-treated astrocyte cell line. In this study, we have identified and cloned the genes derived from the IFN-gamma-treated astrocyte cell line that induce apoptosis of autoreactive T cells. We created subtraction cDNA libraries from the IFN-gamma-treated astrocyte cell line and obtained 100 positive clones. After screening of subtracted cDNAs, we found two candidate genes that induced apoptosis of the PLP-reactive T cell line. The first is a previously unknown gene of 726 base pairs that we named astrocyte-derived immune suppressor factor (AdIF). It contained an open reading frame encoding a polypeptide of 228 amino acids. The second was SPARC/osteonectin, a multifunctional glycoprotein secreted in the extracellular matrix. AdIF protein was found at the inflammatory sites of the EAE brain, and bound to the surface of CD4(+) T cells. Purified recombinant AdIF protein inhibited the proliferation of activated PLP-reactive CD4(+) T cells and induced their apoptosis in vitro. Intravenous administration of recombinant AdIF protein to mice with in which acute EAE was induced prevented the incidence of EAE and suppressed the symptoms. The newly discovered molecule AdIF may render auto-reactive T cells susceptible to the induction of apoptotic cell death and could potentially be a new therapeutic agent for multiple sclerosis. PMID- 21277029 TI - Statin dilemma in the management of chronic heart failure. PMID- 21277030 TI - Letter to the editor: Weekend versus weekday hospital admissions for acute heart failure. PMID- 21277031 TI - The study of copy number variations in the regions of NOTCH1 among Chinese VSD and TOF patients. PMID- 21277032 TI - Assessing the probability of acquisition of meticillin-resistant Staphylococcus aureus (MRSA) in a dog using a nested stochastic simulation model and logistic regression sensitivity analysis. AB - Meticillin-resistant Staphylococcus aureus (MRSA) is an important nosocomial and community-acquired pathogen with zoonotic potential. The relationship between MRSA in humans and companion animals is poorly understood. This study presents a quantitative exposure assessment, based on expert opinion and published data, in the form of a second order stochastic simulation model with accompanying logistic regression sensitivity analysis that aims to define the most important factors for MRSA acquisition in dogs. The simulation model was parameterised using expert opinion estimates, along with published and unpublished data. The outcome of the model was biologically plausible and found to be dominated by uncertainty over variability. The sensitivity analysis, in the form of four separate logistic regression models, found that both veterinary and non-veterinary routes of acquisition of MRSA are likely to be relevant for dogs. The effects of exposure to, and probability of, transmission of MRSA from the home environment were ranked as the most influential predictors in all sensitivity analyses, although it is unlikely that this environmental source of MRSA is independent of alternative sources of MRSA (human and/or animal). Exposure to and transmission from MRSA positive family members were also found to be influential for acquisition of MRSA in pet dogs, along with veterinary clinic attendance and, while exposure to and transmission from the veterinary clinic environment was also found to be influential, it was difficult to differentiate between the importance of independent sources of MRSA within the veterinary clinic. The implementation of logistic regression analyses directly to the input/output relationship within the simulation model presented in this paper represents the application of a variance based sensitivity analysis technique in the area of veterinary medicine and is a useful means of ranking the relative importance of input variables. PMID- 21277033 TI - The effects of hospitals' governance on optimal contracts: bargaining vs. contracting. AB - We propose a two-stage model to study the impact of different hospitals' governance frameworks on the optimal contracts designed by third-party payers when patients' disease severity is the private information of the hospital. In the second stage, doctors and managers interact within either a bargaining or a contracting scenario. In the contracting scenario, managers offer a contract that determines the payment to doctors, and doctors decide how many patients to treat. In the bargaining scenario, doctors and managers strategically negotiate on both the payment to doctors and the number of patients to treat. We derive the equilibrium doctors' payments and number of treated patients under both scenarios. We then derive the optimal contract offered by the government to the hospital in the first stage. Results show that when the cost of capital is sufficiently low, the informational rent is lower, and the social welfare is higher, in the contracting scenario. PMID- 21277034 TI - Effect of large-scale social interactions on body weight. AB - I estimate models of endogenous social interactions in body weight at the county and state levels. The results show that dispersion in body weight across time and space in the U.S. is not clearly excessive, and that much of this variation can be attributed to observable individual and regional characteristics. Models exploiting variants of methods proposed by Glaeser et al. (2003), fixed effects, instrumental variable and split-sample instrumental variable methods to address endogeneity suggest that there are not large social multipliers on body weight outcomes. The evidence suggests there may be small multipliers on BMI, obesity, and morbid obesity. There is no evidence that underweight is subject to a social multiplier. The results are sensitive to specification. PMID- 21277035 TI - Species diversity and toxigenic potential of Fusarium graminearum complex isolates from maize fields in northwest Argentina. AB - Members of the Fusarium graminearum species complex (Fg complex) are the causal agents of ear rot in maize and Fusarium head blight of wheat and other small grain cereals. The potential of these pathogens to contaminate cereals with trichothecene mycotoxins is a health risk for both humans and animals. A survey of ear rot isolates from maize collected in northwest Argentina recovered 66 isolates belonging to the Fg complex. A multilocus genotyping (MLGT) assay for determination of Fg complex species and trichothecene chemotypes was used to identify 56 of these isolates as F. meridionale and 10 isolates as F. boothii. F. meridionale was fixed for the nivalenol (NIV) chemotype, and all of the F. boothii isolates had the 15-acetyldeoxynivalenol (15ADON) chemotype. The results of genetic diversity analysis based on nine variable number tandem repeat (VNTR) loci supported the hypothesis of genetic isolation between F. meridionale and F. boothii, and provided little evidence of geographic substructure among populations of the dominant pathogen species, F. meridionale. This is the first study to indicate that F. meridionale and F. boothii may play a substantial role in the infection and trichothecene contamination of maize in Argentina. In addition, dominance of the NIV chemotype among Fg complex isolates from Argentina is unprecedented, and of significant concern to food safety and animal production. PMID- 21277036 TI - Development of an image-based model for capillary vasculature of retina. AB - The paper presents a method of development of a detailed network model to represent retinal capillary vasculature. The capillary model is a circular mesh consisting of concentric rings with an increasing diameter. Each of the rings has uniformly distributed bifurcation nodes to represent capillary vessels. The model is customized using the data that has been measured from confocal microscopic images of a mouse retina. The capillary model developed can be connected to networks of larger vessels of the vasculature such as arterial and venous networks to form a complete model of the retinal network. A method to automate such interface connections between capillary and other vascular networks using connecting vessels (i.e., pre-capillary and post-capillary) is also presented in the paper. Such a detailed image-based capillary model together with the arterial and venular networks can be used for various circulation simulations to obtain accurate information on hemodynamic quantities such as the spatial distribution of pressure and flow in the vasculature for both physiological and pathological conditions. The method presented for the development of the capillary model can also be adopted for vasculatures of other organs. PMID- 21277037 TI - Bioluminescence imaging for in vivo monitoring of local recurrence mesothelioma model. PMID- 21277038 TI - EUS-FNA for the detection of left adrenal metastasis in patients with lung cancer. AB - In patients with lung cancer, enlarged or (18)Fluoro-deoxyglucose positron emission tomography ((18)FDG-PET) positive left adrenal glands are suspected for distant metastases and require tissue confirmation for a definitive assessment. The aim of this study was to assess the sensitivity of endoscopic ultrasound guided fine-needle aspiration (EUS-FNA) for left adrenal metastases in lung cancer patients with a suspect adrenal gland based on imaging. EUS-FNA findings of patients with (suspected) lung cancer and CT enlarged or (18)FDG-PET positive left adrenal glands were retrospectively evaluated. In the absence of metastases at EUS, clinical and radiological follow-up was obtained. In 85 patients, EUS-FNA demonstrated left adrenal metastases of lung cancer in 53 (62%), benign adrenal tissue in 25 (29%), a metastasis from colon carcinoma in 1 (1%) and a primary adrenocortical carcinoma in 1 (1%) patient. In five patients (5.9%), the aspirates contained non-representative material. EUS outcomes were false negative in two patients. Sensitivity and negative predictive value (NPV) for EUS-FNA of the left adrenal gland were at least 86% (95% CI 74-93%) and 70% (95% CI 50-85%). No complications occurred. EUS-FNA is a sensitive, safe and minimally invasive technique to provide tissue proof of left adrenal metastases in patients with (suspected) lung cancer and enlarged or (18)FDG-PET positive adrenal glands. Therefore, EUS-FNA qualifies as the staging test of choice for patients with lung cancer with suspected left adrenal metastases. PMID- 21277039 TI - Phase II trial of amrubicin and carboplatin in patients with sensitive or refractory relapsed small-cell lung cancer. AB - Amrubicin is a novel, totally synthesized anthracycline derivative, and has antitumor activity against several human tumor xenografts. The combination of amrubicin with platinum derivative showed additive effect against a human small cell lung cancer (SCLC) cell line. Until now, the combination of amrubicin plus carboplatin has not been studied in patients with previously treated SCLC. Therefore, we examined the safety and efficacy of the combination of amrubicin plus carboplatin in patients with sensitive or refractory relapsed SCLC. Patients with previously treated SCLC were eligible if they had a performance status of 2 or less, were 75 years or younger, and had adequate organ function. Twenty-five patients were enrolled (21 men and 4 women; median age, 65 years; age range 55-73 years). Patients received the combination of amrubicin (30 mg/m(2) on days 1-3) plus carboplatin (with a target area under the concentration-versus-time curve of 4 mg min/ml using the Calvert formula on day 1) every 3 weeks. The overall response rate was 36.0% (95% confidence interval [CI], 18.0-57.5%). Response rates differed significantly between patients with sensitive relapse (58.3%; 95% CI, 27.7-84.8%) and those with refractory relapse (15.4%; 95% CI, 1.9-15.4%; p=0.03). The median survival time (MST) from the start of this treatment was 7 months (range: 1-42 months); the MST of patients with sensitive relapse (10 months) was significantly longer than that of patients with refractory relapse (5 months: p=0.004). The median progression-free survival (PFS) time was 3 months (range: 1-14 months): the median PFS time of patients with sensitive relapse (5 months) was significantly longer than that of patients with refractory relapse (2 months; p=0.01). The most frequent grade 3-4 toxicity was myelosuppression, especially neutropenia, which developed in 88% of patients. Grade 3-4 thrombocytopenia developed in 44% of patients, and anemia developed in 56%. Nonhematologic toxicities were generally mild to moderately severe and temporary. None of the patients had cardiotoxicity. In conclusion, this therapy is effective and well tolerated for previously treated SCLC. PMID- 21277040 TI - Lung cancer screening: what is the benefit and what do we do about it? PMID- 21277041 TI - Pemetrexed re-challenge in pleural malignant mesothelioma: an option for a subset of patients initially treated with pemetrexed-platinum doublets in the first-line setting? PMID- 21277042 TI - Evergreens favored by higher responsiveness to increased CO2. AB - Physical CO(2) diffusion from sub-stomatal cavities to the chloroplasts where photosynthesis takes place is an important limitation of photosynthesis largely neglected in research related to global climate change. This limitation is particularly important in leaves with robust structures such as evergreen sclerophylls. In these leaves, photosynthesis is less sensitive to changes in stomatal openness, which is considered to be the primary limitation of photosynthesis. In this review we state that, because of large limitations in internal diffusion in C(3) plants, photosynthesis and the intrinsic efficiency of the use of plant water responds more strongly to elevated levels of CO(2) in leaves with more robust structures. This provides an additional explanation for the current apparent expansion of evergreen sclerophylls in many Earth ecosystems, and adds a new perspective to research of the biological effects of increasing atmospheric CO(2). PMID- 21277043 TI - Occurrence of steroid hormones and antibiotics in shallow groundwater impacted by livestock waste control facilities. AB - Wastewater impoundments at concentrated animal feeding operations (CAFOs) represent a potential source of veterinary pharmaceuticals and steroid hormone contamination to shallow groundwater. This study investigates the occurrence of seventeen veterinary pharmaceuticals and thirteen steroid hormones and hormone metabolites in lagoons and adjacent groundwater at operating swine and beef cattle facilities. These sites were chosen because subsurface geology and previous monitoring of nitrate, ammonia and chloride levels in shallow ground water strongly indicated direct infiltration, and as such represent worst cases for ground water contamination by waste water. Pharmaceutical compounds detected in samples obtained from cattle facilities include sulfamerazine; sulfamethazine; erythromycin; monensin; tiamulin; and sulfathiazole. Lincomycin; ractopamine; sulfamethazine; sulfathiazole; erythromycin; tiamulin and sulfadimethoxine were detected in wastewater samples obtained from swine facilities. Steroid hormones were detected less frequently than veterinary pharmaceuticals in this study. Estrone, testosterone, 4-androstenedione, and androsterone were detected in wastewater impoundments at concentrations ranging from 30 to 3600ng/L, while only estrone and testosterone were detected in groundwater samples at concentrations up to 390ng/L. The co-occurrence of veterinary pharmaceutical and steroid hormone contamination in groundwater at these locations and the correlation between pharmaceutical occurrence in lagoon wastewater and hydraulically downgradient groundwater indicates that groundwater underlying some livestock wastewater impoundments is susceptible to contamination by veterinary pharmaceuticals and steroid hormones originating in wastewater lagoons. PMID- 21277044 TI - Cellular prion protein localizes to the nucleus of endocrine and neuronal cells and interacts with structural chromatin components. AB - Several physiological processes have been purported for cellular prion protein (PrP(C)). However, the physiological function of PrP(C) is still unclear and the cellular localization of PrP(C) remains a subject of debate. PrP(C) is expressed in a wide range of tissues including islets of Langerhans. We previously demonstrated that the function of PrP(C) is associated with blood glucose regulation. Little is known of the function of PrP(C) in islet cells and specifically in beta-cells. To get first insight into the putative role of PrP(C) in beta-cells, we used far-Western immunoblotting and MS to identify candidate PrP(C)-interacting proteins. We also used Western blot, immunofluorescence (IF) and protein overlay IF to characterize the sub-cellular localization of PrP(C). Here we demonstrate in vivo that PrP(C) is abundant in the nuclear lamina of endocrine and neuronal cells and interacts with histone H1(0), histone H3 and lamin B1. The interaction of PrP(C) with histone H3 suggests that it is involved in transcriptional regulation in the nucleus. This study reveals new avenues for the elucidation of the physiological function of PrP(C) in endocrine and neuronal cells as well as the molecular mechanisms leading to prion diseases. PMID- 21277045 TI - Rho proteins of plants--functional cycle and regulation of cytoskeletal dynamics. AB - Rho-related ROP proteins are molecular switches that essentially regulate a wide variety of processes. Of central interest is their influence on the plant cytoskeleton by which they affect vital processes like cell division, growth, morphogenesis, and pathogen defense. ROPs switch between GTP- and GDP-bound conformations by strictly regulated nucleotide exchange and GTP-hydrolysis, and only the active GTP-form interacts with downstream effectors to ultimately provoke a biological response. However, the mode of action of the engaged regulators and effectors as well as their upstream and downstream interaction partners have long been largely unknown. As opposed to analogous systems in animals and fungi, plants use specific GTPase activating proteins (RopGAPs) with a unique domain composition and novel guanine nucleotide exchange factors (RopGEFs) with a probable link to cell surface receptors. Moreover, plants comprise novel effector molecules and adapters connecting ROPs to mostly unknown downstream targets on the route to the cytoskeleton. This review aims to summarize recent knowledge on the molecular mechanisms and reaction cascades involved in ROP dependent cytoskeletal rearrangements, addressing the structure and function of the unusual RopGAPs, RopGEFs and effectors, and the upstream and downstream pathways linking ROPs to cell receptor-like kinases, actin filaments, and microtubules. PMID- 21277046 TI - [Solitary fibrous tumor of the orbit: report of two cases and review of literature]. AB - Solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm that most frequently arises in the pleura and uncommonly involves the orbit. There are 54 cases of SFT of the orbit available in the literature. The authors report tow cases of an orbital SFT and discuss the clinical, radiological, pathological features and differential diagnosis. Long-term follow-up of patients is necessary because SFT may recur many years after operation. Complete surgical resection is the most important prognosis factor of this tumor. PMID- 21277047 TI - [Oculopalpebral and facial synkinesis associated with ptosis: epidemiological, clinical, and therapeutic features]. AB - Synkinetic movements of the upper eyelids may be noted in association with movements of either extraocular muscles or other muscles of the face. Patients with oculopalpebral or facial-palpebral synkinesis may also have ptosis of the involved eyelid. The clinical and therapeutic features of this association are specific. We mainly distinguish two forms of synkinetic movements, characterized either by the elevation of the ptotic eyelid such as in Marcus Gunn phenomenon and in the Fuchs sign or by the falling of the upper lid such as in Marin Amat syndrome. Many surgical techniques have been used to correct the blepharoptosis and the synkinetic movement. Levator resection is often advocated for correction of blepharoptosis with a mild degree of synkinesis. However, when the ptosis is major, eyelid lag is a possible outcome. For moderate or major synkinesis, bilateral frontalis suspension with disinsertion of the levator has been suggested. This procedure generally provides satisfactory cosmetic results. PMID- 21277048 TI - Cross-transmission of Klebsiella pneumoniae in two intensive care units: intra- and inter-hospital spread. PMID- 21277049 TI - Dermatological swab technique. PMID- 21277050 TI - Molecular epidemiology of meticillin-resistant Staphylococcus aureus in a Spanish hospital: low prevalence of community and animal-associated clones. PMID- 21277051 TI - Synthesis, glucose uptake activity and structure-activity relationships of some novel glitazones incorporated with glycine, aromatic and alicyclic amine moieties via two carbon acyl linker. AB - Three series of novel glitazones were designed and prepared by using appropriate synthetic schemes to incorporate glycine, aromatic and alicyclic amines via two carbon linker. Compounds were synthesized both under conventional and microwave methods. Nineteen out of twenty four synthesized compounds were evaluated for their in vitro glucose uptake activity using isolated rat hemi-diaphragm. Compounds, 6, 9a, 13a, 13b, 13c, 13f and 13h exhibited significant glucose uptake activity. Illustration about their synthesis and in vitro glucose uptake activity is described along with the structure-activity relationships. PMID- 21277052 TI - [Assessment of renal function in elderly after eighty years: Cockroft and Gault or Modification of diet in renal disease equation?]. AB - Assessment of renal function is essential in the management of hospitalised patients, particularly in geriatric practice. Impairment of renal function is common in the elderly, aged of 80 years and over, and should be taken into account before prescribing drugs eliminated through the kidneys or performing investigations requiring iodine injection. Renal failure is also a predictor of mortality. In clinical practice, creatinine-based equations are recommended to assess kidney function. The most widely used equations are the Cockroft and Gault (CG) and the simplified Modification of diet in renal disease (MDRD) formulas. The former estimates the clearance of creatinine in millilitres per minute, the latter estimates the glomerular filtration rate in millilitres per minute per 1.73 m(2). In 2002, the French high authority for health recommended the use of the CG formula, but no recommendation was given for the elderly. In the literature, no study has compared CG and MDRD formulas with a reference method in this very old population. In the octogenarians, two studies have compared these formulas with the creatinine clearance calculated on the basis of a 24-hour urine collection and four studies have compared the formulas head to head. All these studies showed that the results obtained with the MDRD formula are higher from 10 to 30 mL/min/1.73 m(2) than the results obtained with the CG formula. Studies simulating drug prescription showed that the use of the MDRD formula would lead to a risk of drug over dosage in 20 to 36% of the elderly. Also, two studies have suggested that only creatinine clearance measured by the CG formula is a predictor of mortality in the very old population. In conclusion, in the octogenarian, none of these two formulas is ideal. However, based on the results of studies targeted to this elderly population, the best solution seems to be the use of the CG formula expecting new methods of evaluation of renal function. PMID- 21277053 TI - Biomechanical properties of the triceps surae muscle-tendon unit in young and postmenopausal women. AB - BACKGROUND: Insufficient and excessive stiffness may increase the risk of soft tissue and bone injuries, respectively, while the resonance frequency seems to be related with energy expenditure and stiffness. With aging and menopause muscle weakness, physical fragility and mobility limitations are also expected. Therefore this study addresses the differences of biomechanical properties of the triceps surae muscle-tendon unit between young and postmenopausal women. METHODS: 39 young and 37 postmenopausal women participated. The biomechanical properties of the triceps surae muscle-tendon unit were assessed in vivo using a free oscillation technique involving 30% of the maximal voluntary isometric contraction load. FINDINGS: The postmenopausal women in this study show significant higher values in the damped natural frequency of oscillation (young 3.84Hz vs. postmenopausal 4.68Hz, P<0.001), muscle-tendon unit stiffness (young 16,446N/m vs. postmenopausal 23,229N/m, P<0.001), and muscle-tendon unit stiffness normalized by mass (young 286.3N/m vs. postmenopausal 325.1N/m, P<0.05). The postmenopausal study group shows significant lower values in the damping ratio (young 0.190 vs. postmenopausal 0.150, P<0.01) than young women. INTERPRETATION: The postmenopausal subjects may not be able to take advantage of resonance as the young subjects, or, the relationship between these frequencies is adjusted according to the musculoskeletal characteristics of each group. The decrease in damping properties and the increase in muscle-tendon unit stiffness suggest that postmenopausal women might be at a greater risk of injury. PMID- 21277054 TI - Hydrogeological and biogeochemical constrains of arsenic mobilization in shallow aquifers from the Hetao basin, Inner Mongolia. AB - Little is known about the importance of drainage/irrigation channels and biogeochemical processes in arsenic distribution of shallow groundwaters from the Hetao basin. This investigation shows that although As concentrations are primarily dependent on reducing conditions, evaporation increases As concentration in the centre of palaeo-lake sedimentation. Near drainage channels, groundwater As concentrations are the lowest in suboxic-weakly reducing conditions. Results demonstrate that both drainage and irrigation channels produce oxygen-rich water that recharges shallow groundwaters and therefore immobilize As. Groundwater As concentration increases with a progressive decrease in redox potential along the flow path in an alluvial fan. A negative correlation between SO42- concentrations and delta34S values indicates that bacterial reduction of SO42- occurs in reducing aquifers. Due to high concentrations of Fe (> 0.5 mg L-1), reductive dissolution of Fe oxides is believed to cause As release from aquifer sediments. Target aquifers for safe drinking water resources are available in alluvial fans and near irrigation channels. PMID- 21277055 TI - Rapid biotransformation of arsenic by a model protozoan Tetrahymena pyriformis GL C. [corrected]. AB - Arsenic biomethylation and biovolatilization are thought to be two important metabolic pathways in aquatic and soil environments. Tetrahymena thermophila is a genus of free-living ciliated protozoan that is widely distributed in freshwater environments around the world. In this study, we studied arsenic accumulation, speciation, efflux, methylation and volatilization in this unicellular eukaryote exposed to various concentrations of arsenate. Our results show that T. thermophila accumulated 187 mg.kg-1 dry weight of arsenic when exposed to 40 MUM for 48 h, with MMAs(V) (monomethylarsenate) and DMAs(V) (dimethylarsenate) as the dominant species, accounting for 66% of the total arsenic. Meanwhile, arsenate, arsenite, MMAs(V) and DMAs(V) were detected in the culture medium; the last three were released by the cells. The production of volatile arsenic increased with increasing external As(V) concentrations and exposure time. To our knowledge, this is the first study on arsenic metabolism, particularly biomethylation and biovolatilization, in protozoa. PMID- 21277056 TI - Quantification of net carbon flux from plastic greenhouse vegetable cultivation: a full carbon cycle analysis. AB - Plastic greenhouse vegetable cultivation (PGVC) has played a vital role in increasing incomes of farmers and expanded dramatically in last several decades. However, carbon budget after conversion from conventional vegetable cultivation (CVC) to PGVC has been poorly quantified. A full carbon cycle analysis was used to estimate the net carbon flux from PGVC systems based on the combination of data from both field observations and literatures. Carbon fixation was evaluated at two pre-selected locations in China. Results suggest that: (1) the carbon sink of PGVC is 1.21 and 1.23 Mg C ha(-1) yr(-1) for temperate and subtropical area, respectively; (2) the conversion from CVC to PGVC could substantially enhance carbon sink potential by 8.6 times in the temperate area and by 1.3 times in the subtropical area; (3) the expansion of PGVC usage could enhance the potential carbon sink of arable land in China overall. PMID- 21277057 TI - Sorption of apolar and polar organic contaminants by waste tire rubber and its chars in single- and bi-solute systems. AB - Single- and bi-solute sorption of organic compounds [1,3-dichlorbenzene (DCB), 1,3-dinitrobenzene (DNB) and 2,4-dichlorophenol (DCP)] on ground tire rubber and its chars was studied. The chars were prepared by pyrolyzing tire rubber at different temperatures (200-800 degrees C). Their surface area, aromaticity and hydrophobicity increase greatly with pyrolytic temperature, and the polymeric phase is partly converted into a condensed phase. The sorption of DNB and DCP increases with pyrolytic temperature and is characterized by a transition from a partition dominant to an adsorption dominant process. However, the sorption of DCB linearly decreases with the pyrolytic temperature. The enhanced adsorption of DNB and DCP on carbonized phase is primarily attributed to nonhydrophobic interactions such as pi-pi electron-donor-acceptor interactions and/or H bonding. The higher partition of DCB to polymeric phase is attributed to its high hydrophobicity. Competitive sorption between DCB and DCP on the tire chars is highly dependent on dissociation of the latter. PMID- 21277058 TI - Migrant networks and pathways to child obesity in Mexico. AB - The purpose of this paper is twofold: 1) to assess the link between migrant networks and becoming overweight or obese and 2) to explore the pathways by which migrant networks may contribute to the increasing overweight and obese population of children in Mexico. Using two waves of the Mexican Family Life Survey (MxFLS), we find that children and adolescents (ages 3 to 15) living in households with migrant networks are at an increased risk of becoming overweight or obese over the period of observation, relative to their peers with no migrant networks. Sedentary behavior and household-level measures of economic wellbeing explain some of the association between networks and changes in weight status, but the role of extended networks remains significant. Community-level characteristics related to migration do not account for any of the observed relationship between household-level networks and becoming overweight or obese. PMID- 21277059 TI - Risk factors affecting postoperative hemorrhage after tooth extraction in patients receiving oral antithrombotic therapy. AB - PURPOSE: We investigated risk factors affecting the onset of postoperative hemorrhage after tooth extraction in patients receiving oral antithrombotic therapy. PATIENTS AND METHODS: A total of 443 tooth extractions were performed in 382 patients. All extractions were performed while continuing conventional antithrombotic therapy, and local hemostatic measures were performed. RESULTS: Among the 17 patients with postoperative hemorrhage, 9 received warfarin monotherapy, 6 received warfarin and antiplatelet combination therapy, and 2 received antiplatelet monotherapy. Postoperative hemorrhage occurred within 6 days in 16 patients (94.1%), with a median of 3 days. The international normalized ratio at the time of extraction was less than 3.0 for all 15 patients receiving warfarin therapy but was prolonged, at 3.0 or greater, in 7 of 12 patients in whom this value was measured at the time of postoperative hemorrhage. As for local hemostatic measures at the time of postoperative hemorrhage, thorough local hemostatic measures were required in 12 (80.0%) of the 15 patients receiving warfarin therapy. Conversely, in the 2 patients receiving antiplatelet therapy, hemostasis was achieved by use of compression alone. Concerning factors affecting postoperative hemorrhage, significant differences were seen in relation to surgical tooth extraction (P = .008) and acute inflammation findings (P = .007). CONCLUSIONS: In patients receiving antithrombotic therapy, surgical tooth extraction and acute inflammatory findings were associated with a significantly increased incidence of postoperative hemorrhage. In more than 90% of cases, postoperative hemorrhage occurred within 6 days of extraction. Thorough local hemostatic measures are therefore required in patients receiving warfarin therapy. PMID- 21277060 TI - Improvement in respiration and craniofacial changes associated with weight loss after bariatric surgery. AB - PURPOSE: To study weight loss, craniofacial changes, and respiratory quality among obese patients before and after bariatric surgery. MATERIAL AND METHODS: The obese group comprised 17 male and female patients aged between 18 and 60 years with body mass index (BMI) >= 40 kg/m(2) who were scheduled to undergo bariatric surgery. All patients were evaluated in the preoperative period and at least 4 months following surgery by means of clinical, physical, anthropometric, facial, nasal, oral, and oropharyngeal examinations as well as radiographic examinations of the facial profile with individual cephalometric analysis. Patients also completed the Nasal Obstruction Symptom Evaluation scale. The control group underwent the same examinations and included 10 male and female volunteers with BMI between 18 and 30 kg/m(2), good dental occlusion, harmonious facial features, and no history of respiratory or sleep disorders. RESULTS: There were significant reductions in weight, BMI, and neck circumference as well as an improvement in Nasal Obstruction Symptom Evaluation scores in the obese group after bariatric surgery (P < .05). There was a reduction in craniocervical length, increase in velopharyngeal air space, and reduction in the distance between the hyoid bone and mentum following weight loss. The Mallampati Scale revealed a significant inversion of palate position categories between evaluations. CONCLUSIONS: There was improvement in respiratory quality and craniofacial changes caused by weight loss, especially in soft tissues around the upper air space, as well as craniocervical length and position of the hyoid bone. PMID- 21277061 TI - Experimental research of accurate reduction of zygomatic-orbitomaxillary complex fractures with individual templates. AB - PURPOSE: To develop a feasible intraoperative guiding device using computer-aided design and computer-aided manufacturing of individual templates to permit anatomic fracture reduction of zygomatic-orbitomaxillary complex (ZOMC) comminuted fractures. The simplicity and accessibility of this method should allow its widespread clinical application. MATERIALS AND METHODS: Under an institutional review board-approved protocol, diverse ZOMC fracture types were created in 6 cadaver heads with a hammer and a saw, and preoperative multislice spiral computerized tomography scan and 3-dimensional reconstruction were performed. Three individual templates were made by computer-aided design and computer-aided manufacturing, and the fractures were repaired under the guidance of individual templates. A clinical case was carried out with this method. After surgery, the outcome evaluation was completed by superimposing the postoperative computed tomographic model onto the planned model. RESULTS: Successful planning and repositioning of the 6 cadavers and a clinical patient were achieved using this method. Computer-aided design and computer-aided manufacturing of individual templates were successfully used in all cases at the time of surgery. Postoperative computed tomographic scans confirmed anatomic repair in all cases. CONCLUSIONS: A feasible intraoperative ZOMC fracture monitoring and reduction guidance device has been developed. This technique is a simple, economical, and readily accessible method of comminuted ZOMC fracture reduction that can be learned and used rapidly. PMID- 21277062 TI - A comparison of the effects of midazolam/fentanyl and midazolam/tramadol for conscious intravenous sedation during third molar extraction. AB - PURPOSE: This study evaluated the effects of fentanyl and tramadol, used in combination, as sedation for third molar surgical extraction. PATIENTS AND METHODS: This prospective, randomized, double-blind, placebo-controlled study included 60 patients undergoing extraction of a horizontal third molar with an Amsterdam Preoperative Anxiety and Information Scale score above 10 points. All of the patients were first given a 0.03-mg/kg bolus of midazolam, and then they were randomized into 3 groups: group A, midazolam only; group B, midazolam and 1 MUg/kg fentanyl; and group C, midazolam and 1-mg/kg tramadol. The vital signs were recorded. Patients were assessed for postoperative pain and adverse effects, and patient and surgeon satisfaction was assessed. RESULTS: No differences were found in the heart rate among groups (P > .05). The mean blood pressure was also similar until the 40th minute, after which the mean blood pressure in the patients in group A was lower than that in the other 2 groups (P < .01). In the postoperative pain assessment, the visual analog scale scores of the patients in group C were lower than those in the other 2 groups in the first postoperative hour (P < .05). The time at which the first rescue analgesic was taken in groups A, B, and C was 3, 3.5, and 5 hours postoperatively, respectively, and was significantly later in group C (P < .01). No difference was found in patient/surgeon satisfaction among the groups. CONCLUSIONS: Tramadol has a better analgesic effect in third molar surgery than fentanyl and placebo. PMID- 21277063 TI - Usefulness of myofascial flap without skin in contemporary oral and maxillofacial reconstruction. AB - PURPOSE: Pedicle myofascial graft should be considered in contemporary oral and maxillofacial reconstruction for the following reasons: 1) the pedicle myofascial unit is reliable and easily handled; 2) on the grafted myofascia in the oral cavity, the mucosa regenerates naturally with regard to suppleness and surface characteristics; and 3) vascularized myofascial coverage of tissues or materials is useful in some clinical situations. The purpose of this retrospective study was to evaluate the usefulness of this graft material. PATIENTS AND METHODS: Using myofascial flaps from the pectoralis major muscle in 15 patients and from the platysma muscle in 11 patients, several types of reconstructive procedures were conducted in the Department of Oral and Maxillofacial Surgery, Wakayama Medical University. RESULTS: Myofascial tissue was used to cover the surgical defect and for regeneration of oral mucosa (24 patients), to prevent exposure of the mandibular reconstruction plate (4 patients), for prevention of wound breakdown and secondary infection in the oral cavity (2 patients), for vascularized coverage of free grafted autologous bone (2 patients), and for protection of large vessels after radical neck dissection (9 patients). Although partial flap necrosis or wound dehiscence was noticed in 3 patients with a platysma-myofascial graft, the healing process of all patients was favorable and required no additional operations. This procedure is most suitable for the reconstruction of small to medium-sized soft tissue defects in the oral cavity, because it induces the formation of nearly normal mucosa through epithelial regeneration without clear scar formation. CONCLUSIONS: Myofascial flap is a useful option in certain oral and maxillofacial reconstruction cases in which mucosal regeneration and/or vascularized soft tissue coverage are required. PMID- 21277064 TI - Malocclusion as a common occurrence in temporomandibular joint arthroscopic disc repositioning: outcomes at 49 days after surgery. AB - PURPOSE: To evaluate the incidence, clinical manifestation, and prognosis of malocclusion after arthroscopic disc repositioning and suturing of the temporomandibular joint (TMJ). PATIENTS AND METHODS: The study included 211 patients (270 joints) with internal derangement of the TMJ who underwent arthroscopic disc repositioning and suturing from November 2005 to August 2006. The occlusion was checked and recorded preoperatively and at different intervals (0, 3, 7, 14, 21, 28, 35, 42, and 49 days after surgery) for all patients. The incidence of malocclusion after surgery was determined for every follow-up period. The chi(2) test was applied to assess the statistical significance of the changes of the incidence of malocclusion. RESULTS: The incidences of malocclusion were 100%, 80.1%, 67.8%, 46.9%, 28.9%, 18.0%, 15.7%, 14.6%, and 14.2% at 0, 3, 7, 14, 21, 28, 35, 42, and 49 days after surgery, respectively. There was a significant difference between neighboring follow-up periods within 28 days after surgery, whereas there was no significant difference from 28 to 49 days after surgery (P > .05). The main clinical manifestations of malocclusion were posterior open bite on the surgery side, incisal prematurities, and mandible midline deviated or nondeviated. CONCLUSION: Malocclusion commonly occurs after TMJ arthroscopic disc repositioning and suturing. However, it will improve within 28 days after surgery in most patients. If malocclusion lasts over 28 days, appropriate treatments should be considered. PMID- 21277065 TI - Lateral canthoplasty by the Micro-Mitek Anchor System: 10-year review of 96 patients. AB - PURPOSE: Lateral canthoplasty is useful to correct lower eyelid malposition, restore eyelid function, and protect the ocular surface. An effective method for fixation of soft tissue in the face, such as the lateral canthus, using the Micro Mitek Anchor System is presented. PATIENTS AND METHODS: We report our experience in 96 patients who underwent lateral canthoplasty by Micro-Mitek Anchor. One hundred twenty-four lateral canthoplasties were performed, including, senile ectropion, tumors, trauma, cicatricial retraction, and lower eyelid malposition after blepharoplasty. RESULTS: The insertion of a bone anchor requires a limited dissection, and the insertion area can be determined accurately. Using the bone anchor to fixate the lateral canthus to the facial skeleton is an effective way to prevent drooping of the canthus due to gravitational forces. CONCLUSIONS: Lateral canthoplasty using the Mitek Anchor System has the advantage of being an easy technique with accurate placement of the anchor, reducing operating time. PMID- 21277066 TI - Real-time radiophotography. PMID- 21277067 TI - Effect of pulsed electromagnetic field on healing of mandibular fracture: a preliminary clinical study. AB - PURPOSE: The aim of the present study was to evaluate the effect of a pulsed electromagnetic field on the healing of mandibular fractures. Pulsed electromagnetic fields have been shown to accelerate healing of fractures of the long bones. PATIENTS AND METHODS: A total of 12 patients with mandibular fractures were selected for the present study. Each patient was treated by closed reduction using maxillomandibular fixation (MMF) and was assigned into 1 of 2 equal groups. The fracture sites of group A only were exposed to pulsed electromagnetic fields (PEMF) 2 hours daily for 12 days, after 2 weeks postoperatively the MMF was removed. For group B (control group), the MMF was removed at 4 weeks postoperatively. The effectiveness of the 2 treatment modalities was evaluated clinically and radiographically using computerized densitometry. The data were statistically analyzed. RESULTS: After releasing the MMF, a bimanual mobility test of the fractured segments showed stability of the segments in all cases. An insignificant difference was found between the mean bone density values of the 2 groups at all study intervals. In contrast, the percentage of changes in bone density of the 2 groups revealed that group A had insignificant decreases at the 15th postoperative day and a significant increase 30 days postoperatively compared with group B. CONCLUSIONS: From the present limited series of patients, PEMF stimulation might have a beneficial effect on the healing of mandibular fractures treated with closed reduction. However, additional research, using randomized controlled trials, should be conducted to ascertain its effectiveness compared with other treatment modalities. PMID- 21277068 TI - Clinical and radiologic features of desmoplastic ameloblastoma. AB - PURPOSE: To evaluate the clinical and radiologic features of desmoplastic ameloblastoma (DA). MATERIALS AND METHODS: Twenty-four cases of DA among Chinese patients were analyzed retrospectively. The clinical and radiologic features of DA at present, as reported in the English-language literature, were reviewed and its radiologic characteristics critically evaluated. RESULTS: This study included 23 cases of intraosseous lesions and 1 case of extraosseous lesion. Clinically, DA is mainly located in the anterior and/or the premolar region of the jaw, with a slight male prominence. Among 23 intraosseous lesions, 9 cases occurred in the maxilla and 14 occurred in the mandible. Radiographically, 69.6% (16 of 23) exhibited ill-defined borders. Root displacement occurred in 47.9% of patients (11 of 23) and root resorption occurred in 8.7% of patients (2 of 23). Three radiologic presentations of DA were identified as follows: type I, which is both radiolucent and radiopaque in appearance (osteofibrosis type); type II, which has a completely radiolucent appearance (radiolucent type); and type III, which is both radiolucent and radiopaque in appearance combined with a large radiolucent change (compound type). The osteofibrosis type (14 cases) is the most common pattern, and the compound type is the least common (only 3 cases). CONCLUSIONS: DA has a potentially aggressive behavior. Moreover, it exhibits 3 different radiologic characteristics. Although DA should be differentiated from osteofibrosis lesions frequently described in the literature, some uncommon radiographic patterns should be considered in the differential diagnosis of this rare odontogenic tumor. PMID- 21277069 TI - Utility of digital volume tomography in maxillofacial trauma. AB - PURPOSE: To assess the diagnostic quality of images generated using the newly developed digital volume tomography (DVT) system and comparing them with conventional images from patients with maxillofacial trauma. MATERIALS AND METHODS: The study population included 22 male patients aged 18 to 60 years with a history of maxillofacial trauma. Each patient had undergone conventional radiographic and DVT examinations to analyze the number of fracture lines in the jaws and to compare the images for their diagnostic quality by an oral radiologist and a general radiologist using the chi(2) test. RESULTS: A statistically significant difference was found between the number of fracture lines evaluated on the conventional radiographs and on DVT, especially for condylar head (7) and the midface (4.41 to 4.57), zygomaticomaxillary complex and Le Fort fractures, respectively. CONCLUSIONS: The detection of fracture lines and visualization within the mandibular-maxillary area using DVT was superior to using conventional radiographs. PMID- 21277070 TI - Game-based assessment of first aid and resuscitation skills. AB - AIM: Effective assessment of motor skills in large-size classes is a challenge in medical education. This case-study investigates whether a game can be considered a valid tool for the summative assessment of first aid and basic life support skills. METHODS: Using a traditional exam as bench-mark, a board game format was experimentally trialed to assess students' competency after taking a first aid course. Fifty-five students were randomly assigned to two groups. Two assessments, a game-based assessment and a traditional test, consisting of a paper-and-pencil test in combination with a skill assessment, were applied to both groups in opposite order. In both formats students acted as judges of other students' efforts. In the game, the student's outcome was equal to the number of cards collected by answering questions correctly as deemed by peers. Similarities between both assessment types included individual testing, type of assessor (peers), content, type of questions and demonstrations, and the use of checklists for skill assessment. The assessment methods differed in format (written or oral test, both in combination with skill assessment) and feedback availability. RESULTS: Both groups performed equally in the game-based assessment as well as in the traditional test, in spite of the opposite order of the assessments. No significant difference was found between the mean scores on the game-based assessment and the traditional test. CONCLUSIONS: These data suggest that use of a game format for assessment purposes may provide an effective means of assessing students' competence at the end of a practical course. PMID- 21277071 TI - The effect of pre-pregnancy counselling for women with pre-gestational diabetes on maternal health status. AB - OBJECTIVE: To assess the impact of pre-pregnancy counselling (PPC) on the health of diabetic women in early pregnancy as compared to their health at the time of PPC. STUDY DESIGN: Retrospective cohort study involving all the diabetic women who attended PPC and subsequently become pregnant in the decade 1997-2007. The proforma had two sections: one for the PPC visit and one for the booking visit. Details on demographic factors, control and complications of diabetes, folic acid, current medication, weight, contraception, smoking and alcohol consumption were documented. RESULTS: Fifty-seven women who became pregnant after PPC were studied. There was optimisation of diabetic control with a significant reduction in HbA1c levels at booking as compared to PPC (7.5% vs 8.8%, p<0.0001). Diabetic surveillance (retinopathy and nephropathy screening) was up to date at the time of booking in >80% of the cases. Alteration of insulin regimes was undertaken in ~ 1 in 5 women. Folic acid was taken by most patients (48/54) at booking. There was no significant reduction in the number of women who smoked at booking compared to PPC. CONCLUSION: The effect of PPC was evident in the improvements in the markers of health of diabetic women in early pregnancy compared to at the time of PPC. PMID- 21277072 TI - Inhibition of the adhesion to catheters of uropathogenic Escherichia coli by sub inhibitory concentrations of cefotaxime. AB - OBJECTIVE: To investigate the effect of sub-inhibitory concentrations of cefotaxime on adherence to siliconized latex urinary catheters of uropathogenic Escherichia coli strains from pregnant and non pregnant patients. STUDY DESIGN: Using random sampling, 30 E. coli strains were selected from hospitalized patients with catheter associated urinary tract infection, 12 from pregnant women and 18 from men and non-pregnant women. The strains were categorized on the basis of cefotaxime susceptibility, adhesion and biofilm production capacity, cell surface hydrophobicity and expression of adhesins and fimbriae in vitro. RESULTS: The overall results indicated that sub-inhibitory concentrations of cefotaxime could reduce the adhesiveness, the biofilm production and hence, potentially, the infection rate associated with indwelling urinary catheters. CONCLUSION: Based on our results, we propose that this reduction is due to decreasing exopolysaccharide production and increasing cell surface hydrophobicity of E.coli strains. PMID- 21277073 TI - Effect of dose escalation of metformin on clinical features, insulin sensitivity and androgen profile in polycystic ovary syndrome. AB - OBJECTIVE: The benefit of metformin on polycystic ovary syndrome (PCOS) has been debated. Varying results have been observed in different studies which could be due to differences in the study cohorts and the heterogeneity of the syndrome. We hypothesized that the dose of metformin generally used may not be adequate for women with higher BMI and observed the effect of dose escalation on PCOS in women with differing BMI and baseline insulin resistance. STUDY DESIGN: Forty women were recruited to the study. Patients were started on 1g/day and increased every 8 weeks by 1-3g at the end of 16 weeks. The study was carried out for 24 weeks. Analysis was carried out based on BMI and baseline insulin sensitivity. There were four groups based on BMI with 10 patients in each group (groups A: 18-24.9 kg/m(2), B: 25-29.9 kg/m(2), C: 30-34.9 kg/m(2) and D: 35-40 kg/m(2)). There were three tertiles based on insulin sensitivity. In order of insulin resistance, tertile 1 (n=13) - high insulin resistance (IR), tertile 2 (n=13) - mid IR, tertile 3 (n=14) - low IR. The outcome measures were clinical features, insulin sensitivity and androgens. RESULTS: A trend towards reduction of fasting insulin concentration was observed which reached statistical significance (p<0.05) in group D. At the highest dose of 3g, groups B and C also showed a decrease in insulin concentrations but statistical significance was not achieved. On examination of changes in insulin resistance over time, groups B, C and D showed a trend towards improvement in sensitivity but QUICKI remained below 0.333. No definite benefit from higher doses was seen. When analyzed based on the three tertiles, there was significant drop in fasting insulin concentration in the first tertile (-16.73 +/- 9.8 nmol/L). Measurement of QUICKI also revealed a significant improvement in the first tertile (p=0.001). CONCLUSION: There is no benefit from increased doses of metformin in PCOS but reduction of insulin resistance is more significant in those patients with a lower insulin sensitivity at baseline. PMID- 21277074 TI - Overactive bladder symptoms and uterine adenomyosis--is there any connection? AB - OBJECTIVE: The aim of this study was to investigate a possible connection between uterine adenomyosis and the prevalence of symptoms of overactive bladder (OAB), and to study the impact of OAB symptoms on the quality of life (QoL) of women with uterine adenomyosis. STUDY DESIGN: In this prospective pilot study, we included 98 women, 54 of them with an ultrasound (US) diagnosis of uterine adenomyosis and 44 with normal-appearing uterine myometrium during transvaginal US examination. After interview all women completed two questionnaires, the Urogenital Distress Inventory (UDI) and the Incontinence Impact Questionnaire. Data were analyzed with SPSS statistical software by means of non-parametric statistics and logistic regression. RESULTS: The average age of all the women was 44 years. Women from the adenomyosis and control groups did not differ in any of the observed clinical variables. Analysis of the UDI questionnaire showed that irritative symptoms were most prevalent in the adenomyosis group as compared to the control group, 22.3% and 7.8%, respectively. Urge urinary incontinence was found in 25.9% of women in the adenomyosis group (3.7% in the control group). Results of logistic regression confirmed the greatest negative impact of irritative symptoms on QoL in women with uterine adenomyosis (p<0.000). CONCLUSION: As compared with healthy controls, women with adenomyosis more often experience OAB symptoms which significantly decrease their QoL. The connection between adenomyosis and OAB remains uncertain. PMID- 21277075 TI - Impact of unconfined sulphur-mine waste on a semi-arid environment (Almeria, SE Spain). AB - Thirty-five soil samples were taken from unconfined mine waste, stream sediments, and surfaces unoccupied by mining and presumably unaffected by it, in a sulphur mining zone surrounded by carbonate material and characterized by a semi-arid climate with short torrential storms. These samples were analysed and the results compared to estimate the spread of pollution in the landscape and to assess potential environmental risk. The mean concentrations of S, Zn, Cd, Pb, and As in mine waste were between 3.5-fold (As) and 50-fold (S) greater than unaffected soils. Oxidation of S led to a sharp drop in pH, strong weathering of minerals, and solubilisation of the constituent elements, forming a toxic acidic mine drainage with highly concentrated pollutants that were discharged into the drainage channels. Successive acid mine drainage into the soil on the valley floor spreads acidification and pollution downstream. The high carbonate content in surrounding soils played an important role in the increase of the pH and precipitation of S, Pb, and Al of the affected soils. Meanwhile, high mobility of Zn, Cd and As under basic conditions and a low Fe concentration explain the broad spread of these elements, as high concentrations were detected in soil more than 2000 m from the source. Only the soil solutions from near the waste dump (first 500 m) were highly phytotoxic, and moderately phytotoxic from 500 to 1500 m away. The concentration of pollutants in the leachates was clearly higher than in soil solutions, even in the soils located over 2000 m from the source, implying that the size of the polluted area will increase with time. PMID- 21277076 TI - Exploratory study assessing efficacy and complications of TVT-O, TVT-Secur, and Mini-Arc: results at 12-month follow-up. AB - BACKGROUND: Contemporary surgical treatment of female stress urinary incontinence (SUI) includes retropubic and transobturator (TO) midurethral slings (MUS). Case series of single-incision slings (SIS) have shown similar outcomes with lower morbidity. OBJECTIVE: Our aim was to assess the cure rates, complications, and quality-of-life impact of one standard TO MUS and two SIS. DESIGN, SETTING, AND PARTICIPANTS: Ninety consecutive patients with clinically and urodynamically proven SUI were enrolled in an exploratory randomised phase 2 trial. Patients with previous SUI surgery, major pelvic organ prolapse, mixed incontinence, or detrusor overactivity were excluded. INTERVENTIONS: Patients were treated randomly with TVT-O, TVT-Secur, or Mini-Arc. MEASUREMENTS: Postoperative visits were scheduled at 6 and 12 mo. The King's Health Questionnaire (KHQ) was repeated at 6 mo. Cure was defined as the absence of urine leakage, no pad use, and a negative cough test at 12 mo. Pain and other complications were also investigated. RESULTS AND LIMITATIONS: Cure rate was 83% after TVT-O, 67% after TVT-Secur, and 87% after Mini-Arc. Improvement was found in 10%, 13%, and 7% of the patients, respectively. Failures were 7% after TVT-O and Mini-Arc and 20% after TVT-Secur. TVT-O and Mini-Arc improved at least 15 points in >80% of the patients in six KHQ domains, whereas TVT-Secur could only achieve improvement in three of the nine domains. The pain score was lower in the Mini-Arc group. Complications were more numerous after TVT-O. This study has the limitations inherent in a phase 2 trial with a follow-up limited to 12 mo. CONCLUSIONS: Mini Arc offers cure and improvement rates similar to TVT-O, whereas TVT-Secur may yield an inferior outcome. These findings recommend the urgent launch of large randomised phase 3 studies comparing conventional MUS with SIS, with Mini-Arc the advised option. PMID- 21277077 TI - The use of 5alpha-reductase inhibitors for the prevention and treatment of prostate cancer. PMID- 21277078 TI - Toxicities of targeted therapy and their management in kidney cancer. AB - CONTEXT: The therapeutic scenario for metastatic renal cell carcinoma (mRCC) has been evolving rapidly, with sunitinib, sorafenib, bevacizumab, everolimus, pazopanib, and temsirolimus being successfully tested and approved in a short period of time. Oncologists must be familiar with the management of toxicity that these biologic agents cause, as such toxicity is different from that of conventional chemotherapeutic agents. OBJECTIVE: To describe toxic effects associated with targeted therapy of mRCC and their proper management on the basis of currently available evidence. EVIDENCE ACQUISITION: We conducted a systematic analysis of the literature on 15th October 2010 by performing a search of Medical Subject Headings (MeSH) on PubMed using the words sorafenib, sunitinib, bevacizumab, everolimus, pazopanib, or temsirolimus combined with the MeSH term kidney neoplasms. Consideration for inclusion was given to articles providing data concerning (1) incidence and grading and (2) management of targeted therapy related toxic effects. A separate search was conducted on PubMed to retrieve meta analyses using each drug name and the word meta-analysis. EVIDENCE SYNTHESIS: Hypertension, fatigue, bone marrow toxicity, skin toxicity, and gastrointestinal side-effects are common with the six targeted agents. Everolimus and temsirolimus are associated with immunosuppression, metabolic alterations, and interstitial pneumonitis, while sunitinib is associated with hypothyroidism. Recommendations for treating these conditions usually follow those for the general population because of the lack of experimental data in this setting (eg, for management of sunitinib-induced hypertension). CONCLUSIONS: The treating oncologist should try to manage side-effects associated with targeted therapy using supportive and pharmacologic interventions. Severe toxicity requires external specialist consultation and treatment suspension and/or dose reduction. Experimental data about the management of targeted therapy-related toxicity in mRCC is lacking and required in this setting. PMID- 21277079 TI - Cadmium adsorption by coal combustion ashes-based sorbents--relationship between sorbent properties and adsorption capacity. AB - A very interesting possibility of coal combustion ashes reutilization is their use as adsorbent materials, that can also take advantage from proper beneficiation techniques. In this work, adsorption of cadmium from aqueous solutions was taken into consideration, with the emphasis on the intertwining among waste properties, beneficiation treatments, properties of the beneficiated materials and adsorption capacity. The characterization of three solid materials used as cadmium sorbents (as-received ash, ash sieved through a 25 MUm-size sieve and demineralized ash) was carried out by chemical analysis, infrared spectroscopy, laser granulometry and mercury porosimetry. Cadmium adsorption thermodynamic and kinetic tests were conducted at room temperature, and test solutions were analyzed by atomic absorption spectrophotometry. Maximum specific adsorption capacities resulted in the range 0.5-4.3 mg g(-1). Different existing models were critically considered to find out an interpretation of the controlling mechanism for adsorption kinetics. In particular, it was observed that for lower surface coverage the adsorption rate is governed by a linear driving force while, once surface coverage becomes significant, mechanisms such as the intraparticle micropore diffusion may come into play. Moreover, it was shown that both external fluid-to-particle mass transfer and macropore diffusion hardly affect the adsorption process, which was instead regulated by intraparticle micropore diffusion: characteristic times for this process ranged from 4.1 to 6.1d, and were fully consistent with the experimentally observed equilibrium times. Results were discussed in terms of the relationship among properties of beneficiated materials and cadmium adsorption capacity. Results shed light on interesting correlations among solid properties, cadmium capture rate and maximum cadmium uptake. PMID- 21277080 TI - Adsorption of chromium (VI) from aqueous solutions by cellulose modified with beta-CD and quaternary ammonium groups. AB - Cellulose powder was grafted with the vinyl monomer glycidyl methacrylate using ceric ammonium nitrate as initiator and was further derived with beta-CD and quaternary ammonium groups to build Cell-g-GMA-beta-CDN(+) adsorbent. Epoxy cellulose was made up of Cell-g-GMA and Cell-hydro-g-GMA, and was found to contain 3.71 mmol g(-1) epoxy groups. The adsorption process of the modified cellulose was described by the Langmuir model of adsorption well, and the maximum adsorption capacity of chromium (VI) reached 61.05 mg g(-1). The adsorption desorption tests of beta-CDN(+)-type cellulose derivatives exhibited that the reproducibility of the adsorbent was well and the adsorbent could be reused five times at least. PMID- 21277081 TI - Increased temperature in the thermophilic stage in temperature phased anaerobic digestion (TPAD) improves degradability of waste activated sludge. AB - Two-stage temperature phased anaerobic digestion (TPAD) is an increasingly popular method to improve stabilisation of sewage waste activated sludge, which normally has inherently poor and slow degradation. However, there has been limited systematic analysis of the impact of the initial thermophilic stage (temperature, pH and retention time) on performance in the main mesophilic stage. In this study, we demonstrate a novel two-stage batch test method for TPAD processes, and use it to optimize operating conditions of the thermophilic stage in terms of degradation extent and methane production. The method determines overall degradability and apparent hydrolysis coefficient in both stages. The overall process was more effective with short pre-treatment retention times (1-2 days) and neutral pH compared to longer retention time (4 days) and low pH (4-5). Degradabilities and apparent hydrolysis coefficients were 0.3-0.5 (fraction degradable) and 0.1-0.4d(-1), respectively, with a margin of error in each measurement of approximately 20% relative (95% confidence). Pre-treatment temperature had a strong impact on the whole process, increasing overall degradability from 0.3 to 0.5 as temperature increased from 50 to 65 degrees C, with apparent hydrolysis coefficient increasing from 0.1 to 0.4d(-1). PMID- 21277082 TI - Fixed-bed column study for Cu2+ removal from solution using expanding rice husk. AB - This paper deals with removal of copper ions from solution by raw rice husk (RRH) and expanding rice husk (ERH). Different column design parameters like bed depth, flow rate and initial copper concentration were investigated. It was found that the equilibrium uptake (q(eq(exp))) of the ERH and RRH increased with increase in initial copper concentration but decreased with increase in flow rate and bed depth, respectively. The higher adsorption capacity and longer breakthrough time were observed for ERH in comparison with RRH, under the same conditions. Compared to coconut-shell activated carbon (C-AC), ERH was also found more effective in removing Cu(2+). 0.01 mol L(-1) HCl solution was used for desorption of column which was prior to absorb copper ion, and 0.01 mol L(-1) NaOH solution was used for re-activation. Column regeneration and reuse studies were conducted for adsorption-desorption cycle. PMID- 21277083 TI - Short-term stabilization of grape marc through earthworms. AB - The winery industry generates vast amounts of organic waste during the various stages of wine production. Among the possible methodological alternatives available for its treatment, vermicomposting is one of the best-known processes for the biological stabilization of solid organic wastes by transforming them into safer and more stabilized materials suitable for application to soil. In this study we carried out a mesocosm experiment to evaluate the effectiveness of the active phase of vermicomposting for the stabilization of grape marc, an enriched lignocellulosic by-product obtained after the grape crushing and pressing stages in wine production. For this we analysed the chemical, biochemical and microbiological properties of the product resulting from this phase, in comparison with those in a control treatment. Earthworm activity reduced the abundance of both bacterial and fungal PLFA biomarkers. Decreases in microbial activity and in protease and cellulase activities were also attributed to the presence of earthworms. The differences in microbial communities were accompanied by a reduction in the labile C pool and the cellulose content. These results indicate that earthworms played a key role in the stabilization of the grape marc in the short-term, via its effects on organic matter decomposition and microbial biomass and activity. PMID- 21277084 TI - WITHDRAWN: Mechanism of inflammatory responses in brain and impairment of spatial memory of mice caused by titanium dioxide nanoparticles. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 21277085 TI - Kinetic and chemical characterization of thermal decomposition of dicumylperoxide in cumene. AB - Dicumylperoxide (DCP) is one of the most used peroxides in the polymer industry. It has been reported that its thermal decomposition can result in runaway phenomena and thermal explosions with significant economic losses and injuries to people. In the present paper thermal behaviour of dicumylperoxide in cumene was investigated over the temperature range of 393-433 K under aerated and de-aerated conditions. The results indicated that when oxygen was present, the decomposition rate did not follow a simple pseudo-first order kinetic as previously reported in literature. A satisfactory fit of the experimental data was, in this case, achieved by means of kinetic expression derived under the assumption of an autocatalytic scheme of reaction. The reaction rate was, on the contrary, correctly described by a pseudo-first order kinetic in absence of oxygen. Under both aerated and de-aerated conditions, chemical analysis showed that the decomposition mainly resulted in the formation of acetophenone and dimethylphenylcarbinol with minor occurrence of 2,3-dimethyl-2,3-diphenylbutane. The formation of methane and ethane was also invariably observed while the appearance of cumylhydroperoxide as a reaction intermediate was detected under only aerated conditions. Therefore, two reaction schemes were proposed to explain system behaviour in the presence of oxygen and after its purging. PMID- 21277086 TI - A reassessment of stress-induced "analgesia" in the rat using an unbiased method. AB - An increased tail-flick latency to noxious heat during or after stress in the rodent is usually interpreted as a stress-induced reduction in pain sensitivity and often described as a form of stress-induced "analgesia." However, this measure is an indirect and flawed measure of the change in nociceptive threshold to noxious heat. A major confound of the latency measure is the initial temperature of the tail, which can drop down to room temperature during stress, the consequence of a marked sympathetically mediated vasoconstriction in the skin of the extremities. We addressed this issue with tail-flick tests during contextual fear using infrared thermography to monitor temperature changes and a CO2 laser to deliver the heat stimulus. The experiment revealed a 4.2 degrees C increase of the nociceptive threshold, confirming a true antinociceptive effect. However, its contribution to the increased withdrawal latency was less than two thirds (63.2%). Nearly one-third (32.2%) was due to the drop in tail temperature (4.4 degrees C), which also slowed conduction along sensory fibers (2.2%, included in the 32.2%). The remaining 4.6% was due to an increase in decisional/motor latency. This new unbiased method establishes beyond doubt that a conditioned stress response is associated with true antinociception to noxious heat. It also confirms that stress-induced changes in skin temperature can be a major confound in tail-flick tests. The present study shows, for the first time, the exact contribution of these two components of the tail-flick latency for a stress response. Less than two-thirds of the increase in tail-flick latency to noxious heat, evoked by conditioned fear, reflects true antinociception. The remaining is due to skin vasoconstriction. PMID- 21277087 TI - Reducing racial disparities in pain treatment: the role of empathy and perspective-taking. AB - Epidemiological evidence indicates that African Americans receive lower quality pain treatment than European Americans. However, the factors causing these disparities remain unidentified, and solutions to this problem remain elusive. Across three laboratory experiments, we examined the hypotheses that empathy is not only causing pain treatment disparities but that empathy-inducing interventions can reduce these disparities. Undergraduates (Experiments 1 and 2) and nursing professionals (Experiment 3) watched videos of real Black and White patients' genuine facial expressions of pain, provided pain treatment decisions, and reported their feelings of empathy for each patient. The efficacy of an empathy-inducing, perspective-taking intervention at reducing pain treatment disparities was also examined (Experiments 2 and 3). When instructed to attempt to provide patients with the best care, participants exhibited significant pro White pain treatment biases. However, participants engaged in an empathy inducing, perspective-taking intervention that instructed them to imagine how patients' pain affected patients' lives exhibited upwards of a 55% reduction in pain treatment bias in comparison to controls. Furthermore, Pro-White empathy biases were highly predictive of pro-White pain treatment biases. The magnitude of the empathy bias experienced predicted the magnitude of the treatment bias exhibited. These findings suggest that empathy plays a crucial role in racial pain treatment disparities in that it appears not only to be one likely cause of pain treatment disparities but also is an important means for reducing racial disparities in pain treatment. PMID- 21277088 TI - Life cycle of Hyalomma anatolicum Koch, 1844 (Acari: Ixodidae) fed on rabbits, sheep and goats. AB - Some aspects of the biology of the tick Hyalomma anatolicum fed on rabbits, sheep and goats were studied. The non-feeding stages were maintained under laboratory conditions at 20-36 degrees C and 75% relative humidity. The longest feeding periods of larvae and nymphs of H. anatolicum were observed when fed on rabbits (mean 4.58 +/- 0.51 and 7 +/- 1.15 days, respectively) while the longest feeding periods of females were observed on goats (9.61 +/- 1.21). The pre-oviposition period (4.8 +/- 0.42 days) and pre-eclosion periods (mean 21.3 +/- 1.16 days) were shortest for females fed on rabbits. Engorged females reached heavier engorgement weights (482.92 +/- 88.08 mg), and produced more eggs (4881.8 +/- 842.71) when fed on rabbits. However, no significant differences were observed between the percentages hatchability of eggs laid by ticks fed on the three hosts studied. Most (94.31%) of the larvae fed on rabbits underwent a 2-host life cycle, while few (5.69%) of them behaved as a 3-host ticks. Few larvae were able to complete feeding as 3-host pattern on both sheep and goats, while the majority of the larvae failed to complete feeding or died on their way to molt on both sheep and goats. PMID- 21277089 TI - Prevalence of dog intestinal nematode parasites in south central West Virginia, USA. AB - Coprological examination was used to determine prevalence of gastrointestinal helminthes in a sample of 231 dogs (117 females and 114 males) during the summer of 2009 at a veterinary clinic in south central West Virginia, USA. Clinical signs (e.g., diarrhea, vomiting, weight gain or loss) were noted in addition to a history of anthelmintic usage. A total of 79 dogs (33.6%) were infected with one or more intestinal nematodes. Most dogs (58) were parasitized with a single species, 19 were parasitized with 2 species, and 2 were parasitized by 3 species. There was no significant difference (i.e., X(2)<3.84; P>0.05) in prevalence of infection between female and male dogs for any of the identified nematode species. The chi-square test for equality of proportions was used to determine prevalence of infection in 3 age categories of dogs (females and males combined): young dogs (<=12 months of age); mature dogs (13-83 months); and old dogs >83 months. Prevalences of infection for Ancylostoma caninum and Toxocara canis were significantly (P<0.005) higher in young dogs, whereas there was no significant difference (P>0.05) in prevalence by age category for Trichuris vulpis. Dogs exhibiting clinical signs were no more likely to harbor intestinal nematodes than dogs that were asymptomatic. Additionally, dogs receiving heartworm treatment were significantly less likely to be parasitized than dogs receiving no heartworm prophylaxis. PMID- 21277090 TI - Resistance of Fasciola hepatica against triclabendazole in cattle in Patagonia (Argentina). AB - In the winter of 2008, cattle on a farm in the province of Neuquen, Argentina died from subacute and chronic liver fluke disease despite four previous treatments with Triclabendazole (TCBZ). In the spring of 2009, a preliminary efficacy test revealed good performance using nitroxynil, whereas TCBZ efficacy was only 18% by egg counts of Fasciola eggs in the faeces. Resistance to Fasciola hepatica to TCBZ has never been reported in South America, so in January of 2010 a controlled trial was conducted to confirm and to define the degree of resistance in this herd. In a clinical trial, the fluke egg output was monitored on Days 14 and 21 and serum enzymes gamma-glutamyl transpeptidase (GGT) and glutamic-oxaloacetic transaminase (GOT) on Days 0 and 21 in 36 calves treated with TCBZ or with closantel. The results showed a reduction of 100% in fluke egg output at Days 14 and 21 for closantel. The mean epg in the TCBZ-treated groups did not decrease. Because of the fact that in this study TCBZ treatment in cattle had no effect, even at double the recommended dose, it is highly indicative that resistance of F. hepatica against TCBZ is present on this farm. The GGT and GOT levels decreased in the closantel-treated group as a result of the treatment at 21 days after dosing. To evaluate the importance of TCBZ resistance in F. hepatica in Argentina, a study on more farms from endemic areas is needed. PMID- 21277091 TI - Molecular characterization of Cryptosporidium spp. in native breeds of cattle in Kaduna State, Nigeria. AB - Despite numerous molecular epidemiologic studies of cryptosporidiosis in dairy cattle in industrialized countries, there are very few studies on the diversity and public health significance of Cryptosporidium species in native cattle in developing countries. In this study, a polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) analysis of the small-subunit (SSU) rRNA gene was used to detect and identify Cryptosporidium spp. in 194 fecal specimens from 2 to 365 days old calves in 20 White Fulani and Sokoto Gudali herds in Nigeria. Thirty one (16.0%) of the specimens were positive for Cryptosporidium. Restriction digestion of the PCR products showed the presence of Cryptosporidium bovis (7.2%), Cryptosporidium ryanae (4.1%), Cryptosporidium andersoni (2.5%), and concurrent occurrence of C. bovis and C. ryanae (1.5%), and C. bovis and C. andersoni (0.5%). There were no significant differences (p>0.05) in Cryptosporidium infection rates by sex, herd location, management system, breed of calves, or fecal consistency. However, calves 180 days or younger had a higher infection rate of Cryptosporidium than older calves (p=0.034). Likewise, younger calves also had higher occurrence of C. bovis and C. ryanae (p=0.022). The absence of zoonotic Cryptosporidium parvum in the calves studied suggests that native breeds of cattle may not be important in the transmission of human cryptosporidiosis in Kaduna State, Nigeria. PMID- 21277092 TI - Determination of the susceptibility of Rhipicephalus (Boophilus) microplus (Acari: Ixodidae) to ivermectin and fipronil by Larval Immersion Test (LIT) in Uruguay. AB - Rhipicephalus (Boophilus) microplus is an important cattle pest in Uruguay, and the law regulates its control. It is resistant to organophosphates, synthetic pyrethroids and, as recently discovered, to fipronil. Resistance to macrocyclic lactones (MLs) and amitraz have not been documented; however, veterinarians and farmers have reported treatment failures. The objective of the present work was to study the susceptibility of cattle tick strains from different Uruguayan counties to ivermectin (IVM) and fipronil by using the Larval Immersion Test (LIT). The Mozo strain was used as the susceptible reference strain. From 2007 to 2009, twenty-eight tick populations were collected from different cattle farms with and without history of IVM or fipronil use. A probit analysis estimated dose mortality regressions, lethal concentrations (LC), and confidence intervals. The resistance ratio (RR) was determined at the LC(50) and LC(90) estimates. To classify a tick population in relation to resistance, three categories based on a statistical analysis of LC and RR between field populations and Mozo strains were defined: susceptible (no differences), incipient resistance (differences and RR(50)<2) and resistant (differences and RR(50)>=2). Eighteen field populations were tested with IVM and five of them presented a RR(50) range between 1.35 and 1.98 and the LC(50/90), which is statistically different from the Mozo strain (incipient resistance). However, the RR(90) increases >=2 in four of the populations, confirming that tick resistance to IVM is emergent. The low RR values obtained could be a result of a low frequency of treatments with IVM. Twenty-seven tick populations were tested with fipronil and six were diagnosed as resistant according to the LIT. Cross-resistance was not observed between fipronil and IVM on these tick populations. The current study presents different R. (B.) microplus populations with an incipient resistance to IVM, and indicates that the fipronil tick resistance is restricted to certain areas in Uruguay. PMID- 21277093 TI - Oral/metronomic cyclophosphamide-based chemotherapy as option for patients with castration-refractory prostate cancer: review of the literature. AB - PURPOSE: Castration-refractory prostate cancer remains a therapeutic challenge even after introduction of docetaxel as first-line treatment. Castration refractory prostate cancer cannot be cured by any available therapeutic option, and chemotherapy still needs to be considered palliative. The survival benefit is modest, and treating physicians are searching for alternative treatment options. Despite new drugs currently under investigation, some conventional and well known chemotherapeutic drugs are experiencing a renaissance. The development of anti angiogenic approaches in cancer treatment has led to the development of metronomic dosing of conventional chemotherapeutic drugs including cyclophosphamide. The intention of this review is to evaluate the efficacy and toxicity of oral/metronomic cyclophosphamide in the treatment of patients with castration-refractory prostate cancer. MATERIALS AND METHODS: A comprehensive literature search was performed in different databases using various key words. Relevant articles and references between 1962 and 2010 were reviewed and analyzed for data regarding the association between oral cyclophosphamide treatment and prostate cancer. RESULTS: Oral cyclophosphamide is active in the treatment for castration-refractory prostate cancer even in patients treated with previous chemotherapy including docetaxel. It yields symptomatic and objective remissions. The side effects are usually grade 1-2 and easy to manage. Grade three to four side effects are less common. CONCLUSIONS: Oral cyclophosphamide treatment for patients with castration-refractory prostate cancer deserves more attention and validation, and warrants further testing of various treatment combinations. Given the fact that castration-refractory prostate cancer includes an extremely heterogeneous group of patients with variability of tumor growth rates, the combination of cyclophosphamide with other active agents such as angiogenesis inhibitors and immunomodulatory compounds need to be explored. PMID- 21277094 TI - A comparison of African-American versus Caucasian men screened for an alcohol administration laboratory study: recruitment and representation implications. AB - African-Americans are under-represented in alcohol research, especially alcohol administration laboratory studies. Specific recruitment of African-Americans into laboratory studies, however, may also inadvertently affect the generalizability of the findings. In the current study, we compared all African-American young adult men (n=53) who volunteered and met criteria for an alcohol administration study to a sample (n=50) of Caucasian men recruited for the same study. Groups were compared on variables including demographics, quantity and frequency of alcohol consumption and other substance use, consequences of use and psychopathology. Compared to their Caucasian counterparts, African-American men reported less drinking frequency and quantity, less use of other substances and fewer negative consequences, but their alcohol and drug use was more likely to be associated with various measures of psychopathology. Results suggest that even when recruiting participants using criteria that should minimize differences (i.e. all participants were "social drinkers"), differences on key variables were evident. These differences may have important implications for alcohol research. PMID- 21277095 TI - Sex differences in smoking cessation outcomes of a tailored program for individuals with substance use disorders and mental illness. AB - Tobacco use is highly prevalent among individuals with a history of substance use disorders (SUD) and/or mental illness (MI). Despite evidence of differences in smoking cessation (SC) outcomes between women and men, few studies have formally evaluated sex differences among SUD and/or MI populations. For 258 participants (62% male, mean age=48.6 years) with an SUD and/or MI enrolled in a tobacco dependence clinic (TDC) program, we examined SC outcomes and compared men's and women's predictors of end-of-treatment abstinence. Individuals with an MI, social support for quitting, and a greater number of visits to the TDC program were more likely to be female; whereas males were characterized by having an SUD, older age, smoking a greater number of cigarettes per day, and having higher confidence in quitting smoking. In the intent-to-treat analysis, end-of-treatment smoking cessation was 32.2% (females=35.4% vs males=30.2, chi(2)=0.74, df=1, p=.390). Among females, baseline expired carbon monoxide (CO) level and a greater number of visits to the program were significantly predictive of SC; among males, having a history of alcohol, heroin and other opioids, and marijuana use were predictive of unsuccessful SC, whereas baseline expired CO level and a greater number of visits to the program were predictive of SC. These factors may be important in the design of enhanced tailored treatments and development of future SC programs for individuals with SUD and MI. PMID- 21277096 TI - Localization accuracy of the clinical target volume during image-guided radiotherapy of lung cancer. AB - PURPOSE: To evaluate the position and shape of the originally defined clinical target volume (CTV) over the treatment course, and to assess the impact of gross tumor volume (GTV)-based online computed tomography (CT) guidance on CTV localization accuracy. METHODS AND MATERIALS: Weekly breath-hold CT scans were acquired in 17 patients undergoing radiotherapy. Deformable registration was used to propagate the GTV and CTV from the first weekly CT image to all other weekly CT images. The on-treatment CT scans were registered rigidly to the planning CT scan based on the GTV location to simulate online guidance, and residual error in the CTV centroids and borders was calculated. RESULTS: The mean GTV after 5 weeks relative to volume at the beginning of treatment was 77% +/- 20%, whereas for the prescribed CTV, it was 92% +/- 10%. The mean absolute residual error magnitude in the CTV centroid position after a GTV-based localization was 2.9 +/- 3.0 mm, and it varied from 0.3 to 20.0 mm over all patients. Residual error of the CTV centroid was associated with GTV regression and anisotropy of regression during treatment (p = 0.02 and p = 0.03, respectively; Spearman rank correlation). A residual error in CTV border position greater than 2 mm was present in 77% of patients and 50% of fractions. Among these fractions, residual error of the CTV borders was 3.5 +/- 1.6 mm (left-right), 3.1 +/- 0.9 mm (anterior-posterior), and 6.4 +/- 7.5 mm (superior-inferior). CONCLUSIONS: Online guidance based on the visible GTV produces substantial error in CTV localization, particularly for highly regressing tumors. The results of this study will be useful in designing margins for CTV localization or for developing new online CTV localization strategies. PMID- 21277097 TI - Experience-based quality control of clinical intensity-modulated radiotherapy planning. AB - PURPOSE: To incorporate a quality control tool, according to previous planning experience and patient-specific anatomic information, into the intensity modulated radiotherapy (IMRT) plan generation process and to determine whether the tool improved treatment plan quality. METHODS AND MATERIALS: A retrospective study of 42 IMRT plans demonstrated a correlation between the fraction of organs at risk (OARs) overlapping the planning target volume and the mean dose. This yielded a model, predicted dose = prescription dose (0.2 + 0.8 [1 - exp(-3 overlapping planning target volume/volume of OAR)]), that predicted the achievable mean doses according to the planning target volume overlap/volume of OAR and the prescription dose. The model was incorporated into the planning process by way of a user-executable script that reported the predicted dose for any OAR. The script was introduced to clinicians engaged in IMRT planning and deployed thereafter. The script's effect was evaluated by tracking delta = (mean dose-predicted dose)/predicted dose, the fraction by which the mean dose exceeded the model. RESULTS: All OARs under investigation (rectum and bladder in prostate cancer; parotid glands, esophagus, and larynx in head-and-neck cancer) exhibited both smaller delta and reduced variability after script implementation. These effects were substantial for the parotid glands, for which the previous delta = 0.28 +/- 0.24 was reduced to delta = 0.13 +/- 0.10. The clinical relevance was most evident in the subset of cases in which the parotid glands were potentially salvageable (predicted dose <30 Gy). Before script implementation, an average of 30.1 Gy was delivered to the salvageable cases, with an average predicted dose of 20.3 Gy. After implementation, an average of 18.7 Gy was delivered to salvageable cases, with an average predicted dose of 17.2 Gy. In the prostate cases, the rectum model excess was reduced from delta = 0.28 +/- 0.20 to delta = 0.07 +/- 0.15. On surveying dosimetrists at the end of the study, most reported that the script both improved their IMRT planning (8 of 10) and increased their efficiency (6 of 10). CONCLUSIONS: This tool proved successful in increasing normal tissue sparing and reducing interclinician variability, providing effective quality control of the IMRT plan development process. PMID- 21277098 TI - Phase II study of concomitant thalidomide during radiotherapy for hepatocellular carcinoma. AB - PURPOSE: Thalidomide has been demonstrated to possess antitumor activity in patients with advanced hepatocellular carcinoma (HCC). The objective of the present study was to determine whether the combined treatment of thalidomide with radiotherapy (RT) is associated with acceptable toxicity and an improved clinical outcome in HCC patients. METHODS AND MATERIALS: A total of 24 patients were enrolled to receive RT combined with thalidomide. A total dose of 50 Gy was delivered in 2-Gy fractions within 5 weeks. Thalidomide was administered 100 mg twice daily starting 3 days before RT until the development of unacceptable toxicity or disease progression. Blood samples were collected before, during, and after treatment to measure the levels of angiogenic factors and cytokines. The results of patients receiving the combined therapy were compared with those from 18 HCC patients receiving RT only. RESULTS: No significant difference in the clinical parameters was noted between the two groups, except for the baseline interleukin-6 level, which was greater in the concomitant group (p = .05). The most common toxicities related to thalidomide use were skin rash (54.2%), somnolence (37.5%), and constipation (33.3%). No significant differences were seen in the response rate (55.6% vs. 58.3%, p = .48), median progression-free survival (182 +/- 48.9 vs. 148 +/- 6.2 days, p = .15), or median overall survival (258 +/- 45.6 vs. 241 +/- 38.6, p = .16) between those who received concomitant therapy and those who received RT alone. Thalidomide suppressed the serum basic fibroblast growth factor level significantly during RT (p = .03) and, to a lesser extent, the interleukin-6 and tumor necrosis factor-alpha levels. After adjusting for other potential prognostic factors in the multivariate analysis, only the baseline interleukin-6 level and stem cell-derived factor-1 during RT independently predicted the progression-free survival. A decreased serum stem cell-derived factor-1 level 1 month after RT completion was a significant predictor of the overall survival of HCC patients receiving RT. CONCLUSIONS: Despite the acceptable toxicity, thalidomide provided no additional benefit for HCC patients undergoing RT. PMID- 21277099 TI - Adamantanyl-histone deacetylase inhibitor H6CAHA exhibits favorable pharmacokinetics and augments prostate cancer radiation sensitivity. AB - PURPOSE: To evaluate pharmacological properties of H6CAHA, an adamantyl hydroxamate histone deacetylase inhibitor, and to investigate its effect on prostate cancer cells following exposure to gamma-radiation in vitro and in vivo. METHODS AND MATERIALS: H6CAHA was assessed for in vitro solubility, lipophilicity and growth inhibition, and in vivo plasma pharmacokinetics. The effect of H6CAHA on radiation clonogenic survival and DNA damage repair was evaluated in human prostate cancer (PC3, DU145, LNCaP) and nonmalignant control epithelial (RWPE1 and 267B1) cell lines. The effect of this agent on the growth of prostate cancer xenografts was also assessed in mice. RESULTS: H6CAHA demonstrated good solubility and permeability profiles and preferentially inhibited the growth of prostate cancer cells over nonmalignant cells. Plasma pharmacokinetics revealed that the area under the curve of H6CAHA was 8.08 +/- 0.91 MUM * h, and its half life was 11.17 +/- 0.87 h. Radiation clonogenic assays revealed that H6CAHA decreased the survival of prostate cancer cells at the dose that exerted limited effect on normal cells. Concomitantly, delayed DNA damage repair following combination treatment was evident in cancer cells, indicated by the prolonged appearance of gammaH2AX and Rad51 foci and suppression of DNA damage repair genes (ATM, BRCA1, and BRCA2). Combined modality of H6CAHA (daily intraperitoneal injections for 10 days) with gamma-radiation (10 * 2 Gy) completely blocked the growth of PC3 tumor xenografts (p < 0.001) over 60 days. CONCLUSION: These results support the potential therapeutic value of H6CAHA in combination with radiation and support the rationale for further clinical investigation. PMID- 21277100 TI - Effect of whole pelvic radiotherapy for patients with locally advanced prostate cancer treated with radiotherapy and long-term androgen deprivation therapy. AB - PURPOSE: To evaluate the effect of whole pelvic radiotherapy (WPRT) in prostate cancer patients treated with RT and long-term (>1 year) androgen deprivation therapy (ADT). METHODS AND MATERIALS: Prostate cancer patients with high-risk features (Stage T3-T4 and/or Gleason score>=7 and/or prostate-specific antigen level>=20 ng/mL) who had undergone RT and long-term ADT were included in the present analysis. Patients with bowel inflammatory disease, colon diverticula, and colon diverticulitis were excluded from WPRT and treated with prostate-only radiotherapy (PORT). Patients were grouped according to nodal risk involvement as assessed by the Roach formula using different cutoff levels (15%, 20%, 25%, and 30%). Biochemical disease-free survival (bDFS) was analyzed in each group according to the RT type (WPRT or PORT). RESULTS: A total of 358 patients treated between 1994 and 2007 were included in the analysis (46.9% with WPRT and 53.1% with PORT). The median duration of ADT was 24 months (range, 12-38). With a median follow-up of 52 months (range, 20-150), the overall 4-year bDFS rate was 90.5%. The 4-year bDFS rate was similar between the patients who had undergone WPRT or PORT (90.4% vs. 90.5%; p=NS). However, in the group of patients with the greatest nodal risk (>30%), a significant bDFS improvement was recorded for the patients who had undergone WPRT (p=.03). No differences were seen in acute toxicity among the patients treated with WPRT or PORT. The late gastrointestinal toxicity was similar in patients treated with PORT or WPRT (p=NS). CONCLUSIONS: Our analysis has supported the use of WPRT in association with long-term ADT for patients with high-risk nodal involvement (>30%), although a definitive recommendation should be confirmed by a randomized trial. PMID- 21277101 TI - Exclusive alternating chemotherapy and radiotherapy in nonmetastatic inflammatory breast cancer: 20 years of follow-up. AB - BACKGROUND: Locoregional treatment of inflammatory breast cancer (IBC) is crucial because local relapses may be highly symptomatic and are commonly associated with distant metastasis. With a median follow-up of 20 years, we report here the long term results of a monocentric clinical trial combining primary chemotherapy (CT) with a schedule of anthracycline-based CT and an alternating split-course of radiotherapy (RT*CT) without mastectomy. METHODS AND MATERIALS: From September 1983 to December 1989, 124 women with nonmetastatic IBC (T4d M0) were treated with three cycles of primary AVCMF chemotherapy (anthracycline, vincristine, cyclophosphamide, methotrexate, and 5-fluorouracil) and then an alternating RT*CT schedule followed by three cycles of FAC. Hormonal therapy was systematically administered: ovarian irradiation (12 Gy in four fractions) or tamoxifen 20 mg daily. RESULTS: Local control was achieved in 82% of patients. The 10- and 20 year local relapse rates were 26% and 33%, respectively, but only 10% of locally controlled cases were not associated with concurrent distant metastasis. The 10- and 20-year overall survival rates were 39% and 19%, respectively. Severe fibrosis occurred in 54% of patients, grade 3 brachial plexus neuropathy in 4%, grade 2 pneumonitis in 9%. Grade 1, 2 and 3 cardiac toxicity was observed in 3.8%, 3.8% and 1.2% of cases respectively. CONCLUSIONS: This combined regimen allowed good long-term local control without surgery. Survival rates were similar to those obtained with conventional regimens (primary chemotherapy, total mastectomy, and adjuvant radiotherapy). Since IBC continues to be an entity with a dismal prognosis, this approach, safely combining preoperative or postoperative radiation therapy and systemic treatments, should be reassessed when suitable targeted agents are available. PMID- 21277102 TI - Extreme-risk prostate adenocarcinoma presenting with prostate-specific antigen (PSA)>40 ng/ml: prognostic significance of the preradiation PSA nadir. AB - PURPOSE: To examine the impact of patient, disease, and treatment characteristics on survival outcomes in patients treated with neoadjuvant androgen deprivation therapy (ADT) and radical external-beam radiotherapy (RT) for clinically localized, extreme-risk prostate adenocarcinoma with a presenting prostate specific antigen (PSA) concentration of >40 ng/ml. METHODS AND MATERIALS: A retrospective chart review was conducted of 64 patients treated at a single institution between 1991 and 2000 with ADT and RT for prostate cancer with a presenting PSA level of >40 ng/ml. The effects of patient age, tumor (presenting PSA level, Gleason score, and T stage), and treatment (total ADT duration and pre RT PSA level) characteristics on rates of biochemical disease-free survival (bDFS), prostate cancer-specific survival (PCSS), and overall survival (OS) were examined. RESULTS: Median follow-up time was 6.45 years (range, 0.09-15.19 years). Actuarial bDFS, PCSS, and OS rates at 5 years were 39%, 87%, and 78%, respectively, and 17%, 64%, and 45%, respectively, at 10 years. On multivariate analysis, the pre-RT PSA level (<=0.1 versus >0.1 ng/ml) was the single most significant prognostic factor for bDFS (p=0.033) and OS (p=0.018) rates, whereas age, T stage, Gleason score, and ADT duration (<=6 versus >6 months) were not predictive of outcomes. CONCLUSION: In prostate cancer patients with high presenting PSA levels, >40 ng/ml, treated with combined modality, neoadjuvant ADT, and RT, the pre-RT PSA nadir, rather than ADT duration, was significantly associated with improved survival. This observation supports the use of neoadjuvant ADT to drive PSA levels to below 0.1 ng/ml before initiation of RT, to optimize outcomes for patients with extreme-risk disease. PMID- 21277103 TI - Outcomes of diffusion tensor tractography-integrated stereotactic radiosurgery. AB - PURPOSE: To analyze the effect of use of tractography of the critical brain white matter fibers created from diffusion tensor magnetic resonance imaging on reduction of morbidity associated with radiosurgery. METHODS AND MATERIALS: Tractography of the pyramidal tract has been integrated since February 2004 if lesions are adjacent to it, the optic radiation since May 2006, and the arcuate fasciculus since October 2007. By visually confirming the precise location of these fibers, the dose to these fiber tracts was optimized. One hundred forty four consecutive patients with cerebral arteriovenous malformations who underwent radiosurgery with this technique between February 2004 and December 2009 were analyzed. RESULTS: Tractography was prospectively integrated in 71 of 155 treatments for 144 patients. The pyramidal tract was visualized in 45, the optic radiation in 22, and the arcuate fasciculus in 13 (two tracts in 9). During the follow-up period of 3 to 72 months (median, 23 months) after the procedure, 1 patient showed permanent worsening of pre-existing dysesthesia, and another patient exhibited mild transient hemiparesis 12 months later but fully recovered after oral administration of corticosteroid agents. Two patients had transient speech disturbance before starting integration of the arcuate fasciculus tractography, but no patient thereafter. CONCLUSION: Integrating tractography helped prevent morbidity of radiosurgery in patients with brain arteriovenous malformations. PMID- 21277104 TI - Variation in the gross tumor volume and clinical target volume for preoperative radiotherapy of primary large high-grade soft tissue sarcoma of the extremity among RTOG sarcoma radiation oncologists. AB - PURPOSE: To evaluate variability in the definition of preoperative radiotherapy gross tumor volume (GTV) and clinical target volume (CTV) delineated by sarcoma radiation oncologists. METHODS AND MATERIALS: Extremity sarcoma planning CT images along with the corresponding diagnostic MRI from two patients were distributed to 10 Radiation Therapy Oncology Group sarcoma radiation oncologists with instructions to define GTV and CTV using standardized guidelines. The CT data with contours were then returned for central analysis. Contours representing statistically corrected 95% (V95) and 100% (V100) agreement were computed for each structure. RESULTS: For the GTV, the minimum, maximum, mean (SD) volumes (mL) were 674, 798, 752+/-35 for the lower extremity case and 383, 543, 447+/-46 for the upper extremity case. The volume (cc) of the union, V95 and V100 were 882, 761, and 752 for the lower, and 587, 461, and 455 for the upper extremity, respectively. The overall GTV agreement was judged to be almost perfect in both lower and upper extremity cases (kappa=0.9 [p<0.0001] and kappa=0.86 [p<0.0001]). For the CTV, the minimum, maximum, mean (SD) volumes (mL) were 1145, 1911, 1605+/ 211 for the lower extremity case and 637, 1246, 1006+/-180 for the upper extremity case. The volume (cc) of the union, V95, and V100 were 2094, 1609, and 1593 for the lower, and 1533, 1020, and 965 for the upper extremity cases, respectively. The overall CTV agreement was judged to be almost perfect in the lower extremity case (kappa=0.85 [p<0.0001]) but only substantial in the upper extremity case (kappa=0.77 [p<0.0001]). CONCLUSIONS: Almost perfect agreement existed in the GTV of these two representative cases. There was no significant disagreement in the CTV of the lower extremity, but variation in the CTV of upper extremity was seen, perhaps related to the positional differences between the planning CT and the diagnostic MRI. PMID- 21277105 TI - Stereotactic body radiotherapy for pulmonary metastases from soft-tissue sarcomas: excellent local lesion control and improved patient survival. AB - PURPOSE: Patients with pulmonary metastases (PM) from soft-tissue sarcomas (STS) have historically been treated with surgery and/or chemotherapy. Since 2001, we have treated PM with stereotactic body radiation therapy (SBRT). We postulated that SBRT for PM from STS would yield excellent local control (LC) and overall survival (OS). METHODS AND MATERIALS: Fifty-two patients with PM from STS, diagnosed between 1990 and 2006 at the University of Rochester, were retrospectively reviewed. Most patients received multimodality treatment comprising of surgery, chemotherapy, and/or radiation. SBRT used the Novalis ExacTrac patient positioning platform, vacuum bag immobilization, and relaxed end expiratory breath hold techniques. RESULTS: Leiomyosarcoma (23%), malignant fibrous histiocytoma (19%), and synovial sarcoma (15%) were the most common histologies. Forty-eight percent initially presented with PM, whereas 52% developed PM at a median of 0.7 (0.3-7.3) years after initial diagnosis. Median follow-up from diagnosis of PM was 0.9 (0.3-7.3) years. Fifteen patients underwent SBRT to 74 lesions. Median number of lesions treated was 4 (1-16) per patient and 3.5 (1-6) per session. Preferred dose and fractionation was 50 Gy in 5 Gy fractions. Three-year LC was 82%. No patients experienced Grade >= 3 toxicity. Median OS was 2.1 (0.8-11.5) years for patients treated with SBRT, and 0.6 (0.1-7.8) years for those who never received SBRT (p = 0.002). CONCLUSIONS: SBRT provides excellent LC of PM and may extend OS. SBRT should be considered for all patients with PM from STS, particularly those who are not surgical candidates. Further investigation is warranted to establish criteria for the use of SBRT for STS patients with PM. PMID- 21277106 TI - Patient preferences and physician practice patterns regarding breast radiotherapy. AB - PURPOSE: There are multiple current strategies for breast radiotherapy (RT). The alignment of physician practice patterns with best evidence and patient preferences will enhance patient autonomy and improve cancer care. However, there is little information describing patient preferences for breast RT and physician practice patterns. METHODS AND MATERIALS: Using a reliable and valid instrument, we assessed the preferences of 5,000 randomly selected women (with or without cancer) undergoing mammography. To assess practice patterns, 2,150 randomly selected physician-members of American Society for Radiation Oncology were surveyed. RESULTS: A total of 1,807 women (36%) and 363 physicians (17%) provided usable responses. The 95% confidence interval is < +/- 2.3% for patients and < +/ 5.3% for physicians. Patient preferences were hypofractionated whole breast irradiation (HF-WBI) 62%, partial breast irradiation (PBI) 28%, and conventionally fractionated whole breast irradiation (CF-WBI) 10%. By comparison, 82% of physicians use CF-WBI for more than 2/3 of women and 56% never use HF-WBI. With respect to PBI, 62% of women preferred three-dimensional (3D)-PBI and 38% favor brachytherapy-PBI, whereas 36% of physicians offer 3D-PBI and 66% offer brachytherapy-PBI. 70% of women prefer once-daily RT over 10 days vs. twice-daily RT over 5 days. 55% of physicians who use PBI do not offer PBI on clinical trial. CONCLUSIONS: HF-WBI, while preferred by patients and supported by evidence, falls behind the unproven and less preferred strategy of PBI in clinical practice. There is a discrepancy between women's preferences for PBI modality and type of PBI offered by physicians. Further alignment is needed between practice patterns, patient preferences, and clinical evidence. PMID- 21277107 TI - Antivascular endothelial growth factor bevacizumab for radiation optic neuropathy: secondary to plaque radiotherapy. AB - PURPOSE: To evaluate the intravitreal antivascular endothelial growth factor, bevacizumab, for treatment of radiation optic neuropathy (RON). METHODS AND MATERIALS: A prospective interventional clinical case series was performed of 14 patients with RON related to plaque radiotherapy for choroidal melanoma. The RON was characterized by optic disc edema, hemorrhages, microangiopathy, and neovascularization. The entry criteria included a subjective or objective loss of vision, coupled with findings of RON. The study subjects received a minimum of two initial injections of intravitreal bevacizumab (1.25 mg in 0.05 mL) every 6-8 weeks. The primary objectives included safety and tolerability. The secondary objectives included the efficacy as measured using the Early Treatment Diabetic Retinopathy Study chart for visual acuity, fundus photography, angiography, and optical coherence tomography/scanning laser ophthalmoscopy. RESULTS: Reductions in optic disc hemorrhage and edema were noted in all patients. The visual acuity was stable or improved in 9 (64%) of the 14 patients. Of the 5 patients who had lost vision, 2 had relatively large posterior tumors, 1 had had the vision decrease because of intraocular hemorrhage, and 1 had developed optic atrophy. The fifth patient who lost vision was noncompliant. No treatment-related ocular or systemic side effects were observed. CONCLUSIONS: Intravitreal antivascular endothelial growth factor bevacizumab was tolerated and generally associated with improved vision, reduced papillary hemorrhage, and resolution of optic disc edema. Persistent optic disc neovascularization and fluorescein angiographic leakage were invariably noted. The results of the present study support additional evaluation of antivascular endothelial growth factor medications as treatment of RON. PMID- 21277108 TI - Analysis of pretreatment FDG-PET SUV parameters in head-and-neck cancer: tumor SUVmean has superior prognostic value. AB - PURPOSE: To evaluate the prognostic significance of different descriptive parameters in head-and-neck cancer patients undergoing pretreatment [F-18] fluoro D-glucose-positron emission tomography (FDG-PET) imaging. PATIENTS AND METHODS: Head-and-neck cancer patients who underwent FDG-PET before a course of curative intent radiotherapy were retrospectively analyzed. FDG-PET imaging parameters included maximum (SUV(max)), and mean (SUV(mean)) standard uptake values, and total lesion glycolysis (TLG). Tumors and lymph nodes were defined on co registered axial computed tomography (CT) slices. SUV(max) and SUV(mean) were measured within these anatomic regions. The relationships between pretreatment SUV(max), SUV(mean), and TLG for the primary site and lymph nodes were assessed using a univariate analysis for disease-free survival (DFS), locoregional control (LRC), and distant metastasis-free survival (DMFS). Kaplan-Meier survival curves were generated and compared via the log-rank method. SUV data were analyzed as continuous variables. RESULTS: A total of 88 patients was assessed. Two-year OS, LRC, DMFS, and DFS for the entire cohort were 85%, 78%, 81%, and 70%, respectively. Median SUV(max) for the primary tumor and lymph nodes was 15.4 and 12.2, respectively. Median SUV(mean) for the primary tumor and lymph nodes was 7 and 5.2, respectively. Median TLG was 770. Increasing pretreatment SUV(mean) of the primary tumor was associated with decreased disease-free survival (p = 0.01). Neither SUV(max) in the primary tumor or lymph nodes nor TLG was prognostic for any of the clinical endpoints. Patients with pretreatment tumor SUV(mean) that exceeded the median value (7) of the cohort demonstrated inferior 2-year DFS relative to patients with SUV(mean) <= the median value of the cohort, 58% vs. 82%, respectively, p = 0.03. CONCLUSION: Increasing SUV(mean) in the primary tumor was associated with inferior DFS. Although not routinely reported, pretreatment SUV(mean) may be a useful prognostic FDG-PET parameter and should be further evaluated prospectively. PMID- 21277109 TI - Preclinical assessment of volumetric modulated arc therapy for total marrow irradiation. AB - PURPOSE: A preclinical investigation was undertaken to explore a treatment technique for total marrow irradiation using RapidArc, a volumetric modulated arc technique. MATERIALS AND METHODS: Computed tomography datasets of 5 patients were included. Plans with eight overlapping coaxial arcs were optimized for 6-MV photon beams. Dose prescription was 12 Gy in 2 Gy per fraction, normalized so that 100% isodose covered 85% of the planning target volume (PTV). The PTV consisted of the whole skeleton (including ribs and sternum), from the top of the skull to the medium distal third of the femurs. Planning objectives for organs at risk (OARs) were constrained to a median dose <6 to 7 Gy. OARs included brain, eyes, oral cavity, parotids, thyroid, lungs, heart, kidneys, liver, spleen, stomach, abdominal cavity, bladder, rectum, and genitals. Pretreatment quality assurance consisted of portal dosimetry comparisons, scoring the delivery to calculation agreement with the gamma agreement index. RESULTS: The median total body volume in the study was 57 liters (range, 49-81 liters), for an average diameter of 47 cm (range, 46-53 cm) and a total length ranging from 95 to 112 cm. The median PTV volume was 6.8 liters (range, 5.8-10.8 liters). The mean dose to PTV was 109% (range, 107-112%). The global mean of median dose to all OARs was 4.9 Gy (range, 4.5-5.1 Gy over the 5 patients). The individual mean of median doses per organ ranged from 2.3 Gy (oral cavity) to 7.3 Gy (bowels cavity). Preclinical quality assurance resulted in a mean gamma agreement index of 94.3 +/ 5.1%. The delivery time measured from quality assurance runs was 13 minutes. CONCLUSION: Sparing of normal tissues with adequate coverage of skeletal bones was shown to be feasible with RapidArc. Pretreatment quality assurance measurements confirmed the technical agreement between expected and actually delivered dose distributions, suggesting the possibility of incorporating this technique in the treatment options for patients. PMID- 21277110 TI - Radiation-induced middle ear and mastoid opacification in skull base tumors treated with radiotherapy. AB - PURPOSE: To assess the incidence of middle ear (ME) pathology in patients treated with radiotherapy (RT) for skull base tumors. METHODS AND MATERIALS: A retrospective analysis of 61 patients treated with RT between 2003 and 2008 for skull base tumors was conducted. Clinical outcomes and demographics were reviewed. Dose-volume histogram analysis was performed on the eustachian canal (EC), ME, mastoid air cells, vestibular apparatus, cochlea, internal auditory canal, lateral and posterior nasopharynx, and temporal lobes to relate doses to symptoms and radiographic change. Otomastoid opacification was rated 0 (none), 1 (mild), 2 (moderate), and 3 (severe) by a neuroradiologist blinded to clinical outcomes and doses. RESULTS: The median prescribed dose was 50.4 Gy (range, 14-74 Gy). The ME mean dose was 14 Gy and 34 Gy for Grade 0-1 and 2-3 opacification, respectively (p<0.0001). The mean mastoid dose was 10 Gy and 26 Gy for Grade 0-1 and 2-3, respectively (p<0.0001). The mean EC dose was 17 Gy and 32 Gy for Grade 0-1 and 2-3, respectively (p=0.0001). Otomastoid opacification resolved in 17 of 40 patients (42.5%), at a mean of 17 months after RT (range, 2-45 months). Otomastoid opacification persisted in 23 of 40 patients (57.5%), with a mean follow-up of 23 months (range, 2-55 months). Multivariate analysis showed that mastoid dose>30 Gy (odds ratio=28.0, p<0.001) and posterior nasopharynx dose of >30 Gy (odds ratio=4.9, p=0.009) were associated with Grade 2-3 effusions, whereas other factors including dose to EC and ME were not significant. CONCLUSIONS: A mean RT dose>30 Gy to the mastoid air cells or posterior nasopharynx is associated with increased risk of moderate to severe otomastoid opacification, which persisted in more than half of patients at 2-year follow-up. PMID- 21277111 TI - Dosimetric comparison of three-dimensional conformal proton radiotherapy, intensity-modulated proton therapy, and intensity-modulated radiotherapy for treatment of pediatric craniopharyngiomas. AB - PURPOSE: Cranial irradiation in pediatric patients is associated with serious long-term adverse effects. We sought to determine whether both three-dimensional conformal proton radiotherapy (3D-PRT) and intensity-modulated proton therapy (IMPT) compared with intensity-modulated radiotherapy (IMRT) decrease integral dose to brain areas known to harbor neuronal stem cells, major blood vessels, and other normal brain structures for pediatric patients with craniopharyngiomas. METHODS AND MATERIALS: IMRT, forward planned, passive scattering proton, and IMPT plans were generated and optimized for 10 pediatric patients. The dose was 50.4 Gy (or cobalt Gy equivalent) delivered in 28 fractions with the requirement for planning target volume (PTV) coverage of 95% or better. Integral dose data were calculated from differential dose-volume histograms. RESULTS: The PTV target coverage was adequate for all modalities. IMRT and IMPT yielded the most conformal plans in comparison to 3D-PRT. Compared with IMRT, 3D-PRT and IMPT plans had a relative reduction of integral dose to the hippocampus (3D-PRT, 20.4; IMPT, 51.3%*), dentate gyrus (27.3, 75.0%*), and subventricular zone (4.5, 57.8%*). Vascular organs at risk also had reduced integral dose with the use of proton therapy (anterior cerebral arteries, 33.3*, 100.0%*; middle cerebral arteries, 25.9%*, 100%*; anterior communicating arteries, 30.8*, 41.7%*; and carotid arteries, 51.5*, 77.6*). Relative reduction of integral dose to the infratentorial brain (190.7*, 109.7%*), supratentorial brain without PTV (9.6, 26.8%*), brainstem (45.6, 22.4%*), and whole brain without PTV (19.4*, 34.4%*) were recorded with the use of proton therapy. (*Differences were significant based on Friedman's test with Bonferroni-Dunn correction, alpha = 0.05) CONCLUSIONS: The current study found that proton therapy was able to avoid excess integral radiation dose to a variety of normal structures at all dose levels while maintaining equal target coverage. Future studies will examine the clinical benefits of these dosimetric advantages. PMID- 21277112 TI - Adjuvant radiotherapy after prostatectomy: does waiting for a detectable prostate specific antigen level make sense? PMID- 21277113 TI - Robotic image-guided stereotactic radiotherapy, for isolated recurrent primary, lymph node or metastatic prostate cancer. AB - PURPOSE: To evaluate the outcome of robotic CyberKnife (Accuray, Sunnyvale, CA) based stereotactic radiotherapy (CBK-SRT) for isolated recurrent primary, lymph node, or metastatic prostate cancer. METHODS AND MATERIALS: Between May 2007 and December 2009, 34 consecutive patients/38 lesions were treated (15 patients reirradiated for local recurrence [P], 4 patients reirradiated for anastomosis recurrence [A], 16 patients treated for single lymph node recurrence [LN], and 3 patients treated for single metastasis [M]). In all but 4 patients, [(11)C]choline positron emission tomography/computed tomography was performed. CBK-SRT consisted of reirradiation and first radiotherapy in 27 and 11 lesions, respectively. The median CBK-SRT dose was 30 Gy in 4.5 fractions (P, 30 Gy in 5 fractions; A, 30 Gy in 5 fractions; LN, 33 Gy in 3 fractions; and M, 36 Gy in 3 fractions). In 18 patients (21 lesions) androgen deprivation was added to CBK-SRT (median duration, 16.6 months). RESULTS: The median follow-up was 16.9 months. Acute toxicity included urinary events (3 Grade 1, 2 Grade 2, and 2 Grade 3 events) and rectal events (1 Grade 1 event). Late toxicity included urinary events (3 Grade 1, 2 Grade 2, and 2 Grade 3 events) and rectal events (1 Grade 1 event and 1 Grade 2 event). Biochemical response was observed in 32 of 38 evaluable lesions. Prostate-specific antigen stabilization was seen for 4 lesions, and in 2 cases prostate-specific antigen progression was reported. The 30-month progression-free survival rate was 42.6%. Disease progression was observed for 14 lesions (5, 2, 5, and 2 in Groups P, A, LN, and M respectively). In only 3 cases, in-field progression was seen. At the time of analysis (May 2010), 19 patients are alive with no evidence of disease and 15 are alive with disease. CONCLUSIONS: CyberKnife-based stereotactic radiotherapy is a feasible approach for isolated recurrent primary, lymph node, or metastatic prostate cancer, offering excellent in-field tumor control and a low toxicity profile. Further investigation is warranted to identify the patients who benefit most from this treatment modality. The optimal combination with androgen deprivation should also be defined. PMID- 21277114 TI - Surgery followed by radiotherapy versus radiotherapy alone for metastatic spinal cord compression from unfavorable tumors. AB - PURPOSE: Despite a previously published randomized trial, controversy exists regarding the benefit of adding surgery to radiotherapy for metastatic spinal cord compression (MSCC). It is thought that patients with MSCC from relatively radioresistant tumors or tumors associated with poor functional outcome after radiotherapy alone may benefit from surgery. This study focuses on these tumors. METHODS AND MATERIALS: Data from 67 patients receiving surgery plus radiotherapy (S+RT) were matched to 134 patients (1:2) receiving radiotherapy alone (RT). Groups were matched for 10 factors and compared for motor function, ambulatory status, local control, and survival. Additional separate matched-pair analyses were performed for patients receiving direct decompressive surgery plus stabilization of involved vertebrae (DDSS) and patients receiving laminectomy (LE). RESULTS: Improvement of motor function occurred in 22% of patients after S+RT and 16% after RT (p=0.25). Posttreatment ambulatory rates were 67% and 61%, respectively (p=0.68). Of nonambulatory patients, 29% and 19% (p=0.53) regained ambulatory status. One-year local control rates were 85% and 89% (p=0.87). One year survival rates were 38% and 24% (p=0.20). The matched-pair analysis of patients receiving LE showed no significant differences between both therapies. In the matched-pair analysis of patients receiving DDSS, improvement of motor function occurred more often after DDSS+RT than RT (28% vs. 19%, p=0.024). Posttreatment ambulatory rates were 86% and 67% (p=0.30); 45% and 18% of patients regained ambulatory status (p=0.29). CONCLUSIONS: Patients with MSCC from an unfavorable primary tumor appeared to benefit from DDSS but not LE when added to radiotherapy in terms of improved functional outcome. PMID- 21277115 TI - The need for physician leadership in creating a culture of safety. PMID- 21277116 TI - Out-of-field cell survival following exposure to intensity-modulated radiation fields. AB - PURPOSE: To determine the in-field and out-of-field cell survival of cells irradiated with either primary field or scattered radiation in the presence and absence of intercellular communication. METHODS AND MATERIALS: Cell survival was determined by clonogenic assay in human prostate cancer (DU145) and primary fibroblast (AGO1552) cells following exposure to different field configurations delivered using a 6-MV photon beam produced with a Varian linear accelerator. RESULTS: Nonuniform dose distributions were delivered using a multileaf collimator (MLC) in which half of the cell population was shielded. Clonogenic survival in the shielded region was significantly lower than that predicted from the linear quadratic model. In both cell lines, the out-of-field responses appeared to saturate at 40%-50% survival at a scattered dose of 0.70 Gy in DU-145 cells and 0.24 Gy in AGO1522 cells. There was an approximately eightfold difference in the initial slopes of the out-of-field response compared with the alpha-component of the uniform field response. In contrast, cells in the exposed part of the field showed increased survival. These observations were abrogated by direct physical inhibition of cellular communication and by the addition of the inducible nitric oxide synthase inhibitor aminoguanidine known to inhibit intercellular bystander effects. Additional studies showed the proportion of cells irradiated and dose delivered to the shielded and exposed regions of the field to impact on response. CONCLUSIONS: These data demonstrate out-of-field effects as important determinants of cell survival following exposure to modulated irradiation fields with cellular communication between differentially irradiated cell populations playing an important role. Validation of these observations in additional cell models may facilitate the refinement of existing radiobiological models and the observations considered important determinants of cell survival. PMID- 21277117 TI - Multi-institutional analysis of solitary extramedullary plasmacytoma of the head and neck treated with curative radiotherapy. AB - PURPOSE: The purpose of this study was to elucidate the efficacy and optimal method of radiotherapy in the management of solitary extramedullary plasmacytoma occurring in the head and neck regions (EMPHN). METHODS AND MATERIALS: Sixty seven patients (43 male and 24 female) diagnosed with EMPHN between 1983 and 2008 at 23 Japanese institutions were reviewed. The median patient age was 64 years (range, 12-83). The median dose administered was 50 Gy (range, 30-64 Gy). Survival data were calculated by the Kaplan-Meier method. RESULTS: The median follow-up duration was 63 months. Major tumor sites were nasal or paranasal cavities in 36 (54%) patients, oropharynx or nasopharynx in 16 (23%) patients, orbita in 6 (9%) patients, and larynx in 3 (5%) patients. The 5- and 10-year local control rates were 95% and 87%, whereas the 5- and 10-year disease-free survival rates were 56% and 54%, respectively. There were 5 (7.5%), 12 (18%), and 8 (12%) patients who experienced local failure, distant metastasis, and progression to multiple myeloma, respectively. In total, 18 patients died, including 10 (15%) patients who died due to complications from EMPHN. The 5- and 10-year overall survival (OS) rates were 73% and 56%, respectively. Radiotherapy combined with surgery was identified as the lone significant prognostic factor for OS (p = 0.04), whereas age, gender, radiation dose, tumor size, and chemotherapy were not predictive. No patient experienced any severe acute morbidity. CONCLUSIONS: Radiotherapy was quite effective and safe for patients with EMPHN. Radiotherapy combined with surgery produced a better outcome according to survival rates. These findings require confirmation by further studies with larger numbers of patients with EMPHN. PMID- 21277118 TI - Palliative radiotherapy for bone metastases: an ASTRO evidence-based guideline. AB - PURPOSE: To present guidance for patients and physicians regarding the use of radiotherapy in the treatment of bone metastases according to current published evidence and complemented by expert opinion. METHODS AND MATERIALS: A systematic search of the National Library of Medicine's PubMed database between 1998 and 2009 yielded 4,287 candidate original research articles potentially applicable to radiotherapy for bone metastases. A Task Force composed of all authors synthesized the published evidence and reached a consensus regarding the recommendations contained herein. RESULTS: The Task Force concluded that external beam radiotherapy continues to be the mainstay for the treatment of pain and/or prevention of the morbidity caused by bone metastases. Various fractionation schedules can provide significant palliation of symptoms and/or prevent the morbidity of bone metastases. The evidence for the safety and efficacy of repeat treatment to previously irradiated areas of peripheral bone metastases for pain was derived from both prospective studies and retrospective data, and it can be safe and effective. The use of stereotactic body radiotherapy holds theoretical promise in the treatment of new or recurrent spine lesions, although the Task Force recommended that its use be limited to highly selected patients and preferably within a prospective trial. Surgical decompression and postoperative radiotherapy is recommended for spinal cord compression or spinal instability in highly selected patients with sufficient performance status and life expectancy. The use of bisphosphonates, radionuclides, vertebroplasty, and kyphoplasty for the treatment or prevention of cancer-related symptoms does not obviate the need for external beam radiotherapy in appropriate patients. CONCLUSIONS: Radiotherapy is a successful and time efficient method by which to palliate pain and/or prevent the morbidity of bone metastases. This Guideline reviews the available data to define its proper use and provide consensus views concerning contemporary controversies or unanswered questions that warrant prospective trial evaluation. PMID- 21277119 TI - Alcohol and distraction interact to impair driving performance. AB - BACKGROUND: Recognition of the risks associated with alcohol intoxication and driver distraction has led to a wealth of simulated driving research aimed at studying the adverse effects of each of these factors. Research on driving has moved beyond the individual, separate examination of these factors to the examination of potential interactions between alcohol intoxication and driver distraction. In many driving situations, distractions are commonplace and might have little or no disruptive influence on primary driving functions. Yet, such distractions might become disruptive to a driver who is intoxicated. METHODS: The present study examined the interactive impairing effects of alcohol intoxication and driver distraction on simulated driving performance in 40 young adult drivers using a divided attention task as a distracter activity. The interactive influence of alcohol and distraction was tested by having drivers perform the driving task under four different conditions: 0.65 g/kg alcohol; 0.65 g/kg alcohol+divided attention; placebo; and placebo+divided attention. RESULTS: As hypothesized, divided attention had no impairing effect on driving performance in sober drivers. However, under alcohol, divided attention exacerbated the impairing effects of alcohol on driving precision. CONCLUSIONS: Alcohol and distraction continue to be appropriate targets for research into ways to reduce the rates of driving-related fatalities and injuries. Greater consideration of how alcohol and distraction interact to impair aspects of driving performance can further efforts to create prevention and intervention measures to protect drivers, particularly young adults. PMID- 21277120 TI - Drug use and sport--a commentary on: Injury, pain and prescription opioid use among former National Football League football players by Cottler et al. AB - The accompanying paper by Cottler et al. reports on findings from a telephone survey study that examined opioid analgesic use and misuse by U.S. professional football players. The study shows high rates of misuse of these medications, and provides an opportunity to consider the intersection between sports and drug use. While in recent years there has been increasing focus upon the use of performance enhancing drugs (e.g., steroids) in athletes, the present report provides valuable information about a relatively unexplored but important topic: opioid analgesic misuse by athletes. The data provided show that misuse of opioids in this population is cause for concern, suggest that study of other groups of athletes should be undertaken, and that further assessment of opioid use in football players is also needed. The study also provides an opportunity to conceptualize drug (and non-drug) use in athletes, as a means to either return athletic functioning to a previous level of performance, or to enhance functioning. Discussions of drug use in sports need to appreciate the complexity of such use, which can be indicated and appropriate under certain circumstances, but which can also be inappropriate and problematic under others-for example, for drugs such as opioid analgesics. PMID- 21277121 TI - Injury, pain, and prescription opioid use among former National Football League (NFL) players. AB - BACKGROUND: Athletes with injury-related pain, especially National Football League (NFL) players, are at increased risk for opioid use and misuse which may result in medical, psychiatric and social problems. This is the first study to evaluate the intersection of sports pain and opioid use and misuse among former NFL players. METHODS: A telephone survey of 644 retired NFL players from the 2009 Retired Players Association Directory was conducted (53.4% completion rate) from March to August 2010. RESULTS: Over half (52%) used opioids during their NFL career with 71% reporting misuse. Additionally, 15% of NFL misusers currently misused vs. 5% among players who used just as prescribed during their NFL career. Prevalence of current opioid use was 7%-3 times the rate of the general population. Multivariate analyses indicated that significant NFL pain increased the adjusted odds (AOR) of any current opioid use vs. non-use (AOR 6.76, 95%CI 2.88-15.87), as did moderate to severe mental impairment (AOR 1.88, 95%CI 1.19 2.98) and heavy drinking in the past week (AOR 2.15, 95%CI 1.17-3.98). Undiagnosed concussions singly predicted current misuse vs. use just as prescribed (AOR 4.25, 95%CI 1.12-16.22). Three variables predicted current misuse vs. non-use: significant pain (AOR 8.33, 95%CI 1.98-35.04), undiagnosed concussions (AOR 3.51, 95%CI 1.98-35.04) and heavy drinking (AOR 3.48, 95%CI 1.63 7.41). CONCLUSIONS: Players who misused during their NFL career were most likely to misuse currently compared to others. Current misuse was associated with more NFL pain, undiagnosed concussions and heavy drinking. Longitudinal studies are needed to determine the long term effects of opioid misuse among athletes. PMID- 21277122 TI - The multicenter Italian birth cohort study on incidence and determinants of lower respiratory tract infection hospitalization in infants at 33 weeks GA or more: preliminary results. AB - BACKGROUND: Respiratory syncytial virus (RSV) causes respiratory infections during the first year of life. Very premature infants have more severe diseases and also 'late preterm infants' may be more susceptible to the infection. AIM OF THE STUDY: To evaluate in an Italian cohort the incidence and risk factors of severe hospitalized lower respiratory tract infection (LRTI) induced or not by RSV during the first year of life. METHODS: A cohort of 33(+0d)-34(+6d) wGA newborns paired with two sex- and age-matched 35(+0d)-37(+6d) wGA and >= 38(+0d) wGA newborns were enrolled. Hospitalization for LRTI induced or not by RSV during the first year of life was assessed through phone interview at the end of the RSV season (November-March) and at the completion of the first year of life. The parents were asked to report hospitalization for any reason. RESULTS: 1064 neonates were enrolled (November 2009-October 2010), 697 had at least one phone follow-up by September 2010. Babies of 33(+0d)-34(+6d) wGA were more frequently conceived through assisted fertilization technologies, born from cesarean delivery had more frequently acute perinatal risk factors and were more frequently twins. After a mean 6 month-follow-up, we registered 29 hospitalizations for LRTI induced or not by RSV. Hospitalizations were slightly and non-significantly more frequent in 33(+0d)-37(+6d) wGA infants. The risk of hospitalization was significantly 60% reduced in breastfed babies and four folds significantly increased during the RSV season. CONCLUSION: The very preliminary data of this ongoing study suggest that in 'late-preterm' infants some individual/environmental characteristics of the infants play a relevant role in determining the risk of severe RSV infection. PMID- 21277123 TI - Aromatase inhibitor-induced arthralgia: is vitamin D deficiency responsible? PMID- 21277124 TI - DNA barcoding as a tool for species identification in three forensic wildlife cases in South Africa. AB - Poaching of wildlife animals for subsistence and commercial purposes has lead to population declines in Africa. In forensic cases, a need exists to identify the species of origin of carcasses, meat or blood. In the study presented here, the mitochondrial COI gene was sequenced to determine the species of unknown samples in three suspect South African forensic wildlife cases. In two cases the unknown samples were identified as originating from domestic cattle (Bos taurus) and in the third case the sample was identified as common reedbuck (Redunca arundinum). This is the first report of the COI sequence of common reedbuck. The study highlights the need for accurate wildlife reference material from each country in order to convict wildlife cases. PMID- 21277125 TI - Carcass mass can influence rate of decomposition and release of ninhydrin reactive nitrogen into gravesoil. AB - To investigate the use of ninhydrin-reactive nitrogen (NRN) in gravesoil to estimate early postmortem interval (PMI), we conducted an experiment to decompose swine (Sus scrofa) carcasses of contrasting mass (~1 kg, ~20 kg, ~40 kg, ~50 kg). Carcasses were placed on the soil surface during June 2007 to monitor mass loss and the concentration of gravesoil NRN over an interval of 15 days. Carcasses of a mass <= 20 kg decomposed more rapidly than larger carcasses. However, 1 kg carcasses were associated with a slower release of NRN into gravesoil but a greater concentration of NRN per kg carcass (NRN(C)). We conclude that carcass mass can affect the rate of decomposition and release of NRN into gravesoil, which reflects an interaction between carcass volume and blow fly colonization. Furthermore, we conclude that neonatal carcasses require a different equation than larger carcasses when using gravesoil chemistry to estimate PMI. PMID- 21277126 TI - Is POSSUM predictive of morbidity and mortality in laryngectomy patients? AB - OBJECTIVES: To test the validity of the comparative audit tool of POSSUM (Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity) against a cohort of 92 consecutive laryngectomies at a major tertiary referral centre for head and neck cancer. The major outcome measurements were 30 day mortality rates, formation of a pharyngo-cutaneous fistula, and length of hospital stay. METHODS: By means of a prospective and retrospective case note analysis. RESULTS: No significant difference between the mean POSSUM morbidity scores of those patients who did, or did not develop a fistula, was found (p=0.535, 95% C.I. -4.36 to 8.33). No significant correlation was observed between POSSUM predicted morbidity and bed occupancy [r=0.137 (95% C.I. -0.070 to 0.334)]. The Portsmouth POSSUM equation for mortality however did accurately predict the mortality rate (observed to expected ratio of 1.05). CONCLUSION: The authors propose that whilst there are many similar factors linked to mortality between cohorts of general surgical and head and neck patients, there are several highly specific risk factors in open surgery of the upper aero-digestive tract in the head and neck which are linked with wound breakdown and morbidity which are omitted from the POSSUM scoring system. The authors warn against the use of this comparative audit tool in its current state for such surgical procedures and recommend the creation of a specific POSSUM for head and neck cancer surgery. PMID- 21277127 TI - Prenatal and lactational exposure to low-doses of bisphenol A alters adult mice behavior. AB - Bisphenol A (BPA) is an endocrine-disrupting chemical, widely used in dentistry and various industries. We previously reported that BPA affected murine neocortical development by accelerating neuronal differentiation/migration, resulting in abnormal neocortical architecture as well as aberrant thalamocortical connections in the brains of adult mice. The aim of this study was to investigate whether prenatal and lactational BPA exposure affected behavior in adult mice. Pregnant mice were injected subcutaneously with 20MUg/kg of BPA daily from embryonic day 0 (E0) until postnatal day 21 (P21). Control animals received a vehicle alone. Behavioral tests (n=15-20) were conducted at postnatal 3weeks (P3W) and P10-15W. After an open-field test, an elevated plus maze and Morris water maze tests were performed. The total distance in the elevated plus maze test at P3W and in the open-field test at P10W was significantly decreased in the BPA-exposed group, compared with the control group. Significant sex differences were observed in the time spent in the central area in the open-field test at P3W and in the total distance in the elevated plus maze test at P11W. These results indicated that prenatal and lactational BPA exposure disturbed the murine behavior in the postnatal development period and the adult mice. PMID- 21277128 TI - Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation in the first Polish patient. AB - Leukoencephalopathy with brain stem and spinal cord involvement and elevated white matter lactate (LBSL) is a very rare autosomal recessive mitochondrial disorder. Clinically patients have slowly progressive ataxia, pyramidal syndrome and dorsal column dysfunction. The disease is defined on the basis of characteristic abnormalities observed on magnetic resonance imaging such as inhomogeneous, spotty involvement of the cerebral white matter, selective involvement of brain stem and spinal cord tracts as well as lactate elevation in the affected white matter on spectroscopy. We present the first identified Polish patient suffering from LBSL confirmed molecularly. PMID- 21277129 TI - Thermolabile CPT II variants and low blood ATP levels are closely related to severity of acute encephalopathy in Japanese children. AB - Despite the decrease in Reye syndrome after the discontinuation of aspirin, acute encephalopathy (non-Reye syndrome type) has been continually reported in Japan. Recent studies suggested that the thermolabile phenotype of carnitine palmitoyltransferase II (CPT II) variation [F352C] was closely related to the pathomechanism of influenza-associated encephalopathy (IAE) in Japanese, causing mitochondrial ATP utilization failure during periods of high fever, resulting in brain edema. So, we analyzed CPT II polymorphism and peripheral blood ATP levels as a signal of "energy crisis" in 12 and 10 patients with acute encephalopathy, respectively. Out of the 12 patients with acute encephalopathy, six showed thermolabile CPT II variants [F352C], and of these six, two patients died in spite of intensive care. In contrast, the remaining six patients with no thermolabile CPT II variant [F352C] showed a relatively mild clinical course. Blood ATP levels of the 10 patients in the acute phase of encephalopathy were significantly lower than those during the convalescent phase and also those of patients with febrile seizure status. Our data suggest that the thermolabile F352C CPT II variant, found only in Japanese, might be one of the predisposing factors to trigger the pathomechanism of acute encephalopathy in the Japanese population, and that it is causally related to the severity of disease. The decreased blood ATP level seems to reflect systemic mitochondrial dysfunction including the blood brain barrier during the acute phase of encephalopathy. PMID- 21277130 TI - Spontaneous development of pseudo-aneurysm of common iliac artery revealing Behcet's disease. PMID- 21277131 TI - [Clusters of respiratory tract infections and alert strategy in nursing homes]. AB - OBJECTIVE: Outbreaks of acute respiratory infections (ARI) are common in institutions for elderly people. We had for objective to investigate clusters of cases (lower respiratory tract infection and influenza-like illness [LRTI/ILI]) in order to improve and validate alert strategies in these institutions. METHODOLOGY: Prospective surveillance for LRTI/ILI was implemented in 11 institutions in Alsace, over five years. Clinical criteria were used to identify infected residents and clusters. Nasopharyngeal swabs were collected and rapid tests (Immunoassay) were performed to identify the influenza virus. RESULTS: The three week periods were analyzed if three cases or more were recorded during the first week. This analysis demonstrated an important risk of epidemic when this number of cases was reached in healthcare units. The influenza virus (10 clusters) and respiratory syncytial virus ([RSV], two clusters) were identified. CONCLUSION: The authors confirmed and emphasized the importance of adequate surveillance for clusters of respiratory tract infection cases. Early identification of an outbreak (three cases) is an important point to prevent transmission, especially during epidemic periods and if a virus is identified in the unit or institution. PMID- 21277132 TI - Cost-effectiveness of substituting dual-energy CT for SPECT in the assessment of myocardial perfusion for the workup of coronary artery disease. AB - PURPOSE: We compared cost-effectiveness and potential lifetime benefits of using dual-energy computed tomography (DECT) for myocardial perfusion assessment instead of single photon emission computed tomography (SPECT) for the workup of coronary artery disease (CAD). MATERIALS AND METHODS: A decision and simulation model was developed to estimate cost and health effects of using DECT myocardial perfusion imaging instead of SPECT for identifying patients in need of invasive imaging and possible revascularization. The model was based on the performance indices of stress/rest DECT compared with stress/rest SPECT for detecting myocardial perfusion deficits in 50 patients (mean age 61+/-10 years) with CAD. Stress/rest perfusion and delayed enhancement cardiac MRI served as reference standard. For DECT a reimbursement of US$1700 was assumed but costs of cardiac MRI were not included in the model. All other actual healthcare costs in these patients were derived from MUSC's hospital billing system. RESULTS: Compared with cardiac MRI, DECT (versus SPECT) had 90% (85%) sensitivity and 71% (58%) specificity for identifying patients with obstructive CAD. Compared with the no imaging and no treatment strategy, routine SPECT gained 13.49 quality-adjusted life-years (QALYs) with an incremental cost-effectiveness ratio (ICER) of US$3557 (in 2010) per QALY. In comparison, DECT ICER was lower (US$3.191 per QALY, p=0.0002) and an additional 0.64 QALYs was obtained (total of 14.13 QALYs) if compared with the SPECT strategy as well as the no imaging and no treatment strategy. CONCLUSION: Using DECT as the first-line imaging test for myocardial perfusion for the workup of patients with CAD has the potential to provide gains in QALYs, while lowering costs if compared to routine myocardial perfusion SPECT. PMID- 21277133 TI - Correlative analysis of metabolite profiling of Danggui Buxue Tang in rat biological fluids by rapid resolution LC-TOF/MS. AB - In this work, the metabolite profiles of Danggui Buxue Tang (DBT) in rat bile and plasma were qualitatively described, and the possible metabolic pathways of DBT were subsequently proposed. Emphasis was put on correlative analysis of metabolite profiling in different biological fluids. After oral administration of DBT, bile and plasma samples were collected and pretreated by solid phase extraction. Rapid resolution liquid chromatography coupled to time-of-flight mass spectrometry (RRLC-TOFMS) was used for characterization of DBT-related compounds (parent compounds and metabolites) in biological matrices. A total of 142 metabolites were detected and tentatively identified from the drug-containing bile and plasma samples. Metabolite profiling shows that rat bile contained relatively more glutathione-derived conjugates, more saponins compounds and more diverse forms of metabolites than urine. The metabolite profile in plasma revealed that glucuronide conjugates of isoflavonoids, dimmers, acetylcysteine conjugates and parent form of phthalides, as well as saponin aglycones were the major circulating forms of DBT. Collectively, the metabolite profile analysis of DBT in different biological matrices provided a comprehensive understanding of the in vivo metabolic fates of constituents in DBT. PMID- 21277134 TI - Analysis of lawsuits filed against emergency physicians for point-of-care emergency ultrasound examination performance and interpretation over a 20-year period. AB - OBJECTIVE: The study aims to define extent of lawsuits filed against emergency physicians (EPs) over point-of-care emergency ultrasound (US) during the last 20 years. METHODS: We performed a nationwide search of the WESTLAW legal database for filed lawsuits involving EPs and US. WESTLAW covers all state and federal lawsuits dating back to 1939. Using an electronic search feature, all states were searched using emergency and US as key words. The database automatically accounts for different variants on US such as sonography. An attorney who is also boarded in and practices emergency medicine, as well as an emergency US expert, reviewed returned cases. Descriptive statistics were used to evaluate the data. RESULTS: Using the search criteria and excluding obvious radiology suits, 659 cases were returned and reviewed. There were no cases of EPs being sued for performance or interpretation of point-of-care US. There was one case alleging EP failure to perform point-of-care US and diagnose an ectopic before it ruptured. This case was won by the defense. There were no cases against EPs for common causes of radiology and obstetric litigation including sexual assault during endovaginal US. Cases of missed testicular torsion on US were frequent in the emergency setting but none linked EP US. CONCLUSIONS: Only one case filed against EPs over the last 2 decades was identified, it was over failure to perform US. Most frequent litigations against radiologists and obstetricians are unlikely to be duplicated in the emergency department, and future litigations may also come from EP failure to perform point-of-care US. PMID- 21277135 TI - A primary cardiac sarcoma presenting with superior vena cava obstruction. AB - Superior vena cava (SVC) obstruction leads to a constellation of symptoms and signs that encompass the SVC syndrome. Today, malignancy accounts for 65% of all cases. The most common neoplastic causes are non-small cell lung cancer (50%), small cell lung cancer (25%), lymphoma, and metastasis. Primary cardiac tumors are an extremely rare cause of SVC obstruction. We describe the case of a 48-year old man who presented with dyspnea, confusion, and facial swelling with cyanosis. The patient developed life-threatening airway obstruction after administration of anxiolytic. The diagnosis of SVC obstruction secondary to a primary cardiac sarcoma was established based on clinical, radiologic, and post-mortem findings. This is one of very few reported cases of a primary cardiac sarcoma causing SVC obstruction. PMID- 21277136 TI - A 61-year-old man with cough and abnormal chest x-ray. PMID- 21277137 TI - Hiccups as the only symptom of non-ST-segment elevation myocardial infarction. AB - Hiccups, which are usually benign and self-limited, occasionally serve as markers of a serious underlying pathology. We present this case report to inform emergency physicians about the potential for hiccups to serve as the only presenting symptom of a myocardial infarction. The patient, a 68-year-old man with a history of diabetes mellitus, hypertension, and current tobacco use, was first seen in the emergency department after 4 days of intractable hiccups with no other complaints or symptoms. After ineffective hiccup treatment on the first visit with 2 mg Ativan and 25 intramuscular (i.m.) thorazine and a normal chest x ray, he was discharged. Two days later, the patient returned to the emergency department with the same complaint of hiccups without any additional complaints or symptoms. An electrocardiogram displayed several abnormalities including Q waves in II, III, and aVF and T-wave inversions in aVL and V6. Troponin I was highly elevated at 4.302 ng/mL. In the catheterization laboratory, the patient exhibited severe stenosis of the left circumflex artery and obtuse marginal 1. Stents were placed in these sites, and the patient recovered uneventfully. This is the first case in which hiccups were the single presenting symptom of a myocardial infarction in the last 50 years. Although extremely common and usually benign, hiccups can occasionally be a sole symptom of serious underlying pathology, which in this case, was a non-ST-segment elevation myocardial infarction. PMID- 21277138 TI - Practice patterns and management strategies for purulent skin and soft-tissue infections in an urban academic ED. AB - BACKGROUND: Community-acquired methicillin-resistant Staphylococcus aureus (MRSA) is the most common cause of purulent skin and soft-tissue infections (SSTIs) in the Unites States. Little is known regarding health care provider management strategies for abscesses in the emergency department (ED). Understanding variability in practice patterns could be an important step in implementing evidence-based guidelines. OBJECTIVES: The objectives of this study are to describe practice patterns for purulent SSTI in a single, urban, academic ED, including antibiotic selection and incision and drainage (I & D) technique, and to compare these practices with current evidence. METHODS: Prospective data were collected on a convenience sample of adults presenting to our urban, academic ED (annual volume, 65 000 per year) between June 2009 and May 2010. Characteristics of patients and their providers were collected as well as specific management strategies including use of irrigation, packing, and antibiotics. RESULTS: One hundred forty-five patients were enrolled. Most SSTIs were single (80.4% abscesses), most commonly on the extremities (29.8%). Both I & D and antibiotics were used 79.9% of the time, with the largest predictor for the addition of antibiotics being erythema more than 2 cm (odds ratio, 4.52; 95% confidence interval, 1.39-14.7); I & D technique varied by provider-type and experience. Providers suspected MRSA in 75% of cases, despite only 48% demonstrating MRSA on culture. Many patients received antimicrobials after I & D, even in those with 2 cm or less abscesses (57.5%). CONCLUSIONS: Practice patterns vary significantly, especially antibiotic overuse, at least in this urban academic ED. Further study should be undertaken to evaluate factors that influence management strategies for SSTI. PMID- 21277139 TI - Early embolization without external fixation in pelvic trauma. AB - PURPOSES: In this retrospective study, we reviewed our protocol consisting of early embolization without acute external fixation in patients with pelvic fracture. PATIENTS AND METHODS: Eighty-eight patients with pelvic fracture were identified by reviewing the records of the Fukui Prefectural Hospital from April 2005 through September 2009. We managed the patients with a treatment protocol consisting of hemodynamic resuscitation and early pelvic embolization. Patients with hemodynamic instability without nonpelvic hemorrhage or extravasation of contrast in the pelvis by computed tomography (CT) were indicated to angiography and embolization. External fixation of the pelvic ring was not used in our protocol. RESULTS: Of the 88 patients with pelvic fractures, 43 underwent angiography. Twenty-eight patients (65%) were hemodynamically unstable. Twenty five patients (58%) had major ligamentous disruption. Computed tomography detected extravasation in 21 patients (48%). Of the 43 patients who underwent angiography, 29 (67%) were positive. The average time from hospital arrival to angiography was 76.3 +/- 34.5 minutes. The packed red blood cell requirement in the initial 24 hours was 8.4 +/- 8.2 U, required in the embolization group. There was no complication-related embolization. Repeat angiography was not required in all patients. The mortality rate of patients requiring angiography was 11%. CONCLUSIONS: Early pelvic embolization without external fixation may be useful for the initial treatment for patients with hemodynamic instability without nonpelvic hemorrhage or with extravasation of contrast in the pelvis by CT. PMID- 21277140 TI - Can mainstream end-tidal carbon dioxide measurement accurately predict the arterial carbon dioxide level of patients with acute dyspnea in ED. AB - OBJECTIVE: This study was designed to determine whether the mainstream end-tidal carbon dioxide (ETCO2) measurement can accurately predict the partial arterial carbon dioxide (Paco2) level of patients presented to emergency department (ED) with acute dyspnea. METHODS: This prospective, observational study was conducted at a university hospital ED, which serves more than 110 000 patients annually. Nonintubated adult patients presented with acute dyspnea who required arterial blood gas analysis were recruited in the study for a 6-month period between January and July 2010. Patients were asked to breathe through an airway adapter attached to the mainstream capnometer. Arterial blood gas samples were obtained simultaneously. RESULTS: We included 162 patients during the study period. The mean ETCO2 level was 39.47 +/- 10.84 mm Hg (minimum, 19 mm Hg; maximum, 82 mm Hg), and mean Paco2 level was 38.95 +/- 12.27 mm Hg (minimum, 16 mm Hg; maximum, 94 mm Hg). There was a positive, strong, statistically significant correlation between ETCO2 and Paco2 (r = 0.911, P < .001). The Bland-Altman plot shows the mean bias +/- SD between ETCO2 and Paco2 as 0.5 +/- 5 mm Hg (95% confidence interval, -1.3165-0.2680) and the limits of agreement as -10.5 and +9.5 mm Hg. Eighty percent (n = 129) of the ETCO2 measurements were between the range of +/-5 mm Hg. CONCLUSION: Mainstream ETCO2 measurement accurately predicts the arterial Paco2 of patients presented to ED with acute dyspnea. Further studies comparing mainstream and sidestream methods in these patients are required. PMID- 21277141 TI - Computed tomography angiography in patients with suspected pulmonary embolism-too often considered? AB - BACKGROUND: Pulmonary embolism (PE) is a major cause of morbidity and mortality associated with surgery and medical illnesses. In recent years, pulmonary computed tomography angiography (CTA) has become the diagnostic method of choice. However, it remains unclear when to perform CTA and how often a decision based on clinical judgment results in positive or negative findings. METHODS: In a retrospective study, 261 patients admitted for suspected PE were evaluated with pulmonary CTA. Decisions to order CTA were based on clinical judgment and optionally quantitative d-dimer assays. Clinical, radiologic, and laboratory data were revisited and compared in patients with and without proven PE. RESULTS: The patients' mean age was 63 +/- 1 years; almost 30% of all participants had at least a moderately reduced renal function. Pulmonary CTA demonstrated PE in only 14.9%; both age and sex distribution was comparable in the PE and non-PE group. Proximal deep vein thrombosis or pathologic chest x-rays were significantly more likely in patients with PE (P < .001 and P < .05), whereas echocardiography results were comparable. d-dimer values were noticeably higher in the PE group (P < .001); however, C-reactive protein and troponin T levels were not helpful. CONCLUSIONS: Pulmonary CTA confirmed PE in only a minority of patients and may be overused. Clinical judgment in conjunction with d-dimer evaluation was of limited help to predict positive results but surprisingly comparable with previous results using pretest probability scoring systems. Using present and previous data, a simplified enhanced algorithm is proposed to reduce use of CTA. PMID- 21277142 TI - Defining metabolic acidosis in patients with septic shock using Stewart approach. AB - PURPOSE: The aim of this study was to define the nature of metabolic acidosis in patients with septic shock on admission to intensive care unit (ICU) using Stewart method. We also aimed to compare the ability of standard base excess (SBE), anion gap (AG), and corrected AG for albumin and lactate (AGcorr) to accurately predict the presence of unmeasured anions (UA). PATIENTS AND METHODS: Thirty consecutive patients with septic shock were prospectively included on ICU admission. Stewart equations modified by Figge were used to calculate the strong ion difference and the strong ion gap (SIG). RESULTS: Most patients had multiple underlying mechanisms explaining the metabolic acidosis. Unmeasured anions and hyperchloremia were present in 70% of the patients. Increased UA were present in 23% of patients with normal values of SBE and [HCO3-]. In these patients, plasma [Cl-] was significantly lower compared with patients with low SBE and increased UA (103 [102-106.6] vs 108 [106-111] mmol/L; P=.01, respectively). Corrected AG for albumin and lactate had the best correlation with SIG (r2=0.94; P<.0001) with good agreement (bias, 0, and precision, 1.22) and highest area under the receiver operating characteristic curve (0.995; 95% confidence interval, 0.87-1) to discriminate SIG acidosis. CONCLUSIONS: Patients with septic shock exhibit a complex metabolic acidosis at ICU admission. High UA may be present with normal values of SBE and [HCO3-] as a result of associated "relative" hypochloremic alkalosis. Corrected AG for albumin and lactate offers the most accurate bedside alternative to Stewart calculation of UA. PMID- 21277143 TI - A comparison of different diagnostic tests in the bedside evaluation of pleuritic pain in the ED. AB - PURPOSES: Bedside lung ultrasound (LUS) is useful in detecting radio-occult pleural-pulmonary lesions. The aim of our study is to compare the value of LUS with other conventional routine diagnostic tools in the emergency department (ED) evaluation of patients with pleuritic pain and silent chest radiography (CXR). METHODS: Ninety patients consecutively admitted to the ED with pleuritic pain and normal CXR were retrospectively (n = 49) and prospectively (n = 41) studied. All patients were blindly examined by LUS and submitted to clinical examination and blood samples. The ability of blood tests and symptoms to predict any radio occult pleural-pulmonary condition confirmed by conclusive image techniques and follow-up was evaluated and compared with LUS. RESULTS: In 57 cases, the final diagnosis was chest wall pain. The other 33 patients were diagnosed with a pleural-pulmonary condition (22 pneumonia, 2 pleuritis, 7 pulmonary embolism, 1 lung cancer, 1 pneumothorax). Lung ultrasound showed a sensitivity of 96.97% (95% confidence interval [CI], 84.68%-99.46%) and a specificity of 96.49% (95% CI, 88.08%-99.03%) in predicting radio-occult pleural-pulmonary lesions and significantly higher area under the curve (AUC) of receiver operating characteristic analysis (AUC, 0.967; 95% CI, 0.929-1.00) than d-dimer (AUC, 0.815; 95% CI, 0.720-0.911) and white blood cell count (AUC, 0.778; 95% CI, 0.678 0.858). None of the other routine tests considered or a combination between them better predicted the final diagnosis. CONCLUSIONS: Chest radiography and blood tests may be inadequate in the diagnostic process of pleuritic pain. In case of silent CXR, LUS is critical for identifying patients with pleural-pulmonary radio occult conditions at bedside and cannot be safely replaced by other conventional methods. PMID- 21277144 TI - A budget impact analysis of rapid human immunodeficiency virus screening in Veterans Administration emergency departments. AB - BACKGROUND: Human immunodeficiency virus (HIV) screening is cost-effective and recommended in populations with low disease prevalence. However, because screening is not cost-saving, its financial feasibility must be understood. STUDY OBJECTIVES: We forecast the costs of two Emergency Department-based HIV testing programs in the Veterans Administration: 1) implementing a non-targeted screening program and providing treatment for all patients thusly identified (Rapid Testing); and 2) treating patients identified due to late-stage symptoms (Usual Care); to determine which program was the most financially feasible. METHODS: Using a dynamic decision-analysis model, we estimated the financial impact of each program over a 7-year period. Costs were driven by patient disease-severity at diagnosis, measured by CD4+ category, and the proportion of patients in each disease-severity category. Cost per CD4+ category was modeled from chart review and database analysis of treatment-naive HIV-positive patients. Distributions of CD4+ counts differed in patients across the Rapid Testing and Usual Care arms. RESULTS: A non-targeted Rapid Testing program was not significantly more costly than Usual Care. Although Rapid Testing had substantial screening costs, they were offset by lower inpatient expenses associated with earlier identification of disease. Assuming an HIV prevalence of 1% and 80% test acceptance, the cost of Rapid Testing was $1,418,088, vs. $1,320,338 for Usual Care (p=0.5854). Results support implementation of non-targeted rapid HIV screening in integrated systems. CONCLUSIONS: This analysis adds a new component of support for HIV screening by demonstrating that rapid, non-targeted testing does not cost significantly more than a diagnostic testing approach. PMID- 21277145 TI - Incidental finding of splenic artery aneurysm on lumbosacral spine radiograph. PMID- 21277146 TI - Transaction logfile analysis in health communication research: challenges and opportunities. AB - OBJECTIVE: To investigate the individualized nature of eHealth communication, it is necessary for us to go beyond the conventional approach to explain the effect of eHealth initiatives. The current article proposes transaction logfile analysis as a unique method to probe the process by which individuals locate needed information and obtains benefits out of it. METHODS: This article discusses the background of logfile analysis along with practical and methodological issues related to the analysis of log data. RESULTS: This article recommends potential solutions to resolve issues discussed in the Section 2. CONCLUSIONS: This article discusses how transaction logfile analysis could benefit eHealth researchers, along with its relevance and application in health communication research. Logfile analysis could provide rich knowledge on how eHealth applications and tools work if performed on a regular basis, incorporated with appropriate measurement techniques and research design, and interpreted carefully. PRACTICE IMPLICATIONS: Logfile analysis can point toward important design implications for more effective eHealth applications. Further, interventions employing logfile analysis require not only well-designed research models but also interdisciplinary research team to handle the multifaceted work involved in the process. PMID- 21277147 TI - Percutaneous endovenous treatment of congenital extratruncular venous malformations with an ultrasound-guided and 810-nm diode laser. AB - BACKGROUND: Venous malformations (VMs) are the commonest vascular anomalies. Treatment of extratruncular venous malformations (EVMs) is difficult. Surgery has been the mainstay therapy for EVMs but can be hazardous, leading to major blood loss and incomplete resection. Recurrence and cosmetic problems are also common after resection. Endovenous laser ablation (EVLA) has been found to be safe and effective for endovenous ablation of incompetent saphenous veins. We report our experience of diode laser ablation in percutaneous ultrasound (US)-guided treatment of congenital EVMs with respect to effectiveness and safety. METHODS: A consecutive series of patients (16 males and 22 females; age, 13-46 years) were treated by US-guided EVLA for EVMs at our institution. A questionnaire was used to assess preoperative and postoperative symptoms. Effectiveness was assessed by procedural success and clinical success. Subjective improvement of symptoms was further assessed simultaneously with objective evidence of improved clinical signs. This included reduction of lesion size, general swelling, or improved range of motion of the joint. Duplex US imaging was used to assess blood flow within lesions. Safety was assessed by morbidity and mortality, including laser related adverse events, postoperative deep vein thrombosis, pulmonary embolism, and hematoma. RESULTS: All patients tolerated the procedure and recovered uneventfully. Fifty-six procedures were undertaken in 38 patients. All procedures were successful. Thirty-three patients had resolution of presenting pain symptoms after laser treatment; the remaining patients were able to significantly reduce the number of pain medications from that used before treatment. For complaints related to swelling and cosmetic effect, clinical success was 70% and 67%, respectively. No patients returned with recurrent symptoms after initial successful treatment at a mean follow-up of 12.7 months. Thirty-six (64%) treated lesions areas were classified as "excellent," 18 (32%) were "good," and 2 (4%) were "fair" using duplex US imaging at final follow-up. Better results were obtained with localized types of VMs, in which palliation was achieved after only one treatment. Complications were minor and improved quickly. CONCLUSIONS: Treatment of congenital EVMs with endovenous laser ablation under US guidance achieved palliation in most symptomatic patients; it was safe, with minimal morbidity during short-term follow-up. PMID- 21277148 TI - The impact of superficial femoral artery (SFA) occlusion on the outcome of proximal sartorius muscle transposition flaps in vascular surgery patients. AB - OBJECTIVES: To demonstrate the feasibility and safety of proximal sartorius muscle rotational flaps in patients with peripheral occlusive artery disease. METHODS: Retrospective analysis of 53 patients with 56 proximal sartorius muscle flaps. Indication for a flap procedure was postoperative calcitrant lymphorrhea in nine, graft at risk in 13, and graft infection in 34 procedures. Pre- and postoperative patencies of the superficial femoral artery (SFA) and profundal femoral artery (PFA) were documented. Flap viability, wound healing, and limb salvage were examined at follow-up. RESULTS: In 59% of the procedures in this series, the SFA was occluded. The PFA was patent in all patients. Flap viability (100% vs 94%), rate of new (4% vs 6%), and recurrent infections (9% vs 6%), loss of vascular reconstruction rate (9% vs 9%), and limb salvage rate (100% vs 88%) did not differ significantly between the SFA patent and the SFA occluded group. There were four new infections (7%) and three recurrent infections (5.5%) during follow-up, five of which led to a loss of reconstruction. In four of those five patients, the sartorius flap was viable. Two patients died during the immediate postoperative period from septic multi-organ failure (3%). At a median follow-up of 6.4 months, 54 flaps were viable and wound closure was achieved in all surviving 51 patients. Limb salvage rate was 93%. CONCLUSIONS: Biologic protection procedures as local muscle flaps are vital adjuncts to vascular surgery techniques in the treatment of complicated wounds in the groin. Occlusion of the SFA in the presence of a patent PFA is not associated with an increased risk of flap loss in proximal sartorius muscle rotational flaps. PMID- 21277149 TI - Matrix metalloproteinases modulated by protein kinase Cepsilon mediate resistin induced migration of human coronary artery smooth muscle cells. AB - BACKGROUND: Emerging evidence showed that resistin induces vascular smooth muscle cell (VSMC) migration, a critical step in initiating vascular restenosis. Adhesion molecule expression and cytoskeletal rearrangement have been observed in this progress. Given that matrix metalloproteinases (MMPs) also regulate cell migration, we hypothesized that MMPs may mediate resistin-induced VSMC migration. METHODS: Human VSMCs were treated with recombinant human resistin at physiologic (10 ng/mL) and pathologic (40 ng/mL) concentrations for 24 hours. Cell migration was determined by the Boyden chamber assay. MMP and tissue inhibitor metalloproteinase (TIMP) mRNA and protein levels were measured with real-time PCR and ELISA. MMP enzymatic activity was measured by zymography. In another experiment, neutralizing antibodies against MMP-2 and MMP-9 were coincubated with resistin in cultured VSMCs. The regulation of MMP by protein kinase C (PKC) was determined by epsilonV1-2, a selective PKCepsilon inhibitor. RESULTS: Resistin induced smooth muscle cell (SMC) migration was confirmed by the Boyden chamber assay. Forty nanograms/milliliter resistin increased SMC migration by 3.7 fold. Additionally, resistin stimulated MMP-2 and -MMP9 mRNA and protein expressions. In contrast, the TIMP-1 and TIMP-2 mRNA levels were inhibited by resistin. Neutralizing antibodies against MMP-2 and MMP-9 effectively reversed VSMC migration. Furthermore, resistin activated PKCepsilon, but selective PKCepsilon inhibitor suppressed resistin-induced MMP expression, activity, and cell migration. CONCLUSIONS: Our study confirmed that resistin increased vascular smooth muscle cell migration in vitro. In terms of mechanism, resistin-stimulated cell migration was associated with increased MMP expression, which was dependent on PKCepsilon activation. PMID- 21277150 TI - Hybrid open-endovascular repair of a contained suprarenal mycotic aneurysm using femoral vein. AB - Mycotic aneurysms have a high mortality rate, predominantly driven by sepsis. We present a 61-year-old patient who was treated with a hybrid open-endovascular repair using autologous femoral vein as a single channel revascularization. This provided a practical and innovative approach to a high-risk situation. PMID- 21277151 TI - R1 resection for aggressive or advanced colorectal liver metastases is justified in combination with effective prehepatectomy chemotherapy. AB - AIMS: Here we reassess anticipated inability to obtain a microscopically clear surgical margin as an absolute contraindication to surgery for colorectal liver metastases in view of improvements in treatment modalities adjunctive to surgery. METHODS: We retrospectively analysed 310 patients treated at our institution to estimate the survival benefit from R1 hepatectomy performed to remove liver metastases from colorectal cancer. RESULTS: Considering all 310 patients evaluated, the R1 resection group (positive margin; n = 55) showed a lower disease-free rate (P < 0.01) and worse overall survival (P < 0.01) than the R0 resection group (negative margin; n = 255). When patients were divided according to initial resectability, similar differences in disease-free rate and overall survival (P = 0.03) between R1 (n = 19) and R0 (n = 182) were observed in patients whose metastases were resectable. However, superior impact of R0 resection (n = 73) compared to R1 resection (n = 36) on disease-free rate (P = 0.44) and overall survival (P = 0.50) was not confirmed in patients with initially unresectable or marginally resectable metastases, especially those with a favourable response to prehepatectomy chemotherapy. CONCLUSIONS: A predicted positive surgical margin after resection no longer should be an absolute contraindication to surgery for aggressive or advanced liver metastases. PMID- 21277152 TI - [Puerperal uterine inversion: a case report]. PMID- 21277153 TI - [Burn resulting from use of a forced air-warming device outside of the manufacturer guidelines]. PMID- 21277154 TI - [Severe bronchospasm using Diprivan(r) in a patient allergic to peanut and birch]. AB - Diprivan(r) is composed of propofol, refined soybean oil and purified egg phosphatide. One must eliminate any allergy to one of its components before use. We report the story of a child who underwent nevus surgery under general anesthesia which was associated with an hypersensitivity reaction. In fact, this child had asthma and allergy to peanuts, raising the problem of cross allergy between birch, peanut, soy and Diprivan(r). PMID- 21277155 TI - [Inhaled methadone-induced non cardiogenic pulmonary edema with Acute Respiratory Distress Syndrome]. PMID- 21277156 TI - [Anorexia nervosa by proxy: An unusual case]. PMID- 21277157 TI - "Revision hip arthroplasty with a short femoral component in fractured hydroxyapatite fully coated femoral stem". PMID- 21277159 TI - Patient vs provider characteristics impacting hospital lengths of stay after total knee or hip arthroplasty. AB - This study aims to identify whether patient-level or provider-level characteristics are most influential on a patient's length of stay in the acute care hospital. A data set containing a nationally representative sample of inpatient discharge abstracts was used. Multilevel linear regression models were used to evaluate the associations between patient-level and provider-level characteristics on patients' lengths of stay. The target population included 322,894 discharges with a primary procedure code for primary total knee arthroplasty and 193,553 discharges for total hip arthroplasty. The variables associated with the greatest increases in length of stay were a higher comorbidity level among patient level attributes (+17.4%) and low surgeon volume among provider-level characteristics (+18.8%). Provider-level characteristics, particularly provider volume, had a greater impact on length of stay. PMID- 21277160 TI - The natural history of anterior knee pain in 2 posterior-stabilized, modular total knee arthroplasty designs. AB - Anterior knee pain (AKP) has been a persistent complaint after total knee arthroplasty; however, the natural course of this complaint has not been fully investigated. This is a 10-year follow-up report of a prospective, randomized study between the Insall-Burstein II (Zimmer, Warsaw, IN) and the Press Fit Condylar Modular (Johnson & Johnson, Raynham, MA) knees. Up to one third of total knee arthroplasties will experience mild to moderate AKP at 1-year follow-up, which will persist in approximately 30% of these previously symptomatic knees at 10-year follow-up. New-onset AKP will develop in approximately 10% of previously asymptomatic knees. PMID- 21277161 TI - Effect of body mass index on range of motion and manipulation after total knee arthroplasty. AB - This study evaluates the effects of increased body mass index (BMI) on postoperative range of motion (ROM) and rate of manipulation under anesthesia (MUA) after total knee arthroplasty (TKA) in 391 primary TKAs. Range of motion and incidence of MUA were retrospectively collected and compared between 4 BMI groups (I, BMI <25; II, BMI 25-29.9; III, BMI 30-34.9; IV, BMI >35) using chi(2) or Fisher exact tests. Patients with higher BMIs had a greater incidence of MUA (I, 9.7%; II, 19%; III, 20%; IV, 15%) and lower preoperative and postoperative ROM. Women had lower ROM and a higher rate of MUA. Age was not a significant predictor of ROM or rate of MUA. Patients at greater risk of complications after TKA should be counseled about realistic surgical outcomes. PMID- 21277162 TI - Receptive field optimisation and supervision of a fuzzy spiking neural network. AB - This paper presents a supervised training algorithm that implements fuzzy reasoning on a spiking neural network. Neuron selectivity is facilitated using receptive fields that enable individual neurons to be responsive to certain spike train firing rates and behave in a similar manner as fuzzy membership functions. The connectivity of the hidden and output layers in the fuzzy spiking neural network (FSNN) is representative of a fuzzy rule base. Fuzzy C-Means clustering is utilised to produce clusters that represent the antecedent part of the fuzzy rule base that aid classification of the feature data. Suitable cluster widths are determined using two strategies; subjective thresholding and evolutionary thresholding respectively. The former technique typically results in compact solutions in terms of the number of neurons, and is shown to be particularly suited to small data sets. In the latter technique a pool of cluster candidates is generated using Fuzzy C-Means clustering and then a genetic algorithm is employed to select the most suitable clusters and to specify cluster widths. In both scenarios, the network is supervised but learning only occurs locally as in the biological case. The advantages and disadvantages of the network topology for the Fisher Iris and Wisconsin Breast Cancer benchmark classification tasks are demonstrated and directions of current and future work are discussed. PMID- 21277163 TI - Global almost sure self-synchronization of Hopfield neural networks with randomly switching connections. AB - In this paper, we discuss Hopfield neural networks with stochastic switching weights, investigating their global almost sure self-synchronization. Sufficient conditions ensuring global almost sure exponential synchronization of Hopfield neural networks with stochastic switching weights are given. PMID- 21277164 TI - Impulsive hybrid discrete-time Hopfield neural networks with delays and multistability analysis. AB - In this paper we investigate multistability of discrete-time Hopfield-type neural networks with distributed delays and impulses, by using Lyapunov functionals, stability theory and control by impulses. Example and simulation results are given to illustrate the effectiveness of the results. PMID- 21277165 TI - Distributed representation of tone frequency in highly decodable spatio-temporal activity in the auditory cortex. AB - Although the place code of tone frequency, or tonotopic map, has been widely accepted in the auditory cortex, tone-evoked activation becomes less frequency specific at moderate or high sound pressure levels. This implies that sound frequency is not represented by a simple place code but that the information is distributed spatio-temporally irrespective of the focal activation. In this study, using a decoding-based analysis, we investigated multi-unit activities in the auditory cortices of anesthetized rats to elucidate how a tone frequency is represented in the spatio-temporal neural pattern. We attempted sequential dimensionality reduction (SDR), a specific implementation of recursive feature elimination (RFE) with support vector machine (SVM), to identify the optimal spatio-temporal window patterns for decoding test frequency. SDR selected approximately a quarter of the windows, and SDR-identified window patterns led to significantly better decoding than spatial patterns, in which temporal structures were eliminated, or high-spike-rate patterns, in which windows with high spike rates were selectively extracted. Thus, the test frequency is also encoded in temporal as well as spatial structures of neural activities and low-spike-rate windows. Yet, SDR recruited more high-spike-rate windows than low-spike-rate windows, resulting in a highly dispersive pattern that probably offers an advantage of discrimination ability. Further investigation of SVM weights suggested that low-spike-rate windows play significant roles in fine frequency differentiation. These findings support the hypothesis that the auditory cortex adopts a distributed code in tone frequency representation, in which high- and low-spike-rate activities play mutually complementary roles. PMID- 21277166 TI - The emotive impact of orthopedic words. AB - Research has shown that effective communication skills are paramount for delivering efficient and quality health care. More recently, research has started to show that in addition to how the medical information is delivered, the words used by health care providers are important factors in how patients cope with illness and their reports of pain intensity and disability. In this article, we discuss the emotional impact of words used by hand specialists, the impact of the nomenclature chosen to describe orthopedic diagnosis and procedures, and provide recommendations consistent with evidence-based practice. PMID- 21277167 TI - Clinicopathological features and proliferation markers in tongue squamous cell carcinomas. AB - The aim of this study was to evaluate the clinicopathological features and immunohistochemical expression of proliferation markers in oral tongue squamous cell carcinomas (OTSCC). Sixty-three patients without previous treatment or distant metastases were selected. Clinical information was retrieved from medical charts, histopathological analysis was performed and expression of proliferation markers (Ki-67, Mcm-2 and geminin) was evaluated. Most patients were men (81%) (male:female ratio 4.25:1). The age range was 31-92 years (mean 57.6 +/- 11.81 years). A high Anneroth score was associated with tumour size (p=0.05), tumoural embolization of the blood vessels (p=0.003), nodal metastasis (p=0.05), nodal capsule rupture (p=0.016) and distant metastasis (p=0.002). Elevated Bryne scores were significantly associated with nodal capsule rupture (p=0.02), distant metastasis (p=0.002), shorter overall survival (OS) (p=0.03) and disease-free survival (DFS) (p=0.05) compared with patients with lower score. Elevated Ki-67+ cells (p=0.05) and Mcm-2+ cells (p=0.008) were associated with nodal metastasis and tumours with a high geminin score demonstrated a significant tendency for neural invasion (p=0.05). Anneroth and Bryne score in association with biomarkers of proliferation can be useful for evaluating the biological behaviour of OTSCC. PMID- 21277168 TI - The acute and chronic effects of the novel anticonvulsant lacosamide in an experimental model of status epilepticus. AB - The effective management of status epilepticus (SE) continues to be a therapeutic challenge. The aim of this study was to investigate the efficacy of lacosamide treatment in an experimental model of self-sustaining SE. Rats were treated with lacosamide (3, 10, 30 or 50mg/kg) either 10 min (early treatment) or 40 min (late treatment) after the initiation of perforant path stimulation. Early lacosamide treatment significantly and dose-dependently reduced acute SE seizure activity; late treatment showed only a non-significant trend toward reduced seizure activity. Early lacosamide treatment also dose-dependently reduced the number of spontaneous recurrent seizures following a 6-week waiting period, with 70% reduction at the highest dose tested (50mg/kg); there was also a significant reduction in the number of spikes and the cumulative time spent in seizures. Late treatment with high-dose lacosamide (30-50mg/kg) reduced the number of animals that developed spontaneous recurrent seizures (33% vs 100% in controls, P<.05), but did not significantly reduce seizure severity or frequency in rats that developed spontaneous recurrent seizures. The results presented here suggest that lacosamide deserves investigation for the clinical treatment of SE. Potential for disease modification in this rat model of self-sustaining SE will require further studies. PMID- 21277169 TI - Antiepileptic drugs modulate P-glycoproteins in the brain: a mice study with (11)C-desmethylloperamide. AB - P-glycoprotein transporters (P-gp) located at the blood-brain barrier (BBB) are likely to play a role in refractory epilepsy. In vitro studies already pointed out that several antiepileptic drugs (AEDs) are substrate of P-gp. This study proposes a new in vivo approach to investigate the interaction between some AEDs and P-gp located at the BBB. (11)C-desmethylloperamide ((11)C-dLop), a radiolabelled substrate of P-gp, was intravenously administrated after pretreatment with saline or AEDs (sodium valproate, levetiracetam, topiramate and phenytoin) at their human therapeutic and four times their therapeutic dose. The effect of the different pretreatment on the intracerebral concentration of (11)C dLop was determined to indirectly investigate possible in vivo interactions between AEDs and P-gp. Pretreatment with levetiracetam, topiramate and phenytoin at therapeutic doses significantly decreased intracerebral concentration of (11)C dLop. Pretreatment with a therapeutic dose of sodium valproate did not influence brain uptake of (11)C-dLop. In case of pretreatment with supratherapeutic doses of AED, (11)C-dLop brain uptake was not different compared to pretreatment with saline. The metabolisation rate of (11)C-dLop in plasma was unaltered, indicating that observed differences in brain uptake of the tracer were not due to pharmacokinetic changes. The following conclusion can be made: levetiracetam, topiramate and phenytoin demonstrate biphasic modulation of the BBB P-gp. At therapeutic doses they act as inducers of efflux, at supratherapeutic doses they have no effect on the efflux rate. Sodium valproate does not interact with P-gp at therapeutic nor at higher doses. PMID- 21277170 TI - Female Wistar rats obtained from different breeders vary in anxiety-like behavior and epileptogenesis. AB - Outbred rats are widely used in biomedical research studies. The genotypic variation, different housing and handling conditions during development, and gender of used rats can be expected to cause variations in behavior and epileptogenesis. We tested the hypothesis that adult female Wistar rats from different breeders vary in anxiety-like behavior, seizure susceptibility, and epileptogenesis in the kindling model of temporal lobe epilepsy. In female Wistar rats from three different commercial breeders ([HsdCpb:WU], [Crl:WI(Han)], and [RjHan:WI]), anxiety-like behavior was monitored in the open field and the elevated plus maze. Wistar rats from Charles River showed lower locomotor activity and higher anxiety-like behavior compared to Wistar rats from Harlan Winkelmann and Janvier. Female Wistar rats from Harlan-Winkelmann showed the lowest anxiety-like behavior and the highest exploratory behavior. Subsequently, rats were kindled by daily electrical stimulation of the right amygdala as a model of temporal lobe epilepsy. Wistar rats from Charles River exhibited significantly increased cumulative motor seizure duration and cumulative afterdischarge duration until seizure generalization compared to Harlan Winkelmann and Janvier rats. In other words, Wistar rats from Charles River showed a longer time of focal seizures until generalization, reflecting a slower epileptogenesis in these rats. The initial afterdischarge threshold did not differ significantly between Wistar rats from the three breeders, indicating that baseline seizure susceptibility is not different between the three groups. In conclusion, female Wistar outbred rats from different breeders showed variations in anxiety-like behavior and epileptogenesis. Decisions about appropriate commercial colonies used for biomedical research should be taken with caution. PMID- 21277171 TI - Reduced prefrontal functional connectivity in the default mode network is related to greater psychopathology in subjects with high genetic loading for schizophrenia. AB - OBJECTIVE: Neuroimaging studies in subjects at genetic high risk (GHR) of schizophrenia can provide clues to the causes for the development of schizophrenia. Little is known about genetic influence on functional connectivity status, although studies on schizophrenia have reported an abnormal default mode network (DMN). We sought to identify putative genetic vulnerability markers by examining whether aberrant DMN connectivity was present in GHR subjects with high genetic loading. METHOD: Sixteen GHR subjects who had at least two relatives with schizophrenia and 16 age- and sex-matched controls were included and scanned using resting-state functional magnetic resonance imaging. A posterior cingulate cortex (PCC) seed region connectivity analysis was used to identify the DMN. Correlations between severity of psychopathology, level of genetic loading and DMN connectivity were calculated. RESULTS: The DMN network in GHR subjects showed reduced functional connectivity in the prefrontal areas, PCC, and precuneus. In addition, this reduced connectivity in the prefrontal cortices correlated with total and general scores on the Positive and Negative Syndrome Scale. GHR subjects having two first-degree relatives with schizophrenia showed a trend toward greater reduction in DMN connectivity in the precuneus and anterior cingulate cortex. CONCLUSION: This study suggests significant abnormalities in the DMN of subjects at GHR of schizophrenia. Alterations of DMN connectivity in the prefrontal cortex may reflect psychopathologies such as an inability to allocate resources properly between internal thoughts and external stimuli. Dysfunction of the anterior cingulate cortex and precuneus might be related to genetic risk for schizophrenia. PMID- 21277172 TI - Post-traumatic reactions to psychosis in people with multiple psychotic episodes. AB - Psychotic symptoms, coercive interventions, and other negative treatment experiences have been found to lead to posttraumatic stress disorder (PTSD) symptoms. However, prior research has not examined the importance of the DSM-IV A1 (perception of threat) and A2 (negative emotion at time of event) criteria for a traumatic event due to a psychotic episode. To address this question, 50 clients with a history of multiple episodes of psychosis were interviewed to identify distressing experiences related to past episodes, with PTSD assessed (including A1/A2 criteria) related to those events, and other psychiatric symptoms, psychosocial functioning, and coping style. Participants reported intense distress related to psychotic symptoms (66%), treatment experiences (25%), and their combination (8%), with 69% meeting symptom criteria for PTSD (excluding A1/A2 criteria), and 31% meeting full diagnostic criteria for PTSD (including A1/A2 criteria). Clients meeting symptom criteria for PTSD, as well as those meeting full diagnostic criteria for PTSD were similar, with both groups reporting more severe symptoms and distress, and more problems in daily functioning, than clients with fewer or no PTSD symptoms. The results are similar to a previous study of PTSD in persons with recent onset of psychosis (Mueser et al., 2010), and suggest that individuals with PTSD symptoms related to psychosis and coercive treatment may benefit from interventions designed to help them integrate their experiences into their lives and reduce PTSD symptoms, regardless of whether the triggering event(s) meet DSM-IV A1/A2 criteria for a traumatic event. PMID- 21277173 TI - The neurotensin-1 receptor agonist PD149163 inhibits conditioned avoidance responding without producing catalepsy in rats. AB - Agonists for neurotensin (NT)-1 receptors have produced antipsychotic-like effects in many animals, including reversal of prepulse inhibition deficits and psychostimulant-induced increases in spontaneous activity. The present study sought to provide a basic assessment of the putative antipsychotic effects of PD149163 in rats using a two way conditioned avoidance response task, which is highly validated for screening antipsychotic drugs, and an inclined grid assessment, which is used to assess extrapyramidal side effect liability. PD149163 (0.0625-8.0 mg/kg) significantly suppressed conditioned avoidance responding (CAR) following administration of a 1.0 or 8.0 mg/kg dose. PD149163 failed to significantly increase catalepsy scores. The typical antipsychotic drug haloperidol (0.01-1.0 mg/kg) significantly suppressed CAR at a 0.1, 0.3, and 1.0 mg/kg dose, and a significant increase in catalepsy scores was found at the 1.0 mg/kg dose. The atypical antipsychotic drug clozapine (2.5-10.0 mg/kg) also produced a significant inhibition of CAR, which occurred following administration of a 10.0 mg/kg dose. Clozapine failed to significantly increase catalepsy scores. Finally, D-amphetamine (1.0 mg/kg), serving as a negative control, failed to suppress CAR or increase catalepsy scores. These data further suggest that PD149163 may have atypical antipsychotic-like properties. PMID- 21277174 TI - Roles of BDNF, dopamine D(3) receptors, and their interactions in the expression of morphine-induced context-specific locomotor sensitization. AB - Drug seeking, craving, and relapse can be triggered by environmental stimuli that acquire motivational salience through repeated associations with the drug's effects. Previous studies indicated that the dopamine D(3) receptor (Drd3) might be involved in the expression of drug-conditioned responses in rats, and brain derived neurotrophic factor (BDNF) could modulate Drd3 expression in the nucleus accumbens (NAc). However, the involvement of neural regions with Drd3 activation and the underlying interaction between BDNF and Drd3 in the expression of behavioral responses controlled by a drug-associated environment have remained poorly understood. The present study used a conditioning procedure to assess the roles of BDNF, Drd3, and their interactions in the NAc in the expression of morphine-induced context-specific locomotor sensitization. We showed that the expression of locomotor sensitization in the morphine-paired environment was accompanied by significantly increased expression of Drd3 mRNA and BDNF mRNA and protein levels. Both sensitized locomotion in morphine-paired rats and enhanced Drd3 mRNA were suppressed by intra-NAc infusion of anti-tyrosine kinase receptor B (TrkB) IgG. Furthermore, intra-NAc infusion of the Drd3-selective antagonist SB 277011A significantly decreased the expression of context-specific locomotor sensitization and upregulated BDNF mRNA. Altogether, these results suggest that BDNF/TrkB signaling and activation of Drd3 in the NAc are required for the expression of morphine-induced context-specific locomotor sensitization. PMID- 21277176 TI - [Much ado about nothing]. PMID- 21277175 TI - Human plasma protein adsorption onto dextranized surfaces: a two-dimensional electrophoresis and mass spectrometry study. AB - Protein adsorption is fundamental to thrombosis and to the design of biocompatible materials. We report a two-dimensional electrophoresis and mass spectrometry study to characterize multiple human plasma proteins adsorbed onto four different types of model surfaces: silicon oxide, dextranized silicon, polyurethane and dextranized polyurethane. Dextran was grafted onto the surfaces of silicon and polyurethane to mimic the blood-contacting endothelial cell glycocalyx surface. Surface topography and hydrophobicity/hydrophilicity were determined and analyzed using atomic force microscopy and water contact angle measurements, respectively. Using two-dimensional electrophoresis, we show that, relative to the unmodified surfaces, dextranization significantly inhibits the adsorption of several human plasma proteins including IGHG1 protein, fibrinogen, haptoglobin, Apo A-IV, Apo A-I, immunoglobulin, serum retinal-binding protein and truncated serum albumin. We further demonstrate the selectivity of plasma protein adsorbed onto the different functionalized surfaces and the potential to control and manipulate proteins adsorption on the surfaces of medical devices, implants and microfluidic devices. This result shows that adsorption experiments using a single protein or a binary mixture of proteins are consistent with competitive protein adsorption studies. In summary, these studies indicate that coating blood contacting biomedical applications with dextran is an effective route to reduce thrombo-inflammatory responses and to surface-direct biological activities. PMID- 21277177 TI - Quantification of direct current in electrically active implants using MRI methods. AB - The aim of this study was to evaluate a variety of phase- and magnitude-based MRI methods at 1.5 T and 3 T regarding their sensitivity and accuracy with respect to the quantification of electrical direct current via the induced magnetic field inhomogeneity. For this, a phantom was constructed which was specially designed to reduce RF effects and which provided a one-dimensional electrical direct current in a thin copper conductor perpendicular to the static magnetic field of the scanner. The current was varied between 4 mA and 472 mA. The analysis of FLASH phase images as well as trueFISP and MAGSUS images revealed that the accuracy of the MR current measurement depended on the method and the field strength: the mean of the absolute deviations of the measured current values from the adjusted current values varied between 9% and 21%. The phase measurement with a FLASH sequence was found to be more sensitive than the trueFISP and MAGSUS measurements. In FLASH magnitude images as well as in images of spin echo sequences with on- and off-resonant frequency selective saturation pulses the extension of the artifact increased with the electrical current. MRI methods for the quantification of electrical direct current might e.g. play a role in functional testing of electrically active devices in the human body in terms of measuring the present current. One-dimensional electrical direct current in a thin, straight conductor could also be applied to the visualization of instruments in interventional MRI procedures. Currents below 100 mA would be sufficient to create distinct artifacts, at least under simplified conditions (homogeneous background etc.). PMID- 21277178 TI - Associations of physical activity and fitness with adipocytokines in adolescents: the AFINOS Study. AB - BACKGROUND AND AIMS: Adipocytokines may have a key role in the development of atherosclerosis and type 2 diabetes. The purpose of this study was to examine the independent and joint associations of physical activity (PA), cardiorespiratory fitness (CRF) and muscular fitness (MF) with adiponectin and leptin in adolescents. METHODS AND RESULTS: A sample of 198 adolescents (96 girls), aged 13 17-year, was selected. Participants completed anthropometric measurements (height, weight, and waist circumference) and percentage of body fat (%BF) was estimated by bioelectrical impedance. PA was measured by accelerometer for 7-day. The 20-m shuttle-run test was used to assess CRF and two MF tests (handgrip strength and standing broad jump) were used to create an MF score. A cluster score of health status (0-3 risks) was created. Serum adiponectin and plasma leptin were also determined. Regression analyses controlling for age, sex, pubertal status and waist circumference showed that PA was not significantly associated with adiponectin and vigorous PA showed a significant inverse association with leptin. Both CRF and MF were significantly and inversely associated with adiponectin and leptin. Further analyses revealed that the 'healthy' group (0 risks) had significantly lower adiponectin and leptin than 'medium-healthy' (1 risk) and 'unhealthy' (2-3 risks) status groups. CONCLUSIONS: PA, CRF and MF are inversely and jointly associated with adiponectin and leptin concentrations in adolescents. PMID- 21277179 TI - Purine-rich foods, protein intake, and the prevalence of hyperuricemia: the Shanghai Men's Health Study. AB - BACKGROUND AND AIMS: Diet may play an important role in the development of hyperuricemia and gout. However, the association between dietary factors and hyperuricemia remains unclear, and few studies have investigated direct links between food intake and hyperuricemia. The aim of this study was to investigate associations between high purine-content foods and protein intake with the prevalence of hyperuricemia by using data from a cross-sectional study of 3978 men aged 40-74 yrs living in Shanghai, China. METHODS AND RESULTS: Hyperuricemia was defined as blood uric acid level >7.0 mg/dl. One quarter of this population had hyperuricemia. Dietary information was collected by using a food frequency questionnaire. We collected information on anthropometric measurements and lifestyle factors and other potential confounding factors and disease history via interviews. Total protein consumption was not associated with hyperuricemia. We found a positive association between protein from animal sources and prevalence of hyperuricemia and an inverse association between protein from plant sources and hyperuricemia. However, these associations failed to reach significance in mutually adjusted analysis. Seafood intake was associated with higher prevalence of hyperuricemia. The ORs for quintiles of seafood intake (including fish and shellfish) were 1.00, 1.49, 1.35, 1.34, and 1.56 (p for trend: 0.01). An inverse association approaching significance between soy food consumption and hyperuricemia was observed (ORs: 1.00, 0.90, 0.70, 0.89, and 0.77 for quintiles of intake; p for trend: 0.07). No associations between consumption of purine-rich vegetables or meat and prevalence of hyperuricemia were observed. CONCLUSIONS: Our data suggest a direct association between seafood consumption and hyperuricemia and an inverse association between consumption of soy food and hyperuricemia among middle-aged, Chinese men. PMID- 21277180 TI - Se bioavailability and glutathione peroxidase activity in iron deficient rats. AB - Little information is available on the relationship of Se deposit in target organs and GPx activity in iron deficiency anemia. As red blood cells (RBCs) play a crucial role on Se metabolism and during Fe deficiency anemia a lower count of RBCs is featured, we aimed to investigate the influence of this pathology on Se bioavailability and the relationship with antioxidant status. 20 male Wistar rats were randomly divided into two groups, a control group receiving AIN-93G diet with normal Fe content (45mg/kg diet) and the Fe-deficient group receiving AIN 93G diet with low Fe content (5mg/kg diet) for 40 days. Both diets were prepared with an adequate Se content (0.180mg/kg diet). The digestive and metabolic utilization of Se, the distribution in target organ, the GPx activity and TBARS production were measured after receiving the diets. Se retention increased (P<0.001) in the anemic group, fact that contributes to keep the enzymatic antioxidant activity of GPx in normal levels and the tendency observed is that stored Se increased in the organs, especially in kidney (P<0.01), however, a lower Se deposit was found in sternum of anemic rats (P<0.001). The lower count of RBCs featured in this pathology (P<0.001) causes a decrease of Se concentration in sternum meanwhile the increase in kidney deposit is a consequence of the lower urinary losses (P<0.001). PMID- 21277181 TI - Protective effects of sodium molybdate on carbon tetrachloride-induced hepatotoxicity in rats. AB - Molybdenum is an essential trace micronutrient element that plays an important role in animal and plant physiology. Molybdenum is a constituent of at least three mammalian metalloflavoproteins: xanthine oxidase, aldehyde oxidase and sulphite oxidase. In the present study, the hepatoprotective potential of sodium molybdate was investigated against carbon tetrachloride (CCl(4))-induced liver damage in rats. Administration of CCl(4) increased the serum alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase levels in rats and reduced levels of the antioxidant enzymes superoxide dismutase and catalase in the liver. Treatment with sodium molybdate significantly attenuated these changes to nearly undetectable levels. The histopathological changes induced by CCl(4) were also significantly attenuated by sodium molybdate treatment. Therefore, the results of this study suggest that sodium molybdate can protect the liver against CCl(4)-induced oxidative damage in rats, and this hepatoprotective effect might be attributable to its modulation of detoxification enzymes and/or its antioxidant and free radical scavenger effects. PMID- 21277182 TI - Circulating antiangiogenic proteins in obstructive sleep apnea and hypertension. AB - INTRODUCTION: Obstructive sleep apnea (OSA) causes endothelial dysfunction and is an independent risk factor for hypertension and cardiovascular diseases. Although vasoactive agents and sympathoexcitation have been implicated and operational in the pathogenesis of hypertension associated with OSA the exact mechanisms underlying hypertension have not been established. Soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) are released under hypoxic stress and cause endothelial dysfunction and hypertension in humans and animals. The present study was conducted to investigate the role of these antiangiogenic proteins in OSA and to determine their clinical significance. METHODS: In 22 untreated OSA patients with apnea-hypopnea index >=30 events/h (11 with hypertension and 11 without hypertension) we measured plasma concentrations of endothelin-1, epinephrine, norepinephrine, nitric oxide metabolites, sFlt-1 and sEng. RESULTS: The apnea-hypopnea indices were 81+/-11 and 76+/-9 events/h (P=ns) and the sleep times with SaO(2)<90% were 42+/-13 and 39+/-13 min (P=ns) for normotensives and hypertensives, respectively. Both groups had similarly elevated levels of catecholamines with normal endothelin-1 levels. Nitric oxide metabolites were depressed in both groups with no inter-group differences. On the other hand, both sFlt-1 (90.0+/-4.6 pg/ml vs. 74.0+/-4.4 pg/ml, P=0. 018) and sEng (4.9+/-0.34 ng/ml vs. 3.50+/-0.42 ng/ml, P=0.016) were significantly elevated in the hypertensive patients compared to the normotensive subjects. CONCLUSION: These data show that sFlt-1 and sEng are increased in the circulation of patients with OSA and hypertension and suggest that they may be involved in the pathogenesis of hypertension. PMID- 21277183 TI - Associations between alcohol consumption and sleep-disordered breathing among Japanese women. AB - BACKGROUND: The associations between alcohol consumption and sleep-disordered breathing in women are uncertain. METHODS: We conducted a cross-sectional study of 3113 women aged 30-69 years. The 3% oxygen desaturation index (3% ODI), based on overnight pulse oximetry findings, was selected as an indicator of sleep disordered breathing. RESULTS: 3% ODI frequencies of >=5 were higher for drinking women with ethanol intakes of >=23.0 g/d than for never drinkers: the respective multivariable odds ratios and 95% confidence intervals was 1.8(1.0-3.4). The corresponding odds ratio was 3.0(1.6-5.8) for habitual snoring. The associations of ethanol intakes of >=23.0 g/d with 3% ODI >= 5 was more evident among women with BMI <23.0 kg/m(2) (median) than those with higher BMI but did not vary by habitual snoring. The multivariable odds ratios of 3%ODI >= 5 for women with ethanol intakes of >=23.0 g/d versus never drinkers were 2.7(1.0-6.7) for lower BMI and 1.5(0.6-3.3) for higher BMI and the corresponding odds ratio were 2.8(1.6 7.2) and 3.2(1.3-7.9) for habitual snoring, respectively. CONCLUSION: Alcohol consumption was associated with higher prevalence of sleep-disordered breathing among Japanese women. PMID- 21277184 TI - Exhaled breath condensate nitrates, but not nitrites or FENO, relate to asthma control. AB - BACKGROUND: Asthma is a chronic respiratory disease, characterised by airways inflammation, obstruction and hyperresponsiveness. Asthma control is the goal of asthma treatment, but many patients have sub-optimal control. Exhaled NO and exhaled breath condensate (EBC) NO metabolites (nitrites and nitrates) measurements are non-invasive tools to assess airways inflammation. Our aim was to investigate the relationships between asthma control and the above-named biomarkers of airways inflammation. METHODS: Thirty-nine non-smoking asthmatic patients (19 women) aged 50 (21-80) years performed measurements of exhaled NO (FENO), EBC nitrates, nitrites and pH, and answered Asthma Control Questionnaire (ACQ) and Asthma Control Test (ACT)-questionnaire. RESULTS: The ACT and ACQ score were strongly interrelated (rho = -0.84, p < 0.001). No relationships between ACT or ACQ score and FENO were found (p > 0.05). EBC nitrates were negatively related to ACT score (rho = -0.34, p = 0.03) and positively related to ACQ score (rho = 0.41, p = 0.001) while no relation of EBC nitrites to either ACQ or ACT score was found (p>0.05). CONCLUSION: EBC nitrates were the only biomarker that was significantly related to asthma control. This suggests that nitrates, but not nitrites or FENO, reflect an aspect of airways inflammation that is closer related to asthma symptoms. Therefore there is a potential role for EBC nitrates in objective assessment of asthma control. PMID- 21277185 TI - Bioactives from bitter melon enhance insulin signaling and modulate acyl carnitine content in skeletal muscle in high-fat diet-fed mice. AB - Bioactive components from bitter melon (BM) have been reported to improve glucose metabolism in vivo, but definitive studies on efficacy and mechanism of action are lacking. We sought to investigate the effects of BM bioactives on body weight, muscle lipid content and insulin signaling in mice fed a high-fat diet and on insulin signaling in L6 myotubes. Male C57BL/6J mice were randomly divided into low-fat diet control (LFD), high-fat diet (HFD) and HFD plus BM (BM) groups. Body weight, body composition, plasma glucose, leptin, insulin and muscle lipid profile were determined over 12 weeks. Insulin signaling was determined in the mouse muscle taken at end of study and in L6 myotubes exposed to the extract. Body weight, plasma glucose, insulin, leptin levels and HOMA-IR values were significantly lower in the BM-fed HFD group when compared to the HFD group. BM supplementation significantly increased IRS-2, IR beta, PI 3K and GLUT4 protein abundance in skeletal muscle, as well as phosphorylation of IRS-1, Akt1 and Akt2 when compared with HFD (P<.05 and P<.01). BM also significantly reduced muscle lipid content in the HFD mice. BM extract greatly increased glucose uptake and enhanced insulin signaling in L6 myotubes. This study shows that BM bioactives reduced body weight, improved glucose metabolism and enhanced skeletal muscle insulin signaling. A contributing mechanism to the enhanced insulin signaling may be associated with the reduction in skeletal muscle lipid content. Nutritional supplementation with this extract, if validated for human studies, may offer an adjunctive therapy for diabetes. PMID- 21277186 TI - Experimental determination of optimum gutter brush parameters and road sweeping criteria for different types of waste. AB - The removal ability of gutter brushes for road sweeping for various debris types and different sweeping parameters is studied through experimental tests. The brushing test rig used comprises two commercial gutter brushes, a concrete test bed, and an asphalt test road with a gutter of 0.25 cm width and 10 degrees slope. The brush-surface contact area is determined by sweeping sand on the concrete test bed. Sweeping problems are identified and discussed, and sweeping criteria for the different debris types are suggested. Also, optimum sweeping parameters are proposed for each debris type. In addition, debris removal mechanisms are discussed and analysed. The results indicate that for large heavy debris such as stones and gravel, it is not difficult to achieve large removal forces, because the steel bristles are relatively stiff. Conversely, high removal forces are not needed for particles of millimetre or micron sizes, but bristle curvature has to be appropriate to remove particles from road concavities. Finally, it is found that mud, especially dry mud on a rough surface, is the hardest debris to sweep, requiring a brush with a large tilt angle and a very large penetration to produce large removal forces. PMID- 21277187 TI - Life cycle assessment of selective non-catalytic reduction (SNCR) of nitrous oxides in a full-scale municipal solid waste incinerator. AB - Selective non-catalytic reduction (SNCR) of nitrous oxides in a full-scale municipal solid waste incinerator was investigated using LCA. The relationship between NO(x)-cleaning and ammonia dosage was measured at the plant. Un-reacted ammonia - the ammonia slip - leaving the flue-gas cleaning system adsorbed to fly ash or in the effluent of the acidic scrubber was quantified from the stoichiometric reaction of NO(x) and ammonia assuming no other reaction products was formed. Of the ammonia slip, 37% was associated with the fly-ash and 63% was in the effluent of the acidic scrubber. Based on NO(x)-cleaning efficiency, the fate of the ammonia slip as well as the environmental impact from ammonia production, the potential acidification and nutrient enrichment from NO(x) cleaning was calculated as a function of ammonia dosage. Since the exact fate of the ammonia slip could not be measured directly, a number of scenarios were set up ranging from "best case" with no ammonia from the slip ending up in the environment to "worst case" where all the ammonia slip eventually ended up in the environment and contributed to environmental pollution. In the "best case" scenario the highest ammonia dosage was most beneficial demonstrating that the environmental load associated with ammonia production is of minor importance. In contrast, in a "worst case" scenario" NO(x)-cleaning using SNCR is not recommendable at all, since the impacts from the ammonia slip exceed the saved impacts from the NO(x) removal. Increased dosage of ammonia for removal of NO(x) is recommendable as long as less than 10-20% of the ammonia slip to the effluent of the acidic scrubber ends up in the environment and less than 40% of the slip to the fly-ash ends up in the environment. The study suggests that the actual fate of the ammonia slip is crucial, but since the release of the ammonia may take place during transport and at the facilities that treat the wastewater and treat the fly-ash this factor depends strongly on local conditions and may be hard to determine. Thus, LCA-modeling proved useful in assessing the balance between ammonia dosage and NO(x)-removal in flue-gas cleaning from waste incineration. PMID- 21277188 TI - Changes in fungal population of fly ash and vinasse mixture during vermicomposting by Eudrilus eugeniae and Eisenia fetida: documentation of cellulase isozymes in vermicompost. AB - Fly ash (FA) and vinasse (VN), two industrial wastes, are generated in huge amounts and cause serious hazards to the environment. In this experiment, different proportions of these two wastes were used as food for two epigeic earthworms (Eisenia fetida and Eudrilus eugeniae) to standardize the recycling technique of these two wastes and to study their effect on fungal especially cellulolytic fungal population, cellulase activity and their isozyme pattern, chitin content and microbial biomass of waste mixture during vermicomposting. Increasing VN proportion from 25% to 50% or even higher, counts of both fungi and cellulolytic fungi in waste mixtures were significantly (P <= 0.05) increased during vermicomposting. Higher cellulase activity in treatments having 50% or more vinasse might be attributed to the significantly (P <= 0.05) higher concentration of group I isozyme while concentrations of other isozymes (group II and III) of cellulase were statistically at par. Higher chitin content in vinasse enriched treatments suggested that fungal biomass and fungi-to-microbial biomass ratio in these treatments were also increased due to vermicomposting. Results revealed that Eudrilus eugeniae and Eisenia fetida had comparable effect on FA and VN mixture during vermicomposting. Periodical analysis of above-mentioned biochemical and microbial properties and nutrient content of final vermicompost samples indicated that equal proportion (1:1, w/w) of FA and VN is probably the optimum composition to obtain best quality vermicompost. PMID- 21277189 TI - Are professional waste associations keeping up with the times? PMID- 21277190 TI - Epilepsy genetics--past, present, and future. AB - Human epilepsy is a common and heterogeneous condition in which genetics play an important etiological role. We begin by reviewing the past history of epilepsy genetics, a field that has traditionally included studies of pedigrees with epilepsy caused by defects in ion channels and neurotransmitters. We highlight important recent discoveries that have expanded the field beyond the realm of channels and neurotransmitters and that have challenged the notion that single genes produce single disorders. Finally, we project toward an exciting future for epilepsy genetics as large-scale collaborative phenotyping studies come face to face with new technologies in genomic medicine. PMID- 21277191 TI - Where are the missing pieces of the schizophrenia genetics puzzle? AB - On the basis of recent data from candidate region/gene and genome-wide association studies (GWAS) and their follow-up investigations, the number of genes potentially implicated in schizophrenia has been estimated to be over 1000. However, with regard to the identified odds ratio, it is likely that genetic variants with more definitive effect on schizophrenia phenotype are still missing. The hunt therefore remains open for the genetic variants that would explain the majority of the missing heritability of schizophrenia. This review aims at summarizing data from recent DNA microarray and target gene/region resequencing in order to propose new insights of where to look next. The review is divided into three sections: GWAS, copy-number variations and rare variant- candidate gene resequencing. PMID- 21277192 TI - Synapse development in health and disease. AB - Recent insights into the genetic basis of neurological disease have led to the hypothesis that molecular pathways involved in synaptic growth, development, and stability are perturbed in a variety of mental disorders. Formation of a functional synapse is a complex process requiring stabilization of initial synaptic contacts by adhesive protein interactions, organization of presynaptic and postsynaptic specializations by scaffolding proteins, regulation of growth by intercellular signaling pathways, reorganization of the actin cytoskeleton, and proper endosomal trafficking of synaptic growth signaling complexes. Many neuropsychiatric disorders, including autism, schizophrenia, and intellectual disability, have been linked to inherited mutations which perturb these processes. Our understanding of the basic biology of synaptogenesis is therefore critical to unraveling the pathogenesis of neuropsychiatric disorders. PMID- 21277193 TI - The genetics of Tourette disorder. AB - Tourette disorder (TD) is a childhood onset neuropsychiatric syndrome defined by persistent motor and vocal tics. Despite a long-standing consensus for a strong genetic contribution, the pace of discovery compared to other disorders of similar prevalence has been slow, due in part to a paucity of studies and both clinical heterogeneity and a complex genetic architecture. However, the potential for rapid progress is high. Recent rare variant findings have pointed to the importance of copy number variation, the overlap of risks among distinct diagnostic entities, the contribution of novel molecular mechanisms, and the value of family based studies. Finally, analysis of a cohort of sufficient size to identify common polymorphisms of plausible effect is underway, promising key information regarding the contribution of common alleles to TD. PMID- 21277194 TI - Impact of induced pluripotent stem cells on the study of central nervous system disease. AB - The derivation of pluripotent stem cells from somatic tissues has provided researchers with a source of patient-specific stem cells. The potential applications of this technology are truly momentous, and include cellular modeling of disease processes, drug discovery, and cell-based therapy. Here, we review the use of induced pluripotent stem cells (iPSCs) to study CNS disease. Since the iPSC field is still in its infancy, we also discuss some of the challenges that will need to be overcome before the potential of this technology to study and to treat neurological and psychiatric disorders can be fully harnessed. PMID- 21277195 TI - Peripheral somatosensation: a touch of genetics. AB - The somatosensory system processes information that organisms 'feel': joint position, muscle stretch, pain, pressure, temperature, and touch. The system is composed of a diverse array of peripheral nerve endings specialized to detect these sensory modalities. Several recent discoveries have shed light on the genetic pathways that control specification and differentiation of these neurons, how they accurately innervate their central and peripheral targets, and the molecules that enable them to detect mechanical stimuli. Here, we review the cadre of genes that control these processes, focusing on mechanosensitive neurons and support cells of the skin that mediate different aspects of the sense of touch. PMID- 21277196 TI - Molecular signals of plasticity at the tetrapartite synapse. AB - The emergence of astroglia as an important participant of the synaptic machinery has led to the 'tripartite synapse' hypothesis. Recent findings suggest that synaptic signaling also involves the surrounding extracellular matrix (ECM). The ECM can incorporate and store molecular traces of both neuronal and glial activities. It can also modulate function of local receptors or ion channels and send diffuse molecular signals using products of its use-dependent proteolytic cleavage. Recent experimental findings implicate the ECM in mechanisms of synaptic plasticity and glial remodeling, thus lending support to the 'tetrapartite synapse' concept. This inclusive view might help to understand better the mechanisms underlying signal integration and novel forms of long-term homeostatic regulation in the brain. PMID- 21277197 TI - Treatment of fresh leachate with high-strength organics and calcium from municipal solid waste incineration plant using UASB reactor. AB - Treatment of a fresh leachate with high-strength organics and calcium from municipal solid waste (MSW) incineration plant by an up-flow anaerobic sludge blanket (UASB) reactor was investigated under mesophilic conditions, emphasizing the influence of organic loading rate (OLR). When the reactor was fed with the raw leachate (COD as high as 70,390-75,480 mg/L) at an OLR of 12.5 kg COD/(m(3)d), up to ~ 82.4% of COD was removed suggesting the feasibility of UASB process for treating fresh leachates from incineration plants. The ratio of volatile solids/total solids (VS/TS) of the anaerobic sludge in the UASB decreased significantly after a long-term operation due to the precipitation of calcium carbonate in the granules. Scanning electron microscopy (SEM) observation shows that Methanosaeta-like species were in abundance, accompanied by a variety of other species. The result was further confirmed by polymerase chain reaction denaturing gradient gel electrophoresis (PCR-DGGE) and sequencing. PMID- 21277198 TI - II. SAR studies of pyridyl-piperazinyl-piperidine derivatives as CXCR3 chemokine antagonists. AB - The structure-human CXCR3 binding affinity relationship of a series of pyridyl piperazinyl-piperidine derivatives was explored. The optimization campaign highlighted the pronounced effect of 2'-piperazine substitution on CXCR3 receptor affinity. Analog 18j, harboring a 2'(S)-ethylpiperazine moiety, exhibited a human CXCR3 IC(50) of 0.2 nM. PMID- 21277199 TI - Exploring subtype selectivity and metabolic stability of a novel series of ligands for the benzodiazepine binding site of the GABAA receptor. AB - A novel series of agonists at the benzodiazepine binding site of the GABA(A) receptor was prepared by functionalizing a known template. Adding substituents to the pyrazolone-oxygen of CGS-9896 led to a number of compounds with selectivities for either alpha2- or alpha1-containing GABA(A) receptor subtypes offering an entry into indications such as anxiety and insomnia. In this communication, structure-activity relationship and efforts to increase in vitro stabilities are discussed. PMID- 21277200 TI - Synthesis and antitubercular activity of monocyclic nitroimidazoles: insights from econazole. AB - We have designed and synthesized econazole-derived nitroimidazoles to investigate the antitubercular activity of the nitroimidazole compounds. The introduction of a nitro group at the 4-position of the imidazole on econazole abolished the antitubercular activity. However, alcoholic nitroimidazoles 4 and 6 compounds were active against Mycobacterium tuberculosis (Mtb). While the MIC value of econazole was 16 MUg/mL, the MIC of 6a and 6f turned out to be 0.5 MUg/mL. In particular, the activity of 6f against non-replicating Mtb was as good as PA-824, which is currently in clinical phase II studies as an antitubercular agent. Overall, alcohol compounds 4 and 6 tend to be more active than ether compounds 5 and 7. PMID- 21277201 TI - Synthesis of cell-permeable stapled peptide dual inhibitors of the p53-Mdm2/Mdmx interactions via photoinduced cycloaddition. AB - We report the first application of a photoinduced 1,3-dipolar cycloaddition reaction to 'staple' a peptide dual inhibitor of the p53-Mdm2/Mdmx interactions. A series of stapled peptide inhibitors were efficiently synthesized and showed excellent dual inhibitory activity in ELISA assay. Furthermore, the positively charged, stapled peptides showed enhanced cellular uptake along with modest in vivo activity. PMID- 21277202 TI - Synthesis of GN8 derivatives and evaluation of their antiprion activity in TSE infected cells. AB - A series of GN8 derivatives were synthesized from various diamines, carboxylic acid derivatives, and nitrogen nucleophiles, and their antiprion activity was tested in TSE-infected mouse neuronal cells. We found that two ethylenediamine units, hydrophobic substituents on the nitrogen atoms, and the diphenylmethane scaffold were essential structural features responsible for the activity. Seven derivatives bearing substituents at the benzylic position exhibited an improved antiprion activity with the IC(50) values of 0.51-0.83 MUM. Conformational analysis of model compounds suggested that the introduction of the substituent at the benzylic position restricted the conformational variability of the diphenylmethane unit. PMID- 21277203 TI - Discovery of substituted 3-(phenylamino)benzoic acids as potent and selective inhibitors of type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3). AB - Aldo-keto reductase 1C3 (AKR1C3) also known as type 5 17beta-hydroxysteroid dehydrogenase has been implicated as one of the key enzymes driving the elevated intratumoral androgen levels observed in castrate resistant prostate cancer (CRPC). AKR1C3 inhibition therefore presents a rational approach to managing CRPC. Inhibitors should be selective for AKR1C3 over other AKR1C enzymes involved in androgen metabolism. We have synthesized 2-, 3-, and 4-(phenylamino)benzoic acids and identified 3-(phenylamino)benzoic acids that have nanomolar affinity and exhibit over 200-fold selectivity for AKR1C3 versus other AKR1C isoforms. The AKR1C3 inhibitory potency of the 4'-substituted 3-(phenylamino)benzoic acids shows a linear correlation with both electronic effects of substituents and the pK(a) of the carboxylic acid and secondary amine groups, which are interdependent. These compounds may be useful in treatment and/or prevention of CRPC as well as understanding the role of AKR1C3 in endocrinology. PMID- 21277204 TI - Serendipitous discovery of a new class of agonists for the melanocortin 1 and 4 receptors and a new class of cyclophanes. AB - A new class of melanocortin 4 receptor (MC4r) agonists was discovered from an unexpected sidereaction in which formaldehyde caused cyclization. These cyclophanes were found to be sub micromolar agonists of the MC1 and MC4 and were less potent on the MC3 and MC5 receptor. They were shown to compete with the peptidic antagonist SHU9119 for binding to the MC4 receptor. In an acute feeding study in Sprague Dawley rats, food intake was reduced more than 50% versus vehicle after 3 h at a dose of 1 mg/kg. PMID- 21277205 TI - Discovery of substituted phenyl urea derivatives as novel long-acting beta2 adrenoreceptor agonists. AB - The synthesis of diverse functionalized ureas in a semi-parallel fashion is described, as well as their beta(1)/beta(2)-adrenergic activities and the corresponding structure-activity relationship (SAR). We have focused on lipophilicity and duration of action, and we have discovered a strong correlation in this series of molecules. A quantitative structure-activity relationship (QSAR) analysis will be presented that quantifies this relationship. PMID- 21277206 TI - Synthesis and biological activity of novel MIF antagonists. AB - Two series of novel furan and indole compounds were synthesized and probed for inhibition of macrophage migration inhibitory factor (MIF) activity. Several compounds from both series inhibited the enzymatic activity of MIF at levels equal to or significantly better than ISO-1 (an early MIF inhibitor). The majority of the compounds that robustly inhibited the spontaneous secretion/release/recognition of MIF from freshly isolated human peripheral blood mononuclear cells were from the furan series (compounds 5, 9, 13, 15, and 16). In contrast, compounds that markedly inhibited the MIF-induced production of pro inflammatory cytokines were predominantly from the indole series (compounds 26, 29, and 32). PMID- 21277207 TI - Muscle satellite cells from GRMD dystrophic dogs are not phenotypically distinguishable from wild type satellite cells in ex vivo culture. AB - Duchenne muscular dystrophy is a neuromuscular degenerative disorder caused by the absence of dystrophin protein. It is characterized by progressive muscle weakness and cycles of degeneration/regeneration accompanying chronic muscle damage and repair. Canine models of muscular dystrophy, including the dystrophin deficient golden retriever muscular dystrophy (GRMD), are the most promising animal models for evaluation of potential therapies, however canine-specific molecular tools are limited. In particular, few immune reagents for extracellular epitopes marking canine satellite cells (muscle stem cells) are available. We generated an antibody to the satellite cell marker syndecan-4 that identifies canine satellite cells. We then characterized isolated satellite cells from GRMD muscle and wildtype muscle by several in vitro metrics, and surprisingly found no significant differences between the two populations. We discuss whether accumulated adverse changes in the muscle environment rather than cell-intrinsic defects may be implicated in the eventual failure of satellite cell efficacy in vivo. PMID- 21277208 TI - Visual crowding is correlated with awareness. AB - Crowding by nearby features causes identification failures in the peripheral visual field. However, prominent visual features can sometimes fail to reach awareness, causing scenes to be incorrectly interpreted. Here we examine whether awareness of the flanking features is necessary for crowding to occur. Flankers that were physically present were rendered perceptually absent with adaptation induced blindness. In a letter identification task, targets were presented unflanked or with up to four flanker letters. On each trial, observers reported both the number of letters they perceived and the identity of a target letter. This paradigm allowed trial-by-trial assessment of awareness and crowding and ensured that both targets and flankers were attended. Target-letter identification performance was correlated with the number of flanking letters that were perceived on a given trial, regardless of the number that were physically present. Our data demonstrate that crowding can be released when flanking elements at attended locations are suppressed from visual awareness. PMID- 21277209 TI - Modeling vesicle traffic reveals unexpected consequences for Cdc42p-mediated polarity establishment. AB - BACKGROUND: Polarization in yeast has been proposed to involve a positive feedback loop whereby the polarity regulator Cdc42p orients actin cables, which deliver vesicles carrying Cdc42p to the polarization site. Previous mathematical models treating Cdc42p traffic as a membrane-free flux suggested that directed traffic would polarize Cdc42p, but it remained unclear whether Cdc42p would become polarized without the membrane-free simplifying assumption. RESULTS: We present mathematical models that explicitly consider stochastic vesicle traffic via exocytosis and endocytosis, providing several new insights. Our findings suggest that endocytic cargo influences the timing of vesicle internalization in yeast. Moreover, our models provide quantitative support for the view that integral membrane cargo proteins would become polarized by directed vesicle traffic given the experimentally determined rates of vesicle traffic and diffusion. However, such traffic cannot effectively polarize the more rapidly diffusing Cdc42p in the model without making additional assumptions that seem implausible and lack experimental support. CONCLUSIONS: Our findings suggest that actin-directed vesicle traffic would perturb, rather than reinforce, polarization in yeast. PMID- 21277211 TI - Estimating functional stability boundaries for bipedal stance. AB - We propose a technique to estimate functional limits of stability (LOS) during bipedal stance using a controlled, low speed, voluntary leaning protocol requiring feet to remain in contact with the ground. LOS are estimated from ellipses fit to center-of-mass position data obtained during the leaning protocol. The LOS of nine healthy subjects were found to be 20-59% closer to the center of stance than the more frequently used anatomical boundaries and were reduced by closing the eyes. We conclude that functional stability boundaries should be used when the outcome measure is related to fall risk. PMID- 21277210 TI - The Three Musketeers of Autophagy: phosphorylation, ubiquitylation and acetylation. AB - Autophagy is a highly conserved process that allows cells, tissues and organs to survive onslaughts such as nutrient deprivation, inflammation, hypoxia and other stresses. The core component proteins that regulate autophagy are well known, and the formation of a double-membrane structure that encompasses cytosolic cargo, including protein aggregates and organelles, has been intensively studied. However, less is known about the inputs that specifically alter recruitment of these components and how post-translational modifications can influence autophagy flux, or the rate at which autophagy substrates are turned over. We propose that three types of post-translational modifications - phosphorylation, ubiquitylation and acetylation - are crucial for autophagy induction, regulation and fine tuning, and are influenced by a variety of stimuli. Understanding these novel mechanisms of autophagy regulation will give us deeper insights into this process and potentially open up therapeutic avenues. PMID- 21277212 TI - Gender differences in distal femoral morphology and the role of gender specific implants in total knee replacement: a prospective clinical study. AB - Gender differences in distal femoral morphology may affect femoral component fit using a standard range of prostheses. The clinical relevance of this is controversial. Standardised measurements were taken from the distal femora of 50 males and 50 females during total knee replacement (TKR). Corresponding measurements were taken from the respective gender specific and standard femoral components. No demographic differences were noted. Significant differences in both frequency and magnitude existed in the medial-lateral femoral component overhang between the sexes. In females, standard implants overhung at the anterior flange width (AFW) by >2mm in 24/50 (48%) and by >3mm in 17/50 (34%) (p<0.001). Also at the anterior medial-lateral width (MLA) 29/50 (58%) overhung by >2mm and 24/50 (48%) by >3mm (p<0.001). In males, standard implants overhung by >2mm in 1/50 (2%). In females, gender specific implants overhung by >2mm in 3/50 (6%). Females had a mean aspect ratio of 1.02 (0.82 to 1.35) and men 0.98 (0.79 to 1.19). Femoral component overhang can occur in females undergoing TKR and a gender specific implant would reduce the potential for medial-lateral overhang. Long term studies are awaited to quantify the clinical implications of overhang. PMID- 21277213 TI - Development and characterization of the integrated fiber-optic radiation sensor for the simultaneous detection of neutrons and gamma rays. AB - Sometimes, detection of thermal neutrons in the presence of gamma rays is required. This study developed and characterized an integrated fiber-optic radiation sensor for the simultaneous detection of thermal neutrons and gamma rays in a mixed radiation field. The performance of the integrated sensor was verified by measuring the distributions of thermal neutrons and gamma rays released from a nuclear fuel rod at the Kyoto University Critical Assembly. The experimental results show that the integrated sensor produced similar distribution patterns to those of thermal neutrons and gamma rays released from a fuel rod. PMID- 21277214 TI - Parameters optimization defined by statistical analysis for cysteine-dextran radiolabeling with technetium tricarbonyl core. AB - The objective of this study was the development of a statistical approach for radiolabeling optimization of cysteine-dextran conjugates with Tc-99m tricarbonyl core. This strategy has been applied to the labeling of 2-propylene-S-cysteine dextran in the attempt to prepare a new class of tracers for sentinel lymph node detection, and can be extended to other radiopharmaceuticals for different targets. The statistical routine was based on three-level factorial design. Best labeling conditions were achieved. The specific activity reached was 5 MBq/MUg. PMID- 21277215 TI - Arabidopsis thaliana lipid phosphate phosphatase 2 is involved in abscisic acid signalling in leaves. AB - Lipid phosphate phosphatases (LPPs, E.C. 3.1.3.4) catalyse the dephosphorylation of diacylglycerol pyrophosphate (DGPP) and phosphatidic acid (PA), which are secondary messengers in abscisic acid (ABA) signalling. In this study, we investigated the effect of ABA on the expression of AtLPP genes as they encode putative ABA-signalling partners. We observed that AtLPP2 expression was down regulated by ABA and we performed experiments on Atlpp2-2, an AtLPP2 knockout mutant, to determine whether AtLPP2 was involved in ABA signalling. We observed that Atlpp2-2 plantlets contained about twice as much PA as the wild-type Col-0 and exhibited higher PA kinase (PAK) activity than Col-0 plants. In addition, we showed that ABA stimulated diacylglycerol kinase (DGK) activity independently of AtLPP2 activity but that the ABA-stimulation of PAK activity recorded in Col-0 was dependent on AtLPP2. In order to evaluate the involvement of AtLPP2 activity in guard cell function, we measured the ABA sensitivity of Atlpp2-2 stomata. The inhibition of stomatal opening was less sensitive to ABA in Atlpp2-2 than in Col 0. Watered and water-stressed plants of the two genotypes accumulated ABA to the same extent, thus leading us to consider Atlpp2-2 an ABA-signalling mutant. Taken together our observations show that AtLPP2 is a part of ABA signalling and participate to the regulation of stomatal movements. PMID- 21277216 TI - Esophagectomy for clinical high-grade dysplasia. AB - OBJECTIVE: Esophageal high-grade dysplasia/tumor in situ (HGD/Tis) management is in evolution. However, treatment decisions must be made on clinical staging, which may not reflect pathologic staging. Long-term randomized trial information, large treatment series, and cancer registry data do not exist to guide treatment decisions. This evaluation of esophagectomy for clinically diagnosed HGD (cHGD) serves as a reference point for future therapies. METHODS: From a 1296-patient prospective esophagectomy database, 134 patients were diagnosed with cHGD (HGD without detectable mass at biopsy) before esophagectomy (mean age 60 +/- 10 years, 120 [90%] male, and 132 [99%] Caucasian). Median follow-up was 7.1 years. RESULTS: Histopathologic cell type was adenocarcinoma in 124 (93%) patients. Pathologic T (tumor) classification (pT) was 77 (57%) pHGD, 46 (34%) pT1a, eight (6%) pT1b, and one each (1%) indefinite for dysplasia, low-grade dysplasia, and pT2. Three (2%) had regional lymph node metastases (pT1N1M0). There was one hospital death (0.7%) and four deaths from recurrent cancer. Survival at 1 month, 6 months, and 5, 10, and 15 years was 99%, 97%, 96%, 94%, 82%, and 75%, respectively. Survival was at least that of a matched population. Older age and poor lung function predicted worse survival. Sixteen patients developed nonesophageal cancers, 6.1 times greater than expected. CONCLUSIONS: Despite clinical staging errors, survival following esophagectomy for cHGD is excellent. The diagnosis of cHGD does not alter survival referenced to the matched general population; however, cHGD patients appear to be at increased risk of second nonesophageal primary cancers. Therapy for cHGD should be patient specific, because patient and not cancer characteristics determine survival. PMID- 21277217 TI - Pregnancy with prosthetic heart valves - 30 years' nationwide experience in Denmark. AB - OBJECTIVE: Pregnancy in women with prosthetic heart valves remains a risk factor for both mother and fetus, but unselected and unbiased outcome and complication data remain scarce. We analyzed nationwide outcome data from 1977 to 2007 for all pregnancies in women with prosthetic valves. METHODS: Cardiac, obstetric, and neonatal data were obtained from obligatory databases and compared with general female population data. Questionnaires were used to corroborate important information. Outcome data were analyzed according to type of anticoagulation used. The data were compared between the two first and the last decades of the study period. In the last decade, patients were compared to an age-adjusted selected population of healthy, pregnant women. RESULTS: Of 356 women between 15 and 40 years of age, 79 women had 155 pregnancies after valve replacement. Two women died during pregnancy, one from heart failure and one from post-partum bleeding. There were four thrombo-embolic episodes in the early study period in women with mitral prosthesis on unfractionated heparin. Important cardiac complications were otherwise almost absent. There were significantly more early miscarriages and terminations in patients compared with controls (last decade 34%, vs 20% (p=0.0036) and 26% vs 13% (p=0.000019)). Post-partum bleeding was more common in the patient group (p=0.0021). Two late fetal losses (one from intracerebral bleeding) were seen. The remaining pregnancies resulted in 60 live births. Cesarean section was the predominant method of delivery in patients as opposed to controls (55% vs 16%, p=0.000000000097). Premature births were more frequent in patients (49% vs 5.5%, p=0.00000000039) as were congenital malformations (14% vs 5.7%, p=0.044). Two of the six malformations were warfarin embryopathy (8% of all first-trimester warfarin exposures), both seen in high risk patients on high warfarin dosing. Small for gestational age did not differ significantly from the general population (9.3% vs 6.0%, p=0.39). CONCLUSION: Data acquired over 30 years confirm that women with prosthetic heart valves, especially aortic prostheses for congenital lesions, generally tolerate pregnancy well, although cardiac mortality, mortality related to anticoagulation and thrombo-embolic risks are raised. Our data provide further documentation on the significance and importance of the risks associated with predominantly warfarin based treatment regimens, which still remains optional for a number of patients. Finally, the data also serve as a comparison for recently published series based on low-molecular-weight heparin (LMWH) regimens. PMID- 21277218 TI - Rare complication of bioprosthetic aortic valve replacement. PMID- 21277219 TI - Endothelium-dependent and endothelium-independent vasodilator response of left and right internal mammary and internal thoracic arteries used as a composite Y graft. AB - OBJECTIVE: The manner in which a blood vessel is for used as a coronary graft may be important in maintaining a viable and functional endothelial lining. Composite internal thoracic arteries (ITAs) in a Y-graft configuration are characterized by the connection of an in situ left ITA with preserved innervation and lymphatics and of a free semi-skeletonized right ITA. METHODS: To determine whether endothelial function differs between left and right ITA segments in a Y-graft configuration, 11 patients were studied 3 years after surgery. The endothelium dependent vasodilator substance P was selectively infused (1.4-22.4 pmol min-1 in doubling dose increments) in the ostium of ITA Y-grafts. A maximal endothelium independent vasodilatory response was then obtained by intragraft infusion of 2mg isosorbide dinitrate (ISDN). Biplane angiograms obtained at 3-min intervals using an automated contrast injection system with fixed preset volume and pressure parameters were analyzed off-line using a quantitative analysis system (CAAS, Pie Medical). RESULTS: A similar dose-dependent vasodilatory response to substance P was observed in the left and in the right ITA. No difference in maximal endothelium-dependent response to substance P (7.4 +/- 4.3% in the left ITA and 8.1 +/- 5.3% in the right ITA) or in maximal endothelium-independent response to ISDN (12.2 +/- 4.4% in the left ITA and 10.6 +/- 8.1% in the right ITA) was observed. CONCLUSIONS: The endothelium-dependent and the endothelium-independent vasodilator capacity of the two branches of a Y-graft ITA configuration appear similar 3 years after bypass surgery. This suggests that the preservation of the ITA pedicle does not significantly affect basal vasomotor tone, long-term endothelial function, or vasodilator reserve. PMID- 21277220 TI - Midterm outcome after aortic root replacement with stentless porcine bioprostheses. AB - OBJECTIVE: Midterm clinical outcome was evaluated after aortic root replacement with Freestyle(r) stentless aortic root bioprostheses. METHODS: Between April 1996 and December 2007, 301 patients underwent aortic valve replacement with stentless Medtronic Freestyle(r) bioprostheses in full-root technique at a single center. Concomitant coronary artery bypass grafting (CABG) was required in 96 patients (32%). In 94 patients (31%), the ascending aorta was replaced. The mean age was 71.6 +/- 9.1 (range: 36-89) years. Follow-up was closed in October 2008, 99% complete and encompassed 916 patient-years. RESULTS: Overall mortality within 30 days was 5%. A total of 62 patients died during the follow-up period. Overall survival at 5 and 9 years was 74 +/- 4% and 53 +/- 6%, respectively. Re operations were required in three patients: in one patient due to structural valve deterioration, and in two patients due to prosthetic valve endocarditis. Non-structural dysfunctions were not observed. In eight patients, prosthetic valve endocarditis occurred, in most of them (N = 6) during the first year after surgery. Rate of freedom from re-operation, structural valve deterioration, prosthetic valve endocarditis, thrombo-embolic and major bleeding events at 9 years was 94 +/- 6%, 94 +/- 6%, 94 +/- 3%, 87 +/- 5%, and 95 +/- 2%, respectively. The linearized rates of late adverse events in percent per patient year were 0.35, 0.12, 0.83, 1.7, and 0.7, respectively, for re-operation, structural valve deterioration, prosthetic valve endocarditis, thrombo-embolic and major bleeding events. A little less than a quarter (22%) of the patients required anticoagulation therapy. CONCLUSIONS: Aortic root replacement with the stentless Freestyle(r) bioprosthesis provided a respectable short-term mortality, optimal valve durability and acceptable rates of valve-related complications within 9 years. PMID- 21277221 TI - How to ensure a good flow to the arm during direct axillary artery cannulation. AB - We herein describe a simple and safe technique to avoid compartment syndrome/arm ischemia during direct right axillary artery cannulation, especially in patients who require long-term extracorporeal membrane oxygenation support. PMID- 21277222 TI - Cumulative inhibitor incidence in previously untreated patients with severe hemophilia A treated with plasma-derived versus recombinant factor VIII concentrates: a critical systematic review. AB - Inhibitor development represents currently the most serious and challenging complication of clotting factor replacement therapy. A number of studies have analyzed the impact of the type of factor VIII (FVIII) replacement therapy (plasma-derived versus recombinant concentrates) on inhibitor development in hemophilia A patients with conflicting results. In order to shed light on this controversial issue, we performed a systematic review and meta-analysis on the published prospective studies evaluating the incidence rate of inhibitors in previously untreated patients (PUPs) with severe hemophilia A. Data from a total of 800 patients enrolled in 25 prospective studies published between 1990 and 2007 were included in this review. The quality of the studies was evaluated using two different systems: the Newcastle-Ottawa Scale (NOS) and STrengthening the Reporting of OBservational studies in Epidemiology (STROBE). Overall, the inhibitor incidence rate did not differ significantly between recipients of plasma-derived and recombinant FVIII concentrates (weighted means: 21%; 95% CI, 14-30 versus 27%; 95% CI, 21-33). Similarly, high titer inhibitors did not differ significantly between patients treated with plasma-derived (weighted means: 14%; 95% CI, 8-25) or recombinant FVIII concentrates (weighted means: 16%; 95% CI, 13 20). Thus, the main conclusion of this systematic review performed using selective criteria is that the type of FVIII product (i.e., plasma-derived versus recombinant FVIII concentrates) does not seem to influence the inhibitor rate in PUPs with severe hemophilia A. PMID- 21277224 TI - Truncal ataxia from infarction involving the inferior olivary nucleus. AB - Truncal ataxia in medullary infarction may be caused by involvement of the lateral part of the medulla; however, truncal ataxia in infarction involving the inferior olivary nucleus (ION) has received comparatively little attention. We report a patient with truncal ataxia due to medial medullary infarction located in the ION. A lesion in the ION could produce a contralateral truncal ataxia due to increased inhibitory input to the contralesional vestibular nucleus from the contralesional flocculus. PMID- 21277223 TI - Targeting human dendritic cell subsets for improved vaccines. AB - Dendritic cells (DCs) were discovered in 1973 by Ralph Steinman as a previously undefined cell type in the mouse spleen and are now recognized as a group of related cell populations that induce and regulate adaptive immune responses. Studies of the past decade show that, both in mice and humans, DCs are composed of subsets that differ in their localization, phenotype, and functions. These progresses in our understanding of DC biology provide a new framework for improving human health. In this review, we discuss human DC subsets in the context of their medical applications, with a particular focus on DC targeting. PMID- 21277225 TI - Effects of eicosapentaenoic acid on asymmetric dimethylarginine in patients in the chronic phase of cerebral infarction: a preliminary study. AB - BACKGROUND: Eicosapentaenoic acid (EPA) possesses a variety of pharmacologic actions and demonstrates protective efficacy against stroke. Meanwhile, asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase inhibitor and is thereby considered one of the risk factors of cardiovascular disease. The effects of the EPA treatment on ADMA in patients in the chronic phase of cerebral infarction accompanied by dyslipidemia were investigated. METHODS: Study subjects were individuals with either atherothrombotic or lacunar cerebral infarction in the chronic phase accompanied by dyslipidemia, of which the onset was at least 4 weeks earlier. Lipid, fatty acid, and ADMA levels in the blood were measured at EPA 1800 mg per day and compared both before and after treatment. Twenty subjects were included in the study (average age, 71.9 +/- 8.9 years). RESULTS: Of these 20 cases, eight were atherothrombotic and 12 were lacunar. Moreover, 17 cases were accompanied by hypertension and 10 cases were accompanied by diabetes mellitus. After EPA treatment (average duration of treatment, 143 +/- 42 days), EPA increased from 65.1 +/- 38.1 MUg/mL to 201.1 +/- 73.4 MUg/mL (P < .01). Arachidonic acid (AA) decreased from 149.1 +/- 34.8 MUg/mL to 129.7 +/- 22.3 MUg/mL (P < .01), and the EPA/AA ratio increased from 0.45 +/- 0.26 to 1.55 +/- 0.46 (P < .01). ADMA decreased from 0.49 +/- 0.07 nmol/mL before treatment to 0.46 +/- 0.05 nmol/mL after treatment (P < .01). CONCLUSIONS: EPA treatment in patients in the chronic phase of cerebral infarction leads to a decrease in ADMA in the blood, suggesting that EPA improves vascular endothelial function and therefore supports the protective efficacy against cerebral infarction. PMID- 21277226 TI - Cerebral infarction developing in a patient without cancer with a markedly elevated level of mucinous tumor marker. AB - Previous studies have shown the possible role of mucin in cerebral infarction associated with coagulation abnormalities in patients with cancer, particularly adenocarcinoma. We report a 42-year-old woman who developed motor aphasia and cerebral infarction in the left frontal lobe and right parietal lobe. A mucinous tumor marker, CA125 level, was markedly elevated at 1750 U/mL (normal, <36 U/mL), and the D-dimer level was 6.0 MUg/mL (normal, <1 MUg/mL). She had adenomyosis and no malignancy was revealed. The CA125 and the D-dimer levels became normal after treatment of adenomyosis. Our findings suggest for the first time that marked elevation of mucinous tumor marker level may cause cerebral infarction even in benign conditions. PMID- 21277227 TI - The irrelevance of folk intuitions to the "hard problem" of consciousness. AB - Recently, a number of philosophers have turned to folk intuitions about mental states for data about qualia and phenomenal consciousness. In this paper I argue that current research along these lines does not tell us about these subjects. I focus on a series of studies, performed by Justin Sytsma and Edouard Machery, to make my argument. Folk judgments studied by these researchers are mostly likely generated by a certain cognitive system - System One - that will generate the same data whether or not we experience phenomenal consciousness. This is a problem for a range of current experimental philosophy research into consciousness or our concept of it. If experimental philosophy is to shed light into phenomenal consciousness, it needs to be better founded in an understanding of how we make judgments. PMID- 21277228 TI - Conducting HIV research in racial and ethnic minority communities: building a successful interdisciplinary research team. AB - HIV infection occurs in disproportionately high rates among racial and ethnic minorities in the United States, making it imperative that individuals from these groups be included in research studies. However, it is often difficult to recruit HIV-infected Hispanics and African Americans in clinical trials, but a skilled interdisciplinary team that includes researchers with racial and ethnic diversity can help. This article describes a successful approach for building an interdisciplinary team that values the participation of racial and ethnic minorities in clinical trials and has the skills to work with these groups. The success of the Adelante (a Spanish word meaning forward) Team can be attributed to team members who actively participate in decision-making, are empowered, and function in a cohesive manner. Successful research teams build relationships with research participants to increase the probability that racial and ethnic minorities will enroll and participate fully in research. PMID- 21277229 TI - Home-based care: a need assessment of people living with HIV infection in Bandung, Indonesia. AB - The increasing number of people living with HIV infection (PLWH) in Indonesia has led to an increased demand for care. Health care facilities are overburdened. Home-based care (HBC) is a valuable strategy to complement existing health care services and to extend the continuum of care for PLWH and their families. This qualitative study explored the care needs of PLWH that might provide baseline data for developing HBC in Bandung, West Java, Indonesia. Data were collected from 12 key and 25 general participants through observations, interviews, and focus group discussions. Findings indicate that HBC is urgently needed for PLWH, particularly for those who need palliative care and those who encounter major barriers to using available health care services. It is recommended that health care providers and policy makers strengthen the role of the family in taking care of PLWH through trainings and knowledge dissemination. PMID- 21277230 TI - HIV and general cardiovascular risk. AB - The incidence of cardiovascular disease (CVD) is increasing in HIV-infected people. Risk factors such as hyperlipidemia, impaired glucose tolerance, and insulin resistance have become common. CVD in HIV may also be related to nontraditional risk factors including accumulation of visceral fat, inflammation secondary to HIV, and effects of some antiretroviral drugs. This cross-sectional study described the CVD risk factors of 123 adults living with HIV and calculated the 10-year estimate for general cardiovascular risk score. Results showed that approximately 25% of the participants were considered to be at high risk for developing CVD in the next 10 years. Increased waist circumference and longer duration of smoking habit were associated with elevated general cardiovascular risk scores. Similar to the general population, most of the identified risks could be modified through lifestyle management. PMID- 21277231 TI - Early treatment after stroke for the prevention of late epileptic seizures: a report on the problems performing a randomised placebo-controlled double-blind trial aimed at anti-epileptogenesis. AB - INTRODUCTION: Epileptic seizures in stroke patients are a common complication and adversely affect neurological outcome. We tried to perform a trial aimed at preventing the development of late poststroke seizures using levetiracetam. Levetiracetam is assumed to have anti-epileptogenic properties and might be suitable to prevent late epileptic seizures in stroke patients. METHODS: Stroke patients with a cortical syndrome and a modified Rankin score >= 3 or NIHSS >= 6 were treated with either levetiracetam 1500 mg daily divided in two doses or placebo during 12 weeks following stroke. Treatment was started within 7 days following stroke onset. RESULTS: Only 16 patients were included in this trial. Problems during the execution of this prophylactic trial concerned the assessment of the occurrence of epileptic seizures, a very slow inclusion rate, the use of anticonvulsive co-medication, continuation of the trial medication after discharge, and the evaluation of possible side effects of the trial medication. DISCUSSION: Due to too few participants, no conclusions could be drawn regarding the ability of levetiracetam to prevent poststroke seizures. The problems encountered during execution of this trial seem to be inherent to performing a trial aimed at preventing the development of epileptic seizures in stroke patients. CONCLUSIONS: A prophylactic trial in stroke patients aimed at preventing poststroke seizures and epilepsy seems not feasible. PMID- 21277232 TI - Imaging of lung cancer in the era of molecular medicine. AB - Recent discoveries characterizing the molecular basis of lung cancer brought fundamental changes in lung cancer treatment. The authors review the molecular pathogenesis of lung cancer, including genomic abnormalities, targeted therapies, and resistance mechanisms, and discuss lung cancer imaging with novel techniques. Knowledge of the molecular basis of lung cancer is essential for radiologists to properly interpret imaging and assess response to therapy. Quantitative and functional imaging helps assessing the biologic behavior of lung cancer. PMID- 21277233 TI - Right atrial scar detection after catheter ablation: Comparison of 2D and high spatial resolution 3D-late enhancement magnetic resonance imaging. AB - RATIONALE AND OBJECTIVES: To prospectively compare the diagnostic performance of two-dimensional (2D) and high spatial resolution three-dimensional (3D) late enhancement magnetic resonance imaging (MRI) for the detection of scar tissue caused by catheter ablation of the right atrium in patients with atrial flutter. MATERIALS AND METHODS: Forty-seven patients were enrolled. In 16 patients, imaging of the cavotricuspid isthmus was performed before and after catheter ablation, 16 subjects were imaged before, and 15 after catheter ablation, resulting in a total of 63 examinations. MRI included a standard 2D breathhold and a high-resolution navigator-gated 3D T1-weighted gradient-echo inversion recovery sequence in right and left anterior oblique views. Two readers assessed the subjective image quality on a 4-point scale (1 = excellent) and the presence of late enhancement (blinded/ in consensus). RESULTS: The average image quality was 1.6 for both imaging approaches. In consensus reading, the sensitivity was 83% versus 100%, specificity 97% versus 89%, accuracy 90% versus 94%, positive predictive value 96% versus 89%, negative predictive value 86% versus 100% for 2D and 3D, respectively. The interobserver agreement was 0.86 for 2D and 0.78 for 3D imaging. CONCLUSIONS: For the noninvasive identification of scars in the cavotricuspid isthmus after right atrial flutter, ablation 2D imaging was more consistent, whereas 3D sequences showed superior sensitivity for the depiction of late enhancement. PMID- 21277234 TI - Curative treatment of pelvic arteriovenous malformation--an alternative strategy: transvenous intra-operative embolisation. AB - OBJECTIVES: Pelvic arteriovenous malformations (AVMs) are difficult to treat. Arterial embolisation is the most common strategy but often has poor results. We report an alternative surgical approach of controlled intra-operative transvenous embolisation with long-term results in seven cases. MATERIALS AND METHODS: Between 1980 and 2008, we treated seven patients (four men, three women, mean age 50 years). Indications were rectal bleeding (one case), urinary tract problems (four cases), oedema of lower limb (one case) and high-output cardiac failure (one case). Four of them had previous operations and three had previous attempts for embolisation. Embolisation of the malformation was performed through the internal iliac vein. This was done after clamping of all the feeding and draining vessels. The agent used was cyanocrylate (one case), Ethibloc (one case) and bone wax (five cases). RESULTS: Mortality was 0%. Complications occurred in two patients (28,5%), one pulmonary embolism and one regressive femoral paresis. Three patients were re-operated for various reasons. The mean follow-up period was 6 years (1-12 years). Symptoms resolved in all patients, while control by computed tomography (CT) angioscan revealed one residual shunt. CONCLUSION: Complete surgical excision of pelvic AVMs is not always possible. Embolisation does not offer a permanent cure. Intra-operative transvenous embolisation of persisting complex AVMs appears to be an alternative approach with good immediate and long-term results. Ethylene glycol appears to be the most suitable agent. PMID- 21277236 TI - Mural thrombus of thoracic aorta: few solutions and more queries. PMID- 21277238 TI - Characterisation of the carboxylesterase enzyme cauxin in the seminal fluid of the cat. AB - The carboxylesterase cauxin is a major urinary protein in cats that is also found in seminal fluid (SF). This study investigated cauxin in feline SF including biochemical features, concentration, distribution and gene expression in epididymal tissue, and its reaction with acylglycerol substrates. Monomeric, dimeric, and/or multimeric forms of cauxin carrying N-glycosylations were detected on Western blots of feline SF but most were monomeric. Cauxin concentrations were markedly lower in SF (0.042+/-0.020 mg/mL) than in urine (~0.5 mg/mL) and cauxin gene expression was 60-fold lower in the epididymis than in the kidney. Immunohistochemical examination localised cauxin within the stereocilia and cytoplasm of epithelial cells lining the caput and corpus epididymis. Cauxin-positive spermatozoa were detected in the lumen of the cauda epididymis but not in the cytoplasm of the epithelial cell lining. Using an in vitro assay, cauxin hydrolysed saturated 1-mono- but not di- and tri acylglycerols. The results suggest that cauxin secreted from the caput and corpus epididymis acts as an esterase on lipid within feline SF. PMID- 21277237 TI - Role of c-Abl in L-selectin shedding from the neutrophil surface. AB - L-selectin is a key molecule that participates in neutrophil tethering and subsequent rolling. It is cleaved from the surface of neutrophils activated in the presence of lipopolysaccharides, N-formyl-methionine-leucine-phenylalanine (fMLP), or Interleukin-8 (IL-8). We previously showed that L-selectin is also shed from the neutrophil surface during rolling on sialyl Lewis-x coated surfaces in a force-, ADAM-17 sheddase-, and p38 MAP kinase-dependent manner under flow. c Abl tyrosine kinase is phosphorylated when L-selectin on the surface of neutrophils is cross-linked with anti-L-selectin antibodies. Here, we study the effect of c-Abl inhibition on L-selectin shedding from primary human neutrophils in static conditions following exposure to fMLP, IL-8, and hypotonic buffer and under flow through sialyl Lewis-x coated microtubes. Results indicate that c-Abl inhibition by STI571 significantly affects neutrophil adhesion via L-selectin, by decreasing the average rolling velocity and increasing the flux of rolling cells. The change in surface receptor expression was verified by flow cytometry. Interestingly, other forms of L-selectin shedding induced by fMLP, IL-8 or osmotic swelling were unaffected by STI571 treatment. These findings implicate the c-Abl signaling molecule in regulating L-selectin mechanical shedding in response to shear stress, setting this type of signaling apart from those triggered by the presence of a hypotonic environment, fMLP, or IL-8. This study sheds light on the role of c-Abl in neutrophil adhesion not previously reported in the literature. PMID- 21277239 TI - A study of the comparative anatomy of the brain of domestic ruminants using magnetic resonance imaging. AB - Although magnetic resonance imaging has been used to examine the brain of domestic ruminants, detailed information relating the precise anatomical features in these species is lacking. In this study the brain structures of calves (Bos taurus domesticus), sheep (Ovis aries), goats (Capra hircus) and a mesaticephalic dog (Canis lupis familiaris) were examined using T2-weighed Turbo Spin Echo sequences; three-dimensional models based on high-resolution gradient echo scans were used to identify brain sulci and gyri in two-dimensional images. The ruminant brains examined were similar in structure and organisation to those of other mammals but particular features included the deep depression of the insula and the pronounced gyri of the cortices, the dominant position of the visual (optic nerve, optic chiasm and rostral colliculus) and olfactory (olfactory bulb, olfactory tracts and piriform lobe) systems, and the relatively large size of the diencephalon. PMID- 21277240 TI - Distribution of a pathological form of prion protein in the brainstem and cerebellum in classical and atypical cases of bovine spongiform encephalopathy. AB - This study evaluated the distribution and signal intensity of a prion protein resistant to proteolysis (PrP(res)) in the brainstem and cerebellum of cattle affected with classical and atypical forms of bovine spongiform encephalopathy (BSE) using a Western immunoblotting technique. In both classical and atypical cases of BSE, a stronger signal was detected in the more rostral brainstem regions relative to the obex. In classical and H-type cases a significant decrease in the PrP(res) signal was found in the cerebellum when compared to that in the obex, whereas L-type BSE cases were characterised by signals of similar intensity in these regions. The uniform distribution of PrP(res) in the region rostral to the obex suggests that when autolysed samples are being tested for BSE, both classical and atypical forms are detectable, even when this target site is missing or cannot be clearly identified. The findings indicate that both the obex and rostral brainstem can be used for BSE diagnosis whereas use of the more caudal brainstem regions and cerebellum is not recommended. PMID- 21277241 TI - Determination of immunoglobulin A concentrations in the serum and cerebrospinal fluid of dogs: an estimation of its diagnostic value in canine steroid-responsive meningitis-arteritis. AB - Previous studies on canine steroid-responsive meningitis-arteritis (SRMA) suggested that elevation of immunoglobulin A (IgA) concentrations in both serum and cerebrospinal fluid (CSF) is specific for SRMA throughout the different disease stages. Recent studies however have raised concerns about the value of this test. The purpose of this study was to investigate the diagnostic value of IgA concentration testing in paired CSF and serum samples. IgA concentrations of 525 paired canine CSF and serum samples were evaluated. Samples were obtained from dogs with SRMA (n=311) and dogs with miscellaneous conditions (n=214) such as other central nervous system (CNS) inflammatory diseases (n=34), CNS tumours (n=46), idiopathic epilepsy (n=42), intervertebral disc disease (n=46) and non CNS diseases (n=46). Serum IgA concentrations were significantly higher in dogs with untreated SRMA compared to those with other diseases. IgA CSF concentrations were significantly higher in dogs with SRMA compared to other disease categories, with the exception of inflammatory CNS disease. The sensitivity for IgA concentrations in serum and CSF was 91% with a specificity of 78%. Analysis of 525 paired samples confirmed that IgA concentrations were higher in dogs with SRMA. Calculation of the diagnostic value of IgA concentration confirmed that the test is highly sensitive for SRMA. Testing paired CSF and serum samples for IgA is still recommended for the diagnosis of suspected cases of SRMA. PMID- 21277242 TI - In pursuit of a prognostic marker in canine mammary tumors. PMID- 21277243 TI - Differential central pain processing following repetitive intramuscular proton/prostaglandin E2 injections in female fibromyalgia patients and healthy controls. AB - BACKGROUND: While the etiology of fibromyalgia syndrome (FMS) remains unclear, it is assumed that both peripheral and central components are involved. AIMS/METHODS: To investigate central activation patterns following chemically induced muscle pain we repetitively injected protons (low pH) and prostaglandin E(2) (PGE(2)) in isotonic solution into the left extensor carpi radialis brevis muscle of female FMS patients and female healthy control subjects (HC). The injection of protons/PGE(2) has the advantage that it is not prone to tachyphylaxis compared to capsaicin and hypotonic saline solution. During the repetitive injections continuous pain ratings were recorded and functional magnetic resonance imaging measurements were conducted. RESULTS: Injection of protons/PGE(2) led to activation of the anterior and medial cingulate cortices, contralateral primary sensory cortex, bilateral insula and thalamus, left basal ganglia, left orbitofrontal cortex and the cerebellum in FMS patients. In HC, activations were found only in the anterior, medial, and posterior cingulate cortices, and the primary somatosensory cortex. The contrast between the groups revealed significantly stronger activation for FMS patients in the left anterior insula. Peak pain ratings were comparable between HC and FMS patients, but pain duration (sustained pain) was prolonged in FM. CONCLUSION: Repetitive proton/PGE(2)-induced excitation of muscle tissue led to a more prolonged perception of pain and more wide-spread activation in pain-related brain areas in FMS, especially in the left (ipsilateral) insula, whereas acute protons/PGE(2) induced pain processing was similar in the two groups. These data provide further evidence for enhanced central pain processing in FMS patients. PMID- 21277244 TI - Cerebral vascular hamartoma in a geriatric cat. AB - An 11-year-old castrated male domestic medium hair cat was presented with neurological signs consistent with a right thalamocortical lesion. Computed tomography (CT) images revealed a heterogeneously, hyperattenuating, poorly contrast enhancing intra-axial mass within the right lateral ventricle. The histological diagnosis at post-mortem examination was vascular hamartoma with hemorrhage and necrosis. This is the first report of a vascular hamartoma affecting the thalamocortex in a geriatric cat. Also, this is the first time that CT images of a feline cerebral vascular hamartoma have been reported. PMID- 21277245 TI - Arterial hypertension in overweight and obese Algerian adolescents: role of abdominal adiposity. AB - OBJECTIVE: This study aimed to estimate the prevalence of hypertension in Algerian overweight and obese adolescents to assess the risk factors associated with hypertension and an increase in arterial stiffness. SUBJECTS AND METHODS: This cross-sectional study included 305 adolescents (133 boys and 172 girls) aged 12-19 years, who were either overweight or obese (IOTF criteria). Their body weight, height, BMI, waist circumference (WC), WC-to-height ratio and blood pressure were also measured. RESULTS: Hypertension and prehypertension were found in 19.7 and 16.1%, respectively, of the study population, with significantly more hypertensives among the obese than among the overweight adolescents. The prevalence of hypertension was also twice as high in boys as in girls (27.1% vs 14%; P=0.004), and WC and WC-to-height ratios were significantly higher in hypertensives than in normotensives. The risk of hypertension was also significantly higher in boys and associated with WC, independent of age and severity of weight excess (whether overweight or obese). Mean pulse pressure (PP) was significantly higher in boys versus girls, in obese versus overweight adolescents and in hypertensives versus normotensives, and was correlated with WC and WC-to-height ratio. PP >45 mmHg was associated with WC and hypertension only in boys, independent of age. CONCLUSION: The prevalence of hypertension is high in overweight and obese adolescents, and higher in boys than in girls. Hypertension and arterial stiffness, as determined by high PP levels, were associated with abdominal adiposity. It is recommended that prehypertension be identified in overweight adolescents and that lifestyle changes be made to avoid its evolution towards obesity and hypertension. PMID- 21277246 TI - [Paraclinoid region: descriptive anatomy and radiological correlations with MR imaging]. AB - OBJECTIVE: The paraclinoid region has a complex anatomy. The purpose of this study was to depict in details its anatomical landmarks and their radiological translations with magnetic resonance imaging (MRI). MATERIAL AND METHOD: Ten anatomical specimens (20 paraclinoid regions) were prepared, then dissected and further analyzed with MRI in order to describe their important radio-anatomical structures (dural folds, osseous surfaces, arteries and nerves) along with their course and measurements, and the reference points of the carotid distal dural ring. The paraclinoid MR protocol consisted in a T2 high-resolution sequence with thin and contiguous slices acquired in a coronal (diaphragmatic) and sagittal oblique (carotid) plane. Reproducibility in living subjects was evaluated on 15 patients (30 paraclinoid regions). Statistical comparison was made between laboratory and MR measurements obtained on cadavers. RESULTS: A detailed description of paraclinoid anatomy and structures was provided. Its landmarks were satisfactorily identified with the dedicated MR protocol. Reproducibility in living subjects was obtained. No statistical difference was found between laboratory and MR measurements. CONCLUSION: This study provides a precise description of paraclinoid anatomical structures and their radiological correlations. This paraclinoid MR protocol allows locating paraclinoid lesions in comparison with the cavernous sinus roof, which is of paramount importance for the management of paraclinoid carotid artery aneurysms. PMID- 21277247 TI - Autopsy findings of a patient with rapidly progressive massive ascites caused by alcoholic cirrhosis. AB - A 54-year-old man, who lived alone, was hospitalized due to rapid deterioration of the general condition over a three-week period caused by alcoholic cirrhosis. One month after he left hospital, he was found dead in his house by his friend. Three days before he was found dead, he had met his friend and seemed to be in poor condition. Autopsy was conducted by a medical examiner to clarify the cause of death. Externally, signs of severe jaundice were apparent over the whole body, along with extensive abdominal swelling and edema of the extremities. Autopsy findings demonstrated that the abdominal cavity contained an amount of massive turbid and slight pale reddish brown ascites (23 l). There were no findings of severe peritoneal inflammation. The liver (650 g) was elastic hard and had a micro-nodular surface, which showed severe atrophy. Microscopic examination of the liver showed clear pseudolobule with severe fibrosis in the stroma. There were no significant changes in the heart or brain. The stomach was empty and only a slight amount of intestinal contents. There was no ethanol detected in the blood or urine. The direct cause of his death was circulatory dysfunction due to massive accumulation of the ascites. The reasons for the massive ascites accumulation over 20 l in this case were (1) that he had no serious complications other than ascites; and (2) he did not have any medical treatment just before his death. PMID- 21277248 TI - System for objective assessment of fetal activity. AB - Fetal activity is an important indicator of fetal well-being. It is proposed to assess this activity using the pulsed wave Doppler method to collect fetal activity data and dedicated software for on-line processing. The system, addressed to 3rd trimester pregnancies, provides information on presence of pseudobreathing, the heart rate trace, the fetal movement trace, the movement velocity spectrogram, histograms of the velocity and acceleration of both the body movements and pseudobreathing, parameters of these histograms (mean values, standard deviations, shape descriptors), and cumulative counts of the velocity histograms. These parameters form the feature vector of the fetal activity. The system was validated by simultaneous echographic and cardiotocographic recordings and during oxytocin challenge tests. Feature vectors obtained from 1h recordings in 61 pregnancies were submitted to multivariate analysis of variance. Activity patterns of physiological cases and "borderline pathologies" were discriminated using reduced feature vectors, containing cumulative counts of velocity histograms. PMID- 21277249 TI - The development of a novel serotyping-NS1-ELISA to identify serotypes of dengue virus. AB - BACKGROUND: Dengue virus (DENV), which causes mosquito-borne disease dengue hemorrhagic fever (DHF), consists of four serotypes co-circulating in endemic areas. Currently, DENV serotypes can be identified by laborious virus isolation followed by immunofluorescent assay and sophisticated RT-PCR. OBJECTIVE: To establish a new assay designated as "serotyping-NS1-ELISA" to detect the NS1 protein and to identify DENV serotypes simultaneously. STUDY DESIGN: The monoclonal antibodies (Mabs) against NS1 of each DENV serotype were produced and characterized for their serotype-specificity. To develop serotyping-NS1-ELISA, the selected serotype-specific anti-NS1 Mabs were applied to detect the NS1 antigen, which was previously captured by a flavivirus cross-reactive anti-NS1 Mab. Serotyping accuracy of the developed assay was validated with NS1 from DENV infected cell culture supernatants and from well-characterized clinical specimens. RESULTS: Of 30 anti-NS1 Mabs, 1 serotype-specific anti-NS1 Mab to each DENV serotype was selected based on NS1 capture ELISA results for developing the serotyping-NS1-ELISA. Using DENV-infected cell culture supernatants for validation, the selected antibodies were shown to be capable of differentiating four DENV serotypes. When acute phase plasma from DENV-infected patients was used for validation, 65 out of 85 specimens (76.5% overall sensitivity) were positive to one of the four serotypes developed in our assay. Interestingly, identification of DENV serotypes by our serotyping-NS1-ELISA was 100% accurate for DENV1, 3 and 4 and 82.4% for DENV2 as compared with standard RT-PCR. Assay specificity was 100% (90/90). CONCLUSIONS: The developed serotyping-NS1-ELISA provides an alternative for simultaneous detection of DENV NS1 and identification of its serotype in acute patients' specimens. The assay would be applicable for dengue diagnosis and epidemiological studies. PMID- 21277250 TI - The effect of saccade spike on saccadic peak velocity. PMID- 21277251 TI - Automated single-trial detection and quantification of evoked potentials, a potential tool for neuromonitoring? PMID- 21277252 TI - Development of natural anti-tumor drugs by microorganisms. AB - Discoveries of tumor-resistant pharmacological drugs have mainly resulted from screening of natural products and their analogs. Some are also discovered incidentally when studying organisms. The great biodiversity of microorganisms raises the possibility of producing secondary metabolites (e.g., mevastatin, lovastatin, epothilone, salinosporamide A) to cope with adverse environments. Recently, natural plant pigments with anti-tumor activities such as beta carotene, lycopene, curcumin and anthocyanins have been proposed. However, many plants have a long life cycle. Therefore, pigments from microorganisms represent another option for the development of novel anti-tumor drugs. Prodigiosin (PG) is a natural red pigment produced by microorganisms, i.e., Serratia marcescens and other gram-negative bacteria. The anti-tumor potential of PG has been widely demonstrated. The families of PG (PGs), which share a common pyrrolylpyrromethene (PPM) skeleton, are produced by various bacteria. PGs are bioactive pigments and are known to exert immunosuppressive properties, in vitro apoptotic effects, and in vivo anti-tumor activities. Currently the most common strain used for producing PGs is S. marcescens. However, few reports have discussed PGs production. This review therefore describes the development of an anti-tumor drug, PG, that can be naturally produced by microorganisms, and evaluates the microbial production system, fermentation strategies, purification and identification processes. The application potential of PGs is also discussed. PMID- 21277253 TI - Modifying the antigen-immunization schedule improves the variety of monoclonal antibodies obtained from immune-phage antibody libraries against HIV-1 Nef and Vif. AB - Immune phage antibody libraries are an attractive technology for isolating antigen-specific monoclonal antibodies (mAbs). Here we show that the immunization schedule affects the immune phage antibody library properties. We subcutaneously (s.c.) administered HIV-1 Nef and Vif antigens with different schedules (25 MUg * 2 s.c. and 10 MUg * 3 s.c.). The variety of isolated mAbs in 25 MUg * 2 s.c. groups (Nef: 11 clones, Vif: 9 clones) was superior to that in the 10 MUg * 3 s.c. groups (Nef: 2 clones, Vif: 1 clone). This finding suggests that it is important to optimize the immunization schedule for isolating a wide variety of mAbs. PMID- 21277254 TI - Quantitative correlation between production rate of melanoma inhibitory activity and aggrecan gene expression level during differentiation from mesenchymal stem cells to chondrocytes and redifferentiation of chondrocytes. AB - The cell-specific production rate of melanoma inhibitory activity was quantitatively proportional to the aggrecan gene expression level in the early and middle phase during not only the redifferentiation culture of human cartilage chondrocytes but also the differentiation culture of human bone marrow mesenchymal stem cells to chondrocytes. PMID- 21277255 TI - Long-term safety and efficacy of ramelteon in Japanese patients with chronic insomnia. AB - OBJECTIVE: To evaluate the safety of ramelteon, a highly selective MT1/MT2 melatonin receptor agonist, during 24 weeks' treatment of Japanese patients with chronic insomnia. METHODS: In a single-blind, flexible-titration, multicenter study incorporating placebo run-in and run-out periods, 190 adults with chronic insomnia received ramelteon 4 or 8 mg, titrated up to 16 mg if necessary, for 24 weeks. Primary endpoints included adverse events, residual effects, rebound insomnia, withdrawal symptoms, and dependence. Secondary endpoints included subjective sleep latency and total sleep time. RESULTS: Drug-related adverse events occurred in 11.6% of patients. No clinically important changes occurred in biochemical, hematological or endocrine parameters. There were no signs of next day residual effect, rebound insomnia, withdrawal symptoms or dependence. Mean subjective sleep latency decreased significantly, and total sleep time increased significantly; both reached a plateau by week 20 and were sustained thereafter (P<0.0001). CONCLUSIONS: Ramelteon was well tolerated in adult Japanese patients with chronic insomnia and did not cause deterioration of efficacy, residual effects, rebound insomnia, withdrawal symptoms, or dependence after 24 weeks' treatment. PMID- 21277257 TI - Uses of mosquito-stage transmission-blocking vaccines against Plasmodium falciparum. AB - A quantitative framework is used to explore the potential applications and probable effects of sexual stage or mosquito stage transmission blocking vaccines (TBVs) against malaria. The combination of TBVs with biocides or other malaria vaccines will increase chances of interrupting transmission, whereas the value of TBVs for morbidity control will be limited. Vaccine combination will also protect against selection of insensitive parasites. Simulations indicate that TBVs will reduce risks of reestablishment of transmission when vector control is withdrawn. Simple mathematical analysis shows that efficacy and coverage are equally important, implying that a vaccine that requires a small number of doses (ideally one) is preferable to one that is difficult to deliver, even if this entails accepting a lower efficacy. PMID- 21277256 TI - The cardiokine story unfolds: ischemic stress-induced protein secretion in the heart. AB - Intercellular communication depends on many factors, including proteins released via the classical or non-classical secretory pathways, many of which must be properly folded to be functional. Owing to their adverse effects on the secretion machinery, stresses such as ischemia can impair the folding of secreted proteins. Paradoxically, cells rely on secreted proteins to mount a response designed to resist stress-induced damage. This review examines this paradox using proteins secreted from the heart, cardiokines, as examples, and focuses on how the ischemic heart maintains or even increases the release of select cardiokines that regulate important cellular processes in the heart, including excitation contraction coupling, hypertrophic growth, myocardial remodeling and stem cell function, in ways that moderate ischemic damage and enhance cardiac repair. PMID- 21277258 TI - The process of developing a framework to guide rural nurse preceptors in the evaluation of student performance. AB - Increasingly, rural preceptorships are sought out for their rich learning opportunities and as an alternative to often over-subscribed urban placements. While rural preceptors view teaching students as a gratifying experience, student evaluation remains an ongoing challenge. Frequently, rural preceptors often lack access to preceptor preparation, faculty support, and other forms of professional development, particularly those learning experiences that are specific to the unique rural setting and nursing culture. In this article, the authors describe Phase Two of a four-phase study which sought to develop and validate, in collaboration with rural nurse preceptors, a framework for conducting student evaluations. Following a grounded theory phase of the study in which the experience of preceptors and students in rural placements were explored, the researchers, project staff, and three rural nurse preceptors met during two working sessions to collate the study results, the nursing education literature, and the preceptors' own experiences to develop a framework for the evaluation process during a rural preceptorship. This framework, using a Who, What, Where, When, Why, and How approach, supported a broader perspective of evaluation of student performance, and provided preceptors with useful strategies for making evaluation an effective component of student learning. PMID- 21277259 TI - The role of molecular immunohematology in sickle cell disease. AB - Red blood cell transfusion therapy is a key component in the treatment of patients with sickle cell disease (SCD). There is no universal standard of care for the appropriate selection of RBC products for patients with SCD. A number of programs extend antigen matching to E and C in the Rh system, and to K, and some attempt to transfuse blood from African-American donors. Although these varied approaches reduce the rate of alloimmunization, patients continue to develop Rh antibodies. Molecular DNA-based analyses of patients alloimmunized to the Rh system, despite serologic Rh antigen matching, invariably reveal altered RH alleles. The prevalence of altered RH alleles in patients with SCD suggests an important emerging role for molecular methods in expanding matching of patients and donors in the Rh system for this patient population. PMID- 21277260 TI - Editorial comment. PMID- 21277261 TI - Platelet activation of platelet concentrates derived from buffy coat and apheresis methods. AB - Preparation for storage may cause platelet activation. The quality of platelet concentrates plays an important role in transfusion therapy. Platelet concentrates are produced by different centrifugation methods; buffy coat (buffy coat-derived platelet concentrates-BC) and plateletpheresis (apheresis-derived platelet concentrates-APC). Their quality was assessed using the following parameters: platelet, WBC and RBC counts pH, volume, platelet factor 4 (PF4) and Annexin V. The present paper compares the quality of both platelet preparations in vitro. In this experimental study, 30 platelet concentrates were harvested with the Haemonetics MCS plus and 30 units via the buffy coat (BC) method. The percentages of Annexin V expression, PF4 levels, platelet, WBC and RBC counts, pH and volume were measure immediately after collection and after 3 days of storage. During storage for up to 3 days, BC units displayed, no significant pH or RBC, difference in comparison with apheresis preparations (p>0.05). During storage for up to 3 days, BC units displayed a significant increase in the PF4 and Annexin V expression, compared to the apheresis preparations on day three (p<0.05). The kinetics of PF4 and Annexin V levels are influenced by the method used to prepare platelets for storage. The different levels of PF4 and Annexin V in BCs and APCs clearly demonstrates a progressive activation of BC platelets exceeding that of APC. However, in vivo studies should be performed to confirm these findings. PMID- 21277263 TI - Familiarity with, knowledge of, and attitudes toward epilepsy in Turkey. AB - The aims of the study described here were to investigate familiarity with, knowledge of, and attitudes toward epilepsy and to assess indicators of positive attitudes toward epilepsy. Questionnaires previously developed for the Turkish population were used to assess knowledge and attitudes. Data were collected from 1354 randomly selected adults. Three-quarters of the sample had heard something about epilepsy, and almost half of the sample personally knew someone with epilepsy. The sample had a moderate level of knowledge of and favorable attitudes toward epilepsy in general. Variables that predicted positive attitudes were young age, male gender, and high level of knowledge of epilepsy. The results for both knowledge and attitudes indicate that the findings of the study are largely in line with previous studies, but where there is wide variability among previous findings, the findings for the Turkish population lie, just as Turkey does geographically, between those of the East and West. PMID- 21277262 TI - Molecular genetics and clinical applications for RH. AB - Rhesus is the clinically most important protein-based blood group system. It represents the largest number of antigens and the most complex genetics of the 30 known blood group systems. The RHD and RHCE genes are strongly homologous. Some genetic complexity is explained by their close chromosomal proximity and unusual orientation, with their tail ends facing each other. The antigens are expressed by the RhD and the RhCE proteins. Rhesus exemplifies the correlation of genotype and phenotype, facilitating the understanding of general genetic mechanisms. For clinical purposes, genetic diagnostics of Rhesus antigens will improve the cost effective development of transfusion medicine. PMID- 21277264 TI - Operative laparoscopy as the mainstay method in management of hemodynamically unstable patients with ectopic pregnancy. AB - STUDY OBJECTIVE: To determine the safety and sustainability of operative laparoscopy in hemodynamically unstable women with ectopic pregnancy according to the effect of operator experience on success rates, whether the volume of hemoperitoneum affects the operative method used, and requirements for admission to the intensive care unit (ICU) and administration of blood transfusion. DESIGN: Prospective cohort study (Canadian Task Force classification II-A). SETTING: University hospital. PATIENTS: Between January 2003 and February 2010, 505 women with ectopic pregnancy (55 tubal, 4 ovarian, 7 cornual, and 1 in the cesarean scar) were seen, including 124 women with hemoperitoneum greater than 500 mL, of whom 67 were hemodynamically unstable. INTERVENTIONS: Operative laparoscopy. MEASUREMENTS AND MAIN RESULTS: The greater the volume of hemoperitoneum, the greater the likelihood of hemodynamic instability. The odds of hemodynamic instability were greater in nontubal ectopic pregnancies. The overall operative laparoscopy rate in hemodynamically unstable patients was 85%, compared with 95% in hemodynamically stable women. The volume of hemoperitoneum did not affect the operative method used. Experienced operators had a 100% success rate at operative laparoscopy in hemodynamically unstable women, compared with a 72% success rate with confident operators. A small number of women required admission to the ICU. Although the laparoscopy group required more blood transfusions, they had a shorter length of hospital stay compared with the laparotomy group. CONCLUSION: Operative laparoscopy is safe and sustainable in most women with hemodynamic instability. Women who undergo operative laparoscopy do no worse than those who undergo laparotomy, and even those who require ICU admission still benefit from the advantages of operative laparoscopy. PMID- 21277265 TI - On-line microdialysis system with poly(amidoamine)-encapsulated Pt nanoparticles biosensor for glutamate sensing in vivo. AB - In this work, an amine-terminated poly (amidoamine) dendrimer containing Pt nanoparticles (PAMAM/Pt) nanocomposite was synthesized and a novel amperometric H(2)O(2) biosensor based on PAMAM/Pt and MWCNTs was developed. The resulting film of MWCNTs/PAMAM/Pt was characterized by transmission electron microscopy (TEM), linear sweep voltammetry (LSV) and amperometric i-t curve. It demonstrates excellent electrocatalytic responses toward the reduction of H(2)O(2) at -200 mV (vs.SCE) without HRP participation. Immobilized with glutamate oxidase (GlutaOx), an effective glutamate biosensor, was fabricated, and the in vivo detection for glutamate was realized combining with the on-line microdialysis system. The glutamate biosensor showed good linear range from 1.0 MUM to 50.0 MUM with the detection limit of 0.5 MUM (S/N=3). The basal level of glutamate in the striatum of rat was detected continuously with this on-line system and was calculated to be 5.80+/-0.12 MUM (n=3). This method was proved to be sensitive and selective and may be feasible in the further application of physiology and pathology. PMID- 21277266 TI - [Low-dose cinacalcet reduces serum calcium in patients with primary hyperparathyroidism not eligible for surgery]. AB - We present our experience with low-dose cinacalcet to normalize serum calcium in patients with primary hyperparathyroidism (PHPT) not eligible for surgery. We analyzed the impact of this drug on various parameters of calcium-phosphorus metabolism and its tolerability profile. We recruited 17 patients diagnosed with PHPT who had hypercalcemia and also met one or more of the following inclusion criteria: elevated risk for parathyroidectomy, persistent/recurrent PHPT after previous parathyroid surgery or refusal to undergo surgery. The starting dose of cinacalcet was 30 or 60 mg/day, which was adjusted depending on the degree of calcemia reduction and tolerance to the drug. We observed a reduction in serum calcium that was already evident in the first post-treatment test. Appropriate dose adjustment was performed when required and normal serum calcium levels were achieved in most patients, remaining stable during follow-up. Parathyroid hormone was reduced but not normalized in most patients. Calciuria decreased while serum phosphate and alkaline phosphatase levels increased. Cinacalcet tolerance was generally good at the doses used. The most common adverse effects were weakness, dizziness and asthenia, leading to treatment withdrawal in only one patient. We conclude that low-dose cinacalcet reduces serum calcium efficiently, normalizes calcium levels in most patients with PHPT not eligible for surgical treatment and has a good tolerability profile. PMID- 21277267 TI - Microvascular surgical training models. PMID- 21277268 TI - The use of custom-made external nipple-areolar prostheses following breast cancer reconstruction. PMID- 21277269 TI - 'Mini' free groin flap for treatment of a tufted angioma of the finger. AB - Tumours in children can be alarming and diagnosis difficult when the pathology is rare. Furthermore tumours on the finger and subsequent treatment may lead to loss of function. The often-difficult decisions regarding treatment of vascular anomalies are often best managed in the multidisciplinary team meeting. Kaposiform hemangioendothelioma (KHE) and tufted angioma (TA) are rare forms of vascular tumours. There is evidence that they may represent variants of the same tumour group. We present a unique case of TA/KHE involving the finger in a three year-old child. PMID- 21277270 TI - Comparison of longitudinal myocardial tissue velocity, strain, and strain rate measured by two-dimensional speckle tracking and by color tissue Doppler imaging in healthy dogs. AB - OBJECTIVES: Two-dimensional speckle tracking (2D-ST) is a new method to measure tissue velocity (TV), strain and strain rate (SR), but it is unclear if results are comparable to color tissue Doppler imaging (TDI). The objective was therefore to compare the two modalities 2D-ST and TDI. ANIMALS: 100 healthy dogs METHODS: TDI images were acquired from the interventricular septal wall (IVS) and the left ventricular free wall (LVFW) to measure longitudinal TV, strain, and SR, and grayscale images were collected for 2D-ST analysis. A software program was developed, that allowed extraction of single points (SP) from the 2D-ST data set to compare SP with averages of segments (AOS) results, which are usually displayed by the 2D-ST software. RESULTS: A good agreement was found between AOS and SP measurements using 2D-ST. Although most data were within limits of agreement, significant differences were found between TDI and 2D-ST measurements for selected parameters. The differences were small in the IVS, but higher and of clinical relevance in the LVFW. 2D-ST was feasible and reproducible in the IVS, but less reliable in the LVFW. CONCLUSIONS: 2D-ST and color TDI can be used interchangeably in the IVS, but the methods reveal different results in the LVFW. PMID- 21277271 TI - The effectiveness of medical interventions aimed at preventing preterm birth: a literature review. AB - BACKGROUND: Preterm birth is a significant global health problem with serious short and long term consequences. This paper reviews the research literature to answer the question how effective are the medical interventions that aim to reduce the rates of preterm birth? METHODS: A systematic search was carried out in CINAHL, Cochrane, Medline and Embase in relation to following medical treatments aimed at preventing preterm births: anti-infective medications, tocolytics, progesterone and cervical cerclage. The research underpinning each type of intervention is critically analysed in order to establish the validity of knowledge claims that are made for each type of intervention. FINDINGS: In relation to reducing the rates of preterm births, anti-infectives are only effective in the presence of known infection. Screening for infections during pregnancy is ineffective. Tocolytic agents are not effective in decreasing the preterm birth rates. Progesterone seems to be effective in a select group of pregnant women at higher risk of preterm birth. Cervical cerclage plays a small and an occasional role in preventing some preterm births. CONCLUSIONS: This literature review demonstrates that medical interventions aimed at preventing, not just delaying, preterm birth, are not effective at a population level. Providing holistic, antenatal midwifery care for women living in socio-economic disadvantage and/or with an increased risk of preterm birth seems to be a promising strategy to address the negative effects of the social determinants of disease and thus to reduce the rate of preterm births at an individual and a population level. PMID- 21277272 TI - Genetic diversity of 17 Y-short tandem repeats in Indian population. AB - Seventeen short tandem repeats (DYS389I, DYS390, DYS389II, DYS19, DYS385a/b, DYS393, DYS391, DYS392, DYS439, DYS438, DYS456, DYS458, DYS635, Y(GATA)H4, DYS437, and DYS448) from the non-recombining region of the human Y-chromosome were analyzed in 750 unrelated males representing four major linguistic families of India using AmpFlSTR((r)) Yfiler((r)) PCR Amplification kit. A total of 612 distinct haplotypes were observed, of which 545 were unique. Rare alleles for the loci DYS456, DYS458, DYS635, Y(GATA)H4, and duplication at the loci DYS389I and DYS389II were also observed. To understand the genetic diversity of the Indian population, and utility of Y-STRs in forensics, the locus diversity, haplotype diversity, and discrimination capacity in all populations was determined. MDS plot based on pairwise Phi(st) and AMOVA revealed the high genetic heterogeneity among the Indian populations due to linguistic diversity and social stratification. PMID- 21277273 TI - Presentation of 17 Y-chromosomal STRs in the population of the Sverdlovsk region. AB - We established a data set of 17 Y-STRs (DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS385a/b, DYS438, DYS439, DYS437, DYS448, DYS456, DYS458, DYS635 and Y-GATA-H4) of 832 unrelated males from the Sverdlovsk region, Russian Federation. In total we observed 773 different haplotypes of which 732 were unique and 41 occurred between two and nine times in the investigated population. The haplotype diversity was 0.9981 and the discrimination capacity was 0.9291. This study represents the Y-STR reference data set for forensic applications in the Sverdlovsk region. PMID- 21277274 TI - Unbiased screening of polymer libraries to define novel substrates for functional hepatocytes with inducible drug metabolism. AB - Maintaining stable differentiated somatic cell function in culture is essential to a range of biological endeavors. However, current technologies, employing, for example, primary hepatic cell culture (essential to the development of a bio artificial liver and improved drug and toxicology testing), are limited by supply, expense, and functional instability even on biological cell culture substrata. As such, novel biologically active substrates manufacturable to GMP standards have the potential to improve cell culture-based assay applications. Currently hepatic endoderm (HE) generated from pluripotent stem cells is a genotypically diverse, cheap, and stable source of "hepatocytes"; however, HE routine applications are limited due to phenotypic instability in culture. Therefore a manufacturable subcellular matrix capable of supporting long-term differentiated cell function would represent a step forward in developing scalable and phenotypically stable hESC-derived hepatocytes. Adopting an unbiased approach we screened polymer microarrays and identified a polyurethane matrix which promoted HE viability, hepatocellular gene expression, drug-inducible metabolism, and function. Moreover, the polyurethane supported, when coated on a clinically approved bio-artificial liver matrix, long-term hepatocyte function and growth. In conclusion, our data suggest that an unbiased screening approach can identify cell culture substrate(s) that enhance the phenotypic stability of primary and stem cell-derived cell resources. PMID- 21277275 TI - Boosting disability research in the engineering sciences. The recommendations of the National Observatory for Training, Research and Innovation on Disability (ONFRIH). AB - In 2005, the National Observatory for Training, Research and Innovation on Disability (ONFRIH) was established by French law (Law 2005-102). The mission of ONFRIH is to provide an overview and recommendations for research, training and prevention in the field of disability. In this paper, the authors, respectively the Chairman and Rapporteur of the ONFRIH Working Group "Research and Innovation", present the Observatory's conclusions reached in its 2009 report about engineering sciences research and innovation. After introducing the ONFRIH and recalling the stakes and working methods, they highlight the current state of French research in this area and their thoughts about innovation chain. They evoke the broad outlines of their working group's analysis of this inventory. They conclude by identifying four action plans that express the Observatory's recommendations and were submitted to the responsible ministers. The four main objectives proposed are: (1) to consolidate disability as a major challenge for engineering sciences applications; (2) to reinforce the cooperation between operators at all levels of research and innovation; (3) to encourage the expression of needs within the research and innovation process, and (4) to facilitate the access of disabled people to technological innovations that promote their autonomy and social inclusion. PMID- 21277276 TI - Targeted biotherapy in metastatic colorectal carcinoma: Current practice. AB - Targeted therapy has become an indispensable tool in the management of metastatic colorectal cancer (mCRC). The combination of monoclonal antibodies with conventional polychemotherapy has proven its efficacy as the median overall survival now exceeds 24 months: these novel molecules act by targeting circulating vascular endothelial growth factor (VEGF) and the receptor of epidermal growth factor (EGFR). At the present time, no factor has been identified to predict the efficacy of bevacizumab, an inhibitor of circulating VEGF. On the other hand, mutation of the KRAS oncogen has been proven to be a factor of non-response, or even of deleterious response to the use of EGFR, therefore limiting its use to patients whose tumors bear the wild type KRAS oncogen. Treatment toxicity for these molecules is moderate, specific, and is not cumulative with chemotherapy-related toxicity. On the other hand, combined targeted therapy (association of several targeted therapy drugs) has not been shown to be of any benefit. Other biotherapies continue to be developed, but there is not yet a consensus of how to best target the tumor nor which anti tumoral molecules to use in the treatment of mCRC. PMID- 21277277 TI - New approach in transanal endoscopy microsurgery. PMID- 21277278 TI - Gastric cancer: So much has changed for surgeons! PMID- 21277279 TI - Surgical treatment of large incisional hernias by intraperitoneal insertion of Parietex(r) composite mesh with an associated aponeurotic graft (280 cases). AB - AIMS OF THE STUDY: To evaluate post-operative complications and the recurrence rate after repair of large ventral incisional hernia with an open technique using intraperitoneal composite mesh and an associated aponeurotic overlay. PATIENTS AND METHODS: This prospective study included a total of 280 patients who underwent repair of large incisional hernia using Parietex((r)) composite mesh. RESULTS: The post-operative mortality rate was 0.35%. Six patients (2%) developed subcutaneous surgical site infection without infection of the prosthesis. Six other patients (2%) developed a deep-seated infection; in three cases, the mesh had to be removed. Nine patients (3.2%) developed recurrent incisional hernia. CONCLUSION: Large ventral incisional hernias can be effectively treated by the intraperitoneal placement of Parietex((r)) composite mesh overlaid by an aponeurotic graft; the incidence of complications in this prospective study was very low. PMID- 21277280 TI - Common peroneal entrapment neuropathy secondary to a popliteal lipoma: ultrasound superior to magnetic resonance imaging for diagnosis. PMID- 21277281 TI - Osteoid osteoma of the spinoglenoid notch mimicking cervical radiculopathy. PMID- 21277283 TI - Identification of novel small molecules that inhibit protein-protein interactions between MAGE and KAP-1. AB - The Class I MAGE proteins are normally expressed only in developing germ cells but are often aberrantly expressed in malignancies, particularly melanoma, making them good therapeutic targets. MAGE proteins promote tumor survival by binding to the RBCC region of KAP-1 and suppressing p53. Although, suppression of MAGE expression, by RNA interference, relieves p53 suppression and inhibits tumor growth, its therapeutic uses are limited by lack of methods for systemic delivery of small interfering RNA. To overcome this barrier, we sought to discover chemical compounds that inhibit binding between MAGE and KAP-1 proteins. Based on previously published effects of MAGE suppression, we developed a strategy for screening a small molecule library based on selective death of MAGE positive cells, activation of p53 and lack of caspase activity. We screened the Maybridge HitFinder library of compounds and eight compounds fulfilled these criteria. Seven of these compounds interfered with co-precipitation of MAGE and KAP-1, and three interfered with binding of MAGE and KAP-1 in a mammalian two hybrid assay. We now report identification of three potential compounds that interfere with MAGE/KAP-1 binding and can be developed as novel chemo-therapeutic agents for treatment of advanced melanoma and other cancers. PMID- 21277284 TI - ER stress-induced protein, VIGG, disturbs plant cation homeostasis, which is correlated with growth retardation and robustness to ER stress. AB - VIGG is a putative endoplasmic reticulum (ER) resident protein induced by virus infection and ER stress, and is correlated with fruit quality in grapevine. The present study was undertaken to determine the biological function of VIGG in grapevine. Experiments using fluorescent protein-VIGG fusion protein demonstrated that VIGG is localized in ER and the ER targeting sequence is in the N-terminus. The overexpression of VIGG in Arabidopsis plant led to growth retardation. The rosette leaves of VIGG-overexpressing plants were smaller than those of the control plants and rolled at 42days after seeding. VIGG-overexpressing plants revealed robustness to ER stress as well as the low expression of ER stress marker proteins, such as the luminal binding proteins. These characteristics of VIGG-overexpressing plants were supported by a microarray experiment that demonstrated the disruption of genes related to ER stress response and flowering, as well as cation mobility, in the plants. Finally, cation homeostasis in the plants was disturbed by the overexpression of VIGG. Taken together, these results suggest that VIGG may disturb cation homeostasis in plant, which is correlated with the robustness to ER stress and growth retardation. PMID- 21277285 TI - Single-particle tracking of quantum dot-conjugated prion proteins inside yeast cells. AB - Yeast is a model eukaryote with a variety of biological resources. Here we developed a method to track a quantum dot (QD)-conjugated protein in the budding yeast Saccharomyces cerevisiae. We chemically conjugated QDs with the yeast prion Sup35, incorporated them into yeast spheroplasts, and tracked the motions by conventional two-dimensional or three-dimensional tracking microscopy. The method paves the way toward the individual tracking of proteins of interest inside living yeast cells. PMID- 21277286 TI - Actin filaments and microtubules of Arabidopsis suspension cells show different responses to changing turgor pressure. AB - Past decades have brought great advances in understanding the relationship between turgor pressure and plant cell growth. New studies have provided evidence that turgor pressure acts as a stimulus for cell growth, and is also a developmental cue for post-embryonic organogenesis. However, the subcellular mechanisms underlying plant cell turgor pressure sensing remain unclear. Here, using the relatively simple undifferentiated cells from suspension cultures, we report real-time in vivo observations of the reorganization of microtubules and actin microfilaments induced by turgor pressure changes. We found that these two cytoskeletal elements differed in their reorganization patterns. Our results will be useful in the understanding of the relationship between the cytoskeleton, turgor pressure, and stress in plant cell morphogenesis. PMID- 21277287 TI - Saccharomyces cerevisiae Gis2 interacts with the translation machinery and is orthogonal to myotonic dystrophy type 2 protein ZNF9. AB - The myotonic dystrophy type 2 protein ZNF9/CNBP is a small nucleic acid binding protein proposed to act as a regulator of transcription and translation. The precise functions and activity of this protein are poorly understood. Previous studies suggested that ZNF9 regulates translation and facilitates the process of cap-independent translation through interactions with mRNA and the translating ribosome. To help determine the role played by ZNF9 in the activation of translation initiation, we combined genetic and biochemical analysis of the putative ZNF9 ortholog GIS2, in the budding yeast Saccharomyces cerevisiae. Purification of the Gis2p protein followed by mass spectrometry based-proteomic analysis identified a large number of co-purifying ribosomal subunits and translation factors, strongly suggesting that Gis2p interacts with the protein translation machinery. Polysome profiling and ribosome isolation experiments confirm that Gis2p physically interacts with the translating ribosome. Interestingly, expression of yeast Gis2p in HEK293T cells activates cap independent translation driven by the 5'UTR of the ODC gene. These data suggest that Gis2 is functionally orthologous to ZNF9 and acts as a cap-independent translation factor. PMID- 21277288 TI - Evaluation of kidney repair capacity using 99mTc-DMSA in ischemia/reperfusion injury models. AB - Quantitative (99m)Tc-DMSA renal uptake was studied in different renal ischemia/reperfusion (I/R) mice models for the assessment of renal repair capacity. Mice models of nephrectomy, uni- and bi-lateral I/R together with sham operated mice were established. At 1h, 1d, 4d, 1, 2 and 3 wk after I/R, (99m)Tc DMSA (27.7 +/- 1.3 MBq) was injected via tail vein and after 3h post-injection, the mice were scanned for 30 min with pinhole equipped gamma camera. Higher uptake of (99m)Tc-DMSA was measured in normal kidneys of uni-lateral I/R model and nephrectomized kidney I/R model at 3 wk post-surgery. Comparing the restoration capacities of the affected kidneys of nephrectomy, uni- and bi lateral I/R models, higher repair capacity was observed in the nephrectomized model followed by bi-lateral then uni-lateral models. The normal kidney may retard the restoration of damaged kidney in uni-lateral I/R model. Moreover, 3 wk after Uni-I/R, the size of injured kidney was significantly smaller than non ischemic contralateral and sham operated kidneys, while nephrectomy I/R kidneys were significantly enlarged compared to all others at 3 wk post-surgery. Very strong correlation between (99m)Tc-DMSA uptake and weight of dissected kidneys in I/R models was observed. Consistent with (99m)Tc-DMSA uptake results, all histological results indicate that kidney recovery after injury is correlated with the amount of intact tubules and kidney sizes. In summary, our study showed good potentials of (99m)Tc-DMSA scan as a promising non-invasive method for evaluation of kidney restoration after I/R injuries. Interestingly, mice with Bi I/R injury showed faster repair capacity than those with uni-I/R. PMID- 21277289 TI - Regulation of aldo-keto reductase AKR1B10 gene expression: involvement of transcription factor Nrf2. AB - Aldo-keto reductase 1B10 (AKR1B10) is an aldose reductase-like oxidoreductase of human origin. The expression of AKR1B10 is highly induced in the cells of various cancers such as lung non-small-cell carcinoma and hepatocellular carcinoma. Since the enzyme exhibits broad substrate specificities toward various xenobiotics such as anti-tumor drugs or various endogenous compounds such as retinaldehyde, AKR1B10 may play an important role in tumor progression or drug resistance. However, very little is known about its gene regulation. In this study, we investigated the regulation of AKR1B10 expression. A -3282bp of the 5'-flanking fragment of AKR1B10 gene was isolated from A549 lung carcinoma cells. This region contains several putative regulatory motifs such as AP-1, NF-kappaB and antioxidant response element. In addition, a complex polymorphic microsatellite with repetitive sequences enriched with C and T was found. However, luciferase reporter assay revealed that the microsatellite polymorphism did not influence the basal promoter activity. We found that an antioxidant ethoxyquin induced the AKR1B10 expression based on RT-PCR analysis and luciferase reporter assay. Since ethoxyquin is known to activate the gene expression mediated through transcription factor Nrf2, the involvement of Nrf2 was examined. Forced expression of dominant-negative Nrf2 mutant suppressed the ethoxyquin-induced AKR1B10 expression, and co-introduction of Nrf2 expression plasmid into the cells significantly augmented the luciferase reporter activity. Deletion analysis revealed that Nrf2-regulating cis-element(s) lay within -539bp of the 5'-flanking region. These results suggest that Nrf2 is one of the major factors involved in the AKR1B10 gene regulation. PMID- 21277290 TI - Serum anti-p53 antibody detection in carcinomas and the predictive values of serum p53 antibodies, carcino-embryonic antigen and carbohydrate antigen 12-5 in the neoadjuvant chemotherapy treatment for III stage non-small cell lung cancer patients. AB - BACKGROUND: The serum p53 antibody (s-p53 Ab) is a valuable prognostic factor for carcinomas, but its common detection method, based on enzyme linked immunosorbent assay (ELISA), needs to be improved due to low sensitivity. Although neoadjuvant chemotherapy (NACT) is widely used in the treatment of non-small cell lung cancer (NSCLC) in China, forecasting chemoresistance is still a pressing problem. METHODS: Hybrid phage and wild-type p53 protein (wt p53 protein) were produced before the establishment of phage-ELISA and p53-ELISA. S-p53 Abs of 829 patients with various types of cancer was detected by a double ELISA system. 47 IotaIotaIota stage NSCLC patients treated with mitomycin, vindesine and cisplatin (MCV)-based NACT were chosen for s-p53 Abs, carcino-embryonic antigen (CEA) and carbohydrate antigen (CA) 12-5 predictive value analysis. RESULTS: Through the combination of p53-ELISA and phage-ELISA (p53-phage ELISA), the sensitivity of s p53 Abs in lung, breast, colorectal, gastric, esophageal, liver and ovarian cancer increased to 39.0%, 33.3%, 41.7%, 32.1%, 30.9%, 23.1% and 43.2% respectively. S-p53 Abs proved to correlate with nodal involvement, TNM stage, histological type (in lung cancer) or tumor size (in gastric cancer). As for the 47 IotaIotaIota stage NSCLC treated with NACT, s-p53 Abs and CA12-5 remarkably decreased after NACT treatment (P=0.034 and P=0.007) and pre-NACT low s-p53 Abs correlated with high objective chemoresponse rate (P=0.016). CONCLUSIONS: p53 phage ELISA system has an edge over single p53-ELISA. S-p53 Abs level correlates with cancer patients' clinicalpathological parameters and can predict the chemoresponse of IotaIotaIota stage NSCLC patients during MCV-based NACT treatment. PMID- 21277291 TI - Use of robust ZB and ZW to evaluate proficiency testing data. AB - BACKGROUND: In PT program, mean is conventionally used as the target after deletion of values which exceed the mean+/-3SD. This computation fails if there are some outliers. METHODS: Creatinine data were divided into Jaffe and enzymatic method groups in accordance with the analytical method used. The results tested by both methods were compared. The normality of standardized sum and difference was tested. The outliers in these data were deleted. The trimmed data were tested for normality. The performance of laboratories was assessed using ZB and ZW, whose values were considered acceptable when |ZB| or |ZW|<=2, questionable when 2<|ZB|<3 or 2<|ZW|<3 and unacceptable when |ZB| or |ZW|>=3. RESULTS: The results tested using Jaffe and enzymatic methods were not comparable. The data of standardized sum and difference were not normally distributed. When the outliers in these data were removed, the trimmed data were normally distributed. In Jaffe group, the acceptable rates of between and within laboratories respectively were 90.2% and 86.0%. In enzymatic group, the acceptable rates of between and within laboratories respectively were 82.6% and 82.4%. CONCLUSION: It was reasonable to choose robust ZB and ZW as assessment indexes because robust z-scores were less influenced by outliers. PMID- 21277292 TI - Origin, translocation and destination of extracellular occurring DNA--a new paradigm in genetic behaviour. AB - The diagnostic value of extracellular occurring DNA (eoDNA) is limited by our lack of understanding its biological function. eoDNA exists in a number of forms, namely vesicle bound DNA (apoptotic bodies, micro particles, micro vesicles and exosomes), histone/DNA complexes or nucleosomes and virtosomes. These forms of DNA can also be categorized under the terms circulating DNA, cell free DNA, free DNA and extracellular DNA. The DNA can be released by means of form-specific mechanisms and seem to be governed by cell cycle phases and apoptosis. Active release is supported by evidence of energy dependent release mechanisms and various immunological- and messenger functions. Sequencing has shown that eoDNA sequences present in the nucleosome reflects traits and distribution of genome sequences and are regulated by ways of release and/or clearance. eoDNA enables the horizontal transfer of gene sequences from one cell to another, over various distances. The ability of eoDNA to partake in horizontal gene transfer makes it an important facet in the field of epigenetic variation. Clinical implementation of eoDNA diagnostics requires that all of the subgroups of eoDNA be properly investigated. PMID- 21277293 TI - Thalassemia and hemoglobinopathies in Southeast Asian newborns: diagnostic assessment using capillary electrophoresis system. AB - BACKGROUND: We have investigated the Capillarys 2 Hemoglobin testing system to assist in presumptive diagnosis of thalassemia and hemoglobinopathies commonly found in Southeast Asia. METHODS: Study was conducted on 226 newborns. Hematological parameters were recorded and Hb profiles were examined on the Capillarys 2 Hemoglobin analyzer (SEBIA). DNA analyses were used to establish the final diagnoses. RESULTS: Among 226 newborns examined, 122 had thalassemias with 17 different genotypes. The capillary electrophoresis system could provide useful data for presumptive diagnoses of cases, especially those with Hb E and alpha thalassemia. Hb E was found to be 2.6-6.2% in heterozygote whereas Hb Bart's were clearly observed in cases with compound heterozygous or homozygous alpha(+) thalassemia and heterozygous alpha(0)-thalassemia. Hb H disease and other forms of alpha-thalassemia could be differentiated based on the presence of Hb Bart's and its percentage. CONCLUSION: The capillary electrophoresis system is applicable to newborn screening for common forms of thalassemia in Southeast Asia. PMID- 21277294 TI - Evaluation of multi- and inter-disciplinary research--the no-peer problem. AB - The advent of peer review is relatively recent, yet it strongly influences the way we perform and evaluate research. The absence of the perfect peer for multi- and inter-disciplinary research makes evaluation more challenging. By recognizing and addressing the no-peer problem multi- and interdisciplinary research can be effectively communicated and evaluated. PMID- 21277295 TI - Evaluation of milnacipran, in comparison with amitriptyline, on cold and mechanical allodynia in a rat model of neuropathic pain. AB - Milnacipran, a serotonin/norepinephrine reuptake inhibitor (SNRI), has shown efficacy against several chronic pain conditions, including fibromyalgia. Here, we evaluated, in rats, its anti-allodynic effects following acute or sub-chronic treatment in a model of neuropathic pain (chronic constriction injury, CCI, of the sciatic nerve). Amitriptyline, a tricyclic antidepressant active pre clinically and clinically against neuropathic pains, was added as a comparison compound. Upon acute i.p. administration, milnacipran was potently efficacious in the CCI model. It significantly reduced thermal allodynia in the cold (4 degrees C) plate test (MED=2.5mg/kg), and attenuated mechanical allodynia in the von Frey filaments test (MED=10mg/kg). Given sub-chronically (7day, b.i.d.), milnacipran was effective at 10mg/kgi.p. in both tests. Acute amitriptyline (10mg/kgi.p.) was efficacious against mechanical, but less so against cold allodynia; under sub chronic conditions, it was only active against mechanical allodynia. These data show that milnacipran is as efficacious as the reference compound amitriptyline in a pre-clinical model of injury-induced neuropathy, and demonstrate for the first time that it is active acutely and sub-chronically against cold allodynia. They also suggest that milnacipran has the potential to alleviate allodynia associated with nerve compression-induced neuropathic pain in the clinic (for example following discal hernia, avulsion or cancer-induced tissue damage). PMID- 21277296 TI - DNA-protective effects of quercetin or naringenin in alloxan-induced diabetic mice. AB - Diabetes mellitus is associated with a high production of reactive oxygen species, which may cause oxidative DNA damage. High levels of genomic damage have been associated with liver and renal failure as well as immune-system decline. Flavonoids are effective antioxidants and may protect against several chronic diseases including diabetes. This study used the comet assay to assess the levels of DNA damage in the blood, liver and kidney cells in untreated and quercetin (QU) or naringenin treated diabetic mice. In addition, the study was designed to establish whether QU or naringenin might have a biological effect in protecting diabetic mice against oxidative stress by using survival studies to observe total body injury at the level of the organism. QU or naringenin were injected to mice intraperitoneally (i.p.) at a dose of 50mg/kg for 7days starting 2days after a single dose (75mg/kg, i.v.) alloxan injection. These findings suggest that QU or naringenin treatment resulted in a significant increase in the body weight, the haematological and immunological parameters of blood, as well as leading to 100% survival of diabetic mice. The tested flavonoids have protective effects against alloxan-induced DNA-damage in peripheral lymphocytes but not in the liver and kidney cells of diabetic mice. It might be hypothesised that diabetic mice with a high intake of flavonoid-rich foods, and specifically foods rich in quercetin or naringenin, might be relatively protected against long-term complications of diabetes due to decreased oxidative stress. Various co-operative and synergistic action mechanisms of the tested flavonoids may lead to the protection of the whole organism against diabetes. PMID- 21277297 TI - Alterations in perivascular adipose tissue structure and function in hypertension. AB - We studied the structural and the functional alterations of perivascular adipose tissue (PVAT) in hypertension with spontaneously hypertensive rats (SHR). Measured with dual energy X-ray absorptiometry, a smaller body fat mass and a greater lean mass were found in SHR than in Wistar-Kyoto (WKY) rats, while body weight was comparable between them. In the thoracic PVAT, the density and the total number of brown adipocytes were greater in SHR than in WKY rats, while the cross section area of PVAT was similar between them. In functional assessment, four types of vessel preparations (with either intact PVAT or intact endothelium, or with both, or without both) were employed. Vessels with intact PVAT from SHR contracted more to phenylephrine than that from WKY rats, while vessels without PVAT exhibited comparable contractile response to phenylephrine between SHR and WKY rats. Both endothelium-dependent and -independent components of PVAT associated attenuation of phenylephrine-induced contraction were reduced in SHR as compared with that of WKY rats. Bioassay experiments were carried out to assess the transferable relaxation factor from the PVAT. Transfer of bathing solution incubated with PVAT-intact vessel caused less relaxation in SHR recipients than in WKY rats, and the relaxation response was abolished by D Ala(7)-angiotensin-(1-7), an angiotensin-(1-7) receptor antagonist. In summary, PVAT-associated inhibition of vessel contractile response to agonist was impaired in SHR, and the impairment involved both endothelium-dependent and -independent mechanisms. The functional impairment observed in SHR PVAT may be related to changes in adipocyte composition but not to reduced PVAT mass in SHR. PMID- 21277298 TI - M(3) muscarinic receptor antagonist bencycloquidium bromide attenuates allergic airway inflammation, hyperresponsiveness and remodeling in mice. AB - M(3) muscarinic receptors are localized on inflammatory cells, airway smooth muscle, and submucosal glands, known to mediate bronchoconstriction, mucus secretion, and airway remodeling. It is hypothesized bencycloquidium bromide (BCQB), a novel M(3) receptor antagonist, might have potential effects on airway hyperresponsiveness, inflammation and airway remodeling in a murine model of asthma. Mice sensitized and challenged with ovalbumin developed airway inflammation. Bronchoalveolar lavage fluid was examined to determine the total and differential cell counts, and cytokine levels. Lung tissues were evaluated for cell infiltration, mucus hypersecretion, airway remodeling, and the expression of inflammatory biomarkers. Airway hyperresponsiveness was monitored by direct airway resistance analysis. Inhalation administration of BCQB significantly not only reduced ovalbumin-induced airway hyperresponsiveness comparing to methacholine, and prevented the ovalbumin-induced increase in total cell counts and eosinophil counts. Reverse transcriptase polymerase chain reaction analysis of whole lung lysates revealed that BCQB markedly suppressed ovalbumin-induced mRNA expression of eotaxin, IL-5, IL-4 and MMP-9, and increased mRNA expression of IFN-gamma and TIMP-1 in a dose-dependent manner. Substantial IFN-gamma/IL-4 (Th1/Th2) levels were recovered in bronchoalveolar lavage fluid after BCQB treatment. In addition, histological studies showed that BCQB dramatically inhibited ovalbumin-induced lung tissue eosinophil infiltration, airway mucus production and collagen deposition in lung tissues. Results reported in current paper suggest that M(3) receptors antagonist may provide a novel therapeutic approach to treat airway inflammation, hyperresponsiveness and remodeling. PMID- 21277299 TI - Human skeletal muscle-derived stem cells retain stem cell properties after expansion in myosphere culture. AB - Human skeletal muscle contains an accessible adult stem-cell compartment in which differentiated myofibers are maintained and replaced by a self-renewing stem cell pool. Previously, studies using mouse models have established a critical role for resident stem cells in skeletal muscle, but little is known about this paradigm in human muscle. Here, we report the reproducible isolation of a population of cells from human skeletal muscle that is able to proliferate for extended periods of time as floating clusters of rounded cells, termed "myospheres" or myosphere derived progenitor cells (MDPCs). The phenotypic characteristics and functional properties of these cells were determined using reverse transcription-polymerase chain reaction (RT-PCR), flow cytometry and immunocytochemistry. Our results showed that these cells are clonogenic, express skeletal progenitor cell markers Pax7, ALDH1, Myod, and Desmin and the stem cell markers Nanog, Sox2, and Oct3/4 significantly elevated over controls. They could be maintained proliferatively active in vitro for more than 20 weeks and passaged at least 18 times, despite an average donor-age of 63 years. Individual clones (4.2%) derived from single cells were successfully expanded showing clonogenic potential and sustained proliferation of a subpopulation in the myospheres. Myosphere-derived cells were capable of spontaneous differentiation into myotubes in differentiation media and into other mesodermal cell lineages in induction media. We demonstrate here that direct culture and expansion of stem cells from human skeletal muscle is straightforward and reproducible with the appropriate technique. These cells may provide a viable resource of adult stem cells for future therapies of disease affecting skeletal muscle or mesenchymal lineage derived cell types. PMID- 21277301 TI - Loss of Runx3 is a key event in inducing precancerous state of the stomach. AB - BACKGROUND & AIMS: RUNX3 is a tumor suppressor originally identified in gastric cancer. The mutation R122C in RUNX3 promotes gastric carcinogenesis by unclear mechanisms. We investigated how Runx3-deficiency contributes to distinct changes in the gastric epithelium that precede neoplasia. METHODS: Runx3-deficient (Runx3(-/-)) and wild-type BALB/c adult mice were subjected to histological analyses. Gastric cancer formation after administration of N-methyl-N-nitrosourea was evaluated. Runx3(+/+) and Runx3(-/-) gastric epithelial cell lines were used to investigate the molecular basis underlying Runx3 function. RESULTS: The gastric epithelia in Runx3(-)/(-) adult mice was hyperplastic, with loss of chief cells and development of mucin 6- and trefoil factor-2-expressing metaplasia. The gastric epithelium of Runx3(-)/(-) mice had an intestinal phenotype that expressed Cdx2. After addition of N-methyl-N-nitrosourea, Runx3- mice, unlike wild-type mice, consistently developed adenocarcinomas, indicating that Runx3 deficiency leads to premalignant changes in the gastric epithelia. RUNX3, but not the RUNX3 mutant R122C, repressed Cdx2 expression by attenuation of oncogenic beta(symbol)-catenin and Tcfs. CONCLUSIONS: Runx3-deficiency leads to a precancerous state in the gastric epithelia of mice, characterized by loss of chief cells but not parietal cells; inflammation did not appear to be involved. PMID- 21277300 TI - Sparing of extraocular muscle in aging and muscular dystrophies: a myogenic precursor cell hypothesis. AB - The extraocular muscles (EOM) are spared from pathology in aging and many forms of muscular dystrophy. Despite many studies, this sparing remains an enigma. The EOM have a distinct embryonic lineage compared to somite-derived muscles, and we have shown that they continuously remodel throughout life, maintaining a population of activated satellite cells even in aging. These data suggested the hypothesis that there is a population of myogenic precursor cells (mpcs) in EOM that is different from those in limb, with either elevated numbers of stem cells and/or mpcs with superior proliferative capacity compared to mpcs in limb. Using flow cytometry, EOM and limb muscle mononuclear cells were compared, and a number of differences were seen. Using two different cell isolation methods, EOM have significantly more mpcs per mg muscle than limb skeletal muscle. One specific subpopulation significantly increased in EOM compared to limb was positive for CD34 and negative for Sca-1, M-cadherin, CD31, and CD45. We named these the EOMCD34 cells. Similar percentages of EOMCD34 cells were present in both newborn EOM and limb muscle. They were retained in aged EOM, whereas the population decreased significantly in adult limb muscle and were extremely scarce in aged limb muscle. Most importantly, the percentage of EOMCD34 cells was elevated in the EOM from both the mdx and the mdx/utrophin(-/-) (DKO) mouse models of DMD and extremely scarce in the limb muscles of these mice. In vitro, the EOMCD34 cells had myogenic potential, forming myotubes in differentiation media. After determining a media better able to induce proliferation in these cells, a fusion index was calculated. The cells isolated from EOM had a 40% higher fusion index compared to the same cells isolated from limb muscle. The EOMCD34 cells were resistant to both oxidative stress and mechanical injury. These data support our hypothesis that the EOM may be spared in aging and in muscular dystrophies due to a subpopulation of mpcs, the EOMCD34 cells, that are retained in significantly higher percentages in normal, mdx and DKO mice EOM, appear to be resistant to elevated levels of oxidative stress and toxins, and actively proliferate throughout life. Current studies are focused on further defining the EOMCD34 cell subtype molecularly, with the hopes that this may shed light on a cell type with potential therapeutic use in patients with sarcopenia, cachexia, or muscular dystrophy. PMID- 21277302 TI - Design and characterization of highly immunogenic heat-stable enterotoxin of enterotoxigenic Escherichia coli K99(+). AB - In this study, STa peptide of enterotoxigenic Escherichia coli K99(+) was purified and successfully covalently cross-linked to modified bovine serum albumin after thorough evaluation of three different hapten-carrier conjugation protocols. Dimethyformamide (DMF) based STa-conjugation protocol demonstrated higher biological activity (10*10(6) STa Total Mouse Units [MU]) and 100% conjugation efficiency. A range of conjugation ratio of 4-12 STa molecules per one molecule of BSA was achieved and confirmed by matrix-assisted laser desorption ionization-time of flight/mass spectroscopy (MALDI-TOF/MS). This conjugate was used for immunization of ten rabbits for STa antibody production. A high antibody binding titer (10(6)) against STa was obtained with a neutralization capacity of 3*10(4) STa MUs/ml serum. These levels of high STa binding and neutralizing antibodies titers propose the potential use of this conjugate for the development of immunotherapeutic reagents and/or STa-based vaccine against ETEC K99(+). PMID- 21277303 TI - Multiparametric luminescence method for quantitative cell surface protein expression analysis and imaging. AB - A luminometric method for quantitative cell surface protein expression analysis has been developed in a microtiter plate format. The method is based on immunocytochemistry, the use of long-lived europium(III) and terbium(III) chelates and platinum(II) porphyrin luminescence labels in addition to short lived syto13 DNA stain, and detection of photoluminescence emission from adhered cells by both time-resolved luminescence and conventional fluorescence. After the immunoreactions, the wells were evaporated to dryness, allowing repeated and postponed luminescence analysis even after months and cellular protein localization studies by microscopy imaging. The multiparametric method assayed the cell surface expression of beta1-integrin, E-selectin and intercellular adhesion molecule 1 (ICAM-1) in HUVE cells (human umbilical vein endothelial cells). The expression of E-selectin and ICAM-1 was enhanced by treating HUVECs with tumor necrosis factor alpha (TNF-alpha), while the expression level of beta1 integrin remained unchanged. The sensitivity limit of TNF-alpha detection by the method was ca. 1 pg/ml and the Z'-factors for the quantification of E-selectin and ICAM-1 were >0.7 suggesting a highly robust method. The novel approach proposed in this paper can be potentially applied to cell surface protein expression analysis in screening applications combined with localization studies of the target proteins by fluorescence microscopy imaging. PMID- 21277304 TI - Development and evaluation of a Luminex multiplex serology assay to detect antibodies to bovine herpes virus 1, parainfluenza 3 virus, bovine viral diarrhoea virus, and bovine respiratory syncytial virus, with comparison to existing ELISA detection methods. AB - Detection of circulating antibodies to bovine herpes virus 1 (BHV-1), parainfluenza 3 virus (PI3V), bovine viral diarrhoea virus (BVDV) and bovine respiratory syncytial virus (BRSV) using ELISA is widely used for veterinary diagnostics and surveillance. In this paper, the potential of a multiplex serology test based on Luminex technology, where all antibodies are simultaneously detected in a single assay was investigated. The performance of "in-house" separate ELISAs which use relatively crude lysates of cultured virus as capture antigens, was compared to the multiplex assay where the same antigens were covalently bound to the fluorescent beads used in the Luminex platform. A panel of field serum samples was tested by the multiplex assay in parallel with the separate routine ELISAs to provide a comparison between tests. The BHV-1 and PI3V components of the multiplex test showed similar sensitivities and specificities to the separate "in-house" ELISAs. The performance of the BVDV and BRSV components was less successful and was attributed to relatively low signal strength for these antigens, leading to higher assay variability and a reduced ability to distinguish positive and negative samples compared to the "in-house" ELISAs. The results illustrated that antigens commonly used successfully in ELISAs cannot always be transferred for use in alternative assay systems. The use of recombinant BVDV E2 protein was investigated and was shown to lead to an appreciable increase in signal strength compared to the use of crude BVDV antigen in the Luminex system. PMID- 21277305 TI - Variables to be controlled in the assessment of blood innate immune responses to Toll-like receptor stimulation. AB - Variability in TLR function influences susceptibility to infectious as well as immune-mediated diseases. Given the outbred nature of humans, identifying functional Toll-like receptor variability and its role in clinical disease requires such analysis to be conducted in large, often multi-centered cohorts. Yet the technically complex measurements involved in innate immune analysis benefit from centralized processing of samples. Centralization requires shipping of samples or prolonged storage, possibly even cryopreservation. Deviation from standard operating procedures (SOP) for sample procurement, storage and processing may alter the final innate immune read out. We here set out to define the impact of variables most likely to be encountered during large, multi-site studies: (i) the source of the sample, (ii) time between sample procurement to processing, and (iii) processing of fresh vs. cryopreserved samples. We found that all of these variables exert a profound impact on the final innate response to TLR stimulation. Specific innate responses appeared to be affected in response to specific TLR stimuli by a particular variable under study, proving it impossible to provide global generalizations. Based on our studies and other published work on this topic, we propose a minimal list of variables that have to be met for samples to be comparable within and across studies: a) timing between procurement and processing cannot vary by more than 10%; b) all samples have to be stored the same; and c) the source of samples needs to be the same. In summary, for innate immune analysis scrupulous adherence to standard operating procedures is paramount. PMID- 21277306 TI - Optimizing high dimensional gene expression studies for immune response following smallpox vaccination using Taqman(r) low density immune arrays. AB - INTRODUCTION: We sought to determine the time and vaccinia virus dose combination that would maximize the number of acute immune response changes in response to vaccinia stimulation in preparation for a large gene expression microarray experiment. METHODS: PBMCs from ten subjects were exposed to five vaccinia virus doses for three lengths of time. Gene expression was measured for 90 immune response genes via Taqman(r) Low Density Immune Arrays. Expression data were normalized via model-based non-linear normalization. Linear mixed effects model results were used to standardize changes across genes and determine the time/multiplicity of infection (MOI) combination with the largest number of changes. RESULTS: The greatest number of changes occurred with a MOI of 5.0 and exposure time of 48 h. Further inspection revealed that most changes had occurred earlier and faded at this combination. The second highest number of changes was found at a MOI of 0.5 PFU/cell and time of 18 h. CONCLUSIONS: We conclude a time of 18 h with a MOI of 0.5 PFU/cell is the optimal time/MOI combination for the full scale gene expression study. The strategy described herein is a general and resource efficient way to make critical decisions regarding experimental parameters for studies utilizing expensive assays that interrogate a large number of variables. PMID- 21277307 TI - Isolation and characterization of recombinant single chain fragment variable anti idiotypic antibody specific to Aspergillus fumigatus membrane protein. AB - Aspergillus fumigatus causes the highly lethal form of invasive aspergillosis (IA). In the present study to develop a novel anti-fungal drug for protection against invasive disease, we identified a single chain fragment variable (scFv) antibody (scFv AF1) by panning against A. fumigatus membrane fraction (AMF) or HM 1 killer toxin (HM-1) neutralizing monoclonal antibody (nmAb-KT) as antigen. The key step was elution of bound phages with phosphate buffered saline (PBS) at pH 7.0 containing AMF. The specificity of soluble scFv AF1 antibody to antigens was verified by ELISA, which specifically binds to both AMF and nmAb-KT. After nucleotide sequencing, clone expression and purification by HisTrap HP affinity column, scFv AF1 showed in vitro anti-fungal activity against A. fumigatus. By SPR analysis it showed high binding affinity to nmAb-KT (K(d)=5.22*10(-11) M). The method used to isolate scFv AF1 was a new method and we believe that it will be applicable to isolate the specific scFv against any kind of membrane protein of yeast or fungus. PMID- 21277308 TI - Catalase and superoxide dismutase-2 enhance survival and protect ovaries during overwintering diapause in the mosquito Culex pipiens. AB - Lifespan extension and stress resistance are two important features of diapause that are essential for successful overwintering. We present several lines of evidence suggesting that genes encoding two antioxidant enzymes, catalase and superoxide dismutase-2, are critical in generating these characteristics during diapause in overwintering adults of the mosquito Culex pipiens. Expression of both catalase and sod-2 was dramatically higher in young diapausing females than in their nondiapausing counterparts at the same age. Suppression of catalase, but not sod-2, resulted in increased damage to the ovaries, as evidenced by signs of apoptosis in ovarian follicle cells. Adult survival time was shortened when levels of either catalase or sod-2 were suppressed using RNAi. Together these results imply that these two antioxidants are particularly important in promoting survival in diapausing females, while elevation of catalase also contributes to protection of the ovaries. In addition, RNAi directed against forkhead transcription factor (foxo), a gene thought to be upstream of the genes encoding these antioxidants, resulted in suppression of both catalase and sod-2. The linkage with FOXO suggests that the genes encoding these two antioxidants are components of an important gene network regulated by this transcription factor. PMID- 21277309 TI - Cell renewal in adjoining intestinal and tracheal epithelia of Manduca. AB - Cell renewal continuously replaces dead or dying cells in organs such as human and insect intestinal (midgut) epithelia; in insects, control of self-renewal determines insects' responses to any of the myriad pathogens and parasites of medical and agricultural importance that enter and cross their midgut epithelia. Regenerative cells occur in the midgut epithelia of many, if not all, insects and are probably derived from a distinctive population of stem cells. The control of proliferation and differentiation of these midgut regenerative cells is assumed to be regulated by an environment of adjacent cells that is referred to as a regenerative cell niche. An antibody to fasciclin II marks cell surfaces of tracheal regenerative cells associated with rapidly growing midgut epithelia. Tracheal regenerative cells and their neighboring midgut regenerative cells proliferate and differentiate in concert during the coordinated growth of the midgut and its associated muscles, nerves and tracheal cells. PMID- 21277310 TI - Sex-pairing pheromones and reproductive isolation in three sympatric Cornitermes species (Isoptera, Termitidae, Syntermitinae). AB - The species-specificity of pairing has been studied in three sympatric Neotropical termites: Cornitermes bequaerti, Cornitermes cumulans and Cornitermes silvestrii (Termitidae, Syntermitinae). Bioassays showed that sex attraction was highly species-specific between C. bequaerti and C. cumulans but not between C. cumulans and C. silvestrii. The sex-pairing pheromone of the three species is secreted by the tergal glands of female alates. It consists of a common compound (3Z,6Z,8E)-dodeca-3,6,8-trien-1-ol. In C. bequaerti, this polyunsaturated alcohol is the only compound of the sex-pairing pheromone, whereas it is associated with the oxygenated sesquiterpene (E)-nerolidol in C. cumulans, and with (E)-nerolidol and (Z)-dodec-3-en-1-ol in C. silvestrii. (3Z,6Z,8E)-Dodeca-3,6,8-trien-1-ol is responsible for sexual attraction, whereas (E)-nerolidol, which is inactive in eliciting attraction of male alates, is responsible for the species-specificity of the attraction. This is the first time that a multicomponent sex-pairing pheromone has been identified in termites. The role of (Z)-dodec-3-en-1-ol present on the surface of the tergal glands of the female alates of C. silvestrii could not be definitively determined, but it is suggested that this compound could be involved in the species-specificity of sex attraction with other sympatric species of Cornitermes. Our study shows that the reproductive isolation in termites is due to a succession of factors, as the chronology of dispersal flights, the species-specificity of sex-pairing pheromones and the species specific recognition. PMID- 21277311 TI - Optimization of the in-silico-designed kemp eliminase KE70 by computational design and directed evolution. AB - Although de novo computational enzyme design has been shown to be feasible, the field is still in its infancy: the kinetic parameters of designed enzymes are still orders of magnitude lower than those of naturally occurring ones. Nonetheless, designed enzymes can be improved by directed evolution, as recently exemplified for the designed Kemp eliminase KE07. Random mutagenesis and screening resulted in variants with >200-fold higher catalytic efficiency and provided insights about features missing in the designed enzyme. Here we describe the optimization of KE70, another designed Kemp eliminase. Amino acid substitutions predicted to improve catalysis in design calculations involving extensive backbone sampling were individually tested. Those proven beneficial were combinatorially incorporated into the originally designed KE70 along with random mutations, and the resulting libraries were screened for improved eliminase activity. Nine rounds of mutation and selection resulted in >400-fold improvement in the catalytic efficiency of the original KE70 design, reflected in both higher k(cat) values and lower K(m) values, with the best variants exhibiting k(cat)/K(m) values of >5*10(4) s(-)(1) M(-1). The optimized KE70 variants were characterized structurally and biochemically, providing insights into the origins of the improvements in catalysis. Three primary contributions were identified: first, the reshaping of the active-site cavity to achieve tighter substrate binding; second, the fine-tuning of electrostatics around the catalytic His-Asp dyad; and, third, the stabilization of the active-site dyad in a conformation optimal for catalysis. PMID- 21277312 TI - Engineered high-affinity affibody molecules targeting platelet-derived growth factor receptor beta in vivo. AB - Platelet-derived growth factor receptor (PDGFR) beta is a marker of stromal pericytes and fibroblasts and represents an interesting target for both diagnosis and therapy of solid tumors. A receptor-specific imaging agent would be a useful tool for further understanding the prognostic role of this receptor in vivo. Affibody molecules constitute a class of very small binding proteins that are highly suited for in vivo imaging applications and that can be selected to specifically recognize a desired target protein. Here we describe the isolation of PDGFRbeta-specific Affibody molecules with subnanomolar affinity. First generation Affibody molecules were generated from a large naive library using phage display selection. Subsequently, sequences from binders having a desired selectivity profile and competing with the natural ligand for binding were used in the design of an affinity maturation library, which was created using a single partially randomized oligonucleotide. From this second-generation library, Affibody molecules with a 10-fold improvement in affinity (K(d)=0.4-0.5 nM) for human PDGFRbeta and a 4-fold improvement in affinity (K(d)=6-7 nM) for murine PDGFRbeta were isolated and characterized. Complete reversible folding after heating to 90 degrees C, as demonstrated by circular dichroism analysis, supports tolerance to labeling conditions for molecular imaging. The binders were highly specific, as verified by dot blot showing staining reactivity only with human and murine PDGFRbeta, but not with human PDGFRalpha, or a panel of control proteins including 16 abundant human serum proteins. The final binder recognized the native conformation of PDGFRbeta expressed in murine NIH-3T3 fibroblasts and human AU565 cells, and inhibited ligand-induced receptor phosphorylation in PDGFRbeta-transfected porcine aortic endothelial cells. The PDGFRbeta-specific Affibody molecule also accumulated around tumoral blood vessels in a model of spontaneous insulinoma, confirming a potential for in vivo targeting. PMID- 21277313 TI - Enhancement of proton conductance by mutations of the selectivity filter of aquaporin-1. AB - Prevention of cation permeation in wild-type aquaporin-1 (AQP1) is believed to be associated with the Asn-Pro-Ala (NPA) region and the aromatic/arginine selectivity filter (SF) domain. Previous work has suggested that the NPA region helps to impede proton permeation due to the protein backbone collective macrodipoles that create an environment favoring a directionally discontinuous channel hydrogen-bonded water chain and a large electrostatic barrier. The SF domain contributes to the proton permeation barrier by a spatial restriction mechanism and direct electrostatic interactions. To further explore these various effects, the free-energy barriers and the maximum cation conductance for the permeation of various cations through the AQP1-R195V and AQP1-R195S mutants are predicted computationally. The cations studied included the hydrated excess proton that utilizes the Grotthuss shuttling mechanism, a model "classical" charge localized hydronium cation that exhibits no Grotthuss shuttling, and a sodium cation. The hydrated excess proton was simulated using a specialized multi state molecular dynamics method including a proper physical treatment of the proton shuttling and charge defect delocalization. Both AQP1 mutants exhibit a surprising cooperative effect leading to a reduction in the free-energy barrier for proton permeation around the NPA region due to altered water configurations in the SF region, with AQP1-R195S having a higher conductance than AQP1-R195V. The theoretical predictions are experimentally confirmed in wild-type AQP1 and the mutants expressed in Xenopus oocytes. The combined results suggest that the SF domain is a specialized structure that has evolved to impede proton permeation in aquaporins. PMID- 21277314 TI - A general approach for population games with application to vaccination. AB - Reconciling the interests of individuals with the interests of communities is a major challenge in designing and implementing health policies. In this paper, we present a technique based on a combination of mechanistic population-scale models, Markov decision process theory and game theory that facilitates the evaluation of game theoretic decisions at both individual and community scales. To illustrate our technique, we provide solutions to several variants of the simple vaccination game including imperfect vaccine efficacy and differential waning of natural and vaccine immunity. In addition, we show how path-integral approaches can be applied to the study of models in which strategies are fixed waiting times rather than exponential random variables. These methods can be applied to a wide variety of decision problems with population-dynamic feedbacks. PMID- 21277315 TI - Synaptic plasticity and addiction: learning mechanisms gone awry. AB - Experience-dependent changes in synaptic strength, or synaptic plasticity, may underlie many learning processes. In the reward circuit for example, synaptic plasticity may serve as a cellular substrate for goal-directed behaviors. Addictive drugs, through a surge of dopamine released from neurons of the ventral tegmental area, induce widespread synaptic adaptations within this neuronal circuit. Such drug-evoked synaptic plasticity may constitute an early cellular mechanism eventually causing compulsive drug-seeking behavior in some drug users. In the present review we will discuss how different classes of addictive drugs cause an increase of dopamine release and describe their effects on synapses within the mesolimbic dopamine system. We will emphasize the early synaptic changes in the ventral tegmental area common to all additive drugs and go on to show how these adaptations may reorganize neuronal circuits, eventually leading to behaviors that define addiction. PMID- 21277316 TI - Antidepressant phenotype by inhibiting the phospholipase Cbeta(1)--protein kinase Cgamma pathway in the forced swim test. AB - Although great advances have recently been made in the study of signal transduction, the pathogenesis of affective disorders is still unknown. There is mounting evidence suggesting that elevated phosphoinositide-protein kinase C (PI PKC) signal transduction pathway may be a pathophysiological feature of bipolar and major depressive disorders. The aim of the present study was to further investigated the phospholipase C-protein kinase C (PLC-PKC) cascade by evaluating the effect produced by an acute blockade of this intracellular pathway at PLC and PKC level. Adult male mice were administered with pharmacological inhibitors of PLC or PKC and then subjected to the forced swim test (FST), an animal model which emulates the behavioural despair paradigm of depression. In this study we also tested the hypothesis that it might be possible to selectively modulate depressive behaviour by inhibiting the expression of specific PLC and PKC isoforms by means of specific antisense oligonucleotides (aODNs). Administration of the PLC inhibitors neomycin and U73122 as well as of the PKC inhibitors calphostin C and chelerytrine dose-dependently reduced the immobility time in the FST producing an antidepressant-like behaviour. Selective knockdown of the PLCbeta(1) and PKCgamma isoforms also induced an antidepressant phenotype. Conversely, the inhibition of the expression of PLCbeta(3) was unable to modify the immobility time values. The PLC and PKC modulators used, at the highest effective doses, altered neither locomotor activity nor motor coordination. We demonstrate that selective blockade of PLCbeta(1)-PKCgamma signalling pathway produces an antidepressant-like phenotype in mice. PMID- 21277317 TI - Abnormal synaptic plasticity in basolateral amygdala may account for hyperactivity and attention-deficit in male rat exposed perinatally to low-dose bisphenol-A. AB - If the pregnant and lactating female rats are exposed to environmental levels of bisphenol-A (BPA), their male offspring will display hyperactivity and attention deficit. In patients with attention-deficit/hyperactivity disorder (ADHD), the size of the amygdala is reported to be reduced. This study examined functional alterations in the basolateral amygdala (BLA) of the postnatal 28-day-old male offspring exposed perinatally to BPA (BPA-rats). We specifically focused on the synaptic properties of GABAergic/dopaminergic systems in the BLA. A single electrical stimulation of the capsule fibers evoked multispike responses with an enhanced primary population spikes (1st-PS) in the BPA-rats. A single train of high-frequency stimulation of the fibers induced NMDA receptor (NMDAR) dependent long-term potentiation (LTP) in BPA-rats, but not in control rats. Also, paired pulse inhibition (PPI, GABA-dependent) in control rats was reversed to paired pulse facilitation (PPF) in BPA-rats. Perfusion of slices obtained from BPA-rats with the GABA(A) receptor (GABA(A)R) agonist muscimol blocked the multispike responses and LTP, and recovered PPI. By contrast, the dopamine D1 receptor antagonist SCH23390 abolished LTP and attenuated the increased amplitude of 1st PS in BPA-rats. Conversely, blockade of GABA(A)R by bicuculline could produce the multispike responses and PPF in BLA in control rats. Furthermore, in BLA the infusion of SCH23390, muscimol or the NMDAR blocker MK801 ameliorated the hyperactivity and improved the deficits in attention. These findings suggest that the perinatal exposure to BPA causes GABAergic disinhibition and dopaminergic enhancement, leading to an abnormal cortical-BLA synaptic transmission and plasticity, which may be responsible for the hyperactivity and attention-deficit in BPA-rats. This article is part of a Special Issue entitled 'Synaptic Plasticity & Interneurons'. PMID- 21277318 TI - Simulation during observation of human actions--theories, empirical studies, applications. AB - Historically, data from brain imaging and brain stimulation studies have supported the idea that the processing of observed actions recruits - among other areas - a distinct sub-set of brain sites in the sensory and motor cortices. These empirical findings have initially been linked with the thesis of direct matching as a mechanism of action understanding, i.e., the idea of motor resonance implemented by mirror neurons. In more recent approaches, it has been proposed that the mirror neuron system plays a role in minimizing prediction error when inferring the most likely cause of an observed action. According to these theories, motor resonance is thought to function as predictive coding. Other theoretical accounts suggest that action understanding might result from a hypothesis testing mechanism in which potential goals are continually fed into the system until the correct one is identified. In this review, we will explore the relationship of these theories to specific empirical findings. Finally, we will discuss the implications of these theoretical structures on action observation-based approaches to the optimization of skilled performance in athletes and patients. PMID- 21277319 TI - A comparison of spatial frequency tuning for the recognition of facial identity and facial expressions in adults and children. AB - We measured contrast thresholds for the identification of faces and facial expressions as a function of the center spatial frequency of narrow-band additive noise. In adults, masking of mid spatial frequencies (11-16c/fw) caused the largest elevation in contrast threshold (Experiment 1). Ideal observer analysis revealed that adults were equally sensitive to available information at low and mid spatial frequencies, both of which they used more efficiently than high spatial frequencies. The drop-off of sensitivity at high spatial frequencies began at a lower spatial frequency for recognizing facial identity than for recognizing facial expression. As a result, the critical band was higher for expression than for identity. The critical band for both identity and expression shifted to slightly lower values as distance increased (Experiment 2), a pattern indicating only partial scale invariance. Children aged 10 and 14 years showed similar tuning but needed more contrast (Experiment 3). The patterns suggest that adults use finer details for recognizing facial expressions than for identifying faces, a tuning that appears as early as age 10. PMID- 21277320 TI - Neuroendocrine contributions to sexual partner preference in birds. AB - A majority of birds are socially monogamous, providing exceptional opportunities to discover neuroendocrine mechanisms underlying preferences for opposite-sex partners where the sexes form extended affiliative relationships. Zebra finches have been the focus of the most systematic program of research to date in any socially monogamous animal. In this species, sexual partner preference can be partially or largely sex reversed with hormone manipulations during early development, suggesting a role for organizational hormone actions. This same conclusion emerges from research with Japanese quail, which do not form long-term pairs. In zebra finches, social experience manipulations during juvenile development also can sex reverse partner preference, either alone or in combination with an early hormone manipulation. Although there are several candidate brain regions where neural mechanisms could underlie these effects of hormones or social experience, the necessary research has not yet been done to determine their involvement. The neuroendocrinology of avian sexual partner preference is still frontier territory. PMID- 21277321 TI - Extracellular glycoconjugates produced by cyanobacterium Wollea saccata. AB - In order to survive in a highly competitive environment, freshwater or marine phototrophic microorganisms have to develop defense strategies that result in a tremendous diversity of compounds from different metabolic pathways. Recent trends in drug research from natural sources have shown that algae and cyanobacteria are promising organisms to furnish novel biochemically active compounds. In this study, we have analysed the extracellular mucilaginous proteoglycan produced by fresh-water heterocytous filamentous cyanobacterium Wollea saccata, strain Hindak 2000/18. This mucilaginous material is an acidic proteoglycan containing 30% protein and 52% carbohydrates on the basis of fraction dry weight. The constituent sugars of the carbohydrate component include glucose, fucose, 3-O-methylfucose, xylose, galactose, 3-O-methylgalactose, mannose, rhamnose, arabinose and glucuronic acid. The extracellular proteoglycan has been separated into five fractions (WF1-WF5) by anion exchange chromatography. Individual polymeric fractions varied in protein (16-57%) and carbohydrate (31-66%) contents, and in the composition of constituent monosaccharides. PMID- 21277322 TI - Preparation and characterization of chitosan-grafted-poly(2-amino-4,5 pentamethylene-thiophene-3-carboxylic acid N'-acryloyl-hydrazide) chelating resin for removal of Cu(II), Co(II) and Ni(II) metal ions from aqueous solutions. AB - The graft copolymerization of ethylacrylate (EA) onto chitosan initiated by potassium persulphate and Mohr's salt combined redox initiator system in limited aqueous medium was carried out in heterogeneous media. Moreover, modification of the grafted chitosan was carried out by reaction of the ester group (-COOEt) with 2-amino-4,5-pentamethylene-thiophene-3-carboxylic acid hydrazide which eventually produce chitosan-grafted-poly(2-amino-4,5-pentamethylene-thiophene-3-carboxylic acid N'-acryloyl-hydrazide) (chitosan-g-ATAH) chelating resin. The application of the modified resin for metal ion uptake was studied using Cu(2+), Co(2+) and Ni(2+) ions. The modified chelating resins were characterized using FTIR spectroscopy, SEM and X-ray diffraction. PMID- 21277323 TI - Preparation of soluble p-aminobenzoyl chitosan ester by Schiff's base and antibacterial activity of the derivatives. AB - Schiff's base of chitosan (BCTS) was obtained by the reaction of chitosan (CTS) and benzaldehyde. Then BCTS reacted with acyl chloride which was synthesized by p aminobenzoic acid and thionyl chloride to get N-benzoyl-O-aminobenzoyl chitosan ester (BABCTSE), removing the groups of amino protection of BABCTSE to get the final product (ABCTSE). The structures of the derivatives were characterized by FT-IR, (1)H NMR, (13)C NMR and elemental analysis. The elemental analysis results indicated that the degrees of substitution (DS) of the products were 16.8% and 40.4%. The synthesized compounds exhibited an excellent solubility in organic solvents. TG and DTG results showed that thermal stability of the derivatives was lower than that of chitosan. In addition, the existence of two different amido in the molecular structures contributed to forming more -NH(3)(+) in the acid solution which could make the derivatives have a greater advantage in the field of bacteriostasis. PMID- 21277324 TI - Emulsion formed in bovine serum album/anionic surfactant/H2O system under acidic condition. AB - At neutral pH, bovine serum album (BSA) conformation is "heart-shaped", and with decreasing pH, BSA may adopt the fast "F" form below a pH of about 4, and expanded "E" form at pH lower than about 3. However, as far as we know, the researches on the interaction between protein and surfactant are all carried out at pH higher than its isoelectric point (pI, which is 4.9), which means only the information about how the "heart-shaped" BSA interacts with surfactant is understood so far. In this paper, we studied the interaction between BSA and anionic surfactant at pH lower than its pI and hope to help understand the role of protein conformation in its interaction with surfactant. We found that BSA and anionic surfactant could form emulsion only when pH value was lower than or about 3, suggesting that the "E" formed BSA was an important criterion for emulsion formation. Moreover, the emulsion formation was companied with increased alpha helix content and decreased beta-sheet content for BSA. In addition, the emulsion formation was closely dependent on the anionic surfactant content; only a moderate anionic surfactant could make emulsion formed. PMID- 21277326 TI - Greg Warr and the genomics era. PMID- 21277325 TI - The genus Xenopus as a multispecies model for evolutionary and comparative immunobiology of the 21st century. AB - The Xenopus model for immunological research offers a collection of invaluable research tools including MHC-defined clones, inbred strains, cell lines, and monoclonal antibodies. Further, the annotated full genome sequence of Xenopus tropicalis and its remarkable conservation of gene organization with mammals, as well as ongoing genome mapping and mutagenesis studies in X. tropicalis, add a new dimension to the study of immunity. In this paper, we review uses of this amphibian model to study: the development of the immune system; vascular and lymphatic regeneration; immune tolerance; tumor immunity; immune responses to important emerging infectious diseases; and the evolution of classical and non classical MHC class I genes. We also discuss the rich potential of the species with different degrees of polypoidy resulting from whole genome-wide duplication of the Xenopodinae subfamily as a model to study regulation at the genome level. PMID- 21277327 TI - Functional connectivity analysis of fMRI data based on regularized multiset canonical correlation analysis. AB - In this paper we describe a method for functional connectivity analysis of fMRI data between given brain regions-of-interest (ROIs). The method relies on nonnegativity constrained- and spatially regularized multiset canonical correlation analysis (CCA), and assigns weights to the fMRI signals of the ROIs so that their representative signals become simultaneously maximally correlated. The different pairwise correlations between the representative signals of the ROIs are combined using the maxvar approach for multiset CCA, which has been shown to be equivalent to the generalized eigenvector formulation of CCA. The eigenvector in the maxvar approach gives an indication of the relative importance of each ROI in obtaining a maximal overall correlation, and hence, can be interpreted as a functional connectivity pattern of the ROIs. The successive canonical correlations define subsequent functional connectivity patterns, in decreasing order of importance. We apply our method on synthetic data and real fMRI data and show its advantages compared to unconstrained CCA and to PCA. Furthermore, since the representative signals for the ROIs are optimized for maximal correlation they are also ideally suited for further effective connectivity analyses, to assess the information flows between the ROIs in the brain. PMID- 21277328 TI - Activated T cells induce rapid CD83 expression on B cells by engagement of CD40. AB - The conserved transmembrane glycoprotein CD83 was originally described as highly specific marker for mature dendritic cells in the peripheral circulation. Besides its regulatory role in thymic T cell maturation and peripheral T cell activation, recent studies suggest, that CD83 is also involved in the regulation of B cell maturation, homeostasis and function. Here we show, that antigen-specific T cell stimulation leads to CD83 induction predominantly on B cells. In vivo activation of T cells by injection of cognate antigenic peptide into T cell receptor transgenic mice induced strong expression of the early activation marker CD69 but only low levels of surface CD83 on T cells. In contrast CD83 was induced on 80% of B cells in the draining lymph node. This T cell mediated induction of CD83 expression on B cells was not mediated by soluble factors but was contact dependent because separation of B cells from an ongoing T cell stimulation in a transwell system abrogated CD83 expression. Since CD83 expression was induced on both MHC-matched and MHC-mismatched B cells present in cultures of activated T cells, cell contact via TCR/MHC binding was not essential. The application of an antibody to the CD40 ligand of T cells, however, strongly interfered with the induction of CD83 expression on bystander B cells. Taken together we provide evidence that activated T cells induce CD83 on B cells via CD40 engagement but independent of TCR/MHC binding and thus independent of antigen-specificity of B cells. PMID- 21277329 TI - High-content screening to distinguish between attachment and post-attachment steps of human cytomegalovirus entry into fibroblasts and epithelial cells. AB - Human cytomegalovirus (HCMV) enters cells through a complex pathway involving the interaction of multiple viral glycoproteins and cellular receptors. While HCMV clinical isolates enter a wide range of cell types, entry has historically been studied using a laboratory strain of virus that can only infect fibroblasts. Herein, we have constructed a HCMV reporter strain that contains GFP fused to the abundant tegument protein pp65 to allow for the direct visualization of virus attachment and entry. Furthermore, the UL131 gene of this strain was restored to clinical isolate sequence to expand our studies of entry into physiologically relevant epithelial cell types. Using the HCMV-GFP reporter virus, we developed an image-based assay and screened a library containing 65,000 compounds for the inhibition of virus entry into fibroblasts. In addition to assessing the effect on virus entry, automated image analysis provided information on compound toxicity and whether the compounds acted as attachment or post-attachment inhibitors. To identify therapeutically viable inhibitors capable of blocking entry in multiple cell types, the inhibitors were screened further for their ability to inhibit virus entry into epithelial cells. Compounds were identified that were able to inhibit virus entry into both cell types at either attachment or post-attachment steps. PMID- 21277330 TI - Oxymatrine inhibits hepatitis B infection with an advantage of overcoming drug resistance. AB - Oxymatrine (OMTR) is an anti-hepatitis drug used in China. Its mechanism of action is unknown. Recently, we found that OMTR inhibits hepatitis B virus (HBV) via down-regulating the expression of heat-stress cognate 70 (Hsc70), a host protein required for HBV DNA replication. Goal of this study was to assess the effect of OMTR on clinical HBV drug-resistance. OMTR monotherapy (oral, 12 months) reduced blood HBV DNA by 96% and HBeAg by 70% in the chronic hepatitis B (CHB) patients resistant to lamivudine (n = 17), equal to its efficacy in the naive CHB cohort (n = 20). Liver biopsy study showed that OMTR treatment caused a decrease of Hcs70 mRNA in liver cells, parallel with a reduction of intracellular HBV DNA. Combination of lamivudine with OMTR (n = 15) (oral, 12 months) showed an enhanced anti-HBV effect as compared to lamivudine monotherapy (n = 25). The incidence of drug resistance against lamivudine in the combination group was significantly lower than that in the lamivudine group (1/15 vs 7/25; p<0.01). The results were further confirmed in vitro. Treatment of HBV(+) HepH2215 cells with sub-optimal dose of OMTR for 8 months suppressed HBV replication without inducing drug resistance, whereas lamivudine monotherapy caused drug-resistant mutation in 3 months. Combination of OMTR with lamivudine prevented HBV from developing drug resistance. PMID- 21277331 TI - Polymorphisms of interferon-inducible genes OAS associated with interferon-alpha treatment response in chronic HBV infection. AB - To evaluate the role of host single nucleotide polymorphisms (SNPs) of 2',5' oligoadenylate synthetase (OAS) in predicting IFN response in patients with HBV infection, OAS gene and four SNPs were examined in 363 patients with chronic HBV infection (including 41 patients with HBsAg seroconversion) and 57 healthy controls. One SNP and three haplotypes were identified after adjustment for age, sex, HBV DNA. The frequency of OAS3T/C heterozygotes is 52.2% in responders (R) and 38.2% in non-responders (NR), with an odds ratio (OR) of 1.511 (P = 0.018). For complete responders (CR) and NR, the OR reached 2.323(P = 0.023). Haplotype analyses revealed significant association between three OAS haplotypes and response to IFN-alpha treatment. Genotype combination and interaction between gene-gene analyses disclosed that there was a positive interaction between OAS2/OAS3 and OAS3/OASL, and the rate of OR was 2.46 (likelihood test, P = 0.004) and 4.46 (likelihood test, P = 0.004), respectively. Our results suggest that OAS gene variations may play an important role in response to IFN-alpha and provide a novel strategy for the resolution of HBV infection. PMID- 21277332 TI - Blocking alpha4beta2 and alpha7 nicotinic acetylcholine receptors inhibits the reinstatement of morphine-induced CPP by drug priming in mice. AB - Investigating the interaction between nicotinic and opioid receptors is of great interest for both basic mechanistic and clinical reasons. Morphine and nicotine, two common drugs of abuse, share several behavioral and rewarding properties. However, little is known about the subtypes of nicotinic acetylcholine receptors (nAChR) in the reinstatement of morphine-induced conditioned place preference (CPP). In this study, we found that a non-specific nAChR agonist, nicotine (0.5mg/kg), had no effects on the reinstatement of morphine-induced CPP. However, we found that pretreatment with specific alpha(4)beta(2) and alpha(7) nAChR subtype antagonists, dihydroxy-beta-erithroidine (DHbetaE, 5mg/kg) and methyllycaconitine (MLA, 4 mg/kg), 20 min prior to administration of morphine, inhibited the reinstatement of morphine-induced CPP by drug priming in mice. Furthermore, depression of the reinstatement of morphine-induced CPP by a single DHbetaE or MLA treatment lasted at least three days later when the reinstatement was induced by morphine priming. The data suggest that specific nAChR subtypes, i.e., alpha(4)beta(2) and alpha(7), may contribute to the reinstatement of morphine-induced CPP by drug priming in mice. PMID- 21277333 TI - Neurochemical, hormonal, and behavioral effects of chronic unpredictable stress in the rat. AB - The high comorbidity of anxiety and depression suggests a potential degree of commonality in their etiologies. The chronic unpredictable stress (CUS) model effectively replicates depressive-like phenotypes; however, the ability of CUS to produce anxiety-like behaviors has not been adequately addressed. Using the CUS paradigm (2 stressors per day for 10 days) in adult Sprague-Dawley rats we identified behavioral, hormonal, and neurochemical changes one day after the cessation of treatment. Stress attenuated weight gain throughout the study and increased locomotor activity one day after treatment, but had no effect on anxiety-behavior as measured by the elevated plus maze. In addition, plasma corticosterone levels were positively correlated with hypothalamic serotonin (5 HT) activity one day after stress treatment as determined by the ratio of the metabolite 5-hydroxyindoleacetic acid (5-HIAA) to the parent compound (5-HIAA/5 HT ratio). These data suggest behavioral phenotypes associated with depression, but not comorbid anxiety, emerge in the immediate period after cessation of stress and that stress related physiology is related to 5-HT activity in the hypothalamus. PMID- 21277334 TI - Evaluation of object-based attention in mice. AB - The deficits of attention result in significant impairment in daily life, and pharmacological intervention to improve attention is the most effective treatment in clinics. However, methods which are suitable for the large scale preclinical screening of attention-improving compounds or drugs are few in the field. In this study, we have developed object-based attention task as a simple and wherever practical method that suitable for quick drug screening in mice. Treatment with p chlorophenylalanine (pCPA) (200mg/kg/day, i.p.) for three consecutive days reduced the prefrontal cortical content of serotonin and dopamine, and increased turn-over of dopamine while decreasing turn-over of norepinephrine in the prefrontal cortex on day 7. Auditory attention and working memory, but not long term object memory after a long (10 min) object (two objects)-exposure period, were impaired on day 7 after the same treatment paradigm with pCPA. Novel object recognition ability immediately (<10s) after a short (3 min) object (on two objects)-exposure period was not impaired after pCPA treatment. However, novel object recognition ability immediately (<10s) after a short (3 min), but not long (6 min), object (five objects)-exposure period was impaired after pCPA treatment. For the verification, the current task, the object-based attention task, was confirmed in an attention deficit model induced by acute phencyclidine (1mg/kg, i.p.) treatment in mice. It was implied that the object-based attention task would assist the behavioral screening process of pharmacological studies on attention-improving drugs. PMID- 21277335 TI - Encoding/retrieval dissociation in working memory for human body forms. AB - The present study was conducted to investigate the effect of working memory (WM) load on body processing mechanisms by using event-related potentials (ERPs). It is well known that WM load modulates the P3b (amplitude decreases as WM load increases). Additionally, WM load for faces modulates earlier ERPs like the N170. The present study aimed to investigate the effect of WM load for bodies on the P3b which is associated with WM. Additionally, we explored the effect of WM load on the N170, which is thought to be associated with configural processing, and P1, which has been observed in body as well as in face processing. Effects were analyzed during the encoding and retrieval phases. WM load was modulated by presenting one to four unfamiliar bodies simultaneously for memory encoding. The present study showed that early encoding processes (reflected by the P1 and N170) might not be modulated by WM load, whereas during the retrieval phase, early processes associated with structural encoding (N170) were affected by WM load. A possible explanation of the encoding/retrieval differences might be that subjects used distinct processing strategies in both phases. Parallel encoding of the simultaneously presented bodies might play an important role during the encoding phase where one to four bodies have to be stored, whereas serial matching might be used to compare the probe with the stored pictures during the retrieval phase. Additionally, WM load modulations were observed in later processing steps, which might be associated with stimulus identification and matching processes (reflected by the early P3b) during the encoding but not during the retrieval phase. The current findings further showed for both the encoding and the retrieval phase that the late P3b amplitude decreased as WM load for body images increased indicating that the late P3b is involved in WM processes which do not appear to be category-specific. PMID- 21277336 TI - Mitochondrial outer membrane permeabilization during apoptosis: the role of mitochondrial fission. AB - Mitochondria continually fuse and divide to yield a dynamic interconnected network throughout the cell. During apoptosis, concomitantly with permeabilization of the mitochondrial outer membrane (MOMP) and cytochrome c release, mitochondria undergo massive fission. This results in the formation of small, round organelles that tend to aggregate around the nucleus. Under some circumstances, preceding their fission, mitochondria tend to elongate and to hyperfuse, a process that is interpreted as a cell defense mechanism. Since many years, there is a controversy surrounding the physiological relevance of mitochondrial fragmentation in apoptosis. In this review, we present recent advances in this field, describe the mechanisms that underlie this process, and discuss how they could cooperate with Bax to trigger MOMP and cytochrome c release. This article is part of a Special Issue entitled Mitochondria: the deadly organelle. PMID- 21277337 TI - Hydrogen peroxide depletes phosphatidylinositol-3-phosphate from endosomes in a p38 MAPK-dependent manner and perturbs endocytosis. AB - Phosphatidylinositol-3-phosphate (PI3P) is a lipid that is enriched specifically in early endosomes. Given that early endosomes containing PI3P act as a microdomain to recruit proteins that contain a PI3P-binding domain (FYVE domain), the equilibrium between the production and degradation of PI3P influences a variety of processes, including endocytosis and signal transduction via endosomes. In the study reported herein, we have developed a novel analytical method to quantify the amount of PI3P in endosomes by introducing a GST-2xFYVE protein probe into semi-intact cells. The GST-2xFYVE probe was targeted specifically to intracellular PI3P-containing endosomes, which retained their small punctate structure, and allowed the semi-quantitative measurement of intracellular PI3P. Using the method, we found that treatment of HeLa cells with H(2)O(2) decreased the amount of PI3P in endosomes in a p38 MAPK-dependent manner. In addition, H(2)O(2) treatment delayed transport through various endocytic pathways, especially post-early endosome transport; the retrograde transport of cholera toxin was especially dependent on the amount of PI3P in endosomes. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. PMID- 21277338 TI - DNA methylation restricts spontaneous multi-lineage differentiation of mesenchymal progenitor cells, but is stable during growth factor-induced terminal differentiation. AB - The progressive restriction of differentiation potential from pluripotent embryonic stem cells, via multipotent progenitor cells to terminally differentiated, mature somatic cells, involves step-wise changes in transcription patterns that are tightly controlled by the coordinated action of key transcription factors and changes in epigenetic modifications. While previous studies have demonstrated tissue-specific differences in DNA methylation patterns that might function in lineage restriction, it is unclear at what exact developmental stage these differences arise. Here, we have studied whether terminal, multi-lineage differentiation of C2C12 myoblasts is accompanied by lineage-specific changes in DNA methylation patterns. Using bisulfite sequencing and genome-wide methylated DNA- and chromatin immunoprecipitation-on-chip techniques we show that in these cells, in general, myogenic genes are enriched for RNA polymerase II and hypomethylated, whereas osteogenic genes show lower polymerase occupancy and are hypermethylated. Removal of DNA methylation marks by 5-azacytidine (5AC) treatment alters the myogenic lineage commitment of these cells and induces spontaneous osteogenic and adipogenic differentiation. This is accompanied by upregulation of key lineage-specific transcription factors. We subsequently analyzed genome-wide changes in DNA methylation and polymerase II occupancy during BMP2-induced osteogenesis. Our data indicate that BMP2 is able to induce the transcriptional program underlying osteogenesis without changing the methylation status of the genome. We conclude that DNA methylation primes C2C12 cells for myogenesis and prevents spontaneous osteogenesis, but still permits induction of the osteogenic transcriptional program upon BMP2 stimulation. Based on these results, we propose that cell type-specific DNA methylation patterns are established prior to terminal differentiation of adult progenitor cells. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. PMID- 21277339 TI - Rapid identification and characterization of Penicillium marneffei using multiplex ligation-dependent probe amplification (MLPA) in paraffin-embedded tissue samples. AB - Penicillium marneffei infection is a deadly disease and early diagnosis leads to prompt and appropriate antifungal therapy. To develop a sensitive method to diagnose P. marneffei infection, a multiplex ligation-dependent probe amplification (MLPA) assay was adapted. This method can rapidly and specifically detect P. marneffei DNA in cultured cells and paraffin-embedded tissue samples. Three pairs of probes were designed for amplifying the internally (intergenic) transcribed spacer (ITS) region of P. marneffei rRNA using a systematic phylogenetic analysis. These three probe sets produced three amplicons of 198, 166, and 152 bp, respectively, specific for P. marneffei. In contrast, there was only one 198 bp amplicon produced for Talaromyces stipitatus, and one 152 bp amplicon for P. funiculosum, T. intermedius and T. derxii. The probes did not amplify any other reference strains. An array of 40 P. marneffei strains isolated from human patients, bamboo rat, and the local environment was tested by using MLPA, and all were positively identified. Most importantly, P. marneffei in paraffin-embedded tissue specimens from infected human patients was positively amplified by MLPA. The sensitivity and specificity of the MLPA assay could be a useful tool for prompt diagnosis, pathogen characterization, and epidemiological studies of fungal infections. PMID- 21277340 TI - Trapped in keratin; a comparison of dermatophyte detection in nail, skin and hair samples directly from clinical samples using culture and real-time PCR. AB - Traditionally, laboratory detection and identification of dermatophytes consists of culture and microscopy which yields results within approximately 2-6 weeks. In 2007 our medical microbiological diagnostic laboratory implemented a molecular method for the detection of dermatophytes. A real-time PCR assay was developed which simultaneously detects and identifies the most prevalent dermatophytes directly in nail, skin and hair samples and has a turnaround time of less than two days. For 1437 clinical samples, received by our diagnostic laboratory, we compared the results obtained from both culture and real-time PCR. This study showed that real-time PCR significantly increased the detection rate of dermatophytes compared to culture. Furthermore, excellent concordance between culture and real-time PCR identification was achieved. PMID- 21277341 TI - Quantification of Campylobacter spp. in pig feces by direct real-time PCR with an internal control of extraction and amplification. AB - The rapid and direct quantification of Campylobacter spp. in complex substrates like feces or environmental samples is crucial to facilitate epidemiological studies on Campylobacter in pig production systems. We developed a real-time PCR assay for detecting and quantifying Campylobacter spp. directly in pig feces with the use of an internal control. Campylobacter spp. and Yersinia ruckeri primers probes sets were designed and checked for specificity with diverse Campylobacter, related organisms, and other bacterial pathogens before being used in field samples. The quantification of Campylobacter spp. by the real-time PCR then was realized on 531 fecal samples obtained from experimentally and naturally infected pigs; the numeration of Campylobacter on Karmali plate was done in parallel. Yersinia ruckeri, used as bacterial internal control, was added to the samples before DNA extraction to control DNA-extraction and PCR-amplification. The sensitivity of the PCR assay was 10 genome copies. The established Campylobacter real-time PCR assay showed a 7-log-wide linear dynamic range of quantification (R2=0.99) with a detection limit of 200 Colony Forming Units of Campylobacter per gram of feces. A high correlation was found between the results obtained by real time PCR and those by culture at both qualitative and quantitative levels. Moreover, DNA extraction followed by real-time PCR reduced the time needed for analysis to a few hours (within a working day). In conclusion, the real-time PCR developed in this study provides new tools for further epidemiological surveys to investigate the carriage and excretion of Campylobacter by pigs. PMID- 21277342 TI - Homogenisation of cystic fibrosis sputum by sonication--an essential step for Aspergillus PCR. AB - The importance of Aspergillus as a lung pathogen in cystic fibrosis (CF) is becoming increasingly recognised. However, fungal culture of CF sputum is unreliable and there is no consensus for identifying phenotypes beyond ABPA that may benefit from antifungal therapy. There are no published studies using real time PCR to detect Aspergillus in CF sputum. The major barrier to sensitive detection of Aspergillus using PCR is sputum homogenisation. This study aimed to optimise sputum homogenisation utilising sonication to improve Aspergillus DNA extraction. Sonication amplitude and duration that enabled sputum homogenisation but ensured preservation of DNA integrity were first determined. 160 sputum samples were collected from CF patients. 49 of the sputum samples were split, one half was used for standard culture and the other half was homogenised with NALC NaOH before undergoing DNA extraction. The subsequent 111 samples were homogenised with dithiothreitol plus sonication prior to culture and DNA extraction. Real-time PCR targeting a portion of the 18S rDNA of Aspergillus was performed on all DNA extractions. In the 49 samples with no sonication 8 (16%) were culture positive but only 4 of these were PCR positive. However, PCR was positive in 11 culture negative samples. PCR after sonication showed a significant improvement in sensitivity: 33 (30%) were culture and PCR positive, 48 (43%) were culture negative, but PCR positive (p<0.0001) and 30 (27%) were culture and PCR negative. The combination of dithiothreitol and sonication to homogenise sputum increases PCR yield, with PCR being substantially more sensitive than culture. PMID- 21277343 TI - Proton Transfer Reaction Mass Spectrometry detects rapid changes in volatile metabolite emission by Mycobacterium smegmatis after the addition of specific antimicrobial agents. AB - The metabolic activity of plants, animals or microbes can be monitored by gas headspace analysis. This can be achieved using Proton Transfer Reaction Mass Spectrometry (PTR-MS), a highly sensitive detection method for trace gas analysis. PTR-MS is rapid and can detect metabolic responses on-line as they occur. Here, we study the headspace of actively growing cultures of paired ciprofloxacin sensitive and resistant bacterial strains (Mycobacterium smegmatis in Middlebrook M7H9 liquid media) after the addition of the antibiotics ciprofloxacin and gentamicin in real time. Following the emission patterns of the mycobacteria over time allowed volatile markers specific for the bacterial response to each antibiotic to be detected. A proportion of the measured responses were very rapid, occurring within three hours after the addition of the compounds and varied between isolates with different resistance phenotypes. Specifically, we observed a two fold increase of m73 (unidentified C4 compound) within 10h after the addition of ciprofloxacin and a threefold increase of m45 (acetaldehyde) within 4h after the addition of gentamicin as compared to values before the addition. Monitoring the emission of specific volatiles into the culture headspace thus has the potential for rapid drug susceptibility testing. Moreover, these and other differences in the measured responses to the two tested compounds provide evidence that monitoring multiple compounds may also give an indication of the mechanism of action of the compound added. PMID- 21277344 TI - De novo formation and ultra-structural characterization of a fiber-producing human hair follicle equivalent in vitro. AB - Across many tissues and organs, the ability to create an organoid, the smallest functional unit of an organ, in vitro is the key both to tissue engineering and preclinical testing regimes. The hair follicle is an organoid that has been much studied based on its ability to grow quickly and to regenerate after trauma. But hair follicle formation in vitro has been elusive. Replacing hair lost due to pattern baldness or more severe alopecia, including that induced by chemotherapy, remains a significant unmet medical need. By carefully analyzing and recapitulating the growth conditions of hair follicle formation, we recreated human hair follicles in tissue culture that were capable of producing hair. Our microfollicles contained all relevant cell types and their structure and orientation resembled in some ways excised hair follicle specimens from human skin. This finding offers a new window onto hair follicle development. Having a robust culture system for hair follicles is an important step towards improved hair regeneration as well as to an understanding of how marketed drugs or drug candidates, including cancer chemotherapy, will affect this important organ. PMID- 21277345 TI - A novel vector for lactic acid bacteria that uses a bile salt hydrolase gene as a potential food-grade selection marker. AB - A novel vector pM4aB for lactic acid bacterial was developed using a bile salt hydrolase gene from Lactobacillus plantarum as a potential food-grade selection marker. The 3.0-kb pM4aB consisted of the replicon of Lactobacillus plasmid pM4, a multiple cloning site and the bsh gene, which was constructed by elimination of a 5.5-kb non-food-grade DNA fragment from an 8.5-kb intermediate vector pBEmpM4aB. For electroporation into Lactobacillus paracasei X9, a high transformation efficiency of 4.0+/-1.0*10(4) CFU/MUg plasmid DNA was yielded with 0.1% (wt/vol) glycodeoxycholic acid sodium selection. A high segregation stability of the vector was also observed as only 0.1% plasmid was lost after 50 generations of growth without selection pressure. The application potential of pM4aB was further confirmed by expression of a catalase gene from Lactobacillus sakei in L. paracasei. These results revealed that the novel vector pM4aB constructed in this study would be a useful tool for genetic modification of the industrially important LAB. PMID- 21277346 TI - A review of the structure of human and bovine dental hard tissues and their physicochemical behaviour in relation to erosive challenge and remineralisation. AB - OBJECTIVES: This review sets out to examine the suitability of bovine hard dental material in lieu of human material when investigating dental erosion, to review the evidence for the major factors popularly attributed to dental erosion: pH, pKa, acid type, erosion duration, temperature and stirring rate as well as examine the case for the use of fluoride in an anti-erosion capacity. DATA SOURCES: Published works were selected using online search software ICI Web of Knowledge and Pubmed, with key terms such as "enamel", "erosion" and "bovine AND human" and cross referenced with relevant papers cited in the indices. RESULTS: The growing trend of dental erosion, coupled to legislative changes has precipitated a recent shortage of human enamel and dentine for experimental work. This in turn has resulted in the increasing use of cheap and readily available alternate supplies being sourced. This alternate supply principally originates from beef cattle under 20 months of age, under the assumption that bovine enamel and dentine will behave in a manner similar to human material. Recent experiments attempting to compare the physicochemical properties of these two species have shown that erosion is not simply a matter of bulk tissue loss resulting from acid exposure, but a multi-factorial event encompassing ever increasing and varied complexity of the inter-relationship between solvent and substrate. CONCLUSIONS: Accurate data from the published literature regarding the comparative properties of human and bovine hard dental tissue remains scarce but consensus appears to accept the continuing use of bovine enamel as a substitute for human enamel. This lack of comparative data is further hampered by the lack of an established, standardised protocol with which to evaluate the two species. In addition, much debate remains regarding the significant principal factors responsible for dental erosion and ways to minimise the pathological manifestation. PMID- 21277347 TI - Exciting times for our field and the Journal. PMID- 21277348 TI - Influence of aluminum oxide on the prebiotic thermal synthesis of Gly-Glu-(Gly Glu)(n) polymer. AB - The effect of the aluminum oxide on the thermal synthesis of the glycine-glutamic acid (Gly-Glu-(Gly-Glu)(n) polymer is described. The thermal synthesis in the molten state was carried out in the absence and presence of the oxide. In both cases, the vibrational spectra showed characteristic group frequencies corresponding predominantly to a Gly-Glu-(Gly-Glu)(n) sequence in the polymeric structure. The theoretical spectral data support the experimental proposed Gly Glu-(Gly-Glu)(n) sequence for the polymer. The SEM-EDX characterization of the solid phase involved in the thermal synthesis showed that the aluminum oxide participates as a site for nucleation and growth of the polymer, explaining the increase of 25% efficiency in the presence of aluminum oxide. Electrophoresis data show shorter polypeptide chains in the presence of aluminum oxide. PMID- 21277349 TI - Increased circulating leptin level inhibits folliculogenesis in vespertilionid bat, Scotophilus heathii. AB - The present study investigates the mechanism by which obesity associated rise in leptin and insulin levels cause anovulation in vespertilionid bat, Scotophilus heathii. In the ovary of S. heathii, leptin and insulin receptors were mainly localized in interstitial and thecal cells and in the granulosa cells of primary follicles suggesting its possible role in androgen synthesis and follicular development. Adiposity associated increase in circulating leptin level down regulate ovarian LH-receptor expression and produce characteristic morphological changes in the antral follicles, such as hypertrophy of granulosa cells and a sharp decline in the rate of proliferation as well as apoptosis in the antral follicles. These follicles are referred as unique antral follicle. The in vitro study confirmed the in vivo findings that the high dose of leptin suppresses apoptosis and LH receptors. The present study thus showed that the adiposity associated increase in leptin during the first phase of follicular development inhibits folliculogenesis and simultaneously suppresses both follicular proliferation and apoptosis by reducing sensitivity to gonadotropin stimulation and decreasing circulating LH levels. PMID- 21277350 TI - Dexamethasone pre-treatment protects brain against hypoxic-ischemic injury partially through up-regulation of vascular endothelial growth factor A in neonatal rats. AB - Dexamethasone (Dex) provides neuroprotection against subsequent hypoxia ischemia (HI) in newborn rats, but the mechanism of this neuroprotection is not well understood. It is known that vascular endothelial growth factor A (VEGF) has neuroprotective effects. The objective of this study was to evaluate the role of the VEGF signaling pathway in the Dex-induced neuroprotection in newborn rats. Seven-day-old rat pups had the right carotid artery permanently ligated followed by 140 or 160 min of hypoxia (8% oxygen). Rat pups received two i.p. injections of either saline or Dex (0.25 mg/kg) at 24 and 4 h before HI exposure. To quantify the effects of a glucocorticoid receptor (GR) blocker, on postnatal day (PD) 6 and 15 min prior to Dex treatment rat pups received s.c. vehicle or RU486 (GR blocker, 60 mg/kg). After 24 h at PD 7, all rat pups had HI as described earlier. To quantify the effects of a VEGFR 2 blocker, at 24 h after Dex/Veh treatment (PD7), SU5416, a VEGFR 2 inhibitor or vehicle was injected intracerebroventricularly in the right hemisphere at 30 min before and 2 h after HI. Dex pre-treatment reduced brain injury and enhanced the HI-induced brain VEGF protein while a GR blocker inhibited these effects. Treatment with VEGFR 2 blocker decreased Dex-induced neuroprotection also. Dex pre-treatment enhanced the HI-induced increase in mRNA expression of VEGF splice variants and decreased the HI-induced reduction of Akt phosphorylation. Additionally, it also decreased HI-induced increase of caspase-3 activity and DNA fragments in neonatal rat brain. We conclude that Dex provides robust neuroprotection against subsequent HI in newborn rats via GR likely with the partial involvement of VEGF signaling pathway. PMID- 21277351 TI - Subtype-specific reduction of voltage-gated calcium current in medium-sized dorsal root ganglion neurons after painful peripheral nerve injury. AB - Sensory neurons express a variety of voltage-gated Ca2+ channel subtypes, but reports differ on their proportionate representation, and the effects of painful nerve injury on each subtype are not established. We compared levels of high voltage activated currents in medium-sized (30-40 MUm) dorsal root ganglion neurons dissociated from control animals and those subjected to spinal nerve ligation, using sequential application of semiselective channel blockers (nisoldipine for L-type, SNX-111 or omega-conotoxin GVIA for N-type, agatoxin IVA or omega-conotoxin MVIIC for P/Q-type, and SNX-482 for a component of R-type) during either square wave depolarizations or action potential waveform voltage commands. Using sequential administration of multiple blockers, proportions of total Ca2+ current attributable to different subtypes and the effect of injury depended on the sequence of blocker administration and type of depolarization command. Overall, however, N-type and L-type currents comprised the dominant components of ICa in sensory neurons under control conditions, and these subtypes showed the greatest loss of current following injury (L-type 26-71% loss, N-type 0-51% loss). Further exploration of N-type current identified by its sensitivity to omega-conotoxin GVIA applied alone showed that injury reduced the peak N-type current during step depolarization by 68% and decreased the total charge entry during action potential waveform stimulation by 44%. Isolation of N-type current by blockade of all other subtypes demonstrated a 50% loss with injury, and also revealed an injury-related rightward shift in the activation curve. Non stationary noise analyses of N-type current in injured neurons revealed unitary channel current and number of channels that were not different from control, which indicates that injury-induced loss of current is due to a decrease in channel open probability. Our findings suggest that diminished Ca2+ influx through N-type and L-type channels may contribute to sensory neuron dysfunction and pain after nerve injury. PMID- 21277352 TI - Volatile anesthetic post-treatment induces protection via inhibition of glycogen synthase kinase 3beta in human neuron-like cells. AB - Application of the volatile anesthetic isoflurane during the early phase of reperfusion reduces ischemic heart and brain injury (anesthetic post conditioning). We hypothesize that inhibition of glycogen synthase kinase 3beta (GSK3beta), a protein whose activation can lead to cell death, participates in anesthetic post-conditioning-induced neuroprotection. SH-SY5Y cells, a human neuroblastoma cell line, were induced by retinoic acid to differentiate into terminal neuron-like cells. The cells were then subjected to a 1-h oxygen-glucose deprivation (OGD), a condition to simulate ischemia in vitro, and a 20-h simulated reperfusion. Isoflurane, sevoflurane or desflurane, three commonly used volatile anesthetics, were applied for 1 h during the early phase of simulated reperfusion. Cell injury was quantified by lactate dehydrogenase (LDH) release. Phospho-GSK3beta at Ser9 and total GSK3beta were quantified at 1 or 3 h after the OGD. OGD increased LDH release, suggesting that OGD induced cell injury. Post treatment with isoflurane, sevoflurane or desflurane reduced this cell injury. This protection was apparent when 2% isoflurane was applied within 1 h after the onset of reperfusion. Isoflurane post-treatment also significantly increased the phosphorylation of GSK3beta at Ser9 at 1 h after the OGD. GSK3beta inhibitors reduced OGD and simulated reperfusion-induced LDH release. The combination of GSK3beta inhibitors and isoflurane post-conditioning did not cause a greater protection than isoflurane post-conditioning alone. These results suggest that volatile anesthetic post-conditioning reduces OGD and simulated reperfusion induced cell injury. Since phospho-GSK3beta at Ser9 decreases GSK3beta activity, our results suggest that volatile anesthetic post-conditioning in human neuron like cells may be mediated by GSK3beta inhibition. PMID- 21277353 TI - Involvement of protein kinase C and protein kinase A in the enhancement of L-type calcium current by GABAB receptor activation in neonatal hippocampus. AB - In the early neonatal period activation of GABAB receptors attenuates calcium current through N-type calcium channels while enhancing current through L-type calcium channels in rat hippocampal neurons. The attenuation of N-type calcium current has been previously demonstrated to occur through direct interactions of the betagamma subunits of Gi/o G-proteins, but the signal transduction pathway for the enhancement of L-type calcium channels in mammalian neurons remains unknown. In the present study, calcium currents were elicited in acute cultures from postnatal day 6-8 rat hippocampi in the presence of various modulators of protein kinase A (PKA) and protein kinase C (PKC) pathways. Overnight treatment with an inhibitor of Gi/o (pertussis toxin, 200 ng/ml) abolished the attenuation of calcium current by the GABAB agonist, baclofen (10 MUM) with no effect on the enhancement of calcium current. These data indicate that while the attenuation of N-type calcium current is mediated by the Gi/o subtype of G-protein, the enhancement of L-type calcium current requires activation of a different G protein. The enhancement of the sustained component of calcium current by baclofen was blocked by PKC inhibitors, GF-109203X (500 nM), chelerythrine chloride (5 MUM), and PKC fragment 19-36 (2 MUM) and mimicked by the PKC activator phorbol-12-myristate-13-acetate (1 MUM). The enhancement of the sustained component of calcium current was blocked by PKA inhibitors H-89 (1 MUM) and PKA fragment 6-22 (500 nM) but not Rp-cAMPS (30 MUM) and it was not mimicked by the PKA activator, 8-Br-cAMP (500 MUM-1 mM). The data suggest that activation of PKC alone is sufficient to enhance L-type calcium current but that PKA may also be involved in the GABAB receptor mediated effect. PMID- 21277354 TI - Threshold for epileptiform activity is elevated in prion knockout mice. AB - Prion protein (PrP) is abundant in the nervous system, but its role remains uncertain. Prion diseases depend on an aggregation of the protein that is likely to interfere with its normal function. Loss of function does not in itself cause neurodegeneration, but whether it contributes to the clinical features of the disease remains an open question. Patients with classical Creutzfeldt-Jakob disease (CJD) have a higher than expected incidence of epilepsy. To study the mechanisms by which loss of PrP function may underlie changes in vulnerability to epilepsy in disease, we used several acute epilepsy models: we applied a variety of convulsant treatments (zero-magnesium, bicuculline, and pentylenetetrazol) to slices in vitro from PrP knockout (Prnp0/0) and control mice. In all three epilepsy models, we found that longer delays and/or higher concentrations of convulsants were necessary to generate spontaneous epileptiform activity in Prnp0/0 mice. These results together indicate an increased seizure threshold in Prnp0/0 mice, suggesting that loss of PrP function cannot explain a predisposition to seizures initiation in CJD. PMID- 21277355 TI - Hypoxia-induced hypothermia mediated by noradrenaline and nitric oxide in the rostromedial preoptic area. AB - Central nitric oxide (NO) has an important role in hypothermia induced by hypoxia as well as in that elicited by noradrenaline (NA) microinjected into the rostromedial preoptic area (POA) of the hypothalamus. Here, I tested the hypothesis that activation of adrenoceptors and NO in the rostromedial POA is involved in hypoxia-induced hypothermia in urethane-chloralose-anesthetized, neuromuscularly blocked, artificially ventilated rats. Hypoxic ventilation (10% O2-90% N2, 5 min) evoked an increase in the tail skin temperature and a decrease in the colonic temperature, though these changes occurred at 30 s to 7 min after returning the rats to ventilation with room air. These responses were eliminated by prior bilateral transection of the carotid sinus nerves, but not by bilateral cervical vagotomy, suggesting the involvement of activated carotid chemoreceptors in the hypoxic ventilation-induced hypothermia. Such responses were also greatly attenuated by the microinjection of an NO synthase (NOS) inhibitor, NG-monomethyl L-arginine (L-NMMA, 25 nmol), but not by that of its inactive enantiomer, NG monomethyl-D-arginine (D-NMMA, 25 nmol), into the NA-sensitive, hypothermia inducing site in the rostromedial POA. Pretreatment with the alpha1-adrenoceptor blocker prazosin (50 pmol), but not vehicle saline, also greatly attenuated the hypoxic ventilation-induced heat loss responses. These results suggest that this hypoxia-induced hypothermia was mediated, at least in part, by activation of alpha1-adrenoceptors and NOS in the rostromedial POA. PMID- 21277356 TI - Nitric oxide production in the perifornical-lateral hypothalamic area and its influences on the modulation of perifornical-lateral hypothalamic area neurons. AB - The perifornical-lateral hypothalamic area (PF-LHA) is a major wake-promoting structure. It predominantly contains neurons that are active during behavioral and cortical activation. PF-LHA stimulation produces arousal and PF-LHA lesions produce somnolence. Nitric oxide (NO) is a gaseous neurotransmitter that has been implicated in the regulation of multiple pathological and physiological processes including the regulation of sleep. NO levels are higher in the cortex and in the basal forebrain (BF) during arousal. In this study we determined whether NO levels increase in the PF-LHA during prolonged arousal and whether increased NO modulates the discharge activity of PF-LHA neurons. Experiments were conducted during lights-on phase between 8.00 and 20.00 h (lights-on at 8.00 h). First, we quantified levels of NO metabolites, NO2- and NO3- (collectively called NOx-) in the microdialysis dialysates collected from the PF-LHA during baseline (undisturbed rats), 6 h of sleep deprivation (SD), and recovery after SD. We further determined the effects of a NO donor, NOC-18, on the discharge activity of PF-LHA neurons in urethane-anesthetized rats. Overall, SD significantly affected NOx- production in the PF-LHA (one way repeated measures ANOVA, F=7.827, P=0.004). The levels of NOx- increased progressively in animals that were subjected to prolonged arousal as compared to the undisturbed predominantly sleeping animals and decreased during the recovery period. Local application of NOC-18 significantly suppressed the discharge of PF-LHA neurons including a majority of stimulus-on neurons or neurons exhibiting activation during electroencephalogram (EEG) desynchronization. The findings of this study suggest that in the PF-LHA, NO production is elevated during prolonged waking and that NO exerts predominantly inhibitory effects on PF-LHA neurons, especially on those neurons that are active during cortical activation. These findings are consistent with a hypothesis that NO in the PF-LHA plays a role in sleep regulation by inhibiting its neurons. PMID- 21277357 TI - Intrasurgical mapping of complex motor function in the superior frontal gyrus. AB - A lesion to the superior frontal gyrus (SFG) has been associated with long lasting deficits in complex motor functions. The aim of this study was to analyze the functional role of the SFG by means of electrical cortical stimulation. Direct intraoperative electrical stimulation was used in a group of 21 subjects with lesions within or close to the SFG while they performed three motor tasks that require high skills or bimanual synergy. The results were compared to functional magnetic resonance imaging (fMRI). Ninety-four of the 98 (94.9%) labels identified were located on the convexity surface of the SFG and only four (4.1%) labels were located on the middle surface of the SFG. Areas of blockage of the three tasks were identified in six of the 12 (50%) hemispheres with lesions that had infiltrated the SFG, compared to all 10 of the 10 hemispheres (100%) with lesions that spared the SFG. The difference between these two proportions was statistically significant (P=0.015). fMRI activation was mainly located on the medial aspect of the SFG. We show that the convexity surface of the SFG has an important role in bilateral control of complex movements and in bimanual coordination. The infiltration of the posterior part of the SFG by a lesion disturbs some of the complex hand motor functions, which may be assumed by the contralesional homologous area. Finally, the current study emphasizes the discrepancies between fMRI and intraoperative electrical stimulation maps in complex hand motor function. PMID- 21277358 TI - Special issue on spinal cord injury in brain research bulletin. PMID- 21277359 TI - Antioxidant and prooxidant properties of flavonoids. AB - The interest in possible health benefits of flavonoids has increased owing to their potent antioxidant and free radical scavenging activities observed in vitro. Nevertheless, the antioxidant efficacy of flavonoids in vivo is less documented and their prooxidant properties have been actually described in vivo. Due to their prooxidant properties, they are able to cause oxidative damage by reacting with various biomolecules, such as lipids, proteins and DNA. Hence, the aim of this review is to discuss both the antioxidant and prooxidant effects of flavonoids. PMID- 21277360 TI - A new coumestan with immunosuppressive activities from Flemingia philippinensis. AB - A new coumestan, 1,3,9-trihydroxy-8-methoxycoumestan, named flemicoumestan A 1 together with nine isoflavone-related compounds were isolated from the ethyl acetate extract of the roots of Flemingia philippinensis. Their structures were elucidated and confirmed by spectroscopic methods and literature data. Compounds 3 and 4 showed strong lymphocyte proliferation inhibitory activity with an IC(50) value of 1.04-2.76 MUM, and the low cytotoxicity with the CC(50) value of 71.01 and 56.36 MUM, respectively. PMID- 21277361 TI - cDNA cloning of porcine PKD2 gene and RNA interference in LLC-PK1 cells. AB - Mutations in the PKD2 gene cause autosomal dominant polycystic kidney disease (ADPKD), a common, inherited disease that frequently leads to end-stage renal disease (ESRD). Swine show substantial similarity to humans physiologically and anatomically, and are therefore a good model system in which to decipher the structure and function of the PKD2 gene and to identify potential therapeutic targets. Here we report the cloning and characterization of the porcine PKD2 cDNA showing that the full-length gene (3370 bases) is highly expressed in kidney, with minimal expression in the liver. RNA interference (RNAi) is a promising tool to enable identification of the essential components necessary for exploitation of the pathway involved in cellular processes. We therefore designed four shRNAs and nine siRNAs targeting the region of the porcine PKD2 gene from exons 3 to 9, which is supposed to be a critical region contributing to the severity of ADPKD. The results from HeLa cells with the dual-luciferase reporter system and porcine kidney cells (LLC-PK1) showed that sh12 could efficiently knock down the PKD2 gene with an efficiency of 51% and P1 and P2 were the most effective siRNAs inhibiting 85% and 77% respectively of PKD2 expression compared with untreated controls. A subsequent functional study of the transient receptor potential polycystic (TRPP) 2 channel protein indicated that the decreased expression of TRPP2 induced by siRNA P1 and P2 could release the arrest of the cell cycle from G0/G1 promoting progression to S and G2 phases. Our data, therefore, provides evidence of potential knock-down target sites in the PKD2 gene and paves the way for the future generation of transgenic ADPKD knock-down animal models. PMID- 21277362 TI - Gene tree discordance of wild and cultivated Asian rice deciphered by genome-wide sequence comparison. AB - Although a large number of genes are expected to correctly solve a phylogenetic relationship, inconsistent gene tree topologies have been observed. This conflicting evidence in gene tree topologies, known as gene tree discordance, becomes increasingly important as advanced sequencing technologies produce an enormous amount of sequence information for phylogenomic studies among closely related species. Here, we aim to characterize the gene tree discordance of the Asian cultivated rice Oryza sativa and its progenitor, O. rufipogon, which will be an ideal case study of gene tree discordance. Using genome and cDNA sequences of O. sativa and O. rufipogon, we have conducted the first in-depth analyses of gene tree discordance in Asian rice. Our comparison of full-length cDNA sequences of O. rufipogon with the genome sequences of the japonica and indica cultivars of O. sativa revealed that 60% of the gene trees showed a topology consistent with the expected one, whereas the remaining genes supported significantly different topologies. Moreover, the proportions of the topologies deviated significantly from expectation, suggesting at least one hybridization event between the two subgroups of O. sativa, japonica and indica. In fact, a genome-wide alignment between japonica and indica indicated that significant portions of the indica genome are derived from japonica. In addition, literature concerning the pedigree of the indica cultivar strongly supported the hybridization hypothesis. Our molecular evolutionary analyses deciphered complicated evolutionary processes in closely related species. They also demonstrated the importance of gene tree discordance in the era of high-speed DNA sequencing. PMID- 21277363 TI - Involvement of CYP3A4/5 and CYP2D6 in the metabolism of aconitine using human liver microsomes and recombinant CYP450 enzymes. AB - Aconitine (AC), a famous major Aconitum alkaloid, has effective antirheumatic function with high toxicity. The aim of our study was to in-depth investigate cytochrome P450 isozymes (CYPs) involved in aconitine metabolism in vitro. We used human liver microsomes (HLMs) as well as recombinant CYPs to investigate the metabolism pathways of aconitine by liquid chromatography-tandem mass spectrometry. Fluvoxamine maleate, gemfibrozil, amiodarone hydrochloride, omeprazole, quinidine, diethyldithiocarbamic acid and ketoconazole were successfully applied as test inhibitors for CYP1A2, CYP2C8, CYP2C9, CYP2C19*1, CYP2D6*1, CYP2E1 and CYP3A4/5 in HLMs, respectively. Six CYP-mediated metabolites were found and characterized in human liver microsomes and eight recombinant CYP isoforms. The inhibitor of CYP 3A had a strong inhibitory effect, the inhibitors of CYP 2C9, 2C8 and CYP2D6 had little inhibitory effects, whereas CYP2C19, 1A2 and 2E1 had no obvious inhibitory effects on AC metabolism. Hydroxylation and di demethylation of aconitine were conducted by human recombinant CYP 3A5 and 2D6, dehydrogenation was only processed by CYP3A4/5, and the main CYP isoforms metabolizing aconitine to demethyl-aconitine and N-deethyl-aconitine were CYP3A4/5 and CYP2D6. In conclusion, aconitine can be transformed into at least six CYP-mediated metabolites in HLMs, CYP 3A4/5 and 2D6 were the most important CYP isoforms responsible for the de-methylation, N-deethylation, dehydrogenation, and hydroxylation of aconitine. PMID- 21277364 TI - Induction of apoptosis and inhibition of PI3K/Akt pathway in PC-3 and LNCaP prostate cancer cells by ethanolic neem leaf extract. AB - AIM OF THE STUDY: The present study is aimed to delineate the effect of ethanolic neem leaf extract on PI3K/Akt and apoptotic pathway in prostate cancer cell lines (PC-3 and LNCaP). MATERIALS AND METHODS: To test the hypothesis, two different prostate cancer cell lines LNCaP (androgen dependent) and PC-3 (androgen independent) were taken. Cells were exposed to various concentrations of ethanolic neem leaf extract (ENLE) (25-125 MUg/ml). The doses were fixed by cell viability (MTT) assay. For apoptotic detection in situ apoptosis assay, caspase-3 activity and protein expression of cytochrome c and Poly-ADP Ribose Polymerase (PARP) were analysed as well as mRNA expression of Bcl-2 family proteins was studied by RT-PCR. The phosphoinositide 3-kinase (PI3K) and p-Akt were analysed by western blotting and mRNA expression of Akt 1 and 2, PTEN was performed by RT PCR. Immunoblotting of cyclin D1 and p21 was done to access the inhibition of cell proliferation. RESULTS: ENLE gives 50% inhibition at a dose of 100 MUg/ml in both PC-3 and LNCaP cells and considered as effective dose. ENLE decreased the protein expression of PI3K as well as p-Akt and the mRNA expression of Akt 1and 2 in both the cells. There was a significant decrease in mRNA expression of PTEN in LNCaP cells. ENLE induced apoptosis and inhibited cell proliferation by inhibiting PI3K/Akt pathway. Decrease in p-Akt leads to increase in the protein level of Bad, p21 and decrease in the cyclin D1, respectively. ENLE treatment increased the cytochrome c expression and caspase-3 activity as well as regulated the mRNA expression of Bcl-2 family proteins thereby inducing apoptosis to both the cell lines. In situ apoptosis assay showed increased red fluorescence in 100 MUg/ml of ENLE in both PC-3 and LNCaP cell lines. CONCLUSIONS: The results suggested that ENLE induces apoptosis and inhibits cell proliferation through inhibiting PI3K/Akt pathway in both PC-3 and LNCaP cells. PMID- 21277365 TI - Effects of Chinese herbal medicine Fuzhisan on autologous neural stem cells in the brain of SAMP-8 mice. AB - Fuzhisan (FZS), a Chinese herbal complex prescription, has been used in the treatment of Alzheimer's disease (AD) for more than 16 years. However the underlying mechanism remains to be explored. The effects of the aqueous extract of FZS on the cognitive functions of the aged mice and the pharmacological basis for its therapeutic efficacy were investigated. The results showed that FZS improved impaired cognitive ability of aged SAMP-8 mice. FZS (2.4, 4.8 g/kg/d) increased hippocampal neurogenesis and the long-term survival of BrdU-labeled cells without affecting the proportion of BrdU-positive neurons and glial cells. FZS also increased the number of BrdU-positive cells in the subventricular zone (SVZ) of the lateral ventricles of 8-month-old SAMP-8 mice. These studies suggest that FZS upregulates neurogenesis by increasing proliferation of neural progenitor cells and prolonging survival of the newborn cells in the hippocampal DG. FZS may be beneficial for the treatment of senile dementia, especially Alzheimer's disease. PMID- 21277366 TI - Erythropoietin for neonatal brain injury: opportunity and challenge. AB - Neonatal brain injury, caused by perinatal hypoxia-ischemia and extreme prematurity, remains a great challenge for prevention and treatment. There is no effective treatment for term hypoxic-ischemic encephalopathy (HIE) except hypothermia which by itself does not afford complete neuroprotection. Erythropoietin (EPO), a pleiotropic cytokine, has neuroprotective effects in a series of neonatal experimental models and recent clinical trials of HIE. However, the mechanisms, dosing, and the toxicity of EPO in these settings are inconsistently reported. This review will focus on the possible mechanisms, recent clinical advances and potential complications of EPO used in research and the clinic. In addition, optimal dose and administrative routes of EPO, and novel EPO mimetics will be discussed. PMID- 21277367 TI - Continuous stress disrupts immunostimulatory effects of IL-12. AB - Immune stimulation by biological response modifiers is a common approach in tumor immunotherapy. IL-12 was found effective in various animal studies, but clinical trials showed limited success. However, among other differences, animal models do not simulate psychological or physiological stress while employing IL-12, whereas cancer patients often experience distress while treated with immunostimulants. Thus, in the current study we assessed the impact of continuous stress on the efficacy of IL-12 immunostimulation. F344 rats were subjected to a pharmacological stress paradigm (continuous administration of a beta-adrenergic agonist) or to a 20 h behavioral stress paradigm (wet cage exposure) commencing 2h before IL-12 administration. Twenty-six hours after stress initiation, we studied indices known to reflect IL-12 immunostimulatory impacts, including NK cell numbers and activity in different immune compartments, and in vivo resistance to MADB106 lung tumor colonization. The results indicated that both the pharmacological and behavioral stress paradigms significantly reduced the increase in the number and activity of marginating-pulmonary NK cells evident in non-stressed IL-12 treated animals. Additionally, stressed animals exhibited a lower IL-12-induced improvement of MADB106 lung clearance, an in vivo index that markedly depends on total marginating-pulmonary NK activity. These deleterious effects of stress were more prominent in males than in females. Overall, the findings demonstrate that prolonged stress exposure can disrupt the efficacy of simultaneous immunostimulatory treatments, irrespective of stress effects on baseline immune measures. Neuroendocrine and cellular mediating mechanisms are yet unknown, but the potential clinical ramifications of these findings warrant consideration in clinical trials employing immunostimulatory agents. PMID- 21277368 TI - Gonadal steroids prevent cell damage and stimulate behavioral recovery after transient middle cerebral artery occlusion in male and female rats. AB - 17beta-estradiol (E) and progesterone (P) are neuroprotective factors in the brain preventing neuronal death under different injury paradigms. Our previous work demonstrates that both steroids compensate neuronal damage and activate distinct neuroprotective strategies such as improving local energy metabolism and abating pro-inflammatory responses. The current study explored steroid hormone mediated protection from brain damage and restoration of behavioral function after 1h transient middle cerebral artery occlusion (tMCAO). Male and ovariectomized female rats were studied 24h after stroke. Both steroid hormones reduced the cortical infarct area in males and females to a similar extent. A maximum effect of ~60-70% reduction of the infarct size was evident after P and a combined treatment with both hormones. No infarct protection was seen in the basal ganglia. Testing of motor and sensory behavioral revealed an equal high degree of functional recovery in all three hormone groups. Gene expression studies in the delineated penumbra revealed that estrogen receptor (ER) alpha and beta are locally up-regulated. tMCAO-mediated induction of the pro-inflammatory chemokines CCL2, CCL5 and interleukin 6 was attenuated by E and P, whereas the expression of vascular endothelial growth factor (VEGF) was fortified. Local expression of microglia/macrophage/lymphocyte markers, i.e. Iba1, CD68 and CD3, were significantly reduced in the penumbra after hormone treatment suggesting attenuation of microglia and lymphocyte attraction. These results demonstrate the neuroprotective potency of a combined treatment with E and P under ischemic conditions in both sexes and point at the regulation of chemokine microglia/lymphocyte interactions as a supposable mechanism implicated in cell protection. PMID- 21277370 TI - Elevated amniotic fluid F2-isoprostane: a potential predictive marker for preeclampsia. AB - In the complex mechanism of preeclampsia, oxidative stress is an important pathogenic factor, and F2-isoprostane is a marker of oxidative stress and lipid peroxidation. The objective of this study was to identify if the amniotic fluid (AF) levels of F2-isoprostanes were elevated in women who later developed preeclampsia. In this study, we analyzed AF F2-isoprostane concentrations with enzyme immunoassay (EIA), and the EIA results could be validated by quantitative mass spectrometry. The mean AF concentration of F2-isoprostanes was significantly higher in pregnancies with subsequent development of preeclampsia (123.1 +/- 57.6 pg/ml, n = 85) than in controls (73.8 +/- 36.6 pg/ml, n = 85). The AF elevation of F2-isoprostanes was even higher in the preeclampsia with intrauterine growth restriction group (138.3 +/- 65.2 pg/ml, n = 39). The area under the curve of the receiver operating characteristics analysis for AF F2-isoprostanes assay was 0.81, supporting its potential as a biomarker for preeclampsia. These results indicate that oxidative stress existed before the onset of clinical preeclampsia, further suggesting that the elevation of AF F2-isoprostanes may be used as a guide for antioxidant supplementation to reduce the risk and/or severity of preeclampsia. PMID- 21277371 TI - Building and searching tandem mass (MS/MS) spectral libraries for peptide identification in proteomics. AB - Spectral library searching is an emerging approach in peptide identifications from tandem mass spectra, a critical step in proteomic data analysis. In spectral library searching, a spectral library is first meticulously compiled from a large collection of previously observed peptide MS/MS spectra that are conclusively assigned to their corresponding amino acid sequence. An unknown spectrum is then identified by comparing it to all the candidates in the spectral library for the most similar match. This review discusses the basic principles of spectral library building and searching, describes its advantages and limitations, and provides a primer for researchers interested in adopting this new approach in their data analysis. It will also discuss the future outlook on the evolution and utility of spectral libraries in the field of proteomics. PMID- 21277372 TI - The silica-binding Si-tag functions as an affinity tag even under denaturing conditions. AB - We recently reported a one-step affinity purification method using a silica binding protein, designated Si-tag, as a fusion partner and silica particles as the specific adsorbents (Ikeda et al., Protein Expr. Purif. 71 [2010] 91-95) [13]. In this study, we demonstrate that the Si-tag also binds to the silica surface even under denaturing conditions, thereby facilitating affinity purification of recombinant proteins from inclusion bodies. A fusion protein of the Si-tag and a biotin acceptor peptide (AviTag), which was expressed as inclusion bodies in Escherichia coli, was used as a model protein. To simplify our purification method, we disrupted recombinant E. coli cells by sonication in the presence of 8M urea with concomitant solubilization of the inclusion bodies. The fusion protein was recovered with a purity of 90 +/- 3% and yield of 92 +/- 6% from the cleared cell lysate. We also discuss the binding mechanism of the Si tag to a silica surface in the presence of high concentrations of denaturant. We propose that the intrinsic disorder of the polycationic Si-tag polypeptide plays an important role in its binding to the silica surface under denaturing conditions. PMID- 21277373 TI - Identification of TMEM45B as a protein clearly showing thermal aggregation in SDS PAGE gels and dissection of its amino acid sequence responsible for this aggregation. AB - SDS-PAGE is one of the most powerful experimental techniques used for the separation of proteins, and most proteins are separated according to their molecular size by this technique. However, exceptional proteins showing abnormal behavior in SDS-PAGE gels are known to exist. Thermal aggregation, rarely observed with membrane proteins, is one of the exceptional behaviors of proteins during SDS-PAGE, but detailed characterization of this aggregation has not yet been achieved. In the present study, we found that a putative membrane protein, TMEM45B, very clearly showed properties of thermal aggregation when it was expressed in COS7 cells and subjected to SDS-PAGE. We dissected the region of TMEM45B responsible for this aggregation, and found that of the seven putative transmembrane domains, a region comprising the 4th to 7th ones was essential for the thermal aggregation properties. We also demonstrated that these transmembrane domains, 4th to 7th, of TMEM45B conferred thermal aggregation properties on other proteins, by fusing this amino acid sequence to target proteins. The molecular mechanism causing thermal aggregation by TMEM45B is still uncertain, but TMEM45B could be utilized as a nice model to show clear thermal aggregation in SDS-PAGE gels. PMID- 21277369 TI - Roles of reactive oxygen and nitrogen species in pain. AB - Peroxynitrite (PN; ONOO-) and its reactive oxygen precursor superoxide (SO; O2*-) are critically important in the development of pain of several etiologies including pain associated with chronic use of opiates such as morphine (also known as opiate-induced hyperalgesia and antinociceptive tolerance). This is now an emerging field in which considerable progress has been made in terms of understanding the relative contributions of SO, PN, and nitroxidative stress in pain signaling at the molecular and biochemical levels. Aggressive research in this area is poised to provide the pharmacological basis for development of novel nonnarcotic analgesics that are based upon the unique ability to selectively eliminate SO and/or PN. As we have a better understanding of the roles of SO and PN in pathophysiological settings, targeting PN may be a better therapeutic strategy than targeting SO. This is because, unlike PN, which has no currently known beneficial role, SO may play a significant role in learning and memory. Thus, the best approach may be to spare SO while directly targeting its downstream product, PN. Over the past 15 years, our team has spearheaded research concerning the roles of SO and PN in pain and these results are currently leading to the development of solid therapeutic strategies in this important area. PMID- 21277374 TI - Smoothness-guided 3-D reconstruction of 2-D histological images. AB - This paper tackles two problems: (1) the reconstruction of 3-D volumes from 2-D post-mortem slices (e.g., histology, autoradiography, immunohistochemistry) in the absence of external reference, and (2) the quantitative evaluation of the 3-D reconstruction. We note that the quality of a reconstructed volume is usually assessed by considering the smoothness of some reconstructed structures of interest (e.g., the gray-white matter surfaces in brain images). Here we propose to use smoothness as a means to drive the reconstruction process itself. From a pair-wise rigid reconstruction of the 2-D slices, we first extract the boundaries of structures of interest. Those are then smoothed with a min-max curvature flow confined to the 2-D planes in which the slices lie. Finally, for each slice, we estimate a linear or flexible transformation from the sparse displacement field computed from the flow, which we apply to the original 2-D slices to obtain a smooth volume. In addition, we present a co-occurrence matrix-based technique to quantify the smoothness of reconstructed volumes. We discuss and validate the application of both our reconstruction approach and the smoothness measure on synthetic examples as well as real histological data. PMID- 21277376 TI - Umbilical cord blood transplantation for children with thalassemia and sickle cell disease. AB - We examined the efficacy of unrelated cord blood (CB) transplantation in children with thalassemia (n = 35) and sickle cell disease (n = 16), using data reported to 3 registries. Donor-recipient pairs were matched at HLA-A and -B (antigen level) and DRB1 (allele level) in 7 or HLA mismatched at 1 (n = 18), 2 (n = 25), or 3 loci (n = 1). Transplant conditioning was myeloablative (n = 39) or reduced intensity (n = 12). Neutrophil recovery with donor chimerism was documented in 24 patients; 11 patients developed grade II-IV acute graft-versus-host disease (aGVHD) and 10 patients, chronic GVHD (cGVHD). Overall survival (OS) and disease free survival (DFS) were 62% and 21% for thalassemia and 94% and 50% for sickle cell disease (SCD), respectively. In multivariate analysis, engraftment rate (hazard ratio [HR] 2.2, P = .05) and DFS (HR 0.4, P = .01) were higher with cell dose >5 * 10(7)/kg. The 2-year probability of DFS was 45% in patients who received grafts with cell dose >5 * 10(7)/kg and 13% with lower cell dose. Primary graft failure was the predominant cause of treatment failure occurring in 20 patients with thalassemia and 7 patients with SCD. Primary graft failure was fatal in 5 patients with thalassemia. These results suggest that only CB units containing an expected infused cell dose >5 * 10(7)/kg should be considered for transplantation for hemoglobinopathy. PMID- 21277377 TI - Total colony-forming units are a strong, independent predictor of neutrophil and platelet engraftment after unrelated umbilical cord blood transplantation: a single-center analysis of 435 cord blood transplants. AB - Graft failure occurs in approximately 20% of patients after unrelated umbilical cord blood transplantation (UCBT). This could be because of inadequate potency of the cord blood unit (CBU). To this end, we investigated the impact of graft characteristics on engraftment and survival of 435 primarily pediatric (median age: 5.3 years) patients receiving a single-unit unrelated UCBT after myeloablative conditioning from 2000 to 2008. Pre-cryopreservation (pre-cryo) graft characteristics were provided by the banks. Post-thaw parameters were measured on dextran/albumin-washed grafts. Post-thaw recovery of the colony forming unit (CFU), a biological assay reflecting functional viability of the cord blood cells was the lowest percent age (median 21.2%, mean 36.5%) of the pre cryo value, regardless of the bank of origin. The cumulative incidences of neutrophil and platelet engraftment were 76.9% (95%, confidence interval [CI], 71.3%-82.5%) and 55% (95% CI, 49.3%-60.7%), respectively. Univariate and separate multivariate models using pre-cryo and post-thaw datasets including clinical parameters identified predictors of engraftment and survival. In multivariate modeling, higher CFU dosing was the only pre-cryo graft characteristic predictive of neutrophil (P = .0024) and platelet engraftment (P = .0063). In the post-thaw model, CFU dose best predicted neutrophil and platelet engraftment (both P < .0001). Comparatively, CD34(+) and total nucleated cell (TNC) were only weakly predictive in post-thaw neutrophil and platelet engraftment models, respectively. In conclusion, CFU dose is a strong independent predictor of engraftment after unrelated UCBT and should be used to assess potency when selecting CBUs for transplantation. PMID- 21277375 TI - Regional specificity of MRI contrast parameter changes in normal ageing revealed by voxel-based quantification (VBQ). AB - Normal ageing is associated with characteristic changes in brain microstructure. Although in vivo neuroimaging captures spatial and temporal patterns of age related changes of anatomy at the macroscopic scale, our knowledge of the underlying (patho)physiological processes at cellular and molecular levels is still limited. The aim of this study is to explore brain tissue properties in normal ageing using quantitative magnetic resonance imaging (MRI) alongside conventional morphological assessment. Using a whole-brain approach in a cohort of 26 adults, aged 18-85years, we performed voxel-based morphometric (VBM) analysis and voxel-based quantification (VBQ) of diffusion tensor, magnetization transfer (MT), R1, and R2* relaxation parameters. We found age-related reductions in cortical and subcortical grey matter volume paralleled by changes in fractional anisotropy (FA), mean diffusivity (MD), MT and R2*. The latter were regionally specific depending on their differential sensitivity to microscopic tissue properties. VBQ of white matter revealed distinct anatomical patterns of age-related change in microstructure. Widespread and profound reduction in MT contrasted with local FA decreases paralleled by MD increases. R1 reductions and R2* increases were observed to a smaller extent in overlapping occipito-parietal white matter regions. We interpret our findings, based on current biophysical models, as a fingerprint of age-dependent brain atrophy and underlying microstructural changes in myelin, iron deposits and water. The VBQ approach we present allows for systematic unbiased exploration of the interaction between imaging parameters and extends current methods for detection of neurodegenerative processes in the brain. The demonstrated parameter-specific distribution patterns offer insights into age-related brain structure changes in vivo and provide essential baseline data for studying disease against a background of healthy ageing. PMID- 21277378 TI - Favorable outcome of unrelated cord blood transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia. AB - Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL) is one of the highest-risk ALL groups. Whenever possible, patients with Ph(+)ALL should undergo allogeneic hematopoietic stem cell transplantation (HSCT) after induction of remission. Although unrelated cord blood transplantation (CBT) has become a common treatment in adult patients who lack a sibling donor, data on the efficacy of CBT for Ph(+)ALL are limited. We analyzed the clinical outcomes of 20 Ph(+)ALL patients who underwent CBT (n = 8) or unrelated bone marrow transplantation (BMT) (n = 12). The median age was 41 years (range, 17-55 years). All but one of the patients were treated with an imatinib-based regimen before HSCT, and 19 patients were in first complete remission (CR) and 1 patient was in second CR at the time of HSCT. Seventeen patients received a myeloablative conditioning regimen containing 12 Gy of total-body irradiation, and 3 received a reduced-intensity conditioning regimen. After a median of 26 months of follow-up, estimated 3-year overall and leukemia-free survival rates were 100% and 85%, respectively, after CBT, and 49% and 38%, respectively, after unrelated BMT. The CBT group had significantly better overall survival than the BMT group (P = .02). Although BCR ABL transcript was detected in 4 of 8 CBT patients at transplantation, 7 patients remained in molecular CR. Our findings suggest that CBT may be a viable option as postinduction therapy for Ph(+)ALL in patients lacking a sibling donor. PMID- 21277379 TI - Independent duplications of alpha-amylase in different strains of Aspergillus oryzae. AB - Aspergillus oryzae is a filamentous fungus that has arisen through the ancient domestication of Aspergillus flavus for making traditional oriental foods and beverages. In the many centuries A. oryzae has been used for fermenting the starch in rice to simple sugars, it has undergone selection for increased secretion of starch-degrading enzymes. In particular, all A. oryzae strains investigated thus far have two or more copies of a gene encoding alpha-amylase, whereas A. flavus has only one. Here we investigate the duplications leading to these copies in three A. oryzae strains. We find evidence of at least three separate duplications of alpha-amylase, an example of parallel evolution in a micro-organism under artificial selection. At least two of these duplications appear to be associated with activity of transposable elements of the Tc1/mariner class. Both involve a 9.1 kb element that terminates in inverted repeats, encodes a putative transposase and another putative protein of unknown function, and contains an unusual arrangement of four short internal imperfect repeats. Although "unusual Mariners" of this size have previously been identified in A. oryzae, Aspergillus fumigatus and Aspergillus nidulans, this is the first evidence we know of that at least some of them are active in modern times and that their activity can contribute to beneficial genetic changes. PMID- 21277380 TI - Can muscle fatty acid signature be used to distinguish diets during the marine trophic phase of sea lamprey (Petromyzon marinus, L.)? AB - Characterization of muscle and liver fatty acid profiles, determination of liver lipogenic and lipolytic activities and estimation of liver fatty elongases and desaturases activities of sea lamprey were realized at the beginning of the spawning migration. The muscle fatty acid profile was consistent with the location of capture, and revealed that animals captured far upstream from the river mouth presented the lowest C18:1omega9 levels and the highest relative proportions of C20:4omega6, C20:5omega3 (EPA), C22:5omega3 (DPA) and C22:6omega3 (DHA). These results suggest: (i) the vital importance of the conservation of C20:4omega6 as a precursor of eicosanoids; (ii) the retention of EPA, DPA and DHA for metabolic energy for reproduction; and (iii) the utilization of C18:1omega9 for metabolic fuel use in the beginning of the spawning period. Hepatic lipolysis and lipogenesis revealed significant differences which could, eventually, result from the diet during the parasitic phase of sea lamprey life cycle. Present results revealed that the muscle act as a fat depot site which explains the few significant correlations observed for fatty acids between muscle and liver. Muscle neutral lipids fatty acid signature at the beginning of the spawning migration can be used to distinguish differences in the diet of sea lampreys during the marine trophic phase of their life cycle. PMID- 21277381 TI - Computational biology approaches for selecting host-pathogen drug targets. AB - The proliferation of genomic platform data, ranging from silencing RNAs through mRNA and microRNA expression to proteomics, is providing new insights into the interplay between human and pathogen genes during infection: the so-called 'host pathogen interactome'. Exploiting the interactome for novel human drug targets could provide new therapeutic avenues towards the treatment of infectious disease, which could ameliorate the growing clinical challenge of drug-resistant infections. Using the hepatitis C virus interactome as an example, here we suggest a computational biology framework for identifying and prioritizing potential human host targets against infectious diseases. PMID- 21277382 TI - Biomarkers for simplifying HTS 3D cell culture platforms for drug discovery: the case for cytokines. AB - In this review, we discuss the microenvironmental cues that modulate the status of cells to yield physiologically more relevant three-dimensional (3D) cell-based high throughput drug screening (HTS) platforms for drug discovery. Evidence is provided to support the view that simplifying 3D cell culture platforms for HTS applications calls for identifying and validating ubiquitous three-dimensionality biomarkers. Published results from avascular tumorigenesis and early stages of inflammatory wound healing, where cells transition from a two-dimensional (2D) to 3D microenvironment, conclusively report regulation by cytokines, providing the physiological basis for focusing on cytokines as potential three-dimensionality biomarkers. We discuss additional support for cytokines that comes from numerous 2D and 3D comparative transcriptomic and proteomic studies, which generally report upregulation of cytokines in 3D compared with 2D culture counterparts. PMID- 21277383 TI - The design and synthesis of libraries for the discovery of antibacterial and antifungal substances. PMID- 21277384 TI - When pigs fly: immunomagnetic separation facilitates rapid determination of Pig-a mutant frequency by flow cytometric analysis. AB - In vivo mutation assays based on the Pig-a null phenotype, that is, the absence of cell surface glycosylphosphatidylinositol (GPI) anchored proteins such as CD59, have been described. This work has been accomplished with hematopoietic cells, most often rat peripheral blood erythrocytes (RBCs) and reticulocytes (RETs). The current report describes new sample processing procedures that dramatically increase the rate at which cells can be evaluated for GPI anchor deficiency. This new method was applied to blood specimens from vehicle, 1,3 propane sultone, melphalan, and N-ethyl-N-nitrosourea treated Sprague Dawley rats. Leukocyte- and platelet-depleted blood samples were incubated with anti CD59-phycoerythrin (PE) and anti-CD61-PE, and then mixed with anti-PE paramagnetic particles and Counting Beads (i.e., fluorescent microspheres). An aliquot of each specimen was stained with SYTO 13 and flow cytometric analysis was performed to determine RET percentage, RET:Counting Bead ratio, and RBC:Counting Bead ratio. The major portion of these specimens were passed through ferromagnetic columns that were suspended in a magnetic field, thereby depleting each specimen of wild-type RBCs (and platelets) based on their association with anti-PE paramagnetic particles. The eluates were concentrated via centrifugation and the resulting suspensions were stained with SYTO 13 and analyzed on the flow cytometer to determine mutant phenotype RET:Counting Bead and mutant phenotype RBC:Counting Bead ratios. The ratios obtained from pre- and post-column analyses were used to derive mutant phenotype RET and mutant phenotype RBC frequencies. Results from vehicle control and genotoxicant-treated rats are presented that indicate the scoring system is capable of returning reliable mutant phenotype cell frequencies. Using this wild-type cell depletion strategy, it was possible to interrogate >= 3 million RETs and >= 100 million RBCs per rat in approximately 7 min. Beyond considerably enhancing the throughput capacity of the analytical platform, these blood-processing procedures were also shown to enhance the precision of the measurements. PMID- 21277385 TI - Development of a dual reporter system to identify regulatory cis-acting elements in untranslated regions of Trypanosoma cruzi mRNAs. AB - In trypanosomatids, transcription is polycistronic and gene expression control occurs mainly at the post-transcriptional level. To investigate the role of sequences present in the 3'UTR of stage-specific mRNAs of Trypanosoma cruzi, we generated a new vector, named pTcDUALuc, containing the firefly and Renilla luciferase reporter genes. To test this vector, sequences derived from the 3'UTR plus intergenic regions of the alpha tubulin gene, which is up-regulated in epimastigotes, and amastin, which is up-regulated in amastigotes, were inserted downstream from the firefly reporter gene and luciferase activity was compared in transient and stable transfected parasites. As expected, increased luciferase activity was detected in epimastigotes transiently transfected with pTcDUALuc containing tubulin sequences. Using stable transfected cell lines that were allowed to differentiate into amastigotes, we observed increased luciferase activity and mRNA levels in amastigotes transfected with pTcDUALuc containing amastin sequences. We also showed that the spliced leader sequence and poly-A tail were inserted in the predicted sites of the firefly luciferase mRNA and that deletions in the alpha tubulin 3'UTR resulted in decreased luciferase expression because it affects polyadenylation. In contrast to the constructs containing 3'UTR sequences derived from tubulin and amastin genes, the presence of the 3'UTR from a trans-sialidase gene, whose expression is higher in trypomastigotes, resulted in increased luciferase activity in trypomastigotes without a corresponding increase in luciferase mRNA levels. PMID- 21277386 TI - Synthesis of enantiopure 2-carba-cyclic phosphatidic acid and effects of its chirality on biological functions. AB - Cyclic phosphatidic acid (cPA) is a naturally occurring phospholipid mediator, which has a quite unique cyclic phosphate ring at sn-2 and sn-3 positions of the glycerol backbone. We have designed and chemically synthesized several metabolically stabilized derivatives of cPA. 2-Carba-cPA (2ccPA) is one of the synthesized compounds in which the phosphate oxygen was replaced with a methylene group at the sn-2 position, and it showed much more potent biological activities than natural cPA. Here, we developed a new method of 2ccPA enantiomeric synthesis. And we examined the effects of 2ccPA enantiomers on autotaxin (ATX) activity, cancer cell invasion and nociceptive reflex. As well as racemic-2ccPA, both enantiomers showed inhibitory effects on ATX activity, cancer cell invasion and nociceptive reflex. As their effects were not significantly different from each other, the chirality of 2ccPA may not be critical for these biological functions of 2ccPA. PMID- 21277387 TI - Mammogram retrieval through machine learning within BI-RADS standards. AB - A content-based mammogram retrieval system can support usual comparisons made on images by physicians, answering similarity queries over images stored in the database. The importance of searching for similar mammograms lies in the fact that physicians usually try to recall similar cases by seeking images that are pathologically similar to a given image. This paper presents a content-based mammogram retrieval system, which employs a query example to search for similar mammograms in the database. In this system the mammographic lesions are interpreted based on their medical characteristics specified in the Breast Imaging Reporting and Data System (BI-RADS) standards. A hierarchical similarity measurement scheme based on a distance weighting function is proposed to model user's perception and maximizes the effectiveness of each feature in a mammographic descriptor. A machine learning approach based on support vector machines and user's relevance feedback is also proposed to analyze the user's information need in order to retrieve target images more accurately. Experimental results demonstrate that the proposed machine learning approach with Radial Basis Function (RBF) kernel function achieves the best performance among all tested ones. Furthermore, the results also show that the proposed learning approach can improve retrieval performance when applied to retrieve mammograms with similar mass and calcification lesions, respectively. PMID- 21277388 TI - Esophageal hyperkeratosis in a healthy adult. PMID- 21277389 TI - Prospective blinded comparison of polyp size on computed tomography colonography and endoscopic colonoscopy. AB - BACKGROUND & AIMS: The size of polyps found on computed tomography colonography (CTC) has been suggested as the major determinant of patient management. We compared polyp size as seen on CTC with endoscopic visualization, in vivo probe measurement, and ex vivo size before and after fixation. METHODS: Polyps measured on CTC sent for endoscopic removal were evaluated for polyp size in a blinded fashion by endoscopic estimation, in vivo probe measurement, and after removal. RESULTS: Fifty-six polyps were included in the study. There was no significant difference between CTC polyp size, real-time colonoscopy size estimation, or probe measurement. The size of polyp measured immediately ex vivo and after pathology fixation was significantly smaller. Management would be altered in 6 of 56 polyps (10.7%) on the basis of differences between size of the polyp on endoscopy and CTC. CONCLUSIONS: (1) CTC polyp size measurement is not significantly different from colonoscopy in vivo visual estimation and linear probe measurement. (2) Differences in size of polyps as measured on CTC and endoscopy will affect patient management in 10% of cases. PMID- 21277390 TI - Giant duodenal ectasia. PMID- 21277391 TI - Eosinophilic esophagitis: it is here to stay. PMID- 21277392 TI - Do not assume symptoms indicate failure of anti-tumor necrosis factor therapy in Crohn's disease. AB - It is a challenge to monitor patients with Crohn's disease who remain symptomatic despite anti-tumor necrosis factor therapy. Clinicians must use a systematic approach for each patient and obtain objective evidence about disease activity and response to therapy. Alternate etiologies for symptoms should be sought and treated, if found. Active Crohn's disease despite therapy requires reassessment and adjustments to management plans. PMID- 21277393 TI - Primary linitis plastica of the sigmoid colon. PMID- 21277394 TI - Long-term budesonide maintenance treatment is partially effective for patients with eosinophilic esophagitis. AB - BACKGROUND & AIMS: Topical corticosteroids are effective in inducing clinical and histologic remission in patients with eosinophilic esophagitis (EoE). However, the best long-term management strategy for this chronic inflammatory disease has not been determined. METHODS: In a randomized, double-blind, placebo-controlled, 50-week trial, we evaluated in 28 patients the efficacy of twice-daily swallowed budesonide (0.25 mg each) to maintain quiescent EoE in remission. Pretreatment and posttreatment activity was assessed clinically, endoscopically, histologically, immunohistologically, and by endosonography. The primary end point was the therapy's ability to maintain EoE in histologic remission. Secondary end points were efficacy in symptom control, prevention of tissue remodeling, and safety. RESULTS: In patients given low-dose budesonide, the load of esophageal eosinophils increased from 0.4 to 31.8 eosinophils/high-power field (P = .017). In patients given placebo, the load increased from 0.7 to 65.0 eosinophils/high-power field (P = .0001); this increase was significantly greater than in patients given budesonide (P = .024). The symptom scores developed in a similar manner in the 2 groups. Budesonide, but not placebo, reduced noneosinophilic markers of inflammation, epithelial cell apoptosis, and remodeling events. Compared with control individuals, patients had significantly thickened esophageal walls, based on endosonography (3.05 vs 2.18 mm; P < .0001). Budesonide therapy was associated with a significant reduction in mucosal thickness (0.75-0.45 mm; P = .025), but epithelial thickness remained stable (261.22 vs 277.23 MUm; P = .576). No serious adverse events occurred. CONCLUSIONS: Low-dose budesonide is more effective than placebo in maintaining EoE in histologic and clinical remission. Signs of esophageal remodeling showed a trend toward normalization. Long-term administration of topical corticosteroids was well tolerated without induction of epithelial atrophy. PMID- 21277395 TI - The ribosomal intergenic spacer (IGS) region in Schistosoma japonicum: structure and comparisons with related species. AB - The intergenic spacer (IGS) between the 28S and 18S ribosomal RNA genes was PCR amplified, sequenced and characterized for Schistosoma japonicum from mainland China, and compared with those of other Schistosoma species. Excluding flanking portions of the 28S and 18S genes, the IGS in the longest sequenced amplicon from S. japonicum IGS was 1457bp in length. However, intra-specific and intra individual variation was noted. The IGS region of S. japonicum is strikingly different in structure from those of African Schistosoma species for which data are available. S. japonicum has a shorter IGS and largely lacks a long region of complex repeats seen in the African species. However, careful comparisons with African species highlighted the presence of a few shared repeat motifs that were not apparent from study of African species only. Such motifs presumably have functional significance. Discovery of such motifs may in general be aided by comparisons of relatively distant taxa rather than of sibling taxa. PMID- 21277396 TI - Mutations in the regulatory network underlie the recent clonal expansion of a dominant subclone of the Mycobacterium tuberculosis Beijing genotype. AB - The Beijing genotype family is an epidemiologically important sub-group of Mycobacterium tuberculosis. It has been suggested that the high frequency of the Beijing isolates in some areas could be explained by selective advantages. Some evidence suggests that the emerging and most frequently isolated "Typical Beijing" lineage has the ability to circumvent BCG-induced immunity. To investigate the phylogeny of the Beijing genotype of M. tuberculosis, the genome of six Beijing strains from three different countries was sequenced with next generation sequencing. The phylogeny of these strains was established using single nucleotide polymorphisms (SNPs). The three Typical Beijing strains clustered very tightly in the Beijing phylogeny suggesting that Typical Beijing strains represent a monophyletic lineage and resulted from recent diversification. Typing of 150 M. tuberculosis strains with a subset of the SNPs and comparison of the IS6110 restriction-fragment length polymorphism (RFLP) patterns of these strains to a database of 1522 Beijing RFLP patterns revealed that about 80% of all Beijing strains belong to the Typical Beijing subclone, which indicates clonal expansion. To identify the genomic changes that are characteristic for all Typical Beijing strains and to reconstruct their most recent common ancestor, the presence of SNPs was assayed in other Beijing strains. We identified 51 SNPs that define the minimal set of polymorphisms for all Typical Beijing strains. Nonsynonymous polymorphisms in genes coding for the regulatory network were over-represented in this set of mutations. We suggest that alterations in the response to environmental signals may have enabled Typical Beijing strains to develop the emerging phenotype. PMID- 21277397 TI - Uniform polymer-protein conjugate by aqueous AGET ATRP using protein as a macroinitiator. AB - In situ aqueous activators generated by electron transfer for atom transfer radical polymerization (AGET ATRP) in air, using an enzyme as a macroinitiator, has been proposed to prepare uniform polymer-protein conjugates with improved stability under adverse conditions. In the first step, an initiator, 2 bromoisobutyryl bromide (BIB), was grafted onto the protein surface by reaction with the amino groups. The second step was in situ AGET ATRP polymerization in air using CuBr(2)/1,1,4,7,7-pentamethyldiethylenetriamine as a catalyst and ascorbic acid as a reducing agent. The effectiveness of this method has been demonstrated using horseradish peroxidase (HRP) as a model protein and acrylamide as the monomer, which yielded HRP-polyacrylamide conjugate with a mean particle size of about 20-30 nm. The grafting of BIB onto HRP and the subsequent polymerization yielding a polyacrylamide chain were confirmed by nuclear magnetic resonance and matrix-assisted laser desorption ionization time-of-flight spectrometry analysis. The size of the conjugate was shown to be a function of monomer loading and reaction time. The HRP conjugates yielded essentially retained the catalytic behavior of HRP in free form, as shown by K(m) and V(max) values, but exhibited significantly enhanced thermal stability against high temperature and trypsin digestion. The use of protein as the macroinitiator prevented the formation of copolymer and thus facilitated purification of the protein conjugate. The uniform size indicates a well-defined composition of protein and polymer, which is essential for applications that request a precise control of the dosage of enzyme activity. PMID- 21277398 TI - Immobilization of an antithrombin-heparin complex on gold: anticoagulant properties and platelet interactions. AB - The anticoagulant properties and platelet interactions of gold surfaces modified with an antithrombin-heparin (ATH) complex are reported. ATH was attached to gold through either a short disulfide (linker) or a thiol-terminated polyethylene oxide (PEO) (linker, spacer). Analogous surfaces were prepared with uncomplexed heparin. Antithrombin (AT) uptake was measured before and after selectively destroying the active pentasaccharide sequence of the heparin moiety, and was found to be predominantly through the active sequence on all of the surfaces. AT binding was higher on the ATH surfaces than on the corresponding heparin surfaces. Heparin activity was assessed by an anti-factor Xa assay. The ratio of active heparin density (from the anti-FXa assay) to total heparin density was taken as a measure of heparin bioactivity. The ratio was greater on the ATH- than on the heparin-modified surfaces, i.e. the PEO-ATH surfaces showed the greater proportion of active heparin. Platelet adhesion from flowing whole blood was found to be reduced on PEO- and ATH-modified surfaces compared to bare gold. The PEO-ATH modified surfaces, but not the heparinized surfaces, were shown to prolong the clotting time of recalcified plasma. PMID- 21277399 TI - Commentary on 'Role of bone biopsy specimen culture in the management of diabetic foot osteomyelitis' IJS in press. PMID- 21277400 TI - The protective role of bone morphogenetic protein-8 in the glucocorticoid-induced apoptosis on bone cells. AB - One of the side effects associated with glucocorticoid therapy is glucocorticoid induced bone loss. Glucocorticoids partly detain bone formation via the inhibition of osteoblastic function, however, the exact mechanism of this inhibition remains elusive. In this study, we examined the effect of dexamethasone, an active glucocorticoid analogue, on cell viability and expression of bone remodelling-related genes in primary mouse calvarial and cloned MC3T3-E1 osteoblasts. Using sensitive biochemical assays, we demonstrated the apoptotic effect of dexamethasone on osteoblastic cells. Then, utilizing Taqman probe-based quantitative RT-PCR technology, gene expression profiles of 111 bone metabolism-related genes were determined. As a result of dexamethasone treatment we have detected significant apoptotic cell death, and six genes, including Smad3, type-2 collagen alpha-1, type-9 collagen alpha-1, matrix metalloproteinase-2, bone morphogenetic protein-4 and bone morphogenetic protein 8 showed (BMP-8) significant changes in their expression on a time- and concentration-dependent manner. BMP-8, (a novel player in bone-metabolism) exhibited a two orders of magnitude elevation in its mRNA level and highly elevated protein concentration by Western blot in response to dexamethasone treatment. The knockdown of BMP-8 by RNA interference significantly increased dexamethasone-induced cell death, confirming a protective role for BMP-8 in the glucocorticoid-induced apoptosis of osteoblasts. Our results suggest that BMP-8 might be an essential player in bone metabolism, especially in response to glucocorticoids. PMID- 21277402 TI - Likely uptake of swine and seasonal flu vaccines among healthcare workers. A cross-sectional analysis of UK telephone survey data. AB - During the 2009 flu pandemic, all frontline UK healthcare workers were encouraged to have both the seasonal and swine flu vaccines. Analysis of six national telephone surveys conducted in the run-up to the UK's swine flu vaccination campaign showed that NHS workers were no more likely to accept the swine flu vaccine than non-NHS workers (55.6% versus 52.4% respectively), although they were more likely to accept the seasonal flu vaccine (38.8% versus 22.6%). Reasons for non-acceptance were similar for both vaccines: low perceived personal benefits together with safety and efficacy concerns. Addressing these factors may improve uptake in future vaccination campaigns. PMID- 21277403 TI - Antibody levels and immune memory 23 years after primary plasma-derived hepatitis B vaccination: results of a randomized placebo-controlled trial cohort from China where endemicity is high. AB - The duration of protection of hepatitis B vaccine remains incompletely understood. To assess the long-term protection provided by a primary vaccine series, the current study again recruited all subjects of a previous randomized placebo-controlled trial cohort 23 years after vaccination. Two hundred and sixty one healthy children aged 5-9 years living in a highly HBV-endemic country were enrolled in the primary trial and received three doses of plasma-derived vaccine or placebo. The primary placebo receivers who did not receive any immunization against hepatitis B were used as non-vaccinated controls in the current study. After eliminating the interference of an early booster dose and vaccines outside the study, 48.1% (39/81) vaccinees still maintained anti-HBs titers >= 10 mI U/mL at Year 23, higher than 34.7% (26/75) in non-vaccinated controls (P=0.088). 75 100% of vaccinees with anti-HBs titer <10 mI U/mL at Year 23 in different sub groups divided according to early immune backgrounds developed a rapid and robust antibody anamnestic response after a booster dose, highly significantly different from non-vaccinated controls who received the same dose of vaccine (7.5%, P<0.01). No case of clinically significant HBV infection was found in the primary cohort during the whole 23 years, but 10 transient HBsAg seroconversions in the primary placebo group and one in the primary vaccine group were determined. Anti HBc positive rate obviously tended to be lower in vaccinees compared with non vaccinated controls at Year 23. These results suggest a persisting immune memory and certain protection for 23 years after primary vaccination in children living in highly HBV-endemic areas. Clinically insignificant infections, which cannot be avoided and may often occur in vaccinees, play a positive role in the maintaining of immunity to HBV. Booster doses should be unnecessary for more than 20 years after a full primary immunization in children (as catch-up vaccination) and, also likely, in newborns living in highly HBV-endemic areas. PMID- 21277404 TI - Role of antibodies in Sm-p80-mediated protection against Schistosoma mansoni challenge infection in murine and nonhuman primate models. AB - Schistosomiasis is an important public health concern in more than 76 developing countries. Advent of an anti-schistosome vaccine would undoubtedly add to the existing control measures and may eventually help in the elimination of this disease. In the present study we have attempted to dissect the role(s) of antibodies in Sm-p80 mediated protection by intravenously transferring pooled sera from mice immunized with Sm-p80-pcDNA3 or purified IgG from baboons immunized with Sm-p80-pcDNA3, into naive C57BL/6 mice, respectively, prior to challenge with cercariae. The passive transfer of antibodies from protected mice (homologous transfers) as well as transfer of total IgG from baboons (heterologous transfers), into naive mice showed statistically significant reductions in worm burden and in the number of eggs in the tissues. Immunizations of antibody knockout mice (MUMt-/-; B10.129S2 (B6)-Igh-6(tm1Cgn)/J) with recombinant Sm-p80 in the presence of CpG-motif oligodeoxynucleotides as an adjuvant, resulted in substantial reduction of Sm-p80-mediated protection, compared to C57BL/6 (normal) control group of mice. Down regulation of cytokines that have important effects on B cell proliferation as well as the recovery of higher number of parasites in antibody knockout indicated a significant role(s) of antibodies in Sm-p80-mediated protection against Schistosoma mansoni in mice. In toto, these studies appear to suggest that antibodies play a significant role in Sm-p80 mediated protection. PMID- 21277405 TI - Modelling the impact of a combined varicella and zoster vaccination programme on the epidemiology of varicella zoster virus in England. AB - This study updates previous work on modelling the incidence of varicella and Herpes Zoster (HZ) following the introduction of childhood vaccination. The updated model includes new data on age-specific contact patterns, as well as data on the efficacy of zoster vaccination in the elderly and allows for HZ among vaccinees. The current study also looks at two-dose varicella childhood programmes, and assesses the combined impact of varicella vaccination in childhood and zoster vaccination of the elderly. The results suggest that a two dose schedule is likely to reduce the incidence of varicella to very low levels, provided first dose coverage is around 90% and second dose coverage is in excess of 70%. Single dose varicella vaccination programmes are expected to result in large numbers of breakthrough cases. Childhood vaccination is expected to increase the incidence of zoster for more than 40 years after introduction of the programme, the magnitude of this increase being influenced primarily by the duration of boosting following exposure to the varicella zoster virus. Though this increase in zoster incidence can be partly offset by vaccination of the elderly, the effectiveness of this combined strategy is limited, as much of the increase occurs in those adults too young to be vaccinated. Childhood vaccination at intermediate levels of coverage (70% and 60% for first and second dose coverage respectively) is expected to lead to an increase in adult varicella. At high coverage (90% and 80% coverage) this is unlikely to be the case. These results will be used to inform a cost-effectiveness analysis of combined varicella and zoster vaccination programmes. PMID- 21277406 TI - Considerations for human papillomavirus (HPV) vaccination of mid-adult women in the United States. AB - In the United States, human papillomavirus (HPV) vaccination is recommended for 11 or 12 year old girls, with catch-up vaccination through age 26 years. Data are available for women over the age of 26 years on immunogenicity for both quadrivalent and bivalent HPV vaccines and on efficacy for the quadrivalent HPV vaccine. If HPV vaccines are licensed for use in women over 26 years of age (mid adult women), recommendations for this age group will need to be considered. This review summarizes vaccine efficacy and immunogenicity data in mid-adult women, and addresses epidemiologic data related to key questions for consideration of vaccine recommendations for women over age 26 years. PMID- 21277407 TI - Bacillus Calmette-Guerin vaccination using a microneedle patch. AB - Tuberculosis (TB) caused by Mycobacterium tuberculosis continues to be a leading cause of mortality among bacterial diseases, and the bacillus Calmette-Guerin (BCG) is the only licensed vaccine for human use against this disease. TB prevention and control would benefit from an improved method of BCG vaccination that simplifies logistics and eliminates dangers posed by hypodermic needles without compromising immunogenicity. Here, we report the design and engineering of a BCG-coated microneedle vaccine patch for a simple and improved intradermal delivery of the vaccine. The microneedle vaccine patch induced a robust cell mediated immune response in both the lungs and the spleen of guinea pigs. The response was comparable to the traditional hypodermic needle based intradermal BCG vaccination and was characterized by a strong antigen specific lymphocyte proliferation and IFN-gamma levels with high frequencies of CD4(+)IFN-gamma(+), CD4(+)TNF-alpha(+) and CD4(+)IFN-gamma(+)TNF-alpha(+) T cells. The BCG-coated microneedle vaccine patch was highly immunogenic in guinea pigs and supports further exploration of this new technology as a simpler, safer, and compliant vaccination that could facilitate increased coverage, especially in developing countries that lack adequate healthcare infrastructure. PMID- 21277408 TI - Immunological responses against Plasmodium falciparum Apical Membrane Antigen 1 vaccines vary depending on the population immunized. AB - Clinical development of malaria vaccines progresses from trials in malaria naive adults to malaria exposed adults followed by malaria exposed children. It is not well known whether immune responses in non-target populations are predictive of those in target populations, particularly in African children. Therefore humoral responses in three different populations (U.S. adults, Malian adults and Malian children) were compared in this study. They were immunized with 80 MUg of Apical Membrane Antigen 1 (AMA1)/alhydrogel on days 0 and 28. Sera were collected on days 0 and 42; antibody levels were determined by ELISA and the functionality of antibodies was evaluated by Growth Inhibition Assay. After immunization, there was no significant difference in antibody levels between the Malian children and the Malian adults, but U.S. adults showed lower antibody levels. Vaccination did not significantly change growth-inhibitory activity in Malian adults, but inhibition increased significantly in both U.S. adults and Malian children. Vaccine-induced inhibitory activity was reversed by pre-incubation with AMA1 protein, but pre-existing infection-induced inhibition was not. This study shows that humoral responses elicited by the AMA1 vaccine varied depending on the population, most likely reflecting different levels of previous malaria exposure. Thus predicting immune responses from non-target populations is not desirable. PMID- 21277409 TI - Gp96 SIV Ig immunization induces potent polyepitope specific, multifunctional memory responses in rectal and vaginal mucosa. AB - The ER-resident chaperone gp96, when released by cell lysis, induces an immunogenic chemokine signature and causes innate immune activation of DC and NK cells. Here we show that intraperitoneal immunization with a genetically engineered, secreted form of gp96, gp96-Ig chaperoning SIV antigens, induces high levels of antigen specific CD8 CTL in the rectal and vaginal mucosa of Rhesus macaques. The frequency of SIV Gag- and SIV Tat-tetramer positive CD8 CTL in the intestinal mucosa reached 30-50% after the third immunization. Tetramer positive CD8 CTL expressed appropriate functional (granzyme B) and migration markers (CD103). The polyepitope specificity of the mucosal CD8 and CD4 response is evident from a strong, multifunctional cytokine response upon stimulation with peptides covering the gag, tat and env proteins. Induction of powerful mucosal effector CD8 CTL responses by cell-based gp96(SIV)-Ig immunization may provide a pathway to the development of safe and effective SIV/HIV vaccines. PMID- 21277410 TI - Evaluation of the safety, reactogenicity and immunogenicity of FluBlok(r) trivalent recombinant baculovirus-expressed hemagglutinin influenza vaccine administered intramuscularly to healthy adults 50-64 years of age. AB - BACKGROUND: Alternative methods for influenza vaccine production are needed to ensure adequate supplies. METHODS: Healthy adults 50-64 years were assigned randomly to receive one intramuscular injection of trivalent recombinant hemagglutinin (rHA) or U.S. licensed trivalent inactivated vaccine (TIV) containing H1, H3 and B antigens (Ag) derived from 2007 to 2008 influenza virus strains A/Solomon Islands/03/2006 (H1N1), A/Wisconsin/67/2005 (H3N2), and B/Malaysia/2506/2004. Each rHA dose contained 45 MUg HA/strain of the 2007-2008 FDA-recommended Ag vs. 15 MUg/strain for TIV. Antibody (Ab) responses were measured using a hemagglutination-inhibition (HAI) assay at baseline and 28 days post-vaccination. Respiratory samples for viral culture were collected from subjects with influenza-like illness (ILI) during the 2007-2008 season in the U.S. RESULTS: 601 subjects were enrolled. Vaccines were well tolerated. Seroconversion (the percentage of subjects with either (a) a pre-vaccination HAI titer <= 10 and a post-vaccination HAI titer >= 40 or (b) a pre-vaccination titer >= 10 and a minimum four-fold rise in post-vaccination HAI antibody titer) in the TIV and rHA groups, respectively, was obtained in 66% vs. 72% for H1; 44% vs. 61% for H3; and 41% vs. 41% for B. Proportions achieving titers >= 40 were 96% vs. 96% for H1, 75% vs. 85% for H3, and 94% vs. 93% vs. B. Geometric mean titer ratios at day 28 (TIV/rHA) were 0.77 for H1; 0.58 for H3; and 1.05 for B, respectively. ILI frequencies were low and similar in both groups. CONCLUSIONS: Both vaccines were safe and immunogenic. Ab responses vs. H1 and H3 Ags were significantly higher in the rHA group, with similar responses to B. Furthermore, the FluBlok group had a statistically significantly higher seroconversion rate against influenza A/H3N2 compared to the TIV group. PMID- 21277411 TI - Fabrication of nanostructured silicon by metal-assisted etching and its effects on matrix-free laser desorption/ionization mass spectrometry. AB - A matrix-free, high sensitivity, nanostructured silicon surface assisted laser desorption/ionization mass spectrometry (LDI-MS) method fabricated by metal assisted etching was investigated. Effects of key process parameters, such as etching time, substrate resistance and etchant composition, on the nanostructured silicon formation and its LDI-MS efficiency were studied. The results show that the nanostructured silicon pore depth and size increase with etching time, while MS ion intensity increases with etching time to 300 s then decreases until 600 s for both low resistance (0.001-0.02Omegacm) and high resistance (1-100Omegacm) silicon substrates. The nanostructured silicon surface morphologies were found to directly affect the LDI-MS signal ion intensity. By characterizing the nanostructured silicon surface roughness using atomic force microscopy (AFM) and sample absorption efficiency using fluorescence microscopy, it was further demonstrated that the nanostructured silicon surface roughness was highly correlated to the LDI-MS performance. PMID- 21277412 TI - Chemiresistors based on conducting polymers: a review on measurement techniques. AB - This review covers the development of measurement configurations for chemiresistors based on conducting polymers. The simplest chemiresistors are based on application of a two-electrode technique. Artifacts caused by contact resistance can be overcome by application of a four-electrode technique. Simultaneous application of the two- and four-electrode measurement configurations provides an internal control of sensor integrity. An incorporation of two additional electrodes controlling the redox state of chemosensitive polymers and connecting to the measurement electrodes through liquid or (quasi)solid electrolyte results in a six-electrode technique; an electrically driven regeneration of such sensors allows one to perform fast and completely reversible measurements. PMID- 21277413 TI - A review of monolithic multichannel quartz crystal microbalance: a review. AB - Monolithic multichannel quartz crystal microbalance (MQCM) is an emerging technology for advanced sensing and measurement applications. In this report, a comprehensive review of MQCM technology is presented. Firstly, basic MQCM's design, simulation and characterization with emphasis on acoustic interference are described. Next, various MQCM schemes to minimize interference and enhance sensitivity of conventional MQCM devices based on modification of quartz substrate structure are digested. These include mesa, convex and x-axis inversion structures. Three important MQCM sensing platforms and their application areas are then discussed. These comprise MQCM as a static multichannel detector, series MQCM as a multichannel detector for the flow injection analysis and multi frequency QCM for multi-sensitivity/multi-dynamic range detection. Finally, potential MQCM applications including electronic noses, bio-sensor arrays, and photocatatalytic measurement are illustrated and prospective MQCM applications including electronic tongues and electrochemical measurement are suggested. PMID- 21277414 TI - Improving the visualization of the Pareto-optimal front for the multi-response optimization of chromatographic determinations. AB - The paper shows tools to visualize and more easily interpret the effect that some experimental factors may exert on analytical responses of interest when optimization of several responses is needed. It is based on an adaptation of the parallel coordinate plot, a tool for graphical representation of points in multidimensional spaces that, theoretically and contrary to the usual Cartesian plots, does not have limits in the dimension of the points being depicted. The joint use of the Pareto-optimal solutions and their visualization allows a deeper knowledge about the problem at hand as well as the wise selection of the conditions of experimental factors for achieving specific goals about the responses. Although the methodology is for a general use, the procedure, its interpretation and usefulness is shown with several analytical cases in chromatography. The first one refers to the experimental conditions to obtain simultaneously the maximum allowable area for both the peak of the malachite green and its metabolite leucomalachite green in fish by liquid chromatography with tandem mass spectrometry detection (LC-MS/MS). The second one is about the simultaneous determination of steroid hormones estrone and 17-alpha ethinylestradiol by gas chromatography-mass spectrometry (GC/MS). In the last case, the chromatographic separation by GC/MS of the diastereoisomers, alpha- and beta-estradiol is needed taking into account that these hormones have the same mass fragments. PMID- 21277415 TI - Electrochemical determination of iodide by poly(3-aminophenylboronic acid) film electrode at moderately low pH ranges. AB - A new potentiometric sensor for the determination of iodide based on poly(3 aminophenylboronic acid) (PAPBA) film electrode was constructed. Poly(3 Aminophenylboronic acid) films were synthesized electrochemically on platinum electrode by cyclic voltammetry. The effect of film thickness, pH, and preconditioning parameters on the electrode performance were examined. The analytical performance was evaluated and linear calibration graphs were obtained in the concentration range of 10-6 to 10-1 M iodide ion. The limit of detection was found to be 8*10-7 M. The response time of the sensor was 5 s and its lifetime is about one week. To check the selectivity of the PAPBA film for iodide ion, potential interferences such as Cl-, Br-, F-, CN-, IO3-, Ca2+, and Mg2+ were tested. The PAPBA electrode was also employed as a sensing platform for the determination of iodide ions in commercial table salt. PMID- 21277416 TI - Role of counteranions in polymeric ionic liquid-based solid-phase microextraction coatings for the selective extraction of polar compounds. AB - A polymeric ionic liquid (PIL) poly(1-vinyl-3-hexylimidazolium chloride) (poly(ViHIm(+)Cl-)) was designed as a coating material for solid phase microextraction (SPME) to extract polar compounds including volatile fatty acids (VFAs) and alcohols. The extracted analytes were analyzed by using gas chromatography (GC) coupled with flame ionization detection (FID). Extraction parameters of the HS-SPME-GC-FID method, such as ionic strength, extraction temperature, pH and extraction time were optimized. Calibration studies were carried out under the optimized conditions to further evaluate the performance of the PIL-based SPME coating. For comparison purposes, the PIL poly(1-vinyl-3 hexylimidazolium bis[(trifluoromethyl)sulfonyl]imide) (poly(ViHIm(+)NTf2-)) was also used as the SPME coating to extract the same analytes. The results showed that the poly(ViHIm(+)Cl-) PIL coating had higher selectivity towards more polar analytes due to the presence of the Cl- anion which provides higher hydrogen bond basicity than the NTf2- anion. The limits of detection (LODs) determined by the designed poly(ViHIm(+)Cl-) PIL coating ranged from 0.02MUgL-1 for octanoic acid and decanoic acid and 7.5MUgL-1 for 2-nitrophenol, with precision values (as relative standard deviation) lower than 14%. The observed performance of the poly(ViHIm(+)Cl-) PIL coating was comparable to previously reported work in which commercial or novel materials were used as SPME coatings. The selectivity of the developed PIL coatings was also evaluated using heptane as the matrix solvent. This work demonstrates that the selectivity of PIL-based SPME coatings can be simply tuned by incorporating different counteranions to the sorbent coating. PMID- 21277417 TI - A modular microfluidic system for deoxyribonucleic acid identification by short tandem repeat analysis. AB - Microfluidic technology has been utilized in the development of a modular system for DNA identification through STR (short tandem repeat) analysis, reducing the total analysis time from the ~6 h required with conventional approaches to less than 3h. Results demonstrate the utilization of microfluidic devices for the purification, amplification, separation and detection of 9 loci associated with a commercially-available miniSTR amplification kit commonly used in the forensic community. First, DNA from buccal swabs purified in a microdevice was proven amplifiable for the 9 miniSTR loci via infrared (IR)-mediated PCR (polymerase chain reaction) on a microdevice. Microchip electrophoresis (ME) was then demonstrated as an effective method for the separation and detection of the chip purified and chip-amplified DNA with results equivalent to those obtained using conventional separation methods on an ABI 310 Genetic Analyzer. The 3-chip system presented here demonstrates development of a modular, microfluidic system for STR analysis, allowing for user-discretion as to how to proceed after each process during the analysis of forensic casework samples. PMID- 21277418 TI - Determination of the nucleosides and nucleobases in Tuber samples by dispersive solid-phase extraction combined with liquid chromatography-mass spectrometry. AB - A simple, fast and inexpensive method based on dispersive solid phase extraction (DSPE) combined with LC-MS was developed for simultaneous determination of 7 nucleosides and nucleobases (i.e., adenine, hypoxanthine, uridine, adenosine, guanine, guanosine, and inosine) in Tuber fruiting-bodies and fermentation mycelia. The DSPE procedure was firstly introduced to remove the protein interference from sample solutions, and D3520 macroporous resin was chosen as the DSPE sorbent because of its high removal capability on protein interferences, but low adsorption rate on analytes. Besides, key parameters on DSPE procedure (i.e., macroporous resin type, macroporous resin amount, methanol concentration, and vortex time) were optimized, and the protein removal efficacy could achieve about 95% after the process optimization. Though the method validation test, the DSPE LC-MS method was confirmed to be precise, accurate and sensitive, and the column blinding problem was solved successfully. By using this established method, the total amount of nucleosides and nucleobases in the fermentation mycelia was determined to range from 4881.5 to 12,592.9MUgg-1, which was about 2-25 times higher than the fruiting-bodies (from 498.1 to 2274.1MUgg-1). The formulation of nucleosides and nucleobases in the fermentation mycelia maintained relatively constant, while the formulation in Tuber fruiting-bodies varied significantly with their species. Hierarchical cluster analysis (HCA) showed the formulation similarity of nucleosides and nucleobases between Tuber fermentation mycelia and the fruiting-bodies of Tuber indicum and Tuber himalayense. From the viewpoint of nucleosides and nucleobases, this work confirms the potentiality of Tuber fermentation mycelia as the alternative resource for its fruiting-bodies. PMID- 21277419 TI - Performance evaluation of fast Fourier-transform continuous cyclic-voltammetry pesticide biosensor. AB - In this work, a method for the fast monitoring of OPs in flow-injection systems was evaluated. The fast Fourier transform continuous cyclic-voltammetry (FFTCCV) at the carbon-paste electrode in a flowing solution system was used for determination of OPs. In this method the S/N ratio is enhanced by using of fast Fourier transform of the analyte and signal integration. FFTCCV can be considered as a new sensitive, accurate and fast method for determination of drugs and some pesticides. However, in order to obtain better sensitivity for a specific target, experimental parameters should be optimized. Response surface methodology (RSM) was applied to optimize three effective parameters (enzyme activity, multiwall carbon nanotube quantity and acidic sol-gel quantity). The optimum values for the tested parameters were enzyme amount H0.169 U cm-2, multiwall carbon nanotube (MWCNT) 0.607 mL and acidic sol-gel 1.012 mL. The optimum feed pH, feed flow rate, ATChCl concentration and sweeping-rate were found to be 7.4, 0.34 mL min-1, 0.750 mM and 10Vs-1, respectively. The long-term stability of this flow-through system was 80% of its initial response after 120 days. Based on an incubation time of 12 min, it was found that the detection limit for paraoxon was equal to 1.7*10-7 mg L-1 (6.2*10-13 M). The developed biosensor exhibited good repeatability and reproducibility. This study provides a new, modern, sensitive tool for the analysis of organophosphate pesticides. PMID- 21277420 TI - Development of glucose amperometric biosensor based on a novel attractive enzyme immobilization matrix: amino derivative of thiacalix[4]arene. AB - Calixarenes and their derivatives may be a promising material for enzyme immobilization owing to their particular configuration, unique molecule recognition function and aggregation properties. In this paper, p-tert butylthiacalix[4]arene tetra-amine (TC4TA) was first used as enzyme immobilization material. This attractive material was exploited for the mild immobilization of glucose oxidase (GOD) to develop glucose amperometric biosensor. GOD was strongly adsorbed on the TC4TA modified electrode to form TC4TA/GOD composite membrane. The adsorption mechanism was driven from the covalent bond between amino-group of TC4TA and carboxyl group of GOD and molecule recognition function of TC4TA. Amperometric detection of glucose was evaluated by holding the modified electrode at 0.60 V (versus SCE) to oxidize the hydrogen peroxide generated by the enzymatic reaction. The sensor (TC4TA/GOD) showed a relative fast response (response time was about 5 s), low detection limit (20 MUM, S/N=3), and high sensitivity (ca. 10.2 mA M-1 cm-2) with a linear range of 0.08-10 mM of glucose, as well as a good operational and storage stability. In addition, optimization of the biosensor construction, the effects of the applied potential as well as common interfering compounds on the amperometric response of the sensor were investigated and discussed herein. PMID- 21277421 TI - Development of a rubber elongation factor, surface-imprinted polymer-quartz crystal microbalance sensor, for quantitative determination of Hev b1 rubber latex allergens present in natural rubber latex products. AB - Molecularly imprinted polymers (MIPs) for screening to detect rubber latex allergens (Hev b1) in natural rubber based products were designed as artificial recognition polymeric materials coated onto a quartz crystal microbalance (QCM). The polymers were prepared using a stamp imprinting procedure after mixing optimum amounts of methacrylic acid-vinylpyrrolidone-dihydroxyethylene bisacrylamide and Hev b1 latex allergen proteins, obtained from rubber gloves. QCM measurements showed that the resulting polymer layers after removal of the proteins used in their preparation could incorporate structures and features down to nanometer scale of protein templates into the imprinted polymer much better than a non-specific control polymer under controlled sensor conditions and an optimized polymerization process. This selective polymer but not the non selective polymer clearly distinguished between the latex allergen Hev b1 and proteins such as lysozyme, ovalbumin and bovine serum albumin, with a selectivity factor of from 2 to 4, and the response of the rubber elongation factors by an astonishing factor of 12. The imprinted cavities recognized specific binding sites and could distinguish among related hevein latex allergenic proteins isolated from fresh natural rubber latex; Hev b1, Hev b2, and Hev b3 with a selectivity factor of from 4 to 6. The different QCM measurements obtained presumably reflected slightly different conformations and affinities to the MIP binding sites. The sensor layers selectively adsorbed Hev b1 within minutes in amounts ranging from 10 to 1500 MUg L-1 and with a detection limit of 1 MUg L-1. This work has demonstrated that this new sensor provides a fast and reliable response to natural rubber latex protein, even after being extracted from the matrix of rubber gloves. PMID- 21277422 TI - Chitosan-g-poly(acrylic acid) hydrogel with crosslinked polymeric networks for Ni2+ recovery. AB - In this study, chitosan-g-poly(acrylic acid) (CTS-g-PAA) hydrogel with crosslinked polymeric networks was prepared from an aqueous dispersion polymerization and then used as the adsorbent to recover a valuable metal, Ni2+. The adsorption capacity of CTS-g-PAA for Ni2+ was evaluated and the adsorption kinetics was investigated using Voigt-based model and pseudo-second-order model. In addition, the effects of pH values and coexisting heavy metal ions such as Cu2+ and Pb2+ on the adsorption capacity were studied. The results indicate that the as-prepared adsorbent has faster adsorption rate and higher adsorption capacity for Ni2+ recovery, with the maximum adsorption capacity of 161.80 mg g( 1). In a wide pH range of 3-7, the adsorption capacity keeps almost the same, and even under competitive conditions, the adsorption capacity of CTS-g-PAA for Ni2+ is observed to be as high as 54.47 mg g(-1). Finally, the adsorption performance of CTS-g-PAA for Ni2+ in real water sample and the reusability of the as-prepared adsorbent were evaluated, and also the controlled adsorption mechanism was proposed. PMID- 21277423 TI - Cardiovascular stem cells revisited. PMID- 21277424 TI - The end of our National Health Service. PMID- 21277425 TI - Statins--should we adjust the risk:benefit ratio? PMID- 21277426 TI - Abortion in the USA. PMID- 21277427 TI - What is publication? The case of eltrombopag. PMID- 21277428 TI - European academic institutions for global health. PMID- 21277431 TI - Carole Presern--versatile new Director of PMNCH. PMID- 21277432 TI - Structural variations in attention-deficit hyperactivity disorder. PMID- 21277434 TI - Structural variations in attention-deficit hyperactivity disorder. PMID- 21277436 TI - SNPs and coronary heart disease. PMID- 21277437 TI - SNPs and coronary heart disease. PMID- 21277438 TI - Early versus delayed treatment of relapsed ovarian cancer. PMID- 21277439 TI - Dengue vaccine prospects: a step forward. PMID- 21277440 TI - Injustice and health: is the health community listening? PMID- 21277441 TI - Blind, breathless, and paralysed from benign malaria. PMID- 21277442 TI - [A journal with impact and future]. PMID- 21277443 TI - Clinical chest medicine. Pulmonary disease and pregnancy. Preface. PMID- 21277444 TI - Respiratory physiology in pregnancy. AB - Pregnancy induces marked changes in the respiratory and cardiovascular systems that are essential for meeting the increased metabolic demands of the mother and fetus. Important respiratory system changes occur in the upper airway, chest wall, static lung volumes, and ventilation and gas exchange. Marked cardiovascular changes also occur during pregnancy including increased plasma volume, increased cardiac output, and reduced vascular resistance. Knowledge of these physiologic adaptations is necessary for the clinician to distinguish the common "physiologic dyspnea" from disease states that occur during pregnancy. PMID- 21277445 TI - Fetal oxygenation and maternal ventilation. AB - In the past 20 years, measurements of umbilical blood flow and umbilical venous PO2, oxygen saturation, pH, and oxygen capacity have provided reliable information about the state of oxygenation of normal and growth restricted human fetuses. However, no comparable information is available about the uterine circulation. Therefore, understanding of oxygen transport across the human placenta and the effect of maternal ventilation on fetal oxygenation is tentative, and currently based on a model that is derived from evidence in another species. The main purpose of this model is to illustrate the kind of information that is needed to make further progress in this area. PMID- 21277446 TI - High altitude during pregnancy. AB - One of the greatest physiologic challenges during pregnancy is to maintain an adequate supply of oxygenated blood to the uteroplacental circulation for fetal development. This challenge is magnified under conditions of limited oxygen availability. High altitude impairs fetal growth, increases the incidence of preeclampsia, and, as a result, significantly increases the risk of perinatal and/or maternal morbidity and mortality. This review summarizes the clinical consequences and physiologic challenges that emerge when pregnancy and high altitude coincide and highlights the adaptations that serve to protect oxygenation and fetal growth under conditions of chronic hypoxia. PMID- 21277447 TI - The pulmonologist's role in caring for pregnant women with regard to the reproductive risks of diagnostic radiological studies or radiation therapy. AB - Radiography of the chest, head, neck, teeth, or extremity exposes the embryo or ovary to insignificant exposures of radiation except when radionuclides are utilized. In some instances, there is no exposure at all. Pulmonologists are fortunate with regard to the specific studies they request to provide clinical care because most of the diagnostic tests do not directly expose the uterus (embryo) or ovary. This article discusses radiation risks and their evaluation and pregnancy-related issues in diagnostic radiological studies. PMID- 21277448 TI - Pharmacotherapy in pregnancy and lactation. AB - Prescribing for patients who are pregnant and breastfeeding can be a challenge for clinicians facing insufficient information regarding medication safety, overestimation of perceived risk of medication both by patients and care providers, and increasing litigation costs. This article aims to guide the clinician in choosing the safest and most effective strategy when prescribing medications to patients who are pregnant and breastfeeding. PMID- 21277449 TI - Management principles of the critically ill obstetric patient. AB - The goals in management of critically ill obstetric patients involve intensive monitoring and physiologic support for patients with life-threatening but potentially reversible conditions. Management principles of the mother should also take the fetus and gestational age into consideration. The most common reasons for intensive care admissions (ICU) in the United States and United Kingdom are hypertensive disorders, sepsis, and hemorrhage. The critically ill obstetric patient poses several challenges to the clinicians involved in her care, because of the anatomic and physiologic changes that take place during pregnancy. PMID- 21277450 TI - Interventional chest procedures in pregnancy. AB - Interventional pulmonology encompasses diagnostic and therapeutic bronchoscopic procedures, and pleural interventions. In the last 10 years older techniques have been refined and exciting new technologies have extended the reach and application of the instruments used. The main areas within pulmonary medicine for which these interventions have a role are malignant and nonmalignant airway disease, pleural effusion, pneumothorax, and artificial airways. There are no data from well-designed prospective trials to guide recommendations for interventional pulmonary procedures in pregnancy. The recommendations provided in this article are based on critical review of reported case series, opinion from recognized experts, and personal observations. PMID- 21277451 TI - Smoking and smoking cessation in pregnancy. AB - Smoking during pregnancy is among the leading preventable causes of adverse maternal and fetal outcomes. Smoking prevalence among young women is the primary determinant of smoking prevalence during pregnancy. Smoking among women of childbearing age is associated with reduced fertility, increased complications of pregnancy, and a variety of adverse fetal outcomes. There is increasing evidence of lasting adverse effects on offspring. Guidelines for smoking cessation during pregnancy have been developed. This article reviews the epidemiology of smoking during pregnancy, the adverse effects of smoking on the mother, fetus, and offspring, and recommended approaches to smoking cessation for pregnant women. PMID- 21277452 TI - Asthma in pregnancy. AB - Worldwide the prevalence of asthma among pregnant women is on the rise, and pregnancy leads to a worsening of asthma for many women. This article examines the changes in asthma that may occur during pregnancy, with particular reference to asthma exacerbations. Asthma affects not only the mother but the baby as well, with potential complications including low birth weight, preterm delivery, perinatal mortality, and preeclampsia. Barriers to effective asthma management and opportunities for optimized care and treatment are discussed, and a summary of the clinical guidelines for the management of asthma during pregnancy is presented. PMID- 21277453 TI - Pregnancy in cystic fibrosis. AB - The challenges posed by cystic fibrosis (CF), including poor nutrition and progressive lung function decline, may pose problems for pregnancy for both mother and child. A multidisciplinary team of providers is optimal to help address the variety of issues that might arise in such a pregnancy. Careful attention to maternal weight gain, pulmonary function and exacerbations, and screening for gestational diabetes is necessary. Pregnancies among women with CF are associated with more frequent use of intravenous antibiotics and hospitalization than is seen in nonpregnant CF women. This article reviews maternal and fetal outcomes for CF in pregnancy. PMID- 21277454 TI - Pneumonia complicating pregnancy. AB - Community-acquired pneumonia (CAP) can affect pregnancy, posing risks to mother and fetus. CAP is the most common fatal nonobstetric infectious complication and a common cause of hospital readmission. Risk factors of pneumonia in pregnancy relate to anatomic and physiologic respiratory changes and immune changes. Aspiration can occur during labor, can cause life-threatening disease, and is more common in cesarean deliveries. Influenza pneumonia can cause severe disease, increasing the risk of preterm delivery, abortion, cesarean section, maternal respiratory failure, and death. CAP treatment requires considering antimicrobial appropriateness and safety, choosing therapy in line with guidelines, but considering maternal and fetal risk. PMID- 21277455 TI - Infiltrative lung diseases in pregnancy. AB - Pregnancy may affect the diagnosis, management, and outcome of infiltrative lung disease (ILD). Conversely, ILD may affect pregnancy. ILD may occur as a result of drugs administered commonly or specifically during pregnancy. Most ILDs predominate in patients older than 40 years and are thus rare in pregnant women. During pregnancy ILD may arise de novo and preexisting ILD may be exacerbated or significantly worsened. Some ILDs generally do not alter the management of pregnancy, labor, or delivery. Preexisting ILD no longer contraindicates pregnancy systematically, but thorough evaluation of ILD before pregnancy is required to identify potential contraindications and adapt monitoring. PMID- 21277456 TI - Peripartum pulmonary embolism. AB - Pregnancy is an example of Virchow's triad predisposing to the development of venous thromboembolism (VTE). Specific risk factors for antepartum and postpartum VTE have been identified. The diagnosis of pulmonary embolism in pregnancy is complicated by the physiologic changes of pregnancy as well as physicians' apprehension about ordering radiologic studies during pregnancy because of concerns with fetal well-being. Therapy for VTE is complicated by pregnancy physiology affecting medication pharmacokinetics and bioavailability, and the unpredictable occurrence of labor during therapeutic anticoagulation. PMID- 21277457 TI - Pregnancy and pulmonary hypertension. AB - When pulmonary hypertension (PH) occurs in pregnancy, physiologic stress can overwhelm an already strained right ventricle resulting in right ventricular failure and death. Mortality remains unacceptably high (25%-30%). Patients with PH should be counseled to avoid pregnancy. This article discusses the physiologic changes of pregnancy that make it difficult for patients with PH, the pitfalls of transthoracic echocardiography in diagnosing PH in pregnancy, and the historical data regarding mortality. The causes of development of PH during pregnancy are discussed, and the limited data on management of patients with PH who choose to carry their pregnancy to term are reviewed. PMID- 21277458 TI - Sleep-disordered breathing in pregnancy. AB - Symptoms of sleep-disordered breathing are more common in pregnant women compared with nonpregnant women. It is likely that physiology of pregnancy predisposes to the development or worsening of sleep-disordered breathing, but some physiologic changes may also be protective against the development of this disease. Clinical presentation may be less predictive of sleep disordered breathing in pregnancy than in the non-pregnant population; nonetheless, snoring is associated with adverse pregnancy outcomes. Treatment strategies are similar to the nonpregnant population, however, pregnancy-specific scenarios may arise and these subtleties are addressed in this review. PMID- 21277459 TI - Cytokines profile and acute bronchiolitis. PMID- 21277460 TI - [Glaucoma genetics: the light at the end of the tunnel fourteen years later]. PMID- 21277461 TI - [Infectious keratitis in 266,191 laser in situ keratomileusis]. AB - OBJECTIVE: To study the incidence of infectious keratitis (IK) after laser assisted in situ keratomileusis (LASIK), along with its diagnosis, therapeutic action taken, its management and the results. MATERIAL AND METHOD: We carried out a retrospective study of 262,191 eyes intervened consecutively with LASIK, in our 20 centres, during the period from September 2002 and December 2009. All the cases susceptible to being diagnosed with IK, either clinically or due to the biological findings were analysed. RESULTS: A total of 82 cases were found with infectious keratitis, which assumed an incidence of 0.031%. Distributions are presented by gender, mean age of the patients, mean days since the surgery, the clinical signs and symptoms, predisposing factors, therapeutic action, complications, details of the causal germ, and the loss of lines of vision. CONCLUSIONS: Infectious keratitis after LASIK is a rare complication. The early diagnosis and management of the process are determining factors when establishing the prognosis. In our series all the cases were resolved without causing any other serious complications. PMID- 21277462 TI - [Effect of surgery on longstanding strabismus on binocular visual evoked potential]. AB - PURPOSE: To analyse the effect of surgery on binocular visual evoked potential (BVEP) in adults with longstanding strabismus. METHODS: A prospective study was performed on 40 patients with a history of longstanding strabismus. Visual evoked potentials to binocular and monocular pattern reversal stimulation were recorded before surgery and 3 months after surgery. Binocular visual function was analysed by Worth and TNO tests before and after surgery. RESULTS: We did not find any differences between deviation and BVEP postoperatively (P = 0.82). The mean of BVEP and the percentage of increment of the BVEP response (10.5 and 27.14%) were larger postoperatively, than preoperatively (9.87 and 16.6%), P = 0.32 and P = 0.17, respectively. There were differences in the TNO results after surgery (P = 0.03) and when compared with postoperative deviation (P = 0.02), but not between TNO and BVEP postoperatively (P = 0.29). There were differences in the Worth results after surgery, and comparing with deviation and BVEP (P = 0.00, P = 0.01 and P = 0.07). CONCLUSIONS: Surgery in adults with longstanding strabismus could improve the deviation and seemed to improve BVEP response, but this point could not be confirmed. The results are not enough to show that the BVEP would be an objective test for binocular function evaluation, although there could be a relationship between BVEP and the TNO response. PMID- 21277463 TI - [Immediate changes in intraocular pressure after an intravitreal injection of 2.5 mg of bevacizumab]. AB - PURPOSE: To report the immediate changes of intraocular (IOP) pressure after an intravitreal injection of 2.5mg (0.1 ml) of bevacizumab. METHODS: Prospective, non-controlled, interventional case series of 45 patients undergoing intravitreal injection of 2.5mg (0.1 mL) of bevacizumab for a variety of retinal disorders. IOP was measured with a Goldmann tonometer at baseline, immediately after, 30 minutes and one day after injection in all of the cases. The main outcome measured was the IOP immediately after injection. RESULTS: At baseline the mean IOP was 16.6+/-2.8mm Hg (range, 10-24 mm Hg; median, 16 mm Hg; 25(th) percentile, 14 mm Hg and 75(th) percentile, 18 mm Hg). IOP rose to 53.9+/-18.2mm Hg (range, 16-78 mm Hg, median, 54 mm Hg; 25(th) percentile, 40 mm Hg and 75(th) percentile, 70 mm Hg; p<0.001) immediately after the injection. After 30 minutes, the IOP normalized but was still higher than baseline with a mean of 19.8+/-5.2 mm Hg (range, 10-36 mm Hg; median,18 mm Hg; 25(th) percentile,16 mm Hg and 75(th) percentile, 24 mm Hg; P<.01). At 24 hours the IOP was 15.7+/-3.1 mm Hg (range,10 24 mm Hg; median, 16 mm Hg; 25(th) percentile,14 mm Hg and 75(th) percentile,18 mm Hg; p>0.05). CONCLUSIONS: An intravitreal injection of 2.5mg (0.1 ml) of bevacizumab causes a transient elevation of IOP that tends to return to normal 30 minutes later. PMID- 21277464 TI - [Long-term clinical outcome of radial optic neurotomy]. AB - PURPOSE: To study the long-term clinical outcome through assessment of anatomical and functional results, as well as complications of eyes affected with central retinal vein occlusion (CRVO) that underwent radial optic neurotomy (RON). METHODS: Retrospective, observational and descriptive study of 47 eyes corresponding to 47 patients affected by CRVO. All the eyes underwent RON performed by the same surgeon since 2002. The main assessed variables were visual acuity (VA), intraocular pressure (IOP), presence of iris neovascularization and opticocilliary veins, vascular recanalization and complications derived from this pathological entity. RESULTS: Surgery was performed in 47 eyes, 21 of them (44.7%) were right sided and 26 left sided (55.3%). Mean age was 58.97 years. Mean post-surgical follow-up was 32.15 months. A total of 70.2% of the patients experienced stabilization or VA improvement, 23.4% iridian neovascularisation and 42.6% developed opticocilliary veins in the head of the optical nerve. CONCLUSIONS: It is noticeable that in selected cases, RON produces a quick resolution of the retinal haemorrhage and papillary congestion and may improve the retinal perfusion. Long-term benefits are stabilization or improvement of the VA and a reduction in complications on the natural history in CRVO. PMID- 21277465 TI - [Bilateral acute anterior uveitis and anticonvulsant hypersensitivity syndrome]. AB - CLINICAL CASE: A case is presented of a patient who developed skin lesions on the legs and a bilateral anterior uveitis after taking Oxcarbazepine (Trileptal). DISCUSSION: The presence of uveitis in the context of an allergic reaction to an anticonvulsant is a very uncommon and can affect the internal organs. For this reason, it should be taken into account when carrying out a full assessment of a patient with a possible hypersensitivity reaction to a particular drug. PMID- 21277467 TI - [Revue des maladies respiratoires in 2011: current status and perspectives]. PMID- 21277468 TI - [Treatment of first spontaneous pneumothorax: drainage or exsufflation?]. PMID- 21277469 TI - [Diagnostic difficulty in bronchopulmonary tuberculous pseudotumor]. AB - Pseudotumour is a rare presentation of bronchopulmonary tuberculosis, occurring in immunocompetent patients, which simulates lung cancer and may thus cause diagnostic difficulty. To assess the frequency and clinical features of tuberculous pseudotumour in immunocompetent patients, we analyzed all cases of pulmonary tuberculosis hospitalized in our department. Tuberculous pseudotumour was defined by the presence of a bronchial or pulmonary lesion suggestive of lung cancer. Over a period of 11 years, 12 cases of tuberculous pseudotumour were collected among 341 cases of pulmonary tuberculosis (3.5%). Mean age was 45 years. All patients were smokers. Symptoms were not specific and were dominated by cough and chest pain. Radiological investigations showed consolidation in five cases and a mass lesion in five cases. Fibreoptic bronchoscopy visualized a tumour in four cases and stenosing bronchial wall infiltration in one case. Mean delay to diagnosis was 47 days. The confirmation of tuberculosis was bacteriologic in only three cases but histological in the others (four bronchial biopsies, two transbronchial biopsies, one pleural biopsy, four surgical specimen). The positive diagnosis of tuberculous pseudotumour is difficult because the clinical and radiological presentation may closely mimic lung cancer, especially as the cases are usually smear negative, leading to a very late diagnosis. PMID- 21277470 TI - [Primary mediastinal sarcomas]. AB - INTRODUCTION: Primary sarcomas of the mediastinum are rare and account for 2 to 8% of malignant mediastinal tumours. The aim of this study is to describe their clinical and pathological characteristics. PATIENTS AND METHODS: Fifteen cases of primary mediastinal sarcoma, diagnosed between 1993 and 2009, were reviewed retrospectively, noting the clinical, radiological and pathological findings, and the treatment given. RESULTS: The patient population consisted of eight females and seven males with mean age of 40 years (14 to 73 years). The symptomatology was predominately respiratory. Imaging showed a mediastinal mass invading adjacent organs in nine cases. The diagnosis was made in all cases by histological examination. These 15 mediastinal sarcoma comprised 12 malignant peripheral nerve tumours, two liposarcomas and one angiosarcoma. Three were grade III, six grade II and six grade I. Ten were treated surgically, of which seven had radical resections. Associated treatments were neoadjuvant (one case) or adjuvant (one case) chemotherapy and postoperative radiotherapy (five cases). Radiotherapy was undertaken alone in three inoperable tumours. Eight patients (53%) had died. CONCLUSION: Management of primary mediastinal sarcoma needs a multidisciplinary approach, and is based mainly on radical resection. The prognosis is poor and depends mainly on surgical excision and histological grade. PMID- 21277471 TI - [Bevacizumab and lung cancer: eligible patients in daily practice]. AB - BACKGROUND: Combining bevacizumab with platinum-based chemotherapy significantly improves survival for patients with advanced non-squamous non-small cell lung cancer. The objective of this study was to assess the proportion of patients who could receive this combined therapy. METHODS: This was a retrospective single centre analysis of patients treated between 2007 and 2008. Exclusion criteria for bevacizumab included: squamous cell carcinoma, contraindication to platinum-based chemotherapy, uncontrolled hypertension, haemoptysis superior to 2.5 mL, recent surgery, and/or tomodensitometric criteria after independent review by two radiologists (contact with a proximal vessel, tracheobronchial involvement, cavitation). Cardiovascular diseases and central tumour location were not systematically considered as contraindications. RESULTS: Among 194 patients analysed, 21 (10.8%) to 35 (18%) patients were eligible for bevacizumab, whether or not cardiovascular diseases and central tumour location were considered as contraindications. The kappa coefficient was 0.49. CONCLUSION: Even though the proportion of patients who can receive chemotherapy plus bevacizumab may vary according to the eligibility criteria chosen and the interpretation of the CT scan, it is unlikely to exceed 25% of patients in daily practice. PMID- 21277472 TI - [Epidemiology of chronic obstructive pulmonary disease in Algiers]. AB - INTRODUCTION: Chronic obstructive pulmonary disease (COPD) and its consequences in terms of disability and mortality are, in current practice, a serious public health problem whose prevalence is unknown in Algeria. This study aims to evaluate this disease in order to plan a better system of management. METHODS: The study used a questionnaire and spirometry and involved a representative sample of the adult population aged over 21 years. It was carried out with the assistance of the National Office of the Statistics (ONS) near the homes of the subjects who were selected according to the random mode in three degrees. The study concerned 1800 adults (50.4% men and 49.6% women) regardless of their tobacco smoking status. They were asked to answer the questionnaire and to perform spirometry. RESULTS: The prevalence of COPD is 4.9% for the whole population. It is rare before forty years of age (0.1%) and reaches 9.2% in those over 40 years old. In this older group the difference according to sex is significant (16.1% for men, 2.5% for women). Tobacco smoking increases the prevalence which reaches 31.5% among smokers, 14.6% among the ex-smokers and 2.5% among non-smokers. It increases with age and affects one man on four over 65 years old and one smoker on two in this age bracket. The prevalence of the various stages of severity is 6%, 2.7%, 0.3% and 0.2% respectively. CONCLUSION: The prevalence of the COPD found approaches that described in the literature. It increases with age and tobacco smoking and 0.2% of the population aged more than 40 years suffer from respiratory handicap. The management of this disease requires better organization at both the medical and social level. PMID- 21277473 TI - [Diversity of incidence trend patterns: implications for carcinogenesis?]. AB - OBJECTIVE: Cancers of the ENT, oesophagus and lungs are caused mainly by alcohol and/or tobacco consumption but have potentially heterogeneous latencies and dose incidence relationships. The incidence of cancers having the same risk factors may vary in a similar way over time and space. The aim of the study was to identify groups of cancers with similar spatio-temporal incidence trends. METHODS: Fifty thousand nine hundred and eighty cases of ten cancer types were collected between 1982 and 2002 in six French departments. The incidence levels and trends were assessed using an age-cohort random-effect model that took into account heterogeneity of incidence levels and trends between departments. RESULTS: Three groups of cancer sites/types with similar spatio-temporal incidence trends were identified: (1) oral cavity, oropharynx, hypopharynx, larynx, oesophagus, and lung squamous cell carcinomas in which the incidence decreased similarly in time and space; (2) other types of lung cancer and lung adenocarcinomas whose incidence increased similarly; and (3) lung large- and small-cell carcinomas whose incidence trends were heterogeneous. CONCLUSION: Using the tools of descriptive epidemiology different cancer groups with different temporal and spatial incidence trends were identified. This diversity suggests different latencies and different sensitivities of those groups to the main risk factors, alcohol and tobacco. PMID- 21277474 TI - [A phase II study of cetuximab, pemetrexed, cisplatin, and concurrent radiotherapy in patients with locally advanced, unresectable, stage III, non squamous, non-small cell lung cancer (NSCLC)]. AB - BACKGROUND: Cisplatin-based chemotherapy and concurrent radiotherapy are the standard treatments for locally advanced unresectable NSCLC. New therapeutic combinations using molecular targeted drugs are needed. METHODS: Eligible patients with previously untreated stage III non squamous, NSCLC will receive thoracic radiation (66 Gy) along with cisplatin (75 mg/m(2)) and pemetrexed (500 mg/m(2)) on day 1 administered intravenously every 21 days for four cycles; weekly cetuximab will be added from the first week of therapy. The primary objective of this phase II study (IFCT 0803) is to assess the disease control rate at the 16th week, one month after the completion of the treatment. Based on a two-stage Simon approach, a total of 106 patients are required with an interim analysis of the first 34 planned. EXPECTED RESULTS: This trial will provide information on the feasibility, efficacy and tolerability of this new therapeutic combination. Should the primary objective be achieved, a phase III randomised study testing the position of cetuximab could be considered. PMID- 21277475 TI - [A phase II study of weekly cisplatine plus oral vinorelbine with concomittant radiotherapy in non-dependent elderly patients with localized inoperable non small cell lung carcinoma (Essai GFPC 08-06, Raccosa)]. AB - A phase II study of weekly cisplatine plus oral vinorelbine with concomittant radiotherapy in non-dependent elderly patients with localized inoperable non small cell lung carcinoma (Essai GFPC 08-06, Raccosa). BACKGROUND: Non small cell lung cancer (NSCLC) in elderly patients is an important problem because of the increasing incidence of NSCLC and the aging of the population. Elderly patients constitute a heterogeneous population including a significant group of relatively fit patients who ought to benefit from the conventional treatment. The standard treatment for a locally advanced NSCLC (inoperable IIIA and IIIB) is concomitant radiochemotherapy, however studies evaluating this treatment to the old subject are few. METHODS: This phase II study aims to evaluate tolerance of concomitant radiochemotherapy in fit elderly patients (more than 70 years old) with locally advanced NSCLC (inoperable IIIAN2 or IIIB). The treatment is oral vinorelbine (30 mg/m(2) per week) and intravenous cisplatine (30 mg/m(2) per week) during 6 weeks in conjunction with radiotherapy (66 Gy, 33 fraction, six and a half weeks). The main criterion of evaluation is acute toxicity. Late toxicity, quality of life, global response, time to progression and overall survival will also be estimated. With a Simon's optimal plan in two steps, the total number of patients to be included is 59 with an intermediate analysis after the inclusion of 19 patients. EXPECTED RESULTS: Our study aims to demonstrate that fit elderly patients can benefit from concomitant radiochemotherapy. It will permit an improvement in the care available for fit elderly patients with locally advanced NSCLC by allowing them to benefit from the reference treatment. PMID- 21277476 TI - [Iatrogenic pulmonary necrosis due to hyperselective chemotherapy]. AB - BACKGROUND: The management of cancer requires regular access to the central venous system. We report here, a case of a central venous access system causing pulmonary necrosis and abscess. CASE REPORT: A 48 year old woman with a past history of B-cell lymphoma presented with a relapse of her disease. A subcutaneous central venous access port was placed in the right brachiocephalic area with puncture of the subclavian vein. She received three doses of chemotherapy. Eight days later, she consulted the emergency department on account of right-sided chest pain. Examination revealed a right-sided pleural effusion. The chest x-ray showed the tip of the catheter at the right pulmonary hilum. A CT scan confirmed that the tip of the central venous catheter was located in a branch of the right lower lobe pulmonary artery and was surrounded by consolidation in the right middle and lower lobes. The progress was marked by the development of a lung abscess despite removal of the central venous access system. Subsequent surgery led to satisfactory resolution. CONCLUSION: We report a dramatic case that reminds us that placement of a central venous access system requires a sound technique and regular radiological surveillance. PMID- 21277477 TI - [Muscle metastasis revealing bronchial adenocarcinoma]. AB - INTRODUCTION: The diagnosis of nonsmall cell lung cancer is made at a metastatic stage in 25% of cases. The most frequent sites are the lung, liver, bone, the adrenal glands and the central nervous system. Skeletal muscle metastases are uncommon and are rarely the first manifestation of a neoplastic process. CASE REPORT: We report the case of 55 years old man presenting with a hard painless swelling of the left arm. A scan guided biopsy revealed infiltration of the muscle by a thyroid transcription factor 1 (TTF1) positive adenocarcinoma. A CT scan of the chest showed a partially necrotic tissue mass with moderate uptake of contrast. The patient was treated by chemotherapy with gemcitabine and carboplatine. The progress was unfavourable with the appearance of a second muscular metastasis in the thigh and the patient died 3 months after diagnosis. CONCLUSION: Skeletal muscle metastases are rarely described in lung cancer and they are an exceptional presentation of the tumour. Their symptoms can be misleading and delay diagnosis. PMID- 21277478 TI - [Boerhaave's syndrome and pleural tuberculosis]. AB - INTRODUCTION: Boerhaave's syndrome is a rare condition involving spontaneous rupture of the oesophagus. The diagnosis is difficult and the prognosis depends on early diagnosis and treatment. CASE REPORT: We report a case of spontaneous rupture of the oesophagus in a 70-year-old woman where the diagnosis was delayed. Initial treatment comprised dual antibiotic therapy and feeding via a jejunostomy. Three months later, direct suture of the oesophagus was performed successfully. A routine pleural biopsy performed during the surgery revealed pleural tuberculosis. Antituberculous treatment was given for 6 months with good progress after 16 months follow up. CONCLUSION: Boerhaave's syndrome is a rare condition, the diagnosis of which remains difficult. The prognosis is related essentially to the speed of diagnosis. The treatment is always surgical within the framework of appropriate medical management (intensive care, antibiotic therapy). There should be a systematic search for associated pathology. PMID- 21277479 TI - [Pleural metastases from bronchial carcinoma: is a cure possible?]. AB - INTRODUCTION: The 2009 TNM classification of lung cancer reclassified patients with pleural invasion from stage IIIB (T4) to stage IV (M+). However, the 2009 TNM separates patients with pleural metastases (M1a) from patients with others visceral metastases (M1b), the patients with stage M1a having the better prognosis. CASE REPORTS: Two cases are reported of patients with non-small cell lung cancer (NSCLC) metastatic to the pleura, having a long disease free survival (50 and 34 months). CONCLUSIONS: Patients with pleural metastases from NSCLC seem to have a better prognosis than other patients with stage IV disease, maybe because of a subgroup of patients with long survival. This long survival is probably related to specific biological characteristics of certain pleural disorders that need to be identified. This would allow a more aggressive treatment of this subgroup of patients regarded today as incurable. PMID- 21277480 TI - [Primary myxoid mediastinal liposarcoma]. AB - Mediastinal liposarcomas (LPS) are rare tumours. We report a case of primary myxoid LPS in a 22-year-old woman suffering from cough, dyspnoea on exercise and asthenia for 3 weeks. Thoracic MRI showed a large tumour on the right side. After neoadjuvant chemotherapy, a complete resection was performed, followed by adjuvant thoracic irradiation. Eighteen months after the diagnosis, no sign of recurrence was detected. Mediastinal LPS include a heterogeneous group of bulky tumours, the progression of which depends on the histological type. The prognosis is dominated by the operability of the tumour. Adjuvant therapies are not established. PMID- 21277481 TI - [Benign trachobronchial schwannoma treated by complete endoscopic resection followed by cryotherapy]. AB - INTRODUCTION: Tracheobronchial schwannoma is a rare benign airway tumour. There is no evidence to guide treatment for this condition. CASE REPORT: A 76-year-old woman with a history of ischemic cardiomyopathy was hospitalized for dyspnoea with bronchial symptoms. Incidentally, the CT scan of the chest identified a tracheal mass. The bronchoscopy revealed a multilobar and regular whitish tumour with moderate vascularisation that was not causing obstruction. The patient was treated by complete resection with a rigid bronchoscope followed by cryotherapy. The histopathologic diagnosis was of a benign schwannoma without malignant elements. There was no recurrence during the follow-up period. CONCLUSIONS: There is no consensus as to the optimal management of tracheal schwannoma because of the rarity of this tumour. Our observation supports the use of endoscopic resection with the additional of local cryotherapy which may reduce the risk of recurrence. PMID- 21277482 TI - [Tuberculosis and pneumocystis: an unusual co-infection]. AB - INTRODUCTION: Modern immunosuppressive therapy may be responsible for toxic, immunologic and infectious pulmonary diseases. CASE REPORT: We report the case of a 58-year old woman treated for rheumatoid arthritis who received leflunomide, corticosteroids, methotrexate and adalimumab. She developed disseminated tuberculosis, which presented with neurological symptoms (brainstem) and also pneumocystis pneumonia. CONCLUSION: Modern immunosuppressive therapy used to treat inflammatory disorders in connective tissue diseases and in transplantation may induce new respiratory diseases, new patterns of known respiratory diseases or co-infections that are very seldom seen outside the context of HIV. Pulmonologists, rheumatologists, internists and intensivists should be aware of this new spectrum of diseases whose presentation may be atypical. PMID- 21277483 TI - [Pneumocystis pneumonia in a patient treated with pemetrexed for non small cell lung cancer]. AB - INTRODUCTION: Pneumocystis pneumonia is a life-threatening infection in patients undergoing chemotherapy for solid malignancies. CASE REPORT: A 49-year-old man developed gradually increasing dyspnoea while receiving pemetrexed as a third line treatment for an adenocarcinoma of the lung. The diagnosis of pneumocystis pneumonia was based on ground-glass opacities on the thoracic CT scan and alveolar lavage revealing occasional cysts of Pneumocystis jiroveci in the context of recent lymphopenia developing during chemotherapy. Treatment with cotrimoxazole for three weeks was only partially successful due to progression of the tumour. CONCLUSIONS: Pneumocystis pneumonia should be considered in cancer patients receiving antifolate drugs and presenting with increasing dyspnoea. It is important to identify a high-risk population among patients undergoing chemotherapy because of the significant morbidity and mortality and in order to administer effective prophylactic agents. PMID- 21277484 TI - [Ovarian metastasis from bronchial carcinoma]. AB - INTRODUCTION: The ovary, being a richly vascular organ, may receive metastases from numerous tissues, particularly of gynecologic origin. Extragenital cancers are dominated by gastro-intestinal and breast tumors. The lung is exceptionally described as a primary site of ovarian metastasis. CASE REPORT: We report a 28 year-old woman who was found to have a right perihilar opacity. The diagnosis of small cell bronchial carcinoma was made by bronchial biopsy. A right-sided uterine mass was also identified. This was resected and histopathology identified it as an ovarian metastasis from the pulmonary tumor. CONCLUSION: We report, through this case, and present a review of the literature on ovarian metastasis originating from bronchopulmonary neoplasms. PMID- 21277485 TI - [Efficacy of recombinant activated factor VII in diffuse alveolar haemorrhage]. AB - INTRODUCTION: Alveolar haemorrhage is a serious complication of a range of different pathologies. Published recent literature has reported only cases unresponsive to the usual treatment (steroids, transfusions, immunosuppressors and mechanical ventilation) as well as multiple secondary complications of these kinds of therapies. Recombinant activated factor VII (rF VIIa) is a new class of agent, which appears to be a successful adjunct therapy in the case of failure of conventional treatments. OBSERVATIONS: We describe two cases of alveolar haemorrhage treated with rF VIIa. The first patient had leukaemia and the second had ANCA-associated granulomatous vasculitis. Both were admitted to the intensive care unit for mechanical ventilation with persistent diffuse alveolar haemorrhage that responded only to a single dose of rF VIIa (90 MUg/kg). DISCUSSION AND CONCLUSION: rF VIIa is a promising treatment for diffuse, persistent alveolar haemorrhage, with only a small dose required to be effective. Future studies are needed in order to establish a clear protocol for the administration of this novel agent. PMID- 21277487 TI - Ocular anatomy and cross-sectional imaging of the eye. AB - Ocular cross-sectional imaging is usually obtained as an adjunct to clinical ophthalmologic examination and ocular ultrasound. Computed tomography/magnetic resonance imaging (CT/MRI) are complimentary for ocular imaging and are performed for evaluation of the vitreous cavity, choroid, retina, sclera, and potential spaces and for the assessment of extension of disease beyond the globe into the orbit or brain. CT has superior spatial resolution aided by the natural contrast between bone, soft tissues, air, and fat. The short scanning time is advantageous to reduce motion effects and the need for sedation. CT is also the modality of choice for evaluation of traumatic injury and for visualization of foreign bodies. Potential clinical indications for MRI include staging of retinoblastoma and other causes of leukocoria, assessment of retinal or choroidal detachments for underlying retinal mass or hemorrhage, uveal melanoma, ocular metastases, choroidal hemangioma, and buphthalmus, staphyloma, and coloboma. Last, but not least, MRI has the advantage of no ionizing radiation. PMID- 21277488 TI - Pediatric ocular sonography. AB - Ultrasound is often used as an adjuvant in the workup of ocular pathology in children. It is particularly useful when ophthalmoscopic examination is limited, such as in the presence of extreme miosis or opaque ocular media. Other indications include assessment of a mass seen at ophthalmoscopy, elucidation of a mass underlying a retinal detachment, ocular trauma, and biometry. In this article, we review normal sonographic technique and ocular anatomy. The sonographic features of common pediatric ocular conditions are presented, with an emphasis on distinguishing features. Correlation, where pertinent, is made with other imaging modalities, such as computed tomography and magnetic resonance imaging. Ultrasound plays a critical role in the clinical diagnostic evaluation of globe pathology. PMID- 21277489 TI - Ocular neoplastic disease. AB - Ocular neoplasms, both primary and metastatic, may present with visual disturbance or vision loss and often are asymptomatic. Clinical ophthalmologic examination may demonstrate leukocoria, abnormal pupillary light reflex, or a mass lesion with or without retinal detachment or hemorrhage. Retinoblastoma in children and uveal melanoma and ocular metastases in adults are the most important ocular malignant neoplasms referred for imaging to aid with diagnosis and staging. Familiarity with their common imaging appearances, the common patterns of spread, and the diagnostic findings of greatest concern to the ocular oncologist will enhance accuracy of imaging interpretation. Clinical ophthalmologic examination and imaging using B-scan ultrasound, A-scan ultrasound, fluorescein angiography, computed tomography and magnetic resonance imaging have complementary roles in ocular tumor staging and treatment assessment. PMID- 21277490 TI - The globe: infection, inflammation, and systemic disease. AB - Infection, inflammation, and systemic diseases affecting the globe encompass a broad range of pathologies which may ultimately lead to progressive vision loss. Clinical symptomatology varies from the inexorably silent progressive visual loss to an acute presentation of ocular pain and/or red eye. Most are diagnosed by clinical ophthalmologic examination with selective use of ultrasound, computed tomography, and magnetic resonance imaging for confirmation of the diagnosis, assessment of disease extent, and signs of associated systemic disease. Knowledge of the differential diagnoses of vision loss, ocular pain, and redness makes imaging analysis of this diverse group of processes more precise. PMID- 21277491 TI - Globe trauma. AB - In the United States, it is estimated that 3% of all emergency room visits are the result of eye injury, with many seen in combination with other orbital injuries. These often result from motor vehicle accidents and sports-related injuries. Clinical ophthalmologic examination is the key to rapid and accurate diagnosis of most ocular injuries. Imaging, in combination with the ophthalmologic examination, can be a powerful tool in the evaluation of traumatic injury to the globe. We review the roles of computed tomography, magnetic resonance imaging, and ultrasound in the evaluation of these patients and illustrate common and uncommon traumatic ocular pathology. PMID- 21277492 TI - Postsurgical imaging of the globe. AB - Interpretation of globe imaging after ophthalmologic surgical intervention, just like postoperative imaging in any location, can create a diagnostic dilemma if the radiologist is not familiar with the type of surgery performed and the nature and location of any implanted devices. Certain implants and devices may create artifacts on computed tomography or magnetic resonance imaging, and some contain ferromagnetic components that may be damaged if inadvertently placed in the magnetic resonance imaging. We review several common ocular surgical procedures, as well as a few orbital surgical procedures and discuss many implants and devices and their appearance on cross-sectional imaging. Familiarity with these procedures and their imaging appearance can diminish the chance of misinterpretation. PMID- 21277493 TI - Gasification: an alternative solution for waste treatment with energy recovery. PMID- 21277495 TI - High-light induced superoxide radical formation in cytochrome b6f complex from Bryopsis corticulans as detected by EPR spectroscopy. AB - The generation of superoxide radical (O2.-) in Cyt b6f of Bryopsis corticulans under high light illumination was studied using electron paramagnetic resonance (EPR) spectroscopy. This could be evidenced by the addition of SOD which specifically reacted with O2.-. The generation of O2.- was lost in the absence of oxygen and was found to be suppressed in the presence of NaN3 and be scavenged by extraneous antioxidants such as ascorbate, beta-carotene and glutathione which could also scavenged 1O2*. These results indicated that O2.- which produced under high light illumination in Cyt b6f of B. corticulans might rise from a reaction which 1O2* could participated in. Also the photo-protection mechanism to Cyt b6f complex by antioxidants which might contain in thylakoid was speculated. PMID- 21277496 TI - Preface. Peripheral trigeminal nerve injury, repair, and regeneration. PMID- 21277497 TI - Peripheral nerve response to injury. AB - Oral and maxillofacial surgeons caring for patients who have sustained a nerve injury to a branch of the peripheral trigeminal nerve must possess a basic understanding of the response of the peripheral nerves to trauma. The series of events that subsequently take place are largely dependent on the injury type and severity. Regeneration of the peripheral nerve is possible in many instances and future manipulation of the regenerative microenvironment will lead to advances in the management of these difficult injuries. PMID- 21277498 TI - Clinical evaluation of peripheral trigeminal nerve injuries. AB - This article presents a standardized method of clinical evaluation of the patient with a peripheral trigeminal nerve injury that provides both subjective and objective information. This evaluation scheme has been used by 1 author for more than 30 years (RAM) and by the other author (SCB) for 10 years. The information is easily obtained and recorded in the patient's record, and it can be used by any clinician who performs subsequent evaluations on the same patient. The NST methods have been used successfully by specialists in other surgical disciplines for many years, and the various test results have been found to be closely correlated with the injuries found when the responsible nerve was surgically explored.Alternate testing methods or equipment are available that are used primarily in clinical and laboratory research rather than clinical practice. The reader who is interested in more information is encouraged to consult (Further Readings). PMID- 21277499 TI - Inferior alveolar and lingual nerve imaging. AB - At present, there are no objective testing modalities available for evaluation of iatrogenic injury to the terminal branches of the trigeminal nerve, making such clinical diagnosis and management complicated for the oral and maxillofacial surgeon. Several imaging modalities can assist in the preoperative risk assessment of the trigeminal nerve as related to commonly performed procedures in the vicinity of the nerve, mostly third molar surgery. This article provides a review of all available imaging modalities and their clinical application relative to preoperative injury risk assessment of the inferior alveolar nerve and lingual nerve, and postinjury and postsurgical repair recovery status. PMID- 21277500 TI - Management of mandibular nerve injuries from dental implants. AB - Treatment of the patient who has sustained a nerve injury from dental implant procedures involves prompt recognition of this complication, evaluation of sensory dysfunction, the position of the nerve vis-a-vis the implant, and timely management of the injured nerve. In some patients, removal or repositioning of the implant and surgical exploration and repair of the injured nerve will maximize the implant patient's potential for a successful recovery from nerve injury. PMID- 21277501 TI - Nerve injuries from mandibular third molar removal. AB - Injuries to peripheral branches (IAN, LN, LBN) of the trigeminal nerve during the removal of M3s are known and accepted risks in oral and maxillofacial surgery practice. These risks might be reduced by modifications of evaluation or surgical techniques, depending on the surgeon's judgment in individual patients. If a nerve injury does occur, prompt recognition, subjective and objective evaluation,and development of a treatment plan, if the sensory deficit fails to resolve in a reasonable period and is unacceptable to the patient, give the patient the best chance of achieving improvement or recovery of sensory function in the distribution of the injured nerve. Microneurosurgery may produce return of useful sensory function or complete sensory recovery, if done in a timely fashion by an experienced microsurgeon, in greater than 80% of patients who sustain nerve injuries during the removal of M3s. PMID- 21277502 TI - Microsurgical techniques for repair of the inferior alveolar and lingual nerves. PMID- 21277503 TI - Autogenous grafts/allografts/conduits for bridging peripheral trigeminal nerve gaps. AB - Nerve repairs and grafting techniques have been around for many years. Autogenous nerve grafts have worked reasonably well in the right circumstances but are associated with difficulties in achieving a proper donor-host match and with postsurgical sequelae at the donor site. Vein grafts seem to work almost as well as autogenous nerve grafts in digital nerve repairs that require a graft less than 3 cm in length. Currently, the most promising nerve graft materials are the polyglycolic acid tubes and processed decellularized allografts, which have shown good results without the morbidity of autogenous nerve grafts. However, more research studies using these materials for TN repairs are essential to validate the superiority of these procedures. PMID- 21277504 TI - Sensory retraining: a cognitive behavioral therapy for altered sensation. AB - Sensory retraining teaches the patient to ignore or blot out postinjury unpleasant orofacial sensations to optimally tune into and decipher the weakened and damaged signals from the tissues. Sensory retraining is a simple, inexpensive, noninvasive exercise program, which initiated shortly after injury, can lessen the objectionable impression of orofacial altered sensations. Sensory retraining exercises are most effective on decreasing the perceived burden associated with hypoesthetic orofacial altered sensations. PMID- 21277505 TI - Advances in bioengineered conduits for peripheral nerve regeneration. AB - Although resorbable NGCs have been developed for peripheral nerve grafting, there has been little published on their use as a material for trigeminal nerve repair. Advances in engineered guidance channels and modifications to the single-lumen conduit with growth-permissive substrates, ECM proteins, neurotrophic factors, and supportive Schwann or stem cells, and anisotropic placement of these within the NGC may translate from animal models to clinical human use in the future. A great deal of research is still needed to optimize the presently available NGCs, and their use in peripheral trigeminal nerve repair and regeneration remains yet to be explored. Bioengineered NGCs and additives remain promising alternatives to autogenous nerve grafting in the future. They can incorporate all of the developing strategies for peripheral nerve regeneration that develop in concert with the ever-increasing understanding of regenerative mechanisms. The use of nanomaterials also may resolve the numerous problems associated with traditional conduit limitations by better mimicking the properties of natural tissues. Since cells directly interact with nanostructured ECM proteins, the biomimetic features of anisotropic-designed nanomaterials coupled with luminal additive ECMs, neurotrophic factors, and Schwann cells may provide for great progress in peripheral nerve regeneration. PMID- 21277507 TI - Alphabet soup: ABAI, ABMS, and MOC vs EBM, VBM, and IRB. PMID- 21277508 TI - The environment, the airway, and the athlete. AB - OBJECTIVE: To review the interaction of environmental factors with host conditions, including atopy, the potential resulting impaired upper and lower airway function, and diagnostic and therapeutic considerations in the athlete. DATA SOURCES: OVID, MEDLINE, and PubMed searches were performed cross-referencing the keywords asthma, athlete, atopy, bronchospasm, exercise, pollution, and rhinitis. STUDY SELECTION: Articles were selected based on relevance to the subject matter. RESULTS: Recent studies have yielded significant advances in our understanding of how intrinsic and extrinsic factors can potentially result in impaired function of the airways of athletes. Extrinsic factors include environmental exposure to temperature, humidity, aeroallergens, irritants, and pollution. Intrinsic factors include atopy, allergic rhinitis, asthma, and anatomical variants. These intrinsic and extrinsic factors can affect both the athlete's quality of life and athletic performance. However, uncertainty remains regarding relative contributions of these factors in explaining the high degree of bronchospasm seen in various populations of athletes with and without asthma, and no consensus exists regarding the most appropriate diagnostic and therapeutic modalities. CONCLUSIONS: Great variability exists in the presentation, laboratory findings, diagnostic maneuvers, and response to therapeutic measures among populations of athletes in different sports and among individuals. An improved understanding of the unique exposures faced by athletes in different disciplines, of the available tests for pursuing the appropriate diagnosis, and of the available therapies will allow the allergist to provide clinical improvement and allow the athlete to find relief and achieve his/her full potential. PMID- 21277509 TI - Mannitol as an indirect bronchoprovocation test for the 21st century. AB - OBJECTIVES: To review mannitol challenge data and advocate the approval of this testing modality in the United States. DATA SOURCES: A literature review was performed using the MEDLINE database for English-language articles published between January 1, 1993, and July 31, 2009, using the following keywords: mannitol bronchoprovocation test, inhaled mannitol, inhaled mannitol and asthma, and inhaled mannitol and exercise-induced asthma. STUDY SELECTION: Trials were selected that established the effect of mannitol as a bronchoprovocation challenge, explored mannitol's mechanism of action, and compared mannitol to other accepted bronchoprovocation challenges. RESULTS: Mannitol has demonstrated the ability to detect airway hyperreactivity in individuals. The mechanism of action is through the release of mast cell mediators. The sensitivity and specificity compare well with other indirect challenge testing methods. CONCLUSION: Mannitol is a polyol sugar that can be converted to a powdered form and encapsulated. Once encapsulated it can be inhaled and causes narrowing of the airways in susceptible individuals. Mannitol likely triggers the release of inflammatory and/or bronchospasm mediators, causing the smooth muscle of the airway to contract and resulting in airway narrowing. The magnitude of decrease in forced expiratory volume in 1 second and the dose of mannitol needed to provoke the airway response provide a readily measurable and clinically useful assessment of airway hyperreactivity. Mannitol challenge is an accepted testing method in Australia, Europe, and Korea. Acceptance of the mannitol challenge in the United States would complement existing methods for assessing bronchial hyperreactivity and likely improve patient care. PMID- 21277510 TI - The role of pseudoephedrine on daytime somnolence in patients suffering from perennial allergic rhinitis (PAR). AB - BACKGROUND: Allergic rhinitis is one of several inflammatory diseases affecting the nasal mucosa. Cellular inflammation of nasal mucosa is a hallmark of this disease and is characterized by the accumulation of eosinophils and the release of various chemical messengers such as chemokines, cytokines, and histamine. This inflammation of the nose leads to nasal congestion and a reduction in sleep quality, resulting in daytime somnolence. OBJECTIVE: Drugs that significantly reduce the symptoms of nasal congestion also may help in alleviating sleep related symptoms of allergic rhinitis. Pseudoephedrine is a sympathomimetic amine that is indicated for treatment of nasal congestion associated with allergic rhinitis. Despite relieving nasal congestion, we speculated that, because of pseudoephedrine's well-known stimulant profile, sleep would not be improved. METHOD: Fourteen subjects who met the inclusion criteria were enrolled into a double-blind, placebo-controlled, randomized study to either pseudoephedrine or placebo once per day in the morning, using the traditional crossover design. Skin testing test was performed to ensure a positive response to a relevant perennial allergen and a negative response to a seasonal allergen. Several questionnaires were used to evaluate the patients' sleep-related symptoms, allergic rhinitis symptoms, and quality of life. RESULTS: Our results showed that pseudoephedrine did not have a positive or negative effect on quality of sleep, daytime sleepiness, or daytime fatigue as compared with placebo. Pseudoephedrine did show a statistical significance in improving stuffy nose (P = .0172). With respect to quality of life, pseudoephedrine led to a statistically significant decrease in intimate relationships and sexual activity as compared with the placebo group (P = .0310). CONCLUSION: Our research suggests that sleep quality is not significantly affected by pseudoephedrine. As expected, congestion is reduced, but side effects such as a decline of intimate relationships and sexual activity may interfere with quality of life. PMID- 21277511 TI - Cockroach exposure independent of sensitization status and association with hospitalizations for asthma in inner-city children. AB - BACKGROUND: Children with asthma living in urban environments experience disproportionately high asthma hospitalization rates. Excessive exposure to perennial allergens, including cockroach and house dust mite (HDM), have been implicated, but data are limited. OBJECTIVE: To examine the relation between cockroach and HDM exposure and measures of asthma morbidity and health care utilization. METHODS: Participants included 86 atopic asthmatic children living in New Orleans, Louisiana. Sensitization status was determined by means of serum specific IgE testing, and vacuum dust samples were collected for allergen analysis. Logistic regression analysis was used to assess the odds of persistent wheezing, emergency department visits, and asthma hospitalization in those with high vs low levels of allergen exposure. RESULTS: Approximately 44% and 40% of children were exposed to Bla g 1 levels greater than 2 U/g and HDM levels greater than 2 MUg/g, respectively, and 24% reported at least 1 hospitalization in the previous 4 months. The median Bla g 1 level was significantly higher in the homes of children hospitalized compared with those with no hospital admissions (7.2 vs 0.8 U/g). In multivariable models, the odds of hospitalization were significantly higher in children exposed to Bla g 1 levels greater than 2 U/g (adjusted odds ratio, 4.2; 95% confidence interval, 1.24-14.17), independent of sensitization status. Exposure to HDMs was not associated with any measure of morbidity. CONCLUSIONS: Exposure to cockroach allergen was strongly associated with increased hospitalization in children with asthma. This effect cannot be explained entirely by IgE-mediated inflammation. Controlled interventional trials are needed to determine whether isolated cockroach abatement improves asthma control. PMID- 21277512 TI - Evaluating quality of life in patients with asthma and rhinitis: English adaptation of the rhinasthma questionnaire. AB - BACKGROUND: Separate health-related quality of life (HRQL) instruments exist for asthma and rhinitis. The Rhinasthma questionnaire, originally developed in Italian, is a unique measure designed for use where both conditions coexist. OBJECTIVE: We sought to assess the performance and validity of a new adaptation of the Rhinasthma questionnaire for use in English-speaking populations. METHODS: We analyzed cross-sectional data from an ongoing study of adults with asthma and rhinitis (n = 450), asthma alone (n = 75), or rhinitis alone (n = 20). Subjects were administered an English translation of the original 30-item Rhinasthma questionnaire. Health status measures simultaneously assessed include the Short Form (SF)-12, EuroQol (EQ)-5D, and Marks Asthma Quality-of-Life. RESULTS: Variable cluster analysis of the original 30-item instrument identified 5 discrete item clusters corresponding to the following domains: nasal (5 items), eye (4 items), respiratory (5 items), activity restriction (9 items), and treatment burden (5 items). Two other items were removed because of poor item cluster correlations. Subjects with concomitant asthma and rhinitis had greater HRQL impairment, as measured by the Rhinasthma, than subjects with either asthma or rhinitis alone. The Rhinasthma correlated significantly (P < .05) with the SF 12, EQ-5D, and Marks Asthma Quality-of-Life in the anticipated direction consistent with the underlying constructs. In multiple logistic regression, poorer Rhinasthma HRQL was associated with significantly (P < .05) increased odds of both asthma- and rhinitis-related disability even after taking into account physical health status as measured by the SF-12. CONCLUSION: The 28-item English adaptation of Rhinasthma performs well in assessing HRQL in patients with asthma, rhinitis, or both conditions combined. PMID- 21277513 TI - Delayed asthmatic response: a new phenotype of bronchial response to allergen challenge and soluble adhesion molecules in the serum. AB - BACKGROUND: Patients with bronchial asthma develop various types of asthmatic response to bronchial challenge with allergen, such as immediate asthmatic response, late asthmatic response, or delayed asthmatic response (DYAR), due to different immunologic mechanisms. OBJECTIVES: To investigate the appearance and possible changes in the concentrations of soluble cell adhesion molecules during the DYAR, to explore the involvement of particular cell types in the mechanism(s) leading to DYAR, and to contribute to a fuller understanding of this clinical phenomenon. METHODS: The DYAR recorded in 28 patients (P < .001), appearing within 26 to 32 hours, reaching maximum within 32 to 48 hours, and resolving within 56 hours after the allergen challenge, was repeated 2 to 6 weeks later. The repeated DYAR (P < .001) was supplemented with blood cell counts and measurement of serum concentrations of soluble adhesion molecules by an enzyme linked immunoassay. RESULTS: The prechallenge concentrations of soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cell adhesion molecule 1 (sVCAM-1), soluble platelet endothelial cell adhesion molecule (sPECAM 1), soluble E-selectin, soluble L-selectin, soluble P-selectin, and soluble E cadherin did not differ significantly from healthy controls. The DYAR was associated with the following changes in the serum: an increase of sICAM-1 at 6 and 12 hours and a decrease at 24 hours; an increase of sVCAM-1 at 24 and 36 hours; an increase of sPECAM-1 at 36 and 48 hours and a decrease at 56 and 72 hours; an increase of soluble E-selectin at 56 hours; an increase of soluble L selectin at 56 and 72 hours; a decrease of soluble E-cadherin at 48 and 56 hours; and increased counts of blood leukocytes at 36, 48, and 56 hours, neutrophils at 24, 36, 48, and 56 hours, lymphocytes at 24, 36, and 48 hours, and monocytes at 6, 12, and 24 hours. The Th1/Th2 ratio in blood increased at 24, 36, 48, and 56 hours. The intracellular concentration of interferon gamma, but not of interleukin 4, increased at 24, 36, 48, and 56 hours. CONCLUSIONS: These results provide evidence of the involvement of neutrophils, Th1 lymphocytes, monocytes, platelets, and endothelial cells, upon participation of various adhesion molecules, in mechanisms(s) underlying the clinical DYAR. PMID- 21277515 TI - Posttussive emesis as a symptom of asthma in children. AB - BACKGROUND: Emesis can be triggered by cough in children, and cough is a common symptom of asthma. OBJECTIVE: To explore the association between posttussive emesis and asthma in the pediatric population. METHODS: A questionnaire was distributed to parents of children between the ages of 2 and 17 years in the pediatric and allergy-immunology clinics at our institution from August 16 through November 3, 2008. Prevalence of posttussive emesis was determined and compared among children with physician-diagnosed asthma, children with no evidence of asthma, and those not formally diagnosed as having asthma but with surrogate markers suggestive of asthma. The predictive value of posttussive emesis was compared with those of known markers of asthma. The prevalence of gastroesophageal reflux and pertussis was evaluated because these conditions might also cause posttussive emesis. RESULTS: The prevalence of posttussive emesis was 33% in our study population of 500 children. Among those with physician-diagnosed asthma (n = 122), 56% reported a history of posttussive emesis. For patients not formally diagnosed as having asthma but with surrogate markers suggestive of asthma (n = 62), 71% had a history of posttussive emesis. Both of these were significantly higher than in those with no evidence of asthma (n = 316), in whom 16% reported a history of posttussive emesis (P < .0005). Children with posttussive emesis were significantly more likely to have asthma than those without posttussive emesis (odds ratio, 7.9; 95% confidence interval, 5.2-12). Neither pertussis nor gastroesophageal reflux accounted for the degree of posttussive emesis reported. CONCLUSIONS: Posttussive emesis is more common among children with asthma than among nonasthmatic children. In children with cough and a history of posttussive emesis, asthma should be strongly considered in the differential diagnosis. PMID- 21277514 TI - Association of maternal anemia with increased wheeze and asthma in children. AB - BACKGROUND: Increasing interest has focused on maternal nutrition and micronutrient status during pregnancy and respiratory disease development in the offspring. OBJECTIVE: To examine the relationship between maternal anemia in pregnancy with wheeze and asthma in early childhood. METHODS: The cohort included children of women followed through pregnancy and recontacted when the child was 6 years of age to evaluate respiratory health. Exposure was assessed using maternal anemia diagnosis and hemoglobin (Hgb) < 11 during delivery hospitalization. Study outcomes include wheezing in early childhood; patterns of wheeze from birth to age 6 (early-onset transient wheeze; late-onset wheeze; early-onset persistent wheeze); and diagnosis of childhood asthma. RESULTS: Maternal anemia was reported by 11.9% of mothers and was associated with recurrent infant wheeze in the first year (adjusted odds ratio [ORa] = 2.17, 95% confidence interval [CI] 1.18, 4.00), wheezing before age 3 (Ora = 2.42, 95% CI 1.38, 4.23), and early-onset transient and early-onset persistent wheeze patterns (Ora = 2.81, 95%CI 1.38, 5.72, and Ora = 2.07, 95% CI 1.02, 4.22), respectively. Among children of mothers with asthma, maternal anemia was associated with recurrent wheeze in year 1 (Ora = 4.22, 95% CI 1.65, 10.80) and wheeze before age 3 (Ora = 2.73, 95% CI 1.17, 6.35). Offspring of mothers with asthma also had increased odds of asthma diagnosis (Ora = 2.53, 95% CI 1.04, 6.17) and current asthma (Ora = 3.46, 95% CI 1.45, 8.26). CONCLUSIONS: Maternal anemia during pregnancy is associated with infant respiratory health outcomes. If this observation is replicated, maternal anemia may be a target for intervention and future research. PMID- 21277516 TI - Olea europaea pollen counts and aeroallergen levels predict clinical symptoms in patients allergic to olive pollen. AB - BACKGROUND: Allergic symptoms are commonly related to atmospheric pollen counts in sensitized allergic individuals. However, concordance between symptoms, pollen counts, and aeroallergen concentrations is not always good. OBJECTIVES: To determine the correlation between olive pollen counts, aeroallergen levels, and clinical symptoms in patients with allergic asthma or rhinitis in Ciudad Real (Spain). METHODS: Two types of samplers were used to determine pollen exposure: a Burkard spore trap to collect pollen grains and a high-volume air sampler to collect airborne particles. A total of 366 air filters were collected. After extraction, they were analyzed by specific immunoglobulin E enzyme-linked immunosorbent assay inhibition using a serum pool containing high titers of olive specific immunoglobulin E. Twenty olive-pollen monosensitized patients were asked to record their daily symptoms before, during, and after the olive pollen season. RESULTS: Olive pollen was detected between April 21 and June 30, 2004. Symptoms showed positive and significant correlations with pollen counts (r = 0.700, P < .001) and aeroallergen levels (r = 0.803, P < .001). Using a Poisson regression model, relative changes in aeroallergen concentrations and pollen counts were found to be similar and significant. Threshold levels for the induction of symptoms were 162 olive pollen grains/m(3) and 22.7 ng of olive pollen allergen/m(3) (equivalent to 0.9 ng/m(3) of Ole e 1). CONCLUSIONS: Olive aeroallergen concentrations and pollen counts are positively associated with symptoms of rhinitis and asthma in olive-allergic patients. Both data may be used in the clinical follow-up of these patients. PMID- 21277517 TI - Analysis of allergen specific IgE cut points to cat and dog in the Childhood Allergy Study. AB - BACKGROUND: The application of a single allergen specific IgE (sIgE) cut point, such as 0.35 kU/L, to determine sensitization for all allergens may be suboptimal. OBJECTIVES: To analyze self-reported symptoms suggestive of dog and cat allergy in relation to the test performance characteristics of low level, but reliably detectable, sIgE and to compare these cut points to the traditional 0.35 kU/L cut point. METHODS: Interviews and blood samples were collected among 564 young adult participants of a general risk birth cohort. Data collected from the participants' parents were analyzed as validation populations. A history of symptoms consistent with allergy on exposure to pets was obtained by standardized questionnaire. Allergen sIgE levels for dog and cat were evaluated with Pharmacia CAP. Receiver operating characteristic curves were constructed and the performance characteristics of the traditional sIgE cut point of 0.35 kU/L were compared with cut points as low as 0.1 kU/L. RESULTS: Using the Youden J criteria, based on the highest sum of sensitivity and specificity for a diagnostic test, cut points of 0.12 kU/L for cat and 0.2 kU/L for dog were identified as performing optimally among the participant population. In 2 validation populations, consisting of the participants' mothers and fathers, the performance of these alternative cut points were superior or similar to the traditional 0.35-kU/L sIgE level. CONCLUSIONS: Accurately measured sIgE at levels approaching the lower limit of detection of current assays may be useful in confirming sensitization. Optimal clinical application of these tests will continue to require careful integration of the result and the strength of the patient's history. PMID- 21277518 TI - Risk factors for systemic reactions to bee venom in British beekeepers. AB - BACKGROUND: There is a high incidence of systemic reactions (SRs) to bee stings in beekeepers, but the factors predisposing individuals to such responses are not well understood. OBJECTIVES: To identify factors that predispose British beekeepers to SRs and to investigate how beekeepers access specialist services after SRs to bee venom. METHODS: A link to an online survey was published in the bimonthly magazine and on the Web site of the British Beekeepers Association. The demographic results are presented using descriptive analysis, and a logistic regression model was used to determine risk factors for SRs. RESULTS: There were 852 responses to the questionnaire of which 63% were from male beekeepers; the most common age range was 51 to 60 years. Twenty-eight percent of all responders had experienced a large local reaction and 21% had experienced a SR. Factors that predisposed beekeepers to SRs included female sex, having a family member with bee venom allergy, more than 2 years of beekeeping before a SR, and premedication with an antihistamine before attending the hives. A total of 44% of beekeepers with SRs attended the emergency department because of their symptoms, 16.6% were reviewed by an allergy specialist, and only 18% carried an adrenaline autoinjector. CONCLUSIONS: Logistic regression analysis identified a number of novel factors to be associated with the development of SRs. Rates of attendance at the emergency department, allergy specialist review, and carriage of adrenaline were low, highlighting a need for education in the beekeeping community and among health care professionals. PMID- 21277519 TI - Should fracture risk influence our decision making in asthma care? PMID- 21277520 TI - Semi-self-administered ear acupressure for persistent allergic rhinitis: a randomised sham-controlled trial. PMID- 21277521 TI - Generalized urticaria after ingestion of Raphanus sativus. PMID- 21277522 TI - Association of genetic variants of CD14 with peanut allergy and elevated IgE levels in peanut allergic individuals. PMID- 21277523 TI - Prescription patterns of long-acting beta-agonist monotherapy for patients with asthma. PMID- 21277524 TI - Systemic contact allergy to penicillin after prick and intradermal tests. PMID- 21277525 TI - Autologous plasma skin test. PMID- 21277526 TI - Dietary prevention, control, and protection toward allergic disorders: a word in favor of immunobiotics. PMID- 21277527 TI - Intranasal antihistamines in the treatment of allergic rhinitis. PMID- 21277528 TI - The economic impact of allergic rhinitis and current guidelines for treatment. AB - OBJECTIVE: To describe the economic burden of allergic rhinitis treatment and current guidelines for treatment. DATA SOURCES: Review articles and original research were retrieved from MEDLINE, OVID, PubMed (1950-November 2009), personal files of articles, and bibliographies of located articles that addressed the topic of interest. STUDY SELECTION: Articles were selected for their relevance to the burden of allergic rhinitis and current guidelines for treatment. Publications included reviews, treatment guidelines, and clinical studies. RESULTS: Despite the common symptoms of allergic rhinitis, its impact on patient quality of life, and the huge cost to society and individuals of treatment, including pharmacotherapy, many patients do not adhere to their medication regimens because the medications do not adequately address their symptoms or are otherwise problematic for them to use. CONCLUSIONS: The economic impact of allergic rhinitis is substantial; the total direct medical cost of allergic rhinitis is approximately $3.4 billion, with almost half of this cost attributable to prescription medications. Multiple treatment options are available, and these were reviewed to provide an update on effectiveness and adverse effects that may affect patient adherence. PMID- 21277529 TI - Suggested updated approaches to patient management. PMID- 21277530 TI - The basics of histamine biology. AB - OBJECTIVE: To review the evolution of our understanding of the basics of histamine biology as it pertains to the treatment of allergic rhinitis. DATA SOURCES: Review articles and original research were retrieved from MEDLINE, OVID, PubMed (1950 to November 2009), personal files of articles, and bibliographies of located articles that addressed the topic of interest. STUDY SELECTION: Key articles were selected that, taken together, provide a history of scientific insight into histamine biology and receptors and mechanism of action of antihistamines. Publications included reviews, treatment guidelines, and clinical studies (primarily randomized controlled trials) of both children and adults. RESULTS: The seminal work on histamine was published in 1910, but histamine was not identified as a mediator of anaphylactic reactions until 1932. Research later showed that histamine is a major mediator responsible for the symptoms of allergic rhinitis, with its activities mediated through 4 G protein-coupled receptors. Most of histamine's effects are exerted through the H1 receptor, but some effects are through the H2 and H3 receptors, and possibly also through the H4 receptor. CONCLUSIONS: We hope that the progress made in understanding the mechanism of action of the histamine response will lead to better targeted treatment options. PMID- 21277531 TI - The efficacy of intranasal antihistamines in the treatment of allergic rhinitis. AB - OBJECTIVES: To discuss the new use of intranasal antihistamines as first-line therapies, compare and contrast this class of medication with the traditionally available medications, and discuss the potential for intranasal antihistamines to provide relief superior to second-generation oral antihistamines. DATA SOURCES: Review articles and original research articles were retrieved from MEDLINE, OVID, PubMed (1950 to November 2009), personal files of articles, and bibliographies of located articles that addressed the topic of interest. STUDY SELECTION: Articles were selected for their relevance to intranasal antihistamines and their role in allergic rhinitis. Publications included reviews, treatment guidelines, and clinical studies (primarily randomized controlled trials) of both children and adults. RESULTS: This panel was charged with reviewing the place of intranasal antihistamines in the spectrum of treatment for allergic rhinitis. Intranasal antihistamines have been shown in numerous randomized, placebo-controlled trials to be more efficacious than the oral antihistamines. Although intranasal corticosteroids are considered by some to be superior to intranasal antihistamines, multiple studies have shown an equal effect of the 2 classes of medication. Both intranasal corticosteroids and intranasal antihistamines have been shown to reduce all symptoms of allergic rhinitis. In addition, some intranasal antihistamines have a more rapid onset of action than intranasal corticosteroids. CONCLUSIONS: The future of allergy treatment will likely involve a combination of both intranasal corticosteroids and intranasal antihistamines because of the benefits of local administration and their additive effect on efficacy. PMID- 21277532 TI - Melanoma. Introduction. PMID- 21277533 TI - Epidemiology of melanoma. AB - Malignant melanoma represents a significant and growing public health burden in the US and worldwide. It is estimated that 68, 130 cases of invasive malignant melanoma and at least 48,000 cases of melanoma in-situ will be diagnosed in the US this year. Melanoma is also one of the few remaining cancers with increasing US incidence. In the 1930s, the lifetime risk of an American developing invasive malignant melanoma was 1 in 1,500. Currently, that risk is 1 in 59. Deaths from malignant melanoma are also increasing. The mortality rate from malignant melanoma has risen about 2% annually since 1960. This year, it is estimated that 8,700 Americans will die from this cancer. The identification of individuals at high risk for malignant melanoma is important for the development of focused and efficient prevention efforts. Acute sun exposure resulting in sunburn remains a significant risk factor for the development of melanoma, but numerous other potential risk factors have been cited. Included among these are atypical mole syndrome/dysplastic nevus syndrome, blistering sunburns, immunosuppression, prior therapy with psoralen with ultraviolet A light (UVA) light, UV exposure at tanning salons, elevated socioeconomic status, and history of melanoma in a first degree relative. With a better understanding of the reasons for the increasing rate of this cancer, and with enhanced early detection approaches, we may be able to decrease the incidence and mortality of malignant melanoma. PMID- 21277534 TI - Pathways to melanoma. AB - Melanoma is one of the most aggressive and yet poorly understood of human malignancies. Advances in genomics has allowed a more nuanced understanding of the disease, moving beyond the traditional dysplastic nevus-to-melanoma model and identifying multiple divergent oncogenic pathways leading to melanoma. An understanding of the molecular mechanisms driving melanoma has opened the doors for the development of targeted therapeutic approaches. As we enter the era of personalized medicine, it will be critical for clinicians to both appreciate and be able to determine the molecular profile of their patients' melanoma because this profile will guide risk stratification, genetic counseling, and treatment customization. A review of the divergent pathways of melanoma development is presented here, with a particular emphasis on recently identified mutations, and their implications for patient care. PMID- 21277535 TI - Dermoscopy of benign and malignant neoplasms in the pediatric population. AB - Dermoscopy is a noninvasive technique that enables visualization of subsurface colors and structures within the skin that are imperceptible to the naked eye. The dermatoscope allows the physician to examine both the macroscopic and microscopic primary morphology of skin lesions, identify subtle clinical clues, confirm naked-eye clinical diagnoses, and monitor treatment progress while posing little threat to the young patient. Dermoscopic findings have been formulated into diagnostic criteria that assist experienced clinicians in differentiating benign and malignant neoplasms. In this review, clinical morphology of melanocytic nevi and melanoma in the pediatric population is examined and the relevant dermoscopic findings and histopathologic correlates that aid in the diagnosis and management of these lesions are described. PMID- 21277536 TI - Office management of melanoma patients. AB - As the incidence of melanoma continues to increase, so does the role of the dermatologist as both medical and surgical oncologist for these patients. The dermatologist holds a key role in all phases of care, including prevention, diagnosis, treatment, and follow-up. The dermatologist is best trained to complete a full and thorough skin examination and is best able to recognize a melanoma in its early stages of growth. Dermatologists have a unique opportunity to prevent melanoma through appropriate patient education concerning sun protection, self skin examinations, and the ABCDEs of melanoma recognition (ie, asymmetry, border irregularity, color variations, dimension and evolution). The dermatologist is well trained to obtain an appropriate full-thickness skin biopsy and is knowledgeable to interpret the pathologist report and understand the significance of the various histologic prognostic indexes. Most patients present with localized disease and with thinner Breslow depth and thus can be skillfully treated in an outpatient setting under local anesthesia by a dermatologist. PMID- 21277537 TI - Sentinel node biopsy for melanoma: an update after two decades of experience. AB - When detected and treated early, melanoma has an excellent prognosis. Unfortunately, as the tumor invades deeper into tissue the risk of metastatic spread to regional lymph nodes and beyond increases and the prognosis worsens significantly. Therefore, accurately detecting any regional lymphatic metastasis would significantly aid in determining a patient's prognosis and help guide his or her treatment plan. In 1991, Don Morton and colleagues presented new paradigm in diagnosing regional lymphatic involvement of tumors termed sentinel lymph node biopsy (SLNB). By mapping the regional lymph system around a tumor and tracing the lymphatic flow, a determination of the most likely lymph node or nodes the cancer will spread to first is made. Then, a limited biopsy of the most likely nodes is performed rather than a more-invasive removal of the entire local lymphatic chain. In 20 years that have followed, a great deal of information has been gained as to its accuracy, prognostic value, appropriate candidates, and its impact on regional disease control and survival. The SLNB has been shown to accurately stage regional lymph node basins in stage I and II melanoma patients with minimal morbidity. More sensitive histologic techniques are now being applied that may allow even greater accuracy in the staging of melanoma patients. Although specific percent risk thresholds are still in question, recommendation for SLNB when melanomas are 1 mm or thicker has gained wide acceptance. SLNB may also be appropriate for patients with melanomas that are between 0.76 and 1 mm thick and have ulceration, high mitotic rates, or reach a Clark level IV. Therefore, melanomas with IB or greater staging should be considered for SLNB. PMID- 21277538 TI - New therapeutic options in the medical management of advanced melanoma. AB - During the past 3 decades, the incidence, morbidity, and mortality of malignant melanoma have increased dramatically. Advanced melanoma has remained a disease that is for the most part incurable and has challenged all therapeutic efforts to make a dent in its natural history. Recent advances in the understanding of the molecular alterations in melanoma and in the immunologic mechanisms playing a role in this malignancy have brought hope that significant progress can be achieved, as evidenced by early encouraging clinical data. This review will summarize these recent developments and their impact on current clinical practice. PMID- 21277539 TI - Managing melanoma in situ. AB - Melanoma is a highly aggressive skin cancer with an increasing incidence. Melanoma in situ is an early, non-invasive form in which the tumor is confined to the epidermis. Treatment of melanoma in situ is challenging due to the frequent subclinical microscopic spread and to the presentation on the head and neck in cosmetically sensitive areas with chronic sun damage. Optimizing tumor eradication is imperative to reduce the potential progression into invasive disease and metastasis, all while maintaining cosmesis. Multiple treatment regimens have been implemented for managing difficult melanoma in situ tumors. We provide a thorough review of surgical, and non-surgical, management of melanoma in situ which can pose therapeutic dilemmas due to size, anatomic location, and subclinical spread. PMID- 21277540 TI - FDA guidance helps facilitate drug co-development. PMID- 21277541 TI - Reducing xerostomia through advanced technology. PMID- 21277542 TI - Mood disorders in patients with cancer. PMID- 21277543 TI - Retraction--Validation of gene signatures that predict the response of breast cancer to neoadjuvant chemotherapy: a substudy of the EORTC 10994/BIG 00-01 clinical trial. PMID- 21277545 TI - HPV types in early-onset cervical cancer. PMID- 21277546 TI - Whole-brain radiotherapy in primary CNS lymphoma. PMID- 21277547 TI - Imatinib discontinuation: realistic for patients with chronic myeloid leukaemia achieving complete molecular remission? PMID- 21277549 TI - Bortezomib-induced peripheral neuropathy: facts and genes. PMID- 21277551 TI - Networking: the new social revolution in health care. PMID- 21277552 TI - New driver mutations in non-small-cell lung cancer. AB - Treatment decisions for patients with lung cancer have historically been based on tumour histology. Some understanding of the molecular composition of tumours has led to the development of targeted agents, for which initial findings are promising. Clearer understanding of mutations in relevant genes and their effects on cancer cell proliferation and survival, is, therefore, of substantial interest. We review current knowledge about molecular subsets in non-small-cell lung cancer that have been identified as potentially having clinical relevance to targeted therapies. Since mutations in EGFR and KRAS have been extensively reviewed elsewhere, here, we discuss subsets defined by so-called driver mutations in ALK, HER2 (also known as ERBB2), BRAF, PIK3CA, AKT1, MAP2K1, and MET. The adoption of treatment tailored according to the genetic make-up of individual tumours would involve a paradigm shift, but might lead to substantial therapeutic improvements. PMID- 21277553 TI - Bob Edwards and the first decade of Reproductive BioMedicine Online. PMID- 21277554 TI - [Inflammatory myofibroblastic tumour of the tonsil: case report and literature review]. AB - Inflammatory myofibroblastic tumour (inflammatory pseudotumor) is an idiopathic lesion, rare in the head and neck, of unknown aetiology. It is primarily a soft tissue, lung and orbital condition. In the world literature, only two cases with tonsillar disease have been found. We report a case of a 10-year-old girl admitted to our hospital with clinical complaints of pain in the neck region, cough with vomiting, dyspnoea and dyslexia. Clinical examination revealed halitosis and a neoformation dependent on the left tonsil. Bilateral tonsillectomy was performed. PMID- 21277555 TI - [Ligation of the sphenopalatine artery in posterior epistaxis. Retrospective study of 50 patients]. AB - OBJECTIVES: The aim of this study was to evaluate the efficacy of endoscopic ligation of the sphenopalatine artery in the treatment of severe posterior epistaxis. METHODS: We have carried out a retrospective study on 50 patients hospitalised with posterior recurrent epistaxis, in whom posterior nasal packing was not effective. All of them underwent surgical treatment, with endoscopic ligation of the sphenopalatine artery to control the epistaxis. RESULTS: Only seven patients had a new epistaxis after surgery. One of them is being studied for some kind of coagulopathy, another patient was controlled by ligation of the anterior ethmoidal artery and it was necessary to ligate the contralateral sphenopalatine artery in a third patient. The other four patients were controlled with posterior nasal packing and discharged two days after surgery, without any complications. CONCLUSIONS: We believe that endoscopic ligation of the sphenopalatine artery is a safe technique, with fewer complications than other methods such as posterior packing or embolisation. PMID- 21277556 TI - [Association between cerebrospinal fluid leakage and persistence of Sternberg's canal: coincidence or cause?]. AB - Endoscopic surgical techniques allow treating various pathological diseases of the cranial base, including cerebrospinal fluid leaks (CSF). These approaches have a high success rate and reduce surgical time and morbidity. However, when they are located in the lateral wall of the sphenoid, the surgery is more complex. In our case, the CSF appeared to be related with a Sternberg's canal. Predisposing factors were also associated with an extensive unilateral pneumatization of the sinus and benign intracranial hypertension. The closure of the leak was achieved using an endoscopic transethmoidal transpterygoid approach for proper exposition of the lateral wall of the sphenoid. After five years of monitoring, the patient has had no more episodes of rhinoliquorrhea. PMID- 21277557 TI - Outcomes of birdshot chorioretinopathy treated with an intravitreal sustained release fluocinolone acetonide-containing device. AB - PURPOSE: To evaluate outcomes in birdshot chorioretinopathy following intravitreal implantation of a fluocinolone acetonide-containing drug delivery device. DESIGN: Retrospective, multicenter, interventional case study. METHODS: University- and community-based tertiary care. Twenty-two HLA-A29+ birdshot patients (36 eyes) were implanted with a sustained-release corticosteroid device and followed for up to 3 years. Main outcome measures were Snellen acuity, intraocular inflammation, adjunctive therapy, cataract, ocular hypertension, or glaucoma. Paired Wilcoxon statistics were used to analyze visual acuities; paired McNemar statistics were used to analyze presence or absence of other outcomes. RESULTS: Nineteen of 22 patients (32 eyes) completed 12 months of follow-up with improvement in median visual acuity (P=.015). Prior to implantation, 18 of 22 patients (82%) received immunosuppressive therapy versus 1 of 19 (5%) by 12 months (P<.001). Eyes with zero vitreous haze increased from 7 of 27 scored eyes (26%) at baseline to 30 of 30 eyes (100%) by 12 months (P<.001). Cystoid macular edema decreased from 13 of 36 eyes (36%) at baseline to 2 of 32 eyes (6%) at 12 months (P=.006). Five of 24 phakic eyes at baseline exited the study before surgery; all other eyes received cataract surgery. One hundred percent of study eyes had ocular hypertension, required intraocular pressure-lowering therapy, or had glaucoma surgery by 12 months. CONCLUSIONS: Implantation of a fluocinolone acetonide-containing intraocular device in birdshot chorioretinopathy can improve vision, control inflammation, and eliminate systemic therapy. There is a high incidence of cataract progression and intraocular hypertension or glaucoma. PMID- 21277558 TI - [Study of the intronic polymorphism of the angiotensin 1 converting enzyme among coronary Tunisians]. AB - BACKGROUND: The acute coronary syndromes (ACS) are classified among the major causes of mortality in the industrialized countries. The increased angiotensin I converting enzyme (ACEI) activity related to a genetic polymorphism constitutes a hereditary predisposition to these syndromes. AIM: Evaluate the ACEI activity in Tunisian patients with coronary heart disease, and investigate the association between this activity and an intronic deletion of 287 pb on the intron 16 of the ACEI gene. PATIENTS AND METHODS: Seventy-two coronary patients and 34 control subjects are recruited for our study. ACEI activity was measured by kinetic method. The intronic deletion was identified by PCR technique. RESULTS: An increased activity of ACEI was observed in patients compared with control subjects (84.38 +/- 33.83 UI/L vs 59.06 +/- 18.2 UI/L, P=10(-5)). The molecular study showed a raised relative frequency of D/D genotype (51.4%) among patients, whereas among the witnesses, I/I genotype prevailed (62%). D/D genotype is always associated with highest ACEI activity for the patients and the control subjects. CONCLUSION: The molecular studies and the biochemical investigations of the various parameters of cardiovascular risk (including the ACEI) direct towards a better treatment. PMID- 21277559 TI - [Tubercular myocarditis: two case reports and review of the literature]. AB - We report here the cases of two patients developing tubercular myocarditis with a different clinical presentation, the first one with a myopericarditis, the second one presenting as pseudo-infarction complicated by cardiogenic shock. We discuss here the different anatomical and clinical presentations, the diagnostic approach, the indications of myocardic biopsy and the prognosis of this pathology. PMID- 21277561 TI - [The QT interval: standardization, limits and interpretation]. AB - Despite clinical importance of ventricular repolarisation, it remains difficult to analyse. Conventionally, quantification of the electrocardiographic ventricular repolarization is usually performed with reference to axis of the T wave and QT interval duration. A variety of factors can prolong the QT interval, such as drug effects, electrolyte imbalances, and myocardial ischemia. The biggest risk with prolongation of the QT interval is the development of torsades de pointes. Commonly accepted reference ranges for the electrocardiogram (ECG) have been in use, with little change, for many years. Populations throughout the world present several differences: age, ethnic compositions, and are exposed to different environmental factors. Recent studies have reported reference data for QT interval in healthy population and have evaluated the influence of age, gender, QRS duration and heart rate on this interval. In this review, we address several issues relative to the measurement, and interpretation of QT interval and its adjustment for rate, age, gender and QRS duration. PMID- 21277560 TI - Calcified disease of the mitral annulus: a spectrum of an evolving disease. AB - Mitral annulus calcification may appear under different forms depending from its evolution stage: mitral annulus calcification; homogeneous calcified mass of the mitral valve; liquefaction necrosis of the mass; reduction or stability of the mass dimension. We report a large calcified mass located in between the posterior mitral valve leaflet and adjacent left ventricular myocardium suggesting the homogeneous calcified phase of the disease. PMID- 21277562 TI - [Bilateral popliteal artery complications of multiple hereditary exostosis]. AB - The osseous exostose is a rare benign tumor of the bone from which the vascular complications can be of venous or arterial order, are translated in various boards. We report the case of a young adult who presents a forgery aneurysm of the right popliteal artery with the popliteal artery booby-trapped to the left. The patient benefited from surgical treatment with good clinical and radiological evolution. PMID- 21277563 TI - [Heart failure and anaphylactic shock. A report of two cases]. AB - Anaphylactic shock can sometimes take the appearance of heart failure, in relation to an acute coronary syndrome, even with normal coronary arteries, that we illustrate by two observations. We firstly report the case of an anaphylactic shock caused by succinylcholine, after anesthesia induction for inguinal hernia surgery in a 50-year-old man with cardiovascular risks, who presented with ventricular fibrillation followed by a cardiac arrest. An acute and severe anterior coronary syndrome was suspected and treated with thrombolysis. Then the electrocardiogram normalized, as well as the left ventricular function. No significant coronary stenosis was retrospectively revealed by coronarography, and a severe coronary vasospasm induced by the anaphylactic reaction was confirmed. We also describe the case of an anaphylactoid shock caused by cisatracurium infusion, that occurred at the beginning of an adnexectomy in a 55-year-old woman without any particular history. She presented with a cardiogenic shock after intravenous administration of epinephrine. The echocardiograpghic evaluation pointed out an aspect of stress-induced cardiomyopathy, and the coronarography showed normal coronary arteries. The left ventricular dysfunction completely normalized, strongly suggesting the diagnosis of Takotsubo-like syndrome after the anaphylactic shock and its treatment. Both of these cases point out the major interest of cardiologic and allergic evaluation in case of heart failure during general anesthesia. Coronary vasospasm and stress-induced cardiomyopathy are two pathologies that may be observed during anaphylactic shock, and their diagnosis should be considered after elimination of coronary thrombosis. PMID- 21277564 TI - Evaluation of thermal and moisture management properties on knitted fabrics and comparison with a physiological model in warm conditions. AB - This study reports on an experimental investigation of physical properties on the textile thermal comfort. Textile properties, such as thickness, relative porosity, air permeability, moisture regain, thermal conductivity, drying time and water-vapour transmission rate have been considered and correlated to the thermal and vapour resistance, permeability index, thermal effusivity and moisture management capability in order to determine the overall comfort performance of underwear fabrics. The results suggested that the fibre type, together with moisture regain and knitted structure characteristics appeared to affect some comfort-related properties of the fabrics. Additionally, thermal sensations, temperature and skin wetness predicted by Caseto(r) software for three distinct activity levels were investigated. Results show that the data obtained from this model in transient state are correlated to the thermal conductivity for the temperature and to Ret, moisture regain and drying time for the skin wetness. This provides potential information to determine the end uses of these fabrics according to the selected activity level. PMID- 21277565 TI - Fate of fluoride-induced subameloblastic cysts in developing hamster molar tooth germs. AB - White opacities and pits are developmental defects in enamel caused by high intake of fluoride (F) during amelogenesis. We tested the hypothesis that these enamel pits develop at locations where F induces the formation of sub ameloblastic cysts. We followed the fate of these cysts during molar development over time. Mandibles from hamster pups injected with 20mg NaF/kg at postnatal day 4 were excised from 1h after injection till shortly after tooth eruption, 8 days later. Tissues were histologically processed and cysts located and measured. Cysts were formed at early secretory stage and transitional stage of amelogenesis and detected as early 1h after injection. The number of cysts increased from 1 to almost 4 per molar during the first 16h post-injection. The size of the cysts was about the same, i.e., 0.46+/-0.29*10(6)MUm(3) at 2h and 0.50+/-0.35*10(7)MUm(3) at 16h post-injection. By detachment of the ameloblasts the forming enamel surface below the cyst was cell-free for the first 16h post-injection. With time new ameloblasts repopulated and covered the enamel surface in the cystic area. Three days after injection all cysts had disappeared and the integrity of the ameloblastic layer restored. After eruption, white opaque areas with intact enamel surface were found occlusally at similar anatomical locations as late secretory stage cysts were seen pre-eruptively. We conclude that at this moderate F dose, the opaque sub-surface defects with intact surface enamel (white spots) are the consequence of the fluoride-induced cystic lesions formed earlier under the late secretory-transitional stage ameloblasts. PMID- 21277566 TI - Acute hydrocortisone treatment increases anxiety but not fear in healthy volunteers: a fear-potentiated startle study. AB - BACKGROUND: The debilitating effects of chronic glucocorticoids excess are well known, but comparatively little is understood about the role of acute cortisol. Indirect evidence in rodents suggests that acute cortisone could selectively increase some forms of long-duration aversive states, such as "anxiety," but not relatively similar, briefer aversive states, such as "fear." However, no prior experimental studies in humans consider the unique effects of cortisol on anxiety and fear, using well-validated methods for eliciting these two similar but dissociable aversive states. The current study examines these effects, as instantiated with short- and long-duration threats. METHODS: Healthy volunteers (n = 18) received placebo or a low (20 mg) or a high (60 mg) dose of hydrocortisone in a double-blind crossover design. Subjects were exposed repeatedly to three 150-sec duration conditions: no shock; predictable shocks, in which shocks were signaled by a short-duration threat cue; and unpredictable shocks. Aversive states were indexed by acoustic startle. Fear was operationally defined as the increase in startle reactivity during the threat cue in the predictable condition (fear-potentiated startle). Anxiety was operationally defined as the increase in baseline startle from the no shock to the two threat conditions (anxiety-potentiated startle). RESULTS: Hydrocortisone affected neither baseline nor short-duration, fear-potentiated startle but increased long duration anxiety-potentiated startle. CONCLUSIONS: These results suggest that hydrocortisone administration in humans selectively increases anxiety but not fear. Possible mechanisms implicated are discussed in light of prior data in rodents. Specifically, hydrocortisone might increase anxiety via sensitization of corticotrophin-releasing hormones in the bed nucleus of the stria terminalis. PMID- 21277567 TI - Chronic low-grade inflammation in elderly persons is associated with altered tryptophan and tyrosine metabolism: role in neuropsychiatric symptoms. AB - BACKGROUND: Neuropsychiatric symptoms are common complaints of elderly persons. Recent data suggest that chronic low-grade inflammation, a fundamental characteristic of aging, plays a role. Effects might rely on the influence of inflammation on the activity of two enzymatic pathways, the indoleamine-2,3 dioxygenase (IDO) and the guanosine-triphosphate-cyclohydrolase-1 (GTP-CH1) pathways, which are involved in the biosynthesis of monoamines. The present study assessed this possibility in 284 healthy elderly subjects drawn from the Three City cohort. METHODS: Assays included the measurement of serum interleukin-6 and C-reactive-protein, as inflammatory markers; tryptophan, kynurenine, and their ratio as index of IDO activity; and neopterin, phenylalanine, tyrosine, and nitrite, as markers of GTP-CH1 activity. In addition, structured assessments of depressive symptomatology, fatigue, and general behavioral/neurovegetative symptoms were performed. RESULTS: As expected, age correlated significantly with concentrations of immune markers and neuropsychiatric symptoms. Increased inflammation was related to reduced tryptophan concentrations and increased kynurenine levels, suggestive of IDO-induced increased tryptophan catabolism. In addition, inflammation was associated with increases in neopterin and nitrite levels and in phenylalanine concentrations at the expense of tyrosine. Interestingly, increased tryptophan catabolism was associated with the depressive symptoms of lassitude, reduced motivation, anorexia, and pessimism. In contrast, variations in markers of GTP-CH1 activity correlated more with neurovegetative symptoms, including sleep disturbance, digestive symptoms, fatigue, sickness, and motor symptoms. CONCLUSIONS: These findings show that chronic low-grade inflammation in aging is associated with alterations in enzymatic pathways involved in monoamine metabolism and suggest that these alterations might participate in the pathophysiology of neuropsychiatric symptoms in elderly persons. PMID- 21277570 TI - [IGF II expressing malignant giant solitary fibrous tumour of the liver]. PMID- 21277571 TI - [Factors that influence interdepartmental referrals between Surgical Departments and Internal Medicine]. AB - INTRODUCTION: To analyse the long term outcome of the age and comorbidity of patients admitted to Surgical Departments, the number of referrals to Internal Medicine made by these Departments, and to assess whether there are seasonal variations and the call/reject effect. MATERIAL AND METHODS: We compared the age, Charlson Comorbidity Index (CCI), and the number of referrals made by Traumatology, General Surgery and Urology of patients discharged in 2000, with those discharged in 2007. Seasonal variations and the call/reject effect were studied by analysing all the interdepartmental referrals made by all the surgical departments from the year 2000 to 2007. RESULTS: Age increased by 5.6% between 2000 and 2007, the CCI by 5.8%, and interdepartmental referrals by 60%. Interdepartmental referrals decreased in July and August, whilst they increased in January, February, June and October, up to 64% more in January, although with variations of almost 50% in the same month. We detected differences of up to 68.2% in the referrals requested to different physicians. CONCLUSIONS: We observed a sharp increase in the requests for referral to Internal Medicine by Surgical Departments of our hospital, which is not explained by the increase in admissions to these Departments, and which could be associated with the increase in age and comorbidity of their patients. Requests for interdepartmental referral have marked monthly variations and also as regards the Consulting Physician. PMID- 21277572 TI - [Supercharged ileocoloplasty: an option for complex oesophageal reconstructions]. AB - INTRODUCTION: Oesophageal reconstruction in a second time is a complex surgical operation which, in some cases, requires combining microvascular techniques to increase vascular flow to the conduit. "Supercharged" ileocoloplasty allows creation of a longer conduit that makes it possible to replace the entire oesophagus. We describe our initial experience with this technique for the total reconstruction of the oesophagus. MATERIAL AND METHODS: A retrospective review of the period from October 2007 to December 2009 identified 4 patients on whom a deferred oesophageal reconstruction was performed with a "supercharged" ileocoloplasty. The indications of this technique, morbidity and mortality, as well as functional results during follow up were evaluated. RESULTS: The indications of this technique were: previous failure of a left colon interposition (1), oesophageal disconnection due to a gastro-pleural fistula (1), total oesophagogastrectomy (1) and partial oesophagogastrectomy (1) due to the ingestion of caustic substances, respectively. Gastrointestinal complications were the most frequent. Two cervical fistulas were diagnosed which were resolved with an absolute diet, antibiotic therapy and enteral nutrition. There was no mortality. After a median follow up of 14.7 months, two patients were nourished exclusively by mouth, one by a mixed route (oral-enteral) and another exclusively by the enteral route due to an oesophageal stenosis 11 centimetres from the dental arch; this patient required dilations and is awaiting a jejunal graft. CONCLUSIONS: "Supercharged" ileocoloplasty is a complex treatment option for the total reconstruction of the oesophagus when no other alternatives are available. Postoperative morbidity is significant but the functional results are good. PMID- 21277574 TI - Development and evaluation of a computerized Mandarin speech test system in China. AB - OBJECTIVES: This study reports the development and evaluation of a Computerized Mandarin Speech Test System (CMSTS). METHODS: Taking into account the rules for developing speech materials and the unique linguistic characteristics of Mandarin, we designed and digitally recorded a set of materials comprised of seven lists of monosyllabic words, nine lists of disyllabic words, and fifteen lists of sentences with a high degree of subject familiarity. The CMSTS was developed with Visual Studio 2008, Access 2003 and DirectX 9. The system included five functions: listener management, a speech test, list management, data management, and system settings. We used the system to measure the speech recognition threshold (SRT) of 76 participants with normal hearing (age range: 20 28 years), and measured performance-intensity functions (PI) for all stimuli. RESULTS: The SRT results were in accord with pure-tone results obtained by pure tone audiometry. In a speech recognition score (SRS) test, changing the presentation level had the strongest effect on sentence recognition, followed by the presence of disyllabic words. Monosyllabic words were least affected by changes in presentation level. The slopes of the linear portion of the PI using the system were in accord with the findings of previous studies using audiometers and CDs with similar materials. CONCLUSION: The CMSTS has sufficient sensitivity, and can facilitate the wider use of speech audiometry in Chinese audiology clinics. PMID- 21277575 TI - Body burdens of mercury, lead, selenium and copper among Baltimore newborns. AB - Umbilical cord blood or serum concentrations of mercury, lead, selenium and copper were measured with inductively coupled plasma mass spectrometry in a population of 300 infants born in Baltimore, Maryland. Geometric mean values were 1.37 MUg/L (95% confidence interval: 1.27, 1.48) for mercury; 0.66 MUg/dL (95% CI: 0.61, 0.71) for lead; and 38.62 MUg/dL (95% CI: 36.73, 40.61) for copper. Mean selenium was 70.10 MUg/L (95% CI: 68.69, 70.52). Mercury, selenium and copper levels were within exposure ranges reported among similar populations, whereas the distribution of lead levels was lower than prior reports; only one infant had a cord blood lead above 10 MUg/dL. Levels of selenium were significantly correlated with concentrations of lead (Spearman's rho=0.20) and copper (Spearman's rho=0.51). Multivariable analyses identified a number of factors associated with one of more of these exposures. These included: increase in maternal age (increased lead); Asian mothers (increased mercury and lead, decreased selenium and copper); higher umbilical cord serum n-3 fatty acids (increased mercury, selenium and copper), mothers using Medicaid (increased lead); increasing gestational age (increased copper); increasing birthweight (increased selenium); older neighborhood housing stock (increased lead and selenium); and maternal smoking (increased lead). This work provides additional information about contemporary prenatal element exposures and can help identify groups at risk of atypical exposures. PMID- 21277576 TI - A disintegrin and metalloprotease protein-12 as a novel marker for the diagnosis of ectopic pregnancy. AB - OBJECTIVE: To evaluate the performance of a novel biomarker, a disintegrin and metalloprotease-12 (ADAM-12), to differentiate an ectopic pregnancy (EP) from normal intrauterine pregnancies (IUPs). DESIGN: Case-control study. SETTING: Three urban academic centers. PATIENT(S): Women who were seen in the emergency department with pain or bleeding in the first trimester of pregnancy. INTERVENTION(S): Sera from women with diagnosed EP or IUP were evaluated via proteomics and an ADAM-12 dissociation-enhanced lanthanide fluoroimmunoassay. MAIN OUTCOME MEASURE(S): Differences between groups, area under the receiver operating curve, sensitivity, and specificity. RESULT(S): Via a proteomics evaluation, we found a statistically significant decrease in ADAM-12 in the sera of patients with EP, which we confirmed in a larger group of 199 patients (median IUP 18.6 ng/mL versus median EP 2.5 ng/mL with good discrimination between the groups as assessed by receiver operating characteristics [area under the curve = 0.82]). At a low cut-point, the sensitivity was 70% and specificity 84%, but, at a higher cut-point optimizing sensitivity, the ADAM-12 test demonstrated a sensitivity of 97%. CONCLUSION(S): ADAM-12 is a promising marker for the diagnosis of EP in women with symptoms in the first trimester, validating the proteomics findings. Further studies in additional patient populations and in combination with other biomarkers are needed. PMID- 21277577 TI - Viscous elements have little impact on measured passive length-tension properties of human gastrocnemius muscle-tendon units in vivo. AB - Several studies have measured the elastic properties of a single human muscle tendon unit in vivo. However the viscoelastic behavior of single human muscles has not been characterized. In this study, we adapted QLV theory to model the viscoelastic behavior of human gastrocnemius muscle-tendon units in vivo. We also determined the influence of viscoelasticity on passive length-tension properties of human gastrocnemius muscle-tendon units. Eight subjects participated in the experiment, which consisted of two parts. First, the stress relaxation response of human gastrocnemius muscle-tendon units was determined at a range of knee and ankle angles. Subsequently, passive ankle torque and ankle angle were collected during cyclic dorsiflexion and plantarflexion at a range of knee angles. Viscous parameters were determined by fitting the stress relaxation experiment data with a two-term exponential function, and elastic parameters were estimated by fitting the QLV model and viscous parameters to the cyclic experiment data. The model fitted the experimental data well at slow speeds (RMSE: 1.7 +/- 0.5N) and at fast speeds (RMSE: 1.9 +/- 0.2N). Muscle-tendon units demonstrated a large amount of stress relaxation. Nonetheless, viscoelastic passive length-tension curves estimated with the QLV model were similar to elastic passive length-tension curves obtained using a model that ignored viscosity. There was little difference in the elastic passive length-tension curves at different loading rates. We conclude that (a) the QLV model can be used to quantify viscoelastic behaviors of relaxed human gastrocnemius muscle-tendon units in vivo, and (b) over the range of velocities we examined, the velocity of loading has little effect on the passive length-tension properties of human gastrocnemius muscle-tendon units. PMID- 21277578 TI - Development and validation of a solid-phase extraction method coupled to high performance liquid chromatography with ultraviolet-diode array detection for the determination of sulfonylurea herbicide residues in bovine milk samples. AB - This study proposes a fast, simple and sensitive liquid chromatography diode array detector (LC/UV-DAD)-based method for the simultaneous determination of eight sulfonylurea herbicides (bensulfuron methyl, chlorsulfuron, metsulfuron methyl, primisulfuron methyl, rimsulfuron, thifensulfuron methyl, triasulfuron and tribenuron methyl) in bovine whole milk at concentrations lower than the default limit of 0.01 mg kg(-1) allowed by current legislation (Regulation EC/396/2005 and following Annexes). An effective one-step solid phase extraction (SPE) and clean up procedure was defined with use of Chem Elut cartridges, providing good recoveries for all the analytes tested and with no matrix effects affecting method accuracy. Separation of herbicides was obtained on a C(18) column by acetonitrile- water gradient elution. Method validation has been performed according to European Commission Decision 2002/657/EC criteria, in terms of linearity, recovery, precision, specificity, decision limit (CC(alpha)) and detection capability (CC(beta)). Typical recoveries ranged between 78.4% and 99.7%, at the maximum residue limits (MRLs) levels established by Regulation EC/396/2005, with relative standard deviations (RSD) no larger than 10%. PMID- 21277579 TI - Ionic liquid-based liquid phase microextraction with direct injection for capillary electrophoresis. AB - Liquid-liquid microextraction using the water immiscible ionic liquid, 1-ethyl-3 methylimidazolium bis(trifluoromethylsulfonyl)imide, EMIM NtfO2, for the concentration and cleanup of basic compounds for analysis by CE has been investigated. Using an electrolyte comprising 1 mol/L alanine and 3 mol/L acetic acid, EMIM NtfO2 could be directly injected into the capillary after liquid phase extraction. Using the basic dye chryisoidine, sensitivity enhancements approaching 1000-fold were obtained by mixing 20 MUL of EMIM NtfO2 with 1500 MUL of aqueous sample, leaving only 5 MUL of the undissolved ionic liquid which was used for injection into the CE. Lower more repeatable enhancement factors of 200 fold were obtained with slightly larger initial 25 MUL volumes of EMIM NtfO2 due to the larger residual volume of ionic liquid which made handling easier. This could be extended to basic pharmaceuticals, and the extraction of clozapine and its two active metabolites, nor-clozapine and clozapine-N-oxide, was demonstrated from urine with enrichment factors greater than 100 obtained. Handling of potentially more dangerous samples, such as serum, through in-vial extraction of clozapine and its metabolites and direct injection of the ionic liquid layer was also demonstrated with enhancements in sensitivity of 80. Limits of detection from 3 to 11 MUg/L and 6 to 55 MUg/L were obtained from urine and serum, respectively, which are sufficiently low to be useful for the determination of these pharmaceuticals clinically for therapeutic drug monitoring and for forensic toxicology. PMID- 21277580 TI - Rapid analysis of carbohydrates in aqueous extracts and hydrolysates of biomass using a carbonate-modified anion-exchange column. AB - Quantitative liquid-chromatography techniques used to characterize carbohydrates present in biomass samples can suffer from long analysis times, limited analyte resolution, poor stability, or a combination of these factors. The current manuscript details a novel procedure enabling resolution of glucose, xylose, arabinose, galactose, mannose, fructose, and sucrose via isocratic elution in less than 5 min. Equivalent conditions also enable analysis of cellobiose and maltose with a minimal increase in chromatographic run time (ca. 3 and 6 min, respectively). Noted chromatographic performance requires that a commercially available anion-exchange column be modified with carbonate prior to analysis. Analytical performance of a modified column was assessed over a 5-day period via repeated analyses of 4 samples, resulting from aqueous extraction or quantitative saccharification of a potential biofuel feedstock (i.e., corn stover or switchgrass). A simple solid phase extraction procedure was utilized to clean up each sample prior to analysis. Analytical accuracy of the extraction protocol was assessed by evaluation of matrix spike recoveries which typically ranged from 84% to 98%. The instrumental variability of measured concentrations in real samples over the 5-day period was generally less than 5% RSD for all detected analytes, independent of sample type. Finally, it is important to note that the modified column exhibited exceptional stability over approximately 800 injections of biofeedstock-based samples. These data demonstrate that a carbonate-modified anion-exchange column can be employed for rapid determination of carbohydrates in biomass samples of lignocellulosic origin. PMID- 21277581 TI - Development of a strategy and process parameters for a green process in counter current chromatography: purification of tanshinone IIA and cryptotanshinone from Salvia miltiorrhiza Bunge as a case study. AB - A strategy for the development of a green process using counter-current chromatography technology is presented in this paper. The strategy began with solvent system selection, followed by linear scale-up from an analytical to a preparative process with optimized operating parameters. A two-stage separation using a multi-injection method was performed with a solvent system of hexane dichloromethane-methanol-water (4:0.75:4:1) for the 1st stage and a hexane ethanol-water (4:2:2) for the 2nd stage. A 191.8 mg of tanshinone IIA was purified, with a 97% purity and 34.4% recovery and a 276.7 mg of cryptotanshinone was separated, with a 95% purity and 31.8% recovery from 2.1g of crude extract. Process parameters (throughput, efficiency, environmental risk factor and general process evaluation) and mass factors (mass intensity, separation mass efficiency and greenness) of a target were developed for monitoring of the counter-current chromatography process. PMID- 21277582 TI - Electrophoretic motion of a nanorod along the axis of a nanopore under a salt gradient. AB - The phoretic translation of a charged, elongated cylindrical nanoparticle, such as a DNA molecule and nanorod, along the axis of a nanopore driven by simultaneous axial electric field and salt concentration gradient, has been investigated using a continuum model, which consists of the Poisson-Nernst-Planck equations for the ionic concentrations and electric potential, and the Stokes equations for the hydrodynamic field. The induced particle motion includes both electrophoresis, driven by the imposed electric field, and diffusiophoresis, arising from the imposed salt concentration gradient. The particle's phoretic velocity along the axis of a nanopore is computed as functions of the imposed salt concentration gradient, the ratio of the its radius to the double-layer thickness, the nanorod's aspect ratio (length/radius), the ratio of the nanopore size to the particle size, the surface-charge density of the particle, and that of the nanopore in KCl solution. The diffusiophoresis in a nanopore mainly arises from the induced electrophoresis driven by the generated electric field, stemming from the double-layer polarization, and can be used to regulate electrophoretic translocation of a nanorod, such as a DNA molecule, through a nanopore. When both the nanorod and the nanopore wall are charged, the induced electroosmotic flow arising from the interaction of the overall electric field with the double layer adjacent to the nanopore wall has a significant effect on both electrophoresis driven by the imposed electric field and diffusiophoresis driven by the imposed salt gradient. PMID- 21277583 TI - Synthesis of zwitterionic shell cross-linked micelles with pH-dependent hydrophilicity. AB - Shell cross-linked (SCL) micelles were constructed based on the diblock copolymer poly(t-butyl acrylate)-b-poly(2-dimethylamino)ethyl methacrylate (PtBA-b-PDMAEMA) which was synthesized by sequential atom transfer radical polymerization (ATRP). Using trifluoroacetic acid (TFA) to hydrolyze the SCL micelles, zwitterionic SCL micelles were prepared. The hydrophilicity, size, and softness of the core and the shell of the micelles can be tuned independently by adjusting the pH. At low pH (3.4), the micelles turned into nanoparticles with compact cores and swollen shells; at neutral medium (6.8), the SCL micelles were entirely hydrophilic; at pH 11.6, a double-layer cage-like nanostructure was observed. Moreover, the inner and outer layers of the nanocage had opposite behaviors to the pH stimulus. The existence of tunable nanostructures of these zwitterionic SCL micelles could be proved by the ratio of gyration radius (R(g)) to hydrodynamic radius (R(h)) and SEM micrographs. PMID- 21277584 TI - Effect of concentration of trimethylchlorosilane (TMCS) and hexamethyldisilazane (HMDZ) silylating agents on surface free energy of silica aerogels. AB - The surface free energy of a solid determines its surface and interfacial behavior in processes like wetting and adhesion which is crucial for silica aerogels in case of organic liquid absorption and transportation of chemicals at nano-scale for biotechnological applications. Here, we have demonstrated that the surface free energy of aerogels can be tuned in wide range from 5.5892 to 0.3073 mJ/m(2) by modifying their surface using TMCS and HMDZ silylating reagents. The alcogels were prepared by two step acid-base catalyzed process where the molar ratio of precursors Tetraethoxysilane (TEOS):Methanol (MeOH):Oxalic acid:NH(4)OH:NH(4)F was kept at optimal value of 1:2.7:0.18*10(-4):0.02:0.22*10( 3), respectively. To modify gel surfaces, TMCS and HMDZ concentration have been varied from 3% to 12% and such alcogels were dried at ambient pressure. It is observed from FTIR for aerogels that increase in concentration of silylating reagent resulted increase in hydrophobicity. This leads to increase in contact angle for water from 123 degrees to 155 degrees but leads to decrease in surface free energy from 5.5892 to 0.3073 mJ/m(2). As there is not direct method, we have used Neumann's equation of state to estimate surface energy of aerogels. PMID- 21277585 TI - Development of various PS-b-P4VP micellar morphologies: fabrication of inorganic nanostructures from micellar templates. AB - We demonstrate a simple route for preparing various micellar nanostructures, like spheres, cylinders, and vesicles, by spin-coating or drop-casting process of polystyrene-block-poly(4-vinylpyridine) (PS-b-P4VP) copolymer solutions in pure tetrahydrofuran (THF), THF/water, and THF/ethanol mixture. Upon drying, a solvent selectivity plays an important role in determining micellar nanostructures in thin films. In solution, micellar sizes and shapes of these PS-b-P4VP copolymers were investigated by dynamic and static light scattering. Immediately after spin coating the polymer solutions, surface and internal morphologies of the films were observed by atomic force microscopy and transmission electron microscopy. As the polymer concentration in THF or the amounts of water or ethanol added in THF solutions was varied, a remarkable difference in the PS-b-P4VP micellar morphologies was observed, from which spherical or cylindrical or vesicular micelles were developed. These micellar films were used as scaffolds or templates for fabricating metal nanodots or nanowires arrays. PMID- 21277586 TI - Leptin's neuroprotective action in experimental transient ischemic damage of the gerbil hippocampus is linked to altered leptin receptor immunoreactivity. AB - Circulating leptin crosses blood-brain barrier to provide control of feeding behavior and energy balance. We investigated changes in leptin and leptin receptor (ObR) in the gerbil hippocampal CA1 region (CA1) after transient cerebral ischemia, and examined effects of leptin on ischemic damage. In vehicle treated ischemia (vehicle-ischemia) group, the number of survived neurons in the CA1 was 16.4% compared to vehicle-treated sham (vehicle-sham) group; however, in 1 mg/kg leptin-treated ischemia (leptin-ischemia) group, 77.5% of neurons of the CA1 has survived. In the vehicle-sham group, weak leptin immunoreactivity was detected in CA1 neurons. From 4 days post-ischemia, moderate leptin immunoreactivity was expressed in CA1 neurons. In the leptin-ischemia group, leptin immunoreactivity at 5 days post-ischemia was higher than the sham group. ObR immunoreaction in the sham group was hardly detected in any cells. From 2 days post-ischemia, ObR immunoreaction was expressed in microglia, showing the highest immunoreactivity at 5 days post-ischemia. Microglial activation in the leptin-ischemia group was hardly detected at 5 days post-ischemia; however, astrocytes in the group were slightly increased compared to the vehicle-ischemia group. These suggest that treatment of leptin has neuroprotective effects against ischemic damage, showing that ObR immunoreactivity is distinctly changed in the ischemic CA1. PMID- 21277587 TI - Ischemic stroke related to intracranial branch atheromatous disease and comparison with large and small artery diseases. AB - BACKGROUND: The mechanism of ischemic stroke in intracranial branch atheromatous disease (BAD) is different from large artery atherothrombotic disease (LAD) or lacunar infarction (LACI). The concept of BAD is underused in clinical practice and research. METHODS: Patients admitted over 24-months with ischemic stroke caused by atherosclerotic disease were reviewed retrospectively and classified according to radiological+/-clinical criteria into LAD, BAD and LACI. The BAD cases were further divided into 5 BAD syndromes. Clinical characteristics, vascular risk factors, results of vascular workup and outcome among these subgroups were compared. RESULTS: 123 cases of LAD (17% of all stroke patients or 33% of all studied patients), 147 BAD (20% or 40%) and 102 LACI (14% or 27%) presented during the study period. Compared to LAD, BAD patients had milder neurological deficits, were less often diabetic and carotid stenosis was less common, while stenosis of the intracranial arteries was more frequent in BAD as compared with LACI patients. Outcome in BAD patients was intermediate between LAD and LACI. Comparisons among the BAD syndromes indicated they were homogenous conditions. CONCLUSIONS: BAD is the most prevalent ischemic stroke subtype in our cohort. The homogeneity among the BAD syndromes suggests they might represent a distinctive stroke entity. PMID- 21277588 TI - Left ventricular remodeling and mitral valve surgery: prospective study with real time 3-dimensional echocardiography and speckle tracking. AB - OBJECTIVES: The aim of the present study was the assessment of left ventricular (LV) remodeling during the surgical management of degenerative mitral valve regurgitation (DMR) with the application of 2 emerging imaging modalities: real time 3-dimensional echocardiography (3DE) and speckle tracking. METHODS: A total of 40 patients with DMR were prospectively recruited. Two-dimensional echocardiography, 3DE, and speckle tracking studies were performed before surgery and 6 months postoperatively. The LV volumes, stroke volume, and ejection fraction were calculated. The strain of all myocardial segments, as well as dyssynchrony, was assessed. Receiver operating characteristic curves and regression analysis were used to assess the independent predictors of mitral regurgitation recurrence and LV remodeling. RESULTS: Of the 40 patients, 21 underwent mitral valve repair and 19 valve replacement. Their mean age was 59.5 +/- 15.4 years. The postoperative LV 3DE analysis revealed a significant reduction in LV end-diastolic volume (103.9 cm(3) from 165.2 cm(3) preoperatively, P < .001). A synchronous decrease in the LV end-diastolic diameter (48 mm from 53.5 mm preoperatively, P < .001) and left atrial diameter (42.8 mm from 53.1 mm preoperatively, P = .005) were identified after DMR surgery. Regression analysis demonstrated incremental favor toward mitral valve repair in reverse ventricular remodeling. Independent factors were identified for regurgitation recurrence after surgery. The most significant were late diastolic (A') wave of the septal apical wall of < 3.2 cm/s (area under the curve [AUC], 0.82), late diastolic (A') wave of the mid-septal wall of <= 3.66 cm/s (AUC, 0.82), mid-lateral radial strain of <= -27 (AUC, 0.81), and apical lateral radial strain of <= -25 (AUC, 0.80). CONCLUSIONS: 3DE and speckle tracking proved to be important imaging tools in assessing reverse LV remodeling after DMR surgery. Subtle regional preoperative changes in diastolic function of the septal and lateral wall could be identified preoperatively, aiding in optimizing the referral timing and recognizing potential culprits as indicators of disease recurrence after mitral repair. PMID- 21277589 TI - Health-related quality of life in patients with congenitally corrected transposition of the great arteries. AB - OBJECTIVE: The study's objectives were to survey the quality of life in patients with congenitally corrected transposition of the great arteries and to compare the responses of those who have undergone anatomic repair with those who have a systemic right ventricle. METHODS: Thirty-eight patients who underwent anatomic repair and 13 patients after either conventional repair or no surgical procedure were enrolled. Subjects completed the PedsQL 4.0 Generic and 3.0 Cardiac Modules. Scores were also compared with those of patients from the literature with at least moderately severe cardiovascular disease. Mean differences between groups were compared, and the association between clinical variables and score in the anatomic repair subgroup was measured. RESULTS: Caregivers of patients in the anatomic repair group reported similar scores compared with the non-anatomic repair group in all functional domains The anatomic repair group self-reported lower school function (63 vs 81, P = .02). On the Cardiac Module, patients in the anatomic repair group self-reported fewer problems related to residual heart disease (75 vs 63), appearance (81 vs 68), and treatment anxiety (74 vs 59), although the differences were not significant. Compared with patients with other heart disease, the anatomic repair group scored lower, with the largest differences in cognition and communication. Prolonged hospital stay and need for a pacemaker were associated with lower quality of life after anatomic repair. CONCLUSIONS: Patients in the anatomic repair group had similar quality of life compared with patients in the non-anatomic group, except in the domain of school functioning. Prolonged hospital stay and need for a pacemaker after anatomic repair may be risk factors for lower quality of life. PMID- 21277590 TI - The effect of blood pressure on cerebral outcome in a rat model of cerebral air embolism during cardiopulmonary bypass. AB - OBJECTIVE: Higher mean arterial pressure during cardiopulmonary bypass may improve cerebral outcome associated with cerebral air embolism by increasing emboli clearance and collateral flow to salvage the ischemic penumbra. However, this may come at the expense of increased delivery of embolic load. This study was designed to investigate the influence of mean arterial pressures on cerebral functional and histologic outcome after cerebral air embolism during cardiopulmonary bypass in an established rat model. METHODS: Male Sprague-Dawley rats were exposed to 90 minutes of normothermic cardiopulmonary bypass with 10 cerebral air embolisms (0.3 MUL/bolus) injected repetitively. Rats were randomized to 3 groups (n = 10, each) that differed in mean arterial pressure management during cardiopulmonary bypass: 50 mm Hg (low mean arterial pressure), 60 to 70 mm Hg (standard mean arterial pressure), and 80 mm Hg (high mean arterial pressure). Neurologic score was assessed on postoperative days 3 and 7 when cerebral infarct volumes were determined. Cognitive function was determined with the Morris water maze test beginning on postoperative day 3 and continuing to postoperative day 7. RESULTS: Neurologic score was better in high and standard mean arterial pressure groups versus low mean arterial pressure groups. High mean arterial pressure resulted in shorter water maze latencies compared with standard and low mean arterial pressure on postoperative days 6 and 7. Total infarct volume and number of infarct areas were not different among groups. CONCLUSIONS: The use of higher mean arterial pressure during cardiopulmonary bypass in a rat model of cerebral air embolism conveyed beneficial effects on functional cerebral outcome with no apparent disadvantage of increased delivery of embolic load. Maintaining higher perfusion pressures in situations of increased cerebral embolic load may be considered as a collateral therapeutic strategy. PMID- 21277591 TI - Medtronic Mosaic porcine bioprosthesis: assessment of 12-year performance. AB - BACKGROUND: The Mosaic porcine bioprosthesis (Medtronic, Inc, Minneapolis, Minn) was approved in 2000 by the US Food and Drug Administration. Clinical performance was evaluated in 6 centers. METHODS: From 1994 to 2000, 797 patients (mean age 69 years) had aortic valve replacement (AVR) and 232 (mean 67 years) had mitral valve replacement (MVR). Concomitant coronary artery bypass grafting was performed with aortic valve replacement (45.4%) and mitral valve replacement (43.5%). Mean follow-ups were 7.5 years for aortic position and 7.3 years for mitral position. RESULTS: Early mortalities were 2.8% for AVR and 3.0% for MVR. Late mortalities were 4.2%/patient-year for AVR and 5.1%/patient-year for MVR. Overall 12-year survivals were 55.8% +/- 3.7% for AVR and 43.9% +/- 7.4% for MVR. Twelve-year freedoms from valve-related mortality were 87.1% +/- 3.1% for AVR and 82.5% +/- 7.7% for MVR. Twelve-year freedoms from reoperation were 84.0% +/- 3.3% for AVR and 82.5% +/- 7.5% for MVR. Freedoms from structural valve deterioration (SVD) by explant reoperation at 12 years for AVR were 93.3% +/- 2.6% for patients at least 60 years old and 75.9% +/- 9.3% for patients younger than 60 years. Freedoms from SVD by explant reoperation at 10 years for MVR were 95.3% +/- 7.8% for patients at least 70 years old and 84.0% +/- 9.3% for patients younger than 70 years. Hemodynamic performance data at 1 year for AVR (sizes 21-27 mm) were mean systolic gradient range 13.7 +/- 4.8 to 10.3 +/- 3.2 mm Hg and effective orifice area range 1.5 +/- 0.3 to 2.5 +/- 0.4 cm(2). For MVR (sizes 25-31 mm), data were mean diastolic gradient range 6.7 +/- 1.7 to 3.7 +/- 0.9 mm Hg and effective orifice area range 1.9 +/- 0.3 to 2.4 +/- 0.6 cm(2). CONCLUSIONS: Overall performance of Mosaic porcine bioprosthesis to 12 years is satisfactory. Freedoms from SVD by explant reoperation were most satisfactory for aortic position in patients at least 60 years old and mitral position in patients at least 70 years old. Overall actuarial freedom from SVD by explant reoperation is encouraging for patients with MVR. PMID- 21277592 TI - Long-term results of the REV (reparation a l'etage ventriculaire) operation. AB - OBJECTIVE: Despite its innovative features, the reparation a l'etage ventriculaire (REV) procedure has not gained large popularity in the treatment of transposition of the great arteries, ventricular septal defect, pulmonary stenosis, and related anomalies, and thus the Rastelli operation remains the preferred type of repair. We try to obviate the alleged lack of long-term results that has been suggested to explain this reluctance to change. METHODS: We reviewed a series of 205 patients who underwent the REV procedure between 1980 and 2003. RESULTS: Hospital mortality was 12% (24 patients). Ten of 181 early survivors residing in distant countries could not be traced for follow-up. There were 13 late deaths (2 of noncardiac causes). Overall survival and freedom from any reoperation at 25 years were 85% and 45%, respectively, as determined by using the Kaplan-Meier method. Reoperation was commonly required because of recurrent right ventricular outflow tract obstruction (36 patients) and rarely by left ventricular outflow tract stenosis (3 patients). By using cumulative method analysis, at the 25-year follow-up interval, the probability of being alive without reoperation was 45%, that of reoperation for right ventricular outflow tract obstruction was 33%, and that of reoperation for left ventricular outflow tract obstruction was 5%. Clinical status is excellent: 137 patients are in New York Heart Association class I (87%), and 131 patients are free of arrhythmias. CONCLUSIONS: These results represent a considerable improvement over those of the Rastelli operation in terms of survival and need for reoperation for right or left ventricular outflow tract obstruction. PMID- 21277593 TI - The sandwich plug technique: simple, effective, and rapid closure of a mechanical aortic valve prosthesis at left ventricular assist device implantation. PMID- 21277594 TI - Management of HeartWare left ventricular assist device thrombosis using intracavitary thrombolytics. PMID- 21277595 TI - Dilatation of the pulmonary autograft and native aorta after the Ross procedure: a comprehensive echocardiographic study. AB - OBJECTIVES: Dilatation of the pulmonary autograft has been observed after the Ross procedure. Whether the remaining native aorta dilates is not known. The aim of the study was to describe the prevalence and severity of autograft and native aortic dilatation over time and to identify possible determinants. METHODS: Ninety-one adult patients underwent the Ross procedure with the full root replacement technique. In 31 (34%) patients, the ascending aorta was downsized during surgical intervention. A baseline postoperative echocardiographic investigation was performed. A comprehensive investigation of the aorta from the annulus to the proximal descending aorta was performed (n = 71) after a median follow-up of 8.9 years. An intermediate investigation was performed (n = 29) after a median of 7.6 years. Autograft and native aortic dimensions were compared over time and with those of a control group (n = 38). For each patient in the study group, the expected aortic dimensions were predicted based on findings in the control group. Enlargement was defined as a z score of greater than 1.96 from the predicted value. RESULTS: The autograft and native aortic dimensions increased significantly from baseline to the intermediate follow-up and continued to increase to the final follow-up. The proportion of patients with enlarged autografts and proximal ascending aortas was 13% and 16% at baseline, increasing to 33% (P = .006) and 44% (P = .0014), respectively, at the end of follow-up. Enlargement of the aorta at the final follow-up was related to larger baseline pulmonary autograft dimensions but not to native bicuspid valve or the need to downsize the aortic root. CONCLUSIONS: Pulmonary autograft dilatation is common after the Ross procedure in adults. The dilatation progresses over time and is often accompanied by dilatation of the native aorta. PMID- 21277596 TI - Total ventricular assist for long-term treatment of heart failure. PMID- 21277597 TI - Functional tricuspid regurgitation at the time of mitral valve repair for degenerative leaflet prolapse: the case for a selective approach. AB - OBJECTIVES: It is not clear whether clinically silent tricuspid valve regurgitation should be addressed at the time of mitral valve repair for severe mitral regurgitation due to leaflet prolapse. We examined the clinical and echocardiographic outcomes of patients with tricuspid regurgitation who underwent only mitral valve repair. METHODS: We retrospectively analyzed records of patients undergoing mitral valve repair for isolated mitral valve prolapse who had coexistent tricuspid valve regurgitation during an 11-year period at our institution. Echocardiographic data were compared preoperatively, intraoperatively, and postoperatively at less than 1, 1 to 3, 3 to 5, and more than 5 years. RESULTS: In 699 patients who underwent mitral valve repair for severe mitral regurgitation, mean age was 60.4 years and 459 (66%) were male. At the time of mitral valve repair, tricuspid valve regurgitation was grade 3 or more in 115 (16%) patients and less than grade 3 in 584 (84%) patients. After mitral valve repair, overall grade of tricuspid valve regurgitation decreased significantly within the first year (P = .01). In patients with grade 3 regurgitation or more, the grade decreased at dismissal and until the third year (P < .001). Female sex, preoperative atrial fibrillation, and diabetes mellitus were independent risk factors for increased tricuspid valve regurgitation with time; preoperative regurgitation of grade 3 or more independently predicted decreased grade with time. Only 1 patient required tricuspid reoperation 4.5 years after mitral repair. CONCLUSIONS: Clinically silent nonsevere tricuspid valve regurgitation in patients with degenerative mitral valve disease is unlikely to progress after mitral valve repair. Tricuspid valve surgery is rarely necessary for most patients undergoing repair of isolated mitral valve prolapse. PMID- 21277598 TI - Natural orifice transluminal endoscopic surgery: a transtracheal approach for the thoracic cavity in a live canine model. AB - BACKGROUND: The present study aimed to evaluate the performance of transtracheal thoracic exploration and pericardial window creation in a canine survival model. METHODS: Transthoracic exploration was performed in 14 dogs. Under general anesthesia, after an incision in the right lateral wall of the middle-lower portion of the trachea was made, a 9-mm metal tube was advanced into the thoracic cavity. For thoracic cavity exploration and pericardial window creation, a flexible bronchoscope was introduced through the metal tube into the thoracic cavity. After thoracoscopy, a Dumon stent (Novatech, Grasse, France) was used to cover the tracheal incision site and facilitate healing. Animals were evaluated by endoscopy 1 and 2 weeks later. Animals were humanely killed, and necropsy was performed 2 weeks after the transtracheal natural orifice transluminal endoscopic surgery. RESULTS: Fourteen dogs underwent transtracheal thoracic exploration lasting for an average of 110 minutes (range, 80-150), with 3 perioperative deaths. At 2 weeks after pericardial window creation, endoscopy revealed normal healing of the tracheal incision sites in all 11 surviving animals. Necropsy on the 11 animals at 2 weeks showed 9 adhesions around the pericardial window and 5 adhesions around the tracheal incision region. No mediastinitis or abscesses could be identified. CONCLUSIONS: Transtracheal thoracic exploration is technically feasible. Increasing surgical experience together with improvement in endoscopic techniques will further facilitate the development of natural orifice transluminal endoscopic surgery for thoracic diseases. PMID- 21277599 TI - The lower limit of the pulmonary artery index for the extracardiac Fontan circulation. AB - OBJECTIVE: In the era of the staged Fontan operation, small pulmonary artery index (<250 mm(2)/m(2)) has not affected the early or midterm results. The lower limit of pulmonary artery index, however, has not yet been determined. We created numeric models of the Fontan circulation to investigate the lower limit of the pulmonary artery size. METHODS: The extracardiac Fontan geometries with pulmonary artery index, ranging from 50 to 200 mm(2)/m(2) with every 10-mm(2)/m(2) increase, were created from the postoperative angiographic data of 17 patients. The superior and inferior vena caval flow rates at rest and on 2 exercise levels (0.5 and 1.0 W/kg) were given by magnetic resonance imaging flow studies. Respiration-driven transient flow analysis was performed with a finite element solver. Energy loss and mean inferior vena caval pressure were obtained from the results. RESULTS: Energy loss and mean inferior vena caval pressure were prominently increased in small pulmonary artery index models, especially during exercise. The pulmonary artery indices sufficient for mean inferior vena caval pressure less than 17 mm Hg were 80 mm(2)/m(2) at rest, 100 mm(2)/m(2) during 0.5 W/kg exercise, and 110 mm(2)/m(2) during 1.0-W/kg exercise. With the increase of pulmonary arterial resistance, mean inferior vena caval pressure increased, but the flow pattern did not change. CONCLUSIONS: A small pulmonary artery causes a high pressure gradient and a high energy loss. The lower limit of pulmonary artery index, considering the exercise tolerance, was 110 mm(2)/m(2). PMID- 21277600 TI - Video-assisted thoracoscopic surgical tracheobronchoplasty for tracheobronchomalacia. PMID- 21277601 TI - Late improvement in graft patency after coronary artery bypass grafting: Serial assessment with multidetector computed tomography in the early and late postoperative settings. AB - OBJECTIVE: Grafts initially showing poor patency after coronary artery bypass grafting have occasionally shown improvement on serial multidetector computed tomography. This study analyzed possible factors associated with this phenomenon. METHODS: Between September 2003 and July 2007, 512 patients underwent multidetector computed tomography within 1 month of isolated coronary artery bypass grafting. Among them, 1720 distal anastomoses were made with 1042 arterial and 302 venous conduits. Of these, 95 grafts (in 73 patients) were faint (n = 67) or nonvisualized (n = 28). Seventy-three of these grafts (in 56 patients) had follow-up multidetector computed tomographic evaluation 1 year after surgery and comprised the study group. RESULTS: Improvement in graft patency (faint to patent or nonvisualization to visualization) occurred in 44 grafts (60.3%). Multivariate analysis revealed proximal target vessel stenosis of at least 90% (relative risk, 3.81; P = .009), larger target coronary size (relative risk, 1.72; P = .002), and radial artery graft use (relative risk, 4.44; P = .003) to be significantly associated with the graft patency restoration. Graft patency restoration was most commonly observed in a group of 28 radial artery grafts that were anastomosed to target vessel with proximal stenosis of at least 90%; of these grafts, 24 (85.7%) showed improved graft patency on follow-up. CONCLUSIONS: A large proportion of radial artery grafts initially showing poor opacification after coronary artery bypass grafting demonstrated patency restoration on serial multidetector computed tomography. Larger target vessel size and target vessel stenosis of at least 90% were significant correlative factors. PMID- 21277602 TI - Successful combined procedure of HeartMate II left ventricular assist device implantation and minimally invasive transapical aortic valve replacement. PMID- 21277603 TI - St Jude Medical Epic porcine bioprosthesis: results of the regulatory evaluation. AB - BACKGROUND: The St Jude Medical Epic heart valve (St Jude Medical, Inc, St Paul, Minn) is a tricomposite glutaraldehyde-preserved porcine bioprosthesis. The St Jude Medical Biocor porcine bioprosthesis is the precursor valve to the St Jude Medical Epic valve. The Epic valve is identical to the Biocor valve except that it is treated with Linx AC ethanol-based calcium mitigation therapy. METHODS: The St Jude Medical Epic valve was implanted in 761 patients (mean age 73.9 +/- 9.2 years) between 2003 and 2006 in the US Food and Drug Administration regulatory study in 22 investigational centers. The position distribution was 557 aortic valve replacements, 175 mitral valve replacements, and 29 double valve replacements. Concomitant coronary artery bypass grafting was performed in 50.8% of patients undergoing aortic valve replacement and 36.6% of those undergoing mitral valve replacement. RESULTS: The early mortality was 3.6% in aortic and 2.3% in mitral valve replacement. The follow-up was 1675.5 patient-years with a mean of 2.2 +/- 1.2 years/patient. Late mortality was 5.2%/patient-year in aortic and 6.6%/patient-year in mitral valve replacement. The late major thromboembolism rate was 0.98%/patient-year for aortic and 2.6%/patient-year for mitral valve replacement. There were 19 reoperations, including 2 for structural valve deterioration, 1 for thrombosis, 9 for nonstructural dysfunction, and 7 for prosthetic valve endocarditis. The actuarial freedom from reoperation owing to structural valve deterioration for aortic valve replacement at 4 years for age 60 years or less was 93.3% +/- 6.4%; for ages 61 to 70 years, 98.1% +/- 1.9%; and for older than 70 years, 100% (P = .0006 > 70 vs <= 60 years). There were no events of structural deterioration with mitral valve replacement. The actuarial freedom from major thromboembolism for all patients at 4 years was 93.6% +/- 1.0%. The 2 cases of structural valve deterioration occurred in aortic valves that became perforated without calcification causing aortic regurgitation. CONCLUSIONS: The performance of the St Jude Medical Epic porcine bioprosthesis is satisfactory at 4 years for both aortic and mitral valve replacement. This study establishes the early clinical performance including durability of this porcine bioprosthesis. PMID- 21277604 TI - Integrative public health: An important guide for public health practice. PMID- 21277605 TI - Prevalence of multiple drug resistance and screening of enterotoxin (stn) gene in Salmonella enterica serovars from water sources in Lagos, Nigeria. AB - OBJECTIVE: To determine the prevalence, antibiotic resistance and carriage of enterotoxin (stn) gene among strains of Salmonella isolated from water sources in Lagos. STUDY DESIGN: A total of 200 samples (60 well water, 60 pipe-borne water and 80 different brands of sachet water) were collected at random from various locations in Lagos. METHODS: The samples were evaluated bacteriologically using standard methods. The identified isolates were subjected to antimicrobial susceptibility tests and were further screened for the presence of stn gene using standard procedures. RESULTS: Thirty-seven of the samples analysed were positive for Salmonella isolates. Seven serotypes were found -Salmonella typhi (n = 3, 8.1%), Salmonella typhimurium (n = 8, 21.6%), Salmonella choleraesuis (n = 5, 13.5%), Salmonella enteritidis (n = 9, 24.3%), Salmonella paratyphi (n = 8, 21.6%) and Salmonella arizonae (n = 4, 10.8%) - with at least one serotype present in all water sources. Over 60% of Salmonella isolates carried stn gene and the risk was higher in pipe-borne water. There was no relationship (P > 0.05) between enterotoxin-producing gene and antibiotic resistance in Salmonella isolates. Thirteen resistance patterns were exhibited by the isolates, with Str. Amp.Tet.Chl.Amo.Gen, Str. Amp.Tet.Amo.Chl.Amo.Nal.Nit, Str.Tet and Str. Amp.Tet.Chl.Amo being the most notable resistance patterns observed. Isolates that carried stn gene developed resistance to more antibiotics. Although reduced susceptibility to ciproflocacin was observed in two strains, none of the isolates developed resistance to ofloxacin. CONCLUSION: Emerging multidrug-resistant Salmonella serotypes with stn gene were found in the water samples, which may pose a threat to public health. Constant monitoring of pipe leakages, the quality of various wells and the quality of sachet water is advocated to avoid possible future outbreaks of salmonellosis due to consumption of contaminated water. PMID- 21277606 TI - Characterization of integrons in multiple antimicrobial resistant Escherichia coli isolates from bovine endometritis. AB - To assess the prevalence of antimicrobial resistance and three classes of integrons in Escherichia coli (E. coli) strains (n=57) isolated from bovine endometritis in Inner Mongolia of China, antimicrobial susceptibility and the presence of three types of integrons were characterized. Most isolates were susceptible to ceftiofur, furazolidone, ciprofloxacin and enrofloxacin, while 57 isolates were all resistant to sulfamethoxydiazine and trimethoprim. High resistant incidence rates were exhibited to sulfadiazine, tetracycline, oxytetracycline, cefazolin, chloramphenicol. Forty-six of 57 E. coli strains were resistant to above 10 antibiotics (80.70%). The integrase gene and gene cassettes of integrons were amplified by PCR. DNA sequencing and analysis were used to identify the genetic content of the integron-variable regions. Neither class II nor class III integron was detected, while 36.8% (n=21) of the isolates were positive for the presence of intI1 gene. Analysis of gene cassettes revealed that six gene cassettes were found, which encoded resistance to trimethoprim (dhfr, dhfrI, dfrA17) and aminoglycosides (aadA1, aadA2, aadA5). Among them, the gene cassette array dfrA17-aadA5 was found most prevalent (66.7%). The resistance profile of positive-integron isolates was relatively broad and they were resistant to more than eight antimicrobials (n >= 8). The correlation analysis revealed the incidence of integrons among the isolates were related to the multiple antibiotic resistance profile, indicating integrons play an important role in the dissemination and spread of the antimicrobial resistant strains. PMID- 21277607 TI - [Multiple mandibular "cysts"]. PMID- 21277608 TI - Gap in the prevalence of neutralising antibodies to polioviruses in antenatal women in southern India. AB - With the disappearance of circulating wild poliovirus and improved sanitation, protective antibody levels may wane over time following oral poliovirus vaccine (OPV) administration. This study evaluated the seroprevalence of neutralising antibodies to vaccine polioviruses among young Indian women who had received at least three doses of OPV as primary immunisation. Of 60 women studied, 27 (45%) had antibody titres of <1:8 to one or more polioviruses, with the lowest levels for poliovirus types 3 and 1. These findings represent a possible immunity gap and this needs to be confirmed with further studies, which could include a challenge with vaccine virus. PMID- 21277609 TI - Differential cytokine responses from primary human Kupffer cells following infection with wild-type or vaccine strain yellow fever virus. AB - Wild-type yellow fever virus (YFV) infections result in a hepatotropic disease which is often fatal, while vaccination with the live-attenuated 17-D strain results in productive infection yet is well-tolerated with few adverse events. Kupffer cells (KCs) are resident liver macrophages that have a significant role in pathogen detection, clearance and immune signaling. Although KCs appear to be an important component of YF disease, their role has been under-studied. This study examined cytokine responses in KCs following infection with either wild type or vaccine strains of YFV. Results indicate that KCs support replication of both wild-type and vaccine strains, yet wild-type YFV induced a prominent and prolonged pro-inflammatory cytokine response (IL-8, TNF-alpha and RANTES/CCL5) with little control by a major anti-inflammatory cytokine (IL-10). This response was significantly reduced in vaccine strain infections. These data suggest that a differentially regulated infection in KCs may play a critical role in development of disease. PMID- 21277610 TI - Novel DNA virus isolated from samples showing endothelial cell necrosis in the Japanese eel, Anguilla japonica. AB - Economic loss due to viral endothelial cell necrosis of eel (VECNE) of Anguilla japonica is a serious problem for the cultured Japanese eel market. However, the viral genome responsible for VECNE is unknown. We recently developed a rapid determination system for viral nucleic acid sequences (RDV) to determine viral genome sequences. In this study, viral DNA fragments were obtained using RDV, and approximately 15-kbp circular full genome sequences were determined using a next generation sequencing system, overlapping PCR, and Southern blot analysis. One open reading frame (ORF) was homologous to the large T-antigen of polyomavirus; other ORFs have no homology with any nucleic or amino acid sequences of polyomavirus. Therefore, as this DNA virus might comprise a novel virus family, we provisionally named it Japanese eel endothelial cells-infecting virus (JEECV). JEECV was detected in both naturally and experimentally infected eels, suggesting that JEECV potentially causes VECNE. PMID- 21277612 TI - Association of Merkel cell polyomavirus infection with morphologic differences in Merkel cell carcinoma. AB - Recently, it has been shown that approximately 80% of Merkel cell carcinomas harbor a novel polyomavirus named Merkel cell polyomavirus, thought to be a carcinogenic agent. However, it is not fully elucidated whether Merkel cell carcinomas differ with regard to the presence or absence of Merkel cell polyomavirus. To address this, we investigated morphologic differences between Merkel cell polyomavirus-positive and -negative Merkel cell carcinomas by morphometry. Using polymerase chain reaction and real-time quantitative polymerase chain reaction, Merkel cell polyomavirus was detected in 20 (77%) of 26 Merkel cell carcinoma cases, including 4 Merkel cell carcinomas combined with squamous cell carcinomas. Interestingly, Merkel cell polyomavirus was detected only in ordinary (pure) Merkel cell carcinomas; none of the 4 combined Merkel cell carcinomas + squamous cell carcinomas was positive for Merkel cell polyomavirus (P = .001). Morphometric analyses revealed that Merkel cell polyomavirus-negative Merkel cell carcinomas had more irregular nuclei (P < .001) and more abundant cytoplasm (P = .001) than Merkel cell polyomavirus-positive Merkel cell carcinomas, which had uniform round nuclei and scant cytoplasm. Reliability of the morphometry was confirmed using intraobserver and interobserver reliability tests. These results demonstrated statistically significant differences in tumor cell morphology between Merkel cell polyomavirus positive and -negative Merkel cell carcinomas and reconfirmed the absence of Merkel cell polyomavirus in combined tumors. Furthermore, the results strongly suggest fundamental biological differences between Merkel cell polyomavirus positive and -negative Merkel cell carcinomas, supporting that Merkel cell polyomavirus plays an important role in the pathogenesis of Merkel cell polyomavirus-positive Merkel cell carcinoma. PMID- 21277611 TI - Virus-encoded microRNAs. AB - MicroRNAs (miRNAs) are the subject of enormous interest. They are small non coding RNAs that play a regulatory role in numerous and diverse cellular processes such as immune function, apoptosis and tumorigenesis. Several virus families have been shown to encode miRNAs, and an appreciation for their roles in the viral infectious cycle continues to grow. Despite the identification of numerous (>225) viral miRNAs, an in depth functional understanding of most virus encoded miRNAs is lacking. Here we focus on a few viral miRNAs with well-defined functions. We use these examples to extrapolate general themes of viral miRNA activities including autoregulation of viral gene expression, avoidance of host defenses, and a likely important role in maintaining latent and persistent infections. We hypothesize that although the molecular mechanisms and machinery are similar, the majority of viral miRNAs may utilize a target strategy that differs from host miRNAs. That is, many viral miRNAs may have evolved to regulate viral-encoded transcripts or networks of host genes that are unique to viral miRNAs. Included in this latter category is a likely abundant class of viral miRNAs that may regulate only one or a few principal host genes. Key steps forward for the field are discussed, including the need for additional functional studies that utilize surgical viral miRNA mutants combined with relevant models of infection. PMID- 21277613 TI - Ratio variation of congener profiles of PCDD/Fs and dioxin-like PCBs in human milk during lactation. AB - This study investigates the compositional variations, changes in concentrations and contribution of particular congeners of PCDDs, PCDFs, non-ortho PCBs and mono ortho PCBs in human milk from two mothers sampled during the 12-month lactation period. Total PCDD/F and dioxin-like PCB concentration in milk sampled from the primiparous mother on day 5 after delivery was 37 pg TEQ/g fat, and this value decreased significantly by 43% at 12 months. In milk sampled from the multiparous mother nursing her second child on day 5 after delivery was 12 pg TEQ/g fat, and this value decreased by 40% at 12 months. The decrease was statistically significant not for PCDD/Fs, but for dioxin-like PCBs. The ratio variance of the congener profiles of PCDD/Fs and dioxin-like PCBs in the milk remained similar during lactation. Moreover, the congener profiles of PCDD/Fs and dioxin-like PCBs in the milk showed similar percentages for both mothers independent of the lactation event and the number of previous births. The mean daily intake of dioxins by the infant nursed by the primiparous mother and the infant nursed by the multiparous mother up to six months of age was 140 and 46 pg TEQ/kg body weight, respectively. From seven to twelve months of age, the mean daily intake was 37 and 13 pg TEQ/kg body weight, respectively. Both values decreased by approximately 70%. The reasons why the mothers' body burden of dioxins decreased by breastfeeding and why the infants' daily intake of human milk per body weight decreased as the infant grows older consequently decreased were considered. PMID- 21277614 TI - Aluminium speciation in streams and lakes of the UK Acid Waters Monitoring Network, modelled with WHAM. AB - The Windermere Humic Aqueous Model (WHAM) incorporating Humic Ion-Binding Model VI was applied to analytical data from the United Kingdom Acid Waters Monitoring Network, collected for 22 streams and lakes over the period 1988-2007, to calculate the chemical speciation of monomeric aluminium (Al(mon)) in 3087 water samples. Model outputs were compared with analytical measurements of labile and non-labile Al(mon) concentrations, the former being equated with inorganic forms of Al(mon) and the latter with organically-complexed metal. Raw analytical data were used, and also data produced by applying a correction for the possible dissociation of organically-complexed Al(mon), and therefore its underestimation, during passage through the analytical cation-exchange column. Model calibration was performed by finding the conversion factor, F(FADOC), between the concentration of isolated fulvic acid, with default ion-binding properties, required by the model, and the measured concentration of dissolved organic carbon, [DOC]. For both uncorrected and corrected data, the value of F(FADOC) for streams was greater than for lakes, indicating greater binding activity towards aluminium. Model fits were better using uncorrected analytical data, but the values of F(FADOC) obtained from corrected data agreed more closely with previous estimates. The model provided reasonably good explanations of differences in aluminium speciation between sampling sites, and of temporal variations at individual sites. With total monomeric concentration as input, WHAM calculations might substitute for analytical speciation measurements, or aid analytical quality control. Calculated Al(3+) activities, a(Al3+), showed a pH-dependence similar to that previously found for other surface waters, and the modelling exercise identified differences between waters of up to two orders of magnitude in the value of a(Al3+) at a given pH. The model gives the net charge of dissolved organic matter, which is calculated to have risen significantly at 15 of the AWMN sites, due to increases in pH and decreases in aluminium concentration. PMID- 21277615 TI - Emission of trace gases and organic components in smoke particles from a wildfire in a mixed-evergreen forest in Portugal. AB - On May 2009, both the gas and particulate fractions of smoke from a wildfire in Sever do Vouga, central Portugal, were sampled. Total hydrocarbons and carbon oxides (CO(2) and CO) were measured using automatic analysers with flame ionisation and non-dispersive infrared detectors, respectively. Fine (PM(2.5)) and coarse (PM(2.5-10)) particles from the smoke plume were analysed by a thermal optical transmission technique to determine the elemental and organic carbon (EC and OC) content. Subsequently, the particle samples were solvent extracted and fractionated by vacuum flash chromatography into different classes of organic compounds. The detailed organic speciation was performed by gas chromatography mass spectrometry. The CO, CO(2) and total hydrocarbon emission factors (g kg(-1) dry fuel) were 170 +/- 83, 1485 +/- 147, and 9.8 +/- 0.90, respectively. It was observed that the particulate matter and OC emissions are significantly enhanced under smouldering fire conditions. The aerosol emissions were dominated by fine particles whose mass was mainly composed of organic constituents, such as degradation products from biopolymers (e.g. levoglucosan from cellulose, methoxyphenols from lignin). The compound classes also included homologous series (n-alkanes, n-alkenes, n-alkanoic acids and n-alkanols), monosaccharide derivatives from cellulose, steroid and terpenoid biomarkers, and polycyclic aromatic hydrocarbons (PAHs). The most abundant PAH was retene. Even carbon number homologs of monoglycerides were identified for the first time as biomarkers in biomass burning aerosols. PMID- 21277616 TI - Trace element concentrations in hair of healthy Chinese centenarians. AB - Trace element concentrations, as indicators of micronutrient status of healthy centenarians, have not been widely analyzed. This study aimed to assess trace element concentrations in the hair of healthy centenarians. The effects of gender and age on element concentrations were also investigated. Eleven trace elements (Al, Ba, Cd, Cr, Cu, Fe, Mo, Pb, Se, Sr and Zn) in the scalp hair of 107 healthy Chinese centenarians were examined. The overall reference values (RVs) in mg/kg for the hair concentrations of trace elements in centenarians were as follows: Al, 14.95; Ba, 2.68; Cd, 0.06; Cr, 0.59; Cu, 6.21); Fe, 19.37; Mo, 0.50; Pb, 4.64; Se, 0.37; Sr, 4.84; and Zn, 154.37. Data analysis found that only Cu and Zn concentrations show a normal distribution, and there is no significant difference between males and females in any element except Zn. However, the levels of Al, Cd, Cr, Fe, Mo, Pb decrease and the levels of Ba, Cu, Se, Sr, Zn increase with age in the centenarian cohort. Results also revealed that sufficient Zn and Se concentrations as well as low exposure to heavy metals pollution contribute to the longevity of centenarians. The results imply the possibility of manipulating trace element concentrations, especially Zn and Se concentrations in tissues, as a means for therapeutic modality in geriatric disease. PMID- 21277617 TI - Encrusting cystitis due to Corynebacterium urealyticum in a patient with ANCA associated vasculitis: case report and review of the literature. AB - OBJECTIVES: To report a patient with systemic ANCA-associated vasculitis, under maintenance treatment, who had persistent microscopic hematuria and developed recurrent pelvic pain due to Corynebacterium urealyticum encrusting cystitis. The relevant literature on this infection is reviewed. METHODS: Descriptive case report and a review of the literature (PubMed search). RESULTS: A 39-year-old woman on maintenance therapy for systemic ANCA-associated vasculitis, diagnosed 10 months earlier and with persistent microscopic hematuria, developed recurrent pelvic pain. She had received several immunosuppressants (including cyclophosphamide and rituximab) since the onset of her vasculitis, as well as cycles of broad-spectrum antibiotics during the acute initial phase of her disease. Computerized tomography of the pelvis and cystoscopy showed several encrusted calcifications in the bladder mucosa, and, finally, urine culture (selective media) led to the diagnosis of C. urealyticum infection. Most of the bladder-encrusted stones were removed during cystoscopy and daily intramuscular teicoplanin injections were given for 14 days. Her symptoms disappeared rapidly and completely. On reviewing the literature, immunosuppression, previous broad spectrum antibiotics, urogenital alkaline pH, and prolonged bladder catheterization are predisposing factors for this rare infection. C. urealyticum encrusting cystitis has been reported in patients with systemic diseases but not yet in ANCA-associated vasculitis. Outcome is almost always good under adequate antibiotic therapy, mainly glycopeptides. CONCLUSION: Physicians should be aware of this unusual but potentially emerging infectious complication that can be challenging in ANCA-associated vasculitis, because the urinary tract can be affected by the vasculitis or as a complication of previous cyclophosphamide therapy. PMID- 21277618 TI - Interstitial lung disease induced or exacerbated by TNF-targeted therapies: analysis of 122 cases. AB - OBJECTIVES: To analyze the clinical characteristics, outcomes, and patterns of association with the different biologic agents used in all reported cases of adult patients developing interstitial lung disease (ILD) after biologic therapy. METHODS: In 2006, the Study Group on Autoimmune Diseases of the Spanish Society of Internal Medicine created the BIOGEAS project. One objective was to collect data on autoimmune diseases secondary to the use of biologic agents by quarterly Medline search surveillance of reported cases. For this study, the baseline included articles published between January 1990 and March 2010, including the MeSH term "lung diseases, interstitial" as the key research term. In addition, we report an unpublished case of ILD secondary to biologic therapy. RESULTS: There are 122 reported cases of new-onset or exacerbation of ILD secondary to administration of biologic therapies. Biologic agents associated with ILD were overwhelmingly anti-tumor necrosis factor agents (etanercept in 58 cases and infliximab in 56) and were administered for rheumatoid arthritis in 108 (89%) patients. ILD appeared a mean of 26 weeks after initiation of biologic agents. ILD was confirmed by pulmonary biopsy in 26 cases, although a specific histopathologic description was detailed in only 20: 7 patients were classified as usual interstitial pneumonia, 6 as nonspecific interstitial pneumonia, 5 as organizing pneumonia, 1 as diffuse alveolar damage, and 1 as lymphoid interstitial pneumonia. Treatment of ILD included withdrawal of biologic agents in all cases but 1. The outcome of ILD was detailed in 52 cases. Complete resolution was reported in 21 (40%) cases, improvement or partial resolution in 13 (25%), and no resolution in 18 (35%). Fifteen (29%) patients died during the follow-up, the majority (70%) during the first 5 weeks after initiating biologic therapy. In comparison with survivors, patients who died were aged >65 years (67% vs 33%, P = 0.036), with later onset of ILD (46 weeks vs 15 weeks, P = 0.006), received immunosuppressive drugs more frequently (33% vs 8%, P = 0.036), and more often had a previous diagnosis of ILD (67% vs 29%, P = 0.025). CONCLUSIONS: We found that 97% of cases of ILD associated with biologic agents were associated with agents blocking tumor necrosis factor-alpha, a cytokine that has been implicated in the pathophysiology of pulmonary fibrosis. Strikingly, drug-induced ILD had a poor prognosis, with an overall mortality rate of around one third, rising to two thirds in patients with preexisting ILD. PMID- 21277619 TI - Interleukin-1 targeting drugs in familial Mediterranean fever: a case series and a review of the literature. AB - OBJECTIVES: Familial Mediterranean fever (FMF) is an autosomal-recessive autoinflammatory disorder common in Mediterranean populations. FMF is associated with mutations of the MEFV gene, which encodes pyrin. Functional studies suggest that pyrin is implicated in the maturation and secretion of IL-1. The IL-1 receptor antagonist or anti-IL1 monoclonal antibody may therefore represent a new approach to treat FMF. The aim of this report was to evaluate and discuss treatment of FMF with interleukin-1 targeting drugs. METHODS: Electronic mailing lists of French pediatric and adult rheumatologist associations were used to call for FMF patients treated with interleukin-1 antagonists. A search for published FMF patients treated with interleukin-1 targeting drugs was performed by screening PubMed. RESULTS: Here, we report 7 cases of FMF patients treated with anakinra and/or canakinumab and discuss the clinical situations that may indicate the use of IL-1 blocking agents in FMF. The use of interleukin-1 targeting drugs was beneficial to all patients. The reasons for using interleukin-1 targeting drugs in FMF patients were as follows: (1) incomplete control of disease activity despite colchicine treatment; (2) high serum amyloid A levels despite colchicine treatment; (3) impossibility to use colchicine treatment because of severe side effects; (4) FMF in association with vasculitis. CONCLUSIONS: Interleukin-1 targeting drugs may be good candidates when looking for an alternative or supplementary treatment to colchicine. These observations highlight the need for controlled trials to further evaluate the safety and efficacy of interleukin-1 antagonists in FMF patients. PMID- 21277620 TI - Anti-neutrophil antibody associated vasculitis in systemic sclerosis. AB - OBJECTIVES: To report 3 cases ANCA-associated vasculitis (AAV) that developed in patients suffering from systemic sclerosis (SSc) and to review previously reported cases. METHODS: We describe 3 patients diagnosed with SSc who developed severe AAV that presented as crescentic glomerulonephritis (GN) and/or alveolar hemorrhage. A retrospective review of the literature was performed using the PubMed database. RESULTS: The first patient presented with rapidly progressive renal failure and then with 2 episodes of massive alveolar hemorrhage. She was partially refractory to treatment with corticosteroids and cyclophosphamide but responded promptly to treatment with rituximab. The second patient suffered from 2 episodes of fulminant alveolar hemorrhage; the first responded to intravenous corticosteroids, but the second was fatal despite aggressive immune suppression with corticosteroids and cyclophosphamide. The third patient presented with a clinical picture compatible with scleroderma renal crisis (SRC) but was later diagnosed with crescentic GN and subsequently died from probable alveolar hemorrhage. Thirty-seven cases of AAV in SSc patients have been described in the English literature. Clinical manifestations include rapidly progressive GN, alveolar hemorrhage, limb ischemia, and vasculitic skin rash. In contrast to SRC that usually develops early in the course of SSc, ANCA-associated GN in SSc patients occurred later, after several years of illness. Hypertension, microangiopathic hemolytic anemia, and thrombocytopenia that are the hallmark of SRC were observed only in a minority of AAV cases. Almost all cases of AAV in SSc were positive for MPO-ANCA. CONCLUSIONS: AAV in the setting of SSc is a diagnostic challenge. Differential diagnosis from SRC is crucial as treatment approach for these conditions completely differs. High doses of corticosteroids and immune suppression are advocated in severe AAV. In resistant cases, treatment with rituximab may be considered. PMID- 21277621 TI - The impact of co-morbid conditions on family history of venous thromboembolism in Whites and Blacks. AB - INTRODUCTION: Our objectives were to compare the magnitude of family history as a risk factor for venous thromboembolism (VTE) risk between Blacks and Whites, and to assess the impact of co-morbid conditions on familial risk for VTE. MATERIALS AND METHODS: We used data from the Genetic Attributes Thrombosis Epidemiology (GATE) study, a matched case-control study which enrolled Blacks and Whites aged 18-70years in Atlanta, Georgia. A total of 1,094 case patients with a deep vein thrombosis (DVT) or pulmonary embolism (PE) and 1,264 control patients were interviewed about their family history. RESULTS: Family history of VTE was a statistically significant risk factor for VTE among Blacks (odds ratio (OR)=2.9, 95% confidence interval (CI) 2.0-4.1; P value<0.0001) and among Whites (OR=2.7, 95% CI 1.9-3.7; P value<0.0001); among Blacks and Whites who were obese or had hypertension; among Blacks who had diabetes mellitus or cancer; as well as among males and females, and across all age categories. Family history of VTE increased the risk of VTE among Blacks with cancer by about 6-fold, whereas among Blacks without cancer the increased risk due to a positive family history was about 3 fold; a 2-fold relative difference. In addition, family history was a risk factor for VTE among case patients with DVT only or with PE only. The effect of family history generally was stronger among those with recurrent episodes of VTE compared with a first episode of VTE. For example, family history of any VTE was a strong risk factor among Black females with recurrent VTE compared with Black females with first VTE (OR=3.9, 95% CI 2.0-7.5; P value<0.0001). CONCLUSION: Our study indicated that the adjusted attributable fraction for VTE was 16.9% among Blacks vs. 18.3% among Whites, and certain co-morbid conditions could further increase the risk of VTE associated with a positive family history of VTE. PMID- 21277622 TI - Coagulation parameters in patients receiving dabigatran etexilate or rivaroxaban: two observational studies in patients undergoing total hip or total knee replacement. AB - INTRODUCTION: Dabigatran and rivaroxaban have recently been added to the armamentarium for thromboprophylaxis in orthopedic surgery. Although this is their first licensed indication, others will soon follow. Owing to their claimed predictable anticoagulant response that dispenses with the need for monitoring coagulation, their effects are poorly described in routine cases. However, interpreting blood coagulation results and evaluating whether a treatment is properly targeted in the case of untoward incidents will become a common concern for clinicians. METHODS: Eighty patients undergoing total hip or knee replacement were included in two studies. Forty of them received dabigatran (study 1) and 40 rivaroxaban (study 2). Blood samples (n = 176 and 166) were taken preoperatively and twice a week from the first postoperative day. RESULTS: Dabigatran increased aPTTr about two-fold and PT about 1.2-fold, and it was mostly an initiation-phase modulator of thrombin generation. Mean circulating concentrations as measured by a diluted thrombin time were 105 +/- 85 ng/mL at T(max) in samples from patients receiving the full dosing. They depended significantly on renal function, body weight and gender. Rivaroxaban increased aPTTr and PTr around 1.5 fold and modified the initiation and amplification phases of thrombin generation, with a lowered and prolonged thrombin burst. Mean circulating concentrations as measured by an antiXa test were 117 +/- 78 ng/mL at T(max). With both drugs, routine coagulation tests, thrombin generation curves and functionally determined concentrations exhibited high interindividual variability. CONCLUSION: Routine coagulation tests are altered in patients receiving dabigatran or rivaroxaban, but their alterations poorly reflect the circulating concentrations as determined by functional approaches. PMID- 21277623 TI - A phase I study with an expanded cohort to assess the feasibility of intraperitoneal carboplatin and intravenous paclitaxel in untreated ovarian, fallopian tube, and primary peritoneal carcinoma: A Gynecologic Oncology Group study. AB - OBJECTIVE: This study aimed to determine the first-cycle maximum tolerated dose (MTD) of intraperitoneal carboplatin in combination with intravenous paclitaxel and then assess the feasibility of this dose over multiple cycles. METHODS: Beginning at an intraperitoneal (IP) carboplatin dose area under the curve (AUC) of 5 and a fixed intravenous dose of 175mg/m(2) paclitaxel, patients were entered on a dose-escalating phase evaluating first-cycle dose-limiting toxicity (DLT). After estimating the MTD, cohorts of 20 patients were then entered in an expanded phase to evaluate DLT over four cycles. RESULTS: Twenty-one patients were entered on the dose-escalating phase. A first-cycle MTD of carboplatin at AUC 8 was tolerated although thrombocytopenia was dose-limiting over multiple cycles. An additional 69 patients were treated in expanded cohorts. Only 5/90 (5.6%) patients discontinued treatment because of a port problem. Four-cycle DLT required de-escalation to a carboplatin AUC of 6, and even at that dose, there were 14 dose-limiting toxic effects in 40 patients (35%). Seven dose-limiting toxicities were due to neutropenia, and 6 were due to grade 3/4 thrombocytopenia. Six cycles of therapy were completed in 75% of eligible patients, but dose adjustments were required. CONCLUSIONS: The first-cycle MTD did not predict the tolerability of this regimen over multiple cycles. Using an IP carboplatin dose of AUC 6 in combination with paclitaxel, the regimen can be administered with a high completion rate over multiple cycles. Because neutropenia is a frequent DLT, the addition of hematopoietic growth factors may permit a high completion rate while maintaining this dose. PMID- 21277624 TI - Mechanisms of immune tolerance relevant to food allergy. AB - The intestine has an unenviable task: to identify and respond to a constant barrage of environmental stimuli that can be both dangerous and beneficial. The proper execution of this task is central to the homeostasis of the host, and as a result, the gastrointestinal tract contains more lymphocytes than any other tissue compartment in the body, as well as unique antigen-presenting cells with specialized functions. When antigen is initially encountered through the gut, this system generates a robust T cell-mediated hyporesponsiveness called oral tolerance. Although seminal observations of oral tolerance were made a century ago, the relevant mechanisms are only beginning to be unraveled with the use of modern investigational techniques. Food allergy is among the clinical disorders that occur from a failure of this system, and therapies that seek to re-establish tolerance are currently under investigation. PMID- 21277625 TI - Future therapies for food allergies. AB - Food allergy is an increasingly prevalent problem in westernized countries, and there is an unmet medical need for an effective form of therapy. A number of therapeutic strategies are under investigation targeting foods that most frequently provoke severe IgE-mediated anaphylactic reactions (peanut, tree nuts, and shellfish) or are most common in children, such as cow's milk and hen's egg. Approaches being pursued are both food allergen specific and nonspecific. Allergen-specific approaches include oral, sublingual, and epicutaneous immunotherapy (desensitization) with native food allergens and mutated recombinant proteins, which have decreased IgE-binding activity, coadministered within heat-killed Escherichia coli to generate maximum immune response. Diets containing extensively heated (baked) milk and egg represent an alternative approach to food oral immunotherapy and are already changing the paradigm of strict dietary avoidance for patients with food allergy. Nonspecific approaches include monoclonal anti-IgE antibodies, which might increase the threshold dose for food allergen in patients with food allergy, and a Chinese herbal formulation, which prevented peanut-induced anaphylaxis in a murine model and is currently being investigated in clinical trials. The variety of strategies for treating food allergy increases the likelihood of success and gives hope that accomplishing an effective therapy for food allergy is within reach. PMID- 21277626 TI - Local allergic rhinitis: allergen tolerance and immunologic changes after preseasonal immunotherapy with grass pollen. PMID- 21277628 TI - The effect of experimental, long-term exposure to low-dose zearalenone mycotoxicosis on the histological condition of ovaries in sexually immature gilts. AB - Farm animals are at risk of exposure to zearalenone (ZEA) in feedstuffs, which may lead to aberrations in their reproductive development, thereby adversely affecting production outcomes. The objective of this study was to determine the effect of long-term (48 days), per os administration of low ZEA doses (50% [20 MUg ZEA/kg body weight (bw)] and 100% [40 MUg ZEA/kg bw] NOAEL values) on anatomopathological changes in the ovaries of sexually immature gilts. The experiment involved 12 clinically healthy gilts aged 2 months with an initial body weight of about 40 kg and a determined immune status. The animals were randomly divided into two experimental groups (E1, E2) and a control group (C; all n = 4). Group E1 received per os 20 MUg ZEA/kg bw for 48 days; group E2 received per os 40 MUg ZEA/kg bw for 48 days; and group C received per os placebo for 48 days. Analytical samples of the mycotoxin were administered daily per os in gelatine capsules before morning feeding. Animals were sacrificed at the end of the experiment. The results of anatomopathological examinations of the ovaries in immature gilts subjected to long-term, low-dose ZEA exposure showed that ZEA induced experimental hyperoestrogenism lowered the proliferative ability of granulosa cells of the ovarian follicle walls and of the connective tissue of the ovarian stroma, in particular at the lower ZEA dose. PMID- 21277629 TI - Ecotoxicological approach for assessing the contamination of a Hawaiian coral reef ecosystem (Honolua Bay, Maui) by metals and a metalloid. AB - The goal of this study was to assess the contamination of Honolua Bay using an ecotoxicological approach. First, the concentrations of 9 contaminants (metals and metalloid) were assessed in sediments and tropical marine organisms (alga Halimeda kanaloana, goatfish Parupeneus multifasciatus and urchin Tripneustes gratilla) sampled from Honolua and surrounding Bays. Then, the ecological parameters characterizing coral health (e.g. coral cover) were evaluated in Honolua Bay in the context of these contaminants. High concentrations of Co, Cr, Mn, Ni, and V in sediments from Honolua and Honokohau Bay were measured, but these concentrations were not mirrored in the organisms examined, except for Mn, suggesting that the metals are generally bound in chemically inert forms in these sediments. Moreover, few anthropogenic activities impact these bays and so the elevated Co, Cr, Mn, Ni and V concentrations in sediments appear to stem from their high natural background in Honolua and Honokohau watersheds. An analysis of the relationship between the ecological parameters and metal concentrations in Honolua Bay revealed a significant correlation between coral cover and Co, Cr, Mn, Ni, V, Zn concentrations in sediments, with coral cover decreasing with increasing metal concentration. Collectively, however, the data suggest that a complex mixture of land-based stressors (e.g. sediment, metals, nutrients) affect the coral health in Honolua Bay, rather than metal stress alone. PMID- 21277630 TI - Dimercaptosuccinic acid-coated magnetite nanoparticles for magnetically guided in vivo delivery of interferon gamma for cancer immunotherapy. AB - As radio- and chemotherapy-based cancer treatments affect both tumors and healthy tissue, cancer immunotherapy attempts to specifically enhance the natural immune response to tumor cells. In mouse models of cancer, we tested uniform dimercaptosuccinic acid (DMSA)-coated monodisperse magnetic nanoparticles as a delivery system for the anti-tumorigenic cytokine IFN-gamma. IFN-gamma-adsorbed DMSA-coated magnetic nanoparticles were targeted to the tumor site by application of an external magnetic field. We analyzed nanoparticle biodistribution before and after IFN-gamma conjugation, as well as the efficiency of nanoparticle accumulation in tumors, IFN-gamma release in the area of interest, and the effects of both on tumor development. At the tumor site, we observed a high degree of nanoparticle accumulation and of cytokine delivery, which led to increased T cell and macrophage infiltration and promoted an anti-angiogenic effect. The combined action led to a notable reduction in tumor size. Our findings indicate that IFN-gamma-adsorbed DMSA-coated magnetite nanoparticles can be used as an efficient in vivo drug delivery system for tumor immunotherapy. PMID- 21277631 TI - Oxytocin does not modify GH, ACTH, cortisol and prolactin responses to Ghrelin in normal men. AB - BACKGROUND: In order to test the possible effect of Oxytocin (OT) on Ghrelin stimulated GH, PRL, ACTH and cortisol, ten healthy normal men were studied. METHODS: TESTS: Ghrelin (0.2 MUg/kg body weight (BW)) as an iv bolus; Ghrelin plus OT (2 IU as bolus plus 0.07 IU/min administered for 90 min). RESULTS: The administration of OT did not change GH, PRL, ACTH and cortisol release induced by Ghrelin. CONCLUSIONS: The data suggests that in humans OT did not modulate the GH, PRL, ACTH and cortisol response to Ghrelin. PMID- 21277632 TI - Quantifying the impact of septic tank systems on eutrophication risk in rural headwaters. AB - Septic tank systems (STS) are a potential source of nutrient emissions to surface waters but few data exist in the UK to quantify their significance for eutrophication. We monitored the impact of STS on nutrient concentrations in a stream network around a typical English village over a 1-year period. Septic tank effluent discharging via a pipe directly into one stream was highly concentrated in soluble N (8-63mgL(-1)) and P (<1-14mgL(-1)) and other nutrients (Na, K, Cl, B and Mn) typical of detergent and household inputs. Ammonium-N (NH(4)N) and soluble reactive P (SRP) fractions were dominant (70-85% of total) and average concentrations of nitrite-N (NO(2)N) were above levels considered harmful to fish (0.1mgL(-1)). Lower nutrient concentrations were recorded at a ditch and a stream site, but range and average values downstream of rural habitation were still 4 to 10-fold greater than those in upstream sections. At the ditch site, where flow volumes were low, annual flow-weighted concentrations of NH(4)N and SRP increased from 0.04 and 0.07mgL(-1), respectively upstream to 0.55 and 0.21mgL(-1) downstream. At the stream site, flow volumes were twice as large and flow weighted concentrations increased much less; from 0.04 to 0.21mgL(-1) for NH(4)N and from 0.06 to 0.08mgL(-1) for SRP. At all sites, largest nutrient concentrations were recorded under low flow and stream discharge was the most important factor determining the eutrophication impact of septic tank systems. The very high concentrations, intercorrelation and dilution patterns of SRP, NH(4)-N and the effluent markers Na and B suggested that soakaways in the heavy clay catchment soils were not retaining and treating the septic tank effluents efficiently, with profound implications for stream biodiversity. Water companies, water regulators and rural communities therefore need to be made more aware of the potential impacts of STS on water quality so that their management can be optimised to reduce the risk of potential eutrophication and toxicity to aquatic ecosystems during summer low flow periods. PMID- 21277633 TI - IL-4 and IL-13 suppress prostaglandins production in human follicular dendritic cells by repressing COX-2 and mPGES-1 expression through JAK1 and STAT6. AB - Originally discovered as a B cell growth and differentiation factor, IL-4 displays a variety of functions in many different cell types. Germinal center T cells are abundant producers of IL-4. In a recent report, we demonstrated that IL 4 inhibits prostaglandins (PGs) production in follicular dendritic cell (FDC) like cells, HK. To understand the inhibitory mechanisms of IL-4, its effects on the biosynthesis of enzymes in charge of PG production were assessed in this study. Although IL-4 did not affect COX-1 expression, it specifically inhibited LPS-induced COX-2 biosynthesis at mRNA and protein levels. Protein expression of mPGES-1, a downstream enzyme of COX-2, was also markedly diminished by IL-4 but not by IL-10, maximizing the inhibitory activity. Next, we attempted to identify the early signaling molecules that led to this inhibition of COX-2 expression. Although IL-4 induced tyrosine phosphorylation of JAK1 and TYK2, RNA interference experiments revealed that only JAK1 was responsible for the IL-4-stimulated STAT6 phosphorylation. Knocking down JAK1 and STAT6 ablated the inhibitory effect of IL 4 on COX-2 expression and significantly reduced production of PGE(2) and prostacyclin. Similar results were obtained with IL-13. Pharmacologic inhibitors of ERK and p38 mitogen-activated protein kinases inhibited the COX-2 upregulation. However, IL-4 did not affect LPS-induced phosphorylation of ERK and p38. These results stress the essential roles of JAK1 and STAT6 in the early signaling pathway of IL-4 and IL-13 leading to suppression of COX-2 expression and repression of PG production by HK cells. Our results suggest that T cells via IL-4 play a regulatory role in PG generation in FDC. IL-4 therapeutics may be applied to immune disorders where normal and ectopic expression of germinal center reactions needs to be regulated. PMID- 21277634 TI - Reliability of the M-FLEXTM: equipment to measure palmar grasp strength in infants. AB - The palmar grasp behavior investigation is frequent in evaluation routine of infants. The aim of this study was to determine the reliability of an instrument for measuring palmar grasp strength in infants from birth to four months of age. Thirty-nine healthy infants from both sexes from birth to four months of age were evaluated and divided into three groups ("SC", "FR", "BL") according to the city they came from. The equipment under test is called M-FLEX((r)), which provides maximum grasp strength (FMAX), mean grasp strength (FMEAN) and grasp time (GRT) values. The repeatability and reproducibility of measures produced by the M FLEXTM were verified. Three measurements were obtained (M1, M2, M3) from both hands, with the infant's face turned to the right. To calculate the repeatability, the three measures were compared to themselves in each group. For reproducibility, the difference between the averages of M1 of the three variables provided by M-FLEXTM was verified in the three sampling sites. The statistical tests used were ANOVA, Pearson's correlation and calculation of the intra-class correlation coefficient (ICC) with their respective confidence intervals (CI). The M-FLEXTM proved to be an outfit that provides measures capable of characterizing the palmar grasp phenomenon in infants. PMID- 21277635 TI - Glutamate cysteine ligase (GCL) and self reported depression: an association study from the HUNT. AB - BACKGROUND: There is increasing evidence suggesting oxidative stress may play a role in the aetiology of depression. Glutathione is the brain's predominant free radical scavenger, and associated polymorphisms of the glutamate cysteine ligase (GCL) gene have been reported for related psychiatric disorders. The aim of the study was to investigate candidate polymorphisms of GCL validated in schizophrenia and their association with current state depression, as measured by the Hospital Anxiety and Depression Scale (HADS). METHODS: Polymorphisms were genotyped on 983 cases and 967 controls selected from a population sample of adults participating in the Nord-Trondelag Health Study. Cases were the top scoring individuals (98.5th percentile) on the HADS depression subscale while the controls were randomly selected from below this cut-off. The polymorphisms comprised three SNPs from GCLM, the gene encoding the GCL modifier and 9 SNPs plus a trinucleotide repeat (TNTR) from intron 1 and the 5'UTR of GCLC, the gene encoding the GCL catalytic subunit. Using the linkage disequilibrium between the GCLC markers we also tested whether SNPs could represent the variation of the TNTR. RESULTS: The candidate polymorphisms showed no evidence for association with depression. The C allele of SNP rs9474592 is coupled with the 9 GAG repeats allele of the TNTR, r2=0.81. None of the other SNPs either individually or as two or three-SNP haplotypes was associated with the TNTR alleles. LIMITATIONS: Depression was self-reported and measured at one time point. CONCLUSIONS: This study provides no evidence to suggest that polymorphisms of GCL are associated with self-reported depression. PMID- 21277636 TI - The role of NGF and IL-2 serum level in assisting the diagnosis in first episode schizophrenia. AB - Development of reliable diagnostic bio-markers for schizophrenia remains a diagnostic challenge. Serum NGF and IL-2 were analyzed to examine the diagnostic efficiency and predictive capability of these two biomarkers in relation to schizophrenia diagnosis. Thirty neuroleptic naive subjects with first-episode schizophrenia, thirty patients with major depressive disorder (MDD) and twenty eight healthy control subjects participated in the study. One-way ANOVA demonstrated significantly lower serum IL-2 and NGF among schizophrenic patients and patients with MDD compared with healthy controls. Receiver operating characteristic (ROC) curve analysis was used to ascertain diagnostic efficiency of serum IL-2 and NGF levels. Area under the ROC curve (AUC) revealed a high level of differentiation between schizophrenic patients and healthy controls for both IL-2 and NGF serum concentrations. Diagnostic efficiency of combined NGF and IL-2 serum levels was also high in schizophrenic patients compared with healthy controls. Serum NGF and IL-2 are promising as potential screening or diagnostic biomarkers for schizophrenia and may be a useful adjunct for clinical assessment. PMID- 21277637 TI - The impact of parasite infections on the course of multiple sclerosis. AB - Previously, we demonstrated that helminth-infected MS patients showed significantly lower number of relapses, reduced disability scores, and lower MRI activity compared to uninfected MS subjects. In the current study, 12 patients with diagnosis of relapsing remitting MS presenting parasite infections were prospectively followed during 90 months; due to exacerbation of helminth infection symptoms after 63 months of follow-up, 4 patients received anti parasite treatment. Helminth-infection control was associated with significant increase in clinical and radiological MS activities. Moreover, these patients showed significant increase in the number of IFN-gamma and IL-12 producing cells, and a fall in the number of TGF-beta and IL-10 secreting cells, as well as CD4+CD25+FoxP3+ Treg cells evident 3 months after anti-helminth treatment began. These new observations on parasite infections associated to MS indicate that parasite regulation of host immunity can alter the course of MS. PMID- 21277638 TI - Infants versus older children fitted with cochlear implants: performance over 10 years. AB - OBJECTIVES: To investigate the efficacy of cochlear implants (CIs) in infants versus children operated at later age in term of spoken language skills and cognitive performances. METHOD: The present prospective cohort study focuses on 19 children fitted with CIs between 2 and 11 months (X=6.4 months; SD=2.8 months). The results were compared with two groups of children implanted at 12-23 and 24-35 months. Auditory abilities were evaluated up to 10 years of CI use with: Category of Auditory Performance (CAP); Infant-Toddler Meaningful Auditory Integration Scale (IT-MAIS); Peabody Picture Vocabulary Test (PPVT-R); Test of Reception of Grammar (TROG) and Speech Intelligibility Rating (SIR). Cognitive evaluation was performed using selected subclasses from the Griffiths Mental Development Scale (GMDS, 0-8 years of age) and Leiter International Performance Scale-Revised (LIPS-R, 8-13 years of age). RESULTS: The infant group showed significantly better results at the CAP than the older children from 12 months to 36 months after surgery (p<.05). Infants PPVT-R outcomes did not differ significantly from normal hearing children, whereas the older age groups never reached the values of normal hearing peers even after 10 years of CI use. TROG outcomes showed that infants developed significantly better grammar skills at 5 and 10 years of follow up (p<.001). Scores for the more complex subtests of the GMDS and LIPS-R were significantly higher in youngest age group (p<.05). CONCLUSION: This study demonstrates improved auditory, speech language and cognitive performances in children implanted below 12 months of age compared to children implanted later. PMID- 21277639 TI - Distributions of interleukin-6 (IL-6) promoter and metallothionein 2A (MT2A) core promoter region gene polymorphisms and their associations with aging in Turkish population. AB - Aging is determined as the product of an interaction among genetic, environmental and lifestyle factors. As interleukin-6 (IL-6) and metallothioneins (MTs) are related to inflammation and oxidative stress response, their genes are appropriate candidate for aging, age related diseases and infections. The aim of this study was to investigate the association between the IL-6 -174 G/C promoter region and MT2A -5 A/G core promoter region single nucleotide polymorphisms (SNPs) with longevity in Turkish population. Blood samples were collected from 354 individuals between 18 and 95 years of age. Individuals were classified into four groups according to their ages as 20-40, 41-60, 61-80, >80. IL-6 and MT2A polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Mean ages of individuals with IL-6 -74 C- carriers and C+ carriers were 49.82+/-20.45 years and 59.82+/-16.82 years, respectively. For the MT2A polymorphism, mean ages were estimated as 56.18+/ 19.50 years for G- carriers and 47.59+/-13.45 years for G+ carriers. As a result, when the IL-6 and MT2A polymorphisms were compared with the mean ages and age groups, statistically significant associations were found (p<0.001 and p<0.05, respectively). In conclusion, these data support that the IL-6 -174 C+ carriers and MT2A -5 G- carriers may be more advantageous for longevity. PMID- 21277640 TI - Fear of falling (FF): Psychosocial and physical factors among institutionalized older Chinese men in Taiwan. AB - Fear of falling (FF) can have multiple adverse consequences in the elderly. Although there are various fall prevention programs, little is known of FF and its associated characteristics. This study examined FF-associated physical and psychosocial factors in older Chinese men living in a veterans home in southern Taiwan. Subjects with a recent episode of delirium, of bed-ridden or wheelchair bound status, severe hearing impairment or impaired cognition were excluded. Overall, 371 residents (mean age 82.1 +/- 5.11 years, all males) participated. The prevalence of FF was 25.3%. Univariate analysis revealed that subjects in the FF group were older age, having lower education level, poorer sitting and standing balance, poorer activities of daily living (ADL), more depressive symptoms, higher chances of using walking aids, neurologic diseases, and a history of fall within the past 6 months. Logistic regression showed that depressive symptoms (odds ratio = OR = 6.73, 95%CI: 3.03-14.93, p < 0.001), activities of daily living (OR = 2.48, 95%CI: 1.08-5.71, p = 0.033), history of fall in the past 6 months (OR = 2.47, 95%CI: 1.04-5.9, p = 0.041), and neurological diseases (OR = 2.75, 95%CI: 1.15-6.56, p = 0.023) were all independent risk factors for FF. PMID- 21277641 TI - Comparison between low-dose multidetector computed coronary angiography and myocardial perfusion imaging test in patients with intermediate pre-test likelihood of coronary artery disease. PMID- 21277642 TI - Routine early invasive strategy and in-hospital mortality in women with non-ST elevation myocardial infarction: results from the Berlin Myocardial Infarction Registry (BMIR). AB - BACKGROUND: It is under discussion whether female patients with non-ST-elevation myocardial infarction (NSTEMI) benefit from routine invasive treatment strategy. We accordingly applied our data from the Berlin Myocardial Infarction Registry (BMIR) to analyze the association between early percutaneous coronary intervention (PCI) and hospital mortality in NSTEMI patients. METHODS: Data prospectively collected in the BMIR between 2004 and 2008 from 2808 patients (m=1820/w=988) directly admitted to hospitals with 24-h PCI facilities were included in the analysis. After adjustment for confounding variables, we compared in-hospital mortality for patients of both sexes with vs. without early PCI. RESULTS: Women with NSTEMI were, on average, 7years older than men and demonstrated significantly more comorbidities. A GPIIb/IIIa antagonist was applied in women less often than in men (31.4% vs. 38.4%, p=0.001), and an early PCI was also performed less often in women than in men (64.0% vs. 76.2%, p<0.001). In-hospital mortality was higher in women than in men (5.4% vs. 3.6%, p=0.027). In female patients with NSTEMI, after adjustment for differences in patients' characteristics, hospital mortality did not differ between those treated with early PCI and those managed conservatively (OR: 1.24, 95% CI 0.53 2.91). In contrast, hospital mortality in male patients was lower in those treated with an early PCI (OR: 0.41, 95% CI 0.21-0.78). CONCLUSION: In our clinical registry, early PCI in female patients with NSTEMI was not associated with lower hospital mortality. Further randomized-controlled trials are needed to better understand which women may benefit from early invasive therapy, and under which conditions such benefits are possible. PMID- 21277643 TI - Incidence, predictors and outcome of upper gastrointestinal bleeding in patients with acute coronary syndromes. AB - BACKGROUND: The broad utilization of revascularization and antithrombotic therapy in patients with acute coronary syndrome (ACS) is associated with a substantial risk of bleeding primarily related to arterial punctures, which can lead to worse outcome. AIM: To define the characteristics and outcome of patients who develop upper gastrointestinal bleeding (UGIB) in the setting of ACS. METHODS: We identified all patients admitted to the coronary care unit between 10/96 and 11/07 with ACS who developed UGIB. For each case 3 control cases were matched. Multiple baseline characteristics, as well as antithrombotic agents, revascularization strategy and endoscopy reports were assessed. Mortality at 30 day was the primary endpoint of the analysis. RESULTS: Of 7240 ACS patients, 64 (0.9%) developed UGIB. There were no significant differences between groups in the prevalence of diabetes and other risk factors, revascularization strategy, or the use of proton pump inhibitors. Patients with UGIB suffered more from renal impairment and left ventricular dysfunction and were more frequently treated with thienopyridines (89% vs. 68%, p=0.002) and glycoprotein IIb/IIIa inhibitors (39% vs. 24%, p=0.03). The combination of unfractionated heparin (UFH) with glycoprotein IIb/IIIa inhibitors was strongly associated with UGIB (OR: 2.87, 95% CI 1.66-4.97). Patients who developed UGIB had a substantially higher 30-day mortality rate (33% vs. 5%, p<0.001). CONCLUSIONS: UGIB in patients with ACS is associated with a markedly increased mortality. Previous peptic disease and the use of combined anti-platelet therapy, especially in conjunction with heparin, are strong risk factors for this serious complication. PMID- 21277644 TI - Self-motion perception and vestibulo-ocular reflex during whole body yaw rotation in standing subjects: the role of head position and neck proprioception. AB - Self-motion perception and vestibulo-ocular reflex (VOR) were studied during whole body yaw rotation in the dark at different static head positions. Rotations consisted of four cycles of symmetric sinusoidal and asymmetric oscillations. Self-motion perception was evaluated by measuring the ability of subjects to manually track a static remembered target. VOR was recorded separately and the slow phase eye position (SPEP) was computed. Three different head static yaw deviations (active and passive) relative to the trunk (0 degrees , 45 degrees to right and 45 degrees to left) were examined. Active head deviations had a significant effect during asymmetric oscillation: the movement perception was enhanced when the head was kept turned toward the side of body rotation and decreased in the opposite direction. Conversely, passive head deviations had no effect on movement perception. Further, vibration (100 Hz) of the neck muscles splenius capitis and sternocleidomastoideus remarkably influenced perceived rotation during asymmetric oscillation. On the other hand, SPEP of VOR was modulated by active head deviation, but was not influenced by neck muscle vibration. Through its effects on motion perception and reflex gain, head position improved gaze stability and enhanced self-motion perception in the direction of the head deviation. PMID- 21277645 TI - ERK phosphorylation predicts synergism between gemcitabine and the epidermal growth factor receptor inhibitor AG1478. AB - BACKGROUND: Clinical trials combining epidermal growth factor receptor (EGFR) inhibitors with gemcitabine-based chemotherapy in non-small cell lung cancer (NSCLC) have not produced a survival advantage. This may be caused by antagonism between the two drugs or mutations that promote such, possibly RAS mutation. Furthermore, ERK, a critical growth regulator downstream of RAS, may play a role. This study aimed to explore the relationship between ERK, synergy/antagonism and cell cycle arrest in combination treatment. METHODS: A549 (mutant KRAS), H322 (wildtype KRAS) and siRNA-mediated KRAS knockdown A549 were treated with gemcitabine and/or the EGFR inhibitor AG1478 and analyzed with median effect analysis. Cell cycle distribution and ERK phosphorylation were assessed using flow cytometry and ELISA, respectively. Effect on cytotoxicity after ERK inhibition by U0126 was also assessed. RESULTS: Cytotoxic interaction was dose dependent with antagonism at high dose AG1478. G1 arrest was observed with both high dose AG1478 and high dose gemcitabine and therefore was inconsistently associated with antagonism. Furthermore, ERK phosphorylation was increased by gemcitabine and its suppression by AG1478 was related to antagonism particularly in H322. ERK's effect in antagonism was further confirmed by using U0126. Greater antagonism was observed in the KRAS mutant cell line and KRAS knockdown by siRNA resulted in increased sensitivity to AG1478 as well as combination treatment. CONCLUSION: Our findings are consistent with a model in which ERK phosphorylation favors synergy and the outcome depends on the balance between gemcitabine-induced and AG1478-inhibited ERK phosphorylation. KRAS mutation confers resistance to AG1478 as well as combination treatment. PMID- 21277647 TI - Validation of a novel method to identify healthcare-associated infections. AB - Despite its potential for use in large-scale analyses, previous attempts to utilise administrative data to identify healthcare-associated infections (HAI) have been shown to be unsuccessful. In this study, we validate the accuracy of a novel method of HAI identification based on antibiotic utilisation patterns derived from administrative data. We contemporaneously and independently identified HAIs using both chart review analysis and our method from four Japanese hospitals (N=584). The accuracy of our method was quantified using sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) relative to chart review analysis. We also analysed the inter-rater agreement between both identification methods using Cohen's kappa coefficient. Our method showed a sensitivity of 0.93 (95% CI: 0.87-0.96), specificity of 0.91 (0.89-0.94), PPV of 0.75 (0.68-0.81) and NPV of 0.98 (0.96-0.99). A kappa coefficient of 0.78 indicated a relatively high level of agreement between the two methods. Our results show that our method has sufficient validity for identification of HAIs in large groups of patients, though the relatively lower PPV may imply limited utilisation in the pinpointing of individual infections. Our method may have applications in large-scale HAI identification, risk-adjusted multicentre studies involving cost of illness, or even as the starting point of future cost-effectiveness analyses of HAI control measures. PMID- 21277646 TI - Telomerase activity in pleural malignant mesotheliomas. AB - New treatments are needed for malignant pleural mesothelioma (MPM), which currently has a poor prognosis. Cellular immortalisation, one of the hallmarks of cancer, depends on the activity of a telomere length maintenance mechanism (TMM) either telomerase or alternative lengthening of telomeres (ALT). The TMMs are widely regarded as potential targets for cancer therapies and telomerase inhibitors have entered clinical trials. The aim of this study was to determine what proportion of MPMs use ALT and/or telomerase. Forty-three MPMs from 42 patients were examined for telomerase and ALT activity. Telomerase activity was detected by immunoaffinity purification followed by the telomere repeat amplification protocol (TRAP), and ALT activity was determined by the C-circle assay and by assessing telomere lengths using terminal restriction fragment analyses. We found that 43 of 43 MPMs were telomerase-positive[+] and ALT negative[-]. Therefore, to investigate whether pleural mesothelial cells are unusually susceptible to activation of telomerase, we examined activation of the TMMs in an in vitro model of cellular immortalisation, in which normal pleural mesothelial cells were transduced with simian virus 40 (SV40) oncogenes. We found that normal mesothelial cells were TMM-negative, and that expression of the SV40 oncogenes did not directly activate telomerase or ALT. Immortalisation, which in this experimental system results from additional genetic changes that have not yet been identified, was accompanied by activation of either TMM. Therefore, pleural mesothelial cells are capable of activating either TMM in vitro, and the observation that 100% of MPMs were telomerase[+] suggests that there are factors in vivo that select for telomerase activity during oncogenesis of this tumour type. We conclude that MPM is a tumour that could be considered for anti telomerase therapy. PMID- 21277648 TI - Rapid testing for respiratory syncytial virus in a paediatric emergency department: benefits for infection control and bed management. AB - Respiratory syncytial virus (RSV) is responsible for annual winter outbreaks of respiratory tract infection among children in temperate climates, placing severe pressure on hospital beds. Cohorting of affected infants has been demonstrated to be an effective strategy in reducing nosocomial transmission of RSV, and may keep cubicles free for other patients who require them. Testing of symptomatic children for RSV is standard practice, but unfortunately traditional laboratory testing is not rapid enough to aid decision-making processes. Rapid point-of-care testing (POCT) in the emergency department has been suggested as an alternative. We performed a prospective study to quantify the amount of cubicle time saved by using POCT results to allow a targeted cohorting strategy. Over the four-month study period, the POCT allowed 183 children to be admitted directly to a designated cohort area, thus saving 568.5 cubicle-days for other patients. This is equivalent to five cubicles being left free for each day of the study period. This is the first time the benefits of using POCT have been quantified in this way. POCT for RSV is a safe, cost-effective and efficient way to improve bed management. PMID- 21277649 TI - Environmental survey to assess viral contamination of air and surfaces in hospital settings. AB - The presence of pathogenic viruses in healthcare settings represents a serious risk for both staff and patients. Direct viral detection in the environment poses significant technical problems and the indirect indicators currently in use suffer from serious limitations. The aim of this study was to monitor surfaces and air in hospital settings to reveal the presence of hepatitis C virus, human adenovirus, norovirus, human rotavirus and torque teno virus by nucleic acid assays, in parallel with measurements of total bacterial count and haemoglobin presence. In total, 114 surface and 62 air samples were collected. Bacterial contamination was very low (<1 cfu/cm(2)) on surfaces, whereas the 'medium' detected value in air was 282 cfu/m(3). Overall, 19 (16.7%) surface samples tested positive for viral nucleic acids: one for norovirus, one for human adenovirus and 17 (14.9%) for torque teno virus (TTV). Only this latter virus was directly detected in 10 air samples (16.1%). Haemoglobin was found on two surfaces. No relationship was found between viral, biochemical or bacterial indicators. The data obtained confirm the difficulty of assessing viral contamination using bacterial indicators. The frequent detection of TTV suggests its possible use as an indicator for general viral contamination of the environment. PMID- 21277650 TI - Sporicides for Clostridium difficile: the devil is in the detail. AB - A taskforce has now been formed with representatives from the Department of Health's Advisory Committee on Antimicrobial Resistance and Healthcare Associated Infection (ARHAI), the Hospital Infection Society (HIS), the Department of Health (England) and the Health Protection Agency. The aims of the ARHAI/HIS Taskforce on Sporicidal Disinfectants are: to develop an accepted standard for laboratory testing of disinfectants which claim to have activity against C. difficile spores; to develop a network of laboratories with capability to perform in vitro assays of sporicidal activity of disinfectants; and to explore the creation of a national quality assessment scheme for laboratories which perform in vitro assays of sporicidal activity of disinfectants. PMID- 21277651 TI - Impact of surgical site infection surveillance in a neurosurgical unit. AB - This article describes a two-year surveillance of neurosurgical site infections and an outbreak of infections in deep brain stimulation (DBS) cases. From April to December 2008, six patients had a DBS surgical site infection (SSI). Audits of hygiene practices, infection control of the healthcare environment, and preoperative antimicrobial prophylaxis characteristics were carried out. The results of surgical audits showed that skin preparation and antimicrobial prophylaxis were not being performed adequately. In 2008, the general SSI rate was 1.8% (27 SSIs/1471 patients). Length of preoperative stay was significantly longer among infected patients (2.7 +/- 2.9 months) compared with uninfected patients (2.2 +/- 4.6 months) (P=0.01). Based on these results, skin preparation and antimicrobial prophylaxis were reviewed with the neurosurgery team. In 2009, the general SSI rate was reduced to 1.1% (16 SSI in 1410 patients), a reduction from 2008 (P=0.12). Although the overall incidence of SSI in 2008 (1.8%) was within the range of published data, this surveillance of SSIs permitted identification of site operative infected patients surgically treated for DBS. A set of actions was then taken to reduce SSI risk. This work demonstrates how an active surveillance programme can successfully change clinical care practice. PMID- 21277652 TI - Qualitative analysis of microbial contamination of inhalers. PMID- 21277653 TI - Investigation of a severe nosocomial outbreak of hepatitis A among healthcare workers and adult patients. PMID- 21277654 TI - Interneuron loss reduces dendritic inhibition and GABA release in hippocampus of aged rats. AB - Aging is associated with impairments in learning and memory and a greater incidence of limbic seizures. These changes in the aged brain have been associated with increased excitability of hippocampal pyramidal cells caused by a reduced number of gamma-aminobutyric acid-ergic (GABAergic) interneurons. To better understand these issues, we performed cell counts of GABAergic interneurons and examined GABA efflux and GABAergic inhibition in area CA1 of the hippocampus of young (3-5 months) and aged (26-30 months) rats. Aging significantly reduced high K(+)/Ca(2+)-evoked GABA, but not glutamate efflux in area CA1. Immunostaining revealed a significant loss of GABAergic interneurons, but not inhibitory boutons in stratum oriens and stratum lacunosum moleculare. Somatostatin-immunoreactive oriens-lacunosum moleculare (O-LM) cells, but not parvalbumin-containing interneurons were selectively lost. Oriens-lacunosum moleculare cells project to distal dendrites of CA1 pyramidal cells, providing dendritic inhibition. Accordingly, inhibition of dendritic input to CA1 from entorhinal cortex was selectively reduced. These findings suggest that the age dependent loss of interneurons impairs dendritic inhibition and dysregulates entorhinal cortical input to CA1, potentially contributing to cognitive impairment and seizures. PMID- 21277655 TI - Synthesis and evaluation of aroylthiourea derivatives of 4-beta-amino-4'-O demethyl-4-desoxypodophyllotoxin as novel topoisomerase II inhibitors. AB - A novel series of aroylthiourea derivatives of 4-beta-amino-4'-O-demethyl-4 desoxy- podophyllotoxin were synthesized. Their cytotoxicities against three cancer cell lines were investigated by MTT assay. The kDNA decatenation assay indicated that compounds 5a, 5f, 5h and 5l inhibited topoisomerase II-mediated kDNA decatenation. DNA flow cytometric analysis revealed that compound 5a induced cell cycle arrest at G2/M phase in HCT-116 cell line. PMID- 21277656 TI - A QSAR study using MTD method and Dragon descriptors for a series of selective ligands of alpha2C adrenoceptor. AB - A QSAR (quantitative structure-activity relationship) analysis of the binding affinities for a series of 43 quinoline derivatives active against the alpha2C adrenergic receptor was performed. Multiple linear regressions (MLR) were obtained using the minimum topological difference (MTD) descriptor and various descriptors which were calculated with Dragon3.0. The variable selection was performed either through the forward stepwise method or backward stepwise combined with forward stepwise methods, providing two satisfactory models. The first one, obtained as a result of the forward stepwise method, contains MTD, Mor24v, MATS5m, MATS7m, G3m, L1s, G_N_N descriptors, while the other one obtained through the combination of backward and forward stepwise methods contains the following descriptors: MTD, ZM2V, X5V, IC5, MATS4v, and E2u. Both models highlight the importance of steric interactions and can be used as tools for predicting the binding affinity of related compounds. PMID- 21277657 TI - [Neurological abnormalities in a 73-year-old woman]. PMID- 21277658 TI - [Rapidly progressive ANCA positive glomerulonephritis as the presenting feature of infectious endocarditis]. AB - The association of positive cytoplasmic antineutrophil antibody (ANCA) necrotizing crescentic glomerulonephritis with endocarditis raises diagnostic issues. Indeed, it is often difficult to determine if the kidney injury is either secondary to an infectious disease or caused by an ANCA-associated small vessel vasculitis. We report a 59-year-old man admitted in nephrology for acute glomerular syndrome in whom the renal biopsy showed a crescentic necrotizing glomerulonephritis. A diagnosis of vasculitis was initially considered in the presence of high titer of ANCA (anti-proteinase 3). Because of associated Staphyloccocus aureus endocarditis the patient received both corticosteroids and antibiotics that allowed remission of both kidney injury and endocarditis. The renal presentation and the disappearance of ANCA support the infectious etiology of this glomerulonephritis rather than an ANCA-associated small vessel vasculitis. It is important to be cautious in the presence of ANCA positive extracapillary glomerulonephritis and endocarditis should be ruled out before initiation of corticosteroids that may be nevertheless necessary in severe acute glomerulonephritis. PMID- 21277659 TI - Enternal [corrected] arginine supplementation stimulates DNA synthesis in skin donor wound. AB - BACKGROUND & AIMS: Arginine infusion has been demonstrated to increase wound protein deposition; however, the effects of its enteral supplementation on wound cell proliferation have not been studied. METHODS: Skin donor wound was created on the back of rabbits. The rabbits were randomly assigned to receive a control enteral diet, or the control enteral diet with supplemental arginine. On day 5 L [ring-(13)C(6)]phenylalanine and D-[U-(13)C(6)]glucose were infused to measure the fractional synthetic rates of DNA (reflecting cell proliferation) and protein in the wound. RESULTS: In the arginine group (n = 6) plasma arginine concentration was increased to 2.8 fold that in the control group (n = 8), which was a less increase than that of 6.4 fold for ornithine. Wound DNA fractional synthetic rate was 5.37 +/- 0.21%/day in the arginine group, greater (p < 0.05) than that of 4.27 +/- 0.35%/day in the control group. Protein fractional synthetic rates in the wound were comparable between the two groups. CONCLUSIONS: Enternal arginine supplementation increased wound DNA synthesis, which is anticipated to promote cell proliferation for wound healing. The failure of enteral arginine to stimulate protein synthesis is explained by limited increase in plasma arginine. Decreased availability of essential amino acids, especially branched chain amino acids, may also contribute to the failure to stimulate protein synthesis. PMID- 21277660 TI - Reconstruction of the alveolar cleft: effect of preoperative extraction of deciduous teeth at the sites of clefts on the incidence of postoperative complications. AB - Our objective was to find out if the extraction of deciduous teeth at the sites of clefts 3-8 weeks before alveolar bone grafting (ABG) would reduce the number of postoperative complications. Chart reviews were reviewed retrospectively of patients who had had ABG from March 2006 to June 2009. To reduce variables only healthy, non-syndromic, cooperative patients were included. Eleven patients had had their deciduous teeth extracted at the cleft sites 3-8 weeks before ABG and 10 patients had had the extractions done intraoperatively at the same time as ABG. There was a single case of postoperative infection and no wound dehiscence in the preoperative extraction group, and there were no delays in postoperative orthodontic treatment. In the intraoperative group there were 3 cases of local wound infection and 6 cases of minor dehiscence, and orthodontic treatment was delayed for 3-6 months in all patients with complications. All patients had successful ABG, eruption of teeth, and orthodontic treatment; but patients who had their deciduous teeth at the cleft sites extracted preoperatively had fewer wound complications than patients whose extractions were done at the same time as the ABG. PMID- 21277661 TI - Lugol's iodine: potential use in invasive carcinoma. Re.: Kanatas AN et al. Lugol's iodine identifies synchronous invasive carcinoma: time for a clinical trial. PMID- 21277662 TI - Microbial growth with vapor-phase substrate. AB - Limited information exists on influences of the diffusive transport of volatile organic contaminants (VOC) on bacterial activity in the unsaturated zone of the terrestrial subsurface. Diffusion of VOC in the vapor-phase is much more efficient than in water and results in effective VOC transport and high bioavailability despite restricted mobility of bacteria in the vadose zone. Since many bacteria tend to accumulate at solid-water, solid-air and air-water interfaces, such phase boundaries are of a special interest for VOC biodegradation. In an attempt to evaluate microbial activity toward air-borne substrates, this study investigated the spatio-temporal interplay between growth of Pseudomonas putida (NAH7) on vapor-phase naphthalene (NAPH) and its repercussion on vapor-phase NAPH concentrations. Our data demonstrate that growth rates of strain PpG7 were inversely correlated to the distance from the source of vapor-phase NAPH. Despite the high gas phase diffusivity of NAPH, microbial growth was absent at distances above 5 cm from the source when sufficient biomass was located in between. This indicates a high efficiency of suspended bacteria to acquire vapor-phase compounds and influence headspace concentration gradients at the centimeter-scale. It further suggests a crucial role of microorganisms as biofilters for gas-phase VOC emanating from contaminated groundwater or soil. PMID- 21277663 TI - Nitrogen deposition effects on Mediterranean-type ecosystems: an ecological assessment. AB - We review the ecological consequences of N deposition on the five Mediterranean regions of the world. Seasonality of precipitation and fires regulate the N cycle in these water-limited ecosystems, where dry N deposition dominates. Nitrogen accumulation in soils and on plant surfaces results in peaks of availability with the first winter rains. Decoupling between N flushes and plant demand promotes losses via leaching and gas emissions. Differences in P availability may control the response to N inputs and susceptibility to exotic plant invasion. Invasive grasses accumulate as fuel during the dry season, altering fire regimes. California and the Mediterranean Basin are the most threatened by N deposition; however, there is limited evidence for N deposition impacts outside of California. Consequently, more research is needed to determine critical loads for each region and vegetation type based on the most sensitive elements, such as changes in lichen species composition and N cycling. PMID- 21277664 TI - A rare cause of mediastinal enlargement: sinus histiocytosis with massive lymphadenopathy. PMID- 21277665 TI - Significance of the presence of lymphocytes in the cytological analysis of transbronchial needle aspiration. AB - AIM: To evaluate the clinical relevance of the presence of lymphocytes in transbronchial needle aspiration (TBNA) samples from pathological mediastinal lymph nodes in patients with suspected lung cancer. METHODS: Retrospective observational study evaluating the negative predictive value (NPV) of TBNA samples containing lymphocytes but not malignant cells. RESULTS: A total of 266 TBNA were performed in 252 patients with pathological lymph nodes. One hundred and fifteen TBNA samples had evidence of malignant cells (43%), and 94 (35%) samples were considered as inadequate (absence of adequate cytological material or exclusive presence of bronchial epithelial cells). Out of the 57 TBNA samples remaining (21%), 15 could not be confirmed; in 32, TBNA samples were confirmed with alternative diagnostic techniques and in 10, they were confirmed after clinical and radiological follow-up. The NPV of the 32 samples that were confirmed with alternative diagnostic techniques was 84% decreasing down to 76% when the 10 TBNA samples confirmed after clinical and radiological follow-up were included. CONCLUSIONS: The presence of lymphocytes in the TBNA sample does not exclude the neoplasic invasion of the specific lymph node analyzed. PMID- 21277666 TI - What is the technique of choice for diagnosing mediastinal lesions? PMID- 21277667 TI - Diagnosis and quantification of patent foramen ovale. Which is the reference technique? Simultaneous study with transcranial Doppler, transthoracic and transesophageal echocardiography. AB - INTRODUCTION AND OBJECTIVES: Patent foramen ovale (PFO) is the most common cause of cryptogenic stroke in patients younger than 55. Transesophageal echocardiography (TEE) has been accepted as the reference diagnostic technique. The purpose of this study was to compare the accuracy of transthoracic echocardiography (TTE), TEE and transcranial Doppler (TCD) in the diagnosis and quantification of patent foramen ovale. METHODS: We studied 134 patients prospectively. Simultaneous TTE with TCD and TEE with TCD were performed, using agitated saline solution to detect right to left shunt. RESULTS: In 93 patients diagnosed with PFO, the shunt was visualized at baseline by TCD in 69% of cases, by TTE in 74% and by TEE in 58%. The Valsalva maneuver produced a similar improvement in shunt diagnosis with all 3 techniques (26%-28%). TTE and TCD showed higher sensitivity (100% vs 97%; non significant difference) than TEE in the diagnosis of PFO (86%; P<.001). TCD performed during TEE did not diagnose 12 (13%) shunts previously diagnosed during TTE. Similarly, TEE underestimated shunt severity. CONCLUSIONS: TTE enables adequate diagnosis and quantification of PFO. TEE is less sensitive and tends to underestimate the severity of the shunt. PMID- 21277668 TI - Update: systemic diseases and the cardiovascular system (i): obesity and the heart. AB - Excess weight is the most prevalent cardiovascular risk factor and certainly the factor that improves the least over time among those with established cardiovascular disease. The association between obesity and cardiovascular disease is complex and not limited to the standard risk factors like hypertension, dyslipidemia, and type 2 diabetes mellitus. In recent years, multiple studies have shown that obesity may cause cardiovascular diseases via multiple disease mechanisms like subclinical inflammation, endothelial dysfunction, increased sympathetic tone, atherogenic lipid profiles, enhanced thrombogenic factors and also through obstructive sleep apnea. Despite the overwhelming data linking obesity to cardiovascular disease, several studies have shown a paradoxical association between obesity and prognosis among those with coronary disease and heart failure, which may be due to limitations of the way we currently define obesity. There is abundant data suggesting that measuring central obesity or total body fat content might be more appropriate than using the body mass index alone. The management of obesity is challenging and studies using lifestyle modification alone or with pharmacologic agents generally have limited success and high levels of weight regain. Bariatric surgery has proven to be an effective and safe way to induce and maintain significant weight loss but is limited to those with medically complicated obesity or people who are severely obese. PMID- 21277669 TI - Giant left atrium investigated by magnetic resonance imaging. PMID- 21277670 TI - A cohort study of maternal and neonatal morbidity in relation to use of sequential instruments at operative vaginal delivery. AB - OBJECTIVE: To evaluate the risk factors and maternal and neonatal morbidity associated with sequential use of instruments (vacuum and forceps) at operative vaginal delivery. STUDY DESIGN: A cohort study of 1360 nulliparous women delivered by a single instrument (vacuum or forceps) or by both instruments, within two university teaching hospitals in Scotland and England. Outcomes were compared for use of sequential instruments versus use of any single instrument. A sub-group analysis compared sequential instruments versus forceps alone. Outcomes of interest included anal sphincter tears, postpartum haemorrhage, urinary retention, urinary incontinence, prolonged hospital admission, neonatal trauma, low Apgar scores, abnormal cord bloods and admission to the neonatal intensive care unit (NICU). RESULTS: Use of sequential instruments at operative vaginal delivery was associated with fetal malpositions, Odds Ratio (OR) 1.8 (95% Confidence Interval (CI) 1.3-2.6), and large neonatal head circumference (>37 cm) (OR 5.0, 95% CI 2.6-9.7) but not with maternal obesity or grade of operator. Sequential use of instruments was associated with greater maternal and neonatal morbidity than single instrument use (anal sphincter tear 17.4% versus 8.4%, adjusted OR 2.1, 95% CI 1.2-3.3; umbilical artery pH <7.10, 13.8% versus 5.0%, adjusted OR 3.3, 95% CI 1.7-6.2). Sequential instrument use had greater morbidity than single instrument use with forceps alone (anal sphincter tear OR 1.8, 95% CI 1.1-2.9; umbilical artery pH <7.10 OR 3.0, 95% CI 1.7-5.5). CONCLUSIONS: The use of sequential instruments significantly increases maternal and neonatal morbidity. Obstetricians need training in the appropriate selection and use of instruments with the aim of completing delivery safely with one instrument. PMID- 21277671 TI - Increased matrix metalloproteinases-1,-9 in the uterosacral ligaments and vaginal tissue from women with pelvic organ prolapse. AB - OBJECTIVES: To investigate the possible association of increased matrix metalloproteinases (MMPs)-1,-9 with pelvic organ prolapse (POP) and to evaluate whether inflammatory processes contribute to its development. STUDY DESIGN: Forty women who underwent hysterectomy, 20 with POP grade 2 and above, and 20 without POP, participated in the study. Biopsies from the uterosacral ligaments and vaginal mucosa were obtained from each woman. Each biopsy was sectioned and stained for MMP-1 and MMP-9 by immunohistochemical methods and with hematoxylin and eosin (H&E). MMP-1,-9 expressions were evaluated on the immunostained slides. H&E stained sections were examined for possible inflammatory changes. RESULTS: A higher stromal (extra-cellular) expression of MMPs-1,-9 was found in POP cases compared with controls in vaginal biopsies (MMP-1: p=0.004; MMP-9: p=0.042) as well as in uterosacral ligament biopsies (MMP-1: p=0.011; MMP-9: p=0.015). Increased intracellular expression of both MMPs was also demonstrated in fibroblasts in biopsies of women with POP (p<0.001 for all). Most of these differences persisted after controlling for age. The degree of inflammatory changes reflected by the number of lymphocytes, plasma cells and capillary-sized blood vessels per 10 high power fields, was similar in specimens obtained from women with and without POP. CONCLUSIONS: The expression of MMPs-1,-9 appears to be increased in tissues from women with POP. This supports an association, although not a causal relation, between increased MMPs-1,-9 and POP. Inflammation does not seem to play an important role in the pathogenesis of POP. PMID- 21277672 TI - Twin pregnancies: guidelines for clinical practice from the French College of Gynaecologists and Obstetricians (CNGOF). AB - The rate of twin deliveries in 2008 was 15.6 per 1000 in France, an increase of approximately 80% since the beginning of the 1970s. It is recommended that chorionicity be diagnosed as early as possible in twin pregnancies (Professional Consensus). The most relevant signs (close to 100%) are the number of gestational sacs between 7 and 10 weeks and the presence of a lambda sign between 11 and 14 weeks (Professional Consensus). In twin pregnancies, nuchal translucency is the best parameter for evaluating the risk of aneuploidy (Level B). The routine use of serum markers during the first or the second trimester is not recommended (Professional Consensus). In the case of a choice about sampling methods, chorionic villus sampling is recommended over amniocentesis (Professional Consensus). Monthly follow-up by a gynaecologist-obstetrician in an appropriate facility is recommended for dichorionic pregnancies (Professional Consensus). A monthly ultrasound examination including an estimation of fetal weight and umbilical artery Doppler is recommended (Professional Consensus). It is recommended to plan delivery of uncomplicated dichorionic diamniotic twin pregnancies from 38 weeks and before 40 weeks (Level C). Monthly prenatal consultations and twice-monthly ultrasound are recommended for monochorionic twins (Professional Consensus). It is reasonable to consider delivery from 36 weeks but before 38 weeks+6 days, with intensified monitoring during that time (Professional Consensus). Prenatal care of monochorionic pregnancies must be provided by a physician working in close collaboration with a facility experienced in the management of this type of pregnancy and its complications (Professional Consensus). The increased risk of maternal complications and the high rate of medical interventions justify the immediate and permanent availability of a gynaecologist-obstetrician with experience in the vaginal delivery of twins (Professional Consensus). It is recommended that the maternity ward where delivery takes place have rapid access to blood products (Professional Consensus). Only obstetric history (history of preterm delivery) (Level C) and transvaginal ultrasound measurement of cervical length (Level B) are predictive factors for preterm delivery. No study has shown that the identification by transvaginal sonography (TVS) of a group at risk of preterm delivery makes it possible to reduce the frequency of such deliveries in asymptomatic patients carrying twins (Professional Consensus). It is important to recognize signs of TTTS early to improve the management of these pregnancies (Professional Consensus). Treatment and counseling must be performed in a center that can offer fetoscopic laser coagulation of placental anastomoses (Professional Consensus). This laser treatment is the first-line treatment (Level B). In the absence of complications after laser treatment, planned delivery is recommended from 34 weeks and no later than 37 weeks (Professional Consensus). For delivery, it is desirable for women with a twin pregnancy to have epidural analgesia (Professional Consensus). The studies about the question of mode of delivery have methodological limitations and lack of power. Active management of the delivery of the second twin is recommended to reduce the interval between the births of the two twins (Level C). In the case of non-cephalic presentation, total breech extraction, preceded by internal version manoeuvres if the twin's position is transverse, is associated with the lowest cesarean rates for second twins (Level C). In the case of high and not yet engaged cephalic presentation and if the team is appropriately trained, version by internal manoeuvres followed by total breech extraction is to be preferred to a combination of resumption of pushing, oxytocin perfusion, and artificial rupture of the membranes, because the former strategy appears to be associated with fewer cesareans for the second twin (Level C). PMID- 21277673 TI - Inflammatory pseudotumor of uterus: an unusual pelvic mass. PMID- 21277674 TI - Contraceptive efficacy of a combined oral contraceptive containing ethinyloestradiol 20 MUg/drospirenone 3mg administered in a 24/4 regimen: a pooled analysis of four open-label studies. AB - OBJECTIVE: To determine the contraceptive efficacy of a low-dose combined oral contraceptive containing ethinyloestradiol (EE) 20 MUg/drospirenone (drsp) 3mg administered for 24 days followed by a four-day hormone-free interval (24/4 regimen), by pooling data from four clinical trials. STUDY DESIGN: Data on the occurrence of pregnancy during treatment in four open-label trials that enrolled healthy female volunteers aged 17-36 years, who received EE 20 MUg/drsp 3mg in a 24/4 regimen for 7 or 13 cycles, were pooled. RESULTS: Sixteen pregnancies occurred among 2386 women during 729,537 days (26,055 cycles) of treatment exposure, resulting in a Pearl Index (PI) of 0.80 (upper two-sided 95% confidence interval (CI) limit of 1.30). Of these pregnancies, seven were defined as method failures, resulting in an adjusted PI of 0.41 (upper two-sided 95% CI limit of 0.85), based on 616,607 days (22,022 cycles) of treatment. The Kaplan-Meier estimate for the one-year cumulative probability of contraceptive protection was 99.21%. CONCLUSIONS: The EE 20 MUg/drsp 3mg combined oral contraceptive administered in a 24/4 regimen has acceptable contraceptive efficacy. PMID- 21277675 TI - Quantitative and nutritional characterization of fruit and vegetable waste from marketplace: a potential use as bovine feedstuff? AB - There are different sources for the generation of solid waste, and marketplaces are considered one of them. Fruit and vegetable waste (FV) from a marketplace in Colombia was quantitatively and nutritionally characterized to contribute to its use in bovine feeding and to contribute minimizing its environmental impact. The evaluation was carried out 7 days per week during 4 periods of the year. FV was grouped by cluster analysis using SAS((r)) 2006. FV was composed of 43% fruit, 30% vegetables and 27% stems, leaves, leaf wrappers, corncobs, roots, refuse and others. FV was defined in four main groups. On average, FV contained 10% crude protein (CP), 36.6% neutral detergent fiber (NDF), 29.6% acid detergent fiber (ADF), 87.8% ruminal degradability at 24 h, 3657 kcal/kg, 0.59% calcium (Ca(+2)), and 0.21% phosphorous (P). There were no statistical differences between days or between periods of evaluation (p > 0.05) for CP or for Ca(+2). As for NDF and ADF, there were statistically significant differences between periods but not between days. The microbiological parameters only increased when the humidity was up to 12%. FV represents a potential feedstuff for bovine feeding, and its recycling could avoid the discharge of a large amount of waste to landfills, which would minimize its environmental impact. PMID- 21277676 TI - Anaerobic treatment of sulfate-rich wastewater in an anaerobic sequential batch reactor (AnSBR) using butanol as the carbon source. AB - Biological sulfate reduction was studied in a laboratory-scale anaerobic sequential batch reactor (14 L) containing mineral coal for biomass attachment. The reactor was fed industrial wastewater with increasingly high sulfate concentrations to establish its application limits. Special attention was paid to the use of butanol in the sulfate reduction that originated from melamine resin production. This product was used as the main organic amendment to support the biological process. The reactor was operated for 65 cycles (48 h each) at sulfate loading rates ranging from 2.2 to 23.8 g SO(4)(2-)/cycle, which corresponds to sulfate concentrations of 0.25, 0.5, 1.0, 2.0 and 3.0 g SO(4)(2-) L(-1). The sulfate removal efficiency reached 99% at concentrations of 0.25, 0.5 and 1.0 g SO(4)(2-) L(-1). At higher sulfate concentrations (2.0 and 3.0 g SO(4)(2-) L( 1)), the sulfate conversion remained in the range of 71-95%. The results demonstrate the potential applicability of butanol as the carbon source for the biological treatment of sulfate in an anaerobic batch reactor. PMID- 21277677 TI - The quest for a better bladder from bowel. PMID- 21277678 TI - A novel myelin protein zero (V136G) homozygous mutation causing late onset demyelinating polyneuropathy with brain white matter lesions. AB - Although less common than peripheral myelin protein 22 (PMP22) duplication, there are mutations in myelin protein zero (MPZ) responsible for Charcot-Marie-Tooth disease (CMT) with a number of different clinical profiles. We report here a novel MPZ homozygous mutation, with a peculiar pattern characterized by a late onset demyelinating profile. In addition, the patient presented brain white matter lesions seemingly ascribable to the mutation. PMID- 21277679 TI - Novel thermally stable poly(vinyl chloride) composites for sulfate removal. AB - BaCO(3) dispersed PVC composites were prepared through a polymer re-precipitation method. The composites were tested for sulfate removal using rapid small scale column test (RSSCT) and found to significantly reduce sulfate concentration. The method was extended to synthesize barium carbonate-loaded silica aero-gels polyvinyl chloride (PVC) polymer composites. The PVC composites were characterized using scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS), X-ray mapping, X-ray diffraction (XRD), thermogravimetric analysis (TGA) and inductively coupled plasma mass spectrometry (ICP-MS) analysis. The method has advantages over conventional sulfate precipitation (sulfate removal process) using BaCO(3) wherein clogging of the filter can be avoided. The method is environmentally friendly and does not interfere with natural organic matter as the conventional resin does. Some of the composites were thermally more stable as compared with the pure PVC discussed in the literature. PMID- 21277680 TI - Does the insula tell our brain that we are in pain? AB - Current knowledge on pain-related cerebral networks has relied so far on stimulus induced brain responses, but not on the analysis of brain activity during spontaneous pain attacks. In this case report, correlation between intracerebral field potentials and online sensations during spontaneously painful epileptic seizures suggests a crucial role of the insula in the development of subjective pain. Attacks originated from a very limited dysplasia located in the posterior third of the right insula and propagated to other areas of the pain matrix, including the parietal operculum and the midcingulate gyrus. Concomitant painful symptoms started on the left hand or the left foot and extended in a few seconds to the whole left side of the body, sparing the head. Continuous during the first seconds of the attack, the painful feeling evolved to throbbing and remained so until it progressively vanished, together with the spike discharge. Stimulation of the insula, but not of other pain matrix regions, induced pain identical to that of seizures. After thermocoagulation of the insular epileptic focus, a short, transient exacerbation of seizures with same painful features but different location was observed before a long-lasting and complete remission of the attacks. Although these preliminary data need to be confirmed, they strongly suggest that if the full pain experience involves the pain matrix network, the posterior insula seems to play a leading role in the triggering of this network and the resulting emergence of subjective pain experience. PMID- 21277681 TI - Fabrication and characterization of APT specimens from high dose heavy ion irradiated materials. AB - The next generations of advanced energy systems will require materials that can withstand high doses of irradiation at elevated temperatures. Therefore, a methodology has been developed for the fabrication of high-dose ion-irradiated atom probe tomography specimens at a specific dose with the use of a focused ion beam milling system. The method also enables the precise ion dose of the atom probe tomography specimen to be estimated from the local concentration of the implanted ions. The method has been successfully applied to the characterization of the distribution of nanoclusters in a radiation-tolerant 14YWT nanostructured ferritic steel under ion irradiation to doses up to 400 displacements per atom. PMID- 21277682 TI - Trypanosomosis and phenotypic features of four indigenous cattle breeds in an Ethiopian field study. AB - We conducted a two-part study in the native home areas of four cattle breeds, Abigar, Gurage, Horro and Sheko, in south-western Ethiopia. The first part of the study investigated livestock keeper knowledge about trypanosomosis and trypanotolerance. For each breed 60 livestock keepers were interviewed, resulting in a total of 240 interviews. The second part of the study focused on biological evidence for trypanotolerance. Blood samples of about 100 head of cattle per breed were collected during peak trypanosomosis challenge period and analyzed for packed cell volume (PCV) and parasitaemia. In addition individual body measurements of the sampled animals were taken and the keepers provided some information regarding their animals. Livestock keeper interviews revealed that trypanosomosis was considered a major problem in all areas (95-100%). Almost all Abigar livestock keepers knew how trypanosomosis is transmitted, whereas only 34 52% of the keepers of the other breeds had that knowledge. Most Sheko keepers (75%) knew of trypanotolerance and claimed to have trypanotolerant animals in their own herds. Among the other three breeds the knowledge of trypanotolerance was much less (8-18%). A majority of the keepers were interested in purchasing trypanotolerant animals. PCV was highest among Horro (26.2) and Sheko (25.1) cattle whereas Abigar had the lowest PCV (20.0). Sheko were least infected by trypanosomes (6%) and had the lowest number of trypanocidal treatments per year (1 treatment/animal and year). Abigar cattle were most infected (23%) followed by Gurage (20%) and Horro (17%). Gurage had by far the highest number of treatments per animal and year (24). There were large differences between the number of cattle perceived by the keepers to be infected, and the number detected from blood sampled, among Abigar, Gurage and Horro. Sheko livestock keepers were better at correctly diagnosing trypanosomosis in their animals. It is concluded that Sheko cattle have higher trypanotolerance attributes of the breeds investigated and a better use of this breed could improve cattle health and household welfare in tsetse-infested areas. PMID- 21277683 TI - Fecundity in adult Haemonchus contortus parasites is correlated with abomasal tissue eosinophils and gammadelta T cells in resistant Canaria Hair Breed sheep. AB - Canaria Hair Breed (CHB) sheep are more resistant than Canaria sheep (CS) to experimental Haemonchus contortus infection. Protective responses appear effective against the adult stage of the parasite, not as commonly reported in other breeds against the larval stages. In this study we have quantified several abomasal immune cells and correlated these with parasitological variables for each breed. A significant negative correlation between CD4+ T cell numbers and worm burden or length at 28 dpi was seen only in CS sheep. Significant negative correlations for both abomasal eosinophils and gammadelta/WC1+ T cells, and fecundity of the adult worms were observed only in the resistant CHB sheep breed. Tissue eosinophils and gammadelta/WC1+ T cells were positively correlated in CHB sheep. We suggest that the two sheep breeds have disparate immune responses following infection with the parasite and that gammadelta+ T cells in association with eosinophils may play a hitherto unrecognised role in modulating fecundity in H. contortus adult female parasites. PMID- 21277684 TI - Gene profiling in breast cancer: time to move forward. AB - Gene signatures may complement clinical and pathological factors to predict prognosis and response to therapy in patients with breast cancer, and can also sub-classify these tumours into entities with different biology and treatment requirements. A number of prognostic gene signatures are commercially available at this moment and two of them have entered phase III evaluation. Specific signatures are also being assessed to predict response to a number of drug therapies. The combined use of prognostic, predictive and subtype-defining signatures will guide therapeutic decisions in the future and will facilitate development of targeted drugs in specific groups of patients. However, cost utility issues and some technical limitations have hindered widespread adoption of gene profiling. Gene signatures will become part of the routine clinical workup only if they help making clinical decisions. The first step to achieve this will consist of the inclusion of gene signatures in the design of clinical trials with new drugs. PMID- 21277685 TI - Severity of alcohol problems and readiness to change alcohol use in primary care. AB - Screening measures for hazardous alcohol use that are efficient and can provide clinically relevant information are essential for primary care providers (PCPs). This study examined the clinical utility of the Alcohol Use Disorders Identification Test (AUDIT) and the AUDIT-Consumption (AUDIT-C) as predictors of readiness to change alcohol use in a primary care setting. In total, 114 veterans completed the AUDIT, readiness to change ruler, and an alcohol use disorders diagnostic interview. Two AUDIT-C scores were obtained; one administered during a primary care visit and one derived from the AUDIT. The AUDIT, both AUDIT-C scores, and number of dependence symptoms significantly predicted readiness to change independent of demographic variables. The AUDIT accounted for the greatest percentage of variance in readiness to change (19%). The AUDIT provides information about alcohol severity and readiness to change, which could be clinically useful for providers identifying patients for brief alcohol interventions. PMID- 21277686 TI - What is a functional locus? Understanding the genetic basis of complex phenotypic traits. AB - A multitude of results from genome-wide association studies have been published in recent years in relation to different human diseases and phenotypic traits. However, the identified polymorphisms explain just a small fraction of the variability of the traits and they are poor predictors of occurrence of disease. Although part of the missing variability may be found in still to be identified rare genetic variants, the present work proposes that a major part of the problem is due to our conceptual limitations regarding functional loci and its variants. Functional variants are currently defined in absolute positional terms; they are just sequence variations in fixed positions along the DNA molecule. In the present study is postulated that functional loci may include different positions in the DNA sequence. As consequence, variants of the same functional locus may be located in different physical positions along the genome and, the observed effect of any particular genetic variant will be then reduced compared to its true effect. The differential use of regulatory regions such as gene promoters and enhancers would be a particular case of the proposed hypothesis. The hypothesis makes predictions that can be tested, offering potential paths of research to elucidate the genetic basis of complex human traits. PMID- 21277687 TI - Tea consumption maybe an effective active treatment for adult attention deficit hyperactivity disorder (ADHD). AB - Adult attention-deficit/hyperactivity disorder (ADHD) is an increasingly recognized Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) psychiatric disorder associated with significant functional impairment in multiple domains. Although stimulant has the most empirical support as treatment for ADHD in adults, because of the poor treatment compliance, many adults with the disorder continue to experience significant residual symptoms. Tea is a kind of stimulant and many adults like to drink it. The caffeine in tea can reduce one's fatigue, increase people's self-confidence, motivation, alertness, vigilance, efficiency, concentration, and cognitive performance. This report proposes that tea consumption maybe an effective active treatment for adult ADHD. PMID- 21277688 TI - Early proteins E6 and E7 of human papillomavirus may attenuate ischemia reperfusion injury. AB - It is well known that human papillomaviruses (HPVs) involve in the pathogenesis of some specific carcinomas such as cervical cancer. Experimental and clinical studies have shown that early proteins E6 and E7 played the most important role in the cervical carcinogenesis. Early proteins E6 and E7 of HPV both are oncoproteins for they disable specific tumor suppressor proteins, p53 and pRb, and disturb apoptosis against carcinogenesis. Both p53 and pRb play an important role in regulating apoptosis and preventing cell immortalization, but they also mediate ischemia/reperfusion-associated apoptosis and give rise to ischemia reperfusion injury (IRI). Several studies showed inhibition of apoptosis may provide promising approaches to ameliorating IRI in ischemia/reperfusion. Both small-molecule chemical inhibitor and siRNA against p53 block p53-dependent apoptosis and protect organ function from IRI. Similarly, inhibiting pRb can restrain ischemia/reperfusion-associated apoptosis. Based on these studies, we propose a novel hypothesis that early proteins E6 and E7 of HPV attenuate ischemia-reperfusion injury by inhibiting apoptosis and inactivating p53 and pRb. It is possible that the two oncoproteins can be used to protect organ function from ischemia-reperfusion injury in special clinical conditions such as organ transplant, stroke, cardiopulmonary bypass, and myocardial infarction. PMID- 21277689 TI - Has prion protein important physiological function? AB - Despite the great effort aimed at uncovering the physiological function of cellular prion protein, its role remains unclear. The highly conserved amino acid sequence of PrP indicates its important function, but normally developing PrP knockout mice and cattle were prepared. Here we propose hypothesis that prion protein has no function or a redundant one and more importantly, that the conserved amino acid sequence of mammalian PrPs is not the result of their important function, but rather due to cytotoxicity of most mutations occurring in the PrP molecule. It is possible that the majority of mutations in PrP dramatically destabilizes the PrP(C) structure and causes a pathological change in conformation, so that natural selection favours individuals with non-mutated PrP. PMID- 21277690 TI - Treat the graft to improve the regenerative ability of the host. AB - The staggering number of publications featuring the use of stem cells has revolutionized regenerative medicine research. Preclinical studies indicate that allogeneic human mesenchymal stem cells (MSCs) may be useful for the treatment of several clinical disorders, including sepsis, acute renal failure, acute myocardial infarction, and more recently, acute lung injury (ALI). However, considerable success would not be obtained in clinical trials due to poor survival of transplanted cells under the influence of inflammatory conditions. Despite robust approaches like cellular reprogramming, scaffolds and conditioned media have been tested to overcome this problem; however the success rate of these approaches remain questionable. Recently, pretreatment of bioactive compounds in vitro have been shown to suppress cell apoptosis and promote cell survival. Quite likely a similar phenomenon can take place in vivo. Based on such studies, we hypothesize that MSCs derived from human post-natal tissues could be conditioned and prepared for targeted disease therapy. Depending on the disease condition, the MSCs could be treated prior to delivery with appropriate bioactive compounds to allow them survive longer and perform a better role as biocatalyst. The advantage of this approach could be the tailor made availability of MSCs preconditioned with appropriate bioactive compounds for disease specific therapy. Therefore, the choice of suitable bioactive molecule is likely to enhance the efficacy of targeted stem cell therapy and preconditioning may provide a novel strategy in maximizing biological and functional properties of MSCs. PMID- 21277691 TI - Focused extracorporeal shockwave therapy in Dupuytren's disease--a hypothesis. AB - Dupuytren's disease is a progressive disease due to unknown causal agents or genetics. An epidemiological analysis of 566 cases in North Germany estimated that around 1.9 million Germans are suffering from Dupuytren's disease. Beside Dupuytren's disease, there are a number of further less common forms of progressive fibromatosis, such as knuckle pads, plantar fibromatosis or Peyronie's disease. Surgery in plantar fasciectomy yields to a 60% recurrence rate depending on the extent of the plantar fasciectomy. Peyronie's disease of the penis affects middle-aged men between 40 and 60 years with penile pain, curvature during erection and potential erectile dysfunction. In a clinical randomized-controlled trial in Peyronie's disease 2000 focused extracorporeal shock waves reduced pain significantly and improved erectile function and quality of life. We hypothesize that focused extracorporeal shock wave therapy is able to reduce Dupuytren's contracture, a fibromatosis of the palm and improve function. Given the fact that recurrence rate in Dupuytren's disease is high und unpredictable extracorporeal shockwave therapy as a non-invasive tool might be applicable both, in primary and secondary prevention of the progression as well as for treatment. As such we have planned a randomized-controlled trial (ClinicialTrials.gov, NCT01184586) studying the effect of high-energy focused extracorporeal shockwave therapy on patients suffering Dupuytren's disease with patient-related outcome measures such as the DASH score and the Michigan Hand Outcome Questionnaire (MHQ) as primary outcome parameters. PMID- 21277692 TI - Low-grade inflammation in chronic diseases: an integrative pathophysiology anticipated by homeopathy? AB - Pro-inflammatory cytokines and their chronic effect - low-grade inflammation - have been associated with diverse chronic conditions. Nonsteroidal anti inflammatory drugs (NSAIDs) were recently proposed as a treatment strategy. Samuel Hahnemann, the founder of homeopathy, had already hypothesized a systemic and progressive disorder as the cause of many chronic diseases - the Psora theory. He also advised of the consequences of palliative use for chronic diseases, as a contrary effect of the "of the life-preserving principle" could worsen the course of those diseases. The hypotheses presented here are that the main aspects of Hahnemann's Psora theory are supported by current data on the role of pro-inflammatory cytokines and that the use of NSAIDs to treat chronic low-grade inflammation can produce a contrary, rebound effect, as anticipated by Hahnemann. By diverting from the "palliative action-rebound effect" course, not only homeopathy but integrative medicine could provide different approaches to the treatment of low-grade chronic inflammation. Studies assessing inflammatory markers in chronic integrative treatments are recommended. PMID- 21277693 TI - Addition of garlic or onion before irradiation on lipid oxidation, volatiles and sensory characteristics of cooked ground beef. AB - Addition of 0.5% onion was effective in reducing lipid oxidation in irradiated cooked ground beef after 7 day storage. Addition of garlic or onion greatly increased the amounts of sulfur volatiles from cooked ground beef. Irradiation and storage both changed the amounts and compositions of sulfur compounds in both garlic- and onion-added cooked ground beef significantly. Although, addition of garlic and onion produced large amounts of sulfur compounds, the intensity of irradiation odor and irradiation flavor in irradiated cooked ground beef was similar to that of the nonirradiated control. Addition of garlic (0.1%) or onion (0.5%) to ground beef produced a garlic/onion aroma and flavor after cooking, and the intensity was stronger with 0.1% garlic than 0.5% onion treatment. Considering the sensory results and the amounts of sulfur compounds produced in cooked ground beef with added garlic or onion, 0.5% of onion or less than 0.1% of garlic is recommended to mask or change irradiation off-odor and off-flavor. PMID- 21277694 TI - Failure to adhere to protocol specified radiation therapy guidelines was associated with decreased survival in RTOG 9704--a phase III trial of adjuvant chemotherapy and chemoradiotherapy for patients with resected adenocarcinoma of the pancreas. AB - PURPOSE: In Radiation Therapy Oncology Group 9704, as previously published, patients with resected pancreatic adenocarcinoma received continuous infusion 5 FU and concurrent radiotherapy (5FU-RT). 5FU-RT treatment was preceded and followed by randomly assigned chemotherapy, either 5-FU or gemcitabine. This analysis explored whether failure to adhere to specified RT guidelines influenced survival and/or toxicity. METHODS AND MATERIALS: RT requirements were protocol specified. Adherence was scored as per protocol (PP) or less than per protocol ( .05). The mean lengths, in tenths of millimeters, were as follows: measure A: index finger 22.0 mm, middle finger 24.4 mm, ring finger 22.0 mm, and little finger 17.9 mm; measure B: index finger 21.9 mm, middle finger 24.2 mm, ring finger 22.3 mm, and little finger 18.1 mm. The average lengths of the A1 pulley were: index finger 9.8 mm, middle finger 10.7 mm, ring finger 9.6 mm, and little finger 8.1 mm. CONCLUSIONS: The distance between the digital-palmar and proximal interphalangeal creases may be used as a cutaneous landmark on the palmar surface for the exact location of the proximal edge of the A1 pulley in the palm of the hand, thereby ensuring greater safety in surgical procedures such as percutaneous release of trigger finger. PMID- 21277698 TI - Rotator cuff defect: acute or chronic? PMID- 21277699 TI - Comparison of wrist and elbow stabilization following pinch reconstruction in tetraplegia. AB - PURPOSE: Individuals with spinal cord injuries resulting in tetraplegia may receive tendon transfer surgery to restore grasp and pinch function. These procedures often involve rerouting the brachioradialis (Br) and the extensor carpi radialis longus tendons volar to the flexion-extension axis of the wrist, leaving the extensor carpi radialis brevis (ECRB) muscle to provide wrist extension strength. The purpose of this study was to determine whether externally stabilizing the wrist after transfer procedures would improve the ability to activate the transferred Br and resulting pinch force, similar to the effect observed when the elbow is externally stabilized. METHODS: We used a one-way repeated-measures study design to determine the effect of 3 support conditions on muscle activation and lateral pinch force magnitude in 8 individuals with tetraplegia and previous tendon transfer surgeries. Muscle activation was recorded from Br and ECRB with intramuscular electrodes and from biceps and triceps muscles with surface electrodes. We quantified pinch strength with a 6 axis force sensor and custom grip. We recorded measurements in 3 support conditions: with the arm self-stabilized, with elbow stabilization, and with elbow and wrist stabilization. Pairwise differences were tested using Wilcoxon signed-rank tests. RESULTS: Maximum effort pinch force magnitude and Br activation were significantly increased in both supported conditions compared with the self-supported trials. The addition of wrist stabilization had no significant effect compared with elbow stabilization alone. CONCLUSIONS: A strong ECRB has adequate strength to extend the wrist, even after multiple transfers that contribute an additional flexion moment from strong activation of donor muscles. Anatomical and functional differences between the wrist and elbow musculature are important determinants for self-stabilizing joints proximal to the tendon transfer. The ability to increase Br activation and resulting pinch force may be determined, in part, by the individual's ability to develop new coordination strategies. PMID- 21277700 TI - Subungual malignant melanoma. PMID- 21277701 TI - Regional anesthesia for outpatient hand surgery: ultrasound-guided peripheral nerve block. PMID- 21277702 TI - [Evaluation of the SD BIOLINE TB Ag MPT64 Rapid(r) for the diagnosis of tuberculosis]. AB - The purpose of this study was to evaluate the SD Bioline Ag MPT64 Rapid((r)) for identification of the Mycobacterium tuberculosis complex. The method uses an immunochromatographic assay and needs 100 MUl of sample taken from liquid culture or colonies suspended. The sensitivity was determined using 99 strains of M. tuberculosis complex and the specificity using 10 nontuberculous mycobacteria and 85 strains other than mycobacteria genus. The test showed excellent sensitivity (99%) and specificity (100%). This technique displays several advantages and is destined to spread in all laboratories and particularly in endemic areas. PMID- 21277703 TI - [Performances of the Amplified Mycobacterium Tuberculosis Direct Test in non respiratory specimens (study about 1538 samples)]. AB - From March 1998 to August 2009, 1538 non-respiratory samples collected from 1182 patients, were tested using the Gen-Probe Amplified Mycobacterium Direct TestTM (AMTD). After decontamination procedure, every sample was tested by AMTD and by culture on solid and liquid media. The "Gold-standard" was considered by the combination of culture results and clinical diagnosis. Tuberculosis was present in 17,59 % (208 patients). For theses 1538 non-respiratory samples (225 culture positive samples, 248 AMTD positive), 279 corresponded to tuberculosis. After resolving the discordant results, the sensitivity, specificity, positive and negative values were 89, 99, 99,6 and 97,3 %. PMID- 21277704 TI - Transitioning opioid-dependent patients from detoxification to long-term treatment: efficacy of intensive role induction. AB - Despite findings that opioid detoxification serves little more than a palliative function, few patients who enter detoxification subsequently transition to long term treatment. The current study evaluated intensive role induction (IRI), a strategy adapted from a single-session intervention previously shown to facilitate engagement of substance-dependent patients in drug-free treatment. IRI was delivered either alone or combined with case management (IRI+CM) to determine the capacity of each condition to enhance transition and engagement in long-term treatment of detoxification patients. Study participants were 240 individuals admitted to a 30-day buprenorphine detoxification delivered at a publicly funded outpatient drug treatment clinic. Following clinic intake, participants were randomly assigned to IRI, IRI+CM, or standard clinic treatment (ST). Outcomes were assessed in terms of adherence and satisfaction with the detoxification program, detoxification completion, and transition and retention in treatment following detoxification. Participants who received IRI and IRI+CM attended more counseling sessions during detoxification than those who received ST (both ps<.001). IRI, but not IRI+CM participants, were more likely to complete detoxification (p=.017), rated their counselors more favorably (p=.01), and were retained in long-term treatment for more days following detoxification (p=.005), than ST participants. The current study demonstrated that an easily administered psychosocial intervention can be effective for enhancing patient involvement in detoxification and for enabling their engagement in long-term treatment following detoxification. PMID- 21277705 TI - Combined Goal Management Training and Mindfulness meditation improve executive functions and decision-making performance in abstinent polysubstance abusers. AB - The clinical relevance of neuropsychological deficits in addicted individuals has fostered interest in treatment strategies aimed to effectively target executive and decision-making dysfunction. One of the best-validated interventions for executive dysfunction is Goal Management Training (GMT) (Robertson et al., 2005), an interactive program aimed at improving participants' organization and ability to achieve goals. Mindfulness-based meditation can complement GMT training in order to improve attentional scanning and "reading" of emotional signals involved in adaptive decision-making. In this pilot study we investigated the efficacy of a 7-week program including GMT+Mindfulness (GMT+MF), as compared to standard treatment alone (STx), for reducing executive and decision-making deficits in an outpatient sample of alcohol and polysubstance abusers. Eighteen participants were enrolled in the GMT+MF group, whereas 16 participants formed the STx group; both groups were matched for relevant demographic and clinical variables, and pre treatment degree of executive dysfunction. Results showed that the individuals enrolled in GMT+MF significantly improved their performance on neuropsychological measures of working memory (Letter Number Sequencing), response inhibition (Stroop) and decision-making (Iowa Gambling Task) after the treatment; whereas individuals enrolled in STx alone failed to show significant changes. These preliminary results indicate that the GMT+MF intervention may be effective in reducing executive and decision-making deficits in polysubstance abusers, and they support future randomized controlled studies aimed at examining the extent to which these improvements may generalize to every day functioning and may affect the capacity of addicted individuals to achieve and maintain abstinence. PMID- 21277706 TI - Acute effects of waterpipe tobacco smoking: a double-blind, placebo-control study. AB - BACKGROUND: Waterpipe tobacco smoking usually involves heating flavored tobacco with charcoal and inhaling the resulting smoke after it has passed through water. Waterpipe tobacco smoking increases heart rate and produces subjective effects similar to those reported by cigarette smokers. These responses are thought to be nicotine-mediated, though no placebo-control studies exist. Accordingly, this double-blind, placebo-control study compared the acute physiological and subjective effects of waterpipe tobacco smoking to those produced when participants used a waterpipe to smoke a flavor-matched, tobacco-free preparation. METHODS: Occasional waterpipe tobacco smokers (n = 37; 2-5 monthly smoking episodes for >= 6 months) completed two double-blind, counterbalanced sessions that differed by product: preferred brand/flavor of waterpipe tobacco or flavor-matched, tobacco-free preparation. For each 45-min, ad lib smoking episode blood and expired air CO were sampled, cardiovascular and respiratory response were measured, and subjective response was assessed. RESULTS: Waterpipe tobacco smoking significantly increased mean (+/- SEM) plasma nicotine concentration (3.6 +/- 0.7 ng/ml) and heart rate (8.6 +/- 1.4 bpm) while placebo did not (0.1 +/- 0.0 ng/ml; 1.3 +/- 0.9b pm). For carboxyhemoglobin (COHb) and expired air CO, significant increases were observed for tobacco (3.8 +/- 0.4%; 27.9 +/- 2.6 ppm) and for placebo (3.9 +/- 0.4%; 27.7 +/- 3.3 ppm) with no differences across condition. Independent of condition, symptoms of nicotine/tobacco abstinence (e.g., "urges to smoke", "anxious") were reduced and direct effects (e.g., "dizzy", "satisfy") increased. DISCUSSION: These results from the first placebo control study of waterpipe tobacco smoking demonstrate that waterpipe-induced heart rate increases are almost certainly mediated by nicotine though the subjective effects observed in these occasional smokers were not. PMID- 21277707 TI - Executive dysfunction in chronic cocaine users: an exploratory study. AB - INTRODUCTION: Chronic cocaine use is associated with some executive deficits. We assessed executive functions using ecologically valid tests in chronic cocaine users. OBJECTIVES: To investigate the relationship between executive deficits and three measures of severity of cocaine use: years of use, quantity used, and frequency of use. METHODS: Twenty-four cocaine users were compared with twenty seven community controls. We used Student's t-test and Chi-squared to compare means and categorical variables, respectively. Linear regression analyses for the adjusted comparative analysis between cases and controls, and severity of cocaine use among cocaine users were performed. RESULTS: Chronic cocaine users performed worse on measures of attention and working memory (Forward and Backward Digit Span, p<.001), set-shifting abilities (difference score between the Trail Making B and A, TMB-A, p=.006), cognitive test of mental flexibility and response inhibition (Rule Shift Cards) (p<.001), and prefrontal functioning (Wisconsin Card Sorting Test, WCST, p=.023) than controls. Years of cocaine use were associated with deficits in the Backward Digit Span (p=.041; CI 95%: -.760 to .002), the TMB-A (p=.026; CI 95%: .687 to 9.761), the Zoo Map (p=.034; CI 95%: .480 to -.021), and the Rule Shift Cards (p=.006; CI 95%: -.836 to -.164), among others. Quantity of cocaine use was associated with executive deficits measured by the Forward Digit Span (p=.007; CI 95%: -.727 to -.133), the TMB-A (p=.021; CI 95%: 5.304-57.945), and the number of perseverative errors in the WSCT (p=.002; CI 95%: -10.654 to -2.800). Frequency of cocaine was associated with deficits in the Backward Digit Span (p=.042; CI 95%: -1.548 to -.030). CONCLUSIONS: Chronic use of cocaine is associated with executive deficits, which may influence patients' functionality, prognosis, and therapeutic failure. PMID- 21277708 TI - The sigma receptor agonist SA4503 both attenuates and enhances the effects of methamphetamine. AB - BACKGROUND: Methamphetamine's behavioral effects have been attributed to its interaction with monoamine transporters; however, methamphetamine also has affinity for sigma receptors. METHOD: The present study investigated the effect of the sigma receptor agonist SA 4503 and the sigma receptor antagonists BD-1047 and BD-1063 on methamphetamine-evoked [(3)H]dopamine release from preloaded rat striatal slices. The effect of SA 4503 on methamphetamine-induced hyperactivity and on the discriminative stimulus properties of methamphetamine also was determined. RESULTS: SA 4503 attenuated methamphetamine-evoked [(3)H]dopamine release in a concentration-dependent manner. BD-1047 and BD-1063 did not affect release. SA 4503 dose-dependently potentiated and attenuated methamphetamine induced hyperactivity. SA 4503 pretreatment augmented the stimulus properties of methamphetamine. CONCLUSIONS: Our findings indicate that SA 4503 both enhances and inhibits methamphetamine's effects and that sigma receptors are involved in the neurochemical, locomotor stimulatory and discriminative stimulus properties of methamphetamine. PMID- 21277709 TI - No evidence of association between 118A>G OPRM1 polymorphism and heroin dependence in a large Bulgarian case-control sample. AB - The MU-opioid receptor is the primary site of action of most opioids. The 118A>G (rs1799971) polymorphism in exon 1 of the MU-opioid receptor gene (OPRM1) leads to an Asn40Asp amino acid change that affects a putative N-glycosylation site. It has been widely investigated for association with alcohol and drug dependence and pain sensitivity, with mixed results. The aim of the current study was to examine whether this polymorphism was associated with heroin dependence in a large Bulgarian cohort of 1842 active users and 1451 population controls. SNP genotyping was done using Real-Time PCR TaqMan technology. Association analyses were conducted, separately for Roma and non-Roma participants. Our results suggest that there is no direct effect of 118A>G genotype on the risk for heroin dependence among active heroin users. PMID- 21277710 TI - Prescription of analgesics to patients in opioid maintenance therapy: a pharmacoepidemiological study. AB - AIMS: The primary aim of the present study is to determine the one year periodic prevalence of dispension of different analgesics to patients in long term opioid maintenance therapy (OMT). The secondary aim is to determine to which extent non opioid analgesics are used as first line analgesics. DESIGN: The study is a pharmacoepidemiological study with cross sectional data and cohort data. Data on patients in long term OMT in Norway were obtained from the complete national Norwegian Prescription Database (NorPD). FINDINGS: The analgesics with the highest one year periodic prevalence were NSAIDs (22%), codeine-paracetamol combinations (9%), paracetamol (7%) and tramadol (2.5%). During both 2007 and 2008 a total of 12% of the study population received at least one dispension of another opioid in addition to the opioid used for OMT. In 55% of the cases where OMT patients had not received an analgesic the preceding year an NSAID was the first or only dispensed analgesic whereas paracetamol-codeine was the first or only dispensed analgesic in 29% of the cases. CONCLUSIONS: This study has documented an equally high one year periodic prevalence of opioid dispensions in OMT patients as in the general population as well as a high one year periodic prevalence of dispensions of NSAIDs. Dispension of codeine-paracetamol has a relatively high one-year prevalence and is frequently used as a first line analgesic. PMID- 21277712 TI - Substance use disorders in Iraq and Afghanistan veterans in VA healthcare, 2001 2010: Implications for screening, diagnosis and treatment. AB - BACKGROUND: The prevalence and correlates of alcohol use disorder (AUD) and drug use disorder (DUD) diagnoses in Iraq and Afghanistan veterans who are new users of Department of Veterans Affairs (VA) healthcare nationwide has not been evaluated. METHODS: VA administrative data were used in retrospective cross sectional descriptive and multivariable analyses to determine the prevalence and independent correlates of AUD and DUD in 456,502 Iraq and Afghanistan veterans who were first-time users of VA healthcare between October 15, 2001 and September 30, 2009 and followed through January 1, 2010. RESULTS: Over 11% received substance use disorder diagnoses: AUD, DUD or both; 10% received AUD diagnoses, 5% received DUD diagnoses and 3% received both. Male sex, age < 25 years, being never married or divorced, and proxies for greater combat exposure were independently associated with AUD and DUD diagnoses. Of those with AUD, DUD or both diagnoses, 55-75% also received PTSD or depression diagnoses. AUD, DUD or both diagnoses were 3-4.5 times more likely in veterans with PTSD and depression (p < 0.001). CONCLUSIONS: Post-deployment AUD and DUD diagnoses were more prevalent in subgroups of Iraq and Afghanistan veterans and were highly comorbid with PTSD and depression. Stigma and lack of universal screening may have reduced the number of DUD diagnoses reported. There is a need for improved screening and diagnosis of substance use disorders and increased availability of integrated treatments that simultaneously address AUD and DUD in the context of PTSD and other deployment-related mental health disorders. PMID- 21277711 TI - Agitated depression in substance dependence. AB - BACKGROUND: Depression with psychomotor agitation (PMA; "agitated depression") is a putative psychiatric phenotype that appears to associate with some forms of substance dependence. However, it is unclear whether such relationships extend across different substances and independent (I-MDE) versus substance-induced (SI MDE) subtypes of major depressive episodes. METHOD: We examined whether lifetime depression with (vs. without) PMA was associated with lifetime substance dependence across individuals with lifetime: (1) I-MDE only (n=575); and (2) SI MDE only (n=1683). Data were pooled from several family and genetic studies of substance dependence in which participants received identical structured interviews to diagnose DSM-IV mental disorders. RESULTS: In I-MDE, PMA was significantly associated with alcohol, cocaine, opioid, other drug (hallucinogen, inhalant, speed-ball), and sedative dependence. After controlling for demographic and clinical co-factors, PMA's relationship to dependence on opioids, other drugs, and sedatives remained significant, but not its relationship to alcohol or cocaine. In SI-MDE, PMA was significantly associated with alcohol, cocaine, opioid, and other drug dependence. After adjusting for co-factors, associations remained significant for dependence on cocaine and opioids, but not alcohol or other drugs. Relationships between PMA and opioid dependence were stronger in I MDE than SI-MDE. Depression subtype (I-MDE vs. SI-MDE) did not moderate relations between PMA and non-opioid forms of substance dependence. CONCLUSIONS: Agitated depression associates with certain forms of substance dependence, particularly opioid dependence. MDE subtype did not alter most PMA-dependence associations, which suggests that the mechanisms underlying this comorbidity are complex and potentially bidirectional. PMID- 21277713 TI - Cost and cost-effectiveness of three strategies for training clinicians in motivational interviewing. AB - OBJECTIVE: To evaluate the cost and cost-effectiveness of three strategies for teaching community program clinicians motivational interviewing (MI): self-study (SS), expert-led (EX), and train-the-trainer (TT). METHODS: This economic analysis was conducted as part of a three-arm clinician training trial comprising 12 community treatment programs randomly assigned to the three conditions (n=92 clinician participants). EX and TT conditions used skill-building workshops and three monthly supervision sessions. SS provided clinicians MI training materials only. The primary outcome measure was the number of clinicians meeting MI performance standards at 12-week follow-up. Unit costs were obtained via surveys administered at the 12 participating programs. Resource utilizations and clinician outcomes were obtained from the training trial. Costs and outcomes were normalized to account for differing numbers of clinicians across programs and conditions. Incremental cost-effectiveness ratios and cost-effectiveness acceptability curves were used to evaluate the relative cost-effectiveness of the three training strategies. RESULTS: SS is likely to be the most cost-effective training strategy if the threshold value to decision makers of an additional clinician meeting MI performance standards at 12-week follow-up is less than approximately $2870, and EX is likely to be the most cost-effective strategy when the threshold value is greater than approximately $2870. CONCLUSIONS: This study provides accurate estimates of the economic costs and relative cost-effectiveness of three different strategies for training community program clinicians in motivational interviewing and should be of interest to decision makers seeking to implement empirically supported addiction treatments with scarce resources. PMID- 21277715 TI - Invasive mould infections in newborns and children. AB - Invasive mould infections represent important complications of different pediatric conditions. Epidemiology and clinical features vary according to the type of underlying conditions that determine the risk of invasive mycosis. No pediatric study has specifically evaluated the efficacy of prophylaxis or therapy invasive moulds infections, while pediatric dosages for the treatment of invasive aspergillosis are available for drugs that produced positive results in clinical trials undertaken in adults. PMID- 21277714 TI - Pharmacokinetics of antifungal agents in children. AB - Invasive fungal infections in immunocompromised children are common and often fatal. The first antifungal agents such as amphotericin B and fluconazole offered effective treatment, but their use was often limited by toxicity and resistance. Numerous new antifungal agents have since been developed and appear to be as effective. Most dosing and safety trials have been done in adults, and extrapolation of this data to children has proven inadequate. We reviewed the literature regarding the pharmacokinetics/pharmacodynamics (PK/PD) and safety of antifungal agents with an emphasis on the newer azoles and echinocandins. From a small but growing number of PK/PD trials, better dosing guidelines have been developed. PMID- 21277716 TI - The suctioning in the delivery room debate. AB - Meconium aspiration syndrome (MAS) is a life threatening respiratory disorder in infants born through meconium-stained amniotic fluid (MSAF). Its obstetric and perinatal management has been changing for over 35 years. In pregnancies complicated by MSAF, suction of the hypopharynx before the delivery of the infant's shoulders and postnatal suction of vigorous infants have been used in an effort to clear the airway and decrease the incidence and the severity of the disease. Based on the results of two large RCTs, international guidelines from scientific societies for intrapartum and postpartum management of pregnancies with MSAF have radically changed. Intrapartum suction and postnatal intubation and suction of vigorous infants are not longer recommended. For depressed infants there are no randomized trials to support or to refute this practice. Other non recommended manoeuvres such as thorax compression and gastric lavage are still sometimes performed. The adherence to norms and recommendations is not uniform. Neonatologists should make efforts to get the new evidence more quickly move to evidence-based clinical practice. PMID- 21277717 TI - Hypothermia: novel approaches for premature infants. AB - Hypothermia for hypoxic ischemic encephalopathy has recently permeated clinical practice for term infants. Speculation regarding a neuroprotective benefit of hypothermia for premature infants with HIE has been raised as a need for further research. Hypothermia for other indications including necrotizing enterocolitis with the hope of tissue preservation following injury is less well studied. A summary of evidence for hypothermia and premature infants is presented in this brief report. PMID- 21277718 TI - Comparative cryopreservation of avian spermatozoa: benefits of non-permeating osmoprotectants and ATP on turkey and crane sperm cryosurvival. AB - A comparative approach was used to evaluate the cryosurvival of turkey and crane sperm frozen in a dimethylacetamide (DMA) cryodiluent supplemented with osmoprotectants and ATP. A range (6-26%) of DMA concentrations was used alone or in combination with ATP (30, 60 or 118mM) or one of the following osmoprotectants: (1) sucrose (turkey, 8.0%; crane, 5.0%); (2) 5.0% sucrose and 5.0% trehalose; or (3) betaine hydrochloride (0.1, 0.2 or 0.4mM). The viability of thawed sperm was assessed using the nigrosin-eosin stain and sperm motility was determined using the hanging-drop technique. For semen frozen only with DMA, post-thaw sperm motility was greatest (P<0.05) for the 6.0%, 10.0% and 18% concentrations, regardless of species. Turkey sperm frozen with the sucrose/trehalose combination had greater (P<0.05) post-thaw motility for all DMA treatments compared to DMA alone. The lowest concentration of the osmoprotectant betaine hydrochloride substantially improved turkey sperm viability post-thaw in all treatments compared to DMA alone (P<0.05). The post-thaw motility of crane sperm was improved (P<0.05) with a combination of 18.0%, 24.0% or 26.0% DMA and 30mM ATP. Moreover, in the presence of osmoprotectants, crane sperm motility decreased as the osmoprotectant concentration increased. The lowest concentration of ATP also improved crane sperm viability post-thaw, especially for DMA concentrations 18% or greater. The combination of sucrose and trehalose improved (P<0.05) crane sperm viability only with 6% and 10% DMA. These data affirm that there are avian-specific differences in sperm survival after cryopreservation and suggest that post-thaw survival can be enhanced by including species-based osmoprotectant/ATP combinations in a cryodiluent where DMA is the cryoprotectant. PMID- 21277719 TI - Analysis and discrimination of architectural paint samples via a population study. AB - This study involved the comparative analysis and discrimination of 964 architectural paint samples collected in the United States and Canada. The samples were evaluated to determine the extent to which randomly collected architectural finishes can be discriminated following standard operating protocols for paint analysis. The study also provides a basis for assessing the significance of a result in which a pair or group are undifferentiated. The techniques utilized were stereomicroscopy, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM) with both backscatter electron imaging (BSI) and energy dispersive spectroscopy (EDS), and pyrolysis gas chromatography/mass spectrometry (Py-GC/MS). To assess the layer characteristics (e.g., number, color, sequence, thickness), stereomicroscopy was used with FTIR and/or SEM as needed. The use of visual and microscopic evaluations in concert with FTIR resulted in 42 undifferentiated pairs, a discrimination of 99.99%. Adding SEM and Py-GC/MS analysis resulted in further discrimination of 31 pairs, resulting in eleven undiscriminated pairs of samples. At the conclusion of the study, samples that remained undifferentiated proved to originate from the same source. Therefore, no random pairs were indistinguishable at the conclusion of all examinations. PMID- 21277720 TI - Advantage of early induction of opioid to control pain induced by irradiation in head and neck cancer patients. AB - OBJECTIVE: Although radiotherapy is effective for head and neck cancer patients, the local pain evoked by the irradiation itself reduces food intake and frequently halts the treatment. Thus, pain control is an important problem in radiotherapy for head and neck cancer. We performed to examine whether early induction of low-dose, opioid from mild pain improves dietary and caloric intake, while reducing weight loss. METHODS: The subjects were 43 patients who were hospitalized for head and neck cancer from 2004 to 2008. They were patients who underwent radiation treatment but those who did not undergo preoperative treatment. They were divided into two groups, depending on whether the pain was mild or moderate when an opioid was introduced (MILD and MODERATE, N=23 and 20, respectively). RESULTS: The visual analog scale scores for pain were significantly lower in the MILD than in the MODERATE group at between 25 and 50 Gy. The amount of oxycodone used for pain was significantly lower in the MILD than the MODERATE group. A regular diet was maintained for significantly longer in the MILD group. Caloric intake was significantly higher in the MILD group at over 20 Gy. Weight loss was significantly lower in the MILD group at over 20 Gy. The incidence of side effects was equal in both groups. CONCLUSION: Our results indicated that the introduction of opioids for mild pain during radiotherapy controls the level of pain, improving food intake in head and neck cancer patients. PMID- 21277721 TI - [Evaluation of imported pediatric malaria management in northern France]. AB - OBJECTIVES: The study's objective was to evaluate the adequacy of treatment to recommendations, for the management of pediatric malaria. METHODS: A descriptive, retrospective, multicentre cohort study was conducted over a 7-year period (2000 2006) in 18 pediatric and infectious diseases units in northern France. All children, under 18 years of age, having consulted in one of these hospitals and for whom the diagnosis of malaria has been made by blood smear and/or thick drop examination, were included. RESULTS: One hundred and thirty-three cases of imported malaria were reported. Among the 120 available files, 23 documented severe malaria. Treatment documentation was available for 115 patients. This treatment was initiated orally in 47 cases and intravenously in 68 cases. Intravenous quinine was the first-line treatment in 58% of cases. Halofantrine was the first-line oral treatment. No change was observed along the 6 years. Only 32% of management was in adequacy with recommendations. Five therapeutic failures were recorded. The optimal application of recommendations would have saved 117 days in terms of hospital stay, corresponding to 54,000 ?. CONCLUSIONS: The French Infectious Disease Society (SPILF) recommendations were not well observed. This inappropriate management was responsible for treatment failures and increased costs. PMID- 21277722 TI - MR imaging of ulnar collateral ligament injury in baseball players: value for predicting rehabilitation outcome. AB - BACKGROUND: To compare the MR findings of the ulnar collateral ligament (UCL) injury in baseball players between rehabilitation and reconstruction surgery. MATERIALS AND METHODS: Thirty nine baseball players with clinical evidence of a UCL injury based on medial elbow pain and valgus instability were included. All patients received the rehabilitation treatment for more than six weeks. The elbow MR images of 27 patients not responding to rehabilitation treatment were reviewed that consequently had reconstruction surgery; in addition to 12 patients with improved symptoms with only rehabilitation treatment. The MR imaging was compared between the two treatment groups using the Pearson's chi-square test, and linear by-linear association for the following features: the degree, signal intensity and site of the UCL injury on fat suppressed T2-weighted images. RESULTS: High grade partial tears and complete tears were more commonly seen in the group that had surgery (14 out of 27 patients, 52%; 8 out of 27 patients, 30%), and low grade partial tears and intact continuity were more common in the group that had rehabilitation only (5 out of 12 patients, 42%; 5 out of 12 patients, 42%) (p=0.001). The injured UCL showed a fluid-like bright high or intermediate high signal intensity in the group that had surgery more frequently (14 out of 27 patients, 52%; 12 out of 27 patients, 44%), and intermediate high or low signal intensity was more frequent in the rehabilitation group (7 out of 12 patients, 58%; 3 out of 12 patients, 25%) (p=0.013). The UCL injury at the origin site was most commonly seen in both groups (23 out of 27 patients, 85%; 11 out of 12 patients, 92%, respectively) (p=0.496). CONCLUSION: Preoperative MR imaging is useful for predicting the rehabilitation outcome of UCL injuries in baseball players. PMID- 21277723 TI - Evaluation of diethylenetriaminepentaacetic acid-manganese(II) complexes modified by narrow molecular weight distribution of chitosan oligosaccharides as potential magnetic resonance imaging contrast agents. AB - Novel conjugates of narrow molecular weight distribution of chitosan oligosaccharides (CSn; n=6, 8, 11) with manganese-diethylenetriaminepentaacetic acid (Mn-DTPA) as potential magnetic resonance imaging (MRI) contrast agents were synthesized. The structures were characterized by means of Fourier transform infrared spectra, (13)C nuclear magnetic resonance, size exclusion chromatography and inductively coupled plasma atomic emission spectrometry. The characterization results showed that Mn-DTPA was successfully linked to aminated CSn by an amide function. The magnetic properties were characterized by in vitro and T(1) weighted FLASH image experiments. Relaxivities studies indicated that Mn-DTPA-CSn (n=8, 11) provided higher relaxivity, either in aqueous or bovine serum albumin solution (0.725 mM), than commercial contrast agent Gd-DTPA. The stability results showed that Mn-DTPA-CSn in aqueous were stable enough to prevent Mn(II) ions from releasing. The preliminary in vitro and T(1)-weighted FLASH image studies suggested that Mn-DTPA-CSn had the advantage of becoming promising MRI contrast agents. PMID- 21277724 TI - Effects of frozen storage and sample temperature on water compartmentation and multiexponential transverse relaxation in cartilage. AB - Multiexponential transverse relaxation in tissue has been interpreted as a marker of water compartmentation. Articular cartilage has been reported to exhibit such relaxation in several studies, with the relative contributions of tissue heterogeneity and tissue microstructure remaining unspecified. In bovine nasal cartilage, conflicting data regarding the existence of multiexponential relaxation have been reported. Imaging and analysis artifacts as well as rapid chemical exchange between tissue compartments have been identified as potential causes for this discrepancy. Here, we find that disruption of cartilage microstructure by freeze-thawing can greatly alter the character of transverse relaxation in this tissue. We conclude that fresh cartilage exhibits multiexponential relaxation based upon its microstructural water compartments, but that multiexponentiality can be lost or rendered undetectable by freeze thawing. In addition, we find that increasing chemical exchange by raising sample temperature from 4 degrees C to 37 degrees C does not substantially limit the ability to detect multiexponential relaxation. PMID- 21277726 TI - A validated chiral liquid chromatographic method for the enantiomeric separation of safinamide mesilate, a new anti-Parkinson drug. AB - A enantioselective reversed-phase high performance liquid chromatographic method was developed for the enantiomeric resolution of safinamide mesilate, 2(S)-[4-(3 fluorobenzyloxy)benzylamino] propionamide methanesulfonate, a neuroprotectant with antiparkinsonian and anticonvulsant activity for the treatment of Parkinson disease. The enantiomers of safinamide mesilate were baseline resolved on a Chiralcel OD-RH (150mm*4.6mm, 5MUm) column using a mobile phase system containing 300mM sodium di-hydrogen phosphate buffer (pH 3.0):methanol:acetonitrile (65:25:10, v/v/v). The resolution between the enantiomers was not less than 3.0. The pH value of buffer solution in the mobile phase has played a key role in enhancing chromatographic efficiency and resolution between the enantiomers. The developed method was validated and proved to be robust. The limit of detection and limit of quantification of (R)-enantiomer were found to be 15 and 50ng/mL, respectively, for 20MUL injection volume. The percentage recovery of (R) enantiomer was ranged from 94.2 to 103.7 in bulk drug samples of safinamide mesilate. The sample solution and mobile phase were found to be stable at least for 48h. The final optimized method was successfully applied to separate (R) enantiomer from safinamide mesilate and was proven to be reproducible and accurate for the quantitative determination of (R)-enantiomer in bulk drugs. PMID- 21277725 TI - Statistical analysis of fiber bundles using multi-tensor tractography: application to first-episode schizophrenia. AB - This work proposes a new method to detect abnormalities in fiber bundles of first episode (FE) schizophrenia patients. Existing methods have either examined a particular region of interest or used voxel-based morphometry or used tracts generated using the single tensor model for locating statistically different fiber bundles. Further, a two-sample t test, which assumes a Gaussian distribution for each population, is the most widely used statistical hypothesis testing algorithm. In this study, we use the unscented Kalman filter based two tensor tractography algorithm for tracing neural fiber bundles of the brain that connect 105 different cortical and subcortical regions. Next, fiber bundles with significant connectivity across the entire population were determined. Several diffusion measures derived from the two-tensor model were computed and used as features in the subsequent analysis. For each fiber bundle, an affine-invariant descriptor was computed, thus obviating the need for precise registration of patients to an atlas. A kernel-based statistical hypothesis testing algorithm, which makes no assumption regarding the distribution of the underlying population, was then used to determine the abnormal diffusion properties of all fiber bundles for 20 FE patients and 20 age-matched healthy controls. Of the 1254 fiber bundles with significant connectivity, 740 fiber bundles were found to be significantly different in at least one diffusion measure after correcting for multiple comparisons. Thus, the changes affecting first-episode patients seem to be global in nature (spread throughout the brain). PMID- 21277727 TI - Quality control of a herbal medicinal preparation using high-performance liquid chromatographic and capillary electrophoretic methods. AB - Two methods based on high-performance liquid chromatography (HPLC) and capillary electrophoresis (CE) were developed for the quality control of "samgiumgagambang" (SGMX), a new herbal medicinal preparation containing 14 herbs. Nine components from SGMX were selected as markers: 5-hydroxymethylfuraldehyde, geniposidic acid, chlorogenic acid, paeoniflorin, 20-hydroxyecdysone, coptisine, berberine, luteolin, and glycyrrhizic acid. The markers were identified and analyzed using HPLC coupled with a UV-diode-array detector and monitored at 250nm with a gradient elution of acetonitrile and water containing formic acid on a C(18) analytical column or using CE with a 70mM borate buffer (pH 9.5) containing 10% methanol on a 60-cm fused silica capillary monitored at 230nm. The marker components in SGMX were well separated using both methods and were readily determined within 60min using HPLC or 13min using CE with good precision and accuracy. PMID- 21277728 TI - Clear margins for invasive lobular carcinoma: a surgical challenge. AB - BACKGROUND: The main goal of breast conservative surgery (BCS) is the complete removal of cancer with clear margins and no deformity of the breast. However, in invasive lobular carcinoma (ILC) this goal is hard to achieve because of the underestimation of tumor size. Our study was the first to show the role of surgical techniques in the achievement of clear margins for ILC. METHODS: We reviewed 73 patients with ILC who underwent BCS at Paris Breast Center between January 2005 and June 2008. Full thickness excision (FTE) was performed in a routine basis and oncoplastic surgery (OPS) upon tumor location, volume ratio and overall density of the breast. Margin status was evaluated as positive, close or clear. RESULTS: Positive/close margins were found in 39% of cases and were lower than what was described in the literature (49-63%). FTE was performed in 47 (64%) patients and OPS in 26 (36%) patients. No positive/close margins were observed in patients with lesions located in the lower/central quadrants. Multivariate analysis showed multifocality, larger tumor size and FTE to be independent risk factors for positive margins at final surgery. CONCLUSIONS: Our rate of positive/close margins for ILC was lower than what was described in the literature. The determinant key difference was in our surgical procedures with FTE or OPS differing from the standard BCS described in the literature and we suggest that OPS is to be considered for ILC. It allows larger breast conservative surgery with good cosmetic results and lower rate of compromised margins. PMID- 21277729 TI - The value of pre operative S-100B and SUV in clinically stage III melanoma patients undergoing therapeutic lymph node dissection. AB - INTRODUCTION: High preoperative serum S-100B values and Standardized Uptake Values (SUV) of Fluorodeoxyglucose (FDG) in PET for clinically stage III melanoma patients could be indicators of recurrence after surgical treatment. Aim was to assess the correlation and the prognostic value of these markers. METHODS: All melanoma patients with palpable nodal metastases, without distant metastases, were included from February 2004 to December 2007. Preoperative SUV and S-100B was determined. The correlation between SUV and S-100B and their relations with DFS and DSS were calculated by Cox Proportional Hazard Analysis. RESULTS: 62 Patients, median age 56.9 years, were included in the study. An elevated S-100B was found in 31 patients (50%) and elevated SUV in 24 patients (38.7%). No relation was found between S-100B and SUV. DFS was reduced (31.1%) for patients with an elevated S-100B (HR = 3.1; p = 0.02) in comparison to a normal S-100B (44.6%). The DFS was 42.0% for patients with a SUV below the cut-off point and 29.0% for patients with an elevated SUV (HR = 1.1; p = 0.8). DSS was 60.7% in a normal S-100B and 44.7% for patients with an elevated S-100B (HR = 2.2; p = 0.07). DSS was 59.1% for patients with a normal SUV and 43.5% for patients with elevated SUV (HR = 1.1; p = 0.8). CONCLUSION: S-100B and SUV in stage III melanoma are not correlated and each have different associations with various histopathological factors. S-100B, in contrast with SUV, is associated with nodal tumor load, and when elevated, predicts a shorter DFS. SYNOPSIS: Preoperative serum S-100B and Fluorodeoxyglucose (FDG) Standardized Uptake Value (SUV) in clinically stage III melanoma are not correlated. S-100B is a strong predictor for Disease Free Survival (DFS) in stage III melanoma. PMID- 21277730 TI - Post-operative imatinib in patients with intermediate or high risk gastrointestinal stromal tumor. AB - AIMS: This study aims to determine whether adjuvant treatment with imatinib improves recurrence-free survival (RFS) in Chinese patients undergoing complete resection of localized primary gastrointestinal stromal tumor (GIST) compared with those not receiving adjuvant therapy. We also sought a correlation between c KIT mutations and RFS. METHODS: Patients who had undergone complete tumor resection with intermediate or high risk of recurrence were enrolled in a single center, non-randomized, prospective study. Patients either received adjuvant imatinib therapy (400 mg once-daily) for 3 years or did not. Mutation analyses of c-KIT were performed on available archival tumor samples. RESULTS: 105 patients were enrolled: 56 in the treatment group and 49 in the control group. Median follow-up was 45(43.1-46.9) months. RFS at 1, 2 and 3 years were higher in the treatment group than in the control group (100% vs. 90% at 1 year; 96% vs. 57% at 2 years; 89% versus 48% at 3 years, P < 0.001, HR = 0.188). Subgroup analyses showed that adjuvant therapy significantly decreased the risk of recurrence in patients whether at high risk or at intermediate risk compared with control patients (3-year RFS: 95% vs. 72%, in intermediate risk; 85% versus 31% in high risk; P < 0.001). In addition, imatinib adjuvant treatment decreased the risk of death (P = 0.025, [corrected] HR = 0.254). CONCLUSIONS: Adjuvant imatinib can improve 1-, 2- and 3-year RFS rates in patients at intermediate or high risk of recurrence after complete tumor resection. CLINICAL TRIALS REGISTRATION NUMBER: ChiCTR-TCC-00000582. PMID- 21277731 TI - Inside-out medial meniscus suture: an analysis of the risk of injury to the popliteal neurovascular bundle. AB - PURPOSE: To assess the risk of damage to the popliteal neurovascular structures when inserting the needle through the posterior aspect of the knee during inside out suture of the posterior horn of the medial meniscus. METHODS: The first stage of our study consisted of simulating a virtual meniscal suture during magnetic resonance imaging by tracing a line from 3 different points (located medially [MP], centrally [CP], and laterally [LP] to the patellar tendon) to the posterior horn of the medial meniscus. This procedure was undertaken both at rest and with valgus stress. The next phase involved the suture of the posterior horns of medial menisci taken from cadaveric specimens, the needle being inserted through 3 separate locations (again located medially [MP], centrally [CP], and laterally [LP] to the patellar tendon). Finally, the distance from each suture thread to the aforementioned neurovascular bundle was measured. RESULTS: During the magnetic resonance imaging study, the measured distances at rest were 26.4 mm for MP, 28.8 mm for CP, and 31 mm for LP, whereas those recorded with valgus stress were 21.7 mm for MP, 23.6 mm for CP, and 26 mm for LP. In the second phase of the study (cadaveric specimen suture), the distances obtained were 22.6 mm for MP, 27.6 mm for CP, and 33 mm for LP. CONCLUSIONS: Our results indicate that when the needle is inserted through the 3 points investigated into the posteromedial region of the knee (10 mm from the posterior horn of the internal meniscus) during inside-out suture, it is far enough from the popliteal neurovascular bundle for the maneuver to be performed with a reasonable safety margin. However, this margin can be increased further still if the needle is inserted into the joint through a point located laterally to the patellar tendon. CLINICAL RELEVANCE: Inside-out suture performed 10 mm from the posterior horn of the internal meniscus through the portals studied offers a sufficient margin of safety to avoid damage to the popliteal neurovascular bundle. PMID- 21277732 TI - Anterior cruciate ligament femoral tunnel drilling through anteromedial portal: axial plane drill angle affects tunnel length. AB - PURPOSE: The purpose of this study was to correlate femoral tunnel length with axial drilling angle through the anteromedial portal. METHODS: Ten anatomically correct Sawbones knee models (Pacific Research Laboratories, Vashon, WA) were used for this study. With the knee flexed to 120 degrees , tunnels were drilled through a simulated anterior medial portal with a custom outrigger guide. The guide provided consistently reproducible drilling angles of 20 degrees , 40 degrees , and 60 degrees in the axial plane. Femoral tunnel lengths were recorded for each knee at each drilling angle. A 1-way analysis of variance (alpha = .05) was conducted to compare tunnel length in the 3 groups. Multiple comparisons were conducted by use of a Tukey post hoc test. RESULTS: The mean femoral tunnel lengths at 20 degrees , 40 degrees , and 60 degrees were 37.0 mm, 36.9 mm, and 32.3 mm, respectively. The tunnels drilled at 20 degrees and 40 degrees were significantly longer than the 60 degrees group (P < .001). CONCLUSIONS: Our findings suggest that drilling femoral tunnels through an anteromedial portal at an axial angle of 20 degrees or 40 degrees produces longer femoral tunnels than with an axial drilling angle of 60 degrees . CLINICAL RELEVANCE: On the basis of this study, we recommend a 40 degrees angle when approaching the lateral wall during femoral tunnel drilling through the anteromedial portal to optimize tunnel length while avoiding the acute angle and oblique entry of a 20 degrees angle. PMID- 21277733 TI - Comparison of completely knotless and hybrid double-row fixation systems: a biomechanical study. AB - PURPOSE: The purpose of this study was to compare the biomechanical performance of a completely knotless double-row repair system (SutureCross Knotless Anatomic Fixation System; KFx Medical, Carlsbad, CA) with 2 commonly used hybrid double row repair (medial knot-tying, lateral knotless) systems (Bio-Corkscrew/PushLock [Arthrex, Naples, FL] and Spiralok/Versalok [DePuy Mitek, Raynham, MA]). METHODS: Fourteen pairs of fresh-frozen cadaveric shoulders were harvested, the supraspinatus tendons were isolated, and full-thickness supraspinatus tears were created. One of each pair was repaired with the completely knotless system, and the contralateral side was repaired with either of the hybrid systems. The repairs were then subjected to cyclic loading followed by load to failure. Conditioning elongation, peak-to-peak elongation, ultimate load, and mechanism of failure were recorded and compared by use of paired t tests. Seven additional shoulders were tested to determine the effect of refrigeration storage on the completely knotless system by use of the same mechanical testing protocol. RESULTS: For the completely knotless repair group, 11 of 14 paired specimens failed during the cyclic loading period. Only 1 of 14 hybrid repair systems had failures during cyclic loading, and both hybrid repair systems had statistically lower conditioning elongation than the completely knotless repair group. The mean ultimate load of the SutureCross group was 166 +/- 87 N, which was significantly lower than that in the Corkscrew/PushLock (310 +/- 82 N) and Spiralok/Versalok (337 +/- 44 N) groups. There was an effect of refrigeration storage on the peak to-peak elongation and stiffness of the SutureCross group; however, there was no difference in ultimate tensile load or conditioning elongation. CONCLUSIONS: The completely knotless repair system has lower time-zero biomechanical properties than the other 2 hybrid systems. CLINICAL RELEVANCE: The SutureCross system has lower time-zero biomechanical properties when compared with other hybrid repair systems. Clinical outcome studies are needed to determine the significance. PMID- 21277734 TI - The presence of fatty infiltration in the infraspinatus: its relation with the condition of the supraspinatus tendon. AB - PURPOSE: We aim to determine the prevalence of fatty infiltration and tears in the infraspinatus and to identify any associated risk factors. METHODS: Shoulder magnetic resonance imaging scans from 2006 to 2009 were reviewed. Arthrograms, inflammatory arthropathies, neoplasms, and fractures were excluded. Rotator cuff tears were graded in 4 categories: no tear, partial tear, and complete tear with and without retraction. Fatty infiltration was graded by radiologists using the modified Goutallier classification. Supraspinatus muscle atrophy (size) was measured by use of the ratio of the cross-sectional area of the muscle to the supraspinatus fossa on a sagittal T1-weighted sequence. RESULTS: Three hundred seventy-seven scans were included. The prevalence of infraspinatus tears was as follows: no tear, 74.8%; partial tear, 17.5%; complete tear, 3.2%; and complete tear with retraction, 4.5%. Fatty infiltration of grade 2 or higher was found in 18.1% of the infraspinatus without tears, 39.4% with partial tears, 66.7% with a complete tear, and 82.4% with a complete tear with retraction. In the infraspinatus without tears, increasing fatty infiltration was correlated with the severity of a concomitant supraspinatus tear. Fatty infiltration of grade 2 or higher in the infraspinatus without tears was found in 7.8% of shoulders with an intact supraspinatus, 18.6% with a partial supraspinatus tear, 23.5% with a complete supraspinatus tear, and 54.6% with a retracted complete supraspinatus tear. Supraspinatus muscle atrophy was correlated with infraspinatus fatty infiltration. CONCLUSIONS: Increased infraspinatus fatty infiltration was correlated with the severity of an infraspinatus tear. However, substantial fatty infiltration of the infraspinatus was seen even in the absence of a tear, and it was correlated with a worsening severity of a concomitant supraspinatus tear and atrophy. Concern over tear progression and increasing fatty infiltration of the infraspinatus may impact the management of isolated supraspinatus tendon tears. LEVEL OF EVIDENCE: Level IV, prognostic case series. PMID- 21277735 TI - Predictors of catheter-related bladder discomfort in the post-anaesthesia care unit. AB - BACKGROUND: Catheter-related bladder discomfort (CRBD) is often reported to be stressful and resistant to conventional opioid therapy in the post anaesthesia care unit (PACU). Tolterodine or oxybutynin or gabapentin given orally 1 hour before induction reduce the incidence and severity of CRBD postoperatively. Nevertheless, side effects may occur with these drugs. Thus, preadministration of these different drugs should be selective in patients with predictors of moderate or severe CRBD. The goal of this study was to determine the incidence and predictors of early postoperative CRBD in post-anesthesia care unit. METHODS: We designed a prospective observational study in two teaching hospitals. Consecutive adult patients undergoing surgery under general anaesthesia necessitating intraoperative urinary catheterization were included during a 6-month period. Bladder discomfort was assessed with a simple four-step severity scale: no pain; mild pain (revealed only by interviewing the patient); moderate (a spontaneous complaint by the patient) and severe discomfort (agitation, loud complaints and attempt to remove the bladder catheter). Predictors of CRBD were identified by univariate and multivariate analysis. RESULTS: 164 patients were included, of which 47% complained of CRBD (mild CRBD: 20%; moderate or severe CRBD: 27%). Multivariate logistic regression analysis showed the diameter of the Foley catheter superior than 18 G Fr (OR=2.2, CI95 [1.0-5.1], P=0.06) and male gender (OR=3.2, CI95 [1.0-10.5], P<0.06) to be independent predictors of moderate or severe CRBD in the PACU. CONCLUSION: This observational study identified the incidence and predictive factors of moderate and severe CRBD in the PACU. Future studies are warranted to assess the impact of preoperative antimuscarinic drugs or Gabapentin on males or patients with 18 G Fr Foley catheters. PMID- 21277736 TI - [Traumatic rupture of aortic isthmus associated with left blunt diaphragmatic rupture discovered after 20 years of latency]. PMID- 21277737 TI - The role of anxiety sensitivity in sleep disturbance in panic disorder. AB - Previous research has demonstrated that individuals with panic disorder (PD) report significant sleep disturbances, although the mechanism of this disturbance is not clear. Patients with PD tend to report abnormally high levels of anxiety sensitivity (AS). Because higher AS involves increases in attention and fearfulness about anxiety and associated physical sensations, which in turn may cause excessive psychological and physiologic arousal, we hypothesized that amongst individuals with PD, higher AS would be associated with sleep disruption, particularly in the form of increased sleep latency. As expected, PD was associated with poorer sleep as measured by the Global Pittsburgh Sleep Quality Index (PSQI) compared to controls and AS was significantly associated with longer sleep latency. Our data suggest that sleep disturbance, and in particular sleep latency, in PD may be partly due to high levels of AS, which can be targeted with cognitive-behavioral therapeutic strategies. PMID- 21277738 TI - The Quality of Care and Support (QOCS) for people with disability scale: development and psychometric properties. AB - This paper describes the development of a Quality of Care and Support (QOCS) scale for use with adult persons with physical and intellectual disabilities. In the pilot phase of the study, 12 centers from around the world carried out focus groups with people with physical and disabilities, their carers, and with professionals in order to identify themes that were relevant for their quality of care. Items generated from the focus groups were then tested in a pilot study with 1400 respondents from 15 different centers worldwide, with items being tested and reduced using both classical and modern psychometric methods. A field trial study was then carried out with 3772 respondents, again with the use of both classical and modern psychometric methods. The outcome of the two rounds of data collection and analysis is a 17-item module for assessment of quality of care in physically or intellectually disabled people. Further modifications are also proposed for the use of the QOCS with adults with intellectual disabilities, including simplification of wording of some of the items, the use of a three point response scale, and the inclusion of smiley faces. PMID- 21277739 TI - Statistically characterizing intra- and inter-individual variability in children with Developmental Coordination Disorder. AB - Previous research investigating children with Developmental Coordination Disorder (DCD) has consistently reported increased intra- and inter-individual variability during motor skill performance. Statistically characterizing this variability is not only critical for the analysis and interpretation of behavioral data, but also may facilitate our understanding of the processes underlying DCD. Thus, the primary purpose of this research was to demonstrate the utility of a flexible statistical technique, a random coefficient model (RCM), that characterizes the increased intra- and inter-individual variability in children with and without DCD. We analyzed data from a sensorimotor adaptation task during which participants executed discrete aiming movements under conditions of rotated visual feedback. To highlight the advantages of this statistical approach, we contrasted the results from the RCM with those from a traditionally employed general linear model (GLM). The RCM revealed differences between the two groups of children that the GLM did not detect; and, characterized trajectories of change for each individual. The RCM provides researchers an opportunity to probe behavioral deficits at the individual level and may provide new insights into the behavioral heterogeneity in children with DCD. PMID- 21277740 TI - Formant frequency characteristics in normal Arabic-speaking Jordanians. AB - This study is designed to test the acoustic characteristics of the normal Arabic voice. The subjects were 300 normal Arabic speakers (100 adult males, 100 adult females, and 100 children). The subjects produced a sustained phonation of the six steady state Arabic vowels (/i:/, /e:/, /a:/, , /o:/, and /u:/). The samples were input into the Time-Frequency Analysis Software (TF32). F0, F1, F2, and F3 of the six Arabic vowels were analyzed. Comparisons among speakers of Jordanian Arabic showed that males' formant frequencies were significantly different in comparison with those of females and children. On the other hand, a significant difference was found between females and children in F1, but not in F2 or F3. Comparison with other ethnicities indicated that adult Arab males' formant frequencies showed a generally lower F1 and F2 and a higher F3; adult Arab females' formant frequencies showed a generally higher F1 and lower F2 and F3; whereas children formant frequencies showed a generally lower F1, F2, and F3. It is recommended that speech-language pathologists in Jordan use the new formant norms when evaluating and/or treating Jordanian Arabic speakers. PMID- 21277741 TI - Posterior cricoarytenoid bellies: relationship between their function and histology. AB - OBJECTIVES/HYPOTHESIS: Complete physiological information about human posterior cricoarytenoid muscle (PCA) is essential and is not only of basic science interest but also could lead directly to understanding phonation and many clinical issues in neurolaryngology. The purpose of the study was to investigate and compare the histochemical and morphological properties to know contractile muscle fiber characteristics of two bellies of the PCA. STUDY DESIGN: Cross sectional experimental study. METHODS: The PCAs were harvested from the total laryngectomy simples. Serial transverse sections of the two PCA bellies were performed and studied by immunohistochemical analysis. RESULTS: Two separate muscle bellies were always identified within 15 PCA. The following muscle fiber types were observed: I, I-IIA, and IIA. Comparisons of the vertical and horizontal bellies of the PCA reveled differences in the fiber-type composition. CONCLUSION: In our experience, the PCA should be considered as a combination of two functional subunits, which significantly differ in their muscle fiber-type composition. PMID- 21277742 TI - Sublingual lymph node metastasis of early tongue cancer: report of two cases and review of the literature. AB - Sublingual lymph node metastasis of early stage squamous cell carcinoma of the tongue (SCCT) is seldom reported. Lymphatic tissue in the floor of mouth, which intervenes between the tongue and neck, will be left behind by a primary tumour resection with discontinuous neck dissection. The authors present two cases of early stage SCCT with sublingual lymph node metastasis, review the literature, and discuss the management of the floor of mouth for early stage SCCT. The authors suggest that more attention should be paid to possible sublingual lymph node metastasis for T1/T2 SCC of the ventral tongue with deeply endophytic infiltration. PMID- 21277743 TI - Lack of anti-NMDA receptor autoantibodies in the serum of subjects with schizophrenia. PMID- 21277744 TI - Understanding the pathophysiology of schizophrenia: are we on the wrong or on the right track? PMID- 21277745 TI - Performance and interview-based assessments of cognitive change in a randomized, double-blind comparison of lurasidone vs. ziprasidone. AB - BACKGROUND: Improving cognitive functioning in people with schizophrenia is a major treatment goal. In addition, interview-based measures have been developed to supplement performance-based assessments. However, few data are available regarding whether interview-based measures are sensitive to treatment-related changes. METHODS: Adult outpatients who met DSM-IV criteria for schizophrenia or schizoaffective disorder were randomized to 21 days of double-blind treatment with lurasidone 120 mg once daily (N=150) or ziprasidone 80 mg BID (N=151). A similar proportion of patients completed the study on lurasidone (67.5%) and ziprasidone (69.3%). Study participants were assessed with the majority of the tests from the MATRICS Consensus Cognitive Battery (MCCB) and an interview-based assessment of cognitive functioning, the Schizophrenia Cognition Rating Scale (SCoRS). SCoRS ratings were based on the interviewer's best judgment, after interviews with the patient and a caregiver when available. The study was conducted from April 2006 to January 2007. RESULTS: There were no between-group treatment differences in performance on the MCCB or the SCoRS ratings. Lurasidone patients demonstrated significant within group-improvement from baseline on the MCCB composite score (p=0.026) and on the SCoRS (p<0.001), but ziprasidone patients did not improve on either the MCCB composite (p=0.254) or the SCoRS (p=0.185). At endpoint there was a statistical trend (p=0.058) for lurasidone to demonstrate greater improvement from baseline in SCoRS ratings. Improvements in interview-based aspects of cognition were not related to MCCB test changes, and had minimal correlations with changes in symptoms. CONCLUSIONS: These data suggest that interview-based cognitive measures such as the SCoRS may be sensitive to changes after 3weeks of treatment in patients with schizophrenia. Lurasidone is being assessed further in ongoing clinical trials with additional outcome measures. PMID- 21277746 TI - Circulating microRNA associated with TNF-alpha signaling pathway in patients with plaque psoriasis. PMID- 21277747 TI - Distributed lags time series analysis versus linear correlation analysis (Pearson's r) in identifying the relationship between antipseudomonal antibiotic consumption and the susceptibility of Pseudomonas aeruginosa isolates in a single Intensive Care Unit of a tertiary hospital. AB - The relationship between antibiotic consumption and selection of resistant strains has been studied mainly by employing conventional statistical methods. A time delay in effect must be anticipated and this has rarely been taken into account in previous studies. Therefore, distributed lags time series analysis and simple linear correlation were compared in their ability to evaluate this relationship. Data on monthly antibiotic consumption for ciprofloxacin, piperacillin/tazobactam, carbapenems and cefepime as well as Pseudomonas aeruginosa susceptibility were retrospectively collected for the period April 2006 to July 2007. Using distributed lags analysis, a significant temporal relationship was identified between ciprofloxacin, meropenem and cefepime consumption and the resistance rates of P. aeruginosa isolates to these antibiotics. This effect was lagged for ciprofloxacin and cefepime [1 month (R=0.827, P=0.039) and 2 months (R=0.962, P=0.001), respectively] and was simultaneous for meropenem (lag 0, R=0.876, P=0.002). Furthermore, a significant concomitant effect of meropenem consumption on the appearance of multidrug resistant P. aeruginosa strains (resistant to three or more representatives of classes of antibiotics) was identified (lag 0, R=0.992, P<0.001). This effect was not delayed and it was therefore identified both by distributed lags analysis and the Pearson's correlation coefficient. Correlation coefficient analysis was not able to identify relationships between antibiotic consumption and bacterial resistance when the effect was delayed. These results indicate that the use of diverse statistical methods can yield significantly different results, thus leading to the introduction of possibly inappropriate infection control measures. PMID- 21277748 TI - Parental bonding and alexithymia: a meta-analysis. AB - AIM: The primary purpose of this meta-analysis was to explore, clarify and report the strength of the relationship between alexithymia, as measured by the Toronto Alexithymia Scale (TAS-20), and parenting style as measured by the Parental Bonding Instrument (PBI). METHODS: Web of Science, PsycInfo, PubMed and ProQuest: Dissertations and Theses searches were undertaken, yielding nine samples with sufficient data to be included in the meta-analysis. RESULTS: Evidence indicated moderate to strong relationships between maternal care and alexithymia, and between maternal care and two of the three TAS-20 alexithymia facets (Difficulties Describing Feelings and Difficulties Identifying Feelings, but not Externally Oriented Thinking). Moderate relationships were observed for both maternal- and paternal-overprotection and alexithymia respectively, and for overprotection (both maternal and paternal) and Difficulties Describing Feelings. CONCLUSION: This study is the first meta-analysis of the relationship between parenting styles and alexithymia, and findings confirm an especially strong association between maternal care and key elements of alexithymia. This review highlights the issues that still remain to be addressed in exploring the link between parenting style and alexithymia. PMID- 21277749 TI - Use of and satisfaction with support received among survivors from three Scandinavian countries after the 2004 Southeast Asian tsunami. AB - INTRODUCTION: There is limited guidance regarding effective preventions for post disaster mental health problems and what kind of support is preferred by disaster survivors. AIM: To describe the use of and satisfaction with support in three Scandinavian countries after the tsunami and analyzing the association between support and posttraumatic stress reactions. METHOD: The sample comprises 6772 responders who returned to Scandinavia from the tsunami-struck countries of Southeast Asia in 2004. RESULTS: Most were satisfied with informal support on site. Support from embassies/consulates was not received well, leaving about 64% of the Danes/Norwegians and 73% of the Swedes dissatisfied. After returning home, support from close relatives rendered highest degree of satisfaction. Consultation with general practitioner (GP) was reported by 63% of Norwegians, 40% of Danes, and 16% of Swedes. Most responders (60-77%) were satisfied with their GP, although Norwegians were least satisfied. Using support was associated with higher levels of posttraumatic stress symptoms. CONCLUSIONS: Informal support was used to a high degree and rendered considerable satisfaction in all three countries, while the use of and satisfaction with formal support varied more. Lack of satisfaction with embassies and consulates may indicate deficiencies in the authorities' preparedness in assisting disaster stricken citizens abroad. PMID- 21277750 TI - Differences in drug consumption, comorbidity and health service use of opioid addicts across six European urban regions (TREAT-project). AB - OBJECTIVES: This comparative study investigated consumption patterns, comorbidity and treatment utilization of opioid addicts in six European cities (Athens, Essen, London, Padua, Stockholm, Zurich). SUBJECTS AND METHODS: Data were collected by structured face-to-face interviews. The representative sample comprises 599 addicts (100 patients per centre, 99 in London) at the start of a treatment episode. RESULTS: Patients were dependent on opioids for about 10 years. Regional differences were significant regarding the patients' drug consumption pattern and their method of heroin administration (up to a fourth of the patients in Essen, London and Zurich usually smoke heroin). Concomitant use of benzodiazepines, cannabis and alcohol was common in all regions with the German and English samples showing the highest level of polydrug use. The prevalence of major depression was high in all regions (50%). Stockholm and London patients worry most about their physical health. Differences in the amount of needle sharing and especially in the use of public health service were prominent between the sites. Opioid addiction was a long-term disorder associated with a high burden of comorbidity and social problems in all cities. CONCLUSION: The results of the study show significant interregional differences of opioid addicts which might require different treatment strategies in European countries to handle the problem. PMID- 21277751 TI - Perceived burden of illness in patients entering for treatment in a university hospital--is the threshold to secondary care higher for patients with depression than for those with somatic disorders? AB - BACKGROUND: The threshold to secondary health care should be similar for all patients independent of the underlying disease. This study compared, using a validated health-related quality of life (HRQoL)-instrument, whether the perceived burden of illness is similar in patients admitted for secondary care treatment into a university hospital because of one of six common conditions. METHODS: HRQoL, assessed by the generic 15D instrument before elective treatment, was compared in six groups: operative treatment of cataract (n=219), operative treatment of cervical or lumbar radicular pain (n=270), hysterectomy due to benign uterine conditions (n=337), hip or knee replacement surgery (n=223), coronary angiography due to suspected coronary artery disease (n=261), and secondary care treatment of depression (n=89). RESULTS: Mean (+/-SD) HRQoL score was clearly highest in patients with benign uterine conditions (0.908+/-0.071) and lowest in patients with depression (0.729+/-0.120) (P<0.001 between the groups). Also all the other groups had a significantly (P<0.001) higher baseline HRQoL score (ranging from 0.802 to 0.824) than patients with depression. Outcome of treatment, in terms of HRQoL improvement, was in depressive patients at least equal, and in some cases even better, than that in the other groups. DISCUSSION: Our results imply that, at least concerning perceived burden of illness, patients with depression are worse off when admitted to secondary care treatment than patients with many somatic conditions. That may be a consequence of poor motivation of depressive patients to seek treatment or that, contradictory to guidelines, the health care system does nor give priority to those worst off and sets a higher threshold for specialized care of patients with depression than of those with common somatic disorders. PMID- 21277752 TI - Violence and phases of illness: differential risk and predictors. AB - This study tested the hypothesis that among patients with schizophrenia the risk and correlates of aggressive behavior differ depending on the level of positive symptoms. Two hundred and fifty-one adults with schizophrenia who were living in the community were assessed by psychiatrists using validated instruments. Patients and collaterals reported aggressive behavior. In a final multivariate model, aggressive behavior was significantly and positively associated with childhood conduct disorder, current use of illicit drugs, positive, threat control-override (TCO), and depression symptoms. While 16% of the patients with two or fewer positive symptoms engaged in aggressive behavior in the previous six months, this was true of 28.4% of those with three or more positive symptoms (X2 (n=251,1)=5.48, P=0.019). Among patients with high positive symptoms, even univariate analyses failed to detect any factors associated with aggressive behavior other than medication non-compliance, typical antipsychotic medication, and clozapine. By contrast, among patients with few positive symptoms, aggressive behavior was associated with TCO and depression symptoms, young age, male sex, the number of childhood conduct disorder symptoms, prior aggressive behavior, and current illicit drug use. In phases of illness characterized by different levels of positive symptoms, the risk of aggressive behavior and the associated factors differ. PMID- 21277753 TI - Evaluation of antidepressant activity of 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro isoquinolin-4-YL)-cyclohexanol, a beta-substituted phenylethylamine in mice. AB - The beta-phenylethylamines are known to act as ligands for the trace amine receptors, a novel family of G-protein-coupled receptors. The trace amines are stored and released along with various neurotransmitter agents such as norepinephrine, serotonin, and dopamine and thus work as neuromodulator or neurotransmitter agents. Trace amines are known to play an important role in the pathophysiology of major depression. In our earlier study, we have demonstrated the synthesis of various beta-substituted phenylethylamine molecules hypothesized to be effective in various central nervous system disorders. The present study is an attempt to evaluate one of such molecules, 1-(7-methoxy-2-methyl-1,2,3,4 tetrahydro-isoquinolin-4-yl)-cyclohexanol, in animal models of depression. Various behavioral paradigms of despair such as forced swim and tail-suspension tests were used to assess the antidepressant-like activity. Further, an alteration in the levels of various neurotransmitters (norepinephrine, serotonin, and dopamine) in the mouse brain following 1-(7-methoxy-2-methyl-1,2,3,4 tetrahydro-isoquinolin-4-yl)-cyclohexanol administration was evaluated. The molecule (4-16 mg/kg., i.p.) dose-dependently inhibited the immobility period in mouse forced swim test, the effect comparable to venlafaxine. The ED50 values of 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-cyclohexanol and venlafaxine in mouse forced swim test were found to be 5.27 [4.38-6.35] mg/kg., i.p and 4.66 [3.48-6.25] mg/kg., i.p., respectively. Further, 1-(7-methoxy-2 methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-cyclohexanol at 4-16 mg/kg., i.p. reversed the immobility period in mouse tail-suspension test. Additionally, the molecule at 8 mg/kg., i.p. reversed reserpine-induced behavioral despair in mouse forced swim test. When administered simultaneously, it (4 and 8 mg/kg., i.p) enhanced the antidepressant activity of sub-effective doses of imipramine (2mg/kg., i.p.) or fluoxetine (2mg/kg., i.p.) in the mouse forced swim test. Neurochemical analysis revealed that the molecule at 8 mg/kg., i.p. increased the levels of norepinephrine (21% increase) without affecting serotonin in the mouse brain. However, at higher dose (16 mg/kg., i.p.), it increased the levels of norepinephrine (13% increase), serotonin (37% increase), and dopamine (42% increase). The molecule enhanced the locomotor activity in mice only at higher doses. The molecule, unlike venlafaxine, which potentiated barbiturate-induced hypnosis, was devoid of any sedative activity. In conclusion, 1-(7-methoxy-2 methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-cyclohexanol, possess antidepressant like activity in animal models of depression by modulating the neurotransmitter levels in the brain. Such an activity might be due to the modulating action of this novel molecule on trace amine receptors. Such a molecule may be the future drugs of choice for the treatment of major depression. PMID- 21277754 TI - Multinuclear NMR study of silica fiberglass modified with zirconia. AB - Silica fiberglass textiles are emerging as uniquely suited supports in catalysis, which offer unprecedented flexibility in designing advanced catalytic systems for chemical and auto industries. During manufacturing fiberglass materials are often modified with additives of various nature to improve glass properties. Glass network formers, such as zirconia and alumina, are known to provide the glass fibers with higher strength and to slow down undesirable devitrification processes. In this work multinuclear (1)H, (23)Na, (29)Si, and (91)Zr NMR spectroscopy was used to characterize the effect of zirconia on the molecular level fiberglass structure. (29)Si NMR results help in understanding why zirconia modified fiberglass is more stable towards devitrification comparing with pure silica glass. Internal void spaces formed in zirconia-silica glass fibers after acidic leaching correlate with sodium and water distributions in the starting bulk glass as probed by (23)Na and (1)H NMR. These voids spaces are important for stabilization of catalytically active species in the supported catalysts. Potentials of high-field (91)Zr NMR spectroscopy to study zirconia-containing glasses and similarly disordered systems are illustrated. PMID- 21277755 TI - Ontogeny of pulmonary cyclooxygenase-1 (COX-1) and -2 (COX-2). AB - Prostaglandins synthesized by enzymatic reactions such as cyclooxygenases have been implicated in lung pathophysiology. The goal of this study was to delineate the pulmonary ontogeny of cyclooxygenase enzymes (COX-1 and COX-2) immunohistochemical expression and cellular localization in various microanatomic locations of lungs from pre-term, term, and post-natal lambs. Lung tissues were obtained at 115 and 130 days of gestation from pre-term lambs, 145 days (term; complete gestation), and 15 days post-natally. No significant differences were seen in lung COX-1 expression at various microanatomic locations during pre-term, term, or postnatally. Moderate to strong COX-1 expression was present in macrophages, alveolar septa, bronchial smooth muscle cells, bronchiolar smooth muscle cells, vascular endothelial cells, and vascular smooth muscle cells. Minimal COX-1 expression was present in bronchial and bronchiolar epithelial cells. Most microanatomic locations lacked COX-2 expression with the exception of weak expression that was present in bronchial and bronchiolar epithelial cells at 145 days of full gestation and 15 days post-natally. This work suggests that: (a) COX-1 is constitutively expressed in lungs from pre-term, term, and post-natal lambs in various microanatomic pulmonary locations, (b) there is differential expression of COX-1 and COX-2 in the developing lung, and (c) COX-2 does not appear to play a role in lung fetal development, at least in neonatal lambs. PMID- 21277756 TI - Thermal performance curves of Paramecium caudatum: a model selection approach. AB - The ongoing climate change has motivated numerous studies investigating the temperature response of various organisms, especially that of ectotherms. To correctly describe the thermal performance of these organisms, functions are needed which sufficiently fit to the complete optimum curve. Surprisingly, model comparisons for the temperature-dependence of population growth rates of an important ectothermic group, the protozoa, are still missing. In this study, temperature reaction norms of natural isolates of the freshwater protist Paramecium caudatum were investigated, considering nearly the entire temperature range. These reaction norms were used to estimate thermal performance curves by applying a set of commonly used model functions. An information theory approach was used to compare models and to identify the best ones for describing these data. Our results indicate that the models which can describe negative growth at the high- and low-temperature branch of an optimum curve are preferable. This is a prerequisite for accurately calculating the critical upper and lower thermal limits. While we detected a temperature optimum of around 29 degrees C for all investigated clonal strains, the critical thermal limits were considerably different between individual clones. Here, the tropical clone showed the narrowest thermal tolerance, with a shift of its critical thermal limits to higher temperatures. PMID- 21277757 TI - From chronic overfeeding to hepatic injury: role of endoplasmic reticulum stress and inflammation. AB - We analyse how chronic overfeeding, by increasing circulating fatty acids, might lead to inflammation, insulin resistance (IR) and injury in the liver. Chronic overfeeding causes an increase in adipose tissue depots and is characterised by an increased presence of hypertrophic adipocytes when adipose tissue expandability is inadequate. Adipocyte hypertrophy is a possible stress condition for the endoplasmic reticulum (ER), which will activate inflammatory and apoptotic pathways and cause IR in adipose tissue. Insulin-resistant adipocytes, being more lipolytic and less liposynthetic, induce an increase in circulating free fatty acids. Moreover, the strongly compromised secretion/function of the adipocyte hormones, adiponectin and leptin, decreases lipid oxidation, particularly in the liver, causing lipid accumulation, ER stress and IR in hepatocytes. ER stress may lead to reduced very-low-density lipoprotein (VLDL) secretion and increased lipogenic gene expression despite the presence of IR. These events and reduced lipid oxidation may lead to further hepatic lipid accumulation. When the triglyceride storage capacity of hepatocytes is exceeded, hepatic injury may occur. ER-stressed steatotic hepatocytes activate apoptotic and inflammatory pathways, which trigger IR and the release of chemokines and cytokines, and these, in turn, elicit an increased influx of Kupffer cells (KCs) and hepatic stellate cells (HSCs) around dying hepatocytes. Soluble mediators, secreted mainly by ER-stressed steatotic hepatocytes and activated KCs, induce the transdifferentiation of HSCs to myofibroblasts, which secrete fibrogenic cytokines and matrix components that trigger fibrosis. In conclusion, chronic lipid overloading due to inadequate fat-storing capacity of adipose tissue can induce hepatic injury when triglyceride storage capacity of hepatocytes is exceeded. PMID- 21277758 TI - GADD45alpha and annexin A1 are involved in the apoptosis of HL-60 induced by resveratrol. AB - Resveratrol (3,4',5-trihydroxy-trans-stilbene), one of secondary metabolites of low molecular weight present in plant, has various important biological effects. It can induce apoptosis in human leukemia cell types in vitro, although the mechanism is not fully understood. In the present study, we demonstrated reduced viability and DNA synthesis, as well as increased proportion of the subdiploid cell population, in HL-60 cells as determined by cell cycle analysis with resveratrol. Resveratrol treatment resulted in a gradual time-dependent decrease in the expression of anti-apoptotic Bcl-2 and increase in that of Bax, annexin A1, growth arrest- and DNA damage-induced gene 45alpha (GADD45alpha), and cleaved caspase-3. In addition, resveratrol markedly increased caspase-3 activity in cells. Our results suggest that resveratrol could inhibit the proliferation and induce apoptosis of HL-60 cells through a GADD45alpha and annexin A1/caspase-3 pathway. PMID- 21277759 TI - Influence of Cu10x copper nanoparticles intramuscular injection on mineral composition of rat spleen. AB - Spleen mineral composition was studied for 25 elements using atomic emission and mass spectrometry (AES-ISP and MS-ISP) for the first time by one- and manifold intramuscular injection of Cu10x copper nanoparticles. This was done, because the spleen is considered to be the organ most amenable of immunological defense and sensitive to exposure. The research is new and based on the necessity to check the accumulation of elements, which can result in toxic effects, and also the character of the influence of nanoparticles on the change of the natural fluctuation rhythm, as well as the interrelation between them. PMID- 21277760 TI - Emergence of the PI3-kinase pathway as a central modulator of normal and aberrant B cell differentiation. AB - Phosphoinositide 3-kinase (PI3K) defines a family of lipid kinases that direct a wide range of cellular processes and cell fate decisions. Since its discovery, and that of its enzymatic antagonist PTEN, much of the focus on PI3K has been on its oncogenic potential. In recent years, studies on PI3K signaling in B lymphocytes have established the importance of this pathway in effecting B cell differentiation and associated molecular events such as V(D)J recombination and class switch recombination. Intriguing new findings also indicate that there is specificity in the PI3K pathway in B cells, including preferential expression or usage of particular PI3K isoforms and counter-regulation by the PTEN and SHIP phosphatases. The role of PI3K adaptor proteins (CD19, BCAP, and TC21) has also undergone revision to reflect both shared and unique properties. The emergence of Foxo1 as a critical PI3K regulatory target for B cell differentiation has united membrane proximal regulatory events orchestrated by PI3K/PTEN/SHIP with key transcriptional targets. Insights into the regulation and impact of PI3K signaling have been brought to bear in new treatments for B cell malignancies, and will also be an important topic of consideration for B cell-dependent autoimmune diseases. PMID- 21277761 TI - Epidemiologic perspective on immune-surveillance in cancer. AB - Common 'themes' in epidemiology related to cancer risk beg a comprehensive mechanistic explanation. As people age, risk for cancer increases. Obesity and smoking increase the risk for many types of cancer. History of febrile childhood diseases lowers the risk for melanomas, leukemias, non-Hodgkin's lymphoma (NHL), and ovarian cancer. Increasing number of ovulatory cycles uninterrupted by pregnancies correlate positively with breast, endometrial, and ovarian cancer risk while pregnancies and breastfeeding lower the risk for these cancers as well as cancers of the colon, lung, pancreas, and NHL. Chronic inflammatory events such as endometriosis or mucosal exposure to talc increase the risk for several types of cancer. Mechanisms so far considered are site specific and do not explain multiple associations. We propose that most of these events affect cancer immunosurveillance by changing the balance between an effective immune response and immune tolerance of an emerging cancer. We review recently published data that suggest that immune mechanisms underlie most of these observed epidemiologic associations with cancer risk. PMID- 21277762 TI - The ISB model (infrastructure, service, behaviour): a tool for waste practitioners. AB - In response to the EU Landfill Directive and the challenge of mitigating climate change, the UK government (nationally and locally) must develop strategies and policies to reduce, recycle, compost and recover waste. Best practice services that yield high recycling rates, such as alternate weekly collections, are now largely mainstream in suitable areas. However, national recycling performance is short of what is needed; policy makers must look for innovative ways to meet challenging recycling targets. Increasingly, local authorities are using behaviour change interventions to encourage the public to recycle; these tend to be based on the premise that an individuals' behaviour is predetermined by their values. In practice, this has led to a host of initiatives that attempt to change individuals' behaviour without addressing situational barriers. In this paper, we argue that that a behaviour-centric approach has limited effectiveness. Using an analysis of the literature and studies that investigated recycling participation in the city of Portsmouth, we have identified three significant clusters that can facilitate effective recycling: infrastructure, service and behaviour (ISB). We present the ISB model - a tool that can be used by waste practitioners when planning interventions to maximise recycling to better understand the situation and context for behaviour. Analysis using the ISB model suggests that current best practice, "business as usual" interventions could realistically achieve a national recycling rate of 50%. If the UK is to move towards zero waste, policy makers must look "upstream" for interventions that change the situational landscape. PMID- 21277763 TI - Cocaine detection via rolling circle amplification of short DNA strand separated by magnetic beads. AB - A novel and sensitive fluorescence biosensor based on aptamer and rolling circle amplification for the determination of cocaine was developed in the present work. Here cocaine aptamers immobilized onto Au nanoparticles modified magnetic beads hybridized with short DNA strand. In the presence of cocaine, the short DNA strand was displaced from aptamer owing to cocaine specially binding with aptamer. Next, the short DNA strand was separated by magnetic beads and used to originate rolling circle amplification as primer. The end products of rolling circle amplification were detected by fluorescence signal generation upon molecular beacons hybridizing with the end products of rolling circle amplification. With rolling circle amplification and the separation by magnetic beads reducing the background signal, the new strategy was suitable for the detection of as low as 0.48 nM cocaine. Compared with reported cocaine sensors, our method exhibited excellent sensitivity. Our new strategy may provide a platform for numerous proteins and low molecular weight analytes to highly sensitively detect by DNA amplification. PMID- 21277764 TI - A DNA sequence-specific electrochemical biosensor based on alginic acid-coated cobalt magnetic beads for the detection of E. coli. AB - A new type of DNA sequence-specific electrochemical biosensor based on magnetic beads for the detection of Escherichia coli is reported in the present work. Alginic acid-coated cobalt magnetic beads, capped with 5'-(NH(2)) oligonucleotide and employed not only for magnetic separation but also as the solid adsorbent, were used as DNA probes to hybridize with the target E. coli DNA sequence. This assay was specific for E. coli detection depending on the uid A gene, which encodes for the enzyme beta-d-glucuronidase produced by E. coli strains. When daunomycin (DNR) was used as DNA hybridization indicator, the target sequences of E. coli hybridized with the probes resulted in the decrease of DNR reduction peak current, which was proportional to the E. coli concentration. The optimization of the hybridization detection was carried out and the specificity of the probes was also demonstrated. This DNA biosensor can be employed to detect a complementary target sequence for 3.0*10(-10) mol/L and denatured PCR products for 0.5 ng/MUL. The linear range of the developed biosensor for the detection of E. coli cells was from 1.0*10(2) to 2.0*10(3) cells/mL with a detection limit of 50 cells/mL. After a brief enrichment process, a concentration of 10 cells/mL E. coli in real water samples was detected by the electrochemical biosensor. PMID- 21277765 TI - Gelfoam first metatarsophalangeal replacement/interposition arthroplasty--a case series with functional outcomes. AB - Reported below are the functional results of a case-series of Gelfoam(r)-based first metatarsophalangeal total joint replacements using an interposition arthroplasty technique carried out between April 1997 and December 2007. All patients who underwent Gelfoam-based arthroplasty under the care of a single surgeon were included; outcome scores and complications were recorded. A total of 31 joints in 31 consecutive patients were followed for a mean duration of 64 (range 24-150) months, and the mean patient age at the time of operation was 48+/ 9 (range 35-80) years. Hallux rigidus was the primary diagnosis in all of the cases except one in which a failed chevron ostetomy was the indication for treatment. The mean American Orthopaedic Foot & Ankle Society Hallux Metatarsophalangeal-Interphalangeal score increased from an average of 35 pre operatively to an average of 74 at final follow-up (range 67-100), with 20 (64.5%) joints rated good to excellent. One (3.5%) joint was fused 6 months after the arthroplasty procedure. Based on these results, we concluded that first MTPJ total joint GelfoamTM-based interpostion arthroplasty is a cheap alternative to other joint replacement systems for the MTP joint. The results appear similar to those achieved using more expensive devices. PMID- 21277766 TI - Structural insights into the retroviral DNA integration apparatus. AB - Retroviral replication depends on successful integration of the viral genetic material into a host cell chromosome. Virally encoded integrase, an enzyme from the DDE(D) nucleotidyltransferase superfamily, is responsible for the key DNA cutting and joining steps associated with this process. Insights into the structural and mechanistic aspects of integration are directly relevant for the development of antiretroviral drugs. Recent breakthroughs have led to biochemical and structural characterization of the principal integration intermediates revealing the tetramer of integrase that catalyzes insertion of both 3' viral DNA ends into a sharply bent target DNA. This review discusses the mechanism of retroviral DNA integration and the mode of action of HIV-1 integrase strand transfer inhibitors in light of the recent visualization of the prototype foamy virus intasome, target DNA capture and strand transfer complexes. PMID- 21277767 TI - Investigation of mircroorganisms colonising activated zeolites during anaerobic biogas production from grass silage. AB - The colonisation of activated zeolites (i.e. clinoptilolites) as carriers for microorganisms involved in the biogas process was investigated. Zeolite particle sizes of 1.0-2.5mm were introduced to anaerobic laboratory batch-cultures and to continuously operated bioreactors during biogas production from grass silage. Incubation over 5-84 days led to the colonisation of zeolite surfaces in small batch-cultures (500 ml) and even in larger scaled and flow-through disturbed bioreactors (28 l). Morphological insights were obtained by using scanning electron microscopy (SEM). Single strand conformation polymorphism (SSCP) analysis based on amplification of bacterial and archaeal 16S rRNA fragments demonstrated structurally distinct populations preferring zeolite as operational environment. via sequence analysis conspicuous bands from SSCP patterns were identified. Populations immobilised on zeolite (e.g. Ruminofilibacter xylanolyticum) showed pronounced hydrolytic enzyme activity (xylanase) shortly after re-incubation in sterilised sludge on model substrate. In addition, the presence of methanogenic archaea on zeolite particles was demonstrated. PMID- 21277768 TI - Implications of short and long term critical flux experiments for laboratory scale MBR operations. AB - This paper evaluates the critical flux obtained by different techniques including tests with different flux step lengths (20 and 40 min and 7 days) and modes of operation (continuous and intermittent) under low and high MLSS concentrations. The paper also analyses a couple of long-term tests (flow rate of 40 and 20 L/day) to obtain the time required to reach the critical flux experimentally and compares those values with the results obtained numerically from a mathematical model. It was found that intermittent mode with membrane relaxation was useful in controlling the fouling of membrane and in restoring the membrane from fouling at lower MLSS. PMID- 21277769 TI - Effects of ammonium concentration and charge exchange on ammonium recovery from high strength wastewater using a microbial fuel cell. AB - Ammonium recovery using a two chamber microbial fuel cell (MFC) was investigated at high ammonium concentration. Increasing the ammonium concentration (from 0.07 to 4 g ammonium-nitrogen/L) by addition of ammonium chloride did not affect the performance of the MFC. The obtained current densities by DC-voltammetry were higher than 6A/m(2) for both operated MFCs. Also continuous operation at lower external resistance (250 Omega) showed an increased current density (0.9A/m(2)). Effective ammonium recovery can be achieved by migrational ion flux through the cation exchange membrane to the cathode chamber, driven by the electron production from degradation of organic substrate. The charge transport was proportional to the concentration of ions. Nonetheless, a concentration gradient will influence the charge transport. Furthermore, a charge exchange process can influence the charge transport and therefore the recovery of specific ions. PMID- 21277770 TI - Effect of the addition mode of carbon nanotubes for the production of chitosan hydrogel core-shell beads on adsorption of Congo red from aqueous solution. AB - The adsorption performance of chitosan (CS) hydrogel beads (CSBs) generated by sodium dodecyl sulfate (SDS) gelation with multi-walled carbon nanotube (CNT) impregnation was investigated for Congo red removal as a model anionic dye. CNT impregnated CSBs were prepared by four different strategies for dispersing CNTs: (a) in CS solution (CSBN1), (b) in SDS solution (CSBN2), (c) in CS solution containing cetyltrimethylammonium bromide (CTAB) (CSBN3), and (d) in SDS solution for gelation with CTAB-containing CS solution (CSBN4). It was observed from FE SEM study that depending on nature of CNT dispersion, CNTs were found on the outer surface of CSBN2 and CSBN4 only. The adsorption capacity of the CSBs varied with the strategy used for CNT impregnation, and CSBN4 exhibited the highest maximum adsorption capacity (375.94 mg/g) from the Sips model. The lowest Sips maximum adsorption capacity by CSBN3 (121.07 mg/g) suggested significant blocking of binding sites of CS by CNT impregnation. PMID- 21277771 TI - Development of biocatalysts for production of commodity chemicals from lignocellulosic biomass. AB - Lignocellulosic biomass is recognized as potential sustainable source for production of power, biofuels and variety of commodity chemicals which would potentially add economic value to biomass. Recalcitrance nature of biomass is largely responsible for the high cost of its conversion. Therefore, it is necessary to introduce some cost effective pretreatment processes to make the biomass polysaccharides easily amenable to enzymatic attack to release mixed fermentable sugars. Advancement in systemic biology can provide new tools for the development of such biocatalysts for sustainable production of commodity chemicals from biomass. Integration of functional genomics and system biology approaches may generate efficient microbial systems with new metabolic routes for production of commodity chemicals. This paper provides an overview of the challenges that are faced by the processes converting lignocellulosic biomass to commodity chemicals. The critical factors involved in engineering new microbial biocatalysts are also discussed with more emphasis on commodity chemicals. PMID- 21277772 TI - Low-liquid pretreatment of corn stover with aqueous ammonia. AB - A low-liquid pretreatment method of corn stover using aqueous ammonia was studied to reduce the severity and liquid throughput associated with the pretreatment step for ethanol production. Corn stover was treated at 0.5-50.0 wt.% of ammonia loading, 1:0.2-5.0 (w/w) of solid-to-liquid ratio, 30 degrees C for 4-12 weeks. The effects of these conditions on the composition and enzyme digestibility of pretreated corn stover were investigated. Pretreatment of corn stover at 30 degrees C for four weeks using 50 wt.% of ammonia loading and 1:5 solid-to-liquid ratio resulted in 55% delignification and 86.5% glucan digestibility with 15 FPU cellulase+30 CBU beta-glucosidase/g-glucan. Simultaneous saccharification and fermentation of corn stover treated at 30 degrees C for four weeks using 50 wt.% ammonia loading and 1:2 solid-to-liquid ratio gave an ethanol yield of 73% of the theoretical maximum based on total carbohydrates (glucan+xylan) present in the untreated material. PMID- 21277773 TI - Prediction model of DnBP degradation based on BP neural network in AAO system. AB - A laboratory-scale anaerobic-anoxic-oxic (AAO) system was established to investigate the fate of DnBP. A removal kinetic model including sorption and biodegradation was formulated, and kinetic parameters were evaluated with batch experiments under anaerobic, anoxic, oxic conditions. However, it is highly complex and is difficult to confirm the kinetic parameters using conventional mathematical modeling. To correlate the experimental data with available models or some modified empirical equations, an artificial neural network model based on multilayered partial recurrent back propagation (BP) algorithm was applied for the biodegradation of DnBP from the water quality characteristic parameters. Compared to the kinetic model, the performance of the network for modeling DnBP is found to be more impressive. The results showed that the biggest relative error of BP network prediction model was 9.95%, while the kinetic model was 14.52%, which illustrates BP model predicting effluent DnBP more accurately than kinetic model forecasting. PMID- 21277774 TI - Dry pretreatment of lignocellulose with extremely low steam and water usage for bioethanol production. AB - Two rarely noticed but important parameters of the dilute sulfuric acid pretreatment of lignocellulose biomass, the feedstock filling ratio to the pretreatment reactor and the solids/liquid presoaking ratio, were extensively studied. The effects of the two parameters on the steam consumption, waste water generation, and pretreatment efficiency were investigated. At the full filling ratio and high solids/liquid presoaking ratio, this "dry" pretreatment method provided at least the following advantages: (1) the steam consumption was significantly reduced; (2) no aqueous acid containing waste water was generated; (3) high solids content of the pretreated materials were obtained and the consequent saccharification and fermentation was carried out at high solids loading easily. This method was applied to various lignocellulose feedstocks successfully and provided a practical means to produce ethanol economically feasible. PMID- 21277775 TI - Preparation of cross-linked lipase-coated micro-crystals for biodiesel production from waste cooking oil. AB - A dual modification procedure composed of cross-linking and protein coating with K(2)SO(4) was employed to modify Geotrichum sp. lipase for catalyzing biodiesel production from waste cooking oil. Compared to single modification of protein coating with K(2)SO(4), the dual modification of cross-linking and lipase coating improved catalytic properties in terms of thermostable stability, organic solvent tolerance, pH stability and operational stability in biodiesel production process, although biodiesel yield and initial reaction rate for CLPCMCs were not improved. After five successive batch reactions, CLPCMCs could still maintain 80% of relative biodiesel yield. CLPCMCs retained 64% of relative biodiesel yield after incubation in a pH range of 4-6 for 4 h, and 85% of relative biodiesel yield after incubation in a range of 45-50 degrees C for 4 h. CLPCMCs still maintained 83% of relative biodiesel yield after both treated in polar organic solvent and non-polar organic solvent for 4 h. PMID- 21277776 TI - Structural comparison and enhanced enzymatic hydrolysis of the cellulosic preparation from Populus tomentosa Carr., by different cellulose-soluble solvent systems. AB - This study aims to establish an efficient pretreatment process using cellulose dissolution solvents to enhance the enzymatic saccharification. LiOH/urea, LiCl/DMAc, concentrated phosphoric acid, ionic liquid (1-butyl-3 methylimidazolium chloride; [BMIM]Cl) and N-methyl-morpholine-N-oxide (NMMO) were selected as the cellulose dissolution agents. Except the cellulosic sample regenerated from LiCl/DMAc system, all the other treated samples exhibited lower cellulose crystallinity and degree of polymerization (DP), and consequently, exhibited a significant enhancement on enzymatic hydrolysis kinetic. Ionic liquid pretreatment offered unique advantages in the hydrolysis rate in the first 10h, probably due to the extensively structural transformation of cellulose from the crystalline to the amorphous region. Meanwhile, the regenerated cellulose from concentrated phosphoric acid almost completely consisted of cellulose II, and achieved the highest saccharification yield. PMID- 21277777 TI - Application of simultaneous saccharification and fermentation (SSF) from viscosity reducing of raw sweet potato for bioethanol production at laboratory, pilot and industrial scales. AB - The aim of this work was to research a bioprocess for bioethanol production from raw sweet potato by Saccharomyces cerevisiae at laboratory, pilot and industrial scales. The fermentation mode, inoculum size and pressure from different gases were determined in laboratory. The maximum ethanol concentration, average ethanol productivity rate and yield of ethanol after fermentation in laboratory scale (128.51 g/L, 4.76 g/L/h and 91.4%) were satisfactory with small decrease at pilot scale (109.06 g/L, 4.89 g/L/h and 91.24%) and industrial scale (97.94 g/L, 4.19 g/L/h and 91.27%). When scaled up, the viscosity caused resistance to fermentation parameters, 1.56 AUG/g (sweet potato mash) of xylanase decreased the viscosity from approximately 30000 to 500 cp. Overall, sweet potato is a attractive feedstock for be bioethanol production from both the economic standpoints and environmentally friendly. PMID- 21277778 TI - The rise and fall of the Mycobacterium tuberculosis genome. AB - When studied from the perspective of non-tuberculous mycobacteria (NTM) it is apparent that Mycobacterium tuberculosis has undergone a biphasic evolutionary process involving genome expansion (gene acquisition and duplication) and reductive evolution (deletions). This scheme can instruct descriptive and experimental studies that determine the importance of ancestral events (including horizontal gene transfer) in shaping the present-day pathogen. For example, heterologous complementation in an NTM can test the functional importance of M. tuberculosis-specific genetic insertions. An appreciation of both phases of M. tuberculosis evolution is expected to improve our fundamental understanding of its pathogenicity and facilitate the evaluation of novel diagnostics and vaccines. PMID- 21277779 TI - Contribution of muscle biopsy and genetics to the diagnosis of chronic progressive external opthalmoplegia of mitochondrial origin. AB - Chronic progressive external opthalmoplegia (CPEO) is the most common phenotypic syndrome of the mitochondrial myopathies. Muscle biopsy, which provides important morphological clues for the diagnosis of mitochondrial disorders, is normal in approximately 25% of patients with CPEO, thus necessitating molecular genetic analysis for more accurate diagnosis. We aimed to study the utility of various histochemical stains in the diagnosis of CPEO on muscle biopsy and to correlate these results with genetic studies. Between May 2005 and November 2007 all 45 patients diagnosed with CPEO were included in the study (23 males; mean age at presentation, 35 years). Thirty-nine patients had CPEO only and six had CPEO plus; two had a positive family history but the remaining 39 patients had sporadic CPEO. Muscle biopsy samples were stained with hematoxylin and eosin, modified Gomori's trichrome stain, succinic dehydrogenase (SDH), cytochrome C oxidase (COX) and combined COX-SDH. Ragged red fibers were seen in 27 biopsies; seven showed characteristics of neurogenic atrophy only, and 11 were normal. The abnormal fibers were best identified on COX-SDH stain. A complete mitochondrial genome was amplified in muscle and blood samples of all patients. Mutations were found in transfer RNA, ribosomal RNA, ND, CYTB, COX I, II and III genes. Mitochondrial gene mutations were found in ten of the 11 patients with a normal muscle biopsy. The genetic mutations were classified according to their significance. The observed muscle biopsy findings were correlated with genetic mutations noted. Histological studies should be combined with genetic studies for the definitive diagnosis of CPEO syndrome. PMID- 21277780 TI - A rare, high cervical traumatic spinal subdural hematoma. AB - Spinal subdural hematomas (SSDH) are rare lesions occurring in association with a wide variety of conditions, including anticoagulation, coagulation disorders, spinal anesthesia, lumbar puncture, spinal tumors and vascular malformations. SSDH resulting from trauma are the exception. We present a 62-year-old woman with a rare post-traumatic focal SSDH at C1 with bulbomedullary compression, treated successfully with surgery. A review of the literature revealed 26 patients with traumatic SSDH. The aim of this report is to describe the clinical presentation, imaging characteristics and management of traumatic SSDH. The controversial pathogenesis is also discussed. PMID- 21277781 TI - Normal and abnormal heme biosynthesis. Part 7. Synthesis and metabolism of coproporphyrinogen-III analogues with acetate or butyrate side chains on rings C and D. Development of a modified model for the active site of coproporphyrinogen oxidase. AB - Analogues of coproporphyrinogen-III have been prepared with acetate or butyrate groups attached to the C and D pyrrolic subunits. The corresponding porphyrin methyl esters were synthesized by first generating a,c-biladienes by reacting a dipyrrylmethane with pyrrole aldehydes in the presence of HBr. Cyclization with copper(II) chloride in DMF, followed by demetalation with 15% H(2)SO(4)-TFA and reesterification, gave the required porphyrins in excellent yields. Hydrolysis with 25% hydrochloric acid and reduction with sodium-amalgam gave novel diacetate and dibutyrate porphyrinogens 9. Diacetate 9a was incubated with chicken red cell hemolysates (CRH), but gave complex results due to the combined action of two of the enzymes present in these preparations. Separation of uroporphyrinogen decarboxylase (URO-D) from coproporphyrinogen oxidase (CPO) allowed the effects of both enzymes on the diacetate substrate to be assessed. Porphyrinogen 9a proved to be a relatively poor substrate for CPO compared to the natural substrate coproporphyrinogen-III, and only the A ring propionate moiety was processed to a significant extent. Similar results were obtained for incubations of 9a with purified human recombinant CPO. Diacetate 9a was also a substrate for URO-D and a porphyrinogen monoacetate was the major product in this case; however, some conversion of a second acetate unit was also evident. The dibutyrate porphyrinogen 9b was only recognized by the enzyme CPO, but proved to be a modest substrate for incubations with CRH. However, 9b was an excellent substrate for purified human recombinant CPO. The major product for these incubations was a monovinylporphyrinogen, but some divinyl product was also generated in incubations using purified recombinant human CPO. The incubation products were converted into the corresponding porphyrin methyl esters, and these were characterized by proton NMR spectroscopy and mass spectrometry. The results extend our understanding of substrate recognition and catalysis for this intriguing enzyme and have allowed us to extend the active site model for CPO. In addition, the competitive action of both URO-D and CPO on the same diacetate porphyrinogen substrate provides additional perspectives on the potential existence of abnormal pathways for heme biosynthesis. PMID- 21277782 TI - Synthesis and SAR of 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines as potent serotonin 5-HT6 receptor antagonists. AB - Syntheses of a series of novel 3-sulfonyl-pyrazolo[1,5-a]pyrimidines and their 5 HT(6) receptor antagonistic structure-activity relationship are disclosed. The nature and position of substituents, which affect their receptor antagonistic activity, are analyzed. Among all synthesized derivatives, {3-(3 chlorophenylsulfonyl)-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-2-yl}-methyl-amine 33 (K(i)=190 pM), (3-phenylsulfonyl-7-methyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methyl amine 44 (K(i)=240 pM), (3-phenylsulfonyl-5-metoxymethyl-7-methyl-pyrazolo[1,5 a]pyrimidin-2-yl)-methyl-amine 50 (K(i)=270 pM), and (3-phenylsulfonyl-5-methyl-7 metoxymethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methyl-amine 52 (K(i)=280 pM) are the most potent antagonists of the 5-HT(6) receptors. PMID- 21277783 TI - Acridone alkaloids as potent inhibitors of cathepsin V. AB - Cathepsin V is a lysosomal cysteine peptidase highly expressed in thymus, testis and corneal epithelium. Eleven acridone alkaloids were isolated from Swinglea glutinosa (Bl.) Merr. (Rutaceae), with eight of them being identified as potent and reversible inhibitors of cathepsin V (IC(50) values ranging from 1.2 to 3.9 MUM). Detailed mechanistic characterization of the effects of these compounds on the cathepsin V-catalyzed reaction showed clear competitive inhibition with respect to substrate, with dissociation constants (K(i)) in the low micromolar range (2, K(i)=1.2 MUM; 6, K(i)=1.0 MUM; 7, K(i)=0.2 MUM; and 11, K(i)=1.7 MUM). Molecular modeling studies provided important insight into the structural basis for binding affinity and enzyme inhibition. Experimental and computational approaches, including biological evaluation, mode of action assessment and modeling studies were successfully employed in the discovery of a small series of acridone alkaloid derivatives as competitive inhibitors of catV. The most potent inhibitor (7) has a K(i) value of 200 nM. PMID- 21277784 TI - Reaction of benzophenone triplet with aliphatic amines. What a potent neurotoxin can tell us about the reaction mechanism. AB - A photochemical model study of benzophenone triplet ((3)BP) with the MAO-B substrate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [MPTP (1)] and two of it's derivatives, 1-cyclopropyl-4-phenyl-1,2,3,6-tetrahydropyridine (2) and (+/-) [trans-2-phenylcyclopropyl-4-phenyl-1,2,3,6-tetrahydropyridine (3) were performed. Literature precedent and calculations reported herein suggest that the barrier to ring opening for aminyl radical cations derived from N-cyclopropyl derivatives of tertiary amines (such as MPTP) will be low. The LFP results reported herein demonstrate that pathways for the reaction of (3)BP with 1, 2, and 3 are very similar. In each instance, disappearance of (3)BP is accompanied solely by appearance of bands corresponding to the diphenylhydroxylmethyl radical and neutral radical derived from MPTP and it's two derivatives 2 and 3. These results suggest that the reaction between benzophenone triplet and tertiary aliphatic amines proceed via a simple hydrogen atom transfer reaction. Additionally these model examinations provide evidence that oxidations of N cyclopropyl derivatives of MPTP catalyzed by MAO-B may not be consistent with a pure SET pathway. PMID- 21277785 TI - Investigations on N-rich protein (NRP) of Arabidopsis thaliana under different stress conditions. AB - Stress response and adaptation are important physiological mechanisms in plants. As plants are not able to avoid stressful environments by moving away, as animals, they have developed diverse mechanisms to respond to stressful situations. One of the genes involved in these mechanisms is NRP (Asparagine-rich protein or N-rich protein). In this study, NRP expression, protein localization and nrp knockout plants were investigated for further understanding of NRP function. NaCl-induced salt stress, oxidative stress (ozone exposure) and mechanical perturbation (touch treatment) were used to induce abiotic stress. NRP expression was up-regulated in the early phase of stress response to all three elicitors. Stressed nrp knockout seedlings revealed a more pronounced growth inhibition compared to wildtype (salt and osmotic stress). Seedlings showed NRP GFP expression in the apical meristem, leaf veins, central cylinder, root hair zone and root tip. Analyses of NRP-GFP localization in root cells and protoplasts revealed cytosolic distribution under non-stress conditions and translocation of NRP-GFP to mitochondria due to stress response. Summarizing, our findings point to a contribution of NRP in signal transduction of the initial phase of general stress response in Arabidopsis thaliana. PMID- 21277786 TI - Sternal surgical site infection prevention - is there any room for improvement? AB - OBJECTIVE: The objectives of this multicenter study are to evaluate current clinical practices in cardiac surgery concerning the prevention and management of sternal wound infections, to identify room for improvement, and to support implementation of systematic measures. METHODS: As a part of a campaign for infection prevention in cardiac surgery in Germany, a multiple-choice questionnaire with two main sections was developed and submitted to all cardiac surgery units in Germany (79). The project was realized in cooperation with the German Society for Thoracic and Cardiovascular Surgery, the BQS Institute for Quality and Patient Safety, and the National Reference Center for Nosocomial Infection Surveillance. RESULTS: A representative number (54 of 79 or 68%) of German cardiac surgery centers participated in the survey, in which heterogeneous procedures and various standards for prevention were observed. Surveillance, standards, and advanced training regarding hygiene measures are present in almost all participating hospitals. Methicillin-resistant Streptococcus aureus (MRSA) screening is performed in 81.5% (44/54) of all participating departments. A little less than one-tenth (7.4%) perform decolonization measures on all patients, while 85.2% perform decolonization measures only on MRSA-positive patients. Application of perioperative antibiotic prophylaxis ranges from single shot application to 3 days of treatment. Longer treatment is expensive and time intensive, and also increases the risk of Clostridium difficile-associated diarrhea. Nearly three-quarters (70.4%) of all participating hospitals perform preoperative hair removal 1 day before surgery. Common techniques are clipping machines (53.7%), razors (40.7%), clipping machines and depilatory cream (1.9%), or depilatory cream only (1.9%). Remanent (37.0%) and non-remanent disinfectants (55.6%) are used for preoperative skin disinfection. The time of the first wound dressing change varies from the day of surgery (1.9%) over the first (42.6%) or second (46.3%) day after surgery to up to 3 or more days after surgery (9.3%). CONCLUSIONS: The results of the evaluation show that basic measures for infection prevention in cardiac surgery in Germany are well implemented. Nevertheless, a relevant heterogeneity in the use of special measures was observed, although research-based guidelines for infection prevention in surgery do exist and many studies have demonstrated the usefulness and feasibility of these measures. PMID- 21277787 TI - The effect of air cooling pain relief on protoporphyrin IX photobleaching and clinical efficacy during dermatological photodynamic therapy. AB - Methyl aminolevulinate photodynamic therapy (MAL-PDT) is utilized to successfully treat licensed indications (e.g. actinic keratosis (AK), superficial basal cell carcinoma (sBCC) and Bowen's disease (BD)) in the UK. Air cooling devices (ACD) are commonly utilized as a method of pain relief, however the effect of this on treatment outcome has never been extensively investigated. This non-randomized, retrospective observational controlled study investigated whether the application of the ACD limited photosensitiser (protoporphyrin IX - PpIX) photobleaching during irradiation and/or subsequent clinical outcome. Patients utilizing the ACD throughout treatment were observed to undergo significantly less PpIX photobleaching than the control group (P<0.001) and complete clinical clearances observed at 3 months were also reduced within the ACD group. Separate analysis of the different lesion types indicated that significantly less photobleaching occurred in AK lesions with ACD and all lesion types failed to fully utilize the accumulated PpIX when ACD was employed. The application of the ACD as pain relief during light irradiation therefore resulted in lower PpIX photobleaching which corresponded to a reduction in the efficacy of PDT treatment. Whilst the ACD is an effective method of dermatological PDT analgesia it should be utilized as sparingly as possible to minimize any deleterious effects on treatment outcome. PMID- 21277788 TI - Update on urodynamic bladder dysfunctions after radical hysterectomy for cervical cancer. AB - INTRODUCTION: Bladder dysfunctions are a common sequela after radical hysterectomy (RH, former type III sec Piver) ranging from 8 to 80%. This discrepancy, probably, reflects the different bladder function evaluation methods utilized in literature. MATERIAL AND METHODS: We searched English-language medical reports published from 1952 to 2010, on MEDLINE. Inclusion criteria were: (1) studies of urological dysfunctions in patients with cervical cancer, treated with type III sec Piver (C2 sec Querleu) radical hysterectomy; (2) use of urodynamic measurement. RESULTS: The overall incidence of urodynamic bladder dysfunctions is 72%. Follow-up >12 months studies report a high incidence of overactive detrusor low compliance (34%). Eight out of 19 studies show a decrease of the maximal urethral closure pressure (MUCP). DISCUSSION AND CONCLUSIONS: Follow-up timing seems to be the major factor influencing the wide range of incidence of bladder dysfunction. Urodynamic data could help physicians to formulate appropriate evaluation and treatment for patients having urge incontinence (UI) after RH. PMID- 21277789 TI - Metabolic syndrome and oocyte quality. AB - Metabolic syndrome affects one in four women in the USA, and the incidence is rising every year. Metabolic syndrome is strongly associated with development of coronary artery disease and diabetes. Women of reproductive age are not spared from the complications of metabolic syndrome, which overlaps with obesity and polycystic ovary syndrome (PCOS), both of which are linked to infertility and poor reproductive outcome. Therefore, the relationship between the metabolic syndrome and reproductive dysfunction is an active area of study. In this review, we discuss the animal and human data available to determine if the abnormality is at the level of the ovary and/or endometrium, and discuss the underlying mechanisms causing the associated poor reproductive outcomes. PMID- 21277790 TI - Inhibiting vitamin A metabolism as an approach to male contraception. AB - Although oral contraceptives have been available to women since the 1960s, contraceptive options for men have remained limited. Spermatogenesis relies on the active metabolite of vitamin A, retinoic acid, to drive spermatogonial differentiation and to allow the production of normal numbers of sperm. Recent evidence describes how the enzymes which control vitamin A metabolism in the testis could be targeted to generate effective male contraceptives; however, the detailed mechanism(s) regarding how vitamin A regulates normal spermatogenesis are still unknown. The essential nature of vitamin A to male germ cell development and the prospects of developing the proteins responsible for the generation, transport, and storage of retinoic acid as targets for male contraceptive development are discussed in this review. PMID- 21277791 TI - The consistency approach for quality control of vaccines - a strategy to improve quality control and implement 3Rs. AB - Current batch release testing of established vaccines emphasizes quality control of the final product and is often characterized by extensive use of animals. This report summarises the discussions of a joint ECVAM/EPAA workshop on the applicability of the consistency approach for routine release of human and veterinary vaccines and its potential to reduce animal use. The consistency approach is based upon thorough characterization of the vaccine during development and the principle that the quality of subsequent batches is the consequence of the strict application of a quality system and of a consistent production of batches. The concept of consistency of production is state-of-the art for new-generation vaccines, where batch release is mainly based on non animal methods. There is now the opportunity to introduce the approach into established vaccine production, where it has the potential to replace in vivo tests with non-animal tests designed to demonstrate batch quality while maintaining the highest quality standards. The report indicates how this approach may be further developed for application to established human and veterinary vaccines and emphasizes the continuing need for co-ordination and harmonization. It also gives recommendations for work to be undertaken in order to encourage acceptance and implementation of the consistency approach. PMID- 21277792 TI - Emergency endovascular repair of two ascending aortic pseudoaneurysms. PMID- 21277793 TI - Antegrade papillary balloon dilation for extrahepatic bile duct stone clearance: lessons learned from treating 300 patients. AB - PURPOSE: To report the authors' experience with percutaneous papillary balloon dilation for extrahepatic bile duct stone clearance to the duodenum in 300 patients. MATERIALS AND METHODS: During a 16-year period, 300 patients with extrahepatic bile duct stones who underwent papillary balloon dilation were retrospectively evaluated. Two hundred eighty-six patients with retained extrahepatic bile duct stones were treated through a postoperative drain placed during cholecystectomy; 245 patients were treated through a T-tube route and 41 through a transcystic approach. In the remaining 14 patients, the procedure was performed through a newly created percutaneous transhepatic route. Success rates, technical features, reasons for failure, and complications were evaluated. RESULTS: Biliary duct stone removal after papillary dilation was successful in 288 patients (96%). In 244 patients, the procedure was successfully completed on the first attempt. Forty-three patients needed two sessions, and in one patient it took three sessions. Stone diameters ranged from 4 mm to 18 mm (mean, 8 mm). Two hundred fourteen patients had four or fewer stones (mean, 2.3), and 86 patients had more than four (mean, 8.8; range, 5-25). Two patients required surgical intervention after loss of transcystic drainage, with subsequent development of peritonitis. During the follow-up period (mean, 26.6 months), no clinical or laboratory abnormalities were observed. CONCLUSIONS: Percutaneous antegrade papillary balloon dilation and stone clearance is a safe and effective tool in removing common bile duct stones. Some technical issues should be considered to achieve complete stone removal while minimizing the incidence of complications. PMID- 21277794 TI - Re: Transcatheter N-butyl cyanoacrylate embolization of pseudoaneurysms. PMID- 21277795 TI - Transcatheter embolization of a type II endoleak after hybrid repair for thoracoabdominal aortic aneurysm. AB - Hybrid stent-graft procedures with visceral revascularization have been reported as an alternative treatment option for thoracoabdominal aortic aneurysms (TAAAs), although the potential advantages of reduced morbidity and mortality compared with open surgical repair have not been definitively demonstrated. Endovascular aneurysm repair is associated with endoleaks in as many as 20% of cases in some series, often requiring repeat intervention. In the present case, during follow up after a hybrid TAAA repair, a patient developed a type II endoleak originating from a celiac artery that was not ligated at its origin. The endoleak was successfully treated by transcatheter coil embolization. PMID- 21277796 TI - Use of retrievable filters in alternative common iliac vein location in high-risk surgical patients. AB - PURPOSE: To evaluate the use of retrievable filters placed in bilateral common iliac veins in high-risk surgical patients. MATERIALS AND METHODS: During the 4 year study period, 10 patients received bilateral common iliac vein placement of retrievable filters for pulmonary embolism (PE) prophylaxis. These patients were at risk for venous thromboembolism (VTE) but had no evidence of VTE at the time of filter placement. In nine patients undergoing bariatric surgery, placement of a filter in the inferior vena cava (IVC) was impossible because of megacava (defined as caval diameter >= 3.0 cm). In one patient who had planned dissection of an extensive retroperitoneal tumor, there was concern that IVC location of the filter would be prone to complications secondary to intraoperative manipulation. Filter placement and retrieval were evaluated. All patients were followed clinically until 4-6 weeks after filter retrieval. RESULTS: There were 20 filters placed in 10 attempts, 18 (nine patients) through the right internal jugular vein and 2 (one patient) through bilateral femoral veins. The mean (+/- standard deviation) dwell time of the filters was 40 days +/- 10 (range 30-71 days). All filters were successfully removed. There were no procedural complications. No clinically evident PE was noted. CONCLUSIONS: Use of retrievable filters in the bilateral common iliac veins was found to be feasible and effective in preventing PE in patients with contraindications to filter placement in the IVC. PMID- 21277797 TI - Endovascular stent-graft placement for retrograde type A aortic dissection. PMID- 21277798 TI - CT fluoroscopy-guided transcaval radiofrequency ablation of insulinoma. PMID- 21277799 TI - Chimney stent technique for treatment of severe abdominal aortic atherosclerotic stenosis. AB - Application of the "chimney" stent technique is described in a case of complex multilevel atherosclerotic disease involving the juxtarenal aorta. A patient with significant comorbidities was unsuitable for major open reconstructive surgery. He was treated with a combined procedure consisting of chimney stent placement in the juxtarenal aorta, iliac "kissing" stent placement, and right-sided common femoral artery (CFA) replacement. This case shows that the chimney stent technique can be a feasible alternative to leaving a safety wire in the renal arteries and observation during primary angioplasty in complex atherosclerotic lesions of the abdominal aorta. PMID- 21277800 TI - Livedo reticularis and bowel ischemia after carbon dioxide arteriography in a patient with CREST syndrome. AB - For 30 years, CO(2) gas has been used as a safe alternative to iodinated contrast agents for angiography in patients with renal insufficiency or allergy to iodine. CO(2) angiography is well tolerated when performed properly, and serious complications are rare. However, severe complications may occur if the physical properties of CO(2) and the specific pathophysiology of an individual patient are not carefully considered. The present report describes a case in which diffuse livedo reticularis, bowel ischemia, and renal insufficiency developed following CO(2) angiography in a patient with CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia). PMID- 21277801 TI - Lipiodol = ethiodol. PMID- 21277802 TI - Removal of a Gunther Tulip filter after 3,006 days. AB - Patients may be denied the opportunity to have their inferior vena cava (IVC) filters removed because of a perception that retrievable filters that have been in place for a long period of time may be more technically difficult or hazardous to remove. A case report on the removal of a Gunther Tulip filter that was implanted for a total of 3,006 days is presented. This case report adds to the literature that suggests that no time limits may exist after which many retrievable IVC filters can no longer be safely removed. PMID- 21277803 TI - Self-reflection and the temporal focus of the wandering mind. AB - Current accounts suggest that self-referential thought serves a pivotal function in the human ability to simulate the future during mind-wandering. Using experience sampling, this hypothesis was tested in two studies that explored the extent to which self-reflection impacts both retrospection and prospection during mind-wandering. Study 1 demonstrated that a brief period of self-reflection yielded a prospective bias during mind-wandering such that participants' engaged more frequently in spontaneous future than past thought. In Study 2, individual differences in the strength of self-referential thought - as indexed by the memorial advantage for self rather than other-encoded items - was shown to vary with future thinking during mind-wandering. Together these results confirm that self-reflection is a core component of future thinking during mind-wandering and provide novel evidence that a key function of the autobiographical memory system may be to mentally simulate events in the future. PMID- 21277804 TI - Qualitative to assessment of barriers and facilitators to HIV treatment. PMID- 21277805 TI - Calcific tendonitis of the shoulder: is subacromial decompression in combination with removal of the calcific deposit beneficial? AB - HYPOTHESIS: We postulated that treatment of patients with calcific tendonitis of the supraspinatus tendon by debridement of the calcific deposit alone was comparable to treatment by debridement and concomitant subacromial decompression. MATERIALS AND METHODS: During a 10-year period, 50 consecutive patients with calcific tendonitis refractory to nonoperative measures were surgically treated by debridement (D) as an isolated procedure (25 patients) or by debridement and concomitant subacromial decompression (D+SAD; 25 patients), and the surgical groups were retrospectively compared. The main outcome of interest was the time to resumption of unrestricted activity without pain. An abbreviated version of disabilities of the Disabilities of Arm, Shoulder and Hand (QuickDASH) score and University of California-Los Angeles (UCLA) shoulder summary scores were compiled at a mean follow-up of 5 years (range, 2-10 years). RESULTS: Average time to return to activity without pain was significantly shorter for the D group compared with the D+SAD group (11 vs 18 weeks; P < .006). At the final evaluation, QuickDASH scores were equally low (group D, 6; group D + SAD, 11; P = .191), indicating that both treatment groups had high levels of function. The mean UCLA shoulder scores at final evaluation were 33 for both groups (P = .678). DISCUSSION: Patients treated by debridement of the calcific deposit and concomitant subacromial decompression required a longer time to return to unrestricted activity without pain. CONCLUSIONS: Debridement of a calcific deposit alone is a better surgical option to treat calcific tendonitis. PMID- 21277806 TI - Suprascapular neuropathy in a shoulder referral practice. AB - HYPOTHESIS: Suprascapular neuropathy (SSN) is considered a rare condition, and few studies have analyzed how commonly it is encountered in practice. Electrophysiologic studies are the gold standard for diagnosis; however, there is no consensus on diagnostic criteria. We hypothesized that SSN would be frequently diagnosed by electrophysiologic testing in a subset of patients with specific clinical and radiographic findings suggestive of the pathology. This study characterizes SSN in an academic shoulder referral practice and documents the electrodiagnostic findings that are currently being used to diagnose the condition. MATERIALS AND METHODS: A retrospective review of a 1-year period was used to identify all patients who completed electrodiagnostic studies to evaluate the suprascapular nerve. Clinical exam findings and associated shoulder pathology was documented. The specific electromyography (EMG) and nerve conduction studies (NCS) findings were analyzed. RESULTS: Electrodiagnostic results were available for 92 patients, and 40 (42%) had confirmed SSN. Patients with a massive rotator cuff tear were more likely to have an abnormal study than those without a tear (P = .006). The most common electrodiagnostic abnormalities were abnormal motor unit action potentials (88%), whereas only 33% had evidence of denervation. The average latency in studies reported as diagnostic of SSN was 2.90 +/- 0.08 milliseconds for the supraspinatus and 3.78 +/- 0.14 milliseconds for the infraspinatus. DISCUSSION: An electrodiagnostically confirmed diagnosis of SSN was seen in 4.3% of all new patients and in 43% of patients with clinical or radiographic suspicion of SSN. Clinical evaluation may be difficult because other shoulder pathology can have overlapping symptoms. CONCLUSION: Shoulder surgeons should consider electrophysiologic evaluation of patients with clinical or radiographic signs of SSN and be cognizant of the parameters that constitute an abnormal study. PMID- 21277807 TI - Partial repair of irreparable supraspinatus tendon tears: clinical and radiographic evaluations at long-term follow-up. AB - BACKGROUND: Irreparable rotator cuff tears are a common source of pain and disability even in middle-aged patients. Although most rotator cuff tears can be completely repaired to bone, a significant proportion of these cannot be sutured by traditional methods. In these cases it is possible to perform a functional repair of the cuff to help restore the force couple of the cuff on the humeral head and to increase the acromion-humeral distance (AHD). This technique provides peripheral repair of the cuff tear without complete closure of the cuff defect. Our hypothesis was that arthroscopic partial suture of the cuff leads to pain relief and functional improvement for the patients while restoring the AHD. MATERIALS AND METHODS: All patients (67 cases) were arthroscopically treated with functional repair of the posterior cuff. The follow-up was at least 5 years. All the patients had clinical and radiographic evaluations and assessment with the Simple Shoulder Test and Constant score. RESULTS: The mean Constant score increased from 44 points to a mean of 73 points, the mean Simple Shoulder Test score increased from 4.6 to 9.0, and the mean AHD increased from 6.1 mm to 9.1 mm. DISCUSSION AND CONCLUSION: Functional repair of the infraspinatus, leaving the greater tuberosity uncovered, in patients with irreparable cuff tears gives good results in terms of patient satisfaction and in restoring the AHD even at long-term follow-up. Complications were rare and in line with the usual sequelae of a rotator cuff repair. PMID- 21277808 TI - Clinical outcomes of suprascapular nerve decompression. AB - BACKGROUND: While the incidence and prevalence of suprascapular neuropathy (SSN) remains largely unknown, the evaluation and treatment of SSN appears to be increasing. Despite multiple technique articles demonstrating nerve decompression, there has been no clinical evidence to support the efficacy of SSN decompression in the absence of rotator cuff disease. METHODS: Between October 2006 and February 2010, 27 patients underwent arthroscopic suprascapular nerve decompression at the suprascapular and/or spinoglenoid notch. Eighty-nine percent (24/27) of patients had preoperative positive electromyography and nerve conduction EMG/NCV studies documenting suprascapular nerve pathology. All patients had either a computed tomography (CT) arthrogram or magnetic resonance imaging (MRI) documenting rotator cuff integrity. All patients were evaluated with pre and postoperative subjective shoulder values (SSV) and American Shoulder and Elbow Society (ASES) self-assessment scores. Additionally, patients were questioned whether they would have the procedure again and approximately at what week they experienced noticeable pain relief. RESULTS: The 27 patients were followed for an average of 22.5 months (range, 3-44). Three patients were lost to follow-up. Seventy-one percent (17/24) of patients reported pain relief (VAS [Visual Analogue Scales] pain scale) that was statistically significant (P = .0001) at an average of 9.4 weeks from surgery. Seventy-five percent (18/24) and 71% (17/24) had statistically significant improvement in ASES (P = .0001) and SSV scores (P = .0014), respectively. Seventy-one percent (17/24) would have the surgery again. CONCLUSION: The present study demonstrates a large series of patients treated for SSN without rotator cuff pathology. Our results show statistically significant improvement in VAS, ASES, and SSV. PMID- 21277809 TI - Development and reliability testing of the frequency, etiology, direction, and severity (FEDS) system for classifying glenohumeral instability. AB - HYPOTHESIS: Classification systems for glenohumeral instability (GHI) are opinion based, not validated, and poorly defined. The hypothesis driving this investigation is that a classification system with content validity will have high inter-observer and intra-observer agreement. MATERIALS AND METHODS: The classification system was developed by first conducting systematic literature review that identified 18 systems for classifying GHI. The frequency of characteristics used was recorded. Additionally, 31 members of the American Shoulder and Elbow Surgeons responded to a survey to identify features important to characterize GHI. Frequency, etiology, direction, and severity (FEDS) were most important. Frequency was defined as solitary (1 episode), occasional (2 to 5 times/y), or frequent (>5 times/year). Etiology was defined as traumatic or atraumatic. Direction referred to the primary direction of instability (anterior, posterior, or inferior). Severity was subluxation or dislocation. For reliability testing, 50 GHI patients completed a questionnaire at their initial visit. One of 6 sports medicine fellowship-trained physicians completed a similar questionnaire after examining the patient. Patients returned after 2 weeks and were examined by the original physician and 2 other physicians. Interrater and intrarater agreement for the FEDS classification system was calculated. RESULTS: Agreement between patients and physicians was lowest for frequency (39%; kappa = 0.130) and highest for direction (82%; kappa = 0.636). Physician intrarater agreement was 84% to 97% for the individual FEDS characteristics (kappa = 0.69-0.87), and interrater agreement was 82% to 90% (kappa = 0.44-0.76). CONCLUSIONS: The FEDS system has content validity and is highly reliable for classifying GHI. Physical examination using provocative testing to determine the primary direction of instability produces very high levels of interrater and intrarater agreement. PMID- 21277810 TI - Renal cell carcinoma with metastases to the gallbladder: four cases from the National Cancer Institute (NCI) and review of the literature. AB - OBJECTIVE: We evaluate presentation and outcome of patients with metastatic RCC to the gallbladder from our institution and published literature. METHODS: Patients with a history of gallbladder metastasis from RCC were selected from our institution's prospective database. A systematic PubMed search was performed to identify articles describing patients with metastatic RCC to the gallbladder. The final cohort included 33 patients: 4 from our institution and 29 from 28 previously published cases. Survival analysis was conducted using log-rank Kaplan Meier analysis. RESULTS: Median patient age was 63 years and the majority of patients were male. Most patients were asymptomatic and diagnosed with gallbladder metastasis on imaging performed for surveillance or staging. The median time to gallbladder metastasis following nephrectomy was 4 years. Metastasis to the gallbladder occurred both synchronously (33%) and metachronously (67%). Of the patients with available histology, all had clear cell RCC (n = 28). Of all patients, 13 (39%) had metastasis only to the gallbladder, while 20 (61%) had additional sites of metastasis. The most common sites of additional metastasis were contralateral kidney (30%), pancreas (21%), lung (18%), adrenal (18%), and lymph nodes (9%). All patients underwent cholecystectomy. At a median follow up time of 1.5 years after cholecystectomy, 54% of patients had no evidence of disease, 14% were alive with metastasis, 23% had died from metastatic RCC, and 9% died from causes unrelated to their cancer. CONCLUSION: Gallbladder metastasis from RCC is a rare event that may occur synchronously or metachronously with most patients being asymptomatic. Clear cell carcinoma appears to be the primary pathology associated with gallbladder metastasis. High rates of bilateral RCC and pancreatic metastasis suggest novel associations in patients with RCC and gallbladder metastasis. PMID- 21277811 TI - Evaluation of the prognostic significance of BCL6 gene expression in canine high grade B-cell lymphoma. AB - The clinical usefulness of BCL6 gene expression was evaluated as a prognostic indicator in dogs with high-grade B-cell lymphoma. Forty-four dogs were diagnosed with centroblastic or B-cell immunoblastic type lymphoma according to the updated Kiel classification. BCL6 mRNA expression was measured by real-time PCR and its relationship with prognosis was analyzed. Progression-free and overall survival was not significantly different between the high BCL6 expression group (higher than the median) and the low BCL6 expression group (lower than the median) (P=0.99 and P=0.61, respectively). No correlation between BCL6 and prognosis was observed in this study, which is inconsistent with findings reported for human diffuse large B-cell lymphoma. BCL6 protein expression was not detected in the 11 dogs evaluated by immunohistochemistry. Furthermore, BCL6 protein expression was assessed in 13 archived paraffin-embedded high-grade canine lymphoma tissues and all were also negative. The results suggest that most canine high-grade B-cell lymphomas correspond to human diffuse large B-cell lymphoma with no immunohistochemical expression of BCL6. PMID- 21277812 TI - Encephalitis after vaccination against H1N1 influenza virus. PMID- 21277813 TI - Off-resonance saturation MRI of superparamagnetic nanoprobes: theoretical models and experimental validations. AB - Off-resonance saturation (ORS) is a new magnetic resonance imaging (MRI) method that has shown greatly improved contrast sensitivity for the detection of cancer specific biomarkers by superparamagnetic nanoprobes in vivo. However, quantitative understanding of the ORS contrast mechanism and its dependence on the structural parameters of superparamagnetic nanoprobes are still lacking. Here we propose a quantitative model of ORS contrast and its experimental validation by superparamagnetic polymeric micelles (SPPM) with precisely controlled structural properties. Size selected, monodisperse Fe3O4 nanoparticles (6.1 +/- 0.2 nm) were used to form a series of SPPM nanoprobes with specifically controlled corona thickness using 1,2-distearoyl-sn-glycero-3-phosphoethanolamine N-methoxypoly(ethylene glycol) (DSPE-PEG) with different PEG molecular weights. Transmission electron microscopy and dynamic light scattering showed that SPPM were uniform in size. The average hydrodynamic diameters of SPPM with PEG lengths of 0.55, 1, 2, and 5 kD were 16.6 +/- 2.8, 18.4 +/- 2.9, 24.1 +/- 3.4, and 28.9 +/- 3.4 nm, respectively. MRI experiments at 7 T determined that r2 values of SPPM with 0.55, 1, 2, and 5 kD PEG as corona were 201 +/- 3, 136 +/- 8, 107 +/- 5, and 108 +/- 8 FemM-1s-1, respectively. ORS intensity from Z-spectra of SPPM showed a significant correlation with the inverse of T2 relaxation rates (1/T2, s 1) of the SPPM nanoprobes regardless of the PEG corona thickness. These data provide the fundamental understanding of the structure-property relationships between the SPPM nanostructures and ORS sensitivity, which offers useful mechanistic insights for the future improvement of SPPM nanoprobes in cancer molecular imaging applications. PMID- 21277814 TI - Spin-label oximetry at Q- and W-band. AB - Spin-lattice relaxation times (T1s) of small water-soluble spin-labels in the aqueous phase as well as lipid-type spin-labels in membranes increase when the microwave frequency increases from 2 to 35 GHz (Hyde, et al., J. Phys. Chem. B 108 (2004) 9524-9529). The T1s measured at W-band (94 GHz) for the water-soluble spin-labels CTPO and TEMPONE (Froncisz, et al., J. Magn. Reson. 193 (2008) 297 304) are, however, shorter than when measured at Q-band (35 GHz). In this paper, the decreasing trends at W-band have been confirmed for commonly used lipid-type spin-labels in model membranes. It is concluded that the longest values of T1 will generally be found at Q-band, noting that long values are advantageous for measurement of bimolecular collisions with oxygen. The contribution of dissolved molecular oxygen to the relaxation rate was found to be independent of microwave frequency up to 94 GHz for lipid-type spin-labels in membranes. This contribution is expressed in terms of the oxygen transport parameter W=T1-1(Air)-T1-1(N2), which is a function of both concentration and translational diffusion of oxygen in the local environment of a spin-label. The new capabilities in measurement of the oxygen transport parameter using saturation-recovery (SR) EPR at Q- and W band have been demonstrated in saturated (DMPC) and unsaturated (POPC) lipid bilayer membranes with the use of stearic acid (n-SASL) and phosphatidylcholine (n-PC) spin-labels, and compared with results obtained earlier at X-band. SR EPR spin-label oximetry at Q- and W-band has the potential to be a powerful tool for studying samples of small volume, ~30 nL. These benefits, together with other factors such as a higher resonator efficiency parameter and a new technique for canceling free induction decay signals, are discussed. PMID- 21277815 TI - Sparsely sampled high-resolution 4-D experiments for efficient backbone resonance assignment of disordered proteins. AB - Intrinsically disordered proteins (IDPs) play important roles in many critical cellular processes. Due to their limited chemical shift dispersion, IDPs often require four pairs of resonance connectivities (H(alpha), C(alpha), C(beta) and CO) for establishing sequential backbone assignment. Because most conventional 4 D triple-resonance experiments share an overlapping C(alpha) evolution period, combining existing 4-D experiments does not offer an optimal solution for non redundant collection of a complete set of backbone resonances. Using alternative chemical shift evolution schemes, we propose a new pair of 4-D triple-resonance experiments--HA(CA)CO(CA)NH/HA(CA)CONH--that complement the 4-D HNCACB/HN(CO)CACB experiments to provide complete backbone resonance information. Collection of high-resolution 4-D spectra with sparse sampling and FFT-CLEAN processing enables efficient acquisition and assignment of complete backbone resonances of IDPs. Importantly, because the CLEAN procedure iteratively identifies resonance signals and removes their associating aliasing artifacts, it greatly reduces the dependence of the reconstruction quality on sampling schemes and produces high quality spectra even with less-than-optimal sampling schemes. PMID- 21277816 TI - Effects of GH deficiency and GH replacement on inter-male aggressiveness in mice. AB - OBJECTIVE: Growth hormone (GH) has been suggested to influence aggressive behavior in several species, but no data are presently available in GH-deficient (GHD) animals. The aim of this study was to elucidate the effects of GHD on aggressive behavior in a mouse model of isolated GHD due to removal of the GHRH gene (GHRH knock out, GHRHKO), and to evaluate the effects of GH replacement. DESIGN: We studied two groups of adult male mice: Ten GH-sufficient animals heterozygous for GHRHKO allele (HTZ), and 30 GHRHKO animals. Behavior was measured by scoring several aggression parameters after isolation, when the animal was challenged against an intruder both in neutral and home cage. Animals were then re-studied after the GHRHKO mice were left untreated (control, Ctrl), or were treated for 2 weeks with daily subcutaneous recombinant GH or with vehicle (Veh). Blood samples were collected before and after GH or Veh treatment, and assayed for serum IGF-I and testosterone. RESULTS: The GHRHKO mice showed significantly reduced aggressiveness compared to HTZ animals. GH (but not Veh) administration normalized isolation-induced aggressive behavior in GHRHKO mice, despite lack of full serum IGF-I normalization. No difference was noted in serum testosterone levels among all groups at any of the time points. CONCLUSIONS: These findings show that GHD reduces aggressive behavior in GHRHKO mice, that GH replacement normalizes aggressiveness, and that this behavior change is not related to an increase in serum testosterone. PMID- 21277817 TI - Genetic variation in the matrix metalloproteinase genes and diabetic nephropathy in type 1 diabetes. AB - Genetic data support the notion that polymorphisms in members of the matrix metalloproteinase (MMP) family of genes play an important role in extracellular matrix remodeling and contribute to the pathogenesis of vascular disease. To identify novel genetic markers for diabetic nephropathy (DN), we examined the relationship between MMP gene polymorphisms and DN in the Genetics of Kidneys in Diabetes (GoKinD) population. Genotypic data from the Genetic Association Information Network (GAIN) type 1 DN project were analyzed for associations across 21 MMP genes in 1705 individual with type 1 diabetes, including 885 normoalbuminuric control subjects and 820 advanced DN case subjects. In total, we investigated the role of 1283 SNPs (198 genotyped SNPs and 1085 imputed SNPs) mapping to the MMP genes. We identified associations at several correlated SNPs across a 29.2kb interval on chromosome 11q at the MMP-3/MMP-12 locus. The strongest associations occurred at 2 highly-correlated SNPs, rs610950 (OR=0.50, P=1.6*10(-5)) and rs1277718 (OR=0.50, P=2.1*10(-5)). Further examination of this locus identified 17 SNPs (2 genotyped SNPs and 15 imputed SNPs) in complete linkage disequilibrium associated with DN (P-values<2.5*10(-4)), including a non synonymous SNP (rs652438, Asn357Ser) located in exon 8 of MMP-12 that significantly reduced the risk of DN among carriers of the serine substitution relative to homozygous carriers of asparagine (OR=0.51; 95% CI=0.37-0.71, P=6.2*10(-5)). Taken together, our study suggests that genetic variations within the MMP-3/MMP-12 locus influence susceptibility of DN in type 1 diabetes. PMID- 21277818 TI - Cone beam computed tomography in the diagnosis of temporomandibular joint alterations in cats. AB - The aim of this study was to describe the use of cone beam computed tomography as an auxiliary method to diagnose changes to the temporomandibular joints in cats. We used five cats of various ages, breeds and genders that showed clinical signs consistent with changes in the temporomandibular joint. Cone beam computed tomography enables a complete and thorough examination of the temporomandibular joints by allowing the evaluation of selected images as a whole. It also enables the identification of all anatomical structures and any changes that may be present. The results showed that this method is effective in confirming or ruling out changes in the temporomandibular joint in cats, such as disjunctions of the palatine raphe; fractures of the mandibular symphisis, zygomatic bone and condylar; and dental resorption. PMID- 21277819 TI - Normal Doppler velocimetry of renal vasculature in Persian cats. AB - Renal diseases are common in older cats. Decreased renal blood flow may be the first sign of dysfunction and can be evaluated by Doppler ultrasound. But previous studies suggest that the resistive index (RI) has a low sensitivity for detecting renal disease. Doppler waveforms of renal and intrarenal arteries demonstrate decreased blood flow before there are any changes in the RI. The purpose of this study was to evaluate the normal Doppler flowmetrics parameters of renal arteries (RAs), interlobar arteries (IAs) and abdominal aorta (AO) in adult healthy, Persian cats. Twenty-five Persian cats (13 females and 12 males with mean age of 30 months and an age range 12-60 months) with normal clinical examinations and biochemical tests and normal systemic blood pressure were given B-mode ultrasonographies in order to exclude all nephropathies, including polycystic kidney disease. All measurements were performed on both kidneys. Both kidneys (n=50) were examined by color mapping of the renal vasculature. Pulsed Doppler was used to examine both RAs, the IAs at cranial, middle and caudal sites, and the AO. The RI was calculated for all of the vessels. Early systolic acceleration (ESA) of RA and IA was obtained with Doppler spectral analysis. Furthermore, the ratio indices between RA/AO, and IA/RA velocities were calculated. The mean values of peak systolic velocity (PSV) and the diameter for AO were 53.17+/-13.46 cm/s and 0.38+/-0.08 cm, respectively. The mean RA diameter for all 50 kidneys was 0.15+/-0.02 cm. Considering the velocimetric values in both RAs, the mean PSV and RI that were obtained were 41.17+/-9.40 cm/s and 0.54+/-0.07. The RA had a mean ESA of 1.12+/-1.14 m/s(2) and the calculated upper limit of the reference value was 3.40 m/s(2). The mean renal-aortic ratio was 0.828+/-0.296. The IA showed PSV and RI values of 32.16+/-9.33 cm/s and 0.52+/ 0.06, respectively. The mean ESA of all IAs was 0.73+/-0.61 m/s(2). The calculated upper limit of the reference value was 2.0m/s(2). The mean renal interlobar artery ratio was 1.45+/-0.57. The RI values obtained in this study were similar to values reported in the literature. Some conditions that lead to a decrease in compliance and to an increase in vascular resistance can affect the Doppler spectral waveforms without changes in RI. To our knowledge, there are no studies that were directed toward to the normal ESA values of the renal vasculature in Persian cats. This study introduced a new ratio between the PSV of the RA and the IA. This index was developed based on the well-known effects of Doppler on the detection of stenosis, regardless of the cause. Further studies are necessary to verify the hemodynamic behavior of this index under pathological conditions in cats as well as the effect of aging, nephropathies and systemic pressure on Doppler velocimetric parameters. PMID- 21277820 TI - Coalfield health effects: variation in health across former coalfield areas in England. AB - Regions affected by deindustrialisation are often characterised by unfavourable local health profiles. This was the situation in coalfield areas in England, where the scale and suddenness of the job losses in the 1980s and 1990s left these communities experiencing difficult socioeconomic conditions, and associated poor health status. Using data from the Health Survey for England, this paper examines whether poorer health outcomes still characterise coalfield areas today. Findings confirm a 'coalfield health effect' related to limiting long-term illness. With regards to self reported general health and mental health outcomes, results are less clear. The population health profile of coalfield communities is not homogeneous, with some coalfield communities faring worse than others, indicating more localised health issues. PMID- 21277821 TI - Towards robust 3D visual tracking for motion compensation in beating heart surgery. AB - In the context of minimally invasive cardiac surgery, active vision-based motion compensation schemes have been proposed for mitigating problems related to physiological motion. However, robust and accurate visual tracking remains a difficult task. The purpose of this paper is to present a robust visual tracking method that estimates the 3D temporal and spatial deformation of the heart surface using stereo endoscopic images. The novelty is the combination of a visual tracking method based on a Thin-Plate Spline (TPS) model for representing the heart surface deformations with a temporal heart motion model based on a time varying dual Fourier series for overcoming tracking disturbances or failures. The considerable improvements in tracking robustness facing specular reflections and occlusions are demonstrated through experiments using images of in vivo porcine and human beating hearts. PMID- 21277822 TI - Recent insights into iron import by bacteria. AB - Bacteria are confronted with a low availability of iron owing to its insolubility in the Fe3+ form or its being bound to host proteins. The bacteria cope with the iron deficiency by using host heme or siderophores synthesized by themselves or other microbes. In contrast to most other nutrients, iron compounds are tightly bound to proteins at the cell surfaces, from which they are further translocated by highly specific proteins across the cell wall of gram-positive bacteria and the outer membrane of gram-negative bacteria. Once heme and iron siderophores arrive at the cytoplasmic membrane, they are taken up across the cytoplasmic membrane by ABC transporters. Here we present an outline of bacterial heme and iron siderophore transport exemplified by a few selected cases in which recent progress in the understanding of the transport mechanisms has been achieved. PMID- 21277823 TI - A Raman and infrared spectroscopic study of the mineral delvauxite CaFe4(3+)(PO4,SO4)2(OH)8.4-6H2O--a 'colloidal' mineral. AB - The mineral delvauxite CaFe(4)(3+)(PO(4),SO(4))(2)(OH)(8).4-6H(2)O has been characterised by Raman spectroscopy and infrared spectroscopy. The mineral is associated with the minerals diadochite and destinezite. Delvauxite appears to vary in crystallinity from amorphous to semi-crystalline. The mineral is often X ray non-diffracting. The minerals are found in soils and may be described as 'colloidal' minerals. Vibrational spectroscopy enables determination of the molecular structure of delvauxite. Bands are assigned to phosphate and sulphate stretching and bending modes. Two symmetric stretching modes for both the phosphate and sulphate symmetric stretching modes support the concept of non equivalent phosphate and sulphate units in the mineral structure. Multiple water bending and stretching modes imply that non-equivalent water molecules in the structure exist with different hydrogen bond strengths. PMID- 21277824 TI - Studies on the interaction of salvianolic acid B with human hemoglobin by multi spectroscopic techniques. AB - The interaction between salvianolic acid B (Sal B) and human hemoglobin (HHb) under physiological conditions was investigated by UV-vis absorption, fluorescence, synchronous fluorescence and circular dichroism spectroscopic techniques. The experimental results indicate that the quenching mechanism of fluorescence of HHb by Sal B is a static quenching procedure, the binding reaction is spontaneous, and the hydrophobic interactions play a major role in binding of Sal B to HHb. Based on Forster's theory of non-radiative energy transfer, the binding distance between Sal B and the inner tryptophan residues of HHb was determined to be 2.64 nm. The synchronous fluorescence experiment revealed that Sal B can not lead to the microenvironmental changes around the Tyr and Trp residues of HHb, and the binding site of Sal B on HHb is located at alpha(1)beta(2) interface of HHb. Furthermore, the CD spectroscopy indicated the secondary structure of HHb is not changed in the presence of Sal B. PMID- 21277825 TI - Role of prenatal diagnosis and counseling in the management of 735 pregnancies complicated by primary human cytomegalovirus infection: a 20-year experience. AB - BACKGROUND: The burden of congenital human cytomegalovirus (HCMV) infection is well recognized. However, screening for maternal infection remains controversial in view of diagnostic challenges, counseling difficulties, and absence of medical treatment. OBJECTIVE: To assess the role of prenatal diagnosis and counseling in the management of pregnancy complicated by primary HCMV infection. STUDY DESIGN: Retrospective study aimed at investigating diagnostic features, options, and pregnancy outcome in 735 women with primary HCMV infection over a period of 20 years (1990-2009). RESULTS: Overall, 25.6% women were found to be seronegative before the actual pregnancy. However, none were informed about HCMV infection and potential prevention strategies. Diagnosis of primary HCMV infection was achieved by seroconversion in 44.4% cases and by different combinations of virus-specific IgM, low IgG avidity, and DNAemia in 43.9% cases. Non-specific symptoms and/or haematological/biochemical alterations were recalled by 73.5% women. The onset of infection could be established, and counseling adjusted accordingly in >90% cases. The overall rate of vertical transmission was 37.1%, ranging from 5.6% for preconceptional infections to 64.1% for third trimester infections. Amniocentesis was chosen by 43.1% women, whereas pregnancy termination was requested by 15.6%. CONCLUSIONS: Reference virology centers and ad hoc trained and experienced physicians are required for accurate diagnosis of primary infection in pregnancy and ensuing counseling. Prenatal diagnosis has a central role in the management of pregnancies complicated by primary HCMV infection. HCMV-seronegative women should receive adequate information. PMID- 21277826 TI - PEGylated antibody in organic media. AB - Antibodies were covalently conjugated with poly(ethylene glycol) (PEG) and the properties of the PEGylated antibodies in organic media were investigated. Two types of monoclonal antibody were used in this study. One was a monoclonal antibody (abzyme) that was prepared against a hapten mimicking a transition state of hydrolysis. Another was a monoclonal antibody against estrogen, which is not soluble in water. By electrophoresis and mass spectral analysis, the covalent conjugation with PEG chains was confirmed. The PEGylated antibodies bound to antigens and the PEGylated abzyme catalyzed a hydrolysis reaction in an aqueous solution. The PEGylated antibodies were soluble in dichloromethane and acetone and interacted with antigen either in dichloromethane or in acetone. In conclusion, PEGylated antibodies can be employed as analytical tools for water insoluble analytes. PMID- 21277827 TI - Electrically modulated attachment and detachment of animal cells cultured on an optically transparent patterning electrode. AB - The purpose of this study was to develop the modulation methods for the attachment and detachment of specifically positioned adhesive animal cells cultured on an electrode surface with the application of a weak electrical potential. A patterned indium tin oxide (ITO) optically transparent working electrode was placed on the bottom of a chamber slide with a counter-(Pt) and reference (Ag/AgCl) electrode. The ITO patterning was formed by a reticulate ITO region and arrayed square glass regions of varying size. Using the 3-electrode culture system, the author succeeded in modulation of the attachment and detachment of animal cells on the working electrode surface. Animal cells suspended in serum or sera containing medium were drawn to and attached on a reticulate ITO electrode region to which a +0.4-V vs. Ag/AgCl-positive potential was applied. Meanwhile, the cells were successfully placed on the square glass regions by -0.3-V vs. Ag/AgCl-negative potential application. Animal cells were detached not only from the ITO electrode but also from the square glass regions after the application of a +/-10-mV vs. Ag/AgCl, 9-MHz [corrected] rectangular wave potential in PBS(-) for 30-60 min. Rectangular wave potential-induced cell detachment is almost completely noncytotoxic, and no statistical differences between trypsinization and the high frequency wave potential application were observed in HeLa cell growth. The electrical modulation of the specifically positioned cell attachment and detachment techniques holds potential for novel optical microscopic cell sorting analysis in lab-on-chip devices. PMID- 21277828 TI - Sleep medicine practice across geopolitical boundaries. PMID- 21277829 TI - Quality control activities associated with registries in interventional cardiology and surgery. AB - OBJECTIVE: To describe and outline audit and quality control activities of the multicentre interventional and cardiac surgery registry in Victoria as a potential model for a national registry. DESIGN, SETTING, AND PATIENTS: The Melbourne Interventional Group (MIG) database is a prospective multicentre registry recording consecutive percutaneous coronary interventional (PCI) procedures across eight Victorian hospitals. Similarly, the Australasian Society of Cardiac and Thoracic Surgeons (ASCTS) database captures cardiac surgical activity across six Victorian hospitals. Auditing of each registry involved systematic selection of baseline, clinical and procedural variables from 5% of procedures to examine for data integrity and mismatches. MAIN OUTCOME MEASURES: Performance trend and data accuracy of each registry was assessed by the number of mismatches detected during the auditing process for different demographic, clinical and procedural variables and across different (de-identified) sites. RESULTS: Over two auditing phases from 2004-2006 and 2007, 10 (4.3%) of variables from 3% of all PCI procedures and 15 (6.4%) variables from 5% of PCI procedures were analysed. There was 96.5% agreement during the first auditing phase of the MIG registry with an average of 0.35 mismatches per audit (CI 0.28-0.42), whereas during the second audit phase, agreement was up to 97% with 0.32 mismatches per 10 fields per audit (CI 0.25-0.40). The ASCTS database audit selected 39 (14.8%) variables from 5% of annual surgical cases across six cardiac surgical centres with an overall 96.7% agreement. CONCLUSION: The current auditing process of these two databases is rigorous, robust and reflects a high degree of accuracy of data collected by participating hospitals. PMID- 21277830 TI - Molecular basis of blood group expression. AB - Antigen diversity arises from changes at the gene level that range from single nucleotide polymorphisms (SNPs) to intra- and inter-genic exchanges, inversions, insertions, and deletions. Nucleotide changes often result in amino acid difference from the wild-type gene product and with those changes new blood group antigens arise. Alternatively, there is loss of expression altogether, which is deemed the 'null' phenotype. Near complete knowledge of the genetic changes underlying the expression of blood group antigens will lead to the reality that red cell genotyping as a test-of-record. The importance of molecular testing in immunohematology necessitates appropriate training and competency programs to ensure that the highly skilled staff has the appropriate knowledge background. This review summarizes the core mechanisms for gene expression and provides a compilation of the molecular basis for blood group expression. PMID- 21277831 TI - Outcome of continence procedures after failed endoscopic treatment with dextranomer-based implants (DEFLUX(r)). AB - PURPOSE: To evaluate outcome of further continence procedures after failure of endoscopic injections of dextranomer-based bulking agent. MATERIALS AND METHODS: From 1997, 89 children (3-18 years) and one young adult were treated for incontinence with 145 endoscopic injections of dextranomer. On evaluation, each patient was classified as: dry, significantly improved, or treatment failure. Eighty-five patients had at least 12 months of follow up. Out of 34 (40%) treatment failures, 24 patients had a subsequent bladder neck procedure: artificial urinary sphincter (7), bladder neck plasty (9), bladder neck closure (1), fascial sling (3). Six patients had further endoscopic treatment (including 2 after bladder neck plasty). RESULTS: At surgery, Deflux((r)) paste was easily identified with minimal surrounding tissue inflammatory reaction. Artificial urinary sphincter: all 7 dry; bladder neck plasty: 7 dry, 1 improved and 1 still incontinent; 1 bladder neck closure patient dry; fascial sling: 1 significantly improved and 2 dry. Repeated endoscopic treatment: 1 dry, 1 improved and 4 failed. Eleven of the 21 (52%) patients who are either dry or improved have voiding abilities. CONCLUSION: Endoscopic injections with dextranomer do not adversely affect the outcome of further surgical procedures. Repeated injections after a previous endoscopic treatment failure have a low success rate. PMID- 21277832 TI - Anticonvulsant profile of the alkaloids (+)-erythravine and (+)-11-alpha-hydroxy erythravine isolated from the flowers of Erythrina mulungu Mart ex Benth (Leguminosae-Papilionaceae). AB - Neural mechanisms underlying the onset and maintenance of epileptic seizures involve alterations in inhibitory and/or excitatory neurotransmitter pathways. Thus, the prospecting of novel molecules from natural products that target both inhibition and excitation systems has deserved interest in the rational design of new anticonvulsants. We isolated the alkaloids (+)-erythravine and (+)-11-alpha hydroxy-erythravine from the flowers of Erythrina mulungu and evaluated the action of these compounds against chemically induced seizures in rats. Our results showed that the administration of different doses of (+)-erythravine inhibited seizures evoked by bicuculline, pentylenetetrazole, and kainic acid at maximum of 80, 100, and 100%, respectively, whereas different doses of (+)-11 alpha-hydroxy-erythravine inhibited seizures at a maximum of 100% when induced by bicuculline, NMDA, and kainic acid, and, to a lesser extent, PTZ (60%). The analysis of mean latency to seizure onset of nonprotected animals, for specific doses of alkaloids, showed that (+)-erythravine increased latencies to seizures induced by bicuculline. Although (+)-erythravine exhibited very weak anticonvulsant action against seizures induced by NMDA, this alkaloid increased the latency in this assay. The increase in latency to onset of seizures promoted by (+)-11-alpha-hydroxy-erythravine reached a maximum of threefold in the bicuculline test. All animals were protected against death when treated with different doses of (+)-11-alpha-hydroxy-erythravine in the tests using the four chemical convulsants. Identical results were obtained when using (+)-erythravine in the tests of bicuculline, NMDA, and PTZ, and, to a lesser extent, kainic acid. Therefore, these data validate the anticonvulsant properties of the tested alkaloids, which is of relevance in consideration of the ethnopharmacological/biotechnological potential of E. mulungu. PMID- 21277833 TI - Diurnal variations in depression-like behavior of Wistar and spontaneously hypertensive rats in the kainate model of temporal lobe epilepsy. AB - The purpose of this study was to explore whether the kainate (KA) model of temporal lobe epilepsy (TLE) can be used as a model of comorbid epilepsy and depression to study diurnal behavioral variations in rats. Development of chronic epilepsy was confirmed by the detection of spontaneous motor seizures (SMS) with video monitoring (24 hours/3-5 months after status epilepticus [SE]). KA-treated spontaneously hypertensive rats (SHRs) exhibited higher seizure frequency than Wistar rats during the light phase in the fourth and fifth months after SE. Although epileptic Wistar rats showed depression-like behavior and reduced anxiety mostly during the light phase, there were no diurnal variations in depression-like patterns in SHRs. Anxiety levels of control and epileptic SHRs were similar. Decreases in serotonin, tryptophan, and dopamine concentrations in the hippocampus were detected in epileptic Wistar rats compared with naive controls. However, monoamine levels of epileptic SHRs were close to those of their controls. Wistar rats and SHRs develop stable depression-like behavior during the chronic epileptic phase with strain-dependent diurnal differences. PMID- 21277834 TI - Epilepsy with centrotemporal spikes: a benign condition with potentially serious consequences. PMID- 21277835 TI - Patients' knowledge about their disorder: perspective of patients with epilepsy in a tertiary health facility in southwestern Nigeria. AB - OBJECTIVE: Previous studies have shown that patients with epilepsy do not have adequate knowledge about their disorder, suggesting that patient education is a vital part of comprehensive care for epilepsy. The goal of this study was to evaluate what Nigerian patients with epilepsy know about their disorder. METHODS: Forty-six patients with EEG- and clinically confirmed epilepsy participated in the study. The patients completed the Epilepsy Patients Knowledge Questionnaire. The questionnaire includes topics related to etiology of epilepsy, safety, compliance, legal issues of driving, and employment. The questionnaire scores were correlated with demographic variables, duration of epilepsy, and level of education of the patients. RESULTS: The mean age of the respondents was 26.78 +/- 9.27 years; there were 27 males and 19 females. The mean duration of epilepsy in the group was 7.6 +/- 7.5 years. The mean rates of correct responses to the issues of safety and compliance were 31.6 and 76.8%, respectively. The mean scores on legal issues of driving and employment were 45.7 and 42.4%, respectively. The lowest score (10.9%) was on the etiology of epilepsy. CONCLUSION: Nigerian patients with epilepsy lack adequate knowledge about their disorder, and there is a need for improved educational intervention in these patients. PMID- 21277836 TI - Race and sex differences in primary appraisals, catastrophizing, and experimental pain outcomes. AB - The aims of this study were: 1) to examine race and sex differences in primary pain appraisals and catastrophizing; 2) to test the unique ability of race, sex, primary pain appraisals, and catastrophizing to predict experimental pain outcomes; and 3) to conduct mediational analyses testing pain appraisals and catastrophizing as explanatory mechanisms for race and sex differences in pain. One hundred and fifty-five college students at The University of Alabama completed a cold pressor experimental pain task and a questionnaire battery. Statistical methods included multivariable regression models and nonparametric bootstrapping methods for tests of mediation. African-Americans reported higher catastrophizing and had lower pain tolerance than white Americans. Males demonstrated higher challenge appraisals, lower pain intensity, and longer pain tolerance. Challenge appraisals were positively related to pain tolerance, threat/harm appraisals were inversely related to pain tolerance, and pain catastrophizing was positively related to both pain intensity and pain unpleasantness. Pain catastrophizing partially mediated race differences in pain tolerance and mediated sex differences in intensity, whereas primary pain appraisals did not significantly mediate race or sex differences in pain variables. Primary appraisals and catastrophizing appear to be separable constructs related to different aspects of the pain experience. PERSPECTIVE: This study found that important race and sex differences exist in relation to pain appraisals and catastrophizing, and that these cognitive variables play unique roles in different aspects of the pain experience. Cognitive-behavioral therapies for pain may be enhanced by including a focus on both pain appraisals and pain catastrophizing. PMID- 21277837 TI - Efficacy and safety of aceclofenac-cr and aceclofenac in the treatment of knee osteoarthritis: a 6-week, comparative, randomized, multicentric, double-blind study. AB - The efficacy and safety of aceclofenac control release (CR) tablets was compared with conventional aceclofenac tablets in patients with knee osteoarthritis (OA). This was a double-blind, double-dummy, randomized, parallel group multicentric study conducted at 6 centers. Two hundred and eighty five patients were randomized to either aceclofenac-CR (n = 143) once daily or conventional aceclofenac tablet (n = 142) twice daily and were followed for 6 weeks. The efficacy parameters were pain intensity score on visual analogue scale, Western Ontario and McMaster (WOMAC) score, patients and investigator's overall study drug assessment and total consumption of acetaminophen and ranitidine tablets. Both treatments showed significant improvement in their efficacy parameters from baseline at the end of therapy. Aceclofenac-CR was comparable to conventional aceclofenac with respect to change in pain intensity and WOMAC score (P > .05) There was no statistically significant difference between the treatment groups in patient's and investigator's overall study drug assessment at the end of therapy (P > .05). Aceclofenac-CR treated patients took fewer acetaminophen and ranitidine tablets during the treatment period as compared to conventional aceclofenac treated patients. Both the study medications were well tolerated with no incidence of serious adverse event (SAE). In conclusion, the new aceclofenac CR formulation was found to be effective and safe while offering practical advantage of once daily administration. PERSPECTIVE: This article represents the advantages of control release aceclofenac over the conventional aceclofenac tablets. Aceclofenac-CR was found to be similar in terms of efficacy as conventional aceclofenac in knee OA patients with fewer adverse events. PMID- 21277838 TI - Increased clearance of morphine in sickle cell disease: implications for pain management. AB - Acute vaso-occlusive painful episodes associated with sickle cell disease (SCD) are frequently treated with morphine. Many SCD individuals require relatively higher doses of morphine to achieve optimal analgesia. We studied pharmacokinetics of morphine in SCD to explore if altered disposition could be a factor contributing to increased requirement of morphine in this population. The study subjects were in steady state of health to avoid the effect of hemodynamic changes associated with vaso-occlusion on morphine disposition. The plasma concentrations of morphine and its major metabolites were measured at timed intervals in 21 SCD subjects after they received a single .1 mg/Kg infusion of morphine sulfate. USCPACK software was used to fit candidate pharmacokinetic models. Noncompartmental pharmacokinetic parameters for morphine were calculated. Morphine clearance was 2.4-3.6 L/h, half-life was .3-.7 hours, AUC(0-infinity) was 27.7-42.5 ng*h/mL, and volume of distribution was .96-3.38 L/kg. Clearance of morphine in the study population was 3-10 folds higher than published estimates in the non-SCD population, with correspondingly lower AUC and half-life. Volume of distribution was similar. This observation suggests that due to increased clearance SCD individuals may require higher dose and frequency of morphine to achieve comparable plasma levels. PERSPECTIVE: Accelerated clearance of morphine likely related to increased hepatic and renal blood flow may be responsible for increased requirement of morphine in SCD. Although SCD individuals may require higher and more frequent doses of morphine, inter-individual variability of morphine disposition highlights the importance of individualization of the therapy. PMID- 21277839 TI - Somatization is associated with non-adherence to opioid prescriptions. AB - Non-adherence to opioid prescriptions can decrease the safety and efficacy of opioid therapy. Identifying factors associated with over- and under-use of opioids in patients presenting with pain may improve prescribing and pain management. Patients presenting with pain often also present with somatization, and somatization is associated with both excessive use of and non-adherence to medications. This study examines the relationship between somatization and non adherence (over- and under-use) to opioid prescriptions in the Veteran sample. One hundred and ninety-one Veterans who received an opioid prescription at a Veterans Affairs Palo Alto Health Care System in the prior year participated by completing a 1.5 hour semistructured interview which included assessments of depressive symptoms, somatization, medication side effects, and opioid pain medication usage. The percentage of patients non-adherent to opioid prescriptions increased as a function of somatization: Compared to no somatization, all levels of somatization were associated with higher rates of underuse, while severe somatization was associated with increased rates of overuse. Consistent with previous studies of medication non-adherence, increased depression and medication side effects were associated with decreased adherence to opioid prescriptions. However, in exploratory analyses, somatization mediated the relationship between depressive symptoms and opioid-use patterns as well as medication side effects and opioid use patterns. PERSPECTIVE: This article sought to explore the relationship between somatization and adherence to prescription opioid medications. Our findings suggest that pain management treatment plans may be optimized by addressing patient distress about physical symptoms when considering the use of prescription opioid medications. PMID- 21277840 TI - Adjusting pulse amplitude during transcutaneous electrical nerve stimulation (TENS) application produces greater hypoalgesia. AB - Transcutaneous electrical nerve stimulation (TENS) is a noninvasive technique used for pain modulation. During application of TENS there is a fading of current sensation. Textbooks of electrophysical agents recommend that pulse amplitude should be constantly adjusted. This seems to be accepted clinically despite the fact that there is no direct experimental evidence. The aim of the current study was to investigate the hypoalgesic effect of adjusting TENS pulse amplitude on pressure pain thresholds (PPTs) in healthy humans. Fifty-six healthy TENS naive participants were recruited and randomly assigned to 1 of 4 groups (n = 14 per group): control, placebo TENS, fixed pulse amplitude TENS, and adjusted pulse amplitude TENS. Both active and placebo TENS were applied to the dominant forearm. PPTs were recorded from 2 points on the dominant forearm and hand before, during, and after 40 minutes of TENS. TENS increased the PPTs on the forearm (P = .003) and hand (P = .003) in the group that received the adjusted pulse amplitude when compared to all other groups. The mean final pulse amplitude for the adjusted pulse amplitude TENS group was 35.51 mA when compared to the fixed pulse amplitude TENS group, which averaged 31.37 mA (P = .0318). PERSPECTIVE: These results suggest that it is important to adjust the pulse amplitude during TENS application to get the maximal analgesic effect. We propose that the fading of current sensation allows the use of higher pulse amplitudes, which would activate a greater number of and deeper tissue afferents to produce greater analgesia. PMID- 21277841 TI - Simultaneous determination of 2-naphthol and 1-hydroxy pyrene in urine by gas chromatography-mass spectrometry. AB - A gas chromatography-mass spectrometric (GC-MS) method was developed for the determination of 2-naphthol (2-NAP) and 1-hydroxypyrene (1-HOP) in human urine. Extraction from urine after the enzyme hydrolysis with beta glucuronidase/arylsulfatase was achieved with a liquid extraction using 5 mL of pentane. After addition of 50 MUL of N-methyl-N-(tert-butyldimethylsilyl) trifluoroacetamide (MTBDMSTFA) to prevent the loss of 2-NAP during drying, the extract was completely dried and derivatized with MTBDMSTFA for 30 min at 60 degrees C. The accuracies were in the range of 96-109% at a concentration of 0.5, 10 and 25 MUg/L and their precisions were less than 15%. Method detection limits of 2-NAP and 1-HOP were 0.07 and 0.01 MUg/L, respectively. This method was used to analyze twenty urine samples, and they were found in the concentration range <0.07-13.7 MUg/L (2-NAP) and <0.01-0.88 MUg/L (1-HOP). The concentrations of 2 NAP and 1-HOP were well correlated to those of naphthalene and pyrene in blood, respectively. PMID- 21277842 TI - Study the effect of a pseudo-carrier on pharmacokinetics of 9-fluoropropyl-(+) dihydrotetrabenazine in rat plasma by ultra-performance liquid chromatography tandem mass spectrometry. AB - To evaluate the effect of a pseudo-carrier (9-hydroxypropyl-(+) dihydrotetrabenazine, AV-149) on pharmacokinetics of 9-fluoropropyl-(+) dihydrotetrabenazine (AV-133), an ultra-performance liquid chromatography-tandem mass spectrometric (UPLC-MS/MS) method was developed and validated for the determination of AV-133 and AV-149 in rat plasma. AV-133 and AV-149 were extracted from plasma following protein precipitation. The chromatographic analysis was performed on an ACQUITY UPLC BEHTM C18 column (50 mm x 2.1 mm x 1.7 MUm) by a gradient elution. The mass spectrometer was operated in positive mode using electrospray ionization. The analytes were measured using the multiple reaction-monitoring mode (MRM). An external calibration was used, and the calibration curves were linear in the range of 1.00-800 ng/mL for AV-133 and AV 149. The accuracy ranged from 90.8% to 113.2% and the precision ranged from 2.7% to 9.9% for each analyte. The effect of a pseudo-carrier on pharmacokinetics of AV-133 was studied using the presented method. PMID- 21277843 TI - Quantitative determination of allele frequency in pooled DNA by using sequencing method. AB - Quantitative determination of the allele frequency of single-nucleotide polymorphism (SNP) in pooled DNA samples is a promising approach to clarify the relationships between SNPs and diseases. Here, we present such a simple, accurate, and inexpensive method for quantitative determining the allele frequency in pooled DNA samples. Three steps of DNA pooling, PCR amplification and sequencing are involved in this assay. Although direct determination of the allele frequency from the two allele-specific fluorescence intensities is possible, correction for differential response of alleles is important. We explored the effect of differential response of alleles on test statistics and provide a solution to this problem based on heterozygous fluorescence intensities. We demonstrate the accuracy and reliability of this assay on pooled DNA samples with pre-determined allele frequencies from 7.1% to 53.9%. The accuracy of allele frequency measurements is high, with a correlation coefficient of r2 = 0.997 between measured and known frequencies. We believe that by providing a means for SNP genotyping up to hundreds of samples simultaneously, inexpensively, and reproducibly, this method is a powerful strategy for detecting meaningful polymorphic differences in candidate gene association studies. PMID- 21277844 TI - Independent predictors of immediate and long-term results after pulmonary balloon valvuloplasty in dogs. AB - OBJECTIVES: Determine whether valve morphology, pulmonary annulus diameter, aortic/pulmonic annulus ratio, balloon-to-annulus ratio (BAR), pre-pulmonary balloon valvuloplasty (PBV), Doppler gradient, and residual Doppler gradient are independent predictors of immediate and long-term results after PBV in dogs as in humans. ANIMALS, MATERIALS AND METHODS: Retrospective study. Medical records of dogs that underwent PBV, from January 1999 to December 2008 were reviewed. All dogs with pre- and immediate (24 h) post-PBV echocardiographic examination were included. 126 dogs were selected. Immediate outcome was optimal when the dog survived the PBV and Doppler gradient was <=50 mmHg. Long-term outcome (1 year) was optimal when the dog survived at least 1-year follow-up without symptoms and Doppler gradient was <=50 mmHg. RESULTS: Only pre-PBV Doppler gradient was identified as a significant independent predictor of immediate results (P < 0.001; OR 0.97, CI 0.96-0.98). Pre-PBV Doppler gradient and residual Doppler gradient were the only independent predictors of long-term results (P = 0.036; OR 0.98, CI 0.96-0.99 and P = 0.005; OR 0.95, CI 0.92-0.98, respectively). CONCLUSION: In dogs as in humans higher pre-PBV Doppler gradient is one of the most important independent predictor of suboptimal immediate and long-term results after PBV and must be considered before scheduling this procedure. Moreover higher valvar residual Doppler gradient is an important independent predictors of suboptimal long-term results. PMID- 21277845 TI - Computed tomography angiography of bilateral peripheral pulmonary arterial stenoses in a dog. AB - Computed tomographic angiography (CTA) is a useful diagnostic modality that is becoming more widely available in veterinary medicine. Its three-dimensional imaging capabilities allow a template for planning surgical procedures, accurate lesion measurements, and it is considerably less expensive than other comparable modalities. Selective CTA is described here, in a case of canine bilateral peripheral pulmonary artery stenoses. PMID- 21277846 TI - Evaluation of dental plaque control in patients wearing fixed orthodontic appliances: a clinical study. AB - Multibracket orthodontic appliances increase dental plaque retention and make teethbrushing more difficult for patients. As a result, advice from the orthodontist on oral hygiene along with patient motivation regarding teethbrushing are particularly important. The aim of this study was to compare the efficacy of electric toothbrushes with that of manual brushing associated with mouth-rinses comprising chlorhexidine (0.12%) and 0% alcohol. To this end, 84 patients receiving current orthodontic treatment were randomly selected from patients treated at the Dento-Facial Orthopedics department in the Casablanca Dental Consultation and Treatment Center. Selected patients were divided into three groups: Group 1: manual teethbrushing; Group 2: electric teethbrushing; Group 3: manual brushing combined with mouth rinse. Oral hygiene was assessed using the Loe-Silness plaque and gingival indices. Measurements were made before and 4 weeks after the observation period. Results were subjected to statistical comparison in order to determine the group showing greatest improvement and to deduce the best means of controlling bacterial plaque. The electric toothbrush and the chlorhexidine mouth rinse appear to control dental plaque more effectively than manual teethbrushing alone. Following this study, patients receiving multibracket treatment were invited to combine manual brushing with short clinical mouth-rinsing sessions or to use an electric toothbrush. PMID- 21277848 TI - Is transverse acetabular ligament an anatomical landmark to reliably orient the cup in primary total hip arthroplasty? AB - INTRODUCTION: Accurate positioning of the acetabular cup in primary total hip arthroplasty is critical to decrease the rate of dislocation. Inaccurate orientation of the cup is the most common error during this procedure. Target acetabular orientation is still controversial. An original study found a dislocation rate of 0.6% when the cup was aligned with the transverse acetabular ligament (TAL). HYPOTHESIS: TAL is a patient-specific anatomical landmark and a tool for cup orientation. MATERIALS AND METHODS: Eight cadaveric pelves (14 hips included for study) were harvested in toto at our research laboratory. Anatomical versions of the TAL, labrum and horns were measured in relation to the anterior pelvic plane. A navigator sensor and an optoelectronic device (Motion AnalysisTM) were used. RESULTS: Anatomical versions of the TAL, horns and labrum averaged 1.9 degrees (range, -8 degrees to +13.3 degrees ), 3 degrees (range, -12.2 degrees to 14 degrees ), and 26.3 degrees (range, 17.4 degrees to 41.8 degrees ), respectively. DISCUSSION: To our knowledge, this is the first study to report the orientation of the periacetabular soft-tissues. TAL anteversion was outside the safe zone described by Lewinnek, while labrum anteversion was within this safe zone. We discuss the reference used, Lewinnek's safe zone, and functional orientation of the implants. Lewinnek's safe-zone does not seem to be valid. The TAL seems to be a specific reference for each patient but its reliability must still be confirmed as an adequate reference for positioning the cup in total hip arthroplasty. PMID- 21277849 TI - The solute carrier family 15A4 regulates TLR9 and NOD1 functions in the innate immune system and promotes colitis in mice. AB - BACKGROUND & AIMS: Solute carrier family 15 (SLC15) A4 is a proton-coupled histidine and oligopeptide cotransporter expressed by the immune and nervous systems and associated with disorders such as inflammatory bowel diseases and systemic lupus erythematosus. High levels of SLC15A4 transcripts were observed in human antigen-presenting cells, including dendritic cells, activated macrophages, and B cells. However, the roles of SLC15A4 in the immune regulation are not known. We investigated the function of SLC15A4 in the innate immune system. METHODS: We created SLC15A4-deficient (SLC15A4(-/-)) mice and compared Toll-like receptor 9 and NOD1-dependent innate immune responses between SLC15A4(-/-) and control (SLC15A4(+/+)) mice. RESULTS: SLC15A4 deficiency impaired CpG-induced production of interleukin-12, interleukin-15, and interleukin-18 by dendritic cells. Correspondingly, SLC15A4(-/-) mice developed a less severe form of Th1 dependent colitis than SLC15A4(+/+) mice. Increased lysosomal histidine, in the absence of SLC15A4, appears to negatively regulate Toll-like receptor 9 function by inhibiting the proteolytic activities of cathepsins B and L. SLC15A4(-/-) mice also had a severe defect in NOD1-dependent cytokine production, indicating that SLC15A4 functions as a transporter of the NOD1 ligand. CONCLUSIONS: SLC15A4 promotes colitis through Toll-like receptor 9 and NOD1-dependent innate immune responses. Histidine homeostasis within intracellular compartments is important for eliciting effective innate immune responses. PMID- 21277850 TI - Tissue transglutaminase does not affect fibrotic matrix stability or regression of liver fibrosis in mice. AB - BACKGROUND & AIMS: The ubiquitous cross-linking enzyme tissue transglutaminase (TG2) has been implicated in irreversible collagen stabilization in liver fibrosis, although functional evidence is lacking. We studied the contribution of TG2 to hepatic fibrotic matrix stability, as well as liver fibrosis progression and regression in TG2-deficient mice. METHODS: Advanced liver fibrosis was induced by carbon tetrachloride or thioacetamide in TG2(-/-) mice and their wild type littermates to study fibrosis progression and its spontaneous regression for up to 36 weeks. Pattern and extent of fibrosis were analyzed by histology and hepatic hydroxyproline quantification. Dynamic changes in hepatic matrix cross linking were assessed by stepwise collagen extraction. Expression of 7 TGs and fibrosis-related genes was determined by quantitative reverse-transcription polymerase chain reaction. RESULTS: Transglutaminase activity was increased in fibrosis, and the level of TG2 messenger RNA correlated with the expression of fibrosis-related genes. Biochemical analysis revealed progressive collagen stabilization, with an up to 6-fold increase in the highly cross-linked, pepsin insoluble fraction (26%). In TG2(-/-) mice, hepatic TG activity was significantly decreased, but chronic administration of carbon tetrachloride or thioacetamide led to a comparable extent and pattern of liver fibrosis, as in wild-type mice. In TG2(-/-) mice, the composition of hepatic collagen fractions and levels of fibrosis-related transcripts were unchanged, and fibrosis reversal was not facilitated. CONCLUSIONS: TG2 and TG activity are up-regulated during hepatic fibrosis progression, but do not contribute to fibrogenesis or stabilization of the collagen matrix. TG2 deletion does not promote regression of liver fibrosis. TG2-independent collagen cross-linking is a remarkable feature of progressing hepatic fibrosis and represents an important therapeutic target for liver fibrosis. PMID- 21277851 TI - Eosinophils express muscarinic receptors and corticotropin-releasing factor to disrupt the mucosal barrier in ulcerative colitis. AB - BACKGROUND & AIMS: Altered intestinal barrier function has been implicated in the pathophysiology of ulcerative colitis (UC) in genetic, functional, and epidemiological studies. Mast cells and corticotropin-releasing factor (CRF) regulate the mucosal barrier in human colon. Because eosinophils are often increased in colon tissues of patients with UC, we assessed interactions among mast cells, CRF, and eosinophils in the mucosal barrier of these patients. METHODS: Transmucosal fluxes of protein antigens (horseradish peroxidase) and paracellular markers ((51)Cr-EDTA, fluorescein isothiocyanate-dextran 4000) were studied in noninflamed, colonic mucosal biopsy samples collected from 26 patients with UC and 53 healthy volunteers (controls); samples were mounted in Ussing chambers. We also performed fluorescence and electron microscopy of human tissue samples, assessed isolated eosinophils, and performed mechanistic studies using in vitro cocultured eosinophils (15HL-60), mast cells (HMC-1), and a colonic epithelial cell line (T84). RESULTS: Colon tissues from patients with UC had significant increases in permeability to protein antigens compared with controls. Permeability was blocked by atropine (a muscarinic receptor antagonist), alpha helical CRF(9-41) (a CRF receptor antagonist), and lodoxamide (a mast-cell stabilizer). Eosinophils were increased in number in UC tissues (compared with controls), expressed the most M2 and M3 muscarinic receptors of any mucosal cell type, and had immunoreactivity to CRF. In coculture studies, carbachol activation of eosinophils caused production of CRF and activation of mast cells, which increased permeability of T84 epithelial cells to macromolecules. CONCLUSIONS: We identified a neuroimmune intercellular circuit (from cholinergic nerves, via eosinophils to mast cells) that mediates colonic mucosal barrier dysfunction in patients with UC. This circuit might exacerbate mucosal inflammation. PMID- 21277852 TI - Activation of corticotropin-releasing factor receptor 2 mediates the colonic motor coping response to acute stress in rodents. AB - BACKGROUND & AIMS: Corticotropin-releasing factor receptor-1 (CRF(1)) mediates the stress-induced colonic motor activity. Less is known about the role of CRF(2) in the colonic response to stress. METHODS: We studied colonic contractile activity in rats and CRF(2)-/-, CRF-overexpressing, and wild-type mice using still manometry; we analyzed defecation induced by acute partial-restraint stress (PRS), and/or intraperitoneal injection of CRF ligands. In rats, we monitored activation of the colonic longitudinal muscle myenteric plexus (LMMP) neurons and localization of CRF(1) and CRF(2) using immunohistochemical and immunoblot analyses. We measured phosphorylation of extracellular signal-regulated kinase 1/2 by CRF ligands in primary cultures of LMMP neurons (PC-LMMPn) and cyclic adenosine monophosphate (cAMP) production in human embryonic kidney-293 cells transfected with CRF(1) and/or CRF(2). RESULTS: In rats, a selective agonist of CRF(2) (urocortin 2) reduced CRF-induced defecation (>50%), colonic contractile activity, and Fos expression in the colonic LMMP. A selective antagonist of CRF(2) (astressin(2)-B) increased these responses. Urocortin 2 reduced PRS induced colonic contractile activity in wild-type and CRF-overexpressing mice, whereas disruption of CRF(2) increased PRS-induced colonic contractile activity and CRF-induced defecation. CRF(2) colocalized with CRF(1) and neuronal nitric oxide synthase in the rat colon, LMMP, and PC-LMMPn. CRF-induced phosphorylation of extracellular signal-regulated kinase in PC-LMMPn; this was inhibited or increased by a selective antagonist of CRF(1) (NBI35965) or astressin(2)-B, respectively. The half maximal effective concentration, EC(50), for the CRF induced cAMP response was 8.6 nmol/L in human embryonic kidney-293 cells that express only CRF(1); this response was suppressed 10-fold in cells that express CRF(1) and CRF(2). CONCLUSIONS: In colon tissues of rodents, CRF(2) activation inhibits CRF(1) signaling in myenteric neurons and the stress-induced colonic motor responses. Disruption of CRF(2) function impairs colonic coping responses to stress. PMID- 21277853 TI - Nitric oxide-sensitive guanylyl cyclase is dispensable for nitrergic signaling and gut motility in mouse intestinal smooth muscle. AB - BACKGROUND & AIMS: The nitric oxide-guanosine 3',5'-cyclic monophosphate (cGMP) signaling pathway has an important role in the control of smooth muscle tone. NO is produced by NO synthases and acts as a major inhibitory neurotransmitter in the gastrointestinal (GI) tract. The main target, NO-sensitive guanylyl cyclase (NO-GC), is stimulated by NO to produce the intracellular messenger cGMP. We investigated the role of NO-GC in nitrergic relaxation and GI motility. METHODS: We tested relaxation of GI smooth muscle in mice that do not express NO-GC or mice with disruption of NO-GC specifically in smooth muscle cells. Different segments of the GI tract (fundus, lower esophageal sphincter, pyloric sphincter, and duodenum) were used in isometric force studies. NO donors and electrical field stimulation were used to assess nitrergic signaling. Whole-gut transit time was measured as an indicator of GI motility. RESULTS: Mice that lack NO-GC do not have NO-induced relaxation of GI smooth muscle. Gut transit time was increased, resulting in GI dysfunction. Surprisingly, in mice that lack NO-GC specifically in smooth muscle, NO-induced relaxation was reduced only slightly, and whole-gut transit time was unchanged compared with wild-type mice. CONCLUSIONS: Lack of NO GC in smooth muscle cells does not impair NO-induced relaxation of GI tissues or GI motility. The NO receptor guanylyl cyclase in GI smooth muscle is therefore dispensable for nitrergic signaling in mice. PMID- 21277854 TI - Accuracy and reproducibility of a multiplex immunoassay platform: a validation study. AB - BACKGROUND: Multiplex immunoassays offer many advantages over singleplex assays for the analysis of multiple analytes in a single sample. We sought to validate a specific multiplex cytokine immunoassay (Human 9-plex cytokine array on the Searchlight(r) platform by Thermoscientific) prior to use in a large clinical study. METHODS: We compared spike and recovery of recombinant proteins on the Searchlight(r) platform to singleplex immunoassays purchased from R&D Systems, measured identical patient samples on the two different platforms, and measured identical patient samples on different days to measure intra- and inter-assay variability. RESULTS: Assays using the Searchlight(r) platform had inefficient recovery of spiked recombinant proteins compared to R&D Systems singleplex assays. Assaying identical patients samples on different days on the Searchlight platform had acceptable intra-assay variability (intra-assay coefficient of variation (CV%) range for all analytes of 9.1-13.7) but unacceptably high inter assay variability (CV% range for all analytes 16.7-119.3) suggesting plate-to plate variability. Similar assays for individual cytokines on the R&D platform had an intra-assay CV% range of 1.6-6.4 and an inter-assay CV% range of 3.8-7.1. Some deficiencies in Searchlight(r) assay performance may be due to irregularities in spotting of capture antibodies during manufacturing. CONCLUSIONS: We conclude that the Searchlight(r) multiplex immunoassay platform would require extensive additional assay optimization prior to widespread clinical research use. PMID- 21277855 TI - The storage of nutritional resources during vitellogenesis of Panstrongylus megistus (Hemiptera: Reduviidae): the pathways of lipophorin in lipid delivery to developing oocytes. AB - In this work, we have analyzed the pathways by which lipophorin (Lp) delivers its lipid cargo to developing oocytes of Panstrongylus megistus, a hematophagous vector of Chagas' disease. Lp, vitellin, total lipids and proteins were measured in ovarian tissues at different stages of the reproductive cycle. Localization of Lp in developing oocytes, mainly at their cortical area, was demonstrated by immunofluorescence assays using an anti-Lp antibody labeled with FITC. In vivo approaches injecting fluorescently labeled Lp to follow the course of the entire particle (Lp-DiI or Lp-Oregon Green) or its lipid cargo (Lp-Bodipy-FA) were monitored by laser scanning confocal microscopy. Significant increases in the amounts of lipids, proteins and vitellin were observed in ovarian tissue with the progress of vitellogenesis. Unexpectedly, an increase in the amount of Lp was also observed. The experiments in vivo demonstrated that the uptake of fluorescent Lp labeled on its protein or lipid moiety by developing oocytes occurred very fast, being impaired at low temperatures. The co-injection of fluorescent Lp and vitellogenin (Vg) showed that both particles co-localized inside yolk bodies, confirming the endocytic pathway for Lp. When the fate of lipids transferred to oocytes was evaluated in vitellogenic females by co injecting Lp-Bodipy-FA and Lp-DiI, the signal for Bodipy-FA was found in both lipid droplets and yolk bodies. In contrast, in injected females kept at 4 degrees C the fluorescence was reduced, being observed exclusively in lipid droplets, implying that lipid transfer to the oocyte was diminished but not abolished. Taken together, the results demonstrate that in the hematophagous P. megistus, the storage of lipid resources by developing oocytes occurs by the convergence of different pathways by which Lp maximizes the delivery of its lipid cargo. In addition, it was also shown that, to some extent, lipids stored in the oocyte lipid droplets can also originate from endocytosed Vg. The relevance of these events in the context of the physiology of reproduction in P. megistus is discussed. PMID- 21277856 TI - Multiple conformations of the nucleotide site of Kinesin family motors in the triphosphate state. AB - Identifying conformational changes in kinesin family motors associated with nucleotide and microtubule (MT) binding is essential to determining an atomic level model for force production and motion by the motors. Using the mobility of nucleotide analog spin probes bound at the active sites of kinesin family motors to monitor conformational changes, we previously demonstrated that, in the ADP state, the open nucleotide site closes upon MT binding [Naber, N., Minehardt, T. J., Rice, S., Chen, X., Grammer, J., Matuska, M., et al. (2003). Closing of the nucleotide pocket of kinesin family motors upon binding to microtubules. Science, 300, 798-801]. We now extend these studies to kinesin-1 (K) and ncd (nonclaret disjunctional protein) motors in ATP and ATP-analog states. Our results reveal structural differences between several triphosphate and transition-state analogs bound to both kinesin and ncd in solution. The spectra of kinesin/ncd in the presence of SLADP*AlFx/BeFx and kinesin, with the mutation E236A (K-E236A; does not hydrolyze ATP) bound to ATP, show an open conformation of the nucleotide pocket similar to that seen in the kinesin/ncd*ADP states. In contrast, the triphosphate analogs K*SLAMPPNP and K-E236A*SLAMPPNP induce a more immobilized component of the electron paramagnetic resonance spectrum, implying closing of the nucleotide site. The MT-bound states of all of the triphosphate analogs reveal two novel spectral components. The equilibrium between these two components is only weakly dependent on temperature. Both components have more restricted mobility than observed in MT-bound diphosphate states. Thus, the closing of the nucleotide pocket when the diphosphate state binds to MTs is amplified in the triphosphate state, perhaps promoting accelerated ATP hydrolysis. Consistent with this idea, molecular dynamics simulations show a good correlation between our spectroscopic data, X-ray crystallography, and the electron microscopy of MT-bound triphosphate-analog states. PMID- 21277857 TI - The crystal structure of l-sorbose reductase from Gluconobacter frateurii complexed with NADPH and l-sorbose. AB - l-Sorbose reductase from Gluconobacter frateurii (SR) is an NADPH-dependent oxidoreductase. SR preferentially catalyzes the reversible reaction between d sorbitol and l-sorbose with high substrate specificity. To elucidate the structural basis of the catalytic mechanism and the substrate specificity of SR, we have determined the structures of apo-SR, SR in complex with NADPH, and the inactive mutant (His116Leu) of SR in complex with NADPH and l-sorbose at 2.83 A, 1.90 A, and 1.80 A resolutions, respectively. Our results show that SR belongs to the short-chain dehydrogenase/reductase (SDR) family and forms a tetrameric structure. Although His116 is not conserved among SDR family enzymes, the structures of SR have revealed that His116 is important for the stabilization of the proton relay system and for active-site conformation as a fourth catalytic residue. In the ternary complex structure, l-sorbose is recognized by 11 hydrogen bonds. Site-directed mutagenesis of residues around the l-sorbose-binding site has shown that the loss of almost full enzymatic activity was caused by not only the substitution of putative catalytic residues but also the substitution of the residue used for the recognition of the C4 hydroxyl groups of l-sorbose (Glu154) and of the residues used for the construction of the substrate-binding pocket (Cys146 and Gly188). The recognition of the C4 hydroxyl group of l-sorbose would be indispensable for the substrate specificity of SR, which recognizes only l sorbose and d-sorbitol but not other sugars. Our results indicated that these residues were crucial for the substrate recognition and specificity of SR. PMID- 21277858 TI - PKN-1, a homologue of mammalian PKN, is involved in the regulation of muscle contraction and force transmission in C. elegans. AB - To examine the in vivo functions of protein kinase N (PKN), one of the effectors of Rho small guanosine triphosphatases (GTPases), we used the nematode Caenorhabditis elegans as a genetic model system. We identified a C. elegans homologue (pkn-1) of mammalian PKN and confirmed direct binding to C. elegans Rho small GTPases. Using a green fluorescent protein reporter, we showed that pkn-1 is mainly expressed in various muscles and is localized at dense bodies and M lines. Overexpression of the PKN-1 kinase domain and loss-of-function mutations by genomic deletion of pkn-1 resulted in a loopy Unc phenotype, which has been reported in many mutants of neuronal genes. The results of mosaic analysis and body wall muscle-specific expression of the PKN-1 kinase domain suggests that this loopy phenotype is due to the expression of PKN-1 in body wall muscle. The genomic deletion of pkn-1 also showed a defect in force transmission. These results suggest that PKN-1 functions as a regulator of muscle contraction relaxation and as a component of the force transmission mechanism. PMID- 21277859 TI - The crystal structure of BamB suggests interactions with BamA and its role within the BAM complex. AB - Escherichia coli BamB is the largest of four lipoproteins in the beta-barrel assembly machinery (BAM) complex. It interacts with the periplasmic domain of BamA, an integral outer membrane protein (OMP) essential for OMP biogenesis. Although BamB is not essential, it serves an important function in the BAM complex, significantly increasing the folding efficiency of some OMPs in vivo and in vitro. To learn more about the BAM complex, we solved structures of BamB in three different crystal forms. BamB crystallized in space groups P2(1)3, I222, and P2(1)2(1)2(1), with one molecule per asymmetric unit in each case. Crystals from the space group I222 diffracted to 1. 65-A resolution. BamB forms an eight bladed beta-propeller with a central pore and is shaped like a doughnut. A DALI search revealed that BamB shares structural homology to several eukaryotic proteins containing WD40 repeat domains, which commonly have beta-propeller folds and often serve as scaffolding proteins within larger multi-protein complexes that carry out signal transduction, cell division, and chemotaxis. Using mutagenesis data from previous studies, we docked BamB onto a BamA structural model and assessed known and possible interactions between these two proteins. Our data suggest that BamB serves as a scaffolding protein within the BAM complex by optimally orienting the flexible periplasmic domain of BamA for interaction with other BAM components and chaperones. This may facilitate integration of newly synthesized OMPs into the outer membrane. PMID- 21277860 TI - Nutritional resources as positional information for morphogenesis in the stony coral Stylophora pistillata. AB - We are interested in deciphering the mechanisms for morphogenesis in the Red Sea scleractinian coral Stylophora pistillata with the help of mathematical models. Previous mathematical models for coral morphogenesis assume that skeletal growth is proportional to the amount of locally available energetic resources like diffusible nutrients and photosynthetic products. We introduce a new model which includes factors like dissolved nutrients and photosynthates, but these resources do not serve as building blocks for growth but rather provide some kind of positional information for coral morphogenesis. Depending on this positional information side branches are generated, splittings of branches take place and branch growth direction is determined. The model results are supported by quantitative comparisons with experimental data obtained from young coral colonies. PMID- 21277861 TI - NL MIND-BEST: a web server for ligands and proteins discovery--theoretic experimental study of proteins of Giardia lamblia and new compounds active against Plasmodium falciparum. AB - There are many protein ligands and/or drugs described with very different affinity to a large number of target proteins or receptors. In this work, we selected Ligands or Drug-target pairs (DTPs/nDTPs) of drugs with high affinity/non-affinity for different targets. Quantitative Structure-Activity Relationships (QSAR) models become a very useful tool in this context to substantially reduce time and resources consuming experiments. Unfortunately most QSAR models predict activity against only one protein target and/or have not been implemented in the form of public web server freely accessible online to the scientific community. To solve this problem, we developed here a multi-target QSAR (mt-QSAR) classifier using the MARCH-INSIDE technique to calculate structural parameters of drug and target plus one Artificial Neuronal Network (ANN) to seek the model. The best ANN model found is a Multi-Layer Perceptron (MLP) with profile MLP 20:20-15-1:1. This MLP classifies correctly 611 out of 678 DTPs (sensitivity=90.12%) and 3083 out of 3408 nDTPs (specificity=90.46%), corresponding to training accuracy=90.41%. The validation of the model was carried out by means of external predicting series. The model classifies correctly 310 out of 338 DTPs (sensitivity=91.72%) and 1527 out of 1674 nDTP (specificity=91.22%) in validation series, corresponding to total accuracy=91.30% for validation series (predictability). This model favorably compares with other ANN models developed in this work and Machine Learning classifiers published before to address the same problem in different aspects. We implemented the present model at web portal Bio-AIMS in the form of an online server called: Non Linear MARCH-INSIDE Nested Drug-Bank Exploration & Screening Tool (NL MIND-BEST), which is located at URL: http://miaja.tic.udc.es/Bio-AIMS/NL-MIND-BEST.php. This online tool is based on PHP/HTML/Python and MARCH-INSIDE routines. Finally we illustrated two practical uses of this server with two different experiments. In experiment 1, we report by first time Quantum QSAR study, synthesis, characterization, and experimental assay of antiplasmodial and cytotoxic activities of oxoisoaporphine alkaloids derivatives as well as NL MIND-BEST prediction of potential target proteins. In experiment 2, we report sampling, parasite culture, sample preparation, 2-DE, MALDI-TOF, and -TOF/TOF MS, MASCOT search, MM/MD 3D structure modeling, and NL MIND-BEST prediction for different peptides a new protein of the found in the proteome of the human parasite Giardia lamblia, which is promising for anti-parasite drug-targets discovery. PMID- 21277862 TI - Circular codes revisited: a statistical approach. AB - In 1996 Arques and Michel [1996. A complementary circular code in the protein coding genes. J. Theor. Biol. 182, 45-58] discovered the existence of a common circular code in eukaryote and prokaryote genomes. Since then, circular code theory has provoked great interest and underwent a rapid development. In this paper we discuss some theoretical issues related to the synchronization properties of coding sequences and circular codes with particular emphasis on the problem of retrieval and maintenance of the reading frame. Motivated by the theoretical discussion, we adopt a rigorous statistical approach in order to try to answer different questions. First, we investigate the covering capability of the whole class of 216 self-complementary, C(3) maximal codes with respect to a large set of coding sequences. The results indicate that, on average, the code proposed by Arques and Michel has the best covering capability but, still, there exists a great variability among sequences. Second, we focus on such code and explore the role played by the proportion of the bases by means of a hierarchy of permutation tests. The results show the existence of a sort of optimization mechanism such that coding sequences are tailored as to maximize or minimize the coverage of circular codes on specific reading frames. Such optimization clearly relates the function of circular codes with reading frame synchronization. PMID- 21277863 TI - Estrogen metabolites in the release of inflammatory mediators from human amnion derived cells. AB - AIMS: Human amnion-derived cells have been used as in vitro models to test the release of inflammatory mediators, such as arachidonic acid (AA) and prostaglandin E(2) (PGE(2)). We compared estrogen metabolites for their ability to induce AA release, to influence PGE(2) production and to interact toward intracellular estrogen receptors (ERs). MAIN METHODS: Metabolite effects on AA and PGE(2) release were examined by radiolabelled substrate incorporation and by colorimetric enzyme immunoassays, respectively. [(3)H]17-beta-estradiol binding displacements were performed on Ro-20-1724 treated whole cells. KEY FINDINGS: In WISH cells, estrone, 2-hydroxy-estrone and estriol induced a rapid dose dependent release of AA that was not inhibited by cycloheximide. Estrone and 2-hydroxy estrone showed biphasic dose-response curves of PGE(2), whereas estriol and 16 alpha-hydroxy-estrone increased PGE(2) levels at high concentrations. 2-methoxy estrone, 4-hydroxy-estradiol and 4-hydroxy-estrone did not significantly affect PGE(2) release. 2-methoxy-estradiol and 2-hydroxy-estradiol decreased the PGE(2) release. Effects of metabolites on PGE(2) were inhibited by cycloheximide and by the ER antagonist tamoxifen. In AV3 cells PGE(2) production was poorly detectable. On Ro-20-1724 treated WISH cells the K(i) of 17-beta-estradiol was 29.2 +/- 5.4 nM. Estrone, 2-methoxy-estrone and 2-methoxy-estradiol showed similar affinity values. The hydroxyl substituent at position 2, 4 and 16 decreased or markedly increased the affinity for estradiol or estrone derivatives, respectively. SIGNIFICANCE: The estrogen metabolites induced nongenomic effects on AA release from WISH cells. The influence on PGE(2) release was detectable only on WISH cells. These effects appeared genomic and mediated by intracellular ERs, whose properties seemed strongly dependent on intracellular cAMP levels. PMID- 21277864 TI - Endogenous cannabinoid receptor agonist anandamide induces peripheral antinociception by activation of ATP-sensitive K+ channels. AB - AIMS: The effects of several potassium (K(+)) channel blockers were studied to determine which K(+) channels are involved in peripheral antinociception induced by the cannabinoid receptor agonist, anandamide. MAIN METHODS: Hyperalgesia was induced by subcutaneous injection of 250 MUg carrageenan into the plantar surface of the hind paw of rats. The extent of hyperalgesia was measured using a paw pressure test 3 h following carrageenan injection. The weight in grams (g) that elicited a nociceptive response, paw flexion, during the paw pressure test was used as the nociceptive response threshold. KEY FINDINGS: Doses of 50, 75, and 100 ng of anandamide elicited a dose-dependent antinociceptive effect. Following a 100 ng dose of anandamide no antinociception was observed in the paw that was contralateral to the anandamide injection site, which shows that anandamide has a peripheral site of action. Pretreatment with 20, 40 and 80 MUg AM251, a CB(1) receptor antagonist, caused a dose-dependent decrease in anandamide-induced antinociception, suggesting that the CB(1) receptor is directly involved in anandamide effect. Treatment with 40, 80 and 160 MUg glibenclamide, an ATP sensitive K(+) channel blocker, caused a dose-dependent reversal of anandamide induced peripheral antinociception. Treatment with other K(+) channel antagonists, tetraethylammonium (30 MUg), paxilline (10 MUg) and dequalinium (50 MUg), had no effect on the induction of peripheral antinociception by anandamide. SIGNIFICANCE: This study provides evidence that the peripheral antinociceptive effect of the cannabinoid receptor agonist, anandamide, is primarily caused by activation of ATP-sensitive K(+) channels and does not involve other potassium channels. PMID- 21277865 TI - Angiotensin receptor blockade improves the net balance of cardiac Ca(2+) handling related proteins in sympathetic hyperactivity-induced heart failure. AB - AIMS: The clinical benefits of angiotensin II type 1 (AT1) receptor blockers (ARB) in heart failure (HF) include cardiac anti-remodeling and improved ventricular function. However, the cellular mechanisms underlying the benefits of ARB on ventricular function need to be better clarified. In the present manuscript, we evaluated the effects of AT1 receptor blockade on the net balance of Ca(2+) handling proteins in hearts of mice lacking alpha(2A) and alpha(2C) adrenoceptors (alpha(2A)/alpha(2C)ARKO), which develop sympathetic hyperactivity (SH) induced-HF. MAIN METHODS: A cohort of male wild-type (WT) and congenic alpha(2A)/alpha(2C)ARKO mice in a C57BL6/J genetic background (5-7mo of age) was randomly assigned to receive either placebo or ARB (Losartan, 10mg/kg for 8wks). Ventricular function (VF) was assessed by echocardiography, and cardiac myocyte width and ventricular fibrosis by a computer-assisted morphometric system. Sarcoplasmic reticulum Ca(2+) ATPase (SERCA2), phospholamban (PLN), phospho Ser(16)-PLN, phospho-Thr(17)-PLN, phosphatase 1 (PP1), Na(+)-Ca(2+) exchanger (NCX), Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and phospho Thr(286)-CaMKII were analyzed by Western blot. KEY FINDINGS: alpha(2A)/alpha(2C)ARKO mice displayed ventricular dysfunction, cardiomyocyte hypertrophy and cardiac fibrosis paralleled by decreased SERCA2 and increased phospho-Thr(17)-PLN, CaMKII, phospho-Thr(286)-CaMKII and NCX levels. ARB induced anti-cardiac remodeling effect and improved VF in alpha(2A)/alpha(2C)ARKO associated with increased SERCA2 and phospho-Ser(16)-PLN levels, and SERCA2:NCX ratio. Additionally, ARB decreased phospho-Thr(17)-PLN levels as well as reestablished NCX, CaMKII and phospho-Thr(286)-CaMKII toward WT levels. SIGNIFICANCE: Altogether, these data provide new insights on intracellular Ca(2+) regulatory mechanisms underlying improved ventricular function by ARB therapy in HF. PMID- 21277866 TI - Expression of the IgSF protein Kirre in the rat central nervous system. AB - AIMS: Immunoglobulin superfamily (IgSF) proteins play a critical role in development of the nervous system. Here, a new member of IgSF gene family was cloned from rat brain, which was subsequently identified as rat homolog of Drosophila Kirre. This new molecule was named as rat Kirre (rKirre). We aimed to reveal the developmental expression of rKirre, both at mRNA and protein levels, in the central nervous system. The deduced amino acid sequence of rKirre showed a putative PDZ binding motif at the C-terminus, which provided a rationale for analyzing the co-localization of rKirre and post-synaptic density protein 95 (PSD 95) in cultured rat cortical neurons. MAIN METHODS: cDNA library screening was used in the isolation of cDNA. Northern blotting and Western blotting were used to reveal the levels of rKirre expression. In situ hybridization and immuno fluorescent staining were used to determine the localization of rKirre. KEY FINDINGS: The rKirre gene was found to be highly expressed in the cerebrum, hippocampus, cerebellum, brain stem and spinal cord of adult rats. In parallel, the protein level of rKirre was also increased in a developing cerebral cortex. In cultured rat cortical neurons, the amount of rKirre was significantly increased during neuronal differentiation. Immuno-cytofluorescent staining indicated that rKirre was present along the neurites of cortical neurons, and was co-localized with PSD-95. SIGNIFICANCE: These results suggested that rKirre might play an essential role in neuronal differentiation and development in the central nervous system. PMID- 21277867 TI - Dietary aloin, aloesin, or aloe-gel exerts anti-inflammatory activity in a rat colitis model. AB - AIMS: Aloe has been a very popular folk remedy for inflammation-related pathological conditions despite the lack of studies reporting its efficacy in vivo. The present study evaluated the anti-inflammatory effects of aloe components (aloin, aloesin and aloe-gel) known to be biologically active in the rat model of colitis. MAIN METHODS: Male Sprague Dawley rats were fed experimental diets for 2 weeks before and during the induction of colitis. Drinking water containing 3% dextran sulfate sodium (DSS) was provided for 1 week to induce colitis. At the end of the experimental period, clinical and biochemical markers were compared. KEY FINDINGS: Plasma leukotriene B(4) (LTB(4)) and tumor necrosis factor-alpha (TNF-alpha) concentrations were significantly decreased in all groups supplemented with aloe components compared to the colitis control group (p<0.05). Animals fed both a 0.1% and 0.5% aloesin supplemented diet showed colonic myeloperoxidase (MPO) activities which were decreased by 32.2% and 40.1%, respectively (p<0.05). Colonic mucosa TNF-alpha and interleukin 1beta (IL-1beta) mRNA expressions were significantly reduced in all animals fed aloin, aloesin, or aloe-gel (p<0.05). SIGNIFICANCE: Dietary supplementation of aloe components ameliorates intestinal inflammatory responses in a DSS-induced ulcerative colitis rat model. In particular, aloesin was the most potent inhibitor. Further studies are required for a more complete understanding of the specific mechanism of the action of these supplements. PMID- 21277868 TI - Functional and molecular effects of imidazoline receptor activation in heart failure. AB - AIMS: Heart failure is a progressive deterioration in heart function associated with overactivity of the sympathetic nervous system. The benefit of inhibition of sympathetic activity by moxonidine, a centrally acting imidazoline receptor agonist, was questioned based on the outcome of a failing clinical trial. The following studies measured cardiac structure and hemodynamics and mechanisms underlying moxonidine-induced changes, in cardiomyopathic hamsters, where the stage of the disease, dose, and compliance were controlled. MAIN METHODS: Male BIO 14.6 hamsters (6 and 10 months old, with moderate and advanced heart failure, respectively) received moxonidine at 2 concentrations: low (2.4 mg/kg/day) and high (9.6 mg/kg/day), or vehicle, subcutaneously, for 1month. Cardiac function was measured by echocardiography, plasma and hearts were collected for histological determination of fibrosis and apoptosis, as well as for measurement cytokines by Elisa and cardiac proteins by Western blotting. KEY FINDINGS: Compared to age-matched vehicle-treated BIO 14.6, moxonidine did not reduce blood pressure but significantly reduced heart rate and improved cardiac performance. Moxonidine exerted anti-apoptotic effect with differential inflammatory/anti inflammatory responses that culminate in attenuated cardiac apoptosis and fibrosis and altered protein expression of collagen types. Some effects were observed regardless of treatment onset, although the changes were more significant in the younger group. Interestingly, moxonidine resulted in upregulation of cardiac imidazoline receptors. SIGNIFICANCE: These studies imply that in addition to centrally mediated sympathetic inhibition, the effects of moxonidine may, at least in part, be mediated by direct actions on the heart. Further investigation of imidazolines/imidazoline receptors in cardiovascular diseases is warranted. PMID- 21277869 TI - Enhanced insulin secretion and sensitization in diabetic mice on chronic treatment with a transient receptor potential vanilloid 1 antagonist. AB - AIMS: Inhibition of transient receptor potential vanilloid 1 (TRPV1) suppresses calcitonin gene-related peptide (CGRP) secretion in pancreatic nerve fiber cells, thereby stimulating insulin secretion. We examined the effects of repeat administration of the TRPV1 antagonist N-(4-tert-butylphenyl)-4-(3-chloropyridin 2-yl)tetrahydropyrazine-1(2H)-carboxamidte monohydrochloride (BCTC) to ob/ob mice, a model of type 2 diabetes with insulin resistance, on whole body glucose and lipid metabolism. MAIN METHODS: We measured blood parameters, including levels of glucose, insulin, and triglycerides, and performed the oral glucose tolerance test (OGTT) after repeat administration of BCTC to ob/ob mice twice a day for four weeks. KEY FINDINGS: We found that BCTC treatment reduced fasting glucose, triglyceride, and insulin levels in the whole body. The effects were comparable to that of pioglitazone, a major insulin-sensitizing agent. Further, we found that administration of BCTC significantly increased plasma insulin secretion in the OGTT, which differed from the effect of pioglitazone treatment. SIGNIFICANCE: Our study is the first to show the anti-diabetic pharmacological effects of the TRPV1 signal inhibitor BCTC. These findings suggest that TRPV1 antagonists may represent a new class of drugs effective in treating type 2 diabetes mellitus because of their dual effects as insulin sensitizers and secretagogues. PMID- 21277870 TI - In vivo gene delivery of XIAP protects against myocardial apoptosis and infarction following ischemia/reperfusion in conscious rabbits. AB - AIMS: We tested the hypothesis that an in vivo gene delivery of the pro-survival protein XIAP (X-chromosome linked inhibitor of apoptosis protein) protects against myocardial apoptosis and infarction following ischemia/reperfusion. MAIN METHODS: Nineteen rabbits were chronically instrumented with a hydraulic occluder placed around the circumflex coronary artery. Adenovirus harboring XIAP (Ad.XIAP; 1*10(10)pfu/ml) or beta-galactosidase (5*10(9)pfu/ml), as a control, was constructed and transfected into the heart using a catheter placed into the left ventricle accompanied by cross-clamping. 1-2weeks after gene delivery, myocardial ischemia was induced by a 30-min occlusion followed by reperfusion for four days. Protein expression was determined by Western blot and apoptosis (% of myocytes) was quantified by TUNEL staining. KEY FINDINGS: Myocardial infarct size, expressed as a fraction of the area at risk, was reduced in Ad.XIAP (n=5) compared to control (n=7) rabbits (21+/-3% vs. 30+/-2%, p<0.05). Apoptosis was reduced in Ad.XIAP rabbits compared to control rabbits (2.96+/-0.68% vs. 8.98+/ 1.84%, p<0.01). This was associated with an approximate 60% decrease in the cleaved caspase-3 level in Ad.XIAP rabbits compared to control rabbits. SIGNIFICANCE: The current findings demonstrate that overexpression of XIAP via in vivo delivery in an adenovirus can reduce both myocardial apoptosis and infarction following ischemia/reperfusion, at least in part, due to the ability of XIAP to inhibit caspase-3. These findings confirm previous work suggesting a link between myocardial apoptosis and infarction i.e., anti-apoptotic therapy was effective in reducing myocardial infarct size. PMID- 21277871 TI - Tumor cells induce COX-2 and mPGES-1 expression in microvascular endothelial cells mainly by means of IL-1 receptor activation. AB - Prostaglandin (PG) E(2) plays a key role in immune response, tumor progression and metastasis. We previously showed that macrovessel-derived endothelial cells do not produce PGE(2) enzymatically because they do not express the inducible microsomal PGE-synthase-1 (mPGES-1). Nevertheless, differences between macro- and micro-vessel-derived endothelial cells regarding arachidonic acid (AAc) metabolism profile have been reported. The present work was conducted to evaluate the expression of PGE(2)-pathway-related enzymes in human microvascular endothelial cells (HMVEC) in culture and to test the hypothesis that the tumor cell-HMVEC cross talk could increase mPGES-1 expression in HMVEC. We treated HMVEC in culture with human recombinant IL-1beta. IL-1beta induced PGE(2) release and COX-2 and mPGES-1 expression in terms of mRNA and protein, determined by real time PCR and immunoblotting, respectively. HMVEC constitutively expressed mPGES-2 and cytosolic PGES (cPGES) and the IL-1beta treatment did not modify their expression. PGE(2) synthesized by HMVEC from exogenous AAc was linked to mPGES-1 expression. Immunohistochemistry analysis confirmed mPGES-1 expression in microvessels in vivo. COX-2 and mPGES-1 were also induced in HMVEC by the conditioned medium from two squamous head and neck carcinoma cell lines. Conditioned medium from tumor cell cultures contained several cytokines including the IL-1beta and IL-1alpha. Tumor cell-induced COX-2 and mPGES-1 in HMVEC was strongly inhibited by the IL-1-receptor antagonist, indicating the important implication of IL-1 in this effect. HMVEC could therefore contribute directly to PGE(2) formed in the tumor. Our findings support the concept that mPGES-1 could be a target for therapeutic intervention in patients with cancer. PMID- 21277872 TI - XRCC1 and ERCC1 variants modify malignant mesothelioma risk: a case-control study. AB - Malignant pleural mesothelioma (MPM) is a rare aggressive tumor associated with asbestos exposure. The possible role of genetic factors has also been suggested and MPM has been associated with single nucleotide polymorphisms (SNPs) of xenobiotic and oxidative metabolism enzymes. We have identified an association of the DNA repair gene XRCC1 with MPM in the population of Casale Monferrato, a town exposed to high asbestos pollution. To extend this observation we examined 35 SNPs in 15 genes that could be involved in MPM carcinogenicity in 220 MPM patients and 296 controls from two case-control studies conducted in Casale (151 patients, 252 controls) and Turin (69 patients, 44 controls), respectively. Unconditional multivariate logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). Two DNA repair genes were associated with MPM, i.e. XRCC1 and ERCC1. Considering asbestos-exposed only, the risk increased with the increasing number of XRCC1-399Q alleles (Casale: OR=1.44, 95%CI 1.02-2.03; Casale+Turin: OR=1.34, 95%CI 0.98-1.84) or XRCC1 -77T alleles (Casale+Turin: OR=1.33, 95%CI 0.97-1.81). The XRCC1-TGGGGGAACAGA haplotype was significantly associated with MPM (Casale: OR=1.76, 95%CI 1.04-2.96). Patients heterozygotes for ERCC1 N118N showed an increased OR in all subjects (OR=1.66, 95%CI 1.06-2.60) and in asbestos-exposed only (OR=1.59, 95%CI 1.01-2.50). When the dominant model was considered (i.e. ERCC1 heterozygotes CT plus homozygotes CC versus homozygotes TT) the risk was statistically significant both in all subjects (OR=1.61, 95%CI 1.06-2.47) and in asbestos-exposed only (OR=1.56, 95%CI 1.02-2.40). The combination of ERCC1 N118N and XRCC1 R399Q was statistically significant (Casale: OR=2.02, 95%CI 1.01-4.05; Casale+Turin: OR=2.39, 95%CI 1.29 4.43). The association of MPM with DNA repair genes support the hypothesis that an increased susceptibility to DNA damage may favour asbestos carcinogenicity. PMID- 21277873 TI - Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer's-like changes. AB - Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide. Pharmacological treatments presently available can slow down the progression of symptoms but can not cure the disease. Currently there is widening recognition that AD is closely associated with impaired insulin signaling and glucose metabolism in brain, suggesting it to be a brain-specific form of diabetes and so also termed as "type 3 diabetes". Hence investigating the role of pharmacological agents that could ameliorate neuronal insulin resistance merit attention in AD therapeutics, however the therapeutics for pathophysiological condition like neuronal insulin resistance itself is largely unknown. In the present study we have determined the effect of metformin on neuronal insulin resistance and AD associated characteristics in an in vitro model of "type 3 diabetes" by differentiating neuronal cell line Neuro-2a under prolonged presence of insulin. We observed that prolonged hyperinsulinemic conditions in addition to generating insulin resistance also led to development of hallmark AD-associated neuropathological changes. Treatment with metformin sensitized the impaired insulin actions and also prevented appearance of molecular and pathological characteristics observed in AD. The results thus demonstrate possible therapeutic efficacy of peripheral insulin-sensitizer drug metformin in AD by its ability to sensitize neuronal insulin resistance. These findings also provide direct evidences linking hyperinsulinemia and AD and suggest a unique opportunity for prevention and treatment of "type 3 diabetes". PMID- 21277874 TI - The viral theory of schizophrenia revisited: abnormal placental gene expression and structural changes with lack of evidence for H1N1 viral presence in placentae of infected mice or brains of exposed offspring. AB - Researchers have long noted an excess of patients with schizophrenia were born during the months of January and March. This winter birth effect has been hypothesized to result either from various causes such as vitamin D deficiency (McGrath, 1999; McGrath et al., 2010), or from maternal infection during pregnancy. Infection with a number of viruses during pregnancy including influenza, and rubella are known to increase the risk of schizophrenia in the offspring (Brown, 2006). Animal models using influenza virus or Poly I:C, a viral mimic, have been able to replicate many of the brain morphological, genetic, and behavioral deficits of schizophrenia (Meyer et al., 2006, 2008a, 2009; Bitanihirwe et al., 2010; Meyer and Feldon, 2010; Short et al., 2010). Using a murine model of prenatal viral infection, our laboratory has shown that viral infection on embryonic days 9, 16, and 18 leads to abnormal expression of brain genes and brain structural abnormalities in the exposed offspring (Fatemi et al., 2005, 2008a,b, 2009a,b). The purpose of the current study was to examine gene expression and morphological changes in the placenta, hippocampus, and prefrontal cortex as a result of viral infection on embryonic day 7 of pregnancy. Pregnant mice were either infected with influenza virus [A/WSN/33 strain (H1N1)] or sham infected with vehicle solution. At E16, placentas were harvested and prepared for either microarray analysis or for light microscopy. We observed significant, upregulation of 77 genes and significant downregulation of 93 genes in placentas. In brains of exposed offspring following E7 infection, there were changes in gene expression in prefrontal cortex (6 upregulated and 24 downregulated at P0; 5 upregulated and 14 downregulated at P56) and hippocampus (4 upregulated and 6 downregulated at P0; 6 upregulated and 13 downregulated at P56). QRT-PCR verified the direction and magnitude of change for a number of genes associated with hypoxia, inflammation, schizophrenia, and autism. Placentas from infected mice showed a number of morphological abnormalities including presence of thrombi and increased presence of immune cells. Additionally, we searched for presence of H1N1 viral-specific genes for M1/M2, NA, and NS1 in placentas of infected mice and brains of exposed offspring and found none. Our results demonstrate that prenatal viral infection disrupts structure and gene expression of the placenta, hippocampus, and prefrontal cortex potentially explaining deleterious effects in the exposed offspring without evidence for presence of viral RNAs in the target tissues. PMID- 21277875 TI - Implication of 5-HT(2B) receptors in the serotonin syndrome. AB - The serotonin (5-HT) syndrome occurs in humans after antidepressant overdose or combination of drugs inducing a massive increase in extracellular 5-HT. Several 5 HT receptors are known to participate in this syndrome in humans and animal models. The 5-HT(2B) receptor has been proposed as a positive modulator of serotonergic activity, but whether it is involved in 5-HT syndrome has not yet been studied. We analyzed here, a putative role of 5-HT(2B) receptors in this disorder by forced swimming test (FST) and behavioral assessment in the open field. In FST, genetic (5-HT(2B)(-/-) mice) or pharmacological (antagonist RS127445 at 0.5 mg/kg) ablation of 5-HT(2B) receptors facilitated selective 5-HT reuptake inhibitors (SSRI)-induced increase of immobility time as well as expression of other symptoms related to 5-HT syndrome like hind limb abduction and Straub tail. Increase in immobility was also developed in FST by both wild type (WT) and 5-HT(2B)(-/-) mice after the administration of 5-HT(1A), 5-HT(2A) or 5-HT(2C) receptor agonists, 8-OH-DPAT (5 mg/kg), DOI (1 mg/kg), or WAY161503 (5 mg/kg), respectively. In contrast, the 5-HT(2B) receptor agonist BW723C86 (3 mg/kg) or 5-HT(1B) receptor agonist CGS12066A (2 mg/kg) decreased immobility time in both genotypes. The 5-HT syndrome induced by fluoxetine at high doses was blocked in WT and 5-HT(2B)(-/-) mice by administration of 5-HT(1A) and 5-HT(2C) receptor antagonists (WAY100635 0.5 mg/kg and SB242084 0.5 mg/kg) but not by the 5-HT(2A) receptor antagonist MDL100907 (1 mg/kg). By behavioral assessment, we confirmed that 5-HT(2B)(-/-) mice were more prone to develop 5-HT syndrome symptoms after administration of high dose of SSRIs or the 5-HT precursor 5 Hydroxytryptophan, 5-HTP, even if increases in 5-HT plasma levels were similar in both genotypes. This evidence suggests that the presence of 5-HT(2B) receptors hinders acute 5-HT toxicity once high levels of 5-HT are attained. Therefore, differential agonism/antagonism of 5-HT receptors should be considered in the search of therapeutic targets for treating this serious disorder. PMID- 21277877 TI - Protective role for type-1 metabotropic glutamate receptors against spike and wave discharges in the WAG/Rij rat model of absence epilepsy. AB - Eight-month old WAG/Rij rats, which developed spontaneous occurring absence seizures, showed a reduced function of mGlu1 metabotropic glutamate receptors in the thalamus, as assessed by in vivo measurements of DHPG-stimulated polyphosphoinositide hydrolysis, in the presence of the mGlu5 antagonist MPEP as compared to age-matched non-epileptic control rats. These symptomatic 8-month old WAG/Rij rats also showed lower levels of thalamic mGlu1alpha receptors than age matched controls and 2-month old (pre-symptomatic) WAG/Rij rats, as detected by immunoblotting. Immunohistochemical and in situ hybridization analysis indicated that the reduced expression of mGlu1 receptors found in symptomatic WAG/Rij rats was confined to an area of the thalamus that excluded the ventroposterolateral nucleus. No mGlu1 receptor mRNA was detected in the reticular thalamic nucleus. Pharmacological manipulation of mGlu1 receptors had a strong impact on absence seizures in WAG/Rij rats. Systemic treatment with the mGlu1 receptor enhancer SYN119, corresponding to compound RO0711401, reduced spontaneous spike and wave discharges spike-wave discharges (SWDs) in epileptic rats. Subcutaneous doses of 10 mg/kg of SYN119 only reduced the incidence of SWDs, whereas higher doses (30 mg/kg) also reduced the mean duration of SWDs. In contrast, treatment with the non-competitive mGlu1 receptor antagonist, JNJ16259685 (2.5 and 5 mg/kg, i.p.) increased the incidence of SWDs. These data suggest that absence epilepsy might be associated with a reduction of mGlu1 receptors in the thalamus, and that compounds that amplify the activity of mGlu1 receptors might be developed as novel anti-absence drugs. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'. PMID- 21277878 TI - GABAergic disinhibition induced pain hypersensitivity by upregulating NMDA receptor functions in spinal dorsal horn. AB - Intense noxious stimuli impair GABAergic inhibition in spinal dorsal horn, which has been proposed as a critical contributor to pathological pain. However, how the reduced inhibition exacerbates the transfer of nociceptive information at excitatory glutamatergic synapses is still poorly understood. The present study demonstrated that one of the striking consequences of GABAergic disinhibition was to enhance the function of N-methyl-D-aspartate subtype glutamate receptors (NMDARs), a well-characterized player in central sensitization. We found that intrathecal application of bicuculline, a GABA(A) receptor antagonist, to remove the inhibition readily elicited mechanical allodynia in naive mice, which could be dose-dependently attenuated by NMDARs antagonist D-APV. Biochemical analysis demonstrated that bicuculline did not affect the total expression levels of the obligatory NMDARs subunit NR1 and the regulatory subunit NR2A and NR2B. However, bicuculline promoted NR1 phosphorylation at Serine 897 (NR1-S897) by cAMP dependent protein kinase (PKA). This PKA-mediated phosphorylation incorporated NR1 along with NR2B into synapses. When PKA inhibitor H-89 was intrathecally applied, it totally eliminated bicuculline-induced NMDARs phosphorylation, synaptic redistribution as well as pain sensitization. Importantly, the reduced inhibition also operated to enhance NMDARs functions after peripheral inflammation, because spinal injection of diazepam to rescue the inhibition in inflamed mice greatly depressed PKA phosphorylation of NR1-S897, reduced the synaptic concentration of NR1/NR2B and meanwhile, alleviated the inflammatory pain. These data suggested that removal of GABAergic inhibition allowed for PKA mediated NMDARs phosphorylation and synaptic accumulation, thus exaggerating NMDARs-dependent nociceptive transmission and behavioral sensitization. PMID- 21277876 TI - GABAergic interneuron origin of schizophrenia pathophysiology. AB - Hypofunction of N-methyl-d-aspartic acid-type glutamate receptors (NMDAR) induced by the systemic administration of NMDAR antagonists is well known to cause schizophrenia-like symptoms in otherwise healthy subjects. However, the brain areas or cell-types responsible for the emergence of these symptoms following NMDAR hypofunction remain largely unknown. One possibility, the so-called "GABAergic origin hypothesis," is that NMDAR hypofunction at GABAergic interneurons, in particular, is sufficient for schizophrenia-like effects. In one attempt to address this issue, transgenic mice were generated in which NMDARs were selectively deleted from cortical and hippocampal GABAergic interneurons, a majority of which were parvalbumin (PV)-positive. This manipulation triggered a constellation of phenotypes--from molecular and physiological to behavioral- resembling characteristics of human schizophrenia. Based on these results, and in conjunction with previous literature, we argue that during development, NMDAR hypofunction at cortical, PV-positive, fast-spiking interneurons produces schizophrenia-like effects. This review summarizes the data demonstrating that in schizophrenia, GABAergic (particularly PV-positive) interneurons are disrupted. PV-positive interneurons, many of which display a fast-spiking firing pattern, are critical not only for tight temporal control of cortical inhibition but also for the generation of synchronous membrane-potential gamma-band oscillations. We therefore suggest that in schizophrenia the specific ability of fast-spiking interneurons to control and synchronize disparate cortical circuits is disrupted and that this disruption may underlie many of the schizophrenia symptoms. We further argue that the high vulnerability of corticolimbic fast-spiking interneurons to genetic predispositions and to early environmental insults- including excitotoxicity and oxidative stress--might help to explain their significant contribution to the development of schizophrenia. PMID- 21277879 TI - Phonological learning in semantic dementia. AB - Patients with semantic dementia (SD) have anterior temporal lobe (ATL) atrophy that gives rise to a highly selective deterioration of semantic knowledge. Despite pronounced anomia and poor comprehension of words and pictures, SD patients have well-formed, fluent speech and normal digit span. Given the intimate connection between phonological STM and word learning revealed by both neuropsychological and developmental studies, SD patients might be expected to show good acquisition of new phonological forms, even though their ability to map these onto meanings is impaired. In contradiction of these predictions, a limited amount of previous research has found poor learning of new phonological forms in SD. In a series of experiments, we examined whether SD patient, GE, could learn novel phonological sequences and, if so, under which circumstances. GE showed normal benefits of phonological knowledge in STM (i.e., normal phonotactic frequency and phonological similarity effects) but reduced support from semantic memory (i.e., poor immediate serial recall for semantically degraded words, characterised by frequent item errors). Next, we demonstrated normal learning of serial order information for repeated lists of single-digit number words using the Hebb paradigm: these items were well-understood allowing them to be repeated without frequent item errors. In contrast, patient GE showed little learning of nonsense syllable sequences using the same Hebb paradigm. Detailed analysis revealed that both GE and the controls showed a tendency to learn their own errors as opposed to the target items. Finally, we showed normal learning of phonological sequences for GE when he was prevented from repeating his errors. These findings confirm that the ATL atrophy in SD disrupts phonological processing for semantically degraded words but leaves the phonological architecture intact. Consequently, when item errors are minimised, phonological STM can support the acquisition of new phoneme sequences in patients with SD. PMID- 21277880 TI - The focus of attention as observed in visual working memory tasks: making sense of competing claims. AB - Recent behavioral and neuroscientific evidence speaks to the question of whether the human focus of attention is limited to a single item or can accommodate several items. This issue is fundamental to an understanding of the nature of human cognition and brain function. Here I review evidence from visual working memory tasks and suggest that it supports the concept of a focus of attention that can include several items at once as a core vehicle of working memory, regardless of the stimulus modality. One brain area in particular, the left intraparietal sulcus (IPS), seems critically important in the network underlying the focus of attention as a working memory storage mechanism. This view is reconciled with evidence previously taken to indicate that the focus of attention only includes a single item at a time, which is reinterpreted here. PMID- 21277881 TI - Effect of ghrelin receptor antagonist on meal patterns in cholecystokinin type 1 receptor null mice. AB - Vagal afferent neurons (VAN) express the cholecystokinin (CCK) type 1 receptor (CCK1R) and, as predicted by the role of CCK in inducing satiation, CCK1R-/- mice ingest larger and longer meals. However, after a short fast, CCK1R-/- mice ingesting high fat (HF) diets initiate feeding earlier than wild-type mice. We hypothesized that the increased drive to eat in CCK1R-/- mice eating HF diet is mediated by ghrelin, a gut peptide that stimulates food intake. The decrease in time to first meal, and the increase in meal size and duration in CCK1R-/- compared to wild-type mice ingesting high fat (HF) diet were reversed by administration of GHSR1a antagonist D-(Lys3)-GHRP-6 (p<0.05). Administration of the GHSR1a antagonist significantly increased expression of the neuropeptide cocaine and amphetamine-regulated transcript (CART) in VAN of HF-fed CCK1R-/- but not wild-type mice. Administration of the GHSR1a antagonist decreased neuronal activity measured by immunoreactivity for fos protein in the nucleus of the solitary tract (NTS) and the arcuate nucleus of both HF-fed wild-type and CCK1R-/ mice. The data show that hyperphagia in CCK1R-/- mice ingesting HF diet is reversed by blockade of the ghrelin receptor, suggesting that in the absence of the CCK1R, there is an increased ghrelin-dependent drive to feed. The site of action of ghrelin receptors is unclear, but may involve an increase in expression of CART peptide in VAN in HF-fed CCK1R-/- mice. PMID- 21277882 TI - A convenient synthesis of the side chain of loteprednol etabonate--an ocular soft corticosteroid from 20-oxopregnanes using metal-mediated halogenation as a key reaction. AB - A facile synthesis of the side chain of loteprednol etabonate, namely, chloromethyl-17alpha-[(ethoxycarbonyl))oxy]-11beta-hydro of loteprednol etabonate, viz., chloromethyl-17alpha-[(ethoxycarbonyl))oxy]-11xy-3-oxoandrosta 1,4-diene-17beta-carboxylate--an ocular soft corticosteroid, has been described starting from a 20-oxopregnane, namely, 3beta-acetoxy-pregn-5(6),16(17)-diene-20 one (16-dehydropregnenolone acetate, i.e., 16-DPA) using our recently developed metal-mediated halogenation as a key reaction. PMID- 21277883 TI - Inference on the strength of balancing selection for epistatically interacting loci. AB - Existing inference methods for estimating the strength of balancing selection in multi-locus genotypes rely on the assumption that there are no epistatic interactions between loci. Complex systems in which balancing selection is prevalent, such as sets of human immune system genes, are known to contain components that interact epistatically. Therefore, current methods may not produce reliable inference on the strength of selection at these loci. In this paper, we address this problem by presenting statistical methods that can account for epistatic interactions in making inference about balancing selection. A theoretical result due to Fearnhead (2006) is used to build a multi-locus Wright Fisher model of balancing selection, allowing for epistatic interactions among loci. Antagonistic and synergistic types of interactions are examined. The joint posterior distribution of the selection and mutation parameters is sampled by Markov chain Monte Carlo methods, and the plausibility of models is assessed via Bayes factors. As a component of the inference process, an algorithm to generate multi-locus allele frequencies under balancing selection models with epistasis is also presented. Recent evidence on interactions among a set of human immune system genes is introduced as a motivating biological system for the epistatic model, and data on these genes are used to demonstrate the methods. PMID- 21277884 TI - Prenatal PCBs disrupt early neuroendocrine development of the rat hypothalamus. AB - Neonatal exposure to endocrine disrupting chemicals (EDCs) such as polychlorinated biphenyls (PCBs) can interfere with hormone-sensitive developmental processes, including brain sexual differentiation. We hypothesized that disruption of these processes by gestational PCB exposure would be detectable as early as the day after birth (postnatal day (P) 1) through alterations in hypothalamic gene and protein expression. Pregnant Sprague-Dawley rats were injected twice, once each on gestational days 16 and 18, with one of the following: DMSO vehicle; the industrial PCB mixture Aroclor 1221 (A1221); a reconstituted mixture of the three most prevalent congeners found in humans, PCB138, PCB153, and PCB180; or estradiol benzoate (EB). On P1, litter composition, anogenital distance (AGD), and body weight were assessed. Pups were euthanized for immunohistochemistry of estrogen receptor alpha (ERalpha) or TUNEL labeling of apoptotic cells or quantitative PCR of 48 selected genes in the preoptic area (POA). We found that treatment with EB or A1221 had a sex-specific effect on developmental apoptosis in the neonatal anteroventral periventricular nucleus (AVPV), a sexually dimorphic hypothalamic region involved in the regulation of reproductive neuroendocrine function. In this region, exposed females had increased numbers of apoptotic nuclei, whereas there was no effect of treatment in males. For ERalpha, EB treatment increased immunoreactive cell numbers and density in the medial preoptic nucleus (MPN) of both males and females, while A1221 and the PCB mixture had no effect. PCR analysis of gene expression in the POA identified nine genes that were significantly altered by prenatal EDC exposure, in a manner that varied by sex and treatment. These genes included brain-derived neurotrophic factor, GABA(B) receptors-1 and -2, IGF-1, kisspeptin receptor, NMDA receptor subunits NR2b and NR2c, prodynorphin, and TGFalpha. Collectively, these results suggest that the disrupted sexual differentiation of the POA by prenatal EDC exposures is already evident as early as the day after birth, effects that may change the trajectory of postnatal development and compromise adult reproductive function. PMID- 21277885 TI - Secretory phospholipase A2-mediated progression of hepatotoxicity initiated by acetaminophen is exacerbated in the absence of hepatic COX-2. AB - We have previously reported that among the other death proteins, hepatic secretory phospholipase A2 (sPLA2) is a leading mediator of progression of liver injury initiated by CCl4 in rats. The aim of our present study was to test the hypothesis that increased hepatic sPLA2 released after acetaminophen (APAP) challenge mediates progression of liver injury in wild type (WT) and COX-2 knockout (KO) mice. COX-2 WT and KO mice were administered a normally non lethal dose (400 mg/kg) of acetaminophen. The COX-2 KO mice suffered 60% mortality compared to 100% survival of the WT mice, suggesting higher susceptibility of COX 2 KO mice to sPLA2-mediated progression of acetaminophen hepatotoxicity. Liver injury was significantly higher at later time points in the KO mice compared to the WT mice indicating that the abatement of progression of injury requires the presence of COX-2. This difference in hepatotoxicity was not due to increased bioactivation of acetaminophen as indicated by unchanged cyp2E1 protein and covalently bound 14C-APAP in the livers of KO mice. Hepatic sPLA2 activity and plasma TNF-alpha were significantly higher after APAP administration in the KO mice. This was accompanied by a corresponding fall in hepatic PGE2 and lower compensatory liver regeneration and repair (3H-thymidine incorporation) in the KO mice. These results suggest that hindered compensatory tissue repair and poor resolution of inflammation for want of beneficial prostaglandins render the liver very vulnerable to sPLA2-mediated progression of liver injury. These findings are consistent with the destructive role of sPLA2 in the progression and expansion of tissue injury as a result of continued hydrolytic breakdown of plasma membrane phospholipids of perinecrotic hepatocytes unless mitigated by sufficient co induction of COX-2. PMID- 21277886 TI - Haemostatically active proteins in snake venoms. AB - Snake venom proteins that affect the haemostatic system can cause (a) lowering of blood coagulability, (b) damage to blood vessels, resulting in bleeding, (c) secondary effects of bleeding, e.g. hypovolaemic shock and organ damage, and (d) thrombosis. These proteins may, or may not, be enzymes. We review the data on the most relevant haemostatically active proteinases, phospholipases A2, L-amino acid oxidases and 5'-nucleotidases from snake venoms. We also survey the non-enzymatic effectors of haemostasis from snake venoms--disintegrins, C-type lectins and three-finger toxins. Medical applications have already been found for some of these snake venom proteins. We describe those that have already been approved as drugs to treat haemostatic disorders or are being used to diagnose such health problems. No clinical applications, however, currently exist for the majority of snake venom proteins acting on haemostasis. We conclude with the most promising potential uses in this respect. PMID- 21277887 TI - Adolescent mice are more vulnerable than adults to single injection-induced behavioral sensitization to amphetamine. AB - Drug-induced behavioral sensitization in rodents has enhanced our understanding of why drugs acquire increasing motivational and incentive value. Compared to adults, human adolescents have accelerated dependence courses with shorter times from first exposure to dependence. We compared adolescent and adult mice in their ability to develop behavioral sensitization to amphetamine following a single injection. Adult (90-day-old) and adolescent (45-day-old) male Swiss mice received an acute intraperitoneal injection of saline or amphetamine (1.0, 2.0 or 4.0 mg/kg). Seven days later, half of the mice from the saline group received a second injection of saline. The remaining animals were challenged with 2.0 mg/kg amphetamine. Following all of the injections, mice were placed in activity chambers and locomotion was quantified for 45 min. The magnitude of both the acute and sensitized locomotor stimulatory effect of amphetamine was higher in the adolescent mice. Previous experience with the test environment inhibited the acute amphetamine stimulation in both adolescent and adult mice, but facilitated the detection of elevated spontaneous locomotion in adolescent animals. These results support the notion that the adolescent period is associated with an increased risk for development of drug abuse. Additionally, they indicate a complex interaction between the environmental novelty, adolescence and amphetamine. PMID- 21277888 TI - Chronic inflammatory pain does not attenuate the development of tolerance to chronic morphine in adult male rats. AB - The overall impact of chronic pain on the response to opioids is ambiguous in the literature, and comparisons between human and animal studies are complicated by vast differences between the manner and dosage of opioids given to humans treated for pain in comparison to rodents as well as a lack of healthy participant studies examining the impact of chronic opioids. The purpose of this study was to evaluate the impact of chronic pain on the development of tolerance to morphine and to assess how the concentration of drug affects this process. Twenty-four hours after the injection of CFA or normal saline in the left hind paw, the level of mechanical hypersensitivity was assessed and animals were randomly assigned to a morphine dose (1, 3 or 8 mg/kg or saline). Morphine was administered by subcutaneous injection twice a day for 5 days. On Day 6, animals were challenged with a single dose of 3 mg/kg morphine prior to formalin testing. Evidence of tolerance was mixed, and the results varied widely among the conditions. Analysis of mean paw withdrawal thresholds indicated that the analgesic efficacy of subcutaneous morphine diminished following repeated dosing. The presence of the chronic inflammatory pain condition during the morphine dosing period produced an increase in formalin pain behaviors compared to saline controls, such that animals given any dose of morphine during the 5-day dosing period showed higher responding to formalin following the 3 mg/kg dose than animals that had received saline injections. These results indicate that chronic pain does influence the development of opioid tolerance, but it does not prevent this phenomenon from occurring as suggested by some researchers. PMID- 21277889 TI - Overweight as predictor of long-term mortality among healthy, middle-aged men: a prospective cohort study. AB - OBJECTIVES: Large epidemiological studies of non-smokers have demonstrated an association between overweight during midlife and increased mortality. However, little is known about whether this association may be explained by physical fitness. Thus, we aimed to examine this association in a long-term follow-up, with adjustment for fitness. METHODS: We prospectively studied mortality in relation to overweight in 2014 healthy Norwegian men 40-59 years of age at enrollment in 1972-1975, and recorded cardiovascular and non-cardiovascular mortality during 25-27 years follow-up. Physical fitness was measured in a maximal exercise tolerance bicycle test. RESULTS: At baseline 717 men had overweight (body mass index 25.0-29.9) and 1221 had normal weight (body mass index<25.0). During follow-up 746 men died, 377 from cardiovascular causes. Among non-smokers with overweight/normal weight, cardiovascular death rates were 19.4%/11.3%, and non-cardiovascular death rates were 13.2%/14.4%. Overweight was related to cardiovascular mortality, even after adjustment for age, physical fitness, blood pressure and cholesterol level (RR: 1.52, p=0.010), but not to non cardiovascular mortality (RR: 0.84, p=0.32). Among smokers overweight was not associated with cardiovascular or non-cardiovascular mortality. The difference in cardiovascular mortality between non-smokers with overweight and normal weight first appeared after 15 years of follow-up. CONCLUSION: Overweight appears to be an independent long-term predictor of cardiovascular mortality in middle-aged healthy non-smoking men, even after adjustment for physical fitness. PMID- 21277890 TI - Parental attitudes and varicella vaccine in Kocaeli, Turkey. AB - OBJECTIVE: To explore what factors influence Turkish parents' decision whether to have their children immunised or not and compare them with other internationally published studies. METHOD: Data from 300 parents were gathered via a survey completed by the parents during their policlinic visit between January 2009 and March 2010 in Kocaeli, Turkey. The survey content was based on 10 Health Belief Model, each question being based on a 5-point Likert scale together with additional 19 questions in order to discover other demographic factors. RESULTS: One of the differences in our study when compared to other published studies is mothers' jobs as employed mothers were significantly willing to have their children vaccinated whereas studies elsewhere have generally shown that demographic background variables do not affect parents' perceptions. The parents who took part in this study were not overly concerned about the side effects in contrast to other published studies. Another major finding is the positive influence of parents being informed by a consultant paediatrician rather than their family general practitioner. CONCLUSIONS: The acceptance of varicella vaccine depends on a complex interaction of factors but parents' perceptions may change dramatically by being well informed as well as having financial support from the government. PMID- 21277891 TI - Time to positivity in blood cultures of staphylococci: clinical significance in bacteremia. PMID- 21277892 TI - Structure, function and pathophysiology of protease activated receptors. AB - Discovered in the 1990s, protease activated receptors(1) (PARs) are membrane spanning cell surface proteins that belong to the G protein coupled receptor (GPCR) family. A defining feature of these receptors is their irreversible activation by proteases; mainly serine. Proteolytic agonists remove the PAR extracellular amino terminal pro-domain to expose a new amino terminus, or tethered ligand, that binds intramolecularly to induce intracellular signal transduction via a number of molecular pathways that regulate a variety of cellular responses. By these mechanisms PARs function as cell surface sensors of extracellular and cell surface associated proteases, contributing extensively to regulation of homeostasis, as well as to dysfunctional responses required for progression of a number of diseases. This review examines common and distinguishing structural features of PARs, mechanisms of receptor activation, trafficking and signal termination, and discusses the physiological and pathological roles of these receptors and emerging approaches for modulating PAR mediated signaling in disease. PMID- 21277893 TI - Therapeutic applications of compounds in the Magnolia family. AB - The bark and/or seed cones of the Magnolia tree have been used in traditional herbal medicines in Korea, China and Japan. Bioactive ingredients such as magnolol, honokiol, 4-O-methylhonokiol and obovatol have received great attention, judging by the large number of investigators who have studied their pharmacological effects for the treatment of various diseases. Recently, many investigators reported the anti-cancer, anti-stress, anti-anxiety, anti depressant, anti-oxidant, anti-inflammatory and hepatoprotective effects as well as toxicities and pharmacokinetics data, however, the mechanisms underlying these pharmacological activities are not clear. The aim of this study was to review a variety of experimental and clinical reports and, describe the effectiveness, toxicities and pharmacokinetics, and possible mechanisms of Magnolia and/or its constituents. PMID- 21277894 TI - Common cardiovascular medications in cancer therapeutics. AB - Cardiac glycosides, statins, beta-blockers, angiotensin-I converting enzyme inhibitors (ACEIs), and angiotensin II type 1 receptor blockers (ARBs) are widely used cardiovascular medications with pleiotropic properties. Many of these medications have been investigated in other diseases, including cancer. Cardiac glycosides and statins have advanced to clinical trial testing in cancer therapeutics, with variable success. Early observations in breast cancer were consistent with a more benign histologic phenotype among women taking digitalis compared to their counterparts who did not receive cardiac glycosides. Cardiac glycosides can induce apoptosis in cancer cells through various mechanisms and sensitize them to the effects of antitumor therapy. By blocking the generation of prenyl units, statins impair prenylation, an important posttranslational modification of proteins whose function depends on membrane anchoring. Statins also impair protein folding and N-glycosylation and inhibit the upregulation of cholesterol synthesis associated with chemotherapy resistance. Stress and catecholamine release promote tumor growth and angiogenesis, effects that can be mitigated by beta-blockers. Components of the renin-angiotensin-aldosterone system are expressed in various cancers and are involved in carcinogenesis and tumor progression. Angiotensin II has potent mitogenic and angiogenic properties that can be blocked with ACEIs and ARBs. Although it is unclear whether the promising preclinical activity of many cardiovascular medications has clinically meaningful implications beyond the benefit in cardiovascular morbidity and mortality, the prevention or improvement of prognosis of common malignancies with medications known to reduce cardiovascular morbidity and mortality is encouraging and deserves further clinical investigation. PMID- 21277895 TI - Reconstruction of complete connectivity matrix for connectomics by sampling neural connectivity with fluorescent synaptic markers. AB - Physical organization of the nervous system is a topic of perpetual interest in neuroscience. Despite significant achievements here in the past, many details of the nervous system organization and its role in animals' behavior remain obscure, while the problem of complete connectivity reconstructions has recently re emerged as one of the major directions in neuroscience research (i.e. connectomics). We describe a novel paradigm for connectomics reconstructions that can yield connectivity maps with high resolution, high speed of imaging and data analysis, and significant robustness to errors. In essence, we propose that physical connectivity in a neural circuit can be sampled using anatomical fluorescent synaptic markers localized to different parts of the neural circuit with a technique for randomized genetic targeting, and that high-resolution connectivity maps can be extracted from such datasets. We describe how such an approach can be implemented and how neural connectivity matrix can be reconstructed statistically using the methods of Compressive Sensing. Use of Compressive Sensing is the key to allow accurate neural connectivity reconstructions with orders-of-magnitude smaller volumes of experimental data. We test described approach on simulations of neural connectivity reconstruction experiments in C. elegans, where real neural wiring diagram is available from past electron microscopy studies. We show that such wiring diagram can be in principle re-obtained using described approach in 1-7 days of imaging and data analysis. Alternative approaches would require currently at least 1-2 years to produce a single comparable reconstruction. We discuss possible applications of described approach in larger organisms such as Drosophila. PMID- 21277896 TI - Cross-phaseogram: objective neural index of speech sound differentiation. AB - We introduce a new approach, the cross-phaseogram, that captures the brain's ability to discriminate between spectrotemporally dynamic speech sounds, such as stop consonants. The goal was to develop an analysis technique for auditory brainstem responses (ABRs) that taps into the sub-millisecond temporal precision of the response but does not rely on subjective identification of individual response peaks. Using the cross-phaseogram technique, we show that time-varying frequency differences in speech stimuli manifest as phase differences in ABRs. By applying this automated and objective technique to a large dataset, we found these phase differences to be less pronounced in children who perform below average on a standardized test of listening to speech in noise. We discuss the theoretical and practical implications of our results, and the extension of the cross-phaseogram method to a wider range of stimuli and populations. PMID- 21277897 TI - Integrated behavioral z-scoring increases the sensitivity and reliability of behavioral phenotyping in mice: relevance to emotionality and sex. AB - Defining anxiety- and depressive-like states in mice (emotionality) is best characterized by the use of complementary tests, leading sometimes to puzzling discrepancies and lack of correlation between similar paradigms. To address this issue, we hypothesized that integrating measures along the same behavioral dimensions in different tests would reduce the intrinsic variability of single tests and provide a robust characterization of the underlying "emotionality" of individual mouse, similarly as mood and related syndromes are defined in humans through various related symptoms over time. We describe the use of simple mathematical and integrative tools to help phenotype animals across related behavioral tests (syndrome diagnosis) and experiments (meta-analysis). We applied z-normalization across complementary measures of emotionality in different behavioral tests after unpredictable chronic mild stress (UCMS) or prolonged corticosterone exposure - two approaches to induce anxious-/depressive-like states in mice. Combining z-normalized test values, lowered the variance of emotionality measurement, enhanced the reliability of behavioral phenotyping, and increased analytical opportunities. Comparing integrated emotionality scores across studies revealed a robust sexual dimorphism in the vulnerability to develop high emotionality, manifested as higher UCMS-induced emotionality z scores, but lower corticosterone-induced scores in females compared to males. Interestingly, the distribution of individual z-scores revealed a pattern of increased baseline emotionality in female mice, reminiscent of what is observed in humans. Together, we show that the z-scoring method yields robust measures of emotionality across complementary tests for individual mice and experimental groups, hence facilitating the comparison across studies and refining the translational applicability of these models. PMID- 21277898 TI - Function of CD27 in helper T cell differentiation. AB - Differentiation of naive CD4(+) T cells to functional effector T-helper (T(H)) cells is driven by both costimulatory molecules and cytokines. Although polarizing cytokines can induce the differentiation into a particular T(H) subset, certain costimulatory molecules also seem to affect this polarization process. We have previously found that CD70-transgenic (CD70TG) mice develop large numbers of IFN-gamma-producing CD4(+) T cells and we therefore questioned whether CD27 triggering provides an instructive signal for T(H)1 differentiation or rather supports T(H) cell formation in general. Although CD70TG mice on a T(H)1-prone C57Bl/6J background develop more T(H)1 cells, we found that this phenotype is lost when CD70TG mice are fully backcrossed on a T(H)2-prone Balb/c background, but is not replaced with more T(H)2 cells. Furthermore, CD70 overexpression is not sufficient to drive T(H)17 cell formation, nor does it affect the generation of FoxP3(+) regulatory T cells. Using an in vitro setting, we found that CD27-triggering does not provide instructive signals for a specific T(H) cell subset, but, depending on the cytokine milieu and genetic background, supports T(H)1 cell formation, while it inhibits the formation of T(H)17 but not T(H)2 cells. Induction of allergic airway inflammation in CD70TG Balb/c mice further illustrates that CD27 plays a supportive role in T(H)1 differentiation in vivo, without modulating the classical T(H)2 response. This supportive role of CD27 in T(H) cell polarization could not be attributed to a specific change of transcription factor expression levels. In summary, this study indicates that CD27 signalling does influence T(H) cell differentiation, but that it is highly dependent on the conditions and genetic background. PMID- 21277899 TI - A novel association between filamin A and NF-kappaB inducing kinase couples CD28 to inhibitor of NF-kappaB kinase alpha and NF-kappaB activation. AB - CD28 costimulatory molecule plays a critical role in the activation of NF-kappaB. Indeed, while stimulation of T cells with either professional APCs or anti-TCR plus anti-CD28 antibodies efficiently activates NF-kappaB, TCR alone fails to do that. Moreover, CD28 stimulation by B7 in the absence of TCR may activate IkappaB kinase alpha (IKKalpha) and a non-canonical NF-kappaB2-like pathway, in human primary CD4(+) T cells. Despite its functional relevance in NF-kappaB activation, the molecules connecting autonomous CD28-mediated signals to IKKalpha and NF kappaB activation remain still unknown. In searching for specific upstream activators linking CD28 to the IKKalpha/NF-kappaB cascade, we identify a novel constitutive association between filamin A (FLNa) and the NF-kappaB inducing kinase (NIK), in both Jurkat and human primary T cells. Following CD28 engagement by B7, in the absence of TCR, FLNa-associated NIK is activated and induces IKKalpha kinase activity. Both proline (P(208)YAP(211)P(212)) and tyrosine residues (Y(206)QPY(209)APP) within the C-terminal proline-rich motif of CD28 are involved in the recruitment of FLNa/NIK complexes to the membrane as well as in the activation of NIK and IKKalpha. PMID- 21277900 TI - Control of mouse graft-versus-host disease following allogeneic bone marrow transplantation by blocking the CD28/B7 signaling pathway with lentiviral vector mediated RNA interference. AB - Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective way to cure hematological malignancies. However, graft-versus-host disease (GVHD) following transplantation limits the clinical application to some extent. The donor T lymphocytes play a central role in the occurrence and development of GVHD. Control of GVHD by inhibition of T cell proliferation by blocking the CD28/B7 signaling pathway with RNA interference has not been examined. In this study, we constructed a lentiviral vector carrying CD28 shRNA and generated genetically engineered splenocytes through transduction in a murine allogeneic bone marrow transplantation model. The survival and the occurrence of GVHD in transplanted mice were monitored every day. Liver, intestine, skin, and other tissues from the mice in each group were used for histological examination. We also determined plasma concentrations of interleukin (IL)-2, IL-4, IL-5, IL-10, IL-13, and interferon gamma (IFN-gamma). Recipient bone marrow from mice that had survived for an extended period was examined to detect chimerism. We succeeded in suppressing the expression of CD28 gene and controlling mouse GVHD following allogeneic bone marrow transplantation in the engineered spleen cell group. These suggest that blocking the CD28/B7 signal transduction pathway with lentiviral vector-mediated RNA interference effectively controlled the occurrence of mouse GVHD following allogeneic bone marrow transplantation. Its mechanism could be due to the inhibition of T cell proliferation and, simultaneously, the promotion of the differentiation of TH0 to TH2 cells, thereby reducing GVHD in the mouse transplantation model. PMID- 21277901 TI - Isolation of human Fab antibodies specific for the low-affinity IgE receptor (CD23) by selecting a hierarchical antibody library system against B lymphoblastic IM-9 cells. AB - The development of human antibodies specific for certain B cell markers is required to generate therapeutic antibody leads with improved therapeutic indices against B-cell lymphomas. To meet this demand, we selected a primary human antibody library, HuDVFab-8L, against human B lymphoblastic IM-9 cells via a 'Biopanning and Rapid Analysis of Selective Interactive Ligands (BRASIL)' cell panning approach. Six Fab clones that specifically bound to IM-9 cells were successfully isolated. Among these clones, two clones (IM-L6-E and IM-L8-G), were found to be specific for CD23 (FcERII). Affinity maturation of these Fab clones was then performed in a hierarchical manner by constructing secondary antibody libraries through combining heavy (H) chains of two Fabs with the human kappa L chain sublibrary HuNL-D3 followed by biopanning against the CD23 antigen. Clone IM-L6-5, one of the affinity maturated Fab derivatives from IM-L6-E, has a binding affinity of k(D)~30 nM to soluble CD23. In addition, IM-L6-5 Fab is able to bind to an inducible form of CD23 expressed on U937 cells upon IL-4 stimulation, and inhibits binding of human IgE to CD23. Since the Fab IM-L6-5 is derived from a fully human naive origin, we believe that IM-L6-5 can be utilized for the development of a therapeutic mAb which may have an improved therapeutic index over lumiliximab, a primatized anti-CD23 mAb, for the treatment of CLL or allergic diseases. PMID- 21277902 TI - IDO metabolite produced by EBV-transformed B cells inhibits surface expression of NKG2D in NK cells via the c-Jun N-terminal kinase (JNK) pathway. AB - Natural Killer cells are known to play a major role in the innate immune response against viral infections and tumor cells. Several viruses, such as CMV, EBV and HIV-1, have acquired strategies to escape elimination by NK cells. In this study, we observed that EBV infection increased expression of IDO on B cells. To evaluate the function of IDO associated with EBV infection, we investigated whether EBV-induced IDO could modulate expression of NK cell-activation receptor, NKG2D. When NK cells were co-incubated with EBV transformed B cells, surface expression of NKG2D was significantly reduced in NK cells. Incubation with L kynurenine, an IDO metabolite, down-modulated NKG2D expression in NK cells in a dose- and time-dependent manner. Incubation with the JNK inhibitor SP600125 also inhibited NKG2D expression in NK cells. In addition, we observed that the effect of L-kynurenine was blocked by JNK agonist, anisomycin, suggesting the involvement of the JNK pathway in the signal transduction of L-kynurenine-reduced NKG2D expression. Furthermore, IL-18 significantly reduced L-kynurenine-induced down-regulation of NKG2D expression in NK cells. Taken together, these data indicate that down-regulation of NKG2D by EBV-induced IDO metabolite provides a potential mechanism by which EBV escapes NKG2D-mediated attack by immune cells. PMID- 21277903 TI - Silencing of HTLV-1 gag and env genes by small interfering RNAs in HEK 293 cells. AB - Since the discovery of RNAi technology, several functional genomic and disease therapy studies have been conducted using this technique in the field of oncology and virology. RNAi-based antiviral therapies are being studied for the treatment of retroviruses such as HIV-1. These studies include the silencing of regulatory, infectivity and structural genes. The HTLV-1 structural genes are responsible for the synthesis of proteins involved in the entry, assembly and release of particles during viral infection. To examine the possibility of silencing HTLV-1 genes gag and env by RNA interference technology, these genes were cloned into reporter plasmids. These vectors expressed the target mRNAs fused to EGFP reporter genes. Three small interference RNAs (siRNAs) corresponding to gag and three corresponding to env were designed to analyze the effect of silencing by RNAi technology. The plasmids and siRNAs were co-transfected into HEK 293 cells. The results demonstrated that the expression of the HTLV-1 gag and env genes decreased significantly in vitro. Thus, siRNAs can be used to inhibit HTLV-1 structural genes in transformed cells, which could provide a tool for clarifying the roles of HTLV-1 structural genes, as well as a therapy for this infection. PMID- 21277904 TI - Preparation of CHO cell-derived rhIFN-omega-Fc with improved pharmacokinetics. AB - Interferon-omega (IFN-omega) may be a useful, promising and alternative antiviral agent, in addition to IFN-alpha-2a and IFN-alpha-2b. To improve the pharmacokinetics of IFN-omega for clinical use, the recombinant human IFN-omega Fc fusion protein (rhIFN-omega-Fc) was expressed in a Chinese hamster ovary cell line (CHO-S), due to the longer serum half-life of rhIFN-omega-Fc compared to the native IFN-omega protein, and purified by affinity chromatography. Physicochemical characterization of the purified fusion protein was performed by SDS-PAGE electrophoresis, dot blot analysis and N-terminal amino acid sequence analysis. The results show that rhIFN-omega-Fc was highly expressed at the predicted size and with the N-terminal amino acid sequence. The antiviral activity was determined by the ability of IFNs to inhibit the cytopathic effects (CPEs) of vesicular stomatitis virus (VSV) on the human amnion WISH cells. The rhIFN-omega-Fc expressed in CHO-S cells has a specific activity of 1.6*10(7) IU/mg compared to rhIFN-omega expressed in yeast, which has a specific activity of 7*10(7) IU/mg. Equimolar concentrations of rhFN-omega and rhIFN-omega-Fc were administered to rabbits for pharmacokinetics comparison. The terminal half-life of rhIFN-omega-Fc was 35 times higher than that of rhIFN-omega. Thus, rhIFN-omega Fc can be used as a prospective antiviral candidate especially for the treatment of chronic viral disease, such as hepatitis C virus (HCV) infection. PMID- 21277905 TI - The effects of selective antagonists of serotonin 5-HT7 and 5-HT1A receptors on MK-801-induced impairment of learning and memory in the passive avoidance and Morris water maze tests in rats: mechanistic implications for the beneficial effects of the novel atypical antipsychotic lurasidone. AB - We have previously reported that lurasidone, a novel atypical antipsychotic with potent serotonin 5-HT(7) antagonist and 5-HT(1A) partial agonist activities, is superior to other antipsychotics in improving the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801-induced learning and memory impairment in the passive avoidance (PA) and Morris water maze (MWM) tests in rats. In this study, we investigated the effects of selective antagonists of 5-HT(7) and 5-HT(1A) receptors (SB-656104-A and WAY-100635, respectively) on MK-801-induced learning and memory impairment in the same tests. In the PA test, either pre-training (3 and 10mg/kg, p.o.) or post-training (0.3mg/kg, i.v.) administration of lurasidone significantly reversed the test response impaired by MK-801, consistent with our previous reports. Pre-training administration of either SB-656104-A (10 and 30 mg/kg, i.p.) or WAY-100635 (1mg/kg, s.c.) also significantly reversed MK-801 induced memory impairment. Furthermore, post-training administration of either SB 656104-A (0.3mg/kg, i.v.) or WAY-100635 (0.01 mg/kg, i.v.) counteracted the effect of MK-801, which suggested that both 5-HT receptor subtype-selective antagonists could restore the memory consolidation process. In the MWM test, SB 656104-A (3mg/kg, i.p.) reversed learning impairment induced by MK-801. On the other hand, WAY-100635 (0.3 and 1mg/kg, i.p.) did not have any effect on the MK 801-induced learning impairment. Taken together, our results showed that 5-HT(7) and 5-HT(1A) receptor antagonists mimic the effect of lurasidone in whole or in part, respectively, to reverse MK-801-induced learning and memory impairment, which warrants further investigation of the interaction of lurasidone with these serotonin receptors as a possible mechanism underlying its procognitive effects in these animal models. PMID- 21277906 TI - Nicotine ameliorates impairment of working memory in methamphetamine-treated rats. AB - Nicotine is hypothesized to have therapeutic effects on attentional and cognitive abnormalities in psychosis. In this study, we investigated the effect of nicotine on impaired spatial working memory in repeated methamphetamine (METH)-treated rats. Rats were administered METH (4 mg/kg, s.c.) once a day for 7 days, and their working memory was assessed with a delayed spatial win-shift task in a radial arm maze. The task consisted of two phases, a training phase and a test phase, separated by a delay. Control animals showed impaired performance in the test phase when the delay time was increased to 120 min or longer, while METH treated rats showed impaired performance with a shorter delay time of 90 min. Memory impairment in METH-treated rats persisted for at least 14 days after drug withdrawal. METH-induced impairment of working memory was reversed by nicotine (0.3mg/kg, p.o., for 7 days), but the effect was diminished 7 days after the withdrawal. In control rats, nicotine decreased the number of working memory errors in the test with delay time of 120 min when administered before the training phase. Neither post-training nor pre-test administration of nicotine had any effect on working memory. These findings suggest that nicotine may have some protective effect against the impairment of working memory. PMID- 21277907 TI - Prenatal exposure to PCP produces behavioral deficits accompanied by the overexpression of GLAST in the prefrontal cortex of postpubertal mice. AB - Altered glutamatergic neurotransmission in the prefrontal cortex (PFC) has been implicated in a myriad of neuropsychiatric disorders. We previously reported that prenatal exposure to PCP produced long-lasting behavioral deficits, accompanied by the abnormal expression and dysfunction of NMDA receptors. In addition, these behavioral changes were attenuated by clozapine treatment. However, whether the prenatal exposure adversely affects pre-synaptic glutamatergic neurotransmission in postpubertal mice remains unknown. In the present study, we investigated the involvement of prefrontal glutamatergic neurotransmission in the impairment of cognitive and emotional behavior after prenatal PCP treatment (5mg/kg/day) from E6 to E18 in mice. The PCP-treated mice showed an impairment of recognition memory in a novel object recognition test and enhancement of immobility in a forced swimming test at 8 weeks of age. Moreover, the prenatal treatment reduced the extracellular glutamate level, but increased the expression of a glial glutamate transporter (GLAST) in the PFC. The microinjection of DL-threo-beta benzyloxyaspartate (DL-TBOA, 10 nmol/site/bilaterally), a potent blocker of glutamate transporters, reversed these behavioral deficits by enhancing the prefrontal glutamatergic neurotransmission. Taken together, prenatal exposure to PCP produced impairments of long-term memory and emotional function which are associated with abnormalities of pre-synaptic glutamate transmission in the PFC of postpubertal mice. These findings suggest the prenatal inhibition of NMDA receptor function to contribute partly to the pathophysiology of neurodevelopment related disorders, such as schizophrenia. PMID- 21277908 TI - Memantine abolishes the formation of cocaine-induced conditioned place preference possibly via its IL-6-modulating effect in medial prefrontal cortex. AB - In this study, we decided to use low doses of memantine pretreatment to examine the roles of the immune function in cocaine-supported conditioning. Cocaine induced conditioned place preference (CPP) was used to assess the hedonic value and/or reinforcing efficacy of cocaine and cocaine-supported conditioning. Systemic pretreatment with memantine (20, 2.0, 0.2, and 0.02 mg/kg/injection) 30 min before each cocaine and saline conditioning trial abolished the acquisition of cocaine-induced CPP in mice. Even a total of 0.12 mg/kg memantine pretreatment in three days was effective in diminishing cocaine-induced CPP. Three consecutive days of cocaine conditioning increased interleukin-6 (IL-6) but decreased tumor necrosis factor (TNF-alpha) levels in medial prefrontal cortex (mPFC) and nucleus accumbens (Acb). Interestingly, pretreatment with memantine at the lowest effective dose (0.02 mg/kg/injection) reversed cocaine conditioning-enhanced IL-6 and -decreased TNF-alpha levels in these brain regions. Nevertheless, such a memantine dosing regimen did not affect dopamine metabolism in mPFC and Acb. Single memantine (0.02 mg/kg) injection did not acutely affect mouse locomotor activity or cocaine-increased locomotor activity. Similar memantine dosing regimen was ineffective to affect the maintenance of cocaine-induced CPP. Finally, intra-mPFC infusion of recombinant IL-6, but not thalidomide, reversed memantine (0.02 mg/kg/injection * 6)-decreased cocaine-induced CPP. These results, taken together, suggest that cocaine conditioning-enhanced IL-6 in mPFC may be, in part, involved in the acquisition of cocaine-induced CPP. Moreover, an extremely low dose of memantine may decrease the acquisition of cocaine-induced CPP by reversing cocaine conditioning-increased IL-6 levels in mPFC. PMID- 21277909 TI - Inadequate early social experience increases the incentive salience of reward related cues in adulthood. AB - The mechanisms by which childhood abuse and/or neglect become risk factors for the development of drug addiction, problem gambling, and other disorders of behavioral inhibition are unknown. The loss of behavioral inhibition is often triggered by reward-related cues that acquire incentive salience. This study examined whether inadequate early-life social experience in rats affects the incentive salience of reward-related cues. Rats were deprived of early-life social experience with the mother and litter through artificial-rearing (AR). A group of AR rats (AR+STM) received additional tactile stimulation that mimicked maternal licking, a critical component of rat maternal care. Control rats were maternally reared (MR). The incentive salience attributed to a food cue was measured in adult rats using a conditioned approach task, where a conditional stimulus (CS; lever) was paired with food delivery, and in a conditional reinforcement task. The dependent measures were approach towards the CS (sign tracking) versus approach towards the place of food delivery (goal-tracking) and instrumental responding for the CS. AR rats made significantly more sign-tracking responses than MR rats. AR rats also made more instrumental responses when reinforced with the CS. AR+STM rats' responses were intermediate to MR and AR rats. Thus, inadequate early-life social experience enhanced the incentive salience of a reward-related cue in adulthood. Replacement of maternal licking partially reversed this effect. These results highlight a potential link between early-life social adversity and susceptibility to disorders of behavioral inhibition. PMID- 21277910 TI - Toxoplasma gondii toxolysin 4 is an extensively processed putative metalloproteinase secreted from micronemes. AB - Proteases play central roles in cell invasion by Toxoplasma gondii and other apicomplexan parasites. Herein we report the cloning and characterization of a novel secretory putative metalloproteinase, Toxolysin 4 (TLN4). T. gondii tachyzoites store TLN4 in the micronemes and secrete it in response to elevated calcium, suggesting a possible role in cell invasion. TLN4 is initially synthesized as a large (~260 kDa) precursor, which is extensively processed into multiple proteolytic fragments within the parasite secretory system. At least some of these proteolytic fragments remain associated in a large molecular complex. Whereas precomplementation with the TLN4 cDNA allowed disruption of the TLN4 gene, multiple attempts to directly knockout TLN4 without precomplementation failed. TLN4 knockout parasites were detected by PCR in transfected populations but were lost from the cultures during drug selection and growth suggesting that TLN4 contributes to parasite fitness. PMID- 21277911 TI - Characterization of sphere-propagating cells with stem-like properties from DU145 prostate cancer cells. AB - While accumulating evidence demonstrates the existence of prostate cancer stem cells (PCSCs), PCSCs have not been isolated and thoroughly characterized. We report here the enrichment and characterization of sphere-propagating cells with stem-like properties from DU145 PC cells in a defined serum-free medium (SFM). Approximately 1.25% of monolayer DU145 cells formed spheres in SFM and 26% of sphere cells formed secondary spheres. Spheres are enriched for cells expressing prostate basal and luminal cytokeratins (34betaE12 and CK18) and for cancer stem cell markers, including CD44, CD24, and integrin alpha2beta1. Upon culturing spheres under differentiating media conditions in the presence of 10% serum, cells positive for CD44 and CD24 were substantially reduced. Furthermore, spheres could be generated from the sphere-derived adherent cell cultures and xenograft tumors, demonstrating the stemness of DU145 spheres. We have maintained spheres for more than 30 passages within 1.5years without noticeable loss of their "stemness". Sphere cells possess self-renewal capacity, display significant increases in proliferation potential, and initiate xenograft tumors with enhanced capacity compared to monolayer DU145 cells. While EGF promoted the generation and maintenance of these stem-like cells, bFGF inhibited these events. Sphere cells proliferate slowly with a significant reduction in the activation of the PI3K-AKT pathway compared to monolayer DU145 cells. While knockdown of PTEN enhanced AKT activation, this did not affect the generation of primary spheres and the propagation of secondary spheres. Consistent with this observation, we were able to demonstrate the generation and propagation of spheres without the addition of external growth factors. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. PMID- 21277912 TI - Ultrabright planar optodes for luminescence life-time based microscopic imaging of O2 dynamics in biofilms. AB - New transparent optodes for life-time based microscopic imaging of O2 were developed by spin-coating a MUm-thin layer of a highly luminescent cyclometalated iridium(III) coumarin complex in polystyrene onto glass cover slips. Compared to similar thin-film O2 optodes based on a ruthenium(II) polypyridyl complex or a platinum(II) porphyrin, the new planar sensors have i) higher brightness allowing for much shorter exposure times and thus higher time resolution, ii) more homogeneous and smaller pixel to pixel variation over the sensor area resulting in less noisy O2 images, and iii) a lower temperature dependency simplifying calibration procedures. We used the new optodes for microscopic imaging of the spatio-temporal O2 dynamics at the base of heterotrophic biofilms in combination with confocal imaging of bacterial biomass and biofilm structure. This allowed us to directly link biomass distribution to O2 distribution under both steady state and non-steady state conditions. We demonstrate that the O2 dynamics in biofilms is governed by a complex interaction between biomass distribution, mass transfer and flow that cannot be directly inferred from structural information on biomass distribution alone. PMID- 21277913 TI - Emotional scenes and facial expressions elicit different psychophysiological responses. AB - We examined if emotional faces elicit physiological responses similar to pictures of emotional scenes. Forty one students viewed emotional scenes (negative, neutral, and positive) and emotional faces (angry, neutral, and happy). Heart rate, orbicularis oculi and electrodermal activity were measured continuously, and the startle reflex was elicited. Although the patterns of valence and arousal ratings were comparable, physiological response patterns differed. For scenes we replicated the valence-specific modulation of the startle response, heart rate deceleration, and the arousal-related modulation of the electrodermal response. In contrast, for faces we found valence-specific modulation only for the electrodermal response, but the startle and heart rate deceleration were modulated by arousal. Although arousal differences may account for some differences in physiological responding this shows that not all emotional material that is decoded similarly leads to the same psychophysiological output. PMID- 21277914 TI - Resting state EEG delta-beta coherence in relation to anxiety, behavioral inhibition, and selective attentional processing of threatening stimuli. AB - Variability in human resting state electroencephalography (EEG) may reflect emotion regulation processes (for a review, see Knyazev, 2007). For instance, it has been suggested that correlation between slow (1-3 Hz) and fast (13-30 Hz) activity (or delta-beta coherence) may reflect functional synchronization between limbic and cortical brain systems. Indirect support comes from several studies reporting relationships between delta-beta coherence and subjectively reported behavioral inhibition and state anxiety. The present study sought to extend this work and tested the prediction that objectively, experimentally, measured threat selective attention should also be related to delta-beta coherence. EEG frequency band power and dot probe task performance were assessed in forty healthy women and results demonstrated a negative association between delta-beta coherence and automatic, anxiety-driven attentional avoidance of threatening pictorial stimuli. These first reported objective measures for cognitive-emotional behavior obtained in relation to delta-beta coherence provide additional support for the hypothesis that this EEG parameter may reflect emotion regulation processes and supports suggestions that delta-beta coherence may be a useful tool in the experimental study of affect and psychopathology. In addition, results showed an unexpected negative association between delta-beta coherence and self-reported trait anxiety (but no association with behavioral inhibition). PMID- 21277915 TI - Sigma factors and promoters in Corynebacterium glutamicum. AB - The Corynebacterium glutamicum genome codes for 7 sigma subunits (factors) of RNA polymerase (RNAP): primary sigma factor SigA (sigma(A)), primary-like SigB and 5 other alternative sigma factors (SigC, SigD, SigE, SigH and SigM). Each sigma factor is responsible for recognizing promoters of genes belonging to a regulon (sigmulon) involved in specific functions of the cell. Most promoters of C. glutamicum housekeeping genes are recognized by RNAP+sigma(A), whereas sigma(B) is involved in transcription of a large group of genes active during the transition phase between the exponential and stationary growth phases when various stress factors threaten to damage the cell. The sigma(H) regulon consists of the genes involved in heat shock response including those coding for regulators and other sigma factors. It seems therefore that sigma(H) occupies a central position in the cross-regulated network of sigma factors and controls their concerted response to various stress conditions in C. glutamicum. The sigma(M) factor was found to regulate genes responding to oxidative stress. The main role of sigma(E) is to activate genes involved in response to a cell surface stress. Promoters of individual classes recognized by different sigma factors are compiled and the respective consensus sequences of their key recognition motifs ( 35 and -10 regions) are derived. In a number of genes, two or more promoters controlled by the same or different sigma factors were discovered. These multiple, overlapping or dual promoters contribute to a complex gene transcription control mechanisms that integrate internal and external signals and tune gene expression in cells as required by environmental and physiological conditions. PMID- 21277916 TI - Transcriptional regulators of multiple genes involved in carbon metabolism in Corynebacterium glutamicum. AB - Corynebacterium glutamicum, a high-GC Gram-positive soil bacterium, has been used in development of bioprocesses for production of various compounds such as amino acids, organic acids, and alcohols. Recently, several transcriptional regulators, each of which is involved in multiple carbon metabolic pathways in this bacterium, have been identified and characterized. These regulators appear to form a complicated network mediating coordinated expression of a number of metabolic genes for efficient utilization of carbon and energy sources in response to changing environmental conditions. The C. glutamicum regulatory system of carbon metabolism is markely different from well-studied model systems of other bacteria such as Escherichia coli and Bacillus subtilis. Thus, elucidation of the C. glutamicum regulatory system should establish a new model for bacterial control of carbon metabolism, providing a rational basis for metabolic engineering of this industrial important microorganism to efficiently direct carbon flow from available carbon resources into useful compounds. Here, recent findings of studies on C. glutamicum transcriptional regulators of carbon metabolism, namely, SugR, RamB, RamA, GlxR, GntR1/2, and LldR, are summarized. PMID- 21277917 TI - Rational design of biodegradable cationic polycarbonates for gene delivery. AB - Polycarbonates provide an attractive option for use as gene delivery vectors owing to their biocompatibility and ease of incorporating functional moieties. In this study, we described an approach to synthesize cationic polymers with well defined molecular weights and narrow polydispersities by an organocatalytic ring opening polymerization of functional cyclic carbonates containing alkyl halide side chains, followed by a subsequent functionalization step with bis-tertiary amines designed to facilitate gene binding and endosomal escape. The cationic polycarbonate effectively condensed DNA at low N/P ratios, generating nanoparticles (83 to 124 nm in diameter) with positive zeta potentials (~27 mV). In addition, reporter gene expression efficiencies in HepG2, HEK293, MCF-7 and 4T1 cell lines were high even in the presence of serum. Importantly, the polycarbonate delivery agent demonstrated minimal cytotoxicity at the optimal N/P ratios determined to confer high gene expression efficiencies. Therefore, this biodegradable polymer is presented as a promising non-viral vector for gene delivery. PMID- 21277918 TI - Functionalized linear poly(amidoamine)s are efficient vectors for intracellular protein delivery. AB - An effective intracellular protein delivery system was developed based on functionalized linear poly(amidoamine)s (PAAs) that form self-assembled cationic nanocomplexes with oppositely charged proteins. Three differently functionalized PAAs were synthesized, two of these having repetitive disulfide bonds in the main chain, by Michael-type polyaddition of 4-amino-1-butanol (ABOL) to cystamine bisacrylamide (CBA), histamine (HIS) to CBA, and ABOL to bis(acryloyl)piperazine (BAP). These water-soluble PAAs efficiently condense beta-galactosidase by self assembly into nanoscaled and positively-charged complexes. Stable under neutral extracellular conditions, the disulfide-containing nanocomplexes rapidly destabilized in a reductive intracellular environment. Cell-internalization and cytotoxicity experiments showed that the PAA-based nanocomplexes were essentially non-toxic. beta-Galactosidase was successfully internalized into cells, with up to 94% of the cells showing beta-galactosidase activity, whereas the enzyme alone was not taken up by the cells. The results indicate that these poly(amidoamine)s have excellent properties as highly potent and non-toxic intracellular protein carriers, which should create opportunities for novel applications in protein delivery. PMID- 21277919 TI - Ultrasound-mediated tumor imaging and nanotherapy using drug loaded, block copolymer stabilized perfluorocarbon nanoemulsions. AB - Perfluorocarbon nanoemulsions can deliver lipophilic therapeutic agents to solid tumors and simultaneously provide for monitoring nanocarrier biodistribution via ultrasonography and/or (19)F MRI. In the first generation of block copolymer stabilized perfluorocarbon nanoemulsions, perfluoropentane (PFP) was used as the droplet forming compound. Although manifesting excellent therapeutic and ultrasound imaging properties, PFP nanoemulsions were unstable at storage, difficult to handle, and underwent hard to control phenomenon of irreversible droplet-to-bubble transition upon injection. To solve the above problems, perfluoro-15-crown-5-ether (PFCE) was used as a core forming compound in the second generation of block copolymer stabilized perfluorocarbon nanoemulsions. PFCE nanodroplets manifest both ultrasound and fluorine ((19)F) MR contrast properties, which allows using multimodal imaging and (19)F MR spectroscopy for monitoring nanodroplet pharmacokinetics and biodistribution. In the present paper, acoustic, imaging, and therapeutic properties of unloaded and paclitaxel (PTX) loaded PFCE nanoemulsions are reported. As manifested by the (19)F MR spectroscopy, PFCE nanodroplets are long circulating, with about 50% of the injected dose remaining in circulation 2h after the systemic injection. Sonication with 1-MHz therapeutic ultrasound triggered reversible droplet-to bubble transition in PFCE nanoemulsions. Microbubbles formed by acoustic vaporization of nanodroplets underwent stable cavitation. The nanodroplet size (200nm to 350nm depending on a type of the shell and conditions of emulsification) as well as long residence in circulation favored their passive accumulation in tumor tissue that was confirmed by ultrasonography. In the breast and pancreatic cancer animal models, ultrasound-mediated therapy with paclitaxel loaded PFCE nanoemulsions showed excellent therapeutic properties characterized by tumor regression and suppression of metastasis. Anticipated mechanisms of the observed effects are discussed. PMID- 21277920 TI - Doxorubicin loaded iron oxide nanoparticles overcome multidrug resistance in cancer in vitro. AB - Multidrug resistance (MDR) is characterized by the overexpression of ATP-binding cassette (ABC) transporters that actively pump a broad class of hydrophobic chemotherapeutic drugs out of cancer cells. MDR is a major mechanism of treatment resistance in a variety of human tumors, and clinically applicable strategies to circumvent MDR remain to be characterized. Here we describe the fabrication and characterization of a drug-loaded iron oxide nanoparticle designed to circumvent MDR. Doxorubicin (DOX), an anthracycline antibiotic commonly used in cancer chemotherapy and substrate for ABC-mediated drug efflux, was covalently bound to polyethylenimine via a pH sensitive hydrazone linkage and conjugated to an iron oxide nanoparticle coated with amine terminated polyethylene glycol. Drug loading, physiochemical properties and pH lability of the DOX-hydrazone linkage were evaluated in vitro. Nanoparticle uptake, retention, and dose-dependent effects on viability were compared in wild-type and DOX-resistant ABC transporter over-expressing rat glioma C6 cells. We found that DOX release from nanoparticles was greatest at acidic pH, indicative of cleavage of the hydrazone linkage. DOX conjugated nanoparticles were readily taken up by wild-type and drug-resistant cells. In contrast to free drug, DOX-conjugated nanoparticles persisted in drug resistant cells, indicating that they were not subject to drug efflux. Greater retention of DOX-conjugated nanoparticles was accompanied by reduction of viability relative to cells treated with free drug. Our results suggest that DOX conjugated nanoparticles could improve the efficacy of chemotherapy by circumventing MDR. PMID- 21277921 TI - Substrates for cardiovascular tissue engineering. AB - Cardiovascular tissue engineering aims to find solutions for the suboptimal regeneration of heart valves, arteries and myocardium by creating 'living' tissue replacements outside (in vitro) or inside (in situ) the human body. A combination of cells, biomaterials and environmental cues of tissue development is employed to obtain tissues with targeted structure and functional properties that can survive and develop within the harsh hemodynamic environment of the cardiovascular system. This paper reviews the up-to-date status of cardiovascular tissue engineering with special emphasis on the development and use of biomaterial substrates. Key requirements and properties of these substrates, as well as methods and readout parameters to test their efficacy in the human body, are described in detail and discussed in the light of current trends toward designing biologically inspired microenviroments for in situ tissue engineering purposes. PMID- 21277922 TI - Ethical and unethical food. Social representations among Finnish, Danish and Italian students. AB - The consumption of ethical food is an area of major growth. The aim of the current study was to identify ethical concerns regarding food. University students (N=403) from Finland, Denmark and Italy completed a word association task, in which the given stimulus words were "ethical food" and "unethical food". The data was first analysed qualitatively. Next, the most relevant, core categories were identified based on the frequency, rank and contextual stability. The results indicated that fourteen categories reflect the content and nature of ethical thinking with respect to food. The identified categories were required/prohibited food, natural/unnatural, local/global, healthy/unhealthy, equality/inequality, good animal welfare/poor animal welfare, rules and descriptions. In all countries, the core categories emerging from the stimulus word "ethical food" were the required food and the natural, while the core category identified from the stimulus word "unethical food" was the prohibited food. The most prevalent differences between the countries concerned the role of health, country of origin and the descriptions. In conclusion, various ethical aspects are considered when food is evaluated in ethical terms, but the relevance of these aspects differ, even in the European context. PMID- 21277923 TI - Psychometric properties of Turkish version of Dutch Eating Behaviour Questionnaire (DEBQ). A preliminary results. AB - The purpose of this study was to test the reliability and validity of Dutch Eating Behaviour Questionnaire (DEBQ) among Turkish university students. The questionnaire was administered to 508 participants. Construct validity was assessed by principal component factor analysis with varimax rotation and reliability was tested by Cronbach's alpha coefficient. For testing criterion related validity, EAT-40 with DEBQ was also administered to 508 participants. Results showed the presence of three major factors (emotional eating, restrained eating and external eating) with loadings similar to those of the original questionnaire. Three subscales of DEBQ had higher internal consistency and test retest reliability. The obtained correlation between EAT-40 and DEBQ was ranged from 0.12 to 0.39. This study clearly demonstrates the factorial validity and the reliability of a Turkish version of the DEBQ. PMID- 21277924 TI - Kid's Choice Program improves weight management behaviors and weight status in school children. AB - The present study examined the effectiveness of the Kid's Choice Program (KCP) for increasing children's weight management behaviors, and decreasing body mass index percentile (BMI%) for overweight and average-weight children. It also evaluated KCP characteristics relevant to long-term application in schools. Participants included 382 children assigned to two groups: a KCP group that received token rewards for three "Good Health Behaviors" including eating fruits or vegetables first at meals (FVFIRST), choosing low-fat and low-sugar healthy drinks (HDRINK), and showing 5000 exercise steps recorded on pedometers (EXERCISE), or a control group that received token rewards for three "Good Citizenship Behaviors." School lunch observations and pedometer records were completed for one month under baseline and three months under reward conditions. The school nurse calculated children's BMI% one year before baseline, at baseline, at the end of KCP application, and six months later. The KCP increased FVFIRST, HDRINK, and EXERCISE from baseline through reward conditions, with ANCOVAs demonstrating that these increases were associated with both the offer of reward and nearby peer models. Overweight (n=112) and average-weight (n=200) children showed drops in BMI% after the three-month KCP, but overweight children re-gained weight six months later, suggesting the need for more ongoing KCP application. HDRINK choice was the behavior most associated with BMI% drops for overweight children. Small teams of parent volunteers effectively delivered the KCP, and school staff endorsed parent volunteers as the best personnel to deliver the KCP, which costs approximately two U.S. dollars per child per month of application. PMID- 21277925 TI - Measuring beliefs about gluten free diet adherence in adult coeliac disease using the theory of planned behaviour. AB - The theory of planned behaviour (TPB) was used to elicit the salient beliefs about gluten free diet (GFD) adherence in adults with coeliac disease (CD) and to design a TPB questionnaire to predict adherence levels. This questionnaire was administered to 265 CD participants with adherence and quality of life (QOL) measures, a GFD knowledge test, and self-reported psychiatric history. Regression analyses were used to test the fit of the TPB in predicting adherence, and to determine the nature of the relationships between adherence, QOL, knowledge, and psychiatric history. The TPB combined with self-reported depression and anxiety, and QOL explained significant variance in intention (41.0%) and adherence (33.7%). Poorer dietary adherence and psychiatric history were also associated with lower QOL. Findings suggest that the TPB provides an adequate model for predicting GFD adherence in CD, and the presence of psychiatric conditions represents a potential intervention target to improve adherence and QOL. PMID- 21277926 TI - Effect of proline position on the antimicrobial mechanism of buforin II. AB - Buforin II (BF2) is a histone-derived antimicrobial peptide that causes cell death by translocating across membranes and interacting with nucleic acids. It contains one proline residue critical for its function. Previous research found that mutations replacing proline lead to decreased membrane translocation and antimicrobial activity as well as increased membrane permeabilization. This study further investigates the role of proline in BF2's antimicrobial mechanism by considering the effect of changing proline position on membrane translocation, membrane permeabilization, and antimicrobial activity. For this purpose, four mutants were made with proline substitution (P11A) or relocation (P11A/G7P, P11A/V12P, P11A/V15P). These mutations altered the amount of helical content. Although antimicrobial activity correlated with the alpha-helical content for the peptides containing proline, membrane translocation did not. This observation suggests that factors in BF2's bactericidal mechanism other than translocation must be altered by these mutations. To better explain these trends we also measured the nucleic acid binding and membrane permeabilization of the mutant peptides. A comparison of mutant and wild type BF2 activity revealed that BF2 relies principally on membrane translocation and nucleic acid binding for antimicrobial activity, although membrane permeabilization may play a secondary role for some BF2 variants. A better understanding of the role of proline in the BF2 antimicrobial mechanism will contribute to the further design and development of BF2 analogs. Moreover, since proline residues are prevalent among other antimicrobial peptides, this systematic characterization of BF2 provides general insights that can promote our understanding of other systems. PMID- 21277927 TI - Analysis of vitamin D receptor gene polymorphisms in women with and without endometriosis. AB - An aberrant immunologic mechanism has been suggested to be involved in the pathogenesis of endometriosis. Genetic alterations in the vitamin D receptor gene (VDR) may lead to important defects in gene activation that principally affect immune function. We have hypothesized a possible relationship between endometriosis and/or infertility and the VDR polymorphisms (ApaI, TaqI, FokI, and BmsI). The study was a case-control study including 132 women with endometriosis related infertility, 62 women with idiopathic infertility, and 133 controls. VDR polymorphisms were studied by restriction fragment length polymorphism. We found relatively similar VDR polymorphism genotype frequencies in cases and controls. When patients with minimal/mild and moderate/severe endometriosis were studied separately, no difference was found. When we compared infertile groups with and without endometriosis there was no statistically significant difference. The data suggest that VDR polymorphisms did not play an important role in the pathogenesis of endometriosis and/or infertility in the Brazilian women studied. PMID- 21277928 TI - Role of DC-SIGN and L-SIGN receptors in HIV-1 vertical transmission. AB - The innate immune system acts in the first line of host defense against pathogens. One of the mechanisms used involves the early recognition and uptake of microbes by host professional phagocytes, through pattern recognition receptors (PRRs). These PRRs bind to conserved microbial ligands expressed by pathogens and initiate both innate and adaptative immune responses. Some PRRs located on the surface of dendritic cells (DCs) and other cells seem to play an important role in human immunodeficiency virus type 1 (HIV-1) transmission. Dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin, CD209 (DC-SIGN) and its homolog, DC-SIGN-related (DC-SIGNR or L-SIGN) receptors are PPRs able to bind the HIV-1 gp120 envelope protein and, because alterations in their expression patterns also occur, they might play a role in both horizontal and vertical transmission as well as in disseminating the virus within the host. This review aims to explore the involvement of the DC-SIGN and L-SIGN receptors in HIV-1 transmission from mother to child. PMID- 21277929 TI - Investigation of cytotoxic T-lymphocyte-associated protein 4 gene polymorphisms in symptomatic gallstone disease. AB - Gallstone disease (GSD), which is increasingly prevalent in Taiwan, develops through a complex process involving genetic, environmental, and immune factors. Cytotoxic T-lymphocyte-associated protein 4 (CTLA4) limits T-cell proliferation. The present study looked for associations between symptomatic GSD and polymorphisms of the CTLA4 gene. For this case-control cross-sectional study among Taiwanese, 275 patients with symptomatic GSD and 852 controls were enrolled. Genotyping of CTLA4-318 C/T, +49 A/G, and CT60 A/G single nucleotide polymorphisms (SNPs) was performed by polymerase chain reaction-restriction fragment length polymorphism. The genotype, allele, carrier, and haplotype frequencies were calculated by direct counting or with Haploview 4.1 software. Genotype, allele, carrier, and haplotype frequencies of the CTLA4 SNPs studied were equally distributed in symptomatic GSD patients and controls. No significant associations between symptomatic GSD and these 3 SNPs were observed. Our data suggest that CTLA4-318 C/T, +49 A/G, and CT60 A/G SNPs do not confer increased susceptibility to symptomatic GSD. PMID- 21277930 TI - Comparisons of methamphetamine psychotic and schizophrenic symptoms: a differential item functioning analysis. AB - The concept of negative symptoms in methamphetamine (MA) psychosis (e.g., poverty of speech, flatten affect, and loss of drive) is still uncertain. This study aimed to use differential item functioning (DIF) statistical techniques to differentiate the severity of psychotic symptoms between MA psychotic and schizophrenic patients. Data of MA psychotic and schizophrenic patients were those of the participants in the WHO Multi-Site Project on Methamphetamine Induced Psychosis (or WHO-MAIP study) and the Risperidone Long-Acting Injection in Thai Schizophrenic Patients (or RLAI-Thai study), respectively. To confirm the unidimensionality of psychotic syndromes, we applied the exploratory and confirmatory factor analyses (EFA and CFA) on the eight items of Manchester scale. We conducted the DIF analysis of psychotic symptoms observed in both groups by using nonparametric kernel-smoothing techniques of item response theory. A DIF composite index of 0.30 or greater indicated the difference of symptom severity. The analyses included the data of 168 MA psychotic participants and the baseline data of 169 schizophrenic patients. For both data sets, the EFA and CFA suggested a three-factor model of the psychotic symptoms, including negative syndrome (poverty of speech, psychomotor retardation and flatten/incongruous affect), positive syndrome (delusions, hallucinations and incoherent speech) and anxiety/depression syndrome (anxiety and depression). The DIF composite indexes comparing the severity differences of all eight psychotic symptoms were lower than 0.3. The results suggest that, at the same level of syndrome severity (i.e., negative, positive, and anxiety/depression syndromes), the severity of psychotic symptoms, including the negative ones, observed in MA psychotic and schizophrenic patients are almost the same. PMID- 21277931 TI - Assessment of general anaesthetic cytotoxicity in murine cortical neurones in dissociated culture. AB - General anaesthetics are proposed to cause unconsciousness by modulating neuronal excitability in the mammalian brain through mechanisms that include enhancement of inhibitory GABA(A) receptor currents and suppression of excitatory glutamate receptor responses. Both intravenous and volatile agents may produce neurotoxic effects during early postnatal rodent brain development through similar mechanisms. In the following study, we investigated anaesthetic cytotoxicity in primary cortical neurones and glia from postnatal day 2-8 mice. Cultures at 4-20 days in vitro were exposed to combinations of ketamine (100 MUM to 3 mM), nitrous oxide (75%, v/v) and/or isoflurane (1.5-5%, v/v) for 6-12 h. Neuronal survival and cell death were measured via microtubule associated protein 2 immunoassay and lactate dehydrogenase release assays, respectively. Clinically relevant anaesthetic concentrations of ketamine, nitrous oxide and isoflurane had no significant neurotoxic effects individually or when given as anaesthetic cocktails, even with up to 12 h exposure. This lack of neurotoxicity was observed regardless of whether cultures were prepared from postnatal day 0-2 or day 8 mice, and was also unaffected by number of days in vitro (DIV 4-20). Significant neurotoxic effects were only observed at supraclinical concentrations (e.g. 1-3 mM ketamine). Our study suggests that neurotoxicity previously reported in vivo is not due to direct cytotoxicity of anaesthetic agents, but results from other impacts of the anaesthetised state during early brain development. PMID- 21277932 TI - Structural basis for both pro- and anti-inflammatory response induced by mannose specific legume lectin from Cymbosema roseum. AB - Legume lectins, despite high sequence homology, express diverse biological activities that vary in potency and efficacy. In studies reported here, the mannose-specific lectin from Cymbosema roseum (CRLI), which binds N glycoproteins, shows both pro-inflammatory effects when administered by local injection and anti-inflammatory effects when by systemic injection. Protein sequencing was obtained by Tandem Mass Spectrometry and the crystal structure was solved by X-ray crystallography using a Synchrotron radiation source. Molecular replacement and refinement were performed using CCP4 and the carbohydrate binding properties were described by affinity assays and computational docking. Biological assays were performed in order to evaluate the lectin edematogenic activity. The crystal structure of CRLI was established to a 1.8A resolution in order to determine a structural basis for these differing activities. The structure of CRLI is closely homologous to those of other legume lectins at the monomer level and assembles into tetramers as do many of its homologues. The CRLI carbohydrate binding site was predicted by docking with a specific inhibitory trisaccharide. CRLI possesses a hydrophobic pocket for the binding of alpha aminobutyric acid and that pocket is occupied in this structure as are the binding sites for calcium and manganese cations characteristic of legume lectins. CRLI route-dependent effects for acute inflammation are related to its carbohydrate binding domain (due to inhibition caused by the presence of alpha methyl-mannoside), and are based on comparative analysis with ConA crystal structure. This may be due to carbohydrate binding site design, which differs at Tyr12 and Glu205 position. PMID- 21277933 TI - S-carbamoylation impairs the oxidant scavenging activity of cysteine: its possible impact on increased LDL modification in uraemia. AB - Carbamoylation is the non-enzymatic reaction of cyanate with amino-, hydroxy- or thiol groups. In vivo, amino group modification (N-carbamoylation) resulting in altered function of proteins/amino acids has been observed in patients suffering from uraemia due to urea-derived cyanate. Uraemia has been linked to impaired antioxidant defense. As thiol-compounds like cysteine, N-acetyl cysteine and GSH have oxidant scavenging properties one may speculate that thiol-group carbamoylation (S-carbamoylation) may impair their protective activity. Here we report on the effect of S-carbamoylation on the ABTS free radical and HOCl scavenging property of cysteine as well on its ability to protect LDL from atherogenic modification induced by AAPH generated peroxylradicals or HOCl. The results show that S-carbamoylation impaired the ABTS free radical and HOCl scavenging property of the thiol-compounds tested. The ability of the thiols to protect LDL from lipid oxidation and apolipoprotein modification was strongly diminished by S-carbamoylation. The data indicate that S-carbamoylation could impair the free radical and HOCl scavenging of thiol-amino acids reducing their protective property against LDL atherogenic modification by these oxidant species. As S-carbamoylation is most effective at pH 7 to 5 in vivo thiol carbamoylation may especially occur at sites of acidic extracellular pH as in hypoxic/inflammatory macrophage rich areas like the atherosclerotic plaque where increased LDL oxidation has been found and may contribute to the higher oxidative stress in uraemia. PMID- 21277935 TI - Threat and trait anxiety affect stability of gaze fixation. AB - Threat accelerates early visual information processing, as shown by shorter P100 latencies of pattern Visual Evoked Potentials in subjects with low trait anxiety, but the opposite is true for high anxious subjects. We sought to determine if, and how, threat and trait anxiety interact to affect stability of gaze fixation. We used video oculography to record gaze position in the presence and in the absence of a fixational stimulus, in a safe and a verbal threat condition in subjects characterised for their trait anxiety. Trait anxiety significantly predicted fixational instability in the threat condition. An extreme tertile analysis revealed that fixation was less stable in the high anxiety group, especially under threat or in the absence of a stimulus. The effects of anxiety extend to perceptual and sensorimotor processes. These results have implications for the understanding of individual differences in occulomotor planning and visually guided behavior. PMID- 21277934 TI - The neural correlates of cognitive effort in anxiety: effects on processing efficiency. AB - We investigated the neural correlates of cognitive effort/pre-target preparation (Contingent Negative Variation activity; CNV) in anxiety using a mixed antisaccade task that manipulated the interval between offset of instructional cue and onset of target (CTI). According to attentional control theory (Eysenck et al., 2007) we predicted that anxiety should result in increased levels of compensatory effort, as indicated by greater frontal CNV, to maintain comparable levels of performance under competing task demands. Our results showed that anxiety resulted in faster antisaccade latencies during medium compared with short and long CTIs. Accordingly, high-anxious individuals compared with low anxious individuals showed greater levels of CNV activity at frontal sites during medium CTI suggesting that they exerted greater cognitive effort and invested more attentional resources in preparation for the task goal. Our results are the first to demonstrate the neural correlates of processing efficiency and compensatory effort in anxiety and are discussed within the framework of attentional control theory. PMID- 21277936 TI - Targeting of active mTOR inhibits primary leukemia T cells and synergizes with cytotoxic drugs and signaling inhibitors. AB - OBJECTIVE: Rationally designed therapies aim at the specific disruption of critical signaling pathways activated by malignant transformation or signals from the tumor microenvironment. Because mammalian target of rapamycin (mTOR) is an important signal integrator and a key translational regulator, we evaluated its potential involvement in T-cell acute lymphoblastic leukemia (T-ALL) and whether mTOR blockade synergizes with chemotherapeutic agents or other signaling antagonists to inhibit primary leukemia T cells. MATERIALS AND METHODS: mTOR signaling status was assessed using biochemical, immunostaining, and molecular regulation studies and functional assays performed to assess the impact of mTOR blockade on T-ALL proliferation, survival, and cell cycle. RESULTS: We observed that mTOR signaling is highly activated in all T-ALL patients tested, with phosphorylation of its downstream substrates eIF4G and S6 ribosomal protein. mTOR activation was detected in vivo and was further increased in vitro by stimulation with interleukin-7, a potentially leukemogenic cytokine normally produced by the bone marrow microenvironment. In T-ALL cells, mTOR blockade was associated with accumulation of the cyclin-dependent kinase inhibitor p27(kip1), which preferentially adopted a nuclear localization. Functional studies using rapamycin or CCI-779 showed a dominant inhibitory effect of mTOR blockade on interleukin-7 induced proliferation, survival, and cell-cycle progression of T-ALL cells. Furthermore, mTOR blockade markedly potentiated the antileukemia effects of dexamethasone and doxorubicin, and showed highly synergistic interactions in combination with specific inhibitors of phosphatidylinositol 3-kinase/Akt and Janus kinase 3 signaling. CONCLUSIONS: This study shows activation of mTOR signaling in primary T-ALL cells evolving in the leukemic bone marrow, and supports the inclusion of mTOR antagonists in current therapeutic regimens for this cancer. PMID- 21277937 TI - Biochemical mechanism of pathogenesis of human gonadotropin-releasing hormone receptor mutants Thr104Ile and Tyr108Cys associated with familial hypogonadotropic hypogonadism. AB - The pathogenic mechanisms whereby the Thr104Ile and Tyr108Cys mutations in the gonadotropin-releasing hormone receptor (GnRHR) gene cause hypogonadotropic hypogonadism in humans are unknown. Transient expression of Thr104Ile and Tyr108Cys mutants in COS-7 cells revealed that both GnRHR mutants neither bind nor respond to agonist. Removal of Lys191 rescued function of both mutants, while addition of a carboxyl-terminal targeting sequence only rescued function of the Thr104Ile mutant. Exposure to the pharmacoperone In3 rescued almost completely Thr104Ile mutant function to wild-type levels, whereas rescue was partial for the Tyr108Cys GnRHR. Additional mutations that block formation of bridges involving Cys108 showed that a Cys108-Cys200 disulfide bridge is the predominant moiety formed in the Tyr108Cys mutant. Thr104Ile and Tyr108Cys GnRHRs are misfolded structures whose function is rescuable by genetic and/or pharmacological strategies. The Tyr108Cys mutant forms an aberrant disulfide bridge that prevents formation of the required Cys14-Cys200 bridge essential for GnRHR plasma membrane expression. PMID- 21277938 TI - Protected from the inside: endogenous histone deacetylase inhibitors and the road to cancer. AB - Histone deacetylases (HDACs) play a crucial role in several physiological and pathological cell functions, including cell development and cancer, by deacetylating both histones and others proteins. HDACs belong to a large family of enzymes including Class I, II and IV as well as Class III or sirtuins subfamilies, that undergo a complex transcriptional and post-translational regulation. In current years, antitumor therapy is attempting to exploit several chemical classes of inhibitors that target HDACs, frequently reported to be misregulated in cancer. Nevertheless, the identity of gene products directly involved in tumorigenesis and preventing HDAC misregulation in cancer is still poorly understood. Recent evidence has demonstrated that the tumor suppressors HIC1 and DBC1 induce direct repression of Sirt1 function, whereas Chfr and REN(KCTD11/KASH family) downregulate HDAC1, by inducing its ubiquitin-dependent degradation. Loss of these gene products leads to imbalanced enhancement of HDAC activity and subsequently to oncogenesis. All these genes are frequently deleted or silenced in human cancers, highlighting the role of endogenous HDAC inhibitors to counteracts HDAC-mediated tumorigenesis. Thus, endogenous HDAC inhibitors represent a promising class of "antitumor agents" thanks to which oncogenic addiction pathways may be selectively therapeutically targeted. PMID- 21277940 TI - Modulation of botulinum toxin-induced changes in neuromuscular function with antibodies directed against recombinant polypeptides or fragments. AB - Botulinum toxin is an agent that is typically encountered in two settings: as an agent that can cause disease (e.g. botulism), and as an agent that can be used to treat disease (i.e., a variety of neurologic disorders). In both cases it would be advantageous to develop a sound understanding of the mechanisms by which antibodies neutralize the toxin. In the present study, recombinant antigens were used to generate antibodies against the carboxyterminal half of the toxin heavy chain (HC50), the entire toxin light chain (LC), and the HA17, HA35 and HA70 components of the progenitor toxin complex. These antibodies were then evaluated for their respective abilities to alter botulinum toxin-induced changes in locomotor behavior in mice. The botulinum toxin type A complex was shown to produce dose-dependent depression of locomotor behavior within the dose range of 0.3-0.7 mouse LD50 units. At a dose of 0.5 LD50, the toxin typically reduced running behavior by 90% or more, and full recovery was not observed for approximately 4 weeks. Mice that were actively or passively vaccinated against the HC50 polypeptide were resistant to toxin action, presumably because the antibodies occluded the toxin binding domain. Interestingly, mice that were actively or passively vaccinated against LC were also resistant to toxin action. This effect may have been due to steric hindrance of the binding process. There was no scenario in which anti-HA antibodies altered the effects of toxin on locomotor behavior. This absence of effect was likely due to the fact that HAs and neurotoxin in the progenitor toxin complex spontaneously dissociate in physiologic media. PMID- 21277939 TI - Mucins in the pathogenesis of breast cancer: implications in diagnosis, prognosis and therapy. AB - Mucins are high molecular weight, multifunctional glycoproteins comprised of two structural classes-the large transmembrane mucins and the gel-forming or secreted mucins. The primary function of mucins is to protect and lubricate the luminal surfaces of epithelium-lined ducts in the human body. Recent studies have identified a differential expression of both membrane bound (MUC1, MUC4 and MUC16) and secreted mucins (MUC2, MUC5AC, MUC5B and MUC6) in breast cancer tissues when compared with the non-neoplastic breast tissues. Functional studies have also uncovered many unique roles of mucins during the progression of breast cancer, which include modulation in proliferative, invasive and metastatic potential of tumor cells. Mucins function through many unique domains that can form complex association with various signaling molecules including growth factor receptors and intercellular adhesion molecules. While there is growing information about mucins in various malignancies including breast cancer, no focused review is there on the expression and functional roles of mucins in breast cancer. In this present review, we have discussed the differential expression and functional roles of mucins in breast cancer. The potential of mucins as diagnostic and prognostic markers and as therapeutic targets in breast cancer have also been discussed. PMID- 21277941 TI - Role of neurotrophins on postnatal neurogenesis in the thalamus: prenatal exposure to ethanol. AB - A second wave of neuronal generation occurs in the ventrobasal nucleus of the rat thalamus (VB) during the first three postnatal weeks. The present study tested the hypotheses (1) that postnatal neurogenesis in the VB is neurotrophin regulated and (2) that ethanol-induced changes in this proliferation are mediated by neurotrophins. The first studies examined the effects of neurotrophins on the numbers of cycling cells in ex vivo preparations of the VB from 3-day-old rats. The proportion of cycling (Ki-67-positive) VB cells was higher in cultured thalamic slices treated with neurotrophins than in controls. Interestingly, this increase occurred with nerve growth factor (NGF) alone or with a combination of NGF and brain-derived neurotrophic factor (BDNF), but not with BDNF alone. Based on these data, the VBs from young offspring of pregnant rats fed an ethanol containing or an isocaloric non-alcoholic liquid diet were examined between postnatal day (P) 1 and P31. Studies used enzyme-linked immunosorbent assays and immunoblots to explore the effects of ethanol on the expression of neurotrophins, their receptors, and representative signaling proteins. Ethanol altered the expression of neurotrophins and receptors throughout the first postnatal month. Expression of NGF increased, but there was no change in the expression of BDNF. The high affinity receptors (TrkA and TrkB) were unchanged but ethanol decreased expression of the low affinity receptor, p75. One downstream signaling protein, extracellular signal-regulated kinase (ERK), decreased but Akt expression was unchanged. Thus, postnatal cell proliferation in the VB of young rat pups is neurotrophin-responsive and is affected by ethanol. PMID- 21277942 TI - Functional neuroanatomy associated with the expression of distinct movement kinematics in motor sequence learning. AB - A broad range of motor skills, such as speech and writing, evolves with the ability to articulate elementary motor movements into novel sequences that come to be performed smoothly through practice. Neuroimaging studies in humans have demonstrated the involvement of the cerebello-cortical and striato-cortical motor loops in the course of motor sequence learning. Nonetheless, the nature of the improvement and brain mechanisms underlying different parameters of movement kinematics are not yet fully ascertained. We aimed at dissociating the cerebral substrates related to the increase in performance on two kinematic indices: velocity, that is the speed with which each single movement in the sequence is produced, and transitions, that is the duration of the gap between these individual movements. In this event-related fMRI experiment, participants practiced an eight-element sequence of finger presses on a keypad which allowed to record those kinematic movement parameters. Velocity was associated with activations in the ipsilateral spinocerebellum (lobules 4-5, 8 and medial lobule 6) and in the contralateral primary motor cortex. Transitions were associated with increased activity in the neocerebellum (lobules 6 bilaterally and lobule 4 5 ipsilaterally), as well as with activations within the right and left putamen and a broader bilateral network of motor cortical areas. These findings indicate that, rather than being the product of a single mechanism, the general improvement in motor performance associated with early motor sequence learning arises from at least two distinct kinematic processes, whose behavioral expressions are supported by partially overlapping and segregated brain networks. PMID- 21277943 TI - Characterisation of a novel model of Parkinson's disease by intra-striatal infusion of the pesticide rotenone. AB - One of the most promising models of Parkinson's disease to have emerged in recent years is one in which the pesticide, rotenone, is administered systemically to laboratory rats. However, this model is associated with peripheral toxicity and high mortality rates which impede its widespread application in preclinical drug discovery research. This study sought to determine if administration of rotenone directly into the rat striatum could also mimic the motor dysfunction and neuropathological features of the human condition while overcoming the toxicity associated with systemic administration. Male Sprague-Dawley rats were infused with control or rotenone solutions into the striatum. The effect of the pesticide on body weight and spontaneous motor function (Corridor, Stepping and Whisker Tests) was assessed ante mortem, and its effect on nigrostriatal integrity (quantitative tyrosine hydroxylase immunohistochemistry), alpha-synuclein expression (quantitative alpha-synuclein immunohistochemistry), and striatal neurotransmitter content (HLPC for dopamine, GABA and noradrenaline) was assessed post mortem. Intra-striatal infusion of rotenone had no detrimental effect on the rats' body weight but caused significant impairments in contralateral motor function. Neuropathologically, rotenone caused significant nigrostriatal degeneration and selective loss of dopamine from the striatum but there was no evidence of any change in alpha-synuclein expression in the rotenone-infused rats. This study shows intra-striatal rotenone to be capable of modelling some of the main behavioural and neuropathological features of human Parkinsonism, while being less toxic than its systemic counterpart. Thus, this model may prove to be useful in future Parkinson's disease drug discovery programmes. PMID- 21277944 TI - Role for protein kinase C in controlling Aplysia bag cell neuron excitability. AB - Targeting signalling molecules to ion channels can expedite regulation and assure the proper transition of changes to excitability. In the bag cell neurons of Aplysia, single-channel studies of excised patches have revealed that protein kinase C (PKC) gates a non-selective cation channel through a close, physical association. This channel drives a prolonged afterdischarge and concomitant neuropeptide secretion to provoke reproductive behaviour. However, it is not clear if PKC alters cation channel function and/or the membrane potential at the whole-cell level. Afterdischarge-like depolarizations can be evoked in cultured bag cell neurons by bath-application of Conus textile venom (CtVm), which triggers the cation channel through an apparent intracellular pathway. The present study shows that the CtVm-induced depolarization was reduced by nearly 50% compared to control following dialysis with the G-protein blocker, guanosine 5'-O-2-thiodiphosphate (GDP-beta-S), or treatment with either the phospholipase C inhibitor, 1-[6-[[(17beta)-3-Methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H pyrrole-2,5-dione (U-73122), or the PKC inhibitor, sphinganine. Neurons exposed to the PKC activator, phorbol 12-myristate 13-acetate (PMA), displayed depolarization with accompanying spiking, and were found to be far more responsive to depolarizing current injection versus control. Immunocytochemical staining for the two typical Aplysia PKC isoforms, Apl I and Apl II, revealed that both kinases were present in unstimulated cultured bag cell neurons. However, in CtVm-treated neurons, the staining intensity for PKC Apl I increased, peaking at 10 min post-application. Conversely, the intensity of PKC Apl II staining decreased over the duration of CtVm exposure. Our results suggest that the CtVm-induced depolarization involves PKC activation, and is consistent with prior work showing PKC closely-associating with the cation channel to produce the depolarization necessary for the afterdischarge and species propagation. PMID- 21277945 TI - The majority of myelinated and unmyelinated sensory nerve fibers that innervate bone express the tropomyosin receptor kinase A. AB - Although skeletal pain is a leading cause of chronic pain and disability, relatively little is known about the specific populations of nerve fibers that innervate the skeleton. Recent studies have reported that therapies blocking nerve growth factor (NGF) or its cognate receptor, tropomyosin receptor kinase A (TrkA) are efficacious in attenuating skeletal pain. A potential factor to consider when assessing the analgesic efficacy of targeting NGF-TrkA signaling in a pain state is the fraction of NGF-responsive TrkA+ nociceptors that innervate the tissue from which the pain is arising, as this innervation and the analgesic efficacy of targeting NGF-TrkA signaling may vary considerably from tissue to tissue. To explore this in the skeleton, tissue slices and whole mount preparations of the normal, adult mouse femur were analyzed using immunohistochemistry and confocal microscopy. Analysis of these preparations revealed that 80% of the unmyelinated/thinly myelinated sensory nerve fibers that express calcitonin gene-related peptide (CGRP) and innervate the periosteum, mineralized bone and bone marrow also express TrkA. Similarly, the majority of myelinated sensory nerve fibers that express neurofilament 200 kDa (NF200) which innervate the periosteum, mineralized bone and bone marrow also co-express TrkA. In the normal femur, the relative density of CGRP+, NF200+ and TrkA+ sensory nerve fibers per unit volume is: periosteum>bone marrow>mineralized bone>cartilage with the respective relative densities being 100:2:0.1:0. The observation that the majority of sensory nerve fibers innervating the skeleton express TrkA+, may in part explain why therapies that block NGF/TrkA pathway are highly efficacious in attenuating skeletal pain. PMID- 21277946 TI - Delta opioid receptors colocalize with corticotropin releasing factor in hippocampal interneurons. AB - The hippocampal formation (HF) is an important site at which stress circuits and endogenous opioid systems intersect, likely playing a critical role in the interaction between stress and drug addiction. Prior study findings suggest that the stress-related neuropeptide corticotropin releasing factor (CRF) and the delta opioid receptor (DOR) may localize to similar neuronal populations within HF lamina. Here, hippocampal sections of male and cycling female adult Sprague Dawley rats were processed for immunolabeling using antisera directed against the DOR and CRF peptide, as well as interneuron subtype markers somatostatin or parvalbumin, and analyzed by fluorescence and electron microscopy. Both DOR- and CRF-labeling was observed in interneurons in the CA1, CA3, and dentate hilus. Males and normal cycling females displayed a similar number of CRF immunoreactive neurons co-labeled with DOR and a similar average number of CRF-labeled neurons in the dentate hilus and stratum oriens of CA1 and CA3. In addition, 70% of DOR/CRF dual-labeled neurons in the hilar region co-labeled with somatostatin, suggesting a role for these interneurons in regulating perforant path input to dentate granule cells. Ultrastructural analysis of CRF-labeled axon terminals within the hilar region revealed that proestrus females have a similar number of CRF-labeled axon terminals that contain DORs compared to males but an increased number of CRF-labeled axon terminals without DORs. Taken together, these findings suggest that while DORs are anatomically positioned to modulate CRF immunoreactive interneuron activity and CRF peptide release, their ability to exert such regulatory activity may be compromised in females when estrogen levels are high. PMID- 21277947 TI - Heightening of the stress response during the first weeks after a mild traumatic brain injury. AB - The effects of a mild traumatic brain injury range from white matter disruption to affective disorders. We set out to determine the response to restraint-induced stress after a mild fluid-percussion injury (FPI), an experimental model for brain injury. Hypothalamic-pituitary-adrenal (HPA) axis regulation of corticosterone (CORT) and adrenocorticotropic hormone (ACTH) was determined during the first post-injury weeks, which corresponds to the same time period when rehabilitative exercise has been shown to be ineffective after a mild FPI. Adult male rats underwent either an FPI or sham injury. Additional rats were only exposed to anesthesia. HPA regulation was evaluated by measuring the effects of dexamethasone (DEX) treatment on CORT and ACTH. Tail vein blood was collected following 30-min restraint stress, at post-injury days (PID) 1, 7 and 14, prior to (0 min) and at 30, 60, 90 and 120 min after stress onset. Results from these studies indicate that the stress response was significantly more pronounced after FPI in that CORT and ACTH restraint-induced increases were more pronounced and longer lasting compared to controls. DEX suppression of CORT and ACTH was observed in all groups, suggesting that stress hyper-responsiveness after mild FPI is not attributable to reduced sensitivity of CORT feedback regulation. The increased sensitivity to stressful events in the first two post-injury weeks after a mild FPI may have a negative impact on early rehabilitative therapies. PMID- 21277948 TI - Mechanical stimulation enhances endothelin-1 hyperalgesia. AB - When comparing a cumulative dose-response curve for endothelin-1 (ET-1)-induced mechanical hyperalgesia to the effect of individual doses (1 ng, 10 ng, 100 ng, and 1 MUg) administered in separate groups of rats, a marked difference was observed in the peak magnitude of hyperalgesia. Hyperalgesia was measured as decrease in the threshold for mechanically-induced withdrawal of the hind paw. The cumulative dosing protocol produced markedly greater maximum hyperalgesia. To determine whether this was due to the cumulative dosing protocol or to the repeated exposure to the mechanical test stimulus, we evaluated the impact of repeated testing on ET-1-induced mechanical hyperalgesia. While ET-1-induced mechanical hyperalgesia was dose- and time-dependent, repeated testing of nociceptive threshold, at 5 min intervals, following a single dose of ET-1, produced further decrease in nociceptive threshold. This mechanical stimulation induced enhancement of ET-1 hyperalgesia lasted only 3-4 h, while the hyperalgesia lasted in excess of 5 days. The stimulation-enhanced hyperalgesia also occurred after a second injection of ET-1, administered 24 h after the initial dose. That this phenomenon is unique to ET-1 is suggested by the observation that while five additional, direct-acting hyperalgesic agents prostaglandin E2 (PGE2), nerve growth factor (NGF), glia-derived neurotrophic factor (GDNF), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFalpha) induced robust mechanical hyperalgesia, none produced mechanical stimulation enhanced hyperalgesia. PMID- 21277949 TI - Age-dependent effects of initial exposure to nicotine on serotonin neurons. AB - Adolescence is a critical vulnerable period during which exposure to nicotine greatly enhances the possibility to develop drug addiction. Growing evidence suggests that serotonergic (5-HT) neurotransmission may contribute to the initiation and maintenance of addictive behavior. As the dorsal raphe (DR) and median raphe (MnR) nuclei are the primary 5-HT source to the forebrain, the current study tested the hypothesis that there are age-dependent effects of acute nicotine administration on activation of 5-HT neurons within these regions. Both adolescent (Postnatal day 30) and adult (Postnatal day 70) male Sprague-Dawley rats received subcutaneous injection of either saline or nicotine (0.2, 0.4, or 0.8 mg/kg). Subsequently, the number of 5-HT cells that were double-labeled for Fos and tryptophan hydroxylase was counted in seven subregions within the DR and the entire MnR. The results show that acute nicotine injection induces Fos expression in 5-HT neurons in a region-specific manner. In addition, adolescents show broader regional activations at either a lower (0.2 mg/kg) and a higher (0.8 mg/kg) dose of nicotine, displaying a unique U-shape response curve across doses. In contrast, 5-HT cells with activated Fos expression were restricted to fewer regions in adults, and the patterns of expression were more consistent across doses. The results reveal dose-dependent effects of nicotine during adolescence with apparent sensitization at different ends of the dosage spectrum examined compared to adults. These data indicate that initial exposure to nicotine may have unique effects in adolescence on the ascending 5-HT system, with the potential for consequences on the affective-motivational qualities of the drug and the subsequent propensity for repeated use. PMID- 21277951 TI - Silent information regulator 1 mediates hippocampal plasticity through presenilin1. AB - Silent information regulator 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase directly implicated in protecting a wide range of organisms against internal and external metabolic insults. However, the identification of SIRT1-specific DNA targets that confer such protection have remained elusive. Using human cells, we show that SIRT1 binds to, and transcriptionally regulates, a gene locus encoding presenilin1 (PSEN1), a protein intrinsically involved in the function of the gamma-secretase protein complex. We also demonstrate that rats fed with resveratrol exhibit a significant increase in sirt1 and psen1 expression. Finally, dietary consumption of resveratrol also leads to an enhanced proliferative state of neuronal stem cells in the rat hippocampus. Our findings reveal a strong link between resveratrol-dependent SIRT1 signaling and hippocampal plasticity in the mammalian brain. PMID- 21277950 TI - Investigation of a central nucleus of the amygdala/dorsal raphe nucleus serotonergic circuit implicated in fear-potentiated startle. AB - Serotonergic systems are thought to play an important role in control of motor activity and emotional states. We used a fear-potentiated startle paradigm to investigate the effects of a motor-eliciting stimulus in the presence or absence of induction of an acute fear state on serotonergic neurons in the dorsal raphe nucleus (DR) and cells in subdivisions of the central amygdaloid nucleus (CE), a structure that plays an important role in fear responses, using induction of the protein product of the immediate-early gene, c-Fos. In Experiment 1 we investigated the effects of fear conditioning training, by training rats to associate a light cue (conditioned stimulus, CS; 1000 lx, 2 s) with foot shock (0.5 s, 0.5 mA) in a single session. In Experiment 2 rats were given two training sessions identical to Experiment 1 on days 1 and 2, then tested in one of four conditions on day 3: (1) placement in the training context without exposure to either the CS or acoustic startle (AS), (2) exposure to 10 trials of the 2 s CS, (3) exposure to 40 110 dB AS trials, or (4) exposure to 40 110 dB AS trials with 10 of the trials preceded by and co-terminating with the CS. All treatments were conducted during a 20 min session. Fear conditioning training, by itself, increased c-Fos expression in multiple subdivisions of the CE and throughout the DR. In contrast, fear-potentiated startle selectively increased c-Fos expression in the medial subdivision of the CE and in serotonergic neurons in the dorsal part of the dorsal raphe nucleus (DRD). These data are consistent with previous studies demonstrating that fear-related stimuli selectively activate DRD serotonergic neurons. Further studies of this mesolimbocortical serotonergic system could have important implications for understanding mechanisms underlying vulnerability to stress-related psychiatric disorders, including anxiety and affective disorders. PMID- 21277952 TI - Cholinergic cells in the tegmentum send branching projections to the inferior colliculus and the medial geniculate body. AB - The pontomesencephalic tegmentum (PMT) provides cholinergic input to the inferior colliculus (IC) and the medial geniculate body (MG). PMT cells are often characterized as projecting to more than one target. The purpose of this study was to determine whether individual PMT cholinergic cells, (1) innervate the auditory pathways bilaterally via collateral projections to left and right auditory thalamus; or, (2) innervate multiple levels of the auditory pathways via collateral projections to the auditory thalamus and inferior colliculus. We used multiple retrograde tracers to identify individual PMT cells that project to more than one target. We combined the retrograde tracer studies with immunohistochemistry for choline acetyltransferase to determine whether the projecting cells were cholinergic. We found that individual PMT cells send branching axonal projections to two or more auditory targets in the midbrain and thalamus. The collateral projection pattern that we observed most frequently was to the ipsilateral IC and ipsilateral MG. Cells projecting to both MGs were somewhat less common, followed by cells projecting to the contralateral IC and ipsilateral MG. Both cholinergic and non-cholinergic cells contribute to each of these projection patterns. Less often, we found cells that project to one IC and both MGs; there was no evidence for non-cholinergic cells in this projection pattern. It is likely that collateral projections from PMT cells could have coordinated effects bilaterally and at multiple levels of the ascending auditory pathways. PMID- 21277953 TI - A calcium-dependent glutamate release induced by metabotropic glutamate receptors I/II promotes GABA efflux from amacrine cells via a transporter-mediated process. AB - Glutamate and GABA are, respectively, the major excitatory and inhibitory neurotransmitters in the retina, participating in the two pathways through which the retina processes light information. It has already been shown that glutamate induces GABA release from amacrine cells through a transporter-mediated mechanism, and that this process is mediated by ionotropic glutamate receptors. It is well established that glutamate can also activate metabotropic glutamate receptors, which are widely distributed in the retina, and can be detected in amacrine cell bodies and synaptic contacts. Thus, we decided to investigate the role of the activation of groups I and II metabotropic glutamate receptors in GABA release from amacrine cells in the chicken retina. Group I/II agonist trans ACPD promoted a 40% decrease in the number of GABA-positive cells in relation to the control, effect that was prevented by antagonists of both groups. Also, the trans-ACPD effect was blocked by GAT-1 inhibitor or by antagonists of ionotropic glutamate receptors. Trans-ACPD induced release of GABA was abolished when the experiment was conducted in absence of calcium ions. Under the superfusing conditions used, trans-ACPD promoted an increase in endogenous glutamate release that was prevented when calcium was omitted from the bathing medium. The results suggest that mGluRI/II regulate the release of glutamate, likely from bipolar cells, that in turn activates GABA release from amacrine cells via a transporter mediated process. PMID- 21277954 TI - Comparative protective action of curcumin, memantine and diclofenac against scopolamine-induced memory dysfunction. AB - The comparative preventive effect of curcumin, memantine, and diclofenac on scopolamine-induced memory dysfunction was investigated in a controlled study. A group of male and female rats was treated with one of these compounds for 15 days, after which a single dosage of scopolamine was administered. The preventive activity of curcumin on memory dysfunction was higher than that of diclofenac or memantine, that was, however, administered at lower dosages. Gender differences were observed. PMID- 21277955 TI - Antioxidant flavanes from Livistona chinensis. AB - Three new flavanes and eight known flavonoids were isolated from the fruits of Livistona chinensis. The structure of the new flavanes were established as 2S,3S 3,5,7,3',5'-pentahydroxyflavane (1), 2R,3R-3,5,6,7,8,4'-hexahydroxyflavane (2) and 2R,3R-3,5,6,7,8,3',5'-heptahydroxyflavane (3), respectively, on the basis of chemical and spectroscopic data. The antiproliferative activity against four human tumor cell lines (HL-60, Mata, HepG2 and CNE-1) was evaluated. 1 had significantly antiproliferative effects against HL-60 and CNE-1 with the IC(50) of 0.2 +/- 0.01 and 1.0 +/- 0.1 MUM, respectively, overpowering the reference compound in the assay (cisplatin). Most compounds also exhibited potent antioxidant activity. PMID- 21277956 TI - Optimal risky choice in humans: effects of amount of variability. AB - The present study investigated whether the predictions of an optimal risk sensitive foraging model (the energy-budget rule) would extend to humans' choices between high- and low-variance monetary response options. In Experiment 1, participants were presented with repeated choices between two options that had the same mean values but different variances across positive- and negative-budget conditions. In Experiment 2, a within-subject comparison was conducted to investigate choice under positive- and negative-budget conditions when the options were either (a) a fixed option and a high-variance option, or (b) a low variance option and a high-variance option. Session-wide choices were analyzed in relation to the predictions of the energy-budget rule and sequential choices were analyzed with dynamic optimization modeling. When both options were variable choice was generally consistent with predictions of the energy-budget rule and was more risk prone under negative-budget than positive-budget conditions. Sequential choices were sensitive to local budget conditions, but choices were less consistent with optimality when both options were variable, possibly because of the greater similarity in expected earnings for optimal and nonoptimal choices in these conditions. Overall, the results provide further evidence that the energy-budget rule may have broad applicability and that it can extend to human risky choice between multiple variable response options. PMID- 21277957 TI - Exceptional human core promoter nucleotide compositions. AB - The proximal promoter sequences contain basic motifs for the expression of the downstream genes. We present genome-scale computational analyses of the 120-bp immediate upstream sequences to the +1 transcription start sites (TSSs) of 10,117 human protein-coding genes, and unravel exceptional genes in respect with the core promoter nucleotide composition. Our data reveal that while in 99% of the genes the absolute purine/pyrimidine ratio ranges between 0.2 and 2.5, certain genes show exceptional skew in this balance (e.g. ratios of 82.3 in VWA3A, 61.5 in Sox5, and 24.0 in BRWD3), and consist of islands of purines or pyrimidines. Furthermore, while over 95% of the genes lack more than one short tandem repeat (STR) in their core promoters, certain gene promoters are exceptionally rich in multiple STRs (e.g. eight consecutive STRs in UBE2QL1, and six STRs in GRIA2). We found sequence bias for the majority of those promoters across species, supporting functional roles for them in gene expression. Genes downstream to those promoters were also found to be of ontologic importance (i.e. we were able to track the majority of those genes to the lower species such as Saccharomyces cerevisiae and Caenorhabditis elegans). The exceptional promoters presented in this study lack the conventional motifs for the TATA, and TATA-less promoters, hence offering novel mechanisms for gene expression. They may also provide potential mechanisms for inter-individual variations in gene expression, and complex traits/disorders. PMID- 21277958 TI - Effect of bisphenol-A on the expression of selected genes involved in cell cycle and apoptosis in the OVCAR-3 cell line. AB - To support the argument that bisphenol-A (BPA) poses a risk for ovarian cancer, OVCAR-3 cell line was exposed to environmentally relevant concentration of BPA. Expression of selected genes involved in cell cycle and apoptosis were evaluated by real-time PCR. In a dose-dependent manner, BPA increased OVCAR-3 cell proliferation and decreased caspase-3 activity, but it had no effect on DNA fragmentation. We noted 1.2-1.5-fold induction of genes responsible for inducing cell proliferation and 1.2-46-fold suppression of genes responsible for inhibition of proliferation. Moreover, 1.6-8-fold suppression of genes involved in the extrinsic apoptotic pathway was observed. In parallel, 1.3-2.5-fold suppression pro-apoptotic genes and 1.6-51-fold induction of pro-survival genes involved in the intrinsic apoptotic pathway were observed. Additionally, 1.7-fold induction of p53 and 5-fold induction of endonuclease G genes involved in CAD independent DNA fragmentation were noted under the influence of BPA. In conclusion, we hypothesize that induction of p53 and suppression of caspase-3 and 7 gene expression observed in this study activate the DNA repair process. Therefore, despite the observed induction of endo G gene expression, the action of BPA on DNA fragmentation was not observed. PMID- 21277959 TI - Photoprotective efficacy and photostability of fifteen sunscreen products having the same label SPF subjected to natural sunlight. AB - The first objective of this study is to show how different can be photoprotection by sunscreens with an identical SPF given on the packaging, when subjected to sunlight radiation. The second objective is to highlight the need for global harmonization of photostability testing and UVA protection labelling. Fifteen products with various combinations of UV filters marketed in Europe were assessed based on transmission measurements of 0.75 mg cm-2 layer covered onto polymethylmethacrylate plate roughness 2 MUm. Two absolute UV spectroscopic indices (in vitro SPF, UVA-PF), four well-known relative UVA indices: the UVA PF/SPF ratio and critical wavelength by European Commission (EC); UVA/UVB ratio by Boots Star Rating system; UVA1/UV ratio by FDA Proposed Ruling and one new relative indices the Spectral Uniformity Index (SUI) by Diffey, were compared before and after sunlight exposure with dose about 42 SEDs. The UVA-PF values before exposure proved a high degree of variation among samples. After exposure only five sunscreens observed UVA protection standard by EC and the same products showed compliance with the first UVA rating by Boots system (three stars). According to the UVA1/UV ratio, except for one product, all sunscreens manifested certain UVA protection level (low, medium or high). In compliance with criteria of new rating proposed by Diffey, exactly all fifteen sunscreens gave some UVA rating exhibited as SUI (low, medium or high). These results mean that the different UVA protection indices can exhibit various data and be confusing for consumer. Photostability of each product was assessed with three indices: the area under curve (Auc) Index for the total UV range, and UVB, UVA, UVA2, UVA1 range separately; the residual effectiveness of in vitro SPF and UVA-PF. All fifteen sunscreens were photostable in the UVB region. Seven products exhibited photoinstability in the total UV range (290-400 nm); all of them contained a combination of the ethylhexyl methoxycinnamate (EHMC) and butyl methoxydibenzoylmethane (BMBM) together with other UV filters. Eight products lacked their stability in the UVA1 range (340-400 nm) thus confirmed that photodegradation of some current sunscreens is primarily problem of this region. The most photoinstability showed sunscreens S1 (EHMC, BMBM and phenylbenzimidazole sulphonic acid) and S6 (EHMC, BMBM, phenylbenzimidazole sulphonic acid and ethylhexyl triazone); Auc-UVA1 Index was 0.15 only. Excellent UVA1 photostability showed sunscreen S8 (EHMC, EHT and methylene bis benzotriazolyl tetramethylbutylphenol); Auc-UVA1 Index was of 1.00. Three sunscreens showed very good UVA1 photostability (Auc-UVA1 Index ranged from 0.98 to 0.93). The fact that these products applied only in the layer of 0.75 mg cm-2 were photostable under the sunlight dose, which corresponds to layer of 2 mg cm 2, is proof of their quality. Comparison of the residual effectiveness of in vitro SPF and UVA-PF values with the Auc-Index showed that methods give a similar ranking of the sunscreens' photostability. PMID- 21277960 TI - Amino acid based amphiphilic copolymer micelles as carriers of non-steroidal anti inflammatory drugs: solubilization, in vitro release and biological evaluation. AB - Three novel amino acid based anionic amphiphilic copolymers poly(sodium N acryloyl-l-valinate-co-alkylacrylamide) (where, alkyl=octyl and dodecyl) with either 9 or 16 mol% hydrophobic substitution were synthesized. These hydrophobically modified polyelectrolytes (HMPs), above a critical concentration, self-assemble in aqueous solution through inter-chain hydrophobic aggregation, forming micelle-like aggregates having hydrodynamic diameter in the range of 50 200 nm. The HMPs were found to undergo conformational changes with the change in solution pH, electrolyte and additive concentration, and temperature. The polymeric micelles were observed to be stable under biological conditions (pH 7.4, [NaCl]=150 mM and temperature (37 degrees C)). The solubilization capacity of the polymeric micelles for six important non-steroidal anti-inflammatory drugs of different hydrophobicity was evaluated. Depending upon the hydrophobicity the solubilities of the drugs were observed to increase ca. 2-10 times in the presence of 1.0 g/L copolymers. The in vitro release kinetics of the loaded drug was studied under physiological pH. To explore their potential application in pharmaceutical industries hemocompatibility and cytotoxicity studies were carried out using hemolytic and MTT assay, respectively. The anionic HMPs were found to be not directly toxic to mammalian cells. PMID- 21277961 TI - Application and use of isothermal calorimetry in pharmaceutical development. AB - There are many steps involved in developing a drug candidate into a formulated medicine and many involve analysis of chemical interaction or physical change. Calorimetry is particularly suited to such analyses as it offers the capacity to observe and quantify both chemical and physical changes in virtually any sample. Differential scanning calorimetry (DSC) is ubiquitous in pharmaceutical development, but the related technique of isothermal calorimetry (IC) is complementary and can be used to investigate a range of processes not amenable to analysis by DSC. Typically, IC is used for longer-term stability indicating or excipient compatibility assays because both the temperature and relative humidity (RH) in the sample ampoule can be controlled. However, instrument design and configuration, such as titration, gas perfusion or ampoule-breaking (solution) calorimetry, allow quantification of more specific values, such as binding enthalpies, heats of solution and quantification of amorphous content. As ever, instrument selection, experiment design and sample preparation are critical to ensuring the relevance of any data recorded. This article reviews the use of isothermal, titration, gas-perfusion and solution calorimetry in the context of pharmaceutical development, with a focus on instrument and experimental design factors, highlighted with examples from the recent literature. PMID- 21277962 TI - Differences in crystallization rate of nitrendipine enantiomers in amorphous solid dispersions with HPMC and HPMCP. AB - To clarify the contribution of drug-polymer interaction to the physical stability of amorphous solid dispersions, we studied the crystallization rates of nitrendipine (NTR) enantiomers with identical physicochemical properties in the presence of hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate (HPMCP) and polyvinylpyrrolidone (PVP). The overall crystallization rate at 60 degrees C and the nucleation rate at 50-70 degrees C of (+)-NTR were lower than those of (-)-NTR in the presence of 10-20% HPMC or HPMCP. In contrast, similar crystallization profiles were observed for the NTR enantiomers in solid dispersions containing PVP. The similar glass transition temperatures for solid dispersions of (-)-NTR and (+)-NTR suggested that the molecular mobility of the amorphous matrix did not differ between the enantiomers. These results indicate that the interaction between the NTR enantiomers and HPMC or HPMCP is stereoselective, and that differences in the stereoselective interaction create differences in physical stability between (-)-NTR and (+)-NTR at 50-70 degrees C. However, no difference in physical stability between the enantiomers was obvious at 40 degrees C. Loss of the difference in physical stability between the NTR enantiomers suggests that the stereoselective interaction between NTR and the polymers may not contribute significantly to the physical stabilization of amorphous NTR at 40 degrees C. PMID- 21277963 TI - Characterization of the colloidal properties, in vitro antifungal activity, antileishmanial activity and toxicity in mice of a di-stigma-steryl-hemi succinoyl-glycero-phosphocholine liposome-intercalated amphotericin B. AB - 1,2-Di-stigma-steryl-hemi-succinoyl-sn-glycero-3-phosphocholine (DSHemsPC) is a new lipid in which two molecules of stigmasterol (an inexpensive plant sterol) are covalently linked via a succinic acid to glycerophosphocholine. Since amphotericin B (AmB) interacts with sterols, we postulated that DSHemsPC could be used in AmB liposome formulations. Thirty-two DSHemsPC-AmB formulations were prepared using various mole ratios of DSHemsPC, phosphatidylcholine and phosphatidylglycerol at different pH. Most formulations had physical properties similar to AmBisomeTM: a particle diameter of about 100 nm, a monomodal distribution and a negative zeta potential. The red blood cell potassium release (RBCPR) IC50s for formulations spanned a range, with some being comparable to or greater than the IC50 observed using AmBisomeTM. A number of formulations had superior in vitro antifungal activity compared to AmBisomeTM against all of the tested pathogenic yeasts and molds. The IC50s of formulations against Leishmania major promastigotes and amastigotes for certain formulations were comparable with AmBisomeTM and FungizoneTM. Most formulations had maximum tolerated intravenous doses (MTD) of less than 10 mg/kg. However the formulation consisting of DSHemsPC/DMPC/DMPG/AmB mole ratio 1.25/5.0/1.5/1.0 (prepared at pH 5.5) had excellent colloidal properties, a high IC50 for RBCPR, antifungal and antileishmanial activity similar to AmBisomeTM and an MTD of 60 mg/kg. The characteristics of this DSHemsPC/DMPC/DMPG/AmB formulation make it suitable for further investigation to treat AmB-responsive pathogens. PMID- 21277964 TI - A novel truncated basic fibroblast growth factor fragment-conjugated poly (ethylene glycol)-cholesterol amphiphilic polymeric drug delivery system for targeting to the FGFR-overexpressing tumor cells. AB - Targeted uptake of therapeutic nanoparticles in tumor cells-specific manner represents a potentially powerful technology in cancer therapy. In present study, we proposed a drug delivery system formulated with biocompatible and biodegradable cholesterol-block-poly (ethylene glycol) (Chol-PEG(2000)-COOH) polymer. And the surface of the polymer was chemically linked with truncated bFGF fragments (tbFGF). The tbFGF could recognize fibroblast growth factor receptors (FGFR) that are highly expressed by a variety of human cancer cells. The micelles had a size distribution of about 10-50 nm and significantly enhanced the cytotoxicity of paclitaxel to LL/2 cells as demonstrated by MTT test (IC50=0.21 MUg/mL for tbFGF conjugated Chol-PEG(2000)-COOH micelles (tbFGF-M-PTX) versus 26.43 MUg/mL for free paclitaxel, respectively). Flow cytometry revealed the cellular uptake of rhodamine B encapsulated in the tbFGF-conjugated micelles was increased by 6.6-fold for HepG2, 6.2-fold for A549, 2.9-fold for C26 and 2.7-fold for LL/2 tumor cells, respectively, compared with micelles without tbFGF. The fluorescence spectroscopy images further demonstrated that the tbFGF conjugated micelles could specifically bind to the tumor cells that over-expressed FGFRs and then release rhodamine B into the cytoplasm. Our results suggest the tbFGF conjugated Chol-PEG(2000)-COOH micelles have great potential application for tumor targeting therapy. PMID- 21277965 TI - Incidence of low bioavailability of leuprolide acetate after percutaneous administration to rats by dissolving microneedles. AB - Two-layered dissolving microneedles of which acral portion contained leuprolide acetate (LA) as solid dispersion were prepared with sodium chondroitin sulfate as the base and the systemic absorption efficiency of LA was studied in rats after administration to their abdominal skin. A patch contained 100 dissolving microneedles of which length and basement diameter were 469.8+/-4.7 MUm and 284.5+/-9.8 MUm, where LA content was 14.3+/-1.6 MUg. In vitro dissolution experiment showed that LA was released from dissolving microneedle patch within 3 min. LA was stable in the patch, % recoveries for 3 months were 102.2+/-1.9 95.3+/-1.9%. One and half-patch of LA dissolving microneedles were administered to the rat skin and plasma LA concentrations were measured by LC-MS/MS. Plasma LA concentrations increased immediately after administration, and reached to the maximum level at 15 min, where C(max) were 6.0+/-0.7 and 16.4+/-0.9 MUg/ml, respectively. The AUC were 5.8+/-0.8 and 14.5+/-0.4 MUg h/ml and BA were 33.8+/ 4.3% and 31.7+/-0.8%. When LA solution was subcutaneously (s.c.) injected to rats, 50 MUg/kg, the BA was 32.0+/-2.1%. Relative BA of LA from dissolving microneedles against s.c. solution was 105.6+/-13.5%. The degradation rate of LA in the rat skin tissue homogenate was very fast where the half-life was 16.3+/ 5.7 min. The degradation of LA in the skin tissue was the cause of the low BA of LA after percutaneous administration to rats. PMID- 21277966 TI - Surface analysis for compositional, chemical and structural imaging in pharmaceutics with mass spectrometry: a ToF-SIMS perspective. AB - We review the application of time-of-flight secondary-ion mass spectrometry (ToF SIMS) for the surface chemical identification and distribution analysis (mapping) of pharmaceutically relevant materials. Specifically we explore the characterization of both solid state pharmaceuticals and bio-pharmaceuticals by ToF-SIMS; highlighting specific case studies concerning the distribution and stability of pharmaceutical actives within solid matrices, the face-specific properties of pharmaceutical crystals and elucidation of the structure/conformation of adsorbed proteins. Finally, potential future applications of ToF-SIMS in pharmaceutics are detailed. PMID- 21277967 TI - Characterisation of the anti-inflammatory and antinociceptive activities of the Hyptis pectinata (L.) Poit essential oil. AB - AIM OF THE STUDY: Hyptis pectinata Poit (Lamiaceae) is grown in the northeastern regions of Brazil and is popularly known as "sambacaita" or "canudinho". It is extensively used in folk medicine to treat inflammatory conditions, bacterial infections, pain, and cancer. MATERIALS AND METHODS: Hyptis pectinata essential oil (EO, 10, 30, and 100mg/kg, p.o.) and the reference drugs morphine (5mg/kg, p.o.) and acetylsalicylic acid (ASA, 200mg/kg, p.o.) were evaluated using models for analgesia (acetic acid-induced contortions and hot plate) or inflammation (formalin-induced licking response and the subcutaneous air-pouch model). To elucidate the EO's mechanism of action, animals were pre-treated with the opioid receptor antagonist naloxone (1mg/kg, i.p.), the cholinergic antagonist atropine (1mg/kg, i.p.), or l-nitro arginine methyl ester (l-NAME, 3mg/kg, i.p.) 30 min prior to the oral administration of the EO. RESULTS: The EO significantly inhibited the number of writhings and the time the animals spent licking their formalin-injected paws (second phase). The EO, at doses of 30 and 100mg/kg, increased baseline measurements and area under the curve measurements in the hot plate model, respectively. The administration of naloxone reversed the antinociceptive effect of the EO in the hot plate model. l-NAME significantly reversed the effects of the EO in the contortions and hot plate models. Atropine completely reversed the antinociceptive activity of the EO in all models. Additionally, the EO inhibited the inflammatory process induced by subcutaneous carrageenan injection by reducing cell migration, exudate volume, protein concentration, and inflammatory mediators (nitric oxide, prostaglandin E2, IL-6, and TNF-alpha) produced in the pouch. CONCLUSIONS: Our results indicate that the Hyptis pectinata essential oil exhibits antinociceptive effects, likely mediated by opioid and cholinergic receptors, and anti-inflammatory activity through the inhibition of nitric oxide and PGE2 production. PMID- 21277968 TI - Cordyceps militaris extract suppresses dextran sodium sulfate-induced acute colitis in mice and production of inflammatory mediators from macrophages and mast cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cordyceps militaris is a well-known medicinal mushroom used for treatment of asthma, and other bronchial and lung inflammatory diseases. AIM OF THE STUDY: To investigate the anti-inflammatory effects and mechanism of Cordyceps militaris extract on a murine model of acute colitis. MATERIALS AND METHODS: We induced colitis using DSS for 1 week. The disease activity index (DAI) took into account body weight loss, diarrhea, and bleeding. Colon length and crypt length were measured using a microscope. Structural changes of the colon were observed by H&E staining. NO, iNOS, and TNF-alpha were determined using the Griess assay. iNOS protein was determined using western blotting and quantitative reverse-transcriptase polymerase chain reaction, respectively. Degranulated mast cells in colon tissue were stained using toluidine blue. The degree of degranulated RBL-2H3 cells was measured by the beta hexosaminidase assay. RESULTS: Cordyceps militaris extract significantly attenuated DSS-induced DAI scores (e.g., body weight loss, diarrhea, gross bleeding). Cordyceps militaris extract also effectively prevented shortening of colon length and crypt length. Histological analysis indicated that Cordyceps militaris extract suppressed epithelial damage, loss of goblet cells, loss of crypts, and infiltration of inflammatory cells induced by DSS. In addition, Cordyceps militaris extract inhibited iNOS and TNF-alpha mRNA expression in colon tissue of DSS-induced colitis and in LPS-stimulated RAW264.7 cells. Cordyceps militaris extract suppressed degranulation of mast cells in the colon of mice with DSS-induced colitis and in antigen-stimulated mast cells. CONCLUSION: These results suggest that Cordyceps militaris extract has anti-inflammatory activity in DSS-induced acute colitis by down-regulating production and expression of inflammatory mediators. These findings suggest that Cordyceps militaris extract might be applied as an agent for prevention or treatment of inflammatory bowel diseases (IBDs). PMID- 21277969 TI - Evaluation of the use of Cocos nucifera as antimalarial remedy in Malaysian folk medicine. AB - ETHNOPHARMACOLOGICAL RELEVANCE: White flesh extract of Cocos nucifera (coconut) was studied to ascertain the ethnopharmacological standing of its antimalarial usage in Malaysian folk medicine. MATERIALS AND METHODS: The crude methanol extract was investigated for phytochemical constituents and acute oral toxicity. Antimalarial activity of different extract doses of 50, 100, 200 and 400mg/kg were investigated in vivo against Plasmodium berghei (NK65) infections in mice during early, established and residual infections. Chloroquine (20mg/kg) and pyrimethamine (1.2mg/kg) were used as reference drugs. RESULTS: The results revealed that the extract contained some phytochemical constituents and is toxicologically safe by oral administration. The extract significantly reduced the parasitaemia by the 200 and 400mg/kg doses in the all three in vivo assessment assays. However, the extract did not significantly increase the survival time of the infected mice. CONCLUSIONS: The observed pharmacological activities suggest that the Malaysian folkloric medicinal application of Cocos nucifera has a pharmacological basis. PMID- 21277970 TI - Antinociceptive activity of ethanolic extract and isolated compounds of Urtica circularis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Urtica circularis (Hicken) Soraru is a medicinal plant commonly used in traditional medicine to relieve pain in inflammatory processes. AIM OF THE STUDY: In the present study, the in vivo antinociceptive effect of Urtica circularis ethanolic extract and its isolated compounds has been investigated. MATERIALS AND METHODS: Antinociceptive activity was evaluated through writhing, formalin and hot plate tests in mice. The phytochemical analysis was performed. RESULTS: The extract produced significant inhibition on nociception induced by acetic acid (ED50: 72.2mg/kg, i.p.) and formalin (ED50: 15.8 mg/kg, i.p.) administered intraperitoneally and also orally. Atropine diminished the activity of the extract in the acetic acid test. In this model, at dose of 10mg/kg i.p., vitexin was the most active of the isolated compounds (inhibition of 91%), and chlorogenic acid, caffeic acid and vicenin-2 (6,8-di-C glucosyl apigenin) produced an inhibition of 72%, 41% and 41%, respectively, whereas apigenin did not show any activity. CONCLUSIONS: These results suggest that Urtica circularis extract produced antinociception possibly related to the presence of vitexin, chlorogenic, caffeic acid and vicenin-2. The activation of cholinergic systems seems to be involved in the mechanism of antinociception of the extract. PMID- 21277971 TI - Activity-induced dendrite and dendritic spine development in human amyloid precursor protein transgenic mice. AB - The amyloid precursor protein is essential for proper neuronal function but an imbalance in processing or metabolism or its overexpression lead to severe malfunction of the brain. The present study focused on dendritic morphology of hippocampal neurons in mice overexpressing the wild-type human amyloid precursor protein (hAPP). In addition, we examined whether enhanced physical activity may affect hAPP-related morphological changes. Overexpression of hAPP resulted in significant enlargement of dendrites, especially within the basal dendritic field but had no effect on spine density. Enhanced physical activity only moderately potentiated hAPP induced changes in dendritic size. Physical activity dependent increases in spine density were, however, augmented by hAPP overexpression. The results suggest that enhanced levels of wild-type hAPP do not result in degenerative changes of neuronal morphology, but rather promote dendritic growth. PMID- 21277972 TI - Gestational chronic mild stress: effects on acoustic startle in male offspring of rats. AB - An increasing number of scientific studies indicate that maternal stress during pregnancy influences fetal development of the nervous system and thereby the behavioural phenotype. We have previously reported attenuated prepulse inhibition (PPI) of the startle reaction in adult female rats derived from dams exposed to chronic mild stress (CMS) during gestation. In humans, decreased PPI has been reported to be associated with anxiety. Because of its potential translational value across species, the modulation of startle reactivity may be a useful tool in examining altered emotional reactivity following prenatal insults. The present study aimed at investigating whether prenatally stressed male offspring would display altered startle phenotype. Stress was induced by maternal gestational exposure to alternating procedures, i.e. CMS. At the age of 3 months, half of the offspring were blood sampled under restraint. At the age of 6 months, i.e. three months later, all animals were tested in the acoustic startle and the light enhanced startle (LES) paradigm. Control and CMS male offspring showed similar basal startle and LES levels. Maternal gestational exposure to the relatively mild, variable paradigm of stressors affected the PPI response pattern in male rats. In prenatally manipulated males, the PPI response differed statistically significantly, depending on prior exposure to an episode of postnatal acute stress (blood sampling under restraint). In contrast, the PPI response in control males was unaffected by this postnatal experience. The present work supports the hypothesis that the maternal environment is a long-term determinant of phenotypic differences in sensitivity to stressors. PMID- 21277973 TI - (-)-Epigallocatechin-3-gallate suppresses growth of AZ521 human gastric cancer cells by targeting the DEAD-box RNA helicase p68. AB - (-)-Epigallocatechin-3-gallate (EGCG), the most abundant and biologically active polyphenol in green tea, induces apoptosis and suppresses proliferation of cancer cells by modulating multiple signal transduction pathways. However, the fundamental mechanisms responsible for these cancer-preventive effects have not been clearly elucidated. Recently, we found that EGCG can covalently bind to cysteine residues in proteins through autoxidation and subsequently modulate protein function. In this study, we demonstrate the direct binding of EGCG to cellular proteins in AZ521 human gastric cancer cells by redox-cycle staining. We comprehensively explored the binding targets of EGCG from EGCG-treated AZ521 cells by proteomics techniques combined with the boronate-affinity pull-down method. The DEAD-box RNA helicase p68, which is overexpressed in a variety of tumor cells and plays an important role in cancer development and progression, was identified as a novel EGCG-binding target. Exposure of AZ521 cells to EGCG lowered the p68 level dose dependently. The present findings show that EGCG inhibits AZ521 cell proliferation by preventing beta-catenin oncogenic signaling through proteasomal degradation of p68 and provide a new perspective on the molecular mechanism of EGCG action. PMID- 21277974 TI - EPR spin trapping of an oxalate-derived free radical in the oxalate decarboxylase reaction. AB - EPR spin trapping experiments on bacterial oxalate decarboxylase from Bacillus subtilis under turn-over conditions are described. The use of doubly (13)C labeled oxalate leads to a characteristic splitting of the observed radical adducts using the spin trap N-tert-butyl-alpha-phenylnitrone linking them directly to the substrate. The radical was identified as the carbon dioxide radical anion which is a key intermediate in the hypothetical reaction mechanism of both decarboxylase and oxidase activities. X-ray crystallography had identified a flexible loop, SENS161-4, which acts as a lid to the putative active site. Site directed mutagenesis of the hinge amino acids, S161 and T165 was explored and showed increased radical trapping yields compared to the wild type. In particular, T165V shows approximately ten times higher radical yields while at the same time its decarboxylase activity was reduced by about a factor of ten. This mutant lacks a critical H-bond between T165 and R92 resulting in compromised control over its radical chemistry allowing the radical intermediate to leak into the surrounding solution. PMID- 21277975 TI - The kinase VRK1 is required for normal meiotic progression in mammalian oogenesis. AB - The kinase VRK1 has been implicated in mitotic and meiotic progression in invertebrate species, but whether it mediates these events during mammalian gametogenesis is not completely understood. Previous work has demonstrated a role for mammalian VRK1 in proliferation of male spermatogonia, yet whether VRK1 plays a role in meiotic progression, as seen in Drosophila, has not been determined. Here, we have established a mouse strain bearing a gene trap insertion in the VRK1 locus that disrupts Vrk1 expression. In addition to the male proliferation defects, we find that reduction of VRK1 activity causes a delay in meiotic progression during oogenesis, results in the presence of lagging chromosomes during formation of the metaphase plate, and ultimately leads to the failure of oocytes to be fertilized. The activity of at least one phosphorylation substrate of VRK1, p53, is not required for these defects. These results are consistent with previously defined functions of VRK1 in meiotic progression in Drosophila oogenesis, and indicate a conserved role for VRK1 in coordinating proper chromosomal configuration in female meiosis. PMID- 21277976 TI - Development of sucrose stearate-based nanoemulsions and optimisation through gamma-cyclodextrin. AB - Nanoemulsions aimed at dermal drug delivery are usually stabilised by natural lecithins. However, lecithin has a high tendency towards self-aggregation and is prone to chemical degradation. Therefore, the aim of this study was to develop nanoemulsions with improved structure and long-term stability by employing a natural sucrose ester mixture as sole surfactant. A thorough comparison between the novel sucrose stearate-based nanoemulsions and corresponding lecithin-based nanoemulsions revealed that the sucrose ester is superior in terms of emulsifying efficiency, droplet formation as well as physical and chemical stability. The novel formulations exhibited a remarkably homogeneous structure in cryo TEM investigations, as opposed to the variable structure observed for lecithin-based systems. The in vitro skin permeation rates of lipophilic drugs from sucrose stearate nanoemulsions were comparable to those obtained with their lecithin based counterparts. Furthermore, it was observed that addition of gamma cyclodextrin led to enhanced skin permeation of the steroidal drug fludrocortisone acetate from 9.99+/-0.46 to 55.10+/-3.67 MUg cm(-2) after 24 h in the case of sucrose stearate-based systems and from 9.98+/-0.64 to 98.62+/-24.89 MUg cm(-2) after 24 h in the case of lecithin-based systems. This enhancement effect was significantly stronger in formulations based on lecithin (P<0.05), which indicates that synergistic mechanisms between the surfactant and the cyclodextrin are involved. Cryo TEM images suggest that the cyclodextrin is incorporated into the interfacial film, which might alter drug release rates and improve the droplet microstructure. PMID- 21277977 TI - Fatty acid esters of steroids: synthesis and metabolism in lipoproteins and adipose tissue. AB - At the end of the last century ideas concerning the physiological role of the steroid fatty acid ester family were emerging. Estrogens, fatty acylated at C-17 hydroxyl group and incorporated in lipoproteins were proposed to provide antioxidative protection to these particles. A large number of studies involving non-estrogenic adrenal steroids, and their fatty acylated forms, demonstrated their lipoprotein-mediated transport into cells and subsequent intracellular activation, suggesting a novel transport mechanism for lipophilic steroid derivatives. After these important advances the main focus of interest has shifted away from C-19 and C-21 steroids to fatty acylated estrogens. However, interest in their lipoprotein-mediated transport has decreased because only minute amounts of these derivatives were detected in circulating lipoproteins, and their antioxidative activity remained unconfirmed under physiological circumstances. It now appears that the overwhelming majority of estradiol in postmenopausal women resides in adipose tissue, most of it in esterified form. This is poorly reflected in plasma levels which are very low. Recent data suggest that estrogen fatty acid esters probably represent a storage form. The future focus of investigation is likely to be on firstly, the enzymatic mechanisms regulating the esterification and de-esterification of estradiol and other steroids residing in adipose tissue and secondly, on the role of insulin and other hormones in the regulation of these enzymatic mechanisms. Thirdly, as a large proportion of fatty acid esterified C-19 and C-21 non-estrogenic steroids is transported in lipoproteins and as they are important precursors of androgens and estrogens, this field should be investigated further. PMID- 21277978 TI - NR4All in the vessel wall. AB - A number of nuclear receptors are involved in maintenance of normal vessel wall physiology as well as in pathophysiological processes such as atherosclerosis, restenosis and remodelling. Recent studies revealed a previously unrecognized function of the NR4A subfamily of nuclear receptors as key regulatory proteins in vascular disease. The NR4A subfamily comprises the members Nur77, Nurr1 and NOR-1 and in the current review a comprehensive overview is given of the data supporting functional involvement of these nuclear receptors in three major cell types in vascular (patho)physiology; endothelial cells, smooth muscle cells and monocytes-macrophages. PMID- 21277979 TI - Ecdysteroid biosynthesis in workers of the European honeybee Apis mellifera L. AB - We previously reported preferential expression of genes for ecdysteroid signaling in the mushroom bodies of honeybee workers, suggesting a role of ecdysteroid signaling in regulating honeybee behaviors. The organs that produce ecdysteroids in worker honeybees, however, remain unknown. We show here that the expression of neverland and Non-molting glossy/shroud, which are involved in early steps of ecdysteroid synthesis, was enhanced in the ovary, while the expression of CYP306A1 and CYP302A1, which are involved in later steps of ecdysone synthesis, was enhanced in the brain, and the expression of CYP314A1, which is involved in converting ecdysone into active 20-hydroxyecdysone (20E), was enhanced in the brain, fat body, and ovary. In in vitro organ culture, a significant amount of ecdysteroids was detected in the culture medium of the brain, fat body, and hypopharyngeal glands. The ecdysteroids detected in the culture medium of the fat body were identified as ecdysone and 20E. These findings suggest that, in worker honeybees, cholesterol is converted into intermediate ecdysteroids in the ovary, whereas ecdysone is synthesized and secreted mainly by the brain and converted into 20E in the brain and fat body. PMID- 21277980 TI - Transplantation of adipose tissue protects BB/OK rats from type 1 diabetes development. AB - B(io) B(reedding)/O(ttawa) K(alsburg) rats spontaneously develop insulin dependent type 1 diabetes. Days before BB/OK rats become diabetic, their body seems to be flabby which may be attributed to loss of subcutaneous fat. However, the rats are normoglycemic and manifest 3-4 days later. This observation prompted us to search for possibilities to avoid the loss of adipose tissue. BB/OK rats were subcutaneously grafted with visceral adipose tissue. In total, 34 (71%) out of 48 male and 23 (49%) out of 47 female BB/OK rats grafted with adipose tissue developed type 1 diabetes so that significantly more females than males were protected from diabetes development (p=0.03). In the control group, 17 (85%) out of 20 male and 20 (95%) out of 21 female BB/OK rats were diabetic. Adipose tissue transplantation can protect BB/OK rats from type 1 diabetes development in a sex specific manner. One could conclude that the manipulations have influenced fat accumulation and/or fat metabolism which prevent type 1 diabetes development in about 50% of BB/OK rats. This idea is supported by the finding that a mutation in the leptin receptor of NOD mice suppresses type 1 diabetes progression. PMID- 21277981 TI - A chimera of green fluorescent protein with single chain variable fragment antibody against ginsenosides for fluorescence-linked immunosorbent assay. AB - A chimera of green fluorescent protein extracted from Aequorea coerulescens (AcGFP), a mutant that has been codon optimized for mammalian expression, with single-chain variable fragment (scFv) antibody against ginsenoside Re (GRe-scFv), named fluobody, has been successfully expressed in Escherichia coli (E. coli) to develop simple, speedy, and sensitive fluorescence-linked immunosorbent assay (FLISA). Two chimera proteins were constructed to contain GRe-scFv at the C terminus of AcGFP (C-fluobody) and at the N-terminus of AcGFP (N-fluobody). These fluobodies were then purified by ion metal affinity chromatography and refolded by stepwise dialysis. The characterization of both fluobodies revealed that C fluobody was found to be appropriate probe for FLISA as compare with N-fluobody. Furthermore, improvement of limit of detection (LOD) was observed in FLISA using C-fluobody (10 ng/mL) due to its strong fluorescence intensity of AcGFP compared with conventional enzyme-linked immunosorbent assay (ELISA) using parental monoclonal antibody against ginsenoside Re (G-Re), MAb-4G10 (100 ng/mL). Since some steps required in ELISA can be avoided in this present FLISA, speedy and sensitive immunoassay also could be performed using fluobody instead of monoclonal antibody and scFv. PMID- 21277982 TI - Quantitative immunofluorescent blotting of the multidrug resistance-associated protein 2 (MRP2). AB - INTRODUCTION: Quantitation of the expression levels of proteins involved in drug transport and disposition is needed to overcome limitations of film-based detection of chemiluminescent immunoblots. PURPOSE: The purpose was to describe and validate a quantitative immunofluorescent blotting method for detection of ATP-binding cassette transporter isoform C2/multidrug resistance-associated protein 2 (ABCC2/MRP2). METHODS: Western blotting was performed by electrophoresis of membrane vesicle protein isolated from Sf9 cells overexpressing MRP2 subsequently blotted with infrared labeled secondary antibody. The bound complex was detected using the Odyssey Infrared Imaging System (Li-Cor; Lincoln, NE). The images were analyzed using the Odyssey Application Software to obtain the integrated intensities, followed by linear regression of the intensity data. RESULTS: The limits of quantitation for the time-insensitive technique described here were from 0.001 MUg to 0.5 MUg of total membrane protein, the coefficient of variation of the slope was 8.9%; r2 values were 0.986 +/- 0.012. The utility and sensitivity of this technique were demonstrated in quantitating expression of MRP2 in human placental tissue samples, in which MRP2 was present in low abundance. DISCUSSION: The immunofluorescent blotting technique described provides sensitive, reproducible, and quantitative determinations of large, integral membrane proteins such as MRP2, all with potential long-term cost savings. PMID- 21277984 TI - Placebo-mediated, Naloxone-sensitive suggestibility of short-term memory performance. AB - Physiological studies of placebo-mediated suggestion have been recently performed beyond their traditional clinical context of pain and analgesia. Various neurotransmitter systems and immunological modulators have been used in successful placebo suggestions, including Dopamine, Cholecystokinin and, most extensively, opioids. We adhered to an established conceptual framework of placebo research and used the MU-opioid-antagonist Naloxone to test the applicability of this framework within a cognitive domain (e.g. memory) in healthy volunteers. Healthy men (n=62, age 29, SD=9) were required to perform a task-battery, including standardized and custom-designed memory tasks, to test short-term recall and delayed recognition. Tasks were performed twice, before and after intravenous injection of either NaCl (0.9%) or Naloxone (both 0.15 mg/kg), in a double-blind setting. While one group was given neutral information (S-), the other was told that it might receive a drug with suspected memory-boosting properties (S+). Objective and subjective indexes of memory performance and salivary cortisol (as a stress marker) were recorded during both runs and differences between groups were assessed. Short-term memory recall, but not delayed recognition, was objectively increased after placebo-mediated suggestion in the NaCl-group. Naloxone specifically blocked the suggestion effect without interfering with memory performance. These results were not affected when changes in salivary cortisol levels were considered. No reaction time changes, recorded to uncover unspecific attentional impairment, were seen. Placebo-mediated suggestion produced a training-independent, objective and Naloxone-sensitive increase in memory performance. These results indicate an opioid-mediated placebo effect within a circumscribed cognitive domain in healthy volunteers. PMID- 21277983 TI - Idiopathic pulmonary arterial hypertension: an avian model for plexogenic arteriopathy and serotonergic vasoconstriction. AB - Idiopathic pulmonary arterial hypertension (IPAH) is a disease of unknown cause that is characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance attributable to vasoconstriction and vascular remodeling of small pulmonary arteries. Vascular remodeling includes hypertrophy and hyperplasia of smooth muscle (medial hypertrophy) accompanied in up to 80% of the cases by the formation of occlusive plexiform lesions (plexogenic arteriopathy). Patients tend to be unresponsive to vasodilator therapy and have a poor prognosis for survival when plexogenic arteriopathy progressively obstructs their pulmonary arteries. Research is needed to understand and treat plexogenic arteriopathy, but advances have been hindered by the absence of spontaneously developing lesions in existing laboratory animal models. Young domestic fowl bred for meat production (broiler chickens, broilers) spontaneously develop IPAH accompanied by semi occlusive endothelial proliferation that progresses into fully developed plexiform lesions. Plexiform lesions develop in both female and male broilers, and lesion incidences (lung sections with lesions/lung sections examined) averaged approximately 40% in 8 to 52 week old birds. Plexiform lesions formed distal to branch points in muscular interparabronchial pulmonary arteries, and were associated with perivascular mononuclear cell infiltrates. Serotonin (5 hydroxytryptamine, 5-HT) is a potent vasoconstrictor and mitogen known to stimulate vascular endothelial and smooth muscle cell proliferation. Serotonin has been directly linked to the pathogenesis of IPAH in humans, including IPAH linked to serotonergic anorexigens that trigger the formation of plexiform lesions indistinguishable from those observed in primary IPAH triggered by other causes. Serotonin also plays a major role in the susceptibility of broilers to IPAH. This avian model of spontaneous IPAH constitutes a new animal model for biomedical research focused on the pathogenesis of IPAH and plexogenic arteriopathy. PMID- 21277985 TI - Botrytis cinerea BcNma is involved in apoptotic cell death but not in stress adaptation. AB - Apoptotic-like programmed cell death (PCD) occurs naturally in fungi during development and might also be induced by external conditions. Candidate apoptotic genes have been characterized in several model fungal species but not in plant pathogenic fungi. Here we report on the isolation and characterization of BcNMA, an orthologue of the human pro-apoptotic gene HtrA2 from the plant pathogen Botrytis cinerea. The predicted BcNma protein shows high homology to the previously characterized Nma111p from Saccharomyces cerevisiae and despite some structural differences it complemented the function of Nma111p in Deltanma111 mutant strains. BcNMA-over-expression and mutant strains had enhanced or reduced appearance of apoptotic markers, respectively. However there was no difference in growth response of the wild type and BcNMA-transgenic strains to application of various stresses, and the effect on pathogenicity was marginal in both the over expression and mutant strains. When considered together these results suggest that although BcNma has a pro-apoptotic activity, it is not a major regulator of apoptosis. The protein probably has additional roles that are unrelated to apoptosis, which lead to the pleotrophic phenotype of the transgenic strains and lack of a clear effect on stress adaptation and pathogenicity. PMID- 21277986 TI - The molecular and genetic basis of conidial pigmentation in Aspergillus niger. AB - A characteristic hallmark of Aspergillus niger is the formation of black conidiospores. We have identified four loci involved in spore pigmentation of A. niger by using a combined genomic and classical complementation approach. First, we characterized a newly isolated color mutant, colA, which lacked pigmentation resulting in white or colorless conidia. Pigmentation of the colA mutant was restored by a gene (An12g03950) which encodes a putative 4'phosphopantetheinyl transferase protein (PptA). 4'Phosphopantetheinyl transferase activity is required for the activation of Polyketide Synthases (PKSs) and/or Non-Ribosomal Peptide Synthases (NRPSs). The loci whose mutation resulted in fawn, olive, and brown color phenotypes were identified by complementation. The fawn phenotype was complemented by a PKS protein (FwnA, An09g05730), the ovlA mutant by An14g05350 (OlvA) and the brnA mutant by An14g05370 (BrnA), the respective homologs of alb1/pksP, ayg1 and abr1 in A. fumigatus. Targeted disruption of the pptA, fwnA, olvA and brnA genes confirmed the complementation results. Disruption of the pptA gene abolished synthesis of all polyketides and non-ribosomal peptides, while the naphtho-gamma-pyrone subclass of polyketides were specifically dependent on fwnA, and funalenone on fwnA, olvA and brnA. Thus, secondary metabolite profiling of the color mutants revealed a close relationship between polyketide synthesis and conidial pigmentation in A. niger. PMID- 21277987 TI - Effects of T- and R-state stabilization on deoxyhemoglobin-nitrite reactions and stimulation of nitric oxide signaling. AB - Recent data suggest that transitions between the relaxed (R) and tense (T) state of hemoglobin control the reduction of nitrite to nitric oxide (NO) by deoxyhemoglobin. This reaction may play a role in physiologic NO homeostasis and be a novel consideration for the development of the next generation of hemoglobin based blood oxygen carriers (HBOCs, i.e. artificial blood substitutes). Herein we tested the effects of chemical stabilization of bovine hemoglobin in either the T (THb) or R-state (RHb) on nitrite-reduction kinetics, NO-gas formation and ability to stimulate NO-dependent signaling. These studies were performed over a range of fractional saturations that is expected to mimic biological conditions. The initial rate for nitrite-reduction decreased in the following order RHb>bHb>THb, consistent with the hypothesis that the rate constant for nitrite reduction is faster with R-state Hb and slower with T-state Hb. Moreover, RHb produced more NO-gas and inhibited mitochondrial respiration more potently than both bHb and THb. Interestingly, at low oxygen fractional saturations, THb produced more NO and stimulated nitrite-dependent vasodilation more potently than bHb despite both derivatives having similar initial rates for nitrite reduction and a more negative reduction potential in THb versus bHb. These data suggest that cross-linking of bovine hemoglobin in the T-state conformation leads to a more effective coupling of nitrite reduction to NO-formation. Our results support the model of allosteric regulation of nitrite reduction by deoxyhemoglobin and show that cross-linking hemoglobins in distinct quaternary states can generate products with increased NO yields from nitrite reduction that could be harnessed to promote NO-signaling in vivo. PMID- 21277989 TI - The Sixth 2010 London International Symposium on Cough: A translational approach. PMID- 21277988 TI - Nitrite as a mediator of ischemic preconditioning and cytoprotection. AB - Ischemia/reperfusion (IR) injury is a central component in the pathogenesis of several diseases and is a leading cause of morbidity and mortality in the western world. Subcellularly, mitochondrial dysfunction, characterized by depletion of ATP, calcium-induced opening of the mitochondrial permeability transition pore, and exacerbated reactive oxygen species (ROS) formation, plays an integral role in the progression of IR injury. Nitric oxide (NO) and more recently nitrite (NO(2)(-)) are known to modulate mitochondrial function, mediate cytoprotection after IR and have been implicated in the signaling of the highly protective ischemic preconditioning (IPC) program. Here, we review what is known about the role of NO and nitrite in cytoprotection after IR and consider the putative role of nitrite in IPC. Focus is placed on the potential cytoprotective mechanisms involving NO and nitrite-dependent modulation of mitochondrial function. PMID- 21277990 TI - Role of neutrophils and NADPH phagocyte oxidase in host defense against respiratory infection with virulent Francisella tularensis in mice. AB - Francisella tularensis subspecies (subsp.) tularensis is a CDC Category A biological warfare agent and inhalation of as few as 15 bacilli can initiate severe disease. Relatively little is known about the cellular and molecular mechanisms of host defense against respiratory infection with subsp. tularensis. In this study, we examined the role of neutrophils and NADPH phagocyte oxidase in host resistance to pulmonary infection in a mouse intranasal infection model. We found that despite neutrophil recruitment to the lungs and increased concentrations of neutrophil-chemotactic chemokines (KC, MIP-2 and RANTES) in the bronchoalveolar lavage fluid following intranasal inoculation of the pathogen, neither depletion of neutrophils nor enhancement of their recruitment into the lungs had any impact on bacterial burdens or survival rate/time. Nevertheless, mice deficient in NADPH phagocyte oxidase (gp91(phox-/-)) did exhibit higher tissue and blood bacterial burdens and succumbed to infection one day earlier than wild-type C57BL/6 mice. These results imply that although neutrophils are not a major effector cell in defense against subsp. tularensis infection, NADPH phagocyte oxidase does play a marginal role. PMID- 21277991 TI - Mammalian Ste20-like protein kinase 3 plays a role in hypoxia-induced apoptosis of trophoblast cell line 3A-sub-E. AB - Mammalian Ste20-like protein kinase 3 (Mst3) is a key player in inducing apoptosis in a variety of cell types and has recently been shown to participate in the signaling pathway of hypoxia-induced apoptosis of human trophoblast cell line 3A-sub-E (3A). It is believed that oxidative stress may occur during hypoxia and induce the expression of Mst3 in 3A cells via the activation of c-Jun N terminal protein kinase 1 (JNK1). This hypothesis was demonstrated by the suppressive effect of dl-alpha-lipoic acid, a reactive oxygen species scavenger, in hypoxia-induced responses of 3A cells such as Mst3 expression, nitrotyrosine formation, JNK1 activation and apoptosis. Similar results were also observed in trophoblasts of human placental explants in both immunohistochemical studies and immunoblot analyses. These suggested that the activation of Mst3 might trigger the apoptotic process in trophoblasts by activating caspase 3 and possibly other apoptotic pathways. The role of nitric oxide synthase (NOS) and NADPH oxidase (NOX) in hypoxia-induced Mst3 up-regulation was also demonstrated by the inhibitory effect of N(G)-nitro-l-arginine and apocynin, which inhibits NOS and NOX, respectively. Oxidative stress was postulated to be induced by NOS and NOX in 3A cells during hypoxia. In conclusion, hypoxia induces oxidative stress in human trophoblasts by activating NOS and NOX. Subsequently, Mst3 is up-regulated and plays an important role in hypoxia-induced apoptosis of human trophoblasts. PMID- 21277992 TI - Neural cell adhesion molecule potentiates invasion and metastasis of melanoma cells through CAMP-dependent protein kinase and phosphatidylinositol 3-kinase pathways. AB - Neural cell adhesion molecule (NCAM) has been implicated in tumor metastasis yet its function in melanoma progression remains unclear. Here, we demonstrate that stably silencing NCAM expression in mouse melanoma B16F0 cells perturbs their cellular invasion and metastatic dissemination in vivo. The pro-invasive function of NCAM is exerted via dual mechanisms involving both cAMP-dependent protein kinase (PKA) and phosphatidylinositol 3-kinase (PI3K) pathways. Pharmacologic inhibition of PKA and PI3K leads to impaired cellular invasion. In contrast, forced expression of constitutively activated Akt, the major downstream target of PI3K, restores the defective cellular invasiveness of NCAM knock-down (KD) B16F0 cells. Furthermore, attenuation of either PKA or Akt activity in NCAM KD cells is shown to affect their common downstream target, transcription factor cAMP response element binding protein (CREB), which in turn down-regulates mRNA expression of matrix metalloproteinase-2 (MMP-2), thus contributes to impaired cellular invasion and metastasis of melanoma cells. Together, these findings indicate that NCAM potentiates cellular invasion and metastasis of melanoma cells through stimulation of PKA and PI3K signaling pathways thus suggesting the potential implication of anti-NCAM strategy in melanoma treatment. PMID- 21277993 TI - Genotoxicity and potential carcinogenicity of cyanobacterial toxins - a review. AB - The occurrence of cyanobacterial blooms has increased significantly in many regions of the world in the last century due to water eutrophication. These blooms are hazardous to humans, animals, and plants due to the production of cyanotoxins, which can be classified in five different groups: hepatotoxins, neurotoxins, cytotoxins, dermatotoxins, and irritant toxins (lipopolysaccharides). There is evidence that certain cyanobacterial toxins are genotoxic and carcinogenic; however, the mechanisms of their potential carcinogenicity are not well understood. The most frequently occurring and widespread cyanotoxins in brackish and freshwater blooms are the cyclic heptapeptides, i.e., microcystins (MCs), and the pentapeptides, i.e., nodularins (NODs). The main mechanism associated with potential carcinogenic activity of MCs and NOD is the inhibition of protein phosphatases, which leads to the hyperphosphorylation of cellular proteins, which is considered to be associated with their tumor-promoting activity. Apart from this, MCs and NOD induce increased formation of reactive oxygen species and, consequently, oxidative DNA damage. There is also evidence that MCs and NOD induce micronuclei, and NOD was shown to have aneugenic activity. Both cyanotoxins interfere with DNA damage repair pathways, which, along with DNA damage, is an important factor involved in the carcinogenicity of these agents. Furthermore, these toxins increase the expression of TNF-alpha and early-response genes, including proto-oncogenes, genes involved in the response to DNA damage, cell cycle arrest, and apoptosis. Rodent studies indicate that MCs and NOD are tumor promotors, whereas NOD is thought to have also tumor-initiating activity. Another cyanobacterial toxin, cylindrospermopsin (CYN), which has been neglected for a long time, is lately being increasingly found in the freshwater environment. The principal mechanism of its toxicity is the irreversible inhibition of protein synthesis. It is pro genotoxic, and metabolic activation by cytochrome P-450 enzymes is needed for its genotoxic activity. In metabolically competent cells, it induces DNA strand breaks and exerts clastogenic and aneugenic activity. In addition, CYN increased the expression of p53 regulated genes involved in cell cycle arrest, DNA damage repair, and apoptosis. It also has cell transforming potential, and limited preliminary rodent studies indicate that CYN could have tumor-initiating activity. In 2010, the International Agency for Research on Cancer (IARC) classified MCLR as possible human carcinogen (Group 2B). Although there is not enough available information for the classification of other cyanobacterial toxins, the existing data from in vitro and in vivo studies indicate that NOD and especially CYN may be even more hazardous than MCLR to human and animal health. In addition in the environment, cyanobacterial toxins occur in complex mixtures as well as together with other anthropogenic contaminants, and numerous studies showed that the toxic/genotoxic potential of the extracts from cyanobacterial scums is higher than that of purified toxins. This means that the mixtures of toxins to which humans are exposed may pose higher health risks than estimated from the toxicological data of a single toxin. Future research efforts should focus on the elucidation of the carcinogenic potential of NOD, CYN, and the mixture of cyanobacterial extracts, as well as on the identification of possible novel toxins. PMID- 21277994 TI - Microbial Baeyer-Villiger oxidation of steroidal ketones using Beauveria bassiana: Presence of an 11alpha-hydroxyl group essential to generation of D-homo lactones. AB - This paper demonstrates for the first time transformation of a series of 17-oxo steroidal substrates (epiandrosterone, dehydroepiandrosterone, androstenedione) by the most frequently used whole cell biocatalyst, Beauveria bassiana, to 11alpha-hydroxy-17a-oxa-d-homo-androst-17-one products, in the following sequence of reactions: 11alpha-hydroxylation and subsequent Baeyer-Villiger oxidation to a ring-D lactone. 11alpha-Hydroxyprogesterone, the product of the first stage of the progesterone metabolism, was further converted along two routes: hydroxylation to 6beta,11alpha-dihydroxyprogesterone or 17beta-acetyl chain degradation leading to 11alpha-hydroxytestosterone, the main metabolite of the substrate. Part of 11alpha-hydroxytestosterone underwent a rare reduction to 11alpha-hydroxy-5beta-dihydrotestosterone. The experiments have demonstrated that the Baeyer-Villiger monooxygenase produced by the strain catalyzes solely oxidation of C-20 or C-17 ketones with 11alpha-hydroxyl group. 17-Oxo steroids, beside the 11alpha-hydroxylation and Baeyer-Villiger oxidation, also underwent reduction to 17beta-alcohols; activity of 17beta-hydroxysteroid dehydrogenase (17beta-HSD) has significant impact on the amount of the formed ring-D delta lactone. PMID- 21277995 TI - Crystalline wax coverage of the cuticle in easy bleeding sawfly larvae. AB - The larvae of some sawfly species belonging to the family Tenthredinidae (Hymenoptera) are capable of 'easy bleeding', an anti-predator defence strategy based on a specialised cuticle that can readily break, which frees droplets of distasteful haemolymph. Using high-resolution cryo-scanning electron microscopy, we compared the cuticle surface between easy bleeder (Rhadinoceraea micans, Phymatocera aterrima, Aneugmenus padi) and non-easy bleeder (Strongylogaster multifasciata, Nematus pavidus, Arge pagana) sawfly species. We detected crystalline waxes only on the cuticle surface of easy bleeders. Wax crystals varied in shape and dimension depending on species. We assume the reduction of surface wettability by oozed haemolymph to be the primary function of the wax crystal coverage in the easy bleeding defence strategy. PMID- 21277996 TI - Learning relational policies from electronic health record access logs. AB - Modern healthcare organizations (HCOs) are composed of complex dynamic teams to ensure clinical operations are executed in a quick and competent manner. At the same time, the fluid nature of such environments hinders administrators' efforts to define access control policies that appropriately balance patient privacy and healthcare functions. Manual efforts to define these policies are labor-intensive and error-prone, often resulting in systems that endow certain care providers with overly broad access to patients' medical records while restricting other providers from legitimate and timely use. In this work, we propose an alternative method to generate these policies by automatically mining usage patterns from electronic health record (EHR) systems. EHR systems are increasingly being integrated into clinical environments and our approach is designed to be generalizable across HCOs, thus assisting in the design and evaluation of local access control policies. Our technique, which is grounded in data mining and social network analysis theory, extracts a statistical model of the organization from the access logs of its EHRs. In doing so, our approach enables the review of predefined policies, as well as the discovery of unknown behaviors. We evaluate our approach with 5 months of access logs from the Vanderbilt University Medical Center and confirm the existence of stable social structures and intuitive business operations. Additionally, we demonstrate that there is significant turnover in the interactions between users in the HCO and that policies learned at the department-level afford greater stability over time. PMID- 21277997 TI - Supporting effective health and biomedical information retrieval and navigation: a novel facet view interface evaluation. AB - There is a need to provide a more effective user interface to facilitate non domain experts' health information seeking in authoritative online databases such as MEDLINE. We developed a new topic cluster based information navigation system called SimMed. Instead of offering a list of documents, SimMed presents users with a list of ranked clusters. Topically similar documents are grouped together to provide users with a better overview of the search results and to support exploration of similar literature within a cluster. We conducted an empirical user study to compare SimMed to a traditional document list based search interface. A total of 42 study participants were recruited to use both interfaces for health information exploration search tasks. The results showed that SimMed is more effective in terms of users' perceived topic knowledge changes and their engagement in user-system interactions. We also developed a new metric to assess users' efforts to find relevant citations. On average, users need significantly fewer clicks to find relevant information in SimMed than in the baseline system. Comments from study participants indicated that SimMed is more helpful in finding similar citations, providing related medical terms, and presenting better organized search results, particularly when the initial search is unsatisfactory. Findings from the study shed light on future health and biomedical information retrieval system and interface designs. PMID- 21277998 TI - The correlation between ventricular repolarization and clinical severity of spinal cord injuries. AB - BACKGROUND: Alteration in ventricular repolarization has been reported in patients with spinal cord injuries (SCIs). However, its clinical impact remains unclear. OBJECTIVE: The purpose of this study was to investigate the correlation between SCIs and ventricular repolarization and the associated clinical impact. METHODS: One hundred forty-four patients with an SCI were retrospectively reviewed and were divided into two groups (SCI level <= T6, n = 110; SCI level >T6, n = 34). The electrocardiograms were reviewed during acute phase (at emergency room) and chronic phase (>1 year). RESULTS: There were no differences in the underlying diseases or in ASIA score between the two groups, except there were more patients with tetraplegia among those with an SCI level <= T6. For the electrophysiological parameters from the electrocardiograms, the patients with an SCI level <= T6 had longer QTc and PR interval than those with an SCI level >T6 during acute phase. In the chronic phase, there were no differences in the electrophysiological parameters between the two groups. Only in patients with an SCI level <= T6 did a Kaplan-Meier analysis show that QTc prolongation could predict 30-day mortality after the acute injury. After multivariate Cox regression analysis, only tetraplegia and QTc prolongation were independent predictors of 30-day mortality (odds ratios 7.85 and 34.62, respectively). In patients with an SCI level <= T6, the QTc intervals were shorter in the chronic phase than those during the acute phase. CONCLUSION: QTc interval was associated with the level of acute SCI and predicted the 30-day mortality. PMID- 21277999 TI - Physiology of the intrinsic cardiac nervous system. PMID- 21278000 TI - Conservative management of pericardial-esophageal fistula complicating robotic atrial fibrillation ablation. PMID- 21278001 TI - Co-enrollment in multiple HIV prevention trials - experiences from the CAPRISA 004 Tenofovir gel trial. AB - BACKGROUND: In settings where multiple HIV prevention trials are conducted in close proximity, trial participants may attempt to enroll in more than one trial simultaneously. Co-enrollment impacts on participant's safety and validity of trial results. We describe our experience, remedial action taken, inter organizational collaboration and lessons learnt following the identification of co-enrolled participants. EXPERIENCES: Between February and April 2008, we identified 185 of the 398 enrolled participants as ineligible. In violation of the study protocol exclusion criteria, there was simultaneous enrollment in another HIV prevention trial (ineligible co-enrolled, n=135), and enrollment of women who had participated in a microbicide trial within the past 12 months (ineligible not co-enrolled, n=50). Following a complete audit of all enrolled participants, ineligible participants were discontinued via study exit visits from trial follow-up. Custom-designed education program on co-enrollment impacting on participants' safety and validity of the trial results was implemented. Shared electronic database between research units was established to enable verification of each volunteer's trial participation and to prevent future co-enrollments. LESSONS LEARNT: Interviews with ineligible enrolled women revealed that high-quality care, financial incentives, altruistic motives, preference for sex with gel, wanting to increase their likelihood of receiving active gel, perceived low risk of discovery and peer pressure are the reasons for their enrollment in the CAPRISA 004 trial. CONCLUSION: Instituting education programs based on the reasons reported by women for seeking enrollment in more than one trial and using a shared central database system to identify co enrollments have effectively prevented further co-enrollments. PMID- 21278002 TI - Hospital training program increases awareness of Good Clinical Practice (GCP). AB - OBJECTIVES: To develop an in-house training program of Good Clinical Practice (GCP) for the whole clinical team and to evaluate the effect of the program on the personnel's knowledge on GCP. BACKGROUND: GCP is a set of ethical and scientific quality requirements to which clinical trials must adhere. Since it is included in the legislation of the member states of European Union, it represents a challenge for research, and therefore more GCP training is needed. METHODS: At the Department of Neurology and Rehabilitation, Tampere University Hospital, Finland, we developed an in-house GCP training program for the whole department, including nurses. Before the training department staff was sent a questionnaire about their knowledge of and attitudes towards GCP as well as their perception of GCP compliance of studies being carried out at the Department. The subjects completed the questionnaire again after the training. RESULTS: Almost all, 95%, of the nurses and 50% of the physicians participated in the entire program. The program was found to increase positive attitudes towards GCP. CONCLUSION: A simple in-house training program is easy to implement and may help to improve GCP compliance. PMID- 21278003 TI - Time resolved thermodynamics associated with ligand photorelease in heme peroxidases and globins: Open access channels versus gated ligand release. AB - Heme proteins represent a diverse class of biomolecules responsible for an extremely diverse array of physiological functions including electron transport, monooxygenation, ligand transport and storage, cellular signaling, respiration, etc. An intriguing aspect of these proteins is that such functional diversity is accomplished using a single type of heme macrocycle based upon iron protoporphyrin IX. The functional diversity originates from a delicate balance of inter-molecular interactions within the protein matrix together with well choreographed dynamics that modulate the heme electronic structure as well as ligand entry/exit pathways from the bulk solvent to the active site. Of particular interest are the dynamics and energetics associated with the entry/exit of ligands as this process plays a significant role in regulating the rates of heme protein activity. Time-resolved photoacoustic calorimetry (PAC) has emerged as a powerful tool through which to probe the underlying energetics associated with small molecule dissociation and release to the bulk solvent in heme proteins on time scales from tens of nanoseconds to several microseconds. In this review, the results of PAC studies on various classes of heme proteins are summarized highlighting how different protein structures affect the thermodynamics of ligand migration. This article is part of a Special Issue entitled: Protein Dynamics: Experimental and Computational Approaches. PMID- 21278004 TI - Lack of improvement after audit assessing the management of voiding dysfunction in patients with spinal cord injury: necessity for institutional guidelines. AB - INTRODUCTION: Standard management guidelines for voiding dysfunction in patients with spinal cord injury (SCI) do not exist and these patients are managed on the basis of institutional protocols or individual judgment of managing physicians. OBJECTIVES: To notice general trends and improvements over a five-year period, in the institutional practices related to management of voiding dysfunction in SCI patients. METHODOLOGY: A retrospective cross-sectional study was conducted by Neurosurgery and Urology services together. A nine years (June 1995-June 2004) internal clinical audit of urological management of SCI patients was compared with a similar audit conducted five years later (January 2008-June 2010). Comparisons were made using chi-square test. A p-value of <0.05 was considered statistically significant. RESULTS: A total of 146 patients were compared (89-pre audit, 57-post-audit). The quality of documentation of examination findings worsened over the two study periods (p = 0.002). Although determination of baseline serum creatinine improved to statistically significant levels (p = 0.019), no imaging for the kidneys was performed as baseline in the post-audit period (p = 0.000). Similarly the number of urodynamic studies performed decreased from 11% to 1.75% (p = 0.045). The number of urological consultations, however, increased from 26% to 31.58% (p = 0.452). During follow-up, only 17 (19.1%) patients in the pre-audit study period and 6 (10.5%) in the post-audit study period were voiding spontaneously. CONCLUSION: Our study of two eras clearly demonstrated a worsening trend in quality of patient management, which can be corrected by agreeing upon and implementing standard guidelines for management of SCI patients. PMID- 21278005 TI - Boric acid gel enrichment of glycosylated proteins in human wound fluids. AB - The enrichment of glycosylated proteins by glycocapturing materials plays a pivotal role for the investigation of polysaccharide containing proteins in disease pathogenesis. Hence, we investigated a boric acid gel as a binding material for glycoprotein enrichment. The bovine proteins alpha-1-acid glycoprotein (A1AG) and alpha-2-HS-glycoprotein (fetuin A) were spiked in human chronic wound fluids and were subsequently enriched by a boric acid gel affinity chromatography (BAGAC). The enrichment efficiency was evaluated by western blot analysis and mass spectrometry. Additionally, glycoproteins of human wound fluids from diabetes mellitus patients with chronic foot ulcers were analyzed after BAGAC enrichments. In total 104 glycoproteins were identified, with reported glycosylation sites. 60 proteins were detected in at least 2 out of 3 biological replicates and were used for quantitative analysis between the bound and unbound fractions. Almost 80% of these glycoproteins were more prominent in the bound fraction. Only 2 glycoproteins revealed higher spectral counts in the flow through fraction compared to the bound fraction. These findings demonstrate the capability of the BAGAC material to enrich glycosylated proteins from complex human wound fluids. PMID- 21278006 TI - Snake population venomics and antivenomics of Bothrops atrox: Paedomorphism along its transamazonian dispersal and implications of geographic venom variability on snakebite management. AB - We describe two geographically differentiated venom phenotypes across the wide distribution range of Bothrops atrox, from the Colombian Magdalena Medio Valley through Puerto Ayacucho and El Pauji, in the Venezuelan States of Amazonas and Orinoquia, respectively, and Sao Bento in the Brazilian State of Maranhao. Colombian and Venezuelan venoms show an ontogenetic toxin profile phenotype whereas Brazilian venoms exhibit paedomorphic phenotypes. Venoms from each of the 16 localities sampled contain both population-specific toxins and proteins shared by neighboring B. atrox populations. Mapping the molecular similarity between conspecific populations onto a physical map of B. atrox range provides clues for tracing dispersal routes that account for the current biogeographic distribution of the species. The proteomic pattern is consistent with a model of southeast and southwest dispersal and allopatric fragmentation northern of the Amazon Basin, and trans-Amazonian expansion through the Andean Corridor and across the Amazon river between Monte Alegre and Santarem. An antivenomic approach applied to assess the efficacy towards B. atrox venoms of two antivenoms raised in Costa Rica and Brazil using Bothrops venoms different than B. atrox in the immunization mixtures showed that both antivenoms immunodepleted very efficiently the major toxins (PIII-SVMPs, serine proteinases, CRISP, LAO) of paedomorphic venoms from Puerto Ayacucho (Venezuelan Amazonia) through Sao Bento, but had impaired reactivity towards PLA(2) and P-I SVMP molecules abundantly present in ontogenetic venoms. The degree of immunodepletion achieved suggests that each of these antivenoms may be effective against envenomations by paedomorphic, and some ontogenetic, B. atrox venoms. PMID- 21278007 TI - A quantitative view on Mycobacterium leprae antigens by proteomics. AB - Leprosy is an ancient disease and the focus of the researchers' scrutiny for more than a century. However, many of the molecular aspects related to transmission, virulence, antigens and immune responses are far from known. Initially, the implementation of recombinant DNA library screens raised interesting antigen candidates. Finally, the availability of Mycobacterium leprae genomic information showed an intriguing genome reduction which is now largely used in comparative genomics. While predictive in silico tools are commonly used to identify possible antigens, proteomic approaches have not yet been explored fully to study M. leprae biology. Quantitative information obtained at the protein level, and its analysis as part of a complex system, would be a key feature to be used to help researchers to validate and understand many of such in silico predictions. Through a re-analysis of data from a previous publication of our group, we could easily tackle many questions regarding antigen prediction and pseudogene expression. Several well known antigens are among the quantitatively dominant proteins, while several major proteins have not been explored as antigens. We argue that combining proteomic approaches together with bioinformatic workflows is a required step in the characterization of important pathogens. PMID- 21278008 TI - Point-of-Care Technologies for Health Care. PMID- 21278009 TI - Tracking biological cells in time-lapse microscopy: an adaptive technique combining motion and topological features. AB - This paper presents a vision-based method for automatic tracking of biological cells in time-lapse microscopy by combining the motion features with the topological features of the cells. The automation of tracking frequently faces problems of segmentation error and of finding correct cell correspondence in consecutive frames, since the cells are of varying size and shape, and may have uneven movement; these problems become more acute when the cell population is very high. To reduce the segmentation error, we introduce a cell-detection method based on h-maxima transformation, followed by the fitting of an ellipse for the nucleus shape. To find the correct correspondence between the detected cells, the topological features, namely, color compatibility, area overlap and deformation are combined with the motion features of skewness and displacement. This reduces the ambiguity of matching and constructs accurately the trajectories of the cell proliferation. Finally, a template-matching-based backward tracking procedure is employed to recover any break in a cell trajectory that may occur due to the segmentation errors or the presence of a mitosis. The tracking procedure is tested using a number of different cell sequences with nonuniform illumination, or uneven cell motion, and is shown to provide high accuracy both in the detection and the tracking of the cells. PMID- 21278010 TI - Microchamber setup characterization for nanosecond pulsed electric field exposure. AB - Intracellular structures of biological cells can be disturbed by exposure to nanosecond pulsed electric field (nsPEF). A microchamber-based delivery system mounted on a microscope setup for real-time exposure to nsPEF is studied in this paper. A numerical and experimental characterization of the delivery system is performed both in frequency and time domains. The microchamber delivery system presents a high impedance compared to classical 50 Omega loads. Its frequency behavior and limits are investigated using an in-house finite-difference time domain (FDTD) simulator and through experimental measurements. High-voltage measurements for two nsPEF generators are carried out. The applied pulse voltage measured across the microchamber electrodes is ~1 kV, corresponding to ~10 MV/m electric fields in the microchamber. Depending on the nsPEF generator used, the measured pulse durations are equal to 3.0 and 4.2 ns, respectively. The voltage distribution provided by FDTD simulations indicates a good level of homogeneity across the microchamber electrodes. Experimental results include permeabilization of biological cells exposed to 3.0-ns, 10-MV/m PEFs. PMID- 21278011 TI - Acoustic events and "optophonic" cochlear responses induced by pulsed near infrared laser. AB - Optical stimulation of neural tissue within the cochlea was described as a possible alternative to electrical stimulation. Most optical stimulation was performed with pulsed lasers operating with near-infrared (NIR) light and in thermal confinement. Under these conditions, the coexistence of laser-induced optoacoustic stimulation of the cochlea ("optophony") has not been analyzed yet. This study demonstrates that pulsed 1850-nm laser light used for neural stimulation also results in sound pressure levels up to 62 dB peak-to-peak equivalent sound pressure level (SPL) in air. The sound field was confined to a small volume along the laser beam. In dry nitrogen, laser-induced acoustic events disappeared. Hydrophone measurements demonstrated pressure waves for laser fibers immersed in water. In hearing rats, laser-evoked signals were recorded from the cochlea without targeting neural tissue. The signals showed a two-domain response differing in amplitude and latency functions, as well as sensitivity to white noise masking. The first component had characteristics of a cochlear microphonic potential, and the second component was characteristic for a compound action potential. The present data demonstrate that laser-evoked acoustic events can stimulate a hearing cochlea. Whenever optical stimulation is used, care must be taken to distinguish between such "optophony" and the true optoneural response. PMID- 21278012 TI - A Bayesian hierarchical correlation model for fMRI cluster analysis. AB - Data-driven cluster analysis is potentially suitable to search for, and discriminate between, distinct response signals in blood oxygenation level dependent functional magnetic resonance imaging (BOLD fMRI), which appear during cerebrovascular disease. In contrast to model-driven methods, which test for a particular BOLD signal whose shape must be given beforehand, data-driven methods generate a set of BOLD signals directly from the fMRI data by clustering voxels into groups with correlated time signals. Here, we address the problem of selecting only the clusters that represent genuine responses to the experimental stimulus by modeling the correlation structure of the clustered data using a Bayesian hierarchical model. The model is empirically justified by demonstrating the hierarchical organization of the voxel correlations after cluster analysis. BOLD signal discrimination is demonstrated using: 1) simulations that contain multiple pathological BOLD response signals; and 2) fMRI data acquired during an event-related motor task. These demonstrations are compared with results from a model-driven method based on the general linear model. Our simulations show that the data-driven method can discriminate between the BOLD response signals, while the model-driven method only finds one signal. For fMRI, the data-driven method distinguishes between the BOLD signals appearing in the sensorimotor cortex and those in basal ganglia and putamen, while the model-driven method combines these signals into one activation map. We conclude that the proposed data-driven method provides an objective framework to identify and discriminate between distinct BOLD response signals. PMID- 21278013 TI - Online removal of eye movement and blink EEG artifacts using a high-speed eye tracker. AB - A novel approach is presented for using an eye tracker-based reference instead of EOG for methods that require an EOG reference to remove ocular artifacts (OA) from EEG. It uses a high-speed eye tracker and a new online algorithm for extracting the time course of a blink from eye tracker images to remove both eye movement and blink artifacts. It eliminates the need for EOG electrodes attached to the face, which is critical for practical daily applications. The ability of two adaptive filters (RLS and H^ ) to remove OA is measured using: 1) EOG; 2) frontal EEG only (fEEG); and 3) the eye tracker with frontal EEG (ET + fEEG) as reference inputs. The results are compared for different eye movements and blinks of varying amplitudes at electrodes across the scalp. Both the RLS and H^ methods were shown to benefit from using the proposed eye tracker-based reference (ET + fEEG) instead of either an EOG reference or a reference based on frontal EEG alone. PMID- 21278014 TI - Diffeomorphic brain registration under exhaustive sulcal constraints. AB - The alignment and normalization of individual brain structures is a prerequisite for group-level analyses of structural and functional neuroimaging data. The techniques currently available are either based on volume and/or surface attributes, with limited insight regarding the consistent alignment of anatomical landmarks across individuals. This article details a global, geometric approach that performs the alignment of the exhaustive sulcal imprints (cortical folding patterns) across individuals. This DIffeomorphic Sulcal-based COrtical (DISCO) technique proceeds to the automatic extraction, identification and simplification of sulcal features from T1-weighted Magnetic Resonance Image (MRI) series. These features are then used as control measures for fully-3-D diffeomorphic deformations. Quantitative and qualitative evaluations show that DISCO correctly aligns the sulcal folds and gray and white matter volumes across individuals. The comparison with a recent, iconic diffeomorphic approach (DARTEL) highlights how the absence of explicit cortical landmarks may lead to the misalignment of cortical sulci. We also feature DISCO in the automatic design of an empirical sulcal template from group data. We also demonstrate how DISCO can efficiently be combined with an image-based deformation (DARTEL) to further improve the consistency and accuracy of alignment performances. Finally, we illustrate how the optimized alignment of cortical folds across subjects improves sensitivity in the detection of functional activations in a group-level analysis of neuroimaging data. PMID- 21278015 TI - Analysis of human fibroadenomas using three-dimensional impedance maps. AB - Three-dimensional impedance maps (3DZMs) are virtual volumes of acoustic impedance values constructed from histology to represent tissue microstructure acoustically. From the 3DZM, the ultrasonic backscattered power spectrum can be predicted and model based scatterer properties, such as effective scatterer diameter (ESD), can be estimated. Additionally, the 3DZM can be exploited to visualize and identify possible scattering sites, which may aid in the development of more effective scattering models to better represent the ultrasonic interaction with underlying tissue microstructure. In this study, 3DZMs were created from a set of human fibroadenoma samples. ESD estimates were made assuming a fluid-filled sphere form factor model from 3DZMs of volume 300*300*300 MUm. For a collection of 33 independent human fibroadenoma tissue samples, the ESD was estimated to be 111+/-40.7 MUm. The 3DZMs were then investigated visually to identify possible scattering sources which conformed to the estimated model scatterer dimensions. This estimation technique allowed a better understanding of the spatial distribution and variability of the estimates throughout the volume. PMID- 21278016 TI - Efficient texture image retrieval using copulas in a Bayesian framework. AB - In this paper, we investigate a novel joint statistical model for subband coefficient magnitudes of the dual-tree complex wavelet transform, which is then coupled to a Bayesian framework for content-based image retrieval. The joint model allows to capture the association among transform coefficients of the same decomposition scale and different color channels. It further facilitates to incorporate recent research work on modeling marginal coefficient distributions. We demonstrate the applicability of the novel model in the context of color texture retrieval on four texture image databases and compare retrieval performance to a collection of state-of-the-art approaches in the field. Our experiments further include a thorough computational analysis of the main building blocks, runtime measurements, and an analysis of storage requirements. Eventually, we identify a model configuration with low storage requirements, competitive retrieval accuracy, and a runtime behavior, which enables the deployment even on large image databases. PMID- 21278017 TI - Smoothlets--multiscale functions for adaptive representation of images. AB - In this paper a special class of functions called smoothlets is presented. They are defined as a generalization of wedgelets and second-order wedgelets. Unlike all known geometrical methods used in adaptive image approximation, smoothlets are continuous functions. They can adapt to location, size, rotation, curvature, and smoothness of edges. The M-term approximation of smoothlets is O(M(-3)). In this paper, an image compression scheme based on the smoothlet transform is also presented. From the theoretical considerations and experiments, both described in the paper, it follows that smoothlets can assure better image compression than the other known adaptive geometrical methods, namely, wedgelets and second-order wedgelets. PMID- 21278018 TI - Hybrid no-reference natural image quality assessment of noisy, blurry, JPEG2000, and JPEG images. AB - In this paper, we propose a new image quality assessment method based on a hybrid of curvelet, wavelet, and cosine transforms called hybrid no-reference (HNR) model. From the properties of natural scene statistics, the peak coordinates of the transformed coefficient histogram of filtered natural images occupy well defined clusters in peak coordinate space, which makes NR possible. Compared to other methods, HNR has three benefits: 1) It is an NR method applicable to arbitrary images without compromising the prediction accuracy of full-reference methods; 2) as far as we know, it is the only general NR method well suited for four types of filters: noise, blur, JPEG2000, and JPEG compression; and 3) it can classify the filter types of the image and predict filter levels even when the image is results from the application of two different filters. We tested HNR on very intensive video image database (our image library) and Laboratory for Image & Video Engineering (a public library). Results are compared to the state-of-the art methods including peak SNR, structural similarity, visual information fidelity, and so on. PMID- 21278019 TI - Image deblurring and super-resolution by adaptive sparse domain selection and adaptive regularization. AB - As a powerful statistical image modeling technique, sparse representation has been successfully used in various image restoration applications. The success of sparse representation owes to the development of the l(1)-norm optimization techniques and the fact that natural images are intrinsically sparse in some domains. The image restoration quality largely depends on whether the employed sparse domain can represent well the underlying image. Considering that the contents can vary significantly across different images or different patches in a single image, we propose to learn various sets of bases from a precollected dataset of example image patches, and then, for a given patch to be processed, one set of bases are adaptively selected to characterize the local sparse domain. We further introduce two adaptive regularization terms into the sparse representation framework. First, a set of autoregressive (AR) models are learned from the dataset of example image patches. The best fitted AR models to a given patch are adaptively selected to regularize the image local structures. Second, the image nonlocal self-similarity is introduced as another regularization term. In addition, the sparsity regularization parameter is adaptively estimated for better image restoration performance. Extensive experiments on image deblurring and super-resolution validate that by using adaptive sparse domain selection and adaptive regularization, the proposed method achieves much better results than many state-of-the-art algorithms in terms of both PSNR and visual perception. PMID- 21278020 TI - Automatic Recognition of Non-Acted Affective Postures. AB - The conveyance and recognition of affect and emotion partially determine how people interact with others and how they carry out and perform in their day-to day activities. Hence, it is becoming necessary to endow technology with the ability to recognize users' affective states to increase the technologies' effectiveness. This paper makes three contributions to this research area. First, we demonstrate recognition models that automatically recognize affective states and affective dimensions from non-acted body postures instead of acted postures. The scenario selected for the training and testing of the automatic recognition models is a body-movement-based video game. Second, when attributing affective labels and dimension levels to the postures represented as faceless avatars, the level of agreement for observers was above chance level. Finally, with the use of the labels and affective dimension levels assigned by the observers as ground truth and the observers' level of agreement as base rate, automatic recognition models grounded on low-level posture descriptions were built and tested for their ability to generalize to new observers and postures using random repeated subsampling validation. The automatic recognition models achieve recognition percentages comparable to the human base rates as hypothesized. PMID- 21278021 TI - Fuzzy Modeling and Synchronization of Two Totally Different Chaotic Systems via Novel Fuzzy Model. AB - In this paper, a new fuzzy model is presented to simulate and synchronize two totally different and complicated chaotic systems, namely, 1) quantum cellular neural networks nanosystem (Quantum-CNN system) and 2) Qi system. Through the new fuzzy model, the following three main advantages can be obtained: 1) only two linear subsystems are needed; 2) the numbers of fuzzy rules can be reduced from 2 N to 2 *N (comparing with the Takagi-Sugeno fuzzy model), where N is the number of nonlinear terms; 3) fuzzy synchronization of two different chaotic systems with different numbers of nonlinear terms can be achieved with only two sets of gain K. There are two examples in numerical simulation results to show the effectiveness and feasibility of our new model. PMID- 21278022 TI - A Hybrid PSO-BFGS Strategy for Global Optimization of Multimodal Functions. AB - Particle swarm optimizer (PSO) is a powerful optimization algorithm that has been applied to a variety of problems. It can, however, suffer from premature convergence and slow convergence rate. Motivated by these two problems, a hybrid global optimization strategy combining PSOs with a modified Broyden-Fletcher Goldfarb-Shanno (BFGS) method is presented in this paper. The modified BFGS method is integrated into the context of the PSOs to improve the particles' local search ability. In addition, in conjunction with the territory technique, a reposition technique to maintain the diversity of particles is proposed to improve the global search ability of PSOs. One advantage of the hybrid strategy is that it can effectively find multiple local solutions or global solutions to the multimodal functions in a box-constrained space. Based on these local solutions, a reconstruction technique can be adopted to further estimate better solutions. The proposed method is compared with several recently developed optimization algorithms on a set of 20 standard benchmark problems. Experimental results demonstrate that the proposed approach can obtain high-quality solutions on multimodal function optimization problems. PMID- 21278023 TI - Generalized sampling-based motion planners. AB - In this paper, generalized versions of the probabilistic sampling-based planners, i.e., probabilistic roadmaps and rapidly exploring random tree, are presented. The generalized planners, i.e., generalized probabilistic roadmap and the generalized rapidly exploring random tree, result in hybrid hierarchical feedback planners that are robust to the uncertainties in the robot motion model and in the robot map or workspace. The proposed planners are analyzed and shown to probabilistically be complete. The algorithms are tested on fully actuated and underactuated robots on several maps of varying degrees of difficulty, and the results show that the generalized methods have a significant advantage over the traditional methods when planning under uncertainty. PMID- 21278024 TI - Point-and-click cursor control with an intracortical neural interface system by humans with tetraplegia. AB - We present a point-and-click intracortical neural interface system (NIS) that enables humans with tetraplegia to volitionally move a 2-D computer cursor in any desired direction on a computer screen, hold it still, and click on the area of interest. This direct brain-computer interface extracts both discrete (click) and continuous (cursor velocity) signals from a single small population of neurons in human motor cortex. A key component of this system is a multi-state probabilistic decoding algorithm that simultaneously decodes neural spiking activity of a small population of neurons and outputs either a click signal or the velocity of the cursor. The algorithm combines a linear classifier, which determines whether the user is intending to click or move the cursor, with a Kalman filter that translates the neural population activity into cursor velocity. We present a paradigm for training the multi-state decoding algorithm using neural activity observed during imagined actions. Two human participants with tetraplegia (paralysis of the four limbs) performed a closed-loop radial target acquisition task using the point-and-click NIS over multiple sessions. We quantified point and-click performance using various human-computer interaction measurements for pointing devices. We found that participants could control the cursor motion and click on specified targets with a small error rate (< 3% in one participant). This study suggests that signals from a small ensemble of motor cortical neurons (~40) can be used for natural point-and-click 2-D cursor control of a personal computer. PMID- 21278025 TI - [Hemorrheological changes and their clinical relevance in pre-eclampsia]. AB - This review summarizes the hemorheological changes during gestation and their clinical relevance in pre-eclampsia. The gestational disease named pre-eclampsia, characterized by proteinuria (more than 0.3 g/day) and hypertension (blood pressure above 140/90 mmHg), exists from the 20th gestational week until the sixth postpartum week. Its etiology is complex; the pathomechanism mainly involves disturbances in cross talks among the vegetative system, the placenta and the circulatory system. Soluble factors of placenta mediate circulatory changes, which result in adaptive responses in both vegetative and circulatory systems. Derailment of this adaption, however, leads to increased turbulence and local damages in cellular elements of the circulatory system. The initial local lesion progresses to a generalized form. Later, these events will continue to strengthen their own cycle. As a result, an unstable circulatory state will be established, which causes organ damages. PMID- 21278026 TI - [Adverse events during biological therapy -- focusing on dermatological side effects]. AB - Biological response modifiers, especially tumour necrosis factor inhibitors have been proved to be very effective in the treatment of various immune mediated rheumatological, gastroenterological and dermatological diseases in the last 15 years. With their increasing use, the incidence of their adverse effects are more precisely defined. The aim of this cohort study was to analyse the adverse effects occurred within the study period in patients receiving biological therapy for rheumatological and dermatological autoimmune diseases. METHODS: 324 patients within a 3 years study period were treated with biological response modifiers (adalimumab: 92, etanercept: 107, infliximab: 125). The primary diagnoses were rheumotoid arthritis (n = 174), ankylosing spondylitis (n = 60), psoriatic arthritis (n = 11), and psoriasis vulgaris (79). RESULTS: Hypersensitive reactions were observed in 11 of the patients (3.4%), 7 of which were serious and needed treatment termination. Infections constituted the majority of side effects, which were localised to skin in 10 (3.1%) and to respiratory tract in 9 (2.8%). However, most of these were mild or moderate reactions. Malignant skin tumour developed in 1 case (0.3%) only. Drug induced inflammatory disorders occurred in some cases: onset of new psoriasis was observed in 1 and flares of the existing disease were detected in additional three. Lichenoid exanthema developed in one. (n = 5, 1.5%) CONCLUSION: The use of TNF-alpha blockers may provoke a broad spectrum of dermatological side effects. Our results suggest that the majority of these are infectious and inflammatory disorders, the latter may relatively often appear as drug induced psoriasis. The occurrence of malignancies was very low in our series. PMID- 21278027 TI - [Genetic background of inherited multiple pituitary hormone deficiency. Mutations of PROP1 gene in Hungary]. AB - In this work I analysed the outcome of growth hormone replacement treatment in patients with inherited form of multiple pituitary hormone deficiency and examined diseased-causing mutations of pituitary transcription factor genes which may underlie this disorder. The results showed that after treatment for a longer than 7-year period with a growth hormone preparation available under well controlled distribution, the mean height of children with growth hormone deficiency reached the normal national reference range adjusted for age and sex. After establishment of clinical criteria for screening PROP1 gene mutations, I performed mutational analysis of all coding exons of this gene in 35 patients with inherited form of multiple pituitary hormone deficiency. With these studies, diseases-causing PROP1 gene mutations were detected in 15 of the 35 patients (43%). It was also found that more than 80% of mutant alleles were accounted for by those containing the 150delA and 301-302delGA mutations of the PROP1 gene. Importantly, these findings indicated a high relevance of mutational "hot spots" of the PROP1 gene in Hungarian patients with inherited form of multiple pituitary hormone deficiency and they also offered an opportunity for the development of rational and cost-effective screening strategy. When clinical and hormonal findings of patients with and without PROP1 gene mutations were compared, results showed that growth hormone deficiency was diagnosed at earlier age of life in patients with PROP1 gene mutations, but the severity of growth retardation at the time of diagnosis of growth hormone deficiency or the age of patients at the time of manifestation of other pituitary hormone deficiencies (TSH, LH, FSH and ACTH) were similar in the two groups of patients. In 15 patients inherited form of multiple pituitary hormone deficiency who had no PROP1 gene mutations, exon 6 of the POU1F1 gene containing a mutational "hot spot" was also examined but no mutations were found. Thus, these results do not support a significant role of the mutational "hot spot" of the POU1F1 gene in Hungarian patients with inherited form of multiple pituitary hormone deficiency. Finally, I introduced a method for the detection of mutations of the PITX2 gene, a pituitary transcription factor that plays a role not only in pituitary development and differentiation but also in the lateralization of organs. With the use of this method, I performed mutational analysis of all coding exons of this gene in an exceptionally unique patient who had both situs inversus totalis and inherited form of multiple pituitary hormone deficiency, but no mutation was found. Thus, the findings in this patient failed to indicate that mutation of the PITX2 gene is involved in the pathomechanism of situs inversus totalis associated with inherited form of multiple pituitary hormone deficiency. PMID- 21278028 TI - [Pharmacognosy in works of Alexander Tschirch (1856-1939)]. PMID- 21278029 TI - [Dr. Antal Genersich M. D. and the "Spis -- then and now"]. PMID- 21278032 TI - Nursing considerations for optimal outpatient management of adult patients with leukemia treated with clofarabine. AB - Despite improvements in treatment, the outcome for some adult patients with acute or chronic leukemias remains poor. Clofarabine, a second-generation purine nucleoside analog, received U.S. Food and Drug Administration approval in 2004 for the treatment of pediatric patients with relapsed or refractory acute lymphocytic leukemia after at least two previous regimens. In addition, clinical studies have shown encouraging safety and efficacy results with clofarabine in the treatment of adult patients with various hematologic malignancies. Although most adult patients with leukemia receive the first course of clofarabine while hospitalized, many can be subsequently treated as outpatients with proper monitoring, support, and education. The most frequent side effects associated with clofarabine are gastrointestinal-related, myelosuppression, hepatotoxicity, renal dysfunction, and anorexia. Careful patient monitoring is essential to ensure early identification and prompt intervention. Younger patients and those of any age with no comorbid health issues, good performance status, and an adequate support network are more likely to tolerate outpatient clofarabine administration. Early identification and proactive pharmacologic and nonpharmacologic interventions may reduce the severity of these toxicities and prevent their progression. Patient education about strategies for prevention and management of symptoms also is essential. PMID- 21278033 TI - Looking beyond recurrence: comorbidities in cancer survivors. AB - Cancer recurrence is a very real concern for cancer survivors. Surveillance for recurrence and vigilance for development of new cancers are top priorities during follow-up visits after active treatment ends. However, the cancer survivor also is at risk for the development of comorbid conditions. These conditions, including obesity, diabetes, dyslipidemia, menopause, decreased bone mass, hypertension, and hypothyroidism, are discussed with their relevance for general health and their relationships to disease-specific cancers. All of these conditions should be routinely addressed as part of the patient's survivorship care when appropriate. The oncology nurse is in a prime position to educate survivors about the risks for these conditions, both through evidence-based practice guidelines specific to each condition and also through the use of a treatment summary and care plan. This article discusses these selected comorbidities and offers strategies for nurses to address them with survivors during follow-up visits. Clinical practice guidelines for comorbidities are included, along with oncology implications and relevance for survivors. Recommendations for modifiable risk factors and healthy living also are included, along with Web sites for survivorship care plans. PMID- 21278034 TI - Top 10 lists. PMID- 21278035 TI - ONS congress inspires nurse. PMID- 21278036 TI - The sexuality discussion: tools for the oncology nurse. AB - Receiving a cancer diagnosis and experiencing the effects of antineoplastic therapies can have a devastating effect on a person's emotional, physical, and psychological well-being and a significant negative effect on sexual desire and function. Oncology nurses are the ideal healthcare professionals to assess the sexual health status of their patients and to intervene to sensitively address sexuality issues. Having this discussion can be uncomfortable for both nurses and patients, but using communication tools can help nurses gain confidence in their abilities to address sexuality concerns in an effective and comfortable manner and to provide patients with useful information and insights. PMID- 21278037 TI - Establishing an evidence-based inpatient medical oncology fluid balance measurement policy. AB - Fluid balance measurement (FBM) is a routine intervention in oncology, but accuracy and compliance issues have been documented. This article describes how a medical oncology nursing clinical practice committee used the Iowa Model for Evidence-Based Practice to establish a policy for FBM. Nursing and medical education was performed with emphasis on oncology-specific defaults in a computerized provider order entry system reflecting the new FBM policy. At two months of implementation, the policy effectively demonstrated improved staff compliance and satisfaction, as well as appropriate orders for patients requiring stricter FBM. PMID- 21278038 TI - Polypharmacy and symptom management in older adults. AB - The following is an excerpt from Chapter 1 of the 2010 Oncology Nursing Society book, A Guide to Oncology Symptom Management (pp. 1-14), edited by Carlton Brown, RN, PhD, AOCN(r). PMID- 21278039 TI - Oncology nurse navigator. AB - The purpose of this integrative review is to explore the presence of the oncology nurse as navigator on measurable patient outcomes. Eighteen primary nursing research studies were found using combinations of the following key words: advocate, cancer, case manager, coach, certification, guide, navigator, nurse, oncology, patient navigator, pivot nurse, and continuity of care. Nurse researchers identified nursing-sensitive patient outcomes related to the time to diagnosis and appropriate treatment, effect on mood states, satisfaction, support, continuity of care, and cost outcomes. Navigator roles are expanding globally, and nurses should continue to embrace opportunities to ensure the safe passage of patients with cancer along the entire trajectory of illness and to evaluate the implications for educational preparation, research, and practice of navigators of all kinds. PMID- 21278040 TI - Evaluation of a patient navigation program. AB - This study examined the value and effectiveness of a patient navigation program in terms of timeliness of access to cancer care, resolution of barriers, and satisfaction in 55 patients over a six-month period. Although not statistically significant, the time interval between diagnostic biopsy to first consultation with a cancer specialist after program implementation was reduced from an average of 14.6 days to 12.8 days. The time interval between diagnostic biopsy to initiation of cancer treatment also was reduced from 30 days to 26.2 days (not statistically significant). In addition, 71% of patient barriers were resolved by the time treatment was initiated. Overall, patients were highly satisfied with their navigated care experience. Consistent evaluation and monitoring of quality of-care indicators are critical to further develop the program and to direct resource allocation. Oncology nurses participating in patient navigation programs should be encouraged to evaluate their importance and impact in this developing concept. Nurses should seek roles that allow them to optimize the effective use of their specialized knowledge and skills to the benefit of patients along the cancer care continuum. PMID- 21278041 TI - Education and health promotion for new patients with cancer. AB - High levels of anxiety negatively affect how education is received by newly diagnosed patients with cancer by decreasing comprehension, retention, and patient satisfaction. Research has repeatedly shown that, after a careful assessment of individual needs, effective patient education delivered during the initial phase of diagnosis and treatment can improve symptoms of anxiety and fear, improve self-care decisions, decrease side effects of treatment, and enhance quality of life. The educational intervention presented in this article aims to improve the current system of providing education for newly diagnosed patients with cancer by assessing each patient and presenting an individualized information program in a controlled environment prior to chemotherapy. PMID- 21278042 TI - Management of treatment-related symptoms in patients with breast cancer. AB - Although the benefits of current treatment strategies are well established, many cancer survivors are at risk for developing physiologic and psychological late effects of cancer treatment that might lead to premature mortality and morbidity and compromise their quality of life. Psychological symptoms include anxiety, depression, fatigue, difficulty sleeping, and loss of self-esteem. Physiologic symptoms include pain, numbness, cognitive impairment, weight gain, loss of sexual interest, spontaneous menopause, and peripheral neuropathy. Both length and quality of survival are important end points. The goal of this review is to summarize the psychological and physiologic symptoms related to breast cancer treatment; the prevalence, contributing therapies, and inter-relatedness of these symptoms; current interventions to prevent, ameliorate, or treat these symptoms; and effectiveness and safety of these interventions. The results of this review will identify the gaps in knowledge and assist in the design of assessments and approaches to improve mortality and quality of life and provide the foundation for the development of evidence-based guidelines to standardize palliative care in cancer survivors. PMID- 21278043 TI - Li-Fraumeni syndrome and the role of the pediatric nurse practitioner. AB - Li-Fraumeni syndrome (LFS) is an inherited cancer syndrome that affects a small percentage of the population worldwide. LFS is characterized by multiple cancers in affected family members and is devastating to all diagnosed patients and their relatives. A link has been identified between LFS and mutations in the tumor suppressor gene that encodes for the P53 protein, and much research has been done on the effect of this mutation in tumorigenesis. However, the natural history of the disease has no definitive pathway, and additional research is under way. LFS is rare, can present in many ways, requires complex management, and has tumors that often first present in childhood. Therefore, pediatric nurse practitioners should be aware of LFS as a potential differential diagnosis in patients with multiple tumors, certain rare tumors, or most importantly, a family history notable for multiple early-onset cancers. PMID- 21278044 TI - Psychosocial impact of cutaneous toxicities associated with epidermal growth factor receptor-inhibitor treatment. AB - Epidermal growth factor receptor inhibitors (EGFRIs) are an increasingly important class of anticancer agents. Cutaneous toxicities, the most common adverse effects of EGFRI therapy, require dose modification or treatment cessation when moderate or severe and may compromise treatment compliance. To date, assessment has focused on physical symptoms associated with cutaneous toxicities; however, the psychosocial impact of those effects requires greater consideration. This article reviews current knowledge of assessment of cutaneous toxicities and identifies gaps in evidence, with particular focus on the psychosocial impact of cutaneous toxicities. Promising new assessment tools and approaches including the use of electronic patient-reported outcome measures are discussed, as well as implications for research in evaluating psychosocial interventions. PMID- 21278045 TI - To screen or not to screen: ongoing debate in the early detection of prostate cancer. AB - Debate about the use of prostate-specific antigen (PSA) tests to screen prostate cancer in men is ongoing. Prostate cancer is the most common cancer after skin cancer in men and the second most deadly after lung cancer. An elevated PSA level can lead to this cancer's diagnosis and treatment even before the onset of symptoms. However, other causes also can create a high PSA level, which may lead to men being unnecessarily treated for prostate cancer. This article will shed some light on the issue and discuss prostate cancer screening. PMID- 21278046 TI - Cutaneous metastases in breast cancer. AB - Cutaneous metastases occur more often in breast cancer than in other diseases in women. Presentation often is ambiguous because the metastases can mimic other common processes (e.g., cellulitis, lymphedema). Accurate differential diagnosis identifies less obvious manifestations of progressive disease and allows for appropriate management. Although interventions are aimed at halting disease progression, cutaneous metastases indicate an incurable diagnosis. Treatment focuses on delaying progressive disease, controlling symptoms, and maintaining quality of life. The care of skin metastases evolves as the tumor spreads and more tissue destruction occurs. Skin management and topical interventions increase comfort, decrease distress, and create feelings of control in this population. PMID- 21278047 TI - Core competencies for bone marrow transplantation nurse practitioners. AB - The role of the bone marrow transplantation nurse practitioner (BMT NP) has been implemented in most major academic transplantation centers; however, little literature supports the scope of practice and core competencies in this setting. With an increasing shortage of oncologists, opportunities exist for BMT NPs to become leaders in the clinical management of BMT recipients. This article reviews the literature and current professional guidelines to develop core professional and clinical competencies for BMT NPs. PMID- 21278048 TI - Origami creations bring peace and hope to patients in transplantation unit. PMID- 21278049 TI - Review of extracting information from the Social Web for health personalization. AB - In recent years the Web has come into its own as a social platform where health consumers are actively creating and consuming Web content. Moreover, as the Web matures, consumers are gaining access to personalized applications adapted to their health needs and interests. The creation of personalized Web applications relies on extracted information about the users and the content to personalize. The Social Web itself provides many sources of information that can be used to extract information for personalization apart from traditional Web forms and questionnaires. This paper provides a review of different approaches for extracting information from the Social Web for health personalization. We reviewed research literature across different fields addressing the disclosure of health information in the Social Web, techniques to extract that information, and examples of personalized health applications. In addition, the paper includes a discussion of technical and socioethical challenges related to the extraction of information for health personalization. PMID- 21278050 TI - Fatigue in multiple sclerosis is closely related to sleep disorders: a polysomnographic cross-sectional study. AB - BACKGROUND: Sleep disorders can cause tiredness. The relationship between sleep disorders and fatigue in patients with multiple sclerosis (MS) has not yet been investigated systematically. OBJECTIVE: To investigate the relationship between fatigue and sleep disorders in patients with MS. METHODS: Some 66 MS patients 20 to 66 years old were studied by overnight polysomnography. Using a cut-off point of 45 in the Modified Fatigue Impact Scale (MFIS), the entire cohort was stratified into a fatigued MS subgroup (n=26) and a non-fatigued MS subgroup (n=40). RESULTS: Of the fatigued MS patients, 96% (n=25) were suffering from a relevant sleep disorder, along with 60% of the non-fatigued MS patients (n=24) (p=0.001). Sleep-related breathing disorders were more frequent in the fatigued MS patients (27%) than in the non-fatigued MS patients (2.5%). Significantly higher MFIS values were detected in all (fatigued and non-fatigued) patients with relevant sleep disorders (mean MFIS 42.8; SD 18.3) than in patients without relevant sleep disorders (mean MFIS 20.5; SD 17.0) (p<0.001). Suffering from a sleep disorder was associated with an increased risk of fatigue in MS (odds ratio: 18.5; 95% CI 1.6-208; p=0.018). CONCLUSION: Our results demonstrate a clear and significant relationship between fatigue and sleep disorders. PMID- 21278051 TI - The utility of the small rodent electrocardiogram in toxicology. AB - Extensive research has lead to a growing appreciation that the heart is acutely sensitive to a broad array of toxicants via multiple routes of exposure. These agents are as diverse as the antineoplastic drug doxorubicin and environmental agents including ambient air pollution. Adverse effects in the heart often manifest as a change in the electrocardiogram (ECG). The ECG has long been used in the clinic to assess human cardiovascular health. Surface electrocardiographic recordings (i.e., those made from the skin) in humans often help to detect abnormal myocardial impulse formation, conduction, cardiac rhythm disturbances, and altered autonomic regulation of the heart. In toxicology, the ECG provides a collection of end points that may be used to assess both the quality and magnitude of cardiac toxicity. Increasingly over the last two decades, the cardiotoxicity of agents have been characterized using small rodent electrocardiography. Additionally, tremendous insight into possible mechanisms of action of known human cardiotoxicants has been gained. Rat and mouse models offer a number of advantages relative to larger animals including lower cost, less variability, the availability of transgenic models, and a plethora of research tools. Modern day advances in small rodent electrocardiography have enabled assessments in conscious unrestrained animals and improved ECG interpretation. Thus, the incorporation of small rodent electrocardiographic assessments into toxicology studies may facilitate the screening of cardiotoxic potential and the elucidation of mechanisms of action. This review will discuss the utility of the small rodent ECG, various methodologies used to derive ECG data in rats and mice, and various applications in toxicology. PMID- 21278052 TI - Epigenetic effect of cadmium on global de novo DNA hypomethylation in the cadmium induced ventral body wall defect (VBWD) in the chick model. AB - Administration of the heavy metal cadmium (Cd) induces ventral body wall defects (VBWD) in the chick embryo. In this model, the expression of most genes involved in body wall formation is altered 4h-posttreatment. However, the mechanism by which Cd results in the initiation of altered gene expression remains unclear. Epigenetic mechanisms can change genome function under exogenous influences. Moreover, Cd is one of the environmental factors that can affect epigenomic programming. De novo DNA methylation is essential for normal embryogenesis and is regulated by the DNA methyltransferases (DNMT)3A and DNMT3B. The objective of this study was to investigate the hypothesis that gene expression levels of DNMT3A/3B were altered, resulting in global DNA methylation changes during the critical period of embryogenesis in the Cd chick model. After 60-h incubation, chick embryos (n = 48) were harvested at 1, 4, and 8 h after treatment with saline or Cd, and divided into controls and Cd groups. Quantitative reverse transcription PCR was performed to evaluate the gene expression levels of DNMT3A/3B in the chick embryos and was statistically analyzed using Student's t test. Immunohistochemistry was performed using a monoclonal antibody against 5 methylcytidine (5'MeC), which labels methyl-rich regions within the nucleus. DNMT3A/3B gene expression levels at 4 h were significantly downregulated in the Cd group compared with controls (p < 0.005/p < 0.00001, respectively). Immunoreactivity of 5'MeC was markedly diminished in the Cd group at 4 h. Our findings demonstrates for the first time that Cd impacts on the expression levels of DNMT3A/3B, which may underlie the pathogenesis of VBWD in the Cd chick model. PMID- 21278053 TI - Differential estrogenic effects of the persistent organochlorine pesticides dieldrin, endosulfan, and lindane in primary neuronal cultures. AB - The organochlorine chemicals endosulfan, dieldrin, and gamma hexachlorocyclohexane (lindane) are persistent pesticides to which people are exposed mainly via diet. Their antagonism of the gamma-aminobutyric acid-A (GABA(A)) receptor makes them convulsants. They are also endocrine disruptors because of their interaction with the estrogen receptor (ER). Here, we study the effects of dieldrin, endosulfan, and lindane on ERs in primary cultures of cortical neurons (CN) and cerebellar granule cells (CGC). All the compounds tested inhibited the binding of [(3)H]-estradiol to the ER in both CN and CGC, with dieldrin in CGC showing the highest affinity. We also determined the effects of the pesticides on protein kinase B (Akt) and extracellular-regulated kinase 1 and 2 (ERK1/2) phosphorylation. Dieldrin and endosulfan increased Akt phosphorylation in CN, which was inhibited by the ERbeta antagonist 4-[2-phenyl 5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol. Instead, Akt and ERK1/2 phosphorylation induced by dieldrin in CGC was mediated by multiple activation of ERalpha, ERbeta, and G protein-coupled receptor 30. Lindane did not activate these pathways, but it inhibited estradiol-mediated Akt and ERK1/2 activation. In CN, all the chemicals activated ERK1/2 through a mechanism involving GABA(A) and glutamate receptors. Long-term exposure to these pesticides reduced the levels of ERalpha, but not of ERbeta. Moreover, extracts of CN treated with endosulfan, dieldrin, or lindane induced cell proliferation in MCF-7 human breast cancer-derived cells, whereas only extracts of CGC treated with dieldrin induced MCF-7 cell proliferation. Overall, the observed alterations on ER-mediated signaling and ER levels in neurons might contribute to the neurotoxicity of these organochlorine pesticides. PMID- 21278054 TI - Propiconazole induces alterations in the hepatic metabolome of mice: relevance to propiconazole-induced hepatocarcinogenesis. AB - Propiconazole is a mouse hepatotumorigenic fungicide and has been the subject of recent investigations into its carcinogenic mechanism of action. The goals of this study were (1) to identify metabolomic changes induced in the liver by increasing doses of propiconazole in mice, (2) to interpret these results with key previously reported biochemical, transcriptomic, and proteomic findings obtained from mouse liver under the same treatment conditions, and (3) to relate these alterations to those associated with the carcinogenesis process. Propiconazole was administered to male CD-1 mice in the feed for 4 days with six mice per feed level (500, 1250, and 2500 ppm). The 2500 ppm dose level had previously been shown to induce both adenocarcinomas and adenomas in mouse liver after a 2-year continuous feed regimen. Endogenous biochemicals were profiled using liquid chromatography/mass spectrometry and gas chromatography/mass spectrometry methods and 261 were detected. The most populous biochemical class detected was lipids, followed by amino acids and then carbohydrates. Nucleotides, cofactors and vitamins, energy, peptides, and xenobiotics were also represented. Of the biochemicals detected, 159 were significantly altered by at least one dose of propiconazole and many showed strong dose responses. Many alterations in the levels of biochemicals were found in the glycogen metabolism, glycolysis, lipolysis, carnitine, and the tricarboxylic acid cycle pathways Several groups of metabolomic responses were ascribed to the metabolism and clearance of propiconazole: glucuronate, glutathione, and cysteine pathways. Groups of metabolic responses supported previous hypotheses on key events that can lead to propiconazole-induced tumorigenesis: oxidative stress and increases in the cholesterol biosynthesis pathway. Groups of metabolomic responses identified biomarkers associated with neoplasia: increases in glycolysis and increases in the levels of spermidine, sarcosine, and pseudouridine. These results extended the companion transcriptomic and proteomic studies and provided a more complete understanding of propiconazole's effects in mouse liver. PMID- 21278055 TI - Involvement of glycogen synthase kinase-3beta in arsenic trioxide-induced p21 expression. AB - Arsenic trioxide (ATO) has been effectively used as a therapeutic agent to treat acute promyelocytic leukemia and solid tumors, via induction of cell cycle arrest or apoptosis. In our previous studies, we suggest that c-Jun might act as an adapter to regulate p21(WAF1/CIP1) (p21) expression in response to ATO. Therefore, how to regulate the c-Jun to bind to the p21 promoter was further elucidated. It has been reported that glycogen synthase kinase-3beta (GSK-3beta) can phosphorylate the C-terminus (Ser243) of c-Jun to decrease its protein stability and DNA-binding ability and can also increase the degradation of p21 in resting condition or under ultraviolet irradiation. Therefore, we hypothesized that ATO-induced p21 expression might be through the inhibition of GSK-3beta. Using the DNA affinity precipitation assay, ATO could dephosphorylate the C terminus (Ser243) of c-Jun to enhance its binding to the p21 promoter and resultant p21 expression. ATO, as well as LiCl (GSK-3beta inhibitor), could induce GSK-3beta(Ser9) phosphorylation and p21 expression in a time- and dose dependent manner. Constitutively active GSK-3beta, FlagGSKCA, and constitutively inactive GSK-3beta, FlagGSKCI, were constructed to further confirm the involvement of GSK-3beta in the ATO-induced p21 expression. However, the stability of p21 protein was increased by ATO, but not LiCl treatment using cycloheximide. Furthermore, ATO-induced GSK-3beta(Ser9) phosphorylation was through the ERK pathway, but not the PI3K/Akt pathway. We suggest that, taken together, ATO-induced ERK phosphorylation could inhibit GSK-3beta activity to dephosphorylate the C-terminus (Ser243) of c-Jun to increase p21 expression and resultant cell death. PMID- 21278056 TI - Sulforaphane-mediated reduction of aflatoxin B1-N7-guanine in rat liver DNA: impacts of strain and sex. AB - Aflatoxin B1 (AFB1) is a DNA-binding toxin that contributes to the burden of liver cancer in tropical areas. AFB1-DNA adducts are powerful biomarkers that discern individual and population risk from exposure to this carcinogen. The discovery of concordance between the metabolic pathways of the male Fischer rat and humans allowed data from rats to guide the development of chemoprevention strategies employed in clinical trials in high-risk regions. In this study, the variables of strain and sex are studied in the rat model, as a step toward understanding how ethnic differences and sex influence DNA adduct formation and the induction of enzymes by chemoprotective agents. Sulforaphane (SF), which induces phase II enzymes including glutathione S-transferases (GSTs), was evaluated for its ability to induce GST activity and reduce the AFB1-DNA adducts in livers of both sexes of two rat strains that differ in susceptibility to AFB1 hepatocarcinogenesis. A dose-dependent relationship was found for SF for both induction of GST and reduction in of AFB1-N7-guanine in both Fischer (sensitive to AFB1) and Sprague-Dawley rats (relatively resistant). Sprague-Dawley rats exhibited the greatest increase in GST levels and the largest reduction in AFB1 N7-guanine in liver DNA. Males and females of each strain were also compared to determine if the ability of SF to induce GST and reduce AFB1-N7-guanine correlated with gender differences in sensitivity to AFB1 carcinogenesis. No gender-specific responses to SF were observed. These results support the view that SF induction of liver GST activity may play a role in its chemoprotective activity. PMID- 21278057 TI - Increase of plasminogen activator inhibitor-1 and decrease of transforming growth factor-b1 in children with dengue haemorrhagic fever in Indonesia. AB - Mortality in children with severe dengue haemorrhagic fever (DHF) in Indonesia is high. The origin of the elevated plasminogen activator inhibitor-1 (PAI-1) levels in these children is unclear. We measured PAI-1, transforming growth factor-beta1 (TGF-beta1), platelet counts, plasma leakage and liver function in 71 children with DHF (3-15 years old) and in 30 healthy children. We found that PAI-1 concentrations in children with DHF were significantly higher on admission than on Day 2. Circulating TGF-beta1 concentrations on admission were significantly lower in DHF than in controls, but on Day 2 increased towards levels in controls. TGF-beta1 and PAI-1 concentrations were not correlated on either day. PAI-1 was correlated with platelet count and serum albumin on admission, and with degree of pleural effusion. Liver function tests were mildly elevated but not correlated with PAI-1. In conclusion, elevated PAI-1 concentrations in DHF were associated with platelet counts and plasma leakage. PMID- 21278058 TI - Continuing professional development for all health workers. PMID- 21278059 TI - Which clinical signs predict severe illness in children less than 2 months of age in resource poor countries? PMID- 21278060 TI - TNF--a antagonists and sarcoidosis. PMID- 21278061 TI - Long-term glycaemic outcome of structured nurse-led diabetes care in rural Africa. AB - BACKGROUND: Diabetes care delivery in rural Africa is difficult. Problems include lack of dedicated personnel, monitoring systems, laboratory support and drugs. Few structured intervention projects have been undertaken, none with long-term follow-up. AIM: To determine the long-term (4 years) glycaemic outcome of a structured nurse-led intervention programme for type 2 diabetic patients in rural Africa. DESIGN: Single-centre, observational cohort study. METHODS: The programme was delivered in the scattered primary health clinics of Hlabisa District, in northern Kwazulu Natal, South Africa. Monthly diabetic clinics were held at which empowerment-based education was delivered and regularly reinforced. Oral hypoglycaemic agents (OHAs) were titrated according to a previously validated clinical algorithm. Outcome was measured by glycated haemoglobin (HbA(1)c), as well as body mass index (BMI). Data were collected at baseline, and then 6, 18, 24 and 48 month's post-intervention. RESULTS: Eighty patients had data available at all time collection points. They were of mean +/- SD, age 56 +/- 11 years, 70% were female, BMI 31.5 +/- 7.2 kg/m(2) and HbA(1)c 10.8 +/- 4.2%. HbA(1)c fell significantly to 8.1 +/- 2.2% at 6 months and 7.5 +/- 2.0% at 18 months. By 24 months, it had risen (8.4 +/- 2.3%), and at 4 years post-intervention it was 9.7 +/- 4.0% (still significantly lower than baseline, P = 0.015). BMI rose significantly at 6 and 18 months, but by 48 months was not significantly different from baseline. CONCLUSION: We conclude that the intervention led to marked HbA(1)c improvements up to 18 months follow-up, but thereafter there was 'glycaemic slippage'. This may be not only due to educational 'wear-off', noted in other education-intervention programmes, but also to the expected glycaemic deterioration with time known to occur in type 2 diabetes. Nevertheless, 4-year HbA(1)c levels were still significantly lower than at baseline. The programme was also well received by staff and patients, and we believe is an appropriate and effective diabetes intervention system in rural Africa. PMID- 21278062 TI - Post-acupuncture shoulder swelling. PMID- 21278063 TI - Preoperative diagnosis of ileal lipoma as the cause of ileal intussusception. PMID- 21278064 TI - Numerical and functional deficiencies of natural killer T cells in systemic lupus erythematosus: their deficiency related to disease activity. AB - OBJECTIVE: This study was designed to examine the frequency of natural killer T (NKT) cells and the response to alpha-galactosylceramide (alpha-GalCer) in SLE patients and to investigate the clinical relevance of NKT cell levels. METHODS: Patients with SLE (n = 128) and age- and sex-matched healthy controls (HCs) (n = 92) were enrolled in the study. NKT cell and CD1d levels were measured by flow cytometry. Gene expression was determined by RT-PCR, and cytokine secretion by multiple cytokine assay. Peripheral blood mononuclear cells (PBMCs) were cultured in vitro with alpha-GalCer. Proliferation indices of NKT cells were estimated by flow cytometry. RESULTS: Percentages and absolute numbers of NKT cells were significantly lower in the peripheral blood of SLE patients than in that of HCs, whereas CD1d levels in PBMCs were comparable between these two groups. Notably, this NKT cell deficiency was found to be correlated with SLEDAI. NKT cell proliferation was found to be impaired in SLE patients, and cytokine production by NKT cells in response to alpha-GalCer was diminished. This poor responsiveness to alpha-GalCer was found to be due to NKT cell dysfunction rather than to an abnormality in CD1d-expressing cells. CONCLUSIONS: Our data show that NKT cell levels and functions are defective in SLE patients. Furthermore, these deficiencies were found to reflect disease activity. It would appear that these NKT cell abnormalities could contribute to immune system dysregulation in SLE. PMID- 21278065 TI - Potential biomarkers of monocyte/macrophage activity in a patient with sarcoidosis, treated with infliximab. PMID- 21278066 TI - Distinguishing between the innate immune response due to ocular inflammation and infection in a child with juvenile systemic granulomatous disease treated with anti-TNFalpha monoclonal antibodies. PMID- 21278067 TI - An analysis of the costs and treatment success of etanercept in juvenile idiopathic arthritis: results from the Dutch Arthritis and Biologicals in Children register. AB - OBJECTIVE: To analyse and report the costs and effects of etanercept therapy in patients with JIA. METHODS: Forty-nine JIA patients were evaluated by means of the JIA core set at the start of etanercept and after 3, 15 and 27 months of therapy. At the same time-points, parents of the patients were asked to complete the Health Utility Index Mark 3 (HUI3). Direct medical costs were collected for 1 year before and 27 months after the start of etanercept and compared with gain in utility. RESULTS: Mean total direct medical costs after the start of etanercept were on average 12 478 euros per patient-year compared with 3720 euros before start. The cost analysis showed that three-quarters of total direct medical costs were from etanercept itself. Other direct medical costs, such as costs concerning hospitalization and concomitant medication, decreased compared with the costs in the period before start of etanercept. Especially a great reduction of consultations at the outpatient clinic was seen. Utility was 0.53 before start of etanercept, according to the multi-attribute utility function of the HUI3 on a scale from 0 (dead) to 1 (perfect health). After 27 months, utility was 0.78. In accordance, also all JIA core set response variables improved significantly over 27 months of etanercept treatment. CONCLUSIONS: Although costs of etanercept therapy are substantial, the gain in utility is even more impressive. Considering that these JIA patients were previously refractory to conventional treatment including MTX, and were at risk of long-time disability and pain, costs are justifiable. PMID- 21278068 TI - Copy number variations of Interleukin-12B and T-bet are associated with systemic lupus erythematosus. AB - OBJECTIVES: Th1 cells have been implicated as the causal agents in the pathogenesis of autoimmunity. SLE represents the classical prototype of systemic autoimmune disease. Copy number variations (CNVs) have been discovered to have phenotypic consequences and associate with various types of diseases. The current study aims to explore a possible association between CNVs of Th1 cell-related genes and the risk of SLE. METHODS: Genomic DNA and RNA from 532 SLE patients and 576 healthy controls were extracted. CNVs of Th1 cell-related genes (T-bet, Stat4, IL-12A, IL-12B, IFN-gamma, IP-10 and CXCR3) as well as Th2 and Treg cell related genes (c-Mef, GATA3, Foxp3, IL-6 and TGF-beta) were examined, and mRNA levels of IL-12B and T-bet were examined. RESULTS: Frequencies of IL-12B and T bet CNVs in SLE patients were significantly higher than those in healthy controls. CNVs of IL-12B and T-bet had no synergistic contribution to SLE. The mRNA levels of IL-12B and T-bet in the samples with more than two copies of DNA were significantly higher than those with two copies of DNA. CONCLUSIONS: CNVs of IL-12B and T-bet are associated with the risk of SLE. PMID- 21278069 TI - Increased phosphorylation of ezrin/radixin/moesin proteins contributes to proliferation of rheumatoid fibroblast-like synoviocytes. AB - OBJECTIVES: Increasing evidence indicates that ezrin/radixin/moesin (ERM) proteins may play a critical role in cell proliferation. This study examined the role of ERM proteins in proliferation of fibroblast-like synoviocytes (FLS) from patients with RA. METHODS: Synovial tissues (STs) were obtained from 18 RA and 6 OA patients. The expression of ERM and its phosphorylated proteins in cultured FLS and ST was assessed by western blots or IF staining. Small interference RNA (siRNA)-mediated ERM knockdown was used to inhibit phosphorylation of ERM. Proliferation of FLS was measured by bromodeoxyuridine (BrdU) incorporation into cell DNA and by PCNA immunoblotting. RESULTS: Our study showed that increased phosphorylation of ERM proteins was found in ST and FLS from patients with RA as compared with OA patients and non-arthritis controls. Treatment with TNF-alpha, IL-1beta or PDGF-induced phosphorylation of ERM proteins in dose- and time dependent manner by RA FLS, but did not affect the expression of total ERM protein. Rho kinase and p38MAPK signal pathways were involved in TNF-alpha induced ERM phosphorylation. We further showed that inhibition of ERM phosphorylation by siRNA-mediated ERM knockdown suppressed TNF-alpha- or IL-1beta induced BrdU incorporation and PCNA expression in RA FLS. CONCLUSIONS: This study provides the novel evidence that increased phosphorylation of ERM proteins may contribute to proliferation of RA FLS, suggesting that specific inhibition of ERM phosphorylation may be a new therapeutic approach for RA. PMID- 21278070 TI - Methotrexate-induced hiccups. PMID- 21278071 TI - The association of body image dissatisfaction and pain with reduced sexual function in women with systemic sclerosis. AB - OBJECTIVE: Pain and body image distress are common among women with SSc, but their relative associations with reduced sexual function have not been assessed. The objective of this study was to assess the independent associations of pain and body image distress with reduced sexual function in women with SSc. METHODS: Female SSc patients completed measures of sexual function (sexual relationships subscale of the Psychosocial Adjustment to Illness Scale-Self-Report), body image dissatisfaction (Satisfaction with Appearance Scale) and pain (visual analogue scale). Multiple regression analysis was used to assess the associations of body image dissatisfaction and pain with reduced sexual function, controlling for sociodemographic and disease variables. RESULTS: The sample included 117 female SSc patients [33 (28.2%) diffuse; mean age 51.4 (11.9) years; mean time since diagnosis 9.1 (8.5) years]. Unadjusted analyses found that reduced sexual function was associated with pain (r = 0.44, P < 0.001), body image dissatisfaction (r = 0.35, P < 0.001) and being married (r = 0.34, P < 0.001). In multivariate linear regression, disease duration (beta = 0.17, P = 0.046), pain (beta = 0.29, P = 0.001) and unmarried status (beta = -0.23, P = 0.006) were independently associated with reduced sexual function. Dissatisfaction with appearance was not significantly associated with reduced sexual function (beta = 0.16, P = 0.067). CONCLUSION: Pain is an important indicator of sexual function among women with SSc. Body image dissatisfaction was not independently associated with sexual impairment and appears to be less important factor than pain in determining sexual function. Future research should focus on isolating specific sources of pain that may be amenable to intervention in order to improve sexual function. PMID- 21278072 TI - Rituximab infusion-related adverse event rates are lower in patients with systemic lupus erythematosus than in those with rheumatoid arthritis. AB - OBJECTIVES: Rituximab (RTX) is a therapeutic option for patients with SLE or RA. We conducted a prospective, longitudinal, observational study to compare rates of RTX-related adverse events (AEs) in these two patient groups. METHODS: RTX was used in 23 patients with SLE that was refractory to conventional therapy and in 31 patients with RA that had been unsuccessfully treated with TNF-alpha inhibitors. Infusion-related and infectious AE rates were calculated for each group. RESULTS: Seven (22.5%) RA patients experienced an infusion-related reaction. These AEs involved 7/91 (7.7%) infusions administered in the RA group. None of the 102 infusions administered to SLE patients was associated with infusion-related AEs (P = 0.038 vs RA group). The mean daily glucocorticoid dose administered during the week preceding RTX treatment in the SLE group was higher than that for the RA group [0.25 (0.2) vs 0.18 (0.14) mg/kg, P = not significant] and significantly higher than that received by the subgroup of the seven RA patients who experienced infusion-related AEs [0.10 (0.02) mg/kg; P = 0.0017]. Infectious AE rates were also lower (but not significantly so) in the SLE group (8.7 vs 12.9% in RA). CONCLUSIONS: Repeated cycles of RTX in combination with different immunosuppressants is a safe therapeutic option for SLE and RA patients. The lower incidence of infusion-related AEs in the SLE patients might reflect the higher dosage glucocorticoid therapy they received during the week before RTX infusion. PMID- 21278073 TI - Comparison of the efficacy of sonography, magnetic resonance imaging and conventional radiography for the detection of bone erosions in rheumatoid arthritis patients: a systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the reproducibility of US and to compare its efficacy with that of MRI and conventional radiography (CR) for the detection of bone erosion in RA patients. METHODS: A systematic literature search was performed in the Medline, Embase and Cochrane databases up to August 2009. Trials evaluating the reproducibility of US for bone erosion detection or comparing the number of erosions detected by the three imaging methods at patient and/or joint level were included. This last parameter was assessed using the odds ratio (OR) and 95% CI with the Mantel-Haenszel method (OR < 1 favours US). We explored the heterogeneity between the studies by subgroup analysis. RESULTS: Twenty-one studies including 913 patients were included in this meta-analysis. Intraobserver and interobserver reproducibility of US for erosion detection was good. US and MRI efficacies were comparable at both joint (OR = 1.19, P = 0.45; seven studies, 869 joints) and patient (OR = 1.76, P = 0.22; nine studies, 338 patients) levels. US detected significantly more erosion than CR at both joint (OR = 0.30, P < 0.00001; 4047 joints studied) and patient (OR = 0.31, P < 0.00001; 592 studied patients) levels. The number of patients to screen in order to detect an additional patient with an erosion in comparison with CR was 4, 95% CI (2.4, 5.9). CONCLUSION: US is more effective for erosion detection than CR and has a comparable efficacy to MRI with good reproducibility. PMID- 21278074 TI - Plasma concentrations of Gas6 and sAxl correlate with disease activity in systemic lupus erythematosus. AB - OBJECTIVES: SLE is a systemic autoimmune disease with an annual incidence of 3.8 per 100,000. Several pathogenic mechanisms are believed to be operating in SLE, including an impaired clearance of apoptotic cells, activation of the type I IFN pathway and generation of autoimmune leucocytes. Growth arrest-specific protein 6 (Gas6) and its receptor Axl are known to regulate inflammation and may be implicated in lupus pathogenesis. We have recently developed immunological methods to quantify the vitamin-K-dependent protein Gas6 and its soluble receptor sAxl in human plasma, which we have used to investigate the role of Gas6 and soluble Axl in SLE. METHODS: We have investigated the relation between the plasma concentrations of Gas6 and sAxl and disease activity and specific symptoms in 96 SLE patients. RESULTS: Gas6 and sAxl concentrations correlated with SLEDAI (r = 0.48, P < 0.001 and r = 0.39, P < 0.001, respectively). Furthermore, concentrations of Gas6 and sAxl correlated with ESR and CRP and inversely with haemoglobin levels. Gas6 and sAxl concentrations were significantly higher in patients with anti-DNA antibodies, leucopenia and GN. CONCLUSION: The plasma concentrations of Gas6 and sAxl vary with disease activity in SLE, in particular GN, and may have a role in lupus pathogenesis. Furthermore, Gas6 and sAxl may be of use as biomarkers of disease activity. PMID- 21278076 TI - Can patient flow be effectively controlled? AB - BACKGROUND Emergency department (ED) overcrowding may affect the ability to provide quality care and maximize patient flow. Study objectives To analyse the impact of the control of the patient flow during a conflict on ED overcrowding. METHODS During a recent military conflict in Israel the Ministry of Health issued a directive aimed at redirecting the patient flow to EDs in a metropolitan area. The admissions were monitored to identify trends and determine if any changes occurred after the policy change. RESULTS Medical admissions in the only level I trauma centre decreased by 6.5% after the notification, while rising in two other level II hospitals by 3.7% and 4.3%, respectively. Pre- and post-conflict trauma admissions in the level I trauma centre dropped by 2.2% and increased by 6.4% and 1.8%, respectively, in the other hospitals. CONCLUSIONS It is possible to direct the flow of patients to EDs and rationalize the use of resources, making it possible for patients to be admitted to EDs best able to care for them. These findings are especially relevant to emergency situations, but also to non emergent situations in which control of patient flow may be required. Direct communication with the public is recommended to minimize the implementation time of directives regarding patient flow. PMID- 21278075 TI - The relevance of citrullinated vimentin in the production of antibodies against citrullinated proteins and the pathogenesis of rheumatoid arthritis. AB - Antibodies against citrullinated proteins (ACPAs) are highly specific for RA. Since the discovery of these antibodies, several of studies that focused on the presence and identity of citrullinated proteins in the joints of RA patients have been carried out. The best-known antigens that bind ACPAs are citrullinated filaggrin, Type II collagen (CII), alpha-enolase, fibrinogen and vimentin. This review compares citrullinated filaggrin, CII, alpha-enolase and fibrinogen with vimentin in their contribution to ACPA triggering, and gives an overview of the literature in which the role of citrullinated and non-citrullinated vimentin in the onset of ACPA production and the pathogenesis of RA is discussed. PMID- 21278077 TI - How to do (or not to do) ... Assessing the impact of a policy change with routine longitudinal data. AB - A lack of good quality evidence on the effect of alternative social policies in low- and middle-income countries has been recently underlined and the value of randomized trials increasingly advocated. However, it is also acknowledged that randomization is not always feasible or politically acceptable. Analyses using longitudinal data series before and after an intervention can also deliver robust results and such data are often reasonably easy to access. Using the example of evaluating the impact on utilization of a change in health financing policy, this article explains how studies in the literature have often failed to address the possible biases that can arise in a simple analysis of routine longitudinal data. It then describes two possible statistical approaches to estimate impact in a more reliable manner and illustrates in detail the more simple method. Advantages and limitations of this quasi-experimental approach to evaluating the impact of health policies are discussed. PMID- 21278078 TI - Changes in the expression of ion channels, connexins and Ca2+-handling proteins in the sino-atrial node during postnatal development. AB - There are important postnatal changes in the sino-atrial node (SAN), the pacemaker of the heart. Compared with the neonate, the adult has a slower intrinsic heart rate and a longer SAN action potential. These changes may be due to differences in ion channel expression. Consequently, we investigated postnatal developmental changes in the expression of ion channels and Ca(2+)-handling proteins in the SAN to see whether this is indeed the case. Using quantitative PCR, in situ hybridization and immunohistochemistry, we investigated the expression of ion channels, Ca(2+)-handling proteins and connexins in the SAN from neonatal (2-7 days of age) and adult (~6 months of age) New Zealand White rabbits. The spontaneous beating rate of adult SAN preparations was 21% slower than that of neonatal preparations. During postnatal development, quantitative PCR revealed a significant decline in the SAN of the following mRNAs: HCN4 (major isoform responsible for I(f)), Na(V)1.5 (responsible for I(Na)), Ca(V)1.3 (in part responsible for I(Ca,L)) and NCX1 (responsible for inward I(NaCa)). These declines could be responsible for the slowing of the pacemaker during postnatal development. There was a significant decline during development in mRNA for delayed rectifier K(+) channel subunits (K(V)1.5, responsible for I(K,ur), K(V)LQT1 and minK, responsible for I(K,s), and ERG, responsible for I(K,r)) and this could explain the prolongation of the action potential. In situ hybridization confirmed the changes observed by quantitative PCR. In addition, immunohistochemistry revealed hypertrophy of nodal cells during postnatal development. Moreover, there were complex changes in the expression of Ca(2+) handling proteins with age. In summary, there are significant postnatal changes in the expression of ion channels and Ca(2+)-handling proteins in the SAN that could explain the established changes in heart rate and action potential duration that occur during normal development. PMID- 21278079 TI - Non-quantal release of acetylcholine in guinea-pig airways: role of choline transporter. AB - In the resting state, motor neurons continuously release ACh through quantal and non-quantal mechanisms, the latter through vesicular ACh transporter (VAChT) and choline transporter (ChT). Although in skeletal muscle these mechanisms have been extensively studied, the non-quantal release (NQR) from parasympathetic neurons of airway smooth muscle has not been described. Here we corroborated that the organophosphate paraoxon (acetylcholinesterase inhibitor) induced a contraction blocked by atropine (muscarinic antagonist) in guinea-pig tracheal rings. This contraction was not modified by two blockers of evoked quantal release, tetrodotoxin (voltage-dependent Na(+) channel blocker) and omega-conotoxin GVIA (N-type Ca(2+) channel blocker), nor by the nicotinic blocker hexamethonium, suggesting that acetylcholine NQR could be responsible of the paraoxon-induced contraction. We confirmed that tetrodotoxin, and to some extent -conotoxin, abolished the evoked quantal ACh release induced by electrical field stimulation. Hemicholinium-3 (ChT inhibitor), but not vesamicol (VAChT inhibitor), caused a concentration-dependent inhibition of the response to paraoxon. The highest concentration of hemicholinium-3 left ~75% of the response to electrical field stimulation, implying that inhibition of paraoxon-induced contraction was not due to depletion of neuronal vesicles. Non-neuronal sources of ACh released through organic cation transporters were discarded because their inhibition by quinine or corticosterone did not modify the response to paraoxon. Calcium-free medium abolished the effect of paraoxon, and NiCl(2), 2-aminoethyl diphenyl-borate and SKF 96365 partly inhibited it, suggesting that non-specific cation channels were involved in the acetylcholine NQR. We concluded that a Ca(2+)-dependent NQR of ACh is present in cholinergic nerves from guinea-pig airways, and that ChT is involved in this phenomenon. PMID- 21278080 TI - Mistreatment in assisted living facilities: complaints, substantiations, and risk factors. AB - PURPOSE OF THE STUDY: Use archived public data from Arizona to explore relationships among selected institutional and resident risk and situation specific factors and complaints and substantiated allegations of various types of mistreatment in assisted living facilities (ALFs). DESIGN AND METHODS: An exploratory/descriptive 2-group design was used. Facilities in the complaint group were identified from narrative data that appeared suspicious for mistreatment based on definitions for physical, verbal, psychological, medication, sexual abuse, neglect, financial exploitation, and physical restraint. Facilities in the comparison group were those that had no citations or complaints in 2007-2008. Narrative data were content analyzed, and chi-square analysis was used to answer 3 research questions. RESULTS: The complaint group was comprised of significantly more assisted living centers, large facilities (51 101+), facilities licensed to provide personal care services, and facilities owned by national corporations. Substantiated allegations were significantly more frequent in assisted living centers, facilities with more than 51 beds, and those owned by national corporations. Facility risk factors were related to some types of substantiated mistreatment and not others. IMPLICATIONS: Findings suggest the need to evaluate use of only unlicensed assistive personnel in facilities, increase oversight of care by professional nurses, rethink the practice of not licensing small facilities, and monitor more closely practices and procedures in facilities operated by national corporations. PMID- 21278081 TI - Functional and systems biology approaches to Huntington's disease. AB - Huntington's disease (HD) is a hereditary, progressively degenerative and fatal brain disorder classified as a rare, or 'orphan', disease. HD is caused by the extension of trinucleotide repeats encoding a stretch of glutamine residues at the amino-terminal end of the large huntingtin (HTT) protein. Since the discovery of the mutated HTT gene in 1993, the mechanisms by which the mutant HTT protein induces neurodegeneration remain poorly understood and no disease-modifying therapy is currently available. Several functional approaches combining different experimental models and experimental technologies have been used to shed some light on the mechanisms underlying this disease. This review presents these functional approaches, highlights their potential and limitations. PMID- 21278082 TI - Genomic approaches to the initiation of DNA replication and chromatin structure reveal a complex relationship. AB - The mechanisms regulating the coordinate activation of tens of thousands of replication origins in multicellular organisms remain poorly explored. Recent advances in genomics have provided valuable information about the sites at which DNA replication is initiated and the selection mechanisms of specific sites in both yeast and vertebrates. Studies in yeast have advanced to the point that it is now possible to develop convincing models for origin selection. A general model has emerged, but yeast data have also revealed an unsuspected diversity of strategies for origin positioning. We focus here on the ways in which chromatin structure may affect the formation of pre-replication complexes, a prerequisite for origin activation. We also discuss the need to exercise caution when trying to extrapolate yeast models directly to more complex vertebrate genomes. PMID- 21278083 TI - Neurofascin as target of autoantibodies in Guillain-Barre syndrome. PMID- 21278084 TI - Neuronal degeneration in striatal transplants and Huntington's disease: potential mechanisms and clinical implications. AB - Cell therapy offers the possibility of replacing degenerated neurons thereby improving the symptoms of neurodegenerative disorders such as Huntington's disease. However, clinical benefits in patients with Huntington's disease, if any, have been transient and modest. Grafts survived well at 18 months in one patient with Huntington's disease, but graft survival was markedly attenuated by 10 years in three other patients from this transplantation cohort. It is critical to delineate the causes of graft degeneration if such therapies will be utilized in patients with a goal of achieving meaningful clinical benefit. Similar challenges may also accrue to future stem cell therapies. Here we discuss the potential causes of suboptimal long-term graft survival in patients with Huntington's disease, including allograft immunoreactivity, microglial responses targeted to grafted cells and cell-to-cell neurotoxicity. We also discuss similar challenges and unique differences comparing neuronal grafts in patients with Parkinson's and Huntington's diseases. PMID- 21278085 TI - The sigma-1 receptor enhances brain plasticity and functional recovery after experimental stroke. AB - Stroke leads to brain damage with subsequent slow and incomplete recovery of lost brain functions. Enriched housing of stroke-injured rats provides multi-modal sensorimotor stimulation, which improves recovery, although the specific mechanisms involved have not been identified. In rats housed in an enriched environment for two weeks after permanent middle cerebral artery occlusion, we found increased sigma-1 receptor expression in peri-infarct areas. Treatment of rats subjected to permanent or transient middle cerebral artery occlusion with 1 (3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride, an agonist of the sigma-1 receptor, starting two days after injury, enhanced the recovery of lost sensorimotor function without decreasing infarct size. The sigma-1 receptor was found in the galactocerebroside enriched membrane microdomains of reactive astrocytes and in neurons. Sigma-1 receptor activation increased the levels of the synaptic protein neurabin and neurexin in membrane rafts in the peri-infarct area, while sigma-1 receptor silencing prevented sigma-1 receptor-mediated neurite outgrowth in primary cortical neuronal cultures. In astrocytic cultures, oxygen and glucose deprivation induced sigma-1 receptor expression and actin dependent membrane raft formation, the latter blocked by sigma-1 receptor small interfering RNA silencing and pharmacological inhibition. We conclude that sigma 1 receptor activation stimulates recovery after stroke by enhancing cellular transport of biomolecules required for brain repair, thereby stimulating brain plasticity. Pharmacological targeting of the sigma-1 receptor provides new opportunities for stroke treatment beyond the therapeutic window of neuroprotection. PMID- 21278087 TI - Injury prevention in Safe Communities. PMID- 21278088 TI - The public policy approach to injury prevention. PMID- 21278089 TI - Injury prevention in child death review. PMID- 21278090 TI - Paediatric low speed vehicle run-over fatalities in Queensland. AB - INTRODUCTION: Child pedestrian fatalities associated with motor vehicles reversing or moving at low speed are difficult to identify in surveillance data. This study aims to determine the incidence of fatalities associated with what is thought to be an under-reported and preventable fatal injury mechanism. METHODS: The term low speed vehicle run-over (LSVRO) incidents encompasses pedestrian fatalities where vehicles run-over a child at low speed. Data were obtained for children aged 0-15 years in the Australian state of Queensland (January 2004 December 2008). RESULTS: There were 15 deaths (12 boys and 3 girls) during 2004 2008 (rate:1.67/100,000). Over half were aged 0 and 1 years of age (n=8; 53.3%, rate: 14.67/100,000), and one quarter were 2 and 3 years of age (n=4, 27%, rate 7.46/100,000). There were no LSVRO deaths recorded among 10-15 year olds. Most (13/15) of the incidents occurred on private property, and only two occurred on a street/road. Almost half of the fatalities were caused by a four wheel drive (4WD) vehicle; large family sedans were involved in four fatalities, and heavy vehicles were involved in three deaths. In 11 of the fatalities, parents were the drivers of the vehicle involved (mothers 5; fathers 6). In nine, the vehicle involved was reversing before it came in contact with the child. Fatalities occurred in each of the Socio-Economic Indexes For Areas (SEIFA) levels. CONCLUSION: The unique data provided by the child death review team has signalled that LSVRO fatalities are a significant problem in Queensland. The Commission for Children and Young People and Child Guardian (CCYPCG) continue to collect data, which, when combined, will provide outcomes that will act as an impetus for promoting intervention and child advocacy. PMID- 21278091 TI - History of maltreatment among unintentional injury deaths: analyses of Texas child fatality review data, 2005-2007. AB - OBJECTIVE: This report examines unintentional injury deaths among children with and without a history of child maltreatment. METHODS: Data are from reviews of 1192 unintentional injury deaths occurring among children in Texas during 2005 2007. The study examined differences in child demographic characteristics, injury mechanism, and supervisor status at time of death between children with and without maltreatment history by using descriptive statistics and chi2 tests. Separate analyses compared characteristics of asphyxia, drowning, and poisoning deaths. RESULTS: In 10% of the unintentional injury deaths that were reviewed, the child had a history of maltreatment. The prevalence of a history of maltreatment was highest among black decedents and lowest among white decedents. Prevalence of a history of maltreatment was highest among infant decedents and lowest among youth decedents, ages 10-14 years. Among deaths where there was no maltreatment history, 54% were due to motor vehicle related incidents, whereas 51% of deaths among children with maltreatment history were caused by drowning, asphyxia, and poisoning. Supervisors of child decedents with a history of maltreatment were significantly more likely to have been alcohol impaired (6.9% vs 1.6%; p<0.0005), or asleep (12.1% vs 6.6%; p=0.03) at the time of death. Differences between child decedents with and without maltreatment history were observed in infant sleep surface in suffocation deaths, location and barrier type in drowning deaths, and substance type in poisoning deaths. CONCLUSIONS: These data show that the mechanisms and circumstances surrounding unintentional injury deaths among children with a history of maltreatment differ from those without a history of maltreatment. This underscores the need for appropriate interventions to prevent unintentional and intentional injuries in families with a history of maltreatment. PMID- 21278092 TI - Role of a child death review team in a small rural county in California. AB - Humboldt County is one of California's most rural counties. Located in far Northern California, it is 6-7 h by car from the nearest major urban areas of San Francisco and Sacramento. In landmass it is one of the largest of the California counties, about the size of Rhode Island. In 1991, the Humboldt County Public Health Branch began a Fetal Infant Mortality Review programme. Because of the county's small size, the Fetal Infant Mortality Review process was combined with the review of child deaths through age 17. Responding to a high proportion of cases of child deaths due to unintentional injury, the team developed a workgroup to explore injury prevention strategies. Funding was identified to hire a coordinator who formed a Childhood Injury Prevention Program and developed a strategic plan. The plan prioritised both motor vehicle/traffic safety related injuries and general childhood injury. Funding was obtained for child passenger safety and youth safe driving programmes. The Childhood Injury Prevention Program also collaboratively addressed other injury prevention areas, including water safety. As a small, rural county in California, committed safety advocates from multiple agencies were able to utilise the child death review process to guide injury prevention efforts. Case reviews provided the motivation and quantitative and qualitative data to design programmes and implement interventions that addressed specific unintentional injuries causing child deaths and injuries in Humboldt County. PMID- 21278093 TI - Use of child death review to inform sudden unexplained infant deaths occurring in a large urban setting. AB - OBJECTIVE: To illustrate the benefits and utility of the child death review (CDR) reporting system when examining risk factors associated with infant death occurring within two subgroups of sudden unexpected infant deaths (SUID) unintentional suffocation and sudden infant death syndrome (SIDS)-in a large urban county in Wisconsin. DESIGN: Retrospective CDR data were analysed, 2007 2008, for Milwaukee County, Wisconsin. PATIENTS OR SUBJECTS: Unintentional suffocation and SIDS infant deaths under 1 year of age in Milwaukee County, Wisconsin, 2007-2008, with a CDR record indicating a death in a sleep environment. Main outcome measure Study examined demographic characteristics, bed sharing, incident sleep location, position of child when put to sleep, position of child when found, child's usual sleep place, crib in home, and other objects found in sleep environment. RESULTS: Unintentional suffocation (n=11) and SIDS (n=40) classified deaths with CDR data made up 18% (51/283) of all infant deaths in Milwaukee County from 2007 to 2008. The majority of infants who died of unintentional suffocation (n=9, 81.8%) or SIDS (n=26, 65.0%) were black and under the age of 3 months. Bed-sharing was involved in most of the unintentional suffocation deaths (n=10, 90.9%) and the SIDS deaths (n=28, 70.0%). All unintentional suffocation deaths (n=11, 100%) and the majority of SIDS deaths (n=31, 77.5%) took place in a non-crib sleeping environment. CONCLUSIONS: The study demonstrates how CDR provides enhanced documentation of risk factors to help steer prevention efforts regarding SUID deaths in a community and reaffirms infants in an unsafe sleep environment have an increased risk of death. PMID- 21278094 TI - Analysis of paediatric drowning deaths in Washington State using the child death review (CDR) for surveillance: what CDR does and does not tell us about lethal drowning injury. AB - BACKGROUND: Drowning is second cause of paediatric injury death in Washington State. Child death review (CDR) data provide the unique opportunity to identify regional risk factors and opportunities for drowning prevention. METHODS: CDR teams' data for drowning deaths of children <18 years between 1999 and 2003 were analysed for victim and event characteristics, and existing prevention/protective factors. A working group made data driven recommendations. Subsequent interventions were noted. RESULTS: Drowning death rates were significantly higher among Asian Pacific Islander children (3.3 per 100,000). Disproportionately, 32% of deaths involved families with prior child protective services (CPS) referrals. Most deaths (73%) occurred in open water; the proportion in open water increased from 42% of <5-year-olds, 83% of 5-9-year-olds, to 90% of 10-17-year-olds. Thirty per cent drowned at parks; 29% drowned in residential settings. Pre-drowning activity for 42% was swimming or playing in the water. Alcohol and drug use were low. Neglect/poor supervision was considered a factor in 68% (21/31) of the deaths of children <5 years of age. State CDR recommendations led to the development of a drowning prevention campaign targeted to an Asian American community, intra-agency changes resulting in reinstatement of lifeguard staffing and addition of lifejacket loaner programmes, collaboration with state commissions to enforce a state pool fencing ordinance, and model legislation prohibiting swimming in dangerous waterways. CONCLUSION: CDR data collection and review process was an effective surveillance tool. It identified specific regional high risk groups and sites for drowning prevention and led to recommendations and implementation of effective local and state injury prevention interventions. PMID- 21278095 TI - The US National Child Death review case reporting system. AB - The National Child Death Review Case Reporting System (NCDR-CRS) was developed in the USA to provide child death review teams with a simple method for capturing, analysing, and reporting on the full set of information shared at a child death or serious injury review. The NCDR-CRS is a web based system currently being used by 35 of the 50 US states. This article describes the purpose, features, limitations, and strengths of the system. It describes current and planned efforts for the dissemination of the data to inform and catalyse local, state, and national efforts to keep children safe, healthy, and alive. PMID- 21278096 TI - The burden of childhood injuries and evidence based strategies developed using the injury surveillance system in Pasto, Colombia. AB - OBJECTIVE: This article characterises the burden of childhood injuries and provides examples of evidence-based injury prevention strategies developed using a citywide injury surveillance system in Pasto, Colombia. METHODS: Fatal (2003 2007) and non-fatal (2006-2007) childhood injury data were analysed by age, sex, cause, intent, place of occurrence, and disposition. RESULTS: Boys accounted for 71.5% of fatal and 64.9% of non-fatal injuries. The overall fatality rate for all injuries was 170.8 per 100,000 and the non-fatal injury rate was 4,053 per 100,000. Unintentional injuries were the leading causes of fatal injuries for all age groups, except for those 15-19 years whose top four leading causes were violence-related. Among non-fatal injuries, falls was the leading mechanism in the group 0-14 years. Interpersonal violence with a sharp object was the most important cause for boys aged 15-19 years. Home was the most frequent place of occurrence for both fatal and non-fatal injuries for young children 0-4 years old. Home, school and public places became an important place for injuries for boys in the age group 5-15 years. The highest case-fatality rate was for self inflicted injuries (8.9%). CONCLUSIONS: Although some interventions have been implemented in Pasto to reduce injuries, it is necessary to further explore risk factors to better focus prevention strategies and their evaluation. We discuss three evidence-based strategies developed to prevent firework-related injuries during festival, self-inflicted injuries, and road traffic-related injuries, designed and implemented based on the injury surveillance data. PMID- 21278097 TI - Injury prevention in child death review: child pedestrian fatalities. AB - OBJECTIVE: This article describes the epidemiology of child pedestrian fatalities in British Columbia using data generated by the province's Child Death Review Unit, to demonstrate the unique capacity of child death review to provide an ecological understanding of child mortality and catalyse evidence based, multi level prevention strategies. METHODS: All child pedestrian fatalities in British Columbia from 1 January 1 2003 to 31 December 2008 were reviewed. Data on demographics, circumstance of injury, and risk factors related to the child, driver, vehicle, and physical environment were extracted. Frequency of sociodemographic variables and modifiable risk factors were calculated, followed by statistical comparisons against the general population for Aboriginal ancestry, gender, ethnicity, income assistance and driver violations using z and t tests. RESULTS: Analysis of child pedestrian fatalities (n=33) found a significant overrepresentation of Aboriginal children (p=0.06), males (p<0.01), and children within low income families (p<0.01). The majority of incidents occurred in residential areas (51.5%), with a speed limit of 50 kph or higher (85.7%). Risky pedestrian behaviour was a factor in 56.7% of cases, and 33% of children under 10 years of age were not under active supervision. Drivers had significantly more driving violations than the comparison population (p<0.01). CONCLUSION: Child pedestrian fatalities are highly preventable through the modification of behavioural, social, and environmental risk factors. This paper illustrates the ability of child death review to generate an ecological understanding of injury epidemiology not otherwise available and advance policy and programme interventions designed to reduce preventable child mortality. PMID- 21278098 TI - Assessment of caregiver responsibility in unintentional child injury deaths: challenges for injury prevention. AB - Most unintentional injury deaths among young children result from inadequate supervision or failure by caregivers to protect the child from potential hazards. Determining whether inadequate supervision or failure to protect could be classified as child neglect is a component of child death review (CDR) in most states. However, establishing that an unintentional injury death was neglect related can be challenging as differing definitions, lack of standards regarding supervision, and changing norms make consensus difficult. The purpose of this study was to assess CDR team members' categorisation of the extent to which unintentional injury deaths were neglect related. CDR team members were surveyed and asked to classify 20 vignettes-presented in 10 pairs-that described the circumstances of unintentional injury deaths among children. Vignette pairs differed by an attribute that might affect classification, such as poverty or intent. Categories for classifying vignettes were: (1) caregiver not responsible/not neglect related; (2) some caregiver responsibility/somewhat neglect related; (3) caregiver responsible /definitely neglect related. CDR team members from five states (287) completed surveys. Respondents assigned the child's caregiver at least some responsibility for the death in 18 vignettes (90%). A majority of respondents classified the caregiver as definitely responsible for the child's death in eight vignettes (40%). This study documents attributes that influence CDR team members' decisions when assessing caregiver responsibility in unintentional injury deaths, including supervision, intent, failure to use safety devices, and a pattern of previous neglectful behaviour. The findings offer insight for incorporating injury prevention into CDR more effectively. PMID- 21278099 TI - Developing effective child death review: a study of 'early starter' child death overview panels in England. AB - AIM: This qualitative study of a small number of child death overview panels aimed to observe and describe their experience in implementing new child death review processes, and making prevention recommendations. METHODS: Nine sites reflecting a geographic and demographic spread were selected from Local Safeguarding Children Boards across England. Data were collected through a combination of questionnaires, interviews, structured observations, and evaluation of documents. Data were subjected to qualitative analysis. RESULTS: Data analysis revealed a number of themes within two overarching domains: the systems and structures in place to support the process; and the process and function of the panels. The data emphasised the importance of child death review being a multidisciplinary process involving senior professionals; that the process was resource and time intensive; that effective review requires both quantitative and qualitative information, and is best achieved through a structured analytic framework; and that the focus should be on learning lessons, not on trying to apportion blame. In 17 of the 24 cases discussed by the panels, issues were raised that may have indicated preventable factors. A number of examples of recommendations relating to injury prevention were observed including public awareness campaigns, community safety initiatives, training of professionals, development of protocols, and lobbying of politicians. CONCLUSIONS: The results of this study have helped to inform the subsequent establishment of child death overview panels across England. To operate effectively, panels need a clear remit and purpose, robust structures and processes, and committed personnel. A multi-agency approach contributes to a broader understanding of and response to children's deaths. PMID- 21278100 TI - Assessing and improving child death review team recommendations. AB - BACKGROUND: Child death review teams (CDRTs) are multi-agency, multidisciplinary teams that review the circumstances surrounding child deaths. Although the potential of CDRTs to promote systems improvement and prevention is well recognised, teams often struggle to translate their findings into effective preventive actions. OBJECTIVE: To present results from a study assessing the quality of written recommendations in published CDRT reports; and provide guidelines for improving the quality and effectiveness of these written recommendations. METHODS: A descriptive, non-experimental design was used to analyse a set of 1093 recommendations from 21 randomly selected, publicly available state and local CDRT reports. An assessment instrument, modelled on the public health approach, was developed to score the quality of recommendations. It consists of three components divided into 10 dimensions: problem assessment; written recommendations; and action on recommendations. RESULTS: CDRT reports scored highest in the problem assessment component (mean score: 2.7/dimension), followed by written recommendations (2.2/dimension), and action on recommendations (1.9/dimension). Even among the highest ranked dimensions, the average scores were only in the mid range of quality on our assessment scale. CONCLUSIONS: The results suggest that CDRTs are doing a better job of 'assessing the problem' than in 'proposing solutions' as indicated by their written recommendations. CDRT reports often do not address follow-up of their written recommendations. Guidelines are offered for use as a practical tool to help CDRTs enhance the likelihood of producing effective recommendations that prevent future child injuries and deaths. PMID- 21278101 TI - Collaborative process improvement to enhance injury prevention in child death review. AB - OBJECTIVE: To increase the number and quality of injury prevention recommendations made by Washington State (USA) child death review teams. DESIGN: Before and after study design involving four intervention teams and 21 comparison teams. METHODS: Intervention teams received injury prevention training, collaborative process improvement coaching, and access to web based prevention resources. An equal number of randomly selected child death review case reports filed with the state before the intervention by the intervention and comparison teams were included in the baseline sample. All reports submitted by the intervention and comparison teams after the intervention were included in the follow-up sample. Reports were scored on the completeness of prevention related data elements and on the quality of written prevention recommendations. RESULTS: Data completion for prevention relevant items increased in intervention teams from 73% at baseline to 88% at follow-up. In comparison teams, this measure fell from 77% to 56% over the same period. The quality of written recommendations produced by intervention teams increased from 4.3 (95% CI 3.4 to 5.1) to 7.6 (95% CI 6.7 to 8.5), while comparison teams showed no significant change (4.0 (95% CI 2.5 to 5.3) to 3.7 (95% CI 2.2 to 5.2)). Specifically, improvements were noted in the identification of evidence based best practices and the development of clear, actionable written recommendations. CONCLUSION: Injury prevention recommendations are generated in the systematic local review of child deaths. This process can be analysed, measured, supported, and improved. PMID- 21278102 TI - Actionable reminders did not improve performance over passive reminders for overdue tests in the primary care setting. AB - Actionable reminders (electronic reminders linked to computerized order entry) might improve care by facilitating direct ordering of recommended tests. The authors implemented four enhanced actionable reminders targeting performance of annual mammography, one-time bone-density screening, and diabetic testing. There was no difference in rates of appropriate testing between the four intervention and four matched, control primary care clinics for screening mammography (OR 0.81, 95% CI 0.64 to 1.02), bone-density exams (OR 1.29, 95% CI 0.82 to 2.02), HbA1c monitoring (OR 0.91, 95% CI 0.58 to 1.42) and LDL cholesterol monitoring (OR 1.40, 95% CI 0.76 to 2.59). Of the survey respondents, 79% almost never used the system or were unaware of the functionality. In the 9/228 (3.9%) cases with indirect evidence of mammography reminder use, there was a significantly lower proportion with test performance. Our actionable reminders did not improve receipt of overdue testing, potentially due to limitations of workflow integration. PMID- 21278103 TI - Commercially produced spray-dried porcine plasma contains increased concentrations of porcine circovirus type 2 DNA but does not transmit porcine circovirus type 2 when fed to naive pigs. AB - The porcine circovirus type 2 (PCV2) antibody and DNA status of porcine plasma products collected during the commercial spray-drying process were evaluated. Samples evaluated included 52 pooled liquid plasma (fresh) samples collected at 14 regional abattoirs before transport to 1 of 2 spray-drying facilities, 32 pooled liquid plasma (concentrated) samples collected after arrival at the spray drying facilities at different stages before the spray-drying process, and 32 samples in powdered form (spray-dried) collected after spray drying. All 116 samples were positive for PCV2 antibody, with PCV2 ELISA sample-to-positive ratios ranging from 9.2 to 13.6 on a DM basis. Porcine circovirus type 2 DNA (4.5 to 7.9 log(10) PCV2 copies/mL, DM basis) was present in 82.7% (43/52) of the fresh plasma samples, 71.9% (23/32) of the concentrated plasma samples and 78.1% (25/32) of the spray-dried plasma samples, with a greater prevalence of PCV2b than PCV2a. To determine the infectivity of PCV2 DNA-positive commercial spray dried plasma, nine 10-wk-old 68-kg PCV2-naive pigs were randomly assigned to 1 of 3 treatment groups and rooms: 1) a negative control (no plasma in the feed, not inoculated with PCV2); 2) a positive control (no plasma in the feed, inoculated with PCV2); and 3) plasma-fed pigs (4% porcine plasma in the feed for 42 d, not inoculated with PCV2). All positive control pigs became viremic by 7 d postinoculation and seroconverted by 42 d postinoculation, whereas pigs in the negative control group and in the spray-dried plasma group were PCV2 PCR negative and did not seroconvert to PCV2 for the duration of the study. The results indicate that PCV2 DNA and antibodies are commonly found in commercial spray dried plasma. However, no evidence of infectivity of the PCV2 DNA was found in naive pigs when commercial spray-dried plasma was included in the diet under the conditions of this study. PMID- 21278104 TI - Relationships between fed cattle traits and Igenity panel scores. AB - Although several previous studies have identified associations between cattle carcass characteristics and various SNP, comparatively little work has sought to validate the marker panels currently sold and marketed by commercial genotyping companies. Panels typically use a handful of SNP, but these range from as few as 2 to more than 100. Data from 764 commercially fed steers and heifers were used to assess the relationships of growth and carcass traits and Igenity panel scores for ADG, marbling (or percentage of USDA Choice), rib-eye area (REA), tenderness, fat thickness, and USDA Yield grade (YG). Results revealed statistically significant, but low, correlations between carcass measurements and corresponding Igenity panel scores. Genetic correlations were computed among the various Igenity panels and demonstrated either that several common markers existed across the panels or that markers across panels were in high linkage disequilibrium. Across all breeds, the genotypic correlations between the Igenity panel scores for ADG, REA, marbling, and YG with observed ADG, REA, USDA Quality grade, and YG at slaughter were 0.51, 0.38, 0.63, and 0.59 (P < 0.01), respectively. The partial effects of the Igenity marbling panel persisted in a multivariate regression model. Net return was significantly affected only by marbling panel score; a 1-unit increase in marbling panel score increased the net return by an estimated $7.53 per animal. PMID- 21278105 TI - Effects of gestation and transition diets, piglet birth weight, and fasting time on depletion of glycogen pools in liver and 3 muscles of newborn piglets. AB - The experiment was conducted to assess the effects of maternal nutrition in late gestation on glycogen pools of newborn piglets of different birth weights and to assess how rapidly the glycogen pools in the liver and 3 muscles are mobilized during fasting. Until d 108 of gestation, 48 sows were fed a gestation standard diet (GSD) with low dietary fiber (DF, 17.1%), or 1 of 3 diets with high DF (32.3 to 40.4%) consisting of pectin residue (GPR), potato pulp (GPP), or sugar-beet pulp (GSP). From d 108 until farrowing, sows were fed 1 of 6 transition diets with low or high dietary fat: one group received a standard diet (TSD; control) containing 3% animal fat, another group received the TSD diet + 2.5 g/d of hydroxy-methyl butyrate as topdressing (THB), and 4 other groups received diets with 8% added fat from coconut oil (TCO), sunflower oil (TSO), fish oil (TFO), or 4% octanoic acid + 4% fish oil (TOA). Two piglets per litter (the second and fifth born) were blood sampled, and 1 was killed immediately after birth, whereas the other, depending on the litter, was killed after 12, 24, or 28.5 to 36 h (mean 32.5 h) of fasting. Samples of liver, LM, M. semimembranousus (SM), and M. diaphragm (DP) were collected and analyzed for glycogen concentration. No dietary effects (P > 0.20) on glycogen concentrations in liver, LM, SM, or DP were observed. The weight of the liver was affected by gestation diet (P < 0.05) and was greater in GSD and GSP piglets (36.7 and 36.3 g) than in GPR piglets (32.6 g), and intermediate (33.6 g) in GPP piglets. Liver weight, estimated muscle mass, and glycogen pools (P < 0.001) were affected by birth weight, whereas glycogen concentrations in liver and LM, SM, and DP muscles were not (P > 0.05). Liver weight; glycogen concentrations in liver, LM, SM, and DP; and glycogen pools in liver and muscles decreased (P < 0.001) with increasing duration of fasting, and at 32.5 h of fasting, glycogen concentration was reduced by 80% in liver, 64% in DP, 46% in SM, and 36% in LM. Based on a broken-line model, labile glycogen in SM, a locomotory muscle, was estimated to be depleted after 16.4 h of fasting. In conclusion, piglet size had a major impact on estimated glycogen pools, whereas sow nutrition in late gestation had a minor impact, if any. Furthermore, varying proportions of pools of glycogen present in liver and selected muscles were mobilized, and data indicate that newborn piglets are fatally depleted of energy after 16 h of fasting. PMID- 21278106 TI - Zilpaterol improves feeding performance and fabrication yield of concentrate finished cull cows. AB - The objective of this study was to quantify the effects of zilpaterol hydrochloride (ZH) on feeding performance and fabrication yield of concentrate finished cull cows. Three hundred twenty commercial cull cows (2 to 10 yr old) were obtained from ranches in Missouri and South Dakota and assigned to 1 of 2 treatments: 1) a control diet containing no ZH and 2) a diet that contained ZH. Cows were fed for 75, 88, or 110 d, and all received the control ration until ZH treatments were initiated. Twenty-four days before slaughter, ZH feeding began for the designated treatment pens; cows were fed ZH [8.33 mg/kg (100% DM basis)] for 20 d with a 4-d withdrawal period before slaughter. No differences (P>0.05) were detected between the 2 treatment groups for initial BW or DMI. Final BW (640.5 vs. 619.1 kg), ADG for the last 24 d (2.75 vs. 2.17 kg), and G:F for the last 24 d (0.160 vs. 0.126) were greater (P<0.01) in cows fed ZH than the control cows. No differences (P > 0.05) were found for lean or skeletal maturity score, fat thickness, LM area, HCW, or calculated yield grade among the 2 treatment groups. Feeding ZH increased (P<0.01) HCW (390.1 vs. 369.2 kg), dressed carcass yield (61.01 vs. 59.45%), and LM area (93.3 vs. 86.5 cm(2)) and decreased (P<0.01) marbling score (Slight(63) vs. Slight(86)) compared with control cows. Cows fed ZH had greater (P<0.05) primal weights for chuck (mock) tender (2.63 vs. 2.28 kg), lip-on rib eye roll (13.54 vs. 12.56 kg), top sirloin butt (12.74 vs. 11.82 kg), top (inside) round (14.58 vs. 12.89 kg), and peeled knuckle (12.87 vs. 11.51 kg) while yielding a decreased percentage of mechanical knife trimmings (1.15 vs. 1.35%; P<0.01) and more top (inside) rounds (3.71 vs. 3.46%; P=0.02) than the control cows. No differences (P>0.07) were found for the remaining fabrication yield attributes. The ZH-treated cows had greater (P<0.05) fabrication dollar values for chuck (mock) tender (8.82 vs. 7.66 $/carcass), lip on rib eye roll (64.20 vs. 59.56 $/carcass), strip loin (0 * 1; 49.13 vs. 44.75 $/carcass), top sirloin butt (35.60 vs. 33.01 $/carcass), bottom round (flat; 44.23 vs. 39.23 $/carcass), top (inside) round (60.30 vs. 53.33 $/carcass), knuckle (peeled; 44.26 vs. 39.57 $/carcass), and total salable yield (879.50 vs. 803.70 $/carcass) than control cows. These results suggest the feeding of ZH to concentrate-finished cull cows enhances production efficiencies and can add new value to the cull cow market. PMID- 21278107 TI - Horse species symposium: pathogenic and reproductive dysfunction in horses. PMID- 21278108 TI - Nonruminant Nutrition Symposium: intestinal glucose sensing and regulation of glucose absorption: implications for swine nutrition. AB - The Na(+/)glucose cotransporter (SGLT1) is the major route for the transport of dietary sugars from the lumen of the intestine into enterocytes. Regulation of this protein is essential for the provision of glucose to the body and avoidance of intestinal malabsorption. This has important nutritional implications in particular for young and growing animals. It has been demonstrated that dietary sugars and artificial sweeteners increase SGLT1 expression and the capacity of the gut to absorb monosaccharides. Furthermore, diets supplemented with artificial sweeteners have been shown to improve growth and performance of weaning piglets. In this review, after describing the organization of intestinal epithelium, the type of gut hormones released in response to dietary carbohydrates, the mechanism underlying the transcellular transport of glucose in the intestine is outlined. Next, a historical background to the work carried out in various laboratories aimed at identifying molecular mechanisms involved in regulation of intestinal glucose transporter, SGLT1, is described. Subsequently, the more recent data on the role of intestinal glucose, or sweet, sensor T1R2 + T1R3, a G protein-coupled receptor, required for upregulation of SGLT1 by dietary sugars and artificial sweeteners, are presented. The glucose sensor subunits, T1R2 + T1R3, are members of the taste receptor family 1, T1R, and are expressed in the gut enteroendocrine cells. Sensing of dietary sugars and artificial sweeteners by T1R2 + T1R3 activates a pathway in endocrine cells leading to secretion of gut hormones. Finally, after describing molecular mechanisms by which a specific gut hormone released by endocrine cells may regulate SGLT1 expression in the neighboring absorptive enterocytes, the application of these findings to enhancing intestinal capacity to absorb dietary sugars in weaning piglets is presented. A better understanding of the molecular events involved in regulation of SGLT1 will allow the identification of nutritional targets with attendant promise of avoiding nutrient malabsorption and enhancing growth and well-being of species. PMID- 21278109 TI - Bovine pyruvate carboxylase 5' untranslated region variant expression during transition to lactation and feed restriction in dairy cows. AB - Pyruvate carboxylase (PC; EC 6.4.1.1) is a critical enzyme for gluconeogenesis and maintenance of tricarboxylic acid (TCA) cycle intermediates, and expression of PC mRNA is increased at calving and during feed restriction. The bovine PC gene contains 3 promoters (3, 2, and 1 from 5' to 3') that produce 6 mRNA 5' variants (A through F). Products of promoter 1, untranslated region (UTR) variants A, B, C, and F are specifically expressed in glucogenic and lipogenic tissues. The objective of this study was to develop a quantitative PCR-based assay for bovine PC 5' UTR variants that would permit simultaneous characterization of PC variant expression and to determine the pattern of PC variant expression during the transition to lactation and during feed restriction. Primer combinations specific to the coding region of PC and the 5' UTR for variants D, E, and F were used with Taqman probes in a real-time PCR multiplex assay to simultaneously determine total PC mRNA and expression of each UTR variant. The intraassay and interassay CV were less than 2 and 10%, respectively. Total PC mRNA and PC 5' UTR variant profile was determined for liver biopsy samples collected from Holstein cows (n = 8) at -28, +1, and +28 d relative to calving (DRTC) and from mid-lactation Holstein cows subjected to either feed restriction (n = 8) or fed for ad libitum intake (n = 8). The expression of PC mRNA corresponding to the coding region of PC and PC 5' UTR variant regions A, B, C, and F increased (P < 0.05) 4-fold with feed restriction and 6-fold at calving. Nuclei isolated from liver biopsy samples and used to determine the rates of PC gene transcription indicate changes in the abundance of PC 5' mRNA variants A, B, C, and F that are due to corresponding changes in the rate of transcription of the bovine PC gene. The data support the use of the multiplex assay described here as a proxy measure of the activity of bovine PC promoter 1. The increased PC mRNA expression observed at calving and during feed restriction is the result of specific increases in 5' UTR variants A, B, C, and F due to increased transcriptional activity of promoter 1 of the PC gene. PMID- 21278110 TI - Comparison of long-term progestin-based protocols to synchronize estrus before fixed-time artificial insemination in beef heifers. AB - Two experiments were conducted to compare pregnancy rates resulting from fixed time AI (FTAI) after administration of 1 of 2 long-term controlled internal drug release (CIDR)-based protocols. Heifers were assigned to treatment by age, BW, and pubertal status. The CIDR Select-treated heifers (Exp. 1, n = 37; Exp. 2, n = 192) received a CIDR (1.38 g of progesterone) from d 0 to 14, followed by 100 ug of GnRH, intramuscularly (i.m.) 9 d after CIDR removal (d 23) and PGF(2alpha) (25 mg, i.m.) 7 d after GnRH treatment (d 30). Heifers assigned to the Show-Me-Synch protocol (Exp. 1, n = 40; Exp. 2, n = 200) received a CIDR from d 0 to 14, followed by PGF(2alpha) 16 d later (d 30). Artificial insemination was performed at 72 or 66 h after PGF(2alpha) treatment for the CIDR Select- and Show-Me-Synch treated heifers, respectively, and each heifer was given GnRH (100 ug, i.m.) at the time of AI. In Exp. 1, ovaries of each heifer were examined by transrectal ultrasonography on d 23 and 30 to characterize follicular dynamics. Follicles >=5 mm and the presence of corpora lutea were recorded. On d 25, ovaries of each heifer were examined to characterize the status of dominant follicles recorded on d 23. Heifers were fitted with HeatWatch (DDx Inc., Denver, CO) estrus-detection transmitters at PGF(2alpha) to characterize estrus distribution up to FTAI. The diameter of dominant follicles on d 23 at PGF(2alpha) and on d 30, and the estrous response after PGF(2alpha) treatment up to the point of FTAI did not differ between CIDR Select- and Show-Me-Synch-treated heifers. Concentrations of progesterone in serum at PGF(2alpha) were greater (P = 0.07) in Show-Me-Synch- than CIDR Select-treated heifers (6.0 vs. 4.8 ng/mL, respectively). Pregnancy rates of heifers resulting from FTAI did not differ (P = 0.33) between CIDR Select- and Show-Me-Synch-treated heifers (CIDR Select, 59%; Show-Me-Synch, 70%). In Exp. 2, FTAI pregnancy rates tended (P = 0.07) to be greater in Show-Me-Synch treated (62%) than in CIDR Select-treated (51%) heifers. Pregnancy rates at the end of the breeding season did not differ (P = 0.72; CIDR Select, 85%; Show-Me Synch, 83%) between treatments. In summary, pregnancy rates resulting from FTAI were comparable for heifers assigned to each of the 2 long-term progestin-based protocols. The reduced treatment cost and animal handling associated with administration of the Show-Me-Synch protocol offer distinct advantages over the CIDR Select protocol despite similarities in pregnancy rates resulting from FTAI. PMID- 21278111 TI - Effect of potential multimicrobe probiotic product processed by high drying temperature and antibiotic on performance of weanling pigs. AB - In this study, the effect of a potential multimicrobe probiotic subjected to high temperature drying was investigated. Potential multimicrobe probiotics produced by solid substrate fermentation were dried at low (LT, 40 degrees C for 72 h) or high (HT, 70 degrees C for 36 h) temperature. In Exp. 1, 288 weaned pigs (BW, 6.43 +/- 0.68 kg) were allotted to 4 treatments on the basis of BW (4 pens per treatment with 18 pigs in each pen). Dietary treatments were negative control (NC; basal diet without any antimicrobial), positive control (PC; basal diet + 0.1% chlortetracycline), basal diet with 0.3% probiotic LT, and basal diet with 0.3% probiotic HT. Diets were fed in 2 phases, phase I (d 0 to 14) and phase II (d 15 to 28); and growth performance, apparent total tract digestibility (ATTD, d 28), and fecal microflora (d 14 and 28) were evaluated. Over the 28-d trial, pigs fed PC and probiotic diets had greater ADG (P < 0.001), ADFI (P < 0.05), and G:F (P < 0.01) than pigs fed NC diet. The ATTD of DM and GE was greater (P < 0.05) in pigs fed probiotic diets when compared with pigs fed the NC diet. At d 28, fewer Clostridia (P < 0.01) were identified in the feces of pigs fed PC and probiotic diets than pigs fed the NC diet. However, the performance, ATTD of DM and GE, and fecal Clostridia population were similar among pigs fed probiotic LT and HT diets. In Exp. 2, 288 weaned pigs (initial BW, 5.84 +/- 0.18 kg) were allotted to 4 treatments in a 2 * 2 factorial arrangement on the basis of BW. The effects of 2 levels of probiotic HT (0.30 or 0.60%), each with or without antibiotic (chlortetracycline, 0 or 0.1%), on performance, ATTD, intestinal morphology, and fecal and intestinal microflora were investigated. Feeding of 0.60% probiotic HT diet improved (P < 0.05) overall ADG, ATTD of DM and GE, and Lactobacillus population in the feces and intestine, and reduced the population of Clostridium and coliforms in feces (d 14) and ileum. Inclusion of antibiotic improved (P < 0.05) the overall ADG, ADFI, and ATTD of DM at d 14 and reduced fecal Clostridium population at d 28. Increased (P < 0.05) villus height at jejunum and ileum, and villus height:crypt depth at the ileum was noticed in pigs fed 0.60% probiotic HT and antibiotic diets. In conclusion, high drying temperature had no effect on the efficacy of potential multimicrobe probiotic product. However, the probiotic product dried at high temperature was more effective at 0.60% inclusion, whereas inclusion of an antibiotic improved pig performance but did not show any interaction with probiotics. PMID- 21278112 TI - The effect of intramuscular injection of dinoprost or gonadotropin-releasing hormone in dairy cows on beef quality. AB - Intramuscular injections of drugs and vaccines cause tissue damage and subsequent effects on tenderness and consumer acceptability of beef. In the 2007 National Market Cow and Bull Beef Quality Audit, 100% of plants reported fabricating subprimal cuts such as rib eyes and tenderloins from cow and bull carcasses. Dairy beef quality should therefore be a consideration when injections are given to dairy animals. The discussion about injection site reactions and tenderness has focused on vaccines and antimicrobial drugs with little concern for the effects of reproductive hormones. The objective of this study was to quantify antemortem the effects of semimembranosis/semitendinosis muscle injection of dinoprost and GnRH in lactating dairy cows by estimating the weight of tissue damaged and comparing that with a drug known to cause extensive tissue damage, flunixin meglumine. Tissue damage was estimated from previously reported equations for grams of muscle tissue damage based on area under the curve of serum concentrations of the muscle enzyme creatine kinase over time. Dinoprost and flunixin injection both caused a significantly increased estimate of muscle tissue damaged compared with needle only (P = 0.0351 and 0.0355, respectively). Dinoprost and flunixin caused a marginally significant increased muscle tissue damage compared with GnRH (P = 0.1394 and 0.1475, respectively). No statistically significant difference was found between the estimated weight of muscle tissue damaged by flunixin compared with dinoprost (P = 1.0000), or by saline compared with GnRH (P = 0.7736) or needle only (P = 0.4902). The assumption that reproductive hormones are less damaging than vaccines and antimicrobial drugs should be examined more closely, including postmortem evaluation of injection site lesions and effects on tenderness. PMID- 21278113 TI - Effect of source and quantity of dietary vitamin D in maternal and creep diets on bone metabolism and growth in piglets. AB - Piglets are born with reduced plasma concentrations of 25-hydroxycholecalciferol (25-OH-D(3)) and are thus highly predisposed to vitamin D deficiency. Furthermore, sow milk contains little vitamin D, and the slow intestinal vitamin D absorption of sows limits the efficacy of dietary vitamin D supplementation. Hence, the neonate depends, to a large extent, on the vitamin D stores built up in fetal tissues from maternal sources. The current study was undertaken to evaluate whether the source and quantity of dietary vitamin D provided to the gestating and lactating sow, and also directly in the form of creep feed to the piglet, would influence the vitamin D status, growth performance, and skeletal development of piglets. A total of 39 primiparous and multiparous sows were randomly assigned to 1 of 3 dietary treatments (13 in each treatment), supplemented with either 5 or 50 MUg of the commonly used cholecalciferol (vitamin D(3)) or 50 MUg of 25-OH-D(3) per kilogram of feed. By wk 3 of lactation, piglets were offered a creep diet with vitamin D supplementation according to the treatment of the dam, and they were offered the same creep diets after weaning at d 35 of age until they reached a BW of approximately 20 kg. When dietary 25-OH-D(3) was provided, circulating concentrations of 25-OH-D(3) in piglet serum increased (P < 0.05) as early as d 21 and later at d 33 and 77, indicating greater body stores in those animals. Bone-breaking strength and cortical bone mineral content and density at the tibial midshaft of piglets were reduced (P < 0.05) when vitamin D(3) was supplemented at 5 MUg/kg compared with the bone traits of other groups, but no differences (P > 0.05) were observed between the 2 other groups. After weaning, ADFI was greater (P < 0.05) and growth performance tended (P = 0.08) to improve when doses of 50 MUg/kg were administered, regardless of the vitamin D source. In conclusion, supplementation of the diet with 50 MUg/kg of either source of vitamin D was proved to be adequate in meeting the needs of gestating sows and in permitting the accumulation of vitamin D in fetal tissues, as well as for normal skeletal mineralization and growth in the offspring. Furthermore, the markedly improved vitamin D status of piglets whose mothers received 25-OH-D(3) possibly resulted from greater tissue reserves present at birth and a greater availability of vitamin D when released from those stores. PMID- 21278114 TI - The impact of ractopamine hydrochloride on growth and metabolism, with special consideration of its role on nitrogen balance and water utilization in pork production. AB - Two experiments were conducted to determine if ractopamine hydrochloride (RAC) could improve nutrient utilization and decrease water utilization, thus reducing the environmental footprint of hog operations. The tissue accretion experiment used comparative slaughter involving 120 barrows (95 +/- 3 kg of BW), including 12 assigned to an initial slaughter group; the remaining pigs were slaughtered at 108 or 120 kg. Growth performance and nutrient retention were determined. The 15 d metabolism experiment consisted of 54 pigs (95 +/- 3 kg of BW). Growth performance, feed and water intake, and urine and fecal output were measured. The metabolism experiment used 9 dietary treatments arranged as a 3 * 3 factorial: 3 quantities of RAC (0, 5, and 10 mg/kg) and 3 standardized ileal digestible-Lys:DE ratios (1.73, 2.14, and 2.63 g/Mcal of DE). The tissue accretion study was designed as a 3 * 3 * 2 factorial arrangement of treatments using the same 9 dietary treatments to include slaughter BW (108 and 120 kg of BW) as an additional factor. In the tissue accretion experiment, RAC had no effect on ADG, ADFI, or G:F (P>0.10). With increased Lys, G:F improved (P=0.029), but not ADG or ADFI (P>0.10). Protein deposition rates increased numerically (P=0.11); water deposition rates increased (P=0.050), whereas lipid deposition tended to decrease with RAC inclusion (P=0.055). With greater RAC and Lys, the pigs had improved ADG (P=0.002) and G:F (P<0.001) in the metabolism experiment. Daily water intake (P=0.017.) and water output (P=0.033) decreased with RAC inclusion. Lysine inclusion did not alter the water balance (P>0.10). Urinary N excretion (P<0.001), total N excretion (P=0.003), and the urine N:fecal N ratio (P<0.001) decreased with the addition of RAC; fecal N (P=0.008) increased with RAC inclusion. Retention of N improved with addition of RAC to the diet (P=0.003). With greater dietary Lys, fecal N was reduced (P<0.001). The pigs fed the 2.14 g of Lys/Mcal tended to have the least urinary N (P = 0.069) and total N excretion (P=0.086) and to have the greatest N retention (P=0.086) and urinary N:fecal N ratio (P=0.009). A RAC * Lys interaction was observed for N digestibility (P=0.001), excretion (P=0.001), and retention (P=0.002) and for fecal (P=0.001) and urinary N (P=0.036). By improving N and water utilization in finishing pigs, RAC-containing diets supplemented with sufficient Lys can reduce N excretion into the environment from swine facilities. PMID- 21278115 TI - Comparison of steer behavior when housed in a deep-bedded hoop barn versus an open feedlot with shelter. AB - The use of hoop barns as an alternative housing system for beef cattle has not been widely researched. The objectives of this study were to determine the main effects of behavior of steers 1) over winter and summer, 2) when housed in either a hoop barn or a conventional feedlot, and 3) interactions between season and housing system. A total of 960 crossbred Bos taurus steers were used [August 2006 to April 2008 (2 winter and 2 summer trials)]. Steers were housed in either 1 deep-bedded hoop barn (n = 12 pens; 4.65 m(2)/steer) or 1 open feedlot with shelter (n = 12 pens; 14.7 m(2)/steer). Steers were ear tagged, implanted, and weighed (414 +/- 36 kg) on arrival and allotted to treatments that were balanced for source, BW, and hide color. Behavioral data (3 postures and 2 behaviors) were collected using a 10-min live scan. The experimental unit for behavior was a pen of steers. Behavioral data were arcsine transformed to achieve a normal distribution. There were no (P > 0.05) differences for time spent at bunk or waterer for steers between housing treatments. Steers housed in an open feedlot with shelter spent less time lying and more time standing and walking (P < 0.05) compared with steers housed in a hoop barn. There were no (P = 0.32) differences between seasons for standing. Steers spent more time at the bunk (P < 0.0001) and waterer (P < 0.0001) in the summer compared with the winter. In the winter, steers engaged in more lying (P = 0.0002) and walking (P < 0.0001). Overall, steers stood less (P = 0.006) and spent more time lying (P = 0.024) when housed in a hoop barn than in the open feedlot with shelter regardless of season. Steers housed in the open feedlot with shelter walked more (P < 0.0001) than steers housed in the hoop barn and walked more (P < 0.0001) in winter than in summer months (6 vs. 3%). There were no (P > 0.05) differences in time spent at bunk and waterer between housing systems within season, but time spent at the waterer and bunk decreased (P < 0.05) for both housing systems during the winter. In conclusion, housing 40 steers per pen in a cornstalk-bedded hoop barn at 4.65 m(2)/steer does not result in adverse behavioral alterations and can be considered as a housing alternative for finishing steers in the Midwestern United States when compared with steers fed in an open feedlot with shelter provided. PMID- 21278116 TI - Predicting breed composition using breed frequencies of 50,000 markers from the US Meat Animal Research Center 2,000 Bull Project. AB - Knowledge of breed composition can be useful in multiple aspects of cattle production, and can be critical for analyzing the results of whole genome-wide association studies currently being conducted around the world. We examine the feasibility and accuracy of using genotype data from the most prevalent bovine genome-wide association studies platform, the Illumina BovineSNP50 array (Illumina Inc., San Diego, CA), to estimate breed composition for individual breeds of cattle. First, allele frequencies (of Illumina-defined allele B) of SNP on the array for each of 16 beef cattle breeds were defined by genotyping a large set of more than 2,000 bulls selected in cooperation with the respective breed associations to be representative of their breed. With these breed-specific allele frequencies, the breed compositions of approximately 2,000 two-, three-, and four-way cross (of 8 breeds) cattle produced at the US Meat Animal Research Center were predicted by using a simple multiple regression technique or Mendel (http://www.genetics.ucla.edu/software/mendel) and their genotypes from the Illumina BovineSNP50 array, and were then compared with pedigree-based estimates of breed composition. The accuracy of marker-based breed composition estimates was 89% when using either estimation method for all breeds except Angus and Red Angus (averaged 79%), based on comparing estimates with pedigree-based average breed composition. Accuracy increased to approximately 88% when these 2 breeds were combined into an aggregate Angus group. Additionally, we used a subset of these markers, approximately 3,000 that populate the Illumina Bovine3K (Illumina Inc.), to see whether breed composition could be estimated with similar accuracy when using this reduced panel of SNP makers. When breed composition was estimated using only SNP in common with the Bovine 3K array, accuracy was slightly reduced to 83%. These results suggest that SNP data from these arrays could be used to estimate breed composition in most US beef cattle in situations where pedigree is not known (e.g., multiple-sire natural service matings, non-source-verified animals in feedlots or at slaughter). This approach can aid analyses that depend on knowledge of breed composition, including identification and adjustment of breed-based population stratification, when performing genome-wide association studies on populations with incomplete pedigrees. In addition, SNP-based breed composition estimates may facilitate fitting cow germplasm to the environment, managing cattle in the feedlot, and tracing disease cases back to the geographic region or farm of origin. PMID- 21278117 TI - Triennial Growth Symposium: effects of polymeric carbohydrates on growth and development in pigs. AB - Polymeric carbohydrates, starch and nonstarch polysaccharides (NSP), quantitatively represent the largest portion of the diets for pigs and are, therefore, the largest energy contributor. The 2 types of polysaccharides, however, have different fates and functions in the gastrointestinal tract and lead to different metabolites upon digestion. Pancreatic and mucosal enzymes in the small intestine break down the majority of starch, whereas NSP primarily are degraded by the microflora in the large intestine. Starch degradation leads to the release of glucose, which is absorbed by an active absorption process that triggers the release of insulin from the pancreas, whereas the fermentation of NSP to short-chain fatty acids (SCFA; i.e., acetate, propionate, and butyrate) occurs at a slower and more constant rate and with SCFA being absorbed by passive diffusion. Type and amounts of polymeric carbohydrates influence growth and development through different mechanisms. First, the proportion of starch to NSP plays an important role for the content of available energy (i.e., DE, ME, and NE); available energy relative to protein is crucial for performance and carcass quality. Second, the proportion of starch to NSP will influence rate and type of metabolites (i.e., glucose vs. SCFA) deriving from carbohydrate assimilation. Third and finally, the type of starch (i.e., types A, B, and C) and soluble NSP will influence the release of insulin, the hormone that facilitates nutrient uptake by tissues, organs, and cells, and thus plays a critically essential role in protein synthesis and muscle growth, as well as lipid synthesis and adipose tissue growth. In conclusion, polymeric carbohydrates influence growth and development through events in the gut and direct and indirect effects of different metabolites deriving from carbohydrate assimilation. PMID- 21278118 TI - A prototype national cattle evaluation for sustained reproductive success in Hereford cattle. AB - The objective of this research was to develop a prototype system for national cattle evaluation that would facilitate selection for improved fertility of daughters from Hereford sires. Raw data for this analysis were the birth dates of calves as reported by breeders to the American Hereford Association. Records from females entered this analysis with the reporting of a birth date for their first calf. At that time, females were required to be in contemporary groups of at least 3 animals and to have at least 2 additional paternal half-sibs also represented in the data. To explicitly define "sustained reproductive success," the philosophy taken was that a female that maintained a calving interval of 425 d or less would be considered successful. Females failing to meet this criterion were considered to be at the end of their successful lifetime. Data were analyzed using methodology for survival analysis with grouped data. Fixed contemporary groups were modeled as being time dependent, reflecting the females exposed for breeding in the same herd-year-season. Sire effects were time independent and considered random. Also included in the analysis were time-independent covariates for maternal weaning weight and total maternal calving ease from the national cattle evaluation of the American Hereford Association. Records from females still successfully in production at the time of this analysis, those that were transferred, those with calving intervals less than 280 d, and those that were successful until becoming donor dams for embryo transfer were considered censored. A total of 36,866 females contributed to this analysis, with 14,143 of these having censored records. The median number of females in a contemporary group was 6. A total of 3,323 sires had daughters with records. The median number of daughters per sire was 7. Heritability of sustained reproductive success on the underlying scale estimated from these data was approximately 0.05. Additional data accumulated over time will improve this genetic evaluation. Sustained reproductive success is important to the commercial beef industry, and results from this evaluation are expected to enhance the assessment of economic value of Hereford seedstock. PMID- 21278119 TI - Estimating feed efficiency: evaluation of mathematical models to predict individual intakes of steers fed in group pens. AB - To evaluate feed efficiency using residual feed intake (RFI), it is necessary to measure and record daily feed intake for each animal. This can be accomplished by housing them in individual pens or by using sophisticated electronic feeders in group pens. All the available options are very expensive and very laborious; therefore, several researchers have developed methods to predict individual DMI of cattle fed in group pens. Three intake models were tested with a data set of 60 Angus * Hereford steers fed a corn-based finishing diet in both group and individual pens. After the first 60 d (period 1) of the study, animals were switched from group to individual pens, and then vice versa for another 60 d (period 2); thus, the entire feeding trial was 120 d long. No difference was observed in DMI between periods for steers fed individually (period 1 = 10.9 kg/d and period 2 = 11.2 kg/d, P = 0.44), but a difference was observed in group pens (period 1 = 12.7 kg/d and period 2 = 10.9 kg/d, P < 0.01). In addition, no difference (P >= 0.15) was observed in carcass characteristics, such as HCW, dressing percentage, quality grade, LM area, KPH percentage, yield grade, or backfat between RFI groups (low, medium, and high). Average daily gain and G:F were not different between RFI groups within each period (P >= 0.06), but there were period differences (P < 0.001). Models 1 and 2 were based on growth, carcass composition, and nutrient requirements, whereas model 3 was based on the heterogeneity of pen intakes when cattle were rotated through the pens on a daily basis. Models 1 and 2 were forced through the mean observed DMI, so the mean bias was zero, but they were not precise, with a slope bias greater than 50%. Model 3 showed low accuracy (mean bias = 20%), but it was precise, with a slope bias of 21%. Because RFI is the error of the DMI equation, any inaccuracy when estimating intake will lead to a bias in the prediction of RFI. In conclusion, these models could be used to predict mean DMI, but they were not adequate for estimating RFI. PMID- 21278120 TI - Calculating economic weights for sheep sire breeds used in different breeding systems. AB - The objective of this paper was to adapt gene-flow methodology for the calculation of economic weights (EW) for direct and maternal traits and trait components in sheep and to apply this methodology to the Suffolk breed in the Czech Republic. Computer programs were developed in which annual-lambing sheep production systems with purebreeding or partial terminal crossing were simulated. Using these programs, the EW for 12 production and functional traits were estimated for i) Suffolk sires whose sons were used both in purebreeding and in terminal crossing with the 4 dual-purpose breeds, Romanov, Sumavska, Romney, and Merinolandschaf; and ii) Suffolk sires used only for terminal crossing. For case (i), the EW were at first calculated separately for the purebreeding system and for the crossing systems with the 4 dual-purpose breeds in dam position. Compound EW for the general breeding goal for Suffolk were then estimated as weighted averages from the EW in the 5 subsystems. Standardized EW were calculated by multiplying the marginal EW with the genetic SD of the trait, and relative EW were defined as absolute values of the standardized EW expressed as percentage of the sum of the absolute values of the standardized EW over all traits. The 5 most important trait components for Suffolk sires whose sons were used both in purebreeding and in terminal crossing were (relative EW given in parentheses): the direct components of survival rate until weaning (21.0%), daily BW gain until weaning (14.1%), survival rate at birth (14.0%), the maternal component of survival rate until weaning (10.7%), and litter size at lambing (7.6%). There were only small differences between the relative EW calculated for the whole system with pure- and crossbreeding and the relative EW for the purebred system within the Suffolk breed. Therefore, selection of Suffolk rams using a selection index based on the compound EW is expected to be of high efficiency in all of the simulated breeding systems. Only direct traits were relevant for Suffolk sires used only for terminal crossing; the most important (range of relative EW calculated for the 4 crossing systems given in parentheses) were survival rate until weaning (35.2 to 36.5%), daily BW gain until weaning (24.2 to 26.3%), and survival rate at birth (23.7 to 24.8%). PMID- 21278121 TI - Genetic parameters for intramuscular fat percentage, marbling score, scrotal circumference, and heifer pregnancy in Red Angus cattle. AB - Selection criteria for yearling bulls commonly include indicators of fertility and carcass merit, such as scrotal circumference (SC) and intramuscular fat percentage (IMF). Genetic correlation estimates between ultrasound traits such as IMF and carcass marbling score (MS) with fertility traits SC and heifer pregnancy (HP) have not been reported. Therefore, the objective of this study was to estimate the genetic parameters among the indicator traits IMF and SC, and the economically relevant traits MS and HP. Records for IMF (n=73,051), MS (n=15,260), SC (n=43,487), and HP (n=37,802) were obtained from the Red Angus Association of America, and a 4-generation ancestral pedigree (n=10,460) was constructed from the 8,915 sires represented in the data. (Co)variance components were estimated using a multivariate sire model and average information REML to obtain estimates of heritability and genetic correlations. Fixed effects included contemporary group and the linear effect of age at measurement for all traits, and an additional effect of age of dam for both HP and SC. The random effect of sire was included to estimate additive genetic effects, which were assumed to be continuous for IMF, MS, and SC, but a probit threshold link function was fitted for HP. Generally moderate heritability estimates of 0.29 +/- 0.01, 0.35 +/- 0.06, 0.32 +/- 0.02, and 0.17 +/- 0.01 were obtained for IMF, MS, SC, and HP on the underlying scale, respectively. The confidence interval for the estimated genetic correlation between MS and HP (0.10 +/- 0.15) included zero, suggesting a negligible genetic association. The genetic correlation between MS and IMF was high (0.80 +/- 0.05), but the estimate for HP and SC (0.05 +/- 0.09) was near zero, as were the estimated genetic correlations of SC with MS (0.01 +/- 0.08) and IMF (0.05 +/- 0.06), and for HP with IMF (0.13 +/- 0.09). These results suggest that concomitant selection for increased fertility and carcass merit would not be antagonistic. PMID- 21278122 TI - Heterodimers of the Arabidopsis transcription factors bZIP1 and bZIP53 reprogram amino acid metabolism during low energy stress. AB - Control of energy homeostasis is crucial for plant survival, particularly under biotic or abiotic stress conditions. Energy deprivation induces dramatic reprogramming of transcription, facilitating metabolic adjustment. An in-depth knowledge of the corresponding regulatory networks would provide opportunities for the development of biotechnological strategies. Low energy stress activates the Arabidopsis thaliana group S1 basic leucine zipper transcription factors bZIP1 and bZIP53 by transcriptional and posttranscriptional mechanisms. Gain-of function approaches define these bZIPs as crucial transcriptional regulators in Pro, Asn, and branched-chain amino acid metabolism. Whereas chromatin immunoprecipitation analyses confirm the direct binding of bZIP1 and bZIP53 to promoters of key metabolic genes, such as ASPARAGINE SYNTHETASE1 and PROLINE DEHYDROGENASE, the G-box, C-box, or ACT motifs (ACTCAT) have been defined as regulatory cis-elements in the starvation response. bZIP1 and bZIP53 were shown to specifically heterodimerize with group C bZIPs. Although single loss-of function mutants did not affect starvation-induced transcription, quadruple mutants of group S1 and C bZIPs displayed a significant impairment. We therefore propose that bZIP1 and bZIP53 transduce low energy signals by heterodimerization with members of the partially redundant C/S1 bZIP factor network to reprogram primary metabolism in the starvation response. PMID- 21278123 TI - Of PAMPs and effectors: the blurred PTI-ETI dichotomy. AB - Typically, pathogen-associated molecular patterns (PAMPs) are considered to be conserved throughout classes of microbes and to contribute to general microbial fitness, whereas effectors are species, race, or strain specific and contribute to pathogen virulence. Both types of molecule can trigger plant immunity, designated PAMP-triggered and effector-triggered immunity (PTI and ETI, respectively). However, not all microbial defense activators conform to the common distinction between PAMPs and effectors. For example, some effectors display wide distribution, while some PAMPs are rather narrowly conserved or contribute to pathogen virulence. As effectors may elicit defense responses and PAMPs may be required for virulence, single components cannot exclusively be referred to by one of the two terms. Therefore, we put forward that the distinction between PAMPs and effectors, between PAMP receptors and resistance proteins, and, therefore, also between PTI and ETI, cannot strictly be maintained. Rather, as illustrated by examples provided here, there is a continuum between PTI and ETI. We argue that plant resistance is determined by immune receptors that recognize appropriate ligands to activate defense, the amplitude of which is likely determined by the level required for effective immunity. PMID- 21278124 TI - Regulation and flexibility of genomic imprinting during seed development. AB - Genomic imprinting results in monoallelic gene expression in a parent-of-origin dependent manner. It is achieved by the differential epigenetic marking of parental alleles. Over the past decade, studies in the model systems Arabidopsis thaliana and maize (Zea mays) have shown a strong correlation between silent or active states with epigenetic marks, such as DNA methylation and histone modifications, but the nature of the primary imprint has not been clearly established for all imprinted genes. Phenotypes and expression patterns of imprinted genes have fueled the perception that genomic imprinting is specific to the endosperm, a seed tissue that does not contribute to the next generation. However, several lines of evidence suggest a potential role for imprinting in the embryo, raising questions as to how imprints are erased and reset from one generation to the next. Imprinting regulation in flowering plants shows striking similarities, but also some important differences, compared with the mechanisms of imprinting described in mammals. For example, some imprinted genes are involved in seed growth and viability in plants, which is similar in mammals, where imprinted gene regulation is essential for embryonic development. However, it seems to be more flexible in plants, as imprinting requirements can be bypassed to allow the development of clonal offspring in apomicts. PMID- 21278125 TI - ATP synthase repression in tobacco restricts photosynthetic electron transport, CO2 assimilation, and plant growth by overacidification of the thylakoid lumen. AB - Tobacco (Nicotiana tabacum) plants strictly adjust the contents of both ATP synthase and cytochrome b(6)f complex to the metabolic demand for ATP and NADPH. While the cytochrome b(6)f complex catalyzes the rate-limiting step of photosynthetic electron flux and thereby controls assimilation, the functional significance of the ATP synthase adjustment is unknown. Here, we reduced ATP synthase accumulation by an antisense approach directed against the essential nuclear-encoded gamma-subunit (AtpC) and by the introduction of point mutations into the translation initiation codon of the plastid-encoded atpB gene (encoding the essential beta-subunit) via chloroplast transformation. Both strategies yielded transformants with ATP synthase contents ranging from 100 to <10% of wild type levels. While the accumulation of the components of the linear electron transport chain was largely unaltered, linear electron flux was strongly inhibited due to decreased rates of plastoquinol reoxidation at the cytochrome b(6)f complex (photosynthetic control). Also, nonphotochemical quenching was triggered at very low light intensities, strongly reducing the quantum efficiency of CO(2) fixation. We show evidence that this is due to an increased steady state proton motive force, resulting in strong lumen overacidification, which in turn represses photosynthesis due to photosynthetic control and dissipation of excitation energy in the antenna bed. PMID- 21278126 TI - Endoplasmic reticulum- and Golgi-localized phospholipase A2 plays critical roles in Arabidopsis pollen development and germination. AB - The phospholipase A(2) (PLA(2)) superfamily of lipolytic enzymes is involved in a number of essential biological processes, such as inflammation, development, host defense, and signal transduction. Despite the proven involvement of plant PLA(2)s in many biological functions, including senescence, wounding, elicitor and stress responses, and pathogen defense, relatively little is known about plant PLA(2)s, and their genes essentially remain uncharacterized. We characterized three of four Arabidopsis thaliana PLA(2) paralogs (PLA(2)-beta, -gamma, and -delta) and found that they (1) are expressed during pollen development, (2) localize to the endoplasmic reticulum and/or Golgi, and (3) play critical roles in pollen development and germination and tube growth. The suppression of PLA(2) using the RNA interference approach resulted in pollen lethality. The inhibition of pollen germination by pharmacological PLA(2) inhibitors was rescued by a lipid signal molecule, lysophosphatidyl ethanolamine. Based on these results, we propose that plant reproduction, in particular, male gametophyte development, requires the activities of the lipid-modifying PLA(2)s that are conserved in other organisms. PMID- 21278127 TI - Distinct roles of protein disulfide isomerase and P5 sulfhydryl oxidoreductases in multiple pathways for oxidation of structurally diverse storage proteins in rice. AB - In the rice (Oryza sativa) endosperm, storage proteins are synthesized on the rough endoplasmic reticulum (ER), in which prolamins are sorted to protein bodies (PBs) called type-I PB (PB-I). Protein disulfide isomerase (PDI) family oxidoreductase PDIL2;3, an ortholog of human P5, contains a conserved structural disulfide in the redox-inactive thioredoxin-like (TRX) domain and was efficiently targeted to the surface of PB-I in a redox active site-dependent manner, whereas PDIL1;1, an ortholog of human PDI, was localized in the ER lumen. Complementation analyses using PDIL1;1 knockout esp2 mutant indicated that the a and a' TRX domains of PDIL1;1 exhibited similar redox activities and that PDIL2;3 was unable to perform the PDIL1;1 functions. PDIL2;3 knockdown inhibited the accumulation of Cys-rich 10-kD prolamin (crP10) in the core of PB-I. Conversely, crP10 knockdown dispersed PDIL2;3 into the ER lumen. Glutathione S-transferase-PDIL2;3 formed a stable tetramer when it was expressed in Escherichia coli, and the recombinant PDIL2;3 tetramer facilitated alpha-globulin(C79F) mutant protein to form nonnative intermolecular disulfide bonds in vitro. These results indicate that PDIL2;3 and PDIL1;1 are not functionally redundant in sulfhydryl oxidations of structurally diverse storage proteins and play distinct roles in PB development. We discuss PDIL2;3-dependent and PDIL2;3-independent oxidation pathways that sustain disulfide bonds of crP10 in PB-I. PMID- 21278131 TI - The lady health worker program in Pakistan--a commentary. PMID- 21278129 TI - The Arabidopsis intracellular Na+/H+ antiporters NHX5 and NHX6 are endosome associated and necessary for plant growth and development. AB - Intracellular Na(+)/H(+) antiporters (NHXs) play important roles in cellular pH and Na(+) and K(+) homeostasis in all eukaryotes. Based on sequence similarity, the six intracellular Arabidopsis thaliana members are divided into two groups. Unlike the vacuolar NHX1-4, NHX5 and NHX6 are believed to be endosomal; however, little data exist to support either their function or localization. Using reverse genetics, we show that whereas single knockouts nhx5 or nhx6 did not differ from the wild type, the double knockout nhx5 nhx6 showed reduced growth, with smaller and fewer cells and increased sensitivity to salinity. Reduced growth of nhx5 nhx6 was due to slowed cell expansion. Transcriptome analysis indicated that nhx5, nhx6, and the wild type had similar gene expression profiles, whereas transcripts related to vesicular trafficking and abiotic stress were enriched in nhx5 nhx6. We show that unlike other intracellular NHX proteins, NHX5 and NHX6 are associated with punctate, motile cytosolic vesicles, sensitive to Brefeldin A, that colocalize to known Golgi and trans-Golgi network markers. We provide data to show that vacuolar trafficking is affected in nhx5 nhx6. Possible involvements of NHX5 and NHX6 in maintaining organelle pH and ion homeostasis with implications in endosomal sorting and cellular stress responses are discussed. PMID- 21278132 TI - Prevalence of depression in granted and refused requests for euthanasia and assisted suicide: a systematic review. AB - BACKGROUND: There is an established link between depression and interest in hastened death in patients who are seriously ill. Concern exists over the extent of depression in patients who actively request euthanasia/physician-assisted suicide (PAS) and those who have their requests granted. OBJECTIVES: To estimate the prevalence of depression in refused and granted requests for euthanasia/PAS and discuss these findings. Methods A systematic review was performed in MEDLINE and PsycINFO in July 2010, identifying studies reporting rates of depression in requests for and cases of euthanasia/PAS. One author critically appraised the strength of the data using published criteria. RESULTS: 21 studies were included covering four countries. There was considerable heterogeneity in methods of assessing depression and selecting patients. In the highest quality studies, in the Netherlands and Oregon, 8-47% of patients requesting euthanasia/PAS had depressive symptoms and 2-17% of completed euthanasia/PAS cases had depressive symptoms. In the Netherlands, depression was significantly higher in refused than granted requests, and there was no significant difference in the rate of depression between euthanasia cases and similar patients who had not made a request for euthanasia. CONCLUSION: It is unclear whether depression increases the probability of making a request for euthanasia/PAS, but in the Netherlands most requests in depressed patients are rejected, leaving a depression rate in cases that is similar to the surrounding population. Less evidence is available elsewhere, but some level of depression has been identified in patients undergoing euthanasia/PAS in all the countries studied. Whether the presence of depression is ever compatible with an ethical decision on euthanasia/PAS is discussed. PMID- 21278133 TI - Antiapoptotic effects of GLP-1 in murine HL-1 cardiomyocytes. AB - Activation of apoptosis contributes to cardiomyocyte dysfunction and death in diabetic cardiomyopathy. The peptide glucagon-like peptide-1 (GLP-1), a hormone that is the basis of emerging therapy for type 2 diabetic patients, has cytoprotective actions in different cellular models. We investigated whether GLP 1 inhibits apoptosis in HL-1 cardiomyocytes stimulated with staurosporine, palmitate, and ceramide. Studies were performed in HL-1 cardiomyocytes. Apoptosis was induced by incubating HL-1 cells with staurosporine (175 nM), palmitate (135 MUM), or ceramide (15 MUM) for 24 h. In staurosporine-stimulated HL-1 cardiomyocytes, phosphatidylserine exposure, Bax-to-Bcl-2 ratio, Bad phosphorylation (Ser(136)), BNIP3 expression, mitochondrial membrane depolarization, cytochrome c release, caspase-3 activation, DNA fragmentation, and mammalian target of rapamycin (mTOR)/p70S6K phosphorylation (Ser(2448) and Thr(389), respectively) were assessed. Apoptotic hallmarks were also measured in the absence or presence of low (5 mM) and high (10 mM) concentrations of glucose. In addition, phosphatidylserine exposure and DNA fragmentation were analyzed in palmitate- and ceramide-stimulated cells. Staurosporine increased apoptosis in HL 1 cardiomyocytes. GLP-1 (100 nM) partially inhibited staurosporine-induced mitochondrial membrane depolarization and completely blocked the rest of the staurosporine-induced apoptotic changes. This cytoprotective effect was mainly mediated by phosphatidylinositol 3-kinase (PI3K) and partially dependent on ERK1/2. Increasing concentrations of glucose did not influence GLP-1-induced protection against staurosporine. Furthermore, GLP-1 inhibited palmitate- and ceramide-induced phosphatidylserine exposure and DNA fragmentation. Incretin GLP 1 protects HL-1 cardiomyocytes against activation of apoptosis. This cytoprotective ability is mediated mainly by the PI3K pathway and partially by the ERK1/2 pathway and seems to be glucose independent. It is proposed that therapies based on GLP-1 may contribute to prevent cardiomyocyte apoptosis. PMID- 21278134 TI - Electromechanical coupling between the atria and mitral valve. AB - Anterior leaflet (AL) stiffening during isovolumic contraction (IVC) may aid mitral valve closure. We tested the hypothesis that AL stiffening requires atrial depolarization. Ten sheep had radioopaque-marker arrays implanted in the left ventricle, mitral annulus, AL, and papillary muscle tips. Four-dimensional marker coordinates (x, y, z, and t) were obtained from biplane videofluoroscopy at baseline (control, CTRL) and during basal interventricular-septal pacing (no atrial contraction, NAC; 110-117 beats/min) to generate ventricular depolarization not preceded by atrial depolarization. Circumferential and radial stiffness values, reflecting force generation in three leaflet regions (annular, belly, and free-edge), were obtained from finite-element analysis of AL displacements in response to transleaflet pressure changes during both IVC and isovolumic relaxation (IVR). In CTRL, IVC circumferential and radial stiffness was 46 +/- 6% greater than IVR stiffness in all regions (P < 0.001). In NAC, AL annular IVC stiffness decreased by 25% (P = 0.004) in the circumferential and 31% (P = 0.005) in the radial directions relative to CTRL, without affecting edge stiffness. Thus AL annular stiffening during IVC was abolished when atrial depolarization did not precede ventricular systole, in support of the hypothesis. The likely mechanism underlying AL annular stiffening during IVC is contraction of cardiac muscle that extends into the leaflet and requires atrial excitation. The AL edge has no cardiac muscle, and thus IVC AL edge stiffness was not affected by loss of atrial depolarization. These findings suggest one reason why heart block, atrial dysrhythmias, or ventricular pacing may be accompanied by mitral regurgitation or may worsen regurgitation when already present. PMID- 21278135 TI - Characterization of potential S-nitrosylation sites in the myocardium. AB - S-nitrosylation (SNO) is a reversible protein modification that has the ability to alter the activity of target proteins. However, only a small number of SNO proteins have been found in the myocardium, and even fewer specific sites of SNO have been identified. Therefore, this study aims to characterize potential SNO sites in the myocardium. We utilized a modified version of the SNO-resin-assisted capture technique in tandem with mass spectrometry. In brief, a modified biotin switch was performed using perfused mouse heart homogenates incubated with or without the S-nitrosylating agent S-nitrosoglutathione. Our modified SNO-resin assisted capture protocol identified 116 unique SNO-modified proteins under basal conditions, and these represent the constitutive SNO proteome. These constitutive SNO proteins are likely to be physiologically relevant targets, since nitric oxide has been shown to play an important role in the regulation of normal cardiovascular physiology. Following S-nitrosoglutathione treatment, we identified 951 unique SNO proteins, many of which contained multiple SNO sites. These proteins show the potential for SNO. This study provides novel information regarding the constitutive SNO proteome of the myocardium, as well as potential myocardial SNO sites, and yields additional information on the SNO sites for many key proteins involved in myocardial contraction, metabolism, and cellular signaling. PMID- 21278136 TI - Restoring leptin signaling reduces hyperlipidemia and improves vascular stiffness induced by chronic intermittent hypoxia. AB - Chronic intermittent hypoxia (IH) during sleep can result from obstructive sleep apnea (OSA), a disorder that is particularly prevalent in obesity. OSA is associated with high levels of circulating leptin, cardiovascular dysfunction, and dyslipidemia. Relationships between leptin and cardiovascular function in OSA and chronic IH are poorly understood. We exposed lean wild-type (WT) and obese leptin-deficient ob/ob mice to IH for 4 wk, with and without leptin infusion, and measured cardiovascular indices including aortic vascular stiffness, endothelial function, cardiac myocyte morphology, and contractile properties. At baseline, ob/ob mice had decreased vascular compliance and endothelial function vs. WT mice. We found that 4 wk of IH decreased vascular compliance and endothelial relaxation responses to acetylcholine in both WT and leptin-deficient ob/ob animals. Recombinant leptin infusion in both strains restored IH-induced vascular abnormalities toward normoxic WT levels. Cardiac myocyte morphology and function were unaltered by IH. Serum cholesterol and triglyceride levels were significantly decreased by leptin treatment in IH mice, as was hepatic stearoyl Coenzyme A desaturase 1 expression. Taken together, these data suggest that restoring normal leptin signaling can reduce vascular stiffness, increase endothelial relaxation, and correct dyslipidemia associated with IH. PMID- 21278137 TI - Suppression of cerebral hemodynamics is associated with reduced functional capacity in patients with heart failure. AB - This investigation elucidated the underlying mechanisms of functional impairments in patients with heart failure (HF) by simultaneously comparing cardiac-cerebral muscle hemodynamic and ventilatory responses to exercise among HF patients with various functional capacities. One hundred one patients with HF [New York Heart Association HF functional class II (HF-II, n = 53) and functional class III (HF III, n = 48) patients] and 71 normal subjects [older control (O-C, n = 39) and younger control (Y-C, n = 32) adults] performed an incremental exercise test using a bicycle ergometer. A recently developed noninvasive bioreactance device was adopted to measure cardiac hemodynamics, and near-infrared spectroscopy was employed to assess perfusions in the frontal cerebral lobe (Delta[THb](FC)) and vastus lateralis muscle (Delta[THb](VL)). The results demonstrated that the Y-C group had higher levels of cardiac output, Delta[THb](FC), and Delta[THb](VL) during exercise than the O-C group. Moreover, these cardiac/peripheral hemodynamic responses to exercise in HF-III group were smaller than those in both HF-II and O-C groups. Although the change of cardiac output caused by exercise was normalized, the amounts of blood distributed to frontal cerebral lobe and vastus lateralis muscle in the HF-III group significantly declined during exercise. The HF-III patients had lower oxygen-uptake efficiency slopes (OUES) and greater Ve-Vo(2) slopes than the HF-II patients and age-matched controls. However, neither hemodynamic nor ventilatory response to exercise differed significantly between the HF-II and O-C groups. Cardiac output, Delta[THb](FC), and Delta[THb](VL) during exercise were directly related to the OUES and Vo(2peak) and inversely related to the Ve-Vco(2) slope. Moreover, cardiac output or Delta[THb](FC) was an effect modifier, which modulated the correlation status between Delta[THb](VL) and Ve-Vco(2) slope. We concluded that the suppression of cerebral/muscle hemodynamics during exercise is associated with ventilatory abnormality, which reduces functional capacity in patients with HF. PMID- 21278138 TI - Use of continuous glucose monitoring in subjects with type 1 diabetes on multiple daily injections versus continuous subcutaneous insulin infusion therapy: a prospective 6-month study. AB - OBJECTIVE: To compare use of continuous glucose monitoring in subjects with type 1 diabetes on multiple daily injection (MDI) therapy versus continuous subcutaneous insulin infusion (CSII) therapy for 6 months. RESEARCH DESIGN AND METHODS: Sixty type 1 diabetic adults with similar baseline characteristics, using either MDI (n = 30) or CSII (n = 30) therapy, were enrolled in this 6-month prospective study. Subjects were instructed to wear the DexCom SevenPLUS continuous glucose monitor at all times throughout the study. All subjects were initially blinded from the continuous glucose monitoring (CGM) glucose data. After 4 weeks of blinded CGM use, the CGM was unblinded, making glucose data available to the patient. The CGM remained in the unblinded state for the remainder of the study (20 weeks). Clinic visits occurred every 4 weeks, at which time A1C values were collected and CGM data were downloaded. RESULTS: Mean baseline (+/- SD) A1C was 7.61 (+/- 0.76) and 7.63 (+/- 0.68) for CSII and MDI, respectively (P > 0.05). Without any significant therapy change, A1C decrease at 12 weeks was similar in both groups (P = 0.03). When compared with the blinded phase, unblinded use of CGM was associated with similar but significant reductions in glycemic control and variability parameters. In addition, both therapy groups had similar changes in mean glucose and glucose variability indexes at 3 and 6 months (ITT analysis, P > 0.05). Predefined per protocol analysis (sensor use at least 6 days/week) showed greater improvement in time spent in target range glycemia, 3.9-10.0 mmol/L (70-180 mg/dL), in the CSII group. CONCLUSIONS: We conclude that CGM provides similar benefits in glucose control for patients using MDI or CSII therapy. PMID- 21278139 TI - Rising rates of all types of diabetes in south Asian and non-south Asian children and young people aged 0-29 years in West Yorkshire, U.K., 1991-2006. AB - OBJECTIVE: To investigate incidence trends of all diabetes types in all children and young people and in the south Asian subpopulation. RESEARCH DESIGN AND METHODS: Annual incidence per 100,000 and time trends (1991-2006) were analyzed for 2,889 individuals aged 0-29 years diagnosed with diabetes while resident in West Yorkshire, U.K. RESULTS: Diagnoses comprised type 1 (83%), type 2 (12%), maturity-onset diabetes of the young (0.7%), "J"-type/other (0.1%), and uncertain/unclassified (4%). There was a lower incidence of type 1 and a threefold excess of type 2 in south Asians compared with non-south Asians. Type 1 incidence leveled out and type 2 increased after the first south Asian case of type 2 was diagnosed in 1999. Type 2 and unclassified diabetes incidence rose in all population subgroups. CONCLUSIONS: The burden of diabetes increased over time for both ethnic groups, with a significant excess of type 2 diabetes in south Asians. The rising incidence of type 1 diabetes in south Asians attenuated as type 2 diabetes increased after 1999. PMID- 21278140 TI - Combined effect of nonalcoholic fatty liver disease and impaired fasting glucose on the development of type 2 diabetes: a 4-year retrospective longitudinal study. AB - OBJECTIVE: To evaluate whether there is a difference in the association between nonalcoholic fatty liver disease (NAFLD) and incident diabetes based on the presence of impaired fasting glucose. RESEARCH DESIGN AND METHODS: A total of 7,849 individuals (5,409 men and 2,440 women) without diabetes, who underwent comprehensive health check-ups annually for 5 years, were categorized into four groups by the presence of impaired fasting glucose and NAFLD at baseline. The association between NAFLD and incident diabetes was evaluated separately in groups with normal and impaired fasting glucose. RESULTS: For 4 years, the incidence of diabetes in the NAFLD group was 9.9% compared with 3.7% in the non NAFLD group, with multivariable-adjusted hazard ratio of 1.33 (95% CI 1.07-1.66). However, this higher risk for diabetes only existed in the impaired fasting glucose group. CONCLUSIONS: Our study suggests that NAFLD has an independent and additive effect on the development of diabetes under conditions of impaired insulin secretion. PMID- 21278141 TI - Resveratrol attenuates doxorubicin-induced cardiomyocyte apoptosis in mice through SIRT1-mediated deacetylation of p53. AB - AIMS: Doxorubicin (DOX) is an anthracycline drug with a wide spectrum of clinical antineoplastic activity, but increased apoptosis has been implicated in its cardiotoxicity. Resveratrol (RES) was shown to harbour major health benefits in diseases associated with oxidative stress. In this study, we aimed to determine the effect of RES on DOX-induced myocardial apoptosis in mice. METHODS AND RESULTS: Male Balb/c mice were randomized to one of the following four treatments: saline, RES, DOX, or RES plus DOX (10 mice in each group). DOX treatment markedly depressed cardiac function, decreased the heart weight, the body weight, and the ratio of heart weight to body weight, but inversely increased the level of protein carbonyl, malondialdehyde, and serum lactate dehydrogenase, and induced mitochondrial cytochrome c release and cardiomyocyte apoptosis. However, these effects of DOX were ameliorated by its combination with RES. Further studies with a co-immunoprecipitation assay revealed an interaction between p53 and Sirtuin 1 (SIRT1). It was found by western blot and electrophoretic mobility shift assay that DOX treatment increased p53 protein acetylation and cytochrome c release from mitochondria, activated p53 binding at the Bax promoter, and up-regulated Bax expression, but supplementation with RES could weaken all these effects. CONCLUSION: The protective effect of RES against DOX-induced cardiomyocyte apoptosis is associated with the up-regulation of SIRT1 mediated p53 deacetylation. PMID- 21278142 TI - SELDI-TOF derived serum biomarkers failed to differentiate between patients with beryllium sensitisation and patients with chronic beryllium disease. AB - BACKGROUND: People exposed to beryllium may develop beryllium sensitisation (BeS) and, in some cases, progress to chronic beryllium disease (CBD). OBJECTIVES: The objective of this study was to test the ability of proteomic technology to identify patterns of serum protein biomarkers that allow differentiation between BeS and CBD and thus remove the need for invasive bronchoscopic procedures. METHODS: Initially, SELDI-TOF methodology and analysis was performed on serum samples from 30 CBD and 31 BeS patients. RESULTS: This 'starter set' yielded two distinct biomarker pattern sets with eight candidate proteins. The first set differentiated between BeS and CBD with 83.3% sensitivity and 82.3% specificity, with 10-fold cross-validation of 75% and 79%, respectively. The second set of biomarkers yielded higher sensitivity (90.0%) and higher specificity (90.3%), with 10-fold cross-validation of 71.7% and 82.3%, respectively. Due to its greater sensitivity and specificity, the second set of biomarkers was used as the framework for differentiating between CBD and BeS in a second set of serum samples from 450 patients with BeS and CBD. When this larger set of samples was subjected to the biomarker framework in a blinded fashion, it yielded a sensitivity of 43.53% and a specificity of 38.93%. CONCLUSIONS: Due to these low sensitivity and specificity values, we have concluded that, currently, the unique set of SELDI-TOF derived biomarkers does not possess the qualities that would allow it to differentiate between a CBD patient and a BeS patient using serum protein biomarkers. Future refinements in sample collection or proteomic technology may be needed to improve biomarker discovery. PMID- 21278143 TI - Biological monitoring of low-level 2-butoxyethanol exposure in decal transfer workers in bicycle manufacturing factories. AB - OBJECTIVES: In this study, exposures to ethylene glycol monobutyl ether (or 2 butoxyethanol, 2-BE) in decal transfer workers in the bicycle manufacturing industry were investigated. Personal air sampling and biological monitoring were used to assess total uptake through inhalation and dermal exposure. Haemoglobin was also analysed to evaluate the effects of exposure on the haematopoietic system. METHODS: 80 workers in two bicycle factories completed a questionnaire. NIOSH method 1403 was adopted for air sampling and analysis of 2-BE. Prework and postwork urine samples were also collected for determination of total 2 butoxyacetic acid (BAA) after hydrolysis. Haemoglobin tests were performed using an automated haemoglobin analysis system. RESULTS: The 31 decal transfer workers whose hands were in direct contact with a dilute aqueous solution of 2-BE, were exposed to an average of 1.7 ppm (8.1 mg/m(3)) of 2-BE in air. Correlation of 2 BE in air and postshift urinary BAA levels (after hydrolysis) was poor. Postshift total BAA levels in urine on Monday and Friday (446.8 and 619.4 mg/g creatinine) were around 223% and 310% of the ACGIH proposed Biological Exposure Index (BEI; 200 mg/g creatinine). Higher levels of total BAA were observed in the urine of subjects exposed to low-level 2-BE in air, presumably because of direct dermal contact. CONCLUSIONS: The mean preshift BAA on Friday was significantly higher than that on Monday, implying that the more days of exposures, the higher the accumulation. Since accumulation occurred with low-level exposure to 2-BE, it is recommended that urine samples be collected at the end of the working week. PMID- 21278144 TI - Surgery-induced reactive oxygen species enhance colon carcinoma cell binding by disrupting the liver endothelial cell lining. AB - OBJECTIVE: Resection of primary colorectal cancer is associated with enhanced risk of development of liver metastases. It was previously demonstrated that surgery initiated an early inflammatory response resulting in elevated tumour cell adhesion in the liver. Because reactive oxygen species (ROS) are shown to be produced and released during surgery, the effects of ROS on the liver vascular lining and tumour cell adhesion were investigated. METHODS: Human endothelial cell monolayers (human umbilical vein endothelial cells (HUVECs) and human microvascular endothelial cells of the lung (HMEC-1s)) were exposed to ROS production, after which electrical impedance, cellular integrity and tumour cell adhesion were investigated. Furthermore, surgery-induced tumour cell adhesion as well as the role of ROS and liver macrophages (Kupffer cells) in this process were studied in vivo. RESULTS: Production of ROS decreased cellular impedance of endothelial monolayers dramatically. Moreover, formation of intercellular gaps in endothelial monolayers was observed, exposing subendothelial extracellular matrix (ECM) on which colon carcinoma cells adhered via integrin molecules. Endothelial damage was, however, prevented in the presence of ROS-scavenging enzymes. Additionally, surgery induced downregulation of both rat and human liver tight junction molecules. Treatment of rats with the ROS scavenger edaravone prevented surgery-induced tumour cell adhesion and downregulation of tight junction proteins in the liver. Interestingly, depletion of Kupffer cells prior to surgery significantly reduced the numbers of adhered tumour cells and prevented disruption of expression of tight junction proteins. CONCLUSIONS: In this study it is shown that surgery-induced ROS production by macrophages damages the vascular lining by downregulating tight junction proteins. This leads to exposure of ECM, to which circulating tumour cells bind. In light of this, perioperative therapeutic intervention, preventing surgery-induced inflammatory reactions, may reduce the risk of developing liver metastases, thereby improving the clinical outcome of patients with colorectal cancer. PMID- 21278145 TI - Absence of hepatic stellate cell retinoid lipid droplets does not enhance hepatic fibrosis but decreases hepatic carcinogenesis. AB - OBJECTIVE: Hepatic stellate cells (HSCs) contain a number of bioactive metabolites or their precursors including retinoids in their characteristic lipid droplets. The loss of lipid droplets and retinoids is a hallmark of HSC activation, but it remains unclear whether this loss promotes HSC activation, liver fibrogenesis or carcinogenesis. DESIGN: Spontaneous and experimental fibrogenesis as well as a diethylnitrosamine-induced hepatocarcinogenesis were investigated in lecithin-retinol acyltransferase (LRAT)-deficient mice which lack retinoid-containing lipids droplets in their HSCs. RESULTS: Following HSC activation, LRAT expression was rapidly lost, emphasising its importance in lipid droplet biology in HSCs. Surprisingly, there was no difference in fibrosis induced by bile duct ligation (BDL) or by eight injections of carbon tetrachloride (CCl4) between wild-type and LRAT-deficient mice. To exclude the possibility that the effects on fibrogenesis were missed due to the rapid downregulation of LRAT following HSC activation, acute as well as spontaneous liver fibrosis was investigated. However, there was no increased fibrosis in 3-, 8- and 12-month-old LRAT-deficient mice and in LRAT-deficient mice after a single injection of CCl4 compared with wild-type mice. To determine whether the absence of retinoids in HSCs affects hepatocarcinogenesis, wild-type and LRAT-deficient mice were injected with diethylnitrosamine. LRAT deficiency decreased diethylnitrosamine-induced injury and tumour load and increased the expression of the retinoic acid responsive genes Cyp26a1, RARb and p21, suggesting that the lower tumour load of LRAT-deficient mice was a result of increased retinoid signalling and subsequent p21-mediated inhibition of proliferation. CONCLUSIONS: The absence of retinoid-containing HSC lipid droplets does not promote HSC activation but reduces hepatocarcinogenesis. PMID- 21278146 TI - A systematic review and meta-analysis of clinical outcomes of vitrectomy with or without intravitreal bevacizumab pretreatment for severe diabetic retinopathy. AB - AIMS: To examine possible benefits of intravitreal bevacizumab (IVB) pretreatment in vitrectomy for severe diabetic retinopathy. METHODS: A comprehensive literature search was performed using the Cochrane Collaboration methodology to identify randomised controlled trials and comparative studies of vitrectomy with or without IVB pretreatment for severe or complicated diabetic retinopathy. Meta analyses were performed for intraoperative (including intraoperative bleeding, endodiathermy, iatrogenic retinal tears and mean surgical time) and postoperative outcome parameters (including best-corrected visual acuity, recurrent vitreous haemorrhage, reabsorption time of blood and other complications). RESULTS: Six randomised controlled trials and one comparative study were identified and used for comparing vitrectomy alone (142 eyes, control group) with vitrectomy with IVB pretreatment (139 eyes). The intraoperative findings showed that the incidence of intraoperative bleeding and frequency of endodiathermy were statistically significantly less in the IVB pretreatment group (p<0.01) than in the vitrectomy alone group. The IVB pretreatment group took significantly less surgical time than the control group (p=0.003). Postoperative results indicated that reabsorption time of blood was significantly shorter (p=0.04), incidence of recurrent VH was almost significantly less (p=0.05), and final best-corrected visual acuity was significantly better (p=0.003) in the IVB group than in the control group. Other complications, including final retinal detachment, and reoperation, were statistically insignificant. CONCLUSION: IVB pretreatment in vitrectomy can achieve excellent clinical outcomes for severe diabetic retinopathy. It potentially facilitates surgeons' manoeuvres and reduces intra- and postoperative complications. PMID- 21278147 TI - Aneurysm of aberrant right subclavian artery (arteria lusoria) presenting as cardiac dyspnoea. PMID- 21278148 TI - A meta-analysis on adjunctive complex fractionated atrial electrogram ablation: comparing the incomparable? PMID- 21278149 TI - Larger coronary sinus diameter predicts the need for epicardial delivery during mitral isthmus ablation. AB - AIMS: Mitral isthmus ablation is technically challenging, often requiring both endocardial and epicardial coronary sinus (CS) ablation. Blood flow in the CS and circumflex artery may act as a 'heat sink' and reduce the efficacy of radiofrequency ablation. This study investigates how the CS and circumflex artery diameters affect mitral isthmus ablation. METHODS AND RESULTS: Thirty-five patients underwent ablation for atrial fibrillation. Irrigated-tip catheters were used during mitral isthmus ablation with the following settings: endocardial surface (maximum power: 40-50 W at the annular end of line; maximum temperature: 48 degrees C); CS (maximum power: 25-30 W; maximum temperature: 48 degrees C). The absence of block after 10 min of endocardial ablation led to CS ablation for up to 5 min. If there was still no block, further ablation was at the discretion of the physician. Coronary angiography and CS venography were performed and analysed with quantitative coronary angiography. Mitral isthmus block was achieved in 31 patients (89%). Twenty-three patients (74%) required CS ablation to achieve block. These patients were found to have significantly larger CS diameters (6.5 +/- 1.2 vs. 5.4 +/- 0.5 mm, P< 0.02). Coronary sinus diameter >59 mm predicted the need for CS ablation (specificity: 100%; sensitivity: 78%). Coronary sinus diameter correlated significantly with total mitral isthmus ablation time (r = 0.52, P < 0.003) and CS ablation time (r = 0.59, P < 0.0005), whereas circumflex diameter did not. CONCLUSION: Larger-diameter CS is associated with a need for CS ablation during mitral isthmus ablation. Coronary sinus but not circumflex diameter was significantly correlated with total and CS ablation time, supporting the hypothesis that the CS but not the circumflex artery acts as a heat sink. PMID- 21278150 TI - Selective site pacing in paediatric patients: how to recreate a new loop in the right atrium to follow body growth. AB - In children, intracardiac loops are created to avoid a lead's fracture due to rapid body growth. Selective site pacing needs the insertion of two 4.1 Fr lumenless leads that do not allow direct manoeuvrability and should be extracted when tension on the lead occurs. We describe an easy, safe, and inexpensive technique to reposition the leads and generate new intracardiac loops. PMID- 21278151 TI - Intracardiac echocardiography for registration of rotational angiography-based left atrial reconstructions: a novel approach integrating two intraprocedural three-dimensional imaging techniques in atrial fibrillation ablation. AB - AIMS: Image integration of three-dimensional (3D) reconstructions of left atrial (LA) and pulmonary vein (PV) anatomy into electroanatomical mapping (EAM) plays a major role in atrial fibrillation (AF) ablation. Point-by-point EAM is commonly used for registration of imported LA and PV anatomy. We aimed to assess the accuracy of intraprocedural rotational angiography-based LA imaging registered by spatial reconstruction of intracardiac echocardiography (ICE) in patients undergoing AF ablation. METHODS AND RESULTS: Twenty-two patients (11 males, 66 +/ 12 years) were studied. Reconstructions of LA and PVs based on rotational angiography were registered by a second 3D reconstruction based on ICE. In a second step, EAM points were added to ICE 3D reconstructions. A 3D image of the LA and PVs was reconstructed in all patients by both imaging modalities. Rotational angiography and ICE-based LA 3D reconstructions took 11.5 +/- 5.2 and 20.4 +/- 11.2 min, respectively. A total of 17 +/- 6 two-dimensional ICE fans were used for spatial reconstruction of ICE. The deviation between the two 3D shells was 2.6 +/- 0.5 mm. Integration of 78 +/- 58 EAM points into ICE 3D reconstruction did not significantly reduce the deviation to rotational angiography-based reconstructions (2.7 +/- 0.6 mm). All PVs were isolated successfully. CONCLUSIONS: Intraprocedural 3D reconstruction of LA and PVs for ablation of AF is feasible based on both rotational angiography and ICE. LA reconstructions based on rotational angiography can accurately be registered using 3D ICE shells. Additional EAM does not enhance accuracy. Therefore, registration of rotational angiography-based 3D reconstructions by 3D reconstructions from ICE seems to be an alternative technique to support AF ablation. PMID- 21278152 TI - Acquired type 2A von Willebrand syndrome caused by aortic valve disease corrects during valve surgery. AB - BACKGROUND: Aortic valve (AV) defects can destroy high molecular weight multimers (HMWM) of von Willebrand factor (VWF), leading to acquired von Willebrand syndrome (aVWS) type IIA. This syndrome is considered a cause for increased perioperative bleeding in AV surgery. If diagnosed before operation, administration of VWF/FVIII concentrates is recommended. However, there is currently no evidence that the VWF HMWM defect persists during surgery long enough to require haemostatic therapy. We hypothesized that the preoperative VWF HMWM defect corrects already during cardiopulmonary bypass (CPB) before any haemostatic therapy. METHODS: This prospective observational study enrolled 17 patients undergoing AV surgery, either isolated or associated with mitral valve or aorta surgery, and also 10 patients undergoing coronary artery bypass surgery (CABG) for comparison. VWF HMWM, VWF antigen (VWF:Ag) concentration, and collagen binding capacity (VWF:CB) were measured before operation, directly after weaning from CPB, and on the first postoperative day. RESULTS: In 12 of the 17 subjects undergoing AV surgery (71%), VWF HMWM were abnormally absent before operation. At the end of CPB, VWF HMWM were normal in 15 of AV subjects (88%), and was normal in 16 subjects on the first postoperative day. VWF:Ag and VWF:CB were within or above the normal range at all three times. Two out of 10 subjects undergoing CABG (20%) had preoperative deficits of VWF HMWM that normalized after operation. CONCLUSIONS: Preoperative VWF HMWM defects corrected at the end of CPB in the absence of haemostatic therapy in most patients undergoing AV surgery. Diffuse bleeding occurring after CPB is unlikely to be related to persisting type 2A von Willebrand syndrome; other causes of coagulopathy should be suspected. Administration of VWF/FVIII concentrates appears unnecessary in this setting. PMID- 21278153 TI - Nottingham Hip Fracture Score as a predictor of one year mortality in patients undergoing surgical repair of fractured neck of femur. AB - BACKGROUND: Surgical repair of hip fractures is associated with high postoperative mortality. The identification of high-risk patients might be of value in aiding clinical management decisions and resource allocation. The Nottingham Hip Fracture Score (NHFS) is a scoring system validated for the prediction of 30 day mortality after hip fracture surgery. It is made up of seven independent predictors of mortality that have been incorporated into a risk score: age (66-85 and >=86 yr); sex (male); number of co-morbidities (>=2), admission mini-mental test score (<=6 out of 10), admission haemoglobin concentration (<=10 g dl(-1)), living in an institution; and the presence of malignancy. We investigated whether the NHFS was a predictor of 1 yr mortality in patients undergoing surgical repair of fractured neck of femur. METHODS: NHFS was retrospectively calculated for 6202 patients who had undergone hip fracture surgery between 1999 and 2009. One year and 30 day postoperative mortality data were collected both from hospital statistics and the Office of National Statistics. RESULTS: Overall mortality was 8.3% at 30 days and 29.3% at 1 yr. An NHFS of <=4 was considered low risk and a score of >=5 high risk. Survival was greater in the low-risk group at 30 days [96.5% vs 86.3% (P<0.001)] and at 1 yr [84.1% vs 54.5% (P<0.001)]. CONCLUSIONS: NHFS can be used to stratify the risk of 1 yr mortality after hip fracture surgery. PMID- 21278154 TI - Heart-lung interactions with different ventilatory settings during acute lung injury and hypovolaemia: an experimental study. AB - BACKGROUND: The functional haemodynamic variables pulse pressure variation (PPV), stroke volume variation (SVV), and systolic pressure variation (SPV) are widely used to assess haemodynamic status. However, it is not known how these perform during acute lung injury (ALI). This study evaluated the effects of different ventilatory strategies on haemodynamic parameters in pigs with ALI during normovolaemia and hypovolaemia. METHODS: Eight anaesthetized Agroceres pigs [40 (1.9) kg] were instrumented with pulmonary artery, PiCCO, and arterial catheters and ventilated. Three ventilatory settings were randomly assigned for 10 min each: tidal volume (VT) 15 ml kg(-1) and PEEP 5 cm H(2)O, VT 8 ml kg(-1) and PEEP 13 cm H(2)O, or VT 6 ml kg(-1) and PEEP 13 cm H(2)O. Data were collected at each setting at baseline, after ALI (lung lavage+Tween 1.5%), and ALI with hypovolaemia (haemorrhage to 30% of estimated blood volume). RESULTS: At baseline, high VT increased PPV, SVV, and SPV (P<0.05 for all). During ALI, high VT significantly increased PPV and SVV [(P = 0.002 and P = 0.008) respectively.]. After ALI with hypovolaemia, ventilation at VT 6 ml kg(-1) and PEEP 13 cm H(2)O decreased the accuracy of functional haemodynamic variables to predict hypovolaemia, with the exception of PPV (area under the curve 0.875). The parameters obtained by PiCCO were less influenced by ventilatory changes. CONCLUSIONS: VT is the ventilatory parameter which influences functional haemodynamics the most. During ventilation with low VT and high PEEP, most functional variables are less able to accurately predict hypovolaemia secondary to haemorrhage, with the exception of PPV. PMID- 21278155 TI - Single molecule imaging of the trans-translation entry process via anchoring of the tagged ribosome. AB - Trans-translation is an eubacterial quality control system to rescue the stalled ribosome, in which multiple components such as transfer messenger RNA (tmRNA) and Small protein B (SmpB) are involved. However, how these molecules interact with ribosome remains elusive. Here, we report the single molecule analysis of the trans-translation process. We developed a new method to label the functional ribosome, in which a tag protein (the HaloTag protein of 297 amino acids) was fused to the 30S ribosomal protein S2 and covalently labelled with specific ligand (HaloTag ligand), resulting in the stable and specific labelling of ribosome. Ribosomes were anchored onto the glass surface using biotinylated derivative of the Cy3 HaloTag ligand (i.e. biotin-Cy3-ligand), and real-time interactions of Cy5-tmRNA/SmpB/EF-Tu ternary complexes with anchored ribosomes are observed as a model of the trans-translation entry. Statistical analysis revealed that Cy5-tmRNA/SmpB/EF-Tu ternary complexes bind to the anchored ribosome with the second-order rate constant of 2.6 * 10(6) (1/M/s) and tmRNAs undergo multi-modal pathway before release from ribosome. The methods presented here are also applicable to the analysis for general translation processes. PMID- 21278156 TI - A sugar chain at a specific position in the nascent polypeptide chain induces forward movement during translocation through the translocon. AB - Nascent polypeptide chains synthesized by membrane bound ribosomes are cotranslationally translocated through and integrated into the endoplasmic reticulum translocon. Hydrophobic segments and positive charges on the chain are critical to halt the ongoing translocation. A marginally hydrophobic segment, which cannot be inserted into the membrane by itself, can be a transmembrane segment depending on its downstream positive charges. In certain conditions, positive charges even 60 residues downstream cause the marginally hydrophobic segment to span the membrane by inducing the segment to slide back from the lumen. Here we systematically examined the effect of a core sugar chain on the fate of a marginally hydrophobic segment using a cell-free translation and translocation system. A sugar chain added within 12 residues upstream of the marginally hydrophobic segment prevents the sliding back and promotes forward movement of the polypeptide chain. The sugar chain apparently functions as a ratchet to keep the polypeptide chain in the lumen. We propose that the sugar chain is a third topology determinant of membrane proteins, in addition to a hydrophobic segment and positive charges of the nascent chain. PMID- 21278157 TI - TNF receptor II fusion protein with tandemly repeated Fc domains. AB - The extracellular domain of tumour necrosis factor (TNF) receptor II fused with the human IgG1 Fc region (TNFRII-Fc), as well as antibodies against TNF, has been used to treat rheumatoid arthritis. However, TNFRII-Fc is less effective than these antibodies in terms of antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) against cells bearing TNF on the cell surface. We hypothesized that these activities could be increased by fusing TNFRII with tandemly repeated Fc (TNFRII-Fc-Fc). The affinities of TNFRII-Fc-Fc for soluble TNF-alpha and transmembrane TNF-alpha and the TNF-alpha cytotoxicity inhibitory activity were as potent as those of TNFRII-Fc. TNFRII-Fc-Fc showed much higher binding avidity for Fcgamma receptors than TNFRII-Fc and was more potent in terms of both ADCC and CDC against cells expressing transmembrane TNF alpha. TNFRII-Fc-Fc of 80 kDa, as well as TNFRII-Fc-Fc of 200 kDa, was detected. TNFRII-Fc-Fc (80 kDa) was as potent as TNFRII-Fc in terms of both ADCC and CDC. These results suggest that Fc multimerization of receptor-Fc fusion proteins can augment effector functions such as ADCC and CDC, and thereby have the potential to provide a superior therapeutic effect. This may be the case not only for TNFRII-Fc but also for other receptor-Fc fusion proteins. PMID- 21278158 TI - Effects of HMGN variants on the cellular transcription profile. AB - High mobility group N (HMGN) is a family of intrinsically disordered nuclear proteins that bind to nucleosomes, alters the structure of chromatin and affects transcription. A major unresolved question is the extent of functional specificity, or redundancy, between the various members of the HMGN protein family. Here, we analyze the transcriptional profile of cells in which the expression of various HMGN proteins has been either deleted or doubled. We find that both up- and downregulation of HMGN expression altered the cellular transcription profile. Most, but not all of the changes were variant specific, suggesting limited redundancy in transcriptional regulation. Analysis of point and swap HMGN mutants revealed that the transcriptional specificity is determined by a unique combination of a functional nucleosome-binding domain and C-terminal domain. Doubling the amount of HMGN had a significantly larger effect on the transcription profile than total deletion, suggesting that the intrinsically disordered structure of HMGN proteins plays an important role in their function. The results reveal an HMGN-variant-specific effect on the fidelity of the cellular transcription profile, indicating that functionally the various HMGN subtypes are not fully redundant. PMID- 21278159 TI - A novel mechanism for target gene-specific SWI/SNF recruitment via the Snf2p N terminus. AB - Chromatin-remodeling complexes regulate the expression of genes in all eukaryotic genomes. The SWI/SNF complex of Saccharomyces cerevisiae is recruited to its target promoters via interactions with selected transcription factors. Here, we show that the N-terminus of Snf2p, the chromatin remodeling core unit of the SWI/SNF complex, is essential for the expression of VHT1, the gene of the plasma membrane H(+)/biotin symporter, and of BIO5, the gene of a 7-keto-8 aminopelargonic acid transporter, biotin biosynthetic precursor. chromatin immunoprecipitation (ChIP) analyses demonstrate that Vhr1p, the transcriptional regulator of VHT1 and BIO5 expression, is responsible for the targeting of Snf2p to the VHT1 promoter at low biotin. We identified an Snf2p mutant, Snf2p-R(15)C, that specifically abolishes the induction of VHT1 and BIO5 but not of other Snf2p regulated genes, such as GAL1, SUC2 or INO1. We present a novel mechanism of target gene-specific SWI/SNF recruitment via Vhr1p and a conserved N-terminal Snf2p domain. PMID- 21278160 TI - Genome-wide quantitative assessment of variation in DNA methylation patterns. AB - Genomic DNA methylation contributes substantively to transcriptional regulations that underlie mammalian development and cellular differentiation. Much effort has been made to decipher the molecular mechanisms governing the establishment and maintenance of DNA methylation patterns. However, little is known about genome wide variation of DNA methylation patterns. In this study, we introduced the concept of methylation entropy, a measure of the randomness of DNA methylation patterns in a cell population, and exploited it to assess the variability in DNA methylation patterns of Alu repeats and promoters. A few interesting observations were made: (i) within a cell population, methylation entropy varies among genomic loci; (ii) among cell populations, the methylation entropies of most genomic loci remain constant; (iii) compared to normal tissue controls, some tumors exhibit greater methylation entropies; (iv) Alu elements with high methylation entropy are associated with high GC content but depletion of CpG dinucleotides and (v) Alu elements in the intronic regions or far from CpG islands are associated with low methylation entropy. We further identified 12 putative allelic-specific methylated genomic loci, including four Alu elements and eight promoters. Lastly, using subcloned normal fibroblast cells, we demonstrated the highly variable methylation patterns are resulted from low fidelity of DNA methylation inheritance. PMID- 21278161 TI - CHILD: a new tool for detecting low-abundance insertions and deletions in standard sequence traces. AB - Several methods have been proposed for detecting insertion/deletions (indels) from chromatograms generated by Sanger sequencing. However, most such methods are unsuitable when the mutated and normal variants occur at unequal ratios, such as is expected to be the case in cancer, with organellar DNA or with alternatively spliced RNAs. In addition, the current methods do not provide robust estimates of the statistical confidence of their results, and the sensitivity of this approach has not been rigorously evaluated. Here, we present CHILD, a tool specifically designed for indel detection in mixtures where one variant is rare. CHILD makes use of standard sequence alignment statistics to evaluate the significance of the results. The sensitivity of CHILD was tested by sequencing controlled mixtures of deleted and undeleted plasmids at various ratios. Our results indicate that CHILD can identify deleted molecules present as just 5% of the mixture. Notably, the results were plasmid/primer-specific; for some primers and/or plasmids, the deleted molecule was only detected when it comprised 10% or more of the mixture. The false positive rate was estimated to be lower than 0.4%. CHILD was implemented as a user-oriented web site, providing a sensitive and experimentally validated method for the detection of rare indel-carrying molecules in common Sanger sequence reads. PMID- 21278162 TI - Mapping interactions between the RNA chaperone FinO and its RNA targets. AB - Bacterial conjugation is regulated by two-component repression comprising the antisense RNA FinP, and its protein co-factor FinO. FinO mediates base-pairing of FinP to the 5'-untranslated region (UTR) of traJ mRNA, which leads to translational inhibition of the transcriptional activator TraJ and subsequent down regulation of conjugation genes. Yet, little is known about how FinO binds to its RNA targets or how this interaction facilitates FinP and traJ mRNA pairing. Here, we use solution methods to determine how FinO binds specifically to its minimal high affinity target, FinP stem-loop II (SLII), and its complement SLIIc from traJ mRNA. Ribonuclease footprinting reveals that FinO contacts the base of the stem and the 3' single-stranded tails of these RNAs. The phosphorylation or oxidation of the 3'-nucleotide blocks FinO binding, suggesting FinO binds the 3'-hydroxyl of its RNA targets. The collective results allow the generation of an energy-minimized model of the FinO-SLII complex, consistent with small-angle X-ray scattering data. The repression complex model was constrained using previously reported cross-linking data and newly developed footprinting results. Together, these data lead us to propose a model of how FinO mediates FinP/traJ mRNA pairing to down regulate bacterial conjugation. PMID- 21278163 TI - TEFM (c17orf42) is necessary for transcription of human mtDNA. AB - Here we show that c17orf42, hereafter TEFM (transcription elongation factor of mitochondria), makes a critical contribution to mitochondrial transcription. Inactivation of TEFM in cells by RNA interference results in respiratory incompetence owing to decreased levels of H- and L-strand promoter-distal mitochondrial transcripts. Affinity purification of TEFM from human mitochondria yielded a complex comprising mitochondrial transcripts, mitochondrial RNA polymerase (POLRMT), pentatricopeptide repeat domain 3 protein (PTCD3), and a putative DEAD-box RNA helicase, DHX30. After RNase treatment only POLRMT remained associated with TEFM, and in human cultured cells TEFM formed foci coincident with newly synthesized mitochondrial RNA. Based on deletion mutants, TEFM interacts with the catalytic region of POLRMT, and in vitro TEFM enhanced POLRMT processivity on ss- and dsDNA templates. TEFM contains two HhH motifs and a Ribonuclease H fold, similar to the nuclear transcription elongation regulator Spt6. These findings lead us to propose that TEFM is a mitochondrial transcription elongation factor. PMID- 21278164 TI - Prevention of cross-talk in conserved regulatory systems: identification of specificity determinants in RNA-binding anti-termination proteins of the BglG family. AB - Each family of signal transduction systems requires specificity determinants that link individual signals to the correct regulatory output. In Bacillus subtilis, a family of four anti-terminator proteins controls the expression of genes for the utilisation of alternative sugars. These regulatory systems contain the anti terminator proteins and a RNA structure, the RNA anti-terminator (RAT) that is bound by the anti-terminator proteins. We have studied three of these proteins (SacT, SacY, and LicT) to understand how they can transmit a specific signal in spite of their strong structural homology. A screen for random mutations that render SacT capable to bind a RNA structure recognized by LicT only revealed a substitution (P26S) at one of the few non-conserved residues that are in contact with the RNA. We have randomly modified this position in SacT together with another non-conserved RNA-contacting residue (Q31). Surprisingly, the mutant proteins could bind all RAT structures that are present in B. subtilis. In a complementary approach, reciprocal amino acid exchanges have been introduced in LicT and SacY at non-conserved positions of the RNA-binding site. This analysis revealed the key role of an arginine side-chain for both the high affinity and specificity of LicT for its cognate RAT. Introduction of this Arg at the equivalent position of SacY (A26) increased the RNA binding in vitro but also resulted in a relaxed specificity. Altogether our results suggest that this family of anti-termination proteins has evolved to reach a compromise between RNA binding efficacy and specific interaction with individual target sequences. PMID- 21278165 TI - Evidence that music listening reduces preoperative patients' anxiety. AB - BACKGROUND: Patients often exhibit preoperative fear and anxiety that may influence the process of induction and recovery from anesthesia. Music is thought to be an alternative to medication for relief of fear and anxiety. OBJECTIVES: The purpose of the present study was to explore the feasibility of using heart rate (HR) variability (HRV) for evaluating the efficacy of music listening to relieve the patients' anxiety during their stay in the operation room waiting area and to compare the HRV measures with subjective Visual Analogue Scale (VAS) scores. METHODS: In total, 140 patients were randomly assigned to the experimental (n = 64) or control group (n = 76). The intervention consisted of a 10-min period of exposure to relaxing music delivered through headphones. Anxiety levels were measured by VAS (a 10-point scale) and 5 min of HRV monitoring before and after the music intervention. RESULTS: The music group demonstrated significant reductions in VAS scores, mean HR, low-frequency HRV, and low- to high-frequency ratio and an increase in high-frequency HRV, while patients in the control group showed no changes. The subjective results of patients' VAS anxiety scores were consistent with the objective results of HRV parameters. CONCLUSIONS: Listening to music can significantly lower the anxiety levels of patients before surgery. The frequency-domain parameters of HRV can be indicators for monitoring the change in anxiety level of preoperative patients. PMID- 21278166 TI - Anti-inflammatory activity of the aqueous extract of ficus deltoidea. AB - Ficus deltoidea (Family Moraceae) leaves have been used traditionally by the Malays to treat ailments such as wounds, sores, and rheumatism. The aim of the present study was to determine the anti-inflammatory activity of the aqueous extract of F. deltoidea leaf (FDA) using acute and chronic inflammatory models. FDA, in the doses of 30, 100, and 300 mg/kg, was administered intraperitoneally in rats (n = 6) before the animals were subjected to the carrageenan-induced paw edema test, cotton pellet-induced granuloma test, and formalin test. The first two tests represent acute and chronic models of inflammation, respectively. The first and second phases of the formalin test represent neurogenic pain and inflammatory-mediated pain, respectively; thus, only the second phase was measured in the present study. Results showed that FDA exerted significant (p < .05) anti-inflammatory activity in all assays, with dose-response effects seen in the paw edema and formalin tests. In conclusion, the leaf of F. deltoidea possesses anti-inflammatory activity against acute and chronic inflammatory responses and against pain-associated inflammatory response. These findings justify the traditional uses of F. deltoidea leaves for treatment of inflammatory mediated ailments. PMID- 21278167 TI - Insufficient sleep in young patients with diabetes and their families. AB - OBJECTIVE: We examined sleep in families of individuals with type 1 diabetes and the relationship of sleep with obesity, diabetes, and insulin resistance. METHODS: Probands with type 1 diabetes diagnosed before age 18 and first- and second-degree relatives were included (n = 323). Demographic, anthropometric and clinical variables, and self-reported sleep duration and napping were assessed. RESULTS: On average, adults (>=20 years) slept 7.5 (SD 1.5) hr, whereas children (5-11 years) and adolescents (12-19 years) slept 9.8 (SD 1.1) and 8.5 (SD 1.9) hr, respectively (p < .01). Based on national recommendations, 40.9% of participants slept insufficiently, particularly young people (vs. adults, p < .01). In age-group stratified analysis, there were no significant associations of insufficient sleep or sleep duration with obesity, diabetes status, or insulin resistance after adjustment for age, race/ethnicity, and gender. In all, 42% of participants reported napping regularly (>=1/week), with adolescents significantly more likely to do so (vs. adults, odds ratio [OR] = 1.95, p < .01). Non-Hispanic Blacks and Hispanics also had higher odds of regular napping (vs. non-Hispanic Whites, OR = 3.74, p < .01 and OR = 2.52, p = .03, respectively). In adjusted analysis, leaner (vs. obese) adolescents, whether measured by body mass index, percentage body fat, or waist circumference, were significantly more likely to nap regularly. CONCLUSIONS: We found that insufficient sleep was significantly more likely in children and adolescents compared with adults in families with type 1 diabetes. Lower adiposity was associated with regular napping in adolescents. The high prevalence of insufficient sleep in young patients with type 1 diabetes and their relatives detected in the current study may have significant health consequences. PMID- 21278168 TI - Stress in migrant farmworkers during premigration. AB - PURPOSE: This study explored the relationship between migrant farmworker (MFW) stress and salivary cortisol (sC) in a sample of MFWs prior to migration. SAMPLE: The sample, 40 (N = 14 male, 26 female) adult MFWs residing in the lower Rio Grande Valley of Texas, primarily comprised middle-aged immigrants with a middle school education. DESIGN: This pilot feasibility study included a self-report farmworker stress inventory and five serial sC specimens in 24 hr. RESULTS: The sC measures reflected an expected diurnal pattern. Lower total cortisol (area under the curve with respect to ground) was significantly associated with greater waist circumference (r = -.63, p <= .01). Repeated measures analysis of variance (ANOVA) indicated that participants who perceived high levels of farmworker stress exhibited a significant change in sC over time; F(2.14, 72.65) = 43.90, p < .001. High- and low-perceived-stress groups differed significantly in the trajectory of changes in sC over the five time points. CONCLUSION: MFWs experienced significant levels of stress during premigration. Their sC responses varied significantly by level of perceived farmworker stress. Lower perceived stress may reflect blunting of the sC response pattern. PMID- 21278169 TI - Endovascular salvage of complications following initial open repair of blunt traumatic thoracic aortic injuries. AB - Endovascular repair of blunt thoracic aortic injuries (BTAI) has largely replaced open repair at many trauma centers despite limited long-term data. It is important to remember that the ''gold standard'' open repair to which it is compared also suffers from a shortage of long-term follow-up and often less than ideal short- and long-term results. The following report describes 2 patients who initially underwent urgent open repair of a BTAI and represented with an acquired coarctation and aneurysmal degeneration 4 and 27 years following their initial repair, respectively. Both patients underwent successful endovascular salvage of these complications. PMID- 21278170 TI - Ultrasound accelerated catheter directed thrombolysis for pulmonary embolus and right heart thrombus secondary to transvenous pacing wires. AB - Acute pulmonary embolism is associated with a significant number of deaths each year, which are commonly attributed to deep venous thrombosis of the lower extremity. Pulmonary embolism due to right-sided cardiac thrombus associated with transvenous wires is a rare occurrence. Treatment considerations have been systemic anticoagulation with heparin or systemic thrombolytic therapy. A unique case of a patient with symptomatic PE and extensive atrial and ventricle thrombus formation associated with transvenous pacing wires treated with ultrasound accelerated catheter directed thrombolysis is presented. PMID- 21278171 TI - Acute radiation syndrome after endovascular AAA repair. AB - Acute radiation syndrome or radiation sickness is a serious illness that occurs after the body receives a high dose of radiation, typically over a short period of time. This condition may be underrecognized by interventionalists and must be considered whenever performing complex endovascular procedures. PMID- 21278172 TI - The results of high-frequency duplex surveillance after iliac arterial stenting in a single center. AB - Frequent duplex surveillance after iliac arterial stenting is time-consuming and costly, so solid benefits of this approach must be available. Frequent duplex surveillance was performed at our center, this was reviewed retrospectively.A total of 117 stents were assessed. Duplex was done for 84 (71.8%) of 117 patients at 1 year and 25 (21.4%) of 117 at 5 years, mean follow-up 27.6 months. Totally, 456 scans were performed; 386 (84.6%) scans were normal, 43 (9.4%) showed an abnormality for which intervention was not necessary, 27 (5.9%) showed abnormalities which needed interventions. The maximum attendance of patients was 62%. In all, 18 patients had interventions unrelated to scheduled follow-up; 15 (83.3%) of 18 had no prior abnormalities on duplex, 3 (16.6%) of 18 had prior abnormalities which were not acted upon after clinical assessment. Our findings demonstrate a high nonattendance rate with frequent emergency presentations due to acute complications. We cannot, therefore, recommend frequent duplex surveillance program both in terms of results or resource allocation. PMID- 21278173 TI - Filter placement for duplicated cava. AB - Anatomic variations of the inferior vena cava (IVC) are found in 3-5% of the population. IVC duplication is a well-known anatomic variation that is important when relevant procedures are being planed. Therefore, the identification of IVC anomalies should be checked prior to pertinent interventions. We report two cases of dual IVC filter placement for duplicated cava including a missing left inferior vena cava and subsequent pulmonary embolism. The rationale of one versus two filters and the current literature are discussed. PMID- 21278174 TI - Spontaneous superior mesenteric artery dissection: report of 2 patients and review of management recommendations. AB - Spontaneous superior mesenteric artery dissection is rare and presents with variable symptomatology. Optimal treatment depends on the presentation; asymptomatic patients can be managed expectantly. Endoluminal intervention or open reconstruction is warranted in patients with persistent symptoms or intestinal ischemia. As more of these patients are identified with increasing utilization of computed tomography (CT), our understanding of the pathophysiology and best treatment will improve. PMID- 21278175 TI - Ascending-to-descending aortic bypass and aortic valve replacement for concomitant severe aortic coarctation and aortic stenosis. AB - We present a 33-year-old male with severe, symptomatic aortic coarctation and aortic stenosis assessed on a humanitarian medical mission to a developing country. Contemplating limited time and available resources, we performed a simultaneous single-stage approach with ascending-to-descending aortic bypass with a reinforced gortex graft and concomitant aortic valve replacement through a median sternotomy. The patient had an uneventful postoperative convalescence and was discharged on postoperative day 5. At 1-year follow-up, he was asymptomatic and doing well with good blood pressure control and complete equalization of upper and lower limb blood pressure measurements. Computed tomography and transthoracic echocardiography demonstrated a widely patent ascending-to descending aortic bypass graft and a normally functioning prosthetic aortic valve, respectively. In developing countries where health care resources are limited, a combined approach with an extra-anatomic, thoracic aortic bypass, and aortic valve replacement resulted in good early and 1-year outcomes. This procedure may represent the most effective surgical option for patients with concomitant aortic coarctation and aortic stenosis. PMID- 21278176 TI - Incidence and survival outcome following femoral artery reconstruction during endovascular abdominal aortic aneurysm repair. AB - BACKGROUND: Planned or unplanned reconstruction of the common femoral artery (femoro-femoral crossover and/or patch closure) may be required following endovascular abdominal aortic aneurysm repair (EVAR) stent graft deployment for arterial closure or maintenance of limb perfusion. The aim of this study was to examine the incidence of common femoral artery reconstruction (FAR) following EVAR and examine the effect on patient survival. METHODS: A total of 178 patients undergoing EVAR were studied retrospectively. RESULTS: In all, 31 patients (17.4%) underwent FAR; 16 (51.6%) femoro-femoral crossover, and 15 (48.4%) endarterectomy and patch closure. All cause survival in patients undergoing FAR was significantly poorer than those undergoing direct closure (P = .010).A total of 3 factors: the need for FAR (hazard ratio [HR] = 0.435, P = .006), chronic obstructive pulmonary disease ([COPD] HR = 0.424, P = .002), and abdominal aortic aneurysm (AAA) size (HR = 1.414, P = .005) were significantly and independently associated with survival on forward conditional analysis. CONCLUSIONS: Femoral artery reconstruction was performed in almost 1 in 5 patients undergoing EVAR and associated with decreased survival. Multidisciplinary teams should be aware of these findings when planning EVAR, especially in borderline candidates. PMID- 21278177 TI - Delayed complications of inferior vena cava filters: case report and literature review. AB - Inferior vena cava (IVC) filters are frequently placed to prevent pulmonary embolism in patients in whom anticoagulation is contraindicated or ineffective. Delayed erosion of the filter into adjacent vital structures is a rare complication. We report 3 complications of IVC filters managed with both surgical and endovascular therapies. A review of the available literature addresses incidence of delayed IVC filter complications, the approach to these problems, and the role of retrievable IVC filters. PMID- 21278178 TI - Combined carotid endarterectomy and coronary artery bypass grafting versus coronary artery bypass grafting alone: a retrospective review of outcomes at our institution. AB - BACKGROUND: It remains controversial whether patients with concomitant carotid and coronary disease should undergo operative repair separately or in combination. METHODS: Patients with documented cerebrovascular disease undergoing coronary artery bypass grafting (CABG) alone were matched by propensity scoring with patients undergoing combined carotid endarterectomy (CEA)/CABG procedures and compared for the occurrence of stroke, myocardial infarction (MI), and mortality. RESULTS: Of the 4943 patients undergoing CABG, 908 had known cerebrovascular disease. Among these, 134 underwent concomitant CEA, and these were propensity matched with 134 patients undergoing CABG only. No differences were observed in the perioperative risks of stroke (4% vs 3%, odds ratio [OR] 1.5, 95% confidence interval [CI] 0.4-5.5), MI (0.7% vs 0.7%, not significant [NS]), or combined cardiovascular events (6% vs 10%, OR 0.5, 95% CI [0.2-1.3]), although mortality (1% vs 8%, OR 0.2, 95% CI [0.04-0.8] was higher with CABG only. DISCUSSION: Addition of CEA to CABG did not significantly alter the risk of perioperative stroke relative to propensity-matched patients undergoing CABG alone. PMID- 21278179 TI - The transition to IVUS-guided IVC filter deployment in the nontrauma patient. AB - While prior reports have demonstrated intravascular ultrasound (IVUS)-guided inferior vena cava filter (IVCF) deployment to be feasible, larger reviews using the latest generation of filters in the nontrauma setting are absent. We review our experience with the deployment of 104 IVCFs using IVUS, whereby we transition from a combined use of IVUS with traditional road mapping techniques (venography and/or renal vein cannulation) to the sole use of the IVUS as the road mapping tool for IVCF insertion. The use of IVUS for IVCF deployment minimizes radiation exposure to patients and staff, minimizes patient contrast exposure, and minimizes dependency on auxiliary staff for fluoroscopy. Intravascular ultrasound IVCF deployments can be performed without increasing morbidity and mortality, case duration, or overall costs when compared to standard deployments. The learning curve for transitioning into the use of the IVUS as the primary road mapping tool for IVCF deployments is approximately 20 cases. PMID- 21278180 TI - Quality of life and functional status after revascularization or conservative treatment in patients with intermittent claudication. AB - Revascularization of patients with intermittent claudication (IC) is recommended only for selected patients who have chronic pain or disabling disease. However, improvement in the quality of life (QoL) could justify more widespread use. OBJECTIVES: To determine the effect of conservative treatment and revascularization on the QoL and physical performance of selected patients with IC. PATIENTS AND METHODS: This nonrandomized, parallel group, follow-up study included 83 patients with IC at Fontaine stage II. On the basis of interventional opportunities and the risks and benefits, combined with the preference of the patient, 47 patients were treated conservatively and 41 were revascularized. The patients were examined at inclusion and 3 months later. The evaluations included the QoL measure Short Form 36 (SF-36), the Walking Impairment Questionnaire (WIQ), pain-free and maximal walking distance (treadmill at 3 km/h, no incline), maximal isometric knee-extension strength and endurance, and ankle-brachial blood pressure index (ABI). RESULTS: At baseline, the SF-36 and WIQ scores and the ABI were significantly lower in the patients selected for revascularization. After revascularization, all dimensions of QoL and functional status increased significantly in the patients who underwent revascularisation compared with the patients treated conservatively. The difference in the change in the physical component summary of SF-36 was 29.4% (P < .001), in the total WIQ 63.6% (P = .0002), and in the pain-free and maximal walking distances 313% (P < .001) and 135% (P < .001), respectively. After adjustment for age, smoking, ABI, body mass index (BMI), and baseline values, the differences remained statistically significant. CONCLUSION: Revascularization above the knee increased QoL, functional status, and walking distance significantly in patients with moderate IC. PMID- 21278181 TI - Spontaneous rupture of a carotid artery aneurysm. AB - Carotid aneurysms are rare, accounting for less than 4% of all aneurysms, and repair of this entity comprises only 0.9% of all carotid procedures at major referral centers. Stroke is the most frequent complication and the possibility of rupture is only rarely considered. Rupture of a nontraumatic, uninfected carotid aneurysm is an exceedingly rare event, with only a handful of cases documented in the world literature, most of which presented as an acute, life-threatening emergency. This report documents the highly unusual circumstance of subacute presentation of a ruptured carotid aneurysm. PMID- 21278182 TI - Pulmonary artery stenosis secondary to fibrosing mediastinitis: management with cutting balloon angioplasty and endovascular stenting. AB - Cutting balloon angioplasty is a common treatment modality in the pediatric population for pulmonary artery stenosis. We present an adult with histoplasmosis induced fibrosing mediastinitis resulting in pulmonary artery stenosis that was successfully treated with cutting balloon angioplasty and subsequent stent deployment. Percutaneous endovascular stent placement has be shown to effectively alleviate pulmonary artery stenosis, however in-stent restenosis does limit durability. Pharmacologic therapy is indicated with either mediastinal adenitis or mediastinal granuloma with anti-fungal agents such as amphotericin B and itraconazole. Surgical intervention for histoplasmosis induced fibrosing mediastinitis is rarely indicated and may result in fatal complications that stem from mediastinal fibrosis due to resultant destruction of surgical planes. To our knowledge, this is the first reported case of utilizing cutting balloon angioplasty and stent insertion for the treatment of histoplasmosis induced fibrosing mediastinitis complicated by pulmonary artery stenosis. PMID- 21278183 TI - Angiotensin-converting enzyme inhibition changes the metabolic response to neuroglucopenic stress. AB - Neuroglucopenia induced by 2-deoxy-D-glucose (2DG) activates hypothalamic glucoreceptors leading to increased hepatic glucose production and insulin inhibition. This response is similar to what is observed with intravenous injection of angiotensin II (Ang II). However, the involvement of an angiotensin converting enzyme inhibitor on neuroglucopenia has not been investigated. The aim of this study was to determine the effects of chronic enalapril treatment on plasma glucose, insulin and lipid levels in response to neuroglucopenia. Male Holtzman rats (120-170 g) were chronically treated with enalapril (10 mg/kg per day) in the drinking water for two weeks. On the day of experiment the animals received an i.v. enalapril final dose one hour before the neuroglucopenic stress by 2DG infusion (500 mg/kg), and blood samples were drawn before and 5, 10, 20, 30 and 60 minutes following infusion. The hyperglycaemic response to 2DG was not significantly changed by enalapril treatment. The enalapril-treated group exhibited a peak of plasma insulin higher than controls. Plasma triglyceride showed a significant increase only in the enalapril group after neuroglucopenic stress (p < 0.05).These data show that chronic enalapril treatment changes insulin and triglyceride responses to neuroglucopenia, suggesting an effect on glucose-induced insulin secretion and the storage of triglycerides. PMID- 21278184 TI - Modular analysis of the probabilistic genetic interaction network. AB - MOTIVATION: Epistatic Miniarray Profiles (EMAP) has enabled the mapping of large scale genetic interaction networks; however, the quantitative information gained from EMAP cannot be fully exploited since the data are usually interpreted as a discrete network based on an arbitrary hard threshold. To address such limitations, we adopted a mixture modeling procedure to construct a probabilistic genetic interaction network and then implemented a Bayesian approach to identify densely interacting modules in the probabilistic network. RESULTS: Mixture modeling has been demonstrated as an effective soft-threshold technique of EMAP measures. The Bayesian approach was applied to an EMAP dataset studying the early secretory pathway in Saccharomyces cerevisiae. Twenty-seven modules were identified, and 14 of those were enriched by gold standard functional gene sets. We also conducted a detailed comparison with state-of-the-art algorithms, hierarchical cluster and Markov clustering. The experimental results show that the Bayesian approach outperforms others in efficiently recovering biologically significant modules. PMID- 21278185 TI - Quality control and preprocessing of metagenomic datasets. AB - SUMMARY: Here, we present PRINSEQ for easy and rapid quality control and data preprocessing of genomic and metagenomic datasets. Summary statistics of FASTA (and QUAL) or FASTQ files are generated in tabular and graphical form and sequences can be filtered, reformatted and trimmed by a variety of options to improve downstream analysis. AVAILABILITY AND IMPLEMENTATION: This open-source application was implemented in Perl and can be used as a stand alone version or accessed online through a user-friendly web interface. The source code, user help and additional information are available at http://prinseq.sourceforge.net/. PMID- 21278186 TI - Modeling and comparing the organization of circular genomes. AB - MOTIVATION: Most prokaryotic genomes are circular with a single chromosome (called circular genomes), which consist of bacteria and archaea. Orthologous genes (abbreviated as orthologs) are genes directly evolved from an ancestor gene, and can be traced through different species in evolution. Shared orthologs between bacterial genomes have been used to measure their genome evolution. Here, organization of circular genomes is analyzed via distributions of shared orthologs between genomes. However, these distributions are often asymmetric and bimodal; to date, there is no joint distribution to model such data. This motivated us to develop a family of bivariate distributions with generalized von Mises marginals (BGVM) and its statistical inference. RESULTS: A new measure based on circular grade correlation and the fraction of shared orthologs is proposed for association between circular genomes, and a visualization tool developed to depict genome structure similarity. The proposed procedures are applied to eight pairs of prokaryotes separated from domain down to species, and 13 mycoplasma bacteria that are mammalian pathogens belonging to the same genus. We close with remarks on further applications to many features of genomic organization, e.g. shared transcription factor binding sites, between any pair of circular genomes. Thus, the proposed procedures may be applied to identifying conserved chromosome backbones, among others, for genome construction in synthetic biology. AVAILABILITY: All codes of the BGVM procedures and 1000+ prokaryotic genomes are available at http://www.stat.sinica.edu.tw/~gshieh/bgvm.htm. PMID- 21278187 TI - Identity-by-descent filtering of exome sequence data for disease-gene identification in autosomal recessive disorders. AB - MOTIVATION: Next-generation sequencing and exome-capture technologies are currently revolutionizing the way geneticists screen for disease-causing mutations in rare Mendelian disorders. However, the identification of causal mutations is challenging due to the sheer number of variants that are identified in individual exomes. Although databases such as dbSNP or HapMap can be used to reduce the plethora of candidate genes by filtering out common variants, the remaining set of genes still remains on the order of dozens. RESULTS: Our algorithm uses a non-homogeneous hidden Markov model that employs local recombination rates to identify chromosomal regions that are identical by descent (IBD = 2) in children of consanguineous or non-consanguineous parents solely based on genotype data of siblings derived from high-throughput sequencing platforms. Using simulated and real exome sequence data, we show that our algorithm is able to reduce the search space for the causative disease gene to a fifth or a tenth of the entire exome. AVAILABILITY: An R script and an accompanying tutorial are available at http://compbio.charite.de/index.php/ibd2.html. PMID- 21278188 TI - PiNGO: a Cytoscape plugin to find candidate genes in biological networks. AB - PiNGO is a tool to screen biological networks for candidate genes, i.e. genes predicted to be involved in a biological process of interest. The user can narrow the search to genes with particular known functions or exclude genes belonging to particular functional classes. PiNGO provides support for a wide range of organisms and Gene Ontology classification schemes, and it can easily be customized for other organisms and functional classifications. PiNGO is implemented as a plugin for Cytoscape, a popular network visualization platform. AVAILABILITY: PiNGO is distributed as an open-source Java package under the GNU General Public License (http://www.gnu.org/), and can be downloaded via the Cytoscape plugin manager. A detailed user guide and tutorial are available on the PiNGO website (http://www.psb.ugent.be/esb/PiNGO. PMID- 21278189 TI - Conveyor: a workflow engine for bioinformatic analyses. AB - MOTIVATION: The rapidly increasing amounts of data available from new high throughput methods have made data processing without automated pipelines infeasible. As was pointed out in several publications, integration of data and analytic resources into workflow systems provides a solution to this problem, simplifying the task of data analysis. Various applications for defining and running workflows in the field of bioinformatics have been proposed and published, e.g. Galaxy, Mobyle, Taverna, Pegasus or Kepler. One of the main aims of such workflow systems is to enable scientists to focus on analysing their datasets instead of taking care for data management, job management or monitoring the execution of computational tasks. The currently available workflow systems achieve this goal, but fundamentally differ in their way of executing workflows. RESULTS: We have developed the Conveyor software library, a multitiered generic workflow engine for composition, execution and monitoring of complex workflows. It features an open, extensible system architecture and concurrent program execution to exploit resources available on modern multicore CPU hardware. It offers the ability to build complex workflows with branches, loops and other control structures. Two example use cases illustrate the application of the versatile Conveyor engine to common bioinformatics problems. AVAILABILITY: The Conveyor application including client and server are available at http://conveyor.cebitec.uni-bielefeld.de. PMID- 21278190 TI - A Ruby API to query the Ensembl database for genomic features. AB - The Ensembl database makes genomic features available via its Genome Browser. It is also possible to access the underlying data through a Perl API for advanced querying. We have developed a full-featured Ruby API to the Ensembl databases, providing the same functionality as the Perl interface with additional features. A single Ruby API is used to access different releases of the Ensembl databases and is also able to query multi-species databases. AVAILABILITY AND IMPLEMENTATION: Most functionality of the API is provided using the ActiveRecord pattern. The library depends on introspection to make it release independent. The API is available through the Rubygem system and can be installed with the command gem install ruby-ensembl-api. PMID- 21278191 TI - Bambino: a variant detector and alignment viewer for next-generation sequencing data in the SAM/BAM format. AB - SUMMARY: Bambino is a variant detector and graphical alignment viewer for next generation sequencing data in the SAM/BAM format, which is capable of pooling data from multiple source files. The variant detector takes advantage of SAM specific annotations, and produces detailed output suitable for genotyping and identification of somatic mutations. The assembly viewer can display reads in the context of either a user-provided or automatically generated reference sequence, retrieve genome annotation features from a UCSC genome annotation database, display histograms of non-reference allele frequencies, and predict protein coding changes caused by SNPs. AVAILABILITY: Bambino is written in platform independent Java and available from https://cgwb.nci.nih.gov/goldenPath/bamview/documentation/index.html, along with documentation and example data. Bambino may be launched online via Java Web Start or downloaded and run locally. PMID- 21278192 TI - SHRiMP2: sensitive yet practical SHort Read Mapping. AB - We report on a major update (version 2) of the original SHort Read Mapping Program (SHRiMP). SHRiMP2 primarily targets mapping sensitivity, and is able to achieve high accuracy at a very reasonable speed. SHRiMP2 supports both letter space and color space (AB/SOLiD) reads, enables for direct alignment of paired reads and uses parallel computation to fully utilize multi-core architectures. AVAILABILITY: SHRiMP2 executables and source code are freely available at: http://compbio.cs.toronto.edu/shrimp/. PMID- 21278193 TI - Clinical management of cardiovascular complications in patients with thalassaemia major: a large observational multicenter study. AB - AIMS: To determine the clinical management of cardiovascular complications, and the extent of cardiac left ventricular (LV) involvement, in a large cohort of homogenously treated patients with thalassaemia major. METHODS AND RESULTS: Participants were >= 16 years of age and diagnosed with thalassaemia major requiring regular blood transfusions since the age of 2. Patient characteristics, clinical and echocardiography data for 524 patients were extracted from Webthal(r), an Internet-shared database. Patients were considered to have evidence of cardiovascular disease if at least one cardiovascular drug was recorded in their file. The majority of patients (422 of 524; 80.5%) had not taken any cardiovascular drug. Among those who had angiotensin-converting enzyme inhibitors were the most commonly used (81 patients) and these were used by significantly more males than females (P < 0.01). Patients in whom cardiovascular drugs were prescribed showed evidence of cardiac structural and/or functional abnormalities, inasmuch as fractional shortening and ejection fraction were significantly lower (31.3 vs. 35% and 54.4 vs. 60.6; both P < 0.001) and LV end diastolic diameter index was significantly higher (32.9 vs. 31.8; P = 0.004). Interestingly, when compared with patients in whom cardiovascular drug therapy was not deemed necessary, transfusion period was longer in treated patients (26.2 vs. 24.5 years; P= 0.002). CONCLUSION: Approximately 19% of regularly transfused and chelated thalassaemia major patients need cardiovascular drug therapy. This subgroup is characterized by a dilated and mildly hypokinetic left ventricle when compared with the majority of thalassaemia major patients, who do not need any cardioactive drug. These data underscore the importance of careful evaluation of cardiac functional status in patients with thalassaemia major. Moreover, this database may serve as a clinically useful reference grid for echocardiograph values in this patient population. PMID- 21278194 TI - Development of the action observation network during early adolescence: a longitudinal study. AB - Adolescence places high demands on inter-personal interactions and, hence, on the extraction and processing of social cues. Here we assess longitudinally the development of brain activity within a network implicated in social cognition- the action observation network. We performed activation likelihood estimation meta-analyses to define regions of interest based upon the mature action observation network of adults. Using functional magnetic resonance imaging, we then examined developmental trajectories of functional brain activity within these brain regions. Using this approach, we reveal quadratic trajectories within a fronto-parietal network previously shown to demonstrate correlated morphological development. PMID- 21278195 TI - Maternal risk of ischaemic heart disease following elective and spontaneous pre term delivery: retrospective cohort study of 750 350 singleton pregnancies. AB - BACKGROUND: Previous studies have demonstrated an overall association between pre term delivery and maternal risk of subsequent ischaemic heart disease (IHD). The underlying mechanism is unknown. We explored whether the association was specific to spontaneous or elective pre-term delivery. METHODS: We linked three Scottish routine data sources. The Scottish Morbidity Record 1 collects data on all acute hospital admissions, Scottish Morbidity Record 2 collects data on all pregnancies and Scotland's Registrar General collates data from all death certificates. Cox proportional hazards models were used to explore associations between pre-term delivery and subsequent IHD events (fatal and non-fatal) and IHD deaths. Analysis was restricted to women aged between 35 and 65 years at either the time of their first IHD event or at the end of follow-up. RESULTS: The cohort comprised 750,350 women who delivered a live, singleton infant following their first pregnancy. We demonstrated independent associations between pre-term delivery and IHD death [hazards ratio (HR) 2.26, 95% confidence interval (CI) 1.88-2.71] and total IHD events (HR 1.58, 95% CI 1.47-1.71). Associations were greater for elective than spontaneous pre-term delivery (P = 0.005). There was a trend whereby the association between pre-term delivery and IHD increased with decreasing age at first event. CONCLUSIONS: We observed a stronger association between elective pre term delivery and IHD, than spontaneous pre-term delivery and IHD. Elective pre term delivery is usually undertaken because of growth restriction or pre eclampsia, resulting from placental dysfunction. The age trend observed suggests an underlying genetic predisposition to both placental dysfunction and IHD. PMID- 21278197 TI - Intact cognition in depressed elderly veterans providing adequate effort. AB - Geriatric depression has been associated with cognitive impairments, but whether suboptimal effort contributes to these deficits is unknown. This study investigated differences in cognitive functioning between depressed and nondepressed elderly veterans, before and after excluding patients who provided suboptimal effort on testing at a memory disorders clinic. Patients diagnosed with a depressive disorder performed more poorly than nondepressed patients on almost all Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) indices, but these differences became nonstatistically significant after excluding patients who provided suboptimal effort. However, when patients were classified as normal, mildly, or severely depressed based on Geriatric Depression Scale scores, these groups were not significantly different on RBANS indices, regardless of whether patients who provided suboptimal effort were included or excluded from analyses. The findings suggest that cognitive deficits in depression reported in previous research may be attributable to suboptimal effort and that identifying depression via clinical diagnosis or psychometric data may affect this trend. PMID- 21278196 TI - Household coal use and lung cancer: systematic review and meta-analysis of case control studies, with an emphasis on geographic variation. AB - BACKGROUND: Emissions from household coal combustion associated with cooking and heating are an important public health issue, particularly in China where hundreds of millions of people are exposed. Although coal emissions are a known human carcinogen, there is still uncertainty about the level of risk for lung and other cancers. METHODS: We performed a meta-analysis on 25 case-control studies (10,142 cases and 13,416 controls) to summarize the association between household coal use and lung cancer risk, and to explore the effect modification of this association by geographical location. RESULTS: Using random-effects models, household coal use was found to be associated with lung cancer risk among all studies throughout the world [odds ratio (OR) = 2.15; 95% confidence interval (CI) = 1.61-2.89, N(studies) = 25], and particularly among those studies carried out in mainland China and Taiwan (OR = 2.27; 95% CI = 1.65-3.12, N(studies) = 20). Stratification by regions of mainland China and Taiwan found a variation in effects across the regions, with south/southeastern (OR = 3.27; 95% CI = 1.27 8.42, N(studies) = 3) and southwestern China (OR = 2.98; 95% CI = 1.18-7.53, N(studies) = 3) experiencing the highest risk. The elevated risk associated with coal use throughout Asia was also observed when stratifying studies by gender, smoking status, sample size, design (population vs hospital case-control) and publication language. No significant publication bias was found (p(Begg's) = 0.15). CONCLUSIONS: Our results provide evidence that although the carcinogenic effect of coal use varies by location, coals from many locations exhibit elevated lung cancer risks. PMID- 21278198 TI - Controversies in fumonisin mycotoxicology and risk assessment. AB - Fusarium verticillioides causes several animal diseases and the contamination maize suggests that it could adversely affect human health. The fumonisin B mycotoxins were characterized from the fungal culture material and shown to be the causative principle responsible for the major mycotoxicological effects of the fungus in experimental and farm animals. The main focus was on the toxicological effects in rats and mice, the outcome of which played an important role in setting risk assessment parameters for exposure of the fumonisins to humans. The International Agency for Research on Cancer characterized the fumonisins as Group 2B carcinogens. Several controversial findings regarding the toxicological effects of the culture material of the fungus, the genotoxicity and carcinogenicity of pure fumonisin B(1) (FB(1)) in rats have been reported that should be clarified prior to assessing the risk in humans. The underlying differences between the diets with the high protein levels are likely to sensitize the kidneys to FB(1)-induced toxic and carcinogenic effects. Several other dietary factors, such as plant extracts (antioxidants) and dietary Fe, could either stimulate or inhibit cancer induction of FB(1), which complicates the comparison of toxicological effects in experimental animals. Cognisance should be taken of the modulating role of dietary constituents as it will determine the outcome of toxicological assays and determine the threshold of an adverse effect in a specific target organ to be used in determining risk assessment parameters. PMID- 21278199 TI - ERK1 and ERK2 are involved in recruitment and maturation of human mesenchymal stem cells induced to adipogenic differentiation. AB - Adipocytes' biology and the mechanisms that control adipogenesis have gained importance because of the need to develop therapeutic strategies to control obesity and the related pathologies. Human mesenchymal stem cells (hMSCs), undifferentiated stem cells present in the bone marrow that are physiological precursors of adipocytes, were induced to adipogenic differentiation. The molecular mechanisms on the basis of the adipogenesis were evaluated, focusing on the MAPKinases ERK1 and ERK2, which are involved in many biological and cellular processes. ERK1 and ERK2 phosphorylation was reduced with different timing and intensity for the two isoforms in treated hMSCs in comparison with control cells until day 10 and then at 14-28 days, it reached the level of untreated cultures. The total amount of ERK1 was also decreased up to day 10 and then was induced to the level of untreated cultures, whereas the expression of ERK2 was not changed following adipogenic induction. Treatment with the specific ERK1/2 inhibitor U0126 during the whole differentiation period hampered hMSCs' adipogenic differentiation, as lipid droplets appeared in very few cells and were reduced in number and size. When U0126 was administered only during the initial phase of differentiation, the number of hMSCs recruited to adipogenesis was reduced while, when it was administered later, hMSCs did not acquire a mature adipocytic phenotype. ERK1 and ERK2 are important for hMSC adipogenic differentiation since any alteration to the correct timing of their phosphorylation affects either the recruitment into the differentiation program and the extent of their maturation. PMID- 21278201 TI - Does acupuncture help in helping the ones you cannot help? The role of acupuncture in facilitating adaptive processes. AB - In the public funded healthcare arena, acupuncture is delivered with 'disease' as the defining label that grants access to funding. This funding process is regulated by recommendations derived from systematic reviews and meta-analyses of randomised controlled trials. However, 'off-label' use of acupuncture, outside established indications like pain or nausea, happens frequently, though there is a paucity of data about this situation. The case of a young man with weakness and fatigue as residuum of relapsing-remitting multiple sclerosis highlights the situation. His treatment goal was well defined. Specific and non-specific needling effects and the provider-patient relationship are explored. The role of technological and adaptive processes in the treatment of long-term conditions, the effect of somatosensory stimulation on different levels and the implication for funding are discussed. PMID- 21278200 TI - Cancer and neurodegenerative disorders: pathogenic convergence through microRNA regulation. AB - Although cancer and neurodegenerative disease are two distinct pathological disorders, emerging evidence indicates that these two types of disease share common mechanisms of genetic and molecular abnormalities. Recent studies show that individual microRNAs (miRNAs) could be involved in the pathology of both diseases, indicating that the mechanisms of these two seemingly dichotomous diseases converge in the dysregulation of gene expression at the post transcriptional level. Given the increasing evidence showing that miRNA-based therapeutic strategies that modulate the activity of one or more miRNAs are potentially effective for a wide range of pathological conditions, the involvement of miRNAs in the common pathways of leading both diseases suggests a bright future for developing common therapeutic approaches for both diseases. Moreover, the miRNAs that are dysregulated in both diseases may hold promise as uniquely informative diagnostic markers. Here, we review recent studies on the miRNAs that have been implicated in both cancer and neurodegenerative diseases. PMID- 21278202 TI - Linking scholarly publications to popular press: an avenue for dissemination. PMID- 21278203 TI - Repeated dosing of nebulised 5% saline improves respiratory scores in inpatients with mild to moderate bronchiolitis at 48 h. PMID- 21278205 TI - Influenza B is now predominant strain, as flu cases continue to fall. PMID- 21278206 TI - US health department recovers $4bn through antifraud action. PMID- 21278207 TI - Radiotherapy in UK is feared and underused. PMID- 21278208 TI - Spain's tougher line on smoking in public places spreads to other countries. PMID- 21278209 TI - Evaluation of therapeutic interventions for vaccinia virus keratitis. AB - BACKGROUND: Vaccinia virus keratitis (VACVK) is a complication of smallpox vaccination that can result in blindness. There are no Food and Drug Administration-approved treatments for VACVK, and vaccinia immunoglobulin (VIG) is contraindicated in isolated VACVK. We used a rabbit model of infection to compare several therapeutic options for VACVK. METHODS: Rabbit eyes were infected with 10(5) plaque-forming units of the Dryvax strain of vaccinia virus and scored daily for 28 days using a modified MacDonald-Shadduck scoring system. Animals were treated for 10 days after the onset of keratitis with albumin, VIG, prednisolone acetate, trifluridine, or combinations thereof. Ocular viral titers and vaccinia-specific antibody titers were determined by plaque assay and enzyme linked immunosorbent assay, respectively. RESULTS: Treatment with intravenous VIG neither exacerbated nor ameliorated VACVK. Topical prednisolone acetate interfered with viral clearance, and ocular disease rebounded in prednisolone treated groups. The most effective treatment was topical trifluridine alone. CONCLUSIONS: We conclude that (1) VIG did not negatively affect the treatment of isolated keratitis, (2) topical corticosteroids should not be used for treating VACVK, and (3) treatment with topical trifluridine, with or without intravenous VIG, is the preferred therapeutic regimen for treating VACVK. PMID- 21278211 TI - Influenza virus primes mice for pneumonia from Staphylococcus aureus. AB - Superinfections from Staphylococcus aureus following influenza are an increasing concern. We assessed several laboratory and clinical strains in a mouse coinfection model with influenza virus. A methicillin-resistant USA300 clone and several recent clinical strains from patients with necrotizing pneumonia caused high mortality following influenza virus infection in mice. Both viral and bacterial lung titers were enhanced during coinfections compared with single infections. However, differences in titers did not correspond with differences in disease outcomes in a comparison of superinfections from a highly pathogenic strain with those from a poorly pathogenic strain. These strains did differ, however, in expression of Panton-Valentine leukocidin and in the degree of inflammatory lung damage each engendered. The viral cytotoxin PB1-F2 contributed to the negative outcomes. These data suggest that additional study of specific bacterial virulence factors involved in the pathogenesis of inflammation and lung damage during coinfections is needed. PMID- 21278212 TI - Microbial translocation: a marker of advanced HIV-1 infection and a predictor of treatment failure? PMID- 21278213 TI - Comparison of patients hospitalized with pandemic 2009 influenza A (H1N1) virus infection during the first two pandemic waves in Wisconsin. AB - BACKGROUND: Wisconsin was severely affected by pandemic waves of 2009 influenza A H1N1 infection during the period 15 April through 30 August 2009 (wave 1) and 31 August 2009 through 2 January 2010 (wave 2). METHODS: To evaluate differences in epidemiologic features and outcomes during these pandemic waves, we examined prospective surveillance data on Wisconsin residents who were hospitalized >= 24 h with or died of pandemic H1N1 infection. RESULTS: Rates of hospitalizations and deaths from pandemic H1N1 infection in Wisconsin increased 4- and 5-fold, respectively, from wave 1 to wave 2; outside Milwaukee, hospitalization and death rates increased 10- and 8-fold, respectively. Hospitalization rates were highest among racial and ethnic minorities and children during wave 1 and increased most during wave 2 among non-Hispanic whites and adults. Times to hospital admission and antiviral treatment improved between waves, but the overall hospital course remained similar, with no change in hospitalization duration, intensive care unit admission, requirement for mechanical ventilation, or mortality. CONCLUSIONS: We report broader geographic spread and marked demographic differences during pandemic wave 2, compared with wave 1, although clinical outcomes were similar. Our findings emphasize the importance of using comprehensive surveillance data to detect changing characteristics and impacts during an influenza pandemic and of vigorously promoting influenza vaccination and other prevention efforts. PMID- 21278214 TI - Host genetic determinants of T cell responses to the MRKAd5 HIV-1 gag/pol/nef vaccine in the step trial. AB - Understanding how human genetic variation impacts individual response to immunogens is fundamental for rational vaccine development. To explore host mechanisms involved in cellular immune responses to the MRKAd5 human immunodeficiency virus type 1 (HIV-1) gag/pol/nef vaccine tested in the Step trial, we performed a genome-wide association study of determinants of HIV specific T cell responses, measured by interferon gamma enzyme-linked immunospot assays. No human genetic variant reached genome-wide significance, but polymorphisms located in the major histocompatibility complex (MHC) region showed the strongest association with response to the HIV-1 Gag protein: HLA-B alleles known to be associated with differences in HIV-1 control were responsible for these associations. The implication of the same HLA alleles in vaccine-induced cellular immunity and in natural immune control is of relevance for vaccine design. Furthermore, our results demonstrate the importance of considering the host immunogenetic background in the analysis of immune responses to T cell vaccines. PMID- 21278215 TI - Essential care after an inpatient fall: summary of a safety report from the National Patient Safety Agency. PMID- 21278217 TI - Benefit of cytoreductive nephrectomy in metastatic RCC: do we learn from retrospective studies and small prospective studies? PMID- 21278218 TI - Utilization of oncology services and receipt of treatment: a comparison between patients with breast, colon, rectal, or lung cancer. AB - BACKGROUND: Higher awareness could translate into better care for patients with breast cancer than for those with other cancers. This study examines utilization of two key oncology services across cancer sites: consultation with an oncologist and receipt of treatment. PATIENTS AND METHODS: All residents of Alberta, Canada, who were diagnosed in 2005 with breast, colon, rectal, or lung cancer and had a disease stage that should be treated with chemotherapy, radiation therapy, or hormonal therapy were included. Data were obtained from the Alberta Cancer Registry and electronic cancer medical records. Percentages of patients who had a consultation and who received treatment were compared. Multivariable log-binomial regression models were used to identify patient characteristics associated with not having the outcomes. RESULTS: A much higher percentage of patients with breast cancer had consultations and received treatment (92% and 83%, respectively) than those with colon (83% and 59%), rectal (86% and 73%), or lung (77% and 66%) cancer. Age, disease stage, region of residence, and surgery status are related to having a consultation and/or receiving treatment but the relationship varies by cancer site. CONCLUSION: Efforts are needed to eliminate disparities in utilization of key cancer services across cancer sites. PMID- 21278219 TI - Auto-antibody production and glomerulonephritis in congenic Slamf1-/- and Slamf2 /- [B6.129] but not in Slamf1-/- and Slamf2-/- [BALB/c.129] mice. AB - Several genes in an interval of human and mouse chromosome 1 are associated with a predisposition for systemic lupus erythematosus. Congenic mouse strains that contain a 129-derived genomic segment, which is embedded in the B6 genome, develop lupus because of epistatic interactions between the 129-derived and B6 genes, e.g. in B6.129chr1b mice. If a gene that is located on chromosome 1 is altered through homologous recombination in 129-derived embryonic stem cells (ES cells) and if the resultant knockout mouse is backcrossed with B6, interpretation of the phenotype of the mutant mouse may be affected by epistatic interactions between the 129 and B6 genomes. Here, we report that knockout mice of two adjacent chromosome 1 genes, Slamf1(-/-) and Slamf2(-/-), which were generated with the same 129-derived ES cell line, develop features of lupus, if backcrossed on to the B6 genetic background. By contrast, Slamf1(-/-) [BALB/c.129] and Slamf2(-/-) [BALB/c.129] do not develop disease. Surprisingly, Slamf1(-/-) [B6.129] mice develop both auto-antibodies and glomerulonephritis between 3 and 6 months of age, while disease fully develops in Slamf1(-/-) [B6.129] mice after 9 14 months. Functional analyses of CD4(+) T cells reveals that Slamf2(-/-) T cells are resistant to tolerance induction in vivo. We conclude that the Slamf2(-/-) mutation may have a unique influence on T-cell tolerance and lupus. PMID- 21278220 TI - Randomized phase III trials of second-line chemotherapy in patients with advanced bladder cancer: progress and pitfalls. PMID- 21278221 TI - Chronic non-communicable diseases, the European Chronic Disease Alliance--and cancer. PMID- 21278222 TI - Receptor status (ER, PgR and HER2) discordance between primary tumor and locoregional recurrence in breast cancer. PMID- 21278223 TI - KRAS let-7 LCS6 SNP predicts cetuximab efficacy in KRASwt metastatic colorectal cancer patients: Does treatment combination partner matter? PMID- 21278224 TI - Total recall of radiotherapy with mTOR inhibitors: a novel and potentially frequent side-effect? PMID- 21278225 TI - Thrombotic microangiopathy related to anti-VEGF agents: intensive versus conservative treatment? PMID- 21278226 TI - In situ identification of follicles in ovarian cortex as a tool for quantifying follicle density, viability and developmental potential in strategies to preserve female fertility. PMID- 21278227 TI - Epitope mapping, expression and post-translational modifications of two isoforms of CD33 (CD33M and CD33m) on lymphoid and myeloid human cells. AB - We have tested the usefulness of several commercial anti-CD33 monoclonal antibodies (mAb) to determine the expression and localization of the two CD33 isoforms on several hematopoietic cell lines. The expression of the isoform CD33m, a CD33 transmembrane splice variant lacking the ligand-binding V immunoglobulin (Ig)-like domain, was detected by RT-polymerase chain reaction, western blot, confocal microscopy and flow cytometry on the membrane of several human cell types. CD33m was only detected by the anti-CD33 mAb HIM3-4 on the cell surface, whereas WM53, P67.6, 4D3, HIM3-4, WM54, D3HL60.251 or MY9 detected the CD33M isoform, indicating that HIM3-4 is the only mAb recognizing CD33 C(2) Ig domain. Accordingly, HIM3-4 binding to CD33 did not interfere with the binding of other antibodies against the CD33 V-domain. P67.6 mAb interfered with recognition by the rest of antibodies specific for the V domain. HIM3-4 staining could be increased after the sialidase treatment of all CD33(+) cells. However, this increase was stronger in activated T cells, suggesting a CD33 masking state in this cell population. Confocal microscopy analysis of CD33m HEK 293T-transfected cells revealed that this protein is expressed on the cell membrane and also detected in the Golgi compartment. CD33 is constitutively located outside the lipid raft domains, whereas cross-linked CD33 is highly recruited to this signaling platform. The unique ability of HIM3-4 mAb to detect the masking state of CD33 on different cell lineages makes it a good tool to improve the knowledge of the biological role of this sialic acid-binding Ig-like lectin. PMID- 21278228 TI - Recent advances in the transcriptional regulation of the flavonoid biosynthetic pathway. AB - Flavonoids are secondary metabolites involved in several aspects of plant development and defence. They colour fruits and flowers, favouring seed and pollen dispersal, and contribute to plant adaptation to environmental conditions such as cold or UV stresses, and pathogen attacks. Because they affect the quality of flowers (for horticulture), fruits and vegetables, and their derivatives (colour, aroma, stringency, etc.), flavonoids have a high economic value. Furthermore, these compounds possess pharmaceutical properties extremely attractive for human health. Thanks to easily detectable mutant phenotypes, such as modification of petal pigmentation and seeds exhibiting transparent testa, the enzymes involved in the flavonoid biosynthetic pathway have been characterized in several plant species. Conserved features as well as specific differences have been described. Regulation of structural gene expression appears tightly organized in a spatial and temporal way during plant development, and is orchestrated by a ternary complex involving transcription factors from the R2R3 MYB, basic helix-loop-helix (bHLH), and WD40 classes. This MYB-bHLH-WD40 (MBW) complex regulates the genes that encode enzymes specifically involved in the late steps of the pathway leading to the biosynthesis of anthocyanins and condensed tannins. Although several genes encoding transcription factors from these three families have been identified, many gaps remain in our understanding of the regulation of this biosynthetic pathway, especially about the respective roles of bHLH and WD40 proteins. A better knowledge of the regulatory mechanisms of the flavonoid pathway is likely to favour the development of new biotechnological tools for the generation of value-added plants with optimized flavonoid content. PMID- 21278229 TI - eIF2alpha kinases control chalone production in Dictyostelium discoideum. AB - Growing Dictyostelium cells secrete CfaD and AprA, two proteins that have been characterized as chalones. They exist within a high-molecular-weight complex that reversibly inhibits cell proliferation, but not growth, via cell surface receptors and a signaling pathway that includes G proteins. How the production of these two proteins is regulated is unknown. Dictyostelium cells possess three GCN2-type eukaryotic initiation factor 2 alpha subunit (eIF2alpha) kinases, proteins that phosphorylate the translational initiation factor eIF2alpha and possess a tRNA binding domain involved in their regulation. The Dictyostelium kinases have been shown to function during development in regulating several processes. We show here that expression of an unregulated, activated kinase domain greatly inhibits cell proliferation. The inhibitory effect on proliferation is not due to a general inhibition of translation. Instead, it is due to enhanced production of a secreted factor(s). Indeed, extracellular CfaD and AprA proteins, but not their mRNAs, are overproduced in cells expressing the activated kinase domain. The inhibition of proliferation is not seen when the activated kinase domain is expressed in cells lacking CfaD or AprA or in cells that contain a nonphosphorylatable eIF2alpha. We conclude that production of the chalones CfaD and AprA is translationally regulated by eIF2alpha phosphorylation. Both proteins are upregulated at the culmination of development, and this enhanced production is lacking in a strain that possesses a nonphosphorylatable eIF2alpha. PMID- 21278230 TI - Regulatable Ras activity is critical for proper establishment and maintenance of polarity in Aspergillus fumigatus. AB - Here we show that expression of a constitutively activated RasA allele, as the sole source of Ras activity, revealed novel Ras-induced phenotypes, including excessive vacuolar expansion and spontaneous lysis of hyphal compartments. These findings highlight the requirement for balanced Ras activity in the establishment and maintenance of polarized growth in filamentous fungi. PMID- 21278231 TI - Role of the Npr1 kinase in ammonium transport and signaling by the ammonium permease Mep2 in Candida albicans. AB - The ammonium permease Mep2 induces a switch from unicellular yeast to filamentous growth in response to nitrogen limitation in Saccharomyces cerevisiae and Candida albicans. In S. cerevisiae, the function of Mep2 and other ammonium permeases depends on the protein kinase Npr1. Mutants lacking NPR1 cannot grow on low concentrations of ammonium and do not filament under limiting nitrogen conditions. A G349C mutation in Mep2 renders the protein independent of Npr1 and results in increased ammonium transport and hyperfilamentous growth, suggesting that the signaling activity of Mep2 directly correlates with its ammonium transport activity. In this study, we investigated the role of Npr1 in ammonium transport and Mep2-mediated filamentation in C. albicans. We found that the two ammonium permeases Mep1 and Mep2 of C. albicans differ in their dependency on Npr1. While Mep1 could function well in the absence of the Npr1 kinase, ammonium transport by Mep2 was virtually abolished in npr1Delta mutants. However, the dependence of Mep2 activity on Npr1 was relieved at higher temperatures (37 degrees C), and Mep2 could efficiently induce filamentous growth under limiting nitrogen conditions in npr1Delta mutants. Like in S. cerevisiae, mutation of the conserved glycine at position 343 in Mep2 of C. albicans to cysteine resulted in Npr1-independent ammonium uptake. In striking contrast, however, the mutation abolished the ability of Mep2 to induce filamentous growth both in the wild type and in npr1Delta mutants. Therefore, a mutation that improves ammonium transport by Mep2 under nonpermissible conditions eliminates its signaling activity in C. albicans. PMID- 21278232 TI - A common mechanism links differently acting complex II inhibitors to cardioprotection: modulation of mitochondrial reactive oxygen species production. AB - In this study, we have analyzed the effect of different cardioprotective complex II inhibitors on the mitochondrial production of reactive oxygen species (ROS) because ROS seem to be essential for signaling during preconditioning to prevent ischemia/reperfusion injury. Despite different binding sites and concentrations required for half-maximal inhibition-ranging from nanomolar for the Q site inhibitor atpenin A5 to millimolar for the succinate analog malonate-all inhibitors modulated ROS production in the same ambivalent fashion: they promoted the generation of superoxide at the Q(o) site of complex III under conditions of "oxidant-induced reduction" but attenuated ROS generated at complex I due to reverse electron transfer. All inhibitors showed these ambivalent effects independent of the presence of K(+). These findings suggest a direct modulation of mitochondrial ROS generation during cardioprotection via complex II inhibition and question the recently proposed role of complex II as a regulatory component of the putative mitochondrial K(ATP) channel. PMID- 21278233 TI - Involvement of caveolin in probucol-induced reduction in hERG plasma-membrane expression. AB - The human ether-a-go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier K(+) current (I(Kr)) important for cardiac repolarization. Dysfunction of the hERG channel causes long QT syndrome (LQTS). Although diverse compounds reduce the hERG current (I(hERG)) by blocking the channel, probucol, a cholesterol-lowering drug that causes LQTS, reduces I(hERG) by decreasing plasma-membrane hERG protein expression. Here, we investigated the mechanisms of probucol effects on hERG expression levels. Our data demonstrate that probucol accelerated the degradation of mature hERG channels, which associated with caveolin-1 (Cav1) in hERG-expressing HEK cells. In human embryonic kidney (HEK) cells without hERG expression, probucol promoted endogenous Cav1 degradation. In hERG-expressing HEK cells, overexpression of Cav1 enhanced, whereas knockdown of Cav1 impeded, probucol-induced reduction of mature hERG channels. Thus, probucol reduces hERG expression through accelerating Cav1 turnover. The effects of probucol on Cav1 and hERG result from probucol's cholesterol-disrupting action, because low-density lipoprotein (LDL), a potent cholesterol carrier, effectively prevented probucol-induced reduction of I(hERG) in hERG-expressing HEK cells and of I(Kr) in neonatal rat cardiomyocytes. Our data provide evidence that targeting hERG-interacting protein caveolin represents a novel mechanism for drugs to decrease hERG expression and cause LQTS. PMID- 21278234 TI - Pivotal advance: CD45RB glycosylation is specifically regulated during human peripheral B cell differentiation. AB - A screen of cell surface markers differentially expressed during peripheral B cell differentiation identified that the CD45RB epitope detected by the mAb MEM 55 was highly expressed on CD27(+) memory B cells and absent on CD27(-) naive B cells. IgG(+)CD27(-) memory and a previously unacknowledged CD27(-) population in blood also expressed high levels of CD45RB(MEM55). Naive and memory B cells from tonsils followed the pattern observed in blood, and CD38(high) B cells had a bimodal expression pattern when analyzed using flow cytometry. No CD38(high) GC B cells, however, expressed the CD45RB(MEM55) epitope when assayed using immunohistochemistry. Rather, CD38(high)CD45RB(MEM55high) B cells had a distinct cellular phenotype and were localized outside of GCs. CD45RB epitopes, detected by other antibody clones, were expressed at high levels through B cell differentiation, and no changes in splicing of the CD45RB exon were observed during B cell differentiation. Instead, B cells regulated their expression of the CD45RB(MEM55) epitope through site-specific modifications of an O-linked glycochain. CD4(+) T cells differentially spliced CD45 but did not vary the glycosylation of the CD45RB(MEM55) epitope, and CD8(+) cells modified CD45RB(MEM55) expression in a similar manner as B cells. Monocytes expressed the CD45RB exon but not the CD45RB(MEM55) epitope. As CD45 is a highly expressed tyrosine phosphatase that regulates antigen receptor signaling strength in lymphocytes, we conclude that regulated O-linked glycosylation of CD45RB can be used to follow B cell differentiation and that this regulation may be involved in fine-tuning antigen signaling in the cell. PMID- 21278235 TI - Suppression of glucosylceramide synthase restores p53-dependent apoptosis in mutant p53 cancer cells. AB - Tumor suppressor p53 plays an essential role in protecting cells from malignant transformation by inducing cell-cycle arrest and apoptosis. Mutant p53 that is detected in more than 50% of cases of cancers loses its role in suppression of tumors but gains in oncogenic function. Strategies to convert mutant p53 into wild-type p53 have been suggested for cancer prevention and treatment, but they face a variety of challenges. Here, we report an alternative approach that involves suppression of glucosylceramide synthase (GCS), an enzyme that glycosylates ceramide and blunts its proapoptotic activity in cancer cells. Human ovarian cancer cells expressing mutant p53 displayed resistance to apoptosis induced by DNA damage. We found that GCS silencing sensitized these mutant p53 cells to doxorubicin but did not affect the sensitivity of cells with wild-type p53. GCS silencing increased the levels of phosphorylated p53 and p53-responsive genes, including p21(Waf1/Cip1), Bax, and Puma, consistent with a redirection of the mutant p53 cells to apoptosis. Reactivated p53-dependent apoptosis was similarly verified in p53-mutant tumors where GCS was silenced. Inhibition of ceramide synthase with fumonisin B1 prevented p53 reactivation induced by GCS silencing, whereas addition of exogenous C6-ceramide reactivated p53 function in p53-mutant cells. Our findings indicate that restoring active ceramide to cells can resuscitate wild-type p53 function in p53-mutant cells, offering preclinical support for a novel type of mechanism-based therapy in the many human cancers harboring p53 mutations. PMID- 21278236 TI - Identification of a tumor suppressor relay between the FOXP3 and the Hippo pathways in breast and prostate cancers. AB - Defective expression of LATS2, a negative regulator of YAP oncoprotein, has been reported in cancer of prostate, breast, liver, brain, and blood origins. However, no transcriptional regulators for the LATS2 gene have been identified. Here we report that spontaneous mutation of the transcription factor FOXP3 reduces expression of the LATS2 gene in mammary epithelial cells. shRNA-mediated silencing of FOXP3 in normal or malignant mammary epithelial cells of mouse and human origin repressed LATS2 expression and increased YAP protein levels. LATS2 induction required binding of FOXP3 to a specific sequence in the LATS2 promoter, and this interaction contributed to FOXP3-mediated growth inhibition of tumor cells. In support of these results, reduced expression and somatic mutations of FOXP3 correlated strongly with defective LATS2 expression in microdissected prostate cancer tissues. Thus, defective expression of LATS2 is attributable to FOXP3 defects and may be a major independent determinant of YAP protein elevation in cancer. Our findings identify a novel mechanism of LATS2 downregulation in cancer and reveal an important tumor suppressor relay between the FOXP3 and HIPPO pathways which are widely implicated in human cancer. PMID- 21278237 TI - NRF2 blockade suppresses colon tumor angiogenesis by inhibiting hypoxia-induced activation of HIF-1alpha. AB - Transcription factor NRF2 is an important modifier of cellular responses to oxidative stress. Although its cytoprotective effects are firmly established, recent evidence suggesting important roles in cancer pathobiology has yet to be mechanistically developed. In the current study, we investigated the role of NRF2 in colon tumor angiogenesis. Stable RNAi-mediated knockdown of NRF2 in human colon cancer cells suppressed tumor growth in mouse xenograft settings with a concomitant reduction in blood vessel formation and VEGF expression. Similar antiangiogenic effects of NRF2 knockdown were documented in chick chorioallantoic membrane assays and endothelial tube formation assays. Notably, NRF2-inhibited cancer cells failed to accumulate HIF-1alpha protein under hypoxic conditions, limiting expression of VEGF and other HIF-1alpha target genes. In these cells, HIF-1alpha was hydroxylated but pharmacological inhibition of PHD domain containing prolyl hydroxylases was sufficient to restore hypoxia-induced accumulation of HIF-1alpha. Mechanistic investigations demonstrated that reduced mitochondrial O(2) consumption in NRF2-inhibited cells was probably responsible for HIF-1alpha degradation during hypoxia; cellular O(2) consumption and ATP production were lower in NRF2 knockdown cells than in control cells. Our findings offer novel insights into how cellular responses to O(2) and oxidative stress are integrated in cancer cells, and they highlight NRF2 as a candidate molecular target to control tumor angiogenesis by imposing a blockade to HIF-1alpha signaling. PMID- 21278238 TI - Joint hypermobility syndrome: A common clinical disorder associated with migraine in women. AB - Preliminary studies suggested that headache disorders are more common in patients with joint hypermobility syndrome (JHS). The objectives of this study were to determine if the prevalence, frequency, and disability of migraine differ between female patients with JHS and a control population. Twenty-eight patients with JHS and 232 controls participated in the case-cohort study. Participants underwent a structured verbal interview and were assigned a diagnosis of migraine based on criteria of the International Classification of Headache Disorders, 2nd Edition. The primary outcome measures were the prevalence, frequency, and headache-related disability of migraine. Logistic regression was used for the prevalence analysis and Poisson regression for the frequency and disability analyses. Results indicated that the prevalence of migraine was 75% in JHS patients and 43% in controls. The adjusted odds ratio for the prevalence of migraine was 3.19 (95% CI 1.24, 8.21] in JHS patients. The rate ratios for migraine frequency and headache related disability were 1.67 (95% CI 1.01, 2.76) and 2.99 (95% CI 1.66, 5.38), respectively, for JHS patients. Our study suggests that JHS is a clinical disorder strongly associated with an increased prevalence, frequency, and disability of migraine in females. PMID- 21278239 TI - Clinical profile of cluster headaches in Japan: low prevalence of chronic cluster headache, and uncoupling of sense and behaviour of restlessness. AB - INTRODUCTION: This study examined the clinical profile of cluster headaches in Japan and the potential presence of features peculiar to Japan. Most previous studies of cluster headaches have focused on Caucasian populations. METHODS: Subjects comprised 86 consecutive new cluster headache patients (68 males, 18 females; mean age, 38.4 +/- 12.2 years; range, 17-73 years). Mean age at onset was 31.0 years and the ratio of males to females was 3.8:1. RESULTS: Chronic cluster headache was observed in 3.5% of patients. More than half of patients (68.9%) reported feelings of restlessness during headache episodes and 42.9% reported restless behaviour. Patients with uncoupling of feelings of restlessness and restless behaviour forced themselves to keep still. Similar findings were reported in a Taiwanese study. CONCLUSION: Japanese patients in this study showed a relatively low prevalence of chronic cluster headaches, and uncoupling of a sense of restlessness and restless behaviour. These features of cluster headache may be more common in Japanese and Taiwanese patients than in Caucasian patients. PMID- 21278240 TI - Further on menstrual paroxysmal hemicrania. PMID- 21278241 TI - Lack of correlation between vasodilatation and pharmacologically induced immediate headache in healthy subjects. AB - BACKGROUND: The causal relationship between experimental headache and vasodilatation has not been fully clarified. In the present study, we combined headache and vascular data from eight experimental studies and conducted detailed statistical analyses. Given that substances used in all these experiments were vasodilators we examined a possible correlation between headache scores and increases in arterial diameter. METHODS: We identified nine studies and retrieved raw data in 89 healthy subjects (46 females, 43 males), mean age 27 years (range 18-59 years). The following variables were collected: maximal median headache intensity scores on a verbal rating scale (VRS) during immediate headache (0-120 minutes); the mean velocity of blood flow in the middle cerebral artery (V(meanMCA)); and the diameter of the frontal branch of the superficial temporal artery (STA) during the maximal median headache intensity. RESULTS: The scatter plots show no relationship between maximal headache score and the relative changes in V(meanMCA) and diameter of the STA. The main analyses of covariance showed a significant effect only of heart rate on headache (p = .014). The interaction tests were insignificant for all variables. CONCLUSIONS: The major outcome is a finding of no linear relationship between experimental immediate headache and dilatation of the MCA or STA. PMID- 21278242 TI - A phase I study of the heat shock protein 90 inhibitor alvespimycin (17-DMAG) given intravenously to patients with advanced solid tumors. AB - PURPOSE: A phase I study to define toxicity and recommend a phase II dose of the HSP90 inhibitor alvespimycin (17-DMAG; 17-dimethylaminoethylamino-17 demethoxygeldanamycin). Secondary endpoints included evaluation of pharmacokinetic profile, tumor response, and definition of a biologically effective dose (BED). PATIENTS AND METHODS: Patients with advanced solid cancers were treated with weekly, intravenous (i.v.) 17-DMAG. An accelerated titration dose escalation design was used. The maximum tolerated dose (MTD) was the highest dose at which <= 1/6 patients experienced dose limiting toxicity (DLT). Dose de escalation from the MTD was planned with mandatory, sequential tumor biopsies to determine a BED. Pharmacokinetic and pharmacodynamic assays were validated prior to patient accrual. RESULTS: Twenty-five patients received 17-DMAG (range 2.5-106 mg/m(2)). At 106 mg/m(2) of 17-DMAG 2/4 patients experienced DLT, including one treatment-related death. No DLT occurred at 80 mg/m(2). Common adverse events were gastrointestinal, liver function changes, and ocular. Area under the curve and mean peak concentration increased proportionally with 17-DMAG doses 80 mg/m(2) or less. In peripheral blood mononuclear cells significant (P < 0.05) HSP72 induction was detected (>= 20 mg/m(2)) and sustained for 96 hours (>= 40 mg/m(2)). Plasma HSP72 levels were greatest in the two patients who experienced DLT. At 80 mg/m(2) client protein (CDK4, LCK) depletion was detected and tumor samples from 3 of 5 patients confirmed HSP90 inhibition. Clinical activity included complete response (castration refractory prostate cancer, CRPC 124 weeks), partial response (melanoma, 159 weeks), and stable disease (chondrosarcoma, CRPC, and renal cancer for 28, 59, and 76 weeks, respectively). CONCLUSIONS: The recommended phase II dose of 17-DMAG is 80 mg/m(2) weekly i.v. PMID- 21278243 TI - ERCC1 and ERCC2 polymorphisms predict clinical outcomes of oxaliplatin-based chemotherapies in gastric and colorectal cancer: a systemic review and meta analysis. AB - PURPOSE: Nucleotide excision repair (NER) modulates platinum-based chemotherapeutic efficacy by removing drug-produced DNA damage. To summarize published data on the association between polymorphisms of NER genes (ERCC1 and ERCC2) and responses to oxaliplatin-based chemotherapies, we carried out a meta analysis of gastric and colorectal cancer for commonly studied polymorphisms ERCC1 rs11615C>T and ERCC2 rs13181T>G. PATIENTS AND METHODS: In 17 previously published studies, 1,787 cancer patients were treated with the oxaliplatin-based regimen. Primary outcomes included therapeutic response (TR; i.e., complete response + partial response vs. stable disease + progressive disease), progression-free survival (PFS), and overall survival (OS). We calculated OR or HR with 95% CIs to estimate the risk or hazard. RESULTS: We found consistent and clinically substantial risk or hazard for TR, PFS, and OS in the oxaliplatin treated gastric and colorectal cancer patients with an ethnic discrepancy. For ERCC1 rs11615C>T, the T allele was associated with reduced response and poor PFS and OS in Asians (TR: OR = 0.53 and 95% CI = 0.35-0.81; PFS: HR = 1.69 and 95% CI = 1.05-2.70; and OS: HR = 2.03 and 95% CI = 1.60-2.59). For ERCC2 rs13181T>G, the G allele was associated with reduced response and poor PFS and OS in Caucasians (TR: OR = 0.56 and 95% CI = 0.35-0.88; PFS: HR = 1.41 and 95% CI = 1.02-1.95; and OS: HR = 1.42 and 95% CI = 1.11-1.81). CONCLUSIONS: NER ERCC1 rs11615C>T and ERCC2 rs13181T>G polymorphisms are useful prognostic factors in oxaliplatin-based treatment of gastric and colorectal cancer. Larger studies and further clinical trials are warranted to confirm these findings. PMID- 21278244 TI - TGF-beta blockade controls ascites by preventing abnormalization of lymphatic vessels in orthotopic human ovarian carcinoma models. AB - PURPOSE: Ovarian cancer patients with malignant ascites have poor prognosis. The accumulation of ascites is caused by an imbalance between fluid extravasation from the blood vessels and reabsorption by lymphatic vessels. Whereas, the role of TGF-beta in tumor progression has been well studied, the role of TGF-beta in lymphatic vessel function is far from understood. Here, we sought to dissect the role of TGF-beta blockade in the formation of ascites. EXPERIMENTAL DESIGN: We used soluble TGF-beta Receptor II (sTbetaRII) to block TGF-beta signaling in two orthotopic human ovarian carcinoma models: SKOV3ip1 and Hey-A8. We measured tumor proliferation, apoptosis, lymphangiogenesis, and angiogenesis by immunohistochemical staining, and examined diaphragm lymphatic vessel network by intraperitoneal injection of a fluorescent dye. Diaphragm lymphatic vessel function was assessed by tracking fluorescent beads in the diaphragm and measuring their drainage rate. RESULTS: TGF-beta blockade impaired tumor growth in both models, accompanied by a decreased tumor cell proliferation and angiogenesis. More strikingly, TGF-beta blockade almost completely abolished ascites formation. TGF-beta blockade significantly inhibited the expression of VEGF, which is the major contributor to ascites formation. At the same time, TGF beta blockade prevent 'abnormalization' of diaphragm lymphatic vessels and improved ascites drainage. CONCLUSIONS: TGF-beta blockade decreased ascites by both inhibiting ascites formation and improving ascites drainage. Based on our finding, it is reasonable to consider the use of TGF-beta blockade as a palliative treatment for symptomatic ascites. PMID- 21278245 TI - Phase I study of decitabine in combination with vorinostat in patients with advanced solid tumors and non-Hodgkin's lymphomas. AB - PURPOSE: This phase I study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the combination of decitabine with vorinostat. PATIENTS AND METHODS: Patients with advanced solid tumors or non-Hodgkin's lymphomas were eligible. Sequential and concurrent schedules were studied. RESULTS: Forty-three patients were studied in 9 different dose levels (6 sequential and 3 concurrent). The maximum tolerated dose (MTD) on the sequential schedule was decitabine 10 mg/m(2)/day on days 1 to 5 and vorinostat 200 mg three times a day on days 6 to 12. The MTD on the concurrent schedule was decitabine 10 mg/m(2)/day on days 1 to 5 with vorinostat 200 mg twice a day on days 3 to 9. However, the sequential schedule of decitabine 10 mg/m(2)/day on days 1 to 5 and vorinostat 200 mg twice a day on days 6 to 12 was more deliverable than both MTDs with fewer delays on repeated dosing and it represents the recommended phase II (RP2D) dose of this combination. Dose-limiting toxicities during the first cycle consisted of myelosuppression, constitutional and gastrointestinal symptoms and occurred in 12 of 42 (29%) patients evaluable for toxicity. The most common grade 3 or higher adverse events were neutropenia (49% of patients), thrombocytopenia (16%), fatigue (16%), lymphopenia (14%), and febrile neutropenia (7%). Disease stabilization for 4 cycles or more was observed in 11 of 38 (29%) evaluable patients. CONCLUSION: The combination of decitabine with vorinostat is tolerable on both concurrent and sequential schedules in previously treated patients with advanced solid tumors or non-Hodgkin's lymphomas. The sequential schedule was easier to deliver. The combination showed activity with prolonged disease stabilization in different tumor types. PMID- 21278246 TI - Expression of p16 and retinoblastoma determines response to CDK4/6 inhibition in ovarian cancer. AB - PURPOSE: PD-0332991 is a selective inhibitor of the CDK4/6 kinases with the ability to block retinoblastoma (Rb) phosphorylation in the low nanomolar range. Here we investigate the role of CDK4/6 inhibition in human ovarian cancer. EXPERIMENTAL DESIGN: We examined the effects of PD-0332991 on proliferation, cell cycle, apoptosis, and Rb phosphorylation using a panel of 40 established human ovarian cancer cell lines. Molecular markers for response prediction, including p16 and Rb, were studied using gene expression profiling, Western blot, and array CGH. Multiple drug effect analysis was used to study interactions with chemotherapeutic drugs. Expression of p16 and Rb was studied using immunohistochemistry in a large clinical cohort of ovarian cancer patients. RESULTS: Concentration-dependent antiproliferative effects of PD-0332991 were seen in all ovarian cancer cell lines, but varied significantly between individual lines. Rb-proficient cell lines with low p16 expression were most responsive to CDK4/6 inhibition. Copy number variations of CDKN2A, RB, CCNE1, and CCND1 were associated with response to PD-0332991. CDK4/6 inhibition induced G0/G1 cell cycle arrest, blocked Rb phosphorylation in a concentration-and time dependent manner, and enhanced the effects of chemotherapy. Rb-proficiency with low p16 expression was seen in 97/262 (37%) of ovarian cancer patients and was independently associated with poor progression-free survival (adjusted relative risk 1.49, 95% CI 1.00-2.24, P = 0.052). CONCLUSIONS: PD-0332991 shows promising biologic activity in ovarian cancer cell lines. Assessment of Rb and p16 expression may help select patients most likely to benefit from CDK4/6 inhibition in ovarian cancer. PMID- 21278247 TI - Genomic and epigenomic integration identifies a prognostic signature in colon cancer. AB - PURPOSE: The importance of genetic and epigenetic alterations maybe in their aggregate role in altering core pathways in tumorigenesis. EXPERIMENTAL DESIGN: Merging genome-wide genomic and epigenomic alterations, we identify key genes and pathways altered in colorectal cancers (CRC). DNA methylation analysis was tested for predicting survival in CRC patients using Cox proportional hazard model. RESULTS: We identified 29 low frequency-mutated genes that are also inactivated by epigenetic mechanisms in CRC. Pathway analysis showed the extracellular matrix (ECM) remodeling pathway is silenced in CRC. Six ECM pathway genes were tested for their prognostic potential in large CRC cohorts (n = 777). DNA methylation of IGFBP3 and EVL predicted for poor survival (IGFBP3: HR = 2.58, 95% CI: 1.37-4.87, P = 0.004; EVL: HR = 2.48, 95% CI: 1.07-5.74, P = 0.034) and simultaneous methylation of multiple genes predicted significantly worse survival (HR = 8.61, 95% CI: 2.16-34.36, P < 0.001 for methylation of IGFBP3, EVL, CD109, and FLNC). DNA methylation of IGFBP3 and EVL was validated as a prognostic marker in an independent contemporary-matched cohort (IGFBP3 HR = 2.06, 95% CI: 1.04-4.09, P = 0.038; EVL HR = 2.23, 95% CI: 1.00-5.0, P = 0.05) and EVL DNA methylation remained significant in a secondary historical validation cohort (HR = 1.41, 95% CI: 1.05-1.89, P = 0.022). Moreover, DNA methylation of selected ECM genes helps to stratify the high-risk stage 2 colon cancers patients who would benefit from adjuvant chemotherapy (HR: 5.85, 95% CI: 2.03-16.83, P = 0.001 for simultaneous methylation of IGFBP3, EVL, and CD109). CONCLUSIONS: CRC that have silenced genes in ECM pathway components show worse survival suggesting that our finding provides novel prognostic biomarkers for CRC and reflects the high importance of integrative analyses linking genetic and epigenetic abnormalities with pathway disruption in cancer. PMID- 21278248 TI - What is the best predictor of the atherogenic LDL subclass phenotype 'pattern B' in patients with type 2 diabetes mellitus? AB - BACKGROUND: The atherogenic lipoprotein phenotype 'pattern B' comprises a predominance of small-dense low-density lipoprotein (sdLDL). Gradient gel electrophoresis (GGE) is considered a 'gold standard' method for identifying this phenotype, but is impractical for routine laboratory use. The low-density lipoprotein cholesterol:apolipoprotein-B (LDL-C:Apo-B) ratio has been advocated as a surrogate marker for sdLDL and a direct assay for sdLDL has recently become available. We compared the sdLDL assay and LDL-C:Apo-B with more established lipid parameters to predict the presence of 'pattern B' phenotype. METHOD: Blood was collected from 97 fasted subjects on three separate occasions. Total cholesterol, triglyceride, Apo-B and sdLDL were measured; LDL- and HDL cholesterol were determined after ultracentrifugation. The predominant LDL particle size and phenotype were assigned by GGE. RESULTS: 'Pattern B' phenotype was identified in 36% of samples. Peak particle size showed a positive correlation with HDL-cholesterol and a negative correlation with triglyceride and Apo-B. Receiver operating curve (ROC) analysis showed triglyceride:HDL-C ratio and triglyceride alone to be the best predictors of 'pattern B' phenotype, with area under the curve (AUC) being 0.87 and 0.84, respectively. AUCs for sdLDL (0.74) and LDL-C:Apo-B (0.71) were significantly lower (P < 0.05). A high sdLDL concentration had the greatest specificity (95%) and positive predictive value (74%) for 'pattern B' phenotype, but low sensitivity (43%). CONCLUSION: Direct measurement of sdLDL provided the most specific predictor of 'pattern B' phenotype, whereas triglyceride:HDL-C ratio or triglycerides alone, parameters readily available in most laboratories, were the best predictors by ROC analysis. PMID- 21278249 TI - Polyubiquitin linkage profiles in three models of proteolytic stress suggest the etiology of Alzheimer disease. AB - Polyubiquitin chains on substrates are assembled through any of seven lysine residues or the N terminus of ubiquitin (Ub), generating diverse linkages in the chain structure. PolyUb linkages regulate the fate of modified substrates, but their abundance and function in mammalian cells are not well studied. We present a mass spectrometry-based method to measure polyUb linkages directly from total lysate of mammalian cells. In HEK293 cells, the level of polyUb linkages was found to be 52% (Lys(48)), 38% (Lys(63)), 8% (Lys(29)), 2% (Lys(11)), and 0.5% or less for linear, Lys(6), Lys(27), and Lys(33) linkages. Tissue specificity of these linkages was examined in mice fully labeled by heavy stable isotopes (i.e. SILAC mice). Moreover, we profiled the Ub linkages in brain tissues from patients of Alzheimer disease with or without concurrent Lewy body disease as well as three cellular models of proteolytic stress: proteasome deficiency, lysosome deficiency, and heat shock. The data support that polyUb chains linked through Lys(6), Lys(11), Lys(27), Lys(29), and Lys(48) mediate proteasomal degradation, whereas Lys(63) chains are preferentially involved in the lysosomal pathway. Mixed linkages, including Lys(48), may also contribute to lysosomal targeting, as both Lys(63) and Lys(48) linkages are colocalized in LC3-labeled autophagosomes. Interestingly, heat shock treatment augments Lys(11), Lys(48), and Lys(63) but not Lys(29) linkages, and this unique pattern is similar to that in the profiled neurodegenerative cases. We conclude that different polyUb linkages play distinct roles under the three proteolytic stress conditions, and protein folding capacity in the heat shock responsive pathway might be more affected in Alzheimer disease. PMID- 21278250 TI - P-glycoprotein retains drug-stimulated ATPase activity upon covalent linkage of the two nucleotide binding domains at their C-terminal ends. AB - P-glycoprotein (Pgp), a member of the ABC transporter family, functions as an ATP hydrolysis-driven efflux pump to rid the cell of toxic organic compounds, including a variety of drugs used in anti-cancer chemotherapy. We have recently obtained EM projection images of lipid-bound Pgp without nucleotide and transport substrate that showed the two halves of the transporter separated by a central cavity (Lee, J. Y., Urbatsch, I. L., Senior, A. E., and Wilkens, S. (2002) J. Biol. Chem. 277, 40125-40131). Addition of nucleotide and/or substrate lead to a close association of the two halves of the transporter, thereby closing the central cavity (Lee, J. Y., Urbatsch, I. L., Senior, A. E., and Wilkens, S. (2008) J. Biol. Chem. 283, 5769-5779). Here, we used cysteine-mediated disulfide cross-linking to further delineate the structural rearrangements of the two nucleotide binding domains (NBD1 and NBD2) that take place during catalysis. Cysteines introduced at or near the C-terminal ends of NBD1 and NBD2 allowed for spontaneous disulfide cross-linking under nonreducing conditions. For mutant A627C/S1276C, disulfide formation was with high efficiency and cross-linked Pgp retained 30-68% drug-stimulated ATPase activity compared with reduced or cysteine less Pgp. Two other cysteine pairs (K615C/S1276C and A627C/K1260C) also formed a disulfide but to a lesser extent, and the cross-linked form of these two mutants had lower drug-stimulated ATPase activity. The data suggest that the C-terminal ends of the two NBDs of Pgp are not required to undergo significant motion with respect to one another during the catalytic cycle. PMID- 21278251 TI - Plant homeodomain (PHD) fingers of CHD4 are histone H3-binding modules with preference for unmodified H3K4 and methylated H3K9. AB - A major challenge in chromatin biology is to understand the mechanisms by which chromatin is remodeled into active or inactive states as required during development and cell differentiation. One complex implicated in these processes is the nucleosome remodeling and histone deacetylase (NuRD) complex, which contains both histone deacetylase and nucleosome remodeling activities and has been implicated in the silencing of subsets of genes involved in various stages of cellular development. Chromodomain-helicase-DNA-binding protein 4 (CHD4) is a core component of the NuRD complex and contains a nucleosome remodeling ATPase domain along with two chromodomains and two plant homeodomain (PHD) fingers. We have previously demonstrated that the second PHD finger of CHD4 binds peptides corresponding to the N terminus of histone H3 methylated at Lys(9). Here, we determine the solution structure of PHD2 in complex with H3K9me3, revealing the molecular basis of histone recognition, including a cation-pi recognition mechanism for methylated Lys(9). Additionally, we demonstrate that the first PHD finger also exhibits binding to the N terminus of H3, and we establish the histone-binding surface of this domain. This is the first instance where histone binding ability has been demonstrated for two separate PHD modules within the one protein. These findings suggest that CHD4 could bind to two H3 N-terminal tails on the same nucleosome or on two separate nucleosomes simultaneously, presenting exciting implications for the mechanism by which CHD4 and the NuRD complex could direct chromatin remodeling. PMID- 21278252 TI - The syntaxin 4 N terminus regulates its basolateral targeting by munc18c dependent and -independent mechanisms. AB - To generate and maintain epithelial cell polarity, specific sorting of proteins into vesicles destined for the apical and basolateral domain is required. Syntaxin 3 and 4 are apical and basolateral SNARE proteins important for the specificity of vesicle fusion at the apical and basolateral plasma membrane domains, respectively, but how these proteins are specifically targeted to these domains themselves is unclear. Munc18/SM proteins are potential regulators of this process. Like syntaxins, they are crucial for exocytosis and vesicle fusion. However, how munc18c and syntaxin 4 regulate the function of each other is unclear. Here, we investigated the requirement of syntaxin 4 in the delivery of basolateral membrane and secretory proteins, the basolateral targeting of syntaxin 4, and the role of munc18c in this targeting. Depletion of syntaxin 4 resulted in significant reduction of basolateral targeting, suggesting no compensation by other syntaxin forms. Mutational analysis identified amino acids Leu-25 and to a lesser extent Val-26 as essential for correct localization of syntaxin 4. Recently, it was shown that the N-terminal peptide of syntaxin 4 is involved in binding to munc18c. A mutation in this region that affects munc18c binding shows that munc18c binding is required for stabilization of syntaxin 4 at the plasma membrane but not for its correct targeting. We conclude that the N terminus serves two functions in membrane targeting. First, it harbors the sorting motif, which targets syntaxin 4 basolaterally in a munc18c-independent manner and second, it allows for munc18c binding, which stabilizes the protein in a munc18c-dependent manner. PMID- 21278253 TI - Transient receptor potential melastatin 1 (TRPM1) is an ion-conducting plasma membrane channel inhibited by zinc ions. AB - TRPM1 is the founding member of the melastatin subgroup of transient receptor potential (TRP) proteins, but it has not yet been firmly established that TRPM1 proteins form ion channels. Consequently, the biophysical and pharmacological properties of these proteins are largely unknown. Here we show that heterologous expression of TRPM1 proteins induces ionic conductances that can be activated by extracellular steroid application. However the current amplitudes observed were too small to enable a reliable biophysical characterization. We overcame this limitation by modifying TRPM1 channels in several independent ways that increased the similarity to the closely related TRPM3 channels. The resulting constructs produced considerably larger currents after overexpression. We also demonstrate that unmodified TRPM1 and TRPM3 proteins form functional heteromultimeric channels. With these approaches, we measured the divalent permeability profile and found that channels containing the pore of TRPM1 are inhibited by extracellular zinc ions at physiological concentrations, in contrast to channels containing only the pore of TRPM3. Applying these findings to pancreatic beta cells, we found that TRPM1 proteins do not play a major role in steroid-activated currents of these cells. The inhibition of TRPM1 by zinc ions is primarily due to a short stretch of seven amino acids present only in the pore region of TRPM1 but not of TRPM3. Combined, our data demonstrate that TRPM1 proteins are bona fide ion-conducting plasma membrane channels. Their distinct biophysical properties allow a reliable identification of endogenous TRPM1-mediated currents. PMID- 21278254 TI - IL-6 increases MMP-13 expression and motility in human chondrosarcoma cells. AB - Chondrosarcoma is a type of highly malignant tumor with a potent capacity to invade locally and cause distant metastasis. Chondrosarcoma shows a predilection for metastasis to the lungs. IL-6 is a multifunctional cytokine that is associated with the disease status and outcomes of cancers. However, the effect of IL-6 on the migration activity of human chondrosarcoma cells is mostly unknown. Here, we found that IL-6 increased the migration and expression of MMP 13 in human chondrosarcoma cells. We also found that human chondrosarcoma tissues had significant expression of IL-6, which was higher than that in normal cartilage. IL-6-mediated migration and MMP-13 up-regulation were attenuated by anti-IL-6 receptor antibody, Ras, Raf-1, and a MEK inhibitor. Activation of the Ras, Raf-1, MEK, ERK, and NF-kappaB signaling pathways after IL-6 treatment was demonstrated, and IL-6-induced MMP-13 expression and migration activity were inhibited by the specific inhibitor and mutant Ras, Raf-1, MEK, ERK, and NF kappaB cascades. In addition, migration-prone sublines demonstrated that cells with increasing migration ability had greater expression of IL-6 and MMP-13. Taken together, these results indicate that IL-6 and IL-6 receptor interaction enhances migration of chondrosarcoma through an increase in MMP-13 production. PMID- 21278255 TI - Antimicrobial activity of community-associated methicillin-resistant Staphylococcus aureus is caused by phenol-soluble modulin derivatives. AB - Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) are causing an ongoing pandemic of mostly skin and soft tissue infections. The success of CA-MRSA as pathogens is due to a combination of antibiotic resistance with high virulence. In addition, it has been speculated that CA-MRSA strains such as the epidemic U.S. clone USA300 have increased capacity to colonize human epithelia, owing to bacteriocin-based bacterial interference. We here analyzed the molecular basis of antimicrobial activity detected in S. aureus strains, including those of the USA300 lineage. In contrast to a previous hypothesis, we found that this activity is not due to expression of a lantibiotic-type bacteriocin, but proteolytically processed derivatives of the phenol-soluble modulin (PSM) peptides PSMalpha1 and PSMalpha2. Notably, processed PSMalpha1 and PSMalpha2 exhibited considerable activity against Streptococcus pyogenes, indicating a role of PSMs in the interference of S. aureus strains with the competing colonizing pathogen. Furthermore, by offering a competitive advantage during colonization of the human body, the characteristically high production of PSMs in USA300 and other CA-MRSA strains may thus contribute not only to virulence but also the exceptional capacity of those strains to sustainably spread in the population, which so far has remained poorly understood. PMID- 21278257 TI - Enforced N-domain proximity stimulates Hsp90 ATPase activity and is compatible with function in vivo. AB - Hsp90 populates distinct open and closed conformations mediated by transient N terminal dimerization. To investigate the mechanistic role of these large conformational changes, we designed Hsp90 with an N-terminal coiled-coil to clamp the termini together and enforce N-domain proximity. Biophysical analyses demonstrate that the coiled-coil effectively maintains N-domain proximity in the absence of ATP, a condition that favors the open state of Hsp90. Enforcing N domain proximity results in increased ATPase activity, indicating that N-terminal dimerization is a rate-limiting step that is sped-up with the coiled-coil due to increased effective N-domain concentration. The relative difference in ATPase activity between coil-Hsp90 and wt was reduced in the presence of both an ATPase activating (Aha1) and an inhibiting (Sba1) co-chaperone. As both of these co chaperones bind preferentially to N-terminally dimerized Hsp90, the buffering effect of these co-chaperones demonstrates the biochemical relevance of Hsp90 conformational properties in addition to N-terminal dimerization. Enforcing N domain proximity is compatible with viability in yeast, underlining the mechanistic relevance of Hsp90 conformational changes that are less dramatic than the transition between fully open and closed. PMID- 21278256 TI - Klebsiella pneumoniae outer membrane protein A is required to prevent the activation of airway epithelial cells. AB - Outer membrane protein A (OmpA) is a class of proteins highly conserved among the Enterobacteriaceae family and throughout evolution. Klebsiella pneumoniae is a capsulated gram-negative pathogen. It is an important cause of community-acquired and nosocomial pneumonia. Evidence indicates that K. pneumoniae infections are characterized by a lack of an early inflammatory response. Data from our laboratory indicate that K. pneumoniae CPS helps to suppress the host inflammatory response. However, it is unknown whether K. pneumoniae employs additional factors to modulate host inflammatory responses. Here, we report that K. pneumoniae OmpA is important for immune evasion in vitro and in vivo. Infection of A549 and normal human bronchial cells with 52OmpA2, an ompA mutant, increased the levels of IL-8. 52145-Deltawca(K2)ompA, which does not express CPS and ompA, induced the highest levels of IL-8. Both mutants could be complemented. In vivo, 52OmpA2 induced higher levels of tnfalpha, kc, and il6 than the wild type. ompA mutants activated NF-kappaB, and the phosphorylation of p38, p44/42, and JNK MAPKs and IL-8 induction was via NF-kappaB-dependent and p38- and p44/42 dependent pathways. 52OmpA2 engaged TLR2 and -4 to activate NF-kappaB, whereas 52145-Deltawca(K2)ompA activated not only TLR2 and TLR4 but also NOD1. Finally, we demonstrate that the ompA mutant is attenuated in the pneumonia mouse model. The results of this study indicate that K. pneumoniae OmpA contributes to attenuate airway cell responses. This may facilitate pathogen survival in the hostile environment of the lung. PMID- 21278258 TI - Creative and stylistic devices employed by children during a storybook narrative task: a cross-cultural study. AB - PURPOSE: The purpose of this study was to analyze the effects of culture on the creative and stylistic features children employ when producing narratives based on wordless picture books. METHOD: Participants included 60 first- and second grade African American, Latino American, and Caucasian children. A subset of narratives based on wordless picture books collected as part of a larger study was coded and analyzed for the following creative and stylistic conventions: organizational style (topic centered, linear, cyclical), dialogue (direct, indirect), reference to character relationships (nature, naming, conduct), embellishment (fantasy, suspense, conflict), and paralinguistic devices (expressive sounds, exclamatory utterances). RESULTS: Many similarities and differences between ethnic groups were found. No significant differences were found between ethnic groups in organizational style or use of paralinguistic devices. African American children included more fantasy in their stories, Latino children named their characters more often, and Caucasian children made more references to the nature of character relationships. CONCLUSION: Even within the context of a highly structured narrative task based on wordless picture books, culture influences children's production of narratives. Enhanced understanding of narrative structure, creativity, and style is necessary to provide ecologically valid narrative assessment and intervention for children from diverse cultural backgrounds. PMID- 21278259 TI - Expository language skills of young school-age children. AB - PURPOSE: This research investigated the expository language skills of young school-age children with the ultimate aim of obtaining normative data for clinical practice. Specifically, this study examined (a) the level of expository language performance of 6- and 7-year-old children with typical development and (b) age-related differences between young and older school-age children. METHOD: Expository discourse was elicited from two groups of children using the favorite game or sport (FGS) task. Performance of the younger age group (n=61), age 6;0 (years;months) to 7;11, was compared to that of a group of twenty 11-year-old children from an earlier study. Samples were analyzed on measures of verbal productivity, syntactic complexity, grammatical accuracy, and verbal fluency. RESULTS: The FGS task was effective in eliciting text-level discourse from young school-age children. These children produced discourse that resulted in a fairly normal distribution across some of the language production measures. Age-related differences were observed on measures of verbal productivity, grammatical accuracy, and verbal fluency, but not on syntactic complexity. CONCLUSION: The findings suggest that expository discourse sampling may be a useful addition to a language assessment protocol, even for very young school-age children. PMID- 21278260 TI - Influence of DMT1 and iron status on inflammatory responses in the lung. AB - Divalent metal transporter 1 (DMT1) is the major iron transporter responsible for duodenal dietary iron absorption and is required for erythropoiesis. Recent studies suggest that loss of DMT1 activity could be involved in metal-related lung injury, but little is known about the effects of iron status and DMT1 function on pulmonary inflammation. To better define the role of DMT1 and iron status in pulmonary inflammatory responses, we performed bronchoalveolar lavage (BAL) following intratracheal instillation of lipopolysaccharide (LPS) to the Belgrade rat, an animal model deficient in DMT1 function. In the basal state, the BAL fluid of Belgrade rats had more macrophages and higher lactate dehydrogenase, myeloperoxidase, albumin, and hemoglobin levels compared with heterozygote control rats. Following LPS instillation, the macrophage fraction relative to total BAL cell content and levels of albumin and IgM were increased in Belgrade rats compared with controls. In contrast, heterozygote Belgrade rats made anemic by diet-induced iron deficiency exhibited attenuated inflammatory responses to LPS. These combined results show that pulmonary inflammation can be modified by both DMT1 and iron status. Loss of DMT1 alters pulmonary responses necessary for lung homeostasis in the basal state and enhances LPS-induced inflammation and therefore would contribute to progression of lung injury. PMID- 21278261 TI - Interplay between RAGE, CD44, and focal adhesion molecules in epithelial mesenchymal transition of alveolar epithelial cells. AB - Fibrosis of the lung is characterized by the accumulation of myofibroblasts, a key mediator in the fibrogenic reaction. Cumulative evidence indicates that epithelial-mesenchymal transition (EMT), a process whereby epithelial cells become mesenchyme-like, is an important contributing source for the myofibroblast population. Underlying this phenotypical change is a dramatic alteration in cellular structure. The receptor for advanced glycation end-products (RAGE) has been suggested to maintain lung homeostasis by mediating cell adhesion, while the family of ezrin/radixin/moesin (ERM) proteins, on the other hand, serve as an important cross-linker between the plasma membrane and cytoskeleton. In the present investigation, we tested the hypothesis that RAGE and ERM interact and play a key role in regulating EMT-associated structural changes in alveolar epithelial cells. Exposure of A549 cells to inflammatory cytokines resulted in phosphorylation and redistribution of ERM to the cell periphery and localization with EMT-related actin stress fibers. Simultaneously, blockade of Rho kinase (ROCK) signaling attenuated these cytokine-induced structural changes. Additionally, RAGE expression was diminished after cytokine stimulation, with release of its soluble isoform via a matrix metalloproteinase (MMP)-9-dependent mechanism. Immunofluorescence microscopy and coimmunoprecipitation revealed association between ERM and RAGE under basal conditions, which was disrupted when challenged with inflammatory cytokines, as ERM in its activated state complexed with membrane-linked CD44. Dual-fluorescence immunohistochemistry of patient idiopathic pulmonary fibrosis (IPF) tissues highlighted marked diminution of RAGE in fibrotic samples, together with enhanced levels of CD44 and double-positive cells for CD44 and phospho (p)ERM. These data suggest that dysregulation of the ERM-RAGE complex might be an important step in rearrangement of the actin cytoskeleton during proinflammatory cytokine-induced EMT of human alveolar epithelial cells. PMID- 21278262 TI - The influence of receiver size on magnitude of acoustic and perceived measures of occlusion. AB - PURPOSE: The current study examined measured and perceived occlusion for a receiver-in-the-canal (RIC) hearing aid with different-sized receivers. The relationship between these measures and ear canal volume was also investigated. METHOD: Thirty adult participants were fitted with an RIC hearing aid and tested with 5 receiver size conditions. Measured occlusion effect was calculated from aided and unaided real-ear responses obtained while subjects vocalized /i/. Perceived occlusion measures were acquired using an occlusion effect scale. RESULTS: Measured occlusion was greatest for the largest receiver. The most common perceived occlusion ratings were none to mild occlusion for all receiver sizes. Perceived ratings were weakly correlated to acoustic measures. There was little to no correlation between receiver size and estimated ear canal volume. CONCLUSIONS: Measured and perceived occlusion was minor in all receiver conditions. Occlusion was not correlated to ear canal volume, suggesting that RIC hearing aids most often result in negligible amounts of measured and perceived occlusion effect, regardless of ear canal size. Because no significant relationship existed between the occlusion measures, clinicians may need to consider that self-rating of occlusion may not match measured occlusion results. PMID- 21278263 TI - Antifungal activity displayed by cereulide, the emetic toxin produced by Bacillus cereus. AB - In this study, the fungistatic activity of Bacillus cereus cereulide-producing strains was demonstrated against nine fungal species. The role of cereulide was confirmed using plasmid-cured derivatives and ces knockout mutants. The fungistatic spectra of cereulide and valinomycin, a chemically related cyclododecadepsipeptide, were also compared and found to be similar but distinct. PMID- 21278264 TI - Ammonia-oxidizing bacteria in biofilters removing trihalomethanes are related to Nitrosomonas oligotropha. AB - Ammonia-oxidizing bacteria (AOB) in nitrifying biofilters degrading four regulated trihalomethanes-trichloromethane, bromodichloromethane, dibromochloromethane, and tribromomethane-were related to Nitrosomonas oligotropha. N. oligotropha is associated with chloraminated drinking water systems, and its presence in the biofilters might indicate that trihalomethane tolerance is another reason that this bacterium is dominant in chloraminated systems. PMID- 21278265 TI - Strong and consistently synergistic inactivation of spores of spoilage-associated Bacillus and Geobacillus spp. by high pressure and heat compared with inactivation by heat alone. AB - The inactivation of spores of four low-acid food spoilage organisms by high pressure thermal (HPT) and thermal-only processing was compared on the basis of equivalent thermal lethality calculated at a reference temperature of 121.1 degrees C (F(z)(121.1)( degrees )(C, 0.1 MPa or 600 MPa)) and characterized as synergistic, not different or protective. In addition, the relative resistances of spores of the different spoilage microorganisms to HPT processing were compared. Processing was performed and inactivation was compared in both laboratory and pilot scale systems and in model (diluted) and actual food products. Where statistical comparisons could be made, at least 4 times and up to around 190 times more inactivation (log(10) reduction/minute at F(T)(z)(121.1)( degrees )(C)) of spores of Bacillus amyloliquefaciens, Bacillus sporothermodurans, and Geobacillus stearothermophilus was achieved using HPT, indicating a strong synergistic effect of high pressure and heat. Bacillus coagulans spores were also synergistically inactivated in diluted and undiluted Bolognese sauce but were protected by pressure against thermal inactivation in undiluted cream sauce. Irrespective of the response characterization, B. coagulans and B. sporothermodurans were identified as the most HPT-resistant isolates in the pilot scale and laboratory scale studies, respectively, and G. stearothermophilus as the least in both studies and all products. This is the first study to comprehensively quantitatively characterize the responses of a range of spores of spoilage microorganisms as synergistic (or otherwise) using an integrated thermal-lethality approach (F(T)(z)). The use of the F(T)(z) approach is ultimately important for the translation of commercial minimum microbiologically safe and stable thermal processes to HPT processes. PMID- 21278266 TI - Novel virulence gene and clustered regularly interspaced short palindromic repeat (CRISPR) multilocus sequence typing scheme for subtyping of the major serovars of Salmonella enterica subsp. enterica. AB - Salmonella enterica subsp. enterica is the leading cause of bacterial food-borne disease in the United States. Molecular subtyping methods are powerful tools for tracking the farm-to-fork spread of food-borne pathogens during outbreaks. In order to develop a novel multilocus sequence typing (MLST) scheme for subtyping the major serovars of S. enterica subsp. enterica, the virulence genes sseL and fimH and clustered regularly interspaced short palindromic repeat (CRISPR) loci were sequenced from 171 clinical isolates from nine Salmonella serovars, Salmonella serovars Typhimurium, Enteritidis, Newport, Heidelberg, Javiana, I 4,[5],12:i:-, Montevideo, Muenchen, and Saintpaul. The MLST scheme using only virulence genes was congruent with serotyping and identified epidemic clones but could not differentiate outbreaks. The addition of CRISPR sequences dramatically improved discriminatory power by differentiating individual outbreak strains/clones. Of particular note, the present MLST scheme provided better discrimination of Salmonella serovar Enteritidis strains than pulsed-field gel electrophoresis (PFGE). This method showed high epidemiologic concordance for all serovars screened except for Salmonella serovar Muenchen. In conclusion, the novel MLST scheme described in the present study accurately differentiated outbreak strains/clones of the major serovars of Salmonella, and therefore, it shows promise for subtyping this important food-borne pathogen during investigations of outbreaks. PMID- 21278267 TI - Campylobacter troglodytis sp. nov., isolated from feces of human-habituated wild chimpanzees (Pan troglodytes schweinfurthii) in Tanzania. AB - The transmission of simian immunodeficiency and Ebola viruses to humans in recent years has heightened awareness of the public health significance of zoonotic diseases of primate origin, particularly from chimpanzees. In this study, we analyzed 71 fecal samples collected from 2 different wild chimpanzee (Pan troglodytes) populations with different histories in relation to their proximity to humans. Campylobacter spp. were detected by culture in 19/56 (34%) group 1 (human habituated for research and tourism purposes at Mahale Mountains National Park) and 0/15 (0%) group 2 (not human habituated but propagated from an introduced population released from captivity over 30 years ago at Rubondo Island National Park) chimpanzees, respectively. Using 16S rRNA gene sequencing, all isolates were virtually identical (at most a single base difference), and the chimpanzee isolates were most closely related to Campylobacter helveticus and Campylobacter upsaliensis (94.7% and 95.9% similarity, respectively). Whole-cell protein profiling, amplified fragment length polymorphism analysis of genomic DNA, hsp60 sequence analysis, and determination of the mol% G+C content revealed two subgroups among the chimpanzee isolates. DNA-DNA hybridization experiments confirmed that both subgroups represented distinct genomic species. In the absence of differential biochemical characteristics and morphology and identical 16S rRNA gene sequences, we propose to classify all isolates into a single novel nomenspecies, Campylobacter troglodytis, with strain MIT 05-9149 as the type strain; strain MIT 05-9157 is suggested as the reference strain for the second C. troglodytis genomovar. Further studies are required to determine whether the organism is pathogenic to chimpanzees and whether this novel Campylobacter colonizes humans and causes enteric disease. PMID- 21278268 TI - Impact of sorbic acid on germinant receptor-dependent and -independent germination pathways in Bacillus cereus. AB - Amino acid- and inosine-induced germination of Bacillus cereus ATCC 14579 spores was reversibly inhibited in the presence of 3 mM undissociated sorbic acid. Exposure to high hydrostatic pressure, Ca-dipicolinic acid (DPA), and bryostatin, an activator of PrkC kinase, negated this inhibition, pointing to specific blockage of signal transduction in germinant receptor-mediated germination. PMID- 21278269 TI - Prevalence, development, and molecular mechanisms of bacteriocin resistance in Campylobacter. AB - Bacteriocins (BCNs) are antimicrobial peptides produced by bacteria with narrow or broad spectra of antimicrobial activity. Recently, several unique anti Campylobacter BCNs have been identified from commensal bacteria isolated from chicken intestines. These BCNs dramatically reduced C. jejuni colonization in poultry and are being directed toward on-farm control of Campylobacter. However, no information concerning prevalence, development, and mechanisms of BCN resistance in Campylobacter exists. In this study, susceptibilities of 137 C. jejuni isolates and 20 C. coli isolates to the anti-Campylobacter BCNs OR-7 and E 760 were examined. Only one C. coli strain displayed resistance to the BCNs (MIC, 64 MUg/ml), while others were susceptible, with MICs ranging from 0.25 to 4 MUg/ml. The C. coli mutants resistant to BCN OR-7 also were obtained by in vitro selection, but all displayed only low-level resistance to OR-7 (MIC, 8 to 16 MUg/ml). The acquired BCN resistance in C. coli could be transferred at intra- and interspecies levels among Campylobacter strains by biphasic natural transformation. Genomic examination of the OR-7-resistant mutants by using DNA microarray and random transposon mutagenesis revealed that the multidrug efflux pump CmeABC contributes to both intrinsic resistance and acquired resistance to the BCNs. Altogether, this study represents the first report of and a major step forward in understanding BCN resistance in Campylobacter, which will facilitate the development of effective BCN-based strategies to reduce the Campylobacter loads in poultry. PMID- 21278270 TI - Epidemiological association of different Campylobacter jejuni groups with metabolism-associated genetic markers. AB - In this study, multilocus sequence typing (MLST) was combined with the genetic detection of six genetic markers, ansB, dmsA, ggt, cj1585c, cjj81176-1367/71 (cj1365c), and the two-gene marker tlp7 (cj0951c plus cj0952c), to assess if their presence correlated with different C. jejuni clonal groups. Using a collection of 266 C. jejuni isolates from (in decreasing order of sample size) humans, chickens, cattle, and turkeys, it was further investigated whether the resulting genotypes correlated with the isolation source. We found combinations of the six marker genes to be mutually exclusive, and their patterns of presence or absence correlated to some degree with animal source. Together with MLST results, the obtained genotypes could be segregated into six groups. An association was identified for ansB, dmsA, and ggt with the MLST-clonal complexes (MLST-CC) 22, 42, 45, and 283, which formed the most prominent group, in which chickens were the most prevalent animal source. Two other groups, characterized by the presence of cj1585c, cjj81176-1367/71, and the two-gene marker tlp7, associated with either MLST-CC 21 or 61, were overrepresented in isolates of bovine origin. Mutually exclusive marker gene combinations were observed for ansB, dmsA, and ggt, typically found in CC 45 and the related CC 22, 42, and 283, whereas the other three marker genes were found mostly in CC 21, 48, and 206. The presence of the two-gene marker tlp7, which is typical for MLST 21 and 53 as well as for MLST-CC 61, strongly correlates with a bovine host; this is interpreted as an example of host adaptation. In cases of C. jejuni outbreaks, these genetic markers could be helpful for more effective source tracking. PMID- 21278271 TI - Thermococcus kodakarensis as a host for gene expression and protein secretion. AB - Taking advantage of the gene manipulation system developed in Thermococcus kodakarensis, here, we developed a system for gene expression and efficient protein secretion using this hyperthermophilic archaeon as a host cell. DNA fragments encoding the C-terminal domain of chitinase (ChiADelta4), which exhibits endochitinase activity, and the putative signal sequence of a subtilisin like protease (TK1675) were fused and positioned under the control of the strong constitutive promoter of the cell surface glycoprotein gene. This gene cassette was introduced into T. kodakarensis, and secretion of the ChiADelta4 protein was examined. ChiADelta4 was found exclusively in the culture supernatant and was not detected in the soluble and membrane fractions of the cell extract. The signal peptide was specifically cleaved at the C-terminal peptide bond following the Ala Ser-Ala sequence. Efficient secretion of the orotidine-5'-monophosphate decarboxylase protein was also achieved with the same strategy. We next individually overexpressed two genes (TK1675 and TK1689) encoding proteases with putative signal sequences. By comparing protein degradation activities in the host cells and transformants in both solid and liquid media, as well as measuring peptidase activity using synthetic peptide substrates, we observed dramatic increases in protein degradation activity in the two transformants. This study displays an initial demonstration of cell engineering in hyperthermophiles. PMID- 21278272 TI - Indirect modulation of the intracellular c-Di-GMP level in Shewanella oneidensis MR-1 by MxdA. AB - The GGDEF domain protein MxdA, which is important for biofilm formation in Shewanella oneidensis MR-1, was hypothesized to possess diguanylate cyclase activity. Here, we demonstrate that while MxdA controls the cellular level of c di-GMP in S. oneidensis, it modulates the c-di-GMP pool indirectly. PMID- 21278273 TI - Proteomic and transcriptomic elucidation of the mutant ralstonia eutropha G+1 with regard to glucose utilization. AB - By taking advantage of the available genome sequence of Ralstonia eutropha H16, glucose uptake in the UV-generated glucose-utilizing mutant R. eutropha G(+)1 was investigated by transcriptomic and proteomic analyses. Data revealed clear evidence that glucose is transported by a usually N-acetylglucosamine-specific phosphotransferase system (PTS)-type transport system, which in this mutant is probably overexpressed due to a derepression of the encoding nag operon by an identified insertion mutation in gene H16_A0310 (nagR). Furthermore, a missense mutation in nagE (membrane component EIICB), which yields a substitution of an alanine by threonine in NagE and may additionally increase glucose uptake, was identified. Phosphorylation of glucose is subsequently mediated by NagF (cytosolic PTS component EIIA-HPr-EI) or glucokinase (GlK), respectively. The inability of the defined deletion mutant R. eutropha G(+)1 DeltanagFEC to utilize glucose strongly confirms this finding. In addition, secondary effects of glucose, which is now intracellularly available as a carbon source, on the metabolism of the mutant cells in the stationary growth phase occurred: intracellular glucose degradation is stimulated by the stronger expression of enzymes involved in the 2-keto-3-deoxygluconate 6-phosphate (KDPG) pathway and in subsequent reactions yielding pyruvate. The intermediate phosphoenolpyruvate (PEP) in turn supports further glucose uptake by the Nag PTS. Pyruvate is then decarboxylated by the pyruvate dehydrogenase multienzyme complex to acetyl coenzyme A (acetyl-CoA), which is directed to poly(3-hydroxybutyrate). The polyester is then synthesized to a greater extent, as also indicated by the upregulation of various enzymes of poly-beta-hydroxybutyrate (PHB) metabolism. The larger amounts of NADPH required for PHB synthesis are delivered by significantly increased quantities of proton-translocating NAD(P) transhydrogenases. The current study successfully combined transcriptomic and proteomic investigations to unravel the phenotype of this hitherto-undefined glucose-utilizing mutant. PMID- 21278274 TI - Correlation of quantitative PCR for a poultry-specific brevibacterium marker gene with bacterial and chemical indicators of water pollution in a watershed impacted by land application of poultry litter. AB - The impact of fecal contamination from human and agricultural animal waste on water quality is a major public health concern. Identification of the dominant source(s) of fecal pollution in a watershed is necessary for assessing the safety of recreational water and protecting water resources. A field study was conducted using quantitative PCR (qPCR) for the 16S rRNA gene of Brevibacterium sp. LA35 to track feces-contaminated poultry litter in environmental samples. Based on sensitivity and specificity characteristics of the qPCR method, the Bayesian conditional probability that detection of the LA35 marker gene in a water sample represented a true-positive result was 93%. The marker's covariance with fecal indicator bacteria (FIB) and metals associated with poultry litter was also assessed in litter, runoff, surface water, and groundwater samples. LA35 was detected in water and soil samples collected throughout the watershed, and its concentration covaried with concentrations of Escherichia coli, enterococci, As, Cu, P, and Zn. Significantly greater concentrations of FIB, As, Cu, P, and Zn were observed in edge-of-field runoff samples in which LA35 was detected, compared to samples in which it was not detected. Furthermore, As, Cu, P, and Zn concentrations covaried in environmental samples in which LA35 was detected and typically did not in samples in which the marker gene was not detected. The covariance of the poultry-specific LA35 marker gene with these known contaminants from poultry feces provides further evidence that it is a useful tool for assessing the impact of poultry-derived fecal pollution in environmental waters. PMID- 21278275 TI - LuxS coexpression enhances yields of recombinant proteins in Escherichia coli in part through posttranscriptional control of GroEL. AB - Cell-to-cell communication, or quorum sensing (QS), enables cell density dependent regulation of bacterial gene expression which can be exploited for the autonomous-signal-guided expression of recombinant proteins (C. Y. Tsao, S. Hooshangi, H. C. Wu, J. J. Valdes, and W. E. Bentley, Metab. Eng. 12:291-297, 2010). Earlier observations that the metabolic potential of Escherichia coli is conveyed via the QS signaling molecule autoinducer-2 (AI-2) suggested that the capacity for protein synthesis could also be affected by AI-2 signaling (M. P. DeLisa, J. J. Valdes, and W. E. Bentley, J. Bacteriol. 183:2918-2928, 2001). In this work, we found that simply adding conditioned medium containing high levels of AI-2 at the same time as inducing the synthesis of recombinant proteins doubled the yield of active product. We have hypothesized that AI-2 signaling "conditions" cells as a natural consequence of cell-to-cell communication and that this could tweak the signal transduction cascade to alter the protein synthesis landscape. We inserted luxS (AI-2 synthase) into vectors which cosynthesized proteins of interest (organophosphorus hydrolase [OPH], chloramphenicol acetyltransferase [CAT], or UV-variant green fluorescent protein [GFPuv]) and evaluated the protein expression in luxS-deficient hosts. In this way, we altered the level of luxS in the cells in order to "tune" the synthesis of AI-2. We found conditions in which the protein yield was dramatically increased. Further studies demonstrated coincident upregulation of the chaperone GroEL, which may have facilitated higher yields and is shown for the first time to be positively regulated at the posttranscriptional level by AI-2. This report is the first to demonstrate that the protein synthesis capacity of E. coli can be altered by rewiring quorum sensing circuitry. PMID- 21278276 TI - Field detection of Schistosoma japonicum cercariae in environmental water samples by quantitative PCR. AB - A species-specific quantitative PCR (qPCR) assay was combined with two novel water-sampling methods and compared with the mouse bioassay for the quantitative detection of S. japonicum in surface waters. The novel methods were capable of capturing cercariae and, with subsequent analysis through qPCR, detecting the presence of a minimum of 1 cercaria. PMID- 21278277 TI - Variable infection frequency and high diversity of multiple strains of Wolbachia pipientis in Perkinsiella Planthoppers. AB - This survey of Wolbachia infections in populations of the planthoppers Perkinsiella saccharicida and Perkinsiella vitiensis revealed variable frequencies, low-titer infections, and high phylogenetic diversities of strains. These observations add to the growing realization that Wolbachia infections may be extremely common within invertebrates and yet occur infrequently within populations and at low titer within individuals. PMID- 21278278 TI - Functional and structural microbial diversity in organic and conventional viticulture: organic farming benefits natural biocontrol agents. AB - Statistically significant differences in the structure and function of above ground grapevine-associated microorganisms from organically and conventionally managed vineyards were found. Aureobasidium pullulans, a copper-detoxifying fungus and biocontrol agent, plays a key role in explaining these differences. The black fungus was strongly enriched in the communities of organically managed plants and yielded a higher indigenous antiphytopathogenic potential. PMID- 21278279 TI - Poly-alpha-glutamic acid synthesis using a novel catalytic activity of RimK from Escherichia coli K-12. AB - Poly-L-alpha-amino acids have various applications because of their biodegradable properties and biocompatibility. Microorganisms contain several enzymes that catalyze the polymerization of L-amino acids in an ATP-dependent manner, but the products from these reactions contain amide linkages at the side residues of amino acids: e.g., poly-gamma-glutamic acid, poly-epsilon-lysine, and cyanophycin. In this study, we found a novel catalytic activity of RimK, a ribosomal protein S6-modifying enzyme derived from Escherichia coli K-12. This enzyme catalyzed poly-alpha-glutamic acid synthesis from unprotected L-glutamic acid (Glu) by hydrolyzing ATP to ADP and phosphate. RimK synthesized poly-alpha glutamic acid of various lengths; matrix-assisted laser desorption ionization time of flight-mass spectrometry showed that a 46-mer of Glu (maximum length) was synthesized at pH 9. Interestingly, the lengths of polymers changed with changing pH. RimK also exhibited 86% activity after incubation at 55 degrees C for 15 min, thus showing thermal stability. Furthermore, peptide elongation seemed to be catalyzed at the C terminus in a stepwise manner. Although RimK showed strict substrate specificity toward Glu, it also used, to a small extent, other amino acids as C-terminal substrates and synthesized heteropeptides. In addition, RimK catalyzed modification of ribosomal protein S6 was confirmed. The number of Glu residues added to the protein varied with pH and was largest at pH 9.5. PMID- 21278281 TI - Deleterious effect of the Qo inhibitor compound resistance-conferring mutation G143A in the intron-containing cytochrome b gene and mechanisms for bypassing it. AB - The mutation G143A in the inhibitor binding site of cytochrome b confers a high level of resistance to fungicides targeting the bc(1) complex. The mutation, reported in many plant-pathogenic fungi, has not evolved in fungi that harbor an intron immediately after the codon for G143 in the cytochrome b gene, intron bi2. Using Saccharomyces cerevisiae as a model organism, we show here that a codon change from GGT to GCT, which replaces glycine 143 with alanine, hinders the splicing of bi2 by altering the exon/intron structure needed for efficient intron excision. This lowers the levels of cytochrome b and respiratory growth. We then investigated possible bypass mechanisms that would restore the respiratory fitness of a resistant mutant. Secondary mutations in the mitochondrial genome were found, including a point mutation in bi2 restoring the correct exon/intron structure and the deletion of intron bi2. We also found that overexpression of nuclear genes MRS2 and MRS3, encoding mitochondrial metal ion carriers, partially restores the respiratory growth of the G143A mutant. Interestingly, the MRS3 gene from the plant-pathogenic fungus Botrytis cinerea, overexpressed in an S. cerevisiae G143A mutant, had a similar compensatory effect. These bypass mechanisms identified in yeast could potentially arise in pathogenic fungi. PMID- 21278282 TI - Iodide accumulation by aerobic bacteria isolated from subsurface sediments of a 129I-contaminated aquifer at the Savannah River site, South Carolina. AB - (129)I is of major concern because of its mobility in the environment, excessive inventory, toxicity (it accumulates in the thyroid), and long half-life (~16 million years). The aim of this study was to determine if bacteria from a (129)I contaminated oxic aquifer at the F area of the U.S. Department of Energy's Savannah River Site, SC, could accumulate iodide at environmentally relevant concentrations (0.1 MUM I(-)). Iodide accumulation capability was found in 3 out of 136 aerobic bacterial strains isolated from the F area that were closely related to Streptomyces/Kitasatospora spp., Bacillus mycoides, and Ralstonia/Cupriavidus spp. Two previously described iodide-accumulating marine strains, a Flexibacter aggregans strain and an Arenibacter troitsensis strain, accumulated 2 to 50% total iodide (0.1 MUM), whereas the F-area strains accumulated just 0.2 to 2.0%. Iodide accumulation by FA-30 was stimulated by the addition of H(2)O(2), was not inhibited by chloride ions (27 mM), did not exhibit substrate saturation kinetics with regard to I(-) concentration (up to 10 MUM I( )), and increased at pH values of <6. Overall, the data indicate that I(-) accumulation likely results from electrophilic substitution of cellular organic molecules. This study demonstrates that readily culturable, aerobic bacteria of the F-area aquifer do not accumulate significant amounts of iodide; however, this mechanism may contribute to the long-term fate and transport of (129)I and to the biogeochemical cycling of iodine over geologic time. PMID- 21278280 TI - Fecal bacteroidales diversity and decay in response to variations in temperature and salinity. AB - Bacteroidales are attractive as water quality indicators because of their potential to discern sources of fecal pollution, and it is presumed that these bacteria do not multiply outside their host organisms. The persistence of a fecal Bacteroidales marker was monitored over 14 days in river water microcosms that varied in temperature from 10 degrees C to 30 degrees C and salinity from 00/00 to 300/00 by quantitative PCR (qPCR). Decay rates were estimated and compared to the results of other studies examining the survival and persistence of Bacteroidales markers by converting decay rates from other studies to a common decay rate unit. The log-linear decay rates estimated in this work ranged from 0.18 to -1.31 ln(C(T)/C(0)) day(-1), where C(T) is the threshold cycle and C(0) is the concentration of cells at time zero, which is comparable to findings in previous studies. Salinity had a positive effect on Bacteroidales marker persistence, while decay was more rapid at higher temperatures. Comparison of 16S rRNA gene clone libraries generated from microcosm samples indicated that most of the operational taxonomic unit (OTU) and phylogenetic diversity was found within samples and not between samples, indicating at least qualitatively that diverse lineages persist and likely have similar survival characteristics under most of the conditions examined. It was noted that the samples at higher salinities also had the smallest amount of diversity between samples as well as the lowest decay rates. This research also highlights the need for a repository of raw survival and persistence data if more sophisticated models of decay are to be employed and compared between different studies. PMID- 21278283 TI - Interactions of green tea catechins with organic anion-transporting polypeptides. AB - Organic anion-transporting polypeptides (OATPs) are multispecific transporters that mediate the uptake of numerous drugs and xenobiotics into cells. Here, we examined the effect of green tea (Camellia sinensis) catechins on the function of the four OATPs expressed in human enterocytes and hepatocytes. Uptake of the model substrate estrone-3-sulfate by cells expressing OATP1A2, OATP1B1, OATP1B3, or OATP2B1 was measured in the absence and presence of the four most abundant flavonols found in green tea. Uptake by OATP1A2, OATP1B1, and OATP2B1 was inhibited by epicatechin gallate (ECG) and epigallocatechin gallate (EGCG) in a concentration-dependent way. In contrast, OATP1B3-mediated uptake of estrone-3 sulfate was strongly stimulated by EGCG at low substrate concentrations. The effect of EGCG on OATP1B3 was also studied with additional substrates: uptake of estradiol-17beta-glucuronide was unchanged, whereas uptake of Fluo-3 was noncompetitively inhibited. Both ECG and EGCG were found to be substrates of OATP1A2 (K(m) values of 10.4 and 18.8 MUM, respectively) and OATP1B3 (34.1 and 13.2 MUM, respectively) but not of OATP1B1 or OATP2B1. These results indicate that two of the major flavonols found in green tea have a substantial effect on the function of OATPs expressed in enterocytes and hepatocytes and can potentially alter the pharmacokinetics of drugs and other OATP substrates. In addition, the diverse effects of EGCG on the transport of other OATP1B3 substrates suggest that different transport/binding sites are involved. PMID- 21278284 TI - Tracing the domestication of a biofilm-forming bacterium. AB - Over the course of more than a century of laboratory experimentation, Bacillus subtilis has become "domesticated," losing its ability to carry out many behaviors characteristic of its wild ancestors. One such characteristic is the ability to form architecturally complex communities, referred to as biofilms. Previous work has shown that the laboratory strain 168 forms markedly attenuated biofilms compared with the wild strain NCIB3610 (3610), even after repair of a mutation in sfp (a gene involved in surfactin production) previously known to impair biofilm formation. Here, we show that in addition to the sfp mutation, mutations in epsC, swrA, and degQ are necessary and sufficient to explain the inability of the laboratory strain to produce robust biofilms. Finally, we show that the architecture of the biofilm is markedly influenced by a large plasmid present in 3610 but not 168 and that the effect of the plasmid can be attributed to a gene we designate rapP. When rapP is introduced into 168 together with wild type alleles of sfp, epsC, swrA, and degQ, the resulting repaired laboratory strain forms biofilms that are as robust as and essentially indistinguishable in architecture from those of the wild strain, 3610. Thus, domestication of B. subtilis involved the accumulation of four mutations and the loss of a plasmid borne gene. PMID- 21278285 TI - A major role for nonenzymatic antioxidant processes in the radioresistance of Halobacterium salinarum. AB - Oxidative stress occurs when the generation of reactive oxygen species (ROS) exceeds the capacity of the cell's endogenous systems to neutralize them. Our analyses of the cellular damage and oxidative stress responses of the archaeon Halobacterium salinarum exposed to ionizing radiation (IR) revealed a critical role played by nonenzymatic antioxidant processes in the resistance of H. salinarum to IR. ROS-scavenging enzymes were essential for resistance to chemical oxidants, yet those enzymes were not necessary for H. salinarum's resistance to IR. We found that protein-free cell extracts from H. salinarum provided a high level of protection for protein activity against IR in vitro but did not protect DNA significantly. Compared with cell extracts of radiation-sensitive bacteria, H. salinarum extracts were enriched in manganese, amino acids, and peptides, supporting an essential role in ROS scavenging for those small molecules in vivo. With regard to chemical oxidants, we showed that the damage caused by gamma irradiation was mechanistically different than that produced by hydrogen peroxide or by the superoxide-generating redox-cycling drug paraquat. The data presented support the idea that IR resistance is most likely achieved by a "metabolic route," with a combination of tightly coordinated physiological processes. PMID- 21278286 TI - EsaD, a secretion factor for the Ess pathway in Staphylococcus aureus. AB - Staphylococcus aureus encodes the Sec-independent Ess secretion pathway, an ortholog of mycobacterial T7 secretion systems which is required for the virulence of this Gram-positive microbe. The Ess (ESX secretion) pathway was previously defined as a genomic cluster of eight genes, esxA, esaA, essA, essB, esaB, essC, esaC, and esxB. essABC encode membrane proteins involved in the stable expression of esxA, esxB, and esaC, genes specifying three secreted polypeptide substrates. esaB, which encodes a small cytoplasmic protein, represses the synthesis of EsaC but not that of EsxA and EsxB. Here we investigated a hitherto uncharacterized gene, esaD, located downstream of esxB. Expression of esaD is activated by mutations in esaB and essB. EsaD, the 617 amino-acid product of esaD, is positioned in the membrane and is also accessible to EsaD-specific antibodies on the bacterial surface. S. aureus mutants lacking esaD are defective in the secretion of EsxA. Following intravenous inoculation of mice, S. aureus esaD mutants generate fewer abscesses with a reduced bacterial load compared to wild-type parent strain Newman. The chromosomes of Listeria and Bacillus species with Ess pathways also harbor esaD homologues downstream of esxB, suggesting that the contributory role of EsaD in Ess secretion may be shared among Gram-positive pathogens. PMID- 21278287 TI - Regulatory control of the Escherichia coli O157:H7 lpf1 operon by H-NS and Ler. AB - Long polar fimbriae 1 (Lpf1) of Escherichia coli O157:H7 is a tightly regulated adhesin, with H-NS silencing the transcriptional expression of the lpf1 operon while Ler (locus of enterocyte effacement-encoded regulator) acts as an antisilencer. We mapped the minimal regulatory region of lpf1 required for H-NS- and Ler-mediated regulation and found that it is 79% AT rich. Three putative sites for H-NS binding were identified. Two of them, named silencer regulatory sequence 1 (SRS1) and SRS2, are located on a region that covers both of the lpf1 promoters (P1 and P2). The third putative H-NS binding site is located within the lpfA1 gene in a region extending from +258 bp to +545 bp downstream of ATG; however, this site does not seem to play a role in lpfA1 regulation under the conditions tested in this work. Ler was also found to interact with Ler binding sites (LBSs). Ler binding site 1 (LBS1) and LBS2 are located upstream of the two promoters. LBS1 overlaps SRS1, while LBS3 overlaps the P1 promoter and SRS2. Based on the experimental data, we propose that H-NS silences lpf1 expression by binding to both of the SRSs on the promoter region, forming an SRS-H-NS complex that prevents RNA polymerase-mediated transcription. A model of the regulation of the lpfA1 operon of E. coli O157:H7 by H-NS and Ler is discussed. PMID- 21278288 TI - The three-layered DNA uptake machinery at the cell pole in competent Bacillus subtilis cells is a stable complex. AB - Many bacteria possess the ability to actively take up DNA from the environment and incorporate it into the chromosome. RecA protein is the key protein achieving homologous recombination. Several of the proteins involved in the transport of DNA across the cell envelope assemble at a single or both cell poles in competent Bacillus subtilis cells. We show that the presumed structure that transports DNA across the cell wall, the pseudopilus, also assembles at a single or both cell poles, while the membrane receptor, ComEA, forms a mobile layer throughout the cell membrane. All other known Com proteins, including the membrane permease, localize again to the cell pole, revealing that the uptake machinery has three distinct layers. In cells having two uptake machineries, one complex is occasionally mobile, with pairs of proteins moving together, suggesting that a complete complex may lose anchoring and become mobile. Overall, the cell pole provides stable anchoring. Only one of two uptake machineries assembles RecA protein, suggesting that only one is competent for DNA transfer. FRAP (fluorescence recovery after photobleaching) analyses show that in contrast to known multiprotein complexes, the DNA uptake machinery forms a highly stable complex, showing little or no exchange with unbound molecules. When cells are converted into round spheroplasts, the structure persists, revealing that the assembly is highly stable and does not require the cell pole for its maintenance. High stability may be important to fulfill the mechanical function in pulling DNA across two cell layers. PMID- 21278289 TI - Identification of genes essential for prey-independent growth of Bdellovibrio bacteriovorus HD100. AB - Bdellovibrio bacteriovorus HD100 is an obligate predatory bacterium that attacks and invades Gram-negative bacteria. The predator requires living bacteria to survive as growth and replication take place inside the bacterial prey. It is possible to isolate mutants that grow and replicate outside prey bacteria. Such mutants are designated host or prey independent, and their nutritional requirements vary. Some mutants are saprophytic and require prey extracts for extracellular growth, whereas other mutants grow axenically, which denotes the formation of colonies on complete medium in the absence of any prey components. The initial events leading to prey-independent growth are still under debate, and several genes may be involved. We selected new mutants by three different methods: spontaneous mutation, transposon mutagenesis, and targeted gene knockout. By all approaches we isolated mutants of the hit (host interaction) locus. As the relevance of this locus for the development of prey independence has been questioned, we performed whole-genome sequencing of five prey independent mutants. Three mutants were saprophytic, and two mutants could grow axenically. Whole-genome analysis revealed that the mutation of a small open reading frame of the hit locus is sufficient for the conversion from predatory to saprophytic growth. Complementation experiments were performed by introduction of a plasmid carrying the wild-type hit gene into saprophytic mutants, and predatory growth could be restored. Whole-genome sequencing of two axenic mutants demonstrated that in addition to the hit mutation the colony formation on complete medium was shown to be influenced by the mutations of two genes involved in RNA processing. Complementation experiments with a wild-type gene encoding an RNA helicase, RhlB, abolished the ability to form colonies on complete medium, indicating that stability of RNA influences axenic growth. PMID- 21278290 TI - Autogenous transcriptional regulation of the regA gene, encoding an AraC-Like, essential virulence regulator in Citrobacter rodentium. AB - We identified several promoters responsible for the expression of regA, which encodes a global virulence regulator in Citrobacter rodentium. Expression of some of the promoters was strongly autoactivated by RegA in conjunction with bicarbonate. Biochemical and mutational analyses were used to determine the consensus sequence of the RegA-binding sites. PMID- 21278291 TI - Retrospective application of transposon-directed insertion site sequencing to a library of signature-tagged mini-Tn5Km2 mutants of Escherichia coli O157:H7 screened in cattle. AB - Massively parallel sequencing of transposon-flanking regions assigned the genotype and fitness score to 91% of Escherichia coli O157:H7 mutants previously screened in cattle by signature-tagged mutagenesis (STM). The method obviates the limitations of STM and markedly extended the functional annotation of the prototype E. coli O157:H7 genome without further animal use. PMID- 21278292 TI - The second RNA chaperone, Hfq2, is also required for survival under stress and full virulence of Burkholderia cenocepacia J2315. AB - Burkholderia cenocepacia J2315 is a highly virulent and epidemic clinical isolate of the B. cepacia complex (Bcc), a group of bacteria that have emerged as important pathogens to cystic fibrosis patients. This bacterium, together with all Bcc strains and a few other prokaryotes, is unusual for encoding in its genome two distinct and functional Hfq-like proteins. In this work, we show results indicating that the 188-amino-acid Hfq2 protein is required for the full virulence and stress resistance of B. cenocepacia J2315, despite the presence on its genome of the functional 79-amino-acid Hfq protein encoded by the hfq gene. Similar to other Hfq proteins, Hfq2 is able to bind RNA. However, Hfq2 is unique in its ability to apparently form trimers in vitro. Maximal transcription of hfq was observed in B. cenocepacia J2315 cells in the early exponential phase of growth. In contrast, hfq2 transcription reached maximal levels in cells in the stationary phase, depending on the CepR quorum-sensing regulator. These results suggest that tight regulation of the expression of these two RNA chaperones is required to maximize the fitness and virulence of this bacterium. In addition, the ability of Hfq2 to bind DNA, not observed for Hfq, suggests that Hfq2 might play additional roles besides acting as an RNA chaperone. PMID- 21278293 TI - Legionella pneumophila LbtU acts as a novel, TonB-independent receptor for the legiobactin siderophore. AB - Gram-negative Legionella pneumophila produces a siderophore (legiobactin) that promotes lung infection. We previously determined that lbtA and lbtB are required for the synthesis and secretion of legiobactin. DNA sequence and reverse transcription-PCR (RT-PCR) analyses now reveal the presence of an iron-repressed gene (lbtU) directly upstream of the lbtAB-containing operon. In silico analysis predicted that LbtU is an outer membrane protein consisting of a 16-stranded transmembrane beta-barrel, multiple extracellular domains, and short periplasmic tails. Immunoblot analysis of cell fractions confirmed an outer membrane location for LbtU. Although replicating normally in standard media, lbtU mutants, like lbtA mutants, were impaired for growth on iron-depleted agar media. While producing typical levels of legiobactin, lbtU mutants were unable to use supplied legiobactin to stimulate growth on iron-depleted media and displayed an inability to take up iron. Complemented lbtU mutants behaved as the wild type did. The lbtU mutants were also impaired for infection in a legiobactin-dependent manner. Together, these data indicate that LbtU is involved in the uptake of legiobactin and, based upon its location, is most likely the Legionella siderophore receptor. The sequence and predicted two-dimensional (2D) and 3D structures of LbtU were distinct from those of all known siderophore receptors, which generally contain a 22-stranded beta-barrel and an extended N terminus that binds TonB in order to transduce energy from the inner membrane. This observation coupled with the fact that L. pneumophila does not encode TonB suggests that LbtU is a new type of receptor that participates in a form of iron uptake that is mechanistically distinct from the existing paradigm. PMID- 21278294 TI - Accessibility and evolutionary conservation mark bacterial small-rna target binding regions. AB - Bacterial small noncoding RNAs have attracted much interest in recent years as posttranscriptional regulators of genes involved in diverse pathways. Small RNAs (sRNAs) are 50 to 400 nucleotides long and exert their regulatory function by directly base pairing with mRNA targets to alter their stability and/or affect their translation. This base pairing is achieved through a region of about 10 to 25 nucleotides, which may be located at various positions along different sRNAs. By compiling a data set of experimentally determined target-binding regions of sRNAs and systematically analyzing their properties, we reveal that they are both more evolutionarily conserved and more accessible than random regions. We demonstrate the use of these properties for computational identification of sRNA target-binding regions with high specificity and sensitivity. Our results show that these predicted regions are likely to base pair with known targets of an sRNA, suggesting that pointing out these regions in a specific sRNA can help in searching for its targets. PMID- 21278295 TI - The main virulence determinant of Yersinia entomophaga MH96 is a broad-host-range toxin complex active against insects. AB - Through transposon mutagenesis and DNA sequence analysis, the main disease determinant of the entomopathogenic bacterium Yersinia entomophaga MH96 was localized to an ~32-kb pathogenicity island (PAI) designated PAI(Ye96). Residing within PAI(Ye96) are seven open reading frames that encode an insecticidal toxin complex (TC), comprising not only the readily recognized toxin complex A (TCA), TCB, and TCC components but also two chitinase proteins that form a composite TC molecule. The central TC gene-associated region (~19 kb) of PAI(Ye96) was deleted from the Y. entomophaga MH96 genome, and a subsequent bioassay of the DeltaTC derivative toward Costelytra zealandica larvae showed it to be innocuous. Virulence of the DeltaTC mutant strain could be restored by the introduction of a clone containing the entire PAI(Ye96) TC gene region. As much as 0.5 mg of the TC is released per 100 ml of Luria-Bertani broth at 25 degrees C, while at 30 or 37 degrees C, no TC could be detected in the culture supernatant. Filter-sterilized culture supernatants derived from Y. entomophaga MH96, but not from the DeltaTC strain grown at temperatures of 25 degrees C or less, were able to cause mortality. The 50% lethal doses (LD50s) of the TC toward diamondback moth Plutella xylostella and C. zealandica larvae were defined as 30 ng and 50 ng, respectively, at 5 days after ingestion. Histological analysis of the effect of the TC toward P. xylostella larva showed that within 48 h after ingestion of the TC, there was a general dissolution of the larval midgut. PMID- 21278296 TI - Genome analyses of Icelandic strains of Sulfolobus islandicus, model organisms for genetic and virus-host interaction studies. AB - The genomes of two Sulfolobus islandicus strains obtained from Icelandic solfataras were sequenced and analyzed. Strain REY15A is a host for a versatile genetic toolbox. It exhibits a genome of minimal size, is stable genetically, and is easy to grow and manipulate. Strain HVE10/4 shows a broad host range for exceptional crenarchaeal viruses and conjugative plasmids and was selected for studying their life cycles and host interactions. The genomes of strains REY15A and HVE10/4 are 2.5 and 2.7 Mb, respectively, and each genome carries a variable region of 0.5 to 0.7 Mb where major differences in gene content and gene order occur. These include gene clusters involved in specific metabolic pathways, multiple copies of VapBC antitoxin-toxin gene pairs, and in strain HVE10/4, a 50 kb region rich in glycosyl transferase genes. The variable region also contains most of the insertion sequence (IS) elements and high proportions of the orphan orfB elements and SMN1 miniature inverted-repeat transposable elements (MITEs), as well as the clustered regular interspaced short palindromic repeat (CRISPR) based immune systems, which are complex and diverse in both strains, consistent with them having been mobilized both intra- and intercellularly. In contrast, the remainder of the genomes are highly conserved in their protein and RNA gene syntenies, closely resembling those of other S. islandicus and Sulfolobus solfataricus strains, and they exhibit only minor remnants of a few genetic elements, mainly conjugative plasmids, which have integrated at a few tRNA genes lacking introns. This provides a possible rationale for the presence of the introns. PMID- 21278297 TI - EAL domain protein YdiV acts as an anti-FlhD4C2 factor responsible for nutritional control of the flagellar regulon in Salmonella enterica Serovar Typhimurium. AB - Flagellar operons are divided into three classes with respect to their transcriptional hierarchy in Salmonella enterica serovar Typhimurium. The class 1 gene products FlhD and FlhC act together in an FlhD(4)C(2) heterohexamer, which binds upstream of the class 2 promoters to facilitate binding of RNA polymerase. In this study, we showed that flagellar expression was much reduced in the cells grown in poor medium compared to those grown in rich medium. This nutritional control was shown to be executed at a step after class 1 transcription. We isolated five Tn5 insertion mutants in which the class 2 expression was derepressed in poor medium. These insertions were located in the ydiV (cdgR) gene or a gene just upstream of ydiV. The ydiV gene is known to encode an EAL domain protein and to act as a negative regulator of flagellar expression. Gene disruption and complementation analyses revealed that the ydiV gene is responsible for nutritional control. Expression analysis of the ydiV gene showed that its translation, but not transcription, was enhanced by growth in poor medium. The ydiV mutation did not have a significant effect on either the steady state level of flhDC mRNA or that of FlhC protein. Purified YdiV protein was shown in vitro to bind to FlhD(4)C(2) through interaction with FlhD subunit and to inhibit its binding to the class 2 promoter, resulting in inhibition of FlhD(4)C(2)-dependent transcription. Taking these data together, we conclude that YdiV is a novel anti-FlhD(4)C(2) factor responsible for nutritional control of the flagellar regulon. PMID- 21278298 TI - Genome sequence of Taylorella equigenitalis MCE9, the causative agent of contagious equine metritis. AB - Taylorella equigenitalis is the causative agent of contagious equine metritis (CEM), a sexually transmitted infection of horses. We herein report the genome sequence of T. equigenitalis strain MCE9, isolated in 2005 from the urethral fossa of a 4-year-old stallion in France. PMID- 21278299 TI - Characterization and acceptor preference of a soluble meningococcal group C polysialyltransferase. AB - Vaccines against Neisseria meningitidis group C are based on its alpha-2,9-linked polysialic acid capsular polysaccharide. This polysialic acid expressed on the surface of N. meningitidis and in the absence of specific antibody serves to evade host defense mechanisms. The polysialyltransferase (PST) that forms the group C polysialic acid (NmC PST) is located in the cytoplasmic membrane. Until recently, detailed characterization of bacterial polysialyltransferases has been hampered by a lack of availability of soluble enzyme preparations. We have constructed chimeras of the group C polysialyltransferase that catalyzes the formation alpha-2,9-polysialic acid as a soluble enzyme. We used site-directed mutagenesis to determine the region of the enzyme necessary for synthesis of the alpha-2,9 linkage. A chimera of NmB and NmC PSTs containing only amino acids 1 to 107 of the NmB polysialyltransferase catalyzed the synthesis of alpha-2,8 polysialic acid. The NmC polysialyltransferase requires an exogenous acceptor for catalytic activity. While it requires a minimum of a disialylated oligosaccharide to catalyze transfer, it can form high-molecular-weight alpha-2,9-polysialic acid in a nonprocessive fashion when initiated with an alpha-2,8-polysialic acid acceptor. De novo synthesis in vivo requires an endogenous acceptor. We attempted to reconstitute de novo activity of the soluble group C polysialyltransferase with membrane components. We found that an acapsular mutant with a defect in the polysialyltransferase produces outer membrane vesicles containing an acceptor for the alpha-2,9-polysialyltransferase. This acceptor is an amphipathic molecule and can be elongated to produce polysialic acid that is reactive with group C specific antibody. PMID- 21278300 TI - Complete genome sequence of the veterinary pathogen Staphylococcus pseudintermedius strain HKU10-03, isolated in a case of canine pyoderma. AB - Staphylococcus pseudintermedius is a member of the coagulase-positive staphylococci and is the commonest cause of canine pyoderma. We report the first genome sequence of S. pseudintermedius, which shows the presence of numerous virulence factors akin to those of the related human pathogen Staphylococcus aureus. PMID- 21278301 TI - Asymmetric dimethylarginine contributes to airway nitric oxide deficiency in patients with cystic fibrosis. AB - RATIONALE: Airway nitric oxide is reduced in cystic fibrosis airways. Asymmetric dimethylarginine is an endogenous nitric oxide synthase inhibitor that may contribute to nitric oxide deficiency in cystic fibrosis. OBJECTIVES: To test the hypothesis that asymmetric dimethylarginine is increased in cystic fibrosis and contributes to nitric oxide deficiency and airway obstruction. METHODS: The concentrations of asymmetric dimethylarginine, symmetric dimethylarginine, and l arginine were measured in sputum of clinically stable patients with cystic fibrosis, in patients with cystic fibrosis before and after treatment for a pulmonary exacerbation, and in healthy control subjects, using liquid chromatography-tandem mass spectrometry. MEASUREMENTS AND MAIN RESULTS: Asymmetric dimethylarginine was increased in cystic fibrosis compared with control sputum, and the l-arginine/asymmetric dimethylarginine ratio was decreased. Symmetric dimethylarginine exceeded asymmetric dimethylarginine concentrations in control sputum, but this ratio was reversed in cystic fibrosis. Treatment for pulmonary exacerbation resulted in a decrease in sputum asymmetric dimethylarginine and an improved l-arginine/asymmetric dimethylarginine ratio. The treatment-related decrease in asymmetric dimethylarginine correlated significantly with an increase in sputum nitric oxide metabolites and improvement in pulmonary function. The activity of the asymmetric dimethylarginine metabolizing enzyme, dimethylarginine dimethylaminohydrolase, was higher in cystic fibrosis sputum before rather than after treatment, suggesting that the accumulation of asymmetric dimethylarginine is caused by increased production, not decreased degradation, of asymmetric dimethylarginine. CONCLUSIONS: Asymmetric dimethylarginine is increased in cystic fibrosis airways and may contribute to airway obstruction in patients with cystic fibrosis by reducing nitric oxide formation. PMID- 21278302 TI - B cells contribute to the antitumor activity of CpG-oligodeoxynucleotide in a mouse model of metastatic lung carcinoma. AB - RATIONALE: CpG-oligodeoxynucleotide (CpG-ODN; CpG), a Toll-like receptor-9 ligand, has been widely studied as a potential antitumor adjuvant. Toll-like receptor-9 is highly expressed on lung carcinoma tissues and some immune cells, such as plasmacytoid dendritic cells and B cells. OBJECTIVES: The aim of our study was to elucidate the effect of CpG on B cells in a mouse model of lung carcinoma. METHODS: C57Bl/6j, B cell-deficient, and Nude mice were intravenously implanted with the lung metastatic B16-F10 melanoma cells and killed 3 and 7 days after CpG administration. MEASUREMENTS AND MAIN RESULTS: Administration of CpG increased lung tumor growth in B16-F10-implanted C57BL/6J mice. The genetic absence of B cells strongly facilitated CpG-induced tumor progression. In contrast, the adoptive transfer of CpG-activated B cells induced tumor arrest, associated with a reduced suppressive immune environment due to the lower recruitment of regulatory T cells, myeloid-derived suppressor cells, and CD8(+) regulatory T cells along with the reduced expression of suppressive cytokines such as IL-10 and transforming growth factor-beta. Furthermore, concomitant with higher production of IFN-gamma, the apoptosis rate in the lungs of mice adoptively transferred with CpG-activated B cells was increased. Depletion of mature CD20(+) B cells increased the lung tumor burden in CpG-treated C57BL/6J mice and nude mice. Moreover, nude mice had the same lung tumor burden as B cell deficient mice when mature CD20(+) B cells were depleted. CONCLUSIONS: Our data demonstrate the protective antitumor activity of CpG-activated B cells and shed light on CpG as an antitumor adjuvant for lung cancer therapy. PMID- 21278303 TI - Exudate macrophages attenuate lung injury by the release of IL-1 receptor antagonist in gram-negative pneumonia. AB - RATIONALE: Exudate macrophages are key players in host defense toward invading pathogens. Their antiinflammatory and epithelial-protective potential in gram negative pneumonia, however, remains elusive. OBJECTIVES: We investigated whether exudate macrophages contributed to preservation of alveolar epithelial barrier integrity and analyzed the molecular pathways involved. METHODS: We evaluated the antiinflammatory and epithelial-protective effects of exudate macrophages in a model of LPS- and Klebsiella pneumoniae-induced lung injury comparing wild-type and CC-chemokine receptor 2 (CCR2)-deficient mice with defective lung macrophage recruitment and in in vitro studies using primary alveolar epithelial cells. MEASUREMENTS AND MAIN RESULTS: CCR2(-/-) mice exhibited enhanced alveolar epithelial cell apoptosis and lung leakage on intratracheal LPS treatment, which could be attributed to lack of exudate macrophage recruitment from the circulating pool as demonstrated in a model of wild-type/CCR2(-/-) bone-marrow chimeric mice. Among various antiinflammatory and proliferative mediators analyzed, the endogenous counterpart of resident macrophage-expressed IL-1beta, IL-1 receptor antagonist (IL-1ra), was highly up-regulated in flow-sorted exudate macrophages in LPS-treated wild-type mice. LPS/IL-1beta-induced impairment of alveolar epithelial cell integrity was antagonized by IL-1ra in vitro. Finally, intratracheal substitution of IL-1ra or intravenous adoptive transfer of IL 1ra(+/+) but not IL-1ra(-/-) blood mononuclear cells attenuated alveolar inflammation, epithelial apoptosis, and loss of barrier function in LPS challenged or K. pneumoniae-infected CCR2(-/-) mice and enhanced survival after K. pneumoniae infection. CONCLUSIONS: We conclude that recruited lung macrophages attenuate IL-1beta-mediated acute lung injury in gram-negative pneumonia by release of IL-1ra. PMID- 21278304 TI - RIG-like helicase innate immunity inhibits vascular endothelial growth factor tissue responses via a type I IFN-dependent mechanism. AB - RATIONALE: Vascular endothelial growth factor (VEGF) regulates vascular, inflammatory, remodeling, and cell death responses. It plays a critical role in normal pulmonary physiology, and VEGF excess and deficiency have been implicated in the pathogenesis of asthma and chronic obstructive pulmonary disease, respectively. Although viruses are an important cause of chronic obstructive pulmonary disease exacerbations and innate responses play an important role in these exacerbations, the effects of antiviral responses on VEGF homeostasis have not been evaluated. OBJECTIVES: We hypothesized that antiviral innate immunity regulates VEGF tissue responses. METHODS: We compared the effects of transgenic VEGF(165) in mice treated with viral pathogen-associated molecular pattern polyinosinic:polycytidylic acid [poly(I:C)], mice treated with live virus, and control mice. MEASUREMENTS AND MAIN RESULTS: Transgenic VEGF stimulated angiogenesis, edema, inflammation, and mucin accumulation. Each of these was abrogated by poly(I:C). These inhibitory effects were dose dependent, noted when poly(I:C) was administered before and after transgene activation, and mediated by a Toll-like receptor-3-independent and RIG-like helicase (RLH)- and type I IFN receptor-dependent pathway. VEGF stimulated the expression of VEGF receptor-1 and poly(I:C) inhibited this stimulation. Poly(I:C) also inhibited the ability of VEGF to activate extracellular signal-regulated kinase-1, Akt, focal adhesion kinase, and endothelial nitric oxide synthase, and aeroallergen-induced adaptive helper T-cell type 2 inflammation. Influenza and respiratory syncytial virus also inhibited VEGF-induced angiogenesis. CONCLUSIONS: These studies demonstrate that poly(I:C) and respiratory viruses inhibit VEGF-induced tissue responses and adaptive helper T-cell type 2 inflammation and highlight the importance of a RLH- and type I IFN receptor-dependent pathway(s) in these regulatory events. They define a novel link between VEGF and antiviral and RLH innate immune responses and a novel pathway that regulates pulmonary VEGF activity. PMID- 21278305 TI - Why do people stop treating contaminated drinking water with Solar Water Disinfection (SODIS)? AB - Solar Water Disinfection (SODIS) is a simple method designed to treat microbiologically contaminated drinking water at household level. This article characterizes relapse behavior in comparison with continued SODIS use after a 7 month nonpromotion period. In addition, different subtypes among relapsers and continuers were assumed to diverge mainly in their intention to use SODIS and their degree of cognition intensity. Data were taken from a longitudinal SODIS promotion study. Cluster analyses were applied to find subtypes among 166 relapsers and 123 continuers. Overall relapsers have lower values for all psychological variables compared to overall continuers. A low-value and a high value relapser subtype as well as a low-value and a high-value continuer subtype were found. Low-value relapsers differ from high-value relapsers in one central belief (taste), in affective connotation, social norms, and dissonance. Interestingly, high-value relapsers have values almost as high as low-value continuers, differing only in their degree of habit. Only high-value continuers seem to be stable and did not show a decrease in critical habit variables over time. The different subtypes are placed along the behavior change process, and possible interventions for each type are highlighted. PMID- 21278306 TI - Salud America! Developing a National Latino Childhood Obesity Research Agenda. AB - U.S. childhood obesity has reached epidemic proportions, with one third of children overweight or obese. Latino children have some of the highest obesity rates, a concern because they are part of the youngest and fastest-growing U.S. minority group. Unfortunately, scarce research data on Latinos hinders the development and implementation of evidence-based, culturally appropriate childhood obesity interventions. In response, the Salud America! network conducted a national Delphi survey among researchers and stakeholders to identify research priorities to address Latino childhood obesity and compare differences by occupation and race or ethnicity. The resulting first-ever National Latino Childhood Obesity Research Agenda provides a framework to stimulate research and collaboration among investigators, providers, and communities, and inform policy makers about the epidemic's seriousness and specific needs for priority funding. The agenda ranks family as the main ecological level to prevent Latino childhood obesity--followed by community, school, society, and individual-and ranks top research priorities in each level. PMID- 21278307 TI - Protein storage vacuoles are transformed into lytic vacuoles in root meristematic cells of germinating seedlings by multiple, cell type-specific mechanisms. AB - We have investigated the structural events associated with vacuole biogenesis in root tip cells of tobacco (Nicotiana tabacum) seedlings preserved by high pressure freezing and freeze-substitution techniques. Our micrographs demonstrate that the lytic vacuoles (LVs) of root tip cells are derived from protein storage vacuoles (PSVs) by cell type-specific sets of transformation events. Analysis of the vacuole transformation pathways has been aided by the phytin-dependent black osmium staining of PSV luminal contents. In epidermal and outer cortex cells, the central LVs are formed by a process involving PSV fusion, storage protein degradation, and the gradual replacement of the PSV marker protein alpha tonoplast intrinsic protein (TIP) with the LV marker protein gamma-TIP. In contrast, in the inner cortex and vascular cylinder cells, the transformation events are more complex. During mobilization of the stored molecules, the PSV membranes collapse osmotically upon themselves, thereby squeezing the vacuolar contents into the remaining bulging vacuolar regions. The collapsed PSV membranes then differentiate into two domains: (1) vacuole "reinflation" domains that produce pre-LVs, and (2) multilamellar autophagosomal domains that are later engulfed by the pre-LVs. The multilamellar autophagosomal domains appear to originate from concentric sheets of PSV membranes that create compartments within which the cytoplasm begins to break down. Engulfment of the multilamellar autophagic vacuoles by the pre-LVs gives rise to the mature LVs. During pre-LV formation, the PSV marker alpha-TIP disappears and is replaced by the LV marker gamma-TIP. These findings demonstrate that the central LVs of root cells arise from PSVs via cell type-specific transformation pathways. PMID- 21278308 TI - Supercomplex formation with photosystem I is required for the stabilization of the chloroplast NADH dehydrogenase-like complex in Arabidopsis. AB - In higher plants, the chloroplast NADH dehydrogenase-like complex (NDH) interacts with photosystem I (PSI) to form the NDH-PSI supercomplex via two minor light harvesting complex I (LHCI) proteins, Lhca5 and Lhca6. Previously, we showed that in lhca5 and lhca6, NDH still associates with PSI to form smaller versions of the NDH-PSI supercomplex, although their molecular masses are far smaller than that of the full-size NDH-PSI supercomplex. In this study, we show that the NDH complex is present in the monomeric form in Arabidopsis (Arabidopsis thaliana) lhca5 lhca6, implying that NDH interacts with multiple copies of PSI. NDH subunit levels were slightly reduced in immature leaves and more drastically (approximately 50%) in mature leaves of the lhca5 lhca6 double mutant compared with the wild type. Chlorophyll fluorescence analyses detected NDH activity of lhca5 lhca6, suggesting that the supercomplex formation is not essential for NDH activity. However, the severe phenotypes of the lhca5 lhca6 proton gradient regulation5 triple mutant in both plant growth rate and photosynthesis suggest that the function of NDH was impaired in this mutant in vivo. Accumulation of NDH subunits was drastically reduced in lhca5 lhca6 when the light intensity was shifted from 50 to 500 MUmol photons m(-2) s(-1). Furthermore, the half-life of NDH subunits, especially that of NDH18, was shorter in monomeric NDH than in the NDH-PSI supercomplex under the high-light conditions. We propose that NDH-PSI supercomplex formation stabilizes NDH and that the process is especially required under stress conditions. PMID- 21278309 TI - Excision and episomal replication of cauliflower mosaic virus integrated into a plant genome. AB - Transgenic Arabidopsis (Arabidopsis thaliana) plants containing a monomeric copy of the cauliflower mosaic virus (CaMV) genome exhibited the generation of infectious, episomally replicating virus. The circular viral genome had been split within the nonessential gene II for integration into the Arabidopsis genome by Agrobacterium tumefaciens-mediated transformation. Transgenic plants were assessed for episomal infections at flowering, seed set, and/or senescence. The infections were confirmed by western blot for the CaMV P6 and P4 proteins, electron microscopy for the presence of icosahedral virions, and through polymerase chain reaction across the recombination junction. By the end of the test period, a majority of the transgenic Arabidopsis plants had developed episomal infections. The episomal form of the virus was infectious to nontransgenic plants, indicating that no essential functions were lost after release from the Arabidopsis chromosome. An analysis of the viral genomes recovered from either transgenic Arabidopsis or nontransgenic turnip (Brassica rapa var rapa) revealed that the viruses contained deletions within gene II, and in some cases, the deletions extended to the beginning of gene III. In addition, many of the progeny viruses contained small regions of nonviral sequence derived from the flanking transformation vector. The nature of the nucleotide sequences at the recombination junctions in the circular progeny virus indicated that most were generated by nonhomologous recombination during the excision event. The release of the CaMV viral genomes from an integrated copy was not dependent upon the application of environmental stresses but occurred with greater frequency with either age or the late stages of plant maturation. PMID- 21278310 TI - Are dropped osteoarticular bone fragments safely reimplantable in vivo? AB - BACKGROUND: There are limited data detailing the appropriate management of nondisposable autologous osteoarticular fragments that have been contaminated by the operating room floor. The goal of the present study was to perform a comprehensive, three-phase investigation to establish an appropriate intraoperative algorithm for the management of the acutely contaminated, but nondisposable, autologous osteoarticular bone fragment. METHODS: Phase I of the study was performed to quantify the rate of contamination and microbial profile of human osteoarticular fragments that were dropped onto the operating room floor (n = 162). Phase II was performed to assess the feasibility and optimal means of decontaminating 340 similar fragments that underwent controlled contamination with bacteria that were identified in Phase I; decontamination was performed with use of cleansing agents that are routinely available in an operating room. Phase III was performed to assess the effect of each decontamination process on fragment chondrocyte viability through histologic evaluation. RESULTS: The contamination rate in Phase I was 70%. Coagulase-negative Staphylococcus was the most commonly cultured organism. In Phase II, varying exposure time to the chemical agents did not make a significant difference in decontamination rates. Mechanical scrubbing was superior to mechanical saline solution lavage (zero of fifty-six cultures compared with twenty of fifty-six cultures were positive for coagulase-negative Staphylococcus; p < 0.001). As a whole, bactericidal agents were found to be more effective decontaminating agents than normal saline solution. Povidone-iodine and 4% chlorhexidine gluconate were the most effective decontaminating agents, with none of the twenty-eight specimens that were decontaminated with each agent demonstrating positive growth on culture. Phase III demonstrated that the groups that were treated with normal saline solution and povidone-iodine retained the greatest number of live cells and the least number of dead cells. Mechanical scrubbing significantly decreased chondrocyte viability as compared with a normal saline solution wash (p < 0.05). CONCLUSIONS: The majority of osteochondral fragments that contact the operating room floor produce positive bacterial cultures. Five minutes of cleansing with a 10% povidone-iodine solution followed by a normal saline solution rinse appears to provide the optimal balance between effective decontamination and cellular toxicity for dropped autologous bone in the operative setting. PMID- 21278311 TI - Commentary on an article by Benjamin Bruce, MD, et al.: "Are dropped osteoarticular bone fragments safely reimplantable in vivo?". PMID- 21278312 TI - Microscopic and early-stage ovarian cancers in BRCA1/2 mutation carriers: building a model for early BRCA-associated tumorigenesis. AB - Risk-reducing salpingo-oophorectomy (RRSO) is the cornerstone of ovarian cancer prevention in BRCA1/2 mutation carriers. Occult fallopian tube and ovarian cancers have been reported in a small percentage of BRCA1/2 mutation carriers undergoing RRSO. Here, we review our single-institution experience with RRSO in BRCA1/2 mutation carriers to characterize cases of microscopic cancers in these patients. At the time of RRSO, 7.9% of BRCA1 mutation carriers were diagnosed with microscopic fallopian tube or ovarian cancers and no cases were diagnosed in BRCA2 mutation carriers. The majority of the microscopic cancers include cases that were confined to the fallopian tubes, although there were also cases involving ovaries only or peritoneal washings only. This suggests that the site of origin may be in the ovary, fallopian tube, or peritoneum for BRCA-associated serous cancers. However, an analysis of early-stage (stages I and II) ovarian and fallopian tube cancers diagnosed in BRCA1/2 mutation carriers confirms that the ovary is a preferred site for tumor growth with 11 of 14 early-stage cancers having a dominant ovarian mass. Overall, these data suggest that cancer initiation may occur in the ovary, fallopian tube, or peritoneum, but tumor growth and progression are favored in the ovary. We present an updated model for BRCA1/2 mutation-associated ovarian and fallopian tube carcinogenesis, which may aid in identifying improved prevention strategies for high-risk women who delay or decline RRSO. PMID- 21278313 TI - Chinese red yeast rice inhibition of prostate tumor growth in SCID mice. AB - Prostate cancer is a slowly developing but very common cancer in males that may be amenable to preventive strategies that are not toxic. Chinese red yeast rice (RYR), a food herb made by fermenting Monascus purpureus Went yeast on white rice, contains a mixture of eight different monacolins that inhibit cholesterogenesis in addition to red pigments with antioxidant properties. Monacolin K is identical to lovastatin (LV), but LV unlike RYR can be used in individuals intolerant to statins due to muscle pain. Both LV and RYR inhibit de novo cholesterogenesis, which is critical to the growth of tumor cells. Long-term use of statin drugs has been associated with a reduced risk of prostate cancer. We have previously shown that RYR inhibited androgen-dependent and androgen receptor-overexpressing androgen-independent prostate cancer cell proliferation in vitro. This study was designed to determine whether RYR and LV inhibit prostate tumor growth in SCID mice. RYR significantly reduced tumor volumes of androgen-dependent and androgen-independent prostate xenograft tumors compared with animals receiving vehicle alone (P < 0.05). Inhibition by RYR was greater than that observed with LV at the dose found in RYR, showing that other compounds in RYR contributed to the antiproliferative effect. There was a significant correlation of tumor volume to serum cholesterol (P < 0.001). RYR decreased gene expression of androgen synthesizing enzymes (HSD3B2, AKR1C3, and SRD5A1) in both type of tumors (P < 0.05). Clinical studies of RYR for prostate cancer prevention in the increasing population of men undergoing active surveillance should be considered. PMID- 21278314 TI - Fight fat with DGAT. PMID- 21278316 TI - Walking cane use in prison: a medical and cultural analysis. AB - This study examined the diagnosis, race, age, and conviction offenses of those using walking canes at California Medical Facility through a random review of 40 charts and 40 conviction folders. Motivating factors were concern about the potential for misuse of canes as weapons and a desire to further understand the clinical challenges faced by patients. Findings suggest that walking canes are most often prescribed for neurological or musculoskeletal problems, sometimes are prescribed with no apparent indication, and are more readily prescribed to violent offenders. Beyond their weight-bearing medical function, it is possible that canes bear cultural significance in prison culture, perhaps symbolizing pugnacious independence. The anthropological literature on aggression, interpersonal violence, and weapon use is explored to help understand the racial variation in use of fighting accoutrements in prison settings. PMID- 21278317 TI - Hydrogen cyanide poisoning in a prison environment: a case report. AB - Cyanide poisoning is an important source of morbidity and mortality from smoke exposure in structural fires. This case involved administration of a cyanide antidote to a prisoner (male, 23 years) in France, discovered in cardiorespiratory arrest after about 30 minutes exposure to smoke from a burning mattress during an apparent suicide attempt. Smoke exposure, circulatory failure during initial resuscitation, and elevated blood cyanide and lactate led to the diagnosis of cyanide poisoning. Hydroxocobalamin (Cyanokit(r)), 5 g intravenous) was given immediately and on arrival at the hospital. Cardiopulmonary resuscitation restored cardiovascular function after 33 minutes. There were no neurological or other sequelae. Timely hydroxocobalamin administration contributed to full recovery from cardiorespiratory arrest secondary to cyanide poisoning from smoke inhalation. Hydroxocobalamin should be available to emergency medical teams attending fire scenes. PMID- 21278318 TI - Risk of comorbid health impairment among older male inmates. AB - This investigation originated from a pilot survey of 261 state prison inmates, aged 45 to 82, in Oklahoma. Logistic regression analyses were computed to assess the relationship of sociodemographic characteristics, physical and mental health, and lifestyle behaviors to comorbid health impairment. (odds ratio (OR) = 1.41, 95% confidence interval (CI) [1.13, 1.77]), smoking (OR = 2.82, 95% CI [1.10, 7.30]), and church attendance (OR = 1.23, 95% CI [1.00, 1.50]) were associated with increased odds of comorbid health impairment. Perceived health (OR = 0.38, 95% CI [0.23, 0.66]), mobility (OR = 0.25, 95% CI [0.09, 0.70]), and physical exercise (OR = 0.56, 95% CI [0.35, 0.88]), were associated with reduced odds of comorbid health impairment. Education, smoking, and church attendance represent key indicators of comorbid health impairment, whereas perceived health, mobility, and physical exercise are more likely to reduce multiple health impairments. PMID- 21278319 TI - Timing of efficacy of thiamine in Wernicke's disease in alcoholics at risk. AB - This study investigated an optimum window of effectiveness of oral thiamine in alcohol withdrawal in a jail setting using a Librium-based protocol. A total of 19 patients were identified with alcohol withdrawal at intake. Clinical Institute Withdrawal Assessment (CIWA-AR), Cut back, Annoyed, Guilty, Eye-opener (CAGE) questionnaire, and therapy were started immediately. Of these patients, 9 were identified as high risk and 2 developed an excited delirium consistent with Wernicke's disease. This study demonstrated an optimum window of 2 hours or less at intake with oral thiamine. The earlier an oral withdrawal protocol is started, the faster is recovery, regardless of initial presentation. Disease progression was significantly dependent on time to treat. Noncompliance with oral management is likely if treatment is delayed. The routine use of thiamine 100 mg daily during withdrawal and continuation for 30 days is recommended as the best clinical practice. PMID- 21278320 TI - Neuropsychological assessment in prisons: ethical and practical challenges. AB - Cognitive deficits, substance abuse, and mental illness are common among prisoners. Thus, for many prisoners, neuropsychological evaluations may be indicated to assess the degree of impairment and how these impairments may affect their behavior in the prison environment. However, many neuropsychological tests were not designed for or normed on prisoners. This article highlights the unique ethical and practical challenges to providing neuropsychological services to incarcerated individuals. Specifically, it discusses (a) limits to confidentiality, (b) issues related to informed consent, (c) how prison conditions may compromise the validity of testing, and (d) the impact of third party observation of the evaluation. Recommendations and suggestions for resolving some of these difficulties are offered. PMID- 21278321 TI - Hazardously drinking women leaving jail: time to first drink. AB - This study evaluated time to first drink in women being released from jail to determine predictors of early relapse among women with hazardous drinking and HIV risk behaviors. Between February 2004 and June 2007, 245 participants were recruited from the Rhode Island Department of Corrections. Following the baseline assessment, participants were randomized to a motivational intervention group or to a control condition. Follow-up assessments at 1, 3, and 6 months were completed for 210 participants. Alcohol use during follow-up occurred in 86.7% of participants, 42.4% initiated alcohol use on Day 1. The rate of initiation was associated with norms favorable to using alcohol (p < .01) and having a partner with an alcohol problem (hazard ratio [HR] = 1.62, p < .01). The rate of drink initiation decreased significantly (HR = 0.82, p < .05) as length of incarceration increased. The intervention was not associated with decreased drinking. Interventions to maintain abstinence need to reach women within their first days postrelease. PMID- 21278322 TI - Implementing opt-out programs at Los Angeles county jail: a gateway to novel research and interventions. AB - Routine opt-out screening and vaccination programs are effective methods for improving public health in correctional populations. Jail-based rapid testing for HIV, hepatitis B and C, tuberculosis, syphilis, gonorrhea, and chlamydia can improve urban health by increasing diagnosis and linkage to care for infectious diseases. In addition, jail-based vaccination programs would significantly benefit community health and lower costs associated with tertiary level care. The paucity of ethical and rigorous scientific research among incarcerated populations excludes these marginalized members of society from potential advancements in correctional medicine and public health. Routine opt-out testing programs would not only benefit the health of the correctional population but also serve as platforms for future research. Trials measuring the efficacy of new rapid tests, screening methods, novel vaccine delivery systems, or accelerated vaccine regimens would be greatly beneficial. PMID- 21278323 TI - Re: Article by Sung on "Prevalence and risk factors of violence-related and accident-related injuries among state prisoners". PMID- 21278324 TI - Toll-like receptor 2 regulates organic dust-induced airway inflammation. AB - Organic dust exposure in agricultural environments results in significant airway inflammatory diseases. Gram-positive cell wall components are present in high concentrations in animal farming dusts, but their role in mediating dust-induced airway inflammation is not clear. This study investigated the role of Toll-like receptor (TLR) 2, a pattern recognition receptor for gram-positive cell wall products, in regulating swine facility organic dust extract (DE)-induced airway inflammation in mice. Isolated lung macrophages from TLR2 knockout mice demonstrated reduced TNF-alpha, IL-6, keratinocyte chemoattractant/CXCL1, but not macrophage inflammatory protein-2/CXCL2 expression, after DE stimulation ex vivo. Next, using an established mouse model of intranasal inhalation challenge, we analyzed bronchoalveolar lavage fluid and lung tissue in TLR2-deficient and wild type (WT) mice after single and repetitive DE challenge. Neutrophil influx and select cytokines/chemokines were significantly lower in TLR2-deficient mice at 5 and 24 hours after single DE challenge. After daily exposure to DE for 2 weeks, there were significant reductions in total cellularity, neutrophil influx, and TNF-alpha, IL-6, CXCL1, but not CXCL2 expression, in TLR2-deficient mice as compared with WT animals. Lung pathology revealed that bronchiolar inflammation, but not alveolar inflammation, was reduced in TLR2-deficient mice after repetitive exposure. Airway hyperresponsiveness to methacholine after dust exposure was similar in both groups. Finally, airway inflammatory responses in WT mice after challenge with a TLR2 agonist, peptidoglycan, resembled DE-induced responses. Collectively, these results demonstrate that the TLR2 pathway is important in regulating swine facility organic dust-induced airway inflammation, which suggests the importance of TLR2 agonists in mediating large animal farming induced airway inflammatory responses. PMID- 21278325 TI - Protein prenylation contributes to the effects of LPS on EFS-induced responses in human isolated bronchi. AB - Rho/Ras signaling pathways may play an important role in the mechanism of LPS induced inflammation and bronchoconstriction. In this study, we investigated the effect of LPS on the transmural contractile tension induced by electrical field stimulation (EFS) of human isolated bronchi. The possible contribution of Rho/Ras signaling pathways was examined by using geranylgeranyl-pyrophosphate (GGPP) and farnesyl-pyrophosphate (FPP), the selective geranylgeranyl-pyrophosphate transferase inhibitor GGTI2133, and the selective farnesyl-pyrophosphate transferase inhibitor FTI276, the hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin and the Rho-associated coiled-coil-forming protein serine/threonine kinase inhibitor Y27632. LPS (300 ng/ml) significantly enhanced the EFS-induced contractile force of human bronchi (P < 0.05). The plateau was reached at 105.0 (+/-4.1) minutes; the maximal effect (Emax) value was 267.47 (+/ 8.88) %, with a time to evoke a half-maximal contraction (t(1/2)) of 40.5 (+/ 2.0) minutes. Pretreatment with GGPP (5 MUM) enhanced the EFS-mediated contractile tension (Emax, 164.56 +/- 9.80% and the t(1/2) 23.0 +/- 2.5 min). Pretreatment with FPP (5 MUM) was effective, as was GGPP, in enhancing the EFS response (Emax, of 189.23 +/- 12.98% and a t(1/2) of 17.0 +/- 4.5 min). Furthermore, GGTI2133 (500 nM) and FTI276 (10 nM) significantly inhibited the effects of GGPP and FPP on EFS-induced response. Pretreatment with GGPP (5 MUM) significantly enhanced the EFS response compared with the control and LPS-treated tissues; GGTI2133 (500 nM) significantly inhibited the EFS-induced contractile tension in LPS (300 ng/ml)-treated tissues, and it was not possible to calculate the t(1/2). In addition, simvastatin and Y27632 (both 1 MUM) were effective in abolishing the contracturant effect of LPS. Our results provide mechanistic evidence for the enhanced bronchoconstriction induced by LPS in human isolated airways, the contribution of Rho/Ras pathways in this LPS response, and the protective role of statins. PMID- 21278326 TI - Treprostinil inhibits the adhesion and differentiation of fibrocytes via the cyclic adenosine monophosphate-dependent and Ras-proximate protein-dependent inactivation of extracellular regulated kinase. AB - Fibrocytes comprise a recently described cell type of blood-derived, fibroblast like cells that are recruited from the circulation to sites of wound repair, vascular remodeling, or fibrotic tissue remodeling. We recently showed that the stable prostacyclin analogue treprostinil, a clinically approved drug for pulmonary arterial hypertension (PAH), significantly reduced the recruitment of fibrocytes to sites of vascular remodeling in experimental hypoxic pulmonary hypertension. Here we report on the molecular mechanism underlying the inhibitory action of treprostinil on the adhesion and differentiation of human fibrocytes. Human fibrocytes expressed the prostanoid receptors, prostaglandin I (IP) receptors and prostaglandin E subtype receptors (EP2 and EP4). The generation of intracellular cyclic adenosine monophosphate (cAMP) by treprostinil reduced the expression of the integrins CD49 and CD29 when freshly isolated human peripheral blood mononuclear cells were treated with treprostinil. Cell-matrix adhesion was significantly impaired by treatment with treprostinil. We present evidence for a treprostinil/cAMP-induced downstream suppression of extracellular regulated kinase (ERK) that is transmitted via a protein kinase A-independent pathway through Rap proteins, which sequester Ras. The resulting dephosphorylated state of c-Raf limits the activity of ERK. The cell-matrix adhesion assay with the ERK inhibitor further confirmed that the adhesion of fibrocytes was impaired. Thus our data suggest that treprostinil inhibits the adhesion and differentiation of fibrocytes by limiting the activity of ERK via the cAMP-Rap axis. PMID- 21278327 TI - Jewish ethnicity and pancreatic cancer mortality in a large U.S. cohort. AB - BACKGROUND: An association between Jewish ethnicity and pancreatic cancer risk was suggested by analyses comparing pancreatic cancer mortality rates between Jews and non-Jews in New York in the 1950s. These analyses lacked information on potential confounding factors and the association between Jewish ethnicity and pancreatic cancer has not been examined in any contemporary U.S. population or in any cohort study. METHODS: We examined the association between Jewish ethnicity and pancreatic cancer mortality among approximately 1 million participants in the Cancer Prevention Study II cohort. Participants completed a questionnaire at enrollment in 1982 which included information on religion, smoking, obesity, and diabetes. During follow-up through 2006, there were 6,727 pancreatic cancer deaths, including 480 among Jewish participants. Proportional hazards modeling was used to calculate multivariable rate ratios (RR). RESULTS: After adjusting for age, sex, smoking, body mass index, and diabetes, pancreatic cancer mortality was higher among Jewish participants than among non-Jewish whites (RR = 1.43; 95% CI, 1.30-1.57). In analyses by birthplace, RRs were 1.59 (95% CI, 1.31-1.93) for North American-born Jews with North American-born parents, 1.43 (95% CI, 1.27 1.61) for North American-born Jews with 1 or more parents born outside North America, and 1.03 (0.73, 1.44) for Jews born outside North America (P(heterogeneity) = 0.07). CONCLUSIONS: These results support a higher risk of developing pancreatic cancer among U.S. Jews that is not explained by established risk factors. IMPACT: Future studies may clarify the role of specific environmental or genetic factors responsible for higher risk among U.S. Jews. PMID- 21278328 TI - Nutrients, food groups, dietary patterns, and risk of pancreatic cancer in postmenopausal women. AB - INTRODUCTION: Identifying modifiable risk factors for pancreatic cancer is important because of its poor prognosis. Previous findings on diet are inconsistent. METHODS: Associations between intake of nutrients, food groups, dietary patterns, and pancreatic cancer risk were examined among 34,642 postmenopausal women in the Iowa Women's Health Study (IWHS). RESULTS: No significant associations were observed between intake of nutrients and food groups or dietary patterns and pancreatic cancer. CONCLUSION: Our findings do not support the hypothesis that fruits, vegetables, and red meat are associated with risk of pancreatic cancer. IMPACT: Dietary intake, assessed in multiple aspects in a large prospective cohort study, was not associated with pancreatic cancer. PMID- 21278329 TI - Use of the predictive sugars biomarker to evaluate self-reported total sugars intake in the Observing Protein and Energy Nutrition (OPEN) study. AB - BACKGROUND: A predictive biomarker for intake of total sugars was recently developed under controlled conditions. We used this biomarker to assess measurement error (ME) structure in self-reported intake of total sugars in free living individuals. METHODS: The Observing Protein and Energy Nutrition (OPEN) study involved 484 participants aged 40 to 69 years. Diet was assessed using two administrations of a food frequency questionnaire (FFQ) and two nonconsecutive 24 hour dietary recalls (24HDR). Two 24-hour urine samples checked for completeness were analyzed on sucrose and fructose. We applied the biomarker calibrated in a feeding study to OPEN data to assess the ME structure and the attenuation factors (AF) for intakes of absolute total sugars and sugars density for the FFQ and 24HDR. RESULTS: The AFs for absolute sugars were similar for a single FFQ and 24HDR, but attenuation decreased with repeated 24HDRs. For sugars density, the AFs for FFQ (men: 0.39; women: 0.33) were greater than for single 24HDR (men: 0.30; women: 0.24), and similar to two 24HDRs (men: 0.41; women: 0.35). The attenuation associated with both instruments was greater in women than in men. CONCLUSIONS: Both the FFQ and 24HDR were found to be biased; hence, incorporation of the sugars biomarker in calibration studies within the cohorts may be necessary to more reliably estimate associations of sugars and disease. IMPACT: In this article, we propose a new dietary reference instrument based on the recently defined class of predictive biomarkers. Using sugars biomarker, we quantify ME in the FFQ- and 24HDR-reported absolute total sugars and total sugars density. PMID- 21278330 TI - Promising antiapoptotic effects of helix B-surface peptide (HBSP) for treatment of heart diseases. PMID- 21278331 TI - High brain lactate is not caused by a shift in the lactate dehydrogenase A/B ratio. PMID- 21278332 TI - Word lengths are optimized for efficient communication. AB - We demonstrate a substantial improvement on one of the most celebrated empirical laws in the study of language, Zipf's 75-y-old theory that word length is primarily determined by frequency of use. In accord with rational theories of communication, we show across 10 languages that average information content is a much better predictor of word length than frequency. This indicates that human lexicons are efficiently structured for communication by taking into account interword statistical dependencies. Lexical systems result from an optimization of communicative pressures, coding meanings efficiently given the complex statistics of natural language use. PMID- 21278333 TI - Structural insights into membrane fusion at the endoplasmic reticulum. PMID- 21278334 TI - Investigating synapse formation and function using human pluripotent stem cell derived neurons. AB - A major goal of stem-cell research is to identify conditions that reliably regulate their differentiation into specific cell types. This goal is particularly important for human stem cells if they are to be used for in vivo transplantation or as a platform for drug development. Here we describe the establishment of procedures to direct the differentiation of human embryonic stem cells and human induced pluripotent stem cells into forebrain neurons that are capable of forming synaptic connections. In addition, HEK293T cells expressing Neuroligin (NLGN) 3 and NLGN4, but not those containing autism-associated mutations, are able to induce presynaptic differentiation in human induced pluripotent stem cell-derived neurons. We show that a mutant NLGN4 containing an in-frame deletion is unable to localize correctly to the cell surface when overexpressed and fails to enhance synapse formation in human induced pluripotent stem cell-derived neurons. These findings establish human pluripotent stem cell derived neurons as a viable model for the study of synaptic differentiation and function under normal and disorder-associated conditions. PMID- 21278335 TI - Different adiabatic quantum optimization algorithms for the NP-complete exact cover problem. PMID- 21278336 TI - Rho activation of mDia formins is modulated by an interaction with inverted formin 2 (INF2). AB - Inverted formin 2 (INF2) encodes a member of the diaphanous subfamily of formin proteins. Mutations in INF2 cause human kidney disease characterized by focal and segmental glomerulosclerosis. Disease-causing mutations occur only in the diaphanous inhibitory domain (DID), suggesting specific roles for this domain in the pathogenesis of disease. In a yeast two-hybrid screen, we identified the diaphanous autoregulatory domains (DADs) of the mammalian diaphanous-related formins (mDias) mDia1, mDia2, and mDia 3 as INF2_DID-interacting partners. The mDias are Rho family effectors that regulate actin dynamics. We confirmed in vitro INF2_DID/mDia_DAD binding by biochemical assays, confirmed the in vivo interaction of these protein domains by coimmunoprecipitation, and observed colocalization of INF2 and mDias in glomerular podocytes. We investigated the influence of this INF2_DID/mDia_DAD interaction on mDia mediated actin polymerization and on serum response factor (SRF) activation. We find that the interaction of INF2_DID with mDia_DAD inhibited mDia-mediated, Rho-activated actin polymerization, as well as SRF-responsive gene transcriptional changes. Similar assays using the disease-causing E184K and R218Q mutations in INF2_DID showed a decreased effect on SRF activation and gene transcription. The binding of INF2_DID to mDia_DAD may serve as a negative regulatory mechanism for mDias' function in actin-dependent cell processes. The effects of disease-causing INF2 mutations suggest an important role for this protein and its interaction with other formins in modulating glomerular podocyte phenotype and function. PMID- 21278337 TI - pH-induced metal-ligand cross-links inspired by mussel yield self-healing polymer networks with near-covalent elastic moduli. AB - Growing evidence supports a critical role of metal-ligand coordination in many attributes of biological materials including adhesion, self-assembly, toughness, and hardness without mineralization [Rubin DJ, Miserez A, Waite JH (2010) Advances in Insect Physiology: Insect Integument and Color, eds Jerome C, Stephen JS (Academic Press, London), pp 75-133]. Coordination between Fe and catechol ligands has recently been correlated to the hardness and high extensibility of the cuticle of mussel byssal threads and proposed to endow self-healing properties [Harrington MJ, Masic A, Holten-Andersen N, Waite JH, Fratzl P (2010) Science 328:216-220]. Inspired by the pH jump experienced by proteins during maturation of a mussel byssus secretion, we have developed a simple method to control catechol-Fe(3+) interpolymer cross-linking via pH. The resonance Raman signature of catechol-Fe(3+) cross-linked polymer gels at high pH was similar to that from native mussel thread cuticle and the gels displayed elastic moduli (G') that approach covalently cross-linked gels as well as self-healing properties. PMID- 21278338 TI - Chikungunya virus envelope-specific human monoclonal antibodies with broad neutralization potency. AB - Chikungunya virus (CHIKV) is an alphavirus responsible for numerous epidemics in Africa and Asia. Infection by CHIKV is often characterized by long-lasting, incapacitating arthritis, and some fatal cases have been described among elderly and newborns. Currently, there is no available vaccine or specific treatment against CHIKV. Blood B cells from a donor with history of CHIKV infection were activated, immortalized, amplified, and cloned. Two human mAbs against CHIKV, 5F10 and 8B10, were identified, sequenced, and expressed in recombinant form for characterization. In a plaque reduction neutralization test, 5F10 and 8B10 show mean IC(50) of 72 and 46 ng/ml, respectively. Moreover, both mAbs lead to a strong decrease in extracellular spreading of infectious viral particles from infected to uninfected cells. Importantly, the mAbs neutralize different CHIKV isolates from Singapore, Africa, and Indonesia, as well as O'nyong-nyong virus, but do not recognize other alphaviruses tested. Both mAbs are specific for the CHIKV envelope: 5F10 binds to the E2 glycoprotein ectodomain and 8B10 to E1 and/or E2. In conclusion, these two unique human mAbs strongly, broadly, and specifically neutralize CHIKV infection in vitro and might become possible therapeutic tools against CHIKV infection, especially in individuals at risk for severe disease. Importantly, these mAbs will also represent precious tools for future studies on host-pathogen interactions and the rational design of vaccines against CHIKV. PMID- 21278339 TI - CX3CR1+ lung mononuclear phagocytes spatially confined to the interstitium produce TNF-alpha and IL-6 and promote cigarette smoke-induced emphysema. AB - Increased numbers of macrophages are found in the lungs of smokers and those with chronic obstructive pulmonary disease. Experimental evidence shows the central role of macrophages in elaboration of inflammatory mediators such as TNF-alpha and the progression toward cigarette smoke-induced emphysema. We investigated the role of CX3CR1 in recruitment of mononuclear phagocytes, inflammatory cytokine responses, and tissue destruction in the lungs after cigarette smoke exposure. Using mice in which egfp is expressed at the locus of the cx3cr1 gene, we show that alveolar macrophages increased transmembrane ligand CX3CL1 expression and soluble CX3CL1 was detectable in the airspaces, but cx3cr1(GFP/GFP) and cx3cr1(GFP/+) mice failed to show recruitment of CX3CR1(+) cells into the airspaces with cigarette smoke. In contrast, cigarette smoke increased the accumulation of CX3CR1(+)CD11b(+) mononuclear phagocytes that were spatially confined to the lung interstitium and heterogenous in their expression of CD11c, MHC class II, and autofluorescent property. Although an intact CX3CL1-CX3CR1 pathway amplified the percentage of CX3CR1(+)CD11b(+) mononuclear phagocytes in the lungs, it was not essential for recruitment. Rather, functional CX3CR1 was required for a subset of tissue-bound mononuclear phagocytes to produce TNF-alpha and IL-6 in response to cigarette smoke, and the absence of functional CX3CR1 protected mice from developing tissue-destructive emphysema. Thus, CX3CR1(+) "tissue resident" mononuclear phagocytes initiate an innate immune response to cigarette smoke by producing TNF-alpha and IL-6 and are capable of promoting emphysema. PMID- 21278340 TI - Cutting edge: tubulin alpha functions as an adaptor in NFAT-importin beta interaction. AB - Upon T cell stimulation, NFAT is dephosphorylated by calcineurin, leading to nuclear translocation via NFAT-importin beta interaction. Whereas the process of NFAT dephosphorylation has been well researched, the molecular mechanism of NFAT importin beta interaction remains unknown. In contrast to NF-kappaB and STAT, no importin alpha family members have been reported as adaptor proteins for NFAT. Our study shows that tubulin alpha, but not tubulin beta, binds to the N-terminal region of NFAT containing the regulatory and Rel homology domains. Importin beta interacts with the NFAT-tubulin alpha complex rather than NFAT or tubulin alpha alone, resulting in cotranslocation of NFAT and tubulin alpha into the nucleus. Furthermore, the interaction is suppressed by acetate-induced tubulin alpha acetylation at lysine 40. In conclusion, tubulin alpha functions as an adaptor in NFAT-importin beta interaction, and this function is regulated by acetate-induced acetylation. PMID- 21278341 TI - Cutting edge: persistently open chromatin at effector gene loci in resting memory CD8+ T cells independent of transcriptional status. AB - Memory CD8(+) T cells are characterized by more rapid and robust effector function upon infection compared with naive T cells, but factors governing effector gene responsiveness are incompletely understood. We sought to understand transcriptional control of the effector genes IFN-gamma (Ifng), granzyme B (Gzmb), and perforin 1 (Prf1) in murine memory CD8(+) T cells by characterizing their transcriptional profiles and chromatin states during lymphocytic choriomeningitis virus infection. Each effector gene has a distinct transcriptional profile in resting memory cells and following restimulation. Primary infection leads to reduced nucleosomal density near the transcription start sites and reduced H3K27 methylation throughout the Ifng and Gzmb loci, and these chromatin changes persist in the memory phase. Despite similarities in chromatin at the memory stage, PolII recruitment and continuous transcription occur at the Ifng locus but not the Gzmb locus. We propose that these chromatin changes poise effector genes for rapid upregulation, but are insufficient for PolII recruitment and transcription. PMID- 21278342 TI - The critical role of IL-1 receptor-associated kinase 4-mediated NF-kappaB activation in modified low-density lipoprotein-induced inflammatory gene expression and atherosclerosis. AB - Exciting discoveries related to IL-1R/TLR signaling in the development of atherosclerosis plaque have triggered intense interest in the molecular mechanisms by which innate immune signaling modulates the onset and development of atherosclerosis. Previous studies have clearly shown the definitive role of proinflammatory cytokine IL-1 in the development of atherosclerosis. Recent studies have provided direct evidence supporting a link between innate immunity and atherogenesis. Although it is still controversial about whether infectious pathogens contribute to cardiovascular diseases, direct genetic evidence indicates the importance of IL-1R/TLR signaling in atherogenesis. In this study, we examined the role of IL-1R-associated kinase 4 (IRAK4) kinase activity in modified low-density lipoprotein (LDL)-mediated signaling using bone marrow derived macrophage as well as an in vivo model of atherosclerosis. First, we found that the IRAK4 kinase activity was required for modified LDL-induced NF kappaB activation and expression of a subset of proinflammatory genes but not for the activation of MAPKs in bone marrow-derived macrophage. IRAK4 kinase-inactive knockin (IRAK4KI) mice were bred onto ApoE(-/-) mice to generate IRAK4KI/ApoE(-/ ) mice. Importantly, the aortic sinus lesion formation was impaired in IRAK4KI/ApoE(-/-) mice compared with that in ApoE(-/-) mice. Furthermore, proinflammatory cytokine production was reduced in the aortic sinus region of IRAK4KI/ApoE(-/-) mice compared with that in ApoE(-/-) mice. Taken together, our results indicate that the IRAK4 kinase plays an important role in modified LDL mediated signaling and the development of atherosclerosis, suggesting that pharmacological inhibition of IRAK4 kinase activity might be a feasible approach in the development of antiatherosclerosis drugs. PMID- 21278343 TI - Innate immune function of the adherens junction protein p120-catenin in endothelial response to endotoxin. AB - Sepsis-induced acute lung injury is a common clinical disorder in critically ill patients that is associated with high mortality. In this study, we investigated the role of p120-catenin (p120), a constituent of endothelial adherens junctions, in regulating the innate immune function of lungs. In mice in which acute lung injury was induced by i.p. administration of LPS, we observed a rapid decrease in the expression of p120 in lungs. The p120 protein expression was correlated inversely with severity of inflammation. Suppression of p120 expression in lung endothelial cells in mice using small interfering RNA resulted in high sensitivity to endotoxin and greatly increased the mortality compared with controls. Knockdown of p120 also increased the expression of ICAM-1, neutrophil recruitment, production of cytokines TNF-alpha and IL-6, pulmonary transvascular protein permeability, and lung water content in response to LPS. We demonstrated that endothelial p120 modulates lung innate immune function by interfering with the association of TLR4 with its adaptor MyD88 to block TLR4 signaling and NF kappaB activation in endothelial cells. In conclusion, these studies have uncovered a novel innate immune function of endothelial p120 in downregulating the lung inflammatory response to endotoxin through the suppression of TLR4 signaling. PMID- 21278344 TI - Cutting edge: cyclic polypeptide and aminoglycoside antibiotics trigger IL-1beta secretion by activating the NLRP3 inflammasome. AB - Clinical use of antibiotics is based on their capacity to inhibit bacterial growth via bacteriostatic or bacteriocidal effects. In this article, we show that the aminoglycoside antibiotic neomycin, the cyclic lipopeptide antibiotic polymyxin B, and the cyclic peptide antibiotics gramicidin and tyrothricin can induce IL-1beta secretion in bone marrow dendritic cells and macrophages. LPS priming was required to trigger the transcription and translation of pro-IL-1beta but was independent of TNFR or IL-1R signaling. All four antibiotics required the NLRP3 inflammasome, the adaptor ASC, and caspase-1 activation to secrete IL 1beta, a process that depended on potassium efflux but was independent of P2X7 receptor. All four antibiotics induced neutrophil influx into the peritoneal cavity of mice, which required NLRP3 only in the case of polymyxin B. Together, certain antibiotics have the potential to directly activate innate immunity of the host. PMID- 21278345 TI - Stromal cell networks regulate thymocyte migration and dendritic cell behavior in the thymus. AB - After entry into thymus, T cell progenitors migrate in the cortex and the medulla while completing their education. Recent reports have documented the dynamic and tortuous behavior of thymocytes. However, other than chemokines and/or segregated thymic substrates, the factors contributing to the dynamic patterns of thymocyte movement are poorly characterized. By combining confocal and dynamic two-photon microscopy, we demonstrate that thymocytes continuously migrate on thymic stromal cell networks. In addition to constituting "roads" for thymocytes, we observed that these networks also provide a scaffold on which dendritic cells attach themselves. These results highlight the central role of stromal microanatomy in orchestrating the multiple cellular interactions necessary for T cell migration/development within the thymus. PMID- 21278346 TI - GCN5 regulates the superoxide-generating system in leukocytes via controlling gp91-phox gene expression. AB - The superoxide anion (O(2)(-))-generating system is an important mechanism of innate immune response against microbial infection in phagocytes and is involved in signal transduction mediated by various physiological and pathological signals in phagocytes and other cells, including B lymphocytes. The O(2)(-)-generating system is composed of five specific proteins: p22-phox, gp91-phox, p40-phox, p47 phox, p67-phox, and a small G protein, Rac. Little is known regarding epigenetic regulation of the genes constituting the O(2)(-)-generating system. In this study, by analyzing the GCN5 (one of most important histone acetyltransferases) deficient DT40 cell line, we show that GCN5 deficiency causes loss of the O(2)(-) generating activity. Interestingly, transcription of the gp91-phox gene was drastically downregulated (to ~4%) in GCN5-deficient cells. To further study the involvement of GCN5 in transcriptional regulation of gp91-phox, we used in vitro differentiation system of U937 cells. When human monoblastic U937 cells were cultured in the presence of IFN-gamma, transcription of gp91-phox was remarkably upregulated, and the cells were differentiated to macrophage-like cells that can produce O(2)(-). Chromatin immunoprecipitation assay using the U937 cells during cultivation with IFN-gamma revealed not only that association of GCN5 with the gp91-phox gene promoter was significantly accelerated, but also that GCN5 preferentially elevated acetylation levels of H2BK16 and H3K9 surrounding the promoter. These results suggested that GCN5 regulates the O(2)(-)-generating system in leukocytes via controlling the gp91-phox gene expression as a supervisor. Our findings obtained in this study should be useful in understanding the molecular mechanisms involved in epigenetic regulation of the O(2)(-) generating system in leukocytes. PMID- 21278347 TI - The endocannabinoid 2-arachidonoyl-glycerol activates human neutrophils: critical role of its hydrolysis and de novo leukotriene B4 biosynthesis. AB - Although endocannabinoids are important players in nociception and obesity, their roles as immunomodulators remain elusive. The main endocannabinoids described to date, namely 2-arachidonoyl-glycerol (2-AG) and arachidonyl-ethanolamide (AEA), induce an intriguing profile of pro- and anti-inflammatory effects. This could relate to cell-specific cannabinoid receptor expression and/or the action of endocannabinoid-derived metabolites. Importantly, 2-AG and AEA comprise a molecule of arachidonic acid (AA) in their structure and are hydrolyzed rapidly. We postulated the following: 1) the released AA from endocannabinoid hydrolysis would be metabolized into eicosanoids; and 2) these eicosanoids would mediate some of the effects of endocannabinoids. To confirm these hypotheses, experiments were performed in which freshly isolated human neutrophils were treated with endocannabinoids. Unlike AEA, 2-AG stimulated myeloperoxidase release, kinase activation, and calcium mobilization by neutrophils. Although 2-AG did not induce the migration of neutrophils, it induced the release of a migrating activity for neutrophils. 2-AG also rapidly (1 min) induced a robust biosynthesis of leukotrienes, similar to that observed with AA. The effects of 2-AG were not mimicked nor prevented by cannabinoid receptor agonists or antagonists, respectively. Finally, the blockade of either 2-AG hydrolysis, leukotriene (LT) B(4) biosynthesis, or LTB(4) receptor 1 activation prevented all the effects of 2 AG on neutrophil functions. In conclusion, we demonstrated that 2-AG potently activates human neutrophils. This is the consequence of 2-AG hydrolysis, de novo LTB(4) biosynthesis, and an autocrine activation loop involving LTB(4) receptor 1. PMID- 21278348 TI - Human cord blood CD4+CD25hi regulatory T cells suppress prenatally acquired T cell responses to Plasmodium falciparum antigens. AB - In malaria endemic regions, a fetus is often exposed in utero to Plasmodium falciparum blood-stage Ags. In some newborns, this can result in the induction of immune suppression. We have previously shown these modulated immune responses to persist postnatally, with a subsequent increase in a child's susceptibility to infection. To test the hypothesis that this immune suppression is partially mediated by malaria-specific regulatory T cells (T(regs)) in utero, cord blood mononuclear cells (CBMC) were obtained from 44 Kenyan newborns of women with and without malaria at delivery. CD4(+)CD25(lo) T cells and CD4(+)CD25(hi) FOXP3(+) cells (T(regs)) were enriched from CBMC. T(reg) frequency and HLA-DR expression on T(regs) were significantly greater for Kenyan as compared with North American CBMC (p < 0.01). CBMC/CD4(+) T cells cultured with P. falciparum blood-stage Ags induced production of IFN-gamma, IL-13, IL-10, and/or IL-5 in 50% of samples. Partial depletion of CD25(hi) cells augmented the Ag-driven IFN-gamma production in 69% of subjects with malaria-specific responses and revealed additional Ag reactive lymphocytes in previously unresponsive individuals (n = 3). Addition of T(regs) to CD4(+)CD25(lo) cells suppressed spontaneous and malaria Ag-driven production of IFN-gamma in a dose-dependent fashion, until production was completely inhibited in most subjects. In contrast, T(regs) only partially suppressed malaria-induced Th2 cytokines. IL-10 or TGF-beta did not mediate this suppression. Thus, prenatal exposure to malaria blood-stage Ags induces T(regs) that primarily suppress Th1-type recall responses to P. falciparum blood-stage Ags. Persistence of these T(regs) postnatally could modify a child's susceptibility to malaria infection and disease. PMID- 21278349 TI - Type III IFNs in pteropid bats: differential expression patterns provide evidence for distinct roles in antiviral immunity. AB - Bats are known to harbor a number of emerging and re-emerging zoonotic viruses, many of which are highly pathogenic in other mammals but result in no clinical symptoms in bats. The ability of bats to coexist with viruses may be the result of rapid control of viral replication early in the immune response. IFNs provide the first line of defense against viral infection in vertebrates. Type III IFNs (IFN-lambdas) are a recently identified IFN family that share similar antiviral activities with type I IFNs. To our knowledge, we demonstrate the first functional analysis of type III IFNs from any species of bat, with the investigation of two IFN-lambda genes from the pteropid bat, Pteropus alecto. Our results demonstrate that bat type III IFN has similar antiviral activity to type I and III IFNs from other mammals. In addition, the two bat type III IFNs are differentially induced relative to each other and to type I IFNs after treatment or transfection with synthetic dsRNA. Infection with the bat paramyxovirus, Tioman virus, resulted in no upregulation of type I IFN production in bat splenocytes but was capable of inducing a type III IFN response in three of the four bats tested. To our knowledge, this is the first report to describe the simultaneous suppression of type I IFN and induction of type III IFN after virus infection. These results may have important implications for the role of type III IFNs in the ability of bats to coexist with viruses. PMID- 21278350 TI - Activated invariant NKT cells regulate osteoclast development and function. AB - Invariant NKT (iNKT) cells modulate innate and adaptive immune responses through activation of myeloid dendritic cells and macrophages and via enhanced clonogenicity, differentiation, and egress of their shared myeloid progenitors. Because these same progenitors give rise to osteoclasts (OCs), which also mediate the egress of hematopoietic progenitors and orchestrate bone remodeling, we hypothesized that iNKT cells would extend their myeloid cell regulatory role to the development and function of OCs. In this study, we report that selective activation of iNKT cells by alpha-galactosylceramide causes myeloid cell egress, enhances OC progenitor and precursor development, modifies the intramedullary kinetics of mature OCs, and enhances their resorptive activity. OC progenitor activity is positively regulated by TNF-alpha and negatively regulated by IFN gamma, but is IL-4 and IL-17 independent. These data demonstrate a novel role of iNKT cells that couples osteoclastogenesis with myeloid cell egress in conditions of immune activation. PMID- 21278351 TI - Human serum amyloid P functions as a negative regulator of the innate and adaptive immune responses to DNA vaccines. AB - The utility of DNA vaccines has been limited by their failure to elicit sufficiently potent immune responses in many human applications, whereas DNA vaccinations in mice have been very successful. However, the underlying mechanisms remain unknown. We hypothesize that serum amyloid P component (SAP), which has a species-specific, DNA-binding ability, contributes to the differences between human and mice and then limits DNA vaccine's efficacy in vivo. In our study, DNA vaccine-induced adaptive immune responses were also significantly decreased in the human SAP (hSAP) transgenic mice. Using human promonocytic cell line THP-1-derived macrophages as a cell model, we found that cells incubated with a hSAP-DNA complex showed significant defects in innate immune activations, whereas mouse SAP had similar, albeit very weak, activities. hSAP also significantly inhibited the functions of two identified DNA sentinels, high mobility group B protein 1 and antimicrobial peptide LL37, and redirected DNA update to FcRs leading to endocytosis and endosomal degradation. We also found that a chemical SAP inhibitor strongly recovered the suppressed innate immune responses to DNA in the presence of human serum and enhanced the immunogenicity of DNA vaccines in vivo. Our data indicated that SAP is a key negative regulator for innate immune responses to DNA and may be partly responsible for the insufficient immune responses after DNA vaccinations in humans. SAP suppression may be a novel strategy for improving efficacy of human DNA vaccines and requires further clinical investigations. PMID- 21278352 TI - Neutrophil survival and c-kit(+)-progenitor proliferation in Staphylococcus aureus-infected skin wounds promote resolution. AB - Polymorphonuclear neutrophils (PMNs) are critical for the formation, maintenance, and resolution of bacterial abscesses. However, the mechanisms that regulate PMN survival and proliferation during the evolution of an abscess are not well defined. Using a mouse model of Staphylococcus aureus abscess formation within a cutaneous wound, combined with real-time imaging of genetically tagged PMNs, we observed that a high bacterial burden elicited a sustained mobilization of PMNs from the bone marrow to the infected wound, where their lifespan was markedly extended. A continuous rise in wound PMN number, which was not accounted for by trafficking from the bone marrow or by prolonged survival, was correlated with the homing of c-kit(+)-progenitor cells from the blood to the wound, where they proliferated and formed mature PMNs. Furthermore, by blocking their recruitment with an antibody to c-kit, which severely limited the proliferation of mature PMNs in the wound and shortened mouse survival, we confirmed that progenitor cells are not only important contributors to PMN expansion in the wound, but are also functionally important for immune protection. We conclude that the abscess environment provides a niche capable of regulating PMN survival and local proliferation of bone marrow-derived c-kit(+)-progenitor cells. PMID- 21278353 TI - High-avidity cytotoxic T lymphocytes specific for a new PRAME-derived peptide can target leukemic and leukemic-precursor cells. AB - The cancer testis antigen (CTA) preferentially expressed antigen of melanoma (PRAME) is overexpressed by many hematologic malignancies, but is absent on normal tissues, including hematopoietic progenitor cells, and may therefore be an appropriate candidate for T cell-mediated immunotherapy. Because it is likely that an effective antitumor response will require high-avidity, PRAME-specific cytotoxic T lymphocytes (CTLs), we attempted to generate such CTLs using professional and artificial antigen-presenting cells loaded with a peptide library spanning the entire PRAME protein and consisting of 125 synthetic pentadecapeptides overlapping by 11 amino acids. We successfully generated polyclonal, PRAME-specific CTL lines and elicited high-avidity CTLs, with a high proportion of cells recognizing a previously uninvestigated HLA-A*02-restricted epitope, P435-9mer (NLTHVLYPV). These PRAME-CTLs could be generated both from normal donors and from subjects with PRAME(+) hematologic malignancies. The cytotoxic activity of our PRAME-specific CTLs was directed not only against leukemic blasts, but also against leukemic progenitor cells as assessed by colony forming-inhibition assays, which have been implicated in leukemia relapse. These PRAME-directed CTLs did not affect normal hematopoietic progenitors, indicating that this approach may be of value for immunotherapy of PRAME(+) hematologic malignancies. PMID- 21278354 TI - Hoxb4-YFP reporter mouse model: a novel tool for tracking HSC development and studying the role of Hoxb4 in hematopoiesis. AB - Hoxb4 overexpression promotes dramatic expansion of bone marrow (BM) hematopoietic stem cells (HSCs) without leukemic transformation and induces development of definitive HSCs from early embryonic yolk sac and differentiating embryonic stem cells. Knockout studies of Hoxb4 showed little effect on hematopoiesis, but interpretation of these results is obscured by the lack of direct evidence that Hoxb4 is expressed in HSCs and possible compensatory effects of other (Hox) genes. To evaluate accurately the pattern of Hoxb4 expression and to gain a better understanding of the physiologic role of Hoxb4 in the hemato poietic system, we generated a knock-in Hoxb4-yellow fluorescent protein (YFP) reporter mouse model. We show that BM Lin(-)Sca1(+)c-Kit(+) cells express Hoxb4 YFP and demonstrate functionally in the long-term repopulation assay that definitive HSCs express Hoxb4. Similarly, aorta-gonad-mesonephrous-derived CD45(+)CD144(+) cells, enriched for HSCs, express Hoxb4. Furthermore, yolk sac and placental HSC populations express Hoxb4. Unexpectedly, Hoxb4 expression in the fetal liver HSCs is lower than in the BM, reaching negligible levels in some HSCs, suggesting an insignificant role of Hoxb4 in expansion of fetal liver HSCs. Hoxb4 expression therefore would not appear to correlate with the cycling status of fetal liver HSCs, although highly proliferative HSCs from young BM show strong Hoxb4 expression. PMID- 21278355 TI - Prevalence and risk factors of the metabolic syndrome in adult survivors of childhood leukemia. AB - We evaluate the prevalence and risk factors of the metabolic syndrome (MS) in young adults surviving childhood leukemia. During the years 2007 to 2008, assessment of MS was proposed to all adults included in the Leucemie de l'Enfant et de l'Adolescent program, a French prospective multicentric cohort of leukemia survivors. Among 220 eligible patients, 184 (83.6%) had complete evaluation. Median age at evaluation and follow-up duration were 21.2 and 15.4 years. Overall prevalence of MS was 9.2% (95% confidence interval, 5.5-14.4). There was no association of MS with sex, age at diagnosis, leukemia subtype, steroid therapy, and central nervous system irradiation. Patients were stratified according to 4 therapeutic modalities: chemotherapy alone (n = 97), chemotherapy and central nervous system irradiation (n = 27), hematopoietic stem cell transplantation (HSCT) without (n = 17) or with (n = 43) total body irradiation (TBI). MS occurred in 5.2%, 11.1%, 5.9%, and 18.6% of them, respectively. The higher risk observed in the HSCT-TBI group was significant in univariate and in multivariate analysis (odds ratio [OR] = 3.9, P = .03). HSCT with TBI was associated with a higher rate of hypertriglyceridemia (OR = 4.5, P = .004), low level of high density lipoprotein cholesterol (OR = 2.5, P = .02), and elevated fasting glucose (OR = 6.1, P = .04) So, TBI is a major risk factor for MS. Further studies are warranted to explain this feature. PMID- 21278356 TI - Breast cancer risk in relation to the interval between menopause and starting hormone therapy. AB - BACKGROUND: Although breast cancer risk is greater in users of estrogen-progestin than estrogen-only formulations of menopausal hormonal therapy, reports on their effects have been somewhat inconsistent. We investigated whether the timing of these therapies affected breast cancer incidence. METHODS: A total of 1,129,025 postmenopausal UK women provided prospective information on hormonal therapy use and other factors relevant for breast cancer risk. We used Cox regression to estimate adjusted relative risks (RRs) of breast cancer in hormonal therapy users vs never users and calculated standardized incidence rates. All statistical tests were two-sided. RESULTS: During 4.05 million woman-years of follow-up, 15,759 incident breast cancers occurred, with 7107 in current users of hormonal therapy. Breast cancer incidence was increased in current users of hormonal therapy, returning to that of never users a few years after use had ceased. The relative risks for breast cancer in current users were greater if hormonal therapy was begun before or soon after menopause than after a longer gap (P(heterogeneity) < .001, for both estrogen-only and estrogen-progestin formulations). Among current users of estrogen-only formulations, there was little or no increase in risk if use began 5 years or more after menopause (RR = 1.05, 95% confidence interval [CI] = 0.89 to 1.24), but risk was statistically significantly increased if use began before or less than 5 years after menopause (RR = 1.43, 95% CI = 1.35 to 1.51). A similar pattern was observed among current users of estrogen-progestin formulations (RR = 1.53, 95% CI = 1.38 to 1.70, and RR = 2.04, 95% CI = 1.95 to 2.14, respectively). At 50-59 years of age, annual standardized incidence rates for breast cancer were 0.30% (95% CI = 0.29% to 0.31%) among never users of hormone therapy and 0.43% (95% CI = 0.42% to 0.45%) and 0.61% (95% CI = 0.59% to 0.64%), respectively, among current users of estrogen-only and estrogen-progestin formulations who began use less than 5 years after menopause. CONCLUSIONS: There was substantial heterogeneity in breast cancer risk among current users of hormonal therapy. Risks were greater among users of estrogen-progestin than estrogen-only formulations and if hormonal therapy started at around the time of menopause than later. PMID- 21278357 TI - The influence of time from menopause and mammography on hormone therapy-related breast cancer risk assessment. PMID- 21278358 TI - Unexpected hemoglobin A1c results. PMID- 21278359 TI - Commentary. PMID- 21278360 TI - Commentary. PMID- 21278363 TI - Delegation of Glucagon(r) in the school setting: a comparison of state legislation. AB - Delegation of nursing procedures and medication in school is fraught with legal and ethical concerns for the school nurse. Because nurses may be responsible for coordinating care for several school buildings, delegation of nursing care and medication administration has occurred out of necessity. Nurse Practice Acts in some states, but not all, allow for delegation of medication to unlicensed assistive personnel. This article explores Glucagon((r)) delegation laws in the United States and presents an argument against such delegation in states where Nurse Practice Acts do not allow for delegation of medication to unlicensed assistive personnel. PMID- 21278364 TI - Sexually active adolescent women: assessing family and peer relationships using event history calendars. AB - The purpose of this qualitative study is to explore family and peer relationships (including support and influence on risk behavior) among sexually active European American and African American adolescent girls in the context of risk behaviors documented on retrospective event history calendars (EHCs) and in interviews. The EHCs were completed by the adolescents prior to a clinic visit with a nurse practitioner at a school-based clinic in Southeast Michigan, and interviews were conducted after the visit. Constant comparative analysis of EHCs and interview data of 19 sexually active 15 to 19-year-old girls revealed that those with positive familial and peer support were less likely to report risk behaviors compared to those with poor family and peer relationships. School nurses and other providers working with adolescents to prevent risk behaviors could utilize the EHC to determine risks and develop education plans and interventions to reduce risk behaviors. PMID- 21278365 TI - HIV/AIDS-Related Stigma and Discrimination: A Study of Health Care Providers in Bangladesh. AB - People living with HIV/AIDS (PLWHA) are stigmatized and looked at negatively by people at large. Stigma, discrimination, and prejudice extend its reach to people associated with HIV-positive people such as health providers, hospital staff, as well as family member and friends. Studies demonstrate that, in low-income countries, especially in South Asia and sub-Saharan Africa, health providers' views toward the HIV-positive individuals is not very much different from the general population. The study has been qualitative in nature and conducted among health providers such as physicians and nurses attached to different hospitals. The study was conducted from March 2005 to May 2007. The study shows that 80% of the nurses and 90% of the physicians' behavior with the HIV-positive individuals were discriminatory. They talk to their patients standing far from them. The interview revealed that the spouses of the physicians and nurses in charge of the HIV-positive individuals put pressure to stop serving the patient or even quit the job. The notion that HIV is only transmitted through sexual activities is prevalent among them. Interestingly, although the physicians know well about the routes of transmission, they do not believe it by heart. Therefore, their fear of being infected makes them discriminate against the HIV-positive individuals. HIV related stigma remains a barrier to effectively fighting this pandemic. Fear of discrimination often prevents people from seeking treatment publicly. There are evidences that they were evicted from home by their families and rejected by their friends and colleagues. The stigma attached to HIV/AIDS can extend into the next generation, placing an emotional burden on them. PMID- 21278366 TI - Small ubiquitin-like modifier (SUMO) conjugation impedes transcriptional silencing by the polycomb group repressor Sex Comb on Midleg. AB - The Drosophila protein Sex Comb on Midleg (Scm) is a member of the Polycomb group (PcG), a set of transcriptional repressors that maintain silencing of homeotic genes during development. Recent findings have identified PcG proteins both as targets for modification by the small ubiquitin-like modifier (SUMO) protein and as catalytic components of the SUMO conjugation pathway. We have found that the SUMO-conjugating enzyme Ubc9 binds to Scm and that this interaction, which requires the Scm C-terminal sterile alpha motif (SAM) domain, is crucial for the efficient sumoylation of Scm. Scm is associated with the major Polycomb response element (PRE) of the homeotic gene Ultrabithorax (Ubx), and efficient PRE recruitment requires an intact Scm SAM domain. Global reduction of sumoylation augments binding of Scm to the PRE. This is likely to be a direct effect of Scm sumoylation because mutations in the SUMO acceptor sites in Scm enhance its recruitment to the PRE, whereas translational fusion of SUMO to the Scm N terminus interferes with this recruitment. In the metathorax, Ubx expression promotes haltere formation and suppresses wing development. When SUMO levels are reduced, we observe decreased expression of Ubx and partial haltere-to-wing transformation phenotypes. These observations suggest that SUMO negatively regulates Scm function by impeding its recruitment to the Ubx major PRE. PMID- 21278367 TI - Easyfig: a genome comparison visualizer. AB - Easyfig is a Python application for creating linear comparison figures of multiple genomic loci with an easy-to-use graphical user interface. BLAST comparisons between multiple genomic regions, ranging from single genes to whole prokaryote chromosomes, can be generated, visualized and interactively coloured, enabling a rapid transition between analysis and the preparation of publication quality figures. AVAILABILITY: Easyfig is freely available (under a GPL license) for download (for Mac OS X, Unix and Microsoft Windows) from the SourceForge web site: http://easyfig.sourceforge.net/. PMID- 21278368 TI - Duplicated C-class MADS-box genes reveal distinct roles in gynostemium development in Cymbidium ensifolium (Orchidaceae). AB - The orchid floral organs represent novel and effective structures for attracting pollination vectors. In addition, to avoid inbreeding, the androecium and gynoecium are united in a single structure termed the gynostemium. Identification of C-class MADS-box genes regulating reproductive organ development could help determine the level of homology with the current ABC model of floral organ identity in orchids. In this study, we isolated and characterized two C-class AGAMOUS-like genes, denoted CeMADS1 and CeMADS2, from Cymbidium ensifolium. These two genes showed distinct spatial and temporal expression profiles, which suggests their functional diversification during gynostemium development. Furthermore, the expression of CeMADS1 but not CeMADS2 was eliminated in the multitepal mutant whose gynostemium is replaced by a newly emerged flower, and this ecotopic flower continues to produce sepals and petals centripetally. Protein interaction relationships among CeMADS1, CeMADS2 and E-class PeMADS8 proteins were assessed by yeast two-hybrid analysis. Both CeMADS1 and CeMADS2 formed homodimers and heterodimers with each other and the E-class PeMADS protein. Furthermore, transgenic Arabidopsis plants overexpressing CeMADS1 or CeMADS2 showed limited growth of primary inflorescence. Thus, CeMADS1 may have a pivotal C function in reproductive organ development in C. ensifolium. PMID- 21278369 TI - Case studies in reproducibility. AB - Reproducible research is a concept of providing access to data and software along with published scientific findings. By means of some case studies from different disciplines, we will illustrate reasons why readers should be given the possibility to look at the data and software independently from the authors of the original publication. We report results of a survey comprising 100 papers recently published in Bioinformatics. The main finding is that authors of this journal share a culture of making data available. However, the number of papers where source code for simulation studies or analyzes is available is still rather limited. PMID- 21278370 TI - Developing a logic model for youth mental health: participatory research with a refugee community in Beirut. AB - Although logic models are now touted as an important component of health promotion planning, implementation and evaluation, there are few published manuscripts that describe the process of logic model development, and fewer which do so with community involvement, despite the increasing emphasis on participatory research. This paper describes a process leading to the development of a logic model for a youth mental health promotion intervention using a participatory approach in a Palestinian refugee camp in Beirut, Lebanon. First, a needs assessment, including quantitative and qualitative data collection was carried out with children, parents and teachers. The second phase was identification of a priority health issue and analysis of determinants. The final phase in the construction of the logic model involved development of an intervention. The process was iterative and resulted in a more grounded depiction of the pathways of influence informed by evidence. Constructing a logic model with community input ensured that the intervention was more relevant to community needs, feasible for implementation and more likely to be sustainable. PMID- 21278371 TI - Learning effect of a conditional cash transfer programme on poor rural women's selection of delivery care in Mexico. AB - BACKGROUND The Mexican programme Oportunidades/Progresa conditionally transfers money to beneficiary families. Over the past 10 years, poor rural women have been obliged to attend antenatal care (ANC) visits and reproductive health talks. We propose that the length of time in the programme influences women's preferences, thus increasing their use not only of services directly linked to the cash transfers, but also of other services, such as clinic-based delivery, whose utilization is not obligatory. OBJECTIVE To analyse the long-term effect of Oportunidades on women's use of antenatal and delivery care. METHODOLOGY 5051 women aged between 15 and 49 years old with at least one child aged less than 24 months living in rural localities were analysed. Multilevel probit and logit models were used to analyse ANC visits and physician/nurse attended delivery, respectively. Models were adjusted with individual and socio-economic variables and the locality's exposure time to Oportunidades. Findings On average women living in localities with longer exposure to Oportunidades report 2.1% more ANC visits than women living in localities with less exposure. Young women aged 15-19 and 20-24 years and living in localities with longer exposure to Oportunidades (since 1998) have 88% and 41% greater likelihood of choosing a physician/nurse vs. traditional midwife for childbirth, respectively. Women of indigenous origin are 68.9% less likely to choose a physician/nurse for delivery care than non indigenous women. CONCLUSIONS An increase in the average number of ANC visits has been achieved among Oportunidades beneficiaries. An indirect effect is the increased selection of a physician/nurse for delivery care among young women living in localities with greater exposure time to Oportunidades. Disadvantaged women in Mexico (indigenous women) continue to have less access to skilled delivery care. Developing countries must develop strategies to increase access and use of skilled obstetric care for marginalized women. PMID- 21278372 TI - Midwifery training in post-conflict Afghanistan: tensions between educational standards and rural community needs. AB - OBJECTIVE: To compare the performance of students selected for midwifery education by three methods: community mobilization in rural Afghanistan, a regional examination by the Institute of Health Sciences (IHS), and the National University Entrance Examination (NUEE). METHODS: A retrospective survey was conducted in January 2009 on academic records of 178 midwives trained at the IHS in Herat, including 147 graduates from 2003-08 and the cohort of 31 final semester students graduating in March 2009. An interview survey of the 31 final semester students was also conducted. Outcome variables included knowledge, skills and employment status, stratified by method of selection. Individual attributes including completion of high school, marital status, age and urban/rural residence were also assessed. Data analysis used STATA version 2009. Significance was measured by appropriate statistical tests. Findings were verified by key informant interviews. RESULTS: Ninety-six per cent of midwifery graduates selected by communities were employed, compared with 74% chosen by the IHS and 82% by the NUEE. Sixty-three per cent of community-selected graduates were working in rural locations, compared with 43% recruited by IHS and 9% by the NUEE. While fewer midwifery graduates selected by communities had completed high school and their academic performance was slightly lower during training, there was no difference in their pass rates and acquisition of practical skills. CONCLUSIONS: Community mobilization for local selection of trainees achieved significantly higher employment levels of trained midwives in high-risk rural communities than usual selection methods, without compromising quality of skills. PMID- 21278373 TI - From drought to deluge: how information overload saturated absorption capacity in a disrupted health sector. AB - Provision of technical assistance is a common form of support to health sectors emerging from prolonged conflicts. But what actions signal that the Ministry of Health (MoH) is, or is not, actively analysing and digesting the output of this assistance? Where are the boundaries between doing with and doing for? This article presents a qualitative description of an early post-conflict policy process in southern Sudan, which represented an opportunity to test these boundaries. The methodology of provision of technical assistance to the MoH in the formulation of a human resource plan is reviewed. Initial objectives are compared with the results accomplished. Shortcomings are discussed and recommendations for technical assistance programmes in similar contexts are provided. Between October 2005 and May 2006, World Health Organization advisers supported the MoH in conducting a human resources assessment to lay the grounds for a human resources development plan. The study employed three consultants, ten data collectors and entailed questionnaires, field visits, interviews and a review of literature. The survey shed new important evidence on the human resources situation in southern Sudan, both in quantitative and qualitative terms, and formulated specific recommendations. The formulation of the human resources plan, however, took another direction, apparently unrelated to the findings of the survey. Various factors contributed to the scope and methodology of the survey being inappropriate to the reality of southern Sudan. In the presence of systemic capacity gaps, including uncertain governance and precarious management systems, the benefit of one-off comprehensive surveys is likely to be negligible. Inaction is not always rooted in the lack of information, as too often assumed; this case study exposes the limits of a rationalistic approach to policy formulation and planning in the field of human resources for health. An alternative approach that entails incremental steps to institutional capacity building is suggested. PMID- 21278374 TI - A guide to web tools to prioritize candidate genes. AB - Finding the most promising genes among large lists of candidate genes has been defined as the gene prioritization problem. It is a recurrent problem in genetics in which genetic conditions are reported to be associated with chromosomal regions. In the last decade, several different computational approaches have been developed to tackle this challenging task. In this study, we review 19 computational solutions for human gene prioritization that are freely accessible as web tools and illustrate their differences. We summarize the various biological problems to which they have been successfully applied. Ultimately, we describe several research directions that could increase the quality and applicability of the tools. In addition we developed a website (http://www.esat.kuleuven.be/gpp) containing detailed information about these and other tools, which is regularly updated. This review and the associated website constitute together a guide to help users select a gene prioritization strategy that suits best their needs. PMID- 21278375 TI - PHAST and RPHAST: phylogenetic analysis with space/time models. AB - The PHylogenetic Analysis with Space/Time models (PHAST) software package consists of a collection of command-line programs and supporting libraries for comparative genomics. PHAST is best known as the engine behind the Conservation tracks in the University of California, Santa Cruz (UCSC) Genome Browser. However, it also includes several other tools for phylogenetic modeling and functional element identification, as well as utilities for manipulating alignments, trees and genomic annotations. PHAST has been in development since 2002 and has now been downloaded more than 1000 times, but so far it has been released only as provisional ('beta') software. Here, we describe the first official release (v1.0) of PHAST, with improved stability, portability and documentation and several new features. We outline the components of the package and detail recent improvements. In addition, we introduce a new interface to the PHAST libraries from the R statistical computing environment, called RPHAST, and illustrate its use in a series of vignettes. We demonstrate that RPHAST can be particularly useful in applications involving both large-scale phylogenomics and complex statistical analyses. The R interface also makes the PHAST libraries acccessible to non-C programmers, and is useful for rapid prototyping. PHAST v1.0 and RPHAST v1.0 are available for download at http://compgen.bscb.cornell.edu/phast, under the terms of an unrestrictive BSD style license. RPHAST can also be obtained from the Comprehensive R Archive Network (CRAN; http://cran.r-project.org). PMID- 21278376 TI - Maternal worries about child underweight mediate and moderate the relationship between child feeding disorders and mother-child feeding interactions. AB - OBJECTIVE: To examine the role of maternal worries about child underweight and undereating in mother-child feeding interactions with children having a feeding disorder (FD). METHOD: Participants were 27 children diagnosed with nonorganic based FD and 28 children without FD. Mothers were interviewed about their worries about child underweight and undereating. Mother-child interactions were videotaped during feeding. RESULTS: Maternal child weight-related worries acted as both a mediator and a moderator. The more negative mother-child interactions found in the FD group, compared to the control group, were explained by greater maternal worry regarding child underweight. Furthermore, mother-child interactions within the FD group were not at risk per se, but only when coupled with high maternal worries about children's underweight. CONCLUSION: Worry about child underweight partially explains the development of negative feeding interactions when having children with FD, signifying clinical implications for the treatment of FD. PMID- 21278377 TI - Commentary: Dyadic analyses of family data. PMID- 21278378 TI - The effects of interactive and passive distraction on cold pressor pain in preschool-aged children. AB - OBJECTIVE: Using a mixed model design, this study examined the effects of interactive versus passive distraction on healthy preschool-aged children's cold pressor pain tolerance. METHODS: Sixty-one children aged 3-5 years were randomly assigned to one of the following: interactive distraction, passive distraction, or no distraction control. Participants underwent a baseline cold pressor trial followed by interactive distraction trial, passive distraction trial, or second baseline trial. One or two additional trials followed. Children originally assigned to distraction received the alternate distraction intervention. Controls participated in both interactive and passive distraction trials in counterbalanced order. RESULTS: Participants showed significantly higher pain tolerance during both interactive and passive distraction relative to baseline. The two distraction conditions did not differ. CONCLUSIONS: Interactive and passive video game distraction appear to be effective for preschool-aged children during laboratory pain exposure. Future studies should examine whether more extensive training would enhance effects of interactive video game distraction. PMID- 21278379 TI - Treatment factors affecting longitudinal quality of life in new onset pediatric epilepsy. AB - OBJECTIVES: Recognizing the importance of patient-reported outcomes, this longitudinal, prospective study examined: Changes in health-related quality of life (HRQOL) over seven months following antiepileptic drug (AED) initiation and the relationship of seizures, AED side-effects, and AED type to HRQOL. METHOD: Parents of 124 children with newly diagnosed epilepsy completed measures of HRQOL and side-effects at each clinic visit. Treatment information was also collected. RESULTS: HRQOL remained stable over time; however, seizures and AED side-effects significantly affected multiple HRQOL domains. Higher seizure activity was associated with decreased Physical HRQOL. Side-effects were negatively associated with all HRQOL domains. Children taking carbamazepine who experienced higher side effects early in therapy demonstrated declining emotional functioning compared to children experiencing no/some side-effects. CONCLUSIONS: AED side-effects, AED type, and seizure frequency were associated with longitudinal HRQOL in children with newly-diagnosed epilepsy. Routine assessment of AED side-effects and HRQOL may be useful for clinical decision making. PMID- 21278380 TI - ATF2 interacts with beta-cell-enriched transcription factors, MafA, Pdx1, and beta2, and activates insulin gene transcription. AB - Pancreatic beta-cell-restricted expression of insulin is established through several critical cis-regulatory elements located in the insulin gene promoter region. The principal cis elements are A-boxes, E1, and C1/RIPE3b. The beta-cell enriched transcription factors Pdx1 and Beta2 bind to the A-boxes and E1 element, respectively. A beta-cell-specific trans-acting factor binding to C1/RIPE3b (termed RIPE3b1 activator) was detected by electrophoretic mobility shift assay and has been identified as MafA, a member of the Maf family of basic leucine zipper (bZip) proteins. Here, ATF2, a member of the ATF/CREB family of basic leucine zipper proteins, was identified as a component of the RIPE3b1 activator. ATF2 alone was unable to bind to the C1/RIPE3b element but acquired binding capacity upon complex formation with MafA. ATF2 also interacted with Pdx1 and Beta2, and co-expression of ATF2, MafA, Pdx1, and Beta2 resulted in a synergistic activation of the insulin promoter. Immunohistochemical analysis of mouse pancreas tissue sections showed that ATF2 is enriched in islet endocrine cells, including beta-cells. RNAi-mediated knockdown of MafA or ATF2 in the MIN6 beta cell line resulted in a significant decrease in endogenous levels of insulin mRNA. These data indicate that ATF2 is an essential component of the positive regulators of the insulin gene expression. PMID- 21278381 TI - Role of insert-1 of myosin VI in modulating nucleotide affinity. AB - Myosin VI is unique in its directionality among myosin superfamily members and also displays a slow and strain-dependent rate of ATP binding that allows for gating between its heads. In this study we demonstrate that leucine 310 is positioned by a class VI-specific insert, insert-1, so as to account for the selective hindrance of ATP versus ADP binding. Mutation of leucine 310 to glycine removes all influence of insert-1 on ATP binding. Furthermore, by analyzing myosin VI structures with either leucine 310 substituted to a glycine or complete removal of insert-1, we conclude that nucleotides may initially bind to myosin by their purine rings before docking their phosphate moieties. Otherwise, insert-1 could not exert a differential influence on ATP versus ADP binding. PMID- 21278382 TI - Beta-agonist-associated reduction in RGS5 expression promotes airway smooth muscle hyper-responsiveness. AB - Although short-acting and long-acting inhaled beta(2)-adrenergic receptor agonists (SABA and LABA, respectively) relieve asthma symptoms, use of either agent alone without concomitant anti-inflammatory drugs (corticosteroids) may increase the risk of disease exacerbation in some patients. We found previously that pretreatment of human precision-cut lung slices (PCLS) with SABA impaired subsequent beta(2)-agonist-induced bronchodilation, which occurred independently of changes in receptor quantities. Here we provide evidence that prolonged exposure of cultured human airway smooth muscle (HuASM) cells to beta(2)-agonists directly augments procontractile signaling pathways elicited by several compounds including thrombin, bradykinin, and histamine. Such treatment did not increase surface receptor amounts or expression of G proteins and downstream effectors (phospholipase Cbeta and myosin light chain). In contrast, beta-agonists decreased expression of regulator of G protein signaling 5 (RGS5), which is an inhibitor of G-protein-coupled receptor (GPCR) activity. RGS5 knockdown in HuASM increased agonist-evoked intracellular calcium flux and myosin light chain (MLC) phosphorylation, which are prerequisites for contraction. PCLS from Rgs5(-/-) mice contracted more to carbachol than those from WT mice, indicating that RGS5 negatively regulates bronchial smooth muscle contraction. Repetitive beta(2) agonist use may not only lead to reduced bronchoprotection but also to sensitization of excitation-contraction signaling pathways as a result of reduced RGS5 expression. PMID- 21278383 TI - Molecular recognition of the Tes LIM2-3 domains by the actin-related protein Arp7A. AB - Actin-related proteins (Arps) are a highly conserved family of proteins that have extensive sequence and structural similarity to actin. All characterized Arps are components of large multimeric complexes associated with chromatin or the cytoskeleton. In addition, the human genome encodes five conserved but largely uncharacterized "orphan" Arps, which appear to be mostly testis-specific. Here we show that Arp7A, which has 43% sequence identity with beta-actin, forms a complex with the cytoskeletal proteins Tes and Mena in the subacrosomal layer of round spermatids. The N-terminal 65-residue extension to the actin-like fold of Arp7A interacts directly with Tes. The crystal structure of the 1-65(Arp7A).LIM2 3(Tes).EVH1(Mena) complex reveals that residues 28-49 of Arp7A contact the LIM2-3 domains of Tes. Two alanine residues from Arp7A that occupy equivalent apolar pockets in both LIM domains as well as an intervening GPAK linker that binds the LIM2-3 junction are critical for the Arp7A-Tes interaction. Equivalent occupied apolar pockets are also seen in the tandem LIM domain structures of LMO4 and Lhx3 bound to unrelated ligands. Our results indicate that apolar pocket interactions are a common feature of tandem LIM domain interactions, but ligand specificity is principally determined by the linker sequence. PMID- 21278384 TI - Compromised myocardial energetics in hypertrophied mouse hearts diminish the beneficial effect of overexpressing SERCA2a. AB - The sarcoplasmic reticulum calcium ATPase (SERCA) plays a central role in regulating intracellular Ca(2+) homeostasis and myocardial contractility. Several studies show that improving Ca(2+) handling in hypertrophied rodent hearts by increasing SERCA activity results in enhanced contractile function. This suggests that SERCA is a potential target for gene therapy in cardiac hypertrophy and failure. However, it raises the issue of increased energy cost resulting from a higher ATPase activity. In this study, we determined whether SERCA overexpression alters the energy cost of increasing myocardial contraction in mouse hearts with pressure-overload hypertrophy using (31)P NMR spectroscopy. We isolated and perfused mouse hearts from wild-type (WT) and transgenic (TG) mice overexpressing the cardiac isoform of SERCA (SERCA2a) 8 weeks after ascending aortic constriction (left ventricular hypertrophy (LVH)) or sham operation. We found that overexpressing SERCA2a enhances myocardial contraction and relaxation in normal mouse hearts during inotropic stimulation with isoproterenol. Energy consumption was proportionate to the increase in contractile function. Thus, increasing SERCA2a expression in the normal heart allows an enhanced inotropic response with no compromise in energy supply and demand. However, this advantage was not sustained in LVH hearts in which the energetic status was compromised. Although the overexpression of SERCA2a prevented the down-regulation of SERCA protein in LVH hearts, TG-LVH hearts showed no increase in inotropic response when compared with WT-LVH hearts. Our results suggest that energy supply may be a limiting factor for the benefit of SERCA overexpression in hypertrophied hearts. Thus, strategies combining energetic support with increasing SERCA activity may improve the therapeutic effectiveness for heart failure. PMID- 21278385 TI - Biochemical characterization of the novel rice kinesin K23 and its kinetic study using fluorescence resonance energy transfer between an intrinsic tryptophan residue and a fluorescent ATP analogue. AB - We previously demonstrated that the rice kinesin K16, which belongs to the kinesin-7 subfamily, has unique enzymatic properties and atomic structure within key functional regions. In this study, we focused on a novel rice plant kinesin, K23, which also belongs to the kinesin-7 subfamily. The biochemical characterization of the K23 motor domain (K23MD) was studied and compared with the rice kinesin K16 and other related kinesins. K23 exhibits ~45-fold (1.3 Pi mol(-1) site mol(-1) s(-1)) lower microtubule-dependent ATPase activity than conventional kinesins, whereas its affinity for microtubules is comparable with conventional kinesins. MgADP-free K23 is unstable compared with the unusually stable MgADP-free K16MD. The enzymatic properties of K23MD are somewhat different from those of K16. We used a fluorescent ATP analogue 2'(3')-O-(N' methylanthraniloyl)-ATP (mant-ATP) for the kinetic characterization of K23. The fluorescence of mant-ATP was not significantly altered during its hydrolysis by K23. However, significant fluorescence resonance energy transfer (FRET) between mant-ATP and W21 in the motor domain was observed. The kinetic study using FRET revealed that K23 has unique kinetic characteristics when compared with other kinesins. PMID- 21278386 TI - Arginine increases the solubility of alkyl gallates through interaction with the aromatic ring. AB - We have recently proposed the application of solubilizing effects of arginine to poorly soluble aromatic compounds for drug discovery research. In this study, we compared the solubilizing effects of arginine with those of other amino acids, salts and a surfactant using alkyl gallates as model drug substances of low aqueous solubility. The solubilizing effects of arginine on the alkyl gallates were distinct compared with those of other amino acids and salts; the effects were even greater than those achieved using a strongly chaotropic guanidinium ion. Transfer free energy of the alkyl gallates from water to arginine solution depended weakly on their dissolution free energy in water, which is in contrast to sodium dodecyl sulphate that showed strong dependence. The present results suggest that arginine solubilizes alkyl gallates through interaction with the aromatic moiety and sodium dodecyl sulphate does so by interacting with alkyl groups. PMID- 21278387 TI - Influence of Ser/Pro-rich domain and kinase domain of double cortin-like protein kinase on microtubule-binding activity. AB - Doublecortin-like protein kinase (DCLK) is a Ser/Thr protein kinase predominantly expressed in brain. DCLK is composed of three functional domains; the N-terminal doublecortin-like (DC) domain, the C-terminal kinase domain and Ser/Pro-rich (SP) domain in between DC and kinase domains. Although the DC domain is known to mediate microtubule association, functional roles of the SP domain and the kinase domain on microtubule association is not known. In this study, we investigated the microtubule-binding activity of zebrafish DCLK (zDCLK) using various deletion mutants and chimeric proteins. The microtubule-binding activity of various mutants of zDCLK was assessed both by immunocytochemical analysis and by biochemical analysis using detergent extraction method. When the kinase domain was removed from zDCLK, the microtubule-binding activity was significantly enhanced. Although the zDCLK(DC + SP) mutant showed a strong microtubule-binding activity, the DC domain alone showed much lower microtubule-binding activity, indicating that the SP domain of zDCLK plays a role in enhancing microtubule binding activity of the DC domain. These results suggest that both the kinase domain and the SP domain are involved in regulating the microtubule-binding activity of DCLK. PMID- 21278388 TI - A homozygous nonsense mutation (c.214C->A) in the biliverdin reductase alpha gene (BLVRA) results in accumulation of biliverdin during episodes of cholestasis. AB - BACKGROUND: Green jaundice is a rare finding usually associated with end-stage liver disease. OBJECTIVE The authors investigated two unrelated Inuit women from different geographical areas in Greenland who had episodes of green jaundice associated with biliary obstruction. METHODS AND RESULTS: The crises were accompanied by increased biochemical markers of cholestasis, together with absent or moderate hyperbilirubinaemia. In contrast, high-performance liquid chromatography tandem mass spectrometry showed hypercholanaemia and high concentrations of biliverdin IXalpha in serum, urine, bile and milk. Hyperbiliverdinaemia disappeared after surgical correction of the cholestasis. Analysis of the coding sequence of the biliverdin reductase alpha (BVRalpha) gene (BLVRA) detected three single-nucleotide polymorphisms: c.90G->A, c.214C->A and c.743A->C, which result in p.Ala3Thr, p.Ser44X and p.Gly220Gly, respectively. With the use of TaqMan probes, homozygosity for c.214C->A was found in both patients. Both parents of one of these patients were heterozygous for the inactivating mutation. Her brother was homozygous for normal alleles. Although her sister was also homozygous for the c.214C->A mutation, she had never had hyperbiliverdinaemia or cholestasis. With the use of human liver RNA, the BVRalpha coding sequence was cloned, and the variant containing c.214C->A was generated by site-directed mutagenesis. Both proteins were expressed in human hepatoma liver cells and Xenopus laevis oocytes. Immunoblotting, immunofluorescence and functional assays of BVRalpha activity revealed that the mutated sequence generates a truncated protein with no catalytic activity. CONCLUSION: This is the first report of a homozygous BLVRA inactivating mutation indicating that the complete absence of BVRalpha activity is a non-lethal condition, the most evident phenotypic characteristic of which is the appearance of green jaundice accompanying cholestasis episodes. PMID- 21278389 TI - Deletions and rearrangements of the H19/IGF2 enhancer region in patients with Silver-Russell syndrome and growth retardation. AB - Silver-Russell syndrome (SRS) is characterised by prenatal and postnatal growth retardation, dysmorphic facial features, and body asymmetry. In 35-60% of SRS cases the paternally methylated imprinting control region (ICR) upstream of the H19 gene (H19-ICR) is hypomethylated, leading to downregulation of IGF2 and bi allelic expression of H19. H19 and IGF2 are reciprocally imprinted genes on chromosome 11p15. The expression is regulated by the imprinted methylation of the ICR, which modulates the transcription of H19 and IGF2 facilitated by enhancers downstream of H19. A promoter element of IGF2, IGF2P0, is differentially methylated equivalently to the H19-ICR, though in a small number of SRS cases this association is disrupted--that is, hypomethylation affects either H19-ICR or IGF2P0. Three pedigrees associated with hypomethylation of IGF2P0 in the probands are presented here, two with paternally derived deletions, and one with a balanced translocation of inferred paternal origin. They all have a breakpoint within the H19/IGF2 enhancer region. One proband has severe growth retardation, the others have SRS. This is the first report of paternally derived structural chromosomal mutations in 11p15 causing SRS. These cases define a novel aetiology of the growth retardation in SRS, namely, dissociation of IGF2 from its enhancers. PMID- 21278390 TI - High incidence of recurrent copy number variants in patients with isolated and syndromic Mullerian aplasia. AB - BACKGROUND: Congenital malformations involving the Mullerian ducts are observed in around 5% of infertile women. Complete aplasia of the uterus, cervix, and upper vagina, also termed Mullerian aplasia or Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome, occurs with an incidence of around 1 in 4500 female births, and occurs in both isolated and syndromic forms. Previous reports have suggested that a proportion of cases, especially syndromic cases, are caused by variation in copy number at different genomic loci. METHODS: In order to obtain an overview of the contribution of copy number variation to both isolated and syndromic forms of Mullerian aplasia, copy number assays were performed in a series of 63 cases, of which 25 were syndromic and 38 isolated. RESULTS: A high incidence (9/63, 14%) of recurrent copy number variants in this cohort is reported here. These comprised four cases of microdeletion at 16p11.2, an autism susceptibility locus not previously associated with Mullerian aplasia, four cases of microdeletion at 17q12, and one case of a distal 22q11.2 microdeletion. Microdeletions at 16p11.2 and 17q12 were found in 4/38 (10.5%) cases with isolated Mullerian aplasia, and at 16p11.2, 17q12 and 22q11.2 (distal) in 5/25 cases (20%) with syndromic Mullerian aplasia. CONCLUSION: The finding of microdeletion at 16p11.2 in 2/38 (5%) of isolated and 2/25 (8%) of syndromic cases suggests a significant contribution of this copy number variant alone to the pathogenesis of Mullerian aplasia. Overall, the high incidence of recurrent copy number variants in all forms of Mullerian aplasia has implications for the understanding of the aetiopathogenesis of the condition, and for genetic counselling in families affected by it. PMID- 21278391 TI - Cranial meningiomas in 411 neurofibromatosis type 2 (NF2) patients with proven gene mutations: clear positional effect of mutations, but absence of female severity effect on age at onset. AB - BACKGROUND: Meningiomas have been reported to occur in approximately 50% of neurofibromatosis type 2 (NF2) patients. The NF2 gene is commonly biallelically inactivated in both schwannomas and meningiomas. The spectrum of NF2 mutations consists mainly of truncating (nonsense and frameshift) mutations. A smaller number of patients have missense mutations, which are associated with a milder disease phenotype. METHODS: This study analysed the cumulative incidence and gender effects as well as the genotype-phenotype correlation between the position of the NF2 mutation and the occurrence of cranial meningiomas in a cohort of 411 NF2 patients with proven NF2 mutations. RESULTS AND CONCLUSION: Patients with mutations in exon 14 or 15 were least likely to develop meningiomas. Cumulative risk of cranial meningioma to age 50 years was 70% for exons 1-3, 81% for exons 4 6, 49% for exons 7-9, 56% for exons 10-13, and 28% for exons 14-15. In the cohort of 411 patients, no overall gender bias was found for occurrence of meningioma in NF2 disease. Cumulative incidence of meningioma was close to 80% by 70 years of age for both males and females, but incidence by age 20 years was slightly increased in males (male 25%, female 18%; p=0.023). Conversely, an increased risk of meningiomas in women with mosaic NF2 disease was also found. PMID- 21278392 TI - A molecular analysis of individuals with neurofibromatosis type 1 (NF1) and optic pathway gliomas (OPGs), and an assessment of genotype-phenotype correlations. AB - BACKGROUND: Neurofibromatosis type 1 (NF1) affects 1 in 2500 people, and 15% of these may develop an optic pathway glioma (OPG). OPGs behave differently in NF1, and, given their frequency, surveillance is important. However, this is difficult because of the additional complications these patients may have, such as learning difficulties. Management is also different given that NF1 results from loss of function of tumour suppressor gene. A genotype-phenotype correlation may help to determine who is at risk of developing these tumours, aid focused screening, and shed light on response to treatments. METHODS: As part of a long-term follow-up study of patients with NF1 OPGs, the authors assessed genotype-phenotype correlation. Fluorescein in situ hybridisation was performed to identify large deletions, and then a full gene screen for mutations, by denaturing high performance liquid chromatography. RESULTS: 80 patients with NF1 OPGs were identified, and molecular analyses were performed in a subset of 29. A clustering of pathogenic changes in the 5' tertile of the gene was found. The authors combined these results with those for another two NF1 OPG cohorts and collectively found the same trend. When compared with a control population of NF1 patients without an OPG, the OR of a mutation being present in the 5' tertile was 6.05 (p=0.003) in the NF1 OPG combined cohorts. CONCLUSION: It is possible that genotype is a significant determinant of the risk of development of OPGs in NF1. PMID- 21278393 TI - Septic arthritis following anterior cruciate ligament reconstruction secondary to Clostridium sporogenes; a rare clinical pathogen. AB - A case of septic arthritis post anterior cruciate ligament reconstruction secondary to Clostridium sporogenes is described in a 19-year-old man. C sporogenes is a rare clinical pathogen and this is believed to be the first case of septic arthritis due to the organism. The patient responded to arthroscopic washout, synovectomy and combination antibiotic therapy. A review of the literature is also presented. PMID- 21278394 TI - Carcinoid tumour associated with enterovirus infection. AB - Enteroviruses commonly infect the gastrointestinal tract, and replication of enteroviruses has been well documented in the Peyer patches of the small bowel. Chronic enterovirus infection has been found in the stomach and terminal ileum of patients with myalgic encephalomyelitis/chronic fatigue syndrome. The authors report the unexpected finding of enterovirus VP1 protein, by immunoperoxidase staining, in carcinoid tumours found in one patient with myalgic encephalomyelitis/chronic fatigue syndrome and another patient with chronic lower quadrant abdominal pain, and suggest a possible association between enteroviruses and tumorigenesis. PMID- 21278395 TI - Peripheral neuropathy as an adverse effect of imatinib therapy. PMID- 21278396 TI - Risk of sports: do we need a pre-participation screening for competitive and leisure athletes? AB - Sudden cardiac arrest is most often the first clinical manifestation of an underlying cardiovascular disease and usually occurs in previously asymptomatic athletes. The risk benefit ratio of physical exercise differs between young competitive athletes and middle-age/senior individuals engaged in leisure-time sports activity. Competitive sports are associated with an increase in the risk of sudden cardiovascular death (SCD) in susceptible adolescents and young adults with underlying cardiovascular disorders. In middle-age/older individuals, physical activity can be regarded as a 'two-edged sword': vigorous exertion increases the incidence of acute coronary events in those who did not exercise regularly, whereas habitual physical activity reduces the overall risk of myocardial infarction and SCD. Although cardiovascular pre-participation evaluation offers the potential to identify athletes with life-threatening cardiovascular abnormalities before onset of symptoms and may reduce their risk of SCD, there is a significant debate among cardiologists about efficacy, impact of false-positive results and cost-effectiveness of routine screening. This review presents an appraisal of the available data and criticisms concerning screening programmes aimed to prevent SCD of either young competitive athletes or older individuals engaged in leisure-time sports activity. PMID- 21278397 TI - Adiponectin expression in patients with inflammatory cardiomyopathy indicates favourable outcome and inflammation control. AB - AIMS: Circulating adiponectin (APN) is an immunomodulatory, pro-angiogenic, and anti-apoptotic adipocytokine protecting against acute viral heart disease and preventing pathological remodelling after cardiac injury. The purpose of this study was to describe the regulation and effects of APN in patients with inflammatory cardiomyopathy (DCMi). METHODS AND RESULTS: Adiponectin expression and outcome were assessed in 173 patients with DCMi, 30 patients with non inflammatory DCM, and 30 controls. Mechanistic background of these findings was addressed in murine experimental autoimmune myocarditis (EAM), a model of human DCMi, and further elucidated in vitro. Adiponectin plasma concentrations were significantly higher in DCMi compared with DCM or controls, i.e. 6.8 +/- 3.9 ug/mL vs. 5.4 +/- 3.6 vs. 4.76 +/- 2.5 ug/mL (P< 0.05, respectively) and correlated significantly with cardiac mononuclear infiltrates (CD3+: r(2)= 0.025, P= 0.038; CD45R0+: r(2)= 0.058, P= 0.018). At follow-up, DCMi patients with high APN levels showed significantly increased left ventricular ejection fraction improvement, decreased left ventricular end-diastolic diameter, and reduced cardiac inflammatory infiltrates compared with patients with low APN levels. A multivariate linear regression analysis implicated APN as an independent prognostic factor for inhibition of cardiac inflammation. In accordance with these findings in human DCMi, EAM mice exhibited elevated plasma APN. Adiponectin gene transfer led to significant downregulation of key inflammatory mediators promoting disease. Mechanistically, APN acted as a negative regulator of T cells by reducing antigen specific expansion (P< 0.01) and suppressed TNFalpha-mediated NFkappaB activation (P< 0.01) as well as release of reactive oxygen species in cardiomyocytes. CONCLUSION: Our results implicate that APN acts as endogenously upregulated anti-inflammatory cytokine confining cardiac inflammation and progression in DCMi. PMID- 21278398 TI - Silent left main obstruction from a hypoplastic aortic cusp. PMID- 21278399 TI - Post-prostatic massage fluid/urine as an alternative to semen for studying male genitourinary HIV-1 shedding. AB - OBJECTIVES: Genitourinary tract samples are required to investigate male HIV-1 infectivity. Because semen collection is often impractical, the acceptability, feasibility and validity of post-prostatic massage fluid/urine (post-PMF/U) was evaluated for studying male genitourinary HIV-1 shedding. METHODS: HIV-1 seropositive men were evaluated after 48 h of sexual abstinence. At each visit, a clinician performed prostatic massage, then post-PMF/U and blood were collected. Participants provided semen specimens 1 week later. An audio computer-assisted self-interview (ACASI) administered after each specimen collection evaluated acceptability, adherence to instructions and recent genitourinary symptoms. HIV-1 RNA was quantified using a real-time PCR assay. Detection and quantitation of HIV 1 RNA and stability over visits were compared for semen, post-PMF/U and blood. RESULTS: Post-PMF/U was successfully obtained at 106 visits (64%) and semen at 136 visits (81%, p<0.001). In ACASI, discomfort was rated higher for post-PMF/U collection (p=0.003), but there was no significant difference in acceptability. Detection of HIV-1 RNA in post-PMF/U was associated with detection in semen (p=0.02). Semen and post-PMF/U HIV-1-RNA levels were correlated (rho=0.657, p<0.001). Concordance of results at repeat visits was 78.9% for post-PMF/U (kappa=0.519, p=0.02) and 89.5% for both blood and semen (kappa=0.774, p=0.001). CONCLUSIONS: Although semen collections were more successful, both post-PMF/U and semen collections were acceptable to many participants. HIV-1 RNA detection and levels were closely associated in semen and post-PMF/U, and results were relatively stable across visits. To assess male HIV-1 infectivity, post-PMF/U may represent a valid alternative when semen cannot be obtained. PMID- 21278400 TI - Reductions in sexually transmitted infections associated with popular opinion leaders in China in a randomised controlled trial. AB - OBJECTIVES: A community level randomised controlled trial of a Community Popular Opinion Leader (C-POL) intervention to reduce bacterial and viral sexually transmitted infections (STIs) and unprotected extramarital sex was carried out over 2 years in five countries. The main study results did not find significant intervention effects. This paper presents a sub-analysis examining the differential intervention impacts among high-risk and low-risk participants in the China site. METHODS: From 2002-2006, 3912 migrant market vendors aged 18 and 49 years were recruited at an urban site in China. Markets were randomly assigned to the C-POL intervention (N=20 markets; n=1979) or standard-care control condition (N=20; n=1933). Both study condition venues received HIV/STI education, free condoms, STI testing and treatment, and training for pharmacists in antibiotic treatments. In intervention markets, C-POLs were identified and trained to diffuse messages regarding safer sex, STI treatment and partner discussions of sex. The primary biological outcome was incidence of new STIs (chlamydia, gonorrhoea, syphilis, trichomonas, herpes or HIV). The primary sexual behaviour risk outcome was any unprotected extramarital sex in the prior 3 months. RESULTS: In unadjusted analyses, women had significantly lower rates of STI infection at 24 months in the C-POL intervention (5.7%) compared to controls (8.3%; p = 0.043). In mixed-effects regression models, intervention participants with STIs at previous assessments were about half as likely to have STIs at 24 months (OR 0.47, 95% CI 0.25 to 0.90) compared to controls. CONCLUSIONS: The C POL intervention lowers HIV risk among those at highest risk (i.e., with a STI or engaging in high-risk sexual activities) rather than the general population. PMID- 21278401 TI - The influence of bacterial vaginosis on the response to Trichomonas vaginalis treatment among HIV-infected women. AB - OBJECTIVE: Trichomonas vaginalis (TV) is common in HIV+ women, and host factors may play a role in TV treatment outcomes. The purpose of this study was to examine the influence of bacterial vaginosis (BV) on the response to TV treatment among HIV+ women. METHODS: A secondary analysis was conducted of a clinical trial which randomised HIV+/TV+ women to metronidazole (MTZ) treatment: 2 g (single dose) versus 7 day 500 mg twice daily (multidose). BV was classified using Nugent scores from baseline Gram stains. Women were recultured for TV at test-of-cure (TOC) and again at 3 months if TV-negative at TOC. Repeat TV infection rates were compared for women with a baseline TV/BV coinfection versus baseline TV infection only, and stratified by treatment arm. RESULTS: Among 244 HIV+/TV+ women (mean age=40.3, +/-9.5; 92.2% African-American), the rate of BV was 66.8%. Women with BV were more likely to report douching and >=1 recent sex partners. HIV+ women with baseline TV/BV coinfection were more likely to be TV-positive at TOC than women with baseline TV infection only (RR 2.42 (95% CI 0.96 to 6.07; p=0.05)). When stratified by treatment arm, the association was only found in the single dose arm (p=0.02) and not in the multidose arm (p=0.92). This interaction did not persist at 3 months. CONCLUSIONS: For HIV+/TV+ women, the rate of BV was high, and BV was associated with early failure of the MTZ single-dose treatment for TV. Biological explanations require further investigation. PMID- 21278402 TI - Should the practice of medicine be a deontological or utilitarian enterprise? AB - There is currently an unrecognised conflict between the utilitarian nature of the overall NHS and the basic deontology of the doctor-patient interaction. This conflict leads to mistrust and misunderstanding between managers and clinicians. This misunderstanding is bad for both doctors and managers, and also leads to waste of time and resources, and poorer services to patients. The utilitarian thinkers (mainly managers and politicians) tend to value finite, short term, evidence based technical interventions, delivered according to specifications and contracts. They appear happy to break care up into smaller pieces, which can then be commissioned from multiple providers. The deontological thinkers (mainly doctors and other clinicians) tend to think about care delivered through a long term continuous relationship, and regard that relationship as therapeutic and salutogenic in itself. To them breaking care up into smaller fragments is a denial of what caring is really about. Very rarely are either or both sides of this debate fully aware of where their powerfully felt and often well argued positions start from. In this paper we offer an appraisal of the strengths and weaknesses of both moral viewpoints as applied in the UK NHS context and we suggest a way in which they can be reconciled, provided neither is pushed too far or too hard against the other. We believe this reconciliation would be good for patients, doctors, managers and improve the service as a whole. PMID- 21278403 TI - Brain. Editorial. PMID- 21278404 TI - Mitochondria and cortical gamma oscillations: food for thought? PMID- 21278405 TI - Pathological network activity in Parkinson's disease: from neural activity and connectivity to causality? PMID- 21278406 TI - The long-term risk of premature mortality in people with epilepsy. AB - People with epilepsy have an increased risk of premature death. The risk is highest soon after onset of seizures. We report the findings of a long-term follow-up population-based study of people with epilepsy with regards to premature mortality. The National General Practice Study of Epilepsy is a prospective study flagged at the National Health Service Information Centre in the UK. Over 1000 people with new onset seizures were followed from the mid 1980s until April 2009. Of these, 564 people were classified at 6 months as having definite epileptic seizures, 228 as having possible epileptic seizures and 220 as having febrile seizures. The remainder were excluded (n=104 because of an unknown prior diagnosis of epilepsy or neonatal seizures) or classified as not having epilepsy (n=79). At median follow-up of 22.8 years there had been 301 deaths in the cohort; 300 of these were in people with definite or possible seizures. Death certificates were obtained for all but three of those who died. The overall standardized mortality ratio for those with definite or possible epilepsy was 2.2 (95% confidence interval 1.97-2.47), and was higher in those with definite seizures (2.6). In those who were alive at 20 years follow-up, the standardized mortality ratio in the subsequent years remained significantly elevated (2.2, 95% confidence interval 1.6-3.2). Pneumonia (standardized mortality ratio 6.6, 95% confidence incidence 5.1, 8.4) was a common cause of death with a consistently elevated standardized mortality ratio throughout follow-up. The standardized mortality ratio for ischaemic heart disease was significantly elevated for the first time in the last 5 years of follow-up (3.3, 95% confidence interval 1.6 7.0). Few people died from epilepsy-related causes. The risk of premature death remains significantly elevated at 20-25 years after the index seizure despite most of the cohort being in terminal remission (defined as 5 years or more seizure-free, on or off anti-epileptic medication) at the last follow-up. Further studies are needed to explore the reasons for this long-term increase in premature mortality. PMID- 21278407 TI - Left inferior frontal cortex and syntax: function, structure and behaviour in patients with left hemisphere damage. AB - For the past 150 years, neurobiological models of language have debated the role of key brain regions in language function. One consistently debated set of issues concern the role of the left inferior frontal gyrus in syntactic processing. Here we combine measures of functional activity, grey matter integrity and performance in patients with left hemisphere damage and healthy participants to ask whether the left inferior frontal gyrus is essential for syntactic processing. In a functional neuroimaging study, participants listened to spoken sentences that either contained a syntactically ambiguous or matched unambiguous phrase. Behavioural data on three tests of syntactic processing were subsequently collected. In controls, syntactic processing co-activated left hemisphere Brodmann areas 45/47 and posterior middle temporal gyrus. Activity in a left parietal cluster was sensitive to working memory demands in both patients and controls. Exploiting the variability in lesion location and performance in the patients, voxel-based correlational analyses showed that tissue integrity and neural activity-primarily in left Brodmann area 45 and posterior middle temporal gyrus-were correlated with preserved syntactic performance, but unlike the controls, patients were insensitive to syntactic preferences, reflecting their syntactic deficit. These results argue for the essential contribution of the left inferior frontal gyrus in syntactic analysis and highlight the functional relationship between left Brodmann area 45 and the left posterior middle temporal gyrus, suggesting that when this relationship breaks down, through damage to either region or to the connections between them, syntactic processing is impaired. On this view, the left inferior frontal gyrus may not itself be specialized for syntactic processing, but plays an essential role in the neural network that carries out syntactic computations. PMID- 21278408 TI - In vivo monitoring of neuronal loss in traumatic brain injury: a microdialysis study. AB - Traumatic brain injury causes diffuse axonal injury and loss of cortical neurons. These features are well recognized histologically, but their in vivo monitoring remains challenging. In vivo cortical microdialysis samples the extracellular fluid adjacent to neurons and axons. Here, we describe a novel neuronal proteolytic pathway and demonstrate the exclusive neuro-axonal expression of Pavlov's enterokinase. Enterokinase is membrane bound and cleaves the neurofilament heavy chain at positions 476 and 986. Using a 100 kDa microdialysis cut-off membrane the two proteolytic breakdown products, extracellular fluid neurofilament heavy chains NfH(476-986) and NfH(476-1026), can be quantified with a relative recovery of 20%. In a prospective clinical in vivo study, we included 10 patients with traumatic brain injury with a median Glasgow Coma Score of 9, providing 640 cortical extracellular fluid samples for longitudinal data analysis. Following high-velocity impact traumatic brain injury, microdialysate extracellular fluid neurofilament heavy chain levels were significantly higher (6.18 +/- 2.94 ng/ml) and detectable for longer (> 4 days) compared with traumatic brain injury secondary to falls (0.84 +/- 1.77 ng/ml, < 2 days). During the initial 16 h following traumatic brain injury, strong correlations were found between extracellular fluid neurofilament heavy chain levels and physiological parameters (systemic blood pressure, anaerobic cerebral metabolism, excessive brain tissue oxygenation, elevated brain temperature). Finally, extracellular fluid neurofilament heavy chain levels were of prognostic value, predicting mortality with an odds ratio of 7.68 (confidence interval 2.15-27.46, P = 0.001). In conclusion, this study describes the discovery of Pavlov's enterokinase in the human brain, a novel neuronal proteolytic pathway that gives rise to specific protein biomarkers (NfH(476-986) and Nf(H476-1026)) applicable to in vivo monitoring of diffuse axonal injury and neuronal loss in traumatic brain injury. PMID- 21278409 TI - Professor P. K. Thomas: clinician, investigator, editor and leader--a retrospective appreciation. AB - P. K. Thomas (1926-2008) occupied a prominent place in British and world neurology during the second half of the 20th century. Here, his lasting achievements as clinical neurologist, clinician scientist and experimentalist, editor of monographs and journals and leader of professional developments in the UK and elsewhere are assessed. PMID- 21278410 TI - Pseudomonas composti sp. nov., isolated from compost samples. AB - Two unusual, Gram-negative, catalase- and oxidase-positive rods, designated C2(T) and C5, were isolated from compost samples. Comparative 16S rRNA gene sequencing studies demonstrated that both isolates were members of the genus Pseudomonas and belonged to the Pseudomonas aeruginosa group. Strain C2(T) was most closely related to Pseudomonas cuatrocienegasensis 1N(T) and Pseudomonas borbori R 20821(T) (97.9 and 97.8% 16S rRNA gene sequence similarity, respectively). However, phylogenetic analysis based on rpoD gene sequences revealed that both isolates could be discriminated from members of the P. aeruginosa group that exhibited >97% 16S rRNA gene sequence similarity. The DNA G+C content of strain C2(T) was 61.5 mol%. The major fatty acids of strain C2(T) were a summed feature (C(16:1)omega7c and/or iso-C(15:0) 2-OH), C(18:1)omega7c/12t/9t, C(16:0) and C(12:0), which supported the isolates' affiliation with the genus Pseudomonas. Moreover, strain C2(T) could be distinguished from its closest phylogenetic neighbours of the genus Pseudomonas by DNA-DNA hybridization studies and biochemical tests. On the basis of both phenotypic and phylogenetic findings, it is proposed that the isolates be classified as a novel species, with the name Pseudomonas composti sp. nov. The type strain is C2(T) (=CECT 7516(T)=CCUG 59231(T)). PMID- 21278411 TI - Methanobacterium movens sp. nov. and Methanobacterium flexile sp. nov., isolated from lake sediment. AB - Two mesophilic methanogenic strains, designated TS-2(T) and GH(T), were isolated from sediments of Tuosu lake and Gahai lake, respectively, in the Qaidam basin, Qinghai province, China. Cells of both isolates were rods (about 0.3-0.5*2-5 um) with blunt rounded ends and Gram-staining-positive. Strain TS-2(T) was motile with one or two polar flagella and used only H(2)/CO(2) for growth and methanogenesis. Strain GH(T) was non-motile, used both H(2)/CO(2) and formate and displayed a variable cell arrangement depending on the substrate: long chains when growing in formate (50 mM) or under high pressure H(2) and single cells under low pressure H(2). Phylogenetic analysis based on 16S rRNA gene sequences placed the two isolates in the genus Methanobacterium. Strain TS-2(T) was most closely related to Methanobacterium alcaliphilum NBRC 105226(T) (96% 16S rRNA gene sequence similarity). Phylogenetic analysis based on the alpha subunit of methyl-coenzyme M reductase also supported the affiliation of the two isolates with the genus Methanobacterium. DNA-DNA relatedness between the isolates and M. alcaliphilum DSM 3387(T) was 39-53%. Hence we propose two novel species, Methanobacterium movens sp. nov. (type strain TS-2(T)=AS 1.5093(T)=JCM 15415(T)) and Methanobacterium flexile sp. nov. (type strain GH(T)=AS 1.5092(T)=JCM 15416(T)). PMID- 21278412 TI - Evolution and variation of the nifD and hupL elements in the heterocystous cyanobacteria. AB - In heterocystous cyanobacteria, heterocyst differentiation is accompanied by developmentally regulated DNA rearrangements that occur within the nifD and hupL genes, referred to as the nifD and hupL elements. These elements are segments of DNA that are embedded within the coding region of each gene and range from 4 to 24 kb in length. The nifD and hupL elements are independently excised from the genome during the later stages of differentiation by the site-specific recombinases, XisA and XisC, respectively, which are encoded within the elements themselves. Here we examine the variation and evolution of the nifD and hupL elements by comparing full-length nifD and hupL element sequences and by phylogenetic analysis of xisA and xisC gene sequences. There is considerable variation in the size and composition of the nifD and hupL elements, however, conserved regions are also present within representatives of each element. The data suggest that the nifD and hupL elements have undergone a complex pattern of insertions, deletions, translocations and sequence divergence over the course of evolution, but that conserved regions remain. PMID- 21278413 TI - Phytomonospora endophytica gen. nov., sp. nov., isolated from the roots of Artemisia annua L. AB - A novel endophytic actinomycete, strain YIM 65646(T), was isolated from the roots of Artemisia annua L. collected from Yunnan Province, south-west China. Growth was observed in the temperature range 10-40 degrees C (optimum 20-28 degrees C) and at pH 6.0-9.0 (optimum pH 7.0). The organism formed well-developed, branched substrate mycelia, but aerial mycelium was not produced. Phenotypic characterization and 16S rRNA gene sequence analysis indicated that strain YIM 65646(T) belonged to the family Micromonosporaceae (sharing <=93.6% sequence similarity with members of this family) and formed a distinct clade in the Micromonosporaceae phylogenetic tree. The strain contained meso-diaminopimelic acid in the cell wall and mannose, ribose, galactose and glucose in whole-cell hydrolysates. The major menaquinones were MK-10(H(4)), MK-10(H(2)), MK-8(H(2)), MK-9(H(2)) and MK-10(H(6)). The major fatty acids were iso-C(15:0), anteiso C(15:0), anteiso-C(17:0), iso-C(17:0) and iso-C(16:0). The DNA G+C content of strain YIM 65646(T) was 70.0 mol%. On the basis of morphological and chemotaxonomic properties and phylogenetic analysis based on 16S rRNA gene sequence data, it is proposed that this strain should be classified in a novel genus and species, Phytomonospora endophytica gen. nov., sp. nov., in the family Micromonosporaceae. The type strain is YIM 65646(T) (=CCTCC AA 209041(T) =DSM 45386(T)). PMID- 21278414 TI - Nocardia artemisiae sp. nov., an endophytic actinobacterium isolated from a surface-sterilized stem of Artemisia annua L. AB - A novel actinobacterium, designated YIM 65623(T), was isolated from a surface sterilized stem of Artemisia annua L. Strain YIM 65623(T) had morphological, biochemical, physiological and chemotaxonomic properties that were consistent with its classification in the genus Nocardia. Growth occurred with 0-7% (w/v) NaCl (optimum 0-3%), at pH 5.0-9.0 (optimum pH 6.0) and at 10-37 degrees C (optimum 20-28 degrees C). Comparative 16S rRNA gene sequence analysis showed that strain YIM 65623(T) constituted a distinct sublineage within the genus Nocardia and displayed 94.1-98.2% sequence similarity to members of established species in the genus Nocardia. However, DNA-DNA relatedness and physiological and biochemical characteristics showed that strain YIM 65623(T) could be differentiated from its closest phylogenetic relatives. The G+C content of the genomic DNA was 69.6 mol%. It is proposed that strain YIM 65623(T) be classified as a representative of a novel species, Nocardia artemisiae sp. nov. The type strain is YIM 65623(T) (=DSM 45379(T) =CCTCC AA 209038(T)). PMID- 21278415 TI - Altererythrobacter ishigakiensis sp. nov., an astaxanthin-producing bacterium isolated from a marine sediment. AB - A Gram-negative, non-motile, non-spore-forming, halophilic rod, designated JPCCMB0017(T), was isolated from a marine sediment of the coastal area of Okinawa, Japan. The isolate formed orange-red colonies on marine agar. Bacteriochlorophyll alpha was absent and sphingoglycolipid 1 and other carotenoids, including astaxanthin, adonixanthin and zeaxanthin, were present. Ubiquinone-10 (Q-10) was the main respiratory quinone and C(18:1)omega7c was the major cellular fatty acid. The G+C content of DNA was 59.1 mol%. Phylogenetic analysis based on 16S rRNA gene sequencing revealed that the isolate was a member of the genus Altererythrobacter in the family Erythrobacteraceae. Strain JPCCMB0017(T) exhibited 96.8% 16S rRNA gene sequence similarity with Altererythrobacter marinus H32(T). Unlike other members of the genus Altererythrobacter, strain JPCCMB0017(T) reduced nitrate. On the basis of genotypic and phenotypic data, a novel species is proposed to accommodate this isolate, with the name Altererythrobacter ishigakiensis sp. nov. The type strain is JPCCMB0017(T) (= NITE-AP48(T)= ATCC BAA-2084(T)=NBRC 107699(T)). PMID- 21278416 TI - Bacillus hemicentroti sp. nov., a moderate halophile isolated from a sea urchin. AB - A novel Gram-staining-positive, moderately halophilic, facultatively alkaliphilic, non-motile, catalase-positive, oxidase-negative, endospore-forming, facultatively anaerobic rod, designated JSM 076093(T), was isolated from a sea urchin (Hemicentrotus pulcherrimus) collected from Naozhou Island in the South China Sea. Growth occurred with 0.5-25% (w/v) NaCl (optimum 5-8%) and at pH 6.0 10.5 (optimum pH 8.0) and 5-40 degrees C (optimum 30-35 degrees C). meso Diaminopimelic acid was present in the cell-wall peptidoglycan. The predominant respiratory quinone was menaquinone 7 and the polar lipids consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol and one unidentified phospholipid. The major cellular fatty acids (>10% of the total) were anteiso-C(15:0), anteiso-C(17:0), iso-C(16:0) and iso-C(14:0). The genomic DNA G+C content was 38.8 mol%. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain JSM 076093(T) belonged to the genus Bacillus and was related most closely to Bacillus hwajinpoensis SW-72(T) (99.1% 16S rRNA gene sequence similarity) and Bacillus algicola KMM 3737(T) (97.3%). The combination of results from the phylogenetic analysis, DNA-DNA hybridization and phenotypic and chemotaxonomic characterization supported the conclusion that strain JSM 076093(T) represents a novel species of the genus Bacillus, for which the name Bacillus hemicentroti sp. nov. is proposed, with JSM 076093(T) (=DSM 23007(T)=KCTC 13710(T)) as the type strain. PMID- 21278417 TI - Characterization of photophysical and base-mimicking properties of a novel fluorescent adenine analogue in DNA. AB - To increase the diversity of fluorescent base analogues with improved properties, we here present the straightforward click-chemistry-based synthesis of a novel fluorescent adenine-analogue triazole adenine (A(T)) and its photophysical characterization inside DNA. A(T) shows promising properties compared to the widely used adenine analogue 2-aminopurine. Quantum yields reach >20% and >5% in single- and double-stranded DNA, respectively, and show dependence on neighbouring bases. Moreover, A(T) shows only a minor destabilization of DNA duplexes, comparable to 2-aminopurine, and circular dichroism investigations suggest that A(T) only causes minimal structural perturbations to normal B-DNA. Furthermore, we find that A(T) shows favourable base-pairing properties with thymine and more surprisingly also with normal adenine. In conclusion, A(T) shows strong potential as a new fluorescent adenine analogue for monitoring changes within its microenvironment in DNA. PMID- 21278418 TI - Structure of p300 bound to MEF2 on DNA reveals a mechanism of enhanceosome assembly. AB - Transcription co-activators CBP and p300 are recruited by sequence-specific transcription factors to specific genomic loci to control gene expression. A highly conserved domain in CBP/p300, the TAZ2 domain, mediates direct interaction with a variety of transcription factors including the myocyte enhancer factor 2 (MEF2). Here we report the crystal structure of a ternary complex of the p300 TAZ2 domain bound to MEF2 on DNA at 2.2A resolution. The structure reveals three MEF2:DNA complexes binding to different sites of the TAZ2 domain. Using structure guided mutations and a mammalian two-hybrid assay, we show that all three interfaces contribute to the binding of MEF2 to p300, suggesting that p300 may use one of the three interfaces to interact with MEF2 in different cellular contexts and that one p300 can bind three MEF2:DNA complexes simultaneously. These studies, together with previously characterized TAZ2 complexes bound to different transcription factors, demonstrate the potency and versatility of TAZ2 in protein-protein interactions. Our results also support a model wherein p300 promotes the assembly of a higher-order enhanceosome by simultaneous interactions with multiple DNA-bound transcription factors. PMID- 21278419 TI - Biophysical analysis and small-angle X-ray scattering-derived structures of MeCP2 nucleosome complexes. AB - MeCP2 is a highly abundant chromatin architectural protein with key roles in post natal brain development in humans. Mutations in MeCP2 are associated with Rett syndrome, the main cause of mental retardation in girls. Structural information on the intrinsically disordered MeCP2 protein is restricted to the methyl-CpG binding domain; however, at least four regions capable of DNA and chromatin binding are distributed over its entire length. Here we use small angle X-ray scattering (SAXS) and other solution-state approaches to investigate the interaction of MeCP2 and a truncated, disease-causing version of MeCP2 with nucleosomes. We demonstrate that MeCP2 forms defined complexes with nucleosomes, in which all four histones are present. MeCP2 retains an extended conformation when binding nucleosomes without extra-nucleosomal DNA. In contrast, nucleosomes with extra-nucleosomal DNA engage additional DNA binding sites in MeCP2, resulting in a rather compact higher-order complex. We present ab initio envelope reconstructions of nucleosomes and their complexes with MeCP2 from SAXS data. SAXS studies also revealed unexpected sequence-dependent conformational variability in the nucleosomes themselves. PMID- 21278420 TI - Not1 mediates recruitment of the deadenylase Caf1 to mRNAs targeted for degradation by tristetraprolin. AB - The carbon catabolite repressor protein 4 (Ccr4)-Negative on TATA (Not) complex controls gene expression at two levels. In the nucleus, it regulates the basal transcription machinery, nuclear receptor-mediated transcription and histone modifications. In the cytoplasm, the complex is required for messenger RNA (mRNA) turnover through its two associated deadenylases, Ccr4 and Caf1. Not1 is the largest protein of the Ccr4-Not complex and serves as a scaffold for other subunits of the complex. Here, we provide evidence that human Not1 in the cytoplasm associates with the C-terminal domain of tristetraprolin (TTP), an RNA binding protein that mediates rapid degradation of mRNAs containing AU-rich elements (AREs). Not1 shows extensive interaction through its central region with TTP, whereas binding of Caf1 is restricted to a smaller central domain within Not1. Importantly, Not1 is required for the rapid decay of ARE-mRNAs, and TTP can recruit the Caf1 deadenylase only in presence of Not1. Thus, cytoplasmic Not1 provides a platform that allows a specific RNA binding protein to recruit the Caf1 deadenylase and thereby trigger decay of its target mRNAs. PMID- 21278421 TI - Differential RNA-binding activity of the hnRNP G protein correlated with the sex genotype in the amphibian oocyte. AB - A proteomic approach has enabled the identification of an orthologue of the splicing factor hnRNP G in the amphibians Xenopus tropicalis, Ambystoma mexicanum, Notophthalmus viridescens and Pleurodeles walt, which shows a specific RNA-binding affinity similar to that of the human hnRN G protein. Three isoforms of this protein with a differential binding affinity for a specific RNA probe were identified in the P. walt oocyte. In situ hybridization to lampbrush chromosomes of P. waltl revealed the presence of a family of hnRNP G genes, which were mapped on the Z and W chromosomes and one autosome. This indicates that the isoforms identified in this study are possibly encoded by a gene family linked to the evolution of sex chromosomes similarly to the hnRNP G/RBMX gene family in mammals. PMID- 21278423 TI - An unusual cause of abdominal pain: gallstone ileus. PMID- 21278422 TI - The intracellular sRNA transcriptome of Listeria monocytogenes during growth in macrophages. AB - Small non-coding RNAs (sRNAs) are widespread effectors of post-transcriptional gene regulation in bacteria. Currently extensive information exists on the sRNAs of Listeria monocytogenes expressed during growth in extracellular environments. We used deep sequencing of cDNAs obtained from fractioned RNA (<500 nt) isolated from extracellularly growing bacteria and from L. monocytogenes infected macrophages to catalog the sRNA repertoire during intracellular bacterial growth. Here, we report on the discovery of 150 putative regulatory RNAs of which 71 have not been previously described. A total of 29 regulatory RNAs, including small non coding antisense RNAs, are specifically expressed intracellularly. We validated highly expressed sRNAs by northern blotting and demonstrated by the construction and characterization of isogenic mutants of rli31, rli33-1 and rli50* for intracellular expressed sRNA candidates, that their expression is required for efficient growth of bacteria in macrophages. All three mutants were attenuated when assessed for growth in mouse and insect models of infection. Comparative genomic analysis revealed the presence of lineage specific sRNA candidates and the absence of sRNA loci in genomes of naturally occurring infection-attenuated bacteria, with additional loss in non-pathogenic listerial genomes. Our analyses reveal extensive sRNA expression as an important feature of bacterial regulation during intracellular growth. PMID- 21278424 TI - Markers for bacterial infection in children with fever without source. AB - OBJECTIVES: To compare the diagnostic properties of procalcitonin (PCT), C reactive protein (CRP), total white blood cells count (WBC), absolute neutrophil count (ANC) and clinical evaluation to detect serious bacterial infection (SBI) in children with fever without source. DESIGN: Prospective cohort study. SETTING: Paediatric emergency department of a tertiary care hospital. PARTICIPANTS: Children aged 1-36 months with fever and no identified source of infection. INTERVENTION: Complete blood count, blood culture, urine analysis and culture. PCT and CRP were also measured and SBI probability evaluated clinically with a visual analogue scale before disclosing tests results. Outcome measure Area under the curves (AUC) of the receiver operating characteristic curves. RESULTS: Among the 328 children included in the study, 54 (16%) were diagnosed with an SBI: 48 urinary tract infections, 4 pneumonias, 1 meningitis and 1 bacteraemia. The AUC were similar for PCT (0.82; 95% CI 0.77 to 0.86), CRP (0.88; 95% CI 0.84 to 0.91), WBC (0.81; 95% CI 0.76 to 0.85) and ANC (0.80; 95% CI 0.75 to 0.84). The only statistically significant difference was between CRP and ANC (Delta AUC 0.08; 95% CI 0.01 to 0.16). It is important to note that all the surrogate markers were statistically superior to the clinical evaluation that had an AUC of only 0.59 (95% CI 0.54 to 0.65). CONCLUSION: The study data demonstrate that CRP, PCT, WBC and ANC had almost similar diagnostic properties and were superior to clinical evaluation in predicting SBI in children aged 1 month to 3 years. PMID- 21278425 TI - Disordered pubertal development. PMID- 21278426 TI - Head-to-head comparison between echocardiography and cardiac MRI in the evaluation of the athlete's heart. AB - OBJECTIVE: Echocardiographic cut-off values are often used for cardiac MRI in athletic persons. This study investigates the difference between echocardiographic and cardiac MRI measurements of ventricular and atrial dimensions and ventricular wall thickness, and its effect on volume and wall mass prediction in athletic subjects compared with non-athletic controls. METHODS: Healthy non-athletic (59), regular athletic (59) and elite athletic (63) persons, aged 18-39 years and training 2.5+/-1.9, 13.0+/-3.0 and 25.0+/-5.4 h/week, respectively (p<0.001), underwent echocardiography and cardiac MRI consecutively. Left ventricular (LV) and right ventricular (RV) dimensions were measured on both modalities. LV and RV end-diastolic and end-systolic volumes and LV wall mass were determined on cardiac MRI. Echocardiographic M-mode LV volumes (Teichholz formula) and LV wall mass (American Society of Echocardiography formula) were calculated. RESULTS: LV and RV dimensions were smaller on echocardiography (p<0.001), and although the correlation with the cardiac MRI volume was good (p<0.01), the difference in volume was large (LV end-diastolic volume difference 93+/-32 g, p<0.001). LV wall thickness and calculated wall mass were significantly (p<0.001) larger on echocardiography (wall mass difference -101+/ 34 g, p<0.001). Differences in absolute dimensions did not change significantly between non-athletic and athletic persons; however, the difference in echocardiographic estimations of LV volumes and wall mass did increase significantly with the larger athlete's heart, requiring possible correction of the standard echocardiographic formulas. CONCLUSIONS: Echocardiography shows systematically smaller atrial and ventricular dimensions and volumes, and larger wall thickness and mass, compared with cardiac MRI. Correction for the echocardiographic formulas can facilitate better intertechnique comparability. These findings should be taken into account in the interpretation of cardiac MRI findings in athletic subjects in whom cardiomyopathy is suspected on echocardiography. PMID- 21278427 TI - Trends in concussion incidence in high school sports: a prospective 11-year study. AB - BACKGROUND: Understanding the risk and trends of sports-related concussion among 12 scholastic sports may contribute to concussion detection, treatment, and prevention. PURPOSE: To examine the incidence and relative risk of concussion in 12 high school boys' and girls' sports between academic years 1997-1998 and 2007 2008. STUDY DESIGN: Descriptive epidemiology study. METHODS: Data were prospectively gathered for 25 schools in a large public high school system. All schools used an electronic medical record-keeping program. A certified athletic trainer was on-site for games and practices and electronically recorded all injuries daily. RESULTS: In sum, 2651 concussions were observed in 10 926 892 athlete-exposures, with an incidence rate of 0.24 per 1000. Boys' sports accounted for 53% of athlete-exposures and 75% of all concussions. Football accounted for more than half of all concussions, and it had the highest incidence rate (0.60). Girls' soccer had the most concussions among the girls' sports and the second-highest incidence rate of all 12 sports (0.35). Concussion rate increased 4.2-fold (95% confidence interval, 3.4-5.2) over the 11 years (15.5% annual increase). In similar boys' and girls' sports (baseball/softball, basketball, and soccer), girls had roughly twice the concussion risk of boys. Concussion rate increased over time in all 12 sports. CONCLUSION: Although the collision sports of football and boys' lacrosse had the highest number of concussions and football the highest concussion rate, concussion occurred in all other sports and was observed in girls' sports at rates similar to or higher than those of boys' sports. The increase over time in all sports may reflect actual increased occurrence or greater coding sensitivity with widely disseminated guidance on concussion detection and treatment. The high-participation collision sports of football and boys' lacrosse warrant continued vigilance, but the findings suggest that focus on concussion detection, treatment, and prevention should not be limited to those sports traditionally associated with concussion risk. PMID- 21278428 TI - Greater than 10-year results of red-white longitudinal meniscal repairs in patients 20 years of age or younger. AB - BACKGROUND: A prospective longitudinal investigation was conducted to determine the long-term outcome of single longitudinal meniscal repairs extending into the central avascular region in patients aged 20 years or younger. PURPOSE: To determine the long-term success rate and reoperation rate of meniscal repairs extending into the avascular zone. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Thirty-three meniscal repairs were performed using an inside-out multiple vertical divergent suture technique. A concomitant anterior cruciate ligament reconstruction was done in 18 patients. The mean follow-up was 16.8 years (range, 10.1-21.9 years). The long-term success rate was determined in 29 repairs (88%) by the presence of normal or nearly normal parameters from 2 validated knee rating systems, assessment of magnetic resonance imaging and weightbearing posteroanterior radiographs by independent physicians, and follow up arthroscopy when required. A 3 Tesla magnetic resonance imaging scanner with cartilage-sensitive pulse sequences was used, and T2 mapping was performed. A comparison was made between the short-term (mean, 4 years) and long-term outcomes. RESULTS: Eighteen (62%) of the meniscal repairs had normal or nearly normal characteristics in all of the parameters assessed. Six repairs (21%) required partial arthroscopic resection, 2 had loss of joint space on radiographs, and 3 that were asymptomatic failed according to magnetic resonance imaging criteria, for a total of 11 documented failures (38%). There was no significant difference in the mean articular cartilage T2 scores in the healed menisci between the involved and contralateral tibiofemoral compartments in the same knee. There were no significant differences between short- and long-term evaluations for pain, swelling, jumping, patient knee condition rating, or the overall Cincinnati rating score. CONCLUSIONS: A chondroprotective joint effect was demonstrated in the healed menisci repairs, which warrants the procedure in select patients. The long-term evaluation of the anterior cruciate ligament reconstructed knees with concurrent successful meniscal repairs demonstrated a low rate of radiographic arthritis. PMID- 21278429 TI - Detection of child abuse in emergency departments: a multi-centre study. AB - OBJECTIVE: This study examines the detection rates of suspected child abuse in the emergency departments of seven Dutch hospitals complying and not complying with screening guidelines for child abuse. DESIGN: Data on demographics, diagnosis and suspected child abuse were collected for all children aged <=18 years who visited the emergency departments over a 6-month period. The completion of a checklist of warning signs of child abuse in at least 10% of the emergency department visits was considered to be compliance with screening guidelines. RESULTS: A total of 24 472 visits were analysed, 54% of which took place in an emergency department complying with screening guidelines. Child abuse was suspected in 52 children (0.2%). In 40 (77%) of these 52 cases, a checklist of warning signs had been completed compared with a completion rate of 19% in the total sample. In hospitals complying with screening guidelines for child abuse, the detection rate was higher (0.3%) than in those not complying (0.1%, p<0.001). CONCLUSION: During a 6-month period, emergency department staff suspected child abuse in 0.2% of all children visiting the emergency department of seven Dutch hospitals. The numbers of suspected abuse cases detected were low, but an increase is likely if uniform screening guidelines are widely implemented. PMID- 21278430 TI - The management of neonatal pulmonary hypertension. AB - Most neonates with clinically significant pulmonary hypertension (PH) will have either persistent PH of the newborn (PPHN) or bronchopulmonary dysplasia. Cyanotic congenital heart disease must be actively ruled out as part of the differential diagnosis of PPHN. The maintenance of ductal patency with prostaglandins E1 or E2 in cases of doubt is safe and potentially beneficial given their pulmonary vasorelaxant properties. Specific tools in the treatment of PPHN include modern ventilatory strategies, inhaled nitric oxide, sildenafil, prostacyclin and extracorporeal membrane oxygenation. Rarely will a cardiac lesion be primarily responsible for neonatal PH although pulmonary vein stenosis and the persistence of an arterial duct must be considered, particularly in the older preterm baby with bronchopulmonary dysplasia. PMID- 21278431 TI - Incidence of severe hyperbilirubinaemia in Switzerland: a nationwide population based prospective study. PMID- 21278432 TI - Predictors of early nasal CPAP failure and effects of various intubation criteria on the rate of mechanical ventilation in preterm infants of <29 weeks gestational age. AB - INTRODUCTION: Delivery room management using early nasal continuous positive airway pressure (nCPAP) may delay surfactant therapy. OBJECTIVE: To identify factors associated with early nCPAP failure and effects of various intubation criteria on rate and time of intubation. DESIGN: Retrospective analysis of the first 48 h in infants of 23-28 weeks gestational age (GA) treated with sustained inflations followed by early nCPAP. RESULTS: Of 225 infants (GA 26.2+/-1.6 weeks) 140 (62%) could be stabilised with nCPAP in the delivery room, of whom 68 (49%; GA 26.9+/-1.5 weeks) succeeded on nCPAP with favourable outcome and 72 infants (51%; GA 26.3+/-1.4 weeks) failed nCPAP within 48 h at a median (IQR) age of 5.6 (3.3-19.3) h. History or initial blood gases were poor predictors of subsequent nCPAP failure. Intubation at fraction of inspired oxygen (FiO(2))>=0.35 versus 0.4 versus 0.45 instead of >=0.6 would have resulted in unnecessary intubations of 16% versus 9% versus 6% of infants with nCPAP success but decreased the age at intubation of infants with nCPAP failure to 3.1 (2.2-5.2) versus 3.8 (2.5-8.7) versus 4.4 (2.7-10.9) h. CONCLUSIONS: Medical history or initial blood gas values are poor predictors of subsequent nCPAP failure. A threshold FiO(2) of >=0.35 0.45 compared to >=0.6 for intubation would shorten the time to surfactant delivery without a relevant increase in intubation rate. An individualised approach with a trial of early nCPAP and prompt intubation and surfactant treatment at low thresholds may be the best approach in very low birthweight infants. PMID- 21278433 TI - Training in acupuncture: a participant's view. PMID- 21278434 TI - Breast cancer: progress and promise. PMID- 21278435 TI - Triple-negative breast cancer: an unmet medical need. AB - Triple-negative breast cancer, characterized by tumors that do not express estrogen receptor (ER), progesterone receptor (PR), or HER-2 genes, represents an important clinical challenge because these cancers do not respond to endocrine therapy or other available targeted agents. The metastatic potential in triple negative breast cancer is similar to that of other breast cancer subtypes, but these tumors are associated with a shorter median time to relapse and death. One important goal is therefore the identification of prognostic factors and markers to reliably select high and low risk subsets of patients with triple-negative disease for different treatment approaches of subtypes with differential responsiveness to specific agents. However, a reliable prognostic marker has been elusive, and markers have been inconsistently useful. For example, epidermal growth factor receptor (EGFR) has been studied, but there is still a lack of agreement on a standard assay or cutoff for EGFR expression levels with respect to prognosis. Similarly, because triple-negative status is sometimes used as a surrogate for basal-like breast cancer, specific basal markers have been explored. Indeed, trials designed to accrue patients with basal-like breast cancer using ER/PR and HER-2 negativity may provide only an approximation of the triple-negative population and are sometimes reanalyzed using more specific indicators like CK 5/6, EGFR status, and others, again marred by discordances. Chemotherapy remains the mainstay of treatment of triple-negative breast cancer, but important limitations still need to be overcome in the next few years if any significant clinical strides are to be made. Current treatment strategies for triple-negative disease include anthracyclines, taxanes, ixabepilone, platinum agents, and biologic agents. More recently, EGFR inhibition has been proposed as a therapeutic mechanism in triple-negative breast cancer, again with mixed results. Agents that target poly(ADP-ribose) polymerase and androgen receptors have also been proposed in these patients or subsets of them, and ongoing trials should result in definitive guidance with respect to the value of these agents in triple-negative disease. Triple-negative breast cancer is clearly a distinct clinical subtype, from the perspective of both ER and HER-2 expression, but further subclassification is needed. At present, there is not a clear, proven effective single agent that targets a defining vulnerability in triple-negative breast cancer. This article will review the clinical problem of triple-negative disease, potential prognostic factors, demonstrated efficacy of currently available therapeutic options, and new potential therapies. PMID- 21278436 TI - Targeting the phosphoinositide-3 (PI3) kinase pathway in breast cancer. AB - The phosphoinositide-3 kinase (PI3K) pathway has been identified as an important target in breast cancer research for a number of years, but is new to most clinicians responsible for the daily challenges of breast cancer management. In fact, the PI3K pathway is probably one of the most important pathways in cancer metabolism and growth. Mutations in the PI3K pathway are frequent in breast cancer, causing resistance to human epidermal growth factor receptor 2-targeted agents and, possibly, to hormonal agents as well. Available agents that affect the PI3K pathway include monoclonal antibodies and tyrosine kinase inhibitors, as well as PI3K inhibitors, Akt inhibitors, rapamycin analogs, and mammalian target of rapamycin (mTOR) catalytic inhibitors. Multiple PI3K inhibitors are currently under development, including pure PI3K inhibitors, compounds that block both PI3K and mTOR (dual inhibitors), pure catalytic mTOR inhibitors, and inhibitors that block Akt. It is likely that these agents will have to be given in combination with other signal inhibitors because anti-mTOR agents and PI3K inhibitors may result in the activation of compensatory feedback loops that would in turn result in decreased efficacy. This article reviews current data related to the PI3K pathway, its role in breast cancer, the frequency with which PI3K is aberrant in breast cancer, and the potential clinical implications of using agents that target the PI3K pathway. PMID- 21278437 TI - Breast cancer management: opportunities and barriers to an individualized approach. AB - A personalized approach to breast cancer management is increasingly possible with state of the art diagnostics and treatments. However, many challenges still exist in choosing the right therapeutic strategy and the right dosing for a specific patient population. Biomarkers such as estrogen receptor, progesterone receptor, and HER-2 status are used to tailor therapy, but success rates with targeted therapy suggest that appropriate patient populations still require greater definition. The introduction of the genomic era has likewise advanced the ability to offer a tailored approach to breast cancer management, but much work is still needed in this area as well. Microarray-based gene expression profiles have demonstrated initial promise, but we need a better understanding of more complex tumor signaling pathways. Strategies include annotated tumor specimens, next generation gene sequencing, proteomics, and metabolomics. An individualized approach to breast cancer management has the potential to offer clear clinical benefits and the ability to bring more tailored, cost-effective strategies to the market. The current issues facing the delivery of individualized breast cancer care will be the focus of this discussion. PMID- 21278438 TI - The biological framework: translational research from bench to clinic. AB - The understanding of cellular signaling pathways in malignant tumors is an important aspect of cancer research and modern targeted therapy strategies. Growth factors and their receptors in particular are critical to modern cancer therapy research, because these factors control all phases of tumor development and metastasis. Most importantly, growth factors are responsible for cell survival under cytotoxic drugs and radiotherapy. These growth factor signaling pathways are composed of complex networks that have adapted to efficiently respond to certain disturbances, such as a single agent that targets one aspect of the pathway. Meanwhile, multiple insults to the pathway, such as combination therapy regimens, are known to be effective in shutting down these pathways and, consequently, killing the tumor cell. Research is currently under way to find new ways to exploit fragile aspects of oncogenic networks, such as uncommon, multiple perturbations that target essential hubs through immunotherapy, combinations of antibodies, heat shock protein inhibitors, or novel drug combinations. Complex growth factor signaling networks and novel methods to shut down these networks are described within a framework of engineering and mathematical concepts. PMID- 21278439 TI - Chemotherapy: updates and new perspectives. AB - Treatment options for patients with breast cancer have progressively improved over the past 40 years, from an era of no chemotherapy to the introduction of taxanes, hormonal therapy, and biologic therapy. These advances have resulted in substantial, 15%-20% improvements in clinical outcomes. However, progress has yet to be made to improve the prognosis in many breast cancer patients, and research is currently under way to test new tools, or new applications of older tools, to advance breast cancer management. Chemotherapy clearly remains a cornerstone of adjuvant breast cancer treatment, because breast cancer can be very sensitive to the currently available agents. Meanwhile, the era of a one-size-fits-all approach to breast cancer management is over, and the maximum potential of chemotherapy should now be reached by targeting specific populations. Effective biomarkers are therefore needed to optimize chemotherapy, define more selective populations, and clearly tailor treatment. This paper discusses recent data, including new trials that are more fully incorporating current knowledge with respect to molecular markers and the underlying biology of breast cancer. PMID- 21278440 TI - New developments in hormone receptor-positive disease. AB - Of more than one million women diagnosed with breast cancer each year, approximately 700,000 have hormone receptor (HR)(+) disease. Although endocrine therapy has revolutionized breast cancer management and substantially improved outcomes in these patients, the optimal management of these patients remains a significant challenge. For instance, the threshold for adding adjuvant chemotherapy is a topic of continuing debate, and the most effective regimens that include endocrine therapy and chemotherapy are still under debate as well. Tumor markers, such as Ki-67, and host markers, such as cytochrome P450 2D6, are being studied as potential tools to offer more tailored adjuvant endocrine therapy. Current research suggests that luminal A and luminal B cancers are two completely different diseases, and work is being performed to better distinguish between these two disease types and deliver more effective therapy to individual patients. This article addresses these important outstanding issues with respect to HR(+) disease. PMID- 21278441 TI - A new look at node-negative breast cancer. AB - Node-negative breast cancer is a prevalent form of the disease worldwide, particularly in regions with rigorous screening and disease awareness efforts. Although there is a common biology between node-negative and node-positive breast tumors, it is still important to specifically address risk assessment and predictive factors in node-negative breast cancer. The relative risks and benefits are more pronounced in these patients, but there is no single prognostic factor available for deciding whether to administer chemotherapy and selecting the best adjuvant chemotherapy regimen. In the absence of universal predictive factors, the trend is to give chemotherapy to all patients to ensure the highest possibility for cure. Tumor grade is important in that it is predictive of risk over time, but lacks standardization. Adjuvant! Online, a web-based algorithm, is also used to guide treatment decisions. Recently, the urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) biomarkers have been used to determine disease risk and, consequently, determine whether or not chemotherapy is needed. However, the assay requires a fresh-frozen tissue sample, which is not always feasible. The oncotype DX(r) genomic assay has also been used to help prognosis estimation and treatment decisions. It is currently under evaluation in conjunction with the uPA/PAI-1 assay in the Plan B trial. The question that remains in adjuvant chemotherapy today for patients with node negative disease is proper patient selection. Node-negative breast cancer does not automatically suggest a good prognosis, or the preclusion of chemotherapy benefits, and additional biomarkers are needed to help identify patients who do benefit from chemotherapy. PMID- 21278442 TI - Molecular stratification of triple-negative breast cancers. AB - Research focused on the analysis and classification of breast tumors, primarily using DNA microarrays and patterns of gene expression, has resulted in distinct tumor subtypes. Although no knowledge of patient survival or outcomes was used to derive these gene descriptions, these different classes based upon patterns of gene expression have important prognostic implications. Predictive markers in estrogen receptor-negative and triple-negative disease will be particularly important because in the absence of therapy, these tumor subtypes tend to have a poor prognosis. In addition, the claudin-low subgroup has been found to be common within the triple-negative cancers and may have further prognostic and therapeutic implications. Patients with triple-negative breast cancer do benefit from chemotherapy, but better treatment options are needed that are less toxic, reduce the risk of disease progression, and are more targeted to this patient population. Potential treatments include poly (ADP-ribose) polymerase inhibitors, and therapies that target cancer stem cells could also have an important impact in these patients. This article will focus on the molecular stratification of triple-negative breast cancers and the therapeutic implications of these classifications. PMID- 21278443 TI - Directed therapy of subtypes of triple-negative breast cancer. AB - In developed countries, there has been a remarkable improvement in mortality from breast cancer, but almost all of that benefit has occurred in the estrogen receptor (ER)(+) and human epidermal growth factor receptor (HER)-2(+) subsets. Triple-negative breast cancer, defined as tumors that are negative for ER, progesterone receptor, and HER-2, represent a minority of breast cancers. However, because of the poor prognosis in this particular subtype, triple negative disease accounts for a disproportionate number of metastatic cases and breast cancer deaths. While chemotherapy is effective in triple-negative disease, research continues to better target therapies and predict prognosis. Recent studies have suggested a link between BRCA mutations and triple-negative disease, but the nature of this link remains opaque. Antiangiogenic agents such as bevacizumab have demonstrated efficacy across subtypes. More recently, poly(ADP ribose) polymerase inhibitors appear to take advantage of the concept of synthetic lethality, or dual pathway inhibition, in attacking triple-negative and BRCA-associated tumors. These and other studies in triple-negative disease will help us to better identify effective treatment options and improve outcomes in these patients. This article addresses the nature of, and therapeutic strategies for, triple-negative breast cancer. PMID- 21278444 TI - Coming of age: breast cancer in seniors. AB - In the U.S., cancer is a disease of aging. The average 65-year-old patient has an anticipated life expectancy of 20 years, and clinicians should take this into account when making breast cancer management decisions. However, older breast cancer patients can present with wide variations in health status, and treatment in older patients should therefore include a careful evaluation of comorbidities, physical function, polypharmacy, and other issues that could potentially impact a patient's ability to undergo chemotherapy without excessive risk. Evaluation tools are under development, including potential molecular markers, to identify which older patients are the best candidates for chemotherapy, as well as those more susceptible to actually developing cancer. Standard chemotherapy regimens are just as effective in older patients as they are in the younger population, and can substantially prolong life expectancy when used in the right patients. This article discusses breast cancer in seniors, including the epidemiology of breast cancer in these patients, the potential impact of comorbidities, and effective adjuvant therapy in selected older patients. PMID- 21278445 TI - Genomic instability and cancer: an introduction. AB - Genomic instability refers to an increased tendency of alterations in the genome during the life cycle of cells. It is a major driving force for tumorigenesis. During a cell division, genomic instability is minimized by four major mechanisms: high-fidelity DNA replication in S-phase, precise chromosome segregation in mitosis, error free repair of sporadic DNA damage, and a coordinated cell cycle progression. This introduction summarizes the major molecular processes that contribute to these mechanisms in the context of prevention of genomic instability and tumorigenesis. PMID- 21278446 TI - More forks on the road to replication stress recovery. AB - High-fidelity replication of DNA, and its accurate segregation to daughter cells, is critical for maintaining genome stability and suppressing cancer. DNA replication forks are stalled by many DNA lesions, activating checkpoint proteins that stabilize stalled forks. Stalled forks may eventually collapse, producing a broken DNA end. Fork restart is typically mediated by proteins initially identified by their roles in homologous recombination repair of DNA double-strand breaks (DSBs). In recent years, several proteins involved in DSB repair by non homologous end joining (NHEJ) have been implicated in the replication stress response, including DNA-PKcs, Ku, DNA Ligase IV-XRCC4, Artemis, XLF and Metnase. It is currently unclear whether NHEJ proteins are involved in the replication stress response through indirect (signaling) roles, and/or direct roles involving DNA end joining. Additional complexity in the replication stress response centers around RPA, which undergoes significant post-translational modification after stress, and RAD52, a conserved HR protein whose role in DSB repair may have shifted to another protein in higher eukaryotes, such as BRCA2, but retained its role in fork restart. Most cancer therapeutic strategies create DNA replication stress. Thus, it is imperative to gain a better understanding of replication stress response proteins and pathways to improve cancer therapy. PMID- 21278447 TI - Prevention of DNA re-replication in eukaryotic cells. AB - DNA replication is a highly regulated process involving a number of licensing and replication factors that function in a carefully orchestrated manner to faithfully replicate DNA during every cell cycle. Loss of proper licensing control leads to deregulated DNA replication including DNA re-replication, which can cause genome instability and tumorigenesis. Eukaryotic organisms have established several conserved mechanisms to prevent DNA re-replication and to counteract its potentially harmful effects. These mechanisms include tightly controlled regulation of licensing factors and activation of cell cycle and DNA damage checkpoints. Deregulated licensing control and its associated compromised checkpoints have both been observed in tumor cells, indicating that proper functioning of these pathways is essential for maintaining genome stability. In this review, we discuss the regulatory mechanisms of licensing control, the deleterious consequences when both licensing and checkpoints are compromised, and present possible mechanisms to prevent re-replication in order to maintain genome stability. PMID- 21278448 TI - Okazaki fragment maturation: nucleases take centre stage. AB - Completion of lagging strand DNA synthesis requires processing of up to 50 million Okazaki fragments per cell cycle in mammalian cells. Even in yeast, the Okazaki fragment maturation happens approximately a million times during a single round of DNA replication. Therefore, efficient processing of Okazaki fragments is vital for DNA replication and cell proliferation. During this process, primase synthesized RNA/DNA primers are removed, and Okazaki fragments are joined into an intact lagging strand DNA. The processing of RNA/DNA primers requires a group of structure-specific nucleases typified by flap endonuclease 1 (FEN1). Here, we summarize the distinct roles of these nucleases in different pathways for removal of RNA/DNA primers. Recent findings reveal that Okazaki fragment maturation is highly coordinated. The dynamic interactions of polymerase delta, FEN1 and DNA ligase I with proliferating cell nuclear antigen allow these enzymes to act sequentially during Okazaki fragment maturation. Such protein-protein interactions may be regulated by post-translational modifications. We also discuss studies using mutant mouse models that suggest two distinct cancer etiological mechanisms arising from defects in different steps of Okazaki fragment maturation. Mutations that affect the efficiency of RNA primer removal may result in accumulation of unligated nicks and DNA double-strand breaks. These DNA strand breaks can cause varying forms of chromosome aberrations, contributing to development of cancer that associates with aneuploidy and gross chromosomal rearrangement. On the other hand, mutations that impair editing out of polymerase alpha incorporation errors result in cancer displaying a strong mutator phenotype. PMID- 21278449 TI - A Blm-Recql5 partnership in replication stress response. AB - Deficiencies in DNA damage response and repair not only can result in genome instability and cancer predisposition, but also can render the cancer cells intrinsically more vulnerable to certain types of DNA damage insults. Particularly, replication stress is both a hallmark of human cancers and a common instigator for genome instability and cell death. Here, we review our work based on the genetic knockout studies on Blm and Recql5, two members of the mammalian RecQ helicase family. These studies have uncovered a unique partnership between these two helicases in the implementation of proper mitigation strategies under different circumstances to promote DNA replication and cell survival and suppress genome instability and cancer. In particular, current studies have revealed the presence of a novel Recql5/RECQL5-dependent mechanism for suppressing replication fork collapse in response to global replication fork stalling following exposure to camptothecin (CPT), a topoisomerase I inhibitor, and a potent inhibitor of DNA replication. The unique partnership between Blm and Recql5 in coping with the challenge imposed by replication stress is discussed. In addition, given that irinotecan and topotecan, two CPT derivatives, are currently used in clinic for treating human cancer patients with very promising results, the potential implication of the new findings from these studies in anticancer treatments is also discussed. PMID- 21278450 TI - The role of RAD9 in tumorigenesis. AB - RAD9 regulates multiple cellular processes that influence genomic integrity, and for at least some of its functions the protein acts as part of a heterotrimeric complex bound to HUS1 and RAD1 proteins. RAD9 participates in DNA repair, including base excision repair, homologous recombination repair and mismatch repair, multiple cell cycle phase checkpoints and apoptosis. In addition, functions including the transactivation of downstream target genes, immunoglobulin class switch recombination, as well as 3'-5' exonuclease activity have been reported. Aberrant RAD9 expression has been linked to breast, lung, thyroid, skin and prostate tumorigenesis, and a cause-effect relationship has been demonstrated for the latter two. Interestingly, human RAD9 overproduction correlates with prostate cancer whereas deletion of Mrad9, the corresponding mouse gene, in keratinocytes leads to skin cancer. These results reveal that RAD9 protein can function as an oncogene or tumor suppressor, and aberrantly high or low levels can have deleterious health consequences. It is not clear which of the many functions of RAD9 is critical for carcinogenesis, but several alternatives are considered herein and implications for the development of novel cancer therapies based on these findings are examined. PMID- 21278451 TI - Tumor suppressor p53 meets microRNAs. AB - Tumor suppressor p53 plays a central role in tumor prevention. As a transcription factor, p53 mainly exerts its function through transcription regulation of its target genes to initiate various cellular responses. To maintain its proper function, p53 is tightly regulated by a wide variety of regulators in cells. Thus, p53, its regulators and regulated genes form a complex p53 network which is composed of hundreds of genes and their products. microRNAs (miRNAs) are a class of endogenously expressed, small non-coding RNA molecules which play a key role in regulation of gene expression at the post-transcriptional level. Recent studies have demonstrated that miRNAs interact with p53 and its network at multiple levels. p53 regulates the transcription expression and the maturation of a group of miRNAs. On the other hand, miRNAs can regulate the activity and function of p53 through direct repression of p53 or its regulators in cells. These findings have demonstrated that miRNAs are important components in the p53 network, and also added another layer of complexity to the p53 network. PMID- 21278452 TI - Epigenetic changes of DNA repair genes in cancer. AB - 'Every Hour Hurts, The Last One Kills'. That is an old saying about getting old. Every day, thousands of DNA damaging events take place in each cell of our body, but efficient DNA repair systems have evolved to prevent that. However, our DNA repair system and that of most other organisms are not as perfect as that of Deinococcus radiodurans, for example, which is able to repair massive amounts of DNA damage at one time. In many instances, accumulation of DNA damage has been linked to cancer, and genetic deficiencies in specific DNA repair genes are associated with tumor-prone phenotypes. In addition to mutations, which can be either inherited or somatically acquired, epigenetic silencing of DNA repair genes may promote tumorigenesis. This review will summarize current knowledge of the epigenetic inactivation of different DNA repair components in human cancer. PMID- 21278453 TI - 'Hide-then-hit' to explain the importance of genotypic polymorphism of DNA repair genes in determining susceptibility to cancer. AB - Interindividual variations in DNA repair capacity/efficiency linked to the presence of polymorphisms in DNA repair-related genes have been suggested to account for different risk of developing cancers. In this review article, on the basis of breast cancer formation as a model, we propose a 'hide-then-hit' hypothesis indicating the importance of escaping checkpoint surveillance for sub optimal DNA repair variants to cause cancer. Therefore, only cells with subtle defects in repair capacity arising from low-penetrance variants of DNA repair genes would have the opportunity to grow and accumulate the genetic changes needed for cancer formation, without triggering cell-cycle checkpoint surveillance. Furthermore, distinct from high-penetrance alleles, these polymorphic alleles of DNA repair genes would predispose carriers to a higher risk of developing cancer but would not necessarily cause cancer. To examine this, we simultaneously genotyped multiple SNPs of cell-cycle checkpoint genes and the DNA repair genes. Support for the hypothesis came from observations that breast cancer risk associated with variant genotypes of DNA repair genes became more significant in the subgroups of women with specific genotypic statuses of checkpoint genes. This 'hide-then-hit' hypothesis is certainly needed to be confirmed by biological evidence in which a cause-effect relationship has to be established. However, based on this, possible gene-gene interaction is considered to play an important role in modifying the cancer risk associated with genotypic polymorphism of DNA repair gene in different study populations. PMID- 21278455 TI - Alcohol industry and non-alcohol industry sponsorship of sportspeople and drinking. AB - AIMS: To examine the relationship between direct alcohol and non-alcohol sponsorship and drinking in Australian sportspeople. METHODS: Australian sportspeople (N = 652; 51% female) completed questionnaires on alcohol and non alcohol industry sponsorship (from bars, cafes etc.), drinking behaviour (Alcohol Use Disorders Identification Test (AUDIT)) and known confounders. RESULTS: 31% reported sponsorship (29.8% alcohol industry; 3.7% both alcohol and non-alcohol industry and 1.5% non-alcohol industry only) Multivariate regression showed that receipt of alcohol industry sponsorship was predictive of higher AUDIT scores (beta(adj) = 1.67, 95% confidence interval (CI): 0.56-2.78), but non-alcohol industry sponsorship and combinations of both were not (beta(adj) = 0.18, 95% CI: -2.61 to 2.68; and beta(adj) = 2.58, 95% CI: -0.60 to 5.76, respectively). CONCLUSION: Governments should consider alternatives to alcohol industry sponsorship of sport. Hypothecated taxes on tobacco have been used successfully for replacing tobacco sponsorship of sport in some countries, and may show equal utility for the alcohol industry's funding of sport. PMID- 21278454 TI - BRCA1, PARP, and 53BP1: conditional synthetic lethality and synthetic viability. AB - BRCA1 plays a critical role in the regulation of homologous recombination (HR) mediated DNA double-strand break repair. BRCA1-deficient cancers have evolved to tolerate loss of BRCA1 function. This renders them vulnerable to agents, such as PARP inhibitors, that are conditionally 'synthetic lethal' with their underlying repair defect. Recent studies demonstrate that BRCA1-deficient cells may acquire resistance to these agents by partially correcting their defect in HR-mediated repair, either through reversion mutations in BRCA1 or through 'synthetic viable' loss of 53BP1. These findings and their clinical implications will be reviewed in this article. PMID- 21278456 TI - From mess to mass: a methodology for calculating storm event pollutant loads with their uncertainties, from continuous raw data time series. AB - With the increasing implementation of continuous monitoring of both discharge and water quality in sewer systems, large data bases are now available. In order to manage large amounts of data and calculate various variables and indicators of interest it is necessary to apply automated methods for data processing. This paper deals with the processing of short time step turbidity time series to estimate TSS (Total Suspended Solids) and COD (Chemical Oxygen Demand) event loads in sewer systems during storm events and their associated uncertainties. The following steps are described: (i) sensor calibration, (ii) estimation of data uncertainties, (iii) correction of raw data, (iv) data pre-validation tests, (v) final validation, and (vi) calculation of TSS and COD event loads and estimation of their uncertainties. These steps have been implemented in an integrated software tool. Examples of results are given for a set of 33 storm events monitored in a stormwater separate sewer system. PMID- 21278457 TI - Studies on photocatalytic activity of the synthesised TiO2 and Ag/TiO2 photocatalysts under UV and sunlight irradiations. AB - Photocatalytic decolorisation and degradation of Reactive Red 120 (RR 120) has been investigated under UV (365 nm) and solar light as radiation sources using synthesised nano titania catalyst prepared via sol-gel method. The study encompassed calcination of synthesised titania catalyst at a range of temperature up to 1,000 degrees C. The effects of calcination temperature on titania catalyst have been evaluated on the decolorisation of RR 120. The analysis revealed complete decolorisation of dye solution in 100 min under UV light with the TiO2 catalyst calcined at 200 degrees C. Only a maximum of 47% dye decolorisation was achieved under sunlight in 4 h with no improvement even after prolonged irradiation. In an endeavour to improve the catalytic activity, bare titania was modified with silver metal and a comprehensive study on the characteristics of silver modified catalyst was made. The result was an enhancement of the rate of decolorisation of dye under both UV and solar light sources. All the catalysts were characterised by XRD and BET analyses. Optimisation of the degradation of RR 120 has been carried out using the unmodified catalyst by varying the amount of catalyst, substrate concentration, pH of dye solution. Effects of addition of small amounts of various oxidants such as H2O2, KBrO3 and (NH4)2S2O8 have also been studied. Pseudo first order kinetics was observed in the photocatalytic decolorisation of dye. The mineralisation of RR 120 was monitored by TOC analysis. PMID- 21278458 TI - The removal of the trivalent chromium from the leather tannery wastewater: the optimisation of the electro-coagulation process parameters. AB - The capacity of the electro-coagulation (EC) process for the treatment of the wastewater containing Cr3+, resulting from a leather tannery industry placed in Medellin (Colombia), was evaluated. In order to assess the effect of some parameters, such as: the electrode type (Al and/or Fe), the distance between electrodes, the current density, the stirring velocity, and the initial Cr3+ concentration on its efficiency of removal (%RCr+3), a multifactorial experimental design was used. The %RCr3+ was defined as the response variable for the statistical analysis. In order to optimise the operational values for the chosen parameters, the response surface method (RSM) was applied. Additionally, the Biological Oxygen Demand (BOD5), the Chemical Oxygen Demand (COD), and the Total Organic Carbon (TOC) were monitored during the EC process. The electrodes made of aluminium appeared to be the most effective in the chromium removal from the wastewater under study. At pH equal to 4.52 and at 28 degrees C, the optimal conditions of Cr3+ removal using the EC process were found, as follows: the initial Cr3+ concentration=3,596 mg/L, the electrode gap=0.5 cm, the stirring velocity=382.3 rpm, and the current density=57.87 mA/cm2. At those conditions, it was possible to reach 99.76% of Cr3+ removal, and 64% and 61% of mineralisation (TOC) and COD removal, respectively. A kinetic analysis was performed in order to verify the response capacity of the EC process at optimised parameter values. PMID- 21278459 TI - Investigation of Cu(II) adsorption from aqueous solutions by NKF-6 zeolite. AB - Adsorption of Cu(II) from aqueous solutions using NKF-6 zeolite was investigated by batch technique under ambient conditions. The adsorption was investigated as a function of pH, ionic strength, fulvic acid (FA), foreign ions and temperature. The results indicated that the adsorption of Cu(II) on NKF-6 zeolite gradually increases from 0 to 90% with increasing pH at pH<6.5, and maintains high level at pH>6.5. Outer-sphere complexation or ion exchange may be the main adsorption mechanism of Cu(II) to NKF-6 zeolite at low pH values, whereas the adsorption of Cu(II) at pH>6.5 is mainly dominated by inner-sphere complexation or precipitation. A positive effect of FA on Cu(II) adsorption onto NKF-6 zeolite is observed at low pH values, while a negative effect of FA is observed at high pH values. The thermodynamic parameters (i.e., DeltaH0, DeltaS0 and DeltaG0) for the adsorption of Cu(II) were determined from the temperature dependent isotherms at 20, 40 and 60 degrees C, respectively, and the results indicated that the adsorption reaction is favoured at low temperature. The results suggested that the adsorption process of Cu(II) on NKF-6 zeolite is spontaneous and exothermic. PMID- 21278460 TI - Study on the removal of acid dyes using chitosan as a natural coagulant/coagulant aid. AB - Chitosan was selected as a natural coagulating agent for the removal of acid dyes (Acid Blue 292; AB292, and Acid Red 398; AR398) from dye-containing solutions. The study was organised in two phases. In phase 1, chitosan was used alone as a natural coagulant for the removal of the dyes. For this purpose, the effect of different parameters including pH, chitosan dosage and initial dye concentration on the dye removal efficiency was examined. In phase 2 of the study, the application of chitosan as a natural coagulant aid in conjunction with polyaluminium chloride (PAC) was assessed. According to the results of phase 1, the best removal efficiencies occurred in an acidic pH range (less than 6) for both of the dyes. Also, excellent dye removal results (about 90%) were achieved with relatively low dosages of chitosan (30-35 mg L(-1) for AB292 and 50-60 mg L( 1) for AR398). However, the initial concentration of the dyes severely influenced the coagulation performance of chitosan, which can constrain the performance of chitosan as a natural coagulant. On the basis of the results of phase 2, chitosan, as a natural coagulant aid, noticeably enhanced the dye removal efficiency of PAC, especially in the case of AB292. Small amounts of chitosan (3 or 5 mg L(-1)) enhanced the dye removal efficiency of PAC up to 2.5 times for AB292. PMID- 21278461 TI - Quantification of umu genotoxicity level of urban river water. AB - In recent years, the request of environmental safety management for carcinogenic substances, mutagenic substances and/or reproductive toxicity substances (CMR) has increased. This study focused on clarifying the genotoxicity level of environmental water and its release source by using the umu test provided in ISO13829. Although a genotoxicity index "induction ratio (IR)" is used in ISO13829, we normalised it to make it possible to compare various environmental water quantitatively to each other as a new index "genotoxic activity (GA=(IR 1)/Dose)". Sample water was collected and concentrated to 100 times or 1,000 times by a solid phase extraction method. As the test results, it was found that GA level in actual river water varied widely from less than the determination limit of 23 [1/L] to 1,100 [1/L] by quantitative comparison, and the value was also equivalent to more than 50 times the level of tap water. The GA level of household wastewater was not so high, but the levels of treated water from wastewater treatment plant (WTP) were from 220 [1/L] to 3,200 [1/L]. Raw sewage of some WTP shows high level genotoxicity. A part of genotoxicity substances, for example 50%, could be removed by conventional wastewater treatment, but it was not enough to reduce the water environmental load of genotoxicity. PMID- 21278462 TI - Influence of natural organic matter on equilibrium adsorption of neutral and charged pharmaceuticals onto activated carbon. AB - Natural organic matter (NOM) can influence pharmaceutical adsorption onto granular activated carbon (GAC) by direct adsorption competition and pore blocking. However, in the literature there is limited information on which of these mechanisms is more important and how this is related to NOM and pharmaceutical properties. Adsorption batch experiments were carried out in ultrapure, waste- and surface water and fresh and NOM preloaded GAC was used. Twenty-one pharmaceuticals were selected with varying hydrophobicity and with neutral, negative or positive charge. The influence of NOM competition and pore blocking could not be separated. However, while reduction in surface area was similar for both preloaded GACs, up to 50% lower pharmaceutical removal was observed on wastewater preloaded GAC. This was attributed to higher hydrophobicity of wastewater NOM, indicating that NOM competition may influence pharmaceutical removal more than pore blocking. Preloaded GAC was negatively charged, which influenced removal of charged pharmaceuticals significantly. At a GAC dose of 6.7 mg/L, negatively charged pharmaceuticals were removed for 0-58%, while removal of positively charged pharmaceuticals was between 32-98%. Charge effects were more pronounced in ultrapure water, as it contained no ions to shield the surface charge. Solutes with higher log D could compete better with NOM, resulting in higher removal. PMID- 21278463 TI - Degradation of surfactant wastewater under microwave irradiation in the presence of activated carbon assisted with nano-sized TiO2 or nano-sized ZnO. AB - An improved method treating surfactant wastewater by the addition of semiconductor material such as nano-sized TiO2 or ZnO to activated carbon (AC) with microwave (MW) irradiation was proposed so as to assist efficient degradation of organic pollutants. A series of degradation experiments of sodium dodecyl benzene sulfonate (SDBS) were carried out under MW irradiation in the presence of AC/TiO2 or AC/ZnO. The influences of catalyst dose, irradiation time, initial SDBS concentration and solution acidity on the degradation were assessed in detail. The results showed that the addition of TiO2 or ZnO obviously promoted the degradation and AC/TiO2 system displayed higher catalytic activity under MW irradiation. Thus the method of MW irradiation with AC/TiO2 or AC/ZnO revealed many advantages of rapid degradation rate, short irradiation time, low cost, no residual intermediates and no secondary pollution in applications. PMID- 21278464 TI - Comparison of four methods to assess biofilm development. AB - Two nondestructive methods of biofilm quantification (optical density via a flatbed scanner and biofilm thickness) have been evaluated and compared to two destructive methods (Crystal Violet staining after biofilm disintegration and dry weight). The methods were tested on biofilms that developed on a modified rotating biological contactor (RBC) that was inoculated with urban wastewater and fed with a synthetic medium that mimicked slaughterhouse wastewater. The results of the different methods were highly correlated (coefficient of correlation greater than 0.8). This validation experiment confirms the ability of the scanning method to easily monitor the biofilm's development over large surfaces without destruction of the biofilm. PMID- 21278465 TI - Evaluation of low-cost cathode catalysts for high yield biohydrogen production in microbial electrolysis cell. AB - As an ideal fuel due to the advantages of no pollution, high combustion heat and abundant sources, hydrogen gas can be produced from organic matter through the electrohydrogenesis process in microbial electrolysis cells. But in many MECs, platinum is often used as catalyst, which limits the practical applications of MECs. To reduce the cost of the MECs, Ni-based alloy cathodes were developed by electrodepositing. In this paper hydrogen production using Ni-W-P cathode was studied for the first time in a single-chamber membrane-free MEC. At an applied voltage of 0.9 V, MECs with Ni-W-P cathodes obtained a hydrogen production rate of 1.09 m3/m3/day with an cathodic hydrogen recovery of 74%, a Coulombic efficiency of 56% and an electrical energy efficiency relative to electrical input of 139%, which was the best result of reports in this study. The Ni-W-P cathode demonstrated a better electrocatalytic activity than the Ni-Ce-P cathode and achieved a comparable performance to the Pt cathode in terms of hydrogen production rate, Coulombic efficiency, cathodic hydrogen recovery and electrical energy efficiency at 0.9 V. PMID- 21278466 TI - Polyhydroxyalkanoates (PHA) biosynthesis from kraft mill wastewaters: biomass origin and C:N relationship influence. AB - The goal of this study is to evaluate the feasibility of PHA biosynthesis from kraft mill effluent using the batch system evaluating the biomass origin and C:N relationship influence. To evaluate feasibility, batch assays were carried out. Also, two levels of the BOD5:N:P relationship (100:5:1 and 100:1:0.2) and three different sludge origins were considered. Inocula were obtained from activated sludge treatment plants for a) sewage (SAS), b) paper mill (PAS) and c) kraft (KAS). The results show that the maximum Biological Oxygen Demand (BOD5) and Chemical Oxygen Demand (COD) removal was 80.5% and 59.7% respectively using KAS as inoculum. In these assays, kinetics constants were 17.9+/-3.2 mg L(-1) and 46.5+/-1.2 d(-1) for (KCOD) and (rmax), respectively under a BOD5:N:P relationship of 100:5:1. The maximum PHA accumulation was obtained under a BOD5:N:P relationship of 100:1:0.2 on the third day of batch assays using PAS sludge with 25.72% of the cells accumulating PHA and on the fifth day in batch using SAS and KAS sludge with 25.85% and 30.40% of cells accumulating PHA, respectively. Yields obtained for the 100:1:0.2 relationships ranged from 0.10 0.14 mg PHA mg(-1) COD. PMID- 21278467 TI - Electrochemical oxidation of tetracycline antibiotics using a Ti/IrO2 anode for wastewater treatment of animal husbandry. AB - In animal husbandry, antibiotics are widely used to treat and prevent diseases or to promote growth. The use of antibiotics for domestic animals enables to promote safety of livestock products and enhance productivity. Tetracycline antibiotics (TCs) are one of the primarily used groups of antibiotics for cattle and swine. However, the unintentional spreading of antibiotics from animal waste to the environment may leave out drug residues, promoting resistant strains of bacteria, and will adversely affect the ecosystem and human health. To prevent the spread of veterinary antibiotics in the environment, it is required to treat residual antibiotics in livestock wastewater. In this study, we investigated the electrochemical oxidation of TCs to treat livestock wastewater. The concentrations of TCs in aqueous solutions were reduced from 100 mg/L to less than 0.6 mg/L by 6 h of electrochemical treatment using a Ti/IrO2 anode with Na2SO4 electrolyte. The concentration of oxytetracycline (OTC) in livestock wastewater was also reduced from 100 mg/L to less than 0.7 mg/L by the same treatment. Thus, the electrochemical oxidation using a Ti/IrO2 anode with Na2SO4 electrolyte was found to be effective for degradation of TCs. The results suggest that the electrochemical oxidation method is a promising treatment for TCs in livestock wastewater. PMID- 21278468 TI - Effects of model schematisation, geometry and parameter values on urban flood modelling. AB - One-dimensional (1D) hydrodynamic models have been used as a standard industry practice for urban flood modelling work for many years. More recently, however, model formulations have included a 1D representation of the main channels and a 2D representation of the floodplains. Since the physical process of describing exchanges of flows with the floodplains can be represented in different ways, the predictive capability of different modelling approaches can also vary. The present paper explores effects of some of the issues that concern urban flood modelling work. Impacts from applying different model schematisation, geometry and parameter values were investigated. The study has mainly focussed on exploring how different Digital Terrain Model (DTM) resolution, presence of different features on DTM such as roads and building structures and different friction coefficients affect the simulation results. Practical implications of these issues are analysed and illustrated in a case study from St Maarten, N.A. The results from this study aim to provide users of numerical models with information that can be used in the analyses of flooding processes in urban areas. PMID- 21278469 TI - Removal of ammonium from rare-earth wastewater using natural brucite as a magnesium source of struvite precipitation. AB - This paper presents a study regarding ammonium removal from rare-earth wastewater by struvite precipitation with natural brucite mineral as a source of magnesium. Experimental results indicated that a pH ranging from 8.5 to 9.5 was the optimum for the removal of ammonium using the soluble form of brucite as a magnesium source. Additionally, when solid brucite was used as a magnesium source as well as an alkali reagent, the initial ammonium concentration of 4,535 mg/L decreased to 239-317 mg/L after an reaction time of 12 h in wastewater treated with the S/L (solid brucite/liquid wastewater) ratios ranging from 31.2 to 63.2 g/L. Furthermore, as some non-reacted brucite still remained in the precipitates obtained at the end of reaction, the precipitates were subjected to reuse. The reuse results demonstrated that the reuse of the precipitates obtained with 63.2 g/L was feasible, and almost half of the brucite dose could be saved. PMID- 21278470 TI - Microbial community analysis in the autotrophic denitrification process using spent sulfidic caustic by denaturing gradient gel electrophoresis of PCR amplified genes. AB - Spent sulfidic caustic (SSC) produced from petrochemical plants contains a high concentration of hydrogen sulfide and alkalinity, and some almost non biodegradable organic compounds such as benzene, toluene, ethylbenzene and xylenes (BTEX). SSC is mainly incinerated with auxiliary fuel, leading to secondary pollution problems. The reuse of this waste is becoming increasingly important from economic and environmental viewpoints. To denitrify wastewater with low COD/N ratio, additional carbon sources are required. Thus, autotrophic denitrification has attracted increasing attention. In this study, SSC was injected as an electron donor for sulfur-based autotrophic denitrification in the modified Ludzack-Ettinger (MLE) process. The efficiencies of nitrification, COD, and total nitrogen (TN) removal were evaluated with varying SSC dosage. Adequate SSC injection exhibited stable autotrophic denitrification. No BTEX were detected in the monitored BTEX concentrations of the effluent. To analyse the microbial community of the MLE process, PCR-DGGE based on 16 S rDNA with EUB primers, TD primers and nirK gene with nirK primers was performed in order to elucidate the application of the MLE process to SSC. PMID- 21278471 TI - Degradation mechanism of 4-chlorophenol with electrogenerated hydrogen peroxide on a Pd/C gas-diffusion electrode. AB - Using a self-made Pd/C gas-diffusion electrode as the cathode and a Ti/IrO2/RuO2 anode, the degradation of 4-chlorophenol has been investigated in an undivided electrolysis device by the electrochemical oxidation processes. The result indicated that the neutral aqueous solutions can accelerate 4-chlorophenol degradation during electrolysis. The removal efficiency of 4-chlorophenol and COD reached about 89.6% and 62.0% after 120 min electrolysis, respectively. It suggested that most of 4-chlorophenol was oxidised to intermediates using the Pd/C gas-diffusion electrode. Furthermore, the biodegradation ability of the solution was increased significantly during the electrolysis. The degradation of 4-chlorophenol was attributed to the cooperative oxidation processes including electrochemical oxidation at the anode and H2O2 and hydroxyl radical (HO.) produced by the reduction of oxygen at the cathode. Finally, main aromatic intermediates (e.g., hydroquinone and benzoquinone) and main aliphatic carboxylic intermediates (e.g., oxalic, malonic, maleic, succinic, fumaric, and dodecanoic acids) were identified by GC-MS. Moreover, a reaction scheme involving all these intermediates was proposed. PMID- 21278472 TI - The effects of nutrient limitation (nitrogen and phosphorus) on BOD removal from post-coagulated Pinus radiata sulfite pulp and paper mill wastewater in a baffled aerated stabilisation basin-laboratory pilot scale study. AB - The use of coagulation and flocculation for tertiary treatment of pulp and paper mill effluent was investigated, where the evaluation was based on the removal of nitrogen (N), phosphorus (P) and BOD from post-coagulated wastewater. The study was undertaken on laboratory scale aerobic stabilisation basins (ASB). Two post coagulated (alum) wastewaters were studied, where the BOD:N:P ratios were 100:1.3:0.06 and 100:1.3:0.3. These wastewaters were treated in two identical concurrent simulations (A & B). The influent ratio for 'A' was selected representing the composition of actual coagulated Pinus radiata sulfite pulp effluent mixed with paper mill effluent. The input composition for 'B' represented a typical P concentration found in existing pulp and paper mill effluents. Unmodified sludge collected from a mill-pond was added at 4% v/v to each simulation replicating the treatment conditions at full-scale. Similar high percentage removals of BOD and COD occurred after 28 days (two HRTs) which were 94 and 67% respectively for 'A', and 98 and 70% respectively for 'B', where both remained at steady state during the third HRT. A statistical analysis of the data revealed that there was no significant difference in the sample variance of the BOD and COD results. PMID- 21278473 TI - Development of a real-time RT-PCR assay combined with ethidium monoazide treatment for RNA viruses and its application to detect viral RNA after heat exposure. AB - A method was developed for discriminating damaged viruses or naked viral RNA from intact viruses by ethidium monoazide (EMA) treatment before RT-PCR. The applied EMA treatment consisted of three steps: (1) EMA dose, (2) exposure to light, and (3) additional purification by spin-column gel filtration. Approximately 4-log reduction in viral RNA concentration was observed by adding a dose of 10 MUg/mL EMA with 300 s of light irradiation. Although residual EMA can be an inhibitor of RT-PCR, its effect was reduced by spin-column gel filtration or a QIAamp(r) Viral RNA Mini Kit. EMA-RT-PCR was applied to the thermally treated PV1. Results of EMA RT-PCR were similar to the plaque assay when PV1 was thermally inactivated. Although this is a preliminary study investigating applicability of the EMA-RT PCR method for RNA viruses, the results suggest that the method is potentially applicable for the selective detection of epidemiologically important enteric viruses in water such as enteroviruses and noroviruses. PMID- 21278474 TI - Simulating organic pollutant flows in urban stormwater: development and evaluation of a model for nonylphenols and phthalates. AB - Stormwater-quality models can be useful tools for predicting pollutant loads and identifying sources of contamination. Most models in current use handle pollutants such as metals, nutrients and suspended solids, whereas models including emerging organic contaminants are rare. This study aims at developing and evaluating a model for simulating stormwater flows of two groups of organic pollutants; nonylphenols and phthalates. Sources, emission patterns and environmental fate were examined to create a model framework for the organic contaminants. The model was calibrated using field data from three urban catchments. The results show that the simulated pollutant concentrations are overestimated compared to the measured concentrations, which are often close to or below the analytical detection limit. The high uncertainty and the low predictive power of the model may be explained by factors such as incorrect catchment data, lack of knowledge on buildup, washoff and other processes involved in substance fate, and an underreporting of pollutant concentrations in stormwater. More data on release patterns and sewer fate are needed to adequately simulate stormwater concentrations of nonylphenols and phthalates. A conventional substance flow analysis based on bookkeeping, evaluated in parallel to the computer model, has proven to be useful for calculating fluxes of nonylphenols and phthalates in urban catchments. PMID- 21278475 TI - A practitioner's perspective on the uses and future developments for wastewater treatment modelling. AB - The modern age of wastewater treatment modelling began with publication of the International Water Association (IWA) Activated Sludge Model (ASM) No.1 and has advanced significantly since. Models are schematic representations of systems that are useful for analysis to support decision-making. The most appropriate model for a particular application often incorporates only those components essential for the particular analyses to be performed (i.e. the simplest model possible). Characteristics of effective models are presented, along with how wastewater modelling is integrated into the wastewater project life cycle. The desirable characteristics of wastewater treatment modelling platforms are then reviewed. Current developments of note in wastewater treatment modelling practice include estimates of greenhouse gas emissions, incorporating uncertainty into wastewater modelling and design practice, more fundamental modelling of process chemistry, and improved understanding of the degradability of wastewater constituents in different environments. Areas requiring greater emphasis include increased use of metabolic modelling, characterisation of the hydrodynamics of suspended and biofilm biological treatment processes, and the integration of biofilm and suspended growth process modelling. Wastewater treatment models must also interface with water and wastewater management software packages. While wastewater treatment modelling will continue to advance and make important contributions to practice, it must be remembered that these are complex systems which exhibit counter-intuitive behaviour (results differ from initial expectations) and multiple dynamic steady-states which can abruptly transition from one to another. PMID- 21278476 TI - Past, present, and future design of urban drainage systems with focus on Danish experiences. AB - Climate change will influence the water cycle substantially, and extreme precipitation will become more frequent in many regions in the years to come. How should this fact be incorporated into design of urban drainage systems, if at all? And how important is climate change compared to other changes over time? Based on an analysis of the underlying key drivers of changes that are expected to affect urban drainage systems the current problems and their predicted development over time are presented. One key issue is management of risk and uncertainties and therefore a framework for design and analysis of urban structures in light of present and future uncertainties is presented. PMID- 21278477 TI - The power efficiency of the Tajo-Segura transfer and desalination. AB - The origin of the water supply system of Tajo-Segura, in 1932, goes back to when it was the unique possible solution to the shortage of hydric resources in the Confederacion Hidrografica del Segura (CHS). Its energy consumption is not homogeneous; it could be bigger or smaller, depending on the different water destination. The energy cost average of water of the Tajo-Segura water supply system is 1.21 kWh/m3. The energy consumption of desalination depends on the type of process used to desalinate the water, the time of operation and the capacity of the plant, and also on the density of water to treat. In any case, the energy consumption of the desalination ranges between 3.8 and 4.2 kWh/m3; obviously that is bigger than those obtained of the Tajo-Segura water supply system (1.21 kWh/m3). PMID- 21278478 TI - The inter-tidal zone is the pathway of input of enterococci to a subtropical recreational marine beach. AB - Efforts were made to evaluate the source of enterococci levels at a recreational beach. Four monitoring efforts were implemented which included tidal studies, hourly sampling, runoff sampling, and spatially intensive sediment sampling. Spatially intensive sediment sampling indicated that enterococci concentrations consistently decreased away from the inter-tidal zone, both seaward and landward. During dry conditions, the highest concentrations in the water were observed during high tide (71+/-48 CFU/100 mL) and lower concentrations were observed during low tide (4+/-3 CFU/100 mL). Runoff was characterised by very high levels (11,700 CFU/100 mL). Results from these monitoring efforts collectively showed that the source of enterococci to the study beach is geographically located within the inter-tidal zone. Wash-in from the inter-tidal zone through tidal action and runoff plays a major role in controlling enterococci levels within the water column. Such results are significant in identifying the source and transport mechanisms of enterococci, which can subsequently be used as part of a modelling effort aimed at predicting enterococci levels at recreational beaches. PMID- 21278479 TI - Photocatalytic oxidation of ammonia by cadmium sulfide/titanate nanotubes synthesised by microwave hydrothermal method. AB - CdS/Titanate nanotubes (TNTs) were successfully synthesised by a simple, rapid, and reliable microwave hydrothermal method. The CdS nanoparticles synthesised using a 140-W microwave irradiation power at 423 K photodegraded 26% ammonia in water, while the photocatalytic efficiency increased to 52.3% using the synthesised CdS/TNTs composites. The results indicated that the CdS/TNTs photocatalysts possess improved photocatalytic activity than that of CdS or TNTs materials alone. PMID- 21278480 TI - Long-term survival of Escherichia coli in lightweight aggregate filter media of constructed wastewater treatment wetlands. AB - A laboratory scale experiment on the survival of Escherichia coli in samples of filter media from a horizontal subsurface flow constructed wetland treating domestic wastewater was performed. A concentration of E. coli was examined in samples collected from a wetland filter filled with lightweight aggregates (LWA). All samples testing positive for E. coli contamination were used to examine the effect of storage time on the survival of E. coli at three temperature regimes: cold (4 degrees C), mild (10 degrees C) and warm (22 degrees C). It was found that the mild storage condition favoured the growth and survival of E. coli in the tested LWA media. The growth in samples of the uppermost layer of the media lasted for 5.5 months, during which E. coli reached a maximum concentration of 6.4*10(3) MPN/100 g dry matter in the media. It was also observed that E. coli had a greater capacity to survive for extended periods of time in samples collected from the upper layer of the LWA filter compared to samples taken from the deeper layers. The survival of E. coli in the shallowest samples of the wetland filter was remarkably long and unexpected, lasting for a period of over 14 months. PMID- 21278481 TI - Life cycle assessment of three water systems in Copenhagen--a management tool of the future. AB - Environmental life-cycle assessment (LCA) was applied to evaluate three different water systems of the water sector in Copenhagen, Denmark, including technologies within water supply, facilities recycling water and treatment of sewer overflow. In these three water systems LCA was used to evaluate the environmental impacts of each of the processes involved. The overall conclusion was that LCA is suitable as a decision support tool in the water sector as it provides a holistic evaluation platform of the considered alternatives categorised in environmental impact categories. The use of LCA in the water sector of this region has limitations since it does not yet consider impact categories assessing freshwater scarcity and ecological sustainability. PMID- 21278482 TI - Chemical monitoring strategy for the assessment of advanced water treatment plant performance. AB - A pilot-scale plant was employed to validate the performance of a proposed full scale advanced water treatment plant (AWTP) in Sydney, Australia. The primary aim of this study was to develop a chemical monitoring program that can demonstrate proper plant operation resulting in the removal of priority chemical constituents in the product water. The feed water quality to the pilot plant was tertiary treated effluent from a wastewater treatment plant. The unit processes of the AWTP were comprised of an integrated membrane system (ultrafiltration, reverse osmosis) followed by final chlorination generating a water quality that does not present a source of human or environmental health concern. The chemical monitoring program was undertaken over 6 weeks during pilot plant operation and involved the quantitative analysis of pharmaceuticals and personal care products, steroidal hormones, industrial chemicals, pesticides, N-nitrosamines and halomethanes. The first phase consisted of baseline monitoring of target compounds to quantify influent concentrations in feed waters to the plant. This was followed by a period of validation monitoring utilising indicator chemicals and surrogate measures suitable to assess proper process performance at various stages of the AWTP. This effort was supported by challenge testing experiments to further validate removal of a series of indicator chemicals by reverse osmosis. This pilot-scale study demonstrated a simplified analytical approach that can be employed to assure proper operation of advanced water treatment processes and the absence of trace organic chemicals. PMID- 21278483 TI - Iron mediates endothelial cell damage and blood-brain barrier opening in the hippocampus after transient forebrain ischemia in rats. AB - Blood cells are transported into the brain and are thought to participate in neurodegenerative processes following hypoxic ischemic injury. We examined the possibility that transient forebrain ischemia (TFI) causes the blood-brain barrier (BBB) to become permeable to blood cells, possibly via dysfunction and degeneration of endothelial cells in rats. Extravasation of Evans blue and immunoglobulin G (IgG) was observed in the hippocampal CA1-2 areas within 8 h after TFI, and peaked at 48 h. This extravasation was accompanied by loss of tight junction proteins, occludin, and zonula occludens-1, and degeneration of endothelial cells in the CA1-2 areas. Iron overload and mitochondrial free radical production were evident in the microvessel endothelium of the hippocampus before endothelial cell damage occurred. Administration of deferoxamine (DFO), an iron chelator, or Neu2000, an antioxidant, blocked free radical production and endothelial cell degeneration. Our findings suggest that iron overload and iron mediated free radical production cause loss of tight junction proteins and degeneration of endothelial cells, opening of the BBB after TFI. PMID- 21278484 TI - Regulation of beta-cell-specific and glucose-dependent MafA expression. AB - MafA, a basic-leucine zipper transcription factor that is important to pancreatic beta-cell function, is regulated by several intricate mechanisms. MafA undergoes extensive posttranslational modification by phosphorylation, ubiquitination and sumoylation, and these modifications regulate the turnover, DNA binding and transactivation function of the protein. Regulation of MafA expression is equally complex. The initial characterization of the beta-cell-specific MafA promoter identified six conserved sequence domains. One of these regions in particular contains consensus motifs and binding sites for several beta-cell-enriched transcription factors which ultimately play critical roles in controlling the expression of the gene. Interestingly, in cell culture, acute high glucose stimulation induces the accumulation of MafA, and MafA, in turn, regulates beta cell function. However, under chronic high glucose conditions, which occurs in the context of the diabetic state, beta-cell function and, coincidentally, MafA levels decline. Currently, the mechanisms controlling the glucose-dependent accumulation of MafA are not well understood. This commentary highlights a recent report that further defines the regulation of beta-cell-specific MafA expression and confirms the longstanding assumption that MafA transcription is upregulated in beta-cells acutely cultured in high glucose similar to what may occur in vivo under normoglycemic conditions. PMID- 21278485 TI - Phosphorylation of EZH2 by CDK1 and CDK2: a possible regulatory mechanism of transmission of the H3K27me3 epigenetic mark through cell divisions. AB - Histone H3 lysine 27 trimethylation (H3K27me3) catalyzed by the enzymatic subunit EZH2 in the Polycomb repressive complex 2 (PRC2) is essential for cells to 'memorize' gene expression patterns through cell divisions and plays an important role in establishing and maintaining cell identity during development. However, how the epigenetic mark is inherited through cell generations remains poorly understood. Recently, we and others demonstrate that CDK1 and CDK2 phosphorylate EZH2 at threonine 350 (T350) and that T350 phosphorylation is important for the binding of EZH2 to PRC2 recruiters, such as noncoding RNAs (ncRNAs) HOTAIR and XIST, and for the effective recruitment of PRC2 to EZH2 target loci in cells. These findings imply that phosphorylation of EZH2 by CDK1 and CDK2 may provide cells a mechanism that enhances EZH2 function during S and G2 phases of the cell cycle, thereby ensuring K27me3 on de novo synthesized H3 incorporated in nascent nucleosomes before sister chromosomes are divided into two daughter cells. Additionally, a potential role of T350 phosphorylation of EZH2 in differing EZH2 from its homolog EZH1 in catalyzing H3K27me3 as well as the interplay between phosphorylation at T350 and other residues (e.g. phosphorylation by p38 at threonine 372 (T372)) in governing EZH2 activity in proliferating versus non dividing cells are also discussed. Together, CDK phosphorylation of EZH2 at T350 may represent a key regulatory mechanism of EZH2 function that is essential for the maintenance of H3K27me3 marks through cell divisions. PMID- 21278486 TI - Cost of acute hospitalization and post-discharge follow-up care for meningococcal disease in the US. AB - The combined costs of acute hospitalization and post-discharge follow-up care in patients with meningococcal disease have not been widely documented. In this study, data were retrospectively analyzed from three large databases of hospital discharge records and commercial insurance claims in the US. Cases of meningococcal disease were defined as admissions with an ICD-9-CM diagnosis code in the range of 036.x. From the 2005 HCUP Nationwide Inpatient Sample, 349 (weighted N=1,710) meningococcal-related hospitalizations were identified with a mean facility cost (in 2009 dollars) of $19,526 per admission. Similar estimates ($18,119 and $20,066, respectively) were obtained from 268 admissions identified in the LifeLink (formerly PharMetrics) database during 1999-2007 and from 1,058 hospitalizations in the Perspective Comparative Database (PCD) during 2000-2007. Using insurance claims from LifeLink, we estimated that payers incur an additional $26,178 in non-facility (professional and other ancillary) costs during the course of a meningococcal admission, as well as $22,230 in additional medical and pharmacy expenses for post-discharge care during the ensuing year. The majority of follow-up costs ($14,637) were attributed to repeat hospitalizations. Mean length of stay for meningococcal disease was consistently estimated across databases at 8 to 9 days. Data from the PCD further suggested that meningococcal disease carries, on average, nearly 2 days of intensive care unit utilization. In conclusion, hospital admissions for meningococcal disease are costly to payers. These costs are heightened when non-facility services and post-discharge care are also considered. Awareness of the full cost burden of meningococcal disease is needed when evaluating vaccination programs targeting the disease. PMID- 21278487 TI - CLE polypeptide signaling gene expression in Arabidopsis embryos. AB - The CLAVATA3 (CLV3)/ESR-related (CLE) family of small polypeptides mediate intercellular signaling events in plants. The biological roles of several CLE family members have been characterized, but the function of the majority still remains elusive. We recently performed a systematic expression analysis of 23 Arabidopsis CLE genes to gain insight into the developmental processes they may potentially regulate during vegetative and reproductive growth. Our study revealed that each Arabidopsis tissue expresses one or more CLE genes, suggesting that they might play roles in many developmental and/or physiological processes. Here we determined the expression patterns of nine Arabidopsis CLE gene promoters in mature embryos and compared them to the known expression patterns in seedlings. We found that more than half of these CLE genes have similar expression profiles at the embryo and seedling stages, whereas the rest differ dramatically. The implications of these findings in understanding the biological processes controlled by these CLE genes are discussed. PMID- 21278488 TI - Expression and localization of the uptake transporters OATP2B1, OATP3A1 and OATP5A1 in non-malignant and malignant breast tissue. AB - Organic anion transporting polypeptides (OATPs, gene family SLCO/SLC21) mediate the uptake of multiple endogenous substances such as estrogens and estrogen metabolites and of several widely prescribed drugs (e.g. statins, antibiotics and anticancer agents) into cells. Since several anticancer agents have been identified as substrates for OATPs, these transporters may also have an impact on cancer treatment. Expression of OATPs has been identified in colon, pancreatic and gastric carcinomas but to date little is known about the expression and localization of OATP family members in non-malignant breast tissue and breast cancer. We therefore analyzed the mRNA expression of all human OATP family members and further evaluated the mRNA amount of the highly-expressed OATPs OATP2B1, OATP3A1 and OATP5A1 in 10 paired samples of normal breast tissue and breast cancer. Furthermore, the tissue-specific localization of these OATPs was investigated. The results demonstrated that the mRNA expression of OATPs in normal and malignant breast tissue shows a high interindividual variability and that no significant differences in the mRNA amount between normal and malignant tissue could be detected. Furthermore, we localized OATP3A1 and OATP5A1 to the plasma membrane of epithelial cells of the lactiferous ducts in normal breast tissue. In breast cancer, both OATPs are highly expressed in the plasma membrane and in the cytoplasm. Since estrogen and estrogen metabolites as well as anticancer agents are substrates for OATPs these results indicate the possibility of OATP-mediated uptake of hormones during breast cancer development and an impact of certain OATPs on chemotherapeutic cancer treatment. PMID- 21278489 TI - Vps34 is a phosphatidylinositol 3-kinase, not a phosphoinositide 3-kinase. PMID- 21278490 TI - GSK-3 inactivation or depletion promotes beta-cell replication via down regulation of the CDK inhibitor, p27 (Kip1). AB - Diabetes (T1DM and T2DM) is characterized by a deficit in beta-cell mass. A broader understanding of human beta-cell replication mechanism is thus important to increase beta-cell proliferation for future therapeutic interventions. Here, we show that p27 (Kip1), a CDK inhibitor, is expressed abundantly in isolated adult human islets and interacts with various positive cell cycle regulatory proteins including D-type cyclins (D1, D2 and D3) and their kinase partners, CDK4 and CDK6. Also, we see interaction of cyclin E and its kinase partner, CDK2, with p27 suggesting a critical role of p27 as a negative cell cycle regulator in human islets. Our data demonstrate interaction of p27 with GSK-3 in beta-cells and show, employing rodent beta-cells (INS-1), isolated human islets and purified beta-cells derived from human islets, that siRNA-mediated depletion of GSK-3 or p27 or 1-AKP / BIO - mediated GSK-3 inhibition results in increased beta-cell proliferation. We also see reduction of p27 levels following GSK-3 inactivation or depletion. Our data show that serum induction of quiescent INS-1 cells leads to sequential phosphorylation of p27 on its S10 and T187 residues with faster kinetics for S10 corresponding with the decreased levels of p27. Altogether our findings indicate that p27 levels in beta-cells are stabilized by GSK-3 and thus p27 down regulation following GSK-3 depletion / inactivation plays a critical role in promoting beta-cell replication. PMID- 21278491 TI - GPR30 is overexpressed in post-puberal testicular germ cell tumors. AB - GPR30 is a 7-transmembrane G protein-coupled estrogen receptor that functions alongside traditional estrogen receptors to regulate cellular responses to 17beta estradiol and environmental estrogens. In this study, we have evaluated by immunohistochemical analysis GPR30 expression in post-puberal testicular germ cell tumours (30 seminomas, 5 teratomas, 12 embryonal carcinomas, and 20 intratubular germ cell tumors). The GPR30 protein expression was detected at high level in all intratubular germ cell tumours, seminomas, and embryonal carcinomas, whereas in teratomas the expression was low. The immunohistochemical data were further confirmed by Western blot analysis. GPR30 protein expression has also been analyzed in GC1 and TCam-2 cell lines, respectively derived from immortalized type B murine spermatogonia and human seminoma. Our results indicate that GPR30 could be a potential therapeutic target; the design of a specific GPR30 inhibitors could be a useful molecular target to block neoplastic germ cells with a high proliferative rate for the treatment of TGCTs. PMID- 21278492 TI - Non-specific and sex-differential effects of routine vaccines: what evidence is needed to take these effects into consideration in low-income countries? AB - None of the original vaccines used in the child immunization programmes in low income countries, including BCG, diphtheria-tetanus-pertussis (DTP), oral polio vaccine (OPV), and measles vaccine (MV), were tested for their overall effect on child mortality before being introduced. It was assumed that the effect on overall child mortality would be equivalent to the proportion of deaths caused by the targeted disease(s) (1). However, this is no longer a tenable assumption. Many studies have shown that these routine vaccines may have more general effects on the immune system than merely protecting against the targeted disease, i.e. so called non-specific effects (NSE) (2). The NSE may well be more important for overall child survival than the lives saved by specific disease prevention (2-4). The WHO's Global Advisory Committee on Vaccine Safety (GACVS) has recently stated that it will keep a watch on the non-specific effects (NSE) of vaccination. GACVS indicated that "conclusive evidence for or against non-specific effects of vaccines on mortality, including a potential deleterious effect of DTP vaccination on children's survival as has been reported in some studies, was unlikely to be obtained from observational studies" (5). By insisting on new RCTs to provide conclusive evidence, GACVS is making it very difficult if not impossible to test the NSEs of the currently recommended vaccines. It would usually be considered unethical to test currently recommended vaccines as part of a trial withholding these vaccines from some children (6). PMID- 21278494 TI - Contemporary intrapartum fetal heart rate monitoring. Foreword. PMID- 21278495 TI - A review of the 2008 NICHD Research Planning Workshop: recommendations for fetal heart rate terminology and interpretation. AB - In 1995 and 1996, the National Institute of Child Health and Human Development (NICHD) convened a panel of experts in electronic fetal monitoring with the goal of reaching consensus on a set of standardized, unambiguous definitions for fetal heart rate tracings. In 2008, the Eunice Kennedy Shriver NICHD, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine sponsored a second research planning workshop to review and clarify the 1997 definitions, to propose a standard classification system for fetal heart rate tracings, to introduce, in consensus form, key concepts of intrapartum fetal heart rate interpretation and to make recommendations for future research. This article summarizes the proposals and recommendations of the 2008 NICHD Research Planning Workshop. PMID- 21278493 TI - c-Myc induction of programmed cell death may contribute to carcinogenesis: a perspective inspired by several concepts of chemical carcinogenesis. AB - The c-Myc protein, encoded by c-myc gene, in its wild-type form can induce tumors with a high frequency and can induce massive programmed cell death (PCD) in most transgenic mouse models, with greater efficiency than other oncogenes. Evidence also indicates that c-Myc can cause proliferative inhibition, i.e. mitoinhibition. The c-Myc-induced PCD and mitoinhibition, which may be attributable to its inhibition of cyclin D1 and induction of p53, may impose a pressure of compensatory proliferation, i.e. regeneration, onto the initiated cells (cancer progenitor cells) that occur sporadically and are resistant to the mitoinhibition. The initiated cells can thus proliferate robustly and progress to a malignancy. This hypothetical thinking, i.e. the concurrent PCD and mitoinhibition induced by c-Myc can promote carcinogenesis, predicts that an optimal balance is achieved between cell death and ensuing regeneration during oncogenic transformation by c-Myc, which can better promote carcinogenesis. In this perspective, we summarize accumulating evidence and challenge the current model that oncoprotein induces carcinogenesis by promoting cellular proliferation and/or inhibiting PCD. Inspired by c-myc oncogene, we surmise that many tumor suppressive or growth-inhibitory genes may also be able to promote carcinogenesis in a similar way, i.e. by inducing PCD and/or mitoinhibition of normal cells to create a need for compensatory proliferation that drives a robust replication of initiating cells. PMID- 21278496 TI - Standardization of intrapartum management and impact on adverse outcomes. AB - Patient safety is currently a critical focus within obstetrics. Standardization of intrapartum management, in particular with regard to fetal heart rate monitoring assessment and management, is an important effort to improve obstetrical adverse outcomes. This study explores various strategies to implement standardization of assessment and management. Such measures can impact significantly perinatal outcomes and safety culture. Investigation of the impact of standardizing intrapartum management remains an important area of further study. PMID- 21278497 TI - Intrapartum fetal heart rate definitions and interpretation: evolving consensus. AB - A review of standardized fetal heart rate (FHR) monitoring definitions and interpretation. Evidence suggests that standardization of intrapartum management can reduce adverse outcomes and professional liability claims. However, standardization of FHR monitoring has been impeded by a lack of consensus on standard definitions and interpretation. In recent years, consensus has been achieved regarding several important aspects of intrapartum FHR monitoring. As a result, the prospect of standardization has become a reality. PMID- 21278498 TI - Intrapartum fetal heart rate monitoring: a standardized approach to management. AB - Recent advances in standardized fetal monitoring nomenclature and interpretation make it possible to construct a standardized approach to intrapartum fetal heart rate management that is evidence-based and reflects consensus in the literature. PMID- 21278499 TI - Intrauterine resuscitation during labor. AB - Intrauterine resuscitative measures are commonly initiated during labor when the fetal heart rate (FHR) pattern is indeterminate or abnormal. The most effective use of these measures is directed at the presumed underlying cause. However, some FHR patterns are nonspecific, while others are such that intrauterine resuscitation will not remedy the situation. The goals of intrauterine resuscitation during labor are, at its best, to reverse any hypoxia that might lead to further deterioration, and at the very least to avoid prolonged periods of indeterminate or abnormal FHR patterns, which may cause unnecessary concern for caregivers and patients and unnecessary operative intervention. PMID- 21278500 TI - Assessment and optimization of uterine activity during labor. AB - Accurate assessment of uterine activity during labor is essential to promote optimal patient outcomes. This review provides clinicians with information to develop an evidence-based, standardized approach to the evaluation and management of uterine activity during labor including identification and treatment of excessive uterine activity. Common terminology is defined in an effort to enhance clear and direct communication and accurate assessment. The latest evidence regarding normal labor is presented along with physiology related to uterine activity and fetal oxygenation. Suggestions for managing excessive uterine activity are offered as well as a synopsis of risk reduction strategies for clinical practice. PMID- 21278501 TI - Intrapartum fetal monitoring: liability and documentation. AB - Litigation in obstetrics is common, and evidence suggests that a disturbingly high number of poor outcomes are preventable. Risk management related to fetal monitoring must include both the creation of systems to provide safer care and the mitigation of liability exposure through the use of protocols and documentation strategies that are designed to provide evidence of clinicians' attentive and appropriate care. A simplified approach to documentation is reviewed, along with suggestions for frequency of documentation, standardization of common abbreviations, and samples of concise but inclusive progress notes. PMID- 21278502 TI - Fetal ECG analysis for intrapartum electronic fetal monitoring: a review. AB - Computerized analysis of the fetal electrocardiogram has been developed during the past 40 years. A mature system for ST analysis (STAN) has resulted from a series of laboratory and clinical studies. The current STAN system provides adjunctive information to the standard interpretation of fetal heart rate (FHR) patterns. This monograph describes the basis for the STAN methodology, including the derivation of its basic measure, the T : QRS ratio. It summarizes the supporting research and clinical trials that have led to its adoption in obstetric practice. The STAN methodology is outlined according to current fetal heart rate classification and management guidelines. Recent clinical experiences with STAN systems in Europe and the United States are discussed. Finally, future directions for this technology are listed. PMID- 21278503 TI - Fetal pulse oximetry. AB - The original expectation of fetal pulse oximetry (FPO) for the field of obstetrics was predicated on the tremendous positive impact pulse oximetry had upon the fields of anesthesiology, critical care medicine, and many other disciplines of medicine. With the general acceptance that many, if not most, concerning fetal heart rate patterns are not associated with significant fetal hypoxemia and acidemia, the additional physiologic information FPO offers (ie, actual arterial blood oxygenation) was believed and hoped by many to be the reassurance that would allow safe avoidance of unnecessary interventions such as cesarean delivery. To date, FPO has not met that expectation, not because of its inability to measure fetal arterial oxygen saturation, but because of its inability to do so with a reduction in overall cesarean deliveries. PMID- 21278504 TI - Labor and fetal heart rate decelerations: relation to fetal metabolic acidosis. AB - Although intrauterine fetal compromise during labor accounts for a small proportion of cerebral palsy cases, fetal hypoxic-ischemic encephalopathy remains an important and sometimes preventable etiology. This paper reviews the mechanisms regulating fetal heart rate responses, pathogenesis of fetal metabolic acidosis, and thresholds for metabolic acidosis associated with hypoxic-ischemic encephalopathy. The knowledge of normal changes in fetal metabolic acidosis during labor together with changes in association with fetal heart rate decelerations, can aid in the interpretation and management of fetal heart rate tracings. PMID- 21278505 TI - Breast cancer: pursuing state-of-the-art care. Foreword. PMID- 21278506 TI - Improving breast care: providing, guiding, expertise, and leadership. AB - Optimal healthcare blends timeless doctor-patient values with state-of-the-art medical knowledge. The physician's role varies from delivering therapies to guiding patients through the healthcare maze to their best decisions. Breast care should not be parceling out of anatomic parts, as if biological relationships do not exist. Instead, it should stem from an understanding of the "total woman"- biological and otherwise--and how important that unity is for quality of life, even when confronting breast cancer. Breast fellowships for gynecologic and general surgeons create superior clinicians and better patient advocates essential in advancing women-centric care and healthcare leadership. PMID- 21278507 TI - Breast development and anatomy. AB - In this article, the development of the female breast, as well as the functional anatomy, blood supply, innervation and lymphatic drainage are described. A thorough understanding of the breast anatomy is an important adjunct to a meticulous clinical breast examination. Breast examination is a complex skill involving key maneuvers, including careful inspection and palpation. Clinical breast examination can provide an opportunity for the clinician to educate patients about their breast and about breast cancer, its symptoms, risk factors, early detection, and normal breast composition, and specifically variability. Clinical breast examination can help to detect some cancers not found by mammography, and clinicians should not override their examination findings if imaging is not supportive of the physical findings. PMID- 21278508 TI - Breast cancer: epidemiology and risk factors. AB - Breast cancer is a worldwide problem affecting more than 1 million women annually. Currently, best care for women with breast cancer involves a multidisciplinary approach requiring a broad understanding of epidemiologic, genetic, prognostic, and predictive factors. This study will discuss the epidemiology and risk factors associated with breast cancer. PMID- 21278509 TI - Breast imaging: screening and evaluation. AB - Breast imaging is a dynamic field, with recent and upcoming innovations aimed at improving the morbidity and mortality associated with breast disease, most importantly, breast cancer. It plays an integral role in the detection and management of breast disease, using a multimodality approach, including x-ray, ultrasound, magnetic resonance imaging, and nuclear medicine techniques. Breast imaging also encompasses image-guided procedures, performed both for the diagnosis and definitive management of breast abnormalities. PMID- 21278510 TI - Benign breast diseases: epidemiology, evaluation, and management. AB - Benign breast diseases are common and encompass a spectrum of disorders. The majority of diagnoses will stem from a patient presenting with symptoms such as a mass or discomfort, or as a result of breast imaging which shows abnormalities leading to percutaneous biopsy. When mammographic and pathologic findings are disconcordant or when a high-risk lesion that can be associated with a preinvasive or invasive malignancy is found, formal excisional biopsy is recommended. PMID- 21278511 TI - Breast cancer screening: why, when, and how many? AB - This article focuses on breast cancer screening in the general population. Using an evidence-based medicine approach, a review of the current literature was undertaken to examine the rationale, risks, and benefits of breast cancer screening. The focus of breast cancer screening is to reduce disease mortality. However, there are additional benefits that are afforded by early detection, such as an early stage of diagnosis and a greater chance of having negative lymph nodes. Currently, we believe mammography offers significant benefits for breast cancer detection and mortality reduction in the general population. Further research is necessary on methods to minimize false-positive results. PMID- 21278512 TI - Premalignant lesions: diagnosis, evaluation, and management. AB - Acceptance and incorporation of widespread mammographic screening has led to an increase in the incidence of detection of "premalignant" breast lesions. Despite advances in our understanding of these diseases, their actual malignant potential remains somewhat unpredictable. Best current management of these diseases requires a multidisciplinary, coordinated approach between the disciplines of breast surgery, radiology, pathology, medical oncology, and radiation oncology at a minimum. Although this strategy has led to excellent outcomes, future advances in our understanding of the biologic determinants and behavior of these diseases will hopefully result in a more accurate assessment of the risk of progression to invasive breast cancer and allow us to individualize treatment more effectively. PMID- 21278513 TI - Surgical and local-regional treatment of "early" invasive breast cancer. PMID- 21278514 TI - Breast cancer: adjuvant modalities. AB - The mortality rate due to breast cancer has declined over the preceding decades to a great extent, secondary to the development and use of effective adjuvant therapy. Tamoxifen remains the standard of care in premenopausal women, whereas aromatase inhibitors have become standard therapy after menopause for women with hormone-sensitive disease. Tumor gene profiling assays are being increasingly used to identify women with hormone-sensitive disease, who would benefit from adjuvant chemotherapy. For those women with hormone negative cancer, systemic chemotherapy provides substantial reduction in the risk of disease recurrence and death. PMID- 21278515 TI - Breast cancer posttreatment surveillance: diagnosis and management of recurrent disease. AB - Invasive breast cancer is the most common malignancy diagnosed in American women. The use of screening mammography and progress in adjuvant therapy has led to a steady decline in breast cancer mortality, and as the number of breast cancer survivors increases, there has been a marked increase in the number of patients enrolled in posttreatment surveillance programs.The majority of breast cancer recurrences occurs during the first decade after initial diagnosis with a peak incidence 2 to 5 years after diagnosis, although the number of recurrences for endocrine responsive cancer continues to rise afterward. The goal of posttreatment follow-up programs in patients with breast cancer is to detect potentially curable locoregional recurrences, second primary tumors, and the detection of systemic relapses. However, contrary to the long-held belief, most recurrences are symptomatic and occur during the interval between scheduled visits. PMID- 21278516 TI - Review of current treatment options for pregnancy-associated breast cancer. AB - Breast cancer is the second most common cancer to occur during pregnancy. Breast cancers occurring during pregnancy or within 1 year postpartum is defined as pregnancy-associated breast cancer (PABC). As more women postpone child bearing until later in life, it is expected that PABC will become increasingly more common. This article will review the current literature on PABC with emphasis on the presentation, work-up, as well as treatment of these cancers. PMID- 21278517 TI - Hormone replacement after breast cancer: is it safe? AB - The use of hormone therapy for climacteric symptoms in patients with breast cancer has become a significant and important point of discussion due in part to the improved survival from this disease in recent years. There is a theoretic risk that exogenous hormones will stimulate the growth of microscopic disease and lead to decreased survival and increased recurrence. In addition, 2 large studies have shown that there is an association between hormone therapy and breast cancer risk in women without an earlier history of breast cancer. Other studies suggest that estrogen alone may have a superior safety profile than estrogen and progesterone in combination. Hormone therapy could be justified for improvement of quality of life when other options have failed and the patient is informed of the risks. PMID- 21278518 TI - Genetics: predisposition and management. PMID- 21278521 TI - Simultaneous sinus-lift and implantation using microthreaded implants and leukocyte- and platelet-rich fibrin as sole grafting material: a six-year experience. AB - PURPOSE: To assess the relevance of simultaneous sinus-lift and implantation with leukocyte- and platelet-rich fibrin (L-PRF, Choukroun's technique) as sole subsinus filling material. MATERIALS: Twenty-three lateral sinus elevations (SA4 sinus) were performed on 20 patients with simultaneous implant placement. Seven patients were treated with 19 Astra implants (AstraTech, Molndal, Sweden) and 13 patients with 33 Intra-Lock implants (Intra-Lock Ossean, Boca Raton, FL). L-PRF membranes were used to cover the Schneiderian membrane, the implant tips served as "tent pegs" for the L-PRF-patched sinus membranes, and the subsinus cavity was finally filled with L-PRF clots. Clinical and radiographic follow-up was performed just after implant placement, after 6 months, 1 year and each following year. RESULTS: Six months after surgery, all implants were clinically stable during abutment tightening. The maximum follow-up was 6 years, and all patients were followed up for a minimum of 2 years. No implant was lost during this 6-year experience, and the vertical bone gain was always substantial, between 8.5 and 12 mm bone gain (10.4 +/- 1.2). The final level of the new sinus floor was always in continuation with the implant apical end, and the periimplant crestal bone height was stable. CONCLUSION: The use of L-PRF as sole filling material during simultaneous sinus-lift and implantation seems to be a reliable surgical option promoting natural bone regeneration. PMID- 21278522 TI - Effect of sinus membrane perforation on dental implant integration: a retrospective study on 128 patients. AB - A common complication of sinus augmentation is perforation of the sinus membrane during augmentation and/or implant placement. This retrospective study examines the effect of sinus membrane perforation with regard to graft survival and implant integration. A total of 175 sinuses were augmented with 115 of the membranes being reported intact at the time of surgery. A total of three infections occurred in patients who sustained perforated sinuses and one infection occurred in a patient who had an intact sinus. All four infections resolved after culture sensitivity and placement of the patient on an appropriate antibiotic for 10 days. Of 438 dental implants placed in the augmented sinuses, five implants failed, four of which were associated with perforated sinuses and and which was not associated with a perforated grafted sinus. PMID- 21278523 TI - Persistent dysesthesia following dental implant placement: a treatment report of 2 cases. AB - Occasionally, a patient has persistent dysesthesia symptoms (eg spontaneous or evoked painful or unpleasant sensations) following the placement of a dental implant. This disorder may be sufficiently superficial that an anesthetic and steroid mixture can be infiltrated into the region and satisfactorily treat the disorder. If an anesthetic infiltration can significantly reduce the patient's pain, this therapy may be beneficial. A 50:50 mixture of local anesthetic and steroid are combined in a dental anesthetic carpule and infiltrated into the painful region. If over the following week, the change in pain is greater than one would expect from an anesthetic infiltration, it suggests that this provided some degree of therapeutic response. A series of these infiltrations can be performed until the patient is symptom free or there is no additional improvement from these infiltrations. Two cases are discussed using this therapy. PMID- 21278524 TI - Postinsertion pain in region of mandibular dental implants: a case report. AB - This report describes the role of severe pain in failure of dental implants. A 27 year-old woman presented to the clinic to replace the missing mandibular right first molar and second premolar. A panoramic radiograph was taken, and a clinical examination was done. A decision was made to extract the mandibular right second molar, which had failing endodontics, and two dental implants were placed. Two days later, the patient reported severe pain in that area. Microscopic examination of the surgical specimen revealed longitudinal section of peripheral nerve in the implant site. PMID- 21278525 TI - Potential induction of bone regeneration by nacre: an in vitro study. AB - PURPOSE: Because of limitations of autogenous grafts, alternative bone substitute material was investigated for its capacity in promoting bone formation. This study compared the osteogenic effects of nacre (mother of pearl) and beta tricalcium phosphate (beta-TCP). MATERIALS AND METHODS: Human bone cells (HBCs) were obtained from the culture of bone tissues after orthognathic surgery. The HBCs were cocultured with nacre chips of the giant oyster Pinctada maxima and with beta-TCP particles for 1, 2, 3, and 4 weeks. Cells of each week specimens were used to study alkaline phosphatase (ALP), bone sialoprotein (BSP), and osteocalcin (OC) gene expression by noncompetitive reverse-transcriptase polymerase chain reaction and to study BSP synthesis by means of an immunocytochemical technique in conjunction with fluorescent microscopy. RESULTS: Reverse-transcriptase polymerase chain reaction demonstrated stronger expression levels of ALP mRNA in HBCs cocultured with the nacre chips than those with beta TCP at weeks 2 and 4. BSP gene expression levels in HBCs with nacre were more intense compared with beta-TCP at weeks 3 and 4. Although the OC gene expression level in HBCs with beta-TCP was higher than those with nacre at week 2, the expression was not different at weeks 3 to 4. Immunocytochemical study revealed that BSP synthesis were presented in the nacre and beta-TCP from week 2 and decreased toward week 4. CONCLUSION: This study indicated that nacre promotes ALP, BSP, and OC gene expression. PMID- 21278526 TI - Implant surface morphology and primary stability: is there a connection? AB - PURPOSE: The aim was to review the influence of surface morphology on the primary stability of dental implants. METHODS: MEDLINE-PubMed databases were explored from 1991 up to and including April 2010 using different combinations of the following terms: "dental," "implant surface roughness," "immediate loading," "initial stability," "primary stability," and "osseointegration." Articles published only in English language were included and hand searching was also performed. Letters to the Editor and unpublished data were excluded. RESULTS: Ten studies (three clinical and seven experimental) were included according to the search databases. In six studies (three experimental and three clinical), the implant stability was measured at least after 4 weeks after implant insertion; and primary implant stability was recorded in four experimental studies, using the insertion and removal torque tests and resonance frequency analysis using implant stability quotient values. CONCLUSION: Rough-surfaced implants have significantly higher success rates compared with dental implants with smooth surfaces; however, the question "Is there a connection between implant surface roughness (microdesign) and primary stability?" remains unanswered. PMID- 21278527 TI - Histological evaluation of the effect of using growth hormone around immediate dental implants in fresh extraction sockets: an experimental study. AB - PURPOSE: The aim of this study was to histologically evaluate the effect of using growth hormone (GH) around immediate dental implants in fresh extraction sockets. MATERIALS AND METHODS: Six mongrel dogs had had their lower right and left first premolars extracted. For the right side, the control side, implants were placed immediately. For the left sides, the study side, GH powder was placed in the socket and then immediate implant placement was done. Animals were killed at 2, 6, and 12 weeks after surgery, and histological sections were stained with hematoxylin and eosin, and trichrome stains, and observed under light microscopy for the newly formed bone. RESULTS: Bone formation was obvious in both groups. But in study group, bone density had denser and well-oriented collagen fibers. An increase in bone response was observed with high local administration of GH. In the first phases of bone repair, the osteons were more organized; they were more organized by the 12th week. CONCLUSION: The use of GH powder around dental implants placed immediately in fresh extraction sockets enhanced periimplant bone response. PMID- 21278528 TI - Chitosan coatings deliver antimicrobials from titanium implants: a preliminary study. AB - OBJECTIVE: Chitosan was investigated as a coating for local delivery of antimicrobials for prevention of acute implant infection. The objectives of this study were to (1) measure the release of 2 antimicrobials from chitosan coatings, (2) determine efficacy of eluted antimicrobials against bacteria, in vitro, and (3) evaluate toxicity of eluted drugs to host cells/tissues. METHODS: Chitosan coatings (80.7% deacetylated, 108 kDa) containing 20% tetracycline or 0.02% chlorhexidine digluconate were bonded to titanium via silane reactions. After elution in culture medium for 7 days, eluates were tested against model pathogens Actinobacillus actinomycetemcomitans and Staphylococcus epidermidis in turbidity tests and in 24-hour cytotoxicity tests using human osteoblasts and fibroblasts. Finally, antibiotic-loaded chitosan-coated titanium pins were implanted for 7 days in muscle of Sprague-Dawley rats to evaluate the initial tissue response. RESULTS: Coatings released 89% of tetracycline in 7 days and 100% chlorhexidine in 2 days. Released tetracycline inhibited growth (95%-99.9%) of pathogens for up to 7 days with no cytotoxicity to human cells. Released chlorhexidine was active against pathogens for 1 to 2 days (56%-99.5% inhibition) but was toxic to cells on the first day of elution. Typical acute inflammatory response was observed to antimicrobial-loaded chitosan coatings similar to unloaded coatings. CONCLUSION: These preliminary data support the hypothesis that chitosan coatings have the potential to locally deliver antimicrobials to inhibit bacteria without being toxic to host cells/tissues and warrant additional studies to evaluate the ability of the coatings to prevent/resist infection and promote osseointegration. PMID- 21278529 TI - Authorship, collaboration, and funding trends in implantology literature: analysis of five journals from 2005 to 2009. AB - PURPOSE: To identify the trend of authorship in dental implant by exploring the prevalence of coauthored articles and to investigate the collaboration efforts, trends in funding involved in original articles, and their relationships. MATERIALS: Articles published in the Clinical Oral Implants Research, International Journal of Oral & Maxillofacial Implants, Clinical Implant Dentistry and Related Research, Implant Dentistry, and Journal of Oral Implantology from 2005 to 2009 were reviewed. Nonoriginal articles were excluded. For each included articles, number of authors, collaboration efforts, and extramural funding were recorded. Descriptive and analytical statistics (alpha = 0.05), including logistic regression analysis and chi2 test, were used. RESULTS: From a total of 2085 articles, 1503 met the inclusion criteria. Publications with 5 or more authors increased over time (P = 0.813). The amount of collaboration among different disciplines, institutions, and countries all increased. The greatest increase of collaboration was seen among institutions (P = 0.09). Nonfunding studies decreased over time (P = 0.031). There was a strong association between collaboration and funding for the manuscripts during the years studied (OR, 1.5). CONCLUSION: The number of authors per articles and collaborative studies increased over time in implant-related journals. Collaborative studies were more likely to be funded. PMID- 21278530 TI - Types of Canadian dentists who are more likely to provide dental implant treatment. AB - OBJECTIVE: We designed to determine the variables that influence the adoption rate of implant technology amongst Canadian dentists. METHODS AND MATERIAL: In this cross-sectional study, an anonymous survey questionnaire was sent to all licensed Canadian dentists, both general practitioners and specialists. A 3-part questionnaire accompanied by a postage prepaid envelope was sent to all licensed Canadian dentists. No second mailing was performed. The plan was to measure the effects of age, gender, language, type of specialties, ownership, association with other dentists, and the location of practice on the adoption of dental implant technology. RESULTS: The multivariate regression analyses indicate that the dentists' gender, province of practice, specialty, and whether they practice alone or in association with other practitioners are significant factors associated with the adoption of implant technology in providing both surgical and prosthetic aspects of implant therapy. Female dentists provided significantly less implant prostheses than their male counterparts (OR: 1.75, P < 0.05). Canadian dentists in Atlantic regions were significantly less likely than those in other provinces to surgically place an implant or restore implant prostheses (OR: 0.34, OR: 0.30). In addition, those dentists who owned their practices were 2.35 (P < 0.05) times more likely to provide implant prostheses. CONCLUSIONS: This study provides an evidence that the rate of adoption of implant technology among Canadian dentists depends mainly on practitioners' age, practice ownership, and their specialties. PMID- 21278531 TI - Assessment of quality of life after implant-retained prosthetically reconstructed maxillae and mandibles postcancer treatments. AB - PURPOSE: The aim of this prospective study was to assess treatment outcome and impact on quality of life with implant-retained prosthesis in reconstructed jaws in head and neck cancer patients. MATERIALS AND METHODS: Twelve patients were rehabilitated with implant-retained dental prosthesis following free fibular graft after segmental resection. These subjects were evaluated by standardized questionnaires European Organization for Research and Treatment of Cancer QLQ-C30 (version 3) and clinical assessment for quality of life. Objective assessment of speech parameters was done with Dr. Speech Software (Tiger DRS Inc., Seattle, WA). The questionnaire consisting of information on evaluation of deglutition, salivation, status of the mandible and teeth in relation to predisease level was used for subjective judgment of speech. RESULTS: Consumption of solid, semisolid, and overcooked food was considerably better with the prosthesis. Drinking ability was not affected. Patients' voice resonance was improved, and they could sustain phonation for longer duration without difficulty. They were able to speak loudly, and their intonation pattern was also slightly better. Failure of the implants to osseointegrate at the end of 18 months was observed in 37% of the patients. This was attributed to radiation before implant insertions and periimplantitis. Despite the observed improvement in some patients, the statistical analysis of speech, swallowing parameters, and quality of life were not significant because of the paucity of numbers in this pilot study. There was no improvement in the symptoms scale scores. CONCLUSION: Reconstruction and rehabilitation of the jaws affected by tumor restores the patient anatomically, esthetically, and functionally to optimum levels. However, a study with larger numbers of patients is necessary to ascertain the benefits of this treatment modality. PMID- 21278532 TI - Dental implant practice among Hong Kong general dental practitioners in 2004 and 2008. AB - OBJECTIVE: To describe the dental implant practice profile of Hong Kong general dental practitioners in 2008 and the trend since 2004. MATERIALS AND METHODS: A self-administered questionnaire was mailed to 630 dentists through systematic sampling of registered dentists. RESULTS: A total of 290 completed questionnaires were returned (response rate, 53%). Implant dentistry was practiced by 61% of the respondents. The survey also revealed that 84% of those respondents who own their private practice performed implant dentistry. About half of the dentists (49%) who performed implant dentistry placed or restored 5 or more implants per quarter. Among those dentists not practicing implant dentistry, the majority (85%) were interested in attending continuing education courses in dental implantology. CONCLUSION: There has been a significant increase in the number of general dental practitioners practicing implant dentistry in Hong Kong since 2004. By 2008, more than half of the general dental practitioners (61%) are practicing implant dentistry. Most of them not practicing implant dentistry expressed a desire to learn more about dental implants. This survey revealed a high demand for continuing professional development in implant dentistry in Hong Kong. PMID- 21278534 TI - Did narrowing the major depression bereavement exclusion from DSM-III-R to DSM-IV increase validity?: evidence from the National Comorbidity Survey. AB - The DSM's major-depression "bereavement exclusion" eliminates bereavement-related depressive episodes (BRDs) from diagnosis unless they are "complicated" by prolonged duration or certain severe symptoms. The exclusion was substantially narrowed in DSM-IV to decrease false-negative diagnoses, but the impact of this change remains unknown. We divided BRDs in the National Comorbidity Survey into uncomplicated versus complicated categories using broader DSM-III-R and narrower DSM-IV exclusion criteria. Using 6 pathology validators (symptom number, melancholic depression, suicide attempt, interference with life, medication for depression, and hospitalization for depression), we compared the validity of the 2 exclusion criteria sets using 2 tests: (1) which criteria set yielded less pathological uncomplicated cases or more pathological complicated cases; (2) which yielded the largest separation between uncomplicated and complicated pathology levels. Results of both tests indicated that the narrower DSM-IV criteria substantially decreased the exclusion's validity. These results suggest caution regarding the current proposal to eliminate the bereavement exclusion in DSM-5. PMID- 21278535 TI - Impact of therapist emotional intelligence on psychotherapy. AB - The concept of emotional intelligence (EI) describes a set of emotional skills that may comprise efficacious therapist variables. The present study is the first to investigate EI among psychotherapists. Based on conceptual overlaps between the EI model and psychotherapy models, as well as a review of empirical evidence from both literatures, we make several predictions of how therapist EI impacts treatment. In a small pilot study, we assessed psychotherapist EI to determine its relation to psychotherapy outcome and process. Therapists with higher ratings of EI achieved better therapist-rated outcome results and lower drop-out rates compared with therapists with lower ratings of EI. Though not hypothesized, higher therapist EI was significantly associated with increased patient assessment compliance. There was no relationship between early working alliance ratings and therapist EI. Findings offer preliminary support for the relevance of therapist EI to psychotherapy. PMID- 21278536 TI - Psychosocial problems in asylum seekers' children: the parent, child, and teacher perspective using the Strength and Difficulties Questionnaire. AB - Children of asylum seekers are at risk for psychosocial problems because of their flight history and exceptional living circumstances. This study aims to assess the association of sociodemographic factors and asylum procedural factors with psychosocial problems of asylum seekers' children, and differences herein by informant (parents, teachers, and children). To this end, we obtained data on psychosocial problems among a random sample of 267 children aged 4 to 16, living in Dutch asylum seekers' centers, using the multi-informant Strength and Difficulties Questionnaire. The results show that the prevalence rate of psychosocial problems among asylum seekers' children was high. The occurrence was not associated with asylum-procedural variables but only with child-contextual factors such as mental health of the mother and leaving behind a parent in the country of origin. The associations varied in strength by informant. Therefore, preventive and supportive measures to improve psychosocial health of young asylum seekers should concentrate on these contextual issues. PMID- 21278537 TI - Mental health service use after the World Trade Center disaster: utilization trends and comparative effectiveness. AB - Previous research suggested that community-level mental health service use was low following the World Trade Center Disaster (WTCD) and that brief interventions were effective. In the current study, we assess service use during a longer follow-up period and compare the effectiveness of brief versus multisession interventions. To assess these, we conducted baseline diagnostic interviews among New York City residents 1 year after the WTCD (N = 2368) and follow-up interviews 2 years afterward (N = 1681). At follow-up, there was an increase in mental health utilization, especially for psychotropic medication use, and a decrease in use of physicians for mental health treatment. The best predictor of service use at follow-up was higher WTCD exposure. Using propensity score matching to control for selection bias, brief mental health interventions appeared more effective than multisession interventions. These intervention findings held even after matching on demographic, stress exposure, mental health history, treatment history, access to care, other key variables. Our study suggested that community level mental health service use increased in the follow-up period and that brief interventions were more effective than conventional multisession interventions. Since this study was designed to assess treatment outcomes, our findings raise clinical questions. PMID- 21278538 TI - Reasons for not receiving treatment in people with posttraumatic stress disorder following war. AB - The aim of the study was to explore why people suffering from posttraumatic stress disorder (PTSD) following war do not receive treatment. A total of 212 participants who have PTSD following war in the Balkans and have never received psychiatric treatment were interviewed (86 in Western Europe and 126 in Balkan countries). Answers were subjected to thematic content analysis. Five major and not mutually exclusive themes were identified: "need no help" (57 participants), "personal ways of coping" (72 participants), "negative attitude towards psychiatric treatment" (91 participants), "comparative insignificance" (24 participants), and "external barriers" (65 participants). While most participants, for different reasons, did not want to seek psychiatric treatment, a significant number, particularly in Western European countries, felt prevented from receiving treatment. PMID- 21278539 TI - Coping strategies and their relationship to psychopathologies in people at ultra high-risk for psychosis and with schizophrenia. AB - This study's aim was to investigate coping strategies and their relationship to symptoms in people at ultra high risk (UHR) for psychosis compared with recent onset schizophrenia (SPR) and healthy controls. Thirty-three UHR participants, 22 SPR patients, and 33 healthy controls completed the Ways of Coping Questionnaire and other clinical measures. People at UHR for psychosis showed significantly more reliance on tension-reduction and less reliance on problem-focused coping than healthy controls. The SPR group showed more reliance on tension-reduction coping than healthy controls at a trend level. Maladaptive coping patterns were associated with higher levels of negative symptoms, depression, and anxiety in both the UHR and SPR groups. These findings suggest that maladaptive coping strategies might have already emerged in the (putative) prodromal stage and could influence symptom severities. PMID- 21278540 TI - Thought disorder severity in compromised, deteriorated, and preserved intellectual course of schizophrenia. AB - Intellectual impairments are commonly found in schizophrenia and may precede onset of illness. Thought disorder (TD), also a key characteristic, entailing bizarre and idiosyncratic speech may be associated with early intellectual impairments. Schizophrenia and schizoaffective patients (n = 149) were characterized as having preserved, deteriorated, or compromised intellect using premorbid and current IQ estimates. TD and severity of cognitive symptom were ascertained using the Gorham's Proverbs Test, PANSS and SAPS. Significant relations were found between performance-based (Gorham's Bizarreness score) and clinically-rated PANSS (r = 0.51) and SAPS (r = 0.50) symptomatology. Group contrasts on bizarreness revealed higher severity TD (p < 0.01) in compromised as compared with deteriorated and preserved groups. Groups did not differ significantly on PANSS and SAPS related TD ratings. Findings support the etiological significance of TD with respect to clinical course. Importantly, groups were distinguished by performance-based but not on clinical ratings of TD, suggesting a more reliable, trait-related, index of mental change relevant to the course of schizophrenia. PMID- 21278541 TI - Schizotypy, alexithymia, and socioemotional outcomes. AB - Studies have found higher levels of alexithymia in schizophrenic subjects relative to controls, with an overall higher level of emotional arousal and social withdrawal. The present study is an extension of this research to the assessment of schizotypy in a nonclinical sample. Seventy-two undergraduate students (40 female; 21.6 +/- 6.38 years) were recruited to participate in this study. Consistent with earlier research, our results show that both schizotypy and alexithymia are associated with relatively poor socioemotional functioning across the variables of depression, anxiety, social functioning, and overall quality of life. Further, our results show that the significant associations found between alexithymia and these 4 outcome variables was predicated on shared variance with schizotypy. When both alexithymia and schizotypy were regressed onto these variables as independent predictors, the contribution of alexithymia was consistently nonsignificant. The implications of these findings are discussed in terms of hypothesized substrates of alexithymia. PMID- 21278542 TI - Axis-I comorbidity in female patients with dissociative identity disorder and dissociative identity disorder not otherwise specified. AB - The aim of this study was to investigate axis-I comorbidity in patients with dissociative identity disorder (DID) and dissociative disorder not otherwise specified (DDNOS). Using the Diagnostic Interview for Psychiatric Disorders, results from patients with DID (n = 44) and DDNOS (n = 22) were compared with those of patients with posttraumatic stress disorder (PTSD) (n = 13), other anxiety disorders (n = 14), depression (n = 17), and nonclinical controls (n = 30). No comorbid disorders were found in nonclinical controls. The average number of comorbid disorders in patients with depression or anxiety was 0 to 2. Patients with dissociative disorders averagely suffered from 5 comorbid disorders. The most prevalent comorbidity in DDNOS and DID was PTSD. Comorbidity profiles of patients with DID and DDNOS were very similar to those in PTSD (high prevalence of anxiety, somatoform disorders, and depression), but differed significantly from those of patients with depression and anxiety disorders. These findings confirm the hypothesis that PTSD, DID, and DDNOS are phenomenologically related syndromes that should be summarized within a new diagnostic category. PMID- 21278543 TI - Object relations and emotional processing deficits among psychiatric outpatients. AB - The aim of this study was to investigate the association between object relations and emotional processing deficits among a general sample of psychiatric outpatients. The sample consisted of 104 patients consecutively referred to 2 outpatient clinics. Participants completed measures of object relations, emotional processing deficits, and general psychiatric distress. After controlling for the effect of current symptom distress, we found that object relations impairment was significantly associated with emotional processing deficits relating to unregulated emotions, signs of unprocessed emotions, and emotion suppression. These findings support the notion that patients with impoverished mental structures possess maladaptive strategies for modulating intense affects. PMID- 21278544 TI - Recoding past experiences: a qualitative study of how patients and family members adjust to the diagnosis of bipolar disorder. AB - Few studies have investigated the processes associated with patients' reactions to the diagnosis of bipolar disorder, yet assisting patients to develop an acceptance of the condition is a core component of effective psychosocial interventions. This study explored the views and experiences of patients and family members about receiving a diagnosis of bipolar disorder and its implications for the future. We interviewed 17 people with bipolar disorder (7 diagnosed within the previous 12 months, 10 diagnosed 3-5 years ago), as well as 9 family members. Using the Phenomenology and Lived Experience framework to analyze the interview transcripts, we identified 3 key themes: (1) Misdiagnosis and growing awareness; (2) Accepting the diagnosis (including initial reactions and adjusting to the diagnosis); and (3) Factors that may have facilitated an earlier acceptance. From the findings, we draw implications for clinicians. PMID- 21278546 TI - Transforming orthopaedic care. PMID- 21278545 TI - Nursing 2011 and beyond. PMID- 21278547 TI - Evidence-based practice: caring for a patient undergoing total knee arthroplasty. AB - More than 500,000 total knee arthroplasty (TKA) surgeries were performed in 2006 and the number is expected to continue to increase (S. ). A background in evidence-based nursing care will assist any nurse assigned in caring for a postoperative TKA patient. Strong pain assessment and reassessment skills with an understanding of multimodal pain management benefits pain control and patient recovery from TKA surgery. Safe mobilization and therapy techniques that reflect evidence-based practice will keep patients safe. Providing nursing interventions that prevent complications from infections or thromboembolism will reduce never events from occurring. This article will present evidence for the care of a postoperative TKA patient. PMID- 21278549 TI - Common pediatric elbow fractures. AB - Fractures of the elbow are a very common injury in children. The most common mechanism of injury is a fall on an outstretched upper extremity during play. Ranging in complexity from low-energy nondisplaced occult fractures to high energy fractures with associated severe soft-tissue and neurovascular injuries, elbow fractures are a challenging problem for all pediatric healthcare providers. Because of the wide spectrum of fracture severity and associated bony and ligamentous injury, a very diverse spectrum of treatment modalities is necessary for optimal results. Management is based on fracture pattern, patient age and bone quality, extent of soft tissue damage, functional needs of the patient, and the presence of associated injuries. This article will give a brief overview of 4 common pediatric fractures, current treatment algorithms, and frequent complications associated with these injuries. PMID- 21278551 TI - Ambulatory orthopaedic surgery patient education and cost of care. AB - PURPOSE: To describe and compare ambulatory orthopaedic surgery patients' reported cost of care (out-of-pocket costs, use of time, and consultations with healthcare organizations) and nurses' cost of care (use of time and consultations with other professionals such as other nurses, physicians, and anesthesiologists) when patients receive 2 different types of patient education (Internet-based or face-to-face). METHOD: Pretest/posttest design. SAMPLE: Random assignment of all ambulatory orthopaedic surgery patients in a university hospital in Finland. INTERVENTION: The experimental group received Web-based patient education and the control group received face-to-face patient education. OUTCOMES OF INTEREST: Financial and time costs. FINDINGS: Pre-, intra-, and postoperative costs did not differ between the groups. However, Internet-based education was more time consuming for the patient and face-to-face education was more time-consuming for the nurse. There were no differences between the groups in patients' use of consultations of healthcare professionals. Nurses' consultations were few and did not differ between the groups. The small number of patients' and nurses' consultations indicates that patients in both education methods had enough knowledge to deal with the surgery. PMID- 21278552 TI - The use of cryotherapy after a total knee replacement: a literature review. AB - There is limited data and research on the effects of cryotherapy on total knee replacements. Eleven studies, including one meta-analysis, have been reviewed on the effects continuous cold flow therapy has on blood loss, pain, swelling, and range of motion of the operative knee versus an ice bag or the use of traditional narcotics. Six of the studies showed significantly lower pain scores in the cold compression group than in a control group, including epidural analgesia, Robert Jones bandage, narcotic administration, and crushed ice. Overall, most studies noted no difference in range of motion of the operative knee, a decrease in swelling, and a decrease in blood loss with the cold compression. Although the use of cryotherapy may not be a statistically effective modality, it may, however, provide benefits for patients undergoing a total knee replacement. PMID- 21278553 TI - Casting: all wrapped up. AB - One of the most important responsibilities of nurses is to understand the basic procedures involved in the care of their patients. Throughout their career, nurses encounter a variety of patients with different diseases and/or injuries. Nurses must rely on the knowledge they possess regarding the care and treatment of these varying diseases and injuries when managing their patients. It is important for nurses to know why casts are used, the materials they are made of, and the application and removal processes. More importantly, nurses need to be aware of proper cast care in order to accurately educate their patients and maintain their health. In this article, we will briefly describe the casting process, materials that are frequently used, methods for cast removal, and the potential life-threatening complications that can be associated with casting and immobilization. PMID- 21278555 TI - The use of continuous femoral nerve blocks versus extended release epidural morphine: a study comparing outcomes in total knee arthroplasty procedures. AB - The purpose of this study was to compare the effectiveness of continuous femoral nerve block (CFNB) protocol, to extended release epidural morphine DepoDur protocol, in patients having a total knee arthroplasty (TKA) enrolled in a structured joint replacement educational program. Overall, the results of this randomized controlled study demonstrate that CFNB and DepoDur protocol pain strategies were well tolerated in TKA patients during this study with expected side effects and appropriate side effect management. Moreover, the DepoDur protocol enhanced pain management experience and satisfaction and provided superior prolonged analgesia compared with CFNB protocol. The occurrence of adverse events, cost, length of stay, and functional outcomes was comparable between groups. PMID- 21278556 TI - The timing of hip fracture surgery and mortality within 1 year: a comparison between the United States and Japan. AB - PURPOSE: This study compared patients who had hip fracture surgery in the United State and Japan, and analyzed whether the timing of surgery was related to mortality within 1 year after surgery. METHODS: This is a retrospective observational study. Data were collected from medical records in 2 hospitals in the United States and 3 hospitals in Japan. A questionnaire was sent to patients and/or their family members about the patients' health outcomes after discharge. RESULTS: The median length of hospital stay before surgery was 1 day in the United States and 5 days in Japan. In the United States, patients who had more number of comorbidities had longer lengths of stay before surgery. In Japan, the timing of surgery was not necessarily related to patients' conditions. Although the length of stay before surgery was longer in Japan, the mortality rate was not higher than that in the United States. After adjusting for patient factors, types of fracture, and country, there were no significant associations between the delaying surgery and higher mortality rate. On the contrary, patients who underwent surgery in 5 days or later after admission indicated better survival. CONCLUSION: Providers should reduce unnecessary delays to surgery and they should carefully identify patients who are not suitable for early surgery. PMID- 21278557 TI - One statin, two statins, three statins, more: similarities and differences of 3 hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. AB - Statin drugs (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are one of the most widely prescribed drugs today. They are considered first-line therapy to lower blood serum cholesterol levels in conjunction with therapeutic lifestyle changes for both primary and secondary prevention of cardiovascular events. In the following discussion, a brief explanation of the background of statins will explain why they are deemed so important today. The similarities and differences between the different statins will be addressed, including a look at dosage, side effects, and cautions for the seven 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors currently available. PMID- 21278559 TI - Results of the 2005 to 2008 Association of Residents in Radiation Oncology surveys of chief residents in the United States: didactics and research experience. AB - OBJECTIVES: To analyze the didactics and research experience reported by chief residents during their residency training. METHODS: During the academic years 2005 to 2006, 2006 to 2007, and 2007 to 2008, the Association of Residents in Radiation Oncology (ARRO) conducted a nationwide survey of all radiation oncology chief residents in the United States. Chi-square statistic was used to assess for changes in didactics and research experience over time. RESULTS: During the years surveyed, an increasing percentage of programs offered curriculum-based didactics in clinical oncology (P=0.042), with a similar trend of borderline significance observed in biostatistics (P = 0.056). Each year, the majority of programs offered >40 hours of curriculum-based training in clinical oncology and physics, >20 hours in radiobiology, and 10 hours or fewer in biostatistics. 11% to 13% of residents reported having no full-time equivalent radiation biologists affiliated with their training program. Less than 64% of programs incorporated mock oral boards into their training. An increasing percentage of programs evaluated residents in a "360 degree" manner, with a trend to significance (P=0.073). Over 80% of programs required resident participation in research activities and allocated dedicated elective research time, typically 4 months or longer. Though the vast majority of programs make clinical research activities available to interested residents, borderline significance (P = 0.051) was observed for a decreasing percentage of such programs during the years analyzed. CONCLUSIONS: Trends in didactics and research experience over three years are documented to allow residents and program directors to assess their residency training. PMID- 21278560 TI - Phase II trial of pegylated liposomal doxorubicin in combination with gemcitabine in metastatic breast cancer patients. AB - OBJECTIVE: To assess the efficacy and toxicity of pegylated liposomal doxorubicin combined with gemcitabine as first-line chemotherapy in metastatic breast cancer patients in a phase II trial. PATIENTS AND METHODS: All breast cancer patients with HER2-negative status, hormone refractory tumor, assessable targets, with preserved performance status, and who had not received chemotherapy earlier as treatment for their metastatic disease were eligible. The patients received pegylated liposomal doxorubicin (30 mg/m(2), venous injection, day 1) concurrently with gemcitabine (1000 mg/m(2), venous injection, days 1 and 8), 1 cycle every 3 weeks. RESULTS: Although 38 patients should have been included, this study was prematurely discontinued after recruiting 20 patients because of excessive toxicity: 75% of the patients experienced grade 3 or 4 treatment related toxicity, including neutropenia, thrombopenia, hand-foot syndrome, and stomatitis, which significantly affected the quality of life. Cardiac toxicity was mild. With regard to efficacy, 50% of the patients (95% confidence interval, 26%-74%) experienced tumor response. The response rate was 40% in patients who had earlier received anthracyclines as adjuvant therapy. Median progression-free survival and median overall survival were 8.8 months and 19 months, respectively. CONCLUSIONS: This combination was efficient, but not well tolerated. From these results, we could not recommend these doses for further assessment and lower doses should be preferred. PMID- 21278561 TI - Integrating radioembolization into the treatment paradigm for metastatic neuroendocrine tumors in the liver. AB - Surgical resection of hepatic metastases from neuroendocrine tumors (mNETs) is controversial because the potential survival benefit of this intervention must be balanced against the risk of surgical morbidity and mortality. In patients with unresectable mNETs in the liver, radioembolization has been used to treat tumors from a range of primary sites, including carcinoid and islet cell carcinomas as well as nonfunctional, asymptomatic tumors. Initial clinical studies and retrospective studies on a large cohort of patients indicate that radioembolization is well tolerated and highly effective in achieving a durable hepatic tumor response and ameliorating symptoms. Radioembolization using Yttrium 90 ((90)Y)-labeled resin or glass microspheres offers effective disease control and possible improved quality of life and thus merits consideration as an option for both functional and nonfunctional mNETs. Benefits of this intervention seem to extend from use in early lines of treatment to salvage of refractory disease. Radioembolization also offers a potential somatostatin analog-sparing effect in symptomatic disease. PMID- 21278562 TI - Integrating radioembolization with chemotherapy in the treatment paradigm for unresectable colorectal liver metastases. AB - Clinical decisions regarding the treatment of metastatic colorectal cancer require consideration of current and evolving modalities to best achieve prolonged patient survival. Clinical trials have established that for first-line treatment of patients with or without extrahepatic metastases, radioembolization augments the response produced by chemotherapy in patients with unresectable liver metastases. This includes progression-free and overall survivals that compare favorably with phase II to III data of current chemotherapy regimens. The increased response rate with radioembolization and first-line chemotherapy may improve the likelihood for potentially curative hepatic lesion resection or ablation. Application of an innovative multidisciplinary treatment approach that integrates radioembolization and local ablative therapy may enable the benefits of curative hepatic resection to be extended to a broader group of patients. PMID- 21278563 TI - Impact of postoperative radiation on survival for high-grade soft tissue sarcoma of the extremities after limb sparing radical resection. AB - OBJECTIVES: To use the Surveillance, Epidemiology, and End Results (SEER) Database to analyze the impact of postoperative radiation after limb sparing surgery for high-grade extremity soft tissue sarcomas (STS). METHODS: We identified patients, aged 20 to 79, who were diagnosed between 1988 and 2006 with high-grade STS of the extremities and underwent radical limb sparing surgery with or without postoperative external beam radiation. Kaplan-Meier and Cox regression analyses were performed to evaluate the effect of postoperative external beam radiation therapy on overall survival (OS) and disease-specific survival (DSS). RESULTS: A total of 983 patients met the selection criteria: 788 (80.2%) received postoperative radiation and 195 (19.8%) underwent surgery alone. For the whole cohort, there were no differences between the groups in OS (P=0.06) or DSS (P=0.20). On subgroup analysis, for tumors <=5 cm there remained no significant differences in OS (P=0.8) or DSS (P=0.93). However, for tumors >5 cm the 3-year OS improved with the addition of postoperative radiation from 55.6% to 73.4% (P<0.001). Similarly, the 3-year DSS improved from 68.1% to 80.6% (P=0.005). CONCLUSIONS: Because of the retrospective nature of this study and inherent limitations of the SEER database, a large prospective study is needed to further elucidate the relationship between postoperative radiation and survival. However, these data do support the use of adjuvant radiation for patients with high-grade extremity STS measuring >5 cm. PMID- 21278564 TI - Variation of neck position with image-guided radiotherapy for head and neck cancer. AB - PURPOSE: An understanding of the setup variation of the low neck in relation to the upper neck is necessary to define appropriate planning margins, while treating the full neck with intensity-modulated radiotherapy (IMRT) technique. MATERIALS AND METHODS: The setup of 20 sequential head and neck cancer patients was studied. Daily position verification was performed with a computed tomography (CT) on rails. An upper neck point was defined as the anterior-most portion of the cervical spine on the lowest CT cut on which both styloid processes are visible. A low neck point was defined as the anterior-most portion of the cervical spine on the lowest CT cut on which the thyroid gland was visible bilaterally. This procedure was carried out on the planning CT and on each daily treatment CT. The variation of the low neck was analyzed, assuming perfect alignment of the upper neck anatomy. RESULTS: Daily treatment CT of upper neck anterior cervical spine points were normalized to the planning CT. Relative to this coordinate system, the low neck cervical spine point was displaced an average of 3.08 mm anteriorly, +/-0.17 mm. There was no systematic lateral or craniocaudal displacement. Random setup errors resulted in low neck standard deviations of 3.9 mm (anteroposterior), 3.3 mm (lateral), and 2.6 mm (craniocaudal). CONCLUSIONS: Position variation in the low neck varied in excess of the planning margins. There was a systematic anterior displacement. Random setup error was greater than expected. The results suggest that the neck volumes located distant from the region of fusion should be drawn with larger planning margins. PMID- 21278565 TI - Managing intraoperative blood pressure with norepinephrine: effects on perfusion and oxygenation of the intestinal tract. PMID- 21278566 TI - When chronic pain can suppress the opioid kick: new insights from preclinical research. PMID- 21278567 TI - Toll-like receptor signaling during myocardial ischemia. PMID- 21278568 TI - Let's just call it "evidence-based practice". PMID- 21278569 TI - Fetal anesthesia and brain development. PMID- 21278572 TI - A new malformation syndrome with congenital arthrogryposis and severe hyperkeratosis. PMID- 21278573 TI - Symmetrical upper limb peromelia and lower limb amelia associated with persistent omphalomesenteric duct: a case report. PMID- 21278574 TI - The effect of presentation level on memory performance. AB - OBJECTIVES: A loss of speech intelligibility at high presentation levels is called rollover. It is a phenomenon that increases in prevalence as people age. Whether the adverse effect of high presentation levels extends to processes subsequent to speech intelligibility, such as memory, is unknown. The present study examined this question on the basis of the previous finding that older but not younger adults showed memory impairment when acoustically distorted words were presented at 50 dB SL compared with an undistorted baseline presented at 65 dB SPL. One question investigated in the present study was whether a presentation level of 50 dB SL put older listeners at the cusp of rollover and whether this subsequently impaired memory. Moreover, we wanted to know whether and at what level it was possible to induce a similar impairment in younger listeners. DESIGN: We used a paired-associate memory paradigm in which five word pairs per list were presented at a rate of 4 secs per word pair. After each list, the first word of one of the pairs was presented again and the listener was asked to recall the second word. Over the course of the experiment, all list positions were tested an equal number of times. The word pairs, which were acoustically distorted using a jittering algorithm, were presented at 40 dB SL to all younger and older participants and just below an uncomfortably loud level for younger listeners only. Intelligibility of the distorted words was equated across age groups for each presentation level. The effect of presentation level on memory performance was investigated and compared with data of a previous study that used the same design but presented the distorted and undistorted words at 50 dB SL to both age groups. A total of 58 younger and 24 older adults were tested in two experiments. RESULTS: The results showed that for older adults, memory performance for distorted words was decreased in all list positions at a presentation level of 50 dB SL compared with 40 dB SL and an undistorted 65 dB SPL baseline. This effect did not occur for younger listeners. However, when younger adults were tested at a very high presentation level, they showed the same memory decrease compared with the baseline as older adults showed for 50 dB SL. CONCLUSIONS: A high presentation level of distorted words can adversely affect memory even after intelligibility is equated for. Moreover, older listeners are affected at lower presentation levels. Hence, the choice of sound level, particularly for older listeners, is important and may affect their level of cognitive performance beyond its effects on intelligibility. Higher presentation levels may not always lead to better performance when the task involves recall of words previously heard. PMID- 21278575 TI - A study of the use of clozapine in old age psychiatry. AB - The aim of this study was to review the use of clozapine in a Sydney area old age psychiatry service. Data were extracted from case files of all people who were treated in a health area's old age psychiatry units with clozapine during a 15 year period. Additional details were obtained from clinicians who provided ongoing care after discharge from the hospital. Note was made of psychiatric diagnoses, length of time taking clozapine, dosage, side effects and outcome. Sixteen patients aged over 65 years commenced or continued taking clozapine while inpatients of the service. Of the 13 patients who had a history of schizophrenia or schizoaffective disorder, four patients (all female) developed neutropenia and therefore clozapine was stopped. In one case, neutropenia was first diagnosed 6 years after commencing the medication. Two women died; the nine other women, and one of the deceased, stopped taking clozapine, usually because of side effects. The mean daily dose at cessation was 236 mg. All five men were still taking clozapine (mean 260 mg daily) when followed at a mean age of 72 years, having taken it for an average of 10 years. This case review adds to evidence of the risk of neutropenia when older people are prescribed clozapine. PMID- 21278576 TI - Adherence and persistence with duloxetine and hospital utilization in patients with major depressive disorder. AB - The aim of this study was to examine the association between duloxetine adherence/persistence and hospital utilization. In a managed care claims database, 8521 patients with a major depressive disorder diagnosis were initiated on duloxetine in 2006. Patients had no active duloxetine prescription for 6 months before initiation and had continuous enrollment for 12 months preinitiation and postinitiation. Adherence was defined as medication possession ratio of 0.8 or more, and persistence was defined as the duration of therapy without exceeding a 30-day gap. Logistic regression and negative binominal regression were conducted. Overall, 55.8% of patients were adherent and the average duration of duloxetine therapy was 118.4 days within 6 months after initiation. Adherent patients had significantly lower rates of hospitalization (19.7 vs. 23.4%, P<0.0001) and emergency room visits (30.6 vs. 36.9%, P<0.0001) than nonadherent patients. Hospitalization and emergency room visits were significantly reduced with treatment persistence (P<0.0001). After adjustment for demographics, comorbidities, and prior hospitalization, adherence was associated with reduced hospitalization (odds ratio=0.86) and emergency room visits (odds ratio=0.80). Patients on duloxetine of more than 90 days, compared with less than 31 days, were 16% less likely to be hospitalized and 22% less likely to have emergency room visits. Duloxetine adherence and persistence appear to be associated with reduced hospital utilization in the 1-year follow-up period. PMID- 21278577 TI - Do early changes in the HAM-D-17 anxiety/somatization factor items affect the treatment outcome among depressed outpatients? Comparison of two controlled trials of St John's wort (Hypericum perforatum) versus a SSRI. AB - To assess whether early changes in Hamilton Depression Rating Scale-17 anxiety/somatization items predict remission in two controlled studies of Hypericum perforatum (St John's wort) versus selective serotonin reuptake inhibitors for major depressive disorder. The Hypericum Depression Trial Study Group (National Institute of Mental Health) randomized 340 patients to Hypericum, sertraline, or placebo for 8 weeks, whereas the Massachusetts General Hospital study randomized 135 patients to Hypericum, fluoxetine, or placebo for 12 weeks. The investigators examined whether remission was associated with early changes in anxiety/somatization symptoms. In the National Institute of Mental Health study, significant associations were observed between remission and early improvement in the anxiety (psychic) item (sertraline arm), somatic (gastrointestinal item; Hypericum arm), and somatic (general) symptoms (placebo arm). None of the three treatment arms of the Massachusetts General Hospital study showed significant associations between anxiety/somatization symptoms and remission. When both study samples were pooled, we found associations for anxiety (psychic; selective serotonin reuptake inhibitors arm), somatic (gastrointestinal), and hypochondriasis (Hypericum arm), and anxiety (psychic) and somatic (general) symptoms (placebo arm). In the entire sample, remission was associated with the improvement in the anxiety (psychic), somatic (gastrointestinal), and somatic (general) items. The number and the type of anxiety/somatization items associated with remission varied depending on the intervention. Early scrutiny of the Hamilton Depression Rating Scale-17 anxiety/somatization items may help to predict remission of major depressive disorder. PMID- 21278578 TI - Natural history of asymptomatic small gastric subepithelial tumors. AB - GOAL: To assess the natural history of gastric subepithelial tumors (SETs) of <=30 mm in size and to determine their optimal management. BACKGROUND: Definitive guidelines have not been formulated for the management of small gastric SETs, owing to a lack of knowledge of their natural history and insufficient long-term follow-up. STUDY: We retrospectively reviewed the upper endoscopy and/or endoscopic ultrasound results of 989 tumors diagnosed as gastric SETs of <=30 mm in size between July 1997 and October 2008 with a minimal follow-up of 3 months. A gastric SET was defined as a mass covered with normal appearing mucosa on upper endoscopy and a tumor located in the second, third, or fourth layer on endoscopic ultrasound. RESULTS: Of the 989 SETs in 948 patients, 84 (8.5%) showed significant changes in size, and/or echogenicity, and/or morphology at a median 24 months (range, 3 to 123 mo). Estimated growth rates differed significantly by initial size (<10 mm, 0.14 mm/mo; 10 to 20 mm, 0.22 mm/mo; 20 to 30 mm, 0.31 mm/mo; P=0.003). Twenty-five patients with tumors showing changes in size and/or echogenicity underwent surgical/endoscopic resection; of these, 19 patients were diagnosed with gastrointestinal stromal tumors (GISTs), of which 3 patients were considered at high risk, 4 at intermediate risk, 10 at low risk, and 2 at very low risk. In a univariate analysis, GISTs showed a significant change in tumor size during follow-up compared with other benign tumors (P=0.037). However, multivariate analysis did not show a statistical significance in size change between GISTs and other benign tumors (hazard ratio 1.754; 95% CI, 0.575 to 5.291; P=0.326). CONCLUSIONS: Only 8.5% of gastric SETs of <=30 mm in size showed significant changes at a median 24 months. SETs of 10 to 30 mm in size grew significantly more rapidly than SETs <10 mm. PMID- 21278579 TI - Endoscopic ultrasound and gastric lesions. AB - Endoscopic ultrasound (EUS) is useful in assessing gastric lesions found on endoscopy. EUS can assess the 5 layers of the gastric wall and is the most useful modality for staging tumors of the stomach, including adenocarcinoma and lymphoma. For subepithelial gastric lesions, EUS can assess the echogenicity of a lesion, which layer of the gastric wall is involved, and assess for the presence of blood flow with Doppler ultrasound. These characteristics help to determine the likely etiology of the lesion. Fine needle aspiration may also provide additional information, especially when mucosal biopsies are nondiagnostic. PMID- 21278580 TI - Long-term efficacy and safety of cyclosporine as a rescue therapy in acute, steroid-refractory severe ulcerative colitis: switching to infliximab is more effective than treating with concomitant immunomodulators. PMID- 21278581 TI - Rosacea in Crohn's Disease: Effect of Rifaximin. PMID- 21278582 TI - Lacking the incentive to cure? Recurring Clostridium difficile diarrhea and our reluctance to use fecal transplantation. PMID- 21278583 TI - Circulating microRNAs as biomarkers for hepatocellular carcinoma. AB - GOALS: We investigated whether measurement of serum levels of the microRNAs (miRNAs) miR-16, miR-195, and miR-199a, alone or in combination with conventional serum markers, can help to differentiate hepatocellular carcinoma (HCC) from chronic liver diseases (CLDs). BACKGROUND: Recent reports suggest a link between aberrant expression of miRNA, and HCC. STUDY: This retrospective analysis was conducted using sera from 105 HCC patients, 107 CLD patients, and 71 normal control subjects. The miRNAs were measured using real-time reverse transcription polymerase chain reaction. The conventional HCC markers alpha-fetoprotein (AFP), lens culinaris agglutinin-reactive AFP (AFP-L3%), and des-gamma carboxyprothrombin (DCP) were measured with commercial kits. RESULTS: Serum levels of miR-16 and miR-199a were significantly lower in HCC than in CLD patients or control subjects (P<0.01). As a single marker, miR-16 had the highest sensitivity for HCC, followed by miR-199a, AFP, DCP, AFP-L3%, and miR-195. The combination of miR-16, AFP, AFP-L3%, and DCP yielded the optimal combination of sensitivity (92.4%) and specificity (78.5%) for HCC, overall and when analysis was restricted to patients with tumors size smaller than 3 cm. As a second-line HCC marker, miR-16 yielded positive HCC predictions in 18 of the 26 (69.2%) HCC patients with negative results on all 3 conventional markers, most of whom had tumors size smaller than 3 cm; miR-16 was falsely positive in only 12 of 96 (12.5%) CLD patients. CONCLUSIONS: The addition of miR-16 to conventional serum markers improved sensitivity and specificity for HCC. Use of miR-16 for second line testing in cases considered negative on the basis of conventional HCC markers should be explored in larger, prospective studies. PMID- 21278584 TI - Biodegradable implant for tissue repair after glaucoma drainage device surgery. AB - AIM/BACKGROUND: To report a novel technique using biodegradable material to cover exposed glaucoma tube shunts. METHODS: A case report of a single patient who underwent drainage tube shunt surgery with the Baerveldt drainage device for intractable glaucoma. Four months post operation the tube became exposed through necrosis of the overlying scleral flap and conjunctiva. The defect was repaired by fixation of the tube to the sclera, with a slice of an ologen implant as a patch, covered by the adjacent conjunctiva. The patient was followed over a period of 1 year after the surgery. RESULTS: Successful, lasting closure of the conjunctival defect was achieved without any side effects or complications. CONCLUSIONS: Erosion of the drainage tube after shunt surgery is a potentially serious problem. It can be successfully managed using a biodegradable implant as a patch before closing the conjunctiva. PMID- 21278585 TI - Different transillumination property in Chinese and White irides. AB - PURPOSE: To compare the least light density (LLD) required to elicit iris transillumination defects in donor Chinese and White irides with radial posterior iris pigment epithelium (IPE) scratches. MATERIALS AND METHODS: Seven Chinese and 7 White irides were used in this study, in which 10 to 11 radial posterior IPE scratches were made under biomicroscopy. LLD for at least 3 and 6 IPE scratches was determined with a digital light meter. Histologic studies and transmission electron microscopy were carried out on each iris specimen after LLD measurement. RESULTS: Six Chinese and all 7 White irides had qualified IPE scratch model verified by the histologic study. The average LLD required to elicit at least 3 and 6 IPE scratches in these Chinese irides were 476.5+/-135.7 and 855.9+/-290.2 Lux, respectively. In the White irides, they were 5.3+/-2.3 and 69.3+/-25.4 Lux, respectively. In histologic and transmission electron microscopy study, moderate to heavy pigmentation was seen uniformly in the Chinese irides in the IPE layer, iris stroma, and anterior surface; whereas minimal pigmentation was visualized in their White counterparts. CONCLUSIONS: LLD in IPE scratched Chinese irides were considerably higher than that of the White irides. Dense pigmentation in iris stroma and anterior surface may be the mechanism for the greater LLD in the Chinese irides and lack of iris transillumination defects in Chinese pigment dispersion syndrome patients. PMID- 21278586 TI - Are there filtering blebs after canaloplasty? AB - PURPOSE: Aim of the study was to assess the development of filtering blebs after canaloplasty. METHODS: Twenty eyes of 20 consecutive patients receiving canaloplasty were included. All eyes were examined clinically (slit lamp), and by anterior segment optical coherence tomography and high-frequency ultrasound biomicroscopy to detect filtering blebs. Preoperative and postoperative intraocular pressure (IOP) and medications were recorded. No antimetabolites were used at any time. Two success criteria were defined to assess a possible correlation of bleb formation and success: (1) IOP <=21 mm Hg and minimum 20% IOP reduction without medication and (2) IOP <18 mm Hg without medication. RESULTS: No filtering blebs were detected clinically. One patient had a filtering bleb like structure as detected by anterior segment optical coherence tomography and ultrasound biomicroscopy. Mean IOP decreased significantly from 22.15+/-9.5 mm Hg preoperatively to 13.3+/-9.9 mm Hg at last follow-up (at 245+/-120.0 d). The number of medications was reduced significantly from 3.15+/-1.2 preoperatively to 0.55+/-0.94 postoperatively. Complete success rate was 65% for both success criteria. CONCLUSIONS: Filtering blebs occur rarely after canaloplasty. In canaloplasty, IOP reduction seems to be independent of subconjunctival aqueous drainage, thus, avoiding the problems of conjunctival scarring. PMID- 21278587 TI - Canaloplasty in one eye compared with viscocanalostomy in the contralateral eye in patients with bilateral open-angle glaucoma. AB - PURPOSE: To compare the safety and efficacy of canaloplasty with viscocanalostomy when performed in both eyes of patients with bilateral open-angle glaucoma. PATIENTS AND METHODS: This comparative case series investigated 30 eyes of 15 adult patients with bilateral primary open-angle glaucoma who had canaloplasty performed in one eye and viscocanalostomy performed in the contralateral eye. Qualifying preoperative intraocular pressures (IOP) were at least 18 mm Hg with historical IOPs of at least 21 mm Hg. In canaloplasty, a microcatheter was used to viscodilate the full circumference of Schlemm canal in conjunction with the placement of a trabecular meshwork tensioning suture. Primary outcome measures included IOP, glaucoma medication usage, and adverse events. RESULTS: With a follow-up period of 18 months, both the canaloplasty and viscocanalostomy groups showed statistically significant reductions in mean IOP (P<0.01) and number of supplemental medications (P<0.01) as compared with preoperative values. In the canaloplasty cohort, eyes had a mean IOP of 14.5+/-2.6 mm Hg on 0.3+/-0.5 medications at 18 months postoperatively as compared with preoperative levels of 26.5+/-2.7 mm Hg on 2.1+/-1.0 medications. In the viscocanalostomy cohort, eyes had a mean IOP of 16.1+/-3.9 mm Hg on 0.4+/-0.5 medications at 18 months as compared with preoperative levels of 24.3+/-2.8 mm Hg on 1.9+/-0.8 medications (P=0.02). No patient in either cohort experienced significant complications. CONCLUSIONS: Canaloplasty and viscocanalostomy were safe and effective in the surgical management of open-angle glaucoma. Canaloplasty procedures showed superior efficacy to viscocanalostomy in the reduction of IOP (P=0.02) and both procedures demonstrated excellent safety profiles. PMID- 21278588 TI - Selective laser trabeculoplasty in the treatment of open-angle glaucoma. AB - PURPOSE: To determine the effect of selective laser trabeculoplasty (SLT) on different types of open-angle glaucoma (OAG) in terms of intraocular pressure (IOP). METHODS AND MATERIALS: In this prospective, nonrandomized, interventional study, patients with OAG, unresponsive to maximum tolerable antiglaucoma medication, were enrolled. One thirty six eyes were studied. Distribution of glaucoma type was 91 primary OAG eyes (POAG, 66.9%), 22 pseudoexfoliative glaucoma (PEX, 16.2%) eyes, and 23 pigmentary glaucoma (PG, 16.9%) eyes. Main outcome measures were IOP and number of antiglaucoma medications used before operation, at 1 day, at 1 week, and at 1 to 18 months after surgery. Using the standard approach 360-degree SLT was done. RESULTS: The mean follow-up was 16.6+/ 4.3 months. The mean preoperative IOP was 22.0+/-3.7 mm Hg, and reduced to 18.3+/ 3.7 mm Hg at last visit. The overall mean IOP decrease was 3.6+/-2.6 mm Hg (16.3%) on the last visit compared with before surgery, indicating a reduction of 16.7% in POAG, 16.6% in PEX, and 14.5% in PG. Comparison of IOP values at 6 and 16 months showed an increase of 0.5 and 2.7 mm Hg in total sample and PG group. IOP reduction was significantly less among diabetic patients. CONCLUSIONS: SLT resulted in a significant IOP reduction of 16.3% at 16 months after surgery. The level of IOP reduction did not vary in POAG, PEX, and PG groups. A significant increase in IOP was observed in PG group after 6 months. The procedure seemed least effective in diabetic patients. PMID- 21278589 TI - Long-term effect of BAK-free travoprost on ocular surface and intraocular pressure in glaucoma patients after transition from latanoprost. AB - PURPOSE: To assess the efficacy and tolerability of benzalkonium chloride (BAK) free travoprost after transition from BAK-preserved latanoprost. METHODS: This was a prospective, open-label, multicenter study in patients with open-angle glaucoma or ocular hypertension who had been treated with latanoprost monotherapy for at least 3 months. The main outcome measures were superficial punctate keratopathy (SPK), hyperemia, and intraocular pressure (IOP). At baseline, 1, 3, and 12 months, hyperemia, SPK, and IOP were consecutively assessed. Hyperemia was assessed using a 4-grade scale. SPK was assessed by fluorescence staining observed by Area-Density classification. The IOP was measured by Goldmann applanation tonometry. RESULTS: One hundred and fourteen patients participated in this study. Twenty-eight patients discontinued medications by 1 month. Sixty seven patients completed the study. Transition from latanoprost to BAK-free travoprost showed no significant effect on hyperemia at 1 month, but showed significant decreases at 3 and 12 months compared with baseline (P<0.05). The prevalence of SPK, especially its severity score, at all points were significantly reduced compared with baseline (P<0.05). The IOP at baseline and at 12 months after transition was 14.9+/-3.4 and 14.3+/-3.3 mm Hg, indicating a significant reduction after the change in regimen compared with baseline (P<0.05). CONCLUSIONS: Treatment for 12 months with BAK-free travoprost after BAK preserved latanoprost resulted in fewer ocular surface complications, as indicated by the reduced prevalence of SPK and decreased hyperemia, and no clinically relevant changes in IOP. BAK-free travoprost may have beneficial effects on the ocular surface while showing IOP-lowering efficacy comparable with BAK-preserved eye drops. PMID- 21278590 TI - Factors influencing laser peripheral iridotomy outcomes in white eyes: an anterior segment optical coherence tomography study. AB - PURPOSE: To determine the pre-laser anterior segment optical coherence tomography (AS-OCT) features in White eyes which may predict the outcome after laser peripheral iridotomy (PI). PATIENTS AND METHODS: Consecutive White patients who underwent laser PI at Capital Eye Specialists over a 25-month period (November 2007 to November 2009) were identified, and the AS-OCT images of the temporal and nasal angles (in light and dark) before laser were analyzed. The PI was considered unsuccessful if there was still iridotrabecular apposition in the dark in >=2 quadrants at follow up. The parameters studied were anterior chamber depth, trabecular-iris angle (TIA), angle opening distance (AOD), trabecular-iris space area, trabecular-iris contact length (TICL), iris thickness, and maximum iris bow height (MIBH). RESULTS: Images of 71 eyes (71 patients) were assessed. The mean age at laser PI was 60.3 (+/-10.0) years. The mean time from laser PI to the follow-up AS-OCT scan was 5.92 (+/-3.22) weeks. The TIA 500 (P=0.002 temporal; P=0.024 nasal), AOD 500 (P=0.004 temporal; P=0.022 nasal), and TICL (P<0.001 temporal; P=0.013 nasal) in light were significantly different between the successful and unsuccessful groups. The MIBH in light was significant temporally (P=0.021) and approached significance nasally (P=0.052). Iris thickness measurements demonstrated no statistical significance. CONCLUSIONS: An unsuccessful PI outcome is associated with pre-laser greater angle closure (decreased TIA 500 and AOD 500, increased TICL) and less anterior iris bowing (decreased MIBH) in light conditions in the temporal and nasal angles. PMID- 21278591 TI - Axenfeld-Rieger syndrome in monozygotic twins. AB - Two teenaged monozygotic twin sisters with Axenfeld-Rieger syndrome (ARS) were referred to our center for uncontrolled glaucoma from the local hospital in December 2006. At presentation, typical components of ARS could be found in both patients, including iris anomaly, maxillary hypoplasia, hypodontia, and umbilical skin fold. Both sisters received trabeculectomy in both the eyes later in our center. Intraocular pressure was well controlled in both the eyes in both patients 1 year after the surgeries. No mutations were found by direct sequencing of PITX2 and FOXC1 genes, in the twin sisters. As far as we know, no earlier report has described monozygotic twins with ARS in the international literature. PMID- 21278592 TI - Substance use disorder and the risk of open-angle glaucoma. AB - PURPOSE: To test the hypothesis that cocaine use (abuse and/or dependency) is associated with open-angle glaucoma. METHODS: A case-control study. Potential case patients were identified from the Veterans Health Administration national clinical database using International Classification of Disease, Version 9, Clinical Modification for open-angle glaucoma for fiscal year 2009. Inclusion criteria included consecutive prescriptions for 1 or more topical antiglaucoma medications. Cocaine exposure was identified through International Classification of Disease, Version 9, Clinical Modification codes. The odds of cocaine exposure were compared with the overall outpatient population of national Veterans Health Administration beneficiaries and adjusted for age and other illicit drug use. A nested case-control study was conducted to examine the confounding influence of race. RESULTS: Age-adjusted odds ratios of cocaine exposure among patients with glaucoma were statistically significant for both men [3.52 (95% confidence interval, CI: 3.21-3.86)] and women [1.87 (95% CI: 1.79-1.96)], and did not change significantly when analyzed according to drug-dependency status. Subset analysis adjusted for age, other illicit drugs, and race remained significant for men [1.45 (95% CI: 1.27-1.66)], but not women. Persons with substance use disorder and glaucoma were nearly 18 years younger than glaucoma patients without a drug exposure history. CONCLUSIONS: This pilot study suggests the use of cocaine and possibly other illicit drugs are predictive of glaucoma. Should the association of substance use disorder (cocaine or cocaine/poly-drug abuse) and open-angle glaucoma be verified, it represents a potentially modifiable risk factor for vision loss. PMID- 21278593 TI - Relationship between standard automated perimetry and retinal nerve fiber layer parameters obtained with optical coherence tomography. AB - PURPOSE: To determine the relationship between retinal nerve fiber layer (RNFL) parameters obtained using optical coherence tomography (OCT) and the outcome of standard automated perimetry (SAP) in normal, ocular hypertensive, glaucoma suspect, and glaucomatous patients. METHODS: Four hundred twenty-three patients were enrolled in the study and classified based on basal intraocular pressure, optic nerve head morphology, and SAP results into 4 groups: 87 normal eyes, 192 ocular hypertensive eyes, 70 glaucoma suspects, and 74 glaucomatous eyes. In the different diagnostic groups, Pearson correlation coefficients were calculated between RNFL parameters and visual field indices, number of points altered at different probability levels, and threshold values at each SAP point. RESULTS: In the normal and ocular hypertensive groups, very few mild correlations were found between the OCT parameters and SAP results. The strength and number of significant correlations was increased in the glaucoma suspect group. In the glaucoma group, the correlations were stronger, particularly between the inferior RNFL parameters and the superior hemifield. CONCLUSIONS: The greater the visual field damage, the stronger the correlations between OCT and SAP. There was mild to-moderate agreement between the structural and functional data assessed by OCT and SAP in glaucoma patients. PMID- 21278594 TI - Central corneal thickness and corneal curvature in pseudoexfoliation syndrome with and without glaucoma. AB - PURPOSE: To determine the central corneal thickness (CCT) and corneal curvature (CC) in pseudoexfoliative (PE) eyes with and without glaucoma. METHODS: Charts of 551 consecutive patients undergoing preoperative examinations for cataract surgery between April 2006 and May 2009 in our clinic were reviewed retrospectively. Fourty-eight PE patients (48 eyes; 19 with glaucoma, 29 without glaucoma) and 48 age-matched and sex-matched control patients were enrolled in the study. The CCT, CC, intraocular pressure, and axial length were measured by ultrasonic pachymeter, autorefractokeratometer, Goldmann applanation tonometry, and ultrasound biometry, respectively. The independent samples t test and paired samples t test was used for the comparisons of the groups. RESULTS: Mean CCT was significantly thinner in all PE and nonglaucomatous PE (Pseudoexfoliation syndrome "PES") eyes than in control eyes (P=0.004 and P=0.005, respectively). There was no difference in CCT between PE glaucoma (PEG) and control eyes (P=0.089). There was no difference in mean keratometry (K) and axial length in the study and control groups. In 22 unilateral PE eyes, mean CCT and K readings were insignificant between the PE eyes and fellow non-PE eyes. CONCLUSIONS: CCT was significantly thinner in eyes with PES compared with control eyes; however, difference between the PEG and control eyes was insignificant. In addition, mean K readings were not different in study and control eyes. Thinner CCT in eyes with PES, both as it is an independent risk factor and as a result of artificially lower intraocular pressure readings, may be an illuminating cause for development and rapid progression of glaucoma in the patients with PES. PMID- 21278595 TI - Achieving quality improvement in the nursing home: influence of nursing leadership on communication and teamwork. AB - Leadership, communication, and teamwork are essential elements of organizational capacity and are linked to organizational performance. How those organizations actually achieve improved performance, however, is not clearly understood. In this comparative case study, nursing leadership who facilitated open communication and teamwork achieved improvement while nursing leadership who impeded open communication and teamwork did not. PMID- 21278596 TI - Soft on sticks: an evidence-based practice approach to reduce children's needlestick pain. AB - Soft on Sticks is a comprehensive, interdisciplinary, evidence-based practice initiative that was implemented to ensure consistent use of pharmacologic and nonpharmacologic interventions to reduce pain associated with needlestick procedures performed on children. Pre- and postimplementation data from children, parents, and nurses showed positive results from the practice change and identified areas for further improvement. PMID- 21278597 TI - Use of an intervention bundle to eliminate pressure ulcers in critical care. AB - Nursing staff chose to eliminate hospital-acquired pressure ulcers in their intensive care unit through implementation of an intervention bundle. A bundle of 7 interventions (pressure ulcer bundle, PUB) was developed through review of current evidence. After implementation, quarterly hospital-acquired pressure ulcer rates decreased and continued to remain below 1% throughout the year, and the goal of no pressure ulcers was met for 2 months. The PUB interventions have potential for use in a variety of settings where there are bed-bound patients. PMID- 21278598 TI - Trends in work-related musculoskeletal disorders: a comparison of risk factors for symptoms using quality of work life data from the 2002 and 2006 general social survey. AB - OBJECTIVE: To assess trends in risk factors for work-related musculoskeletal disorders (MSDs). METHODS: Results from two similar national surveys (2002 and 2006) examined trends in relationships between individual, psychosocial, and physical factors and MSDs. RESULTS: Findings between years were similar, but important differences included a stronger effect of "Work Stress" on "Pain in Arms," and a stronger combined effect of "Hand Movement" and "Work Stress" on "Pain in Arms." Also, two interactions were statistically significant in the 2006 data, but not in the 2002 data, revealing potentially increased risks. These were "Hand Movement" and "Work Stress" on "Back Pain," and "Heavy Lifting" and "Work Stress" on "Pain in Arms." CONCLUSION: New strategies for preventing both low back and upper extremity MSDs should focus on work stress, heavy lifting, and hand movement, individually and in combination. PMID- 21278599 TI - Fat emboli syndrome in a nondisplaced tibia fracture. AB - Fat emboli syndrome is a well-recognized complication of displaced long bone fractures, often times requiring internal fixation. Treatment is generally supportive and is most successful with early diagnosis. This article describes a case of fat emboli syndrome resulting from a nondisplaced tibia fracture treated with long leg casting. This case demonstrates that fat emboli should be considered as a potential complication of any long bone fracture and should be part of the differential diagnosis for any patient unconscious or in respiratory distress that has sustained a recent long bone fracture. PMID- 21278600 TI - Selection of surgical approaches to the posterolateral tibial plateau fracture by its combination patterns. PMID- 21278601 TI - A little proposal of the new open fractures classification. PMID- 21278602 TI - The initial pin site of external fixation conversion to internal fixation. PMID- 21278603 TI - Invited commentary. PMID- 21278604 TI - Single-stage surgical treatment of infected nonunion of the distal tibia. AB - OBJECTIVE: An infected nonunion of the distal tibia after plating is uncommon, and the traditional methods for its treatment have unique disadvantages (time consuming and patient discomfort being great). A single-stage surgical technique was developed to improve the outcome in this situation. DESIGN: Retrospective. SETTING: University hospital. PATIENTS AND METHODS: We treated 25 consecutive adult patients with 25 infected nonunions of the distal tibia after plating. The inclusion criteria consisted of infected nonunions of the distal tibia with an intact ankle space and a plate in situ. The surgical technique used with all participants called for the removal of all implants, intra-/extramedullary debridement, and placement of cancellous bone graft and antibiotics (vancomycin and gentamicin) followed by the application of an Ilizarov external fixator. Postoperatively, patients ambulated early with protected weightbearing and performed range-of-motion exercises of the ankle. RESULTS: Twenty-two patients were followed up for at least 2 years (range, 2.0-4.5 years; median, 3.2 years). All infected nonunions healed without recurrence of infection. The median time to union was 4.5 months (range, 3.5-6.0 months). Eighteen cultures had single bacterial flora, whereas five cultures had mixed flora. Two cultures showed no growth of microorganisms. All bacteria were sensitive to vancomycin or gentamicin. Methicillin-resistant Staphylococcus aureus (13 of 25) and methicillin-sensitive S. aureus (seven of 25) were the most commonly detected microorganisms. Patients' ankle function improved with "satisfactory" grades increasing from 0% preoperatively to 86% postoperatively (P < 0.001). CONCLUSIONS: This single-stage surgical technique had a high success rate with significant reduction in patient discomfort during the course of treatment. However, further revision of the technique may be necessary to ensure high success rates in further series. PMID- 21278605 TI - The role of debridement in low-velocity civilian gunshot injuries resulting in pelvis fractures: a retrospective review of acute infection and inpatient mortality. AB - OBJECTIVES: To determine the use of surgical debridement in the management of low velocity gunshot injuries (GSIs) resulting in pelvis fractures. DESIGN: : Retrospective chart review. SETTING: Level I trauma center in a major metropolitan area. PATIENTS: Fifty-six patients from 1991 to 2007 treated for pelvis GSIs with resulting pelvis fractures with six acute mortalities and 40 patients with at least 1-year follow-up. INTERVENTION: Patient data were reviewed for incidence of infection related to pelvis GSIs. Information regarding surgical debridement of pelvis GSI wounds, retained foreign bodies, and/or concomitant gastrointestinal (GI) injury was analyzed for relationships of such events to infection rate. MAIN OUTCOME MEASUREMENTS: Incidence of infection related to pelvis GSIs at least 1 year after GSI date. RESULTS: Three patients (6%) developed a deep infection related to their pelvis GSIs. There were no cases of osteomyelitis. The rate of concomitant GI injuries was 36% and the overall infection rate among those with GI injuries was 12% versus 3% for those without a GI injury (P = 0.34). There were infection rates of 7% and 6% among patients who underwent surgical debridement and those who did not, respectively. Of those with GI injuries, 41% underwent primary surgical debridement and none developed infection. In the group of remaining patients with GI injuries who did not undergo debridement of their GSI wounds, two (20%) developed an infection. The mortality rate of low-energy GSIs to the pelvis was six of 53 (11%). CONCLUSION: There was no increased incidence of infection in the absence of aggressive surgical debridement of pelvis GSI wounds. The study also demonstrated that retained bullets and bullet fragments did not increase the risk of infection, even after penetrating the GI tract organs. Finally, this study suggests there may be an increased risk of infection related to pelvis GSIs compared with reported infection rates related to GSIs of the extremities, likely secondary to a high rate of concomitant GI injuries associated with pelvis GSIs; however, there was no incidence of osteomyelitis. PMID- 21278606 TI - Penetrating and orthopaedic trauma from blast versus gunshots caused by terrorism: Israel's National Experience. AB - OBJECTIVE: Evaluation of the demographics, features, and outcomes of musculoskeletal injury patterns caused by terrorism in the civil setting and comparing injuries from explosions with gunshot injuries. DESIGN: Retrospective cohort analysis of a prospective database. SETTING: National trauma registry consisting of all the six Level I and four Level II trauma centers. PATIENTS: A total of 1245 casualties with terror-related musculoskeletal trauma. Five hundred fifty-one had high-velocity gunshot wound and 694 blast wounded (BW) caused by explosion. MAIN OUTCOME MEASUREMENTS: Demographic and injury data analyzed for age, gender, New Injury Severity Score, and associated injuries. Outcome of were analyzed according to length of hospital stay, intensive care unit stay, surgical procedures, and mortality. RESULTS: Severe injuries (New Injury Severity Score 16 or greater) were more common in the BW group (P < 0.01). In the BW group, a significantly higher proportion of casualties had associated injuries (73% versus 43%), intensive care unit care, longer length of stay, and mortality. Orthopaedic injuries were similar among the two groups with more open extremity fractures in the gunshot wound group and less significant injuries in the BW group. With casualties matched to the same New Injury Severity Score groups, the ones with the musculoskeletal injuries had longer hospitalization than those without. CONCLUSIONS: Musculoskeletal injury caused by blast is associated with multiple penetrating injuries, differing from more "conventional" penetrating trauma such as caused by gunshot injuries. Although the treatment of specific injuries caused by both mechanisms is essentially similar, the systemic effect of the blast must be taken into consideration in anticipation of an increased overall injury severity. PMID- 21278607 TI - Necrotizing streptococcal myositis of an extremity: a rare case report. AB - Necrotizing myositis is a severe and very rare streptococcal soft tissue infection involving the superficial fascia and muscle. Its clinical symptoms are nonspecific until the appearance of a fulminant clinical course with soft tissue destruction and septic shock. A high mortality and morbidity rate has been reported in the few cases over the last century. Despite several attempts to better define the different entities causing this necrotizing soft tissue infection, no clear treatment has been outlined. We present the case of a 47-year old woman who had an acute necrotizing myositis after a stab wound. The diagnosis of necrotizing myositis was only established after surgical treatment with a pathology report. We reviewed the literature to highlight the clinical difficulty of a preoperative diagnosis and surgical treatment. PMID- 21278608 TI - The biomechanics of varied proximal locking screw configurations in a synthetic model of proximal third tibial fracture fixation. AB - OBJECTIVE: To determine if 1) angularly stable devices created by compressing ("locking") proximal locking screws to intramedullary nails using end caps or compression screws or 2) increasing the number of proximal screws from two to three increases the stiffness of intramedullary constructs that stabilize proximal third tibia fractures in a nonosteopenic bone model. METHODS: Four proximal locking screw configurations were examined in a synthetic composite tibia model with a 2-cm gap simulating a comminuted proximal third tibia fracture with no bony contact: 1) two proximal screws not compressed to the nail; 2) one of two proximal screws compressed to the nail; 3) two proximal screws compressed to the nail; and 4) three proximal screws with only the most proximal screw compressed to the nail. An 11-mm tibial nail with two distal locking screws was used. Stiffness was measured in axial and torsional loading. An analysis of variance was performed to compare results of the screw configurations for each testing mode. RESULTS: Compressing two screws to the nail produced 22% to 39% greater (P <= 0.01) axial and 16% to 29% greater (P <= 0.03) torsional stiffness than securing neither or only one of the screws. Adding a third proximal transverse locking screw increased the axial stiffness by 28% (P = 0.005) and the torsional stiffness by 15% to 28% (P <= 0.04) compared with using two oblique proximal screws. CONCLUSIONS: "Locking" two proximal locking screws to the nail through compression or adding a third proximal screw increases the axial and torsional stiffness of intramedullary nails used to fix unstable proximal third tibia fractures. PMID- 21278609 TI - Delay in surgical debridement of open tibia fractures: an analysis of national practice trends. AB - BACKGROUND: Debridement and irrigation (D&I) of open tibia fractures less than 6 hours from the time of injury has been promoted as orthopaedic dogma despite limited evidence. The goal of this study was to determine the duration between emergency room presentation and D&I in open tibia fractures and to examine factors associated with delay in treatment. METHODS: The National Trauma Data Bank Version 3.0 identified 6099 blunt trauma patients with open tibia fractures. Time was calculated from emergency room arrival to first D&I. Risk factors associated with delay in treatment greater than 6 hours and greater than 24 hours were then calculated using univariate and multivariate statistical methods. RESULTS: Median time to D&I was 4.9 hours. Forty-two percent of patients with open tibia fractures experienced a delay in treatment of greater than 6 hours and 24% of patients experienced a delay to treatment of greater than 24 hours. Risk factors associated with greater than 6- and 24-hour delay on univariate and multivariate logistic regression were age, head or thoracic injury with Abbreviated Injury Score greater than 2, and presentation between 6 pm and 2 am. Level I and university hospitals carry a greater risk of delay that was independent of injury severity in multivariate analysis. CONCLUSIONS: A significant percentage of patients with open tibia fractures undergo their first surgical intervention of D&I greater than 6 hours after presentation to the emergency room. Patients with delayed D&I have more severe injuries, are treated at university or Level I centers, and present later in the day. PMID- 21278610 TI - Correlation of IHC and FISH for ALK gene rearrangement in non-small cell lung carcinoma: IHC score algorithm for FISH. AB - INTRODUCTION: Accurate, cost-effective methods for testing anaplastic lymphoma kinase gene rearrangement (ALK+) are needed to select patients with non-small cell lung carcinoma for ALK-inhibitor therapy. Fluorescent in situ hybridization (FISH) is used to detect ALK+, but it is expensive and not routinely available. We explored the potential of an immunohistochemistry (IHC) scoring system as an affordable, accessible approach. METHODS: One hundred one samples were obtained from an enriched cohort of never-smokers with adenocarcinoma from the Mayo Clinic Lung Cancer Cohort. IHC was performed using the ALK1 monoclonal antibody with ADVANCE detection system (Dako) and FISH with dual-color, break-apart probe (Abbott Molecular) on formalin-fixed, paraffin-embedded tissue. RESULTS: Cases were assessed as IHC score 0 (no staining; n = 69), 1+ (faint cytoplasmic staining, n = 21), 2+ (moderate, smooth cytoplasmic staining; n = 3), or 3+ (intense, granular cytoplasmic staining in >=10% of tumor cells; n = 8). All IHC 3+ cases were FISH+, whereas 1 of 3 IHC 2+ and 1 of 21 IHC 1+ cases were FISH+. All 69 IHC 0 cases were FISH-. Considering FISH a gold-standard reference in this study, sensitivity and specificity of IHC were 90 and 97.8%, respectively, when 2+ and 3+ were regarded as IHC positive and 0 and 1+ as IHC negative. CONCLUSIONS: IHC scoring correlates with FISH and may be a useful algorithm in testing ALK+ by FISH in non-small cell lung carcinoma, similar to human epidermal growth factor-2 testing in breast cancer. Further study is needed to validate this approach. PMID- 21278611 TI - Penile fracture: long-term results of surgical and conservative management. AB - BACKGROUND: Penile fracture usually results from direct trauma to the erected penis. We evaluate the outcomes of surgical and conservative treatment. METHODS: Between February 2000 and February 2007, 77 patients with mean age 29 +/- 2.5 years (range, 20-57 years) with penile fracture were evaluated retrospectively. A total of 56 patients (group A) were treated with immediate surgical repair and 21 patients (group B) were treated conservatively as they refused surgical intervention. Data on erectile function and any penile sequel were obtained during follow-up using the International Index of Erectile Function (IIEF-15) questionnaire, local examination, and color Doppler ultrasonography reports. RESULTS: Only 69 patients were available for median follow-up period of 20.8 months (range, 17-30 months), 51 patients of the group A and 18 of the group B. Injury involved unilateral and bilateral corporeal rupture in 50 and 6 cases, respectively. Concomitant urethral injury was detected in three cases. During follow-up, 49 cases (96%) of the surgical group (A) and 9 cases (50%) of the conservative group (B) reported erection adequate for intercourse, with no voiding dysfunction and no penile curvature. However, the remaining nine patients (50%) from the conservative group (B) reported erectile dysfunction and penile deviation. CONCLUSIONS: Immediate surgical repair of the penile fracture gave good results and is superior to conservative treatment; however, we cannot distinguish false from true penile fracture accurately to determine on whom we can use the conservative treatment. PMID- 21278612 TI - Loss of synaptic vesicles from neuromuscular junctions in aged MRF4-null mice. AB - MRF4 belongs to the basic helix-loop-helix class of transcription factors and this and other members of its family profoundly influence skeletal muscle development. Less is known about the role of these factors in aging. As MRF4 is preferentially expressed in subsynaptic nuclei, we postulated it might play a role in maintenance of the neuromuscular junction. To test this hypothesis, we examined the junctional regions of 19-20-month-old mice and found decreased levels of SV2B, a marker of synaptic vesicles, in MRF4-null mice relative to controls. There was a corresponding decrease in grip strength in MRF4-null mice. Taken together, these data suggest that the intrinsic muscle factor, MRF4 plays an important role in maintenance of neuromuscular junctions. PMID- 21278613 TI - Detecting gradual visual changes in colour and brightness agnosia: a double dissociation. AB - Two patients, one with colour agnosia and one with brightness agnosia, performed a task that required the detection of gradual temporal changes in colour and brightness. The results for these patients, who showed anaverage or an above average performance on several tasks designed to test low-level colour and luminance (contrast) perception in the spatial domain, yielded a double dissociation; the brightness agnosic patient was within the normal range for the coloured stimuli, but much slower to detect brightness differences, whereas the colour agnosic patient was within the normal range for the achromatic stimuli, but much slower for the coloured stimuli. These results suggest that a modality specific impairment in the detection of gradual temporal changes might be related to, if not underlie, the phenomenon of visual agnosia. PMID- 21278614 TI - Sound energy and the magnitude of change: effects on mismatch negativity. AB - The mismatch negativity (MMN) of event-related potential generally increases in amplitude, as a function of magnitude of change. This study examined whether this relation holds true for intensity decrement, in which the stimulus energy that conveys the change falls in inverse proportion to magnitude of change. The MMN was recorded from healthy young adults for intensity decrements of 10, 20, 30, 40, and 50 dB. As the change increased, the MMN amplitude also increased first and thereafter diminished; thus, an inverted U-shaped relation was found between the MMN amplitude and the magnitude of change. These results, therefore, suggest a possible interplay between the energy of deviant stimulus and magnitude of change in the MMN elicitation. PMID- 21278615 TI - Impact of 123I-FP-CIT (DaTSCAN) SPECT on the diagnosis and management of patients with dementia with Lewy bodies: a retrospective study. AB - OBJECTIVE: To assess the impact of imaging the presynaptic dopaminergic terminal using DaTSCAN single-photon emission computed tomography (SPECT) on the clinical diagnosis and subsequent management of patients with possible dementia with Lewy bodies (DLB), who were referred for imaging. METHODS: A retrospective case note study was undertaken, involving a series of consecutive patients who had undergone DaTSCAN SPECT 12-24 months earlier. RESULTS: Case notes of 80 patients were reviewed. DaTSCAN imaging results were abnormal (indicating DLB) in 20 (25%) and normal (suggesting an alternative diagnosis or absence of disease) in 60 (75%) patients. Of the 20 patients with an abnormal scan, 18 had a postscan working clinical diagnosis of DLB (90%), one had diagnosis of vascular dementia (5%) and another had no recorded outcome (5%). Fifty-eight out of the 60 patients with a normal DaTSCAN image result had an alternative clinical diagnosis of DLB (95%). Consequently, DaTSCAN findings were concordant with the outcome clinical diagnosis in 76 out of the 80 (95%) cases. Subsequent to DaTSCAN SPECT, scan findings and diagnoses were discussed with patients and/or their carers in 94% of cases and subsequent treatment options discussed in 93% of cases. CONCLUSION: It would seem that DaTSCAN imaging has a marked influence on the working clinical diagnosis and subsequent management of patients with suspected DLB. PMID- 21278616 TI - Prognostic value of 18F-fluorodeoxyglucose-positron emission tomography in patients with differentiated thyroid carcinoma and circulating antithyroglobulin autoantibodies. AB - OBJECTIVE: To explore the prognostic value of F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) in radioiodine-negative patients with differentiated follicular cell-derived thyroid carcinoma with circulating antithyroglobulin autoantibodies (TgAb). METHODS: We retrospectively reviewed cases of all patients with differentiated thyroid cancer and increased TgAb referred for FDG-PET at Mayo Clinic, Rochester, Minnesota, from August 2001 to December 2004. PET findings were compared with results of other imaging and laboratory studies. Follow-up information was recorded until 19 December 2009. RESULTS: Of the 17 patients identified, PET results were true positive in 10 and false negative in two. In eight of these 12 patients with confirmed residual or recurrent disease, the increased TgAb level persisted and the disease progressed. In four of the 12 patients, TgAb decreased or disappeared after further treatment. In five patients, no residual or recurrent disease was found during follow-up. PET results were true negative in these five patients; TgAb disappeared spontaneously in four of these patients. CONCLUSIONS: Negative PET results were associated with the absence of active disease and disappearing TgAb over time. FDG-avid residual lesions were associated with more aggressive disease and persistently increased TgAb. PMID- 21278617 TI - Immunogenicity of a single dose of tetravalent meningococcal serogroups A, C, W 135, and Y conjugate vaccine administered to 2- to 10-year-olds is noninferior to a licensed-ACWY polysaccharide vaccine with an acceptable safety profile. AB - BACKGROUND: Meningococcal disease remains an important cause of invasive bacterial infections in children less than 5 years of age. Immunogenicity and safety of the investigational ACWY vaccine conjugated with tetanus toxoid (ACWY TT, GlaxoSmithKline Biologicals) were evaluated in 1501 healthy 2- to 10-year-old children in the Philippines, India, Lebanon, and Saudi Arabia. METHODS: Children were randomized (3:1) to receive ACWY-TT or licensed tetravalent meningococcal polysaccharide vaccine (Mencevax, GlaxoSmithKline, Men-PS). Diary cards were used to collect solicited symptoms for 4 days after vaccination. Serious adverse events were reported for 6 months. Serum bactericidal activity (rSBA, rabbit complement) was measured before and 1 month after vaccination in the first 75% of subjects enrolled in each country. RESULTS: The statistical criteria for noninferiority in terms of rSBA vaccine responses were reached. Exploratory analyses showed that postvaccination rSBA titers >= 1:8 and >= 1:128 were significantly higher after ACWY-TT than Men-PS for serogroups C, W-135, and Y, and rSBA vaccine responses and geometric mean antibody titers were significantly higher for all 4 serogroups after administration of ACWY-TT. Noninferiority in terms of incidences of grade 3 general symptoms was not demonstrated. ACWY-TT was well tolerated with grade 3 events reported in <1% of subjects per group. No serious adverse events were considered related to vaccination. CONCLUSION: ACWY TT was immunogenic in children between 2 to 10 years of age with a clinically acceptable safety profile that resembled licensed Men-PS. These data support a positive benefit/risk ratio for the ACWY-TT vaccine. PMID- 21278618 TI - Long-term impact of treated congenital toxoplasmosis on quality of life and visual performance. AB - BACKGROUND: Long-term evolution of congenital toxoplasmosis is not documented. We assessed the outcome of treated congenital toxoplasmosis in a cohort of adult individuals who had undergone ante- and postnatal treatment to provide information for pediatricians and parents on the evolution of the disease. METHODS: We conducted a questionnaire study on 126 adults with congenital toxoplasmosis (mean age: 22.2 years; age range: 18-31 years) monitored regularly until the time of inclusion. The main outcome measures were quality of life (Psychological General Well-Being Index) and visual function (VF14 questionnaire), and the outcomes were correlated with disease-specific factors. RESULTS: Of the 102 patients (80.9%) who were finally included in the study, 12 (11.8%) presented neurologic effects and 60 (58.8%) manifested ocular lesions; in the latter category, 13 individuals (12.7%) had reduced visual function. The overall global quality-of-life score (74.7 +/- 14.2) was close to the expected normal range for the general population (73.7 +/- 15.3). Overall, visual function was only slightly impaired (M = 97.3; 95% confidence interval, 95.8-98.8). Although disease-independent critical life circumstances were associated with a reduced Psychological General Well-Being Index, this index was not influenced by any of the clinical characteristics of congenital toxoplasmosis. Neurologic pathologies, reduced visual acuity, foveal location of the retinal lesion, and squinting contributed to decreased visual function at follow-up. CONCLUSIONS: Our data reveal that treated congenital toxoplasmosis has little effect on the quality of life and visual function of the affected individuals. These encouraging findings may help to alleviate the anxiety of affected individuals and their parents. PMID- 21278619 TI - Metabolic acidosis with topiramate and zonisamide: an assessment of its severity and predictors. AB - OBJECTIVE: Carbonic anhydrase (CA) inhibitors topiramate and zonisamide can induce metabolic acidosis in some patients. Our aims were to assess the prevalence and severity of this acidosis and to determine its predictors. METHODS: For 70 patients established on treatment with topiramate (n=55) or zonisamide (n=14) or both (n=1), we measured electrolytes, and genotyped single nucleotide polymorphisms (SNPs) in the main renal CA isoenzymes (II, IV and XII). RESULTS: Twenty-six percent of patients had a metabolic acidosis (serum bicarbonate <20 mmol/l). The mean serum bicarbonate of patients taking topiramate was significantly lower than those taking zonisamide (P=0.002). We found no association between serum bicarbonate and the dose of drug or the duration of treatment. Serum bicarbonate levels were associated with the CA type XII SNPs rs2306719 (P=0.006 by one-way analysis of variance) and rs4984241 (P=0.015), but this association was not strong enough to survive correction for multiple testing. CONCLUSION: The development of acidosis with topiramate and zonisamide is not determined by drug dose or by treatment duration, but may be influenced by polymorphisms in the gene for CA type XII. The aforementioned SNPs lie 9.8 kb apart in intron 1 of the CA type XII gene, and deserve further study in a larger cohort of patients. PMID- 21278620 TI - Association of GSTM1 null polymorphism with isosorbide-5-mononitrate cardiovascular response and involvement of CGRP in healthy Chinese male volunteers. AB - OBJECTIVES: To determine whether functional polymorphisms of glutathione S transferase MU type 1 (GSTM1) and aldehyde dehydrogenase-2 (ALDH2) affect the isosorbide 5-mononitrate (IS-5-MN) response, and the role of the calcitonin gene related peptide (CGRP) in IS-5-MN response in healthy volunteers. METHODS: A two phase, placebo-controlled study was carried out in 24 healthy Chinese volunteers with their ALDH2 and GSTM1 genotypes known. During each phase, either 20-mg IS-5 MN tablet or placebo was orally administered; blood pressure (BP), heart rate, and plasma concentration of CGRP was determined before and at several time points after drug administration. Pharmacokinetic parameters of IS-5-MN were determined. RESULTS: GSTM1 null individuals showed significantly lower systolic BP (SBP) and diastolic BP (DBP), and higher degree of decreases in SBP (DeltaSBP) and DBP (DeltaDBP) after IS-5-MN administration. GSTM1 null individuals showed significantly decreased IS-5-MN area under the plasma concentration-time curve than GSTM1 wild-type individuals (P<0.05). Plasma concentration of CGRP was increased significantly at 0.5 (P<0.01), 1 (P<0.05), and 2 h (P<0.05) after IS-5 MN administration in GSTM1 null individuals but not wild-type individuals. GSTM1 null individuals also showed significantly higher degree of percentage increase in the plasma concentration of CGRP than GSTM1 wild-type individuals at 1 h after IS-5-MN administration (P<0.05). IS-5-MN upregulated CGRP I and CGRP II mRNA expressions in cultured peripheral blood mononuclear cells, and the IS-5-MN induced CGRP II mRNA expression was inhibited by GSTs inhibitor, ethacrynic acid. No difference in the IS-5-MN response was observed between ALDH2 genotypes. CONCLUSION: We suggest that GSTM1, but not ALDH2, may interfere with the bioactivation of IS-5-MN, and CGRP contributes to the IS-5-MN response in a GSTM1 genotype-dependent manner. PMID- 21278622 TI - The five-step lower blepharoplasty: blending the eyelid-cheek junction. AB - BACKGROUND: Lower lid blepharoplasty has potential for significant long-lasting complications and marginal aesthetic outcomes if not performed correctly, or if one disregards the anatomical aspects of the orbicularis oculi muscle. This has detracted surgeons from performing the technical maneuvers necessary for optimal periorbital rejuvenation. A simplified, "five-step" clinical approach based on sound anatomical principles is presented. METHODS: A review of 50 lower lid blepharoplasty patients (each bilateral) using the five-step technique was conducted to delineate the efficacy in improving lower eyelid aesthetics. Digital images from 50 consecutive primary lower blepharoplasty patients (100 lower lids: 37 women and 13 men) were measured using a computer program with standardized data points that were later converted to ratios. RESULTS: Of the 100 lower eyelid five-step blepharoplasties analyzed, complication rates were low and data points measured demonstrated improvements in all aesthetic parameters. The width and position of the tear trough, position of the lower lid relative to the pupil, and the intercanthal angle were all improved. There were no cases of lower lid malposition. CONCLUSIONS: Aesthetic outcomes in lower lid blepharoplasty can be improved using a five-step technical sequence that addresses all of the anatomical findings. Lower lid blepharoplasty results are improved when (1) the supportive deep malar fat compartment is augmented; (2) lower lid orbicularis oculi muscle is preserved with minimal fat removal (if at all); (3) the main retaining structure (orbicularis retaining ligament) is selectively released; (4) lateral canthal support is established or strengthened (lateral retinacular suspension); and (5) minimal skin is removed. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 21278621 TI - Identification of novel functional organic anion-transporting polypeptide 1B3 polymorphisms and assessment of substrate specificity. AB - OBJECTIVE: The uptake carrier organic anion-transporting polypeptide 1B3 (OATP1B3, gene SLCO1B3) is involved in the hepatic clearance of xenobiotics including statins, taxanes, and mycophenolic acid. We thought to assess the SLCO1B3 coding region for yet unidentified polymorphisms and to analyze their functional relevance. METHODS: We used DNA of ethnically diverse individuals for polymerase chain reaction, and determined polymorphisms by sequencing or temperature-dependent capillary electrophoresis. We then created variant OATP1B3 expression plasmids by site-directed mutagenesis, which were transiently expressed and functionally characterized in human cervical carcinoma (HeLa) cells using radiolabeled substrates. RESULTS: We identified six nonsynonymous polymorphisms including novel variants such as 439A>G (Thr147Ala), 767G>C (Gly256Ala), 1559A>C (His520Pro), and 1679T>C (Val560Ala). Allelic frequencies occurred to be ethnicity-dependent, with the latter observed only in African Americans (3.6%). After expression in HeLa cells, His520Pro, Val560Ala, and Met233Ile or Met233Ile_Ser112Ala haplotype variants showed decreased uptake activity compared with wild type for cholecystokinin-8 and rosuvastatin, but not for atorvastatin. Kinetic cholecystokinin-8 analysis showed reduced Vmax without altering Km. His520Pro and Val560Ala exhibited decreased total and plasma membrane protein expressions. Val560 mapped onto a structural model of OATP1B3 showed that this is a key region for substrate-transporter interaction. His520 resides in a predicted extracellular region thought to be critical to the pH dependent component of OATP1B3 activity. Loss of activity at pH 7.4 and 8.0 relative to pH 6.5 was significantly greater for the Pro520 variant. CONCLUSION: OATP1B3 polymorphisms that result in altered expression, substrate specificity, and pH-dependent activity may be of potential relevance to hepatic clearance of substrate drugs in vivo. PMID- 21278623 TI - Sexually transmitted diseases program performance measures: how are they performing? AB - BACKGROUND: Performance measures were developed in order to improve the performance of sexually transmitted disease (STD) prevention programs. METHODS: A consultant worked with persons from STD programs and Centers for Disease Control and Prevention to identify possible measures. Measures were pilot tested for feasibility and relevance in several programs, then implemented nationwide in 2004. Data were collated and shared with programs and presented at national meetings. Site visits, webinars, and technical assistance focused on program improvement related to the measures. Reported data were analyzed to see if national performance improved on the activities measured. RESULTS: Some measures were dropped or revised, and quality of reported data improved over time. There was little evidence that overall program performance improved. CONCLUSIONS: Performance measures are one way to monitor performance, and might contribute to program improvement, but additional efforts are needed to improve performance. PMID- 21278624 TI - African women recently infected with HIV-1 and HSV-2 have increased risk of acquiring Neisseria gonorrhoeae and Chlamydia trachomatis in the Methods for Improving Reproductive Health in Africa trial. AB - BACKGROUND: Neisseria gonorrhoeae and Chlamydia trachomatis are 2 common causative agents of cervical bacterial sexually transmitted infections (STI). Against the background of the concurrent epidemics of STIs and HIV in sub-Saharan Africa, we examined the effect of HIV-1 and HSV-2 on acquiring N. gonorrhoeae and C. trachomatis in a cohort of southern African women at risk for HIV infection. METHODS: We examined incidence of first infection with N. gonorrhoeae and C. trachomatis in the multisite randomized controlled trial Methods for Improving Reproductive Health in Africa. Multivariable Cox proportional hazards models with time-dependent covariates were used. RESULTS: The incidence rates of C. trachomatis and N. gonorrhoeae infections were 6.14 per 100 woman-years and 2.42 per 100 women-years, respectively. In multivariable analyses, women who became infected with HIV-1 were more likely to acquire C. trachomatis (adjusted hazard ratio [adj. HR], 1.86; 95% confidence interval [CI], 1.34-2.57) and N. gonorrhoeae (adj. HR, 2.29; 95% CI, 1.47-3.56) compared with HIV-uninfected women. Similarly, HSV-2 infected women were more likely to acquire C. trachomatis (adj. HR, 1.29; 95% CI, 1.05-1.58) and N. gonorrhoeae (adj. HR, 1.57; 95% CI, 1.11-2.21). Women who were of younger age, who did not live with their primary male partner, and who changed sex partners during the study were also more likely to acquire a cervical STI. CONCLUSIONS: Women recently infected with HIV-1 and HSV-2 were at increased risk of acquiring N. gonorrhoeae and C. trachomatis. Proactive screening and treatment of these common cervical infections, particularly among those infected with HIV-1 and HSV-2, should be considered for young sexually active women in settings with a high prevalence of HIV/STIs. PMID- 21278625 TI - Prevalence and correlates of herpes simplex virus type-2 infection among men who have sex with men, san francisco, 2008. AB - BACKGROUND: Most herpes simplex virus type 2 (HSV-2) infections are asymptomatic or unrecognized, so periodic serological surveys are necessary in order to measure the true prevalence of infection, track trends over time, and identify correlates of infection, including coinfection with human immunodeficiency virus (HIV). METHODS: We conducted a community-based, cross-sectional, serological survey among 500 men who have sex with men (MSM) in San Francisco during 2008. RESULTS: The seroprevalence of HSV-2 infection was 26.1% (95% confidence interval [CI], 18.3-33.9), of HIV infection was 18.6% (95% CI, 13.0-24.4), and of HSV 2/HIV coinfection was 12.0% (95% CI, 7.3-16.8; categories not mutually exclusive). HSV-2 prevalence was 3.7 (95% CI, 2.3-5.9) times as high among HIV infected MSM as among HIV-uninfected MSM. Strong predictors of HSV-2 infection among both HIV-infected and HIV-uninfected MSM were older age and black race. CONCLUSIONS: The prevalence of HSV-2 infection among MSM in San Francisco is similar to that among MSM nationwide and is higher than that among all men nationwide. Prevalence rates are highly disparate among subpopulations of MSM in San Francisco, with the strongest predictors of infection being HIV-positive serostatus, older age, and black race. Primary prevention of HSV-2, particularly among populations at the highest risk for infection with HSV-2 or HIV, should remain a major public health goal to reduce the substantial morbidity caused by both of these infections. PMID- 21278626 TI - Assessing male condom failure and incorrect use. AB - BACKGROUND: It has not been well established whether common indices of male condom failure are valid predictors of biologically meaningful exposure during condom use. METHODS: To address this gap, the authors compared self-reported condom malfunctions (i.e., breakage and slippage) and incorrect condom practices to 2 following objective measures of failure: prostate-specific antigen (PSA) detected in vaginal swabs collected after condom use and structural integrity of used condoms. The study, conducted in 2000-2001, evaluated 635 male condoms used by 77 women attending an outpatient, reproductive-health clinic in Birmingham, AL. RESULTS: Women reported breakage or slippage for 7.9% of condoms; 3.5% of postcoital swabs had moderate or high levels of PSA; and laboratory testing of used condoms revealed breaks (1.1%) and leaks (2.0%). Self-reported breakage and slippage was associated with moderate/high PSA concentrations in postcoital swabs only when the malfunctions were not accompanied by reports of corrective actions to reduce exposure (adjusted odds ratio [aOR], 6.9; 95% confidence interval [CI], 1.8-26.2). Defects observed in postcoital laboratory testing were related to PSA detection (aOR, 8.0; 95% CI, 1.5-42.6). Incorrect practices defined on the condom label were frequent, but not all types were associated with semen exposure. Furthermore, other practices not currently label-defined were associated with semen exposure: touching the tip of the penis with his hands (aOR, 6.2; 95% CI, 2.3-17.0) or with her hands (aOR, 2.8; 95% CI, 1.1-72) before donning the condom. CONCLUSIONS: Used correctly, male condoms afforded good protection based on objective measures of failure. PMID- 21278627 TI - Did national HIV prevention programs contribute to HIV decline in Eastern Zimbabwe? Evidence from a prospective community survey. AB - OBJECTIVE: To add to the evidence on the impact of national HIV prevention programs in reducing HIV risk in sub-Saharan African countries. METHODS: Statistical analysis of prospective data on exposure to HIV prevention programs, relatives with AIDS and unemployment, and sexual behavior change and HIV incidence, in a population cohort of 4047 adults, collected over a period (1998 2003) when HIV prevalence and risk-behavior declined in eastern Zimbabwe. RESULTS: Exposure to HIV prevention programs and relatives with AIDS-but not unemployment-increased from 1998 to 2003. Men and women exposed to media campaigns and HIV/AIDS meetings had greater knowledge and self-efficacy, attributes that were concomitantly protective against HIV infection. Women attending community HIV/AIDS meetings before recruitment were more likely than other women to adopt lower-risk behavior (96.4% vs. 90.8%; adjusted odds ratio, 3.09; 95% confidence interval [CI], 1.27-7.49) and had lower HIV incidence (0.9% vs. 1.8%; adjusted incidence rate ratio, 0.63; 95% CI, 0.32-1.24) during the intersurvey period. Prior exposure to relatives with AIDS was not associated with differences in behavior change. More newly unemployed men as compared with employed men adopted lower-risk behavior (84.2% vs. 76.0%; adjusted odds ratio, 2.13; 95% CI, 0.98-4.59). CONCLUSIONS: Community-based HIV/AIDS meetings reduced risk-behavior amongst women who attended them, contributing to HIV decline in eastern Zimbabwe. PMID- 21278628 TI - Anatomical connection between the rectus capitis posterior major and the dura mater. AB - STUDY DESIGN: Anatomic study performed on 13 cadaveric specimens focused on muscles of the suboccipital triangle, specifically, the rectus capitis posterior major (RCPma). OBJECTIVE: To investigate a connection between the RCPma and the cervical dura mater. SUMMARY OF BACKGROUND DATA: In a study of the posterior intervertebral spaces, a connection between the RCPma and the dura mater was briefly described. To the best of our knowledge, no study has been conducted specifically on this communication. METHODS: Anatomic dissections were performed in the suboccipital regions of 13 embalmed, adult cadaveric specimens. Findings were recorded via photographic documentation. RESULTS: In 11 of the 13 specimens, the RCPma attached to the spinous process of the axis and then continued to establish a gross anatomical connection with the dura mater in the atlantoaxial interspace. Manual traction of the RCPma resulted in gross dural movement from the spinal root level of the axis to the spinal root level of the first thoracic vertebra. CONCLUSION: A connection was found to exist between the RCPma and the cervical dura mater. Various clinical manifestations may be linked to this anatomical relationship. PMID- 21278629 TI - Nuclei pulposi formation from the embryonic notochord occurs normally in GDF-5 deficient mice. AB - STUDY DESIGN: The transition of the mouse embryonic notochord into nuclei pulposi was determined ("fate mapped") in vivo in growth and differentiating factor-5 (GDF-5)-null mice using the Shhcre and R26R alleles. OBJECTIVE: To determine whether abnormal nuclei pulposi formation from the embryonic notochord was responsible for defects present in adult nuclei pulposi of Gdf-5-null mice. SUMMARY OF BACKGROUND DATA: The development, maintenance, and degeneration of the intervertebral disc are not understood. Previously, we demonstrated that all cells in the adult nucleus pulposus of normal mice are derived from the embryonic notochord. Gdf-5-null mice have been reported to contain intervertebral discs in which the nucleus pulposus is abnormal. It is currently unclear if disc defects in Gdf-5-null mice arise during the formation of nuclei pulposi from the notochord during embryogenesis or result from progressive postnatal degeneration of nuclei pulposi. METHODS: Gdf-5 messenger RNA expression was examined in the discs of wild-type embryos by RNA in situ hybridization to determine when and where this gene was expressed. To examine nucleus pulposus formation in Gdf-5 null mice, intervertebral discs in which embryonic notochord cells were marked were analyzed in newborn and 24-week-old mice. RESULTS: Our Gdf-5 messenger RNA in situ experiments determined that this gene is localized to the annulus fibrosus and not the nucleus pulposus in mouse embryos. Notochord fate-mapping experiments revealed that notochord cells in Gdf-5-null mice correctly form nuclei pulposi. CONCLUSION: Our data suggest that the defects reported in the nucleus pulposus of adult Gdf-5-null mice do not result from abnormal patterning of the embryonic notochord. The use of mouse alleles to mark cells that produce all cell types that reside in the adult nucleus pulposus will allow for a detailed examination of disc formation in other mouse mutants that have been reported to contain disc defects. PMID- 21278630 TI - Abnormal spontaneous activities on needle electromyography and their relation with pain behavior and nerve fiber pathology in a rat model of lumbar disc herniation. AB - STUDY DESIGN: This longitudinal experimental study was conducted to investigate electrophysiologic characteristics, pain behavior, and histological changes in a rat model of lumbar disc herniation. OBJECTIVE: To observe abnormal spontaneous activity (ASA) on needle electromyography (EMG) and to determine its relation with neuropathic pain behavior and histological changes longitudinally in a rat model of lumbar disc herniation. SUMMARY OF BACKGROUND DATA: Needle EMG is generally performed to determine the existence and the degree of radiculopathy caused by disc herniation. The local application of autologous nucleus pulposus to the spinal nerve has been shown to induce neuropathic pain. However, little is known about the relations between neuropathic pain and abnormal EMG findings and the manner in which they change with time in rat models of lumbar disc herniation. METHODS: Twenty-five Sprague-Dawley rats were randomly assigned to either sham or experimental groups. In the experimental group, autologous nucleus pulposus was grafted on the left L5 dorsal root ganglion. All rats were evaluated for mechanical allodynia and thermal hyperalgesia and underwent needle EMG examinations before and on days 1, 5, 10, 20, 30, 40, and 50 after surgery. Morphologic changes of L5 spinal nerves and of sciatic nerves were assessed by toluidine blue staining on days 1, 5, and 50 after surgery. RESULTS: A dramatic decrease in mechanical withdrawal threshold and in thermal withdrawal latency was observed on day 1 after surgery, and these changes persisted until day 50 after surgery. ASAs on needle EMG were observed on day 1 (33%), peaked on day 5 (93%), and gradually decreased from day 10 (69%) to day 40 (18%) after surgery. Pathologic findings of nerve fibers, such as swelling of myelin sheaths, demyelination, and degeneration of axoplasms were observed from day 1. These findings were exaggerated on day 5 and then diminished but were still evident on day 50. CONCLUSION: Neuropathic pain and pathologic changes in spinal nerve fibers probably remain even after ASAs in EMG have disappeared in our rat model of lumbar disc herniation. These results provide baseline data concerning the natural courses of electrophysiologic findings and of radicular pain in patients with intervertebral disc herniation. PMID- 21278631 TI - Transplantomics and biomarkers in organ transplantation: a report from the first international conference. PMID- 21278633 TI - Good management is the key to success. PMID- 21278634 TI - Simple wound care facilitates full healing in post-earthquake Haiti. AB - The author provides an insight into the basic health care needs of two spinal cord injury patients who were cared for in a specially set up 25-bedded spinal cord injury unit in Haiti. While focusing on their extreme wound care requirements, the author highlights the need for adequate fluid, nutrition, hygiene and aseptic technique. Both patients were victims of the January 2010 earthquake in Port au Prince, Haiti. The author describes the basic wound care strategy for a patient with a category IV sacral pressure ulcer and another with a broken down thoracic spine surgical wound with visible metal work. This article describes how simple wound care effected the complete healing of large sacral pressure ulcers and broken down spinal surgical wounds without the need for further surgical intervention. PMID- 21278635 TI - Does the postoperative dressing regime affect wound healing after hip or knee arthroplasty? AB - OBJECTIVE: The aim of this literature review is to enable practitioners to make informed decisions about how to manage patients with hip or knee arthroplasty wounds. METHOD: A systematic critique of the evidence in relation to how the postoperative dressing regime may affect wound healing after hip or knee arthroplasty, was undertaken. RESULTS: No single treatment emerged as the ideal postoperative dressing regime for hip and knee arthroplasty wounds. CONCLUSION: A selection of dressings is recommended for hip and knee arthroplasty wounds, on the basis of reducing the incidence of postoperative blistering and wound infection. PMID- 21278636 TI - Retrospective study of pressure ulcer prevalence in Dutch general hospitals since 2001. AB - OBJECTIVE: To investigate whether factors such as patient characteristics, pressure ulcer (PU) prevention strategies and the structural quality indicators used by institutions and wards can explain an apparent decline in PU prevalence from 2001 to 2008. METHOD: The Dutch National Prevalence Survey of Care Problems (known as LPZ) database from 2001 to 2008 was used to explore differences in patient characteristics, PU prevention strategies and structural quality indicators used by institutions and wards between two periods, 2001-2004 (PU as an internal health-care quality indicator) and 2005-2008 (PU as an external health-care quality indicator). RESULTS: Compared with 2001-2004, fewer participants with CVA /hemiparesis (OR 0.485), infectious diseases (OR 0.861), surgery lasting >2 hours (OR 0.637), at-risk Braden scale scores (OR 0.844), and more participants with diabetes mellitus (OR 1.693) were found in the 2005-2008 group. More special beds/mattresses (OR 2.216) and special cushions in wheelchairs (OR 2.277) were used in the 2005- 2008 period, as well as slightly more repositioning, dehydration/malnutrition prevention and PU prevention and treatment information. More institutions had information leaflets (OR 5.894), PU prevention guidelines (OR 4.625), a PU committee (OR 2.503), and a PU-wound care nurse at ward level (OR 2.434) in the 2005-2008 period. CONCLUSION: The decline in PU prevalence at Dutch general hospitals after 2004 may be partly explained by differences in patient characteristics, improved structural quality indicators and a slight improvement in PU prevention. Further research is needed to find evidence of which individual factors can explain the decline in PU prevalence after 2004 and whether any changes in health care policy have impacted on these prevalence rates. PMID- 21278638 TI - Heel damage and epidural analgesia: is there a connection? AB - OBJECTIVE: To determine heel pressure injury prevalence in surgical patients prescribed epidural analgesia and identify intrinsic and extrinsic factors associated with heel damage in this patient cohort. METHOD: A descriptive study was used to investigate intrinsic and extrinsic variables associated with recorded heel observations at a private hospital in Victoria, Australia. We recruited a sample of 29 consecutive non-emergency participants undergoing general anaesthesia for major surgery, who were prescribed epidural analgesia postoperatively. A total of 58 heel observations were made. RESULTS: Heel damage prevalence in the study sample was 13.8% (n=8). CONCLUSION: Intrinsic factors associated with this complication included intra- and postoperative hypotension, vascular disease, smoking, chronic obstructive pulmonary disease, and multiple disease burdens. Extrinsic factors associated with heel damage included thromboembolic deterrent stockings and the postoperative ward use of heel protectors designed for use in operating theatres. It is hoped that the study findings will assist improvements in the assessment of heel damage risk and promote the pressure prevention strategies required by this patient cohort. PMID- 21278639 TI - Negative pressure wound therapy as an adjunct to compression for healing chronic venous ulcers. AB - OBJECTIVE: To determine the efficacy of negative pressure wound therapy (NPWT), when used in combination with compression bandaging, for healing chronic resistant venous ulcers. METHOD: In this pilot study, seven patients (with a total of 12 chronic resistant venous ulcers) received adjunctive NPWT and compression bandaging for 4 weeks. Their wounds were monitored for a total of 12 weeks. RESULTS: Dormant ulcers were seen to rapidly develop into healthy wounds, with a granulating base. CONCLUSION: This regimen may have a role in stimulating chronic venous ulcers into healing wounds, or in preparing them for skin grafting. PMID- 21278640 TI - Survey of fungi and yeast in polymicrobial infections in chronic wounds. AB - OBJECTIVE: To assess the incidence, abundance and species diversity of fungi in chronic wounds, as well as to describe the associations of major fungi populations. METHOD: Comprehensive molecular diagnostic reports were evaluated from a total of 915 chronic wounds in a retrospective study. RESULTS: Of the 915 clinical specimens, 208 (23%) were positive for fungal species. These samples were further compared in a compiled dataset, and sub-classified among the four major chronic wound types (decubitus ulcer, diabetic foot ulcer, non-healing surgical wound, and venous leg ulcer). The most abundant fungi were yeasts in the genus Candida; however, Curvularia, Malessezia, Aureobasidium, Cladosporium, Ulocladium, Engodontium and Trichtophyton were also found to be prevalent components of these polymicrobial infections. A notable bacterial/fungal negative correlation was found to be apparent between Staphylococcus and Candida. There were also significant relationships between both bacterial and fungal genera and patient metadata including gender, diabetes status and cardiovascular comorbidities. CONCLUSION: This microbial survey shows that fungi are more important wound pathogens and opportunistic pathogens than previously reported, exemplifying the impact of these under-reported pathogens. With the application of modern cost-effective and comprehensive molecular diagnostics, clinicians can now identify and address this significant component of chronic wound bioburden with targeted therapies, thereby improving healing trajectories. PMID- 21278641 TI - Effectively assessing risk: maintaining quality. PMID- 21278642 TI - Managing dysphagia in older people with dementia. AB - In the UK there is an increasing ageing population, bringing with it a host of degenerative conditions such as dementia. Dementia is a common condition among older people. In the UK there are estimated to be over 750 000 people with dementia and numbers are expected to double in the next 30 years (Comas-Herrera et al, 2007). The term 'dementia' is used to describe a syndrome which may be caused by a number of illnesses and is associated with ongoing decline of the brain and its abilities. There are many types of dementia, the most common are Alzheimer's disease, vascular dementia and dementia with Lewy bodies. The most common form of dementia is Alzheimer's which accounts for 62% of all cases. Vascular dementia either alone or co-existent with Alzheimer's, is the second most common subtype of dementia (Knapp et al, 2007). Dementia is associated with complex needs especially in the later stages, and can have a devastating effect on the individual, their family and friends. The care needs often challenge the skills and capacity of carers especially when normal every-day activities decline. Food and drink are fundamental to living. Consequently observing individuals struggling with eating and drinking not only poses difficulties for professionals but also raises emotional issues for the individual and their family. PMID- 21278643 TI - Activity promotion for community-dwelling older people: a survey of the contribution of primary care nurses. AB - STUDY AIMS: To discover the current level of nurse-led involvement in activity promotion for older people in primary care and to explore the knowledge and attitudes of primary care nurses about health benefits of activity promotion for older people. BACKGROUND: The importance of improving and maintaining activity levels in later life is well established. However, intervention studies show that the uptake of and adherence to physical activity programmes by older people are highly variable. The optimal approach to activity promotion for older people is not well understood. Although many activity promotion schemes and evaluations assume that specialist exercise trainers are needed, it remains unclear who is best placed to facilitate activity promotion for older people, and if this is something in which existing primary care practitioners (specifically nurses) could and should take a leading role. METHODS: This study surveyed all nurses and health visitors working in five primary care organizations in an inner city area. A semi-structured postal questionnaire asked about their knowledge and attitudes to the benefits of exercise in later life, their current levels of involvement in promoting physical activity with older people, and their personal activity levels. FINDINGS: The overall response rate was 54% (n=521). The responses of 391 district nurses and practice nurses are presented here. Nurses had the commitment and (depending on the focus of their work) different opportunities to promote physical activity with older patients. There were organizational and individual constraints on their ability to be involved in this aspect of health promotion work themselves, or to refer older people to local activity promotion schemes. Nurses did not have a structured approach when promoting physical activity with older people and had only a partial awareness of the limitations of their knowledge or skills when promoting activity with older people. CONCLUSIONS: For promotion of physical activity by older people to be meaningfully incorporated into primary care nursing work there is a need to develop a more strategic approach that can optimize the opportunities and interest of primary care nurses and develop the knowledge and skills of the workforce in this area of nursing work. PMID- 21278644 TI - Changing times: preparing to meet palliative needs in the 21st Century. AB - Globally, 56 million people die each year and for many, in resource-rich as well as resource-poor countries, the process of dying is associated with significant but preventable suffering (Sepulveda et al, 2002; Seymour at al, 2010). Since the introduction of the modern hospice movement in the 1960s, marked by the opening of St Christopher's Hospice in Sydenham, London by the late Dame Cicely Saunders, the principles and practice of palliative care have been disseminated round the world, to the extent that palliative care has been coined by some commentators as a human right (Brennan, 2007). At the end of the first decade of the 21st Century, the provision of palliative care is beginning to feature in the political and policy agendas of many different countries as they seek to respond the challenges of epidemiological and socio-demographic change. The changing age structure of the countries in the developed world has given rise to a growth of palliative care needs among older people, often in association with long-term conditions other than cancer in which the onset of 'dying' is often hard to ascertain; while younger people with complex palliative care needs owing to life limiting disease or disability are living longer than at any time previously because of changes in medical technology (Davies and Higginson, 2004). In the resource-poor nations, the tragedies of the AIDS pandemic pose a challenge of gargantuan proportions, especially in sub-Saharan Africa. PMID- 21278645 TI - Legal basis for standards of driving with diabetes. AB - The tragic case of a district nurse killed when a car driven by a man in a hypoglycaemic state struck her while she took her regular evening walk highlights the dangers that can occur when a person with diabetes drives without regard to their condition. The man was later jailed for four and a half years for causing death by dangerous driving having been found criminally responsible for his actions because he failed to control his blood sugar levels during the journey (Valek, 2007). This article considers the legal basis for the medical standards for driving imposed on individuals with diabetes and sets out the likely consequences of failing to comply with those standards. PMID- 21278646 TI - Assessment of neuropathic pain in the community. AB - The purpose of this paper is to provide the reader with evidence basedclinical guidance regarding assessing neuropathic pain. Persistent pain is a huge burden on health-care provision and the prevalence of persistent neuropathic pain is likely to increase owing to the ageing population. The provision of appropriate relieving interventions depends on accurate assessment. This paper sets out to provide the reader with simple neuropathic assessment tools that can be applied to community care. This will allow the community nurse to identify patients who have neuropathic pain and will therefore enable appropriate management. PMID- 21278647 TI - District nurses' and aseptic technique: where did it all go wrong? AB - Concerns have been raised about whether it is possible to perform aseptic procedures within a community setting. Hallett (2000) has described how community nurses often have a fatalistic view about whether such procedures can really be performed at home. At the same time there has been an increase in the number of patients being cared for at home who need interventions which must adhere to the principles of asepsis. While it has been acknowledged for some time that community nurses must be resourceful and adapt the procedure, the view that community nurses cannot really perform aseptic procedures is a fairly new phenomenon. This article explores the reasons why concerns about the performance of aseptic procedures in the community may have arisen and what steps can be taken to address these concerns to ensure that care at home is both safe and effective. PMID- 21278648 TI - The District Nursing Clinical Error Reduction Programme. AB - The District Nursing Clinical Error Reduction (DANCER) Programme was initiated in NHS Islington following an increase in the number of reported medication errors. The objectives were to reduce the actual degree of harm and the potential risk of harm associated with medication errors and to maintain the existing positive reporting culture, while robustly addressing performance issues. One hundred medication errors reported in 2007/08 were analysed using a framework that specifies the factors that predispose to adverse medication events in domiciliary care. Various contributory factors were identified and interventions were subsequently developed to address poor drug calculation and medication problem solving skills and incorrectly transcribed medication administration record charts. Follow up data were obtained at 12 months and two years. The evaluation has shown that although medication errors do still occur, the programme has resulted in a marked shift towards a reduction in the associated actual degree of harm and the potential risk of harm. PMID- 21278649 TI - Overview of depression: epidemiology and implications for community nursing practice. AB - Depressive disorders are among the most common psychological conditions currently affecting individuals living in the Westernized world. Yet, available data indicate that fewer than one third of adults with depression obtain appropriate professional treatment. This is attributed, among other reasons, to the under recognition of the problem by health professionals, including district nurses. In order to improve recognition of the problem, it is imperative for nurses and especially those working in community settings, to appreciate the importance of prompt diagnosis which presumes both an understanding and knowledge of basic aspects of the problem and, an understanding of their role in dealing with depression. This overview presents epidemiological data and identifies the potential consequences of depression on daily functioning and other aspects of life among adults in Westernized countries, aiming to raise awareness and sensitize district nurses about the issue The article discusses how the role of district nurses can be enhanced to improve recognition rates. PMID- 21278650 TI - Have you had the flu jab? AB - Influenza is a serious viral infection which can cause major complications or even death in vulnerable groups. The most effective way to prevent influenza and its spread is vaccination which requires good vaccination coverage of vulnerable groups and health professionals in contact with these patient groups. However, current data show that vaccine uptake levels are slightly lower this year than at the same time last year (Department of Health, 2010). Less than half of those aged 65 years and over and just over a quarter of those in risk groups have been vaccinated, which is worrying if we wish to prevent avoidable illness and hospital admissions arising from complications. PMID- 21278651 TI - Taking the N out of NHS. PMID- 21278652 TI - Petroleum, oats, shea butter: are 'natural' emollients best? PMID- 21278653 TI - The vital role of emollients in the treatment of eczema. AB - Eczema is one of the most common dermatological diseases, with the number of cases in the UK rising. The use of emollients to maintain skin hydration and help restore barrier function, remains the principal treatment. Unfortunately, many health professionals, and patients themselves, fail to consider emollients an active treatment and may overlook the vital role they play in the maintenance of intact, healthy skin. Despite the overwhelming acceptance of the importance of emollient therapy, there remains a lack of good quality evidence on their effectiveness or whether one is better than another. Even when appropriate emollients are supplied, they are often used incorrectly or accompanied by conflicting/limited advice from health professionals. This article aims to explore normal skin barrier function, the disruption caused by eczema, and some of the contemporary issues surrounding emollient therapy. PMID- 21278654 TI - Effective management strategies for osteoarthritis. AB - Osteoarthritis (OA) is a chronic disease which affects a significant number of people during working life and retirement. The principle symptoms of OA are pain, stiffness, and potentially reduced movement and function of the affected joint. In severe OA the ability to engage in work or social activity may be restricted and as a result, the health-related quality of life of the patient may be affected. There are a variety of approaches which can be implemented to manage symptoms, including the use of orthoses, exercise programmes or in severe cases, arthroplasty. It is important that emphasis is placed on patient empowerment and shared decision-making with regard to managing symptoms and preserving or improving function or the affected joint(s). PMID- 21278655 TI - The role of the clinical nurse specialist in MS: a literature review. AB - The purpose of this review was to determine the role of nurse specialists in multiple sclerosis (NSMS) in providing care for carers of people with multiple sclerosis (PwMS). The databases searched from inception to April 2010 include: CINAHL, PsycINFO, British Nursing Index, PubMed, AMED, Nursing and Allied Health Source, Academic Search Complete, Cochrane Library Database, Web of Knowledge, Ovid Nursing Database, Social Science Index, and Joanna Briggs Institute. Eighteen articles were included in the review. However, only three research-based articles were found that evaluated the role of the NSMS. The remaining articles were discussion-based and provided insight into the contribution of the NSMS to service provision. The review highlights the continuing lack of research evaluating the impact of the role of the nurse specialist in multiple sclerosis and in particular, the lack of recognition of the support role that nurse specialists provide for carers of PwMS. PMID- 21278656 TI - Stroke mood screening on an inpatient stroke unit. AB - Psychological problems, and post-stroke depression in particular, are common following stroke. This article describes the development and evaluation of a mood screening pathway on a hospital-based stroke unit. The pathway is evaluated against the criteria of the national stroke guidelines, particularly the National Stroke Sentinel Audit (Royal College of Physicians, 2008a). The outcome reveals that the Stroke Mood Screening pathway meets the target of assessing every patient in 88.9% of cases. This places the performance of this procedure within the top quarter of stroke units in the UK. The Stroke Mood Screening pathway enabled the rehabilitation team to identify mood disturbances very early following patients' admission to the unit. Good communication pathways between rehabilitation staff and easy referral routes to neuropsychology made rapid and efficient responses to emerging mood problems possible. The outcomes of this evaluation also give useful guidance for service improvements and consequently, could optimize the provision of psychological support for the patients on the unit. PMID- 21278657 TI - Academic skills: using literature to support your discussion. AB - A good academic piece of work aims to locate itself within the available body of knowledge on the subject area. Knowledge can come from a range of different sources, each contributing to the body of knowledge on the subject. The final article in this three-part series discusses the importance of appraising and making sense of literature when considering the knowledge relating to a particular subject area. Guidelines and methods are described to help organize, collate and make sense of the knowledge obtained, so that a logical plan can be created to structure academic work. The academic requirements of different levels are then briefly explained to give guidance on how best to use the literature to support and inform discussions. PMID- 21278658 TI - Myocardial infarction: a turning point in meaning in life over time. AB - Finding meaning in illness appears to give individuals purpose in life, which may motivate them to maintain a healthy lifestyle. Research to date has mainly used cross-sectional designs in the acute phase of recovery. This article describes a longitudinal exploratory study which explored patients' search for meaning in life across the first 5 years following myocardial infarction (MI). Interviews were conducted between 2000 and 2007 on patients with first MI (n=70; mean=61.9 years; SD=12.1). The qualitative data underwent thematic analysis guided by the analysis framework of Burnard (1991). Finding meaning appeared to increase patients' awareness of their current holistic state of life, and to provide impetus for making lifestyle changes. In the immediate aftermath of MI, patients restructured and re-evaluated their attitudes towards self, life, religious beliefs and others. However, from the third year onwards, as time passed patients lapsed in their behaviour, tending to become non-compliant with treatment and less aware or concerned about the risk of another heart attack. Further education on the spiritual dimension in care may guide nurses and health professionals in order to promote patients' rehabilitation process and persevere with a long-term healthy lifestyle. Further longitudinal comparative research with mixed method approach on various groups of patients is recommended to support these findings. PMID- 21278660 TI - Preventing adverse healthcare events: lessons from abroad. AB - John Tingle discusses a patient safety report from Minnesota, USA which contains some important lessons for maintaining and developing a safe and proper healthcare treatment environment. PMID- 21278661 TI - Promoting healthy living in 2011: can nurses lead by example? AB - Professor Alan Glasper discusses the Great Swapathon-making small, manageable changes to encourage healthier behaviours-and how nursing professionals can lead by example. PMID- 21278662 TI - Writing for professional publication. Part 6: writing the abstract. AB - How to get your work published is the essence of this series on writing for professional publication. The first four articles focused on the preparation required before you start writing a potential article, and the previous article examined the importance of creating interest in the reader's mind. In this sixth part of the series, John Fowler, an experienced nursing lecturer and author, discusses the importance of writing the abstract. It examines the content to include and also the importance of writing it in a way which encourages others to read the full article. PMID- 21278663 TI - Simple skills save lives: airway management. AB - When a patient comes into hospital they expect to be entering a safe environment where health professionals are able to handle any and all emergencies (National Institute for Health and Clinical Excellence (NICE), 2007). However, a recent analysis of serious patient events by the National Patient Safety Agency (2007) made for sober reading. The report identified three broad themes that have impacted on patients' safety in the hospital setting: PMID- 21278664 TI - Disinfectants: their values and uses. AB - The use of disinfectants appeared in an article in the BJN 100 years ago and gives us a fascinating insight in to nursing practice to maintain infection control at the time. 'Objections have been raised against the use of sulphur, principal among which are the bleaching action of the fumes upon vegetable colouring matters; its destructive effect upon certain fabrics; its tarnishing action upon all metals; the lack of penetration of the fumes, and the danger of fire from its use. As a disinfectant and antiseptic, its use dates back to a remote period in the world's history, and, by reason of its cheapness and the ease with which reason of its cheapness and the ease with which it may be used, it is still popular, more especially in the smaller centres of population. To secure the best results from its use, and to minimise the danger from fire, the following method is suggested: PMID- 21278665 TI - Updating the nursing process. AB - It's nearly 30 years since I wrote my first book on the 'nursing process'. At the time it was the talking point of nursing and considered to be the way forward for the profession in the UK and Europe. The subject had already been implemented in the USA, and there was some resentment at the time that Britain was going to have to follow America. In fact, Professor Jean McFarlane (the first English Professor of Nursing) had given a seminar in the Department of Nursing at the University of Manchester in 1973, relating to the importance of evaluating nursing practice. As part of her paper she proposed that the department should experiment with the nursing process. This it did, firstly in planning nursing care in its course leading to the Diploma in Advanced Nursing Studies for experienced registered nurses. It was then gradually introduced into the undergraduate programme. PMID- 21278666 TI - Valuing patient contact and nursing skills. PMID- 21278667 TI - Maximizing palliative care provision in economic downturns. PMID- 21278668 TI - Nurses' views of the coping and support mechanisms experienced in managing terminal haemorrhage. AB - INTRODUCTION: Although palliative care is a rewarding specialty, it presents emotive personal challenges for the health professionals working within it. Terminal haemorrhage is arguably the most feared and distressing event in the palliative care setting, both for the patient and for the health professionals looking after them. The aim of this study was to explore and reflect on the coping and support mechanisms that have helped nurses to manage these events. METHOD: Purposive sampling was used to recruit nurses from palliative care and oncology who had personal experience of managing terminal haemorrhage. Semi structured interviews were used to collect qualitative data that were then analysed using interpretative phenomenological analysis. Saturation of data was reached after 11 participants had been interviewed. RESULTS: The participants had a combined experience of managing 37 patients with a terminal haemorrhage. The key themes that emerged were the role of the 'autopilot', having a plan, education and training, the value of debriefing and peer support, and the importance of supporting the whole team. Education and training specifically about terminal haemorrhage and structured debriefing after such events were both identified by the participants as currently unmet needs. CONCLUSION: Professionals working in areas in which patients are at particular risk of terminal haemorrhage require adequate training and education prior to these events and a structure for formal debriefing and peer support afterwards. PMID- 21278669 TI - Accessing vulnerable research populations: an experience with gatekeepers of ethical approval. AB - Accessing vulnerable populations for research purposes can be difficult, as participants must be sheltered from research that might be insensitive, intrusive, and potentially distressing. People diagnosed with a life-limiting condition may be vulnerable, and involving such people in research samples may be fraught with difficulties. Nevertheless, it is important that these vulnerable populations participate in health and social-care research so that their requirements and opinions can be learnt. This paper describes an experience of proceeding through an ethical approval process for a proposed qualitative research study into the preferred place of death of a group of potentially vulnerable hospice patients. Research of this nature had never been undertaken at the hospice before, and the researchers expected to encounter a degree and variety of gatekeeping when seeking access to this sensitive population. PMID- 21278670 TI - Multidisciplinary palliative care teams' understanding of Mental Capacity Act 2005 'best interest' determinations. AB - AIM: To explore multidisciplinary palliative care teams' implementation of the concept of 'best interests' as stated in the Mental Capacity Act 2005 (MCA). BACKGROUND: The MCA for England and Wales provides a statutory framework to protect people who are unable to make their own decisions. No previous research has tackled the specific aim of this investigation. METHOD: Qualitative research methods were used to interview professionals from two multidisciplinary palliative care teams. The interviews were audio-recorded and thematically analysed. RESULTS: Participants reported that the best interests concept is part of their daily practice, but they had limited understanding of the MCA formulation of best interests. Team location influences the setting and process of best interests decision making. CONCLUSION: Palliative care professionals' process of considering their patients' best interests may not directly reflect the specific guidance of the MCA. PMID- 21278671 TI - Palliative care needs of chronically ill nursing home residents in Germany: focusing on living, not dying. AB - OBJECTIVES: To explore the palliative care needs of nursing home residents in Germany who had not yet entered the dying phase. METHODS: Semi-structured interviews were conducted with a sample of nine residents suffering from chronic disease or frailty. The interviews were audio-recorded, transcribed, and analysed using a grounded theory approach. FINDINGS: The residents described multidimensional needs, which were categorized as 'being recognized as a person', 'having a choice and being in control', 'being connected to family and the world outside', 'being spiritually connected', and 'physical comfort'. They emphasized their desire to control everyday matters. Physical impairment was a problem, especially when independence was threatened, e.g. by immobility or a reliance on pain killers. CONCLUSION: The desire for self-determination is key when designing and evaluating primary and palliative care programmes for nursing homes. Early integration of palliative care can improve the quality of life of chronically ill residents. PMID- 21278672 TI - Factors influencing the referral of non-cancer patients to community specialist palliative care nurses. AB - AIM: To understand why non-cancer patients are under-represented on the caseloads of community Macmillan specialist palliative care nurses by exploring what influences community health professionals' referral patterns of non-cancer patients in one locality of a primary care trust. DESIGN: The study adopted a qualitative design, making use of semi-structured interviews with a purposive sample of community health professionals comprising three GPs, three district nurses, and three community matrons. The framework approach was used for analysis. FINDINGS: The classification of patients, the perception of the palliative care service, the existence of different pathways of care for cancer and non-cancer patients, and the role of other specialist nurses all seem to influence the referral patterns of community health professionals. CONCLUSION: Although further research is required to fully understand all of the relevant viewpoints, in particular those of patients and carers, it appears that innovative new models of service delivery could be developed that address the engrained perception of the Macmillan nursing service as being for dying cancer patients only, as well as the blurred boundaries between Macmillan nurses and other senior clinical nurses. PMID- 21278673 TI - Palliative care in advanced kidney disease: a nurse-led joint renal and specialist palliative care clinic. AB - The National Service Framework for Renal Services Part 2 identifies quality requirements for end-of-life care for individuals with kidney failure, recognizing the potential to forge closer relationships between renal and specialist palliative care providers. This article describes a pilot project set up by two Clinical Nurse Specialists, one working in hospice specialist palliative care and the other in renal palliative care within an acute trust. The purpose of the pilot was to work in collaboration to run a streamlined nurse-led clinic that would meet the palliative care needs of chronic kidney disease (CKD) Stage 5 patients and their carers. To achieve this the clinic would have to provide optimal symptom management, empower patients to make their own choices, and support them with advance care planning underpinned by the End of Life Care Strategy. The partnership also aimed to promote service improvement and practice development using transference of knowledge, skills, and expertise. Initial informal feedback, including a very small patient survey, suggests that the clinic was well received by patients, carers, and other health professionals. The clinic is ongoing and deserves more formal evaluation to encourage future service development. PMID- 21278676 TI - Selection of peptides targeting helix 31 of bacterial 16S ribosomal RNA by screening M13 phage-display libraries. AB - Ribosomal RNA is the catalytic portion of ribosomes, and undergoes a variety of conformational changes during translation. Structural changes in ribosomal RNA can be facilitated by the presence of modified nucleotides. Helix 31 of bacterial 16S ribosomal RNA harbors two modified nucleotides, m2G966 and m5C967, that are highly conserved among bacteria, though the degree and nature of the modifications in this region are different in eukaryotes. Contacts between helix 31 and the P-site tRNA, initiation factors, and ribosomal proteins highlight the importance of this region in translation. In this work, a heptapeptide M13 phage display library was screened for ligands that target the wild-type, naturally modified bacterial helix 31. Several peptides, including TYLPWPA, CVRPFAL, TLWDLIP, FVRPFPL, ATPLWLK, and DIRTQRE, were found to be prevalent after several rounds of screening. Several of the peptides exhibited moderate affinity (in the high nM to low uM range) to modified helix 31 in biophysical assays, including surface plasmon resonance (SPR), and were also shown to bind 30S ribosomal subunits. These peptides also inhibited protein synthesis in cell-free translation assays. PMID- 21278677 TI - Tannin fingerprinting in vegetable tanned leather by solid state NMR spectroscopy and comparison with leathers tanned by other processes. AB - Solid state 13C-NMR spectra of pure tannin powders from four different sources- mimosa, quebracho, chestnut and tara--are readily distinguishable from each other, both in pure commercial powder form, and in leather which they have been used to tan. Groups of signals indicative of the source, and type (condensed vs. hydrolyzable) of tannin used in the manufacture are well resolved in the spectra of the finished leathers. These fingerprints are compared with those arising from leathers tanned with other common tanning agents. Paramagnetic chromium (III) tanning causes widespread but selective disappearance of signals from the spectrum of leather collagen, including resonances from acidic aspartyl and glutamyl residues, likely bound to Cr (III) structures. Aluminium (III) and glutaraldehyde tanning both cause considerable leather collagen signal sharpening suggesting some increase in molecular structural ordering. The 27Al-NMR signal from the former material is consistent with an octahedral coordination by oxygen ligands. Solid state NMR thus provides easily recognisable reagent specific spectral fingerprints of the products of vegetable and some other common tanning processes. Because spectra are related to molecular properties, NMR is potentially a powerful tool in leather process enhancement and quality or provenance assurance. PMID- 21278678 TI - Chemical and pharmacological aspects of capsaicin. AB - Capsaicin is a unique alkaloid found primarily in the fruit of the Capsicum genus and is what provides its spicy flavor. Generally extracted directly from fruit, high demand has driven the use of established methods to increase production through extraction and characterization. Over time these methods have improved, usually be applying existing techniques in conjunction. An increasingly wide range of potential applications has increased interest in capsaicin. Especially compelling are the promising results of medical studies showing possible beneficial effects in many diseases. Capsaicin's pungency has limited its use in clinical trials to support its biological activity. Characterization and extraction/ synthesis of non-pungent analogues is in progress. A review is made of capsaicin research focusing mainly on its production, synthesis, characterization and pharmacology, including some of its main potential clinical uses in humans. PMID- 21278679 TI - Oligomeric nucleic acids as antivirals. AB - Based on the natural functions and chemical characteristics of nucleic acids, a variety of novel synthetic drugs and tools to explore biological systems have become available in recent years. To date, a great number of antisense oligonucleotides, RNA interference-based tools, CpG-containing oligonucleotides, catalytic oligonucleotides, decoys and aptamers has been produced synthetically and applied successfully for understanding and manipulating biological processes and in clinical trials to treat a variety of diseases. Their versatility and potency make them equally suited candidates for fighting viral infections. Here, we describe the different types of nucleic acid-based antivirals, their mechanism of action, their advantages and limitations, and their future prospects. PMID- 21278680 TI - Synthesis, characterization and antifungal evaluation of 5-substituted-4-amino 1,2,4-triazole-3-thioesters. AB - A series of 5-substituted-4-amino-1,2,4-triazole-3-thioesters was synthesized by converting variously substituted organic acids successively into the corresponding esters, hydrazides, 5-substituted-1,3,4-oxadiazole-2-thiols, 5 substituted-1,2,4-triazole-2-thiols and 5-substituted-1,3,4-oxadiazole-2 thioesters. Finally the target compounds were obtained by refluxing 5-substituted 1,3,4-oxadiazole-2-thioesters in the presence of hydrazine hydrate and absolute alcohol. The structures of the synthesized compounds were established by physicochemical and spectroscopic methods. The synthesized compounds were evaluated for their in vitro antifungal activity. Some of the evaluated compounds possessed significant antifungal activity as compared to a terbinafine standard. PMID- 21278681 TI - Triterpene composition and bioactivities of Centella asiatica. AB - Leaves of Centella asiatica (Centella) were analysed for their triterpene composition and bioactivity such as collagen enhancement, antioxidant, anticellulite and UV protection capacity properties. Triterpenes of Centella were measured using HPLC-PAD on an Excil ODS 5 mm (C18) column for the simultaneous determination of asiatic acid, madecassic acid, asiaticoside and madecassoside. Centella was found to contain significant amounts of madecassoside (3.10 +/- 4.58 mg/mL) and asiaticoside (1.97 +/- 2.65 mg/mL), but was low in asiatic and madecassic acid. The highest collagen synthesis was found at 50 mg/mL of Centella extracts. The antioxidant activity of Centella (84%) was compared to grape seed extract (83%) and Vitamin C (88%). Its lipolytic activity was observed by the release of glycerol (115.9 umol/L) at 0.02% concentration. Centella extracts exhibited similar UV protection effect to OMC at 10% concentration. In view of these results, the potential application of Centella in food and pharmaceutical industries is now widely open. PMID- 21278682 TI - Behaviors in ethylene polymerization of MgCl2-SiO2/TiCl4/THF Ziegler-Natta catalysts with differently treated SiO2. AB - The present research focuses on investigation of the catalytic behaviors of MgCl2 SiO2/TiCl4/THF Ziegler-Natta (ZN) catalysts with fumed SiO2 variously treated with silane compounds. The non-treated silica (NTS) and other silicas treated with dimethylsilicone fluid (TSDMSF), dimethyldichlorosilane (TSDMDCS), and hexamethyl-disilazane (TSHMDS) were employed. It was found that the Cat-TSDMDCS and Cat-TSHMDS exhibited remarkably high activity, even with a similar bulk Ti content as the others. Thus, the more powerful technique of XPS analysis was used to determine the Ti content at the catalyst surface. It was evident that the surface concentrations of Ti could play important role on the catalyst activity. As the result, the increased activity is proportional to the surface concentration of Ti. It was mentioned that the change in surface concentration of Ti with different treated silica can be attributed to the effect of silane spacer group and steric hindrance. The distribution of Ti on the external surface can be also proven by means of EDX mapping, which matched the results obtained by XPS analysis. The treated silica also resulted in narrower molecular weight distribution (MWD) due to the more uniform active sites produced. There was no significant change in polymer morphology upon treatment of the silica. PMID- 21278683 TI - Glucagon-like peptide-1 improves proliferation and differentiation of endothelial progenitor cells via upregulating VEGF generation. AB - BACKGROUND: Glucagon-like peptide-1(GLP-1), released from enteroendocrine cells of the intestine, exerted cardiovascular protective effect. Circulating endothelial progenitor cells (EPCs) play an important role in maintaining endothelial integrity regulating neovascularization and reendothelialization after endothelial injury. Vascular endothelial growth factor (VEGF) is an important cytokine in the process of EPCs vascular differentiation and proliferation. MATERIAL/METHODS: This study was designed to investigate the association between VEGF changes and the proliferation/differentiation function of EPCs in the presence of GLP-1. RESULTS: We demonstrated that GLP-1 markedly enhanced the EPCs proliferation and expression of EC-specific markers, and simultaneously upregulated VEGF secretion in EPCs. Exogenous VEGF augmented EPCs proliferation/differentiation abilities in a dose-dependent manner. However, all of the beneficial effects of GLP-1were suppressed by anti-VEGFmAb or the KDR specific tyrosine kinase inhibitor SU1498. CONCLUSIONS: These findings suggest that GLP-1 improves VEGF generation, which contributed to improvement of EPCs biological function, partly by tyrosine kinase KDR. VEGF is a necessary intermediate, mediating the effects of GLP-1 on EPCs. These changes offer a novel explanation that upregulation EPCs bioactivities may be one of the mechanisms of GLP-1 cardiovascular protective effect. PMID- 21278684 TI - Retrospective analysis of the HIV-1 reverse transcriptase inhibitors' resistance in Silesia, Poland. AB - BACKGROUND: This study was a retrospective analysis of drug resistance mutations among HIV-1 strains prevalent in Silesia, Poland, from the origin of the epidemic to 2004. The investigations included both type and frequency of the reverse transcriptase inhibitors' resistance mutations and estimation of the drugs' resistance levels. MATERIAL/METHODS: Proviral DNA, obtained from peripheral blood mononuclear cells of the 101 HIV-1-infected patients, was amplified and sequenced in the pol gene fragment covering the first 256 codons of the reverse transcriptase (RT). Reverse transcriptase inhibitors resistance mutations were determined and interpreted with the HIVdb: Genotypic Resistance Interpretation Algorithm available from the Stanford University HIV Drug Resistance Database. In the examined population, 35 subjects (34.7%) received no antiretroviral treatment by the time of specimen collection. RESULTS: The overall frequency of the RT inhibitors resistance mutations in the studied population was 15.8%. Substitutions related to the reverse transcriptase inhibitors resistance were identified in 10 pol gene sequences (9.9%), all of them were present in the HIV-1 sequences obtained from persons receiving antiretroviral therapy. CONCLUSIONS: Lack of drug-resistant viruses among treatment-naive Silesian patients HIV-1 infected before the year 2004 may indicate that there was no transmission of the drug-resistant viruses in the studied population to that time. PMID- 21278686 TI - PSA mass as a marker of prostate cancer progression after radical prostatectomy. AB - BACKGROUND: Obese patients with prostate cancer may have lower preoperative PSA concentration due to hemodilution. Lower PSA concentration may falsely affect assessing the risk of progression after radical prostatectomy (RP). The aim of this study was to determine preoperative PSA mass as the absolute amount of PSA protein secreted into circulation, and evaluation of its usefulness in prediction of biochemical recurrence after RP. MATERIAL/METHODS: 177 patients after RP due to prostate cancer were included in the study. On the basis of formulas, PSA mass was calculated {PSA mass [ug] = (weight [kg])0.425 * (height [cm])0.72 * 0.007184 * 1.670 * PSA concentration [ng/ml]}. Patients were divided into 3 groups according to increasing values of PSA mass. The following features were assessed and compared between these groups (chi-square test): pathologic stage T3, nodal metastases, positive surgical margins, biochemical and local recurrence and the rate of death. Cancer-specific survival was assessed depending on PSA mass (Kaplan-Meier curves with log rank test). The usefulness of PSA mass in prediction of biochemical recurrence was compared with PSA concentration (logistic regression with ROC curves). RESULTS: Pathologic stage T3, nodal metastases, positive surgical margins and progression were more common in patients with higher levels of PSA mass (p<0.01). Cancer-specific survival was significantly shorter in patients with elevated values of PSA mass (p=0.02). Preoperative PSA mass was a more sensitive predictor of biochemical recurrence than was PSA concentration (p=0.04). CONCLUSIONS: The preoperative PSA mass is a better predictor of biochemical recurrence after RP than PSA concentration. PMID- 21278685 TI - Phenotypic and genotypic study of macrolide, lincosamide and streptogramin B (MLSB) resistance in clinical isolates of Staphylococcus aureus in Tehran, Iran. AB - BACKGROUND: Resistance to antimicrobial agents among Staphylococcus aureus is an increasing problem. Two common genes responsible for resistance to macrolide, lincosamide and streptogramin B (MLSB) antibiotics are the ermA and ermC genes. Three resistance phenotypes have been detected to these antibiotics: strains containing cMLSB (constitutive MLSB) and iMLSB (inducible MLSB), which are resistant to macrolide, lincosamide and streptogramin B antibiotics, and MS, which is only resistant to macrolide and streptogramin B antibiotics. The aim of this study was to determine the prevalence of MLSB phenotypes and genotypes in erythromycin-resistant strains of S. aureus isolated from patients in 4 university hospitals in Tehran, Iran. MATERIAL/METHODS: S. aureus strains were isolated from various clinical specimens and identified by routine phenotypic methods and PCR for nuc gene. Erythromycin resistance was determined by disk diffusion testing. Prevalence of MLSB phenotypes was determined by use of the D test. ermA and ermC genes were detected by PCR. RESULTS: Altogether, 126 erythromycin-resistant strains of S. aureus were detected. Prevalence of cMLSB, iMLSB and MS resistance phenotypes were 92.8%, 6.4%, and 0.8%, respectively; 60.3% of strains had ermA gene and 54.8% ermC gene; 61 strains (48.4%) contained 2 studied erm genes and 42 strains (33.3%) did not have any studied erm genes. CONCLUSIONS: Due to the high prevalence of clindamycin resistance among S. aureus isolated from patients in Iran, we recommend clindamycin therapy only after proper antimicrobial susceptibility testing.
PMID- 21278687 TI - A descriptive analysis of abnormal postural patterns in children with hemiplegic cerebral palsy. AB - BACKGROUND: Functional classification systems generally divide children with cerebral palsy (CP) into mild, moderate, and severe types. Although depending on functional limitations, they do not seem to evaluate abnormal postural patterns in standing. Since the most asymmetrical patterns can be observed in hemiplegia, the goal of this case series study was to provide their objective analysis and to establish any potential clinical value for evaluation and management of CP. MATERIAL/METHODS: A group of 36 children (aged 5-10 years) with spastic hemiplegic CP, who could stand and ambulate independently, were selected. The photogrammetric and pedobarographic studies were obtained for the postural analysis in standing. RESULTS: Two different anti- and pro- gravitational postural patterns were identified. They seem not only to affect functional status and rehabilitation potential, but also clinical value for evaluation and management of CP hemiplegia. CONCLUSIONS: The importance of strong study design cannot be overemphasized. The 2 different postural patterns indicate dissimilar compensatory tendencies, which may help in prognosis of deformity and functional outcomes of rehabilitation. The use of objective photogrammetric and the pedobarographic studies may also help to develop a more specific therapeutic intervention in order to facilitate the pattern leading towards better outcome (orthosis in the anti-gravitational postural pattern vs focal spasticity management in the pro-gravitational postural pattern). PMID- 21278688 TI - Lack of effect of the CD14 promoter gene C-159T polymorphism on nutritional status parameters in hemodialysis patients. AB - BACKGROUND: CD14 is a membrane glycoprotein that acts as a co-receptor for the detection of bacterial lipopolysaccharide (LPS). Mutual interaction between CD14 and LPS plays an important role in the innate immune system. Increased serum soluble CD14 levels have been described in hemodialysis (HD) patients, and linked to increased mortality risk, inflammation and protein-energy wasting. The expression of CD14 may be influenced by CD14 promoter gene C-159T polymorphism. This study aimed to clarify the possible association between CD14 promoter gene C 159T polymorphism and nutritional status in hemodialysis patients. MATERIAL/METHODS: The study population consisted of 185 (104 males; 81 females) long-term HD patients treated in 5 dialysis centers. The control group consisted of 112 apparently healthy volunteers (32 males and 80 females). Nutritional status was assessed using a modified SGA scale, and anthropometric methods (BMI, WHR, waist, hip and mid-arm circumferences, biceps, triceps, subocular and subscapular skinfolds). Biochemical parameters evaluated included: CRP, albumin, creatinine, urea, cholesterol, triglycerides and TIBC. CD14 promoter gene C-159T polymorphism was determined by restriction fragment length polymorphism, after digestion of the PCR product with Hae III restriction endonuclease. RESULTS: Genotype and allele frequencies were similar to controls and compliant with Hardy Weinberg equilibrium. No between-group differences were detected in measured variables with the exception of lower triglyceride levels in carriers of C allele in comparison to TT genotype. CONCLUSIONS: CD14 promoter gene C-159T polymorphism does not seem to be associated with nutritional status parameters in HD patients. It does seem, however, to influence triglyceride blood levels. PMID- 21278689 TI - Determination of comprehensive arterial blood inflow in abdominal-pelvic organs: impact of respiration and posture on organ perfusion. AB - BACKGROUND: Arterial blood flow (BF) to all abdominal-pelvic organs (AP) shows potential for an indicator of comprehensive splanchnic organ circulation (reservoir of blood supply for redistribution) in cardiovascular disease, hepato gastrointestinal disease or hemodynamic disorders. Our previous assessment of splanchnic hemodynamics, as magnitude of BFAP [measuring by subtracting BF in both femoral arteries (FAs) from the upper abdominal aorta (Ao) above the celiac trunk] using Doppler ultrasound, was reported as the relationship between Ao and FAs, day-to-day variability and response to exercise. For accurate determination of BFAP, it is important to consider the various factors that potentially influence BFAP. However, little information exists regarding the influence of respiration (interplay between inspiration and expiration) and posture on BFAP. MATERIAL/METHODS: Ten healthy males were evaluated in sitting/supine positions following a 12 hr fast. Magnitude of BFAP was determined as measurement of Ao and FAs hemodynamics (blood velocity and vessel diameter) using pulsed Doppler with spectral analysis during spontaneous 4-sec inspiration/4-sec expiration phases. RESULTS: BF/blood velocity in the Ao and FAs showed significant lower in inspiration than expiration. BFAP showed a significant (P<0.005) reduction of ~20% in inspiratory phase (sitting, 2213 +/- 222 ml/min; supine, 2059 +/- 215 ml/min) compared with expiratory phase (sitting, 2765 +/- 303 ml/min; supine, 2539 +/- 253 ml/min), with no difference between sitting and supine. CONCLUSIONS: Respiratory-related to alterations in BFAP were observed. It may be speculated that changes in intra-abdominal pressure during breathing (thoracic-abdominal movement) is possibly reflecting transient changes in blood velocity in the Ao and FAs. Respiratory effects should be taken into account for evaluation of BFAP. PMID- 21278690 TI - Longitudinal trends with improvement in quality of life after TVT, TVT O and Burch colposuspension procedures. AB - BACKGROUND: Comparison of the quality of life (QoL) trends after TVT, TVT O and Burch colposuspension (BCS) procedures and comparison of long-term subjective and objective outcomes. MATERIAL/METHODS: The study included 215 women who underwent a TVT, TVT O or BCS procedure. We monitored QoL after each procedure and the effect of complications on the QoL as assessed by the IQOL questionnaire over a 3 year period. RESULTS: The study was completed by 74.5% of women after TVT, 74.5% after TVT O, and 65.2% after BCS procedure. In the long-term, the QoL improved from 46.9 to 88.7 and remained stable after BCS; after TVT and TVT O, it declined, but only after TVT O was the decline statistically significant compared to BCS. The IQOL for women with post-operative complications has a clear descending tendency. The effect of the complications is highly significant (p<0.001). Only the OAB complication had a statistically significant effect on QoL p<0.001. Preexistent OAB does not negatively affect postoperative results of anti-incontinence surgery. CONCLUSIONS: There was a statistically significant decline with the longitudinal values of IQOL with TVT O, but not with TVT or BCS. Anti-incontinence operations significantly improve quality of life for women with MI, but compared to the SI group, the quality of life is worse when measured at a longer time interval after the operation. Anti-incontinence operations significantly improve quality of life, and the difference in preoperative status in the long-term follow-up is demonstrable. PMID- 21278691 TI - Endothelial function and left ventricular remodeling in diabetic and non-diabetic patients after acute coronary syndrome. AB - BACKGROUND: Endothelial dysfunction is an independent predictor of future cardiac events. MATERIAL/METHODS: We evaluated the relationship between flow-mediated dilation (FMD) in brachial artery and coronary risk factors in 93 patients (70 males, mean age: 62 +/- 8 years) with ACS treated with primary angioplasty (PCI). The patients were divided into 2 subgroups: 43 patients with diabetes mellitus type 2 (DM) and 50 non-diabetics (non-DM). Patients were examined on the 3rd day after ACS and after 6 months. FMD on the 3rd day were significantly lower in DM than in non-DM (5.8 +/- 2.2% vs. 8.8 +/- 4.9%, p=0.0007) and after 6 months (6.2 +/- 2.6% vs. 9.4 +/- 4.4%, p<0.0001). It was also observed that the improvement of FMD in both groups after a 6-month follow-up inversely correlated with the increase of left ventricular end-diastolic volume (LVEDV) (r=-0.41, p<0.001). RESULTS: There was an inverse relationship between FMD and age (r=-0.26, p<0.01), BMI (r=-0.26, p<0,005), total cholesterol (r=-0.56, p<0.001) and LDL cholesterol (r=-0.53, p<0.001). There was no relationship between triglycerides, hypertension and history of smoking. In the DM group, FMD negatively correlated with HbA1c (r= 0.68, p<0.001). Restenosis rate was significantly higher in the DM group (19% vs. 6%, p<0.001) but there was no relationship between FMD and restenosis. CONCLUSIONS: Impaired FMD is more significant in diabetics than in non-diabetic patients with ACS. Lack of improvement of FMD after acute coronary syndrome can be a predictor of detrimental left ventricular remodeling in patients with ACS. PMID- 21278692 TI - Total hip arthroplasty in advanced osteonecrosis: the short-term results by metal on-metal hip resurfacing. AB - BACKGROUND: Characteristically, osteonecrosis affects younger patients who typically refer to the orthopedic surgeon for the first time in the third to fifth decades of life, in the late stages of the disease. Femoral metal-on-metal hip resurfacing is as an alternative to conventional total hip arthroplasty in treating osteoarthritis of the hip. Since there are already many reports regarding the successful outcome of resurfacing in advanced osteoarthritis, the purpose of this study was to analyze the clinical outcomes of this procedure in patients with osteonecrosis of the femoral head and to compare them with a matched group of patients with osteoarthritis. MATERIAL/METHODS: This retrospective cohort study evaluated a consecutive series of 52 patients with end stage osteonecrosis (28 patients) and osteoarthritis (24 patients) of the femoral head, managed by metal-on-metal hip resurfacing in a referral orthopedic center from Feb 2002 to May 2007. Pain, function and deformity were evaluated with the use of the Harris hip score after the operation. Patients were clinically followed for a mean of 41 months. RESULTS: The patients in the osteoarthritis group had a significantly higher mean age than those in the osteonecrosis group (47.88 +/- 12.6 vs 30.86 +/- 7.5, p=0.003). The clinical outcomes were similar for both groups. There was no significant difference in mean Harris hip score (p=0.347) and hip joint range of motion (p=0.346) between osteonecrosis and osteoarthritis groups after surgery. CONCLUSIONS: On the basis of these initial findings, we recommend MOM resurfacing as a viable treatment option for patients with advanced stages of osteonecrosis. PMID- 21278693 TI - Brace and deformity-related stress level in females with adolescent idiopathic scoliosis based on the Bad Sobernheim Stress Questionnaires. AB - BACKGROUND: Psychopathological symptoms occur more often in chronically ill patients than in healthy populations. The aim of this study was to analyze the associations between different types of treatment and stress levels. MATERIAL/METHODS: The study group consisted of 69 females, of whom 35 were treated conservatively with a Cheneau brace; the other 34 subjects were treated operatively and, after correction of scoliosis with thoracoplasty, wore a brace for 12 weeks during the postoperative period. Patients completed the Polish versions of the Bad Sobernheim Stress Questionnaire-Deformity and the Bad Sobernheim Stress Questionnaire-Brace. RESULTS: Patients who were treated surgically felt a moderate level of stress connected with wearing the brace and with body deformation. The group treated conservatively felt moderate stress connected with wearing the brace, but a low level of stress in relation to body deformation. The groups differed significantly statistically in the level of stress felt regarding body deformation (p=0.004). In the group treated conservatively, the correlation between the level of stress, the age at which treatment was initiated, and degree of apical translation proved to be significant. CONCLUSIONS: Patients treated surgically in comparison with patients treated conservatively report higher stress levels connected with body deformation. A higher level of stress depends on the degree of trunk deformation on the frontal plane; stress is also higher in patients who begin conservative treatment at a later age. PMID- 21278694 TI - The diameter of the ileal J-pouch-anal anastomosis as an important risk factor of pouchitis - clinical observations. AB - BACKGROUND: Patients' quality of life after restorative proctocolectomy depends on the potential complications. Stricture of the ileal pouch-anal anastomosis is one of the complications following restorative proctocolectomy. MATERIAL/METHODS: We analyzed the correlation between the diameter of the anastomosis and clinical parameters, including pouchitis disease activity index (PDAI), the activity of fecal M2-pyruvate kinase and maximum tolerable volume of the pouch. The study group consisted of 31 patients in whom covering ileostomy had been closed 72 +/- 50 months before enrolement to the study. Restorative proctocolectomy for ulcerative colitis or familial adenomatous polyposis coli had been performed in this group. RESULTS: The study did not show any correlation between the diameter of the anastomosis and primary indication for surgery, the time elapsed after restoration of the bowel continuity, the activity of fecal M2-pyruvate kinase, or maximum tolerable volume. However, meaningful correlations between the stricture of the anastomosis and the presence and activity of pouchitis, together with the ileal villi atrophy, were detected. CONCLUSIONS: Stricture of the anastomosis appears to be an important factor increasing the incidence of pouchitis, and is independent of the underlying condition and time after the operation. Dilation of the anastomosis and prevention of stricture should constitute a permanent element of postoperative follow-up. PMID- 21278695 TI - Birth after cesarean section. AB - BACKGROUND: The number of incoming expectant women who have previously experienced cesarean section has increased. This work sought to find the frequency and connections between vaginal deliveries, cesarean sections, and iterative cesarean sections from 2004 to 2008. MATERIAL/METHODS: In all, 828 women with previous cesarean sections were included. From this group, 8282 vaginal deliveries were performed. During these years, 828 women had a history of the cesarean section; in these women, iterative cesarean sections were indicated. To evaluate knowledge of educational material designed for women being prepared for the iterative delivery, we used information compiled on experience from 2002 to 2003; the same approach was used to evaluate the nursing process on interventions and diagnoses of cesarean sections. RESULTS: From 2004 to 2008, 11 279 deliveries were performed in the Perinatological Center in Ceske Budejovice; this was significant (P<.001). The same result was obtained in the relation for the total number of deliveries and those performed by the iterative cesarean section. The number of iterative cesarean sections in women who had already experienced the cesarean section (828) and delivered by cesarean section again is 620. Other data were not significant. Only 2 to 3 pregnancies next to the first cesarean section were statistically significant in 2004 and 2005. CONCLUSIONS: If a trial of labor after cesarean does not proceed to vaginal birth, the woman will need support and encouragement to express feelings about another cesarean birth. PMID- 21278696 TI - Metastatic renal cell carcinoma diagnosed by capsule endoscopy and double balloon endoscopy. AB - BACKGROUND: Renal cell carcinoma commonly metastasizes to lung, liver, and bone. Small intestinal metastases are exceedingly rare. CASE REPORT: A 75-year-old man presented at our hospital with tarry stools. He had undergone a right nephrectomy for renal cell carcinoma (RCC) 6 years previously; in addition, he had received antiplatelet treatment for ischemic heart disease. Esophagogastroduodenoscopy, total colonoscopy, and computed tomography did not identify any cause for the gastrointestinal bleeding. He underwent capsule endoscopy (CE), which revealed an ulcerated submucosal tumor in the jejunum. We performed a double-balloon endoscopy (DBE), and histological findings identified a clear cell carcinoma. We diagnosed metastasis from the RCC. We performed a jejunectomy to resect the tumor and thus eliminate the source of the bleeding. CONCLUSIONS: CE and DBE are useful diagnostic tools. We recommend investigating the possibility of small intestinal metastases in cases of intestinal bleeding or anemia in patients with a history of malignant tumor. PMID- 21278697 TI - A case of "borrowed identity syndrome" after severe traumatic brain injury. AB - BACKGROUND: It is well known that traumatic brain injury often changes the way the patient perceives reality, which often means a distortion of the perception of self and the world. The purpose of this article is to understand the processes of identity change after traumatic brain injury. CASE REPORT: We describe progressive deterioration in personal identity in a former physician who had sustained a serious head injury (1998), resulting in focal injuries to the right frontal and temporal areas. He regained consciousness after 63 days in coma and 98 days of post-traumatic amnesia, but has since displayed a persistent loss of autobiographical memory, self-image, and emotional bonds to family and significant others. Qualitative 'life-story' interviewing was undertaken to explore the mental state of a patient whose subjective, "first person" identity has been disengaged, despite the retention of significant amounts of objective, "third person" information about himself and his personal history (though this was also lost at a later stage in the patient's deterioration). Identity change in our patient was characterized by a dynamic and convoluted process of contraction, expansion and tentative balance. Our patient tends to cling to the self of others, borrowing their identities at least for the period he is able to remember. Identity is closely connected with the processes of memory. CONCLUSIONS: The results will be examined in relation to the microgenetic theory of brain function. The brain mechanisms that may account for these impairments are discussed. Findings from this study have important implications for the delivery of person-focused rehabilitation. PMID- 21278698 TI - Evaluation of the accuracy of manual and automatic scoring of a single airflow channel in patients with a high probability of obstructive sleep apnea. AB - BACKGROUND: ApneaLink (AL) is a single-channel type-4 device that measures airflow. A limited number of studies have assessed AL's usefulness in diagnosing obstructive sleep apnea (OSA) using automated scoring alone. This study was conducted to assess the sensitivity and specificity of AL in a selected group of people with clinical suspicion of OSA, using both automatic and manual scoring and comparing the results with those obtained for polysomnography (PSG). MATERIAL/METHODS: Simultaneous overnight recordings of in-laboratory PSG and AL were performed for 95 patients (mean age 46.3 +/- 12.6 yr) with a high clinical suspicion of OSA. PSG was scored manually according to the American Academy of Sleep Medicine (AASM) guidelines. AL data were analyzed automatically using a manufacturer-provided computerized algorithm. Manual scoring of the AL flow signal followed the AASM guidelines for reduction in flow. RESULTS: The mean apnea hypopneas index (AHI) for PSG was 34.1 +/- 32.4/hr. The AL Auto-AHI was 20.1 +/- 25.2/h, and the AL Manual-AHI was 39.5 +/- 30.4/h. The Pearson correlation coefficients were r=0.883 between PSG-AHI and AL Auto-AHI, and r=0.966 between PSG-AHI and AL Manual-AHI. At AHIs of 5, 10, 15, and 30, the AL Auto sensitivity/specificity was 0.79/0.68, 0.70/0.89, 0.64/0.94 and 0.63/0.98, and the AL Manual sensitivity/specificity was 1.00/0.43, 1.00/0.56, 0.98/0.58 and 1.00/0.80. CONCLUSIONS: Combining auto and manual scoring of data (automatic scoring followed by manual scoring) recorded by single-channel ApneaLink provides good diagnostic agreement with conventional PSG recordings. PMID- 21278699 TI - A modified Matti-Russe technique for the treatment of scaphoid waist non-union and pseudarthrosis. AB - BACKGROUND: The aim of this study was to analyze the long-term results of a modified Matti-Russe technique for the treatment of scaphoid non-union and pseudarthrosis. The modification was based on the use of bone graft taken from the ipsilateral distal radius, rather than from the iliac crest, as originally described. MATERIAL/METHODS: Between 1987 and 2000, 23 consequent male patients with scaphoid waist non-union or pseudarthrosis underwent surgery by a modified Matti-Russe technique. During the 5-year follow-up, patient evaluation was based on radiological findings and the Green and O'Brien scoring system. RESULTS: Anatomy was restored and healing of the non-union was achieved in 21 (91.3%) patients. The other 2 patients failed to achieve union and underwent the same operation a second time, which was successful. According to the Green and O'Brien scoring system, 82.6% (19/23) of patients showed excellent results and 17.4% (4/23) showed good results at 2-year follow-up. At 5-year follow-up, 73.9% of patients (19/23) had excellent results and 26.0% (4/23) had good results. No early post-operative complications developed. Two patients demonstrated mild radiological radio-scaphoid arthritis at 2.5 years postoperatively. All patients returned to previous levels of activity. CONCLUSIONS: The standard Matti-Russe technique is an old but reliable and inexpensive method for the treatment of long standing or neglected scaphoid non-unions or pseudarthroses. The modification of this established method, based on use of the distal radius as a donor site, reduces operative time, can be performed through a single approach, does not show donor site morbidity, and allows the use of regional anaesthesia. PMID- 21278700 TI - Determination of pain intensity risk factors among school children with nonspecific low back pain. AB - BACKGROUND: Low back pain (LBP) is a common disease among people under the age of 20. To the best of our knowledge few studies have been carried out on LBP among school children in Turkey, and none of them studied the correlation between pain intensity and related variables with LBP. MATERIAL/METHODS: This cross-sectional study was carried out to investigate the risk factors and their correlations with pain intensity among 222 school children (106 girls and 116 boys) aged 10-18 years in the city of Denizli. A self-reported questionnaire was used to collect the data. The regression tree method (RTM) was used to determine the risk factors by using the STATISTICA program package. Pain intensity was the outcome variable, and 8 independent variables (body mass index (BMI), sex, regular exercise habit, studying posture, transportation to/from school, duration of studying, bag handling, and type of bed) were used to detect their effect on pain intensity. RESULTS: The results showed that pain intensity is significantly affected by 4 independent variables: duration of studying, type of bed, transportation to/from school, and BMI. The overall mean and standard deviation of pain intensity was 2.58 +/- 0.86 (minimum=1, maximum=5). CONCLUSIONS: Results from the literature, as well as our study, show that taking parents' and teachers' concerns seriously is of vital importance. Our results indicate that parents and teachers should be informed about duration of studying, type of bed, transportation and obesity as risk factors predicting NLBP in school children. PMID- 21278701 TI - The incidence of hepatocellular carcinoma associated with hepatitis C infection decreased in Kyushu area. AB - BACKGROUND: The incidence of hepatocellular carcinoma (HCC) in Japan has still been increasing. The aim of the present study was to analyze the epidemiological trend of HCC in the western area of Japan, Kyushu. MATERIAL/METHODS: A total of 10,010 patients with HCC diagnosed between 1996 and 2008 in the Liver Cancer study group of Kyushu (LCSK), were recruited for this study. Cohorts of patients with HCC were categorized into five year intervals. The etiology of HCC was categorized to four groups as follows; B: HBsAg positive, HCV-RNA negative, C: HCV-RNA positive, HBsAg negative, B+C: both of HBsAg and HCV-RNA positive, nonBC: both of HBsAg and HCV-RNA negative. RESULTS: B was 14.8% (1,485 of 10,010), whereas 68.1% (6,819 of 10,010) had C, and 1.4% (140 of 10,010) had HCC associated with both viruses. The remaining 1,566 patients (15.6%) did not associate with both viruses.
Cohorts of patients with HCC were divided into six-year intervals (1996-2001 and 2002-2007). The ratio of C cases decreased from 73.1% in 1996-2001 to 64.9% in 2002-2007. On the other hand, B and -nonBC cases increased significantly from 13.9% and 11.3% in 1996-2001 to 16.2% and 17.6% in 2002-2007, respectively. CONCLUSIONS: The incidence of hepatocellular carcinoma associated with hepatitis C infection decreased after 2001 in Kyushu area. This change was due to the increase in the number and proportion of the HCC not only nonBC patients but also B patients. PMID- 21278702 TI - Review of the randomized clinical stroke rehabilitation trials in 2009. AB - BACKGROUND: Recent review of the available evidence on interventions for motor recovery after stroke, showed that improvements in recovery of arm function were seen for constraint-induced movement therapy, electromyographic biofeedback, mental practice with motor imagery, and robotics. Similar improvement in transfer ability or balance were seen with repetitive task training, biofeedback, and training with a moving platform. Walking speed was improved by physical fitness training, high-intensity physiotherapy and repetitive task training. However, most of these trials were small and had design limitations. MATERIAL/METHODS: In this article, randomized control trials (RCT's) published in 2009 of rehabilitation therapies for acute (<= 2 weeks), sub-acute (2 to 12 weeks) and chronic (>= 12 weeks) stroke was reviewed. A Medline search was performed to identify all RCT's in stroke rehabilitation in the year 2009. The search strategy that was used for PubMed is presented in the Appendix 1. The objective was to examine the effectiveness of these treatment modalities in stroke rehabilitation. RESULTS: This generated 35 RCT's under 5 categories which were found and analyzed. The methodological quality was assessed by using the PEDro scale for external and internal validity. CONCLUSIONS: These trials were primarily efficacy studies. Most of these studies enrolled small numbers of patient which precluded their clinical applicability (limited external validity). However, the constraint induced movement therapy (CIT), regularly used in chronic stroke patients did not improve affected arm-hand function when used in acute stroke patients at <= 4 weeks. Intensive CIT did not lead to motor improvement in arm-hand function. Robotic arm treatment helped decrease motor impairment and improved function in chronic stroke patients only. Therapist provided exercise programs (when self administered by patients during their off-therapy time in a rehabilitation setting) did improve arm-hand function. Tai Chi exercises helped improve balance and weight bearing. Exercise programs for community dwelling stroke patient helped maintain and even improve their functional state. PMID- 21278703 TI - Roles of the nitric oxide signaling pathway in cardiac ischemic preconditioning against myocardial ischemia-reperfusion injury. AB - Nitric oxide (NO), a vasoactive gas that can freely diffuse into the cell, has many physiological effects in various cell types. Since 1986, numerous studies of ischemic preconditioning against ischemia-reperfusion (I/R) injury have been undertaken and the roles of the NO signaling pathway in cardioprotection have been explored. Many studies have confirmed the effect of NO and that its relative signaling pathway is important for preconditioning of the cardioprotective effect. The NO signaling against I/R injury targeted on the mitochondria is believed to be the end-target for cardioprotection. If the NO signaling pathway is disrupted or inhibited, cardioprotection by preconditioning disappears. During preconditioning, signaling is initiated from the sarcolemmal membrane, and then spread into the cytoplasm via many series of enzymes, including nitric oxide synthase (NOS), the NO-producing enzyme, soluble guanylyl cyclase (sGC), and protein kinase G (PKG). Finally, the signal is transmitted into the mitochondria, where the cardioprotective effect occurs. It is now well established that mitochondria act to protect the heart against I/R injury via the opening of the mitochondrial ATP-sensitive K+ channel and the inhibition of mitochondrial permeability transition (MPT). This knowledge may be useful in developing novel strategies for clinical cardioprotection from I/R injury. PMID- 21278704 TI - Hepatic encephalopathy: an updated approach from pathogenesis to treatment. AB - One of the most serious complications of chronic or fulminant liver failure is hepatic encephalopathy (HE), associated most commonly with cirrhosis. In the presence of chronic liver disease, HE is a sign of decompensation, while in fulminant liver failure its development represents a worrying sign and usually indicates that transplantation will be required. Despite the significance of HE in the course of liver disease, the progress in development of new therapeutic options has been unremarkable over the last 20 years. An up-to-date review regarding HE, including both research and review articles. HE is a serious and progressive, but potentially reversible, disorder with a wide spectrum of neuropsychiatric abnormalities and motor disturbances that ranges from mild alteration of cognitive and motor function to coma and death. Although a clear pathogenesis is yet to be determined, elevated ammonia in serum and the central nervous system is the mainstay for pathogenesis and treatment of HE. Management includes early diagnosis and prompt treatment of precipitating factors. Clinical trials and extensive clinical experience have established the efficacy of diverse substances in HE treatment. Novel therapies with clinical promise include: L ornithine L-aspartate, sodium benzoate, phenylacetate, AST-120, and the molecular adsorbent recirculating system. Eventually, liver transplantation is often the most successful long-term therapy for HE. PMID- 21278705 TI - The minimally-invasive thyroidectomy incision: a histological analysis. AB - BACKGROUND: Minimally invasive thyroidectomy (MIT) has gained popularity in the surgical management of benign and malignant pathology of the thyroid. One of the main benefits of utilizing this technique is the use of smaller incisions resulting in increased cosmetic satisfaction. Unfortunately, the retraction required for adequate exposure during MIT may lead to skin damage, impaired wound healing and poor cosmetic outcomes. Some have proposed that excising incision edges prior to closure may improve cosmesis. A review of the literature does not reveal any histologic evidence to support this technique. MATERIAL/METHODS: In this prospective observational study, nine subjects undergoing MIT were identified. Both the superior and inferior skin edges were excised and labeled for orientation. Specimens were sent for hematoxylin and eosin staining and histologic analysis by a staff pathologist. RESULTS: All specimens showed no significant findings such as damage to the architecture of the dermis, acute inflammation, edema or evidence of hemorrhage. Focal blood vessel ectasia within the dermis was identified in three of nine subjects. CONCLUSIONS: Our findings do not yield a histological basis supporting the routine trimming of incisions during MIT. Although no significant findings were noted histologically, further studies are warranted to investigate the long-term cosmetic outcome of MIT incisions. PMID- 21278706 TI - Polyglutamine Atrophin provokes neurodegeneration in Drosophila by repressing fat. AB - Large alterations in transcription accompany neurodegeneration in polyglutamine (polyQ) diseases. These pathologies manifest both general polyQ toxicity and mutant protein-specific effects. In this study, we report that the fat tumour suppressor gene mediates neurodegeneration induced by the polyQ protein Atrophin. We have monitored early transcriptional alterations in a Drosophila model of Dentatorubral-pallidoluysian Atrophy and found that polyQ Atrophins downregulate fat. Fat protects from neurodegeneration and Atrophin toxicity through the Hippo kinase cascade. Fat/Hippo signalling does not provoke neurodegeneration by stimulating overgrowth; rather, it alters the autophagic flux in photoreceptor neurons, thereby affecting cell homeostasis. Our data thus provide a crucial insight into the specific mechanism of a polyQ disease and reveal an unexpected neuroprotective role of the Fat/Hippo pathway. PMID- 21278707 TI - Controlled and stochastic retention concentrates dynein at microtubule ends to keep endosomes on track. AB - Bidirectional transport of early endosomes (EEs) involves microtubules (MTs) and associated motors. In fungi, the dynein/dynactin motor complex concentrates in a comet-like accumulation at MT plus-ends to receive kinesin-3-delivered EEs for retrograde transport. Here, we analyse the loading of endosomes onto dynein by combining live imaging of photoactivated endosomes and fluorescent dynein with mathematical modelling. Using nuclear pores as an internal calibration standard, we show that the dynein comet consists of ~55 dynein motors. About half of the motors are slowly turned over (T(1/2): ~98 s) and they are kept at the plus-ends by an active retention mechanism involving an interaction between dynactin and EB1. The other half is more dynamic (T(1/2): ~10 s) and mathematical modelling suggests that they concentrate at MT ends because of stochastic motor behaviour. When the active retention is impaired by inhibitory peptides, dynein numbers in the comet are reduced to half and ~10% of the EEs fall off the MT plus-ends. Thus, a combination of stochastic accumulation and active retention forms the dynein comet to ensure capturing of arriving organelles by retrograde motors. PMID- 21278708 TI - Linkage between the bacterial acid stress and stringent responses: the structure of the inducible lysine decarboxylase. AB - The Escherichia coli inducible lysine decarboxylase, LdcI/CadA, together with the inner-membrane lysine-cadaverine antiporter, CadB, provide cells with protection against mild acidic conditions (pH~5). To gain a better understanding of the molecular processes underlying the acid stress response, the X-ray crystal structure of LdcI was determined. The structure revealed that the protein is an oligomer of five dimers that associate to form a decamer. Surprisingly, LdcI was found to co-crystallize with the stringent response effector molecule ppGpp, also known as the alarmone, with 10 ppGpp molecules in the decamer. ppGpp is known to mediate the stringent response, which occurs in response to nutrient deprivation. The alarmone strongly inhibited LdcI enzymatic activity. This inhibition is important for modulating the consumption of lysine in cells during acid stress under nutrient limiting conditions. Hence, our data provide direct evidence for a link between the bacterial acid stress and stringent responses. PMID- 21278710 TI - FTO gene polymorphisms are associated with obesity and type 2 diabetes in East Asian populations: an update. PMID- 21278712 TI - Predialysis chronic kidney disease in 2010: Novel targets for slowing CKD progression. AB - Several 2010 trials have provided novel information on how best to manage patients with predialysis chronic kidney disease (CKD). Armed with these new findings, nephrologists can find new means of slowing CKD progression by targeting blood-pressure control, acidosis and serum uric acid levels. PMID- 21278713 TI - End-stage renal disease in 2010: Timing of dialysis initiation and choice of dialysis modality. AB - Few, if any, doubt that renal transplantation should be the first choice of renal replacement therapy whenever this option is possible. But, at which level of remaining kidney function should patients start on dialysis and which dialysis modality should be used? Several studies published in 2010 addressed these questions and will influence dialysis initiation strategies worldwide for years to come. PMID- 21278714 TI - End-stage renal disease in 2010: Innovative approaches to improve outcomes in transplantation. AB - Renal transplantation offers the potential for improved quality and length of life to patients with end-stage renal disease; however, graft rejection and immunosuppression-related toxicities can hamper the effectiveness of this therapy. Seminal publications from 2010 have addressed these obstacles, and provide insight into new and innovative approaches to improve outcomes in renal transplant recipients. PMID- 21278715 TI - Acute kidney injury in 2010: Advances in diagnosis and estimating disease prognosis. AB - Acute kidney injury (AKI) is a serious complication associated with morbidity and mortality. Studies from 2010 have provided insights into the diagnosis and clinical course of AKI, the ability of novel biomarkers to guide therapy, and the quality of life of survivors of severe AKI. It is hoped that these findings will lead to improvements in the diagnosis and prognosis of affected individuals. PMID- 21278716 TI - Diabetic nephropathy in 2010: Alleviating the burden of diabetic nephropathy. AB - Many patients with diabetic nephropathy progress to end-stage renal disease. New research in disease detection, diagnosis, and novel treatments will hopefully alleviate the burden of diabetic nephropathy in the future. PMID- 21278717 TI - Hypertension in 2010: Blood pressure and the kidney. AB - 2010 saw the publication of a number of papers that provide new information on the relationship between blood pressure and the kidney. The data reinforce the need for future studies to jointly consider cardiovascular and renal outcomes. PMID- 21278718 TI - Pathophysiology and management of hypokalemia: a clinical perspective. AB - Potassium (K(+)) ions are the predominant intracellular cations. K(+) homeostasis depends on external balance (dietary intake [typically 100 mmol per day] versus excretion [95% via the kidney; 5% via the colon]) and internal balance (the distribution of K(+) between intracellular and extracellular fluid compartments). The uneven distribution of K(+) across cell membranes means that a mere 1% shift in its distribution can cause a 50% change in plasma K(+) concentration. Hormonal mechanisms (involving insulin, beta-adrenergic agonists and aldosterone) modulate K(+) distribution by promoting rapid transfer of K(+) across the plasma membrane. Extrarenal K(+) losses from the body are usually small, but can be marked in individuals with chronic diarrhea, severe burns or prolonged sweating. Under normal circumstances, the kidney's distal nephron secretes K(+) and determines final urinary excretion. In patients with hypokalemia (plasma K(+) concentration <3.5 mmol/l), after the exclusion of extrarenal causes, alterations in sodium ion delivery to the distal nephron, mineralocorticoid status, or a specific inherited or acquired defect in distal nephron function (each of which affects distal nephron K(+) secretion), should be considered. Clinical management of hypokalemia should establish the underlying cause and alleviate the primary disorder. This Review aims to inform clinicians about the pathophysiology and appropriate treatment for hypokalemia. PMID- 21278719 TI - Resources for proteomics in mouse embryonic stem cells. PMID- 21278720 TI - Data transformation practices in biomedical sciences. PMID- 21278722 TI - Five challenges to bringing single-molecule force spectroscopy into living cells. AB - In recent years, single-molecule force spectroscopy techniques have been used to study how inter- and intramolecular interactions control the assembly and functional state of biomolecular machinery in vitro. Here we discuss the problems and challenges that need to be addressed to bring these technologies into living cells and to learn how cellular machinery is controlled in vivo. PMID- 21278723 TI - Unrestrained worms bridled by the light. PMID- 21278724 TI - New approaches to modeling complex biochemistry. PMID- 21278725 TI - A new way to look at fat. PMID- 21278726 TI - Habenular alpha5 nicotinic receptor subunit signalling controls nicotine intake. AB - Genetic variation in CHRNA5, the gene encoding the alpha5 nicotinic acetylcholine receptor subunit, increases vulnerability to tobacco addiction and lung cancer, but the underlying mechanisms are unknown. Here we report markedly increased nicotine intake in mice with a null mutation in Chrna5. This effect was 'rescued' in knockout mice by re-expressing alpha5 subunits in the medial habenula (MHb), and recapitulated in rats through alpha5 subunit knockdown in MHb. Remarkably, alpha5 subunit knockdown in MHb did not alter the rewarding effects of nicotine but abolished the inhibitory effects of higher nicotine doses on brain reward systems. The MHb extends projections almost exclusively to the interpeduncular nucleus (IPN). We found diminished IPN activation in response to nicotine in alpha5 knockout mice. Further, disruption of IPN signalling increased nicotine intake in rats. Our findings indicate that nicotine activates the habenulo interpeduncular pathway through alpha5-containing nAChRs, triggering an inhibitory motivational signal that acts to limit nicotine intake. PMID- 21278727 TI - Embryonic lethal phenotype reveals a function of TDG in maintaining epigenetic stability. AB - Thymine DNA glycosylase (TDG) is a member of the uracil DNA glycosylase (UDG) superfamily of DNA repair enzymes. Owing to its ability to excise thymine when mispaired with guanine, it was proposed to act against the mutability of 5 methylcytosine (5-mC) deamination in mammalian DNA. However, TDG was also found to interact with transcription factors, histone acetyltransferases and de novo DNA methyltransferases, and it has been associated with DNA demethylation in gene promoters following activation of transcription, altogether implicating an engagement in gene regulation rather than DNA repair. Here we use a mouse genetic approach to determine the biological function of this multifaceted DNA repair enzyme. We find that, unlike other DNA glycosylases, TDG is essential for embryonic development, and that this phenotype is associated with epigenetic aberrations affecting the expression of developmental genes. Fibroblasts derived from Tdg null embryos (mouse embryonic fibroblasts, MEFs) show impaired gene regulation, coincident with imbalanced histone modification and CpG methylation at promoters of affected genes. TDG associates with the promoters of such genes both in fibroblasts and in embryonic stem cells (ESCs), but epigenetic aberrations only appear upon cell lineage commitment. We show that TDG contributes to the maintenance of active and bivalent chromatin throughout cell differentiation, facilitating a proper assembly of chromatin-modifying complexes and initiating base excision repair to counter aberrant de novo methylation. We thus conclude that TDG-dependent DNA repair has evolved to provide epigenetic stability in lineage committed cells. PMID- 21278728 TI - Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions. AB - The corollaries of the obesity epidemic that plagues developed societies are malnutrition and resulting biochemical imbalances. Low levels of essential n-3 polyunsaturated fatty acids (n-3 PUFAs) have been linked to neuropsychiatric diseases, but the underlying synaptic alterations are mostly unknown. We found that lifelong n-3 PUFAs dietary insufficiency specifically ablates long-term synaptic depression mediated by endocannabinoids in the prelimbic prefrontal cortex and accumbens. In n-3-deficient mice, presynaptic cannabinoid CB(1) receptors (CB(1)Rs) normally responding to endocannabinoids were uncoupled from their effector G(i/o) proteins. Finally, the dietary-induced reduction of CB(1)R functions in mood-controlling structures was associated with impaired emotional behavior. These findings identify a plausible synaptic substrate for the behavioral alterations caused by the n-3 PUFAs deficiency that is often observed in western diets. PMID- 21278729 TI - An optogenetic toolbox designed for primates. AB - Optogenetics is a technique for controlling subpopulations of neurons in the intact brain using light. This technique has the potential to enhance basic systems neuroscience research and to inform the mechanisms and treatment of brain injury and disease. Before launching large-scale primate studies, the method needs to be further characterized and adapted for use in the primate brain. We assessed the safety and efficiency of two viral vector systems (lentivirus and adeno-associated virus), two human promoters (human synapsin (hSyn) and human thymocyte-1 (hThy-1)) and three excitatory and inhibitory mammalian codon optimized opsins (channelrhodopsin-2, enhanced Natronomonas pharaonis halorhodopsin and the step-function opsin), which we characterized electrophysiologically, histologically and behaviorally in rhesus monkeys (Macaca mulatta). We also introduced a new device for measuring in vivo fluorescence over time, allowing minimally invasive assessment of construct expression in the intact brain. We present a set of optogenetic tools designed for optogenetic experiments in the non-human primate brain. PMID- 21278730 TI - Parvalbumin-positive CA1 interneurons are required for spatial working but not for reference memory. AB - Parvalbumin-positive GABAergic interneurons in cortical circuits are hypothesized to control cognitive function. To test this idea directly, we functionally removed parvalbumin-positive interneurons selectively from hippocampal CA1 in mice. We found that parvalbumin-positive interneurons are dispensable for spatial reference, but are essential for spatial working memory. PMID- 21278731 TI - New views of Arc, a master regulator of synaptic plasticity. AB - Many proteins have been implicated in synaptic and experience-dependent plasticity. However, few demonstrate the exquisite regulation of expression and breadth of functional importance as the immediate early gene product Arc. Here we review and attempt to synthesize the disparate views of Arc in neuronal function. The main conclusion garnered from this body of work is that Arc is a critical effector molecule downstream of many molecular signaling pathways and that dysregulation of Arc expression can have dire consequences for normal brain function. PMID- 21278732 TI - Learning the microstructure of successful behavior. AB - Reinforcement signals indicating success or failure are known to alter the probability of selecting between distinct actions. However, successful performance of many motor skills, such as speech articulation, also requires learning behavioral trajectories that vary continuously over time. Here, we investigated how temporally discrete reinforcement signals shape a continuous behavioral trajectory, the fundamental frequency of adult Bengalese finch song. We provided reinforcement contingent on fundamental frequency performance only at one point in the song. Learned changes to fundamental frequency were maximal at this point, but also extended both earlier and later in the fundamental frequency trajectory. A simple principle predicted the detailed structure of learning: birds learned to produce the average of the behavioral trajectories associated with successful outcomes. This learning rule accurately predicted the structure of learning at a millisecond timescale, demonstrating that the nervous system records fine-grained details of successful behavior and uses this information to guide learning. PMID- 21278733 TI - Nestin negatively regulates postsynaptic differentiation of the neuromuscular synapse. AB - Positive and negative regulation of neurotransmitter receptor aggregation on the postsynaptic membrane is a critical event during synapse formation. Acetylcholine (ACh) and agrin are two opposing signals that regulate ACh receptor (AChR) clustering during neuromuscular junction (NMJ) development. ACh induces dispersion of AChR clusters that are not stabilized by agrin via a cyclin dependent kinase 5 (Cdk5)-mediated mechanism, but regulation of Cdk5 activation is poorly understood. We found that the intermediate filament protein nestin physically interacts with Cdk5 and is required for ACh-induced association of p35, the co-activator of Cdk5, with the muscle membrane. Blockade of nestin dependent signaling inhibited ACh-induced Cdk5 activation and the dispersion of AChR clusters in cultured myotubes. Similar to the effects of Cdk5 gene inactivation, knockdown of nestin in agrin-deficient mouse embryos substantially restored AChR clusters. These results suggest that nestin is required for ACh induced, Cdk5-dependent dispersion of AChR clusters during NMJ development. PMID- 21278734 TI - Conversion of mouse fibroblasts into cardiomyocytes using a direct reprogramming strategy. AB - Here we show that conventional reprogramming towards pluripotency through overexpression of Oct4, Sox2, Klf4 and c-Myc can be shortcut and directed towards cardiogenesis in a fast and efficient manner. With as little as 4 days of transgenic expression of these factors, mouse embryonic fibroblasts (MEFs) can be directly reprogrammed to spontaneously contracting patches of differentiated cardiomyocytes over a period of 11-12 days. Several lines of evidence suggest that a pluripotent intermediate is not involved. Our method represents a unique strategy that allows a transient, plastic developmental state established early in reprogramming to effectively function as a cellular transdifferentiation platform, the use of which could extend beyond cardiogenesis. Our study has potentially wide-ranging implications for induced pluripotent stem cell (iPSC) factor-based reprogramming and broadens the existing paradigm. PMID- 21278735 TI - Epithelial microRNAs regulate gut mucosal immunity via epithelium-T cell crosstalk. AB - Colonic homeostasis entails epithelium-lymphocyte cooperation, yet many participants in this process are unknown. We show here that epithelial microRNAs mediate the mucosa-immune system crosstalk necessary for mounting protective T helper type 2 (T(H)2) responses. Abolishing the induction of microRNA by gut specific deletion of Dicer1 (Dicer1(Deltagut)), which encodes an enzyme involved in microRNA biogenesis, deprived goblet cells of RELMbeta, a key T(H)2 antiparasitic cytokine; this predisposed the host to parasite infection. Infection of Dicer1(Deltagut) mice with helminths favored a futile T(H)1 response with hallmarks of inflammatory bowel disease. Interleukin 13 (IL-13) induced the microRNA miR-375, which regulates the expression of TSLP, a T(H)2-facilitating epithelial cytokine; this indicated a T(H)2-amplification loop. We found that miR 375 was required for RELMbeta expression in vivo; miR-375-deficient mice had significantly less intestinal RELMbeta, which possibly explains the greater susceptibility of Dicer1(Deltagut) mice to parasites. Our findings indicate that epithelial microRNAs are key regulators of gut homeostasis and mucosal immunity. PMID- 21278736 TI - Germline CYBB mutations that selectively affect macrophages in kindreds with X linked predisposition to tuberculous mycobacterial disease. AB - Germline mutations in CYBB, the human gene encoding the gp91(phox) subunit of the phagocyte NADPH oxidase, impair the respiratory burst of all types of phagocytes and result in X-linked chronic granulomatous disease (CGD). We report here two kindreds in which otherwise healthy male adults developed X-linked recessive Mendelian susceptibility to mycobacterial disease (MSMD) syndromes. These patients had previously unknown mutations in CYBB that resulted in an impaired respiratory burst in monocyte-derived macrophages but not in monocytes or granulocytes. The macrophage-specific functional consequences of the germline mutation resulted from cell-specific impairment in the assembly of the NADPH oxidase. This 'experiment of nature' indicates that CYBB is associated with MSMD and demonstrates that the respiratory burst in human macrophages is a crucial mechanism for protective immunity to tuberculous mycobacteria. PMID- 21278737 TI - Fate mapping of IL-17-producing T cells in inflammatory responses. AB - Here we describe a reporter mouse strain designed to map the fate of cells that have activated interleukin 17A (IL-17A). We found that IL-17-producing helper T cells (T(H)17 cells) had distinct plasticity in different inflammatory settings. Chronic inflammatory conditions in experimental autoimmune encephalomyelitis (EAE) caused a switch to alternative cytokines in T(H)17 cells, whereas acute cutaneous infection with Candida albicans did not result in the deviation of T(H)17 cells to the production of alternative cytokines, although IL-17A production was shut off in the course of the infection. During the development of EAE, interferon-gamma (IFN-gamma) and other proinflammatory cytokines in the spinal cord were produced almost exclusively by cells that had produced IL-17 before their conversion by IL-23 ('ex-T(H)17 cells'). Thus, this model allows the actual functional fate of effector T cells to be related to T(H)17 developmental origin regardless of IL-17 expression. PMID- 21278738 TI - Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5. AB - Interleukin 2 (IL-2), a cytokine linked to human autoimmune disease, limits IL-17 production. Here we found that deletion of the gene encoding the transcription factor STAT3 in T cells abrogated IL-17 production and attenuated autoimmunity associated with IL-2 deficiency. Whereas STAT3 induced IL-17 and the transcription factor RORgammat and inhibited the transcription factor Foxp3, IL-2 inhibited IL-17 independently of Foxp3 and RORgammat. STAT3 and STAT5 bound to multiple common sites across the locus encoding IL-17. The induction of STAT5 binding by IL-2 was associated with less binding of STAT3 at these sites and the inhibition of associated active epigenetic marks. 'Titration' of the relative activation of STAT3 and STAT5 modulated the specification of cells to the IL-17 producing helper T cell (T(H)17 cell) subset. Thus, the balance rather than the absolute magnitude of these signals determined the propensity of cells to make a key inflammatory cytokine. PMID- 21278739 TI - XPB, a subunit of TFIIH, is a target of the natural product triptolide. AB - Triptolide (1) is a structurally unique diterpene triepoxide isolated from a traditional Chinese medicinal plant with anti-inflammatory, immunosuppressive, contraceptive and antitumor activities. Its molecular mechanism of action, however, has remained largely elusive to date. We report that triptolide covalently binds to human XPB (also known as ERCC3), a subunit of the transcription factor TFIIH, and inhibits its DNA-dependent ATPase activity, which leads to the inhibition of RNA polymerase II-mediated transcription and likely nucleotide excision repair. The identification of XPB as the target of triptolide accounts for the majority of the known biological activities of triptolide. These findings also suggest that triptolide can serve as a new molecular probe for studying transcription and, potentially, as a new type of anticancer agent through inhibition of the ATPase activity of XPB. PMID- 21278740 TI - Defining the geometry of the two-component proteasome degron. AB - The eukaryotic 26S proteasome controls cellular processes by degrading specific regulatory proteins. Most proteins are targeted for degradation by a signal or degron that consists of two parts: a proteasome-binding tag, typically covalently attached polyubiquitin chains, and an unstructured region that serves as the initiation region for proteasomal proteolysis. Here we have characterized how the arrangement of the two degron parts in a protein affects degradation. We found that a substrate is degraded efficiently only when its initiation region is of a certain minimal length and is appropriately separated in space from the proteasome-binding tag. Regions that are located too close or too far from the proteasome-binding tag cannot access the proteasome and induce degradation. These spacing requirements are different for a polyubiquitin chain and a ubiquitin-like domain. Thus, the arrangement and location of the proteasome initiation region affect a protein's fate and are important in selecting proteins for proteasome mediated degradation. PMID- 21278741 TI - An octave-bandwidth negligible-loss radiofrequency metamaterial. AB - Metamaterials provide an unprecedented ability to manipulate electromagnetic waves and are an enabling technology for new devices ranging from flat lenses that focus light beyond the diffraction limit to coatings capable of cloaking an object. Nevertheless, narrow bandwidths and high intrinsic losses arising from the resonant properties of metamaterials have raised doubts about their usefulness. New design approaches seek to turn the perceived disadvantages of dispersion into assets that enhance a device's performance. Here we employ dispersion engineering of metamaterial properties to enable specific device performance over usable bandwidths. In particular, we design metamaterials that considerably improve conventional horn antennas over greater than an octave bandwidth with negligible loss and advance the state of the art in the process. Fabrication and measurement of a metahorn confirm its broadband, low-loss performance. This example illustrates the power of clever implementation combined with dispersion engineering to bring metamaterials into their full potential for revolutionizing practical devices. PMID- 21278743 TI - Codon adaptation-based control of protein expression in C. elegans. AB - We present a method to control protein levels under native genetic regulation in Caenorhabditis elegans by using synthetic genes with adapted codons. We found that the force acting on the spindle in C. elegans embryos was related to the amount of the G-protein regulator GPR-1/2. Codon-adapted versions of any C. elegans gene can be designed using our web tool, C. elegans codon adapter. PMID- 21278744 TI - Quantification of PtdInsP3 molecular species in cells and tissues by mass spectrometry. AB - Class I phosphoinositide-3-kinase (PI3K) isoforms generate the intracellular signaling lipid, phosphatidylinositol(3,4,5)trisphosphate (PtdIns(3,4,5)P(3)). PtdIns(3,4,5)P(3) regulates major aspects of cellular behavior, and the use of both genetic and pharmacological intervention has revealed important isoform specific roles for PI3Ks in health and disease. Despite this interest, current methods for measuring PtdIns(3,4,5)P(3) have major limitations, including insensitivity, reliance on radiolabeling, low throughput and an inability to resolve different fatty-acyl species. We introduce a methodology based on phosphate methylation coupled to high-performance liquid chromatography-mass spectrometry (HPLC-MS) to solve many of these problems and describe an integrated approach to quantify PtdIns(3,4,5)P(3) and related phosphoinositides (regio isomers of PtdInsP and PtdInsP(2) are not resolved). This methodology can be used to quantify multiple fatty-acyl species of PtdIns(3,4,5)P(3) in unstimulated mouse and human cells (>=10(5)) or tissues (>=0.1 mg) and their increase upon appropriate stimulation. PMID- 21278745 TI - A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohn's disease. AB - Susceptibility to Crohn's disease, a complex inflammatory disease, is influenced by common variants at many loci. The common exonic synonymous SNP (c.313C>T) in IRGM, found in strong linkage disequilibrium with a deletion polymorphism, has been classified as non-causative because of the absence of an alteration in the IRGM protein sequence or splice sites. Here we show that a family of microRNAs (miRNAs), miR-196, is overexpressed in the inflammatory intestinal epithelia of individuals with Crohn's disease and downregulates the IRGM protective variant (c.313C) but not the risk-associated allele (c.313T). Subsequent loss of tight regulation of IRGM expression compromises control of intracellular replication of Crohn's disease-associated adherent invasive Escherichia coli by autophagy. These results suggest that the association of IRGM with Crohn's disease arises from a miRNA-based alteration in IRGM regulation that affects the efficacy of autophagy, thereby implicating a synonymous polymorphism as a likely causal variant. PMID- 21278746 TI - Common variants in ZNF365 are associated with both mammographic density and breast cancer risk. AB - High-percent mammographic density adjusted for age and body mass index is one of the strongest risk factors for breast cancer. We conducted a meta analysis of five genome-wide association studies of percent mammographic density and report an association with rs10995190 in ZNF365 (combined P = 9.6 * 10(-10)). Common variants in ZNF365 have also recently been associated with susceptibility to breast cancer. PMID- 21278747 TI - Mutations in TTC19 cause mitochondrial complex III deficiency and neurological impairment in humans and flies. AB - Although mutations in CYTB (cytochrome b) or BCS1L have been reported in isolated defects of mitochondrial respiratory chain complex III (cIII), most cIII defective individuals remain genetically undefined. We identified a homozygous nonsense mutation in the gene encoding tetratricopeptide 19 (TTC19) in individuals from two families affected by progressive encephalopathy associated with profound cIII deficiency and accumulation of cIII-specific assembly intermediates. We later found a second homozygous nonsense mutation in a fourth affected individual. We demonstrated that TTC19 is embedded in the inner mitochondrial membrane as part of two high-molecular-weight complexes, one of which coincides with cIII. We then showed a physical interaction between TTC19 and cIII by coimmunoprecipitation. We also investigated a Drosophila melanogaster knockout model for TTC19 that showed low fertility, adult-onset locomotor impairment and bang sensitivity, associated with cIII deficiency. TTC19 is a putative cIII assembly factor whose disruption is associated with severe neurological abnormalities in humans and flies. PMID- 21278748 TI - Ultrasensitive human prion detection in cerebrospinal fluid by real-time quaking induced conversion. AB - The development of technologies for the in vitro amplification of abnormal conformations of prion protein (PrP(Sc)) has generated the potential for sensitive detection of prions. Here we developed a new PrP(Sc) amplification assay, called real-time quaking-induced conversion (RT-QUIC), which allows the detection of >=1 fg of PrP(Sc) in diluted Creutzfeldt-Jakob disease (CJD) brain homogenate. Moreover, we assessed the technique first in a series of Japanese subjects and then in a blind study of 30 cerebrospinal fluid specimens from Australia, which achieved greater than 80% sensitivity and 100% specificity. These findings indicate the promising enhanced diagnostic capacity of RT-QUIC in the antemortem evaluation of suspected CJD. PMID- 21278749 TI - Amine-modified single-walled carbon nanotubes protect neurons from injury in a rat stroke model. AB - Stroke results in the disruption of tissue architecture and is the third leading cause of death in the United States. Transplanting scaffolds containing stem cells into the injured areas of the brain has been proposed as a treatment strategy, and carbon nanotubes show promise in this regard, with positive outcomes when used as scaffolds in neural cells and brain tissues. Here, we show that pretreating rats with amine-modified single-walled carbon nanotubes can protect neurons and enhance the recovery of behavioural functions in rats with induced stroke. Treated rats showed less tissue damage than controls and took longer to fall from a rotating rod, suggesting better motor functions after injury. Low levels of apoptotic, angiogenic and inflammation markers indicated that amine-modified single-walled carbon nanotubes protected the brains of treated rats from ischaemic injury. PMID- 21278750 TI - Time-dependent, protein-directed growth of gold nanoparticles within a single crystal of lysozyme. AB - Gold nanoparticles are useful in biomedical applications due to their distinct optical properties and high chemical stability. Reports of the biogenic formation of gold colloids from gold complexes has also led to an increased level of interest in the biomineralization of gold. However, the mechanism responsible for biomolecule-directed gold nanoparticle formation remains unclear due to the lack of structural information about biological systems and the fast kinetics of biomimetic chemical systems in solution. Here we show that intact single crystals of lysozyme can be used to study the time-dependent, protein-directed growth of gold nanoparticles. The protein crystals slow down the growth of the gold nanoparticles, allowing detailed kinetic studies to be carried out, and permit a three-dimensional structural characterization that would be difficult to achieve in solution. Furthermore, we show that additional chemical species can be used to fine-tune the growth rate of the gold nanoparticles. PMID- 21278751 TI - Nanomedicine: Nanotubes reduce stroke damage. PMID- 21278752 TI - Single-layer MoS2 transistors. AB - Two-dimensional materials are attractive for use in next-generation nanoelectronic devices because, compared to one-dimensional materials, it is relatively easy to fabricate complex structures from them. The most widely studied two-dimensional material is graphene, both because of its rich physics and its high mobility. However, pristine graphene does not have a bandgap, a property that is essential for many applications, including transistors. Engineering a graphene bandgap increases fabrication complexity and either reduces mobilities to the level of strained silicon films or requires high voltages. Although single layers of MoS(2) have a large intrinsic bandgap of 1.8 eV (ref. 16), previously reported mobilities in the 0.5-3 cm(2) V(-1) s(-1) range are too low for practical devices. Here, we use a halfnium oxide gate dielectric to demonstrate a room-temperature single-layer MoS(2) mobility of at least 200 cm(2) V(-1) s(-1), similar to that of graphene nanoribbons, and demonstrate transistors with room-temperature current on/off ratios of 1 * 10(8) and ultralow standby power dissipation. Because monolayer MoS(2) has a direct bandgap, it can be used to construct interband tunnel FETs, which offer lower power consumption than classical transistors. Monolayer MoS(2) could also complement graphene in applications that require thin transparent semiconductors, such as optoelectronics and energy harvesting. PMID- 21278753 TI - Single-molecule analysis of a molecular disassemblase reveals the mechanism of Hsc70-driven clathrin uncoating. AB - Heat shock cognate protein-70 (Hsc70) supports remodeling of protein complexes, such as disassembly of clathrin coats on endocytic coated vesicles. To understand how a simple ATP-driven molecular clamp catalyzes a large-scale disassembly reaction, we have used single-particle fluorescence imaging to track the dynamics of Hsc70 and its clathrin substrate in real time. Hsc70 accumulates to a critical level, determined by kinetic modeling to be one Hsc70 for every two functional attachment sites; rapid, all-or-none uncoating then ensues. We propose that Hsc70 traps conformational distortions, seen previously by cryo-EM, in the vicinity of each occupied site and that accumulation of local strains destabilizes the clathrin lattice. Capture of conformational fluctuations may be a general mechanism for chaperone-driven disassembly of protein complexes. PMID- 21278754 TI - Competing allosteric mechanisms modulate substrate binding in a dimeric enzyme. AB - Allostery has been studied for many decades, yet it remains challenging to determine experimentally how it occurs at a molecular level. We have developed an approach combining isothermal titration calorimetry, circular dichroism and nuclear magnetic resonance spectroscopy to quantify allostery in terms of protein thermodynamics, structure and dynamics. This strategy was applied to study the interaction between aminoglycoside N-(6')-acetyltransferase-Ii and one of its substrates, acetyl coenzyme A. It was found that homotropic allostery between the two active sites of the homodimeric enzyme is modulated by opposing mechanisms. One follows a classical Koshland-Nemethy-Filmer (KNF) paradigm, whereas the other follows a recently proposed mechanism in which partial unfolding of the subunits is coupled to ligand binding. Competition between folding, binding and conformational changes represents a new way to govern energetic communication between binding sites. PMID- 21278755 TI - Common architecture of the flagellar type III protein export apparatus and F- and V-type ATPases. AB - The proteins that form the bacterial flagellum are translocated to its distal end through the central channel of the growing flagellum by the flagellar-specific protein export apparatus, a family of the type III protein secretion system. FliI and FliJ are soluble components of this apparatus. FliI is an ATPase that has extensive structural similarity to the alpha and beta subunits of F(o)F(1)-ATP synthase. FliJ is essential for export, but its function remains obscure. Here we show that the structure of FliJ derived from Salmonella enterica serovar Typhimurium is remarkably similar to that of the two-stranded alpha-helical coiled-coil part of the gamma subunit of F(o)F(1)-ATP synthase and that FliJ promotes the formation of FliI hexamer rings by binding to the center of the ring. These results suggest that the type III protein export system and F- and V type ATPases share a similar mechanism and an evolutionary relationship. PMID- 21278756 TI - Retinal dynamics underlie its switch from inverse agonist to agonist during rhodopsin activation. AB - X-ray and magnetic resonance approaches, though central to studies of G protein coupled receptor (GPCR)-mediated signaling, cannot address GPCR protein dynamics or plasticity. Here we show that solid-state (2)H NMR relaxation elucidates picosecond-to-nanosecond-timescale motions of the retinal ligand that influence larger-scale functional dynamics of rhodopsin in membranes. We propose a multiscale activation mechanism whereby retinal initiates collective helix fluctuations in the meta I-meta II equilibrium on the microsecond-to-millisecond timescale. PMID- 21278757 TI - Mechanics of Hsp70 chaperones enables differential interaction with client proteins. AB - Hsp70 chaperones interact with a wide spectrum of substrates ranging from unfolded to natively folded and aggregated proteins. Structural evidence suggests that bound substrates are entirely enclosed in a beta-sheet cavity covered by a helical lid, which requires structural rearrangements including lid opening to allow substrate access. We analyzed the mechanics of the lid movement of bacterial DnaK by disulfide fixation of lid elements to the beta-sheet and by electron paramagnetic resonance spectroscopy using spin labels in the lid and beta-sheet. Our results indicate that the lid-forming helix B adopts at least three conformational states and, notably, does not close over bound proteins, implying that DnaK does not only bind to extended peptide stretches of protein substrates but can also accommodate regions with substantial tertiary structure. This flexible binding mechanism provides a basis for the broad spectrum of substrate conformers of Hsp70s. PMID- 21278758 TI - MutS switches between two fundamentally distinct clamps during mismatch repair. AB - Single-molecule trajectory analysis has suggested DNA repair proteins may carry out a one-dimensional (1D) search on naked DNA encompassing >10,000 nucleotides. Organized cellular DNA (chromatin) presents substantial barriers to such lengthy searches. Using dynamic single-molecule fluorescence resonance energy transfer, we determined that the mismatch repair (MMR) initiation protein MutS forms a transient clamp that scans duplex DNA for mismatched nucleotides by 1D diffusion for 1 s (~700 base pairs) while in continuous rotational contact with the DNA. Mismatch identification provokes ATP binding (3 s) that induces distinctly different MutS sliding clamps with unusual stability on DNA (~600 s), which may be released by adjacent single-stranded DNA (ssDNA). These observations suggest that ATP transforms short-lived MutS lesion scanning clamps into highly stable MMR signaling clamps that are capable of competing with chromatin and recruiting MMR machinery, yet are recycled by ssDNA excision tracts. PMID- 21278759 TI - Androgen deprivation therapy for prostate cancer: not so simple. PMID- 21278761 TI - Vitamin D and autoimmune thyroid diseases. AB - The role of vitamin D as an immune modulator has been emphasized in recent years, and low levels of the hormone were observed in several autoimmune diseases including multiple sclerosis and systemic lupus erythematosus. Vitamin D mediates its effect though binding to vitamin D receptor (VDR), and activation of VDR responsive genes. While VDR gene polymorphism was found to associate with autoimmune thyroid diseases (AITDs), few studies examined levels of vitamin D in these patients and those that did yielded conflicting results. We therefore undertook to evaluate the levels of vitamin D in patients with AITDs compared to patients with non-AITDs and healthy controls. Serum vitamin D (25-OH) levels were measured in 50 patients with AITDs, 42 patients with non-AITDs and 98 healthy subjects, utilizing the LIAISON chemiluminescence immunoassay (DiaSorin, Saluggia, Italy). Vitamin D deficiency was designated at levels lower than 10 ng/ml. Antithyroid antibodies, thyroid functions and demographic parameters were evaluated in all patients. The prevalence of vitamin D deficiency was significantly higher in patients with AITDs compared with healthy individuals (72% versus 30.6%; P<0.001), as well as in patients with Hashimoto's thyroiditis compared to patients with non-AITDs (79% versus 52%; P<0.05). Vitamin D deficiency also correlated to the presence of antithyroid antibodies (P=0.01) and abnormal thyroid function tests (P=0.059). Significantly low levels of vitamin D were documented in patients with AITDs that were related to the presence of anti thyroid antibodies and abnormal thyroid function tests, suggesting the involvement of vitamin D in the pathogenesis of AITDs and the advisability of supplementation. PMID- 21278760 TI - The role of gut microbiota (commensal bacteria) and the mucosal barrier in the pathogenesis of inflammatory and autoimmune diseases and cancer: contribution of germ-free and gnotobiotic animal models of human diseases. AB - Metagenomic approaches are currently being used to decipher the genome of the microbiota (microbiome), and, in parallel, functional studies are being performed to analyze the effects of the microbiota on the host. Gnotobiological methods are an indispensable tool for studying the consequences of bacterial colonization. Animals used as models of human diseases can be maintained in sterile conditions (isolators used for germ-free rearing) and specifically colonized with defined microbes (including non-cultivable commensal bacteria). The effects of the germ free state or the effects of colonization on disease initiation and maintenance can be observed in these models. Using this approach we demonstrated direct involvement of components of the microbiota in chronic intestinal inflammation and development of colonic neoplasia (i.e., using models of human inflammatory bowel disease and colorectal carcinoma). In contrast, a protective effect of microbiota colonization was demonstrated for the development of autoimmune diabetes in non-obese diabetic (NOD) mice. Interestingly, the development of atherosclerosis in germ-free apolipoprotein E (ApoE)-deficient mice fed by a standard low-cholesterol diet is accelerated compared with conventionally reared animals. Mucosal induction of tolerance to allergen Bet v1 was not influenced by the presence or absence of microbiota. Identification of components of the microbiota and elucidation of the molecular mechanisms of their action in inducing pathological changes or exerting beneficial, disease-protective activities could aid in our ability to influence the composition of the microbiota and to find bacterial strains and components (e.g., probiotics and prebiotics) whose administration may aid in disease prevention and treatment. PMID- 21278762 TI - The effects of Spirulina on anemia and immune function in senior citizens. AB - Anemia and immunological dysfunction (i.e. immunosenescence) are commonly found in older subjects and nutritional approaches are sought to counteract these phenomena. Spirulina is a filamentous and multicellular bule-green alga capable of reducing inflammation and also manifesting antioxidant effects. We hypothesized that Spirulina may ameliorate anemia and immunosenescence in senior citizens with a history of anemia. We enrolled 40 volunteers of both sexes with an age of 50 years or older who had no history of major chronic diseases. Participants took a Spirulina supplementation for 12 weeks and were administered comprehensive dietary questionnaires to determine their nutritional regimen during the study. Complete cell count (CCC) and indoleamine 2,3-dioxygenase (IDO) enzyme activity, as a sign of immune function, were determined at baseline and weeks 6 and 12 of supplementation. Thirty study participants completed the entire study and the data obtained were analyzed. Over the 12-week study period, there was a steady increase in average values of mean corpuscular hemoglobin in subjects of both sexes. In addition, mean corpuscular volume and mean corpuscular hemoglobin concentration also increased in male participants. Older women appeared to benefit more rapidly from Spirulina supplements. Similarly, the majority of subjects manifested increased IDO activity and white blood cell count at 6 and 12 weeks of Spirulina supplementation. Spirulina may ameliorate anemia and immunosenescence in older subjects. We encourage large human studies to determine whether this safe supplement could prove beneficial in randomized clinical trials. PMID- 21278763 TI - Celiac disease: diagnostic criteria in progress. AB - Until a few years ago, celiac disease (CD) was thought to be a rare food intolerance that was confined to childhood and characterized by severe malabsorption and flat intestinal mucosa. Currently, CD is regarded as an autoimmune disorder that is common in the general population (affecting 1 in 100 individuals), with possible onset at any age and with many possible presentations. The identification of CD is challenging because it can begin not only with diarrhea and weight loss but also with atypical gastrointestinal (constipation and recurrent abdominal pain) and extra-intestinal symptoms (anemia, raised transaminases, osteoporosis, recurrent miscarriages, aphthous stomatitis and associated autoimmune disorders), or it could be completely symptomless. Over the last 20 years, the diagnostic accuracy of serology for CD has progressively increased with the development of highly reliable tests, such as the detection of IgA tissue transglutaminase and antiendomysial and IgG antideamidated gliadin peptide antibodies. The routine use of antibody markers has allowed researchers to discover a very high number of 'borderline' cases, characterized by positive serology and mild intestinal lesions or normal small intestine architecture, which can be classified as potential CD. Therefore, it is evident that the 'old celiac disease' with flat mucosa is only a part of the spectrum of CD. It is possible that serology could identify CD in its early stages, before the appearance of severe intestinal damage. In cases with a positive serology but with mild or absent intestinal lesions, the detection of HLA-DQ2 and HLA-DQ8 can help reinforce or exclude the diagnosis of gluten sensitivity. PMID- 21278764 TI - Immunostimulation in the era of the metagenome. AB - Microbes are increasingly being implicated in autoimmune disease. This calls for a re-evaluation of how these chronic inflammatory illnesses are routinely treated. The standard of care for autoimmune disease remains the use of medications that slow the immune response, while treatments aimed at eradicating microbes seek the exact opposite-stimulation of the innate immune response. Immunostimulation is complicated by a cascade of sequelae, including exacerbated inflammation, which occurs in response to microbial death. Over the past 8 years, we have collaborated with American and international clinical professionals to research a model-based treatment for inflammatory disease. This intervention, designed to stimulate the innate immune response, has required a reevaluation of disease progression and amelioration. Paramount is the inherent conflict between palliation and microbicidal efficacy. Increased microbicidal activity was experienced as immunopathology-a temporary worsening of symptoms. Further studies are needed, but they will require careful planning to manage this immunopathology. PMID- 21278765 TI - Novel trends in celiac disease. AB - Celiac disease (CD) is one of the most common food intolerances in developed world. It affects genetically susceptible individuals and has severe consequences if it remains undiagnosed. A disease known for more than a century, it is still the focus for experts from various fields of research and development. Geneticists, pathologists, immunologists, food engineers and dieticians share their knowledge and expertise to improve the conditions of CD patients. With new insights in the pathomechanism of gluten processing and antigen presentation in CD, it was possible to improve the diagnostic antigen mimicking the primary epitope in CD. These celiac neo-epitopes are comprised of a complex of gliadin peptides crosslinked with transglutaminase (tTg). They are an early diagnostic marker for CD which occurs up to 6 months earlier than classical markers known to miss a certain amount of CD patients. PMID- 21278766 TI - The epigenetics of autoimmunity. AB - The etiology of autoimmune diseases remains largely unknown. Concordance rates in monozygotic twins are lower than 50% while genome-wide association studies propose numerous significant associations representing only a minority of patients. These lines of evidence strongly support other complementary mechanisms involved in the regulation of genes expression ultimately causing overt autoimmunity. Alterations in the post-translational modification of histones and DNA methylation are the two major epigenetic mechanisms that may potentially cause a breakdown of immune tolerance and the perpetuation of autoimmune diseases. In recent years, several studies both in clinical settings and experimental models proposed that the epigenome may hold the key to a better understanding of autoimmunity initiation and perpetuation. More specifically, data support the impact of epigenetic changes in systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis and other autoimmune diseases, in some cases based on mechanistical observations. We herein discuss what we currently know and what we expect will come in the next future. Ultimately, epigenetic treatments already being used in oncology may soon prove beneficial also in autoimmune diseases. PMID- 21278767 TI - Dysfunctions of the Iga system: a common link between intestinal and renal diseases. AB - Immunoglobulin A (Iga)-isotype antibodies play an important role in immunity owing to their structure, glycosylation, localization and receptor interactions. Dysfunctions in this system can lead to multiple types of pathology. This review describes the characteristics of Iga and discusses the involvement of abnormalities in the Iga system on the development of celiac disease and Iga nephropathy. PMID- 21278768 TI - Antibodies in celiac disease: implications beyond diagnostics. AB - Celiac disease is a multisystemic dietary, gluten-induced autoimmune disorder characterized by the presence of transglutaminase (TG) 2 serum autoantibodies. Distinct autoantibodies targeting members of the TG family (TG2, TG3 and TG6) are found deposited in small-bowel mucosa and in extraintestinal tissues affected by the disease. Serum autoantibodies against other self-antigens also emerge in untreated celiac disease patients. Although villous atrophy and crypt hyperplasia in small-bowel biopsy samples are still the gold standards in diagnostics, celiac disease-specific antibodies are widely used as diagnostic aids. Gluten-induced small-bowel mucosal T-cell response is the cornerstone in the pathogenesis of the disorder, but humoral immunity may also play a central role. This review article is focused on the autoantibodies that occur in the context of celiac disease. The article summarizes the diagnostic utility of different celiac-related antibodies and discusses their roles in the pathogenesis of the disease. PMID- 21278769 TI - Breast cancer in 2010: Novel targets and therapies for a personalized approach. AB - 2010 has been another prolific year in breast cancer research with a number of original observations bringing us closer to personalized care. Studies with novel targeted agents in defined breast cancer subgroups have revealed exciting developments and highlight the importance of patient selection. PMID- 21278770 TI - Hematology in 2010: New therapies and standard of care in oncology. AB - 2010 was not a year of survival breakthroughs in hematologic malignancies. However, in Hodgkin's disease and multiple myeloma new therapies emerged as the standard of care and nilotinib may be considered the treatment choice for newly diagnosed chronic myeloid leukemia. PMID- 21278771 TI - Lung cancer in 2010: One size does not fit all. AB - Advances in non-small-cell lung cancer over the past decade have resulted in new treatments with minimal toxic effects and dramatic clinical benefits. 2010 saw continued advancement in our understanding of the molecular genetics of lung cancer and of specific targeted inhibitors with remarkable clinical benefit in selected populations. PMID- 21278772 TI - GI cancers in 2010: New standards and a predictive biomarker for adjuvant therapy. AB - Randomized phase III trials have established new standards of care for advanced biliary cancer, HER2-positive advanced gastric or gastro-esophageal junction cancer, and preliminarily, for metastatic pancreatic cancer. There is now a validated predictive biomarker to guide use of adjuvant chemotherapy in patients with stage II colon cancer. PMID- 21278773 TI - Head and neck cancer in 2010: Maximizing survival and minimizing toxicity. AB - Outcomes for patients with oropharyngeal cancer are determined by their tumor characteristics and associated demographics. The role of human papilloma virus related disease for prognosis and outcomes with chemoradiotherapy is being more clearly defined. EGFR inhibitors are used in conjunction with radiotherapy, and the importance of optimizing radiation quality and minimizing toxicity is the focus of ongoing studies. PMID- 21278776 TI - Angiotensin II: a candidate for an aldosterone-independent mediator of potassium preservation during volume depletion. AB - Two different stimulators of aldosterone secretion, high-potassium diet and low sodium diet, have disparate effects on potassium secretion in the distal nephron. The mechanism by which the kidney preserves potassium in the face of a high aldosterone, volume-depleted state has engendered much thought. Yue et al. now propose that angiotensin II inhibits the renal outer medullary potassium channel (ROMK1) through stimulation of the protein tyrosine kinase c-Src, perhaps acting as a signal to differentiate volume depletion from a high-potassium diet. PMID- 21278777 TI - Nanocrystals seed calcification in more ways than one. AB - Although much progress has been made in the past five years in understanding the mechanisms leading to accelerated vascular calcification in patients with chronic kidney disease, it remains unclear how an environment high in phosphate can impinge so significantly on the calcification process. The study by Sage et al. highlights an important and novel role for calcium phosphate nanocrystals, produced in a high-phosphate environment, in rapidly driving calcification of vascular smooth muscle cells via enhanced production of bone morphogenetic protein-2. PMID- 21278778 TI - Raging hormones: gender and renal disease. AB - Gender affects the progression of renal disease. In a variety of animal models and in certain human renal diseases, females exhibit a more modest course of kidney disease. Estrogens and testosterone have been implicated in this gender disparity. Doublier and colleagues explore the direct effects of sex hormones on podocyte viability in the alpha-estrogen receptor knockout (alphaERKO) mouse. They report that testosterone induces, and estradiol inhibits, podocyte damage in this model. PMID- 21278780 TI - The KDIGO guideline on dialysate calcium and patient outcomes: need for hard evidence. PMID- 21278781 TI - Down-regulation of ALKBH2 increases cisplatin sensitivity in H1299 lung cancer cells. AB - AIM: To elucidate the combined effect of alkylated DNA repair protein alkB homolog 2 (ALKBH2)-targeting gene therapy and cisplatin (cDDP) chemotherapy on the non-small cell lung cancer (NSCLC) H1299 cell line. METHODS: ALKBH2 was down regulated in H1299 cells by lentivirus-mediated RNA interference (RNAi). Changes in ALKBH2 expression were determined using real-time RT-PCR and Western blotting. Cell viability was evaluated using MTT assay. DNA synthesis in proliferating cells was determined using BrdU incorporation assay. Cell apoptosis was determined using flow cytometry. RESULTS: Lentivirus-mediated ALKBH2 silencing alone did not induce apoptosis or attenuate the growth potential of H1299 cells within five days post-infection. Combined treatment modalities with lentivirus mediated ALKBH2 down-regulation and cDDP (333 MUmol/L) were significantly more potent in inhibiting cell growth and inducing apoptosis than mono-chemotherapy. CONCLUSION: Combined treatment modalities of ALKBH2 knockdown and cDDP chemotherapy have the potential to improve the efficacy in the treatment of NSCLC. PMID- 21278782 TI - Generation and characterization of the human neutralizing antibody fragment Fab091 against rabies virus. AB - AIM: To transform the human anti-rabies virus glycoprotein (anti-RABVG) single chain variable fragment (scFv) into a Fab fragment and to analyze its immunological activity. METHODS: The Fab gene was amplified using overlap PCR and inserted into the vector pComb3XSS. The recombinant vector was then transformed into E coli Top10F' for expression and purification. The purified Fab was characterized using SDS-PAGE, Western blotting, indirect ELISA, competitive ELISA, and the fluorescent antibody virus neutralization test (FAVN), respectively, and examined in a Kunming mouse challenge model in vivo. RESULTS: A recombinant vector was constructed. The Fab was expressed in soluble form in E coli Top10F'. Specific binding of the Fab to rabies virus was confirmed by indirect ELISA and immunoprecipitation (IP). The neutralizing antibody titer of Fab was 10.26 IU/mL. The mouse group treated with both vaccine and human rabies immunoglobulin (HRIG)/Fab091 (32 IU/kg) showed protection against rabies, compared with the control group (P<0.05, Logrank test). CONCLUSION: The antibody fragment Fab was shown to be a neutralizing antibody against RABVG. It can be used together with other monoclonal antibodies for post-exposure prophylaxis of rabies virus in future studies. PMID- 21278783 TI - Expression of elongation factor-2 kinase contributes to anoikis resistance and invasion of human glioma cells. AB - AIM: To determine whether elongation factor-2 kinase (eEF-2 kinase) contributes to the malignant phenotype of glioblastoma multiforme by promoting the migration and invasion of glioma cells. The mechanism involved was also explored. METHODS: Human glioma cell lines T98G and LN-229 were used. The expression of eEF-2 kinase was silenced using siRNA, and the invasive potential of tumor cells was assessed using a wound-healing assay and a Matrigel invasion assay. Apoptosis was determined using propidium iodide (PI) staining and Western blot analysis of cleaved caspase-3. RESULTS: Silencing the expression of eEF-2 kinase by siRNA significantly suppressed both the migration and invasion of human glioma cells. Silencing eEF-2 kinase expression also sensitized glioma cells to anoikis, thereby decreasing tumor cell viability in the absence of attachment. Treatment of tumor cells with the caspase inhibitor z-VAD-fmk down-regulated Bim accumulation and abolished glioma cell sensitivity to anoikis. CONCLUSION: The results suggest that the expression of eEF-2 kinase contributes to migration and invasion of human glioma cells by protecting them from anoikis. eEF-2 kinase expression may serve as a prognostic marker and a novel target for cancer therapy. PMID- 21278784 TI - MicroRNA-221 inhibits CDKN1C/p57 expression in human colorectal carcinoma. AB - AIM: To investigate the regulatory effect of microRNA-221 (miR-221) on CDKN1C/p57 expression in colorectal carcinoma (CRC). METHODS: Thirty four CRC and adjacent non-tumorous tissue samples were collected individually. Total RNA and protein were isolatedand from these samples and four human CRC-derived cell lines (including HT-29, Lovo, SW-480 and Caco2). MiR-221 expression was examined using real-time RT-PCR. CRC cells were treated with or without anti-p57-siRNA prior to the addition of pre-miR-221 or anti-miR-221. The mRNA and protein levels of CDKN1C/p57 were examined using semi-quantitative RT-PCR and Western blot, respectively. CRC cell proliferation and apoptosis were assessed using MTT assay and flow cytometry, respectively. The CDKN1C/p57 3'-UTR fragment was amplified using PCR from the genomic DNA of human colon cells and inserted into a luciferase reporter construct. The reporter construct was then transfected into CRC cells together with pre-miR-221 or anti-miR-221, and the luciferase activity in the transfected cells was examined. RESULTS: MiR-221 expression was significantly up-regulated in 90% of CRC samples compared to that in the adjacent non-tumorous tissue, and the expression level was positively correlated to an advanced TNM stage and local invasion. There was no significant difference in CDKN1C/p57 mRNA expression between CRC and corresponding non-tumorous tissues, whereas CDKN1C/p57 protein expression was markedly decreased in the CRC samples. A significant inverse correlation between miR-221 and CDKN1C/p57 expression was found in CRC cells. Moreover, a miR-221-specific inhibitor significantly increased CDKN1C/p57 protein expression in CRC cells. Anti-miR-221 markedly inhibited CRC cell proliferation and induced apoptosis. This inhibitory effect was abolished by pretreatment with anti-p57-siRNA, suggesting that the inhibition was mediated by CDKN1C/p57. A significant increase of the luciferase activity was observed in CRC cells co-transfected with the luciferase reporter construct and anti-miR-221. CONCLUSION: MiR-221 binds to the target site in the 3'-UTR of the CDKN1C/p57 mRNA to inhibit CDKN1C/p57 expression by post-transcriptional gene silencing to promote CRC occurrence and progress, therefore serving as a potential therapeutic target for the prevention and treatment of CRC. PMID- 21278785 TI - Evodiamine improves congnitive abilities in SAMP8 and APP(swe)/PS1(DeltaE9) transgenic mouse models of Alzheimer's disease. AB - AIM: To investigate the effect of evodiamine (a quinolone alkaloid from the fruit of Evodia rutaecarpa) on the progression of Alzheimer's disease in SAMP8 and APP(swe)/PS1(DeltaE9) transgenic mouse models. METHODS: The mice at age of 5 months were randomized into the model group, two evodiamine (50 mg.kg(-1).d(-1) and 100 mg.kg(-1).d(-1)) groups and an Aricept (2 mg.kg(-1).d(-1)) group. The littermates of no-transgenic mice and senescence accelerated mouse/resistance 1 mice (SAMR1) were used as controls. After 4 weeks of treatment, learning abilities and memory were assessed using Morris water-maze test, and glucose uptake by the brain was detected using positron emission tomography/computed tomography (PET/CT). Expression levels of IL-1beta, IL-6, and TNF-alpha in brain tissues were detected using ELISA. Expression of COX-2 protein was determined using Western blot. RESULTS: In Morris water-maze test, evodiamine (100 mg.kg( 1).d(-1)) significantly alleviated the impairments of learning ability and memory. Evodiamine (100 mg.kg(-1).d(-1)) also reversed the inhibition of glucose uptake due to development of Alzheimer's disease traits in mice. Furthermore, the dose of evodiamine significantly decreased the expression of IL-1beta, IL-6, TNF alpha, and COX-2 that were involved in the inflammation due to Alzheimer's disease. CONCLUSION: The results indicate that evodiamine (100 mg.kg(-1).d(-1)) improves cognitive abilities in the transgenic models of Alzheimer's disease. PMID- 21278786 TI - PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer. AB - There is a strong rationale to therapeutically target the phosphatidylinositol 3 kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway in breast cancer since it is highly deregulated in this disease and it also mediates resistance to anti-HER2 therapies. However, initial studies with rapalogs, allosteric inhibitors of mTORC1, have resulted in limited clinical efficacy probably due to the release of a negative regulatory feedback loop that triggers AKT and ERK signaling. Since activation of AKT occurs via PI3K, we decided to explore whether PI3K inhibitors prevent the activation of these compensatory pathways. Using HER2-overexpressing breast cancer cells as a model, we observed that PI3K inhibitors abolished AKT activation. However, PI3K inhibition resulted in a compensatory activation of the ERK signaling pathway. This enhanced ERK signaling occurred as a result of activation of HER family receptors as evidenced by induction of HER receptors dimerization and phosphorylation, increased expression of HER3 and binding of adaptor molecules to HER2 and HER3. The activation of ERK was prevented with either MEK inhibitors or anti-HER2 monoclonal antibodies and tyrosine kinase inhibitors. Combined administration of PI3K inhibitors with either HER2 or MEK inhibitors resulted in decreased proliferation, enhanced cell death and superior anti-tumor activity compared with single agent PI3K inhibitors. Our findings indicate that PI3K inhibition in HER2 overexpressing breast cancer activates a new compensatory pathway that results in ERK dependency. Combined anti-MEK or anti-HER2 therapy with PI3K inhibitors may be required in order to achieve optimal efficacy in HER2-overexpressing breast cancer. This approach warrants clinical evaluation. PMID- 21278787 TI - Combined effects of novel heat shock protein 90 inhibitor NVP-AUY922 and nilotinib in a random mutagenesis screen. AB - To overcome imatinib resistance, more potent ABL tyrosine kinase inhibitors (TKIs), such as nilotinib and dasatinib have been developed, with demonstrable preclinical activity against most imatinib-resistant BCR-ABL kinase domain mutations, with the exception of T315I. However, imatinib-resistant patients already harboring mutations have a higher likelihood of developing further mutations under the selective pressure of potent ABL TKIs. NVP-AUY922 (Novartis) is a novel 4,5-diaryloxazole adenosine triphosphate-binding site heat shock protein 90 (HSP90) inhibitor, which has been shown to inhibit the chaperone function of HSP90 and deplete the levels of HSP90 client protein including BCR ABL. In this study, we investigated the combined effects of AUY922 and nilotinib on random mutagenesis for BCR-ABL mutation (Blood, 109; 5011, 2007). Compared with single agents, combination with AUY922 and nilotinib was more effective at reducing the outgrowth of resistant cell clones. No outgrowth was observed in the presence of 2 MUM of nilotinib and 20 nM of AUY922. The observed data from the isobologram indicated the synergistic effect of simultaneous exposure to AUY922 and nilotinib even in BaF3 cells expressing BCR-ABL mutants including T315I. In vivo studies also demonstrated that the combination of AUY922 and nilotinib prolonged the survival of mice transplanted with mixture of BaF3 cells expressing wild-type BCR-ABL and mutant forms. Taken together, this study shows that the combination of AUY922 and nilotinib exhibits a desirable therapeutic index that can reduce the in vivo growth of mutant forms of BCR-ABL-expressing cells. PMID- 21278788 TI - Translationally controlled tumor protein induces human breast epithelial cell transformation through the activation of Src. AB - Translationally controlled tumor protein (TCTP) is implicated in cell growth and malignant transformation. TCTP has been found to interact directly with the third cytoplasmic domain of the alpha subunit of Na,K-ATPase, but whether this interaction has a role in tumorigenesis is unclear. In this study, we examined TCTP-induced tumor progression signaling networks in human breast epithelial cells, using adenoviral infection. We found that TCTP (a) induces Src release from Na,K-ATPase alpha subunit and Src activation; (b) phosphorylates tyrosine residues 845, 992, 1086, 1148 and 1173 on anti-epidermal growth factor receptor (EGFR); (c) activates PI3K (phosphatidylinositol 3-kinase )-AKT, Ras-Raf-MEK ERK1/2, Rac-PAK1/2, MKK3/6-p38 and phospholipase C (PLC)-gamma pathways; (d) enhances NADPH oxidase-dependent reactive oxygen species (ROS) generation; (e) stimulates cytoskeletal remodeling and cell motility and (f) upregulates matrix metalloproteinase (MMP) 3 and 13. These findings suggest that TCTP induces tumorigenesis through distinct multicellular signaling pathways involving Src dependent EGFR transactivation, ROS generation and MMP expression. PMID- 21278789 TI - Downregulation of Spry2 by miR-21 triggers malignancy in human gliomas. AB - Gliomas are associated with high mortality because of their exceedingly invasive character. As these tumors acquire their invasiveness from low-grade tumors, it is very important to understand the detailed molecular mechanisms of invasion onset. Recent evidences suggest the significant role of microRNAs in tumor invasion. Thus, we hypothesized that deregulation of microRNAs may be important for the malignant progression of gliomas. We found that the aberrant expression of miR-21 is responsible for glioma invasion by disrupting the negative feedback circuit of Ras/MAPK signaling, which is mediated by Spry2. Upregulation of miR-21 was triggered by tumor microenvironmental factors such as hyaluronan and growth factors in glioma cells lacking functional phosphatase and tensin homolog (PTEN), but not harboring wild-type PTEN. Consistently with these in vitro results, Spry2 protein levels were significantly decreased in 79.7% of invasive WHO grade II-IV human glioma tissues, but not in non-invasive grade I and normal tissues. The Spry2 protein levels were not correlated with their mRNA levels, but inversely correlated with miR-21 levels. Taken together, these results suggest that the post-transcriptional regulation of Spry2 by miR-21 has an essential role on the malignant progression of human gliomas. Thus, Spry2 may be a novel therapeutic target for treating gliomas. PMID- 21278790 TI - alpha-Catulin knockdown induces senescence in cancer cells. AB - Cellular senescence functions as a tumor suppressor that protects against cancer progression. alpha-Catulin, an alpha-catenin-related protein, is reported to have tumorigenic potential because it regulates the nuclear factor-kappaB (NF-kappaB) pathway, but little is known about its clinical relevance and the mechanism through which it regulates cancer progression. Here, we found that alpha-catulin mRNA levels were significantly upregulated in cancer cell lines and clinical oral squamous cell carcinomas, which positively correlated with tumor size (P=0.001) and American Joint Committee on Cancer (AJCC) stage (P=0.004). alpha-Catulin knockdown in the OC2 and A549 cancer cell lines dramatically decreased cell proliferation and contributed to cellular senescence, and inhibited OC2 xenograft growth. Mechanistic dissection showed that alpha-catulin depletion strongly induced the DNA-damage response (DDR) in both cell lines, via a p53/p21-dependent pathway in A549 cells, but a p53/p21-independent pathway in OC2 cells carrying mutant p53. Global gene expression analysis revealed that alpha-catulin knockdown altered cell-cycle regulation and DDR pathways at the presenescent stage as well as significantly downregulate several crucial genes related to mitotic chromosome condensation, DDR and DNA repair systems, which suggests that its depletion induced cellular senescence might be caused by chromosome condensation failures, severe DNA damage and impaired DNA repair ability. Our study provides evidence that alpha-catulin promotes tumor growth by preventing cellular senescence and suggests that downregulating alpha-catulin may be a promising therapeutic approach for cancer treatment. PMID- 21278791 TI - Nucleophosmin and its complex network: a possible therapeutic target in hematological diseases. AB - Nucleophosmin (NPM, also known as B23, numatrin or NO38) is a ubiquitously expressed phosphoprotein belonging to the nucleoplasmin family of chaperones. NPM is mainly localized in the nucleolus where it exerts many of its functions, but a proportion of the protein continuously shuttles between the nucleus and the cytoplasm. A growing number of cellular proteins have been described as physical interactors of NPM, and consequently, NPM is thought to have a relevant role in diverse cellular functions, including ribosome biogenesis, centrosome duplication, DNA repair and response to stress. NPM has been implicated in the pathogenesis of several human malignancies and intriguingly, it has been described both as an activating oncogene and a tumor suppressor, depending on cell type and protein levels. In fact, increased NPM expression is associated with different types of solid tumors whereas an impairment of NPM function is characteristic of a subgroup of hematolologic malignancies. A large body of experimental evidence links the deregulation of specific NPM functions to cellular transformation, yet the molecular mechanisms through which NPM contributes to tumorigenesis remain elusive. In this review, we have summarized current knowledge concerning NPM functions, and attempted to interpret its multifaceted and sometimes apparently contradictory activities in the context of both normal cellular homeostasis and neoplastic transformation. PMID- 21278792 TI - Commentary. A picture of Mitf in melanoma immortality. AB - The Mitf gene has a key role in melanocytes and melanoma by regulating cell cycle progression, survival and differentiation. Two papers in this issue of Oncogene (Cheli et al., 2011; Strub et al., 2011) reveal that low-Mitf cells can initiate tumors with high efficiency, and that Mitf blocks senescence by regulating genes implicated in S-phase progression and mitosis. PMID- 21278793 TI - Integrin-linked kinase regulates melanoma angiogenesis by activating NF kappaB/interleukin-6 signaling pathway. AB - Integrin-linked kinase (ILK) is a highly conserved serine-threonine protein kinase involved in cell-extracellular matrix interactions, cytoskeletal organization and cell signaling. Overexpression of ILK in epithelial cells leads to anchorage-independent growth with increased cell cycle progression. Previously, we have shown that ILK upregulation strongly correlates with melanoma progression, invasion and inversely correlates with 5-year survival of melanoma patients. However, the molecular mechanism by which ILK enhances melanoma progression is currently unknown. In the present study, we found that proangiogenic molecule interleukin-6 (IL-6) is the downstream target of ILK in melanoma cells. ILK overexpression increased IL-6, whereas silencing of ILK suppressed IL-6 expression at both messenger RNA and protein levels. ILK also altered the activity and subcellular localization of nuclear factor-kappaB (NF kappaB) subunit p65. We further found that ILK enhanced the IL-6 gene transcription by promoting the binding of NF-kappaB p65 to IL-6 promoter. Moreover, ILK overexpression in melanoma cells enhanced the tube-forming ability of endothelial cells in vitro and microvessel formation in vivo. ILK-induced tube and blood vessel formation of endothelial cells was significantly reduced upon IL 6 inhibition in ILK-overexpressing melanoma cells. To delineate the mechanism by which ILK-induced IL-6 production can enhance angiogenesis, further analysis of the downstream targets of IL-6 signaling showed an increased activity of the signal transducer and activator of transcription 3 (STAT3) in ILK-overexpressing cells. As STAT3 binds to vascular endothelial growth factor (VEGF) promoter, we found that VEGF levels were elevated in ILK-overexpressing cells and declined upon transfection of IL-6 small interfering RNA, suggesting that ILK may regulate VEGF expression through IL-6 pathway by activating STAT3. PMID- 21278794 TI - NF-kappaB-dependent cytokine secretion controls Fas expression on chemotherapy induced premature senescent tumor cells. AB - Induction of a senescent phenotype in tumor cells has been linked to anticancer immune response, however, the molecular mechanisms mediating these phenomenon have not yet been determined. In this study, we present evidence that induction of premature senescence in human cancer cell lines induces Fas expression, and loss of resistance to Fas-induced apoptosis. Triggering of Fas by using the agonistic antibody CH11 or the recombinant ligand APO010, activates an apoptotic pathway responsible for cell death. Secretion of pro-inflammatory cytokines by the senescent cells, particularly TNF-alpha and IFN-gamma, mediates Fas upregulation. Indeed, treatment of proliferating cancer cell lines with TNF-alpha and IFN-gamma, upregulates Fas expression, while blocking TNF-alpha and IFN-gamma by using neutralizing antibodies, decreases Fas expression in senescent cells. We also demonstrate that NF-kappaB has a central role in controlling the senescence associated secretory phenotype (SASP) by the premature senescent cells, and that TNF-alpha and IFN-gamma, transcriptionally controlled by NF-kappaB, are the main mediators of Fas upregulation. Our data suggest the existence of an NF-kappaB dependent autocrine loop, mediated by TNF-alpha and IFN-gamma, responsible for expression of Fas on the surface of senescent cells, and for their killing. PMID- 21278795 TI - TGF-beta-induced IRAK-M expression in tumor-associated macrophages regulates lung tumor growth. AB - Tumor-associated macrophages (TAMs) constitute a major component of the immune cell infiltrate observed in the tumor microenvironment (TME). Factors present in the TME, including tumor growth factor-beta (TGF-beta), allow tumors to circumvent host-mediated immune responses to promote tumor progression. However, the molecular mechanism(s) involved are not clear. Toll-like receptors (TLRs) are important mediators of innate immune responses by immune cells, whose activation triggers the production of molecules required for anti-tumoral responses. Interleukin (IL) receptor-associated kinase (IRAK)-M is an inactive serine/threonine kinase, predominantly expressed in macrophages and is a potent negative regulator of TLR signaling. In this study, we show that TAMs express significantly higher levels of IRAK-M compared with peritoneal macrophages in a syngeneic mouse model of lung cancer. Subcutaneous implantation of Lewis lung carcinoma cells in IRAK-M(-/-) mice resulted in a five-fold reduction in tumor growth as compared with tumors in wild-type (WT) animals. Furthermore, compared with WT TAMs, TAMs isolated from IRAK-M(-/-) mice displayed features of a classically activated (M1) rather than alternatively activated (M2) phenotype, as manifest by greater expression of IL-12, interferon-gamma (IFN-gamma) and inducible nitric oxide synthase. Human lung cancer cells induced IRAK-M expression in human peripheral blood mononuclear cells (PBMCs) when co-cultured together. Tumor cell-induced expression of IRAK-M was dependent on the activation of TGF-beta pathway. Similarly, treatment of human PBMCs or mouse macrophage cell line, RAW 264.4, with TGF-beta, induced IRAK-M expression. Interestingly, IRAK-M gene expression in 439 human lung adenocarcinoma tumors correlated with poor survival in patients with lung cancer. Together, our data demonstrates that TGF beta-dependent induction of IRAK-M expression is an important, clinically relevant mechanism by which tumors may circumvent anti-tumor responses of macrophages. PMID- 21278796 TI - Efficacy of and resistance to anti-IGF-1R therapies in Ewing's sarcoma is dependent on insulin receptor signaling. AB - Identification of patient selection criteria and understanding of the potential mechanisms involved in the development of resistance are crucial for an appropriate and successful design of clinical trials with anti-insulin-like growth factor (IGF)-1R therapies. Few Ewing's sarcomas are highly sensitive to IGF-1R targeting and understanding the reason why, may hold the secret to improve successful treatments. In this paper, we show that a major mechanism of resistance to highly specific inhibitors of IGF-1R, either antibodies or tyrosine kinase inhibitors may involve enhanced insulin receptor (IR)-A homodimer formation and IGF-2 production. Resistant cells are able to switch from IGF-1/IGF 1R to IGF-2/IR-A dependency to maintain sustained activation of AKT and ERK1/2, proliferation, migration and metastasis. These cells also showed higher proliferative response to insulin, in keeping with a switch towards insulin pathways sustaining proliferation and malignancy, rather than metabolism. Our findings demonstrate a role for IR-A in eliciting intrinsic and adaptive resistance to anti-IGF-1R therapies. Thus, we indicate that tumors with low IGF 1R:IR ratio are unlikely to greatly benefit from anti-IGF-1R therapies and that the efficacy of anti-IGF-1R therapies should be evaluated in relationship to the IR-A:IGF-1R ratio in cancer cells. Moreover, we provide evidences supporting IR-A as an important target in sarcoma therapy. PMID- 21278797 TI - Mitf is the key molecular switch between mouse or human melanoma initiating cells and their differentiated progeny. AB - In melanoma, as well as in other solid tumors, the cells within a given tumor exhibit strong morphological, functional and molecular heterogeneity that might reflect the existence of different cancer cell populations, among which are melanoma-initiating cells (MICs) with 'stemness' properties and their differentiated, fast-growing progeny. The existence of a slow-growing population might explain the resistance of melanoma to classical chemotherapies that target fast growing cells. Therefore, elucidating the biologic properties of MICs and, more importantly, the molecular mechanisms that drive the transition between MICs and their proliferating progeny needs to be addressed to develop an efficient melanoma therapy. Using B16 mouse melanoma cells and syngeneic mice, we show that the inhibition of microphthalmia-associated transcription factor (Mitf), the master regulator of melanocyte differentiation, increases the tumorigenic potential of melanoma cells and upregulates the stem cell markers Oct4 and Nanog. Notably, p27, the CDK inhibitor, is increased in Mitf-depleted cells and is required for exacerbation of the tumorigenic properties of melanoma cells. Further, a slow-growing population with low-Mitf level and high tumorigenic potential exists spontaneously in melanoma. Ablation of this population dramatically decreases tumor formation. Importantly, these data were confirmed using human melanoma cell lines and freshly isolated human melanoma cell from lymph node and skin melanoma metastasis. Taken together our data, identified Mitf and p27 as the key molecular switches that control the transition between MICs and their differentiated progeny. Eradication of low-Mitf cells might be an appealing strategy to cure melanoma. PMID- 21278798 TI - Changes in echocardiographic measures of systolic and diastolic function in children 1 year after hematopoietic SCT. AB - Hematopoietic SCT (HSCT) is a life-saving therapy in children, but has been associated with heart failure. Little is known about subclinical changes in cardiac function. We examined changes in systolic and diastolic function from pre to 1-year post HSCT by echocardiography. All patients (n=74, 61% men, median age 9.1 years, mean left-ventricular (LV) ejection fraction 61.3+/-4.9%) who underwent HSCT at Children's Hospital Boston between 2005 and 2008, were <21 years at time of HSCT, and had routine pre- and 1-year post echocardiograms were included. Systolic function parameters, including LV ejection fraction, rate corrected velocity of fiber shortening (Vcfc) and stress-velocity index and diastolic parameters, including tissue Doppler imaging (TDI)-derived velocities, and left-ventricular flow propagation, were compared before and after transplant. At 1-year post HSCT, systolic function, as measured by Vcfc (1.10+/-0.15 vs 1.04+/-0.12 circ/s; P=0.03) and stress-velocity index (z-score 0.40+/-1.4 vs 0.20+/-1.1; P=0.02), had worsened; diastolic function parameters, including mitral E' velocity (16.6+/-3.9 vs 15.0+/-3.4 cm/s; P=0.01) and tricuspid E' velocity (14.3+/-3.6 vs 12.4+/-2.8 cm/s; P=0.002) had also decreased. At 1-year post HSCT, children have subclinical declines in systolic and diastolic function. These small changes might become clinically important over time. Serial non invasive assessment of cardiac function should be considered in all children following HSCT. PMID- 21278799 TI - Successful treatment with rituximab and donor lymphocyte infusions for fulminant EBV-associated lymphoproliferative disorder that developed 14 years after unrelated BMT. PMID- 21278800 TI - RASSF7 negatively regulates pro-apoptotic JNK signaling by inhibiting the activity of phosphorylated-MKK7. AB - Members of the Ras-association domain family (RASSF) of proteins influence apoptosis and cell cycling but little is known about the mechanisms. Here, we show that RASSF7 interacts with N-Ras and mitogen-activated protein kinase kinase 7 (MKK7) to negatively regulate c-Jun N-terminal kinase (JNK) signaling. Stress induced JNK activation and apoptosis were markedly enhanced in cells depleted of RASSF7 or N-Ras by RNAi knockdown. An interaction with RASSF7 promoted the phosphorylated state of MKK7 but inhibited this kinase's ability to activate JNK. RASSF7 required its RA domain for both interaction with GTP-bound N-Ras and the anti-apoptotic response to stress stimuli. Following prolonged stress, however, RASSF7's anti-apoptotic effect was eliminated because of degradation of RASSF7 protein via the ubiquitin-proteasome pathway. Our results indicate that RASSF7 acts in concert with N-Ras to constitute a stress-sensitive temporary mechanism of apoptotic regulation. With initial stress, RASSF7/N-Ras promotes cell survival by inhibiting the MKK7/JNK pathway. However, with prolonged stress, RASSF7 protein undergoes degradation that allows cell death signaling to proceed. Our findings may account for the association of elevated RASSF7 with tumorigenesis. PMID- 21278801 TI - Bnip3 impairs mitochondrial bioenergetics and stimulates mitochondrial turnover. AB - Bnip3 (Bcl-2/adenovirus E1B 19-kDa-interacting protein 3) is a mitochondrial BH3 only protein that contributes to cell death through activation of the mitochondrial pathway of apoptosis. Bnip3 is also known to induce autophagy, but the functional role of autophagy is unclear. In this study, we investigated the relationship between mitochondrial dysfunction and upregulation of autophagy in response to Bnip3 in cells lacking Bax and Bak. We found that Bnip3 induced mitochondrial autophagy in the absence of mitochondrial membrane permeabilization and Bax/Bak. Also, co-immunoprecipitation experiments showed that Bnip3 interacted with the autophagy protein LC3 (microtubule-associated protein light chain 3). Although Bax-/Bak-deficient cells were resistant to Bnip3-mediated cell death, inhibition of mitochondrial autophagy induced necrotic cell death. When investigating why these mitochondria had to be removed by autophagy, we discovered that Bnip3 reduced both nuclear- and mitochondria-encoded proteins involved in oxidative phosphorylation. Interestingly, Bnip3 had no effect on other mitochondrial proteins, such as Tom20 and MnSOD, or actin and tubulin in the cytosol. Bnip3 did not seem to reduce transcription or translation of these proteins. However, we found that Bnip3 caused an increase in mitochondrial protease activity, suggesting that Bnip3 might promote degradation of proteins in the mitochondria. Thus, Bnip3-mediated impairment of mitochondrial respiration induces mitochondrial turnover by activating mitochondrial autophagy. PMID- 21278802 TI - Singular Value Decomposition of Pinhole SPECT Systems. AB - A single photon emission computed tomography (SPECT) imaging system can be modeled by a linear operator H that maps from object space to detector pixels in image space. The singular vectors and singular-value spectra of H provide useful tools for assessing system performance. The number of voxels used to discretize object space and the number of collection angles and pixels used to measure image space make the matrix dimensions H large. As a result, H must be stored sparsely which renders several conventional singular value decomposition (SVD) methods impractical. We used an iterative power methods SVD algorithm (Lanczos) designed to operate on very large sparsely stored matrices to calculate the singular vectors and singular-value spectra for two small animal pinhole SPECT imaging systems: FastSPECT II and M(3)R. The FastSPECT II system consisted of two rings of eight scintillation cameras each. The resulting dimensions of H were 68921 voxels by 97344 detector pixels. The M(3)R system is a four camera system that was reconfigured to measure image space using a single scintillation camera. The resulting dimensions of H were 50864 voxels by 6241 detector pixels. In this paper we present results of the SVD of each system and discuss calculation of the measurement and null space for each system. PMID- 21278803 TI - Maximum Likelihood Event Estimation and List-mode Image Reconstruction on GPU Hardware. AB - The scintillation detectors commonly used in SPECT and PET imaging and in Compton cameras require estimation of the position and energy of each gamma ray interaction. Ideally, this process would yield images with no spatial distortion and the best possible spatial resolution. In addition, especially for Compton cameras, the computation must yield the best possible estimate of the energy of each interacting gamma ray. These goals can be achieved by use of maximum likelihood (ML) estimation of the event parameters, but in the past the search for an ML estimate has not been computationally feasible. Now, however, graphics processing units (GPUs) make it possible to produce optimal, real-time estimates of position and energy, even from scintillation cameras with a large number of photodetectors. In addition, the mathematical properties of ML estimates make them very attractive for use as list entries in list-mode ML image reconstruction. This two-step ML process-using ML estimation once to get the list data and again to reconstruct the object-allows accurate modeling of the detector blur and, potentially, considerable improvement in reconstructed spatial resolution. PMID- 21278804 TI - Metoclopramide in the treatment of diabetic gastroparesis. AB - Gastroparesis is a chronic disorder that affects a significant subset of the population. Diabetes mellitus is a risk factor for the development of gastroparesis. Currently, metoclopramide is the only US FDA-approved medication for the treatment of gastroparesis. However, the FDA recently placed a black-box warning on metoclopramide because of the risk of related side effects, including tardive dyskinesia, the incidence of which has been cited to be as high as 15% in the literature. This review will investigate the mechanisms by which metoclopramide improves the symptoms of gastroparesis and will focus on the evidence of clinical efficacy supporting metoclopramide use in gastroparesis. Finally, we seek to document the true complication risk from metoclopramide, especially tardive dyskinesia, by reviewing the available evidence in the literature. Potential strategies to mitigate the risk of complications from metoclopramide will also be discussed. PMID- 21278805 TI - Towards a dynamical network view of brain ischemia and reperfusion. Part III: therapeutic implications. AB - The general failure of neuroprotectants in clinical trials of ischemic stroke points to the possibility of a fundamental blind spot in the current conception of ischemic brain injury, the "ischemic cascade". This is the third in a series of four papers whose purpose is to work towards a revision of the concept of brain ischemia by applying network concepts to develop a bistable model of brain ischemia. Here the bistable model of brain ischemia is compared to the ischemic cascade concept. The core weakness of the ischemic cascade concept is revealed to be its assumption of superposition, or that the elements of the ischemic cascade can be summed as linearly independent events. This assumption leads to a concept of neuroprotection as a subtraction of ostensibly independent damage events. The bistable model offers a different concept of neuroprotection where the role of individual molecular pathways decreases in relevance with respect to the efficacy of outcome. Network thinking provides a framework for critical assessment of widely-used preclinical experimental approaches. The importance of allometric scaling is also discussed. We illustrate that the bistable model provides a viable alternative to the ischemic cascade as an explanatory framework and as a guide for therapeutic development. PMID- 21278806 TI - Does weight status influence weight-related beliefs and the consumption of sugar sweetened beverages and fast food purchases in adolescents? AB - OBJECTIVE: To determine if weight status affects the relationship between weight related beliefs and consumption of sugar-sweetened beverages (SSB) and fast and convenience store food purchases (FCFP). DESIGN: Observational, cross-sectional. SETTING: Twin Cities Metropolitan area, Minnesota, USA. METHODS: Body composition and psychosocial survey were obtained for 345 adolescents. General Linear Models tested adjusted (age and sex) associations between weight-related beliefs and consumption of SSB and FCFP. Significant associations were tested for moderation by weight status. RESULTS: SSB was positively related to perceptions that people worry too much about their weight (beta = 0.103, p = 0.016), with no moderation present. FCFP were positively associated to perceived barriers to maintaining a healthy weight (beta = 0.042, p = 0.004) with a subsequent significant interaction by weight status. Stratified models showed a significant association between perceived barriers to a healthy weight and FCFP for overweight adolescents (beta = 0.345, p = 0.022). CONCLUSIONS: Addressing perceived barriers to a healthy diet may lead to important risk reduction. PMID- 21278807 TI - Conflict Resolution in Mexican-Origin Couples: Culture, Gender, and Marital Quality. AB - This study examined associations between Mexican-origin spouses' conflict resolution strategies (i.e., nonconfrontation, solution orientation, and control) and (a) gender-typed qualities and attitudes, (b) cultural orientations, and (c) marital quality in a sample of 227 couples. Results of multilevel modeling revealed that Mexican cultural orientations were positively associated with solution orientation, and Anglo cultural orientations were negatively associated with nonconfrontation. Expressive personal qualities were negatively associated with control, whereas instrumental qualities were positively related to control. Links between conflict resolution and marital quality revealed that control and nonconfrontation were associated with spouses' ratings of marital negativity. In some cases, different patterns emerged for husbands and wives. Discussion highlights the role of culture and gender dynamics in marital relationships. PMID- 21278808 TI - STOCHASTIC KINETIC MODELS: DYNAMIC INDEPENDENCE, MODULARITY AND GRAPHS. AB - The dynamic properties and independence structure of stochastic kinetic models (SKMs) are analyzed. An SKM is a highly multivariate jump process used to model chemical reaction networks, particularly those in biochemical and cellular systems. We identify SKM subprocesses with the corresponding counting processes and propose a directed, cyclic graph (the kinetic independence graph or KIG) that encodes the local independence structure of their conditional intensities. Given a partition [A, D, B] of the vertices, the graphical separation A ? B|D in the undirected KIG has an intuitive chemical interpretation and implies that A is locally independent of B given A ? D. It is proved that this separation also results in global independence of the internal histories of A and B conditional on a history of the jumps in D which, under conditions we derive, corresponds to the internal history of D. The results enable mathematical definition of a modularization of an SKM using its implied dynamics. Graphical decomposition methods are developed for the identification and efficient computation of nested modularizations. Application to an SKM of the red blood cell advances understanding of this biochemical system. PMID- 21278809 TI - 3D gradient echo sequence provides better images in contrast-enhanced imaging of the pituitary gland at 3 T. PMID- 21278810 TI - An RNA Sensor Platform for CTC Detection: Nanotechnology for Detection of Tumour Cell Marker RNAs. AB - There is great interest in the detection of circulating tumour cells (CTCs) as an important diagnostic and prognostic indicator for patients with many (if not all) types of cancer, and many studies have established that the absolute level of CTCs is a critical determinant. Given that, most studies in the field now utilise reverse transcription/polymerase chain reaction-based measurements, focussing on selected marker RNAs for the particular tumour type. However, such measurements mandate choosing the marker RNAs in advance, and only a limited number of markers can be examined in the reactions. Clearly, a more robust assay would allow simultaneous measurement of many different RNAs, and the ability to look for many different types of cancer would provide a major advantage as a potential screening tool. PMID- 21278811 TI - Effect of low doses of lipopolysaccharide prior to ozone exposure on bronchoalveolar lavage: Differences between wild type and surfactant protein A deficient mice. AB - BACKGROUND: Several aspects of the inflammatory response to a single insult, i.e., exposure to 2 ppm of ozone (O(3)) for 3 h or 6 h, are less pronounced in surfactant protein A deficient (SP-A -/-) mice (KO) than in wild type mice (WT). It was hypothesized that a mild insult, specifically low doses of lipopolysaccharide (LPS), would adversely affect host defense and differentially potentiate O(3)-induced injury in WT and KO mice. METHODS: WT and KO mice were treated with different doses of LPS or LPS (2 ng) + O(3) (2 ppm) or filtered air (FA) for 3 h, then sacrificed 4 h following exposure (O(3), FA) or 20 h after LPS treatment alone. Several endpoints of inflammation were measured in bronchoalveolar lavage (BAL). RESULTS: 1) At 20 h after LPS treatment alone, both WT and KO mice exhibited signs of inflammation, but with differences in the macrophage inflammatory protein 2 (MIP-2) response pattern, total cells (at 0.5 ng LPS) and basal levels of oxidized protein and phospholipids; 2) After LPS + O(3), KO compared to WT showed decrease in polymorphonuclear leukocytes (PMNs) and MIP-2 and increase in phospholipids, and after LPS + FA an increase in total cells; 3) WT after LPS + FA showed an increase in SP-A with no further increase after LPS + O(3), and an increase in oxidized SP-A dimer following O(3) or LPS + O(3). CONCLUSIONS: LPS treatment has negative effects on inflammation endpoints in mouse BAL long after exposure and renders KO mice less capable of responding to a second insult. LPS and O(3) affect SP-A, quantitatively and qualitatively, respectively. PMID- 21278812 TI - The Behavioral and Pharmacological Actions of NMDA Receptor Antagonism are Conserved in Zebrafish Larvae. AB - Dizocilpine maleate (MK-801) is one of several NMDA receptor antagonists that is widely used to pharmacologically model the symptoms of psychosis and schizophrenia in animals. MK-801 elicits behaviors in adult zebrafish (Danio rerio) that are phenotypically consistent with behaviors observed in humans and rodents exposed to tbhe drug. However, the molecular and cellular processes that mediate the psychotomimetic, cognitive and locomotive behaviors of MK-801 are unclear. We exposed zebrafish larvae to MK-801 to assess their merit as a model organism to elucidate the behavioral effects of NMDA receptor blockade. Zebrafish larvae were acutely immersed in MK-801 to assess the effect on spontaneous swimming. MK-801 caused a time- and dose-dependent increase in larval swim speed, and the peak response (a five-fold increase in swim speed) was evoked by a three h exposure to a 20 uM dose. Zebrafish larvae did not exhibit sensitivity to the locomotor effects of MK-801 until 5 dpf, suggesting a critical role for developmental in sensitivity to the drug. Exposure to the low potency NMDA antagonist, memantine, did not alter the swim speed of zebrafish larvae. Co immersion in D(1) or D(2) dopamine receptor antagonists did not disrupt the time course or magnitude of the increase in swim speed, suggesting dopaminergic signaling is not required for the locomotor actions of MK-801. Our findings of the behavioral actions of MK-801 in zebrafish larvae are consistent with previous observations in mammals and imply that the physiological, cellular and molecular processes disrupted by MK-801 are conserved in zebrafish larvae. These data suggest that the zebrafish larvae is a valid and useful model to elucidate neurobehavioral aspects of NMDA receptor antagonism and may provide insight to the neurobiology of psychosis and schizophrenia. PMID- 21278814 TI - The effect of varying alkaloid concentrations on the feeding behavior of gypsy moth larvae, Lymantria dispar (L.) (Lepidoptera: Lymantriidae). AB - Nine alkaloids (acridine, aristolochic acid, atropine, berberine, caffeine, nicotine, scopolamine, sparteine, and strychnine) were evaluated as feeding deterrents for gypsy moth larvae (Lymantria dispar (L.); Lepidoptera: Lymantriidae). Our aim was to determine and compare the taste threshold concentrations, as well as the ED(50) values, of the nine alkaloids to determine their potency as feeding deterrents. The alkaloids were applied to disks cut from red oak leaves (Quercus rubra) (L.), a plant species highly favored by larvae of this polyphagous insect species. We used two-choice feeding bioassays to test a broad range of biologically relevant alkaloid concentrations spanning five logarithmetic steps. We observed increasing feeding deterrent responses for all the alkaloids tested and found that the alkaloids tested exhibited different deterrency threshold concentrations ranging from 0.1 mM to 10 mM. In conclusion, it appears that this generalist insect species bears a relatively high sensitivity to these alkaloids, which confirms behavioral observations that it avoids foliage containing alkaloids. Berberine and aristolochic acid were found to have the lowest ED(50) values and were the most potent antifeedants. PMID- 21278813 TI - LINCing lamin B2 to neuronal migration: growing evidence for cell-specific roles of B-type lamins. AB - Nuclear lamins are major components of the nuclear lamina, and play essential roles in supporting the nucleus and organizing nuclear structures. While a large number of clinically important mutations have been mapped to the LMNA gene in humans, very few mutations have been associated with the B-type lamins. We have shown that lamin B2-deficiency in mice results in severe brain abnormalities. While the early stages of forebrain development in lamin B2-deficient mice appear to be normal, cortical neurons fail to migrate and organize into proper layers within the cerebral cortex. The morphogenesis of the hippocampus and cerebellum is also severely impaired. These phenotypes are reminiscent of lissencephaly, a human brain developmental disorder characterized by an abnormal neuronal migration. Most mutations in lissencephaly patients affect cytoplasmic regulators of nuclear translocation, which is a crucial step in neuronal migration. The phenotypes of lamin B2-deficient mice suggest that lamin B2 may also play a key role in nuclear translocation. Potential mechanisms for lamin B2 involvement, which include mechanical and non-mechanical roles, and participation in LINC complexes in the nuclear envelope, are discussed along with evidence that lamins B1 and B2 play distinct, cell-specific functions. PMID- 21278815 TI - Hybrid, elastomeric hydrogels crosslinked by multifunctional block copolymer micelles. AB - Amphiphlic block copolymers consisting of hydrophilic, poly(acrylic acid) randomly decorated with acrylate groups and hydrophobic, rubbery poly(n-butyl acrylate) self-assembled into well-defined micelles with an average diameter of ~21 nm. Radical polymerization of acrylamide in the presence of the crosslinkable micelles gave rise to hybrid, elastomeric hydrogels whose mechancial properties can be readily tuned by varying the BCM concentration. PMID- 21278816 TI - TETRAHEDRAL MESH GENERATION FOR MEDICAL IMAGES WITH MULTIPLE REGIONS USING ACTIVE SURFACES. AB - In this paper, we present a method for automatically generating tetrahedral meshes from 3D images with multiple region labels. The first step consists of constructing an adaptively sized tetrahedral mesh that conforms exactly to the voxelized regions in the image. Active surfaces (active contours in 2D) are then employed to smooth the region boundaries and remove the voxelization. Specifically, an energy with three terms is minimized: a smoothing term to remove the voxelization, a fidelity term to keep the mesh from moving too far away from the image data, and an elasticity term to keep the tetrahedra from becoming flattened or inverted as the mesh deforms. The algorithm for tetrahedral mesh generation is applied to an MRI image that has been automatically segmented using an existing method. The resulting mesh has a number of desirable properties such as tetrahedra with all dihedral angles away from 0 and 180 degrees, smoothness, and a high level of detail for the number of tetrahedra used. PMID- 21278817 TI - Perceptions of and Experience With System Responses to Female Same-Sex Intimate Partner Violence. AB - Female same-sex intimate partner violence (FSSIPV) is a significant problem that affects the physical and mental health and the safety of sexual minority women. A mixed-methods study was conducted to (a) identify risk and protective factors for victimization and perpetration of repeat violence in abusive same-sex relationships and (b) examine participant experiences with system responses (by domestic violence services, criminal justice systems, and health care services) to FSSIPV. The purpose of the article is to report the findings from the qualitative component (e.g., focus groups and individual interviews) of the parent study that are specific to survivors' perceptions of and experiences with domestic violence services, criminal justice systems, and health care services. The findings indicate a significant need across all systems for increased awareness, enhanced understanding, and provision of services specific to survivors of FSSIPV. PMID- 21278818 TI - What do conscientious people do? Development and validation of the Behavioral Indicators of Conscientiousness (BIC). AB - Typical assessments of personality traits collapse behaviors, thoughts, and feelings into a single measure without distinguishing between these different manifestations. To address this lack of specification, the current study develops and validates a measure that assesses a number of broad behaviors associated with the personality trait of conscientiousness (the Behavioral Indicators of Conscientiousness; BIC). Findings suggest that the lower-order structure of conscientious behaviors is mostly similar to the lower-order structure in extant trait measures. Furthermore, a daily diary method was used to validate the BIC against frequency counts of conscientious behavior. Overall, the results identify specific behaviors that conscientious individuals tend to perform and highlight possible advantages of this approach over broad trait assessment. PMID- 21278819 TI - Cell Free Translation in Engineered Picoliter Volume Containers. AB - Engineers seek to use biological design principles to manipulate information and import new functionality to synthetic devices. Such devices inspired by natural systems could, in turn, play a crucial role in allowing biologists to explore the effects of physical transport and extreme conditions of temperature and pH on reaction systems. For example, engineered reaction containers can be physically and chemically defined to control the flux of molecules of different sizes and charge. The design and testing of such a container is described here. It has a volume of 19pL with defined slits of 200nm. The device successfully contained DNA and protein molecules and is evaluated for carrying out cell-free protein synthesis. The effect of DNA concentration and slit size on protein yield is discussed. PMID- 21278820 TI - Intelligent Interfaces for Mining Large-Scale RNAi-HCS Image Databases. AB - Recently, High-content screening (HCS) has been combined with RNA interference (RNAi) to become an essential image-based high-throughput method for studying genes and biological networks through RNAi-induced cellular phenotype analyses. However, a genome-wide RNAi-HCS screen typically generates tens of thousands of images, most of which remain uncategorized due to the inadequacies of existing HCS image analysis tools. Until now, it still requires highly trained scientists to browse a prohibitively large RNAi-HCS image database and produce only a handful of qualitative results regarding cellular morphological phenotypes. For this reason we have developed intelligent interfaces to facilitate the application of the HCS technology in biomedical research. Our new interfaces empower biologists with computational power not only to effectively and efficiently explore large-scale RNAi-HCS image databases, but also to apply their knowledge and experience to interactive mining of cellular phenotypes using Content-Based Image Retrieval (CBIR) with Relevance Feedback (RF) techniques. PMID- 21278821 TI - A New Stopping Rule for Computerized Adaptive Testing. AB - The goal of the current study was to introduce a new stopping rule for computerized adaptive testing. The predicted standard error reduction stopping rule (PSER) uses the predictive posterior variance to determine the reduction in standard error that would result from the administration of additional items. The performance of the PSER was compared to that of the minimum standard error stopping rule and a modified version of the minimum information stopping rule in a series of simulated adaptive tests, drawn from a number of item pools. Results indicate that the PSER makes efficient use of CAT item pools, administering fewer items when predictive gains in information are small and increasing measurement precision when information is abundant. PMID- 21278822 TI - Bipolar and ADHD Comorbidity: Both Artifact and Outgrowth of Shared Mechanisms. AB - Published rates of comorbidity between pediatric bipolar disorder (PBD) and attention-deficit/hyperactivity disorder (ADHD) have been higher than would be expected if they were independent conditions, but also dramatically different across different studies. This review examines processes that could artificially create the appearance of comorbidity or substantially bias estimates of the ADHD BPD comorbidity rate, including: categorization of dimensional constructs, overlap among diagnostic criteria, over-splitting, developmental sequencing, and referral or surveillance biases. Evidence also suggests some mechanisms for "true" BPD-ADHD comorbidity, including shared risk factors, distinct subtypes, and weak causal relationships. Keys to differential diagnosis include focusing on episodic presentation and non-overlapping symptoms unique to mania. PMID- 21278823 TI - AIs: implications for fractures in perimenopausal women with breast cancer. PMID- 21278824 TI - Automatically Detecting Pain Using Facial Actions. AB - Pain is generally measured by patient self-report, normally via verbal communication. However, if the patient is a child or has limited ability to communicate (i.e. the mute, mentally impaired, or patients having assisted breathing) self-report may not be a viable measurement. In addition, these self report measures only relate to the maximum pain level experienced during a sequence so a frame-by-frame measure is currently not obtainable. Using image data from patients with rotator-cuff injuries, in this paper we describe an AAM based automatic system which can detect pain on a frame-by-frame level. We do this two ways: directly (straight from the facial features); and indirectly (through the fusion of individual AU detectors). From our results, we show that the latter method achieves the optimal results as most discriminant features from each AU detector (i.e. shape or appearance) are used. PMID- 21278825 TI - DIRECT RECONSTRUCTION OF DYNAMIC PET PARAMETRIC IMAGES USING SPARSE SPECTRAL REPRESENTATION. AB - To generate parametric images for dynamic PET, direct reconstruction from projection data is statistically more efficient than conventional indirect methods that perform image reconstruction and kinetic modeling in two separate steps. Existing direct reconstruction methods often use nonlinear compartmental models, which require the knowledge of model order. This paper presents a direct reconstruction approach using a linear spectral representation and does not require model order assumption. A Laplacian prior is used to ensure sparsity in the spectral representation. The resultant maximum a posteriori (MAP) formulation is solved by an expectation maximization shrinkage algorithm. A bias correction step is developed to improve the MAP estimate. Computer simulations show that the proposed method achieves better bias-variance tradeoff than a conventional indirect method for estimating parametric images from dynamic PET data. PMID- 21278826 TI - Statistical Three-Dimensional Positioning Algorithm for High-Resolution dMiCE PET Detector. AB - Our laboratory is developing a high-resolution PET detector capable of providing depth-of-interaction information (dMiCE) by tailoring the light sharing between two adjacent detector elements. Each detector element in the prototype system has a 2*2 mm(2) cross section and is directly coupled to a micro-pixel avalanche photodiode (MAPD). In this setup the distribution of the ratio of light shared between two adjacent detector elements can be expressed as a function of the depth of interaction. The three-dimensional points of interaction of a coincidence pair of photons within the detector module is estimated by numerical calculation of an expectation of the points of interaction conditioned on the signals measured by the MAPDs (Bayesian estimate). This conditional expectation is computed from estimates of the probability density function of the light collection process and a model of the kinetics of photon interactions in the detector module. Our algorithm is capable of handling coincidences where each photon interacts any number of times within the detector module before being completely absorbed or escaping. In the case of multiple interactions our algorithm estimates the position of the first interaction for each of the coincidence photons. PMID- 21278827 TI - Smoking Cessation Services in Adolescent Substance Abuse Treatment: Opportunities Missed? AB - The majority of adolescents receiving substance abuse treatment also use tobacco, yet there are few data regarding the adoption of tobacco use assessment and smoking cessation services by adolescent treatment programs. Using data from a national sample of adolescent-only treatment programs (n = 154), this research measures the adoption of aspects of assessment and treatment from the Public Health Service's (2000) guideline, Treating Tobacco Use and Dependence. When adoption of four intake/assessment practices was measured, adoption appeared high, but only 45% of programs had adopted all four practices. About 43% of programs offered some type of smoking cessation services. However, there was no association between adoption of intake procedures and the odds of availability of smoking cessation services, suggesting a lack of connection between the identification of treatment needs and the availability of services. The lack of smoking cessation services may represent a missed opportunity for early intervention with this population. PMID- 21278828 TI - AN EFFICIENT NUMERICAL METHOD FOR THE SOLUTION OF THE L(2) OPTIMAL MASS TRANSFER PROBLEM. AB - In this paper we present a new computationally efficient numerical scheme for the minimizing flow approach for the computation of the optimal L(2) mass transport mapping. In contrast to the integration of a time dependent partial differential equation proposed in [S. Angenent, S. Haker, and A. Tannenbaum, SIAM J. Math. Anal., 35 (2003), pp. 61-97], we employ in the present work a direct variational method. The efficacy of the approach is demonstrated on both real and synthetic data. PMID- 21278829 TI - Propositions for the Study of Moral Personality Development. AB - Most of us have at one point speculated about why one individual grew up to be honest and fair while another became wicked and untrustworthy. In the current review, we present the case that new directions in the empirical study of moral personality development are needed. We set the stage for this future work by presenting six propositions that should serve as the foundation for future research in the field. We conclude by providing an example of how using a more integrative and inclusive framework for studying personality can readily incorporate these propositions. PMID- 21278830 TI - Disposition kinetics of a dipeptide ester prodrug of acyclovir and its metabolites following intravenous and oral administrations in rat. AB - The objective of this work was to study the disposition kinetics of valine-valine acyclovir (VVACV), a dipeptide ester prodrug of acyclovir following intravenous and oral administrations in rat. A validated LC-MS/MS analytical method was developed for the analysis VVACV, Valine-Acyclovir (VACV), and Acyclovir (ACV) using a linear Ion Trap Quadrupole. ACV was administered orally for comparison purpose. In the VVACV group, both blood and urine samples and in the ACV group only blood samples were collected. All the samples were analyzed using LC-MS/MS. The LLOQ for ACV, VACV, and VVACV were 10, 10, and 50 ng/ml, respectively. Relevant pharmacokinetic parameters were obtained by non-compartmental analyses of data with WinNonlin. Following i.v. administration of VVACV, AUC(0-inf) (min*uM) values for VVACV, VACV, and ACV were 55.06, 106, and 466.96, respectively. The AUC obtained after oral administration of ACV was 178.8. However, following oral administration of VVACV, AUC(0-inf) values for VACV and ACV were 89.28 and 810.77, respectively. Thus the exposure of ACV obtained following oral administration of VVACV was almost 6-fold higher than ACV. This preclinical pharmacokinetic data revealed that VVACV has certainly improved the oral bioavailability of ACV and is an effective prodrug for oral delivery of ACV. PMID- 21278832 TI - Recent advances in the synthetic and mechanistic aspects of the ruthenium catalyzed carbon-heteroatom bond forming reactions of alkenes and alkynes. AB - The group's recent advances in catalytic carbon-to-heteroatom bond forming reactions of alkenes and alkynes are described. For the C-O bond formation reaction, a well-defined bifunctional ruthenium-amido catalyst has been successfully employed for the conjugate addition of alcohols to acrylic compounds. The ruthenium-hydride complex (PCy(3))(2)(CO)RuHCl was found to be a highly effective catalyst for the regioselective alkyne-to-carboxylic acid coupling reaction in yielding synthetically useful enol ester products. Cationic ruthenium-hydride catalyst generated in-situ from (PCy(3))(2)(CO)RuHCl/HBF(4).OEt(2) was successfully utilized for both the hydroamination and related C-N bond forming reactions of alkenes. For the C-Si bond formation reaction, regio- and stereoselective dehydrosilylation of alkenes and hydrosilylation of alkynes have been developed by using a well-defined ruthenium-hydride catalyst. Scope and mechanistic aspects of these carbon-to heteroatom bond-forming reactions are discussed. PMID- 21278831 TI - Neuropharmacology of Sleep and Wakefulness. AB - The development of sedative/hypnotic molecules has been empiric rather than rational. The empiric approach has produced clinically useful drugs but for no drug is the mechanism of action completely understood. All available sedative/hypnotic medications have unwanted side effects and none of these medications creates a sleep architecture that is identical to the architecture of naturally occurring sleep. This chapter reviews recent advances in research aiming to elucidate the neurochemical mechanisms regulating sleep and wakefulness. One promise of rational drug design is that understanding the mechanisms of sedative/hypnotic action will significantly enhance drug safety and efficacy. PMID- 21278833 TI - Phantom experiments on a PSAPD-based compact gamma camera with submillimeter spatial resolution for small animal SPECT. AB - We demonstrate a position sensitive avalanche photodiode (PSAPD) based compact gamma camera for the application of small animal single photon emission computed tomography (SPECT). The silicon PSAPD with a two-dimensional resistive layer and four readout channels is implemented as a gamma ray detector to record the energy and position of radiation events from a radionuclide source. A 2 mm thick monolithic CsI:Tl scintillator is optically coupled to a PSAPD with a 8mm*8mm active area, providing submillimeter intrinsic spatial resolution, high energy resolution (16% full-width half maximum at 140 keV) and high gain. A mouse heart phantom filled with an aqueous solution of 370 MBq (99m)Tc-pertechnetate (140 keV) was imaged using the PSAPD detector module and a tungsten knife-edge pinhole collimator with a 0.5 mm diameter aperture. The PSAPD detector module was cooled with cold nitrogen gas to suppress dark current shot noise. For each projection image of the mouse heart phantom, a rotated diagonal readout algorithm was used to calculate the position of radiation events and correct for pincushion distortion. The reconstructed image of the mouse heart phantom demonstrated reproducible image quality with submillimeter spatial resolution (0.7 mm), showing the feasibility of using the compact PSAPD-based gamma camera for a small animal SPECT system. PMID- 21278834 TI - Rethinking Resynch: Exploring Mechanisms of Cardiac Resynchroniztion Beyond Wall Motion Control. AB - Cardiac resynchronization (CRT) is a widely used clinical treatment for heart failure patients with depressed function and discoordinate contraction due to conduction delay. It is unique among heart failure treatments as it both acutely and chronically enhances systolic function yet also prolongs survival. While improved chamber mechano-energetics has been considered a primary mechanism for CRT benefit, new animal model data are revealing novel and in many instances unique cellular and molecular modifications from the treatment. Examples of these changes are the reversal of marked regional heterogeneity of the transcriptome and stress kinase signaling, improved ion channel function involved with electrical repolarization, enhanced sarcomere function and calcium handling and upregulation of beta-adrenergic responses, and improved mitochondrial energetic efficiency associated with targeted changes in the mitochondrial proteome. Exploration of these mechanisms may reveal key insights into how CRT can indeed get the failing heart to contract more and perform more work, yet not worsen long term failure. These changes may provide a more biological marker for both the appropriate patients for CRT as well as point the way for new therapeutic avenues for heart failure in general. PMID- 21278835 TI - Towards an Understanding of Change in Physical Activity from Pregnancy Through Postpartum. AB - OBJECTIVE: The purpose of this paper was to describe the rationale, data collection, and proposed analyses for examination of mediators of change in physical activity from pregnancy to postpartum among a cohort of pregnant women. METHOD: The Pregnancy Infection and Nutrition 3 (PIN3) Study enrolled 2006 pregnant women into the cohort from 2001 to 2005. All women lived in central North Carolina upon enrollment. Physical activity was assessed using a self reported one week recall, measured twice during pregnancy and once each at 3- and 12-months postpartum. On a subset of women, one-week accelerometer measures were also collected during the two postpartum time periods. Potential mediators (intrapersonal, interpersonal, community) were collected during pregnancy and postpartum through interviews and take home questionnaires. RESULTS: To assess mediation of physical activity among our cohort, we will first describe change in physical activity and the mediators, as well as their associations, through pregnancy into the postpartum period. Following this, the product of coefficients approach will be applied to examine whether each measure had indirect effects on change in physical activity. Each individual level mediator will be examined one at a time and across the time points in which it was available. The Sobel standard error approximation formula will be used to test for significance of the mediation effect. CONCLUSIONS: This study will provide evidence to develop appropriate interventions targeted at physical activity and will help focus efforts on the appropriate time periods between pregnancy and postpartum. PMID- 21278836 TI - Planar differential mobility spectrometer as a pre-filter for atmospheric pressure ionization mass spectrometry. AB - Ion filters based on planar DMS can be integrated with the inlet configuration of most mass spectrometers, and are able to enhance the quality of mass analysis and quantitative accuracy by reducing chemical noise, and by pre-separating ions of similar mass. This paper is the first in a series of three papers describing the optimization of DMS / MS instrumentation. In this paper the important physical parameters of a planar DMS-MS interface including analyzer geometry, analyzer coupling to a mass spectrometer, and transport gas flow control are considered. The goal is to optimize ion transmission and transport efficiency, provide optimal and adjustable resolution, and produce stable operation under conditions of high sample contamination. We discuss the principles of DMS separations and highlight the theoretical underpinnings. The main differences between planar and cylindrical geometries are presented, including a discussion of the advantages and disadvantages of RF ion focusing. In addition, we present a description of optimization of the frequency and amplitude of the DMS fields for resolution and ion transmission, and a discussion of the influence and importance of ion residence time in DMS. We have constructed a mass spectrometer interface for planar geometries that takes advantage of atmospheric pressure gas dynamic principles, rather than ion focusing, to minimize ion losses from diffusion in the analyzer and to maximize total ion transport into the mass spectrometer. A variety of experimental results has been obtained that illustrate the performance of this type of interface, including tests of resistance to high contamination levels, and the separation of stereoisomers. In a subsequent publication the control of the chemical interactions that drive the separation process of a DMS / MS system will be considered. In a third publication we describe novel electronics designed to provide the high voltages asymmetric waveform fields (SV) required for these devices as well as the effects of different waveforms. PMID- 21278837 TI - The Big Picture of Individual Differences in Physical Activity Behavior Change: A Transdisciplinary Approach. AB - The goal of this research is to utilize a transdisciplinary framework to guide the selection of putative moderators of the effectiveness of an intervention to promote physical activity behavior adoption and maintenance in the context of a randomized controlled intervention trial. Effective interventions to increase physical activity are sorely needed, and one barrier to the identification and development of such interventions is the lack of research targeted at understanding both the mechanisms of intervention efficacy and for whom particular interventions are effective. The purpose of this paper is to outline our transdisciplinary approach to understanding individual differences in the effectiveness of a previously successful exercise promotion intervention. We explain the rationale for and operationalization of our framework, characteristics of the study to which we apply the framework, and planned analyses. By embracing a transdisciplinary orientation for individual differences important in the prediction of physical activity (spanning molecular approaches, animal models, human laboratory models, and social psychological models), we hope to have a better understanding of characteristics of individuals that are important in the adoption and maintenance of physical activity. PMID- 21278838 TI - Developing small molecules to inhibit kinases unkind to the heart: p38 MAPK as a case in point. AB - Over the last 40 years targeting G protein-coupled receptors and their ligands has had a major impact on the treatment of cardiovascular disease. However, the last decade has seen little progress and focus has shifted, particularly in the field of cancer biology, to downstream kinases. This review focuses on the kinases within the heart that become active during myocardial infarction and heart failure and contribute to cardiac dysfunction, with a special emphasis on p38 mitogen-activated protein kinase (MAPK). PMID- 21278839 TI - Enduring an Economic Crisis: The Effect of Macroeconomic Shocks on Intragenerational Mobility in Japan. AB - After the burst of its "bubble" economy in 1989, Japan experienced an astonishingly long economic recession whose gravity surpassed any seen in the industrialized world since the 1930s. While this recession is likely to have important consequences on the well-known workplace arrangements and career mobility patterns in that country, systematic analyses of such consequences are nearly absent. This study examines changes in the rates and directions of job mobility in Japan using work history data collected in 2005 from a nationally representative sample of men and women. I find evidence that Japanese firms have largely retained the core elements of the permanent employment system. The norm that stresses men's loyalty to their employers, however, appears to have weakened, resulting in higher voluntary job turnover among male workers. In addition, the gender gap in lifetime mobility processes has narrowed, but not because Japanese women have gained opportunities in the workplace. Rather, economic stagnation has led to greater fluctuations in employment and wages over men's life course, thereby closing the gender gap. Beyond illustrating the changing stratification process in Japan, the findings have general implications for understanding how economic crises impact employment relations, institutional transformations, and social change in advanced industrialized countries. PMID- 21278840 TI - Miniaturization of Mass Spectrometry Analysis Systems. AB - The key concepts and technologies developed in our laboratories in Purdue University for the miniaturization of mass spectrometry analysis systems are introduced. Mass analyzers of simple geometries with a novel atmospheric pressure interface were employed allowed reduction in the size of the ion trap mass spectrometer. Ambient ionization methods were developed and coupled to miniature mass spectrometers to allow direct MS analysis of complex samples without sample preparation and chemical separation. The performance of desorption electrospray ionization, low temperature plasma probe, paper spray as well as two handheld MS systems, Mini 10 and Mini 11, are described with demonstrations of capabilities for chemical analysis. PMID- 21278841 TI - The effects of alcohol use on academic achievement in high school. AB - This paper examines the effects of alcohol use on high school students' quality of learning. We estimate fixed-effects models using data from the National Longitudinal Study of Adolescent Health. Our primary measure of academic achievement is the student's GPA abstracted from official school transcripts. We find that increases in alcohol consumption result in small yet statistically significant reductions in GPA for male students and in statistically non significant changes for females. For females, however, higher levels of drinking result in self-reported academic difficulty. The fixed-effects results are substantially smaller than OLS estimates, underscoring the importance of addressing unobserved individual heterogeneity. PMID- 21278842 TI - Neurological surgery at the National Institutes of Health. AB - The Surgical Neurology Branch (SNB) in the intramural program of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health has been a unique setting for academic neurosurgery for nearly 60 years. Every patient evaluated and treated in the SNB is enrolled in a clinical research protocol, which underscores a singular focus on advancing neurosurgical research and patient care. Since the inception of the SNB, this research effort has been driven by dedicated clinician-investigators and basic scientists including Maitland Baldwin, Igor Klatzo, John M. Van Buren, Ayub K. Ommaya, Richard J. Youle, and Edward H. Oldfield. These and other SNB investigators have studied and advanced treatment of a number of neuropathologic processes, including delineation of differences between cytotoxic and vasogenic edema, head injury, Cushing disease, the effects of vascular endothelial growth factor in nervous system tissues, tumor suppressor syndromes, the pathophysiology of syringomyelia, mechanisms underlying cerebral vasospasm after subarachnoid hemorrhage, spinal arteriovenous malformations, mechanisms of cell death, and drug delivery. Currently, SNB efforts are focused on central nervous system drug delivery, the natural history of familial tumor syndromes, functional neurosurgery, epilepsy, vasospasm, and development of chemotherapeutics for malignant glioma. Throughout its history, the SNB has also been dedicated to training neurosurgeon clinician investigators; 23 previous fellows/staff have become chairs of their respective neurosurgical departments. Recently, the commitment to training future neurosurgeon clinician-investigators has been further defined with the development of a residency-training program in neurological surgery approved in 2010. PMID- 21278843 TI - Arousal and activity choice in autism: A single case assessment integrating autonomic and behavioral analysis. AB - Theoretical accounts of autism have hypothesized links between arousal and behavior but research translations of theory to real-world contexts have been limited. In this single-subject experimental analysis, a school-age subject chose between high and low arousing activities with real time monitoring of behavior and heart rate (HR). Time series statistical analysis showed significant changes in HR associated with activity type and no association with motor movement. Sequential analysis showed that activity choice and HR were significantly associated (i.e., activity choice sequentially dependent with the preceding level of HR). Highly arousing activities were more likely to be chosen following high HR and vice versa. Results provide evidence of the feasibility of an integrative bio-behavioral approach to understand behavior in neurodevelopmental disorders. PMID- 21278844 TI - Unmet Expectations and Symptoms of Depression among the Three Gorges Project Resettlers. AB - To successfully resettle 1.27 million Chinese for the construction of the Three Gorges Project (TGP), the Chinese government employed a new re-resettlement policy which emphasizes infrastructural development of the resettlement sites to assure resettlers a sustainable livelihood following resettlement. Unfortunately, many benefits the policy promised have not materialized. As a result, many resettlers have suffered an increase in depressive symptoms associated with unmet expectations. Using panel data collected before and after relocation from a sample of Three Gorges resettlers, we found that a high proportion of resettlers reported unmet expectations which were significantly associated with an increase in depressive symptoms. Our findings indicate that undeliverable promises can backfire and further aggravate the harm inflicted on the displaced caused by the project-induced displacement. From the perspective of resettlers, a sound coping strategy to minimize the harm caused by the displacement on their mental wellbeing is to expect for the worst. PMID- 21278845 TI - Caregiver Depression and Youth Disruptive Behavior Difficulties. AB - This study examines the rates of depressive symptoms and service use among caregivers whose children receive treatment for disruptive behavior disorders. Descriptive analyses examined preliminary baseline data from the Family Groups for Urban Youth with Disruptive Behaviors study for 212 caregivers to determine rates of caregiver depressive symptoms and lifetime mental health service use. Findings indicate that caregivers manifest substantially higher rates of depressive symptoms compared to national norms. Of those caregivers with clinically significant depressive symptoms, less than half reported ever receiving mental health services. Findings suggest that greater attention should be paid to identifying and treating caregiver depression among children receiving treatment for disruptive behavior disorders. PMID- 21278846 TI - Cationic 1,2-Azaborine Adducts of Trimethylphosphine, Triphenylphosphine oxide, and Pyridine-N-oxide. AB - The first cationic 1,2-azaborine adducts of neutral phosphorous- and oxygen-based nucleophiles have been synthesized and characterized via spectroscopic and single crystal X-ray diffraction analysis. PMID- 21278847 TI - A dynamic model for functional mapping of biological rhythms. AB - Functional mapping is a statistical method for mapping quantitative trait loci (QTLs) that regulate the dynamic pattern of a biological trait. This method integrates mathematical aspects of biological complexity into a mixture model for genetic mapping and tests the genetic effects of QTLs by comparing genotype specific curve parameters. As a way of quantitatively specifying the dynamic behavior of a system, differential equations have proven to be powerful for modeling and unraveling the biochemical, molecular, and cellular mechanisms of a biological process, such as biological rhythms. The equipment of functional mapping with biologically meaningful differential equations provides new insights into the genetic control of any dynamic processes. We formulate a new functional mapping framework for a dynamic biological rhythm by incorporating a group of ordinary differential equations (ODE). The Runge-Kutta fourth order algorithm was implemented to estimate the parameters that define the system of ODE. The new model will find its implications for understanding the interplay between gene interactions and developmental pathways in complex biological rhythms. PMID- 21278848 TI - An Efficient Synthesis of de novo Imidates via Aza-Claisen Rearrangements of N Allyl Ynamides. AB - A novel thermal 3-aza-Claisen rearrangement of N-allyl ynamides for the synthesis of alpha-allyl imidates is described. Also, a sequential aza-Claisen, Pd catalyzed Overman rearrangement is described for the synthesis of azapine-2-ones. PMID- 21278849 TI - Evaluating the spectral distinction between sibilant fricatives through a speaker centered approach. AB - This study was designed to examine the feasibility of using the spectral mean and/or spectral skewness to distinguish between alveolar and palato-alveolar fricatives produced by individual adult speakers of English. Five male and five female speaker participants produced 100 CVC words with an initial consonant /s/ or /?/. The spectral mean and skewness were derived every 10 milliseconds throughout the fricative segments and plotted for all productions. Distinctions were examined for each speaker through visual inspection of these time history plots and statistical comparisons were completed for analysis windows centered 50 ms after the onset of the fricative segment. The results showed significant differences between the alveolar and palato-alveolar fricatives for both the mean and skewness values. However, there was considerable inter-speaker overlap, limiting the utility of the measures to evaluate the adequacy of the phonetic distinction. When the focus shifted to individual speakers rather than average group performance, only the spectral mean distinguished consistently between the two phonetic categories. The robustness of the distinction suggests that intra speaker overlap in spectral mean between prevocalic /s/ and /?/ targets may be indicative of abnormal fricative production and a useful measure for clinical applications. PMID- 21278850 TI - An adaptive nonparametric method in benchmark analysis for bioassay and environmental studies. AB - We present a novel nonparametric method for bioassay and benchmark analysis in risk assessment, which averages isotonic MLEs based on disjoint subgroups of dosages. The asymptotic theory for the methodology is derived, showing that the MISEs (mean integrated squared error) of the estimates of both the dose-response curve F and its inverse F(-1) achieve the optimal rate O(N(-4/5)). Also, we compute the asymptotic distribution of the estimate zeta~p of the effective dosage zeta(p) = F(-1) (p) which is shown to have an optimally small asymptotic variance. PMID- 21278851 TI - Preclinical Pharmacology, Efficacy and Safety of Varenicline in Smoking Cessation and Clinical Utility in High Risk Patients. AB - Smoking is still the most prominent cause of preventable premature death in the United States and an increasing cause of morbidity and mortality throughout the world. Although the current treatments such as nicotine replacement therapy (NRT) and bupropion are effective, long-term abstinence rates are low. Mechanism studies suggest that the pleasurable effects of smoking are mediated predominantly by nicotine, which activates the brain reward system by activation of brain alpha(4)beta(2) nicotinic acetylcholine receptors (nAChRs). Varenicline is a novel alpha(4)beta(2) nAChR partial agonist and has been found to be even more effective than NRT or bupropion in attenuating smoking satisfaction and in relieving craving and withdrawal symptoms after abstinence. Thus, varenicline has been recently approved to be a first-line medication for smoking cessation in the United States and European countries. Varenicline is generally well tolerated in healthy adult smokers, with the most commonly reported adverse effects being nausea, insomnia, and headache. However, growing post-marketing data has linked varenicline to an increase in neuropsychiatric symptoms such as seizures, suicidal attempts, and depression, psychosis, as well as serious injuries potentially relating to unconsciousness, dizziness, visual disturbances, or movement disorders. Therefore, new safety warnings are issued to certain high risk populations, such as patients with mental illness and operators of commercial vehicles or heavy machinery. In particular, pilots, air traffic controllers, truck and bus drivers have been banned from taking varenicline. PMID- 21278852 TI - Money Isn't Everything: Wives' Earnings and Housework Time. AB - The autonomy perspective of housework time predicts that wives' housework time falls steadily as their earnings rise, because wives use additional financial resources to outsource or forego time in housework. We argue, however, that wives' ability to reduce their housework varies by household task. That is, we expect that increases in wives' earnings will allow them to forego or outsource some tasks, but not others. As a result, we hypothesize more rapid declines in wives' housework time for low-earning wives as their earnings increase than for high-earning wives who have already stopped performing household tasks that are the easiest and cheapest to outsource or forego. Using fixed-effects models and data from the Panel Study of Income Dynamics, we find considerable support for our hypothesis. We further conclude that past evidence that wives who out-earn their husbands spend additional time in housework to compensate for their gender deviant success in the labor market is due to the failure to account for the non linear relationship between wives' absolute earnings and their housework time. PMID- 21278853 TI - Quasistatic Modeling of Concentric Tube Robots with External Loads. AB - Concentric tube robots are a subset of continuum robots constructed by combining pre-curved elastic tubes. As the tubes are rotated and translated with respect to each other, their curvatures interact elastically, enabling control of the robot's tip configuration as well as the curvature along its length. This technology is projected to be useful in many types of minimally invasive medical procedures. Because these robots are flexible by design, they deflect considerably when applying forces to the external environment. Thus, in contrast to rigid-link robots, their kinematic and static force models are coupled. This paper derives a multi-tube quasistatic model that relates tube rotations and translations together with externally applied loads to robot shape and tip configuration. The model can be applied in robot design, procedure planning as well as control. For validation, the multi-tube model is compared experimentally to a computationally-efficient single-tube approximate model. PMID- 21278854 TI - Profile Likelihood and Incomplete Data. AB - According to the law of likelihood, statistical evidence is represented by likelihood functions and its strength measured by likelihood ratios. This point of view has led to a likelihood paradigm for interpreting statistical evidence, which carefully distinguishes evidence about a parameter from error probabilities and personal belief. Like other paradigms of statistics, the likelihood paradigm faces challenges when data are observed incompletely, due to non-response or censoring, for instance. Standard methods to generate likelihood functions in such circumstances generally require assumptions about the mechanism that governs the incomplete observation of data, assumptions that usually rely on external information and cannot be validated with the observed data. Without reliable external information, the use of untestable assumptions driven by convenience could potentially compromise the interpretability of the resulting likelihood as an objective representation of the observed evidence. This paper proposes a profile likelihood approach for representing and interpreting statistical evidence with incomplete data without imposing untestable assumptions. The proposed approach is based on partial identification and is illustrated with several statistical problems involving missing data or censored data. Numerical examples based on real data are presented to demonstrate the feasibility of the approach. PMID- 21278855 TI - Alternative mRNA polyadenylation in eukaryotes: an effective regulator of gene expression. AB - Alternative RNA processing mechanisms, including alternative splicing and alternative polyadenylation, are increasingly recognized as important regulators of gene expression. This article will focus on what has recently been described about alternative polyadenylation in development, differentiation, and disease in higher eukaryotes. We will also describe how the evolving global methodologies for examining the cellular transcriptome, both experimental and bioinformatic, are revealing new details about the complex nature of alternative 3' end formation, as well as interactions with other RNA-mediated and RNA processing mechanisms. PMID- 21278856 TI - Ancestral populations perform better in a novel environment: domestication of medfly populations from five global regions. AB - Geographically isolated populations of a species may differ in several aspects of life-history, morphology, behavior, and genetic structure as a result of adaptation in ecologically diverse habitats. We used a global invasive species, the Mediterranean fruit fly to investigate, whether adaptation to a novel environment differs among geographically isolated populations that vary in major life history components such as life span and reproduction. We used wild populations from five global regions (Kenya, Hawaii, Guatemala, Portugal, and Greece). Adult demographic traits were monitored in F(2), F(5), F(7) and F(9) generations in captivity. Although domestication in constant laboratory conditions had a different effect on the mortality and reproductive rates of the different populations, a general trend of decreasing life span and age of first reproduction was observed for most medfly populations tested. However, taking into account longevity of both sexes, age-specific reproductive schedules, and average reproductive rates we found that the ancestral Kenyan population kept the above life history traits stable during domestication compared to the other populations tested. These findings provide important insights in the life-history evolution of this model species, and suggest that ancestral medfly populations perform better than the derived - invasive ones in a novel environment. PMID- 21278857 TI - Measurement of pH by NMR Spectroscopy in Concentrated Aqueous Fluoride Buffers. AB - An NMR spectroscopic technique has been developed to give rapid, accurate pH measurements on tenth-milliliter samples of concentrated acidic aqueous solutions buffered by fluoride ion in the pH 1.5 - 4.5 range. The fluoride (19)F chemical shift has been calibrated as a function of pH at 0.1 and 1.0 M concentration by reference to an internal 3-fluoropyridine standard. Subsequent measurements of fluoride buffer pH required no additives and only two NMR spectra in the presence of an external reference standard. PMID- 21278858 TI - Predictive spelling with a P300-based brain-computer interface: Increasing the rate of communication. AB - This study compared a conventional P300 speller brain-computer interface (BCI) to one used in conjunction with a predictive spelling program. Performance differences in accuracy, bit rate, selections per minute, and output characters per minute (OCM) were examined. An 8*9 matrix of letters, numbers, and other keyboard commands was used. Participants (n = 24) were required to correctly complete the same 58 character sentence (i.e., correcting for errors) using the predictive speller (PS) and the non-predictive speller (NS), counterbalanced. The PS produced significantly higher OCMs than the NS. Time to complete the task in the PS condition was 12min 43sec as compared to 20min 20sec in the NS condition. Despite the marked improvement in overall output, accuracy was significantly higher in the NS paradigm. P300 amplitudes were significantly larger in the NS than in the PS paradigm; which is attributed to increased workload and task demands. These results demonstrate the potential efficacy of predictive spelling in the context of BCI. PMID- 21278859 TI - The Behaviors of Ferro-Magnetic Nano-Particles In and Around Blood Vessels under Applied Magnetic Fields. AB - In magnetic drug delivery, therapeutic magnetizable particles are typically injected into the blood stream and magnets are then used to concentrate them to disease locations. The behavior of such particles in-vivo is complex and is governed by blood convection, diffusion (in blood and in tissue), extravasation, and the applied magnetic fields. Using physical first-principles and a sophisticated vessel-membrane-tissue (VMT) numerical solver, we comprehensively analyze in detail the behavior of magnetic particles in blood vessels and surrounding tissue. For any blood vessel (of any size, depth, and blood velocity) and tissue properties, particle size and applied magnetic fields, we consider a Krogh tissue cylinder geometry and solve for the resulting spatial distribution of particles. We find that there are three prototypical behaviors (blood velocity dominated, magnetic force dominated, and boundary-layer formation) and that the type of behavior observed is uniquely determined by three non-dimensional numbers (the magnetic-Richardson number, mass Peclet number, and Renkin reduced diffusion coefficient). Plots and equations are provided to easily read out which behavior is found under which circumstances (Figures 5, 6, 7, and 8). We compare our results to previously published in-vitro and in-vivo magnetic drug delivery experiments. Not only do we find excellent agreement between our predictions and prior experimental observations, but we are also able to qualitatively and quantitatively explain behavior that was previously not understood. PMID- 21278860 TI - Bayesian Variable Selection via Particle Stochastic Search. AB - We focus on Bayesian variable selection in regression models. One challenge is to search the huge model space adequately, while identifying high posterior probability regions. In the past decades, the main focus has been on the use of Markov chain Monte Carlo (MCMC) algorithms for these purposes. In this article, we propose a new computational approach based on sequential Monte Carlo (SMC), which we refer to as particle stochastic search (PSS). We illustrate PSS through applications to linear regression and probit models. PMID- 21278861 TI - National rural health mission: turning into reality. PMID- 21278863 TI - National Response to HIV/AIDS in India. PMID- 21278862 TI - Successful efforts toward elimination iodine deficiency disorders in India. AB - Iodine deficiency (ID) is the world's single most important preventable cause of brain damage and mental retardation. Iodine deficiency disorders (IDDs) is a public health problem in 130 countries, affecting 13% of the world population. The simplest solution to prevent the IDD is to consume iodized common salt every day. In India, significant progress has been achieved toward elimination of IDD, in the last 30 years. Satisfactory levels of urinary iodine excretion and iodine content of salt have been documented by the research surveys conducted by research scientists. The results indicate that we are progressing toward elimination of IDD. IDD is due to a nutritional deficiency, which is prima-rily that of iodine, in soil and water. IDD is known to re-appear if the IDD Control Program is not sustained. To ensure that the population continues to have intake of adequate amount of iodine, there is a need of i) periodic surveys to assess the magnitude of the IDD with respect to impact of iodized salt (IS) intervention; ii) strengthening the health and nutrition education activities to create demand for IS and iii) development of a monitoring information system (MIS) for ensuring that the adequately IS is available to the beneficiaries. PMID- 21278864 TI - Association of poultry farms with housefly and morbidity: a comparative study from raipur rani, haryana. AB - BACKGROUND: Large poultry belt is located in the residential areas of rural Haryana in North India. Housefly problem has become a big nuisance in this area. Policy makers require evidence of the association of poultry farming with houseflies and its possible impact on the health of the population. MATERIALS AND METHODS: Across-sectional two-group comparison study was conducted. Six villages within 3 km and another six villages beyond 5 km from any poultry farms were selected as the study and the control villages, respectively. We measured indoor and outdoor housefly density and family morbidity in the last 1 month and observed the poultry hygiene and manure management practices. FINDINGS: The mean fly density was 1737 (95% CI 697-2778) houseflies in study villages compared to 100 (95% CI 2-197) houseflies in the control area. The mean all-cause morbidity was also significantly higher in study village families compared to control village families. Poultry farm hygiene and use of insecticides and growth regulators were inadequate. INTERPRETATION: Poultry farms are associated strongly with high fly density and high infectious morbidity in this area.Monitoring and regulation for poultry manure management practices and insecticide use practices need to be strengthened. PMID- 21278865 TI - Client satisfaction on maternal and child health services in rural bengal. AB - BACKGROUND: Services are being provided by health functionaries to the community with the objective of fulfilling their satisfaction but sometimes this is not working for the target population. OBJECTIVES: The study was conducted to assess the satisfaction of clients' receiving maternal and child health services and to elicit clients' suggestion for improving the services. MATERIALS AND METHODS: Anexit interview was employed to collect data using a predesigned and pretested schedule. RESULTS: Most of the populations were adult clients. In respect of satisfaction, responses of the clients were either satisfactory (54.31%) or good (23.56%) on maternal and child health services; 'poor or very poor around 20% and it was significantly worse in respect of satisfaction'. Most of the clients (63.06 to 73.94%) expressed their responses as satisfactory and good regarding the assessment of doctors and it was significant. Most of them (73.31%) expressed satisfactory "response" on the quality of services given by nursing staffs. Suggestions of clients for improving the level of satisfactionwere sought and in this respect, response was little. CONCLUSIONS: Mostly satisfactory observations on maternal and child health services were found in respect of clients' satisfaction and there was scope to improve the quality and quantity of services, and accordingly actions may be taken in the working field. PMID- 21278866 TI - Study on obesity and influence of dietary factors on the weight status of an adult population in jamnagar city of gujarat: a cross-sectional analytical study. AB - BACKGROUND: Obesity has reached epidemic proportions globally and is a major contributor to the global burden of chronic diseases. Dietary factors are the major modifiable factors through which many of the external forces promoting weight gain act. OBJECTIVES: The objectives were to find the prevalence of overweight and obesity in the urban population of Jamnagar and to explore the effect of dietary factors on the weight status of the people. MATERIALS AND METHODS: A cross-sectional study was conducted among the adult population of Jamnagar city. Cluster sampling technique was used to select study samples. Data were collected in a prestructured questionnaire by interviewing subjects through house-to-house visits. Data were analyzed in Epi Info and appropriate statistical methods were used. RESULTS: The prevalence of overweight and obesity was found to be 22.04% and 5.20%, respectively. Overweight was more prevalent in females than males. The prevalence rose with an increase in age up to 60 years. Among dietary factors, the total calorie intake and habit of snacking had a positive association with weight gain (P < 0.05). The mean intake of oil was more and the mean intake of vegetables was less among overweight subjects than nonoverweight subjects (P < 0.05). CONCLUSION: The prevalence of overweight and obesity in the urban population in Jamnagar was found to be 22.04% and 5.20%, respectively. Total calorie intake as well as composition of diet was the important dietary factor affecting weight gain. PMID- 21278867 TI - A survey on the occupational health status of gardeners in bhopal, India. AB - BACKGROUND: Occupational gardeners are exposed to various risk factors like dust, allergens, sharp tools, and pesticides, which make them vulnerable to many diseases. This study was designed to survey the health status of this occupational group. OBJECTIVES: The objective was to collectsociodemographic and health status information of occupational gardeners. MATERIALS AND METHODS: The study group comprised 75 male occupational gardeners of the Bhopal city and suburb. A pretested proforma questionnaire was used to record the necessary information like medical history, sociodemographic factors, and findings of clinical investigations. RESULT AND DISCUSSION: This survey reveals that 50% of gardeners are underweight, 31.99% with high normal to high blood pressure, and none with diabetes. The prevalence of vision disturbance (26.66%), eye inflammation (29.33%), stiff nose (21.33%), joint pain, swelling and muscle stiffness (29.33%), and accidental injury (28%) was significantly high among gardeners. Gardeners should be educated to use protective clothing, quit smoking and tobacco consumption, adopt proper body posture, and ensure vaccination. PMID- 21278868 TI - Evaluation of the prevention of parent to child transmission program in a rural tertiary care hospital of west bengal, India. AB - BACKGROUND: In India, 67,500 infants acquire HIV infection yearly due to mother to child transmission. OBJECTIVE: The objective was to assess the operational aspect of the Prevention of Parent to Child Transmission (PPTCT) program in a tertiary care hospital and explore its bottleneck. MATERIALS AND METHODS: A 5 year (2004-2008) prospective evaluation study was conducted among the pregnant women attending Obstetrics Department of a rural tertiary care hospital, since the year of implementation. Indicators were used according to UNAIDS/WHO guideline. RESULTS: Out of 40,140 registered pregnant women, 23,812 were counseled of which 19,794 were agreed to undergo HIV testing and 111 were found HIV positive with a prevalence of 0.56%. Overall HIV counseling and testing rates were 59.32% and 83.13%, respectively. The nevirapine (NVP) dispensing rate of the mother and newborn were 29.72% and 85.4%, respectively. At 18 months of age, 85% babies were found HIV negative in the mother baby pair who received NVP with absolutely formula feeding but it was 42.8% without such intervention. CONCLUSION: Majority of the pregnant women who came to the labor room directly were deprived of the program (PPTCT) coverage. Although the HIV testing rate reached the WHO target which was excellent, but the NVP dispensing rate lagged far behind. PMID- 21278869 TI - Effectiveness of Different Models of DOTS Providers under RNTCP in Ahmedabad City, Gujarat. AB - BACKGROUND: The most effective DOTS provider will be the one who is accessible, acceptable to the patient, and accountable to the health system. OBJECTIVES: The objective was to assess the effectiveness of the different types of DOTS providers functioning under Revised National Tuberculosis Control Programme (RNTCP). MATERIALS AND METHODS: Atotal of 200 patients, treated under RNTCP during September to December 2004, were selected for the study. RESULTS: A total of 105 and 95 patients were under the supervision of tuberculosis health visitors (TBHVs) and non-TBHVs, respectively. During the intensive phase, around 95% of the patients took the medicine under the direct observation in both the groups. Supervision of the first dose of treatment in a week during the continuation phase was significantly better with the TBHV (94.74%) as compared to the non-TBHV (79.31%). However, there was no significant difference in the cure and the completed rate which was 76.19% with the TBHV and 86.13% with the non-TBHV. CONCLUSION: The available community workforce could be involved in supervising the intermittent short course chemotherapy. PMID- 21278870 TI - Knowledge, attitude, and practice of dyeing and printing workers. AB - BACKGROUND: Millions of workers are occupationally exposed to dyes in the world, but little is known about their knowledge and attitudes toward the effects of dye on their health.. OBJECTIVES: The aim of this study was to assess the fabric dyers' and fabric printers' knowledge, attitude, and practice toward the health hazard of dyes. MATERIALS AND METHODS: The present study was taken up in the Madurai district which is situated in the Southern Tamil Nadu, India. One hundred and forty-two workers employed in small-scale dyeing and printing units participated in a face-to-face confidential interview. RESULTS: The mean age of fabric dyers and fabric printers was 42 years (+/-10.7). When enquired about whether dyes affect body organ(s), all the workers agreed that dye(s) will affect skin, but they were not aware that dyes could affect other parts of the body. All the workers believed that safe methods of handling of dyes and disposal of contaminated packaging used for dyes need to be considered. It was found that 34% of the workers were using personal protective equipment (PPE) such as rubber hand gloves during work. CONCLUSION: The workers had knowledge regarding the occupational hazards, and their attitudinal approach toward the betterment of the work environment is positive. PMID- 21278871 TI - Determinants of Pre-eclampsia: A Case-control Study in a District Hospital in South India. AB - OBJECTIVE: The objective was to study the determinants of pre-eclampsia among pregnant women admitted for delivery in a district hospital. MATERIALS AND METHODS: A case-control study was conducted at District Lady Goschen Hospital, Dakshina Kannada district, Karnataka, South India. The group of pregnant women with pre-eclampsia comprised those with hypertension after the 20th week of gestation with associated proteinuria, and controls were pregnant women not diagnosed with pre-eclampsia. A total of 100 cases and 100 controls were selected for the year 2006. Study variables included mother's age, parity, body mass index, history of chronic hypertension, history of diabetes, history of renal disease, family history of hypertension, and history of pre-eclampsia in earlier pregnancy. STATISTICAL ANALYSIS: Chi-square test, and crude and adjusted odds ratio with 95% confidence intervals were used for statistical analysis. RESULTS: Significant risk factors identified in univariate analysis included prepregnancy body mass index (BMI > 25) (OR = 11.27), history of chronic hypertension (OR = 8.65), history of diabetes (OR = 11.0), history of renal disease (OR = 7.98), family history of hypertension (OR = 5.4), history of pre-eclampsia in earlier pregnancy (OR = 9.63), and multiple pregnancy (OR = 4.85). Multiple logistic regression analysis revealed that the prepregnancy BMI of >25 (OR = 7.56), history of chronic hypertension (OR = 6.69), history of diabetes (OR = 8.66), history of renal disease (OR = 5.6), family history of hypertension (OR = 5.48), and multiple pregnancy (OR = 5.73) are the significant risk factors of pre eclampsia. CONCLUSION: Pregnant women at risk of pre-eclampsia should be identified and high-quality antenatal care should be given in order to minimize the complications of pre-eclampsia both for the mother and the fetus. PMID- 21278872 TI - Risk of Complications in HIV-TB Co-Infection: A Hospital-Based Pair-Matched Case Control Study. PMID- 21278873 TI - Epidemiolgical study of burn injuries admitted in two hospitals of north karnataka. PMID- 21278874 TI - Socio-demographic Correlates of Dietary Energy Intakes in an Indian Community. PMID- 21278875 TI - Study of seroprevalence of dengue Fever in central India. PMID- 21278876 TI - Adherence to malaria diagnostic guidelines in field area of chhattisgarh. PMID- 21278877 TI - Presenting features of diabetes mellitus. PMID- 21278878 TI - Health Care Workers and Universal Precautions: Perceptions and Determinants of Non-compliance. PMID- 21278879 TI - Knowledge Regarding Reproductive Health among Urban Adolescent Girls of Haryana. PMID- 21278880 TI - Prediction and prevention of preterm birth after cervical conization. PMID- 21278881 TI - Major clinical research advances in gynecologic cancer in 2010. AB - This review summarizes 11 major clinical research advances in gynecologic oncology in 2010. For ovarian cancer, bevacizumab as a leading molecular targeted agent, pegylated liposomal doxorubicin in recurrent disease, the role of neoadjuvant chemotherapy in an advanced setting, an effective screening method, and ARID1A mutations as a clue to the origin of clear cell carcinoma are mentioned. For cervical cancer, confirmation of the efficacy and the introduction of a self collection method of the human papillomavirus (HPV) test, and the association between the HPV vaccine and miscarriage are examined. For endometrial cancer, the superiority of laparoscopy in staging operation, the role of vaginal brachytherapy in an adjuvant setting, and the effect of para-aortic lymph node dissection are reviewed. In addition, the trend of geriatric oncology and chemotherapy in carcinosarcomas is also assessed. PMID- 21278882 TI - The twenty-first century role of Piver-Rutledge type III radical hysterectomy and FIGO stage IA, IB1, and IB2 cervical cancer in the era of robotic surgery: a personal perspective. AB - Type III radical hysterectomy reported in 1974 by Piver, Rutledge, and Smith is considered worldwide by many as the standard surgical therapy for invasive cervical carcinoma stage IB and IIA. With the increasing number of robotic surgeries being performed for early stage cervical cancer worldwide, the purpose of the paper is to present our personal perspective of the 21st century role of Piver-Rutledge type III radical hysterectomy for stage IB cervical cancer in the era of robotic surgery using the da Vinci robot. PMID- 21278883 TI - Pregnancy outcome after cervical conization: risk factors for preterm delivery and the efficacy of prophylactic cerclage. AB - OBJECTIVE: This study examined the risk factors for preterm birth and the efficacy of prophylactic cerclage in patients who had undergone cervical conization due to cervical intraepithelial neoplasia before pregnancy. METHODS: We reviewed the medical records of all patients who gave live singleton births between May 1996 and April 2009, after having cervical conization. Delivery before 37 gestational weeks was considered as preterm birth. The pregnancy outcomes were analyzed with independent sample t-test, chi-square test, and multiple logistic regression using the SPSS ver. 12.0. RESULTS: Sixty five cases were found. The mean gestational age at delivery was 37 weeks (SD, 3.5). Eighteen patients (27.7%) had preterm delivery. The type of conization, the volume of the specimen, and second trimester cervical length were related to preterm birth (p<=0.001, p=0.019, p<=0.001, respectively). In multivariate analysis, only mid trimester cervical length was statistically significant for preterm birth (p=0.012; odds ratio, 0.194; confidence interval, 0.055 to 0.693). Six out of 65 patients had undergone prophylactic cerclage, and three (50%) of them had preterm births, while 15 (25%) patients without cerclage had preterm births. CONCLUSION: The type of conization, the volume of specimen, and second trimester cervical length may be the risk factors for preterm birth in patients who have a prior history of cervical conization. Prophylactic cerclage may not be helpful in preventing preterm birth, therefore more careful consideration should be paid in deciding cerclage after conization during prenatal counseling. PMID- 21278884 TI - The role of prophylactic cerclage in preventing preterm delivery after electrosurgical conization. AB - OBJECTIVE: To evaluate pregnancy outcomes after electrosurgical conization. METHODS: We retrospectively analyzed the outcomes of 56 singleton pregnancies after electrosurgical conization of the uterine cervix. Of the 56 cases, 25 women underwent prophylactic cerclage with McDonald procedure (cerclage group), and 31 were managed expectantly (expectant group). Pregnancy outcomes including rate of preterm delivery were compared, and the effect of potential risk factors such as depth of cone, interval between conization and pregnancy, and cervical length on the risk of preterm delivery was assessed. RESULTS: The rate of preterm delivery was significantly higher in women with a history of electrosurgical conization than those without (32.1% vs. 15.2%, p<0.001). However, preterm delivery rate was not different between the two groups (expectant group vs. cerclage group; <28 week, 6.5% vs. 8.0%, p=1.000; <34 week, 19.4% vs. 20.0%, p=1.000; <37 week, 29.0% vs. 36.0%, p=0.579). All obstetric and neonatal outcomes were similar in the two groups. Even when we confined the study subjects to 19 women (19/56, 33.9%) with cervical length less than 25 mm, the preterm delivery rate also was not significantly different between the expectant (n=7) and cerclage group (n=12). Finally, the potential risk factors for preterm delivery were not associated with risk of preterm delivery in patients with a history of electrosurgical conization. CONCLUSION: The rate of preterm delivery was significantly higher in women with a history of electrosurgical conization before pregnancy. However, prophylactic cervical cerclage did not prevent preterm delivery in these patients. PMID- 21278885 TI - Outcomes of advanced and recurrent cervical cancer treated with cisplatin and generic topotecan: retrospective analysis in a tertiary care hospital in Thailand. AB - OBJECTIVE: Retrospective evaluation of the outcome of stage IVB, recurrent or persistent cervical cancer treated with cisplatin and generic topotecan (CT) in a tertiary care hospital in Thailand. METHODS: The medical records of patients treated with CT regimen at Chiang Mai University Hospital between January 2005 and December 2007 were reviewed and analyzed. The treatment protocol consisted of IV topotecan 0.75 mg/m(2) on days 1, 2, and 3; combined with cisplatin 50 mg/m(2) IV on day 1 and repeated every 21 days until progression or unacceptable toxicity for a maximum of 6 cycles. The outcomes were evaluated based on the response rate, progression free survival (PFS), and overall survival (OS) by using the World Health Organization criteria. The adverse effects of the treatments were also determined. RESULTS: Twenty-one cervical cancer patients received the CT regimen. The tumor response rate was 28.6%. The median PFS and OS was 4 and 11 months, respectively. With 87 cycles of chemotherapy, the most common grade 3 & 4 hematologic toxicity was neutropenia (57.9%). CONCLUSION: Advanced and recurrent cervical cancer patients treated with cisplatin and generic topotecan had a favorable outcome with manageable toxicity. PMID- 21278886 TI - Epidemiological characteristics of ovarian cancer in Korea. AB - OBJECTIVE: This study was conducted to examine recent trends in ovarian cancer incidence and mortality and secular trends in demographic factors in Korea. METHODS: With the data from Korea Central Cancer Registry, International Agency for Research on Cancer, Korean Death Registry, and World Health Organization's Statistical Information System, we calculated age-standardized incidence and mortality rates for ovarian cancer. Also we estimated future incidence of ovarian and cervical cancer using linear regression model. To assess the demographic trend, data from national surveys in Korea or results from published papers were searched. RESULTS: Ovarian cancer incidence rate was similar to that in women worldwide but lower than those in Western countries, and the trend has been increased steadily. Ovarian cancer-related mortality rates have been increasing in Korea, even though those in western and some Asian countries, such as China, have been decreasing. Age-specific incidence rate and mortality rate showed steep increases with advancing age. The incidence rate of ovarian cancer was estimated to surpass that of uterine cervix cancer in 2015. Korea showed rapid changes in nutritional, reproductive, and anthropometric factors. CONCLUSION: These recent trends in ovarian cancer incidence and mortality may be partly attributed to gradual westernizing of life styles and to changes in socio-demographic behavior factors. In particular, the increasing trend in ovarian cancer mortality in Korea may be attributed to a real rise in mortality as well as, in part, a decline in misclassification bias related to an increase in the proportion of deaths confirmed by physician diagnosis. PMID- 21278887 TI - Comparison of total plasma lysophosphatidic acid and serum CA-125 as a tumor marker in the diagnosis and follow-up of patients with epithelial ovarian cancer. AB - OBJECTIVE: To evaluate the role of lysophosphatidic acid (LPA) as a tumor marker in diagnosis and follow-up of patients with epithelial ovarian cancer. METHODS: Eighty-seven epithelial ovarian cancer patients, 74 benign ovarian tumor patients, and 50 healthy women were enrolled in the study. Twenty-nine of 87 epithelial ovarian cancer patients were followed up for 6 cycles of paclitaxel carboplatin chemotherapy. CA-125 and total plasma LPA levels were measured preoperatively and before each chemotherapy cycle. RESULTS: Preoperative total plasma LPA and serum CA-125 levels were significantly higher in patients with epithelial ovarian cancer compared to patients with benign ovarian tumors and healthy women. Cut-off value for LPA was determined as 1.3 umol/L and sensitivity, specificity, positive predictive value and negative predictive value were 95%, 92%, 95% and 92%, respectively. Mean total plasma LPA level of 29 patients who received chemotherapy was 7.21+/-6.63 umol/L preoperatively and 6.84+/-6.34 umol/L, 6.34+/-5.92 umol/L, 6.14+/-5.79 umol/L, 5.86+/-5.68 umol/L, 5.23+/-5.11 umol/L and 5.21+/-5.32 umol/L in measurements held just before the 1st, 2nd, 3rd, 4th, 5th and 6th chemotherapy cycles, respectively (ANOVA, p=0.832). Total plasma LPA levels decreased slightly with chemotherapy administration and there was a weak negative correlation (Spearman, r(s)=-0.151, p=0.034), compared to a significant negative correlation in CA-125 (Spearman, r(s)=-0.596, p<0.001). CONCLUSION: LPA is a better biomarker for diagnosis of epithelial ovarian cancer compared to CA-125. However, measurement of total plasma LPA levels during chemotherapy administration have no superiority to the serum CA-125 levels. PMID- 21278888 TI - Apoptosis-related mRNA expression profiles of ovarian cancer cell lines following cisplatin treatment. AB - OBJECTIVE: The aim of this study was to identify apoptosis-related genes of ovarian cancer cell lines following cisplatin treatment. METHODS: We used IC(50) values and fluorescence-activated cell sorting analysis to compare cell death in 2 ovarian cancer cell lines, namely, SKOV-3 and OVCAR-3, upon treatment with cisplatin. Moreover, the change in transcriptional levels of apoptosis-associated genes was measured with a dendron-modified DNA microarray. RESULTS: The protein levels for the up-regulated genes in each cell line were validated to identify the molecules that may determine the cellular behavior of cisplatin resistance. Eight genes were over-expressed in the 2 cell lines. The cisplatin-induced up regulation of DAD1 in transcriptional and protein levels contributed to the cisplatin resistance of OVCAR-3, and the up-regulation of FASTK and TNFRSF11A in SKOV-3 resulted in its higher sensitivity to cisplatin than that of OVCAR-3. CONCLUSION: In the present study, we have identified a set of genes responsible for apoptosis following cisplatin treatment in ovarian cancer cell lines. These genes may give information about the understanding of cisplatin-induced apoptosis in ovarian cancer. PMID- 21278889 TI - The effect of combined treatment with cisplatin and histone deacetylase inhibitors on HeLa cells. AB - OBJECTIVE: To investigate the combined effects of cisplatin and the histone deacetylase (HDAC) inhibitors suberoylanilide hydroxamic acid (SAHA) or sirtinol on HeLa cells and assess the mechanism underlying HDAC inhibitor-cisplatin synergy. METHODS: The antineoplastic actions of cisplatin, SAHA and sirtinol, alone and in combination, were evaluated using the tetrazolium dye-based MTT cell proliferation assay, DAPI nuclear staining and cytotoxicity analysis. RESULTS: Exposure to cisplatin, SAHA or sirtinol alone induced a dose-dependent reduction in HeLa cell viability. Combined treatment with cisplatin and SAHA or sirtinol was significantly more cytotoxic than cisplatin alone. Individually, cisplatin, SAHA and sirtinol activated caspase-3 and induced apoptosis, but the effects of combined treatment were greater. Importantly, both HDAC inhibitors dose dependently inhibited the expression of the antiapoptotic proteins Bcl-2 and x linked inhibitor of apoptosis protein (XIAP). CONCLUSION: The combination of cisplatin and SAHA or sirtinol had synergistic effect on the HeLa cell viability. This potentiation of cisplatin activity was associated with HDAC inhibitor mediated down-regulation of Bcl-2 and XIAP. These may result from the relaxation of chromatin by these HDAC inhibitors that increase cisplatin sensitivity by enhancing the accessibility of DNA to cisplatin and transcriptional regulators. PMID- 21278890 TI - Endometrial mullerian adenosarcoma after toremifene treatment in breast cancer patients: a case report. AB - Toremifene is an anti-estrogen which has been shown to be effective in the treatment of breast cancer, and is thought to be a less uterotrophic agent than tamoxifen. The risk assessment concerning endometrial cancer has been inconclusive because of its rare use up to the mid-1990s. We report a case of an adenosarcoma, which is a very rare type of uterine malignancy, after toremifene treatment for 5 years in a breast cancer patient. After 1 year of toremifene use, the patient had a benign Mullerian adenofibroma. After an additional 4 years of toremifene treatment, the endometrial polypoid lesion was transformed into a Mullerian adenosarcoma. Although toremifene is a promising anti-estrogenic agent in the treatment of breast cancer patients, clinicians should not neglect the possibility of a uterine malignancy. PMID- 21278891 TI - Sarcoma botryoides (embryonal rhabdomyosarcoma) of the uterine cervix in sisters. AB - Sarcoma botryoides (embryonal rhabdomyosarcoma) rarely arises in the uterine cervix. We report a case of a 14-year-old female with sarcoma botryoides who presented with prolonged vaginal bleeding and cervical polyp. The biopsy specimen confirmed sarcoma botryoides. The patient underwent radical surgery of the tumor and hysterectomy without adjuvant chemotherapy. The sister of the patient had died previously due to the same diagnosis at the age of 17. We achieved a satisfactory outcome in short-term period with radical surgery and hysterectomy. Presence of sarcoma botryoides of the cervix in two sisters in the family highlights the possible role of genetic factors in the development of sarcoma botryoides. PMID- 21278892 TI - Combined open surgical and endovascular management of ruptured femoral artery from recurrent vulvar cancer. AB - We report on the case of a 50-year-old woman with exsanguinating haemorrhage from the common femoral artery as a complication of recurrent vulvar cancer in the groin which was managed successfully with combined open surgical and endovascular intervention. She survived another three months and died from progressive disease without further episodes of bleeding. This complication is rare, presents dramatically, and is usually a terminal event. For those cases where intervention is considered appropriate, the option of combined open surgical and endovascular repair should be kept in mind. PMID- 21278893 TI - Parvovirus B19 nonstructural protein-induced damage of cellular DNA and resultant apoptosis. AB - Parvovirus B19 is a widespread virus with diverse clinical presentations. The viral nonstructural protein, NS1, binds to and cleaves the viral genome, and induces apoptosis when transfected into nonpermissive cells, such as hepatocytes. We hypothesized that the cytotoxicity of NS1 in such cells results from chromosomal DNA damage caused by the DNA-nicking and DNA-attaching activities of NS1. Upon testing this hypothesis, we found that NS1 covalently binds to cellular DNA and is modified by PARP, an enzyme involved in repairing single-stranded DNA nicks. We furthermore discovered that the DNA nick repair pathway initiated by poly(ADPribose)polymerase and the DNA repair pathways initiated by ATM/ATR are necessary for efficient apoptosis resulting from NS1 expression. PMID- 21278894 TI - Positioning effects of KillerRed inside of cells correlate with DNA strand breaks after activation with visible light. AB - Fluorescent proteins (FPs) are established tools for new applications, not restricted to the cell biological research. They could also be ideal in surgery enhancing the precision to differentiate between the target tissue and the surrounding healthy tissue. FPs like the KillerRed (KRED), used here, can be activated by excitation with visible day-light for emitting active electrons which produce reactive oxygen species (ROS) resulting in photokilling processes. It is a given that the extent of the KRED's cell toxicity depends on its subcellular localization. Evidences are documented that the nuclear lamina as well as especially the chromatin are critical targets for KRED-mediated ROS-based DNA damaging. Here we investigated the damaging effects of the KRED protein fused to the nuclear lamina and to the histone H2A DNA-binding protein. We detected a frequency of DNA strand breaks, dependent first on the illumination time, and second on the spatial distance between the localization at the chromatin and the site of ROS production. As a consequence we could identify defined DNA bands with 200, 400 and (600) bps as most prominent degradation products, presumably representing an internucleosomal DNA cleavage induced by KRED. These findings are not restricted to the detection of programmed cell death processes in the therapeutic field like PDT, but they can also contribute to a better understanding of the structure-function relations in the epigenomic world. PMID- 21278895 TI - The emergence of mycophenolate mofetilin dermatology: from its roots in the world of organ transplantation to its versatile role in the dermatology treatment room. PMID- 21278896 TI - Multisource, Phase-controlled Radiofrequency for Treatment of Skin Laxity: Correlation Between Clinical and In-vivo Confocal Microscopy Results and Real Time Thermal Changes. AB - OBJECTIVE: The objective of this study was to analyze the correlation between degrees of clinical improvement and microscopic changes detected using confocal microscopy at the temperature gradients reached in patients treated for skin laxity with a phase-controlled, multisource radiofrequency system. DESIGN AND SETTING: Patients with skin laxity in the abdominal area were treated in six sessions with radiofrequency (the first 4 sessions were held at 2-week intervals and the 2 remaining sessions at 3-week intervals). Patients attended monitoring at 6, 9, and 12 months. PARTICIPANTS: 33 patients (all women). MEASUREMENTS: The authors recorded the following: variations in weight, measurements of the contour of the treated area and control area, evaluation of clinical improvement by the clinician and by the patient, images taken using an infrared camera, temperature (before, immediately after, and 20 minutes after the procedure), and confocal microscopy images (before treatment and at 6, 9, and 12 months). The degree of clinical improvement was contrasted by two external observers (clinicians). The procedure was performed using a new phase-controlled, multipolar radiofrequency system. RESULTS: The results reveal a greater degree of clinical improvement in patients with surface temperature increases greater than 11.5oC at the end of the procedure and remaining greater than 4.5oC 20 minutes later. These changes induced by radiofrequency were contrasted with the structural improvements observed at the dermal-epidermal junction using confocal microscopy. Changes are more intense and are statistically correlated with patients who show a greater degree of improvement and have higher temperature gradients at the end of the procedure and 20 minutes later. CONCLUSION: Monitoring and the use of parameters to evaluate end-point values in skin quality treatment by multisource, phased controlled radiofrequency can help optimize aesthetic outcome. PMID- 21278897 TI - Electrosurgical excision of acne keloidalis nuchae with secondary intention healing. AB - Acne keloidalis nuchae is an idiopathic, scarring folliculitis characterized by the formation of papules and pustules that may ultimately develop into tumor-like masses distributed on the nape of the neck and occipital region of the scalp. This hyperproliferative disorder is most commonly seen in African-American men. While the pathogenesis remains uncertain, precipitating factors include localized trauma, chronic irritation, seborrhea, and androgen excess. The treatment of acne keloidalis nuchae is challenging and depends on the clinical stage of the disease; however, a multifaceted approach involving combination therapies has proven to be effective in some cases. Excision with healing by secondary intention is a recommended option for patients with large plaque- and tumor-stage acne keloidalis nuchae. This case report reviews the management of a patient with tumor-stage acne keloidalis nuchae successfully treated with electrosurgical excision and secondary intention healing with excellent cosmetic results and no recurrence of the disease. PMID- 21278898 TI - Rational management of papulopustular rosacea with concomitant facial seborrheic dermatitis: a case report. AB - OBJECTIVE: To report a case of papulopustular rosacea with concomitant seborrheic dermatitis and discuss how signs and symptoms were ameliorated using a rational therapeutic approach. DESIGN: Patient case report. SETTING: Clinical practice. PARTICIPANT: One male patient with rosacea, seborrheic dermatitis, and actinic keratoses. MEASUREMENTS: Change in signs and symptoms over time. RESULTS: Improved skin care practices and treatment with azelaic acid 15% gel twice daily in combination with low-dosage oral isotretinoin resulted in improvement in symptoms of both rosacea and seborrheic dermatitis. CONCLUSION: In patients with multiple skin disorders, use of medications with benefits for more than one of the skin conditions may, in some cases, reduce the overall number of medications needed, thus simplifying treatment. PMID- 21278899 TI - Eruptive xanthomas as a cutaneous manifestation of hypertriglyceridemia: a case report. AB - A 28-year-old veteran presented to the Wilford Hall dermatology clinic in San Antonio, Texas, with a six-month history of a rash that his primary care physician diagnosed as molluscum contagiosum. The rash consisted of clusters of 3 to 6mm yellowish papules with erythematous borders that concentrated on the extensor surfaces of his extremities, lower back, and buttocks. A biopsy determined that the patient had a case of eruptive xanthoma. Subsequent laboratory testing revealed that the patient had a type IV familial hyperlipidemia with a triglyceride count of 1718mg/dL. PMID- 21278900 TI - Optimization of an HTRF Assay for the Detection of Soluble Mutant Huntingtin in Human Buffy Coats: A Potential Biomarker in Blood for Huntington Disease. AB - A means for measuring levels of soluble huntingtin proteins in clinical samples is essential for assessing the biological effects of potential mutant huntingtin (mtHtt) modifying treatments being developed for Huntington's disease (HD). We have optimized a previously described cell-based Homogeneous Time Resolved Fluorescence method that can measure soluble mtHtt and its ratio to the total Htt (tHtt) in blood buffy coats [1]. The results of the optimization and assay qualification indicate the assay to be specific for mtHtt in HD compared to Control subjects, highly sensitive, and technically and biologically reproducible. We therefore generated a Good Laboratory Practice Standard Operating Procedure which we validated, using 30 HD and 8 control buffy coat samples in which significant differences in mtHtt levels were found. We intend to deploy the assay to evaluate sample sets from observational and therapeutic studies enrolling HD subjects to further validate soluble mtHtt measurement by HTRF as a biomarker for HD and to explore its potential uses. PMID- 21278901 TI - Interleukin-28B genotype testing to determine response to the combination of pegylated-interferon and ribavirin for the treatment of hepatitis C virus. AB - Hepatitis C virus (HCV) is a bloodborne infection that is one of the leading causes of liver disease. If left untreated, HCV can lead to cirrhosis, hepatocellular carcinoma, and death. The current standard of care for HCV is a combination of pegylated-interferon (peg-IFN) and ribavirin (RBV) in which the goal of treatment is to decrease complications and death due to HCV. HCV displays genetic polymorphism, where patients with HCV genotype 1 may have higher viral replication rates and are less likely to respond to treatment. These patients require a longer duration of treatment and a higher RBV dose. The interleukin (IL) 28B genotype test is associated with a sustained virologic response (SVR), defined as an undetectable HCV ribonucleic acid (RNA) upon completion of treatment and 24 weeks thereafter. PMID- 21278902 TI - Genetic risk profiling for prediction of type 2 diabetes. AB - Type 2 diabetes (T2D) is a common disease caused by a complex interplay between many genetic and environmental factors. Candidate gene studies and recent collaborative genome-wide association efforts revealed at least 38 common single nucleotide polymorphisms (SNPs) associated with increased risk of T2D. Genetic testing of multiple SNPs is considered a potentially useful tool for early detection of individuals at high diabetes risk leading to improved targeting of preventive interventions. PMID- 21278903 TI - Mothers, Fathers, Peers, and Mexican-Origin Adolescents' Sexual Intentions. AB - Drawing on a symbolic-interaction perspective and a compensation model, the processes linking mother-and father-adolescent relationship qualities, deviant peer affiliations, and adolescents' sexual intentions were investigated for 246 Mexican-origin youths born in the United States and in Mexico using multiple group structural equation models. Deviant peer affiliations significantly mediated the relations between paternal acceptance and sexual intentions and between disclosure to mothers and sexual intentions for U.S.-born youths but not for Mexico-born youths. Findings highlight the importance of examining variability as a function of youth nativity. PMID- 21278904 TI - Self-Regulation Mediates the Relationship between Learner Typology and Achievement in At - Risk Children. AB - A person-centered approach was used to explore the mediating role of self regulation between learner typology at age 8 and academic achievement at age 14while controlling for domain-specific achievement in a longitudinal sample of 113 children born to adolescent mothers. Children were classified into one of 5 learner typologies at age 8based on interactive patterns of intellectual, achievement, and adaptive abilities. Typology classification explained significant variance in both reading and mathematics achievement at age 14. A bootstrapping approach confirmed that self-regulation mediated the relationship between typology and reading and mathematical achievement for children from all typologies except those classified as Cognitively and Adaptively Challenged. Implications of person-centered approaches for understanding processes involved with achievement are discussed. PMID- 21278905 TI - Regulation of mitochondrial processes: a target for heart failure. AB - Cardiac mitochondria, the main source of energy as well as free radicals, are vital organelles for normal functioning of the heart. Mitochondrial number, structure, turnover and function are regulated by processes such as mitochondrial protein quality control, mitochondrial fusion and fission and mitophagy. Recent studies suggest that abnormal changes in these mitochondrial regulatory processes may contribute to the pathology of heart failure (HF). Here we discuss these processes and their potential as therapeutic targets. PMID- 21278906 TI - Modeling the Impact of Control on the Attractiveness of Risk in a Prospect Theory Framework. AB - Many decisions involve a degree of personal control over event outcomes, which is exerted through one's knowledge or skill. In three experiments we investigated differences in decision making between prospects based on a) the outcome of random events and b) the outcome of events characterized by control. In Experiment 1, participants estimated certainty equivalents (CEs) for bets based on either random events or the correctness of their answers to U.S. state population questions across the probability spectrum. In Experiment 2, participants estimated CEs for bets based on random events, answers to U.S. state population questions, or answers to questions about 2007 NCAA football game results. Experiment 3 extended the same procedure as Experiment 1 using a within subjects design. We modeled data from all experiments in a prospect theory framework to establish psychological mechanisms underlying decision behavior. Participants weighted the probabilities associated with bets characterized by control so as to reflect greater risk attractiveness relative to bets based on random events, as evidenced by more elevated weighting functions under conditions of control. This research elucidates possible cognitive mechanisms behind increased risk taking for decisions characterized by control, and implications for various literatures are discussed. PMID- 21278907 TI - Emotionally meaningful targets enhance orienting triggered by a fearful gazing face. AB - Studies investigating the effect of emotional expression on spatial orienting to a gazed-at location have produced mixed results. The present study investigated the role of affective context in the integration of emotion processing and gaze triggered orienting. In three experiments, a face gazed nonpredictively to the left or right, and then its expression became fearful or happy. Participants identified (Experiments 1 and 2) or detected (Experiment 3) a peripheral target presented 225 or 525 ms after the gaze cue onset. In Experiments 1 and 3 the targets were either threatening (a snarling dog) or nonthreatening (a smiling baby); in Experiment 2 the targets were neutral. With emotionally-valenced targets, the gaze-cuing effect was larger when the face was fearful compared to happy--but only with the longer cue-target interval. With neutral targets, there was no interaction between gaze and expression. Our results indicate that a meaningful context optimizes attentional integration of gaze and expression information. PMID- 21278908 TI - Characterization and quantification of biological micropatterns using Cluster SIMS. AB - Micropatterning is used widely in biosensor development, tissue engineering and basic biology. Creation of biological micropatterns typically involves multiple sequential steps that may lead to cross-contamination and may contribute to sub optimal performance of the surface. Therefore, there is a need to develop novel strategies for characterizing location-specific chemical composition of biological micropatterns. In this paper, C(60) (+) ToF-SIMS operating in the event-by-event bombardment-detection mode was used for spatially resolved chemical analysis of micropatterned indium tin oxide (ITO) surfaces. Fabrication of the micropatterns involved multiple steps including self-assembly of poly (ethylene glycol) (PEG)-silane, patterning of photoresist, treatment with oxygen plasma and adsorption of collagen (I). The ITO surfaces were analyzed with 26 keV C(60) (+)SIMS run in the event-by-event bombardment-detection mode at different steps of the modification process. We were able to evaluate the extent of cross contamination between different steps and quantify coverage of the immobilized species. The methodology described here provides a novel means for characterizing the composition of biological micropatterns in a quantitative and spatially resolved manner. PMID- 21278909 TI - DYNAMICS OF SINGLE-MOLECULE ROTATIONS ON SURFACES DEPEND ON SYMMETRY, INTERACTIONS AND MOLECULAR SIZES. AB - Rotating surface-mounted molecules have attracted attention of many research groups as a way to develop new nanoscale devices and materials. However, mechanisms of motion of these rotors at the single-molecule level are still not well understood. Theoretical and experimental studies on thioether molecular rotors on gold surfaces suggest that the size of the molecules, their flexibility and steric repulsions with the surface are important for dynamics of the system. A complex combination of these factors leads to the observation that the rotation speeds have not been hindered by increasing the length of the alkyl chains. However, experiments on diferrocene derivatives indicated that a significant increase in the rotational barriers for longer molecules. We present here a comprehensive theoretical study that combines molecular dynamics simulations and simple models to investigate what factors influence single-molecule rotations on the surfaces. Our results suggest that rotational dynamics is determined by the size and by the symmetry of the molecules and surfaces, and by interactions with surfaces. Our theoretical predictions are in excellent agreement with current experimental observations. PMID- 21278911 TI - Sticky Dollars: Inertia in the Evolution of Federal Allocations for HIV Care through the Ryan White HIV/AIDS Program. AB - While substantial research examines the dynamics prompting policy adoption, few studies have assessed whether enacted policies are modified to meet distributional equity concerns. Past research suggests that important forces limit such adaptation, termed here "policy inertia." We examine whether block grant allocations to states from the Ryan White HIV/AIDS Program have evolved in response to major technological and political changes. We assess the impact of initial allocations on later funding patterns, compared to five counterfactual distributional equity standards. Initial allocations strongly predict future allocations; in comparison, the standards are weak predictors, suggesting the importance of policy inertia. Our methodology of employing multiple measures of equity as a counterfactual to policy inertia can be used to evaluate the adaptability of federalist programs in other domains. PMID- 21278910 TI - Response Conflict and Affective Responses in the Control and Expression of Race Bias. AB - Models of racial attitudes traditionally have assumed that individual differences in the strength of underlying, 'implicit' associations between racial categories and stereotypical traits are the primary determinant of the expression of race bias. Thus, individual differences in performance on laboratory tasks designed to assess implicit race bias tend to be interpreted in terms of association strength. Here, we argue that such associations tell only part of the story, and probably the least interesting part. We posit that response conflict and its regulation are critical to understanding the need for control, and that affect related processes help to determine the extent to which control resources will be implemented to overcome biased associations. We present data from a number of recent behavioral and psychophysiological studies in support of this idea, as well as conceptual accounts that point toward a model of race bias regulation that depends upon processes identified as important for regulation of thought, affect and action more generally. PMID- 21278912 TI - Reaction time, memory strength, and fMRI activity during memory retrieval: Hippocampus and default network are differentially responsive during recollection and familiarity judgments. AB - Retrieval is often subdivided into recollection and familiarity. Memory-strength and reaction time (RT) differ for each, complicating fMRI studies of these processes. Recollection leads to greater activity in the hippocampus and default network (DN). Increased DN activity with recollection is thought to reflect self referential processes, but prior studies have not accounted for varying RT, which modulates DN activity and is consistently faster for recollection than familiarity. This study examined the influence of RT and memory-strength on recollection and familiarity activity. The results show the hippocampus functionally dissociated from DN during retrieval. DN was generally influenced by RT and signal was suppressed when subjects were task-engaged in recollection or familiarity; suppression was greater for slower trials of either type. The hippocampus showed a positive deflection of fMRI activity only for recollection trials; activation was greater for slower recollection trials, but RT did not influence hippocampal activity during familiarity trials. PMID- 21278913 TI - Graphene-Dielectric Integration for Graphene Transistors. AB - Graphene is emerging as an interesting electronic material for future electronics due to its exceptionally high carrier mobility and single-atomic thickness. Graphene-dielectric integration is of critical importance for the development of graphene transistors and a new generation of graphene based electronics. Deposition of dielectric materials onto graphene is of significant challenge due to the intrinsic material incompatibility between pristine graphene and dielectric oxide materials. Here we review various strategies being researched for graphene-dielectric integration. Physical vapor deposition (PVD) can be used to directly deposit dielectric materials on graphene, but often introduces significant defects into the monolayer of carbon lattice; Atomic layer deposition (ALD) process has also been explored to to deposit high-kappa dielectrics on graphene, which however requires functionalization of graphene surface with reactive groups, inevitably leading to a significant degradation in carrier mobilities; Using naturally oxidized thin aluminum or polymer as buffer layer for dielectric deposition can mitigate the damages to graphene lattice and improve the carrier mobility of the resulted top-gated transistors; Lastly, a physical assembly approach has recently been explored to integrate dielectric nanostructures with graphene without introducing any appreciable defects, and enabled top-gated graphene transistors with the highest carrier mobility reported to date. We will conclude with a brief summary and perspective on future opportunities. PMID- 21278915 TI - Effects of Water Placement on Predictions of Binding Affinities for p38alpha MAP Kinase Inhibitors. AB - Monte Carlo free energy perturbation (MC/FEP) calculations have been applied to compute the relative binding affinities of 17 congeneric pyridazo-pyrimidinone inhibitors of the protein p38alpha MAP kinase. Overall correlation with experiment was found to be modest when the complexes were hydrated using a traditional procedure with a stored solvent box. Significant improvements in accuracy were obtained when the MC/FEP calculations were repeated using initial solvent distributions optimized by the water placement algorithm JAWS. The results underscore the importance of accurate placement of water molecules in a ligand binding site for the reliable prediction of relative free energies of binding. PMID- 21278916 TI - Inexact Local Alignment Search over Suffix Arrays. AB - We describe an algorithm for finding approximate seeds for DNA homology searches. In contrast to previous algorithms that use exact or spaced seeds, our approximate seeds may contain insertions and deletions. We present a generalized heuristic for finding such seeds efficiently and prove that the heuristic does not affect sensitivity. We show how to adapt this algorithm to work over the memory efficient suffix array with provably minimal overhead in running time.We demonstrate the effectiveness of our algorithm on two tasks: whole genome alignment of bacteria and alignment of the DNA sequences of 177 genes that are orthologous in human and mouse. We show our algorithm achieves better sensitivity and uses less memory than other commonly used local alignment tools. PMID- 21278917 TI - Prediction of human disease-related gene clusters by clustering analysis. AB - Since genes associated with similar diseases/disorders show an increased tendency for their protein products to interact with each other through protein-protein interactions (PPI), clustering analysis obviously as an efficient technique can be easily used to predict human disease-related gene clusters/subnetworks. Firstly, we used clustering algorithms, Markov cluster algorithm (MCL), Molecular complex detection (MCODE) and Clique percolation method (CPM) to decompose human PPI network into dense clusters as the candidates of disease-related clusters, and then a log likelihood model that integrates multiple biological evidences was proposed to score these dense clusters. Finally, we identified disease-related clusters using these dense clusters if they had higher scores. The efficiency was evaluated by a leave-one-out cross validation procedure. Our method achieved a success rate with 98.59% and recovered the hidden disease-related clusters in 34.04% cases when removed one known disease gene and all its gene-disease associations. We found that the clusters decomposed by CPM outperformed MCL and MCODE as the candidates of disease-related clusters with well-supported biological significance in biological process, molecular function and cellular component of Gene Ontology (GO) and expression of human tissues. We also found that most of the disease-related clusters consisted of tissue-specific genes that were highly expressed only in one or several tissues, and a few of those were composed of housekeeping genes (maintenance genes) that were ubiquitously expressed in most of all the tissues. PMID- 21278918 TI - Lipocalin-2-induced cytokine production enhances endometrial carcinoma cell survival and migration. AB - Lipocalin-2 (Lcn-2) is an acute-phase protein that has been implicated in diverse physiological processes in mice, including: apoptosis, ion transport, inflammation, cell survival, and tumorigenesis. This study characterized the biological activity of Lcn-2 in human endometrial carcinoma cells (RL95-2). Exposure of RL95-2 cells to Lcn-2 for >24 h reduced Lcn-2-induced cell apoptosis, changed the cell proliferation and up-regulated cytokine secretions, including: interleukin-8 (IL-8), inteleukin-6 (IL-6), monocyte chemotatic protein-1 (MCP-1) and growth-related oncogene (GRO). However, IL-8 mRNA and protein levels were dramatically increased in Lcn-2-treated RL95-2 cells. To determine the IL-8 effect on Lcn-2-treated RL95-2 cells was our major focus. Adding recombinant IL-8 (rIL-8) resulted in decreased caspase-3 activity in Lcn-2-treated cells, whereas the addition of IL-8 antibodies resulted in significantly increased caspase-3 activity and decreased cell migration. Data indicate that IL-8 plays a crucial role in the induction of cell migration. Interestingly, Lcn-2-induced cytokines, secretion from RL95-2 cells, could not show the potent cell migration ability with the exception of IL-8. We conclude that Lcn-2 triggered cytokine secretions to prevent RL95-2 cells from undergoing apoptosis and subsequently increased cell migration. We hypothesize that Lcn-2 increased cytokine secretion by RL95-2 cells, which in turn activated a cellular defense system. This study suggests that Lcn-2 may play a role in the human female reproductive system or in endometrial cancer. PMID- 21278919 TI - Chicken HOXA3 gene: its expression pattern and role in branchial nerve precursor cell migration. AB - In vertebrates, the proximal and distal sensory ganglia of the branchial nerves are derived from neural crest cells (NCCs) and placodes, respectively. We previously reported that in Hoxa3 knockout mouse embryos, NCCs and placode derived cells of the glossopharyngeal nerve were defective in their migration. In this report, to determine the cell-type origin for this Hoxa3 knockout phenotype, we blocked the expression of the gene with antisense morpholino oligonucleotides (MO) specifically in either NCCs/neural tube or placodal cells of chicken embryos. Our results showed that HOXA3 function was required for the migration of the epibranchial placode-derived cells and that HOXA3 regulated this cell migration in both NCCs/neural tube and placodal cells. We also report that the expression pattern of chicken HOXA3 was slightly different from that of mouse Hoxa3. PMID- 21278920 TI - Local rheology of human neutrophils investigated using atomic force microscopy. AB - During the immune response, neutrophils display localized mechanical events by interacting with their environment through the micro-vascular transit, trans endothelial, and trans-epithelial migration. Nano-mechanical studies of human neutrophils on localized nano-domains could provide the essential information for understanding their immune responsive functions. Using the Atomic Force Microscopy (AFM)-based micro-rheology, we have investigated rheological properties of the adherent human neutrophils on local nano-domains. We have applied the modified Hertz model to obtain the viscoelastic moduli from the relatively thick body regions of the neutrophils. In addition, by using more advanced models to account for the substrate effects, we have successfully characterized the rheological properties of the thin leading and tail regions as well. We found a regional difference in the mechanical compliances of the adherent neutrophils. The central regions of neutrophils were significantly stiffer (1,548 +/- 871 Pa) than the regions closer to the leading edge (686 +/- 801 Pa), while the leading edge and the tail (494 +/- 537 Pa) regions were mechanically indistinguishable. The frequency-dependent elastic and viscous moduli also display a similar regional difference. Over the studied frequency range (100 to 300 Hz), the complex viscoelastic moduli display the partial rubber plateau behavior where the elastic moduli are greater than the viscous moduli for a given frequency. The non-disparaging viscous modulus indicates that the neutrophils display a viscoelastic dynamic behavior rather than a perfect elastic behavior like polymer gels. In addition, we found no regional difference in the structural damping coefficient between the leading edge and the cell body. Thus, we conclude that despite the lower loss and storage moduli, the leading edges of the human neutrophils display partially elastic properties similar to the cell body. These results suggest that the lower elastic moduli in the leading edges are more favorable for the elastic fluctuation of actin filaments, which supports the polymerization of the actin filaments leading to the active protrusion during the immune response. PMID- 21278923 TI - Initial Evaluation of Direct 4D Parametric Reconstruction with Human PET Data. AB - Previously, we presented a direct EM method for producing kinetic parameter images from list mode PET data, where the time-activity curve for each voxel is described by a one-tissue compartment model (1T). The initial evaluations were performed with simulations, without motion, randoms, or scatter effects included. By extension of our previous frame-based physics correction methods, a practical direct 4D parametric reconstruction algorithm is now proposed and implemented for human data. Initial evaluations were performed using 3 human subjects with the serotonin transporter tracer [(11)C]AFM. Comparisons with the 2-step approach (frame-based reconstruction followed by voxel-by-voxel parameter estimation) provided encouraging initial results. Regional analysis showed that the 2-step and 4D methods have similar K(1) and V(T) values, but with a consistent difference. Visual analysis showed some noise reduction in 4D. These initial results suggest that direct 4D parametric reconstruction can be performed with real data, and offers the potential for improved accuracy and precision over the 2-step frame method. PMID- 21278922 TI - MicroRNA-137 targets carboxyl-terminal binding protein 1 in melanoma cell lines. AB - Carboxyl-terminal binding protein 1 (CtBP1) is a transcriptional co-repressor that represses expression of various tumor suppressor genes. In the present study, we identified miR-137 as a potential regulator of CtBP1 expression in melanoma cells. Expression of miR-137 in melanoma cell lines was found to inversely correlate with CtBP1 levels. Target Scan predicted a putative site for miR-137 within the CtBP1 3' untranslated region (3'UTR) at nt 710-716, which is highly conserved across species. To explore the mechanism of miR-137 targeting CtBP1, we performed an Argonaute 2 (Ago2)-pull down assay, and miR-137 was identified in complex with CtBP1 mRNA. miR-137 suppressed CtBP1 3' UTR luciferase reporter activity, and this effect was lost with deletion of the putative 3' UTR target-site. Consistent with the results of the reporter assay, ectopic expression of miR-137 reduced expression levels of CtBP1. Furthermore, expression of miR-137 increased the immediate downstream effectors of CtBP1, such as E cadherin and Bax. The human miR-137 gene is located at chromosome 1p22, which has previously been determined to be a susceptive region for melanoma. This study suggests miR-137 may act as a tumor suppressor by directly targeting CtBP1 to inhibit epithelial-mesenchymal transition (EMT) and inducing apoptosis of melanoma cells, thus illustrating a functional link between miR-137 and CtBP1 in melanoma development. PMID- 21278921 TI - Finite element method (FEM), mechanobiology and biomimetic scaffolds in bone tissue engineering. AB - Techniques of bone reconstructive surgery are largely based on conventional, non cell-based therapies that rely on the use of durable materials from outside the patient's body. In contrast to conventional materials, bone tissue engineering is an interdisciplinary field that applies the principles of engineering and life sciences towards the development of biological substitutes that restore, maintain, or improve bone tissue function. Bone tissue engineering has led to great expectations for clinical surgery or various diseases that cannot be solved with traditional devices. For example, critical-sized defects in bone, whether induced by primary tumor resection, trauma, or selective surgery have in many cases presented insurmountable challenges to the current gold standard treatment for bone repair. The primary purpose of bone tissue engineering is to apply engineering principles to incite and promote the natural healing process of bone which does not occur in critical-sized defects. The total market for bone tissue regeneration and repair was valued at $1.1 billion in 2007 and is projected to increase to nearly $1.6 billion by 2014.Usually, temporary biomimetic scaffolds are utilized for accommodating cell growth and bone tissue genesis. The scaffold has to promote biological processes such as the production of extra-cellular matrix and vascularisation, furthermore the scaffold has to withstand the mechanical loads acting on it and to transfer them to the natural tissues located in the vicinity. The design of a scaffold for the guided regeneration of a bony tissue requires a multidisciplinary approach. Finite element method and mechanobiology can be used in an integrated approach to find the optimal parameters governing bone scaffold performance.In this paper, a review of the studies that through a combined use of finite element method and mechano regulation algorithms described the possible patterns of tissue differentiation in biomimetic scaffolds for bone tissue engineering is given. Firstly, the generalities of the finite element method of structural analysis are outlined; second, the issues related to the generation of a finite element model of a given anatomical site or of a bone scaffold are discussed; thirdly, the principles on which mechanobiology is based, the principal theories as well as the main applications of mechano-regulation models in bone tissue engineering are described; finally, the limitations of the mechanobiological models and the future perspectives are indicated. PMID- 21278924 TI - GROUPWISE REGISTRATION FROM EXEMPLAR TO GROUP MEAN: EXTENDING HAMMER TO GROUPWISE REGISTRATION. AB - We extend the pairwise HAMMER registration algorithm to work in a groupwise manner for improving structural alignment of different individual brain images of a group. To achieve this, a tentative group mean is first generated from the previous aligned brain images (initially with affine registration), and all brain images are then registered onto the tentative group mean by HAMMER to obtain a refined group mean. Eventually, by repeating these two steps, a refined group mean image can be constructed. To obtain a better estimate of the group mean, we propose to average the aligned image according to anatomical shape, instead of intensity. Also, to alleviate possible large anatomical misalignment in the initial stages of the registration, a minimum risk estimator is employed for refining the correspondences before averaging, to prevent averaging across irrelevant anatomical structures, which, if not avoided, will render the group mean fuzzy. The performance of our groupwise registration method is evaluated by using real data (NIREP) in a ROI overlap analysis, and simulated data in an atrophy detection experiment. The results show that our groupwise registration algorithm yields better performance in both registration consistency and accuracy than the original pairwise HAMMER algorithm. PMID- 21278925 TI - The roles of TTP and BRF proteins in regulated mRNA decay. AB - Adenylate- and uridylate-rich element (ARE) motifs are cis-acting elements present in the 3' untranslated region of mRNA transcripts that encode many inflammation- and cancer-associated genes. The TIS11 family of RNA-binding proteins, composed of tristetraprolin (TTP) and butyrate response factors 1 and 2 (BRF-1 and -2), plays a critical role in regulating the expression of ARE containing mRNAs. Through their ability to bind and target ARE-containing mRNAs for rapid degradation, this class of RNA-binding proteins serves a fundamental role in limiting the expression of a number of critical genes, thereby exerting anti-inflammatory and anti-cancer effects. Regulation of TIS11 family members occurs on a number of levels through cellular signaling events to control their transcription, mRNA turnover, phosphorylation status, cellular localization, association with other proteins, and proteosomal degradation, all of which impact TIS11 members' ability to promote ARE-mediated mRNA decay along with decay independent functions. This review summarizes our current understanding of posttranscriptional regulation of ARE-containing gene expression by TIS11 family members and discusses their role in maintaining normal physiological processes and the pathological consequences in their absence. PMID- 21278926 TI - Endothelial Cell Vascular Smooth Muscle Cell Co-Culture Assay For High Throughput Screening Assays For Discovery of Anti-Angiogenesis Agents and Other Therapeutic Molecules. AB - Drug development for many diseases would be aided greatly by accurate in vitro model systems that replicate key elements of in vivo physiology. The recent development of co-culture systems of endothelial cells and vascular smooth muscle cells can be extended to high throughput systems for the identification of compounds for angiogenesis, vascular repair and hypertension. In this review, the various co-culture systems are reviewed and biological interactions between endothelial cells and vascular smooth muscle cells are discussed. Key considerations in the design of high throughput systems are presented and selected examples are discussed. PMID- 21278927 TI - Prescription Drug Abuse & Diversion: Role of the Pain Clinic. AB - The goal of this research is to better understand the role that South Florida pain management clinics may be playing in the abuse and diversion of prescription drugs. This study explores 1) the characteristics and practices of pain clinics that may be facilitating the drug-seeking endeavors of prescription drug abusers and 2) the drug-seeking behaviors of prescription drug abusers who use pain clinics as a primary source for drugs. Thirty in-depth interviews were conducted with prescription drug abusers in South Florida. Interviews were transcribed verbatim and codes were generated based on thematic analyses of the data. Using grounded theory strategies, the analysis revealed six main themes: "pill mills", on-site pharmacies, liberal prescribing habits, "sponsoring" drug diversion, pain doctor/pharmacy shopping, and faking symptoms/documentation. These findings should provide insights for law enforcement, regulatory agencies, and industry as they attempt to develop appropriate policy initiatives and recommendations for best practices. PMID- 21278928 TI - Says who? A treatise on references. PMID- 21278929 TI - [Not Available]. PMID- 21278930 TI - [Not Available]. PMID- 21278931 TI - 'Tobasco throat'. PMID- 21278932 TI - A word on the Canada health act. PMID- 21278933 TI - Use of cimetidine. PMID- 21278934 TI - Criticism of article on neurolinguistic programming. PMID- 21278935 TI - Benzodiazepine use. PMID- 21278937 TI - Food sensitivities. PMID- 21278936 TI - Monilial infections in moms and babies. PMID- 21278938 TI - NSAIDs and menstruation. PMID- 21278939 TI - Patient recall of tetanus immunization status. AB - Tetanus is a serious, often fatal disease that should be completely preventable by appropriate immunization. The present study, done in an urban family practice group, examined the correlation between patients' recollection of their most recent tetanus booster, and the actual date, obtained from office records. Forty three of the 62 patients (69%) estimated within a year of the correct date; 33 (53%) recalled the date accurately. Recent information on the epidemiology of tetanus is discussed, as are previous studies of tetanus immunization practice. PMID- 21278940 TI - Antimicrobial use in a small rural hospital. AB - An audit was done to determine the pattern of antimicrobial use in a small rural Canadian hospital. Over a three-month period, 85 (33.7%) of 252 hospitalized patients received systemic antimicrobials. The group comprised 19 children and 66 adults. Respiratory infections were most common in both children and adults, and ampicillin/amoxicillin was the most frequently used agent. Treatment was judged to be appropriate in all the children, but was inappropriate in 15% of the adults. Adults who had superficial skin infections, and urinary tract infections with catheters in place, were most often inappropriately treated with systemic antimicrobials. The causes of inappropriate antimicrobial use and how to prevent it are discussed. PMID- 21278941 TI - Is gestational diabetes a clinical entity? AB - 'Gestational diabetes' is defined as abnormal glucose tolerance appearing for the first time in pregnancy. However, it is difficult to establish an important relationship between this diagnosis and poor perinatal outcome. There is little evidence, therefore, that screening for the condition with a glucose tolerance test (GTT) will provide significant improvement in obstetrical results. It is likely that maternal age and weight can predict women at risk of perinatal loss with equal or greater effectiveness. Focus on GTTs may lead the clinician to neglect more important factors associated with perinatal loss. Attention to the currently accepted risk factors of maternal age, stature, and post-obstetric history, together with careful assessment of fetal growth, should be the approach to care in patients at risk from gestational diabetes. PMID- 21278942 TI - Infections in the diabetic foot. AB - Minor infections of the foot in elderly diabetic patients, with associated degenerative diseases, may lead to a devastating major infection of the foot, with subsequent loss of limb or life. Understanding the spread of infection from toe to foot to leg requires some understanding of anatomy, knowledge of the nature of bacteria and the body's response to skin organisms. The role of inadequate nerve supply is still obscure. Appearance of the first 'black spot' indicates that a minor break in the skin has become a major infection with a grave prognosis. Reconstruction of arteries has helped in the management of these infections. To properly manage these patients, the physician must provide longterm support and meticulous foot care. Treatment of a wound is time consuming, difficult and, unfortunately, not always successful. However, because some wounds heal and a functional foot may be the result in a few patients, the effort is worthwhile. PMID- 21278943 TI - Functional hypoglycemia: facts and fancies. AB - When blood glucose decreases below a given threshold, symptoms of cerebral dysfunction and/or adrenergic hyperactivity appear. If this occurs postprandially in otherwise normal subjects, a diagnosis of reactive or functional hypoglycemia may be proposed. However, these symptoms are not specific, and they should coincide with low blood glucose values and be rapidly relieved by glucose ingestion before a diagnosis of hypoglycemia is confirmed. The oral glucose tolerance test, often used in the evaluation of such patients, also may give misleading results, because many normal subjects have glucose values below the 'normal' range during the test. This may explain why functional hypoglycemia has probably been overdiagnosed during the last several years, giving rise to a description of the syndrome of non-hypoglycemia, in which the patient's symptoms are falsely attributed to hypoglycemia, either by himself or by his physician. Nevertheless, functional hypoglycemia exists and can be improved by proper management. PMID- 21278944 TI - Silent thyroiditis. AB - Silent or painless thyroiditis is a frequent cause of transient hyperthyroidism, which is characterized by recent onset of symptoms in a patient with a normal to modestly enlarged and firm thyroid gland. The hallmarks of the disease are the absence of thyroidal pain or tenderness and a markedly reduced radioiodine uptake. Histologically, the gland is characterized by an important lymphocytic infiltration, occasionally to the point of lymphoid follicle formation. However, other indices of an autoimmune cause are usually absent. The disease appears to have a predilection for the postpartum period. Relapses may occur with subsequent pregnancies. Otherwise, the course is usually benign and transient, requiring moderate doses of beta-adrenergic blocking agents for symptomatic relief. No pathogenetic factors are known, but the disease may conceivably have an autoimmune basis, particularly in the postpartum patient. PMID- 21278945 TI - Hormones and cancer. AB - Hormonal therapy is the first systemic therapy to have been used successfully in the treatment of cancer. Developments in steroid hormone receptor assays in the last decade have resulted in the first predictable assays for cancer therapy. The role of hormones, in both the development and treatment of breast, prostate and uterine cancer, is reviewed. Because hormonal therapy is generally a less toxic palliative treatment than other treatments (e.g., chemotherapy and radiation), it has been used for malignancies such as malignant melanoma, hypernephroma, and carcinoid. PMID- 21278946 TI - Good advice for a bad back. AB - Providing useful information to patients with chronic low back pain can be difficult. Patients tend to have many preconceived ideas and are often skeptical of medical advice. The physician should resist undue caution without being overly dogmatic. The basic principles of treatment are to be positive and specific but to avoid absolute statements. Encourage the patient's participation and do not directly challenge conflicting opinions. Inform patients that chairs should have wide seats, lumbar supports, arm rests and a 10 degrees -20 degrees slope to the back. Sleeping surfaces should be firm and offer uniform support. Braces, footstools, shoes and back supports provide passive assistance to active back care. PMID- 21278947 TI - Management of rheumatoid arthritis. AB - Rheumatoid arthritis is a common disease, for which every physician should have a sound approach. This paper details the global management of the disease. Guidelines are given for educating the patient and assessing the level of disease activity. Common questions about the indications and uses of non-steroidal anti inflammatory drugs, local corticosteroid injections, slow-acting agents, immunosuppressive drugs and steroids are discussed. PMID- 21278948 TI - A new approach to geriatric institutional care. AB - A new approach to 'deinstitutionalize' the geriatric institution is 'milieu therapy', which tries to create a sense of community. The geriatric resident is encouraged to wear his own clothes, and to use his own belongings and furniture. Residents eat meals together, and they are encouraged to take as much responsibility as possible for their own care. A very important part of milieu therapy is a weekly multidisciplinary staff meeting. One or two residents are discussed in detail. Their day-to-day activities and ways to improve general function are discussed. Three case histories illustrate how milieu therapy is used at the Manor, a 93-bed home for senior citizens in Woodstock, New Brunswick. PMID- 21278949 TI - Panic attacks and panic disorders. AB - The diagnosis and treatment of panic attacks and panic disorders have progressed markedly during the last decade. Unlike phobic disorders, the key feature of panic disorders is the many panic attacks that are mostly spontaneous or not caused by a particular situation. Recent studies linking its pathogenesis with lactate infusion tests are reviewed. For treatment, psychotherapy combined with in vivo exposure and pharmacotherapy is more efficacious than either treatment alone. In most cases, psychological treatment is supportive psychotherapy. The use of imipramine, as reported by Klein et al., is described, and alprazolam is presented as an alternative. PMID- 21278950 TI - Spontaneous regression of metastatic visceral malignant melanoma. AB - Spontaneous regressions of malignant tumors are rare. This report describes a patient who, after local recurrence of melanoma in his neck, developed pulmonary metastases which subsequently regressed. The patient was a 72-year-old retired farmer. Over the four years and five months from the discovery of the metastases to his death, this patient's pulmonary nodules regressed. Treatment was palliative, and there is no evidence that his immune system was artificially stimulated. He died from complications of a surgical repair of a hiatus hernia. No increase in the size of the pulmonary nodules was noted in chest X-rays taken during the three months before his death. PMID- 21278951 TI - Meigs' syndrome. AB - A 52-year-old female physician was admitted to hospital because of severe dyspnea and massive pleural effusion. At first, it seemed she may have been suffering from heart failure with an associated malignant disease. The patient was seemingly unaware of her progressive illness. During her hospital stay, it became evident that she was denying the possibility of cancer because of her husband's death from adenocarcinoma of the esophagus three years earlier. The carcinoma was inoperable and he was treated with chemotherapy. The patient was very upset about her husband's untimely death, and his treatment convinced her that she did not want chemotherapy if she was found to have cancer. Fortunately, it was discovered that she had benign cystic teratoma of the ovary with ascites and hydrothorax (Meigs' syndrome). PMID- 21278952 TI - Breastfeeding: religious experience or hard work? PMID- 21278953 TI - [Not Available]. PMID- 21278954 TI - Bourses et distinctions honorifiques du College pour 1984. PMID- 21278956 TI - Testing for food sensitivities. PMID- 21278955 TI - Reader Upset at CFPC's Involvement in Prescribing Survey. PMID- 21278957 TI - What Do FPs Earn For On Call Time? PMID- 21278958 TI - Author has something to add. PMID- 21278959 TI - Factors related to breastfeeding duration. AB - The purpose of this study was to discover factors related to breastfeeding duration. Of the 131 women who volunteered to complete questionnaires at one, three and six months postpartum, 46 provided baseline data, and 37 and 48 (randomly assigned) constituted low and high intervention groups respectively. Comparisons were made between breastfeeding and bottle feeding. Factors shown at three and six months to be related to duration of breastfeeding at the p < .05 level were: identified high risk factors in labor and delivery, admission of the infant to the intensive care nursery, and length of mother's and/or infant's hospitalization. The three months' data also showed a significant relationship between spontaneous births and 'breastfeeding only'. No positive relationship was found between breastfeeding duration and support from nursing staff. The results suggest that when mothers and infants experience intrapartum high risk factors, delivery by cesarean section and long hospital stay, the mothers are likely to stop breastfeeding early. PMID- 21278960 TI - The diagnostic challenge of multiple sclerosis. AB - Multiple sclerosis is a common cause of many neurological complaints and disabilities among young, adult Canadians. In the absence of a reliable and specific laboratory test for the disease, the diagnosis is established primarily by clinical criteria, which are outlined in this article. Recent advances in immunology, neurophysiology and neuroimaging have provided techniques to improve diagnostic confidence, particularly in early or atypical cases. PMID- 21278961 TI - Osteoarthrosis. AB - Osteoarthrosis is a common disorder of synovial joints, seen most often in older patients. The joints affected most commonly are the knee, hip, hands and the first metatarsophalangeal joint. Involvement of other joints such as the ankle, wrist and shoulder is uncommon, and suggests a secondary etiology. Although osteoarthrosis may be present in many joints, symptoms are usually evident in one or two joints at the most. The three main symptoms are pain, morning stiffness and a tendency for the affected joint to gel with immobility. Treatment includes rest; weight loss; physiotherapy; aids such as canes, shoe lifts, and elastic knee supports; and judicious use of anti-inflammatory medications. PMID- 21278962 TI - Posttraumatic arthritis. AB - Posttraumatic arthritis (i.e., degenerative joint disease secondary to injury) is a particular problem in young, active patients. It limits the activities of these vigorous individuals, and the compromised joint must be endured for a long time. The knee is used as an example of a joint commonly involved in this process. Conditions predisposing patients to posttraumatic arthritis are discussed, as are some treatment modalities, including rest, ice therapy, anti-inflammatory medications, physiotherapy, muscle strengthening programs, intra-articular steroid injections, joint arthroplasty, and patient education. PMID- 21278963 TI - The management of chronic headaches. AB - Most patients who complain of recurrent headaches have migraine, muscle contraction headache, or both. At a patient's first office visit for headache, the family physician should carry out a physical and neurological examination. The type of headache and factors that can precipitate it may then be explained, and the patient should be advised to take only simple analgesics for pain, as soon as he recognizes the first symptom of headache. A daily diary can help reveal specific factors that precipitate the patient's headaches. He can also benefit from educational material, and be taught relaxation techniques to ease headache pain. At least one follow up office visit is necessary in order to emphasize and review instructions from the previous assessment, and to give the patient an opportunity to consider the explanation and problems and voice any remaining concerns or questions. PMID- 21278964 TI - Pregnancy and schizophrenia. AB - Schizophrenia occurs in one percent of the population during the reproductive years. Although schizophrenics' fertility is reduced, most family doctors who practice obstetrics will occasionally care for a pregnant, schizophrenic patient. The particular problems of the prenatal period, labor and delivery, and postpartum care of these patients are discussed. The physical, psychological, and social problems of a schizophrenic patient's child are outlined, with a recommendation for careful follow up in the community of both parent and child. PMID- 21278965 TI - You don't say: protecting patients' privacy. PMID- 21278966 TI - [Not Available]. PMID- 21278967 TI - Reducing drug use in retarded epileptics. PMID- 21278968 TI - Taxing dilemma. PMID- 21278969 TI - Upper abdominal bruit. PMID- 21278970 TI - Problems with life annuities. PMID- 21278971 TI - Non-gonococcal urethritis: a comparison of therapy with minicycline, tetracycline and erthromycin. AB - A clinical trial compared treatment with tetracycline hydrochloride 500 mg qid for seven days, minocycline 50 mg bid for 14 days, erythromycin stearate 250 mg qid for 14 days and minocycline 100 mg bid for seven days in 164 men with non gonococcal urethritis. However, only 88 patients returned for two follow-up visits, and results are based on these patients alone. Chlamydia trachomatis was isolated from 26% of the patients. The clinical cure rate three weeks after therapy was completed was 77% for tetracycline, 74% for minocycline 50 mg, 61% for erythromycin and 80% for minocycline 100 mg. There was no significant difference between cure rates with the two doses of minocycline and tetracycline, but erythromycin was less effective. Adverse reactions were minimal. PMID- 21278972 TI - Eating difficulties in the toddler and preschool child. AB - Parents frequently bring toddlers and preschool children with eating problems to the family physician. Eating problems are seldom caused by major, organic pathology. Eating is a cultural and social activity; children's nutritional history, their growth and development and the role of the family in defining, maintaining and/or resolving the problem are important components in the management of eating difficulties. The family doctor can help the family cope by giving information, specific suggestions, and support. Referral to a nutritionist may be necessary if the problem is complex or prolonged. PMID- 21278973 TI - Anorexia nervosa and bulimia: problems of "the pleasing child". AB - Widespread media publicity has resulted in increased case findings of eating disorders such as anorexia nervosa and bulimia. The etiology of these conditions is complex and multifactorial, and they may have devastating effects on physical and psychological health. Family physicians have an important role to play in recognizing, evaluating and managing eating disorders. Severe anorexics-those who have lost 25% or more of the average weight for their age and height-require specialist management, but milder forms respond to treatment which can be undertaken by an interested family physician. Most cases of uncomplicated bulimia can be treated successfully in a family practice setting. PMID- 21278974 TI - Nutrition and cancer. AB - Nutrition has a close association with cancer. Carcinogens in foods, macronutrients, micronutrients such as vitamins A, C and E and selenium, dietary fiber, the modulation of metabolism by diet, food additives and anticarcinogens in foods all affect the development of cancer. In particular, macronutrients (especially meat and animal fat) appear to have a significant effect on the development of cancer of the colon, breast and uterus. This article discusses research on the links between nutrition and cancer, and describes current dietary recommendations to decrease the likelihood of cancer. PMID- 21278975 TI - Nutrition education in a family practice residency program. AB - Although there is increased recognition of the importance of teaching nutrition skills during medical school, there is still a great need for residents to learn applied nutrition. Over the past eight years, a nutrition curriculum has been developed and implemented for the two family practice residency programs at the University of Manitoba. Patient education about nutrition is the resident's responsibility, and the faculty dietitian acts as a consultant. Case-oriented seminars and group teaching experiences give residents the opportunity to further develop their nutrition counselling skills. The dietitian is responsible for evaluating resident performance, according to selected learning objectives. PMID- 21278976 TI - Nutrition and sports. AB - Family physicians are often asked for advice by patients of all ages who participate in regular exercise programs. The knowledgeable family physician can be very helpful to athletes, who are swamped with information and misinformation about nutrition. This article describes the dietary needs of recreational and competitive athletes, illustrates the way in which diet can prevent the development of some pathological conditions, considers athletes at different stages of the life cycle, and discusses the dietary requirements of the exercising diabetic patient. PMID- 21278977 TI - Screening and management of diethylstilbestrol exposed offspring. AB - Prenatal diethylstilbestrol (DES) exposure in pregnancy has been associated with adenocarcinoma of the vagina and/or cervix as well as teratogenic abnormalities of the genital tract in both female and male offspring. DES Action groups are alerting the public to the dangers inherent in being a 'DES daughter' or a 'DES son'. Family physicians must be able to reassure those patients who are not DES offspring, manage those who are, and detect those who didn't know they were. The screening and management of DES problems, including history-taking, physical examination, relevant laboratory exams and consultation for diagnosis and treatment of both male and female patients are discussed. In addition, psychological support, patient education, longterm follow up, the management of contraception and pregnancy in DES daughters, and infertility in DES sons are considered. PMID- 21278978 TI - A Middle-Aged Doctor's Wife Returns to the Workforce. PMID- 21278979 TI - Suivons la foule. PMID- 21278980 TI - Caring for burn patients. PMID- 21278981 TI - Monilial infections in mothers and babies. PMID- 21278983 TI - On framing spitzer. PMID- 21278982 TI - Benzodiazepine dependence. PMID- 21278984 TI - Contracts between patients/physicians. PMID- 21278985 TI - 'Insightful problem-solving' in family practice. PMID- 21278986 TI - Subcuticular tears in a rape victim. PMID- 21278987 TI - Review of the vancouver sexual assault assessment project. AB - This paper reviews the first year's experience of an emergency sexual assault assessment service provided by a roster of female family physicians. All 100 patients seen were female. The youngest was 13 and the oldest was 92 (mean 25.3). Seventy-three percent were seen between 5 p.m. and 9 a.m. on weekdays. A further 13% were seen on holidays or weekends. In 29% of patients, sperm were seen on immediate microscopy. In 68%, bruises, abrasions or lacerations were noted. Seventeen percent of the women had no abnormal physical findings. The psychological effects of assault on the victims and physicians are described. PMID- 21278988 TI - Warning to dog owners. AB - More than one percent of all emergency department visits are secondary to dog bites. Larger and more aggressive breeds of dogs cause most of the morbidity from dog bites, and most victims are bitten by the family dog. Four hundred and twenty patients presenting to an emergency department with dog bite wounds were studied in 1982. Forty-six percent of the patients were bitten by German shepherds; 80% of these dogs were owned by the patients' families. Twenty-one patients (five percent) had serious injuries requiring hospitalization. Although large breeds make good guard dogs, they also are a threat to household members, especially children; 35% of the victims were under ten years old. Physicians should advise parents not to leave children alone with dogs. PMID- 21278989 TI - Patients' knowledge of hypertension. AB - A group of hypertensive patients attending a family practice were surveyed in order to determine their level of knowledge compared with a group of controls who were not hypertensive. The results indicated the hypertensive group had significantly greater knowledge, although there were deficits in their knowledge. Most patients identified the physician as their main source of information about hypertension. For this reason, family doctors should consider adding new educational tools to those currently in use. For example, a check list and/or written material could contain information that the physician considers essential for patient education. PMID- 21278990 TI - The problems and concerns of middle age. AB - Middle age is not defined solely by chronological age, but is a product of biological, social, and psychological factors. As a period in the life cycle, middle age poses many obstacles, or developmental tasks, to personal growth. Failure to deal successfully with these tasks may have a negative impact on a person's physical and psychological health. The family physician's role should be to learn the middle-aged patient's problems and concerns, to allow him to express such concerns, and to help place problems in perspective. PMID- 21278991 TI - Comforting the after-coronary patient. AB - A recent five-year study monitored the life stresses of patients with coronary heart disease. The patients were telephoned once a month, and attempts to reduce stress, when appropriate, resulted in significant reductions in mortality. The program's results suggest that the major therapeutic ingredients, over and above usual medical care, are providing patients with the sense of being 'watched over', and giving those who are more distressed several extra hours of relatively unsophisticated psychotherapy or comforting. Brief, frequent, and perhaps even unsolicited contacts with the health care system over the first post-coronary year are important for all patients; lengthier, more relaxed sessions with the anxious and depressed are indicated. PMID- 21278992 TI - Cosmetic surgery in mid life. AB - The aging of the skin and supportive tissues in mid-life causes a deterioration in appearance and/or accentuates preexisting deformities. This can adversely affect the patient's self image and self-respect. Cosmetic or esthetic surgery helps to rejuvenate the aging features to improve the patient's self-image and restore self-confidence. This article discusses the various corrective procedures, their indications, extent, morbidity, complications and cost. PMID- 21278993 TI - The ovulation method of family planning. AB - With the Billings Ovulation Method of natural family planning, women chart the symptoms of changes of their cervical mucus to determine when they are ovulating. The Ovulation Method is simple to learn, and some studies have shown it to be 98.5% effective. It can be used throughout a woman's child-bearing years. Unlike other methods of natural family planning, a woman need not have regular menstrual cycles to use the Ovulation Method. Usually, volunteer married couples trained in the method teach it; however, the physician's support can greatly increase the competence of these instructors. PMID- 21278994 TI - Women and work: the more, the better? AB - An increasing number of women work outside the home, and one might think that the resulting strain would have an adverse effect on women's health. However, studies conducted up to now have disclosed no evidence of harm. Rather, working outside the home often appears to benefit women. However, such results could be due to the 'healthy worker effect', whereby the least healthy people do not enter the work force in the first place. When their skills are underutilized and superiors are indifferent to their accomplishments, women show as much vulnerability to stress as men do. Far more research is needed to confirm or disprove these preliminary results, and to understand the various factors involved. PMID- 21278995 TI - The 'age of never'. AB - Specific clinical problems emerge in middle-aged men, not so much because of aging, but as a result of the path they have chosen to follow and their reaction to life experiences. For instance, the middle-aged executive has probably spent a lifetime working towards success. His daily existence is characterized by aggression, and his drive to conquer may make him prone to heart disease. Mild depression due to anxious self scrutiny also is common in middle age. Depression and fatigue may lead some patients to overindulge in food, alcohol and/or drugs. Others may become addicted to exercise. These patients look on pain as an ominous threat to their finely balanced daily ritual, and therefore may disregard the warning signs of injury or illness. In treating the problems of middle age, physicians should remember that most middle-aged patients have acquired some practical wisdom. PMID- 21278996 TI - Treating back problems better. AB - Back and neck pain are two of the most common and potentially most expensive complaints which patients bring to their family doctors. These problems can be helped when the physician listens, examines, and explains. Reasonable amounts of rest, specific exercises, home remedies, medications, manipulation, and other remedies may help. One must understand the natural history of the specific problem in order to treat it successfully. Generally, simple remedies are best. PMID- 21278997 TI - The impact of hypertension in the middle years. AB - Hypertension is a prevalent condition in the middle years. About 25% of visits to family physicians are by patients with hypertension. Both case-detection and control of hypertension are important parts of practice. Unfortunately, the criteria used to diagnose and treat hypertension are variable, partly because of the lack of agreement on the need to treat mild hypertension. Patients have a fairly good knowledge of hypertension, but many think it is caused by, or the same thing as, nervous tension. The diagnosis and treatment of hypertension frequently have adverse effects on patients. These effects include increased absences from work, psychological distress, complaints of decreased sexual appetite and satisfaction, impotence, headaches, dizziness, fatigue, and drowsiness. Several strategies can improve patient compliance with treatment. PMID- 21278998 TI - Hypertension in the elderly: to treat or not to treat. AB - Hypertension is a common condition in the elderly. It is not a normal aging change and leads to serious sequelae at any age. Both diastolic/systolic hypertension and isolated systolic hypertension present serious risk at all ages, but the efficacy of therapy is more certain for the diastolic/systolic hypertension. Treatment consists of the usual non-drug therapy as well as the classic 'stepped-care' approach. If therapy is sensible and careful, side effects of the drugs can be minimized and controlled. In choosing from among the numerous antihypertensive agents, the physician must consider patients' concomitant illnesses as well as drugs that they are already taking for other reasons. PMID- 21278999 TI - Marriage enrichment: friend or foe? AB - Marriage enrichment programs seem to have particular appeal to couples who hope to improve their relationship in their middle years. These programs usually take the form of a weekend retreat, and are limited to and usually led by married couples. Marriage enrichment programs should not be confused with encounter groups which flourished in the 1950s and 1960s. Some encounter groups deliberately used confrontation to bring anger or fear to the surface; enrichment programs emphasize the positive elements of the marriage relationship and avoid cathartic releases, which are more appropriate in a counselling or therapy framework. Encounter groups sometimes had negative effects on sensitive or fragile participants, while enrichment programs generally have a limited but positive effect on couples. PMID- 21279000 TI - Blended families: issues of remarriage. AB - Canada's divorce rate increased by 50% between 1968 and 1982. This has resulted in new family forms. One of these, the family which has been 'blended' through remarriage of a parent, has some unique developmental hardships and differences from traditional nuclear families. Blended families are subject to a number of myths that may adversely affect their formation. In addition, members of these families need more time and patience to form a stable and functioning family group than do traditional families. Family physicians can aid the blended family with frank discussion, preparation and specific information. PMID- 21279001 TI - Did you identify these conditions? PMID- 21279003 TI - Should doctors be guaranteed access to medicare under federal law? PMID- 21279002 TI - A case of proctalgia fugax. AB - The syndrome called proctalgia fugax may be a repository of various conditions, because there are no distinctive signs or supporting tests. Usually, the pain of this condition is described as cramping, gnawing or tight, and lasts about ten to 15 minutes. It occurs most frequently at night and is localized to the rectal region above the anus. One subgroup may be diagnosed by the existence of a 'shelf sign' in the rectum. This shelf is probably caused by pubococcygeus spasm. Patients suffering from proctalgia fugax tend to be perfectionists and above average in intelligence. A literature review and the case history of one patient illustrate the difficulties, frustrations and pitfalls associated with this incurable condition. PMID- 21279004 TI - Family medicine: the guerilla force in the war against disease. PMID- 21279005 TI - Le service national de sante de la Finlande: une opinion personnelle. PMID- 21279006 TI - [Not Available]. PMID- 21279007 TI - Calcium compounds for treating osteoporosis. PMID- 21279008 TI - Respite care in a small community. PMID- 21279009 TI - 'Misleading' drug ad. PMID- 21279010 TI - Can Hypertensive Patients Tell When Their Blood Pressure is Elevated? A Cross Sectional Study of 104 Patients. AB - A study was undertaken to see if a group of patients could estimate their blood pressure (BP). One hundred and thirteen hypertensive patients were asked whether they could tell when their BP was high, and if so, how. Patients were also asked to give a categorical and a numerical estimate of their current BP. We found that patients did not appear to be able to predict their BP any more accurately than they could be expected to by chance. Patients who predicted correctly, and those who were incorrect, used the same symptoms to predict elevated BP. These were headache, a feeling of warmth, nervousness, dizziness, and pounding heart. PMID- 21279011 TI - Definition of the catchment area for a small rural hospital near a large city. AB - Practicing physicians, hospital directors, members of the hospital's board of directors and government health care planners can benefit from an accurate description of a hospital catchment area. The sociodemographic and geographic characteristics of the catchment area of Wakefield, PQ.'s 31-bed Gatineau Memorial Hospital (GMH) were studied. A randomized, door-to-door survey was conducted among permanent residents in the catchment area. The response rate was 96.1%. We found language to be an important and complex determinant of hospital utilization patterns. Orientation towards the city also affected the pattern of hospital use; those who lived between Wakefield and Ottawa-Hull were more likely to use a city hospital, as were those who had recently moved to the area, or who commuted to work in the city. PMID- 21279012 TI - Emergency department medicine in a rural cottage hospital. AB - The demographic and medical characteristics of patients using the emergency department of the Gatineau Memorial Hospital in Wakefield, Quebec were studied. These characteristics are compared with those reported in the medical literature. A youthful, predominantly male population presented to the emergency department, usually because of trauma or respiratory illness. Seventy-five percent of the patients were seen within 20 minutes of their arrival. Medications were prescribed slightly over 50% of the time, but laboratory and radiology services were infrequently used. Of the patients seen, 6.4% were transferred to larger city hospitals. These transferred patients most frequently were trauma victims needing complicated surgery or specialized services. PMID- 21279013 TI - Consultant obstetricians/gynecologists' practice profiles in an ontario community. AB - There is a perceived shortage of obstetricians/gynecologists in Canada. One recommendation to address this shortage is for obstetricians/gynecologists to restrict their practice to consultation. Such a move would have a direct effect on family physicians' patterns of practice. This paper compares the practice profiles of four consultant obstetricians/gynecologists working in an Ontario community of 150,000 people served by 82 family doctors and one community hospital, with the profiles of their provincial counterparts. The four consultants performed substantially more consultative and procedural services, particularly surgery, and on average earned approximately 25% more than other Ontario obstetricians/gynecologists. The Hospital Medical Records Institute data obtained from the community hospital demonstrated that the 82 family doctors performed over 90% of the uncomplicated and 60% of the complicated deliveries. The authors conclude that a shift to a consultant type of practice by obstetricians/gynecologists could significantly alter the specialist-to population ratio required for this specialty, but that further study is needed to determine the impact of this shift on the quality of care. PMID- 21279014 TI - Seeing the person behind the psychosis. AB - The psychotic patient may lose his sense of individuality and his physician may see him in a way that stereotypes or depersonalizes him. Three principles or attitudes of the physician help prevent this depersonalization. They include judging all interventions by whether they improve the patient's confidence and sense of self-control; understanding the reason behind the patient's behavior, and avoiding the view that he is author of his own fate. Specific methods help the physician to manage a patient who has suffered a psychosis. These include: treating the patient sympathetically; taking time to discover his fears; setting limits so he observes the basic rules of human interaction; individualizing medication regimens; being attentive to his physical complaints; allotting sufficient time for counselling; recognizing his positive attributes; treating crises as opportunities to help him understand his problems better; encouraging him to record problems in a diary; and recognizing one's own needs and limits. PMID- 21279015 TI - Common psychoses in the elderly. AB - Psychoses in late life constitute a number of distinct clinical entities. It is particularly important to distinguish between the functional and organic psychoses, and with the organic psychoses to search for the underlying cause, which may be reversible. Functional and organic psychoses can usually be differentiated after careful psychiatric and medical evaluation. Often it is difficult to separate psychiatric geriatric disorders from medical disorders because the presenting symptoms can be mixed or atypical. A sudden change in an elderly patient's psychiatric condition should alert the attending physician that the condition might be caused by a delirium superimposed upon the original psychiatric illness. PMID- 21279016 TI - Intensive care unit psychosis. AB - Patients who become psychotic in intensive care units are usually suffering from delirium. Underlying causes of delirium such as anxiety, sleep deprivation, sensory deprivation and overload, immobilization, an unfamiliar environment and pain, are often preventable or correctable. Early detection, investigation and treatment may prevent significant mortality and morbidity. The patient/physician relationship is one of the keystones of therapy. More severe cases may require psychopharmacological measures. The psychotic episode is quite distressing to the patient and family; an educative and supportive approach by the family physician may be quite helpful in patient rehabilitation. PMID- 21279017 TI - Electroconvulsive therapy. AB - Electroconvulsive therapy (ECT) is becoming primarily a tool for treating major depressive illness, where there is substantial evidence for its success. The use of ECT to treat schizophrenia, mania and other conditions has markedly decreased, reflecting the development of effective drug treatment. Recommended indications for ECT are suicidal patients and those who refuse to eat or who are otherwise seriously disturbed or unmanageable. ECT is also indicated when chemotherapy has or is likely to fail or is contraindicated because of cardiac difficulties or pregnancy. ECT compares favorably with chemotherapy in terms of safety and effectiveness. The only absolute contraindication is raised intracranial pressure. Unilateral electrode placement using brief pulse current minimizes post treatment confusion and memory impairment. PMID- 21279018 TI - The epidemiology of schizophrenia. AB - Depending on the criteria used to diagnose schizophrenia, the incidence, prevalence and morbidity risk figures vary. Schizophrenia is probably a group of diseases with separate etiology for which biological markers are still lacking. Genetics and environment both play a part in schizophrenia, but their roles have not been specified. The illness starts in early adult life and is precipitated in vulnerable people by biopsychosocial stress. Historical, demographic, and evolutionary considerations suggest the possibility of a viral pathogen. Birth trauma and family environment also play a role. Schizophrenia usually involves a marked personality change and there are many secondary effects of illness. Improvement generally occurs after many years. PMID- 21279019 TI - The management of schizophrenia in family practice. AB - While the pattern of treatment for schizophrenia varies from province to province, in the past 20 years there has been a general shift away from treatment in psychiatric hospitals to general hospital psychiatric units. The emphasis is on a shorter hospital stay, and greater use of community resources on discharge. Family physicians are therefore more likely to see their schizophrenic patients soon after an admission or readmission to hospital and will be more directly involved in their on going care. It is important for FPs to be aware of community resources which may help their schizophrenic patients. Resources include outpatient medical clinics where injections of long-acting neuroleptics can be regularly administered; public health nurses and community health workers; patients' families; alternative housing programs; social organizations' volunteer programs and community colleges and retraining programs. PMID- 21279020 TI - [Not Available]. AB - Schizophrenia is a major public health problem, mainly because of its prevalence and the medical and social costs it generates. Because of his privileged position with the patient, the family physician is often requested not only to provide care but also to give the patient some orientation and support regarding his future and his daily problems. After reviewing some important factors generating handicaps from the disease, treatment and reactions to treatment, this paper aims to give the family physician some answers he can give when facing more specific problems, such as whether to tell the diagnosis, family reactions, motor vehicle driving, work and studies, sexual and marital life, procreation and divorce. PMID- 21279021 TI - Fear of death in a sample of physicians. AB - Recently, reliable and valid methods of assessing fear of death have been developed. In this study, three well established questionnaires (the Threat Index, the Death Anxiety Scale and the Collett-Lester Fear of Death Scale) were used to assess and compare fear of death in a group of physicians (n = 30) with a group of non-physicians (n = 30). T-tests and hierarchical multiple regression analyses revealed no significant differences between physicians' and non physicians' fear of death as measured by the Threat Index and Templer's Death Anxiety Scale. The Collett-Lester Fear of Death Scale revealed that physicians were less fearful of death. More specifically, physicians demonstrated less fear on the Collett-Lester subscales, 'fear of dying of self' and 'fear of dying of others', than did non-physicians. These findings and those of earlier, contradictory research, are discussed. PMID- 21279022 TI - Managing cancer pain. AB - Despite the existence of effective analgesic drugs, many cancer patients live and die with ineffective pain control. The control of cancer pain is largely achievable with the appropriate use of available analgesics and co-analgesics. It requires attention to detail by a sympathetic physician who will treat the patient as a whole person. The support of knowledgeable nursing, social work, and chaplaincy staff in hospital and at home is essential to the on-going care of these patients. The major obstacles to the control of cancer pain are the physician's lack of detailed inquiry and attention, combined with the inappropriate and inadequate use of analgesics. The misinformation, prejudice and fear surrounding narcotic analgesics are largely unfounded in treating this group of patients. This article addresses issues of management and details a logical approach to analgesic use in patients with cancer pain. PMID- 21279023 TI - The role of a rural team in preventing sexual abuse of children. AB - Sexual abuse of children has become a major concern in recent years. Interdisciplinary teams have been established to deal with this and other forms of child abuse. Unfortunately, information is scarce about methods of preventing sexual abuse, particularly in a rural setting. A team in rural Manitoba has identified 22 cases of sexual abuse in the last 30 months. Methods of preventing such cases include educating adults and children about normal and abnormal sexual behavior. Early detection and intervention can be effected by establishing a registry of those at high risk for abusing their children, and listening to children carefully to detect signs of abuse early. When sexual abuse has already occurred, its effects may be minimized with family therapy sessions involving the victim and offender. Community awareness, education and an interdisciplinary team have been shown to be effective in stopping abuse and appear to have significant potential in preventing sexual abuse. PMID- 21279024 TI - Acute allergic vaginitis caused by Candida albicans. AB - Vaginitis is a common condition observed in family practice and in office gynecology. One of the organisms which commonly causes vaginitis is candida albicans, which is commonly found as a saprophytic organism. However, apparently allergic reactions to candida causing vaginitis are not commonly known or recognized. In fact, only one series has been reported in the literature, and this was related to chronic monilial infections. In my practice I have encountered five cases of acute vaginal allergic responses to monilia over the past 15 years. These cases, with an account of control subjects, form the basis of this article. PMID- 21279025 TI - Following the crowd. PMID- 21279026 TI - [Not Available]. PMID- 21279027 TI - [Not Available]. PMID- 21279028 TI - Treatment of migraine. PMID- 21279029 TI - Daily care or supportive care? PMID- 21279030 TI - Preventive activity. PMID- 21279031 TI - Nutrients in therapy. PMID- 21279032 TI - Thanks! PMID- 21279033 TI - Update. PMID- 21279034 TI - Reducing the number of anticonvulsant drugs taken by severely retarded epileptic patients. AB - Recent reports imply potential benefits to patients taking longterm, multiple anticonvulsants if the number of concurrent drugs could be safely reduced. Attempts to reduce the doses of one anticonvulsant were made at monthly intervals in a selected group of 33 closely supervised, ambulatory, chronic epileptic patients with severe mental retardation. Phenytoin dosage was increased in over half the patients as the other drug was decreased. Over 18 months of observation, phenobarbital was completely withdrawn from 19 patients, primidone from four, ethosuximide from one and phensuximide from one. There was no deterioration of behavior or loss of seizure control in these patients. Seizures reappeared after a year in five patients who continued to take phenytoin after phenobarbital or primidone was withdrawn. A second anticonvulsant was given to these patients. This study shows that one anticonvulsant can be successfully withdrawn from many, but not all, chronic epileptic patients with multiple handicaps. PMID- 21279035 TI - Human torture: description and sequelae of 104 cases. AB - We examined 104 torture victims, 99 of whom were from Chile. Most of our patients were young men who had been arrested for political reasons. All the patients had been beaten; other common methods of torture included the application of electricity, cigaret burns, forced physical activity resulting in exhaustion, threats of death, sham execution and isolation. The only signs specific to torture were picana (electrical burn scars) and scars from cigaret burns. The most common psychological sequelae were anxiety, insomnia and recurrent nightmares. Psychological symptoms were similar to those documented in other populations who have suffered severe trauma. PMID- 21279036 TI - Introducing the computer to family practice. AB - The medical profession has been far more reluctant than the general business community to adopt the computer as a useful business tool. The experience of a group of five family physicians who have been using a computer since 1979 demonstrates that it is possible to achieve significant financial benefits, and to reduce the stress and workload of both physicians and office staff. The computerization of medical records, scheduling, and patient billing is discussed in detail. Physicians have controlled the paper load of the modern medical office by pioneering their own medical software system. PMID- 21279037 TI - Choosing a microcomputer: what to look for and what to avoid. AB - Many family physicians are considering purchasing a computer in the near future. This article explains some of the jargon of the computer industry and describes the various specifications that will make a computer most useful to a medical practice. Some of the most popular microcomputers are mentioned in terms of their suitability for family practice. PMID- 21279038 TI - Can a computer save you money in your practice? AB - In the past few years, it has become feasible and practical for family physicians to acquire a computerized office management system. These systems vary in price from $5,000-$40,000, depending upon the sophistication of the programs and the choice of equipment. This article attempts to establish the costs of acquiring such an office computer system, so family physicians can realistically appraise whether an office computer is suitable for their practices. It is important to remember that once a system has been selected, several other practice costs must be included in the total cost of the system. PMID- 21279039 TI - Computers and medical decision making. AB - Several researchers are exploring the role of computers in medical decision making, and many large organizations have developed systems and data bases for the practicing physician. These data banks will probably expand over the next few years and become easily accessible to any physician with a telephone and a microcomputer. Other researchers are examining computers as an aid to diagnosis or problem solving, and several programs have been developed which allow computers to make uncomplicated medical decisions without interacting with a physician. Other computer programs have been developed to teach medical decision making theory and practice. The trend towards increased computer portability and memory capability will enhance physicians' use of computers in the future. PMID- 21279040 TI - A computer in the waiting room: who needs the doctor? AB - Computers have been characterized as impersonal machines destined to take the humanity out of being human. Although computers are machines and can be impersonal, they can also be programmed to be tireless, patient, supportive interviewers or teachers and to give individually tailored feedback and encouragement. This article explores some of the uses of the computer as a physician aid or substitute in patient interviewing and health education. Microcomputers have made this use of computers more accessible to the practicing family physician, but it is the programmer and not just the hardware who will make it a practical reality. PMID- 21279041 TI - Computers and research in family practice. AB - In the 1960s and 1970s, computers required user expertise and were expensive, relatively inflexible, and not 'user friendly'.Consequently, the use of computers in family practice research was limited to a few centres where facilities and personnel were available. However, by the end of the 1970s, 'user friendly' microcomputers were available. These allow a physician to store, study and analyze large sets of data at a reasonable cost. At present, microcomputers can be used for word processing, data management, data surveillance, statistical analysis, simulated patient encounters and modelling. They can also assist with medical decision making. In future, family physicians may be able to combine their individual practice data bases to produce community, district or nationwide data banks, and to manage large clinical trials with the aid of computers. PMID- 21279042 TI - The computer: an effective research assistant. AB - The development of software packages such as data management systems and statistical packages has made it possible to process large amounts of research data. Data management systems make the organization and manipulation of such data easier. Floppy disks ease the problem of storing and retrieving records. Patient information can be kept confidential by limiting access to computer passwords linked with research files, or by using floppy disks. These attributes make the microcomputer essential to modern primary care research. PMID- 21279043 TI - Teenage pregnancy. AB - More liberal teenage behavior has made pregnancy in this age group an important issue. Live births to adolescent mothers have decreased, while therapeutic abortions for this age group have increased by 27.9% in Canada. The obstetrical and psychosocial risks of the pregnant teenager are related more to inadequate care than to her age. There is a higher perinatal mortality rate among infants born of teenaged mothers. Risk of abuse, neglect, or developmental delay is mitigated by family and societal support. Management of the pregnant adolescent is multi-faceted. She needs nutritional counselling, optimal antenatal and obstetrical care, and access to continuing education or job training. After the child is born, follow up should be directed towards health care, nutrition, education, employment, financial counselling or support, and family and community support. PMID- 21279044 TI - Monitoring drugs by dose response graph. AB - The response to drugs of 30 agitated, noisy, restless, aggressive patients in an extended care unit was monitored over two years. A graph was used to record the patients' response to sedatives, tranquillizers and hypnotic drugs in each four hour interval for 24 hours. The object was to keep patients relaxed so that they could participate in ward activities. This monitoring method requires close teamwork between the physician and ward nurse. The nurse observes and records the patients' moods every four hours, and the physician changes the dose, timing, or drug as needed. PMID- 21279045 TI - Pathological grief: causes, recognition, and treatment. AB - Although the incidence of pathological grief does not appear to be high, the morbidity and mortality of sufferers is significant. Because of attitudes about grieving and the reluctance to experience grief, patients may avoid sharing grief with the family physician, who may then fail to recognize pathological grief. This article discusses clinical manifestations and situations which can lead to pathological grief. The types of pathological grief-chronic, inhibited, delayed, and atypical-are also discussed, along with personality variables which predispose some people to difficult grieving. Failure to grieve may also lead to a higher incidence of physical disease and various forms of mental illness. In order to manage grief, the physician must encourage the patient to express all his feelings of sadness, anger, and guilt; reassure him that his anger and guilt are a normal reaction to loss; and later, give him permission to stop grieving. PMID- 21279046 TI - A surviving child with complete proximal tracheal atresia. AB - An infant was born with an unusual combination of primitive foregut anomalies consisting of complete proximal tracheal atresia, proximal esophageal atresia and distal tracheoesophageal fistula. Before the birth, the family physician suspected an anomaly of the upper airway or esophageal occlusion on the basis of hydramnios evident at the thirty-third to thirty-fourth week of gestation, and earlier amniocentesis which indicated a normal level of alpha-fetoprotein. He consulted the hospital obstetrics and neonatology departments, which were thus prepared to deal with a potential airway problem at the birth. At birth, prompt airway management, including tracheostomy, prevented anoxic damage to the child. Features which should alert the physician to tracheal obstruction include antenatal polyhydramnios; severe respiratory distress without an audible cry and palpable distal trachea in the newborn; and failure to advance the endotracheal tube beyond the infant's vocal cords. PMID- 21279047 TI - A Mother's Reactions to an Infant With an Abnormality. AB - A mother describes her reaction to the birth of a child with complete tracheal atresia. Interpretation of the mother's observations and feelings illustrates the various stages of reaction, which include denial, guilt, grief, depression, anger and acceptance. By understanding these stages, and by providing appropriate support and advice, the physician can help families with abnormal newborns to accept and understand. The doctor can also provide emotional support and a framework for rational decision making and planning. PMID- 21279048 TI - Individualizing instruction in family medicine preceptorships. AB - By tailoring the objectives, rate, content, strategy, and control of instruction to match each medical student's aptitudes, it is possible to increase his level of achievement and satisfaction. The preceptorship setting is ideally suited to such individualized instruction, which can best be accomplished by matching the student to a preceptor, and continually adjusting instruction during the preceptorship. However, any program of individualized instruction requires the medical school's support in terms of time, resources, and faculty development. PMID- 21279049 TI - The patient, the family physician, and the coronary care unit. PMID- 21279050 TI - [Not Available]. PMID- 21279052 TI - New association. PMID- 21279051 TI - [Not Available]. PMID- 21279053 TI - Routine episiotomy: a possible answer. PMID- 21279054 TI - Assessing symptom control in palliative home care. AB - Control of symptoms in cancer patients on a home care program was studied, to identify problems related to caring for these patients at home. The study was based on independent physician assessments of patients' medical charts, as well as interviews with the home care providers. The results showed problems in control of pain, nausea and constipation; the causes were less than optimal care and non-compliance. There is an urgent need to improve palliative care to home care patients and to provide better, more frequent reassessment of patients with uncontrolled symptoms. PMID- 21279055 TI - What do family practice graduates do? A comparative study. AB - Two groups of medical graduates from Universite Laval were compared for their subsequent place and type of practice, age of patients, type and level of remuneration, and average costs generated per patient and per visit. The study group had completed a two year residency program in family medicine; the controls had completed a one-year internship. The family medicine graduates were more likely to have a varied practice in a community of less than 50,000 population, to make house calls and do nursing home or chronic hospital care, to earn in the middle range of income and to generate comparable costs per patient, but lower costs per visit. The internship graduates were more likely to limit their practices to one activity, and to be in the higher range of income. These findings could not be tested for statistical significance, but have implications for training programs and paying agencies. PMID- 21279056 TI - The role of the family physician in the hospital. AB - The trend amongst urban family physicians away from hospital practice is a major threat to the family physician's role in the health care system. Continuity and comprehensiveness in patient care are the basis for a family physician's involvement in hospital care. The family physician brings the valuable perspective of the generalist to the specialized hospital environment and benefits from the educational stimulus that environment provides. PMID- 21279057 TI - Family physicians and teaching hospitals: a litany of woes. AB - Retreat of family physicians from caring for their patients in teaching hospitals has been partly imposed and partly passively accepted. Confusion of patient, family doctor and consultant relationships has resulted. Town/gown and family physician/specialist communication problems disrupt a proper model of care. Family physicians need to take individual and group action to initiate change, but little action has been evident. Everyone is the loser. We should reinstitute a model in which family physicians are the closest professionals to their patients, wherever they are in the health care system. Demonstrating the value of family physician coordination of care and continuity of care will positively affect the current financial 'loss leader' status of this work. PMID- 21279058 TI - An adolescent medicine service: a role for a family physician in a pediatric teaching hospital. AB - A family physician was appointed director of the Adolescent and Youth Medicine Service at the Montreal Children's Hospital. He was assigned a leadership role in the adolescent outpatient clinics and the adolescent inpatient ward. As team leader, he coordinates the work of allied health professionals and provides personal ongoing care to patients, fostering a comprehensive care approach in service, teaching and in links with the community. There are of course certain conceptual and practical problems in the situation of a primary care physician in a tertiary care setting; university departments of family medicine must face the challenge of altering consultants' thinking about their role. PMID- 21279059 TI - [Not Available]. AB - THE AUTHOR REVIEWS TWO SYNDROMES WHICH AFFECT THE ELDERLY IN A GENERAL HOSPITAL: "dumping" and "blocked beds". The term "dumping" is often misused for the aged becoming increasingly dependent and who require assessment, treatment and active rehabilitation. "Blocked beds" not only result from insufficient home care resources, but also from inadequate services offered by the hospital to senior citizens. The proposed solutions are the implementation of geriatric assessment units where global and multidisciplary care are best suited to meet the specific needs of the elderly. The multidisciplanary team also works as a consultant, especially in the emergency room, to assess and take care of the aged who are at risk, and whose cases are wrongly labelled as "dumping". PMID- 21279060 TI - 20 years of practicing anesthesia in a small hospital. AB - Anesthesia has developed from being a procedure each doctor performed on his own patients when necessary, to a specialty, sometimes practiced part time by family physicians. Training varies considerably. There have been dramatic changes in the pharmacology. Since there will likely always be a need for part time anesthetists, family physicians who will fill this need must be well prepared for the task. The benefits are a greater understanding of applied pharmacology, and a heightened sense of selection for surgery. PMID- 21279061 TI - Hearts too good to die: an evaluation of coronary care. AB - Intensive coronary care has become the standard treatment for acute myocardial infarction, and no self-respecting hospital would be without its coronary care unit. However, literature review to evaluate the contribution of coronary care shows that its promise may have been overstated and its benefits overestimated. PMID- 21279062 TI - The rural physician and myocardial infarction: part 1: pre-hospital management. AB - The majority of patients who succumb to myocardial infarction die before they reach a hospital. Three types of services have been developed to reach and treat patients immediately: the mobile coronary team (Belfast model), the coronary ambulance (American model) and family doctor services. Of the three types, only the family doctor service is practical in most rural communities. Evidence in the literature suggests that it is possible for rural physicians to reduce the mortality from MI in the community by visiting the patient with a suspected attack in the home as quickly as possible. The alternative of bringing the patient to hospital by ambulance before he has received any treatment is probably much less desirable. PMID- 21279063 TI - The rural physician and myocardial infarction: part 2: the hospital phase of treatment. AB - A critical review of the literature reveals several facts which are important in helping the rural physician decide where and how patients with myocardial infarction should be treated. The effectiveness of coronary care units has not been well established, even for patients admitted during the early phase of the disease; they do not benefit the majority of patients admitted five or more hours after the onset of symptoms. Transporting patients over relatively long distances during the early phase results in increased mortality. The survival rates for patients treated in small hospitals is quite comparable to that of patients treated in coronary care units. The majority of rural patients with myocardial infarction are therefore more appropriately treated in a small local hospital than by being transferred to a coronary care unit. Those coronary care units which have been established in small hospitals do not appear to have reduced mortality. Patients with myocardial infarction who are being treated in small hospitals should be observed carefully, but electronic monitoring should be used only when there is a specific indication. PMID- 21279065 TI - The impact of pain on patient and physician. AB - A patient's pain has lost its status as an expression of personal suffering and is seen by both physician and patient as a strictly physical attribute. Because of this, their communication may become oblique and subversive, effectively destroying a therapeutic relationship. The patient's failure to recover causes the physician to suffer unease and begin assuming pain-reducing postures of anger, indifference and assertiveness. The physician, to avoid this scenario, must acknowledge the existential component of the patient's pain, the reality of his own discomfort, and be open enough to give personal suffering a place in the relationship. PMID- 21279064 TI - FANTASTIC Lifestyle Assessment: Part 5 Measuring Lifestyle in Family Practice. AB - Family physicians generally agree that they should play an active role in disease prevention and health promotion. However, until recently no valid and reliable tool was available to help physicians clinically assess patients' lifestyle. The authors have studied the validity and reliability of a new five point-scale version of the FANTASTIC Lifestyle Assessment, used in a family practice. Also, the authors polled their patients on their opinions of their doctor assessing lifestyle. They found that the FANTASTIC was a reliable instrument, which their patients thought was useful and appropriate for their physician to be using. PMID- 21279066 TI - Do family physicians differ from specialists? A particular care in continuing medical education patterns. AB - This study contrasts specialists with family physicians in use, preference for and perceived effectiveness of different CME methods. Results indicate that FPs differ substantially from specialists in their CME choices. CME providers can utilize the patterns reported here in designing continuing education programs to match more specifically the learning habits of their clients. Individual physicians can also plan their CME choices in the light of these differences. PMID- 21279067 TI - Confessions of a medical editor. PMID- 21279068 TI - [Not Available]. PMID- 21279069 TI - [Not Available]. PMID- 21279070 TI - Medicare bled dry by lifestyle habits. PMID- 21279071 TI - Faith and skepticism. PMID- 21279072 TI - Physician as teacher. PMID- 21279073 TI - Statistical confusions. PMID- 21279074 TI - 'Aggressive' prenatal care? PMID- 21279075 TI - The cellular basis of aging. AB - Biological aging involves physiological decline and the emergence of pathology that are increasingly understandable in cellular and molecular terms. Studies on human cells grown in vitro support the concept of a replicative 'clock' that counts the number of cell divisions to a maximum limit. Under normal conditions, there is excess capacity for cell division but accelerated turnover following chronic trauma may lead to replicative exhaustion, first focally and then more generally. DNA undergoes rearrangements that are evident in older cells in vitro and in vivo. This may contribute to the loss of replicative capacity which simultaneously leads to physiological decline and the rising likelihood of malignancy and other age-dependent disorders. Application of such research data to medical practice should help to promote vigorous longevity and improve the quality of life in elderly people. PMID- 21279076 TI - Psychological problems in the elderly. AB - Intellectual changes in healthy old people are slight and not of practical significance. When intellectual changes are suspected, patients should be examined very carefully in a relaxed situation so they do not feel they are being 'tested'. The physician should be aware of the differential diagnosis of psychiatric disorders in the elderly and not simply label patients as 'senile'. The elderly are subject to acute brain syndromes caused by physical illness or drug toxicity. When acute brain syndromes are excluded, the illness is as likely to be a functional one as a chronic organic brain syndrome. The most common functional illness in old age is depression. More accurate diagnosis of elderly, mentally ill patients will lead to more effective treatment and management. PMID- 21279077 TI - Alzheimer's disease: a current review. AB - Alzheimer's disease is characterized by a progressive decline in cognitive function from a previously established level, and is the most common cause of all the dementias. While the exact etiology remains to be determined, there are several theories about possible genetic, immunological, biochemical and viral causes. Clinical diagnosis is by exclusion of other established causes of dementia and requires a careful history, physical examination and, often, psychological testing. Definitive diagnosis is made at post-mortem, although some cases show none of the histological hallmarks such as neurofibrillary tangles or senile plaques. There is no effective preventive or therapeutic treatment. Symptomatic management includes pharmacotherapy, socialization, support for the patient and his family and, ultimately, institutionalization. Patients are best managed by an interdisciplinary team using community resources. PMID- 21279078 TI - [Not Available]. AB - The general approach to prevention in elderly patients differs from that for younger patients. In the elderly, most of the preventive activites performed by family physicians are tertiary. Prevention and cure of disease often overlap. The major health problem in elderly patients is the development of progressive incapacity. The evaluation of risk factors for this condition is the principal purpose of the periodic health examination of these patients. This article summarizes the principal recommendations for the periodic health examination of the elderly and discusses barriers to their implementation. PMID- 21279079 TI - Maintaining ability in the elderly. AB - Elderly people frequently visit their family physician, who has the opportunity to maximize their ability. In order to do so, it is important to recognize that elderly patients who have a particular disease usually present with atypical symptoms, that there is a limited correlation between disability and disease in the elderly, and that their diseases are under-reported. A knowledge of the physiological changes of aging is essential. With judicious medical treatment, an emphasis on prevention, rehabilitation and cardiorespiratory fitness, the family physician can do much to improve elderly patients' quality of life. PMID- 21279080 TI - Hearing impairment in the elderly. AB - Hearing impairment is a common but not inevitable accompaniment of aging. It is partly due to the natural involution of irreplaceable neurones; environment also plays a large role. Although they may have difficulty in hearing all frequencies of sound, elderly people have particular difficulty with high-pitched sounds. They find it hard to focus on sounds, and serious social problems may arise as a result. Elderly people with hearing losses are particularly vulnerable to psychological sequelae, many of which are serious, but may also be correctable. Unfortunately, there is limited understanding of the causes of hearing handicaps, their prevalence, incidence and implications for the elderly, health professionals and the health care system. PMID- 21279081 TI - Sex after sixty. AB - Although sexuality is an intrinsic part of one's humanity throughout the lifespan, health professionals frequently ignore the sexual needs and concerns of the elderly. Deterrents to sexual activity may include society's disapproval of sexual expression by the elderly, lack of a partner, the elderly person's own lack of sexual knowledge or belief that nonreproductive sexuality is wrong, and lack of privacy. Physicians must accept elderly people's sexuality and develop attitudes and skills which facilitate communication. It is particularly important to make elderly patients aware that they do not have to have intercourse in order to express their sexuality, and to educate them about the physiological and pathological changes with aging, so they realize these changes need not mean the end of sexual expression. PMID- 21279082 TI - Helping older patients to eat well. AB - Because increase in chronic disease and illness, and changes in physiological, social, economic, and psychological status may adversely affect food intake, it is important to assess the nutritional status of elderly patients. Canada's Food Guide provides a rapid screening tool for evaluating food intake and may also be used as a teaching aid. Nutritional goals in the elderly include preventing deficiencies or excesses and maintaining a desirable body weight. Diet can help manage nutrition-related diseases, including hypertension, diabetes, and osteoporosis. Special attention should be paid to the social aspects of nutrition. PMID- 21279083 TI - Special foods. AB - Special foods include all foods that have been modified to meet either a real or perceived health need. They include enriched foods which are so readily available that they are generally no longer considered special foods. More recently, calorie-reduced, carbohydrate-reduced, low-fat, high fiber and other types of modified foods have been introduced to the market in response to several sets of dietary guidelines which recommend specific dietary changes for the general public. More specialized food products for people with prescribed diets or food allergies are not as readily available. The Specialty Food Shop in Toronto is attempting to supply both the need for very special foods and information for their use. PMID- 21279084 TI - Alternatives to institutionalizing the elderly. AB - For economic and humanitarian reasons, the present trend to institutionalize elderly people who could remain in their own homes if they were given adequate support, must be challenged. It is important that the family physician, who knows his patients' needs well, is aware of the resources available. When these are deficient, or poorly coordinated, efforts must be made to improve them. After the patient has been properly assessed, the key to proper alternate services is the availability of a coordinated continuum of care, which includes day hospitals, day therapy centres, social daycare centres and a comprehensive home care program. PMID- 21279085 TI - Home care of the frail elderly and the terminally ill. AB - This article discusses general principles of managing both elderly and terminally ill patients. The decision to care for the chronically sick in their homes is necessarily a joint one, made by the patient and supported by his or her family and physician. The physician must understand the patient's medical problems, and determine that the home environment is conducive to care and that one family member is available as a fulltime caregiver. The physician can call upon other professionals, including physiotherapists, pharmacists, dietitians, social workers, and clergymen, to help him care for the patient at home. PMID- 21279086 TI - Loss, grief, mourning: what to do. AB - Physicians should be familiar with the stages of grief, so that they can assist patients who are grieving. There are two interventions which the physician can use to help the grieving patient. The 'seemingly simple' intervention is for patients who have reserves for adapting to change. The physician should reassure them that their feelings are legitimate and perhaps encourage them to cry and to reminisce. More extensive intervention is needed for patients with few reserves and resources. There are certain warning signs that a patient is finding it difficult to work through the process of grieving. These include no apparent emotional reaction to the loss, noticeable weight loss and malnutrition, grossly inappropriate dress, extreme changes in appearance, substance abuse, and lost work time that jeopardizes the patient's job. The physician can help by answering questions about the loss, interpreting medical terminology, and giving specific advice to help ensure the patient remains physically and mentally healthy. PMID- 21279087 TI - Social support in normal aging. AB - The role of social support in helping elderly people deal with stressful life events is quite complex. This complexity exists because it is difficult to define exactly what social support is, and because the experiences of 'normal' aging vary. This article uses the example of adaptation to widowhood to examine the relationship between normal aging and sources, types, and patterns of social support. These factors influence the extent to which support lessens the impact of age-related stressful events. The physician has a role in primary social support, and also in facilitating the supportive functions of family and others. PMID- 21279088 TI - The aging couple. AB - Most elderly Canadians are married, and marriage both protects against morbidity and provides the best caretaker when sickness does occur. Changes in marital homeostasis after retirement may lead to illness, which in turn impacts on the marriage. The 'worried wife syndrome', whereby an elderly wife worries excessively about her husband's health, and the problems of a partner (usually the wife) who adopts a 'caretaker' role, are described. A framework for understanding the lifecycle of systems (i.e., the lifecyle of the individual, marriage, family life, and community) emphasizes the importance of assessment before intervention. The family physician can offer support, facilitate communication, make specific suggestions, intervene in crises, and make referrals. PMID- 21279089 TI - What Do You Think of Doctors' Strikes If the Canada Health Act is Passed? PMID- 21279090 TI - Dear sir/madam. PMID- 21279091 TI - [Not Available]. PMID- 21279092 TI - Holistic approach: to hypoglycemia. PMID- 21279093 TI - Breastfeeding editorial: tells the good and bad. PMID- 21279094 TI - [Not Available]. AB - The physician must act as primary medical advisor on behalf of the patient. Because the basis of prevention is epidemiology, problems of validity in the epidemiologic literature ought to be recognized by the primary medical advisor, so that he may optimize prevention. This article addresses the question of validity from the standpoint of the material, analysis, and interpretation. Validity of the material is discussed from four main points of reference: the diagnostic criteria of the disease, selection biases, misclassification of exposure, and control group relevance. Validity of the analysis is considered from the standpoint of the etiologic hypothesis; the notion of the "expected minimum analysis" is discussed. The three main aspects of this are the control of confounders, the introduction of test-variables, and the concept of refinement of the independent and dependent variables. Validity of interpretation is presented as a function of the introduction of test-variables. A relevant analysis may help discriminate between alternate interpretations, defined as the inverse path relationship, the confounded relationship, and the common cause pathway. PMID- 21279095 TI - The safety of blood transfusions. AB - Blood transfusion therapy carries a small risk of complications-usually minor which include allergic reactions, hemolysis, and the transmission of infections. Fatal hemolytic transfusion reactions are rare and are usually due to human error resulting in administration of ABO incompatible blood. Viral hepatitis (usually non-A, non-B) remains the major infectious complication, with a risk of two to five percent. The transmission by transfusion of AIDS has also been reported, but the risk is much lower-about 0.001%. As yet, no blood substitute is available for clinical use. Routine hepatitis B testing and the volunteer blood donor system ensure that transfusion risks are minimal in Canada. By limiting transfusion to those patients who truly need it, a high therapeutic index can be maintained. PMID- 21279096 TI - Blood component therapy. AB - Human blood has been transfused for about 60-70 years. Over this time, the practice of blood transfusion has changed dramatically. One major change is the separation of blood into its various components. As a result, the patient can receive only the blood component in which he is deficient. In this way, the risk of side effects-particularly hepatitis-is lessened. This article briefly reviews the various blood products, the indications for their use, and some associated risks. These products include oxygen-carrying products, plasma products, blood products used to correct hemostatic defects, and immune globulin. PMID- 21279097 TI - Iron therapy. AB - Iron deficiency is a very common disorder. It is always worthwhile to confirm the diagnosis by measuring both serum iron and serum iron binding capacity, before instituting treatment. A diagnosis of iron deficiency demands that its cause be established. Therapy requires that the lost iron be replaced, and that the underlying condition be treated. Replacement may be achieved safely, cheaply and effectively with oral iron therapy. There is very rarely a need to treat an iron deficient patient with parenteral therapy. PMID- 21279098 TI - Anticoagulant therapy. AB - Venous thromboembolic diseases are among the most important causes of morbidity and mortality in Canada. Agents which interfere with the coagulation mechanism are highly effective in treating these disorders, but at the potentially high cost of serious hemorrhagic complications. The optimal prevention of both serious outcomes and complications of therapy can be achieved by prophylactic treatment of high risk patients. Heparin and vitamin K antagonists remain the mainstays of antithrombotic therapy. The pharmacology of these agents is reviewed, and a rational approach to their clinical use is presented. PMID- 21279099 TI - Chronic idiopathic thrombocytogenic purpura. AB - Chronic idiopathic thrombocytopenic purpura (ITP) is a relatively common cause of an acquired hemostatic defect. It is important for family physicians to recognize this disorder, because of its insidious onset and the fact that it most commonly affects women of childbearing age. Chronic ITP is due to an antibody in the plasma which attaches to platelets and leads to their destruction in the reticuloendothelial system. The antibody can cross the placenta and affect the fetus. Although the condition may not disappear, in the vast majority of patients it can be controlled with current therapy, including prednisone, splenectomy and immunosuppressive agents. Although the mortality rate is low, patients with severe thrombocytopenia may have significant bleeding problems requiring special measures such as platelet transfusions, intravenous gammaglobulin, plasmapheresis and emergency splenectomy. Upon diagnosis, these patients should be referred to a large, specialized centre. PMID- 21279100 TI - The etiology and management of leukopenia. AB - Leukopenia is an abnormal reduction of circulating white blood cells, especially the granulocytes. The term leukopenia is often used interchangeably with neutropenia. It may result from reduced production of white blood cells or increased utilization and destruction, or both. Infection, drugs, malignancy, megaloblastosis, hypersplenism and immunoneutropenia are responsible for most cases of neutropenia. Primary neutropenia is very rare. Sometimes, particularly in children, primary neutropenia is hereditary and may be associated with other developmental defects. The major danger of neutropenia is the risk of infection. Management requires identification of the cause and effective antimicrobial therapy, especially when serious systemic infection is present. PMID- 21279101 TI - Easy bruising in women. AB - Women who complain that they bruise easily are commonly seen in the family physician's office. Although the vast majority of patients will be found, on investigation, to be normal, they all present a difficult diagnostic challenge. A careful history and physical examination are important in deciding which patients should be investigated further. For most, screening tests consisting of a platelet count, prothrombin time, partial thromboplastin time, and bleeding time will be adequate to rule out any significant bleeding problem, or to define the hemostatic mechanism which should be investigated further. If the screening tests are abnormal, or there is a strong family or personal history of abnormal bleeding, extensive and repeated investigation will be required at a specialized hemostasis centre. PMID- 21279102 TI - FANTASTIC Lifestyle Survey of University of Waterloo Employees. AB - The purpose of this study was to survey selected health behaviors of University of Waterloo employees. The FANTASTIC lifestyle questionnaire was distributed to all employees. Results indicate that, overall, the university's employees' health behaviors are good. However, there is room for improvement in the areas of physical activity, tobacco use, insight and career, particularly for the women surveyed. The data from the study will be used to direct the university's Campus Health Promotion program planning. PMID- 21279103 TI - The clinical significance of hemoglobinopathies. AB - Hemoglobinopathies may be a significant clinical problem in certain racial groups. A patient presenting with obscure hemolytic anemia should, therefore, be investigated for hemoglobinopathies, particularly if he is of Mediterranean or southeast Asian descent. Longterm iron therapy should not be instituted on the basis of a hypochromic microcytic blood picture without documenting iron deficiency. When investigating polycythemia in young patients with normal white blood cell and platelet counts, hemoglobin oxygen affinity (P50) should be measured. PMID- 21279104 TI - The diagnosis of anemia and its cause. AB - Screening patients for anemia and determining its cause is challenging and rewarding. Ordinarily, the cause can be readily diagnosed and treatment is available. A clinical approach to the diagnosis of anemia is presented. After clinically determining whether the anemia is due to decreased production of red blood cells, increased destruction, or loss of blood, initial laboratory investigations are specifically chosen to confirm the clinical impression or to answer basic clinical questions. The clinical features and initial laboratory findings should direct subsequent diagnostic and/or treatment approaches. PMID- 21279105 TI - Adult leukemias. AB - Over the past several years, advances have been made in the classification, diagnosis and therapy of the adult leukemias. The overall prognosis and quality of life have improved greatly, especially for patients with acute nonlymphoblastic leukemias. Some of the advances are described in this article. The importance of the clinical, laboratory and diagnostic tests for acute, chronic granulocytic and chronic lymphocytic leukemia are stressed. The therapy and prognosis for patients with the various types of leukemia are also described. PMID- 21279106 TI - Obstructive jaundice: a case of idiopathic cholestasis. AB - A 44-year-old man presented to his family physician with intrahepatic cholestatic jaundice, which he had had for seven days. He was admitted to the Family Medicine Service of University Hospital, Saskatoon, and the jaundice was extensively investigated. Initially, it was thought to be induced by antibiotics, but this was not confirmed on controlled drug rechallenge. The precise cause was not found. This article outlines a rational and systematic method for investigating obstructive jaundice. The method and importance of drug rechallenges to identify drugs suspected of causing cholestasis are reviewed. PMID- 21279107 TI - Assessing Educational Needs in Medical Practice: Guidelines for the CME Planning Committee Member. AB - The most relevant and effective continuing medical education activities are those which address carefully identified and prioritized learning needs. As a consequence, discussions and activities of CME planning committees frequently focus upon the identification and assessment of physicians' educational needs. The physicians who serve as representatives of learners on such committees are often new to the planning, educational terms, approaches, and techniques. The basic ideas, definitions and concepts outlined in this paper are given as guidelines for physicians who are not experienced in formal CME planning. These guidelines should enhance the effectiveness of a physician's participation in CME planning committee activities. PMID- 21279108 TI - Should the Canada health act be challenged? PMID- 21279109 TI - Why women want midwives. PMID- 21279110 TI - Babies and bilirubin-a jaundiced view. PMID- 21279111 TI - Cher monsieur/madame. PMID- 21279112 TI - [Not Available]. PMID- 21279113 TI - Are super tampons a health hazard? PMID- 21279114 TI - A Case of 'Sailor's Eye'. PMID- 21279115 TI - Back exercises can be overdone. PMID- 21279116 TI - Hospital admission: cause for complaint? PMID- 21279117 TI - Tutorial groups unite. PMID- 21279118 TI - A case of undiagnosed twins. AB - A pregnant patient may not be found to be 'high risk' until labor or delivery. There were no abnormalities found during a family physician's prenatal care of a P3 G4 29-year-old, apart from fluctuations of fundal height. Labor began spontaneously at 41-5/7 weeks. Brow presentation was diagnosed during the second stage, and after a healthy baby was delivered by cesarean section, an undiagnosed twin was discovered. The second twin had low Apgar scores, hypoxia associated with meconium aspiration and subsequent cerebral palsy. A lawsuit followed and it was alleged that the family physician's failure to diagnose twins constituted negligence. The prenatal record and care were scrutinized closely at trial. PMID- 21279119 TI - Influence of a phototherapy unit on detection of neonatal jaundice and hyperbilirubinemia. AB - The introduction of a phototherapy unit in a rural community hospital resulted in a significant increase in the detection of neonatal jaundice and hyperbilirubinemia in otherwise healthy term infants. Jaundiced newborns who were either missed or ignored in the past were now identified and monitored. Both the number of breast-fed infants and the number of primiparous women delivered increased significantly after the unit was obtained. However, these factors alone did not account for the marked increase in the detection rate of jaundice and hyperbilirubinemia. A sub-population of 94 infants was selected to evaluate the clinical assessment of jaundice in the term infant. The accuracy rate for clinical assessment was 70%; 13.8% of newborns with serum bilirubins above 10 mg/dl (170 umol/L) were not identified clinically. PMID- 21279120 TI - Electronic fetal monitoring in a small hospital. Part 1: antepartum use. AB - A case series analysis was performed at a 40-bed hospital in Newfoundland to assess the antepartum use of an electronic fetal heart rate monitor; 339 nonstress tests were performed on 98 patients. One stillbirth occurred 12 days after a reactive nonstress test. One patient had persistently nonreactive tests and underwent cesarean section; the infant was distressed at birth. Antepartum fetal heart rate monitoring may provide a useful measure in prenatal risk assessment in small hospitals for patients at risk of perinatal morbidity or mortality. Potential benefits for those at no predictable risk need to be investigated further. PMID- 21279121 TI - Electronic fetal monitoring in a small hospital. Part 2: intrapartum use. AB - A case series analysis assessed the intrapartum use of an electronic fetal heart rate monitor at a 40-bed hospital in Newfoundland. Seventy-five patients at risk and 52 patients at no predictable risk were monitored during labor. Fetal distress was the sole reason for cesarean section or instrumental delivery in nine of the group at risk and six of the group at no predictable risk. Of these 15 babies, all had five minute Apgar scores greater than six. Intrapartum monitoring is indicated for patients at risk, either because they develop a problem at a time when transfer to a regional centre is precluded, or because they have been judged safe to deliver at the small hospital. PMID- 21279122 TI - A necklace of telangiectases: an early clinical sign of alcohol abuse. AB - The prevalence of a necklace of telangiectases increases with the quantity and duration of regular alcohol intake. The necklace was present in 7%, 61.4%, 88.6%, and 98.5% of four groups of patients acknowledging less than 27 grams of ethanol intake per day for ten years, 77 grams per day for seven years, 112 grams per day for 11 years, and 113 grams per day for 15 years, respectively. The necklace first appeared after three to eight years of drinking 77 grams of ethanol (five to six drinks) per day, seems to be permanent and to appear before other skin changes associated with alcohol abuse such as 'gooseflesh', palmar erythema, and spider nevi. Recognition of the necklace indicates the need for further assessment, to determine if alcohol abuse is contributing significantly to any other symptoms or signs (e.g., hypertension, intellectual impairment, or gastrointestinal disease). If the patient is taught to recognize the necklace, he or she may be able to differentiate 'social drinking' from 'alcohol abuse', and be motivated to seek treatment early. PMID- 21279123 TI - Obstetrical practice and training in canadian family medicine: conserving an endangered species. AB - Family practice obstetricians are an endangered species. Our practices and teaching sites must provide the correct attitudinal as well as technical messages to result in a practitioner who will be able to meet the psychosocial and medical needs of the pregnant couple. Family practice obstetrics can be as safe as care given by obstetricians provided that the family practice group functions well, that obstetrical consultants are available and supportive, and assuming that technical approaches are reserved for those truly in need. In rural areas, obstetrical ability is essential, whilst in the urban setting it helps the family physician maintain a practice involving young families. Those trainees who fail to learn basic obstetrical skills (including family centered attitudes and approaches) may in any setting come to feel, belatedly, that their training programs failed in this respect. PMID- 21279124 TI - Obstetrical consultations in a community hospital. AB - This paper describes the pattern of obstetrical consultations in a family practice oriented obstetric service to a mixed urban/farming community of 60,000 living within a 60 km radius of a well-equipped community hospital. Over the past few years the annual number of deliveries has been 700-750. Referral patterns are affected by changing patterns of practice, availability of diagnostic techniques, and consumer expectations. Early risk assessment by the family physician is the key to improved prenatal care. More than 60% of obstetrical patients in this community are totally managed by family physicians; the remainder involve collaboration with a consultant at some stage. Indications for referral occur throughout the phases of pregnancy. The success of this family physician service is the result of good family physician/consultant relationships in the small community hospital. PMID- 21279125 TI - Birthing rooms in Canada. AB - Birthing rooms are part of a trend to family-centred maternity care in hospitals. The room is decorated in a homelike fashion, and is a place where a family can labor, deliver and spend uninterrupted time together following birth. It also offers more privacy than traditional labor and delivery areas. Because birthing room programs are relatively new, the Canadian Institute of Child Health conducted a survey to determine how they began and how they are operated in Canadian hospitals. Forty-six hospitals were surveyed, of which 23 indicated they had a birthing room program. This article discusses the planning and cost of implementing the programs, physical aspects of the rooms, patients' eligibility to use them, indications for transferring patients to the delivery room, staffing, family participation, problems and benefits. While the programs increased patient satisfaction, most organized birthing rooms are used by a small segment of the population and are directed only at those families considered to be at low risk. PMID- 21279126 TI - Prenatal psychology: implications for the practice of medicine. AB - Through the combined efforts of embryologists, neuro-embryologists, physiologists, obstetricians, pediatricians, nurses, psychiatrists, psychologists and many other health professionals a new science of pre- and perinatal psychology has begun to emerge. This science explores the psychology of conception, pregnancy, labor, delivery and the postpartum period, as well as the unborn and newborn child's intellectual and emotional development. Implications of this new knowledge for the family physician counselling pregnant women will be discussed. PMID- 21279127 TI - Management of common postpartum problems. AB - Difficulties in the postpartum period detract from new parents' enjoyment of their child. Practical approaches to episiotomy care, timing of discharge from hospital, breast-feeding and drugs, bladder dysfunction, fever, depression, vaginal bleeding, contraception and the 'postpartum check' assure continuing good health of the new mother. The art and science of medicine must be judiciously mixed with knowledge, compassion and reassurance. PMID- 21279128 TI - Antinauseants in pregnancy: teratogens or not? AB - Nausea and/or vomiting affect 50% of all pregnant women. For most women, this is a self-limited problem which responds well to conservative management. However, there are some situations where the risk to the mother and fetus posed by the illness are greater than the possible risks of teratogenicity of antinauseant drugs. Antihistamines have had the widest testing, and to date, there has been no evidence linking doxylamine, dimenhydrinate or promethazine to congenital malformations. Since no available drugs have official approval for use in nausea and vomiting of pregnancy the physician is left alone to make this difficult decision. PMID- 21279129 TI - Teratogenic risk of drugs used in early pregnancy. AB - Treatment of common illnesses in early pregnancy is complicated because of the risk of teratogenic effects of drugs on the fetus. The period of greatest risk is between the first and eighth week of pregnancy. Since much of this period occurs before a diagnosis of pregnancy is made, care must be used in treatment of common illnesses in all women susceptible to becoming pregnant. Few, if any, drugs have been tested for teratogenicity in controlled clinical trials. Risk must therefore be based on epidemiological studies, individual case reporting and extrapolation from animal studies. Sufficient information is available on commonly used drugs to establish such risks. It is important that drugs of least known risk but adequate efficacy be used in treating intercurrent illness in the first trimester. PMID- 21279130 TI - Episiotomy in low risk patients. AB - In a literature search on episiotomy in low risk obstetric patients, no study could be found comparing low risk patients who had had an episiotomy with those who had not. Evidence was sought for physicians' widely held beliefs about episiotomy, but very little information was available. Available information contradicted common beliefs (e.g., that episiotomy helps prevent rectal tears, improves a woman's sexual functioning after she has given birth, and reduces hypoxia in the low risk fetus). Because of the lack of scientific information and the public's growing resistance to episiotomy, a prospective study is needed to determine the true indications for and outcomes of this procedure. PMID- 21279131 TI - A library for family physicians: recommended list of books and journals. PMID- 21279132 TI - A plea for rape victims. AB - A woman was seen in the office several days after emergency department treatment for sexual assault. A cervical swab taken in the office grew Chlamydia trachomatis. No cultures for this organism had been taken in the emergency department, and the patient had not been given prophylactic antibiotics against Chlamydia. Physicians dealing with rape victims should culture for and cover with appropriate antibiotics for Chlamydia trachomatis, which is capable of causing pelvic inflammatory disease and eventual infertility or ectopic pregnancy. PMID- 21279133 TI - CFP's On The Move. PMID- 21279134 TI - From the edge of the circle: the non-physician who teaches physicians. PMID- 21279136 TI - [Not Available]. PMID- 21279135 TI - From two monologues to one dialogue: the relationship between physicians and social scientists. PMID- 21279137 TI - [Not Available]. PMID- 21279138 TI - Viewpoints on childbirth: . . . The obstetrician. PMID- 21279139 TI - Should public health take over immunization? PMID- 21279140 TI - The family doctor. PMID- 21279142 TI - The family doctor. PMID- 21279141 TI - And the patient. PMID- 21279143 TI - A study of health maintenance protocols in family practice. AB - A series of color-coded health maintenance protocols for four age groupings were introduced into a community health centre. In a pilot study of the 16-49 year age range, levels of recording before introduction of the protocols were below 50% in all categories, except "blood pressure" "coping skills" and "sexuality/contraception". After one year, it was not possible to assess changes in recording of screening maneuvers reliably due to the short study period and major changes in staffing that coincidentally occurred during the study period. Further studies should use stable solo practices and a much longer follow up period. PMID- 21279144 TI - Primary Care's Denominator Problem. AB - It is usually impossible to determine the size of a primary care practice for use as a denominator in calculating rates of morbid and other events within a practice. Although this denominator problem has been a major hurdle for primary care researchers, its nature and significance are not broadly appreciated. This article describes the need for a denominator, defines the term 'practice population', outlines the need for the practice population as a valid denominator, and identifies the areas in which the practice population is the denominator of choice. PMID- 21279145 TI - The well child exam: what, when, and why? AB - The goal of the well child examination is to determine whether the child's needs at different ages and stages are being met. Although many parents need repeated visits to gain the confidence and knowledge required to meet those needs, other parents can do very well with the minimum number of visits. Once the child reaches school the required number of well child visits is unknown; each physician has to individualize a schedule to suit the needs of individual children and their families. The needs of adolescents and their reticence to discuss their problems require a special sensitivity from the physician in identifying the problems and helping the teenager to solve them. PMID- 21279146 TI - Immunization in Canada: current controversies. AB - Immunization, once used solely to control a disease, is now sufficiently widespread that elimination or even eradication of certain diseases has become possible. However, with greater control of disease, adverse reaction to immunization has taken on new prominence. Reporting of adverse reactions varies widely across Canada, and may be due to administrative differences-some provinces rely mostly on the public sector for immunizations, others on the private sector. Several controversies over immunizing agents remain, for example, live versus killed poliovirus vaccine, but generally immunization in Canada is now relatively uniform and safe. PMID- 21279147 TI - Screening for breast cancer: current status, problems, prospects. AB - The effect on breast cancer mortality of physical screening examinations and/or mammography will only be clear when current prospective studies are complete. The National Breast Screening Study will materially advance understanding of the value of current screening techniques. Until this information is available, however, physicians should consider practicing annual physical examinations of the breast in women over age 45, provided at least five minutes is spent in such examinations, which should consist of inspection as well as palpation of the breast in both the sitting and reclining position. If mammography of the caliber available to the American Breast Cancer Detection Project Centres is available, clinicians should consider periodic screening mammographic examinations. PMID- 21279148 TI - [Not Available]. AB - The family physician's role in health promotion must be looked at in a broader perspective than the traditional clinical setting, and better articulated to public health organizations. Medical faculties should consider including sociology, medical anthropology, and communication skills in both the undergraduate and postgraduate curriculum. Family physicians of the future will be called upon for more community-wide basis interventions and a more systematic approach to health promotion in patient care. PMID- 21279149 TI - Routine hemoccult screening: the current evidence. AB - Screening for colorectal carcinoma with the Hemoccult(r) test has been widely recommended for routine use in those over age 45. This review critically evaluates current evidence for the maneuver's efficacy, effectiveness, and efficiency. To date, no controlled trials have demonstrated clear-cut improvements in cancer survival or quality-of-life after Hemoccult screening. However, significant risks and costs attend the test's administration because of the invasive confirmatory investigations now recommended for each positive screening result. In view of the uncertain benefits, substantial risks and high costs of occult-blood screening, further evidence should be available of its ability to produce cancer mortality reductions before this intervention is included in the periodic health examination at any age. PMID- 21279150 TI - Hyperlipidemia: time to treat? AB - This review emphasizes the practical management of hyperlipidemia (HLD), based on five key references published since 1982. It answers seven basic questions: Who should be screened for HLD? How should they be screened? When should they be screened? What should be expected of the laboratory? Why screen for and treat HLD? What should be expected from treatment of HLD? How should HLD be treated? Dietary and drug management are described. PMID- 21279151 TI - Screening for glaucoma in family practice. AB - Glaucoma is the most common cause of preventable blindness in the western world. Vision can be preserved by early diagnosis and early treatment. The technique of Schiotz tonometry is simple and should be part of a general physical examination. Optic disc cupping can be discovered by ophthalmoscopy. The features of glaucomatous optic disc cupping are described so that the primary care physician can easily make the diagnosis of glaucoma. PMID- 21279152 TI - Hepatitis A, B and nAnB: The Viruses and their Prevention. AB - THREE VIRUSES COMMONLY INFECT THE LIVER: hepatitis A virus (HAV), hepatitis B virus (HBV) and the virus(es) responsible for non A non B hepatitis (nAnB). HAV infection occurs predominantly by the fecal-oral route and thus is more common in areas where living conditions are poor and personal hygiene suboptimal. Immune serum globulin (ISG) prevents this form of hepatitis. HBV infection can be spread by either parenteral (e.g. drug abuse) or non-parenteral (e.g. intimate contact) routes. High risk, susceptible individuals should be vaccinated with the HBV vaccine for longterm protection. Hepatitis B immune globulin (HBIG) remains the treatment of choice after exposure, but its protective effect does not exceed three to four months. The nAnB agent is spread by the same routes as HBV infection. At present there is no convincing evidence that any form of active or passive prophylaxis is beneficial for this form of hepatitis. PMID- 21279153 TI - Health consequences of selected lifestyle factors: a review of the evidence, part 2. AB - Generalized resistance to disease and reduced tendency to depression have been related to the extent of social relationships, with a greater association for females than males. Cigaret smoking is the largest cause of preventable death: smokers' mortality rates are almost double those for non-smokers. Coronary heart disease and lung cancer are the main causes of death. Morbidity is also higher among smokers, who are more prone to bronchitis, emphysema, sinusitis, peptic ulcers, and influenza. Abuse of drugs, both prescribed and unprescribed, is linked directly to drug dependency and death, often suicide. Misuse of prescribed drugs is a major concern in the elderly. High caffeine consumption has been related to chronic insomnia, persistent anxiety and depression, and stomach upset. Use of properly adjusted seatbelts halves the number of deaths and the severity of injury in motor vehicle accidents. Type A personality behaviors are associated with an increased risk of coronary heart disease. "Insight" requires further study to assess its affect on health and wellbeing. Quality of working life is an important determinant of an individual's identity and health status: frequency of symptoms increase as job strain increases. PMID- 21279154 TI - Isotretinoin use in severe acne. AB - Isotretinoin, an oral vitamin A derivative, is highly effective in, and at present indicated only for, the treatment of cystic acne, conglobate acne, or severe acne which has failed to respond to conventional therapy, including systemic antibiotics. Isotretinoin use usually results in a prolonged remission, often with complete disappearance of previously resistant lesions. Virtually all patients experience reversible integumentary side effects, which can almost always be controlled with emollients or lubricants. Isotretinoin is a known teratogen. The longterm effects of the transient vitamin A imbalance produced by this medication are not yet known. PMID- 21279155 TI - Blastomycosis in northwestern ontario. AB - Nine cases of blastomycosis were seen at the Sioux Lookout Zone Hospital in northwestern Ontario from 1970 to 1983. Although this region has been described as a focus of endemic infection, little published information is available. Seven male and two female Canadian Indians, aged 4-54 years, acquired the infection. Three children were infected; a mother and her son became ill one month apart. All cases presented as progressive pulmonary disease and no extrapulmonary involvement was found. Delay in diagnosis ranged from 11 days to eight weeks, with a mean of 31 days. Patients generally responded favorably to treatment with amphotericin B. Epidemiologic data suggest that environmental, geographic, occupational and recreational determinants are necessary factors in disease acquisition. PMID- 21279156 TI - Psychiatry training in canadian family medicine residency programs. AB - Family physicians may spend up to 50% of their time diagnosing and managing mental disorders and emotional problems, but this is not always reflected in the training they receive. This study of the teaching of psychiatry in the 16 family medicine residency programs in Canada showed that although the majority of program directors are reasonably satisfied with the current training, they see room for improvement-particularly in finding psychiatrists with a better understanding of family practice, in integrating the teaching to a greater degree with clinical work, thereby increasing its relevance, and in utilizing more suitable clinical settings. PMID- 21279157 TI - Should heroin be available on prescription? PMID- 21279158 TI - Immunoexpression of Survivin in non-neoplastic lymphoid tissues and malignant lymphomas using a new monoclonal antibody reactive on paraffin sections. AB - Survivin is a member of the inhibitor of apoptosis gene family, which is also implicated in mitosis regulation. Most reports in the literature impute poor prognosis to neoplasms with overexpression of this protein. The purpose of the present study is to validate and compare the immunohistochemical reactivity of malignant lymphomas and reactive lymphoid tissue using a new mouse monoclonal antibody to Survivin produced in our laboratory, 6-78. Survivin was detected by immunohistochemistry on tissue microarrays. It was shown that the antibody anti Survivin 6-78 reliably stains formalin-fixed, paraffin-embedded reactive and neoplastic lymphoid tissues, mostly in a nuclear pattern. We confirmed using this novel antibody that Survivin immunostaining has a tendency to be lower in reactive lymphoid tissues and low-grade B cell lymphomas than in aggressive lymphomas. This antibody may represent a useful tool for standardizing the study of the immunoexpression of Survivin in neoplasms. PMID- 21279159 TI - Divided stimulus control: a replication and a quantitative model. AB - Four pigeons were trained on a conditional discrimination. The conditional stimuli were compounds of pairs of stimuli from two different dimensions, fast versus slow cycles of red or green stimuli, and short- versus long-duration presentations of these cycles. Across conditions, the probability of reinforcers for correctly responding to each dimension was varied from 0 to 1. Discriminability, measured by log d, for stimuli on a dimension increased as the relative frequency of reinforcers for that dimension increased, replicating the results of Shahan and Podlesnik (2006). Two further conditions showed that discriminability between stimuli on each dimension was unaffected by whether the stimuli on the other dimension varied or were constant. Finally, maximal discriminability was unchanged in a redundant-relevant cues condition in which either of the stimuli comprising a compound signaled the same correct response. Davison and Nevin's (1999) model provided an excellent quantitative account of the effect of relative reinforcer frequency on discriminability, and thus of the way in which divided stimulus control is itself controlled by relative reinforcement. PMID- 21279161 TI - Derived relational responding: a comparison of match-to-sample and the relational completion procedure. AB - Previous research suggests that the Relational Completion Procedure may be an effective alternative procedure for studying derived relational responding. However, the parameters that make it effective, relative to traditional match-to sample, remain to be determined. The present experiment compared the Relational Completion Procedure and match-to-sample protocols for training and testing Same and Opposite derived stimulus relations. Trials to criterion and overall pass rate (i.e., yield) in both procedures were compared across three variables: presence versus absence of a confirmatory response requirement, three versus five comparison stimuli, and top-to-bottom versus left-to-right presentation format. Findings demonstrated a facilitative effect of the confirmatory response requirement in both procedures. Training trials to criterion were nominally but not significantly lower during the nonarbitrary training phase in the Relational Completion Procedure compared to match-to-sample, and the overall yield on the arbitrary relational test was greater in the former procedure compared to the latter. The present findings support the further development of the Relational Completion Procedure as an efficient alternative procedure for establishing Same and Opposite relations with adult humans, and with potential applicability to other types of derived relations. PMID- 21279160 TI - Acute and chronic effects of cocaine on the spontaneous behavior of pigeons. AB - The present experiment examined the effects of acute and daily cocaine on spontaneous behavior patterns of pigeons. After determining the acute effects of a range of doses, 9 pigeons were divided into three groups that received one of three doses of cocaine daily, either 1.0, 3.0, or 10.0 mg/kg cocaine. Measures were taken of spontaneous locomotion, pecking, preening, and emesis. Under daily administration, cocaine induced consistent and substantial enhancements of its locomotor effects in all 9 pigeons, consistent with the phenomenon of locomotor sensitization. The maximum locomotor output did not differ according to the size of the daily dose. Locomotion was not elevated following tests of the saline vehicle, suggesting the effect was due to cocaine, not to a change in baseline or reactivity to the injection procedure. Cocaine dose-dependently decreased preening when given acutely, and those effects were not altered by repeated cocaine administration. Pecking occurred at very low rates and was unresponsive to cocaine treatment. Cocaine-induced emesis showed a dose-dependent increase under initial tests with cocaine, and those effects were attenuated following daily exposure. In a final condition, cocaine was replaced with daily saline for 30 days to assess the persistence cocaine-related increases in locomotion. Approximately half of the pigeons continued to show enhanced effects even after 30 days without cocaine, so although persistence was obtained, it showed marked intersubject variability. The data indicate that the effects of repeated cocaine administration on the behavior of pigeons shows parallels with many effects commonly reported with rodents (i.e., increased locomotion following repeated treatment, decrease in preening or grooming, persistence following drug withdrawal). PMID- 21279162 TI - Disruptive effects of stimulus intensity on two variations of a temporal discrimination procedure. AB - Previous reports using stimulus intensity changes to disrupt temporal discrimination have shown shifts in the psychophysical curve for time, while studies using other disruptors have shown a flattening of the curve. The current study investigated the impact of increases and decreases in stimulus intensity on temporal discrimination in pigeons, to determine if a flattening of the curve could be extended to this disruptor. The brightness of the sample to be timed was manipulated under two procedural variations, in which the response alternatives were differentiated by color or location. Results showed that all subjects in the color procedure, and one in the location procedure, showed a flattening of the psychophysical curve when they experienced increased stimulus intensity in descending order. No subjects exposed to an ascending order of stimulus intensities, and none of the other subjects in the location procedure, showed any impact of changed stimulus intensity. Minimal disruption was found when test sessions presented decreased stimulus intensity levels in a second series. These results, together with those using other types of disruptors, add to the evidence of a flattening of the psychophysical curve when temporal discrimination is disrupted. PMID- 21279163 TI - Titrating-delay matching-to-sample in the pigeon. AB - The titrating-delay matching-to-sample (TDMTS) procedure offers researchers an additional behavioral task thought to capture some important features of remembering. In this procedure, the delay between sample offset and comparison onset adjusts as a function of the subject's performance. Specifically, correct matches increase the delay and incorrect matches decrease the delay, and steady state titrated delays serve as the primary dependent measure. The present series of experiments investigated the effects of several procedural variables on performance in TDMTS procedures in an effort to elucidate better its features to allow for more precision in future use. Experiment 1 reports results from a parametric analysis of fixed-ratio response requirements on the sample key that indicated improved remembering in the form of higher daily titrated delay values as the requirement was increased. Experiment 2 investigated the extent to which the initial delay value in each session affected session-wide delay values. Results indicated that regardless of value of the initial delay, the subjects' performances adjusted the delay values in the direction of the known baseline delay-value levels. Experiment 3 manipulated the step size by which delay values were adjusted and the results indicated that larger step sizes increased both session-to-session variability and within-session range of titrated delay values, although the average values remained approximately the same. These results suggest that the TDMTS task serves as a promising procedure to study what many refer to as memory. PMID- 21279164 TI - Psychophysics of remembering: to bias or not to bias. AB - Delayed matching to sample is typically a two-alternative forced-choice procedure with two sample stimuli. In this task the effects of varying the probability of reinforcers for correct choices and the resulting receiver operating characteristic are symmetrical. A version of the task where a sample is present on some trials and absent on others is analogous to a yes/no recognition task. We describe data from two experiments where an asymmetry in performance in the yes/no task could be attributed to a change in response bias with increasing retention-interval duration from a matching-law perspective, but not from a signal-detection perspective. Both approaches make explicit assumptions about response bias. The apparent inconsistency between the two approaches to the treatment of response bias is resolved in terms of a model proposed by K. G. White and J. T. Wixted (1999) which predicts asymmetrical matching-law functions and receiver operating characteristics without making any assumptions about response bias. PMID- 21279165 TI - Registration of clinical trials: An idea whose time has come! PMID- 21279167 TI - Mechanisms responsible for the vascular effect of aqueous Trigonella foenum graecum leaf extract in diabetic rats. AB - BACKGROUND AND OBJECTIVE: Since a beneficial vascular effect of aqueous leaf extract of Trigonella foenum-graecum (TFG) has previously been reported, this study was conducted to evaluate the underlying mechanisms, including the role of nitric oxide (NO) and cyclooxygenase pathways, in diabetic rats. MATERIALS AND METHODS: Male Wistar rats were divided into control, extract-treated control, diabetic, and extract-treated diabetic groups. Diabetes was induced by a single i.p. injection of streptozotocin (STZ; 60 mg/kg). Treatment groups received TFG extract (200 mg/kg; ip.) every other day for 1 month. Contractile reactivity of the thoracic aorta to KCl and noradrenaline (NA) and relaxation response to acetylcholine (ACh) were determined. For determination of the participation of NO and prostaglandins in the relaxation response to ACh, aortic rings were incubated for 30 min before the experiment with N-nitro-l-arginine methyl ester (L-NAME) and/or indomethacin (INDO). RESULTS: The diabetic state significantly increased the maximum contractile response to KCl and NA (P < 0.01-0.005) and reduced the maximum relaxation due to ACh (P < 0.01) as compared to controls and treatment with TFG extract in the diabetic group significantly improved these changes relative to the untreated diabetic group (P < 0.05). With L-NAME pretreatment, no significant difference between diabetic and extract-treated diabetic groups was found out. On the other hand, there was a significant difference between these two groups following INDO pretreatment (P < 0.05). CONCLUSION: Intraperitoneal administration of aqueous leaf extract of TFG for one month could improve some functional indices of the vascular system in the diabetic state and endothelium derived prostaglandins are essential in this respect. PMID- 21279166 TI - A review on plant-derived natural products and their analogs with anti-tumor activity. AB - Traditional medicines, including Chinese herbal formulations, can serve as the source of potential new drugs, and initial research focuses on the isolation of bioactive lead compound(s). The development of novel plant-derived natural products and their analogs for anticancer activity details efforts to synthesize new derivatives based on bioactivity- and mechanism of action-directed isolation and characterization coupled with rational drug design - based modification. Also, the anticancer activity of certain natural products and their analogs can be enhanced by synthesizing new derivatives based on active pharmacophore models; drug resistance and solubility and metabolic limitations can be overcome by appropriate molecular modifications; and new biological properties or mechanisms of action can be added by combining other functional groups or molecules. Preclinical screening for in vitro human cell line panels and selected in vivo xenograft testing then identifies the most promising drug development targets. PMID- 21279168 TI - Paralytic effect of alcoholic extract of Allium sativum and Piper longum on liver amphistome, Gigantocotyle explanatum. AB - OBJECTIVE: To investigate the effects of alcoholic extract of Allium sativum and Piper longum on the muscular activity of a parasitic amphistome, Gigantocotyle explanatum. MATERIALS AND METHODS: Amphistomes were isometrically mounted to record the spontaneous muscular activity by using Chart 4 software program (Power Lab, AD Instruments, Australia) and to examine the effects of cumulative doses (100, 300, 1000, and 3000 MUg/ml) of the plant extracts on the amplitude (g), frequency (per 10 min), and baseline tension (g) of the spontaneous muscular activity of the amphistome. RESULTS: Alcoholic extract of A. sativum produced significant reduction in the frequency and amplitude of contractile activity of the amphistome at 1000 and 3000 MUg/ml bath concentrations. Complete paralysis of the amphistome was observed after 15 min of addition of 3000 MUg/ml concentration. Alcoholic extract of P. longum also caused paralysis following 15 20 min exposure of the amphistome to 3000 MUg/ml concentration. In both the cases the amphistomes did not recover from paralysis following 2-3 washes. CONCLUSION: The observations demonstrate the paralytic effect of alcoholic extract of A. sativum and P. longum on G. explanatum. PMID- 21279169 TI - Effects of low-level lead exposure on blood pressure and function of the rat isolated heart. AB - OBJECTIVE: Exposure to low levels of lead acetate can induce hypertension in both humans and experimental animals. The exact mechanisms of lead-induced hypertension are not well understood, but its pathogenesis could be explained by the changes in heart rate and contractility. MATERIALS AND METHODS: In the present study, the effects of exposure to 100 ppm of lead in drinking water (for periods of 4, 8, and 12 weeks) on blood pressure and some physiologic parameters (eg, electrocardiography [ECG], heart rate [HR], cardiac contractility, and coronary flow) of isolated beating rat heart was investigated using the Langendorff isolated heart apparatus. The isolated hearts were perfused with Krebs-Henseleit solution (37 degrees C; pH 7.4; gassed with 95% O(2) + 5% CO(2)). All data were digitized by a software program for further analysis. RESULTS: The blood pressure in the 8- and 12-week lead-exposed groups was significantly increased as compared to the control group. The ECG showed arrhythmias and conduction abnormalities only in the late phases of exposure (12 weeks). The HR and contractility were significantly higher in the 8- and 12-week lead-treated rats but not in the 4-week group. No significant changes were observed in coronary flow. CONCLUSION: THESE RESULTS INDICATE THAT: 1) low levels of lead exposure do not significantly affect the ECG in the early phase, 2) low levels of lead exposure causes ECG changes in the late phases of exposure, and 3) this level of lead exposure can increase HR and cardiac contractility but has no effect on coronary flow. PMID- 21279170 TI - Protective effect of palm vitamin E and alpha-tocopherol against gastric lesions induced by water immersion restraint stress in Sprague-Dawley rats. AB - OBJECTIVE: Stress can lead to various changes in the gastrointestinal tract of rats. The present study was designed to compare the effect of palm vitamin E (PVE) and alpha-tocopherol (alpha-TF) supplementations on the gastric parameters important in maintaining gastric mucosal integrity in rats exposed to water immersion restraint stress (WRS). These parameters include gastric acidity, plasma gastrin level, gastric prostaglandin E(2) (PGE(2)), and gastric lesions. MATERIALS AND METHODS: Sixty male Sprague-Dawley rats (200-250 g) were divided into three equal groups: a control group, which received a normal rat diet (RC), and two treatment groups, receiving oral supplementation of either PVE or alpha TF at 60 mg/kg body weight for 28 days. Each group was further divided into two groups: the nonstress and stress groups. The stress groups were subjected to 3.5 h of WRS once at the end of the treatment period. Blood samples were then taken to measure the gastrin level, after which the rats were killed. Gastric juice was collected for measurement of gastric acidity and gastric tissue was taken for measurement of gastric mucosal lesions and PGE(2). RESULTS: Exposure to stress resulted in the production of gastric lesions. PVE and alpha-TF lowered the lesion indices as compared to the stress control group. Stress reduced gastric acidity but pretreatment with PVE and alpha-TF prevented this reduction. The gastrin levels in the stress group were lower as compared to that in the nonstress control. However, following treatment with PVE and alpha-TF, gastrin levels increased and approached the normal level. There was also a significant reduction in the gastric PGE(2) content with stress exposure, but this reduction was blocked with treatment with both PVE and alpha-TF. CONCLUSION: In conclusion, WRS leads to a reduction in the gastric acidity, gastrin level, and gastric PGE(2) level and there is increased formation of gastric lesions. Supplementation with either PVE or alpha-TF reduces the formation of gastric lesions, possibly by blocking the changes in the gastric acidity, gastrin, and gastric PGE(2) induced by stress. No significant difference between PVE and alpha-TF was observed. PMID- 21279171 TI - Economic impact of interventional study on rational use of antiseptics and disinfectants in Super Speciality Hospital of Nagpur. AB - OBJECTIVE: To measure the impact of interventions on rational use of antiseptics and disinfectants (A and D) for cost containment in Super Speciality Hospital (SSH) of Government Medical College, Nagpur (GMCN), India. MATERIALS AND METHODS: This study was conducted from October 2003 to March 2007 in SSH of GMCN. In the pre-interventional phase (Phase-I), purchase, stocking and distribution of A and D was studied to find problem areas. Based on this formative data an intervention was planned (Phase-II) during which rationing of the A and D was done. Rational quantities needed for different A and D procedures were calculated based on recommendations of National Aids Control Organization (NACO) with modifications to suit our hospital setup. Detailed information, education, communication and training about rational use of A and D were provided to the hospital staff. In the post-interventional phase (Phase-III), the use of A and D was rationalized at the distribution level and the efficacy of in-use A and D was tested at user sites. Data about medicine expenditure, patient record and A and D usage in various departments was obtained from hospital records. Savings on A and D as against total annual medicine expenditure was calculated taking the cost of A and D in the post-intervention period. RESULTS: The expenditure on A and D as a result of intervention decreased by 20.7%. Out of the total medicine expenditure, the expenditure on A and D which accounted for 6.2% before intervention, decreased to 1.95% after the intervention. CONCLUSION: The information, education and communication (IEC) interventions attempted by us resulted in significant decrease in the use and expenditure of A and D. PMID- 21279172 TI - Effect of erythromycin and rifampicin on monoethylglycinexylidide test. AB - BACKGROUND: The dynamic liver function test based on the hepatic conversion of lidocaine to monoethylglycinexylidide (MEGX) provides a direct measure of the actual functional state of the liver. Cytochrome P450 (CYP) 3A4 has been proposed as the main CYP isoform responsible for MEGX formation. The concomitant use of either CYP3A4 inducer rifampicin or CYP3A4 inhibitor erythromycin may influence the results of MEGX test. Hence, the objective of this study was to evaluate the effect of a CYP3A4 inhibitor erythromycin and inducer rifampicin on the MEGX test. MATERIALS AND METHODS: The study included 20 healthy male volunteers whose routine laboratory tests were normal. As per study protocol, MEGX test was carried out in all the participants after an overnight fast. All the participants were given 1 mg/kg lidocaine dose intravenously and MEGX concentration at 30 and 60 min after IV dose was measured using HPLC. These MEGX values served as control values. Ten subjects received 600 mg/day erythromycin orally for six days while remaining ten participants received 600 mg/day rifampicin orally for six days. On the sixth day, MEGX test was carried out two hours after the last dose. RESULT: Rifampicin increased the mean plasma concentration of MEGX(30) from 93.94 +/- 26.31 to 98.54 +/- 24.94 MUg/ml (P = 0.085) and MEGX(60) from 134.34 +/- 35.42 to 136.36 +/- 33.14 MUg/ml (P = 0.051). Erythromycin lowered the serum concentration of MEGX(30) from 101.37 +/- 39.39 to 96.67 +/- 36.09 MUg/ml (P = 0.128) and MEGX(60) from 142.52 +/- 42.65 to 138.98 +/- 40.23 MUg/ml (P = 0.159). CONCLUSION: It can be concluded from this study that the MEGX test is not affected by concomitant administration of CYP3A4 modifiers rifampicin and erythromycin. PMID- 21279173 TI - Isoniazid causing pleural effusion. AB - Isoniazid (INH) is a first-line antitubercular drug. We report a case of a patient who developed a pleural effusion 2 months after starting antitubercular treatment for spinal tuberculosis. Isoniazid was found to be the culprit and its discontinuation caused subsidence of the effusion. PMID- 21279174 TI - Demonstration of LanthaScreenTM TR-FRET-based nuclear receptor coactivator recruitment assay using PHERAstar, a multi-detection HTS microplate reader. AB - An attempt was made to demonstrate the possibility of performing LanthaScreenTM TR-FRET based nuclear receptor coactivator recruitment assay using PHERAstar, a multi-detection HTS microplate reader. LanthaScreenTM nuclear receptor coactivator recruitment assay (M/s Invitrogen corporation, USA) was performed using PPAR-gamma receptor preparation in the agonist mode. TR-FRET measurements were done on PHERAstar, a multimode microplate reader (BMG LABTECH, Germany). The Lanthascreen PPAR gamma coactivator recruitment assay was successfully performed in the PHERAstar, multimode microplate reader. This was evidenced by an assay robustness score (Z') of 0.71. The current work demonstrates the suitability of using PHERAstar, a multi-detection HTS microplate reader.for performing LanthaScreenTM TR-FRET based nuclear receptor coactivator recruitment assays. PMID- 21279176 TI - 41 annual conference. PMID- 21279175 TI - Is the combination of enalapril and losartan irrational? PMID- 21279177 TI - Phase 0 - Microdosing strategy in clinical trials. AB - Drug development is an activity that is long, complex and expensive. In 2004, attrition in the drug development paradigm prompted the US Food and Drug Administration (FDA) to introduce its 'Critical Path' document, which highlighted the serious discordance between major scientific advances and limited drug development process. One issue addressed was that of microdosing. The concept of microdosing involves the use of extremely low, nonpharmacologically active doses of a drug to define the pharmacokinetic profile of the medication in human subjects. Microdosing, thus, appears as a new viable concept in the 'toolbox' of the drug development activity. It appears that microdosing strategy could complement standard animal-to-human scaling, redefining the existing concept of phase I clinical research. In future, when research methods and technology involved in Phase 0 studies become more sophisticated, human microdosing may be applied to a number of drugs developed subsequently. PMID- 21279178 TI - Assessment of prescription pattern at the public health facilities of Lucknow district. AB - OBJECTIVES: To study the prescription pattern at the different levels of public health facilities of Lucknow district and to assess the average cost of drugs prescribed. METHODS: Multi-stage stratified random sampling was done to select 1625 prescriptions of the patients attending the different level of public health facilities in Lucknow district, from August 2005 to September 2006, which was used for the development of study tools, collection of data and analysis. RESULTS: The important components of prescription viz. examination findings, weight of the child, follow up visit and the signatures of the prescribers were absent in the prescriptions at the primary level. Polypharmacy was common (3.1 +/ 1.6 drugs per prescription). The prescription of drugs by generic name was low (27.1%). The prescriptions at the secondary level health facilities were incomplete with respect to mentioning the suffix/prefix of the drug, full name, dose, frequency and strength of the drugs, and directions specifying the route and duration of the treatment. The average cost of drugs/prescription/day in US$ (Mean, SD) was found to be the highest at the tertiary level (0.34, 0.43), which decreased significantly at the primary level health facilities. CONCLUSION: The pattern of prescription in terms of completeness and rationality was poor. There is an urgent need to improve the standards of drug prescription. PMID- 21279179 TI - The effect of sodium valproate on the biochemical parameters of reproductive function in male albino Wistar rats. AB - OBJECTIVE: To assess the effects of sodium valproate on intratesticular testosterone and lactic dehydrogenase level in rats. METHODS: Male Wistar rats (12 weeks old) were treated with sodium valproate and sacrificed at the end of the 2(nd), 4(th), 5(th), 7(th), 10(th) and 15(th) week, after the last exposure to sodium valproate. The testes were removed, weighed and processed for biochemical analysis. RESULTS: The intratesticular testosterone level was significantly (P<0.001) reduced in 200 mg/kg and 400 mg/kg treated rats. The intratesticular lactate dehydrogenase (LDH) level was significantly (P<0.001) increased by valproate in a time dependent manner. CONCLUSION: Valproate causes reversible change in intratesticular testosterone and LDH level. PMID- 21279180 TI - Prescribing knowledge and skills of final year medical students in Nigeria. AB - OBJECTIVES: To assess the knowledge of final year medical students in Nigeria, about good prescribing and the application of this knowledge to their prescribing skills. MATERIALS AND METHODS: Thirty four final year medical students of the Lagos State University College of Medicine (LASUCOM), Ikeja, were interviewed with a structured questionnaire that assessed their knowledge on the principles of good prescribing. They were also requested to write a prescription, based on a paediatric clinical scenario of malaria and upper respiratory tract infection. The prescription was used to assess their prescribing skills. RESULTS: Thirty one (91.18%) students knew that rational prescribing involved prescribing correct dosage of an appropriate medicine formulation. Factors considered important by the students to prescribe rationally were: Potential benefit: risk ratio of a medicine - 33 (97.06%); good knowledge of pharmacology - 29 (85.29%) and pathophysiology of the disease to be treated - 24 (70.59%); and safety of an alternative medicine to be used - 24 (70.59%). An average of 3.71 medicines was prescribed for a child suspected to have malaria. Antimalarials (38.24%) and paracetamol (20%) were the most frequently prescribed medicines. The name and signature of the prescriber were available in 51.61% and 58.06% prescriptions, respectively. Less than 50% prescriptions had the name, case file number, age and gender of the patient. CONCLUSION: The final year medical students of LASUCOM would require theoretical and practical teaching of principles of rational prescribing to improve their prescribing knowledge and skills. PMID- 21279181 TI - Antidiabetic activity of flower buds of Michelia champaca Linn. AB - OBJECTIVE: To identify the antihyperglycemic activity of various extracts, petroleum ether (60-80 degrees ), chloroform, acetone, ethanol, aqueous and crude aqueous, of the flower buds of Michelia champaca, and to identify the antidiabetic activity of active antihyperglycemic extract. MATERIALS AND METHODS: Plant extracts were tested for antihyperglycemic activity in glucose overloaded hyperglycemic rats. The effective antihyperglycemic extract was tested for its hypoglycemic activity at two-dose levels, 200 and 400 mg/kg respectively. To confirm its utility in the higher model, the effective extract of M. champaca was subjected to antidiabetic study in alloxan induced diabetic model at two dose levels, 200 and 400 mg/kg respectively. The biochemical parameters, glucose, urea, creatinine, serum cholesterol, serum triglyceride, high density lipoprotein, low density lipoprotein, hemoglobin and glycosylated hemoglobin were also assessed in the experimental animals. RESULTS: The ethanolic extract of M. champaca exhibited significant antihyperglycemic activity but did not produce hypoglycemia in fasted normal rats. Apart from this extract, the crude aqueous and petroleum ether extracts were found active only at the end of the first hour. Treatment of diabetic rats with ethanolic extract of this plant restored the elevated biochemical parameters significantly (P<0.05) (P<0.01) and the activity was found dose dependent. CONCLUSION: This study supports the traditional claim and the ethanolic extract of this plant could be added in traditional preparations for the ailment of various diabetes-associated complications. PMID- 21279182 TI - The effect of Allium sativum on ischemic preconditioning and ischemia reperfusion induced cardiac injury. AB - In the present study, the effect of garlic (Allium sativum) extract on ischemic preconditioning and ischemia-reperfusion induced cardiac injury has been studied. Hearts from adult albino rats of Wistar strain were isolated and immediately mounted on Langendorff's apparatus for retrograde perfusion. After 15 minutes of stabilization, the hearts were subjected to four episodes of 5 min ischemia, interspersed with 5 min reperfusion (to complete the protocol of ischemic preconditioning), 30 min global ischemia, followed by 120 min of reperfusion. In the control and treated groups, respective interventions were given instead of ischemic preconditioning. The magnitude of cardiac injury was quantified by measuring Lactate Dehydrogenase and creatine kinase concentration in the coronary effluent and myocardial infarct size by macroscopic volume method. Our study demonstrates that garlic extract exaggerates the cardio protection offered by ischemic preconditioning and per se treatment with garlic extract also protects the myocardium against ischemia reperfusion induced cardiac injury. PMID- 21279183 TI - Antioxidant potential of the methanol-methylene chloride extract of Terminalia glaucescens leaves on mice liver in streptozotocin-induced stress. AB - AIM: The antioxidant effect of the methanol-methylene chloride extract of Terminalia glaucescens (Combretaceae) leaves was investigated in streptozotocin (STZ)-induced oxidative stress. METHODS: Oxidative stress was induced in mice by a daily dose of STZ (45 mg/kg body weight i.p.) for five days. From day one, before STZ injection, normal and diabetic-test mice received an oral dose of the extract (100 or 300 mg/kg b.w.) daily. Plasma metabolites, lipid peroxidation, and antioxidant enzymes in the liver were assessed and gain in body weight recorded. RESULTS: In normal mice the plant extract reduced food and water intake, blood glucose and LDL-C level and body weight gain, did not affect the lipid peroxidation in the liver, while the antioxidant enzyme activities seemed increased. Blood glucose was decreased (P < 0.05) in normal mice treated with 300 mg/kg extract. Diabetic mice pretreated with 100 mg/kg extract as diabetic control mice (DC) showed significant (P < 0.001) body weight loss, polyphagia and polydipsia, high plasma glucose level, decrease in the liver catalase, peroxidase, and superoxide dismutase activities, and increase in lipid peroxidation. The HDL-C level was lowered (P < 0.05) whereas LDL-C increased. In 300 mg/kg extract-pretreated diabetic mice the extract prevented body weight loss, increase of blood glucose level, lipid peroxidation in liver, food and water intake, and lowering of plasma HDL-C level and liver antioxidants; this extract prevented LDL-C level increase. CONCLUSION: These results indicate that T. glaucescens protects against STZ-induced oxidative stress and could thus explain its traditional use for diabetes and obesity treatment or management. PMID- 21279184 TI - Gastroprotective effect of Benincasa hispida fruit extract. AB - OBJECTIVES: The antiulcer activity of Benincasa hispida (Thunb.) Cogn. fruit was evaluated in rats against ethanol-induced gastric mucosal damage, pylorus ligated (PL) gastric ulcers, and cold restraint-stress (CRS)-induced gastric ulcer models. METHODS: Petroleum ether and methanol extracts were administrated orally at the dose of 300 mg/kg, and omeprazole (reference standard) at the dose of 20 mg/kg. Ulcer index was common parameter studied in all the models. Further, vascular permeability was evaluated in ethanol model, and effect on lipid peroxidation, viz. melondialdehyde (MDA) content, superoxide dismutase (SOD), and catalase (CAT) levels were studied in CRS model. RESULTS: Both the extracts produced significant reduction in ulcer index (P < 0.05) in all the models and the results were comparable with that of omeprazole-treated group. Further, significant reduction in vascular permeability (P < 0.05) was observed. In CRS model, MDA content was significantly reduced along with increase in CAT levels as compared to control group. CONCLUSIONS: Petroleum ether and methanol extracts of B. hispida possess significant antiulcer as well as antioxidant property. PMID- 21279185 TI - Infertility improved by etanercept in ankylosing spondylitis. AB - The effect of TNF-alpha and TNF-alpha antagonists on semen quality in men is controversial. TNF-alpha levels are usually low in seminal plasma, but they tend to increase in inflammatory and infectious diseases. Etanercept is a highly specific antagonist of TNF-alpha. In this report, we describe the development of pregnancy in a couple with a previously infertile husband, who received etanercept for ankylosing spondylitis. PMID- 21279186 TI - Ocular adverse effects of Topiramate: Two case reports. AB - Topiramate, an antiepileptic drug is reported to cause various ocular adverse effects like acute onset myopia, glaucoma. Visual field defect is an uncommon, serious treatment emergent adverse effect. We are reporting two cases of suspected topiramate induced visual field defects.Both the cases were on topiramate for more than 6 months as add-on therapy at daily doses ranging from 100-150mg. The presenting complaints were insidious onset visual disturbances. Diagnosis was based of temporal association with drug intake, clinical examination and investigations. Automated perimetry revealed bilateral superior quadrantic and arcuate field defects in the two cases respectively. Marked improvement with drug dechallenge was noted which was also corroborated by perimetry. Using Naranjo's ADR Probability Scale, both cases revealed a "probable" association with topiramate. This report intends to improve awareness amongst clinicians to facilitate early diagnosis and intervention. PMID- 21279187 TI - The concept of personal drugs in the undergraduate pharmacology practical curriculum. PMID- 21279188 TI - Authors' reply. PMID- 21279189 TI - An overview of the articles published in the Indian Journal of Pharmacology during the year 2007. PMID- 21279190 TI - P-drug concept and the undergraduate teaching. PMID- 21279191 TI - A non-iterative, flexible, and highly stereoselective synthesis of polydeoxypropionates--synthesis of (+)-vittatalactone. AB - A short sequence comprising an oxy-Cope rearrangement, iridium-catalyzed hydrogenation, and enolate methylation provides trideoxypropionates with excellent diastereocontrol. A straightforward synthesis of the cucumber beetle pheromone (+)-vittatalactone illustrates this new strategy. PMID- 21279192 TI - Hydrogen dissociation on Cu(111): the influence of lattice motion. Part I. AB - We have studied the effect of lattice displacement on the interaction of H(2) with the Cu(111) surface using the Specific Reaction Parameter (SRP) approach to Density Functional Theory (DFT). We have systematically investigated how the motion of the surface atoms affects some features of the Potential Energy Surface (PES), such as the dissociation barrier height and the barrier geometry corresponding to some representative reaction pathways, and the anisotropy of the potential at these geometries. This analysis has allowed us to identify the surface degrees of freedom that are likely to be most relevant for H(2) dissociation. In particular, we have found that the lattice coordinate displacements that have the largest effect on the H(2)/Cu(111) DFT-SRP barrier heights and locations concern the motion of the 1st layer and 2nd layer Cu atoms in the Z direction, and motion of the 1st layer atoms in the directions parallel to the surface. Whereas the first degree of freedom mostly affects the barrier geometry, the second and third motions can lower or raise the barrier height. The latter effect cannot be described with the usual surface oscillator dynamical models employed in the past to include surface motion, and its dynamical influence on the dissociative adsorption needs to be further investigated. PMID- 21279193 TI - Conductive indium-tin oxide nanowire and nanotube arrays made by electrochemically assisted deposition in template membranes: switching between wire and tube growth modes by surface chemical modification of the template. AB - Tin-doped indium hydroxide (InSnOH) nanowires (NWs) and nanotubes (NTs) were grown from acidic aqueous solutions of inorganic precursors in a simple one-step electrochemically assisted deposition (EAD) process inside Au-plugged anodic aluminium oxide and polycarbonate membranes. When the membranes were used without any pre-treatment, InSnOH crystals nucleated on the both the Au-cathode and pore wall surfaces. By adjusting the surface chemistry of Au or the pore walls, it was possible to switch between NW and NT growth modes. InSnOH was converted into indium tin oxide (ITO) by annealing the InSnOH-filled membranes at 300 degrees C. The resulting wires and tubes were characterized by field emission scanning electron microscopy, transmission electron microscopy, X-ray and electron diffraction, Auger electron spectroscopy and electrical conductivity measurements. InSnOH and ITO NWs and NTs consisted of ~25-50 nm in size crystalline grains with the cubic crystal structures of In(OH)(3) and In(2)O(3), respectively, and showed essentially the same morphological features as planar ITO films made by the same method. Separate tin oxide/hydroxide phases were not observed by any of the characterization methods. After heating in air at 600 degrees C, the ITO NWs had resistivity on the order of 10 degrees Omega cm. EAD is an inexpensive and scalable solution-based technique, and allows one to grow dense arrays of vertically aligned, crystalline and conductive ITO NWs and NTs. PMID- 21279194 TI - Carbon-bonded silver nanoparticles: alkyne-functionalized ligands for SERS imaging of mammalian cells. AB - Silver nanoparticles bonded to terminal alkynes form stable particles in aqueous solution, produce strong SERS signals for molecular imaging that arise from the carbon-metal bond, and expand the scope of molecules that can be used to stably functionalize plasmonic particles for mammalian cell imaging applications. beta Lactams represent a class of biologically important molecules that can be adapted to SERS studies in this manner. PMID- 21279195 TI - Improved performances of beta-Ni(OH)2@reduced-graphene-oxide in Ni-MH and Li-ion batteries. AB - Incorporation of reduced graphene oxide into beta-Ni(OH)(2) presents high performances with specific discharge capacity of 283 mA hg(-1) after 50 cycles in Ni-MH batteries, and 507 mA hg(-1) after 30 cycles in Li ion batteries. PMID- 21279196 TI - Co and Mn polysiloxanes as unique initiator-catalyst-systems for the selective liquid phase oxidation of o-xylene. AB - Co and Mn polysiloxanes are unique catalyst/initiator systems for the liquid phase oxidation of o-xylene showing higher activity than Co naphthenates, which is related to the weak interaction of the polar products with the hydrophobic surface as well as the absence of hydroxyl groups and surrounding oxygenates limiting radical quenching. PMID- 21279197 TI - Chromogenic and fluorogenic chemosensors and reagents for anions. A comprehensive review of the year 2009. AB - This critical review is focused on examples reported in the year 2009 dealing with the design of chromogenic and fluorogenic chemosensors or reagents for anions (264 references). PMID- 21279198 TI - Hydrodynamic optical alignment for microflow cytometry. AB - A microfabricated flow cytometer has been developed that is capable of detecting nearly all of the microparticles in an aqueous suspension. Current design allows for integrated coupling between an optical fiber-based detection system and the particle stream via hydrodynamic focusing. By adjusting the relative flow-rates at the auxiliary inputs of the focusing manifold, the particle stream can be steered out-of-plane relative to the illuminating laser, and similarly the particle stream can be squeezed or expanded. The microfabricated device was constructed in polydimethylsiloxane with cross-sectional microfluidic dimensions of 125 um*125 um. Using the present device and method, fluorescent microparticles in aqueous solution were counted at an absolute counting efficiency of 91+/-4%. The coefficient of variation of the fluorescence pulse-heights for far-red fluorescent microparticles was 15%. The device exhibited a linear response to fluorescence intensity calibration microparticles as shown by comparison with a commercial cytometer instrument. PMID- 21279199 TI - The association reaction between C2H and 1-butyne: a computational chemical kinetics study. AB - The potential energy surfaces (PES) for the reaction of the C(2)H radical with 1 butyne (C(4)H(6)) have been studied using the CBS-QB3 method. Density functional B3LYP/cc-pVTZ and M06-2X/6-311++G(d,p) calculations have also been performed to analyze the reaction energetics. For detailed theoretical calculation on the total reaction mechanism, the initial association reactions on more and less substituted C atoms of 1-butyne are treated separately followed by a variational transition state theory (VTST) calculation to obtain reaction rates. The successive unimolecular reactions from the association reaction complexes are subjected to Rice-Ramsperger-Kassel-Marcus (RRKM) calculations for reaction rate constants and product branching ratios. The calculated rate constants in the temperature range 70-295 K for both the association reactions are found to be highly temperature dependent at low temperatures, which is contrary to the experimental findings of temperature independent association rates. We have explained this observation with the help of variational nature of the transition states, and we found a "loose" transition state at low temperatures. The calculated product branching ratios for the unimolecular reactions generally agree with the available experimental data, although some channels show a significant method dependency and therefore the correlation with experiment is lost to some extent. Our detailed reaction energetics calculations confirm that the C(2)H + C(4)H(6) reaction proceeds without an entrance barrier and leads to the important products ethynylallene + CH(3), 1,3-hexadiyne + H, 3,4-hexadiene-1 yne + H, 2-ethynyl-1,3-butadiene + H, 3,4-dimethylenecyclobut-1-ene + H and fulvene + H exothermic by 25-75 kcal mol(-1), with strong dependence of the product distribution on the association mode of C(2)H with C(4)H(6), making these reactions fast under low temperature conditions of Titan's atmosphere. Therefore this study can provide a detailed picture of the complex hydrocarbon formation mechanism in the upper atmosphere. PMID- 21279200 TI - The separation of immiscible liquid slugs within plastic microchannels using a metallic hydrophilic sidestream. AB - This paper describes experiments and related modelling on a new method for separating aqueous phase slugs from the surrounding organic matrix phase in segmented two phase flow in a plastic microcapillary film (MCF). Kerosene or paraffin oil was metered through a plastic capillary of 630 microns diameter and aqueous phase slugs were generated within the capillary by the continuous sidestream injection of water. It was found that the resulting aqueous phase slugs formed in the MCF could be subsequently easily separated from the organic phase by piercing the downstream sidewall of the plastic capillary with a hydrophilic metal hypodermic needle to draw off an aqueous sidestream. Optical scrutiny of the phase separation process indicated that two distinct disengagement mechanisms are involved, in which the metal needle tip either remains submerged in the aqueous phase or becomes periodically exposed to the organic phase at certain stages of the segregation process. The separation efficiency, i.e. the degree of residual phase cross-contamination, was determined as a function of both the sidestream needle angle and the depth of needle penetration into the capillary for a given flow rate and phase ratio. It was established that the separation efficiency was very sensitive to the downstream pressure balance between the organic mainstream flow in the plastic capillary and the aqueous sidestream flow through the needle. A mathematical model for the pressure balance conditions was developed by making certain simplifying assumptions and taking the Laplace interfacial pressure into account. The model predictions agreed surprisingly well with the experimental findings, thus providing circumstantial evidence for the validity of the insights into the phase separation mechanism. PMID- 21279201 TI - Finding co-mutated genes and candidate cancer genes in cancer genomes by stratified false discovery rate control. AB - Finding candidate cancer genes playing causal roles in carcinogenesis is an important task in cancer research. The non-randomness of the co-mutation of genes in cancer samples can provide statistical evidence for these genes' involvement in carcinogenesis. It can also provide important information on the functional cooperation of gene mutations in cancer. However, due to the relatively small sample sizes used in current high-throughput somatic mutation screening studies and the extraordinary large-scale hypothesis tests, the statistical power of finding co-mutated gene pairs based on high-throughput somatic mutation data of cancer genomes is very low. Thus, we proposed a stratified FDR (False Discovery Rate) control approach, for identifying significantly co-mutated gene pairs according to the mutation frequency of genes. We then compared the identified co mutated gene pairs separately by pre-selecting genes with higher mutation frequencies and by the stratified FDR control approach. Finally, we searched for pairs of pathways annotated with significantly more between-pathway co-mutated gene pairs to evaluate the functional roles of the identified co-mutated gene pairs. Based on two datasets of somatic mutations in cancer genomes, we demonstrated that, at a given FDR level, the power of finding co-mutated gene pairs could be increased by pre-selecting genes with higher mutation frequencies. However, many true co-mutation between genes with lower mutation rates will still be missed. By the stratified FDR control approach, many more co-mutated gene pairs could be found. Finally, the identified pathway pairs significantly overrepresented with between-pathway co-mutated gene pairs suggested that their co-dysregulations may play causal roles in carcinogenesis. The stratified FDR control strategy is efficient in identifying co-mutated gene pairs and the genes in the identified co-mutated gene pairs can be considered as candidate cancer genes because their non-random co-mutations in cancer genomes are highly unlikely to be attributable to chance. PMID- 21279202 TI - Label-free cell-based assays using photonic crystal optical biosensors. AB - Biosensor technologies that have been primarily used in the past for characterizing biomolecular interactions are now being used to develop new approaches for performing cell-based assays. Biosensors monitor cell attachment to a transducer surface, and thus provide information that is fundamentally different from that provided by microscopy, as the sensor is capable of monitoring temporal evolution of integrin-surface interactions that are difficult to measure by other means. Label-free biosensor technologies are especially advantageous for monitoring the behavior of cells because they do not require stains that typically result in cell death, and are not subject to effects such as photobleaching. As a result, cells can be quantitatively monitored in their culture environment over an extended period of time while processes such as proliferation, apoptosis, cytotoxicity, chemotaxis, ion channel activation, and membrane-bound protein activation are modulated by the introduction of a variety of chemical or biological stimuli. This review describes the application of photonic crystal optical biosensor microplates to a variety of cell-based assays. Detection instruments for photonic crystals measure the aggregate behavior of large cell populations, or, using recently developed biosensor imaging detection, independent monitoring of individual cells. These technological developments offer the ability to perform assays with a limited number of available cells for applications such as high throughput screening with primary cells or stem cells. PMID- 21279203 TI - Dissociative electron attachment to glycyl-glycine, glycyl-alanine and alanyl alanine. AB - The processes of negative ions formation of dipeptides glycyl-glycine, glycyl alanine and alanyl-alanine in the conditions of resonant electron capture have been studied with a help of negative ions mass spectrometry. Using a thermochemical approach, the main channels of fragment negative ions formation were found and the structure of the ions were established. The isobaric ions have been identified by the experiments with high mass resolution. The cross sections of fragment ions formation were measured. The metastable fragmentation of [M-H]( ) and [M-COOH](-) ions in the energy range 4.5-7.5 eV have been found. PMID- 21279204 TI - A fluorescent molecular ruler as a selective probe for omega-aminoacids. AB - A fluorescent probe for omega-aminoacids behaves as a molecular ruler, changing the yellow fluorescent emission into blue as a function of the distance between the terminal ammonium and the carboxylate groups, permitting the quantitative detection of omega-aminoacids, their metabolites and related drugs, such as pregabalin or gabapentin, from pharmaceutical formulations. PMID- 21279205 TI - A general approach for prediction of motional EPR spectra from Molecular Dynamics (MD) simulations: application to spin labelled protein. AB - A general approach for the prediction of EPR spectra directly and completely from single dynamical trajectories generated from Molecular Dynamics (MD) simulations is described. The approach is applicable to an arbitrary system of electron and nuclear spins described by a general form of the spin-Hamiltonian for the entire motional range. It is shown that for a reliable simulation of motional EPR spectra only a single truncated dynamical trajectory generated until the point when correlation functions of rotational dynamics are completely relaxed is required. The simulation algorithm is based on a combination of the propagation of the spin density matrix in the Liouville space for this initial time interval and the use of well defined parameters calculated entirely from the dynamical trajectory for prediction of the evolution of the spin density matrix at longer times. A new approach is illustrated with the application to a nitroxide spin label MTSL attached to the protein sperm whale myoglobin. It is shown that simulation of the EPR spectrum, which is in excellent agreement with experiment, can be achieved from a single MD trajectory. Calculations reveal the complex nature of the dynamics of a spin label which is a superposition of the fast librational motions within dihedral states, of slow rotameric dynamics among different conformational states of the nitroxide tether and of the slow rotational diffusion of the protein itself. The significance of the slow rotameric dynamics of the nitroxide tether on the overall shape of the EPR spectrum is analysed and discussed. PMID- 21279206 TI - Comment on "Optical conversion of conical intersection to avoided crossing" by Y. Arasaki and K. Takatsuka, Phys. Chem. Chem. Phys., 2010, 12, 1239. AB - A recent paper in this journal proposed the conversion of conical intersections to avoided crossings by lowering the symmetry with an optical field. The article also claimed that the characters of nonadiabatic transitions caused by avoided crossings and conical intersections are qualitatively different. The present comment shows that this proposal and this claim result from an incorrect appreciation of the nature of conical intersections and avoided crossings. Conical intersections are moved, not removed, by almost all perturbations. Furthermore, there is no dichotomy between avoided crossing mechanisms and conical intersection mechanisms; as the parameters of the problem change and the typical locally avoided crossing involved in nonadiabatic dynamics becomes farther from the conical intersection, there is a gradual shift in the nature of the nonadiabatic transitions, with a continuum of possible behaviors, not just two. PMID- 21279207 TI - Rydberg rings. AB - Atoms in highly excited Rydberg states exhibit remarkable properties such as large polarizability and strong interactions. This makes them interesting for a manifold of applications ranging from electric field sensors to carriers and mediators of quantum information and renders them into a powerful tool for studying quantum phenomena in strongly interacting many-particle systems. In this article we illuminate perspectives for the study of the relaxation and thermalization dynamics of closed many-body quantum systems using alkali atoms that are held in a ring lattice and excited to Rydberg states. Moreover, we show that Rydberg atoms confined to lattices offer exciting possibilities for the creation of entangled many-body quantum states which can serve as a resource for the generation of non-classical light. PMID- 21279208 TI - A momentum space view of the surface chemical bond. AB - Well-ordered and oriented monolayers of conjugated organic molecules can offer new perspectives on surface bonding. We will demonstrate the importance of the momentum distribution, or symmetry, of the adsorbate molecules' pi orbitals in relation to the states available for hybridization at the metal surface. Here, the electronic band structure of the first monolayer of sexiphenyl on Cu(110) has been examined in detail with angle-resolved ultraviolet photoemission spectroscopy over a large momentum range and will be compared to measurements of a multilayer thin film and to density functional calculations. In the monolayer, the one-dimensional intramolecular band structure can still be recognized, allowing an accurate determination of orbital modification upon bonding and the relative energetic positions of the electronic levels. It is seen that the character of the molecular pi orbitals is largely maintained despite strong mixing between Cu and molecular states and that the lowest unoccupied molecular orbital (LUMO) is filled by hybridization with Cu s,p states rather than through a charge transfer process. It is also shown that the momentum distribution of the substrate states involved and the periodicity of the molecular overlayer play a large role in the final E(k) distribution of the hybrid states. The distinct momentum distribution of the LUMO, interacting with the Cu substrate s,p valence bands around the gap in the surface projection of the bulk band structure, make this system a particularly illustrative example of momentum resolved hybridization. This system demonstrates that, for hybridization to occur, not only do states require overlap in energy and space, but also in momentum. PMID- 21279209 TI - The effect of coordinating and non-coordinating additives on the transport properties in ionic liquid electrolytes for lithium batteries. AB - In the present study we expand our analysis of using two contrasting organic solvent additives (toluene and THF) in an ionic liquid (IL)/Li NTf(2) electrolyte. Multinuclear Pulsed-Field Gradient (PFG) NMR, spin-lattice (T(1)) relaxation times and conductivity measurements over a wide temperature range are discussed in terms of transport properties and structuring of the liquid. The conductivity of both additive samples is enhanced the most at low temperatures, with THF slightly more effective than toluene. Both the anion and lithium self diffusivity are enhanced in the same order by the additives (THF > toluene) while that of the pyrrolidinium cation is marginally enhanced. (1)H spin-lattice relaxation times indicate a reasonable degree of structuring and anisotropic motion within all of the samples and both (19)F and (7)Li highlight the effectiveness of THF at influencing the lithium coordination within these systems. PMID- 21279210 TI - Simulation of generation-collection experiments with homogeneous kinetics: application to electrochemical investigation of superoxide radical anion generation by osteoclasts on bone. AB - We report simulations of electrochemical generation-collection experiments in which the generator is a small disc producing a specified time-dependent flux of the analyte and the collector is a large planar electrode which collects the analyte at the mass transport-controlled rate. This geometry corresponds to many experiments in bioelectrochemistry where a relatively large sensor is used to detect the products of a cell's metabolism at low concentration. In particular, our simulations are motivated by attempts to understand our results on the detection of the superoxide radical anion burst generated by osteoclasts (bone resorbing cells) in response to various stimuli. Superoxide is present at low levels and disproportionates in aqueous media; however, the homogeneous kinetics are included in our simulations and the results show that it is possible to estimate the magnitude of the flux of superoxide produced by the cells and to accurately determine the time-dependence of the flux in response to stimuli such as injection of parathyroid hormone, vitamin D(3) and pertussis toxin. In all these cases, the superoxide anion flux was successfully modeled as uniform across the cell surface with time-dependence of the form j(0)e(-k(d)t) + j(infinity). j(infinity) is the sustained flux of superoxide and the first-order rate constant k(d) and the magnitude j(0) describe the transient component of the flux. The simulations indicate that for cell-electrode gaps D approximately < ?(D/k(d)), where D is the diffusion coefficient, the value of k(d) can be accurately extracted from the time-dependence of the collector current without detailed knowledge of parameters which are hard to measure during the experiment, e.g., the cell radius a and cell-electrode separation d. In the case of parathyroid hormone, the first-order rate constant describing the decay of the transient component was k(d) = 1.8 +/- 0.8 * 10(-1) s(-1), but much slower decays were observed in response to pertussis toxin (k(d) = 1.5 +/- 0.5 * 10(-2) s(-1)) and vitamin D(3) (k(d) = 1.1 +/- 0.5 * 10(-3) s(-1)). PMID- 21279211 TI - A gas-phase crossed-beam study of OH produced in the radical-radical reaction of O((3)P) with iso-propyl radical (CH3)2CH. AB - The gas-phase radical-radical reaction dynamics of ground-state atomic oxygen [O((3)P)] with iso-propyl radicals, (CH(3))(2)CH, were investigated by applying a combination of high-resolution laser-induced fluorescence spectroscopy in a crossed-beam configuration and ab initio calculations. The nascent distributions of OH (X(2)Pi: upsilon'' = 0) from the major reaction channel O((3)P) + (CH(3))(2)CH -> C(3)H(6) (propene) + OH showed substantial internal excitations with a bimodal feature of low- and high-N'' components with neither spin-orbit nor Lambda-doublet propensities. Unlike previous kinetic results, proposed to proceed only through the direct H-atom abstraction process, on the basis of the population analysis and comparison with the statistical theory, the title reaction can be described in terms of two competing mechanisms at the molecular level: direct abstraction process and indirect short-lived addition-complex forming process with a ratio of 1.25 : 1. PMID- 21279212 TI - Vacancy-induced magnetism in BaTiO3(001) thin films based on density functional theory. AB - The origin of magnetism induced by vacancies on BaTiO(3)(001) surfaces is investigated systematically by first-principles calculations within density functional theory. The calculated results show that O vacancy is responsible for the magnetism of the BaO-terminated surface and the magnetism of the TiO(2) terminated surface is induced by Ti vacancy. For the BaO-terminated surface, the magnetism mainly arises from the unpaired electrons that are localized in the O vacancy basin. In contrast, for the TiO(2)-terminated surface, the magnetism mainly originates from the partially occupied O-2p states of the first nearest neighbor O atoms surrounding the Ti vacancy. These results suggest the possibility of implementing magneto-electric coupling in conventional ferroelectric materials. PMID- 21279213 TI - Stereodynamics of the F + HD(v = 0, j = 1) reaction: direct vs. resonant mechanisms. AB - The stereodynamics and mechanism of the F + HD(v = 0, j = 1) -> HF (DF) + D (H) reactions have been thoroughly analysed at collision energies in the 0-160 meV range. Specifically, this study is focused on (i) the comparison between the stereodynamics of the collisions leading to HF and DF formation, and (ii) the stereodynamical fingerprints of the resonance that occurs at low collision energies in the HF channel and whose manifestation in the total cross section is greatly diminished for initial j > 0. While previous studies were limited to the analysis of integral cross sections (ICS), differential cross sections (DCS) and reaction probabilities, in the present work we have included the analysis of vectorial quantities such as the direction of the initial rotational angular momentum and internuclear axis, and their effect on reactivity. In particular, polarisation parameters (PP) and polarisation dependent differential cross sections (PDDCS), quantities that describe how the intrinsic HD rotational angular momentum and molecular axis polarisations contribute to reaction, are calculated and examined. The evolution of the PPs with the collision energy differs markedly between the two reaction channels. For the DF channel, the PP values are small and change very little in the energy range in which DF formation is appreciable. In contrast, rapid fluctuations in the magnitude and sign of the PPs are observed in the HF channel at low collision energies in and around the resonance. As the collision energy increases, direct (non-resonant) scattering prevails, and the various quantities are reasonably well accounted for by the QCT calculations, as in the case of the DF channel. The intrinsic directional information has been used to access the extent of control that can be achieved through polarisation of the HD molecule prior to collision. It was found that the same extrinsic preparation leads to very different outcomes on the HF channel DCS when the collision energy is close to the resonance. It is also shown that polarisation of the HD internuclear axis along the initial relative velocity enhances the effect of the resonance and allows its clear identification. Finally, the effect of different extrinsic preparations on the angle-velocity DCS is found to be strong, thus allowing considerable control of product angular distributions. PMID- 21279215 TI - Porous SnO2 nanospheres as sensitive gas sensors for volatile organic compounds detection. AB - Porous SnO(2) nanospheres with high surface areas have been synthesized through a solvothermal method in the absence of any templates. The structure and morphology of the resultant products were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS) and nitrogen adsorption-desorption technique. The as-prepared SnO(2) porous nanospheres with the diameters ranging from 90-150 nm are composed of small nanocrystals with average sizes of less than 10 nm. Results demonstrated that the formation of porous SnO(2) nanospheres is ascribed to etching the center part of the nanospheres. It was found that hydrochloric acid and NaClO played important roles in determining the final morphologies of the porous SnO(2) nanospheres. The gas sensing properties of the as-prepared porous SnO(2) nanospheres were investigated. By the comparative gas sensing tests, the porous SnO(2) nanospheres exhibited a superior gas sensing performance toward ppb level 2-chloroethanol and formaldehyde vapor, implying promising applications in detecting toxic volatile organic compounds (VOCs). PMID- 21279216 TI - Conversion of gaseous nitrogen dioxide to nitrate and nitrite on aqueous surfactants. AB - The hydrolytic disproportionation of gaseous NO(2) on water's surface (2 NO(2) + H(2)O -> HONO + NO(3)(-) + H(+)) (R1) has long been deemed to play a key, albeit unquantifiable role in tropospheric chemistry. We recently found that (R1) is dramatically accelerated by anions in experiments performed on aqueous microjets monitored by online electrospray mass spectrometry. This finding let us rationalize unresolved discrepancies among previous laboratory results and suggested that under realistic environmental conditions (R1) should be affected by everpresent surfactants. Herein, we report that NO(2)(g) uptake is significantly enhanced by cationic surfactants, weakly inhibited by fulvic acid (FA, a natural polycarboxylic acid) and anionic surfactants, and unaffected by 1 octanol. Surfactants appear to modulate interfacial anion coverage via electrostatic interactions with charged headgroups. We show that (R1) should be the dominant mechanism for the heterogeneous conversion of NO(2)(g) to HONO under typical atmospheric conditions throughout the day. The photoinduced reduction of NO(2) into HONO on airborne soot might play a limited role during daytime. PMID- 21279217 TI - The critical re-evaluation of the aromatic/antiaromatic nature of Ti3(CO)3: a missed opportunity? AB - The nature of bonding and aromaticity of Ti(3)(CO)(3), a mill-shaped metal carbonyl complex, is studied carefully. A unique bonding mechanism between metal and carbonyl groups is found in this species. Ti(3)(CO)(3) is an example of a metal-carbonyl complex with prominent metal to carbonyl donation. Moreover, it is proven that not only is Ti(3)(CO)(3) not an antiaromatic complex but also it is the first synthesized example of d-block, sigma+pi aromatic species. A quick survey among the first row of transition metals in the periodic table shows that other local minima with similar structures and aromaticity are present and Ti(3)(CO)(3) is the first synthesized species of an unknown family. PMID- 21279218 TI - Prolonged toxicity characteristic leaching procedure for nickel and copper aluminates. AB - The toxicity characteristic leaching procedure (TCLP) is a regulatory testing method widely employed to evaluate the environmental friendliness of waste materials. TCLP analysis provides a fast, easy and economical way to determine the mobility of waste pollutants under simulated landfill conditions. Recent studies on metal stabilization have reported the potential for nickel and copper aluminates to form in thermal treatment conditions, and suggested a more reliable method of stabilizing hazardous metals, particularly when products are to be reused. There is thus an urgent need for a convenient and effective method of quantifying metal leachability and identifying the metal leaching behavior of sparingly soluble materials. In this study, standard TCLP analysis was modified into a prolonged leaching experiment to investigate the leaching behavior of nickel and copper oxides (NiO and CuO) and their aluminates (NiAl(2)O(4), CuAl(2)O(4) and CuAlO(2)). The results demonstrate the difficulty of differentiating the leachability of highly insoluble phases, such as NiO and NiAl(2)O(4), using the standard TCLP. The prolonged TCLP method, however, confirmed NiAl(2)O(4) to have a lower degree of intrinsic leachability than NiO and that it could be expected to undergo congruent dissolution under landfill conditions. For the more soluble copper system, the aluminates were still found to possess a much lower degree of leachability, and their leaching behavior to follow an incongruent dissolution pattern. The results of this study prove prolonged TCLP analysis to be a convenient and effective way to evaluate the environmental friendliness of metal waste and to identify the leaching behavior of waste materials. PMID- 21279219 TI - Spectroscopic characterization of diverse amyloid fibrils in vitro by the fluorescent dye Nile red. AB - The fluorescence of Nile red (9-diethylamino-5H-benzophenoxazine-5-one) is quenched in aqueous solutions but shows augmented fluorescence in hydrophobic environments. Nile red fluorescence was blue shifted and strongly augmented in the presence of various amyloid fibrils assayed under acidic as well as neutral pH conditions. Fibrils grown from lysozyme and insulin (at pH 1.6 and 65 degrees C), transthyretin (TTR) fibrils grown from the acid unfolded monomer (pH 2.0, 21 degrees C) or from the dissociated tetramer starting from native protein under less acidic conditions (pH 4.4, 37 degrees C) were detected. Nile red was also successfully employed in detecting Abeta1-42 and human prion protein (PrP90-231) amyloid fibrils grown at neutral pH. Nile red was amyloid fibril specific and did not fluoresce appreciably in the presence of the monomeric precursor proteins. Stoke's shifts of the wavelength maximum of Nile red bound to various fibrils were different (ranging from 615 nm to 638 nm) indicating sensitivity to the tertiary structure in its respective binding sites of different amyloid proteins. A polarity assay using ethanol-water mixtures and pure octanol ranging from dielectric constants between 10 and 70 showed a linear correlation of Nile red Stoke's shift and allowed assignment of amyloid fibril binding site polarity. Fluorescence resonance energy transfer between Thioflavin T (ThT) and Nile red was proven to be efficient and co-staining was employed to discriminate between conformational isoforms of Abeta1-42 amyloid fibrils grown under agitated and quiescent conditions. This paper demonstrates the complementary use of this fluorometric method for conformational typing of amyloid structures. PMID- 21279220 TI - Nano- and microcrystals of a Mn-based metal-oligomer framework showing size dependent magnetic resonance behaviors. AB - A robust 3D Mn-based metal-organic framework containing metallosalen hexamers is synthesized and its nano- and microcrystals are fabricated by using surfactant mediated hydrothermal and solvent precipitation methods; the particles exhibit an inverse size-dependent effect of magnetic resonance relaxivity behaviors. PMID- 21279221 TI - Catalytic asymmetric conjugate addition of Grignard reagents to coumarins- synthesis of versatile chiral building blocks. AB - A new protocol for the Cu-catalysed asymmetric conjugate addition of Grignard reagents to coumarins has been developed. The corresponding products are formed in high yields and enantioselectivities. Through a sequential protocol involving conjugate addition followed by nucleophilic ring opening of the chiral enolate, chiral esters and amides are readily accessible. PMID- 21279222 TI - New layered cobalt oxyfluoride, Sr2CoO3F. AB - The first Ruddlesden-Popper type layered cobalt oxyfluoride, Sr(2)CoO(3)F, has been synthesized under a pressure of 6 GPa at 1700 degrees C and shown to adopt a K(2)NiF(4)-type structure with distorted square pyramidal coordination around Co and with O/F disorder at the apical sites. PMID- 21279223 TI - X-ray crystal structure of a heterobimetallic Al-Zn-oxide complex. AB - OH/R (R = H, Me, i-Bu) exchange was observed in reactions of [MesnacnacZn(MU OH)](2) (1) with metal complexes L(n)MR, whereas DippnacnacAl(Me)OH reacts with MesnacnacZnH with elimination of H(2) and formation of the heterobimetallic Al-Zn oxide complex MesnacnacZnOAl(Me)Dippnacnac 2. PMID- 21279224 TI - In situ Raman and in situ XRD analysis of PdO reduction and Pd degrees oxidation supported on gamma-Al2O3 catalyst under different atmospheres. AB - Reduction of Pd degrees and decomposition of palladium oxide supported on gamma alumina were studied at atmospheric pressure under different atmospheres (H(2), CH(4), He) over a 4 wt% Pd/Al(2)O(3) catalyst (mean palladium particle size: 5 nm with 50% of small particles of size below 5 nm). During temperature programmed tests (reduction, decomposition and oxidation) the crystal domain behaviour of the PdO/Pd degrees phase was evaluated by in situ Raman spectroscopy and in situ XRD analysis. Under H(2)/N(2), the reduction of small PdO particles (<5 nm) occurs at room temperature, whereas reduction of larger particles (>5 nm) starts at 100 degrees C and is achieved at 150 degrees C. Subsequent oxidation in O(2)/N(2) leads to reoxidation of small crystal domain at ambient temperature while oxidation of large particles starts at 300 degrees C. Under CH(4)/N(2), the small particle reduction occurs between 240 and 250 degrees C while large particle reduction is fast and occurs between 280 and 290 degrees C. Subsequent reoxidation of the catalyst reduced in CH(4)/N(2) shows that small and large particle oxidation of Pd degrees starts also at 300 degrees C. Under He, no small particle decomposition is observed probably due to strong interactions between particles and support whereas large particle reduction occurs between 700 and 750 degrees C. After thermal decomposition under He, the oxidation starts at 300 degrees C. Thus, the reduction phenomenon (small and large crystal domain) depends on the nature of the reducing agent (H(2), CH(4), He). However, whatever the reduction or decomposition treatment or the crystal domain, Pd degrees oxidation starts at 300 degrees C and is completed only at temperatures higher than 550 degrees C. Under lean conditions, with or without water, the palladium consists of reduced sites of palladium (Pd degrees , Pd(delta+) with delta < 2 or PdO(x) with x < 1) randomly distributed on palladium particles. PMID- 21279225 TI - pH-responsive luminescent properties of Ag@PPy nanoparticles. AB - We measure the emission spectra and quantum yields of Ag@PPy nanoparticles with different volume ratios of Ag core and PPy shell, and ascribe the emission peaks around 460 and 520 nm, respectively, to the S(1) -> S(0) transition of the PPy molecule, and to the charge transfer between Ag and PPy, as well as the Ag plasmon. The two peaks shift with the changed doping level of the PPy shell, which can be elucidated by consideration of the energy levels of Ag and PPy. According to these results, we investigate the fast and reversible pH-sensing function of Ag@PPy nanoparticles on the basis of the doping effect on the interaction between the Ag core and the PPy shell. PMID- 21279226 TI - Unprecedented gas-phase chiroselective logic gates. AB - The gas-phase encounters between 2-aminobutane and proton-bound chiral resorcin[4]arene/nucleoside complexes behave in the gas phase as supramolecular "chiroselective logic gates" by releasing the nucleoside depending on the resorcin[4]arene and the 2-aminobutane configurations. PMID- 21279227 TI - Efficient solid phase strategy for preparation of modified xanthene dyes for biolabelling. AB - An efficient solid phase strategy for the versatile functionalisation of xanthene dyes for conjugation and labelling of biomolecules is presented. The low cost, high purity and excellent spectral properties of the obtained materials provide an attractive alternative for the labelling of a wide range of molecules. PMID- 21279228 TI - Efficient iron-mediated approach to pyrano[3,2-a]carbazole alkaloids--first total syntheses of O-methylmurrayamine A and 7-methoxymurrayacine, first asymmetric synthesis and assignment of the absolute configuration of (-)-trans dihydroxygirinimbine. AB - Iron-mediated oxidative cyclisation provides an efficient approach to pyrano[3,2 a]carbazole alkaloids. Thus, improved routes to girinimbine and murrayacine as well as the first total syntheses of O-methylmurrayamine A and 7 methoxymurrayacine are reported. Asymmetric epoxidation of girinimbine led to (-) trans-dihydroxygirinimbine and the assignment of its absolute configuration. PMID- 21279229 TI - Synthetic biology themed issue. PMID- 21279230 TI - Access to highly active and thermally stable iron procatalysts using bulky 2-[1 (2,6-dibenzhydryl-4-methylphenylimino)ethyl]-6-[1-(arylimino)ethyl]pyridine ligands. AB - Ethylene polymerization was performed using a series of 2-[1-(2,6 dibenzhydrylphenylimino)ethyl]-6-[1-(arylimino)ethyl]pyridyliron(II) chlorides with the activity in the range of 10(7) g PE mol(-1) (Fe) h(-1), which is the highest observed in iron procatalysts at elevated reaction temperatures such as 80 degrees C in the presence of MMAO and 60 degrees C in the presence of MAO, without any trace of ethylene oligomerization. PMID- 21279231 TI - Singlet-triplet energy gap of a diarylnitroxide diradical by an accurate many body perturbative approach. AB - We report on the calculation of the spin-spin coupling term J in a diarylnitroxide diradical system which is a slightly simplified version of a recently synthesized stable species with a triplet ground state. We have applied our complementary space perturbative approach using virtual orbitals appropriately modified with the aim of investigating, through molecular fragmentation, the effects of the non-bridge aryls. We show how by using multireference CI techniques it is now possible to obtain accurate and reliable values of J even for large organic radicals, the basic units of longer chain polyradical systems. PMID- 21279232 TI - The effect of solvent on the catalytic properties of microperoxidase-11. AB - The effect of a range of solvents on the catalytic oxidation of methyl phenyl sulfide to methyl phenyl sulfoxide by MP-11 and by a cyclodextrin derivative of MP-11 was examined. The addition of low concentrations of alcohols enhanced the initial rate of sulfoxidation, most likely due to dispersion of MP-11 aggregates. Higher alcohol concentrations resulted in a decrease in activity arising from solvation of the hydrophobic sulfide, disrupting binding to the catalyst. In alcohols, the yield of product was decreased due to increased rates of MP-11 deactivation via the formation of aldehydes (for primary alcohols) or by peroxide based deactivation. The catalytic activity of the cyclodextrin modified MP-11 was similar to that of MP-11 itself, demonstrating that it is the N-terminal side of MP-11 which is the determinant of catalytic activity. PMID- 21279233 TI - Optical waveguides at micro/nanoscale based on functional small organic molecules. AB - Optical waveguides synthesized at the micro/nanoscale have drawn great interest for their potential applications in high speed miniaturized photonic integrations. In this Perspective article, we mainly focus on the related works on active optical waveguides based on functional small organic molecules in micro/nano regime. We begin with a general overview of recent progress in sub wavelength optical waveguides, including the development of waveguide materials of inorganic semiconductors, polymers, and small organic molecules. Then brief highlights are put on the recently reported organic optical waveguides with various unique optical properties induced by the ordered molecular aggregations in the micro/nano-sized solid-state structures, such as polarized emission, lasing, aggregation-induced enhanced emission, etc. This article concludes with a summary and our personal view about the direction of future development in organic opto-functional waveguides as photonic devices. PMID- 21279234 TI - A new floating electrode structure for generating homogeneous electrical fields in microfluidic channels. AB - In this article a new parallel electrode structure in a microfluidic channel is described that makes use of a floating electrode to get a homogeneous electrical field. Compared to existing parallel electrode structures, the new structure has an easier production process and there is no need for an electrical connection to both sides of the microfluidic chip. With the new chip design, polystyrene beads suspended in background electrolyte have been detected using electrical impedance measurements. The results of electrical impedance changes caused by beads passing the electrodes are compared with results in a similar planar electrode configuration. It is shown that in the new configuration the coefficient of variation of the impedance changes is lower compared to the planar configuration (0.39 versus 0.56) and less dependent on the position of the beads passage in the channel as a result of the homogeneous electrical field. To our knowledge this is the first time that a floating electrode is used for the realization of a parallel electrode structure. The proposed production method for parallel electrodes in microfluidic channels can easily be applied to other applications. PMID- 21279235 TI - Improved evaluation of measurement uncertainty from sampling by inclusion of between-sampler bias using sampling proficiency testing. AB - A realistic estimate of the uncertainty of a measurement result is essential for its reliable interpretation. Recent methods for such estimation include the contribution to uncertainty from the sampling process, but they only include the random and not the systematic effects. Sampling Proficiency Tests (SPTs) have been used previously to assess the performance of samplers, but the results can also be used to evaluate measurement uncertainty, including the systematic effects. A new SPT conducted on the determination of moisture in fresh butter is used to exemplify how SPT results can be used not only to score samplers but also to estimate uncertainty. The comparison between uncertainty evaluated within- and between-samplers is used to demonstrate that sampling bias is causing the estimates of expanded relative uncertainty to rise by over a factor of two (from 0.39% to 0.87%) in this case. General criteria are given for the experimental design and the sampling target that are required to apply this approach to measurements on any material. PMID- 21279236 TI - Photosensitive azobispyridine gold(I) and silver(I) complexes. AB - The neutral and cationic dinuclear gold(I) compounds [(MU-N-N)(AuR)(2)] (N-N = 2,2'-azobispyridine (2-abpy), 4,4'-azobispyridine (4-abpy); R = C(6)F(5), C(6)F(4)OC(12)H(25)-p, C(6)F(4)OCH(2)C(6)H(4)OC(12)H(25)-p) and [(MU-N N){Au(PR(3))}(2)](CF(3)SO(3))(2) (N-N = 2-abpy, 4-abpy, R = Ph, Me) have been obtained by displacement of a weakly coordinated ligand by an azobispyridine ligand. The corresponding silver(I) dinuclear [(MU-2 abpy){Ag(CF(3)SO(3))(PPh(3))}(2)] and polynuclear [{Ag(CF(3)SO(3))(4-abpy)}(n)] compounds have been obtained. The molecular structures of [(MU-2 abpy){Au(PPh(3))}(2)](CF(3)SO(3))(2) and [(MU-4 abpy){Au(PMe(3))}(2)](CF(3)SO(3))(2) have been confirmed by X-ray diffraction studies and feature linear gold(I) centers coordinated by pyridyl groups, and non coordinated azo groups. In contrast the X-ray structure of [(2 abpy){Ag(CF(3)SO(3))(PPh(3))}(2)] shows tetracoordinated silver(I) centers involving chelating N-N coordination by pyridyl and azo nitrogen atoms. The gold(I) compounds with a long alkoxy chain do not behave as liquid crystals, and decompose before their melting point. The soluble gold(I) derivatives are photosensitive in solution and isomerize to the cis azo isomer under UV irradiation, returning photochemically or thermally to the most stable initial trans isomer. The silver(I) derivative [(2-abpy){Ag(CF(3)SO(3))(PPh(3))}(2)] also photoisomerizes in solution under UV irradiation, showing that its solid state structure, which would block isomerization by azo coordination, is easily broken. These processes have been monitored by UV-vis absorption and (1)H NMR spectroscopy. All these compounds are non-emissive in the solid state, even at 77 K. PMID- 21279237 TI - High-valent iron and manganese complexes of corrole and porphyrin in atom transfer and dioxygen evolving catalysis. AB - Manganese(V) imido complexes of 5,10,15-tris(pentafluorophenyl)corrole (H(3)tpfc) can be prepared by the reaction of Mn(III)(tpfc) and organic nitrene generated from either photolytic or thermal activation of organic azides. The terminal imido complexes of manganese(V) were among the first structurally characterized examples of Mn(V) terminal imido complexes in the literature. They feature a short Mn=N triple bond and a nearly linear M[triple bond, length as m-dash]N-C angle. The ground state of (tpfc)Mn(V)(NAr) is singlet. Contrary to expectations, arylimido complexes of manganese(V) were stable to moisture and did not undergo [NR] group transfer to olefins. Manganese(V) imido corrole with an activated tosyl imido ligand was prepared from iodoimine (ArINTs) and manganese(III) corrole. The resulting complex (tpfc)Mn(NTs) is paramagnetic (S = 1), hydrolyzes to (tpfc)Mn(O) in the presence of water, abstracts hydrogen atoms from benzylic C H bonds, and catalyzes aziridination of alkenes. Mechanistic studies on the aziridination and hydrogen atom transfer reactions are reviewed. This perspective also describes the reaction chemistry of the heme enzyme chlorite dismutase, the mechanism by which dioxygen is formed on a single-metal site, and recent advances in functional modelling of this enzyme. We also compare the reactivity of water soluble iron versus manganese porphyrins towards the chlorite anion. PMID- 21279238 TI - A highly ordered mesostructured material containing regularly distributed phenols: preparation and characterization at a molecular level through ultra-fast magic angle spinning proton NMR spectroscopy. AB - Highly ordered organic-inorganic mesostructured material containing regularly distributed phenols is synthesized by combining a direct synthesis of the functional material and a protection-deprotection strategy and characterized at a molecular level through ultra-fast magic angle spinning proton NMR spectroscopy. PMID- 21279239 TI - The role of tautomers in the UV absorption of urocanic acid. AB - Tautomeric effects in the UV-absorption of trans-urocanic acid in the gas phase are investigated by means of quantum chemical calculations of sixteen tautomers at different levels, followed by absorption cross section simulations. It is shown that several trans tautomers give significant contributions to the total spectrum and that cis tautomers should not contribute to the spectrum at room temperature. The spectra of tautomers protonated at the N1 site of the imidazole ring are strongly red shifted in comparison to the spectra of tautomers protonated at the N3 site. As a consequence, excitation of the first absorption band at different wavelengths produces very different tautomeric populations. This effect helps to explain specific features observed in dispersion emission spectroscopy as well as the anomalous photophysics of urocanic acid. PMID- 21279240 TI - Nanoscale changes induce microscale effects in Turing patterns. AB - A water-in-oil microemulsion loaded with a reaction-diffusion chemical system (Belousov-Zhabotinsky reaction) is able to exhibit Turing patterns that are believed to be responsible for differentiation processes in Nature. Using polymers, such as polyethylene oxide, longer than the droplet size changes the distribution of droplets due to cluster formation. This difference in the nanoscale has relevant consequences in the observed the Turing pattern's wavelength, which is three orders of magnitude larger than the droplet size. PMID- 21279241 TI - Simultaneous detection of two lung cancer biomarkers using dual-color fluorescence quantum dots. AB - Quantum dots (QDs) have the potential to simplify the performance of multiplexed analysis. In this work, a novel protocol for performing a simultaneous dual protein immunoassay, i.e. two lung cancer biomarkers, carcinoembryonic antigen (CEA) and neuron-specific enolase (NSE), based on dual-color QDs, is described. First, two capture antibodies (both with biotin tags), two antigens and two detection antibodies were mixed together and the sandwich complexes were thus formed in the homogeneous solution, and then streptavidin coated polystyrene beads were directly added into the resultant system. Bead aggregation can be made self-limiting by controlling the shaker speed during the immunoassay. A distinct transition occurs between limited and complete aggregation as a function of the shaker speed during the immunoassay. Second, dual-color QDs with emission maxima at 525 and 655 nm were added after washing and reacted with the corresponding detection antibodies. Third, the bead-QD conjugates were dissociated in the dissociation buffer and then free QDs were directly used for the fluorescence detection of CEA and NSE. The results show that CEA and NSE could be sensitively determined with a common 96-well fluorescence plate reader and with equal detection limits down to the 1.0 ng mL(-1) level. Within the calibrated amount, the protocol had excellent precision within 0.53% for each target and was comparable in performance to commercial single-analyte ELISAs. Furthermore, the proposed method has been successfully applied to the determination of dual markers in real samples without cross-reaction, and a good correlation was achieved after comparison with the conventional assay for CEA and NSE in 25 human serum samples. PMID- 21279242 TI - Electrochemical polymerization of aniline over tetracyanoquinodimethane encapsulated ormosil matrix: application in the electrocatalytic oxidation of ascorbic acid and acetylthiocholine. AB - Organically modified sol-gel glass (ormosil) matrix is utilized as a template for the electrochemical polymerization of aniline. The ormosil matrix is further modulated by encapsulation of: (a) tetracyanoquinodimethane (TCNQ), and (b) tetracyanoquinodimethane together with palladium (Pd). The presence of tetracyanoquinodimethane within ormosil matrix considerably influences the polymerization process of aniline and the same is significantly enhanced as compared to that of control. The presence of palladium within ormosil network further influence the polymerization process as compared to that of TCNQ only. The polyaniline obtained as PAni-TCNQ and PAni-TCNQ-Pd composites has been utilized for fabricating the modified electrodes. These modified electrodes are used to study the electrochemical sensing of ascorbic acid and acetylthiocholine. The results based on cyclic voltammetry, differential pulse voltammetry and amperometry justify that the electrode material exhibits excellent electrocatalytic activity for the oxidation of ascorbic acid and acetylthiocholine with major findings as compared to the control: (1) a negative shift to the order of ~340 mV vs. Ag/AgCl in the anodic overpotential for the electro-oxidation of ascorbic acid, (2) a significant increase in the anodic peak current for the oxidation of ascorbic acid, (3) an increase in the sensitivity of ascorbic acid analysis to the order of 7-fold for the modified electrodes, (4) acetylthiocholine undergoes direct oxidation with considerable increase in both anodic and cathodic peak currents and (5) an increase in the sensitivity of acetylthiocholine analysis to the order of 5-fold for the modified electrodes. PMID- 21279243 TI - Construction and use of a library of bona fide heparins employing 1H NMR and multivariate analysis. AB - In contrast to most pharmaceutical agents, the major anticoagulant agent, heparin, lacks a uniquely defined chemical structure. It is an inherently structurally varying, poly-disperse polymer, rendering quality control problematic. Structural modifications introduced during manufacture and the presence of possible contaminants are dangers. The comparison of any heparin test sample to a library of bona fide, but intrinsically variable heparins, is limited fundamentally to measuring the degree of similarity between them. A general approach for constructing a suitable illustrative heparin library employing (1)H NMR and multivariate analysis, is proposed and examples shown. Heparin samples contaminated with non-N-acetylated, persulfated, non-glycosaminoglycan carbohydrates (10%) were detected, some of which would not be easily detected under current regulatory guidelines. The ability to identify contaminated heparin is fundamentally dependent on the contents of the library, which should contain all the 'normal' variability within 'heparin'. Oversulfated chondroitin sulfate can be detected (~5%) (using components 1 and 2, but is detectable at 3% using additional components, e.g. 1 and 5) analysing the full spectrum and at <1% if only the N-acetyl region is used. Signals arising from oxidation during the manufacturing processes can also be found. The design, properties and limitations of this approach are discussed. Assembly of such a library of market heparin can be termed the 'Current Statistical Definition of Heparin' (CSDH) and will form the basis of future quantitative methods. PMID- 21279244 TI - High-sensitivity visualisation of contaminants in heparin samples by spectral filtering of 1H NMR spectra. AB - A novel application of two-dimensional correlation analysis has been employed to filter (1)H NMR heparin spectra distinguishing acceptable natural variation and the presence of foreign species. Analysis of contaminated heparin samples, compared to a dataset of accepted heparin samples using two-dimensional correlation spectroscopic analysis of their 1-dimensional (1)H NMR spectra, allowed the spectral features of contaminants to be recovered with high sensitivity, without having to resort to more complicated NMR experiments. Contaminants, which exhibited features distinct from those of heparin and those with features normally hidden within the spectral mass of heparin could be distinguished readily. A heparin sample which had been pre-mixed with a known contaminant, oversulfated chondroitin sulfate (OSCS), was tested against the heparin reference library. It was possible to recover the (1)H NMR spectrum of the OSCS component through difference 2D-COS power spectrum analysis of as little as 0.25% (w/w) with ease, and of 2% (w/w) for more challenging contaminants, whose NMR signals fell under those of heparin. The approach shows great promise for the quality control of heparin and provides the basis for greatly improved regulatory control for the analysis of heparin, as well as other intrinsically heterogeneous and varied products. PMID- 21279245 TI - [Human papillomavirus genotyping of cervical uterine preneoplastic lesions in a high risk area]. AB - BACKGROUND: The relationship between human papillomavirus (HPV) and uterine cervical cancer (UCC) is widely known and accepted. AIM: To determine the frequency of genotypes of HPV in cervical preneoplastic lesions in a high risk area of UCC. MATERIAL AND METHODS: Using a combination of PCR and Reverse Line Blot technique, 235 formalin fixed paraffin embedded samples, with diagnosis of low-grade squamous intraepithelial lesion (LSIL) or high-grade squamous intraepithelial lesion (HSIL) were genotyped. RESULTS: HPV was detected in 61.2% of LSIL and 78.1% of HSIL. The main genotypes found were HPV 16, 18, 31, 45, 56 y 58. HPV 16 was the most common in both LSIL (18.1%) and HSIL (36.9%). HPV 16 or 18 were present in 25.1% and 47.1% of the LSIL and HSIL respectively. In both LSIL and HSIL, the predominant viral genotypes were those types classified as with a high oncogenic risk. CONCLUSIONS: HPV genotypes 16, 18, 31, 45, 56 y 58 were the most common in our series. HPV 16 and 18, viral types with high oncogenic risk and included in commercial vaccines, were found in 25.1% and 47.1% of LSIL and HSIL, respectively. PMID- 21279246 TI - [Heart auscultatory assessment of pulmonary artery systolic pressure]. AB - BACKGROUND: The clinical assessment of pulmonary artery systolic pressure (PASP) by means of heart auscultation may be comparable to the measures obtained by Doppler echocardiography. AIM: To compare PASP estimated by heart auscultation and echocardiography. MATERIAL AND METHODS: Thirty consecutive patients aged 70 +/- 16 years (68% women) were evaluated prospectively, all of whom had an echocardiogram requested by their attending physician. Echocardiographic evaluation of PASP was made by tricuspid regurgitation velocity plus right a trial pressure estimate. Two trained clinicians, blinded for the clinical history and rest of physical examination, auscultated the patients. PASP was estimated from the auscultatory intensity of the pulmonary component in comparison to the aortic component of the second heart sound and its propagation towards the apex, in accordance to a pre-established algorithm. Correlation between auscultatory and echocardiographic measures of PASP was made by Pearson test. Variability between both methods and among observers was evaluated with Bland-Altman analysis. RESULTS: Fifty two per cent of patients were hypertensive and 20% diabetic. Admission diagnoses were heart failure in 50% of cases, exacerbation of chronic obstructive pulmonary disease in 20%, pulmonary thromboembolism in 10% and other clinical entities in 20%. A significant correlation was found between auscultatory and echocardiographic estimation of PASP (r = 0.64, p = 0, 01). Bland-Altman analysis showed a mean difference between both determinations of 7.6 +/- 7.6 mmHg. Bland-Altman analysis between both operators showed an average difference of 5.4 +/- 8.4 mm Hg. CONCLUSIONS: Heart auscultatory evaluation allows a precise and reproducible estimation of PASP and compares favorably with echocardiographic assessment. PMID- 21279247 TI - [Mortality due to gallbladder cancer: retrospective analysis in three Chilean hospitals]. AB - BACKGROUND: Chile has the highest gallbladder cancer (GBC) death rate world-wide, affecting mainly Southern areas of the country. AIM: To compare the survival of GBC patients treated in hospitals located in areas with low and high risk for GBC. MATERIAL AND METHODS: Medical records of all patients with GBC admitted to one public hospital located in southern Chile, a public hospital and a private clinic, both located in Metropolitan Santiago, were reviewed. Cases were analyzed by age, sex, stage at diagnosis, ethnicity, socioeconomic status (SES) and rural residence. Survival was calculated using Kaplan Meier method. RESULTS: A total of 598 cases (469 women), were analyzed. No differences in age or sex among hospitals were detected. At the moment of diagnosis, 75, 50 and 44% of cases from the hospital in southern Chile, the public hospital in Santiago and the private clinic in Santiago, were in stage IV, respectively. Five years survival was lower in the public hospital in southern Chile than in the public hospital in Santiago (10.7 and 14.4% respectively, p < 0.05) but not statistically different from the figure at the private clinic in Santiago (13.0%). However, when adjusting for stage at the moment of diagnosis, no difference in survival between the three hospitals, was found. The median days of survival were 1,559, 188, 70 and 69 for stages I, II, III and IV respectively. CONCLUSIONS: GBC mortality is high. The stage at the moment of diagnosis is only significant predictor of survival. PMID- 21279248 TI - [Frequency of obesity and overweight among school age children living in southern Chile]. AB - BACKGROUND: The frequency of obesity is increasing steadily in Chile. AIM: To assess the prevalence of obesity and overweight in children and teenagers living in three southern Chilean cities. MATERIAL AND METHODS: The database of an evaluation performed in 2006 in schools, was used to obtain weight and height of 32514 subjects aged 12 +/- 4 years (48% males). Criteria proposed by the International Obesity Task Force (IOTF) and the Centers for Disease Control (CDC) were used to define obesity and overweight. RESULTS: According to CDC criteria the prevalence of overweight and obesity was 11.2% and 6.5%, respectively. According to IOTF criteria, the fgures were 13.2 and 4%, respectively. The higher frequency of overweight and obesity was observed among children aged less than eight years. CONCLUSIONS: There is a high frequency of obesity and overweight in the studied sample. PMID- 21279249 TI - [Anthropometry as predictor of gestational diabetes mellitus]. AB - BACKGROUND: Gestational diabetes mellitus (GDM) is a high incidence disease. Easily measured predictor factors could help to implement preventive policies and early detection tests. AIM: To measure recognizable risk factors for GDM such as skinfolds and analyze the association between these factors and the development of GDM in a cohort of pregnant women. MATERIAL AND METHODS: Evaluation of 76 mothers that developed gestational diabetes, aged 32.2 +/- 0.6 years and 324 control mothers that did not develop the disease, aged 30.1 +/- 0.3 years. Weight, height, arm circumference, tricipital, bicipital, subscapular, suprailiac, knee, costal and mid-thigh skinfolds were measured in the pre diseased stage. History of diabetes, fasting glucose and insulin levels were also evaluated. RESULTS: Age, body mass index (BMI), fasting blood glucose, the homeostasis model assessment of insulin resistance (HOMA), bi-cipital, tricipital, costal, subscapular, suprailiac, and knee skinfolds were associated with GDM development. Age, fasting blood glucose and subscapular skinfolds were independent predictors in the logistic regression model. The odds ratio for a subscapular skinfold over percentile 90 was 1.7 (95% confdence intervals: 1.07 3.04). CONCLUSIONS: Age and fasting blood glucose are independent risk factors for GDM. Subscapular skinfold is also an independent risk factor and could be used to detect high risk pregnant women and implement preventive policies. PMID- 21279250 TI - [Waist height ratio, ultrasensitive c reactive protein and metabolic syndrome in children]. AB - BACKGROUND: Waist to height ratio and ultrasensitive C-reactive protein are predictors of the presence of the metabolic syndrome in children. AIM: To determine the proportional risk of metabolic syndrome component clustering in children, using waist to height ratio and ultrasensitive C-reactive protein. MATERIAL AND METHODS: Anthropometric measures, blood pressure, fasting serum lipid profile, blood glucose and ultrasensitive C-reactive protein were determined in 209 children aged 11.5 +/- 2 years (50% females). The presence of the metabolic syndrome as a function of waist to height ratio and C-reactive protein was modeled using logistic regression equations. The risk of clustering one, two or more components of the metabolic syndrome was calculated. RESULTS: Metabolic syndrome was present in 5% of all children and 18% of those that were obese. The cut off points for waist to hip ratio and ultrasensitive C-reactive protein were 0.55 and 0.61 mg/L, respectively. For each 0.01 increment in waist to height ratio, the odds ratio of increasing one component of the metabolic syndrome was 1.2 (1.15-1.25) or 15 to 25%. The odds ratio for log-transformed ultrasensitive C-reactive protein was 1.62 (1.26-2.09). Excluding waist circumference, the odds ratio of adding one or more components of the metabolic syndrome was 1.05 (1.01-1.09) per 0.01 increment in waist to height ratio, but the odds ratio for C-reactive protein was no longer significant. CONCLUSIONS: Waist to height ratio and ultrasensitive C-reactive protein predict the risk of clustering components of the metabolic syndrome in these children. PMID- 21279251 TI - [Muscle dysmorphia, body image and eating behaviors in two male populations]. AB - BACKGROUND: Muscle dysmorphia or vigorexia is a disorder in which a person becomes obsessed with the idea that he or she is not muscular enough. AIM: To assess physical exercise, eating behaviors and the presence of muscle dysmorphia among weightlifters and medical students. SUBJECTS AND METHODS: Cross sectional evaluation of 88 male weightlifters aged 27 +/- 7 years and 84 male medical students aged 22 +/- 1 year was made. Eating behaviors were evaluated using the Eating Attitudes Test (EAT-40) and the Eating Disorders Inventory (EDI). The perception of body image was assessed using the Graduate Hannover Scale (GHS). RESULTS: Prevalence of muscle dysmorphia among weightlifters was 13.6%. Both groups did not differ in body dissatisfaction. Interest in appearance among weightlifters was significantly higher than in students and ranged significantly higher in EAT-40 and EDI (p < 0.001). Other sports were practiced with the same frequency by weightlifters and students. Weightlifters expended more time than students exercising to improve their appearance (p < 0.005). Forty two percent of weightlifters with muscle dysmorphia displayed abuse of anabolics and 67% used other substances to improve their performance (p < 0.005). CONCLUSIONS: The presence of muscle dysmorphia among weightlifters was confirmed. They were dissatisfied with their body image and more concerned with their physical appearance than those without muscle dysmorphia and/or students. Their anabolic abuse rate was high. Our findings were similar to those reported in the international literature. PMID- 21279252 TI - [Hypothetical health and economic benefits associated with a reduction in air pollution in a Chilean city (Talca)]. AB - BACKGROUND: Environmental air pollution is associated with a higher incidence of respiratory diseases, absenteeism and costs. AIM: To model the health related economic benefits associated to a reduction in air pollution and the resulting lower prevalence of respiratory diseases, in a Chilean city. MATERIAL AND METHODS: A time series model for year 2006 was elaborated. The dependent variable was the number of consultations for respiratory disease. The independent variables were air pollution expressed as particulate matter of 10 micrometers or less (PM10), minimum and maximum environmental temperatures, environmental humidity and number of consultations for chronic diseases. RESULTS: The variables that best explained the number of consultations for respiratory diseases were PM10, minimal environmental temperatures and preexisting respiratory diseases. In a hypothetical scenery of a 67% reduction in PM10, 69% of medical consultations for respiratory diseases would be avoided. This would result in a net saving of US$ 345,000 per year. CONCLUSIONS: The reduction in PM10 emissions would result in an important reduction in consultations for respiratory diseases and monetary savings. PMID- 21279253 TI - [Adverse cutaneous reactions to drugs among hospitalized patients: a one year surveillance]. AB - BACKGROUND: Adverse cutaneous reactions to Drugs (CDRs) are of particular interest among all adverse Drug reactions (ADR) due to their frequency, potential severity and because of the importance of an early diagnosis. Antimicrobial agents, anticonvulsants and non-steroidal anti-inflammatory Drugs are the Drugs associated to the highest risk of CDRs. AIM: To assess CDRs in hospitalized patients and identify the Drugs involved. MATERIAL AND METHODS: All patients hospitalized in the Hospital de Clinicas in Montevideo, Uruguay, with suspected CDRs, detected during one year, were included in this prospective study. The imputability was established using the Karch and Lasagna algorithm modified by Naranjo. We analyzed age, gender, Drugs involved, causal disease, severity, latency and evolution. RESULTS: Seventeen patients, aged 17 to 85 years (15 females) with CDRs were identifed. Twelve had morbilliform exanthemas, four had reactions with eosinophilia and systemic symptoms and one had a Stevens Johnson syndrome. The Drugs involved were antimicrobials in nine cases, hypouricemic agents in four cases, anticonvulsants in three cases and aspartic insulin in one. Twelve patients had a life threatening reaction and one required admission to the intensive care unit. No deaths occurred. CONCLUSIONS: CDRs were more common in women and most of them were caused by antimicrobial agents. PMID- 21279254 TI - [Orthostatic tremor causing postural instability in Parkinson disease: report of one case]. AB - Parkinson disease (PD) is a movement disorder characterized clinically by the variable combination of rigidity, bradykinesia, rest tremor and postural instability. Usually postural instability is a late-onset manifestation and is frequently associated with axial manifestations and with a poor prognosis. We report a 67-year-old female with orthostatic tremor as the etiology of her postural instability. The patient was treated with increasing doses of clonazepam, reaching 2 mg/day, and levodopa. There was an improvement of postural instability with a good response of parkinsonian symptoms. PMID- 21279255 TI - [Bone hydatidosis: report of five patients and review of the literature]. AB - Bone location of hydatid cysts occurs in 0.5 to 3% of all cases of hydatidosis. The most common bones involved are spine, long bones and pelvis. We report five patients with bone hydatidosis. A 24-year-old male consulting for paraparesis and numbness of lower limbs; CAT scan showed hydatid cysts located in D2, D3 and D4 vertebral bodies. A 47-year-old male consulting for a fracture of the femur; X rays disclosed multiple hydatid cysts in the femur. A 13-year-old female consulting for claudication of the right lower limb; X ray examination showed a hydatid cyst in the iliac bone. A 21-year-old women presenting with weakness of the lower limbs and voiding problems; CAT scan showed a vertebral hydatidosis and spinal cord compression. A 67-year-old female presenting with weakness of the lower limb and loss of sphincter control; CAT scan showed hydatid cysts in D4 vertebral body. PMID- 21279256 TI - [Hairy cell leukemia during pregnancy: report of one case]. AB - Hairy cell leukemia (HCL) is a rare chronic B cell lymphoproliferative disorder that affects mostly men. It usually presents with pancytopenia, splenomegaly and bone marrow infiltration, without lymphadenopathy. Diagnosis is based on the presence of mononuclear cells with cytoplasmic projections in a blood smear, the typical bone marrow infiltration pattern and the immunophenotypic profile. HCL occurs seldom in young women and even more exceptionally during pregnancy. We report a 31-year-old woman in whom a splenomegaly was detected during routine prenatal care. Pancytopenia with 25% of hairy cells was found in her blood count. The patient was subjected to an open splenectomy and had an uneventful pregnancy. After two years of follow up, she has a normal blood count and has not required chemotherapy. PMID- 21279257 TI - [Thyrotoxic hypokalemic periodic paralysis: report of one case]. AB - Thyrotoxic hypokalemic periodic paralysis is characterized by attacks of generalized weakness associated to hypokalemia in patients with hyperthyroidism. We report a 25-year-old man with a history of spontaneously relapsing episodes of muscular weakness, who consulted for a rapidly evolving upper and lower limb paresis. Hypokalemia associated to a primary hyperthyroidism was detected. Treatment with antithyroid Drugs and potassium supplementation reverted symptoms and the episodes of acute muscular weakness did not reappear. PMID- 21279258 TI - [Psychiatric and cognitive problems associated to hepatitis C and its treatment with interferon]. AB - This article is a literature search about the psychopathology related to hepatitis C and its treatment with interferon. An overview of the methodology of the available studies is presented. New theories for a better understanding and diagnosis of the psychiatric alteration associated to hepatitis C or interferon treatment are proposed, to improve future research. We discuss neurobiological aspects, clinical manifestations, psychosocial features and pharmacotherapy of the psychiatric manifestations of hepatitis C and its treatment with interferon. PMID- 21279259 TI - [PET/CT in lung cancer]. AB - Metabolic imaging studies are an integral part of oncology practice, particularly with 18 fuorodeoxyglucose PET scanning. Lung cancer is one of the primary indications of a PET/CT study. It is helpful in staging, evaluating treatment response and follow-up of these patients. The recent development of PET/CT, which incorporates a multislice CT scanner to the PET detector, improves results, combining metabolic information from the PET with anatomic data obtained with CT. It reduces false positive results from PET in cases of inflammatory disease such as pneumonia or Drug reactions, which are frequent in this group of patients. These conditions are easily recognized by CT. It also improves the detection of primary tumors, when they are adjacent to atelectasis or desmoplastic reactions. PET-CT studies are able to characterize the metabolism of mediastinal and hilar lymph nodes, thus obviating the need for further related imaging studies or invasive procedures. In the assessment of metastatic disease, it allows a whole body analysis in only one study, with high predictive value and optimal cost benefit relation. The detection of a second primary tumor is not infrequent in these patients. PET-CT is useful in the evaluation of treatment response after chemotherapy, and for the long term follow-up. PMID- 21279260 TI - [Scientific journals of medical students in Latin-America]. AB - This article deals with the history and evolution of student's scientific journals in Latin-America, their beginnings, how many still exist and which is their future projection. Relevant events show the growth of student's scientific journals in Latin-America and how are they working together to improve their quality. This article is addressed not only for Latin American readers but also to worldwide readers. Latin American medical students are consistently working together to publish scientific research, whose quality is constantly improving. PMID- 21279261 TI - [The possible causes of the tragedy of "Port Famine" in the Strait of Magellan]. AB - The attempts to colonize the Strait of Magellan soon followed the discovery of this route. PeDro Sarmiento de Gamboa, a Spanish sailor, established human settlements to fortify those lands and control the transit of vessels, especially those of English corsairs, which devastated Chilean and Peruvian coasts. During the summer of 1584, approximately 500 soldiers, artisans, priests, women and children established two villages called "Nombre de Jesus" and "Rey Don Felipe". From the beginning, these settlers had leadership and communication problems and difficulties to obtain food. After three winters only 17 to 18 people survived according to the testimony of one of the survivors, that was rescued by an English sailor named Cavendish, which renamed the village "Rey Don Felipe" as "Port Famine". When he observed the scenes of abandonment and death, he supposed that the settlers died due to lack of food. Other factors that facilitated the desolation were hypothermia, execution, anthropophagy and lesions caused by natives. There is also a possibility that intoxication by red tide (harmful algal bloom) could explain in part the finding of unburied corpses in the strait beaches. PMID- 21279262 TI - [Arterial cerebral and coronary gas embolism]. PMID- 21279263 TI - [Family oriented primary care: a proposal to improve the health of all]. PMID- 21279264 TI - [Political will and scientific evidence in the UK: Long-term friendship or temporary dialogue?]. PMID- 21279265 TI - [Physical activity and cardiovascular risk factors among Chilean young men and women]. AB - BACKGROUND: Physical activity (PA) has a protective role in cardiovascular diseases. AIM: To quantify PA in young adults and to correlate it with cardiovascular risk factors. MATERIAL AND METHODS: A cross-sectional study was performed employing the international physical activity questionnaire (IPAQ), to measure the PA of 983 randomly selected young adults from Valparaiso region born between 1974 and 1978. Its results were associated with levels of obesity, insulin resistance and cardiovascular risk factors defined by the National Cholesterol Education Program-Adult Treatment Panel III (NCEP- ATP III) RESULTS: Mean physical activity among men and women was 3731 +/- 3923 and 1360 +/- 2303 METs-minutes/week, respectively (p < 0.001). Fifty percent of women and 21.5% of men had an insufficient level of physical activity (p < 0.001). Sixty percent of men and 23.4% of women had an intense level of physical activity (p < 0.001). There was an inverse association of physical activity and insulin resistance. A high physical activity was protective, specially among men, against a low HDL cholesterol level and high triglyceride levels with Odds Ratios of 0.59 (confidence interval (CI): 0,35-0.98) and 0.49 (CI: 0,27-0,87) respectively, after adjusting for body mass index and age. CONCLUSIONS: In this sample, men had higher levels of physical activity, that was protective against insulin resistance and the presence of cardiovascular risk factors. PMID- 21279266 TI - [Effects of psychological support as an adjunct to a weight reducing program among obese children]. AB - BACKGROUND: Disrupted eating behaviors and psychological issues can have a role in the development of childhood obesity. AIM: To assess the effects of psychological support as an adjunct to the treatment of obesity among children. MATERIAL AND METHODS: Retrospective analysis of a group of 152 obese children aged 3 to 16 years, who received medical, Nutritional and physical training treatment. Seventy three (Group I) were invited to participate in a protocol of psychological support and 79 formed the control group (Group 2). Body mass index, body fat mass, waist circumference, insulin sensitivity, lipid profile, eating and physical activity habits were evaluated. Family structure, history of food rejection, psychological, physical and social development, and adherence to the program were also analyzed. To analyze responses to treatment, Group I was further divided into those who attended the psychology sections (intervened group) and those who did not attend (non intervened group). RESULTS: At baseline, there were no differences in anthropometric, metabolic, familial and psychological profile among Groups I and 2. Family structure, eating behaviors and physical and social development were normal. Those associated with lack of control appeared as negative characteristics. There was a significant improvement in eating habits and physical activity among intervened children of Group 1 and Group 2. No significant change in weight was recorded in all three groups. Compliance with the program was significantly better among intervened children in Group 1 (62.1% at sixth months), compared with non intervened children of Group 1 (15.9%) and Group 2 (30.3%). CONCLUSIONS: Obese children who attended psychological support therapy as an adjunct to a weight reducing program, had a better compliance with treatment but did not achieve a higher weight loss. PMID- 21279267 TI - [Association between a cardiovascular risk score and early markers of atherosclerotic disease in Chilean children]. AB - BACKGROUND: A cardiovascular risk score for children, that includes traditional risk factors, obesity, sedentary habits and a family history of cardiovascular disease, has been recently proposed by Spanish researchers. AIM: To apply this score in school age children in Santiago de Chile and correlate its results with markers of subclinical atherosclerotic disease. MATERIAL AND METHODS: Retrospective analysis of data obtained from 209 children, aged 11.5 +/- 2 years, studied between 2005 and 2006. Weight, height, blood pressure, ultrasound measurement of carotid intimamedia thickness and fow mediated dilatation of brachial artery and ultrasensible C reactive protein (us PCR) were measured. The Spanish cardiovascular risk score was calculated and correlated with ultrasound parameters and C reactive protein. RESULTS: According to the score, 173 children (83%) had a low cardiovascular risk, 28 (13%) an intermediate risk and 8 (4%) a high risk. There was no association between the cardiovascular risk score and carotid intima-media thickness, fow mediated arterial dilatation and us PCR. CONCLUSIONS: No significant association was observed between the proposed cardiovascular risk score and early markers of atherosclerotic disease in this group of children. PMID- 21279268 TI - [Levels of physical activity in an urban population from Temuco, Chile]. AB - BACKGROUND: Physical activity plays a crucial role in the protection against cardiovascular diseases. AIM: To assess the level of physical activity in a group of subjects living in urban Temuco. MATERIAL AND METHODS: Cross sectional study in a random sample of 1091 women aged 52 +/- 10 years and 444 men aged 54 +/- 10 years , living in Temuco, Chile. The level of physical activity was measured using the long form of the International Physical Activity Questionnaire (IPAQ). Age, gender, educational and socioeconomic level were also determined in study subjects. RESULTS: Median energy expenditure was 2150 and 1600 MET-minute/ week in men and women, respectively (p = 0,001). It decreased with age from a median of 1965 MET-minute/ week in those younger than 50 years old to 1647 MET-minute/ week among subjects aged between 51 and 60 years old and to 1485 MET-minute/ week among those older than 60 years. (p = 0,001). The frequency of high, moderate and low physical activity levels were 15.6, 66 and 18.4 % respectively. These levels were associated with gender, age, educational and socioeconomic level. CONCLUSIONS: There was a high frequency of low and moderate levels of physical activity in the urban population of Temuco, associated with female gender, advanced age and middle socioeconomic level. PMID- 21279269 TI - [Association between motherhood postponement and socioeconomic status]. AB - BACKGROUND: Delayed motherhood is a common phenomenon in the developed world, where the age at first delivery is around 30 years. In Chile the National Institute of Statistics established that this age has remained around 23 years for more than two decades. Motherhood postponement may be modulated by socioeconomic status. AIM: To determine whether the age at first delivery is higher in a private clinic compared to a public hospital. PATIENTS AND METHODS: Two cohorts of primiparous women delivering in 1998 and 2008 in the public hospital San Borja Arriaran (HSBA) and a private setting Clinica Las Condes (CLC), were analyzed. RESULTS: The age of all delivering women was significantly lower in HSBA than in CLC in both study periods (26.3 +/- 0.8 and 25.7 +/- 0.9 compared to 31.6 +/- 0.1 and 32.7 +/- 0.1 years, respectively). Likewise, the frequency of adolescent pregnancy was significantly higher in HSBA than CLC in both study periods (38.8 and 42.2% compared to 1.7 and 1.6% respectively). The age at first delivery was significantly lower in both periods in HSBA (21.8 and 21.3 years compared to 28.6 and 30.6 years, respectively). Excluding primiparous women of less than 20 years, the difference in age was smaller, but remained still significant (24.6 and 24.2 versus 29.9 and 31.0 years, respectively). CONCLUSIONS: In Santiago, the postponement of motherhood is more marked among women of high socioeconomic status. PMID- 21279270 TI - [Effects of glycine on auditory evoked potentials among diabetic patients with auditory pathway neuropathy]. AB - BACKGROUND: Glycine inhibits the formation of advanced glycation end products that may cause central and peripheral neuronal damage, affecting also the auditory nerve. AIM: To evaluate the effect of glycine on auditory nerve conduction and hearing level among patients with type 2 diabetes mellitus and auditory neuropathy. MATERIAL AND METHODS: Twenty grams of oral glycine per day were administered during 6 months to 28 type 2 diabetic patients aged 58 +/- 6 years, with auditory pathway neuropathy. Hearing tests and evoked otoacustic potentials were performed regularly. Fifteen diabetic patients aged 49 +/- 8 years, without auditory nerve neuropathy did not receive glycine and were followed as a control group. RESULTS: Among patients receiving glycine, a significant improvement in left ear audiometry at 125, 250 and 500 Hz and right ear audiometry at 500 Hz, was observed. Waves I, III and V (p= 0.02) of evoked otoacustic potentials improved significantly in the left ear and wave I in the right ear. Among controls, waves V and III of evoked otoacoustic potentials had a significant impairment in the left ear. CONCLUSIONS: There was an improvement in auditory evoked potentials in patients receiving glycine and an impairment in untreated control patients. PMID- 21279271 TI - [Mortality trend from liver cirrhosis in Chile from 1990 to 2007]. AB - BACKGROUND: There is a worldwide tendency towards a reduction in the rates of deaths due to cirrhosis. In Chile, a decrease in the number of hospital admissions due to this disease has been recorded. AIM: To assess general characteristics and temporal evolution of liver cirrhosis mortality in Chile between 1990 and 2007. MATERIAL AND METHODS: National death records and population databases were reviewed. Crude and age-adjusted mortality rates for alcoholic and non-alcoholic cirrhosis were calculated, evaluating their evolution in the study period and the relative risk by gender. RESULTS: In the study period, 44,894 deaths caused by cirrhosis were recorded. Mortality rate was 16.6 deaths per 100,000 inhabitants. 54% of deaths were attributed to non-alcoholic cirrhosis. There was a reduction in mortality rates for both types of cirrhosis. Males accounted for 83 and 65% of deaths caused by alcoholic and non-alcoholic cirrhosis, respectively. The figures for relative risk of death were 5 and 1.9, respectively. CONCLUSIONS: Alcoholic cirrhosis was the preponderant cause among liver cirrhosis deaths. A decrease in mortality rates was observed in the study period. Improvements in disease treatment and control could possibly explain this trend. PMID- 21279272 TI - [Tumor necrosis factor-alpha and interleukin-6 levels among patients suffering a bile duct injury during cholecystectomy]. AB - BACKGROUND: During cholecystectomy, the bile duct may be injured. When this complication occurs, Kupffer cells are activated and produce tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL6) to phagocyte toxic products AIM: To measure serum levels of TNF-alpha and IL-6 among patients that suffered a bile duct injury after a cholecystectomy. PATIENTS AND METHODS: Serum levels of TNF alpha and IL-6 were measured prior to the bile-enteric derivation and after one year of follow up, in 31 patients that had a complete bile duct obstruction after open or laparoscopic cholecystectomy and in 5 healthy controls. RESULTS: At baseline TNF-alpha levels in healthy subjects and patients with bile duct injury were 0 and 43.9 +/- 2.9 ng/mL, respectively (p < 0.01). At one year of follow up, TNF-a became undetectable among patients. At baseline, the values for IL-6 among healthy controls and patients were 3.0 +/- 2.0 and 72.0 +/- 94.7 pg/mL respectively, (p < 0,004). After one year of follow up, IL-6 levels decreased to 6.4 +/- 0.3 pg/mL among patients. CONCLUSIONS: TNF-alpha and IL-6 levels were elevated before bile-enteric derivation among patients with bile duct injury and became normal one year later. PMID- 21279273 TI - [Central pontine myelinolysis after liver transplantation. Report of five cases]. AB - BACKGROUND: Central Pontine Myelinolysis (CPM) is the most severe neurological complication after liver transplantation and apparently is not related to changes in osmolarity. AIM: To report five transplanted patients with CPM. PATIENTS AND METHODS: In a series of 27 patients subjected to liver transplantation between 2005 and 2008, we found five patients who developed CPM. RESULTS: All patients presented a severe hepatic encephalopathy. In the absence of alterations in osmolality, they developed, between the second to seventh day after transplantation, a central quadriplegia, hyperreflexia and Babinski sign, with preservation of sensorium. Magnetic resonance imaging showed demyelination of the motor pathway only in the protuberance. Motor recovery first began in the fingers and hands, followed by forearms, toes, feet, arms and finally the legs, defining a somatotopic recovery of the cortico-spinal pathway. CONCLUSIONS: This form of regaining motility shows that the selective involvement of the pyramidal tract in CPM, is according to its location in the pons and suggests a local entrapment. It is due to the structural rigidity of the protuberance that limits the expansive requirements of cytotoxic and vasogenic edema, and only affects the long fibers of cortico-spinal tracts, sensitized by encephalopathy. The entrapment syndromes generally preserve the axons, injure myelin and have no inflammatory reactions. PMID- 21279274 TI - [Tuberculous spondylodiscitis. Report of six patients]. AB - BACKGROUND: Tuberculous spondylodiscitis is relatively uncommon but represents the most common location of osseous tuberculosis. AIM: To describe clinical features, imaging studies and laboratory tests to establish the diagnosis in a group of patients living in Cadiz (Spain). MATERIAL AND METHODS: Retrospective analysis of medical records of patients with tuberculous spondylodiscitis diagnosed between 2000 and 2009. The diagnosis was based on microorganism recovery from vertebral samples obtained by imaging guided biopsies. RESULTS: Six patients with positive Mycobac-terium tuberculosis cultures from vertebral samples, were identified (10% of extra-pulmonary tuberculosis). In only 2 patients the Ziehl-Nielsen stain was positive, and histology was compatible in 4 cases. Four patients were females, their mean age was 54.3 years and the mean duration of symptoms was 7.3 months. Three patients had lumbar location and a positive Mantoux test. A soft tissue abscess was present in 4 cases. None of these patients had neurological complications. The treatment with four tuberculostatic agents (isoniazid, rifampicin, pyrazinamide and ethambutol) was effective in 5 patients. CONCLUSIONS: Tuberculous spondylodiscitis may become a serious disease due to diagnostic and treatment delays. The main examinations to establish diagnosis are magnetic resonance imaging and biopsy with microbiological culture. Generally, antituberculous therapy is effective in this clinical situation. PMID- 21279275 TI - [Celiac disease presenting as an intestinal intussusception: report of one case]. AB - Acute abdominal pain caused by perforation, intestinal lymphoma or intussusception is an uncommon manifestation in adult celiac disease. We report a 49 year-old female with history of irritable bowel syndrome and osteoporosis consulting for acute abdominal pain and severe abdominal distention. Abdominal CT scan and magnetic resonance imaging showed a jejunal intussusception and other radiological alterations that suggested the possibility of celiac disease. Serological antibodies (endomysial and transglutaminase antibodies), endoscopy and the pathological study of duodenal biopsies confirmed the diagnosis. With a gluten free diet, the patient remains asymptomatic. PMID- 21279276 TI - [Acquired reactive perforating collagenosis: report of two cases]. AB - Acquired reactive perforating collagenosis is a perforating dermatosis characterized by transepidermal elimination of collagen. It is frequently associated to diabetes mellitus and chronic renal insufficiency, but it is also related to other systemic diseases. The lesions tend to resolve once the underlying condition is treated. We report two patients with the condition. A 65 year-old diabetic female on hemodialysis consulted for multiple itching cutaneous ulcers lasting one year. On physical examination, hyperpigmented papules and nodules were observed. A 65 year-old female with chronic renal failure in hemodialysis consulted for itching lesions in hands, forearms and arms. On physical examination, hyperpigmented lesions with ulcers, erosions and crusts were observed. In both cases, the pathological study of the lesions disclosed a reactive perforating collagenosis. PMID- 21279277 TI - [Cognitive impairment probably related to repeated episodes of hypoglycemia. Report of one case]. AB - We report a 78 year-old diabetic woman, treated with gliburide and metformin, consulting in the emergency room for a non fuctuating impairment in consciousness. She had a history of similar episodes in the last two months. A brain CAT scan showed an old putamen lacunar infarction. Noteworthy was the presence of a low glycosilated hemoglobin level of 5.2%. Hypoglycemic medications were discontinued and the patient was discharged in good conditions. After six months of follow up, the patient did not have further episodes of impairment of consciousness. PMID- 21279278 TI - [Origins and situation of phytotherapy in Chile]. AB - Phytotherapy is defined as the use of medicinal plants for therapeutic purposes and it uses a variety of complex vegetal structures. In public health, it is considered a type of alternative medicine, in which auto medication with herbs is common and there is a lack of quality assurance of herbal products. While the World Health Organization is proposing strategies to include complementary and alternative therapies as public health tools, in Chile this type of therapy is emerging. There is a lack of interest and underestimation of conventional medicine towards popular knowledge. At the present time, the Chilean Ministry of Health has recognized 103 plants aiming to promote the use of medicinal plants that are registered and certified, according to the regulations of the National Control System of Pharmaceutical Products. Therefore, health care professionals should be educated about the association between pharmaceutical products and medicinal plants. Consultation systems about Phytotherapy should also be available, information should be provided about where to purchase safe herbal products and publicity about these products should be regulated. PMID- 21279279 TI - [Adipose tissue as an endocrine modulator: hormonal changes associated with obesity]. AB - Adipose tissue not only stores fat, but secretes factors and hormones, which modify the regulation, metabolism and secretion of several other hormones. The objective of this review is to describe the hormonal disorders associated with increased adipose tissue, which acts as a modulator or disruptor of the endocrine physiology, with special reference to cortisol, androgens, growth hormone and thyroid axis, and discuss the implications for the management and treatment of these patients. PMID- 21279280 TI - Hepatitis viruses: not always what it seems to be. AB - The classic hepatotropic viruses, hepatitis A through E, are not the only viral agents able to infect the liver. Other systemic viruses may cause hepatic injury that can range from mild and transient elevation of aminotransferases to acute hepatitis and occasionally acute liver failure and fulminant hepatitis. The clinical presentation may be indistinguishable from that associated with classic hepatotropic viruses. These agents include cytomegalovirus; Epstein-Barr virus; herpes simplex virus; varicella-zoster virus; human herpesvirus 6, 7, and 8; human parvovirus B19; adenoviruses among others. Wide spectrums of clinical syndromes are associated with cytomegalovirus disease. Unique clinical syndromes may present in neonates, young adults and immunocompromised hosts infected with cytomegalovirus. Cases of fulminant hepatitis have been reported in both immunocompromised and immunocompetent hosts infected with Epstein Barr virus. Occasionally, these patients with acute hepatic failure may need liver transplantation. Herpes simplex viruses may involve the liver in neonatal infections, pregnancy, immunocompromised hosts and occasionally, immunocompetent adults. Varicella-Zoster virus has also been associated with severe acute hepatitis and fulminant hepatitis in adults. The drug of choice for these conditions is intravenous acyclovir. These may also need liver transplantation in the more severe forms of clinical presentation. Typical liver biopsy findings can be useful in determining the diagnosis of these viral infections. Human herpesviruses 6, 7, and 8, human parvovirus B19, and adenoviruses can also be present with features of acute liver injury and occasionally as fulminant hepatitis. The clinical syndromes are less well delineated than those associated with herpesviruses. It is important to consider these viruses as possible etiologic agents in patients who have acute liver injury and their serologic markers for the classic hepatotropic viruses are not indicative of an active infection. PMID- 21279281 TI - [Association between vitamin D deficiency and metabolic syndrome]. AB - Vitamin D has an essential role in calcium metabolism and bone health. Vitamin D3 or cholecalciferol is synthesized from 7-dehydrocholesterol or provitamin D3, by sunlight ultraviolet radiation to the skin. 7-dehydrocholesterol is subsequently hydroxylated in the liver and then in the kidney to produce 1,25-(OH)2D3, the active metabolite that binds to specific receptors (VDR) in target tissues, mainly bone and intestine. Other tissues, such as the immune and cardiovascular system, have also VDR. Vitamin D deficiency can induce rickets in children and osteomalacia and osteoporosis in adults. A possible inverse association between vitamin D levels and the prevalence of metabolic syndrome has been proposed. Vitamin D deficiency increases the risk of type 1 diabetes, insulin resistance, and hypertension, key components of this syndrome. However, other studies have not confirmed this association. Further clinical and experimental studies are needed to ascertain the role of vitamin D in metabolic syndrome. PMID- 21279282 TI - [History of gluten and its effects on celiac disease]. AB - The global prevalence of celiac disease is of one person per 250 inhabitants. The disease is induced by gluten, a peptide contained in wheat, rye and barley that during small intestinal digestion generates smaller peptides. Some of these are resistant to hydrolysis and cross through the epithelium into the mucosa, inducing a cascade of immune reactions leading to the appearance of the disease in susceptible individuals. Gluten appeared as a consequence of agricultural practices initiated 10000 years ago in the Fertile Crescent of southwest Asia. Celiac disease epidemiology is complicated since consumption of gluten differs depending on the origin of populations. Treatment of celiac disease consists of withdrawing gluten from the diet, a task that becomes difficult in the long term. The concept of gluten-free food has changed along time. This article updates the concept of celiac disease, the history of gluten consumption in the world, the characteristics of a gluten free diet and the difficulties to adhere to it. PMID- 21279283 TI - [Bisphosphonate-related osteonecrosis of the jaw]. PMID- 21279284 TI - [Kayser-Fleischer ring as a diagnostic sign in medicine]. PMID- 21279285 TI - [Bloodstream infection in a neonatology unit of Medellin-Colombia, 2008-2009]. AB - Bloodstream infection (BSI) is one of the main causes of sepsis and death in newborns. The relative importance of nosocomial and non-nosocomial agents in developing countries is not clear. We conducted a prospective study of newborns hospitalized with a first episode of BSI in order to classify it as early, late or nosocomial, describe the clinical and microbiological characteristics, and explore risk factors between hospital-acquired vs community-acquired BSI (HA-BSI vs CA-BSI). Twenty-seven newborns with a first episode of BSI were identified. Streptococcus agalactiae and coagulase negative Staphylococcus were the main agents in CA-BSI and HA-BSI, respectively. The only significant intrinsic risk factor between HA-BSI and CA-BSI was gestational age. The frequent finding of S. agalactiae warrants routine screening and prophylaxis in pregnant women. The risk factors for HA-BSI were mostly extrinsic, and thus, susceptible of being modified. PMID- 21279286 TI - [Evaluation of an IgG avidity commercial test: contribution to diagnosis of primary infection caused by Toxoplasma gondii]. AB - INTRODUCTION: Toxoplasmosis (T) is a major chronic parasitic infection in immunocompromised patients and pregnant women. It is important to discriminate between acute phase (AT) and chronic phase (CT). Diagnosis is serological in immunocompetent patients (concentration of IgG and IgM). OBJECTIVE: To evaluate the utility of an IgG avidity test (A-IgG) to identify the acute and chronic stage. Avidity is the strength of affinity between a specific immunoglobulin and the protein antigenic epitope of the infecting agent, an affinity that increases over time. PATIENTS AND METHODS: We used a qualitative kit that measures the avidity of IgG, discriminating the two phases. In 35 patients with clinical diagnosis of AT and/or CT, IgG, IgM and IgG A (VIDAS(r)) were performed. RESULTS: Patients with AT were positive for IgM and IgG, but presented weak avidity. In the 21 cases with CT, 52% (n: 11) were IgM positive and 100% (n: 21) had positive IgG with strong avidity. DISCUSSION: The results confirm that the test of A-IgG may be useful in the diagnosis of AT, and has 100% concordance with reference test (qualitative IgM + quantitative IgG). The result is available within 24 hrs, and may be useful in diagnosis of AT in pregnant women. PMID- 21279287 TI - [Acute viral hepatitis during pregnancy]. AB - Acute hepatitis has a very low incidence disease during pregnancy. However, it may be an important cause of jaundice during gestation which in cases of viral etiology can have a very high morbidity and mortality risk to the mother and the fetus. The purpose of this review is to update the available knowledge regarding viral hepatitis during pregnancy including description of the main etiologies, transmission route, maternal-fetal risk and possible management. PMID- 21279288 TI - [Risk analysis of foodborne diseases: microbial risk assessment]. AB - The basic goals of risk assessment include the following: to identify potentially hazardous situations and apply appropriate methods to estimate the likelihood that a hazard occurs. In The uncertainty in that estimate, to provide alternative solutions to reduce the risk, estimate the effectiveness of those solutions, provide information to base a risk management decision, and estimate the uncertainty associated with the analysis. Risk analysis provides the rational framework for assembling and then analysing the evidence relating to risk and presenting the results in a form that is easy to understand and then act upon fairly and effectively. Progress made is no excuse for arrogance. The present review is definitely not designed as the last word on risk analysis for foodborne diseases. Rather, this review has been designed to continue an evolving and necessary process and to provide a reference point that indicates the state of development in 2010. PMID- 21279289 TI - [Ocular syphilis: ten new cases and review of the literature]. AB - INTRODUCTION: Ocular manifestations in patients with syphilis may involve almost any of the structures of the eye. OBJECTIVES: To describe ten new cases of syphilis with eye involvement and to briefly discuss the management and therapy of such condition. MATERIAL AND METHODS: Ten cases were retrospectively studied over 13 years. Demographic factors, ophthalmologic examination, and laboratory tests were assessed. RESULTS: Seven of the 10 cases were male and 3 were female. The mean age of patients was 39,7 years. Disease presentation included: panuveitis (6 patients), optic neuritis (3), retinal vasculitis (1) and Argyll Robertson pupil (1). Cerebrospinal fluid VDRL test was positive in 6 patients and 3 patients were HIV (+). CONCLUSIONS: Syphilis is able to display diverse ophthalmologic manifestations. Not in all the cases the CSF-VDRL test was positive. Antitreponemal therapy generates a fast and effective response in the affected patients. PMID- 21279291 TI - [A nosocomial outbreak of epidemic keratoconjunctivitis]. AB - We describe a nosocomial outbreak of keratoconjunctivitis at the Ophthalmology Clinic in Hospital Carlos Van Buren, that affected 150 patients, during August and September of 2006. This outbreak was concomitant with a community outbreak produced by the same agent in the city of Valparaiso that affected 681 other patients. Although adenovirus was not isolated in the nosocomial cases, positive cultures were obtained from community cases, so the diagnosis was based on clinical and epidemiological criteria. The infection rate within the Clinic patients was 5.2% considering the population that attended the Clinic in this period. The evaluation of patient care practices showed that common risk factors among affected cases were measurement of ocular tension with a tonometer in the Ophthalmology Clinic (without disinfection of the tonometer between patients), contamination of work surfaces (equipment, furniture), and poor compliance of hand hygiene. Control measures adopted were cleaning, disinfection of tonometer, equipment and work surfaces, and reinforcement of hand hygiene measures. With these measures, it was possible to control the nosocomial outbreak, despite the continued outpatient care of community-acquired cases. PMID- 21279292 TI - [Mycobacterium tuberculosis]. PMID- 21279293 TI - [Importance of images and etiological diagnosis of central nervous system involvement in immunocompromised patient]. AB - We report a 16 years old boy with diagnosis of Acute Myeloid Leukemia with severe immune suppression secondary to his primary disease and to leukemia's treatment. Early during the course of his chemotherapy he developed symptoms and signs compatible with invasive fungal disease (IFD). Lungs were primarily compromised followed by CNS involvement with manifestations of intracranial hypertension. Laboratory exams were remarkable for prolonged neutropenia and indirect evidence of Aspergillus sp infection, with successive detection of positive and increasing levels of galactoman antigen in serum. With this case we want emphasize the great importance of invasive fungal disease in immune suppressed patients and particularly the CNS compromise. This represents a medical emergency which deserves to start a complete and comprehensive microbiology diagnosis and concomitantly start an empiric antifungal treatment. The importance of neuroimaging for a correct identification of the number, location and size of CNS lesions must be highlighted. The election of MRI, if available, should be preferred due to a better performance than CT scan. Brain biopsy should be discussed when all the non invasive attempts for etiology identification have failed. The invasive fungal CNS compromise has medical treatment and the surgical drainage has to be considered for lesions greater than 2 cm or for those making a mass effect or have failed with medical treatment. PMID- 21279294 TI - [Detection of expanded-espectrum-betalactamases by DIRAMIC system: comparison with the double-disk synergy test and E-test]. AB - The capacity of the DIRAMIC system to detect strains producing extended-spectrum betalactamase (ESBL) was evaluated through the comparison with two phenotypic confirmatory tests: double-disk synergy test and E-test. Ninety seven clinical isolates of Escherichia coli y Klebsiella spp. previously characterized; not repeated and suspected of being ESBL producers were studied by the three methods. In comparison with E-test and double-disk synergy test, DIRAMIC system showed a sensitivity of 85.7% and 92.7% as well as specificity of 100% and 92.9%; respectively. The values found have a very high degree of concordance (kappa index > 0.80). The results obtained vouch for the utility of the DIRAMIC as a rapid method to alert about the presence of strains producing ESBL enzymes. PMID- 21279295 TI - [Paracoccidioidomicosis and multidrug-resistant tuberculosis (TBC-MDR) in patient coinfected with HIV and hepatitis C]. AB - A case of an adult male patient diagnosed with HIV and Hepatitis C co infection is presented. He had granu-lomatuos hepatitis and blood smear positive to Paracoccidioides brasiliensis concomitant to the detection of MDR Mycobacterium tuberculosis in sputum further complicated with reactivation of cytomegalovirus (possible pancreatitis and retinitis). Difficulties in diagnostic and therapeutic approach in a patient with multiple infections are reviewed. PMID- 21279296 TI - [Retroperitoneal hydatid cyst: a common disease in a rare location]. AB - Echinococcal disease remains a major problem within some endemic areas. We report a case of a single primary echinococcal cyst located in the retroperitoneal space. A 54-year-old woman, born in a rural area of southern Chile, was admitted with a 3-month history of right hip pain and painful swelling of the gluteal region. Hidatid disease was confirmed with serologic test, radiological examinations and histo-pathology. There were no cysts in any other location. A percutaneous drainage was performed and antihelminthics were administered for 12 weeks and is now being closely followed up, with good response to therapy. Especially in the endemic areas hydatid cyst should be considered when evaluating retroperitoneal cystic masses. PMID- 21279297 TI - [Historic memory and commentary about "typhoid fever epidemic at Huar Island": Llanquihue province]. AB - An article by Dr. Carlos Martin in the first published number of the Revista Medica de Chile (1872-73) journal is remembered and commented. It describes an outbreak in Huar Island in Seno de Reloncavi, an estuary located in the Los Lagos Region in Chile, named "typhoid epidemic". The clinical characteristics are presented and two types of diseases are deducted: acute respiratory infections and typhoid fever. PMID- 21279298 TI - [The roles that the environment, the sanitary conditions, the epidemiology and vaccines play in the challenge of infectious diseases]. AB - This commentary uses a recent article in the press about the failure of the Gates Foundation's plans to eradicate poliomyelitis in Asia and Africa as a basis for discussing the often limited historical role that vaccines have played in controlling many infectious diseases when compared to increases in living standards. A recent book on the Epidemic Intelligence Service of the Centers for Disease Control and Prevention, USA, is used to illustrate the importance of epidemiological surveillance and public health laboratories in past and present efforts to control infectious diseases. On the basis of these publications, the author discusses and proposes solutions for some of the shortcomings of the Chilean sanitary services demonstrated when dealing with a recent epidemic of more than 26, 000 cases of acute diarrhea in the Northern Chilean city of Antofagasta. PMID- 21279299 TI - Skin problems of the stump in lower-limb amputees: 2. Influence on functioning in daily life. AB - The aim of this study was to analyse the influence of stump skin problems on functioning in daily life in lower-limb amputees. A cross-sectional study was performed by means of a questionnaire containing 9 questions assessing functioning in daily life. Question scores were added to give a total score (range 0 (no influence) to 27 (maximum negative influence)). Two thousand and thirty-nine people were invited to participate, with 805 participants completing a questionnaire. Of these, 507 reported one or more skin problems. Skin problems had a negative influence on ability to perform household tasks, prosthesis use, social functioning, and participation in sports. The mean total score was 5.5 +/- 4.1. This correlated significantly with the number of skin complaints (r = 0.483; p = 0.01). In linear regression analyses, gender (beta = -0.15) and number of skin problems (beta = 0.25) accounted for 23% of the total score. This study confirms the influence of skin problems on functioning in daily life. PMID- 21279300 TI - Ultraviolet light-induced Kobner phenomenon contributes to the development of skin eruptions in multicentric reticulohistiocytosis. AB - Multicentric reticulohistiocytosis is a rare systemic disease of unknown aetiology characterized by erosive arthritis and cutaneous lesions consisting of multiple reddish-brown papules and nodules, mainly involving the face and distal upper extremities. It has been suggested that skin eruptions in multicentric reticulohistiocytosis are associated with Kobner phenomenon due to their characteristic distribution, such as on the dorsal aspects of the hands and fingers. We report here a case of a Japanese woman with multicentric reticulohistiocytosis, in whom erythematous macules and papules were widely distributed over the face, ears, neck and the V-area of the chest. Notably, repeated irradiation of ultraviolet (UV) B on the uninvolved back skin resulted in the induction of erythematous macules with infiltration of reticulohistiocytes, indicating the association of UVB-induced Kobner phenomenon with the development of skin lesions, especially on the sun-exposed area. This is the first known report demonstrating the contribution of UV-light-induced Kobner phenomenon for the development of skin eruptions in patients with multicentric reticulo-histiocytosis. PMID- 21279301 TI - Haemophagocytosis-related intravascular large B-cell lymphoma associated with skin eruption. PMID- 21279302 TI - Efficacy of thalidomide in the treatment of prurigo nodularis. PMID- 21279303 TI - Rapid resolution of erythema marginatum after icatibant in acquired angioedema. PMID- 21279304 TI - Basophils infiltrate skin lesions of eosinophilic pustular folliculitis (Ofuji's disease). PMID- 21279305 TI - Zosteriform venous malformations with an atypical presentation. PMID- 21279306 TI - Intra-familial variability of ectodermal defects associated with WNT10A mutations. PMID- 21279307 TI - Notalgia paresthetica: successful treatment with exercises. PMID- 21279308 TI - Adeno-associated virus-mediated survivin mutant Thr34Ala cooperates with oxaliplatin to inhibit tumor growth and angiogenesis in colon cancer. AB - Colon cancer is one of the most common cancers. Survivin is overexpressed in human colon cancer and correlate with chemoresistance, angiogenesis and poor prognosis. Oxaliplatin, a platinum derivative cancer drug, has been used for treating human colorectal cancers. In the present study, we investigated the effect of the adeno-associated virus (AAV)-mediated survivin mutant Thr34Ala [rAAV-Sur-Mut(T34A)] on colon cancer growth. Infection with rAAV-Sur-Mut(T34A) inhibited cell proliferation, induced apoptosis and mitotic catastrophe, and sensitized colon cancer cells to chemotherapeutic drugs in vitro. Treatment with rAAV-Sur-Mut(T34A) significantly induced apoptosis, reduced angiogenesis and inhibited colon cancer growth in vivo. More importantly, rAAV-Sur-Mut(T34A) treatment strongly enhanced the anti-tumor activity of oxaliplatin and prolonged animal survival. Thus, the use of rAAV-Sur-Mut(T34A) in combination with chemotherapy may be a promising strategy for colon cancer therapy. PMID- 21279309 TI - Protective role of parnaparin in reducing systemic inflammation and atherosclerotic plaque formation in ApoE-/- mice. AB - Atherosclerosis is a degenerative disease whose role in the onset and development of cardiovascular pathologies and complications is of importance. Due to its silent but progressive development, and considering the endothelial, immunological and inflammatory processes that are involved in its clinical course, this still relatively unknown pathological condition has been and continues to be a matter of investigation worldwide. Our experience with previous studies on atherosclerosis led us to investigate the possible influence of a low molecular weight heparin (LMWH) - Parnaparin(r) on the development and clinical course of atherosclerosis in double knock-out laboratory animals (ApoE-/- mice). Our experiments demonstrated a possible role of Parnaparin (PNP) in the control of atherogenic disease. In fact, in treated mice vs. untreated ones, PNP reduced the number and the size of atherosclerotic lesions in the aortic wall, as well as the development of liver steatosis, which was massive in untreated animals and moderate in treated ones. These preliminary observations require further clinical studies, but demonstrate a possible role of Parnaparin in the control of the development and clinical evolution of atherosclerosis and liver steatosis in laboratory animals. PMID- 21279310 TI - [Graft-versus-Host Disease (GvHD) - an update : Part 1: Pathophysiology, clinical features and classification of GvHD]. AB - GvHD remains associated with significant morbidity and mortality despite new techniques for allogeneic stem cell transplantation (SCT), such as optimized conditioning regimens. Within the past ten years, the incidence of acute GvHD has remained unchanged and the incidence of chronic GvHD has even increased. The traditional classification of GvHD according to the time of clinical manifestation is now out-dated. Acute GvHD symptoms may even occur after 100 days; vice versa, primary chronic GvHD may already be observed one month after stem cell transplantation. The current classification introduced by the National Institutes of Health includes classic acute GvHD (up to 100 days), late-onset acute GvHD (after 100 days), as well as an overlap syndrome showing features of acute and chronic GvHD and classic chronic GvHD without any time limit. Diagnosis of GvHD of the skin remains difficult because of histological similarities to drug eruptions and viral exanthems. In this first part of the article the pathophysiology, classification, skin manifestations of acute and chronic GvHD and the histopathology will be presented. In a second part the prognosis, prophylaxis and therapy of GvHD will be discussed. PMID- 21279311 TI - [Hereditary metabolic diseases with cutaneous manifestations : An update]. AB - Hereditary metabolic diseases are very diverse with variable pathogenetic mechanisms and clinical findings. They can manifest in different organs and, in this respect, dermatologists may play a crucial role in making the right diagnosis if they know to interpret the signs on the skin correctly. Although these are usually rare diseases, the elucidation of the underlying genetic defects has delivered an invaluable contribution to the better pathogenetic understanding of several common diseases over the last years. This is mainly attributable to the fact that the proteins encoded by these genes are often key players within important metabolic signaling pathways of the human organism. We report on new developments in the field of selected porphyria types, hereditary angioedema, pseudoxanthoma elasticum, and hereditary cutaneous leiomyomatosis, all of which constitute a challenge for both dermatologists and other specialists. PMID- 21279312 TI - [Intralabyrinthine schwannoma from a radiological perspective]. PMID- 21279313 TI - [Medical law update. For the period November 2009 to October 2010]. PMID- 21279314 TI - [Posttraumatic arteriovenous fistula of the orbit: a rare differential diagnosis of an orbital complication]. AB - We report the rare case of a posttraumatic intraorbital fistula. The patient was referred to our clinic with a suspected complication of acute sinusitis. The patient reported recurrent swelling of the eyelid with a temporal fluctuation during the day. Eyesight was normal. In the presence of acute rhinogenic infection, computer tomography of the paranasal sinuses demonstrated a shadow on the ethmoid bone and ipsilateral maxillary sinus. Clinical investigation and laboratory parameters excluded an infection. A kick to the head by a horse could be documented on patient interview. By means of angio-MRI an arteriovenous fistula of the orbit could be diagnosed. PMID- 21279315 TI - [Bronchial carcinoma]. PMID- 21279316 TI - [Nosocomial diarrhea]. AB - Hospital acquired or nosocomial diarrhea affects up to one third of hospitalized patients. It increases mortality rates as well as length and costs of the hospital stay. Drug side effects are the predominant cause of nosocomial diarrhea whilst clostridium difficile is the most common infectious agent, whose development is closely linked to antibiotic usage. The causal therapy of mild clostridium difficile infections is controversially discussed. Nevertheless, the use of Metronidazol for mild cases and of vancomycin for severe forms of the disease is recommended. Diarrhea outbreaks might be caused by viruses and less often by Salmonella and Listeria. Norovirus infections are of outstanding importance. Rehydration and isolation to prevent the spread of this highly contagious virus are the only reasonable options as we still lack a proper therapy. PMID- 21279317 TI - [Epidemiology of lung cancer]. AB - In 2005 approximately 45,000 people contracted lung cancer in Germany and at the same time a total of 40,641 patients died from the disease, making lung carcinoma the most frequent cause of tumor death in men. The peak age for the disease is between 70 and 85 years. The main risk factor of inhaling tobacco smoke is responsible for 85% of the cases of lung cancer. There is a direct correlation between the number of cigarettes smoked and the risk of developing lung cancer. Screening programs, e.g., low-dose computed tomography, are currently undergoing clinical assessment worldwide, but at the present time are not yet being comprehensively established. PMID- 21279318 TI - Nuptial coloration of red shiners (Cyprinella lutrensis) is more intense in turbid habitats. AB - Communication is shaped and constrained by the signaling environment. In aquatic habitats, turbidity can reduce both the quantity and quality of ambient light and has been implicated in the breakdown of visual signaling. Here, we examined the relationship between turbidity (quantified with long-term data) and the expression of carotenoid-based nuptial coloration in the red shiner (Cyprinella lutrensis), a small-bodied cyprinid. Males in more turbid habitats displayed redder fins, and an experimental manipulation of adult diet suggested that carotenoid intake alone did not explain among-population color differences. These results run counter to similar studies where signal expression decreased in turbid conditions, and may be explained by the non-territorial red shiner mating system, interactions between the mechanism of coloration and the signaling environment, or reduced cost of color expression in turbid habitats (e.g., reduced predation risk). Our results highlight how the behavioral and ecological contexts in which signals function can shape evolutionary responses to the environment. PMID- 21279319 TI - Body mass dependence of glycogen stores in the anoxia-tolerant crucian carp (Carassius carassius L.). AB - Glycogen is a vital energy substrate for anaerobic organisms, and the size of glycogen stores can be a limiting factor for anoxia tolerance of animals. To this end, glycogen stores in 12 different tissues of the crucian carp (Carassius carassius L.), an anoxia-tolerant fish species, were examined. Glycogen content of different tissues was 2-10 times higher in winter (0.68-18.20% of tissue wet weight) than in summer (0.12-4.23%). In scale, bone and brain glycogen stores were strongly dependent on body mass (range between 0.6 and 785 g), small fish having significantly more glycogen than large fish (p < 0.05). In fin and skin, size dependence was evident in winter, but not in summer, while in other tissues (ventricle, atrium, intestine, liver, muscle, and spleen), no size dependence was found. The liver was much bigger in small than large fish (p < 0.001), and there was a prominent enlargement of the liver in winter irrespective of fish size. As a consequence, the whole body glycogen reserves, measured as a sum of glycogen from different tissues, varied from 6.1% of the body mass in the 1-g fish to 2.0% in the 800-g fish. Since anaerobic metabolic rate scales down with body size, the whole body glycogen reserves could provide energy for approximately 79 and 88 days of anoxia in small and large fish, respectively. There was, however, a drastic difference in tissue distribution of glycogen between large and small fish: in the small fish, the liver was the major glycogen store (68% of the stores), while in the large fish, the white myotomal muscle was the principal deposit of glycogen (57%). Since muscle glycogen is considered to be unavailable for blood glucose regulation, its usefulness in anoxia tolerance of the large crucian carp might be limited, although not excluded. Therefore, mobilization of muscle glycogen under anoxia needs to be rigorously tested. PMID- 21279320 TI - Ultrastructure of spermatozoa of Onthophagus taurus (Coleoptera, Scarabaeidae) exhibits heritable variation. AB - Sperm competition is thought to be an important selective pressure shaping sperm form and function. However, few studies have moved beyond gross examinations of sperm morphology. Sperm length is subject to sexual selection via sperm competition in the scarab beetle Onthophagus taurus. Here, the structure and ultrastructure of spermatozoa in this species were investigated using light and electron microscopy. Spermatozoa were found to be filiform, measuring about 1,200 mm in length. The sperm head consists of a three-layered acrosome and a nuclear region bearing the anterior extension of the centriole adjunct. Acrosome and nuclear regions are bilaterally symmetric, with their axes of symmetry being orthogonal to each other. Head and flagellar structures are connected by a well developed centriole adjunct. The sperm heads are asymmetrically surrounded by accessory material and embedded into the cytoplasm of the spermatocyst cell. The accessory material is produced inside the spermatids and then transferred to the outside due to a new membrane formed around the sperm's organelles. The old spermatid membrane separates the accessory material from the cyst cell. The flagellum contains a 9+9+2 axoneme, two accessory bodies, and two mitochondrial derivatives of unequal size. The major mitochondrial derivative is significantly larger than the minor one. The axoneme is arranged in a sinusoidal manner parallel along the major mitochondrial derivative. The spermatozoa show no progressive motility when released in buffer solution which is likely to be the result of the flagellar arrangement and the structure of the major mitochondrial derivative. The cross-sectional area of the minor and the major mitochondrial derivatives show different patterns of genetic variation. The data provide the first estimates of genetic variation in sperm ultrastructure for any species, and give evidence for the persistence of genetic variation in ultrastructure required for the rapid and divergent evolution that characterizes spermatozoa generally. PMID- 21279321 TI - Histological, chemical, and morphological reexamination of the "heart" of a small Late Cretaceous Thescelosaurus. AB - A three-dimensional, iron-cemented structure found in the anterior thoracic cavity of articulated Thescelosaurus skeletal remains was hypothesized to be the fossilized remains of the animal's four-chambered heart. This was important because the finding could be interpreted to support a hypothesis that non-avian dinosaurs were endothermic. Mammals and birds, the only extant organisms with four-chambered hearts and single aortae, are endotherms. The hypothesis that this Thescelosaurus has a preserved heart was controversial, and therefore, we reexamined it using higher-resolution computed tomography, paleohistological examination, X-ray diffraction analysis, X-ray photoelectron spectroscopy, and scanning electron microscopy. This suite of analyses allows for detailed morphological and chemical examination beyond what was provided in the original work. Neither the more detailed examination of the gross morphology and orientation of the thoracic "heart" nor the microstructural studies supported the hypothesis that the structure was a heart. The more advanced computed tomography showed the same three areas of low density as the earlier studies with no evidence of additional low-density areas as might be expected from examinations of an ex situ ostrich heart. Microstructural examination of a fragment taken from the "heart" was consistent with cemented sand grains, and no chemical signal consistent with a biological origin was detected. However, small patches of cell like microstructures were preserved in the sandstone matrix of the thoracic structure. A possible biological origin for these microstructures is the focus of ongoing investigation. PMID- 21279322 TI - Genetic diversity and structure of a worldwide collection of Phaseolus coccineus L. AB - Phaseolus coccineus L. is closely related to P. vulgaris and is the third most important cultivated Phaseolus species. Little is known about the patterns of its diversity. In this work, a representative collection of its worldwide diversity was initially developed. The collection includes 28 wild forms (WFs) and 52 landraces (LRs) from Mesoamerica (the crop domestication area), and 148 LRs from Europe (where the crop was introduced in the sixteenth century). The collection was studied by using 12 SSR molecular markers that were developed for the P. vulgaris genome. They were proved to be effective and reliable in P. coccineus in this work. Fourteen LRs of P. dumosus (previously identified as a subspecies of P. coccineus) were also studied. The genetic diversity, population structure and phylogenetic relationships were investigated. The results indicate that: (a) the European and Mesoamerican gene pools are clearly differentiated, (b) a certain reduction of diversity occurred with introduction into Europe, and (c) the Mesoamerican LRs (P. dumosus included) and WFs are closely related and are connected by a high gene flow. Inferences on the domestication process of P. coccineus are also presented. This study provides a picture of the genetic diversity distribution and outcomes with introduction into the Old World, which was not available before. It also underlines that the genetic diversity of both WFs and LRs is an important source for Phaseolus spp. breeding programs and deserves to be preserved in situ and ex situ. PMID- 21279323 TI - Homozygous staggerer (sg/sg) mice display improved insulin sensitivity and enhanced glucose uptake in skeletal muscle. AB - AIMS/HYPOTHESIS: Homozygous staggerer (sg/sg) mice, which have decreased and dysfunctional Roralpha (also known as Rora) expression in all tissues, display a lean and dyslipidaemic phenotype. They are also resistant to (high fat) diet induced obesity. We explored whether retinoic acid receptor-related orphan receptor (ROR) alpha action in skeletal muscle was involved in the regulation of glucose metabolism. METHODS: We used a three-armed genomic approach, including expression profiling, ingenuity analysis and quantitative PCR validation to identify the signalling pathway(s) in skeletal muscle that are perturbed in sg/sg mice. Moreover, western analysis, functional insulin and glucose tolerance tests, and ex vivo glucose uptake assays were used to phenotypically characterise the impact of aberrant v-AKT murine thymoma viral oncogene homologue (AKT) signalling. RESULTS: Homozygous and heterozygous (sg/sg and sg/+) animals exhibited decreased fasting blood glucose levels, mildly improved glucose tolerance and increased insulin sensitivity. Illumina expression profiling and bioinformatic analysis indicated the involvement of RORalpha in metabolic disease and phosphatidylinositol 3-kinase-AKT signalling. Quantitative PCR and western analysis validated increased AKT2 (mRNA and protein) and phosphorylation in sg/sg mice in the basal state. This was associated with increased expression of Tbc1d1 and Glut4 (also known as Slc2a4) mRNA and protein. Finally, in agreement with the phenotype, we observed increased (absolute) levels of AKT and phosphorylated AKT (in the basal and insulin stimulated states), and of (ex vivo) glucose uptake in skeletal muscle from sg/sg mice relative to wild-type littermates. CONCLUSIONS/INTERPRETATION: We propose that Roralpha plays an important role in regulation of the AKT2 signalling cascade, which controls glucose uptake in skeletal muscle. PMID- 21279324 TI - Stress index in presence of pleural effusion: does it have any meaning? PMID- 21279325 TI - Non-pulmonary factors strongly influence the stress index. AB - PURPOSE: A quantitative measure of the airway pressure-time tracing during passive inflation [stress index (SI)] has been suggested as an indicator of tidal lung recruitment and/or overinflation. If reliable, this simple index could help guide positive end-expiratory pressure (PEEP) and tidal volume selection. The compartment surrounding the lungs should impact airway pressure and could, therefore, affect SI validity. To explore the possibility, we determined SI in a swine model of pleural effusion (PLEF). METHODS: Unilateral PLEF was simulated by instilling fluid (13 ml/kg-moderate, 26 ml/kg-large) into the right pleural space of five anesthetized, paralyzed, mechanically ventilated pigs. Animals were ventilated with constant flow ventilation: tidal volume (V (T)) 9 ml/kg, f set to end-tidal CO2 (ETCO2) of 30-40 mmHg, inspiratory to expiratory ratio (I/E) 1:2, PEEP 1 or 10 cmH2O. Respiratory system mechanics and computed tomography (CT) were acquired at end-inspiration and end-expiration to determine % tidal recruitment and overinflation. RESULTS: Prior to PLEF instillation, SI values derived at PEEP = 1 and 10 cmH2O were 0.90 and 1.22, respectively. Moderate PLEF increased these SI values to 1.06 and 1.24 and large PLEF further increased SI to 1.23 and 1.27 despite extensive tidal recruitment and negligible overdistention by CT. The initial half of the tidal pressure curve produced SI values (range 0.82-1.17) that were significantly lower than those of the second half (0.98 1.37). CONCLUSIONS: In the presence of pleural fluid, SI indicated overinflation when virtually none was present and tidal lung recruitment predominated. When the extrapulmonary environment is abnormal, caregivers are advised to interpret the SI with caution. PMID- 21279326 TI - Glucose variability measures and their effect on mortality: a systematic review. AB - OBJECTIVE: To systematically review the medical literature on the association between glucose variability measures and mortality in critically ill patients. METHODS: Studies assessing the association between a measure of glucose variability and mortality that reported original data from a clinical trial or observational study on critically ill adult patients were searched in Ovid MEDLINE(r) and Ovid EMBASE(r). Data on patient populations, study designs, glucose regulations, statistical approaches, outcome measures, and glucose variability indicators (their definition and applicability) were extracted. RESULT: Twelve studies met the inclusion criteria; 13 different indicators were used to measure glucose variability. Standard deviation and the presence of both hypo- and hyperglycemia were the most common indicators. All studies reported a statistically significant association between mortality and at least one glucose variability indicator. In four studies both blood glucose levels and severity of illness were considered as confounders, but only one of them checked model assumptions to assert inference validity. CONCLUSIONS: Glucose variability has been quantified in many different ways, and in each study at least one of them appeared to be associated with mortality. Because of methodological limitations and the possibility of reporting bias, it is still unsettled whether and in which quantification this association is independent of other confounders. Future research will benefit from using an indicator reference subset for glucose variability, metrics that are linked more directly to negative physiological effects, more methodological rigor, and/or better reporting. PMID- 21279327 TI - Honokiol rescues sepsis-associated acute lung injury and lethality via the inhibition of oxidative stress and inflammation. AB - PURPOSE: Sepsis has a high mortality rate despite the recent advances in intensive care medicine and antibiotics. Honokiol, a low molecular weight natural product, is known to possess anti-inflammatory activity. Here, we investigate whether honokiol can ameliorate acute lung injury and lethal response in murine models of sepsis. METHODS: Mice were intraperitoneally given vehicle or honokiol 30 min after the induction of sepsis by cecal ligation and puncture (CLP) and endotoxemia by administration of E. coli lipopolysaccharide (LPS). RESULTS: The productions of serum tumor necrosis factor-alpha (TNF-alpha), nitric oxide (NO), and high mobility group box 1 (HMGB 1) were increased in mice during sepsis, which could be reversed by honokiol. Honokiol could also effectively reduce the increased blood lipid peroxidation and nitrotyrosine in septic mice. Honokiol significantly reversed the inductions of inducible NO synthase and nuclear factor kappaB (NF-kappaB) activation in the lungs of mice during sepsis. Honokiol also effectively rescued the lung edema, lung pathological changes, and lethality in septic mice. CONCLUSIONS: These findings suggest that honokiol is capable of suppressing the lethal response and acute lung injury associated with sepsis, and support the potential use of honokiol as a therapeutic agent for the conditions associated with septic shock. PMID- 21279328 TI - Validity and reliability of patient selected goals as an outcome measure in overactive bladder. AB - INTRODUCTION AND HYPOTHESIS: The purpose of this study is to assess the validity of patient goal achievement in overactive bladder (OAB). METHODS: Data were taken from a placebo-controlled randomised trial of transdermal oxybutynin and open label extension study. Face validity was assessed using qualitative analysis. Convergent validity was assessed by comparison with objective symptom improvement. Responsiveness was assessed at 4 s, using the standardised effect size. Reliability was assessed between 4 and 12 weeks of treatment. RESULTS: Ninety-six women were randomised. There were moderate correlations (0.50-0.51) between goal achievement and symptom improvement for urinary urgency and urge incontinence. Mean goal achievement demonstrated good reliability (intraclass correlation = 0.82) but low responsiveness (r = 0.14) between transdermal oxybutynin and placebo-treated groups. CONCLUSIONS: Although patient goals have good face validity and can be reliably measured, they have limited convergence with conventional measures of OAB severity and improvement and low responsiveness. PMID- 21279329 TI - Oxidized low-density lipoprotein and tissue factor are involved in monocrotaline/lipopolysaccharide-induced hepatotoxicity. AB - These studies were aimed at characterizing an animal model of inflammation induced hepatotoxicity that would mimic features of idiosyncratic liver toxicity observed in humans. An attempt was made to identify oxidative damage and the involvement of coagulation system in liver after monocrotaline (MCT) administration under the modest inflammatory condition induced by lipopolysaccharide (LPS) exposure. Mice were given MCT (200 mg/kg) or an equivalent volume of sterile saline (Veh.) po followed 4 h later by ip injection of LPS (6 mg/kg) or vehicle. Mice co-treated with MCT and LPS showed increased plasma alanine aminotransferase (ALT), decrease in platelet number, and a reduction in hematocrit. Accumulation of oxidized low-density lipoprotein (ox LDL) was remarkably higher in the liver sections of mice co-treated with MCT and LPS compared to those given MCT or LPS alone. A similar trend was observed in the expression of CXCL16 receptor in the same liver sections. Elevated expression of tissue factor (TF) and fibrinogen was also observed in the liver sections of MCT/LPS co-treated mice. The in vitro results showed that incubation of HepG2 cells with CXCL16 antibody strongly diminished uptake of ox-LDL. Expression of ox LDL, CXCL16, and TF represents an early event in the onset of hepatotoxicity induced by MCT/LPS; thus, it may contribute to our understanding of idiosyncratic liver injury and points to potential targets for protection or intervention. PMID- 21279330 TI - Pharmacological characterization of adenylyl cyclase isoforms in rabbit kidney membranes. AB - Polycystic kidney disease (PKD) is the most common life-threatening genetic disorder with bilateral cysts caused by increased level of cyclic adenosine 3',5' monophosphate (cAMP). Since adenylyl cyclases (ACs) catalyze cAMP formation, pharmacological characterization of renal AC isoforms is essential. Therefore, we analyzed differences in activation, inhibition, and regulation of AC isoforms in rabbit cortex and medulla membranes. Glucagon, [8-arginine]vasopressin (AVP) and catecholamines significantly activated cortical AC. However, in medulla only glucagon and AVP activated AC. Under Mg(2+) conditions the profile of cortical membrane AC enzyme kinetics and the inhibitory profile of 2'(3')-O-(N methylanthraniloyl) (MANT) nucleotides resembled recombinant AC5. In contrast, the K (i) values of MANT nucleotides for medullary membrane AC and its kinetic properties were similar to those of recombinant AC1. Reverse-transcriptase PCR confirmed the presence of AC1 and AC5 in medulla and cortex, respectively. Cortical AC was sensitive to inhibition by Ca(2+), corroborating the importance of AC5. However, Ca(2+)/CaM dependency specific for AC1 was not found in medulla. In conclusion, according to expression, kinetics and inhibition by MANT nucleotides both parts of the kidney differ in their AC isoforms. Whereas Ca(2+) inhibitable AC5 was confirmed in renal cortex, the initially assumed AC1 activation in medulla could not be confirmed, pointing to the involvement of another AC isoform with some similarity to AC1. Since PKD is characterized by predominant involvement of the collecting duct and the distal nephrons located in renal cortex, AC5 may be the major AC isoform in this part of the kidney where cAMP increases cyst growth. Thus, potent and selective AC5 inhibitors could constitute a novel approach to treat PKD. PMID- 21279331 TI - Effect of dronedarone on Na+, Ca2+ and HCN channels. AB - Previous studies showed that amiodarone causes state-dependent inhibition of Na(+) channels thereby mediating an atrial-selective drug effect. The aim of the present study was to investigate the impact of the new antiarrhythmic compound dronedarone on Na(+), Ca(2+) and hyperpolarization-activated cyclic nucleotide gated ion channels. Monophasic action potentials (MAP) and effective refractory period (ERP) were studied in arterially perfused left atria and ventricular wedge preparations of the pig. Fast Na(+) and Ca(2+) currents in isolated guinea pig ventricular myocytes as well as human HCN4 channels expressed in Chinese hamster ovary (CHO) cells were investigated with the patch-clamp technique. In left atrial epicardial tissue, dronedarone (3 MUM) had no effect on the MAP duration, but the drug caused a significant prolongation of the ERP from 145 +/- 9 to 184 +/- 17 ms (n = 6; p < 0.05). In guinea pig ventricular myocytes, dronedarone exhibited a state-dependent inhibition of the fast Na(+) channel current with an IC(50) of 0.7 +/- 0.1 MUM, when the holding potential (V (hold)) was -80 mV. The maximal block at the highest concentration used was 77 +/- 8%. In contrast, when V (hold) was -100 mV, inhibition with 10 MUM dronedarone was only 9 +/- 3% (n = 7). Dronedarone blocked Ca(2+) currents elicited by rectangular pulses at V (hold) = -40 mV with an IC(50) value of 0.4 +/- 0.1 MUM (maximal block by 10 MUM dronedarone, 80 +/- 6%), whereas at V (hold) = -80 mV, 10 MUM dronedarone blocked only 20 +/- 6% (n = 4) of the current. Applying an action potential clamp (V (hold) = -80 mV) yielded an IC(50) of 0.4 +/- 0.3 MUM. Human HCN4 channels expressed in CHO cells were blocked by dronedarone with an IC(50) of 1.0 +/- 0.1 MUM. Inhibition of fast Na(+) and Ca(2+) channels by dronedarone depends on the cell's resting membrane potential (state-dependent block) favouring an atrial selective mode of action. Besides fast Na(+) and Ca(2+) channels, dronedarone also inhibits HCN4 currents. This might contribute to the clinically observed reduction in heart rate seen in patients in sinus rhythm after dronedarone treatment. PMID- 21279332 TI - Maslinic acid induces apoptosis in salivary gland adenoid cystic carcinoma cells by Ca2+-evoked p38 signaling pathway. AB - Maslinic acid (MA) is a triterpenoid with a high concentration that exists in olives. This natural compound, which has shown multiple biological activities, was proved to be an anti-tumoral agent more recently. We have investigated the mechanisms of MA with regard to its inhibitory effects on the growth of salivary gland adenoid cystic carcinoma (ACC). We demonstrated that MA at 10-100 MUM reduced cell viability in a dose-dependent manner, IC(50) of 43.68 MUM, and 45.76 MUM, respectively in cultured ACC-2 and ACC-M cells. Fifty micromolars of MA efficiently induced apoptosis as indicated by AO/EB staining, electronic microscopy, flow cytometry, and activation of caspase-3 activity. MA induced an elevation of [Ca(2+)](i) in a dose-dependent manner, and cell viability inhibition and cell apoptosis induced by MA were blocked by an intracellular Ca(2+) chelator, BAPTA-AM. The elevation of [Ca(2+)](i) induced by MA was blocked by EGTA or TRPV channel inhibitor suggesting TRPV channel involved in calcium influx induced by MA. MA also activated ERK and p38 MAPK in a time-dependent manner. MA induced cell apoptosis and activation of caspase-3 activity were reversed by SB203580, but not by PD98059, suggesting that the apoptosis induction of MA was via p38 MAPK, but not via ERK. Chelation of intracellular Ca(2+) with BAPTA reversed MA induced p38 MAPK phosphorylation, but SB203580 did not block MA evoked elevation of [Ca(2+)](i), suggesting a Ca(2+)-evoked p38 MAPK signaling involved in MA-induced apoptosis in ACC cells. Taken together, in ACC cells, maslinic acid induced an increase in [Ca(2+)](i), which evoked p38 MAPK phosphorylation, subsequently activated caspase-3 leading to apoptosis. PMID- 21279334 TI - The role of vision, speed, and attention in overcoming directional biases during arm movements. AB - Previous research has revealed directional biases (preferences to select movements in specific directions) during horizontal arm movements with the use of a free-stroke drawing task. The biases were interpreted as a result of a tendency to generate motion at either the shoulder or elbow (leading joint) and move the other (subordinate) joint predominantly passively to avoid neural effort for control of interaction torque. Here, we examined influence of vision, movement speed, and attention on the directional biases. Participants performed the free stroke drawing task, producing center-out strokes in randomly selected directions. Movements were performed with and without vision and at comfortable and fast pace. A secondary, cognitive task was used to distract attention. Preferred directions remained the same in all conditions. Bias strength mildly increased without vision, especially during fast movements. Striking increases in bias strength were caused by the secondary task, pointing to additional cognitive load associated with selection of movements in the non-preferred directions. Further analyses demonstrated that the tendency to minimize active interference with interaction torque at the subordinate joint matched directional biases in all conditions. This match supports the explanation of directional biases as a result of a tendency to minimize neural effort for interaction torque control. The cognitive load may enhance this tendency in two ways, directly, by reducing neural capacity for interaction torque control, and indirectly, by decreasing capacity of working memory that stores visited directions. The obtained results suggest strong directional biases during daily activities because natural arm movements usually subserve cognitive tasks. PMID- 21279333 TI - Effect of methamphetamine dependence on inhibitory deficits in a novel human open field paradigm. AB - RATIONALE: Methamphetamine (MA) is an addictive psychostimulant associated with neurocognitive impairment, including inhibitory deficits characterized by a reduced ability to control responses to stimuli. While various domains of inhibition such as exaggerated novelty seeking and perseveration have been assessed in rodents by quantifying activity in open-field tests, similar models have not been utilized in human substance abusers. We recently developed a cross species translational human open-field paradigm, the human behavior pattern monitor (hBPM), consisting of an unfamiliar room containing novel and engaging objects. Previous work demonstrated that manic bipolar subjects exhibit a disinhibited pattern of behavior in the hBPM characterized by increased object interactions. OBJECTIVES: In the current study, we examined the effect of MA dependence on inhibitory deficits using this paradigm. hBPM activity and object interactions were quantified in 16 abstinent MA-dependent individuals and 18 matched drug-free comparison subjects. The Wisconsin card sorting task (WCST) and the positive and negative syndrome scale (PANSS) were administered to assess executive function and psychopathology. RESULTS: MA-dependent participants exhibited a significant increase in total object interactions, time spent with objects, and perseverative object interactions relative to comparison subjects. Greater object interaction was associated with impaired performance on the WCST, higher PANSS scores, and more frequent MA use in the past year. CONCLUSIONS: Abstinent MA-dependent individuals exhibited impaired inhibition in the hBPM, displaying increased interaction with novel stimuli. Utilization of this measure may enable assessment of inhibitory deficits relevant to drug-seeking behavior and facilitate development of intervention methods to reduce high-risk conduct in this population. PMID- 21279335 TI - Tactile recalibration of auditory spatial representations. AB - In the well-known spatial ventriloquism effect, auditory stimuli are mislocalized towards the location of synchronous but spatially disparate visual stimuli. Recent studies have demonstrated a similar influence of tactile stimuli on auditory localization, which predominantly operates in an external coordinate system. Here, we investigated whether this audio-tactile ventriloquist illusion leads to comparable aftereffects in the perception of auditory space as have been observed previously for audiovisual stimulation. Participants performed a relative sound localization task in which they had to judge whether a brief sound was perceived at the same or a different location as a preceding tactile stimulus ("Experiment 1") or to the left or right of a preceding visual stimulus ("Experiment 2"). Sound localization ability was measured before and after exposure to synchronous audio-tactile stimuli with a constant spatial disparity. After audio-tactile adaptation, unimodal sound localization was shifted in the direction of the tactile stimuli during the preceding adaptation phase in both tasks. This finding provides evidence for the existence of an audio-tactile ventriloquism aftereffect and suggests that auditory space (rather than specific audio-tactile connections) can be rapidly recalibrated to compensate for audio tactile spatial disparities. PMID- 21279336 TI - Static versus dynamic judgments of spatial extent. AB - Research exploring how scanning affects judgments of spatial extent has produced conflicting results. We conducted four experiments on line bisection judgments measuring ocular and pointing behavior, with line length, position, speed, acceleration, and direction of scanning manipulated. Ocular and pointing judgments produced distinct patterns. For static judgments (i.e., no scanning), the eyes were sensitive to position and line length with pointing much less sensitive to these factors. For dynamic judgments (i.e., scanning the line), bisection biases were influenced by the speed of scanning but not acceleration, while both ocular and pointing results varied with scan direction. We suggest that static and dynamic probes of spatial judgments are different. Furthermore, the substantial differences seen between static and dynamic bisection suggest the two invoke different neural processes for computing spatial extent for ocular and pointing judgments. PMID- 21279337 TI - Combination therapy with diltiazem plus CsA/MMF/Pred or CsA/Aza/Pred triple immunosuppressive regimens for use in clinical kidney transplantation in Northwestern China. AB - OBJECTIVE: The effects of diltiazem on 1692 kidney transplant recipients under the immunosuppressive regimen of cyclosporine A (CsA) in combination with either mycophenolate mofetil or azothioprine were assessed. The two treatment groups were compared for blood concentrations of CsA, the extent of acceptable dosage reduction for the maintenance of immunotherapy, potential effects of kidney protection, and promotion of graft function. METHOD: We monitored changes of blood concentrations of CsA in the two different patient treatment groups for post-transplant graft function, episodes of acute rejection, and hepatic and renal toxicity in 1640 renal transplant recipients after treatment with diltiazem. RESULTS: In patients treated with the triple immunosuppressive regimen consisting of CsA, azothioprine, and prednisolone (Pred), the sub-group of patients receiving the diltiazem treatment saw a significantly reduced CsA dosage in comparison to the non-diltiazem group (control group 1) (P < 0.05), but the blood concentrations of CsA of the diltiazem group were higher than those of control group 1 (P < 0.01). Of the patients treated with CsA, mycophenolate mofetil, and Pred, the sub-group of patients also treated with diltiazem showed similar effects: CsA dosage was reduced (P < 0.01) and the blood concentrations of CsA significantly increased (P < 0.01) in comparison with those of control group 2. In addition, recovery time of graft function decreased to 4.7 +/- 1.8 days and 3.9 +/- 1.4 days in the two diltiazem treatment groups, respectively (P < 0.05), and the rate of acute rejection decreased to 21 (p < 0.05) and 7.9% (P < 0.01), respectively. CONCLUSION: In our cohort of renal transplantation patients, co-administration of CsA and diltiazem increased CsA blood concentration, thereby resulting in a reduction in its required dosage treatment, which lightened the patients' economic burden while improving primary and long-term kidney function by promoting the recovery of graft function and decreasing hepatic and renal toxicity. The co-administration of diltiazem may also reduce the rate of acute rejection, especially in patients who also receive the triple immunosuppressive regimen consisting of CsA, mycophenolate mofetil, and Pred. PMID- 21279338 TI - The use of hypnosedative drugs in a university hospital: has anything changed in 10 years? AB - AIM: Our goal was to investigate the use of hypnosedatives (HSs) before and during hospitalization, explore the relationship between their use and various demographic and clinical variables, and compare the results with data from a similar 2000 study with particular interest in adherence to hospital formulary guidelines. METHODS: A cross-sectional observational survey of 326 hospitalized patients recruited from ten wards of the Ghent University Hospital, Gent, Belgium, with a patient interview and by evaluating medical and nursing files. RESULTS: In 30.7% of patients, the use of a HS before admission was reported. According to the patient interview, 33.1% used a HS during hospitalization. However, according to medical and nursing files, use of HSs in the hospital was 10% higher (43.3%). In 19.4% of patients who took HSs before admission, their use was discontinued in the hospital. In 15.6% of patients who took no HS before admission, a HS was started in the hospital, according to the formulary guidelines (data from files). There was a positive correlation between HS use in the hospital and older age, longer hospitalization, not coming from home, higher number of HSs taken before hospitalization, sleeping problems emerging during hospitalization, and central nervous system (CNS) disorders. In comparison with 2000, we registered a slight decrease in HS use during hospitalization and a decrease in the number of newly started patients. CONCLUSIONS: The prevalence of HS use in our university hospital is high, mostly as a result of continuation of HSs started before admission, as there seems to be no general policy of active cessation. Compared with the survey performed 10 years ago, fewer hospitalized patients are newly started on HSs, and when this is the case, the formulary guidelines are followed. PMID- 21279339 TI - Atypical Shone's complex diagnosed by echocardiography. AB - Shone's complex is a rare and severe type of congenital left-sided obstructive lesion of multiple cardiovascular levels. This report aims to present the authors' experience diagnosing atypical Shone's complex using echocardiography. Atypical Shone's complex was diagnosed for 38 consecutive patients (18 boys and 20 girls, ages 1 day to 15 years) using echocardiography. All the diagnoses were confirmed by cardioangiography, surgery, or both. Among the congenital left-sided obstructive lesions, four levels of obstruction coexisted in 3 cases (7.9%), three levels in 10 cases (26.3%), and two levels in 25 cases (65.8%). Supra annular mitral stenosis caused by a supravalvular mitral ring was diagnosed in 1 case. Mitral valvular stenosis was diagnosed in 24 cases including a parachute mitral valve (4 cases), a double-orifice mitral valve (1 case), and partly fused thickened mitral valvular leaflets (19 cases). Subaortic stenosis was diagnosed in 10 cases including circumferential membranous subaortic stenosis (1 case), tunnel-type subaortic narrowing (2 cases), and asymmetric obstructive fibrous ridge below the aortic valve (7 cases). Aortic stenosis was diagnosed in 25 cases including the bicuspid aortic valve (12 cases), the hypoplasia aortic annulus (3 cases), and partly fused or thickened tri-leaflet aortic valves (10 cases). Supra aortic stenosis was diagnosed in 6 cases including the localized type (4 cases) and the diffused type (2 cases). Coarctation of the aorta was diagnosed in 26 cases. Of these, focal coarctation was described in 15 cases, long segment coarctation in 7 cases, and dysplastic isthmus and/or descending aorta in 4 cases. Secondary changes in Shone's complex manifested as left atrial dilation (26 cases), left ventricular hypertrophy (26 cases), and pulmonary hypertension (19 cases). Echocardiography plays an important role in the diagnosis of atypical Shone's complex, in comprehensive evaluation of the number, position, morphology, and severity of left-sided obstructions. PMID- 21279340 TI - Mechanism of cardioprotection: what can we learn from females? AB - This review examines the mechanism of estrogen signaling in cardiomyocytes, with an emphasis on mechanisms that might be important in cardioprotection. It investigates estrogen signaling mediated by the nuclear estrogen receptors alpha and beta and the G-protein-coupled receptor (GPR 30/GPER). Estrogen signaling via nitric oxide and the PI3K pathway are discussed. PMID- 21279341 TI - Spica MRI after closed reduction for developmental dysplasia of the hip. AB - Spica MRI is a fast and effective tool to assess morphology after closed reduction for developmental dysplasia of the hip (DDH) without the need for sedation. The multiplanar capabilities allow depiction of coronal and axial reduction of the hips. Due to MRI's inherent ability to delineate soft tissue structures, both intrinsic and extrinsic obstacles to failed reduction may be identified. Technical and interpretative challenges of spica MRI are discussed. PMID- 21279342 TI - Fibrous hamartoma of infancy mimicking teratoma in the parapharyngeal space on multidetector row CT. AB - To the best of our knowledge, fibrous hamartoma of infancy (FHI) mimicking teratoma presenting in the parapharyngeal space has not been reported to date. We present one case of this tumour and describe its characteristic findings on multidetector-row CT (MDCT). This case is of interest in that the parapharyngeal space was involved and the mass mimicked teratoma on MDCT. We present the MDCT findings and briefly review the relevant literature. PMID- 21279343 TI - Adsorption and decolorization kinetics of methyl orange by anaerobic sludge. AB - Adsorption and decolorization kinetics of methyl orange (MO) by anaerobic sludge in anaerobic sequencing batch reactors were investigated. The anaerobic sludge was found to have a saturated adsorption capacity of 36 +/- 1 mg g MLSS(-1) to MO. UV/visible spectrophotometer and high-performance liquid chromatography analytical results indicated that the MO adsorption and decolorization occurred simultaneously in this system. This process at various substrate concentrations could be well simulated using a modified two-stage model with apparent pseudo first-order kinetics. Furthermore, a noncompetitive inhibition kinetic model was also developed to describe the MO decolorization process at high NaCl concentrations, and an inhibition constant of 3.67 g NaCl l(-1) was estimated. This study offers an insight into the adsorption and decolorization processes of azo dyes by anaerobic sludge and provides a better understanding of the anaerobic dye decolorization mechanisms. PMID- 21279344 TI - A thermostable feruloyl-esterase from the hemicellulolytic bacterium Thermobacillus xylanilyticus releases phenolic acids from non-pretreated plant cell walls. AB - A gene (Tx-est1) encoding a thermostable feruloyl-esterase was isolated from the genome of the gram-positive hemicellulolytic thermophilic bacterium Thermobacillus xylanilyticus. This gene contains an open reading frame of 1,020 bp encoding a protein with molecular mass of 37.4 kDa, similar to feruloyl esterases from cellulolytic bacteria and fungi. The recombinant enzyme Tx-Est1 was expressed and produced in Escherichia coli. Tx-Est1 contains the conserved putative lipase residues Ser 202, Asp 287, and His 322 which act as catalytic triad in its C-terminus part. Purified Tx-Est1 was active against phenolic acid derivatives and stable at high temperatures. Optimal activity was observed at 65 degrees C and the optimal pH was around 8.5. The kinetic parameters of the esterase were determined on various substrates. The enzyme displayed activity against methyl esters of hydrocinnamic acids and feruloylated arabino xylotetraose, exhibiting high specificity and affinity for the latter. Our results showed that Tx-Est1 is a thermostable feruloyl-esterase which could be useful to hydrolyze arabinoxylans from graminaceous plant cell walls as the enzyme is able to release phenolic acids from a lignocellulose biomass. PMID- 21279345 TI - Growth and polyhydroxybutyrate production by Ralstonia eutropha in emulsified plant oil medium. AB - Polyhydroxyalkanoates (PHAs) are natural polyesters synthesized by bacteria for carbon and energy storage that also have commercial potential as bioplastics. One promising class of carbon feedstocks for industrial PHA production is plant oils, due to the high carbon content of these compounds. The bacterium Ralstonia eutropha accumulates high levels of PHA and can effectively utilize plant oil. Growth experiments that include plant oil, however, are difficult to conduct in a quantitative and reproducible manner due to the heterogeneity of the two-phase medium. In order to overcome this obstacle, a new culture method was developed in which palm oil was emulsified in growth medium using the glycoprotein gum arabic as the emulsifying agent. Gum arabic did not influence R. eutropha growth and could not be used as a nutrient source by the bacteria. R. eutropha was grown in the emulsified oil medium and PHA production was measured over time. Additionally, an extraction method was developed to monitor oil consumption. The new method described in this study allows quantitative, reproducible R. eutropha experiments to be performed with plant oils. The method may also prove useful for studying growth of different bacteria on plant oils and other hydrophobic carbon sources. PMID- 21279346 TI - Evaluation of promoters for gene expression in polyhydroxyalkanoate-producing Cupriavidus necator H16. AB - Five kinds of promoters were evaluated as tools for regulated gene expression in the PHA-producing bacterium Cupriavidus necator. Several broad-host-range expression vectors were constructed by which expression of a reporter gene gfp was controlled by P(lac), P(tac), or P(BAD) derived from Escherichia coli, or promoter regions of phaC1 (P(phaC)) or phaP1 (P(phaP)) derived from C. necator. Then, the gfp-expression profiles were determined in C. necator strains harboring the constructed vectors when the cells were grown on fructose or soybean oil. P(lac), P(tac), P(phaC), and P(phaP ) mediated constitutive gene expression, among which P(tac) was the strongest promoter. lacI-P(tac) was not thoroughly functional even after addition of isopropyl-beta-D-thiogalactopyranoside (IPTG), probably due to inability of C. necator to uptake IPTG. Gene expression by araC P(BAD) could be regulated by varying L-arabinose concentration in the medium, although P(3HB) production rate was slightly decreased in the recombinant. phaR P(phaP) exhibited an expression profile tightly coupled with P(3HB) accumulation, suggesting application of the vector harboring phaR-P(phaP ) for gene expression specific at the PHA-biosynthesis phase. The properties of these promoters were expected to be useful for effective engineering of PHA biosynthesis in C. necator. PMID- 21279347 TI - Synthesis of polyhydroxyalkanoate from palm oil and some new applications. AB - Polyhydroxyalkanoate (PHA) is a potential substitute for some petrochemical-based plastics. This biodegradable plastic is derived from microbial fermentation using various carbon substrates. Since carbon source has been identified as one of the major cost-absorbing factors in PHA production, cheap and renewable substrates are currently being investigated as substitutes for existing sugar-based feedstock. Plant oils have been found to result in high-yield PHA production. Malaysia, being the world's second largest producer of palm oil, is able to ensure continuous supply of palm oil products for sustainable PHA production. The biosynthesis and characterization of various types of PHA using palm oil products have been described in detail in this review. Besides, by-products and waste stream from palm oil industry have also demonstrated promising results as carbon sources for PHA biosynthesis. Some new applications in cosmetic and wastewater treatment show the diversity of PHA usage. With proper management practices and efficient milling processes, it may be possible to supply enough palm oil-based raw materials for human consumption and other biotechnological applications such as production of PHA in a sustainable manner. PMID- 21279348 TI - Formation of new polyhydroxyalkanoate containing 3-hydroxy-4-methylvalerate monomer in Burkholderia sp. AB - Burkholderia sp. synthase has been shown to polymerize 3-hydroxybutyrate (3HB), 3 hydroxyvalerate, and 3-hydroxy-4-pentenoic acid monomers. This study was carried out to evaluate the ability of Burkholderia sp. USM (JCM 15050) and its transformant harboring the polyhydroxyalkanoate (PHA) synthase gene of Aeromonas caviae to incorporate the newly reported 3-hydroxy-4-methylvalerate (3H4MV) monomer. Various culture parameters such as concentrations of nutrient rich medium, fructose and 4-methylvaleric acid as well as harvesting time were manipulated to produce P(3HB-co-3H4MV) with different 3H4MV compositions. The structural properties of PHA containing 3H4MV monomer were investigated by using nuclear magnetic resonance and Fourier transform infrared spectroscopy (FTIR). The relative intensities of the bands at 1,183 and 1,228 cm-1 in the FTIR spectra enabled the rapid detection and differentiation of P(3HB-co-3H4MV) from other types of PHA. In addition, the presence of 3H4MV units in the copolymer was found to considerably lower the melting temperature and enthalpy of fusion values compared with poly(3-hydroxybutyrate) (P(3HB)). The copolymer exhibited higher thermo-degradation temperature but similar molecular weight and polydispersity compared with P(3HB). PMID- 21279349 TI - FDG PET coregistered to MRI for diagnosis and monitoring of therapeutic response in aggressive phenotype of sarcoidosis. PMID- 21279350 TI - In vivo positron emission tomography imaging with [11C]ABP688: binding variability and specificity for the metabotropic glutamate receptor subtype 5 in baboons. AB - PURPOSE: Metabotropic glutamate receptor subtype 5 (mGluR5) dysfunction has been implicated in several disorders. [(11)C]ABP688, a positron emission tomography (PET) ligand targeting mGluR5, could be a valuable tool in the development of novel therapeutics for these disorders by establishing in vivo drug occupancy. Due to safety concerns in humans, these studies may be performed in nonhuman primates. Therefore, in vivo characterization of [(11)C]ABP688 in nonhuman primates is essential. METHODS: Test-retest studies were performed in baboons (Papio anubis) to compare modeling approaches and determine the optimal reference region. The mGluR5-specific antagonist 3-((2-methyl-1,3-thiazol-4 yl)ethynyl)pyridine (MTEP) was then used in test-block studies, in which ligand binding was measured before and after MTEP administration. Test/block data were analyzed both by calculating changes in binding and using a graphical approach, which allowed estimation of both MTEP occupancy and nonspecific binding. RESULTS: Test-retest results, which have not been previously reported for [(11)C]ABP688, indicated that [(11)C]ABP688 variability is low using an unconstrained two-tissue compartment model. The most appropriate, though not ideal, reference region was found to be the gray matter of the cerebellum. Using these optimal modeling techniques on the test/block data, about 90% occupancy was estimated by the graphical approach. CONCLUSION: These studies are the first to demonstrate the specificity of [(11)C]ABP688 for mGluR5 with in vivo PET in nonhuman primates. The results indicate that, in baboons, occupancy of mGluR5 is detectable by in vivo PET, a useful finding for proceeding to human studies, or performing further baboon studies, quantifying the in vivo occupancy of novel therapeutics targeting mGluR5. PMID- 21279351 TI - Current state of data-based gating technology in PET imaging. PMID- 21279353 TI - Assessment of the treatment response of HCC. AB - Surgical hepatectomy or liver transplantation are considered as curative treatment modalities for hepatocellular carcinoma (HCC). However, many patients are not surgical candidates at the time of diagnosis. Great improvements in locoregional therapies including local ablative therapy [radiofrequency (RF) ablation or ethanol ablation] and transarterial techniques (transarterial embolization or transarterial radioembolization) have made possible local control of HCC. For unresectable HCC, a targeted therapy with sorafenib may improve survival. Unlike treatment of other oncologic tumor, the locoregional therapies are mainstay in the treatment of HCC. Therefore, the application of classical criteria such as the World Health Organization (WHO) guideline may not be suitable for accurate treatment response assessment of locoregional therapies or targeted therapy of HCC. An understanding of the imaging features of post treatment imaging after various treatment modalities for HCC is crucial for treatment response assessment and for determining further therapy. In this article, we review the role of various imaging modalities in assessing treatment response of locoregional therapies and the targeted molecular therapy. PMID- 21279352 TI - Functional imaging in phaeochromocytoma and neuroblastoma with 68Ga-DOTA-Tyr 3 octreotide positron emission tomography and 123I-metaiodobenzylguanidine. AB - PURPOSE: (68)Ga-DOTA-Tyr(3)-octreotide positron emission tomography ((68)Ga-DOTA TOC PET) has proven to be superior to (111)In-DTPA-D-Phe(1)-octreotide ((111)In octreotide) planar scintigraphy and SPECT imaging in neuroendocrine tumours (NETs). Because of these promising results, we compared the accuracy of (123)I metaiodobenzylguanidine ((123)I-MIBG) imaging with PET in the diagnosis and staging of metastatic phaeochromocytoma and neuroblastoma, referring to radiological imaging as reference standard. METHODS: Three male and eight female patients (age range 3 to 68 years) with biochemically and histologically proven disease were included in this study. Three male and three female patients were suffering from phaeochromocytoma, and five female patients from neuroblastoma. Comparative evaluation included morphological imaging with CT or MRI, functional imaging with (68)Ga-DOTA-TOC PET and (123)I-MIBG imaging. Imaging results were analysed on a per-patient and on a per-lesion basis. RESULTS: On a per-patient basis, both (68)Ga-DOTA-TOC and (123)I-MIBG showed a sensitivity of 100%, when compared with anatomical imaging. In phaeochromocytoma patients, on a per-lesion basis, the sensitivity of (68)Ga-DOTA-TOC was 91.7% and that of (123)I-MIBG was 63.3%. In neuroblastoma patients, on a per-lesion basis, the sensitivity of (68)Ga-DOTA-TOC was 97.2% and that of (123)I-MIBG was 90.7%. Overall, in this patient cohort, (68)Ga-DOTA-TOC PET identified 257 lesions, anatomical imaging identified 216 lesions, and (123)I-MIBG identified only 184 lesions. In this patient group, the overall sensitivity of (68)Ga-DOTA-TOC PET on a lesion basis was 94.4% (McNemar p<0.0001) and that of (123)I-MIBG was 76.9% (McNemar p<0.0001). CONCLUSION: Our analysis in this relatively small patient cohort indicates that (68)Ga-DOTA-TOC PET may be superior to (123)I-MIBG gamma scintigraphy and even to the reference CT/MRI technique in providing particularly valuable information for pretherapeutic staging of phaeochromocytoma and neuroblastoma. PMID- 21279354 TI - What is the demarcating line between anatomy and exhibitionism? PMID- 21279355 TI - Superior and middle thyroid arteries arising from the common carotid artery. AB - We report a rare case of a left middle thyroid artery in a 71-year-old male cadaver. The middle thyroid artery arose from the anterior surface of the left common carotid artery. This artery ran anteroinferiorly and then bifurcated as it entered the lower lateral part of the left thyroid lobe. Both the right and left superior thyroid arteries arose from the common carotid arteries below the carotid bifurcation. The presence of a middle thyroid artery may cause unexpected bleeding during thyroid or neck surgery, and this rare variation needs to be kept in mind during the surgery. PMID- 21279356 TI - Danazol as first-line therapy for aplastic anemia. AB - Immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG) plus cyclosporine A (CsA) is the standard treatment for aplastic anemia (AA) patients not eligible for allogeneic hematopoietic stem cell transplantation (HSCT). In the absence of ATG + CsA, androgens continue to be a treatment option. We documented the clinical evolution of AA patients treated with danazol instead of ATG + CsA. AA patients lacking both, human leukocyte antigen-matched donor and access to IST, were treated with danazol and modern support therapy and compared with those receiving a HSCT. Overall survival (OS), response rates, and death risk odds were calculated. Fifty AA patients were studied. Thirteen received a HSCT and 37 danazol and support therapy. Median daily dose of danazol was 400 mg (300 to 600 mg), administered during a median of 12 months. Five-year OS was higher for patients receiving HSCT (92%) compared to the danazol group (41%) (P = 0.001). Overall response rate was 46% (17/37) in the danazol-treated group and the median time to initial response was 3 months (1-27). Tendency to achieve remission was similar among severity groups (P = 0.094). The only adverse side effect recorded on the danazol group was an episode of gastrointestinal bleeding. No patient treated with danazol suffered clonal evolution of his/her disease. Although ATG plus CsA is the therapy of choice for AA patients without a donor when neither HSCT nor IST is available, danazol remains an acceptable therapeutic option for AA patients. PMID- 21279358 TI - Tissue engineering on matrix: future of autologous tissue replacement. AB - Tissue engineering aims at the creation of living neo-tissues identical or close to their native human counterparts. As basis of this approach, temporary biodegradable supporter matrices are fabricated in the shape of a desired construct, which promote tissue strength and provide functionality until sufficient neo-tissue is formed. Besides fully synthetic polymer-based scaffolds, decellularized biological tissue of xenogenic or homogenic origin can be used. In a second step, these scaffolds are seeded with autologous cells attaching to the scaffold microstructure. In order to promote neo-tissue formation and maturation, the seeded scaffolds are exposed to different forms of stimulation. In cardiovascular tissue engineering, this "conditioning" can be achieved via culture media and biomimetic in vitro exposure, e.g., using flow bioreactors. This aims at adequate cellular differentiation, proliferation, and extracellular matrix production to form a living tissue called the construct. These living autologous constructs, such as heart valves or vascular grafts, are created in vitro, comprising a viable interstitium with repair and remodeling capabilities already prior to implantation. In situ further in vivo remodeling is intended to recapitulate physiological vascular architecture and function. The remodeling mechanisms were shown to be dominated by monocytic infiltration and chemotactic host-cell attraction leading into a multifaceted inflammatory process and neo tissue formation. Key molecules of these processes can be integrated into the scaffold matrix to direct cell and tissue fate in vivo. PMID- 21279360 TI - [Histopathology of graft-versus-host disease]. AB - Graft-versus-host disease (GvHD) occurs as a major complication in 35%-50% of all patients undergoing allogeneic stem cell transplantation. A distinction is made between acute and chronic GvHD depending on the time of onset, type of clinical symptoms and histology. Both forms preferably show manifestations in the skin, mucosal membranes, gastrointestinal tract, liver and (less often) lung. As the clinical presentation is rather unspecific, particularly for the diagnosis of acute GvHD, histology is important to exclude infectious diseases or drug reactions. This review covers the diagnostic morphological criteria and differential diagnoses of GvHD in the skin, gastrointestinal tract and the liver. PMID- 21279359 TI - Differential geometry based solvation model II: Lagrangian formulation. AB - Solvation is an elementary process in nature and is of paramount importance to more sophisticated chemical, biological and biomolecular processes. The understanding of solvation is an essential prerequisite for the quantitative description and analysis of biomolecular systems. This work presents a Lagrangian formulation of our differential geometry based solvation models. The Lagrangian representation of biomolecular surfaces has a few utilities/advantages. First, it provides an essential basis for biomolecular visualization, surface electrostatic potential map and visual perception of biomolecules. Additionally, it is consistent with the conventional setting of implicit solvent theories and thus, many existing theoretical algorithms and computational software packages can be directly employed. Finally, the Lagrangian representation does not need to resort to artificially enlarged van der Waals radii as often required by the Eulerian representation in solvation analysis. The main goal of the present work is to analyze the connection, similarity and difference between the Eulerian and Lagrangian formalisms of the solvation model. Such analysis is important to the understanding of the differential geometry based solvation model. The present model extends the scaled particle theory of nonpolar solvation model with a solvent-solute interaction potential. The nonpolar solvation model is completed with a Poisson-Boltzmann (PB) theory based polar solvation model. The differential geometry theory of surfaces is employed to provide a natural description of solvent-solute interfaces. The optimization of the total free energy functional, which encompasses the polar and nonpolar contributions, leads to coupled potential driven geometric flow and PB equations. Due to the development of singularities and nonsmooth manifolds in the Lagrangian representation, the resulting potential-driven geometric flow equation is embedded into the Eulerian representation for the purpose of computation, thanks to the equivalence of the Laplace-Beltrami operator in the two representations. The coupled partial differential equations (PDEs) are solved with an iterative procedure to reach a steady state, which delivers desired solvent-solute interface and electrostatic potential for problems of interest. These quantities are utilized to evaluate the solvation free energies and protein-protein binding affinities. A number of computational methods and algorithms are described for the interconversion of Lagrangian and Eulerian representations, and for the solution of the coupled PDE system. The proposed approaches have been extensively validated. We also verify that the mean curvature flow indeed gives rise to the minimal molecular surface and the proposed variational procedure indeed offers minimal total free energy. Solvation analysis and applications are considered for a set of 17 small compounds and a set of 23 proteins. The salt effect on protein protein binding affinity is investigated with two protein complexes by using the present model. Numerical results are compared to the experimental measurements and to those obtained by using other theoretical methods in the literature. PMID- 21279361 TI - [Current aspects of liver allograft pathology]. AB - Liver allograft pathology continues to play an important role in the diagnosis and management of complications in the course of liver transplantation. This article summarizes important patterns of liver damage and also considers new aspects of transplant pathology from the literature. In the context of transplant rejection, late cellular rejection has aroused new interest. Histopathological changes in late rejection differ from acute cellular rejection and there seem to be similarities to de novo autoimmune hepatitis and idiopathic post-transplant hepatitis. Central perivenulitis is a typical change in late cellular rejection and should be differentiated from central toxic necrosis. Other important areas of transplant pathology include vascular and biliary changes resulting from surgical complications or as sequelae of immunosuppressive therapy. Furthermore, disease recurrence plays an important role and combined patterns of disease poses a challenge for the pathologist. PMID- 21279362 TI - Trapping with high-flow bypass for a traumatic giant pseudoaneurysm of the supraclinoid carotid artery in an adolescent: case report. PMID- 21279363 TI - Solitary infantile myofibromatosis of the cranial vault: case report. AB - Infantile myofibromatosis is a mesenchymal disorder of early childhood characterized by the formation of tumors in the skin, muscle, viscera, bone, and subcutaneous tissue. Although relatively rare overall, it represents the most common fibrous tumor of infancy. The etiology of this disorder is unknown. Infantile myofibromatosis can present as a solitary or multicentric form. With the multicentric form, bone is often involved, but solitary bone lesions account for only 10% of the cases. Imaging findings are not pathognomonic, and the differential diagnosis usually includes eosinophilic granuloma (Langerhans cell histiocytosis), osteomyelitis, metastasis, osteoblastoma, epidermoid cyst, hemangioma, fibrous dysplasia, fibrosarcoma, and meningioma. A histological pattern is typical, but there are no histopathological differences between the solitary and multicentric forms. Solitary lesions generally have a favorable prognosis if totally removed, with a 10% recurrence rate; incompletely resected lesions recur. We report the case of a 9-year-old boy who came to our attention with a solitary infantile myofibroma of the calvarium, appearing as a tight elastic, lightly tender mass in the left frontal area, eroding both the inner and the outer tables. Histopathologically, the specimens showed a spindle-cell tumor with dense reticulin fiber network and expression of smooth muscle actin. Fifty eight months MR follow-up after total removal showed no residual or relapse. PMID- 21279364 TI - Visual field loss in children with craniosynostosis. AB - AIMS: To identify visual field deficits in a group of children with syndromic craniosynostosis. METHODS: Kinetic visual field examination and visual evoked potentials (VEPs) were recorded in 16 children with syndromic craniosynostosis as part of their ophthalmic evaluation. VEPs were analyzed for inter-hemispheric asymmetries and component amplitude and latency, while visual fields were analyzed both qualitatively and quantitatively. RESULTS: All children with craniosynostosis were found to have visual field deficits compared to controls. In the Crouzon group, deficits tended to involve the nasal field, while infero nasal field deficits were the most consistent finding in children with Apert syndrome. Children with Pfeiffer's demonstrated the greatest deficits, with severe constrictions affecting the whole visual field. VEPs were asymmetrical in four cases while the P100 component was subnormal in ten of the 16 patients for either amplitude and/or latency. CONCLUSION: Although we may speculate about the mechanisms that cause visual field deficits, we currently are unable to explain the reason for the differing types and extent of visual field loss in the different syndromic groups. We can conclude that the visual field deficits do indicate previous or ongoing visual dysfunction that cannot be monitored employing central vision tests alone. PMID- 21279365 TI - Surgical resection of locally advanced primary transverse colon cancer--not a worse outcome in stage II tumor. AB - BACKGROUND AND AIMS: In locally advanced primary transverse colon cancer, a tumor may cause perforation or invade adjacent organs. Extensive resection is the best choice of treatment, but such procedures must be weighed against the potential survival benefits. This study was performed to identify the clinicopathological features and treatment outcomes of such tumors. MATERIALS AND METHODS: We retrospectively reviewed the database of the Colorectal Cancer Registry of Chang Gung Memorial Hospital between February 1995 and December 2005. Patients with colon cancer sited between the hepatic and splenic flexure that involved an adjacent organ without distant metastasis were defined as having locally advanced transverse colon cancer. RESULTS: A total of 827 patients who underwent surgery for transverse primary colon cancer were enrolled in the study. Stage II and stage III colon cancer were diagnosed in 548 patients. Thirty-two (5.8%) patients were diagnosed with locally advanced tumors. Multivariate analysis revealed that stage III, preoperative carcinoembryonic antigen >=5 ng/mL, a tumor with perforation or obstruction, and the presence of a locally advanced tumor were significant prognostic factors for both overall and cancer-specific survival. Postoperative morbidity rates differed significantly between the locally advanced and non-locally advanced tumor groups (22.7% vs. 12.3%, P < 0.01). No significant overall survival difference was observed among the stage II transverse colon tumors (P = 0.21). CONCLUSION: Surgical resection of locally advanced transverse colon tumors resulted in a higher morbidity and mortality than that of non locally advanced tumors, but the benefit of extensive surgery in the case of locally advanced tumors cannot be underestimated. Furthermore, this benefit is more pronounced in the case of stage II tumors. PMID- 21279366 TI - Seton drainage in high anal fistula. PMID- 21279367 TI - Flatus vaginalis a distressing symptom. PMID- 21279368 TI - The clinical impact of primary sclerosing cholangitis in patients with an ileal pouch-anal anastomosis for ulcerative colitis. AB - INTRODUCTION: Primary sclerosing cholangitis (PSC), a chronic inflammatory disease affecting the liver, is associated with ulcerative colitis (UC) in up to 75% of Northern European patients. These patients are at increased risk for the development of colorectal cancer, and the operation of choice is restorative proctocolectomy with an ileal pouch-anal anastomosis. However, complications such as pouchitis can occur, and studies have suggested that PSC is an independent risk factor for the development of pouchitis. AIM: The aim of this study is to review and discuss the available literature on the effect of PSC on clinical outcomes of patients who undergo pouch surgery for UC. The outcomes reviewed comprise the incidence of pouchitis and pouch dysplasia/cancer and quality of life, including sexual function in UC patients with or without PSC. METHODS: Pubmed/Medline and Embase searches were undertaken to obtain papers in English between 1966 and 2008. The keywords used were primary sclerosing cholangitis, ulcerative colitis, ileal pouch-anal anastomosis, quality of life, sexual function, dysplasia or cancer, pouchitis and orthotopic liver transplantation. RESULTS: The incidence of pouchitis, pouch mucosal atrophy and risk of dysplasia appear to be greater in patients with associated PSC than in UC patients without PSC. Quality of life does not appear to be worse than in patients without PSC. Sexual function has not been studied in this subgroup of patients. CONCLUSION: Pouchitis appears to be more common in the subset of UC patients with PSC, although there is clearly a need for further well-designed studies. PMID- 21279369 TI - Surveillance colonoscopy in patients with inflammatory bowel disease: comparison of random biopsy vs. targeted biopsy protocols. AB - BACKGROUND: Endoscopic surveillance in patients with long-standing inflammatory bowel disease (IBD) improves early detection of intraepithelial neoplasia (IEN). We aimed to compare three different endoscopic surveillance strategies in the detection of IEN. METHODS: One hundred fifty surveillance colonoscopies (ulcerative colitis, UC n = 141; Crohn's disease, CD n = 9) were carried out. Random quadrant biopsies were taken (group I, n = 50). Chromoendoscopy with indigo carmine was performed and subsequently quadrant biopsies were collected (group II, n = 50). Patients in group III (n = 50) underwent confocal endomicroscopy (CEM), and CEM-guided as well as random quadrant biopsies were taken (group III, n = 50). The findings of CEM were correlated to conventional histology. Patients with high-grade IEN underwent surgery or strict follow-up by patients' request. RESULTS: In group I (1531 biopsies), no IEN was detected by histology. In group II (1,811 biopsies), chromoendoscopy-guided biopsies revealed high-grade IEN in two patients (4% detection rate). In four patients of group III (1477 biopsies), areas with high-grade IEN were clearly visible by CEM and confirmed by histology (8% detection rate, p < 0.05). Of six patients with high grade IEN, five patients underwent proctocolectomy. Colorectal cancer was detected in one out of five patients. CONCLUSION: Targeted biopsy protocols guided by either chromoendoscopy or CEM led to higher detection rates of IEN and are thus mandatory for surveillance colonoscopies in patients with long-standing UC. Random biopsy protocols should be replaced by chromoendoscopy-guided protocols. PMID- 21279370 TI - Meta-analysis: sacral nerve stimulation versus conservative therapy in the treatment of faecal incontinence. AB - AIM: Sacral nerve stimulation (SNS) has recently been used in the management of faecal incontinence (FI). This study compared SNS to conservative management with regards to functional and quality of life outcomes. METHODS: Meta-analysis of studies published between 1995 and 2008 on SNS for FI was performed. Outcomes evaluated were functional, physiological and quality of life. A random-effects model was used and sensitivity analyses performed. Subgroup analyses were performed on age and sphincter status. RESULTS: Thirty-four studies were included, reporting on 944 patients undergoing peripheral nerve evaluation; 665 underwent permanent SNS. Weekly incontinence episodes (weighted mean difference [WMD] -6.83; 95% confidence intervals [CI] -8.05, -5.60; p < 0.001) and incontinence scores (WMD -10.57; 95% CI -11.89, -9.24; p < 0.001) were significantly reduced with SNS; ability to defer defecation (WMD 7.99 min; 95% CI 5.93, 10.05; p < 0.001) was increased. Most SF-36 and FIQL domains improved following SNS, and mean anal pressures increased significantly (p < 0.001). Results remained consistent on sensitivity analysis. The under-56 years age group showed smaller functional but greater physiological and quality of life improvements. Results were similar between sphincter intact and impaired subgroups. The complication rate was 15% for permanent SNS, with 3% resulting in permanent explantation. CONCLUSION: SNS results in significant improvements in objective and subjective measures for faecally incontinent patients. PMID- 21279371 TI - [Coping with chronic illness and multiple medicines in older age: self-management support as an obligation in nursing]. AB - In later stages of chronic disease and especially in older age, chronically ill people are often dependent on multiple medicines. Coming to terms with complex medication regimes in everyday life is a challenging task. To provide the support actually needed, patient-centered interventions are essential, not only taking into account the patients' needs and preferences, but also promoting their ability to self manage their disease(s) and their medication regime. This paper outlines the results of a research project aimed at developing and evaluating an intervention to integrate self-management support into primary care, based on a qualitative exploration of the patients' and professionals' views. The findings stress that home care nurses should take an active part in self-management support but need to be prepared adequately. Therefore, a two-tier intervention was developed and evaluated in a prospective control study, consisting of a qualified training and guidelines for practice. The intervention serves to expand the nurses' professional competence to provide the needed individually tailored self-management support in home care. PMID- 21279372 TI - ['Deciphering aging': excerpts of the BMBF foresight process]. PMID- 21279373 TI - Increased expression of TRAIL and its death receptors DR4 and DR5 in plaque psoriasis. AB - TNF-related apoptosis-inducing ligand (TRAIL) is recognized as an important regulator of immune responses during infections and various autoimmune-mediated pathologies. Its role in inflammatory dermatoses is largely unknown. We aimed to investigate the expression of TRAIL and its receptors DR4 and DR5 in psoriasis vulgaris. Immunohistochemistry for TRAIL, DR4 and DR5 was performed on samples of lesional (n = 10) and non-lesional (n = 10) skin of patients with plaque psoriasis and skin of healthy volunteers (n = 10). Expression of TRAIL and its receptors was further examined by means of double immunofluorescence staining and co-localization with CD4, CD8, CD11c, CD68, CD16 and CD56 markers. Immunohistochemical staining for TRAIL was significantly enhanced in psoriatic lesional as well as non-lesional epidermis compared to the epidermis of healthy skin. Lesional epidermis also showed increased immunoreactivity for DR5. In addition, expression of TRAIL and both of its receptors was significantly increased in the dermis of lesional skin. As evidenced by double immunofluorescence, TRAIL was readily expressed by most of the examined cells of the inflammatory infiltrate in psoriatic lesions. In contrast, the expression of DR4 was found mostly among CD4+ and CD8+ cells but was only nuclear, while DR5 showed cytoplasmic staining in rare CD16+, CD56+ and CD68+ cells. According to abundant in situ presence of TRAIL and its receptors in lesional psoriatic skin, it seems that this cytokine participates in the complex interplay between keratinocytes and cells of the dermal infiltrate and thus contributes to the inflammatory cycle in psoriasis vulgaris. PMID- 21279374 TI - When backyard fun turns to trauma: risk assessment of blunt ballistic impact trauma due to potato cannons. AB - Although potato cannons are an area of great interest among internet users, they are almost completely unknown in the medical community. These simple ballistic devices are made from plastic plumbing pipes and are powered with propellant gas from aerosol cans. By combustion of the gas-oxygen mixture, a high pressure is produced which propels the potato chunks through the barrel. It is the aim of this study to investigate the hazardous potential of these shooting devices. Test shots were performed using three illegally manufactured potato cannons that were confiscated by police authorities. Velocity, impulse, kinetic energy, and energy density were calculated. The risk of head and chest injuries was investigated by using Sturdivan's Blunt Criterion (BC), an energy based five parametric trauma model assessing the vulnerability to blunt weapons, projectile impacts, and behind-body-armor exposures. The probability of lethality due to blunt impact trauma to the chest was assessed using Sturdivan's lethality model. For potential head impacts, all test shots far exceeded the critical BC (head) value which corresponds to a 50% risk of skull fracture. The risk of injury with regard to chest impacts was similar. All but two test shots far exceeded the critical BC (chest) value corresponding to a 50% risk of sustaining a thoracic skeletal injury of Abbreviated Injury Scale 2 or 3. The probability of a lethal injury due to blunt chest impact was as high as 20%. To conclude, this work demonstrates that potato cannons should be considered dangerous weapons rather than as toys used by adventurous adolescents. PMID- 21279375 TI - Longterm cultures of the aged human RPE do not maintain epithelial morphology and high transepithelial resistance. PMID- 21279377 TI - Visualization of superparamagnetic nanoparticles in vascular tissue using XMUCT and histology. AB - In order to increase the dose of antineoplastic agents in the tumor area, the concept of magnetic drug targeting (MDT) has been developed. Magnetic nanoparticles consisting of iron oxide and a biocompatible cover layer suspended in an aqueous solution (ferrofluid) serve as carriers for chemotherapeutics being enriched by an external magnetic field after intra-arterial application in desired body compartments (i.e., tumor). We established an ex vivo model to simulate in vivo conditions in a circulating system consisting of magnetic iron oxide nanoparticles passing an intact bovine artery and being focused by an external magnetic field to study their distribution in the vessel. Micro-computed X-ray tomography (XMUCT) and histology can elucidate the arrangement of these particles after application. XMUCT-analysis has been performed on arterial sections after MDT in order to determine the distribution of the nanoparticles. These measurements have been carried out with a cone X-ray source and corresponding histological sections were stained with Prussian blue. It could be shown that combining XMUCT and histology offers the opportunity for a better understanding of the mechanisms of nanoparticle deposition in the vascular system after MDT. PMID- 21279378 TI - Human mercury exposure associated with small-scale gold mining in Burkina Faso. AB - PURPOSE: In Burkina Faso, gold ore is one of the main sources of income for an important part of the active population. Artisan gold miners use mercury in the extraction, a toxic metal whose human health risks are well known. The aim of the present study was to assess mercury exposure as well as to understand the exposure determinants of gold miners in Burkinabe small-scale mines. METHODS: The examined gold miners' population on the different selected gold mining sites was composed by persons who were directly and indirectly related to gold mining activities. But measurement of urinary mercury was performed on workers most susceptible to be exposed to mercury. Thus, occupational exposure to mercury was evaluated among ninety-three workers belonging to eight different gold mining sites spread in six regions of Burkina Faso. Among others, work-related exposure determinants were taken into account for each person during urine sampling as for example amalgamating or heating mercury. All participants were medically examined by a local medical team in order to identify possible symptoms related to the toxic effect of mercury. RESULTS: Mercury levels were high, showing that 69% of the measurements exceeded the ACGIH (American Conference of Industrial Hygienists) biological exposure indice (BEI) of 35 MUg per g of creatinine (MUg/g Cr) (prior to shift) while 16% even exceeded 350 MUg/g-Cr. Basically, unspecific but also specific symptoms related to mercury toxicity could be underlined among the persons who were directly related to gold mining activities. Only one-third among the studied subpopulation reported about less than three symptoms possibly associated to mercury exposure and nearly half of them suffered from at least five of these symptoms. Ore washers were more involved in the direct handling of mercury while gold dealers in the final gold recovery activities. These differences may explain the overexposure observed in gold dealers and indicate that the refining process is the major source of exposure. CONCLUSIONS: This study attests that mercury exposure still is an issue of concern. North-South collaborations should encourage knowledge exchange between developing and developed countries, for a cleaner artisanal gold mining process and thus for reducing human health and environmental hazards due to mercury use. PMID- 21279376 TI - Histochemistry and cell biology: the annual review 2010. AB - This review summarizes recent advances in histochemistry and cell biology which complement and extend our knowledge regarding various aspects of protein functions, cell and tissue biology, employing appropriate in vivo model systems in conjunction with established and novel approaches. In this context several non expected results and discoveries were obtained which paved the way of research into new directions. Once the reader embarks on reading this review, it quickly becomes quite obvious that the studies contribute not only to a better understanding of fundamental biological processes but also provide use-oriented aspects that can be derived therefrom. PMID- 21279379 TI - How to make rapid eye movements "rapid": the role of growth factors for muscle contractile properties. AB - Different muscle functions require different muscle contraction properties. Saccade-generating extraocular muscles (EOMs) are the fastest muscles in the human body, significantly faster than limb skeletal muscles. Muscle contraction speed is subjected to plasticity, i.e., contraction speed can be adjusted to serve different demands, but little is known about the molecular mechanisms that control contraction speed. Therefore, we examined whether myogenic growth factors modulate contractile properties, including twitch contraction time (onset of force to peak force) and half relaxation time (peak force to half relaxation). We examined effects of three muscle-derived growth factors: insulin-like growth factor 1 (IGF1), cardiotrophin-1 (CT1), and glial cell line-derived neurotrophic factor (GDNF). In gain-of-function experiments, CT1 or GDNF injected into the orbit shortened contraction time, and IGF1 or CT1 shortened half relaxation time. In loss-of-function experiments with binding proteins or neutralizing antibodies, elimination of endogenous IGFs prolonged both contraction time and half relaxation time, while eliminating endogenous GDNF prolonged contraction time, with no effect on half relaxation time. Elimination of endogenous IGFs or CT1, but not GDNF, significantly reduced contractile force. Thus, IGF1, CT1, and GDNF have partially overlapping but not identical effects on muscle contractile properties. Expression of these three growth factors was measured in chicken and/or rat EOMs by real-time PCR. The "fast" EOMs express significantly more message encoding these growth factors and their receptors than skeletal muscles with slower contractile properties. Taken together, these findings indicate that EOM contractile kinetics is regulated by the amount of myogenic growth factors available to the muscle. PMID- 21279381 TI - Root hair-specific disruption of cellulose and xyloglucan in AtCSLD3 mutants, and factors affecting the post-rupture resumption of mutant root hair growth. AB - The glycosyl transferase encoded by the cellulose synthase-like gene CSLD3/KJK/RHD7 (At3g03050) is required for cell wall integrity during root hair formation in Arabidopsis thaliana but it remains unclear whether it contributes to the synthesis of cellulose or hemicellulose. We identified two new alleles, root hair-defective (rhd) 7-1 and rhd7-4, which affect the C-terminal end of the encoded protein. Like root hairs in the previously characterized kjk-2 putative null mutant, rhd7-1 and rhd7-4 hairs rupture before tip growth but, depending on the growth medium and temperature, hairs are able to survive rupture and initiate tip growth, indicating that these alleles retain some function. At 21 degrees C, the rhd7 tip-growing root hairs continued to rupture but at 5oC, rupture was inhibited, resulting in long, wild type-like root hairs. At both temperatures, the expression of another root hair-specific CSLD gene, CSLD2, was increased in the rhd7-4 mutant but reduced in the kjk-2 mutant, suggesting that CSLD2 expression is CSLD3-dependent, and that CSLD2 could partially compensate for CSLD3 defects to prevent rupture at 5 degrees C. Using a fluorescent brightener (FB 28) to detect cell wall (1 -> 4)-beta-glucans (primarily cellulose) and CCRC M1 antibody to detect fucosylated xyloglucans revealed a patchy distribution of both in the mutant root hair cell walls. Cell wall thickness varied, and immunogold electron microscopy indicated that xyloglucan distribution was altered throughout the root hair cell walls. These cell wall defects indicate that CSLD3 is required for the normal organization of both cellulose and xyloglucan in root hair cell walls. PMID- 21279380 TI - Ion channels in inflammation. AB - Most physical illness in vertebrates involves inflammation. Inflammation causes disease by fluid shifts across cell membranes and cell layers, changes in muscle function and generation of pain. These disease processes can be explained by changes in numbers or function of ion channels. Changes in ion channels have been detected in diarrhoeal illnesses, pyelonephritis, allergy, acute lung injury and systemic inflammatory response syndromes involving septic shock. The key role played by changes in ion transport is directly evident in inflammation-induced pain. Expression or function of all major categories of ion channels like sodium, chloride, calcium, potassium, transient receptor potential, purinergic receptor and acid-sensing ion channels can be influenced by cyto- and chemokines, prostaglandins, leukotrienes, histamine, ATP, reactive oxygen species and protons released in inflammation. Key pathways in this interaction are cyclic nucleotide, phosphoinositide and mitogen-activated protein kinase-mediated signalling, direct modification by reactive oxygen species like nitric oxide, ATP or protons and disruption of the cytoskeleton. Therapeutic interventions to modulate the adverse and overlapping effects of the numerous different inflammatory mediators on each ion transport system need to target adversely affected ion transport systems directly and locally. PMID- 21279382 TI - Early diagnosis of cerebral X-linked adrenoleukodystrophy in boys with Addison's disease improves survival and neurological outcomes. AB - Approximately one third of boys with X-linked adrenoleukodystophy (X-ALD) develop an acute, progressive inflammatory process of the central nervous system, resulting in rapid neurologic deterioration and death. Hematopoietic cell transplantation (HCT) can halt the progression of neurologic disease if performed early in the course of the cerebral form of X-ALD. We describe a retrospective cohort study of 90 boys with X-ALD evaluated at our institution between 2000 and 2009, to determine if early diagnosis of X-ALD following the diagnosis of unexplained adrenal insufficiency (AI) improves outcomes. We describe seven cases with a delay in the diagnosis of X-ALD and compare their outcomes to ten controls with the diagnosis of ALD made within 12 months following diagnosis of AI. At the time of evaluation for HCT, boys with a delay in the diagnosis of X-ALD had more extensive cerebral involvement and more limited functioning. These boys also were 3.9 times more likely to die and had significant advancement of cerebral disease after HCT, compared with boys with a timely diagnosis of X-ALD. In conclusion, the early diagnosis of cerebral X-ALD following the diagnosis of unexplained AI, and subsequent treatment with HCT improves both neurological outcomes and survival in boys with cerebral X-ALD. PMID- 21279383 TI - Proteaese activity of Blastocystis hominis subtype3 in symptomatic and asymptomatic patients. AB - Despite accumulating evidence indicating that Blastocystis hominis is pathogenic and that cysteine proteases are involved in its pathogenesis, few researches discussed the protease activity of B. hominis genetic subtypes. Therefore, the present study aims to identify the underlying pathogenic role of the proteases of B. hominis subtype 3 at different molecular weights in correlation to gastrointestinal symptoms. Of 65 patients with various clinical presentations referred to our laboratory for stool examination, 26 (40%) were B. hominis positive by stool culture. Of 26 (group I) B. hominis patients, 18 (69.2%) were symptomatic (group IA) and 8(30.8%) were asymptomatic (group IB). Of 25 normal control group (group II), 5 (20%) were B. hominis positive. Subtype 3 was the only genotype recovered by polymerase chain reaction. Of 26 patients in group I, 19 (73.1%) were immunocompetent and 7 (26.9%) were immunocompromised. Protease activities of B. hominis subtype 3 were recognized at 32-kDa (46.2%), 39-kDa (7.7%), 120-kDa (38.5%), 140-kDa (11.5%), and 215-kDa (19.2%) bands in gelatin sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Proteases were recognized in 17 (94.4%) out of 18 symptomatic Blastocystis patients versus 2 (25.0%) out of 8 asymptomatic patients. Proteases at 32 kDa were reported in 61.1% of symptomatic versus 12.5% of asymptomatic patients. It was concluded that proteases of B. hominis genetic subtype 3, particularly those at 32 kDa, could be considered a virulence factor that is responsible for protein degradation and have a possible pathogenic role in host immune evasion. PMID- 21279384 TI - Giardia and other intestinal parasites in dogs from veterinary clinics in Japan. AB - The present study is the first report that describes the national survey of intestinal parasites in private household dogs brought to veterinary clinics in Japan. A total of 2,365 fresh feces were collected. Giardia-specific coproantigen was examined by ELISA kit (SNAP((r)) Giardia, IDEXX Laboratories, Inc.; Maine, USA). Other intestinal parasites were determined microscopically using the formalin-ethyl acetate sedimentation technique. According to age categories, Giardia duodenalis, Cystoisospora spp., Toxocara canis, Toxascaris leonina, and Strongyloides spp., at ?6-months-old showed significantly (P < 0.0001, P < 0.001 or P < 0.01, respectively) higher prevalence compared to >6 months old (31.5% vs. 2.3%, 9.1% vs. 0.05%, 1.8% vs. 0.4%, 1.1% vs. 0%, and 1.1% vs. 0.05%, respectively). In clinical categories, prevalences of G. duodenalis (14.8%) and Cystoisospora spp. (4.7%) in symptomatic dogs were significantly (P < 0.05, respectively) higher than those in asymptomatic ones (7.9% and 1.6%, respectively). G. duodenalis and Cystoisospora spp. were dominant parasites in private household dogs in Japan, especially ?6-month-old dogs. PMID- 21279385 TI - Early detection and estimation of infection burden by real-time PCR in rats experimentally infected with Clonorchis sinensis. AB - A real-time PCR assay targeting the cytochrome c oxidase gene of Clonorchis sinensis was developed and its diagnostic value was investigated in experimentally infected rats. The PCR assay amplified as little as 0.1 pg of C. sinensis genomic DNA and a single egg from experimentally spiked negative feces. The assay could detect C. sinensis DNA in feces 2 weeks post-infection (PI), whereas the Kato-Katz method and formalin-ether concentration techniques could detect the eggs in the feces from 3 weeks PI. Inverse correlations between eggs per gram of feces (EPG) and Ct values were observed 4, 6, and 8 weeks PI. Worm burden was positively correlated with EPG but negatively correlated with Ct values in different groups at 8 weeks PI. Fecal real-time PCR provides a potential tool for the diagnosis of clonorchiosis before eggs can be detected by conventional methods, and may be used to estimate the worm burden in the host. PMID- 21279386 TI - Dominant species, rather than diversity, regulates temporal stability of plant communities. AB - A growing body of empirical evidence suggests that the temporal stability of communities typically increases with diversity. The counterview to this is that dominant species, rather than diversity itself, might regulate temporal stability. However, empirical studies that have explicitly examined the relative importance of diversity and dominant species in maintaining community stability have yielded few clear-cut patterns. Here, using a long-term data set, we examined the relative importance of changes in diversity components and dominance hierarchy following the removal of a dominant C4 grass, Bouteloua gracilis, in stabilizing plant communities. We also examined the relationships between the variables of diversity and dominance hierarchy and the statistical components of temporal stability. We found a significant negative relationship between temporal stability and species richness, number of rare species, and relative abundance of rare species, whereas a significant positive relationship existed between temporal stability and relative abundance of the dominant species. Variances and covariances summed over all species significantly increased with increasing species richness, whereas they significantly decreased with increasing relative abundance of dominant species. We showed that temporal stability in a shortgrass steppe plant community was controlled by dominant species rather than by diversity itself. The generality of diversity-stability relationships might be restricted by the dynamics of dominant species, especially when they have characteristics that contribute to stability in highly stochastic systems. A clear implication is that dominance hierarchies and their changes might be among the most important ecological components to consider in managing communities to maintain ecosystem functioning. PMID- 21279387 TI - Shifts in bryophyte carbon isotope ratio across an elevation * soil age matrix on Mauna Loa, Hawaii: do bryophytes behave like vascular plants? AB - The carbon isotope ratio (delta(13)C) of vascular plant leaf tissue is determined by isotope discrimination, primarily mediated by stomatal and mesophyll diffusion resistances and by photosynthetic rate. These effects lead to predictable trends in leaf delta(13)C across natural gradients of elevation, irradiance and nutrient supply. Less is known about shifts in delta(13)C for bryophytes at landscape scale, as bryophytes lack stomata in the dominant gametophyte phase, and thus lack active control over CO(2) diffusion. Twelve bryophyte species were sampled across a matrix of elevation and soil ages on Mauna Loa, Hawaii Island. We tested hypotheses based on previous findings for vascular plants, which tend to have less negative delta(13)C at higher elevations or irradiances, and for leaves with higher leaf mass per area (LMA). Across the matrix, bryophytes spanned the range of delta(13)C values typical of C(3) vascular plants. Bryophytes were remarkably similar to vascular plants in exhibiting less negative delta(13)C with increasing elevation, and with lower overstory cover; additionally delta(13)C was related to bryophyte canopy projected mass per area, a trait analogous to LMA in vascular plants, also correlated negatively with overstory cover. The similarity of responses of delta(13)C in bryophytes and vascular plants to environmental factors, despite differing morphologies and diffusion pathways, points to a strong direct role of photosynthetic rate in determining delta(13)C variation at the landscape scale. PMID- 21279389 TI - Dialysate CA125 levels after 5 years on continuous peritoneal dialysis. AB - The aim of this study was to evaluate longitudinal changes in dialysate cancer antigen 125 (dCA125) levels over time and to analyze relationships between dCA125 and peritoneal glucose exposure (PGE) in children undergoing long-term peritoneal dialysis (PD). The study group included seven boys and four girls (mean age 13 +/ 5.1 years) with a mean PD duration of 84.0 +/- 1.1 months. A peritoneal equilibration test (PET) was performed, and dCA125 levels were measured in all patients. Peritoneal appearance rates (AR) of dCA125, the velocity of the decrease in dCA125AR values, and annual PGE levels were also calculated. The final tests were performed at a mean of 63.3 +/- 3.5 months after the initial ones. Both dCA125 and dCA125AR levels showed statistically significant decrements during the follow-up period (p = 0.003), with the velocity of decrease in dCA125AR found to be 52.6 +/- 19.4%. There were no significant differences in peritoneal transport parameters between the beginning and end of the study period. PGE values were significantly higher in the last year of the study than in the first year (p = 0.014), but the velocity of the decrease in dCA125AR levels was not related to total PGE. In conclusion, a significant decline was found in dCA125 and CA125 AR levels, reflecting mesothelial cell mass, in children undergoing long-term PD (>5 years), but these were not related to PGE. PMID- 21279390 TI - Glomerular filtration rate and prevalence of chronic kidney disease in Wilms' tumour survivors. AB - Glomerular filtration rate (GFR) was evaluated in 32 Wilms' tumour survivors (WTs) in a cross-sectional study using 99 Tc-diethylene triamine pentaacetic acid (99 Tc-DTPA) clearance, the Schwartz formula, the new Schwartz equation for chronic kidney disease (CKD), cystatin C serum concentration and the Filler formula. Kidney damage was established by beta-2-microglobulin (B-2-M) and albumin urine excretion, urine sediment and ultrasound examination. Blood pressure was measured. No differences were found between the mean GFR in 99 Tc DTPA and the new Schwartz equation for CKD (91.8 +/- 11.3 vs. 94.3 +/- 10.2 ml/min/1.73 m(2) [p = 0.55] respectively). No differences were observed between estimated glomerular filtration rate (eGFR) using the Schwartz formula and the Filler formula either (122.3 +/- 19.9 vs. 129.8 +/- 23.9 ml/min/1.73 m(2) [p = 0.28] respectively). Increased urine albumin and B-2-M excretion, which are signs of kidney damage, were found in 7 (22%) and 3 (9.4%) WTs respectively. Ultrasound signs of kidney damage were found in 14 patients (43%). Five patients (15.6%) had more than one sign of kidney damage. Eighteen individuals (56.25%) had CKD stage I (10 with signs of kidney damage; 8 without). Fourteen individuals (43.75%) had CKD stage II (6 with signs of kidney damage; 8 without). The new Schwartz equation for CKD better estimated GFR in comparison to the Schwartz formula and the Filler formula. Furthermore, the WT survivors had signs of kidney damage despite the fact that GFR was not decreased below 90 ml/min/1.73 m(2) with 99 Tc- DTPA. PMID- 21279391 TI - Collapsing glomerulopathy in a girl with systemic lupus erythematosus. AB - Collapsing glomerulopathy has increasingly been recognised in patients with conditions other than HIV. The non-HIV form of collapsing glomerulopathy generally shows little response to standard therapies. We describe a 12-year-old girl with a pre-existing diagnosis of systemic lupus erythematosus presenting with renal failure. A renal biopsy gave the histological diagnosis of collapsing glomerulopathy with evidence of "full-house" immunostaining. We propose collapsing glomerulopathy in her case, as no other cause was found was secondary to systemic lupus erythematosus. The immunophenotype of her podocytes suggested a partial de-differentiation that might have been important in her partial response to immunosuppression. PMID- 21279392 TI - Long-term reduction in pain and disability after surgery with the interspinous device for intervertebral assisted motion (DIAM) spinal stabilization system in patients with low back pain: 4-year follow-up from a longitudinal prospective case series. AB - Patients with low back pain (LBP) suffer chronic disability. In 40% of LBP patients degenerative disc disease (DDD) seems to be the cause. This prospective case series assessed the efficacy of the interspinous device for intervertebral assisted motion (DIAMTM) in patients with LBP resulting from DDD. All patients were initially assessed by physical examinations, magnetic resonance imaging, dynamic X-rays and provocative discography. Eligible patients (n = 52) had LBP for a minimum of 4 months, and received surgery with the DIAMTM system 2-4 weeks after diagnosis. Patients were evaluated pre-/post-operatively for pain severity using a visual analogue scale (VAS), and for dysfunction and disability with the Roland-Morris Disability Questionnaire (RMDQ). VAS and RMDQ score changes were assessed using the appropriate contrasts and Bonferroni-corrected P values. As a result, significant (P < 0.0001) pain score reductions were observed between baseline values, and 2 (3.7, 95% CI 3.1; 4.2) and 48 (3.1, 95% CI 2.5; 3.6) months follow-up (intent-to-treat population). Disability scores were significantly (P < 0.0001) reduced between baseline and 2 (8.6, 95% CI 7.4; 9.9) and 48 (7.5, 95% CI 6.1; 8.9) months. Disability scores were similar from months 2 to 48. At 48 months, 67.3% of patients reached the minimum clinically important difference (MCID; >=1.5-unit improvement) in VAS score and 78.9% of patients reached the MCID (>=30% improvement) in RMDQ score. No complications were associated with surgery. In conclusion, patients with LBP treated with the interspinous DIAMTM system showed significant and clinically meaningful improvements in pain and disability for up to 4 years. PMID- 21279393 TI - Freehand determination of the trajectory angle for cervical lateral mass screws: how accurate is it? AB - Different methods of lateral mass screw placement in the cervical spine have been described with separate trajectories for each technique in the sagittal and parasagittal planes. In the latter, plane 30 degrees has been recommended in the modified Magerl's technique as the optimum angle to avoid injury to the vertebral artery and nerve root. The estimation of this angle remains arbitrary and very much operator dependant. The aim of this study was to assess how accurately the lateral trajectory angle of 30 degrees is achieved by visual estimation amongst experienced surgeons in a tertiary spinal unit and to determine the likelihood of neurovascular injury during the procedure. We chose an anatomical 'sawbone' model of the cervical spine with simulated lordosis. The senior author marked the entry points. Five spinal consultants and five senior spinal fellows were asked to insert 1.6-mm K wires into the lateral masses of C3 to C6 bilaterally at 30 degrees to the midsagittal plane using the marked entry points. The lateral angulation in the transverse plane was measured using a custom protractor and documented for each surgeon at each level and side. The mean and standard deviation (SD) of the data were obtained to determine the inter observer variability. Utilising this data, measurements were then made on a normal axial computerised tomography (CT) scan of the cervical spine of an anonymous patient to determine if there would have been any neurovascular compromise. Among the 10 surgeons, a total of 80 insertion angles were measured from C3 to C6 on either side. The overall mean angle of insertion was 25.15 (range 20.4-34.8). The overall SD was 4.78. Amongst the 80 measurements between the ten surgeons, two episodes of theoretical vertebral artery violation were observed when the angles were simulated on the CT scan. A moderate but notable variability in trajectory placement exists between surgeons during insertion of cervical lateral mass screws. Freehand estimation of 30 degrees is not consistently achieved between surgeons and levels. In patients with gross degenerative or deformed cervical spine anatomy, this may increase the risk of neurovascular injury. The use of the ipsilateral lamina as an anatomical reference plane is supported. PMID- 21279394 TI - Contribution of technological progress, inter-operator difference and experience of operators in Gamma Knife radiosurgery for arteriovenous malformation. AB - BACKGROUND: Outcomes of microsurgical resection for cerebral arteriovenous malformation (AVM) largely depend on the skill and experience of the operator, but it is still unknown whether such individual differences similarly exists in stereotactic radiosurgery (SRS) for AVM. The purpose of this study was to assess the influence of the inter-operator difference and technological progress in SRS for AVM. METHODS: During the past 20 years, 514 patients with AVM were treated by SRS by four neurosurgeons. Until 1992, angiography was solely used for dose planning, and computed tomography (CT) or magnetic resonance imaging (MRI) was jointly used thereafter. In the early years, dose planning was calculated with the first-generation computer system, KULA, and manually superimposed on the radiographical images. After 1998, treatment planning was made on the computer monitor with sophisticated dose-planning software, GammaPlan. The influence of inter-operator difference, the operator's experience, and radiographical or radiosurgical technologies on the rates of obliteration and morbidity was assessed by multivariate analyses. RESULTS: The factors associated with higher obliteration rates were higher margin dose (p = 0.003) and the presence of hemorrhagic event before SRS (p = 0.002). There was no significant difference in either obliteration rate or morbidity among the five operators. However, after introduction of CT and MRI on dose planning, the risk of adverse events was significantly decreased. Especially for AVM larger than 3 cm in maximum diameter, each operator's experience (p = 0.040) and use of GammaPlan (p = 0.015) reduced morbidity. CONCLUSIONS: Inter-operator difference was not a significant factor associated with the rates of obliteration and the risk of adverse events after SRS for AVM in the multivariate analyses. Progress of the sophisticated planning software and the experience of the operator were associated with lower morbidity for larger lesions. PMID- 21279395 TI - Molecular epidemiology of foot-and-mouth disease virus serotypes A and O with emphasis on Korean isolates: temporal and spatial dynamics. AB - We determined complete 1D gene sequences for one serotype A and seven additional serotype O Korean foot-and-mouth disease viruses (FMDV) and then analyzed them together with published sequences for 180 type A and 300 type O isolates from throughout the world using a Bayesian coalescent approach. Here, Korean serotype A virus was linked with those from Laos. Korean serotype O viruses were divided into three clades and were closely related to isolates from Japan, Thailand, the UK, France, Ireland, South Africa, and Singapore, as well as Laos. There was no apparent correlation between time, country, or host species and the evolution of global FMDVs. Additionally, our results showed that purifying selection acts on the overall 1D sequences and there was no evidence of recombination among the FMDV sequences. The evolutionary rates were 5.77 * 10(-3) substitutions/site/year for serotype A and 4.81 * 10(-3) substitutions/site/year for serotype O. Serotype A viruses diverged approximately 110 years ago, while serotype O isolates segregated approximately 127 years before the present. In both serotype isolates, the effective number of infections remained constant until the late 1990 s, after which the virus population size underwent a rapid, sharp decline until the present. PMID- 21279396 TI - Chemoenzymatic routes to enantiomerically pure 2-azatyrosine and 2-, 3- and 4 pyridylalanine derivatives. AB - Enantiomerically pure 2-, 3- or 4-pyridylalanine (pya) and 2-azatyrosine (azatyr) are known to present various biological activities. After incorporation into appropriate peptide sequences, these heterocyclic non natural alpha-amino acids could behave as new substrates or inhibitors of elastase from Pseudomonas aeruginosa. This enzyme is known to be involved in nosocomial infections and infections related to the cystic fibrosis disease. New efficient chemoenzymatic preparations of those compounds using alpha-chymotrypsin (alpha-CT) are presented. PMID- 21279397 TI - Entire liver as the only content of hernia of the umbilical cord. AB - Hernia of the umbilical cord is a small omphalocoele with the abdominal defect being less than 4 cm and the small intestine being the usual content. We report a rare case of hernia of the umbilical cord with the whole of the liver herniating through the small defect into the sac as the only content. The pertinent literature is also reviewed. PMID- 21279398 TI - Analysis of outcome of Lichtenstein groin hernia repair by surgeons-in-training versus a specialized surgeon. AB - PURPOSE: Groin hernia repair is a common procedure in general surgery, and is taught to and performed by surgeons early in their training. The aim of this observational study was to compare hernia repair performance and results of surgical trainees with those of a specialized surgeon, to identify what factors may influence short and long-term outcome, and areas for improvement in surgical training. METHODS: A non-randomized parallel cohort study was designed; 200 Lichtenstein repairs in adult males were included, of which 96 were performed by surgical trainees. Patient characteristics, surgical experience, and operative data, including duration of procedural parts and surgical complexity, were noted at surgery. Postoperative complications, recurrence, chronic pain and residual symptoms were assessed at long-term follow-up after a median of 34.5 months. RESULTS: Surgical trainees required longer overall operative time, with a disproportionally longer time for mobilizing the sac and cord. They perceived exposure and mobilization as more difficult than the specialist, and also a greater demand on their own experience during surgery. The trainee repairs had a higher rate of postoperative complications (14.7% vs 5.0%) but recurrence rate was the same as for specialist repairs. At long-term follow-up, specialist repairs had higher symptom burden and more chronic pain. CONCLUSIONS: It was more efficient, but not necessarily better, to let a specialized surgeon perform the repairs. It seems likely that targeted training in dissection and mobilization could decrease level of perceived complexity and shorten the operative time required by surgical trainees. PMID- 21279399 TI - Transinguinal preperitoneal groin hernia repair using a preperitoneal mesh preformed with a permanent memory ring: a good alternative to Lichtenstein's technique. AB - PURPOSE: The transinguinal preperitoneal (TIPP) technique uses a preperitoneal mesh preformed with a permanent memory ring, which greatly facilitates application of Rives' technique. The purpose of this retrospective study was to evaluate our primary results by systematic clinical and ultrasound evaluations more than 1 year after surgery. METHODS: This unicentric study included all consecutive adult patients treated with surgery for a groin hernia by the same surgeon using the same technique between December 2006 and December 2008. Any patient who participated in this study had both a systematic clinical and ultrasound control between 6 months and 3 years after surgery. RESULTS: In this study, we performed 145 hernia repairs. There was no infection of the mesh and no clinical recurrence; additionally there was an ultrasound recurrence (n = 3) in 2% of asymptomatic patients and chronic pain in 4.8% of patients who did not require the consumption of systematic painkillers and are not limited in their activities. CONCLUSIONS: It is feasible to correct a groin hernia using a preperitoneal preformed mesh with a permanent memory ring. Our study confirms the positive results of Pelissier and colleagues (Pelissier and Ngo, Ann Chir 131:590 594, 2006; Pelissier et al. J Chir 144(4):5S35-5S40, 2007; Pelissier et al. Hernia 11:229-234, 2007; Pelissier et al. Hernia 12:51-56, 2007) and Berrevoet et al. (Hernia 13:243-249, 2009; Langenbeck's Arch Surg 395:557-562, 2010) and is the first study to use a systematic clinical and ultrasound control more than 1 year after surgery. This technique has a low rate of complications, including ultrasound recurrence in 2% of patients without any clinical recurrence and chronic pain in 4.8% of patients who did not require the consumption of systematic painkillers and are not limited in their activities. This technique consisted of the placement of a patch in the preperitoneal space, which combines the benefits of the anterior approach (i.e., easy technique, short learning curve, low cost) and the preperitoneal placement of the mesh (less recurrence, less pain). This procedure is a good alternative to Lichtenstein's technique. PMID- 21279400 TI - New clinical findings in the fragile X-associated tremor ataxia syndrome (FXTAS). AB - The objective of this paper was to assess the phenotypic variance in patients with the Fragile X-associated Tremor Ataxia Syndrome (FXTAS) and to further elucidate genotype-phenotype correlations in the illness. A second goal was to generate hypotheses regarding symptom progression based on careful histories in our sample that can now be tested in ongoing longitudinal studies. The variability of clinical signs and symptom progression in FXTAS complicates our understanding of its phenotype and presents a series of problems in clinical trial design. Similarly, pre-motor and non-motor symptoms have not been adequately explored to answer outstanding questions regarding genotype-phenotype associations in FXTAS. This was a cross-sectional study of FMR1 premutation carriers from known fragile X syndrome pedigrees. We report on the first 50 subjects who have completed a full neurologic evaluation and a brain MRI. Subjects were selected on the basis of motor symptoms or abnormal results (>1 SD) on a quantitative instrument designed to detect mild tremor and ataxia (CATSYS 1994). A neuropsychological battery included the WAIS-III, COWA, and WCST. Statistical analysis used ANOVA and Fisher's exact test with p < 0.05. All FMR1 premutation carriers were men of mean age 65 +/- 7 years. According to the diagnostic criteria of Jacquemont et al. (Am J Hum Genet 72(4):869-878, 2003), 21 subjects met criteria for definite FXTAS, 10 for probable, 9 for possible, and 10 were indeterminate. Duration of motor symptoms was significantly longer in the definitive group (8.6 +/- 6) compared to the other groups (p < 0.01). The presentations in 40 subjects, excluding the indeterminate group, included: tremor 24, ataxia 5, memory symptoms 3, parkinsonism 2, and torticollis 1. The data suggest at least two dominant phenotypic presentations: (a) a tremor-dominant subtype in which the onset of ataxia is delayed; (b) a second in which ataxia is the dominant presentation from the outset. In both subtypes, once ataxia emerges it tends to track frontal cognitive changes (p < 0.01). The data support the view that FXTAS is a late-life neurodegenerative disorder with involvement of motor, non-motor, and cognitive systems. The results suggest at least two presentations with tremor- and ataxia-predominant phenotypes. In both, global cognitive decline appears to track ataxia. Prospective longitudinal studies are needed to validate this proposed evolution of FXTAS and its relevance to future clinical trials design. PMID- 21279401 TI - In vivo quantification of photosensitizer fluorescence in the skin-fold observation chamber using dual-wavelength excitation and NIR imaging. AB - A major challenge in biomedical optics is the accurate quantification of in vivo fluorescence images. Fluorescence imaging is often used to determine the pharmacokinetics of photosensitizers used for photodynamic therapy. Often, however, this type of imaging does not take into account differences in and changes to tissue volume and optical properties of the tissue under interrogation. To address this problem, a ratiometric quantification method was developed and applied to monitor photosensitizer meso-tetra(hydroxyphenyl) chlorin (mTHPC) pharmacokinetics in the rat skin-fold observation chamber. The method employs a combination of dual-wavelength excitation and dual-wavelength detection. Excitation and detection wavelengths were selected in the NIR region. One excitation wavelength was chosen to be at the Q band of mTHPC, whereas the second excitation wavelength was close to its absorption minimum. Two fluorescence emission bands were used; one at the secondary fluorescence maximum of mTHPC centered on 720 nm, and one in a region of tissue autofluorescence. The first excitation wavelength was used to excite the mTHPC and autofluorescence and the second to excite only autofluorescence, so that this could be subtracted. Subsequently, the autofluorescence-corrected mTHPC image was divided by the autofluorescence signal to correct for variations in tissue optical properties. This correction algorithm in principle results in a linear relation between the corrected fluorescence and photosensitizer concentration. The limitations of the presented method and comparison with previously published and validated techniques are discussed. PMID- 21279402 TI - Effect of a newly synthesized Zn sulfophthalocyanine derivative on cell morphology, viability, proliferation, and cytotoxicity in a human lung cancer cell line (A549). AB - Photodynamic therapy (PDT) is a photochemotherapeutic process that is used for the treatment of cancer. Photofrin is the most widely used photosensitizer, however, the chemical composition of Photofrin is unclear and it has a low absorption in the therapeutic wavelength (600-900 nm). This factor has stimulated research in synthesis and testing of new photosensitizers. This in vitro study evaluated the effectiveness of a Zn sulfophthalocyanine (ZnPcS(mix)) as a potential photosensitizer in the treatment of human lung cancer. Lung cancer cells (A549) were divided into four groups: group 1 was control cells receiving neither light nor drug; group 2 was light control for cells exposed to laser irradiation at a fluence of 4.98 J/cm(2); group 3 was drug control for cells incubated with 15.8 MUM photosensitizer and not exposed to laser irradiation, while group 4 was cells receiving the experimental treatment with 15.8 MUM photosensitizer and irradiation with 4.98 J/cm(2). Laser irradiations were performed using a 636-nm diode laser with an output power of 110 mW at 4.98 J/cm(2). Changes in cellular responses were evaluated by cell morphology, viability, proliferation, and cytotoxicity. While control groups 1, 2, and 3 showed no changes in cell morphology, viability, proliferation, or cytotoxicity, group 4 receiving both photosensitizer and irradiation showed changes in cell morphology, a decrease in cell viability and proliferation, and an increase in cytotoxicity, cell death, and cell membrane damage. Irradiation or photosensitizer alone had no effect on the lung cancer cells since the cells remained viable and showed no evidence of damage. However, irradiation in the presence of a photosensitizer induced cell death. PMID- 21279403 TI - Impact of measuring multiple or single occlusal lesions on estimates of diagnostic accuracy using fluorescence methods. AB - Carious lesions can occur at different sites on the occlusal surfaces of teeth and may differ in appearance and severity. This study aimed to evaluate how scoring several lesions on occlusal surfaces, as opposed to only one representative lesion, affects estimates of reproducibility and accuracy of fluorescence-based devices. Thirty-six permanent teeth with 2-3 investigation sites (n = 82) were examined by two examiners using the laser fluorescence device DIAGNOdent pen (LF) and the fluorescence camera VistaProof (FC). Lesion depth was then assessed histologically in serial sections of the teeth. Intra-class correlation coefficients (ICC) and areas under the ROC-curves were calculated for all investigation sites and for one randomly selected site per tooth. Comparing the reproducibility and the performance for the whole sample and the independent sites showed only a small effect or no effect. Measuring multiple sites on teeth with fluorescence devices only moderately influences performance compared to one site being investigated. PMID- 21279404 TI - Superpulsed laser therapy on healing process after tooth extraction in patients waiting for liver transplantation. AB - Alveolar healing following tooth extraction is a complex repair process involving different tissues, including epithelium and bone. This research aimed to study the effect of laser therapy on alveolar healing process in patients waiting for liver transplantation, evaluating some inflammation, osteogenesis, and clinical parameters. Twelve patients with hepatic failure waiting for liver transplantation, with indications to bilateral extraction, entered the split mouth study. One post-extractive defect was treated with laser while the other was left without treatment. Specimens of soft tissues were removed from around the tooth before extraction and after 7 days. Superpulsed laser irradiation prevented IL-1beta increase and induced IL-6, IL-10, and collagen III increase at 7 days in comparison to their level before extraction, whereas the other parameters were unmodified. Moreover, the epithelial regeneration evidenced a positive result of laser therapy, and the patients reported less pain in the site treated with laser. In conclusion, laser therapy appears to be the treatment of choice for patients due to its clinical efficacy, safety, good tolerance, and its ability to prevent inflammation. PMID- 21279405 TI - Structural characterization of extracellular polysaccharides produced by the marine fungus Epicoccum nigrum JJY-40 and their antioxidant activities. AB - Two extracellular polysaccharides, ENP1 and ENP2, were isolated from the fermentation liquid of the marine fungus Epicoccum nigrum JJY-40 by anion exchange chromatography and gel-filtration chromatography, and their structures were investigated using chemical and spectroscopic methods including methylation analysis and NMR spectroscopy. The results demonstrated that ENP1 was composed of mannose, glucose, and galactose in the molar ratio of 5.0:2.1:1.0, and the main chain of the polysaccharide consisted of (1 -> 2)-linked mannose, (1 -> 3)-linked mannose, terminal mannose, (1 -> 6)-linked glucose, (1 -> 4)-linked glucose, and (1 -> 4)-linked galactose. ENP2 was composed of mannose, galactose, glucose, and glucuronic acid in a molar ratio of 12.4:11.2:8.3:1.0, and its glycosidic linkage patterns included terminal mannose, (1 -> 6)-linked glucose, (1 -> 4)-linked galactose, and (1 -> 3)-linked mannose. The two polysaccharides had a partially branched structure with branch point located at C-3 position of (1 -> 6)-linked glucose residue. The molecular weights of ENP1 and ENP2 were 19.2 kDa and 32.7 kDa, respectively. Antioxidant properties of the two polysaccharides were evaluated with hydroxyl, superoxide, and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activities and lipid peroxidation inhibition in vitro, and results showed that ENP2 and ENP1 had good antioxidant activities, especially ENP2. ENP2 could be effective as a potential antioxidant. PMID- 21279406 TI - Genetic sex identification and the potential evolution of sex determination in Pacific halibut (Hippoglossus stenolepis). AB - The discovery of genetic markers linked to physiological traits in wild populations is increasingly desired for ecological and evolutionary studies, as well as to inform management decisions. However, identifying such markers often requires a large investment of both time and money. Serendipitously, in a recent microsatellite survey, we discovered three out of 16 microsatellite loci that were correlated to the female sex in Pacific halibut (Hippoglossus stenolepis). These three loci were screened in 550 Pacific halibut to determine their accuracy at identifying sex. Genetic assignment successfully identified sex in 92% of individuals from sample collections spanning 3,000 km and 9 years. All but two of 287 females had one copy of a characteristic allele for at least one of the three microsatellite loci, resulting in consistent heterozygote excess in females. This pattern is consistent with the hypothesis that females are the heterogametic sex in Pacific halibut, which thus may have a different sex-determination pattern than the closely related Atlantic halibut (Hippoglossus hippoglossus). A rapid divergence of sex-determining mechanisms could be either a cause or consequence of speciation between Pacific and Atlantic halibut. In either case, the ability to genetically identify sex in individual Pacific halibut provides a new tool for ecological studies, fisheries management, and insight into the evolution of sex determination in flatfish. PMID- 21279407 TI - Induced gynogenesis in grass carp (Ctenopharyngodon idellus) using irradiated sperm of allotetraploid hybrids. AB - Grass carp (Ctenopharyngodon idellus) eggs were activated by UV-irradiated diploid sperm of allotetraploid hybrids derived from red crucian carp (?) * common carp (?) and then duplicated by cold shock in 4-6 degrees C water for 10 12 min. Different cold shock initiation times resulted in two types of diploid gynogenetic grass carp: meiotic gynogenetic (meiG) and mitotic gynogenetic (mitG). Over a 5-year period, a total of 17,170 meiG and 1,080 mitG fry were produced and 6,862 meiG and 372 mitG grass carp survived. The gynogenetic fish were confirmed by morphological characteristics, chromosome examination, and microsatellite DNA analysis. The morphological traits of the gynogenetic grass carp were similar to those of wild diploid grass carp. Normal gynogenetic fish were identified as diploid with 48 chromosomes by chromosomal metaphases examination, while nonviable abnormal embryos were detected as haploid with 24 chromosomes. Microsatellite DNA analysis indicated that after one generation of gynogenesis, the genetic purity of meiG and mitG grass carp was significantly increased over that of wild grass carp. In addition, both meiG and mitG grass carp groups were 100% female, and 88% of these showed normal ovary development. Thus, the sex determination mechanism in female grass carp was homogamety. The ability to establish pure all-female groups of meiG and mitG grass carp should be a valuable contribution to both fish genetics and grass carp breeding. PMID- 21279408 TI - A new method to extract matrix proteins directly from the secretion of the mollusk mantle and the role of these proteins in shell biomineralization. AB - Considering the continuous and substantive secretory ability of the mantle in vitro, we report a new technique to produce shell-matrix proteins by inducing the mantle, after removal from the organism's body, to secrete soluble-matrix proteins into phosphate buffer. By this method, a large amount of matrix proteins could be obtained in 2 h. Experiments involving in vitro calcium carbonate crystallization and organic framework calcium carbonate crystallization indicated that these proteins retain high bioactivity and play key roles in shell biomineralization. Phosphate buffer-soluble proteins secreted by the margin of the mantles (MSPs) were used to reconstruct the stages in the growth of the prismatic layer of the decalcified organic frameworks. The MSPs were observed to aggregate calcites in vitro, and this ability enabled the mollusk to form big calcites in the prismatic layer. During shell biomineralization, an important stage after the self-assembly of the biomacromolecules and the formation of crystals is the assembly of the two parts to form a firm structure. Moreover, a new type of matrix protein, functioning as the binding factor between the crystals and the organic frameworks, was shown to exist in the phosphate buffer soluble proteins secreted by the central part of mantles (CSPs). Nanoscale-sized bowl-like aragonites, with heights of ~800 nm, were induced by CSPs in vitro. This method is a successful example of obtaining functional proteins through secretion by animal tissues. PMID- 21279409 TI - Assessment of the roles of copepod Apocyclops royi and bivalve mollusk Meretrix lusoria in white spot syndrome virus transmission. AB - Here, we investigate the roles of copepods and bivalve mollusks in the transmission of white spot syndrome virus (WSSV), which is the causative pathogen of an acute, contagious disease that causes severe mortalities in cultured shrimp. Copepods are common components in seawater ponds and are often eaten as live food by shrimp post-larvae. WSSV has been detected in these animals, but it is unknown whether this was due to contamination or infection. Meanwhile, the bivalve mollusk Meretrix lusoria is often used as live food for brooders, and in Taiwan, this hard clam is sometimes co-cultured with shrimp in farming ponds. However, mollusks' ability to accumulate, or allow the replication of, shrimp viruses has not previously been studied. In this study, WSSV, the copepod Apocyclops royi and bivalve mollusk M. lusoria were experimentally challenged with WSSV and then assayed for both the presence of the virus and for viral gene expression. Results showed that the WSSV genome could be detected and that the viral loads were increased in a time-dependent manner after challenge both in A. royi and M. lusoria. Reverse transcriptase PCR monitoring of WSSV gene expression showed that WSSV could replicate in A. royi but not in M. lusoria, which suggested that WSSV, while could infect A. royi, was only accumulated in M. lusoria. A bioassay further showed that the WSSV accumulated in M. lusoria could be transmitted to Litopenaeus vannamei and cause severe infection. PMID- 21279410 TI - Metagenomic analysis of 0.2-MUm-passable microorganisms in deep-sea hydrothermal fluid. AB - We pyrosequenced the bulk DNA extracted from microorganisms that passed through 0.2-MUm-pore-size filters and trapped by 0.1-MUm-pore-size filters in the hydrothermal fluid of the Mariana Trough. Using the 454-FLX sequencer, we generated 202,648 sequences with an average length of 173.8 bases. Functional profiles were assigned by the SEED Annotation Engine. In the metagenome of the 0.2-MUm-passable microorganisms, genes related to membrane function, including potassium homeostasis classified as membrane transport, and multidrug-resistance efflux pumps classified as virulence, were dominant. There was a higher proportion of genes pertinent to the subsystem of membrane transport in our metagenomic library than in other oceanic and hydrothermal vent metagenomes. Genes associated with a RND-type efflux transporter for exogenous substances were specifically identified in the present study. After a comparative analysis with the genome of the known ultramicrobacterium Sphingopyxis alaskensis RB2256, we discovered 1,542 cases of significant hits (E < 1 * 10(-2)) in our metagenome, and 1,172 of those were related to the DNA repair protein RadA. In this way, the microbial functional profile of 0.2-MUm-passable fraction in the present study differs from oceanic metagenomes in the 0.2-MUm-trapped fractions and hydrothermal vent metagenomes reported in previous research. PMID- 21279411 TI - Musculoskeletal: what's different in children? Fell out of bed and now the right foot hurts. PMID- 21279412 TI - Acute traumatic gonadal vein rupture in a pregnant patient involved in a major motor vehicle collision. AB - We present a case of a 29-year-old female in her second trimester of pregnancy with twin gestations who was involved in a major motor vehicle collision and subsequently diagnosed by multidetector computed tomography with retroperitoneal hemorrhage from a traumatic ruptured right ovarian vein. Gonadal vein rupture should be considered as a rare cause of hemorrhage when evaluating a pregnant patient who has sustained blunt abdominal trauma. PMID- 21279413 TI - Antigen-binding abilities of anti-nephrin antibody are prescribed by signal sequence of expression vector in genetic immunization. AB - BACKGROUND: Nephrin is an essential protein for maintaining the normal structure of podocyte foot processes and the glomerular filtration barrier. To analyze the mechanism of proteinuria and nephrotic syndrome, we previously reported on a new method of producing polyclonal anti-nephrin antibody by genetic immunization. In the present paper, we investigate the effect of signal peptide sequence cDNA on the characteristics of polyclonal anti-nephrin antibodies induced by genetic immunization. METHODS: Five fragments of nephrin cDNA with or without signal peptide sequence were inserted into the pTARGETTM vector. Rats were immunized with these vectors by the gene gun method. Sera obtained from rats at 14 weeks following immunization were analyzed by Western blotting, immunoprecipitation, flow cytometry and immunohistochemistry. RESULTS: Four different antibodies induced by cDNA encoding nephrin protein fragments without signal peptide showed antigen site-specific binding to fragmented glycosylation-disturbed nephrin proteins. These antibodies also reacted to a glycosylation-disturbed full-length nephrin protein (inhibited by tunicamycin), but did not react to either a native nephrin protein or a fully glycosylated conformational nephrin protein. Four different antibodies induced by cDNA encoding nephrin fragments with signal peptide showed an antigen site-specific binding to glycosylation-disturbed nephrin protein fragments. In addition, these antibodies reacted to both a native nephrin protein and a full-length glycosylated conformational nephrin protein. CONCLUSIONS: The absence of signal peptide sequence cDNA in the expression vector produced antibodies specific for glycosylation-disturbed proteins, while its presence produced antibodies that bound to native or fully glycosylated conformational protein. PMID- 21279414 TI - Low frequency power of heart rate variability reflects baroreflex function, not cardiac sympathetic innervation. AB - BACKGROUND: Power spectral analysis of heart rate variability is used to assess cardiac autonomic function. The relationship of low frequency (LF) power to cardiac sympathetic tone has been unclear. We reported previously that LF power may reflect baroreflex modulation. In this study we attempted to replicate our findings in additional subject cohorts, taking into account possible influences of respiration and using different methods to measure baroreflex-cardiovagal gain (BCG). OBJECTIVE: We assessed relationships of LF power, including respiration adjusted LF power (LFa), with cardiac sympathetic innervation and baroreflex function in subjects with or without neuroimaging evidence of cardiac sympathetic denervation. METHODS: Values for LF power at baseline supine, seated, and during the Valsalva maneuver were compared between subject groups with low or normal myocardial concentrations of 6-[(18)F]fluorodopamine-derived radioactivity. BCG was calculated from the slope of cardiac interbeat interval vs. systolic pressure during Phase II of the Valsalva maneuver or after i.v. nitroglycerine injection (the Oxford technique). RESULTS: LF and LFa were unrelated to myocardial 6 [(18)F]fluorodopamine-derived radioactivity. During sitting rest and the Valsalva maneuver logs of LF and LFa correlated positively with the log of Phase II BCG (r = 0.61, p = 0.0005; r = 0.47, p = 0.009; r = 0.69, p < 0.0001; r = 0.60, p = 0.0006). Groups with Low BCG (<= 3 ms/mmHg) had low LF and LFa regardless of cardiac innervation. The log of LF power during supine rest correlated with the log of Oxford BCG (r = 0.74, p < 0.0001). CONCLUSION: LF power, with or without respiratory adjustment, reflects baroreflex modulation and not cardiac sympathetic tone. PMID- 21279415 TI - Prevalence and complications of orthostatic dizziness in the general population. AB - Although orthostatic dizziness (OD) is a common complaint, its prevalence and medical impact in the general population are unknown. The study aims to assess prevalence, medical sequelae and healthcare and social impact of OD in the general population. Participants of the representative German National Health Interview Survey 2003 (n = 4077, age 18-89 years, response rate 52%) were screened for moderate or severe dizziness or vertigo. As part of a larger study on the epidemiology of dizziness and vertigo, a consecutive subsample of screen positive participants (n = 825) underwent a structured medical interview for OD based on the criteria: (1) non-vestibular dizziness (i.e. diffuse non-rotational dizziness, light headedness, feeling of impeding faint), (2) provocation by sudden postural change (i.e. standing up from supine or sitting), (3) duration of seconds to several minutes, (4) absence of vestibular vertigo according to a validated neurotologic interview. The 12-month prevalence of OD was 10.9% (women 13.1%, men 8.2%), lifetime prevalence was 12.5% (women 15.0%, men 9.6%). OD accounted for 42% of all participants with dizziness/vertigo and for 55% of non vestibular dizziness diagnoses. The prevalence of OD was highest in young people, although the proportion with severe OD steadily increased with age. OD led to syncope in 19%, falls in 17% and traumatic injury in 5% of affected subjects. Almost half of the individuals with OD (45%) had consulted a physician and 4% had been treated in hospital. OD is a frequent cause of non-vestibular dizziness for which patients often seek medical advice. It carries a considerable risk of syncope, falls and traumatic injury. PMID- 21279416 TI - Anti-inflammatory effects of ivermectin in mouse model of allergic asthma. AB - BACKGROUND AND OBJECTIVE: Asthma is an inflammatory disease of the lungs that is characterised by increased inflammatory cell infiltration into the airways and poor respiratory function. Ivermectin is a semi-synthetic derivative of a family of macrocyclic lactones that shows broad-spectrum anti-parasitic activity. This drug has been shown to possess anti-inflammatory activity, but whether it can be used in asthma treatment has not yet been investigated. In this study, we aimed to investigate the inhibitory effects of ivermectin on allergic asthma symptoms in mice. METHODS AND RESULTS: We used a mouse asthma model, in which allergic airway inflammation and airway remodelling were induced by ovalbumin (OVA) sensitisation and challenge. Ivermectin or PBS treatment was administered 1 h before OVA challenge. Ivermectin at 2 mg/kg significantly diminished recruitment of immune cells, production of cytokines in the bronchoalveolar lavage fluids and secretion of OVA-specific IgE and IgG1 in the serum. Histological studies indicated that ivermectin suppressed mucus hypersecretion by goblet cells in the airway. CONCLUSIONS: This is the first study to demonstrate that ivermectin is an effective suppressor of inflammation and may be efficacious in the treatment of non-infectious airway inflammatory diseases such as allergic asthma. PMID- 21279417 TI - SHP-dependent and -independent induction of peroxisome proliferator-activated receptor-gamma by the bile acid sensor farnesoid X receptor counter-regulates the pro-inflammatory phenotype of liver myofibroblasts. AB - OBJECTIVE: The regulation of hepatic stellate cells (HSCs) by bacterial lipopolysaccharide (LPS) represents a recently-discovered and novel mechanism for hepatic injury and fibrosis. Stimulation of HSCs with LPS results in a rapid and marked induction of interleukin (IL)1beta, IL6 and tumor necrosis factor alpha. These events lead to the development of the activated phenotype in the HSCs associated with fibrosis and inflammation in the injured liver. We have previously demonstrated that farnesoid X receptor (FXR) activation increases transcription of rat peroxisome proliferator-activated receptor-gamma (PPARgamma) gene in HSCs. We aimed at evaluating the molecular mechanism of the transcriptional regulation of the PPARgamma gene by FXR. METHODS: Real-time PCR, ELISA, transactivations, EMSA and ChIP experiments were performed in HSC-T6 cells, in primary HSCs, in HEK293T cells and in CCl(4)-treated rats. RESULTS: In vivo and in vitro activation of FXR downregulates cytokines and collagen(alpha)1 while inducing PPARgamma and small heterodimer partner (SHP). NUBIScan analysis of rat PPARgamma promoter revealed the presence of a putative FXR response element. Cotransfection with FXR/retinoic acid receptor significantly enhanced chenodeoxycholic acid-induced luciferase activity. EMSA experiments demonstrated that FXR was able to bind to an inverted repeat-1 sequence and ChIP experiments confirmed that FXR is recruited on the PPARgamma promoter. CONCLUSION: The present study provides a molecular basis for the physiological cross-talk between FXR and PPARgamma pathways in HSCs. PMID- 21279418 TI - The repeatability of the Goldmann-Weekers adaptometer for measuring cone adaptation. AB - To assess the inter-session repeatability of the Goldmann-Weekers adaptometer for the measurement of cone dark adaptation in a population of healthy subjects. Data were obtained from 31 healthy adults (mean age 21.5 +/- 2.5) on 2 days. At each visit, pupils were dilated and a 96% bleach of cone photopigment was administered to the test eye before threshold was monitored continuously for 5 min in the dark using the Goldmann-Weekers adaptometer. A single exponential function was fitted to the threshold recovery data on a least squares basis. The coefficient of repeatability (CoR) was calculated to assess the repeatability of the time constant of recovery (tau), initial threshold and final threshold. Cone dark adaptation functions were successfully recorded from all subjects on both visits. The CoR was 79.48 s for tau, 0.71 log cdm(-2) for the initial threshold, and 0.58 log cdm(-2) for the final threshold. Paired samples t-tests showed that there were no significant differences between visits for any of the parameters assesed. Although the Goldmann-Weekers adaptometer was capable of monitoring the rapid changes in threshold that occur during cone dark adaptation, the CoR for tau was relatively large compared to the mean recovery time constants (126.48 +/- 40.33 and 119.94 +/- 33.25 s at the first and second visits, respectively). This indicates that the Goldmann-Weekers adaptometer is unlikely to be a useful instrument to chart changes in an individual's vision over time. PMID- 21279419 TI - Monocular and binocular steady-state flicker VEPs: frequency-response functions to sinusoidal and square-wave luminance modulation. AB - Steady-state VEPs to full-field flicker (FFF) using sinusoidally modulated light were compared with those elicited by square-wave modulated light across a wide range of stimulus frequencies with monocular and binocular FFF stimulation. Binocular and monocular VEPs were elicited in 12 adult volunteers to FFF with two modes of temporal modulation: sinusoidal or square-wave (abrupt onset and offset, 50% duty cycle) at ten temporal frequencies ranging from 2.83 to 58.8 Hz. All stimuli had a mean luminance of 100 cd/m(2) with an 80% modulation depth (20-180 cd/m(2)). Response magnitudes at the stimulus frequency (F1) and at the double and triple harmonics (F2 and F3) were compared. For both sinusoidal and square wave flicker, the FFF-VEP magnitudes at F1 were maximal for 7.52 Hz flicker. F2 was maximal for 5.29 Hz flicker, and F3 magnitudes are largest for flicker stimulation from 3.75 to 7.52 Hz. Square-wave flicker produced significantly larger F1 and F2 magnitudes for slow flicker rates (up to 5.29 Hz for F1; at 2.83 and 3.75 Hz for F2). The F3 magnitudes were larger overall for square-wave flicker. Binocular FFF-VEP magnitudes are larger than those of monocular FFF VEPs, and the amount of this binocular enhancement is not dependant on the mode of flicker stimulation (mean binocular: monocular ratio 1.41, 95% CI: 1.2-1.6). Binocular enhancement of F1 for 21.3 Hz flicker was increased to a factor of 2.5 (95% CI: 1.8-3.5). In the healthy adult visual system, FFF-VEP magnitudes can be characterized by the frequency-response functions of F1, F2 and F3. Low-frequency roll-off in the FFF-VEP magnitudes is greater for sinusoidal flicker than for square-wave flicker for rates <= 5.29 Hz; magnitudes for higher-frequency flicker are similar for the two types of flicker. Binocular FFF-VEPs are larger overall than those recorded monocularly, and this binocular summation is enhanced at 21.3 Hz in the mid-frequency range. PMID- 21279420 TI - Development and characterization of wheat-Psathyrostachys huashanica partial amphiploids for resistance to stripe rust. AB - Two partial amphiploid lines, B113 (32 plants) and B21 (13 plants), derived from a wheat-Psathyrostachys huashanica intergeneric cross were characterized by Giemsa C-banding and SDS-PAGE and evaluated for stripe rust resistance. All 15 partial amphiploid plants were aneuploids with either 50 (8 plants), 51 (6 plants) or 54 (1 plant) chromosomes. Some showed regular meiosis and all the P. huashanica chromosomes were included, although not in a single plant. Of 45 plants 34 showed specific bands on SDS-PAGE representing high molecular weight glutenin subunit (HMW-GS) and 41 had bands representing P. huashanica low molecular weight glutenin subunit (LMW-GS), including two new subunits. All 45 plants were highly resistant (10) or immune (35) to stripe rust mixed races CYR 30, CYR-31, Shuiyuan 7 and Shuiyuan 14. These amphiploid plants could be useful germplasm for enhancing stripe rust resistance and might improve wheat grain quality. PMID- 21279421 TI - Low-molecular-mass purine nucleoside phosphorylase: characterization and application in enzymatic synthesis of nucleoside antiviral drugs. AB - Purine nucleoside phosphorylase (PNP) that catalyzes the reversible phosphorolysis of various purine nucleosides is widely distributed in prokaryotes and eukaryotes. Four pnp genes from Bacillus subtilis 168, Escherichia coli K-12 and Pseudoalteromonas sp. XM2107 were cloned by PCR and expressed in E. coli XL1 Blue. Recombinant PNPs (rPNPs) were purified by Ni(2+)-NTA chromatography. Compared with other rPNPs, PNP(816) was a low-molecular-mass homotrimer, which exhibited 11-, 4- and 1.5-fold higher values in k (cat)/K (m) using inosine as the substrate at 37 degrees C. The PNP(816) or engineered strain XBlue (pQE-816) had a higher catalytic activity than other rPNPs or engineered strains during the enzymatic synthesis of ribavirin, which suggested that the low-molecular-mass homotrimer derived from microorganisms has higher catalytic activity for synthesis of nucleoside antiviral drugs. PMID- 21279422 TI - An efficient downstream box fusion allows high-level accumulation of active bacterial beta-glucosidase in tobacco chloroplasts. AB - Production of enzymes for lignocellulose hydrolysis in planta has been proposed as a lower-cost alternative to microbial production, with plastid transformation as a preferred method due to high foreign protein yields. An important regulator of chloroplast protein production is the downstream box (DB) region, located immediately downstream of the start codon. Protein accumulation can vary over several orders of magnitude by altering the DB region. Experiments in bacteria have suggested that these differences in protein accumulation may result from changes in translation efficiency, though the precise mechanism of DB function is not known. In this study, three DB regions were fused to the bglC ORF encoding a beta-glucosidase from the thermophilic bacterium Thermobifida fusca and inserted into the tobacco (Nicotiana tabacum) plastid genome. More than a two order of magnitude of difference in BglC protein accumulation was observed, dependent on the identity of the DB fusion. Differential transcript accumulation explained some the observed differences in protein accumulation, but in addition, less 3' degradation of bglC transcripts was observed in transgenic plants that accumulated the most BglC enzyme. Chloroplast-produced BglC was active against both pure cellobiose and against tobacco lignocellulose. These experiments demonstrate the potential utility of transplastomic plants as a vehicle for heterologous beta-glucosidase production for the cellulosic ethanol industry. PMID- 21279423 TI - 5,7-Dimethoxyflavone and multiple flavonoids in combination alter the ABCG2 mediated tissue distribution of mitoxantrone in mice. AB - PURPOSE: The objective of our study was to investigate the effect of 5,7-DMF on the accumulation of mitoxantrone (MX) in BCRP-expressing normal cells and to investigate its impact on the PK and tissue distribution of MX in mice. METHODS: The in vitro effect of 5,7-DMF on MX accumulation was examined in MDCK cells transfected with BCRP. The pharmacokinetic and tissue distribution of mitoxantrone, with and without co-administration of 5,7-DMF or multiple flavonoid combinations, were determined in mice. RESULTS: In the presence of 2.5 MUM or 25 MUM of 5,7-DMF, the intracellular concentration of MX was significantly increased in MDCK/Bcrp1 and MDCK/BCRP cells, but not in MDCK/Mock cells. The AUC values of MX in several tissues were significantly increased when MX was co-administered with 5,7-DMF. The most substantial elevations of MX AUC in the presence of 5,7 DMF occurred in the liver (94.5%) and kidneys (61.9%), which is in apparent agreement with the relatively high levels of mouse Bcrp1 expression in these two tissues. CONCLUSIONS: Bcrp1-mediated DMF-MX interactions occur both in vitro and in vivo. 5,7-DMF represents a novel and very promising chemosensitizing agent for the BCRP-mediated MDR due to its low toxicity and potent BCRP inhibition. PMID- 21279424 TI - Resorption of elastic fibers in monkey gingival connective tissue: ultrastructural and immunocytochemical evidence. AB - Little is known about the remodeling of elastic fibers in gingival connective tissue. In this study, elastic fibers in the lamina propria of monkey gingiva were examined by transmission electron microscopy and immunocytochemistry. Some elastic fibers were localized at invagination on the surface of the narrow processes of fibroblasts distributed among dense assemblies of collagen fibrils, and also within coated pits, which were pinching off as coated vesicles. At a higher magnification, the coated vesicles contained filamentous structures, as well as pentagonal structures similar those previously reported in elastic fibers. Immunoelectron microscopy demonstrated positive staining for fibrillin, one of the main components of microfibril, localized either in the coated pits or vesicles. These observations indicate that at least some elastic fibers were resorbed by fibroblasts, and that, in spite of the general belief that little remodeling of elastic fibers occurs under normal conditions, resorption of elastic fibers does occur in monkey gingival connective tissue. The functional significance of this is not yet clear, but it may be involved in facilitating the delicate and efficient adaptation of tissue to physical requirements during mastication. PMID- 21279425 TI - Self-efficacy and health locus of control: relationship to occupational disability among workers with back pain. AB - OBJECTIVES: Although self-efficacy and health locus of control (HLC) have been extensively studied in health research, little is known about their contribution to occupational disability among workers with back pain. This 2 year prospective study examined the association between these control belief constructs and "return to work in good health" (RWGH), a four-category, composite index of back pain outcome. METHODS: The participants (n = 1,007, participation = 68.4%, follow up = 86%) were workers with occupational disruptions who sought a medical consultation for non specific back pain in primary care and emergency settings in the Quebec City area, Canada. Information about self-efficacy for return to work (SERW) and HLC, as well as potential confounders, was collected during a telephone interview about 3 weeks after the baseline medical consultation. Polytomous logistic regression was used to assess the relationship between the baseline control variables and RWGH at 2 year. Odds ratios (OR) and their 95% confidence intervals were used to quantify the strength of associations. For all analyses, the "success" category was considered the reference group. RESULTS: Although bivariate analyses showed a significant association between external HLC and RWGH at 2 year, this relationship was not significant in multivariate analyses. Higher scores on the self-efficacy questionnaire were however protective of "failure to return to work after attempt(s)" (OR: 0.28; 95% CI: 0.14-0.57) and of "failure to return to work" (OR: 0.19; 95% CI: 0.07-0.48) in multivariate analyses. CONCLUSION: Self-efficacy is an important determinant of the occupational outcome of back pain. PMID- 21279426 TI - Occupational rehabilitation policy and practice in the Philippines: initiatives and challenges. AB - INTRODUCTION: Challenges to occupational rehabilitation or work integration or reintegration which include the socio-political system, poor labour infrastructure, legislation implementation and monitoring limit work participation of an estimated eight million Filipinos with disabilities. This paper aims to present government-level initiatives and ongoing challenges of occupational rehabilitation as a field of practice and research in the Philippines. METHODS: We performed a review of occupational rehabilitation literature relevant to the Philippines looking at legislation, policies, and practice. RESULTS: While several socio-political mechanisms exists, we found no concrete information on the surveillance or distinction of services and their effectiveness provided under occupational rehabilitation and there was also no systemic reporting of the characteristics of the population (persons with disabilities vs. injured workers) requiring those services--despite the effort of the Philippines in adopting a state policy for the total development of persons with disabilities towards gainful employment. CONCLUSIONS: The dearth of information and literature in occupational rehabilitation is likely related to the scarcity of research in the broader area of occupational safety and health and work disability management in the Philippines. The findings of this study could guide work disability management and address further development of infrastructure in occupational rehabilitation in the Philippines. PMID- 21279427 TI - Specific effects of reactive thiol drugs on mitochondrial bioenergetics. AB - In this minireview, the more recent findings about the effects of peculiar reactive thiol drugs on mitochondria are presented. These include the following compounds: metallo meso-tetrakis porphyrins, palladacycles, telluranes and phenothiazines. Metallo meso-tetrakis porphyrins can exhibit both beneficial and deleterious effects on mitochodria that are modulated by the central metal, cell location, and availability of axial ligands. Therefore, these compounds have the versatility to be used for cell and mitochondria protection and death. The antioxidant activity of manganese porphyrins is related to a glutathione peroxidase-like activity. By attacking exclusively the membrane protein thiol groups without glutathione depletion, palladacycles are able to induce mitochondrial permeability transition (MPT) and cytochrome c release in the absence of oxidative stress. In hepatoma cells, the mitochondrial action of palladacycles was able to induce apoptotic death. As opposed to palladacycles, telluranes and phenothiazines are able to conjugate the capacity to promote the MPT in a dose-dependent manner in association with efficient antioxidant activity toward lipids. These studies demonstrated that the action of drugs on mitochondrial bioenergetics can be modulated by peculiar reactivity with thiol groups. Therefore, they contribute to studies of toxicity as well as the design of new drugs. PMID- 21279428 TI - Pubertal timing and early sexual intercourse in the offspring of teenage mothers. AB - Early puberty is associated with stressful family environments, early sexual intercourse, and teenage pregnancy. We examined pubertal timing and sexual debut among the 14-year-old offspring of teenage mothers. Mothers (71% Black, 29% White) were recruited as pregnant teenagers (12-18 years old). Data were collected during pregnancy and when offspring were 6, 10 and 14 years old (n = 318). Adolescents (50% male) compared the timing of their pubertal maturation to same-sex peers. There was a significant 3-way interaction effect of race, sex, and pubertal timing on sexual debut (n = 305). This effect remained significant in a model controlling for maternal age at first intercourse, substance use, exposure to trauma, authoritative parenting, and peer sexual activity (n = 255). Early maturation was associated with early sex in daughters, and may be one pathway for the inter-generational transfer of risk for teenage pregnancy among daughters of teenage mothers. PMID- 21279429 TI - Information theory in neuroscience. PMID- 21279430 TI - Relationship between brain and cognitive processes in Down syndrome. AB - We investigated regional grey matter (GM) density in adolescents with Down syndrome (DS) compared to age-matched controls and correlated MRI data with neuropsychological measures in the DS group. Inter-group comparisons documented several GM concentration abnormalities in the participants with DS compared to controls. In the adolescents with DS, intra-group results also showed associations between regional GM density and the neuropsychological measures considered. In particular, GM density of the cerebellum and middle and inferior temporal gyrus was associated with linguistic measures. Short-term memory performances were correlated with the inferior parietal lobule, insula, superior temporal gyrus, medial occipital lobe, and cerebellum. Long-term memory abilities were correlated with GM density in the orbitofrontal cortex, lateral and medial temporal lobe regions, and anterior cingulum and visuo-perceptual abilities with GM density the left middle frontal gyrus. Results of this preliminary study are consistent with a not always efficient brain organization in DS. PMID- 21279431 TI - 'Never testing for HIV' among men who have sex with men recruited from a sexual networking website, United States. AB - HIV testing was assessed online among men accessing a sexual networking website for men who have sex with men. Most of the 8,040 participants reported HIV testing (58.2% <= 1 year; 33.1% > 1 year) and 17.1% were HIV-positive. Overall, 8.6% of men including 24% of those 18-24 years of age had never been tested. Among never testers, 25% did not know where to get tested. Predictors of never being tested included younger age (18-24), bisexual or heterosexual orientation, living outside of large metropolitan areas, and not having a healthcare provider. Increasing access to and knowledge of HIV testing sites is needed. PMID- 21279433 TI - Fresh Start: a multilevel community mobilization plan to promote youth development and prevent violence. AB - While much has been written about community mobilization for health, few detailed expositions of the formation of community mobilization, especially focused on youth violence prevention exist. The Columbia Center for Youth Violence Prevention, in collaboration with the UNIDOS Inwood Coalition, developed a Community mobilization plan to guide youth violence prevention in Inwood. The plan was developed within the context of an evidence-based organizing framework Communities that Care (CTC) and takes a multi-level approach to service coordination that includes activities at the Individual, Family, Block, Organizational and Built Environment levels. This article describes how the Community mobilization plan was created, illustrates the use of evidence-based practices to lead to the development of the plan, outlines the plan's community/organizational activities, and summarizes the principles and processes that can be replicated in other communities seeking to start their own community mobilization efforts to reduce youth violence. PMID- 21279434 TI - Latanoprost promotes neurite outgrowth in differentiated RGC-5 cells via the PI3K Akt-mTOR signaling pathway. AB - Latanoprost, a synthetic derivative of the natural prostaglandin F(2a) (PGF(2a)), is a powerful antiglaucoma agent with ocular hypotensive and neuroprotective effects. However, the neuroregenerative effect and signaling pathway of latanoprost in retinal ganglion cells (RGCs) are still unknown. The purpose of this study is to investigate the regenerative effect of latanoprost in differentiated RGC-5 cells and its underlying mechanisms. Cell viability was determined by Cell Counting Kit-8 (CCK-8) assay and neurite length was examined by ArrayScan HCS Reader and Neurite outgrowth BioApplication. Expressions of Akt phosphorylation (p-Akt) and mammalian target of rapamycin phosphorylation (p mTOR) were investigated by Western blot analysis. The results indicated that 0.1 MUM latanoprost (at a clinically therapeutic concentration) significantly increased cell viability as compared with control. Meanwhile, 0.1 MUM latanoprost resulted in the obvious promotion of neurite outgrowth similar to ciliary neurotrophic factor (CNTF) and simultaneously increased the levels of p-Akt and p mTOR expression. The effects of latanoprost were blocked by the Prostaglandin F receptor (FP receptor) inhibitor AL8810, the phosphoinositide 3-kinase (PI3K) inhibitor LY294002 and the mTOR inhibitor rapamycin. This study presents novel in vitro evidence that latanoprost could promote neurite outgrowth through an FP receptor-mediated modulation of the PI3K-Akt-mTOR signaling pathway. This finding may provide insight into a better understanding of a new mechanism of latanoprost for glaucoma therapy and into the physiological-modulating activities of prostaglandins. PMID- 21279435 TI - Inspection of a deviation from Hardy-Weinberg equilibrium in familial breast cancer cases from a case-control study in a meta-analysis. PMID- 21279436 TI - Green tea consumption and breast cancer risk: three recent meta-analyses. PMID- 21279437 TI - Assessment of multiple physician competencies in postgraduate training: utility of the structured oral examination. AB - Competency based medical education involves assessing physicians-in-training in multiple roles. Training programs are challenged by the need to introduce appropriate yet feasible assessment methods. We therefore examined the utility of a structured oral examination (SOE) in the assessment of the 7 CanMEDS roles (Medical Expert, Communicator, Collaborator, Manager, Health Advocate, Scholar and Professional) in a Neonatal-Perinatal Medicine subspecialty training program. Between 2004 and 2008, 68 trainees participated in an annual SOE. Each SOE consisted of 4 1st year and 4 2nd year clinical scenarios with standardized questions written by neonatologists that addressed all 7 CanMEDS roles. Examiners assigned a checklist score and global rating scores for knowledge and organization. A satisfaction survey was completed at the end of 3 examinations. Across the 5 SOEs, questions related to each competency were tabulated and an overall checklist score for each competency calculated. Inter-station reliability was determined for each CanMEDS role. Values for Cronbach's alpha were 0.62 +/- 0.2 (Medical Expert), 0.43 (Communicator), 0.40 +/- 0.34 (Collaborator), 0.19 +/- 0.17 (Manager), 0.46 +/- 0.32 (Advocate), 0.67 +/- 0.18 (Scholar) and 0.79 (Professional). Inter-rater reliability, determined for the first examination when there were 2 examiners per case, was moderate to substantial for 67% of cases. Participant satisfaction was high. Electronic communication facilitated exam development and costs were minimal. The SOE demonstrates psychometric properties suitable for a formative, in-training assessment as well as low cost, ease of administration and acceptability. It may be a useful way to assess physician competencies in training programs. PMID- 21279438 TI - Cytokines reduce toxic effects of ethanol on oligodendroglia. AB - To characterize immunomodulatory mechanisms that affect oligodendroglia (OL) and white matter following ethanol exposure during early CNS development, we investigated the direct effects of ethanol and cytokines on glia. Mixed glial cultures from newborn rat brain were exposed to 6.5-130 mM ethanol for 1-3 days. OL were sensitive to ethanol, with death ranging from 32 to 88% with increasing time and ethanol concentrations. Little cell death occurred in astroglia or microglia. Mixtures of cytokines representative of those produced by pro inflammatory Th1 and monocyte/macrophage (M/M) cells as well as those produced by anti-inflammatory Th2 cells were all protective. Three of the cytokines in the Th1 mixture, IL-2, TNF-alpha and IFN-gamma, were protective individually, although no single cytokine was as effective as the mixture. The protective effects of the Th1 mixture and of IL-2 were reversed by inhibition of both MAP kinase and PI-3 kinase signaling pathways. We conclude that cytokines can act either directly on OL or indirectly through effects on astroglia or microglia to protect OL from ethanol toxicity. PMID- 21279439 TI - New one-pot synthesis of spiro[furo[2,3-d]pyrimidine-6,5'-pyrimidine]pentaones and their sulfur analogues. AB - Reaction of barbituric acid (BA), 1,3-dimethyl barbituric acid (DMBA) and 2 thiobarbituric acid (TBA) with cyanogen bromide and various aldehydes in presence of triethylamine afforded a new class of heterocyclic stable 5-alkyl and/or 5 aryl-1H, 1'H-spiro[furo[2,3-d]pyrimidine-6,5'-pyrimidine]2,2',4,4',6'(3H,3'H,5H) pentaones which are dimeric forms of barbiturate (uracil and thiouracil derivatives) at 0 degrees C to ambient temperatures. Structure elucidation is proved by X-ray crystallography, (1)H NMR, (13)C NMR, FT-IR, CHN and mass analyses techniques. Mechanisms of the formations are discussed. PMID- 21279440 TI - In vivo evolutionary engineering of a boron-resistant bacterium: Bacillus boroniphilus. AB - Boron is an industrially and biologically important element. However, the mechanisms of boron tolerance and its transport in bacteria and many other living systems are still not clearly understood. In this study, the boron resistance level of a boron-tolerant bacterium, Bacillus boroniphilus DSM 17376, was improved up to 300 mmol l(-1) boron, by employing an in vivo evolutionary engineering strategy based on batch selection under continuous exposure to gradually increasing boron stress levels. The resistance was heterogeneous within the final mutant population which ranged from about 1- to 16-fold of the wild type resistance at 150 mmol l(-1) boron stress level. Boron-resistant mutants had significant cross-resistance to iron and copper stresses, and were also cross resistant to salt (NaCl) stress, suggesting a common resistance mechanism between these stress types. Additionally, highly boron-resistant mutants had up to 2.8 fold higher boron contents than the wild-type, when exposed to high levels of (150 mmol l(-1)) continuous boron stress throughout their cultivation. It was shown that evolutionary engineering is a successful approach to significantly increase bacterial boron resistance and investigate the complex mechanism of boron tolerance and transport in microbial systems. PMID- 21279441 TI - Correlation between local hemodynamics and lesion distribution in a novel aortic regurgitation murine model of atherosclerosis. AB - Following surgical induction of aortic valve regurgitation (AR), extensive atherosclerotic plaque development along the descending thoracic and abdominal aorta of Ldlr-/- mice has been reported, with distinct spatial distributions suggestive of a strong local hemodynamic influence. The objective of this study was to test, using image-based computational fluid dynamics (CFD), whether this is indeed the case. The lumen geometry was reconstructed from micro-CT scanning of a control Ldlr-/- mouse, and CFD simulations were carried out for both AR and control flow conditions derived from Doppler ultrasound measurements and literature data. Maps of time-averaged wall shear stress magnitude (TAWSS), oscillatory shear index (OSI) and relative residence time (RRT) were compared against the spatial distributions of plaque stained with oil red O, previously acquired in a group of AR and control mice. Maps of OSI and RRT were found to be consistent with plaque distributions in the AR mice and the absence of plaque in the control mice. TAWSS was uniformly lower under control vs. AR flow conditions, suggesting that levels (> 100 dyn/cm2) exceeded those required to alone induce a pro-atherogenic response. Simulations of a straightened CFD model confirmed the importance of anatomical curvature for explaining the spatial distribution of lesions in the AR mice. In summary, oscillatory and retrograde flow induced in the AR mice, without concomitant low shear, may exacerbate or accelerate lesion formation, but the distinct anatomical curvature of the mouse aorta is responsible for the spatial distribution of lesions. PMID- 21279443 TI - Light- and sodium azide-induced death of RGC-5 cells in culture occurs via different mechanisms. AB - Previous studies have shown that light impinging on the retina in situ has the capacity to kill neuronal and non-neuronal cells in vitro by interacting directly with mitochondrial constituents. A number of fluorophores are associated with mitochondria which can potentially absorb different wave-lengths of light, including cytochrome oxidase. The aim of the present study was to compare the death mechanism of a light insult to RGC-5 cells in culture with that of sodium azide. Sodium azide's main toxic action is in inhibiting the function of cytochrome oxidase in the mitochondrial electron transport chain. Our studies showed that light and sodium azide kill RGC-5 cells via different mechanisms although some similarities do occur. Both inducers of cell death caused the generation of reactive oxygen species (ROS), the expression of phosphatidylserine, the breakdown of DNA and the activation of p38 MAPK, resulting in its translocation from the nucleus to the cytoplasm. However, light induced cell death occurs via necroptosis, in that it was inhibited by necrostatin-1 and was caspase-independent. This was not the case for sodium azide, where the death process was caspase-dependent, occurred via apoptosis and was unaffected by necrostatin-1. Moreover, light caused an activation of the apoptosis inducing factor (AIF), c-Jun, JNK and HO-1, but it did not affect alpha fodrin or caspase-3. In contrast, sodium azide caused the activation of alpha fodrin and the stimulation of caspase-3 content without influencing AIF, c-Jun, JNK or HO-1. Therefore we conclude that light does not have a specific action on cytochrome oxidase in mitochondria to cause cell death. PMID- 21279444 TI - Exploiting osmosis for blood cell sorting. AB - Blood is a valuable tissue containing cellular populations rich in information regarding the immediate immune and inflammatory status of the body. Blood leukocytes or white blood cells (WBCs) provide an ideal sample to monitor systemic changes and understand molecular signaling mechanisms in disease processes. Blood samples need to be processed to deplete contaminating erythrocytes or red blood cells (RBCs) and sorted into different WBC sub populations prior to analysis. This is typically accomplished using immuno affinity protocols which result in undesirable activation. An alternative is size based sorting which by itself is unsuitable for WBCs sorting due to size overlap between different sub-populations. To overcome this limitation, we investigated the possibility of using controlled osmotic exposure to deplete and/or create a differential size increase between WBC populations. Using a new microfluidic cell docking platform, the response of RBCs and WBCs to deionized (DI) water was evaluated. Time lapse microscopy confirms depletion of RBCs within 15 s and creation of > 3 MUm size difference between lymphocytes, monocytes and granulocytes. A flow through microfluidic device was also used to expose different WBCs to DI water for 30, 60 and 90 s to quantify cell loss and activation. Results confirm preservation of ~100% of monocytes, granulocytes and loss of ~30% of lymphocytes (mostly CD3+/CD4+) with minimal activation. These results indicate feasibility of this approach for monocyte, granulocyte and lymphocyte (sub-populations) isolation based on size. PMID- 21279445 TI - Forces affecting double-stranded DNA translocation through synthetic nanopores. AB - One of the recent applications of nanopores is to use them as detectors/analyzers for bio-molecules and nanopore based sequencing has been studied to quickly sequence DNA. In this paper, three categories of forces proposed in the literature to oppose the electrical driving forces in the DNA translocation process are analyzed, (1) the entropic forces of DNA uncoiling/recoiling at the pore entrance/exits, (2) the viscous drag acting on the blob like DNA outside the nanopore, and (3) the viscous drag acting on the linear DNA inside the nanopore. The magnitudes of these forces are calculated based on the parameters used in experiments and it is shown that the first two of the aforementioned categories of forces are usually small compared to the electrical driving force, while the last one is of the same order as the electrical driving force. To evaluate the viscous drag force acting on the linear DNA inside the nanopore, a hydrodynamic model based on the lubrication approximation is used to calculate the flow field and the viscous drag force acting on a DNA immobilized in a nanopore. This model is validated by good agreement with the experimental data for the tethering force used to immobilize a DNA inside the nanopore. PMID- 21279446 TI - A knowledge translation challenge: clinical use of quality of life data from cancer clinical trials. AB - PURPOSE: Measurement and reporting of health-related quality of life (HRQL) data have evolved considerably over the past 10 years. Our goal was to identify the current barriers to, and enablers of, the effective translation of HRQL outcome data from randomized clinical trials by investigating physician attitudes, knowledge, and education needs. METHODS: We undertook a mixed qualitative and quantitative study of 33 oncologists' attitudes and educational needs around the value, interpretation, and application of HRQL data from cancer clinical trials. The approach was designed to identify barriers and enablers relating to the characteristics of the knowledge itself, to the potential users of the knowledge, and to the environment in which the knowledge is used. RESULTS: The majority of barriers and enablers identified were "second order", i.e., related to the understandability and generalizability of the data, its presentation, its accessibility within the medical literature, and its relevance to specific patient populations. CONCLUSIONS: Our results suggest knowledge translation (KT) of HRQL results would improve if the clinical trial HRQL data were easily accessible to clinicians, and presented in a comprehensible and clinically applicable format, which includes discussion of the relevance of the measurement domains and implications of the findings. We recommend that standards of clinical trial HRQL reporting be implemented in clinical journals. PMID- 21279447 TI - Validation of POMS questionnaire in postmenopausal women. AB - PURPOSE: To evaluate the psychometric properties of the Profile of Mood States (POMS) in postmenopausal women with moderate to severe vasomotor symptoms. METHODS: Internal consistency, validity, and reliability of the POMS were examined using blinded data from 539 postmenopausal women with >=50 moderate to severe hot flushes per week at baseline enrolled in a multicenter, randomized, double-blind, placebo-controlled study of the efficacy and safety of desvenlafaxine (administered as desvenlafaxine succinate) for vasomotor symptoms. RESULTS: The POMS subscales and total score demonstrated sound internal consistency reliability (alpha >= 0.84). Comparisons between POMS subscales and Total Mood Disturbance (TMD) scores with Greene Climacteric Scale domains provided consistent known-groups and construct validity. Results from the confirmatory factor analysis were supportive of the second-order factor structure (root-mean-square error of approximation = 0.078). For women with POMS TMD scores below the US adult female norms, there was little mean change at Week 12 but marked mean improvement in women with greater mood symptoms scoring worse than the norm at baseline. CONCLUSION: These data demonstrate the internal consistency and validity of the POMS to measure mood among postmenopausal women with moderate to severe hot flushes and the responsiveness of the POMS among these women with greater mood symptoms. PMID- 21279448 TI - Quality of life in Brazil: normative values for the WHOQOL-bref in a southern general population sample. AB - PURPOSE: Normative data for WHOQOL-bref are scarce in the literature and unavailable in Latin American countries. The main objective of this study was to provide normative scores of WHOQOL-bref in a general population sample in Brazil and to describe differences in mean scores according to some socio-demographic characteristics. METHODS: WHOQOL-bref was applied to a randomly selected sample of the general population of Porto Alegre. Participants were literate people aged 20 to 64 years. The questionnaires were self-administered in the presence of an interviewer in the respondent's home. RESULTS: The response rate was 68%, and the final sample contained 751 respondents (38% men, 62% women). Low quality of life was observed in the following subgroups: female gender, lower economic class, lower educational level, and the subgroup reporting a chronic medical condition. The mean scores of the WHOQOL-bref and percentiles of scores are reported as normative data for the general population. CONCLUSION: Our results can be useful to researchers using the WHOQOL-bref to compare their results with normative data from a randomly selected sample of general population. Additionally, the ability of WHOQOL-bref to discriminate different population subgroups makes it an important tool to identify vulnerable groups in epidemiological surveys. PMID- 21279449 TI - Distinctive growth pattern in a patient with a delayed diagnosis of Langerhans' cell histiocytosis. AB - We present a 22-year old male patient previously treated with radiotherapy and surgery at the age of 7 for an undefined suprachiasmatic mass. Following treatment he gradually became morbidly obese and besides subsequent panhypopituitarism he achieved his target height probably due to obesity-induced severe hyperinsulinemia. At the age of 21 Langerhans' cell histiocytosis was diagnosed at the right mandible and was surgically treated. One year later he developed a further painful osteolytic hip lesion and a single zoledronate infusion eliminated all symptoms. We highlight the importance of obtaining a histological diagnosis before initiating treatment, and the distinctive course of the disease in a patient who continued to growth besides GH deficiency. PMID- 21279450 TI - Individual- and neighborhood-level characteristics associated with support of in pharmacy vaccination among ESAP-registered pharmacies: pharmacists' role in reducing racial/ethnic disparities in influenza vaccinations in New York City. AB - New York State (NYS) passed legislation authorizing pharmacists to administer immunizations in 2008. Racial/socioeconomic disparities persist in vaccination rates and vaccine-preventable diseases such as influenza. Many NYS pharmacies participate in the Expanded Syringe Access Program (ESAP), which allows provision of non-prescription syringes to help prevent transmission of HIV, and are uniquely positioned to offer vaccination services to low-income communities. To understand individual and neighborhood characteristics of pharmacy staff support for in-pharmacy vaccination, we combined census tract data with baseline pharmacy data from the Pharmacies as Resources Making Links to Community Services (PHARM Link) study among ESAP-registered pharmacies. The sample consists of 437 pharmacists, non-pharmacist owners, and technicians enrolled from 103 eligible New York City pharmacies. Using multilevel analysis, pharmacy staff who expressed support of in-pharmacy vaccination services were 69% more likely to support in pharmacy HIV testing services (OR, 1.69; 95% CI 1.39-2.04). While pharmacy staff who worked in neighborhoods with a high percent of minority residents were less likely to express support of in-pharmacy vaccination, those in neighborhoods with a high percent of foreign-born residents were marginally more likely to express support of in-pharmacy vaccination. While educational campaigns around the importance of vaccination access may be needed among some pharmacy staff and minority community residents, we have provided evidence supporting scale-up of vaccination efforts in pharmacies located in foreign-born/immigrant communities which has potential to reduce disparities in vaccination rates and preventable influenza-related mortality. PMID- 21279451 TI - Differential access to digital communication technology: association with health and health survey recruitment within an African-American underserviced urban population. AB - Digital communication technologies (DCT), such as cell phones and the internet, have begun to replace more traditional technologies even in technology-poor communities. We characterized access to DCT in an underserved urban population and whether access is associated with health and study participation. A general probability community sample and a purposive high-turnover housing sample were recruited and re-interviewed after 3 months. Selected characteristics were compared by sample type and retention. Associations between DCT access and self reported health were examined using multivariable logistic regression. Of 363 eligible individuals, 184 (general community = 119; high-turnover housing = 65) completed the baseline survey. Eighty-four percent of respondents had a cell phone and 62% had ever texted. Ever use of the internet was high (69%) overall, but frequency and years of internet use were higher in the general community sample. Self-reported fair or poor health was more common for residents of cell phone-only households and those with less frequent internet use. Technology use was similar for those retained and not retained. Overall, access to DCT was high in this underserved urban population but varied by sample type. Health varied significantly by DCT use, but study retention did not. These data have implications for incorporating DCT into health-related research in urban populations. PMID- 21279452 TI - Community-based support among African American public housing residents. AB - Recent shifts from federally owned public housing toward tenant-based housing assistance in the form of vouchers raise important questions about the health and wellbeing of rent-assisted households. In particular, little is known about how these shifts in housing policy will affect access to critical sources of community-based social support among those who receive rent assistance. Using the Survey of Income and Program Participation, we estimate the relationship between residence in a federally owned public housing project and the reported presence of social support among a nationally representative sample of blacks who receive rent assistance. We find that in comparison to other rent-assisted households, public housing residents are significantly more likely to report that people in their neighborhood count on each other, watch each other's children, and have access to help from a family nearby. We also find that these measures of community-situated social support are associated with reduced odds of school expulsion among children and food insecurity among adults. In conclusion, we find evidence suggesting that public housing communities contain social resources that are important to the wellbeing of their residents and are less accessible to other rent-assisted households. PMID- 21279454 TI - Stress management and resilience training among Department of Medicine faculty: a pilot randomized clinical trial. AB - BACKGROUND: Physician distress is common and related to numerous factors involving physicians' personal and professional lives. The present study was designed to assess the effect of a Stress Management and Resiliency Training (SMART) program for increasing resiliency and quality of life, and decreasing stress and anxiety among Department of Medicine (DOM) physicians at a tertiary care medical center. PARTICIPANTS: Forty DOM physicians were randomized in a wait list controlled clinical trial to either the SMART intervention or a wait-list control group for 8 weeks. The intervention involved a single 90 min one-on-one training in the SMART program. Primary outcome measures assessed at baseline and week 8 included the Connor Davidson Resilience Scale (CDRS), Perceived Stress Scale (PSS), Smith Anxiety Scale (SAS) and Linear Analog Self Assessment Scale (LASA). RESULTS: Thirty-two physicians completed the study. A statistically significant improvement in resiliency, perceived stress, anxiety, and overall quality of life at 8 weeks was observed in the study arm compared to the wait list control arm: CDRS: mean +/- SD change from baseline +9.8 +/- 9.6 vs. -0.8 +/ 8.2, t(30) = 3.18, p = 0.003; PSS: -5.4 +/- 8.1 vs. +2.2 +/- 6.1, t(30) = -2.76, p = 0.010; SAS: -11.8 +/- 12.3 vs.+ 2.9 +/- 8.9, t(30) = -3.62, p = 0.001; and LASA: +0.4 +/- 1.4 vs. -0.6 +/- 1.0, t(30) = 2.29, p = 0.029. CONCLUSIONS: A brief training to enhance resilience and decrease stress among physicians using the SMART program was feasible. Further, the intervention provided statistically significant improvement in resilience, stress, anxiety, and overall quality of life. In the future, larger clinical trials with longer follow-up and possibly wider dissemination of this intervention are warranted. PMID- 21279453 TI - HIV-1 Vif interaction with APOBEC3 deaminases and its characterization by a new sensitive assay. AB - The human APOBEC3 (A3) cytidine deaminases, such as APOBEC3G (A3G) and APOBEC3F (A3F), are potent inhibitors of Vif-deficient human immunodeficiency virus type 1 (HIV-1). HIV-1 Vif (viral infectivity factor) binds A3 proteins and targets these proteins for ubiquitination and proteasomal degradation. As such, the therapeutic blockage of Vif-A3 interaction is predicted to stimulate natural antiviral activity by rescuing APOBEC expression and virion packaging. In this study, we describe a successful application of the Protein Fragment Complementation Assay (PCA) based on the enzyme TEM-1 beta-lactamase to study Vif-A3 interactions. PCA is based on the interaction between two protein binding partners (e.g., Vif and A3G), which are fused to the two halves of a dissected marker protein (beta lactamase). Binding of the two partners reassembles beta-lactamase and hence reconstitutes its activity. To validate our assay, we studied the effect of well described Vif (DRMR, YRHHY) and A3G (D128K) mutations on the interaction between the two proteins. Additionally, we studied the interaction of human Vif with other members of the A3 family: A3F and APOBEC3C (A3C). Our results demonstrate the applicability of PCA as a simple and reliable technique for the assessment of Vif-A3 interactions. Furthermore, when compared with co-immunoprecipitation assays, PCA appeared to be a more sensitive technique for the quantitative assessment of Vif-A3 interactions. Thus, with our results, we conclude that PCA could be used to quantitatively study specific domains that may be involved in the interaction between Vif and APOBEC proteins. PMID- 21279456 TI - Diagnostic performance of multislice CCTA: is it ready for clinical use? PMID- 21279455 TI - Food insufficiency and health services utilization in a national sample of homeless adults. AB - BACKGROUND: Homeless people have high rates of hospitalization and emergency department (ED) use. Obtaining adequate food is a common concern among homeless people and may influence health care utilization. OBJECTIVE: We tested the hypothesis that food insufficiency is related to higher rates of hospitalization and ED use in a national sample of homeless adults. DESIGN: We analyzed data from the 2003 Health Care for the Homeless (HCH) User Survey. PARTICIPANTS: Participants were 966 adults surveyed at 79 HCH clinic sites throughout the US. The study sample was representative of over 436,000 HCH clinic users nationally. MEASURES: We determined the prevalence and characteristics of food insufficiency among respondents. Using multivariable logistic regression, we examined the association between food insufficiency and four past-year acute health services utilization outcomes: (1) hospitalization for any reason, (2) psychiatric hospitalization, (3) any ED use, and (4) high ED use (>= 4 visits). RESULTS: Overall, 25% of respondents reported food insufficiency. Among them, 68% went a whole day without eating in the past month. Chronically homeless (p = 0.01) and traumatically victimized (p = 0.001) respondents were more likely to be food insufficient. In multivariable analyses, food insufficiency was associated with significantly greater odds of hospitalization for any reason (AOR 1.59, 95% CI 1.07, 2.36), psychiatric hospitalization (AOR 3.12, 95% CI 1.73, 5.62), and high ED utilization (AOR 2.83, 95% CI 1.32, 6.08). CONCLUSIONS: One-fourth of homeless adults in this national survey were food insufficient, and this was associated with increased odds of acute health services utilization. Addressing the adverse health services utilization patterns of homeless adults will require attention to the social circumstances that may contribute to this issue. PMID- 21279457 TI - From the editors' desk: disparities near and far. PMID- 21279458 TI - Anorexia nervosa: Russell's sign with concurrent tetany. PMID- 21279459 TI - The value of axillary ultrasound with fine needle aspiration as a pre-operative staging procedure in breast cancer: Northern Irish experience. AB - INTRODUCTION: In our unit sentinel lymph node biopsy (SLNB) is performed without intra-operative pathological nodal assessment. If node biopsies are positive the patients have to return at a later date for a complete axillary node clearance (ANC). METHODS: We conducted a retrospective study to ascertain if the use of pre operative ultrasound assessment of the axilla with fine needle aspiration (FNA) sampling could identify patients with nodal metastases and therefore identify patients who should proceed primarily to ANC. RESULTS: Our study showed that 40 patients out of 119 had nodal metastases, and ultrasound correctly identified 19 of those patients. PMID- 21279460 TI - Sudden death due to 4th ventricle arachnoid cyst. PMID- 21279461 TI - A novel sequence-based coa genotyping method to discriminate nosocomial methicillin-resistant Staphylococcus aureus isolates. AB - AIM: To evaluate a novel sequence-based coa typing method in classification for nosocomial methicillin-resistant Staphylococcus aureus. METHOD: D1 and D2 regions of coa gene were used to discriminate methicillin-resistant Staphylococcus aureus and compared with other classical sequence-based methods with discriminate power. RESULTS: All MRSA isolates were divided into 11 types and about 20 subtypes with coa typing method here. The discriminate power of this coa typing method was better than MLST or spa method. CONCLUSION: It was demonstrated that this coa method is a simple, rapid, and effective technique applicable for outbreak or local nosocomial MRSA investigations in the future. PMID- 21279462 TI - Agreement between Framingham-DORICA and SCORE scales in estimation of cardiovascular risk in the patients suffering from metabolic syndrome in Granada (Spain). AB - BACKGROUND AND OBJECTIVE: The aim of the present study was to compare the risk stratification obtained with the Framingham function, recommended by the National Cholesterol Education Program (ATP-III), and the risk charts of the Systematic Coronary Risk Evaluation (SCORE) program, in a cohort of subjects between 20 and 75 years (mean 59 years, 70% females) with metabolic syndrome. SUBJECTS AND METHOD: Participants were classified as low, moderate, or high risk by ATP-III and by SCORE of risk at 10 years, respectively. RESULTS: 8.3% of males and 7.4% of women from our study were classified as high risk in 10 years time by Framingham-DORICA. Regarding SCORE program 50% men and 29.6% of women were considered to have high coronary risk. CONCLUSIONS: Risk estimation with SCORE and Framingham function shows significant gender and quantitative differences. There is no concordance between Framingham and SCORE function to estimate cardiovascular risk on subjects included on the high-risk group. PMID- 21279463 TI - Caring for dementia carers: the role of general practitioners in Ireland. AB - BACKGROUND: Dementia patients in Ireland live 8 years on average after diagnosis and health policy aims to ensure patients are cared for in the home for as long as possible. AIM: To assess the role of general practitioners in Ireland caring for dementia carers. METHODS: A PubMed search (1980-2010) was performed using MeSH terms "caregivers or carers", "Dementia or Alzheimer's disease", "family physician or general practitioner". An English language restriction was imposed and the search continued to June 24th 2010. RESULTS: Psychosocial multidisciplinary interventions that unite education, skills training, management of psychological problems and family support in the community are effective in managing the problems of carers and should be facilitated by general practitioners. CONCLUSIONS: Dementia carers form an important yet understated patient group who present unique challenges for general practitioners in Ireland. PMID- 21279464 TI - Effects of progesterone, beta-estradiol, and androsterone on the changes of inorganic element content in barley leaves. AB - The present study was performed to determine the changes in inorganic element content in barley leaves of mammalian sex hormones (MSH). Barley leaves were sprayed with 10(-4), 10(-6), 10(-9), 10(-12), 10(-15) M concentrations of progesterone, beta-estradiol, and androsterone at 7th day after sowing. The plants were harvested at the end of 18 days after treatment with MSH solutions. The inorganic element concentrations were determined using wavelength dispersive X-ray fluorescence spectroscopy technique. Although the all MSH concentrations significantly (p < 0.05) increased the concentrations of calcium, magnesium, phosphorus, sulfur, copper, manganese, aluminum, zinc, iron, potassium, and chlorine, it decreased those of sodium concentration in barley leaves. The maximum changes in the element concentrations were obtained at 10(-9) M for plant leaves treated with progesterone, 10(-6) M for plant leaves treated with beta estradiol and androsterone. The present study elucidated that MSH significantly (p < 0.05) affected the inorganic element concentrations in barley leaves. PMID- 21279465 TI - Effects of subchronic aluminum exposure on the immune function of erythrocytes in rats. AB - This study assessed effects of aluminum (Al) exposure on the immune function of erythrocytes in rats. Forty male Wistar rats (5 weeks old) weighed 110-120 g were randomly allocated equally into four groups according to their weights and were orally exposed to 0, 64.18, 128.36, and 256.72 mg/kg body weight aluminum trichloride in drinking water for 120 days. Levels of erythrocytes C(3b) receptor rate (RBC-C(3b)RR), erythrocytes C(3b) immune complex rosette rate (RBC-ICR), erythrocytes rosette forming enhancing rate (ERER) and erythrocytes rosette forming inhibitory rate (ERIR) were determined by the end of experiment. The three Al-treated groups had lower values of RBC-C(3b)RR and ERER, and higher values of RBC-ICR and ERIR than those in control group. The levels of RBC-C(3b)RR and ERER decreased, while the levels of RBC-ICR and ERIR increased with the increases of Al content in drinking water. The results suggest that the immune function of erythrocytes in rats is suppressed by Al exposure. PMID- 21279466 TI - A pilot study on zinc levels in patients with rheumatoid arthritis. AB - The aim of the study was to evaluate zinc levels in three biological compartments (serum, erythrocytes and hair) in patients with rheumatoid arthritis (RA) as compared to healthy individuals. Zinc levels in serum, erythrocytes and hair (in 74 patients with RA and 30 healthy individuals) were assessed by atomic absorption spectroscopy. The mean hair zinc content was significantly lower in RA patients as compared to healthy individuals (p<0.001). Moreover, a positive correlation was observed in the RA patient group between the erythrocyte zinc levels and the prednisone dose (rs=0.48, p<0.05), and a negative correlation was found in this population between the serum zinc levels and disease duration (rs= 0.42, p<0.0006). In conclusion, it seems that hair may be a useful complementary study material for evaluating "zinc status" in rheumatoid arthritis patients. PMID- 21279467 TI - Molybdenum content of Canadian and US infant formulas. AB - Molybdenum is an essential trace nutrient in the human diet. Our purpose was to provide a comprehensive analysis of Mo content of various types of powdered infant formulas across Canada and the USA. All infant formulas, available on the day of sampling, were purchased from random supermarkets in Grand Forks, ND, USA; San Diego, CA, USA; Washington, DC, USA; and Winnipeg, MB, Canada. Reference powdered milk, human milk (HM), and formula samples were weighed and acid digested prior to analysis by graphite furnace atomic absorption spectroscopy. Mo content in all formulas ranged from 15.4 to 80.3 MUg/L (mean+/-SE, 37.7+/-1.7 MUg/L). HM Mo concentration ranged from 1.5 to 9.5 MUg/L (5.09+/-0.81 MUg/L). Formulas intended for full-term or for premature infants feeding contained, on average, more Mo than HM. Formulas intended for infants with special needs contained similar mean Mo levels to HM. No significant differences were detected between mean Mo values of formulas of a same type purchased from different brands and/or at different locations. High Mo intake may pose health risks, despite lower bioavailability of Mo from formula compared with HM. PMID- 21279468 TI - Construction, expression, and characterization of a single-chain variable fragment antibody against 2,4-dichlorophenoxyacetic acid in the hemolymph of silkworm larvae. AB - A single-chain variable fragment antibody against herbicide, 2,4 dichlorophenoxyacetic acid (2,4-D-scFv) has been successfully expressed in the hemolymph of silkworm larvae using a rapid Bombyx mori nucleopolyhedrovirus (BmNPV) bacmid DNA system. Variable heavy- and light-chain domains were cloned directly from the cDNA of the hybridoma cell line 2C4 and assembled together with flexible peptide linker (Gly(4)Ser)(3) between two domains. The yield of functional 2,4-D-scFv after purification was 640 MUg per 30 ml of hemolymph, which is equivalent to 21.3 mg per liter of hemolymph. The characterization of 2,4-D-scFv using an indirect competitive enzyme-linked immunosorbent assay (icELISA) revealed that it has wide cross-reactivities against 2,4,5 trichlorophenoxyacetic acid (65.5%), 2,4-dichlorophenol (47.9%), and 2,4 dichlorobenzoic acid (26.0%), making it possible to apply 2,4-D-scFv to icELISA for detecting/determining 2,4-D and its metabolites. Judging from its cost and time requirements and its ease of handling, this BmNPV bacmid DNA expression system is more useful for expressing functional scFv than bacterial systems, which frequently require costly and time-consuming refolding. PMID- 21279469 TI - Effect of the conformational stability of the CH2 domain on the aggregation and peptide cleavage of a humanized IgG. AB - To examine the effect of the conformational stability of the CH2 domain on aggregation and peptide cleavage of a humanized IgG1, we carried out size exclusion chromatography and sodium dodecyl sulfate polyacrylamide gel electrophoresis analyses of incubated sample solutions. By comparing the residual percentage of monomer after incubation at 60 and 80 degrees C at various pH levels, we found that aggregation and peptide cleavage of the humanized IgG1 occurred during long incubation at 60 degrees C under acidic conditions. Next, we confirmed cleavage of the Asp272-Pro273 peptide bond in the CH2 domain. Comparison of the cleavage rates of the IgG1 monomer and a peptide containing the same Asp-Pro sequence revealed that the conformational stability of the CH2 domain retards cleavage of the Asp272-Pro273 peptide bond at 60 degrees C and pH 4.0. The finding of aggregation and peptide cleavage of the humanized IgG1 after long incubation at 60 degrees C under acidic conditions was supported by another finding: there were lower unfolding temperatures of the CH2 domain at pH 4.0 and 5.0. We conclude that the conformational stability of the CH2 domain is closely related to aggregation and peptide cleavage of the humanized IgG1 under acidic conditions. We also found that the 2-[N-morpholino] ethane sulfonate buffer inhibits aggregation of the IgG1 at pH 4.0-5.0 and 7.0-8.0. PMID- 21279470 TI - Propyl gallate synthesis using acidophilic tannase and simultaneous production of tannase and gallic acid by marine Aspergillus awamori BTMFW032. AB - Marine Aspergillus awamori BTMFW032, recently reported by us, produce acidophilic tannase as extracellular enzyme. Here, we report the application of this enzyme for synthesis of propyl gallate by direct transesterification of tannic acid and in tea cream solubilisation besides the simultaneous production of gallic acid along with tannase under submerged fermentation by this fungus. This acidophilic tannase enabled synthesis of propyl gallate by direct transesterification of tannic acid using propanol as organic reaction media under low water conditions. The identity of the product was confirmed with thin layer chromatography and Fourier transform infrared spectroscopy. It was noted that 699 U/ml of enzyme could give 60% solubilisation of tea cream within 1 h. Enzyme production medium was optimized adopting Box-Behnken design for simultaneous synthesis of tannase and gallic acid. Process variables including tannic acid, sodium chloride, ferrous sulphate, dipotassium hydrogen phosphate, incubation period and agitation were recognized as the critical factors that influenced tannase and gallic acid production. The model obtained predicted 4,824.61 U/ml of tannase and 136.206 MUg/ml gallic acid after 48 h of incubation, whereas optimized medium supported 5,085 U/ml tannase and 372.6 MUg/ml of gallic acid production after 36 and 84 h of incubation, respectively, with a 15-fold increase in both enzyme and gallic acid production. Results indicated scope for utilization of this acidophilic tannase for transesterification of tannic acid into propyl gallate, tea cream solubilisation and simultaneous production of gallic acid along with tannase. PMID- 21279471 TI - A mathematical model of HIV dynamics in the presence of a rescuing virus with replication deficiency. AB - Recently, an enzyme (Cre recombinase) has been developed by directed evolution that successfully removes the HIV genome from the nuclear DNA of infected cells. To explore this idea further, we hypothesized that a replication deficient virus (called "police virus"), added externally, can deliver such a recombinase which excises the integrated HIV DNA from the genome of infected cells. Such a "police virus" could attack and remove the integrated provirus which is not possible using contemporary strategies. The hypothesis was tested by developing a mathematical model that describes the dynamics of virus-host cell interaction and the consequences of introducing the "police virus". The simulations show that such a therapeutic vector may eradicate all HIV viruses from the system in the long term. All components of the HIV infection (free virus, latently, and actively infected cells) can be cleared and the system ends up only with susceptible CD4+ cells. The proposed model may provide new insights in the dynamical behavior and future alternative treatments of HIV. PMID- 21279473 TI - Astrocyte dysfunction associated with cerebellar attrition in a Nijmegen breakage syndrome animal model. AB - Nijmegen breakage syndrome (NBS) is a genomic instability disorder caused by hypomorphic mutations in the Nbs1 gene. When Nbs1 is conditionally inactivated in the central nervous system of mice (Nbs1-CNS-Delta), they suffer from severe cerebellar atrophy, ataxia, and white matter damage. Here, we show that conditional inactivation of the murine Nbs1 gene has a profound effect on the integrity and the functionality of the glial cells, which suggests their crucial role in the pathogenesis of NBS. Interestingly, in Nbs1-CNS-Delta mice, the dramatic reduction in the numbers of Purkinje and granule cells was also linked to a reduction of microglial cells but not to astrocytes (GFAP+), suggesting an impairment in astrocytic functionality. Nbs1 levels were dramatically reduced in adult astrocyte isolated from Nbs1-CNS-Delta mice, suggesting a major role in cerebellar pathology. In order to investigate the effect of Nbs1 deletion on astrocyte activity, we investigated glutamine synthetase levels in astrocyte and discovered 40% reduction as compared to WT. Furthermore, we found a significant reduction in the secretion of neurotrophic factors, such as brain-derived neurotrophic factor and neurotrophin 3. Understanding the contribution of malfunctioning astrocytes to the etiology of NBS can elucidate a hitherto unknown aspect of this disorder. PMID- 21279474 TI - Therapeutic approaches in hereditary angioedema. AB - Hereditary angioedema (HAE) is characterized by acute attacks of edema with multiple localizations, the laryngeal angioedema being the most potentially lethal. In HAE, C1-INH impairments cause episodic increase in kallikrein activity leading to attacks of angioedema. Several therapies have recently become available to treat or to prevent HAE attacks, and others are under evaluation for this indication. Plasma-derived C1-INH, bradykinin receptor antagonists (icatibant), kallikrein inhibitors (ecallantide), or recombinant C1-INH is authorized on the market for HAE attack therapy or prophylaxis. Some of these compounds can be used exclusively to treat HAE attacks, whereas others can also be used as prophylactic therapies. Such therapies, although not available worldwide, can improve disease outcome due to their different mechanisms of action. PMID- 21279476 TI - The past, present, and future of single neuron reconstruction. PMID- 21279475 TI - A novel algorithm for the diagnosis of celiac disease and a comprehensive review of celiac disease diagnostics. AB - There is an urgent clinical need for a better laboratory celiac disease diagnosis with both less false positive results and minimal underdetection. The aim of the present study was to evaluate the performance and diagnostic accuracy of different assays in an outpatient population setting for the diagnosis for celiac disease (CD) in order to design an optimal algorithm. We used 15 different ELISA assays to assess 47 blood samples of newly diagnosed children (positive biopsy results) and 52 samples from age- and sex-matched children with negative biopsy results for CD. Scoring criteria were established for grading the assays performance and characteristics. The combined gliadin and tTG assays exhibited the best sensitivity (100%). The addition of other assays to the CeliCheck neo epitopes assay improved specificity so that the final algorithm had 100% sensitivity, 96.2% specificity, and 98.1% accuracy. The clinical demand for both maximal sensitivity and maximal specificity cannot be achieved with a single test. Using a combination of a sensitive assay together with specific assays improved celiac disease detection rates, with an acceptable number of false positive results. This model, however, needs to be confirmed prospectively in both children and adults. PMID- 21279477 TI - Use and efficacy of saline hydration and N-acetyl cysteine to prevent contrast induced nephropathy in low-risk populations undergoing coronary artery angiography. AB - Contrast-induced nephropathy (CIN) is most commonly defined as acute renal failure occurring within 48-72 h of exposure to an intravascular radiographic contrast medium that is not attributable to other causes. In the international literature, a 25% increase in serum creatinine levels or an increase in absolute values of 0.5 mg/dl from baseline has been suggested to define CIN. The reported incidence of CIN varies widely, ranging from 2 to 50%. This variability results from differences in the presence or absence of risk factors. With a retrospective analysis we evaluated the use of saline hydration plus N-acetyl cysteine (NAC) to prevent CIN in a low-risk population of patients undergoing coronary artery angiography compared with an historic low risk group not treated. From January 2009 to December 2009, 152 consecutive patients who underwent coronary artery angiography with a low osmolarity contrast agent were enrolled in our study, and compared with an historic control group consisting of 172 low-risk patients. Nephrotoxic drugs such as diuretics, ACE-I and ARBs were stopped at least 24 h before the procedure. Inclusion criteria to define low-risk population were the absence of: diabetes, age >65 years, or baseline creatinine >1.4 mg/dl. We have treated group A (152 patients, 47.3%) with a saline hydration (1 ml/kg/h) plus N acetyl cysteine 600 mg 12 h before and 12 h after the procedure; group B (group control of 170 patients, 52.7%) were not treated. The overall incidence of CIN was 7.1% (23 patients). In particular, the incidence of CIN was 2.6% (4 patients) in the group A and 11.2% (19 patients) in the group B (p = 0.002). In the multivariate analysis, including risk factor such as age, hypertension, hypercholesterolemia, current smoking habit baseline creatinine level, contrast index and hydration, the last variable was the only one inversely correlated independently with the incidence of CIN (p = 0.001). In conclusion, intravenous hydration with saline and NAC is an effective and low cost tool in preventing CIN in patients undergoing coronary artery angiography, and, according to the current guidelines, should be used in all high-risk patients for CIN. Our results show that even in patients at low risk, hydration with saline 0.9% plus NAC is useful and significantly reduces the incidence of CIN. PMID- 21279478 TI - Long-term treatment with mesalazine in patients with symptomatic uncomplicated diverticular disease. AB - The aim of this work was to compare the recurrence of diverticulitis during a 5 year follow-up in a population of patients affected by symptomatic uncomplicated diverticular disease (SUDD), taking either 800 mg of mesalamine b.i.d for 10 days every month or no 5-ASA. Sixty-seven consecutive patients affected by SUDD followed-up every 6 months for 5 years. All patients in this group (M-group) were requested to consume mesalamine 800 mg b.i.d for 10 days every month. A control group (C-group) of 82 subjects with SUDD allocated in an institution for the elderly and taking no 5-ASA medications was also followed-up for the same period. As a result in the M-group 14.9% of patients did not complete the follow-up, and diverticulitis developed in two patients (4%; 95% CI 1.1-13.5). In the C-group 6.1% patients did not complete the follow-up, and diverticulitis developed in 8 patients (10.4%; 95% CI 5.4-19.2). The difference between the two groups was not significant (difference = -6.4%; 95% CI -15.6 to 4.3; log rank test: p = 0.1256). Cyclic treatment with mesalazine seems to be clinical, although not statistically effective in reducing the incidence of diverticulitis. In future well-designed RCTs are necessary to demonstrate the therapeutic gain of the use of mesalazine, if any, in the management of patients with SUDD. PMID- 21279479 TI - Mammalian cell dedifferentiation as a possible outcome of stress. AB - Differentiation cascades are arranged hierarchically; stem cells positioned at the top of the hierarchy generate committed progenitors that, in turn, proliferate and further differentiate stepwise into mature progeny. This rigid, irreversible structure ensures the phenotypic stability of adult tissues. However, such rigidity may be problematic under conditions of tissue damage when reconstitution is required. Although it may seem unlikely that the restrictions on changes in cell phenotypes would be lifted to enable tissue reconstitution, it is nevertheless possible that mammalian tissues are endowed with sufficient flexibility to enable their adaptation to extreme conditions. PMID- 21279481 TI - Publishing SNP genotypes of human embryonic stem cell lines: policy statement of the International Stem Cell Forum Ethics Working Party. AB - Novel methods and associated tools permitting individual identification in publicly accessible SNP databases have become a debatable issue. There is growing concern that current technical and ethical safeguards to protect the identities of donors could be insufficient. In the context of human embryonic stem cell research, there are no studies focusing on the probability that an hESC line donor could be identified by analyzing published SNP profiles and associated genotypic and phenotypic information. We present the International Stem Cell Forum (ISCF) Ethics Working Party's Policy Statement on "Publishing SNP Genotypes of Human Embryonic Stem Cell Lines (hESC)". The Statement prospectively addresses issues surrounding the publication of genotypic data and associated annotations of hESC lines in open access databases. It proposes a balanced approach between the goals of open science and data sharing with the respect for fundamental bioethical principles (autonomy, privacy, beneficence, justice and research merit and integrity). PMID- 21279480 TI - Effects of cryopreservation on the transcriptome of human embryonic stem cells after thawing and culturing. AB - Human embryonic stem cells (hESCs) can be propagated indefinitely in vitro in an undifferentiated pluripotent state, can differentiate into derivatives of all three germ layers and are of considerable interest for applications in regenerative medicine. Clinical application of hESCs, however, requires reliable protocols for cryopreservation. Current protocols for cryopreservation of hESCs suffer from low recovery rates of hESCs and loss of pluripotency after thawing. We therefore studied the effects of cryopreservation on the viability, proliferation potential, and the pluripotency status of hESCs by combining cellular readouts and transcriptomics. We identified biological processes and pathways affected by cryopreservation in order to understand the limited survival rate of hESCs by comparing transcriptomes of hESCs at different time points after thawing with cells that did not undergo cryopreservation. While the transcriptomes of cells post thawing were very similar to those of control non frozen hESCs for the early time points, we observed increased expression of genes involved in apoptosis, embryonic morphogenesis, ossification, tissue morphogenesis, regeneration, vasculature development and cell death at later time points. Our data suggest that inhibition of anoikis apoptosis and the stress induced differentiation pathways are promising targets for improving the survival rate and maintaining pluripotency of hESCs after cryopreservation. PMID- 21279483 TI - Ischial spine sign reveals acetabular retroversion in Legg-Calve-Perthes disease. AB - BACKGROUND: Acetabular retroversion has been identified in mature patients with sequelae of Legg-Calve-Perthes (LCP) disease. Whether this is a contributing etiologic factor that leads to the disease process or result of the head deformity is not known. The prominence of the ischial spine (PRIS) sign, which reflects retroversion, can be observed before ossification of the anterior and posterior walls in a skeletally immature patient and could help determine whether the retroverted acetabulum is present before or after head involvement in patients with LCP disease. QUESTIONS/PURPOSE: We therefore determined (1) the prevalence of the PRIS sign in patients with LCP disease compared with healthy control subjects, (2) whether the PRIS sign is seen at the time of head involvement in patients with LCP disease, and (3) the prevalence of bilaterality of the PRIS sign in patients with LCP disease and control subjects. PATIENTS AND METHODS: Of 295 patients with LCP disease, 47 (49 hips) met our inclusion criteria. Of these, 39 (41 hips) had open triradiate cartilage and comprised the study group. Twenty-five pediatric patients with polytrauma (50 hips) with standardized radiographs comprised the control group. RESULTS: A positive PRIS sign was noted in 37 of the 41 skeletally immature hips compared with only 16 of the 50 control hips. We observed a positive PRIS sign early in the LCP disease process with eight of nine patients in the fragmentation phase having a positive PRIS sign. The PRIS sign was seen bilaterally in 25 of 39 patients with unilateral LCP disease and in only five of 25 control patients. CONCLUSIONS: Acetabular retroversion, as evidenced by a positive PRIS, was present in nine of 10 children with LCP disease. It is uncertain if retroversion is a cause or a sequela of the disease, but it was seen early in the disease process at the time of head involvement in the majority of patients. LEVEL OF EVIDENCE: Level III, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 21279484 TI - High revision rate at 5 years after hip resurfacing with the Durom implant. AB - BACKGROUND/RATIONALE: There is growing evidence that different resurfacing implants are associated with variable survival and revision rates. A registry analysis indicated the Durom resurfacing implant had high revision rates at 5 years, whereas three original studies reported low revision rates at short-term followups. Thus, the revision rates appear controversial. QUESTIONS/PURPOSES: We therefore assessed (1) the survivorship including differences between women and men at a mean of 5 years after resurfacing with the Durom implant, and (2) clinical scores and radiographic parameters. PATIENTS AND METHODS: We prospectively followed all 100 Durom hip resurfacings implanted in 91 patients (25 women and 66 men; mean age, 52 years) between 2003 and 2004. Survivorship analysis was performed with pending revision or revision for any reason as the endpoint. The minimum followup was 47 months (mean, 60 months; range, 47-72 months). RESULTS: At a mean of 5 years, 11 hips were revised for various reasons. Cumulative survival was 88.2% for all patients and 81.5% for women. The mean Oxford (OHS) and Harris hip (HHS) scores were 14.6 and 94.7, respectively. The mean UCLA activity level was 7.9. Sclerotic changes around the short femoral stem (pedestal sign) were detected in 40% of the hips. We observed considerable femoral neck thinning with component-to-neck ratios of 0.85 preoperatively and 0.82 at 5 years. CONCLUSIONS: Our study highlights a high revision rate 5 years after hip resurfacing with the Durom implant. This observation underlines previous findings from registry data and suggests that revision rates increase with time. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 21279485 TI - Breakout session: Gender and ethnic disparities in pain management. AB - BACKGROUND: Pain management is a complex and evolving topic. Treatment of pain must account for biochemical as well as social and economic factors. Sex, gender, and ethnic differences exist in the pathophysiology, diagnosis, and provision of care for patients with pain. QUESTIONS/PURPOSES: We sought to identify the sex, gender, and ethnic disparities leading to care inequalities with respect to pain management. Our purposes were to (1) clarify the state of where we are now, (2) outline ways to approach where we need to go, and (3) generate solutions for how we get there. WHERE ARE WE NOW?: Studies are beginning to uncover the biologic mechanisms underlying the pain response in sex, gender, and ethnic subgroups. Patient characteristics that increase the risk of postoperative pain are being identified. WHERE DO WE NEED TO GO?: Much work needs to be done in medical education with respect to sex, gender, and ethnic disparities in pain management. Research efforts must better describe differences in physiology of pain, incidence of pain, coping strategies, patient-doctor relationships, and gender/ethnic-specific modes of care for the patient with pain. HOW DO WE GET THERE?: Future work will involve combined efforts with pain/anesthesia specialty societies, developing a disparities and pain management curriculum for medical providers, endorsing health literacy, performing high-quality Level I/II research, and exploring systems processes in pain management in the acute hospital setting. PMID- 21279486 TI - Orthopaedic case of the month: A 16-year-old boy with a recurrent mass of the first toe. PMID- 21279487 TI - Short-term and long-term orthopaedic issues in patients with fragility fractures. AB - BACKGROUND: Patients with impaired bone quality who suffer a fragility fracture face substantial challenges in both their short- and long-term care. In addition to poor bone quality, many of these patients have multiple medical comorbidities that alter their surgical risk and affect their ultimate functional recovery. Some medical issues can contribute to the altered bone quality and must be addressed to prevent future fractures. QUESTIONS/PURPOSES: This review summarizes the modifications in perioperative management and fracture fixation in patients with common fragility fractures who have impaired bone quality. It also summarizes the postoperative diagnosis and treatment of secondary causes of impaired bone quality in these patients. METHODS: We performed a PubMed search, and literature published after 2000 was prioritized, with the exception of benchmark clinical trial studies published before 2000. RESULTS: Patients with altered bone quality require rapid perioperative management of multiple medical comorbidities. Implant selection in patients with poor quality bone should permit early weightbearing, and constructs should maximize surface area contact with the remaining bone. Long-term diagnosis and treatment of other disease states contributing to poor bone quality (vitamin D deficiency/insufficiency, hypothyroidism, hyperthyroidism, hyperparathyroidism, Cushing's disease, and hypogonadism) must occur to minimize the chances of future fractures. CONCLUSIONS: Recognition of patients with impaired bone quality and proper treatment of their special needs in both the short and long term are essential for their best opportunity for maximal functional recovery and prevention of future fractures. PMID- 21279488 TI - Hsp-27 induction requires POU4F2/Brn-3b TF in doxorubicin-treated breast cancer cells, whereas phosphorylation alters its cellular localisation following drug treatment. AB - POU4F2/Brn-3b transcription factor (referred to as Brn-3b) is elevated in >60% of breast cancers and profoundly alters growth and behaviour of cancer cells by regulating distinct subsets of target genes. Previous studies showed that Brn-3b was required to maximally transactivate small heat shock protein, HSPB1/Hsp-27 (referred to as Hsp-27), and consequently, Brn-3b expression correlated well with Hsp27 levels in human breast biopsies. In these studies, we showed that Brn-3b is increased in MCF7 breast cancer cells that survive following treatment with chemotherapeutic drug doxorubicin (Dox) with concomitant increases in Hsp-27 expression. Targeting of Brn-3b using short interfering RNA reduced Hsp-27 in Dox treated cells, suggesting that Brn-3b regulates Hsp-27 expression under these conditions. Wound healing assays showed increased Brn-3b in Dox-treated migratory cells that also express Hsp-27. Interestingly, Hsp-27 phosphorylation and cellular localisation are also significantly altered at different times following Dox treatment. Thus, phospho-Hsp-27 (p-Hsp27) protein displayed widespread distribution after 24 hrs of Dox treatment but was restricted to the nucleus after 5 days. However, in drug-resistant cells (grown in Dox for > 1 month), p Hsp-27 was excluded from nuclei and most of the cytoplasm and appeared to be associated with the cell membrane. Studies to determine how this protein promotes survival and migration in breast cancer cells showed that the protective effects were conferred by unphosphorylated Hsp-27 protein. Thus, complex and dynamic mechanisms underlie effects of Hsp-27 protein in breast cancer cells following treatment with chemotherapeutic drugs such as Dox, and this may contribute to invasiveness and drug resistance following chemotherapy. PMID- 21279490 TI - Trigeminal neuralgia caused by an anomalous posterior inferior cerebellar artery from the primitive trigeminal artery: case report. AB - A 61-year-old woman presented with typical trigeminal neuralgia (TN), caused by an aberrant posterior inferior cerebellar artery (PICA) associated with the primitive trigeminal artery (PTA). Magnetic resonance angiography and digital subtraction angiography clearly showed an anomalous artery directly originating from the PTA and coursing into the PICA territory at the cerebellum. During microvascular decompression (MVD), we confirmed and decompressed vascular compression of the trigeminal nerve by this anomalous, PICA-variant type of PTA. The PTA did not conflict with the trigeminal nerve, and the anomalous PICA only compressed the caudolateral part of the trigeminal nerve, without the more common compression at its root entry zone. This case is informative due not only to its very unusual angioanatomical variation but also to its helpfulness for surgeons preparing a MVD for a TN associated with such a rare vascular anomaly. PMID- 21279489 TI - Lesion of the cerebellar noradrenergic innervation enhances the harmaline-induced tremor in rats. AB - Abnormal synchronous activation of the glutamatergic olivo-cerebellar pathway has been suggested to be crucial for the harmaline-induced tremor. The cerebellum receives two catecholaminergic pathways: the dopaminergic pathway arising from the ventral tegmental area/substantia nigra pars compacta, and the noradrenergic one from the locus coeruleus. The aim of the present study was to examine a contribution of the cerebellar catecholaminergic innervations to the harmaline induced tremor in rats. Rats were injected bilaterally into the cerebellar vermis with 6-hydroxydopamine (6-OHDA; 8 MUg/0.5 MUl) either alone or this treatment was preceded (30 min earlier) by desipramine (15 mg/kg ip). Harmaline was administered to animals in doses of 7.5 or 15 mg/kg ip. Tremor of forelimbs was measured as a number of episodes during a 90-min observation. Rats were killed by decapitation 30 or 120 min after harmaline treatment. The levels of dopamine, noradrenaline, serotonin, and their metabolites were measured by HPLC in the cerebellum, substantia nigra, caudate-putamen, and frontal cortex. 6-OHDA injected alone enhanced the harmaline-induced tremor. Furthermore, it decreased the noradrenaline level by ca. 40-80% in the cerebellum and increased the levels of serotonin and 5-HIAA in the caudate-putamen and frontal cortex in untreated and/or harmaline-treated animals. When 6-OHDA treatment was preceded by desipramine, it decreased dopaminergic transmission in some regions of the cerebellum while inducing its compensatory activation in others. The latter lesion did not markedly influence the tremor induced by harmaline. The present study indicates that noradrenergic innervation of the cerebellum interacts with cerebral serotonergic systems and plays an inhibitory role in the harmaline induced tremor. PMID- 21279491 TI - The cerebellar nuclei take center stage. PMID- 21279492 TI - Uptake of F-18 FDG and ultrasound analysis of carotid plaque. AB - OBJECTIVES: To elucidate the relation between the echolucent plaque on carotid ultrasound and acute inflammation on F-18 FDG carotid PET/CT. METHODS: Thirty nine patients (M:F ratio = 23:16, mean age = 63 +/- 11 years) that underwent coronary angiography and carotid ultrasound were divided into three groups echolucent plaque (n = 22), calcified (n = 10), and no plaque(n = 7). All the patients underwent F-18 FDG carotid PET/CT. The mean standardized uptake values (SUV), namely target to background ratio (TBR) on 180 minutes delayed F-18 FDG carotid PET/CT images were compared with levels of serum inflammatory markers and lipid profiles, and in terms of the presence of carotid plaque on carotid US. RESULTS: 180 minutes TBR of carotid arterial wall at echolucent plaque, calcified plaque, and no plaque were 1.40 +/- 0.05, 1.23 +/- 0.03, 1.17 +/- 0.03 in both carotid artery. TBR of carotid arterial walls for echolucent plaque were significantly larger than TBR for calcified, and no plaque respectively at the both side of carotid artery (P < .05). Serum HDL levels were found to be inversely correlated with F-18 FDG uptake at both carotid arteries (r = -0.43, P = .005) on 180 minutes delayed phase images. Also serum hs-CRP levels were found to be correlated with F-18 FDG TBR values of right carotid arteries (r = 0.41, P = .04). CONCLUSIONS: Our results show that F-18 FDG carotid PET/CT can depict metabolically active atherosclerotic plaques, and suggest that F-18 FDG carotid PET/CT can be used as a noninvasive imaging modality for functional evaluation of atherosclerosis. PMID- 21279493 TI - Factor structure of decisional balance and temptations scales for smoking: cross validation in urban female African-American adolescents. AB - BACKGROUND: The transtheoretical model is an influential theoretical model in health psychology, particularly in its application to smoking cessation research. Decisional Balance (DB) and Temptations are key constructs within this framework. PURPOSE: This study examines the psychometric properties of the DB and Temptations scales for smoking in a predominantly African-American sample of urban adolescent girls. METHODS: We used confirmatory factor analysis to compare the fit of previously published factor structures in smokers (n = 233) and nonsmokers (n = 598). External validity was tested by examining stages of change differences in the retained subscales. RESULTS: Results supported the internal and external validity of the DB scale for smokers and nonsmokers. Notably, previously published three-factor (Social Pros, Coping Pros, Cons) and four factor (Cons split into "Aesthetic Cons" and "Health Cons") models fit equally well, with Cons subscales correlating highly. For Temptations, a previously published three-factor (Negative Affect, Social, Weight Control) hierarchical model fit well in nonsmokers. In smokers, previously published subscales were reliably measured, but their structural relationship remained unclear. Stage difference tests showed medium to large effect sizes of DB and Temptation subscales in smokers and nonsmokers. CONCLUSIONS: The use of DB was validated for both smokers and nonsmokers in this sample of primarily African-American adolescent females, where Cons can be combined or separated into "Aesthetic Cons" and "Health Cons" based on practical utility and preference. For Temptations, more research is needed but large stage differences in Temptations subscales underscore the importance of this concept in smoking acquisition and cessation. PMID- 21279494 TI - [Positive impact of a video and TV documentary on attendance of women to catch-up collective vaccinations and reasons for non-attendance]. AB - The impact of medical documentaries on attendance to immunization sessions is not documented in developing countries. The impact of a video and TV medical documentary on women's vaccination during a catch-up tetanus collective immunization was studied in Cambodia (2002-2004). A medical video documentary produced locally was publicly shown in 10 villages chosen at random among 63 villages to be covered by collective tetanus immunization. In each village where the video was shown, 33 women, older than age 11, were selected at random and questioned about their tetanus vaccination records, to assess if they attended the video and to evaluate their knowledge about tetanus. A second interview was conducted after the first collective vaccination to check their attendance and to record reasons for non-attendance. The same interview was conducted 10 months later, after the documentary was shown on a local TV channel and a second collective tetanus vaccination conducted. Data were collected from 323 (98%) women. Seventy-eight (24%) women saw the video documentary and only eight (2.4%) saw it on TV. Compared to farmers, shopkeepers saw significantly less the documentary (chi2 of Yates: 5.77,P = 0.016; 95% CI: 0.10 < RR = 0.29 < 0.88) and no home keeper or civil servant attended it. Women of childbearing age with no school education were significantly more attracted by the video documentary (chi2 of Yates: 5.99,P = 0.01; 95% CI: 1.10 < RR = 1.57 < 2.22) than other childbearing aged women, although their final immunization coverage was not better. The documentary did not increase the knowledge that contamination for tetanus may come from earth and tools, but not from air and water, and that all ages are at risk for tetanus, but it increased significantly the knowledge that vaccination can prevent the disease (chi2 of Yates: 13.98;P = 0.0001; 95% CI: 1.28 < RR = 1.57 < 1.93). Women who saw the video documentary attended the first collective session more often than those who did not (chi2 of Yates: 11.00; P = 0.0006; 95% CI: 1.23 < RR = 1.51 < 1.84)in spite of their better vaccination status before the immunization, and this was mostly significant for farmers and women more than 45 years of age. Women who saw the documentary either on video or on TV also attended more the second collective session, but not significantly (chi2 of Yates: 1.23;P = 0.266; 95% CI: 0.91 < RR = 1.23 < 1.66). Forty-nine percent of women had not attended school and the video documentary was re-run twice after the first performance. Women older than 45 years (55%) completely escaped immunization significantly more often than women of childbearing age (35%) (chi2 of Yates: 17.26;P = 0.00003, 95% CI: 1.53 < RR = 2.13 < 2.97), who did it more often than schoolgirls (2%) (chi2 of Yates: 9.69;P = 0.002; 95% CI: 0.01 < RR = 0.09 < 0.65). The main reasons for not being vaccinated during catch-up collective tetanus vaccinations were a too short interval between doses according to the WHO schedule (25%), agricultural task (18%), leisure travel (8%), fear of injections (7%), and being completely vaccinated according to the WHO schedule (7%). Only 2% of women were not informed, showing that vaccination was well publicized. This educational technique should be re-used in all villages during coming catch-up tetanus collective immunizations in Cambodia, mostly in urban contexts where coverage during these sessions is lower. Video is still the best method in rural context if some education is also provided to the audience. According to the WHO schedule, the interval between two catch-up tetanus sessions should be extended to over a year to be able to give booster shots to women who already received three or more tetanus doses. Vaccination of schoolgirls is significantly easier to achieve with the help of the teachers. Vaccinating women aged over 45 should be encouraged as they are at risk of tetanus even in developed Asian countries. PMID- 21279495 TI - A differential-outcome effect in pigeons using spatial hedonically nondifferential outcomes. AB - We examined the extent to which nonhedonically different differential outcomes involving feeder location control pigeons' comparison choices in matching to sample. In Experiment 1, we showed that differential feeder location outcomes associated with each of two samples can facilitate delayed-matching accuracy. In Experiment 2, we found positive transfer following training on two matching tasks with differential feeder location outcomes when samples from one task were replaced by samples from the other task. In Experiment 3, we found that when differential-outcome expectations could no longer serve as the cues for comparison choice, sample stimuli continued to exert some control over choice of comparisons. The results indicate that differential outcomes (involving feeder location) that presumably do not differ in hedonic value are sufficient to control comparison choice. Thus, the differential hedonic value of the outcome elicited by the sample does not appear to be a requirement of the differential outcome effect. Furthermore, these differential outcomes appear to augment matching accuracy, but they do not eliminate control by the samples. PMID- 21279496 TI - Renewal after the extinction of free operant behavior. AB - Four experiments were performed to explore the role of context in operant extinction. In all experiments, leverpressing in rats was first reinforced with food pellets on a variable interval 30-s schedule, then extinguished, and finally tested in the same and a different physical context. The experiments demonstrated a clear ABA renewal effect, a recovery of extinguished responding when conditioning, extinction, and testing occurred in contexts A, B, and A, respectively. They also demonstrated ABC renewal (where conditioning extinction and testing occurred in contexts A, B, and C) and, for the first time in operant conditioning, AAB renewal (where conditioning, extinction, and testing occurred in contexts A, A, and B). The latter two phenomena indicate that tests outside the extinction context are sufficient to cause a recovery of extinguished operant behavior and, thus, that operant extinction, like Pavlovian extinction, is relatively specific to the context in which it is learned. AAB renewal was not weakened by tripling the amount of extinction training. ABA renewal was stronger than AAB, but not merely because of context A's direct association with the reinforcer. PMID- 21279497 TI - Subliminal priming with nearly perfect performance in the prime-classification task. AB - The subliminal priming paradigm is widely used by cognitive scientists, and claims of subliminal perception are common nowadays. Nevertheless, there are still those who remain skeptical. In a recent critique of subliminal priming, Pratte and Rouder (Attention, Perception, & Psychophysics, 71, 1276-1283, 2009) suggested that previous claims of subliminal priming may have been due to a failure to control the task difficulty between the experiment proper and the prime-classification task. Essentially, because the prime-classification task is more difficult than the experiment proper, the prime-classification task results may underrepresent the subjects' true ability to perceive the prime stimuli. To address this possibility, prime words were here presented in color. In the experiment proper, priming was observed. In the prime-classification task, subjects reported the color of the primes very accurately, indicating almost perfect control of task difficulty, but they could not identify the primes. Thus, I conclude that controlling for task difficulty does not eliminate subliminal priming. PMID- 21279498 TI - MCP-3/CCL7 production by astrocytes: implications for SIV neuroinvasion and AIDS encephalitis. AB - Monocyte/macrophages and activated lymphocytes traffic through normal brain, and this trafficking is increased in inflammatory conditions such as HIV encephalitis (HIVE). HIVE is characterized in part by perivascular accumulations of macrophages. The earliest events in this process are poorly understood and difficult or impossible to address in humans. The SIV-infected macaque model of neuroAIDS has demonstrated migration of monocytes into the brain early in disease, coincident with peak SIV viremia. The chemotactic signals that initiate the increased emigration of mononuclear cells into the CNS have not been described. Here, we describe astrocytes as a primary source of chemokines to facilitate basal levels of monocyte trafficking to CNS and that increased chemokine (C-C motif) ligand 7 (CCL7) production may be responsible for initiating the increased trafficking in neuroAIDS. We have previously published complementary in vivo work demonstrating the presence of monocyte chemoattractant protein 3 (MCP-3)/CCL7 within the brain of SIV-infected macaques. Here, we demonstrate that MCP-3/CCL7 is a significant chemokine produced by astrocytes, that basal monocyte migration may be facilitated by astrocyte-derived CCL7, that production of CCL7 is rapidly increased by TNF-alpha and thus likely plays a critical role in initiating neuroinvasion by SIV/HIV. PMID- 21279500 TI - Recent developments in drug-eluting stents. AB - Percutaneous coronary intervention (PCI) is an important treatment approach in the management of symptomatic coronary artery disease (CAD). A significant development in PCI in the mid 1970s was balloon angioplasty, followed by bare metal stents a decade later, and now, the widespread use of drug-eluting stents (DES). While PCI has conferred remarkable benefit to millions of CAD patients, restenosis, and late stent thrombosis associated with DES remain problematic, and improvements are keenly sought. This article reviews recent developments in DES. PMID- 21279502 TI - [Dorsomedial talocalcaneal coalition: a rare condition]. AB - Talocalcaneal coalitions are rare but a posterior facet talocalcaneal coalition is even rarer. There are three different types: fibrous, cartilaginous and osseous coalitions. Besides conventional x-rays computed tomography is essential for assessment of the subtarsal joint. In the absence of concomitant coalitions and foot deformity resection of the coalition is advocated due to good clinical results when there is an adequate size of the talocalcaneal joint (>50%) and without osteoarthrosis. A case of a rare posterior facet talocalcaneal coalition is reported. PMID- 21279501 TI - Is CaMKII a link between inflammation and hypertrophy in heart? AB - Myocardial infarction is a major cause of morbidity and mortality in the developing and developed world. Although current interventions have been successful in prolonging life, they are inadequate because mortality is still high among MI patients. The multifunctional Ca(2+)/calmodulin-dependent protein kinase (CaMKII) plays a key role in the structure and contractility of the myocardium. CaMKII activity is increased in MI hearts and CaMKII promotes cardiac hypertrophy and inflammation, processes consistently activated by myocardial injury. Hypertrophy and inflammation are also related to neurohumoral and redox signaling which uncouple CaMKII activation from Ca(2+)/calmodulin dependence. Thus, CaMKII may act as a nodal point for integrating hypertrophic and inflammatory signaling in myocardium. PMID- 21279503 TI - [Effect of lumbar hybrid instrumentation and rigid fusion on the treated and the adjacent segments. A biomechanical study]. AB - BACKGROUND: Degeneration of the upper adjacent segment after operative treatment of degenerative spinal diseases of the lumbar spine (degenerative disc disease DDD) is an unsolved problem. There is also no consensus on whether a rigid or dynamic treatment of DDD should be carried out to protect the segments. This study was carried out to evaluate the effect of bisegmental rigid 360 degrees fusion and bisegmental hybrid fusion on the treated segment as well as on the upper adjacent segment under the aspect of segment protection. MATERIAL AND METHODS: A total of six human spinal column preparations (L2-5) were tested under native conditions (NAT), with bisegmental rigid fusion (RIG 360 degrees ) and with hybrid fusion (Hybrid) in all three movement directions under physical load and with an preload. The range of motion (ROM) and neutral zone (NZ) were evaluated. The intradiscal pressure (IDP) was measured in the upper adjacent segment (OAS). RESULTS: The RIG 360 degrees led to a significant reduction in movement in all directions compared to NAT but Hybrid only in lateral bending (LB). In the OAS the NZ was showed a much greater increase than the ROM. The RIG 360 degrees showed an increase of the NZ in flexion-extension of 86.8% and in LB of 49.6% as well as a significant increase in axial rotation of 52.5%. The increase in the Hybrid was not significant compared to NAT in all directions. Pressure measurements in OAS showed no significant differences for RIG 360 degrees and for Hybrid compared to NAT for both load scenarios. DISCUSSION: The range of motion of the treated segments for Hybrid were close to NAT in comparison to RIG 360 degrees indicating a segment-protective effect. The hypothesis that rigid fusion has a significant effect on intersegmental mobility and the increase in intradiscal pressure in the upper adjacent segment could not be confirmed. The data indicate that the primary effect of fusion on the adjacent segment is very low but the fusion-linked increased frequency of extreme loads of the OAS falling within the significance level leads to degeneration. Even if the NZ values for Hybrid and RIG 360 degrees do not significantly differ from NAT, the NZ alterations between the instrumentations tend to be strongly shifted in favor of Hybrid. CONCLUSIONS: The data confirm that the clear and sometimes significant alterations of the NZ can be an essential factor for development of adjacent segment degeneration. A dynamic conclusion of instrumentation in the sense of a topping-off would appear to be useful if pathoanatomical indications for an intervertebral disc prosthesis are present. PMID- 21279504 TI - Fracture risk prediction using FRAX(r): a 10-year follow-up survey of the Japanese Population-Based Osteoporosis (JPOS) Cohort Study. AB - We evaluated the predictive ability of FRAX(r) in a cohort of 815 Japanese women. The observed 10-year fracture rate did not differ significantly from that predicted by FRAX(r). The predictive ability of FRAX(r) without femoral neck bone mineral density (BMD) was similar to that with femoral neck BMD. INTRODUCTION: We evaluated the ability of the Japanese version of FRAX(r), a World Health Organization fracture risk assessment tool, to predict the 10-year probability of osteoporotic fracture. METHODS: Self-reported major osteoporotic fracture (N = 43) and hip fracture (N = 4) events were ascertained in the 10-year follow-up survey of the Japanese Population-Based Osteoporosis Cohort Study. Participants were 815 women aged 40-74 years at the baseline survey. Receiver operating characteristic curve analysis compared FRAX(r) with multiple logistic models based on age, body weight, and femoral neck BMD. RESULTS: The number of observed major osteoporotic or hip fracture events did not differ significantly from the number of events predicted by the FRAX(r) model (with or without BMD). The area under the curve (AUC) value for FRAX(r) with BMD for predicting major osteoporotic fractures was similar to that of a logistic model with age, body weight, and BMD (0.69 vs. 0.71, respectively; p = 0.198); the AUC of FRAX(r) with BMD for predicting hip fractures was similar to that of a model based on age and BMD (0.88 vs. 0.89, respectively; p = 0.164). The AUCs of FRAX(r) without BMD for predicting major osteoporotic and hip fractures were similar to those with BMD (0.69 vs. 0.67, respectively; p = 0.121; 0.88 vs. 0.86, respectively; p = 0.445). CONCLUSIONS: The Japanese version of FRAX(r) without BMD estimated the 10-year probability of osteoporotic fracture in this population with few clinical risk factors as similar to that of FRAX(r) with BMD. PMID- 21279505 TI - Where now with NICE? PMID- 21279507 TI - Comments on Sandhu et al.: prognosis of fracture: evaluation of predictive accuracy of the FRAX(TM) algorithm and Garvan nomogram. PMID- 21279508 TI - Determination of chlorinated solvents in industrial water and wastewater by DAI GC-ECD. AB - A very simple and quick analytical method, based on direct aqueous injection, for determination of halogenated solvents in refinery water and wastewater, is described. There is a need to determine halogenated solvents in refinery water streams, because they may originate from several processes. There is also a need to develop methods enabling VOX to be determined in samples containing oil fractions. The method described enables simultaneous determination of 26 compounds with low detection limits (sub-MUg L(-1)) and excellent precision, especially for highly halogenated solvents. The matrix effects of four types of sample were evaluated--the method seemed to be relatively insensitive to variations in matrix composition. Deuterated 1,2-dichloroethane was used as internal standard and surrogate compound in quantitative analysis; application of isotopically labelled compounds is rarely reported when non-mass spectrometric detectors are used for analysis. Analysis of real samples showed that the most frequently detected compounds were dichloromethane and 1,2-dichloroethane. PMID- 21279509 TI - Magnetic resonance imaging spectrum of medulloblastoma. AB - INTRODUCTION: Two medulloblastoma variants were recently added to the WHO classification of CNS tumours. We retrospectively analysed the imaging findings of 37 classic and 27 cases of variant medulloblastomas to identify imaging characteristics that might suggest a particular MB subtype. METHODS: Sixty-four patients from three institutions were included. Location, tumour margins, signal intensities on conventional MRI, enhancement pattern, the presence of haemorrhage, calcifications and hydrocephalus were recorded and analysed. Signal characteristics on diffusion-weighted MR images and MR spectra were evaluated when available. RESULTS: Thirty-seven classic type of MB (CMB), twelve cases of desmoplastic/nodular medulloblastoma (DMB), nine medulloblastomas with extensive nodularity (MB-EN), five cases of anaplastic and one of large-cell medulloblastoma were included. Fifty of 64 tumours were located in the 4th ventricle region. On T2WI, CMB were all hyperintense, whereas DMB and MB-EN showed isointensity in up to 66%. One third of the classic MB showed only subtle marginal or linear enhancement. All medulloblastoma variants showed marked enhancement. CONCLUSION: The results of our study suggest: (a) an age-dependent distribution of MB variants, with DMB and MB-EN more common in younger children; (b) a female predominance in DMB; (c) a more common off-midline location in DMB (50%) and MB-EN (33%) variants. PMID- 21279510 TI - Vertebroplasty: where do we go from here? PMID- 21279511 TI - Effects of glutamine on gastrointestinal motor activity in patients following gastric surgery. AB - BACKGROUND: Postoperative ileus (POI) is one of the most common complications of gastrointestinal surgery. The present study was performed to evaluate the effects of glutamine administration on POI after gastric surgery in humans. SUBJECTS AND METHODS: The subjects were 31 patients who underwent partial distal gastrectomy for gastric cancer and who were randomly assigned to one of two groups based on postoperative treatment: the glutamine group (3 g/day) and the control group. Manometric recording was done 12 days after surgery, and plasma glutamine concentrations were measured preoperatively and on postoperative day 12. RESULTS: Motor activities of the duodenum in the glutamine group were significantly greater than those of the control group in the interdigestive state. The incidence of phase III motor activity (interdigestive migrating motor contractions) in the glutamine group was significantly higher than that in the control group (60 versus 19%). The glutamine group showed a significantly smaller decrease of plasma glutamine levels compared with the control group. CONCLUSIONS: Glutamine could act as a motility-recovery agent after gastrectomy in humans. PMID- 21279512 TI - Isolation of cellulolytic fungi from waste of castor (Ricinus communis L.). AB - This is the first report of isolation of fungi present in fatty and defatted castor bean meal as well as the first of crop's selection to test the cellulolytic potential, in order to verify the diversity and potential of cellulolytic fungi in castor bean waste (Ricinus communis L.). For the screening on solid medium, it was used carboxymethylcellulose (CMC) as the sole carbon source. The microcrystalline cellulose (Avicel) was used as a substrate for submerged fermentation for production of cellobiohydrolase (FPase) and the CMC to produce endoglucanases (CMCase) and beta-glycosidases (BG). 189 cultures of fungi were isolated, including 40 species of filamentous fungi and three yeasts. The Aspergillus was the most frequent found genus. Regarding the distribution of isolated species from defatted castor bean meal, the A. niger was the most frequent one; and within the fatty castor bean meal, the Emericela variecolor prevailed among other species. Among the 67 fungal cultures tested in the initial screening on solid media to assess the cellulolytic potential, 54 disclosed Cellulolytic Index (CI) ranging from 1.04 to 6.00 mm. The isolates were selected for enzyme production in liquid medium with values above 2.0 CI. They were obtained with A. japonicus URM5620 FPase activity (4.99 U/ml) and BG (0.05 U/ml), and Rhodotorula glutinis URM5724 activity of CMCase 3.58 U/ml. These cases occurred after 168 h of submersion for both species of fungi. In our study, we could conclude that the castor bean is a promising source of fungi capable of producing cellulolytic enzymes. PMID- 21279513 TI - Multiplex PCR assay for the detection of five putative virulence genes encoded in verotoxigenic Escherichia coli plasmids. AB - The aim was to perform a pentavalent PCR assay for the detection of putative virulence genes encoded in VTEC plasmids, katP, espP, subA, stcE, and ehxA. The five-specific primer pairs used in the assay do not interfere with each other and generate amplification products of 914, 774, 556, 399, and 262 bp. It was selected at random 39 strains belonged to 20 serotypes in order to evaluate the multiplex in a wide variety of strains. The results of this study indicate that it is possible to perform simultaneous amplification and search for recognized plasmid-encoded virulence markers from different E. coli serotypes and apply this technique to the genetic characterization of E. coli strains isolated from reservoirs, foods or patients. This complementary technique is a useful tool to detect interstrain differences for epidemiological studies and to provide information that could be related to the risk of human infection. PMID- 21279514 TI - Soil and plant contamination with Mycobacterium avium subsp. paratuberculosis after exposure to naturally contaminated mouflon feces. AB - The aim of this study was to demonstrate the persistence of Mycobacterium avium subsp. paratuberculosis (MAP) in soil and colonization of different plant parts after deliberate exposure to mouflon feces naturally contaminated with different amounts of MAP. Samples of aerial parts of plants, their roots, and the soil below the roots were collected after 15 weeks and examined using IS900 real-time quantitative PCR (qPCR) and cultivation. Although the presence of viable MAP cells was not demonstrated, almost all samples were found to be positive using qPCR. MAP IS900 was not only found in the upper green parts, but also in the roots and soil samples (from 1.00 * 10(0) to 6.43 * 10(3)). The level of soil and plant contamination was influenced mainly by moisture, clay content, and the depth from which the samples were collected, rather than by the initial concentration of MAP in the feces at the beginning of the experiment. PMID- 21279515 TI - Prosthetic heart valve assessment with multidetector-row CT: imaging characteristics of 91 valves in 83 patients. AB - OBJECTIVES: Multidetector CT (MDCT) has shown potential for prosthetic heart valve (PHV) assessment. We assessed the image quality of different PHV types to determine which valves are suitable for MDCT evaluation. METHODS: All ECG-gated CTs performed in our institutions since 2003 were reviewed for the presence of PHVs. After reconstruction in 3 specific PHV planes, image quality of the supravalvular, perivalvular, subvalvular and valvular regions was scored on a four-point scale (1 = non-diagnostic, 2 = moderate, 3 = good and 4 = excellent) by two independent observers. RESULTS: Eighty-four CT examinations (66 cardiac, 18 limited-dose aortic protocols) of 83 patients with a total of 91 PHVs in the aortic (n = 71), mitral (n = 17), pulmonary (n = 1) and tricuspid (n = 2) position were included. CT was performed on a 16-slice (n = 4), 64-slice (n = 28) or 256-slice (n = 52) MDCT system. Median image quality scores for the supra-, peri- and subvalvular regions and valvular detail were (3.5, 3.3, 3.5 and 3.5, respectively) for bileaflet PHV; (3.0, 3.0, 3.5 and 3.0, respectively) for Medtronic Hall PHV; (1.0, 1.0, 1.0 and 1.0, respectively) for Bjork-Shiley and Sorin monoleaflet PHV and (3.5, 3.5, 4.0 and 2.0 respectively) for biological PHV. CONCLUSION: Currently implanted PHVs have good image quality on MDCT and are suitable for MDCT evaluation. PMID- 21279516 TI - STAT3alpha interacts with nuclear GSK3beta and cytoplasmic RISK pathway and stabilizes rhythm in the anoxic-reoxygenated embryonic heart. AB - Activation of the Janus Kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) pathway is known to play a key role in cardiogenesis and to afford cardioprotection against ischemia-reperfusion in adult. However, involvement of JAK2/STAT3 pathway and its interaction with other signaling pathways in developing heart transiently submitted to anoxia remains to be explored. Hearts isolated from 4-day-old chick embryos were submitted to anoxia (30 min) and reoxygenation (80 min) with or without the antioxidant MPG, the JAK2/STAT3 inhibitor AG490 or the PhosphoInositide-3-Kinase (PI3K)/Akt inhibitor LY-294002. Time course of phosphorylation of STAT3alpha(tyrosine705) and Reperfusion Injury Salvage Kinase (RISK) proteins [PI3K, Akt, Glycogen Synthase Kinase 3beta (GSK3beta), Extracellular signal-Regulated Kinase 2 (ERK2)] was determined in homogenate and in enriched nuclear and cytoplasmic fractions of the ventricle. STAT3 DNA-binding was determined. The chrono-, dromo- and inotropic disturbances were also investigated by electrocardiogram and mechanical recordings. Phosphorylation of STAT3alpha(tyr705) was increased by reoxygenation, reduced (~50%) by MPG or AG490 but not affected by LY-294002. STAT3 and GSK3beta were detected both in nuclear and cytoplasmic fractions while PI3K, Akt and ERK2 were restricted to cytoplasm. Reoxygenation led to nuclear accumulation of STAT3 but unexpectedly without DNA-binding. AG490 decreased the reoxygenation-induced phosphorylation of Akt and ERK2 and phosphorylation/inhibition of GSK3beta in the nucleus, exclusively. Inhibition of JAK2/STAT3 delayed recovery of atrial rate, worsened variability of cardiac cycle length and prolonged arrhythmias as compared to control hearts. Thus, besides its nuclear translocation without transcriptional activity, oxyradicals-activated STAT3alpha can rapidly interact with RISK proteins present in nucleus and cytoplasm, without dual interaction, and reduce the anoxia-reoxygenation-induced arrhythmias in the embryonic heart. PMID- 21279517 TI - Comorbidity profile of poliomyelitis survivors in a Chinese population: a population-based study. AB - Previous reports of comorbid conditions in poliomyelitis survivors mainly focused on some disease categories, such as respiratory diseases, gastrointestinal diseases, psychiatric diseases, neurological diseases and cancer. Data regarding a wide spectrum of medical comorbidities in patients with poliomyelitis is still sparse. This study aimed to investigate and profile the wide range of comorbidities among the survivors of paralytic poliomyelitis in a Chinese population. In total, 2,032 paralytic poliomyelitis patients were selected as the study group and the comparison group consisted of 10,160 randomly selected enrollees. The comorbidities for analysis were based on a modified version of the Elixhauser Comorbidity Index. Conditional logistic regression analyses were computed to investigate the risk of comorbidities for these two groups. As compared to controls, patients with paralytic poliomyelitis had significantly higher prevalence of hypertension, ischemic heart disease, hyperlipidemia, congestive heart failure, cardiac arrhythmias, peripheral vascular disorder, stroke, paralysis, migraines, Parkinson's disease, rheumatoid arthritis, ankylosing spondylitis, pulmonary circulation disorders, chronic pulmonary disease, liver disease, peptic ulcers, hepatitis B or C, deficiency anemias, depression, and lymphoma. Most of the differences are of clinical interest, ORs often being between 2 and 3. No significant difference between poliomyelitis patients and controls was observed in the prevalence of SLE, tuberculosis, alcohol abuse and drug abuse. Our findings demonstrate that survivors of paralytic poliomyelitis in Taiwan are at higher risk of having multiple medical comorbidities although some potential confounding factors including educational level, marital status, obesity and physical activity are not available in our database. The pattern is generally consistent with previous observations from Western populations. Nevertheless, we found several novel associations which have rarely, if ever, been reported previously. PMID- 21279518 TI - PDCD4 nuclear loss inversely correlates with miR-21 levels in colon carcinogenesis. AB - Programmed cell death 4 (PDCD4) has recently been demonstrated to be a new tumor suppressor gene involved in colon carcinogenesis. PDCD4 immunohistochemical expression was assessed in 300 polypoid lesions of the colon mucosa (50 hyperplastic polyps [HP], 50 serrated adenomas [SA], 50 tubular adenomas with low grade-intraepithelial neoplasia [LG-IEN], 50 tubular adenomas with high-grade-IEN [HG-IEN]), and in 50 colon adenocarcinomas (CRC). As normal controls, we considered 50 biopsy samples obtained from patients with irritable bowel syndrome (N). We further investigated PDCD4 messenger RNA (mRNA) levels by quantitative real-time polymerase chain reaction (PCR) in a different series of N, LG-IEN, HG IEN, and CRC biopsy samples. miR-21 expression (an important PDCD4-expression regulator) was also determined by quantitative real-time PCR and in situ hybridization. Normal colocytes and HP featured strong PDCD4 nuclear immunostaining whereas a significantly lower PDCD4 nuclear expression was observed in dysplasia (low- and high-grade adenomas and SA) and invasive CRC. PDCD4 immunostaining and mRNA levels decreased significantly as the phenotypic changes occurring during colon carcinogenesis progressively increased (p < 0.001). As expected, miR-21 expression was significantly upregulated in preneoplastic/neoplastic samples, consistent with PDCD4 downregulation. These results consistently support the use of nuclear PDCD4 immunohistochemical downregulation as a novel biomarker for the diagnosis of dysplastic/neoplastic lesions in colon biopsy samples. PMID- 21279519 TI - Stromal expression of vascular endothelial growth factor C is relevant to predict sentinel lymph node status in melanomas. AB - The dissemination of tumour cells to the lymph nodes is a complex process involving the formation of new lymph vessels, or lymphangiogenesis, produced by the tumour itself. The main growth factor involved in lymphangiogenesis is vascular endothelial growth factor C (VEGF-C), which is secreted by several different malignant tumours, including melanoma. Not only has VEGF-C expression been found in tumour cells, it has also been detected in tumour stromal cells like macrophages and fibroblasts. This study aimed to determine whether the expression of VEGF-C in tumour and stromal cells in cutaneous melanoma determines lymphangiogenesis and neoplastic dissemination to lymph nodes. We examined cases from 50 patients with melanoma who underwent selective biopsy of the sentinel lymph node. Immunohistochemical study was done with D2-40 to label lymph vessels, and the expression of VEGF-C was evaluated in tumour and stromal cells. Lymph vessel density was greater in sentinel lymph node-positive than in sentinel lymph node-negative cases, though the difference was not significant (P = 0.075). A significant correlation was seen between lymph vessel density and tumour thickness and the presence of ulceration. The main finding was that the expression of VEGF-C in fibroblasts was highly associated with the presence of metastasis in the sentinel node and with the Clark level. However, VEGF-C expression showed no relation in either tumour cells or macrophages with node status or other prognostic factors, such as the Breslow index or Clark level. Our results highlight the relevance of the stroma in tumour progression in cutaneous melanoma and its role in the spread to lymph nodes. PMID- 21279520 TI - Frequent loss of heterozygosity on chromosome 12q in non-small-cell lung carcinomas. AB - Chromosomal aberrations in non-small-cell lung carcinomas (NSCLCs) are common events. In our study, the lung cancer cell lines (NCI-H446 and SPC-A-1) displayed numerous numerical and structural alterations in their chromosomes by G-banded karyotypic analysis, and abnormalities of chromosome 12 by fluorescence in situ hybridization. Sequentially, we used 14 microsatellite markers within 12q to analyze loss of heterozygosity (LOH) in lung cancer cell lines and NSCLCs. Possible LOH on 12q were statistically inferred to occur in five lung cell lines. Importantly, 17 out of 25 NSCLCs (68%) showed LOH at chromosome 12q. Frequencies of LOH for individual markers ranged from 18% to 44%. Several deletions which were marked with D12S1301, D12S2196, D12S398, D12S90, D12S1056, D12S1713, D12S375, D12S1040, D12S326, and D12S106 were newly detected. Allelic loss on 12q15-q21 detected with D12S1040 occurred at the later stages of NSCLC progression (p < 0.05, Fisher's exact test). LOH on 12q marked with D12S2196, D12S398, D12S326, and D12S106 were frequently found in NSCLCs from the patients without smoking history (p < 0.05, Fisher's exact test). These findings indicated that allelic loss on 12q is commonly involved in NSCLCs, and new tumor suppressor genes may occur within 12q. PMID- 21279522 TI - Quality of life in oncological patients with oropharyngeal dysphagia: validity and reliability of the Dutch version of the MD Anderson Dysphagia Inventory and the Deglutition Handicap Index. AB - Quality of life is an important outcome measurement in objectifying the current health status or therapy effects in patients with oropharyngeal dysphagia. In this study, the validity and reliability of the Dutch version of the Deglutition Handicap Index (DHI) and the MD Anderson Dysphagia Inventory (MDADI) have been determined for oncological patients with oropharyngeal dysphagia. At Maastricht University Medical Center, 76 consecutive patients were selected and asked to fill in three questionnaires on quality of life related to oropharyngeal dysphagia (the SWAL-QOL, the MDADI, and the DHI) as well as a simple one-item visual analog Dysphagia Severity Scale. None of the quality-of-life questionnaires showed any floor or ceiling effect. The test-retest reliability of the MDADI and the Dysphagia Severity Scale proved to be good. The test-retest reliability of the DHI could not be determined because of insufficient data, but the intraclass correlation coefficients were rather high. The internal consistency proved to be good. However, confirmatory factor analysis could not distinguish the underlying constructs as defined by the subscales per questionnaire. When assessing criterion validity, both the MDADI and the DHI showed satisfactory associations with the SWAL-QOL (reference or gold standard) after having removed the less relevant subscales of the SWAL-QOL. In conclusion, when assessing the validity and reliability of the Dutch version of the DHI or the MDADI, not all psychometric properties have been adequately met. In general, because of difficulties in the interpretation of study results when using questionnaires lacking sufficient psychometric quality, it is recommended that researchers strive to use questionnaires with the most optimal psychometric properties. PMID- 21279521 TI - Detection of ASPL/TFE3 fusion transcripts and the TFE3 antigen in formalin-fixed, paraffin-embedded tissue in a series of 18 cases of alveolar soft part sarcoma: useful diagnostic tools in cases with unusual histological features. AB - Alveolar soft part sarcoma (ASPS) is a rare malignancy; diagnostic problems may occur when cases present as a metastasis or with unusual morphologic features. In this study, a series of 18 cases with follow-up information were analysed with regard to the ASPL/TFE3 fusion transcripts and immuno-detection of TFE3 using archival formalin-fixed, paraffin-embedded tissues. Novel primers to detect ASPL/TFE3 fusion transcripts, type 1 and 2, were designed. The patients, ten female and eight male, ranged in age from 3 to 46 years; 16 involved soft tissues of the extremities (nine, lower; seven, upper), one involved the uterine cervix and one was a primary bone tumour of the foot. Seven ASPS had unusual morphologic features lacking the typical alveolar pattern. Seven had lung metastases at the time of diagnosis, and three developed lung and brain metastases later. Four patients died of disease (after 1-5 years); four are alive with metastases (after 2-15 years), and ten are alive and well (after 1-10 years). Vascular invasion correlated with metastatic disease. All 18 ASPS, four granular cell tumours (one of which was malignant) and one adrenal cortical carcinoma showed TFE3 immuno positivity. The 18/18 ASPS showed ASPL/TFE3 fusion transcripts (nine, type 1; nine, type 2), four of which had a balanced translocation. ASPL/TFE3 fusion transcripts were not detected in 25 controls. We conclude that immuno-detection of TFE3 and RT-PCR-based identification of ASPL/TFE3 fusion transcripts in formalin-fixed, paraffin-embedded tissues are powerful tools in the diagnosis of ASPS, particularly in cases with unusual morphologic features. PMID- 21279523 TI - Allergy to human insulin and specific immunotherapy with glargine; case report with review of literature. AB - Insulin has an important role in the treatment of diabetic patients. Further, it can result in undesirable side effects. One of the problems that are associated with insulin therapy is allergic reactions. Although insulin allergy is uncommon, especially in patients with type-2 diabetes, but when it occurs, its management can be difficult. We report a 55-year-old woman with poorly controlled type-2 diabetes and insulin allergy. She revealed hypersensitivity reactions including urticaria and respiratory symptoms, immediately after injection. So, specific immunotherapy with other insulin preparations was done. Finally, after specific immunotherapy, we were able to treat the patient with short- and long-acting analogs successfully. PMID- 21279524 TI - A comparative study of HIV-1 and HTLV-I protease structure and dynamics reveals a conserved residue interaction network. AB - The two retroviruses human T-lymphotropic virus type I (HTLV-I) and human immunodeficiency virus type 1 (HIV-1) are the causative agents of severe and fatal diseases including adult T-cell leukemia and the acquired immune deficiency syndrome (AIDS). Both viruses code for a protease that is essential for replication and therefore represents a key target for drugs interfering with viral infection. The retroviral proteases from HIV-1 and HTLV-I share 31% sequence identity and high structural similarities. Yet, their substrate specificities and inhibition profiles differ substantially. In this study, we performed all-atom molecular dynamics (MD) simulations for both enzymes in their ligand-free states and in complex with model substrates in order to compare their dynamic behaviors and enhance our understanding of the correlation between sequence, structure, and dynamics in this protein family. We found extensive similarities in both local and overall protein dynamics, as well as in the energetics of their interactions with model substrates. Interestingly, those residues that are important for strong ligand binding are frequently not conserved in sequence, thereby offering an explanation for the differences in binding specificity. Moreover, we identified an interaction network of contacts between conserved residues that interconnects secondary structure elements and serves as a scaffold for the protein fold. This interaction network is conformationally stable over time and may provide an explanation for the highly similar dynamic behavior of the two retroviral proteases, even in the light of their rather low overall sequence identity. PMID- 21279525 TI - Initial reactions of methyl-nitramine confined inside armchair (5,5) single walled carbon nanotube. AB - The dissociation and isomerization reactions of methyl-nitramine(MNA) confined inside armchair CNT(5,5) single-walled carbon nanotube were investigated by using the ONIOM (B3LYP/6-311++G:UFF) method. The results showed that some geometries of the confined MNA were modified by the CNT(5,5) in comparison with the structure of the isolated MNA. By analyzing the relevant structures and energies involved in the dissociation and isomerization reactions, we found that the transition state structures of the isomerization reactions to form CH(3)NHONO (R1) and CH(3)NNOOH (R2) were modified by the confinement of CNT(5,5). However, this confinement does not evidently affect the transition state structure of the HONO elimination reaction (R3). In addition, no transition state was found for the N-N bond dissociation (R4) of the isolated MNA, but this dissociation process occurred via a transition state for the confined MNA. When MNA was confined inside CNT(5,5), the activation energies of R1, R2, and R4 were decreased obviously but the energy barrier of R3 was increased slightly. The order of activation energy for these four initial reactions was also changed by the confinement of CNT(5,5). Furthermore, it was found that the relative energies of the intermediates formed by the isomerization and dissociation of MNA were also modified by the confinement of CNT(5,5). These intermediates become more stable in the confined case than in the isolated case. It was concluded that the initial reactions of MNA could be modified evdiently by confinement within a carbon nanotube. PMID- 21279526 TI - From sequence to 3D structure of hyperbranched molecules: application to surface modified PAMAM dendrimers. AB - The molecular modeling of hyperbranched molecules is currently constrained by difficulties in model building, due partly to lack of parameterization of their building blocks. We have addressed this problem with specific relevance to a class of hyperbranched macromolecules known as dendrimers by describing a new concept and developing a method that translates monomeric linear sequences into a full atomistic model of a hyperbranched molecule. Such molecular-modeling-based advances will enable modeling studies of important biological interactions between naturally occurring macromolecules and synthetic macromolecules. Our results also suggest that it should be possible to apply this sequence-based methodology to generate hyperbranched structures of other dendrimeric structures and of linear polymers. PMID- 21279527 TI - DFT investigation of the thermodynamics and mechanism of electrophilic chlorination and iodination of arenes. AB - Quantum chemical calculations at the B3LYP/6-311G level have been carried out in order to investigate the reaction mechanisms of the iodination of benzene and its monosubstituted derivatives with ICl, I(+), I (3) (+) and reagents containing N-I and O-I bonds as the iodinating agents. The results are compared with those obtained for chlorination by Cl(+) and Cl(2), both in the gas phase and in methanol solution using the PCM solvent model. We have also used the MP2/DGDZVP level of theory and the IEFPCM model to perform comparisons in a few cases. The thermodynamic parameters for the reactions have been calculated, the structures of the intermediate products (pi- and sigma-complexes) and transition states have been optimized, and the profiles of the free energy surfaces have been constructed. PMID- 21279528 TI - Computational study of proton and methyl cation affinities of imidazole-based highly energetic ionic liquids. AB - The present study deals with the evaluation of gas phase proton and methyl cation affinities for alkyl- and nitrosubstituted imidazoles using DFT (B3LYP)/6-31 + G(d) and MP2 methods in the Gaussian 03 software package. The extent of charge delocalization of these cations is correlated with proton affinity. The study reveals that weakly electron-donating alkyl groups at position 1 of the imidazole enhance its proton affinity, which also increases with increasing alkyl chain length. This is expected to result in an increased tendency to form salts. In contrast, the presence of strongly electron-withdrawing nitro groups lowers proton affinity, which decreases as the number of nitro groups on the ring increases. The same trend is observed for the methyl cation affinity, but to a lower degree. These trends in the proton and methyl cation affinities were analyzed to study the effects of these substituents on the basicity of the energetic imidazole moieties and their tendency to form salts. This, in turn, should aid searches for better highly energetic ionic liquids. In addition, calculations performed on different isomers of mono and dinitroimidazoles show that 5-nitro-1H-imidazole and 2,4-dinitro-1H-imidazole are more stable than the other isomers. Amongst the many nitro derivatives of imidazoles considered in the present study, cations resulting from these two would be the best choice for creating highly energetic ionic liquids when coupled with appropriate energetic anions. PMID- 21279529 TI - Adsorption mechanism of single guanine and thymine on single-walled carbon nanotubes. AB - Bio-nano hybrids introduce magnificent applications of nanomaterials to various fields. The choice of carbon nanotube as well as sequence selection of the nucleic acid bases play a crucial role in shaping DNA-carbon nanotube hybrids. To come up with a clear vision for the choice of carbon nanotube and nucleic acid bases to create bio-nano hybrids, we studied the adsorption mechanism of the nucleic acid bases guanine and thymine on four different types of nanotubes based on density functional theory. Nucleic acid bases exhibit differential binding strengths according to their structural geometry, inter-molecular distances, the carbon nanotube diameter, and charge transfer. The pi-pi interaction mechanism between the adsorbent and adsorbate is discussed in terms of charge density profile and electronic band structure analysis. PMID- 21279530 TI - Prospective observational cohort study of cerebrovascular CO2 reactivity in patients with inflammatory CNS diseases. AB - The purpose of this study was to evaluate the significance of cerebrovascular CO(2) reactivity (CO(2) R) in the course and outcome of inflammatory central nervous system (CNS) diseases. Sixty-eight patients with inflammatory CNS diseases and 30 healthy volunteers were included in this prospective observational cohort study. The observational period was between January 2005 and May 2009. The CO(2) R was measured by transcranial Doppler (TCD) ultrasound using the breath-holding method. We compared patients with normal CO(2) R (breath holding index [BHI(m)] >= 1.18 = BHI(N) group) with patients who showed impaired CO(2) R (BHI(m) < 1.18 = BHI(R) group). We also analyzed the association of impaired CO(2) R with the etiology, severity, and outcome of disease. When compared to the BHI(N) group, the patients from the BHI(R) group were older, had a heavier consciousness disturbance, experienced more frequent respiratory failure, and, subsequently, had worse outcomes. There were no fatalities among the 28 patients in the BHI(N) group. The comparison of subjects with bacterial and non-bacterial meningitis revealed no significant differences. The unfavorable outcome of disease (Glasgow Outcome Scale [GOS] score 1-3) was significantly more common in subjects with impaired CO(2) R (62.5% vs. 10.7%). Logistic regression analysis was performed in order to establish the prognostic value of BHI(m). The outcome variable was unfavorable outcome (GOS 1-3), while the independent variables were age, Glasgow Coma Scale (GCS) score, and BHI(m). The age and BHI(m) showed the strongest influence on disease outcome. A decrease of BHI(m) for each 0.1 unit increased the risk of unfavorable outcome by 17%. Our study emphasizes the importance of CO(2) R assessment in patients with inflammatory CNS diseases. PMID- 21279531 TI - Staphylococcus aureus skin and soft tissue infections in primary healthcare in Denmark: a 12-year population-based study. AB - A rise in community-onset Staphylococcus aureus infections has been observed in European countries. To ascertain secular trends of S. aureus infections in primary healthcare in Denmark, we conducted this register-based study in the North Denmark region, during the period 1997-2008. We identified all skin and mucosa specimens obtained by general practitioners and all prescriptions for the preferred oral anti-staphylococcal antibiotic, dicloxacillin. Repeat observations within a 12-month period were excluded prior to the calculation of age and gender standardised incidence rates per 100,000 person-years. We included 108,758 specimens, of which 42,778 (39%) yielded S. aureus. The annual incidence rate of specimens doubled during the study period, reaching 2,399 in 2008. The overall rate of S. aureus isolates increased 2-fold to a stable rate at about 850, but for isolates from children and for impetigo specimens, the increase was steeper, with a peak in 2002. A total of 156,462 dicloxacillin prescriptions had been redeemed and the annual prescription rate increased 2.5-fold, peaking at 3,714 in 2007. In conclusion, the annual rates of specimens, S. aureus infections and dicloxacillin prescriptions more than doubled in primary healthcare during the 12 year study period. A major impetigo epidemic and calls for antibiotic stewardship with increased utilisation of specimens were contributing factors. PMID- 21279532 TI - Use of procalcitonin (PCT) to guide discontinuation of antibiotic use in an unspecified sepsis is an antimicrobial stewardship program (ASP). AB - Clinicians have used procalcitonin (PCT) (biomarker to differentiate bacterial from non-bacterial sepsis) to guide use of antibiotics in patients. As the data for utility of PCT to discontinue antibiotics in an antimicrobial stewardship program (ASP) are lacking, we aim to describe the outcomes of patients in whom PCT was used to discontinue antibiotics under our ASP. An antimicrobial stewardship (AS) team intervened to discontinue antibiotics in patients with persistent fever or leucocytosis, source of sepsis unknown or negative bacteriological cultures, who had completed an adequate course of antibiotic therapy and had a PCT of <0.5 MUg/L. Main outcomes evaluated were 14-day re infection, 30-day mortality and readmission. Antibiotic therapy was discontinued in 42 patients in 1 year. Unknown source of sepsis was found in 38% of the patients (including possible malignant fever) and culture-negative pneumonia was found in 21%. Two patients died of advanced cancer. One patient decided for comfort care and died one week later. One patient died due to a second episode of pneumonia 37 days after first PCT test. Six patients were readmitted within 30 days due to non-infectious causes. Three patients were readmitted due to culture negative pneumonia. None had a 14-day re-infection. PCT used to discontinue antibiotics under our ASP did not compromise patients' outcome. PMID- 21279533 TI - Expression of a radish defensin in transgenic wheat confers increased resistance to Fusarium graminearum and Rhizoctonia cerealis. AB - Fusarium head blight (scab), primarily caused by Fusarium graminearum, is a devastating disease of wheat (Triticum aestivum L.) worldwide. Wheat sharp eyespot, mainly caused by Rhizoctonia cerealis, is one of the major diseases of wheat in China. The defensin RsAFP2, a small cyteine-rich antifungal protein from radish (Raphanus sativus), was shown to inhibit growth in vitro of agronomically important fungal pathogens, such as F. graminearum and R. cerealis. The RsAFP2 gene was transformed into Chinese wheat variety Yangmai 12 via biolistic bombardment to assess the effectiveness of the defensin in protecting wheat from the fungal pathogens in multiple locations and years. The genomic PCR and Southern blot analyses indicated that RsAFP2 was integrated into the genomes of the transgenic wheat lines and heritable. RT-PCR and Western blot proved that the RsAFP2 was expressed in these transgenic wheat lines. Disease tests showed that four RsAFP2 transgenic lines (RA1-RA4) displayed enhanced resistance to F. graminearum compared to the untransformed Yangmai 12 and the null-segregated plants. Assays on Q-RT-PCR and disease severity showed that the express level of RsAFP2 was associated with the enhanced resistance degree. Two of these transgenic lines (RA1 and RA2) also exhibited enhanced resistance to R. cerealis. These results indicated that the expression of RsAFP2 conferred increased resistance to F. graminearum and R. cerealis in transgenic wheat. PMID- 21279534 TI - Extensive unilateral visual field loss due to peripapillary arteriovenous malformation. AB - We report on a case of extensive unilateral visual field loss due to a peripapillary arteriovenous communication. Interventional case report. A 27-year old Caucasian woman who was initially managed for retrobulbar optic neuritis underwent fundus fluorescein angiography (FFA) and indocyanine green angiography (ICGA) 6 months later that revealed an unusual course of the central retinal vein with focal dilatation and co-existent aneurysmal distention of the adjacent large choroidal vein. Subsequent colour Doppler flow imaging of the dilated area confirmed the existence of arterial flow suggesting a "vascular steal" phenomenon resulting in choroidal and optic disc ischaemia. Brain magnetic resonance imaging (MRI) revealed small focal capillary vessel abnormalities in the parietal cortex. The present case highlights the important role of ICGA and FFA in the assessment of patients with optic disc pallor and visual field loss. In our case an unusual ocular vascular abnormality was attributed to a congenital malformation and therefore an unnecessary therapeutic intervention was avoided. PMID- 21279535 TI - Capsular contraction syndrome following insertion of hydrophilic acrylic lens. AB - A 52-year-old female of Asian Indian origin underwent uncomplicated phacoemulsification with insertion of a foldable hydrophilic acrylic single-piece intraocular lens which resulted in good postoperative vision. Five weeks later she presented with decreased vision and examination revealed fibrosis as well as phimosis of the anterior capsular opening. Surgical capsulotomy was performed as there was an extremely thick fibrotic membrane, thereby clearing the visual axis and improving her vision. Capsular contraction syndrome (CCS) is very rare following insertion of hydrophilic acrylic lenses. We describe a case of anterior capsular contraction syndrome following uneventful surgery and without any known predisposing factors. PMID- 21279536 TI - Correlation between urological alpha1-AR antagonist medication and changed intraoperative iris behavior. AB - The aim of our study was to report on the incidence, the etiology and the management of intraoperative floppy iris syndrome (IFIS) during phacoemulsification. A non-randomized, observational, prospective study was performed for 1 year, in which 439 eyes of 438 patients (320 men and 118 women) undergoing cataract surgery by the same surgeon were enrolled. The surgeon was blinded to the patients' drug history. The use or non-use of alpha blockers (especially tamsulosin for benign prostatic hyperplasia), duration of the treatment, presence or absence of IFIS, management of IFIS and intraoperative complications were recorded. A 3.2 mm incision was performed on 316 eyes and a 2.4 mm incision on 123 eyes. IFIS occurred in 2.96% of the patients who were taking an alpha1 antagonist. In 5.47% we identified an intraoperative iris behaviour which imitated an incipient IFIS stage called IFI-like syndrome. In cases of insufficiently dilated pupils, diluted intracameral epinephrine as well as irrigation fluid was used. Vertical chop, stability of the anterior chamber by decreasing the corneal wound size, and reducing turbulence into the anterior chamber, enhanced the surgery on eyes with IFIS. There were no intraoperative or postoperative complications. The incidence of IFIS in our study was linked to alpha blocker medication. We postulate that IFIS may be caused by other medication, but this could not be demonstrated statistically. IFIS can be well controlled during surgery, intracameral epinephrine being the main stabilizing factor. PMID- 21279537 TI - Effect of trichomes on the predation of Tetranychus urticae (Acari: Tetranychidae) by Phytoseiulus macropilis (Acari: Phytoseiidae) on tomato, and the interference of webbing. AB - The two-spotted spider mite, Tetranychus urticae Koch, is an important pest of tomato in different parts of the world. Biological control of this pest on this crop has not been very successful. Phytoseiulus macropilis (Banks) has been used commercially for the control of T. urticae on different crops, but no information has been published on its potential to control T. urticae on tomato. The objective of this work was to compare the performance of a Brazilian population of P. macropilis on tomato with its performance on other plant species, relating the observed variation to the respective types and densities of trichomes. It has been hypothesized that the presence of the webbing produced by T. urticae could help the predator to avoid contact with trichomes and consequently to improve its performance on tomato plants. This hypothesis was also evaluated. Phytoseiulus longipes Evans was included in the work as a control, given that it has been reported to be a promising predator of Tetranychus species on tomato. The study was conducted under laboratory conditions. It was found that the performance of P. macropilis was similar to that of P. longipes and that trichomes hampered the locomotion as well as prey consumption and oviposition rate of both predators; that the presence of webbing resulted in higher levels of prey consumption and of predator oviposition; and that the presence of webbing eliminated the negative effect of trichomes of eggplants and partially eliminated the negative effect of trichomes of the 'cerasiforme' tomato variety. The observed density of trichomes in 'Carmem' one of the most common tomato varieties grown in Brazil, seems not to have interfered significantly with the prey consumption and the oviposition rate of P. macropilis. The results suggest that the latter is a promising predator of T. urticae on tomato. Complementary studies are warranted, to further evaluate the potential of P. macropilis for use as a biological control agent of this pest. PMID- 21279538 TI - Detection of Brevipalpus-transmitted viruses in their mite vectors by RT-PCR. AB - The diagnosis of plant diseases caused by Brevipalpus-transmitted viruses (BrTVs) has been done through the analyses of symptoms, transmission electron microscopy, and RT-PCR of infected plant tissues. Here, we report the detection of Citrus leprosis virus C, Orchid fleck virus, Clerodendrum chlorotic spot virus and Solanum violaefolium ringspot virus in their viruliferous vectors Brevipalpus spp. using specific primer pairs for each of the viruses. The efficiency of virus transmission by Brevipalpus mites is low, so the detection of these pathogens in their vectors could constitute an important tool for studies involving virus vector relationships, transmission, and monitoring the pathogen prior to the appearance of symptoms in the field. PMID- 21279539 TI - Comparative study of alternating low-band-gap benzothiadiazole co-oligomers. AB - The benzothiadiazole-arylene alternating conjugated oligomers have been designed and synthesized via Suzuki coupling reaction. The structures and properties of the conjugated oligomers were characterized by (1)HNMR, (13)CNMR, UV-vis absorption spectroscopy, photoluminescence (PL) spectroscopy. The luminescent measurements demonstrate that polybenzothiadiazoles are good chromophores able to form thin films by Langmuir-Blodgett (LB) technique, making them suitable for further applications. Also the electrical properties of obtained films confirm the good potential of these novel aryl-based pi-conjugated polymers for the development of various electrical and electrochemical solid-state devices. PMID- 21279540 TI - Synthesis and photophysical characterizations of thermal-stable naphthalene benzimidazoles. AB - Microwave-assisted synthesis, photophysical and electrochemical properties of thermal-stable naphthalene benzimidazoles and naphthalimides are studied in this paper. Microwave-assisted synthesis of naphthalene benzimidazoles provide higher yields than the conventional thermal synthesis. Comparative photophysical properties of naphthalene benzimidazoles and naphthalimides are revealed that conjugation of electron-donating group onto naphthalimide moiety increases fluorescence quantum yields. Fluorophore-solvent interactions are also investigated using Lippert-Mataga equation for naphthalimides and naphthalene benzimidazoles. Thermal stabilities of naphthalene benzimidazoles are better than naphthalimides due to increased aromaticity. The experimental E(LUMO) levels of naphthalene benzimidazoles are found to be between 3.15 and 3.28 eV. Therefore, naphthalene benzimidazole derivatives consisting of anchoring groups are promising materials in organic dye sensitized solar cells. PMID- 21279541 TI - Spectroscopic properties, energy transfer and structural analysis of Sr2CeO4:M+ and Sr2CeO4:Eu3+, M+ (M+ = Li+, Na+, K+). AB - The room-temperature luminescent emission characteristics of Sr(2)CeO(4):M(+) and Sr(2)CeO(4):Eu(3+),M(+) (M(+) = Li(+), Na(+), K(+)) have been investigated under UV excitation. By introducing appropriate alkali metal cations dopants (Li(+), Na(+), K(+)) into the crystalline lattice, not only emission color of the blue white-emitting Sr(2)CeO(4) doped with low Eu(3+) content can be tuned to green, but also the red emission intensity of Sr(2)CeO(4) doped with high Eu(3+) concentration is strengthened significantly. The relevant mechanisms have been elucidated in detail. PMID- 21279542 TI - Twenty-five years of implantable defibrillator practice in the USA: are we ready for globalization? PMID- 21279543 TI - Cancer survival among Latinos and the Hispanic Paradox. AB - BACKGROUND: Cancer survival is a key indicator of the effectiveness and social justice of health services. However, little is known about cancer survival among Hispanics, how it varies by Hispanic subgroup (Mexicans, Puerto Ricans, Cubans, and Others), and how their survival patterns relate to the Hispanic Paradox. METHODS: We studied all 1.2 million cancer cases diagnosed during 1995-2003, in two states, Florida and Texas, according to three categories of outcome: highly fatal outcome, poor outcome, and moderate outcome. All were followed up until December 31, 2006. We calculated survival rates for each Hispanic subgroup, and using Cox regression, we studied the risk of death for each Hispanic subgroup compared with non-Hispanic Whites, adjusted for age, cancer site, and stage at diagnosis. RESULTS: Important differences in cancer survival were found according to Hispanic subgroup. For cancers of moderate outcome, the adjusted risk of death was higher among all Hispanic populations in comparison with non-Hispanic Whites: 6% higher for Cubans, 11% for Puerto Ricans, and 13% for US-born Mexicans. Foreign-born Mexicans, even with incomplete follow-up, had a 24% higher risk of death. For foreign-born Hispanics, except Cubans, the mortality follow-up of cancers of highly fatal outcome was insufficient, resulting in missing deaths and thus unrealistically high survival rates. CONCLUSIONS: No evidence of a Hispanic advantage was found in cancer survival. Improvement in mortality follow-up procedures for Latinos, especially for those without a valid social security number, is critical. By considering Hispanics as a whole rather than by subgroup, existing survival disparities are being missed. PMID- 21279544 TI - Maternal anxiety, behaviors, and expectations during a behavioral task: relation to children's self-evaluations. AB - This study examined the associations between maternal anxiety, behaviors, and expectations and children's self-evaluations of distress, coping, and performance during a stressful performance evaluation task. Seventy-five mothers (38 clinically anxious and 37 nonanxious) along with one of their children aged 6-14 (52.0% female; 78.7% Caucasian) were videotaped while preparing the child to deliver a speech about themselves. Child and parent assessments were obtained before and after the speech, and independent coders rated maternal behavior during the speech preparation. Maternal anxiety and behaviors accounted for a greater proportion of variance in children's self-evaluations than did maternal expectations, such that children of mothers who reported higher task anxiety and demonstrated more overcontrol and anxious behavior during the task evaluated themselves more negatively. These findings extend the literature by providing information about the relative associations between maternal factors and children's self-evaluations within the context of an in vivo stressful situation. PMID- 21279545 TI - Likelihood ratio procedures and tests of fit in parametric and semiparametric copula models with censored data. AB - Copula models for multivariate lifetimes have become widely used in areas such as biomedicine, finance and insurance. This paper fills some gaps in existing methodology for copula parameters and model assessment. We consider procedures based on likelihood and pseudolikelihood ratio statistics and introduce semiparametric maximum likelihood estimation leading to semiparametric versions. For cases where standard asymptotic approximations do not hold, we propose an efficient simulation technique for obtaining p-values. We apply these methods to tests for a copula model, based on embedding it in a larger copula family. It is shown that the likelihood and pseudolikelihood ratio tests are consistent even when the expanded copula model is misspecified. Power comparisons with two other tests of fit indicate that model expansion provides a convenient, powerful and robust approach. The methods are illustrated on an application concerning the time to loss of vision in the two eyes of an individual. PMID- 21279547 TI - When is the story in the subgroups? Strategies for interpreting and reporting intervention effects for subgroups. AB - This paper examines strategies for interpreting and reporting estimates of intervention effects for subgroups of a study sample. The paper considers: why and how subgroup findings are important for applied research, alternative ways to define subgroups, different research questions that motivate subgroup analyses, the importance of pre-specifying subgroups before analyses are conducted, the importance of using existing theory and prior research to distinguish between subgroups for whom study findings are confirmatory (hypothesis testing) as opposed to exploratory (hypothesis generating), and the conditions under which study findings should be considered confirmatory. Each issue is illustrated by selected empirical examples. PMID- 21279549 TI - Ghrelin suppression of Helicobacter pylori-induced S-nitrosylation-dependent Akt inactivation exerts modulatory influence on gastric mucin synthesis. AB - Loss of mucus coat integrity and the impairment in its mucin component as well as the disturbance in nitric oxide (NO) generation are well-recognized features of gastric disease associated with H. pylori infection. As ghrelin plays a major role in the regulation of nitric oxide synthase system, we investigated the influence of this hormone on H. pylori LPS-induced interference with gastric mucin synthesis. The results revealed that the LPS-induced impairment in mucin synthesis and accompanied induction in inducible nitric oxide synthase (iNOS) expression, were associated with the suppression in Akt kinase activity and the impairment in constitutive nitric oxide synthase (cNOS) phosphorylation. The LPS effect on Akt inactivation was manifested in the kinase protein S-nitrosylation and a decrease in its phosphorylation at Ser(473). Further, we show that the countering effect of ghrelin, on the LPS-induced impairment in mucin synthesis was reflected in the suppression of iNOS and the increase in Akt activation, associated with the loss in S-nitrosylation and the increase in phosphorylation, as well as cNOS activation through phosphorylation. Our findings demonstrate that up-regulation in iNOS with H. pylori infection and subsequent Akt kinase inactivation through S-nitrosylation exerts the detrimental effect on the processes dependent on Akt activation, including that of cNOS activation and mucin synthesis. We also show that ghrelin protection against H. pylori-induced impairment in mucin synthesis is intimately linked to the events of Akt activation and reflected in a decrease in the kinase S-nitrosylation and the increase in its phosphorylation. PMID- 21279548 TI - Diagnosis and treatment of primary aldosteronism. AB - Primary aldosteronism is the most common form of secondary hypertension. The detection of primary aldosteronism is of particular importance, not only because it provides an opportunity for a targeted treatment (surgical for APA and medical with mineralocorticoid receptor antagonists for BAH), but also because it has been extensively demonstrated that patients affected by PA are more prone to cardiovascular events and target organ damage than essential hypertensives. According to the Endocrine Society Guidelines diagnosis of PA is made following a rigorous flow-chart comprising screening, confirmation/exclusion testing and subtype diagnosis. In the present review we describe briefly the published diagnostic strategies of the Guidelines, highlighting new evidence that has become recently available and discuss issues that still need to be addressed by future research. PMID- 21279550 TI - Elective resection of colon cancer by high-volume surgeons is associated with decreased morbidity and mortality. AB - BACKGROUND: The purpose of this study was to determine whether morbidity and mortality in patients undergoing elective resection of colon cancer are associated with surgeon or hospital volume. METHODS: Using the Nationwide Inpatient Sample database, we identified all adult patients who underwent elective resection for colon cancer as their primary procedure between 2003 and 2007. Cases were divided into three groups according to the mean number of resections performed annually by each surgeon: low volume (<=4/year), intermediate volume (5-9/year), or high volume (>=10/year). Annual hospital case load was also categorized as low volume (<=30/year), intermediate volume (31 60/year), and high volume (>=61/year). Multiple logistic regression models were used to identify differences in morbidity and mortality. RESULTS: A total of 54,000 patients underwent resection of colon cancer by 7,313 surgeons in 1,398 hospitals. After adjusting for important covariates including hospital volume, colon cancer resection by high-volume surgeons was an independent predictor of decreased morbidity (odds ratio [OR], 0.91; 95% CI, 0.85-0.97) and mortality (OR, 0.75; 95% CI, 0.65-0.86). Mortality was lowest among patients operated on by high volume surgeons in high-volume hospitals (2.2% vs. 3.9%; OR, 0.56; 95% CI, 0.46 0.68). CONCLUSIONS: In patients undergoing elective resection of colon cancer, procedures done by high-volume surgeons are associated with decreased morbidity and mortality. PMID- 21279551 TI - Effect of zymosan on antioxidant and immune function of S180 tumor-bearing mice. AB - The objective is to study the effect of zymosan on antioxidant and immune function of S(180) tumor-bearing mice. Seventy Kunming mice were randomly divided into seven groups: a normal control group (NC), a tumor control group (TC), three dose groups of zymosan (low, medium, high), a cyclophosphamide (Cy) group, and a combination of zymosan and Cy group. The S(180) tumor-bearing mice model was established by the inoculation of cancer cell suspension subcutaneously in the mouse's right anterior limb. At the 19th day, malondialdehyde (MDA), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) activity in liver homogenate were analyzed. The reverse transcriptase-polymerase chain reaction was used to determine the mRNA expression levels of IL-2, TNF-alpha, and TGF-beta(1). The activity of GSH-Px and SOD in the liver increased with the dose of zymosan, whereas the activity of MDA significantly decreased in the higher-dose groups of zymosan, compared to the TC group (P < 0.01). In the zymosan groups, mRNA expression levels in tissues of S(180) tumor-bearing mice were significantly higher for TNF-alpha and IL-2, but lower for TGFbeta(1) than in the Cy or TC group (P < 0.01). The high-dose of zymosan markedly showed a depressant effect on S(180) tumor, enhanced by the action of Cy that increased mRNA expression levels of TNF-alpha and IL-2. The mechanism of zymosan on the inhibition of tumor growth may be due to its ability to enhance the antioxidant and immune function in a dose-dependent manner. PMID- 21279552 TI - Pancreatic ductal adenocarcinoma and transcription factors: role of c-Myc. AB - INTRODUCTION: Deregulated expression/activation of transcription factors is a key event in the establishment and progression of human cancer. Furthermore, most oncogenic signaling pathways converge on sets of transcription factors that ultimately control gene expression patterns resulting in cancer development, progression, and metastasis. METHODS: Ductal pancreatic adenocarcinoma (PDA) is the main type of pancreatic cancer and the fourth leading cause of cancer mortality in the Western world. The early stage of the disease is characterized by pancreatic intraepithelial neoplasia lesions bearing mutations in the K-RAS proto-oncogene, which progress to malignant PDA by accumulating additional mutations in the tumor suppressor gene CDKN2A (p16) and in SMAD4 and TP53 transcription factors. The involvement of other signaling pathways in PDA development and progression is an active area of research which may help to clarify the critical steps of this devastating disease. RESULTS: In this regard, several in vitro and in vivo data have demonstrated the contribution of the transcription factor c-Myc to pancreatic carcinogenesis although the molecular mechanisms are poorly understood. c-Myc is a proto-oncogene which has a pivotal function in growth control, differentiation and apoptosis and is known to act as a downstream transcriptional effector of many signaling pathways involved in these processes. It is regulated at multiple levels and its abnormal expression contributes to the genesis of many human tumors. CONCLUSIONS: This review focuses on the role of c-Myc in pancreatic embryonic development and homeostasis as well as its involvement on pancreatic tumorigenesis. Evidences showing that c-Myc function is highly dose and cell context dependent, together with its recently demonstrated ability to reprogram somatic cells towards a pluripotent stem cell like state, indicate that the role of c-Myc in pancreas pathophysiology might have been previously underscored. PMID- 21279553 TI - Transcriptional control of gene expression in pancreatic cancer: from sequence specific transcription factors to nuclear architecture. AB - Transcription plays a central role in the regulation of gene expression during neoplastic transformation in different tissues. Using this nuclear process as a common topic in this special issue of the Journal of Gastrointestinal Cancer we have covered with five review articles key aspects of gene transcription and its impact in pancreatic carcinogenesis. We are confident that the knowledge included in these review articles will help understand the contribution of this molecular event to the pathogenesis of this devastating disease and serve as foundation for the development of new therapeutic tools. PMID- 21279556 TI - Proportionate cancer mortality in methyl methacrylate-exposed orthopedic surgeons compared to general surgeons. AB - Methyl methacrylate (MMA), a volatile liquid used to make dentures, hearing aids, joint prostheses, and medical adhesives, has been associated with colorectal carcinomas in acrylic sheet manufacturing workers. A case-control proportionate cancer mortality investigation was conducted to determine cancer death differences in orthopedic surgeons performing total joint replacements (TJRs) (MMA-exposed cases) and general surgeons not performing TJRs (unexposed controls). The American Colleges of Orthopedic Surgeons and General Surgeons provided complete demographic information on 468 male orthopedic surgeons and 1,890 male general surgeons who died during 1991-2001. Decedent data was submitted to the National Death Index for matching with underlying causes of death on state death certificates. Proportionate differences in ages at death, deaths from cancer, and deaths from site-specific cancers were analyzed for statistically significant differences by unpaired, two-tailed t tests for continuous variables and by both proportionate cancer mortality ratios and Yates corrected chi squares for categorical variables. Orthopedic surgeons died of cancer more often (chi (2) = 7.699, P = 0.006) and at younger (t = 5.53, P < 0.001) ages (mean = 69.4 years) than general surgeons (mean = 79.2 years). For site-specific cancers, orthopedic surgeons died of esophageal cancer (chi (2) = 4.372, P = 0.037) and myeloproliferative malignancies (chi (2) = 4.369, P = 0.037) more often than general surgeons. Orthopedic surgeons are chronically exposed to MMA and are proportionately more likely to die from cancer, especially esophageal and myeloproliferative cancers, than general surgeons. MMA-exposed healthcare workers may be at increased risks of untimely deaths from site specific malignancies. PMID- 21279555 TI - Gastrointestinal stromal tumors: morphological, immunohistochemical and molecular changes associated with kinase inhibitor therapy. AB - Recurrent or metastatic GISTs are currently treated with kinase inhibitors since they achieves disease control in 70-85% of patients but this response depend on KIT and PDGFRA gene mutation status. We review the morfological and molecular findings associated to kinase inhibitors administration in GISTs based on the literature on Medline and authors' own experience. The initial response to kinase inhibitors (imatinib mesylate, Gleevec, Novartis) usually is partial and depend on the mutational KIT or PDGFRA state. Amongst patients wih KIT mutations, the best results are achived in those harboring exon 11 (85%) and exon 9 (45%) mutations. GISTs harboring PDGFRA gene mutations generally respond favorably except those involving the Asp842Val mutation. In the absence of KIT/PDGFRA gene mutations, partial response or disease stabilization is reported in 23% and 50% of patients, respectively, and disease progression in 19%. Histological examination of tumors displaying an initial response to imatinib reveals a highly variable reduction in the number of tumor cells, a decline in the proliferative index, myxohyaline or sclerohyaline stroma, and a varying degree of bleeding and edema, necrosis and cystification. 72% of patients with initial good response to imatinib, display metastases or new nodule growth within an existing clinically quiescent tumor after 12-36 months of treatment. This secondary resistance is characterized by a number of well-defined morphological and molecular changes. Histologically, the new growths display increased mitotic activity, pleomorphism, an epithelioid or mixed phenotype and persistent KIT expression although more rarely, dedifferentiation and loss of KIT expression (Fig. 4), as well as trans differentiation into a rhabdomyosarcoma or epithelial phenotype has been reported. Molecularly, 46-67% of patients present additional KIT mutations, generally in the kinase domain (exons 13, 14 and 17) but also in the ATP-binding domain (exons 15,16) of the same allele. Secondary PDGFRA mutations are very rare. Secondary mutations have not been observed in GISTs not harboring KIT/PDGFRA mutations, or in tumors displaying an unusual morphology or loss of CD117 expression. A number of studies highlight the presence of different resistance mutations within different new tumor nodules, as well as the simultaneous development of distinct resistant tumor subclones within a single lesion (acquired polyclonal resistance). Secondary mutation in genes other than KIT/PDGFRA has only been reported in BRAF (Val600Glu). PMID- 21279557 TI - Biotechnological advancements in alfalfa improvement. AB - Review of biotechnology research in alfalfa shows that molecular techniques are extensively being used for basic and applied research toward alfalfa improvement. Biotechnological approaches have been used in two major areas, genomics and transgenics. In genomics, molecular markers, structural and functional genomics allowed identification of genes of interest and their regulatory components. Alfalfa being obstinate to genetic and genomic analysis, comparative genomics is used for molecular and genetic dissection of various plant processes in alfalfa. Alternatively, transgenic approach involves incorporation of specific and useful genes into alfalfa to improve the traits of interest. Input traits to improve agronomic performance and output traits to improve forage quality, or to produce novel industrial/pharmaceutical proteins, are the focus of current transgenic research in alfalfa. However, transgenic approach is controversial requiring cautious experimental design to combat bioisafety concerns. Ideally, forage alfalfa needs to possess more fermentable carbohydrates, proteins with balanced amino acid profile that degrade slower in rumen, improved winter hardiness, better water use efficiency, pest resistance and no anti-quality factors. Concerted efforts are required to bring together maximum of these characteristic features into the alfalfa plant. PMID- 21279554 TI - Evolutionary aspects of diet: the omega-6/omega-3 ratio and the brain. AB - Several sources of information suggest that human beings evolved on a diet that had a ratio of omega-6 to omega-3 fatty acids (FA) of about 1/1; whereas today, Western diets have a ratio of 10/1 to 20-25/1, indicating that Western diets are deficient in omega-3 FA compared with the diet on which humans evolved and their genetic patterns were established. Omega-6 and omega-3 FA are not interconvertible in the human body and are important components of practically all cell membranes. Studies with nonhuman primates and human newborns indicate that docosahexaenoic acid (DHA) is essential for the normal functional development of the brain and retina, particularly in premature infants. DHA accounts for 40% of the membrane phospholipid FA in the brain. Both eicosapentaenoic acid (EPA) and DHA have an effect on membrane receptor function and even neurotransmitter generation and metabolism. There is growing evidence that EPA and DHA could play a role in hostility and violence in addition to the beneficial effects in substance abuse disorders and alcoholism. The balance of omega-6 and omega-3 FA is important for homeostasis and normal development throughout the life cycle. PMID- 21279558 TI - Two new species of creagrocercid nematodes parasitic in earthworms, with comments on the phylogenetic affiliations of the Creagrocercidae Baylis, 1943. AB - Two new species of the rare nematode family Creagrocercidae from earthworms are described and illustrated. Creagrocercus braziliensis n. sp. is distinguished from the type-species, C. barbatus Baylis, 1943, by: the presence of four cephalic papillae (vs a pair of finger-shaped latero-ventral processes) on the head; larger amphids; a more posterior excretory pore position; a shorter pharynx which is remarkably expanded at the base; the nerve-ring situated just posterior to the base of the pharynx (vs at mid-pharyngeal level); an anal aperture present in the females; anterior ovary and testis reach just into the anterior half of the body (vs closely posterior to the pharynx); equal, similar (vs unequal, dissimilar) spicules; and a prominent, unpaired precloacal papilla in males. Creagrocercus drawidae n. sp. is related to C. barbatus by a similar pharyngeal shape and the presence of a tail 'hook', and to C. braziliensis n. sp. by: the lack of finger-shaped processes on the head and the presence of four cephalic papillae; a similar position of the excretory pore; a similar arrangement and length of the reproductive system; the presence of unpaired precloacal papilla in males; similar, almost equal spicules; and the presence of a tail 'hook'. From both of these species C. drawidae differs by having: a much shorter body and pharynx; larger amphids; a more posterior nerve-ring position; larger and less numerous eggs; greatly inflated (vs flat) vulval lips; shorter spicules; and a smaller caudal 'hook'. For C. drawidae, the partial sequences of the SSU (18S) rDNA and the D2D3 segment of LSU (28S) rDNA were obtained and subjected to phylogenetic analyses. The phylogenetic affiliations of the Creagrocercidae are discussed. PMID- 21279559 TI - Cucullanid nematodes (Nematoda: Cucullanidae) from deep-sea marine fishes off New Caledonia, including Dichelyne etelidis n. sp. AB - Three nematode species of the family Cucullanidae, intestinal parasites of marine perciform fishes, are reported from off New Caledonia: Cucullanus bourdini Petter & Le Bel, 1992 from the crimson jobfish Pristipomoides filamentosus (Valenciennes) and the goldflag jobfish Pristipomoides auricilla (Jordan, Evermann & Tanaka) (new host record) (both Lutjanidae); Dichelyne etelidis n. sp. from the deep-water red snapper Etelis carbunculus Cuvier (type-host) and the deep-water longtail red snapper Etelis coruscans Valenciennes (both Lutjanidae); and Dichelyne sp. (only one female) from the trumpet emperor Lethrinus miniatus (Forster) (Lethrinidae). Detailed light and electron microscopical studies revealed in C. bourdini some taxonomically important, previously unreported features, such as the location of the excretory pore, nature of the vulva and the size of fully-developed eggs. The new species, D. etelidis, is characterised mainly by the length of the spicules (462-748 MUm), a single intestinal caecum, the location of the deirids and excretory pore, the arrangement of the genital papillae and the host group. PMID- 21279560 TI - A new species of Acanthobothrium van Beneden, 1850 (Tetraphyllidea: Onchobothriidae) from Pastinachus atrus (Macleay) (Batoidea: Dasyatidae) in Australian waters, with a reassessment of the host associations of Acanthobothrium spp. parasitising Pastinachus spp. AB - A new Category 1 species of Acanthobothrium van Beneden, 1850 is described from the cowtail stingray Pastinachus atrus (Macleay) collected from the Gulf of Carpentaria near Weipa, Queensland, Australia. This species is unique among Acanthobothrium Category 1 species in that it retains gravid proglottids on its strobila. It differs further from the 34 other Category 1 species in total length, proglottid number and testis number. The host identities of other Acanthobothrium species reported from Pastinachus are revised based on recent taxonomic work on rays of this genus. Given the revised host taxonomy, according to which P. atrus is the only member of its genus occurring off Australia, this should be considered to be the fifth species of Acanthobothrium reported from this Australian endemic species. PMID- 21279561 TI - A new species of Caryospora Leger, 1904 (Apicomplexa: Eimeriidae) from the endangered Round Island boa Casarea dussumieri (Schlegel) (Serpentes: Bolyeridae) of Round Island, Mauritius: an endangered parasite? AB - A new species of Caryospora Leger, 1904 (Apicomplexa: Eimeriidae), C. durelli n. sp., is described from the endangered Round Island boa Casarea dussumieri (Schlegel) (Serpentes: Bolyeridae) from Round Island, Mauritius. Six of 11 hosts were infected. Oocysts are spherical to subspherical, 19.2 * 18.2 (17.5-21 * 16 21) MUm, n = 20, and have a shape index (mean length/mean width) of 1.05 (1.02 1.09). The bi-layered wall is composed of an outer layer of c.0.6 MUm thick and an inner layer of c.0.4 MUm thick. A micropyle, oocyst residuum and polar granule are absent. Sporocysts are ellipsoidal, 14.7 * 11.0 (13-16 * 9.5-11.5) MUm, n = 20, and have a shape index of 1.33. Both Stieda and substieda bodies are present. The sporocyst residuum measures c.12 * 4.5 MUm, is surrounded by sporozoites and composed of numerous granules. Refractile bodies are present but not clearly visible. This is the first coccidian parasite reported from the family Bolyeridae and the first species of Caryospora durrelli [corrected] reported from the Mascarenes. Conservation issues concerning parasites of endangered host species are discussed. PMID- 21279562 TI - Two new species of ancyrocephalid monogeneans from Lethrinus rubrioperculatus Sato (Perciformes: Lethrinidae) off New Caledonia, with the proposal of Lethrinitrema n. g. AB - Lethrinitrema gibbus n. g., n. sp. and L. dossenus n. sp. are described from the fish Lethrinus rubrioperculatus Sato collected off New Caledonia, South Pacific. Members of Lethrinitrema n. g. (Ancyrocephalidae) are characterised by having two pyriform haptoral reservoirs and ventral anchors with lateral grooves. The elongate tubular distal end of each reservoir bifurcates, draining into a superficial lateral groove on each side of the ventral anchors. The haptoral reservoirs are postulated to store secretory products which assist in attachment to the host. Lethrinitrema spp. also possess tandem gonads, a male copulatory organ without an accessory piece or with thinly sclerotised accessory piece, and a dextrolateral, non-sclerotised vaginal bulb. The two new species have small, poorly demarcated haptors with small haptoral armament and a crown-like piece on the tip of the inner root of the ventral anchors. They differ from each other in the shape and size of the ventral bar and male copulatory organ (40-45 MUm in length in L. gibbus vs 24-30 MUm in L. dossenus). Three other species, previously included in Haliotrema Johnston & Tiegs, 1922, are transferred to Lethrinitrema, i.e. L. chrysostomi (Young, 1968) n. comb., L. fleti (Young, 1968) n. comb. (both briefly redescribed from paratypes) and L. lethrini (Yamaguti, 1937) n. comb. All species of Lethrinitrema parasitise Lethrinus spp. (Lethrinidae), and there is evidence for the existence of further Lethrinitrema spp. on Lethrinus spp. in the Indo-Pacific region. PMID- 21279563 TI - Two new species of Cucullanus Muller, 1777 (Nematoda: Cucullanidae) from marine fishes off Thailand. AB - Based on light and scanning electron microscopical observations, two new species of Cucullanus Muller, 1777 (Nematoda: Cucullanidae) are described from the intestine of marine perciform fishes in the coastal region of the Gulf of Thailand, Thailand: Cucullanus rastrelligeri n. sp. from the short mackerel Rastrelliger brachysoma (Bleeker) (Scombridae) and Cucullanus thaiensis n. sp. from the brownstripe red snapper Lutjanus vitta (Quoy & Gaimard) (Lutjanidae). The former species, C. rastrelligeri, is mainly characterised by an elongate pseudobuccal capsule, the presence of a ventral sucker, markedly short spicules (306-360 MUm), a median papilla-like formation on the anterior anal lip and a distinctly elevated posterior anal lip, the location of the deirids and excretory pore, and by the distribution of genital papillae in the male. The latter species, C. thaiensis, is characterised by a broad pseudobuccal capsule, the presence of a ventral sucker and spicules 680 MUm long. It is morphologically closest to C. pargi Gonzalez-Solis, Tuz-Paredez & Quintal-Loria, 2007, but differs from it mainly in the distribution of the genital papillae in the male and apparently larger gravid females, and, whereas C. thaiensis occurs in the West Pacific (Gulf of Thailand), C. pargi was described from the West Atlantic (Caribbean Sea). C. rastrelligeri and C. thaiensis are the first nominal species of cucullanid nematodes reported from marine fishes in Thai waters. Indocucullanus thapari Gupta & Srivastava, 1984 is transferred to Cucullanus as C. thapari (Gupta & Srivastava, 1984) n. comb. PMID- 21279564 TI - World distribution and host range of Podapolipoides spp. (Acari: Heterostigmatina: Podapolipidae), with the description of a new species. AB - The ectoparasitic mite Podapolipoides anacridii n. sp. (Heterostigmatina: Podapolipidae), collected from the basal hindwings of Anacridium sp. (Orthoptera: Acrididae) in central Iran, is described. Podapolipoides Regenfuss, 1968 is defined, and the distribution, host-specificity and host range of its constituent species are discussed. PMID- 21279570 TI - Elements of a chemical orbital theory. AB - Interaction is important in chemistry. Interactions of atoms form chemical bonds. Bonds interact with each other in molecules to determine the molecular properties. Interactions of molecules give rise to chemical reactions. Electrons control atoms, bonds, and molecules. The behavior of electrons is simply and effectively represented by orbitals, which contain wave properties, i.e., phase and amplitude. In our chemical orbital theory we consider the interactions of the orbitals of atoms, bonds and molecules. The elements of the chemical orbital theory are separated into three groups: (1) interactions of two orbitals, (2) interactions of three orbitals, and (3) cyclic interactions of more than two orbitals. Here, general aspects of the interactions of two orbitals are summarized to show the background of this volume and assist nonspecialists to read the following chapters. Among the keywords are: phase and amplitude of orbitals, strength of orbital interactions, electron delocalization, electron localization, exchange repulsion, ionization energy, electronic spectrum, frontier orbitals, reactivity, selectivity, orbital symmetry, and so on. The remaining elements of the chemical orbital theory, i.e., an orbital mixing rule for the three-orbital interactions and an orbital phase theory for the cyclic interactions, are introduced briefly. PMID- 21279571 TI - A mechanistic spectrum of chemical reactions. AB - The mechanism of chemical reactions between electron donors and acceptors continuously changes with the power of the donors and the acceptors. The interaction between the HOMO (d) of the donors and the LUMO (a*) of the acceptors or delocalization of electrons is important for the reactions. The electron d-to a* transferred configuration mixes to a significant extent. As the donors and/or the acceptors are strong, their excited configurations appreciably mixes together with the transferred configuration. The d-a and d*-a* orbital interactions are important in addition to the d-a* interaction. Reactions have features characteristic of the excited-state reactions although the donor-acceptor system is not really excited, but in the ground state. This process is termed pseudoexcitation. The a-d-a*-d* interaction is important. For much stronger donors and acceptors, the electron transferred configuration is stable and predominant. Covalent bonds do not form but instead ionic pairs, and electron transfer results. A mechanistic spectrum of chemical reactions is composed of the delocalization, pseudoexcitation, and electron transfer bands. PMID- 21279572 TI - Orbital mixing rules. PMID- 21279573 TI - An orbital phase theory. PMID- 21279574 TI - Orbital phase environments and stereoselectivities. AB - Facial selections are reviewed to propose a new theory, orbital phase environment, for stereoselectivities of organic reactions. The orbital phase environment is a generalized idea of the secondary orbital interaction between the non-reacting centers and the unsymmetrization of the orbitals at the reacting centers arising from in-phase and out-of-phase overlapping with those at the neighboring non-reacting sites. In this context, the nucleophilic addition preferentially occurs on the face of the carbonyl functionality opposite to the better electron-donating orbital at the beta position. In a similar manner to the carbonyl cases, the preferred reaction faces of olefins in electrophilic addition reactions are opposite to the better electron-donating orbitals at the beta positions. The orbital phase environments in Diels-Alder reactions are also reviewed. PMID- 21279575 TI - pi-Facial Selectivity of Diels-Alder Reactions. AB - Diels-Alder reaction is one of the most fundamental and important reactions for organic synthesis. In this chapter we review the studies of the pi-facial selectivity in the Diels-Alder reactions of the dienes having unsymmetrical pi plane. The theories proposed as the origin of the selectivity are discussed. PMID- 21279576 TI - Orbital phase design of diradicals. AB - Over the last three decades the rational design of diradicals has been a challenging issue because of their special features and activities in organic reactions and biological processes. The orbital phase theory has been developed for understanding the properties of diradicals and designing new candidates for synthesis. The orbital phase is an important factor in promoting the cyclic orbital interaction. When all of the conditions: (1) the electron-donating orbitals are out of phase; (2) the accepting orbitals are in phase; and (3) the donating and accepting orbitals are in phase, are simultaneously satisfied, the system is stabilized by the effective delocalization and polarization. Otherwise, the system is less stable. According to the orbital phase continuity requirement, we can predict the spin preference of pi-conjugated diradicals and relative stabilities of constitutional isomers. Effects of the intramolecular interaction of bonds and unpaired electrons on the spin preference, thermodynamic and kinetic stabilities of the singlet and triplet states of localized 1,3-diradicals were also investigated by orbital phase theory. Taking advantage of the ring strains, several monocyclic and bicyclic systems were designed with appreciable singlet preference and kinetic stabilities. Substitution effects on the ground state spin and relative stabilities of diradicals were rationalized by orbital interactions without loss of generality. Orbital phase predictions were supported by available experimental observations and sophisticated calculation results. In comparison with other topological models, the orbital phase theory has some advantages. Orbital phase theory can provide a general model for both pi-conjugated and localized diradicals. The relative stabilities and spin preference of all kinds of diradicals can be uniformly rationalized by the orbital phase property. The orbital phase theory is applied to the conformations of diradicals and the geometry-dependent behaviors. The insights gained from the orbital phase theory are useful in a rational design of stable 1,3-diradicals. PMID- 21279577 TI - Relaxation of ring strains. PMID- 21279578 TI - Orbitals in inorganic chemistry: metal rings and clusters, hydronitrogens, and heterocyles. AB - A chemical orbital theory is useful in inorganic chemistry. Some applications are described for understanding and designing of inorganic molecules. Among the topics included are: (1) valence electron rules to predict stabilities of three- and four-membered ring metals and for those of regular octahedral M(6) metal clusters solely by counting the number of valence electrons; (2) pentagon stability (stability of five- relative to six-membered rings in some classes of molecules), predicted and applied for understanding and designing saturated molecules of group XV elements; (3) properties of unsaturated hydronitrogens N( m )H( n ) in contrast to those of hydrocarbons C( m )H( n ); (4) unusually short nonbonded distances between metal atoms in cyclic molecules. PMID- 21279595 TI - From molecules to man: the dawn of a vitreous man. AB - One of the greatest challenges to study the structure, function, and molecules in the living brain is that it is enclosed within the skull and difficult to access. Although biopsies are feasible, they are invasive, could lead to functional impairments, and in any case will only provide a small regional sample that is not necessarily reflecting the entire brain. Since the beginning of the twentieth century, in vivo imaging has gradually, and steadily, matured into non-invasive techniques that enable the repeated investigation of the structural, functional, cellular, and molecular composition of the brain. Not only is this information of great importance to scientists aiming to understand how the brain works, but these techniques are also essential to physicians who use imaging to diagnose and treat disease. The current book is a collection of 29 cutting-edge methods and protocols that are used in the current field of neuroimaging. PMID- 21279596 TI - Magnetic resonance safety. AB - The safe operation of both clinical and pre-clinical MR systems is critical. There are a wide range of potential MR hazards. This chapter covers both the theoretical background to issues of MR safety and the guidance on more practical issues. The main sources of information on national and international MR safety guidance and advice are discussed, as well as local safety policies which are required for all MR installations. The projectile effect and other MR safety issues due to static and time-varying magnetic fields are considered, such as peripheral nerve stimulation, tissue heating and RF burns. Finally, contrast agents, auditory effects and medical implants and devices are discussed, as well as the less thought about issue of biological safety of clinical and pre-clinical MR systems. PMID- 21279597 TI - Measuring the absolute water content of the brain using quantitative MRI. AB - Methods for quantitative imaging of the brain are presented and compared. Highly precise and accurate mapping of the absolute water content and distribution, as presented here, requires a significant number of corrections and also involves mapping of other MR parameters. Here, either T(1) and T(2)(*) or T(2) is mapped, and several corrections involving the measurement of temperature, transmit and receive B(1) inhomogeneities and signal extrapolation to zero TE are applied. Information about the water content of the whole brain can be acquired in clinically acceptable measurement times (10 or 20 min). Since water content is highly regulated in the healthy brain, pathological changes can be easily identified and their evolution or correlation with other manifestations of the disease investigated. In addition to voxel-based total water content, information about the different environments of water can be gleaned from qMRI. The myelin water fraction can be extracted from the fit of very high-SNR multiple-echo T(2) decay curves with a superposition of a large number of exponentials. Diseases involving de- or dysmyelination can be investigated and lead to novel observations regarding the water compartmentalisation in tissue, despite the limited spatial coverage. In conclusion, quantitative MRI is emerging as an unparalleled tool for the study of the normal and diseased brain, replacing the customary time-space environment of the sequential mixed-contrast MRI with a multi-NMR-parametric space in which tissue microscopy is increasingly revealed. PMID- 21279598 TI - Magnetic resonance relaxation and quantitative measurement in the brain. AB - Underlying the exquisite soft tissue contrast provided by magnetic resonance imaging are the inherent biophysical processes of relaxation. Through the intricate relationships between tissue microstructure and biochemistry and the longitudinal and transverse relaxation rates, quantitative measurement of these relaxation parameters is informative of tissue change associated with disease, neural plasticity, and other biological processes. Quantitative imaging studies can further facilitate more detailed characterizations of tissue, providing a more direct link between modern MR imaging and classic histochemical and histological studies. In this chapter, we briefly review the biophysical basis of relaxation, introducing and focusing specifically on the T(1), T(2), and T(2)(*) relaxation times and detail some of the more widely used and clinically feasible techniques for their in vivo measurement. Methods for analyzing relaxation data are covered, and a summary of significant results from reported neuroimaging studies is provided. Finally, the combination of relaxation time data with other quantitative imaging data, including diffusion tensor and magnetization transfer, is examined, with the aim of providing more thorough characterization of brain tissue. PMID- 21279599 TI - Magnetic resonance brain image processing and arithmetic with FSL. AB - Medical imaging has been transformed by a move from qualitative to quantitative approaches where image processing is used to enhance visual information and image analysis is used to derive structural and functional measurements. The ideal quantitative analysis methods are automatic and require no user intervention, and so-called image analysis pipelines exist for some applications. However, in the majority of cases automatic methods seldom live up to their name, may fail when prior assumptions are not met, and may not exist at all for new applications. The identification and careful use of well-known image processing and analysis techniques is a vital part of imaging and invaluable when problems arise with automatic methods. Here a number of key image analysis tasks in brain imaging are presented with particular reference to the freely available FMRIB Software Library. PMID- 21279600 TI - Diffusion tensor imaging. AB - Diffusion tensor MRI (DT-MRI) is the only non-invasive method for characterising the microstructural organization of tissue in vivo. Generating parametric maps that help to visualise different aspects of the tissue microstructure (mean diffusivity, tissue anisotropy and dominant fibre orientation) involves a number of steps from deciding on the optimal acquisition parameters on the scanner, collecting the data, pre-processing the data and fitting the model to generating final parametric maps for entry into statistical data analysis. Here, we describe an entire protocol that we have used on over 400 subjects with great success in our laboratory. In the 'Notes' section, we justify our choice of the various parameters/choices along the way so that the reader may adapt/modify the protocol to their own time/hardware constraints. PMID- 21279601 TI - Manganese-enhanced magnetic resonance imaging (MEMRI). AB - The use of manganese ions (Mn(2+)) as an MRI contrast agent was introduced over 20 years ago in studies of Mn(2+) toxicity in anesthetized rats (1). Manganese enhanced MRI (MEMRI) evolved in the late nineties when Koretsky and associates pioneered the use of MEMRI for brain activity measurements (2) as well as neuronal tract tracing (3). Currently, MEMRI has three primary applications in biological systems: (1) contrast enhancement for anatomical detail, (2) activity dependent assessment and (3) tracing of neuronal connections or tract tracing. MEMRI relies upon the following three main properties of Mn(2+): (1) it is a paramagnetic ion that shortens the spin lattice relaxation time constant (T(1)) of tissues, where it accumulates and hence functions as an excellent T(1) contrast agent; (2) it is a calcium (Ca(2+)) analog that can enter excitable cells, such as neurons and cardiac cells via voltage-gated Ca(2+) channels; and (3) once in the cells Mn(2+) can be transported along axons by microtubule dependent axonal transport and can also cross synapses trans-synaptically to neighboring neurons. This chapter will emphasize the methodological approaches towards the use of MEMRI in biological systems. PMID- 21279602 TI - Sodium MRI. AB - Sodium ((23)Na) imaging has a place somewhere between (1)H-MRI and MR spectroscopy (MRS). Like MRS it potentially provides information on metabolic processes, but only one single resonance of ionic (23)Na is observed. Therefore pulse sequences do not need to code for a chemical shift dimension, allowing (23)Na images to be obtained at high resolutions as compared to MRS. In this chapter the biological significance of sodium in the brain will be discussed, as well as methods for observing it with (23)Na-MRI. Many vital cellular processes and interactions in excitable tissues depend on the maintenance of a low intracellular and high extracellular sodium concentration. Healthy cells maintain this concentration gradient at the cost of energy. Leaky cell membranes or an impaired energy metabolism immediately leads to an increase in cytosolic total tissue sodium. This makes sodium a biomarker for ischemia, cancer, excessive tissue activation, or tissue damage as might be caused by ablation therapy. Special techniques allow quantification of tissue sodium for the monitoring of disease or therapy in longitudinal studies or preferential observation of the intracellular component of the tissue sodium. New methods and high-field magnet technology provide new opportunities for (23)Na-MRI in clinical and biomedical research. PMID- 21279603 TI - MR spectroscopy and spectroscopic imaging of the brain. AB - Magnetic resonance spectroscopy (MRS) and the related technique of magnetic resonance spectroscopic imaging (MRSI) are widely used in both clinical and preclinical research for the non-invasive evaluation of brain metabolism. They are also used in medical practice, although their ultimate clinical value continues to be a source of discussion. This chapter reviews the general information content of brain spectra and commonly used protocols for both MRS and MRSI and also touches on data analysis methods and quantitation. The main focus is on proton MRS for application in humans, but many of the methods are also applicable to other nuclei and studies of animal models as well. PMID- 21279604 TI - Amide proton transfer imaging of the human brain. AB - Amide proton transfer (APT) imaging is a new MRI technique that detects endogenous mobile proteins and peptides in tissue via saturation of the amide protons in the peptide bonds. Initial studies have shown promise in detecting tumor and stroke, but this technique was hampered by magnetic field inhomogeneity and a low signal-to-noise ratio. Several important prerequisites for performing APT imaging experiments include designing an effective APT imaging pulse sequence based on the hardware capability, optimizing the experimental protocol for the best clinical imaging quality, and developing data-processing approaches for effective image assessment. In this chapter, technical issues, such as pulse sequence design and optimization, magnetic field inhomogeneity correction, specific absorption rate minimization, and scan duration, are addressed. PMID- 21279605 TI - High-field MRI of brain iron. AB - Recent developments in high-field MRI have provided opportunities to detect iron in human brain with much improved sensitivity. The combination of increased magnetic field strength with multi-channel detectors has made it possible to routinely obtain images at about 300 MUm resolution. These images can be sensitized to tissue iron by exploiting the improved magnetic susceptibility contrast at high field. Together, these techniques have the potential to map the fine scale distribution of iron in human brain at the level of fiber bundles and cortical laminae, and may aid in the understanding of the role and transport of iron in normal brain and in disease. In this chapter, we will look at these techniques in detail and present some examples of high-field MRI data of human brain. PMID- 21279606 TI - Magnetic resonance imaging-based mouse brain atlas and its applications. AB - In this chapter, we introduce modern magnetic resonance imaging (MRI)-based mouse brain atlases. Although unable to match the resolution and specificity of their histology-based counterparts, MRI-based mouse brain atlases feature higher anatomical fidelity and can facilitate high-throughput computer-assisted analysis of certain brain phenotypes. This chapter discusses several technical aspects of MRI-based mouse brain atlases, which are important to understand the usefulness as well as limitations of existing atlases. We focus on a novel MRI technique, diffusion tensor imaging (DTI), which provides rich tissue contrasts and is uniquely suited for studying white matter structures and immature mouse brains. The chapter then demonstrates several applications of MRI-based mouse brain atlases in anatomical phenotyping and guiding stereotaxic operations. PMID- 21279607 TI - CEST MRI reporter genes. AB - In recent years, several reporter genes have been developed that can serve as a beacon for non-invasive magnetic resonance imaging (MRI). Here, we provide a brief summary of recent advances in MRI reporter gene technology, as well as detailed "hands-on" protocols for cloning, expression, and imaging of reporter genes based on chemical exchange saturation transfer (CEST). PMID- 21279609 TI - Combining EEG and fMRI. AB - The combination of electroencephalography (EEG) with functional magnetic resonance imaging (fMRI) forms a powerful tool for the investigation of brain function, but concurrent implementation of EEG and fMRI poses many technical challenges. Here, the motivation for combining EEG and fMRI is explored and methods underlying the combination are described. After a brief introduction to the two different techniques, the advantages and disadvantages of different methods of data recording are detailed, followed by a description of the artefacts encountered when performing EEG and fMRI measurements simultaneously, and the methods which have been developed to eliminate these artefacts. Important safety considerations and potential pitfalls associated with simultaneous recording are also described. The ways in which EEG and fMRI data analysis can be integrated are then described along with examples of key work which illustrate the power of combined EEG/fMRI measurements. The chapter concludes with a brief discussion of future directions for combined EEG/fMRI research. PMID- 21279608 TI - Longitudinal functional magnetic resonance imaging in animal models. AB - Functional magnetic resonance imaging (fMRI) has had an essential role in furthering our understanding of brain physiology and function. fMRI techniques are nowadays widely applied in neuroscience research, as well as in translational and clinical studies. The use of animal models in fMRI studies has been fundamental in helping elucidate the mechanisms of cerebral blood-flow regulation, and in the exploration of basic neuroscience questions, such as the mechanisms of perception, behavior, and cognition. Because animals are inherently non-compliant, most fMRI performed to date have required the use of anesthesia, which interferes with brain function and compromises interpretability and applicability of results to our understanding of human brain function. An alternative approach that eliminates the need for anesthesia involves training the animal to tolerate physical restraint during the data acquisition. In the present chapter, we review these two different approaches to obtaining fMRI data from animal models, with a specific focus on the acquisition of longitudinal data from the same subjects. PMID- 21279610 TI - MR angiography and arterial spin labelling. AB - MRI offers the ability to visualise and measure blood flow in the human body non invasively. MR angiography (MRA) provides images of the arterial blood vessels within the body and allows measurement of blood velocities along these arteries. Arterial spin labelling (ASL) is a method for measuring the perfusion of blood into tissue (i.e. blood flow at the capillary level). This provides a key indicator of nutrient supply to the tissue. In this chapter, we have described the technical basis and practical implementation of these methods, emphasising their non-invasive (no contrast agents required) and quantitative nature. PMID- 21279611 TI - MRI phenotyping of genetically altered mice. AB - The laboratory mouse, with its genetic similarity to humans and rich set of tools for manipulating its genome, has emerged as one of the key models for experimental investigation of the genotype/phenotype relationships in mammals. Recent innovations have made MRI an increasingly popular tool for examining the phenotype of genetically altered mice. Advances in field strengths, mouse handling, image analysis and statistics have contributed greatly in this regard. In this chapter, we illustrate the methods necessary to achieve high-throughput phenotyping of genetically altered mice using multiple-mouse MRI combined with advanced image analysis techniques and statistics. PMID- 21279612 TI - Gene targeting MRI: nucleic acid-based imaging and applications. AB - Gene action plays a role in neural cell migration, learning processes, stress response, drug addiction, cancer, mental health, psychiatric and neurological disorders, as well as neurodegenerative diseases. Studies also show that upregulation of certain gene activities in neurons may contribute to the development of Alzheimer's disease and other progressive cognitive disorders many decades after the alteration itself occurs. Endogenous, environmental stress related, or drug-induced chemical imbalances in the brain affect the homeostasis of gene activities in neurons in specific brain regions and contribute to the comorbidity of mental illness and substance dependence. On the other hand, altered gene activities are also a necessary part of repair processes after brain injury. Our general well-being is governed by the highly regulated gene activities in our brains. A better understanding of gene activities and their relationship to the progression of neurological disease can help the research and medical communities develop necessary measures for early intervention, as well as plan more appropriate interventions or new therapeutic approaches that can benefit a broad spectrum of patients who will be or have been affected by brain diseases. We developed a non-invasive imaging technique that allows real-time assessment of gene transcription profiles in live brains. This imaging method has the potential to provide first-hand information about the progression of neurological disorders by gene targeting and cell typing, and it could elucidate a surrogate marker for therapeutic efficacy for future planning of treatments for human diseases. We have established a workable and reproducible MRI technique in live rodent brains. PMID- 21279613 TI - Molecular MRI approaches to the detection of CNS inflammation. AB - Inflammation is a key component of many neurological diseases, yet our understanding of the contribution of these processes to tissue damage remains poor. For many such diseases, magnetic resonance imaging (MRI) has become the method of choice for clinical diagnosis. However, many of the MRI parameters that enable disease detection, such as passive contrast enhancement across a compromised blood-brain barrier, are weighted towards late-stage disease. Moreover, whilst these methods may report on disease severity, they are not able to provide information on either disease activity or the underlying molecular processes. There is a need, therefore, to develop methods that enable earlier disease detection, potentially long before clinical symptoms become apparent, together with identification of specific molecular processes that may guide specific therapy. This chapter describes the methodology for the synthesis and validation of two novel, functional MRI-detectable probes, based on microparticles of iron oxide (MPIO), which target endothelial adhesion molecules. These contrast agents enable the detection of acute brain inflammation in vivo, at a time when pathology is undetectable by conventional MRI. Such molecular MRI methods are opening new vistas for the acute diagnosis of CNS disease, together with the possibility for individually tailored therapy and earlier, more sensitive assessment of the efficacy of novel therapies. PMID- 21279614 TI - Brain redox imaging. AB - Nitroxyl contrast agents (nitroxyl radicals, also known as nitroxide) are paramagnetic species, which can react with reactive oxygen species (ROS) to lose paramagnetism to be diamagnetic species. The paramagnetic nitroxyl radical forms can be detected by using electron paramagnetic resonance imaging (EPRI), Overhauser MRI (OMRI), or MRI. The time course of in vivo image intensity induced by paramagnetic redox-sensitive contrast agent can give tissue redox information, which is the so-called redox imaging technique. The redox imaging technique employing a blood-brain barrier permeable nitroxyl contrast agent can be applied to analyze the pathophysiological functions in the brain. A brief theory of redox imaging techniques is described, and applications of redox imaging techniques to brain are introduced. PMID- 21279615 TI - Systems biology approach to imaging of neural stem cells. AB - Over the past decade, the advances in human brain magnetic resonance imaging (MRI) have significantly improved our ability to gain insightful information about the structure and function of the brain. One of the MRI imaging modalities that still awaits more comprehensive data mining is magnetic resonance spectroscopy (MRS). MRS provides information on the functional status of the brain tissue and can detect metabolic abnormalities that precede structural changes. The chemical specificity of proton MRS ((1)H-MRS) allows detection of several biomarkers that are specific for neurons (N-acetyl aspartate, NAA) and astrocytes (myoinositol (mI) and choline (Cho)), the two most abundant cell types present in the brain tissue. However, apart from a dozen metabolites, current methodologies utilized for MRS analysis do not allow further biomarker discoveries. Herein, we introduce a bioinformatics approach to MRS data processing and discuss possible discoveries that such approach may provide. Specifically, we describe the methodology for neural stem/progenitor cell (NPC) detection in vitro and in vivo, utilizing metabolomic profiling and singular value decomposition analyses. PMID- 21279616 TI - MRI of transplanted neural stem cells. AB - Stem cell-based therapy has the potential to improve the prospect of patients suffering from many untreatable diseases. Applications of stem cells for therapy of neurological conditions, such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, or stroke, are particularly appealing as damage of the central nervous system is irreversible and the efficacy of conventional therapy is limited. Despite a broad interest among researchers and clinicians, progress in this field has been slow due to the remarkable complexity of the brain, which makes the task of repairing damaged tissue with stem cells extremely challenging. Making advances can be expedited by novel technologies that can monitor transplanted cells non-invasively. In vivo cellular imaging allows for the repetitive, real-time observation of targeted cells over the course of treatment without the need for invasive biopsies. Magnetic resonance imaging (MRI) is an excellent non-invasive cellular imaging modality as it has superior resolution, is widely used clinically, and has no radiation. This technique currently requires magnetic labeling of cells using superparamagnetic iron oxide particles (SPIOs) and transfection agents. In this chapter, methods for cellular labeling with SPIOs, transplantation of stem cells into the mouse brain, and MR imaging of the cells both in vivo and postmortem will be described. Additional histological and immunohistochemical procedures for analysis of the transplanted cells and the diseased brain environment are also provided. PMID- 21279617 TI - MRI of experimental gliomas. AB - Malignant gliomas are the most frequent primary brain tumours and they are associated with a grim prognosis. In order to elucidate the biological properties of these tumours and to assess treatment responses, valid animal models are needed. We have developed a model where human glioma specimens are operated into the brains of immunodeficient animals. Tumour development is followed by MR imaging and proton spectroscopy. In this chapter, operating procedures and the MR techniques are presented. PMID- 21279618 TI - MRI in experimental stroke. AB - Stroke is the third leading cause of death and the leading cause of long-term disability in the United States. Brain imaging data from experimental stroke models and stroke patients have shown that there is often a gradual progression of potentially reversible ischemic injury toward infarction. A central core with severely compromised cerebral blood flow (CBF) is surrounded by a rim of moderately ischemic tissue with diminished CBF and impaired electrical activity but preserved cellular metabolism, often referred to as the "ischemic penumbra." Re-establishing tissue perfusion and/or treating with neuroprotective drugs in a timely fashion is expected to salvage some ischemic tissues. Diffusion-weighted imaging (DWI) based on magnetic resonance imaging (MRI) in which contrast is based on water apparent diffusion coefficient (ADC) can detect ischemic injury within minutes after onsets, whereas computed tomography and other imaging modalities fail to detect stroke injury for at least a few hours. Along with quantitative perfusion imaging, the perfusion-diffusion mismatch which approximates the ischemic penumbra could be defined non-invasively. This chapter describes stroke modeling, perfusion, diffusion, and some other MRI techniques commonly used to image acute stroke and, finally, image analysis pertaining to experimental stroke imaging. PMID- 21279619 TI - Non-invasive MR imaging of neurodegeneration in a rodent model of Parkinson's disease. AB - Neurotoxin-based rodent models of Parkinson's disease (PD) are widely used for pre-clinical evaluation of novel therapeutics for PD and have provided insights into mechanisms underlying motor dysfunction and nigrostriatal degeneration in PD. Predominantly, magnetic resonance imaging (MRI) studies in such models have focused on alterations in T(2) water (1)H relaxation or (1)H MR spectroscopy (MRS), whilst potential morphological changes and their relationship to histological or behavioural outcomes have not been fully investigated. Identification of MR signal changes that are significantly related to behavioural and histological outcomes in pre-clinical PD models may identify useful non invasive surrogate markers of nigrostriatal degeneration in vivo. Development of such in vivo imaging-based biomarkers may provide a simple, efficient and comprehensive means to study lesion progression and therapeutic interventions in rodent models of PD, which may also have translational value. PMID- 21279620 TI - Detecting amyloid-beta plaques in Alzheimer's disease. AB - One of the major neuropathological changes characteristic of Alzheimer's disease (AD) is deposits of beta-amyloid plaques and neurofibrillary tangles in neocortical and subcortical regions of the AD brain. The histochemical detection of these lesions in postmortem brain tissue is necessary for definitive diagnosis of AD. Methods for their in vivo detection would greatly aid the diagnosis of AD in early stages when neuronal loss and related functional impairment are still limited and would also open the opportunity for effective therapeutic interventions. Magnetic resonance imaging (MRI) theoretically provides the spatial resolution needed to resolve amyloid-beta plaques. Although currently limited for clinical applications due to unfavorable long acquisition times, MRI has been used to visualize Abeta plaques in AD mouse models. The ability to detect amyloid-positive brain lesions in vivo using non-invasive imaging would allow to track disease progression and to monitor the efficacy of potential therapies in disease-modifying studies using transgenic models resembling AD pathology. Here, we provide MRI protocols for in vivo (mouse) and ex vivo (AD tissue samples) amyloid plaque imaging and the procedure for correlating these with thioflavin-S and iron-staining histology. Current challenges and limitations are discussed. PMID- 21279621 TI - Assessing subtle structural changes in Alzheimer's disease patients. AB - Magnetic resonance imaging (MRI) allows the assessment of structural changes in subjects with Alzheimer's disease (AD). Early studies used visual assessments of MRI or manual measurements of structures of interest, although these methods were limited by inter-rater variability. Techniques have now been developed which allow automated analysis of both cross-sectional and longitudinal MRI data and have provided valuable information concerning the patterns and progression of atrophy in subjects with AD. It is also now possible using machine learning-based techniques to provide individual-level diagnostic information from MRI scans. Various analysis techniques have been applied to validate the use of MRI to capture subtle structural changes due to atrophy in AD and its usefulness in providing diagnostic and prognostic information, as well as tracking the disease progression in AD. PMID- 21279622 TI - Pharmacological application of fMRI. AB - Magnetic resonance imaging (MRI) allows the assessment of functional changes consequent to drug administration. Two main approaches have been used: changes in functional MRI signal following drug injection compared to the signal prior to injection and changes in task-related brain networks on drug compared to placebo. Here we describe the additional constraints drug studies place on subject selection, study designs and additional technical requirements. Critical issues in the design of statistical analysis routines are described, including the incorporation of peripheral markers of drug action, such as heart and respiration rate, as well as pharmacokinetic data. Finally, we address methods to minimise the potential influence of non-specific drug effects and side effects on the MRI signal allowing interpretation more closely aligned to the precise research questions. PMID- 21279623 TI - MRI of neuronal plasticity in rodent models. AB - Modifications in the behavior and architecture of neuronal networks are well documented to occur in association with learning and memory, as well as following injury. These plasticity mechanisms are crucial to ensure adequate processing of stimuli, and they also dictate the degree of recovery following peripheral or central nervous system injury. Nevertheless, the underlying neuronal mechanisms that determine the degree of plasticity of neuronal pathways are not fully understood. Recent developments in animal-dedicated magnetic resonance imaging (MRI) scanners and related hardware afford a high spatial and temporal resolution, making functional MRI and manganese-enhanced MRI emerging tools for studying reorganization of neuronal pathways in rodent models. Many of the observed changes in neuronal functions in rodent's brains following injury discussed here agree with clinical human fMRI findings. This demonstrates that animal model imaging can have a significant clinical impact in the neuronal plasticity and rehabilitation arenas. PMID- 21279624 TI - MR-guided focused ultrasound for brain ablation and blood-brain barrier disruption. AB - MR-guided transcranial focused ultrasound (FUS) has been demonstrated as a non invasive tool for treating various brain diseases. First, FUS can thermally ablate brain tissues under real-time MR thermometry monitoring. The MRI guidance significantly improves the precision of the thermal dose deposition. Second, in conjunction with microbubble contrast agents, FUS can reversibly disrupt the blood-brain barrier for delivery of macromolecular drugs to the brain parenchyma. This offers huge potential for treating brain diseases with a much higher local drug concentration than other drug delivery methods. In this chapter, a detailed protocol of MR-guided focused ultrasound for brain thermal ablation and BBB disruption in an animal research setting is presented. PMID- 21279625 TI - Mixed model association scans of multi-environmental trial data reveal major loci controlling yield and yield related traits in Hordeum vulgare in Mediterranean environments. AB - An association panel consisting of 185 accessions representative of the barley germplasm cultivated in the Mediterranean basin was used to localise quantitative trait loci (QTL) controlling grain yield and yield related traits. The germplasm set was genotyped with 1,536 SNP markers and tested for associations with phenotypic data gathered over 2 years for a total of 24 year * location combinations under a broad range of environmental conditions. Analysis of multi environmental trial (MET) data by fitting a mixed model with kinship estimates detected from two to seven QTL for the major components of yield including 1000 kernel weight, grains per spike and spikes per m(2), as well as heading date, harvest index and plant height. Several of the associations involved SNPs tightly linked to known major genes determining spike morphology in barley (vrs1 and int c). Similarly, the largest QTL for heading date co-locates with SNPs linked with eam6, a major locus for heading date in barley for autumn sown conditions. Co localization of several QTL related to yield components traits suggest that major developmental loci may be linked to most of the associations. This study highlights the potential of association genetics to identify genetic variants controlling complex traits. PMID- 21279626 TI - HvFT1 (VrnH3) drives latitudinal adaptation in Spanish barleys. AB - In barley, three genes are responsible for the vernalization requirement: VrnH1, VrnH2 and VrnH3. The winter growth habit of barley requires the presence of a recessive VrnH1 allele, together with an active VrnH2 allele. The candidate for VrnH3 (HvFT1) has been recently identified, with evidences pointing at a central role in the integration of the vernalization and photoperiod pathways. Functional polymorphisms have been proposed, but experimental evidence of their role on agronomic performance and adaptation is needed. We examined allelic variation at the promoter and intron 1 of the HvFT1 gene in a landrace collection of barley, finding a high diversity level, with its geographic distribution correlated with latitude. Focusing on genotypes with winter alleles in VrnH1 and VrnH2, an association analysis of the four main HvFT1 haplotypes found in the landrace collection detected differences in time to flowering. Landraces with the intron 1 TC allele, prevalent in the south, flowered 6-7 days earlier than those with the AG allele, under natural conditions. These results were validated in an independent F(2) population. In both data sets, the effect found was similar, but in opposite direction to that described in literature. The polymorphism reported at intron 1 contributes to variation in flowering time under field conditions. We have found that polymorphisms at the promoter also contribute to the effect of the gene on flowering time under field and controlled conditions. The variety of HvFT1 alleles described constitutes an allelic series that may have been a factor in agro-ecological adaptation of barley. PMID- 21279627 TI - Impact analysis of IPM programs in Basmati rice by estimation of pesticide residues. AB - Samples of Basmati rice grain, soil and water were collected, from IPM and non IPM field trials conducted at four regions of Haryana, Uttar Pradesh and Uttarakhand in India, for pesticide residue analysis. Out of 45 soil samples collected, only four non-IPM samples indicated the presence of chlorpyrifos and endosulfan in the range of ND (<0.001) to 0.05 mg/kg. Carbendazim used at two locations of Dehradun and Kaithal was found below detectable limit (<0.05 mg/kg) in both IPM and non-IPM trials. Out of total 22 samples of water analyzed, chlorpyriphos was detected in samples from Kaithal and Pant Nagar in the range 0.003-0.006 MUL/L, alpha -endosulfan isomer was detected in the range 0.005-0.03 MUL/L and the beta-isomer in the range 0.005-0.02 MUL/L in sample from Pant Nagar and Kaithal. The residues in all the grain sample of paddy were below detectable limit (<0.001-0.05 mg/kg). The insecticides applied in IPM as well as non-IPM trials were found to be below maximum residue level (MRL). PMID- 21279628 TI - Effect of glucose on xylose utilization in Saccharomyces cerevisiae harboring the xylose reductase gene. AB - We have constructed recombinant Saccharomyces cerevisiae JH1 harboring a xylose reductase gene (xyl1) isolated from Pichia stipitis. However, JH1 still utilizes glucose more easily than xylose. Therefore, in this study, we characterized the effect of a glucose supplement on xylose utilization, the expression level of xylose reductase as a recombinant gene in JH1, and the expression levels of two hexose transporters (Hxt4 and Hxt7) due to co-fermentation of different concentrations of glucose and xylose. Co-fermentation using 20 g/l of glucose increased xylose consumption up to 11.7 g/l, which was 7.9-fold that of xylose fermentation without a glucose supplement. In addition, we found xyl1 mRNA levels dramatically increased as cells grew under co-fermentation conditions with supplementary glucose; this result is consistent with a significant decrease in the xylose concentration 48 h after cultivation. In addition, the expression levels of Hxt4 and Hxt7 were strongly activated by the presence of glucose and xylose; in particular, Hxt7 showed a 2.9-fold increased expression relative to that of recombinant S. cerevisiae JHM with only a backbone vector, pYES2. The results of this study suggest that xylose utilization would be improved by activation of hexose transporters induced by glucose (rather than xylose) reductase expression. PMID- 21279629 TI - Use of dispersive liquid-liquid microextraction for the determination of carbamates in juice samples by sweeping-micellar electrokinetic chromatography. AB - Dispersive liquid-liquid microextraction (DLLME) has been proposed for the extraction and preconcentration of 12 carbamate pesticides in juice samples, followed by their determination by micellar electrokinetic chromatography with diode-array detection. To improve sensitivity, an on-capillary sample concentration method based on sweeping has been developed. Also, separations were performed in an extended light path fused-silica capillary; the separation buffer consisted of 100 mM borate and 50 mM SDS (pH 9.0) with 5% acetonitrile. Samples were introduced by hydrodynamic injection, dissolved in the separation buffer, but free of micelles. Several parameters of the DLLME procedure (such as type and volume of extraction and dispersive solvents, pH, salt addition, and extraction time) were optimized. Recoveries obtained for fortified juice samples (banana, pineapple, and tomato) at three different concentration levels, ranged from 78% to 105%, with relative standard deviations lower than 9%. The limits of detection ranged from 1 to 7 MUg l(-1). Moreover, the method is fast, simple, and environmentally friendly. PMID- 21279630 TI - Influence of amino acid relative position on the oxidative modification of histidine and glycine peptides. AB - The radical oxidation of isomeric peptides containing one reactive amino acid [histidine (H)] and another less reactive amino acid [glycine (G)] in the form of dipeptides (HG and GH) and tripeptides (HGG, GHG, and GGH) was studied by mass spectrometry coupled to liquid chromatography (LC-MS) for detection and LC-MS(n) for structural characterization. The oxidation products identified were keto, hydroxy, keto-hydroxy, and hydroperoxide derivatives for both di- and tripeptides. Among these, it was found that insertion of oxygen atoms occurred at histidine for HG and HGG, and both histidine and glycine for GH, GHG, and GGH. In addition, oxidation products formed by alkoxyl rearrangement reactions with cleavage of the peptide chain were also identified for GH, GHG, and GGH, corroborating hydrogen abstraction step in G residues. These findings were supported through the identification of radical intermediate species formed and trapped with 5,5-dimethyl-1-pyrrolidine-N-oxide (DMPO) spin trap. The observation of DMPO adducts bearing two spin trap molecules reinforced the abstraction of two hydrogen atoms from the same molecule. Overall, modification sites identified showed that the outcome of oxidative behavior of peptides is influenced not only by the reactivity of the amino acid in the peptide sequence but also by its relative position within the sequence. PMID- 21279631 TI - Adaptation to rotated visual feedback depends on the number and spread of target directions. AB - It has been proposed in the past that adaptation to rotated visual feedback is based on directionally tuned modules. Here, we investigate whether adaptation depends on the number of modules that are concurrently activated. To disambiguate the number of modules and their spatial overlap, we decided to vary the number of target directions and their spacing independently. In light of recent work on the existence of fast and slow adaptive processes, we analyzed the role of target number and spacing separately for the first eight movements under rotated visual feedback and for later movements. We found that during the first eight movements, adaptation progressed three times faster when targets were spaced across a 42 degrees rather than across a 360 degrees range, irrespective of their number. During the subsequent movements, adaptation progressed 1.66 times faster with two than with eight targets, irrespective of their spacing. This differential dependence of early and late adaptation on target metrics confirms the existence of adaptive processes with different time scales and suggests that those processes differ not only by their clocking speed, but also by their functional properties. Specifically, the speed of fast processes seems to be constrained by the directional tuning width of adaptive modules, and the speed of slow processes by the number of presentations per target direction. PMID- 21279632 TI - Postural instability and fall risk in Parkinson's disease: impaired dual tasking, pacing, and bilateral coordination of gait during the "ON" medication state. AB - The interplay between gait and specific cognitive faculties, in particular executive function (EF) and dual tasking abilities, has been described in healthy adults and in patients with Parkinson's disease (PD). There is, however, little direct evidence on the relationship between cognitive function, gait, and fall risk in PD, especially in the "ON" state (i.e., under the influence of the anti parkinsonian medications). To address this issue, we evaluated cognitive function and gait under usual walking and dual-task conditions in 30 patients with PD in the ON state of the medication cycle. Subjects were classified as fallers or non fallers based on their history. A computerized battery quantified cognitive function. Gait was assessed under three conditions: (1) Usual walking, (2) While subtracting serial 3 s, and (3) While subtracting serial 7 s. The EF and attention scores were lower in the fallers, compared to non-fallers (P <= 0.037), but general measures of cognition, e.g., memory, (P = 0.341) were not. Gait speed, variability, and the bilateral coordination of gait were worse in the fallers in all conditions. The DT effects on gait variability and bilateral coordination were larger in the fallers (P = 0.044, P = 0.061, respectively). These results suggest that patients with PD who have a high risk of falling are more sensitive to DT effects, perhaps as a result of relatively poor EF. These cognitive and motor deficits may increase the likelihood of loss of balance during everyday attention-demanding tasks among patients with PD. PMID- 21279633 TI - Improved change detection with nearby hands. AB - Recent studies have suggested altered visual processing for objects that are near the hands. We present three experiments that test whether an observer's hands near the display facilitate change detection. While performing the task, observers placed both hands either near or away from the display. When their hands were near the display, change detection performance was more accurate and they held more items in visual short-term memory (experiment 1). Performance was equally improved for all regions across the entire display, suggesting a stronger attentional engagement over all visual stimuli regardless of their relative distances from the hands (experiment 2). Interestingly, when only one hand was placed near the display, we found no facilitation from the left hand and a weak facilitation from the right hand (experiment 3). Together, these data suggest that the right hand is the main source of facilitation, and both hands together produce a nonlinear boost in performance (superadditivity) that cannot be explained by either hand alone. In addition, the presence of the right hand biased observers to attend to the right hemifield first, resulting in a right bias in change detection performance (experiments 2 and 3). PMID- 21279634 TI - Observation learning versus physical practice leads to different consolidation outcomes in a movement timing task. AB - Motor learning is a process that extends beyond training sessions. Specifically, physical practice triggers a series of physiological changes in the CNS that are regrouped under the term "consolidation" (Stickgold and Walker 2007). These changes can result in between-session improvement or performance stabilization (Walker 2005). In a series of three experiments, we tested whether consolidation also occurs following observation. In Experiment 1, participants observed an expert model perform a sequence of arm movements. Although we found evidence of observation learning, no significant difference was revealed between participants asked to reproduce the observed sequence either 5 min or 24 h later (no between session improvement). In Experiment 2, two groups of participants observed an expert model perform two distinct movement sequences (A and B) either 10 min or 8 h apart; participants then physically performed both sequences after a 24-h break. Participants in the 8-h group performed Sequence B less accurately compared to participants in the 5-min group, suggesting that the memory representation of the first sequence had been stabilized and that it interfered with the learning of the second sequence. Finally, in Experiment 3, the initial observation phase was replaced by a physical practice phase. In contrast with the results of Experiment 2, participants in the 8-h group performed Sequence B significantly more accurately compared to participants in the 5-min group. Together, our results suggest that the memory representation of a skill learned through observation undergoes consolidation. However, consolidation of an observed motor skill leads to distinct behavioural outcomes in comparison with physical practice. PMID- 21279635 TI - The efficacy and safety of tubeless percutaneous nephrolithotomy: a systematic review and meta-analysis. AB - The objective of this study was to conduct a systematic review and meta-analysis to evaluate the efficacy and safety of tubeless versus standard percutaneous nephrolithotomy (PCNL). Relevant randomized or quasi-randomized controlled trials studies were identified from electronic database (Cochrane CENTRAL, Medline and EMBASE et al.). The retrieval time ended in August 2010. The quality of the included trials was assessed and the data were extracted independently by two reviewers. We divided the participants who received standard PCNL into two subgroups: small tube (4-10 F) group and big tube (14-24 F) group to reduce heterogeneity and bias. Efficacy (hospital stay time, operative time, stone-free rate) and safety (postoperative pain and analgesia requirement, postoperative fever, blood transfusion, urine leakage) were explored by using review manager v5.0. Fourteen randomized controlled trials comprising 776 subjects met the inclusion criteria. Our meta-analysis showed that there were statistically significant differences in hospital stay, postoperative analgesic requirement and urine leakage between tubeless and standard PCNL. In operative time, significant difference was found between tubeless and big tube group. No statistically significant differences were found in stone-free rate, postoperative fever, and blood transfusion between tubeless and standard PCNL. In conclusion, Tubeless PCNL was an effective and safe procedure for treatment of renal stones in selected patients, with shorter hospital stay, less analgesic requirement, lower urine leakage and without increased complications. Patients can receive great benefit from tubeless PCNL and it will become more palatable to patients as well as more cost-effective than standard PCNL in the future. PMID- 21279636 TI - P-wave dispersion and heart rate variability in children with mitral valve prolapse. AB - Previous studies have reported that patients with mitral valve prolapse (MVP) may display autonomic dysfunction. Measurement of heart rate variability (HRV) and P wave dispersion (PWD) may provide insights into the functional state of the autonomic nervous system. Heart rate variability (HRV) has been used as a noninvasive marker of autonomic activity. However, to the authors' knowledge, PWD has not been studied in the context of MVP. This study aimed to examine HRV and PWD in patients with MVP and to determine whether differences exist between symptomatic and asymptomatic patients. The study population consisted of 54 healthy children (17 boys and 37 girls) ages 6-18 years and 76 patients with MVP (20 boys and 56 girls) ages 6-18 years. The duration and dispersion of the P-wave were measured by surface 12-lead electrocardiograms (ECGs). Heart rate variability was quantified using both time-domain and frequency-domain analyses of Holter ECGs. The minimum duration of the P-wave was significantly lower in the MVP patients (42.4 +/- 10.0 ms) than in the control subjects (54.4 +/- 12.8 ms) (p < 0.01), and the PWD was significantly increased in the MVP group (42.7 +/- 10.8 ms) compared with the control subjects (31.8 +/- 10.9 ms) (p < 0.01). However, no significant differences were found between the symptomatic and asymptomatic patients. In addition, the HRV parameters were not statistically different between the two groups. In conclusion, although HRV parameters were not significantly different between the MVP and control groups, the findings show that PWD was increased for the children with MVP. However, no relationship could be established between PWD and clinical symptoms. PMID- 21279637 TI - Akt2: a critical regulator of cardiomyocyte survival and metabolism. AB - Akt proteins are serine/threonine protein kinases that participate in several important intracellular signal transduction cascades. Akt1 and Akt2 are expressed in cardiomyocytes, and both are activated by the action of a variety of growth factors and extracellular ligands. In work with genetically modified mice that had targeted disruption of the genes encoding Akt1 or Akt2, findings showed that Akt1 specifically regulated the physiologic growth of cardiomyocytes that occurred in response to exercise training. In contrast, Akt2 does not regulate physiologic growth but instead regulates glucose metabolism in response to insulin stimulation in cardiomyocytes. Furthermore, Akt2 plays a critical role in antagonizing cardiomyocyte apoptosis that occurs in response to a variety of stimuli, including pathologic remodeling after experimental myocardial infarction. In addition, the protein tribbles 3 (TRB3), an Akt antagonist, was found to be expressed in cardiomyocytes and to be induced by stimuli that cause endoplasmic reticulum stress. Endoplasmic reticulum stress-mediated antagonism of Akt signaling in cardiomyocytes was dependent on TRB3 induction. Finally, myocardial infarction caused endoplasmic reticulum stress in the infarct border zone that was associated with TRB3 induction. These results demonstrate the differential roles of Akt family members and the importance of Akt2 in cardiomyocyte survival. PMID- 21279638 TI - Coding single-nucleotide polymorphisms of interleukin-1 gene cluster are not associated with Kawasaki disease in the Korean population. AB - This study aimed to examine whether coding single-nucleotide polymorphisms (cSNPs) of the interleukin-1 gene cluster [interleukin-1-alpha (IL1alpha), IL1beta, IL-1-receptor antagonist (IL1RN)] are genetic markers of susceptibility to Kawasaki disease (KD) in the Korean population. The study enrolled 109 KD patients and 287 healthy control subjects. Four cSNPs [rs17561 (Ala114Ser) of IL1alpha, rs1143634 (Phe105Phe) of IL1beta, and rs419598 (Ala23Ala) and rs315952 (Ser96Ser) of IL1RN] were genotyped using the restriction fragment-length polymorphism (RFLP) and direct sequencing. The KD patients were divided into two groups according to the presence of coronary artery lesions (CALs). For genetic analysis, SNPStats, HapAnalyzer, Helixtree, and SNPAnalyzer were used. The allele and genotype frequencies of the IL1 gene cluster polymorphisms in the KD patients had a pattern similar to that in the control subjects. Furthermore, no association was observed between four cSNPs of the IL1 gene cluster and the development of CALs in KD. These results suggest that the IL1 gene cluster may not be associated with susceptibility to KD and the development of CALs in the Korean population. PMID- 21279639 TI - Two methods of temperature control for single-molecule measurements. AB - Modern single-molecule biophysical experiments require high numerical aperture oil-immersion objectives in close contact with the sample. We introduce two methods of high numerical aperture temperature control which can be implemented on any microscope: objective temperature control using a ring-shaped Peltier device, and stage temperature control using a fluid flow cooling chip in close thermal contact with the sample. We demonstrate the efficacy of each system by showing the change in speed with temperature of two molecular motors, the bacterial flagellar motor and skeletal muscle myosin. PMID- 21279640 TI - Microsurgical anatomy of the vein of Labbe. AB - OBJECTIVE: Venous drainage of the temporal lobe is of great importance in various neurosurgical and combined skull base approaches. The most significant draining vein of the temporal lobe is the inferior anastomotic vein (vein of Labbe). The purpose of this study was to examine the detailed anatomy and variations of the vein of Labbe (VL) from microsurgical perspective. METHODS: Fourteen fixed human cadaver heads (28 sides) with perfused vessels were included to define microsurgical anatomy and variations of the VL. RESULTS: The main findings of the present study were as follows: (1) drainage pattern of the VL was found to be very variable in cadaveric dissections; (2) VL drained around the sinus confluence at the tentorium in one specimen (3.5%), into the large meningeal vein in the occipital dura mater in another specimen (3.5%). The VL rarely (7%) drains into the superior petrosal sinus (SPS) which may make combined skull base approaches very difficult or impossible. CONCLUSION: Results of this study suggest that careful and thorough evaluation of the VL is of great importance, especially in surgeries combining a subtemporal route with petrosal approaches by sectioning the SPS and the tentorium. PMID- 21279641 TI - Differentiation of fecal Escherichia coli from human, livestock, and poultry sources by rep-PCR DNA fingerprinting on the shellfish culture area of East China Sea. AB - The rep-PCR DNA fingerprinting performed with REP, BOX A1R, and (GTG)(5) primers was investigated as a way to differentiate between human, livestock, and poultry sources of fecal pollution on the area of Xiangshan Bay, East China Sea. Of the three methods, the BOX-PCR DNA fingerprints analyzed by jack-knife algorithm were revealed high rate of correct classification (RCC) with 91.30, 80.39, 89.39, 86.14, 93.24, 87.72, and 89.28% of human, cattle, swine, chicken, duck, sheep, and goose E. coli isolates classified into the correct host source, respectively. The average rate of correct classification (ARCC) of REP-, BOX-, and (GTG)(5)-PCR patterns was 79.88, 88.21, and 86.39%, respectively. Although the highest amount of bands in (GTG)(5)-PCR fingerprints could be observed, the discriminatory efficacy of BOX-PCR was superior to both REP- and (GTG)(5)-PCR. Moreover, the similarity of 459 isolates originated from shellfish and growing water was compared with fecal-obtained strains. The results showed that 92.4 and 96.2% E. coli strains isolated from midstream and downstream shellfish samples, respectively, had a >= 80% similarity with corresponding strains isolated from fecal samples. It was indicated that E. coli in feces could spread from human sewage or domestic farms to the surrounding shellfish culture water, and potentially affect the quality of shellfish. This work suggests that rep-PCR fingerprinting can be a promising genotypic tool applied in the shellfish growing water management on East China Sea for source identification of fecal pollution. PMID- 21279643 TI - Plant biotechnology in support of the Millennium Goals. PMID- 21279642 TI - Analysis of expressed sequence tags derived from a compatible Mycosphaerella fijiensis-banana interaction. AB - Mycosphaerella fijiensis, a hemibiotrophic fungus, is the causal agent of black leaf streak disease, the most serious foliar disease of bananas and plantains. To analyze the compatible interaction of M. fijiensis with Musa spp., a suppression subtractive hybridization (SSH) cDNA library was constructed to identify transcripts induced at late stages of infection in the host and the pathogen. In addition, a full-length cDNA library was created from the same mRNA starting material as the SSH library. The SSH procedure was effective in identifying specific genes predicted to be involved in plant-fungal interactions and new information was obtained mainly about genes and pathways activated in the plant. Several plant genes predicted to be involved in the synthesis of phenylpropanoids and detoxification compounds were identified, as well as pathogenesis-related proteins that could be involved in the plant response against M. fijiensis infection. At late stages of infection, jasmonic acid and ethylene signaling transduction pathways appear to be active, which corresponds with the necrotrophic life style of M. fijiensis. Quantitative PCR experiments revealed that antifungal genes encoding PR proteins and GDSL-like lipase are only transiently induced 30 days post inoculation (dpi), indicating that the fungus is probably actively repressing plant defense. The only fungal gene found was induced 37 dpi and encodes UDP-glucose pyrophosphorylase, an enzyme involved in the biosynthesis of trehalose. Trehalose biosynthesis was probably induced in response to prior activation of plant antifungal genes and may act as an osmoprotectant against membrane damage. PMID- 21279644 TI - A novel MYH7 mutation occurring independently in French and Norwegian Laing distal myopathy families and de novo in one Finnish patient. AB - Laing early-onset distal myopathy is a rare autosomal dominant myopathy and caused by mutations in the MYH7 gene, encoding the slow beta myosin heavy chain. We report the first molecularly verified Laing distal myopathy in a French family caused by a novel p.Glu1508del mutation in the MYH7 gene. Interestingly, we identified the identical mutation in an unrelated Norwegian family and, as a de novo mutation, in one sporadic Finnish patient. Described in detail are the clinical and electrophysiological characteristics of 5 patients from the French family. The phenotype in the Finnish patient and the Norwegian patients is largely similar. This mutation causes a benign myopathy within the range of previously reported Laing myopathy phenotype variations. Onset of weakness in the tibialis anterior (TA) muscles occurred in early childhood in all patients. Finger extensor and neck flexor weakness together with Achilles tendon retractions were other frequent findings. The independent recurrence of the identical mutation without any founder background may reflect a mutational susceptibility of this residue, in accordance with some other MYH7 mutations previously reported. De novo mutations seem to be frequent in Laing distal myopathy. This is of clinical importance since a dominant family history is missing, which may confuse differential diagnostic efforts. PMID- 21279645 TI - Allergic asthma after flour inhalation in subjects without occupational exposure to flours: an experimental pilot study. AB - OBJECTIVE: Cross-reactivity between grass pollen and grain flour allergens is well known, but their significance in apprentice bakers with primary sensitization to grass pollen is not known. METHODS: Twenty-five subjects with mild asthma (most of them with hay fever), but without prior occupational flour exposure, underwent standardized experimental inhalation challenges with placebo and wheat and rye flours in randomized order on three consecutive days. Sensitization to flours and environmental allergens was assessed by skin prick tests and specific IgE antibodies in sera. IgE inhibition experiments were performed with wheat and rye flours as solid phases, and grass and tree pollen as inhibitors. RESULTS: Five subjects experienced a positive reaction after flour inhalation (responders), whereas 20 subjects did not show such a reaction (non responders). All responders showed sensitizations to flours, whereas only 25% of the non-responders demonstrated the same sensitization. Specific IgE concentrations to flours, but also to grass and tree pollen, were higher in responders. Inhibition experiments demonstrated cross-reactivity between flours and grass or tree pollen, with higher inhibition rates in responders. CONCLUSIONS: Subjects with pronounced sensitizations to grass or tree pollen, but without prior occupational exposure to flours, may experience both sensitization and allergic asthmatic reactions to flours due to cross-reactive grass and tree pollen allergens. PMID- 21279646 TI - Diagnostic performance of cold provocation test with hands immersion in water at 10 degrees C for 5 min evaluated in vibration-induced white finger patients and matched controls. AB - PURPOSE: This study aimed to explore the diagnostic ability of the cold provocation test with hands immersion in water at 10 degrees C for 5 min in diagnosing vibration-induced white finger (VWF). METHODS: Finger skin temperature (FST) was measured in 20 VWF patients and 20 matched healthy controls, at palmar side of the distal phalanges of fingers from both hands before, during, and after hands immersion in water at 10 degrees C (for 5 min with waterproof coverings put on both hands). Data from 4 fingers (except thumb) were evaluated at five time points: just before immersion, last minute during immersion, and at 5th, 10th, and 15th min during the post-immersion or recovery period. RESULTS: A positive group difference between patients and controls was revealed during the recovery period. During recovery at 95 and 70% specificity, the sensitivity ranged from 20 to 30% and 50 to 70% for evaluation with average FST for 4 fingers and 15-35% and 60-65% for evaluation with minimum FST among 4 fingers, respectively. Overall, evaluation of absolute FST at 15th min of recovery offered better diagnostic ability. CONCLUSIONS: The cold provocation test with hands immersion in water at 10 degrees C for 5 min could discriminate VWF patients from healthy controls; however, this test has a limited diagnostic value in diagnosing patients with VWF. PMID- 21279647 TI - Transcriptional control of aspartate kinase expression during darkness and sugar depletion in Arabidopsis: involvement of bZIP transcription factors. AB - Initial steps of aspartate-derived biosynthesis pathway (Asp pathway) producing Lys, Thr, Met and Ile are catalyzed by bifunctional (AK/HSD) and monofunctional (AK-lys) aspartate kinase (AK) enzymes. Here, we show that transcription of all AK genes is negatively regulated under darkness and low sugar conditions. By using yeast one-hybrid assays and complementary chromatin immunoprecipitation analyses in Arabidopsis cells, the bZIP transcription factors ABI5 and DPBF4 were identified, capable of interacting with the G-box-containing enhancer of AK/HSD1 promoter. Elevated transcript levels of DPBF4 and ABI5 under darkness and low sugar conditions coincide with the repression of AK gene expression. Overexpression of ABI5, but not DPBF4, further increases this AK transcription suppression. Concomitantly, it also increases the expression of asparagines synthetase 1 (ASN1) that shifts aspartate utilization towards asparagine formation. However, in abi5 or dpbf4 mutant and abi5, dpbf4 double mutant the repression of AK expression is maintained, indicating a functional redundancy with other bZIP-TFs. A dominant-negative version of DPBF4 fused to the SRDX repressor domain of SUPERMAN could counteract the repression and stimulate AK expression under low sugar and darkness in planta. This effect was verified by showing that DPBF4-SRDX fails to recognize the AK/HSD1 enhancer sequence in yeast one-hybrid assays, but increases heterodimmer formation with DPBF4 and ABI5, as estimated by yeast two-hybrid assays. Hence it is likely that heterodimerization with DPBF4-SRDX inhibits the binding of redundantly functioning bZIP-TFs to the promoters of AK genes and thereby releases the repressing effect. These data highlight a novel transcription control of the chloroplast aspartate pathway that operates under energy limiting conditions. PMID- 21279648 TI - Comparison of a novel tomato sucrose synthase, SlSUS4, with previously described SlSUS isoforms reveals distinct sequence features and differential expression patterns in association with stem maturation. AB - Sucrose synthase (SUS) plays a role in many contexts of sugar metabolism, including low-oxygen and low-ATP respiration and the synthesis of cellulose. In tomato (Solanum lycopersicum), as in many plants, SUS is encoded by genes at several independent loci. Here, we report the isolation of a novel tomato SUS (SlSUS) isoform, SlSUS4, that is homologous to potato SUS isoform 1 (StSUS1) and also shows greater homology to SUS isoforms of other plants than to the other tomato SUS isoforms. All three tomato isoforms are very similar in genomic structure and sequence, yet each is located on a separate chromosome. Real-time expression analysis of the three distinct isoforms revealed widely varying patterns of expression, in terms of both tissue specificity and overall magnitude of expression. Analysis of SlSUS expression along the tomato stem revealed opposing expression gradients for two of the SlSUS isoforms, in apparent correlation with vascular tissue maturation. Western-blot analysis of SlSUS protein showed an increasing SlSUS concentration gradient along the developmental axis of the tomato stem, with the protein concentrated mainly in the vascular tissue of the stem. These gene expression and protein accumulation patterns indicate that each isoform may play a discrete role in the development of tomato plants, most notably in the development of vascular tissue in the stem. PMID- 21279649 TI - Genomic organization, induced expression and promoter activity of a resistance gene analog (PmTNL1) in western white pine (Pinus monticola). AB - Cronartium ribicola causes white pine blister rust (WPBR) in subgenus Strobus. Various genetic and molecular approaches were used to detect white pine genes contributing to host resistance. The molecular role of the NBS-LRR family is highly related to plant immuno-activity against various pathogens and pests. In the present study, genomic organization of a resistance gene analog (RGA), designated as PmTNL1, and its allelic variants were characterized in Pinus monticola. PmTNL1 showed high identity with TIR-NBS-LRR proteins from other plants. qRT-PCR revealed that the PmTNL1 transcript was expressed at low basal levels in different tissues and exhibited similar patterns during compatible and incompatible interactions of P. monticola with C. ribicola at early stages post inoculation. In comparison, PmTNL1 was up-regulated significantly in diseased P. monticola tissues with WPBR symptoms. Expression of the PmTNL1 promoter::GUS fusion gene in transgenic Arabidopsis demonstrated that GUS signal appeared only inside phloem tissues of young seedlings and at hydathodes and branching and organ-connecting points in mature Arabidopsis plants. Similar to the endogenous expression pattern for this gene in pine, GUS activity was up-regulated significantly around vascular tissues locally at pathogen infection sites, but little or no induction was observed in response to abiotic stresses. A DNA marker was developed based on variation of the LRR-coding region, and PmTNL1 was mapped to one genetic linkage group using a pedigree with major dominant gene (Cr2) conferring HR resistance to C. ribicola. These results suggest that PmTNL1 may play an important role in white pine partial resistance against C. ribicola. PMID- 21279650 TI - Differential expression of two beta-amylase genes (Bmy1 and Bmy2) in developing and mature barley grain. AB - Two barley (Hordeum vulgare L.) beta-amylase genes (Bmy1 and Bmy2) were studied during the late maturation phase of grain development in four genotypes. The Bmy1 and Bmy2 DNA and amino acid sequences are extremely similar. The largest sequence differences are in the introns, seventh exon, and 3' UTR. Accumulation of Bmy2 mRNA was examined in developing grain at 17, 19, and 21 days after anthesis (DAA). One genotype, PI 296897, had significantly higher Bmy2 RNA transcript accumulation than the other three genotypes at all developmental stages. All four genotypes had Bmy2 mRNA levels decrease from 17 to 19 DAA, and remain the same from 19 to 21 DAA. Levels of Bmy1 mRNA were twenty thousand to over one hundred thousand times more than Bmy2 mRNA levels in genotypes Legacy, Harrington, and Ashqelon at all developmental stages and PI 296897 at 19 and 21 DAA. PI 296897 had five thousand times more Bmy1 mRNA than Bmy2 mRNA at 17 DAA. However, Bmy2 protein was not found at 17 DAA in any genotype. The presence of Bmy2 was immunologically detected at 19 DAA and was present in greater amounts at 21 DAA. Also, Bmy2 protein was found to be stored in mature grain and localized in the soluble fraction. However, Bmy1 protein was far more prevalent than Bmy2 at all developmental stages in all genotypes. Thus, the vast majority of beta-amylase activity in developing and mature grain can be attributed to endosperm-specific beta-amylase. PMID- 21279651 TI - Analysis of Chlamydia pneumoniae infection in mononuclear cells by reverse transcription-PCR targeted to chlamydial gene transcripts. AB - Chlamydia pneumoniae (C. pneumoniae) is an important etiological agent of respiratory infections including pneumonia. C. pneumoniae DNA can be detected in peripheral blood mononuclear cells indicating that monocytes can assist the spread of infection to other anatomical sites. Persistent infection established at these sites could promote inflammation and enhance pathology. Thus, the mononuclear cells are in a strategic position in the development of persistent infection. To investigate the intracellular replication and fate of C. pneumoniae in mononuclear cells, we have established an in vitro model in the human Mono Mac 6 cell line. In the present study, we analyzed the transcription of 11 C. pneumoniae genes in Mono Mac 6 cells during infection by real-time RT-PCR. Our results suggest that the transcriptional profile of the studied genes in monocytes is different from that seen in epithelial cells. Furthermore, our study shows that genes related to secretion are transcribed, and secreted bacterial proteins are also translated during infection of monocytes, creating novel opportunities for the management of chlamydial infection of monocytes. PMID- 21279652 TI - New QTL for resistance to Salmonella carrier-state identified on fowl microchromosomes. AB - Chicken's ability to carry Salmonella without displaying disease symptoms leads to an invisible propagation of Salmonella in poultry stocks. Using chicken lines more resistant to carrier state could improve both animal health and food safety. Previous studies identified several QTL for resistance to carrier state. To improve genome coverage and QTL detection power we produced a new set of 480 informative SNP markers and genotyped a larger number of animals. Ten additional microchromosomes could be covered when compared with previous studies. These new data led to the identification of 18 QTL significant at the chromosome-wide level. The only QTL significant at the genome-wide level were identified on microchromosomes 14 and 22 and have never been identified previously. Using a higher number of animals improved the power and the precision of QTL detection. Some of the QTL newly identified are located close to candidate genes or microsatellite markers previously identified for their involvement in the genetic control of resistance to Salmonella, which confirms their interest for selection purposes. PMID- 21279653 TI - Multiple measures elucidate glucocorticoid responses to environmental variation in predation threat. AB - Predator-induced changes in the glucocorticoid responses of prey have been proposed to mediate indirect predator effects on prey demography. Ambiguities exist, however, as to whether differences in predation threat in the environment at large affect the mean glucocorticoid response in wild birds and mammals, and whether this is likely to affect reproduction. Most studies to date that have examined glucocorticoid responses to environmental variation in predation threat have evaluated just one of the several potential measures of the glucocorticoid response, and this may be the source of many ambiguities. We evaluated multiple measures of the glucocorticoid response [plasma total CORTicosterone, corticosteroid binding globulin (CBG) and free CORT] in male and female song sparrows (Melospiza melodia) sampled at locations differing in predation threat in the environment at large, where we have previously reported reproductive differences suggestive of indirect predator effects. Total CORT varied markedly with predation threat in males but not females whereas the opposite was true for CBG, and both sexes demonstrated the same moderately significant free CORT response. Considering all three indices, a glucocorticoid response to environmental variation in predation threat was evident in both sexes, whereas there were ambiguities considering each index singly. We conclude that collecting multiple physiological measures and conducting multivariate analyses may provide a preferable means of assessing glucocorticoid responses to environmental variation in predation threat, and so help clarify whether such glucocorticoid changes affect reproduction in wild birds and mammals. PMID- 21279654 TI - Balancing positive and negative plant interactions: how mosses structure vascular plant communities. AB - Our understanding of positive and negative plant interactions is primarily based on vascular plants, as is the prediction that facilitative effects dominate in harsh environments. It remains unclear whether this understanding is also applicable to moss-vascular plant interactions, which are likely to be influential in low-temperature environments with extensive moss ground cover such as boreal forest and arctic tundra. In a field experiment in high-arctic tundra, we investigated positive and negative impacts of the moss layer on vascular plants. Ramets of the shrub Salix polaris, herb Bistorta vivipara, grass Alopecurus borealis and rush Luzula confusa were transplanted into plots manipulated to contain bare soil, shallow moss (3 cm) and deep moss (6 cm) and harvested after three growing seasons. The moss layer had both positive and negative impacts upon vascular plant growth, the relative extent of which varied among vascular plant species. Deep moss cover reduced soil temperature and nitrogen availability, and this was reflected in reduced graminoid productivity. Shrub and herb biomass were greatest in shallow moss, where soil moisture also appeared to be highest. The relative importance of the mechanisms by which moss may influence vascular plants, through effects on soil temperature, moisture and nitrogen availability, was investigated in a phytotron growth experiment. Soil temperature, and not nutrient availability, determined Alopecurus growth, whereas Salix only responded to increased temperature if soil nitrogen was also increased. We propose a conceptual model showing the relative importance of positive and negative influences of the moss mat on vascular plants along a gradient of moss depth and illustrate species-specific outcomes. Our findings suggest that, through their strong influence on the soil environment, mat-forming mosses structure the composition of vascular plant communities. Thus, for plant interaction theory to be widely applicable to extreme environments such as the Arctic, growth forms other than vascular plants should be considered. PMID- 21279656 TI - Modifiers of the temperature-mortality association in Shanghai, China. AB - Various factors can modify the health effects of temperature. Prior findings about modifiers are inconsistent, and such studies have been conducted mostly in developed countries. We conducted a time-series analysis to examine the modifying effect of gender, age and education on the association between temperature and daily mortality in Shanghai, China, using 4 years (2001-2004) of daily data. A natural spline model was used to analyze the data. Elderly subjects were found to be more vulnerable to temperature health effects compared with younger people. We observed no significant modifying effect of gender or education level. These findings may provide useful information for local governments seeking to take steps to protect vulnerable sub-populations. PMID- 21279657 TI - Computer algorithms and applications used to assist the evaluation and treatment of adolescent idiopathic scoliosis: a review of published articles 2000-2009. AB - Adolescent idiopathic scoliosis (AIS) is a complex spinal deformity whose assessment and treatment present many challenges. Computer applications have been developed to assist clinicians. A literature review on computer applications used in AIS evaluation and treatment has been undertaken. The algorithms used, their accuracy and clinical usability were analyzed. Computer applications have been used to create new classifications for AIS based on 2D and 3D features, assess scoliosis severity or risk of progression and assist bracing and surgical treatment. It was found that classification accuracy could be improved using computer algorithms that AIS patient follow-up and screening could be done using surface topography thereby limiting radiation and that bracing and surgical treatment could be optimized using simulations. Yet few computer applications are routinely used in clinics. With the development of 3D imaging and databases, huge amounts of clinical and geometrical data need to be taken into consideration when researching and managing AIS. Computer applications based on advanced algorithms will be able to handle tasks that could otherwise not be done which can possibly improve AIS patients' management. Clinically oriented applications and evidence that they can improve current care will be required for their integration in the clinical setting. PMID- 21279658 TI - Bow hunter's stroke due to instability at the uncovertebral C3/4 joint. AB - Bow hunter's stroke is typically due to mechanical compression or stretching of the dominant vertebral artery (VA) during contralateral head rotation against the bony elements of the atlas and axis. We report a case of vertebrobasilar insufficiency due to bilateral vertebral artery occlusion at the left C3-4 and the right C1-2 junction on rightward head rotation. A 64-year-old man experienced ischemic symptoms during 90 degrees head rotation to the right with complete resolution of symptoms after returning his head to the neutral position. Dynamic cervical angiography with rightward head rotation showed severe compression of the right VA at the transverse foramen of C3-4 and mechanical stenosis of the left VA at the C1-2 level. During head rotation, the flow of the right VA was decreased more than the left side. Cervical 3-D computed tomography (CT) on rightward head rotation demonstrated displacement of the uncovertebral C3-4 joint, with excessive rotation of the C3 vertebral body. Based on these findings, instability at C3-4 was suspected to be the main cause of the vertebrobasilar insufficiency. Anterior discectomy and fusion at the C3/4 level were performed. Postoperatively, the patient experienced complete resolution of symptoms, and dynamic cervical angiography showed disappearance of the compression of the right VA. To our knowledge, this is the first reported case of bow hunter's stroke diagnosed by dynamic cerebral angiography and cervical 3-D CT without angiography, and treated by anterior decompression and fusion without decompression of the VA. PMID- 21279659 TI - Comment concerning: Intraoperative 5-aminolevulinic-acid-induced fluorescence in meningiomas, Acta Neurochir DOl 1O.1007/s00701-010-0708-4, Intratumoral heterogeneity and fluorescence intensity in meningioma after 5-ALA pretreatment. PMID- 21279660 TI - Incidental major artery aneurysms in patients with non-hemorrhagic moyamoya disease. AB - BACKGROUND: Major artery aneurysms may be found incidentally while evaluating moyamoya disease (MMD). The purpose of this study was to delineate the prevalence and characteristics of these uncommon aneurysms with a brief mention of their management and outcomes. METHODS: We conducted a retrospective review of 249 adult patients who were diagnosed with non-hemorrhagic MMD. Cerebral angiograms obtained at the time of initial diagnosis were carefully reviewed to identify incidental aneurysms located on a major intracranial artery or near its tributaries. Aneurysms originating from distal peripheral arteries or moyamoya vessels were ineligible for this study. RESULTS: Nine patients (3.6%) were found to have 13 major artery aneurysms, 7 (54%) of which were located in the posterior circulation, especially in older patients with bilateral MMD. The sizes of all aneurysms were less than 10 mm. Surgical clipping was performed on two aneurysms, and endovascular coiling on six (five posterior circulation aneurysms). Ischemic complications occurred in two patients after clipping of an anterior communicating artery aneurysm and in one patient after the second coiling of a recanalized basilar tip aneurysm. CONCLUSIONS: Incidental major artery aneurysms can be found in 3.6% of adult patients with non-hemorrhagic MMD, an observed frequency that increases with age. About half of these aneurysms are located in the posterior circulation, particularly in older patients with bilateral MMD. Considering the risks of treatment-related complications, more information about the natural course of these aneurysms is needed to design proper management strategies both for the aneurysms and MMD. PMID- 21279661 TI - In vivo self-hydroxylation of an iron-substituted manganese-dependent extradiol cleaving catechol dioxygenase. AB - The homoprotocatechuate 2,3-dioxygenase from Arthrobacter globiformis (MndD) catalyzes the oxidative ring cleavage reaction of its catechol substrate in an extradiol fashion. Although this reactivity is more typically associated with non heme iron enzymes, MndD exhibits an unusual specificity for manganese(II). MndD is structurally very similar to the iron(II)-dependent homoprotocatechuate 2,3 dioxygenase from Brevibacterium fuscum (HPCD), and we have previously shown that both MndD and HPCD are equally active towards substrate turnover with either iron(II) or manganese(II) (Emerson et al. in Proc. Natl. Acad. Sci. USA 105:7347 7352, 2008). However, expression of MndD in Escherichia coli under aerobic conditions in the presence of excess iron results in the isolation of inactive blue-green iron-substituted MndD. Spectroscopic studies indicate that this form of iron-substituted MndD contains an iron(III) center with a bound catecholate, which is presumably generated by in vivo self-hydroxylation of a second-sphere tyrosine residue, as found for other self-hydroxylated non-heme iron oxygenases. The absence of this modification in either the native manganese-containing MndD or iron-containing HPCD suggests that the metal center of iron-substituted MndD is able to bind and activate O(2) in the absence of its substrate, employing a high-valence oxoiron oxidant to carry out the observed self-hydroxylation chemistry. These results demonstrate that the active site metal in MndD can support two dramatically different O(2) activation pathways, further highlighting the catalytic flexibility of enzymes containing a 2-His-1-carboxylate facial triad metal binding motif. PMID- 21279662 TI - Parastomal hernia repair outcomes in relation to stoma site with diisocyanate cross-linked acellular porcine dermal collagen mesh. AB - PURPOSE: Biologic meshes are increasingly used in parastomal hernia repair. This study evaluates the efficacy and safety of diisocyanate cross-linked acellular porcine dermal collagen mesh for parastomal hernia repair, with particular reference to the relationship of the stoma site to the rectus sheath. METHODS: Hernias were repaired via a lateral approach, with onlay placement of the biologic mesh. A retrospective case note review and analysis of clinical outcomes was performed. The relationship of the stoma to the rectus sheath was determined by abdominal computed tomography (CT) and intraoperative findings. RESULTS: Over a 16-month period, 27 consecutive patients, median age 72 years, underwent parastomal hernia repair utilising onlay biologic mesh to reinforce the external oblique aponeurosis. There were 20 paracolostomy and seven paraileostomy hernias. Eleven stomas passed through the rectus sheath and 16 were lateral to it. Recurrences occurred in 3 of 11 stomas within and 12 of 16 stomas lateral to the rectus sheath (P = 0.022). The median time to recurrence was 10.1 months. The median follow up of patients without recurrence was 16.6 months (range 0.2-39.3). There was one perioperative death. One patient developed a superficial post operative abscess that was managed conservatively, but there were no complications related to the biologic mesh and no mesh required removal. CONCLUSIONS: For parastomal hernias within the rectus sheath, diisocyanate cross linked porcine dermal collagen mesh onlay repair gives good results and is safe to use. Repair of a parastomal hernia where the stoma is lateral to the rectus sheath has a significantly higher risk of recurrence and is not recommended. PMID- 21279663 TI - Histologic and biomechanical evaluation of a novel macroporous polytetrafluoroethylene knit mesh compared to lightweight and heavyweight polypropylene mesh in a porcine model of ventral incisional hernia repair. AB - PURPOSE: To evaluate the biocompatibility of heavyweight polypropylene (HWPP), lightweight polypropylene (LWPP), and monofilament knit polytetrafluoroethylene (mkPTFE) mesh by comparing biomechanics and histologic response at 1, 3, and 5 months in a porcine model of incisional hernia repair. METHODS: Bilateral full thickness abdominal wall defects measuring 4 cm in length were created in 27 Yucatan minipigs. Twenty-one days after hernia creation, animals underwent bilateral preperitoneal ventral hernia repair with 8 * 10 cm pieces of mesh. Repairs were randomized to Bard((r))Mesh (HWPP, Bard/Davol, http://www.davol.com), ULTRAPRO((r)) (LWPP, Ethicon, http://www.ethicon.com), and GORE((r))INFINIT Mesh (mkPTFE, Gore & Associates, http://www.gore.com). Nine animals were sacrificed at each timepoint (1, 3, and 5 months). At harvest, a 3 * 4 cm sample of mesh and incorporated tissue was taken from the center of the implant site and subjected to uniaxial tensile testing at a rate of 0.42 mm/s. The maximum force (N) and tensile strength (N/cm) were measured with a tensiometer, and stiffness (N/mm) was calculated from the slope of the force versus-displacement curve. Adjacent sections of tissue were stained with hematoxylin and eosin (H&E) and analyzed for inflammation, fibrosis, and tissue ingrowth. Data are reported as mean +/- SEM. Statistical significance (P < 0.05) was determined using a two-way ANOVA and Bonferroni post-test. RESULTS: No significant difference in maximum force was detected between meshes at any of the time points (P > 0.05 for all comparisons). However, for each mesh type, the maximum strength at 5 months was significantly lower than that at 1 month (P < 0.05). No significant difference in stiffness was detected between the mesh types or between timepoints (P > 0.05 for all comparisons). No significant differences with regard to inflammation, fibrosis, or tissue ingrowth were detected between mesh types at any time point (P > 0.09 for all comparisons). However, over time, inflammation decreased significantly for all mesh types (P < 0.001) and tissue ingrowth reached a slight peak between 1 and 3 months (P = 0.001) but did not significantly change thereafter (P > 0.09). CONCLUSIONS: The maximum tensile strength of mesh in the abdominal wall decreased over time for HWPP, LWPP, and mkPTFE mesh materials alike. This trend may actually reflect inability to adequately grip specimens at later time points rather than any mesh-specific trend. Histologically, inflammation decreased with time (P = 0.000), and tissue ingrowth increased (P = 0.019) for all meshes. No specific trends were observed between the polypropylene meshes and the monofilament knit PTFE, suggesting that this novel construction may be a suitable alternative to existing polypropylene meshes. PMID- 21279664 TI - Risk factors for wound complications in midline abdominal incisions related to the size of stitches. AB - BACKGROUND: Midline abdominal incisions should be closed continuously with a suture length (SL) to wound length (WL) ratio above 4 using small stitches. The effect on the rate of wound complications of a very high ratio and other potential risk factors when closure is performed with small stitches is unknown. METHODS: Patients operated on through a midline incision were randomised to closure with small stitches, placed 5-8 mm from the wound edge and less than 5 mm apart, or with large stitches, placed more than 1 cm from the wound edge. Patient and operative variables were registered. Surgical site infection and incisional hernia were recorded. RESULTS: Three hundred and twenty-one patients were randomised to closure with small stitches and 370 with large stitches. Infection and herniation were less common with small stitches. With small stitches, no risk factors for infection or herniation were identified. With large stitches, wound contamination and the patient being diabetic were independent risk factors for infection, and long operation time and surgical site infection were risk factors for herniation. A very high SL to WL ratio did not affect the complication rates. CONCLUSIONS: In midline abdominal incisions closed with small stitches, no risk factors for surgical site infection or incisional hernia were identified. Increasing the ratio very much above 4 had no adverse effects on the rate of wound complications. The higher rates of infection and herniation with an SL to WL ratio over 5 and in overweight patients in previous reports were probably related to wounds being closed with large stitches. PMID- 21279665 TI - Some considerations about the biological appearance of pacing stimuli in visuomotor finger-tapping tasks. AB - Sensorimotor synchronization is a crucial function for human daily activities, which relies on the ability of predicting external events. Synchronization performance, as assessed in finger-tapping (FT) tasks, is characterized by an anticipation tendency, as the tap generally precedes the pacing event. This synchronization error (SE) depends on many factors, in particular on the features of the pacing stimulus. Interest is growing in the facilitation effect that action observation has on motor execution. So far, neuroimaging and neurophysiology studies of motor priming via action observation have mainly employed tasks requiring single action instances. The impact of action observation on motor synchronization to periodic stimuli has not yet been tested; to this aim, a synchronization FT task may be an eligible probing task. The purpose of this study was to characterize a biological pacer at the behavioral level and provide information for those interested in studying the brain processes of continuous observation/execution coupling in timed actions using FT tasks. We evaluated the influence of the biological appearance of a pacer (a tapping finger) on SE, when compared to an abstract, kinematically equivalent pacer (a tilting hinged bar) and a more standard stimulus (a pulsating dot). We showed that the continuous visual display of a biological pacer yields comparable results to the abstract pacer, and a more robust performance and larger anticipations than a traditional pulsating stimulus. PMID- 21279666 TI - The Giessen virtual environment laboratory: human wayfinding and landmark salience. AB - In our virtual environment laboratory, we focus on different topics in human spatial cognition with projects on landmark salience, route knowledge, and survey knowledge. Within this laboratory note, we provide an overview of previous, current, and future work with our virtual environment SQUARELAND. PMID- 21279667 TI - An NF-kappaB p65-cIAP2 link is necessary for mediating resistance to TNF-alpha induced cell death in gliomas. AB - Malignant gliomas are diffusively infiltrative and remain among the deadliest of all cancers. NF-kappaB is a transcription factor that mediates cell growth, migration and invasion, angiogenesis and resistance to apoptosis. Normally, the activity of NF-kappaB is tightly regulated by numerous mechanisms. However, in many cancers, NF-kappaB is constitutively activated and may function as a tumor promoter. Herein, we show that in gliomas, NF-kappaB is constitutively activated and the levels of cIAP2, Bcl-2, Bcl-xL and Survivin are elevated. These genes are regulated by NF-kappaB and can inhibit apoptosis. To understand the potential role of NF-kappaB p65 in suppressing apoptosis, we generated human glioma cell lines that inducibly express shRNA molecules specific for p65. We demonstrate that in the absence of p65, TNF-alpha induced cIAP2 expression is significantly reduced while the levels of Bcl-2, Bcl-xL and Survivin are not affected. These data suggest that of these genes, only cIAP2 is a direct target of p65, which was confirmed using RT-PCR and chromatin immunoprecipitation (ChIP) assays. By reducing the levels of p65 and/or cIAP2 levels, we demonstrate that the levels of RIP poly-ubiquitination are reduced, and that p65-deficient glioma cells are more sensitive to the cytotoxic effects of TNF-alpha. Specifically, in the presence of TNF-alpha glioma cells lacking p65 and/or cIAP2 showed cellular proliferation defects and underwent cell death. These data suggest that NF-kappaB and/or cIAP2 may be therapeutically relevant targets for the treatment of malignant gliomas. PMID- 21279668 TI - Suppression of phospholipid biosynthesis by cerulenin in the condensed Single Protein-Production (cSPP) system. AB - Using the single-protein-production (SPP) system, a protein of interest can be exclusively produced in high yield from its ACA-less gene in Escherichia coli expressing MazF, an ACA-specific mRNA interferase. It is thus feasible to study a membrane protein by solid-state NMR (SSNMR) directly in natural membrane fractions. In developing isotope-enrichment methods, we observed that (13)C was also incorporated into phospholipids, generating spurious signals in SSNMR spectra. Notable, with the SPP system a protein can be produced in total absence of cell growth caused by antibiotics. Here, we demonstrate that cerulenin, an inhibitor of phospholipid biosynthesis, can suppress isotope incorporation in the lipids without affecting membrane protein yield in the SPP system. SSNMR analysis of ATP synthase subunit c, an E. coli inner membrane protein, produced by the SPP method using cerulenin revealed that (13)C resonance signals from phospholipid were markedly reduced, while signals for the isotope-enriched protein were clearly present. PMID- 21279669 TI - Mechanism of gallic acid biosynthesis in bacteria (Escherichia coli) and walnut (Juglans regia). AB - Gallic acid (GA), a key intermediate in the synthesis of plant hydrolysable tannins, is also a primary anti-inflammatory, cardio-protective agent found in wine, tea, and cocoa. In this publication, we reveal the identity of a gene and encoded protein essential for GA synthesis. Although it has long been recognized that plants, bacteria, and fungi synthesize and accumulate GA, the pathway leading to its synthesis was largely unknown. Here we provide evidence that shikimate dehydrogenase (SDH), a shikimate pathway enzyme essential for aromatic amino acid synthesis, is also required for GA production. Escherichia coli (E. coli) aroE mutants lacking a functional SDH can be complemented with the plant enzyme such that they grew on media lacking aromatic amino acids and produced GA in vitro. Transgenic Nicotiana tabacum lines expressing a Juglans regia SDH exhibited a 500% increase in GA accumulation. The J. regia and E. coli SDH was purified via overexpression in E. coli and used to measure substrate and cofactor kinetics, following reduction of NADP(+) to NADPH. Reversed-phase liquid chromatography coupled to electrospray mass spectrometry (RP-LC/ESI-MS) was used to quantify and validate GA production through dehydrogenation of 3 dehydroshikimate (3-DHS) by purified E. coli and J. regia SDH when shikimic acid (SA) or 3-DHS were used as substrates and NADP(+) as cofactor. Finally, we show that purified E. coli and J. regia SDH produced GA in vitro. PMID- 21279670 TI - Hydroxyapatite-collagen composites. Part I: can the decrease of the interactions between the two components be a physicochemical component of osteoporosis in aged bone? AB - The interactions of Type I acid soluble collagen (Col) with both carbonate-free hydroxyapatite (HA(1100)) and carbonate-rich one (CHA) were investigated. The aim was to ascertain whether the increase of bone CO(3) (2-) with ageing could relate to the disease known as osteoporosis. HA(1100)-Col and CHA-Col composites with various ratios were prepared and examined. Scanning electron microscopy and differential scanning calorimetry showed a stronger adhesion of the Col matrix to the granules of HA(1100) than to those of CHA. FT-IR spectroscopy showed that with HA(1100) both multiple hydrogen bonds of Col peptide -NH groups with HA PO(4) (3-), and electrochemical interactions between Col peptide -C=O groups and HA Ca(2+) were present. In the presence of CO(3) (2-), the interactions between NH and phosphate were diminished, and Ca(2+) interacted more strongly with CO(3) (2-) than with peptide -C=O, so causing a separation between the two components of the bone extra-cellular matrix. The results obtained strengthen the hypothesis that the substitution of PO(4) (3-) ions by CO(3) (2-) ions in the HA lattice might be a significant component of osteoporosis, although further investigation is needed. PMID- 21279671 TI - Freeze extrusion fabrication of 13-93 bioactive glass scaffolds for bone repair. AB - A solid freeform fabrication technique, freeze extrusion fabrication (FEF), was investigated for the creation of three-dimensional bioactive glass (13-93) scaffolds with pre-designed porosity and pore architecture. An aqueous mixture of bioactive glass particles and polymeric additives with a paste-like consistency was extruded through a narrow nozzle, and deposited layer-by-layer in a cold environment according to a computer-aided design (CAD) file. Following sublimation of the ice in a freeze dryer, the construct was heated according to a controlled schedule to burn out the polymeric additives (below ~500 degrees C), and to densify the glass phase at higher temperature (1 h at 700 degrees C). The sintered scaffolds had a grid-like microstructure of interconnected pores, with a porosity of ~50%, pore width of ~300 MUm, and dense glass filaments (struts) with a diameter or width of ~300 MUm. The scaffolds showed an elastic response during mechanical testing in compression, with an average compressive strength of 140 MPa and an elastic modulus of 5-6 GPa, comparable to the values for human cortical bone. These bioactive glass scaffolds created by the FEF method could have potential application in the repair of load-bearing bones. PMID- 21279672 TI - Surface grafting of blood compatible zwitterionic poly(ethylene glycol) on diamond-like carbon-coated stent. AB - Blood compatibility is the most important aspect for blood-contacting medical devices including cardiovascular stents. In this study, the surface of nickel titanium (TiNi) stent was coated with diamond-like carbon (DLC) and then subsequently grafted by using zwitterion (N(+) and SO(3) (-))-linked poly(ethylene glycol) (PEG). We hypothesize that this coupling of zwitterion and PEG may significantly improve blood compatibility of DLC-coated TiNi stent. The surface modified TiNi stents, including PEG-grafted stent (DLC-PEG) and zwitterionic PEG-grafted one (DLC-PEG-N-S) were the main focus on the tests of surface characteristics and blood compatibility. The zwitterionic PEG derivatives were obtained from a series of chemical reactions at room temperature. The results exhibited that as compared to the DLC-PEG, the hydrophilicity was much better with DLC-PEG-N-S and significantly increased atomic percentage of oxygen and nitrogen proved the entity of zwitterions on the surface of DLC-PEG-N-S. Meanwhile, the adsorption of blood proteins such as, human serum albumin (HSA) and fibrinogen was found considerably down-regulated in DLC-PEG-N-S, due mainly to the protein-repellent effect of PEG and zwitterion. Microscopic observation also revealed that as compared with the other substrates without zwitterion, the degree of platelet adhesion was the lowest with DLC-PEG-N-S. In addition, DLC-PEG N-S retained an extended blood coagulation time as measured by activated partial thromboplastin time (APTT). The present results suggested that surface grafting of zwitterionic PEG derivatives could substantially enhance the blood compatibility of TiNi-DLC stent. In conclusion, anti-fouling properties of PEG and zwitterions are expected to be very useful in advancing overall stent performance. PMID- 21279673 TI - Porous calcium alginate-gelatin interpenetrated matrix and its biomineralization potential. AB - Artificial bone composites exhibit distinctive features by comparison to natural tissues, due to a lack of self-organization and intimate interaction apatite matrix. This explains the need of "bio-inspired materials", in which hydroxyapatite grows in contact with self-assembling natural polymers. The present work investigates the function of a rational design in the hydroxyapatite forming potential of a common biopolymer. Gelatin modified through intrinsic interactions with calcium alginate led through freeze-drying to porous hydrogels, whose architecture, constitutive features and chemistry were investigated with respect to their role on biomineralization. The apatite-forming ability was enhanced by the porosity of the materials, while the presence of alginate reinforced Gel elastic chains, definitely favored this phenomenon. Depending on the concentration, polysaccharide chains act as "ionic pumps" enhancing the biomineralization. The mineralization-promoting effect of the peptide polysaccharide network strictly depends on the hydrogels structural, compositional and morphological features derived from the interaction between the above mentioned two components. PMID- 21279674 TI - Magnetic resonance imaging probes for labeling of chondrocyte cells. AB - Recent progress in cell therapy research has raised the need for non-invasive monitoring of transplanted cells. Magnetic resonance imaging (MRI) of superparamagnetic iron oxide (SPIO) labeled cells have been widely used for high resolution monitoring of the biodistribution of cells after transplantation. Here we report that self-assembly of amphiphilic polyethylenimine (PEI)/SPIO nanocomposites can lead to the formation of ultrasensitive MRI probes, which can be used to label chondrocyte cells with good biocompatibility. The labeled cells display strong signal contrast compared to unlabeled ones in a clinical MRI scanner. This probe may be useful for noninvasive MR tracking of implanted cells for tissue regeneration. PMID- 21279675 TI - Is the presence of depression independent from signs of disease activity in patients with neurocysticercosis? AB - Neurocysticercosis (NCC) is a common central nervous system (CNS) infection caused by Taenia solium metacestodes. Depression is present in 53-85% of the NCC patients. The present study was aimed to evaluate the correlation of signs of NCC activity (evolution phase of NCC cysts and CSF characteristics) with depression. The study group consisted of 65 patients subdivided into two groups: NCC with epilepsy (48) and NCC without epilepsy [17]. Depression was assessed and quantified by the Hamilton Rating Scale for Depression (HRSD-21) and compared with CSF inflammatory characteristics (increase of WBCs and total protein) and presence of calcifications or cysts. There was no difference between the scores of depression in the group with CNS calcifications or cysts. CSF signs of active disease, specifically increase of CSF TP, were significantly more frequent in patients with mild depression and in non-depressant patients. The depression scores were inversely proportional to the CSF TP levels in the groups with depression. Although immunological factors could be associated with the development of depression, the data above lead us to make assumptions about the association of other factors such as genetic predisposition, or social and cultural factors. PMID- 21279676 TI - Do family and parenting factors in adolescence influence condom use in early adulthood in a multiethnic sample of young adults? AB - Studies show that positive family factors help protect adolescents from engaging in risky sexual activities, but do they continue to protect adolescents as they transition to late adolescence/early adulthood? Using data from the National Longitudinal Study of Adolescent Health, we examined whether family support, parent-child closeness, parental control/monitoring of adolescent behaviors and parent-child communication about sex, assessed in adolescence, were related to condom use in late adolescence/early adulthood among African American (n = 1,986), Chinese American (n = 163), Mexican American (n = 1,011) and White (n = 6,971) youth. Controlling for demographic variables and number of sex partners, the results showed that family support was positively related and parent-child communication was negatively related to condom use for the sample as a whole and for the white sample, but not for the other groups. Parent-child communication about sex and parental control were negatively related to condom use in the Chinese American sample. None of the family factors was related to condom use in the African American or Mexican American samples. Overall, parents talked more with daughters than sons about sexual matters. Condom use was most common among African Americans and among males. Greater attention to cultural expectations regarding sex and gender roles, as well as the causal ordering of effects, are important directions for future research. PMID- 21279677 TI - Complete genomic characterization of cell culture adapted human G12P[6] rotaviruses isolated from South Korea. AB - Two unusual human rotavirus G12 strains, CAU195 and CAU214, were isolated from female pediatric diarrhea patients under 12 months of age in 2006 using a cell culture system and their full genome sequences were analyzed. The 11 gene segments of both Korean G12 strains were classified as G12-P[6]-R1-C1-M1-I1-A1-N1 T1-E1-H1 genotypes. Notably, the Korean strains were of the same genotypes as previously reported strains isolated from Bangladesh in 2003 (Dhaka12-03), from the United States in 2005-2006 (US6597), and from Germany in 2008 (GER126-08 and GER172-08), suggesting that closely related G12P[6] strains are persistent and widespread. PMID- 21279678 TI - Neglected issues and hypotheses regarding the impact of sexual concurrency on HIV and sexually transmitted infections. PMID- 21279679 TI - Understanding clinicians' diagnostic practices: attitudes toward the utility of diagnosis and standardized diagnostic tools. AB - Data on clinician diagnostic practices suggest they may not align with evidence based guidelines. To better understand these practices, a multidisciplinary survey of 1,678 child clinicians examined attitudes toward the utility of diagnosis and standardized diagnostic tools. Psychiatrists were more likely than other disciplines to value diagnosis, whereas psychologists were more likely than others to value standardized diagnostic tools. Private practitioners held less positive views in both domains than other practitioners. Both attitude scales predicted self-reported diagnostic practices, although views of diagnosis utility were more associated with diagnosing in general, whereas views of diagnostic tools were more predictive of standardized tool use. PMID- 21279680 TI - Regulation of hemocytes in Drosophila requires dappled cytochrome b5. AB - A major category of mutant hematopoietic phenotypes in Drosophila is melanotic tumors or nodules, which consist of abnormal and overproliferated blood cells, similar to granulomas. Our analyses of the melanotic mutant dappled have revealed a novel type of gene involved in blood cell regulation. The dappled gene is an essential gene that encodes cytochrome b5, a conserved hemoprotein that participates in electron transfer in multiple biochemical reactions and pathways. Viable mutations of dappled cause melanotic nodules and hemocyte misregulation during both hematopoietic waves of development. The sexes are similarly affected, but hemocyte number is different in females and males of both mutants and wild type. Additionally, initial tests show that curcumin enhances the dappled melanotic phenotype and establish screening of endogenous and xenobiotic compounds as a route for analysis of cytochrome b5 function. Overall, dappled provides a tractable genetic model for cytochrome b5, which has been difficult to study in higher organisms. PMID- 21279681 TI - Generation of TrkA/TrkB chimeric receptor constructs reveals molecular mechanisms underlying BDNF-induced dendritic outgrowth in hippocampal neurons. AB - Neurotrophins (NTs) regulate neuronal survival, differentiation, and synaptic plasticity through tropomyosin receptor kinases (Trks). The molecular mechanisms underlying these functions, however, have remained incompletely understood. In the present study, we first showed that brain-derived neurotrophic factor (BDNF) increased both the number of primary dendrites and dendritic complexity in cultured hippocampal neurons. Since hippocampal neurons predominantly express the BDNF receptor TrkB, but not the nerve growth factor (NGF) receptor Trk, we generated DNA constructs encoding the extracellular domain of TrkA fused with the transmembrane and intracellular domain of TrkB and introduced these constructs into cultured hippocampal neurons. To visualize the dendrites, the TrkA/TrkB fusion proteins were bicistronically expressed with green fluorescence protein (GFP). Interestingly, the GFP-labeled neurons grew dendrites and activated the TrkA/TrkB receptors in response to NGF, but not BDNF. We next generated a series of TrkA/TrkB receptors with mutations at tyrosine residues in the TrkB kinase domain, and sought to identify the signaling pathway required for NT-induced dendrite outgrowth. Sholl analyses demonstrated that TrkB signaling through Shc, but not through PLC-gamma, plays a crucial role in NT-elicited dendritic outgrowth in hippocampal neurons. PMID- 21279682 TI - Agonists and antagonists of GnRH-I and -II reduce metastasis formation by triple negative human breast cancer cells in vivo. AB - Metastasis to bone is a frequent problem of advanced breast cancer. Particularly breast cancers, which do not express estrogen and progesterone receptors and which have no overexpression/amplification of the HER2-neu gene, so called triple negative breast cancers, are considered as very aggressive and possess a bad prognosis. About 60% of all human breast cancers and about 74% of triple-negative breast cancers express receptors for gonadotropin-releasing hormone (GnRH), which might be used as a therapeutic target. Recently, we could show that bone-directed invasion of human breast cancer cells in vitro is time- and dose-dependently reduced by GnRH analogs. In the present study, we have analyzed whether GnRH analogs are able to reduce metastases of triple-negative breast cancers in vivo. In addition, we have evaluated the effects of GnRH analogs on tumor growth. To quantify formation of metastasis by triple-negative MDA-MB-435 and MDA-MB-231 human breast cancers, we used a real-time PCR method based on detection of human specific alu sequences measuring accurately the amount of human tumor DNA in athymic mouse organs. To analyze tumor growth, the volumes of breast cancer xenotransplants into nude mice were measured. We could demonstrate that GnRH analogs significantly reduced metastasis formation by triple-negative breast cancer in vivo. In addition, we could show that GnRH analogs significantly inhibited the growth of breast cancer into nude mice. Side effects were not detectable. In conclusion, GnRH analogs seem to be suitable drugs for an efficacious therapy for triple-negative, GnRH receptor-positive human breast cancers to prevent metastasis formation. PMID- 21279683 TI - Effects of acupuncture on glycometabolic enzymes in multi-infarct dementia rats. AB - Acupuncture has exhibited therapeutic effects on vascular dementia in our previous research. The mechanism of its anti-dementia effects involves energy metabolism. For brain cells, glucose metabolism is almost the only source of energy, and glucose metabolism disorders are early signs of dementia. In addition, glucose metabolism associates closely with glycometabolic enzymes, thereby maintains normal energy supply in brains and neurological and mental activities. In order to investigate its anti-dementia mechanism, we studied the effects of acupuncture on behavior of multi-infarct dementia (MID) rats and glycometabolic enzymes protein expression and activities in their brains. Results showed acupuncture improved the cognitive disorder, and increased the activities of hexokinase, pyruvate kinase, and glucose 6 phosphate dehydrogenase. Accordingly, it suggests that the anti-dementia effects of acupuncture may be mediated by up regulation of hexokinase, pyruvate kinase, and glucose 6 phosphate dehydrogenase activities, influencing energy metabolic system and thus overcoming the dysfunctional cognition of MID. PMID- 21279684 TI - Government regulation and public opposition create high additional costs for field trials with GM crops in Switzerland. AB - Field trials with GM crops are not only plant science experiments. They are also social experiments concerning the implications of government imposed regulatory constraints and public opposition for scientific activity. We assess these implications by estimating additional costs due to government regulation and public opposition in a recent set of field trials in Switzerland. We find that for every Euro spent on research, an additional 78 cents were spent on security, an additional 31 cents on biosafety, and an additional 17 cents on government regulatory supervision. Hence the total additional spending due to government regulation and public opposition was around 1.26 Euros for every Euro spent on the research per se. These estimates are conservative; they do not include additional costs that are hard to monetize (e.g. stakeholder information and dialogue activities, involvement of various government agencies). We conclude that further field experiments with GM crops in Switzerland are unlikely unless protected sites are set up to reduce these additional costs. PMID- 21279685 TI - Deep vein thrombosis and pulmonary embolism in hospitalized patients with cirrhosis: a nationwide analysis. AB - BACKGROUND AND AIMS: Recent studies have shown conflicting results regarding the risk of venous thromboembolism (VTE) in cirrhotics despite the often-associated coagulopathy. Our aim was to determine burden and risk factors for VTE in cirrhotics from a national sample. METHODS: Using data from the Nationwide Inpatient Sample 2005, we identified cirrhosis-related hospitalizations using appropriate discharge codes. Our outcomes of interest were deep venous thrombosis (DVT) or pulmonary embolism (PE). Cirrhotics without VTE formed the controls. Multivariate regression models were used to identify factors independently associated with VTE and the impact of VTE diagnosis on in-hospital outcomes. RESULTS: There were 449,798 hospitalizations for cirrhosis in 2005 of which 8,231 were for VTE (1.8%). This rate was lower than the rate for chronic hepatitis C (2.4%) or all-cause hospitalizations (3.7%). Patients with VTE were older than controls and had greater co-morbidity and were more likely to have malnutrition, parenteral nutrition, prolonged mechanical ventilation, and central venous line (CVL) placement. Complications of cirrhosis including hepatic encephalopathy, variceal bleeding, ascites, and coagulopathy were less frequent in those with VTE than controls. On multivariate regression, greater co-morbidity, black race, malnutrition, and CVL placement were independently associated with VTE. Neither DVT nor PE was associated with greater in-hospital mortality. DVT, but not PE, was associated with a 52% increase in LOS and hospitalization charges. CONCLUSIONS: Despite the often-associated coagulopathy, VTE contributes to a significant burden in patients with cirrhosis. Efforts directed at VTE prevention in this cohort, especially high-risk patients, should be actively pursued. PMID- 21279686 TI - Emotional intelligence and clinical symptoms in outpatients with generalized anxiety disorder (GAD). AB - Generalized anxiety disorder (GAD) is the anxiety disorder with the highest prevalence rate in mental health centers. Empirical researches concerning its diagnosis and treatment have not yet explored the potential implications of deficits in emotional intelligence (EI) as a vulnerability factor in its development. The present study aimed to investigate the relationship between EI and clinical symptoms in a group of psychiatric patients with GAD compared to the control group. Seventy outpatients (82.9% female) with a DSM-IV-TR diagnosis of GAD and 70 control individuals (72.9% female) completed self-report instruments assessing EI and clinical symptoms in a cross-sectional study. Significant correlations were observed between EI dimensions such as clarity (r = .327) and repair (r = .405) and symptoms of anxiety. Also, the dimensions of attention and repair allowed a clear discrimination between clinical patients and control group. The results of the present study showed that deficits in EI abilities were a vulnerability factor in the development of GAD. PMID- 21279687 TI - Alcohol use among Arab Americans: what is the prevalence? AB - Information is limited on alcohol use among Arab Americans. The purpose of this study was to describe and analyze the alcohol use pattern among Arab Americans by reviewing existing surveys using an acculturation model. Secondary data analysis. Nationally, English-speaking immigrant Arab Americans reported lower rates of lifetime alcohol use (50.8%), past month use (26.4%) and binge drinking (10%) than the White majority group. In a state survey, self-identified English speaking Arab Americans were less likely to report past month use (45.6%) than the White majority group but reported similar rate of binge drinking (17.0%). Locally, lifetime drinking was reported by 46.2% of the immigrants but only 13.4% of refugees fleeing war. Few databases are available to estimate alcohol use pattern among Arab Americans; the limited data suggest a drinking pattern consistent with acculturation. However, the potential influence of other factors is unknown and needs to be investigated. PMID- 21279688 TI - Utility of transthoracic echocardiography to estimate severity of right ventricular dysfunction: an MRI comparison study. AB - Prognostic implications of severe right ventricular (RV) dysfunction are difficult to assess because of limitations in functional characterization using standard echocardiography (TTE) and the cost and availability of options such as MRI. We sought to determine how assessments of RV dysfunction via TTE correlate with RV ejection fraction (EF) by MRI. Patients undergoing MRI and TTE within 21 days of one another were included. Left ventricular (LV) and RV EF were recorded from MRI and subjective assessment of RV function (normal, mild, moderate, or severe dysfunction), right ventricular index of myocardial performance (RIMP), and right ventricular systolic pressure (RVSP) were recorded from TTE. Patients were considered to have significant RV dysfunction if EF <= 35% on MRI and normal function if EF >= 45%. A total of 474 patients were included (age 50 +/- 12, 57% male). Of these, 363 (76.6%) had normal function, 54 (11.4%) had mild dysfunction, 41 (8.6%) had moderate dysfunction, and 16 (3.4%) had severe dysfunction on TTE. Moderate or severe dysfunction had good sensitivity (80%) and specificity (97%) for RV EF <= 35%. Furthermore, RIMP > 0.70 and RVSP > 70 mm Hg were very specific for RV EF <= 35% (sensitivity = 29%, 22%, respectively; specificity = 98%, 99%, respectively). Specificity and sensitivity of TTE assessments did not change if LV function or disease indication was considered. A subjective assessment of moderate to severe RV dysfunction on TTE compares favorably with quantitative MRI assessment of the RV EF. Further study is needed to evaluate whether this comparability is true across institutions. PMID- 21279689 TI - Reliability of myocardial salvage assessment by cardiac magnetic resonance imaging in acute reperfused myocardial infarction. AB - Myocardial salvage assessed by cardiac magnetic resonance imaging (CMRI) holds promise as a surrogate endpoint in studies comparing different treatment strategies for ST-elevation myocardial infarction (STEMI). The aim of this study was to evaluate the reliability of salvaged myocardium measurements by CMRI. Twenty patients underwent CMRI on 2 consecutive days early after reperfused STEMI to assess the area at risk (AAR) on T2-weighted and final infarct size (IS) on delayed enhancement images. Myocardial salvage index (MSI) was calculated (AAR minus IS). Agreement between scans 1 and 2 for the AAR, IS and MSI were analyzed using Bland-Altman analyses. Inter- and intraobserver reliability were assessed. Paired t testing revealed a trend for a significant difference for MSI between scans 1 and 2 (scan 1: 43.8 +/- 22.5; scan 2: 45.5 +/- 22.0; P = 0.052). The average difference for AAR and IS between scan 1 and scan 2 was -0.5 (upper limit of agreement 5.4% of left ventricular [LV] volume; lower limit of agreement 6.4%LV) and 0.1%LV (upper limit of agreement 2.3%LV; lower limit of agreement 2.1%LV). The corresponding calculated MSI measurements showed a mean bias of -1.7 (upper limit of agreement 5.5; lower limit of agreement -8.9). Coefficients of repeatability for interobserver variability were 3.6%LV for AAR, 2.4%LV for IS and 5.4 for MSI. Likewise, for intraobserver variability, coefficients of repeatability were 5.0%LV (AAR), 2.4%LV (IS) and 4.8 (MSI). Assessment of myocardial salvage by CMRI shows acceptable reliability. Further validation studies and trials showing the prognostic value of myocardial salvage by CMRI are needed before routine implementation as a surrogate endpoint in STEMI trials. PMID- 21279690 TI - Assessment of atherosclerotic plaques in a rabbit model by delayed-phase contrast enhanced CT angiography: comparison with histopathology. AB - The aim of this study was to compare delayed-phase computed tomography angiography (CTA) attenuation values with histopathology, in ability to differentiate between fibrous and lipid-rich plaques in an experimental rabbit model. Twelve atherosclerotic rabbits underwent CTA of the abdominal aorta. The scan protocol included early-phase scans (EP), delayed scans at 90 s after contrast injection (DP(90s)), delayed scans at 10 min after contrast injection (DP(10min)), and delayed scan with saline infusion (DP(Saline)). Plaque composition was analyzed by histopathology (% of lipid-rich, fibrous and macrophage areas) and CT attenuation values in Hounsfield units. Using histopathology as the reference standard (n = 119), the overall sensitivity, specificity and accuracy of 64-slice CTA for the detection of plaques was 59, 100 and 79% for the EP scans; 88, 100 and 94% for the DP(90s) scans; 81, 100 and 90% for the DP(10min) scans; and 53, 100 and 76% for the DP(Saline) scans. CT density measurements showed a substantial overlap between fibrous and lipid-rich plaques, and poor correlations with the percentage of macrophage areas in both fibrous and lipid-rich plaques (r = 0.408, and r = 0.333). In delayed-phase 64-slice CTA, DP(90s) images have the best diagnostic performance for the detection of aortic plaques. PMID- 21279691 TI - 320-row CT: does beat-to-beat motion of the coronary arteries affect image quality? PMID- 21279692 TI - Assessment of drug-eluting stents and bioresorbable stents by grayscale IVUS and IVUS-based imaging modalities. AB - Grayscale IVUS and IVUS-based imaging modalities during the last years have become useful in the assessment not only of drug eluting stent, but also of new bioresorbable vascular scaffolds. Although IVUS resolution is not sufficient for determining stent coverage (optical coherence tomography is the gold standard), serial IVUS can measure intimal hyperplasia, assess acute and late incomplete stent apposition, detect the presence and persistence of edge dissections, study edge effects and look for causes of restenosis and thrombosis. In addition other IVUS-based imaging modalities, such as IVUS-VH, iMAP or palpography, can be used to study the serial compositional and mechanical changes of the plaque behind stent struts and also to follow the bioresorption of the new bioresorbable scaffolds, analyzing the backscattering signal coming from the polymeric struts. This review details and evaluates grayscale IVUS and IVUS-based techniques findings in clinical trials, highlighting the usefulness of these imaging modalities in the study of drug eluting stents and bioresorbable vascular scaffold. PMID- 21279693 TI - Preoperative quantification of aortic valve stenosis: comparison of 64-slice computed tomography with transesophageal and transthoracic echocardiography and size of implanted prosthesis. AB - Precise measurements of aortic complex diameters are essential for preoperative examinations of patients with aortic stenosis (AS) scheduled for aortic valve (AV) replacement. We aimed to prospectively compare the accuracy of transthoracic echocardiography (TTE), transoesophageal echocardiography (TEE) and multi-slice computed tomography (MSCT) measurements of the AV complex and to analyze the role of the multi-modality aortic annulus diameter (AAd) assessment in the selection of the optimal prosthesis to be implanted in patients surgically treated for degenerative AS. 20 patients (F/M: 3/17; age: 69 +/- 6.5 years) with severe degenerative AS were enrolled into the study. TTE, TEE and MSCT including AV calcium score (AVCS) assessment were performed in all patients. The values of AAd obtained in the long AV complex axis (TTE, TEE, MSCT) and in multiplanar perpendicular imaging (MSCT) were compared to the size of implanted prosthesis. The mean AAd was 24 +/- 3.6 mm using TTE, 26 +/- 4.2 mm using TEE, and 26.9 +/- 3.2 in MSCT (P = 0.04 vs. TTE). The mean diameter of the left ventricle out-flow tract in TTE (19.9 +/- 2.7 mm) and TEE (19.5 +/- 2.7 mm) were smaller than in MSCT (24.9 +/- 3.3 mm, P < 0.001 for both). The mean size of implanted prosthesis (22.2 +/- 2.3 mm) was significantly smaller than the mean AAd measured by TTE (P = 0.0039), TEE (P = 0.0004), and MSCT (P < 0.0001). The implanted prosthesis size correlated significantly to the AAd: r = 0.603, P = 0.005 for TTE, r = 0.592, P = 0.006 for TEE, and r = 0.791, P < 0.001 for MSCT. Obesity and extensive valve calcification (AV calcium score >= 3177Ag.U.) were identified as potent factors that caused a deterioration of both TTE and MSCT performance. The accuracy of AAd measurements in TEE was only limited by AV calcification. In multivariate regression analysis the mean value of the minimum and maximum AAd obtained in MSCT-multiplanar perpendicular imaging was an independent factor (r = 0.802, P < 0.0001) predicting the size of implanted prosthesis. In patients with AS echocardiography remains the main diagnostics tool in clinical practice. MSCT as a 3-dimentional modality allows for accurate measurement of entire AV complex and facilitates optimal matching of prosthesis size. PMID- 21279694 TI - Performance of adenosine "stress-only" perfusion MRI in patients without a history of myocardial infarction: a clinical outcome study. AB - To assess the diagnostic value of adenosine "stress-only" myocardial perfusion MR for ischemia detection as an indicator for coronary angiography in patients without a prior myocardial infarction and a necessity to exclude ischemia. Adenosine perfusion MRI was performed at 1.5 T in 139 patients with a suspicion of ischemia and no prior myocardial infarction. After 3 min of adenosine infusion a perfusion sequence was started. Patients with a perfusion defect were referred to coronary angiography (CAG). Patients with a normal perfusion were enrolled in follow-up. Fourteen out of 139 patients (10.1%) had a perfusion defect indicative of ischemia. These patients underwent a coronary angiogram, which showed complete agreement with the perfusion images. 125 patients with a normal myocardial perfusion entered follow-up (median 672 days, range 333-1287 days). In the first year of follow-up one Major Adverse Coronary Event (MACE) occurred and one patient had new onset chest pain with a confirmed coronary stenosis. Reaching a negative predictive value for MACE of 99.2% and for any coronary event of 98.4%. At 2 year follow-up no additional MACE occurred. Sensitivity of adenosine perfusion MR for MACE is 93.3% and specificity and positive predictive value are 100%. Adenosine myocardial perfusion MR for the detection of myocardial ischemia in a "stress-only" protocol in patients without prior myocardial infarctions, has a high diagnostic accuracy. This fast examination can play an important role in the evaluation of patients without prior myocardial infarctions and a necessity to exclude ischemia. PMID- 21279695 TI - The expression of interleukin (IL)-17 and IL-17 receptor and MMP-9 in human pituitary adenomas. AB - The IL-17 plays a crucial role in the invasion of tumors. However, the effects of IL-17 on the invasion of human pituitary adenomas are still unknown. The current study is designed to investigate the possible involvement of IL-17 in the invasion of adenomas. By collecting invasive and non-invasive pituitary adenomas, the mRNA and protein levels of IL-17, IL-17R and MMP-9 are investigated. The results obtained from IHC showed that the strong positive rate and the total positive rate of IL-17, IL-17R and MMP-9 expression cells in the non-invasive group were 17.1 and 51.43%, 14.3 and 54.3%, 17.1 and 57.1%, respectively. In contrast, the strong positive rate and the total positive rate of the invasive group were significantly higher than that of the non-invasive group, which were 37.5 and 82.5%, 52.5 and 87.5%, 67.5 and 92.5%, respectively. Meanwhile, the serum IL-17 level in the invasive pituitary adenomas patients was significantly higher than in the non-invasive groups (P < 0.05). Furthermore, the mRNA levels of IL-17, IL-17R and MMP-9 were also higher in the invasive group than in the non invasive group with statistical differences (P < 0.05), and where the expression levels of IL-17 and IL-17R had positive correlation with that of MMP-9 in the invasive group. These results suggested that IL-17 may promote the invasion of pituitary adenomas. PMID- 21279697 TI - Green pigment from Bacillus cereus M(1)(16) (MTCC 5521): production parameters and antibacterial activity. AB - A bacterial strain, Bacillus cereus M(1)(16) (MTCC 5521), isolated and identified in our laboratory produces a green pigment when grown in nutrient broth at stationary condition. Optimum fermentation parameters for maximum pigment production are pH 7.0, temperature 30 degrees C, time of incubation 72 h and inoculum volume 1% from 20 h grown cell suspension. Magnesium ion enhances pigment production whereas calcium and zinc ions inhibit the process. The pigment is better extracted from the fermented broth with chloroform in comparison with diethyl ether, ethyl acetate, and butanol. The extracted crude pigment consists of three fractions as revealed from thin layer chromatogram on silica gel GF254 using ethyl acetate and hexane (1:1) solvent system. The major fraction C(3) shows antibacterial activity against different gram positive bacteria. The proposed structure of C(3) is 9-methyl-1,4,5,8-tetra-azaphenanthrene obtained by elemental analysis, GC-MS, and NMR spectra studies. PMID- 21279696 TI - Validation and modification of the Epworth Sleepiness Scale in Peruvian population. AB - PURPOSE: The main purpose of this study was to develop a cross-cultural adaptation of the Epworth Sleepiness Scale for Peruvian population (ESS-VP) and to provide evidence of reliability and validity to this scale. We also modified the ESS-VP for non-driving Peruvian population (ESS-MPV). METHODS: Participants were Peruvians between 18 and 65 years. Five-phase design: Translation and retranslation of the original scale; comprehension evaluation (n = 60); reliability or test-retest (n = 75); internal consistency and construct validity (n = 219); and change of sensibility (n = 36). Just as in the ESS-PV, the same procedure was applied to ESS-MPV except the first phase. RESULTS: The ESS-PV and ESS-MPV had an adequate comprehension. They were reliable over time (test retest), being better within a period of 2 weeks. They also had adequate internal consistency (Cronbach's alpha: 0.790 and 0.789). Two factors were extracted in both scales, being only the first factor in which all items showed statistically significant loads. Both scales are sensitive to sleepiness change in patients with obstructive sleep apnea during treatment. CONCLUSIONS: The ESS-VP and ESS MPV, adapted to adult Peruvian population, are comparable to the original scale, reliable, valid, and change-sensitive. It is proposed that the ESS-MPV should be applied in Peruvian population who do not drive motorized vehicles. PMID- 21279698 TI - Actinobacterial peroxidases: an unexplored resource for biocatalysis. AB - Peroxidases are redox enzymes that can be found in all forms of life where they play diverse roles. It is therefore not surprising that they can also be applied in a wide range of industrial applications. Peroxidases have been extensively studied with particular emphasis on those isolated from fungi and plants. In general, peroxidases can be grouped into haem-containing and non-haem-containing peroxidases, each containing protein families that share sequence similarity. The order Actinomycetales comprises a large group of bacteria that are often exploited for their diverse metabolic capabilities, and with recent increases in the number of sequenced genomes, it has become clear that this metabolically diverse group of organisms also represents a large resource for redox enzymes. It is therefore surprising that, to date, no review article has been written on the wide range of peroxidases found within the actinobacteria. In this review article, we focus on the different types of peroxidases found in actinobacteria, their natural role in these organisms and how they compare with the more well described peroxidases. Finally, we also focus on work remaining to be done in this research field in order for peroxidases from actinobacteria to be applied in industrial processes. PMID- 21279699 TI - Reduced survival of patients with hepatocellular carcinoma expressing hexokinase II. AB - Hexokinase II is a key enzyme in the glycolytic pathway and possesses anti apoptotic properties in tumor cells. The present study aimed to analyze the expression of hexokinase II and its clinical correlation with clinical factors in patients with hepatocellular carcinoma who treated surgically in China. Reverse transcription-polymerase chain reaction and real-time quantitative polymerase chain reaction were performed to determine hexokinase II mRNA expression in cancer tissues. Protein expression of hexokinase II was evaluated immunohistochemically. Correlation of hexokinase II expression with clinical data was analyzed by the chi(2) or Fisher exact test. Survival was estimated by the Kaplan-Meier method, compared by log-rank test and Cox regression model. A total of 97 specimens were analyzed. Fifty-four tumors showed strong expression of hexokinase II (55.67% expression rate). There were no statistical associations between hexokinase II expression and age, gender, tumor size, TNM stage, serum AFP level, and hepatitis virus infection. Kaplan-Meier curves showed an association between positive Hexokinase II expression and worse overall survival (P value = 0.043). Furthermore, patients expressing hexokinase II had a relatively higher risk for poor prognosis (hazard ratio = 2.049). These results suggest that hexokinase II is highly expressed in hepatocellular carcinoma and has prognostic significance. Hexokinase II represents a potential new therapeutic target in this malignancy. PMID- 21279700 TI - The analysis of CD45 isoforms expression on HBV-specific T cells after liver transplantation. AB - This study aimed to analyze the expression of CD45 on HBV-specific T cells in patients who underwent liver transplantation (LT). We detected the distribution of two CD45 isoforms (CD45RA, CD45RO) and CD27 on peripheral blood lymphocytes including two HBV-specific pentamer cells by flow cytometry. Meanwhile, the levels of tacrolimus, plasma IL-7, and IL-15 were tested by ELISA. CD45RA decreased sharply after LT, whereas the expression of CD45RO(+) changed a very little. The proportion of CD4(+) CD27(+) subsets increased in the span from first 6-36 months after LT. With the up-regulation of IL-7, CD45RA(+) CD27(+) was reduced and CD45RO(+) was increased on HBV-specific T cells in LT group compared with CHB. Therefore, the switch from CD45RA to CD45RO probably depended on IL-7, without being stimulated by hepatitis B virus (HBV) and proliferated by IL-15. IL 7 could aid in maintaining HBV-specific T cells effectively during 3 years. PMID- 21279701 TI - Smoking reduces survival in young females with lung adenocarcinoma after curative resection. AB - The aim of this study was to investigate effects of smoking on the overall survival of young female lung adenocarcinoma patients after curative resection. A total of 282 surgically treated young females (younger than 40) with histologically confirmed primary lung adenocarcinoma were studied retrospectively. Overall survivals (OS) and related prognostic factors were analyzed. The 5-year OS of current-smokers and non-smokers were 20 and 36.6%, respectively (P = 0.03). As for patients with stage I disease, the 5-year OS of current-smokers and non-smokers were 50 and 68.8%, respectively, (P = 0.02). Smoking (RR = 3.15, CI 1.726-8.786) was identified as an independent prognostic factor. Current-smokers (21.4 vs. 14.5%, P = 0.03) and non-smokers (37.9 vs. 28.8%, P = 0.02) all benefited from adjuvant chemotherapy. Among young female patients with adenocarcinoma, current-smokers have a lower survival rate than non smokers, especially patients with stage I disease. PMID- 21279702 TI - Sequential treatment with sorafenib and sunitinib in metastatic renal cell carcinoma: clinical outcomes from a retrospective clinical study. AB - Sorafenib and sunitinib are inhibitors of receptor protein tyrosine kinases (TKIs) and are approved for the treatment of metastatic renal cell carcinoma (mRCC). Although the mTOR inhibitor everolimus is effective for the treatment of patients who have failed TKI therapy, it is important to consider all available treatment options before switching therapy mode of action. Herein, we report outcomes in patients with mRCC switched to sorafenib following disease progression on sunitinib treatment. The medical records of 35 patients treated between November 2006 and November 2009 at two large referral centers in Greece were retrospectively analyzed for time-to-progression (TTP), overall survival (OS), and tolerability of sorafenib after sunitinib. Median TTP and OS on sorafenib were 4.9 and 11.5 months, respectively. Among 33 patients evaluable for tumor response, three had a partial response and 17 achieved disease stabilization (objective response rate 8.5%; total clinical benefit rate 57%). Sorafenib was well tolerated, with mostly grade 1/2 adverse events and no treatment-related deaths. Sorafenib was effective and well tolerated in this group of patients. The TTP with sorafenib following sunitinib was comparable to outcomes reported previously, providing further support that TKIs should be used in sequence before switching to an mTOR inhibitor. PMID- 21279703 TI - Concomitant chemoradiotherapy using low-dose weekly gemcitabine versus low-dose weekly paclitaxel in locally advanced head and neck squamous cell carcinoma: a phase III study. AB - The objective of this study was to compare concomitant chemoradiotherapy based on weekly low-dose gemcitabine versus weekly low-dose paclitaxel in locally advanced head and neck squamous cell carcinoma. Previously, untreated patients with locally advanced squamous cell carcinoma of the head and neck were randomly assigned to one of the two concomitant chemoradiation regimens: (1) weekly gemcitabine at a dose of 100 mg/m(2) over 30 min 1-2 h before radiotherapy and (2) weekly paclitaxal at a dose of 20 mg/m(2) over 60 min 4-6 h before radiotherapy. The planned radiotherapy dose was 65 Gy over 6.5 weeks in 32 settings. Two hundred and sixteen patients were randomly divided into 2 groups: group A (110 patients) and group B (106 patients) who received concomitant weekly low-dose gemcitabine and low-dose paclitaxal, respectively, with the radiotherapy protocol. The hematological toxicity was generally mild. On the contrary, non hematologic toxicities were severe. Grade III mucositis occurred in 36% in group A and in 24% in group B (P = 0.04). Moreover, grade III dermatitis were encountered in 24% in group A and 13% in group B (P = 0.049). Thirty-two (29%) of group A and 18(17%) of group B patients required enteral or parenteral feeding (P = 0.01). Sixteen (15%) of group A and 6 (6%) of group B required enteral or parenteral feeding that lasted for 6 months (P = 0.03). Regarding the late effect on swallowing, 8% of patients in group A and 2% of patients in group B required enteral or parenteral feeding for more than 6 months (P = 0.035). Response rates were 78 and 89% in groups A and B, respectively (P = 0.038). The 2-year progression-free survival figures were 54 and 64% of groups A and B, respectively; however, the 2-year overall survival figures were 56 and 67%, respectively. On the other hand, the 3-year progression-free survival figures were 39 and 48% for groups A and B, respectively, while the 3-year overall survival figures were 45 and 49%, respectively (P = 0.05). Both concomitant chemoradiotherapy regimens were easily given in the outpatient clinic. The regimen based on paclitaxel was significantly more tolerable and effective; however, the difference was not enormous. PMID- 21279704 TI - Preliminary results of a phase III randomized study comparing chemotherapy neoadjuvantly or concurrently with radiotherapy for locoregionally advanced nasopharyngeal carcinoma. AB - The current study was conducted to compare neoadjuvant chemotherapy (NACT) with concurrent chemotherapy for efficacy, toxicities and compliance of locoregionally advanced nasopharyngeal carcinoma (NPC). Eligible patients were randomized to NACT + radiotherapy (RT) + adjuvant chemotherapy (AC) arm or concurrent chemoradiotherapy(CCRT) + AC arm. Two arms received same conventional RT at a planned dose of 70 Gy. Neoadjuvant chemotherapy comprised cisplatin 90 mg/m(2) (30 mg/m(2)/day) and 5-fluorouracil 1,500 mg/m(2) (500 mg/m(2)/day) over 3 days for two 21-day cycles. The same regimen at equal dosage was administered on the 1st and 22nd days of the radiotherapy as concurrent chemotherapy. Four cycles of the same chemotherapy regimen were given to both two arms as AC. A total of 338 NPC patients were recruited. 170 patients were randomized to NACT arm and 168 patients to CCRT arm. The median duration of follow-up was 38 months. The 3-year OS and DFS rates were 95.9 versus 94.5% (P = 0.54) and 78.5 versus 82.5% (P = 0.16), respectively, in NACT and CCRT arms. An unplanned subgroup analysis according to the N-classification suggested that CCRT improves MFS in patients with N0-1 disease (80.1 vs. 94.9%, P = 0.034). Among the acute toxicities observed, the rates of grade 3/4 mucositis (52.4 vs. 35.9% P = 0.023) and vomiting (13.7 vs. 4.7% P = 0.000) were significantly higher in CCRT arm. Our preliminary results only showed an advantage of CCRT over NACT in NPC patients with limited N disease in MFS. More acute toxicities were observed in CCRT arm and a trend of better tolerance was observed in NACT arm. PMID- 21279705 TI - Fatal human monocytic ehrlichiosis: a case study. AB - Human ehrlichiosis is the term for a collection of tick-borne diseases caused primarily by obligate intracellular bacteria of the Ehrlichia species. Ehrlichiosis is characterized by a mild to severe illness, with approximately 3 5% of cases proving fatal despite receiving appropriate care. This report presents the case of a 60 year-old woman who was found collapsed and unresponsive in her home after an indeterminate time; possibly for up to 48 h. Despite rigorous resuscitative care and antibiotic treatment, the patient lapsed into multi-organ failure and died. Subsequent analysis by microscopic examination, PCR and immunohistochemistry revealed the patient died from an infection of Ehrlichia chaffeensis. Clinicians and pathologists must be aware of this emergent disease in order to make a timely and appropriate diagnosis. Discussion of the patient's clinical, laboratory and autopsy findings as well as treatment of Ehrlichia chaffeensis infections is presented. PMID- 21279706 TI - Did the participants of the mass fatality exercise Operation Torch learn anything? AB - There are a number of reasons why facilitating and participating in a mass fatality exercise may be viewed as continuous professional development for those ultimately engaged in the response to a mass fatality incident. These include, amongst other objectives; team integration, organization and preparedness, psychological and emotional effects, developing attitudes and behavioral responses as well as testing infrastructure, equipment, command and control. The objectives of attending an exercise from a player or observers point of view however may be completely different to those planning and running an exercise. This was identified at the exercise Operation Torch. The paper illustrates this and questions whether these two separate purposes can be fully achieved in one exercise. It puts forward proposals to assist exercise planners identify, plan, exercise, evaluate and implement both capability gap or educational exercises by assisting planners to deliver the purpose of the exercise which needs to be decided at the early stage of planning. It makes recommendations for the need for a national mass fatality exercise database to ensure that the correct exercise is delivered and a wider audience can be informed of the exercise outcome. PMID- 21279707 TI - Genetic polymorphisms of 17 short tandem repeat loci on Y chromosome in central Croatian population. AB - In forensic casework, Y-chromosome short tandem repeat (STR) haplotyping is used in human identification, paternity testing and sexual assault cases where Y-STRs provide a male-specific DNA profile. The aim of this study was to describe the genetic structure of Y chromosome in a central Croatian population. We carried out a statistical analysis of the data from previously performed genetic analyses collected during routine forensic work by the Forensic Science Centre "Ivan Vucetic". A total of 220 unrelated healthy men from central Croatia were selected for the purpose of this study. Genomic DNA was extracted using a Chelex procedure from FTA((r)) cards. Y-chromosomal STRs were determined using the AmpFISTR Yfiler PCR amplification kit. The haplotype frequencies were determined by direct counting and analyzed using Arlequin 3.1 and analysis of molecular variance calculated with the Y chromosome haplotype reference database online analysis tool. A total of 212 haplotypes were identified, 204 of which were unique. Total haplotype diversity was 0.993. Locus diversity varied from 0.325 for DYS392 to 0.786 for DYS385. Discrimination capacity was 92.7%. Allele frequencies diversity was 0.615. Intermediate alleles 17.2, 18.2 and 19.2 were found at DYS458 locus. A comparison with published data for the European minimal haplotype set showed the closest relationship to the Croatian capital of Zagreb and Bosnia and Herzegovina with significant genetic distance from Slovenia and Austria. The central Croatian population is now well characterized in terms of Y-chromosome STRs, thus providing a solid basis for further forensic and genetic epidemiology studies. PMID- 21279708 TI - Systemic inflammation and the dynamics of HDL cholesterol-associated residual cardiovascular risk. PMID- 21279709 TI - Confirmatory factor analysis of the stagnation scale--a traditional Chinese medicine construct operationalized for mental health practice. AB - BACKGROUND: Traditional Chinese medicine stagnation ("yu") syndrome is characterized by a cluster of mind/body obstruction-like symptoms. Previous studies have operationalized the concept as a psychological construct through scale development, producing a three-factor 16-item inventory with good psychometric properties. PURPOSE: The study aimed to further validate the Stagnation Scale by confirmatory factor analysis (CFA) and examine self-appraisal of stagnation as an illness. METHOD: A cross-sectional questionnaire survey was conducted on a random community sample of 755 adults recruited by cluster sampling in Hong Kong. RESULTS: CFA revealed a good fit of the three-factor model (CFI = .95; RMSEA = .077; SRMR = .043). ROC analysis suggested a cutoff score at 50 on stagnation total score for predicting self-appraisal of an illness condition, with false positive and negative rates at 25.8% and 23.3%, respectively. Overall, 6.2% participants self-appraised to suffer stagnation symptoms to a degree of an illness, and for it, 1.9% participants intended to seek treatment. Stagnation showed positive correlations with physical distress, depression, and anxiety (r = .59-.76, p < .01) and negative correlation with age (r = -.22, p < .01). CONCLUSION: The Stagnation Scale appeared to be robust in factorial and construct validity. With prevalence of illness by self-appraisal at 6.2% and intention for treatment at 1.9%, stagnation is a fairly common condition associated with treatment-seeking behaviors. PMID- 21279716 TI - Fenvalerate induces germ cell apoptosis in mouse testes through the Fas/FasL signaling pathway. AB - Fenvalerate has a potentially adverse effect on male reproduction and spermatogenesis, whereas the precise mechanism remains obscure. The present study investigated the effects of fenvalerate on germ cell apoptosis in testes. Adult male mice were administered with fenvalerate (15 or 60 mg/kg) by gavage for 28 days. Germ cell apoptosis was determined by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL). The number of TUNEL+ germ cells per tubule and the percentage of tubules with TUNEL+ germ cells were significantly increased in testes of mice treated with fenvalerate in a dose dependent manner. TUNEL+ germ cells were observed mainly in stages VII-VIII and also stages IX-XII seminiferous tubules in testes. Additional experiments showed that fenvalerate increased the level of active caspase-8 and caspase-3 in testes. In addition, fenvalerate upregulated the expression of Fas and FasL in testes. No significant difference on the expression of Bcl-2 and Bax in testes was observed between fenvalerate-treated mice and controls. Fenvalerate did not affect the leakage of cytochrome c from mitochondria into cytoplasm. In addition, fenvalerate did not cause the activation of caspase-9 in testes. Taken together, these results suggest that fenvalerate induces germ cell apoptosis in testes through the Fas/FasL signaling pathway. PMID- 21279717 TI - Shiga toxin type 2 (Stx2), a potential agent of bioterrorism, has a short distribution and a long elimination half-life, and induces kidney and thymus lesions in rats. AB - Shiga toxin type 2, a major virulence factor produced by the Shiga toxin producing Escherichia coli, is a potential toxin agent of bioterrorism. In this study, iodine-125 (125I) was used as an indicator to describe the in vivo Stx2 biodistribution profile. The rats were injected intravenously (i.v.) with 125I Stx2 at three doses of 5.1-127.5 MUg/kg body weight. Stx2 had a short distribution half-life (t (1/2)alpha, less than 6 min) and a long elimination half-life in rat. The toxicokinetics of Stx2 in rats was dose dependent and nonlinear. Stx2 concentrations in various tissues were detected at 5-min, 0.5-h, and 72-h postinjection. High radioactivity was found in the lungs, kidneys, nasal turbinates, and sometimes in the eyes, which has never been reported in previous studies. In a preliminary assessment, lesions were found in the kidney and thymus. PMID- 21279718 TI - Antioxidant response of three Tillandsia species transplanted to urban, agricultural, and industrial areas. AB - To evaluate the physiological response of Tillandsia capillaris Ruiz & Pav. f. capillaris, T. recurvata L., and T. tricholepis Baker to different air pollution sources, epiphyte samples were collected from a noncontaminated area in the province of Cordoba (Argentina) and transplanted to a control site as well as three areas categorized according to the presence of agricultural, urban, and industrial (metallurgical and metal-mechanical) emission sources. A foliar damage index (FDI) was calculated with the physiological parameters chlorophyll a, chlorophyll b, malondialdehyde (MDA), hydroperoxyconjugated dienes, sulfur (S) content, and dry weight-to-fresh weight ratio. In addition, electrical conductivity (E-cond), relative water content (RWC), dehydration kinetics (Kin H(2)O), total phenols (T-phen), soluble proteins (S-prot), and activities of superoxide dismutase (SOD), catalase (CAT), and ascorbate peroxidase were determined. The parameters E-cond, FDI, SOD, RWC, and Kin-H(2)O can serve as suitable indicators of agricultural air pollution for T. tricholepis and T. capillaris, and CAT, Kin-H(2)O, and SOD can do the same for T. recurvata. In addition, MDA, T-phen, and S-prot proved to be appropriate indicators of urban pollution for T. recurvata. Moreover, FDI, E-cond, and SOD for T. recurvata and MDA for T. tricholepis, respectively, could be used to detect deleterious effects of industrial air pollution. PMID- 21279719 TI - The need for flexibility in conservation practices: exotic species as an example. AB - To garner support for biodiversity from the World's human population, conservation biologists need an open-minded, integrated conservation strategy. We suggest that this strategy should include efforts to (1) preserve existing high quality, diverse ecosystems, (2) remediate impaired systems, (3) balance the needs of people and ecological resources, and (4) engender appreciation of nature and its services. We refer to these four key tenets as reservation, restoration, reconciliation, and reconnection. We illustrate these concepts by presenting the debate surrounding the management of exotic species from an unusual perspective, the benefits of exotic species. By this example we hope to encourage an integrated approach to conservation in which management strategies can be flexible, adjusting to society's needs and the overall goals of conservation. PMID- 21279720 TI - A thermal hysteresis-producing xylomannan glycolipid antifreeze associated with cold tolerance is found in diverse taxa. AB - The presence of large-molecular-mass, thermal hysteresis (TH)-producing antifreezes (e.g., antifreeze proteins) has been reported in numerous and diverse taxa, including representative species of fish, arthropods, plants, fungi, and bacteria. However, relatively few of these antifreeze molecules have been chemically characterized. We screened diverse species by subjecting their homogenates to ice-affinity purification and discovered the presence of a newly identified class of antifreeze, a xylomannan-based TH-producing glycolipid that was previously reported in one species of freeze-tolerant Alaskan beetle. We isolated xylomannan-based antifreeze glycolipids from one plant species, six insect species, and the first frog species to be shown to produce a large molecular-mass antifreeze. (1)H NMR spectra of the ice-purified molecules isolated from these diverse freeze-tolerant and freeze-avoiding organisms were nearly identical, indicating that the chemical structures of the glycolipids were highly similar. Although the exact functions remain uncertain, it appears that antifreeze glycolipids play a role in cold tolerance. PMID- 21279722 TI - Genetic analysis of biological pathway data through genomic randomization. AB - Genome Wide Association Studies (GWAS) are a standard approach for large-scale common variation characterization and for identification of single loci predisposing to disease. However, due to issues of moderate sample sizes and particularly multiple testing correction, many variants of smaller effect size are not detected within a single allele analysis framework. Thus, small main effects and potential epistatic effects are not consistently observed in GWAS using standard analytical approaches that consider only single SNP alleles. Here, we propose unique methodology that aggregates variants of interest (for example, genes in a biological pathway) using GWAS results. Multiple testing and type I error concerns are minimized using empirical genomic randomization to estimate significance. Randomization corrects for common pathway-based analysis biases, such as SNP coverage and density, linkage disequilibrium, gene size and pathway size. Pathway Analysis by Randomization Incorporating Structure (PARIS) applies this randomization and in doing so directly accounts for linkage disequilibrium effects. PARIS is independent of association analysis method and is thus applicable to GWAS datasets of all study designs. Using the KEGG database as an example, we apply PARIS to the publicly available Autism Genetic Resource Exchange GWAS dataset, revealing pathways with a significant enrichment of positive association results. PMID- 21279723 TI - Contribution of the IBD5 locus to inflammatory bowel disease: a meta-analysis. AB - To evaluate the association of the IBD5 locus to the predisposition of inflammatory bowel diseases (IBDs), a series of meta-analyses between five IBD5 variants (OCTN1 C1672T, OCTN2 G-207C, OCTN1/2 TC haplotype, IGR2096a_1, IGR2198a_1 and IGR2230a_1) and Crohn's disease (CD) and ulcerative colitis (UC) were performed, which included a total of 26 studies. Overall, five IBD5 variants in a per-allele model of inheritance were significantly associated with elevated CD risk (for OCTN1: OR = 1.23, 95% CI = 1.16-1.30, P < 0.001; for OCTN2: OR = 1.20, 95% CI = 1.11-1.30, P < 0.001; for IGR2096a_1: OR = 1.36, 95% CI = 1.24 1.46, P < 0.001; for IGR2198a_1: OR = 1.34, 95% CI = 1.24-1.46, P < 0.001; for IGR2230a_1: OR = 1.35, 95% CI = 1.23-1.48, P < 0.001) and OCTN1/2 TC haplotype (OR = 1.32, 95% CI = 1.22-1.43, P < 0.001). In the subgroup analysis, the statistically significant associations were also observed in adult- and pediatric onset CD and in Caucasians for five IBD5 variants and the OCTN1/2 TC haplotype. A statistically significant increase in the risk of UC was detected in a recessive model of inheritances for OCTN1 (OR = 1.23, 95% CI = 1.08-1.40, P < 0.001), OCTN2 (OR = 1.18, 95% CI = 1.05-1.33, P = 0.006), IGR2096a_1 (OR = 1.37, 95% CI = 1.15 1.62, P < 0.001) and IGR2198a_1 (OR = 1.35, 95% CI = 1.10-1.66, P = 0.004); the increased risks of UC were maintained in the adult and Caucasian subgroups, but not the pediatric subgroup. In summary, our results suggested that the IBD5 locus contributes to the susceptibility of CD in a per-allele manner in adults, children and Caucasians, and the locus contributes to the susceptibility of UC in a recessive manner in adult and Caucasian populations. PMID- 21279725 TI - Rituximab for refractory cases of childhood nephrotic syndrome. AB - Rituximab has been used over the last decade as a rescue therapy for refractory cases of nephrotic syndrome (NS). Here we report the use of rituximab in four children with idiopathic steroid-resistant nephrotic syndrome (SRNS) with various histological backgrounds (two cases with focal segmental glomerulosclerosis, one case with IgM nephropathy, and one case with minimal change disease), who failed to respond to other immunsuppressions. Their median age (range) was 10 (8-11) years. NPHS2 genetic mutation was negative in all of them. All patients received a single dose of rituximab (375 mg/m(2)) and achieved complete B cell depletion as CD19 was <1% for 3 months following rituximab infusion. Only one patient achieved non-sustained remission as he relapsed after 4 months despite zero CD19 level. Patients received no further doses of rituximab as B cell was depleted in the peripheral circulation. We conclude that a single dose of rituximab was not effective in inducing sustained remission in children with idiopathic SRNS, despite complete B cell depletion in the peripheral circulation. Further doses might be indicated to deplete non-circulating B cells. PMID- 21279724 TI - Mutations in Fanconi anemia genes and the risk of esophageal cancer. AB - The incidence of esophageal squamous cell carcinoma (ESCC) is very high in northeastern Iran. Previously, we reported a strong familial component of ESCC among Turkmens, who constitute approximately one-half of the population of this region. We hypothesized that the genes which cause Fanconi anemia might be candidate genes for ESCC. We sequenced the entire coding regions of 12 Fanconi anemia genes in the germline DNA of 190 Turkmen cases of ESCC. We identified three heterozygous insertion/deletion mutations: one in FANCD2 (p.Val1233del), one in FANCE (p.Val311SerfsX2), and one in FANCL (p.Thr367AsnfsX13). All three patients had a strong family history of ESCC. In addition, four patients (out of 746 tested) were homozygous for the FANCA p.Ser858Arg mutation, compared to none of 1,373 matched controls (OR = 16.7, 95% CI = 6.2-44.2, P = 0.01). The p. Lys3326X mutation in BRCA2 (also known as Fanconi anemia gene FANCD1) was present in 27 of 746 ESCC cases and in 16 of 1,373 controls (OR = 3.38, 95% CI = 1.97 6.91, P = 0.0002). In summary, both heterozygous and homozygous mutations in several Fanconi anemia-predisposing genes are associated with an increased risk of ESCC in Iran. PMID- 21279726 TI - Orange-colored diapers in infants from families with gout. PMID- 21279727 TI - Children with chronic kidney disease: are they insured as adults? PMID- 21279728 TI - Renal artery stenosis: is angiography still the gold standard in 2011? AB - Renovascular hypertension (RVH) is an unusual cause of hypertension in children that is important to diagnose as it is potentially curable with angioplasty or surgery. Digital subtraction angiography is the gold standard for diagnosing RVH; for other methods like ultrasound, isotope studies, magnetic resonance angiography and computed tomography angiography sensitivity is still too low to reliably exclude RVH. Clinical and laboratory criteria that suggest RVH will be proposed and recommendations when digital subtraction angiography should be performed will be made. A treatment algorithm that suggests when to use medical treatment, interventional radiology and surgery in children with RVH will be given. PMID- 21279729 TI - Agroinoculation of Nicotiana benthamiana with cloned honeysuckle yellow vein virus isolated from Lonicera japonica. AB - A new honeysuckle yellow vein geminivirus (HYVV) isolate (2,763 nucleotides) and the HYVV-beta satellite (1,227 nucleotides) from Korea were cloned and characterized from symptomatic leaves of Lonicera japonica with a yellow net mosaic appearance. Phylogenetic analysis of HYVV and 13 other begomoviruses revealed that HYVV has the highest nucleotide sequence homology to HYVV-UK2. Grafting challenge of a virus-free L. japonica (scion) on an HYVV-infected L. japonica (stock) resulted in the appearance of typical HYVV disease symptoms on the newly developed leaves of the scion. Two pMon521 plasmids containing 1.3 copies and 2.0 copies of the cloned HYVV isolate, respectively, were infectious and produced disease symptoms in Nicotiana benthamiana after agroinoculation. We conclude that the causal agent of yellow net mosaic in L. japonica is a new Korean isolate of HYVV, based on sequence comparisons, agroinoculation-induced disease symptoms, electron microscopy, and phylogenetic analysis. PMID- 21279730 TI - Achromobacter xylosoxidans respiratory tract infection in cystic fibrosis patients. AB - The aims of this study were to evaluate the frequency of Achromobacter xylosoxidans infection in a cohort of cystic fibrosis patients, to investigate antimicrobial sensitivity, to establish possible clonal likeness among strains, and to address the clinical impact of this infection or colonization on the general outcome of these patients. The study was undertaken between January 2004 and December 2008 on 300 patients receiving care at the Regional Cystic Fibrosis Center of the Naples University "Federico II". Sputum samples were checked for bacterial identification. For DNA fingerprinting, pulsed-field gel electrophoresis (PFGE) was carried out. Fifty-three patients (17.6%) had at least one positive culture for A. xylosoxidans; of these, 6/53 (11.3%) patients were defined as chronically infected and all were co-colonized by Pseudomonas aeruginosa. Of the patients, 18.8% persistently carried multidrug-resistant isolates. Macrorestriction analysis showed the presence of seven major clusters. DNA fingerprinting also showed a genetic relationship among strains isolated from the same patients at different times. The results of DNA fingerprinting indicate evidence of bacterial clonal likeness among the enrolled infected patients. We found no significant differences in the forced expiratory volume in 1 s (FEV(1)) and body mass index (BMI) when comparing the case group of A. xylosoxidans chronically infected patients with the control group of P. aeruginosa chronically infected patients. PMID- 21279731 TI - MLVA and SNP analysis identified a unique genetic cluster in Bulgarian Bacillus anthracis strains. AB - A collection of 40 Bacillus anthracis strains mostly isolated from soil in Bulgaria between 1960 and 1980 were investigated. All strains were proven to be B. anthracis by culture and amplification of a B. anthracis-specific chromosomal marker. PCR demonstrated that in nine strains both virulence plasmids (pX01+/pX02+) and in four strains only one plasmid (pX02+) were present, whereas the majority of strains (n = 27) lacked both plasmids (pX01-/pX02-). Multi-locus variable number of tandem repeat-analysis (MLVA) using 15 markers differentiated three genotypes. Comparison with typing data of more than 1,000 different B. anthracis strains revealed that Bulgarian genotypes affiliated with the A1.a cluster and form their own unique cluster different from clusters containing strains isolated in geographical proximity, e.g., Turkey, Georgia, Hungary, Albania or Italy. In addition, a new allele of one marker (vrrC2) was identified. Canonical single nucleotide polymorphisms analysis allocated 31 Bulgarian strains into the A.Br.008/009 and nine strains into the A.Br.WNA group, which is the first description of B. anthracis strains of the A.Br.WNA group on the Eurasian continent. PMID- 21279732 TI - BioMetals: a historical and personal perspective. AB - Understanding of BioMetals developed basically from a starting point about 60 years ago to current mechanistic understanding of the biological behavior of many metal ions from protein structural and functional studies. Figure 1 shows a Biochemical Periodic Table, element by element, with requirements, roles and biochemistry of the specific ions indicated. With few exceptions, the biology is of the ions formed and not of the elemental state of each. Early BioMetals efforts defined nutritional growth needs for animals, plants and microbes for inorganic "macro-nutrients" such as magnesium, calcium, potassium, sodium, and phosphate and of "micronutrients" such as copper, iron, manganese and zinc. Surprises came early with regard to microbes, for example the finding that Escherichia coli (then and now the standard microbial model) grows happily in the apparent total absence of calcium, sodium, and chloride, which are certainly major animal nutrients. Some elements such as mercury and arsenic are never required by living cells, but are always toxic, often at very low levels. Therefore, the division into nutrient elements and toxic elements came soon. For most inorganic nutrients, excessive amounts can be toxic as well, for example for copper and iron. PMID- 21279733 TI - Religious struggle as a predictor of subsequent mental and physical well-being in advanced heart failure patients. AB - Patients with congestive heart failure (CHF) often report high levels of religiousness, which may mitigate the stressfulness of their condition. However, religious struggle, reflecting negative attitudes toward God and a strained meaning system, may be detrimental to well-being. Little is known about religious struggle in those with CHF, particularly in relation to physical health and well being over time. We examined associations of religious struggle and subsequent mental and physical well-being in 101 endstage CHF patients who completed questionnaires twice over 3 months. Religious struggle predicted higher number of nights subsequently hospitalized, higher depression, and marginally lower life satisfaction. When controlling for baseline levels of well-being, effectively assessing change in those outcomes, religious struggle remained a significant predictor of hospitalization and also emerged as a marginally significant predictor of lower physical functioning. Struggle was unrelated to health-related quality of life. Post-hoc analyses suggest that these effects were particularly strong for those endorsing greater religious identification. Religious struggle appears to have a potentially negative impact on well-being in advanced CHF; therefore, helping patients to address issues of struggle may meaningfully lessen the personal and societal costs of CHF. PMID- 21279734 TI - Exposure to environmental tobacco smoke in childhood and incidence of cancer in adulthood in never smokers in the European Prospective Investigation into Cancer and Nutrition. AB - The association between childhood environmental tobacco smoke (ETS) exposure and adult cancer risk is controversial; we examined this relationship in never smokers within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Over an average of 10 years, 8,372 cases of cancer were diagnosed in 112,430 never smokers in EPIC. Childhood ETS was self-reported by participants at baseline, along with other lifestyle factors. Hazard ratios (HR) for ETS exposure in childhood and their 95% confidence intervals (CI) were estimated by Cox proportional hazards models stratified by age, sex, and study center and adjusted for education, alcohol drinking, body mass index, physical activity, non alcoholic energy intake, fruit and vegetable intake, and adulthood ETS exposure. Models were further adjusted for reproductive factors for female cancers, for meat intake for digestive system cancers, and for diabetes status for pancreatic cancer. No association was observed between childhood ETS exposure and overall cancer risks (HR = 0.97, 95% CI = 0.92-1.02), and for selected sites. The only exception was pancreatic cancer, as previously reported by Vrieling et al., among those who had been exposed daily in childhood (overall HR = 2.09, 95% CI = 1.14 3.84). In conclusion, childhood ETS exposure might not be a major risk factor for common cancers in adulthood. PMID- 21279735 TI - Subchronic effects of cyanobacterial cells on the transcription of antioxidant enzyme genes in tilapia (Oreochromis niloticus). AB - The increasing occurrence of toxic cyanobacterial blooms in eutrophic water bodies is nowadays of worldwide concern due to their ability to produce toxins such as microcystins (MCs). These cyanobacterial toxins have been shown to affect aquatic organisms such as fish, resulting in oxidative stress. Among the antioxidant enzymes, glutathione peroxidase (GPx) and soluble glutathione-S transferases (sGST) play an important role in the detoxification of MCs. In the present work tilapia (Oreochromis niloticus) were orally exposed to cyanobacterial cells containing MCs and non-containing MCs for 21 days. The activity and relative mRNA expression by real-time PCR of both enzymes and the GST protein abundance by Western blot analysis were evaluated in liver and kidney. Also the induction of lipid peroxidation (LPO) was assayed. MCs containing cyanobacterial cells induced an increase of LPO products in both organs, and MCs containing and MCs non-containing cyanobacterial cells altered the activity, gene expression and protein abundance of the enzymes, indicating the importance of GPx and sGST in MCs detoxification. Moreover, liver, the main organ involved in biodegradation and biotransformation, experienced an adaptative response to the toxic insult. These results show for the first time that the subchronic exposure to cyanobacterial cells causes changes in antioxidant and detoxification enzymes and that GPx and GST gene expression are good markers of these alterations in tilapia. PMID- 21279736 TI - A culture system for the live analysis of successive developmental processes and the morphological control of mammalian vertebral cartilage. AB - The mesoderm-derived segmental somite differentiates into dermomyotome and sclerotome, the latter of which undergoes vertebrogenesis to spinal cartilage and ultimately to vertebral bones. However, analysis and manipulation of the developing mammalian vertebrae in the same embryo has been infeasible because of their placental-dependent embryogenesis. Here, we report a novel culture system of the mouse embryonic tailbud, by which the developmental processes of mammalian vertebral cartilage are traceable and manipulatable in the same sample. The anaplastic segmental somites/sclerotomes in the tailbud of 13 gestational day (g.d.) embryo that are structurally continuous to the vertebral column underwent progressive vertebrogenesis when (1) the ectoderm-derived nascent epidermis was microsurgically removed prior to cultivation, and (2) the sample was incubated at the air-medium interface. After cultivation for 5 days, the size and shape of the instructed vertebral cartilage showed features comparable to well-differentiated body vertebra along with the expression of the cartilage marker collagen type II, suggesting that aggressive differentiation of the sclerotomal cell lineage was achieved. In the presence of recombinant bone morphogenic protein (BMP) and Noggin, or adenoviral particles for extracellular epimorphin, dramatic alteration of the vertebral morphology ensued in the explants. Thus, this model system provides an approach to study the detailed molecular mechanisms of mammalian vertebrogenesis and enables pretreatment strategies of precartilagious fragments for improving the efficacy of subsequent transplantation. PMID- 21279737 TI - Comparative analysis of carboxysome shell proteins. AB - Carboxysomes are metabolic modules for CO(2) fixation that are found in all cyanobacteria and some chemoautotrophic bacteria. They comprise a semi-permeable proteinaceous shell that encapsulates ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) and carbonic anhydrase. Structural studies are revealing the integral role of the shell protein paralogs to carboxysome form and function. The shell proteins are composed of two domain classes: those with the bacterial microcompartment (BMC; Pfam00936) domain, which oligomerize to form (pseudo)hexamers, and those with the CcmL/EutN (Pfam03319) domain which form pentamers in carboxysomes. These two shell protein types are proposed to be the basis for the carboxysome's icosahedral geometry. The shell proteins are also thought to allow the flux of metabolites across the shell through the presence of the small pore formed by their hexameric/pentameric symmetry axes. In this review, we describe bioinformatic and structural analyses that highlight the important primary, tertiary, and quaternary structural features of these conserved shell subunits. In the future, further understanding of these molecular building blocks may provide the basis for enhancing CO(2) fixation in other organisms or creating novel biological nanostructures. PMID- 21279738 TI - Family quality of life in dementia: a qualitative approach to family-identified care priorities. AB - OBJECTIVE: To characterize factors contributing to quality of life (QOL) in families providing care to people with dementia. BACKGROUND: Assessing QOL in dementia has proved difficult. Individuals with dementia often possess limited insight, leading them to self-rate QOL differently from those who provide care for them. A majority of people with dementia receive care in the context of family units, but measures of whole-family QOL have not been previously described in the literature on dementia. The concept of family quality of life (FQOL) was developed and validated among families caring for children with developmental disabilities. FQOL measures have the potential to improve determinations of effectiveness in dementia care. DESIGN/METHODS: Fifty-four questionnaires requesting information on priorities for care were collected from families of patients obtaining care at an academic dementia clinic. Forms were completed by family members, patients, or both. The mean age of the patients was 73.6 years; 61% were women. Qualitative analyses of the responses were conducted by two evaluators. Comments from 54 questionnaires were assigned by consensus to five categories based on domains validated for FQOL in families of individuals with developmental disabilities. Eleven cases from the 54 were rated by both evaluators to assess inter-rater reliability. RESULTS: Five domains were identified as follows: (1) family interactions, (2) direct care/activities of daily living support, (3) emotional/behavioral well-being, (4) physical and cognitive well-being, and (5) disability-related support/medical care. Not surprisingly for clinic encounters, medical care requests and inquiries were expressed by a high proportion of families. Concerns about physical and cognitive well-being were expressed nearly as often. Issues regarding family interactions and emotional well-being were less frequently raised. CONCLUSIONS/RELEVANCE: A FQOL model developed for developmental disability provided useful information for qualitative characterization of priorities among families receiving dementia care. Ongoing research will be useful to explore the validity and utility of the FQOL concept in dementia, especially in domains not well addressed by the current questionnaire. PMID- 21279739 TI - Merits of non-invasive rat models of left ventricular heart failure. AB - Heart failure (HF) is characterized as a limitation to cardiac output that prevents the heart from supplying tissues with adequate oxygen and predisposes individuals to pulmonary edema. Impaired cardiac function is secondary to either decreased contractility reducing ejection (systolic failure), diminished ventricular compliance preventing filling (diastolic failure), or both. To study HF etiology, many different techniques have been developed to elicit this condition in experimental animals, with varying degrees of success. Among rats, surgically induced HF models are the most prevalent, but they bear several shortcomings, including high mortality rates and limited recapitulation of the pathophysiology, etiology, and progression of human HF. Alternatively, a number of non-invasive HF induction methods avoid many of these pitfalls, and their merits in technical simplicity, reliability, survivability, and comparability to the pathophysiologic and pathogenic characteristics of HF are reviewed herein. In particular, this review focuses on the primary pathogenic mechanisms common to genetic strains (spontaneously hypertensive and spontaneously hypertensive heart failure), pharmacological models of toxic cardiomyopathy (doxorubicin and isoproterenol), and dietary salt models, all of which have been shown to induce left ventricular HF in the rat. Additional non-invasive techniques that may potentially enable the development of new HF models are also discussed. PMID- 21279745 TI - Beyond the demographic transition. PMID- 21279740 TI - The role of aldosterone in the metabolic syndrome. AB - The metabolic syndrome associates metabolic abnormalities such as insulin resistance and dyslipidemia with increased waist circumference and hypertension. It is a major public health concern, as its prevalence could soon reach 30% to 50% in developed countries. Aldosterone, a mineralocorticoid hormone classically involved in sodium balance regulation, is increased in patients with metabolic syndrome. Besides its classic actions, aldosterone and mineralocorticoid receptor (MR) activation affect glucose metabolism, inducing insulin resistance through various mechanisms that involve oxidative stress, inflammation, and downregulation of proteins involved in insulin signaling pathways. Aldosterone and MR signaling exert deleterious effects on the cardiovascular system and the kidney that influence the cardiovascular risk associated with metabolic syndrome. Salt load plays a major role in cardiovascular injury induced by aldosterone and MR signaling. Large multicenter, randomized clinical trials testing the beneficial effects of MR antagonists on cardiovascular events and mortality in patients with metabolic syndrome are needed. PMID- 21279746 TI - The formal dynamics of controlled populations and the echo, the boom and the bust. AB - This paper analyzes the pattern of fluctuations of births in an age-structured population whose growth is subject to environmental or economic constraint. It synthesizes the traditional demographic analysis of age-structured renewal with constant vital rates and the economic analysis which treats population change endogenously. When cohort fertility depends on relative cohort size, or when period fertility depends on labor force size, fluctuations of forty or more years replace the traditional "echo" or generation-length cycle. Twentieth-century U. S. fertility change agrees well with the theory, as the "Easterlin Hypothesis" suggests; but the period model fits better than the cohort model. PMID- 21279747 TI - The measurement of family size preferences and subsequent fertility. AB - A new method for measuring preferences for number of children is presented and related to the subsequent fertility of a panel of married women over a five-year period. TheI-scales, developed on the basis of unfolding theory, reflect the individual's utility function for children. They differ from global stated preferences and are more fine-grained measures, sensitive to variations from a first choice. Scales obtained at an initial interview were found to be consistently predictive of fertility in the prospective period, net of a number of other variables usually associated with differential fertility. Their potential both as independent and dependent variables in research is discussed. PMID- 21279748 TI - Economic determinants of family size in West Africa. AB - The economic theory of fertility postulates that income and prices, broadly defined, are important determinants of family size. What follows is an attempt to test this theory against the behavior of 717 predominantly urban households in Sierra Leone. Husband's education is used as a proxy for income; the "price" of a child is accounted for by wife's education and wife's wage rate. Other important variables are wife's age, a measure of child "quality," wife's age at first birth, and child mortality. The findings of the study tend to lend support to the economic theory of fertility but contain certain peculiarities which indicate a need for further research. PMID- 21279749 TI - Ethnic variations in the relationship between income and fertility. AB - The effects of husband'spotential andrelative incomes on completed fertility, as well as their effects on certain parity progression probabilities, are examined within samples of Anglos, Blacks and Mexican Americans. Relationships are estimated using data from the one-percent 1960 and 1970 U.S. Public Use Samples. The results reveal different patterns of relationship by ethnicity between the measures of income and the measures of fertility. The effects on completed fertility of the income measures are positive for Anglos and negative for Blacks, while in the case of Mexican Americans the effect ofpotential income is negative and that ofrelative income is positive. Income effects on the parity progression probabilities are similar in pattern to those from the analyses using completed fertility, although somewhat different patterns tend to appear at different birth orders, especially among Anglos. PMID- 21279750 TI - Age at marriage, family planning practices, and other variables as correlates of fertility in Korea. AB - The relationships between fertility and thirteen variables are examined in three groups of married Korean women, about 400 each from urban, rural, and semi-rural areas. Data were obtained by interview. Age at marriage and family planning practice are the strongest predictors of fertility and account for about 10 percent and 7 percent of the total variance, respectively. Other factors which accounted for lesser fractions of variability are ideal number of children, rural versus urban residence, education, aspiration for daughters, exposure to mass media, and economic status. Most of the relationships appear to be stable over time; others, which are associated with modernization, appear to be changing. The thirteen variables combined can account for a maximum of 40 percent of the variance in fertility. PMID- 21279751 TI - Natural population decrease in Iowa counties. AB - As a follow-up on the studies by Dorn and Beale, this paper examines differences between Iowa counties with natural decrease and those with natural increase and analyzes the part that migration and fertility played in bringing about an excess of deaths over births in Iowa counties. The county groups are distinctly different in demographic and socioeconomic characteristics. Out-migration as a mode of response adopted by the rural population in Iowa is by far the most dominant factor leading to natural decrease. Sustained net out-migration is more likely to touch off natural decrease in counties of comparatively low fertility than in those with higher fertility. Low fertility is, therefore, a contributing factor to the imbalance between births and deaths, but the amount of influence of fertility adjustment over the fertility differentials among county groups cannot be ascertained in this study because of the correlation between fertility and Catholic Church membership in counties. The data of this study were obtained from the population censuses and vital statistics. PMID- 21279752 TI - Computer display of population age structure. AB - The standard human population pyramid contains only current information; it is often inadequate when making comparisons of different countries or years. A graphic computer program superimposes current population, life table survivor ships, stable population, and past population projected up to the present. Fertility, health conditions, migration, and demographic transition stage are better revealed by this expanded graph form. A time series of the modified pyramids reveals detailed age-specific trends for a country or region. With 'minor modifications the computer program is applicable to all machines with a Fortran IV compiler. PMID- 21279753 TI - Generating functions for partial sex control problems. AB - If at: each conception couples have some control over the sex of their intended offspring, their chances of reaching a desired ultimate family composition will be influenced by the specific order in which they try for sons and daughters. This article introduces and discusses the mathematics of the strategy decisions that arise where probabilities remain constant at each birth. In the Appendix probabilities and their generating functions for distributions ofi children of one sex and 1-2 children of the other sex are given. PMID- 21279754 TI - Fertility and per apita income: Acomment on Janowitz's results. PMID- 21279755 TI - Review symposium. PMID- 21279756 TI - Reply. PMID- 21279757 TI - Erratum to: New Estimates of the vital rates of the United States black population during the nieneteenth centrury. PMID- 21279759 TI - Vector representation of migration streams among selected state economic areas during 1955 to 1960. AB - This paper uses in-migration, out-migration, and net migration vectors to measure and portray the migration streams occurring between April 1, 1955, and April 1, 1960, for all persons five years old and over on April 1, 1960, among 38 contiguous state economic areas (SEA's) in Oklahoma, Colorado, Kansas, Missouri, Arkansas, Texas, and New Mexico. Both rectangular and polar coordinates were employed in computing three different types of vector representations. First, migration vectors for each SEA, expressed in total people-miles of in-movement, out-movement, and net movement represent the resultant direction of movement and the total people-miles of movement. Second, in- and out-migration vectors of the total people-miles of movement, with the widths of the vectors drawn proportional to the number of migrants, show the total size of each migration stream for each SEA, the resultant direction of movement, and the distance moved in total people miles of movement. p ]Third, in- and out-migration vectors of the average distances moved to and from each SEA, with the widths of the vectors drawn proportional to the number of migrants, show the magnitude of movement, the average distance moved per migrant, and the resultant direction of movement. This study shows that migration vectors based upon polar coordinates are more accurate than the migration vectors based upon rectangular coordinates. Also, the in- and out-migration vectors are superior to net migration vectors in representing migratory streams among geographic areas. PMID- 21279760 TI - Early work experience of graduates and dropouts. AB - For the past seven years, the Bureau of Labor Statistics has reported on the differential work-force status of recent high school graduates and dropouts. Their definition of graduate and dropout populations and a failure to distinguish inter-cohort differences from intra-cohort changes may have led to an erroneous assessment of progress in the work force subsequent to entry. Emphasis on the value of a high-school diploma at the time of work-force entry rather than on the value of an incremental school year appears misplaced. Current data-collection programs are not generating the statistics needed to answer the policy questions to which these reports are addressed. PMID- 21279761 TI - A quantitative study of the determinants of fertility behavior. AB - Recent literature shows great interest in the quantitative study of the determinants of fertility. In a similar way, this study takes an across-country approach to specify independent variables, to separate economic from social and political variables, to make distinct comparisons of fertility responses in developed and underdeveloped countries, and to examine a wide range of hypotheses. The key is empirical analysis by separate regressions. This permits direct comparisons of countries at different levels of development, increases the probability of obtaining statistically significant regression coefficients, and standardizes the analysis for factors which vary with level of development.In this way, the authors determine positive and statistically significant relations between fertility and illiteracy, child mortality, proportion of agricultural population, proportion of nonfarm selfemployment, and overcrowded housing and show a negative significant relationship between fertility and communism. The study does not establish statistically significant relations, however, for population density, social mobility, substitutes for sexual intercourse, achievement motivation, protein in the diet, and religion.In general, the signs of the regression coefficients for the separate levels of development are the same as those for all countries combined. Any failure to attain statistical significance may be explained by small sample size and insufficient variation in the variables for separate levels of development. PMID- 21279762 TI - Measurement and evaluation of national family planning programs. AB - RESUMEN: En los ultimos quince anos diez paises han inaugurado programas nacionales de planeamiento familiar: India, Pakistan, Corea del Sur, Taiwan, Turquia, Malasia, Ceilan, Tuez, la Republica Arabe Unida, y Marruecos. Otros paises, incluyendo Tailandia, Hong Kong, Singapur, Kenya, Barbados, Trinidad y los Estados Unidos, apoyan y/o estimulan actividades de planeamiento familiar. En la mayor parte de los casos la razon fundamental del programa ha sido que si la tasa de crecimiento poblacional disminuyera, aumentaria la tasa de crecimiento economico.Las metas de largo alcance, expresadas tipicamente en terminos de reducir las tasa.de de natalidad o de crecimiento, tienen su ejemplo en el proposito de Pakistan de reducir su tasa de crecimiento a 26 para 1970; el de Corea de reducir su tasa de natalidad a 20 para 1971; y el de India de reducir su tasa de natalidad a 25 para 1973.Los objectivos intermedios, que cubren diversos aspectos del pro grama, incluyen metas especificas para un determinado mes a ano, considerando personal, la adquisicion de anticonceptivos, y el numero de usarios por metodo. Las metas especificas anuales de aceptantes de dispositivos intrauterinos (IUD), para Taiwan, Corea, Tunez, Pakistan e India, son comunes, tanto por la naturaleza del artefacto, como por la facilidad de medicion de los que continuan utilizandolos. El programa de evaluacion en Taiwan, que trata de medir por diversos medios los efectos inmediatos, mediatos y de largo plazo del programa de planeamiento familiar sirve de modelo. El proposito de la evaiuacion de un programa de planeamiento familiar es contribuir a la efectividad y eficiencia del programa, midiendo y analizando su progreso. Las areas a medir pueden ser clasificadas como- (1) conocimiento acerca de; (2) actitudes hacia; (3) practica de control de natalidad; y (4) nivel de fecundidad.Un buen sistema de evaluacion deberia incluir: A. Un buen conjunto de estadisticas de servicio presentadas en formularios estandarizados, en las siguienies formas: 1. Informes nensuales por areas administrativas, sobre los actuales servicios de planeamiento familiar proporcionados en la actualidad, de caracter permanente o de larga duracion (al presente, esterilizacion y IUD de acuerdo a las siguientes caracteristicas del receptor: residencia, edad, paridad (numero de hijos vivos por sexo), y donde se entero del programa, si es posible "clase";(probablemente educacion de la madre, pero posiblemente ocupacion del esposo, ingreso, o equivalente); practicas anticonceptivas anteriores; intervalo; y deseo de tener mas hijos. En un programa grande estos datos pueden obtenerse en base a una muestra. 2. Informes mensuales sobre la distribucion de suministros anticonceptivos (condones, pildoras, sustancias efervescentes, etc.), los primeros suministros deben ir acompanados de un registro de las caracteristicas del recipiente, como anteriormente; los suministros subsecuentes se regietraran solo en volumen bruto. Esto tambien se aplicara al ritmo, donde este metodo se ensene a un numero considerable de mujeres. 3. Informes regulares sobre las actividades de planeamiento familiar de medicos privados, como una estimacion del efecto catalitico del programa del gobierno sobre ci sector privado. 4. Datos generates mensuales, ppr areas admirtistrativas importantes, sabre: visitas domiciliarias, reuniones, cunas radiates y televisadas, avisos en los periodicos y personal que trabaja. 5. Para propositos de seguimiento una entrevi eta de campo cada 6 a 12 meses a cada N mujer de las listas para (1) y (2) arriba, en un total de 300 o 400, para conocer las tasas de continuacion y las razones de abandono (ej: desea otro hijo, insatisfecha can ci metodo, otras). Las mue.stras podrian ser de 300 cada una, con una supuesta experiencia de 6, 12, 18 y 24 meses. B. Un buen conjunto de datos sobre costa (datos sobre cotos actulaes atribuibles directamente al programa de planeamiento familiar) fraccionados par areas principales y cinco a seis categorias de costos importantes tales coma: adminietracion, personal de campo, publicidad, suministros, etc. C. Un buen conjunto de dates globales sobre la distribucion de los suministros comerciales que puedan llegar tan cerca como sea posible del ultimo consumidor, to cual significa probablemente obtener informacion de los mayoristas. D. Una encuesta de conocimientos, actitudes y practicas (KAP) para una evaluacion general cada dos anos. Las preguntas basicas (ademas de las antes mencionadas y estatus marital y etnico cuando sea pertinente) son: actitud hacia e interes por la anticoncepcion, numero de ninos por sexo, deseo de tener mas hijos, practicas anticonceptivas, experiencia sobre abortos, tal vez historia de embarazo (especialmente si esta producira una tasa de fecundidad valida), aprobacion del programa gubernamental (para uso politico), y si esta actualmente embarazada (la unica y mejor pregunta cuya respuesta habla del efecto sobre la tasa de natalidad). Administrativamente, la responsabilidad por la evalucion debe estar cerca al director, se debe tomar provisiones para obtener informes regulares (meneulaes) y especiales dirigidos a preguntar sobre politica. El corolario es que el jefe de evaluacion debe tener la confianza del director y debe estar al dia en cuanto a las decisiones sabre la politics a seguir. Su trabajo consiste en extractar los aspectos principales que funcionan bien y los no operantes. En cuanto a costos, la evaluacion debe hacerse sobre no mas del 10 par ciento del costa del programa en paises pequenos (de menos de 30 milliones) y sabre no mas del 5 per ciento en paises mas grandes.Para medir en que forma el programa satisface el criterio final-la magnitud en que cambia la fecundidad-se debe realizar un trabajo mas elaborado en el centro (Universidades, Consejos de poblacion, etc.) para desarrollar una forma (a formas) segura de traducir las estadisticas de servicio en praticas y tal vez aun datos sobre suministro comercial en datos sabre tasas de natalidad. Esto incluye, par ejemplo, los esfuerzos para consolidar observaciones coma "cinco anos-mujer de usa de IUD, a 400 condones equivalen a la prevencion de un nacimiento," y esfuerzos como los de Pakistan de calcular tasas coma "anos de proteccion de una pareja contra el embarazo."In the belief that a decrease in the rate of population growth will increase economic development, more than ten countries have inaugurated family planning programs in the past fifteen years. To provide a model for measuring the immediate, intermediate, and long-term effects of any such program, the authors use the Taiwan evaluation.The model suggests that a good system of evaluation should include monthly statistics on (1) participants, who are grouped by characteristics; (2) the distribution of supplies, reported at first by the characteristics of recipients, but after by gross volume only; (3) family planning activities of private physicians to measure the catalytic effect on the private sector; (4) new contacts and amount of advertising in mass media; (5) costs broken down by areas and by cost categories; and (6) distribution of commercial supplies. In addition, the program should conduct 300-400 interviews every 6-12 months to learn the rates of continuation and the rates and reasons for discontinuation. Finally, a KAP survey should be conducted every two years.The administration of the evaluation should be close to the director for policy decisions and for the ultimate work of evaluation-the finding of new ways to measure the main goal of change in fertility by the translation of statistics on Services provided and commercial supplies into birth rate data. PMID- 21279763 TI - Educational efforts in the implementation of rural family planning programs in East Pakistan. AB - The pilot family planning studies reported in this paper were conducted in a rural area adjacent to the city of Dacca in East Pakistan. It reports the preliminary findings of action-research in the implementation of educational efforts to reach rural villagers of a developing country.Preliminary analyses of the records identify two significant educational problems: (1) most of the villagers (85-90 percent of the couples) who initially accepted contraceptives do not truly adopt and become continuing users and (2) the continuing users (10-15 percent of the initial users) are generally characterized by large families. (Later data show an even lower percentage of continuing users.)The field activities in the development of various educational approaches to family planning are described. Three separate geographic areas (from 15,000 to 20,000 population) were each approached in a different way, varying in the number and educational qualifications of the workers and in the degree of involvement of village leadership. Preliminary analyses of field records indicate that these variations of approach apparently have little effect on the percentage of the population willing to accept contraceptive supplies.It is the opinion of the writers that more intensive educational efforts are necessary at the village level to develop social support for continuing use of contraception and to gain adoption of contraception by younger married couples primarily for spacing of births.The impact of introduction of the IUCD in populations where condoms and foam tablets have been available for one to two years has also been reported. Preliminary findings indicate that the IUCD encourages adoption by previous non users and may increase the over-all percentage of contraceptive users. PMID- 21279764 TI - New frontiers in demography and social psychology. AB - The topics of demography are those of human fate: birth, illness, marriage, occupation, and death. The methods of demography therefore relate global rates to major events, submerging the individual decision. The social psychologist observes the regularities of people's behavior in different social conditions and builds models from individual decisions. Since he looks at patterns independent of the event, the kind of event does not matter, and he tends to concentrate on trivial events which are amenable to research.To the degree that man has obtained control over his environment, he is able to look at demographic events as less than fate. Social conditions have also given more control to the individual over many events over which he had no control previously, such as choice of a marriage partner or an occupational career. Thus, the classical methods of demography are frequently insufficient to deal with demographic data, and abrupt changes may occur because of vagaries of individual decisions. The more the demographic trends can be affected by individual decisions, the more the methods of social psychology become useful in understanding changes in population composition.The possibilities of micro-demography, of building up demographic trends from individual decisions, become stronger as more individual control can be exerted over the events. Such disparate events as control of infectious disease, air pollution, birth control, civil rights, and changes in the educational system and occupational structure have given individuals more control over different demographic variables, made the study of individual decisions with demographic consequences important, and led to joint efforts by demographers and social psychologists. PMID- 21279765 TI - Rural-urban mortality in developing countries: An index for detecting rural underregistration. AB - This study begins with a brief analysis of past and present urban-rural mortality in those countries which are presently considered to be developed. The same analysis centers in developing countries, for it is thought that their rural mortality should be greater than their urban mortality. Since available statistics generally show the contrary, a way is presented for constructing possible means of sub-registering vital statistics in some areas of these countries. The index would vary to agree with the system of the registry of vital statistics in a given area. Mexico is used as an example-the result of constructing and analyzing the index is to show in which areas there should be a subregistry of deaths. Finally, the cases of India and Taiwan are analyzed in order to confirm the hypothesis that in developing countries there will be a higher mortality rate in. rural than in urban areas. PMID- 21279766 TI - Educational attainment as a selective factor in marital status transitions in the United States. AB - Data on marital status from the 1940, 1950, and 1960 censuses of the United States are organized to show (1) trends in percentages of men and women who were single, by age and education (grades of school completed); (2) relative education levels of husbands and wives for selected groups of couples in 1940 and I960 with comparisons for the two years; and (3) education levels of women in 1950 by marital status, controlling for age and year of entry into the 1950 marital status. The rate at which single persons married for the first time increased markedly during the decade of the 1940's but much less in the next decade. The 1940's increases occurred for both sexes at all educational levels and at all ages except the oldest. However, the rate of increase was greatest for both sexes in the ages from about 20 to 34 for women and 22 to S4for men (modal age for first marriage is 18 for women and 21 for men). The distribution of percents single by age was about the same in all three censuses for persons with elementary schooling.A trend toward smaller proportions of the single, both men and women, among young persons with college education continued for the entire twenty-year period, despite the lack of such a trend in the 1950's at other age and education levels. However, the available data on education of first-married husbands and wives indicate that the ratio of college-educated husbands to college-educated wives was higher in 1960 than in 1940. Part of the explanation may lie in the relatively high proportions of college-educated women found in the marital statuses "divorced" and "married more than once" in the 1950 Census, particularly at the younger ages and shorter durations; but the data are not adequate for a very satisfactory explanation. For the younger first-married for whom education of partners was cross-tabulated in 1940 and 1960, the proportions of college-educated persons were so much higher in 1960 than in 1940 that the proportions also increased of both husbands and wives at all educational levels who were married to college-educated partners. There was a marked decline in proportions of couples with only elementary schooling.Finally, based on data from the 1950 Census for women (15-59 years of age), the separated group included more with only elementary schooling, as did the widowed. Those remaining single and those married once usually included the highest proportions of college-educated women. PMID- 21279767 TI - Widow remarriages in some rural areas of Northern India. AB - It is commonly believed thai widows belonging to high-caste Hindus in India do not remarry because of various social restrictions imposed on their remarriage. Though some information on widowhood and widow remarriages is available, there is need for more detailed information. A study, carried out by the author, of 1 percent of the rural households in Mathura and Saharanpur districts in Uttar Pradesh and in Rohtak district in Panjab has brought out that nearly SO percent of the ever-widowed are remarried. The survey covered 6,211 households, of which 887 were Muslim and the remaining were Hindu.Of the ever-widowed females, 84 percent in Saharanpur, 25 percent in Rohtak, and 19 percent in Mathura were found to have remarried. With a view to finding out whether differences in widow remarriage percentages by districts were real or were due to variations in the distribution of the ever-widowed females by age, occupation, caste, and the number of living children, the standardized widow remarriage rates were obtained. The population of Saharanpur district was taken to be the standard population. As a result of standardization for age, number of living children, and caste, the difference narrowed down considerably; and, while the widow remarriage percentage was 34.2 in Saharanpur. it was found to be 334 in Rohtak and 31.1 in Mathura. A 3 percent lower figure for Mathura district could be a result of the Brahminic influence.Widow remarriages were found to be very common among younger widows, since nearly 90 percent of those below age 16 and 80 percent of those in the age group 15-19 were remarried. Also, roughly 80 percent of those who did not have a child at the time of their widowhood were remarried. But the per-centage of remarried widows declined with an increase in age and in the number of living children. The percentage of widow remarriages was highest among the Muslims between 35 and 37-because they put no restrictions on such remarriages. Among the Hindus, the lower castes, such as Chamars, Bhangis, and artisan castes, had the highest percentage of widow remarriages-around 30-because of the absence of social restrictions on such remarriages. Among the high-caste Hindus, the Jats (one of the warrior castes) had the highest percentage of remarried widows. The reason for this is that they have socially permitted such remarriages. Widow remarriages, though on a smaller scale, were also found prevailing among other warrior castes, such as Gujjars, Ahirs, and Rajputs. Among other high-caste Hindus, such as Brahmins, Banias, Khatris, and Aroras, cases of widow remarriages were very few-only around 7 percent. This is the result of a long standing religious sanction against such remarriages.On the basis of our data, we are inclined to say that in the rural areas of northern India no marked change in the social position regarding widow remarriages is noticeable. PMID- 21279768 TI - Estimating marital fertility rates by educational attainment using a survey of new mothers. AB - Marital fertility rates by educational attainment of mother are estimated for the United States for 1963. These calculations are based upon information collected in a probability sample survey of women having births in 1963 and are prepared by relating birth estimates for educational attainment groups to estimates of married women in corresponding groups.The rates do not display a negative association between educational attainment and the annual level of fertility, thus differing from the pattern observed in other measures of period fertility. Women who completed some high school but did not graduate and women with one or more years of college had higher annual fertility rates than women in other attainment classes.Alternative estimation procedures are discussed which illustrate difficulties in obtaining satisfactory correspondence between two independent surveys which are used to obtain the rate calculation components. PMID- 21279769 TI - Fertility and development in Brazil. AB - In the past, one of the concomitants of development has been a sustained reduction in fertility. As a result of this experience, demographers hypothesize that in a society in which fertility is lower in urban areas, among the upper socioeconomic status groups and the better-educated, fertility will decline to a moderate level as the country changes from a rural, agricultural socioeconomic structure, with low levels of living and education, to an urban, industrial structure, with rising levels of living and education.The data analyzed in this study indicate, however, that though substantial social and economic development (as measured by changes in industrial structure, per capita income, urbanization, and education) occurred in Brazil from at least 1920-40 to 1960, during which time fertility differentials of the kind indicated above existed, fertility has shown little or no tendency to decline. Between 1940 and 1960, in fact, the birth rate appears to have remained fairly constant around 43. With the death rate steadily dropping, the rate of natural increase and population growth (given a small net in-migration) has been accelerating. p ]From a theoretical point of view, these facts reinforce a growing realization, based on similar findings in some other developing countries, that the prevailing theoretical ideas concerning the relationship between development and fertility require modification, particularly in the direction of greater specificity. On the practical side, the question is raised whether Brazil's rate of economic development during the postwar period up to 1960 can be maintained, let alone increased, in the face of a population growth rate which will probably average 3.2-3.5 percent for the period 1960-70 and which, in the absence of a decline in fertility, is likely to accelerate further. PMID- 21279770 TI - Measuring acceptances in a family planning program: the decomposition of rates by eligibility criteria. AB - Acceptance rates in family planning programs can be broken into components useful in analyzing programs and in evaluating success. In almost any program some couples can be defined as "ineligible" on the basis of alternative criteria. (Sterilized couples are an obvious example.) Then, the total acceptance rate can be initially separated into two components-the proportion eligible and the acceptance rate among the eligible. If some of those initially defined as ineligible become acceptors, there is a third component-the ratio of all acceptances to acceptances among the eligible only. These various components can be used to analyze the basis for varying acceptance rates between different strata of a population. PMID- 21279771 TI - Fertility among ethnic groups in the USSR. AB - Thirty-six ethnie groups in the USSR are analyzed as to fertility differentials. The analysis is based on data from the 1959 nationwide census. To explain the fertility differentials found, ethnographic and sociological features of these groups are traced as a possible contributing factor. One of the poignant observations of the study is the fact that almost all ethnic groups with fertility above the median are those belonging to Moslem and Buddhist traditions. They are primarily located in the Central Asian republics, the Caucasus, and some parts of southern Siberia. Low fertility levels are by and large associated with the Eastern Orthodox Slavs and the Protestant Balts.Ratios of the number of children aged 0-9 to the number of women in the 20-49 age group are related to independent variables in the following order of importance: traditional religion, percentage of married women in the 20-49 age group, degree of literacy, male female literacy differential, and sex ratio. The multiple correlation of 0.911 was obtained between the child-woman ratio and the first four of the most important independent variables. Sex ratio appeared significant only after the influence of the percentage of married women was eliminated from the analysis of multiple and partial correlations.The data suggest that the urban-rural differential is a non-linear function of the urban-rural migration. A more complete explanation of the divergence between urban and rural child-woman fertility ratios should be made the subject of separate studies. PMID- 21279772 TI - Fertility of the jews. AB - The objectives of this paper were to review and summarize the existing literature on Jewish fertility and to discuss the highlights of data on fertility trends and differentials based on survey data obtained on the Jewish population of the metropolitan area of Providence, Rhode Island. The literature consistently confirmed the finding of lower fertility among Jews since the 1880's in the United States and for the last seventy-five years in a variety of European countries.A review of available data on fertility trends and differentials within the Jewish population indicated contradictory and inconsistent findings. The Providence survey data pointed to changing patterns of fertility among Jews and clarified a number of seeming inconsistencies. These data suggested (1) the pre World War II decline and postwar recovery of Jewish fertility; (2) the change from an inverse relationship of social class and Jewish fertility among first generation Jews to a direct relationship among second- and third-generation Jews; (3) the changing relationship of religiosity and Jewish fertility, which reflects social class changes.Finally, an attempt is made to clarify the interpretation of these and related findings by placing the analysis of Jewish fertility in the context of assimilation and acculturation. PMID- 21279773 TI - Female working roles and fertility. AB - Using survey data gathered in Turkey in 1963, the relationship between female employment status and fertility is examined. Controlling for urban-rural residence, education, and exposure to conception within marriage, no differences in fertility by labor force status appear. Although there is a slightly greater tendency for employed than for non-employed women to hold attitudes more favorable to small families and family size limitation, the observed differences are slight and not significant statistically. A typology is constructed wherein the nature and causal direction of any existing relationship between female employment and fertility are predicted, based on the availability of birth control technology and the presence or absence of conflict between the roles of mother and worker. PMID- 21279774 TI - Mobility, non-familial activity, and fertility. AB - In this analysis of fertility data from a sample of non-Catholic faculty couples in an American university, temporal patterns and variations in education, employment, marriage, and parenthood of the husbands and wives are discussed in reference to (1) the social mobility-fertility hypothesis and (2) a non-familial activity-fertility hypothesis.The couples are divided into four groups on the basis of family size and mobility status: (1) mobile-small, (2) non-mobile-small, (3) mobile-large, and (4) non-mobile-large. Whatever their mobility status, the four groups of husbands successfully completed requirements for the doctoral degree at about the same age and became established at about the same time in life and within the profession. Whatever their husbands' social origins, the wives also differ little with respect to educational attainment and in their work experiences in prematrimonial days. However, a different pattern is found in the work experiences of the wives since marriage. Those with two children are more likely to be employed after marriage and parenthood.On the other hand, a good many more wives with four or more children not only never worked before marriage but also remained outside the labor force after marriage (in the earlier years of marriage as well as after the tenth anniversary). The present data thus seem to support an analytically useful distinction between the "working wives" and the "working mothers." PMID- 21279775 TI - Field experience in estimating population growth. AB - This paper reports on some of the aspects of implementing the population estimation studies now being carried out-the Population Growth Estimation Study (PGE) in Pakistan, the Survey of Population Change (SPC) in Thailand, and the Demographic Survey in Turkey (TDS). The basic purpose of all these surveys is to provide reliable estimates of population growth rates for various areas within each of the countries.All the surveys under consideration are single-purpose, continuing, nation-wide studies, using fixed, area samples. The basic methodology of the studies is similar in that they au utilize the technique of collecting data on births and deaths by two separate systems and then comparing individual events to determine whether events were recorded by both systems or only one. One list is based on periodic enumerations and the other on continuous registration.Some of the problems encountered in the various phases of the field work required to assemble the two independent lists-such as identification of enumeration units, the de facto approach vs. the de jure approach, assuring completeness of registration, and reconciliation of unmatched cases-are described and the steps taken toward their solution outlined.The author concludes that the studies are on sound methodological grounds but that their implementation, especially in developing countries, poses additional burdens. PMID- 21279776 TI - Cultural complications in fertility interviewing. AB - A description is presented of interviewing and other field work problems in a fertility and KAP survey among village women in East Pakistan. The female population studied had a very low literacy rate and no previous contact with social research.In the survey described, village women were interviewed through the use of many standard questions concerning fertility and family planning. Inappropriate responses to these items were produced by the women. Many women misunderstood the questions or did not have the requisite information. This necessitated special explanations to respondents. One standard survey procedure which had to be modified in the field work was the maintenance of privacy in the interview situation.Prior to the survey (which was done in conjunction with a pilot family planning project), an attempt was made to develop a corps of indigenous village data-collectors. PMID- 21279777 TI - Concept, measurement, and data in migration analysis. AB - Two methods of computing migration rates-one relating moves to population at risk in place of origin and the other using as a denominator the cross-product of population in places of origin and destination-are discussed. It is concluded that the second assumes implicitly that moves originate and terminate as a random population variable.Some difficulties with this particular model are pointed out and the author suggests that other analytical approaches to migration data be sought and in this connection refers to the literature on the mathematical theory of epidemics. PMID- 21279778 TI - Immigration data and national population estimates for the United States. AB - The immigration component in national population estimates is comparatively small, but it is not insignificant and may indeed be an important source of error. Therefore, it warrants the considera-tion of those concerned with population estimates. The paper considers alternative methods for deriving estimates of immigration from the raw data and presents estimates of net immigration from 1950 to 1965. They are developed from estimates previously published by the Bureau of the Census, but they differ at some points where new data have become available or where a review of the data has led to a change in judgment on how best to use them. The paper also presents suggestions on how immigration statistics might be altered for purposes of improving the estimates.Census data may be used to estimate net immigration by three different methods, but upon analysis each method proves to be inadequate. Hence, data based on visas surrendered at the port of entry must be the principal source of immigration estimates. These data have their limitations because (1) they do not cover net arrivals of citizens from abroad and from Puerto Rico, (2) they do not report departures of aliens, and (3) they do not allocate all immigrants to year of entry. Alien registration and passenger data offer possible alternative estimates.The paper attempts to measure unrecorded immigration, discusses how net arrivals of citizens from abroad and from Puerto Rico may be estimated, and how the age, sex, and race of immigrants may be treated. PMID- 21279779 TI - From new entries to retirement: The changing age composition of the U.S. male labor force by industry. AB - The process whereby the age composition of an industry is formed appears to be largely a function of past rates of growth in employment; the social (or institutional) framework sets limits and affects the ensuing age composition but relatively little. The following types will illustrate this process. 1. Consider an industry which has increased considerably more rapidly in employment over several decades than has the total labor force. The rapid growth brings in a disproportionately large share of youth who are first entering the labor market; other younger workers move from slowly growing (or declining) industries. These movements add many more younger workers. On the other hand, there is little, if any, unemployment in the industry so that there are few pressures being exerted on the older workers to retire, and relatively few will retire. Under these circumstances the age composition will be younger than tliat of the entire male working force. 2. Consider an industry which has grown slowly, if at all, for some time. There will be comparatively fewer (in comparison with the first example) new entries and less mobility from other industries. The men already engaged in this industry will continue to work there; they gradually become older and are not counterbalanced by increasing numbers of young workers. Unemployment is likely to be higher, leading to a higher retirement rate. There are also likely to be large numbers of men a decade or two under the retirement age-the heritage of an "ancient" period when the industry had experienced significant increases in employment; these add pressure on the older men and more retire. The age composition of such an industry gradually veers toward the older side; it is considerably older than that of the entire male working force. At any given moment of time most industries will reflect variable past growth rates. For example, one industry may have a very large proportion of young workers because it grew very rapidly in employment only during the decade prior to the time of study (i.e., the time of a decennial census); another may have a large proportion in the middle ages reflecting very rapid growth two or three decades earlier, followed by very slow growth in the decade prior to the time of study; and so forth.In light of the foregoing analysis, it appears that technological change, as measured by average annual changes in output per worker, has little bearing on the age composition of an industry. Conversely, the latter probably does not affect changes in output per worker. PMID- 21279780 TI - Vertical mobility and community type as factors in the migration of college graduates. AB - Internal migration statistics are generally inadequate. One of the chief sources of this is the lack of direct data relating to migration. There appears also to be a lack of interest on the part of researchers in pursuing the study of the relationship between vertical mobility and migration. This study is designed to determine the relative importance of intergenerational vertical mobility and type of community or place of origin in contributing to the migration of college graduates by using direct mobility and migration data.The study sample consists of 850 employed male graduates of eight private colleges in Iowa between 1954 and 1958. Data were obtained through the colleges and consist, among other things, of information about fathers' occupations, graduates' occupations, and the addresses of graduates both at matriculation and at the time of the study. Information about communities or places of origin is dichotomized on the basis of whether they are located in Standard Metropolitan Areas (SMA's) in 1950 or whether they are located in non-SMA's (NSMA's). Upward mobility is treated as a product of higher education and as an antecedent of migration.Hypotheses asserting the existence of associations between mobility and migration and between type of community or place of origin and migration are tested. Associations are established showing (1) that upwardly mobile graduates are more likely to migrate than others and (2) that graduates from NSMA's are more likely to migrate than graduates from SMA's.The relative influence of the two factors is determined by partialing the associations between each factor and migration while holding the other factor constant. Type of community or place of origin is found to be of greater importance for migration than is upward mobility. Graduates from NSMA's are more likely to migrate than those from SMA's, regardless of their relative mobility. Graduates from SMA's are likely to migrate only if they are also upwardly mobile. PMID- 21279781 TI - Sources of geographic mobility among professional workers: A multivariate analysis. AB - Using the 1960 Census of Population one-in-a-thousand sample, this study investigates determinants of geographic mobility among professional, technical, and kindred workers. Multiple regression analysis reveals that age accounts for most of the explained variance in mobility, followed by income, education, regional location, sex, family size, and marital status. Additional variables class of worker, race, nativity, professional type, size of place and industry add no significant increments to explained variance.More specifically, low income and high education stimulate mobility and increases in family size and age slacken it. Young married professionals move the most and farthest, males somewhat more than females. Mobility is greatest in the West, least in the Northeast. Age reduces or reverses contrasts between single and married, large and small families, high and low incomes, little and much education, and residents of East and West.Factor analysis suggests that migration is part of two orderly processes-occupational career mobility and family life cycle. The bearing of these findings on the relationship between geographic mobility and social integration for the middleclass in the United States is considered. PMID- 21279782 TI - Evaluating the relative accuracy and significance of net migration estimates. AB - This paper presents the elements of a theory for evaluating the quality of a set of net migration estimates. The total error in a net migration estimate is decomposed into total bias and total variation. The bias is further decomposed into three bias elements-selection bias, estimator bias, and measurement bias. Tables of bounds for measurement and estimator biases in the vital statistics and the forward survival ratio estimates of net intercensal migration are presented. Both net migration levels and net migration ratios are treated, and provision is made for both life table and census survival ratio estimates. Some of the statistical tables are applied illustratively to net migration data for Canadian counties or census divisions during the 1951-61 decade. Tests of significance and confidence intervals are indicated for net migration estimates, and the basic technical notes are presented in appendices. PMID- 21279783 TI - A design for a census information retrieval system. AB - This article explores the methodology of designing a storage and retrieval system for information on the nature and subjects of censuses published internationally over the past two decades. The essential key is neither data storage nor bibliography but an index which will tell a researcher what censuses provide information on particular population characteristics and how those characteristics are defined, mapped, cross-indexed, compared, and discussed.The index should be based on specific, inclusive, and flexible classifying terms. The authors arrive at 24 variables which are grouped on two levels-category and specific item-by the use of either main tables or indexes. The use of indexes is preferred for its reduction of clerical and computer time.In addition to the index (which should be made available in machine-readable form), the authors suggest the concomitant publication (on the basis of unified classifications) of an analysis of the relative value of different definitions of population characteristics, a merged-item vocabulary, and indexes to various censuses. Once the study has developed beyond an experimental phase limited in geographic extent and in time, the authors envision a continuing service which will provide indexes to all new censuses. PMID- 21279784 TI - A new technique for measuring household changes. AB - Because many recent policy decisions have been aimed at effecting changes in the socioeconomic characteristics of families or households, it has become necessary to isolate policy-induced changes from demographic changes in households over time. To obtain such longitudinal data, the family records from three panels of the Current Population Survey that were interviewed both in March, 1964, and March, 1965, were used in a computer record-matching operation.The resulting data confirm that approximately 20 percera of all households are mobile in the period of a year as evidenced by the nonmatched households that were found in 1964 but not present in 1965. More important, the data indicate that S percent of the nonmobile family households became individual households, or the reverse, and 15 percent of all the remaining households changed in family size. These last two statistics represent the first national estimates of gross changes in the demographic characteristics of households.In addition to data on changes in households, this relatively inexpensive method can be used to match Current Population Survey persons' records and provide longitudinal data on the persons within households. Over all, this prototype technique offers policy planners an analytical tool with the necessary statistical controls for assessing the effects of policy decisions and predicting policy success. PMID- 21279785 TI - Forensic demography and civil rights. AB - In the summer of 1965, the legislature of the state of Mississippi passed a law which required children whose parents were living in another state to pay up to $350 tuition in order to attend public school. On the belief that this law discriminated against Negroes and was therefore unconstitutional, the Department of Justice began litigation procedures to repeal it. But evidence was needed to prove that the law was in fact discriminatory. The lawyers contacted demographers at the Bureau of the Census to provide data to determine if the majority of persons affected were Negro and too poor to pay the tuition. They sought information which could tell them, ideally, how many parents of children in Mississippi had left the state and what the economic position and racial characteristics of the children were.An attempt was made to get this information from already published sources, such as census reports and other research findings. These could give a hurried impression of the situation but could not deal directly with the issue of the whereabouts of parents not living with their children, since such a question had not been asked in the 1960 Census. An additional bit of information was obtained from the NAAGP Legal Defense and Education Fund in Jackson, Mississippi, from forms showing characteristics of persons actually affected by the law. But this limited sample did not provide evidence solid enough upon which to build a case.It was decided to rely on a retabulation of 1960 Census records to describe accurately the base population from which children with parents out of state would be drawn-namely, the children not living with either parent. This showed that of all school-age children living without either parent, 82 percent are Negro. The average Negro household, which contains at least one "parentless" child, houses 6.8 persons and has an annual income of $1,429. This allows less than $250 annually per person. Tuition for just one child eats up more than one person's yearly allotment. These data showed that the law, in fact, did discriminate racially, since most of the persons affected were Negro and too poor to pay tuition.This was one instance in which demographers were able to use their special skills in implementing public policy notably, the law. PMID- 21279786 TI - A note on the time spent on the journey to work. AB - The notions that most people travel to the center of the city to work and that the farther out they live the longer it takes are only appropriate for middle sized cities. In larger urban areas, many people work outside the center, and it is the speed of travel which most affects the time that it takes to get to work. As a result, those who live in the central cities of the twelve largest metropolitan areas spend the longest time getting to work and back, because the closer one is to the center and the larger the urban area, the slower the travel speeds. PMID- 21279787 TI - Fertility in urban areas of Mexico: Implications for the theory of the demographic transition. AB - Recent investigations indicate that fertility is not universally associated with urbanization and economic development in the manner predicted by the theory of the demographic transition. It is possible, however, that these investigations only partially test the theory, for the degree of industrialization in urbanareas is rarely taken into account. Two hypotheses are tested based upon Mexican census and vital registration data for 1940-60: (a) urban fertility is inversely related to the proportion of the urban population employed in the secondary sector of the economy and (b) changes in urban fertility are inversely related to changes in the proportion of the urban population employed in the secondary sector of the economy.At each census date from 1940 to 1960, the association between urban fertility (age-standardized child-woman ratio adjusted for infant mortality) and the percent in the secondary sector is low and positive. In 1960, however, the association is negative (suggesting a possible change in the direction of the association), but city growth rates and the proportion of females married are more closely related to fertility than percent in the secondary sector. Hypothesis a, then, receives little support from the data.Much the same is true of hypothesis b. The association between changes in urban fertility and changes in the percent in the secondary sector is positive. Moreover, city growth rates and changes in the proportion literate explain more of the variation in fertility change than does the percent in the secondary sector.In addition, over-all fertility has risen since 1940, and this rise is pronounced in large urban areas. It is suggested that among certain segments of Mexican society, the response to economic development has been an increase rather than a reduction in fertility. It is further suggested that if city growth is indicative of rural-urban migration, the presence of large numbers of rural migrants in urbanareas may help to explain the decreasing size of the urban-rural fertility differential in Mexico.If this interpretation is correct, the theory of the demographic transition is in need of further modification, specification, and verification. PMID- 21279788 TI - Sample registration in India. AB - India's ad hoc sample registration scheme for obtaining current estimates of rural birth and death rates for the whole country is being implemented quite rapidly. Five states have 140 sample units, and eleven states will have from 20 to 100 units in the study depending upon the stage of implementation by March, 1967.Essential elements of the project for each unit are: (1) continuous registration of vital events by a paid part-time local enumerator, (2) a six month household survey to detect births and deaths which occurred during the previous six months, and (3) matching events from registration and surveys and field recheck of unmatched events to obtain the "best" count of real number of events. Preliminary results in a non-random sample indicate that the crude birth and death rates are around 37.1 and 15.7 per 1,000, respectively, for India's rural population, but these probably will be found to be on the low side.Most of the problems of implementation are operational or administrative rather than statistical: (1) For various reasons, some states are slow in agreeing to assume financial and other responsibilities for the scheme. (2) In many states, even after the scheme has been accepted, there are delays in recruiting the staff, training, and so forth. (3) The most serious problem in the whole project is maintaining control of field operations well enough at each stage to insure that prescribed instructions and methodology are being followed.Experience in India indicates that staged implementation of such projects is highly desirable when trained staff are limited. There still are a number of methodological problems which must be tested as the sample registration evolves. Sample registration is one of the first steps in the Indian program to. develop an adequate vital statistics system. Exploratory studies to measure completeness of civil registration are being done now in an effort to develop means of using civil registration data alone for measurement of vital rates. PMID- 21279789 TI - The growth of American families studies an assessment of significance. AB - This is a review focused mainly upon the book Fertility and Family Planning in the United States, by Pascal K. Whelpton, Arthur A. Campbell, and John E. Patterson, published by Princeton University Press in 1966, and representing the results of the second GAF survey (1960). The initial GAF survey was conducted in 1955 and resulted in the book Family Planning, Sterility, and Population Growth, by Ronald Freedman, Pascal K. Whelpton, and Arthur A. Campbell, published by McGraw-Hill in 1958.A basic purpose of the GAF studies, as contrived by Whelpton, was that of trying to improve the bases for population estimates by learning from young women themselves the number of children that they expected to have altogether and during the next five years. By repeating the study five years later, it was hoped to test the validity of replies on expectations by comparing them with subsequent performance. This involved interviewing not the same women but the same types of women in 1955 and 1960.The GAF studies have indicated the usefulness of questions on number of children expected. They suggest that the replies of 1955 have low predictive value for individual behavior but high predictive value for group behavior. They have provided invaluable data on other aspects of fertility unavailable from official sources, such as family planning, fecundity, and the influence of religion. The chief inadequacies of the GAF studies have been those associated with small numbers. Moreover, definitive comparisons of expectations with performance would seem to require longitudinal studies of the same women rather than periodic studies of the same types of women. On the other hand, the latter type of design doubtless is preferable for other purposes.Besides the yield of new data on fertility, the GAF studies have been significant in that one government agency provided the funds for the National Fertility Survey of 1965, which was essentially a third round of the GAF studies, and another government agency is considering the institution of regular surveys of the GAF type in order to provide a wider scope of data relating to fertility. The volume under review is at once a fitting living memorial to the senior author and the Scripps Foundation, a credit to the coauthors, and a worthy model for future studies. PMID- 21279791 TI - Selectivity of migrants to a metropolis in a developing country: a mexican case study. AB - A proper evaluation of native-migrant differences requires information on migrant selectivity. Are migrants positively or negatively selective or are they representative of the populations from which they originate? This question was posed for a sample of male migrants to Monterrey, Mexico, a rapidly growing metropolis in a developing country. A comparison was made between the characteristics of migrants and census information for the origin populations for 1940 and 1960. Overall, in terms of education and occupational position, migrants are positively selective. However, using three time-of-arrival cohorts, it is shown that migrants have become less selective over time. There has been a shift from a "pioneer" to a "mass" pattern of migration, with the latter group more closely approximating the characteristics of the origin population. Besides having lower educational and skill levels, the "mass" migrants are more likely to be made up of married men and their families. To the extent that the Monterrey pattern will be encountered in other large and fast-growing urban areas in Latin America, it suggests that the assimilation of migrants in these places will become more rather than less difficult. PMID- 21279792 TI - Demographic responses and population change. AB - Most Western societies have gone through a process of population change during the past 100-150 years. One important aspect is the socalled demographic transition: the shift from high to low birth and death rates, and accelerated growth resulting from the lag between falling mortality and falling fertility, in national populations. Equally important has been the "rural-to-urban" transition, which involved the migration of millions of people from rural areas. It is hypothesized, following the suggestion of Davis (Theory of the Multi-Phasic Demographic Response), that the adjustment in reproductive behavior made by a community in response to a rising "strain," such as that resulting from higher natural increase, is likely to differ depending upon the ease with which the community can relieve the strain through out migration. Relationships among such characteristics of modernization as intensity of industrialization, speed of urbanization, structural changes in the agricultural system, and declining fertility are implied. Case studies of England and Sweden lend support to the hypothesis: more rapid urban-industrial development, larger-scale movement from rural areas, and a delayed decline in the rural birth rate distinguish the English transition. PMID- 21279793 TI - Marriage patterns and cumulative fertility in west malaysia: 1966-1967. AB - Differentials in age at first marriage and being married more than once are discussed for a probability sample of West Malaysian currently married women 15 44 years of age. Both marriage ages and the incidence of multiple marriages vary greatly by race, place of current residence, wife's education, and husband's occupation; and the marriage variables are shown to have significant effects on the cumulative fertility of West Malaysian women. Early marriage leads to higher cumulative fertility and multiple marriages lead to lower cumulative fertility. Since the social groups with the highest proportions of early marriages are also those with the highest incidence of multiple marriages, the marriage variables explain some but not all of the variance in cumulative fertility for West Malaysian social groups. After adjustment for the effects of the marriage variables, rural Indian or Pakistani women still have the highest cumulative fertility and urban Chinese women with more than five years of schooling still have the lowest cumulative fertility. PMID- 21279794 TI - Sample registration in gujarat, india. AB - Since October, 1965, births and deaths in rural Gujarat State, India, have been recorded under two independent systems in a random sample of units. First, a part time local "registrar" is appointed in each sample unit (village or segment thereof) who: prepares a house list; conducts a baseline survey showing the individuals in each household; and maintains a list of the vital events reported by informants whom he contacts fortnightly. Second, a staff member at the rural health centre is assigned part-time supervisory and survey duties: to check the initial listings of the registrar; thereafter, to inspect the registrar's records at least quarterly; and to conduct a household survey each six months, updating the household register and recording births and deaths independently. The registrar's list is sent to the district office immediately before the survey, where it is matched with the survey list forwarded by the local supervisor. A list of unmatched events is returned to the supervisor who with the registrar revisits households to resolve the discrepancies. Under-registration is estimated to be 13 to 20 percent by the registrar method, 8 to 17 percent by the survey method. The birth rate is estimated to be about 44 and the death rate about 19. PMID- 21279795 TI - Comparison of information on death certificates and matching 1960 census records: age, marital status, race, nativity and country of origin. AB - A sample of death certificates matched with 1960 Census records permitted comparison of response data for items asked on both records. Estimates of bias in death rates which are based on information from the two records are derived from the comparison data. Most of the comparisons yielded small discrepancies of inconsequential effect on the mortality rates. Some large inconsistencies, however, of potentially serious impact on the death rates were observed. The comparisons are examined and the implications of the results for the relevant mortality rates are discussed. In addition, age-specific death rates "corrected" for the disparities found in the age information on the two records are presented. PMID- 21279796 TI - Registration completeness and international comparisons of infant mortality. AB - The physical development of the live born infant is the single most important variable governing its survival: infant mortality among those weighing 2,500 grams (5 1/2 pounds) or less at birth is 17 times the mortality among those weighing more than 2,500 grams at birth. The variation in mortality according to birth weight (or gestation) is greater than for subclasses of color, sex, maternal age, or birth order. Infant mortality in the United States is significantly higher than in a number of other countries e.g., Sweden, Netherlands, Norway. The difference is thought, by some, to be due to underregistration of low birth weight infants in other countries. In this paper, distributions of live births by birth weight for Denmark, England and Wales, New Zealand, and the United States, and infant mortality data for Denmark and the United States are examined. The data do not support a hypothesis of gross underregistration of live born infants in other countries. The results indicate that some index of physical development (birth weight, gestation, or a combination of both) should be included in any appraisal of infant mortality. PMID- 21279797 TI - Fertility planning status: united states, 1965. AB - Data concerning the planning circumstances of the interval preceding each pregnancy, collected from a national sample of 4810 married women, are used to establish the fertility planning status of each respondent as one of five classes: (1) never-pregnant; (2) number failure; (3) at least one timing failure; (4) at least one timing success; (5) neither success nor failure. For the ever pregnant women who intended no more children, 32 percent of the exposed were number failures and 62 percent of the rest were timing failures. For the ever pregnant women who intended more children, 67 percent of the exposed were timing failures. Women not exposed to the risk of timing failure because they claimed to want all of their pregnancies as soon as possible had similar characteristics to women reporting failures; accordingly the reliability of their reports is suspect. The probabilities of failure are well-patterned by race, religion and education: higher for Blacks than for Whites; within the latter, higher for Catholics than for Non-Catholics; and inversely related to education, except among White Catholics. Although uniformly high, the proportions classified as failures are probably under-estimates of the true values for completed families, because of misreporting and continuing exposure to risk, subsequent to interview. PMID- 21279798 TI - The prediction of completed fertility. AB - There has been considerable interest in the relation between familysize desires and completed fertility. Longitudinal data from the Princeton Fertility Study provide a unique opportunity to compare the number of children desired after the birth of a second child to the size of completed families. The average number of children desired by women after the birth of their second child predicts very well the average size of their completed families. The average family size desired at the first interview and average estimated completed family size some eight years later are identical for the total sample, and vary hardly at all within religious or education subgroups. One-third of the variance in the completed fertility of couples is "explained" by wife's family-size desires and the proportion of explained variance increases to two-fifths when we include the husband's first interview desires and the interval between marriage and second birth. Yet in spite of the relatively high correlation between desires and achievement, only 41 percent of these women achieved exactly the number of children they desired at the first interview, while 14 percent had two children more or fewer than originally desired. Nevertheless, data on contraceptive efficiency indicate that desires after the birth of the second child constitute meaningful goals in terms of which the respondents regulate their subsequent behavior-efficacy of contraceptive practice shows substantial improvement after the desired number has been achieved. PMID- 21279799 TI - Southern negro migration: social and economic components of an ecological model. AB - This paper considers social and economic correlates of age-specific 1950-1960 net migration of Negro males from a sample of 150 southern counties. A model is developed with five components: (1) economic activity and urbanization, (2) white traditionalism, (3) demographic and ecological pressure, (4) nonwhite poverty, and (5) nonwhite home ownership. The dominant migration forces, as evidenced by correlations with component indicator variables, are the "pull" factor of change in nonprimary industrial employment, the "push" factor of population pressure in the nonwhite rural-farm sector, and the "push" of white traditionalism. However, the significance of model components varied when analyzed along age and industrial development continua. In the younger age groupings, industrial employment growth, population pressure, and white traditionalism were dominant migratory forces while in the older age groupings, industrial employment growth and non-home ownership were most significant. For Negro males in agricultural counties, the major migration propellents appeared to be the "push" of population pressure in the rural farm sector and non-ownership of homes. On the other hand the statistical explanation for Negro migration in more industrialized southern counties rests primarily with the "pull" of increased employment in non-primary industries along with population pressure. The importance of the findings for migration theory is discussed. PMID- 21279800 TI - Patterns of residence in poona, India, by caste and religion: 1822-1965. AB - An analysis of the residential distribution of caste and religious groups in Poona (India) over the past century and a half shows distinctive patterns of segregation and centralization that have largely remained unchanged despite the city's growth and development. The upper castes are residentially centralized and the lower castes are decentralized in Poona. Such a centralization of the elite has been observed in most other past and present cities of the world, although the pattern is less common in the contemporary United States. The Jews and Parsees, and the Christians, tend to be highly segregated and decentralized in Poona. However, Negroes in large American cities are generally more highly segregated residentially than the Jews, Parsees, Christians, and even the depressed and untouchable castes in Poona. The American cities show an average degree of segregation of the foreign-born white ethnic groups, and of the native whites of foreign or mixed parentage, from the native whites that is as great, if not greater, than the mean extent of segregation of caste groups in this Indian city. PMID- 21279801 TI - Erratum to: The Applicability of the Burgess Zonal Hypothesis to Urban Canada. PMID- 21279806 TI - Kinetic model of atomic and molecular emissions in laser-induced breakdown spectroscopy of organic compounds. AB - A kinetic model previously developed to predict the relative intensities of atomic emission lines in laser-induced breakdown spectroscopy has been extended to include processes related to CN and C(2) molecular emissions. Simulations with this model were performed to predict the relative excited-state populations. The results from the simulations are compared with experimentally determined excited state populations from 1,064 nm laser irradiation of organic residues on aluminum foil. The model reasonably predicts the relative intensity of the molecular emissions. Significantly, the model reproduces the vastly different temporal profiles of the atomic and molecular emissions. The latter are found to extend to much longer times after the laser pulse, and this appears to be due to the increasing concentration of the molecules versus time. From the simulations, the important processes affecting the CN and C(2) concentrations are identified. PMID- 21279807 TI - Classification and identification of organic binding media in artworks by means of Fourier transform infrared spectroscopy and principal component analysis. AB - Fourier transform infrared spectroscopy is a powerful analytical technique to study organic materials. However, in Cultural Heritage, since the sample under analysis is always a complicated matrix of several materials, data analysis performed through peak-by-peak comparisons of sample spectra with those of standard compounds is a tedious method that does not always provide good results. To overcome this problem, a chemometric model based on principal component analysis was developed to classify and identify organic binding media in artworks. The model allows the differentiation of five families of binders: drying oils, waxes, proteins, gums, and resins, taking into account the absorption bands in two characteristic spectral windows: C-H stretching and carbonyl band. This new methodology was applied in the characterization of binders in three kinds of artworks: papers of historical, archeological, and artistic value, easel paintings, and polychromed stone-based sculptures. PMID- 21279808 TI - Role of Th17 cells and IL-17 in lung transplant rejection. AB - In the past decade, advances in immunology have led to the recognition that T cell differentiation is not simply Th1 or Th2 but involves differentiation to other subsets, such as T regulatory cells, T follicular helper cells, and Th17 cells. Th17 cells, characterized by production of IL-17, IL-22, and IL-21, have been implicated in the pathogenesis of autoimmune diseases, like rheumatoid arthritis and multiple sclerosis, but also play an important role in host defense and mucosal immunity. IL-17, with its pleiotropic effects on stromal cells, as well as hematopoietic cells, has long been recognized as a possible mediator of rejection after lung transplantation. Recent data have implicated IL-17 and Th17 cells in the development of autoimmunity and chronic rejection after lung transplantation in both animal models and humans. In this review, we will discuss the current data on Th17 and the prospects for the future for lung transplantation. PMID- 21279809 TI - Prognostic significance of autoimmunity during treatment of melanoma with interferon. AB - Since the pivotal cooperative group trials in the 1980's-90's,, high-dose interferon (HDI) has been the standard of adjuvant therapy. Despite multiple other trials evaluating potential new therapies in melanoma, HDI remains the only FDA-approved therapy for stage IIB and III melanoma. Initial reports from the more recent phase III international trials of modifications of the original HDI regimen linked the appearance of autoimmunity with improved outcomes of disease. Trials of high-dose interleukin-2, many years earlier, reported anecdotal observations that were consistent with the hypothesis that autoimmunity and clinical benefit of immunotherapies of melanoma are linked with one another. The only prospectively conducted study examining the appearance of clinical and laboratory evidence of autoimmunity during HDI therapy was published by Gogas and colleagues, demonstrating statistically significant impact on relapse-free survival and overall survival. Retrospectively conducted studies of different intermediate dosage regimens of interferon (IFN) have not fully confirmed the linkage of serological evidence of autoimmunity and improved survival outcomes. With the emergence of new immunotherapies in treatment of melanoma, this review highlights the importance of autoimmunity for future applications in melanoma and reviews significant differences of past studies evaluating the appearance of autoimmunity during IFN therapy in high-risk melanoma. PMID- 21279810 TI - KIM-1 and NGAL: new markers of obstructive nephropathy. AB - Congenital obstructive nephropathy is the primary cause of chronic renal failure in children. Rapid diagnosis and initiation of the treatment are vital to preserve function and/or to slow down renal injury. The aim of our study was to determine whether urinary (u) kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) may be useful non-invasive biomarkers in children with congenital hydronephrosis (HN) caused by ureteropelvic junction obstruction. The study cohort consisted of 20 children with severe HN who required surgery (median age 2.16 years) and two control groups (control group 1: 20 patients with mild, non-obstructive HN; control group 2: 25 healthy children). All of the children had normal renal function. Immunoenzymatic ELISA commercial kits were used to measure uKIM-1 and uNGAL concentrations. The preoperative median uKIM-1/creatinine (cr.) and uNGAL levels were significantly greater in the children with severe HN than in both control groups. Three months after surgery, uNGAL had decreased significantly (p<0.05) in the children with severe HN, but was still higher than that in control group 2 children (p<0.05). Receiver operator characteristic analyses revealed a good diagnostic profile for uKIM-1 and uNGAL in terms of identifying a differential renal function of <40% in HN patients (area under the curve (AUC) 0.8 and 0.814, respectively) and <45% in all examined children (AUC 0.779 and 0.868, respectively). Based on these results, we suggest that increasing uNGAL and uKIM-1 levels are associated with worsening obstruction. Further studies are required to confirm a potential application of uKIM-1 and uNGAL as useful biomarkers for the diagnosis and progression of chronic kidney disease. PMID- 21279811 TI - Liver fibrosis in recessive multicystic kidney diseases: transient elastography for early detection. AB - Cystic renal diseases are characterized by intrarenal cysts of different size and number. Further important diagnostic criteria include, e.g., liver fibrosis. The latter represents a significant cause of morbidity and mortality in autosomal recessive polycystic kidney disease (ARPKD), whereas patients with autosomal dominant polycystic kidney disease (ADPKD) can develop hepatic cysts without fibrosis. We report the use of transient elastography [FibroScan(r), (FS)] for early and noninvasive detection of increased liver stiffness as marker of liver fibrosis. Compared with matched healthy controls, ADPKD patients (n = 7) showed no significant difference in liver stiffness (5.3 kPa vs. 4.5 kPa; ns). ARPKD patients (n = 7) had significantly increased median liver stiffness compared with controls (12.0 kPa vs. 4.5 kPa, p = 0.002) and ADPKD patients (12.0 kPa vs. 5.3 kPa, p = 0.002). Conventional ultrasound revealed evidence of liver fibrosis in only four of seven ARPKD patients (57%) compared with 100% detection by FS. Additional laboratory examinations showed no pathologic liver parameters. In conclusion, our data found FS to be a valuable, sensitive, and noninvasive new tool for early evaluation of liver fibrosis in cystic kidney diseases. This could facilitate diagnosis, monitoring, and management of liver involvement in ARPKD or any other cystic kidney disease. PMID- 21279812 TI - A rare case of malignant-phase hypertension with pulmonary alveolar hemorrhage. AB - Malignant-phase hypertension is characterized clinically by severe accelerating hypertension with neuroretinopathy or papilledema and by evidence of renal damage. A Japanese male in his early thirties presented with hemoptysis and general fatigue. He had a 5-year history of hypertension, but had not received any treatment. His blood pressure was 290/150 mmHg and his serum creatinine level was 8.24 mg/dL. Chest X-rays and computed tomography scans of the chest revealed a pulmonary alveolar hemorrhage. He was suspected of having vasculitis syndrome or Goodpasture's syndrome, but his renal biopsy specimen showed malignant nephrosclerosis. Myeloperoxidase antineutrophil cytoplasmic antibody (ANCA), proteinase-3 ANCA and antiglomerular basement membrane antibody were negative. He was treated with a calcium antagonist and a beta-blocker, followed by an angiotensin-converting enzyme inhibitor. After the administration of the beta blocker, his blood pressure decreased and his renal function gradually improved. This is a rare case of malignant-phase hypertension with pulmonary alveolar hemorrhage; this condition should be considered in the differential diagnosis in order to avoid unnecessary treatment such as immunosuppressive therapy. PMID- 21279813 TI - The extreme dwarf phenotype of the GA-sensitive mutant of sunflower, dwarf2, is generated by a deletion in the ent-kaurenoic acid oxidase1 (HaKAO1) gene sequence. AB - A dwarf mutant, dw arf 2 (dw2), was isolated from sunflower (Helianthus annuus). The most obvious alterations of dw2 plants were the lack of stem growth, reduced size of leaves, petioles and flower organs, retarded flower development. Pollen and ovules were produced but the filaments failed to extrude the anthers from the corolla. The dw2 phenotype was mainly because of reduced cell size. In dw2 leaves, the dark-green color was not so much due to higher pigment content, but was correlated with a changed leaf morphology. The mutant responded to the application of bioactive gibberellins (GAs). The levels of ent-7alpha hydroxykaurenoic acid, GA(19), GA(20) and GA(1) in dw2 seedlings were severely decreased relative to those in its wild type (WT). ent-Kaurenoic acid was actively converted to ent-7alpha-hydroxykaurenoic acid in WT plants but quite poorly in dw2 plants. All together these data suggested that the dw2 mutation severely reduced the flux through the biosynthetic pathway leading to active GAs by hampering the conversion of ent-kaurenoic acid to GA(12). Two ent-kaurenoic acid oxidase (KAO) genes were identified. HaKAO1 was expressed everywhere in sunflower organs, while HaKAO2 was mainly expressed in roots. We demonstrated that a DNA deletion in HaKAO1 of dw2 generated aberrant mRNA-splicing, causing a premature stop codon in the amino acid sequence. In dw2 calli, Agrobacterium mediated transfer of WT HaKAO1 cDNA restored the WT endogenous levels of GAs. In segregating BC(1) progeny, the deletion co-segregated with the dwarf phenotype. The deletion was generated near to a breakpoint of a more complex chromosome rearrangement. PMID- 21279814 TI - Streptococcus uberis-specific T cells are present in mammary gland secretions of cows and can be activated to kill S. uberis. AB - The presence, phenotype and function of Streptococcus uberis-specific T cells in the mammary gland secretion (MGS) and blood of cows exposed to S. uberis were assessed. MGS T cells in the udder were purified and incubated with autologous blood monocytes as antigen-presenting cells (APC). Most cows, irrespective of prior S. uberis infection status and lactation status, were shown to have S. uberis-specific T cells both in MGS and in the blood. When cells from a subgroup of cows were studied, it was found that the S. uberis-specific T cells produced high levels of interferon-gamma (IFN-gamma), but low levels of interleukin-10 (IL 10). A high percentage of responding T cells were of the CD8(+) memory (CD45RO) subset. T cells from the MGS specific for S. uberis were propagated from animals during the drying off period and expanded in vitro using interleukin-2 (IL-2) and S. uberis antigens. This led to the accumulation of T cells of the CD8(+) subset bearing memory cell markers (CD45A(-), CD45RO(+)), which released high levels of IFN-gamma. Four of the five T cell lines derived from the MGS of three animals had substantial direct killing activity towards S. uberis in vitro. It is concluded that there is an emergence of S. uberis-specific bactericidal T cells in the MGS of cows after infection or environmental exposure to S. uberis. Vaccines aimed at activating and expanding this T cell population in the mammary glands of cattle may offer an avenue for the prevention of mastitis caused by S. uberis. PMID- 21279815 TI - Patterns of progression in malignant glioma following anti-VEGF therapy: perceptions and evidence. AB - Antiangiogenic treatment has recently become an integral part of modern cancer therapy targeting the vasculature of numerous aggressive malignancies including glioblastoma. There is preclinical evidence that antiangiogenic therapies promote glioma cell invasiveness. In clinical series, upon progression on antiangiogenic therapy with the vascular endothelial growth factor-directed antibody bevacizumab (BEV), glioblastoma has been reported to display a more infiltrative pattern of recurrence. This distant spread at recurrence or progression and a gliomatosis cerebri-like growth pattern is best detectable on fluid-attenuated inversion recovery MRI. The frequency of up to 20% to 30% of such a pattern in BEV-treated patients is higher than expected to occur without BEV. Older reports and common clinical knowledge estimate the frequency of diffuse or distant spread in recurrent glioblastoma at 10%. This observation stimulated two streams of research. One is to overcome this often insidious adverse effect of antiangiogenic treatment, to optimize antiangiogenic therapies and to face this major challenge, integrating antiangiogenic with anti-invasive mechanisms into one combined treatment concept. The second is questioning a specific property of antiangiogenic therapy to induce diffuse or distant spread. Here, alternative hypotheses of increased awareness and better imaging as well as invasiveness being part of the natural course of the disease have been tested. Without doubt, migration and invasiveness are major obstacles to successful glioma therapy, notably local therapies, both in the natural course of the disease and in the concept of "evasive resistance." However, clinical analyses of case series, matched pairs analyses, and follow-up on the BRAIN trial (A Study to Evaluate Bevacizumab Alone or in Combination with Irinotecan for Treatment of Glioblastoma Multiforme), which led to accelerated approval of BEV for recurrent glioblastoma in the United States, have not supported a specific propensity of BEV to induce diffuse growth or distant spread at recurrence. PMID- 21279816 TI - Ribosome defects in disorders of erythropoiesis. AB - Over the past decade, genetic lesions that cause ribosome dysfunction have been identified in both congenital and acquired human disorders. These discoveries have established a new category of disorders, known as ribosomopathies, in which the primary pathophysiology is related to impaired ribosome function. The protoptypical disorders are Diamond-Blackfan anemia, a congenital bone marrow failure syndrome, and the 5q- syndrome, a subtype of myelodysplastic syndrome. In both of these disorders, impaired ribosome function causes a severe macrocytic anemia. In this review, we will discuss the evidence that defects in ribosomal biogenesis cause the hematologic phenotype of Diamond-Blackfan anemia and the 5q- syndrome. We will also explore the potential mechanisms by which a ribosomal defect, which would be expected to have widespread consequences, may lead to specific defects in erythropoiesis. PMID- 21279817 TI - Transient inflammatory reaction during lenalidomide plus reduced-dose dexamethasone therapy in two patients with relapsed multiple myeloma. PMID- 21279818 TI - Transcriptional regulation by GATA1 and GATA2 during erythropoiesis. AB - The transcription factor GATA1 regulates multiple genes in erythroid lineage cells. However, the means by which GATA1 regulates the expression of target genes during erythropoiesis remains to be elucidated. Three mechanisms have been postulated for the regulation of genes by GATA1. First, individual target genes may have multiple discrete thresholds for cellular GATA1. GATA1 has a dynamic expression profile during erythropoiesis, thus the expression of a set of GATA1 target genes may be triggered at a given stage of differentiation by cellular GATA1. Second, the expression of GATA1 target genes may be modified, at least in part, by GATA2 occupying the GATA-binding motifs. GATA2 is expressed earlier in erythropoiesis than GATA1, and prior GATA2 binding may afford GATA1 access to GATA motifs through epigenetic remodeling and thus facilitate target gene expression. Third, other regulatory molecules specific to each target gene may function cooperatively with GATA1. If GATA1 is required for the expression of such cofactors, a regulatory network will be formed and relevant gene expression will be delayed. We propose that the stage-specific regulation of erythroid genes by GATA1 is tightly controlled through a combination of these mechanisms in vivo. PMID- 21279819 TI - Successful treatment with nilotinib after imatinib failure in a CML patient with a four-way Ph chromosome translocation and point mutations in BCR/ABL gene. AB - Chronic myelogenous leukemia (CML) is characterized by Philadelphia (Ph) chromosome with a chimeric gene BCR-ABL created by reciprocal t(9:22) (q34;q11) translocation. Variant Ph chromosome translocations involving chromosomes other than 9 and 22 are found in 5-10% of CML cases. We here report a CML patient who carries a four-way Ph chromosome translocation, t(9;22;15;19) (q34;q11;q15;q13). The patient was diagnosed in 1997 and initially treated with hydroxyurea. In 2002, treatment with imatinib, a selective BCR-ABL tyrosine kinase inhibitor (TKI), was started but Ph-positive chromosomes remained at the levels of 42-65%, indicating imatinib failure. In 2006, the point mutations of F359I and L387M were detected in BCR/ABL gene, which may be related to imatinib failure. Treatment with nilotinib, a TKI with high target specificity, was then started which resulted in durable major molecular response. Administration of nilotinib offered an effective treatment in a CML patient with variant Ph chromosome translocations and BCR-ABL point mutations after imatinib failure. PMID- 21279821 TI - Surgical treatment of gastrointestinal neuroendocrine tumors. AB - INTRODUCTION: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are uncommon but clinically challenging and fascinating tumors. GEP-NETs present as either functional or as nonfunctional tumors. Functional tumors are commonly associated with a specific hormonal syndrome directly related to a hormone secreted by the tumor, like gastrinomas with a Zollinger-Ellison syndrome or carcinoid syndrome in patients with neuroendocrine tumors (NET) of the ileum. Nonfunctional tumors do not secrete a hormone resulting in a clinical syndrome. METHODS: The natural course of GEP-NETs is highly variable. Small, benign neoplasms such as 90% of all insulinomas or gastric endocrine tumors type 1 are readily curable by surgical resection; however, most other GEP-NETs have a much less favorable prognosis. Patients with completely resected tumors generally have a good prognosis, and an aggressive surgical approach in patients with advanced disease may also prolong survival. CONCLUSIONS: This review focuses on the current standards of surgical treatment of gastric endocrine tumors, NETs of the pancreas (PNET) and NETs of the ileum. Although the evidence level is low in many instances due to the lack of randomized controlled trials, important treatment recommendations can be given. PMID- 21279822 TI - Chronological evaluation of inflammatory mediators during peritoneal adhesion formation using a rat model. AB - PURPOSE: The inflammatory response to peritoneal injury is considered to be of particular importance in adhesion formation. The aim of this study was to investigate the dynamics of inflammatory mediators in peritoneal adhesions. METHODS: In 60 male rats, a peritoneal defect was performed using a standardized cecal abrasion model. On days 3, 5, 14, 30, 60, and 90, ten animals were sacrificed. The expression of five integral mediators for the cellular immune response (macrophages, T lymphocytes), inflammation (COX-2), cell differentiation, and proliferation (beta-catenin, c-myc) in visceral and parietal adhesions were analyzed. RESULTS: A distinct infiltration of macrophages was observed in all animals up to the 90th postoperative day with a peak on day 3 for visceral adhesions (26.3 +/- 5.6%) and on day 14 for parietal adhesions (5.1 +/- 1.1%). Compared to parietal adhesions, macrophage levels were significantly higher on day 3 (p = 0.001) and 5 (p = 0.002) but significantly lower on days 30, 60, and 90 in visceral adhesions (p = 0.041; p = 0.001; p = 0.017). T lymphocytes were detected over time with the highest levels on day 3 (visceral 4.0 +/- 0.7%; parietal 6.7 +/- 2.9%). High levels of COX-2 expression could be detected for the whole observation period. Positive expression of both beta-catenin and c-myc was detected in persistent adhesions; however, no expression of c-myc was observed in parietal adhesions. CONCLUSIONS: The inflammatory reaction in adhesions is not limited to the early postoperative phase. Macrophages may be fundamental in triggering adhesions, and the presence of T cells indicates an additional role of the adoptive immune system. Identification of chemokines and chemokine receptors that trigger the cellular immune response might be a potential option to minimize adhesion formation. PMID- 21279823 TI - Microsatellite standardization and evaluation of genotyping error in a large multi-partner research programme for conservation of Atlantic salmon (Salmo salar L.). AB - Microsatellite genotyping is a common DNA characterization technique in population, ecological and evolutionary genetics research. Since different alleles are sized relative to internal size-standards, different laboratories must calibrate and standardize allelic designations when exchanging data. This interchange of microsatellite data can often prove problematic. Here, 16 microsatellite loci were calibrated and standardized for the Atlantic salmon, Salmo salar, across 12 laboratories. Although inconsistencies were observed, particularly due to differences between migration of DNA fragments and actual allelic size ('size shifts'), inter-laboratory calibration was successful. Standardization also allowed an assessment of the degree and partitioning of genotyping error. Notably, the global allelic error rate was reduced from 0.05 +/ 0.01 prior to calibration to 0.01 +/- 0.002 post-calibration. Most errors were found to occur during analysis (i.e. when size-calling alleles; the mean proportion of all errors that were analytical errors across loci was 0.58 after calibration). No evidence was found of an association between the degree of error and allelic size range of a locus, number of alleles, nor repeat type, nor was there evidence that genotyping errors were more prevalent when a laboratory analyzed samples outside of the usual geographic area they encounter. The microsatellite calibration between laboratories presented here will be especially important for genetic assignment of marine-caught Atlantic salmon, enabling analysis of marine mortality, a major factor in the observed declines of this highly valued species. PMID- 21279857 TI - Lost in translation: the impact of publication language on citation frequency in the scientific dental literature. AB - PRINCIPLES: Citation metrics are commonly used as a proxy for scientific merit and relevance. Papers published in English, however, may exhibit a higher citation frequency than research articles published in other languages, though this issue has not yet been investigated from a Swiss perspective where English is not the native language. METHODS: To assess the impact of publication language on citation frequency we focused on oral surgery papers indexed in PubMed MEDLINE that were published by Swiss Dental Schools between 2002 and 2007. Citation frequency of research papers was extracted from the Institute for Scientific Information (ISI) and Google Scholar database. A univariate and multivariate logistic regression model was used to assess the impact of publication language (English versus German/French) on citation frequency, adjusted for journal impact factor, number of authors and research topic. RESULTS: Papers published in English showed a 6 (ISI database) and 7 (Google Scholar) times higher odds for being cited than research articles published in German or French. CONCLUSIONS: Our results suggest that publication language substantially influences the citation frequency of a research paper. Researchers should publish their work in English to render them accessible to the international scientific community. PMID- 21279858 TI - The FIRE project: a milestone for research in primary care in Switzerland. AB - QUESTIONS UNDER STUDY/PRINCIPLES: Research is scarce where most patients are found. One of the main reasons is the difficulty in extracting data from traditionally conducted paper-based medical records. Thus, until now most existing patient records have originated from invoicing-tools. Endeavours to truly reflect a doctor's consultation have been rare. FIRE (Family Medicine ICPC Research using Electronic Medical Records) is an ambitious project to establish a proper knowledge base in primary care by using the ongoing implementation of EPR (electronic patient records). FIRE will enable many questions on epidemiology and performance within the PC (primary care) setting to be answered. METHODS: GPs (general practitioners) throughout Switzerland working with EPR were eligible for participation. Workshops were held to train and standardise ICPC-coding (International Classification of Primary Care), a classification system especially designed for the PC-setting. The recorded data included administrative information on the GP and patient, vital signs, ICPC codes, laboratory analysis and medication. Data exporter software was developed for extracting anonymised data automatically from the EPR onto a database for further statistical analysis. RESULTS: From 1.1.2009 until the beginning of April 2010 24 GPs were successfully recruited providing standardised information on 127,922 consultations in 29,398 patients and 159,956 medical problems according to the ICPC-2 classification. CONCLUSION: The project proves the feasibility of standardised ongoing collection of research data embedded in routine clinical practice. FIRE provides a unique database for research in PC and highlights the potential of broad implementation of EPR in a PC-setting. Studies resulting from the ongoing project have the potential to assess the quality of care provided by GP's. PMID- 21279859 TI - Risk factors for a first epileptic seizure symptomatic of brain tumour or brain vascular malformation. A case control study. AB - PRINCIPLES: The risk of seizures increases in patients with brain tumours (BT) and brain vascular malformations (BVM), but not all risk factors are known. We aimed to identify factors that increase the risk of a first seizure in patients with BT or BVM. METHODS: Multicentre case-control study; 102 cases with a first seizure as a presenting symptom of BT or BVM; 121 hospital controls with BT or BVM, but without seizures, matched by centre, gender and age. RESULTS: In the univariate analysis, the risk of first seizure (Odds Ratio, 95% Confidence Limits) was 6.4 (2.3-17.6) for supratentorial lesions, 4.7 (2.4-9.3) for cortical involvement, 2.5 (1.0-7.7) for family history of seizures, and 2.1 (1.2-4.1) for frontal location. The types of lesion with higher risk were low grade glioma (4.7; 1.7-13.9) and cavernous malformations (13.2; 2.1-58.0). After multivariate analysis, including all the imaging characteristics and family history, the strongest independent predictors of first seizure were cortical involvement (OR 4.0; 2.0-8.1) and type of lesion (low grade glioma: 4.0; 1.3-12.8; cavernous malformations: 12.6 (1.5-103.5). CONCLUSIONS: Cortical involvement and type of lesion are the independent risk factors for a first-ever seizure as a presenting symptom of BT or BVM. PMID- 21279860 TI - Chemical and antimicrobial treatments change the viscoelastic properties of bacterial biofilms. AB - Changes in the viscoelastic material properties of bacterial biofilms resulting from chemical and antimicrobial treatments were measured by rheometry. Colony biofilms of Staphylococcus epidermidis or a mucoid Pseudomonas aeruginosa were subjected to a classical creep test performed using a parallel plate rheometer. Data were fit to the 4-parameter Burger model to quantify the material properties. Biofilms were exposed to the chloride salts of several common mono-, di-, and tri- valent cations, and to urea, industrial biocides, and antibiotics. Many of these treatments resulted in statistically significant alterations in the material properties of the biofilm. Multivalent cations stiffened the P. aeruginosa biofilm, while ciprofloxacin and glutaraldehyde weakened it. Urea, rifampin, and a quaternary ammonium biocide weakened the S. epidermidis biofilm. In general, there was no correspondence between the responses of the two different types of biofilms to a particular treatment. These results underscore the distinction between the killing power of an antimicrobial agent and its ability to alter biofilm mechanical properties and thereby influence biofilm removal. Understanding biofilm rheology and how it is affected by chemical treatment could lead to improvements in biofilm control. PMID- 21279861 TI - Prevention of Pseudomonas aeruginosa adhesion by electric currents. AB - The process of controlling bacterial adhesion using an electric current deserves attention because of its ease of automation and environmentally friendly nature. This study investigated the role of electric currents (negative, positive, alternating) for preventing adhesion of Pseudomonas aeruginosa and achieving bacterial inactivation. Indium tin oxide (ITO) film was used as a working electrode to observe adhesion and inactivation under electric polarization. Electric current types were classified into negative, positive, and alternating current. The working electrode acted as a cathode or anode by applying a negative or positive current, and an alternating current indicates that the negative current was combined sequentially with the positive current. The numbers of adhered cells were compared under a flow condition, and the in situ behavior of the bacterial cells and the extent of their inactivation were also investigated using time-lapse recording and live/dead staining, respectively. The application of a negative current prevented bacterial adhesion significantly (~81% at 15.0 MUA cm(-2)). The positive current did not significantly inhibit adhesion (<20% at 15.0 MUA cm(-2)), compared to the nonpolarized case. The alternating current had a similar effect as the negative current on preventing bacterial adhesion, but it also exhibited bactericidal effects, making it the most suitable method for bacterial adhesion control. PMID- 21279862 TI - Crash-related factors associated with the severity of road traffic injuries in Iran. AB - Although the impact of traffic crashes is very high in Iran, there are few works on the association of crash-related factors with injury severity. This study was conducted on 145 drivers injured on the Qazvin-Loshan road in order to assess this association. The New Injury Severity Score (NISS), based on the conditions of the injured drivers during their first visit to regional hospitals, was used as the main outcome measure. Multiple linear regression analysis was performed by considering logarithmic scale for NISS as response variable and adjusting for the confounding effects, including the transfer to hospital variables. The results showed that high-vehicle damage (i.e. damage with repair cost more than 25% of the pre-crash value of the driver's vehicle) and being trapped inside the motor vehicle raised the NISS by 5.25 (95% confidence interval (CI) 2.51-10.71) and 2.34 (95% CI 1.20-4.67), respectively. PMID- 21279863 TI - Effects of cold water immersion on knee joint position sense in healthy volunteers. AB - The purpose of this study was to determine the effects of cryotherapy, in the form of cold water immersion, on knee joint position sense. Fourteen healthy volunteers, with no previous knee injury or pre-existing clinical condition, participated in this randomized cross-over trial. The intervention consisted of a 30-min immersion, to the level of the umbilicus, in either cold (14 +/- 1 degrees C) or tepid water (28 +/- 1 degrees C). Approximately one week later, in a randomized fashion, the volunteers completed the remaining immersion. Active ipsilateral limb repositioning sense of the right knee was measured, using weight bearing and non-weight-bearing assessments, employing video-recorded 3D motion analysis. These assessments were conducted immediately before and after a cold and tepid water immersion. No significant differences were found between treatments for the absolute (P = 0.29), relative (P = 0.21) or variable error (P = 0.86). The average effect size of the outcome measures was modest (range -0.49 to 0.9) and all the associated 95% confidence intervals for these effect sizes crossed zero. These results indicate that there is no evidence of an enhanced risk of injury, following a return to sporting activity, after cold water immersion. PMID- 21279864 TI - Caffeine withdrawal and high-intensity endurance cycling performance. AB - In this study, we investigated the impact of a controlled 4-day caffeine withdrawal period on the effect of an acute caffeine dose on endurance exercise performance. Twelve well-trained and familiarized male cyclists, who were caffeine consumers (from coffee and a range of other sources), were recruited for the study. A double-blind placebo-controlled cross-over design was employed, involving four experimental trials. Participants abstained from dietary caffeine sources for 4 days before the trials and ingested capsules (one in the morning and one in the afternoon) containing either placebo or caffeine (1.5 mg . kg(-1) body weight . day(-1)). On day 5, capsules containing placebo or caffeine (3 mg . kg(-1) body weight) were ingested 90 min before completing a time trial, equivalent to one hour of cycling at 75% peak sustainable power output. Hence the study was designed to incorporate placebo-placebo, placebo-caffeine, caffeine placebo, and caffeine-caffeine conditions. Performance time was significantly improved after acute caffeine ingestion by 1:49 +/- 1:41 min (3.0%, P = 0.021) following a withdrawal period (placebo-placebo vs. placebo-caffeine), and by 2:07 +/- 1:28 min (3.6%, P = 0.002) following the non-withdrawal period (caffeine placebo vs. caffeine-caffeine). No significant difference was detected between the two acute caffeine trials (placebo-caffeine vs. caffeine-caffeine). Average heart rate throughout exercise was significantly higher following acute caffeine administration compared with placebo. No differences were observed in ratings of perceived exertion between trials. A 3 mg . kg(-1) dose of caffeine significantly improves exercise performance irrespective of whether a 4-day withdrawal period is imposed on habitual caffeine users. PMID- 21279865 TI - Prevalence of illicit drug use among the Italian athlete population with special attention on drugs of abuse: a 10-year review. AB - The objective of this study was to assess the prevalence of illicit drugs use among young adults, in particular elite athletes. This study considers the data obtained from anti-doping analyses performed on nearly 100,000 urine samples from 2000 to 2009 by the World Anti-Doping Agency accredited Italian Anti-Doping Laboratory. The percentage of adverse analytical findings varies on a yearly basis, but it is in the range 1.0-1.8% (not considering atypical findings, such as an altered endogenous steroid profile). Among positive results, there is a high prevalence of stimulants and drugs of abuse. The drug of abuse found most frequently is the tetrahydrocannabinol (cannabis) metabolite, accounting for 0.2 0.4% of the total samples analysed (18% of the positive results). The second most frequently encountered drug is cocaine, as detected from cocaine metabolites, accounting for 0.1% of the total samples analysed (7% of positive results). Other stimulants found included amphetamines, ephedrines, carphedon, modafinil, and anorexic compounds. No amphetamine-like designer drugs were detected. These data are indicative of the widespread prevalence of cocaine and cannabis use among the young adult population. However, due to the particular population studied, it must be considered an underestimation of the phenomenon among elite athletes with respect to the general population. PMID- 21279866 TI - Recall agreement between actual and retrospective reports of competitive anxiety: a comparison of intensity and frequency dimensions. AB - Using a mixed-method design, we compared athletes' abilities to recall intensity and frequency of competitive anxiety. In Phase 1, performers (n = 35) completed the Competitive State Anxiety Inventory-2 (Martens, Burton, Vealey, Bump, & Smith, 1990) at four pre-competition and four post-competition intervals to compare actual and recalled responses. In Phase 2, follow up interviews (n = 6) explored the perceived mechanisms underpinning the quantitative results. Limits of agreement (Bland & Altman, 1999) analysis on the quantitative data indicated that, compared with intensity, memory for frequency was generally more reliable, and recall ability of this dimension was less biased for symptoms that occurred earlier in the week. Inductive analysis of the qualitative interviews suggested athletes were more attuned to the frequency rather than the intensity of their competitive anxiety symptoms. These findings provide support for the notion that the frequency of symptoms may act as a precursor for increasing anxiety levels and this dimension may be a more accurate reflection of experienced symptoms when recalling emotional accounts. The implications are that researchers and practitioners need to consider frequency in addition to intensity when seeking to manage anxiety responses during the time preceding competition. PMID- 21279867 TI - Motor inhibition associated with the affordance of briefly displayed objects. AB - Research has demonstrated that left- and right-hand responses are facilitated when they are performed with the hand compatible with the orientation of a viewed object. This suggests that graspable objects automatically activate the motor representations that correspond to their orientation. It has recently been proposed that similar positive stimulus-response compatibility effects (PCE) may turn into negative compatibility effects (NCE) when a prime object is displayed very briefly. These NCEs are suggested to reflect motor inhibition mechanisms- motor activation triggered by briefly viewed objects may be treated by the motor system as unwanted, and thus it is rapidly inhibited. We examined whether the motor activation triggered by the orientation of a task-irrelevant object is similarly inhibited when the object is displayed briefly. In Experiment 1, a NCE was observed between the orientation of an object and the responding hand when the object was displayed for 30 or 70 ms. The effect turned into a PCE when the object was displayed for 370 ms. Experiment 2 confirmed that this motor inhibition effect was produced by the handle affordance of the object rather than some abstract visual properties of the object. PMID- 21279868 TI - Grammaticality is inferred from global similarity: A reply to Kinder (2010). AB - Jamieson and Mewhort (2009b) proposed an account of performance in the artificial grammar judgement-of-grammaticality task based on Hintzman's (1986) model of retrieval, Minerva 2. In the account, each letter is represented by a unique vector of random elements, and each exemplar is represented by concatenating its constituent letter vectors. Although successful in simulating several experiments, Kinder (2010) showed that the model fails for three selected experiments. We track the model's failure to a constraint introduced by concatenating letter vectors to construct the exemplar representation. To fix the problem, we use a holographic representation. Holographic representation not only provides the flexibility missing with the concatenation scheme but also acknowledges variability in what subjects notice when they inspect training exemplars. Armed with holographic representations, we show that the model successfully captures the three problematic data sets. We argue for retrospective accounts, like the present one, that acknowledge subjects' skill in drawing unexpected inferences based on memory of studied items against prospective accounts that require subjects to learn statistical regularities in the training set in anticipation of an undefined classification test. PMID- 21279869 TI - Anti-barnacle activity of novel simple alkyl isocyanides derived from citronellol. AB - Twenty novel simple alkyl isocyanides derived from citronellol were synthesized and evaluated for their antifouling activity and toxicity against cypris larvae of the barnacle, Balanus amphitrite. The anti-barnacle activity of the synthesized isocyanides was in the EC(50) range of 0.08-1.49 MUg ml(-1). Simple isocyanides containing a benzoate and chloro group showed the most potent anti barnacle activity. In addition, none of the synthesized compounds showed significant toxicity and LC(50) values were <10 MUg ml(-1). The LC(50)/EC(50) ratios of almost all of the synthesized compounds were >10(2). The results indicate that these simple isocyanides are promising low-toxicity antifouling agents. PMID- 21279870 TI - A hospital-initiated multisectoral road safety campaign with speed-adapted coconut drop test in Northern Laos. AB - We investigate the efficacy of a multisectoral road safety campaign initiated at Luang Namtha Provincial Hospital (LNPH), North-Laos. Road safety days (RSD) with helmet promotion were organised prior to the Lao and International New Year 2007. Motorbike helmet protectiveness was demonstrated by dropping peeled versus unpeeled coconuts from 6-m high sticks simulating city speed-limit (40 km/h). The primary outcome was the number of road traffic injuries (RTI) needing admission (severe RTI) before and after the first RSD. Secondary outcomes were helmet usage, total RTI, hospital staff's behavioural changes and law enforcement. Neighbouring Bokeo Provincial Hospital (BPH) had no intervention. Severe RTI dropped by 34.7% within 12 months (from 449 to 293, p <= 0.0001, BPH +123% [from 88 to 196]). Total RTI increased by 10.8% (from 772 to 855, p = 0.0396, BPH +260.8% [from 186 to 671]). Police started the law enforcement right after the RSD. Helmet use increased from 11.2 to 42.5% (p < 0.0001). Coconut test was the main reason for safer behaviour among RSD participants seven months later (16/32). The intervention effectively prevented severe RTI. The speed-adapted coconut drop test was a simple, convincing and efficient educational tool, easily adaptable to other settings. PMID- 21279871 TI - Selaginellins I and J, two new alkynyl phenols, from Selaginella tamariscina (Beauv.) Spring. AB - Selaginellins I (1) and J (2), two new compounds, were isolated from Selaginella tamariscina (Beauv.) Spring and were characterized as (R,S)-4-((2',4'-dihydroxy-4 (hydroxymethyl)-3-((4-hydroxyphenyl)ethynyl)biphenyl-2-yl)(4 hydroxyphenyl)methylene)cyclohexa-2,5-dienone (1) and (R,S)-4-((3-((3,4 dihydroxyphenyl)ethynyl)-4'-hydroxy-4-(hydroxymethyl)biphenyl-2-yl)(4 hydroxyphenyl)methylene)cyclohexa-2,5-dienone (2) on the basis of UV, IR, 1D and 2D NMR, and HR-ESI-MS spectroscopic analysis. PMID- 21279872 TI - Total synthesis and cytotoxic activity of stellatin. AB - Stellatin (3,4-dihydro-8-hydroxy-7-hydroxymethyl-6-methoxyisocoumarin) (8), an extrolite of fungal genera Emericella and Aspergillus, was synthesized. Thus, Vilsmeier-Haack formylation of methyl ester of 3,5-dimethoxy-4-methylphenylacetic acid (1) to afford the formyl ester (2) followed sulfamic acid-sodium chlorite oxidation of the aldehydic function to yield the carboxy ester (3). Chemoselective reduction of ester function in the latter using NaBH(4)/THF/MeOH furnished the corresponding hydroxy acid (4) that on cyclodehydration afforded the 3,4-dihydro-6,8-dimethoxy-7-methylisocoumarin (5). Benzylic bromination of the C-7 methyl in 5 using NBS/benzoyl peroxide to give the 7 bromomethyldihydroisocoumarin (6) followed the nucleophilic substitution using aqueous acetone to provide 7-hydroxymethyl-dihydroisocoumarin (7). Finally, the regioselective demethylation of 8-methoxyl group using anhydrous magnesium iodide furnished the stellatin (8). The dihydroisocoumarins (5-8) were screened for cytotoxic activity against human keratinocyte cell line and were found to exhibit moderate to good activity. PMID- 21279873 TI - Triterpenoids from Viburnum betulifolium. AB - Two new triterpenoids, ursa-12-sene-3beta,11beta-diol 3-O-palmitate (1) and ursa 12-sene-1beta,3beta,11alpha-triol 3-O-palmitate (2), were isolated from the 70% aqueous acetone extract of the aerial parts of Viburnum betulifolium, together with the artificial diene derivative of 2, ursa-12-dien-1beta,3beta-diol 3-O palmitate (2a). Their structures were characterized by various spectroscopic methods, including 1D NMR, 2D NMR, and HR-ESI-MS. PMID- 21279874 TI - Cytotoxic constituents from the skin of the toad Bufo bufo gargarizans. AB - To study the chemical composition of the skin of Bufo bufo gargarizans, various chromatographic methods were used in the isolation procedures and the structures of isolated compounds were determined based on NMR and MS analysis. As a result, two new compounds were isolated from its ethanolic extract and characterized as N [2-hydroxy-2-(4-hydroxyphenyl)ethyl]-N-methylurea (1) and 19-oxocinobufotalin 3 adipoylarginine ester (2), together with 11 known compounds. Isolated bufadienolides showed significant inhibition effect against human hepatocellular carcinoma cell line SMMC-7721 in vitro. PMID- 21279875 TI - Pharmacokinetic properties of albiflorin and paeoniflorin after oral administration of pure compound, Radix Paeoniae alba extract and danggui-shaoyao san extract to rats. AB - This study compared the pharmacokinetics of albiflorin (ALB) and paeoniflorin (PAE), respectively, after oral administration of ALB, PAE, Radix Paeoniae alba (RPA) extract, and Danggui-Shaoyao-San (DSS) extract to rats on separate occasions. Analytes were detected simultaneously with liquid chromatography tandem mass spectrometry. Noncompartmental pharmacokinetic parameters were calculated. After oral administration of RPA and DSS extract to rats, ALB reached maximum concentrations of 4637 +/- 2774 ng/ml (0.40 +/- 0.14 h) and 226 +/- 122 ng/ml (0.35 +/- 0.14 h) and PAE reached maximum concentrations of 2132 +/- 560 ng/ml (0.40 +/- 0.14 h) and 143 +/- 65 ng/ml (0.45 +/- 0.11 h), respectively. Compared to the AUC(0 - t) value (1122 +/- 351 and 722 +/- 158 ng h/ml for ALB and PAE, respectively) after administration of monomers, larger AUC(0 - t) value of ALB (4755 +/- 2560 ng h/ml) and PAE (2259 +/- 910 ng h/ml) after administration of RPA extract and smaller AUC(0 - t) value of ALB (411 +/- 118 ng h/ml) and PAE (242 +/- 126 ng h/ml) after administration of DSS extract were obtained. The C(max), AUC, and K(el) of ALB and PAE were remarkably increased (P < 0.05, 0.01 or 0.005) during oral administration of RPA extract in comparison to that of DSS extract. PMID- 21279876 TI - Practical and efficient approach to the synthesis of guineensine. AB - A total synthesis of guineensine, a secondary metabolite of the Piperaceae family, has been executed in 12 steps with an overall yield of 27%. Key steps in the synthesis featured novel application of a Julia-Kocienski olefination reaction which effectively constructed alkenamide skeleton. This contributes a unique approach to the synthesis of the piperamide alkaloids. PMID- 21279877 TI - Three new flavonoids from the active extract of Fallopia convolvulus. AB - Five solvent extracts (ethanol, petroleum ether, EtOAC, n-butanol, and water) from Fallopia convolvulus (L.) Love were separated and their inhibitory effects on nitric oxide production in lipopolysaccharide-activated macrophages were evaluated. Three new flavonoids, falloconvolin A (1), falloconvolin B (2), and quercetin-3-O-(2-E-sinapoxyl)-glucopyranoside (3), together with 17 known phenolic compounds, were isolated from the active EtOAC extract, and their structures were elucidated on the basis of spectroscopic analysis and literature data. PMID- 21279878 TI - Two new amides with cytotoxic activity from the fruits of Piper longum. AB - Bioassay-guided fractionation of the fruits of Piper longum afforded two new minor amides, piperlongimin A (2) [2E-N-isobutyl-hexadecenamide] and piperlongimin B (4) [2E-octadecenoylpiperidine] together with five known compounds with moderate cytotoxic activity. The structures were elucidated on the basis of spectroscopic evidences. All these compounds inhibited cell proliferation of human leukemia, HL-60 cell lines, and displayed major apoptosis inducing effects. PMID- 21279879 TI - In vitro study of the effects of plaunotol on oral cell proliferation and wound healing. AB - Plaunotol is an acyclic diterpene alcohol extracted from a medicinal plant called plau-noi, Croton stellatopilosus Ohba, and has been widely used for the treatment of gastric ulcers in Japan. The aim of this study was to examine the effects of plaunotol on human gingival fibroblasts (HGFs) and human oral keratinocytes (HOKs). To assess the cytotoxic effect, HGFs and HOKs were treated with plaunotol. Subsequently, the morphology of cells was recorded and cells were subjected to MTT assay. To investigate cell proliferation effect, cells were treated with plaunotol and counted with a haemocytometer. To determine wound healing effect, the number of cells repopulated into the wounded areas in monolayer culture and in fibroblast-populated collagen lattice (FPCL) was measured. The results showed that 10 and 1 MUg/ml (33 and 3.3 MUmol/l) plaunotol induced toxicity in HGFs and HOKs, respectively. However, 0.1 MUg/ml (0.33 MUmol/l) plaunotol promoted HGF proliferation and wound healing in monolayer and FPCL models. In contrast, 0.1 MUg/ml plaunotol could not induce HOK proliferation nor in vitro wound healing using monolayer culture, but it induced wound healing in a modified FPCL model. Our data suggested that plaunotol could promote oral cell proliferation and wound healing in vitro and may have an implication on oral wound healing. PMID- 21279880 TI - Biotransformation of oleanolic acid by Alternaria longipes and Penicillium adametzi. AB - Microbial transformation of oleanolic acid (1) was carried out. Six transformed products (2-7) from 1 by Alternaria longipes and three transformed products (8 10) from 1 by Penicillium adametzi were isolated. Their structures were elucidated as 2alpha,3alpha,19alpha-trihydroxy-ursolic acid-28-O-beta-d glucopyranoside (2), 2alpha,3beta,19alpha-trihydroxy-ursolic acid-28-O-beta-d glucopyranoside (3), oleanolic acid 28-O-beta-d-glucopyranosyl ester (4), oleanolic acid-3-O-beta-d-glucopyranoside (5), 3-O-(beta-d-glucopyranosyl) oleanolic acid-28-O-beta-d-glucopyranoside (6), 2alpha,3beta,19a-trihydroxy oleanolic acid-28-O-beta-d-glucopyranoside (7), 21beta-hydroxyl oleanolic acid-28 O-beta-d-glucopyranoside (8), 21beta-hydroxyl oleanolic acid (9), and 7alpha,21beta-dihydroxyl oleanolic acid (10) based on the extensive NMR studies. Among them, 10 was a new compound and compounds 5 and 8-10 had stronger cytotoxic activities against Hela cell lines than the substrate. At the same time, it was reported for the first time in this paper that the skeletons of compounds 2 and 3 were changed from oleanane to uranane and seven glycosidation products were obtained by biotransformation. PMID- 21279881 TI - Triterpenoid saponins from Gynostemma pentaphyllum. AB - Four new dammarane-type triterpene saponins, 1-4, were isolated from the aerial parts of Gynostemma pentaphyllum (Thunb.) Makino. Their structural elucidations were accomplished mainly on the basis of spectroscopic methods, such as IR, HR TOF-MS, and NMR. Compounds 1-4 showed moderate cytotoxic activities against cancer cell lines HL-60, Colon205, and Du145 in vitro. PMID- 21279882 TI - Minor dammarane saponins from the hongshen extract of Shenmai injection. AB - A new dammarane-type triterpenoid saponin, (20R)-ginsenoside ST(2) (1), along with five known saponins was isolated from the hongshen extract of Shenmai injection. The structure of 1 was elucidated to be (20R)-dammar-23(E)-ene 3beta,6alpha,12beta,20,25-pentol 6-O-beta-D-glucopyranoside by means of spectroscopic methods. PMID- 21279883 TI - bis-Sigmodiol: a new prenylflavanone dimer from Erythrina sigmoidea Hua (Fabaceae) of Nigeria. AB - A new prenylflavanone dimer named bis-sigmodiol was isolated from Erythrina sigmoidea, along with six known constituents isobavachin, lupiwighteone, orientanol A, ergosta-4, 6, 8 (14), 22-tetraen-3-one, lupenyl acetate, and p hydroxybenzoic acid. These known constituents have not been reported so far from E. sigmoidea. Their structures were elucidated by spectroscopic methods. PMID- 21279884 TI - Chemical constituents from Astilbe chinensis. AB - A new compound, 11-O-(3'-O-methylgalloyl)-bergenin (1), along with 11 known compounds (2-12), has been isolated from the rhizome of Astilbe chinensis. The chemical structure of compound 1 was determined by IR, MS, and NMR spectral data. All compounds were evaluated for the cytotoxic activity in vitro, and compound 4 showed a moderate cytotoxic activity against HepG2 cells. PMID- 21279885 TI - Uncertain lives, uncertain health for children of Latino day laborers. AB - Latino children of parents who work as day laborers are particularly vulnerable for poor health through economic difficulty and unstable living conditions. The purpose of this community-based participatory research was to explore the perceptions of Latino day laborer parents regarding barriers and assets to health for the children, and to identify strategies for change. Two focus groups were conducted with parent participants and interviews were conducted with community stakeholders. Findings revealed themes of difficulty accessing healthcare, perceptions of poor healthcare, and experiences of fear and chronic uncertainty. Strategies for change included help negotiating the healthcare system, family support, and relationship-based care. Findings give insight into the experience of Latino day laborer parents and inform strategies for community healthcare providers. PMID- 21279886 TI - Is it worth it? Measuring the long-term effects of an international experience for nursing students in Ecuador. AB - In 1999, a community college in Florida initiated a study abroad program that included a transcultural nursing Web-based course and a 2-week clinical component in Ecuador. The investigator collected data from 36 participants using Zorn's International Education Survey to measure 4 dimensions of impact of the international experience. Results revealed that impact on the professional role dimension was most significant, followed by the international perspective dimension, the personal development dimension, and the intellectual development dimension. Conclusions were that nursing international experiences do influence nurses' future professional and personal development. PMID- 21279887 TI - Role of nursing students at rural nurse-managed clinics. AB - With stiff competition for clinical sites, one Midwestern university partners nursing students with faculty who provide primary healthcare to clients in 2 rural nurse-managed clinics. Some students are also assigned to follow select clients during weekly home visit rotations for their public health clinical course. The result has been a successful faculty practice and preceptor model that benefits rural communities, a clinical setting that provides opportunities for students to experience client care needs of the underinsured or uninsured in small communities, and student exposure to the financial burdens and challenges of today's healthcare environment in the United States. PMID- 21279888 TI - Using the Health Belief Model to understand caregiver factors influencing childhood influenza vaccinations. AB - OBJECTIVE: This study applied the Health Belief Model to investigate factors in the decision by caregivers to vaccinate their children for influenza. DESIGN: Cross-sectional study. SAMPLE AND MEASUREMENTS: Purposive sampling obtained 2,778 useable responses to surveys of 33 public health centers and 40 medical institutions participating in vaccination programs in southern Taiwan. Data were collected using the Caregiver Demographics and Children's Health History Questionnaire, Children's Influenza Vaccination History Questionnaire, and a Health Belief Model Questionnaire. Multiple logistic regression was used to analyze predictors of influenza vaccinations in children. RESULTS: Predictors of vaccination revealed by logistic regression analysis included age, current employment, and residence of the caregiver as well as chronic disease, hospitalization, and influenza histories of the child. Other predictors revealed by the Health Belief Model were perceived susceptibility of the children to influenza, perceived benefits of vaccinations to children, perceived barriers to vaccinations, and cues to action. Eleven items in the model were also significant predictors of vaccination. CONCLUSIONS: The survey results can be used to develop strategies for increasing influenza vaccination rates. PMID- 21279889 TI - Postpartum depression among White, African American, and Hispanic low-income mothers in rural southeastern North Carolina. AB - The purpose of this study was to assess factors impacting postpartum depression (PPD) among the 61 White, African American, and Hispanic low-income Medicaid recipients who enrolled in a prenatal program at a local health department in rural Southeastern North Carolina. The findings indicate that mothers who experienced mood changes, such as depression and anxiety, before or during pregnancy reported an increased level of PPD (p = 0.035). Nearly a third of the mothers displayed either minor (17.3%) or major (15.4%) depressive symptoms. Community health nurses working with this population need to be increasingly aware of the underlying causes and prevalence of PPD among low income mothers for early screening and intervention. PMID- 21279891 TI - Removal of arsenic from water by iron oxide nanoparticles impregnated on carbon nanotubes. AB - The removal of Arsenic (As (III)) ions from water using modified multi-walled carbon nanotubes (MCNTs) was demonstrated in this study. Results of the study showed that raw (non-modified) MCNTs have very poor efficiency in removing As (III) from water by conventional adsorption mechanisms. However, when MCNTs were modified with iron oxide (Fe-MCNTs), a significant improvement in the As (III) removal efficiency was observed. Results of the study also showed that Fe-MCNTs have much higher efficiency in removing As (III) than MCNTs modified with carboxyl group (COOH-MCNTs). Under the experimental conditions used in the study, about 77.5% of As (III) removal was achieved by the Fe-MCNTs, while COOH-MCNTs removed only 11% at pH 5. In addition, the adsorption kinetics of MCNTs indicated that there is a strong affinity of As (III) ions to the surface of the Fe-MCNTs. PMID- 21279892 TI - Diurnal fluctuations in oxygen release from roots of Acorus calamus Linn in a modeled constructed wetland. AB - Oxygen is known to be released from plant roots, but has seldom been quantified for wetland plants. Our study aims to quantify oxygen release from the roots of one wetland species in China, and use this knowledge as a basis for future modeling. We measured diurnal fluctuations in oxygen release from the roots of Acorus calamus Linn in a modeled constructed wetland (CW) using a titanium ([image omitted]) citrate buffer. Oxygen release was monitored every two hours. Maximum oxygen release was recorded in the range of 215.2-750.8 MUmolg(-1)h(-1) and occurred around 15:00. The maximum value of photosynthetically active radiation (PAR) was in the range of 1281.8-1712.0 mmolm(-2)s(-1) and occurred around 13:00. Both the oxygen release rate and PAR were found to approach zero at night. Our results indicate that oxygen release depends largely on light intensity and exhibits a diurnal periodicity with release occurring only during daytime. Rate of root oxygen release varied during the daytime and this temporal variation was well described by the Gaussian function. While further validation is needed, we suggest that the Gaussian function may be used as the basis for modeling root oxygen release in natural and constructed wetlands. PMID- 21279893 TI - Assessment of neurobehavioral and biochemical effects in rats exposed to copper smelter dusts. AB - Female Wistar rats were instilled per os by gavage with different copper dust samples: P-25 obtained by passing the test material through a 25 MUmsieve, and P 0.1 containing soluble matter and ultra-fine, non-soluble<100 nm particulate matter (PM) fraction. The control group received sterile saline. The effects were studied at day 1, 7, and 30 post-exposure, focusing on bronchoalveolar lavage fluid (BALF) analysis (including biochemistry, cell morphology, cell viability, and Clara cell 16 protein concentration) and pathomorphology of lung. Results of biochemical tests showed a strong pro-inflammatory effect of both particulate fractions. The morphological studies after exposure to P-25 and P-0.1 fractions showed multi-focal infiltrations in the alveoli. Changes in behavioral (radial maze and passive avoidance tests) have shown that memory in groups exposed to dust was impaired. Our findings indicate that both samples of dust from Copper Smelter cause greater and lesser intensity (P-25 > P-0.1) of the symptoms of acute inflammatory reaction immediately 24 h after instillation to rats. Exposure results in dropping CC16 protein level in serum of rats. After one month, previous acute inflammation was resolved and transformed in persistent low-grade inflammation. The low-grade inflammation resulted in induction of neurobehavioral effects probably by changes in "cholinergic anti-inflammatory pathway" in which acetylcholine modulates neurotransmission. PMID- 21279894 TI - Assimilation of 17alpha-ethinylestradiol by sludge and its stress on microbial communities under aerobic and anaerobic conditions. AB - The efficiency of 2 common types sludge, activated sludge and digesting sludge, to biodegrade ethinylestradiol (EE2) under aerobic and anaerobic conditions, and the impacts of EE2 on microbial community structure were investigated. The results showed that 75%-88% EE2 were removed under aerobic conditions and the values were 75%-84% under anaerobic conditions. The diversity of microbial species in the tested sludge decreased when exposed to EE2 and the shift of microbial community structures was dependent on both sludge types and process conditions. Predominant bacteria were identified as Proteobacteria class which was considered to have EE2 degradation capacities. Twelve strains were found, 8 of them belonged to the Class of gamma-proteobacterium, 1 of beta proteobacterium, 1 of Actinobacterium, and 2 of unclassified strains. PMID- 21279895 TI - Application of UV-rays in removal of polycyclic aromatic hydrocarbons from treated wastewater. AB - This study was undertaken to investigate the removal of PAHs by UV-rays from treated wastewater. Samples of wastewater originating from a municipal treatment plant were taken twofold (series I and series II). The initial concentration of PAHs ranged: 0.8 MUg/L (in series I) and 1.2 MUg/L (in series II), respectively. A standard mixture of 16 compounds was added to the wastewater samples. The amount of individual hydrocarbons in the added mixture was equal to 40 MUg/L, (in series I) and 50 MUg/L, (in series II), respectively. The samples of wastewater without the added standard mixture were treated as a control samples. All samples of wastewater were exposed to UV-rays during 10, 20, 30 and 60 seconds, respectively. Afterwards, the PAHs concentration in both the wastewater samples containing the standard mixture and in the control samples was determined. Determinations of PAHs concentration in wastewater samples in each series were made in triplicates. A quantitative analysis of PAHs was provided by gas chromatography-mass spectrometry (GC-MS). It was found that exposition to ultraviolet rays resulted in the decrease in the concentration of PAHs in the wastewater samples without added standard mixture up to 65%. The efficiency of the removal of hydrocarbons grouped according to a number of rings was in the range of 0 (for 5- ring and 6-ring of PAHs) to 71% (for naphthalene). It was also found that exposure of wastewater samples to UV-rays resulted in a decrease of PAHs concentration in wastewater samples with the added standard mixture up to 84%. The efficiency of the removal of hydrocarbons grouped according to a number of rings differed significantly (to 94% for naphthalene). PMID- 21279896 TI - Introduction to the special issue on lesbians of African descent: contemporary perspectives. AB - This article serves as an introduction to the special issue entitled, "Lesbians of African Descent: Contemporary Perspectives." We briefly discuss our framing of this collection as a contemporary contribution to the canon of Black lesbian writing and art, and identify themes that appear to transcend both earlier and current works of lesbians of African descent. PMID- 21279902 TI - Brief report: the relationship between multiple forms of oppression and subjective health among Black lesbian and bisexual women. AB - This study was designed to explore the relationships between multiple forms of oppression and subjective physical health among a community sample of 85 Black lesbian and bisexual women. Self-report surveys assessing health behaviors, physical and mental health status, and experiences with discrimination were administered during a weekend retreat of a community-based organization serving this population. Structural equation modeling showed there were significant, but different, relationships between subjective health and two types of oppression, heterosexism and weight-based discrimination. Further research on the independent and intersectional effects of multiple forms of oppression on health is needed. PMID- 21279906 TI - Sensitivities: emotion-work and resulting personal effects in researching Black lesbians. AB - The issues of self-disclosure, empathy, sharing the lives of others, developing rapport, and emotional memories are presented in relationship to the conduct of qualitative research interviews with Black lesbian students attending a historically Black university within a southern U.S. regional context. The challenge of doing such sensitive research is discussed from my perspective of also being a Black lesbian researcher, and the questions that this raised for me. Specific examples from the interview experiences are provided of self disclosure, empathy, and rapport with the student participants. Conclusions suggest the need for building a community of social support for female scholars of African descent who study and serve Black lesbian populations. PMID- 21279907 TI - Queer like me: black girlhood sexuality on the playground, under the covers, and in the halls of academia. AB - Using Laura Alexandra Harris' conception of a queer Black feminism, I evaluate stories from my girlhood to learn what lessons can be learned about young female sexuality when the researcher works from a position of pleasure. I contend that my secret quests to satisfy my same-sex sexual desires led me to begin the process of cultivating self-awareness, or subjectivity, and personal agency at an early age. PMID- 21279908 TI - Body of knowledge: Black queer feminist pedagogy, praxis, and embodied text. AB - This article examines the "body as text" in the Black women's studies classroom. I transparently name this method of teaching "Black queer feminist pedagogy," an ordered and practical teaching method that relies on both the teaching of realities and teaching through interdisciplinary practices, while recognizing the body as a site of learning and knowledge. Illustrated by autoethnographic narratives drawn from classroom experiences, I discuss how the body inspires teachable moments, and consider how embodiment and subjectivity function as "equipment" for teaching and learning. PMID- 21279909 TI - Two sides of the same coin: revising analyses of lesbian sexuality and family formation through the study of Black women. AB - The present work analyzes results from a three-year, mixed-methods sociological study of Black lesbian-headed families. It identifies four points of departure Black women make from what the existing literature has assumed about lesbian families and lesbian practice. It links these ideologies and behaviors to the experiences of African-American women growing up in Black heterosexual families and communities, particularly the mother-centered quality of many Black households and the history of female labor force participation and economic contributions to the household. PMID- 21279913 TI - Coming out and coming through. AB - In this essay, the author recounts how therapy helped her in her journey of personal wholeness. She explores the intersectionality of sexual orientation, disability, race, and gender. PMID- 21279914 TI - Identifying blues: an interview with lesbian blues musician and lyricist Gaye Adegbalola. Interview by Carmen Phelps. AB - In this interview, blues lyricist and musician Gaye Adegbalola shares with audiences how various political, social, and artistic influences have inspired her work since her activist years during the Black Arts Movement leading up to the present day. As a lesbian blues artist, Adegbalola's personal and artistic development implicates the often inextricable and intimate relationships between artistic production, political involvement, and individual fulfillment. PMID- 21279917 TI - Isolated, invisible, and in the closet: the life story of a Scottish Muslim lesbian. AB - In the last three decades, there has been a significant growth in the literature on lesbian identity and relationships, but the study of lesbians from a Muslim background is conspicuously absent. This article was prompted partly by the relative absence of research into the lives of Muslim lesbians in Britain, and partly by the fact that much of the literature on Islam and homosexuality has tended to focus on homosexual men, ignoring the position of lesbian sexuality in Islam. It also charts the difficulties faced by a heterosexual researcher in conducting an interview with a lesbian and calls attention to the invisibility of self-identified Muslim lesbians in Glasgow. The life story interview is used to explore the very hidden and untold story of a Muslim lesbian; as such the article draws heavily on the subject's narrative. PMID- 21279918 TI - Discourse and identity in a corpus of lesbian erotica. AB - This article uses corpus linguistic methodologies to explore representations of lesbian desires and identities in a corpus of lesbian erotica from the 1980s and 1990s. We provide a critical examination of the ways in which "lesbian gender," power, and desire are represented, (re-)produced, and enacted, often in ways that challenge hegemonic discourses of gender and sexuality. By examining word frequencies and collocations, we critically analyze some of the themes, processes, and patterns of representation in the texts. Although rooted in linguistics, we hope this article provides an accessible, interdisciplinary, and timely contribution toward developing understandings of discursive practices surrounding gender and sexuality. PMID- 21279919 TI - [Consensus statement of the Austrian Society of Radiology, the Austrian Society of Gastroenterology and Hepatology and the Austrian Society of Surgery on CT colonography (Virtual Colonoscopy)]. PMID- 21279921 TI - Gastrointestinal symptoms, fluid loss and haematological parameters. PMID- 21279924 TI - [Laparotomy closure and incisional hernia prevention - what are the surgical requirements?]. AB - In the light of an incisional hernia incidence of between 10 and 20 % that remains constantly high in spite of modifications of suture materials and suture techniques, intensified scientific efforts aiming at incisional hernia prevention are -required. This article reviews the scientific results dealing with incisional hernia incidence, time of manifestation, risk factors and the influence of suture material and suture technique. A lack of evidence-based data and no current consensus concerning the ideal material and technique to close laparotomies has to be mentioned. To encourage a novel approach to incisional hernia -prevention, the results of experimental studies which demonstrate the negative effects of conventional laparotomy closure on the abdominal wall are discussed. Histology and additionally -laser-fluorescence angiography reveal the weak-en-ing of abdominal wall structures and abdominal wall perfusion after directly suturing the -incisional edges. Additionally, inadequate suture -tension has an influence on collagen quantity and quality in the healing incision. Further investigations with a suture simulator have made clear that surgical sutures vary widely in precision and reproducibility of suture tension when completed only under visual and tactile control. As suture tension dynamics cannot be measured due to the lack of adequate devices, an implantable sensor has been developed that reveals a loss of suture tension of up to 60 % of the initial tension in the first 2 hours after completion of laparotomy closure. These results have led to the development and experimental use of a bridging closure with a tension-banding technique. This technique has almost no influence on abdominal wall per-fusion, leaves the architecture and dynamics of the abdominal wall intact, and results in a favour-able ultra-structural composition of collagen and a mechanically stable laparotomy healing after 15 months. Measures to prevent incisional hernia formation - which is in fact the post-operative complication in surgery most frequently leading to re-operation - require intensified research activities. Success will only be achieved if the development of -unconventional closure techniques is encouraged and the beaten path of suturing the incisional edges is discarded. PMID- 21279925 TI - [Vascular surgery in the elderly - recommendations for clinical practice]. AB - Due to the increasingly aging populations of the industrialised countries, the prevalence of vascular disorders is increasing, with an emerging patient subgroup of 80 years and older (octogenarians), often multi-morbid with an increased risk of anaesthesiological and surgical complications. This review article presents evidence-based indications for vascular surgery in the elderly (> 80 years), and the influence of advanced age on surgical results. Guidelines for daily practice were drawn from a thorough analysis of current treatment recommendations for three vascular disorders (carotid artery stenosis, abdominal aortic aneurysm, and peripheral arterial disease) with the aim of assisting the primary care physician in deciding upon the therapeutic management. In summary, evidence indicates that CEA (carotid endarterectomy) is the gold standard therapy for carotid artery stenosis, as opposed to the "best medical treatment" and CAS (carotid artery stenting). With suitable morphology of the aneurysm, endovascular aneurysm repair (EVAR) is the therapy of choice for abdominal aortic aneurysm (AAA). In elderly patients unfit for open repair and with a life expectancy of less than 4 years, EVAR does not offer any survival benefit compared with no intervention. In such patients, conservative therapy should be taken into consideration. Due to the significantly reduced life expectancy after a major amputation, the value of infrainguinal revascularisation is high, with the exception of patients aged > 90 years. PMID- 21279926 TI - [Is it possible to perform a laparoscopic assisted Hartmann's procedure and a subsequent laparoscopically assisted reversal in complicated diverticulitis?]. AB - Surgery of complicated sigmoid diverticulitis should be as gentle as possible. Serious time pressure, unpredictable operation fields and unprepared bowel determine the surgical strategy. Hence, we examine whether minimal invasive surgery (MIS) (i. e., Hartmann procedure) is suited for emergency conditions in selected patients. Furthermore, the objective of the study was to -assess the feasibility of the reversal of Hartmann procedure in appropriate patients after a preceding classical or laparoscopic intervention. -Between 2005 and 2009 128 patients with sigma diverticulitis were operated, 72 patients of them with complicated sigmoid diverticulitis (peritonitis, haemorrhage, ileus, perforation), The classical Hartmann procedure was performed in 45 (35 %) patients, 39 of them being treated within 24 hours. The laparoscopically assisted Hartmann procedure was realised in 15 patients and could be successfully completed in 13 cases. The cor-responding mortality rate was 0 %. A Hartmann reversal could be performed in 26 patients (58 %). A laparoscopic approach was chosen in 16 patients and could be successfully completed in 14 cases. 12 patients were operated with classical Hartmann reversal. The respective mortality rates in both groups were 0 %. We therefore conclude that in cases of peritonitis due to sigmoid diverticulitis laparoscopic surgery, like laparoscopically assisted Hartmann procedure and a subsequent laparoscopically assisted reversal could be recommended in selected patients. PMID- 21279927 TI - Sister Mary Joseph's nodule as primary localized malignant mesothelioma. Report of a case. PMID- 21279928 TI - [Friedrich Voelcker - one of the fathers of surgical urology]. PMID- 21279929 TI - Pharmacotherapy of schizophrenia: ploypharmacy approaches. AB - Schizophrenia is a debilitating illness, rating as one of the leading causes of lost years of quality of life. The illness imposes a disproportionate burden on patients and their families, healthcare systems and society. Pharmacological management is the cornerstone of treatment of schizophrenia, and antipsychotics, both first generation of antipsychotics and second generation of antipsychotics, are efficacious in reducing levels of psychopathology in acute episodes of schizophrenia. Clearly a need for innovative treatment strategies in schizophrenia that will ensure increased effectiveness against negative symptoms and cognitive dysfunction dysfunction. Therefore, in majority of cases polypharmacy is one of the effective approaches. This review focused on polypharmacy in the treatment of schizophrenia and in particular negative symptoms. PMID- 21279930 TI - Lectin histochemical study of cell surface glycoconjugate in gastric carcinoma using helix pomatia agglutinin. AB - Altered glycosylation of proteins in cancer cells is one of the main processes responsible for anaplasia, invasion and metastatic potential of neoplastic cells. Lectins are nonimmunogenetic compounds which specifically detect certain terminal sugars of glycoconjugates. The aim of the present study was to identify the N acetylgalactosamine (GalNac) containing glycoconjugates in cancer cells in all grades of gastric carcinoma. Paraffin blocks belong to 30 patients of gastric carcinoma (10 cases from each grade) was collected from pathology file of Ali-Ebn Abitaleb Hospital in Zahedan during 2005-2007. Prepared sections (5-7 MUm in thickness) were stained by Alcian Blue, hematoxylin and eosin (H&E) and helix pomatia agglutinin (HPA) conjugated lectin. Lectin diluted up to 10 MUg/ml in PBS (0.1M, pH=6.8). Lectin reactivity was visualized by 0.03% diaminobenzidine (DAB) solution. Sections were graded according to staining intensity to lectin (0-4+). Although there was some difference for lectin staining intensity between cancer cells in different grades of gastric carcinoma, statistical analysis showed that there was only a significant difference for cancer cells reactivity between histopathological grades of II and III. The pattern of reactivity to HPA lectin were also different from all histopathological grades. It seems that in cancer cells, the amount and distribution of GalNac containing glycoconjugate differ from neoplastic cells of different histopathological grades in gastric carcinoma. PMID- 21279931 TI - Comparison of sole to palm reconstruction using the combined medial plantar and medial pedis free flaps and abdominal pedicle flap for extensive palm injuries. AB - The coverage of soft- tissue defects of the hand specially volar side needs special consideration. Although certain local flaps have been described and used for resurfacing the palm, Extensive injury requires distant or free flaps for coverage. Abdominal pedicle flap has been traditionally used for extensive hand injuries, however there is no doubt that one of the ideal tissues for resurfacing the volar of hand is plantar tissue. We reconstructed the hand with a new procedure of combined medial plantar and medial pedis free flap , and compared it with 15 cases, whom their extensive palm injuries reconstructed with abdominal pedicle flap. The result was significantly better in respect to sensation, Texture of the Hand and patient satisfaction in compare of abdominal flap. PMID- 21279932 TI - Short-term therapy with high dose atorvastatin in patients with coronary artery disease can reduce inflammatory process. AB - Coronary heart disease is the leading cause of death and disability in adults. The association between acute coronary syndrome (ACS) and elevated serum high sensitivity c-reactive protein (hsCRP) suggests that chronic inflammation of the coronary arterial wall may play an important role. A number of drugs used in the treatment of cardiovascular disease reduce serum CRP. It* is therefore possible that reduced inflammation contributes to the beneficial effects of these medications. This was a double blind randomized clinical trial on 52 patients were admitted because of ACS at the Mazandaran Heart Center, Iran in 2007. The patients were divided to three randomized groups which received 20, 40, 80* mg Atorvastatin daily for 6 months. At the time of study enrollment and 1, 3 and 6 months after initiation hsCRP were measured. 1 and 3 month after 20mg atorvastatin therapy the median serum concentration of hsCRP did not decrease significantly, but at the end of 6th month it was* significant difference. At 40 mg dosage from 3rd month to 6th month versus 1st month to 3rd month it was significant decrease, at the end of 1st month and 3rd month it was not significant. At 80 mg dose at the end of 1st month it was not significant but at the* end of 3rd month and end of 6th month it was significant. Intensive lipid lowering therapy with high-dose atorvastatin therapy relative to moderate lipid lowering therapy with low-dose atorvastatin reduces hsCRP better. We found that treatment with greater dose of atorvastatin might decrease greater in plasma level of hsCRP. PMID- 21279933 TI - Overnight dexamethasone suppression test in the diagnosis of Cushing's disease. AB - Realizing the cause of Cushing's syndrome (CS) is one of the most challenging processes in clinical endocrinology. The long high dose dexamethasone suppression test (standard test) is costly and need an extended inpatient stay. In this study we want to show the clinical utility of the overnight 8 mg dexamethasone suppression test (DST) for differential diagnosis of CS in a referral center. Retrospectively from 2002-2005 we selected the patients of endocrinology ward in Imam Hospital who were admitted with the diagnosis of Cushing syndrome and had 8 mg DST (modified test) along with classic DST. In modified test a decrease in an 8 AM serum cortisol level of 50% or more is thought to indicate suppression and we compared the results of modified test with standard test. This test had been done on 42 patients: 10 male (23%) and 32 female (76%). The mean age of patients was 31.39 (15-63), 32 with proven pituitary Cushing's disease, 7 with primary adrenal tumors and 3 with ectopic ACTH syndrome. The standard test according to 50% suppression of UFC had 90.62% sensitivity, and according to 90% suppression had 43.75% sensitivity. The sensitivity of this test was 71.85% for serum cortisol suppression. The modified test (8 mg overnight DST) had 78% sensitivity. All of these tests had 100% specificity for the diagnosis of Cushing's disease. The positive predictive vale (PPV) of all of these tests was 100%. The negative predictive value (NPV) of modified test for the diagnosis of Cushing's disease was 58.82%. In standard test the NPV of serum cortisol was 52.6%, UFC 50% had 76.9% NPV and UFC 90% had 35.7% NPV. The results of serum cortisol suppression in modified test is better than standard test. Although 50% suppression of UFC in standard test had greater sensitivity than modified test, collecting of urine is difficult, time consuming and needing hospitalization, so we advice modified test that is much simpler and more convenient instead of standard test in the first step of evaluating the cause of Cushing's syndrome in referral centers. PMID- 21279934 TI - Spirometric indices after bronchodilator test in obstructive lung disease. AB - Bronchial responsiveness to bronchodilator medications is usually tested to establish reversibility of airflow obstruction. Among the various tests to establish bronchodilator response, FEV1, FEF(25-75%) or FEF50%, and FVC are the most widely used. In a cross-sectional study, we assessed spirometric responses after administration of bronchodilator in 187 workers with obstructive pattern in spirometry. Considering responsiveness to bronchodilator (200 cc and 12% increase in FEV1 or FVC), the study cases were divided into responsive or non-responsive groups, and the average increase in spirometric indices were measured and compared between two groups. 35.8% of cases were responsive to bronchodilator. Among responsive cases, FEV1 was the most frequent index increased significantly; And PEF and FVC were the least frequent ones. The highest mean increase from baseline after administration of bronchodilator was observed in FEF75%. Increases in all indices were significantly higher in responsive group. The increase in FEV1% predicted was inversely correlated with baseline FEV1. In conclusion, we consider that FEV1 is the most reliable spirometric index for assessing bronchodilator response. And Bronchial reversibility has an inverse relationship with baseline measures. PMID- 21279935 TI - A comparative study of blood culture sampling from umbilical catheter line versus peripheral site. AB - Neonatal sepsis is an important cause of death and morbidity in newborns and is diagnosed by isolation of organism in blood culture. In several reports,reliability of blood cultures were done from umbilical catheters,have been demonstrated. The objective of the present study was to determine, wether an indewelling umbilical catheter, could be an alternative site for blood culture. In a prospective study over 6 months during 2006, 141 paired blood cultures from 134 infant,were done simultaneously from peripheral site and umbilical catheter (mostly U. V. C),during the first four days of life. Majority of these infants were preterm and admitted to NICU for special care. these infants had indwelling umbilical line and had indication of sepsis workup. A total of 141 pairs of blood cultures were obtained from 134 infants. In 16 infants blood culture pairs were positive for one organism in both peripheral vein and umbilical site. 71. 6% of total cultures (n=11) pairs were negative in both sites. A total of 22 pairs were positive in one site only,with 5 positive from peripheral vein only and the other 17 from umbilical site. Two pairs were positive in both sites with two different organism. In over all 16 infant (11%) of blood were considered to be contaminated. Contamination rate were 2. 4% and 9. 2% for peripheral and umbilical catheter site. Contamination rate increased after 48 hours of age in umbilical catheter. The result showed that after 2 days contamination rate for blood culture taken from catheter line increased and specificity decreased. We recommended that blood culture via umbilical catheter in first 2 days in sick neonates with indwelling catheter can be a alternate site of blood culture sampling. PMID- 21279936 TI - The association between second-trimester maternal serum alpha-fetoprotein in 14 22 weeks and adverse pregnancy outcome. AB - Aim of this study is to determine the risk of adverse pregnancy outcome by maternal serum alpha-fetoprotein (MSAFP) level. We followed 295 pregnant women from MSAFP screening in the 14th to 22th week of gestation until the end of pregnancy and information on pregnancy outcome have been recorded in questionnaires. Of 295 pregnant women, 270 had term labor and 25 had preterm labor. The frequencies of pregnancy outcomes were as following: 3 (1.01%) stillbirths, 25 (8.47%) preterm labor, and 10 (3.4%) preterm rupture of membranous (PROM), 15 (5.1%) pre-eclampsia, 23 (7.8%) oligohydramnious, and 1 (0.33%) miscarriage. The mean of preterm labor was significantly associated with the higher level of MSAFP (P = 0.021). The mean was 55.1 ng/cc in preterm labor and 41.1 ng/cc in term labor. Also, second trimester MSAFP levels were higher in women with pre-eclampsia (P < 0.001). The significant association was found between higher level of MSAFP with oligohydramnious (P < 0.001) and low birth weight (P < 0.001). Pregnancies with an elevated MSAFP level are associated with adverse obstetric outcomes and need more prenatal care. PMID- 21279937 TI - Extra pulmonary tuberculosis in children: two years study. AB - Tuberculosis (TB) is an important health problem in developing countries, with varying clinical presentations depending on the organs/systems involved. To study the spectrum of clinical and paraclinical aspects of extra pulmonary TB in children suffering from pulmonary TB. This study has been carried out on 65 children with tuberculosis, admitted in TB wards of National Research Institute of Tuberculosis and Lung Disease (N.R.I.T.L.D) during 2004-2006. All patients were investigated according to specific diagnostic criteria including; history of contact with TB patient, clinical manifestations, radiological findings, tuberculin test and bacteriologic or pathologic results and after confirmation, treatment was administered. Out of 65 cases, 14 had different types of extra pulmonary tuberculosis, and data concerning following factors were studied: age, gender, race, site of involvement, bacteriology, pathology, ADA (ascitic fluid), PCR (tissue specimens), history of close contact, HIV tests (ELISA), tuberculin test, radiological findings, and immunological studies (in disseminated TB). Of 14 cases, 8 were girls and 6 were boys with mean age of 8.75 +/- 4.2. Nine patients were Iranian and 5 were Afghan. History of close contact was detected in 4 cases. Type of involvement was: 5 cervical adenitis, 3 osteoarticular disease, 2 peritonitis and 2 disseminated form of tuberculosis, one pericarditis, one renal tuberculosis. Radiological findings showed 4 pulmonary disease and 3 osteoarticular involvement. Tuberculin skin tests greater than 15 mm observed in 5 cases, 9 patients had 0-5 mm induration. 4 cases had concomitant pulmonary and extra pulmonary involvement. Positive AFB in gastric lavage was recognized in 4 cases, in which 3 showed positive cultures for MTB. Pathological examinations in 10 cases revealed granuloma with caseation compatible with tuberculosis, five in lymphadenopathy, three in osteoarticular, two in abdominal tuberculosis. According to this study, 20% of patients had extra pulmonary involvement, which is comparable to other reports (20-25%) and TB lymphadenitis is the most common from of presentation. PMID- 21279938 TI - Radiologic manifestation of pulmonary tuberculosis in children admitted in pediatric ward-Massih Daneshvari Hospital: a 5-year retrospective study. AB - Despite the extensive preventive and therapeutic measures present against tuberculosis (TB), this disease still remains as one of the important causes of mortality and morbidity in the world. Considering the high incidence of TB in children, rareness of its' clinical features and complexity of bacteriologic diagnosis in this age group paraclinical studies, especially radiologic evaluations, is useful for reaching a final diagnosis. This 5 year study was conducted in National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Massih Daneshvari Hospital, Tehran, Iran. This retrospective study was conducted on 70 children (43 (61%) female and 27 (38.5%) male) aged between 5 months to 15 years old during a five year period (from 2001-2006) in pediatric ward. It was performed on children who were confirmed to have TB by various clinical, bacteriologic and radiologic features and tuberculin skin test. We studied the radiologic features of pulmonary TB in these children. Right lung involvement was observed in 65%, left lung 23% and bilateral involvement was detected in 12%. Also middle and superior lobes were the most common lobes affected. The commonest radiographic feature was hilar (mediastinal) lymphadenopathy; 70% detected on chest x-ray (CXR) and 85% on CT scan. Lymph nodes on right side were affected more; 25% were calcified. Also nodular infiltration of lung parenchyma was observed in 35% of CXRS and 61% of CT scans. This was followed by patchy consolidation detected in 25% and 35% of CXRs and CT scans respectively. We also observed that children <3 yr. of age had the highest lymph node involvement but the least parenchymal lesions as compared to older children. It is concluded that primary TB is the most common form of pulmonary TB in children. This could be in the form of hilar lymphadenopathy with or without lung parenchymal involvement. Also radiologic features could provide valuable information in regard to diagnosis, treatment and follow-up of pulmonary TB in children. PMID- 21279939 TI - Depression in mothers of children with cerebral palsy and its relation to severity and type of cerebral palsy. AB - Children with cerebral palsy (CP) suffer from several problems, so the family especially the mothers undertake a lot of social and emotional difficulties. The purpose of this study was to determine the severity of depression in mothers of children with CP in comparison with mothers who have normal children and its relation to the type of CP and severity of the disability. During this descriptive-analytic study, 43 mothers who had younger than 8 year-old children with CP under rehabilitation services in SABA clinic, related to the University of Social Welfare and Rehabilitation Sciences (USWR), Tehran, Iran, were selected as the case group by simple sampling. A data registration form and the Beck Depression Inventory II were completed by them. The type of CP and the severity of disability were determined by a pediatrician and an occupational therapist respectively, using the Gross Motor Function Classification System (GMFCS). Seventy-seven mothers of normal children, serving as the control group for comparing with case group, filled in the same questionnaires. There were significant differences in the mean depression scores (P=0.003) between the two groups. Having a child with CP also increases the risk of developing depression in mothers as much as 2.26 times (OR=2.26). There were no statistically significant differences in depression scores and the severity of disability and also among the five types of CP. It seems that having a child with CP is probably associated with higher prevalence and severity of depression in mothers. So treatment or prevention of depression in mothers of children with CP is highly recommended for improving the rehabilitation process and achieve better results in these children. PMID- 21279940 TI - The study of life change unit as stressor agents among Tehran University of Medical Sciences Hospitals' employees. AB - Life crises as stressor agents can disrupt the best stress management regime. Different life crises have different impacts. A standard scale to rate change and its related stress impact has been developed commonly referred to as LCU (life change unit) rating. This allocates a number of life crisis units or life change units (LCUs) to different event and then evaluates them and takes action accordingly. This idea behind this approach of is to rundown the LCU table, totaling the LCUs for life crisis that have occurred in the previous one year. A cross-sectional, descriptive and analytical study was conducted among 900 Tehran University of Medical Sciences (TUMS) employees by a Holms and Rahe LCU questionnaire at 15 hospitals. The respondents were asked to determine their demographic information, list of stress symptoms which suffered from these diseases in the previous one year and finally, responded to 45 Life Change Unit as stressful life events and the value of each in "stress units" which occurred in the previous one year. The results showed that there is significant correlation between the employees LCU rating by sex, educational degree and size of hospital. Also we found that there are significant correlations between the employees stress symptoms with their LCU rating. Totally, 40% of the employees have less than 150 LCU rating (normal range) and 60% of them have 150-300 or more than 300 LCU rating (abnormal range). In conclusion most of TUMS hospitals' employees who had stress symptoms have more LCU rating. One third of these employees are not in danger of suffering the illness effect, while two third of them are in danger. PMID- 21279941 TI - Incidence of intraventricular hemorrhage and post hemorrhagic hydrocephalus in preterm infants. AB - Germinal matrix-intraventricular hemorrhage (IVH) is the most common variety of neonatal intracranial hemorrhage and is characteristics of the premature infant. The importance of the lesion relates not only to its high incidence but to their attendant complications (IC: hydrocephalus). Brain sonography is the procedure of choice in diagnosis of germinal matrix- intraventricular hemorrhage and hydrocephalus. In this study we have used brain sonography for detection of intraventricular hemorrhage and post hemorrhagic hydrocephalus and their incidences. The studied population was consisted of premature neonate (birth weight equal or less than 1500 g and gestational age equal or less than 37 weeks) who admitted in Mofid Hospital NICU (Tehran, Iran) during a one year period. For all neonate (including criteria) brain sonography in first week of life was done and in presence of IVH, serial Brain sonography was done weekly for detection of hydrocephalus. A total of 57 neonate entered the study. Intraventricular-germinal matrix hemorrhage was seen in 64.4% (35 patients). Forty percent of patients with intraventricular-germinal matrix hemorrhage had grade I, 11% grade II, 25.7% grade III, 2.8% grade VI. Hydrocephalus was detected in 20 percent of patients who had intraventricular-germinal matrix hemorrhage. That incidence of IVH in our study in comparison with other area and situation is higher. Hydrocephaly had direct relation with severity of IVH. This shows that with control of risk factor of IVH, we can control Post hemorrhagic hydrocephalus. PMID- 21279942 TI - Incidence of rotavirus diarrhea in children under 6 years referred to the Pediatric Emergency and Clinic of Ghaem Hospital, Mashhad, Iran. AB - Rotavirus is the most important pathogen responsible for acute diarrhea in infants and young children. The incidence of rotavirus infection was studied in 156 children less than six years of age who were suffering from acute gastroenteritis, between February 22, 2006 and February 21, 2007 in Mashhad. Rotavirus antigen was detected by latex agglutination test (Rotascreen) in 28.8% of the stool samples examined. The frequency of rotavirus infection was significantly higher among patients under 24 months of age (69%) than among children two years old or more (31%). The peak of incidence was in the winter. This study revealed that rotavirus is an important etiological agent of acute gastroenteritis among children in Mashhad. PMID- 21279943 TI - A survey of suicide by burning in Tehran, Iran. AB - To identify the characteristics of completed suicide by burning in Tehran. A retrospective analysis of data obtained from Tehran's Legal Medicine Organization and judiciary system over 5-years (from 2002 to 2006). During the 5 years, 374 decedents (64.2% female and 35.8% male) were diagnosed as suicide by self burning, and the annual incidence rate was 0.9 per 100,000 general population years. The most at risk group was young females. Sixty-five decedents (17.4%) had died at the scene of incidents. The location at the time of attempted suicide in all female victims and 75.4% of male decedents was home. Sixty-one percent of decedents were married and 26.2% of them had no education. Most victims were residents of suburban areas. The annual incidence rate of self-burning suicide in Tehran was found to be lower than other Iran's geographic areas, although it was higher than developed countries. Self-burning was more frequent in females than in males and was noted mainly in young age groups' residents of suburban areas with low level of education. These characteristics suggest that social factors are the main drive leading to an unacceptably high rate of suicide by self burning among women in Tehran. PMID- 21279944 TI - Leukocyte adhesion deficiency: report of two family related newborn infants. AB - Leukocyte adhesion deficiency type 1 (LAD 1) is an autosomal recessive hereditary disorder resulting from deficiency of CD18, characterized by recurrent bacterial infections. We report two consanguineous patients with Leukocyte adhesion deficiency type 1( LAD1). These two infant boy patients were referred to us, within a short period of time, with the complaints of recurrent infections at the age of 38 and 75 days -old, respectively. Parents of two patients were first cousins and their grandmothers also were first cousins. The history of delayed umbilical cord separation was shown in both patients. Patient 1 had history of omphalitis, conjunctivitis, skin lesion of groin area and abscess formation of vaccination site, and had infective wound of eye-lid at the last admission. Patient 2 had history of omphalitis and soft tissue infection of right wrist at the last admission. Laboratory findings showed marked leukocytosis and low CD18 levels (6.6% in Patient 1 and 2.4 % in Patient 2). In Patient 1 recurrent infections were treated with antibiotic regimens and received bone marrow transplantation but Patient 2 died because of septicemia, generalized edema, ascites and progression to acute renal failure at 4 months of age. Due to considerable rate of consanguineous marriages in parents of Leukocyte adhesion deficiency patients, sequence analysis especially for prenatal diagnosis in subsequent pregnancies and genetic counseling is recommended. PMID- 21279945 TI - A case of brainstem cavernous angioma presenting with persistent hiccups. AB - Intractable hiccup most be considered as a symptom of underlying serious pathologies. We report a case of medulla oblongata cavernous angioma presented with persistent hiccup and without any improvement during routine nonpharmacologic and pharmacologic treatment regimens. The patient is under our follow up visits and surgery is very high risk for this young girl. PMID- 21279946 TI - An innovative technology for safe needle disconnection after hemodialysis. AB - PURPOSE: Vascular access care is a key topic for hemodialysis patients. The most cost-effective and lasting vascular access for chronic hemodialysis is the native arteriovenous fistula (AVF); however, bleeding after dialysis session from puncture site is a relevant problem. Achieving hemostasis is necessary and requires hand compression by the nurse or the patient if he or she is capable and cooperative. METHODS: We assessed a new vascular closure device, VITACLIP(r) (Serumwerk Bernburg Vertriebs GmbH) that is an adhesive silicone seal device, which can be set onto the skin and punctured by dialysis needle. After withdrawal of the needle, VITACLIP(r) prevents bleeding from the punctured vessels, making hand compression unnecessary. RESULTS: We used this device in 5 chronic hemodialysis patients with native lateral-terminal AVFs. The patients' hemodialysis prescription and anticoagulants dose were not changed. This device allowed puncture of vascular access without complications such as bleeding at the end of hemodialysis; we did not observe any mechanical complications due to needle dislocation or any dermatological lesions at skin puncture site. However, the cannulation proved to be more difficult for the nurses with this device because the silicone hampers identification of the vessel for puncture for deeper AVFs. CONCLUSIONS: This device helps patient management and improves patient safety by reducing the risk of AVF bleeding at the end of dialysis, decreasing the risk of staff contact with patients' blood, and theoretically eliminating the risk of massive bleeding in the case of an inadvertent needle dislodgement going unnoticed during treatment. PMID- 21279947 TI - Dislocation of a Groshong catheter from a titanium Dome(r) Port after thoracic trauma caused by airbag activation. PMID- 21279948 TI - Safety and efficacy of electrospun polycarbonate-urethane vascular graft for early hemodialysis access: first clinical results in man. AB - OBJECTIVES: The purpose of this study was to assess the safety and efficacy of an electrospun multilayered, self-sealing polycarbonate-urethane graft for early hemodialysis access in patients. METHOD: Seventeen eligible consenting patients had a polycarbonate-urethane graft (AVfloTM) implanted and followed up prospectively for 12 months or to the end of secondary patency. Performance measures included graft patency, complications, time to first cannulation, and hemostasis times after needle withdrawal. RESULTS: All patients were of Asian origin (mean age 57 years, range 29-78). Diabetes mellitus was the most common cause of renal failure (52.9%). There were no systemic or local reactions to the graft. Five patients (29.4%) died due to medical complications unrelated to the device. There was 1 pseudoaneurysm, 3 infected grafts that subsequently thrombosed, and 1 primary thrombosis associated with thrombophilia. One venous stenosis needed balloon angioplasty. Primary and secondary patency rates at 6 months were 72.7% and 81.8%, and at 12 months, 54.5% and 72.7%, respectively. Postimplantation vascular access needs were met entirely by the graft in every instance and prevented the need for venous catheters. Fifty-six percent were accessed within 8 days, the earliest being 48 hours. Finally, all arterial punctures and 98% of venous punctures had sealed in less than 5 minutes, with two thirds sealing off within 3 minutes of needle withdrawal. CONCLUSION: The electrospun polycarbonate-urethane graft is safe in humans, permits early access obviating the need for venous catheters, and has equivalent patency to other prosthetic grafts at 1 year. PMID- 21279949 TI - Treatment of long-term catheter-related bloodstream infections with a taurolidine block: a single cancer center experience. AB - PURPOSE: Catheter-related bloodstream infections (CRBSIs) are a common problem in cancer patients with long-term catheters. The effectiveness of taurolidine, a new antimicrobial solution, in the management of CRBSIs is still unknown. A retrospective analysis of patients with proven CRBSIs treated with a taurolidine block in combination with systemic antibiotic treatment was performed to define its role in the management of CRBSIs. METHODS: Twenty-four episodes of CRBSIs in 23 cancer patients with permanent use of the long-term catheter were treated with a taurolidine block for 3 consecutive days in combination with systemic antibiotic treatment. RESULTS: Treatment was successful in 16 of 24 events (67%). Explantation was performed in 8 cases (33%): in 3 patients due to a second positive blood culture, and in 1 patient due to recurrent fever after the conservative treatment. In 4 patients, the conservative approach was prematurely stopped due to persisting fever. CONCLUSION: Taurolidine-based treatment may be a promising, noninvasive therapeutical approach in the management of long-term catheter-related bloodstream infections in cancer patients. PMID- 21279950 TI - Forearm vein transposition for hemodialysis autogenous vascular access. PMID- 21279951 TI - Frequent accesses to totally implanted vascular ports in pediatric oncology patients are associated with higher infection rates. AB - PURPOSE: Totally implanted vascular (TIVA) ports are used in children for repeated blood samples or intravenous treatments. We have recently published a prospective evaluation of surgical incidents and early complications associated with these devices. This work is the final part of the same study, assessing late complications over a follow-up of 2 yrs. METHODS: From January 2006 to January 2008, children older than 1 yr of age with a diagnosis of solid or blood cell malignancy were included. Insertion technique and care of the device were standardized. Every manipulation was prospectively recorded by specialized nurses. Obstruction was documented clinically. When bacteremia was suspected, routine central and peripheral blood cultures were drawn. RESULTS: Forty-five consecutive patients were enrolled in the study. Mean age at the time of the procedure was 8.5 yrs. There was no catheter-related infection within the first 4 weeks post-surgery. No device had to be removed because of infection or obstruction during follow-up. Frequent accesses to the port (=3 per day over a 10 day period) were associated with an 8-fold risk of infection. CONCLUSION: Insertion and use of TIVA devices were frequently associated with complications. No device had to be removed because of infection or obstruction over the follow up period, although no prophylactic antibiotic agent was used. Restrictive use of antibiotics may prevent opportunistic infection. Frequent access to the device was significantly associated with line infection (odds ratio=8.43). No risk factor was identified for obstruction which occurred at a rate of 5.3 per 10,000 accesses. PMID- 21279952 TI - Aspirin resistance in patients with chronic renal failure. AB - BACKGROUND: Chronic renal failure (CRF) is associated with increased risk of cardiovascular morbidity and mortality. Aspirin resistance worsens clinical prognosis. The aim of this study was to explore the prevalence of aspirin resistance in CRF. METHODS: Two hundred and forty-five CRF patients (115 patients undergoing chronic hemodialysis and 130 patients with stage 3-4 chronic kidney disease [CKD]) and 130 patients with normal renal functions (control group) were consecutively recruited. All subjects were taking aspirin regularly. Aspirin responsiveness was determined by Ultegra Rapid Platelet Function Assay-ASA (VerifyNow Aspirin). Aspirin resistance was defined as aspirin reaction unit (ARU) =550. RESULTS: Aspirin resistance was detected in 53 patients undergoing hemodialysis, 32 patients with stage 3-4 CKD and 22 controls. The frequency of aspirin resistance was significantly higher in the CRF group compared with controls (34.7% vs. 16.9%, p<0.001) and in hemodialysis patients (46.1%) compared with stage 3-4 CKD patients (24.6%, p<0.001) and controls (16.9%, p<0.001). Multivariate analysis revealed female sex (odds ratio [OR] = 2.201; 95% confidence interval [95% CI], 1.173-4.129; p=0.014), hemodialysis (OR=3.636; 95%CI, 1.313-10.066; p=0.013) and HDL cholesterol (OR=0.974; 95% CI, 0.950-0.999; p=0.043) as independent predictors of aspirin resistance in this cohort of patients. CONCLUSION: Patients with CRF have higher frequency of aspirin resistance. This might further increase the risk of cardiovascular morbidity and mortality in these patients. PMID- 21279953 TI - Role of the fixed-dose combination lercanidipine-enalapril in renal protection. AB - Even with the availability of novel and efficacious antihypertensive agents, an insufficient number of hypertensive patients achieve their desired blood pressure (BP) target. This failure is partly due to the fact that many patients do not strictly adhere to their drug therapy and/or they report the presence of adverse effects. Traditionally, monotherapy is used as first-line treatment to achieve BP targets; however, when this fails, combination therapy is then required. In light of the need to attain BP goals, combination therapy (especially fixed-dose) is currently recommended. The main advantages of combination therapy over monotherapy are not only that of reduced dose, improved efficacy and reduced adverse effects, but also of target protection and reduced cardiovascular (CV) risk. Therefore, the development of single-administration drug combinations should also improve patient adherence to therapy and therefore help in achieving BP control. Among the various combinations available, calcium channel blockers (CCBs) and angiotensin-converting enzyme (ACE) inhibitors have been proven to be extremely effective, while also displaying good tolerability. Individually, both the third-generation CCB lercanidipine and the ACE inhibitor enalapril are effective antihypertensive agents. In addition, both of these agents also show other beneficial effects when administered as monotherapy. Of particular importance is the fact that when lercanidipine plus enalapril are administered in combination, they show synergism, thus providing added efficacy with reduced side effects. The present report provides an overview of the main clinical studies examining lercanidipine and enalapril administered as monotherapy, with particular focus on the potential renoprotective effects afforded by the fixed dose combination lercanidipine-enalapril. PMID- 21279954 TI - Common genetic variants of MUTYH are not associated with cutaneous malignant melanoma: application of molecular screening by means of high-resolution melting technique in a pilot case-control study. AB - MUTYH glycosylase recognizes the 8-oxoG:A mismatch and is able to excise the adenine base using proofreading mechanisms. Some papers have reported a strong association between cancer development or aggressiveness and MUTYH gene mutations. The aim of this study was to find a possible association between the most frequent MUTYH mutations and melanoma in the context of a case-control pilot study. One hundred ninety-five melanoma patients and 195 healthy controls were matched for sex and age. Clinical and laboratory data were collected in a specific database and all individuals were analyzed for MUTYH mutations by high resolution melting and direct sequencing techniques. Men and women had significantly different distributions of tumor sites and phototypes. No significant associations were observed between the Y165C, G382D and V479F MUTYH mutations and risk of melanoma development or aggressiveness. Our preliminary findings therefore do not confirm a role for MUTYH gene mutations in the melanoma risk. Further studies are necessary for the assessment of MUTYH not only in melanoma but also other cancer types with the same embryonic origin, in the context of larger arrays studies of genes involved in DNA stability or integrity. PMID- 21279955 TI - Association of APC and MCC polymorphisms with increased breast cancer risk in an Indian population. AB - The adenomatous polyposis coli (APC) and mutated in colorectal cancer (MCC) genes are key regulatory genes of the Wnt/beta-catenin signaling pathway, which are independently involved in maintaining low levels of beta-catenin in the cell. In addition to genetic and epigenetic alterations, some genetic polymorphisms in the genes associated with the Wnt signaling pathway have been reported to be associated with an increased risk of cancer, including breast cancer. In the present study we analyzed the association of genotype and haplotype status of two single nucleotide polymorphisms (SNPs), rs2229992 and rs11283943, in the APC and MCC genes, respectively, with an increased risk of breast carcinogenesis in a breast cancer and control population from eastern India. We observed a significant association of the rs11283943 SNP with increased breast cancer risk. Two specific haplotypes involving the minor allele of rs11283943 were found to be associated with an increased breast cancer risk. Kaplan-Meier curves showed a significant association of the 2-2 genotype (genotype homozygous for the rs11283943 minor allele) with decreased survival (p=0.045) of the breast cancer patients in our study, in particular patients with early-onset BC. PMID- 21279956 TI - Recent advances in breast cancer metastasis suppressor 1. AB - Metastasis is a complex process divided into a number of steps including detachment of tumor cells from the primary tumor, invasion, migration, intravasation, survival in the vasculature, extravasation, and colonization of the secondary site. Proteins that block metastasis without inhibiting primary tumor formation are known as metastasis suppressors; examples are NM23, Maspin, KAI1, KISS1, and MKK4. Breast cancer metastasis suppressor 1 (BRMS1) was identified as a suppressor of breast cancer metastasis in the late 1990s. In vitro and in vivo studies have confirmed that BRMS1 is a potent metastasis suppressor not limited to breast cancer. However, conflicting clinical observations regarding its role as a metastasis suppressor and its validity as a diagnostic biomarker warrant more in-depth clinical study. In this review, the authors provide an overview of its biology, function, action mechanism and pathological significance. PMID- 21279957 TI - Clinical utility of serum tumor markers in the diagnosis of malignant intestinal occlusion. A prospective observational study. AB - AIM: The aim of the present observational study was to evaluate the diagnostic accuracy of CEA, CA 19-9 and CA 72-4 in patients with bowel obstruction. METHODS: One-hundred three patients admitted to an emergency unit with clinical and radiological signs of intestinal occlusion of unknown origin were prospectively studied. Patients submitted to emergency surgery were excluded. All patients underwent standard diagnostic procedures and serological assay of tumor markers. RESULTS: Colorectal cancer was diagnosed in 22 patients (21.4%), while 81 patients (78.6%) presented a benign condition. The sensitivity of CEA, CA 19-9 and CA 72-4 for colorectal cancer was 36.4%, 31.8% and 9.1%, respectively. Marker specificity was 91.4%, 90.1% and 95.1%, respectively. The combination of CEA and CA 19-9 increased the sensitivity to 45.5% but decreased the specificity to 83.9%. The overall accuracy was 79.6%, 77.7% and 76.7%, respectively. All positive cancer cases had advanced disease. All patients with CEA levels >10 ng/mL or CA 19-9 >100 U/mL had colorectal cancer. CONCLUSIONS: Even in a highly selected population, tumor marker sensitivity was rather low and specificity incomplete. However, elevated levels may guide the diagnostic and therapeutic course in patients with obstructing colorectal cancer. PMID- 21279958 TI - Expression of CD44s and CD44v6 in lung cancer and their correlation with prognostic factors. AB - BACKGROUND: CD44, a transmembrane glycoprotein receptor, plays a major role in tumor progression and metastasis. OBJECTIVE: To evaluate the expression of CD44 standard (CD44s) and its variant 6 (CD44v6) in normal and neoplastic lung tissue and correlate it with prognostic factors in lung cancer. METHODS: The study included 52 non-small cell lung carcinomas (NSCLC) (21 squamous cell carcinomas and 31 adenocarcinomas), 15 small cell lung carcinomas (SCLC) and 8 carcinoid tumors. Expression of CD44s and CD44v6 was evaluated by immunohistochemistry and correlated with lung cancer prognostic factors. RESULTS: All squamous cell carcinomas expressed both CD44s and CD44v6. Adenocarcinomas expressed CD44s in 39% of cases and CD44v6 in 45%. Carcinoid tumors expressed only CD44s in 88% of cases. All SCLCs were negative for both CD44s and CD44v6. A restricted panel consisting of CD44s and CD44v6 will discriminate NSCLC from SCLC with a sensitivity of 67% and a specificity of 100%. In adenocarcinoma CD44s expression was significantly correlated with lymph node metastases (p=0.007) while CD44v6 expression was more significantly associated with tumor size (p=0.0032). CONCLUSIONS: CD44s and CD44v6 are expressed in certain types of lung cancer. In adenocarcinoma CD44s and CD44v6 expression is significantly correlated with lymph node metastases and tumor size. PMID- 21279959 TI - Choosing the optimum swab for canal drying in cemented total hip replacement. AB - During total hip replacement, the reamed medullary canal of the femur should represent a clean, dry surface. We compared the effectiveness of 4 different cotton swabs in a synthetic femur that had been reamed to receive a size 1 Exeter trial prosthesis. Swab sizes included a 2.5 cm and a 7.5 cm diameter ribbon gauze, a pair of 10 x 7.5 cms square swabs and a larger surgical packing swab (20 x 22 cms). The ability of the swabs to pack the femur was assessed using both plain radiographs and colour photography (after femoral section). After retrieval from the canal, the total dry weight of the cotton inserted was recorded as was the time required to withdraw each swab type. Only the narrowest (2.5 cm diameter) ribbon gauze was found to achieve comprehensive packing as far as the cement restrictor but it required a longer time for removal, and there may be a case for using larger ribbon gauze in larger femora. The mass of cotton delivered to the canal using small square swabs was half of that delivered using narrow ribbon gauze. PMID- 21279960 TI - Neck reconstruction (AIIMS Box Technique) in the management of large femoral neck defects. AB - Large femoral neck defects are frequently associated with neglected femoral neck fractures, sequelae of infection, and failed fixation devices. The AIIMS box technique of neck reconstruction has the objectives of femoral head preservation and restoration of hip function in such cases. 32 patients (age range 20-56, average 38 years) with large femoral neck defects were treated from January 1990 to May 1997 and were followed up for a minimum of 10 years (range 10 to 17 years). The neck defect was converted into a box using osteal flaps (base from greater trochanter, anterior wall from head, quadratus femoris muscle pedicle graft posteriorly), which was filled with cancellous bone autograft, and stabilized with cancellous screws. Union occurred in all patients in a mean time of 16 weeks (range 12-20 weeks). One patient developed avascular necrosis (AVN) of femoral head. 8 out of 32 results were classified as excellent, 22 good and 2 fair. Good functional mobility was seen in all but two patients. Complications included coxa vara in two patients, and fixation problems in four patients. Large femoral neck defects can be managed successfully by this technique with preservation of the viability of the femoral head, and therefore the procedure should be considered in appropriate cases, particularly in young adults. PMID- 21279961 TI - Avascular necrosis following fracture-dislocation of the hip and spontaneous relocation. AB - Injuries occurring during soccer tend to occur with lower energy transfer than in some other contact sports. Tibial and femoral shaft fractures occasionally occur, but pelvic fractures are rare. We report a case of a missed posterior acetabular rim fracture, caused by a low energy trauma playing soccer, complicated by the development of avascular necrosis (AVN) of the femoral head and subsequent osteoarthritis. PMID- 21279962 TI - Clinical experience of revision of metal on metal hip arthroplasty for aseptic lymphocyte dominated vasculitis associated lesions (ALVAL). AB - There has been growing concern regarding the systemic and local effects of metal ions released from metal-on-metal hip resurfacings and total hip replacements, including the development of aseptic lymphocyte dominated vasculitis associated lesions (ALVAL). We describe our experience of treating 13 patients with failed metal on metal bearing hip prostheses secondary to this condition. Hip revision occurred at mean of 45 months following primary surgery. Groin pain was present in all patients. Other common features included large bursal swelling and mechanical symptoms. 3 patients developed their symptoms immediately postoperatively. The mean time to presentation was 21 months. Radiographic abnormalities noted included 3 patients with cup loosening and 2 patients with neck thinning. The mean cup inclination was 52 degrees. Surgical findings included bursal swellings and creamy brown fluid. Osteolysis was rarely seen. 12 revisions were achieved with primary implants and all patients had immediate symptomatic improvement. One patient was left with a pseudoarthrosis due to extensive soft tissue destruction. Diagnosis of ALVAL was confirmed histologically. The diagnosis of ALVAL should be considered in patients with unexplained pain from a metal on metal bearing hip arthroplasty. Surgical findings are typical and symptoms tend to resolve reliably following conversion to an alternative bearing surface. PMID- 21279963 TI - Cemented impaction grafting with moulded intramedullary mesh for femoral stem revision--long-term results. AB - To address femoral bone loss in revision total hip arthroplasty (THA) we developed a technique involving impaction allografting with intramedullary mesh moulded around the revision stem, to prevent excessive cement penetration of the allograft. The length of the revision stem was determined by the extent of femoral bone loss. Between 1986 and 1998, 32 such procedures were undertaken on 28 patients. The mean pre-operative HHS for function was 22 (range 5 to 42), improving to 41 (range 12 to 47) at final follow-up. Only 1 patient presented with aseptic loosening after revision at 147 months (12.2 years). The 12.5 year survivorship for the stem was 92.8%. The technique has provided stable and durable reconstruction, with good new bone formation visible radiologically. It is technically demanding and time consuming, but it avoids the previously published problem of massive subsidence within the bone graft. PMID- 21279964 TI - Medium term follow up of the Biodynamic neck sparing prosthesis. AB - Hip resurfacing (HR) and neck sparing prostheses (NSP) have been advocated for the treatment of arthritis in younger patients. Some complications following HR have been documented in the recent literature, but NSP are not yet supported by clinical follow-up studies of sufficient duration. We present an assessment of the neck sparing "Biodynamic" prosthesis. 153 patients were evaluated in a longitudinal cohort prospective study, with survival analysis, clinical score and radiographic assessment of stability and osteointegration at 41.8 months average follow up. Survival and clinical outcome were similar to most traditional prostheses in the literature. On radiographic analysis we recorded good neck preservation and osteointegration. Only two stem failures were recorded. Poor clinical outcome was related to misalignment of prostheses implanted during the 'learning curve'. The NSP system described may be a good alternative to HR for younger patients. The system is characterized by good survival and clinical and radiographic outcome combined with bone stock preservation. PMID- 21279965 TI - Clinical experience in femoral revision with the modular Profemur R stem. AB - The application of modular femoral stems is constantly increasing in revision hip surgery. From March 2001 to March 2006, we employed the Profemur R modular stem in 35 cases of femoral component revision (31 first revisions and 4 re revisions). The reasons for revision surgery included aseptic loosening in 17 cases, periprosthetic femoral fracture in 8 cases, stem fracture in 3 cases, septic loosening in 2 cases and recurrent dislocation in 1 case. According to the Merle d'Aubugne-Postel score clinical results were very good in 11 cases, good in 9 cases, medium in 5 cases, fair in 4 cases and poor in 4 cases. The main complications included 2 intraoperative diaphyseal fractures treated with multiple cerclage wires and 2 early infections treated with debridement and prolonged antibiotic therapy. One fracture healed in association with temporary wound discharge, and the other resulted in non-union with a femoral varus deformity. This required revision with internal fixation (LCP plate) at 3 months, with a successful result. In one case of stem subsidence femoral revision with a larger Profemur R implant was required. In our retrospective study the Profemur R modular stem has been an effective prosthetic system for femoral reconstruction in case of loosening with Paprosky grade III bone loss and following periprosthetic femoral fractures. PMID- 21279966 TI - Evaluation of intra-pelvic screw position prior to revision total hip arthroplasty--a report of 2 cases. AB - Neurovascular injury during total hip revision arthroplasty is rare, but potentially catastrophic. We report two patients requiring revision total hip arthroplasty with intrapelvic screw tips located close to the iliac artery. The screw tips were separated from artery by a retroperitoneal exposure prior to revision surgery. Assessment of screw position by computed tomography (CT) is important prior to revision total hip arthroplasty. PMID- 21279967 TI - Clinical outcome of Zweymuller total hip arthroplasty for patients with high congenital hip dislocation. AB - Treatment of high congenital dislocation of the hip (CDH) remains controversial. We report the outcome of hip arthroplasty using a cementless threaded cup and a cementless straight stem in patients with high congenital hip dislocation. Between January 2001 and August 2004, 17 patients with high congenital hip dislocation were treated. During surgery, at least 25% of the cup was anchored in bone. By monitoring somatosensory-evoked potentials (SEPs) of the common peroneal nerve we were able to reduce the femoral head into position in the true acetabulum by releasing soft tissues. A bulk autogenous femoral head bone graft was implanted in 5 patients to achieve at least 75% bony coverage of the acertabular component. Follow-up ranged from 48 months to 91 months with an average of 69.7 months. The mean Harris hip score increased from 43 points preoperatively to 89 points at the time of final follow-up (P<0.001). Radiographic analysis showed bony union of the bone graft in all cases. PMID- 21279968 TI - Sciatic palsy after total hip arthroplasty associated with vascular graft occlusion. AB - Sciatic nerve palsy is a well-recognised complication of total hip arthroplasty, and causes include direct injury during surgery (crushing or electrocautery), compression or stretching of the nerve, thermal damage caused by leaked bone cement, trauma during dislocation or reduction of the hip, haematoma, traction caused by leg lengthening or inadvertent intraneural injection from nerve blocks. We describe what we believe to be a case of sciatic nerve ischemia due to intra operative arterial occlusion, and we discuss the vascular anatomy which may have contributed. PMID- 21279969 TI - Growth of the acetabular lateral cartilage in relation to congenital and developmental dysplasia of the hip. An histological study. AB - There are no clear explanations for the spectrum of hip dysplasia nor for the observation that in normal and dysplastic hips, final development may be unpredictable with or without treatment. Immunohistochemical and histological studies of a three month old child's acetabulae were performed. Multiple inclusions were found in the lateral ring epiphysis and in the three flanges of the triradiate cartilage. These inclusions may represent cartilage vessel systems pre-destined to form the secondary centres of ossification. Damage to the primary acetabular growth plates may occur congenitally and help to explain the spectrum of acetabular dysplasia. Damage to one or more of these centres, whether due to instability, displacement or iatrogenic injury, may cause failure of late acetabular development. Hips at risk of damage to the acetabular cartilages should be followed up longer. PMID- 21279970 TI - Hip resurfacing arthroplasty: a series of 140 consecutive hips with a minimum five year follow-up. A clinical, radiological and histological analysis. AB - We reviewed the clinical and radiological outcome at a minimum of five years of 140 consecutive metal-on-metal hip resurfacing (HR) arthroplasties in 132 patients. The mean follow-up was 73 months (62 to 105). Revision of either component was defined as failure. The average Harris hip score (HHS) was 58.6 (25 to 88) preoperatively and 94.4 (60 to 100) at the latest follow-up (p<0.0005). Average University of California Los Angeles (UCLA) activity score was 3.1 (1 to 9) pre-operatively and 6.7 (2 to 10) post-operatively (p<0.0005). The survival after 6 years was 97.8% overall and 98.5% (excluding a post traumatic femoral neck fracture). These good medium-term results suggest that HR is an effective procedure in young and active patients. PMID- 21279971 TI - Relationship between sacral pelvic incidence and acetabular orientation. AB - The importance of the sacral pelvic incidence (SPI) in relation to individual variations of sagittal spinal curvature has become well-recognised. We attempted to determine the relationship between SPI and acetabular orientation. The three dimensional coordinates of 47 homologous points were observed on 51 adult anatomical pelvises (26 female and 25 male). The reference vertical plane was Lewinnek's anterior pelvic plane. 10 angular parameters and 11 linear parameters were defined and calculated. These were expressed both in absolute value (in millimetres) and in "acetabular unit" (relative to the mean value of the right and left acetabular rays). Mean values of the parameters were calculated for all pelvises and according to gender. There were two dominant parameters: the "sacral slope" and the "V pubic angle". "Acetabular tilting" was primarily dependent on the "sacral slope" and its intermediary on the "SPI", while "acetabular anteversion" dependent on the "V pubic angle" via the "angle of prow". It is recommended that positioning of the acetabular cup in total hip arthroplasty relates to anatomical parameters, and to the global sagittal balance of the pelvi spinal unit. PMID- 21279972 TI - More than just a bump: cam-type femoroacetabular impingement and the evolution of the femoral neck. AB - Recent orthopaedic literature has implicated femoroacetabular impingement, the pathologic abutment of structural aberrancies in the proximal femur and acetabular rim, as an important cause of groin pain in young individuals and a potential factor in early idiopathic osteoarthritis. The etiology and risk factors for developing cam-type morphology are still unknown. The osseous anatomy of the proximal femur in humans is the culmination of nearly 400 million years of evolution. Coxa recta and coxa rotunda are the two predominant morphologies in modern animals. While the former, characterized by a straight head-neck junction, is often present in cursorial creatures, the latter, [corrected] distinguished by high offset at this junction, is exemplified in most humans. Based on the ontology and phylogeny of the proximal femur, coxa rotunda probably developed from a more primitive coxa recta. We believe that cam-type morphology is neither a redevelopment of coxa recta nor a malformation such as slipped capital epiphysis. The aspherical osteocartilaginous bump is associated with an extended physis and has been noted to appear during mid-adolescence. While this protuberance may contribute to future pathology, the authors feel that increased loading of the hip, not impingement activities, during late childhood and early adolescence predispose patients to develop this morphology. PMID- 21279973 TI - Expression of c-Kit and its ligand SCF in primary uveal melanoma. AB - PURPOSE: To evaluate the concurrent rate of expression of c-Kit and its ligand stem cell factor (SCF) in uveal melanoma in respect to the further clinical course and the correlation of these markers. METHODS: Paraffin sections from 35 primary uveal melanomas were evaluated immunohistochemically for the expression of c-Kit and SCF. Sixteen cases developed systemic metastasis during the follow up (median: 5 years after diagnosis). The patients who did not develop metastasis (n = 19) had a mean follow-up of 10.6 (9-13) years. Radiation was performed in 6 patients. RESULTS: c-Kit and SCF were expressed in all patients who did or did not develop metastasis in the further clinical course. A mean SCF expression of 77.2% (range 52.7%-97.5%) of tumors that did not develop systemic metastasis and 30.1% (range 2.9%-61.5%) of tumors with systemic metastasis were evident. Uveal melanomas revealing an increased SCF expression were found to develop no metastasis more frequently (p<0.0001; hazard ratio (HR) = 0.963, 95% confidence interval (CI) 0.945-0.981). A mean c-Kit expression of 58.01% (range 5.9%-97.9%) in the group who did not develop metastasis and 48.9% (range 5.0%-95.9%) in the group with systemic metastasis were observed. c-Kit expression was not associated with increased rates of metastasis formation (p = 0.7329; HR = 0.997, 95% CI 0.982-1.013). The correlation between SCF and c-Kit is weak (0.39; 95% CI 0.06 0.63). CONCLUSIONS: c-Kit expression was not found to be associated with metastasis formation. A high SCF expression of primary choroidal melanomas was significantly associated with a lower incidence of systemic metastasis, which indicated SCF as a benign prognostic factor in the further clinical course. PMID- 21279974 TI - Contrast-enhanced magnetic resonance imaging of fibrovascular tissue ingrowth within synthetic hydroxyapatite orbital implants in children. AB - PURPOSE: To assess the usefulness of magnetic resonance imaging (MRI) in assessing fibrovascularization progression into synthetic hydroxyapatite (HA) implants inserted in anophthalmic sockets of children submitted to enucleation. METHODS: We studied 23 HA orbital implants in 23 children who underwent enucleation for retinoblastoma. Each patient was examined by MRI within to 9 to 69 weeks after implant insertion (mean 34 weeks, median 30 weeks). No patient had received chemotherapy or radiotherapy at MRI examination. From each T1-weighted, fat-suppressed enhanced axial examination, the image depicting the center of the implant was identified. Enhancement was evaluated using a 5-point scale. Additionally, possible associated orbital and intracranial pathologies and implant migration or extrusion were evaluated. RESULTS: All patients showed areas of enhancement of the implant consistent with the presence of fibrovascular ingrowth. There was no grade 1 enhancement in our series. Grade 2 was observed in 1 patient (4.34%), grade 3 in 7 patients (30.43%), grade 4 in 11 patients (47.82%), and grade 5 in 4 patients (17.39%). During follow-up there were no cases of clinically evident orbital infection, implant migration, or implant extrusion. No second tumor, optic nerve invasion, orbital extension, tumor relapse, or leptomeningeal brain seeding were noted. CONCLUSIONS: In this series, enhanced MRI showed satisfactory fibrovascular ingrowth of orbital implants since the 13th week after HA spheres insertion, with a trend towards progressive enhancement during the following weeks. The data also confirm the advice to wait at least 5-6 months after enucleation to perform drilling and peg placement. PMID- 21279975 TI - Standard versus bolus photodynamic therapy in circumscribed choroidal hemangioma: functional outcomes. AB - PURPOSE: To compare standard versus bolus photodynamic therapy (PDT) in the treatment of symptomatic circumscribed choroidal hemangioma (CCH). METHODS: Twenty consecutive cases of CCH were included in this prospective randomized study. Each patient was randomly assigned to receive either standard PDT (10 minute 6 mg/mq2 verteporfin infusion; treatment at 15 min; 50 J/cm2; 83 s) or bolus PDT (6 mg/mq2 verteporfin infusion bolus in 1 min; treatment at 5 min; 100 J/cm2; 166 s). Best-corrected visual acuity (BCVA), fundus photography, optical coherence tomography, fluorescein, and indocyanine green angiography were performed at baseline and during follow-up. Retinal sensitivity was tested with microperimetry before and after treatment. Follow-up was longer than 32 months. RESULTS: Mean follow-up was 58+/-11 months. All cases (100%) showed clinical regression of the treated lesion. Neuroretinal and retinal pigment epithelium (RPE) changes were found in 9 (90%) bolus PDT over treated area. No similar RPE changes were found in patients treated with standard PDT. There was a no statistically significant difference in BCVA outcome between the 2 groups (p=0.078). Microperimetry revealed reduced sensitivity over the treated area in 7 bolus PDT vs 1 in standard treated eyes (p=0.008). CONCLUSIONS: Both standard and bolus PDT induce regression of symptomatic CCH. Bolus PDT may cause RPE and retinal changes associated with reduced retinal sensitivity. PMID- 21279976 TI - Pentoxifylline (anti-tumor necrosis factor drug): effective adjuvant therapy in the control of ocular cicatricial pemphigoid. AB - PURPOSE: The detection of tumor necrosis factor-a (TNF-a) in conjunctiva affected by ocular cicatricial pemphigoid (OCP) may indicate that this cytokine plays an important role in its pathogenesis. The purpose of this randomized, controlled, comparative, blinded study was to evaluate the effectiveness of adding pentoxifylline as an anti-TNF-a drug to the well-documented therapy of steroids and cyclophosphamide in controlling OCP. METHODS: Thirty patients with different grades of OCP were included. They were randomly divided into 2 equal groups. Group A patients received pulse steroid and cyclophosphamide therapy; in addition, group B patients received intravenous pentoxifylline. Patients were evaluated before and after therapy clinically, histopathologically, and serologically (serum level of TNF-a). Twenty controls were included to compare their serum TNF-a level with that measured in patients with OCP. RESULTS: Group B patients showed a more significant improvement in their clinical and histopathologic evaluation. The serum TNF-a was significantly higher in OCP cases prior to therapy compared to the control group (p = 0.0001). Following therapy, serum TNF-a showed a more significant reduction in group B patients (77.4 +/- 26.1 to 19.2 +/- 15.6) compared to group A patients (50.3 +/- 14.3 to 36.2 +/- 18.3). CONCLUSIONS: The significantly increased level of serum TNF-a in OCP as compared to controls proves that TNF-a has an important role in the pathogenesis of this disease. The study illustrates that the addition of pentoxifylline to pulse steroid cyclophosphamide therapy is an effective, safe, and economical method in controlling OCP through directly reducing TNF-a levels, with long periods of remission as detected in our 18-month follow-up period. PMID- 21279977 TI - Retinal nerve fiber layer measurement and diagnostic capability of spectral domain versus time-domain optical coherence tomography. AB - PURPOSE: To compare retinal nerve fiber layer (RNFL) thickness and diagnostic capability of spectral-domain (CirrusTM) versus time-domain (Stratus(r)) optical coherence tomography (OCT). METHODS: A total of 123 eyes of 123 subjects including 68 normal, 32 glaucoma suspect, and 23 patients with glaucoma were prospectively recruited for the study. All subjects were scanned by Stratus(r) and CirrusTM OCT in the same session. Average and quadrant peripapillary RNFL measurements by both machines were correlated using Spearman correlation coefficient, and agreement between testing methods was analyzed by Bland-Altman plots. The area under receiver operating characteristic curves (AUC) for glaucoma diagnosis was calculated. RESULTS: Average RNFL thickness were significantly thinner on the CirrusTM compared to the Stratus(r) OCT in normal subjects and glaucoma suspects (p<0.001), but thicker on the CirrusTM OCT in glaucoma patients, though the difference was not statistically significant (p = 0.53). There was good correlation between the measurements in all 3 groups. In normal controls, the average, superior, nasal, inferior, and temporal correlations were r = 0.668, 0.601, 0.508, 0.620, and 0.660, p<0.001, respectively. In glaucomatous eyes, the corresponding values were r = 0.560, p = 0.005; r = 0.423, p = 0.04; r = 0.117, p = 0.596; r = 0.742, p<0.001; r = 0.669, p<0.001, respectively. The 95% limits of agreement of average RNFL thickness were -30.2 to 13.8 um. Area under receiver operating characteristic curves for diagnosing glaucoma were comparable (superior RNFL thickness by CirrusTM 0.925; average RNFL thickness by Stratus(r) 0.987). Highest correlated AUCs were for inferior and temporal quadrants. CONCLUSIONS: Retinal nerve fiber layer measurements on the CirrusTM and Stratus(r) OCT correlate well but do not have clinically acceptable agreement between their measurements. The instruments may not be used interchangeably. PMID- 21279978 TI - Ultrasound biomicroscopic assessment of angle parameters in patients with primary angle closure glaucoma undergoing phacoemulsification. AB - PURPOSE: To evaluate the effect of phacoemulsification and foldable intraocular lens (IOL) implantation on biometric determinants of the anterior chamber angle in primary angle closure glaucoma (PACG) using ultrasound biomicroscopy (UBM). METHODS: Forty-six eyes of 46 patients with chronic PACG and cataract having a patent laser iridotomy were included in this prospective, interventional case series. Angle parameters were measured using UBM before surgery and 3 months after phacoemulsification with IOL implantation. Intraocular pressure (IOP) was measured by applanation tonometer and records of glaucoma medication administered were maintained. Main outcome measures were IOP, central anterior chamber depth (ACD), trabecular iris angle (TIA), and angle opening distance at 250 and 500 um from scleral spur (AOD250 and AOD500). RESULTS: The mean age of study participants was 56.5 +/- 9.9 years (range 44-75). The preoperative mean IOP was 25.0 +/- 5.4 mmHg on maximum antiglaucoma medication, which was reduced to 15.8 +/- 3.8 mmHg (p = 0.0001) at 3 months. Number of antiglaucoma medications also decreased from 2.4 +/- 1.1 to 0.4 +/- 1.1 (p = 0.0001). There was a significant widening of the anterior chamber angle with the TIA increasing significantly after phacoemulsification (p<0.001) with an associated increase in AOD250, AOD500, and ACD (p<0.001). CONCLUSIONS: Phacoemulsification in eyes with PACG results in significant widening of the anterior chamber angle. This results in better IOP control after surgery and decreases the need for glaucoma medications. These findings are of clinical significance in obviating the need for simultaneous filtering surgery in eyes with PACG undergoing phacoemulsification cataract surgery. PMID- 21279979 TI - Risk factors for the development of macular edema in noninfectious uveitis. AB - PURPOSE: Macular edema (ME) is a vision-limiting complication of uveitis. The aim of the present study was to identify risk factors for the development of ME. METHODS: This was an observational, cross-sectional study including 350 patients with noninfectious uveitis. Data were acquired by using a questionnaire. Associations with ME were analyzed for age,alcohol consumption, coffee consumption, cardiovascular risk factors, and level of education. RESULTS: On univariate analysis, patients with ME were older (p<0.001, odds ratio [OR] 1.03) and had a longer history of uveitis (p=0.006, OR 1.03). Patients with university certificate or high school diploma had a significantly reduced risk (OR 0.25, p<0.001) to develop ME compared to patients with less education. For smoking, the number of pack-years was significantly but weakly associated with the presence of ME (p=0.02, OR 1.02). Smokers with a smoking history of more than 20 pack-years had a higher risk for ME (OR = 2.46, confidence interval 1.2-5.2). Daily coffee consumption predisposed to ME (p=0.02, OR 2.1). Arterial hypertension, body mass index, alcohol consumptions, and hypercholesterinemia were not associated with ME. Multivariate analysis confirmed age, coffee consumption,and low education to be risk factors for ME, whereas smoking was lost on multivariate analysis. CONCLUSIONS: Age, low level of education, daily coffee consumption, and possibly smoking are risk factors for ME in patients with noninfectious uveitis. PMID- 21279980 TI - Peripheral visual field thresholds using Humphrey Field Analyzer program 60-4 in normal eyes. AB - PURPOSE: Various methods have been used for testing peripheral visual field disturbances such as defects caused by drug toxicity. Static threshold perimetry with Humphrey Field Analyzer (HFA) is widely available. The aim of this study was to better define the normal thresholds for peripheral visual field (PVF) sensitivity and to refine analysis strategies. METHODS: Automated PVF testing was performed with HFA 60-4 program in 33 normal subjects. Test locations were organized into inner, middle, and outer eccentricity rings and divided into 4 zones: nasal, temporal, superior, and inferior. The threshold visual sensitivity (TVS) in decibels was established for each point. RESULTS: The majority of points with the lowest TVS and highest between-subject variability were located within the nasal area of the outer ring. Points with the highest TVS and least variability were detected in the inner ring and in the temporal area of the middle and outer rings. Mean zone TVS decreased and variability increased with increasing eccentricity. CONCLUSIONS: The areas that demonstrate the highest between-subject consistency and thus might best reveal peripheral visual abnormalities with HFA 60-4 are the inner ring, inferior and temporal zone of the middle ring, and temporal zone of the outer ring. These observations may be useful for developing strategies to detect peripheral field loss at an early stage when central vision is not yet affected. PMID- 21279981 TI - Retinitis pigmentosa inversa with unilateral high myopia with fellow eye optic disc pitting. AB - PURPOSE: To report a possible rare association of bilateral retinitis pigmentosa inversa (RPI) with unilateral high myopia with fellow eye optic disc pitting. METHODS: A 55-year-old man with a history of reduced vision in the right eye since childhood presented with gradually decreasing vision in the left eye. On examination, a -23.00 diopter refractive error and diffuse chorioretinal atrophy consistent with pathologic myopia was found in the right eye. An optic disc pit with posterior pole pigmentary alterations thought to be consequent to a previous neurosensory detachment was found in the left eye. Though the retinal arteriolar attenuation seen in both eyes with an inconsistent history of night blindness since childhood pointed towards the possibility of a concurrently existing rod or rod-cone dystrophy, the posterior pole pigmentary alterations characteristic of RPI were clearly masked by the above pathologies. RESULTS: Optical coherence tomography demonstrated prominent foveal atrophy and an optic disc pit in the left eye. Electroretinography (ERG) demonstrated moderately attenuated amplitudes with prolonged implicit times of rod and cone responses bilaterally. The patient was diagnosed with bilateral RPI and anisometropic amblyopia in the right eye. CONCLUSIONS: This report documents a unique constellation of findings which include bilateral RPI and unilateral high myopia with an optic disc pit in the fellow eye. An ERG confirmation of a dystrophic etiology should be sought in suspicious cases, especially when findings are masked by the concurrent presence of other pathologies. PMID- 21279982 TI - Intravitreal bevacizumab to treat choroidal neovascularization following photodynamic therapy in central serous choroidopathy. AB - PURPOSE: To report the anatomic and functional outcome of intravitreal bevacizumab (IVB) to treat choroidal neovascularization (CNV) following photodynamic therapy (PDT) to treat recurrent central serous choroidopathy (CSC). METHODS: This was an interventional case report in which verteporfin PDT was performed in a case of recurrent CSC. RESULTS: Following PDT, the patient developed juxtafoveal CNV that was later treated by IVB, achieving CNV closure and recovery of visual acuity. CONCLUSIONS: Photodynamic therapy is a useful therapy to treat recurrent CSC, though it may be associated with potentially severe complications such as CNV. Intravitreal bevacizumab seems a good alternative treatment in the management of this condition. PMID- 21279985 TI - Why the ACR? PMID- 21279986 TI - Should bisphosphonates be used for long-term treatment of glucocorticoid-induced osteoporosis? PMID- 21279987 TI - Syk kinase inhibitors for rheumatoid arthritis: trials and tribulations. PMID- 21279988 TI - Histidyl-transfer RNA synthetase: a key participant in idiopathic inflammatory myopathies. PMID- 21279989 TI - How does interferon-alpha insult the vasculature? Let me count the ways. PMID- 21279990 TI - An oral Syk kinase inhibitor in the treatment of rheumatoid arthritis: a three month randomized, placebo-controlled, phase II study in patients with active rheumatoid arthritis that did not respond to biologic agents. AB - OBJECTIVE: To assess the efficacy and safety of R788 (fostamatinib disodium), an inhibitor of spleen tyrosine kinase (Syk), in patients with active rheumatoid arthritis (RA) that did not respond to biologic therapies. METHODS: A total of 219 patients with active RA in whom treatment with biologic agents had failed were enrolled in a 3-month multicenter, randomized, double-blind, placebo controlled trial of R788. The primary end point was the percentage of patients who met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at month 3. Secondary end points included changes in inflammation and damage, as assessed by magnetic resonance imaging (MRI), and changes in the Disease Activity Score. RESULTS: The ACR20 response in the R788 100 mg twice daily group was 38%, versus 37% in the placebo group, at month 3. No significant differences were achieved in the ACR20, ACR50, or ACR70 response levels at 3 months. There were differences between the groups from baseline to month 3 in the secondary end points C-reactive protein (CRP) level and synovitis score on MRI. There were baseline differences in steroid use, prior biologic use, and synovitis score on MRI between the R788 group and the placebo group that may have affected the outcomes. A high placebo response rate was seen in this trial, and exploratory analysis suggested that this may in part have been driven by patients who entered the trial with an elevated erythrocyte sedimentation rate but normal CRP level. CONCLUSION: Our findings indicate that there were no differences in the primary end point between the R788 and placebo groups. Differences were observed between the R788 and placebo groups in secondary end points, particularly in those patients who entered the study with an elevated CRP level. PMID- 21279991 TI - The risk of cancer in patients with rheumatoid arthritis: a nationwide cohort study in Taiwan. AB - OBJECTIVE: The association of rheumatoid arthritis (RA) and malignancy has rarely been explored in Asian populations. The aim of this study was to investigate the relative risk of cancer in Taiwanese patients with RA and to identify groups of patients with a high risk of cancer. METHODS: We conducted a nationwide cohort study of the risk of cancer among 23,644 patients with RA who had no history of malignancies, using the National Health Insurance database of Taiwan from 1996 to 2007. Standardized incidence ratios (SIRs) for various cancers were analyzed. RESULTS: Among the patients with RA, 935 cancers were observed. Patients with RA had an increased risk of cancer (SIR 1.23, 95% confidence interval [95% CI] 1.22 1.23), especially hematologic cancers (SIR 2.74, 95% CI 2.68-2.81). The relative risk of cancer was higher among younger patients. Most cancer cases were detected within the first year following the diagnosis of RA. The relative risk of cancer decreased as the duration of observation increased. Among hematologic cancers, the risk of non-Hodgkin's lymphoma was greatest (SIR 3.54, 95% CI 3.45-3.63). Among solid tumors, the risk of cancers of the kidney and vagina/vulva was highest. A decreased risk of cancers of the cervix and nonmelanoma skin cancer in patients with RA was also observed. CONCLUSION: Patients with RA have an increased risk of cancer, especially hematologic and kidney cancers. The relative risk of cancer in patients with RA decreased with long-term followup. Cancer screening with continued vigilance is recommended for patients with RA. PMID- 21279992 TI - Body mass index and clinical response to infliximab in rheumatoid arthritis. AB - OBJECTIVE: Adipose tissue has immunomodulating effects in rheumatoid arthritis (RA), although the exact role is, at present, unclear. The purpose of this study was to determine whether body mass index (BMI) affects response to infliximab in RA patients investigated prospectively. METHODS: In 89 patients with active RA, the BMI was calculated before initiation of infliximab treatment (3 mg/kg intravenously). After 16 weeks of treatment, changes in disease activity were assessed with the Disease Activity Score in 28 joints (DAS28). RESULTS: The mean +/- SD BMI was 26 +/- 5 kg/m(2) (range 17-42). The BMI correlated positively with the DAS28 at baseline (r = 0.34, P = 0.001). Since selection of study patients according to DAS28 values could influence the clinical response to tumor necrosis factor (TNF) blockade due to regression to the mean because the clinical response is itself based on the change in the DAS28 values, analysis of covariance was used to correct for the baseline DAS28. A highly significant, negative association between the BMI and the absolute decrease in the DAS28 after 16 weeks (P = 0.001) was found also when adjusted for anti-citrullinated protein antibodies. CONCLUSION: Although the infliximab dosage is based on body weight, RA patients with a high BMI responded less well to infliximab, a finding that held true when adjusted for the baseline DAS28 or anti-citrullinated protein antibody status. These results support the notion that adipose tissue may be involved in the pathophysiology of RA and could have implications for other immune-mediated inflammatory conditions treated with TNF antagonists. PMID- 21279993 TI - The PTPN22 R263Q polymorphism is a risk factor for rheumatoid arthritis in Caucasian case-control samples. AB - OBJECTIVE: Recently, a functional PTPN22 variant (R263Q; rs33996649) was found to be associated with systemic lupus erythematosus (SLE). This study was undertaken to analyze the influence of this polymorphism on the risk of rheumatoid arthritis (RA). METHODS: RA patients (n = 5,579) were recruited from outpatient clinics from 6 different countries (Spain, New Zealand, the UK, Norway, The Netherlands, and Germany). Healthy controls (n = 5,392) were recruited from the same areas. There was 100% power to detect an effect equivalent to that observed in SLE. Samples were genotyped for the PTPN22 R263Q (rs33996649) and PTPN22 R620W (rs2476601) polymorphisms using a TaqMan 5'-allele discrimination assay. The effect of the R263Q variant was analyzed in isolation and in combination with the effect of R620W, using Unphased and Stata 10 software. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were determined. RESULTS: The minor allele A of PTPN22 R263Q was significantly associated with a lower risk of RA in the pooled analysis of the 6 populations (P = 0.016, Mantel-Haenszel pooled OR 0.80 [95% CI 0.67-0.96]), independent of the effect of the R620W polymorphism. Both polymorphisms had an additive effect. The more RA risk alleles carried (R263Q G allele, R620W T allele), the higher the RA risk (for 2 versus 1 risk allele P = 0.014, OR 1.28 [95% CI 1.05-1.55], for 3 versus 1 risk allele P = 6.67 * 10(-11) , OR 2.01 [1.63-2.48], and for 4 versus 1 risk allele P = 6.50 * 10(-11) , OR 3.55 [2.42-5.20]). CONCLUSION: Our findings indicate that the minor allele of the PTPN22 R263Q polymorphism is associated with a lower risk of RA. This association is independent of the well-established association between PTPN22 R620W and RA. Both polymorphisms have an additive effect on the risk of RA. PMID- 21279994 TI - Altered expression of microRNA-203 in rheumatoid arthritis synovial fibroblasts and its role in fibroblast activation. AB - OBJECTIVE: MicroRNA (miRNA) are recognized as important regulators of a variety of fundamental biologic processes. Previously, we described increased expression of miR-155 and miR-146a in rheumatoid arthritis (RA) and showed a repressive effect of miR-155 on matrix metalloproteinase (MMP) expression in RA synovial fibroblasts (RASFs). The present study was undertaken to examine alterations in expression of miR-203 in RASFs and analyze its role in fibroblast activation. METHODS: Differentially expressed miRNA in RASFs versus osteoarthritis synovial fibroblasts (OASFs) were identified by real-time polymerase chain reaction (PCR) based screening of 260 individual miRNA. Transfection of miR-203 precursor was used to analyze the function of miR-203 in RASFs. Levels of interleukin-6 (IL-6) and MMPs were measured by real-time PCR and enzyme-linked immunosorbent assay. RASFs were stimulated with IL-1beta, tumor necrosis factor alpha (TNFalpha), lipopolysaccharide (LPS), and 5-azacytidine (5-azaC). Activity of IkappaB kinase 2 was inhibited with SC-514. RESULTS: Expression of miR-203 was higher in RASFs than in OASFs or fibroblasts from healthy donors. Levels of miR-203 did not change upon stimulation with IL-1beta, TNFalpha, or LPS; however, DNA demethylation with 5-azaC increased the expression of miR-203. Enforced expression of miR-203 led to significantly increased levels of MMP-1 and IL-6. Induction of IL-6 by miR-203 overexpression was inhibited by blocking of the NF kappaB pathway. Basal expression levels of IL-6 correlated with basal expression levels of miR-203. CONCLUSION: The current results demonstrate methylation dependent regulation of miR-203 expression in RASFs. Importantly, they also show that elevated levels of miR-203 lead to increased secretion of MMP-1 and IL-6 via the NF-kappaB pathway and thereby contribute to the activated phenotype of synovial fibroblasts in RA. PMID- 21279995 TI - Treatment response, drug survival, and predictors thereof in 764 patients with psoriatic arthritis treated with anti-tumor necrosis factor alpha therapy: results from the nationwide Danish DANBIO registry. AB - OBJECTIVE: To investigate disease activity, treatment response, and drug survival, and predictors thereof, among Danish patients with psoriatic arthritis (PsA) receiving their first treatment series with a tumor necrosis factor alpha (TNFalpha) inhibitor. METHODS: Patients with PsA were identified from a prospective nationwide rheumatologic database, the Danish biologics registry DANBIO, using data registered from 2000-2009. Information was obtained on the patients' clinical response to anti-TNFalpha treatment (defined as achievement of the American College of Rheumatology 20% [ACR20], ACR50, and ACR70 improvement criteria or a European League Against Rheumatism [EULAR] good response at least once during the first 6 months of treatment) and duration and rate of drug adherence (referred to as drug survival), as well as predictors thereof. RESULTS: Of 764 patients with PsA, 320 received adalimumab, 260 infliximab, and 184 etanercept. Median drug survival was 2.9 years, and 1-year and 2-year drug survival rates were 70% and 57%, respectively. Clinical parameters that showed improvement over 6 months were the C-reactive protein (CRP) level, Health Assessment Questionnaire score, and 28-joint Disease Activity Score. Male sex, CRP level >10 mg/liter, concomitant methotrexate use, and low patient health visual analog scale score at baseline were associated with longer drug survival. Improvement was achieved by 59%, 45%, 24%, and 54% of patients according to the ACR20, ACR50, ACR70 response criteria and EULAR good response, respectively. A CRP level >10 mg/liter was predictive of the improvement responses (odds ratio [OR] 2.6 for ACR20, OR 3.0 for ACR50, OR 3.6 for ACR70, and OR 2.2 for EULAR good response). CONCLUSION: In these patients with PsA treated with their first TNFalpha inhibitor in clinical practice, high drug adherence and responder rates were observed. Moreover, increased levels of CRP at baseline were associated with both good treatment responses and continued treatment, which may be of clinical value in selecting the patients most likely to benefit from treatment with TNFalpha inhibitors. PMID- 21279996 TI - Synovial inflammation in patients undergoing arthroscopic meniscectomy: molecular characterization and relationship to symptoms. AB - OBJECTIVE: Traumatic and degenerative meniscal tears have different anatomic features and different proposed etiologies, yet both are associated with the development or progression of osteoarthritis (OA). In established OA, synovitis is associated with pain and progression, but a relationship between synovitis and symptoms in isolated meniscal disease has not been reported. Accordingly, we sought to characterize synovial pathology in patients with traumatic meniscal injuries and determine the relationships between inflammation, meniscal and cartilage pathology, and symptoms. METHODS: Thirty-three patients without evidence of OA who were undergoing arthroscopic meniscectomy for meniscal injuries were recruited. Pain and function were assessed preoperatively; meniscal and cartilage abnormalities were documented at the time of surgery. Inflammation in synovial biopsy specimens was scored, and associations between inflammation and clinical outcomes were determined. Microarray analysis of synovial tissue was performed, and gene expression patterns in patients with and those without inflammation were compared. RESULTS: Synovial inflammation was present in 43% of the patients and was associated with worse preoperative pain and function scores, independent of age, sex, or cartilage pathology. Microarray analysis and real time polymerase chain reaction revealed a chemokine signature in synovial biopsy specimens with increased inflammation scores. CONCLUSION: Our findings indicate that in patients with traumatic meniscal injury undergoing arthroscopic meniscectomy without radiographic evidence of OA, synovial inflammation occurs frequently and is associated with increased pain and dysfunction. Synovia with increased inflammation scores exhibit a unique chemokine signature. Chemokines may contribute to the development of synovial inflammation in patients with meniscal pathology; they also represent potential therapeutic targets for reducing inflammatory symptoms. PMID- 21279997 TI - Proteomic analysis of articular cartilage vesicles from normal and osteoarthritic cartilage. AB - OBJECTIVE: Articular cartilage vesicles (ACVs) are extracellular organelles found in normal articular cartilage. While they were initially defined by their ability to generate pathologic calcium crystals in cartilage of osteoarthritis (OA) patients, they can also alter the phenotype of normal chondrocytes through the transfer of RNA and protein. The purpose of this study was to analyze the proteome of ACVs from normal and OA human cartilage. METHODS: ACVs were isolated from cartilage samples from 10 normal controls and 10 OA patients. We identified the ACV proteomes using in-gel trypsin digestion, nanospray liquid chromatography tandem mass spectrometry analysis of tryptic peptides, followed by searching an appropriate subset of the Uniprot database. We further differentiated between normal and OA ACVs by Holm-Sidak analysis for multiple comparison testing. RESULTS: More than 1,700 proteins were identified in ACVs. Approximately 170 proteins satisfied our stringent criteria of having >1 representative peptide per protein present, and a false discovery rate of <=5%. These proteins included extracellular matrix components, phospholipid binding proteins, enzymes, and cytoskeletal components, including actin. While few proteins were seen exclusively in normal or OA ACVs, immunoglobulins and complement components were present only in OA ACVs. Compared to normal ACVs, OA ACVs displayed decreases in matrix proteoglycans and increases in transforming growth factor beta-induced protein betaig-H3, DEL-1, vitronectin, and serine protease HtrA1 (P < 0.01). CONCLUSION: These findings lend support to the concept of ACVs as physiologic structures in articular cartilage. Changes in OA ACVs are largely quantitative and reflect an altered matrix and the presence of inflammation, rather than revealing fundamental changes in composition. PMID- 21279998 TI - Using allopurinol above the dose based on creatinine clearance is effective and safe in patients with chronic gout, including those with renal impairment. AB - OBJECTIVE: To determine the efficacy and safety of increasing the allopurinol dose above the proposed creatinine clearance-based dose in patients with gout. METHODS: Patients with gout who had been receiving a stable dose of allopurinol for >= 1 month were recruited. The dose of allopurinol was increased to obtain the target serum urate level of <0.36 mmoles/liter (<6 mg/dl). Patients were seen monthly until the serum urate concentration was <0.36 mmoles/liter for 3 consecutive months and then were seen every 3 months for at least 12 months. Data were analyzed using the dosage of allopurinol (mg/day) greater than the recommended dosage, as defined by the Hande criteria. RESULTS: Ninety patients were enrolled. The mean age of the patients was 58.7 years (range 27-83 years), 87.9% were male, and 81.9% were of European ancestry. Forty-five patients had a serum urate concentration of >= 0.36 mmoles/liter, and the dose of allopurinol was increased in these patients. Rashes developed in 3 patients, and either allopurinol was discontinued or dose escalation was ceased in these patients. Seven patients were lost to followup or developed intervening medical problems that precluded dose escalation. In 31 (88.8%) of 35 patients who completed the study, the serum urate level was <0.36 mmoles/liter at 12 months. Two of the 5 patients who had a serum urate level >= 0.36 mmoles/liter had undetectable levels of plasma oxypurinol, indicating noncompliance with allopurinol treatment. A significant reduction in the serum urate concentration was observed for all allopurinol doses above the recommended dose. Eighteen of 45 patients were receiving furosemide; those receiving furosemide were just as likely as those not receiving furosemide to achieve a serum urate concentration of <0.36 mmoles/liter (72% versus 88.5%; P = 0.24). Patients receiving furosemide required a higher dose of allopurinol to achieve the target serum urate concentration. No serious adverse events were observed. CONCLUSION: Increasing the dose of allopurinol above the proposed creatinine clearance-based dose led to a significant reduction in the serum urate concentration. Approximately 89% of patients achieved a serum urate concentration of <0.36 mmoles/liter. In this cohort, toxicity was not increased in patients receiving higher doses of allopurinol, including those with renal impairment. PMID- 21279999 TI - Octacalcium phosphate crystals induce inflammation in vivo through interleukin-1 but independent of the NLRP3 inflammasome in mice. AB - OBJECTIVE: To determine the mechanisms involved in inflammatory responses to octacalcium phosphate (OCP) crystals in vivo. METHODS: OCP crystal-induced inflammation was monitored using a peritoneal model of inflammation in mice with different deficiencies affecting interleukin-1 (IL-1) secretion (IL-1alpha(-/-) , IL-1beta(-/-) , ASC(-/-) , and NLRP3(-/-) mice) or in mice pretreated with IL-1 inhibitors (anakinra [recombinant IL-1 receptor antagonist] and anti-IL-1beta). The production of IL-1alpha, IL-1beta, and myeloid-related protein 8 (MRP-8)-MRP 14 complex was determined by enzyme-linked immunosorbent assay. Peritoneal neutrophil recruitment and cell viability were determined by flow cytometry. Depletion of mast cells or resident macrophages was performed by pretreatment with compound 48/80 or clodronate liposomes, respectively. RESULTS: OCP crystals induced peritoneal inflammation, as demonstrated by neutrophil recruitment and up modulation of IL-1alpha, IL-1beta, and MRP-8-MRP-14 complex, to levels comparable with those induced by monosodium urate monohydrate crystals. This OCP crystal induced inflammation was both IL-1alpha- and IL-1beta-dependent, as shown by the inhibitory effects of anakinra and anti-IL-1beta antibody treatment. Accordingly, OCP crystal stimulation resulted in milder inflammation in IL-1alpha(-/-) and IL 1beta(-/-) mice. Interestingly, ASC(-/-) and NLRP3(-/-) mice did not show any alteration in their inflammation status in response to OCP crystals. Depletion of the resident macrophage population resulted in a significant decrease in crystal induced neutrophil infiltration and proinflammatory cytokine production in vivo, whereas mast cell depletion had no effect. Finally, OCP crystals induced apoptosis/necrosis of peritoneal cells in vivo. CONCLUSION: These data indicate that macrophages, rather than mast cells, are important for initiating and driving OCP crystal-induced inflammation. Additionally, OCP crystals induce IL-1 dependent peritoneal inflammation without requiring the NLRP3 inflammasome. PMID- 21280000 TI - Galectin 3 aggravates joint inflammation and destruction in antigen-induced arthritis. AB - OBJECTIVE: Galectin 3, an endogenous beta-galactoside-binding lectin, plays an important role in the modulation of immune responses. The finding that galectin 3 is present in the inflamed synovium in patients with rheumatoid arthritis suggests that the protein is associated with the pathogenesis of this disease. We undertook this study to investigate the influence of galectin 3 deficiency in a murine model of arthritis. METHODS: Wild-type (WT) and galectin 3-deficient (galectin 3(-/-) ) mice were subjected to antigen-induced arthritis (AIA) through immunization with methylated bovine serum albumin. The concentration of serum cytokines (interleukin-6 [IL-6] and tumor necrosis factor alpha [TNFalpha]) and antigen-specific antibodies was evaluated using a cytometric bead array platform and enzyme-linked immunosorbent assay (ELISA). Cellular IL-17 responses were examined by flow cytometry, ELISA, and enzyme-linked immunospot assay. RESULTS: The joint inflammation and bone erosion of AIA were markedly suppressed in galectin 3(-/-) mice as compared with WT mice. The reduced arthritis in galectin 3(-/-) mice was accompanied by decreased levels of antigen-specific IgG and proinflammatory cytokines. The frequency of IL-17-producing cells in the spleen was reduced in galectin 3(-/-) mice as compared with WT mice. Exogenously added recombinant galectin 3 could partially restore the reduced arthritis and cytokines in galectin 3(-/-) mice. CONCLUSION: Our findings show that galectin 3 plays a pathogenic role in the development and progression of AIA and that the disease severity is accompanied by alterations of antigen-specific IgG levels, systemic levels of TNFalpha and IL-6, and frequency of IL-17-producing T cells. To our knowledge, this is the first report of in vivo evidence that galectin 3 plays a crucial role in the development of arthritis. PMID- 21280001 TI - Regulation of human neutrophil Fcgamma receptor IIa by C5a receptor promotes inflammatory arthritis in mice. AB - OBJECTIVE: Rheumatoid arthritis culminates in joint destruction that, in mouse models of disease, is supported by innate immune molecules, including Fcgamma receptors (FcgammaR) and complement. However, these findings may not be predictive of the outcome in humans, given the structural differences between murine and human activating FcgammaR on neutrophils, a prominent component of joint exudates. The aim of this study was to examine the role of human neutrophil FcgammaRIIa in the development of arthritis and probe the underlying mechanism by which FcgammaRIIa initiates disease. METHODS: K/BxN mouse serum transfer-induced arthritis was examined in mice expressing human FcgammaRIIa on neutrophils but lacking their own activating FcgammaR (gamma-chain-deficient mice). The role of mast cells, complement (C3 and C5a), and CD18 integrins in FcgammaRIIa-initiated disease was examined using cell reconstitution approaches, inhibitors, and functional blocking antibodies, respectively. Crosstalk between the complement receptor C5aR and FcgammaRIIa on neutrophils was evaluated in vitro. RESULTS: The expression of human FcgammaRIIa on neutrophils was sufficient to restore susceptibility to K/BxN serum-induced neutrophil recruitment, synovitis, and bone destruction in gamma-chain-deficient mice. Joint inflammation was robust and proceeded even in the absence of mast cells and vascular permeability, features shown to contribute to disease in wild-type mice. Neutrophil recruitment was dependent on the presence of a CD18 integrin, lymphocyte function-associated antigen 1, and C5aR. In addition, C5aR significantly enhanced FcgammaRIIa mediated phagocytosis and oxidative burst in vitro. CONCLUSION: Human and murine activating FcgammaR on neutrophils are not functionally equivalent, and in humans, they may play a primary role in arthritis. Crosstalk between neutrophil C5aR and FcgammaRIIa is essential for disease progression, thus highlighting a new aspect of complement during the effector phase of inflammatory arthritis. PMID- 21280002 TI - Role of innate immunity in a murine model of histidyl-transfer RNA synthetase (Jo 1)-mediated myositis. AB - OBJECTIVE: Previous studies in humans and in animal models support a key role of histidyl-transfer RNA synthetase (HisRS; also known as Jo-1) in the pathogenesis of idiopathic inflammatory myopathy. While most investigations have focused on the ability of HisRS to trigger adaptive immune responses, in vitro studies clearly indicate that HisRS possesses intrinsic chemokine-like properties capable of activating the innate immune system. The purpose of this study was therefore to examine the ability of HisRS to direct innate immune responses in a murine model of myositis. METHODS: Following intramuscular immunization with soluble HisRS in the absence of exogenous adjuvant, selected strains of mice were evaluated at different time points for histopathologic evidence of myositis. Enzyme-linked immunosorbent assay-based assessment of autoantibody formation and carboxyfluorescein succinimidyl ester proliferation studies provided complementary measures of B cell and T cell responses triggered by HisRS immunization. RESULTS: Compared to appropriate control proteins, a murine HisRS fusion protein induced robust, statistically significant muscle inflammation in multiple congenic strains of C57BL/6 and NOD mice. Time course experiments revealed that this inflammatory response occurred as early as 7 days postimmunization and persisted for up to 7 weeks. Parallel immunization strategies in DO11.10/RAG-2(-/-) and C3H/HeJ (TLR-4(-/-) ) mice indicated that the ability of murine HisRS to drive muscle inflammation was not dependent on B cell receptor or T cell receptor recognition and did not require Toll-like receptor 4 signaling. CONCLUSION: Collectively, the findings of these experiments support a model in which HisRS can trigger both innate and adaptive immune responses that culminate in severe muscle inflammation that is the hallmark of idiopathic inflammatory myopathy. PMID- 21280003 TI - Disease exacerbation by etanercept in a mouse model of alphaviral arthritis and myositis. AB - OBJECTIVE: Mosquito-borne alphaviruses such as chikungunya virus, o'nyong-nyong virus, and Ross River virus (RRV) cause sporadic, sometimes large, outbreaks of rheumatic disease worldwide. This study was designed to test the effect of treating RRV-induced arthritis using the anti-tumor necrosis factor (anti-TNF) drug etanercept in a mouse model of rheumatic disease. METHODS: Mice were infected with RRV and treated with etanercept. Weight gain was measured, tissue viral titers were determined, and histologic changes in muscle and joint tissues were assessed. RESULTS: RRV-infected mice treated with etanercept showed decreased weight gain, higher viral titers in muscle, joints, and blood, and more tissue damage and inflammatory cell recruitment than RRV-infected mice without treatment. CONCLUSION: Anti-TNF therapy is unlikely to be useful in treating alphaviral arthritides. During alphaviral epidemics, careful monitoring of patients being treated with anti-TNF agents may be warranted. PMID- 21280004 TI - Interferon-alpha priming promotes lipid uptake and macrophage-derived foam cell formation: a novel link between interferon-alpha and atherosclerosis in lupus. AB - OBJECTIVE: An increased risk of premature atherosclerosis has been associated with systemic lupus erythematosus (SLE), and type I interferon (IFN) has been shown to play a pathogenic role in human SLE. The aim of this study was to determine whether IFNalpha is involved in the development of atherosclerosis in patients with SLE by promoting lipid uptake and macrophage-derived foam cell formation, which is a crucial step in early atherosclerosis. METHODS: The effects of IFNalpha on lipid uptake and foam cell formation were determined by flow cytometry and oil red O staining. Messenger RNA and protein expression of scavenger receptors (SRs) was examined. Promoter activity was detected by luciferase reporter assay. Expression of macrophage SR class A (SR-A) and IFN inducible genes (IFIGs) was measured in peripheral blood mononuclear cells obtained from 42 patients with SLE and 42 healthy donors. RESULTS: IFNalpha priming increased the uptake of oxidized low-density lipoprotein and hence enhanced foam cell formation by up-regulating SR-A expression. IFNalpha increased SR-A expression via enhancing its promoter activities. Examination using signaling inhibitors revealed that a phosphatidylinositol 3-kinase/Akt signaling pathway appeared to be involved in this process. Notably, SR-A messenger RNA was significantly increased in patients with SLE compared to normal subjects and positively correlated with IFIG expression. CONCLUSION: Our data suggest that IFNalpha priming up-regulated the expression of SR-A in human monocyte/macrophages, leading to increased lipid uptake and foam cell formation. Activation of the IFN signaling pathway may be linked to the risk of atherosclerosis by affecting plaque formation in patients with SLE. These findings provide novel insights into the mechanisms of and potential therapeutic approaches to premature atherosclerosis in patients with SLE. PMID- 21280005 TI - Systemic lupus erythematosus serum deposits C4d on red blood cells, decreases red blood cell membrane deformability, and promotes nitric oxide production. AB - OBJECTIVE: Systemic lupus erythematosus (SLE) is characterized by intravascular activation of the complement system and deposition of complement fragments (C3 and C4) on plasma membranes of circulating cells, including red blood cells (RBCs). The aim of this study was to address whether this process affects the biophysical properties of RBCs. METHODS: Serum and RBCs were isolated from patients with SLE and healthy controls. RBCs from healthy universal donors (type O, Rh negative) were incubated with SLE or control serum. We used flow cytometry to assess complement fragment deposition on RBCs. RBC membrane deformability was measured using 2-dimensional microchannel arrays. Protein phosphorylation levels were quantified by Western blotting. RESULTS: Incubation of healthy universal donor RBCs with sera from patients with SLE, but not with control sera, led to deposition of C4d fragments on the RBCs. Complement-decorated RBCs exhibited significant decreases in both membrane deformability and flickering. Sera from SLE patients triggered a transitory Ca(++) influx in RBCs that was associated with decreased phosphorylation of beta-spectrin and with increased phosphorylation of band 3, two key proteins of RBC cytoskeleton. Finally, incubation with SLE sera led to the production of nitric oxide by RBCs, whereas this did not occur with control sera. CONCLUSION: Our data suggest that complement activation in patients with SLE leads to calcium-dependent cytosketeletal changes in RBCs that render them less deformable, probably impairing their flow through capillaries. This phenomenon may negatively affect the delivery of oxygen to the tissues. PMID- 21280006 TI - Alterations in Wnt pathway activity in mouse serum and kidneys during lupus development. AB - OBJECTIVE: The canonical Wnt/beta-catenin pathway was recently identified as a factor in the pathogenesis of several renal diseases. The aim of this study was to evaluate Wnt signaling activity during disease development in a murine model of lupus nephritis. METHODS: Wnt activity and Dkk-1 expression were serially assayed in the serum and kidneys of (NZB * NZW)F(1) mice during progression of lupus nephritis. The effects of serum obtained from mice with lupus and serum equivalent concentrations of Dkk-1 on mesangial cells were assessed in vitro. RESULTS: Gene expression analyses revealed increased canonical Wnt pathway activity in kidneys during development of lupus nephritis, paralleled by an increase in renal and serum levels of the Wnt inhibitor Dkk-1. Sera obtained from proteinuric-stage (NZB * NZW)F(1) mice showed strong Wnt-inhibitory effects in vitro. Dkk-1 concentrations comparable to those observed in lupus-prone mice induced apoptosis in tubular and mesangial cells in vitro, whereas no such effect was seen for the range of concentrations observed in young prediseased mice and control BALB/c mice. CONCLUSION: These data demonstrate that renal Wnt signaling activity is increased in lupus and is accompanied by an increase in renal and serum levels of Dkk-1. The Wnt pathway is involved in the turnover of extracellular matrix constituents and represents a potential mediator of the morphologic changes that occur within the glomerulus during the development of nephritis. Furthermore, increased levels of Dkk-1 serve as a potential proapoptotic stimulus in vitro and possibly in vivo and could be an important element in the initiation and progression of systemic and end-organ disease manifestations in systemic lupus erythematosus. PMID- 21280007 TI - HLA-DRB1*0407 and *1304 are risk factors for scleroderma renal crisis. AB - OBJECTIVE: To examine the predictive role of HLA genetic markers in scleroderma renal crisis (SRC), beyond the known clinical correlates, in a large population of patients with systemic sclerosis (SSc). METHODS: SSc patients from the Scleroderma Family Registry and DNA Repository, the Genetics versus Environment in Scleroderma Outcomes Study, and the rheumatology division registry at the University of Texas Health Science Center at Houston were included in the study. Relevant clinical data were obtained by chart review, and autoantibodies were detected utilizing commercially available kits. HLA class II genotyping was performed on extracted and purified genomic DNA. RESULTS: Overall, 1,519 SSc patients were included in the study, of whom 90 (6%) had developed SRC. Among the 90 patients with SRC, the diffuse cutaneous disease subtype was found in 76%, antitopoisomerase antibodies (antitopo) in 9%, anticentromere antibodies (ACAs) in 2%, and anti-RNA polymerase III (anti-RNAP III) in 50% of patients. In multivariate analyses of clinical and demographic parameters, diffuse disease type and anti-RNAP III were strong risk factors for the presence of SRC, whereas ACAs and antitopo were protective. In the final multivariate analysis, which included HLA alleles, HLA-DRB1*0407 (odds ratio [OR] 3.21, 95% confidence interval [95% CI] 1.27-8.08; P = 0.013) and DRB1*1304 (OR 4.51, 95% CI 1.30 15.65; P = 0.018) were identified as independent risk factors for SRC. Only 3 clinical characteristics, diffuse disease type, anti-RNAP III, and ACAs, remained significantly associated with SRC in the final model. CONCLUSION: The results of this study suggest that DRB1*0407 and *1304 are independent risk factors, beyond the known clinical correlates, for the development of SRC. PMID- 21280008 TI - MicroRNA expression profiles as biomarkers of minor salivary gland inflammation and dysfunction in Sjogren's syndrome. AB - OBJECTIVE: MicroRNA reflect physiologic and pathologic processes and may be used as biomarkers of concurrent pathophysiologic events in complex settings such as autoimmune diseases. We generated microRNA microarray profiles from the minor salivary glands of control subjects without Sjogren's syndrome (SS) and patients with SS who had low-grade or high-grade inflammation and impaired or normal saliva production, to identify microRNA patterns specific to salivary gland inflammation or dysfunction. METHODS: MicroRNA expression profiles were generated by Agilent microRNA arrays. We developed a novel method for data normalization by identifying housekeeping microRNA. MicroRNA profiles were compared by unsupervised mathematical methods to test how well they distinguish between control subjects and various subsets of patients with SS. Several bioinformatics methods were used to predict the messenger RNA targets of the differentially expressed microRNA. RESULTS: MicroRNA expression patterns accurately distinguished salivary glands from control subjects and patients with SS who had low-degree or high-degree inflammation. Using real-time quantitative polymerase chain reaction, we validated 2 microRNA as markers of inflammation in an independent cohort. Comparing microRNA from patients with preserved or low salivary flow identified a set of differentially expressed microRNA, most of which were up-regulated in the group with decreased salivary gland function, suggesting that the targets of microRNA may have a protective effect on epithelial cells. The predicted biologic targets of microRNA associated with inflammation or salivary gland dysfunction identified both overlapping and distinct biologic pathways and processes. CONCLUSION: Distinct microRNA expression patterns are associated with salivary gland inflammation and dysfunction in patients with SS, and microRNA represent a novel group of potential biomarkers. PMID- 21280009 TI - Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series. AB - OBJECTIVE: To examine the safety and efficacy of the interleukin-1 (IL-1) receptor antagonist anakinra as first-line therapy for systemic juvenile idiopathic arthritis (JIA). METHODS: Patients with systemic JIA receiving anakinra as part of initial disease-modifying antirheumatic drug (DMARD) therapy were identified from 11 centers in 4 countries. Medical records were abstracted using a standardized instrument, and resulting data were analyzed to characterize concomitant therapies, clinical course, adverse events, and predictors of outcome. RESULTS: Among 46 patients meeting inclusion criteria, anakinra monotherapy was used in 10 patients (22%), while 67% received corticosteroids and 33% received additional DMARDs. Outcomes were evaluated at a median followup interval of 14.5 months. Fever and rash resolved within 1 month in >95% of patients, while C-reactive protein and ferritin normalized within this interval in >80% of patients. Active arthritis persisted at 1 month in 39% of patients, at 3 months in 27%, and at >6 months of followup in 11%. Approximately 60% of patients, including 8 of 10 receiving anakinra monotherapy, attained a complete response without escalation of therapy. Disease characteristics and treatment were similar in partial and complete responders, except that partial responders were markedly younger at onset (median age 5.2 years versus 10.2 years; P = 0.004). Associated adverse events included documented bacterial infection in 2 patients and hepatitis in 1 patient. Tachyphylaxis was not observed. CONCLUSION: Anakinra as first-line therapy for systemic JIA was associated with rapid resolution of systemic symptoms and prevention of refractory arthritis in almost 90% of patients during the interval examined. These results justify further study of IL-1 inhibition as first-line, rather than rescue, therapy in systemic JIA. PMID- 21280012 TI - Osteopontin receptor-dependent regulation of Th1 and Th17 responses in autoimmune diseases: comment on the article by Chen et al. PMID- 21280010 TI - DEK in the synovium of patients with juvenile idiopathic arthritis: characterization of DEK antibodies and posttranslational modification of the DEK autoantigen. AB - OBJECTIVE: DEK is a nuclear phosphoprotein and autoantigen in a subset of children with juvenile idiopathic arthritis (JIA). Autoantibodies to DEK are also found in a broad spectrum of disorders associated with abnormal immune activation. We previously demonstrated that DEK is secreted by macrophages, is released by apoptotic T cells, and attracts leukocytes. Since DEK has been identified in the synovial fluid (SF) of patients with JIA, this study was undertaken to investigate how DEK protein and/or autoantibodies may contribute to the pathogenesis of JIA. METHODS: DEK autoantibodies, immune complexes (ICs), and synovial macrophages were purified from the SF of patients with JIA. DEK autoantibodies and ICs were purified by affinity-column chromatography and analyzed by 2-dimensional gel electrophoresis, immunoblotting, and enzyme-linked immunosorbent assay. DEK in supernatants and exosomes was purified by serial centrifugation and immunoprecipitation with magnetic beads, and posttranslational modifications of DEK were identified by nano-liquid chromatography tandem mass spectrometry (nano-LC-MS/MS). RESULTS: DEK autoantibodies and protein were found in the SF of patients with JIA. Secretion of DEK by synovial macrophages was observed both in a free form and via exosomes. DEK autoantibodies (IgG2) may activate the complement cascade, primarily recognize the C-terminal portion of DEK protein, and exhibit higher affinity for acetylated DEK. Consistent with these observations, DEK underwent acetylation on an unprecedented number of lysine residues, as demonstrated by nano-LC-MS/MS. CONCLUSION: These results indicate that DEK can contribute directly to joint inflammation in JIA by generating ICs through high-affinity interaction between DEK and DEK autoantibodies, a process enhanced by acetylation of DEK in the inflamed joint. PMID- 21280013 TI - A perspective from India on the 2010 rheumatoid arthritis classification criteria: comment on the article by Aletaha et al. PMID- 21280015 TI - Anti-interleukin-17 therapy for degenerated and herniated human intervertebral disc tissues? Comment on the article by Shamji et al. PMID- 21280017 TI - The molecular structure and solution conformation of an acidic heteropolysaccharide from Auricularia auricula-judae. AB - A water soluble acidic heteropolysaccharide named WAF was isolated from Auricularia auricula-judae by extracting with 0.9% NaCl solution. By using gas chromatography, gas chromatography-mass spectrometry, and NMR, its chemical structure was determined to be composed of a backbone of alpha-(1->3)-linked D mannopyranose residues with pendant side groups of beta-D-xylose, beta-D-glucose, or beta-D-glucuronic acid at position O6 or O2. Six fractions prepared from WAF with a weight-average molecular mass (M(w)) between 5.9 * 104 and 64.7 * 104 g/mol were characterized with laser light scattering and viscometry in 0.1M NaCl at 25 degrees C. The dependence of intrinsic viscosity ([eta]) and radius of gyration (R(g)) on M(w) for this polysaccharide were found to be [eta] = 1.79 * 10-3 M(w) 0.96 cm3 g-1 and R(g) = 6.99 * 10-2 M(w) (0.54) nm. The molar mass per unit contour length (M(L)) and the persistence length (L(p)) were estimated to be 1124 nm-1 and 11 nm, respectively. The WAF exhibited a semirigid character typical of linear polysaccharides. Molecular modeling was then used to predict the ordered and disordered states of WAF; the simulated M(L) and L(p) were however much smaller than the experimental values. Taken altogether, the results suggested that WAF formed a duplex in solution. PMID- 21280018 TI - Influence of glycosidic linkage on solution conformational entropy of oligosaccharides: Malto- vs. isomalto- and cello- vs. laminarioligosaccharides. AB - Carbohydrate flexibility can influence a variety of recognition, processing, and end-use properties, at both the polymeric and oligomeric levels. The influence of glycosidic linkage, in particular, on carbohydrate flexibility is manifested in properties such as bacterial selectivity, solution viscosity, and the ability to regulate the spread of disease. Here, we apply size-exclusion chromatography, an entropically controlled technique, to determine the solution conformational entropy (DeltaS) of various oligosaccharide series. The aim of the present study is to highlight how, for a given anomeric configuration, glycosidic linkage affects DeltaS, and to do so quantitatively as a function of degree of polymerization (DP). To this end, we compare DeltaS values for DP 1-7 for malto- and isomaltooligosaccharides, and for DP 1-5 for cello- and laminarioligosaccharides. To do so, we realize previously unattainable separations of disaccharides via a strict size-exclusion mechanism. Also given here are the requirements for extending our method to other oligomers, as well as to biopolymers PMID- 21280019 TI - Nano-fibers produced by viral infection of amoeba visualized by atomic force microscopy. AB - In the course of an atomic force microscopy investigation of mimivirus, we observed that disrupted virions released masses of fibers that were several hundreds of nanometers in length and that could not be explained as nucleic acid or polysaccharide. The fibers exhibited a strong 7 nm periodicity along their lengths. They existed singly, and also as ribbons, cables, and in multi stranded coils. In the aggregate structures, the periodic bands of the individual fibers aligned laterally to produce ribbons and other superstructures having a corresponding pattern of 7 nm periodic transverse bands. We have not observed such fibers in studies of other virus and cellular systems. The fibers are mechanically flexible and resistant to breakage. Occasionally fibers were associated with toroidal protein complexes, assumed to be processive enzyme complexes, apparently in the act of modifying the fibers. PMID- 21280020 TI - Nonadditivity in the alpha-helix to coil transition. AB - The Lifson-Roig Model (LRM) and all its variants describe the alpha-helix to coil transition in terms of additive component-free energies within a free energy decomposition scheme, and these contributions are interpreted through sequence context dependent nucleation and propagation parameters. Although this phenomenological approach is able to adequately fit experimental data on helix content and heat capacity, the number of required parameters increases dramatically with additional sequence variation. Moreover, due to nonadditive competing microscopic effects that are difficult to disentangle within a LRM, large uncertainties within the parameters emerge. We offer an alternative view that removes the need for sequence-context parameterization by focusing on individual microsopic interactions within a free energy decomposition and explicitly account for nonadditivity in conformational entropy through network rigidity using a Distance Constraint Model (DCM). We apply a LRM and a DCM to previously published experimental heat capacity and helix content data for a series of heterogeneous polypeptides. Both models describe the experimental data well, and the parameters from both models are consistent with prior work. However, the number of DCM parameters is independent of sequence-variability, the parameter values exhibit better transferability, and the helix nucleation is predicted by the DCM explicitly through the nonadditive nature of conformational entropy. The importance of these results is that the DCM offers a system independent approach for modeling stability within polypeptides and proteins, where the demonstrated accuracy for the alpha-helix to coil transition over a series of heterogeneous polypeptides described here is one case in point. PMID- 21280021 TI - Nucleic-acid structural deformability deduced from anisotropic displacement parameters. AB - The growing numbers of very well resolved nucleic-acid crystal structures with anisotropic displacement parameters provide an unprecedented opportunity to learn about the natural motions of DNA and RNA. Here we report a new Monte-Carlo approach that takes direct account of this information to extract the distortions of covalent structure, base pairing, and dinucleotide geometry intrinsic to regularly organized double-helical molecules. We present new methods to test the validity of the anisotropic parameters and examine the apparent deformability of a variety of structures, including several A, B, and Z DNA duplexes, an AB helical intermediate, an RNA, a ligand-DNA complex, and an enzyme-bound DNA. The rigid-body parameters characterizing the positions of the bases in the structures mirror the mean parameters found when atomic motion is taken into account. The base-pair fluctuations intrinsic to a single structure, however, differ from those extracted from collections of nucleic-acid structures, although selected base-pair steps undergo conformational excursions along routes suggested by the ensembles. The computations reveal surprising new molecular insights, such as the stiffening of DNA and concomitant separation of motions of contacted nucleotides on opposite strands by the binding of Escherichia coli endonuclease VIII, which suggest how the protein may direct enzymatic action. PMID- 21280022 TI - Temperature-dependent higher order structures of the (Pro-Pro-Gly)10-modified dendrimer. AB - Collagen is the most abundant protein in mammals and is widely used as a biomaterial for tissue engineering and drug delivery. We previously reported that dendrimers and linear polymers, modified with collagen model peptides (Pro-Pro Gly)5, form a collagen-like triple-helical structure; however, its triple helicity needs improvement. In this study, a collagen-mimic dendrimer modified with the longer collagen model peptides, (Pro-Pro-Gly)10, was synthesized and named PPG10-den. Circular dichroism analysis shows that the efficiency of the triple helix formation in PPG10-den was much improved over the original. The X ray diffraction analysis suggests that the higher order structure was similar to the collagen triple helix. The thermal stability of the triple helix in PPG10-den was higher than in the PPG10 peptide itself and our previous collagen-mimic polymers using (Pro-Pro-Gly)5. Interestingly, PPG10-den also assembled at low temperatures. Self-assembled structures with spherical and rod-like shapes were observed by transmission electron microscopy. Furthermore, a hydrogel of PPG10 den was successfully prepared which exhibited the sol-gel transition around 45 degrees C. Therefore, the collagen-mimic dendrimer is a potential temperature dependent biomaterial. PMID- 21280023 TI - A structurally driven analysis of thiol reactivity in mammalian albumins. AB - Understanding the structural basis of protein redox activity is still an open question. Hence, by using a structural genomics approach, different albumins have been chosen to correlate protein structural features with the corresponding reaction rates of thiol exchange between albumin and disulfide DTNB. Predicted structures of rat, porcine, and bovine albumins have been compared with the experimentally derived human albumin. High structural similarity among these four albumins can be observed, in spite of their markedly different reactivity with DTNB. Sequence alignments offered preliminary hints on the contributions of sequence-specific local environments modulating albumin reactivity. Molecular dynamics simulations performed on experimental and predicted albumin structures reveal that thiolation rates are influenced by hydrogen bonding pattern and stability of the acceptor C34 sulphur atom with donor groups of nearby residues. Atom depth evolution of albumin C34 thiol groups has been monitored during Molecular Dynamic trajectories. The most reactive albumins appeared also the ones presenting the C34 sulphur atom on the protein surface with the highest accessibility. High C34 sulphur atom reactivity in rat and porcine albumins seems to be determined by the presence of additional positively charged amino acid residues favoring both the C34 S- form and the approach of DTNB. PMID- 21280024 TI - Moving toward the future of single-molecule-based super-resolution imaging. PMID- 21280025 TI - Free energy simulation to investigate the effect of amino acid sequence environment on the severity of osteogenesis imperfecta by glycine mutations in collagen. AB - Molecular dynamics simulations were carried out to calculate the free energy change difference of two collagen-like peptide models for Gly --> Ser mutations causing two different osteogenesis imperfecta phenotypes. These simulations were performed to investigate the impact of local amino acid sequence environment adjacent to a mutation site on the stability of the collagen. The average free energy differences for a Gly --> Ser mutant relative to a wild type are 3.4 kcal/mol and 8.2 kcal/mol for a nonlethal site and a lethal site, respectively. The free energy change differences of mutant containing two Ser residues relative to the wild type at the nonlethal and lethal mutation sites are 4.6 and 9.8 kcal/mol, respectively. Although electrostatic interactions stabilize mutants containing one or two Ser residues at both mutation sites, van der Waals interactions are of sufficient magnitude to cause a net destabilization. The presence of Gln and Arg near the mutation site, which contain large and polar side chains, provide more destabilization than amino acids containing small and nonpolar side chains. PMID- 21280026 TI - Probing phenylalanine environments in oligomeric structures with pentafluorophenylalanine and cyclohexylalanine. AB - Stabilization of protein structures and protein-protein interactions are critical in the engineering of industrially useful enzymes and in the design of pharmaceutically valuable ligands. Hydrophobic interactions involving phenylalanine residues play crucial roles in protein stability and protein protein/peptide interactions. To establish an effective method to explore the hydrophobic environments of phenylalanine residues, we present a strategy that uses pentafluorophenylalanine (F5Phe) and cyclohexylalanine (Cha). In this study, substitution of F5Phe or Cha for three Phe residues at positions 328, 338, and 341 in the tetramerization domain of the tumor suppressor protein p53 was performed. These residues are located at the interfaces of p53-p53 interactions and are important in the stabilization of the tetrameric structure. The stability of the p53 tetrameric structure did not change significantly when F5Phe containing peptides at positions Phe328 or Phe338 were used. In contrast, the substitution of Cha for Phe341 in the hydrophobic core enhanced the stability of the tetrameric structure with a T(m) value of 100 degrees C. Phe328 and Phe338 interact with each other through pi-interactions, whereas Phe341 is buried in the surrounding alkyl side-chains of the hydrophobic core of the p53 tetramerization domain. Furthermore, high pressure-assisted denaturation analysis indicated improvement in the occupancy of the hydrophobic core. Considerable stabilization of the p53 tetramer was achieved by filling the identified cavity in the hydrophobic core of the p53 tetramer. The results indicate the status of the Phe residues, indicating that the "pair substitution" of Cha and F5Phe is highly suitable for probing the environments of Phe residues. PMID- 21280027 TI - Low temperature removal of inorganic sulfur compounds from mining process waters. AB - Process water and effluents from mining operations treating sulfide rich ores often contain considerable concentrations of metastable inorganic sulfur compounds such as thiosulfate and tetrathionate. These species may cause environmental problems if released to downstream recipients due to oxidation to sulfuric acid catalyzed by acidophilic microorganisms. Molecular phylogenic analysis of the tailings pond and recipient streams identified psychrotolerant and mesophilic inorganic sulfur compound oxidizing microorganisms. This suggested year round thiosalt oxidation occurs. Mining process waters may also contain inhibiting substances such as thiocyanate from cyanidation plants. However, toxicity experiments suggested their expected concentrations would not inhibit thiosalt oxidation by Acidithiobacillus ferrivorans SS3. A mixed culture from a permanently cold (4-6 degrees C) low pH environment was tested for thiosalt removal in a reactor design including a biogenerator and a main reactor containing a biofilm carrier. The biogenerator and main reactors were successively reduced in temperature to 5-6 degrees C when 43.8% of the chemical oxidation demand was removed. However, it was found that the oxidation of thiosulfate was not fully completed to sulfate since low residual concentrations of tetrathionate and trithionate were found in the discharge. This study has demonstrated the potential of using biotechnological solutions to remove inorganic sulfur compounds at 6 degrees C and thus, reduce the impact of mining on the environment. PMID- 21280028 TI - Consolidated bioprocessing (CBP) performance of Clostridium phytofermentans on AFEX-treated corn stover for ethanol production. AB - Consolidated bioprocessing (CBP) is believed to be a potentially cost-efficient and commercially viable way to produce cellulosic biofuels. In this study, we have evaluated the performance of the CBP organism Clostridium phytofermentans (ATCC 700394) on AFEX-treated corn stover (AFEX-CS). Fermentation conditions including temperature, inoculation size, nutrients, and initial pH were investigated. At optimal conditions with 0.5% (w/w) glucan loading of AFEX-CS, C. phytofermentans hydrolyzed 76% of glucan and 88.6% of xylan in 10 days. These values reached 87% and 102% of those obtained by simultaneous saccharification and co-fermentation (SSCF) using commercial enzymes and S. cerevisiae 424A. Ethanol titer for CBP was found to be 2.8 g/L which was 71.8% of that yielded by SSCF (3.9 g/L). Decomposition products from AFEX-CS helped to increase ethanol yield somewhat during CBP. Particle size played a crucial role in the enhancement of sugar conversion by CBP. PMID- 21280029 TI - Biofilm image reconstruction for assessing structural parameters. AB - The structure of biofilms can be numerically quantified from microscopy images using structural parameters. These parameters are used in biofilm image analysis to compare biofilms, to monitor temporal variation in biofilm structure, to quantify the effects of antibiotics on biofilm structure and to determine the effects of environmental conditions on biofilm structure. It is often hypothesized that biofilms with similar structural parameter values will have similar structures; however, this hypothesis has never been tested. The main goal was to test the hypothesis that the commonly used structural parameters can characterize the differences or similarities between biofilm structures. To achieve this goal (1) biofilm image reconstruction was developed as a new tool for assessing structural parameters, (2) independent reconstructions using the same starting structural parameters were tested to see how they differed from each other, (3) the effect of the original image parameter values on reconstruction success was evaluated, and (4) the effect of the number and type of the parameters on reconstruction success was evaluated. It was found that two biofilms characterized by identical commonly used structural parameter values may look different, that the number and size of clusters in the original biofilm image affect image reconstruction success and that, in general, a small set of arbitrarily selected parameters may not reveal relevant differences between biofilm structures. PMID- 21280030 TI - Resection of hepatocellular carcinoma in patients without cirrhosis. AB - BACKGROUND: Outcomes for patients with hepatocellular carcinoma (HCC) without cirrhosis and factors associated with disease progression remain unclear. The goals of this single-institution study were to define the outcomes for such patients, and to determine factors associated with survival and disease progression. METHODS: This was a retrospective review of consecutive patients with HCC without cirrhosis who underwent hepatic resection between 1985 and 2003. Survival was estimated by the Kaplan-Meier method and risk factors were identified by Cox proportional hazards models. RESULTS: A total of 143 patients were enrolled, of whom 29.4 per cent had identifiable risk factors for chronic liver disease. Major resection (at least three segments) was undertaken in 63.6 per cent of patients. The operative mortality rate was 3.5 per cent. Median disease-free survival was 2.4 years. Multivariable analysis revealed presence of multiple tumours as the only independent predictor of tumour recurrence. Median overall survival was 3.3 years. Factors independently associated with decreased overall survival were multiple tumours, high histological grade, perioperative transfusion, male sex and age at least 66 years. CONCLUSION: Patients with HCC but without cirrhosis have acceptable outcomes after resection. Specific risk factors for the development of HCC in these patients have yet to be defined. PMID- 21280032 TI - Directed in vivo angiogenesis assay and the study of systemic neoangiogenesis in cancer. AB - Targeting neoangiogenesis is a well-established anticancer strategy, however, one of the major problems in angiogenesis research, both at the basic and applied levels, remains the development of suitable in vivo methods for assessing and quantifying the systemic angiogenic response. Therefore, there is an urgent need to adopt technically simple and reproducible methodologies which allow to easily quantify neoangiogenesis independently of morphological parameters. Recently, a reproducible and quantitative method was developed, the directed in vivo angiogenesis assay (DIVAA) consisting of the subcutaneous implantation of surgical grade silicone cylinders closed at one end, called angioreactors, into the dorsal flanks of nude mice. In the past few years, DIVAA has been successfully used in evaluating the inhibition and or enhancement of systemic perturbation of angiogenesis by several molecules. Thus, DIVAA studies systemic angiogenesis and its therapeutic modulation associated to cancer progression and metastasis. PMID- 21280033 TI - Hospital-related morbidity among childhood cancer survivors in British Columbia, Canada: report of the childhood, adolescent, young adult cancer survivors (CAYACS) program. AB - Our study examines inpatient, hospital-related morbidity in a geographically defined cohort of long-term cancer survivors diagnosed before age 20 years in the province of British Columbia (BC), Canada. A total of 1374 survivors diagnosed from 1981 to 1995 surviving at least 5-years postdiagnosis, and a matched sample of 13,740 BC residents, were identified from population registers, and linked to provincial hospitalization records from 1986 to 2000. Logistic regression was used to assess relative risk and effect of sociodemographic, clinical, and temporal factors on risk. Approximately 41% of survivors vs. 17% of the population sample had at least one type of hospitalization-related late morbidity in the observation period (adjusted RR 4.1, 95% CI 3.7-4.5). Those at highest risk were survivors of leukemia (RR 4.8, 95% CI 4.0-5.8), central nervous system tumors (RR 4.8, 95% CI 4.0-5.8), bone and soft tissue sarcomas (RR 4.9, 95% CI 3.8-6.2), and kidney cancer (RR 4.9, 95% CI 3.4-7.0). Adjusted relative risk was elevated for all types of morbidity except pregnancy and birth complications, and highest for neoplasms (including second primary cancers) (RR 21.7, 95% CI 16.3 28.7). Morbidity was elevated for all combinations of primary treatment and highest for those with previous radiation, chemotherapy, and surgery (RR 7.1, 95% CI 5.5-9.0). Over time, morbidity for late effects other than neoplasms became more prevalent. These results suggest that survivors are at increased ongoing risk of many types of hospital-related late morbidity, implying that long-term monitoring for multiple health problems is warranted. PMID- 21280034 TI - Early life exposure to infections and risk of childhood acute lymphoblastic leukemia. AB - Evidence from a growing number of studies indicates that exposure to common infections early in life may be protective against childhood acute lymphoblastic leukemia (ALL). We examined the relationship between three measures of early life exposure to infections-daycare attendance, birth order and common childhood infections in infancy-with the risk of ALL in non-Hispanic white and Hispanic children, two ethnicities that show sociodemographic differences. The analysis included 669 ALL cases (284 non-Hispanic whites and 385 Hispanics) and 977 controls (458 non-Hispanic whites and 519 Hispanics) ages 1-14 years enrolled in the Northern California Childhood Leukemia Study (NCCLS). When the three measures were evaluated separately, daycare attendance by the age of 6 months (odds ratio [OR] for each thousand child-hours of exposure = 0.90, 95% confidence interval [CI]: 0.82-1.00) and birth order (OR for having an older sibling = 0.68, 95% CI: 0.50-0.92) were associated with a reduced risk of ALL among non-Hispanic white children but not Hispanic children, whereas ear infection before age 6 months was protective in both ethnic groups. When the three measures were assessed simultaneously, the influence of daycare attendance (OR = 0.83, 95% CI: 0.73 0.94) and having an older sibling (OR = 0.59, 95% CI: 0.43-0.83) became stronger for non-Hispanic white children. In Hispanic children, a strong reduction in risk associated with ear infections persisted (OR = 0.45, 95% CI: 0.25-0.79). Evidence of a protective role for infection-related exposures early in life is supported by findings in both the non-Hispanic white and Hispanic populations within the NCCLS. PMID- 21280035 TI - Endometrial cancer associated with various forms of postmenopausal hormone therapy: a case control study. AB - This study evaluates the effect of different modes of estradiol-progestagen therapy (EPT) regimens on the postmenopausal endometrial cancer risk in Finland. Women diagnosed with endometrial cancer in 1995-2007 at the age of 50-80 years were identified from the Finnish Cancer Registry (N = 7,261). For each case, three age-matched controls were retrieved from the Finnish Population Register. The use of EPT since 1994 was ascertained from the national Medical Reimbursement Register. Odds ratios (ORs) for different EPT regimens were calculated with conditional logistic regression analysis, adjusted for parity and ages at the deliveries. For use of <5 years, the OR for sequential EPT was 0.67 (95% confidence interval 0.52-0.86), for continuous EPT 0.45 (0.27-0.73), and for estradiol plus levonorgestrel-releasing intrauterine device system (LNG-IUS) 0.39 (0.17-0.88). A decreased risk persisted for the use of continuous EPT and estradiol plus LNG-IUS of up to 10 years. The use of long-cycle EPT showed a tendency toward an elevated risk both for exposure of <5 years (1.40; 0.82-2.38) and for estimated use of >5 years (1.63; 1.12-2.38). For an estimated exposure of >10 years, the risk for endometrial cancer was elevated for both users of long cycle EPT (2.95; 2.40-3.62) and sequential EPT (1.38; 1.15-1.66). Norethisterone acetate and medroxyprogesterone acetate as parts of EPT did not differ in their endometrial cancer risk. The use of tibolone showed no endometrial risk. The use of sequential and long-cycle EPT is associated with an increased risk of endometrial cancer, whereas the use of continuous EPT or estradiol plus LNG-IUS shows a decreased risk. PMID- 21280038 TI - Flybrain neuron database: a comprehensive database system of the Drosophila brain neurons. AB - The long history of neuroscience has accumulated information about numerous types of neurons in the brain of various organisms. Because such neurons have been reported in diverse publications without controlled format, it is not easy to keep track of all the known neurons in a particular nervous system. To address this issue we constructed an online database called Flybrain Neuron Database (Flybrain NDB), which serves as a platform to collect and provide information about all the types of neurons published so far in the brain of Drosophila melanogaster. Projection patterns of the identified neurons in diverse areas of the brain were recorded in a unified format, with text-based descriptions as well as images and movies wherever possible. In some cases projection sites and the distribution of the post- and presynaptic sites were determined with greater detail than described in the original publication. Information about the labeling patterns of various antibodies and expression driver strains to visualize identified neurons are provided as a separate sub-database. We also implemented a novel visualization tool with which users can interactively examine three dimensional reconstruction of the confocal serial section images with desired viewing angles and cross sections. Comprehensive collection and versatile search function of the anatomical information reported in diverse publications make it possible to analyze possible connectivity between different brain regions. We analyzed the preferential connectivity among optic lobe layers and the plausible olfactory sensory map in the lateral horn to show the usefulness of such a database. PMID- 21280039 TI - A molecular mechanism that regulates medially oriented axonal growth of upper layer neurons in the developing neocortex. AB - During development, cortical neurons extend axons to their targets based on their laminar locations and cell types. Here we studied the molecular mechanism that regulates medially oriented axonal growth of upper layer neurons in the developing mouse cortex. Upper layer neurons were labeled with enhanced yellow fluorescent protein (EYFP) by in utero electroporation at E15.5. Cortical slices containing EYFP-labeled cells were dissected at E16, when axonal outgrowth from upper layer neurons is not initiated, and were cultured in an organotypic manner. After 3 days in culture, most labeled cells were found to extend axons medially in the same fashion as those observed in vivo. This oriented growth was disrupted when the lateral side of the cortical slice was removed, indicating that a laterally located repellent is involved in the medially oriented growth. Strikingly, the medially directed growth within the slices was reduced in the medium containing Semaphorin3A (Sema3A) or soluble form of Neuropilin-1 (Npn1), a receptor for Sema3A. Importantly, we found that Sema3A was expressed in a gradient from lateral-high to medial-low within the cortex, and callosal axons originating from upper layer neurons uniquely expressed Npn1. Consistent with these findings, ectopically expressed Sema3A repelled medially oriented elongation of upper layer cell axons in vivo. These results therefore suggest the operation of a repulsive mechanism for medially oriented axon growth of upper layer neurons, and further point to a role for a gradient expression of Sema3A in this directional axon growth along the mediolateral axis within the neocortex. PMID- 21280040 TI - Transmitter release in the neuromuscular synapse of the protein kinase C theta deficient adult mouse. AB - We studied structural and functional features of the neuromuscular junction in adult mice (P30) genetically deficient in the protein kinase C (PKC) theta isoform. Confocal and electron microscopy shows that there are no differences in the general morphology of the endplates between PKC theta-deficient and wild-type (WT) mice. Specifically, there is no difference in the density of the synaptic vesicles. However, the myelin sheath is not as thick in the intramuscular nerve fibers of the PKC theta-deficient mice. We found a significant reduction in the size of evoked endplate potentials and in the frequency of spontaneous, asynchronous, miniature endplate potentials in the PKC theta-deficient neuromuscular preparations in comparison with the WT, but the mean amplitude of the spontaneous potentials is not different. These changes indicate that PKC theta has a presynaptic role in the function of adult neuromuscular synapses. PMID- 21280041 TI - Confocal immunofluorescence study of rat aortic body chemoreceptors and associated neurons in situ and in vitro. AB - Aortic bodies (ABs) are putative peripheral arterial chemoreceptors, distributed near the aortic arch. Though presumed to be analogous to the well-studied carotid bodies (CBs), their anatomical organization, innervation, and function are poorly understood. By using multilabel confocal immunofluorescence, we investigated the cellular organization, innervation, and neurochemistry of ABs in whole mounts of juvenile rat vagus and recurrent laryngeal (V-RL) nerves and in dissociated cell culture. Clusters of tyrosine hydroxylase-immunoreactive (TH-IR) glomus cells were routinely identified within these nerves. Unlike the CB, many neuronal cell bodies and processes, identified by peripherin (PR) and neurofilament/growth associated protein (NF70/GAP-43) immunoreactivity, were closely associated with AB glomus clusters, especially near the V-RL bifurcation. Some neuronal cell bodies were immunopositive for P2X2 and P2X3 purinoceptor subunits, which were also found in nerve terminals surrounding glomus cells. Immunoreactivity against the vesicular acetylcholine transporter (VAChT) was detected in local neurons, glomus cells, and apposed nerve terminals. Few neurons were immunopositive for TH or neuronal nitric oxide synthase. A similar pattern of purinoceptor immunoreactivity was observed in tissue sections of adult rat V-RL nerves, except that glomus cells were weakly P2X3-IR. Dissociated monolayer cultures of juvenile rat V-RL nerves yielded TH-IR glomus clusters in intimate association with PR- or NF70/GAP-43-IR neurons and their processes, and glial fibrillary acidic protein IR type II (sustentacular) cells. Cocultures survived for several days, wherein neurons expressed voltage-activated ionic currents and generated action potentials. Thus, this coculture model is attractive for investigating the role of glomus cells and local neurons in AB function. PMID- 21280042 TI - Projection patterns of single mossy fiber axons originating from the dorsal column nuclei mapped on the aldolase C compartments in the rat cerebellar cortex. AB - Although cerebellar mossy fibers are the most abundant cerebellar afferents and are deeply involved in cerebellar function, the organization of their projection has remained obscure, particularly in relation to cerebellar compartmentalization. The dorsal column nuclei (DCN) are a major source of cerebellar mossy fibers and possess distinct somatotopic representations of specific somatosensory submodalities. We reconstructed individual dextran-labeled DCN axons completely from serial sections and mapped their terminals on the longitudinal cerebellar compartments that were visualized by aldolase C immunostaining to clarify their projection pattern. Individual axons branched and formed about 100 rosette terminals in the cerebellar cortex, but infrequently projected to the cerebellar nuclei (1 out of 15 axons). Cortical terminals were clustered in multiple areas in the vermis and pars intermedia mostly, but not exclusively, ipsilateral to the origin of the axon. The gracile, cuneate, and external cuneate nuclei (ECuN) mainly projected to the copula pyramidis and lobule V, paramedian and simple lobules, and lobules I-V and VIII-IX, respectively, although there was some overlap. The majority of terminals were located within aldolase C negative or lightly positive compartments. However, terminals of a single axon can be located on aldolase C-negative as well as on aldolase C-positive compartments. In particular, the rostral ECuN, which is responsive to shoulder movements, projected consistently to lobule IX, which were mostly aldolase C-positive. In sum, DCN-cerebellar axons project to multiple compartments with terminals clustered mainly in the conventional spinocerebellar region with a coarse topography, which shows some relationship to the cortical compartments defined by aldolase C. PMID- 21280043 TI - Nitric oxidergic cells related to ejaculation in gerbil forebrain contain androgen receptor and respond to testosterone. AB - Two clusters of forebrain neurons-one in the posterodorsal preoptic nucleus (PdPN) and one in the lateral part of the posterodorsal medial amygdala (MeApd) are activated at ejaculation in male rats and gerbils as seen with Fos immunocytochemistry. To understand the functions of these cells and how they respond synchronously, it may be useful to identify their neurotransmitters. Nitric oxide (NO) was of interest because its levels in the preoptic area affect ejaculation, and it could synchronize clustered neurons through paracrine/volume transmission. Thus, we determined whether the ejaculation-related cells produce NO by assessing Fos co-localization with NO synthase (NOS) in recently mated male gerbils. We also studied NOS-Fos co-localization in the medial part of the medial preoptic nucleus (MPNm), where half of the neurons that express Fos after mating reflect ejaculation. We also quantified NOS co-localization with androgen receptor (AR) and NOS sensitivity to androgens at these sites. Without quantification, we extended these analyses throughout the hypothalamus and amygdala. Many mating-activated PdPN, lateral MeApd, and MPNm cells contained NOS (32-54%), and many NOS neurons at these sites expressed Fos (34-51%) or AR (25 69%). PdPN and MPNm NOS cells were sensitive to testosterone but not its androgenic metabolite dihydrotestosterone. The overall distribution of NOS and NOS-AR cells was similar to that in rats. These data suggest that NO may help to synchronize the activation of PdPN and lateral MeApd neurons at ejaculation and that NOS in PdPN and MPNm cells is regulated by testosterone acting via estradiol or without undergoing metabolism. PMID- 21280044 TI - Differential expression of SNAP-25 family proteins in the mouse brain. AB - Soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP)-25 is a neuronal SNARE protein essential for neurotransmitter release from presynaptic terminals. Three palmitoylated SNAP-25 family proteins: SNAP-25a, SNAP-25b, and SNAP-23, are expressed in the brain, but little is known about their distributions and functions. In the present study, we generated specific antibodies to distinguish these three homologous proteins. Immunoblot and immunohistochemical analyses revealed that SNAP-25b was distributed in synapse enriched regions throughout almost the entire brain, whereas SNAP-25a and SNAP-23 were expressed in relatively specific brain regions with partially complementary expression patterns. SNAP-25a and SNAP-25b, but not SNAP-23, were also present in the axoplasm of nerve fibers. The intracellular localization was also different, and although SNAP-25b and SNAP-23 were found primarily in membrane and lipid raft enriched fractions of mouse brain homogenates, a substantial amount of SNAP-25a was recovered in soluble fractions. In PC12 cells, SNAP-25b was localized to the plasma membrane, but SNAP-25a and SNAP-23 were distributed throughout the cytoplasm. The expression and distribution of these three proteins were also differentially regulated in the early postnatal period. These results indicate that the three SNAP-25 family proteins display a differential distribution in the brain as well as in neuronal cells, and possibly play distinct roles. PMID- 21280045 TI - Reassessment of the structural basis of the ascending arousal system. AB - The "ascending reticular activating system" theory proposed that neurons in the upper brainstem reticular formation projected to forebrain targets that promoted wakefulness. More recent formulations have emphasized that most neurons at the pontomesencephalic junction that participate in these pathways are actually in monoaminergic and cholinergic cell groups. However, cell-specific lesions of these cell groups have never been able to reproduce the deep coma seen after acute paramedian midbrain lesions that transect ascending axons at the caudal midbrain level. To determine whether the cortical afferents from the thalamus or the basal forebrain were more important in maintaining arousal, we first placed large cell-body-specific lesions in these targets. Surprisingly, extensive thalamic lesions had little effect on electroencephalographic (EEG) or behavioral measures of wakefulness or on c-Fos expression by cortical neurons during wakefulness. In contrast, animals with large basal forebrain lesions were behaviorally unresponsive and had a monotonous sub-1-Hz EEG, and little cortical c-Fos expression during continuous gentle handling. We then retrogradely labeled inputs to the basal forebrain from the upper brainstem, and found a substantial input from glutamatergic neurons in the parabrachial nucleus and adjacent precoeruleus area. Cell-specific lesions of the parabrachial-precoeruleus complex produced behavioral unresponsiveness, a monotonous sub-1-Hz cortical EEG, and loss of cortical c-Fos expression during gentle handling. These experiments indicate that in rats the reticulo-thalamo-cortical pathway may play a very limited role in behavioral or electrocortical arousal, whereas the projection from the parabrachial nucleus and precoeruleus region, relayed by the basal forebrain to the cerebral cortex, may be critical for this process. PMID- 21280046 TI - Developmental expression of delta-opioid receptors during maturation of the parasympathetic, sympathetic, and sensory innervations of the neonatal heart: early targets for opioid regulation of autonomic control. AB - Evidence is accumulating regarding the local opioid regulation of heart function. However, the exact anatomical location of delta-opioid receptors (DORs) and expression during maturation of the autonomic and sensory innervations of the neonatal heart is unknown. Therefore, we aimed to characterize target sites for opioids in neonatal rat heart intracardiac ganglia at postnatal day (P)1, P7 and adulthood (P56-P84). Rat heart atria were subjected to reverse-transcriptase polymerase chain reaction, Western blot, radioligand binding, and immunofluorescence confocal analysis of DORs with the neuronal markers vesicular acetylcholine transporter (VAChT), tyrosine hydroxylase (TH), calcitonin gene related peptide (CGRP), and substance P (SP). Our results demonstrated DOR mRNA, protein, and binding sites that gradually increased from P1 toward adulthood. Immunofluorescence confocal microscopy showed DOR co-localized with VAChT in large-diameter principal neurons, TH-immunoreactive (IR) small intensely fluorescent (SIF) catecholaminergic cells, and CGRP- or SP-IR afferent nerve terminals arborizing within intracardiac ganglia and atrial myocardium. Co expression of DOR with VAChT-IR neurons was observed from the first day of birth (P1). In contrast, DORs on TH-IR SIF cells or CGRP-IR fibers were not observed in intracardiac ganglia of P1, but rather in P7 rats. The density of nerve fibers in atrial myocardium co-expressing DORs with different neuronal markers increased from neonatal age toward adulthood. In summary, the enhanced DOR expression parallel to the maturation of cardiac parasympathetic, sympathetic, and sensory innervation of the heart suggests that the cardiac opioid system is an important regulator of neonatal and adult heart function through the autonomic nervous system. PMID- 21280050 TI - Development of quality-by-design analytical methods. AB - Quality-by-design (QbD) is a systematic approach to drug development, which begins with predefined objectives, and uses science and risk management approaches to gain product and process understanding and ultimately process control. The concept of QbD can be extended to analytical methods. QbD mandates the definition of a goal for the method, and emphasizes thorough evaluation and scouting of alternative methods in a systematic way to obtain optimal method performance. Candidate methods are then carefully assessed in a structured manner for risks, and are challenged to determine if robustness and ruggedness criteria are satisfied. As a result of these studies, the method performance can be understood and improved if necessary, and a control strategy can be defined to manage risk and ensure the method performs as desired when validated and deployed. In this review, the current state of analytical QbD in the industry is detailed with examples of the application of analytical QbD principles to a range of analytical methods, including high-performance liquid chromatography, Karl Fischer titration for moisture content, vibrational spectroscopy for chemical identification, quantitative color measurement, and trace analysis for genotoxic impurities. PMID- 21280047 TI - SNAP25 expression in mammalian retinal horizontal cells. AB - Horizontal cells mediate inhibitory feedforward and feedback lateral interactions in the outer retina at photoreceptor terminals and bipolar cell dendrites; however, the mechanisms that underlie synaptic transmission from mammalian horizontal cells are poorly understood. The localization of a vesicular gamma aminobutyric acid (GABA) transporter (VGAT) to horizontal cell processes in primate and rodent retinae suggested that mammalian horizontal cells release transmitter in a vesicular manner. Toward determining whether the molecular machinery for vesicular transmitter release is present in horizontal cells, we investigated the expression of SNAP25 (synaptosomal-associated protein of 25 kDa), a key SNARE protein, by immunocytochemistry with cell type-specific markers in the retinae of mouse, rat, rabbit, and monkey. Different commercial antibodies to SNAP25 were tested on vertical sections of retina. We report the robust expression of SNAP25 in both plexiform layers. Double labeling with SNAP25 and calbindin antibodies demonstrated that horizontal cell processes and their endings in photoreceptor triad synapses were strongly labeled for both proteins in mouse, rat, rabbit, and monkey retinae. Double labeling with parvalbumin antibodies in monkey retina verified SNAP25 immunoreactivity in all horizontal cells. Pre-embedding immunoelectron microscopy in rabbit retina confirmed expression of SNAP25 in lateral elements within photoreceptor triad synapses. The SNAP25 immunoreactivity in the plexiform layers and outer nuclear layer fell into at least three patterns depending on the antibody, suggesting a differential distribution of SNAP25 isoforms. The presence of SNAP25a and SNAP25b isoforms in mouse retina was established by reverse transcriptase-polymerase chain reaction. SNAP25 expression in mammalian horizontal cells along with other SNARE proteins is consistent with vesicular exocytosis. PMID- 21280048 TI - Differential structural plasticity of corticostriatal and thalamostriatal axo spinous synapses in MPTP-treated Parkinsonian monkeys. AB - Striatal spine loss is a key pathological feature of Parkinson's disease (PD). Knowing that striatal glutamatergic afferents target dendritic spines, these data appear difficult to reconcile with evidence for an increased expression of the vesicular glutamate transporter 1 (vGluT1) in the striatum of PD patients and 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys, as well as in some electrophysiological studies showing overactivity of the corticostriatal glutamatergic system in models of parkinsonism. To address the possibility that structural changes in glutamatergic afferents may underlie these discrepancies, we undertook an ultrastructural analysis of vGluT1-positive (i.e., corticostriatal) and vGluT2-positive (i.e., mostly thalamostriatal) axo-spinous glutamatergic synapses using a 3D electron microscopic approach in normal and MPTP-treated monkeys. Three main conclusions can be drawn: 1) spines contacted by vGluT1-containing terminals have larger volume and harbor significantly larger postsynaptic densities (PSDs) than those contacted by vGluT2-immunoreactive boutons; 2) a subset of vGluT2-, but not vGluT1-immunoreactive, terminals display a pattern of multisynaptic connectivity in normal and MPTP-treated monkeys; and 3) VGluT1- and vGluT2-positive axo-spinous synapses undergo ultrastructural changes (larger spine volume, larger PSDs, increased PSD perforations, larger presynaptic terminal) indicative of increased synaptic activity in parkinsonian animals. Furthermore, spines contacted by cortical terminals display an increased volume of their spine apparatus in MPTP-treated monkeys, suggesting an increased protein synthesis at corticostriatal synapses. These findings demonstrate that corticostriatal and thalamostriatal glutamatergic axo-spinous synapses display significantly different ultrastructural features, and that both systems undergo complex morphological changes that could underlie the pathophysiology of corticostriatal and thalamostriatal systems in PD. PMID- 21280051 TI - Polymorphs and hydrates of acyclovir. AB - Acyclovir (ACV) has been commonly used as an antiviral for decades. Although the crystal structure of the commercial form, a 3:2 ACV/water solvate, has been known since 1980s, investigation into the structure of anhydrous ACV has been limited. Here, we report the characterization of four anhydrous forms of ACV and a new hydrate in addition to the known hydrate. Two of the anhydrous forms appear as small needles and are stable to air exposure, whereas the third form is morphologically similar but quickly absorbs water from the atmosphere and converts back to the commercial form. The high-temperature modification is achieved by heating anhydrous form I above 180 degrees C. The crystal structures of anhydrous form I and a novel hydrate are reported for the first time. PMID- 21280052 TI - Application of a high-throughput screening procedure with PEG-induced precipitation to compare relative protein solubility during formulation development with IgG1 monoclonal antibodies. AB - Protein solubility is a critical attribute in monoclonal antibody (mAb) formulation development as insolubility issues can negatively impact drug stability, activity, bioavailability, and immunogenicity. A high-throughput adaptation of an experimental method previously established in the literature to determine apparent protein solubility is described, where polyethylene glycol (PEG) is used to reduce protein solubility in a quantitatively definable manner. Utilizing an automated, high-throughput system, an immunoglobulin G (IgG)1 mAb in a variety of buffer conditions was exposed to increasing concentrations of PEG and the amount of protein remaining in solution was determined. Comparisons of PEG(midpt) values (the weight% PEG in solution required to decrease the protein concentration by 50%) to extrapolated values of apparent protein solubility (in the absence of PEG) were performed. The determination of PEG(midpt) by using sigmoidal curve fitting of the entire data set was shown to be the most precise and reproducible approach for use during high-throughput screening experiments. The high-throughput PEG methodology was then applied to the screening of different formulations to optimize relative protein solubility profiles (weight% PEG vs. protein concentration and their corresponding PEG(midpt) values) in terms of solution pH and buffer ions for both human and chimeric IgG1 mAbs. Other comparisons included evaluating relative solubility profiles of an IgG1 mAb produced from different cell lines (Chinese hamster ovary vs. murine) as well as for different IgG1 mAbs (produced from the same cell line) in a series of formulation buffers. Based on these comparisons, it was concluded that rapid, high-throughput determinations of relative protein solubility profiles can be used as a practical, experimental tool to compare mAb preparations and to rank order buffer and pH conditions during formulation development. PMID- 21280053 TI - Synthesis and in vitro studies of cross-linked hydrogel nanoparticles containing amoxicillin. AB - In this paper, we report the synthesis and characterization of a novel cross linked N-isopropylacrylamide-acrylic acid-hydroxyethyl methacrylate [P (NIPASM-AA HEM)] hydrogel nanoparticles (NPs) containing amoxicillin. The aim of present study was to investigate whether these hydrogel NPs have the potential to be used in antibiotic delivery to stomach for treatment of Helicobacter pylori. Amoxicillin-loaded hydrogel NPs were prepared using cross-linked P (NIPASM-AA HEM) as mucoadhesive polymer for the potential use of treating gastric and duodenal ulcers. Aiming at predicting the in vivo behavior of the amoxicillin loaded NPs, the physicochemical properties in terms of entrapment efficiency (EE%), mean diameter, and morphology of NPs was evaluated. The dependence of the EE% of the drug on the organic to aqueous phase ratio was also studied. The profile of amoxicillin release from P (NIPASM-AA-HEM) NPs system was studied under various conditions. In all these experiments, amoxicillin release in the free form was studied by ultraviolet (UV) spectrophotometric analysis. Experimental results showed that at pH 7.4, drug release rises when polymer concentration in the formulation increases; in human plasma on the contrary, drug release is reduced as concentration of the polymer in the formulation rises. In vitro amoxicillin release rate was also higher in pH 1 than that in pH 7.4. About 88.5% of amoxicillin entrapped in the NPs was released in 4 h in the pH 1.0 medium, whereas in phosphate buffer at pH 7.4 no more than 45% was released after 4 h incubation at 37 degrees C. Amoxicillin concentration in rat's gastric tissue was determined. The results of in vivo studies showed that the hydrogel NPs enhance drug concentration at topical site than powder amoxicillin. Thus, amoxicillin-loaded hydrogel NPs may provide therapeutic concentration at a much lower dose that may reduce the adverse effects of amoxicillin in high doses. PMID- 21280054 TI - Detection of chiral defects in crystalline organic solids using solid-state NMR spectroscopy. AB - The marketing of enantiopure pharmaceuticals has become more common due to regulatory and safety concerns surrounding the potential differences in biological activity of opposite enantiomers. However, achieving the desired enantiopurity can be a challenge, and low levels of the undesired enantiomer (chiral impurity) may be present in the final product. The location and nature of this impurity can potentially alter pharmaceutically relevant properties. In this article, we show that it is possible to identify and quantitate the crystallographic locations of small amounts of one enantiomer (l) in the presence of predominantly the opposite D-enantiomer using solid-state nuclear magnetic resonance (NMR) spectroscopy. Proline was used as a model compound, and crystalline samples containing both D- and L-proline were prepared by solvent evaporation, lyophilization, spray drying, and cryogrinding. Isotopic labeling, (13)C cross polarization-magic angle spinning NMR spectral subtractions, and (1)H T(1) spin-lattice relaxation measurements allowed selective observation and characterization of the crystal environments into which the L-proline impurity was incorporated upon concurrent crystallization with D-proline. Results show that L-proline was incorporated in up to four different crystalline forms, including L-proline as a kinetically trapped substitutional chiral defect in the D-proline host crystal lattice. PMID- 21280055 TI - Co-infection with influenza A/H1N1 and A/H3N2 viruses in a patient with influenza like illness during the winter/spring of 2008 in Shanghai, China. AB - Co-infection with different influenza viruses occurs naturally and plays an important role in epidemiology and pathogenicity. To monitor the prevalence of influenza viruses in humans during seasonal influenza epidemics in Shanghai, China, and to analyze the genetic characteristics of the viruses, 365 nasopharyngeal swabs collected from patients with influenza-like illness between January and April 2008, were tested by a colloidal gold assay, viral isolation in Madin-Darby canine kidney (MDCK) cells, direct immunofluorescence assay and multiplex RT-PCR. The genetic characteristics of the viruses were analyzed by full-length PCR amplification of the HA segment. One case of co-infection with influenza A/H1N1 and A/H3N2 viruses was detected among the 7 cases of A/H1N1, 84 cases of A/H3N2 and 48 cases of influenza B virus during the winter/spring of 2008. All influenza A/H1N1 and A/H3N2 isolates were similar, including the co infecting isolates. The present study demonstrates the possibility of natural co infection with different types of influenza viruses in humans, which could provide the opportunity for the occurrence of viral genetic reassortment within the human respiratory tract. PMID- 21280056 TI - Letter to the editor. PMID- 21280057 TI - On a possible mechanistic association of QRS duration and atrial fibrillation. PMID- 21280058 TI - Prenatal diagnosis of congenital vascular rings and slings: sonographic features and perinatal outcome in 81 consecutive cases. AB - OBJECTIVE: To describe the sonographic features and perinatal outcome of congenital vascular rings diagnosed prenatally at a single tertiary care institution. METHODS: All cases of congenital vascular rings diagnosed by prenatal ultrasound between July 2005 and December 2009 were identified at a single referral center using an established perinatal database. The diagnosis was confirmed by postnatal echocardiography for live-born infants or autopsy for terminated cases. RESULTS: The overall incidence of vascular ring during this 5 year period was 0.086% (81 cases among 94 321 women undergoing perinatal ultrasound examination). Forty-four cases had complete O-shaped (n = 3) or U shaped (n = 41) vascular rings, and 37 cases had incomplete C-shaped vascular rings (vascular slings). The most common type of vascular ring seen in 50.6% (41/81) of cases was a right aortic arch with aberrant left subclavian artery. The second most common type was a left aortic arch with an aberrant right subclavian artery [39.5% (32/81)]. Chromosomal analysis was performed prenatally in 46 pregnancies, and six cases (13.0%) of fetal aneuploidy were identified. CONCLUSIONS: Congenital vascular rings can be diagnosed with prenatal ultrasound using the three-vessel trachea view and subsequent fetal echocardiography with particular attention to the relationship of the aortic arches, ductal arches, and the trachea. PMID- 21280059 TI - Cytostatic response of NB69 cells to weak pulse-modulated 2.2 GHz radar-like signals. AB - The present study investigates the response of two human cancer cell lines to a 24-h treatment with a 2.2-GHz, pulse-modulated (5 us pulse duration, 100 Hz repetition rate) radar-like signal at an average SAR = 0.023 W/kg, using a newly designed setup for in vitro exposure to radiofrequency (RF) fields. A complete discretized model of the setup was created for numerical dosimetry using finite difference time-domain (FDTD) software, SEMCAD X. The average dose of RF radiation absorbed by the cultures was calculated to be subthermal (DeltaT < 0.1 degrees C). The RF exposure induced a consistent, statistically significant reduction in the cell number (13.5% below controls, P < 0.001) in the neuroblastoma NB69 line. This effect was accompanied with slight but statistically significant increases in the proportions of cells in phases G0/G1 and G2/M of the cell cycle (6% and 9%, respectively; P < 0.05 over controls). By contrast, the hepatocarcinoma cell line HepG2 did not respond to the same RF treatment. These results indicate that a pulse-modulated RF radiation with high instantaneous amplitude and low average power can induce cytostatic responses on specific, sensitive cancer cell lines. The effect would be mediated, at least in part, by alterations in the kinetics of the cell cycle. PMID- 21280060 TI - Time trends (1998-2007) in brain cancer incidence rates in relation to mobile phone use in England. AB - Mobile phone use in the United Kingdom and other countries has risen steeply since the early 1990's when the first digital mobile phones were introduced. There is an ongoing controversy about whether radio frequency (RF) exposure from mobile phones increases the risk of brain cancer. However, given the widespread use and nearly two decades elapsing since mobile phones were introduced, an association should have produced a noticeable increase in the incidence of brain cancer by now. Trends in rates of newly diagnosed brain cancer cases in England between 1998 and 2007 were examined. There were no time trends in overall incidence of brain cancers for either gender, or any specific age group. Systematic increases in rates for cancers of the temporal lobe in men (0.04 new cases/year) and women (0.02/year) were observed, along with decreases in the rates of cancers of the parietal lobe (-0.03/year), cerebrum (-0.02/year) and cerebellum (-0.01/year) in men only. The increased use of mobile phones between 1985 and 2003 has not led to a noticeable change in the incidence of brain cancer in England between 1998 and 2007. The observed increase in the rate of cancers in the temporal lobe, if caused by mobile phone use, would constitute <1 additional case per 100,000 people in that period. These data do not indicate a pressing need to implement a precautionary principle by means of population-wide interventions to reduce RF exposure from mobile phones. PMID- 21280061 TI - Electromagnetic exposure of scaffold-free three-dimensional cell culture systems. AB - In recent years, a number of in vitro studies have reported on the possible athermal effects of electromagnetic exposure on biological tissue. Typically, this kind of study is performed on monolayers of primary cells or cell lines. However, two-dimensional cell layer systems lack physiological relevance since cells in vivo are organized in a three-dimensional (3D) architecture. In monolayer studies, cell-cell and cell-ECM interactions obviously differ from live tissue and scale-ups of experimental results to in vivo systems should be considered carefully. To overcome this problem, we used a scaffold-free 3D cell culture system, suitable for the exploration of electrophysiological effects due to electromagnetic fields (EMF) at 900 MHz. Dissociated cardiac myocytes were reaggregated into cellular spheres by constant rotation, and non-invasive extracellular recordings of these so-called spheroids were performed with microelectrode arrays (MEA). In this study, 3D cell culture systems were exposed to pulsed EMFs in a stripline setup. We found that inhomogeneities in the EMF due to electrodes and conducting lines of the MEA chip had only a minor influence on the field distribution in the spheroid if the exposure parameters were chosen carefully. PMID- 21280062 TI - Superoxide dismutase deficiency enhances superoxide levels in brain tissues during oxygenation and hypoxia-reoxygenation. AB - To determine whether the mitochondria or cytoplasm produces superoxide during ischemia-reperfusion of the brain, we analyzed lucigenine-enhanced chemiluminescence emission in slices of brain tissue prepared from manganese superoxide dismutase (Mn-SOD)-deficient (Sod2-deficient) and copper and zinc superoxide dismutase (Cu,Zn-SOD)-deficient (Sod1-deficient) mice during oxygenation and hypoxia-reoxygenation. The steady-state level of chemiluminescence under oxygenated conditions was significantly enhanced by a lack of either Sod. We hypothesize that the enhanced chemiluminescence produced by Sod2 and Sod1 deficiency reflects in situ superoxide generation in the mitochondria and cytoplasm, respectively. Based on this hypothesis, the major site of intracellular superoxide generation was assumed to be the cytoplasm. However, mitochondria occupy less cellular space than the cytoplasm. In terms of volume, the superoxide concentration is assumed to be higher in mitochondria than in the cytoplasm. Mn-SOD activity was 18% of the Cu,Zn-SOD activity observed in the wild-type mouse brain. However, when mitochondrial SOD activity was expressed as per volume, it was assumed to be equal to that observed in the cytoplasm. This imbalance between superoxide and SOD activity is expected to cause mitochondrial oxidative damage. The chemiluminescence intensity increased significantly during reoxygenation and was enhanced by Sod2 deficiency but was not significantly affected by Sod1 deficiency. The superoxide concentration in the reoxygenated brain would be higher in the mitochondria than in the cytoplasm. The present study indicated that the major site of intracellular superoxide generation in the brain during oxygenation is the cytoplasm, whereas it is the mitochondria during reoxygenation. PMID- 21280063 TI - NerveCenter: to immortalize a neurology pioneer. PMID- 21280064 TI - NerveCenter: applying the lessons of HeLa cells to today's research. PMID- 21280065 TI - NerveCenter: the future of DNA databanks. PMID- 21280068 TI - The death panel for Charcot-Marie-Tooth panels. PMID- 21280069 TI - New pathway links gamma-secretase to inflammation and memory while sparing notch. PMID- 21280070 TI - Targeting amyloid precursor protein. PMID- 21280071 TI - Dissecting the familial risk of multiple sclerosis. PMID- 21280072 TI - Pain and death: neurodegenerative disease mechanisms in the nociceptor. AB - Chronic peripheral neuropathic pain is the result of abnormal activity in sensory nerves. It is well recognized that this sensory nerve dysfunction can be caused by traumatic, toxic, or metabolic insult to the nerve. In addition, there is growing recognition that neuropathic pain is a frequent manifestation of neurodegenerative diseases. In this regard, important clues to the cellular mechanisms of neuropathic pain may be found by close examination of neurodegenerative diseases (including Parkinson's disease) in which neuropathic pain is often an underappreciated but important clinical manifestation. This approach identifies specific mitochondrial and cytoskeletal mechanisms, previously implicated in the pathophysiology of neurodegenerative diseases in the central nervous system, that might contribute to neuropathic dysfunction in peripheral sensory nerve fibers. Investigations in preclinical models of common peripheral neuropathic pain conditions have supported the idea that a subset of these cellular mechanisms of neurodegeneration can produce painful hyperactivity in primary afferent nociceptors. Importantly, this emerging concept of neurodegenerative disease mechanisms in the primary afferent nociceptor identifies novel molecular targets for the treatment neuropathic pain. PMID- 21280073 TI - Charcot-Marie-Tooth disease subtypes and genetic testing strategies. AB - OBJECTIVE: Charcot-Marie-Tooth disease (CMT) affects 1 in 2,500 people and is caused by mutations in more than 30 genes. Identifying the genetic cause of CMT is often necessary for family planning, natural history studies, and for entry into clinical trials. However genetic testing can be both expensive and confusing to patients and physicians. METHODS: We analyzed data from 1,024 of our patients to determine the percentage and features of each CMT subtype within this clinic population. We identified distinguishing clinical and physiological features of the subtypes that could be used to direct genetic testing for patients with CMT. RESULTS: Of 1,024 patients evaluated, 787 received CMT diagnoses. A total of 527 patients with CMT (67%) received a genetic subtype, while 260 did not have a mutation identified. The most common CMT subtypes were CMT1A, CMT1X, hereditary neuropathy with liability to pressure palsies (HNPP), CMT1B, and CMT2A. All other subtypes accounted for less than 1% each. Eleven patients had >1 genetically identified subtype of CMT. Patients with genetically identified CMT were separable into specific groups based on age of onset and the degree of slowing of motor nerve conduction velocities. INTERPRETATION: Combining features of the phenotypic and physiology groups allowed us to identify patients who were highly likely to have specific subtypes of CMT. Based on these results, we propose a strategy of focused genetic testing for CMT, illustrated in a series of flow diagrams created as testing guides. PMID- 21280074 TI - 5-lipoxygenase as an endogenous modulator of amyloid beta formation in vivo. AB - OBJECTIVE: The 5-lipoxygenase (5-LO) enzymatic pathway is widely distributed within the central nervous system, and is upregulated in Alzheimer's disease. However, the mechanism whereby it may influence the disease pathogenesis remains elusive. METHODS: We evaluated the molecular mechanism by which 5-LO regulates amyloid beta (Abeta) formation in vitro and in vivo by pharmacological and genetic approaches. RESULTS: Here we show that 5-LO regulates the formation of Abeta by activating the cAMP-response element binding protein (CREB), which in turn increases transcription of the gamma-secretase complex. Preventing CREB activation by pharmacologic inhibition or dominant negative mutants blocks the 5 LO-dependent elevation of Abeta formation and the increase of gamma-secretase mRNA and protein levels. Moreover, 5-LO targeted gene disruption or its in vivo selective pharmacological inhibition results in a significant reduction of Abeta, CREB and gamma-secretase levels. INTERPRETATION: These data establish a novel functional role for 5-LO in regulating endogenous formation of Abeta levels in the central nervous system. Thus, 5-LO pharmacological inhibition may be beneficial in the treatment and prevention of Alzheimer's disease. PMID- 21280075 TI - SORCS1 alters amyloid precursor protein processing and variants may increase Alzheimer's disease risk. AB - OBJECTIVE: Sorting mechanisms that cause the amyloid precursor protein (APP) and the beta-secretases and gamma-secretases to colocalize in the same compartment play an important role in the regulation of Abeta production in Alzheimer's disease (AD). We and others have reported that genetic variants in the Sortilin related receptor (SORL1) increased the risk of AD, that SORL1 is involved in trafficking of APP, and that underexpression of SORL1 leads to overproduction of Abeta. Here we explored the role of one of its homologs, the sortilin-related VPS10 domain containing receptor 1 (SORCS1), in AD. METHODS: We analyzed the genetic associations between AD and 16 SORCS1-single nucleotide polymorphisms (SNPs) in 6 independent data sets (2,809 cases and 3,482 controls). In addition, we compared SorCS1 expression levels of affected and unaffected brain regions in AD and control brains in microarray gene expression and real-time polymerase chain reaction (RT-PCR) sets, explored the effects of significant SORCS1-SNPs on SorCS1 brain expression levels, and explored the effect of suppression and overexpression of the common SorCS1 isoforms on APP processing and Abeta generation. RESULTS: Inherited variants in SORCS1 were associated with AD in all datasets (0.001 < p < 0.049). In addition, SorCS1 influenced APP processing. While overexpression of SorCS1 reduced gamma-secretase activity and Abeta levels, the suppression of SorCS1 increased gamma-secretase processing of APP and the levels of Abeta. INTERPRETATIONS: These data suggest that inherited or acquired changes in SORCS1 expression or function may play a role in the pathogenesis of AD. PMID- 21280076 TI - Aggregation of multiple sclerosis genetic risk variants in multiple and single case families. AB - OBJECTIVE: Multiple sclerosis (MS) is a multifactorial neurologic disease characterized by modest but tractable heritability. Genome-wide association studies have identified and/or validated multiple polymorphisms in approximately 16 genes associated with susceptibility. We aimed at investigating the aggregation of genetic MS risk markers in individuals by comparing multiple- and single-case families. METHODS: A weighted log-additive integrative approach termed MS genetic burden (MSGB) was used to account for the well-established genetic variants from previous association studies and meta-analyses. The corresponding genetic burden and its transmission was analyzed in 1,213 independent MS families (810 sporadic and 403 multicase families). RESULTS: MSGB analysis demonstrated a higher aggregation of susceptibility variants in multicase compared to sporadic MS families. In addition, the aggregation of non major histocompatibility complex single nucleotide polymorphisms depended neither on gender nor on the presence or absence of HLA-DRB1*15:01 alleles. Interestingly, although a greater MSGB in siblings of MS patients was associated with an increased risk of MS (odds ratio, 2.1; p = 0.001), receiver operating characteristic curves of MSGB differences between probands and sibs (area under the receiver operator curves, 0.57 [95% confidence interval, 0.53-0.61]) show that case-control status prediction of MS cannot be achieved with the currently available genetic data. INTERPRETATION: The primary interest in the MSGB concept resides in its capacity to integrate cumulative genetic contributions to MS risk. This analysis underlines the high variability of family load with known common variants. This novel approach can be extended to other genetically complex diseases. Despite the emphasis on assembling large case-control datasets, multigenerational, multiaffected families remain an invaluable resource for advancing the understanding of the genetic architecture of complex traits. PMID- 21280077 TI - Phase III dose-comparison study of glatiramer acetate for multiple sclerosis. AB - OBJECTIVE: To evaluate the safety, tolerability, and efficacy of glatiramer acetate (GA) 40 mg compared to a 20mg dose. METHODS: Patients with multiple sclerosis (MS) with >= 1 documented relapse in 12 months prior to screening, or >= 2 documented relapses in 24 months prior to screening, and Expanded Disability Status Scale (EDSS) score 0 to 5.5 were enrolled. Patients were evaluated at screening, baseline, and at months 1, 2, 3, 6, 9, and 12. Primary endpoint was rate of confirmed relapses observed during 12-month study. Analysis was by intent to-treat. RESULTS: A total of 1,155 patients randomized to GA 20 mg (n = 586) or 40 mg (n = 569). The groups were well-matched at baseline on demographic, clinical, and magnetic resonance imaging (MRI) characteristics. The primary endpoint was similar in both groups (relative risk [RR] = 1.07; 95% confidence interval [CI], 0.88-1.31; p = 0.486) with mean annualized relapse rates (ARRs) of 0.33 for the 20 mg group, 0.35 for the 40 mg group, and 0.27 for patients from both groups who completed the entire 1-year treatment. A total of 77% of patients remained relapse-free in both groups. Both groups showed a reduction in mean number of gadolinium-enhancing and new T2 lesions over time with trend for faster reduction in the first trimester with the 40 mg dose compared with 20 mg dose. Both doses were well-tolerated with a safety profile similar to that observed in previous studies of 20 mg GA. INTERPRETATION: In relapsing-remitting MS patients, both the currently-approved GA 20 mg and 40 mg doses were safe and well tolerated, with no gain in efficacy for the higher dose. PMID- 21280078 TI - Axonal damage in relapsing multiple sclerosis is markedly reduced by natalizumab. AB - OBJECTIVE: The impact of present disease-modifying treatments (DMTs) in multiple sclerosis (MS) on nerve injury and reactive astrogliosis is still unclear. Therefore, we studied the effect of natalizumab treatment on the release of 2 brain-specific tissue damage markers into cerebrospinal fluid (CSF) in MS patients. METHODS: CSF samples from 92 patients with relapsing forms of MS were collected in a prospective manner prior to natalizumab treatment and after 6 or 12 months. In 86 cases, natalizumab was used as second-line DMT due to breakthrough of disease activity. The levels of neurofilament light (NFL) and glial fibrillary acidic protein (GFAP) were determined using highly sensitive in house developed enzyme-linked immunosorbent assays. RESULTS: Natalizumab treatment led to a 3-fold reduction of NFL levels, from a mean value of 1,300 (standard deviation [SD], 2,200) to 400 (SD, 270) ng/l (p < 0.001). The later value was not significantly different from that found in healthy control subjects (350 ng/l; SD, 170; n = 28). Subgroup analysis revealed a consistent effect on NFL release, regardless of previous DMT or whether patients had relapses or were in remission within 3 months prior to natalizumab treatment. No differences between pre- and post-treatment levels of GFAP were detected. INTERPRETATION: Our data demonstrate that natalizumab treatment reduces the accumulation of nerve injury in relapsing forms of MS. It is anticipated that highly effective anti inflammatory treatment can reduce axonal loss, thereby preventing development of permanent neurological disability. PMID- 21280079 TI - No evidence of chronic cerebrospinal venous insufficiency at multiple sclerosis onset. AB - OBJECTIVE: An impaired cerebrospinal venous drainage, defined as chronic cerebrospinal venous insufficiency (CCSVI), has been recently hypothesized to be the possible cause of multiple sclerosis (MS). We investigated this hypothesis by studying the occurrence of CCSVI in clinically isolated syndromes (CISs) suggestive of MS. METHODS: Fifty consecutive patients presenting with a CIS and evidence of dissemination in space of the inflammatory lesions (ie, possible MS [pMS]) underwent a detailed diagnostic workup, including extracranial and transcranial venous echo-color Doppler sonography (ECDS-TCDS). Those with CCSVI underwent selective venography. Fifty healthy subjects (HCs) age-matched and gender-matched with pMS patients (HC1); 60 patients with transient global amnesia (TGA); and 60 healthy subjects age-matched and gender-matched with TGA patients (HC2) constituted the control groups and underwent ECDS-TCDS. RESULTS: Mean age of pMS patients was 33.0 +/- 8.5 years (range, 14-50); 35 (70%) were female (female:male ratio, 2.3). TCDS was normal in all pMS patients. One or more abnormal ECDS findings were observed in 26 of 50 (52.0%) pMS patients, in 35 of 110 (31.8%) HCs (HC1+HC2), and in 41 of 60 (68.3%) TGA patients. Eight (16%) pMS patients fulfilled the diagnosis of CCSVI. Selective phlebography performed in 7 of these patients (1 denied consent) did not show venous anomalies. INTERPRETATION: Our findings do not support a cause-effect relationship between CCSVI and pMS. Further studies are warranted to clarify whether CCSVI is associated with later disease stages and characterizes the progressive forms of MS. PMID- 21280080 TI - Mitochondrial dysfunction in distal axons contributes to human immunodeficiency virus sensory neuropathy. AB - OBJECTIVE: Accumulation of mitochondrial DNA (mtDNA) damage has been associated with aging and abnormal oxidative metabolism. We hypothesized that in human immunodeficiency virus-associated sensory neuropathy (HIV-SN), damaged mtDNA accumulates in distal nerve segments, and that a spatial pattern of mitochondrial dysfunction contributes to the distal degeneration of sensory nerve fibers. METHODS: We measured levels of common deletion mutations in mtDNA and expression levels of mitochondrial respiratory chain complexes of matched proximal and distal nerve specimens from patients with and without HIV-SN. In mitochondria isolated from peripheral nerves of simian immunodeficiency virus (SIV)-infected macaques, a model of HIV-SN, we measured mitochondrial function and generation of reactive oxygen species. RESULTS: We identified increased levels of mtDNA common deletion mutation in postmortem sural nerves of patients with HIV-SN as compared to uninfected patients or HIV patients without sensory neuropathy. Furthermore, we found that common deletion mutation in mtDNA was more prevalent in distal sural nerves compared to dorsal root ganglia. In a primate model of HIV-SN, freshly isolated mitochondria from sural nerves of macaques infected with a neurovirulent strain of SIV showed impaired mitochondrial function compared to mitochondria from proximal nerve segments. INTERPRETATION: Our findings suggest that mtDNA damage accumulates in distal mitochondria of long axons, especially in patients with HIV-SN, and that this may lead to reduced mitochondrial function in distal nerves relative to proximal segments. Although our findings are based on HIV-SN, if confirmed in other neuropathies, these observations could explain the length-dependent nature of most axonal peripheral neuropathies. PMID- 21280081 TI - The COMT Val158Met polymorphism affects the response to entacapone in Parkinson's disease: a randomized crossover clinical trial. AB - OBJECTIVE: In Parkinson disease (PD), the selective C-O-methyltransferase (COMT) inhibitor entacapone prolongs the effect of levodopa on motor symptoms (ON time) by increasing its bioavailability. The COMT Val158Met polymorphism is equally distributed in PD patients and modulates COMT activity, which can be high (Val/Val, COMT(HH) ), intermediate (Val/Met, COMT(HL) ), or low (Met/Met, COMT(LL) ). The objective of this study was to determine the response to entacapone in COMT(HH) and COMT(LL) PD patients. METHODS: Thirty-three PD patients, homozygous for the COMT alleles COMT(HH) (n = 17) and COMT(LL) (n = 16), were randomized in a double-blind crossover trial consisting of 2 successive acute levodopa challenges associated with 200mg entacapone or placebo. The primary endpoint was the gain in the best ON time. Secondary endpoints were levodopa pharmacokinetics and COMT activity in red blood cells. RESULTS: The gain in the best ON time was higher in COMT(HH) than in COMT(LL) patients (39 +/- 10 vs 9 +/- 9 minutes, p = 0.04, interaction between treatment and genotype). Area under the concentration over time curve of levodopa increased more after entacapone in COMT(HH) than in COMT(LL) patients (+62 +/- 6% vs +34 +/- 8%, p = 0.01). COMT inhibition by entacapone was higher in COMT(HH) than in COMT(LL) patients (-0.54 +/- 0.07 vs -0.31 +/- 0.06 pmol/min/mg protein, p = 0.02). INTERPRETATION: The COMT(HH) genotype in PD patients enhances the effect of entacapone on the pharmacodynamics and pharmacokinetics of levodopa. The response to entacapone after repeated administrations and in heterozygous patients remains to be determined. PMID- 21280082 TI - Fingolimod provides long-term protection in rodent models of cerebral ischemia. AB - OBJECTIVE: The sphingosine-1-phosphate (S1P) receptor agonist fingolimod (FTY720), that has shown efficacy in advanced multiple sclerosis clinical trials, decreases reperfusion injury in heart, liver, and kidney. We therefore tested the therapeutic effects of fingolimod in several rodent models of focal cerebral ischemia. To assess the translational significance of these findings, we asked whether fingolimod improved long-term behavioral outcomes, whether delayed treatment was still effective, and whether neuroprotection can be obtained in a second species. METHODS: We used rodent models of middle cerebral artery occlusion and cell-culture models of neurotoxicity and inflammation to examine the therapeutic potential and mechanisms of neuroprotection by fingolimod. RESULTS: In a transient mouse model, fingolimod reduced infarct size, neurological deficit, edema, and the number of dying cells in the core and periinfarct area. Neuroprotection was accompanied by decreased inflammation, as fingolimod-treated mice had fewer activated neutrophils, microglia/macrophages, and intercellular adhesion molecule-1 (ICAM-1)-positive blood vessels. Fingolimod treated mice showed a smaller infarct and performed better in behavioral tests up to 15 days after ischemia. Reduced infarct was observed in a permanent model even when mice were treated 4 hours after ischemic onset. Fingolimod also decreased infarct size in a rat model of focal ischemia. Fingolimod did not protect primary neurons against glutamate excitotoxicity or hydrogen peroxide, but decreased ICAM 1 expression in brain endothelial cells stimulated by tumor necrosis factor alpha. INTERPRETATION: These findings suggest that anti-inflammatory mechanisms, and possibly vasculoprotection, rather than direct effects on neurons, underlie the beneficial effects of fingolimod after stroke. S1P receptors are a highly promising target in stroke treatment. PMID- 21280083 TI - Arterial ischemic stroke risk factors: the International Pediatric Stroke Study. AB - OBJECTIVE: To describe presumptive risk factors (RFs) for childhood arterial ischemic stroke (AIS) and explore their relationship with presentation, age, geography, and infarct characteristics. METHODS: Children (29 days-18 years) were prospectively enrolled in the International Pediatric Stroke Study. Risk factors, defined conditions thought to be associated with childhood AIS, were divided into 10 categories. Chi-square tests were used to compare RFs prevalence across regions and age; logistic regression was used to determine whether RFs were associated with particular features at presentation or infarct characteristics. RESULTS: A total of 676 children were included. No identifiable RFs was present in 54 (9%). RFs in others included arteriopathies (53%), cardiac disorders (CDs) (31%), infection (24%), acute head and neck disorders (AHNDs) (23%), acute systemic conditions (ASCs) (22%), chronic systemic conditions (CSCs) (19%), prothrombotic states (PTSs) (13%), chronic head and neck disorders (CHNDs) (10%), atherosclerosis-related RFs (2%), and other (22%). Fifty-two percent had multiple RFs. There was lower prevalence of arteriopathy in Asia, lower prevalence of CSCs in Europe and Australia, higher prevalence of PTSs in Europe, and higher prevalence of ASCs in Asia and South America. Prevalence of CDs and ASCs was highest in preschoolers, arteriopathies in children 5 to 9 years old, and CHNDs were highest in children aged 10 to 14 years. Arteriopathies were associated with focal signs and ASCs, CHNDs, and AHNDs with diffuse signs. Arteriopathies, CSCs, and ASCs were associated with multiple infarcts and CDs with hemorrhagic conversion. INTERPRETATION: RFs, especially arteriopathy, are common in childhood AIS. Variations in RFs by age or geography may inform prioritization of investigations and targeted preventative strategies. PMID- 21280084 TI - Identification of active loci of a human endogenous retrovirus in neurons of patients with amyotrophic lateral sclerosis. AB - OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of motor neurons, of unknown etiology. Previous studies showed reverse transcriptase in serum of ALS patients at levels comparable to human immunodeficiency virus-infected patients; however, the source and significance of the retroviral elements is uncertain. METHODS: Expression of a human endogenous retrovirus (HERV-K) was determined in autopsy brain tissue of patients with ALS and compared to control populations by real-time polymerase chain reaction followed by sequencing of the amplified genes and confirmed by immunostaining. RESULTS: HERV-K pol transcripts were increased in patients with ALS compared to those with chronic systemic illness, but could not be detected in Parkinson disease or in the accidental death controls. Sequencing revealed several actively transcribed loci in the HML-2 and 3 subfamilies of HERV-K, with a specific pattern of expression including intact open reading frames and the transcription of a unique locus in ALS. The frequency of intact pol transcripts was highest in the motor cortex, and the reverse transcriptase protein was localized to cortical neurons of ALS patients. HERV-K expression strongly correlated with TDP-43, a multifunctional protein known to be dysregulated in ALS. INTERPRETATION: We have identified a specific pattern of HERV-K expression in ALS, which may potentially define the pathophysiology of ALS. Targeting of activated genome-encoded retroviral elements may open new prospects for the treatment of ALS. PMID- 21280085 TI - Nuclear transport impairment of amyotrophic lateral sclerosis-linked mutations in FUS/TLS. AB - OBJECTIVE: The fused in sarcoma/translated in liposarcoma (FUS/TLS) protein was recently identified as a cause of familial amyotrophic lateral sclerosis (ALS), as well as a major component of the inclusion bodies found in subtypes of frontotemporal lobar degeneration (FTLD). These diseases now are collectively known as the novel clinical spectrum, FUS proteinopathy. ALS-linked mutations of FUS are clustered in the C-terminal region; however, the molecular properties of mutant FUS remain unclear. To gain insight into the pathogenesis of FUS proteinopathy, we examined the biochemical and cellular characteristics of mutant FUS in expressing cells. METHODS AND RESULTS: Expression of ALS-linked FUS mutations resulted in their assembly into cytoplasmic stress granules (SGs), cellular structures that package mRNA and RNA-binding proteins during cell stress. A deletion mutant series revealed that the C-terminal region in FUS is critical for nuclear retention via Ran guanosine triphosphatase-dependent transport machinery. A parallel study of subcellular distribution revealed that ALS-linked mutants additively disturb the function of the C-terminus for nuclear traffic, resulting in cytoplasmic accumulation and the formation of SGs. INTERPRETATION: This study demonstrates that mutant FUS, which is missing the nuclear traffic activity of the C-terminus, is dislocated to cytoplasm and assembled into SGs, indicating that disruption of translational regulation and metabolism of mRNA via inappropriate/excessive SGs may be crucial for FUS proteinopathies. Our findings provide new biological and pathological insights into the FUS protein that should help our understanding of the pathogenesis of ALS/FTLD. PMID- 21280086 TI - Timing of hormone therapy and dementia: the critical window theory revisited. AB - OBJECTIVE: Although previous research has shown that initiation of postmenopausal estrogen hormone therapy (HT) in late life increases risk of dementia, animal studies and some observational studies have suggested that midlife use of HT may be beneficial; however, this has not been rigorously investigated in large population-based studies. Our objective was to compare HT use in midlife with that in late life on risk of dementia among 5,504 postmenopausal female members of an integrated healthcare delivery system. METHODS: HT use was determined at midlife (mean age, 48.7 years) from a survey in 1964 and in late life (mean age, 76 years) using pharmacy databases from 1994 to 1998. Risk of dementia diagnosis was evaluated with inpatient and outpatient diagnoses made in Neurology, Neuropsychology, and Internal Medicine from 1999 to 2008. Cox proportional hazard models were used to examine effects of HT use at different times on dementia risk with adjustment for age, education, race, body mass index, number of children, and comorbidities. RESULTS: A total of 1,524 women (27%) were diagnosed with dementia during the follow-up period. Compared to women never on HT, those taking HT only at midlife had a 26% decreased risk (multivariate adjusted hazards ratio [aHR], 0.74; 95% confidence interval [CI], 0.58-0.94 ), whereas those taking HT only in late life had a 48% increased risk (aHR, 1.48; 95% CI, 1.10-1.98), and women taking HT at both mid and late life had a similar risk of dementia (aHR, 1.02; 95% CI, 0.78-1.34 ). INTERPRETATION: These findings suggest that use of HT in midlife only may protect against cognitive impairment, whereas HT initiation in late life could have deleterious effects. PMID- 21280087 TI - gamma-Secretase component presenilin is important for microglia beta-amyloid clearance. AB - OBJECTIVE: The cleavage of amyloid precursor protein by gamma-secretase is an important aspect of the pathogenesis of Alzheimer's disease. gamma-Secretase also cleaves other membrane proteins (eg, Notch), which control cell development and homeostasis. Presenilin 1 and 2 are considered important determinants of the gamma-secretase catalytic site. Our aim was to investigate whether gamma secretase can be important for microglial phagocytosis of Alzheimer's disease beta-amyloid. METHODS: We investigated the role of gamma-secretase in microglia activity toward beta-amyloid phagocytosis in cell culture using gamma-secretase inhibitors and small hairpin RNA and presenilin-deficient mice. RESULTS: We found that gamma-secretase inhibitors impair microglial activity as measured in gene expression, protein levels, and migration ability, which resulted in a reduction of soluble beta-amyloid phagocytosis. Moreover, microglia deficient in presenilin 1 and 2 showed impairment in phagocytosis of soluble beta-amyloid. Dysfunction in the gamma-secretase catalytic site led to an impairment in clearing insoluble beta-amyloid from brain sections taken from an Alzheimer's disease mouse model when compared to microglia from wild-type mice. INTERPRETATION: We suggest for the first time, a dual role for gamma-secretase in Alzheimer's disease. One role is the cleavage of the amyloid precursor protein for pathologic beta-amyloid production and the other is to regulate microglia activity that is important for clearing neurotoxic beta-amyloid deposits. Further studies of gamma-secretase mediated cellular pathways in microglia may provide useful insights into the development of Alzheimer's disease and other neurodegenerative diseases, providing future avenues for therapeutic intervention. PMID- 21280089 TI - Gait alterations in healthy carriers of the LRRK2 G2019S mutation. AB - To test for an association between the LRRK2-G2019S mutation and gait, we studied 52 first-degree relatives of patients with Parkinson's disease (PD) who carry this mutation. An accelerometer quantified gait during usual-walking, fast walking, and dual-tasking. Noncarriers (n = 27) and carriers (n = 25) were similar with respect to age, gender, height, and gait speed during all conditions. During dual-tasking and fast-walking, gait variability and the amplitude of the dominant peak of the accelerometer signal were significantly altered among the carriers. These findings support the possibility of previously unidentified, presymptomatic motor changes among relatives who have an increased risk of developing PD. PMID- 21280090 TI - Motor nerve biopsy: clinical usefulness and histopathological criteria. AB - Early differential diagnosis of motor neuropathies (MN) and lower motor neuron diseases (LMND) is important, as prognosis and therapeutic approaches are different. We evaluated the diagnostic contribution of the biopsy of the motor branch of the obturator nerve and gracilis muscle in 21 consecutive patients in which, after proper clinical and neurophysiological studies, the differential diagnosis was still open. At baseline, motor biopsy was performed; diagnostic confirmation was obtained by 2-year clinical follow-up. Our results support the usefulness of this diagnostic procedure for selected cases of MN and LMND. PMID- 21280088 TI - Longitudinal assessment of Abeta and cognition in aging and Alzheimer disease. AB - OBJECTIVE: Assess Abeta deposition longitudinally and explore its relationship with cognition and disease progression. METHODS: Clinical follow-up was obtained 20 +/- 3 months after [11C]Pittsburgh compound B (PiB)-positron emission tomography in 206 subjects: 35 with dementia of the Alzheimer type (DAT), 65 with mild cognitive impairment (MCI), and 106 age-matched healthy controls (HCs). A second PiB scan was obtained at follow-up in 185 subjects and a third scan after 3 years in 57. RESULTS: At baseline, 97% of DAT, 69% of MCI, and 31% of HC subjects showed high PiB retention. At 20-month follow-up, small but significant increases in PiB standardized uptake value ratios were observed in the DAT and MCI groups, and in HCs with high PiB retention at baseline (5.7%, 2.1%, and 1.5%, respectively). Increases were associated with the number of apolipoprotein E epsilon4 alleles. There was a weak correlation between PiB increases and decline in cognition when all groups were combined. Progression to DAT occurred in 67% of MCI with high PiB versus 5% of those with low PiB, but 20% of the low PiB MCI subjects progressed to other dementias. Of the high PiB HCs, 16% developed MCI or DAT by 20 months and 25% by 3 years. One low PiB HC developed MCI. INTERPRETATION: Abeta deposition increases slowly from cognitive normality to moderate severity DAT. Extensive Abeta deposition precedes cognitive impairment, and is associated with ApoE genotype and a higher risk of cognitive decline in HCs and progression from MCI to DAT over 1 to 2 years. However, cognitive decline is only weakly related to change in Abeta burden, suggesting that downstream factors have a more direct effect on symptom progression. PMID- 21280091 TI - Ictal very low frequency oscillation in human epilepsy patients. AB - Using intracranial electroencephalographic recordings, we identified a distinct brain activity in 3 patients with refractory epilepsy characterized by very early occurrence from 8 minutes 10 seconds to 22 minutes 40 seconds prior to clinical seizure onset, periodical appearance of slow negative baseline shift, long interpeak interval of 40 to 120 seconds, and disappearance after clinical seizure. We named this activity "very low frequency oscillation" (VLFO), which reflected a dynamic process during the preictal state. This observation may render new insight into epileptogenesis and provide additional information concerning the epileptogenic zone as well as prediction of epileptic seizures. PMID- 21280092 TI - Large genomic deletions: a novel cause of Ullrich congenital muscular dystrophy. AB - Two mutational mechanisms are known to underlie Ullrich congenital muscular dystrophy (UCMD): heterozygous dominant negatively-acting mutations and recessively-acting loss-of-function mutations. We describe large genomic deletions on chromosome 21q22.3 as a novel type of mutation underlying recessively inherited UCMD in 2 families. Clinically unaffected parents carrying large genomic deletions of COL6A1and COL6A2also provide conclusive evidence that haploinsufficiency for COL6A1and COL6A2is not a disease mechanism for Bethlem myopathy. Our findings have important implications for the genetic evaluation of patients with collagen VI-related myopathies as well as for potential therapeutic interventions for this patient population. PMID- 21280094 TI - Comment on validation of diagnostic criteria for variant Creutzfeldt-Jakob disease. PMID- 21280095 TI - Is pathological gambling in Parkinson's disease reduced by amantadine? PMID- 21280097 TI - Assessment of JC virus DNA in blood and urine from natalizumab-treated patients. PMID- 21280099 TI - A 2-year-old girl positive for 2009 AH1N1 pandemic influenza. PMID- 21280101 TI - 4-Aminopyridine: new life for an old drug. Reply. PMID- 21280103 TI - Synthesis of 2-mercaptobenzimidazole derivatives as potential anti-microbial and cytotoxic agents. AB - A series of novel 2-(1H-benzimidazol-2-ylsulfanyl)-N-(4-oxo-2-phenyl-thiazolidin 3yl)-acetamide 5a-j have been synthesized from various aldehydes and 2-(5-phenyl [1,3,4]-oxadiazol-2-ylmethylsulfanyl)-1H-benzimidazole 6a-j from various benzoic acids. These compounds were screened for their in-vitro anti-bacterial activity against Staphylococcus aureus and Enterococcus faecalis as Gram positive, Klebsiella pneumoniae and Escherichia coli as Gram negative bacterial strains and for in-vitro anti-fungal activity against Asperigillus fumigatus and Candida albicans. The in vitro cytotoxic properties were studied using brine shrimp bioassay. Results revealed that, compounds 5b, 5d, 5g, 5i, 6b, 6e, 6f, and 6i showed excellent activity against a panel of microorganisms. The cytotoxic activities of 5b, 5g, 5i, 6b, 6f, 6h, and 6i were found to be good. All the newly synthesized compounds were characterized by elemental analysis, IR, (1)H-NMR, (13)C-NMR and MS. PMID- 21280104 TI - Salvage of compromised free flaps in trauma cases with combined modalities. AB - Using the microsurgical technique for reconstruction in trauma cases represents a challenge for the reconstructive surgeon. Several methods of salvaging of a compromised free flap have been reported, among them: intravenous heparin washing, thrombolitic therapy, thrombectomy, use of grafts and others. Here, we present our experience from nine cases and a review of the literature regarding the use of various modalities for free flap salvage in trauma cases, and their results. Data was collected from trauma cases in our institutions over a period of 2 years, where reconstruction was performed using microsurgical techniques, and where subsequent complications required some type of salvage procedure. The techniques that were used for the salvage included: intravascular irrigation with heparin, papaverine and lidocaine; administration of continuous intravenous heparin, use of the Fogarty catheter, flap washing with streptokinase, and adventitia stripping. The free flaps used were latissimus dorsi, serratus anterior, and the anteromedial thigh flap. Either vein or artery thromboses were identified during the procedure or immediately after surgery in seven patients. Two patients had prolonged spasms of the recipient artery with low flow. In all cases, the No. 2 Fogarty catheter was used for thrombectomy and also for release of the vessel spasm. There was only one complete failure among these patients, and partial necrosis was encountered in three. From our experience and review of the literature, we offer an algorithm for determining treatment strategies in a range of flap salvage situations. PMID- 21280105 TI - A novel and inexpensive retractor individually usable for microsurgical training. PMID- 21280106 TI - Histological evaluation of microsurgical revascularized bone in the intraoral cavity: does it remain alive? AB - INTRODUCTION: Microsurgical revascularized fibula graft is a standard for the reconstruction of mandible or maxilla after major resection. Usually, screwed implants are inserted as a second procedure for dental rehabilitation. A lot has been published about the advantages of vascularized bone grafts, but until now there is only little information about long-term viability of inserted bone grafts. MATERIAL AND METHODS: In this study, previously inserted vascularized fibula bone grafts were examined histologically. Bone biopsies were taken during dental implant insertion procedure in average of 19 months after insertion of bone grafts from 10 patients. RESULTS: All bone biopsies showed partially or totally necrotic bone, although clinical examination and postoperative monitoring of the revascularized bone remained unremarkable. CONCLUSION: The results of histological examination are surprising, due to the fact of previous insertion of a vascularized bone graft and pretended osseointegration of inserted dental implants with satisfying primary stability. Therefore, one would expect vital bone. For better understanding how much viability is really necessary for sufficient remodeling of inserted bone grafts for adequate functional load, further studies should be performed. PMID- 21280107 TI - Pd-catalyzed borylative polycyclization of enediynes to alkylboronates. AB - Pd-catalyzed bicyclization of 1-ene-6,11-diynes with bis(pinacolato)diboron smoothly affords synthetically useful homoallylic alkylboronates under mild conditions, avoiding the use of highly nucleophilic or basic reagents. One C-B bond and two new C-C bonds are created, and two new stereogenic centers are stereospecifically formed in a single tandem operation. The obtained products suggest a cascade reaction in which the last step is the transmetalation of bis(pinacolato)diboron, this being faster than a possible beta-hydride elimination process. The reaction is general and has been applied to enediynes with different substituents on the alkene unit, the bridging groups, and the alkyne moiety. The bicyclized alkylboronates thus obtained can be functionalized by oxidation to alcohols, formation of trifluoroborate salts, or by Suzuki coupling reactions. PMID- 21280108 TI - Size- and shape-dependent activity of metal nanoparticles as hydrogen-evolution catalysts: mechanistic insights into photocatalytic hydrogen evolution. AB - The catalytic activity of Pt nanoparticles (PtNPs) with different sizes and shapes was investigated in a photocatalytic hydrogen-evolution system composed of the 9-mesityl-10-methylacridinium ion (Acr(+)-Mes: photocatalyst) and dihydronicotinamide adenine dinucleotide (NADH: electron donor), based on rates of hydrogen evolution and electron transfer from one-electron-reduced species of Acr(+)-Mes (Acr.-Mes) to PtNPs. Cubic PtNPs with a diameter of (6.3+/-0.6) nm exhibited the maximum catalytic activity. The observed hydrogen-evolution rate was virtually the same as the rate of electron transfer from Acr.-Mes to PtNPs. The rate constant of electron transfer (k(et)) increased linearly with increasing proton concentration. When H(+) was replaced by D(+), the inverse kinetic isotope effect was observed for the electron-transfer rate constant (k(et)(H)/k(et)(D)=0.47). The linear dependence of k(et) on proton concentration together with the observed inverse kinetic isotope effect suggests that proton coupled electron transfer from Acr.-Mes to PtNPs to form the Pt-H bond is the rate-determining step for catalytic hydrogen evolution. When FeNPs were used instead of PtNPs, hydrogen evolution was also observed, although the hydrogen evolution efficiency was significantly lower than that of PtNPs because of the much slower electron transfer from Acr.-Mes to FeNPs. PMID- 21280109 TI - Pd- and Ni-catalyzed cross-coupling reactions of functionalized organozinc reagents with unsaturated thioethers. AB - A variety of unsaturated thioethers have been subjected to cross-coupling reactions with functionalized zinc reagents in the presence of a transition-metal catalyst. Three different catalytic systems based on Pd(OAc)(2) or [Ni(acac)(2)] and the ligands S-Phos or DPE-Phos gave the best results. N-Heterocyclic thioethers based on a pyridine, pyrimidine, pyrazine, pyridazine, triazine, benzothiazole, benzoxazole, pyrrole, or quinazoline ring, as well as thiomethylacetylenes, serve as electrophiles in this cross-coupling reaction. Aryl-, heteroaryl-, benzylic, and alkylzinc halides with sensitive functionalities, such as ester, nitrile, or ketone groups react at ambient temperature with unsaturated thioethers using a Ni catalyst. The corresponding Pd catalyzed reactions require slightly higher temperatures. Large-scale cross coupling experiments (10-20 mmol) with N-heterocycles are also reported. PMID- 21280110 TI - Low-symmetry uranyl pyrophosphate cage clusters. PMID- 21280111 TI - Neurotransmitter metabolic enzymes and antioxidant status on Alzheimer's disease induced mice treated with Alpinia galanga (L.) Willd. AB - Amyloid beta25-35 (Abeta) peptide may be neurotoxic during the progression of Alzheimer's disease by eliciting reactive oxygen species. The use of folklore medicine is prevalent and plants which possess a rejuvenating property are a large source of natural antioxidants that might afford leads for the development of novel drugs in neurodegenerative disorders. The study was designed to investigate the effect of an ethanol extract of Alpinia galanga (L.) Willd (EAG) on oxidative stress induced Alzheimer's type amnesia in mice. Mice were treated with an experimental extract at 200 mg/kg and 400 mg/kg dose for 14 days and injected with neurotoxic Abeta and the doses were continued for 21 days. Behavioural studies with open field, step-down inhibitory avoidance and a water maze after treatment indicated the acceleration in cognitive function. The elevated levels of acetylcholinesterase and monoamine oxidase enzymes in amnesia induced mice were attenuated by treatment with EAG. The generation of free radicals was decreased due increased activity of antioxidant enzymes after treatment with EAG. These findings suggested that EAG exerts an antiamnesiac effect in Abeta induced neurodegeneration through an antioxidant property. PMID- 21280112 TI - Hypolipidemic effect of n-butanol Extract from Asparagus officinalis L. in mice fed a high-fat diet. AB - During industrial processing of Asparagus (Asparagus officinalis L.), around half of each spear is discarded. However, these discarded asparagus (by-products) might be used as food supplements for their potential therapeutic effects. This study evaluated the hypolipidemic effect of n-butanol extract (BEA) from asparagus by-products in mice fed a high-fat diet (HFD). Continuous HFD feeding caused hyperlipidemia, oxidative stress and liver damage in mice. Interestingly, while BEA significantly decreased the levels of body weight gain, serum total cholesterol and low density lipoprotein cholesterol, it dramatically increased the high density lipoprotein level when administered at three different doses (40, 80 or 160 mg/kg body weight) for 8 weeks in hyperlipidemic mice. In addition, BEA decreased the levels of alanine transaminase, aspartate transaminase and alkaline phosphatase in serum. Finally, superoxide dismutase activity and the total antioxidation capacity were evidently increased, while the malondialdehyde level and the distribution of lipid droplets were reduced in liver cells of BEA-treated mice. Taken together, the findings of this study suggested that BEA had a strong hypolipidemic function and could be used as a supplement in healthcare foods and drugs or in combination with other hypolipidemic drugs. PMID- 21280113 TI - Investigations into the antiadhesive activity of herbal extracts against Campylobacter jejuni. AB - Campylobacter jejuni is one of the most common bacterial causes of diarrhoea in the industrialized world, being associated with the occurrence of Guillain-Barre Syndrome, and inducing diseases partially through intestinal adherence. With increasing reports of C. jejuni drug resistance against standard antibiotics, investigations into antiadhesive agents for the prevention of bacterial infection are highly significant. Given the consumer-driven development towards holistic and integrative healthcare, research into additional anti-Campylobacter effects of herbal medicines that are already used for their beneficial effects on bowel and digestive functions is important. Twenty-one herbal extracts were screened for antiadhesive activity against C. jejuni using modifications of previously published antiadhesion assays. Antiadhesion effects with IC(50) values <3 mg/mL were obtained for seven ethanol plant extracts, with Zingiber officinale (ginger), Capsicum annum (cayenne) and Glycyrrhiza glabra (licorice) displaying the highest antiadhesion activity against C. jejuni (IC(50) : <0.1 mg/mL, 0.29 mg/mL and 0.65 mg/mL, respectively). Differences in antiadhesion activity were found for two different Echinacea species, with E. purpurea displaying significantly higher and dose dependent antiadhesion activity than E. angustifolia. No significant antiadhesion activity (IC(50) values >35 mg/mL) was found for Agrimonia eupatoria (agrimony), Andrographis paniculata (andrographis), Matricaria recutita (chamomile), Foeniculum vulgare (fennel), Filipendula ulmaria (meadowsweet) and Artemisia absinthium (wormwood) extracts. This study provides evidence for additional beneficial effects of marketed herbal medicines in gastrointestinal disorders. PMID- 21280114 TI - Displacement of bilirubin from albumin in plasma from jaundiced newborns. An in vitro study of purified Chinese herbal constituents and sulfisoxazole. AB - The aim of the present study was to clarify the in vitro potential of the purified Chinese herbal constituents LZX-A (neferine), QTJ (sinomenine), YHS (tetrahydropalmitine) and SQZG (notoginsenoside R1) to displace the highly bound bilirubin from albumin binding sites in plasma from jaundiced newborn infants. Sulfisoxazole (1.32 mM) was used as a positive control for bilirubin displacement. The displacing potential of the herbal constituents was investigated at assumed therapeutic concentrations and up to 100 times higher. Total (TB) and unbound (UB) bilirubin in plasma were measured by the peroxidase method. Sulfisoxazole increased the UB concentration in plasma by more than 60%. An increased % displacement of bilirubin was found at higher TB levels confirming the presence also of lower affinity binding sites for bilirubin in plasma. None of the purified herbal constituents showed any bilirubin displacing properties and were unaffected by the level of TB in plasma. The combination of sulfisoxazole and the herbal constituents showed no synergistic effect. It is concluded that none of the investigated purified herbal constituents possess any significant potential in vitro to increase the UB concentration in plasma from jaundiced newborn infants. PMID- 21280116 TI - Exploring sparsely populated states of macromolecules by diamagnetic and paramagnetic NMR relaxation. AB - Sparsely populated states of macromolecules, characterized by short lifetimes and high free-energies relative to the predominant ground state, often play a key role in many biological, chemical, and biophysical processes. In this review, we briefly summarize various new developments in NMR spectroscopy that permit these heretofore invisible, sparsely populated states to be detected, characterized, and in some instances visualized. Relaxation dispersion spectroscopy yields detailed kinetic information on processes involving species characterized by distinct chemical shifts with lifetimes in the ~50 MUs-10 ms range and populations as low as 0.5%. In the fast exchange regime (time scale less than ~250-500 MUs), the footprint of sparsely populated states can be observed on paramagnetic relaxation enhancement profiles measured on the resonances of the major species, thereby yielding structural information that is directly related to paramagnetic center-nuclei distances from which it is possible, under suitable circumstances, to compute a structure or ensemble of structures for the minor species. Finally, differential transverse relaxation measurements can be used to detect lifetime broadening effects that directly reflect the unidirectional rates for the conversion of NMR-visible into high-molecular weight NMR-invisible species. Examples of these various approaches are presented. PMID- 21280117 TI - Modeling of the Toll-like receptor 3 and a putative Toll-like receptor 3 antagonist encoded by the African swine fever virus. AB - African swine fever virus (ASFV) is a large double-stranded DNA virus responsible for a lethal pig disease, to which no vaccine has ever been obtained. Its genome encodes a number of proteins involved in virus survival and transmission in its hosts, in particular proteins that inhibit signaling pathways in infected macrophages and, thus, interfere with the host's innate immune response. A recently identified novel ASFV viral protein (pI329L) was found to inhibit the Toll-like receptor 3 (TLR3) signaling pathway, TLR3 being a crucial "danger detector." pI329L has been predicted to be a transmembrane protein containing extracellular putative leucine-rich repeats similar to TLR3, suggesting that pI329L might act as a TLR3 decoy. To explore this idea, we used comparative modeling and other structure prediction protocols to propose (a) a model for the TLR3-Toll-interleukin-1 receptor homodimer and (b) a structural fold for pI329L, detailed at atomistic level for its cytoplasmic domain. As this later domain shares only remote sequence relationships with the available TLR3 templates, a more complex modeling strategy was employed that combines the iterative implementation of (multi)threading/assembly/refinement (I-TASSER) structural prediction with expertise-guided posterior refinement. The final pI329L model presents a plausible fold, good structural quality, is consistent with the available experimental data, and it corroborates our hypothesis of pI329L being a TLR3 antagonist. PMID- 21280118 TI - NMR determination of pKa values in alpha-synuclein. AB - The intrinsically unfolded protein alpha-synuclein has an N-terminal domain with seven imperfect KTKEGV sequence repeats and a C-terminal domain with a large proportion of acidic residues. We characterized pK(a) values for all 26 sites in the protein that ionize below pH 7 using 2D (1) H-(15) N HSQC and 3D C(CO)NH NMR experiments. The N-terminal domain shows systematically lowered pK(a) values, suggesting weak electrostatic interactions between acidic and basic residues in the KTKEGV repeats. By contrast, the C-terminal domain shows elevated pK(a) values due to electrostatic repulsion between like charges. The effects are smaller but persist at physiological salt concentrations. For alpha-synuclein in the membrane-like environment of sodium dodecylsulfate (SDS) micelles, we characterized the pK(a) of His50, a residue of particular interest since it is flanked within one turn of the alpha-helix structure by the Parkinson's disease linked mutants E46K and A53T. The pK(a) of His50 is raised by 1.4 pH units in the micelle-bound state. Titrations of His50 in the micelle-bound states of the E46K and A53T mutants show that the pK(a) shift is primarily due to interactions between the histidine and the sulfate groups of SDS, with electrostatic interactions between His50 and Glu46 playing a much smaller role. Our results indicate that the pK(a) values of uncomplexed alpha-synuclein differ significantly from random coil model peptides even though the protein is intrinsically unfolded. Due to the long-range nature of electrostatic interactions, charged residues in the alpha-synuclein sequence may help nucleate the folding of the protein into an alpha-helical structure and confer protection from misfolding. PMID- 21280119 TI - Structural characterization reveals that a PilZ domain protein undergoes substantial conformational change upon binding to cyclic dimeric guanosine monophosphate. AB - PA4608 is a single PilZ domain protein from Pseudomonas aeruginosa that binds to cyclic dimeric guanosine monophosphate (c-di-GMP). Although the monomeric structure of unbound PA4608 has been studied in detail, the molecular details of c-di-GMP binding to this protein are still uncharacterized. Hence, we determined the solution structure of c-di-GMP bound PA4608. We found that PA4608 undergoes conformational changes to expose the c-di-GMP binding site by ejection of the C terminal 3(10) helix. A dislocation of the C-terminal tail in the presence of c di-GMP implies that this region acts as a lid that alternately covers and exposes the hydrophobic surface of the binding site. In addition, mutagenesis and NOE data for PA4608 revealed that conserved residues are in contact with the c-di-GMP molecule. The unique structural characteristics of PA4608, including its monomeric state and its ligand binding characteristics, yield insight into its function as a c-di-GMP receptor. PMID- 21280120 TI - Loss of recognition by cross-reactive T cells and its relation to a C-terminus induced conformational reorientation of an HLA-B*2705-bound peptide. AB - The human major histocompatibility complex class I antigen HLA-B*2705 binds several sequence-related peptides (pVIPR, RRKWRRWHL; pLPM2, RRRWRRLTV; pGR, RRRWHRWRL). Cross-reactivity of cytotoxic T cells (CTL) against these HLA B*2705:peptide complexes seemed to depend on a particular peptide conformation that is facilitated by the engagement of a crucial residue within the binding groove (Asp116), associated with a noncanonical bulging-in of the middle portion of the bound peptide. We were interested whether a conformational reorientation of the ligand might contribute to the lack of cross-reactivity of these CTL with a peptide derived from voltage-dependent calcium channel alpha1 subunit (pCAC, SRRWRRWNR), in which the C-terminal peptide residue pArg9 could engage Asp116. Analyses of the HLA-B*2705:pCAC complex by X-ray crystallography at 1.94 A resolution demonstrated that the peptide had indeed undergone a drastic reorientation, leading it to adopt a canonical binding mode accompanied by the loss of molecular mimicry between pCAC and sequence-related peptides such as pVIPR, pLMP2, and pGR. This was clearly a consequence of interactions of pArg9 with Asp116 and other F-pocket residues. Furthermore, we observed an unprecedented reorientation of several additional residues of the HLA-B*2705 heavy chain near the N-terminal region of the peptide, including also the presence of double conformations of two glutamate residues, Glu63 and Glu163, on opposing sides of the peptide binding groove. Together with the Arg-Ser exchange at peptide position 1, there are thus multiple structural reasons that may explain the observed failure of pVIPR-directed, HLA-B*2705-restricted CTL to cross-react with HLA-B*2705:pCAC complexes. PMID- 21280121 TI - Subunit arrangement in the dodecameric chloroplast small heat shock protein Hsp21. AB - Unfolding proteins are prevented from irreversible aggregation by small heat shock proteins (sHsps) through interactions that depend on a dynamic equilibrium between sHsp subunits and sHsp oligomers. A chloroplast-localized sHsp, Hsp21, provides protection to client proteins to increase plant stress resistance. Structural information is lacking concerning the oligomeric conformation of this sHsp. We here present a structure model of Arabidopsis thaliana Hsp21, obtained by homology modeling, single-particle electron microscopy, and lysine-specific chemical crosslinking. The model shows that the Hsp21 subunits are arranged in two hexameric discs, similar to a cytosolic plant sHsp homolog that has been structurally determined after crystallization. However, the two hexameric discs of Hsp21 are rotated by 25 degrees in relation to each other, suggesting a role for global dynamics in dodecamer function. PMID- 21280122 TI - The role of the local environment of engineered Tyr to Trp substitutions for probing the denaturation mechanism of FIS. AB - Factor for inversion stimulation (FIS), a 98-residue homodimeric protein, does not contain tryptophan (Trp) residues but has four tyrosine (Tyr) residues located at positions 38, 51, 69, and 95. The equilibrium denaturation of a P61A mutant of FIS appears to occur via a three-state (N(2) ? I(2) ? 2U) process involving a dimeric intermediate (I(2)). Although it was suggested that this intermediate had a denatured C-terminus, direct evidence was lacking. Therefore, three FIS double mutants, P61A/Y38W, P61A/Y69W, and P61A/Y95W were made, and their denaturation was monitored by circular dichroism and Trp fluorescence. Surprisingly, the P61A/Y38W mutant best monitored the N(2) ? I(2) transition, even though Trp38 is buried within the dimer removed from the C-terminus. In addition, although Trp69 is located on the protein surface, the P61A/Y69W FIS mutant exhibited clearly biphasic denaturation curves. In contrast, P61A/Y95W FIS was the least effective in decoupling the two transitions, exhibiting a monophasic fluorescence transition with modest concentration-dependence. When considering the local environment of the Trp residues and the effect of each mutation on protein stability, these results not only confirm that P61A FIS denatures via a dimeric intermediate involving a disrupted C-terminus but also suggest the occurrence of conformational changes near Tyr38. Thus, the P61A mutation appears to compromise the denaturation cooperativity of FIS by failing to propagate stability to those regions involved mostly in intramolecular interactions. Furthermore, our results highlight the challenge of anticipating the optimal location to engineer a Trp residue for investigating the denaturation mechanism of even small proteins. PMID- 21280123 TI - OCAM: a new tool for studying the oligomeric diversity of MscL channels. AB - We have developed a new technique to study the oligomeric state of proteins in solution. OCAM or Oligomer Characterization by Addition of Mass counts protein subunits by selectively shaving a protein mass tag added to a protein subunit via a short peptide linker. Cleavage of each mass tag reduces the total mass of the protein complex by a fixed amount. By performing limited proteolysis and separating the reaction products by size on a blue native PAGE gel, a ladder of reaction products corresponding to the number of subunits can be resolved. The pattern of bands may be used to distinguish the presence of a single homo oligomer from a mixture of oligomeric states. We have applied OCAM to study the mechanosensitive channel of large conductance (MscL) and find that these proteins can exist in multiple oligomeric states ranging from tetramers up to possible hexamers. Our results demonstrate the existence of oligomeric forms of MscL not yet observed by X-ray crystallography or other techniques and that in some cases a single type of MscL subunit can assemble as a mixture of oligomeric states. PMID- 21280124 TI - Residual interactions in unfolded bile acid-binding protein by 19F NMR. AB - The folding initiation mechanism of human bile acid-binding protein (BABP) has been examined by (19) F NMR. Equilibrium unfolding studies of BABP labeled with fluorine at all eight of its phenylalanine residues showed that at least two sites experience changes in solvent exposure at high denaturant concentrations. Peak assignments were made by site-specific 4FPhe incorporation. The resonances for proteins specifically labeled at Phe17, Phe47, and Phe63 showed changes in chemical shift at denaturant concentrations at which the remaining five phenylalanine residues appear to be fully solvent-exposed. Phe17 is a helical residue that was not expected to participate in a folding initiation site. Phe47 and Phe63 form part of a hydrophobic core region that may be conserved as a site for folding initiation in the intracellular lipid-binding protein family. PMID- 21280125 TI - Calorimetric study of a series of designed repeat proteins: modular structure and modular folding. AB - Repeat proteins comprise tandem arrays of a small structural motif. Their structure is defined and stabilized by interactions between residues that are close in the primary sequence. Several studies have investigated whether their structural modularity translates into modular thermodynamic properties. Tetratricopeptide repeat proteins (TPRs) are a class in which the repeated unit is a 34 amino acid helix-turn-helix motif. In this work, we use differential scanning calorimetry (DSC) to study the equilibrium stability of a series of TPR proteins with different numbers of an identical consensus repeat, from 2 to 20, CTPRa2 to CTPRa20. The DSC data provides direct evidence that the folding/unfolding transition of CTPR proteins does not fit a two-state folding model. Our results confirm and expand earlier studies on TPR proteins, which showed that apparent two-state unfolding curves are better fit by linear statistical mechanics models: 1D Ising models in which each repeat is treated as an independent folding unit. PMID- 21280126 TI - The Dynameomics rotamer library: amino acid side chain conformations and dynamics from comprehensive molecular dynamics simulations in water. AB - We have recently completed systematic molecular dynamics simulations of 807 different proteins representing 95% of the known autonomous protein folds in an effort we refer to as Dynameomics. Here we focus on the analysis of side chain conformations and dynamics to create a dynamic rotamer library. Overall this library is derived from 31,000 occurrences of each of 86,217 different residues, or 2.7 * 10(9) rotamers. This dynamic library has 74% overlap of rotamer distributions with rotamer libraries derived from static high-resolution crystal structures. Seventy-five percent of the residues had an assignable primary conformation, and 68% of the residues had at least one significant alternate conformation. The average correlation time for switching between rotamers ranged from 22 ps for Met to over 8 ns for Cys; this time decreased 20-fold on the surface of the protein and modestly for dihedral angles further from the main chain. Side chain S(2) axis order parameters were calculated and they correlated well with those derived from NMR relaxation experiments (R = 0.9). Relationships relating the S(2) axis order parameters to rotamer occupancy were derived. Overall the Dynameomics rotamer library offers a comprehensive depiction of side chain rotamer preferences and dynamics in solution, and more realistic distributions for dynamic proteins in solution at ambient temperature than libraries derived from crystal structures, in particular charged surface residues are better represented. Details of the rotamer library are presented here and the library itself can be downloaded at http://www.dynameomics.org. PMID- 21280127 TI - Metals affect the structure and activity of human plasminogen activator inhibitor 1. I. Modulation of stability and protease inhibition. AB - Human plasminogen activator inhibitor type 1 (PAI-1) is a serine protease inhibitor with a metastable active conformation. Under physiological conditions, half of the inhibitor transitions to a latent state within 1-2 h. The interaction between PAI-1 and the plasma protein vitronectin prolongs this active lifespan by ~50%. Previously, our group demonstrated that PAI-1 binds to resins using immobilized metal affinity chromatography (Day, U.S. Pat. 7,015,021 B2, March 21, 2006). In this study, the effect of these metals on function and stability was investigated by measuring the rate of the transition from the active to latent conformation. All metals tested showed effects on stability, with the majority falling into one of two types depending on their effects. The first type of metal, which includes magnesium, calcium and manganese, invoked a slight stabilization of the active conformation of PAI-1. A second category of metals, including cobalt, nickel and copper, showed the opposite effects and a unique vitronectin-dependent modulation of PAI-1 stability. This second group of metals significantly destabilized PAI-1, although the addition of vitronectin in conjunction with these metals resulted in a marked stabilization and slower conversion to the latent conformation. In the presence of copper and vitronectin, the half-life of active PAI-1 was extended to 3 h, compared to a half-life of only ~30 min with copper alone. Nickel had the largest effect, reducing the half life to ~5 min. Together, these data demonstrate a heretofore-unknown role for metals in modulating PAI-1 stability. PMID- 21280128 TI - Metals affect the structure and activity of human plasminogen activator inhibitor 1. II. Binding affinity and conformational changes. AB - Human plasminogen activator inhibitor type 1 (PAI-1) is a serine protease inhibitor with a metastable active conformation. The lifespan of the active form of PAI-1 is modulated via interaction with the plasma protein, vitronectin, and various metal ions. These metal ions fall into two categories: Type I metals, including calcium, magnesium, and manganese, stabilize PAI-1 in the absence of vitronectin, whereas Type II metals, including cobalt, copper, and nickel, destabilize PAI-1 in the absence of vitronectin, but stabilize PAI-1 in its presence. To provide a mechanistic basis for understanding the unusual modulation of PAI-1 structure and activity, the binding characteristics and conformational effects of these two types of metals were further evaluated. Steady-state binding measurements using surface plasmon resonance indicated that both active and latent PAI-1 exhibit a dissociation constant in the low micromolar range for binding to immobilized nickel. Stopped-flow measurements of approach-to equilibrium changes in intrinsic protein fluorescence indicated that the Type I and Type II metals bind in different modes that induce distinct conformational effects on PAI-1. Changes in the observed rate constants with varying concentrations of metal allowed accurate determination of binding affinities for cobalt, nickel, and copper, yielding dissociation constants of ~40, 30, and 0.09 MUM, respectively. Competition experiments that tested effects on PAI-1 stability were consistent with these measurements of affinity and indicate that copper binds tightly to PAI-1. PMID- 21280129 TI - Structural determinants of ligand imprinting: a molecular dynamics simulation study of subtilisin in aqueous and apolar solvents. AB - The phenomenon known as "ligand imprinting" or "ligand-induced enzyme memory" was first reported in 1988, when Russell and Klibanov observed that lyophilizing subtilisin in the presence of competitive inhibitors (that were subsequently removed) could significantly enhance its activity in an apolar solvent. (Russell and Klibanov, J Biol Chem 1988;263:11624-11626). They further observed that this enhancement did not occur when similar assays were carried out in water. Herein, we shed light on the molecular determinants of ligand imprinting using a molecular dynamics (MD) approach. To simulate the effect of placing an enzyme in the presence of a ligand before its lyophilization, an inhibitor was docked in the active site of subtilisin and 20 ns MD simulations in water were performed. The ligand was then removed and the resulting structure was used for subsequent MD runs using hexane and water as solvents. As a control, the same simulation setup was applied using the structure of subtilisin in the absence of the inhibitor. We observed that the ligand maintains the active site in an open conformation and that this configuration is retained after the removal of the inhibitor, when the simulations are carried out in hexane. In agreement with experimental findings, the structural configuration induced by the ligand is lost when the simulations take place in water. Our analysis of fluctuations indicates that this behavior is a result of the decreased flexibility displayed by enzymes in an apolar solvent, relatively to the aqueous situation. PMID- 21280130 TI - Conserved core of amyloid fibrils of wild type and A30P mutant alpha-synuclein. AB - The major component of neural inclusions that are the pathological hallmark of Parkinson's disease are amyloid fibrils of the protein alpha-synuclein (aS). Here we investigated if the disease-related mutation A30P not only modulates the kinetics of aS aggregation, but also alters the structure of amyloid fibrils. To this end we optimized the method of quenched hydrogen/deuterium exchange coupled to NMR spectroscopy and performed two-dimensional proton-detected high-resolution magic angle spinning experiments. The combined data indicate that the A30P mutation does not cause changes in the number, location and overall arrangement of beta-strands in amyloid fibrils of aS. At the same time, several residues within the fibrillar core retain nano-second dynamics. We conclude that the increased pathogenicity related to the familial A30P mutation is unlikely to be caused by a mutation-induced change in the conformation of aS aggregates. PMID- 21280131 TI - Crystal structure of the functional region of Uro-adherence factor A from Staphylococcus saprophyticus reveals participation of the B domain in ligand binding. AB - Staphylococci use cell wall-anchored proteins as adhesins to attach to host tissues. Staphylococcus saprophyticus, a uropathogenic species, has a unique cell wall-anchored protein, uro-adherence factor A (UafA), which shows erythrocyte binding activity. To investigate the mechanism of adhesion by UafA, we determined the crystal structure of the functional region of UafA at 1.5 A resolution. The structure was composed of three domains, designated as the N2, N3, and B domains, arranged in a triangular relative configuration. Hemagglutination inhibition assay with domain-truncated mutants indicated that both N and B domains were necessary for erythrocyte binding. Based on these results, a novel manner of ligand binding in which the B domain acts as a functional domain was proposed as the adhesion mechanism of S. saprophyticus. PMID- 21280132 TI - Counting peptide-water hydrogen bonds in unfolded proteins. AB - It is often assumed that the peptide backbone forms a substantial number of additional hydrogen bonds when a protein unfolds. We challenge that assumption in this article. Early surveys of hydrogen bonding in proteins of known structure typically found that most, but not all, backbone polar groups are satisfied, either by intramolecular partners or by water. When the protein is folded, these groups form approximately two hydrogen bonds per peptide unit, one donor or acceptor for each carbonyl oxygen or amide hydrogen, respectively. But when unfolded, the backbone chain is often believed to form three hydrogen bonds per peptide unit, one partner for each oxygen lone pair or amide hydrogen. This assumption is based on the properties of small model compounds, like N methylacetamide, or simply accepted as self-evident fact. If valid, a chain of N residues would have approximately 2N backbone hydrogen bonds when folded but 3N backbone hydrogen bonds when unfolded, a sufficient difference to overshadow any uncertainties involved in calculating these per-residue averages. Here, we use exhaustive conformational sampling to monitor the number of H-bonds in a statistically adequate population of blocked polyalanyl-six-mers as the solvent quality ranges from good to poor. Solvent quality is represented by a scalar parameter used to Boltzmann-weight the population energy. Recent experimental studies show that a repeating (Gly-Ser) polypeptide undergoes a denaturant induced expansion accompanied by breaking intramolecular peptide H-bonds. Results from our simulations augment this experimental finding by showing that the number of H-bonds is approximately conserved during such expansion?compaction transitions. PMID- 21280133 TI - Insights into the conformational flexibility of Bruton's tyrosine kinase from multiple ligand complex structures. AB - Bruton's tyrosine kinase (BTK) plays a key role in B cell receptor signaling and is considered a promising drug target for lymphoma and inflammatory diseases. We have determined the X-ray crystal structures of BTK kinase domain in complex with six inhibitors from distinct chemical classes. Five different BTK protein conformations are stabilized by the bound inhibitors, providing insights into the structural flexibility of the Gly-rich loop, helix C, the DFG sequence, and activation loop. The conformational changes occur independent of activation loop phosphorylation and do not correlate with the structurally unchanged WEI motif in the Src homology 2-kinase domain linker. Two novel activation loop conformations and an atypical DFG conformation are observed representing unique inactive states of BTK. Two regions within the activation loop are shown to structurally transform between 3(10)- and alpha-helices, one of which collapses into the adenosine-5'-triphosphate binding pocket. The first crystal structure of a Tec kinase family member in the pharmacologically important DFG-out conformation and bound to a type II kinase inhibitor is described. The different protein conformations observed provide insights into the structural flexibility of BTK, the molecular basis of its regulation, and the structure-based design of specific inhibitors. PMID- 21280134 TI - Characterizing diffusion dynamics of a membrane protein associated with nanolipoproteins using fluorescence correlation spectroscopy. AB - Nanolipoprotein particles (NLPs) represent a unique nanometer-sized scaffold for supporting membrane proteins (MP). Characterization of their dynamic shape and association with MP in solution remains a challenge. Here, we present a rapid method of analysis by fluorescence correlation spectroscopy (FCS) to characterize bacteriorhodopsin (bR), a membrane protein capable of forming a NLP complex. By selectively labeling individual components of NLPs during cell-free synthesis, FCS enabled us to measure specific NLP diffusion times and infer size information for different NLP species. The resulting bR-loaded NLPs were shown to be dynamically discoidal in solution with a mean diameter of 7.8 nm. The insertion rate of bR in the complex was ~55% based on a fit model incorporating two separate diffusion properties to best approximate the FCS data. More importantly, based on these data, we infer that membrane protein associated NLPs are thermodynamically constrained as discs in solution, while empty NLPs appear to be less constrained and dynamically spherical. PMID- 21280135 TI - 2-Methyl-2,4-pentanediol induces spontaneous assembly of staphylococcal alpha hemolysin into heptameric pore structure. AB - Staphylococcal alpha-hemolysin is expressed as a water-soluble monomeric protein and assembles on membranes to form a heptameric pore structure. The heptameric pore structure of alpha-hemolysin can be prepared from monomer in vitro only in the presence of deoxycholate detergent micelles, artificially constructed phospholipid bilayers, or erythrocytes. Here, we succeeded in preparing crystals of the heptameric form of alpha-hemolysin without any detergent but with 2-methyl 2,4-pentanediol (MPD), and determined its structure. The structure of the heptameric pore was similar to that reported previously. In the structure, two molecules of MPD were bound around Trp179, around which phospholipid head groups were bound in the heptameric pore structure reported previously. Size exclusion chromatography showed that alpha-hemolysin did not assemble spontaneously even when stored for 1 year. SDS-PAGE analysis revealed that, among the compounds in the crystallizing buffer, MPD could induce heptamer formation. The concentration of MPD that most efficiently induced oligomerization was between 10 and 30%. Based on these observations, we propose MPD as a reagent that can facilitate heptameric pore formation of alpha-hemolysin without membrane binding. PMID- 21280136 TI - Off-label drug use evaluation in paediatrics--applied to ciprofloxacin when used as treatment of cholangitis. AB - PURPOSE: To evaluate drug and indication specific off-label use in paediatrics, applied to ciprofloxacin (CPFX) in cholangitis. METHODS: We collected four different sets of data for an off-label drug use evaluation. (1) Literature review from medical journals, (2) the use and safety profile from the whole Swedish paediatric population by extracting data from national registers, (3) locally performed retrospective drug chart reviews, and (4) interviews regarding paediatric patients with CPFX treated cholangitis. RESULTS: The literature reviews show a lack of information for paediatric use of CPFX in cholangitis. The prescribing of CPFX to Swedish children has grown over the last decade and generated a small number of reports for adverse drug reactions. In our local biliary atresia population 32 patients had suffered from at least one episode of cholangitis and 13 patients had been prescribed CPFX. The dosing strategy had an empirical prescribing approach, since monitoring of bacterial resistance and efficacy is difficult in the biliary ducts. No clear relationship was seen between dosing and age/weight. Reports of suspected side effects could not be found in the retrospective chart reviews. The interviews show that the existing dosage forms are well accepted. CONCLUSIONS: This drug use evaluation creates awareness of the off-label situation. The international and national data are sparse for the paediatric use of CPFX in cholangitis. Locally we have highlighted a heterogeneous dosing strategy of CPFX, drug/drug interactions, and the need to monitor and report the risk of short- and long-term adverse drug reactions. PMID- 21280137 TI - Physicians' perception of demand-induced supply in the information age: a latent class model analysis. AB - This paper introduces a concept called 'demand-induced supply' that reflects the excess supply of services due to an increase in demand initiated by patients. We examine its association with the proportion of information-savvy patients in physicians' practice. Using data from a national representative physician survey, we apply latent class models to analyze this association. Our analyses categorize physicians into three 'types' according to the frequency with which they provided additional medical services at their patients' requests: frequent, occasional, and rare. The proportion of information-savvy patients is significantly and positively correlated with demand-induced supply for the frequent or occasional type, but not among physicians in the rare type. Efforts to contain healthcare costs through utilization control need to recognize the pattern of responses from physicians who treat an increasing number of information-savvy patients. PMID- 21280138 TI - Disentangling cancer patients' trust in their oncologist: a qualitative study. AB - OBJECTIVE: Patients' trust in their physician is crucial for an optimal treatment. Yet, among oncology patients, for whom trust might be especially important, research into trust is limited. A qualitative interview study was carried out to investigate (1) to what extent aspects of trust important to cancer patients reflect the aspects described in other patient populations and (2) which additional themes emerge. METHODS: In-depth, semi-structured interviews were performed with a purposefully selected heterogeneous sample of 29 cancer patients. Transcribed interviews were analyzed using MAXqda. Data were clustered across interviews to derive common themes related to trust. RESULTS: Three commonly described aspects, i.e., fidelity, competence and honesty, were strongly reflected in patients' accounts of trust in their oncologist. Confidentiality was irrelevant to many. An additional aspect, labeled 'caring', was distinguished. Central to the accounts of these patients was their need to trust the oncologist, arising from the severe and life-threatening nature of their disease. This necessity to trust led to the quick establishment of a competence-based trust alliance. A deeper, more emotional bond of trust was developed only after repeated interaction and seemed primarily based on the oncologist's interpersonal skills. CONCLUSIONS: The need for trust encountered in this study underscores the power imbalance between cancer patients and their oncologist. Additionally, these results imply that when aiming to measure cancer patients' trust, what we might actually be assessing is patients' intention and determination to trust their oncologist. PMID- 21280139 TI - Accuracy of the Danish version of the 'distress thermometer'. AB - OBJECTIVE: Short screening instruments have been suggested to improve the detection of psychological symptoms. We examined the accuracy of the Danish version of the 'Distress Thermometer'. METHODS: Between October 2008 and October 2009, 426 women with newly diagnosed primary breast cancer who were operated at the Breast Surgery Clinic of the Rigshospitalet, Copenhagen, were eligible for this study. Of these, 357 participated (84%) and 333 completed a questionnaire. The distress thermometer was evaluated against the 'hospital anxiety and depression scale' (HADS). We also examined the women's wish for referral for psychological support. RESULTS: A cut-off score of 6 vs 7 (low: <=6, high: >=7) on the distress thermometer was optimal for confirming distress, with a sensitivity of 42%, a specificity of 93%, a positive predictive value (PPV) of 78% and a negative predictive value (NPV) of 73%. A cut-off score of 2 vs 3 was optimal for screening, with a sensitivity of 99%, a specificity of 36%, a PPV of 47% and a NPV of 99%. Of those who were distressed using the cut-off score of 2 vs 3 on the distress thermometer, 17% (n = 41) wished to be referred for psychological support and 57% (n = 140) potentially wanted a later referral. CONCLUSION: The distress thermometer performed satisfactorily relative to the HADS in detecting distress in our study. A screening procedure in which application of the distress thermometer is a first step could be useful for identifying persons in need of support. PMID- 21280140 TI - Massive parallel DNA pyrosequencing analysis of the tumor suppressor BRG1/SMARCA4 in lung primary tumors. AB - The tumor suppressor gene, SMARCA4 (or BRG1), which encodes the ATPase component of the chromatin remodeling complex SWI/SNF, is commonly inactivated by mutations and deletions in lung cancer cell lines. However, SMARCA4 alterations appear to be rare in lung primary tumors. Ultra-deep sequencing technologies provide a promising alternative to achieve a sensitivity superior to that of current sequencing strategies. Here we used ultra-deep pyrosequencing to screen for mutations over the entire SMARCA4 coding region in 12 lung tumors without detectable BRG1 protein. While automatic-fluorescence-based sequencing detected one somatic mutation (p.K586X), the pyrosequencing revealed additional variants, thus increasing the sensitivity. One of the variants, which affected a consensus splice site, was confirmed by individual cloning of PCR products, ruling out the possibility of PCR or pyrosequencing artifacts. This mutation, confirmed to be somatic, was present at a frequency of ten percent, suggesting normal cell contamination in the tumor. Our analysis also allowed us to determine the sensitivity and to identify some limitations of the technology. In conclusion, in addition to cell lines, SMARCA4 is biallelically inactivated in a significant proportion of lung primary tumors, thereby constituting one of the most important genes contributing to the development of this type of cancer. PMID- 21280141 TI - MLL2 mutation spectrum in 45 patients with Kabuki syndrome. AB - Kabuki Syndrome (KS) is a rare syndrome characterized by intellectual disability and multiple congenital abnormalities, in particular a distinct dysmorphic facial appearance. KS is caused by mutations in the MLL2 gene, encoding an H3K4 histone methyl transferase which acts as an epigenetic transcriptional activator during growth and development. Direct sequencing of all 54 exons of the MLL2 gene in 45 clinically well-defined KS patients identified 34 (75.6%) different mutations. One mutation has been described previously, all others are novel. Clinically, all KS patients were sporadic, and mutations were de novo for all 27 families for which both parents were available. We detected nonsense (n=11), frameshift (n=17), splice site (n=4) and missense (n=2) mutations, predicting a high frequency of absent or non-functional MLL2 protein. Interestingly, both missense mutations located in the C-terminal conserved functional domains of the protein. Phenotypically our study indicated a statistically significant difference in the presence of a distinct facial appearance (p=0.0143) and growth retardation (p=0.0040) when comparing KS patients with an MLL2 mutation compared to patients without a mutation. Our data double the number of MLL2 mutations in KS reported so far and widen the spectrum of MLL2 mutations and disease mechanisms in KS. PMID- 21280142 TI - A missense mutation within the fork-head domain of the forkhead box G1 Gene (FOXG1) affects its nuclear localization. AB - The forkhead box G1 (FOXG1)gene has recently been associated with the congenital variant of Rett syndrome, and so far 17 mutations have been reported. We screened the coding region in 150 patients affected by postnatal microcephaly, and identified two mutations: the c.326C>T (p.P109L) substitution inherited from the healthy father; and the de novo c.730C>T transition, which induces the p.R244C mutation within the DNA-binding forkhead domain. This latter mutation is carried by an 8-year-old girl, who presented a phenotype reminiscent of the congenital variant of Rett syndrome. Immunofluorescence analysis of the wild-type protein revealed a homogeneous nuclear staining excluding the nucleoli, while the p.R244C mutant showed abnormal nuclear foci in a large proportion of cells, suggesting that its mislocalization may reduce and/or impair target recognition. Interestingly, this missense mutation results in a mislocalization of FoxG1 to specific nuclear foci referred to as nuclear speckles, and affects the cyclin dependent kinase inhibitor p21 CDKN1A expression. Because CDKL5, which is involved in the early-onset variant of Rett syndrome, is also located in these speckles, we suggest that disregulation of the dynamic behaviour of nuclear speckles may functionally link these two proteins, which are both involved in atypical forms of Rett syndrome. PMID- 21280143 TI - Tiling resolution array-CGH shows that somatic mosaic deletion of the EXT gene is causative in EXT gene mutation negative multiple osteochondromas patients. AB - Multiple osteochondromas (MO) is a hereditary skeletal disorder characterized by the presence of cartilage capped bony outgrowths at bone surface. Causative mutations in EXT1 or EXT2 genes have been described in 85-90 % of MO cases. However, in about 10-15 % of the MO cases, genomic alterations can not be detected, implying the potential role of other alterations. We have designed a custom-made Agilent oligonucleotide-based microarray, containing 44,000 probes, with tiling coverage of EXT1/2 genes and addition of 68 genes involved in heparan sulfate biosynthesis and other related pathways. Out of the 17 patient samples with previously undetected mutations, a low level of deletion of the EXT1 gene in about 10-15% of the blood cells was detected in two patients and mosaic deletion of the EXT2 was detected in one patient. Here we show that for the first time somatic mosaicism with large genomic deletions as the underlying mechanism in MO formation was identified. We propose that the existence of mosaic mutations and not alterations of other heparan sulfate biosynthesis related genes play a significant role in the development of MO in patients who are tested negative for mutations in Exostosins. PMID- 21280146 TI - Novel genomic techniques open new avenues in the analysis of monogenic disorders. AB - The molecular genetic cause of over 3,000 monogenic disorders is currently unknown. This review discusses how novel genomic techniques like Next-Generation DNA Sequencing (NGS) and genotyping arrays open new avenues in the elucidation of genetic defects causing monogenic disorders. They will not only speed up disease gene identification but will enable us to systematically tackle previously intractable monogenic disorders. These are mainly disorders not amenable to classic linkage analysis, for example, due to insufficient family size. Most monogenic diseases are caused by exonic mutations or splice-site mutations changing the amino acid sequence of the affected gene. These mutations can be identified by sequencing of all exons in the human genome (exome sequencing) rendering whole genome sequencing unnecessary in most cases. Genotyping arrays containing 105 -2*106 single nucleotide polymorphisms (SNPs) and nonpolymorphic markers allow highly accurate mapping of genomic deletions and duplications not detectable by exome sequencing, which are the second most common cause of monogenic disorders. However, several hundred rare, previously unknown sequence variants affecting the amino acid sequence of the encoded protein are found in the exome of every human individual. Therefore, the main challenge will be the differentiation between the many rare benign variants detected by novel genomic techniques and disease causing mutations. PMID- 21280145 TI - Mapping structural landmarks, ligand binding sites, and missense mutations to the collagen IV heterotrimers predicts major functional domains, novel interactions, and variation in phenotypes in inherited diseases affecting basement membranes. AB - Collagen IV is the major protein found in basement membranes. It comprises three heterotrimers (alpha1alpha1alpha2, alpha3alpha4alpha5, and alpha5alpha5alpha6) that form distinct networks, and are responsible for membrane strength and integrity.We constructed linear maps of the collagen IV heterotrimers ("interactomes") that indicated major structural landmarks, known and predicted ligand-binding sites, and missense mutations, in order to identify functional and disease-associated domains, potential interactions between ligands, and genotype phenotype relationships. The maps documented more than 30 known ligand-binding sites as well as motifs for integrins, heparin, von Willebrand factor (VWF), decorin, and bone morphogenetic protein (BMP). They predicted functional domains for angiogenesis and haemostasis, and disease domains for autoimmunity, tumor growth and inhibition, infection, and glycation. Cooperative ligand interactions were indicated by binding site proximity, for example, between integrins, matrix metalloproteinases, and heparin. The maps indicated that mutations affecting major ligand-binding sites, for example, for Von Hippel Lindau (VHL) protein in the alpha1 chain or integrins in the alpha5 chain, resulted in distinctive phenotypes (Hereditary Angiopathy, Nephropathy, Aneurysms, and muscle Cramps [HANAC] syndrome, and early-onset Alport syndrome, respectively). These maps further our understanding of basement membrane biology and disease, and suggest novel membrane interactions, functions, and therapeutic targets. PMID- 21280147 TI - Mutation screening of the EYA1, SIX1, and SIX5 genes in a large cohort of patients harboring branchio-oto-renal syndrome calls into question the pathogenic role of SIX5 mutations. AB - Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder characterized by branchial, ear, and renal anomalies. Over 80 mutations in EYA1 have been reported in BOR. Mutations in SIX1, a DNA binding protein that associates with EYA1, have been reported less frequently. One group has recently described four missense mutations in SIX5 in five unrelated patients with BOR. Here, we report a screening of these three genes in a cohort of 140 patients from 124 families with BOR. We identified 36 EYA1 mutations in 42 unrelated patients, 2 mutations, and 1 change of unknown significance in SIX1 in 3 unrelated patients, but no mutation in SIX5. We did not find correlation between genotype and phenotype, and observed a high phenotypic variability between and within BOR families. We show the difficulty in establishing a molecular diagnosis strategy in BOR syndrome: the screening focusing on patients with typical BOR would detect a mutation rate of 76%, but would also miss mutations in 9% of patients with atypical BOR. We detected a deletion removing three EYA1 exons in a patient who was previously reported to carry the SIX5 Thr552Met mutation. This led us to reconsider the role of SIX5 in the development of BOR. PMID- 21280148 TI - Mosaic type-1 NF1 microdeletions as a cause of both generalized and segmental neurofibromatosis type-1 (NF1). AB - Mosaicism is an important feature of type-1 neurofibromatosis (NF1) on account of its impact upon both clinical manifestations and transmission risk. Using FISH and MLPA to screen 3500 NF1 patients, we identified 146 individuals harboring gross NF1 deletions, 14 of whom (9.6%) displayed somatic mosaicism. The high rate of mosaicism in patients with NF1 deletions supports the postulated idea of a direct relationship between the high new mutation rate in this cancer predisposition syndrome and the frequency of mosaicism. Seven of the 14 mosaic NF1 deletions were type-2, whereas four were putatively type-1, and three were atypical. Two of the four probable type-1 deletions were confirmed as such by breakpoint-spanning PCR or SNP analysis. Both deletions were associated with a generalized manifestation of NF1. Independently, we identified a third patient with a mosaic type-1 NF1 deletion who exhibited segmental NF1. Together, these three cases constitute the first proven mosaic type-1 deletions so far reported. In two of these three mosaic type-1 deletions, the breakpoints were located within PRS1 and PRS2, previously identified as hotspots for nonallelic homologous recombination (NAHR) during meiosis. Hence, NAHR within PRS1 and PRS2 is not confined to meiosis but may also occur during postzygotic mitotic cell cycles. PMID- 21280149 TI - Dymeclin, the gene underlying Dyggve-Melchior-Clausen syndrome, encodes a protein integral to extracellular matrix and golgi organization and is associated with protein secretion pathways critical in bone development. AB - Dyggve-Melchior-Clausen syndrome (DMC), a severe autosomal recessive skeletal disorder with mental retardation, is caused by mutation of the gene encoding Dymeclin (DYM). Employing patient fibroblasts with mutations characterized at the genomic and, for the first time, transcript level, we identified profound disruption of Golgi organization as a pathogenic feature, resolved by transfection of heterologous wild-type Dymeclin. Collagen targeting appeared defective in DMC cells leading to near complete absence of cell surface collagen fibers. DMC cells have an elevated apoptotic index (P< 0.01) likely due to a stress response contingent upon Golgi-related trafficking defects. We performed spatiotemporal mapping of Dymeclin expression in zebrafish embryos and identified high levels of transcript in brain and cartilage during early development. Finally, in a chondrocyte cDNA library, we identified two novel secretion pathway proteins as Dymeclin interacting partners: GOLM1 and PPIB. Together these data identify the role of Dymeclin in secretory pathways essential to endochondral bone formation during early development. PMID- 21280150 TI - Allele-specific methylated multiplex real-time quantitative PCR (ASMM RTQ-PCR), a powerful method for diagnosing loss of imprinting of the 11p15 region in Russell Silver and Beckwith Wiedemann syndromes. AB - Many human syndromes involve a loss of imprinting (LOI) due to a loss (LOM) or a gain of DNA methylation (GOM). Most LOI occur as mosaics and can therefore be difficult to detect with conventional methods. The human imprinted 11p15 region is crucial for the control of fetal growth, and LOI at this locus is associated with two clinical disorders with opposite phenotypes: Beckwith-Wiedemann syndrome (BWS), characterized by fetal overgrowth and a high risk of tumors, and Russell Silver syndrome (RSS), characterized by intrauterine and postnatal growth restriction. Until recently, we have been using Southern blotting for the diagnosis of RSS and BWS. We describe here a powerful quantitative technique, allele-specific methylated multiplex real-time quantitative PCR (ASMM RTQ-PCR), for the diagnosis of these two complex disorders. We first checked the specificity of the probes and primers used for ASMM RTQ-PCR. We then carried out statistical validation for this method, on both retrospective and prospective populations of patients. This analysis demonstrated that ASMM RTQ-PCR is more sensitive than Southern blotting for detecting low degree of LOI. Moreover, ASMM RTQ-PCR is a very rapid, reliable, simple, safe, and cost effective method. PMID- 21280151 TI - Searching for the missing heritability of complex diseases. PMID- 21280152 TI - Law, ethics, religion, and clinical translation in the 21st century--a conversation with Cinzia Rota. Interview by Majlinda Lako, Alan O. Trounson, and Susan Daher. PMID- 21280153 TI - Twist, epithelial-to-mesenchymal transition, and stem cells. PMID- 21280154 TI - Concise review: Mesenchymal stem cell treatment of the complications of diabetes mellitus. AB - Mesenchymal stem cells (MSCs) are multipotent, self-renewing cells that can be found in almost all postnatal organs and tissues. The main functional characteristics of MSCs are their immunomodulatory ability, capacity for self renewal, and differentiation into mesodermal tissues. The ability of MSCs to differentiate into several cell types, including muscle, brain, vascular, skin, cartilage, and bone cells, makes them attractive as therapeutic agents for a number of diseases including complications of diabetes mellitus. We review here the potential of MSCs as new therapeutic agents in the treatment of diabetic cardiomyopathy, diabetic nephropathy, diabetic polyneuropathy, diabetic retinopathy, and diabetic wounds. Also, in this review we discuss the current limitations for MSCs therapy in humans. PMID- 21280155 TI - Concise review: Dissecting a discrepancy in the literature: do mesenchymal stem cells support or suppress tumor growth? AB - The discovery that mesenchymal stem cells (MSCs) are recruited into tumors has led to a great deal of interest over the past decade in the function of MSCs in tumors. To address this, investigators have used a variety of tumor models in which MSCs are added exogenously to determine their impact on tumor development. Interestingly, many studies have reported contradicting results, with some investigators finding that MSCs promote tumor growth and others reporting that MSCs inhibit tumor growth. Many mechanisms have been reported to account for these observations, such as chemokine signaling, modulation of apoptosis, vascular support, and immune modulation. In this review, we analyzed the differences in the methodology of the studies reported and found that the timing of MSC introduction into tumors may be a critical element. Understanding the conditions in which MSCs enhance tumor growth and metastasis is crucial, both to safely develop MSCs as a therapeutic tool and to advance our understanding of the role of tumor stroma in carcinogenesis. PMID- 21280156 TI - Kruppel-like family of transcription factor 9, a differentiation-associated transcription factor, suppresses Notch1 signaling and inhibits glioblastoma initiating stem cells. AB - Tumor-initiating stem cells (alternatively called cancer stem cells, CSCs) are a subpopulation of tumor cells that plays unique roles in tumor propagation, therapeutic resistance, and tumor recurrence. It is becoming increasingly important to understand the molecular signaling that regulates the self-renewal and differentiation of CSCs. Transcription factors are critical for the regulation of normal and neopolastic stem cells. Here, we examined the expression and function of the Kruppel-like family of transcription factors (KLFs) in human glioblastoma (GBM)-derived neurosphere lines and low-passage primary GBM-derived neurospheres that are enriched for tumor-initiating stem cells. We identify KLF9 as a relatively unique differentiation-induced transcription factor in GBM derived neurospheres. KLF9 is shown to induce neurosphere cell differentiation, inhibit neurosphere formation, and inhibit neurosphere-derived xenograft growth in vivo. We also show that KLF9 regulates GBM neurosphere cells by binding to the Notch1 promoter and suppressing Notch1 expression and downstream signaling. Our results show for the first time that KLF9 has differentiating and tumor suppressing functions in tumor-initiating stem cells. PMID- 21280157 TI - Aldehyde dehydrogenase activity of breast cancer stem cells is primarily due to isoform ALDH1A3 and its expression is predictive of metastasis. AB - Cancer stem cells (CSCs) are proposed to initiate cancer and propagate metastasis. Breast CSCs identified by aldehyde dehydrogenase (ALDH) activity are highly tumorigenic in xenograft models. However, in patient breast tumor immunohistological studies, where CSCs are identified by expression of ALDH isoform ALDH1A1, CSC prevalence is not correlative with metastasis, raising some doubt as to the role of CSCs in cancer. We characterized the expression of all 19 ALDH isoforms in patient breast tumor CSCs and breast cancer cell lines by total genome microarray expression analysis, immunofluorescence protein expression studies, and quantitative polymerase chain reaction. These studies revealed that ALDH activity of patient breast tumor CSCs and cell lines correlates best with expression of another isoform, ALDH1A3, not ALDH1A1. We performed shRNA knockdown experiments of the various ALDH isoforms and found that only ALDH1A3 knockdown uniformly reduced ALDH activity of breast cancer cells. Immunohistological studies with fixed patient breast tumor samples revealed that ALDH1A3 expression in patient breast tumors correlates significantly with tumor grade, metastasis, and cancer stage. Our results, therefore, identify ALDH1A3 as a novel CSC marker with potential clinical prognostic applicability, and demonstrate a clear correlation between CSC prevalence and the development of metastatic breast cancer. PMID- 21280158 TI - Mesenchymal lineage stem cells have pronounced anti-inflammatory effects in the twitcher mouse model of Krabbe's disease. AB - The twitcher mouse is an animal model of Krabbe's disease (KD), which is a neurodegenerative lysosomal storage disorder resulting from the absence of functional lysosomal enzyme galactocerebrosidase (GALC). This disease affects the central and peripheral nervous systems and in its most severe form results in death before the age of 2 in humans and approximately 30-40 days in mice. This study evaluates the effect of intracerebroventricular administration of mesenchymal stem cells derived from adipose tissue (ASCs) and bone marrow (BMSCs) on the pathology of KD. Subsequent to the intracerebroventricular injection of ASCs or BMSCs on postnatal day (PND) 3-4, body weight, lifespan, and neuromotor function were evaluated longitudinally beginning on PND15. At sacrifice, tissues were harvested for analysis of GALC activity, presence of myelin, infiltration of macrophages, microglial activation, inflammatory markers, and cellular persistence. Survival analysis curves indicate a statistically significant increase in lifespan in stem cell-treated twitcher mice as compared with control twitcher mice. Body weight and motor function were also improved compared with controls. The stem cells may mediate some of these benefits through an anti inflammatory mechanism because the expression of numerous proinflammatory markers was downregulated at both transcriptional and translational levels. A marked decrease in the levels of macrophage infiltration and microglial activation was also noted. These data indicate that mesenchymal lineage stem cells are potent inhibitors of inflammation associated with KD progression and offer potential benefits as a component of a combination approach for in vivo treatment by reducing the levels of inflammation. PMID- 21280159 TI - Tracking stem cell differentiation in the setting of automated optogenetic stimulation. AB - Membrane depolarization has been shown to play an important role in the neural differentiation of stem cells and in the survival and function of mature neurons. Here, we introduce a microbial opsin into ESCs and develop optogenetic technology for stem cell engineering applications, with an automated system for noninvasive modulation of ESC differentiation employing fast optogenetic control of ion flux. Mouse ESCs were stably transduced with channelrhodopsin-2 (ChR2)-yellow fluorescent protein and purified by fluorescence activated cell sorting (FACS). Illumination of resulting ChR2-ESCs with pulses of blue light triggered inward currents. These labeled ESCs retained the capability to differentiate into functional mature neurons, assessed by the presence of voltage-gated sodium currents, action potentials, fast excitatory synaptic transmission, and expression of mature neuronal proteins and neuronal morphology. We designed and tested an apparatus for optically stimulating ChR2-ESCs during chronic neuronal differentiation, with high-speed optical switching on a custom robotic stage with environmental chamber for automated stimulation and imaging over days, with tracking for increased expression of neural and neuronal markers. These data point to potential uses of ChR2 technology for chronic and temporally precise noninvasive optical control of ESCs both in vitro and in vivo, ranging from noninvasive control of stem cell differentiation to causal assessment of the specific contribution of transplanted cells to tissue and network function. PMID- 21280160 TI - Sox1 maintains the undifferentiated state of cortical neural progenitor cells via the suppression of Prox1-mediated cell cycle exit and neurogenesis. AB - Neural stem/progenitor cells maintain their identity via continuous self-renewal and suppression of differentiation. Gain-of-function experiments in the chick revealed an involvement for Sox1-3 transcription factors in the maintenance of the undifferentiated neural progenitor (NP) identity. However, the mechanism(s) employed by each factor has not been resolved. Here, we derived cortical neural/stem progenitor cells from wild-type and Sox1-null mouse embryos and found that Sox1 plays a key role in the suppression of neurogenic cell divisions. Loss of Sox1 leads to progressive depletion of self-renewing cells, elongation of the cell cycle of proliferating cells, and significant increase in the number of cells exiting the cell cycle. In proliferating NP cells, Sox1 acts via a prospero related homeobox 1 (Prox1)-mediated pathway to block cell cycle exit that leads to neuronal differentiation in vivo and in vitro. Thus, our results demonstrate that Sox1 regulates the size of the cortical NP pool via suppression of Prox1 mediated neurogenic cell divisions. PMID- 21280161 TI - Repression of mammary stem/progenitor cells by p53 is mediated by Notch and separable from apoptotic activity. AB - Breast cancer is the most common tumor among women with inherited mutations in the p53 gene (Li-Fraumeni syndrome). The tumors represent the basal-like subtype, which has been suggested to originate from mammary stem/progenitor cells. In mouse mammary epithelium, mammosphere-forming potential was increased with decreased dosage of the gene encoding the p53 tumor suppressor protein (Trp53). Limiting dilution transplantation also showed a 3.3-fold increase in the frequency of long-term regenerative mammary stem cells in Trp53-/- mice. The repression of mammospheres by p53 was apparent despite the absence of apoptotic responses to radiation indicating a dissociation of these two activities of p53. The effects of p53 on progenitor cells were also observed in TM40A cells using both mammosphere-forming assays and the DsRed-let7c-sensor. The frequency of long term label-retaining epithelial cells was decreased in Trp53-/- mammary glands indicating that asymmetric segregation of DNA is diminished and contributes to the expansion of the mammary stem cells. Treatment with an inhibitor of gamma secretase (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester) reduced the number of Trp53-/- mammospheres to the level found in Trp53+/+ cells. These results demonstrate that basal levels of p53 restrict mammary stem/progenitor cells through Notch and that the Notch pathway is a therapeutic target to prevent expansion of this vulnerable pool of cells. PMID- 21280162 TI - Prospective identification and isolation of enteric nervous system progenitors using Sox2. AB - The capacity to identify and isolate lineage-specific progenitor cells from developing and mature tissues would enable the development of cell replacement therapies for disease treatment. The enteric nervous system (ENS) regulates important gut functions, including controlling peristaltic muscular contractions, and consists of interconnected ganglia containing neurons and glial cells. Hirschsprung's disease (HSCR), one of the most common and best understood diseases affecting the ENS, is characterized by absence of enteric ganglia from the distal gut due to defects in gut colonization by neural crest progenitor cells and is an excellent candidate for future cell replacement therapies. Our previous microarray experiments identified the neural progenitor and stem cell marker SRY-related homoebox transcription factor 2 (Sox2) as expressed in the embryonic ENS. We now show that Sox2 is expressed in the ENS from embryonic to adult stages and constitutes a novel marker of ENS progenitor cells and their glial cell derivatives. We also show that Sox2 expression overlaps significantly with SOX10, a well-established marker of ENS progenitors and enteric glial cells. We have developed a strategy to select cells expressing Sox2, by using G418 selection on cultured gut cells derived from Sox2(betageo/+) mouse embryos, thus allowing substantial enrichment and expansion of neomycin-resistant Sox2 expressing cells. Sox2(betageo) cell cultures are enriched for ENS progenitors. Following transplantation into embryonic mouse gut, Sox2(betageo) cells migrate, differentiate, and colocalize with the endogenous ENS plexus. Our studies will facilitate development of cell replacement strategies in animal models, critical to develop human cell replacement therapies for HSCR. PMID- 21280163 TI - Distinct roles for Wnt-4 and Wnt-11 during retinoic acid-induced neuronal differentiation. AB - Retinoic acid and Wnt/beta-catenin signals play important roles during neuronal differentiation but less is known about noncanonical Wnt signals in this context. We examined retinoic acid and Wnt signaling in two human embryonal carcinoma cell lines, NTERA-2 (clone D1), which undergoes neuronal differentiation in response to retinoic acid, and 2102Ep, which does not. Retinoic acid treatment inhibited beta-catenin/Tcf activity in NTERA-2 cells but not in 2102Ep cells. Inhibition occurred downstream of beta-catenin but did not involve competition between retinoic acid receptors and beta-catenin for binding to p300 or Tcf-4. Ectopic expression of FZD1 partially restored inhibition in 2102Ep cells, suggesting the involvement of Wnt ligands. Retinoic acid treatment of NTERA-2 cells induced the expression of Wnt-4 and Wnt-11, both of which were able to inhibit beta catenin/Tcf activity. Wnt-4 and Wnt-11 were found at cell borders in islands of cells that expressed OCT4 and GFAP and were predominantly negative for Nestin, PAX6, and GATA6. Gene silencing of Wnt-4, but not Wnt-11, reduced retinoic acid downregulation of OCT4 and Nanog and upregulation of PAX6, ASCL1, HOXC5, and NEUROD1, suggesting that Wnt-4 promotes early neuronal differentiation. Gene expression analysis of NTERA-2 cells stably overexpressing Wnt-11 suggested that Wnt-11 potentiates retinoic acid induction of early neurogenesis. Consistent with this, overexpression of Wnt-11 maintained a population of proliferating progenitor cells in cultures treated with retinoic acid for several weeks. These observations highlight the distinct roles of two noncanonical Wnts during the early stages of retinoic acid-induced neuronal differentiation. PMID- 21280164 TI - Epithelial-connective tissue interactions induced by thyroid hormone receptor are essential for adult stem cell development in the Xenopus laevis intestine. AB - In the amphibian intestine during metamorphosis, stem cells appear and generate the adult absorptive epithelium, analogous to the mammalian one, under the control of thyroid hormone (TH). We have previously shown that the adult stem cells originate from differentiated larval epithelial cells in the Xenopus laevis intestine. To clarify whether TH signaling in the epithelium alone is sufficient for inducing the stem cells, we have now performed tissue recombinant culture experiments using transgenic X. laevis tadpoles that express a dominant-positive TH receptor (dpTR) under a control of heat shock promoter. Wild-type (Wt) or dpTR transgenic (Tg) larval epithelium (Ep) was isolated from the tadpole intestine, recombined with homologous or heterologous nonepithelial tissues (non-Ep), and then cultivated in the absence of TH with daily heat shocks to induce transgenic dpTR expression. Adult epithelial progenitor cells expressing sonic hedgehog became detectable on day 5 in both the recombinant intestine of Tg Ep and Tg non Ep (Tg/Tg) and that of Tg Ep and Wt non-Ep (Tg/Wt). However, in Tg/Wt intestine, they did not express other stem cell markers such as Musashi-1 and never generated the adult epithelium expressing a marker for absorptive epithelial cells. Our results indicate that, while it is unclear why some larval epithelial cells dedifferentiate into adult progenitor/stem cells, TR-mediated gene expression in the surrounding tissues other than the epithelium is required for them to develop into adult stem cells, suggesting the importance of TH-inducible epithelial-connective tissue interactions in establishment of the stem cell niche in the amphibian intestine. PMID- 21280165 TI - Is anorexia nervosa a version of autism spectrum disorders? AB - OBJECTIVES: Similarities have been noted between cognitive profiles of anorexia nervosa (AN) and autism spectrum disorders (ASD). However, there are no direct comparison studies. This study aimed to compare the cognitive profile of AN against published ASD data on tasks measuring empathy, executive function and central coherence. METHODS: Currently ill AN outpatients (n = 40) were statistically compared against published ASD scores on Reading the Mind in the Eyes, Voice and Films tasks (assessing empathy), Wisconsin Card Sorting Task (WCST) (assessing executive function) and Embedded Figures Task (EFT) (assessing detail focus aspect of central coherence). RESULTS: Cognitive profiles of the groups were statistically similar, except for differences in the relative patterns of empathy scores. CONCLUSIONS: The cognitive profile in current AN resembles that of ASD with important clinical implications. Replication studies with planned comparisons, examination of the state-or trait-nature of AN profile and clarification of factors underpinning similarities are required in order to broaden understanding of both disorders. PMID- 21280166 TI - A case series evaluation of the Maudsley Model for treatment of adults with anorexia nervosa. AB - OBJECTIVE: Outpatient psychotherapy has been largely unsuccessful in assisting adults with anorexia nervosa (AN) to achieve weight restoration. The aim of the current study was to evaluate change and attainment of good and moderate outcome at 12-month follow-up using the Maudsley Model for Treatment of Adults with AN (MANTRA). METHODS: Of 33 people assessed, 28 people commenced therapy, and 23 completed it (82%). RESULTS: At post-treatment, seven people (30%) met the criteria for good outcome and one person met the criteria for moderate outcome. At 12-month follow-up, six people (26%) achieved good outcome, a further five achieved a moderate outcome, and there were significant improvements in body mass index, eating psychopathology and motivation, with large intention to treat effect sizes (ES) of 0.85, 1.19 and 1.57, respectively. Those people who dropped out of therapy were significantly more likely to binge or purge, and this behaviour was also associated with a moderate effect size (0.71) when examining differences between people who obtained good/moderate outcome versus poor outcome. Also predicting poor outcome status was lower baseline self-esteem and ineffectiveness. CONCLUSION: Further evaluation of the use of MANTRA as an outpatient therapy for AN appears justified. Improvements to this therapy could include an early focus on binge and purge behaviour, as well as modules addressing low self-esteem and ineffectiveness. PMID- 21280167 TI - Understanding your own and other's minds: the relationship to eating disorder related symptoms. AB - A study using a cross-sectional survey design examined whether eating disorder (ED) related symptoms are associated with understanding one's own and others' minds. A non-clinical sample of 145 women completed self-report questionnaires and recorded their emotional, cognitive and behavioural responses to descriptions of scenarios (vignettes). Responses to scenarios were made from the perspective of self, an attachment figure and a same sex acquaintance. Data were analysed using multiple regression statistics with ED related symptoms as the dependent variable. High levels of ED related symptoms were associated with 'concretised' understanding of own emotions (i.e. a greater number of food related responses), but sophisticated understanding of same sex acquaintance's emotions. They were associated with fewer positive thoughts for self, fewer negative emotions about their own behaviour, and more food responses for same sex acquaintance's behaviour. Similarities and differences were observed in the different perspectives. Limitations are discussed. Implications for further research related to this topic and relevant to EDs are briefly summarised. PMID- 21280168 TI - Improved temporal resolution and linked hidden Markov modeling for switchable single-molecule FRET. AB - Switchable FRET is the combination of single-molecule Forster resonance energy transfer (smFRET) with photoswitching, the reversible activation and deactivation of fluorophores by light. By photoswitching, multiple donor-acceptor fluorophore pairs can be probed sequentially, thus allowing observation of multiple distances within a single immobilized molecule. Control of the photoinduced switching rates permits adjustment of the temporal resolution of switchable FRET over a wide range of timescales, thereby facilitating application to various dynamical biological systems. We show that fast total internal reflection (TIRF) microscopy can achieve measurements of two FRET pairs with 10 ms temporal resolution within less than 2 s. The concept of switchable FRET is also compatible with confocal microscopy on immobilized molecules, providing better data quality at high temporal resolution. To identify states and extract their transitions from switchable FRET time traces, we also develop linked hidden Markov modeling (HMM) of both FRET and donor-acceptor stoichiometry. Linked HMM successfully identifies transient states in the two-dimensional FRET-stoichiometry space and reconstructs their connectivity network. Improved temporal resolution and novel data analysis make switchable FRET a valuable tool in molecular and structural biology. PMID- 21280170 TI - Liver glucokinase: An overview on the regulatory mechanisms of its activity. AB - Blood glucose is the primary cellular substrate and in vivo must be tightly maintained. The liver plays a key role in glucose homeostasis increasing or decreasing glucose output and uptake during fasting and feeding. Glucokinase (GCK) is central to this process. Its activity is modulated in a coordinated manner via a complex set of mechanisms: in the postprandial period, the simultaneous rise in glucose and insulin increases GCK activity by enhanced gene expression, changes in cellular location, and interaction with regulatory proteins. Conversely, in the fasting state, the combined decrease in glucose and insulin concentrations and increase in glucagon concentrations, halt GCK activity. Herein we summarize the current knowledge regarding the regulation of hepatic GCK activity. PMID- 21280171 TI - The application of the glycemic index and glycemic load in weight loss: A review of the clinical evidence. AB - Obesity is rapidly becoming a global epidemic. As it is a significant risk factor for several chronic diseases, including type 2 diabetes and cardiovascular disease, it is imperative to study dietary and lifestyle approaches that help reduce its prevalence. Recently, due to its possible link to appetite control and metabolism, several clinical studies have assessed the effect of low glycemic index (GI) and glycemic load (GL) diets on weight loss. To determine the application of GI/GL in the prevention and treatment of obesity, we searched several databases and identified 23 clinical trials that examined low GI/GL diets and weight loss as the primary outcome measure. In general, these studies showed much inconsistency in their findings. While a few studies found significantly greater weight loss on the low GI/GL diets, most of the other studies showed a non-significant trend that favored low GI/GL diets; suggesting that factors other than GI/GL may play a role. It would be helpful if a pooled analysis were undertaken to clarify the current findings and outline the limitations of these studies. There is also a need for more long-term randomized, controlled trials that not only focus on weight loss but also on weight maintenance and body composition. PMID- 21280172 TI - Interaction of glycyrol with calcineurin A studied by spectroscopic methods and docking. AB - We have shown previously that glycyrol has an inhibitory effect on the immune response in mice by reducing calcineurin activity (Li et al., 2010, Pharm Biol 48:1177-1184). Here, we investigated the interaction of glycyrol with calcineurin A (CNA, catalytic A subunit of calcineurin) by spectroscopic methods and docking. We showed that glycyrol binds to CNA via hydrophobic interactions in a ratio of 1:1, and the main binding site is in the catalytic domain of CNA close to the calcineurin B subunit-binding domain. Binding of glycyrol changes the secondary structure of CNA, and this effect may possibly inhibit CN activity. PMID- 21280173 TI - Giardia intestinalis escapes oxidative stress by colonizing the small intestine: A molecular hypothesis. AB - Giardia intestinalis is the microaerophilic protozoon causing giardiasis, a common infectious intestinal disease. Giardia possesses an O(2) -scavenging activity likely essential for survival in the host. We report that Giardia trophozoites express the O(2) -detoxifying flavodiiron protein (FDP), detected by immunoblotting, and are able to reduce O(2) to H(2) O rapidly (~3 MUM O(2) * min * 10(6) cells at 37 degrees C) and with high affinity (C(50) = 3.4 +/- 0.7 MUM O(2)). Following a short-term (minutes) exposure to H(2) O(2) >= 100 MUM, the O(2) consumption by the parasites is irreversibly impaired, and the FDP undergoes a degradation, prevented by the proteasome-inhibitor MG132. Instead, H(2) O(2) does not cause degradation or inactivation of the isolated FDP. On the basis of the elevated susceptibility of Giardia to oxidative stress, we hypothesize that the parasite preferentially colonizes the small intestine since, compared with colon, it is characterized by a greater capacity for redox buffering and a lower propensity to oxidative stress. PMID- 21280174 TI - Physicochemical analysis of poly-L-lysine: An insight into the changes induced in lysine residues of proteins on modification with glucose. AB - Nonenzymatic glycation of macromolecules, especially proteins, takes place mainly due to hyperglycemia in diabetes mellitus. Increased glycolysis during cancer and inflammation during rheumatoid arthritis also contribute to the process of glycation. As lysine residues of proteins are a potential site for glycation, it could be used as a marker for early glycation induced changes in lysine-rich proteins. In the present study, a lysine polymer was incubated with increasing concentrations of glucose for 24 h, and the early glycation product was evaluated by nitroblue tetrazolium assay. The modified polymer together with unmodified one was characterized by gel electrophoresis and UV, fluorescence spectroscopy. Results of the study clearly demonstrate that structural perturbation in the lysine polymer was caused by the early glycation. Further study on detection of antibodies against theglycated proteins in diseased patients might be helpful in early diagnosis of the disease. PMID- 21280175 TI - Effect of substrate binding loop mutations on the structure, kinetics, and inhibition of enoyl acyl carrier protein reductase from Plasmodium falciparum. AB - Enoyl acyl carrier protein reductase (ENR), which catalyzes the final and rate limiting step of fatty acid elongation, has been validated as a potential drug target. Triclosan is known to be an effective inhibitor for this enzyme. We mutated the substrate binding site residue Ala372 of the ENR of Plasmodium falciparum (PfENR) to Methionine and Valine which increased the affinity of the enzyme towards triclosan to almost double, close to that of Escherichia coli ENR (EcENR) which has a Methionine at the structurally similar position of Ala372 of PfENR. Kinetic studies of the mutants of PfENR and the crystal structure analysis of the A372M mutant revealed that a more hydrophobic environment enhances the affinity of the enzyme for the inhibitor. A triclosan derivative showed a threefold increase in the affinity towards the mutants compared to the wild type, due to additional interactions with the A372M mutant as revealed by the crystal structure. The enzyme has a conserved salt bridge which stabilizes the substrate binding loop and appears to be important for the active conformation of the enzyme. We generated a second set of mutants to check this hypothesis. These mutants showed loss of function, except in one case, where the crystal structure showed that the substrate binding loop is stabilized by a water bridge network. PMID- 21280176 TI - Ubiquinol-induced gene expression signatures are translated into altered parameters of erythropoiesis and reduced low density lipoprotein cholesterol levels in humans. AB - Studies in vitro and in mice indicate a role for Coenzyme Q(10) (CoQ(10) ) in gene expression. To determine this function in relationship to physiological readouts, a 2-week supplementation study with the reduced form of CoQ(10) (ubiquinol, Q(10) H(2) , 150 mg/d) was performed in 53 healthy males. Mean CoQ(10) plasma levels increased 4.8-fold after supplementation. Transcriptomic and bioinformatic approaches identified a gene-gene interaction network in CD14 positive monocytes, which functions in inflammation, cell differentiation, and peroxisome proliferator-activated receptor-signaling. These Q(10) H(2) -induced gene expression signatures were also described previously in liver tissues of SAMP1 mice. Biochemical and NMR-based analyses showed a reduction of low density lipoprotein (LDL) cholesterol plasma levels after Q(10) H(2) supplementation. This effect was especially pronounced in atherogenic small dense LDL particles (19-21 nm, 1.045 g/L). In agreement with gene expression signatures, Q(10) H(2) reduces the number of erythrocytes but increases the concentration of reticulocytes. In conclusion, Q(10) H(2) induces characteristic gene expression patterns, which are translated into reduced LDL cholesterol levels and altered parameters of erythropoiesis in humans. PMID- 21280177 TI - 17beta-estradiol regulates estrogen receptor alpha monoubiquitination. AB - Monoubiquitination is a nonproteolytic signal involved in a network of several different physiological processes. Recently, monoubiquitination has been discovered as a new post-transductional modification of the estrogen receptor alpha (ERalpha). However, at present no information is available about the role of the cognate ligand 17beta-estradiol (E2) in modulating this receptor post transductional modification. Thus, we studied the E2-dependent modulation of ERalpha monoubiquitination in different cell lines. Here, we report that ERalpha monoubiquitination isnegatively modulated by E2. These results demonstrate thatERalpha monoubiquitination represents a new signalling modification that may modulate the E2:ERalpha-regulated cellular processes. PMID- 21280178 TI - Myocardin-related transcription factor-A induces cardiomyocyte hypertrophy. AB - Myocardin is a remarkably potent transcriptional coactivator expressed specifically in cardiac muscle lineages and smooth muscle cells during postnatal development. Myocardin shares homology with myocardin-related transcription factor-A (MRTF-A), which are expressed in a broad range of embryonic and adult tissues. Our previous results show that myocardin induces cardiac hypertrophy. However, the effects of MRTF-A in cardiac hypertrophy remain poorly understood. Our present work further demonstrates that myocardin plays an important role in inducing hypertrophy. At the same time, we find that overexpression of MRTF-A in neonatal rat cardiomyocytes might induce cardiomyocyte hypertrophy. Furthermore, MRTF-A expression is induced in phenylephrine, angiotensin-II, and transforming growth factor-beta-stimulated cardiac hypertrophy, whereas a dominant-negative form of MRTF-A or MRTF-A siRNA strongly inhibited upregulation of hypertrophy genes in response to hypertrophic agonists in neonatal rat cardiomyocytes. Our studies indicate that besides myocardin, MRTF-A might play an important role in cardiac hypertrophy. Our findings provide novel evidence for the future studies to explore the roles of MRTFs in cardiac hypertrophy. PMID- 21280179 TI - Activating transcription factor 3 regulates survivability and migration of vascular smooth muscle cells. AB - Activating transcription factor 3 (ATF3) is a member of the ATF/CREB (CAMP responsive element binding protein) family of transcription factors. The expression and the function of ATF3 in vascular smooth muscle cells (VSMCs) remain unknown. The aim of this work is to determine the expression and possible function of ATF3 in VSMCs. We found that VSMCs expressed ATF3, and expression of ATF3 in VSMCs was induced by a variety of stimuli including serum, angiotensin II, and H(2)O(2). Knockdown of ATF3 induced apoptosis of VSMCs, caspase-3 cleavage, and cytochrome c release. The results suggest that ATF3 regulates survivability of VSMCs. Moreover, we found that overexpression of ATF3 promoted migration of VSMCs and induced expression of matrix metalloproteinase 1, 3, and 13. These results suggest that ATF3 plays a role in regulating migration of VSMCs. In addition, we found that the expression of ATF3 was upregulated in smooth muscle cells in the injured mouse femoral arteries compared with the uninjured control group. These results suggest that ATF3 is relevant to disease physiology. PMID- 21280180 TI - Liver cell implants: a long road. PMID- 21280181 TI - How much is too much? PMID- 21280182 TI - Primary human hepatocytes on biodegradable poly(l-lactic acid) matrices: a promising model for improving transplantation efficiency with tissue engineering. AB - Liver transplantation is an established treatment for acute and chronic liver disease. However, because of the shortage of donor organs, it does not fulfill the needs of all patients. Hepatocyte transplantation is promising as an alternative method for the treatment of end-stage liver disease and as bridging therapy until liver transplantation. Our group has been working on the optimization of matrix-based hepatocyte transplantation. In order to increase cell survival after transplantation, freshly isolated human hepatocytes were seeded onto biodegradable poly(l-lactic acid) (PLLA) polymer scaffolds and were cultured in a flow bioreactor. PLLA discs were seeded with human hepatocytes and exposed to a recirculated medium flow for 6 days. Human hepatocytes formed spheroidal aggregates with a liver-like morphology and active metabolic function. Phase contrast microscopy showed increasing numbers of spheroids of increasing diameter during the culture period. Hematoxylin and eosin histology showed viable and intact hepatocytes inside the spheroids. Immunohistochemistry confirmed sustained hepatocyte function and a preserved hepatocyte-specific cytoskeleton. Albumin, alpha-1-antitrypsin, and urea assays showed continued production during the culture period. Northern blot analysis demonstrated increasing albumin signals. Scanning electron micrographs showed hepatocyte spheroids with relatively smooth undulating surfaces and numerous microvilli. Transmission electron micrographs revealed intact hepatocytes and junctional complexes with coated pits and vesicles inside the spheroids. Therefore, we conclude that primary human hepatocytes, precultured in a flow bioreactor on a PLLA scaffold, reorganize to form morphologically intact liver neotissue, and this might offer an optimized method for hepatocyte transplantation because of the expected reduction of the initial cell loss, the high regenerative potential in vivo, and the preformed functional integrity. PMID- 21280183 TI - Portal inflow and pressure changes in right liver living donor liver transplantation including the middle hepatic vein. AB - The middle hepatic vein may be included in right liver living donor liver transplantation (LDLT) to optimize hepatic venous outflow. We studied the graft's ability to relieve portal hypertension and accommodate portal hyperperfusion with portal manometry and ultrasonic flowmetry. Surgical outcomes with respect to portal hemodynamometry were also investigated. The ages of the recipients and donors for 46 consecutive LDLT procedures were 50 (range, 16-66 years) and 31 years (range, 18-54 years), respectively. The graft to standard liver volume ratio was 47.4% (range, 32.4%-69.0%). The hospital mortality rate was 4.4% as 2 recipients died from a subarachnoid hemorrhage and sepsis. The portal pressure dropped by 8 mm Hg (range, -7 to 19 mm Hg) from 23 (range, 8-37 mm Hg) to 14 mm Hg (range, 10-26 mm Hg) after graft implantation. The portal inflow positively correlated with the portal pressure before native liver hepatectomy (R(2) = 0.305, P = 0.001) and not with the graft size. The portal inflow increased from 81 mL/minute/100 g (range, 35-210 mL/minute/100 g) before donor right hepatectomy to 318 mL/minute/100 g (range, 102-754 mL/minute/100 g) after graft implantation. The graft portal inflow had a positive linear correlation with the recipient portal pressure before native liver total hepatectomy (R(2) = 0.261, P = 0.001) but not after graft implantation, and it had a negative correlation with the graft to standard liver volume ratio (R(2) = 0.247, P = 0.001). Only 1 of the graft biopsies showed moderate sinusoidal congestion. Twelve recipients had Clavien grade 2+ complications that were not related to the portal inflow and pressure or graft size. Right liver LDLT including the middle hepatic vein effectively lowered the recipient portal pressure by allowing unimpeded venous outflow. PMID- 21280184 TI - Continuous development of arrhythmia is observed in Swedish transplant patients with familial amyloidotic polyneuropathy (amyloidogenic transthyretin Val30Met variant). AB - In patients with familial amyloidotic polyneuropathy (FAP), heart complications are prognostic factors for mortality and morbidity after liver transplantation (LT). However, only a few studies have analyzed the development of arrhythmia in transplant patients with FAP. We investigated the development of arrhythmia requiring pacemaker insertion (PMI) in Swedish transplant patients with FAP, and we related the findings to gender, age at disease onset, and survival. One hundred four transplant patients with the amyloidogenic transthyretin Val30Met mutation were included in the study. Twenty-six (25%) received a pacemaker during the observation period (a median of 11 years after disease onset). This frequency was comparable to that noted in a previous study describing the natural course of FAP. No significant differences in PMI between early-onset cases (<50 years old) and late-onset cases (>= 50 years old) or between genders were observed. PMI was not significantly related to patient survival. Our study confirms our previously reported short-time observation: LT does not prevent the development of heart arrhythmia necessitating PMI. The development of arrhythmia is unrelated to gender or age at disease onset, and the yearly risk does not appear to decrease with time after LT. PMID- 21280185 TI - Moderate ascites identifies patients with low model for end-stage liver disease scores awaiting liver transplantation who have a high mortality risk. AB - Donor livers are offered to patients with the highest risk of death. How ascites could inform risk models to reduce liver transplant wait-list mortality is unclear. All adult candidates for primary liver transplantation for cirrhosis without exception points who were registered with the Organ Procurement and Transplantation Network from 2005 to 2007 composed our study cohort. Using Cox models and advanced discriminative metrics and paying attention to geographic disparities, we evaluated the additional risk discrimination of moderate ascites over that of the Model for End-Stage Liver Disease (MELD) or the Model for End Stage Liver Disease plus serum sodium (MELD-Na) alone for the prediction of 90 day wait-list mortality. Additional analyses examined lower mortality risk candidates and those listed in high-demand, low-supply United Network for Organ Sharing regions in which accounting for ascites may most significantly affect wait-list mortality. Between 2005 and 2007, 18,124 subjects were listed for liver transplantation. Mortality was higher in patients with moderate ascites (15.4% versus 6.0%, P < 0.0001), and this risk persisted despite adjustments for MELD (hazard ratio = 1.58, 95% confidence interval = 1.42-1.76) and MELD-Na (hazard ratio = 1.42, 95% confidence interval = 1.28-1.58). The effect of moderate ascites was more prominent with a MELD score <21 (equal to 4.7 MELD units) or with a MELD-Na score <21 (equal to 3.5 MELD-Na units). Wait-list mortality was higher in patients with moderate ascites who were listed in high-demand, limited supply regions (25.8% versus 17.5% at 1 year, P < 0.01). With the addition of moderate ascites, there was improvement in the overall risk model, particularly with a MELD score <21, as measured by the C index and integrated discrimination improvement. Moderate ascites informed risk prediction, particularly with a MELD score <21 and in high-demand, limited-supply regions. Under the MELD system, the presence of moderate ascites should prompt clinicians to consider strategies to expand access to transplantation, such as the use of extended donor liver grafts. PMID- 21280186 TI - Portopulmonary hypertension as an indication for combined heart, lung, and liver or lung and liver transplantation: literature review and case presentation. AB - End-stage liver disease with severe portopulmonary hypertension (PPHTN), which is refractory to vasodilator therapies, is a contraindication for isolated liver transplantation (LT) because of the high mortality rate. Combined heart, lung, and liver transplantation (CHLLT) and combined lung and liver transplantation (CLLT) can be lifesaving options for these patients; however, these procedures have rarely been performed. A 52-year-old man had end-stage liver disease due to hepatitis C and PPHTN; the latter showed a suboptimal response to pulmonary vasodilator therapy with continuous intravenous treprostinil sodium and oral sildenafil citrate and was considered a contraindication to isolated LT. His preoperative left ventricular function was normal, and he had mild to moderate right ventricular dysfunction. He underwent CLLT, which consisted of sequential double-lung transplantation under cardiopulmonary bypass followed by standard LT under venovenous bypass. Re-exploration of the chest cavity was necessary because of bleeding, and respiratory failure developed; however, the patient recovered, was discharged home on day 26, and remained well 1 year after CLLT with the standard immunosuppressants (similar to those used for heart and lung transplantation). For PPHTN, combined thoracic organ and liver transplantation has been reported in only 10 patients. Six of these patients, including our case, underwent CLLT, whereas 4 patients underwent CHLLT. Notably, 2 of the 6 CLLT patients expired within 24 hours of transplantation because of acute right heart failure. CHLLT should be considered for patients with refractory PPHTN. The assessment of preoperative cardiac function is a vital part of the decision to include heart transplantation in CLLT. PMID- 21280187 TI - Immediate noninvasive ventilation may improve mortality in patients with hepatopulmonary syndrome after liver transplantation. AB - Hepatopulmonary syndrome (HPS) is defined as hypoxemia induced by intrapulmonary vascular dilations associated with liver disease. Although liver transplantation (LT) is the only effective therapy established for severe HPS, patients with a partial pressure of arterial oxygen (PaO(2) ) less than 60 mm Hg have a poor prognosis. We treated a 4-year-old boy with HPS whose preoperative PaO(2) level was 48.8 mm Hg. After LT, he had persistent severe hypoxemia, although he was receiving high-flow oxygen. Noninvasive ventilation (NIV) was introduced, and his respiratory insufficiency promptly improved. Therefore, NIV therapy immediately after extubation following transplantation was administered to the next 4 consecutive HPS patients whose preoperative PaO(2) was less than 60 mm Hg. The NIV treatment of these 5 patients could have been responsible for preventing severe postoperative complications as well as reintubation and hospital death. NIV therapy for both pediatric and adult patients with severe HPS immediately after extubation might protect them from severe hypoxemia after transplantation and from complications necessitating reintubation and might improve their prognosis. PMID- 21280189 TI - Dual catheter placement technique for treatment of biliary anastomotic strictures after liver transplantation. AB - The purpose of this study was to evaluate the results of percutaneous transhepatic management of anastomotic biliary strictures using the dual catheter placement technique (2 drainage catheters inserted via single percutaneous tract). The protocol of this retrospective study was approved by the institutional review board of our institution and written informed consent was waived. Percutaneous transhepatic biliary drainage and subsequent balloon dilation of anastomotic strictures were performed in 79 patients. Serial exchanges of drainage via catheter with larger diameters up to 14-French were performed at 1-month intervals followed by 3 exchanges of dual catheters at 2 month intervals. Drainage catheters were removed when follow-up cholangiography revealed improved strictures without recurrence of symptoms or elevation of biochemical findings. Technical success was achieved in all 79 (100%) patients after percutaneous transhepatic treatment. The mean period of dual catheter placement was 6.5 +/- 1.1 months (range, 5.5-14.2 months). Clinical success was achieved in 78 (98.7%) of 79 patients and drainage catheters were removed 23.8 +/ 8.8 months (range, 11.4-43.3 months) after the initial percutaneous transhepatic biliary drainage. Procedure-related complications occurred in 14 (17.8%) patients. During the mean follow-up period of 34.5 +/- 3 months (range, 24.4-38.5 months) in the 78 patients, the primary patency rates were 96%, 92%, and 91% at 1, 2, and 3 years, respectively. Seven (9%) of the 78 patients experienced recurrent symptoms at a mean of 15.4 +/- 8.9 months (range, 6.1-26.2 months) after catheter removal. In conclusion, the dual catheter placement technique seems to be an easy, safe, and effective method with an acceptable catheter intervention period for the treatment of anastomotic strictures following LDLT. PMID- 21280188 TI - Differential effects of plasma and red blood cell transfusions on acute lung injury and infection risk following liver transplantation. AB - Patients with chronic liver disease have an increased risk of developing transfusion-related acute lung injury (TRALI) from plasma-containing blood products. Similarly, red blood cell transfusions have been associated with postoperative and nosocomial infections in surgical and critical care populations. Patients undergoing liver transplantation receive large amounts of cellular and plasma-containing blood components, but it is presently unclear which blood components are associated with these postoperative complications. A retrospective cohort study of 525 consecutive liver transplant patients revealed a perioperative TRALI rate of 1.3% (7/525, 95% confidence interval = 0.6%-2.7%), which was associated with increases in the hospital mortality rate [28.6% (2/7) versus 2.9% (15/518), P = 0.02] and the intensive care unit length of stay [2 (1 11 days) versus 0 days (0-2 days), P = 0.03]. Only high-plasma-containing blood products (plasma and platelets) were associated with the development of TRALI. Seventy-four of 525 patients (14.1%) developed a postoperative infection, and this was also associated with increased in-hospital mortality [10.8% (8/74) versus 2.0% (9/451), P < 0.01] and a prolonged length of stay. Multivariate logistic regression determined that the number of transfused red blood cell units (adjusted odds ratio = 1.08, 95% confidence interval = 1.02-1.14, P < 0.01), the presence of perioperative renal dysfunction, and reoperation were significantly associated with postoperative infection. In conclusion, patients undergoing liver transplantation have a high risk of developing postoperative complications from blood transfusion. Plasma-containing blood products were associated with the development of TRALI, whereas red blood cells were associated with the development of postoperative infections in a dose-dependent manner. PMID- 21280190 TI - Pharmacokinetics for once-daily versus twice-daily tacrolimus formulations in de novo liver transplantation: a randomized, open-label trial. AB - Tacrolimus, a cornerstone immunosuppressant, is available as a twice-daily formulation (tacrolimus bid). A once-daily prolonged-release formulation (tacrolimus qd) has been developed. This 6-week, randomized, phase 2, multicenter, open-label, prospective trial in primary liver transplant recipients investigated and compared the pharmacokinetics (PK) of tacrolimus for qd and bid formulations. All patients received tacrolimus-based immunosuppression (tacrolimus qd, n = 67; bid, n = 62). PK data were available for 77 patients (tacrolimus qd, n = 45; bid, n = 32). Tacrolimus area under the curve (AUC) from 0 to 24 hours (AUC(0-24) ) at equivalent doses was approximately 50% lower for tacrolimus qd than for bid on day 1 (146 versus 264 ng . h/mL, respectively), but by day 14 was comparable between treatments (324 and 287 ng . h/mL, respectively) with higher tacrolimus qd doses. There was a strong correlation between AUC(0-24) and concentration at 24 hours for tacrolimus qd and bid (r = 0.92 and r = 0.76, respectively). Furthermore, the relationship between these 2 parameters (ie, the slope of the line) was also similar for the 2 formulations. Efficacy endpoints were comparable for both formulations at 6 weeks with no marked differences in incidence, nature, or severity of adverse events between treatments (although the study was not powered to draw efficacy conclusions). These results suggest that targeting the same trough levels will achieve similar total AUC over 24 hours for both tacrolimus qd and tacrolimus bid in de novo liver transplant recipients. PMID- 21280191 TI - Digital image analysis of liver collagen predicts clinical outcome of recurrent hepatitis C virus 1 year after liver transplantation. AB - Clinical outcomes of recurrent hepatitis C virus after liver transplantation are difficult to predict. We evaluated collagen proportionate area (CPA), a quantitative histological index, at 1 year with respect to the first episode of clinical decompensation. Patients with biopsies at 1 year after liver transplantation were evaluated by Ishak stage/grade, and biopsy samples stained with Sirius red for digital image analysis were evaluated for CPA. Cox regression was used to evaluate variables associated with first appearance of clinical decompensation. Receiver operating characteristic (ROC) curves were also used. A total of 135 patients with median follow-up of 76 months were evaluated. At 1 year, median CPA was 4.6% (0.2%-36%) and Ishak stage was 0-2 in 101 patients, 3-4 in 23 patients, and 5-6 in 11 patients. Decompensation occurred in 26 (19.3%) at a median of 61 months (15-138). Univariately, CPA, tacrolimus monotherapy, and Ishak stage/grade at 1 year were associated with decompensation; upon multivariate analysis, only CPA was associated with decompensation (P = 0.010; Exp(B) = 1.169; 95%CI, 1.037-1.317). Area under the ROC curve was 0.97 (95%CI, 0.94-0.99). A cutoff value of 6% of CPA had 82% sensitivity and 95% specificity for decompensation. In the 89 patients with hepatic venous pressure gradient (HVPG) measurement, similar results were obtained. When both cutoffs of CPA > 6% and HVPG >= 6 mm Hg were used, all patients decompensated. Thus, CPA at 1-year biopsy after liver transplantation was highly predictive of clinical outcome in patients infected with hepatitis C virus who underwent transplantation, better than Ishak stage or HVPG. PMID- 21280192 TI - Endoplasmic reticulum stress is a mediator of posttransplant injury in severely steatotic liver allografts. AB - Hepatic steatosis continues to present a major challenge in liver transplantation. These organs have been shown to have increased susceptibility to cold ischemia/reperfusion (CIR) injury in comparison with otherwise comparable lean livers; the mechanisms governing this increased susceptibility to CIR injury are not fully understood. Endoplasmic reticulum (ER) stress is an important link between hepatic steatosis, insulin resistance, and metabolic syndrome. In this study, we investigated ER stress signaling and blockade in the mediation of CIR injury in severely steatotic rodent allografts. Steatotic allografts from genetically leptin-resistant rodents had increased ER stress responses and increased markers of hepatocellular injury after liver transplantation into strain-matched lean recipients. ER stress response components were reduced by the chemical chaperone taurine-conjugated ursodeoxycholic acid (TUDCA), and this resulted in an improvement in the allograft injury. TUDCA treatment decreased nuclear factor kappa B activation and the proinflammatory cytokines interleukin-6 and interleukin-1beta. However, the predominant response was decreased expression of the ER stress cell death mediator [CCAAT/enhancer-binding protein homologous protein (CHOP)]. Furthermore, activation of inflammation-associated caspase-11 was decreased, and this linked ER stress/CHOP to proinflammatory cytokine production after steatotic liver transplantation. These data confirm ER stress in steatotic allografts and implicate this as a mediating mechanism of inflammation and hepatocyte death in the steatotic liver allograft. PMID- 21280193 TI - Native macrophages genetically modified to express heme oxygenase 1 protect rat liver transplants from ischemia/reperfusion injury. AB - We investigated whether native macrophages overexpressing heme oxygenase 1 (HO-1) could protect rat orthotopic liver transplant (OLT) against cold ischemia/reperfusion injury (IRI). Livers from Sprague-Dawley rats were stored at 4 degrees C in University of Wisconsin solution for 24 hours, and then they were transplanted into syngeneic recipients. Bone marrow-derived macrophages (BMMs) that were transfected ex vivo with heme oxygenase 1 adenovirus (Ad-HO-1), beta galactosidase adenovirus (Ad-beta-gal), or HO-1 small interfering RNA (siRNA) were infused directly into the OLT before reperfusion. Controls were OLT conditioned with unmodified or scrambled siRNA-transfected cells. The transfer of Ad-HO-1/BMMs increased the survival of OLT to 100% (versus 40%-50% for controls) and decreased serum alanine aminotransferase levels and histological features of hepatocellular damage. In contrast, an infusion of macrophages transfected with HO-1 siRNA/Ad-beta-gal failed to affect IRI. Gene therapy-induced HO-1 suppressed toll-like receptor 4 expression, decreased expression of proinflammatory tumor necrosis factor alpha, interleukin-1beta, monocyte chemoattractant protein 1, and chemokine (C-X-C motif) ligand 10, and attenuated endothelial intercellular cell adhesion molecule 1 expression with resultant diminished OLT leukocyte sequestration. Although Ad-HO-1/BMMs decreased the frequency of apoptotic cells positive for terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling and ameliorated caspase-3 activity, the expression of interleukin-10 and antiapoptotic B cell lymphoma 2/B cell lymphoma extra large increased in well-functioning OLT. Thus, the transfer of native macrophages transfected ex vivo with HO-1 can rescue rat iso-OLT from IRI. Our study validates a novel and clinically attractive concept: native macrophages transfected ex vivo with the antioxidant HO-1 can be applied at the time of transplantation to mitigate otherwise damaging antigen-independent liver inflammation and injury resulting from the peritransplant harvesting insult. If this new, refined strategy is proven to be effective in allo-OLT recipients, it should be considered in clinical settings to increase the supply of usable donor organs and ultimately improve the overall success of liver transplantation. PMID- 21280194 TI - Endovascular closure of a portocaval shunt after left lobe liver transplantation using an Amplatzer muscular ventricular septal occluder device. PMID- 21280195 TI - The influence of seeking God in the association between religiosity and prolonged survival in liver transplant recipients. PMID- 21280197 TI - Safety assessment of intensive induction therapy in childhood anaplastic large cell lymphoma: report of the ALCL99 randomised trial. AB - BACKGROUND: ALCL99 protocol including six courses of chemotherapy derived from the NHL-BFM protocol is widely used for the treatment of paediatric anaplastic large-cell lymphoma. In the ALCL99 trial, patients were randomised to receive MTX 1 g/m2 in 24 hr with intrathecal injection (MTX1) versus MTX 3 g/m2 in 3 hr without intrathecal (MTX3); then to receive or not vinblastine (high-risk patients). The present study provides information about the acute adverse reactions (ARs) during the six courses of the ALCL99 treatment, assesses risk factors for ARs and evaluates the risk of overweight related to treatment. METHODS: Data concerning ARs were assessed using CTCv2 and analysed overall and according to the type of course. RESULTS: Between 1999 and 2005, 352 patients were recruited. Toxicity assessed after 2050 courses included grade 4 neutropaenia (70% of courses), grade 3-4 stomatitis (13%), grade 3-4 transaminase elevation (10%) and grade 3-4 infection (5%). Four patients (1%) died of toxicity. The toxicity profile differed between courses-A (significantly more haematological toxicity) and courses-B (significantly more stomatitis). The percentage of ARs was higher after the first course than after subsequent courses. Severe toxicity was more frequent after MTX1 than after MTX3 courses but did not differ between courses with or without vinblastine. Overall 20% of patients had a weight gain exceeding 20%. CONCLUSIONS: The high rate of acute toxicity should be considered when using the ALCL99 protocol. Chemotherapy including MTX 3 g/m2 in 3 hr was less toxic than the same regimen with MTX 1 g/m2 in 24 hr. Adding vinblastine did not increase the risk of toxicity. PMID- 21280198 TI - Characteristics and outcome of radiation and chemotherapy-related mucoepidermoid carcinoma of the salivary glands. AB - BACKGROUND: Mucoepidermoid carcinoma (MEC) of the salivary glands has been reported to occur in patients previously treated with chemotherapy and/or radiation. The purpose of our study is to review the patient, tumor, and treatment characteristics of patients who develop a treatment-related MEC. PROCEDURE: A PubMed search of English language articles was performed using the keywords and MeSH terms: mucoepidermoid, salivary gland, radiation-induced, second malignancy, radiotherapy, and chemotherapy. RESULTS: The search yielded 23 articles describing 58 patients who received chemotherapy and/or radiotherapy (RT) and subsequently developed MEC. The most common initial diagnoses were acute lymphoblastic leukemia (n = 18), acne (n = 9), and Hodgkin lymphoma (n = 6). Patients were divided into three groups according to chemotherapy and RT treatment: chemotherapy alone (n = 14), RT alone (n = 14), or chemotherapy and RT (n = 30). The parotid gland was the most common site for secondary MEC. Latent time (LT) to development of MEC from initial tumor treatment was significantly shorter in the patients treated with chemotherapy +/- RT versus RT alone (7.9 years vs. 27.2 years, P < 0.01). The most common treatment for MEC was surgery alone followed by surgery and postoperative RT. The 2- and 5-year overall survival rates were 98% and 93.4% while the 2- and 5-year locoregional control rates were 97.7% and 92.5%, respectively. There was no difference in survival or locoregional control between groups exposed to RT alone, chemotherapy alone, or chemotherapy with RT for the initial tumor. CONCLUSION: Radiation and chemotherapy-related MEC has an excellent prognosis. PMID- 21280199 TI - Outcomes of informed consent among parents of children in cancer clinical trials. AB - BACKGROUND: Clinical trials are central to pediatric oncology, yet the process and outcomes of informed consent are poorly understood. We evaluated correlates of understanding among parents of pediatric trial participants, and explored differences in the process and outcome of informed consent between parents and a comparison group of adult participants. PROCEDURE: We administered the Quality of Informed Consent (QuIC) to parents of children who were newly enrolled onto a cancer trial. We identified independent correlates of knowledge among parents, and compared parents' knowledge to that of a contemporaneous group of adult participants, using multiple linear regression models. RESULTS: Parents (n = 47) were less likely than adult participants (n = 204) to report having enough time to learn about the trial (64% vs. 87%, P = 0.001) or sufficient opportunity for questions (79% vs. 93%, P = 0.01), and reported lower overall satisfaction with the consent process (71% vs. 90%, P = 0.002). The mean parental knowledge score was 73.6 (95% confidence interval [CI] 69.5-77.8, theoretical maximum 100). Knowledge did not differ between parents and adult trial participants. In multivariate analysis, two predictors were significantly associated with higher parent knowledge scores: consent sought by the study's principal investigator (increment 13.6, CI 2.7-24.6) and physician-reported poor prognosis (increment 13.8, 95% CI 5.4-22.1). CONCLUSIONS: Although we observed no differences in knowledge between parents of pediatric cancer trial participants and their adult counterparts, parents report more problems with the informed consent process for their trials. The increased prevalence of problems is likely due to clinical and contextual differences between pediatric and adult trials. PMID- 21280200 TI - Childhood chronic ITP. PMID- 21280201 TI - Echocardiographic surveillance for asymptomatic late-onset anthracycline cardiomyopathy in childhood cancer survivors. AB - BACKGROUND: The optimal frequency of echocardiographic surveillance in asymptomatic childhood cancer survivors exposed to anthracyclines has not been established. We evaluated the effectiveness of performing surveillance echocardiograms according to the Children's Oncology Group's (COG) Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers in survivors >=1 year from concluding therapy. METHODS: We reviewed all children treated at our institution with anthracycline chemotherapy from 1995 to 2003. We assessed the frequency of abnormal echocardiograms according to risk groups defined in the COG guidelines, and evaluated the risk factors for an abnormal echocardiogram using Cox proportional hazards modeling. RESULTS: At least one echocardiogram was completed by 469/603 (77.8%) eligible survivors. Mean diagnosis age was 7.7 (SD = 4.6) years. Mean cumulative doxorubicin equivalent dose was 205 mg/m(2) (SD = 115). Survivors completed 1,013 echocardiograms (median = 2, range =1-10) beyond 1 year after concluding therapy. Seventy-nine (16.8%) survivors had an abnormal echocardiogram at a median of 2.9 years (range 0.01-9.8) from 1 year after concluding therapy. Anthracycline dose >300 mg/m(2) (hazard ratio [HR] 3.00; 95% CI 1.51-5.98), age 1 4 years at treatment (HR 1.89; 95% CI 1.08-3.31) and radiation to a field involving the heart (HR 1.73; 95% CI 1.08-2.76) predicted an increased risk of an abnormal echocardiogram; however, even survivors in the lower COG risk groups demonstrated abnormalities. CONCLUSION: Periodic echocardiographic surveillance in childhood cancer survivors can yield abnormalities that require further evaluation. Abnormalities may become evident as early as 1 year after the conclusion of therapy and can impact even those survivors considered to be at low risk. PMID- 21280202 TI - Symptoms of attention-deficit/hyperactivity disorder in long-term survivors of childhood leukemia. AB - BACKGROUND: Survivors of childhood acute lymphoblastic leukemia (ALL) sometimes have clinical features that suggest attention-deficit/hyperactivity disorder (ADHD), though few studies have examined specific symptoms in survivors. PROCEDURE: Long-term survivors of childhood ALL (n = 161) received a neurological examination, while parents completed rating scales to establish formal criteria for ADHD. Symptom profiles were generated and compared across demographic and treatment characteristics, as well as medical tests associated with brain pathology. RESULTS: Prevalence rates of ADHD were similar in survivors (10.5%) compared to those reported in the general population (7-10%). However, 25.5% of survivors reported symptoms that impair functioning in multiple settings, with attention problems being most common. These symptoms were associated with cranial radiation therapy (CRT) (mean inattentive symptoms [SD] = 3.6 [3.19] for group treated with CRT vs. 1.6 [2.40] for non-CRT group, P = 0.0006), and survivors who demonstrated impaired anti-saccades during the neurologic exam (mean inattentive symptoms [SD] = 3.4 [3.29] for those with impaired anti-saccades vs. 1.4 [2.41] for those with normal anti-saccades; P = 0.0004). CONCLUSIONS: The presence of a neurologically-based phenotype of attention problems in survivors of leukemia that is not fully captured by the syndrome of ADHD suggests that treatments specific to childhood ALL should be explored. PMID- 21280203 TI - Sex, BMI and age in addition to dietary intakes influence blood concentrations and congener profiles of dioxins and PCBs. AB - SCOPE: The aim of this study was to i) characterize dietary polychlorinated biphenyls (PCBs) and dioxin exposure in consumers of fish from the PCB contaminated Lake Mjosa in Norway ii) examine the influence of demographic factors on blood concentrations and congener composition of dioxins and PCBs, iii) characterize dietary sources and possible exposures above tolerable intake. METHODS AND RESULTS: Blood samples were analysed for dioxin-like (dl) compounds (PCDD/Fs and dl-PCBs) and non-dl-PCBs (ndl-PCBs). Dietary exposures were calculated using food frequency questionnaires (n=64). Men had higher median intake of dl-compounds than women (1.2 and 0.85 pg TEQ/kg bw/day), but similar blood concentrations (23.3 and 25.8, pg TEQ/g lipid weight (lw)). For non-dl PCBs, intakes (6.5 and 4.5 ng/kg bw/day) and blood concentrations (381 and 224 ng/g lw) were higher in men than in women. Blood concentrations correlated with dietary intakes in men only. Increasing BMI and age elevated blood concentrations mainly in women. Men and women had different blood congener profiles, with a higher share of PCB-126 in women, despite similar dietary congener profiles. Eleven participants exceeded the tolerable intake for dl-compounds. Fish from Lake Mjosa was the main dietary source. CONCLUSION: The higher influence of BMI and age for women than for men may have implications for risk assessment. PMID- 21280204 TI - Anthocyanin-rich extracts suppress the DNA-damaging effects of topoisomerase poisons in human colon cancer cells. AB - SCOPE: The effect of two anthocyanin-rich berry extracts (A, bilberry; B, red grape) on topoisomerases was investigated in a cell-free system and in human HT29 colon carcinoma cells. In parallel, their impact on DNA integrity was determined. METHODS AND RESULTS: The berry extracts suppressed the activity of topoisomerase I at concentrations >=50 MUg/mL. The activity of the topoisomerase II isoform was preferentially diminished (>=1 MUg/mL). Within HT29 cells, the extracts were found to act as catalytic inhibitors without stabilizing the cleavable complex. Although topoisomerase activity was inhibited, none of the extracts induced DNA strand breaks up to 50 MUg/mL. Moreover, pre- and coincubation of HT29 cells with A (>=1 MUg/mL) significantly suppressed (p-value <=0.001) the strand-breaking effects of camptothecin, whereas B was found to be less effective (1 MUg/mL; p value <=0.05). Both extracts were found to significantly diminish doxorubicin mediated DNA strand breaks at concentrations >=1 MUg/mL (p-value <=0.001). Consistent with these results, the extracts suppressed doxorubicin-mediated enhancement of levels of topoisomerase II covalently linked to DNA in HT29 cells. CONCLUSION: These results raise the possibility that high intake of berry extracts may protect DNA and thus counteract the therapeutic effectiveness of orally applied topoisomerase poisons during chemotherapy. PMID- 21280205 TI - Effect of flavonoids on basal and insulin-stimulated 2-deoxyglucose uptake in adipocytes. AB - SCOPE: The adipose tissue is a major site of insulin action and contributes substantially to energy homeostasis. Insulin increases the extraction of glucose from circulation into adipose tissue by recruiting the glucose transporter GLUT4 to the plasma membrane. It has been proposed that dietary flavonoids may interfere with glucose transport processes. METHODS AND RESULTS: We have used murine 3T3-L1 adipocytes and isolated mature human adipocytes to assess the interaction of selected flavonoids with glucose uptake, both in the basal state and after insulin stimulation. Kinetic characterization of 2-deoxyglucose uptake in the basal state revealed in both cell types an apparent K(m) of around 8 mM with no change in affinity but a significant increase in maximal influx in the presence of insulin. A screening of representative flavonoids of different structural classes revealed the flavanone naringenin and the isoflavone daidzein to affect glucose transport significantly with half-maximal inhibition at concentrations of around 60-80 MUM for basal and 70-110 MUM for insulin stimulated glucose uptake in both 3T3-L1 adipocytes and mature human adipocytes. CONCLUSION: Considering attainable plasma concentrations of flavonoids in vivo, we assume that even under physiological conditions naringenin and daidzein could impair glucose removal from plasma, which may pose a risk to patients with diabetes mellitus. PMID- 21280206 TI - Impact of the synbiotic combination of Lactobacillus casei shirota and oligofructose-enriched inulin on the fecal volatile metabolite profile in healthy subjects. AB - SCOPE: Hypothesis-driven approaches have mainly focused on the quantification of SCFAs as mediators of beneficial effects of synbiotics. However, the emergence of metabolite profiling strategies allows to evaluate the colonic metabolism from a top-down approach. In the present study, we evaluated the impact of a synbiotic combination on fecal metabolite profiles. METHODS AND RESULTS: A synbiotic combination (Lactobacillus casei Shirota cells+oligofructose-enriched inulin) was evaluated in nine healthy volunteers. Before the start, during and after 4-wk treatment, fecal samples were obtained. GC-MS technology was applied to analyze the volatile metabolites. Application of a Type III test revealed that the metabolite profiles from the three conditions were significantly different. We identified three volatile organic compounds, acetate, dimethyl trisulfide and ethyl benzene, which were significantly affected. The acetate levels increased, whereas the dimethyl trisulfide levels decreased during and after the intervention. For ethyl benzene only an effect during the synbiotic intervention period was observed. CONCLUSION: We report a detailed analysis of the influence of L. casei Shirota combined with oligofructose-enriched inulin on fermentation metabolites. Our results indicated a stimulation of saccharolytic fermentation and, importantly, a reduction of potentially toxic protein fermentation metabolites dimethyl trisulfide and ethyl benzene attended these effects. PMID- 21280207 TI - Stabilization of small heterodimer partner mRNA by grape seed procyanidins extract in cultured hepatocytes. AB - SCOPE: Consumption of dietary grape seed procyanidins extract (GSPE) has improved the plasma lipid profile in humans and experimental animals. The effect of GSPE on the reduction of the postprandial plasma triglyceride (TG) levels has been attributed to the activation of the small heterodimer partner (SHP). GSPE increases SHP gene expression in rat liver and the TG-lowering effect of GSPE is abolished in SHP-deficient mice. However, the mechanism by which GSPE increases SHP mRNA levels remains unclear. This study addressed the effect of GSPE on SHP mRNA stability. METHODS AND RESULTS: The present study shows for the first time that SHP mRNA is rapidly degraded, as measured by actinomycin D-based mRNA chase experiments, and GSPE transiently stabilizes SHP mRNA in HepG2 cells. This degradative effect was completely abolished with 2 h of prolonged treatment with GSPE. However, treatment of fresh HepG2 cells with a pretreated GSPE-containing medium also stabilized SHP mRNA, indicating that GSPE inactivation is not responsible for the transient effects that GSPE has on SHP mRNA stability. CONCLUSION: SHP expression is intricately controlled by mRNA stabilization, which is transiently increased by GSPE, along with at the transcriptional and posttranslational levels. PMID- 21280208 TI - Nutrigenomics in human intervention studies: current status, lessons learned and future perspectives. AB - Nutrigenomics applications comprise transcript-, proteome- and metabolome profiling techniques in which responses to diets or individual ingredients are assessed in biological samples. They may also include the characterization of heterogeneity in relevant genes that affect the biological processes. This review explores various areas of nutrition and food sciences in which transcriptome-, proteome- and metabolome-analyses have been applied in human intervention studies, including nutrigenetics aspects and discusses the advantages and limitations of the methodologies. Despite the power of the profiling techniques to generate huge data sets, a critical assessment of the study outcomes emphasizes the current constraints in data interpretation, including huge knowledge gaps, the need for improved study designs and more comprehensive phenotyping of volunteers before selection for study participation. In this respect, nutrigenomics faces the same problems as all other areas of the life sciences, employing the same tools. However, there is a growing trend toward systemic approaches in which different technologies are combined and applied to the same sample, allowing physiological changes to be assessed more robustly throughout all molecular layers of mRNA, protein and metabolite changes. Nutrigenomics is thereby maturing as a branch of the life sciences and is gaining significant recognition in the scientific community. PMID- 21280209 TI - Vitamin D intestinal absorption is not a simple passive diffusion: evidences for involvement of cholesterol transporters. AB - SCOPE: It is assumed that vitamin D is absorbed by passive diffusion. However, since cholecalciferol (vitamin D(3) ) and cholesterol display similar structures, we hypothesized that common absorption pathways may exist. METHODS AND RESULTS: Cholecalciferol apical transport was first examined in human Caco-2 and transfected Human embryonic kidney (HEK) cells. Cholecalciferol uptake was then valuated ex vivo and in vivo, using either wild-type mice, mice overexpressing Scavenger Receptor class B type I (SR-BI) at the intestinal level or mice treated or not with ezetimibe. Cholecalciferol uptake was concentration-, temperature- and direction-dependent, and was significantly impaired by a co-incubation with cholesterol or tocopherol in Caco-2 cells. Moreover Block Lipid Transport-1 (SR BI inhibitor) and ezetimibe glucuronide (Niemann-Pick C1 Like 1 inhibitor) significantly decreased cholecalciferol transport. Transfection of HEK cells with SR-BI, Cluster Determinant 36 and Niemann-Pick C1 Like 1 significantly enhanced vitamin D uptake, which was significantly decreased by the addition of Block Lipid Transport-1, sulfo-N-succinimidyl oleate (Cluster Determinant 36 inhibitor) or ezetimibe glucuronide, respectively. Similar results were obtained in mouse intestinal explants. In vivo, cholecalciferol uptake in proximal intestinal fragments was 60% higher in mice overexpressing SR-BI than in wild-type mice (p<0.05), while ezetimibe effect remained non-significant. CONCLUSION: These data show for the first time that vitamin D intestinal absorption is not passive only but involves, at least partly, some cholesterol transporters. PMID- 21280210 TI - Local surface potential of pi-conjugated nanostructures by Kelvin probe force microscopy: effect of the sampling depth. AB - Kelvin probe force microscopy (KPFM) is usually applied to map the local surface potential of nanostructured materials at surfaces and interfaces. KPFM is commonly defined as a 'surface technique', even if this assumption is not fully justified. However, a quantification of the surface sensitivity of this technique is crucial to explore electrical properties at the nanoscale. Here a versatile 3D model is presented which provides a quantitative explanation of KPFM results, taking into account the vertical structure of the sample. The model is tested on nanostructured films obtained from two relevant semiconducting systems for field effect transistor and solar cell applications showing different interfacial properties, i.e., poly(3-hexylthiophene) (P3HT) and perylene-bis-dicarboximide (PDI). These findings are especially important since they enable quantitative determination of the local surface potential of conjugated nanostructures, and thereby pave the way towards optimization of the electronic properties of nanoscale architectures for organic electronic applications. PMID- 21280211 TI - Analyses of polychlorinated biphenyls in waters and wastewaters using vortex assisted liquid-liquid microextraction and gas chromatography-mass spectrometry. AB - A method was developed for viable and rapid determination of seven polychlorinated biphenyls (PCBs) in water samples with vortex-assisted liquid liquid microextraction (VALLME) using gas chromatography-mass spectrometry (GC MS). At first, the most suitable extraction solvent and extraction solvent volume were determined. Later, the parameters affecting the extraction efficiency such as vortex extraction time, rotational speed of the vortex, and ionic strength of the sample were optimized by using a 2(3) factorial experimental design. The optimized extraction conditions for 5 mL water sample were as follows: extractant solvent 200 MUL of chloroform; vortex extraction time of 2 min at 3000 rpm; centrifugation 5 min at 4000 rpm, and no ionic strength. Under the optimum condition, limits of detection (LOD) ranged from 0.36 to 0.73 ng/L. Mean recoveries of PCBs from fortified water samples are 96% for three different fortification levels and RSDs of the recoveries are below 5%. The developed procedure was successfully applied to the determination of PCBs in real water and wastewater samples such as tap, well, surface, bottled waters, and municipal, treated municipal, and industrial wastewaters. The performance of the proposed method was compared with traditional liquid-liquid extraction (LLE) of real water samples and the results show that efficiency of proposed method is comparable to the LLE. However, the proposed method offers several advantages, i.e. reducing sample requirement for measurement of target compounds, less solvent consumption, and reducing the costs associated with solvent purchase and waste disposal. It is also viable, rapid, and easy to use for the analyses of PCBs in water samples by using GC-MS. PMID- 21280212 TI - Preparative separation of chromones in plant extract of Saposhnikovia divaricata by high-performance counter-current chromatography. AB - Four chromones, prim-O-glucosylcimifugin, 4'-O-beta-D-glucosyl-5-O methylvisamminol, cimifugin and sec-O-glucosylhamaudol, were isolated and purified from Saposhnikovia divaricata for the first time by high-performance counter-current chromatography (HPCCC) using a system consisting of ethyl acetate/n-butanol/ethanol/water (1:1:0.1:2, v/v/v/v). The separation parameters were first performed on the analytical HPCCC and the optimized conditions were then scaled up to preparative HPCCC. A total of 72.1 mg of prim-O glucosylcimifugin, 27 mg of 4'-O-beta-D-glucosyl-5-O-methylvisamminol, 14.1 mg of cimifugin and 1.1 mg of sec-O-glucosylhamaudol were purified from 960 mg of the n butanol extract of S. divaricata, each at over 90% purity as determined by high performance liquid chromatography (HPLC). The structures of four compounds were identified by their retention time, the liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) in the positive ion mode, and confirmed by NMR. The characteristic LC-ESI-MS fragmentation patterns of the four compounds were discussed, and found to be a very specific and useful tool for the structural identification of chromones from S. divaricata. PMID- 21280213 TI - Reversed-phase liquid chromatographic separation of antiretroviral drugs on a monolithic column using ionic liquids as mobile phase additives. AB - The use of 3-methylimidazolium cation-based ionic liquids (ILs) was evaluated as mobile phase additives for separation of antiretroviral drugs on a monolithic column by RP-HPLC. Separation of eight commonly used antiretroviral drugs was achieved on a Chromolith Flash, RP-18e column (25 * 4.6 mm, porous material) using water (pH 4.0 adjusted with acetic acid)/methanol v/v as a mobile phase containing ILs in a gradient elution mode. The effects of concentrations of ILs on retention, resolution and peak shape were studied and a regression equation correlating the interactions between stationary phase and the ILs was established. The retention of all the drugs was decreased notably by using 1 butyl-3-methylimidazolium tetrafluoroborate, while 1-ethyl-3-methylimidazolium methylsulfate reduced gradient drift drastically when compared to triethylamine. PMID- 21280214 TI - Milli-free flow electrophoresis: I. Fast prototyping of mFFE devices. AB - We coin a term of milli-free flow electrophoresis (mFFE) to describe mid-scale FFE with flow rates intermediate to macro-FFE and micro-FFE (MUFFE). Introduced decades ago, mFFE did not find practical applications. We revive mFFE, as we view it as a viable purification complement to continuous synthesis in capillary reactors with product flow rates of ~5 to 2000 MUL/min, too small for macro-FFE but too large for MUFFE. The development of the tandem of continuous synthesis/purification will require the production and evaluation of a large number of prototypes of mFFE devices. As the first step, we developed a fast (<24 h) and economical (~$10) method for prototyping mFFE devices using a robotic milling machine. mFFE prototypes are constructed from two machined matching poly(methyl methacrylate) (PMMA) substrates, which are bonded in 10 min using dichloromethane to provide a strong and irreversible seal. Using the developed prototyping technology, we designed and evaluated 25 prototypes of mFFE devices. By optimizing the feed rates and rotational speeds of the drills, the depth of the electrode channels, the dimensions of the entrance and exit reservoirs, the sample flow rate, and the diameter and position of the sample input, we were able to achieve indefinitely long operation of the device with cycles of alternating 15-min electrophoresis and 0.5-min regeneration (bubble removal). The test analytes, rhodamine B and fluorescein, were baseline resolved by mFFE for flow rates ranging from 10 to 600 MUL/min. These results prove that our prototyping approach is suitable for the challenging task of multi-parameter optimization of mFFE devices. PMID- 21280215 TI - Preparation and chiral recognition in HPLC of cellulose 3,5 dichlorophenylcarbamates immobilized onto silica gel. AB - The 3,5-dichlorophenylcarbamates (2) of cellulose bearing a small amount of 3 (triethoxysilyl)propyl residues were synthesized by a one-pot process and immobilized onto a silica gel through intermolecular polycondensation of the triethoxysilyl groups. The obtained cellulose derivatives were characterized by (1) H NMR and elemental analysis (EA), and their recognition abilities were evaluated by high-performance liquid chromatography (HPLC). The cellulose derivatives containing about 1-5% of the 3-(triethoxysilyl)propyl residue were efficiently immobilized with a high chiral recognition ability. The immobilized chiral packing materials (CPMs) could be used with the eluents containing chloroform and tetrahydrofuran (THF), which cannot be used with the conventional coated-type chiral packing materials. By using these eluents, the chiral recognition for many racemates was improved. PMID- 21280216 TI - Determination of polyphenols in wines by liquid chromatography with UV spectrophotometric detection. AB - This paper describes a new chromatographic method for the determination of polyphenolic compounds in wines. The method is based on the separation of analytes by reversed-phase mode in a C18 column (2.6 MUm particle size) and UV absorption spectroscopy. The elution gradient is generated from 0.1% formic acid aqueous solution and acetonitrile as an organic modifier. Experimental conditions including pH, percentage of organic modifier and elution gradient profile have been thoroughly optimized using experimental design. A multi-objective function has been defined as a criterion for obtaining a satisfactory compromise among number of compounds separated, resolution and analysis time. Multi-detection at 280, 310 and 370 nm has been utilized in order to work under the most appropriate wavelengths for each compound. Figures of merit including linearity ranges, precisions, detection limits and recoveries have been established under selected experimental conditions using synthetic standards and commercial red wines. The method has been applied to analyze red wines from various Spanish regions. PMID- 21280217 TI - Investigation of solubilization and digestion methods for microsomal membrane proteome analysis using data-independent LC-MSE. AB - To evaluate the implementation of various denaturants and their efficacy in bottom-up membrane proteomic methods using LC-MS analysis, microsomes isolated from tomato roots were treated with MS-compatible surfactants (RapiGest SF Surfactant from Waters and PPS Silent Surfactant from Protein Discovery), a chaotropic reagent (guanidine hydrochloride), and an organic solvent (methanol). Peptides were analyzed in triplicate sample and technical replicates by data independent LC-MS(E) analysis. Overall, 2333 unique peptides matching to 662 unique proteins were detected with the order of denaturant method efficacy being RapiGest SF Surfactant, PPS Silent Surfactant, guanidine hydrochloride, and methanol. Using bioinformatic analysis, 103 proteins were determined to be integral membrane proteins. When normalizing the data as a percentage of the overall number of peptides and proteins identified for each method, the order for integral membrane protein identification efficacy was methanol, guanidine hydrochloride, RapiGest SF Surfactant, and PPS Silent Surfactant. Interestingly, only 8% of the proteins were identified in all four methods with the silent surfactants having the greatest overlap at 17%. GRAVY analysis at the protein and peptide level indicated that methanol and guanidine hydrochloride promoted detection of hydrophobic proteins and peptides, respectively; however, trypsin activity in the presence of each denaturant was determined as a major factor contributing to peptide identification by LC-MS(E) . These results reveal the complementary nature of each denaturant method, which can be used in an integrated approach to provide a more effective bottom-up analysis of membrane proteomes than can be achieved using only a single denaturant. PMID- 21280218 TI - Redox-sensitive proteome and antioxidant strategies in wheat seed dormancy control. AB - Oxidative signalling by ROS has been demonstrated to play a role in seed dormancy alleviation, but the detailed molecular mechanisms underlying this process remain largely unknown. Here, we show dynamic differences in redox-sensitive proteome upon wheat seed dormancy release. Using thiol-specific fluorescent labelling, solubility-based protein fractionation, 2-D IEF PAGE, and MS analysis in conjunction with wheat EST sequence libraries, proteins with reversible oxidoreductive changes were characterized. Altogether, 193 reactive Cys were found in 79 unique proteins responding differentially in dormant, non-dormant, abscisic, or gibberellic acid-treated seed protein extracts from RL4137, a wheat cultivar with extreme dormancy. The identified proteins included groups that are redox-, stress-, and pathogen-responsive, involved in protein synthesis and storage, are enzymes of carbohydrate metabolism, proteases, and those involved in transport and signal transduction. Two types of redox response could be detected: (i) a dramatic increase in protein thiol redox state in seeds during imbibition and hormonal treatment; (ii) higher antioxidant capacity related to sensing of a threshold redox potential and balancing the existing redox pools, in dry dormant versus non-dormant seeds. These results highlight occurrence of the antioxidant defence mechanisms required for the protection of seed during a dormancy stage. PMID- 21280219 TI - Proteome analysis of wheat leaf rust fungus, Puccinia triticina, infection structures enriched for haustoria. AB - Puccinia triticina (Pt) is a representative of several cereal-infecting rust fungal pathogens of major economic importance world wide. Upon entry through leaf stomata, these fungi establish intracellular haustoria, crucial feeding structures. We report the first proteome of infection structures from parasitized wheat leaves, enriched for haustoria through filtration and sucrose density centrifugation. 2-D PAGE MS/MS and gel-based LC-MS (GeLC-MS) were used to separate proteins. Generated spectra were compared with a partial proteome predicted from a preliminary Pt genome and generated ESTs, to a comprehensive genome-predicted protein complement from the related wheat stem rust fungus, Puccinia graminis f. sp. tritici (Pgt) and to various plant resources. We identified over 260 fungal proteins, 16 of which matched peptides from Pgt. Based on bioinformatic analyses and/or the presence of a signal peptide, at least 50 proteins were predicted to be secreted. Among those, six have effector protein signatures, some are related and the respective genes of several seem to belong to clusters. Many ribosomal structural proteins, proteins involved in energy, general metabolism and transport were detected. Measuring gene expression over several life cycle stages of ten representative candidates using quantitative RT PCR, all were shown to be strongly upregulated and four expressed solely upon infection. PMID- 21280220 TI - Tyrosine 656 in topoisomerase IIbeta is important for the catalytic activity of the enzyme: Identification based on artifactual +80-Da modification at this site. AB - Topoisomerase (topo) II catalyzes topological changes in DNA. Although both human isozymes, topo IIalpha and beta are phosphorylated, site-specific phosphorylation of topo IIbeta is poorly characterized. Using LC-MS/MS analysis of topo IIbeta, cleaved with trypsin, Arg C or cyanogen bromide (CNBr) plus trypsin, we detected four +80-Da modified sites: tyr656, ser1395, thr1426 and ser1545. Phosphorylation at ser1395, thr1426 and ser1545 was established based on neutral loss of H(3) PO(4) (-98 Da) in the CID spectra and on differences in 2-D-phosphopeptide maps of (32) P-labeled wild-type (WT) and S1395A or T1426A/S1545A mutant topo IIbeta. However, phosphorylation at tyr656 could not be verified by 2-D-phosphopeptide mapping of (32) P-labeled WT and Y656F mutant protein or by Western blotting with phosphotyrosine-specific antibodies. Since the +80-Da modification on tyr656 was observed exclusively during cleavage with CNBr and trypsin, this modification likely represented bromination, which occurred during CNBr cleavage. Re evaluation of the CID spectra identified +78/+80-Da fragment ions in CID spectra of two peptides containing tyr656 and tyr711, confirming bromination. Interestingly, mutation of only tyr656, but not ser1395, thr1326 or ser1545, decreased topo IIbeta activity, suggesting a functional role for tyr656. These results, while identifying an important tyrosine in topo IIbeta, underscore the importance of careful interpretation of modifications having the same nominal mass. PMID- 21280221 TI - In silico discovery and experimental validation of new protein-protein interactions. AB - We introduce a framework for predicting novel protein-protein interactions (PPIs), based on Fisher's method for combining probabilities of predictions that are based on different data sources, such as the biomedical literature, protein domain and mRNA expression information. Our method compares favorably to our previous method based on text-mining alone and other methods such as STRING. We evaluated our algorithms through the prediction of experimentally found protein interactions underlying Muscular Dystrophy, Huntington's Disease and Polycystic Kidney Disease, which had not yet been recorded in protein-protein interaction databases. We found a 1.74-fold increase in the mean average prediction precision for dysferlin and a 3.09-fold for huntingtin when compared to STRING. The top 10 of predicted interaction partners of huntingtin were analysed in depth. Five were identified previously, and the other five were new potential interaction partners. The full matrix of human protein pairs and their prediction scores are available for download. Our framework can be extended to predict other types of relationships such as proteins in a complex, pathway or related disease mechanisms. PMID- 21280222 TI - Landscape of the SOX2 protein-protein interactome. AB - SOX2 is a key gene implicated in maintaining the stemness of embryonic and adult stem cells that appears to re-activate in several human cancers including glioblastoma multiforme. Using immunoprecipitation (IP)/MS/MS, we identified 144 proteins that are putative SOX2 interacting proteins. Of note, SOX2 was found to interact with several heterogeneous nuclear ribonucleoprotein family proteins, including HNRNPA2B1, HNRNPA3, HNRNPC, HNRNPK, HNRNPL, HNRNPM, HNRNPR, HNRNPU, as well as other ribonucleoproteins, DNA repair proteins and helicases. Gene ontology (GO) analysis revealed that the SOX2 interactome was enriched for GO terms GO:0030529 ribonucleoprotein complex and GO:0004386 helicase activity. These findings indicate that SOX2 associates with the heterogeneous nuclear ribonucleoprotein complex, suggesting a possible role for SOX2 in post transcriptional regulation in addition to its function as a transcription factor. PMID- 21280223 TI - A combined free-flow electrophoresis and DIGE approach to identify proteins regulated by butyrate in HT29 cells. AB - Many biologically active agents exert a pleiotropic response in cells and tissues. This presents challenges in descriptive and comparative analysis of the proteome in response to these agents. Although free-flow electrophoresis has been applied in a number of proteomic studies as a protein separation technique, the combination of free-flow electrophoresis and DIGE has not yet been investigated for comparative proteomic analysis. In this study, we have compared the effects of butyrate on HT29 colorectal cancer cells with a particular focus on apoptosis and describe the utility of a novel approach combining free-flow electrophoresis with DIGE to identify differentially expressed proteins. We verify the results obtained by the combined free-flow electrophoresis and DIGE approach with Western blot analysis of selected proteins. We also report for the first time the regulation of a number of proteins by butyrate in HT29 colorectal cells including peptidyl-prolyl cis-trans isomerase A (cyclophilin A) and profilin-1. PMID- 21280224 TI - Layered electrophoretic transfer - A method for pre-analytic processing of histological sections. AB - Current technologies for measuring protein expression across a tissue section are based on MS or in situ detection such as immunohistochemistry. However, due to the inherent molecular complexity of tissue samples and the large dynamic range of protein expression in cells, current approaches are often unable to measure moderate- and low-abundant proteins. In addition, they do not provide information on the physico-chemical properties of the proteins studied. To address these problems, we are developing a new pre-analytic methodology termed layered electrophoretic transfer (LET) that selectively separates and processes proteins from an intact tissue section without compromising important two-dimensional histological information. LET offers two potential advantages over standard techniques: (i) A reduced complexity of the tissue proteome for subsequent analysis; (ii) An opportunity to assess the biochemical status of proteins as they exist in situ. As an initial proof-of-concept, we demonstrate here that the protein content from a mixture of molecular weight standards, human tissue lysates, and tissue sections can be successfully transferred and separated using LET, and further demonstrate that the method can be coupled with immunoblotting or MS for downstream measurements. LET technology represents a new pre-analytic tool for interrogating the proteome in tissue sections while preserving valuable spatial information. PMID- 21280225 TI - Efficient proteolysis using a regenerable metal-ion chelate immobilized enzyme reactor supported on organic-inorganic hybrid silica monolith. AB - A metal-ion chelate immobilized enzyme reactor (IMER) supported on organic inorganic hybrid silica monolith was developed for rapid digestion of proteins. The monolithic support was in situ prepared in a fused silica capillary via the polycondensation between tetraethoxysilane hydrolytic sol and iminodiacetic acid conjugated glycidoxypropyltrimethoxysilane. After activated by Cu(2+) , trypsin was immobilized onto the monolithic support via metal chelation. Proteolytic capability of such an IMER was evaluated by the digestion of myoglobin and BSA, and the digests were further analyzed by microflow reversed-phase liquid chromatography with ESI-MS/MS. Similar sequence coverages of myoglobin and BSA were obtained by IMER, in comparison to those obtained by in-solution digestion (91 versus 92% for 200 ng myoglobin, and 26 versus 26% for 200 ng BSA). However, the digestion time was shortened from 12 h to 50 s. When the enzymatic activity was decreased after seven runs, the IMER could be easily regenerated by removing Cu(2+) via EDTA followed by trypsin immobilization with fresh Cu(2+) introduced, yielding the equal sequence coverage (26% for 200 ng BSA). For ~5 MUg rat liver extract, even more proteins were identified with the immobilized trypsin digestion within 150 s in comparison to the in-solution digestion for 24 h (541 versus 483), demonstrating that the IMER could be a promising tool for efficient and high-throughput proteome profiling. PMID- 21280226 TI - The endosomal proteome of macrophage and dendritic cells. AB - The essential roles of the endovacuolar system in health and disease call for the development of new tools allowing a better understanding of the complex molecular machinery involved in endocytic processes. We took advantage of the floating properties of small latex beads (sLB) on a discontinuous sucrose gradient to isolate highly purified endosomes following internalization of small latex beads in J774 macrophages and bone marrow-derived dendritic cells (DC). We particularly focused on the isolation of macrophages early endosomes and late endosomes/lysosomes (LE/LYS) as well as the isolation of LE/LYS from immature and lipopolysaccharide-activated (mature) DC. We subsequently performed a comparative analysis of their respective protein contents by MS. As expected, proteins already known to localize to the early endosomes were enriched in the earliest fraction of J774 endosomes, while proteins known to accumulate later in the process, such as hydrolases, were significantly enriched in the LE/LYS preparations. We next compared the LE/LYS protein contents of immature DC and mature DC, which are known to undergo massive reorganization leading to potent immune activation. The differences between the protein contents of endocytic organelles from macrophages and DC were underlined by focusing on previously poorly characterized biochemical pathways, which could have an unexpected but important role in the endosomal functions of these highly relevant immune cell types. PMID- 21280227 TI - pH-Sensitive pentablock copolymer nanocapsules as nontoxic and efficient gene carriers. AB - A biodegradable amphiphilic pentablock copolymer PAE-PCL-PEG-PCL-PAE with a pH sensitive unit was synthesized for use as a nontoxic, biodegradable carrier for gene delivery by forming nanocapsules entrapping nucleic acid drugs. The PAE block can interact with plasmid DNA to form polyelectrolyte complexes in an acidic environment. At physiological pH, the PAE blocks are deprotonated and form an insoluble skin, resulting in the formation of nanocapsules that encapsulate plasmid DNA. The surface charges of the nanocapsules became almost neutral at pH = 7.4, and their size ranged from 210 to 280 nm. The nanocapsule maintained most of its transfection efficiency even in the presence of serum. These nanocapsules are therefore potential carriers for systemic gene therapy. PMID- 21280228 TI - Combinatorial pharmacologic effects of gemcitabine and its metabolite dFdU. AB - Recent evidence has shown that the gemcitabine metabolite, dFdU, is pharmacologically active. Though less potent, dFdU has a longer half-life and could potentiate or antagonize the activity of gemcitabine. Hence, studies were undertaken to evaluate the combined effects. Following chemical synthesis, an improved purification procedure for dFdU was developed (80 % yield; >99 % purity). Zebrafish phenotype-based embryo screens revealed no acute toxicity after gemcitabine or dFdU treatment. Only gemcitabine affected zebrafish development in a dose-dependent manner. Synergy or antagonism for the combination was not observed. Antitumor effects for dFdU were dose dependent. Antagonism was tumor cell-line dependent and did not depend on formation of the intracellular active metabolite of gemcitabine, suggesting that the drug-metabolite interaction occurs later. These studies highlight a platform for testing the pharmacologic activity for anticancer agent and metabolite combinations. Such analyses are expected to provide insight into the beneficial or harmful effect(s) of metabolites towards parent drug activity. PMID- 21280229 TI - BZM055, an iodinated radiotracer candidate for PET and SPECT imaging of myelin and FTY720 brain distribution. AB - FTY720 (fingolimod, Gilenya(r)) is a sphingosine 1-phosphate (S1P) receptor modulator that shows significant therapeutic efficacy after oral administration to patients of multiple sclerosis. Because FTY720 does not contain any atom whose PET or SPECT radioisotope would have a half-life compatible with its pharmacokinetic properties, it cannot be used directly for imaging. Instead, we propose BZM055 as a surrogate tracer to study its pharmacokinetics and organ distribution in patients and, given that FTY720 accumulates in myelin sheaths, for myelin imaging. BZM055 (2 a, 2-iodo-FTY720) can be easily radiolabeled with 123I (for SPECT) or 124I (for PET). Not only does it closely mimic the pharmacokinetics and organ distribution of FTY720, but also its affinity, selectivity for S1P receptors, phosphorylation kinetics, and overall physicochemical properties. [123I]BZM055 is currently under development for clinical imaging. PMID- 21280232 TI - Proteomics - Clinical Applications Reviews 2011. PMID- 21280234 TI - CE-MS in biomarker discovery, validation, and clinical application. AB - CE coupled MS (CE-MS) has become an increasingly employed technology in proteome analysis with focus on the identification of biomarker peptides in clinical proteomics. In this review, we will cover technical aspects of CE-MS coupling and highlight the improvements made in the last few years. We examine CE-MS from an application point of view, and evaluate its merits and vices for biomarker discovery and clinical applications. We discuss the principal theoretical and practical obstacles encountered when employing CE-MS (and most other proteomic technologies) for the analysis of body fluids for biomarker discovery. We will present several examples of a successful application of CE-MS for biomarker discovery, implications for disease diagnosis, prognosis, and therapy evaluation, and will discuss current challenges and possible future improvements. PMID- 21280235 TI - Proteomic analysis of multiple myeloma: current status and future perspectives. AB - Multiple myeloma (MM) is a malignant plasma cell neoplasm that accounts for slightly more than 10% of all hematologic cancers and remains incurable. The major challenge remains the identification of better diagnosis and prognostic biomarkers. The advent of proteomic technologies creates new opportunities and challenges for those seeking to gain greater understanding of MM. Although there is a limited number of proteomic studies to date in MM, those performed highlight the potential impact of these technologies in our understanding of MM pathogenesis and the identification of novel therapeutic targets. In this review, we introduce the proteomic technologies available for the study of MM, summarize results of the published proteomic studies on MM, and discuss the novel developments and applications for the analysis of protein PTM in MM. The application of proteomic technologies will be valuable to better understand the pathogenesis of MM and may in the future open novel avenues in the treatment of MM. PMID- 21280236 TI - Quantitative proteomics for investigating psychiatric disorders. AB - The underlying pathophysiology of psychiatric disorders remains elusive. The use of quantitative proteomics to investigate disease-specific protein signatures holds great promise to improve the understanding of psychiatric disorders and identify relevant biomarkers. In this review, we discuss quantitative proteomic approaches for elucidating molecular mechanisms of psychiatric disorders, i.e. anxiety, schizophrenia, bipolar disorder and depression, by studying specimens from animal models and patients. We present gel-based, label-free and stable isotope-labeling methodologies and evaluate their strengths and limitations in the context of psychiatric research, with a focus on (15)N metabolic labeling of live animals due to its increased accuracy and potential for future applications. We also review biomarker candidate validation methods and present quantitative proteomic studies from the literature that aim to disentangle the molecular pathobiology of psychiatric disorders and identify candidate biomarkers. Finally, we explore the applicability of implementing proteomic methods as a routine diagnostic tool in the clinical laboratory. PMID- 21280237 TI - Lectin-affinity chromatography brain glycoproteomics and Alzheimer disease: insights into protein alterations consistent with the pathology and progression of this dementing disorder. AB - Alzheimer disease (AD) is a neurodegenerative disorder characterized pathologically by the accumulation of senile plaques and neurofibrillary tangles, and both these pathological hallmarks of AD are extensively modified by glycosylation. Mounting evidence shows that alterations in glycosylation patterns influence the pathogenesis and progression of AD, but the vast number of glycan motifs and potential glycosylation sites of glycoproteins has made the field of glycobiology difficult. However, the advent of glycoproteomics has produced major strides in glycoprotein identification and glycosylation site mapping. The use of lectins, proteins that have strong affinity for specific carbohydrate epitopes, to enrich glycoprotein fractions coupled with modern MS, have yielded techniques to elucidate the glycoproteome in AD. Proteomic studies have identified brain proteins in AD and arguably the earliest form of AD, mild cognitive impairment, with altered affinity for Concanavalin-A and wheat germ agglutinin lectins that are consistent with the pathology and progression of this disorder. This is a relatively nascent field of proteomics research in brain, so future studies of lectin-based brain protein separations may lead to additional insights into AD pathogenesis and progression. PMID- 21280238 TI - Proteomic analysis of acute kidney injury: biomarkers to mechanisms. AB - Acute kidney injury (AKI) is a devastating clinical condition, both in terms of mortality and costs, and is occurring with increasing incidence. Despite better clinical care, the outcomes of AKI have changed little in the last 50 years. This lack of progress is due in part to a lack of early diagnostic biomarkers and a poor understanding of the disease mechanisms. This review will focus on the rapid progress being made in both the understanding of AKI and the promising panel of early biomarkers for AKI that have come out of both direct proteomic analysis of body fluids of AKI patients and more targeted proteomic approaches using clues from other methods such as transcriptomics. This review concludes with a discussion of the future of proteomics and personalized medicine in AKI and the challenges presented in translating these exciting proteomic results to the clinic. PMID- 21280244 TI - Climate change talks stumble on. PMID- 21280243 TI - Analysis of the upper airway by the acoustic reflection method in children with mucopolysaccharidosis. AB - BACKGROUND: Upper airway obstruction is common in children with mucopolysaccharidosis. The acoustic reflection method is a noninvasive technique that can analyze the caliber of the upper airways. The aim of the study was to evaluate the feasibility of the acoustic reflection method in children with mucopolysaccharidosis, and to compare the characteristics of the upper airways evaluated by the acoustic reflection method in patients with mucopolysaccharidosis to matched healthy counterparts. METHODS: Open, single center, prospective, study. RESULTS: Accurate acoustic reflection measurements could be obtained in 7 of 10 patients (mean age: 10.4 +/- 3.9 years; mucopolysaccharidosis type II (n = 3); type IV (n = 2), type VI (n = 1), and fucosidosis (n = 1)). The mean minimum cross-sectional area was lower in mucopolysaccharidosis patients (1.6 +/- 0.3 cm(2) ) as compared to 14 healthy counterparts (1.8 +/- 0.3 cm(2); P = 0.03). The mean resistance of the airways was significantly higher in the MPS group (7.9 +/- 1.8 cmH(2) O l(-1) sec) as compared to the controls (5.5 +/- 1.2 cmH(2) O l(-1) sec; P = 0.006). CONCLUSION: This study is the first to analyze the upper airways by the noninvasive acoustic reflection method in children with mucopolysaccharidosis. Due to a lack of cooperation, reliable measurements could only be obtained in 70% of a selected group of patients. Children with mucopolysaccharidosis have significant upper airway obstruction as assessed by the reduction of the minimal cross-sectional area of the upper airways and the increase in airway resistance. PMID- 21280245 TI - Biodiversity boost to African crop. PMID- 21280246 TI - Marcus Stensmyr. PMID- 21280247 TI - Battling infringement. PMID- 21280248 TI - A hangover remedy for the holidays? PMID- 21280249 TI - Ophthalmological numismatics. Brettauer. PMID- 21280250 TI - Ophthalmic images. Traumatic anterior subluxation of natural lens with aniridia and blood lining Descemet folds. PMID- 21280251 TI - [10 years advanced nursing practice in Switzerland: retrospect and prospects]. PMID- 21280252 TI - [Advanced nursing practice in Germany. Focusing on legal limits instead of creating the possibilities]. PMID- 21280253 TI - [Parallel actions, a marker of organizing new fields in Austrian nursing]. PMID- 21280255 TI - Personal digressions on epidemiology in a lame Italy. PMID- 21280254 TI - Reflections: neurology and the humanities. Haitian on the comfort: doctor and patient. PMID- 21280256 TI - The road to prevention. AB - There are even too many books, magazines, and articles dedicated to prevention that involve the latest scientific findings, prejudices and commercial interests. The aim of this prevention column article is to critically analyse, in this overwhelming material, what is true, false or blatant propaganda, setting off the successful experiences with sometimes modest resources and without sophisticated technology. The goal is to promote synergy among potential players of prevention, as prevention is everyone's business: starting from international organisms, through institutional entities, and ending with families. PMID- 21280257 TI - [Primo Levi: chemist-scholar]. PMID- 21280259 TI - How intellectual property rights affect innovation. PMID- 21280260 TI - Another summer of hematology. PMID- 21280261 TI - Oral pathology quiz. Case number 3. Lateral periodontal cyst. PMID- 21280262 TI - Oral pathology quiz. Case number 4. Ameloblastoma. PMID- 21280263 TI - Salary 'logjam' breaks, compensation improves although economy does not. PMID- 21280264 TI - MO: Charge nurse accused of resident abuse courts upheld reversal of judgment v. nurse. Stone v. Missouri Department of Health and Senior Services, WD 71813 KMO CAW (8/1 7/2010)-MO. PMID- 21280265 TI - Europe fisheries policy protest. PMID- 21280266 TI - Herbaria source of new plant species. PMID- 21280267 TI - The effects of the SLCO2B1 c.1457C > T polymorphism and apple juice on the pharmacokinetics of fexofenadine and midazolam in humans. AB - OBJECTIVE: The objective was to determine the effects of the SLCO2B1 c.1457C> T polymorphism and apple juice on the pharmacokinetics of fexofenadine and midazolam in humans. METHODS: Individuals were divided based on the genotype of SLCO2B1 c.1457C> T (n = 14, c.[1457C]+ c.[= ] 5,c.[1457C]+ c.[1457C> T] 5, and c.[1457C> T]+c.[1457C> T] 4). The oral pharmacokinetics of 60 mg fexofenadine and 5mg midazolam were assessed with water or apple juice (1200 ml/day) in a randomized crossover study. OATP2B1-mediated uptake of fexofenadine and midazolam was evaluated with Xenopus laevis oocyte gene-expression system. RESULTS: When fexofenadine was administered with water, subjects with c.[1457C> T] allele showed a significant decrease in fexofenadine in the area under the plasma concentration-time curve (AUC) compared with c.[1457C] + c[= ] subjects (1110 +/- 347 vs. 1762 +/- 542 ng . h/ml, P< 0.05). When administered with apple juice, a significant decrease in the fexofenadine AUC was observed compared with water (1342 +/- 519 vs. 284 +/- 79.2 ng . h/ml, P < 0.05). The apple juice induced decrease in fexofenadine AUC was significantly lower in subjects carrying the c.[1457C> T] allele. Neither the genotype nor the apple juice showed significant effects on the pharmacokinetics of midazolam except for a marginally significant decrease in Cmax after administration with apple juice. The uptake of fexofenadine by OATP2B1 cRNA-injected oocytes was significantly higher than that by water-injected oocytes. Apple juice, but not midazolam, significantly decreased the uptake of fexofenadine by OATP2B1 cRNA-injected oocytes. CONCLUSION: The results suggest that fexofenadine is a substrate of OATP2B1, and the transport function of OATP2B1 is subject to the genotype of SLCO2B1 c.1457C> T and apple juice. It is likely that apple juice has little effect on CYP3A. PMID- 21280268 TI - H1N1 and this flu season. The pandemic may be over, but the virus is still around, and children, young adults, and pregnant women are susceptible. PMID- 21280269 TI - Rules to eat by. Some tidbits from the expert committee that advised the government on the creation of new Dietary Guidelines. PMID- 21280270 TI - Sex in the second half. Sex isn't just for the young. Research is showing that older Americans are sexually active. PMID- 21280271 TI - Creative thinking and the brain. PMID- 21280272 TI - By the way, doctor. I have a severely arthritic hip. It's pretty clear that I'm a candidate for hip replacement. When I looked on the Internet, there were a lot of Web sites promoting "anterior hip replacement." What is it, and is it any better than the traditional approach? PMID- 21280273 TI - By the way, doctor. I am starting to have trouble reading. But I have heard that wearing glasses to help me read will make my eyesight worse. Is that true? PMID- 21280274 TI - [Histopathological classification of idiopathic interstitial pneumonias]. AB - The classification scheme of interstitial lung diseases has undergone numerous revisions. The criteria for distinguishing seven distinct subtypes of idiopathic interstitial pneumonias are now well defined by consensus in the recently published ATS/ERS classification of these lung diseases. In our present review the histological patterns of the different types are described and the differential diagnosis of idiopathic interstitial pneumonias is discussed. Surgical lung biopsy remains the gold standard for the diagnosis of interstitial pneumonias, and sampling from at least 2 sites is recommended. Video-assisted thoracoscopic surgical biopsy is the preferred method for obtaining lung tissue as this procedure offers a similar yield as an open thoracotomy The most common histological subtype of chronic interstitial lung disease is the usual interstitial pneumonia [UIP] which makes up 47-71% of cases. The key histologic features include patchy subpleural and paraseptal distribution of remodeling lung architecture with dense fibrosis, frequent honeycombing, and large fibroblastic foci. Temporal and spatial heterogeneity are the hallmarks. Nonspecific interstitial pneumonia [NSIP] occurs primarily in middle-aged women who have never smoked, with more than 5-years survival rate in 80% of patients. The major feature of NSIP is a uniform interstitial thickening of alveolar septa by a fibrosing or cellular process. The cardinal histological feature in respiratory bronchiolitis and desquamative pneumonia is an excess of intraalveolar histiocytes. In both patterns, there is variable interstitial fibrosis and chronic inflammation, and a strong association with a history of smoking. Organizing pneumonia (idiopathic bronchiolitis obliterans-organizing pneumonia [BOOP]) is not strictly an interstitial process, because the alveoli and bronchioles are filled by intraluminal polyps of fibroblastic tissue and the expansion of the interstitium is mild. Lymphocytic interstitial pneumonia [LIP] is currently viewed as a pattern of diffuse reactive pulmonary hyperplasia associated in most cases with EB virus, immunosuppression, or a connective tissue disorder. Malignant transformation may rarely occur. A dense mixed interstitial lymphoid infiltrate is a typical histological finding. Diffuse alveolar damage [DAD] from unknown causes is termed acute interstitial pneumonia [AIP], and is synonymous with cases of Hamman-Rich disease. Hyaline membranes in the exsudative phase and marked expansion of the interstitium later are present. PMID- 21280275 TI - [Caspase 1, superoxide dismutase (D-mutase) and calretinin expression in the placenta and in the basal decidua in preeclampsia]. AB - OBJECTIVE: To determine new data related to the expression of caspase 1, superoxiddismutase and calretinin in the placenta and basal decidua in preeclampsia. MATERIAL AND METHODS: Placental and basal decidua samples from 9 preeclamptic and 9 normotensive controls were analyzed using expressions of caspase 1, superoxiddismutase and calretinin assessed by immunohistochemistry. RESULTS: Caspase 1 was expressed in placental syncythium in preeclampsia constantly, while in the control group the expression was weak or absent. In Langhans cells, in fetal sinusoidal capillary endothelia and in Hofbauer cells the expression was equal in both groups. Stronger expression was observed in stromal myofibroblasts in preeclampsia. In preeclampsia, expression of superoxiddismutase in syncythium, in Langhans cells and in decidual cells was weaker. Calretinin was not found in any placental structure. Sporadically, calretinin was expressed in the interstitial extravillous trophoblast cells, in decidual cells and in spiral arterioles in preeclampsia. CONCLUSION: The obtained morphological data correlating with some clinical and biochemical features contribute to understanding of the molecular background of preeclampsia etiopathogenesis. PMID- 21280276 TI - [What is your diagnosis? Answer: maxillary sinus ameloblastoma with invasion into the ethmoidal vault and nasal cavity]. PMID- 21280277 TI - [Analysis of bone marrow angiogenesis in multiple myeloma]. AB - The authors studied angiogenesis in trephine biopsy samples taken from the hip bone from a total of 51 patients with an as yet untreated plasma cell myeloma / multiple myeloma (MM). Microvessel density calculated to 1 mm2 was represented by monoclonal antibodies against CD34 and nestin. It was discovered that proliferating vessels labeled with anti-nestin antibody nearly never occur in the interstitial type of infiltration. The amount of proliferating vessels in nodular infiltrates is significantly lower compared to the capillary network labeled with antibodies against CD34. The density of proliferating vessels in nodular infiltrates significantly correlates with the proliferation index Ki67 of myeloma cells, not, however, with the degree of MM differentiation. PMID- 21280278 TI - [Lymphoma of the small intestine]. AB - A series of eight small intestine lymphomas comprised two cases of follicular lymphoma (FL), one anaplastic large cell lymphoma (ALCL) ALK negative, and five cases of diffuse large B-cell lymphoma. The lymphomas were diagnosed by routine hematoxylin-eosin staining, immunohistochemistry and the FISH method for translocation t(14;18). Immunohistochemistry revealed that the diffuse large B cell lymphomas were of the non-germinal center type (non GC-DLBCL). In most cases, the tumors formed solid well-circumscribed nodules or resulted in diffuse infiltration of the intestinal wall. In one case of follicular lymphoma, microscopic foci of tumor were found in the intestinal mucosa which spread far from the primary nodule and probably beyond the resection border. It is difficult to ascertain whether this phenomenon represents colonization of pre-existing non neoplastic follicles by lymphoma or spreading of the tumor within the same tissue. In this case, surgical removal of the lymphoma is problematic. PMID- 21280279 TI - [Fibroblasts--known or unknown cells]. AB - Fibroblasts form the main component of the cell tissue microenvironment, and their basic function is to maintain cell integrity and tissue homeostasis. Fibroblasts essentially participate in wound repair. Recently, increased interest has been focused on the role of fibroblasts in cancers, where they are involved in the ransformation of a tumour stroma, and via production of numbers of cytokines and growth factors participate in tumour progression. With regard to their impact in cancerogenesis, fibroblasts become a new target of cancer therapy. PMID- 21280280 TI - [What is your diagnosis? Answer: paraduodenal pancreatitis]. PMID- 21280281 TI - [The forensic-anthropological expertise of a historically important person's relics, destroyed by fire--the contribution of forensic experts to the preservation of a historical heritage]. AB - The forensic-anthropological expertises of the human remains being destroyed by the external heat are rather rare in general practice of the medical examiner (burned body remains in the fired houses, in traffic accidents, air crashes, explosions in coal mines etc.). In the aim to restore the identity of the burned person, such an expertises have to solve a complex set of problems, which--on the site of a forensic expert--need the application of a very specific approaches and know how. The authors describe a rare case of forensic and anthropological expertise of the 400 years old relics of a person, being important in the slovak history, whose body in the coffin was intentionally exposed to open fire. PMID- 21280282 TI - [Forensic interpretation of postmortal ethanol neogenesis in blood samples of cadaverously decomposed bodies]. AB - There is no real possibility for detail knowledge of postmortal changes of blood alcohol concentration in the near future, so that it is necessary to comment alcoholaemia with special aspect on empirical practice. Potential use of alternative (more resistant to putrefaction) body fluid or tissue can help to distinguish ratio of endogenous and exogenous ethanol. It seems that using of vitreous (eventually urine) is the best way to avoid desinterpretation mistakes of alcoholemia in cadavers. In cases where these fluids are missing we are not able to comment alcoholaemia of saprogenic blood. PMID- 21280283 TI - [The correlation of results of breath analysers and laboratory blood examinations of blood-ethanol concentration (Czech and Slovak study)]. AB - The target of this study was to compare the results of breath analysers and "lege artis" laboratory blood examinations when determining alcohol levels. This was then used to determine whether any differences exist between the two methods, and how large these differences are. 610 cases from 11 workplaces in the Czech Republic and Slovakia were analysed. The type of breath analyser was not taken into consideration. All cases had to be in the elimination phase. Difference of time between breath test and blood test were rectified through the use of reverse recomputation. It was detected that only 20.8% of the results of respiratory analyser tests correspond to the detected real alcohol level in blood. The maximum difference when a respiratory analyser measured more than a blood test was 1.34 g x kg(-1). and the maximum difference when the analyse measured less was 1.86 g x kg(-1). PMID- 21280284 TI - [Anabolic/catabolic imbalance in chronic heart failure]. AB - A metabolic imbalance between anabolic drive and catabolic forces is commonly observed in chronic heart failure (CHF) patients, with the latter prevailing over anabolic hormones. Moreover, anabolic deficiencies are independent markers of poor prognosis. This finding represents a solid background for the implementation of therapeutic trials based on replacement therapy. The somatotropic axis (GH/IGF 1) is the most powerful anabolic axis of the body and its decline is related with a poor outcome and a worse clinical status. Growth hormone (GH) administration may enter the therapeutic arena as adjunctive treatment in patients affected by CHF and GH/IGF-1 deficiency. The T.O.S.CA. project aims at investigating the relationship between CHF and hormonal deficiency. PMID- 21280285 TI - [Continued care in patients with cardiac failure in Regione Lombardia: central role of Cardiac Rehabilitation reaffirmed]. PMID- 21280286 TI - [Continuity of care in patients with cardiac failure after acute event]. PMID- 21280287 TI - [Diagnosis and management of dysphagia in patients with tracheostomy tube after cardiac surgery: an early screening protocol]. AB - SCOPE: Patients with tracheostomy tube after major cardiac surgery undergoing Cardiac Rehabilitation Program often present swallowing disorders that need a specific evaluation. This study aimed at validating the usefulness of a swallowing screen protocol in order to obtain an early assessment of dysphagia and to prevent aspiration, malnutrition and dehydration risks. MATERIALS AND METHODS: The protocol has been applied to 38 consecutive patients with tracheostomy tube after cardiac surgery between September 2007 and December 2009. The average age of patients was 73 +/- 6 years; the average value of left ventricular ejection fraction was 41 +/- 4%. The protocol included a water swallowing test and a specific swallowing test with blue dye. During tests, the presence of signs of swallowing dysfunction was evaluated and oxygen saturation levels were monitored. RESULTS: Out of 38 patients, 2 did not show any swallowing deficits; 18 showed deficits in the water swallowing test even though they presented a preserved swallowing function during specific swallowing test. All these 20 patients (53%), before discharge, restarted an oral feeding and obtained an adequate body mass index and effective coughing, so they were soon decannulated. Twelve patients (31%) showed deficits during the water swallowing test, confirmed by the specific swallowing test with blue dye: the tracheostomy tube was not removed and a specific program of swallowing rehabilitation was performed. Before discharge all patients restarted an oral feeding, recovered an effective coughing and were decannulated. Six patients (16%), because of persistent dysphagia, underwent percutaneous endoscopic gastrostomy. None of these 38 patients developed ab ingestis pneumonia, dehydration or malnutrition. CONCLUSIONS: An early assessment of swallowing in patients with tracheostomy tube after cardiac surgery allows the selection of patients with higher aspiration risk, preventing possible severe complications. PMID- 21280288 TI - [Nurse involvement in primary care: it is the key to improve the outcomes in primary and secondary prevention?]. AB - Difficulties in management of risk factors, lifestyle and medications adherence to achieve secondary prevention of ischemic heart disease were described. Many studies indicate that the benefit of cardiac rehabilitation therapy after acute coronary events is only partially maintained during the following year. Thereafter, new strategies of medical care are needed to improve the long-term outcomes in coronary patients. Nurse co-ordinated, multidisciplinary cardiac rehabilitative programme could help patients to improve their lifestyle, to control their risk factors and to achieve their therapeutic goals for secondary prevention of ischemic heart disease. PMID- 21280289 TI - [Antithrombotic therapy in patients with stable manifestations of atherothrombosis Russian advice. Part 1]. PMID- 21280290 TI - [Dynamics of the incidence of major amputations and mortality rates in peripheral arterial diseases over 1993-2007: findings of a population-based study]. AB - Analysed were a total of 17,695 cases of hospital admission of patients presenting with arterial insufficiency of extremities, complications of diabetes mellitus, ulcers and necroses of the lower limbs, including 11,773 cases of hospitalization of patients diagnosed with peripheral artery diseases according to ICD-9 (till 1998) or ICD-10 (commencing from 1999) over the periods from 1993 1997 (period 1), 1998-2002 (period 2) and 2003-2007 (period 3). The correlation dependence was studied using the Pearson criterion, with the statistical significance of differences between the relative incidence of the parameters being calculated by means of the chi-square (chi2) test. The obtained findings showed a decrease in the number of amputees, the incidence of lethal outcomes and mortality rates, being most significant in the group of patients under 60 years of age. There was an inverse correlation between the above measures and the indices of the number of operations on the arteries performed in grade IV limb ischaemia. PMID- 21280291 TI - [Randomized placebo-controlled studies of iloprost in treatment of lower limb critical ischaemia]. AB - The article deals with the analysis of the treatment outcomes obtained in management of patients suffering from lower-limb critical ischaemia treated with iloprost, a stable analogue of the prostacyclin. The results of six randomized placebo-controlled trials and eleven trials of other drugs are described in this article. The meta-analysis of the iloprost studies confirmed the efficacy of the drug in decreasing the size of ulcers, pain relief, extremity amputation rate. Whereas the other examined drugs have not demonstrated such properties with rare exception. PMID- 21280292 TI - [Intestinal microcirculation in health and in acute impairment of mesenteric blood flow]. AB - The authors attempted to determine instrumental criteria for vitality and non vitality of the intestine with the help of laser Doppler flowmetry and absorption spectroscopy. The material used was subdivided into two study groups: in group one, the indices of microcirculation of the viable small and large intestine were determined during elective cavitary operations; group two comprised 20 portions of resected necrotised segments of the large and small intestine, wherein we registered the indices of microcirculation of the non-viable devitalized intestine. We thus obtained instrumental indices of microcirculation of various intestinal portions in health, as well as in the setting of acute impairment of intestinal blood circulation and intestinal gangrene. Statistically significant differences were revealed only for the parameter of microcirculation and the coefficient of variation of the "viable" and necrotized intestine; blood oxygen saturation and volumetric blood filling of tissue between the two groups did not differ significantly. The instrumental criteria for intestinal vitality and non vitality of may be used while making a decision as to the scorife of resection of the intestine affected which would thus make it possible to decrease the rate of progression of intestinal necrosis in the postoperative period. We believe that this would make it possible to substantially improve the outcomes of surgical management and to decrease lethality in patients presenting with acute impairment of mesenteric circulation. PMID- 21280293 TI - [Hemolytic thrombectomy and stenting of the superior mesenteric artery in acute mesenteric thrombosis (a clinical case report)]. AB - Presented herein is a clinical case report concerning successful rheolytic thrombectomy (using the AngioJet catheter) followed by stenting and having yielded a good angiographic and clinical outcome in a female patient suffering from thrombosis of the superior mesenteric artery. PMID- 21280294 TI - [Prevention of recurrent varicose veins after surgery caused by phenomenon of neovascularization]. AB - The aim of study was to evaluate the effectiveness of surgical "barrier techniques" in prevention of phenomenon of inguinal neovascularization in patients with varicose veins of lower limbs. There were 68 patients (80 limbs) treated with flush ligation of saphenofemoral junction, stripping of great saphenous vein and avulsion of varicosities. Patients were divided in three groups: I (no "barrier techniques")--40 limbs; II (anatomical barrier)--20 limbs and III (synthetic barrier)--20 limbs. Duplex ultrasound was performed at interval of 24 months postoperatively. Signs of neovascularization were found more frequently in group I--22.5% of limbs vs 7.5% of limbs in patients with utilization of "barrier techniques". There were types B1, B2a and B2b of neovascularization only, according to Fischer classification. We conclude that use of a "barrier techniques", either anatomic or synthetic, is associated with a decreased incidence of neovascularization at the level of the saphenofemoral junction compared with a control group. PMID- 21280295 TI - [Functional venous insufficiency: diagnosis and treatment (review of the literature)]. AB - Reviewed herein are the available literature data concerning functional venous insufficiency (phlebopathies). Part I analyses the data on terminology, epidemiology, effect on quality of life, aetiology and pathogenesis, risk factors, as well as possible methods of diagnosis of this pathological condition. METHOD: search in the MEDLINE database by means of the PubMed system. PMID- 21280296 TI - [Assessment of dose-dependent effect during phlebotropic therapy of chronic diseases of lower-limb veins]. AB - Described herein are the findings of an open, prospective, comparative study of 2 month use of Antistax in a total of one hundred and nineteen patients presenting with clinical manifestations of chronic venous disease of class C0 (60 subjects) and class C2,3 (59 patients). Each group was subdivided into two subgroups of patients receiving Antistax at a daily dose of 360 and 720 mg, respectively. The authors studied the dynamics of the extremity's volume during direct plethysmography by means of liquid displacement, measuring the extremity's circumference under the ankles and in the muscular portion of the crus. The degree of subjective symptoms of CVI (increased fatigue of the legs and pain) was assessed by means of a 10-point visual analogue scale. The points of the study were the baseline state and the condition 2 months after medicamentous therapy. It was determined that administration of Antistax at daily doses of 360 and 720 mg for 2 months resulted in a significant decrease in the volume of the affected extremity, which was accompanied by regression of complaints related to venous insufficiency. The patients with class C0 and C2,3 CVI showed a pronounced dose dependent effect, being more significant in class C2,3 CVI. We conceive it to be expedient that patients presenting with clinically pronounced variants of CVI inducing an increase in the extremity's volume should be given Antistax at a daily dose of 720 mg. PMID- 21280297 TI - [59-th International Congress of the European Society of Cardiovascular Surgeons (Izmir, Turkey, 15-18th April, 2010)]. AB - This article is the review of the 59-th International Congress which had taken part in Izmir, Turkey at 15-18th April of 2010 year. There had been discussed important problems of cardiovascular surgery, especially endovascular treatment of the aortic diseases. PMID- 21280298 TI - [Videoendoscopically assisted operations on the abdominal aorta and iliac arteries from the retroperitoneal minimal access using the retractor "KA 1"]. AB - The author has worked out and been using a retroperitoneal minimal access to the aorta and iliac arteries, as well as a technique of a videoendoscopically assisted operation on these vessels using the retractor "KA 1" and a set of tools for laparoscopic interventions on the aorta manufactured by the "Karl Stortz" Company. The technical procedure of the operation is described. To this is added assessment of the outcomes of 37 reconstructive interventions in patients diagnosed with atherosclerotic lesions of the aorto-iliac-femoral segment. The proposed technique has proved to confer certain advantages over the conventional procedures employed. PMID- 21280299 TI - [Analysis of long-term outcomes after carotid endarterectomy for stenosing lesions of carotid arteries]. AB - Surgical management of patients presenting with stenosing lesions of carotid arteries is currently included into the International standards of treatment for transient ischaemic attacks (TIAs) and stroke. The present work was aimed at assessing long-term outcomes following carotid endarterectomy (CEA) in patients diagnosed with stenosing lesions of carotid arteries based on the results ofa 6 month follow-up. The study comprised the analysis of remote outcomes after reconstructive operations on carotid arteries as compared to those of conservative methods of treatment in a total of 120 patients suffering from haemodynamically significant stenoses of carotid arteries. The obtained findings demonstrated that managing the patients suffering from stage I-II chronic cerebrovascular insufficiency by means of conservative methods only turned out less efficient and was associated -with a substantially larger percentage of patients who later on experienced ischaemic strokes, as well as with a higher mortality rate versus those in the group of patients subjected to CEA. PMID- 21280300 TI - [Comprehensive monitoring of cerebral haemodynamics during surgical interventions on brachiocephalic arteries]. AB - The authors analysed a total of 152 surgical interventions on the brachiocephalic arteries (BCAs) performed in 142 patients. All the patients were subjected to intraoperative monitoring of cerebral haemodynamics by means of transcranial Doppler (TCD) ultrasonography simultaneously accompanied by electroencephalography (EEG). Additionally, the state of the reconstructed carotid arteries was controlled by means of ultrasonographic duplex scanning (USDS). Comparing the findings of the TCD recording and EEG made it possible to single out 5 groups of the operated patients. The EEG technique turned out to have more informative value as compared with TCD ultrasonography in determining the degree of cerebral ischaemia during clamping of the carotid arteries (CAs). Nine (5.9%) patients demonstrated lower tolerance of the brain to ischaemia, and the operation on the BCA was performed with the use of a temporal intraluminal bypass graft. Microembolic signals (MES) were registered in 54.6% of cases. Single MES were detected in six patients, sporadic MES--in 53, and multiple MES- in 24. Mention should be made that the--MES associated with the placement of the bypass graft appeared to be multiple and were registered in all the operated patients. Diffusion-weighted magnetic resonance tomography revealed fresh foci of lacunar cerebral infarctions in 14 (25%) of the 56 patients thus examined. Intraoperative USDS of the reconstructed carotid arteries revealed floatation of the residual remnants of the intima in two patients, which was the cause of a repeat intervention. Combined monitoring of cerebral haemodynamics makes it possible to timely prevent cerebral ischaemia, to narrow the indications for placement of an intraluminal bypass graft, and to dramatically decrease the rate of postoperative complications. PMID- 21280301 TI - [Peculiarities of surgical policy in simultaneous reconstruction of the carotid and subclavian arteries]. AB - The authors summarize herein their experience gained in surgical management of twenty-nine patients suffering from multiple lesions of the brachiocephalic arteries. Depending on the pattern of vascular lesions, the patients were subjected either to simultaneous correction of stenosis of the internal carotid and subclavian arteries on the ipsilateral side or to stagewise intervention in the presence of contralateral stenosis of the carotid artery. Surgical policy and stages of simultaneous intervention are described in detail. PMID- 21280302 TI - [Concomitant and combined operations in patients with infrarenal abdominal aortic aneurysms]. AB - The authors have retrospectively studied the outcomes of surgical management of 421 patients diagnosed with infrarenal atherosclerotic variants of an abdominal aortic aneurysm (AAA) operated on over the period from 1982 to 2007. Of these, there were a total of 389 (92.4%) patients operated on electively, with the remaining 32 (7.6%) patients operated on expeditiously. 264 (67.9%) patients had only been subjected to resection of the aneurysm with linear or bifurcation prosthetic repair of the aorta, 86 (22.1%) endured resection of the aneurysm in a combination with correction of blood flow in other arterial basins, and 39 (10%) patients parallel to AAA resection sustained operations for other surgical and oncological diseases. The authors analysed the effect of comorbidities, the patients' age, AAA size, duration of surgery and the volume of blood loss on the outcomes of surgical treatment. Also studied were the immediate outcomes of surgical treatment, with the remote results followed up in 427 patients having endured AAA resection. The obtained findings confirm a promising nature of combined and concomitant operations in AAA. PMID- 21280303 TI - [First-stage surgical correction of dissecting aortic aneurysm according to the Borst's technique using of a new-type stent graft]. AB - Exemplified by clinical experience, shown herein is feasibility of practical application of the Borst's technique for endovascular aortic aneurysm repair using a new-type multiple-branch stent graft provided with a cuff. This method considerably facilitates the establishment of a distal anastomosis of the graft with the aorta. PMID- 21280304 TI - [Peculiarities of revascularizing operations in traumatic amputations of hand fragments]. AB - The article deals with one of the currently important problems encountered in modern microsurgery, i. e., a possibility of performing restorative operations in complete and incomplete traumatic amputations of hand fragments. Our experience gained in managing a total of one hundred and fifty-one patients has confirmed the necessity of performing primary reconstructive operations on vessels, which in the majority of cases makes it possible to save the damaged segments. Also given herein are the main indications for carrying out restorative operations, with the appropriate conclusions drawn. PMID- 21280305 TI - [Acute thrombosis of abdominal aortic aneurysm: three case reports]. AB - Presented herein are three clinical case reports concerning patients with acute thrombosis of an abdominal aortic aneurysm. In all three instances, the true cause of the acute limb ischaemia syndrome had been recognized not immediately at admission but only after instrumental examination or during laparotomy. The mechanisms of the development of acute thrombosis of the aneurysmatic sac in all three cases turned out to be different. Two patients endured direct reconstruction of the abdominal aorta, and the remaining one sustained extra anatomical bypass grafting. Of these, two patients survived, and one patient subjected to aortofemoral bypass grafting unfortunately died of renal failure on postoperative day 3. PMID- 21280306 TI - [Simultaneous revascularization of both limbs by means of transplantation of the greater omentum on a vascular pedicle in patients with thromboangiitis obliterans]. AB - Presented herein are favourable outcomes of surgical management in six patients suffering from thromboangiitis obliterans (TO) with accompanying critical ischaemia of either the both lower extremities (5 subjects) or the both upper limbs (1 patient). They were all treated by means of a surgical intervention with simultaneous transplantation of the greater omentum on a vascular pedicle onto the both limbs. A total of 12 revascularizing procedures were performed. With an overall of the 12 extremities eventually spared, the remote limb-salvage rate amounted to 100%. A detailed description of the procedural technique is followed by analysing long-term therapeutic outcomes having proved encouraging. The obtained results confirmed a possibility of reliably relieving critical ischaemia inpatients with TO by means of transplanting the greater omentum on a vascular pedicle simultaneously onto the both limbs. PMID- 21280307 TI - [Peculiarities of creating permanent vascular access in diabetic patients on programmed haemodialysis]. AB - Over the period from 2004 to 2009, we performed a total of 18 procedures aimed at forming a permanent vascular access in diabetic patients on programmed haemodialysis. Of these, an arteriovenous fistula (AVF) was created in eight patients and a polytetrafluoroethylene (PTFE) graft was implanted in ten subjects. We than carried out a comparative assessment of the permanent vascular accesses (PVA) prepared based on AVF versus those based on PTFE graft. The assessment criteria were as follows: time interval between the operative intervention and the commencement of the haemodialysis procedure via the PVA, the duration of the functioning and adequate amount of blood flow the PVA provides during the haemodialysis procedure, the presence of antebrachial ischaemia symptoms, as well as infectious complication rates. PMID- 21280308 TI - [Prediction of outcomes after arterial reconstructions and likelihood of atherosclerosis progression based on cytokines blood plasma level (a review of the literature)]. AB - The article is dedicated to a review of the contemporary-literature data concerning the role of cytokines in the mechanisms of atherosclerosis progression, citing the findings of worldwide studies on predicting the outcomes of arterial reconstructions and the probability of atherosclerosis progression depending on the blood plasma cytokines level. PMID- 21280309 TI - [Clinical and morphological parallels of various degrees of chronic arterial insufficiency of lower limbs (review of the literature)]. AB - The article deals with the main clinical and instrumental methods of determining severity of chronic arterial insufficiency of the lower extremities, showing possibilities of morphological studies for an accurate diagnosis of the ischaemia degree. Also determined are promising trends of studying the hypoxia-inducible factor (HIF) and vascular endothelial growth factor (VEGF) in assessment of ischaemic impairments of lower-extremities tissue. PMID- 21280310 TI - [Personal anti-vectorial protection, and indispensible agent of prevention]. PMID- 21280311 TI - [Morphological variations of the nuclear apparatus of astome ciliates Almophrya bivacuolata and A. maediovacuolata (protozoa: ciliophora) endocommensal of terricolous oligochaetes in Cameroon]. AB - The silver impregnation supplemented by DAPI and Feulgen nuclear coloration enabled us to study the morphological variations of the nuclear apparatus of two species of endocommensal Astome ciliates, Almophrya bivacuoloata (de Puytorac & Dragesco, 1968) and A. mediovocuolata (Ngassam, 1983). We highlighted important digitations and the presence of dark bands in the structure of the "H" macronucleus of the small cellular types as well as the presence of intermediate forms between "H" and "X" in these two species. PMID- 21280312 TI - [Variation of the V3 loop tip motifs and primary drug resistance of HIV-1 strains]. AB - OBJECTIVE: To study the characteristics of the variation of the V3 loop tip motifs and the drug resistance in the primary treatment patients. METHODS: The partial region of the HIV-1 env and pol gene in 51 samples was amplified by nested polymerase chain reaction (PCR) ,purified products were cloned into the vectors, the obtained were analyzed by MEGA soft wares. RESULTS: The V3 loop tip motifs had four types in our study (GPGR, GPGQ, GPGK, GQGR); the study on the drug resistance in primary treatment patients, showed that there were not major resistance associated with PI, and the resistance were minor mutations in protease gene. In the RT region, there were nine resistance mutants were single NRTIs or NNRTIs. CONCLUSION: The GPGR which was the typical western V3 loop tip motifs attained to 44.44%. This results showed that the percentage of primary drug resistance was still low in our study region, suggesting no need for genotyping detection in blood donor patients before primary therapy. PMID- 21280313 TI - [Genetic characteristics of entervirus 71 isolated in Ningxia Hui Autonomous region in 2009]. AB - OBJECTIVE: To analyze the genetic characteristics of EV71 strains isolated from HFMD cases in Ningxia Hui Autonomous Region in 2009. METHODS: In 2009, totally 385 specimens from 344 HFMD cases were collected from Ningxia. Enterovirus isolation was performed in RD cell line from all the specimens. EV71 isolates were identified by specific RT-PCR from the positive cultures, and sequences of complete EV71 VP1 encoding region were determined for farther analyses. RESULTS: Totally from 126 EV strains isolated in this study, 58 EV71 strains (46%) were identified. And complete VP1 sequences of 46 EV71 strains were determined, and genetic analyses were performed. It was showed that the nucleotide identity of 46 Ningxia strains with the representatives of A and B genotypes were 81.7%-82.8% and 83.1%-85.2%, and the amino acid identity were 93.9%-95.9% and 96. 2%-97.9% respectively. The nucleotide identity of NingXia EV71 isolates with representatives of subgenotype C1, C2, C3, C4a, C4b, and C5 were 88.3%-90.6% (97.9%-99.6%), 88.3%-90.1% (97.9%-99.3%), 87.8%-89.0% (97.6%-98.9%), 94.2%-98.9% (97.9%-100%), 91.8%-94.1% (98.6%-99.6%), and 86.7%-89.1% (97.9%-98.9%). Phylogenetic tree analysis revealed that 46 stains were clustered with reference stains of subgenotype C4 and the Ningxia EV71 isolates were belonged to subgenotype C4a. CONCLUSION: EV71 of subgenotype C4a had spread widely in Ningxia in 2009, which was absolutely predominant type in Ningxia in 2009 and also as the predominant type in China mainland since 2005. PMID- 21280314 TI - [Association of serum HBV DNA level with cytotoxic T lymphocytes in patients with HBV-induced hepatic cirrhosis]. AB - OBJECTIVE: To explore the association of serum HBV DNA level with HBV-specific and nonspecific cytotoxic T lymphocytes (CTL) in patients with HBV-induced hepatic cirrhosis. METHODS: 120 patients with HBV-induced hepatic cirrhosis who were positive for HBV DNA, HBeAg and human leucocyte antigen (HLA)-A2 were enrolled in this study. The level of HBV DNA was determined by real time fluorescence quantitative polymerase chain reaction (PCR). HBV-specific and nonspecific CTL were detected by flow cytometry. Liver function tests were done in the 120 patients. The 120 patients were divided into group A and B based on their HBV DNA levels. In group A, there were 68 patients with HBV DNA level of 3 4 log10 copy/ml, and in group B, 52 with 5-6 log10 copy/ml. HBV-specific and nonspecific CTL and liver function were compared between the two groups. RESULTS: HBV DNA levels were (3.68 +/- 0.19) and (5.97 +/- 0.32) log10 copy/ml in Group A and B respectively with P < 0.001. HBV-specific CTL was higher in group A (0.33% +/- 0.04%) than in group B (0.11% +/- 0.01%) with P < 0.001. HBV-nonspecific CTL were (11.99% +/- 1.51% ) and (11.91% +/- 1.61%) in group A and B respectively with P > 0. 05. CONCLUSION: The level of serum HBV DNA is related to the levels of HBV-specific CTL in patients with HBV-induced hepatic cirrhosis. Patients with higher HBV DNA had lower levels of HBV-specific CTL, and the damage to liver function was severe because of higher levels of HBV DNA. Patients with lower HBV DNA had higher levels of HBV-specific CTL which predict good anti-viral effect. PMID- 21280315 TI - [Changes and analysis of peripheral white blood cells and lymphocyte subsets for patients with pandemic influenza A virus (H1N1) infection]. AB - OBJECTIVE: To investigate the characters and changes of peripheral white blood cells and lymphocyte subsets of patients with pandemic influenza A virus (H1N1) infection and to provide evidences for diagnosis, treatment and prognosis of influenza A (H1N1) infection. METHODS: Peripheral white blood cell parameters and the percentages of lymphocyte subsets in acute and recovery phases of 59 cases of influenza A virus (H1N1) infectious patients (42 mild cases and 17 severe cases) were investigated and analyzed, and compared respectively with those of 43 cases of healthy adults as control (HC) and 24 cases of general influenza A virus (no H1N1) infectious using whole blood cell analysis and flow cytometry. RESULTS: Peripheral white blood cell counts of mild cases decreased greatly but those of severe cases did not decrease significantly; the neutrophils of severe cases increased significantly in acute phase; similar to general influenza A virus (no H1N1) infectious, the peripheral lymphocytes, CD3, CD4, CD8 and B cells of all patients with influenza A virus (H1N1) infection decreased greatly in acute phase and quickly recovered in recovery phase; NK and NKT cells absolute counts of severe cases decreased significantly in acute phase, and the decreasing extent of which were more than 20%. CONCLUSION: There were similar characteristics of change in peripheral white blood cells and lymphocyte subsets between patients with pandemic influenza A virus (H1N1) infection and general pandemic A virus (No H1N1); the great decrease of NK and NKT cells absolute counts may suggest the severe tendency of diseases. PMID- 21280316 TI - [Evaluation on clinical value of serum CA-125 level in hepatitis cirrhosis]. AB - OBJECTIVE: To determine the association between elevated levels of serum cancer antigen (CA) 125 and hepatitis cirrhosis in different stage, and also to explore the clinical application value of serum CA-125. METHODS: During June to December in 2008, 200 cases with hepatitis cirrhosis were random selected in our hospital. CA-125 levels were measured by electrochemiluminescence immunization assay in sera collected from these cases which were termed with Child-Paugh classification and analyzed by SAS. RESULTS: Serum CA-125 levels were correlated closely with ascites, primary peritonitis and liver function Child-Paugh classification, but no associated with primary carcinoma of liver and other liver function index,such as ALT, AST, ALB, TBIL and PT. CONCLUSION: The levels of serum CA-125 in hepatitis cirrhosis patients were osculating correlating with lesion of liver and ascite degree, could serve as a sensitive and conventional laboratory index for liver lesion degree and monitoring ascite generation. It was necessary to further study on the association with serum CA-125 level with primary hepatic carcinoma. PMID- 21280317 TI - [Genetic characterization of measles virus caused the measles outbreak in Xinjiang]. AB - OBJECTIVE: To analyze the genetic characterizations of wild type measles viruses caused the measles outbreak in Xinjiang. METHODS: Vero/Slam cell were used for measles viruses isolation from the specimens collected from measles outbreaks patients. Fragment of 676 nucleotide acids of the carboxylend of nucleoprotein gene were amplified using reverse transcription-polymerase chain reaction (RT PCR) method and then the PCR products were directly sequenced and analyzed. Phylogenetic tree was constructed based on 450 nucleotide acids of the N-terminus of nucleoprotein gene, and homological analysis was performed at nucleotide acid level. RESULTS: 11 measles viruses were sequenced and all belonged to H1a subgenotype. The nucleotide difference was 0-0.2% between 11 Xinjiang isolates. And the nucleotide difference was 2.2%-2.4% between Xinjiang isolates and H1 genotype reference strain. CONCLUSION: The Measles viruses causing the measles outbreak in Xinjiang were H1a subgenotype. PMID- 21280318 TI - [Transmission electron microscopy investigation of the denudation of the envelope of influenza virus treated with Nonidet P-40 and the binding influence of antibody]. AB - OBJECTIVE: Through observing the morphological changes of the prepared influenza viruses (H1N1) treated with the different concentration of Nonidet P-40 solutions and added with antibody against the influenza virus using transmission electron microscopy (TEM), to explore the principle of application of the internal antibody for immunoassay of influenza virus. METHODS: Through treating the virus samples with serial diluted Nonidet P-40 solutions from 0.01% to 0.2% and/or not adding antibody against the influenza virus, then investigating the samples by TEM to obtain the morphological changes of the virions. RESULTS: The serial images show that the denudation degree of the virions is proportional with the rise of NP-40 concentration, and partly denuded virion image appeared at 0.1% NP 40 treatment, also under this condition no influence was observed on antibody binding to the virus. CONCLUSION: This work demonstrated the interaction between influenza virion and its antibody under nonionic surfactants existing, which supports the advantages of sample preparation for immunoassay enveloped virus using internal antibody theoretically. PMID- 21280319 TI - [Comparison of viremia formation between guinea-pigs infected with wild and attenuated (SA14-14-2) Japanese encephalitis viruses]. AB - OBJECTIVE: To study the viremia formation in guinea-pigs infected with wild type and attenuated Japanese encephalitis virus (JEV). METHODS: Guniea pigs were inoculated intraperitoneally with different wild JEV strains and the attenuated vaccine strain and its parent virulent strain. Viremia was detected on different days following virus inoculation. RESULTS: All the guinea-pigs inoculated with the wild JEV strains induced different levels of viremia (1.00-3.40 Lg pfu) on the 1st and 3rd day post inoculation. Using a virus titer of 10(4) pfu for inoculation, the animals inoculated with the SA14 parent strain induced relatively high viremia (10(2.4)-10(3.4) pfu), however no viremia coulds be detected on any tested days. CONCLUSION: The degree of viremia in guinea pigs can be used as a new method to evaluate the attenuation of JEV. PMID- 21280320 TI - [Relationship between mycoplasma and chlamydia infection and lesions in the cervical tissue in high-risk HPV-positive patients]. AB - OBJECTIVE: Discussion of the relationship between Mycoplasma and chlamydia infection and lesions in the cervical tissue in high-risk HPV-positive infertile patients with cervical. METHODS: HPV-negative patients with cervical as the control, retrospective analysis the relationship of Mycoplasma hominis and chlamydia infection, cervical histological graded, and inflammation graded. RESULTS: The rate of HPV infection in mycoplasma-positive and those with negative mycoplasma has significant difference (P < 0.01), The rate of HPV infection in chlamydia-positive and those with negative chlamydia has no significant difference (P > 0.05). CIN and the incidence of cervical erosion and CIN grade were higher in HPV-positive than HPV-negative group (P < 0.01). The cervical erosion of HPV-positive was no difference in the degree (P > 0.05). Compared with the simple HPV-positive group, CIN and the incidence of severe cervical erosion in mixed infection of Mycoplasma was no difference (P > 0.05). CONCLUSION: Mycoplasma infection increases the rate of high risk HPV infection, high-risk HPV infection increased cervical pathological damage, Mycoplasma infection might be the factor of persistent infection with high risk HPV, the degree of cervical pathological is the factor of cervical infertility which can not be ignored. PMID- 21280321 TI - [Clinical significance of measuring hepatitis B virus large surface protein in serum]. AB - OBJECTIVE: To explore the significance of serum hepatitis B virus large protein( HBV-LP), HBV-DNA and markers of hepatitis B virus (HBV-M)in the diagnosis of viral replication. METHODS: Serum HBV-DNA level was quantitatively detected using PCR Real-time polymerase chain reaction, HBV-LP was detected by enzyme-linked immunosorbent assay (ELISA) and HBV markers expression were measured by chemiluminescence immunoassay method in 1886 cases of seurm. RESULTS: The results of hepatitis virus large protein (HBV-LP) detection and the detection results of HBV-DNA was no significant difference (chi2 = 1.142, P > 0.05). HBV-DNA logarithm of copies and A vaule of HBV-LP was a positive correlation (r = 0.487, P < 0.01). HBV-DNA copies of different groups was significantly different from HBV-LP A values (F = 7.772, P < 0.01). The results of HBV-LP and HBV-DNA detected in different patterns of HBV-M were not significantly different. In 36 healthy people,the detecting results of HBV-DNA and HBV-LP are negative. CONCLUSION: There is a good correlation between the copies of HBV-DNA and the levels of HBV LP. HBV-LP expression can reflect the replication of HBV. PMID- 21280322 TI - [Analysis of neutralized antibody level of the poliomyelitis in healthy population in Fujian province]. AB - OBJECTIVE: To understand the neutralized antibody level of the poliomyelitis among healthy people and provide scientific evidence for the immunization strategy since routine and intensified immunization with oral polio vaccine (OPV) in Fujian province. METHODS: The poliomyelitis antibody level of healthy people were detected by neutralization test of the micro cells. RESULTS: The neutralizing antibody positive rates were 99.0%, 99.3%, 97.5% and GMTs were 1:79.1, 1:31.2, 1:24.7 for polio I, II, III respectively in 400 serum specimens from 1-59 years old. GMTs present a trend of decreasing as age's increasing. CONCLUSION: A protective barrier had been built against poliomyelitis in healthy people in Fujian province through routine and intensified immunization with OPV. PMID- 21280323 TI - [The expression of periphery blood leucocyte CCR3 and CCR5 in the children with Epstein-Barr virus associated infectious mononucleosis]. AB - OBJECTIVE: To explore the expression of periphery blood leucocyte CCR3 and CCR5 and to comprehend T helper cell in the Children with Epstein-Barr virus associated infectious mononucleosis. METHODS: We defined the children according to the diagnosis criterion through Paul-Bunnell test inspecting the children's periphery blood unusual lymphocyte and detecting their anti-EBV-CA-IgM, anti-EBV CA-IgG and anti-EBV-NA-IgG by ELISA and counted the ratio of CCR3 + and CCR5 + cells in lymphocytes with flow cytometry. RESULTS: The ratio of unusual lymphocyte in IM was higher than that of the healthy control group (P < 0.05). The ratio of CCR3 + cells in IM group was higher than that of the healthy control group (P < 0.05). The ratio of CCR5 + cells in IM group was significantly lower than that of the healthy control group. CCR3 + had direct interrelation with fever continued time and the ratio of unusual lymphocyte. There was a negative interrelation between CCR5 and fever continued time (P < 0.05). CONCLUSIONS: Children infectious of IM expressed higher level of CCR3 + and lower level of CCR5 + and there was a tendency of Th2 polarization with over production of T helper cell divide imbalance. CCR3 + and CCR5 + may be important targets to judge the degree of seriousness of IM. PMID- 21280324 TI - [Effect of Itk down regulation on cytokines production in Jurkat cell]. AB - OBJECTIVE: To study the effect of Itk down regulation on Jurkat cell proliferation and inflammatory cytokines production, and provide useful data for Itk as an attractive target for potential drugs. METHODS: Three shRNAs against different region of Itk were constructed and cotransfected with pEGFP-C1-hItk. The shRNA, which can knock down Itk, was selected and packed into lentivirus. After Jurkat cells were transfected with shRNA lentivirus, the change of Itk protein expression, cell proliferation and cytokines production was observed. RESULTS: Itk mRNA was reduced about 55% in Jurkat cells transfected with Itk shRNA1, compared with that in control cells shRNAnon (P < 0.05). Knocking down Itk expression had a profound inhibitory effect on Jurkat cell proliferation. In addition, there was a substantial decrease in level of cytokines, such as IL-2, IL-5, IL-10 and IFN-gamma, produced by cell transfected with Itk-shRNA1. CONCLUSION: Knocking down Itk expression can inhibit Jurkat cell proliferation and inflammatory cytokines production. PMID- 21280326 TI - [Efficacy of antiviral treatment on patients with acute-on-chronic hepatitis B liver failure with low viral load]. AB - OBJECTIVE: To investigate the efficacy of antiviral treatment on patients with acute-on-chronic hepatitis B liver failure with low viral load. METHODS: 352 patients with acute-on-chronic hepatitis B liver failure including 175 cases of low HBV viral load and 177 cases of high HBV viral load were enrolled into this study. The patients were divided into the antiviral group which received antiviral therapy (Lamivudine, Entecavir or Telbivudine) plus routine supportive therapy and the control group which received supportive therapy only. The clinical features and the 24-week short-term efficacy of antiviral therapy were assessed. RESULTS: At week 24,total survival rate in antiviral group was higher than that in control group (P = 0.010). The survival rate of patients with low viral load in the antiviral group was higher than that in the control group (P = 0.001). But there was no significant difference between the antiviral group and the control group with high viral load (P = 0.856). But in the antiviral group, there was no significant difference in survival rate between the patients with high HBV viral load and those with low viral load (P = 0.755). CONCLUSIONS: Antiviral therapy can significantly improve survival rate of patients of acute-on chronic hepatitis B liver failure with low viral load. Liver failure; PMID- 21280325 TI - [Influence of adefovir dipivoxil on HBV specific CTL in patients with chronic hepatitis B]. AB - OBJECTIVE: To explore the influence of adefovir dipivoxil on HBV specific CTL in patients with chronic hepatitis B (CHB). METHODS: 10 mg adefovir dipivoxil (Zhengda Tianjing Pharmaceutical Company) was used for CHB patients with positive HBV DNA (HBV DNA > or = 1 x 10(4) copies/ml), ALT > 2 x upper limit of normal value (ULN) and positive human leucocyte antigen (HLA)-A2, orally, once a day for 3 months. Real time fluorescent quantitative PCR was used to determine HBV DNA and flowcytometer was used to determine HBV specific CTL. RESULTS: After treatment with adefovir dipivoxil for 3 months, HBV specific CTL (0.52 +/- 0.11)% was higher than that before treatment (0.34 +/- 0.14)%, t = 6.78 P < 0.01, HBV DNA of 28 cases turned to negative (<1 x 10(3) copies/ml) (62.22%). HBV DNA of 17 cases failed to turn negative 3 months after treatment, but their HBV DNA level was lower [(4. 18 +/- 0.4) log 10 copies/ml] than that before treatment [(6.23 +/ 0.73) log 10 copies/ml], t = 9.99, P < 0.01. CONCLUSION: Adefovir dipivoxil can improve HBV specific cellular immunity in patients CHB. PMID- 21280327 TI - [Detection of BK virus infection in renal transplant recipients and clinical application]. AB - OBJECTIVE: To study the detection methods of BK virus infection in kidney transplant recipients, and to explore the clinical application. METHODS: 132 cases of renal transplant recipients were undertaken BK virus detection including presence of decoy cells in urinary sediment, urine and serum BKV-DNA to demonstrate the BK virus replication. RESULT: Among 132 cases of renal transplant recipients, urinary decoy cell was found in 37 (28.0%) patients and the median time was 12 months after surgery. 32 (24.2%) patients were diagnosed as BK viruria at a median of 11 months after surgery, and 16 (12.1%) recipients were diagnosed as BK viremia at a median of 15 months after surgery, 5 patients with BK viruria were diagnosed as BK virus associated nephropathy according to allograft biopsy. CONCLUSION: To make early diagnosis of BK virus infection, detection of urine decoy cells and BKV-DNA in urine and plasma sample is important,which provides an important basis for the prevention of BK virus associated nephropathy. PMID- 21280328 TI - [Prognosis comparison in middle and later stage severe hepatitis B patients treat with plasma exchange or unified medicine therapy]. AB - OBJECTIVE: To observe the influence on the prognosis of the patients with severe hepatitis B in middle and later stage treated with plasma exchange or unified medicine therapy, and search the therapy methods on the middle and later stage severe hepatitis B. METHODS: To observe the liver function, complications and prognosis of the patients treated with plasma exchange on the basis of unified medicine therapy. To compare with that of the corresponding period patients with unified medicine therapy and analysis the clinical data with statistics methods. RESULTS: 36 cases of the plasma exchange group, 18 cases survived and 18 cases died. 32 cases of the unified medicine therapy group, 13 cases survived and 19 cases died. The survival rates between the two groups patients does not appear statistics difference;liver function index (ALT, AST, SB, ALB, TC, ChE) and PT also appear the same results in statistics. CONCLUSIONS: Compare with unified medicine therapy, plasma exchange on the basis of the unified medicine therapy does not appear to improve survival rate of the patients with the middle and later stage severe hepatitis B. The prognosis of these patients determined by the liver failure extent itself. PMID- 21280329 TI - [Efficacy of peginterferon alpha-2a in combination with ribavirin in treatment of eldly patients with chronic hepatitis C]. AB - OBJECTIVE: To study the clinical efficacy of PEG-Interferon alpha-2a combined with ribavirin in eldly chronic hepatitis. METHODS: Forty patients with chronic hepatitis C were divided into treatment group and comparative group. The twenty eldly patients of treatment group receive peg-interferon alpha-2a 135-180 microg subcutaneous injection every week combined with ribavirin 600-1000 mg/d for 48 weeks, and twenty adult patients of control group receive peg-interferon 135-180 microg subcutaneous injection every week combined with ribavirin 800-1200 mg/d for 48 weeks. The rapid virological response (RVR) rate, early virological response (EVR) rate, end of treatment virological response (ETVR) rate, sustained virological response (SVR) rate, nonresponder rate, relapse rate and the side reaction was assessed, then to compare the differences between the two groups. RESULTS: The RVR rate, EVR rate, ETVR rate, SVR rate, nonresponder rate, relapse rate was 60%, 70%, 75%, 60%, 10%, 10% respectively, accordingly the rate in control group was 75%, 80%, 85%, 75%, 5%, 10%. The difference between the two group were not statistically significant (P > 0.05). Compared with the control group, the rate of neutropenia was higher in treatment group (P < 0.05). There was no difference between the two groups in influenza-like side effect, anemia, thrombocytopenia and gastrointestinal side reaction. CONCLUSIONS: The eldly patients with Chronic Hepatitis C using general dose peg-IFNalpha-2a combined with lower dose ribavirin can still obtain the similar efficiency and excellent tolerance when the basic diseases such as hypertension, diabetes and side effects were treated successfully. PMID- 21280330 TI - [Development of serological detection assays for human coronavirus HKU1 infection and its application]. AB - OBJECTIVE: To express the nuclear capsid protein (N protein) and the spike protein (S protein) of HCoV-HKU1, and to develop the corresponding serum assay for antibody detection. METHODS: The N protein of HCoV-HKU1 was expressed in E. Coli, anti-N antibody assay was established using Western Blotting with turn based membrane. HCoV-HKU1 S protein was constructed in the eukaryotic expression plasmids, and confirmed by Western Blotting, S antibody assay was established using indirect immunofluorescence assay (IFA). We analyzed anti-S and anti-N antibody among 100 normal adult serum. RESULTS: Expression of S and N protein were confirmed; 100 normal adult serum were analyzed using the established serological detection assay, in which HCoV-HKU1 S antibody positive rate was 47%, N antibody positive rate was 48%, Both S and N antibodies positive were 21%, Both S and N antibodies negative were 22%. Co-detection S and N antibody was achieved 74% positive rate. CONCLUSION: The methods we established here could be used for serological analysis of HCoV-HKU1. Either detection of HCoV-HKU1 S or N antibodies achieved good results. Higher positive detection rate of anti-S or anti-N antibody was found in the normal adults. PMID- 21280331 TI - [Preparation and identification of the monoclonal antibodies against programmed death-1 ligant 1]. AB - OBJECTIVE: To prepare monoclonal antibodies (McAbs) against human programmed death-1 ligant 1(PD-L1) and identify its bioactivity. METHODS: We immunized the BALB/c mice with Thioredoxin-(PD-L1) recombination protein which expressed by prokaryotic system. Prepare hybridoma cell by hybridoma technology and used enzyme-linked immunosorbent assay(ELISA) and Western-blotting assays to select positive hybridoma identify cell. Competition inhibition ELISA was carried out to identify the special bioactivity of antibody. RESULTS: 4 hybridoma cell strains which could secrete anti-(PD-L1) antibodies stably were selected. The McAbs has good affinity with its receptor. Purify anti-(PD-L1) with title 1:32 000 was obtained after large quantity preparation. At the same time we obtained 1 cell stain which could secret special anti-Trx McAbs. CONCLUSIONS: We obtained anti (PD-L1) McAbs with good bioactivity successfully, which lay the foundation for further study. PMID- 21280332 TI - [The study of multiple RT-PCR-based reverse dot blot hybridization technique for detecting influenza viruses]. AB - OBJECTIVE: To establish a multiplex RT-PCR-based reverse dot blot hybridization technique to detect influenza viruses. METHODS: Obtain the HA nucleotide sequences of seasonal influenza H1N1, seasonal influenza H3N2, influenza H1N1 and human avian influenza H5N1 from GenBank. Design primers in conservative district and probes t in high variable region respectively, after analyzing the HA nucleotide sequences of influenza virus through the Vector NTI 9.0. Establish and optimize multiple RT-PCR system by comparing amplification efficiency and specificity at different primer concentrations. Establish the reverse dot hybridization system after optimizing the concentration of probes. To compare the sensitivity and specificity of this technique and the general RT-PCR Method through extracting the viral RNA of the mentioned influenza virus which are to be the reference substance. RESULTS: Successfully establish a multiplex RT-PCR-based reverse dot blot hybridization technique for detecting influenza viruses. This technique is 100-1000 times more sensitive than gel electrophoresis method, and it has a good specificity. CONCLUSION: Successfully established multiplex RT-PCR based reverse dot blot hybridization technique for detecting influenza viruses. PMID- 21280333 TI - [Integration sites in HCC biopsy]. AB - OBJECTIVE: To compare the performance of Inverse-PCR, Alu-PCR and Cassette ligation-mediated PCR (CLM-PCR) in HBV DNA integration sites identification. METHODS: One HCC biopsy was obtained from surgically resected sample. The patient was positive for serum hepatitis B surface antigen (HBsAg). The genomic DNA was purified by the standard phenol/chloroform extraction and ethanol precipitation method. Seperated set of primers were designed to amplify the HBV DNA integration region by means of 3 different PCR methods respectively. The PCR products were analyzed by electrophoresis, then cloned to PMD18-T vector for DNA sequencing. The sequence alignment was performed under Blast software. RESULTS: 7 bands and 22 sequencing results was obtained from IPCR and 3 integration sites was identified. Alu-PCR provided 12 bands and 32 sequencing results, and CLM-PCR showed 12 bands and 4 sequencing results. No integration site was identified from the latter two. CONCLUSION: IPCR compared with another two methods showed a reliable capacity in HBV DNA integration site identification. PMID- 21280334 TI - [Establishment of microarray for detecting mutation in HBV pre-core/core and basic core promoter regions]. AB - OBJECTIVE: To develop a sensitive and specific microarray for detecting mutations of HBV pre-core/core and basic core promoter regions in the clinic. METHODS: Site specific oligonucleotide probes were designed and immobilized to microarray slides and hybridized to HBV gene fragments amplified with specific biotin labeled primer using asymmetrical PCR. The specificity and sensitivity of the method were estimated. And the microarray was applied to detect 138 clinical serum samples with HBV-DNA. RESULTS: The mutations of HBV pre-core/core and basic core promoter regions can be specifically detected using the microarray, and the sensitivity was 1 x 10(1) copies/microl. Among 138 samples, 40 samples had T1762/ A1764 mutation, 11 samples had C1814 mutation, and 16 samples had A1896 mutation. The A1896 mutation rate in high HBV-DNA load group was significantly higher than that in low HBV-DNA load group (P < 0.01). CONCLUSION: An DNA microarray assay was successfully established to detect the mutations in HBV pre-core/core and basic core promoter regions. The A1896 mutation in pre-core/core region maybe involve in duplication of HBV. PMID- 21280335 TI - [Long-term outcome of neurologic development after extremely premature birth]. PMID- 21280336 TI - [Toilet training and elimination behavior as topics for pediatric nursing]. PMID- 21280337 TI - [Antibiotics in premature rupture of fetal membranes: is there a benefit for the newborn infant?]. PMID- 21280338 TI - [Fetal surgery intervention exemplified by spina bifida aperta]. PMID- 21280339 TI - [Amplitude integrated electroencephalography (aEEG) in premature and newborn infants--an overview]. PMID- 21280340 TI - ["Cooperation in health professions" memorandum. Quality and protection of health care of tomorrow]. PMID- 21280342 TI - [Sickness certificates as a basis for decisions regarding work capacity not always sufficient for legal trials. Difficult for the physician to understand law -and for the lawyer to understand medicine]. PMID- 21280343 TI - [Good possibilities of reconstructing grip function in tetraplegia. Care measures in a life-long patient perspective after cervical spinal cord injuries]. PMID- 21280344 TI - [Necessary to understand the context when evidence is to be implemented in health care]. PMID- 21280345 TI - [Assessment of renal function--unclear which method is best. Background to SBU investigation of endogenous markers]. PMID- 21280346 TI - [Toes of the newborns can reveal serious diagnosis. Fibrodysplasia ossificans progressiva can cause severe disability]. PMID- 21280347 TI - [Don't change the blood pressure limit in diabetes!]. PMID- 21280348 TI - [Dexamethasone should be administered in meningitis in children and adults]. PMID- 21280349 TI - [Underutilization of anticancer agents--an example]. PMID- 21280350 TI - [Level of stress among American and Swedish students--some lessons learned]. PMID- 21280351 TI - [Do the government and the Swedish Medical Association agree to repress those with functional disabilities?]. PMID- 21280352 TI - [Beneficial with Kierkegaard in the palliative care?]. PMID- 21280353 TI - Confessions of a Wannabe (American Folklore Society Presidential Invited Plenary Address, October 2009). AB - This paper is a written rendering of a plenary address delivered at the 2009 Annual Meeting of the American Folklore Society. Drawing on materials from his forthcoming book Confessions of a Wannabe, the author provides a personal account of the deeply emotional sense of responsibility, obligation, and reciprocity involved in long-term ethnographic research among Native American communities, particularly the Omaha and Pawnee tribes of Nebraska. The author details the ways in which personal relations with the people and communities he has observed have shaped his personal and professional life, and he calls into question the ideal of purportedly neutral or distanced ethnography. Details are provided of the author's experiences in converting his farm into an appropriate reburial site for repatriated Pawnee remains recovered under the aegis of the Native American Graves Repatriation and Protection Act (NAGPRA). PMID- 21280356 TI - "A human treasure": Europe's displaced children between nationalism and internationalism. PMID- 21280357 TI - Internationalism in relief: the birth (and death) of UNRRA. PMID- 21280359 TI - The Majelis Ulama's Fatwa on abortion in contemporary Indonesia. PMID- 21280360 TI - Medical experts & Islamic scholars deliberating over brain death: gaps in the applied Islamic bioethics discourse. PMID- 21280361 TI - If Seebohm Rowntree had studied Sweden - how poverty changed in the city of Goteborg from 1925 to 2003. AB - This paper investigates the development of poverty in Sweden using micro data derived from tax files for the city of Goteborg for the years 1925, 1936, 1947 and 1958, as well as more recent (1983, 1994 and 2003) information. We define poverty as living in a household with a disposable income lower than a poverty line that represents a constant purchasing power all years, as well as poverty lines defined as 60% of contemporary median income. Clear reductions of poverty from 1925 to 1947, as well as from 1958 to 1983, are found. We argue that an important poverty-reducing mechanism during both periods was narrowing earnings disparities. Further, we claim that the poverty reduction from the end of the 1950s to the first half of the 1980s was the outcome of improved transfer systems as well as the establishment of pronounced characteristics of present-day Sweden: the dual earner system. PMID- 21280362 TI - Talking about gendered headship: how do women and men working in schools conceive and articulate notions of gender? AB - In this paper I explore how a woman secondary school headteacher and her colleagues talk about her gendered headship. To facilitate and contextualise the semi-structured interviews, participants were asked to categorise a range of attributes and qualities that have been seen as 'masculine' or 'feminine'. They attempted to plot their perceptions of her gendered headship on a continuum from 'extremely masculine' to 'extremely feminine' in relation to her appearance and interactions in various contexts. Their talk, as they explained and illustrated their thinking, reveals that even from a dualist starting point many have an understanding of the fluid nature of complex, subjective, gendered identities. The rejection of binary notions of gender by some participants disrupts the perpetuation of gender as a dualist concept. In particular, the headteacher forces open a space in which to consider the complexity of her own gendered headship. PMID- 21280364 TI - The role of the demographic transition in the process of urbanization. PMID- 21280365 TI - Long-term effects of the demographic transition on family and kinship networks in Britain. PMID- 21280366 TI - How much does family matter? Cooperative breeding and the demographic transition. PMID- 21280368 TI - Generational transfers and population aging in Latin America. PMID- 21280369 TI - Population aging and the future of the welfare state: the example of Sweden. PMID- 21280370 TI - The future of a demographic overachiever: long-term implications of the demographic transition in China. PMID- 21280371 TI - Achievers and laggards in demographic transition: a comparison of Indonesia and Nigeria. PMID- 21280372 TI - Who's afraid of population decline? A critical examination of its consequences. PMID- 21280373 TI - Population policy and the demographic transition: performance, prospects, and options. PMID- 21280374 TI - Torture, sex and military Orientalism. AB - This article revisits the debate about recent American torture practices, particularly the use of discredited anthropological texts to validate long-held Orientalist assumptions about the sexual vulnerability of Muslim males. Such practices are placed in an historical context of older imperial constructions of sexually deviant Muslims as well as of more general forms of gendered and sexual subordination required for war. American torturers intended to produce very particular objects of torture-ones willing and able to confess their 'true' orientation in terms of a binary hetero/homo sexual code established in 19th century Europe. The torturers had the power to confirm through confession and re enactment their crude assumptions, irrespective of the actual sexualities of those being tortured, with consequences for the transnational and reactionary politics of sexual identity. PMID- 21280375 TI - Gene therapy: Have the risks associated with viral vectors been solved? AB - Gene therapy has the potential to cure monogenic diseases through the replacement of the deleterious gene with a functional copy. While the field of gene therapy has been plagued by serious adverse events associated with therapy, it is hoped that new, safer viral vectors have reduced these risks greatly. However, recently published reports indicate that these new viral vectors are a potential risk to patients receiving gene therapy. Thus, caution is required when recruiting patients for clinical trials of gene therapies to ensure the benefit of the therapy outweighs the risks. PMID- 21280378 TI - African Americans and HIV/AIDS - the epidemic continues: an intervention to address the HIV/AIDS pandemic in the black community. AB - The Black community continues to be ravished by HIV/AIDS infection despite the marked expenditures utilized to reduce incidence among this cohort. Efforts to produce culturally appropriate programs that work continues to elude officials and HIV/AIDS has become endemic among specific subgroups in this cohort (e.g., Black men who have sex with men). Large-scale prevention programs have not worked and although community-based interventions have proven to be effective in eliciting behavior change, the numbers that they have been producing have not been enough to make a substantial impact on HIV incidence. The purpose of this exploratory article is to rehash how HIV/AIDS infection continues to devastate the African American community in an effort to elicit renewed vigilance in combating the disease in this community, describe the elements that continue to impede prevention and risk reduction efforts, and present a potential framework that may work to decrease incidence in this community. This article presents a multi-pronged approach to addressing the epidemic of HIV/AIDS in the African American community. PMID- 21280379 TI - "Hating the sin but not the sinner": a study about heterosexism and religious experiences among black men. AB - This article explored the religious experiences of nine Black men who are married (to a woman) and have sex with men (BMMSM). These men do not refer to themselves as men on the down low but self-identify as heterosexual. Using data collected in 2005 in South Carolina, the authors examined the complex relationship of homosexuality and the Black Church. Specifically, they examined the notion of coping with same-sex behavior, concealment, and its impact on BMMSM. Findings from the thematic analysis suggest that men found ways to manage their religious traditions and same-sex behaviors. This research presents an opportunity to locate and access a hidden population. The authors found a pervasive experience of growing up in social and family environments that expose them to heterosexism. PMID- 21280380 TI - A solution from hell: the United States and the rise of humanitarian interventionism, 1991-2003. AB - This article traces the rise of humanitarian interventionist ideas in the US from 1991 to 2003. Until 1997, humanitarian intervention was a relatively limited affair, conceived ad hoc more than systematically, prioritized below multilateralism, aiming to relieve suffering without transforming foreign polities. For this reason, US leaders and citizens scarcely contemplated armed intervention in the Rwandan genocide of 1994: the US 'duty to stop genocide' was a norm still under development. It flourished only in the late 1990s, when humanitarian interventionism, like neoconservatism, became popular in the US establishment and enthusiastic in urging military invasion to remake societies. Now inaction in Rwanda looked outrageous. Stopping the genocide seemed, in retrospect, easily achieved by 5,000 troops, a projection that ignored serious obstacles. On the whole, humanitarian interventionists tended to understate difficulties of halting ethnic conflict, ignore challenges of postconflict reconstruction, discount constraints imposed by public opinion, and override multilateral procedures. These assumptions primed politicians and the public to regard the Iraq war of 2003 as virtuous at best and unworthy of strenuous dissent at worst. The normative commitment to stop mass killing outstripped US or international capabilities-a formula for dashed hopes and dangerous deployments that lives on in the 'responsibility to protect'. PMID- 21280381 TI - The modernizing bias of human rights: stories of mass killings and genocide in Central America. AB - This article analyses selected cases of mass killings and genocide during the civil wars in El Salvador and Guatemala in the 1980s and the way in which the truth commissions in both countries reframed locally grounded narratives to fit the state-centred language of human rights. Redefining wrongdoings as human rights violations produces stories that communicate poorly with local worldviews because the 'truths' that human rights language proposes disregard local realities and transform local conflicts into a type of 'modern', nationwide struggles. Thus, while the concept of genocide might capture well the horrendous nature of a mass killing, it will also ethnify the conflict. Comparisons between local readings and human rights-based reinterpretations reveal a 'modernizing' or 'Westernizing' bias of international law; the article argues for more awareness about such effects in analysis as well as in policy-making. PMID- 21280382 TI - Is inequality harmful for the environment? An empirical analysis applied to developing and transition countries. AB - The object of this article is to examine the relation between social inequalities and pollution. First of all we provide a survey demonstrating that, from a theoretical point of view, a decrease in inequality has an uncertain impact on the environment. Second, on the basis of these conceptual considerations, we propose an econometric analysis based on panel data (fixed-effects and dynamic panel data models) concerning developing and transition countries for the 1988 2003 period. We examine specifically the effect of inequality on the extent of local pollution (sulphur dioxide emissions and organic water pollution) by integrating the Gini index into the formulation of the environmental Kuznets' curve. PMID- 21280383 TI - Identity and environmentalism: the influence of community characteristics. AB - This paper examines the influence of community characteristics on self-proclaimed environmentalism. We find that the composition of a community affects the likelihood that a person claims to be a strong environmentalist even after controlling for individual political leaning, socio-economic characteristics, and pro-environment behaviors. Individuals are more likely to claim to be strong environmentalists if they live in areas where a larger share of the population has post-graduate degrees, if they live in heavily Democratic areas, or if they live in heavily Republican areas. These community effects occur only when individuals are predisposed to take on an environmental identity. PMID- 21280384 TI - Modernizing the Estonian farmhouse, redefining the family, 1880s-1930s. AB - In the nineteenth century, the transition from a Baltic-German-controlled manor and-serf economy to individually owned farmsteads transformed all aspects of life including the spatial organization and form of farmhouses in the western provinces of Tsarist Russia. Agricultural experts and social reformers discussed how to update the traditional threshing-room dwelling house (rehielamu) into a healthy dwelling for successful farmers and, after the Estonian War of Independence, for new settlers. Using material culture such as contemporary plans, I show that changing household relationships, in addition to economic and technological factors, helped to transform the ancient rehielamu into a modern dwelling. PMID- 21280385 TI - "In my opinion, work would be in first place and family in second": young women's imagined gender-work relations in post-Soviet Lithuania. AB - This article explores young women's orientation to work and motherhood in the post-communist context of radical socio-economic transformation in Europe. Based on a qualitative-explorative study into meanings of work and unemployment among young people in post-Soviet Lithuania, the paper introduces an empirically grounded classification of imagined gender-work arrangements. The single patterns of the classification are based on the three configurations of work and motherhood, work and partnership, and work and provision. The findings inform the reconstruction of the 'landscape' of imagined gendered adulthoods in Europe as well as the analysis of emerging gender relations under conditions of rapid social change. PMID- 21280386 TI - Treating viral respiratory tract infections with antibiotics in hospitals: no longer a case of mistaken identity. AB - Widespread use of antibiotics in hospitalized patients contributes to the development of multidrug resistant organisms that make many infections increasingly difficult to treat. Despite calls to prescribe antibiotics judiciously, many physicians continue to order antibiotics for inpatients who do not need them. This Issue Brief investigates antibiotic use in hospitalized adults with a confirmed viral infection, a group of patients that may not benefit from such therapy. Understanding the factors that lead to inappropriate antibiotic use may help change clinical practice and limit antibiotic resistance. PMID- 21280387 TI - [Cerebral injury and strategy for protection against it after cardiac arrest]. PMID- 21280388 TI - [The use of dexmedetomidine hydrochloride in intensive care unit]. PMID- 21280389 TI - A primary problem: more patients under federal health reform with fewer primary care doctors spell trouble. PMID- 21280390 TI - Uninsured, illegal, and in need of long-term care; the repatriation of undocumented immigrants by U.S. hospitals. PMID- 21280391 TI - Transition and beyond for individuals with autism spectrum disorders (ASD): a New Jersey case study of the adult service sector, its inherent shortcomings, and hope for the future. PMID- 21280392 TI - Facing reality: the Pregnancy Discrimination Act falls short for women undergoing infertility treatment. PMID- 21280393 TI - Making tuba in the Torres Strait Islands: the cultural diffusion and geographic mobility of an alcoholic drink. AB - There is relatively scant evidence of the Indigenous production and consumption of intoxicating drinks on the Australian mainland prior to the arrival of outsiders. Although Australian Aboriginal peoples had mastered fermentation in some regions, the Indigenous manufacture of much stronger drinks by distillation was unknown on the Australian mainland. However, following contact with Pacific Island and Southeast Asian peoples in the 19th century, Islanders in the Torres Strait adopted techniques for fermenting and distilling what became a quasi indigenous alcoholic drink known as tuba. This paper discusses the historical process of the diffusion of this substance as a result of labour migration and internationalisation in the Strait, and provides present-day accounts of tuba production from Torres Strait Islanders. PMID- 21280394 TI - Maternal incest as moral panic: envisioning futures without fathers in the South African lowveld. AB - During 2008, rumours about revolting incestuous encounters between sons and their mothers circulated in the Bushbuckridge municipality of the South African lowveld. This article views these rumours as expressing moral panic, paying particular attention to the historical contexts of their emergence and circulation, and to their temporal orientation. I locate these rumours in the periphery of South Africa's de-industrialising economy, marked by increased unemployment and criminality among men and by a growing prominence of women headed households. They express a regressive temporalisation and pessimistic vision, not of development, progress and civilisation, but rather of deterioration and de-civilisation. Through the alleged act of incest, sons who engage in crime usurp the authority of fathers who once produced value in strategic industries and mines. As such the rumours envision a dystopia marked by the 'death of the father' and chaotic disorder without morality and law. PMID- 21280395 TI - International migration, "domestic struggles" and status aspiration among nurses in South Africa. AB - The achievement of upward mobility through participation in international labour markets has become possible for nurses in the context of a 'new' democratic South Africa, but this contrasts sharply with the predicament of many in the post apartheid context, for whom economic vulnerability and unemployment are the prevailing norm. Such a stark contrast has tended to complicate the domestic relations experienced by nurses who, as working professionals, often have significantly greater financial resources and career flexibility than their husbands. Looking at the possibilities and constraints that are created for nurses in their social relationships particularly with their husbands, I draw on Belinda Bozzoli's concept of 'domestic struggles' in order to emphasise the multiplicity and changeability of gendered relations, instead of assuming a single patriarchal status quo.1 Fixed representations of gender roles nonetheless play an important part in nurses' own commentary on migration. While many nurses speak enthusiastically of the possibilities of seeking work overseas, others draw upon familiar representations of female domestic duty to condemn migrants for neglecting their family in pursuit of financial gain. I argue that this criticism is rooted in a fear of the threat that migration presents to existing nursing hierarchies, as a new and powerful tool for status acquisition in the post apartheid context. PMID- 21280396 TI - "Blame it on the weeds": politics, poverty, and ecology in the new South Africa. AB - In January of 2000, spectacular fires burned in the natural veld of Cape Town, South Africa. As the fire-fighting effort finished, a theory emerged: invasive alien species, trees from other countries, such as Australia and the United States, were to blame for the fires. While the invasive alien hypothesis captured the attention of media and policy makers alike, there was little ecological evidence to support it. This article places the fires of 2000 in a longer history of post-apartheid policy and science surrounding invasive alien floral species, arguing that the fires allowed for a synergy between concerns over poverty relief, nature conservation, and scientific research. The most visible example of this synergy was an increased commitment to the Working for Water programme on the Cape Peninsula, a large-scale employment programme utilising unskilled labour to clear invasive alien species in order to conserve South African water resources. In addition to providing employment for South Africa's poorest citizens, Working for Water provided funding for ecological research about invasive alien species. The studies that resulted from this funding focused on gathering information to make practical suggestions for invasive species control. Although the focus of these studies was on management, the science used was itself as rigorous as it had ever been. In the post-apartheid era, as poverty relief and nature conservation came together, scientists ensured that they would continue to play a role in nature conservation by making their research relevant to both invasive species control and to poverty relief. PMID- 21280397 TI - Liminal cultural work in family childcare: Latino immigrant family childcare providers and bicultural childrearing in the United States, 2002-2004. AB - Immigrants find themselves in a liminal state of limbo between two societies. In this zone, competing cultural ideas coexist. This essay examines how Latino immigrant family childcare providers in the United States questioned US norms of childrearing and how they engaged in liminal cultural work to produce a bicultural childrearing. They are exposed to US norms through family childcare certification programmes that they were legally required to participate in, in order to receive the accreditation required to care for young children in their homes. They were simultaneously critical and embracing of US mainstream ideas of childrearing. Two contested areas for them are the emphasis on individual child development and the levelling of authority relations between adults and children. Their traditional values are absent from the training programmes, yet they develop a process of selective adaptation which both maintains and discards traditional ideas of childrearing and integrates them with some of the new ideas they learn in the US. The liminal cultural work that immigrant family childcare workers do is both for themselves and for the children and the families for whom they provide care. The providers experience a process of ongoing liminal cultural work. PMID- 21280398 TI - Blurring boundaries, distant companions: non-kin female caregivers for children in colonial India (nineteenth and twentieth centuries). AB - This paper examines the history of child-care by non-kin, "non-family" members and their representations in colonial India. It focuses primarily on Bengal and relies on several genres of literary documents. Bengal harboured the seat of the British imperial capital in the city of Calcutta until 1911 and its culture was shaped in unique ways compared with other Indian cities. Based on a reading of select literary documents such as European advice manuals and Bengali personal narratives, the paper argues that the relationship between caregivers and children in colonial households attests to the building of new ties and deep ambiguous, multi-dimensional relationships with non-kin members thereby revealing the plasticity of Indian families where sociocultural boundaries were blurred and intimate relationships forged. Beginning with the literary representation of a wet-nurse in Mahasweta Devi's short story Breast-Giver, the paper delves into the world of European and Indian accounts to recuperate the history of the caregivers. It demonstrates that despite the emphasis of recent scholars that the construction of a respectable middle-class identity was based on a sharp distinction from lower social groups, such as working women and prostitutes, the history of child-care by hired domestics reveals the sharing of a common world by different caste-class groups and the interpenetration of the two domains of culture. PMID- 21280399 TI - Who cares for me? Grandparents, nannies and babysitters caring for children in contemporary Italy. AB - This paper illustrates the factors and features of the revival of paid care and domestic work in Italy. While Italy is experiencing a boom in the recourse to carers for the elderly, there is not a corresponding expansion in paid private childcare, in spite of growing female employment and limited public services for children. One of the reasons for this is the growing involvement of grandparents in childcare. In Italy, a country characterised by a "Mediterranean welfare regime", people also have recourse to their own mothers (and fathers) to care for their children, in spite of the fact that they can afford to pay for childminding and babysitting. Thus it is not only (migrant) domestic workers who frequently rely on their parents to care for their own children, an issue widely discussed in the literature on global care chains. Their employers, too, may rely on them. Grandparents, however, have turned out to play an important role in childcare not only in Italy but also in Western countries with better childcare services. Focusing on these issues, the paper contributes both to the debate on global care chains and to that on the role of the family within different welfare systems. PMID- 21280400 TI - The expertise of participation: mass housing and urban planning in post-war France. AB - This article analyses the advent of participation in French planning as the historical touchstone of a larger shift in urban thinking. It investigates how the interactions between inhabitants, developers, state officials and social scientific experts in the production of large-scale modern housing areas and new towns helped bring about user participation as a category of action and discourse. The article argues that the transformation of inhabitants into active participants entails the development of legitimate 'user knowledge' and therefore - perhaps paradoxically - the continuing involvement of experts. The first part of the article examines how the turn towards mass housing production during the 1950s prompted the question of the user and established the ground for debates about participation. The second part of the article explores the relationship between inhabitant contestation and changing urban planning and policy-making during the 1960s. The focus here is on Sarcelles, which served both as a national urban model, a key object of sociological study, and the main target of national public outcry, and helps to reveal relations between local contestation, national policy and shifts in urban thinking. The last part of the article looks at the concrete influence of ideas of participation on subsequent urban policies during the 1970s. PMID- 21280402 TI - A case of exemplarity: C. F. Rottboll's history of smallpox inoculation in Denmark-Norway, 1766. AB - Smallpox inoculation was one of the great discoveries of the 18th century and has been written into the grand narrative of medical progress, describing the taming of epidemic disease. Setting the perspective of progress aside, the article explores how this medical innovation was situated in 18th-century society and culture. The aim is to investigate how medical practice was intertwined with social structure and cultural patterns. The article takes its case from a book published in Copenhagen in 1766 by Professor C. F. Rottboll, former Head Physician of the Royal Inoculation House in Copenhagen. Being the first medical treatise on inoculation in Denmark-Norway, the book also has a historical section followed by a collection of reports and letters written by a number of other authors from various parts of the kingdom. Through close reading, the article explores how the introduction of the new technique was described in the texts. The reports were written to present practice and discuss cases. In doing so, they also presented a variety of other concerns so that a diversity of aims and intentions are added to the medical ones. The social and rhetorical strategies employed illuminate social ambition and systems of patronage, as well as understandings of history and of truth. PMID- 21280401 TI - Planning, housing and participation in Britain, 1968-1976. AB - The history of planning and social housing in post-war Britain has been dominated by the role of the state, local government, professionals (planners, architects, civil servants) and developers. This is hardly surprising, given that the partnerships created around these groups dominated the slum clearance and building process. The tenants have been absent from the 'history' because they were missing from the process. However, in the 1960s and 1970s the concept of participation began to emerge. It grew from broader social and cultural changes brought about through the emergence of welfare, consumerism and an ever greater awareness of 'rights'. The idea of participation was to increase participatory democracy by involving people in the planning process, by recognizing their rights to be involved in decisions which impacted on their lives. The state promoted the idea through legislation, but in practice the concept proved difficult to implement. Local authorities saw participation, at best, as a means of smoothing the planning process through the dissemination of ideas, thus limiting any scope for meaningful participation schemes. This article will look at the tension between the ideal and practice. It will also consider the reaction of many tenants who, frustrated at the attitude and policies forced on them by local government, became galvanized into action, creating tenant groups that would give their communities a voice. PMID- 21280403 TI - Poor relief, taxes and the first Universal Pension Reform: the origin of the Swedish welfare state reconsidered. AB - In the year 1900, Sweden probably had the oldest population in the contemporary world. It was also the first nation to implement a universal pension system in 1913. The universal character in early social legislation has certainly been decisive for the development of the Swedish welfare state. This alternative has not been self-evident. Why did the reforms turn universal, when the continental model, the Bismarck social security system, was exclusively directed at industrial workers? Research has concentrated on demographic factors and growing demands for social security, or on the fact that Sweden was still a predominantly rural society with about 2,400 local authorities. This article examines the development of social legislation in the light of local government expenditures and incomes, and suggests an overlooked possibility: the formulation of the first universal national social security reform was a redistributional response to uneven distribution of incomes and general expenditures among the rural districts in Sweden. PMID- 21280405 TI - Biodiversity and sectoral responsibility in the development of Swedish Forestry Policy, 1988-1993. AB - In 1993 the Swedish parliament deregulated national forestry policy and established an environmental goal in parallel with the previous, long-standing goal of high wood production. This paper shows how the change occurred in the context of major changes in Swedish environmental policy during the late 1980s and early 1990s. Within a short time, new environmental legislation and the introduction of legal protection for small forest and agricultural habitats of high ecological value reoriented national forestry policy, away from an overriding focus on wood production to an increased awareness of nature conservation and biodiversity preservation. Reflecting a major compromise with the state, forest owners have gained greater freedom to manage their land, but must also improve environmental conditions while achieving high wood production, a policy known as 'freedom under responsibility'. The paper explains how both the parliament and industry supported increased nature conservation and biodiversity to maintain forest health and support the forestry industry, by favouring responsible resource use and not simply protection from human influence. PMID- 21280408 TI - "Now the African reigns supreme": the rise of African boxing on the Witwatersrand, 1924-1959. AB - This essay explores the growth of boxing among the African populations on the Witwatersrand region of South Africa between 1924 and 1959. It details how the sport's jump in popularity with Africans paralleled migration to Johannesburg. Africans increasingly saw boxing as an activity and skill conducive with survival in this new environment, and thus the sport grew in popularity, stature, and skill-level amongst this emergent urban population. The essay further explores the various ways that the sport was disseminated and popularized during the era, thus detailing how the sport reached both the African masses and petit-bourgeois educated elite. As their presence in Johannesburg became more and more permanent, boxing came to encompass various meanings and ideals, such as notions of discipline, independence and civility, to these urban populations. PMID- 21280409 TI - "A man's game": cricket, war and masculinity, South Africa, 1899-1902. AB - As practitioners of the imperial sport of the Victorian age, cricketers rallied whenever war descended upon England and its colonies. The South African War of 1899-1902 was no different. Adding to existing work on cricket's imperial development within South Africa, this study marks a significant contribution to research on the link between masculinity, war and sport during the Victorian era. A concept emerging from the English public schools of the mid- to late nineteenth century, the masculine ethos of sport and military honour had reached colonial South Africa by the outbreak of war in 1899. In its analysis of cricket and masculinity, this essay examines the events surrounding the war in South Africa and provides an example of the distinct relationship that existed between the military and the masculinity of sport and its organisation during this era. PMID- 21280412 TI - "Neither cricketers nor ladies": towards a history of women and cricket in South Africa, 1860s-2000s. AB - There is a dearth of research and writing on women's cricket in South Africa. In an attempt to enhance understanding of the nature and effects of women's involvement in the game of cricket over the past 200 years, this essay offers a chronological account of the sport and the role women played in it. It draws on readings from the international scholarship on women's early involvement in sport, the fragments that have existed to date about women's cricket in South Africa and some newly discovered primary material from the 1950s onwards. The essay aims to provide a historical context and open a window for historians and social analysts into an area few knew existed before. There is now a distinctive history and subculture of cricket with multiple social dimensions for scholars to explore; here I offer some preliminary insights. PMID- 21280413 TI - Tackling femininity: the heterosexual paradigm and women's soccer in South Africa. AB - Sport is a social institution that perpetuates gendered ideologies in the wider society through appealing to discourses of the naturalness of men's privilege and domination in society. Heteronormativity regulates the roles, behaviours, appearances and sexualities of, and relationships between and among, women and men. Moreover, heteronormative discourses normalise a particular relationship between sex, gender and sexuality that posits woman/feminine/heterosexual (and man/masculine/heterosexual) as a natural order from which variance is considered a punishable deviance. This paper outlines the effects of heteronormative discourses in the lives of women footballers in South Africa, through drawing on interviews with a wide range of women footballers. The paper shows how heteronormative discourses nurture homophobic attitudes that serve to regulate the appearances and performances of South African women. PMID- 21280414 TI - Cross-country disparity in agricultural productivity: quantifying the role of modern seed adoption. AB - Inequality of agricultural labour productivity across the developing world has increased substantially over the past 40 years. This article asks: to what extent did the diffusion of Green Revolution seed varieties contribute to increasing agricultural labour productivity disparity across the developing countries? We find that 22 per cent of cross-country variation in agricultural labour productivity can be attributed to the diffusion of high-yielding seed varieties across countries, and that the impact of such diffusion differed significantly across regions. We discuss the implications of these findings for policy directed at increasing agricultural labour productivity in the developing world. PMID- 21280415 TI - Son preference and household income in rural China. AB - Why is it that couples who have a son or whose last child is a son earn higher conditional income? To solve this curious case we tell a detective story: evidence of a phenomenon to be explained, a parade of suspects, a process of elimination from the enquiry, and then the denouement. Given the draconian family planning policy and a common perception that there is strong son preference in rural China, we postulate two main hypotheses: income-based sex selection making it more likely that richer households have sons, and an incentive for households with sons to raise their income. Tests of each hypothesis are conducted. Taken as a whole, the tests cannot reject either hypothesis but they tend to favour the incentive hypothesis; and there is evidence in support of the channels through which the incentive effect might operate. To our knowledge, this is the first study to test these hypotheses against each other in rural China and more generally in developing countries. PMID- 21280416 TI - Women's property rights and gendered policies: implications for women's long-term welfare in rural Tanzania. AB - This paper evaluates effects of community-level women's property and inheritance rights on women's economic outcomes using a 13 year longitudinal panel from rural Tanzania. In the preferred model specification, inverse probability weighting is applied to a woman-level fixed effects model to control for individual-level time invariant heterogeneity and attrition. Results indicate that changes in women's property and inheritance rights are significantly associated with women's employment outside the home, self-employment and earnings. Results are not limited to sub-groups of marginalised women. Findings indicate lack of gender equity in sub-Saharan Africa may inhibit economic development for women and society as a whole. PMID- 21280418 TI - Parallel realities: exploring poverty dynamics using mixed methods in rural Bangladesh. AB - This paper explores the implications of using two methodological approaches to study poverty dynamics in rural Bangladesh. Using data from a unique longitudinal study, we show how different methods lead to very different assessments of socio economic mobility. We suggest five ways of reconciling these differences: considering assets in addition to expenditures, proximity to the poverty line, other aspects of well-being, household division, and qualitative recall errors. Considering assets and proximity to the poverty line along with expenditures resolves three-fifths of the qualitative and quantitative differences. Use of such integrated mixed-methods can therefore improve the reliability of poverty dynamics research. PMID- 21280419 TI - An advanced stannous-containing sodium fluoride dentifrice. PMID- 21280420 TI - Innovations in global dentifrice technology: an advanced stannous-containing sodium fluoride dentifrice. AB - PURPOSE: Despite oral health improvements in many geographies, the prevalence of oral concerns, including caries, gingivitis, dentin hypersensitivity, breath malodor, calculus, and extrinsic staining remains unacceptably high across the globe. Dentifrice offers a convenient and accessible vehicle to deliver ingredients--such as antimicrobials, fluoride, and esthetic-enhancing agents--to treat a broad range of common oral conditions. Recently, a novel stannous containing sodium fluoride (1450 ppm F-) dentifrice was introduced that has been tested in the lab and/or clinically in diverse geographic regions for its impact on major oral conditions. METHODS: This next-generation dentifrice, marketed as Crest Pro-Health in China and blend-a-med Pro-Expert in parts of Europe, has been extensively clinically tested in the lab and/or clinically on multiple continents in a broad range of subject populations with varying levels of disease and/or cosmetic concerns. This special issue features a few of the many laboratory and clinical investigations conducted on this formulation. RESULTS: The findings reported here demonstrate the product's anticaries potential as well as its ability to reduce plaque, improve dentin hypersensitivity, inhibit extrinsic stain, and improve breath malodor. PMID- 21280421 TI - The anti-plaque efficacy of a novel stannous-containing sodium fluoride dentifrice: a randomized and controlled clinical trial. AB - PURPOSE: To evaluate the anti-plaque efficacy of a novel stannous-containing sodium fluoride dentifrice compared to a negative control regular anti-caries dentifrice and a positive control marketed triclosan-containing dentifrice. METHODS: This was a randomized and controlled, single-center, double-blind, three treatment, three-period, crossover clinical trial in generally healthy adults. A prophylaxis was followed by three 4-day treatment periods of limited brushing, each separated by an approximate 7-day washout phase. Subjects used the test dentifrice on Days 0-3 of each period according to their randomly assigned sequence; either Crest Cavity Protection (negative control); an experimental stannous-containing sodium fluoride dentifrice; or a marketed triclosan positive control (Colgate Total). A dental polishing was given at Day 0 of each treatment period, and subjects brushed the lingual surfaces only and then swished the entire dentition with a dentifrice slurry twice daily under supervision through Day 3. At baseline and Day 4 of each treatment period, plaque levels were assessed via the Turesky Modification of the Quigley-Hein Plaque Index (TMQHPI). RESULTS: Twenty-eight fully evaluable subjects completed the trial. Both the experimental and positive control dentifrices provided significantly lower mean whole mouth TMQHPI plaque scores after treatment compared to the negative control: 11.4% lower for the experimental stannous-containing dentifrice and 8.4% for Colgate Total (P< 0.0001). The experimental stannous-containing dentifrice group resulted in directionally lower whole mouth plaque scores when compared to Colgate Total (P= 0.07). The experimental stannous-containing dentifrice had significantly lower mean plaque scores post-treatment at lingual sites compared with Total (P= 0.0355). All dentifrices were well-tolerated. PMID- 21280422 TI - The desensitizing efficacy of a novel stannous-containing sodium fluoride dentifrice: an 8-week randomized and controlled clinical trial. AB - PURPOSE: To assess the efficacy of a novel stannous-containing dentifrice in the reduction of dentin hypersensitivity when compared to a marketed positive control dentifrice. METHODS: An 8-week, single-center, randomized, parallel group, two treatment, double-blind clinical study was conducted in a generally healthy adult population with moderate thermal and tactile dentin hypersensitivity. A total of 60 adults were enrolled into the study. Participants were stratified at baseline by age, gender, and cold air sensitivity scores, and randomly assigned to either an experimental stannous-containing sodium fluoride dentifrice or a marketed potassium nitrate positive control. Brushing was supervised on site after baseline and Week 4 examinations. All other product usage was unsupervised. Subjects brushed 2 minutes twice daily. At baseline, Week 4 and Week 8, efficacy outcomes were assessed for tactile sensitivity via the Yeaple Probe, and for thermal sensitivity with air-blast/SchiffAir Index. RESULTS: Fifty-eight subjects completed all evaluations. Both the experimental stannous-containing and positive control dentifrices provided significant (P< 0.05) reductions in both tactile and thermal dentin hypersensitivity compared to baseline at both Weeks 4 and 8. There were no significant differences in Yeaple Probe or Schiff Air Index results between the dentifrices with either efficacy measurement at Week 4 and Week 8 (P > or = 0.5375). PMID- 21280423 TI - A randomized clinical study to assess the extrinsic staining profiles of stannous and triclosan-containing dentifrices. AB - PURPOSE: To evaluate the extrinsic stain profiles of two experimental stannous containing dentifrice prototypes compared to two marketed control dentifrices. METHODS: This was a 5-week, randomized, four-treatment, parallel group, double blind clinical trial of healthy adults. Following a baseline Lobene Stain Index evaluation, subjects received a prophylaxis limited to the 12 anterior teeth to remove surface stain and calculus. They were randomly assigned based on stain scores to one of the four treatment groups: one of two experimental stannous containing sodium fluoride dentifrices; a non-staining marketed triclosan dentifrice (Colgate Total); or a 0.454% stannous fluoride dentifrice (Crest Gum Care). Subjects brushed for 1 minute twice daily at home with their assigned dentifrice. Stain examinations were repeated at Week 3 and Week 5 to assess treatment differences. RESULTS: For the 96 subjects completing the study, Lobene stain composite mean scores--as well as extent (area) and intensity average scores--were significantly lower in the two experimental stannous-containing dentifrice groups and the Colgate Total group when compared to Crest Gum Care (P < 0.0001) at both Weeks 3 and 5. There were no statistically significant differences (P > 0.145) in stain accumulation at either time point between the experimental stannous groups and the Colgate Total group by any Lobene stain measure (composite, extent, intensity). All dentifrices were well-tolerated. PMID- 21280424 TI - Breath malodor reduction with use of a stannous-containing sodium fluoride dentifrice: a meta-analysis of four randomized and controlled clinical trials. AB - PURPOSE: To determine the effectiveness of a novel stannous-containing sodium fluoride dentifrice in reducing malodor-causing volatile sulfur compound (VSC) levels versus a standard marketed fluoride (negative control) anti-caries dentifrice using pooled data from independent clinical trials. METHODS: Four randomized and controlled, evaluator-blinded, 3- or 4-period, 2-treatment crossover clinical studies were conducted at four separate centers in Asia and the United States in subjects with a baseline VSC score of > 100 ppb. Following a week-long acclimation period, subjects were randomly assigned to a treatment sequence specifying the order of use of a stannous-containing sodium fluoride dentifrice and a negative control dentifrice (Crest Cavity Protection). VSC levels were assessed at four time points using a Halimeter during each treatment period: (1) baseline prior to treatment; (2) 3-4 hours after baseline and a single brushing; (3) 24 hours post-baseline and after two total brushings ("overnight"/"morning breath"); and (4) 27-28 hours post-baseline following three total product uses. Brushing instructions were standardized and required two minutes of timed toothbrushing with the assigned dentifrice. Washout periods of at least 2 days separated the treatment periods. RESULTS: A total of 100 subjects were included in the meta-analysis. The stannous-containing dentifrice showed statistically significantly greater breath benefits via VSC reduction compared to the negative control dentifrice (P < 0.047) at all three time points. The stannous-containing dentifrice provided increasingly greater superior relative breath protection benefits of 7.7% at Hour 3-4 post-baseline, 10.6% after 24 hours ("overnight"/"morning breath"), and 24.5% at Hour 27-28. Similar malodor reduction benefits in favor of the stannous-containing dentifrice relative to the negative control were observed for each individual study. PMID- 21280425 TI - Anticaries potential of a stabilized stannous-containing sodium fluoride dentifrice. AB - PURPOSE: To evaluate the anticaries potential of a stabilized stannous-containing sodium fluoride dentifrice relative to appropriate control products. METHODS: A series of in vitro studies was conducted using the following standard anticaries efficacy measures: (1) fluoride uptake; (2) pH cycling remineralization/inhibition of demineralization; and (3) surface microhardness. In each study, the stannous-containing sodium fluoride test dentifrice (1450 ppm F) was compared to a negative control dentifrice (0 ppm F) and a positive control fluoride dentifrice (either 1100 ppm F or 1450 ppm F). RESULTS: Fluoride uptake: The mean fluoride uptake from both the test dentifrice and the positive control dentifrice was significantly greater than the negative control. There was no statistically significant difference between the two fluoride dentifrices, although the test dentifrice was directionally higher. pH cycling: The remineralization measured with the test dentifrice was directionally higher though not significantly different from the positive control dentifrice. Remineralization by both fluoride-containing dentifrices was significantly greater versus the negative control. Surface microhardness: The percent increase in surface microhardness measured on enamel surfaces after treatments with the test dentifrice was found to be significantly higher than that measured for the positive control and the negative control. PMID- 21280426 TI - Introducing vaccine against H1N1 influenza virus in schools. PMID- 21280427 TI - An estimate of the magnitude and trend of HIV/AIDS epidemic using data from the routine VCT services as an alternative data source to ANC sentinel surveillance in Addis Ababa, Ethiopia. AB - BACKGROUND: Since early 1980s when AIDS was first recognized, there has been uncertainty about the future trend and the ultimate dimensions of the pandemic. This uncertainty persists because of difficulties in measuring HIV incidence and prevalence with a substantial degree of precision in a given population. One of the many factors for the lack of precision is the problem of obtaining representative data sources that can be extrapolated to the general population. National and regional HIV estimates for Ethiopia are derived from ANC based HIV surveillance data. Alternative data sources have not been exhaustively explored as potential tools to monitor the trend of HIV/ AIDS epidemic in the country. OBJECTIVE: To estimate the magnitude and trend of HIV/AIDS epidemic using data from the routine VCT services as an alternative data source to ANC sentinel surveillance data. METHODS: The study used secondary data sources from all government, private and NGO VCT centers, of the period of 2003-2005 in Addis Ababa. For the purpose of making comparative analysis of the VCT based estimations and projections, records of all five sentinel sites in Addis Ababa for the period 1983-2003 were reviewed. RESULTS: Both ANC and VCT data sources showed similar and regular trends from the beginning of the HIV epidemic till the year 1995 where the ANC showed a relatively higher prevalence rates than VCT data, with a maximum difference in HIV prevalence of 1.06% in 1993. However, a higher HIV prevalence was noted for the VCT than the ANC data source for the period of 1996-2002, with a maximum difference of 1.4% in 1998, the year when both the ANC and VCT modeled HIV prevalence reached the highest peak in Addis Ababa. On the contrary, the ANC based prevalence was higher than the VCT data for the period 2004-2010, with a maximum difference of 2.2%. CONCLUSION: This study suggests that VCT based HIV prevalence data closely approximates the ANC based data. Therefore VCT data source can be valuable to complement the ANC data in monitoring the HIV epidemic and trend. PMID- 21280428 TI - Hysterosalpingography in the evaluation of infertility: a five years review. (FGAE, 2001 -5). AB - BACKGROUND: Internal genital occlusion, mainly the fallopian tubes, secondary to pelvic inflammatory disease, is the most common causes of female infertility in sub-Saharan Africa and hysterosalpingography is a common diagnostic modality. OBJECTIVE: This was to discuss the findings of HSG and compare among primary and secondary infertility. PATIENTS AND METHODS: All infertility clinical records of five years (2001-2005) at FGAE central clinic were retrieved and those women who had undergone HSG procedure selected. The type and duration of infertility, socio demographic factors and the recorded results of HSG were analyzed. RESULTS: Among the total of 8582 attendants of the infertility clinic, 96% were women and 4% males. HSG was undertaken on 1716 (21%) women. Secondary and primary infertility were 894 (53%) and 804 (47%) respectively. Addis Ababa residents were 84%; married 93%; house wives 61% and office workers were 25%. About 39% (n = 662) of the women came to the clinic for investigation after 30 years of age and 42% (n = 714) after five years duration of infertility. There were 55% (n = 934) with secondary and above level of education while 10% had no formal school. Normal HSG was 604 (36%); significantly more in primary than secondary (p = 0.0002). The uterine cavity was normal in 1253 (73%) of which 21% had bilateral tubal blockage while among the abnormal, 44% showed bilateral block (P = 0.0000000). Tubal abnormalities were significantly associated with the acquired uterine defects than that of the 2.8% congenital uterine abnormalities. Of the 847 (49%) bilateral tubal patency, 14% had luminal defects. Unilaterally patent tubes were demonstrated in 324 (19%) women: more in secondary type (p = 0.0001) without significant difference between the right and the left. Bilateral tubal obstructions were noted in 527 (31%) of which 25% were symmetrical and 6% asymmetrical. Of the blocked tubes, the sites were 60% terminal and 37% proximal. CONCLUSION: The review showed that most of the HSG were abnormal commonly tubal blockage: significantly more in secondary than primary infertility. End block was the commonest site and is associated with hydrosalpinx. The association of acquired uterine and tubal defects and secondary infertility is indicative of damage of internal genital tract following the previous pregnancies. Though applicable also to the primary infertility group, other infections (STI, TB) may contribute to the damage. PMID- 21280429 TI - Detection of acid fast bacilli (AFB) in tuberculous lymphadenitis among adult Ethiopians. AB - BACKGROUND: The sensitivity of conventional methods used in mycobacteriology laboratories may not exceed 40% in extrapulmonary cases of tuberculosis. Fine needle aspiration cytology (FNAC) is the best and affordable alternative method of diagnosing tuberculous (TB) lymphadenitis. However detection of acid fast bacilli (AFB) remains the corner stone of confirming diagnosis of TB. OBJECTIVES: To investigate the detection rate of AFB in FNAC specimens using the Ziehl Neelsen staining method and see if bacillary detection depends on cytomorphologic features of inflammation. METHODS: All consecutive adult patients having solitary or multiple peripheral lymphnode enlargements and diagnosed cytologically as TB lymphadenitis were included in the study. Aspirated samples were expressed on two glass slides and one is stained with Wright's stain for cytology, while the other is stained using the Ziehl Neelsen method for AFB. Cytologic findings were categorized in to three groups as non-caseating granuloma, caseating granuloma and pyo-histiocytic inflammation. RESULTS: Only 52 (21.9%) aspirated samples were found to be positive for AFB. The most interesting finding in this study is that among the 52 AFB positive cases, 47 (53.4%) were cytomorphologically of the pyo histiocytic type. CONCLUSION: Detection of AFB varies with the cytomorphology of inflammation, being very high in pyo-histiocytic type. PMID- 21280431 TI - Bacteriological profile and resistant pattern of clinical isolates from pediatric patients, Gondar University Teaching Hospital, Gondar, Northwest Ethiopia. AB - BACKGROUND: Infectious diseases are major causes of morbidity and mortality among children in the developing world Antibiotic resistance is increasing. Knowledge of pathogens causing infection in pediatrics patients is essential for devising management strategies. OBJECTIVES: To assess the bacteriologic profile and the resistance pattern of clinical isolates from pediatric patients in Gondar University Hospital, Northwest Ethiopia. MATERIAL AND METHODS: Retrospective analysis was done on different clinical specimens that were submitted and processed for culture and antimicrobial susceptibility testing during a period of September 2000 and October 2007. RESULTS: A total of 823 bacterial pathogens were isolated from 7886 different clinical specimens. The overall culture positivity rate was 10.4%. The three most frequent isolates were S. aureus (30%), E. coli (16.5%) and Shigella spp. (11.7%). All isolates showed intermediate level of resistance (60-80%) to ampicillin, trimethoprim-sulphamethoxazole and tetracycline. Low level of resistance (< 60%) observed to chloramphenicol, gentamicin, penicillin, erythromycin and ciprofloxacin. Majority of the isolates (80.3%) showed multiple drug resistance (resistance to two or more drugs). In general ciprofloxacin and gentamicin were the most effective drugs against the tested gram-positive and gram-negative bacteria. CONCLUSION: This study shows resistance to the commonly accessible and affordable drugs has been observed in most bacterial pathogens. The detection of multi drug resistant isolates may further limit therapeutic options. Timely microbiologic surveillance and assessment of antimicrobial resistance is important for dealing with pediatric infections. PMID- 21280430 TI - Artemether-Lumefantrin (Coartem) and artesunate with sulfadoxine-pyrimethamine therapeutic efficacy in the treatment of uncomplicated malaria at Gilgel Gibe II (GGII) South-Western Ethiopia. AB - BACKGROUND: Artesunate derivative drugs are newly introduced antimalaria drugs developed in response to the increasing drug resistance malaria spread. OBJECTIVE: To determine the parasitological resistance and the clinical failure to Artemether-Lumefantrin (Coartem); and artesunate plus sulfadoxine pyrimethamine (SP) by the WHO 14 day in vivo test. METHODS: The WHO 14 day in vivo efficacy study for coartem and artesunate with sulfadoxine-pyrimethamine covered the period from Nov 28 to Dec. 26, 2006 with 141 patients of ages 2 - 35 years with uncomplicated malaria around the big hydroelectric power dam region of Gilgel Gibe II (GGII). There was close clinical follow up and included parasitic load and clearance. Packed red cell volume (Hematocrit) was measured at day 0 and 14. RESULTS: Parasitological resistance (RI, RII, RIII) to Coartem; and artesunate plus SP was not observed. There was no early as well as late clinical failure. All patients had adequate clinical response. The prevalence of malarial anemia (Hct < 33%) was 14.9% at day 0 and had decreased to 7.5% by day 14 in both groups. CONCLUSION: Coartem and artesunate with SP are highly efficacious in the treatment of uncomplicated malaria in the GGII hydroelectric dam area. PMID- 21280432 TI - Pattern of recurrence of trachomatous trichiasis after surgery in Enemor and Ener district, Central Ethiopia. AB - INTRODUCTION: For the surgical correction of trachomatous trichiasis (TT), the WHO has approved the bilamellar tarsal rotation procedure (BTR). However, studies have shown that recurrence rates after surgery can be high. OBJECTIVES: to determine the recurrence rate of trachomatous trichiasis after two commonly practiced surgeries, BTR and posterior lamellar tarsal rotation (PLTR). MATERIALS AND METHOD: A survey was conducted to assess the recurrence of TT among subjects who underwent single trichiasis surgery three months or more before the commencement of the study. Participants were evaluated for the presence of recurrent TT. For patients with trichiatic lashes, the number and location of lashes touching the globe overall and the number of lashes specifically touching the cornea were recorded. RESULT: Of all 1317 eye lids of 780 subjects, 308 lids had one or more inwardly misdirected eye lashes touching the globe and the recurrence rate by operated eye was 23.4% (95% CI: 19.0, 27.8). Recurrence was higher in the left eye than the right (24.8% vs. 21.9%) in all the surgical eyes; yet the difference was not statistically significant (OR 1.2, 95% CI: 0.9, 1.5, P < 0.2). Overall, the highest rate of recurrence occurred centrally. Conjunctival and eye lid inflammation was evident in 32.4% of people who had TT recurrence and it was associated with recurrence (OR 3.8, 95% CI: 2.7, 5.4, p < .005). CONCLUSION: Trichiasis recurrence is high and commonly central which represents a significant threat to the sight of many people. About 43% occurs within the first 3 years indicating the need for close follow up during this period. Conjunctival and eye lid inflammation has been found to be strong risk factors for recurrence. PMID- 21280433 TI - A case of secretory (functioning) pituitary macro adenoma:-prolactinoma and acromegaly. AB - We are reporting a rare case of secretory pituitary macro adenoma in a 25 years old man from Addis Ababa with head ache and visual difficulty of 8 months. Clinical chemistry revealed prolactinomas and plain radiography (Skull & extremities) revealed features of acromegaly. Brain CT scan showed features of pituitary macro adenoma. Current literature states that macro adenomas are not secretory while micro adenomas are, and prolactinomas are the most common of all these micro adenomas, followed by acromegaly. Our case is probably the first ever reported macro adenoma in Ethiopia with features of prolactinoma and acromegaly. PMID- 21280434 TI - Tuberous sclerosis complex (TSC) and Klippel-Trenaunay-Weber (KTW) syndromes association of two complete phakomatoses in a single individual. AB - Tuberous sclerosis or tuberous sclerosis complex (TSC) and Klippel-Trenaunay Weber (KTW) syndromes are phakomatoses which are believed to be inherited separately were associated in a 21 years old female, with no family history of similar illness presented with facial rash of reddish spots or bumps, facial angiofibroma (adenoma cebaceum), which appeared on the nose and cheeks in a butterfly distribution, and sub ependymal calcific nodules on brain CT, and multiple liver, pancreas hamartomas and multiple angiomyolipomas and cysts of both kidney on ultrasound, which is consistent with a sporadic TSC, in addition, the diagnostic triad of KTW involved the left upper limb : cutaneous naevi a vascular anomaly, soft tissue and osteohypertrophy. This is the second reported association of the fully developed symptomatology of TSC and KTW in one person in Ethiopian setting. PMID- 21280435 TI - Breeding of high-oil Jatropha curcas L for biodiesel production. AB - Different geographic seed sources (80) of Jatropha curcas L. were collected in South China and planted in a germplasm resource garden to study their biological and agricultural properties. The average ground diameter, tree height and crown size of two-year old plants of the 80 sources was 7.6 cm, 167 cm and 114 cm, respectively, the average 1000-seed weight was 0.676 (0.477-0.876) kg. The trees grew further to the average size of 12.6 cm diameter, 2.69 m height and 2.1 m crown at the 4th year. Among the 80 sources, six sources had higher oil yield (seed oil content of 40%-42%) and better behaving in expression of phenotype were selected for a small-scale trial of forestation to determine oil yield. Among them a provenance with outstand in expression of phenotype yielded 964.3, 2000.6 and 2858.7 kg/ha was achieved for two- three- and four-year old trees, respectively. Additionally, a new Jatropha mutant was found in the wild and hybridization experiments showed that its oil content increased by 6%. PMID- 21280436 TI - Transformation: the Institute of Medicine report on the future of nursing. PMID- 21280437 TI - The future of nursing (our future): leading change, advancing health. PMID- 21280438 TI - Transforming prelicensure nursing education: preparing the new nurse to meet emerging health care needs. AB - The Carnegie Foundation for the Advancement of Teaching joins a chorus of calls for transformation of prelicensure nursing education (Benner, Sutphen, Leonard, & Day, 2009). Citing the shift of significant responsibility to nurses for managing complex medical regimens, as well as the increasing complexity of community-based practices, Benner and colleagues concluded that nurses entering the field are not equipped with the essential knowledge and skills for today's practice nor prepared to continue learning for tomorrow's nursing (p. 31). They found: a) weak curricula in natural sciences, technology, social sciences, and humanities, and in developing cultural competency; b) weak classroom instruction and limited integration between classroom and clinical experiences; c) limited strategies in helping students develop habits of inquiry, raising clinical questions, seeking evidence for practices; d) faculty and student perception that students are ill prepared for their first job and dissatisfaction with the teaching preparation of current nursing faculty; and e) multiple pathways to eligibility for the licensure examination, with tremendous variability in prerequisites, curricular requirements, and the quality of offerings. PMID- 21280439 TI - Transformational partnerships in nursing education. AB - Although the nursing care environment has changed significantly over the past 30 years, little has changed in the educational methods used to prepare new nurses. Since the 1930s, most clinical education in nursing has been structured with a faculty member supervising a small group of students on one or more inpatient units. Students usually move to new settings for each clinical rotation. This traditional model is heavily dependent on nursing faculty and often requires students to wait for direct faculty supervision. Students often are "strangers" to the registered nurses providing patient care in these settings. This arrangement can compromise the cohesiveness of the nursing team and limit opportunities for building professional relationships between students, registered nurses, and other members of the health care team. Developing a more structured and cohesive partnership between the registered nurse and the student, both of whom are providing care to the same patients, has the potential to revitalize clinical education in nursing. PMID- 21280440 TI - Innovative nursing educational curriculum for the 21st century. AB - The changing landscape of health care in America requires that clinicians be skilled in responding to varying patient expectations and values; provide ongoing patient management; deliver and coordinate care across teams, settings, and time frames; and support patients' endeavors to change behavior and lifestyle- education that is in short supply in today's academic and clinical settings (Institute of Medicine, 2003). Nursing education needs to innovate at the micro and macro system levels for the 21st century. It cannot be business as usual. In order to truly transform care, practice and education will need to partner on curriculum development and the professional socialization of the new nurse. PMID- 21280441 TI - The student perspective on RN-Plus-10 legislation: a survey of associate degree and diploma nursing program students. AB - This article reports on a survey of associate degree and diploma nursing students in Pennsylvania designed to elicit their future educational goals and opinions regarding proposed educational advancement legislation. Results indicated the majority of respondents (86.3 percent) planned to pursue the bachelor's degree in nursing; most (94.8 percent) hoped to be enrolled in a BSN program within four years of graduation. The majority (78.9 percent) indicated that even if they were mandated to complete the bachelor's degree in nursing within 10 years, they would still enroll in their current associate degree or diploma program. Asked if 10 years is a reasonable amount of time to complete the BSN, 79.4 percent agreed it is. If money were not an obstacle, 95.8 percent of participants indicated they would pursue a BSN or higher. The results of this survey suggest that the vast majority of associate degree and diploma nursing students value and hope to pursue higher education in nursing. PMID- 21280442 TI - Attrition and retention in the nursing major: understanding persistence in beginning nursing students. AB - To meet the challenges of the ongoing nursing shortage, it is imperative to increase the retention of students enrolled in schools of nursing. This article reports on findings from a larger research study on faculty-directed strategies to address the attrition of beginning students during the early, nonclinical phase of nursing education. Four themes that influenced students' persistence in the nursing major were uncovered during interviews: Keeping Up, Not Giving Up, Doing It, and Connecting to the use of resources. Diekelmann's concernful practices as enacted by faculty are linked to student narratives. PMID- 21280443 TI - Faculty involvement in undergraduate research: considerations for nurse educators. AB - Undergraduate research has become a hallmark of outstanding colleges and universities over the past decade and is now one of the items included on the National Survey of Student Engagement. Like faculty in other fields, nurse faculty are being asked not only to pursue their own programs of research, but are called upon to promote, facilitate, and supervise undergraduate research. The purpose of this article is to review current research related to the issue of undergraduate research from the perspective of a faculty member's professional career development and overall scholarship in accordance with Boyer's highly regarded model. Significant professional issues related to faculty involvement in undergraduate research are discussed, and suggested strategies for nurse educators are presented. PMID- 21280444 TI - Report card: an evaluation of a concept-based curriculum. AB - This article describes the evaluation of an innovative, concept-based baccalaureate nursing curriculum. Curriculum evaluation is an ongoing process that serves to ensure the delivery of quality education. Findings from surveys and focus groups identified strengths of the new curriculum as the conceptual approach, interactive small-group learning activities, clinical intensives, and early patient care experiences. Issues and challenges identified in the evaluation included perceived repetition of content in the Professional Nursing concept courses, coordination of community-based clinical experiences, a perceived need for greater age-span, pharmacology, and pathophysiology content, and NCLEX-RN preparation. Curriculum revisions based on these findings are described. PMID- 21280445 TI - A paradigm shift in nursing education: a new model. AB - Nurse educators are being inspired to rethink historically teacher-centered curriculum designs and to embrace new ideologies that have a stronger focus on student-centered learning. The paradigm shift is reflected in the National League for Nursing's call for nursing education to respond to the changing needs of our student population by providing an educational learning environment substantiated in evidence for both curriculum and pedagogical practice. To meet these expectations, education should provide active learning that promotes critical thinking and analysis and problem-solving skills. This article presents a model for higher education in nursing that takes into account the learner, the instructor, and the systems that influence their relationships, providing congruence for educational outcomes. PMID- 21280446 TI - Collaboration of nursing faculty and college administration in creating organizational change. AB - At schools of nursing nationwide, surging enrollments in the early 2000s necessitated changes in administrative structures and departmental organization. The authors describe a collaboration between faculty and administrators at their midwestern liberal arts college that aided a reorganization of the school of nursing. Kurt Lewin's 1951 change theory provided the framework for the restructuring, from the initial phases of data collection through implementation of the new administrative structure. The reorganization has resulted in a more efficient use of resources in the school of nursing. PMID- 21280447 TI - Using online exercises and patient simulation to improve students' clinical decision-making. AB - Faced with increasingly complex clinical situations, nurses must respond with accurate clinical judgment. But del Bueno (2005) reports that only 35 percent of new graduate nurses exhibit entry-level expectations of the necessary critical thinking skills. Croskerry (2003) argues that clinicians' education should be directed at developing cognitive strategies that reduce errors in clinical decision-making. A challenge for nurse educators is finding activities to help students analyze their thinking as they address clinical problems. The author describes an assignment, given to third-year baccalaureate students, that used both online learning and high-fidelity patient simulation. Through discussions with instructors and peers, as well as personal reflection, students gained insight into both their sound and faulty critical thinking and clinical decisions. PMID- 21280448 TI - The future of nursing and the informatics agenda. PMID- 21280449 TI - Eliminate border , wars: a call for action. PMID- 21280450 TI - Peer mentoring for multiple levels of nursing students. PMID- 21280451 TI - Michelle L. Foley, MA, RN, CNE. PMID- 21280452 TI - Findings from the 2009 Faculty Census: study confirms reported demographic trends and inequities in faculty salaries. PMID- 21280453 TI - Reshaping nursing through excellence in education. PMID- 21280454 TI - We do, therefore we think: time, motility, and consciousness. AB - This article is a philosopher's expanded review of two recent books on neurophysiology: Rodolfo Llinas's I of the Vortex and Gyorgy Buszaki's Rhythms of the Brain. Researchers such as these are converging on a view of consciousness as originating in motility and as inherently temporal due to the brainwave oscillations that underlay it. Most current discussions of consciousness include implicit philosophical presuppositions inherited from the canon of Plato, Aristotle, Descartes, and Kant, e.g. that consciousness is self-reflective, passive, and timeless. Because of this, Llinas's and Buszaki's insights may not be fully appreciated. Western philosophy, however, also includes what might be described as a counter-tradition--and one that is more compatible with empirical biological science than the usual canon. Heraclitus, Spinoza, Schopenhauer, Nietzsche, and especially the 20th century French philosopher and psychologist, Merleau-Ponty, all anticipated aspects of Llinas's and Buszaki's approaches. Their alternative conceptual vocabularies are useful for strengthening Llinas's and Buszaki's approaches, sketching out a notion of consciousness emerging from motility, and generating new hypotheses for neurophysiological research. PMID- 21280455 TI - Estradiol acts through nuclear- and membrane-initiated mechanisms to maintain a balance between GABAergic and glutamatergic signaling in the brain: implications for hormone replacement therapy. AB - Estradiol (E2) is a potent neuroactive steroid that acts through both nuclear and membrane estrogen receptors (ER) found widely distributed in the brain. Although long known for its role in the neural control of reproduction, more recent work demonstrates that E2 also affects learning and memory, as well as anxiety and depressive symptoms. These findings prompted studies on the neural consequences of long-term E2 deprivation in postmenopausal women. Despite hundreds of studies in animal models and women, the advisability of hormone replacement therapy (HRT) for neuroprotection remains a contentious issue because the effects of estrogen vary among studies. One difficulty in reconciling the conflicting results is the lack of integration across the neuroscience sub-disciplines that contribute to the field. To address this issue, we first review data on E2 regulation of cognition and mood, as well as on factors that may contribute to the disparate findings across studies. GABA and glutamate are proximal regulators of cognition and mood; therefore we next review review data showing that E2 acts through nuclear- and membrane-initiated mechanisms to regulate GABA and glutamate signaling, respectively. We also review evidence that these E2 signaling mechanisms change with age. Finally, we propose a molecular and cellular model of how E2 can have positive, negative, or no effects on neural functions in the aging brain, and we highlight the current gaps in the literature. Addressing these gaps will facilitate development of the mechanism-based strategies needed for designing more effective HRT regimens. PMID- 21280456 TI - Relief expectation and sleep. AB - Originally, a role for sleep in learning and memory has been advocated following the observation of sleep-dependent performance enhancements at simple procedural tasks. With the investigation of a variety of cognitive and behavioral abilities, multiple stages of memory were further suggested to benefit from the off-line reprocessing believed to occur during specific sleep stages. In particular, REM sleep has been implicated in the integration of new information into associative networks as well as in the abstraction and generalization of implicit rules allowing adaptive behaviors. In a recent study, we extended these observations by demonstrating that the mediating effect of expectation on placebo-induced analgesia is strengthened by sleep, and that the individual amount of REM sleep is predictive of the relief expected on the next morning. However, this relation is strongly modulated by the level of concordance between expectations and sensory information available prior to sleep. As placebo responses derive from the learned association between contextual cues and subsequent relief, these results are discussed in relation to the proposed roles of REM sleep in the integrative stages of memory processing. In light of the responsiveness of REM sleep to waking events, its expression is also proposed to reflect the cognitive demand associated with the offline reprocessing of information necessary for the assimilation of new expectations to one's belief system. PMID- 21280457 TI - Gap junction disorders of myelinating cells. AB - Gap junctions (GJs) are channels that allow the diffusion of ions and small molecules across apposed cell membranes. In peripheral nerves, Schwann cells express the GJ proteins connexin32 (Cx32) and Cx29, which have distinct localizations. Cx32 forms GJs through non-compact myelin areas, whereas Cx29 forms hemichannels in the innermost layers of myelin apposing axonal Shaker-type K+ channels. In the CNS, rodent oligodendrocytes express Cx47, Cx32 and Cx29. Cx47 is expressed by all types of oligodendrocytes both in the white and grey matter and forms GJs on cell bodies and proximal processes, as well as most of the intercellular channels with astrocytes. Cx32 is expressed mostly by white matter oligodendrocytes and is localized in the myelin sheath of large diameter fibers. Cx29, and its human ortholog Cx31.3, appear to be restricted to oligodendrocytes that myelinate small caliber fibers, likely forming hemichannels. The importance of intercellular and intracellular GJs in myelinating cells are demonstrated by human disorders resulting from mutations affecting GJ proteins. The X-linked Charcot Marie Tooth disease (CMT1X) is caused by hundreds of mutations affecting Cx32. Patients with CMT1X present mainly with a progressive peripheral neuropathy, which may be accompanied by CNS myelin dysfunction. Mutations in Cx47 may cause a devastating leukodystrophy called Pelizaeus-Merzbacher-like disease or a milder spastic paraplegia. In addition, CNS demyelination may be caused by defects in genes expressing astrocytic GJ proteins, which are essential for oligodendrocytes. Findings from in vitro and in vivo models of these disorders developed over the last decade indicate that most mutations cause loss of function and an inability of the mutant connexins to form functional GJs. Here we review the clinical, genetic, and neurobiological aspects of GJ disorders affecting the PNS and CNS myelinating cells. PMID- 21280458 TI - Acupoint electrical stimulation reduces acute postoperative pain in surgical patients with patient-controlled analgesia: a randomized controlled study. AB - OBJECTIVES: The purpose of this study was to evaluate the effect of acupoint electrical stimulation with patient-controlled analgesia (PCA) on reducing acute pain, nausea, and vomiting after surgery for nontraumatic spinal cord injury. METHODS: A randomized, controlled, repeated measures research design was used. Ninety-nine patients undergoing lumbar spinal surgery were randomly assigned to one of three groups. Patients in experimental group 1 (EG1) received true acupoint electrical simulation three times, whereas those in experimental group 2 (EG2) received sham acupoint manually. Patients in the control group (CG) received no acupoint intervention. All patients were measured for pain, initial demand for PCA, demand for opiates, opiate dose, vital signs, and postoperative nausea and vomiting (PONV). RESULTS: Significant differences were found in postoperative pain, respiratory rate, blood pressure, and opiate doses across time in the three groups with better outcomes observed in EG1 than in EG2. However, no between-group difference was found in initial demand for PCA or in PONV. CONCLUSIONS: The study demonstrates that acupoint electrical stimulation improves acute postoperative pain management without adversely affecting vital signs after surgery for nontraumatic spinal injury. More studies are needed to evaluate the effects ofacupoint electrical stimulation on PONV and postoperative pain following other surgical procedures. PMID- 21280459 TI - Uncovering the expectancy effect: the validation of the acupuncture expectancy scale. AB - PURPOSE: Research suggests that expectancy may modulate the response to medical interventions, including acupuncture. However, the paucity of validated tools to measure expectancy limits rigorous evaluation. We sought to validate a previously developed Acupuncture Expectancy Scale (AES) as an instrument to measure patients' expected responses to acupuncture. PURPOSE: Participants were patients with stage I to III cancers seen in outpatient medical and radiation oncology clinics. They were drawn from three study cohorts that included 404 participants. We examined the reliability, validity, and responsiveness of the AES. RESULTS: The scores on the AES had internal consistency (Cronbach's alpha coefficient) of 0.95 and test-retest reliability of 0.62 over 4 weeks without acupuncture treatment. Those who had previously used acupuncture had higher AES scores compared to those who were acupuncture naive (12.4 vs 9.5, P = .002). AES scores were higher in those who reported willingness to participate in an acupuncture trial compared to those who did not want to participate in an acupuncture trial (11.5 vs 8.1, P < .001). Patients who enrolled in a pilot trial of acupuncture had higher AES scores than the general outpatient population (13.0 vs 9.8, P = .02), and expectancy increased during the course of acupuncture treatment (13.0 to 16.5, P < .017). CONCLUSION: The AES is reliable and valid, and scores appear to increase during or after prior therapy. Incorporation of AES in clinical trials and outcome studies can evaluate the role of expectancy on acupuncture outcomes. PMID- 21280460 TI - A systematic review on acupuncture for trigeminal neuralgia. AB - BACKGROUND: Trigeminal neuralgia (TN) is a commonly seen pain condition with limited treatments available, and acupuncture is widely used for pain conditions, including TN. OBJECTIVES: To review the efficacy of acupuncture treatment for TN. METHODS: English and Chinese databases were searched extensively to identify randomized controlled studies of acupuncture treatment for TN. Selected studies were assessed for methodological quality. Odds ratios (OR) between treatment and control groups were used to assess efficacy. RESULTS: Twelve studies met the inclusion criteria with 506 people in the acupuncture arm and 414 people in the control arm, in which carbamazepine (CBZ) was used as the control treatment. They were all low-quality studies, hence precluding meta-analysis. Only four trials reported that acupuncture was superior to CBZ, and the remaining eight studies showed no difference between the treatment and control groups. Adverse effects of acupuncture, which were reported in three studies, were mild. CONCLUSION: The evidence reviewed previously suggests that acupuncture is of similar efficacy as CBZ but with fewer adverse effects in treatment of TN. However, the evidence is weak because of low methodological quality of the reviewed studies. Further studies with improved methodologies are recommended to support the use of acupuncture for TN. PMID- 21280461 TI - Active research fields of acupuncture research: a document co-citation clustering analysis of acupuncture literature. AB - OBJECTIVE: This study aims to gain an overview of the active fields of acupuncture research in the last 5 to 10 years and before that. METHODS: Document co-citation clustering analysis method was used in this article. ISI web of knowledge-SCI-EXPANDED was used to retrieve the cited references of the documents published under the topic "acupuncture." In order to identify the highly frequently cited articles, the cited references were ranked by occurrence frequency; the frequent threshold value of highly frequently cited articles was set at 20, and their cumulative frequency percentage was nearly 10%. In order to identify the correlation between these highly frequently cited articles, a references co-occurrence matrix was constructed and then transformed into a correlation matrix for co-citation cluster analysis with SPSS 11.5 (SPSS Inc, Chicago, Illinois). RESULTS: Between 2006 and 2008, 985 original articles involving acupuncture were published, and their nearly 20000 references were downloaded. Forty-one frequently cited references ranging from 1976 to 2005 were identified, and a 41x41 co-citation matrix was acquired. The active fields of acupuncture research were identified after co-citation cluster analysis. CONCLUSION: The active fields in the last 5 to 10 years and previously could be identified as follows. (1) Clinical research on acupuncture; (a) studies on the safety of acupuncture; (b) the quest for the "placebo" needle and assessment of the placebo effect; (c) assessment of the efficacy of acupuncture for chronic back pain, osteoarthritis of the knee, and chronic headache. (2) Usage of acupuncture: (a) surveys on the trends of acupuncture use; (b) ethical guidelines of acupuncture experiments and quality assessment. (3) Experimental research on acupuncture mechanism: (a) the neurochemical basis of acupuncture analgesia and (b) evaluation of the effects of acupuncture using functional magnetic resonance imaging. PMID- 21280462 TI - Wet cupping therapy for treatment of herpes zoster: a systematic review of randomized controlled trials. AB - BACKGROUND: Wet cupping is a traditional Chinese medicine therapy commonly used in treating herpes zoster in China, and clinical studies have shown that wet cupping may have beneficial effect on herpes zoster compared with Western medication. METHODS: We included randomized controlled trials (RCTs) on wet cupping for herpes zoster. We searched PubMed, the Cochrane Library (Issue 3, 2008), China Network Knowledge Infrastructure (CNKI), Chinese Scientific Journals Fulltext Database VIP, and Wan Fang Database. All searches ended in February 2009. Two authors extracted data and assessed the trials' quality independently. RevMan 5.0.18 software (The Cochrane Collaboration, The Nordic Cochrane Centre, Copenhagen, Denmark) was used for data analysis with effect estimate presented as relative risk (RR) and mean difference (MD) with a 95% confidence interval (CI). RESULTS: Eight RCTs involving 651 patients were included, and the methodological quality of trials was generally fair in terms of randomization, blinding, and intention-to-treat analysis. Meta-analyses showed wet cupping was superior to medication in the number of cured patients (RR 2.49, 95% CI 1.91 to 3.24, P < .00001), the number of patients with improved symptoms (RR 1.15, 95% CI 1.05 to 1.26, P = .003), and reducing the incidence rate of postherpetic neuralgia (RR 0.06, 95% CI 0.02 to 0.25, P = .0001). Wet cupping plus medication was significantly better than medication alone on number of cured patients (RR 1.93, 95% CI 1.23 to 3.04, P = .005) but demonstrated no difference in symptom improvement (RR 1.00, 95% CI 0.92 to 1.08, P = .98). There were no serious adverse effects related to wet cupping therapy in the included trials. CONCLUSION: Wet cupping appears to be effective in the treatment of herpes zoster. However, further large, rigorously designed PMID- 21280463 TI - The therapeutic value of laughter in medicine. AB - OBJECTIVE: The aim of this review is to identify, critically evaluate, and summarize the laughter literature across a number of fields related to medicine and health care to assess to what extent laughter health-related benefits are currently supported by empirical evidence. DATA SOURCES AND STUDY SELECTION: A comprehensive laughter literature search was performed. A thorough search of the gray literature was also undertaken. A list of inclusion and exclusion criteria was identified. DATA EXTRACTION: It was necessary to distinguish between humor and laughter to assess health-related outcomes elicited by laughter only. DATA SYNTHESIS: Thematic analysis was applied to summarize laughter health-related outcomes, relationships, and general robustness. CONCLUSIONS: Laughter has shown physiological, psychological, social, spiritual, and quality-of-life benefits. Adverse effects are very limited, and laughter is practically lacking in contraindications. Therapeutic efficacy of laughter is mainly derived from spontaneous laughter (triggered by external stimuli or positive emotions) and self-induced laughter (triggered by oneself at will), both occurring with or without humor. The brain is not able to distinguish between these types; therefore, it is assumed that similar benefits may be achieved with one or the other. Although there is not enough data to demonstrate that laughter is an all around healing agent, this review concludes that there exists sufficient evidence to suggest that laughter has some positive, quantifiable effects on certain aspects of health. In this era of evidence-based medicine, it would be appropriate for laughter to be used as a complementary/alternative medicine in the prevention and treatment of illnesses, although further well-designed research is warranted. PMID- 21280464 TI - Lixing Lao, Md, PhD, LAc: promoting acceptance of acupuncture and traditional Chinese medicine. Interview by Anne Lanctot and Suzanne Snyder. PMID- 21280465 TI - Echocardiography in acute coronary syndromes. AB - Echocardiography including 2 Dimensional, Color Doppler, Tissue Doppler Imaging, Myocardial Contrast Echocardiography, Strain and Strain rate, etc are the most powerful modalities for the assessment of myocardial performance in patients with established orsuspected acute coronary syndrome and acute myocardial infarction with a high accuracy, sensitivity and specificity. Dobutamine Stress Echocardiography has tremendous potential of evaluating microcirculation impairment especially in diagnosing the extent of myocardial damage, reversibility component at rest and at the peak levels of stress with appropriate drugs, mechanical (percutaneous coronary intervention) or surgical intervention. Echocardiography and its newer modalities are therefore, promising and valuable tools for assessment of myocardial perfusion in the setting of myocardial infarction. This article provides an overview of clinical evidence supporting the efficacy of echocardiography and its newer modalities in assessment of myocardial function and performance. Timely effective evaluation of acute coronary syndrome and myocardial infarction by echocardiography and its newer modalities may help in early diagnosis,prognositification and warrant specific therapeutic intervention, thereby help in reducing morbidity and mortality. PMID- 21280466 TI - Rationale, design & preliminary findings of the Indian Atherosclerosis Research Study. AB - AIMS & OBJECTIVES: Cardiovascular disease is highly prevalent among Asian Indians. The objective of the Indian Atherosclerosis Research Study (IARS) is to understand the molecular basis of Coronary Artery Disease (CAD) in this population. METHODS & RESULTS: Over 12,500 subjects from 2500 families and 2500 healthy matched controls will be enrolled by year 2010 in the IARS. Selection of participants will be based on stringent inclusion/exclusion criteria. Blood samples will be analyzed for various genes and biomarkers implicated in CAD by employing commercial or in-house developed assays as for indices of early vascular changes. To date, over 6053 individuals from 1644 families with associated demographics, clinical information and bio specimen have been enrolled and comprise of 2131 CAD patients with mean age, 55.02 +/- 0.19 years and 3901 unaffected relatives with mean age, 40.15 +/- 0.22 years. Over 70% of the CAD patients were males. There was significant association of diabetes, hypertension and smoking with CAD status (OR 2.43-4.75; 95% CI 2.01-5.59). Subjects with metabolic syndrome (MS) showed 3 times higher risk of CAD than the non MS group (OR 3.04; 95% CI 2.71-3.41). Preliminary analyses on various atherothrombotic genes relating to lipids, inflammation and growth have identified novel variants as well as unique haplotypes associated with CAD. Proteomic studies revealed strong heritability for plasma TG, IL6, hsCRP and HDL-c levels (h2 46%-86%; p < 0.01). Baseline levels of pro-inflammatory like CRP, sPLA2 and sTWEAK were significantly higher in patients with recurrent or new coronary event. Affected subjects had higher serum antibody titers to CMV, H. pylori and C Pneumoniae infections. Early results from non-invasive assessment of endothelial dysfunction using Periscope suggest that this method is a sensitive tool for delineation of sub clinical atherosclerosis. CONCLUSION: The clinical and molecular data will be systematically integrated to develop a refined algorithm for risk prediction in the Asian Indian population. PMID- 21280467 TI - Enhanced external counterpulsation (EECP) therapy: current evidence for clinical practice and who will benefit? PMID- 21280468 TI - Head-to-head comparison between redo percutaneous mitral valvuloplasty for mitral restenosis and percutaneous mitral valvuloplasty for de novo mitral stenosis. AB - AIMS: In a retrospective study design, we explored the immediate results of redo percutaneous mitral valvuloplasty in comparison with initial percutaneous mitral valvuloplasty. METHODS AND RESULTS: We included 30 consecutive patients with de novo mitral stenosis (group A) and 40 consecutive patients with mitral restenosis after successful initial percutaneous mitral valvuloplasty (group B). Echocardiographic assessment of the mitral valve was performed in all patients by trans-thoracic echocardiography and transesophageal echocardiography excluded left atrial thrombosis. Percutaneous mitral valvuloplasty was performed by the antegrade trans-septal approach using either the standard Inoue technique or the multi-track technique. Patient assessment by trans-thoracic echocardiography was repeated 48 hours following the procedure. Procedural success was defined as a 50% or more increase of mitral valve area with a final mitral valve area > or = 1.5 cm2, without major complications. Procedural success was achieved in 28 (93.3%) patients in group A and in 37 (92.5%) patients in group B (p > 0.05). The two groups were similar concerning the final mitral valve area, gain of mitral valve area, mean pressure gradient across the mitral valve and complication rate (p > 0.05 for all). The final mitral valve area correlated negatively with the initial mitral valve score in both group A and B. CONCLUSION: Redo-percutaneous mitral valvuloplasty for mitral restenosis achieves comparable immediate results to initial percutaneous mitral valvuloplasty. PMID- 21280469 TI - Patterns of ventricular dyssynchrony in congestive heart failure- comparison with controls and implications for patient selection for cardiac resynchronization therapy. AB - BACKGROUND: Assessment of ventricular dyssynchrony by Tissue Doppler Imaging (TDI) is being increasingly used in patient selection for Cardiac Resynchronization Therapy (CRT). Regional distribution of dyssynchrony has been sparingly addressed in dyssynchrony studies in heart failure population. METHODS: TDI was used to assess prevalence and regional distribution patterns of ventricular dyssynchrony in heart failure (HF) patients with systolic LVdysfunction (LVEF equal or less than 40%) in sinus rhythm. Inter-ventricular dyssynchrony (IVD) and left ventricular dyssynchrony (LVD) equal or greater than 40 msec were considered significant and LVD equal or greater than 65 m sec indicated severe dyssynchrony. RESULTS: 100 HF patients (Wide QRS, Gp I, N =70 & Normal QRS Gp II, N=30, and 25 normal individuals with complete LBBB (n=14) or RBBB (n=11) underwent TDI. IVD was seen in 35 (35%) patients (74% LV delay & 26% RV delay) and LVD in 68 patients (68%). The relative prevalence of lVD and LVD respectively in Group land Group II HF patients was47% vs. 7% (p < 0.001) and 70% vs. 67%. (p=ns) while LVD in Groups A (LBBB, n=41) & B (RBBB, n=26) was 76% and 58%, p=ns. The prevalence ofsevere LVD was similar in Gp I & II (37% and 57%, p=ns), and in Gp A & B (46% & 26%, p=ns). Regional distribution patterns of LVD in normal individuals with bundle branch block showed septal delay in 20%, a prevalence of similar to heart failure population (23%, Gp I, and 21% Gp II, p=ns). Lateral wall delay was demonstrated only in the HF population seen in 33% of Gp I and 47% of Gp II patients, p=ns. CONCLUSIONS: LVD is distributed amongst HF patients with narrow or wide QRS and with LBBB or RBBB with a similar regional distribution. Dyssynchrony in normal individuals with bundle branch block is in the form of septal delay. These findings may have implications for patient selection for CRT and site of LV pacing. PMID- 21280470 TI - Role of tenecteplase in peripheral embolic disease. PMID- 21280471 TI - "Simpson's right ventricle ejection fraction versus tricuspid annular plane systolic excursion in patients with isolated left ventricle anterior myocardial infarction". AB - BACKGROUND: Unlike left ventricular, right ventricular (RV) function has not been widely studied after anterior myocardial infarction. This is because standard 2 dimensional echocardiographic evaluation of RV volumes and ejection fraction is cumbersome due to difficulty in exact delineation of RV endocardial borders because of prominent trabeculations and crescentric shape of the chamber. METHODS AND RESULTS: 50 patients of isolated LV anterior myocardial infarction subdivided into two subgroups--Group-1 with stenosis of Left anterior descending artery (LAD) and Group-2 with stenosis of both LAD and left circumflex artery were studied. Any associated RV infarction was excluded in all patients by ECG, Echocardiography and Right Coronary Angiography .From apical four chamber view of echocardiography, right ventricular ejection fraction (RVEF) was measured by Simpson's method and the systolic motion of the tricuspid annulus (TAPSEx) was recorded with the use of 2 dimensional guided M-Mode tracings both at lateral and the septal side of annulus. There was no significant difference in RVEF between study patients and control subjects. (p > 0.05). However septal TAPSEx was significantly reduced in patients of anterior myocardial infarction as compared to healthy subjects. Reduction was more marked in subgroup-2 patients having stenosis of both LAD and LCx arteries.(p < 0.005). CONCLUSION: Our study results suggests that TAPSEx is simple, quick and better non geometric echocardiographic parameter than RVEF to assess RV functions in patients of anterior infarction. PMID- 21280472 TI - A new marker of carotid atherosclerosis in middle aged adults: cystatin C or microalbuminuria. AB - OBJECTIVE: Cystatin C and microalbuminuria, the new markers of atherosclerosis, have been shown to predict cardiovascular outcome in older individuals. However there is limited data regarding their role in middle aged individuals with preserved renal functions. Hence this study. METHODS: Patients aged 45 to 65 years irrespective of presence or absence of diabetes, hypertension or coronary artery disease were subjected to high resolution B mode ultrasonography for carotid artery intimal-medial complex thickness (IMT). Patients with maximal intimal-medial complex thickness greater than 800 microm at the far wall of the common carotid artery, excluding raised lesions and plaques, were selected for the study. Study participants were subjected to biochemical tests for serum cystatin-C, serum creatinine, glomerular filtration rate (GFR) and for presence of microalbuminuria. The relationship of carotid artery intimal-medial complex thickness with serum cystatin C and microalbuminuria was compared. RESULTS: The mean carotid IMT of the study group was 928 +/- 117 microm. Carotid IMT was significantly associated with advancing age, raised systolic blood pressure, ESR, GFR, LDL cholesterol and microalbuminuria but not with cystatin C. Carotid IMT has significant association with systolic blood pressure but not with diastolic blood pressure. There was a statistically significant difference in ESR across tertiles (p < 0.05). There was a statistically significant difference in GFR across tertiles (p < 0.05) and an inverse relationship was found between GFR and IMT. Carotid IMT was positively and significantly correlated with microalbuminuria but there was no significant correlation of carotid IMT with serum cystatin C. CONCLUSION: Microalbuminuria was found to be associated with carotid atherosclerosis in middle aged individuals. However cystatin C was not associated with carotid atherosclerosis in patients with preserved renal functions. PMID- 21280473 TI - Requirement of pharmacological treatment for primary prevention of cardiovascular disease in asymptomatic office-executives in north-India. AB - BACKGROUND: Recently, a concept of multi-drug treatment of all individuals in the form of a polypill, irrespective of their risk factor profile, has been proposed with a view to provide an effective means for prevention of cardiovascular disease (CVD). While the rationale, benefits and ethicality of such an approach continue to remain a matter ofdebate, it is not known what proportion of asymptomatic adult population does actually require pharmacological therapy for primary prevention of CVD according to the existing guidelines. METHODS: 1927 consecutive office executives, free of any CVD, undergoing routine health check up at a tertiary care centre in North-India during the year 2005 were included in the study. For all subjects, information was collected based on their case records comprising of comprehensive clinical evaluation and the results of biochemical investigations. Requirement of treatment with three anti atherosclerotic drugs- aspirin, statin and an anti-hypertensive agent was estimated as per the current guidelines. RESULTS: Mean age of the subjects was 45.2 +/- 10.3 years and 71.6% were males. Diabetes was present in 14.3%, hypertension in 46.3% and dyslipidemia in 76.0%. Metabolic syndrome was diagnosed in 47.5% subjects. According to the currently accepted guidelines, 47.0% of all the individuals were candidates for at least one of the three aforementioned drugs--22.9% needed only one drug, 17.8% needed only two drugs and 6.3% needed all the three drugs. Requirement of the treatment was much higher in the highest age-tertile (>50 years of age) with 78.0% needing at least one medication, 45.1% needing at least two medications and 12.6% needing all the three drugs (p value < 0.001). Of the different drugs, aspirin was the most commonly required medicine (38.3% of all) and a combination of aspirin and statin was the most commonly required two-drug combination. CONCLUSIONS: The present study shows that, in spite of high prevalence of CV risk factors, a majority of office-executives who are free of CVD do not require multi-drug therapy for primary prevention of CVD as per the current recommendations. Though a greater proportion of the individuals > 50 years of age require drug therapy, even among them, a triple drug combination is warranted only in a small proportion of subjects. When needed, a combination of statin and aspirin is the most commonly required combination. PMID- 21280474 TI - Echocardiographic profile of ART naive human immunodeficiency virus (HIV) infected patients in a tertiary care hospital in Kolkata. AB - AIMS AND OBJECTIVE: Cardiac affection in human iummunodeficiency virus (HIV) infection is a recognized entity. Some form of heart disease is demonstrable at autopsy in approximately 40 percent of cases and by echocardiography in approximately 25 percent of patients with HIV. the studies indicate that cardiac involvements associated with HIV are mainly characterized by cardiomyopathy and pericardial disease. HIV infection is a global pandemic which is also rapidly spreading in india. We conducted the study to have some insight into the profile oflndian patients. MATERIAL & METHODS: In this cross sectional hospital based study, we evaluated immunological (CD4 count) and echocardiographic status of 45 asymptomatic HIV seropositive patients who did not receive anti-retroviral therapy. The results were compared with age and sex matched controls. Statistical analysis was done using appropriate statistical methods. RESULTS: Most common cardiovascular abnormalities were diastolic dysfunction (18%) followed by pericardial effusion (13%) and systolic dysfunction (7%). When compared with controls the study population had statistically higher number of diastolic dysfunction (p value = 0.035) but not systolic dysfunction (p value = 0.61); none of the control population was having pericardial effusion. Low CD4 count was significantly associated with pericardial effusion (p value 0.048) but the association with diastolic dysfunction (p value = 0.46) or systolic dysfunction (p value = 0.84) was not statistically significant. CONCLUSION: Cardiovascular complications are common among HIV infected patients in india, most common being diastolic dysfunction and pericardial effusion. Low CD4 counts are associated significantly with pericardial effusion. These abnormalities are likely to be found with greater frequency in clinical practice as management of opportunistic infections continues to improve. PMID- 21280475 TI - Coronary hardware part 3--balloon angioplasty catheters. PMID- 21280476 TI - Tenecteplase in acute pulmonary embolism. PMID- 21280477 TI - Left-sided biventricular pacemaker implantation in the presence of persistent left superior vena cava. AB - Persistent Left Superior Vena Cava (PLSVC) is the most common thoracic venous anomaly encountered during device implantation. The most common problems related to the unusual anatomic access to the heart are reaching a convenient pacing site and ensuring stable lead placement. This report describes left sided implantation of RA, RV and LV leads in a patient with a PLSVC who was referred for cardiac resynchronizaiton therapy. The literature regarding the interventional approach for device implantation in patients with PLSVC is reviewed. PMID- 21280478 TI - Substrate map based electrical isolation of an apical aneursym--a strategy for ablation in ischemic scar ventricular tachycardia. PMID- 21280479 TI - Unique phenotypes of typical and inverted Takotsubo cardiomyopathy in young females. AB - Takotsubo cardiomyopathy is an acute cardiac syndrome characterized by transient left ventricular regional wall motion abnormalities (with peculiar apical ballooning appearance), chest pain or dyspnea, electrocardiographic changes and minor elevations of cardiac enzyme level in the absence of coronary artery disease. We present 3 cases of a transient cardiomyopathy, noted in young women with associated emotional, physical or pharmacologic triggering events, that are distinct in that they all manifested initially with acute pulmonary edema with systolic akinesis involving different LV segments with rapid recovery. It is a reversible cardiac condition that should be differentiated from ischemic and peripartum cardiomyopathy. PMID- 21280480 TI - An unusual tachy-brady syndrome. Torsades de pointes. PMID- 21280481 TI - "Inverted bulb": A rare complication of myocardial infarction--a new sign! PMID- 21280482 TI - Stent strut fracture after PCI. Damage to stent strut during post stent dilatation (possibly with an oversized ballon). PMID- 21280483 TI - An uncommon presentation of a cardiac pseudoaneurysm. AB - Cardiac pseudoaneurysms are more likely than true aneurysms to rupture causing sudden death. Although pseudoaneurysms are typically managed surgically, medical management is reasonable in certain scenarios. We present the case of a sixty four-year-old gentleman with an unusual initial presentation of left ventricular free wall rupture, which was treated medically. We stress the usefulness of two dimensional echocardiography over ventriculography in diagnosing such lesions. PMID- 21280484 TI - A clinically masked normotensive aortic coarctation. AB - A rare variety of aortic coarctation in which both the left subclavian and aberrant right subclavian arteries arose at the coarcted segment is described. Clinically this case was misleading since pulse volume and the blood pressure in all four limbs were equal and chest radiograph was lacking classical features of coarctation of aorta. Multi slice CT aortogram typically demonstrated the relationship of major aortic arch branches. Later he underwent balloon coarctoplasty and stenting with success. The literature relating to unusual coarctation is reviewed in brief PMID- 21280485 TI - Straddling patent foramen ovale thrombus associated with pulmonary embolism managed with thrombolysis. AB - A straddling patent foramen ovale thrombus protruding into both atria and ventricles is rare. We hereby describe a case of an acutely ill young male with deep Venous Thrombosis and sub massive pulmonary embolism with a large straddling patent foramen ovale thrombus detected on echocardiography and effectively dissolved with chemical lysis. PMID- 21280486 TI - Images in cardiology: dual LAD circulation. a rare coronary anomaly. AB - AIM: We report a case of type IV dual Left anterior descending (LAD) coronary artery detected incidentally in a female who presented with atypical chest pain. METHOD: She underwent coronary angiography which showed dual LAD--one from the LMCA and another from right coronary sinus. RESULTS: Coronary angiography helped in the diagnosis of the rare coronary anomaly. CONCLUSIONS: The identification of anomalous coronary artery is important. PMID- 21280487 TI - Neurosurgery: a culture of excellence. Congress of neurological surgeons. Presidential address, 2009. PMID- 21280488 TI - Defining and achieving excellence in surgical neuro-oncology. PMID- 21280489 TI - Excellence in spinal neurosurgery. PMID- 21280490 TI - Defining excellence in pediatric neurosurgery. PMID- 21280491 TI - Defining excellence in vascular neurosurgery. AB - Success as a vascular neurosurgeon almost always begins with passion, an inherent love for the work that drives an insatiable desire for personal improvement. A personal definition of excellence in vascular neurosurgery includes several fundamental qualities: mastery of the basics, refinement of technique, advancement of technology, investigative study, advanced decision making, microsurgical innovation, a well-rounded surgical armamentarium, and a lifelong commitment to teaching. Ultimately, the reward for these efforts is the ability to influence generations to come, particularly as one follows the rising careers of former trainees, each redefining the term "excellence" in vascular neurosurgery. PMID- 21280492 TI - Defining excellence in evidence-based medicine clinical practice guidelines. PMID- 21280493 TI - Excellence in neurosurgical research: the neuro-oncology paradigm. PMID- 21280494 TI - Neurosurgery education: the pursuit of excellence. AB - The pursuit of excellence in education is a noble endeavor. Such has been the object of education and the goal of educators for eons. Neurosurgery education is no different from other domains in this regard. As with any discipline, this pursuit is complex and obligatorily multifaceted. It involves the use of what is often a broad and deep foundation of experience and knowledge. On this foundation, a modern and evolving infrastructure/suprastructure should be developed and nurtured. Once the infrastructure/suprastructure has taken form, a resident education plan can be derived. This plan, once enacted and executed, should be revisited, revised, and re-executed over and over again. One should never become satisfied with the status quo. A continued search for strategies and tools that achieve improvements over prior renditions of the education plan is mandatory if we hope to perpetually upgrade our process of education. Neurosurgical educators should seek criticism, admit mistakes, and modify educational behaviors accordingly. A strategy for achieving these goals regarding the pursuit of excellence in neurosurgical education is described in the pages that follow. PMID- 21280495 TI - Pursuing excellence in neurosurgical innovation. PMID- 21280496 TI - Pursuing excellence in healthcare delivery: American neurosurgery. AB - The field of healthcare delivery is a large one, and neurosurgical health services research can be said to have only just begun. This chapter briefly addresses 3 components of excellence in health care delivery-quality, access, and cost-from a neurosurgical perspective. PMID- 21280497 TI - Excellence in clinical neurosurgery: practice and judgment make perfect. PMID- 21280498 TI - Neurological Society of India Guest Lecture: optimally invasive skull base surgery. PMID- 21280499 TI - Measuring excellence in neurosurgical competence and certification. PMID- 21280500 TI - Measuring excellence in clinical translation: what are the top works in the field of neurosurgery? PMID- 21280501 TI - Measuring excellence in healthcare delivery: Canada. PMID- 21280502 TI - Excellence in neurosurgery program building: enhancing the academic mission. PMID- 21280503 TI - Working toward rational and evidence-based treatment of chronic subdural hematoma. AB - Chronic subdural hematoma (CSDH) is one of the most common neurosurgical conditions that can usually be treated with relatively simple and effective surgical procedures. It affects primarily the elderly, a rising population worldwide. Together with improved awareness among the medical profession and greater access to modern imaging facilities, the incidence of CSDH is set to rise significantly. Maximization of the efficiency of management of CSDH is therefore a priority. To this end, a review of the findings of clinical and laboratory research underpinning the basis of the modern management of CSDH has been carried out. This review focuses on the pathophysiology and briefly discusses the epidemiology, clinical presentation, and surgical treatments of CSDH, concluding that a one-for-all management strategy is not appropriate. Creating rational bases for the selection of an ideal treatment strategy for an individual patient should be the target. This can be achieved through better understanding of the nature of the condition through systematic basic science research, ascertaining the merits of different surgical techniques in well-designed and rigorously executed clinical trials, using advances in imaging techniques to classify CSDH (a subject not addressed here), and training in and ongoing refinement of clinical acumen and surgical skills of individual surgeons. PMID- 21280504 TI - Mechanisms of evasion to antiangiogenic therapy in glioblastoma. PMID- 21280505 TI - The measurement of pain in patients with trigeminal neuralgia. PMID- 21280506 TI - Biochemical serum markers in head injury: an emphasis on clinical utility. PMID- 21280507 TI - Enhancing competence in graduates through a transition to practice program in neurological surgery. PMID- 21280508 TI - Facilitation of visuomotor associative learning by the basal ganglia. PMID- 21280509 TI - Embryonic stem cell markers distinguishing cancer stem cells from normal human neuronal stem cell populations in malignant glioma patients. PMID- 21280510 TI - Differentiating radiation effect from tumor progression after stereotactic radiosurgery: T1/T2 matching. PMID- 21280511 TI - The prevalence of common mental disorders among inpatient Thai Army Personnel. AB - BACKGROUND: The purpose of the present study was to determine the prevalence of common mental disorders among Thai Army personnel who attended the inpatient psychiatric ward, Department of Psychiatry and Neurology, Phramongkutklao hospital in 2007. MATERIAL AND METHOD: The author retrospectively reviewed and analyzed all inpatient medical records in 2007 of Thai Army Personnel who received treatment at the inpatient psychiatric ward, Department of Psychiatry and Neurology, Phramongkutklao hospital from January 2007 to December 2007. RESULTS: There were 213 Thai Army Personnel medical records recruited in the present study. From the records, 207 were from male patients and 6 were from females. The most common age range was 41-50 years (38.5%). The prevalence of the first ten rank of mental disorders among Thai Army personnel were alcohol dependence (39.9%), schizophrenia (28.6%), bipolar disorder (9.4%), amphetamine dependence (5.2%), adjustment disorder (4.7%), major depressive disorder (3.3%), personality disorder (2.3%), dementia (1.9%), dysthymia (0.9%) schizoaffective disorder (0.9%), delusional disorder (0.9%), anxiety disorder (0.5%) and polysubstance dependence (0.5%). CONCLUSION: The three common prevalence of mental disorders among inpatient psychiatric Thai Army personnel in the year 2007 were alcohol dependence, schizophrenia and bipolar disorder. PMID- 21280512 TI - The treatment outcome of adenocarcinoma of uterine cervix at Phramongkutklao Hospital. AB - OBJECTIVE: To determine the survival rate of patients with adenocarcinoma of the cervix after completing treatment at Phramongkutklao Hospital. MATERIAL AND METHOD: Retrospective review of medical records of 229 patients with adenocarcinoma of the cervix who had completed treatment at Phramongkutklao Hospital between October 1991 to September 2006. RESULTS: Overall 2, 5 and 10 year survival for patients with adenocarcinoma of the cervix was 78.9%, 70.1% and 67.0%, respectively. The 5-year survival rates for stages I, II, III and IV were 94.6%, 76.1%, 49.2% and 0, respectively. Five-year survival of patients with locally advanced adenocarcinoma of the cervix treated with concurrent chemoradiation was comparable to that of patients treated with radiation alone (64.0 vs. 62.4%). Survival of group treated by radiation plus surgery was not significantly different to the group recieved radiation alone. There have been no serious complications from the treatments. CONCLUSION: Survival of patients with adenocarcinoma of the cervix shows a direct correlation with stage. The survival for each treatment modality was comparable. Adjuvant hysterectomy after radiation in adenocarcinoma of the cervix stage IIB and IIIB did not improve long-term survival. PMID- 21280513 TI - Critical value of the clinical laboratory test in Thailand. AB - BACKGROUND: The critical values are the values of laboratory testing results which required attention or action by the physicians. It is an essential component of good laboratory practice and widely used throughout the world. The present study examined the current situation on implementing of critical value list (CVL) of Thai clinical laboratory and what factors were involved in their consideration. MATERIAL AND METHOD: A questionnaire composed of 3 main categories made up of 34 questions was mailed to 450 Thai clinical laboratories. These participated laboratories were randomly selected from both private-and government hospitals. Participated ones were requested to answer the questionnaire and return via mail within two months. Data were analyzed by Chi-square test on Microsoft Excel. RESULTS: The results showed that there were only 48.9% of Thai laboratories implemented the CVL. It was found that there were many factors which governed the implementation of critical values. These factors were significantly different between those who implement the critical values and those did not (p < 0.01). In regard to private- and government-hospital laboratories, implementation of CVL was not significant difference (p > 0.1). However, it was found that assigned persons who responded to notify and act on the critical value was significantly different (p < 0.01). Moreover there were no significant differences on laboratory policy, communication method as well as standard operating procedures on critical values between the private- and government hospital laboratories (p > 0.1). There were only 20.2% of those who implemented the CVL and considered this action as a non-troublesome matter. But, a large group of 95.7% considered this matter as an extra-ordinary tool for quality control of result reporting system. CONCLUSION: Thai laboratories perceived the implementation of critical values list differently. There were some factors beyond their consideration. However utilizing of CVL would be an extra-ordinary tool for assuring test results. PMID- 21280514 TI - Malignant proliferating trichilemmal tumors with CD34 expression. AB - Malignant proliferating trichilemmal tumors (MPTT) are rare neoplasm arising from outer root sheath of hair follicle, the diagnosis of which is base essentially on histological features resulting in occasionally misdiagnosis of squamous cell carcinoma. In difficult cases, however evaluation of additional parameters may be needed to differentiate benign proliferating trichilemmal tumor from MPTT or differentiate PTT and MPTT from squamous cell carcinoma. We report two cases of MPTT on which, in addition to histologic features, we have determined p53 immunohistochemical expression pattern, proliferative fraction, and CD34 expression. For comparison, concurrent proliferating trichilemmal tumors (PTT) and trichilemmal cysts (TC) as well as well-differentiated squamous cell carcinoma (SCC) were studied. The two MPTTs show expression of p53 with increased proliferative index as well as all three SCC. The PTTs and TCs stained negative and few basal cells for p53 and Ki-67, respectively. MPTTs exhibit CD34 immunoreactivity, indicating trichilemmal differentiation. The contrast p53 and Ki-67 expression pattern in MPTT and PTT may be helpful in the diagnosis of MPTT. Expression of CD34 may be an additional feature to distinguish MPTT from SCC. PMID- 21280515 TI - Prevalence of aspirin resistance in stroke patients in Phramongkutklao Hospital. AB - OBJECTIVE: To study the prevalence of aspirin resistance in cerebrovascular disease patients in Phramongutklao hospital. MATERIAL AND METHOD: The acute ischemic and stable stroke patients who received aspirin at least 60 mg, at least 7 days and the last dose of aspirin at least 24 hours before blood test for platelet aggregation. ADP and Collagen were used as platelet aggregator. RESULTS: During July 2007- December 2008, 141 cases of ischemic stroke were enrolled. "Aspirin resistant" was defined as mean aggregation more than 60% both ADP and Collagen. "Aspirin semi-responder" was mean aggregation less than 60% for ADP or Collagen. CONCLUSION: Prevalence of aspirin resistance in Phramonkutklao hospital is 56 % (79/141), and there are relationship between aspirin resistance and timing in the first episode of stroke. PMID- 21280516 TI - The association between risk factors for ischemic stroke and microalbuminuria. AB - OBJECTIVE: To determine the relationship between the risk factors for ischemic stroke and microalbuminuria. MATERIAL AND METHOD: We enrolled 173 patients older than 25 years who had at least two risk factors for stroke. The patients were assessed by questionnaire, blood pressure, microalbuminuria, height and weight measurement. The patients were given health education. RESULTS: The common risk factors were hypertension (80.3%), dyslipidemia (56.6%), and multiple cerebral infarction (39.9%). The hypertensive patients had 5 times risk of microalbuminuria 5.0 compared to normotensive patients (95% CI, 1.13-21.90; p value < 0.05). Among diabetes patients had risk of microalbuminuria 27.1 times compared to non-diabetic patients (95% CI, 9.58-76.82; p-value < 0.01). However, the patients who had dyslipidemia had risk of microalbuminuria 1.784 times of who did not, but no statistically significant (95% CI, 0.79-4.03; p-value > 0.05). CONCLUSION: Diabetes mellitus and hypertension are significantly risk factor of ischemic stroke related to microalbuminuria. PMID- 21280517 TI - Prevalence of poststroke depression in Thai stroke survivors studied in Phramongkutklao Hospital. AB - OBJECTIVE: To study prevalence of depression in poststroke survivors in Phramongkutklao Hospital and factors associated with depression. MATERIAL AND METHOD: From 150 stroke survivors, therefor 101 patients who met inclusion criteria. These subjects were screened with Thai Geriatric Depressive Scale (TGDS) and interviewed. Demographic data that would effect depression were evaluated. RESULTS: During 9 months of studying period, 101 of 150 patients diagnosed with poststroke survivors were eligible. The prevalence of depression was 46.53%. Severity of depression were mild depression 20.79%, moderate 18.81% and severe depression 6.93%. There were no statistically significant among sex, diabetes mellitus, hypertension, smoking, hyperlipidemia, and site of stroke between depression and non-depression groups. Risk factors for severe poststroke depression were younger age, duration within one year after stroke onset and history of coronary artery disease. CONCLUSION: The prevalence of poststroke depression was 46.53%. Risk factors of severe depression were younger age, duration within one year of stroke onset and history of coronary artery disease. PMID- 21280518 TI - High levels of uric acid correlate with decline of glomerular filtration rate in chronic kidney disease. AB - BACKGROUND: Clinical studies have suggested that high levels of uric acid may contribute to the development of hypertension and kidney disease. However the relation between uric acid and chronic kidney disease (CKD) has been inconsistent. OBJECTIVE: To examine the association between plasma concentration of uric acid, and estimated glomerular filtration rate (GFR) in CKD subjects. MATERIAL AND METHOD: In a cross-sectional study, authors surveyed 5,558 subjects, but only 750 CKD subjects in whom GFR was between 15 and 60 ml/min/1.73 m2 were included in the study. The GFR values were calculated by Cockcroft-Gault formula. RESULTS: There were 65.5% males, mean age of 50.29 +/- 6.39 years and body mass index (BMI) of 21.68 +/- 2.64 kg/m2. The mean value of estimated GFR was 53.86 +/ 6.29 ml/min/1.73 m2. In subjects with serum uric acid fourth quartile displayed significantly higher BMI, higher systolic blood pressure (BP), higher diastolic BP, higher BUN, and higher serum creatinine, and lower estimated GFR as compared with the three lower quartiles. The correlation analysis showed that estimated GFR was negatively correlated with serum uric acid (r = -0.208, p < 0.01), age (r = -0.171, p < 0.01), systolic BP (r = -0.148, p < 0.01) and BMI (r = -0.147, p < 0.01). Multiple regression analysis, the presence of high serum uric acid levels were independently associated with a decline of GFR. CONCLUSION: In CKD subjects, high levels of uric acid were independent associated with GFR decline. Our finding suggests that early detection and prevention on hyperuricemia in CKD subjects are critical. PMID- 21280519 TI - Comparison of changes of body water measured by using bioelectrical impedance analysis between lercanidipine and amlodipine therapy in hypertensive outpatients. AB - OBJECTIVE: To compare changes of body water measured by using bioelectrical impedance analysis (BIA), between lercanidipine and amlodipine therapy. MATERIAL AND METHOD: This is a prospective randomized open-label study in hypertensive outpatients. Eighty patients were randomized into two groups; 1) amlodipine 5 mg/d and 2) lercanidipine 10 mg/d. Patients were assessed for changes in total body water (TBW), extracellular water (ECW) and intracellular water (ICW) at week 4 and 8 after treatment. RESULTS: At baseline body water in both groups were similar. After treatment, both groups did not have significant changes in body water from baseline. Seven patients in amlodipine group (17.5%) and none of lercanidipine group developed edema; p = 0.012. Among those seven patients, TBW, ECW and ICW all increased significantly from baseline. CONCLUSION: BIA did not detected changes of body water in most patients. However, in patients who developed edema, TBW, ECW and LCW significantly increased from baseline with the greatest changes seen in extracellular compartment. PMID- 21280520 TI - Orthostatic hypotension: a non-motor complication assessment in 82 patients with idiopathic Parkinson's disease in Phramongkutklao Hospital. AB - OBJECTIVE: Parkinson's disease (PD) is one of the neurogenic etiologies of orthostatic hypotension, a non-motor symptoms complex, that tends to be under recognized and under-treated leading to a major cause of disability for PD patients. This complication is associated with one or recurrent falls causing mortality and morbidity. To the authors' knowledge, there is no study about this condition in Thai PD population. The authors therefore aimed to determine the frequency, clinical and risk factors of orthostatic hypotension in PD patients treated in Phramongkutklao Hospital. MATERIAL AND METHOD: The authors enrolled consecutive patients with idiopathic PD over a 10-month period. Supine and standing blood pressure (BP) were measured sequentially as the standard techniques. Orthostatic hypotension (OH) was diagnosed if there was a reduction in systolic or diastolic BP of at least 20 or 10 mmHg respectively within 3 minutes after standing. The authors analyzed for the frequency of this condition as well as determined the risk factors between the OH and non-OH groups. RESULTS: The number of patients enrolled was 82 with the mean age of 69 years. The median duration of PD was 4 years. Eighty-five percent were in Hoehn & Yahr stage 1-3. Thirty-three patients (40.2%) had orthostatic hypotension and 70% of them were asymptomatic. By univariate and multivariate analysis, the risk factors for this condition were the longer duration of PD diagnosis, the more advanced staging and the use of selegiline. CONCLUSIONS: The frequency of orthostatic hypotension among the present PD was 40.2%. The longer duration of disease, the more advanced stage of Parkinson's disease and selegiline usage were the factors associated with this non-motor condition. PMID- 21280521 TI - Attitude and knowledge of patients with asthma and allergic rhinitis who received allergen immunotherapy in Phramongkutklao Hospital. AB - OBJECTIVE: To determine attitude and knowledge of patients with asthma and allergic rhinitis who received AIT (Allergen Immunotherapy). STUDY DESIGN: A cross-sectional analytical study. MATERIAL AND METHOD: A cross-sectional descriptive study was conducted in the patients with allergic asthma and allergic rhinitis whom were treated with AIT at the Allergy Clinic, Phramongkutklao Hospital between February 1st 2008 to October 31st 2008. Standardized questionnaires were used to collect patients demographic data, attitude and knowledge. RESULTS: A total of 100 patients were enrolled in this study. Sixty six percents of patients expected that AIT would improve their quality of lifes and could prevent their disease recurrence. Fifty three percents of patients expected that their allergic diseases could be cured completely while 22 percents of patients expected that AIT could prevent the occurrence of a new allergic disease. Only 42 percents of patients understood that AIT would improve the conditions after treatment at least 6 months. Twenty two percent of patients knew that AIT was safe and there was no serious side effect. CONCLUSION: Patients treated with AIT had still lack of knowledge about AIT treatment and the potential serious side effect that could occur. PMID- 21280522 TI - Drug hypersensitivity in Phramongkutklao Hospital. AB - OBJECTIVE: To evaluate the prevalence of drug hypersensitivity, clinical manifestations, type of drugs involved, severity, and patients demographic data. STUDY DESIGN: A cross-sectional descriptive study. MATERIAL AND METHOD: The study was performed from January 1st, 2008 to December 31th, 2008 at Phramongkutklao Hospital. Data were collected from Pharmaceutical Department, Dermatology Unit, Department of Medicine including adverse events reported by pharmacists. All records of in-patients and out-patients including gender, age, causative drugs, type of drug hypersensitivity and severity of hypersensitivity were collected. RESULTS: A total of 140 patients who had drug hypersensitivity were recorded. The most common drug hypersensitivity was due to antimicrobial agents which penicillin group was the most frequently involved. Of 61 patients (43.57%), 27 (19.28%) received anti-inflammatory and muscle relaxant drugs and 18 (12.85%) had drugs acting on the central nervous system. The most common manifestration of drug allergy was maculopapular rash (34.99%), followed by nonspecific erythrematous rash (16.42%), fixed drug eruption (9.28%) and Stevens-Johnson syndrome (8.57%), respectively. Majority (80.71%) of drug hypersensitivity was mild in severity. Moderate, severe and lethal hypersensitivity accounted for 8.51%, 10.0%, 0.71% respectively. Female were 51.77% while 48.22% were male. The mean age was 47.0 years (ranged from 8-100 years). There were 57 (40.71%) patients over 50 years of age and 103 (73.57%) patients had taken more than one medication. CONCLUSION: Antimicrobial agents were the common cause while maculopapular rash was the most frequent clinical manifestation of drug hypersensitivity. PMID- 21280523 TI - Positive expiratory pressure to enhance cough effectiveness in tracheomalacia. AB - OBJECTIVE: To determine the effectiveness of increasing levels of Positive Expiratory Pressure (PEP) during coughing to enhance expiratory flow and improve efficiency of the cough. MATERIAL AND METHOD: Forty children aged 8 to 18 years, with repaired tracheo-oespohageal fistula (TOF) and twenty-one age matched controls performed spirometry followed by cough spirometry with PEP of 0, 5, 10, 15 and 20 cmH2O using an adjustable PEP valve. Cough expiratory flow between 75 and 25% of vital capacity (CEF25-75) for each curve was calculated to represent the effectiveness of cough at mid-lung volume, the region of the flow volume curve most vulnerable in tracheomalacia. RESULTS: In the TOF group, CEF25-75 increased by a mean (95% CI) of 18.8% (4.4, 33.2), 1.7% (-2.6, 26.0) and 0.5% ( 13.7, 14.7) at PEP of 5, 10 and 15 cmH2O respectively, but decreased by 2.4% ( 13.4, 8.5) at PEP of 20 cmH2O. In the control group the CEF25-75 decreased. The values were -3.1% (-16.7, 10.4), -6.3%(-18.1, 5.6), -22.2% (-33, -11.5) and -19% (-29.3, -8.7) at PEP of 5, 10, 15 and 20cmH2O respectively. CONCLUSION: The use of a simple adjustable PEP valve increases CEF25-75 during cough spirometry and may provide a useful adjunct to chest physiotherapy in children with tracheomalacia. PMID- 21280524 TI - Assessment of the association between Blastocystis infection and irritable bowel syndrome. AB - OBJECTIVE: To assess the association between Blastocystis infection and irritable bowel syndrome (IBS) in Thai patients, Phramongkutklao Hospital. MATERIAL AND METHOD: A case-control study was conducted at Phramongkutklao Hospital, Bangkok, Thailand during 2007-2008. A total of 126 subjects were enrolled into the study. Sixty-six persons were enrolled in the IBS group and 60 persons were enrolled in the control group. Intestinal parasitic infections were determined using wet preparation and formalin-ethyl acetate concentration. Short-term in vitro culture was performed to detect Blastocystis sp. Additionally, stool specimens were cultured for pathogenic bacteria. Patients' history and physical examination were also recorded. RESULTS: Of 66 IBS patients, 61 (92.4%) had abdominal pain, 50 (78.1%) had diarrhea, and 14 (21.9%) had constipation. In vitro cultivation revealed that 10.0% and 16.7% were positive for Blastocystis sp. in the control and IBS group, respectively. There was no significant difference of the prevalence of Blastocystis infection between these 2 groups (p = 0.203). CONCLUSION: Blastocystis infection was a common parasitic infection which was predominant in both IBS and control group. The presence of Blastocystis sp. in stool did not imply gastrointestinal symptoms in the IBS patients. Further study of subtype characterization of Blastocystis sp. in a larger sample size of the case-control study might reveal a possible relationship between Blastocystis sp. and IBS patients. PMID- 21280525 TI - Health-related quality of life and disease severity of SLE patients in Phramongkutklao Hospital. AB - BACKGROUND: The studies of association of disease activity and damage with health related quality of life (HRQOL) in lupus have shown equivocal results and has not been studied in Thailand. OBJECTIVE: To examine the HRQOL and to examine the association between HRQOL and SLE disease severity (disease activity and damage) in Thai SLE patients. MATERIAL AND METHOD: The Short Form-36 (SF-36) was applied in 95 consecutive SLE patients. At the time of HRQOL assessment, all patients were evaluated for disease severity [disease activity as measured by Mexican Systemic Lupus Erythematosus Disease Activity Index (Mex-SLEDAI) and damage as measured by the Systemic Lupus International Collaborating Clinic/American College of Rheumatology (SLICC/ACR) damage index (SDI)]. The association between physical (PCS) and mental component summary (MCS) of the SF-36 and disease severity were examined by Pearson's correlation. RESULTS: Ninety-five SLE patients (93 females and 2 males) were included (mean age 39.84 +/- 10.91). The mean disease duration was 115 +/- 83 months. The mean scores of MCS and PCS were 45.5 +/- 9.5 and 41.1 +/- 9.3, respectively. The higher SDI scores were correlated with lower PCS but not the MCS (PCS, r = -0.411, p < 0.001). There was no correlation between HRQOL (both MCS and PCS) and disease activity. CONCLUSION: PCS of the SF-36 was inversely correlated with damage index in Thai SLE patients. PMID- 21280526 TI - Successful strategy to improve glucose tolerance in Thai obese youth. AB - BACKGROUND: Childhood obesity is an emerging national health problem in Thailand. Our previous study found that one third of obese children and adolescents had impaired glucose tolerance (IGT) and 2.6 percent had already developed type 2 diabetes mellitus. An immediate strategy needs to be established in order to improve these metabolic problems. OBJECTIVE: To determine whether diet and exercise education for lifestyle modification with or without metformin therapy in our diabetes clinic is enable to improve these metabolic problems. MATERIAL AND METHOD: Twenty-six Thai obese children and adolescents with IGT, who received at least 6 months of treatment consisting of lifestyle modification alone or lifestyle modification and metformin (combined treatment) were enrolled into this study. Each patient underwent the second 2-hour oral glucose tolerance test (OGTT). Plasma glucose, insulin levels, HbA1C and lipid profiles were measured. The results were compared with historical pre-treatment data. RESULTS: Approximately 1 year after intervention, 19 out of 26 patients with IGT completed the second 2-hour OGTT. Sixteen patients (84.2%) successfully reversed to be normal glucose tolerance whereas 3 patients (15.8%) remained IGT. Body mass index (BMI), BMISDS, 2-hour plasma glucose, basal insulin level, 2-hour insulin level were significantly decreased after treatment in normal OGTT group (Ps < 0.05). Treatment with lifestyle modification alone and combined treatment indifferently improved the abnormal glucose tolerance in our patient (83.3% vs. 84.6%). CONCLUSION: Impaired glucose tolerance in obese youth is a reversible abnormality by lifestyle modification with or without metformin. PMID- 21280527 TI - The efficacy and safety of transradial approach in comparison with transfemoral approach for coronary angiography and ad hoc coronary angioplasty in Thailand. AB - OBJECTIVE: To assess the efficacy and safety of transradial approach compared with transfemoral approach for coronary angiography and ad hoc angioplasty in Phramongkutklao hospital at the time of initiation of transradial program. MATERIAL AND METHOD: Prospective data collection of consecutive patients who underwent coronary angiography with ad hoc angioplasty during October 2004 to January 2005 was conducted. Baseline demographic data and the details of the procedure were recorded. The complications were assessed by a single doctor using standard protocol. RESULTS: There were 75 included in our study. Transradial approach and transfemoral approach was performed in 23 cases (30.7%) and 52 cases (69.3%), respectively. The baseline characteristics, procedure results were similar except the there was higher prevalence of NST-ACS symptoms (92.31% vs. 65.22%, p = 0.004) and access site complications in transfemoral group (23.08% vs. 4.35%, p = 0.035). The success rate was very high (> 90%) and not significantly different in both groups. However the transradial group was associated with lower assess site complications earlier ambulation and better patient's satisfaction. CONCLUSION: Even at the time of initiation of transradial program, transradial approach for coronary angiography and ad hoc angioplasty can be performed with similar efficacy, less local complication, earlier ambulation and better patient's satisfaction compared to the standard transfemoral approach. PMID- 21280528 TI - Effect of curcumin in the amelioration of pancreatic islets in streptozotocin induced diabetic mice. AB - OBJECTIVE: To evaluate the antidiabetic effect of curcumin and its potential in amelioration of pancreatic islets against damage under diabetic condition. MATERIAL AND METHOD: Diabetic mice were induced by injection of STZ (60 mg/kg body weight). Male mice were divided into 3 groups: group I was normal mice, group II was diabetic mice and group III diabetic mice were treated with curcumin (200 mg/kg body weight). The blood glucose levels and body weights were recorded every two weeks. After 4 weeks, 8 weeks and 12 weeks, the animals in each group were sacrificed. Histopathology of pancreatic tissues, pancreatic islets areas and numbers were observed under light microscope. RESULTS: The weight loss and the elevation of blood glucose levels were observed in diabetic mice and diabetic mice treated with curcumin at 4 weeks, 8 weeks and 12 weeks. The reduction of pancreatic islets areas and numbers were presented in diabetic mice and diabetic mice fed with curcumin at 4 weeks. At 8 weeks of diabetic mice, the numbers of pancreatic islets were decreased however the pancreatic islets hyperplasia was prominently investigated, whereas the noticeable increase in numbers of small pancreatic islets were observed in diabetic mice fed with curcumin. Histopathological observation at 12 weeks revealed the accumulation of lymphocytes in the shrunken pancreatic islets of diabetic mice, while an absent lymphocytes infiltration in the pancreatic islets and the increase in numbers of small islets of Langerhans appeared nearly the ducts in the pancreas of diabetic mice treated with curcumin at 12 weeks. CONCLUSION: Curcumin treatment at 12 week can exert beneficial effect in diabetes mellitus, regarding the improvement of pancreatic islets. The islets of Langerhans neogenesis is characterize by the presentation of small islets increase in numbers nearly the ducts and no insulitis. PMID- 21280529 TI - Effect of temperature on cyclodextrin production and characterization of paracetamol/cyclodextrin complexes. AB - OBJECTIVE: To compare the effect of different reaction temperatures on the cyclization and coupling reactions of the Toruzyme CGTase influencing the yield of cyclodextrins (CDs) and to study the solubility of paracetamol with CDs. MATERIAL AND METHOD: Type and amount of CDs were analyzed by HPAEC-PAD. The stability constants for the inclusion complex formed between CDs and paracetamol were determined using the phase solubility method. The solubility of paracetamol with CDs was measured by UV-spectrophotometer at 240 nm. RESULTS: The result has shown that the reaction temperature has effect on the Toruzyme CGTase reactions in production of CDs. The CDs yield after 30 min of incubation was higher at 60 degrees C than at 80 degrees C. The catalytic efficiency (k(cat)/K(m)) of this enzyme indicated the higher value of the cyclization reaction at 60 degrees C compared to 80 degrees C while the opposite was found for the coupling reaction. Paracetamol is used as an analgesic and antipyretic but it is poorly water soluble drug. To improve the solubility of paracetamol CDs obtained were used to study for paracetamol/CDs complexes. The phase-solubility diagrams of paracetamol with alpha-, beta- and gamma-CD were A(N) type while that of paracetamol with maltosyl-beta-CD (G2-beta-CD) complex was A(L) type. The stability constants (K(c)) for the inclusion complex of paracetamol with alpha-, beta-, gamma-CD and G2-beta-CD were 5.69, 16.75, 4.73 and 2,223.25 M(-1), respectively. CONCLUSION: The optimum temperature for CDs production was at 60 degrees C and the low solubility of paracetamol was significantly improved by complexation with CDs, where the enhancing effect was in the order of G2-beta-CD > beta-CD > alpha-CD > gamma-CD. PMID- 21280530 TI - Apolipoprotein B level in patients with type 2 diabetes who achieved goal of low density lipoprotein cholesterol and non-high density lipoprotein cholesterol. AB - OBJECTIVE: To demonstrate an apolipoprotein B (apo B) level in type 2 diabetic patients who achieved goal of low density lipoprotein cholesterol (LDL-c) and non high density lipoprotein cholesterol (non-HDL-c). To identify the percentage of type 2 diabetes patients who achieved goal of apo B level. MATERIAL AND METHOD: A cross-sectional study was carried out from 1 October to 31 December 2008. Type2 diabetes patients who attended at diabetes clinics in the Phramongkutklao hospitals have determined the risk for develop cardiovascular diseases (CVD) and set up the goal for lipid level according to consensus statement from the American Diabetes Association (ADA) and the American College of Cardiology (ACC) foundation. Blood test for apo B will be done only the patients who achieved goal of LDL-c and non-HDL-c. RESULTS: 133 of the 162 registered diabetic patients can achieve goal of lipid level In this population, 9.7 percent (%) (n = 13) had a history of CVD. ApoB level in diabetic patients with and without CVD is 61.72 +/- 12.63 and 67.2 +/- 12.92 milligram per deciliter (mg/dL), respectively. Nearly ninety-eight percent of patients without cardiovascular diseases (CVD) have achieved apo B (< 90 mg/dL) goal, and 92.3% of patients with CVD have achieved apo B (< 80 mg/dL) goal. The two most commonly used lipid-lowering agents were statins and fibrates. CONCLUSION: In patients with type 2 diabetes who achieved goal of LDL-c and non-HDL-c have also achieved apo B level. Thus, apo B measurement in addition to reached LDL-c and non-HDL-c targets may be not necessary especially in diabetic patients who did not previous CVD. PMID- 21280531 TI - The study of medical students' attitudes toward exercise for health promotion in Phramongkutklao College of Medicine. AB - BACKGROUND: Phramongkutklao College of Medicine is a military medical school and also a health promotion school. As a result, encouraging these medical students to have good attitude toward exercise is considered an important mission for the college. OBJECTIVES: To study the attitudes of medical students at Phramongkutklao College of Medicine about exercise for health promotion. MATERIAL AND METHOD: This survey research was carried out in 382 medical students in Academic Year 2008 using questionnaires including personal information, attitude testing and open-ended questions. Statistical analysis was conducted using descriptive analysis: percentage and mean and comparative analysis: t-test and F test. RESULTS: The overall attitudes of medical students toward exercise were good. The attitudes of the medical cadets were better than those of the civilian medical students. The attitudes and also knowledge about exercise of the higher year students were generally better than those of the lower-year ones. The attitudes of healthy medical students were higher than those of unhealthy ones. No significant difference in attitude was found between male and female students and between those with different Body Mass Indexes (BMI) and those with different in exercise duration and frequency. CONCLUSION: The overall medical students' attitudes toward exercise for health promotion in Phramongkutklao College of Medicine were good. The influencial factors were found to be status of medical students, stage of medical study and health status. PMID- 21280532 TI - Prevalence of significant weight loss and hypernatremia in breast feeding jaundice infants readmitted to Phramongkutklao Hospital within 1 month of age. AB - BACKGROUND: Neonatal jaundice, especially breast feeding jaundice is the most common cause of neonatal re-admission within the first month of life. Good maternal support and closed follow-up of newborn infants can promote successful breast feeding without causing any complications. OBJECTIVE: To determine the rate of significant weight loss and hypernatremia in infants with breast feeding jaundice readmitted to Phramongkutklao Hospital within 1 month of age. MATERIAL AND METHOD: Cross-sectional descriptive study was conducted in infants of gestational age > or = 35 weeks and birth weight > or = 2,000 grams who had breast feeding jaundice readmitted between January, 1st and December 31st, 2008. Maternal and neonatal history, laboratory result, complications and treatment were reviewed. STATISTICAL ANALYSIS: Rates of significant weight loss and hypernatremia were calculated. The associations between weight loss and factors, serum sodium, serum bilirubin and weight loss were analyzed using Chi-square and Mann-Whitney U test. RESULTS: There were 30 infants in the study. 12 (40%) were male. The median gestational age and birth weight were 37 (35-40) weeks and 2,945 (2,100-3,810) grams, respectively. Three infants had significant weight loss more than 10% of birth weights. No infant had hyperbilirubinemia. Severity of weight loss was associated with weight loss at the time before discharge from hospital. Weight loss was not associated with gestational age, sex, parity, cesarean section, exclusive breast feeding, serum sodium level, and serum bilirubin level. CONCLUSION: Complications of dehydration such as hypernatremia was not observed in infants with breast feeding jaundice in this study. Maternal education, serial weight measurements and awareness of breast-feeding jaundice problems are helpful strategies to promote successful breast feeding. PMID- 21280533 TI - Improved near vision with ready-made spectacles for presbyope in Chachoengsao province. AB - The Objective of the present research was to study the improvement of near vision with ready-made spectacles for presbyope in Chachoengsao province. Retrospective cross-sectional analytic study was conducted in 309 volunteers at Sanamchaiket district whose ages were 35 years and above. Visual acuity was measured in presbyopic patients, and then ready-made spectacles were given as a trial. Visual acuity of near distance was measured at the time before and after correction with ready-made spectacles. Aim was to achieve the visual acuity of 20/50 or better. The number of volunteers was 129. Out of these, 96.12 percent (124 of 129) achieved the aim of the visual acuity (124 of 129). In conclusion, ready-made spectacles were effective in correcting near vision for presbyope at any group of ages and both sexes in Chachoeungsao province. If the difference of refractive error between both eyes was greater than +1.25 Diopter ready-made spectacles were ineffective. PMID- 21280534 TI - Probing and syringing with 3% solution of NaCl and/or 0.2 mg/ml mitomycin-C in nasolacrimal duct obstruction patients. AB - OBJECTIVE: To compare the efficacy of lacrimal probing and syringing among 3% solution of Sodium Chloride and/or 0.2 mg/ ml Mitomycin-C as an adjunctive medication. DESIGN: A prospective, randomized, 2 by 2 factorial design study. MATERIAL AND METHOD: Forty-eight of nasolacrimal duct obstruction patients with epiphora symptom were randomly assigned to receive either Normal Saline Solution or 3% solution of Sodium Chloride or 0.2 mg/ml Mitomycin-C solution or combined 3% solution of Sodium Chloride with 0.2 mg/ml Mitomycin-C solution, during office probing and syringing. The intervention was performed repeatedly at week 0, weeks 2 and 4. An assessment of epiphora with Visual Analogue Scale were evaluated at week 0, weeks 2, 4, 8 and 12. RESULTS: Probing and syringing was successfully reducing epiphora symptom. Mitomycin-C group showed a significant reduction in mean difference of Visual Analogue Scale score compared with Normal Saline Solution group (2.85, 95% CI: 1.164-4.536, p < 0.001) and 3% Sodium Chloride group (2.175, 95% CI: 0.489-3.861, p < 0.01). No complication or adverse event was found. CONCLUSION: 0.2 mg/ml Mitomycin-C solution of was the most effective medication for office probing and syringing in reducing epiphora symptom in nasolacrimal duct obstruction patients. PMID- 21280535 TI - A smart model for clinical laboratory personnel development. AB - BACKGROUND: To become a quality clinical laboratory, personnel development is the most important factor. In order to achieve this goal, it should emphasize that clinical laboratory is not only a testing laboratory; it must be a knowledge based service laboratory. A smart model for clinical laboratory personnel development under the Human Asset Development (HAD) program had been launched since 2003. OBJECTIVE: To strengthen the competency of clinical laboratory personnel, an appropriate model was developed and apply to the clinical laboratory personnel. MATERIAL AND METHOD: Medical technologist who currently worked in clinical laboratory participated in this study. The proposed model consisted of 3 phases. 1) The knowledge providing via update and refresher courses. 2) Application of learned knowledge to practice under close supervision. 3) Training on special topic and self oriented research activity. RESULTS: The outcome of 5 years project was evaluated. After the first phase, they were able to identify and solve their own troublesome under ours close supervision. There were 25 projects presented within 3 years. The last phase, they were very constructive. Nine projects of self created had been presented. Those projects contained clear objectives and were able to implement. CONCLUSION: The smart model for clinical laboratory personnel development leaded to many self created projects in a few years. Thus, this implies its important role in human resource development that should be continued. The keys index of success were ours strong intention, with providing motivation and periodically encouragement to the participants, and keep going on consistently. PMID- 21280536 TI - A case report of limited Wegener's granulomatosis presenting with a chronic scalp ulcer. AB - Wegener's granulomatosis (WG) is manifested by granulomatous necrotizing inflammatory lesions involving multiple organs. Limited WG is classification of WG with the absence of disease features that pose immediate threats to either a critical individual organ or to the patient's life. The most common skin lesions are palpable purpura, necrotic ulcerations, papules and nodules with many histological pattern, leukocytoclastic vasculitis, granulomatous vasculitis, and palisading granulomas. We report a patient with a limited form of WG who presented with a chronic large scalp ulcer that rapidly responded to an immunosuppressive therapy. PMID- 21280537 TI - Recurrent skull metastasis of hepatocellular carcinoma at 2 month post operation. AB - Several cases with skull metastases hepatocellular carcinoma have so far been reported in the English literature. However, recurrent skull metastasis hepatocellular carcinoma at 2 month post operation after craniectomy and total tumor removal has never been published. We reported a 57-year-old Thai female presented with a recurrent enlarging painless left parieto-occipital skull mass after 2 month post operation which confirmed by Cranial computerized tomography (CT). This case showed that the skull metastases of hepatocellular carcinoma can rapidly recur although closely monitored by clinical evaluation, laboratory and radiological finding had been done. PMID- 21280538 TI - Generalized morphea: a case report. AB - Generalized morphea is a subtype of localized scleroderma that lacks systemic manifestations. It is a rare condition in which idiopathic sclerosis of the skin occurs in a widespread manner. We report a 37-year old Thai female who presented with multiple hypopigmented lesions on right leg and right arm with a skin biopsy showing the typical sclerotic change. The patient responded to treatment with topical calcipotriol. PMID- 21280539 TI - Kleine-Levin syndrome: the first typical case in Thailand. AB - Kleine-Levin syndrome (KLS) is a rare disorder characterized by periodic hypersomnia, cognitive and behavioral disturbances. Other unique symptoms in KLS are megaphagia, hypersexuality and some psychiatric disturbances such as compulsion and depression. Definite diagnosis requires the elimination of other potential etiologies. We reported a typical case of KLS in a young Thai man who suffered from seven episodes of periodic hypersomnia within 1.5 years and eventually he was diagnosed with Kleine-Levin syndrome after excluding known possible neurological conditions and sleep disorders. PMID- 21280540 TI - Late manifestation of congenital cystic adenomatoid malformation with lung abscess: a case report. AB - Congenital cystic adenomatoid malformation (CCAM) is a rare congenital cystic abnormality of the lung. Most of cases are usually diagnosed and managed in the newborn period even though some are asymptomatic and present in childhood or adult. The authors report a 7-year-old girl who presented with chronic cough, hemoptysis and clubbing of fingers. Physical examination revealed decreased breath sound and dullness on percussion at right upper chest. A chest radiograph showed a large thin-walled cyst with air fluid and a small thin-walled cyst occupied the whole right upper lobe. Computed tomography (CT) of the chest showed two large thin-walled cavities with air fluid level in the right upper lobe with few small cavities nearby. She was given antibiotics and cardiovascular and thoracic surgeon was consulted. The patient underwent right upper lobectomy. Microscopic examination was compatible with CCAM type 1. The post operative course was uneventful and the recovery was complete. She continued to be healthy at a follow-up visit about 8 months postoperatively but chest radiograph showed soft tissue density at right upper lung field. Chest CT findings were compatible with recurrent CCAM. A follow-up chest radiograph at 13 months postoperatively showed significant reduction in size of the lesion. PMID- 21280541 TI - Review on pathophysiology and treatment of diabetic kidney disease. AB - Diabetes is the leading cause of chronic kidney disease, which in the Thailand is the most common cause of end stage renal disease (ESRD) requiring dialysis. Patients with diabetic kidney disease (DKD) are at a higher risk of mortality, mostly from cardiovascular complications, than other patients with diabetes. The development of DKD is determined by environmental and genetic factors. This review focuses on the latest published data dealing with mechanisms and treatment of DKD. DKD has several distinct phases of development of the disease and hyperglycemia-induced metabolic and hemodynamic pathways are recognized to be mediators of kidney disease. Multiple biochemical pathways have been postulated that explain how hyperglycemia causes tissue damage: nonenzymatic glycosylation that generates advanced glycosylation end products, activation of protein kinase C, and acceleration of the polyol pathway. Oxidative stress also seems to be a theme common pathway. These derangements, along with hemodynamic changes, activate various cytokines and growth factors such as vascular endothelial growth factor, transforming growth factor-beta2 Interleukin 1 (IL 1), IL-6 and IL-18. Current renoprotective treatments for DKD include optimization of glycemic, blood pressure, lipid and weight control blockade of the renin-angiotensin system, salt and protein restriction. Multiple intensive interventions reduce cardiovascular events as well as nephropathy by about half when compared with a conventional multifactorial treatment. PMID- 21280542 TI - Roles of meditation on alleviation of oxidative stress and improvement of antioxidant system. AB - According to MEDLINE/Pubmed search to December 2009, the modulation effects of meditation on oxidative stress have been increasingly investigated for acute, short and long-term effects. Both invasive and noninvasive measurements have been utilized. Long-term transcendental and Zen meditators have been showed to diminish oxidative stress seen by a reduction of lipid peroxidation and biophoton emission. Glutathione level and activity of antioxidant enzymes (catalase, superoxide dismutase, glutathione peroxidase and glutathione reductase) have been facilitated in Yoga and Sudarshan Kriya practitioners. One year of Tai Chi training has been reported to promote superoxide dismutase activity and lessen lipid peroxidation. Performing diaphragmatic breathing after exhaustive exercise has attenuated oxidative stress faster than control. These data suggest possible roles of meditation and meditation-based techniques on the decrease of oxidative stress which may assist to prevent and/or alleviate deterioration of related diseases. However, further research needs to elucidate the cellular and molecular mechanisms which remain challenge to accomplish. PMID- 21280543 TI - The dilemma of transfer cases. PMID- 21280544 TI - Miniscrew-supported Class III treatment with the Hybrid RPE Advancer. PMID- 21280545 TI - The space-closure alternative for missing maxillary lateral incisors: an update. PMID- 21280546 TI - Multi-purpose attachment for direct-bonded lingual retainers. PMID- 21280547 TI - Precise insertion of the Forsus fatigue resistant device. PMID- 21280548 TI - Interdisciplinary treatment of a patient with amelogenesis imperfecta. PMID- 21280549 TI - The readers' corner. PMID- 21280550 TI - Swelling of vallate papillae of the tongue following arsenic exposure. AB - This cross-sectional study was carried out in some selected arsenic contaminated rural areas of Bangladesh to determine any clinical changes in oral cavity, among the arsenic exposed population through drinking water. Total 600 respondents (200 arsenicosis patients, 200 non-patients but having the history of taking arsenic contaminated water and another 200 arsenic non-exposed). 75.5% of arsenicosis patients had swelled vallate papillae whereas only 44.5% and 8.5% in case of arsenic exposure and non-exposure subjects respectively. The differences were found statistically significant (p < 0.001). This study suggests that there is a tendency of developing swelled vallate papillae among the arsenic exposed population. PMID- 21280551 TI - Cardiac troponins and oxidative stress markers in non-pregnant, pregnant and preeclampsia women. AB - Free radicals play an important role in the pathogenesis of tissue damage in many clinical disorders, including atherosclerosis. This study was to investigate lipids and oxidative stress markers among women with 50 healthy non-pregnant compare with 50 healthy pregnant and 50 pregnancy-induced hypertensive subjects and correlate with cardiac troponin I (cTnI) and troponin T (cTnT). The level of plasma thiobarbituric acid reactive substances (TBARS), cTnI and cTnT levels significantly increase in pregnancy-induced hypertension compare with other groups. The level of lipids significantly altered in pregnancy-induced hypertension. Conversely, the activities of both enzymatic and non-enzymatic antioxidants were significantly decreased in pregnancy-induced hypertension compared to nonpregnant and healthy pregnant. Our data suggest that there is an imbalance between lipoperoxidation and antioxidants levels during pregnancy and preeclampsia. Serum cTnI and cTnT are elevated in women with pregnancy-induced hypertension indicating some degree of cardiac myofibrillar damage and cardiac dysfunction. PMID- 21280552 TI - Prevalence of anticardiolipin antibody in Bangladeshi patients with recurrent pregnancy loss. AB - The objective of the present study was to see the prevalence of anticardiolipin antibody (ACA) in Bangladeshi patients (35) with recurrent pregnancy loss. Thirty seven women with normal pregnancy were included as control. Serum levels (mean +/ SD) of ACA (u/mL) was significantly higher, whereas ANA (Ab-index) and anti dsDNA (Ab-index) were similar in cases compared to controls (Cases vs Controls - > ACA: 31.8 +/- 24.3 vs 10.5 +/- 3.4, p < 0.001; ANA: 1.07 +/- 0.34 vs 0.92 +/- 0.15, p > 0.5; A-dsDNA: 0.53 +/- 0.16 vs 0.52 +/- 0.18, p > 0.5). The cases positive for ACA, ANA and anti-dsDNA were 37.1% (p < 0.001), 20% (p > 0.05) and 2.8% (p > 0.1) respectively. Among the seropositive cases 4/35 (11.4%) and 4/13 (30.8%) were positive for both ACA and ANA. In controls only 2/37 (5.4%) and 2/37 (5.4%) were positive for ACA and ANA respectively and none were positive for both ACA and ANA together simultaneously. Significantly high proportion of cases had O positive blood group (23/35: 65.7%, 10/13: 76.9%) (p < 0.01). The prevalence of ACA varies according to population being 37.1% (13/35) in our patients with recurrent pregnancy loss and 5.4% in controls. PMID- 21280553 TI - Comparative study of hydrochlorothiazide and indapamide on the anti-atherogenic potential of losartan in cholesterol fed rat. AB - The study was conducted to evaluate the anti-atherogenic potential of losartan and to assess the effects of hydrochlorothiazide and indapamide on losartan activity in rat. Cholesterol diet (0.5%) for 12 weeks led to significant hyperlipidemia, increased body weight and oxidative stress in erythrocyte. While, losartan, hydrochlorothiazide and indapamide treatment continued for next 12 weeks, losartan showed anti-atherogenic activity reflected by hypolipidemic effect and antioxidant effect in erythrocyte. This activity was abolished by addition of hydrochlorothiazide with losartan but remained unaltered by addition of indapamide with losartan. Atherosclerotic change and oxidative stress were not found in rat aorta, which may be due to short duration and low dose of cholesterol feeding. Hydrochlorothiazide treatment was associated with hypokalemia, which was not present in losartan or indapamide treatment. This study suggests that indapamide might be co-administered with losartan conserving the essential anti-atherogenic potential of losartan. PMID- 21280554 TI - Effects of isometric quadriceps muscle strengthening exercise on chronic osteoarthritis of the knee. AB - A total of 64 patients of osteoarthritis of the knee joints were studied to observe the effects of isometric quadriceps muscle strengthening exercise plus non-steroidal anti-inflammatory drugs (NSAIDs) on osteoarthritis of knee joints. Another 75 patients were treated with NSAIDs as control. They were assessed by visual analogue scale, OMAC scale and range of motion of the knee joints and followed-up weekly for six weeks. Improvement was found in both groups (p = 0.001) after treatment. In comparison, more improvement was found in the exercise group after four weeks (p = 009). Then improvement was gradually increased day by day and finally there was highly significant improvement (p = 0.001). This study suggests that isometric quadriceps muscle strengthening exercise has its beneficial role to reduce symptoms in osteoarthritis knee. PMID- 21280555 TI - Assessment of low ABSPI among arsenic exposed and non-exposed populations: a pilot study. AB - This cross-sectional study was carried out to assess and compare Ankle Brachial Systolic Pressure Index (ABSPI) amongst 120 arsenic exposed and 120 non-exposed populations of Samta village in Bangladesh. Abnormal ABSPI was more prevalent in arsenic exposed (13.3%) than in non-exposed (2.5%) group. The prevalence of abnormal ABSPI for respondents when adjusted for age, sex, BMI, blood pressure status and diabetic status, the prevalence remain significantly different. The findings suggest that those exposed to arsenic have increased chance of having abnormal ABSP and hence increased chance of peripheral arterial disease in Bangladesh. PMID- 21280556 TI - Diagnostic value of fingerprint patterns: an explorative study on beta thalassemia diagnosis. AB - Rapid diagnosis of major beta thalassemia along with certain preventive measures is of utmost significance. The present study aims to compare the fingerprints in Major beta thalassemic patients (67) and in their parents (76 with minor thalassemia) with the normal fingerprints of control group (144). A forensic medical examiner determined fingerprint types of arch, loop, whorl and other types. Like normal individuals, loop fingerprint pattern was found to be the most common fingerprint type among thalassemic patients. However, the number of whorl fingerprints in all fingers in thalassemic patients was greater than that of normal individuals and the number of loop fingerprints was smaller (p < 0.05). Arch type fingerprint pattern was less frequent in major thalassemic patients compared to minor thalassemic ones (p < 0.05). The findings show that the number of whorl fingerprint patterns in thalassemic patients was greater than that of normal individuals, while the number of loop fingerprint patterns being smaller and the frequency of arch fingerprint pattern in patients with major thalassemia was lower than that of minor thalassemic patients. Therefore, one may choose fingerprint pattern as a simple, affordable and appropriate screening method to help detect the afflicted patients and prevent severe cases of thalassemia. PMID- 21280557 TI - Diarrhea in Bangladeshi infants and its association with postnatal depression. PMID- 21280558 TI - Ascitic fluid lipid profile and albumin level. PMID- 21280559 TI - Comparative study of efficacy of brush cytology and transthoracic fine needle aspiration cytology in the diagnosis of bronchogenic carcinoma. PMID- 21280560 TI - Angiographic profile in patients with congenital anomalous origin of the coronary arteries. PMID- 21280561 TI - Seroprevalence of HBs antibody among the newly admitted medical students in Bangladesh and seroconversion one year after vaccination. PMID- 21280562 TI - Adaptation of microsomal glutathione transferase 1 in PC12 cells with modified PMCA isoforms composition. AB - Microsomal glutathione transferase 1 (MGST1) is an integral homo-trimeric membrane protein with transferase and peroxidase activities. With glutathione as a co-substrate, it scavenges toxic compounds and may exert anti-apoptotic effect. We examined the effect of suppression of plasma membrane Ca(2+)-ATPase isoforms- PMCA2 or PMCA3 on MGST1 in PC12 cells. GSH level was significantly higher in PMCA2-reduced line, but similar GSSG/GSH ratios in all cell lines suggested an efficient protection or absence of oxidative stress. The ATP concentration decreased in both modified lines, although in PMCA2-suppressed cells the decrease was higher. Total GSTs activity in postmitochondrial fraction increased by 30% in the cells with reduced PMCA3. After treatment with MGST1 activator N ethylmaleimide (NEM), the activity increased in both transfected lines by 30-40%. Real-time PCR also showed a higher mRNA expression of MGST1 in these lines. Staining with antibody recognizing all cytosolic and membrane-bound GSTs revealed the difference in oligomeric forms of GSTs, and specific anti-MGST1 antibody showed the presence of MGST1 hexamers in the transfected cells. Formation of similar hexamers was detected in the control line after treatment with peroxynitrite. Modification of MGST1 under reduced PMCAs amount may represent an adaptive mechanism that offers protection against the cytotoxicity mediated by increased Ca2+. PMID- 21280563 TI - Long-term caloric restriction up-regulates PPAR gamma co-activator 1 alpha (PGC 1alpha) expression in mice. AB - The peroxisome proliferator-activated receptor (PPAR) gamma co-activator 1 alpha (PGC-1alpha), a signal-sensing transcriptional co-activator in association with many nuclear receptors regulates various genes that control energy balance in animals. In this study, the effect of long-term caloric restriction (CR) (alternate days of fasting for 3 months) on the expression of PGC-1alpha protein in various tissues was investigated in mice. Western blot analyses showed positive immunoreactive PGC-1alpha (approximately 92 kDa) signal from various tissues. Heart, kidney and skeletal muscles expressed significant levels of PGC 1alpha, while a comparatively lower level was detected in the liver, small intestine and brain. The expression of PGC-1alpha was the highest and lowest in the heart and liver respectively. CR mice exhibited a significant increase in PGC 1alpha level in the heart (5.13-fold), kidney (3.57-fold), skeletal muscle (3.02 fold), liver (2.60-fold), small intestine (2.45-fold) and brain (2.05-fold), compared to normal (ad libitum) fed. The elevation in PGC-1alpha level, especially in highly oxidative tissues such as heart, kidney and skeletal muscle of CR mice might synergistically up-regulate genes that require PGC-1alpha co activation. Taken together, the up-regulation of PGC-1alpha expression might potentially support optimal energy metabolism and biochemical adaptation, necessary for maintaining energy homeostasis during long-term CR. PMID- 21280564 TI - Induction of acute respiratory distress syndrome in rats by lipopolysaccharide and its effect on oxidative stress and antioxidant status in lung. AB - Acute lung injury (ALI) or its severe form, acute respiratory distress syndrome (ARDS) is an important cause of mortality in the human population. Despite significant advances made, the mortality associated with ALI remains unchanged. The objective of the present study was to evaluate the role of oxidative stress, alveolar antioxidant status and multiple organ injury in ARDS induced by lipopolysaccharide (LPS) in rats. Rats were divided into 4 groups, group I control rats were given saline intraperitoneally, whereas groups II, III and IV (LPS-treated) rats received an intraperitoneal injection of LPS (10 mg/kg body weight) and sacrificed after various time intervals. In LPS-treated rats, we observed increased levels of oxidative products, decreased levels of antioxidants in lung tissues and increased levels of serum marker enzymes, suggesting multiple organ injury. Bronchoalveolar lavage fluid (BALF) neutrophil content and protein concentration in LPS-treated rats were significantly elevated in a time-dependent manner. Histological studies revealed neutrophil influx and diffused alveolar damage in LPS-administered rats. These results clearly suggested that increased oxidant levels led to oxidative stress, antioxidant deficiency attenuating lung inflammation and tissue damage. LPS administration resulted in multiple organ failure, leading to increased mortality. PMID- 21280565 TI - Celecoxib mitigates cigarette smoke induced oxidative stress in mice. AB - Cigarette smoke (CS) is a rich source of radicals, predisposing the cell to oxidative stress resulting in inflammation. Chronic inflammation is a recognized risk factor for carcinogenesis. Cyclooxygenase-2 (COX-2) is a mediator of inflammatory pathway and may, therefore, contribute to carcinogenesis. There are several reports that suggest the association between CS and COX-2 associated risk to cancer. In the present study, we examined the role of celecoxib (a selective COX-2 inhibitor) in modulating the oxidative stress caused by CS inhalation in mice. CS exposure for a period of 10 weeks caused oxidative stress in the pulmonary and hepatic tissues, as evident from the increase in lipid peroxidation levels (LPO) and decrease in reduced glutathione (GSH) levels. Celecoxib (125 mg/kg body weight for 8 weeks) administration to CS inhaling mice reduced the oxidative stress by decreasing the LPO levels and enhancing the GSH levels in comparison to the CS-exposed group. CS exposure repressed the enzymatic antioxidant defense system, as evident from the decrease in catalase (CAT) and superoxide dismutase (SOD) activities. Co-adminstration of celecoxib considerably reversed the changes in the enzymatic antioxidant defense system. Histopathological studies of lungs showed that CS exposure induced alveolar wall destruction and air space enlargement. In co-treated group, the alveolar septa were thicker than normal with apparent infiltration of inflammatory cells. In CS exposed group, hepatic tissue exhibited vacuolization and macrophage infiltration. Co-treatment with celecoxib restored the normal histoarchitechture in hepatic tissues of CS inhaling mice. Thus, the present study demonstrated that celecoxib adminstration reduced the oxidative stress-mediated risk to carcinogenesis, due to its ability to boost the antioxidant defense system. PMID- 21280566 TI - Kinetics and mechanisms of oxidation of some antioxidants with photochemically generated tert-butoxyl radicals. AB - Dietary antioxidants play an important role in the prevention of several chronic diseases including cardiovascular diseases, cancer, ageing and diabetes. In order to understand the mechanism of oxidation of antioxidants viz., gallic acid (GA), caffeic acid (CA), rosmarinic acid (RA) and chlorogenic acid (CGA), a systematic kinetic study of these antioxidants with photochemically generated tertiary butoxyl (t-BuO) radicals was carried out. The oxidation of antioxidants by t-BuO radicals was followed spectrophotometrically by measuring the absorbance of GA (266 nm), CA (310 nm), RA (324 nm) and CGA (328 nm) at their respective lambda(max). The initial rates of oxidation of antioxidants were calculated from the plot of absorbance vs time and were found to increase with increase in [antioxidant], [t-BuOOH] and light intensity in all the cases. The quantum yields (phi) were calculated from the initial rates of oxidation of antioxidant and the measured light intensity at 254 nm, the wavelength at which the tert-butyl hydroperoxide (t-BuOOH) was activated to radicals. The quantum yields were found to depend on [antioxidant] and [t-BuOOH], and were independent of light intensity. The order with respect to [antioxidant], [t-BuOOH] were found to be fractional whereas order with respect to intensity was one. The order of reactivity was found to be: CA > CGA > RA > GA. The products were identified by mass spectral data. On the basis of kinetic results and product analysis, probable mechanisms were suggested. PMID- 21280567 TI - Isolation of choline monooxygenase (CMO) gene from Salicornia europaea and enhanced salt tolerance of transgenic tobacco with CMO genes. AB - Glycinebetaine (GB) is an osmoprotectant accumulated by certain plants in response to high salinity, drought, and cold stress. Plants synthesize GB via the pathway choline --> betaine aldehyde --> glycinebetaine, and the first step is catalyzed by choline monooxygenase (CMO). In the present study, by using RT-PCR and RLM-RACE, a full-length CMO cDNA (1844 bp) was cloned from a halophyte Salicornia europaea, which showed high homology to other known sequences. In order to identify its function, the ORF of CMO cDNA was inserted into binary vector PBI121 to construct the chimeric plant expression vector PBI121-CMO. Using Agrobacterium (LBA4404) mediation, the recombinant plasmid was transferred into tobacco (Nicotiana tabacum). The PCR, Southern blot and RT-PCR analysis indicated the CMO gene was integrated into the tobacco genome, as well as expressed on the level of transcription. The transgenic tobacco plants were able to survive on MS medium containing 300 mmol/L NaCl and more vigorous than those of wild type with the same concentration salt treatment. In salt-stress conditions, transgenic plants had distinctly higher chlorophyll content and betaine accumulation than that of the control, while relative electrical conductivity of transgenic plants was generally lower. The results suggested the CMO gene transformation could effectively contribute to improving tobacco salt-resistance. PMID- 21280568 TI - Reinstate hydrogen peroxide as the product of alternative oxidase of plant mitochondria. AB - Chill treatment of potato tubers for 8 days induced mitochondrial O2 consumption by cyanide-insensitive alternative oxidase (AOX). About half of the total O2 consumption in such mitochondria was found to be sensitive to salicylhydroxamate (SHAM), a known inhibitor of AOX activity. Addition of catalase to the reaction mixture of AOX during the reaction decreased the rate of SHAM-sensitive O2 consumption by nearly half, and addition at the end of the reaction released half of the O2 consumed by AOX, both typical of catalase action on H2O2. This reaffirmed that the product of reduction of O2 by plant AOX was H2O2 as found earlier and not H2O as reported in some recent reviews. PMID- 21280569 TI - Characterization of water distribution and activities of enzymes during germination in magnetically-exposed maize (Zea mays L) seeds. AB - Magnetic seed treatment is one of the physical pre-sowing seed treatments to enhance the performance of crop plants. In our earlier experiment, we found significant increase in germination and vigour characteristics of maize (Zea mays L.) seeds subjected to magnetic fields. Among various combinations of magnetic field (MF) strength and duration, best results were obtained with MF of 100 mT for 2 h and 200 mT for 1 h exposure. The quicker germination in magnetically exposed seeds might be due to greater activities of germination related enzymes, early hydration of membranes as well as greater molecular mobility of bulk and hydration water fractions. Thus, in the present study, changes in water uptake during imbibition and its distribution and activities of germinating enzymes during germination were investigated in maize seeds exposed to static magnetic fields of 100 and 200 mT for 2 and 1 h respectively by nuclear magnetic resonance (NMR) spectroscopy. The magnetically-exposed seed showed higher water uptake in phase II and III than unexposed seed. The longitudinal relaxation time T1 of seed water showed significantly higher values and hence greater molecular mobility of cellular water in magnetically-exposed seeds as compared to unexposed. Component analysis of T2 relaxation times revealed the early appearance of hydration water with least mobility and higher values of relaxation times of cytoplasmic bulk water and hydration water in magnetically-exposed over unexposed seeds. Activities of alpha-amylase, dehydorgenase and protease during germination were higher in magnetically-exposed seeds as compared to unexposed. The quicker germination in magnetically-exposed seeds might be due to greater activities of germination related enzymes, early hydration of membranes as well as greater molecular mobility of bulk and hydration water fractions. PMID- 21280570 TI - Age-associated changes in erythrocyte glutathione peroxidase activity: correlation with total antioxidant potential. AB - Oxidative stress is believed to play a central role in aging and age-associated diseases. It leads to oxidative changes in human red blood cells (RBCs) in vivo and in vitro. In this study, we evaluated the oxidative damage to the erythrocytes during aging in the humans using RBC as a model, by measuring the cytosolic antioxidant enzyme glutathione peroxidase (GPx) activity. GPx activity was found to be significantly decreased as a function of human age and positively correlated with total antioxidant capacity, while negatively correlated with SOD activity. Thus, results of the present study showed involvement of oxidative stress as one of the risk factors, which can initiate and/or promote human aging. PMID- 21280571 TI - Pilot-scale waste activated sludge alkaline fermentation, fermentation liquid separation, and application of fermentation liquid to improve biological nutrient removal. AB - The use of sludge fermentative short-chain fatty acids (SCFA) as an additional carbon source of biological nutrient removal (BNR) has drawn much attention recently as it can reuse sludge organics, reduce waste activated sludge production, and improve BNR performance. Our previous laboratory study had shown that the SCFA production was significantly enhanced by controlling sludge fermentation at pH 10 with NaOH. This paper focused on a pilot-scale study of alkaline fermentation of waste activated sludge, separation of the fermentation liquid from the alkaline fermentation system, and application of the fermentation liquid to improve municipal biological nitrogen and phosphorus removal. NaOH and Ca(OH)(2) were used respectively to adjust the alkaline fermentation pH, and their effects on sludge fermentation and fermentation liquid separation were compared. The results showed that the use of Ca(OH)(2) had almost the same effect on SCFA production improvement and sludge volatile suspended solids reduction as that of NaOH, but it exhibited better sludge dewatering, lower chemical costs, and higher fermentation liquid recovery efficiency. When the fermentation liquids, adjusted with Ca(OH)(2) and NaOH respectively, were added continuously to an anaerobic-anoxic-aerobic municipal wastewater BNR system, both the nitrogen and phosphorus removals, compared with the control, were improved to the same levels. This was attributed to the increase of not only influent COD but also denitrifying phosphorus removal capability. It seems that the use of Ca(OH)(2) to control sludge fermentation at pH 10 for efficiently producing a carbon source for BNR is feasible. PMID- 21280572 TI - Anomaly of CH4 molecular assembly confined in single-wall carbon nanohorn spaces. AB - Vibrational-rotational properties of CH(4) adsorbed on the nanopores of single wall carbon nanohorns (SWCNHs) at 105-140 K were investigated using IR spectroscopy. The difference vibrational-rotational bands of the nu(3) and nu(4) modes below 130 K show suppression of the P and R branches, while the Q branches remain. The widths of the Q branches are much narrower than in the bulk gas phase due to suppression of the Doppler effect. These results indicate that the rotation of CH(4) confined in the nanospaces of SWCNHs is highly restricted, resulting in a rigid assembly structure, which is an anomaly in contrast to that in the bulk liquid phase. PMID- 21280573 TI - One-pot synthesis of Cu1.94S-CdS and Cu1.94S-Zn(x)Cd(1-x)S nanodisk heterostructures. AB - Nanodisk heterostructures consisting of monoclinic Cu(1.94)S and wurtzite CdS have been colloidally synthesized for the first time. Initially, hexagonal-shaped nanodisks of Cu(1.94)S were produced upon thermolysis of a copper complex in a solvent mixture of HDA and TOA at 250 degrees C. Rapid addition of Cd precursor to the reaction mixture resulted in the partial conversion of Cu(1.94)S into CdS, yielding Cu(1.94)S-CdS nanoheterostructures. The original morphology of the Cu(1.94)S nanodisks was conserved during the transformation. When Zn precursor was added together with the Cd precursor, Cu(1.94)S-Zn(x)Cd(1-x)S nanodisks were generated. These two-component nanostructures are potentially useful in the fabrication of heterojunction solar cells. PMID- 21280574 TI - How and why nanoparticle's curvature regulates the apparent pKa of the coating ligands. AB - Dissociation of ionizable ligands immobilized on nanopaticles (NPs) depends on and can be regulated by the curvature of these particles as well as the size and the concentration of counterions. The apparent acid dissociation constant (pK(a)) of the NP-immobilized ligands lies between that of free ligands and ligands self assembled on a flat surface. This phenomenon is explicitly rationalized by a theoretical model that accounts fully for the molecular details (size, shape, conformation, and charge distribution) of both the NPs and the counterions. PMID- 21280575 TI - Probing microscopic wetting properties of superhydrophobic surfaces by vibrated micrometer-sized droplets. AB - We determine contact angles of micrometer-sized NaCl-water droplets on superhydrophobic surfaces by analyzing their lowest-order axisymmetric vibrational resonances driven by vertical oscillations of the surface. Fluorescence spectra of the dye-doped droplets excited by laser light feature whispering-gallery modes (WGMs) whose spectral widths depend on the droplet vibration amplitude, thus enabling precise measurements of the droplet mechanical resonant frequency. Following droplet size determination by WGM mode-matching, we calculate the contact angles from the dependence of the measured mechanical resonant frequency on the droplet size for two surfaces with different superhydrophobicity levels, and find a good correlation with the values measured by direct imaging of millimeter-sized droplets. PMID- 21280576 TI - Venomic and antivenomic analyses of the Central American coral snake, Micrurus nigrocinctus (Elapidae). AB - The proteome of the venom of Micrurus nigrocinctus (Central American coral snake) was analyzed by a "venomics" approach. Nearly 50 venom peaks were resolved by RP HPLC, revealing a complex protein composition. Comparative analyses of venoms from individual specimens revealed that such complexity is an intrinsic feature of this species, rather than the sum of variable individual patterns of simpler composition. Proteins related to eight distinct families were identified by MS/MS de novo peptide sequencing or N-terminal sequencing: phospholipase A(2) (PLA(2)), three-finger toxin (3FTx), l-amino acid oxidase, C-type lectin/lectin-like, metalloproteinase, serine proteinase, ohanin, and nucleotidase. PLA(2)s and 3FTxs are predominant, representing 48 and 38% of the venom proteins, respectively. Within 3FTxs, several isoforms of short-chain alpha-neurotoxins as well as muscarinic-like toxins and proteins with similarity to long-chain kappa-2 bungarotoxin were identified. PLA(2)s are also highly diverse, and a toxicity screening showed that they mainly exert myotoxicity, although some are lethal and may contribute to the known presynaptic neurotoxicity of this venom. An antivenomic characterization of a therapeutic monospecific M. nigrocinctus equine antivenom revealed differences in immunorecognition of venom proteins that correlate with their molecular mass, with the weakest recognition observed toward 3FTxs. PMID- 21280577 TI - Structural fine-tuning of a multifunctional cytochrome P450 monooxygenase. AB - AurH is a unique cytochrome P450 monooxygenase catalyzing the stepwise formation of a homochiral oxygen heterocycle, a key structural and pharmacophoric component of the antibiotic aureothin. The exceptional enzymatic reaction involves a tandem oxygenation process including a regio- and stereospecific hydroxylation, followed by heterocyclization. For the structural and biochemical basis of this unparalleled sequence, four crystal structures of AurH variants in different conformational states and in complex with the P450 inhibitor ancymidol were solved, which represent the first structures of the CYP151A group. Structural data in conjunction with computational docking, site-directed mutagenesis, and chemical analyses unveiled a switch function when recognizing the two substrates, deoxyaureothin and the hydroxylated intermediate, thus allowing the second oxygenation-heterocyclization step. Furthermore, we were able to modify the chemo and regioselectivity of AurH, yielding mutants that catalyze the regioselective six-electron transfer of a nonactivated methyl group to a carboxylic acid via hydroxyl and aldehyde intermediates. PMID- 21280578 TI - One-pot synthesis, photoluminescence, and electrocatalytic properties of subnanometer-sized copper clusters. AB - Subnanometer-sized copper nanoclusters were prepared by a one-pot procedure based on wet chemical reduction. The structural characteristics of the 2-mercapto-5-n propylpyrimidine-protected nanoclusters, Cu(n) (n <= 8), were determined by mass spectrometry. The Cu nanoclusters displayed apparent luminescence, with dual emissions at 425 and 593 nm, with quantum yields of 3.5 and 0.9%, respectively, and high electrocatalytic activity in the electoreduction of oxygen. PMID- 21280579 TI - Single-crystal metal-organic framework arrays. AB - A novel, versatile pen-type lithography-based methodology was developed to control the growth of HKUST-1 crystals on surfaces by direct delivery of femtoliter droplets containing both inorganic and organic building block precursors. This approach shows that through the use of surfaces with low wettability it is possible to control the crystallization of a single submicrometer metal-organic framework crystal at a desired location on a surface. PMID- 21280580 TI - Novel domino oxidative coupling: C-C bond formation sequence to highly functionalized dibenzo[a,c]cycloheptenes. AB - A domino sequence involving various MoCl(5)-mediated oxidations followed by trapping and supposed [3,3]-sigmatropic rearrangement provides a fast access to the full carbon skeleton of metasequirin-B. A variety of different moieties R(1) and R(2) are tolerated. PMID- 21280581 TI - First principles studies of the effect of ostwald ripening on carbon nanotube chirality distributions. AB - The effect of Ostwald ripening of metal particles attached to carbon nanotubes has been studied using density functional theory. It has been confirmed that Ostwald ripening may be responsible for the termination of growth of carbon nanotube forests. It was seen that the Ostwald ripening of metal particles attached to carbon nanotubes is governed by a critical factor that depends on both the cluster size and the carbon nanotube chirality. For example, clusters attached to armchair and zigzag nanotubes of similar diameters will have different critical factors although the exact behavior may depend on which molecules are present in the surrounding medium. The critical factor was also observed to have a critical point with the effect that clusters with a narrow size distribution close to the critical point may experience a narrowing rather than a widening of the size distribution, as is the case for free clusters. PMID- 21280582 TI - One-step production of superhydrophobic coatings on flat substrates via atmospheric Rf plasma process using non-fluorinated hydrocarbons. AB - This paper describes the direct deposition of hydrocarbon coatings with a static water contact angle higher than 150 using simple C6 hydrocarbons as a reactive gas in helium plasma generated in ambient air without any preroughening of the silicon (100) substrate. The film morphology and hydrophobicity are found to strongly depend on the structure of the reagent hydrocarbon. The films deposited with n-hexane and cyclohexane exhibited relatively smooth morphology and the water contact angle was only ~95 degrees , similar to polypropylene. When benzene was used as a main reactive gas, the deposited film surface showed nanoscale textured morphology and superhydrophobicity with a water contact angle as high as 167 degrees . Because the plasma is generated in air, all films show some degree of oxygen incorporation. These results imply that the incorporation of a small amount of oxygenated species in hydrocarbon films due to excitation of ambient air is not detrimental for superhydrophobicity, which allows the atmospheric rf plasma with the benzene precursor to produce rough surface topography needed for superhydrophobicity. PMID- 21280583 TI - Real-time electrochemical PCR with a DNA intercalating redox probe. AB - The proof-of-principle of a nonoptical real-time PCR method based on the electrochemical monitoring of a DNA intercalating redox probe that becomes considerably less easily electrochemically detectable once intercalated to the amplified double-stranded DNA is demonstrated. This has been made possible thanks to the finding of a redox intercalator that (i) strongly and specifically binds to the amplified double-stranded DNA, (ii) does not significantly inhibit PCR, (iii) is chemically stable under PCR cycling, and (iv) is sensitively detected by square wave voltammetry during PCR cycling. Among the different DNA intercalating redox probes that we have investigated, namely, methylene blue, Os[(bpy)(2)phen](2+), Os[(bpy)(2)DPPZ](2+), Os[(4,4'-dimethyl-bpy)(2)DPPZ](2+) and Os[(4,4'-diamino-bpy)(2)DPPZ](2+) (with bpy = 2,2'-bipyridine, phen = phenanthroline, and DPPZ = dipyrido[3,2-a:2',3'-c]phenazine), the one and only compound with which it has been possible to demonstrate the proof-of-concept is the Os[(bpy)(2)DPPZ](2+). In terms of analytical performances, the methodology described here compares well with optical-based real-time PCRs, offering finally the same advantages than the popular and routinely used SYBR Green-based real time fluorescent PCR, but with the additional incomes of being potentially much cheaper and easier to integrate in a hand-held miniaturized device. PMID- 21280584 TI - Induction of apoptosis in cancer cells at low silver nanoparticle concentrations using chitosan nanocarrier. AB - We report the development of a chitosan nanocarrier (NC)-based delivery of silver nanoparticles (Ag NPs) to mammalian cells for induction of apoptosis at very low concentrations of the NPs. The cytotoxic efficacy of the Ag NP-nanocarrier (Ag-CS NC) system in human colon cancer cells (HT 29) was examined by morphological analyses and biochemical assays. Cell viability assay demonstrated that the concentration of Ag NPs required to reduce the viability of HT 29 cells by 50% was 0.33 MUg mL(-1), much less than in previously reported data. The efficient induction of apoptosis by Ag-CS NCs was confirmed by flow cytometry. Additionally, the characteristic nuclear and morphological changes during apoptotic cell death were investigated by fluorescence and scanning electron microscopy (SEM), respectively. The involvement of mitochondrial pathway of cell death in the Ag-CS NCs induced apoptosis was evident from the depolarization of mitochondrial membrane potential (DeltaPsi(m)). Real time quantitative RT-PCR analysis demonstrated the up-regulation of caspase 3 expression which was further reflected in the formation of oligo-nucleosomal DNA "ladders" in Ag-CS NCs treated cells, indicating the important role of caspases in the present apoptotic process. The increased production of intracellular ROS due to Ag-CS NCs treatment indicated that the oxidative stress could augment the induction of apoptosis in HT 29 cells in addition to classical caspase signaling pathway. The use of significantly low concentration of Ag NPs impregnated in chitosan nanocarrier is a much superior approach in comparison to the use of free Ag NPs in cancer therapy. PMID- 21280585 TI - Affinity of Cu+ for the copper-binding domain of the amyloid-beta peptide of Alzheimer's disease. AB - The role of metal ions in Alzheimer's disease etiology is unresolved. For the redox-active metal ions iron and copper, the formation of reactive oxygen species by metal amyloid complexes has been proposed to contribute to Alzheimer's disease neurodegeneration. For copper, reactive oxygen species are generated by copper redox cycling between its 1+ and 2+ oxidation states. Thus, the AbetaCu(I) complex is potentially a critical reactant associated with Alzheimer's disease etiology. Through competitive chelation, we have measured the affinity of the soluble copper-binding domain of the amyloid-beta peptide for Cu(I). The dissociation constants are in the femtomolar range for both wild-type and histidine-to-alanine mutants. These results indicate that Cu(I) binds more tightly to monomeric amyloid-beta than Cu(II) does, which leads us to propose that Cu(I) is a relevant in vivo oxidation state. PMID- 21280586 TI - MAPping the chiral inversion and structural transformation of a metal-tripeptide complex having ni-superoxide dismutase activity. AB - The metal abstraction peptide (MAP) tag is a tripeptide sequence capable of abstracting a metal ion from a chelator and binding it with extremely high affinity at neutral pH. Initial studies on the nickel-bound form of the complex demonstrate that the tripeptide asparagine-cysteine-cysteine (NCC) binds metal with 2N:2S, square planar geometry and behaves as both a structural and functional mimic of Ni superoxide dismutase (Ni-SOD). Electronic absorption, circular dichroism (CD), and magnetic CD (MCD) data collected for Ni-NCC are consistent with a diamagnetic Ni(II) center. It is apparent from the CD signal of Ni-NCC that the optical activity of the complex changes over time. Mass spectrometry data show that the mass of the complex is unchanged. Combined with the CD data, this suggests that chiral rearrangement of the complex occurs. Following incubation of the nickel-containing peptide in D(2)O and back-exchange into H(2)O, incorporation of deuterium into non-exchangeable positions is observed, indicating chiral inversion occurs at two of the alpha carbon atoms in the peptide. Control peptides were used to further characterize the chirality of the final nickel-peptide complex, and density functional theory (DFT) calculations were performed to validate the hypothesized position of the chiral inversions. In total, these data indicate Ni-SOD activity is increased proportionally to the degree of structural change in the complex over time. Specifically, the relationship between the change in CD signal and change in SOD activity is linear. PMID- 21280587 TI - In vivo participation of artificial porphyrins in electron-transport chains: electrochemical and spectroscopic analyses of microbial metabolism. AB - The effects of artificial porphyrins on the electron-transport chains of living microbes were investigated. The participation of porphyrins in the microbial electron-transport chains was demonstrated by spectroscopic and current generation measurements. Large enhancement of the microbial current generation was accomplished by adding a cationic water-soluble manganese porphyrin as an electron mediator. PMID- 21280588 TI - Magnetic behaviors of heterospin chains consisting of cobalt(II) complexes and dipyridylcarbenes. AB - The 1:1 mixture of Co(Brhfpip)(2) and D1py(2) gave isomeric diazocobalt complexes, 1 and 2, formulated by [Co(Brhfpip)(2)(D1py(2))](n). Complexes 1 and 2 have zigzag and linear chain structures by the cis and trans coordination of pyridine units in D1py(2), respectively. After irradiation of microcrystalline samples, the generated carbene interacted with the cobalt ion to form ferromagnetic chains, 1c and 2c. Those isomeric chains exhibited slow magnetic relaxation with U(eff) = 93 and 87 K and H(c) = 20 and 13 kOe at 1.9 K for 1c and 2c, respectively. PMID- 21280589 TI - Dinoxin B, a withanolide from Datura inoxia leaves with specific cytotoxic activities. AB - A new withanolide, dinoxin B (12,21-dihydroxy-1-oxowitha-2,5,24-trienolide-27-O beta-D-glucopyranoside, 1), was isolated from a methanol extract of Datura inoxia leaves, using bioassay-guided fractionation. The structure was determined by spectroscopic techniques, including (1)H, (13)C, and 2D NMR experiments as well as by HRMS. Extracts and the purified compound were tested for their antiproliferative activities toward a panel of human normal and cancer cell lines. Dinoxin B (1) and its aglycone (2) exhibited submicromolar IC(50) values against multiple human cancer cell lines. Among the most sensitive were several breast cancer cell lines. Dinoxin B (1) was found only in D. inoxia and was not detected in D. metel or D. stramonium. The accumulation of this compound was limited largely to leaf tissue, with little to none detected in extracts from the flowers, fruits, roots, or stems of D. inoxia. PMID- 21280590 TI - Synthetically functionalized retroviruses produced from the bioorthogonally engineered cell surface. AB - Conjugation of desired molecules onto retroviral surfaces through the ease of the bioorthogonal functionalization method was demonstrated. Oxidation of surface sialic acids using periodate and further p-anisidine-catalyzed conjugation with aminooxy-bearing molecules were used to directly label retroviral envelope with a fluorescent dye. The retroviral particles that were produced from a bioorthogonally functionalized virus producing cell surface and further tethered with magnetic nanoparticles were efficiently purified by simple magnetic column separation and capable of magnet-directed transduction. PMID- 21280591 TI - Mirabamides E-H, HIV-inhibitory depsipeptides from the sponge Stelletta clavosa. AB - Four new depsipeptides, mirabamides E-H (1-4), and the known depsipeptide mirabamide C (5) have been isolated from the sponge Stelletta clavosa, collected from the Torres Strait. The planar structures were determined on the basis of extensive 1D and 2D NMR and HRESIMS. The absolute configurations were established by the advanced Marfey's method, NMR, and GC-MS. The four new compounds all showed strong inhibition of HIV-1 in a neutralization assay with IC(50) values of 121, 62, 68, and 41 nM, respectively. PMID- 21280592 TI - Formal total synthesis of cyanolide A. AB - Formal total synthesis of cyanolide A, aglycosidic dimeric macrolide is accomplished. The key reactions involved are asymmetric acetate aldol reaction, CBS reduction, and Shiina's lactonization. PMID- 21280593 TI - Effects of external electric field on film growth, morphology, and nanostructure of polyelectrolyte and nanohybrid multilayers onto insulating substrates. AB - Electric-field-enhanced layer-by-layer (LbL) assembly of polyelectrolyte and nanohybrid multilayers onto insulating rigid substrates was successfully accomplished using two independent capacitor cells. The influence of external electric field on the multilayer formation was intensively investigated by UV-vis adsorption spectrometry, profilometry, atomic force microscopy, and small-angle X ray diffraction. This approach was also attempted as a means of fabricating selective layer on flat sheet polymeric porous substrates to obtain the dense composite membranes with high pervaporation performance. PMID- 21280594 TI - Nanoscale organic-inorganic hybrid lubricants. AB - Silica (SiO2) nanoparticles densely grafted with amphiphilic organic chains are used to create a family of organic-inorganic hybrid lubricants. Short sulfonate functionalized alkylaryl chains covalently tethered to the particles form a dense corona brush that stabilizes them against aggregation. When these hybrid particles are dispersed in poly-alpha-olefin (PAO) oligomers, they form homogeneous nanocomposite fluids at both low and high particle loadings. By varying the volume fraction of the SiO2 nanostructures in the PAO nanocomposites, we show that exceptionally stable hybrid lubricants can be created and that their mechanical properties can be tuned to span the spectrum from simple liquids to complex gels. We further show that these hybrid lubricants simultaneously exhibit lower interfacial friction coefficients, enhanced wear and mechanical properties, and superior thermal stability in comparison with either PAO or its nanocomposites created at low nanoparticle loadings. Profilometry and energy dispersive X-ray spectroscopic analysis of the wear track show that the enhanced wear characteristics in PAO-SiO2 composite lubricants originate from two sources: localization of the SiO2 particles into the wear track and extension of the elastohydrodynamic lubrication regime to Sommerfeld numbers more than an order of magnitude larger than for PAO. PMID- 21280595 TI - Effect of surface binding on heterogeneous DNA melting equilibria: a Monte Carlo simulation study. AB - Deoxyribonucleic acid (DNA) microarrays are constructed with a surface immobilized single-stranded probe sequence that hydrogen bonds with its complementary target strand from solution and is subsequently detected, making their hybridization equilibrium of central importance. Unexpectedly, the effect of surface immobilization is that if the sequences of probe and target are exchanged, the hybridization equilibrium shifts. Here, configurational-bias Monte Carlo simulations using a coarse-grained model for DNA were carried out for an undecamer double helix both in solution and bound to a surface to determine dissociation equilibria. Four possible surface binding orientations were independently investigated. Analysis shows that the effect of surface binding is to destabilize hydrogen-bonding interactions of bases proximal to the binding site and enhance those of distal bases due to the double helix lying flat on the surface. Results have implications for predicting surface-bound DNA hybridization equilibria. PMID- 21280596 TI - Effect of processing parameters on the electrophoretic deposition of carbon black nanoparticles in moderately viscous systems. AB - Polymer-melt-based manufacturing processes for nanostructures offer high-rate, environmentally friendly, and commercially viable alternatives to solution-based methods. In this work, electrophoresis of a model carbon black and polystyrene system with moderate viscosity was used to investigate the viability of adapting nanoassembly processes to the high viscosity environment of polymer melts. The presence of polystyrene did not prevent deposition of carbon black, but deposition rates decreased at shorter deposition times; deposition was not linear with increasing applied voltage; and greater solution concentrations reduced the critical voltages (i.e., the voltage at which the rate of deposition changed). X ray photoelectron spectroscopy (XPS) results and comparison of experimental data with Hamaker's model showed that about 1.6% of the available polystyrene was initially deposited with the carbon black. At voltages above the critical voltage, the deposited mass was less than the Hamaker prediction, indicating the formation of electrically insulating layers on the electrodes. The overall behavior suggests that polymer melt-based processes could be employed for high rate fabrication of nano-optical devices, biochemical sensors, and nanoelectronics. PMID- 21280597 TI - Topological and experimental approach to the pressure-temperature-composition phase diagram of the binary enantiomer system d- and l-camphor. AB - In 1981, Jacques, Collet, and Wilen already put forward the idea to use pressure to influence equilibria in binary enantiomer systems in analogy with temperature (Jacques et al. Enantiomers, Racemates and Resolutions; John Wiley & Sons: New York, 1981). Whereas temperature is used routinely to study phase equilibria, pressure is an all but forgotten parameter. This is therefore possibly the first paper on the influence of pressure on a binary enantiomer system: d- and l camphor. The study consists of two parts, a topological approach, which uses data obtained from routine measurements (differential scanning calorimetry, X-ray diffraction), and the experimental determination of phase transitions as a function of pressure and temperature. This has resulted in two topological pressure-temperature phase diagrams of the pure enantiomer d-camphor and of the racemic mixture dl-camphor; both have been verified by the experiments as a function of pressure. In turn, these results have been used to construct part of the pressure-temperature-composition phase diagram of d- and l-camphor. A method to obtain the excess Gibbs energy from these binary phase diagrams as a function of pressure is proposed. PMID- 21280598 TI - Effects of chemical structure on the thermodynamic efficiency of radical chain carriers for organic synthesis. AB - The chain carrier index (CCI), defined as the ratio of the bond dissociation free energies (BDFE) of corresponding chain carrier halides and hydrides, is proposed as a measure of the thermodynamic efficiency of chain carriers for radical dehalogenation. The larger this value is relative to the corresponding value of the organic substrate, the more thermodynamically efficient the process. The chloride and bromide CCIs were evaluated at the G3(MP2)-RAD(+) level of theory for 120 different R-groups, covering a broad range of carbon-centered and noncarbon-centered species; the effects of solvent and temperature have also been studied. The broad finding from this work is that successful chain carriers generally maximize the strength of their halide (versus hydride bonds) through charge-shift bonding. As a result, the thermodynamic efficiency of a chain carrier tends to increase down the periodic table, and also with the inclusion of stronger electron donating substituents. The CCIs of carbon-centered species fall into a relatively narrow range so that, even when the CCI is maximized through inclusion of lone pair donor OMe or NMe(2) groups, the thermodynamic driving force for dehalogenation of other organic substrates is modest at best, and the process is likely to be kinetically hampered. Among the noncarbon-centered species studied, bismuth- and borane-centered compounds have some of the highest CCI values and, although their kinetics requires further optimization, these classes of compounds would be worth further investigation as tin-free radical reducing agents. PMID- 21280599 TI - Phosphorylation of annexin A1 by TRPM7 kinase: a switch regulating the induction of an alpha-helix. AB - TRPM7 is an unusual bifunctional protein consisting of an alpha-kinase domain fused to a TRP ion channel. Previously, we have identified annexin A1 as a substrate for TRPM7 kinase and found that TRPM7 phosphorylates annexin A1 at Ser5 within the N-terminal alpha-helix. Annexin A1 is a Ca(2+)-dependent membrane binding protein, which has been implicated in membrane trafficking and reorganization. The N-terminal tail of annexin A1 can interact with either membranes or S100A11 protein, and it adopts the conformation of an amphipathic alpha-helix upon these interactions. Moreover, the existing evidence indicates that the formation of an alpha-helix is essential for these interactions. Here we show that phosphorylation at Ser5 prevents the N-terminal peptide of annexin A1 from adopting an alpha-helical conformation in the presence of membrane-mimetic micelles as well as phospholipid vesicles. We also show that phosphorylation at Ser5 dramatically weakens the binding of the peptide to S100A11. Our data suggest that phosphorylation at Ser5 regulates the interaction of annexin A1 with membranes as well as S100A11 protein. PMID- 21280600 TI - Evaluation of compositional equivalence for multitrait biotechnology crops. AB - Compositional analysis is an important tool in the evaluation of the safety and nutritional status of biotechnology-derived crops. As part of the comparative assessment of a biotechnology-derived crop, its composition is evaluated by quantitative measurement of the levels of key nutrients, antinutrients, and secondary metabolites and compared to that of conventional crops. To evaluate the effect of combining multiple biotech traits through conventional breeding, the forage and grain compositions of the double combinations MON 810 * NK603, MON 863 * MON 810, and MON 863 * NK603 and the triple combination MON 863 * NK603 * MON 810 were compared to their respective near-isogenic, conventional control hybrids. Overall, a total of 241 statistical comparisons between the multitrait biotechnology crop and its corresponding conventional controls were conducted. Of these comparisons 192 (79.7%) were not statistically significantly different (p > 0.05), and all 49 of the differences were within the 99% tolerance interval for commercial hybrids grown in the same field or related field trials. These data on combined trait biotechnology-derived products demonstrated that the forage and grain were compositionally equivalent to their conventional comparators, indicating the absence of any influence of combining insect protection and herbicide tolerance traits by conventional breeding on compositional variation. PMID- 21280601 TI - Ethanesulfohydroxamic acid ester prodrugs of nonsteroidal anti-inflammatory drugs (NSAIDs): synthesis, nitric oxide and nitroxyl release, cyclooxygenase inhibition, anti-inflammatory, and ulcerogenicity index studies. AB - The carboxylic acid group of the anti-inflammatory (AI) drugs indo-methacin, (S) naproxen and ibuprofen was covalently linked via a two-carbon ethyl spacer to a sulfohydroxamic acid moiety (CH(2)CH(2)SO(2)NHOH) to furnish a group of hybrid ester prodrugs that release nitric oxide (NO) and nitroxyl (HNO). Biological data acquired for this hitherto unknown class of ethanesulfohydroxamic acid ester prodrugs showed (i) all compounds exhibited superior NO, but similar HNO, release properties relative to arylsulfohydroxamic acids, (ii) the (S)-naproxen and ibuprofen prodrug esters are more potent AI agents than their parent NSAID, (iii) the indomethacin prodrug ester, in contrast to indomethacin which is highly ulcerogenic, showed no visible stomach lesions [ulcer index (UI) = 0 for a 80 MUmol/kg oral dose] while retaining potent AI activity, and iv) that the indomethacin prodrug ester, unlike indomethacin which is an ulcerogenic selective COX-1 inhibitor, is a selective COX-2 inhibitor (COX-2 selectivity index = 184) devoid of ulcerogenicity that is attributed to its high COX-2 SI and/or ability to release cytoprotective NO. PMID- 21280602 TI - Biotin ergopeptide probes for dopamine receptors. AB - The incorporation of chemical modifications into the structure of bioactive compounds is often difficult because the biological properties of the new molecules must be retained with respect to the native ligand. Ergopeptides, with their high affinities at D(1) and D(2) dopamine receptors, are particularly complex examples. Here, we report the systematic derivatization of two ergopeptides with different peptide-based spacers and their evaluation by radioligand binding assays. Selected spacer-containing ergopeptides with minimal biological alteration and a proper anchoring point were further derivatized with a biotin reporter. Detailed characterization studies identified 13 as a biotin ergopeptide maintaining high affinity and agonist behavior at dopamine receptors, being a useful tool for the study of heteromers involving D(1)R, D(2)R, or D(3)R. PMID- 21280603 TI - Vibrational spectroscopy of water in narrow nanopores. AB - Inside narrow pores, for instance, realized as carbon nanotubes, water forms structures that strongly differ from the structure of bulk liquid water or ice. Here we compute vibrational spectra of such systems using molecular dynamics simulation combined with quantum mechanical perturbation theory. We focus on the spectroscopic response of single-file water chains in pores with subnanometer diameter, finding characteristic signatures of dangling and hydrogen-bonded hydrogen configurations occurring in this particular form of water. These features in the absorption spectra permit us to distinguish single-file water from the stacked-ring structures that form in wider pores. As previously observed in bulk liquid water, the vibrational frequency of the OH stretch of an HDO molecule in a system of D(2)O molecules is essentially determined by the electric field acting at the position of the hydrogen atom, providing a way to link the spectroscopic response to the local charge distribution of specific molecular arrangements. PMID- 21280604 TI - Long-lived and temperature-independent emission from a novel ruthenium(II) complex having an arylborane charge-transfer unit. AB - We report the redox, absorption, and emission characteristics of the tris(1,10 phenanthroline)ruthenium(II) complexes [Ru(phen)(3)](2+) bearing a (dimesityl)boryldurylethynyl (DBDE) charge-transfer (CT) unit at the 4 (4BRu(2+)) or 5 (5BRu(2+)) position of one of the three phen ligands. In acetonitrile at 298 K, 4BRu(2+) showed absorption and emission maximum wavelengths at 473 and 681 nm, respectively, which were shifted to longer wavelengths by 25 and 74 nm, respectively, compared with the relevant value of 5BRu(2+), 448 and 607 nm, respectively. The effects of a fluoride ion on the absorption and emission spectra of the complexes demonstrated that the CT interaction between the pi electron system in the phen ligand (pi(aryl)) and the vacant p orbital on the boron atom (p(B)) in the DBDE group (i.e., pi(aryl)-p(B) CT) participated in the excited states of the complexes in addition to the Ru(II)-to-phen metal-to-ligand CT (MLCT) interaction. Reflecting such synergistic MLCT/pi(aryl)-p(B) CT, both 4BRu(2+) and 5BRu(2+) exhibited intense emission at 298 K with a quantum yield of 0.11. Furthermore, the emission lifetime of 4BRu(2+) was as long as 12 MUs and almost independent of the temperature (T = 280-330 K). The present study indicated that the nonemissive dd excited triplet state did not participate to nonradiative decay in the MLCT excited triplet state of 4BRu(2+). The effects of the synergistic MLCT/pi(aryl)-p(B) CT interactions on the redox, absorption/emission, and photophysical characteristics of 4BRu(2+) and 5BRu(2+) are discussed in detail. PMID- 21280605 TI - Sequential energy and electron transfer in polyisocyanopeptide-based multichromophoric arrays. AB - We report on the synthesis and detailed photo-physical investigation of four model chromophore side chain polyisocyanopeptides: two homopolymers of platinum porphyrin functionalized polyisocyanopeptides (Pt-porphyrin-PIC) and perylene bis(dicarboximide) functionalized polyisocyanopeptides (PDI-PIC), and two statistical copolymers with different ratios of Pt-porphyrin and PDI molecules attached to a rigid, helical polyisocyanopeptide backbone. (1)H NMR and circular dichroism measurements confirm that our model compounds retain a chiral architecture in the presence of the chromophores. The combination of Pt-porphyrin and PDI chromophores allows charge- and/or energy transfer to happen. We observe the excitation and relaxation pathways for selective excitation of the Pt porphyrin and PDI chromophores. Studies of photoluminescence and transient absorption on nanosecond and picosecond scales upon excitation of Pt-porphyrin chromophores in our multichromophoric assemblies show similar photophysical features to those of the Pt-porphyrin monomers. In contrast, excitation of perylene chromophores results in a series of energy and charge transfer processes with the Pt-porphyrin group and forms additional charge-transfer states, which behave as an intermediate state that facilitates electronic coupling in these multichromophoric systems. PMID- 21280606 TI - Fast characterization of functionalized silica materials by silicon-29 surface enhanced NMR spectroscopy using dynamic nuclear polarization. AB - We demonstrate fast characterization of the distribution of surface bonding modes and interactions in a series of functionalized materials via surface-enhanced nuclear magnetic resonance spectroscopy using dynamic nuclear polarization (DNP). Surface-enhanced silicon-29 DNP NMR spectra were obtained by using incipient wetness impregnation of the sample with a solution containing a polarizing radical (TOTAPOL). We identify and compare the bonding topology of functional groups in materials obtained via a sol-gel process and in materials prepared by post-grafting reactions. Furthermore, the remarkable gain in time provided by surface-enhanced silicon-29 DNP NMR spectroscopy (typically on the order of a factor 400) allows the facile acquisition of two-dimensional correlation spectra. PMID- 21280607 TI - 11-Step enantioselective synthesis of (-)-lomaiviticin aglycon. AB - Lomaiviticins A and B are complex antitumor antibiotics that were isolated from a strain of Micromonospora. A confluence of several unusual structural features renders the lomaiviticins exceedingly challenging targets for chemical synthesis. We report an 11-step, enantioselective synthetic route to lomaiviticin aglycon. Our route proceeds by late-stage, stereoselective dimerization of two equivalent monomeric intermediates, a transformation that may share parallels with the natural products' biosyntheses. The route we describe is scalable and convergent, and it lays the foundation for determination of the mode of action of these natural products. PMID- 21280608 TI - Solution structure of a DNA duplex containing the potent anti-poxvirus agent cidofovir. AB - Cidofovir (1(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine, CDV) is a potent inhibitor of orthopoxvirus DNA replication. Prior studies have shown that, when CDV is incorporated into a growing primer strand, it can inhibit both the 3'-to 5' exonuclease and the 5'-to-3' chain extension activities of vaccinia virus DNA polymerase. This drug can also be incorporated into DNA, creating a significant impediment to trans-lesion DNA synthesis in a manner resembling DNA damage. CDV and deoxycytidine share a common nucleobase, but CDV lacks the deoxyribose sugar. The acyclic phosphonate bears a hydroxyl moiety that is equivalent to the 3' hydroxyl of dCMP and permits CDV incorporation into duplex DNA. To study the structural consequences of inserting CDV into DNA, we have used (1)H NMR to solve the solution structures of a dodecamer DNA duplex containing a CDV molecule at position 7 and of a control DNA duplex. The overall structures of both DNA duplexes were found to be very similar. We observed a decrease of intensity (>50%) for the imino protons neighboring the CDV (G6, T8) and the cognate base G18 and a large chemical shift change for G18. This indicates higher proton exchange rates for this region, which were confirmed using NMR-monitored melting experiments. DNA duplex melting experiments monitored by circular dichroism revealed a lower T(m) for the CDV DNA duplex (46 degrees C) compared to the control (58 degrees C) in 0.2 M salt. Our results suggest that the CDV drug is well accommodated and stable within the dodecamer DNA duplex, but the stability of the complex is less than that of the control, suggesting increased dynamics around the CDV. PMID- 21280609 TI - Properties and application of double-walled carbon nanotubes sorted by outer-wall electronic type. AB - Double-walled carbon nanotubes (DWNTs) can adopt four distinct permutations arising from the electronic type (metallic or semiconducting) of their inner and outer walls. This polydispersity limits the utility of DWNTs in applications such as thin film electronics. We demonstrate that density gradient ultracentrifugation can be employed to address this source of heterogeneity by producing DWNTs with well-defined outer-wall electronic types. Optical absorption measurements of sorted DWNTs reveal outer-wall purities of 96% and 98% for sorted semiconducting and metallic samples, respectively. Electrical characterization of semiconducting and metallic outer-wall DWNTs in thin film transistors directly confirms the efficacy of these separations, with semiconducting DWNT devices yielding on/off ratios 2 orders of magnitude higher than comparable metallic DWNT devices. PMID- 21280610 TI - Encaging the Verkade's superbases: thermodynamic and kinetic consequences. AB - Proazaphosphatranes, also known as Verkade's superbases, are nonionic species, which exhibit catalytic properties for a wide range of reactions. The properly designed host molecule 3 and its protonated counterpart [3.H](+)Cl(-) were synthesized to study how confinement can modify the stability and the reactivity of a Verkade's superbase. The results show that the encapsulation does not alter the strong basicity of the proazaphosphatrane, but dramatically decreases the rate of proton transfer. PMID- 21280611 TI - Regioselectivity in the nitration of dialkoxybenzenes. AB - Dinitrodialkoxybenzene derivatives are important precursors for Schiff base macrocycles and a variety of other molecules. During our investigations, we have found that the dinitration reaction of 1,2-dialkoxybenzenes proceeds with unusual regioselectivity, giving exclusively the desired 1,2-dialkoxy-4,5-dinitrobenzene product, but we have been unable to find a good explanation for this result. The dinitration of 1,4-dialkoxybenzene derivatives also exhibits surprising regioselectivity that has hitherto been left unexplained. Herein, we report a detailed DFT analysis of the regioselective dinitration of both 1,2- and 1,4 dimethoxybenzene. These results show that the reaction mechanism likely involves a single electron transfer (SET) process. In the case of the former isomer, the regioselectivity is mainly determined by the symmetry of the HOMO of the aromatic moiety that defines the structure of the SHOMO of the aromatic radical cation formed by the SET process. In the case of the latter isomer, the selectivity is due mainly to solvation effects and may thus be altered depending on the solvent environment. Synthetic studies of the nitration of 1,4-dialkoxybenzene derivatives using different solvent conditions support this conclusion and provide practical information for tuning the regioselectivity of the reaction. PMID- 21280612 TI - Bifunctional peptidomimetic prodrugs of didanosine for improved intestinal permeability and enhanced acidic stability: synthesis, transepithelial transport, chemical stability and pharmacokinetics. AB - Five peptidomimetic prodrugs of didanosine (DDI) were synthesized and designed to improve bioavailability of DDI following oral administration via targeting intestinal oligopeptide transporter (PepT1) and enhancing chemical stability. The permeability of prodrugs was screened in Caco-2 cells grown on permeable supports. 5'-O-L-valyl ester prodrug of DDI (compound 4a) demonstrated the highest membrane permeability and was selected as the optimal target prodrug for further studies. The uptake of glycylsarcosine (Gly-Sar, a typical substrate of PepT1) by Caco-2 cells could be inhibited by compound 4a in a concentration dependent manner. The Caco-2 cells were treated with 0.2 nM leptin for enhanced PepT1 expression. The uptake of compound 4a was markedly increased in the leptin treated Caco-2 cells compared with the control Caco-2 cells, both of which were obviously inhibited by 20 mM Gly-Sar. The K(m) and V(max) values of kinetic study of compound 4a transported by PepT1 in Caco-2 cells were 0.91 mM and 11.94 nmol/mg of protein/10 min, respectively. The chemical stability studies were performed in simulated gastric fluid (SGF), phosphate buffers under various pH conditions, rat tissue homogenates and plasma at 37 degrees C. The concentrations of DDI could not be detected in the two minutes in SGF. But compound 4a could significantly increase DDI acidic stability, and its t(1/2) was extended to as long as 36 min in SGF. Compound 4a was stable in pH 6.0 phosphate buffer but could be quickly transformed into DDI in plasma and tissue homogenates. The oral absolute bioavailability of DDI was 47.2% and 7.9% after compound 4a and DDI were orally administered to rats at a dose of 15 mg/kg, respectively. The coadministration with antiacid agent could also suggest that compound 4a was more stable under harsh acidic conditions compared with DDI. Compound 4a bioavailability in rats was reduced to 33.9% when orally co administered with Gly-Sar (100 mg/kg). The In Vivo bioactivation mechanism of compound 4a was investigated by comparing the levels of DDI and compound 4a in the jugular and portal veins in rats. The plasma concentration of intact compound 4a was very low in portal veins and could hardly be detected in the jugular vein. In conclusion, compound 4a could significantly improve the oral bioavailability of DDI in rats through PepT1-mediated absorption and enhanced acidic stability, followed by rapid and mostly intracellular bioactivation, the majority in the intestinal cells but the minority in the liver. Additionally, the prodrug strategy targeted to intestinal PepT1 could offer a promising strategy to improve oral bioavailability of poorly absorbed didanosine. PMID- 21280613 TI - Near-infrared fluorescent dye-doped semiconducting polymer dots. AB - Near-infrared (NIR) fluorescence sensing is desirable for in vivo biological measurements, but the method is currently limited by the availability of NIR fluorescent markers as well as by their poor performance, such as self aggregation and dim fluorescence, in a physiological environment. To address this issue, this paper describes a NIR fluorescent polymer dot (Pdot) that emits at 777 nm. This Pdot was comparable in size to a water-soluble NIR quantum dot that emits at 800 nm (ITK Qdot800) but was about four times brighter and with a narrower emission peak. We formed the NIR Pdot by doping the NIR dye, silicon 2,3 naphthalocyanine bis(trihexylsilyloxide) (NIR775), into the matrix of poly (9,9 dioctylfluorene-co-benzothiadiazole) (PFBT) as the Pdot formed using a nanoscale precipitation technique. Free molecules of NIR775 aggregate in aqueous solution, but encapsulating them into the hydrophobic Pdot matrix effectively introduced them into aqueous solution for use in biological studies. Most importantly, the brightness of NIR775 was dramatically enhanced because of the excellent light harvesting ability of PFBT and the very efficient energy transfer from PFBT to NIR775. We anticipate this bright NIR Pdot will be useful in biological measurements and cellular imaging where strong NIR emission is beneficial. PMID- 21280614 TI - Electron beam fabrication of birefringent microcylinders. AB - Numerous biological and biotechnological applications rely on the use of micrometer- and nanometer-scale particles, benefiting tremendously from quantitative control of their physical and chemical properties. Here, we describe the use of electron beam lithography for the design, fabrication, and functionalization of micrometer-scale birefringent quartz cylinders for use in sensing and detection. We demonstrate excellent control of the cylinders' geometry, fabricating cylinders with heights of 0.5-2 MUm and diameters of 200 500 nm with high precision while maintaining control of their side-wall angle. The flexible fabrication allows cylinders to be selectively shaped into conical structures or to include centered protrusions for the selective attachment of biomolecules. The latter is facilitated by straightforward functionalization targeted either to a cylinder's face or to the centered protrusion alone. The fabricated quartz cylinders are characterized in an optical torque wrench, permitting correlation of their geometrical properties to measured torques. Lastly, we tether individual DNA molecules to the functionalized cylinders and demonstrate the translational and rotational control required for single-molecule studies. PMID- 21280615 TI - Enzyme kinetic measurements using a droplet-based microfluidic system with a concentration gradient. AB - In this paper, we propose a microfluidic device that is capable of generating a concentration gradient followed by parallel droplet formation within channels with a simple T-junction geometry. Linear concentration gradient profiles can be obtained based on fluid diffusion under laminar flow. Optimized conditions for generating a linear concentration gradient and parallel droplet formation were investigated using fluorescent dye. The concentration gradient profile under diffusive mixing was dominated by the flow rate at sample inlets, while parallel droplet formation was affected by the channel geometry at both the inlet and outlet. The microfluidic device was experimentally characterized using optimal layout and operating conditions selected through a design process. Furthermore, in situ enzyme kinetic measurements of the beta-galactosidase-catalyzed hydrolysis of resorufin-beta-d-galactopyranoside were performed to demonstrate the application potential of our simple, time-effective, and low sample volume microfluidic device. We expect that, in addition to enzyme kinetics, drug screening and clinical diagnostic tests can be rapidly and accurately performed using this droplet-based microfluidic system. PMID- 21280616 TI - Grain boundary mapping in polycrystalline graphene. AB - We report direct mapping of the grains and grain boundaries (GBs) of large-area monolayer polycrystalline graphene sheets, at large (several micrometer) and single-atom length scales. Global grain and GB mapping is performed using electron diffraction in scanning transmission electron microscopy (STEM) or using dark-field imaging in conventional TEM. Additionally, we employ aberration corrected TEM to extract direct images of the local atomic arrangements of graphene GBs, which reveal the alternating pentagon-heptagon structure along high angle GBs. Our findings provide a readily adaptable tool for graphene GB studies. PMID- 21280617 TI - Nano approach investigation of the conduction mechanism in polyaniline nanofibers. AB - A nanotechnological approach is applied to measurements of the electric field dependence of resistance under a high electric field while in low voltage. With this technique, the conduction mechanism on a mesoscopic scale is explored in a single, nonagglomerated nanofiber. Polyaniline nanofibers are prepared by vigorous mixing of aniline and oxidation agent ammonium persulfate in acid solution. They exhibit a uniform nanoscale morphology rather than agglomeration as that produced via conventional chemical oxidation. The as-synthesized polyaniline nanofibers are doped (dedoped) with a HCl acid (NH(3) base), and their temperature behaviors of resistances follow an exponential function with an exponent of T(-1/2). To measure the conduction mechanism in a single nanofiber, the dielectrophoresis technique is implemented to position nanofibers on top of two electrodes with a nanogap of 100-600 nm, patterned by electron-beam lithography. After the devices are irradiated by electron beam to reduce contact resistances, their temperature behaviors and electric field dependences are unveiled. The experimental results agree well with the theoretical model of charging energy limited tunneling. Other theoretical models such as Efros Shklovskii and Mott's one-dimensional hopping conduction are excluded after comparisons and arguments. Through fitting, the size of the conductive grain, separation distance between two grains, and charging energy per grain in a single polyaniline nanofiber are estimated to be about 4.9 nm, 2.8 nm, and 78 meV, respectively. The nanotechnological approach, where the nanogap and the dielectrophoresis technique are used for single nanofiber device fabrication, is applied for determination of mesoscopic charge transport in a polyaniline conducting polymer. PMID- 21280618 TI - Ring-opening reactions of 2-alkoxy-3,4-dihydropyrans with thiols or thiophenols. AB - An electrophilic ring-opening reaction of 2-alkoxy-3,4-dihydropyran with a thiophenol or thiol is developed for the first time. The generated product contains not only a 1,3-dicarbonyl moiety but also a fragment of bis(alkylthio)methane. A possible mechanism is also proposed on the basis of postulating a ring-opening monotransthioacetalization product, which was prepared by using LiBr as catalyst as an intermediate. PMID- 21280619 TI - Kinetic studies of dextransucrase enzyme reactions on a substrate- or enzyme immobilized 27 MHz quartz crystal microbalance. AB - Catalytic elongation by dextransucrase (DSase) was monitored directly on a dextran-acceptor- or DSase-immobilized 27 MHz quartz crystal microbalance (QCM). Kinetic parameters for the binding of the enzyme to the dextran acceptor (k(on), k(off), and K(d)) and enzymatic elongation in the presence of a sucrose monomer (K(m) for sucrose and k(cat)) were determined. The kinetic parameters obtained by both methods were consistent. PMID- 21280620 TI - Scope and limitations of the photooxidations of 2-(alpha-hydroxyalkyl)furans: synthesis of 2-hydroxy-exo-brevicomin. AB - Photooxygenation of 2-(alpha-hydroxyalkyl)furans at 5 degrees C in MeOH followed by in situ reduction affords, in one synthetic operation, 6-hydroxy-3(2H) pyranones and/or 5-hydroxy-2(5H)-furanones. The relative ratio of the final products is highly dependent on the substitution of the starting furan substrate. Photooxygenation of 2-(alpha,beta-dihydroxyalkyl)furans followed by in situ reduction and ketalization with acid rapidly provides the 6,8 dioxabicyclo[3.2.1]oct-3-en-2-one framework. This new methodology was successfully applied to the synthesis of 2-hydroxy-exo-brevicomin. PMID- 21280621 TI - In situ antibody detection and charge discrimination using aqueous stable pentacene transistor biosensors. AB - Pentacene-based organic thin-film transistors were used to create highly sensitive, real-time electronic sensors for selective antibody detection. Bovine serum albumin was covalently attached to a modified pentacene surface to selectively detect the label free monoclonal antiBSA. These sensors displayed a high affinity constant (K(A)) of (1.1 +/- 3) * 10(7) M(-1) at pH 7, which is 1 order of magnitude higher than those obtained with a highly sensitive surface plasmon resonance spectroscopy detection system. Furthermore, a high degree of discrimination in the hybrid antiBSA charges was achieved at different pH values. This demonstration of fast, label-free, real-time detection of nanoscale biomolecules in aqueous buffer solutions using the organic transistor sensing platform will have a significant impact on high-performance microarrays in addition to discriminating the presence of ionizable groups. PMID- 21280622 TI - Production of the seed germination stimulant karrikinolide from combustion of simple carbohydrates. AB - The naturally occurring seed germination stimulant karrikinolide is formed from the combustion of plant material including cellulose. It has previously been reported that combustion of simple carbohydrates such as d-glucose does not produce extracts containing karrikinolide. Moreover, it was reported that extracts with germination-promoting ability could be obtained only by combustion of simple carbohydrates in the presence of amino acids such as l-glycine. By employing a (13)C-labeled karrikinolide to physically quantify natural karrikinolide, we now show that it is produced from combustion of simple carbohydrates in similar amounts regardless of whether l-glycine is present or not. The addition of l-glycine appears to be beneficial in reducing the inhibitory effect of smoke extracts and provides a greater concentration range for effective germination-promoting activity. PMID- 21280624 TI - N-cyclic bay-substituted perylene G-quadruplex ligands have selective antiproliferative effects on cancer cells and induce telomere damage. AB - A series of bay-substituted perylene derivatives is reported as a new class of G quadruplex ligands. The synthesized compounds have differing N-cyclic substituents on the bay area and differing side chains on the perylene major axis. ESI-MS and FRET measurements highlighted the strongest quadruplex binders in this series and those showing the highest quadruplex/duplex selectivity. Several biological assays were performed on these compounds, which showed that compound 5 (PPL3C) triggered a DNA damage response in transformed cells with the formation of telomeric foci containing phosphorylated gamma-H2AX and 53BP1. This effect mainly occurred in replicating cells and was consistent with Pot1 dissociation. Compound 5 does not induce telomere damage in normal cells, which are unaffected by treatment with the compound, suggesting that this agent preferentially kills cancer cells. These results reinforce the notion that G quadruplex binding compounds can act as broad inhibitors of telomere-related processes and have potential as selective antineoplastic drugs. PMID- 21280625 TI - Redox-neutral indole annulation cascades. AB - Aminobenzaldehydes react with indoles in an unprecedented cascade reaction. This acid-catalyzed redox-neutral annulation proceeds via a condensation/1,5-hydride shift/ring-closure sequence. Polycyclic azepinoindoles and related compounds are obtained in a single step with good to excellent yields. PMID- 21280626 TI - Use of stimulatory agents to enhance the production of bioactive exopolysaccharide from pleurotus tuber-regium by submerged fermentation. AB - Fatty acids, organic solvents and surfactants were investigated for their stimulatory effects on the growth of fungal mycelium and production of exopolysaccharide (EPS) by submerged fermentation of an edible mushroom Pleurotus tuber-regium. Addition of 3.0 g/L Tween 80 at the late stage of exponential growth phase provided the best stimulatory effect on mycelial biomass and fungal EPS production with a 51.3 and 41.8% increase, respectively. The chemical structure of the EPS produced with addition of Tween 80 was found to be a glucomannan with similar monosaccharide composition and glycosidic linkages but a significantly lower molecular weight (3.18 +/- 0.09 * 10(6) Da), compared to the control (4.30 +/- 0.12 * 10(6) Da). These two EPS could significantly inhibit the growth of chronic myelogenous leukemia K562 cells in a dose dependent manner, with an estimated IC(50) value of 43.7 and 47.6 MUg/mL, respectively. The use of stimulatory agents to enhance production of bioactive fungal EPS can be applied in other fungal fermentation processes for enhancing production of useful metabolites. PMID- 21280627 TI - Modeling and benchmark data set for the inhibition of c-Jun N-terminal kinase-3. AB - The goal of this paper is to present and describe a novel 2D- and 3D-QSAR (quantitative structure-activity relationship) binary classification data set for the inhibition of c-Jun N-terminal kinase-3 with previously unpublished activities for a diverse set of compounds. JNK3 is an important pharmaceutical target because it is involved in many neurological disorders. Accordingly, the development of JNK3 inhibitors has gained increasing interest. 2D and 3D versions of the data set were used, consisting of 313 (70 actives) and 249 (60 actives) compounds, respectively. All compounds, for which activity was only determined for the racemate, were removed from the 3D data set. We investigated the diversity of the data sets by an agglomerative clustering with feature trees and show that the data set contains several different scaffolds. Furthermore, we show that the benchmarks can be tackled with standard supervised learning algorithms with a convincing performance. For the 2D problem, a random decision forest classifier achieves a Matthew's correlation coefficient of 0.744, the 3D problem could be modeled with a Matthew's correlation coefficient of 0.524 with 3D pharmacophores and a support vector machine. The performance of both data sets was evaluated within a nested 10-fold cross-validation. We therefore suggest that the data set is a reasonable basis for generating QSAR models for JNK3 because of its diverse composition and the performance of the classifiers presented in this study. PMID- 21280628 TI - Experimental, SOPPA(CCSD), and DFT analysis of substitutent effects on NMR 1JCF coupling constants in fluorobenzene derivatives. AB - Interesting insight into the electronic molecular structure changes associated with substituent effects on the Fermi contact (FC) and paramagnetic spin-orbit (PSO) terms of (1)J(CF) NMR coupling constants (SSCCs) in o-X-, m-X-, and p-X fluorobenzenes (X = NH(2); NO(2)) is presented. The formulation of this approach is based on the influence of different conjugative and hyperconjugative interactions on a second-order property, which can be qualitatively predicted if it is known how they affect the main virtual excitations entering into that second-order property. A set of consistent approximations are introduced in order to analyze the behavior of occupied and virtual orbitals, which define some experimental trends for (1)J(CF) spin-spin coupling constants. In addition, DFT hybrid functionals were used, and a similar degree of confidence to compute the (1)J(CF) with those observed for the SOPPA(CCSD) method was obtained. The (1)J(CF) SSCCs for ezetimibe, a commercially fluorinated drug used to reduce cholesterol levels, were measured and DFT-calculated, and the qualitative approach quoted above was applied. As a byproduct, a possible method to determine experimentally a significant PSO contribution to (1)J(CF) SSCCs is discussed. PMID- 21280629 TI - Controlled synthesis and size-dependent polarization domain structure of colloidal germanium telluride nanocrystals. AB - Germanium telluride (GeTe) exhibits interesting materials properties, including a reversible amorphous-to-crystalline phase transition and a room-temperature ferroelectric distortion, and has demonstrated potential for nonvolatile memory applications. Here, a colloidal approach to the synthesis of GeTe nanocrystals over a wide range of sizes is demonstrated. These nanocrystals have size distributions of 10-20% and exist in the rhombohedral structure characteristic of the low-temperature polar phase. The production of nanocrystals of widely varying sizes is facilitated by the use of Ge(II) precursors with different reactivities. A transition from a monodomain state to a state with multiple polarization domains is observed with increasing size, leading to the formation of richly faceted nanostructures. These results provide a starting point for deeper investigation into the size-scaling and fundamental nature of polar-ordering and phase-change processes in nanoscale systems. PMID- 21280630 TI - New isoflavonoid glycosides and related constituents from astragali radix ( Astragalus membranaceus ) and their inhibitory activity on nitric oxide production. AB - Twenty-four secondary metabolites, including 16 isoflavonoids, 7 astragalasides, and 1 benzoquinone, have been isolated from the roots of Astragalus membranaceus (Astragali radix). Among these isolated isoflavonoids, (-)-methylinissolin 3-O beta-d-(6'-acetyl)-glucoside (1), (-)-methylinissolin 3-O-beta-d-{6'-[(E)-but-2 enoyl]}-glucoside (2), and calycosin 7-O-beta-d-(6''-acetyl)-glucoside (3) have been identified as new compounds on the basis of spectroscopic analysis; (-) methylinissolin 3-O-beta-d-glucoside (4) was isolated from the natural products for the first time. The nitric oxide (NO) production inhibitory activity of the major compounds has been assessed in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. To identify A. membranaceus, a fingerprint method was developed by using a high-performance liquid chromatography-evaporative light scattering detector (HPLC-ELSD) method. Furthermore, characteristic peaks for the 11 major compounds in the chromatogram were unambiguously confirmed. PMID- 21280631 TI - Effect of soyasaponins-rich extract from soybean on acute alcohol-induced hepatotoxicity in mice. AB - The protective effects of soyasaponins-rich extract (SRE) from soybean against acute alcohol-induced hepatotoxicity were first investigated in the Institute of Cancer Research mice. Administration of SRE prior to alcohol significantly prevented the increases in serum aspartate transaminase, alanine transaminase, alkaline phosphatase, and lactate dehydrogenase caused by alcohol, as well as hepatic triglyceride, total cholesterol, and malondialdehyde levels. Mice treated with SRE showed a better profile of the antioxidant system with normal superoxide dismutase, glutathione S-transferase, and glutathione peroxidase activities, which were associated with the increase of hepatic glutathione levels relative to the acute alcohol-treated group. Supplement of SRE prevented alcohol-induced hepatic steatosis necrosis, inflammation, and swelling, as indicated by liver histopathological studies. All of these findings demonstrate that SRE has protective effects on acute alcohol-induced liver damage. PMID- 21280632 TI - Isolation and identification of compounds responsible for antioxidant capacity of Euryale ferox seeds. AB - Euryale ferox seed is consumed medicinally or for food in China. The present study revealed it to contain significant antioxidant activity, which may be associated with its medical applications as a proteinuria inhibitor of diabetic nephropathy. This study resulted in the identification of 3 new sesquineolignans, named euryalins A-C (1-3), and 16 known compounds, which were all first isolated from this plant apart from 5,7,4-trihydroxy-flavanone. The antioxidant potential of the partial isolates was evaluated using the DPPH radical scavenging assay and mesangial cellular assay. Compounds 2, rel-(2alpha,3beta)-7-O-methylcedrusin (4), syringylglycerol-8-O-4-(sinapyl alcohol) ether (5), and (+)-syringaresinol (7) were found to be most active on DPPH assay, whereas compounds 2, 4, 7, (1R,2R,5R,6S)-2-(3,4-dimethoxyphenyl)-6-(3,4-dihydroxyphenyl)-3,7 dioxabicyclo[3.3.0]octane, and buddlenol E could significantly inhibit high glucose-stimulated reactive oxygen species production in mesangial cells. The results suggested that E. ferox seed could be considered as an excellent source of natural antioxidants and is useful in the prevention of diabetic nephropathy. PMID- 21280633 TI - Enhancement of the catalytic activity of supported gold nanoparticles for the Fenton reaction by light. AB - Laser flash photolysis of supported gold nanoparticles exciting at the surface plasmon band (532 nm) has allowed in the case of Au/CeO(2) and Au/OH-npD (OH-npD: Fenton-treated diamond nanoparticles) detection of transients decaying in the microsecond time scale that have been attributed as indicating photoinduced electron ejection from gold based on N(2)O quenching and the observation of the generation of methyl viologen radical cations. This photochemical behavior has led us to hypothesize that there could be assistance to the catalytic activity of these materials by irradiation in those cases wherein the mechanism involves electron transfer to or from a substrate to the gold. This hypothesis has been confirmed by observing that the catalytic activity of Au/OH-npD for the Fenton degradation of phenol with hydrogen peroxide can be increased over 1 order of magnitude by irradiation at 532 nm. Moreover, there is a linear relationship between the initial reaction rate and the incident photon flux. This photoenhancement allows promoting Fenton activity at pH 8 in which the catalytic activity of Au/OH-npD is negligible. The same photo enhancement activity for the Fenton degradation of phenol was observed for other supported gold catalysts including those that do not exhibit microsecond transients in the nanosecond laser flash photolysis (Au/TiO(2) and Au/SiO(2)) due to their lifetime shorter than microseconds. It is proposed that the photo enhancement should be a general phenomenon in gold catalysis for those reaction mechanisms involving positive and/or negative gold species. PMID- 21280634 TI - Identification of new strawberry sulfur volatiles and changes during maturation. AB - Two Florida strawberry cultivars, 'Strawberry Festival' and 'Florida Radiance', were harvested at five fruit developmental stages (white, half red, three-quarter red, full ripe, and overripe) at four harvest dates. A static headspace solid phase microextraction (SPME) sampling technique coupled with gas chromatography (GC) using pulsed flame photometric detection (PFPD) was employed to measure 16 sulfur volatiles in these strawberries. A total of 7 sulfur volatiles have been previously reported, and 9 are reported for the first time in strawberries. Newly identified sulfur volatiles include methyl thiopropionate, ethyl thiobutanoate, methyl thiohexanoate, methyl (methylthio)acetate, ethyl (methylthio)acetate, methyl 2-(methylthio)butyrate, methyl 3-(methylthio)propionate, ethyl 3 (methylthio)propionate, and methyl thiooctanoate. Identifications were based on matching sulfur peak linear retention indexes (LRIs) of unknowns with authentic standards and gas chromatography-mass spectrometry (GC-MS) data. Concentrations were determined using both internal and external standards. Most sulfur volatiles increased with increasing maturity, with only concentrations of hydrogen sulfide and methanethiol remaining relatively consistent at all five stages. At the white and half red stages, most sulfur volatiles consisted of various alkyl sulfides. At three-quarter red (commercial ripe), full ripe, and overripe stages, the majority of sulfur volatiles consisted of sulfur esters. Most sulfur volatiles increased dramatically between the commercial ripe, full ripe, and overripe stages, increasing as much as 100% between full ripe and overripe. Principal component analysis indicated that sulfur volatiles could be used to distinguish overripe from full ripe and commercial ripe berries. PMID- 21280635 TI - Characterization of a designed vascular endothelial growth factor receptor antagonist helical peptide with antiangiogenic activity in vivo. AB - Angiogenesis is a fundamental process underlining physiological and pathological conditions. It is mainly regulated by the vascular endothelial growth factor (VEGF) and its receptors, which are the main targets of molecules able to modulate the angiogenic response. Pharmaceutical therapies based on antiangiogenic drugs represent a promising approach for the treatment of several socially important diseases. We report the biological and structural characterization of a VEGF receptor binder peptide designed on the N-terminal helix of VEGF. The reported experimental evidence shows that the peptide assumes in water a well-defined helical conformation and indicates that this peptide is a VEGF receptor antagonist and possesses antiangiogenic biological activity. In particular, it inhibits VEGF stimulated endothelial cell proliferation, activation, and survival, as well as angiogenesis and tumor progression in vivo. This peptide is a candidate for the development of novel peptide-based drugs for the treatment of diseases associated with excessive VEGF-dependent angiogenesis. PMID- 21280636 TI - Microwave promoted simple, efficient and regioselective synthesis of trisubstituted imidazo[1,2-a]benzimidazoles on soluble support. AB - An efficient microwave-assisted and soluble polymer-supported synthesis of medicinally important imidazole-fused benzimidazoles has been developed. The protocol involves the rapid condensation of polymer-bound amino benzimidazoles with various alpha-bromoketones and subsequent in situ intramolecular cyclization under microwave irradiation resulting in a one pot synthesis of imidazole interlacing benzimidazole polymer conjugates. The condensed product was obtained with excellent regioselectivity. The biologically interesting imidazo[1,2 a]benzimidazoles was released from polymer support at ambient temperature. Diversity in the triheterocyclic nucleus was achieved by the different substitutions at its 2, 3, and 9 positions. The new protocol has the advantages of short reaction time, easy workup process, excellent yields, reduced environmental impact, wide substrate scope and convenient procedure. PMID- 21280637 TI - Multireference configuration interaction study of bromocarbenes. AB - Multireference configuration interaction (MRCI) calculations of the lowest singlet X(1A') and triplet a((3)A'') states as well as the first excited singlet A((1)A'') state have been performed for a series of bromocarbenes: CHBr, CFBr, CClBr, CBr(2), and CIBr. The MRCI calculations were performed with correlation consistent basis sets of valence triple-zeta plus polarization quality, employing a full-valence active space of 18 electrons in 12 orbitals (12 and 9, respectively, for CHBr). Results obtained include equilibrium geometries and harmonic vibrational frequencies for each of the electronic states, along with a((3)A'') <- X((1)A') singlet-triplet gaps and A((1)A'') <- X((1)A') transition energies. Comparisons have been made with previous computational and experimental results where available. The MRCI calculations presented in this work provide a comprehensive series of results at a consistent high level of theory for all of the bromocarbenes. PMID- 21280638 TI - Nanoengineered surfaces enhance drug loading and adhesion. AB - To circumvent the barriers encountered by macromolecules at the gastrointestinal mucosa, sufficient therapeutic macromolecules must be delivered in close proximity to cells.(1) Previously, we have shown that silicon nanowires penetrate the mucous layer and adhere directly to cells under high shear.(2) In this work, we characterize potential reservoirs and load macromolecules into interstitial space between nanowires. We show significant increases in loading capacity due to nanowires while retaining adhesion of loaded particles under high shear. PMID- 21280639 TI - Manipulating coupling between a single semiconductor quantum dot and single gold nanoparticle. AB - Using atomic force microscopy nanomanipulation, we position a single Au nanoparticle near a CdSe/ZnS quantum dot to construct a hybrid nanostructure with variable geometry. The coupling between the two particles is varied in a systematic and reversible manner. The photoluminescence lifetime and blinking of the same quantum dot are measured before and after assembly of the structure. In some hybrid structures, the total lifetime is reduced from about 30 ns to well below 1 ns. This dramatic change in lifetime is accompanied by the disappearance of blinking as the nonradiative energy transfer from the CdSe/ZnS quantum dot to the Au nanoparticle becomes the dominant decay channel. Both total lifetime and photoluminescence intensity changes are well described by simple analytical calculations. PMID- 21280640 TI - AC field-induced polymer electroluminescence with single wall carbon nanotubes. AB - We developed a high-performance field-induced polymer electroluminescence (FPEL) device consisting of four stacked layers: a top metal electrode/thin solution processed nanocomposite film of single wall carbon nanotubes (SWNTs) and a fluorescent polymer/insulator/transparent bottom electrode working under an alternating current (AC) electric field. A small amount of SWNTs that were highly dispersed in the fluorescent polymer matrix by a conjugate block copolymer dispersant significantly enhanced EL, and we were able to realize an SWNT-FPEL device with a light emission of approximately 350 cd/m(2) at an applied voltage of +/-25 V and an AC frequency of 300 kHz. The brightness of the SWNT-FPEL device is much greater than those of other AC-based organic or even inorganic ELs that generally require at least a few hundred volts. Light is emitted from our SWNT FPEL device because of the sequential injection of field-induced holes and then electron carriers through ambipolar carbon nanotubes under an AC field, followed by exciton formation in the conjugated organic layer. Field-induced bipolar charge injection provides great material design freedom for our devices; the energy level does not have to be aligned between the electrode and the emission layer, and the balance of the carrier injected and transported can be altered in contrast to that in conventional organic light-emitting diodes, leading to an extremely cost-effective and unified device architecture that is applicable to all red-green-blue fluorescent polymers. PMID- 21280641 TI - Anomalous light transmission from plasmonic-capped nanoapertures. AB - We report an anomalous light transmission phenomenon for a nanoaperture on an opaque screen when the aperture is covered with an opaque cap. In conventional optics, light transmission must decrease when the aperture is capped. However, we found that light transmission is enhanced when the nanodisk is in close proximity to the aperture at a wavelength close to the plasmon resonance. This effect even occurs when the disk is larger than the aperture. PMID- 21280642 TI - High thermoelectric figure-of-merit in kondo insulator nanowires at low temperatures. AB - We predict a large thermoelectric figure-of-merit in Kondo insulator nanowires at low temperatures. The high ZT values are due to the Kondo effect for electrons and boundary scattering on phonons. We simulated the electron properties of the bulk Kondo insulators within the framework of dynamical mean field theory and found that electrons have short mean free path. In nanowire structures, electron transport is hardly affected by the boundary scattering due to their small intrinsic mean free paths while phonons are strongly scattered due to classical size effect. The results suggest that the nanostructures of Kondo insulators can be designed for high performance thermoelectric cooling devices at low temperatures. PMID- 21280643 TI - A conformation- and ion-sensitive plasmonic biosensor. AB - The versatile optical and biological properties of a localized surface plasmon resonance (LSPR) sensor that responds to protein conformational changes are illustrated. The sensor detects conformational changes in a surface-bound construct of the calcium-sensitive protein calmodulin. Increases in calcium concentration induce a 0.96 nm red shift in the spectral position of the LSPR extinction maximum (lambda(max)). Addition of a calcium chelating agent forces the protein to return to its original conformation and is detected as a reversal of the lambda(max) shift. As opposed to previous work, this work demonstrates that these conformational changes produce a detectable shift in lambda(max) even in the absence of a protein label, with a signal:noise ratio near 500. In addition, the protein conformational changes reversibly switch both the wavelength and intensity of the resonance peak, representing an example of a bimodal plasmonic component that simultaneously relays two distinct forms of optical information. This highly versatile plasmonic device acts as a biological sensor, enabling the detection of calcium ions with a biologically relevant limit of detection of 23 MUM, as well as the detection of calmodulin-specific protein ligands. PMID- 21280644 TI - Electrically actuatable smart nanoporous membrane for pulsatile drug release. AB - We report on the fabrication of electrically responsive nanoporous membrane based on polypyrrole doped with dodecylbenzenesulfonate anion (PPy/DBS) that was electropolymerized on the upper part of anodized aluminum oxide membrane. The membrane has regular pore size and very high pore density. Utilizing a large volume change of PPy/DBS depending on electrochemical state, the pore size was acutated electrically. The actuation of the pores was experimentally confirmed by in situ atomic force microscopy and in situ flux measurement. We also demonstrated successfully pulsatile (or on-demand) drug release by using fluorescently labeled protein as a model drug. Because of a fast switching time (less than 10 s) and high flux of the drugs, this membrane could be used for emergency therapy of angina pectoris and migraine, which requires acute and on demand drug delivery, and hormone-related disease and metabolic syndrome. PMID- 21280645 TI - Highly effective, water-soluble, hemocompatible 1,3-propylene oxide-based antimicrobials: poly[(3,3-quaternary/PEG)-copolyoxetanes]. AB - This study focuses on the solution antimicrobial effectiveness of a novel class of copolyoxetanes with quaternary ammonium and PEG-like side chains. A precursor P[(BBOx-m)(ME2Ox)] copolyoxetane was prepared by cationic ring-opening copolymerization of 3-((4-bromobutoxy)methyl)-3-methyloxetane (BBOx) and 3-((2-(2 methoxyethoxy)ethoxy)methyl)-3-methyloxetane (ME2Ox) to give random copolymers with 14-100 (m) mol % BBOx. Reaction of P[(BBOx-m)(ME2Ox)] with dodecyl dimethylamine gave the corresponding quaternary P[(C12-m)(ME2Ox)] polycation salts, designated C12-m, as viscous liquids in 100% yield. BBOx/ME2Ox and C12/ME2Ox ratios were obtained by (1)H NMR spectroscopy. C12-m molecular weights (M(n), 3.5-21.9 kDa) were obtained from (1)H NMR end group analysis. DSC studies up to 150 degrees C showed only thermal transitions between -69 and -34 degrees C assigned to T(g) values. Antibacterial activity for the C12-m copolyoxetanes was tested by determining minimum inhibitory concentrations (MICs) against Gram(+) Staphylococcus aureus and Gram(-) Escherichia coli and Pseudomonas aeruginosa . MIC decreased with increasing C12 mol percent, reaching a minimum in the range C12-43 to C12-60. Overall, the antimicrobial with consistently low MICs for the three tested pathogenic bacteria was C12-43: (bacteria, MIC, MUg/mL) E. coli (6), S. aureus (5), and P. aeruginosa (33). For C12-43, minimum biocidal concentration (MBC) to reach 99.99% kill in 24 h required 1.5* MIC for S. aureus and 2* MIC for E. coli and P. aeruginosa . At 5* MIC against a challenge of 10(8) cfu/mL, C12-43 kills >=99% S. aureus , E. coli , and P. aeruginosa within 1 h. C12-m copolyoxetane cytotoxicity toward human red blood cells was low, indicating good prospects for biocompatibility. The tunability of C12-m copolyoxetane compositions, effective antimicrobial behavior against Gram(+) and Gram(-) bacteria, and promising biocompatibility offer opportunities for further modification and potential applications as therapeutic agents. PMID- 21280646 TI - Preparation of mineralized nanofibers: collagen fibrils containing calcium phosphate. AB - We report a straightforward, bottom-up, scalable process for preparing mineralized nanofibers. Our procedure is based on flowing feed solution, containing both inorganic cations and polymeric molecules, through a nanoporous membrane into a receiver solution with anions, which leads to the formation of mineralized nanofibers at the exit of the pores. With this strategy, we were able to achieve size control of the nanofiber diameters. We illustrate this approach by producing collagen fibrils with calcium phosphate incorporated inside the fibrils. This structure, which resembles the basic constituent of bones, assembles itself without the addition of noncollagenous proteins or their polymeric substitutes. Rheological experiments demonstrated that the stiffness of gels derived from these fibrils is enhanced by mineralization. Growth experiments of human adipose derived stem cells on these gels showed the compatibility of the fibrils in a tissue-regeneration context. PMID- 21280647 TI - Toxicity of ZnO nanoparticles to Escherichia coli: mechanism and the influence of medium components. AB - Water chemistry can be a major factor regulating the toxicity mechanism of ZnO nanoparticles (nano-ZnO) in water. The effect of five commonly used aqueous media with various chemical properties on the toxicity of nano-ZnO to Escherichia coli O111 (E. coli) was investigated, including ultrapure water, 0.85% NaCl, phosphate buffered saline (PBS), minimal Davis (MD), and Luria-Bertani (LB). Combined results of physicochemical characterization and antibacterial tests of nano-ZnO in the five media suggest that the toxicity of nano-ZnO is mainly due to the free zinc ions and labile zinc complexes. The toxicity of nano-ZnO in the five media deceased as follows: ultrapure water > NaCl > MD > LB > PBS. The generation of precipitates (Zn(3)(PO(4))(2) in PBS) and zinc complexes (of zinc with citrate and amino acids in MD and LB, respectively) dramatically decreased the concentration of Zn(2+) ions, resulting in the lower toxicity in these media. Additionally, the isotonic and rich nutrient conditions improved the tolerance of E. coli to toxicants. Considering the dramatic difference of the toxicity of nano ZnO in various aqueous media, the effect of water chemistry on the physicochemical properties of nanoparticles should be paid more attention in future nanotoxicity evaluations. PMID- 21280648 TI - The red mud accident in Ajka (Hungary): characterization and potential health effects of fugitive dust. AB - As a result of a tragic industrial accident, a highly alkaline red mud sludge inundated settlements and agricultural areas near Ajka, Hungary on October 4, 2010. One of the major concerns about the aftermaths of the accident is the potential health effects of vast amounts of fugitive dust from red mud sediment. Thus, we studied the chemical and physical properties of particles of red mud and its respirable fugitive dust, and performed toxicity measurements. Under unfavorable meteorological conditions dry red mud sediment could emit very high amounts of respirable alkaline particles into the air. The number size distribution of fugitive dust peaks above 1 MUm aerodynamic diameter; therefore, its inhalation is unlikely to affect the deep regions of the lungs. No significant mineralogical or elemental fractionation was observed between the sediment and dust, with the major minerals being hematite, cancrinite, calcite, and hydrogarnet. Although the high resuspension potential and alkalinity might pose some problems such as the irritation of the upper respiratory tract and eyes, based on its size distribution and composition red mud dust appears to be less hazardous to human health than urban particulate matter. PMID- 21280649 TI - Including carbon emissions from deforestation in the carbon footprint of Brazilian beef. AB - Effects of land use changes are starting to be included in estimates of life cycle greenhouse gas (GHG) emissions, so-called carbon footprints (CFs), from food production. Their omission can lead to serious underestimates, particularly for meat. Here we estimate emissions from the conversion of forest to pasture in the Legal Amazon Region (LAR) of Brazil and present a model to distribute the emissions from deforestation over products and time subsequent to the land use change. Expansion of cattle ranching for beef production is a major cause of deforestation in the LAR. The carbon footprint of beef produced on newly deforested land is estimated at more than 700 kg CO(2)-equivalents per kg carcass weight if direct land use emissions are annualized over 20 years. This is orders of magnitude larger than the figure for beef production on established pasture on non-deforested land. While Brazilian beef exports have originated mainly from areas outside the LAR, i.e. from regions not subject to recent deforestation, we argue that increased production for export has been the key driver of the pasture expansion and deforestation in the LAR during the past decade and this should be reflected in the carbon footprint attributed to beef exports. We conclude that carbon footprint standards must include the more extended effects of land use changes to avoid giving misleading information to policy makers, retailers, and consumers. PMID- 21280650 TI - Global gene expression profiling in larval zebrafish exposed to microcystin-LR and microcystis reveals endocrine disrupting effects of Cyanobacteria. AB - Microcystis blooms occur worldwide and threaten aquatic ecosystems and human health. Sublethal effects on early developmental stages of fish are largely unknown, and research has mainly focused on microcystin toxins (such as MC-LR) rather than Microcystis cells. We exposed (96 h) zebrafish larvae to purified MC LR (0-1000 MUg/L) or lyophilized Microcystis aeruginosa containing 4.5 MUg/L MC LR and evaluated changes in global gene expression (Affymetrix GeneChip zebrafish genome arrays). Significant changes in gene expression (>= 1.7-fold change, p < 0.0001) were determined with Rosetta Resolver 7.0, and ontology analysis was conducted with the DAVID bioinformatics tool. The number of differentially expressed genes relative to control increased with MC-LR concentration and included genes related to known mechanisms of action for MC-LR in mammals and older life stages of fish, as well as genes unique to larval zebrafish. Up regulation of vitellogenin genes (vtg) (19.2-fold to >100-fold on arrays; 619.3 fold confirmed by quantitative PCR) was observed in Microcystis-exposed larvae but not in larvae exposed to MC-LR. Up-regulation of vtg indicates exposure to estrogenic substance(s) and suggests that Microcystis may be a natural source of environmental estrogens. Concerns about effects of Microcystis blooms may extend beyond those associated with the microcystin toxin. PMID- 21280651 TI - Evolution of potent and stable placental-growth-factor-1-targeting CovX-bodies from phage display peptide discovery. AB - Novel phage-derived peptides are the first reported molecules specifically targeting human placental growth factor 1 (PlGF-1). Phage data enabled peptide modifications that decreased IC(50) values in PlGF-1/VEGFR-1 competition ELISA from 100 to 1 MUM. Peptides exhibiting enhanced potency were bioconjugated to the CovX antibody scaffold 1 (CVX-2000), generating bivalent CovX-Bodies with 2 nM K(D) against PlGF-1. In vitro and in vivo peptide cleavage mapping studies enabled the identification of proteolytic hotspots that were subsequently chemically modified. These changes decreased IC(50) to 0.4 nM and increased compound stability from 5% remaining at 6 h after injection to 35% remaining at 24 h with a beta phase half-life of 75 h in mice. In cynomolgus monkey, a 78 h beta half-life was observed for lead compound 2. The pharmacological properties of 2 are currently being explored. PMID- 21280652 TI - Gold nanoparticle-quantum dot-polystyrene microspheres as fluorescence resonance energy transfer probes for bioassays. AB - The paper describes the development of highly sensitive particle-based fluorescence resonance energy transfer (FRET) probes that do not use molecular fluorophores as donors and acceptors. In these probes, CdSe/ZnS luminescent quantum dots (QDs) were capped with multiple histidine-containing peptides to increase their aqueous solubility while maintaining their high emission quantum yield and spectral properties. The peptide-modified QDs (QD-His) were covalently attached to carboxyl-modified polystyrene (PS) microspheres to form highly emitting PS microspheres (QD-PS). Gold nanoparticles (AuNPs) were then covalently attached to the QD-PS surface to form AuNP-QD-PS composite microspheres that were used as FRET probes. Attachment of AuNPs to QD-PS completely quenched the QD emission through FRET interactions. The emission of QD-PS was restored when the AuNPs were removed from the surface by thiol ligand displacement. The new AuNP-QD PS FRET platform is simple to prepare and highly stable, and it opens many new possibilities for carrying out FRET assays on microparticle-based platforms and in microarrays. The versatility of these assays could be greatly increased by replacing the linkers between the QDs and AuNPs with ones that selectively respond to specific cleaving agents or enzymes. PMID- 21280653 TI - ABC transporters required for export of wall teichoic acids do not discriminate between different main chain polymers. AB - The cell envelopes of Gram-positive bacteria comprise two major constituents, peptidoglycan and teichoic acids. Wall teichoic acids (WTAs) are anionic glycophosphate polymers that play important roles in bacterial cell growth, division, and pathogenesis. They are synthesized intracellularly and exported by an ABC transporter to the cell surface, where they are covalently attached to peptidoglycan. We address here the substrate specificity of WTA transporters by substituting the Bacillus subtilis homologue, TagGH(Bs), with the Staphylococcus aureus homologue, TarGH(Sa). These transporters export structurally different substrates in their indigenous organisms, but we show that TarGH(Sa) can substitute for the B. subtilis transporter. Hence, substrate specificity does not depend on the WTA main chain polymer structure but may be determined by the conserved diphospholipid-linked disaccharide portion of the WTA precursor. We also show that the complemented B. subtilis strain becomes susceptible to a S. aureus-specific antibiotic, demonstrating that the S. aureus WTA transporter is the sole target of this compound. PMID- 21280654 TI - Electronically excited states of vitamin B12: benchmark calculations including time-dependent density functional theory and correlated ab initio methods. AB - Time-dependent density functional theory (TD-DFT) and correlated ab initio methods have been applied to explore the electronically excited states of vitamin B(12) (cyanocobalamin or CNCbl). Different experimental techniques have been used to probe the excited states of CNCbl, revealing many issues that remain poorly understood from an electronic structure point of view. Due to its efficient scaling with size, TD-DFT emerges as one of the most practical tools that can be used to study the electronic properties of these fairly complex molecules. However, the description of excited states is strongly dependent on the type of functional used in the calculations. In the present contribution, the choice of a proper functional for vitamin B(12) was evaluated in terms of its agreement with both experimental results and correlated ab initio calculations. Three different functionals, i.e., B3LYP, BP86, and LC-BLYP, were tested. In addition, the effect of the relative contributions of DFT and HF to the exchange-correlation functional was investigated as a function of the range-separation parameter, MU. The issues related to the underestimation of charge-transfer excitation energies by TD-DFT were validated by the Lambda diagnostic, which measures the spatial overlap between occupied and virtual orbitals involved in the particular excitation. The nature of the low-lying excited states was also analyzed based on a comparison of TD-DFT and ab initio results. Based on an extensive comparison with experimental results and ab initio benchmark calculations, the BP86 functional was found to be the most appropriate in describing the electronic properties of CNCbl. Finally, an analysis of electronic transitions and reassignment of some excitations were discussed. PMID- 21280655 TI - Manganese alkane complexes: an IR and NMR spectroscopic investigation. AB - Manganese propane and manganese butane complexes derived from CpMn(CO)(3) were generated photochemically at 130-136 K with the alkane as solvent and characterized by FTIR spectroscopy and by (1)H NMR spectroscopy with in situ laser photolysis. Time-resolved IR spectroscopic measurements were performed at room temperature with the same laser wavelength. The nu(CO) bands in the IR spectra of the photoproducts in propane are shifted to low frequency with respect to CpMn(CO)(3), consistent with formation of CpMn(CO)(2)(propane). The (1)H NMR spectra conform to the criteria for alkane complexes: a high-field resonance for the eta(2)-CH protons that shifts substantially on partial deuteration of the alkane and exhibits a coupling constant J(C-H) on (13)C-labeling of ca. 120 Hz. The NMR spectrum of each system exhibits two diagnostic product resonances in the high-field region for the eta(2)-CH protons, corresponding to CpMn(CO)(2)(eta(2) C1-H-alkane) and CpMn(CO)(2)(eta(2)-C2-H-alkane) isomers. Partial deuteration of the alkane at C1 results in characteristic strong isotopic perturbation of equilibrium of the eta(2)-CH resonance of CpMn(CO)(2)(eta(2)-C1-H-alkane). With propane-(13)C(1), the eta(2)-CH resonance of CpMn(CO)(2)(eta(2)-C1-H-alkane) isomer exhibits (13)C satellites with J(C-H) = 119 Hz. The corresponding resonance of CpMn(CO)(2)(eta(2)-C2-H-alkane) is identified by use of propane-2,2 d(2). The lifetimes of the (eta(2)-C1-H-alkane) isomers of the manganese complexes were determined by NMR spectroscopy as 22 +/- 2 min at 134 K (propane) and 5.5 min at 136 K (butane). The corresponding spectra and lifetimes of the CpRe(CO)(2)(alkane) complexes were measured for reference (CpRe(CO)(2)(propane) lifetime ca. 60 min at 161 K; CpRe(CO)(2)(butane) 13 min at 171 K). The lifetimes determined by IR spectroscopy were similar to those determined by NMR spectroscopy, thereby supporting the assignments. These measurements extend the range of alkane complexes characterized by NMR spectroscopy from rhenium and rhodium derivatives to include less stable manganese derivatives. PMID- 21280656 TI - Transfer, amplification, and inversion of helical chirality mediated by concerted interactions of C3-supramolecular dendrimers. AB - The synthesis, structural, and retrostructural analysis of two libraries containing 16 first and second generation C(3)-symmetric self-assembling dendrimers based on dendrons connected at their apex via trisesters and trisamides of 1,3,5-benzenetricarboxylic acid is reported. A combination of X-ray diffraction and CD/UV analysis methods demonstrated that their C(3)-symmetry modulates different degrees of packing on the periphery of supramolecular structures that are responsible for the formation of chiral helical supramolecular columns and spheres self-organizable in a diversity of three dimensional (3D) columnar, tetragonal, and cubic lattices. Two of these periodic arrays, a 3D columnar hexagonal superlattice and a 3D columnar simple orthorhombic chiral lattice with P222(1) symmetry, are unprecedented for supramolecular dendrimers. A thermal-reversible inversion of chirality was discovered in helical supramolecular columns. This inversion is induced, on heating, by the change in symmetry from a 3D columnar simple orthorhombic chiral lattice to a 3D columnar hexagonal array and, on cooling, by the change in symmetry from a 2D hexagonal to a 2D centered rectangular lattice, both exhibiting intracolumnar order. A first-order transition from coupled columns with long helical pitch, to weakly or uncorrelated columns with short helical pitch that generates a molecular rotator, was also discovered. The torsion angles of the molecular rotator are proportional to the change in temperature, and this effect is amplified in the case of the C(3)-symmetric trisamide supramolecular dendrimers forming H-bonds along their column. The structural changes reported here can be used to design complex functions based on helical supramolecular dendrimers with different degree of packing on their periphery. PMID- 21280657 TI - Graphene-based bimorph microactuators. AB - A novel graphene-on-organic film fabrication method that is compatible with a batch microfabrication process was developed and used for electromechanically driven microactuators. A very thin layer of graphene sheets was monolithically integrated and the unique material characteristics of graphene including negative thermal expansion and high electrical conductivity were exploited to produce a bimorph actuation. A large displacement with rapid response was observed while maintaining the low power consumption. This enabled the successful demonstration of transparent graphene-based organic microactuators. PMID- 21280658 TI - Patterned paper as a low-cost, flexible substrate for rapid prototyping of PDMS microdevices via "liquid molding". AB - This report describes the use of patterned paper as a low-cost, flexible substrate for rapidly prototyping PDMS microdevices via "liquid molding". The entire fabrication process consists simply of three steps: (1) fabrication of patterned paper in NC membrane by direct wax printing (or modified wax printing that we call "transfer wax printing"); (2) formation of liquid mold on wax patterned NC membrane; (3) PDMS molding and curing on wax-patterned NC membrane anchored with liquid micropatterns. All these procedures can be finished within only 1.5 h without the use of a photomask, photoresist, UV lamp, etc. Through the use of wax-patterned NC membrane coupled with a liquid mold as a template, different PDMS microdevices such as microwells and microchannels have been fabricated to demonstrate the usefulness of the method for PDMS microfabrication. The height of microwells and microchannels can also be tailored flexibly by adjusting the liquid filling volume. This method for prototyping PDMS microdevices has some favorable merits including simple operation procedures, fast concept-to-device time, and low cost, indicating its potential for simple PDMS microdevice fabrication and applications. PMID- 21280659 TI - Vertical plasmonic resonant nanocavities. AB - We demonstrate plasmonic modes in a vertical nanocavity with an air output window at the top surface and Ag reflectors. The resonances of surface plasmon polaritons are investigated using cathodoluminescence spectroscopy. The resonant modes are determined by comparing experiment and theoretical simulations. The plasmon dispersion relation in the vertical nanocavities shows a strong confinement to the electromagnetic field, and the smallest modal volume is only 0.0014 MUm(3). Our work provides insights into the development of nanoscale plasmonic vertical cavity surface-emitting lasers. PMID- 21280660 TI - Scanning gate spectroscopy and its application to carbon nanotube defects. AB - A variation of scanning gate microscopy (SGM) is demonstrated in which this imaging mode is extended into an electrostatic spectroscopy. Continuous variation of the SGM probe's electrostatic potential is used to directly resolve the energy spectrum of localized electronic scattering in functioning, molecular scale devices. The technique is applied to the energy-dependent carrier scattering that occurs at defect sites in carbon nanotube transistors, and fitting energy resolved experimental data to a simple transmission model determines the electronic character of each defect site. For example, a phenolic type of covalent defect is revealed to produce a tunnel barrier 0.1 eV high and 0.5 nm wide. PMID- 21280661 TI - Balancing redox activity allowing spectrophotometric detection of Au(I) using tetramethylbenzidine dihydrochloride. AB - Aqueous, acid solutions containing balanced amounts of a strong reductant (formaldehyde, HCHO) and a strong oxididant (N-bromosuccinimide, NBS) allow the first sensitive spectrophotometric analysis of monovalent gold ion, Au(I), using oxidation of color reagent 3,3',5,5'-tetramethylbenzidine dihydrochloride (TMB). This new method enables various oxidation states of Au ion to be quantified by balancing reduction potential in a Au solution. At low reductant levels, NBS oxidizes Au(I), which linearly suppresses subsequent oxidation of TMB by NBS to its blue charge-transfer complex of diamine and diimine to 2.00 mg L(-1) of Au, resulting in reduced color formation. The linear range of Au(I) quantitation was increased substantially relative to existing methods: from 0.005 to 1.00 mg L(-1) (R(2) = 0.988). For this range, the limit of detection was 0.0025 mg L(-1), which is comparable to the best reported spectroscopic method to analyze Au(III). At relatively high reductant levels, Au(I) is reduced to Au(0), then subsequently oxidized from Au(0) to Au(III) by addition of NBS. TMB is oxidized to its blue charge-transfer complex via the reduction of the reoxidized Au(III) to Au(0). Balancing redox conditions of HCHO/NBS at a molar ration of 22.7 allows quantitative measurement of Au(I) across a linear concentration range of 0.05 2.00 mg L(-1) (R(2) = 0.997). This balancing redox condition could allow sensitive, quantitative, spectrophotometric analysis of other metal ions besides Au by targeting the metal ion's reduction potential with an associated redox sensitive color reagent. PMID- 21280662 TI - Structural analysis of glycans by NMR chemical shift prediction. AB - Structural determination of N- and O-linked glycans as well as polysaccharides is hampered by the limited spectral dispersion. The computerized approach CASPER, an acronym for computer assisted spectrum evaluation of regular polysaccharides, uses liquid state NMR data to elucidate carbohydrate structure based on agreement with predicted (1)H and (13)C chemical shifts. We here demonstrate developments based on multiple through-bond J-based correlations that significantly enhance the credence to the sequence connectivities proposed in the analysis exemplified by an oligosaccharide and a bacterial polysaccharide. The approach is also suitable for predicting (1)H and (13)C NMR chemical shifts of synthesized oligosaccharides and glycoconjugates, thereby corroborating a proposed structure. PMID- 21280663 TI - Photoinduced ordering of block copolymers. AB - Photoinduced ordering of disordered block copolymers (BCPs) would provide an on demand, nonintrusive route for formation of well-ordered nanostructures in arbitrarily defined regions of an otherwise disordered material. Here we achieve this objective using a rapid and simple approach in which photoconversion of an additive blended with the BCP introduces strong interactions between the additive and one of the chain segments and induces strong order in the BCP blend. The strategy is generally applicable to block copolymers containing chain segments capable of hydrogen bonding with the additive. PMID- 21280664 TI - Switching regioselectivity in crossed acyloin condensations between aromatic aldehydes and acetaldehyde by altering N-heterocyclic carbene catalysts. AB - An unprecedented high level of regioselectivities (up to 96%) in the intermolecular crossed acyloin condensations of various aromatic aldehydes with acetaldehyde was realized by an appropriate choice of N-heterocyclic carbene catalysts. PMID- 21280665 TI - Controlled effect of ultrasonic cavitation on hydrophobic/hydrophilic surfaces. AB - Controlling cavitation at the solid surface is of increasing interest, as it plays a major role in many physical and chemical processes related to the modification of solid surfaces and formation of multicomponent nanoparticles. Here, we show a selective control of ultrasonic cavitation on metal surfaces with different hydrophobicity. By applying a microcontact printing technique we successfully formed hydrophobic/hydrophilic alternating well-defined microstructures on aluminium surfaces. Fabrication of patterned surfaces provides the unique opportunity to verify a model of heterogeneous nucleation of cavitation bubbles near the solid/water interface by varying the wettability of the surface, temperature and ultrasonic power. At the initial stage of sonication (up to 30 min), microjets and shock waves resulting from the collapsing bubbles preferably impact the hydrophobic surface, whereas the hydrophilic areas of the patterned Al remain unchanged. Longer sonication periods affect both surfaces. These findings confirm the expectation that higher contact angle causes a lower energy barrier, thus cavitation dominates at the hydrophobic surfaces. Experimental results are in good agreement with expectations from nucleation theory. This paper illustrates a new approach to ultrasound induced modification of solid surfaces resulting in the formation of foam-structured metal surfaces. PMID- 21280666 TI - Large pore size nanoporous materials from the self-assembly of asymmetric bottlebrush block copolymers. AB - Asymmetric polystyrene-polylactide (PS-PLA) bottlebrush block copolymers have been shown to self-assemble into a cylindrical morphology with large domain spacings. PLA cylinders can be selectively etched out of the shear-aligned polymer monoliths to generate nanoporous materials with an average cylindrical pore diameter of 55 nm. The remaining bottlebrush backbone provides a functional, hydrophilic coating inside the nanopores. This methodology significantly expands the range of pore sizes attainable in block copolymer based nanoporous materials. PMID- 21280667 TI - Coordination structure of adsorbed Zn(II) at water-TiO2 interfaces. AB - The local structure of aqueous metal ions on solid surfaces is central to understanding many chemical and biological processes in soil and aquatic environments. Here, the local coordination structure of hydrated Zn(II) at water TiO(2) interfaces was identified by extended X-ray absorption fine structure (EXAFS) and X-ray absorption near-edge structure (XANES) spectroscopy combined with density functional theory (DFT) calculations. A nonintegral coordination number of average ~4.5 O atoms around a central Zn atom was obtained by EXAFS analysis. DFT calculations indicated that this coordination structure was consistent with the mixture of 4-coordinated bidentate binuclear (BB) and 5 coordinated bidentate mononuclear (BM) metastable equilibrium adsorption (MEA) states. The BB complex has 4-coordinated Zn, while the monodentate mononuclear (MM) complex has 6-coordinated Zn, and a 5-coordinated adsorbed Zn was found in the BM adsorption mode. DFT calculated energies showed that the lower-coordinated BB and BM modes were thermodynamically more favorable than the higher-coordinated MM MEA state. The experimentally observed XANES fingerprinting provided additional direct spectral evidence of 4- and 5-coordinated Zn-O modes. The overall spectral and computational evidence indicated that Zn(II) can occur in 4 , 5-, and 6-oxygen coordinated sites in different MEA states due to steric hindrance effects, and the coexistence of different MEA states formed the multiple coordination environments. PMID- 21280668 TI - Examination of the possibility of negative capacitance using ferroelectric materials in solid state electronic devices. AB - We show here, using fundamental energy storage relationships for capacitors, that there are severe constraints upon what can be realized utilizing ferroelectric materials as FET dielectrics. A basic equation governing all small signal behavior is derived, a negative capacitance quality factor is defined based upon it, and thousands of carefully measured devices are evaluated. We show that no instance of negative capacitance occurs within our huge database. Furthermore, we demonstrate that highly nonlinear biasing behavior in a series stack could be misinterpreted as giving a negative capacitance. PMID- 21280669 TI - Distinguishing between pathways for transmetalation in Suzuki-Miyaura reactions. AB - We report a systematic study of the stoichiometric reactions of isolated arylpalladium hydroxo and halide complexes with arylboronic acids and aryltrihydroxyborates to evaluate the relative rates of the two reaction pathways commonly proposed to account for transmetalation in the Suzuki-Miyaura reaction. On the basis of the relative populations of the palladium and organoboron species generated under conditions common for the catalytic process and the observed rate constants for the stoichiometric reactions between the two classes of reaction components, we conclude that the reaction of a palladium hydroxo complex with boronic acid, not the reaction of a palladium halide complex with trihydroxyborate, accounts for transmetalation in catalytic Suzuki-Miyaura reactions conducted with weak base and aqueous solvent mixtures. PMID- 21280670 TI - Multilevel, multicomponent microarchitectures of vertically-aligned carbon nanotubes for diverse applications. AB - A simple multiple contact transfer technique has been developed for controllable fabrication of multilevel, multicomponent microarchitectures of vertically aligned carbon nanotubes (VA-CNTs). Three dimensional (3-D) multicomponent micropatterns of aligned single-walled carbon nanotubes (SWNTs) and multiwalled carbon nanotubes (MWNTs) have been fabricated, which can be used to develop a newly designed touch sensor with reversible electrical responses for potential applications in electronic devices, as demonstrated in this study. The demonstrated dependence of light diffraction on structural transfiguration of the resultant CNT micropattern also indicates their potential for optical devices. Further introduction of various components with specific properties (e.g., ZnO nanorods) into the CNT micropatterns enabled us to tailor such surface characteristics as wettability and light response. Owing to the highly generic nature of the multiple contact transfer strategy, the methodology developed here could provide a general approach for interposing a large variety of multicomponent elements (e.g., nanotubes, nanorods/wires, photonic crystals, etc.) onto a single chip for multifunctional device applications. PMID- 21280671 TI - Multiplexed PET probes for imaging breast cancer early response to VEGF121/rGel treatment. AB - In this study, we applied multiplexed positron emission tomography (PET) probes to monitor glucose metabolism, cellular proliferation, tumor hypoxia and angiogenesis during VEGF121/rGel therapy of breast cancer. Two doses of 12 mg/kg VEGF121/rGel, administered intraperitoneally, resulted in initial delay of tumor growth, but the growth resumed 4 days after tumor treatment was stopped. The average tumor growth rate expressed as V/V(0), were 1.11 +/- 0.07, 1.21 +/- 0.10, 1.58 +/- 0.36 and 2.64 +/- 0.72 at days 1, 3, 7 and 14, respectively. Meanwhile, the VEGF121/rGel treatment group showed V/V0 ratios of 1.04 +/- 0.06, 1.05 +/- 0.11, 1.09 +/- 0.17 and 1.86 +/- 0.36 at days 1, 3, 7 and 14, respectively. VEGF121/rGel treatment led to significantly decreased uptake of 18F-FPPRGD2 at day 1 (24.0 +/- 8.8%, p < 0.05) and day 3 (36.3 +/- 9.2%, p < 0.01), relative to the baseline, which slowly recovered to the baseline at day 14. 18F-FMISO uptake was increased in the treated tumors at day 1 (23.9 +/- 15.7%, p < 0.05) and day 3 (51.4 +/- 29.4%, p < 0.01), as compared to the control group. At days 7 and 14, 18F-FMISO uptake restored to the baseline level. The relative reductions in FLT uptake in treated tumors were approximately 13.0 +/- 4.5% at day 1 and 25.0 +/- 4.4% (p < 0.01) at day 3. No significant change of 18F-FDG uptake was observed in VEGF121/rGel treated tumors, compared with the control group. The imaging findings were supported by ex vivo analysis of related biomarkers. Overall, longitudinal imaging studies with 4 PET tracers demonstrated the feasibility and usefulness of multiplexed probes for quantitative measurement of antitumor effects of VEGF121/rGel at the early stage of treatment. This preclinical study should be helpful in accelerating anticancer drug development and promoting the clinical translation of molecular imaging. PMID- 21280672 TI - Assessing the components of the eIF3 complex and their phosphorylation status. AB - The eukaryotic initiation factor 3 (eIF3) is an essential, highly conserved multiprotein complex that is a key component in the recruitment and assembly of the translation initiation machinery. To better understand the molecular function of eIF3, we examined its composition and phosphorylation status in Saccharomyces cerevisiae. The yeast eIF3 complex contains five core components: Rpg1, Nip1, Prt1, Tif34, and Tif35. 2-D LC-MS/MS analysis of affinity purified eIF3 complexes showed that several other initiation factors (Fun12, Tif5, Sui3, Pab1, Hcr1, and Sui1) and the casein kinase 2 complex (CK2) copurify. In Vivo metabolic labeling of proteins with (32)P revealed that Nip1 is phosphorylated. Using 2-D LC-MS/MS analysis of eIF3 complexes, we identified Prt1 phosphopeptides indicating phosphorylation at S22 and T707 and a Tif5 phosphopeptide with phosphorylation at T191. Additionally, we used immobilized metal affinity chromatography (IMAC) to enrich for eIF3 phosphopeptides and tandem mass spectrometry to identify phosphorylated residues. We found that three CK2 consensus sequences in Nip1 are phosphorylated: S98, S99, and S103. Using in vitro kinase assays, we showed that CK2 phophorylates Nip1 and that a synthetic Nip1 peptide containing S98, S99, and S103 competitively inhibits the reaction. Replacement of these three Nip1 serines with alanines causes a slow growth phenotype. PMID- 21280673 TI - Serum clusterin levels are not increased in presymptomatic Alzheimer's disease. AB - Increased plasma levels of clusterin have recently been found to be associated with severity and progression in Alzheimer's disease (AD). We have investigated clusterin levels in serum of elderly people with presymptomatic AD from a population-based prospective cohort study. During 10 years follow-up, 43 participants were diagnosed with AD after on average 4.2 years (+/-2.6 years SD) after the initial blood sampling. At the time of blood sampling, these participants showed normal cognitive function. For each presymptomatic AD case, a control was matched on gender and age. Furthermore, the selected controls had to remain dementia-free and still be alive at the end of follow-up. Quantitative serum clusterin levels were measured with a newly developed multiple reaction monitoring (MRM) assay. Results of the assay showed no significant difference in clusterin levels between presymptomatic AD and controls (p-value 0.54). In conclusion, serum clusterin is not an early, presymptomatic biomarker for AD. PMID- 21280674 TI - Photochemical preparation of pyrimidin-2(1H)-ones by rhenium(I) complexes with visible light. AB - With visible light irradiation (lambda > 400 nm) of rhenium(I) complexes (P1-P4), a photochemical conversion from 3,4-dihydropyrimidin-2(1H)-ones to pyrimidin 2(1H)-ones at room temperature has been achieved with good to excellent yields in CH(3)CN-H(2)O solution containing CCl(4) and K(2)CO(3). Luminescence quenching study and product analysis reveal that photoinduced electron transfer between rhenium(I) complex P and 3,4-dihydropyrimidin-2(1H)-ones plays an important role in the initial event. PMID- 21280675 TI - An evolved aminoacyl-tRNA synthetase with atypical polysubstrate specificity. AB - We have employed a rapid fluorescence-based screen to assess the polyspecificity of several aminoacyl-tRNA synthetases (aaRSs) against an array of unnatural amino acids. We discovered that a p-cyanophenylalanine specific aminoacyl-tRNA synthetase (pCNF-RS) has high substrate permissivity for unnatural amino acids, while maintaining its ability to discriminate against the 20 canonical amino acids. This orthogonal pCNF-RS, together with its cognate amber nonsense suppressor tRNA, is able to selectively incorporate 18 unnatural amino acids into proteins, including trifluoroketone-, alkynyl-, and halogen-substituted amino acids. In an attempt to improve our understanding of this polyspecificity, the X ray crystal structure of the aaRS-p-cyanophenylalanine complex was determined. A comparison of this structure with those of other mutant aaRSs showed that both binding site size and other more subtle features control substrate polyspecificity. PMID- 21280676 TI - Communication: An exact short-time solver for the time-dependent Schrodinger equation. AB - The short-time integrator for propagating the time-dependent Schrodinger equation, which is exact to machine's round off accuracy when the Hamiltonian of the system is time-independent, was applied to solve dynamics processes. This integrator has the old Cayley's form [i.e., the Pade (1,1) approximation], but is implemented in a spectrally transformed Hamiltonian which was first introduced by Chen and Guo. Two examples are presented for illustration, including calculations of the collision energy-dependent probability passing over a barrier, and interaction process between pulse laser and the I(2) diatomic molecule. PMID- 21280677 TI - Communication: Highest occupied molecular orbital-lowest unoccupied molecular orbital gaps of doped silicon clusters from core level spectroscopy. AB - A method to determine band gaps of size-selected and isolated nanoparticles by combination of valence band and core-level photoionization spectroscopy is presented. This approach is widely applicable and provides a convenient alternative to current standard techniques for the determination of band gaps by optical or photoelectron spectroscopy. A first application to vanadium doped silicon clusters confirms a striking size-dependence of their highest occupied lowest unoccupied molecular orbital gaps. PMID- 21280678 TI - Communication: Thermodynamic scaling of the Debye process in primary alcohols. AB - The molecular dynamics of hydrogen-bonded liquids usually does not satisfy the thermodynamic scaling. However, very recently, two opposite conclusions about validity of thermodynamical scaling in monohydroxy alcohol, 2-ethyl-1-hexanol, were presented by Reiser et al. [J. Chem. Phys. 132, 181101 (2010)] and Fragiadakis et al. [J. Chem. Phys. 132, 144505 (2010)]. In this communication we present new experimental results that can explain this ostensible contradiction. PMID- 21280679 TI - Communication: Reactions and adsorption at the surface of silver nanoparticles probed by second harmonic generation. AB - Even though nanoparticles have dimensions much smaller than the optical wavelength and shapes commonly with inversion symmetry, we show, for the first time, direct experimental evidence that second harmonic generation (SHG) can be detected from the surface layer of metallic nanoparticles, in this case 40 nm radius Ag particles. The SH intensity detected is shown to substantially decrease upon chemical bonding of thiol molecules to the Ag particle surface. The surface generated SH intensity can be used for probing properties and processes at the nanoparticle surface. PMID- 21280680 TI - Communication: Free-energy analysis of hydration effect on protein with explicit solvent: equilibrium fluctuation of cytochrome c. AB - The relationship between the protein conformation and the hydration effect is investigated for the equilibrium fluctuation of cytochrome c. To elucidate the hydration effect with explicit solvent, the solvation free energy of the protein immersed in water was calculated using the molecular dynamics simulation coupled with the method of energy representation. The variations of the protein intramolecular energy and the solvation free energy are found to compensate each other in the course of equilibrium structural fluctuation. The roles of the attractive and repulsive components in the protein-water interaction are further examined for the solvation free energy. The attractive component represented as the average sum of protein-water interaction energy is dominated by the electrostatic effect and is correlated to the solvation free energy through the linear-response-type relationship. No correlation with the (total) solvation free energy is seen, on the other hand, for the repulsive component expressed as the excluded-volume effect. PMID- 21280681 TI - On the construction of quasidiabatic state representations of bound adiabatic state potential energy surfaces coupled by accidental conical intersections: incorporation of higher order terms. AB - The quadratic vibronic coupling model is an important computational tool for simulating photoelectron spectra involving strongly coupled electronic states in polyatomic molecules. However, recent work has indicated the need for higher order terms, with most of the initial studies focusing on molecules with symmetry required degeneracies. In this study we report an extension of our approach for constructing fully quadratic representations of bound electronic states coupled by conical intersections, which allows for the inclusion of higher order terms, demonstrated here employing a quartic expansion. Procedures are developed that eliminate unphysical behavior for large displacements, a problem likely to be an endemic to anharmonic expansions. Following work on representing dissociative electronic states, Lagrange multipliers are used to constrain the constructed representation to reproduce exactly the energy, energy gradients, and/or derivative couplings at specific points, or nodes, in nuclear coordinate space. The approach is illustrated and systematically studied using the four lowest electronic states of triazolyl, (CH)(2)N(3). PMID- 21280682 TI - Accurate all-electron correlation energies for the closed-shell atoms from Ar to Rn and their relationship to the corresponding MP2 correlation energies. AB - All-electron correlation energies E(c) are not very well-known for atoms with more than 18 electrons. Hence, coupled-cluster calculations in carefully designed basis sets are combined with fully converged second-order Moller-Plesset perturbation theory (MP2) computations to obtain fairly accurate, nonrelativistic E(c) values for the 12 closed-shell atoms from Ar to Rn. These energies will be useful for the evaluation and parameterization of density functionals. The results show that MP2 overestimates ?E(c)? for heavy atoms. Spin-component scaling of the MP2 correlation energy is used to provide a simple explanation for this overestimation. PMID- 21280683 TI - Toward making the mean spherical approximation of primitive model electrolytes analytic: an analytic approximation of the MSA screening parameter. AB - The mean spherical approximation (MSA) for the primitive model of electrolytes provides reasonable estimates of thermodynamic quantities such as the excess chemical potential and screening length. It is especially widely used because of its explicit formulas so that numerically solving equations is minimized. As originally formulated, the MSA screening parameter Gamma (akin to the reciprocal of the Debye screening length) does not have an explicit analytic formula; an equation for Gamma must be solved numerically. Here, an analytic approximation for Gamma is presented whose relative error is generally ?10(-5). If more accuracy is desired, one step of an iterative procedure (which also produces an explicit formula for Gamma) is shown to give relative errors within machine precision in many cases. Even when ion diameter ratios are ~10 and ion valences are ~10, the relative error for the analytic approximation is still ?10(-3) and for the single iterative substitution it is ?10(-9). PMID- 21280684 TI - Order parameters for macromolecules: application to multiscale simulation. AB - Order parameters (OPs) characterizing the nanoscale features of macromolecules are presented. They are generated in a general fashion so that they do not need to be redesigned with each new application. They evolve on time scales much longer than 10(-14) s typical for individual atomic collisions/vibrations. The list of OPs can be automatically increased, and completeness can be determined via a correlation analysis. They serve as the basis of a multiscale analysis that starts with the N-atom Liouville equation and yields rigorous Smoluchowski/Langevin equations of stochastic OP dynamics. Such OPs and the multiscale analysis imply computational algorithms that we demonstrate in an application to ribonucleic acid structural dynamics for 50 ns. PMID- 21280685 TI - Ionic solvation studied by image-charge reaction field method. AB - In a preceding paper [J. Chem. Phys. 131, 154103 (2009)], we introduced a new, hybrid explicit/implicit method to treat electrostatic interactions in computer simulations, and tested its performance for liquid water. In this paper, we report further tests of this method, termed the image-charge solvation model (ICSM), in simulations of ions solvated in water. We find that our model can faithfully reproduce known solvation properties of sodium and chloride ions. The charging free energy of a single sodium ion is in excellent agreement with the estimates by other electrostatics methods, while offering much lower finite-size errors. Similarly, the potentials of mean force computed for Na-Cl, Na-Na, and Cl Cl pairs closely reproduce those reported previously. Collectively, our results demonstrate the superior accuracy of the proposed ICSM method for simulations of mixed media. PMID- 21280686 TI - Efficient moves for global geometry optimization methods and their application to binary systems. AB - We show that molecular dynamics based moves in the minima hopping method are more efficient than saddle point crossing moves. For binary systems we incorporate identity exchange moves in a way that allows one to avoid the generation of high energy configurations. Using this modified minima hopping method, we re-examine the binary Lennard-Jones benchmark system with up to 100 atoms and we find a large number of new putative global minima. PMID- 21280687 TI - Imaginary time Gaussian dynamics of the Ar3 cluster. AB - Semiclassical Gaussian approximations to the Boltzmann operator have become an important tool for the investigation of thermodynamic properties of clusters of atoms at low temperatures. Usually, numerically expensive thawed Gaussian variants are applied. In this article, we introduce a numerically much cheaper frozen Gaussian approximation to the imaginary time propagator with a width matrix especially suited for the dynamics of clusters. The quality of the results is comparable to that of thawed Gaussian methods based on the single-particle ansatz. We apply the method to the argon trimer and investigate the dissociation process of the cluster. The results clearly show a classical-like transition from a bounded moiety to three free particles at a temperature T ~ 20 K, whereas previous studies of the system were not able to resolve this transition. Quantum effects, i.e., differences with the purely classical case manifest themselves in the low-temperature behavior of the mean energy and specific heat as well as in a slight shift of the transition temperature. We also discuss the influence of an artificial confinement of the atoms usually introduced to converge numerical computations. The results show that restrictive confinements often implemented in studies of clusters can influence the thermodynamic properties drastically. This finding may have implications on other studies of atomic clusters. PMID- 21280688 TI - Exciton-polariton transmission in quantum dot waveguides and a new transmission path due to thermal relaxation. AB - Exciton-polariton transmission in quantum dot waveguides is investigated with quantum time-evolution equations in Liouville space for exciton wave packet dynamics. The transmission efficiency of the exciton-polariton wave with the longitudinal and transverse mode transformations strongly depends on the geometric parameters (bending angle and interdot distance) of the waveguides and on configuration of an additional branch attached to the waveguide. We have numerically demonstrated that the transmission efficiency significantly improves by controlling these geometric parameters and the configuration of the branched waveguide. The optimal bending angle for efficient transmission with the longitudinal and transverse mode transformations deviates from the right angle owing to more than nearest-neighbor-site interactions through a shortcut. We have also found that existence of thermal relaxation enables to open a new transmission channel along which the exciton-polariton transmission through the Coulomb interaction is suppressed. PMID- 21280689 TI - Thermodynamical approach to sympathetic cooling of neutral particles. AB - We present a "toy" classical model for sympathetic cooling of the neutral Brownian particle in the frame of robust thermodynamical approach. The cooling time is expressed with the parameters of the Brownian particle and the particles from the cooling reservoir. Qualitative and numerical estimations of the model confirm that the sympathetic cooling can be efficient for heavy neutral molecules and clusters. PMID- 21280690 TI - Automated estimation of rare event probabilities in biochemical systems. AB - In biochemical systems, the occurrence of a rare event can be accompanied by catastrophic consequences. Precise characterization of these events using Monte Carlo simulation methods is often intractable, as the number of realizations needed to witness even a single rare event can be very large. The weighted stochastic simulation algorithm (wSSA) [J. Chem. Phys. 129, 165101 (2008)] and its subsequent extension [J. Chem. Phys. 130, 174103 (2009)] alleviate this difficulty with importance sampling, which effectively biases the system toward the desired rare event. However, extensive computation coupled with substantial insight into a given system is required, as there is currently no automatic approach for choosing wSSA parameters. We present a novel modification of the wSSA--the doubly weighted SSA (dwSSA)--that makes possible a fully automated parameter selection method. Our approach uses the information-theoretic concept of cross entropy to identify parameter values yielding minimum variance rare event probability estimates. We apply the method to four examples: a pure birth process, a birth-death process, an enzymatic futile cycle, and a yeast polarization model. Our results demonstrate that the proposed method (1) enables probability estimation for a class of rare events that cannot be interrogated with the wSSA, and (2) for all examples tested, reduces the number of runs needed to achieve comparable accuracy by multiple orders of magnitude. For a particular rare event in the yeast polarization model, our method transforms a projected simulation time of 600 years to three hours. Furthermore, by incorporating information-theoretic principles, our approach provides a framework for the development of more sophisticated influencing schemes that should further improve estimation accuracy. PMID- 21280691 TI - Effects of finite size nuclei in relativistic four-component calculations of hyperfine structure. AB - The effect of a finite size model for both the nuclear charge and magnetic moment distributions on calculated EPR hyperfine structure have been studied using a relativistic four-component method based on density functional theory. This approach employs a restricted kinetically balanced basis (mDKS-RKB) and includes spin-polarization using noncollinear spin-density exchange-correlation functionals in the unrestricted fashion. Benchmark calculations have been carried out for a number of small molecules containing Zn, Cd, Ag, and Hg. The present results are compared with those obtained at the Douglas-Kroll-Hess second order (DKH-2) method. The dependence of the results on the quality of the orbital and auxiliary basis sets has been studied. It was found that some basis sets contain irregularities that deteriorate the results. Especial care has to be taken also on the construction of the auxiliary basis for fitting the total electron and spin-densities. PMID- 21280692 TI - Ab initio mass tensor molecular dynamics. AB - Mass tensor molecular dynamics method was first introduced by Bennett [J. Comput. Phys. 19, 267 (1975)] for efficient sampling of phase space through the use of generalized atomic masses. Here, we show how to apply this method to ab initio molecular dynamics simulations with minimal computational overhead. Test calculations on liquid water show a threefold reduction in computational effort without making the fixed geometry approximation. We also present a simple recipe for estimating the optimal atomic masses using only the first derivatives of the potential energy. PMID- 21280693 TI - Evaluation of the performance of single root multireference coupled cluster method for ground and excited states, and its application to geometry optimization. AB - The complete model space (CAS) based "genuine" single root multireference (MR) coupled cluster (sr-MRCC) method [Mahapatra and Chattopadhyay, J. Chem. Phys. 133, 074102 (2010)] has been extended to enable geometry optimizations by adopting the numerical gradient scheme. The sr-MRCC theory is designed to treat quasidegeneracies of varying degrees through the computation of essential static and dynamic correlation effects in a balanced way while bypassing the intruder states problem in a size-extensive manner. The efficacy of our sr-MRCC gradient approach has been illustrated by the optimization of the geometries of N(2)H(2),CH(2),C(2)H(4),C(4)H(4),O(3) as well as trimethylenemethane (TMM) molecular systems, since such cases, by virtue of their complexity, warrant truly multireference description. We have explored the capability of the sr-MRCC approach to yield rotational energy surfaces for the ground and first singlet excited states of N(2)H(2). We also intend to explore the ground and the excited state energetics of some model systems (such as P4, H4, and H(8)) for the computation of excitation energies by relying on the sr-MRCC method. An analysis of the results and a comparison with previous pertinent theoretical works including state specific MRCC (SS-MRCC) theory of Mukherjee and co-workers have also been presented. Although in most of the cases, we observe a close behavior between the sr-MRCC and SS-MRCC method, the error in the sr-MRCC is lower than the overall error of the SS-MRCC calculations in the vicinity of the transition region (manifesting a significant quasidegenerate character). The present results show that the sr-MRCC method and its numerical gradient variant are generally applicable to very demanding model and realistic chemical problems at acceptable accuracy and affordable computational expense which together attests the efficacy and viability of the sr-MRCC formalism for handling of static and dynamic correlations simultaneously thereby ensuring a balanced description for bond breaking and other quasidegenerate situations with a various degree of MR character. Our preliminary results illustrate that our sr-MRCC method is a potential competitor for other state specific MRCC theories. PMID- 21280694 TI - Molecular-orbital-free algorithm for the excited-state force in time-dependent density functional theory. AB - Starting from the equation of motion in the density matrix formulation, we reformulate the analytical gradient of the excited-state energy at the time dependent density functional theory level in the nonorthogonal Gaussian atom centered orbital (AO) basis. Analogous to the analytical first derivative in molecular-orbital (MO) basis, a Z-vector equation has been derived with respect to the reduced one-electronic density matrix in AO basis, which provides a potential possibility to exploit quantum locality of the density matrix and avoids the matrix transformation between the AO and the MO basis. Numerical tests are finished for the excited-state geometry optimization and adiabatic excitation energy calculation of a series of small molecules. The results demonstrate the computational efficiency and accuracy of the current AO-based energy gradient expression in comparison with the MO-based scheme. PMID- 21280695 TI - Fluid-solid transition in hard hypersphere systems. AB - In this work we present a numerical study, based on molecular dynamics simulations, to estimate the freezing point of hard spheres and hypersphere systems in dimension D = 4, 5, 6, and 7. We have studied the changes of the radial distribution function (RDF) as a function of density in the coexistence region. We started our simulations from crystalline states with densities above the melting point, and moved down to densities in the liquid state below the freezing point. For all the examined dimensions (including D = 3), it was observed that the height of the first minimum of the RDF changes in an almost continuous way around the freezing density and resembles a second order phase transition. With these results we propose a numerical method to estimate the freezing point as a function of the dimension D using numerical fits and semiempirical approaches. We find that the estimated values of the freezing point are very close to the previously reported values from simulations and theoretical approaches up to D = 6, reinforcing the validity of the proposed method. This was also applied to numerical simulations for D = 7 giving new estimations of the freezing point for this dimensionality. PMID- 21280696 TI - Designing the plasmonic response of shell nanoparticles: spectral representation. AB - A spectral representation formalism in the quasistatic limit is developed to study the optical response of nanoparticles, such as nanospheres, nanospheroids, and concentric nanoshells. A transfer matrix theory is formulated for systems with an arbitrary number of shells. The spectral representation formalism allows us to analyze the optical response in terms of the interacting surface plasmons excited at the interfaces by separating the contributions of the geometry from those of the dielectric properties of each shell and surroundings. Neither numerical nor analytical methods can do this separation. These insights into the physical origin of the optical response of multishelled nanoparticles are very useful for engineering systems with desired properties for applications in different fields ranging from materials science and electronics to medicine and biochemistry. PMID- 21280697 TI - A generalized-gradient approximation exchange hole model for dispersion coefficients. AB - A simple method for computing accurate density-dependent dispersion coefficients is presented. The dispersion coefficients are modeled by a generalized gradient type approximation to Becke and Johnson's exchange hole dipole moment formalism. Our most cost-effective variant, based on a disjoint description of atoms in a molecule, gives mean absolute errors in the C(6) coefficients for 90 complexes below 10%. The inclusion of the missing long-range van der Waals interactions in density functionals using the derived coefficients in a pair wise correction leads to highly accurate typical noncovalent interaction energies. PMID- 21280698 TI - Critical comparison of electrode models in density functional theory based quantum transport calculations. AB - We study the performance of two different electrode models in quantum transport calculations based on density functional theory: parametrized Bethe lattices and quasi-one-dimensional wires or nanowires. A detailed account of implementation details in both the cases is given. From the systematic study of nanocontacts made of representative metallic elements, we can conclude that the parametrized electrode models represent an excellent compromise between computational cost and electronic structure definition as long as the aim is to compare with experiments where the precise atomic structure of the electrodes is not relevant or defined with precision. The results obtained using parametrized Bethe lattices are essentially similar to the ones obtained with quasi-one-dimensional electrodes for large enough cross-sections of these, adding a natural smearing to the transmission curves that mimics the true nature of polycrystalline electrodes. The latter are more demanding from the computational point of view, but present the advantage of expanding the range of applicability of transport calculations to situations where the electrodes have a well-defined atomic structure, as is the case for carbon nanotubes, graphene nanoribbons, or semiconducting nanowires. All the analysis is done with the help of codes developed by the authors which can be found in the quantum transport toolbox ALACANT and are publicly available. PMID- 21280699 TI - Two-channel conduction through polyacenes--extension of the source-sink potential method to multichannel coupling to leads. AB - The source and sink potential method of Goyer et al. [J. Chem. Phys. 126, 144104 (2007)] is extended to the case of multichannel coupling to leads. The formulation leads to a nonlinear equation for just one (the elastic) reflection coefficient. Solution of this equation, in general, requires repeated computation of an n * n determinant, where n is the number of supermolecule basis functions directly coupled to the source lead, as opposed to a determinant with order equal to the full size of supermolecule basis. The method is applied to a Huckel model of two-channel polyacene conduction. A simple model of resonance lineshapes is developed in case of weak coupling to leads. The model accurately relates peak characteristics to orbital probabilities associated with the eigenvectors of the isolated molecule Hamiltonian. The model shows how orbital probabilities that give rise to transmission resonances (i.e., 100% transmission), in the case of single-channel conduction, give rise to equal probabilities (of 1/4) for the two reflections and two transmissions, in the case of two-channel conduction. The model also shows how splitting of degenerate eigenvalues of the isolated molecule Hamiltonian results in overlapping resonances characterized by a single complex lineshape. PMID- 21280700 TI - An algorithm for calculating atomic D states with explicitly correlated gaussian functions. AB - An algorithm for the variational calculation of atomic D states employing n electron explicitly correlated gaussians is developed and implemented. The algorithm includes formulas for the first derivatives of the hamiltonian and overlap matrix elements determined with respect to the gaussian nonlinear exponential parameters. The derivatives are used to form the energy gradient which is employed in the variational energy minimization. The algorithm is tested in the calculations of the two lowest D states of the lithium and beryllium atoms. For the lowest D state of Li the present result is lower than the best previously reported result. PMID- 21280701 TI - Super-fermion representation of quantum kinetic equations for the electron transport problem. AB - We discuss the use of super-fermion formalism to represent and solve quantum kinetic equations for the electron transport problem. Starting with the Lindblad master equation for the molecule connected to two metal electrodes, we convert the problem of finding the nonequilibrium steady state to the many-body problem with non-hermitian liouvillian in super-Fock space. We transform the liouvillian to the normal ordered form, introduce nonequilibrium quasiparticles by a set of canonical nonunitary transformations and develop general many-body theory for the electron transport through the interacting region. The approach is applied to the electron transport through a single level. We consider a minimal basis hydrogen atom attached to two metal leads in Coulomb blockade regime (out of equilibrium Anderson model) within the nonequilibrium Hartree-Fock approximation as an example of the system with electron interaction. Our approach agrees with exact results given by the Landauer theory for the considered models. PMID- 21280702 TI - Self-consistent, constrained linear-combination-of-atomic-potentials approach to quantum mechanics. AB - Variational fitting gives a stationary linear-combination of atomic potentials (LCAP) approximation to the Kohn-Sham (KS) potential, V. That potential is central to density-functional theory because it generates all orbitals, occupied as well as virtual. Perturbation theory links two self-consistent field (SCF) calculations that differ by the perturbation. Using the same variational LCAP methods and basis sets in the two SCF calculations gives precise KS potentials for each order. Variational V perturbation theory, developed herein through second order, gives stationary potentials at each order and stationary even-order perturbed energies that precisely link the two SCF calculations. Iterative methods are unnecessary because the dimension of the matrix that must be inverted is the KS basis size, not the number of occupied times virtual orbitals of coupled-perturbed methods. With variational perturbation theory, the precision of derivatives and the fidelity of the LCAP KS potential are not related. Finite differences of SCF calculations allow the precision of analytic derivatives from double-precision code to be verified to roughly seven significant digits. For a simple functional, the fourth derivatives of the energy and the first and second derivative of the KS potentials with respect to orbital occupation are computed for a standard set of molecules and basis sets, with and without constraints on the fit to the KS potential. There is no significant difference between the constrained and unconstrained calculations. PMID- 21280703 TI - Tensor factorizations of local second-order Moller-Plesset theory. AB - Efficient electronic structure methods can be built around efficient tensor representations of the wavefunction. Here we first describe a general view of tensor factorization for the compact representation of electronic wavefunctions. Next, we use this language to construct a low-complexity representation of the doubles amplitudes in local second-order Moller-Plesset perturbation theory. We introduce two approximations--the direct orbital-specific virtual approximation and the full orbital-specific virtual approximation. In these approximations, each occupied orbital is associated with a small set of correlating virtual orbitals. Conceptually, the representation lies between the projected atomic orbital representation in Pulay-Saebo local correlation theories and pair natural orbital correlation theories. We have tested the orbital-specific virtual approximations on a variety of systems and properties including total energies, reaction energies, and potential energy curves. Compared to the Pulay-Saebo ansatz, we find that these approximations exhibit favorable accuracy and computational times while yielding smooth potential energy curves. PMID- 21280704 TI - Velocity scaling for optimizing replica exchange molecular dynamics. AB - We discuss the use of velocity rescaling for generating rejection-free exchange moves in replica exchange molecular dynamics. We test the efficiency of this approach for a common test case, the trp-cage protein. Advantages and limitations of the approach are discussed and possible extensions outlined. PMID- 21280705 TI - Electrokinetic motion of a charged colloidal sphere in a spherical cavity with magnetic fields. AB - The magnetohydrodynamic (MHD) effects on the translation and rotation of a charged colloidal sphere situated at the center of a spherical cavity filled with an arbitrary electrolyte solution when a constant magnetic field is imposed are analyzed at the quasisteady state. The electric double layers adjacent to the solid surfaces may have an arbitrary thickness relative to the particle and cavity radii. Through the use of a perturbation method to the leading order, the Stokes equations modified with the electric/Lorentz force term are dealt by using a generalized reciprocal theorem. Using the equilibrium double-layer potential distribution in the fluid phase from solving the linearized Poisson-Boltzmann equation, we obtain explicit formulas for the translational and angular velocities of the colloidal sphere produced by the MHD effects valid for all values of the particle-to-cavity size ratio. For the limiting case of an infinitely large cavity with an uncharged wall, our result reduces to the relevant solution for an unbounded spherical particle available in the literature. The boundary effect on the MHD motion of the spherical particle is a qualitatively and quantitatively sensible function of the parameters a/b and kappaa, where a and b are the radii of the particle and cavity, respectively, and kappa is the reciprocal of the Debye screening length. In general, the proximity of the cavity wall reduces the MHD migration but intensifies the MHD rotation of the particle. PMID- 21280706 TI - Colored non-gaussian noise driven open systems: generalization of Kramers' theory with a unified approach. AB - In this paper we have calculated escape rate from a meta stable state in the presence of both colored internal thermal and external nonthermal noises. For the internal noise we have considered usual gaussian distribution but the external noise may be gaussian or non-gaussian in characteristic. The calculated rate is valid for low noise strength of non-gaussian noise such that an effective gaussian approximation of non-gaussian noise wherein the higher order even cumulants of order "4" and higher are neglected. The rate expression we derived here reduces to the known results of the literature, as well as for purely external noise driven activated rate process. The latter exhibits how the rate changes if one switches from non-gaussian to gaussian character of the external noise. PMID- 21280707 TI - Free energy calculation using molecular dynamics simulation combined with the three-dimensional reference interaction site model theory. II. Thermodynamic integration along a spatial reaction coordinate. AB - We propose the thermodynamic integration along a spatial reaction coordinate using the molecular dynamics simulation combined with the three-dimensional reference interaction site model theory. This method provides a free energy calculation in solution along the reaction coordinate defined by the Cartesian coordinates of the solute atoms. The proposed method is based on the blue moon algorithm which can, in principle, handle any reaction coordinate as far as it is defined by the solute atom positions. In this article, we apply the present method to the complex formation process of the crown ether 18-Crown-6 (18C6) with the potassium ion in an aqueous solution. The separation between the geometric centers of these two molecules is taken to be the reaction coordinate for this system. The potential of mean force (PMF) becomes the maximum at the separation between the molecular centers being ~4 A, which can be identified as the free energy barrier in the process of the molecular recognition. In a separation further than the free energy barrier, the PMF is slightly reduced to exhibit a plateau. In the region closer than the free energy barrier, approach of the potassium ion to the center of 18C6 also decreases the PMF. When the potassium ion is accommodated at the center of 18C6, the free energy is lower by -5.7 +/- 0.7 kcal/mol than that at the above mentioned plateau or converged state. By comparing the results with those from the free energy calculation along the coupling parameters obtained in our previous paper [T. Miyata, Y. Ikuta, and F. Hirata, J. Chem. Phys. 133, 044114 (2010)], it is found that the effective interaction in water between 18C6 and the potassium ion vanishes beyond the molecular-center-separation of 10 A. Furthermore, the conformation of 18C6 is found to be significantly changed depending upon the 18C6-K(+) distance. A proper conformational sampling and an accurate solvent treatment are crucial for realizing the accurate PMF, and we believe that the proposed method is useful to evaluate the PMF in a solution. A discussion upon the PMF in terms of the three dimensional distribution function for the solvent is also presented. PMID- 21280708 TI - A multidimensional pseudospectral method for optimal control of quantum ensembles. AB - In our previous work, we have shown that the pseudospectral method is an effective and flexible computation scheme for deriving pulses for optimal control of quantum systems. In practice, however, quantum systems often exhibit variation in the parameters that characterize the system dynamics. This leads us to consider the control of an ensemble (or continuum) of quantum systems indexed by the system parameters that show variation. We cast the design of pulses as an optimal ensemble control problem and demonstrate a multidimensional pseudospectral method with several challenging examples of both closed and open quantum systems from nuclear magnetic resonance spectroscopy in liquid. We give particular attention to the ability to derive experimentally viable pulses of minimum energy or duration. PMID- 21280709 TI - Integral tau methods for stiff stochastic chemical systems. AB - Tau leaping methods enable efficient simulation of discrete stochastic chemical systems. Stiff stochastic systems are particularly challenging since implicit methods, which are good for stiffness, result in noninteger states. The occurrence of negative states is also a common problem in tau leaping. In this paper, we introduce the implicit Minkowski-Weyl tau (IMW-tau) methods. Two updating schemes of the IMW-tau methods are presented: implicit Minkowski-Weyl sequential (IMW-S) and implicit Minkowski-Weyl parallel (IMW-P). The main desirable feature of these methods is that they are designed for stiff stochastic systems with molecular copy numbers ranging from small to large and that they produce integer states without rounding. This is accomplished by the use of a split step where the first part is implicit and computes the mean update while the second part is explicit and generates a random update with the mean computed in the first part. We illustrate the IMW-S and IMW-P methods by some numerical examples, and compare them with existing tau methods. For most cases, the IMW-S and IMW-P methods perform favorably. PMID- 21280710 TI - A tight binding model for water. AB - We demonstrate for the first time a tight binding model for water incorporating polarizable oxygen atoms. A novel aspect is that we adopt a "ground up" approach in that properties of the monomer and dimer only are fitted. Subsequently we make predictions of the structure and properties of hexamer clusters, ice-XI and liquid water. A particular feature, missing in current tight binding and semiempirical hamiltonians, is that we reproduce the almost two-fold increase in molecular dipole moment as clusters are built up toward the limit of bulk liquid. We concentrate on properties of liquid water, particularly dielectric constant and self diffusion coefficient, which are very well rendered in comparison with experiment. Finally we comment on the question of the contrasting densities of water and ice which is central to an understanding of the subtleties of the hydrogen bond. PMID- 21280711 TI - Bimolecular reaction rates from ring polymer molecular dynamics: application to H + CH4 -> H2 + CH3. AB - In a recent paper, we have developed an efficient implementation of the ring polymer molecular dynamics (RPMD) method for calculating bimolecular chemical reaction rates in the gas phase, and illustrated it with applications to some benchmark atom-diatom reactions. In this paper, we show that the same methodology can readily be used to treat more complex polyatomic reactions in their full dimensionality, such as the hydrogen abstraction reaction from methane, H + CH(4) -> H(2) + CH(3). The present calculations were carried out using a modified and recalibrated version of the Jordan-Gilbert potential energy surface. The thermal rate coefficients obtained between 200 and 2000 K are presented and compared with previous results for the same potential energy surface. Throughout the temperature range that is available for comparison, the RPMD approximation gives better agreement with accurate quantum mechanical (multiconfigurational time dependent Hartree) calculations than do either the centroid density version of quantum transition state theory (QTST) or the quantum instanton (QI) model. The RPMD rate coefficients are within a factor of 2 of the exact quantum mechanical rate coefficients at temperatures in the deep tunneling regime. These results indicate that our previous assessment of the accuracy of the RPMD approximation for atom-diatom reactions remains valid for more complex polyatomic reactions. They also suggest that the sensitivity of the QTST and QI rate coefficients to the choice of the transition state dividing surface becomes more of an issue as the dimensionality of the reaction increases. PMID- 21280712 TI - Application of the projection operator formalism to non-hamiltonian dynamics. AB - Reconstruction of equations of motion from incomplete or noisy data and dimension reduction are two fundamental problems in the study of dynamical systems with many degrees of freedom. For the latter, extensive efforts have been made, but with limited success, to generalize the Zwanzig-Mori projection formalism, originally developed for hamiltonian systems close to thermodynamic equilibrium, to general non-hamiltonian systems lacking detailed balance. One difficulty introduced by such systems is the lack of an invariant measure, needed to define a statistical distribution. Based on a recent discovery that a non-hamiltonian system defined by a set of stochastic differential equations can be mapped to a hamiltonian system, we develop such general projection formalism. In the resulting generalized Langevin equations, a set of generalized fluctuation dissipation relations connect the memory kernel and the random noise terms, analogous to hamiltonian systems obeying detailed balance. Lacking of these relations restricts previous application of the generalized Langevin formalism. Result of this work may serve as the theoretical basis for further technical developments on model reconstruction with reduced degrees of freedom. We first use an analytically solvable example to illustrate the formalism and the fluctuation-dissipation relation. Our numerical test on a chemical network with end-product inhibition further demonstrates the validity of the formalism. We suggest that the formalism can find wide applications in scientific modeling. Specifically, we discuss potential applications to biological networks. In particular, the method provides a suitable framework for gaining insights into network properties such as robustness and parameter transferability. PMID- 21280713 TI - Modeling gas permeation through membranes by kinetic Monte Carlo: applications to H2, O2, and N2 in hydrated Nafion(r). AB - We present a simulation tool in order to predict gas permeation through heterogeneous, microphase separated structures. The method combines dissipative particle dynamics (DPD) with kinetic Monte Carlo (KMC). Morphologies obtained from DPD are mapped onto a high density grid on which gas diffusion takes place. Required input parameters for the KMC calculations are the gas solubility and gas diffusion constant within each of the pure phase components. Our method was tested and validated for permeation of H(2), O(2), and N(2) gasses through hydrated Nafion membranes at various temperatures and water contents. We predict that membranes that contain an equal volume fraction of water, those with the highest ion exchange capacity exhibit the largest N(2) and O(2) permeation rates. For membranes of the same ion exchange capacity the H(2), O(2), and N(2) and permeability increases approximately linearly with Bragg spacing. We also predict that O(2) gas permeation depends much more on bottleneck phenomena within the phase separated morphologies than H(2) gas permeation. Overall, the calculated H(2) and O(2) permeability is found to be slightly lower than experimental values. This is attributed to the robustness of DPD resulting in ~7% larger Bragg spacing as compared with experiment and/or increased gas solubility within the polymer phase with water uptake. PMID- 21280714 TI - The coupled cluster approach with a hybrid treatment of connected triple excitations based on the restricted Hartree-Fock reference. AB - A generalization of the coupled cluster (CC) singles, doubles, and a hybrid treatment of connected triples [denoted as CCSD(T)-h] [Shen et al., J. Chem. Phys. 132, 114115 (2010)] to the restricted Hartree-Fock (RHF) reference is presented. In this approach, active (or pseudoactive) RHF orbitals are constructed automatically by performing unitary transformations of canonical RHF orbitals so that they spatially mimic the natural orbitals of the unrestricted Hartree-Fock reference. The present RHF-based CCSD(T)-h approach has been applied to study the potential energy surfaces in several typical bond breaking processes and the singlet-triplet gaps in a diradical (HFH)(-1). For all systems under study, the overall performance of CCSD(T)-h is very close to that of the corresponding CCSD(T) (CC singles, doubles, and triples), and much better than that of CCSD(T) (CC singles, doubles, and perturbative triples). PMID- 21280715 TI - Multilayer multiconfiguration time-dependent Hartree method: implementation and applications to a Henon-Heiles hamiltonian and to pyrazine. AB - The multilayer multiconfiguration time-dependent Hartree (ML-MCTDH) method is discussed and a fully general implementation for any number of layers based on the recursive ML-MCTDH algorithm given by Manthe [J. Chem. Phys. 128, 164116 (2008)] is presented. The method is applied first to a generalized Henon-Heiles (HH) hamiltonian. For 6D HH the overhead of ML-MCTDH makes the method slower than MCTDH, but for 18D HH ML-MCTDH starts to be competitive. We report as well 1458D simulations of the HH hamiltonian using a seven-layer scheme. The photoabsorption spectrum of pyrazine computed with the 24D hamiltonian of Raab et al. [J. Chem. Phys. 110, 936 (1999)] provides a realistic molecular test case for the method. Quick and small ML-MCTDH calculations needing a fraction of the time and resources of reference MCTDH calculations provide already spectra with all the correct features. Accepting slightly larger deviations, the calculation can be accelerated to take only 7 min. When pushing the method toward convergence, results of similar quality than the best available MCTDH benchmark, which is based on a wavepacket with 4.6*10(7)time-dependent coefficients, are obtained with a much more compact wavefunction consisting of only 4.5*10(5) coefficients and requiring a shorter computation time. PMID- 21280716 TI - Nonequilibrium molecular transport photoinduced by potential energy fluctuations. AB - The mechanism of directed substrate-parallel motion of molecules caused by photoinduced potential energy fluctuations is investigated. Unlike simplistic models (e.g., an on-off ratchet), the approach suggested implies that the necessary asymmetry of the potential energy can arise not only from the asymmetry of the substrate potential but also from an asymmetric distribution of the fluctuating charge density in the molecule. The thus induced asymmetry of the potential energy governs the direction motion and enables, under certain conditions, its reversal at some frequencies of resonant laser pulses or temperature. These inferences are exemplified by the model charge distributions in the molecule and substrate, and the charge density fluctuations which are obtained by quantum chemical calculations for the realistic molecule of a substituted phenylpyrene compound on a model substrate. PMID- 21280717 TI - Phase-field modeling of two-dimensional solute precipitation/dissolution: solid fingers and diffusion-limited precipitation. AB - Two-dimensional dendritic growth due to solute precipitation was simulated using a phase-field model reported earlier [Z. Xu and P. Meakin, J. Chem. Phys. 129, 014705 (2008)]. It was shown that diffusion-limited precipitation due to the chemical reaction at the solid-liquid interface has similarities with diffusion limited aggregation (DLA). The diffusion-limited precipitation is attained by setting the chemical reaction rate much larger compared to the solute diffusion to eliminate the effect of the interface growth kinetics. The phase-field simulation results were in reasonable agreement with the analytical solutions. The fractal solid fingers can be formed in the diffusion-limited precipitation and have a fractal dimension measured d(f)=1.68, close to 1.64, the fractal dimensionality of large square lattice DLA clusters. PMID- 21280718 TI - A comparison of the Liptay theory of electroabsorption spectroscopy with the sum over-state model and its modification for the degenerate case. AB - This study has theoretically clarified the relationship between two descriptions of electroabsorption (EA) spectrum: the Liptay equation and the sum-over-state (SOS) model. The former describes the EA spectrum by the linear combination of derivatives of the linear absorption and the latter describes it by a third-order nonlinear optical susceptibility. The EA spectrum described by the SOS model is equivalent to that by the Liptay equation except the coefficient of the zeroth order derivative, when the optically forbidden (dark) state is not degenerate with the optically allowed (bright) state. Also when the dark state is degenerate with the bright state, the EA spectrum can be described by a formal Liptay equation with some modifications of the coefficients, as well as by the SOS model. Such a modified Liptay equation can bring us new information on the transition dipole moment concerned with the dark state, as demonstrated in an experiment for beta-carotene homologs. Differences between the two descriptions are discussed, and our results are compared with the previous two-state model. PMID- 21280719 TI - Dissociation and multiple ionization energies for five polycyclic aromatic hydrocarbon molecules. AB - We have performed density functional theory calculations for a range of neutral, singly, and multiply charged polycyclic aromatic hydrocarbons (PAHs), and their fragmentation products for H-, H(+)-, C(2)H(2)-, and C(2)H(2)(+)-emissions. The adiabatic and vertical ionization energies follow linear dependencies as functions of charge state for all five intact PAHs (naphthalene, biphenylene, anthracene, pyrene, and coronene). First estimates of the total ionization and fragmentation cross sections in ion-PAH collisions display markedly different size dependencies for pericondensed and catacondensed PAH species, reflecting differences in their first ionization energies. The dissociation energies show that the PAH(q+)-molecules are thermodynamically stable for q <= 2 (naphthalene, biphenylene, and anthracene), q <= 3 (pyrene), and q <= 4 (coronene). PAHs in charge states above these limits may also survive experimental time scales due to the presence of reaction barriers as deduced from explorations of the potential energy surface regions for H(+)-emissions from all five PAHs and for C(2)H(2)(+) emission from naphthalene--the smallest PAH. PMID- 21280720 TI - Shedding light on a dark state: the energetically lowest quintet state of C2. AB - In this work we present a deperturbation study of the d (3)Pi(g), v=6 state of C(2) by double-resonant four-wave mixing spectroscopy. Accurate line positions of perturbed transitions are unambiguously assigned by intermediate level labeling. In addition, extra lines are accessible by taking advantage of the sensitivity and high dynamic range of the technique. These weak spectral features originate from nearby-lying dark states that gain transition strength through the perturbation process. The deperturbation analysis of the complex spectral region in the (6,5) and (6,4) bands of the Swan system (d(3)Pi(g)-a (3)Pi(u)) unveils the presence of the energetically lowest high-spin state of C(2) in the vicinity of the d (3)Pi(g), v=6 state. The term energy curves of the three spin components of the d state cross the five terms of the 1 (5)Pi(g) state at rotational quantum numbers N <= 11. The spectral complexity for transitions to the v = 6 level of d (3)Pi(g) state is further enhanced by an additional perturbation at N = 19 and 21 owing to the b (3)Sigma(g)(-), v=19 state. The spectroscopic characterization of both dark states is accessible by the measurement of 122 "window" levels. A global fit of the positions to a conventional Hamiltonian for a linear diatomic molecule yields accurate molecular constants for the quintet and triplet perturber states for the first time. In addition, parameters for the spin-orbit and L-uncoupling interaction between the electronic levels are determined. The detailed deperturbation study unravels major issues of the so-called high pressure bands of C(2). The anomalous nonthermal emission initially observed by Fowler in 1910 [Mon. Not. R. Astron. Soc. 70, 484 (1910)] and later observed in numerous experimental environments are rationalized by taking into account "gateway" states, i.e., rotational levels of the d (3)Pi(g), v=6 state that exhibit significant (5)Pi(g) character through which all population flows from one electronic state to the other. PMID- 21280721 TI - Ab initio configuration interaction study of the B- and C-band photodissociation of methyl iodide. AB - Multireference spin-orbit configuration interaction calculations have been carried out for the valence and low-lying Rydberg states of CH(3)I. Potential energy surfaces along the C-I dissociation coordinate (minimal energy paths with respect to the umbrella angle) have been obtained as well as transition moments for excitation of the Rydberg states. It is shown that the B and C absorption bands of CH(3)I are dominated by the perpendicular (3)R(1),(1)R (E)<-X A(1) transitions, while the (3)R(2)(E), (3)R(0(+) )(A(1))<-X A(1) transitions are very weak. It is demonstrated that the bound Rydberg states of the B and C bands are predissociated due to the interaction with the repulsive E and A(2) components of the (3)A(1) state, with the (3)A(1)(E) state being the main decay channel. It is predicted that the only possibility to obtain the I((2)P(3/2)) ground state atoms from the CH(3)I photodissociation in the B band is by interaction of the (3)R(1)(E) state with the repulsive (1)Q(E) valence state at excitation energies above 55,000 cm(-1). The calculated ab initio data are used to analyze the influence of the Rydberg state vibrational excitation on the decay process. It is shown that, in contrast to intuition, excitation of the nu(3) C-I stretching mode supresses the predissociation, whereas the nu(6) rocking vibration enhances the predissociation rate. PMID- 21280722 TI - Analysis of the HOOO torsional potential. AB - Torsional levels of cis and trans HOOO and DOOO, observed previously via infrared action spectroscopy [E. L. Derro, T. D. Sechler, C. Murray, and M. I. Lester, J. Chem. Phys. 128, 244313 (2008)], have been used in conjunction with ab initio theory to obtain a torsional potential energy surface for the hydrotrioxy radical. High level electronic structure calculations based on the equation-of motion coupled-cluster method for ionized states (EOMIP-CCSD) are utilized to produce a torsional potential. Eigenvalues of the potential are computed by diagonalizing the torsional hamiltonian in a free-rotor basis. Uniform scaling of the theoretical potential by a factor of 1.35 yields vibrational frequencies in good agreement with the experiment, and allows prediction of the barrier height to isomerization of ~340 cm(-1) and relative stability of trans-HOOO with respect to cis-HOOO of ~70 cm(-1). Examination of the optimized nuclear coordinates with respect to the torsional angle, suggests that the central O-O bond length is strongly coupled to the torsion and is important in determining the relative stabilities of the two conformers. The scaled potential is then used to determine the torsional contribution to the partition function for atmospheric modeling of HOOO. PMID- 21280723 TI - On the equilibrium structures of the complexes H2C3H+ . Ar and c-C3H3(+) . Ar: results of explicitly correlated coupled cluster calculations. AB - Explicitly correlated coupled cluster theory at the CCSD(T)-F12x (x = a, b) level [T. B. Adler et al., J. Chem. Phys. 127, 221106 (2007)] has been employed in a study of the potential energy surfaces for the complexes H(2)C(3)H(+) . Ar and c C(3)H(3)(+) . Ar. For the former complex, a pronounced minimum with C(s) symmetry was found (D(e) ~ 780 cm(-1)), well below the local "H-bound" minimum with C(2v) symmetry (D(e) ~ 585 cm(-1)). The absorption at 3238 cm(-1) found in the recent infrared photodissociation spectra [A. M. Ricks et al., J. Chem. Phys. 132, 051101 (2010)] is, thus, interpreted as an essentially free acetylenic CH stretching vibration of the propargyl cation. A global minimum of C(s) symmetry was also obtained for c-C(3)H(3)(+) (D(e) ~ 580 cm(-1)), but the energy difference with respect to the local C(2v) minimum is only 54 cm(-1). PMID- 21280724 TI - Pulsed-field ionization zero electron kinetic energy spectrum of the ground electronic state of BeOBe+. AB - The ground electronic state of BeOBe(+) was probed using the pulsed-field ionization zero electron kinetic energy photoelectron technique. Spectra were rotationally resolved and transitions to the zero-point level, the symmetric stretch fundamental and first two bending vibrational levels were observed. The rotational state symmetry selection rules confirm that the ground electronic state of the cation is (2)Sigma(g)(+). Detachment of an electron from the HOMO of neutral BeOBe results in little change in the vibrational or rotational constants, indicating that this orbital is nonbonding in nature. The ionization energy of BeOBe [65480(4) cm(-1)] was refined over previous measurements. Results from recent theoretical calculations for BeOBe(+) (multireference configuration interaction) were found to be in good agreement with the experimental data. PMID- 21280725 TI - Photoisomerization mechanism of 4-methylpyridine explored by electronic structure calculations and nonadiabatic dynamics simulations. AB - In the present paper, different electronic structure methods have been used to determine stationary and intersection structures on the ground (S(0)) and (1)pipi* (S(2)) states of 4-methylpyridine, which is followed by adiabatic and nonadiabatic dynamics simulations to explore the mechanistic photoisomerization of 4-methylpyridine. Photoisomerization starts from the S(2)((1)pipi*) state and overcomes a small barrier, leading to formation of the prefulvene isomer in the S(0) state via a S(2)/S(0) conical intersection. The ultrafast S(2) -> S(0) nonradiative decay and low quantum yield for the photoisomerization reaction were well reproduced by the combined electronic structure calculation and dynamics simulation. The prefulvene isomer was assigned as a long-lived intermediate and suggested to isomerize to 4-methylpyridine directly in the previous study, which is not supported by the present calculation. The nonadiabatic dynamics simulation and electronic structure calculation reveal that the prefulvene isomer is a short lived intermediate and isomerizes to benzvalene form very easily. The benzvalene form was predicted as the stable isomer in the present study and is probably the long-lived intermediate observed experimentally. A consecutive light and thermal isomerization cycle via Dewar isomer was determined and this cycle mechanism is different from that reported in the previous study. It should be pointed out that formation of Dewar isomer from the S(2)((1)pipi*) state is not in competition with the isomerization to the prefulvene form. The Dewar structure observed experimentally may originate from other excited states. PMID- 21280726 TI - Nonadiabatic molecular dynamics of photoexcited Li2(+) Ne(n) clusters. AB - We investigate the relaxation of photoexcited Li(2)(+) chromophores solvated in Ne(n) clusters (n = 2-22) by means of molecular dynamics with surface hopping. The simplicity of the electronic structure of these ideal systems is exploited to design an accurate and computationally efficient model. These systems present two series of conical intersections between the states correlated with the Li+Li(2s) and Li+Li(2p) dissociation limits of the Li(2)(+) molecule. Frank-Condon transition from the ground state to one of the three lowest excited states, hereafter indexed by ascending energy from 1 to 3, quickly drives the system toward the first series of conical intersections, which have a tremendous influence on the issue of the dynamics. The states 1 and 2, which originate in the Frank-Condon area from the degenerated nondissociative 1(2)Pi(u) states of the bare Li(2)(+) molecule, relax mainly to Li+Li(2s) with a complete atomization of the clusters in the whole range of size n investigated here. The third state, which originates in the Frank-Condon area from the dissociative 1(2)Sigma(u)(+) state of the bare Li(2)(+) molecule, exhibits a richer relaxation dynamics. Contrary to intuition, excitation into state 3 leads to less molecular dissociation, though the amount of energy deposited in the cluster by the excitation process is larger than for excitation into state 1 and 2. This extra amount of energy allows the system to reach the second series of conical intersections so that approximately 20% of the clusters are stabilized in the 2(2)Sigma(g)(+) state potential well for cluster sizes n larger than 6. PMID- 21280727 TI - Theoretical study of isomerization and decomposition of propenal. AB - We investigated the dynamics of isomerization and multi-channel dissociation of propenal (CH(2)CHCHO), methyl ketene (CH(3)CHCO), hydroxyl propadiene (CH(2)CH(2)CHOH), and hydroxyl cyclopropene (cyclic-C(3)H(3)-OH) in the ground potential-energy surface using quantum-chemical calculations. Optimized structures and vibrational frequencies of molecular species were computed with method B3LYP/6-311G(d,p). Total energies of molecules at optimized structures were computed at the CCSD(T)/6-311+G(3df,2p) level of theory. We established the potential-energy surface for decomposition to CH(2)CHCO + H, CH(2)CH + HCO, CH(2)CH(2)/CH(3)CH + CO, CHCH/CH(2)C + H(2)CO, CHCCHO/CH(2)CCO + H(2), CHCH + CO + H(2), CH(3) + HCCO, CH(2)CCH + OH, and CH(2)CC/cyclic-C(3)H(2) + H(2)O. Microcanonical rate coefficients of various reactions of trans-propenal with internal energies 148 and 182 kcal mol(-1) were calculated using Rice-Ramsperger Kassel-Marcus and Variational transition state theories. Product branching ratios were derivable using numerical integration of kinetic master equations and the steady-state approximation. The concerted three-body dissociation of trans propenal to fragments C(2)H(2) + CO + H(2) is the prevailing channel in present calculations. In contrast, C(3)H(3)O + H, C(2)H(3) + HCO and C(2)H(4) + CO were identified as major channels in the photolysis of trans-propenal. The discrepancy between calculations and experiments in product branching ratios indicates that the three major photodissociation channels occur mainly on an excited potential energy surface whereas the other channels occur mainly on the ground potential energy surface. This work provides profound insight in the mechanisms of isomerization and multichannel dissociation of the system C(3)H(4)O. PMID- 21280728 TI - Potential energy surface and rovibrational calculations for the Mg+-H2 and Mg+-D2 complexes. AB - A three-dimensional potential energy surface is developed to describe the structure and dynamical behavior of the Mg(+)-H(2) and Mg(+)-D(2) complexes. Ab initio points calculated using the RCCSD(T) method and aug-cc-pVQZ basis set (augmented by bond functions) are fitted using a reproducing kernel Hilbert space method [Ho and Rabitz, J. Chem. Phys. 104, 2584 (1996)] to generate an analytical representation of the potential energy surface. The calculations confirm that Mg(+)-H(2) and Mg(+)-D(2) essentially consist of a Mg(+) atomic cation attached, respectively, to a moderately perturbed H(2) or D(2) molecule in a T-shaped configuration with an intermolecular separation of 2.62 A and a well depth of D(e) = 842 cm(-1). The barrier for internal rotation through the linear configuration is 689 cm(-1). Interaction with the Mg(+) ion is predicted to increase the H(2) molecule's bond-length by 0.008 A. Variational rovibrational energy level calculations using the new potential energy surface predict a dissociation energy of 614 cm(-1) for Mg(+)-H(2) and 716 cm(-1) for Mg(+)-D(2). The H-H and D-D stretch band centers are predicted to occur at 4059.4 and 2929.2 cm(-1), respectively, overestimating measured values by 3.9 and 2.6 cm(-1). For Mg(+)-H(2) and Mg(+)-D(2), the experimental B and C rotational constants exceed the calculated values by ~1.3%, suggesting that the calculated potential energy surface slightly overestimates the intermolecular separation. An ab initio dipole moment function is used to simulate the infrared spectra of both complexes. PMID- 21280729 TI - Dissipative many-electron dynamics of ionizing systems. AB - In this paper, we perform many-electron dynamics using the time-dependent configuration-interaction method in its reduced density matrix formulation (rho TDCI). Dissipation is treated implicitly using the Lindblad formalism. To include the effect of ionization on the state-resolved dynamics, we extend a recently introduced heuristic model for ionizing states to the rho-TDCI method, which leads to a reduced density matrix evolution that is not norm-preserving. We apply the new method to the laser-driven excitation of H(2) in a strongly dissipative environment, for which the state-resolve lifetimes are tuned to a few femtoseconds, typical for dynamics of adsorbate at metallic surfaces. Further testing is made on the laser-induced intramolecular charge transfer in a quinone derivative as a model for a molecular switch. A modified scheme to treat ionizing states is proposed to reduce the computational burden associated with the density matrix propagation, and it is thoroughly tested and compared to the results obtained with the former model. The new approach scales favorably (~N(2)) with the number of configurations N used to represent the reduced density matrix in the rho-TDCI method, as compared to a N(3) scaling for the model in its original form. PMID- 21280730 TI - Fourier transform infrared isotopic study of linear MnC3: identification of the nu1(sigma) fundamental. AB - Linear MnC(3) has been detected in the products from the dual laser ablation of carbon and manganese rods trapped in solid Ar at ~12 K. The nu(1)(sigma) vibrational fundamental, an asymmetric carbon stretching mode, has been identified at 1846.9 cm(-1). Fourier transform infrared measurements of (13)C isotopic shift are in good agreement with the predictions of density functional theory calculations using the mPW1PW91 functional with 6-311+G(3df) basis set. This is the first optical detection of the linear isomer of MnC(3) for which previous photoelectron spectroscopy studies have reported evidence of a cyclic isomer. PMID- 21280731 TI - Theoretical study of the rovibrational spectrum of H2O-H2. AB - In this paper we report transition frequencies and line strengths computed for H(2)O-H(2) and compare with the experimental observations of [M. J. Weida and D. J. Nesbitt, J. Chem. Phys. 110, 156 (1999)]. To compute the spectra we use a symmetry adapted Lanczos algorithm and an uncoupled product basis set. Our results corroborate the assignments of Weida and Nesbitt and there is good agreement between calculated and observed transitions. Possible candidates for lines that Weida and Nesbitt were not able to assign are presented. Several other bands that may be observable are also discovered. Although all the observed bands are associated with states localized near the global potential minimum, at which H(2)O acts as proton acceptor, a state with significant amplitude near the T shape secondary potential minimum at which H(2)O acts as proton donor is identified by examining many different probability density plots. PMID- 21280732 TI - Rovibrational states of the H2O-H2 complex: an ab initio calculation. AB - All bound rovibrational levels of the H(2)O-H(2) dimer are calculated for total angular momentum J = 0-5 on two recent intermolecular potential surfaces reported by Valiron et al. [J. Chem. Phys. 129, 134306 (2008)] and Hodges et al. [J. Chem. Phys. 120, 710 (2004)] obtained through ab initio calculations. The method used handles correctly the large amplitude internal motions in this complex; it involves a discrete variable representation of the intermolecular distance coordinate R and a basis of coupled free rotor wave functions for the hindered internal rotations and the overall rotation of the dimer. The basis is adapted to the permutation symmetry associated with the para/ortho (p/o) nature of both H(2)O and H(2) as well as to inversion symmetry. Dimers containing oH(2) are more strongly bound than dimers with pH(2), as expected, with dissociation energies D(0) of 33.57, 36.63, 53.60, and 59.04 cm(-1)for pH(2)O-pH(2), oH(2)O-pH(2), pH(2)O-oH(2), and oH(2)O-oH(2), respectively, on the potential of Valiron et al. that corresponds to a binding energy D(e) of 235.14 cm(-1). Rovibrational wave functions are computed as well and the nature of the bound states in the four different dimer species is discussed. Converged rovibrational levels on both potentials agree well with the high-resolution spectrum reported by Weida and Nesbitt [J. Chem. Phys. 110, 156 (1999)]; the hindered internal rotor model that was used to interpret this spectrum is qualitatively correct. PMID- 21280733 TI - Photoelectron imaging of several 5d and 6p Rydberg states Xe2 and improving the Xe2(+) I(1/2g) potential. AB - Velocity map photoelectron imaging was used to study the photoionization of Xe(2) in several low-lying 5d and 6p Rydberg states. The Rydberg states were prepared by two-photon excitation and ionized by either one additional photon from the pump laser (2+1 ionization), or by one photon of a second color (2+1(') ionization). The 2+1 images and associated photoelectron spectra were consistent with previous results, although some adjustment of previously proposed equilibrium bond lengths was necessary to fit the spectra with Franck-Condon factor calculations. The 2+1(') images provided higher resolution photoelectron spectra and, in conjunction with the Xe(2)(+) potentials reported by Zehnder and co-workers [J. Chem. Phys. 128, 234306 (2008)] and the 6p and 5d Xe(2)* potentials calculated by Jonin and Spiegelmann [J. Chem. Phys. 117, 3059 (2002)], provided a means for improving the Xe(2)* potentials. New experimental data are also presented for photoionization populating the Xe(2)(+) I(1/2g) state, and are used to provide a better description of its potential curve. PMID- 21280734 TI - Laser-induced UV photodissociation of 2-bromo-2-nitropropane: dynamics of OH and Br formation. AB - Photoexcitation of 2-bromo-2-nitropropane (BNP) at 248 and 193 nm generates OH, Br, and NO(2) among other products. The OH fragment is detected by laser-induced fluorescence spectroscopy, and its translational and internal state distributions (vibration, rotation, spin-orbit, and Lambda-doubling components) are probed. At both 248 and 193 nm, the OH fragment is produced translationally hot with the energy of 10.8 and 17.2 kcal/mol, respectively. It is produced vibrationally cold (v" = 0) at 248 nm, and excited (v" = 1) at 193 nm with a vibrational temperature of 1870 +/- 150 K. It is also generated with rotational excitation, rotational populations of OH(v" = 0) being characterized by a temperature of 550 +/- 50 and 925 +/- 100 K at 248 and 193 nm excitation of BNP, respectively. The spin-orbit components of OH(X(2)Pi) are not in equilibrium on excitation at 193 nm, but the Lambda-doublets are almost in equilibrium, implying no preference for its pi lobe with respect to the plane of rotation. The NO(2) product is produced electronically excited, as detected by measuring UV-visible fluorescence, at 193 nm and mostly in the ground electronic state at 248 nm. The Br product is detected employing resonance-enhanced multiphoton ionization with time-of-flight mass spectrometer for better understanding of the dynamics of dissociation. The forward convolution analysis of the experimental data has provided translational energy distributions and anisotropy parameters for both Br((2)P(3/2)) and Br*((2)P(1/2)). The average translational energies for the Br and Br* channels are 5.0 +/- 1.0 and 6.0 +/- 1.5 kcal/mol. No recoil anisotropies were observed for these products. Most plausible mechanisms of OH and Br formation are discussed based on both the experimental and the theoretical results. Results suggest that the electronically excited BNP molecules at 248 and 234 nm relax to the ground state, and subsequently dissociate to produce OH and Br through different channels. The mechanism of OH formation from BNP on excitation at 193 nm is also discussed. PMID- 21280735 TI - Quantum state-resolved energy redistribution in gas ensembles containing highly excited N2. AB - A computational model is used to quantify the evolution of quantum state populations as highly vibrationally excited (14)N(2) ((14)N(2)*) equilibrates in various bath gases. Multicollision energy disposal follows general principles established in related single collision processes. Thus when state-to-state routes permit, maximum amounts of energy are deposited into partner species by direct vibration-to-vibration (V-V) exchange. When these pathways are absent, e.g., when Ar is the bath species, relaxation is very slow and multistaged. Conversely, in a bath of v = 0 (14)N(2) molecules, 16 vibrational quanta (Deltav = +/- 8) are resonantly exchanged from (v;j) = (8;10) with vibrational equilibration so rapid that rotation and translation still lag far behind after 1000 collisions. Near-resonant V-V exchange dominates the initial phase when (15)N(2) forms the bath gas and although some rotational warming occurs, vibrational modes remain decoupled from, and significantly hotter than, the low heat capacity modes. These forms of behavior seem likely to characterize excited and bath species that have closely similar vibration and rotation constants. More generic in nature is (14)N(2) in O(2) or in a mixture that closely resembles air. Here, asymmetric V-V exchange is a dominant early feature in ensemble evolution but energy differences in the key vibration and rotation quanta lead to V-V energy defects that are compensated for by the low energy modes. This results in much more rapid ensemble equilibration, generally within 400-500 collisions, when O(2) is present even as a minor constituent. Our results are in good general agreement with those obtained from experimental studies of N(2) plasmas both in terms of modal temperatures and initial (first collision cycle) cross-sections. PMID- 21280736 TI - Are asymmetric stretch Raman spectra by centrosymmetric molecules depolarized?: the 2nu3 overtone of CO2. AB - Molecular vibrations that are not totally symmetrical give rise to depolarized lines [P. Atkins and J. de Paula, Atkins' Physical Chemistry (Oxford University Press, UK, 2006), p. 464]. But in the case of stretching vibrations in centrosymmetric molecules, the statement has so far not been conclusively verified. It is the purpose of this article to report a rigorous experimental and theoretical analysis of the 2nu(3) band of CO(2)--the first overtone of the asymmetrical stretch vibration. The anisotropic spectrum was extracted and its spectral moment calculated from light-scattering measurements, taken at room temperature and for a wide range of CO(2)-gas densities. Evidence for a near entirely depolarized Raman band is provided, with integrated depolarization ratio eta(int)=6/7.16, closely approaching the upper bound eta(max)=6/7. Agreement with theoretical predictions is found, on the basis of quality ab initio data for polarizability properties, provided that electro-optical and mechanical anharmonicity and intermode coupling effects between symmetric nu(1) and antisymmetric nu(3) stretching vibrations are incorporated. PMID- 21280737 TI - Spectroscopic detection of the most stable carbonic acid, cis-cis H2CO3. AB - Carbonic acid had not been detected by any spectroscopic means for a long period. Recently, we have reported the detection of its second most stable conformer, cis trans H(2)CO(3), as the first spectroscopic detection of the isolated carbonic acid molecule. In the present work, the most stable conformer of carbonic acid, cis-cis H(2)CO(3), in the gas phase has been successfully produced in a supersonic jet using a pulsed discharge nozzle, and pure rotational transitions of this molecule have been observed by a Fourier-transform microwave spectrometer. In addition to cis-cis H(2)CO(3), its deuterated isotopologue, cis cis D2CO3, has been observed, yielding the r(0) structure of the cis-cis conformer. Furthermore, hyperfine constants of the deuterated cis-trans conformers were also determined. The two structures for the stable isolated carbonic acid molecule, those of the cis-cis and cis-trans conformers, are considered to provide basic information for the understanding of chemical reactions involving carbonic acid The present result is accurate enough to be used in radio astronomical observations, where the ortho/para ratio of cis-cis H(2)CO(3) may be used as an important probe of interstellar chemistry. PMID- 21280738 TI - Rovibrational spectra of ammonia. I. Unprecedented accuracy of a potential energy surface used with nonadiabatic corrections. AB - In this work, we build upon our previous work on the theoretical spectroscopy of ammonia, NH(3). Compared to our 2008 study, we include more physics in our rovibrational calculations and more experimental data in the refinement procedure, and these enable us to produce a potential energy surface (PES) of unprecedented accuracy. We call this the HSL-2 PES. The additional physics we include is a second-order correction for the breakdown of the Born-Oppenheimer approximation, and we find it to be critical for improved results. By including experimental data for higher rotational levels in the refinement procedure, we were able to greatly reduce our systematic errors for the rotational dependence of our predictions. These additions together lead to a significantly improved total angular momentum (J) dependence in our computed rovibrational energies. The root-mean-square error between our predictions using the HSL-2 PES and the reliable energy levels from the HITRAN database for J = 0-6 and J = 7/8 for (14)NH(3) is only 0.015 cm(-1) and 0.020/0.023 cm(-1), respectively. The root mean-square errors for the characteristic inversion splittings are approximately 1/3 smaller than those for energy levels. The root-mean-square error for the 6002 J = 0-8 transition energies is 0.020 cm(-1). Overall, for J = 0-8, the spectroscopic data computed with HSL-2 is roughly an order of magnitude more accurate relative to our previous best ammonia PES (denoted HSL-1). These impressive numbers are eclipsed only by the root-mean-square error between our predictions for purely rotational transition energies of (15)NH(3) and the highly accurate Cologne database (CDMS): 0.00034 cm(-1) (10 MHz), in other words, 2 orders of magnitude smaller. In addition, we identify a deficiency in the (15)NH(3) energy levels determined from a model of the experimental data. PMID- 21280739 TI - Rovibrational spectra of ammonia. II. Detailed analysis, comparison, and prediction of spectroscopic assignments for 14NH3, 15NH3, and 14ND3. AB - Several aspects of ammonia rovibrational spectra have been investigated using the new HSL-2 potential energy surface that includes an approximate correction for nonadiabatic effects. The unprecedented accuracy of rovibrational energy levels and transition energies computed using HSL-2 was demonstrated in Part I of this study. For (14)NH(3), new assignments for a few nu(3) + nu(4) band transitions and energy levels are suggested, and discrepancies between computed and HITRAN energy levels in the 2nu(4) band are analyzed (2nu(4) is the most difficult band below 5000 cm(-1)). New assignments are suggested for existing or missing 2nu(4) levels. Several new vibrational bands are identified from existing, unassigned HITRAN data, including 2nu(2) + nu(4), (nu(3) + nu(4)) -A(')/A("), nu(1) + 2nu(2), and 2nu(2) + 2nu(4). The strong mixing between the 2nu(4) and 2nu(2) + nu(4) bands is carefully examined and found to be the source of the difficulties in the experimental modeling of 2nu(4). Discussion is presented for preliminary J = 10 results, where the overall root-mean-square error is estimated to be less than 0.039 cm(-1). The analysis of the 4nu(2) band demonstrates both the reliability and the accuracy of predictions from HSL-2. The full list of computed J = 0 band origins (with assignments) and the inversion splittings up to 7000 8000 cm(-1) above the zero-point energy are presented. J = 0-2 levels are reported for those bands below 5100 cm(-1) that are missing from the HITRAN database. For (15)NH(3), excellent agreement is found for the available nu(2) and nu(3) + nu(4)(E) transition energies, but significant deficiencies are shown for HITRAN levels and several corrections are suggested. The (15)N isotopic effects are presented for the J = 0-6 levels of 13 HITRAN bands. For (14)ND(3), we reproduce the pure rotational inversion spectra line frequencies with an accuracy similar to that for (14)NH(3). However, it is not possible to reproduce simultaneously all four pairs of inversion-split vibrational fundamentals to better than 0.05 cm(-1) uncertainty. It is suggested that a reanalysis of some suspicious (14)ND(3) fundamental bands is required. The analyses presented here and in Part I show that rovibrational energy levels and transition frequencies computed with HSL-2 (with nonadiabatic corrections) remain highly accurate well beyond the experimental data used in the refinement procedure. Calculations using HSL-2 are capable of revealing many deficiencies in experimental analyses of ammonia spectra and provide reliable predictions with similar accuracy. It is expected that the results of this study will be useful in the future interpretation of high-resolution spectra from laboratory experiments or from astronomical observations. The present work represents a very significant advance in the state of our knowledge of the spectroscopy of ammonia and its isotopologues. PMID- 21280740 TI - Lithium cluster anions: photoelectron spectroscopy and ab initio calculations. AB - Structural and energetic properties of small, deceptively simple anionic clusters of lithium, Li(n)(-), n = 3-7, were determined using a combination of anion photoelectron spectroscopy and ab initio calculations. The most stable isomers of each of these anions, the ones most likely to contribute to the photoelectron spectra, were found using the gradient embedded genetic algorithm program. Subsequently, state-of-the-art ab initio techniques, including time-dependent density functional theory, coupled cluster, and multireference configurational interactions methods, were employed to interpret the experimental spectra. PMID- 21280741 TI - Kinetics of electron attachment to SF3CN, SF3C6F5, and SF3 and mutual neutralization of Ar+ with CN- and C6F5(-). AB - The additions of two sulfur fluoride derivatives (SF(3)C(6)F(5) and SF(3)CN) to a flowing afterglow were studied by variable electron and neutral density mass spectrometry. Data collection and analysis were complicated by the high reactivity of the neutral species. Both species readily dissociatively attach thermal electrons at 300 K to yield SF(3) + X(-) (X = C(6)F(5), CN). Attachment to SF(3)C(6)F(5) also results in SF(3)(-) + C(6)F(5) as a minor product channel. The determined electron attachment rate constants were 1(-0.6) (+1) * 10(-7) cm(3) s(-1) for SF(3)C(6)F(5), a lower limit of 1 * 10(-8) cm(3) s(-1) for SF(3)CN, and 4 +/- 3 * 10(-9) cm(3) s(-1) for SF(3). Mutual neutralization rate constants of C(6)F(5)(-) and CN(-) with Ar(+) at 300 K were determined to be 5.5( 1.6) (+1.0) * 10(-8) and 3.0 +/- 1 * 10(-8) cm(3) s(-1), respectively. PMID- 21280742 TI - A polarizable ion model for the structure of molten CuI. AB - The results are reported of the molecular dynamics simulations of the coherent static structure factor of molten CuI at 938 K using a polarizable ion model. This model is based on a rigid ion potential to which the many body interactions due to the anions induced polarization are added. The calculated structure factor reproduces the clear sharp prepeak observed in neutron diffraction data. The corresponding partial structure factors and the related radial distribution functions calculated by molecular dynamics are compared with those found in the literature derived from a combination of neutron and x-ray diffraction data with the aid of the reverse Monte Carlo simulation technique, as well as those calculated by ab initio MD simulations. PMID- 21280743 TI - Proton transport in biological systems can be probed by two-dimensional infrared spectroscopy. AB - We propose a new method to determine the proton transfer (PT) rate in channel proteins by two-dimensional infrared (2DIR) spectroscopy. Proton transport processes in biological systems, such as proton channels, trigger numerous fundamental biochemical reactions. Due to the limitation in both spatial and time resolution of the traditional experimental approaches, describing the whole proton transport process and identifying the rate limiting steps at the molecular level is challenging. In the present paper, we focus on proton transport through the Gramicidin A channel. Using a kinetic PT model derived from all-atom molecular dynamics simulations, we model the amide I region of the 2DIR spectrum of the channel protein to examine its sensitivity to the proton transport process. We demonstrate that the 2DIR spectrum of the isotope-labeled channel contain information on the PT rate, which may be extracted by analyzing the antidiagonal linewidth of the spectral feature related to the labeled site. Such experiments in combination with detailed numerical simulations should allow the extraction of site dependent PT rates, providing a method for identifying possible rate limiting steps for proton channel transfer. PMID- 21280744 TI - Mesoscopic dynamics of diffusion-influenced enzyme kinetics. AB - A particle-based mesoscopic model for enzyme kinetics is constructed and used to investigate the influence of diffusion on the reactive dynamics. Enzymes and enzyme-substrate complexes are modeled as finite-size soft spherical particles, while substrate, product, and solvent molecules are point particles. The system is evolved using a hybrid molecular dynamics-multiparticle collision dynamics scheme. Both the nonreactive and reactive dynamics are constructed to satisfy mass, momentum, and energy conservation laws, and reversible reaction steps satisfy detailed balance. Hydrodynamic interactions among the enzymes and complexes are automatically accounted for in the dynamics. Diffusion manifests itself in various ways, notably in power-law behavior in the evolution of the species concentrations. In accord with earlier investigations, regimes where the product production rate exhibits either monotonic or nonmonotonic behavior as a function of time are found. In addition, the species concentrations display both t(-1/2) and t(-3/2) power-law behavior, depending on the dynamical regime under investigation. For high enzyme volume fractions, cooperative effects influence the enzyme kinetics. The time dependent rate coefficient determined from the mass action rate law is computed and shown to depend on the enzyme concentration. Lifetime distributions of substrate molecules newly released in complex dissociation events are determined and shown to have either a power-law form for rebinding to the same enzyme from which they were released or an exponential form for rebinding to different enzymes. The model can be used and extended to explore a variety of issues related concentration effects and diffusion on enzyme kinetics. PMID- 21280745 TI - On the density scaling of liquid dynamics. AB - Superpositioning of relaxation data as a function of the product variable TV(gamma), where T is temperature, V the specific volume, and gamma a material constant, is an experimental fact demonstrated for approximately 100 liquids and polymers. Such scaling behavior would result from the intermolecular potential having the form of an inverse power law (IPL), suggesting that an IPL is a good approximation for certain relaxation properties over the relevant range of intermolecular distances. However, the derivation of the scaling property of an IPL liquid is based on reduced quantities, for example, the reduced relaxation time equal to T(1/2V - 1/3) times the actual relaxation time. The difference between scaling using reduced rather than unreduced units is negligible in the supercooled regime; however, at higher temperature the difference can be substantial, accounting for the purported breakdown of the scaling and giving rise to different values of the scaling exponent. Only the gamma obtained using reduced quantities can be sensibly related to the intermolecular potential. PMID- 21280746 TI - Large heat capacity anomaly near the consolute point of the binary mixture nitromethane and 3-pentanol. AB - The large critical anomaly in the isobaric heat capacity C(p,x)(T) of the binary mixture nitromethane + 3-pentanol is measured using high-resolution adiabatic scanning calorimetry. The unique features of this technique provided an alternative approach to the study of the critical behavior of C(p,x)(T), providing further C(p,x)(T) related quantities from which valuable information could be extracted. Our data are in full agreement with the predictions of the Modern Theory of Critical Phenomena; specifically, 3D-Ising model values for the critical exponent alpha and the universal amplitude ratio values of the leading critical amplitudes, as well as for the first correction-to-scaling ones, provide the optimum fits to represent the experimental data. Evidence for the need of higher-order terms, i.e., first correction-to-scaling term, is given. The large value of the coefficient E for the linear temperature dependence of the background obtained is ascribed to a possible contribution of the regular linear background term, of a higher-order asymmetry term, and of the second correction to-scaling term. Internal consistency of C(p,x)(T) and its related quantities is successfully checked. PMID- 21280747 TI - Association structures of ionic liquid/DMSO mixtures studied by high-pressure infrared spectroscopy. AB - Using high-pressure infrared methods, we have investigated close interactions of charge-enhanced C-H-O type in ionic liquid/dimethyl sulfoxide (DMSO) mixtures. The solvation and association of the 1-butyl-3-methylimidazolium tetrafluoroborate (BMI(+)BF(4)(-)) and 1-butyl-2,3-dimethylimidazolium tetrafluoroborate (BMM(+)BF(4)(-)) in DMSO-d(6) were examined by analysis of C-H spectral features. Based on our concentration-dependent results, the imidazolium C-H groups are more sensitive sites for C-H-O than the alkyl C-H groups and the dominant imidazolium C-H species in dilute ionic liquid/DMSO-d(6) should be assigned to the isolated (or dissociated) structures. As the dilute mixtures were compressed by high pressures, the loss in intensity of the bands attributed to the isolated structures was observed. In other words, high pressure can be used to perturb the association-dissociation equilibrium in the polar region. This result is remarkably different from what is revealed for the imidazolium C-H in the BMM(+)BF(4)(-)/D(2)O mixtures. DFT-calculations are in agreement with our experimental results indicating that C(4)-H-O and C(5)-H-O interactions seem to play non-negligible roles for BMM(+)BF(4)(-)/DMSO mixtures. PMID- 21280748 TI - Excited electron-bubble states in superfluid 4He: a time-dependent density functional approach. AB - We present a systematic study on the excited electron-bubble states in superfluid (4)He using a time-dependent density functional approach. For the evolution of the 1P bubble state, two different functionals accompanied with two different time-development schemes are used, namely an accurate finite-range functional for helium with an adiabatic approximation for electron versus an efficient zero range functional for helium with a real-time evolution for electron. We make a detailed comparison between the quantitative results obtained from the two methods, which allow us to employ with confidence the optimal method for suitable problems. Based on this knowledge, we use the finite-range functional to calculate the time-resolved absorption spectrum of the 1P bubble, which in principle can be experimentally determined, and we use the zero-range functional to real-time evolve the 2P bubble for several hundreds of picoseconds, which is theoretically interesting due to the break down of adiabaticity for this state. Our results discard the physical realization of relaxed, metastable configurations above the 1P state. PMID- 21280749 TI - Correlations among residual multiparticle entropy, local atomic-level pressure, free volume and the phase-ordering rule in several liquids. AB - A modified Wang-Landau density-of-states sampling approach has been performed to calculate the excess entropy of liquid metals, Lennard-Jones (LJ) system and liquid Si under NVT conditions; and it is then the residual multiparticle entropy (S(RMPE)) is obtained by subtraction of the pair correlation entropy. The temperature dependence of S(RMPE) has been investigated along with the temperature dependence of the local atomic-level pressure and the pair correlation functions. Our results suggest that the temperature dependence of the pair correlation entropy is well described by T(-1) scaling while T(-0.4) scaling well describes the relationship between the excess entropy and temperature. For liquid metals and LJ system, the -S(RMPE) versus temperature curves show positive correlations and the -S(RMPE) of liquid Si is shown to have a negative correlation with temperature, the phase-ordering criterion (based on the S(RMPE)) for predicting freezing transition works in liquid metals and LJ but fails in liquid Si. The local atomic-level pressure scaled with the virial pressure (sigma(al)/sigma(av)) exhibits the much similar temperature dependence as S(RMPE) for all studied systems, even though simple liquid metals and liquid Si exhibit opposite temperature dependence in both sigma(al)/sigma(av) and -S(RMPE). The further analysis shows that the competing properties of the two effects due to localization and free volume on the S(RMPE) exist in simple liquid metals and LJ system but disappear in liquid Si, which may be the critical reason of the failure of the phase-ordering criterion in liquid Si. PMID- 21280750 TI - A heuristic model of damped quantum rotation effects in nuclear magnetic resonance spectra. AB - The damped quantum rotation (DQR) theory describes temperature effects in NMR spectra of hindered molecular rotators composed of identical atoms arranged in regular N-gons. In the standard approach, the relevant coherent dynamics are described quantum mechanically and the stochastic, thermally activated motions classically. The DQR theory is consistent. In place of random jumps over one, two, etc., maxima of the hindering potential, here one has damping processes of certain long-lived coherences between spin-space correlated eigenstates of the rotator. The damping-rate constants outnumber the classical jump-rate constants. The jump picture is recovered when the former cluster appropriately around only as many values as the number of the latter. The DQR theory was confirmed experimentally for hindered methyl groups in solids and even in liquids above 170 K. In this paper it is shown that for three-, four-, and sixfold rotators, the Liouville space equations of NMR line shapes, derived previously with the use of the quantum mechanical reduced density matrix approach, can be be given a heuristic justification. It is based on an equation of motion for the effective spin density matrix, where the relevant spin hamiltonian contains randomly fluctuating terms. The occurrence of the latter can be rationalized in terms of fluctuations of the tunneling splittings between the torsional sublevels of the rotator, including momentary liftings of the Kramers degeneracies. The question whether such degeneracy liftings are physical or virtual is discussed. The random terms in the effective hamiltonian can be Monte Carlo modeled as piecewise constant in time, which affords the stochastic equation of motion to be solved numerically in the Hilbert spin space. For sixfold rotators, this way of calculating the spectra can be useful in the instances where the Liouville space formalism of the original DQR theory is numerically unstable. PMID- 21280751 TI - Temperature and pressure dependence of secondary process in an epoxy system. AB - Dielectric spectroscopy as a function of temperature and pressure was used to study the secondary relaxation in poly [(phenyl glycidyl ether)-co-formaldehyde] at hydrostatic pressure up to 600 MPa and at different temperatures between 315 and 243 K. From the analysis of the isothermal measurements, we observe that the activation volume of the secondary relaxation has nonmonotonic temperature dependence with a maximum at the temperature of the glass transition at ambient pressure. An interpretation in terms of mean hole volume dispersion is proposed based on literature data. Moreover, from isobaric data, we studied the effect of pressure on activation entropy and enthalpy of the secondary relaxation evidencing its local nature but also the presence of a certain complexity of the motion, which supports the idea that this process reflects the motion of a large part of the molecule. PMID- 21280752 TI - Molecular structural property and potential energy dependence on nonequilibrium thermodynamic state point of liquid n-hexadecane under shear. AB - Extensive computer experiments have been conducted in order to shed light on the macroscopic shear flow behavior of liquid n-hexadecane fluid under isobaric isothermal conditions through the nonequilibrium molecular dynamic methodology. With respect to shear rates, the accompanying variations in structural properties of the fluid span the microscopic range of understanding from the intrinsic to extrinsic characteristics. As drawn from the average value of bond length and bond angle, the distribution of dihedral angle, and the radius distribution function of intramolecular and intermolecular van der Waals distances, these intrinsic structures change with hardness, except in the situation of extreme shear rates. The shear-induced variation of thermodynamic state curve along with the shear rate studied is shown to consist of both the quasiequilibrium state plateau and the nonequilibrium-thermodynamic state slope. Significantly, the occurrence of nonequilibrium-thermodynamic state behavior is attributed to variations in molecular potential energies, which include bond stretching, bond bending, bond torsion, and intra- and intermolecular van der Waals interactions. To unfold the physical representation of extrinsic structural deformation, under the aggressive influence of a shear flow field, the molecular dimension and appearance can be directly described via the squared radius of gyration and the sphericity angle, R(g)(2) and phi, respectively. In addition, a specific orientational order S(x) defines the alignment of the molecules with the flow direction of the x-axis. As a result, at low shear rates, the overall molecules are slightly stretched and shaped in a manner that is increasingly ellipsoidal. Simultaneously, there is an obvious enhancement in the order. In contrast to high shear rates, the molecules spontaneously shrink themselves with a decreased value of R(g)(2), while their shape and order barely vary with an infinite value of phi and S(x). It is important to note that under different temperatures and pressures, these three parameters are integrated within a molecular description in response to thermodynamic state variable of density and rheological material function of shear viscosity. PMID- 21280753 TI - The free volume of poly(vinyl methylether) as computed in a wide temperature range and at length scales up to the nanoregion. AB - In the present work, we focus on the free volume evaluations from different points of view, including the aspect of probe sizes, temperature, and cavity threshold. The free volume structure is analyzed on structures of poly(vinyl methylether) prepared by fully atomistic molecular dynamics. At first, the temperature behavior of an overall free volume and a free volume separated into individual cavities is shown. The origin of large free volume cavities is explained. A complex view on the cavity number is provided, while a complicated behavior previously observed is now explained. The number of large cavities remained almost constant with the temperature. Oppositely, the number of small cavities related to the atomic packing changes with temperature in a distinct way for glassy and supercooled regions. The cavity number maxima determine a percolation threshold according to percolation theory. The change in polymer properties with temperature can be related to a percolation of the free volume according to the free volume theory, when proper probe radii ~0.8 A are used for its observation. A construction of probabilistic distribution of free volume sizes is suggested. The free volume distributions reported here are bimodal. The bimodal character is explained by two different packings--atomic and segmental- forming a prepeak and a main peak on the distribution. Further attention is dedicated to comparisons of the computed free volume sizes and the ortho positronium (o-Ps) lifetimes. The prepeak of the free volume distribution is probably unseen by o-Ps because of a cavity threshold limit. The effect of the shape factor on the computed o-Ps lifetimes is tested. The quasicavities obtained by redistributing the free volume maintain the ratio of the main dimensions with temperature. Finally, novel data on the cavity environment are provided, while it is suggested how these can be useful with the recent developments in the positron annihilation methods. The coordination number of large cavities with the polymer segments is around 1, as predicted in the free volume theory. Similarly to the percolation and the cavity number, the coordination number exhibits a change when explored by a suitable probe radius ~0.8 A. The insightful visualizations showed properties of interest investigated within the actual work. PMID- 21280754 TI - Vibrational interference effects in x-ray emission of a model water dimer: implications for the interpretation of the liquid spectrum. AB - We apply the Kramers-Heisenberg formula to a model water dimer to discuss vibrational interference in the x-ray emission spectrum of the donor molecule for which the core-ionized potential energy surface is dissociative but bounded by the accepting molecule. A long core-hole lifetime leads to decay from Zundel like, fully delocalized vibrational states in the intermediate potential without involvement of a specific dissociated component. Comparison is made to a model with an unbound intermediate state allowing dissociation to infinity which gives a sharp, fully dissociated feature, and a broad molecular peak at long core-hole life time. The implications of the vibrational interference effect on the liquid water spectrum are discussed and it is proposed that this mainly gives rise to an isotope-dependent asymmetrical broadening of the lone pair peak. PMID- 21280755 TI - Benchmarking the multipole shielding polarizability/reaction field approach to solvation against QM/MM: applications to the shielding constants of N methylacetamide. AB - We present a benchmark study of a combined multipole shielding polarizability/reaction field (MSP/RF) approach to the calculation of both specific and bulk solvation effects on nuclear magnetic shielding constants of solvated molecules. The MSP/RF scheme is defined by an expansion of the shielding constants of the solvated molecule in terms of electric field and field gradient property derivatives derived from single molecule ab initio calculations. The solvent electric field and electric field gradient are calculated based on data derived from molecular dynamics simulations, thereby accounting for solute solvent dynamical effects. The MSP/RF method is benchmarked against polarizable quantum mechanics/molecular mechanics (QM/MM) calculations. The best agreement between the MSP/RF and QM/MM approaches is found by truncating the electric field expansion in the MSP/RF approach at the linear electric field level which is due to the cancelation of errors. In addition, we investigate the sensitivity of the results due to the choice of one-electron basis set in the ab initio calculations of the property derivatives and find that these derivatives are affected by the basis set in a way similar to the shielding constants themselves. PMID- 21280756 TI - Is there a relation between excess volume and miscibility in binary liquid mixtures? AB - Molecular dynamics computer simulations of various symmetrical Lennard-Jones (LJ) models are used to elucidate how the excess volume in dense binary liquids is related to the microscopic interactions between the particles. Both fully miscible systems and systems with a liquid-liquid phase separation are considered by varying systematically the parameters of the LJ potentials. The phase diagrams with the critical points of the demixing systems are determined by means of Monte Carlo simulations in the semigrandcanonical ensemble. The different LJ models are investigated by computing Bhatia-Thornton structure factors, enthalpy of mixing, and excess volume. For the demixing systems, the LJ models show a positive enthalpy of mixing while it is negative for the systems without miscibility gap. In contrast to that, the excess volume can be negative and positive for both demixing and fully miscible systems. This behavior is explained in terms of the interplay between the repulsive and attractive terms in the LJ potential. Whereas repulsions dominate the packing of particles as reflected by the number-density structure factor, the chemical ordering and thus the concentration structure factor are strongly affected by attractive interactions, leading to the "anomalies" of the excess volume. PMID- 21280757 TI - Orientational relaxation dynamics in aqueous ionic solution: polarization selective two-dimensional infrared study of angular jump-exchange dynamics in aqueous 6M NaClO4. AB - The dynamics of hydrogen bond (H-bond) formation and dissociation depend intimately on the dynamics of water rotation. We have used polarization resolved ultrafast two-dimensional infrared (2DIR) spectroscopy to investigate the rotational dynamics of deuterated hydroxyl groups (OD) in a solution of 6M NaClO(4) dissolved in isotopically mixed water. Aqueous 6M NaClO(4) has two peaks in the OD stretching region, one associated with hydroxyl groups that donate a H bond to another water molecule (OD(W)) and one associated with hydroxyl groups that donate a H-bond to a perchlorate anion (OD(P)). Two-dimensional IR spectroscopy temporally resolves the equilibrium inter conversion of these spectrally distinct H-bond configurations, while polarization-selective 2DIR allows us to access the orientational motions associated with this chemical exchange. We have developed a general jump-exchange kinetic theory to model angular jumps associated with chemical exchange events. We use this to model polarization-selective 2DIR spectra and pump-probe anisotropy measurements. We determine the H-bond exchange induced jump angle to be 49 +/- 5 degrees and the H-bond exchange rate to be 6 +/- 1 ps. Additionally, the separation of the 2DIR signal into contributions that have or have not undergone H-bond exchange allows us to directly determine the orientational dynamics of the OD(W) and the OD(P) configurations without contributions from the exchanged population. This proves to be important because the orientational relaxation dynamics of the populations that have undergone a H-bond exchange differ significantly from the populations that remain in one H-bond configuration. We have determined the slow orientational relaxation time constant to be 6.0 +/- 1 ps for the OD(W) configuration and 8.3 +/- 1 ps for the OD(P) configuration. We conclude from these measurements that the orientational dynamics of hydroxyl groups in distinct H-bond configurations do differ, but not significantly. PMID- 21280759 TI - The possibility of regime changing in chain reactions with degenerate branching under the influence of external magnetic field. AB - A reaction of hydrocarbons oxidation in the liquid phase is treated theoretically. The reaction system under discussion is a flow reactor, to the inlet of which the hydrocarbon is constantly delivered in the mixture with an inhibitor under oxygen saturation conditions; the reaction mixture constantly flows from the chamber at the same rate. The reaction gives rise to radicals that can subsequently recombine. It is shown that under certain conditions in this reaction system, three steady states may arise, two of which are stable and the third state is unstable. By varying rate constants of radical reactions by means of an external magnetic field, one can disturb the steady state stability and transfer the system to another steady state, which will be accompanied by an abrupt change in the concentration of reacting substances. PMID- 21280758 TI - Molecular dynamics at ambient and elevated pressure of the amorphous pharmaceutical: nonivamide (pelargonic acid vanillylamide). AB - Broadband dielectric spectroscopy was employed to investigate the relaxation dynamics of supercooled and glassy nonivamide-the synthetic form of capsaicin being the most spicy-hot substance known to man. The material is of great importance in the pharmaceutical industry because it has wide usage in the medical field for relief of pain, and more recently it has been shown to be effective in fighting cancers. Dielectric measurements carried out at various isobaric and isothermal conditions (pressure up to 400 MPa) revealed very narrow alpha-loss peak and unresolved secondary relaxations appearing in the form of an excess wing on the high frequency flank. Moreover, our studies have shown the shape of dielectric loss spectrum at any fixed loss peak frequency is invariant to different combinations of temperature and pressure, i.e., validity of the time temperature-pressure superpositioning. We also found the fragility index is nearly constant on varying pressure. This property is likely due to the unusual structure of nonivamide, which has a part characteristic of van der Waals glass former and another part characteristic of hydrogen-bonded glass-former. PMID- 21280760 TI - Highly repulsive interaction in novel inclusion D2-N2 compound at high pressure: Raman and x-ray evidence. AB - We present spectral and structural evidences for the formation of a homogeneous cubic delta-N(2)-like, noncrystalline solid and an incommensuratelike hexagonal (P6(3)22) inclusion compound (N(2))(12)D(2), formed by compressing a nitrogen rich mixture to 5.5 and 10 GPa, respectively. A strong repulsive coupling in (N(2))(12)D(2) is evident from a blue shift, discontinuous changes, and the absence of turnover of the D(2) vibron to 70 GPa--all in sharp contrast to both pure D(2) and other inclusion compounds. This repulsive interaction is responsible to the observed incommensuratelike structure and large internal pressure. PMID- 21280761 TI - pi-conjugation and charge polarization in fluorene-dibenzothiophene-S,S-dioxide co-oligomers by Raman spectroscopy and quantum chemistry. AB - The Raman spectra of a series of fluorine (F)/dibenzothiophene-S,S-dioxide co oligomers (S) of different length and alternation sequences in their backbones (FSF, FFSFF, FSFSF, and FASAF; A is the -C=C- bridge) have been recorded and simulated theoretically. It is shown that Raman spectroscopy is useful to probe pi conjugation and ground state electron polarization in these molecules, phenomena directly related with the existence of intramolecular charge-transfer processes owing to the combination of electron donor (fluorene) and acceptor (dibenzothiophene-S,S-dioxide) groups. Their geometric, electronic, and vibrational properties have been studied by density functional theory B3LYP/6 311G(2d,p) quantum chemical calculations and compared with those for fluorene homo-oligomers. Comparative studies in solution/solid/melted phase led to the conclusion that the Raman wavenumbers are also sensitive to intermolecular interactions. PMID- 21280762 TI - Detailed intermolecular structure of molecular liquids containing slightly distorted tetrahedral molecules with C(3v) symmetry: chloroform, bromoform, and methyl-iodide. AB - Analyses of the intermolecular structure of molecular liquids containing slightly distorted tetrahedral molecules of the CXY(3)-type are described. The process is composed of the determination of several different distance-dependent orientational correlation functions, including ones that are introduced here. As a result, a complete structure classification could be provided for CXY(3) molecular liquids, namely for liquid chloroform, bromoform, and methyl-iodide. In the present work, the calculations have been conducted on particle configurations resulting from reverse Monte Carlo computer modeling: these particle arrangements have the advantage that they are fully consistent with structure factors from neutron and x-ray diffraction measurements. It has been established that as the separation between neighboring molecules increases, the dominant mutual orientations change from face-to-face to edge-to-edge, via the edge-to-face arrangements. Depending on the actual liquid, these geometrical elements (edges and faces of the distorted tetrahedra) were found to contain different atoms. From the set of liquids studied here, the structure of methyl-iodide was found to be easiest to describe on the basis of pure steric effects (molecular shape, size, and density) and the structure of liquid chloroform seems to be the furthest away from the corresponding "flexible fused hard spheres" like reference system. PMID- 21280763 TI - An upper limit to kinetic fragility in glass-forming liquids. AB - The kinetic fragility of a liquid is correlated to the magnitude of enthalpy hysteresis in various glass-forming materials during thermal cycling across the glass transition. While the lower bound of liquid fragility is well known, there has been little research into the possibility of an inherent upper limit to fragility. In this paper, we present a theoretical argument for the existence of a maximum fragility and show that the correlation between fragility and enthalpy hysteresis allows for an empirical evaluation of the upper limit of fragility. This upper limit occurs as the enthalpy hysteresis involved in thermal cycling about the glass transition approaches zero, leading to m(max)~175. This result agrees remarkably well with our previous estimate. The dynamics of maximum fragility liquids are discussed, and a critical temperature of ~1.5 T(g) (where T(g) is the glass transition temperature) is revealed where a transition from nonexponential to exponential structural relaxation occurs. PMID- 21280764 TI - Complex phase behavior of the system of particles with smooth potential with repulsive shoulder and attractive well. AB - We report a detailed simulation study of the phase behavior of core-softened system with attractive well. Different repulsive shoulder widths and attractive well depths are considered which allows to monitor the influence of repulsive and attractive forces on the phase diagram of the system. Thermodynamic anomalies in the systems are also studied. It is shown that the diffusion anomaly is stabilized by small attraction. PMID- 21280765 TI - Measurement of the Soret and diffusion coefficients for benchmark binary mixtures by means of digital interferometry. AB - We report on the development of the optical digital interferometry (ODI) technique for measuring diffusion and Soret coefficients. The unique feature of this method is that it traces the transient path of the system in the entire two dimensional cross section of a cell. In this way, it is applicable not only for measurements of Soret coefficients, but also for studying diffusive transport mechanism and convection. Presently, this method is not widely used and, in our view, not because of fundamental limitations but rather due to a lack of properly developed postexperimental procedures of the raw data analysis. Thus, in this paper our attention is focused on the successive analysis of different steps: the fringe analysis, the choice of reference images, the thermal design of the cell, and multiparameter fitting procedure. Using the ODI technique, we have measured the diffusion and the Soret coefficients for three binary mixtures composed of dodecane (C(12)H(26)), isobutylbenzene, and 1,2,3,4-tetrahydronaphtalene at a mean temperature of 25(?)C and 50 wt. % in each component. These measurements were compared with their benchmark values and show an agreement within less than 3%. PMID- 21280766 TI - Debye process and dielectric state of an alcohol in a nonpolar solvent. AB - To investigate the origin of the first order molecular kinetics of the most prominent, Debye-type polarization, a detailed dielectric relaxation study of 66.5, 40, and 20 mole% solutions of 5-methyl-2-hexanol in 2-methylpentane (2:1, 0.67:1, and 0.25:1 molar ratios) was performed. The Debye-type polarization remains prominent in the solutions, despite the extensive loss of intermolecular hydrogen bonds. At high temperatures, its contribution to permittivity extrapolates close to the statistically scaled values for the 2:1 solution. For others, the measured values of its contribution crossover the scaled values in a temperature plane. The faster relaxation process of about 4% magnitude has an asymmetric distribution of times in the solutions and, relative to those of the pure alcohol, their values decrease on heating more at high temperatures and less at low. This is attributed to an increase in the alcohol cluster size by consumption of monomers as well as the growth of smaller clusters as the solution is cooled. It is argued that structural fluctuation in solutions, as in the pure alcohol, is determined by the rates of both the Debye-type and the faster polarizations in the ultraviscous state. PMID- 21280767 TI - Lithium hydroxide dihydrate: a new type of icy material at elevated pressure. AB - We show that, in addition to the known monohydrate, LiOH forms a dihydrate at elevated pressure. The dihydrate involves a large number of H-bonds establishing chains along the <001> direction. In addition, the energy surface exhibits a saddle point for proton locations along certain O interatomic distances, a feature characteristic for superprotonic conductors. However, MD simulations indicate that LiOH . 2H(2)O is not a superprotonic conductor and suggest the relevant interpolyhedral O-O distances being too large to allow for proton transfer between neighboring Li-coordinated polyhedra at least on the time scale of the MD-simulations. PMID- 21280768 TI - Nonequilibrium restructuring in two-dimensional Lennard-Jones system induced by a simple square start configuration. AB - In the present paper, we report a molecular dynamics simulation of two dimensional Lennard-Jones system with a simple square start configuration. Mean square displacement was computed showing interesting dependence on high pressure conditions in short time scale, corresponding to an abrupt restructurization. This paper is the first to report the qualitative and quantitative details of this phenomenon. PMID- 21280769 TI - On the mode-coupling treatment of collective density fluctuations for quantum liquids: para-hydrogen and normal liquid helium. AB - A novel quantum mode coupling theory combined with a kinetic approach is developed for the description of collective density fluctuations in quantum liquids characterized by Boltzmann statistics. Three mode-coupling approximations are presented and applied to study the dynamic response of para-hydrogen near the triple point and normal liquid helium above the lambda-transition. The theory is compared with experimental results and to the exact imaginary time data generated by path integral Monte Carlo simulations. While for liquid para-hydrogen the combination of kinetic and quantum mode-coupling theory provides semi quantitative results for both short and long time dynamics, it fails for normal liquid helium. A discussion of this failure based on the ideal gas limit is presented. PMID- 21280770 TI - Effects of electrostatic potential and shape on diffusion-controlled reaction at an elliptic site. AB - The calculation of the diffusion-controlled reaction rate of an ionic reactant on a charged elliptic site is performed in order to examine the interaction of the site charge and shape. In the absence of site charge, the reaction rate for a fixed site area is always enhanced with decrease in circularity (ratio of minor to major axis lengths), going to infinity as the circularity vanishes to zero. In the case of attractive ion-site charge forces for any finite circularity, but a very large site charge, the shape enhancement is suppressed. For repulsive ion site forces with a very large site charge and the same finite circularity, the shape enhancement effect on the site reaction rate is increased. Away from these large site charge limits for more typical ion-site charge pairs and site circularities the same trends are observed. The results shed light on experimental and numerical simulation phenomena observed for both repulsive and attractive reactant ion-charged site pairs. PMID- 21280771 TI - Inertial and bias effects in the rotational brownian motion of rodlike molecules in a uniaxial potential. AB - Inertial effects in the rotational brownian motion in space of a rigid dipolar rotator (needle) in a uniaxial potential biased by an external field giving rise to asymmetry are treated via the infinite hierarchy of differential-recurrence relations for the statistical moments (orientational correlation functions) obtained by averaging the Euler-Langevin equation over its realizations in phase space. The solutions of this infinite hierarchy for the dipole correlation function and its characteristic times are obtained using matrix continued fractions showing that the model simultaneously predicts both slow overbarrier (or interwell) relaxation at low frequencies accompanied by intermediate frequency Debye relaxation due to fast near-degenerate motion in the wells of the potential (intrawell relaxation) as well as the high frequency resonance (Poley) absorption due to librations of the dipole moments. It is further shown that the escape rate of a brownian particle from a potential well as extended to the Kramers turnover problem via the depopulation factor yields a close approximation to the longest (overbarrier) relaxation time of the system. For zero and small values of the bias field parameter h, both the dipole moment correlation time and the longest relaxation time have Arrhenius behavior (exponential increase with increasing barrier height). While at values of h in excess of a critical value however far less than that required to achieve nucleation, the Arrhenius behavior of the correlation time disappears. PMID- 21280772 TI - Fast motion in molecular solids at low temperatures: evidence from a pulsed electron paramagnetic resonance study of nitroxyl radical relaxation. AB - We have investigated the electron phase-memory relaxation time of the nitroxyl radical 2,2,6,6-tetramethylpiperidine-1-oxyl at temperatures between 5 and 80 K in crystalline and glassy states of ethanol using pulsed X-band electron paramagnetic resonance spectroscopy. The results indicate that the transition from the slow to fast motion regimes of the paramagnetic center occurs upon further cooling of the sample below ~20 K. We provide experimental evidence that this phenomenon cannot be ascribed to the impact of hyperfine interactions with methyl protons in the system, but it can be instead a signature of the coupling of the electron spin with the boson peak excitations of the lattice. PMID- 21280773 TI - Pair structure of the hard-sphere Yukawa fluid: an improved analytic method versus simulations, Rogers-Young scheme, and experiment. AB - We present a comprehensive study of the equilibrium pair structure in fluids of nonoverlapping spheres interacting by a repulsive Yukawa-like pair potential, with special focus on suspensions of charged colloidal particles. The accuracy of several integral equation schemes for the static structure factor, S(q), and radial distribution function, g(r), is investigated in comparison to computer simulation results and static light scattering data on charge-stabilized silica spheres. In particular, we show that an improved version of the so-called penetrating-background corrected rescaled mean spherical approximation (PB-RMSA) by Snook and Hayter [Langmuir 8, 2880 (1992)], referred to as the modified PB RMSA (MPB-RMSA), gives pair structure functions which are in general in very good agreement with Monte Carlo simulations and results from the accurate but nonanalytical and therefore computationally more expensive Rogers-Young integral equation scheme. The MPB-RMSA preserves the analytic simplicity of the standard rescaled mean spherical (RMSA) solution. The combination of high accuracy and fast evaluation makes the MPB-RMSA ideally suited for extensive parameter scans and experimental data evaluation, and for providing the static input to dynamic theories. We discuss the results of extensive parameter scans probing the concentration scaling of the pair structure of strongly correlated Yukawa particles, and we determine the liquid-solid coexistence line using the Hansen Verlet freezing rule. PMID- 21280774 TI - Geometry and quadratic nonlinearity of charge transfer complexes in solution using depolarized hyper-Rayleigh scattering. AB - We report large quadratic nonlinearity in a series of 1:1 molecular complexes between methyl substituted benzene donors and quinone acceptors in solution. The first hyperpolarizability, beta(HRS), which is very small for the individual components, becomes large by intermolecular charge transfer (CT) interaction between the donor and the acceptor in the complex. In addition, we have investigated the geometry of these CT complexes in solution using polarization resolved hyper-Rayleigh scattering (HRS). Using linearly (electric field vector along X direction) and circularly polarized incident light, respectively, we have measured two macroscopic depolarization ratios D=I(2omega,X,X)/I(2omega,Z,X) and D(')=I(2omega,X,C)/I(2omega,Z,C) in the laboratory fixed XYZ frame by detecting the second harmonic scattered light in a polarization resolved fashion. The experimentally obtained first hyperpolarizability, beta(HRS), and the value of macroscopic depolarization ratios, D and D('), are then matched with the theoretically deduced values from single and double configuration interaction calculations performed using the Zerner's intermediate neglect of differential overlap self-consistent reaction field technique. In solution, since several geometries are possible, we have carried out calculations by rotating the acceptor moiety around three different axes keeping the donor molecule fixed at an optimized geometry. These rotations give us the theoretical beta(HRS), D and D(') values as a function of the geometry of the complex. The calculated beta(HRS), D, and D(') values that closely match with the experimental values, give the dominant equilibrium geometry in solution. All the CT complexes between methyl benzenes and chloranil or 1,2-dichloro-4,5-dicyano-p-benzoquinone investigated here are found to have a slipped parallel stacking of the donors and the acceptors. Furthermore, the geometries are staggered and in some pairs, a twist angle as high as 30 degrees is observed. Thus, we have demonstrated in this paper that the polarization resolved HRS technique along with theoretical calculations can unravel the geometry of CT complexes in solution. PMID- 21280775 TI - Geometry and quadratic nonlinearity of charge transfer complexes in solution: a theoretical study. AB - In this paper, we have computed the quadratic nonlinear optical (NLO) properties of a class of weak charge transfer (CT) complexes. These weak complexes are formed when the methyl substituted benzenes (donors) are added to strong acceptors like chloranil (CHL) or di-chloro-di-cyano benzoquinone (DDQ) in chloroform or in dichloromethane. The formation of such complexes is manifested by the presence of a broad absorption maximum in the visible range of the spectrum where neither the donor nor the acceptor absorbs. The appearance of this visible band is due to CT interactions, which result in strong NLO responses. We have employed the semiempirical intermediate neglect of differential overlap (INDO/S) Hamiltonian to calculate the energy levels of these CT complexes using single and double configuration interaction (SDCI). The solvent effects are taken into account by using the self-consistent reaction field (SCRF) scheme. The geometry of the complex is obtained by exploring different relative molecular geometries by rotating the acceptor with respect to the fixed donor about three different axes. The theoretical geometry that best fits the experimental energy gaps, beta(HRS) and macroscopic depolarization ratios is taken to be the most probable geometry of the complex. Our studies show that the most probable geometry of these complexes in solution is the parallel displaced structure with a significant twist in some cases. PMID- 21280776 TI - Multiple emissions of benzil at room temperature and 77 K and their assignments from ab initio quantum chemical calculations. AB - Multiple emissions have been observed from benzil under different conditions in solutions at room temperature as well as in low temperature glass matrices at 77 K. Low temperature emission has been monitored in rigid matrices frozen under different conditions of illumination. Steady state and time-resolved results together with the ab initio quantum chemical calculations provide, for the first time, the assignments of the different fluorescence bands to the different geometries and/or electronic states of the fluorophore molecule. It is revealed that the skew form of benzil emits from the first (S(1)) as well as the second excited singlet (S(2)) states depending on the excitation wavelength, while the relaxed transplanar conformer fluoresces only from the S(1) state. The yet unexplored emission band peaking at around 360 nm has been assigned to originate from the S(2) state. Ab initio calculations using the density functional theory at B3LYP/6-31G** level corroborate well with the experimental observations. PMID- 21280777 TI - Unraveling the properties of octamethylcyclotetrasiloxane under nanoscale confinement: atomistic view of the liquidlike state from molecular dynamics simulation. AB - We developed an atomistic model of octamethylcyclotetrasiloxane (OMCTS) liquid confined within the nanospace between two flat mica surfaces. Molecular dynamics simulation was carried out for the liquidlike state where OMCTS liquid is not frozen, while forming molecular layers parallel to the surface. With the aid of a layer by layer analysis of the intra- and interlayer microscopic structures and the dynamics, it is found that the difference in the properties of the inner layers and the bulk liquid are relatively small in spite of the clear differences in the structure. This leads to the conclusion that the layered structure itself is an appearance of the microscopic structure that already exists in the bulk liquid. The most striking difference from the bulk liquid is mainly seen in the contact layer, where characteristic molecular orientations that are not seen in the crystalline phase appeared, and the dynamics of the liquid becomes 2-3 orders of magnitude slower than that of the bulk. PMID- 21280778 TI - Mutual diffusion coefficients of heptane isomers in nitrogen: a molecular dynamics study. AB - The accurate knowledge of transport properties of pure and mixture fluids is essential for the design of various chemical and mechanical systems that include fluxes of mass, momentum, and energy. In this study we determine the mutual diffusion coefficients of mixtures composed of heptane isomers and nitrogen using molecular dynamics (MD) simulations with fully atomistic intermolecular potential parameters, in conjunction with the Green-Kubo formula. The computed results were compared with the values obtained using the Chapman-Enskog (C-E) equation with Lennard-Jones (LJ) potential parameters derived from the correlations of state values: MD simulations predict a maximum difference of 6% among isomers while the C-E equation presents that of 3% in the mutual diffusion coefficients in the temperature range 500-1000 K. The comparison of two approaches implies that the corresponding state principle can be applied to the models, which are only weakly affected by the anisotropy of the interaction potentials and the large uncertainty will be included in its application for complex polyatomic molecules. The MD simulations successfully address the pure effects of molecular structure among isomers on mutual diffusion coefficients by revealing that the differences of the total mutual diffusion coefficients for the six mixtures are caused mainly by heptane isomers. The cross interaction potential parameters, collision diameter sigma(12), and potential energy well depth E(12) of heptane isomers and nitrogen mixtures were also computed from the mutual diffusion coefficients. PMID- 21280779 TI - C6H6/Au(111): interface dipoles, band alignment, charging energy, and van der Waals interaction. AB - We analyze the benzene/Au(111) interface taking into account charging energy effects to properly describe the electronic structure of the interface and van der Waals interactions to obtain the adsorption energy and geometry. We also analyze the interface dipoles and discuss the barrier formation as a function of the metal work-function. We interpret our DFT calculations within the induced density of interface states (IDIS) model. Our results compare well with experimental and other theoretical results, showing that the dipole formation of these interfaces is due to the charge transfer between the metal and benzene, as described in the IDIS model. PMID- 21280780 TI - Reversible uptake of water on NaCl nanoparticles at relative humidity below deliquescence point observed by noncontact environmental atomic force microscopy. AB - The behavior of NaCl nanoparticles as a function of relative humidity (RH) has been characterized using non-contact environmental atomic force microscopy (e AFM) to measure the heights of particles deposited on a prepared hydrophobic surface. Cubic NaCl nanoparticles with sides of 35 and 80 nm were found to take up water reversibly with increasing RH well below the bulk deliquescence relative humidity (DRH) of 75% at 23(?)C, and to form a liquid-like surface layer of thickness 2 to 5 nm, with measurable uptake (>2 nm increase in particle height) beginning at 70% RH. The maximum thickness of the layer increased with increasing RH and increasing particle size over the range studied. The liquid-like behavior of the layer was indicated by a reversible rounding at the upper surface of the particles, fit to a parabolic cross-section, where the ratio of particle height to maximum radius of curvature increases from zero (flat top) at 68% RH to 0.7 +/ 0.3 at 74% RH. These observations, which are consistent with a reorganization of mass on the solid NaCl nanocrystal at RH below the DRH, suggest that the deliquescence of NaCl nanoparticles is more complex than an abrupt first-order phase transition. The height measurements are consistent with a phenomenological model that assumes favorable contributions to the free energy of formation of a liquid layer on solid NaCl due both to van der Waals interactions, which depend partly upon the Hamaker constant, A(film), of the interaction between the thin liquid film and the solid NaCl, and to a longer-range electrostatic interaction over a characteristic length of persistence, xi; the best fit to the data corresponded to A(film)= 1 kT and xi = 2.33 nm. PMID- 21280781 TI - Sampling the structure of calcium carbonate nanoparticles with metadynamics. AB - Metadynamics is employed to sample the configurations available to calcium carbonate nanoparticles in water, and to map an approximate free energy as a function of crystalline order. These data are used to investigate the validity of bulk and ideal surface energies in predicting structure at the nanoscale. Results indicate that such predictions can determine the structure and morphology of particles as small as 3-4 nm in diameter. Comparisons are made to earlier results on 2 nm particles under constant volume conditions which support nanoconfinement as a mechanism for enhancing the stability of amorphous calcium carbonate. Our results indicate that crystalline calcitelike structure is thermodynamically preferred for nanoparticles as small as 2 nm in the absence of nanoconfinement. PMID- 21280783 TI - Complex phase behavior of a fluid in slits with semipermeable walls modified with tethered chains. AB - We study the phase behavior of a two-component fluid in a pore with the walls modified by tethered chains. The walls are completely permeable for one component of the fluid and completely impenetrable for the second component. The fluid is perfectly mixed in a bulk phase. We have found that depending on the details of the model the fluid undergoes capillary condensation inside the pore and wetting and layering transitions at the outer walls. Moreover, we have found transitions connected with the change of symmetry of the distribution of chains and fluid inside the pore. PMID- 21280782 TI - Binding structures of propylene glycol stereoisomers on the Si(001)-2*1 surface: a combined scanning tunneling microscopy and theoretical study. AB - The binding configuration of propylene glycol stereoisomer molecules adsorbed on the Si(001)-2*1 surface was investigated using a combination of scanning tunneling microscopy (STM) and density functional theory calculations. Propylene glycol was found to adsorb dissociatively via two hydroxyl groups exclusively as a bridge between the ends of two adjacent dimers along the dimer row. The chirality was preserved during bonding to Si atoms and was identifiable with STM imaging. The large number of propylene glycol conformers in the gas phase was reduced to a single configuration adsorbed on the surface at low molecular coverage. PMID- 21280784 TI - Faster proton transfer dynamics of water on SnO2 compared to TiO2. AB - Proton jump processes in the hydration layer on the iso-structural TiO(2) rutile (110) and SnO(2) cassiterite (110) surfaces were studied with density functional theory molecular dynamics. We find that the proton jump rate is more than three times faster on cassiterite compared with rutile. A local analysis based on the correlation between the stretching band of the O-H vibrations and the strength of H-bonds indicates that the faster proton jump activity on cassiterite is produced by a stronger H-bond formation between the surface and the hydration layer above the surface. The origin of the increased H-bond strength on cassiterite is a combined effect of stronger covalent bonding and stronger electrostatic interactions due to differences of its electronic structure. The bridging oxygens form the strongest H-bonds between the surface and the hydration layer. This higher proton jump rate is likely to affect reactivity and catalytic activity on the surface. A better understanding of its origins will enable methods to control these rates. PMID- 21280785 TI - Molecular orientations and interfacial structure of C60 on Pt(111). AB - Molecular orientations and assembled structures of C(60) molecules on Pt(111) have been characterized by low-temperature scanning tunneling microscopy for coverage between 0.1 ML and 1.5 ML. At room temperature, C(60) molecules preferentially decorate the steps and nucleate into single layer islands (SLIs) with hexagonal close-packed structures upon increasing coverage. C(60) islands comprise two differently oriented C(60)/Pt(111)-(?13 * ?13) R13.9 degrees phases, in which five types of molecular orientation of C(60) carbon cage configurations are clearly identified by the high-resolution scanning tunneling microscopy image. Further annealing treatment leads to more uniform molecular orientation without apparent aggregation of C(60) SLIs. As coverage increases above 1 ML, domains corresponding to (2?3 * 2?3) R30 degrees superstructure appear. To explain the above transformation, an interfacial reconstruction model is proposed according to the detailed study of the molecular adsorption structures in different domains. PMID- 21280786 TI - Tuning the transport properties of a (C60)2 bridge with electron and hole dopings. AB - The tuning effects of substitutional B and N dopings on the electron transport properties of a C(60) dimer bridge [(C(60))(2)] are investigated by nonequilibrium Green's functions in combination with density functional theory. It is found that, unlike C(60), the equilibrium conductance of (C(60))(2) is very small. However, it can be controlled by electron (N) doping or hole (B) doping, which shifts the molecular energy levels so that the LUMOs or HOMOs align well with the Fermi level and results in LUMO-mediated transport or HOMO-mediated transport. The conductance increases accordingly with a certain number of N or B atoms doped in the C(60)s. Interestingly, when one C(60) is doped with N atoms and the other is doped with B atoms, new transport behaviors arise and rectification is achieved due to the special alignment of the energy levels of the individual C(60)s with the Fermi level. It suggests that cluster or molecule assembling can often realize specific functions which are not available by single molecules and should be taken into consideration in the design of molecular devices. PMID- 21280787 TI - Surface tension of water-alcohol mixtures from Monte Carlo simulations. AB - Monte Carlo simulations are reported to predict the dependence of the surface tension of water-alcohol mixtures on the alcohol concentration. Alcohols are modeled using the anisotropic united atom model recently extended to alcohol molecules. The molecular simulations show a good agreement between the experimental and calculated surface tensions for the water-methanol and water propanol mixtures. This good agreement with experiments is also established through the comparison of the excess surface tensions. A molecular description of the mixture in terms of density profiles and hydrogen bond profiles is used to interpret the decrease of the surface tension with the alcohol concentration and alcohol chain length. PMID- 21280788 TI - Adsorption of nitrogen oxides on graphene and graphene oxides: insights from density functional calculations. AB - The interactions of nitrogen oxides NO(x) (x = 1,2,3) and N(2)O(4) with graphene and graphene oxides (GOs) were studied by the density functional theory. Optimized geometries, binding energies, and electronic structures of the gas molecule-adsorbed graphene and GO were determined on the basis of first principles calculations. The adsorption of nitrogen oxides on GO is generally stronger than that on graphene due to the presence of the active defect sites, such as the hydroxyl and carbonyl functional groups and the carbon atom near these groups. These active defect sites increase the binding energies and enhance charge transfers from nitrogen oxides to GO, eventually leading to the chemisorption of gas molecules and the doping character transition from acceptor to donor for NO(2) and NO. The interaction of nitrogen oxides with GO with various functional groups can result in the formation of hydrogen bonds OH???O (N) between -OH and nitrogen oxides and new weak covalent bonds C???N and C???O, as well as the H abstraction to form nitrous acid- and nitric acidlike moieties. The spin-polarized density of states reveals a strong hybridization of frontier orbitals of NO(2) and NO(3) with the electronic states around the Fermi level of GO, and gives rise to the strong acceptor doping by these molecules and remarkable charge transfers from molecules to GO, compared to NO and N(2)O(4) adsorptions on GO. The calculated results show good agreement with experimental observations. PMID- 21280789 TI - Dangling bond-induced graphitization process on the (111) surface of diamond nanoparticles. AB - The intrinsic mechanism of graphitization occurring on the (111) surface of nanodiamonds (NDs) during the transformation from NDs into bucky diamonds are explored using density functional theory (DFT) computations in conjunction with density functional based tight-binding simulations. The DFT results indicate that dangling bonds (DBs) on the ND surfaces play an important role in the graphitization process, and the orientation of the DBs on different ND surfaces determines whether there will be a graphitization process or not. Moreover, a criterion is proposed to estimate rupturing of the C-C bonds between different layers on the [111] direction in the NDs and is verified to be applicable to illustrate the phase transformation from sp(3) into sp(2) bonding structures. The energy contributions of the four-coordinated carbon atoms located at different positions on the (111) surface are exhibited for the first time and discussed in detail to gain a clear picture for the transition from NDs into bucky diamonds. The outcome may provide a deeper understanding on the influence of DBs upon the transformation from sp(3) into sp(2) bonding structures. PMID- 21280790 TI - Phase measurement in nondegenerate three-wave mixing spectroscopy. AB - A detailed model is presented that describes the temporal and spectral interference patterns resulting from phase-recovery infrared-visible sum frequency spectroscopy. Included in this model are the effects of dispersive elements other than the phase shifting unit placed between the sample and local oscillator signals. This inclusion is critical when considering the interference patterns arising from studies of buried interfaces. Furthermore, in the midinfrared where it is difficult to have high visibility of the fringes, it is demonstrated that local field corrections have a significant effect on the shape of the interference pattern. By collecting and subsequently fitting a two dimensional interference pattern displaying both temporal and spectral fringes, a complete characterization of all these effects is possible. PMID- 21280791 TI - A free-space density functional theory for polymer adsorption: influence of packing effect on conformations of polymer. AB - We propose a free-space density functional theory for polymer adsorption. The derivation within the framework of density functional theory leads to the splitting of the intrinsic free energy into an ideal-gas term and a residual term responsible for the intrinsic energy and the nonbonded interactions between monomers, respectively. A more reasonable treatment is adopted for the residual free energy to count for the monomer-monomer correlation underestimated by the local density approximation. An approach using propagators is proposed to calculate the single-chain partition function and the segment-density distributions, the three adsorption conformations as trains, loops, and tails are further described by propagators. Dirac's bra-ket notation used makes the derivation simpler and provides clearer physical meanings. The theoretical calculations for the adsorption of hard-sphere chains onto a nonadsorbing and an adsorbing hard wall show that the structure of the adsorption layer is strongly affected by the packing effect which has been underestimated by the previous lattice adsorption theory. PMID- 21280792 TI - Long-time growth kinetics of first order phase transitions in the presence of a boundary layer. AB - The late stage growth mechanism for a first order phase transition, either through nucleation growth or spinodal decomposition, is well understood to be an Ostwald ripening or coarsening process, in which larger domains grow at the expense of smaller ones. The growth kinetics in this regime was shown by Lifshitz and Slyozov to follow at(1/3) law. However, the kinetics is altered if there exists a barrier ahead of the growth front, irrespective of the physical origin of the boundary layer. We present an analytic calculation for the growth kinetics in the presence of a boundary layer, showing that in the limit of barrier dominated growth, the domains grow with at(1/2) law. This result holds true in the dilute regime independent of whether the growing nuclei are spherical or cylindrical. PMID- 21280793 TI - Collapse of a two-state sticky hard sphere chain. AB - The collapse of a homopolymer gaussian chain into a globule is represented as a transition between two states, viz., extended and collapsed. Appropriately, this model has been labeled as the all-or-none view of chain collapse. In the collapsed state, the single polymer partition function is expressed by a single Mayer diagram with the maximum number of f-bonds arising from nonbonded square well interactions. Our target is the dependence of the transition temperature on chain length and the interaction range of the square well, as indicated through the behavior of the radius of gyration and the constant volume heat capacity. Properties of the collapse transition are calculated exactly for chains with three to six backbone atoms and heuristically for long chains using arguments derived from the small chains and from conditions of integrability. Comparison with simulation studies is made. PMID- 21280794 TI - Phase diagram of spherical particles interacted with harmonic repulsions. AB - We construct the phase diagram of spherical particles interacted with harmonic repulsions, which are ultrasoft and bounded at fully overlapping. This simple potential form can be used for describing the thermodynamic properties and dynamic behavior of interpenetrable globular micelles, microgels, starlike polymer solutions, and so on. Using dissipative particle dynamics simulations combined with thermodynamic integration, we compute chemical potentials of fluid phase and a number of crystal structures. In addition to the face-centered cubic and body-centered cubic structures, we also find the tetragonal, hexagonal, orthorhombic, and diamond crystal structures stable for this system. In the phase diagram, we identify multiple re-entrant melting regions and polymorphic transitions between the crystals. PMID- 21280795 TI - Magnetic field effects on tactoids of plate-like colloids. AB - We investigate the effect of a magnetic field on the shape and director field of nematic droplets in dispersions of sterically stabilized and charge-stabilized colloidal gibbsite platelets with a negative diamagnetic anisotropy. Depending on the magnetic field strength and tactoid size, we observe with polarized light microscopy several interesting structures, with different shapes and director fields both with and without defects. In particular, our findings provide the first experimental evidence for the existence of the split-core defect structure predicted ten years ago by Mkaddem and Gartland [Phys. Rev. E 62, 6694 (2000)]. The split-core structure is a metastable director-field configuration that can be stabilized by a sufficiently strong externally applied magnetic field but only if the diamagnetic anisotropy of the particles is negative. To account for our observations, we present a calculation of the stability regions of different shapes and director-field structures as a function of tactoid size, anchoring conditions, surface tension, elastic constants, and magnetic field strength. By fitting the experimental data to the theoretically predicted structures, we are able to extract values for the splay elastic constant, interfacial tension, and anchoring strength. Remarkably, we find significant differences between the two systems studied: for sterically stabilized gibbsite in bromotoluene the anchoring strength is one order of magnitude larger than that of aqueous gibbsite, with the latter exhibiting weak and the former strong anchoring of the director field to the interface. The splay elastic constants that we obtain are in agreement with earlier experiments, simulations, and theory, while the interfacial tension and anchoring strength are considerably larger than what was found in earlier experiments. PMID- 21280796 TI - Structure and dynamics of water in mixed solutions including laponite and PEO. AB - To investigate the structure and dynamics of water in mixed solutions including laponite clay particles and poly(ethylene oxide) (PEO), we measured the Raman spectra of the mixed solutions in the temperature range 283-313 K. The results show that the vibrational energies of the O-H stretching modes in the mixed solutions depend on the water content and temperature. The energy shifts of the O H stretching modes are attributed to changes in the water structure. By applying a structural model of bulk water to the spectra in the O-H stretching region, the local structures of water in the solutions were analyzed. The result shows that the formation probability of hydrogen bonds in the solutions decreases as the water content decreases. Laponite and PEO have effects to disrupt the network structure of hydrogen bonds between water molecules. Further, it was found that laponite and PEO cause increase in the strength of hydrogen bonds of surrounding water,although the strength of the hydrogen bonds increases with the order water laponite < water-water < water-PEO. It is concluded that water in laponite-PEO mixed solutions has a less-networked structure with strong hydrogen bonds compared with bulk water. PMID- 21280797 TI - Scattering process between polaron and exciton in conjugated polymers. AB - Scattering process between a negative polaron and an exciton in a polymer chain is investigated by using the Su-Schrieffer-Heeger model modified to include electron-electron interactions, the Brazovskii-Kirova symmetry breaking term, and an external electric field. It is found that the scattering process is spin dependent. If the polaron and the exciton have parallel spins, the polaron can easily pass through the exciton as if it "do not see" the exciton. If the polaron and the exciton have antiparallel spins, there exist strong repulsion between them. The polaron may be bounced back, be dissociated or pass through the exciton depending on the strength of the external electric field. In any of these cases, the polaron cannot break the exciton. PMID- 21280798 TI - Precise dipolar coupling constant distribution analysis in proton multiple quantum NMR of elastomers. AB - In this work we present an improved approach for the analysis of (1)H double quantum nuclear magnetic resonance build-up data, mainly for the determination of residual dipolar coupling constants and distributions thereof in polymer gels and elastomers, yielding information on crosslink density and potential spatial inhomogeneities. We introduce a new generic build-up function, for use as component fitting function in linear superpositions, or as kernel function in fast Tikhonov regularization (ftikreg). As opposed to the previously used inverted Gaussian build-up function based on a second-moment approximation, this method yields faithful coupling constant distributions, as limitations on the fitting limit are now lifted. A robust method for the proper estimation of the error parameter used for the regularization is established, and the approach is demonstrated for different inhomogeneous elastomers with coupling constant distributions. PMID- 21280799 TI - Multicomponent ballistic transport in narrow single wall carbon nanotubes: analytic model and molecular dynamics simulations. AB - The transport of gas mixtures through molecular-sieve membranes such as narrow nanotubes has many potential applications, but there remain open questions and a paucity of quantitative predictions. Our model, based on extensive molecular dynamics simulations, proposes that ballistic motion, hindered by counter diffusion, is the dominant mechanism. Our simulations of transport of mixtures of molecules between control volumes at both ends of nanotubes give quantitative support to the model's predictions. The combination of simulation and model enable extrapolation to longer tubes and pore networks. PMID- 21280800 TI - Chain stiffness, salt valency, and concentration influences on titration curves of polyelectrolytes: Monte Carlo simulations. AB - Monte Carlo simulations have been used to study two different models of a weak linear polyelectrolyte surrounded by explicit counterions and salt particles: (i) a rigid rod and (ii) a flexible chain. We focused on the influence of the pH, chain stiffness, salt concentration, and valency on the polyelectrolyte titration process and conformational properties. It is shown that chain acid-base properties and conformational properties are strongly modified when multivalent salt concentration variation ranges below the charge equivalence. Increasing chain stiffness allows to minimize intramolecular electrostatic monomer interactions hence improving the deprotonation process. The presence of di and trivalent salt cations clearly promotes the chain degree of ionization but has only a limited effect at very low salt concentration ranges. Moreover, folded structures of fully charged chains are only observed when multivalent salt at a concentration equal or above charge equivalence is considered. Long-range electrostatic potential is found to influence the distribution of charges along and around the polyelectrolyte backbones hence resulting in a higher degree of ionization and a lower attraction of counterions and salt particles at the chain extremities. PMID- 21280801 TI - Control of structure formation in phase-separating systems. AB - In this paper, we study the evolution of phase-separating binary mixtures which are subjected to alternate cooling and heating cycles. An initially homogeneous mixture is rapidly quenched to a temperature T(1)T(c). These cycles are repeated to create a domain morphology with multiple length scales, i.e., the structure factor is characterized by multiple peaks. For phase separation in d = 2 systems, we present numerical and analytical results for the emergence and growth of this multiple-scale morphology. PMID- 21280802 TI - Dissimilar bouncy walkers. AB - We consider the dynamics of a one-dimensional system consisting of dissimilar hardcore interacting (bouncy) random walkers. The walkers' (diffusing particles') friction constants xi(n), where n labels different bouncy walkers, are drawn from a distribution rho(xi(n)). We provide an approximate analytic solution to this recent single-file problem by combining harmonization and effective medium techniques. Two classes of systems are identified: when rho(xi(n)) is heavy tailed, rho(xi(n))?xi(n) (-1-alpha) (0=50%, compression/von Mises stress>=2 kPa, and strain energy density>=0.5 kPa). Progressive intramuscular fat infiltration increased all the aforementioned outcome measures. Increase in size of scar patterns that were contained in both muscle and fat tissues similarly elevated the outcome measures. Spasms increased muscle stresses and volumetric exposures to stress, but tissue volumes at risk were ~1-2% and increases due to spasticity were slight. We conclude that the above potential risk factors can be listed according to the following order of importance: (i) fat infiltration, (ii) scars contained in both muscle and fat tissues, and (iii) spasms. This information should be considered when prioritizing prevention means and resources for patients with SCI. PMID- 21280884 TI - Biomechanical validation of finite element models for two silicone metacarpophalangeal joint implants. AB - Silicone implants are used for prosthetic arthroplasty of metacarpophalangeal (MCP) joints severely damaged by rheumatoid arthritis. Different silicone elastomer MCP implant designs have been developed, including the Swanson and the NeuFlex implants. The goal of this study was to compare the in vitro mechanical behavior of Swanson and NeuFlex MCP joint implants. Three-dimensional (3D) finite element (FE) models of the silicone implants were modeled using the commercial software ANSYS and subjected to angular displacement from 0 deg to 90 deg. FE models were validated using mechanical tests of implants incrementally bent from 0 deg to 90 deg in a joint simulator. Swanson size 2 and 4 implants were compared with NeuFlex size 10 and 30 implants, respectively. Good agreement was observed throughout the range of motion for the flexion bending moment derived from 3D FE models and mechanical tests. From 30 deg to 90 deg, the Swanson 2 demonstrated a greater resistance to deformation than the NeuFlex 10 and required a greater bending moment for joint flexion. For larger implant sizes, the NeuFlex 30 had a steeper moment-displacement curve, but required a lower moment than the Swanson 4, due to implant preflexion. On average, the stress generated at the implant hinge from 30 deg to 90 deg was lower in the NeuFlex than in the Swanson. On average, starting from the neutral position of 30 deg for the preflexed NeuFlex implant, higher moments were required to extend the NeuFlex implants to 0 deg compared with the Swanson implants, which returned spontaneously to resting position. Implant toggling within the medullary canals was less in the NeuFlex than in the Swanson. The differential performance of these implants may be useful in implant selection based on the preoperative condition(s) of the joint and specific patient functional needs. PMID- 21280885 TI - A high throughput system for long term application of intermittent cyclic hydrostatic pressure on cells in culture. AB - The process of bone remodeling is governed by mechanical stresses and strains. Studies on the effects of mechanical stimulation on cell response are often difficult to compare as the nature of the stimuli and differences in parameters applied vary greatly. Experimental systems for the investigation of mechanical stimuli are mostly limited in throughput or flexibility and often the sum of several stimuli is applied. In this work, a flexible system that allows the investigation of cell response to isolated intermittent cyclic hydrostatic pressure (icHP) on a high throughput level is shown. Human bone derived cells were cultivated with or without mechanical stimulus in the presence or absence of chemical cues triggering osteogenesis for 7-10 days. Cell proliferation and osteogenic differentiation were evaluated by cell counting and immunohistochemical staining for bone alkaline phosphatase as well as collagen 1, respectively. In either medium, both cell proliferation and level of differentiation were increased when the cultures were mechanically stimulated. These initial results therefore qualify the present system for studies on the effects of isolated icHP on cell fate and encourage further investigations on the details behind the observed effects. PMID- 21280886 TI - A comparison of uniaxial and biaxial mechanical properties of the annulus fibrosus: a porcine model. AB - The annulus fibrosus of the intervertebral disk experiences multidirectional tension in vivo, yet the majority of mechanical property testing has been uniaxial. Therefore, our understanding of how this complex multilayered tissue responds to loading may be deficient. This study aimed to determine the mechanical properties of porcine annular samples under uniaxial and biaxial tensile loading. Two-layer annulus samples were isolated from porcine disks from four locations: anterior superficial, anterior deep, posterior superficial, and posterior deep. These tissues were then subjected to three deformation conditions each to a maximal stretch ratio of 1.23: uniaxial, constrained uniaxial, and biaxial. Uniaxial deformation was applied in the circumferential direction, while biaxial deformation was applied simultaneously in the circumferential and compressive directions. Constrained uniaxial consisted of a stretch ratio of 1.23 in the circumferential direction while holding the tissue stationary in the axial direction. The maximal stress and stress-stretch ratio (S-S) moduli determined from the biaxial tests were significantly higher than those observed during both the uniaxial tests (maximal stress, 97.1% higher during biaxial; p=0.002; S-S moduli, 117.9% higher during biaxial; p=0.0004) and the constrained uniaxial tests (maximal stress, 46.8% higher during biaxial; S-S moduli, 82.9% higher during biaxial). These findings suggest that the annulus is subjected to higher stresses in vivo when under multidirectional tension. PMID- 21280887 TI - Metallic foil-assisted laser cell printing. AB - Laser direct-write technology such as modified laser-induced forward transfer (LIFT) is emerging as a revolutionary technology for biological construct fabrication. While many modified LIFT-based cell direct writing successes have been achieved, possible process-induced cell injury and death is still a big hurdle for modified LIFT-based cell direct writing to be a viable technology. The objective of this study is to propose metallic foil-assisted LIFT using a four layer structure to achieve better droplet size control and increase cell viability in direct writing of human colon cancer cells (HT-29). The proposed four layers include a quartz disk, a sacrificial and adhesive layer, a metallic foil, and a cell suspension layer. The bubble formation-induced stress wave is responsible for droplet formation. It is found that the proposed metallic foil assisted LIFT approach is an effective cell direct-write technology and provides better printing resolution and high post-transfer cell viability when compared with other conventional modified LIFT technologies such as matrix-assisted pulsed laser evaporation direct-write; at the same time, the possible contamination from the laser energy absorbing material is minimized using a metallic foil. PMID- 21280888 TI - Special section guest editorial: special section honoring professor Michael Feld. PMID- 21280889 TI - Remembering Michael Stephen Feld: physics and biomedicine pioneer (1940-2010). PMID- 21280890 TI - Design and validation of an angle-resolved low-coherence interferometry fiber probe for in vivo clinical measurements of depth-resolved nuclear morphology. AB - We present a novel Fourier-domain angle-resolved low-coherence interferometry (a /LCI) fiber probe designed for in vivo clinical application in gastrointestinal endoscopy. The a/LCI technique measures the depth-resolved angular scattering distribution to determine the size distribution and optical density of cell nuclei for assessing the health of epithelial tissues. Clinical application is enabled by an endoscopic fiber-optic probe that employs a 2.3-m-long coherent fiber bundle and is compatible with the standard 2.8-mm-diam biopsy channel of a gastroscope. The probe allows for real-time data acquisition by collecting the scattering from multiple angles in parallel, enabled by the Fourier domain approach. The performance of the probe is characterized through measurement of critical parameters. The depth-resolved sizing capability of the system is demonstrated using single- and double-layer microsphere phantoms with subwavelength sizing precision and accuracy achieved. Initial results from a clinical feasibility test are also presented to show in vivo application in the human esophagus. PMID- 21280891 TI - Effect of photobleaching on calibration model development in biological Raman spectroscopy. AB - A major challenge in performing quantitative biological studies using Raman spectroscopy lies in overcoming the influence of the dominant sample fluorescence background. Moreover, the prediction accuracy of a calibration model can be severely compromised by the quenching of the endogenous fluorophores due to the introduction of spurious correlations between analyte concentrations and fluorescence levels. Apparently, functional models can be obtained from such correlated samples, which cannot be used successfully for prospective prediction. This work investigates the deleterious effects of photobleaching on prediction accuracy of implicit calibration algorithms, particularly for transcutaneous glucose detection using Raman spectroscopy. Using numerical simulations and experiments on physical tissue models, we show that the prospective prediction error can be substantially larger when the calibration model is developed on a photobleaching correlated dataset compared to an uncorrelated one. Furthermore, we demonstrate that the application of shifted subtracted Raman spectroscopy (SSRS) reduces the prediction errors obtained with photobleaching correlated calibration datasets compared to those obtained with uncorrelated ones. PMID- 21280892 TI - Video-rate tomographic phase microscopy. AB - Tomographic phase microscopy measures the 3-D refractive index distribution of cells and tissues by combining the information from a series of angle-dependent interferometric phase images. In the original device, the frame rate was limited to 0.1 frames per second (fps) by the technique used to acquire phase images, preventing measurements of moving or rapidly changing samples. We describe an improved tomographic phase microscope in which phase images are acquired via a spatial fringe pattern demodulation method, enabling a full tomogram acquisition rate of 30 fps. In addition, in this system the refractive index is calculated by a diffraction tomography algorithm that accounts for the effects of diffraction in the 3-D reconstruction. We use the instrument to quantitatively monitor rapid changes in refractive index within defined subregions of cells due to exposure to acetic acid or changes in medium osmolarity. PMID- 21280893 TI - Optical techniques for tracking multiple myeloma engraftment, growth, and response to therapy. AB - Multiple myeloma (MM), the second most common hematological malignancy, initiates from a single site and spreads via circulation to multiple sites in the bone marrow (BM). Methods to track MM cells both in the BM and circulation would be useful for developing new therapeutic strategies to target MM cell spread. We describe the use of complementary optical techniques to track human MM cells expressing both bioluminescent and fluorescent reporters in a mouse xenograft model. Long-term tumor growth and response to therapy are monitored using bioluminescence imaging (BLI), while numbers of circulating tumor cells are detected by in-vivo flow cytometry. Intravital microscopy is used to detect early seeding of MM cells to the BM, as well as residual cancer cells that remain in the BM after the bulk of the tumor is eradicated following drug treatment. Thus, intravital microscopy provides a powerful, albeit invasive, means to study cellular processes in vivo at the very early stage of the disease process and at the very late stage of therapeutic intervention when the tumor burden is too small to be detected by other imaging methods. PMID- 21280894 TI - Integrated system for combined Raman spectroscopy-spectral domain optical coherence tomography. AB - Raman spectroscopy (RS) and optical coherence tomography (OCT) are powerful tools for optical analysis of tissues with mutually complementary strengths and limitations. OCT excels at visualizing tissue microstructure but lacks molecular specificity, while RS can relay tissue biochemical composition but typically cannot relate microstructure. Previous implementations of combined RS-OCT have utilized a common sample arm while maintaining independent RS and OCT detection arms. We present the design and application of an integrated RS-OCT instrument with a common detection arm for both RS and OCT. The detector is a spectrograph capable of sequential detection of the 855-nm OCT signal and the Raman scatter generated by a 785-nm source. The capabilities of the instrument are demonstrated ex vivo in the calvaria and retina of rodents, as well as in vivo in human skin. PMID- 21280895 TI - Gender variations in the optical properties of skin in murine animal models. AB - Gender is identified as a significant source of variation in optical reflectance measurements on mouse skin, with variation in the thickness of the dermal layer being the key explanatory variable. For three different mouse strains, the thickness values of the epidermis, dermis, and hypodermis layers, as measured by histology, are correlated to optical reflectance measurements collected with elastic scattering spectroscopy (ESS). In all three strains, males are found to have up to a 50% increase in dermal thickness, resulting in increases of up to 80% in reflectance values and higher observed scattering coefficients, as compared to females. Collagen in the dermis is identified as the primary source of these differences due to its strong scattering nature; increased dermal thickness leads to a greater photon path length through the collagen, as compared to other layers, resulting in a larger scattering signal. A related increase in the observed absorption coefficient in females is also observed. These results emphasize the importance of considering gender during experimental design in studies that involve photon interaction with mouse skin. The results also elucidate the significant impact that relatively small thickness changes can have on observed optical measurements in layered tissue. PMID- 21280896 TI - Multimodal spectroscopy detects features of vulnerable atherosclerotic plaque. AB - Early detection and treatment of rupture-prone vulnerable atherosclerotic plaques is critical to reducing patient mortality associated with cardiovascular disease. The combination of reflectance, fluorescence, and Raman spectroscopy-termed multimodal spectroscopy (MMS)-provides detailed biochemical information about tissue and can detect vulnerable plaque features: thin fibrous cap (TFC), necrotic core (NC), superficial foam cells (SFC), and thrombus. Ex vivo MMS spectra are collected from 12 patients that underwent carotid endarterectomy or femoral bypass surgery. Data are collected by means of a unitary MMS optical fiber probe and a portable clinical instrument. Blinded histopathological analysis is used to assess the vulnerability of each spectrally evaluated artery lesion. Modeling of the ex vivo MMS spectra produce objective parameters that correlate with the presence of vulnerable plaque features: TFC with fluorescence parameters indicative of collagen presence; NC/SFC with a combination of diffuse reflectance beta-carotene/ceroid absorption and the Raman spectral signature of lipids; and thrombus with its Raman signature. Using these parameters, suspected vulnerable plaques can be detected with a sensitivity of 96% and specificity of 72%. These encouraging results warrant the continued development of MMS as a catheter-based clinical diagnostic technique for early detection of vulnerable plaques. PMID- 21280897 TI - Instrument independent diffuse reflectance spectroscopy. AB - Diffuse reflectance spectroscopy with a fiber optic probe is a powerful tool for quantitative tissue characterization and disease diagnosis. Significant systematic errors can arise in the measured reflectance spectra and thus in the derived tissue physiological and morphological parameters due to real-time instrument fluctuations. We demonstrate a novel fiber optic probe with real-time, self-calibration capability that can be used for UV-visible diffuse reflectance spectroscopy in biological tissue in clinical settings. The probe is tested in a number of synthetic liquid phantoms over a wide range of tissue optical properties for significant variations in source intensity fluctuations caused by instrument warm up and day-to-day drift. While the accuracy for extraction of absorber concentrations is comparable to that achieved with the traditional calibration (with a reflectance standard), the accuracy for extraction of reduced scattering coefficients is significantly improved with the self-calibration probe compared to traditional calibration. This technology could be used to achieve instrument-independent diffuse reflectance spectroscopy in vivo and obviate the need for instrument warm up and post/premeasurement calibration, thus saving up to an hour of precious clinical time. PMID- 21280898 TI - Mechanism of ceroid formation in atherosclerotic plaque: in situ studies using a combination of Raman and fluorescence spectroscopy. AB - Accumulation of the lipid-protein complex ceroid is a characteristic of atherosclerotic plaque. The mechanism of ceroid formation has been extensively studied, because the complex is postulated to contribute to plaque irreversibility. Despite intensive research, ceroid deposits are defined through their fluorescence and histochemical staining properties, while their composition remains unknown. Using Raman and fluorescence spectral microscopy, we examine the composition of ceroid in situ in aorta and coronary artery plaque. The synergy of these two types of spectroscopy allows for identification of ceroid via its fluorescence signature and elucidation of its chemical composition through the acquisition of a Raman spectrum. In accordance with in vitro predictions, low density lipoprotein (LDL) appears within the deposits primarily in its peroxidized form. The main forms of modified LDL detected in both coronary artery and aortic plaques are peroxidation products from the Fenton reaction and myeloperoxidase-hypochlorite pathway. These two peroxidation products occur in similar concentrations within the deposits and represent ~40 and 30% of the total LDL (native and peroxidized) in the aorta and coronary artery deposits, respectively. To our knowledge, this study is the first to successfully employ Raman spectroscopy to unravel a metabolic pathway involved in disease pathogenesis: the formation of ceroid in atherosclerotic plaque. PMID- 21280899 TI - Probe pressure effects on human skin diffuse reflectance and fluorescence spectroscopy measurements. AB - Diffuse reflectance and fluorescence spectroscopy are popular research techniques for noninvasive disease diagnostics. Most systems include an optical fiber probe that transmits and collects optical spectra in contact with the suspected lesion. The purpose of this study is to investigate probe pressure effects on human skin spectroscopic measurements. We conduct an in-vivo experiment on human skin tissue to study the short-term (<2 s) and long-term (>30 s) effects of probe pressure on diffuse reflectance and fluorescence measurements. Short-term light probe pressure (P0<9 mN/mm2) effects are within 0 +/- 10% on all physiological properties extracted from diffuse reflectance and fluorescence measurements, and less than 0+/-5% for diagnostically significant physiological properties. Absorption decreases with site-specific variations due to blood being compressed out of the sampled volume. Reduced scattering coefficient variation is site specific. Intrinsic fluorescence shows a large standard error, although no specific pressure-related trend is observed. Differences in tissue structure and morphology contribute to site-specific probe pressure effects. Therefore, the effects of pressure can be minimized when the pressure is small and applied for a short amount of time; however, long-term and large pressures induce significant distortions in measured spectra. PMID- 21280900 TI - Light scattering of human red blood cells during metabolic remodeling of the membrane. AB - We present the light scattering properties of individual human red blood cells (RBCs). We show that both the RBC static and dynamic scattering signals are altered by adenosine 5'-triphosphate (ATP)-driven membrane metabolic remodeling. To measure the light scattering signal from individual RBCs, we use diffraction phase microscopy together with a Fourier transform light scattering technique. RBC cytosolic ATPs are both chemically and metabolically depleted, and the corresponding scattering signals are compared with the light scattering signal of normal RBCs having physiologic levels of ATP. PMID- 21280901 TI - Fiber-laser-based photoacoustic microscopy and melanoma cell detection. AB - For broad applications in biomedical research involving functional dynamics and clinical studies, a photoacoustic microscopy system should be compact, stable, and fast. In this work, we use a fiber laser as the photoacoustic irradiation source to meet these goals. The laser system measures 45*56*13 cm3. The stability of the laser is attributed to the intrinsic optical fiber-based light amplification and output coupling. Its 50-kHz pulse repetition rate enables fast scanning or extensive signal averaging. At the laser wavelength of 1064 nm, the photoacoustic microscope still has enough sensitivity to image small blood vessels while providing high optical absorption contrast between melanin and hemoglobin. Label-free melanoma cells in flowing bovine blood are imaged in vitro, yielding measurements of both cell size and flow speed. PMID- 21280902 TI - Multispectral imaging of tissue absorption and scattering using spatial frequency domain imaging and a computed-tomography imaging spectrometer. AB - We present an approach for rapidly and quantitatively mapping tissue absorption and scattering spectra in a wide-field, noncontact imaging geometry by combining multifrequency spatial frequency domain imaging (SFDI) with a computed-tomography imaging spectrometer (CTIS). SFDI overcomes the need to spatially scan a source, and is based on the projection and analysis of periodic structured illumination patterns. CTIS provides a throughput advantage by simultaneously diffracting multiple spectral images onto a single CCD chip to gather spectra at every pixel of the image, thus providing spatial and spectral information in a single snapshot. The spatial-spectral data set was acquired 30 times faster than with our wavelength-scanning liquid crystal tunable filter camera, even though it is not yet optimized for speed. Here we demonstrate that the combined SFDI-CTIS is capable of rapid, multispectral imaging of tissue absorption and scattering in a noncontact, nonscanning platform. The combined system was validated for 36 wavelengths between 650-1000 nm in tissue simulating phantoms over a range of tissue-like absorption and scattering properties. The average percent error for the range of absorption coefficients (MUa) was less than 10% from 650-800 nm, and less than 20% from 800-1000 nm. The average percent error in reduced scattering coefficients (MUs') was less than 5% from 650-700 nm and less than 3% from 700 1000 nm. The SFDI-CTIS platform was applied to a mouse model of brain injury in order to demonstrate the utility of this approach in characterizing spatially and spectrally varying tissue optical properties. PMID- 21280903 TI - New testing software for quantifying discrimination capacity in subjects with ocular pathologies. AB - We develop a new visual test, designed as software for quantifying discrimination capacity under low-illumination conditions. This is an important task in the presence of visual disturbances, such as those perceived by subjects with some ocular pathologies. For this purpose, we propose a visual-disturbance index, checking the test with two groups of observers having different ocular pathologies: a group with unilateral keratitis and another group affected with age-related macular degeneration (ARMD). To compare the test results to objective data, we use a double-pass device to measure the Strehl ratio, a parameter that quantifies the retinal-image quality, taking into account aberrations, retinal reflection, and intraocular scattering working jointly. Diseased eyes present higher disturbance indexes and a lower Strehl ratio compared to their healthy fellow eyes, registering a significant descending correlation between the disturbance index and the Strehl ratio. The lower the Strehl ratio is, the higher the disturbance index for the eyes studied. Therefore, in keratitis and ARMD eyes, our results demonstrate a deterioration in the retinal-image quality and a lower discrimination capacity to peripheral stimuli, reducing visual performance. The test presented here could be useful for the study and time course in different eye diseases, especially those involving an increase in scattered light or alterations in the ocular media, as shown in this work. PMID- 21280904 TI - Optoelectrophysiological stimulation of the human eye using fundus-controlled silent substitution technique. AB - We design, characterize, and apply a novel optoelectrophysiological setup for a fundus-controlled silent substitution technique that accounts for interindividual variability in retina morphology and simultaneously monitors the stimulation site under investigation. We connect a digital color liquid crystal on silicon projector, an electron-multiplying imager, and a light-emitting diode to a fundus camera. The temporal and spatial characterization reveal a maximal contrast loss of 7% for the highest stimulation frequency (30 Hz) and maximum cutoff spatial frequencies of ~120 cycles/deg. Two silent substitution flash sequences are applied to modulate selective activity in the short-wavelength-sensitive cone (S cone) and combined long- and middle-wavelength-sensitive cone (LM-cone) pathways. Simultaneously, the visual evoked potentials are recorded. The data are compared to the grand average responses from a previous study that employed standard computer-screen presentation and showed very good latency matches. All the volunteers in the present examination exhibit differences between the S-cone and LM-cone evoked potentials (parameters mean values: peak-to-peak amplitude, N1 latency, and P1 latency for S-cone/LM-cone responses: 8 MUV/15 MUV, 113 ms/89 ms, 170 ms/143 ms). We demonstrate that the developed optoelectrophysiological setup simultaneously provides imaging, functional stimulation, and electrophysiological investigation of the retina. PMID- 21280905 TI - Light penetration in the human prostate: a whole prostate clinical study at 763 nm. AB - Photodynamic therapy (PDT) is being investigated as a treatment for localized prostate cancer. Photodynamic therapy uses a photosensitizing drug which is activated by a specific wavelength of light, in the presence of oxygen. The activated drug reacts with tissue oxygen to produce reactive oxygen species which are responsible for localized tissue necrosis. One of the determinants of the PDT effect is the penetration of light in the prostate. This study assesses the penetration depth of 763 nm light throughout the prostate. Eight men undergoing multiple hollow needle insertion for high dose rate brachytherapy were recruited. 763 nm light, produced by a diode laser, was delivered to the prostate using cylindrically diffusing optical fibers within the plastic needles. Light was detected at different distances from the source, using an isotropic detector within nearby needles. Penetration depth was calculated using the Boltzmann approximation to the diffusion equation. Delivery detector fiber separation was measured on computed tomography. The mean penetration depth was 0.57 cm, but there was within patient variation of a mean factor of 4.3. Further work is ongoing to assess the effect of such variability in light penetration, on the PDT effect. PMID- 21280906 TI - Iris as a reflector for differential absorption low-coherence interferometry to measure glucose level in the anterior chamber. AB - We present a method of glucose concentration detection in the anterior chamber with a differential absorption optical low-coherent interferometry (LCI) technique. Back-reflected light from the iris, passing through the anterior chamber twice, was selectively obtained with the LCI technique. Two light sources, one centered within (1625 nm) and the other centered outside (1310 nm) of a glucose absorption band were used for differential absorption measurement. In the eye model and pig eye experiments, we obtained a resolution glucose level of 26.8 mg/dL and 69.6 mg/dL, respectively. This method has a potential application for noninvasive detection of glucose concentration in aqueous humor, which is related to the glucose concentration in blood. PMID- 21280907 TI - Intraoperative imaging of cortical cerebral perfusion by time-resolved thermography and multivariate data analysis. AB - A new approach to cortical perfusion imaging is demonstrated using high sensitivity thermography in conjunction with multivariate statistical data analysis. Local temperature changes caused by a cold bolus are imaged and transferred to a false color image. A cold bolus of 10 ml saline at ice temperature is injected systemically via a central venous access. During the injection, a sequence of 735 thermographic images are recorded within 2 min. The recorded data cube is subjected to a principal component analysis (PCA) to select slight changes of the cortical temperature caused by the cold bolus. PCA reveals that 11 s after injection the temperature of blood vessels is shortly decreased followed by an increase to the temperature before the cold bolus is injected. We demonstrate the potential of intraoperative thermography in combination with multivariate data analysis to image cortical cerebral perfusion without any markers. We provide the first in vivo application of multivariate thermographic imaging. PMID- 21280908 TI - Multifunctional optical imaging using dye-coated gold nanorods in a turbid medium. AB - We report multifunctional optical imaging using dye-coated gold nanorods. Three types of useful information, namely, Raman, fluorescence signals, and absorption contrast, can be obtained from a phantom experiment. These three kinds of information are detected in a nanoparticle-doped-phantom using diffuse optical imaging. Our novel nanoparticle could be used as a multimodality marker for future bioimaging applications. PMID- 21280909 TI - Two-dimensional singlet oxygen imaging with its near-infrared luminescence during photosensitization. AB - Photodynamic therapy is a promising cancer treatment that involves activation of photosensitizer by visible light to create singlet oxygen. This highly reactive oxygen species is believed to induce cell death and tissue destruction in PDT. Our approach used a near-infrared area CCD with high quantum efficiency to detect singlet oxygen by its 1270-nm luminescence. Two-dimensional singlet oxygen images with its near-infrared luminescence during photosensitization could be obtained with a CCD integration time of 1 s, without scanning. Thus this system can produce singlet oxygen luminescence images faster and achieve more accurate measurements in comparison to raster-scanning methods. The experimental data show a linear relationship between the singlet oxygen luminescence intensity and sample concentration. This method provides a detection sensitivity of 0.0181 MUg/ml (benzoporphyrin derivative monoacid ring A dissolved in ethanol) and a spatial resolution better than 50 MUm. A pilot study was conducted on a total of six female Kunming mice. The results from this study demonstrate the system's potential for in vivo measurements. Further experiments were carried out on two tumor-bearing nude mice. Singlet oxygen luminescence images were acquired from the tumor-bearing nude mouse with intravenous injection of BPD-MA, and the experimental results showed real-time singlet oxygen signal depletion as a function of the light exposure. PMID- 21280910 TI - Tracer-cocktail injections for combined pre- and intraoperative multimodal imaging of lymph nodes in a spontaneous mouse prostate tumor model. AB - To improve surgical guidance toward prostate draining lymph nodes, we investigate the potential of intraoperative fluorescence imaging and combined pre- and intraoperative multimodality imaging approaches. Transgenic adenocarcinoma mouse prostate mice with spontaneous prostate tumors are injected intratumorally with: 1. a cocktail of patent blue (Pb) and indocyanine green (ICG); 2. a cocktail of albumin radiocolloids (99mTc-NanoColl), Pb, and ICG; or 3. a cocktail of radiolabeled albumin (99mTc-Vasculosis), Pb, and ICG. The distribution of these imaging agents over the lymph nodes (LNs) are studied at different time points after injection. We find that at 60-min postinjection, ICG significantly improves the detection of the LNs compared to Pb, 53 versus 7%, respectively. Moreover, a cocktail of ICG and 99mTc-NanoColl improves the fluorescent detection rate to 86%, equalling that of the clinically applied 99mTc-NanoColl. A similar overlap is observed in our initial clinical pilot data. Fluorescent detection of the LNs using a ICG with 99mTc-Vasculosis gives similar results as "free" ICG (58%; 60 min). A 99mTc-NanoColl, Pb, and cocktail ICG enriches the standard 99mTc-NanoColl approach by adding optical detection of the sentinel lymph nodes. Furthermore, this approach improves fluorescent-based guidance and enables both accurate surgical planning and intraoperative detection, based on a single injection. PMID- 21280911 TI - Method for optical coherence elastography of the cornea. AB - The material properties of the cornea are important determinants of corneal shape and refractive power. Corneal ectatic diseases, such as keratoconus, are characterized by material property abnormalities, are associated with progressive thinning and distortion of the cornea, and represent a leading indication for corneal transplantation. We describe a corneal elastography technique based on optical coherence tomography (OCT) imaging, in which displacement of intracorneal optical features is tracked with a 2-D cross-correlation algorithm as a step toward nondestructive estimation of local and directional corneal material properties. Phantom experiments are performed to measure the effects of image noise and out-of-plane displacement on effectiveness of displacement tracking and demonstrated accuracy within the tolerance of a micromechanical translation stage. Tissue experiments demonstrate the ability to produce 2-D maps of heterogeneous intracorneal displacement with OCT. The ability of a nondestructive optical method to assess tissue under in situ mechanical conditions with physiologic-range stress levels provides a framework for in vivo quantification of 3-D corneal elastic and viscoelastic resistance, including analogs of shear deformation and Poisson's ratio that may be relevant in the early diagnosis of corneal ectatic disease. PMID- 21280912 TI - Monte Carlo simulation of the spatial resolution and depth sensitivity of two dimensional optical imaging of the brain. AB - Absorption or fluorescence-based two-dimensional (2-D) optical imaging is widely employed in functional brain imaging. The image is a weighted sum of the real signal from the tissue at different depths. This weighting function is defined as "depth sensitivity." Characterizing depth sensitivity and spatial resolution is important to better interpret the functional imaging data. However, due to light scattering and absorption in biological tissues, our knowledge of these is incomplete. We use Monte Carlo simulations to carry out a systematic study of spatial resolution and depth sensitivity for 2-D optical imaging methods with configurations typically encountered in functional brain imaging. We found the following: (i) the spatial resolution is <200 MUm for NA<=0.2 or focal plane depth<=300 MUm. (ii) More than 97% of the signal comes from the top 500 MUm of the tissue. (iii) For activated columns with lateral size larger than spatial resolution, changing numerical aperature (NA) and focal plane depth does not affect depth sensitivity. (iv) For either smaller columns or large columns covered by surface vessels, increasing NA and/or focal plane depth may improve depth sensitivity at deeper layers. Our results provide valuable guidance for the optimization of optical imaging systems and data interpretation. PMID- 21280913 TI - Multispectral fluorescence imaging to assess pH in biological specimens. AB - Simple, quantitative assays to measure pH in tissue could improve the study of complicated biological processes and diseases such as cancer. We evaluated multispectral fluorescence imaging (MSFI) to quantify extracellular pH (pHe) in dye-perfused, surgically-resected tumor specimens with commercially available instrumentation. Utilizing a water-soluble organic dye with pH-dependent fluorescence emission (SNARF-4F), we used standard fluorimetry to quantitatively assess the emission properties of the dye as a function of pH. By conducting these studies within the spectroscopic constraints imposed by the appropriate imaging filter set supplied with the imaging system, we determined that correction of the fluorescence emission of deprotonated dye was necessary for accurate determination of pH due to suboptimal excitation. Subsequently, employing a fluorimetry-derived correction factor (CF), MSFI data sets of aqueous dye solutions and tissuelike phantoms could be spectrally unmixed to accurately quantify equilibrium concentrations of protonated (HA) and deprotonated (A-) dye and thus determine solution pH. Finally, we explored the feasibility of MSFI for high-resolution pHe mapping of human colorectal cancer cell-line xenografts. Data presented suggest that MSFI is suitable for quantitative determination of pHe in ex vivo dye-perfused tissue, potentially enabling measurement of pH across a variety of preclinical models of disease. PMID- 21280914 TI - Functional connectivity in the prefrontal cortex measured by near-infrared spectroscopy during ultrarapid object recognition. AB - Near-infrared spectroscopy (NIRS) is a developing technology for low-cost noninvasive functional brain imaging. With multichannel optical instruments, it becomes possible to measure not only local changes in hemoglobin concentrations but also temporal correlations of those changes in different brain regions which gives an optical analog of functional connectivity traditionally measured by fMRI. We recorded hemodynamic activity during the Go-NoGo task from 11 right handed subjects with probes placed bilaterally over prefrontal areas. Subjects were detecting animals as targets in natural scenes pressing a mouse button. Data were low-pass filtered<1 Hz and cardiac/respiration/superficial layers artifacts were removed using Independent Component Analysis. Fisher's transformed correlations of poststimulus responses (30 s) were averaged over groups of channels unilaterally in each hemisphere (intrahemispheric connectivity) and the corresponding channels between hemispheres (interhemispheric connectivity). The hemodynamic response showed task-related activation (an increase/decrease in oxygenated/deoxygenated hemoglobin, respectively) greater in the right versus left hemisphere. Intra- and interhemispheric functional connectivity was also significantly stronger during the task compared to baseline. Functional connectivity between the inferior and the middle frontal regions was significantly stronger in the right hemisphere. Our results demonstrate that optical methods can be used to detect transient changes in functional connectivity during rapid cognitive processes. PMID- 21280915 TI - Real-time blood flow visualization using the graphics processing unit. AB - Laser speckle imaging (LSI) is a technique in which coherent light incident on a surface produces a reflected speckle pattern that is related to the underlying movement of optical scatterers, such as red blood cells, indicating blood flow. Image-processing algorithms can be applied to produce speckle flow index (SFI) maps of relative blood flow. We present a novel algorithm that employs the NVIDIA Compute Unified Device Architecture (CUDA) platform to perform laser speckle image processing on the graphics processing unit. Software written in C was integrated with CUDA and integrated into a LabVIEW Virtual Instrument (VI) that is interfaced with a monochrome CCD camera able to acquire high-resolution raw speckle images at nearly 10 fps. With the CUDA code integrated into the LabVIEW VI, the processing and display of SFI images were performed also at ~10 fps. We present three video examples depicting real-time flow imaging during a reactive hyperemia maneuver, with fluid flow through an in vitro phantom, and a demonstration of real-time LSI during laser surgery of a port wine stain birthmark. PMID- 21280916 TI - Defocus correction in the optical system of the eye: unconventional degrees of freedom. AB - Despite the interest in developing improved formulas for intraocular lens power calculation, there are several sources of uncertainty that may well give rise to a significant residual refractive error. Those concerning the estimation of the corneal power are reviewed. In addition, we explore the possibility of introducing changes in some unconventional parameters of the eye to compensate for defocus and illustrate their effectiveness in two cases: a natural eye and an eye that has undergone previous surgical actions (anterior refractive surgery and cataract surgery with an intraocular lens implant). The results show that changes in the refractive index, thickness, or posterior radius of the cornea have relatively little effect on the overall refractive error. However, small changes in the refractive indexes of the aqueous or the vitreous humors are highly effective, much more so than a similar amount of change in the anterior curvature of the cornea. This fact opens new and attractive possibilities to compensate for refractive error through the introduction of changes in degrees of freedom so far considered unconventional. PMID- 21280918 TI - Label-free imaging of Drosophila in vivo by coherent anti-Stokes Raman scattering and two-photon excitation autofluorescence microscopy. AB - Drosophila is one of the most valuable model organisms for studying genetics and developmental biology. The fat body in Drosophila, which is analogous to the liver and adipose tissue in human, stores lipids that act as an energy source during its development. At the early stages of metamorphosis, the fat body remodeling occurs involving the dissociation of the fat body into individual fat cells. Here we introduce a combination of coherent anti-Stokes Raman scattering (CARS) and two-photon excitation autofluorescence (TPE-F) microscopy to achieve label-free imaging of Drosophila in vivo at larval and pupal stages. The strong CARS signal from lipids allows direct imaging of the larval fat body and pupal fat cells. In addition, the use of TPE-F microscopy allows the observation of other internal organs in the larva and autofluorescent globules in fat cells. During the dissociation of the fat body, the findings of the degradation of lipid droplets and an increase in autofluorescent globules indicate the consumption of lipids and the recruitment of proteins in fat cells. Through in vivo imaging and direct monitoring, CARS microscopy may help elucidate how metamorphosis is regulated and study the lipid metabolism in Drosophila. PMID- 21280917 TI - Detection of CXCR4 receptors on cell surface using a fluorescent metal nanoshell. AB - Fluorescence cell imaging can be used for disease diagnosis and cellular signal transduction. Using a metal nanoshell as molecular imaging agent, we develop a cellular model system to detect CXCR4 chemokine receptor on T-lymphatic cell surface. These metal nanoshells are observed to express enhanced emission intensity and shortened lifetimes due to the near-field interactions. They are covalently bound with anti-CXCR4 monoclonal antibodies for immunoreactions with the target sites of the CXCR4 receptors on the CEM-SS cells. The fluorescence intensity and lifetime cell images are recorded with a time-resolved confocal microscopy. As expected, the emission signals from the metal nanoshells are clearly isolated from the cellular autofluorescence due to strong intensities and distinctive lifetimes. The number of emission spots on the single cell image is estimated by direct count to the emission signals. Analyzing a pool of cell images, a maximal count number is obtained in a range of 200+/-50. Because there is an average of approximately 6000 binding sites on the cell surface, we estimate that one emission spot from the metal nanoshell may represent approximately 30 CXCR5 receptors. In addition, the CXCR4 receptors are estimated to distribute on approximately 70% area of the cell surface. PMID- 21280919 TI - Homogenized tissue phantoms for quantitative evaluation of subsurface fluorescence contrast. AB - The use of phantoms comprising diluted tissue homogenates with a buried capillary containing quantum dots is demonstrated as a method to investigate the optical and biophysical factors influencing the imaging of subsurface fluorescence contrast agents. Validation of the method is demonstrated using both liquid phantoms of known optical absorption and reduced scattering and Monte Carlo computer simulations of photon transport. Conclusions regarding the optimal excitation wavelength are given and quantified with respect to the tissue optical properties. The tissue homogenate method should be of value for quantitative optimization studies relevant to, for example, endoscopic imaging. PMID- 21280920 TI - Optically sectioned in vivo imaging with speckle illumination HiLo microscopy. AB - We present a simple wide-field imaging technique, called HiLo microscopy, that is capable of producing optically sectioned images in real time, comparable in quality to confocal laser scanning microscopy. The technique is based on the fusion of two raw images, one acquired with speckle illumination and another with standard uniform illumination. The fusion can be numerically adjusted, using a single parameter, to produce optically sectioned images of varying thicknesses with the same raw data. Direct comparison between our HiLo microscope and a commercial confocal laser scanning microscope is made on the basis of sectioning strength and imaging performance. Specifically, we show that HiLo and confocal 3 D imaging of a GFP-labeled mouse brain hippocampus are comparable in quality. Moreover, HiLo microscopy is capable of faster, near video rate imaging over larger fields of view than attainable with standard confocal microscopes. The goal of this paper is to advertise the simplicity, robustness, and versatility of HiLo microscopy, which we highlight with in vivo imaging of common model organisms including planaria, C. elegans, and zebrafish. PMID- 21280922 TI - Broadband optical ultrasound sensor with a unique open-cavity structure. AB - High-resolution ultrasound imaging requires quality sensors with wide bandwidth and high sensitivity, as shown in a wide range of applications, including intravascular imaging of cardiovascular diseases. However, piezoelectric technology, the current dominant approach for hydrophone fabrication, has encountered many technical limitations in the high-frequency range. Using optical techniques for the detection of high-frequency ultrasound signals has attracted much recent attention. One of the most studied approaches is based on a Fabry Perot interferometer, consisting of an optical cavity sandwiched between two mirrors. This technique offers promising sensitivity and bandwidth, and a potential alternative to piezoelectric polyvinylidene fluoride (PVDF) hydrophones. We propose an innovative optical ultrasound sensor using only a single mirror in a total-internal-reflection configuration. Besides retaining the advantages of Fabry-Perot interferometer-based ultrasound sensors, this unique design provides a bandwidth of at least 160 MHz, a potential decrease in fabrication cost, and an increase in signal fidelity. PMID- 21280921 TI - In vivo photoacoustic microscopy of human cutaneous microvasculature and a nevus. AB - In several human volunteers, photoacoustic microscopy (PAM) has been utilized for noninvasive cutaneous imaging of the skin microvasculature and a melanocytic nevus. Microvascular networks in both acral and nonacral skin were imaged, and multiple features within the skin have been identified, including the stratum corneum, epidermal-dermal junction, and subpapillary vascular plexus. Several vascular and structural differences between acral and nonacral skin were also observed in the photoacoustic images. In addition, a nevus was photoacoustically imaged, excised, and histologically analyzed. The photoacoustic images allowed for in vivo measurement of tumor thickness, depth, and microvasculature-values confirmed by histologic examination. The presented images demonstrate the potential of PAM to aid in the study and evaluation of cutaneous microcirculation and analysis of pigmented lesions. Through its ability to three-dimensionally image the structure and function of the microvasculature and pigmented lesions, PAM can have a clinical impact in diagnosis and assessment of systemic diseases that affect the microvasculature such as diabetes and cardiovascular disease, cutaneous malignancies such as melanoma, and potentially other skin disorders. PMID- 21280923 TI - Respiration and body movement analysis during sleep in bed using hetero-core fiber optic pressure sensors without constraint to human activity. AB - We describe respiration monitoring in sleep using hetero-core fiber optic pressure sensors. The proposed hetero-core fiber optic sensor is highly sensitive to macrobending as a result of the core diameter difference due to stable single mode transmission. Pressure sensors based on hetero-core fiber optics were fabricated to have a high sensitivity to small pressure changes resulting from minute body motions, such as respiration, during sleep and large pressure changes, such as those caused by a rollover. The sensors are installed in a conventional bed. The pressure characteristic performance of all the fabricated hetero-core fiber optic pressure sensors is found to show a monotonic response with weight changes. A respiration monitoring test in seven subjects efficiently demonstrates the effective use of eight hetero-core pressure sensors installed in a bed. Additionally, even in the case of different body postures, such as lying on one's side, a slight body movement due to respiration is detected by the hetero-core pressure sensors. PMID- 21280924 TI - Early detection of biomolecular changes in disrupted porcine cartilage using polarized Raman spectroscopy. AB - We evaluate the feasibility of applying polarized Raman spectroscopy in probing the early biochemical compositions and orientation changes in impacted porcine cartilage explants. We divide 100 fresh tibial cartilage explants into four groups: control (unimpacted) and 3 groups of single impact at 15, 20, and 25 MPa. Each group is examined for biochemical changes using Raman microscopy, cell viability changes using confocal fluorescence microscopy, and histological changes using the modified Mankin score. For the 15-MPa impact group, the modified Mankin score (p>0.05, n=15) and cell viability test (p>0.05, n=5) reveal no significant changes when compared to the control, but polarized Raman spectroscopy detects significant biochemical changes. A significant decrease in the parallel polarized intensity of the pyranose ring band at 1126 cm(-1) suggests a possible decrease in the glycoaminoglycan content in early cartilage damage (one-way analysis of variance with a post hoc Bonferonni test, p<0.05, n=10). For impacts greater than 15 MPa, cell viability and modified Mankin score are consistent with the changes in the observed polarized Raman signals. This suggests that the polarized Raman spectroscopy technique has potential for diagnosis and detection of early cartilage damage at the molecular level. PMID- 21280925 TI - Miniature refractometer based on modal interference in a hollow-core photonic crystal fiber with collapsed splicing. AB - A miniature modal interferometer based on a hollow-core photonic crystal fiber (HC-PCF) for refractive index measurement is demonstrated. The modal interferometer is fabricated by splicing the two ends of a 1.2-mm-long HC-PCF to a single-mode fiber (SMF). The air holes of the HC-PCF are fully collapsed by the discharge arc during the splicing procedure, and the length of each collapsed region is about 300 MUm. The transmission spectra with different refractive indices outside the HC-PCF are measured. Measurement resolutions of an 8.1*10(-4) refractive index unit (RIU) in the range of 1.35 to 1.39, and 4.3*10(-4) RIU in the range of 1.39 to 1.43 are achieved, respectively. The temperature effect of the proposed refractometer is also analyzed. PMID- 21280926 TI - Biodistribution and photodynamic effects of polyvinylpyrrolidone-hypericin using multicellular spheroids composed of normal human urothelial and T24 transitional cell carcinoma cells. AB - Polyvinylpyrrolidone (PVP)-hypericin is a potent photosensitizer that is used in the urological clinic to photodiagnose with high-sensitivity nonmuscle invasive bladder cancer (NMIBC). We examined the differential accumulation and therapeutic effects of PVP-hypericin using spheroids composed of a human urothelial cell carcinoma cell line (T24) and normal human urothelial (NHU) cells. The in vitro biodistribution was assessed using fluorescence image analysis of 5-MUm cryostat sections of spheroids that were incubated with PVP-hypericin. The results show that PVP-hypericin accumulated to a much higher extent in T24 spheroids as compared to NHU spheroids, thereby reproducing the clinical situation. Subsequently, spheroids were exposed to different PDT regimes with a light dose ranging from 0.3 to 18 J/cm2. When using low fluence rates, only minor differences in cell survival were seen between normal and malignant spheroids. High light fluence rates induced a substantial difference in cell survival between the two spheroid types, killing ~80% of the cells present in the T24 spheroids. It was concluded that further in vivo experiments are required to fully evaluate the potential of PVP-hypericin as a phototherapeutic for NMIBC, focusing on the combination of the compound with methods that enhance the oxygenation of the urothelium. PMID- 21280927 TI - Analysis and applications of accommodative lenses for vision corrections. AB - Analysis and applications of vision correction via accommodating intraocular lens (AIOL) are presented. By Gaussian optics, analytic formulas for the accommodation rate function (M) for two-optics and three-optics systems are derived and compared with the exact numerical results. In a single-optics AIOL, typical value of M is (0.5-1.5) D/mm, for an IOL power of (10-20) diopter. For a given IOL power, higher M is achieved in positive-IOL than negative-IOL. In the dual-optics AIOL, maximum accommodation is predicted when the front positive-optics moves toward the corneal plan and the back negative-optics moves backward. Our analytic formulas predict that greater accommodative rate may be achieved by using a positive-powered front optics, a general feature when either front or back optics is mobile. The M function is used to find the piggy-back IOL power for customized design based on the individual ocular parameters. Many of the new features demonstrated in this study can be easily realized by our analytic formulas, but not by raytracing method. PMID- 21280929 TI - The backward masking red light effect in schizophrenia: relationship to clinical features and neurocognitive performance. AB - The "backward masking red light effect" involves a change in visual backward masking performance with a red (compared with a green or gray) background that is in the opposite direction relative to nonpsychiatric controls. This effect has been previously reported in individuals with schizophrenia, their first-degree relatives, and a schizotypy sample. The current study provides the first examination of the relationship of this effect with clinical and neurocognitive measures in a new sample of higher functioning patients with schizophrenia. A location backward masking by pattern task was administered to 16 outpatients with schizophrenia and 21 nonpsychiatric controls. The task was presented on red, green, and gray backgrounds. There was a significant group by color interaction at the 60-ms stimulus onset asynchrony: Participants with schizophrenia tended to decrease accuracy with a red (compared with a gray) background, whereas controls tended to increase accuracy. This interaction remained significant after covarying for baseline (gray) backward masking accuracy. In the schizophrenia patients, a decrease in backward masking accuracy to the red background was correlated with more negative symptoms, lower estimated premorbid IQ, and greater color-word Stroop interference but was not related to positive or disorganized symptoms, age of onset, duration of illness, digit symbol coding performance, or baseline (gray) backward masking accuracy. In contrast, there was no relationship between the red light change score and any of the neurocognitive variables in the control group. PMID- 21280930 TI - Parental criticism and externalizing behavior problems in adolescents: the role of environment and genotype-environment correlation. AB - Genetic factors are important for the association between parental negativity and child problem behavior, but it is not clear whether this is due to passive or evocative genotype-environment correlation (rGE). In this study, we applied the extended children-of-twins model to directly examine the presence of passive and evocative rGE as well as direct environmental effects in the association between parental criticism and adolescent externalizing problem behavior. The cross sectional data come from the Twin and Offspring Study in Sweden (N = 909 pairs of adult twins) and from the Twin Study of Child and Adolescent Development (N = 915 pairs of twin children). The results revealed that maternal criticism was primarily due to evocative rGE emanating from their adolescent's externalizing behavior. On the other hand, fathers' critical remarks tended to affect adolescent problem behavior in a direct environmental way. This suggests that previously reported differences in caretaking between mothers and fathers also are reflected in differences in why parenting is associated with externalizing behavior in offspring. PMID- 21280931 TI - Suicidality as a function of impulsivity, callous-unemotional traits, and depressive symptoms in youth. AB - Suicidality represents one of the most important areas of risk for adolescents, with both internalizing (e.g., depression, anxiety) and externalizing-antisocial (e.g., substance use, conduct) disorders conferring risk for suicidal ideation and attempts (e.g., Bridge, Goldstein, & Brent, 2006). However, no study has attended to gender differences in relationships between suicidality and different facets of psychopathic tendencies in youth. Further, very little research has focused on disentangling the multiple manifestations of suicide risk in the same study, including behaviors (suicide attempts with intent to die, self-injurious behavior) and general suicide risk marked by suicidal ideation and plans. To better understand these relationships, we recruited 184 adolescents from the community and in treatment. As predicted, psychopathic traits and depressive symptoms in youth showed differential associations with components of suicidality. Specifically, impulsive traits uniquely contributed to suicide attempts and self-injurious behaviors, above the influence of depression. Indeed, once psychopathic tendencies were entered in the model, depressive symptoms only explained general suicide risk marked by ideation or plans but not behaviors. Further, callous-unemotional traits conferred protection from suicide attempts selectively in girls. These findings have important implications for developing integrative models that incorporate differential relationships between (a) depressed mood and (b) personality risk factors (i.e., impulsivity and callous unemotional traits) for suicidality in youth. PMID- 21280932 TI - The role of aesthetic sensitivity in body dysmorphic disorder. AB - Individuals with a higher aesthetic sensitivity may be more vulnerable to developing body dysmorphic disorder (BDD). Aesthetic sensitivity has 3 components: (a) perceptual, (b) emotional, and (c) evaluative. Individuals with BDD (n = 50) were compared with a control group of individuals with an education or employment in art and design related fields (n = 50) and a control group of individuals without aesthetic training (n = 50). A facial photograph of each participant was manipulated to create a 9-image symmetry continuum. Presented with the continuum on a computer, participants were required to select and rate the image representing their self-actual, self-ideal, idea of perfect, most physically attractive, most pleasure, and most disgust. Control symmetry continua examined the specificity of the disturbance. As predicted, BDD participants displayed no distortion in their perceptual processing but were disturbed in their negative emotional/evaluative processing of their self-image. A significant discrepancy between their self-actual and self-ideal, resulting from an absent self-serving bias in their self-actual (a bias exhibited by controls) appears to be the source of their disturbance. They also overvalued the importance of appearance and self-objectified. These aesthetic evaluations may predispose individuals to BDD and/or maintain the disorder. PMID- 21280933 TI - When distress hits home: the role of contextual factors and psychological distress in predicting employees' responses to abusive supervision. AB - We developed a model of the relationships among aggressive norms, abusive supervision, psychological distress, family undermining, and supervisor-directed deviance. We tested the model in 2 studies using multisource data: a 3-wave investigation of 184 full-time employees (Study 1) and a 2-wave investigation of 188 restaurant workers (Study 2). Results revealed that (a) abusive supervision mediated the relationship between aggressive norms and psychological distress, (b) psychological distress mediated the effects of abusive supervision on spouse undermining, (c) abusive supervision had a direct positive relationship with supervisor-directed deviance, (d) the positive relationship between psychological distress and spouse undermining was stronger for men as opposed to women, and (e) employees engaged in relationship-oriented occupations reported greater levels of abusive supervision and psychological distress. Implications for theory and practice are discussed. PMID- 21280934 TI - The role of automatic obesity stereotypes in real hiring discrimination. AB - This study examined whether automatic stereotypes captured by the implicit association test (IAT) can predict real hiring discrimination against the obese. In an unobtrusive field experiment, job applications were sent to a large number of real job vacancies. The applications were matched on credentials but differed with respect to the applicant's weight. Discriminatory behavior was quantified by the extent to which the hiring managers invited normal-weight versus obese applicants to a job interview. Several months after the behavioral data were obtained, the hiring managers completed an obesity IAT and explicit hiring preference measures. Only the IAT scores reliably predicted interview decisions. More specifically, hiring managers holding more negative automatic stereotypes about the obese were less likely to invite an obese applicant for an interview. The present research is the first to show that automatic bias predicts labor market discrimination against obese individuals. Practical implications are discussed. PMID- 21280935 TI - Motor preparation and the effects of practice: evidence from startle. AB - To examine sequential movement preparation, participants practiced unimanual movements that differed in amplitude and number of elements for 4 days in either a simple (Experiment 1) or choice (Experiment 2) reaction time (RT) paradigm. On Day 1 and 4, a startling stimulus was used to probe the preparation process. For simple RT, we found increased premotor RT for the two component movement during control trials on Day 1, which was minimized with practice. During startle trials, all movements were triggered at a short latency with similar consistency to control trials, suggesting full advance preparation of all movements. For choice RT, we also found increased premotor RT for control trials for the two component movement. As advance preparation could not occur, the startling stimulus did not trigger any of the movements. We hypothesized that complexity may relate to the neural commands needed to produce the movement, rather than a sequencing requirement. PMID- 21280936 TI - Differential rearing conditions and alcohol-preferring rats: consumption of and operant responding for ethanol. AB - Exposing rats to differential rearing conditions during early postweaning development has been shown to produce changes in a number of behaviors displayed during adulthood. The purpose of the present studies was to investigate whether rearing alcohol-preferring (P) and nonpreferring (NP) rats in an environmental enrichment condition (EC), a social condition (SC), or an impoverished condition (IC) would differentially affect self-administration of 10% ethanol. In Experiment 1, rats were tested for consumption of 10% ethanol in limited- and free-access tests. For Experiment 2, rats were trained to respond in an operant chamber for ethanol and then provided concurrent access to 10% ethanol and water. Each solution was presented in a separate liquid dipper after meeting the schedule of reinforcement on distinct levers. After concurrent access tests, the water lever/dipper was inactivated and a progressive ratio (PR) schedule was initiated. Three successive solutions (10% ethanol, 15% ethanol, and 10% sucrose) were tested under the PR. For P rats, rearing in an EC reduced ethanol consumption, preference, and motivation to obtain ethanol, relative to P rats reared in an IC. Thus, exposure to a novel environment immediately after weaning acted to decrease the reinforcing properties of ethanol in an animal model for alcoholism. PMID- 21280937 TI - Processing of expected and unexpected monetary performance outcomes in healthy older subjects. AB - The feedback-related negativity (FRN), an event-related potential (ERP) component reflecting feedback processing in the anterior cingulate cortex (ACC), has consistently been found to be reduced in healthy aging, whereas behavioral findings regarding age-related changes in decision making and feedback-based learning are inconsistent. This study aimed to elucidate similarities and differences between healthy younger and older subjects in the processing of monetary performance feedback focusing on effects of reward expectancy. Eighteen younger and 20 older subjects completed a feedback learning task, in which a rule could be learned to predict the reward probabilities associated with particular stimuli. Older subjects showed evidence of slower learning than younger subjects. In both younger and older subjects, the amplitude difference between nonreward and reward in the FRN time window was larger for unexpected than expected outcomes, driven by modulations of negative feedback ERPs. Consistent with previous findings, the amplitude difference tended to be generally reduced in older subjects. P300 amplitude was larger for reward than nonreward in both groups, and interactions between valence and probability indicated that only the P300 for reward was modulated by expectancy. Despite general changes of outcome related ERPs in healthy aging, older subjects show evidence of preserved effects of expectancy on the processing of monetary feedback. PMID- 21280938 TI - Automatic imitation. AB - "Automatic imitation" is a type of stimulus-response compatibility effect in which the topographical features of task-irrelevant action stimuli facilitate similar, and interfere with dissimilar, responses. This article reviews behavioral, neurophysiological, and neuroimaging research on automatic imitation, asking in what sense it is "automatic" and whether it is "imitation." This body of research reveals that automatic imitation is a covert form of imitation, distinct from spatial compatibility. It also indicates that, although automatic imitation is subject to input modulation by attentional processes, and output modulation by inhibitory processes, it is mediated by learned, long-term sensorimotor associations that cannot be altered directly by intentional processes. Automatic imitation provides an important tool for the investigation of the mirror neuron system, motor mimicry, and complex forms of imitation. It is a new behavioral phenomenon, comparable with the Stroop and Simon effects, providing strong evidence that even healthy adult humans are prone, in an unwilled and unreasoned way, to copy the actions of others. PMID- 21280939 TI - A meta-analysis of work-family conflict and various outcomes with a special emphasis on cross-domain versus matching-domain relations. AB - A literature review of studies analyzing work-family conflict and its consequences was conducted, and 427 effect sizes were analyzed meta-analytically. Work-family conflict was analyzed bidirectionally in terms of work interference with family (WIF) and family interference with work (FIW). We assessed 3 categories of potential outcomes: work-related outcomes, family-related outcomes, and domain-unspecific outcomes. Results show that WIF and FIW are consistently related to all 3 types of outcomes. Both types of interrole conflict showed stronger relationships to same-domain outcomes than to cross-domain outcomes. Thus, WIF was more strongly associated with work-related than with family-related outcomes, and FIW was more strongly associated with family-related than with work related outcomes. In moderator analyses, parenthood could not explain variability in effect sizes. However, time spent at work did moderate the relationships between WIF and family-related outcomes, as well as FIW and domain-unspecific outcomes. PMID- 21280941 TI - Effects of war exposure on air force personnel's mental health, job burnout and other organizational related outcomes. AB - Longitudinal data from a stratified representative sample of U.S. Air Force personnel (N = 1009) deployed to the wars in Iraq, Afghanistan, and other locations were analyzed in this study. Using structural equation models, we examined the effects of war exposure on traumatic experiences, Post Traumatic Stress (PTS) symptoms, resource loss, and on subsequent functioning, perceived health, and on job and organizationally relevant outcomes. The job and organizational outcomes included job burnout, job involvement, job strain, job satisfaction, work-family conflict, organizational commitment, deployment readiness, and intention to reenlist. We found that deployment to the theater of the war increased risk of exposure to trauma, which in turn, predicted elevated PTS symptoms and resource loss. PTS symptoms predicted later loss of resources and deterioration in perceived health and functioning. In turn, resource loss predicted negative job and organizational outcomes. Exposure to trauma fully mediated the effects of deployment to the theater of war on PTS symptoms and resource loss and had additional significant indirect effects on several job and organizational relevant outcomes. For returning veterans, deployment to the theater of war, exposure to trauma, PTS symptoms, and resource loss represents a "cascading" chain of events that over time results in a decline of health and functioning as well as in adverse job and organizationally relevant outcomes that may affect organizational effectiveness. PMID- 21280942 TI - Resilience to traumatic exposure among soldiers deployed in combat. AB - We examined the influence of positive psychological capital (PsyCap), a metaconstruct that combines established psychological predispositions to be resilient to stress, on the well-being of soldiers during combat deployment. Among U.S. Army personnel deployed in Iraq, cognitive appraisal of stress mediated the effects of trait PsyCap on health symptoms. The indirect effects through appraisal were moderated by levels of exposure to potentially traumatic stimuli. Trait PsyCap covaried more strongly with cognitive appraisals, and had stronger indirect effects through appraisal on health, among soldiers in units with higher levels of potentially traumatic exposures. We discuss implications for research on resilience to trauma in the workplace and for helping workers cope with potentially traumatic exposures. PMID- 21280943 TI - Bringing the troops back home: Modeling the postdeployment reintegration experience. AB - Using a sample of Canadian Forces personnel (N = 490) returning from deployment in Afghanistan, we tested a model of reintegration experiences, with a focus on affective organizational commitment, support factors, posttraumatic stress symptoms, changes in alcohol use, and turnover intentions. The model provided an excellent fit to the data, although homecoming experiences were not associated with commitment as predicted. No differences emerged between novice (single tour) and experienced (multiple tours) personnel, although the number of tours was associated with increased affective commitment as expected. PMID- 21280944 TI - Relations among occupational hazards, attitudes, and safety performance. AB - This study examined psychological empowerment and organizational identification as outcomes of occupational context and predictors of occupational safety performance. In this study, 171 hospital employees from 17 units and 21 occupations completed surveys measuring psychological empowerment, organizational identification, and supervisor safety practices. They also completed measures of 2 dimensions of safety performance: use of personal protective equipment and safety participation. These data were merged with Occupational Information Network (O*NET) context ratings of occupational hazards and physical demands. Results indicated that occupational hazards were negatively related to individual level psychological empowerment and organizational identification, which were in turn positively related to safety participation. Psychological empowerment and organizational identification also interacted with perceptions of supervisor safety actions in the prediction of personal protective equipment use. Results have implications for organizational safety performance and point to the role of occupational context in psychological empowerment and the extent to which employees participate in the safety of their worksite. PMID- 21280945 TI - The "is" and the "ought": How do perceived social norms influence safety behaviors at work? AB - Despite a widespread view that social norms have an important contextual influence on health attitudes and behaviors, the impact of normative influences on safety behaviors has received very little attention. The current study proposes that supervisors' and coworkers' descriptive and injunctive safety norms influence proactive and compliance safety behaviors. Longitudinal results from 132 workers in a passenger transportation company support the link between coworkers' descriptive safety norms (at Time 1) and proactive safety practices (at Time 2). Crystallization of supervisor' injunctive safety norms (at Time 2) moderated the effect of coworkers' descriptive safety norms (at Time 1) on self reported proactive safety behavior (at Time 2). These findings emphasize the differences between supervisors' and coworkers' descriptive and injunctive norms as sources of social influence on compliance and proactive safety behavior. PMID- 21280946 TI - I know what you did: The effects of interpersonal deviance on bystanders. AB - Using social information processing theory, we explore how interpersonally directed deviance affects work group members who observe or are aware of these insidious behaviors. In a field study, we find that indirect knowledge of work group member interpersonal deviance leads to subsequent interpersonal deviance of a focal individual. We also find that when work group cohesion is high, direct observation of deviance is more likely to result in subsequent bystander deviance. These findings add concretely to theory and research on the bystander effects of workplace deviance. PMID- 21280947 TI - Work and nonwork outcomes of workplace incivility: Does family support help? AB - This study extended incivility research beyond the confines of the workplace by exploring the relationships between incivility, work-to-family conflict and family support. Data collected from 180 employees from various organizations in Singapore showed that incivility is not a rare phenomenon in Asian cultures. Employees experienced more incivility from superiors than coworkers or subordinates, and these experiences were related to different outcomes. Coworker initiated incivility was associated with decreased coworker satisfaction, increased perceptions of unfair treatment, and increased depression. On the other hand, superior-initiated incivility was associated with decreased supervisor satisfaction and increased work-to-family conflict. Results also revealed that employees with high family support showed stronger relationships between workplace incivility and negative outcomes, compared with employees with low family support. PMID- 21280948 TI - Crossover of work engagement among Japanese couples: Perspective taking by both partners. AB - This study among 426 Japanese couples working in different occupational sectors tested the hypothesis that perspective taking moderates the crossover of work engagement. More specifically, we predicted that husbands' work engagement would cross over to their wives, particularly when wives scored high on perspective taking (the spontaneous tendency to adopt the psychological perspective of other people). A similar effect was predicted from wives to husbands. In addition, we hypothesized that the crossover effect would be most pronounced when both partners were high in perspective taking (i.e., a 3-way interaction effect). The results of moderated structural equation modeling analyses confirmed the moderating role of perspective taking, but only for women; women who took the perspective of their partner scored higher on engagement with increasing partner engagement. Moreover, the results showed that engagement crossover was strongest when both men and women were high (vs. low) in perspective taking. This 3-way interaction effect was found from husbands to wives, and vice versa. These findings expand the crossover literature by shedding light on the crossover process. PMID- 21280949 TI - Coping with work-family conflict: A leader-member exchange perspective. AB - Leader-member exchange (LMX) theory is applied as a framework for understanding coping with work-family conflict. The effectiveness of four work-family coping strategies (i.e., preventive and episodic forms of both problem-focused and emotion-focused coping) is considered with emphasis on how the LMX relationship contributes to each form of coping with work interference with family. The LMX based model of work-family coping accounts for the development of family-friendly work roles, use of organizational family-friendly policies, and the negotiation of flextime and flexplace accommodations. Constraints on the relationship between LMX and work-family coping associated with supervisor authority and resources and aspects of the organizational context are also discussed. Research and applied implications of the model are offered. PMID- 21280950 TI - Change in job strain and progression of atherosclerosis: The Cardiovascular Risk in Young Finns study. AB - Evidence of the association between job strain, that is, a combination of high psychological demands and low job control, and markers of atherosclerosis is mixed, but few studies with repeat measures are available. The purpose of this study was to examine cross-sectional and longitudinal associations between job strain and atherosclerosis. The participants were 335 men and 374 women from the prospective Cardiovascular Risk in Young Finns study (mean age 38.5 years). Two sequential measurements of job strain and carotid intima-media thickness (IMT) were analyzed. No cross-sectional or longitudinal association between job strain and IMT was observed in women. In men, a cross-sectional association was found in 2001, but not in 2007. No dose-response effect was visible, nor a simple association between progression of job strain and progression of IMT. Instead, a more complex pattern of correlation was found in men with large decreases in job strain being associated with slower progression of IMT and combined decreases in job control and demands (a change toward passive jobs) being associated with greater IMT progression. These data suggest that temporal changes in job demands and control are associated with IMT in men via multiple mechanisms. PMID- 21280951 TI - Emotion perception explains age-related differences in the perception of social gaffes. AB - Young (<36 years) and older (>59) adults viewed videos in which the same individual committed a faux pas, or acted appropriately, toward his coworkers. Older participants did not discriminate appropriate and inappropriate behaviors as well as young participants. Older participants also scored lower than young participants on an extensive battery of emotion recognition tests, and emotion performance fully mediated age differences in faux pas discrimination. The results provide further evidence for the role of emotion perception in a range of important social deficits. PMID- 21280952 TI - The PANAS structure revisited: on the validity of a bifactor model in community and forensic samples. AB - The Positive and Negative Affect Schedule (PANAS) is a widely used inventory for the assessment of affect in psychology and other applied sciences. Despite its popularity, the structure of the PANAS is still under debate. On the one hand, there is evidence of the traditional 2-factor model with Positive Affect (PA) and Negative Affect (NA) as uncorrelated factors. On the other hand, a more complex structure of the PANAS has been discussed. To shed further light on the core dimensions of the PANAS, 2 studies investigated the structure of the PANAS in 2 German samples (N = 354 and N = 364, respectively) by means of confirmatory factor analysis. The factor analysis results of Study 1 for a traitlike time frame instruction suggested a suboptimal model fit for the uncorrelated 2-factor model and the 3-factor model with PA, Afraid, and Upset as factors, whereas a superior model fit occurred for a bifactor model with traitlike PA, NA, and a general 3rd factor named Affective Polarity. In Study 2, the bifactor model was replicated for a statelike PANAS time frame instruction and evidence of criterion validity was provided for PA, NA, and Affective Polarity factors in 2 sex offender subgroups and in a community sample. With Affective Polarity, we introduce an affect dimension that captures additional variance beyond PA and NA. Because of the adjectives with relevant loadings on Affective Polarity, this general factor represents an individual's orientation toward approach and withdrawal, respectively. PMID- 21280953 TI - The Relationship Quality Interview: evidence of reliability, convergent and divergent validity, and incremental utility. AB - Relationship satisfaction and adjustment have been the target outcome variables for almost all couple research and therapies. In contrast, far less attention has been paid to the assessment of relationship quality. The present study introduces the Relationship Quality Interview (RQI), a semistructured, behaviorally anchored individual interview. The RQI was designed to provide a more objective assessment of relationship quality as a dynamic, dyadic construct across 5 dimensions: (a) quality of emotional intimacy in the relationship, (b) quality of the couple's sexual relationship, (c) quality of support transactions in the relationship, (d) quality of the couple's ability to share power in the relationship, and (e) quality of conflict/problem-solving interactions in the relationship. Psychometric properties of RQI ratings were examined through scores obtained from self-report questionnaires and behavioral observation data collected cross sectionally from a sample of 91 dating participants and longitudinally from a sample of 101 married couples. RQI ratings demonstrated strong reliability (internal consistency, interrater agreement, interpartner agreement, and correlations among scales), convergent validity (correlations between RQI scale ratings and questionnaire scores assessing similar domains of relationship quality), and divergent validity (correlations between RQI scale ratings and (a) behavioral observation codes assessing related constructs, (b) global relationship satisfaction scores, and (c) scores on individual difference measures of related constructs). Clinical implications of the RQI for improving couple assessment and interventions are discussed. PMID- 21280954 TI - The Perceived Stress Reactivity Scale: measurement invariance, stability, and validity in three countries. AB - There is accumulating evidence that individual differences in stress reactivity contribute to the risk for stress-related disease. However, the assessment of stress reactivity remains challenging, and there is a relative lack of questionnaires reliably assessing this construct. We here present the Perceived Stress Reactivity Scale (PSRS), a 23-item questionnaire with 5 subscales and 1 overall scale, based on an existing German-language instrument. Perceived stress reactivity and related constructs were assessed in N = 2,040 participants from the United Kingdom, the United States, and Germany. The 5-factor structure of the PSRS was found to be similar in the 3 countries. In the U.S. sample the questionnaire was applied using 2 modes of administration (paper-pencil and computerized), and measures were repeated after 4 weeks. Measurement invariance analyses demonstrated full invariance across mode of administration and partial invariance across gender and countries. Scale scores differed between countries and genders, with women scoring higher on most scales. Overall, reliability analysis suggested good stability of PSRS scores over a 4-week period, and validation analysis showed expected associations with related constructs such as self-efficacy, neuroticism, chronic stress, and perceived stress. Perceived stress reactivity was also associated with depressive symptoms and sleep. These associations were particularly strong when individuals scoring high on perceived stress reactivity were exposed to chronic stress. In sum, our findings suggest that the PSRS is a useful and easy-to-administer instrument to assess perceived stress reactivity. PMID- 21280955 TI - Is risky sexual behavior continuous or categorical? A taxometric analysis of the Sexual Risk Survey. AB - Risky sexual behaviors are behaviors that involve the possibility of an adverse outcome, such as contracting a sexually transmitted infection or unwanted pregnancy. The question of whether risky sexual behavior exists as a discrete class (i.e., taxon) or as a dimensional construct has not previously been explored. The authors performed a set of taxometric analyses on 4 factor scales derived from the Sexual Risk Survey (Turchik & Garske, 2009) with data from 1,103 college students. The results provided consistent support for a dimensional latent structure in which variations in reported risky sexual behavior reflect differences in degree and not differences in kind. The implications of these findings for the assessment of risky sexual behavior are discussed. PMID- 21280956 TI - Involuntary subordination and its relation to personality, mood, and submissive behavior. AB - According to social rank theory, involuntary subordination may be adaptive in species that compete for resources as a mechanism to switch off fighting behaviors when loss is imminent (thus saving an organism from injury). In humans, major depression is thought to occur when involuntary subordination becomes prolonged. The present study sought to operationalize involuntary subordination. Study 1 involved a reanalysis of a Gilbert and Allan (1998) study, with the hypothesis that social comparison (i.e., perceived status), submissive behavior, feelings of defeat, and entrapment would load on a common factor (interpreted as involuntary subordination). Exploratory and confirmatory factor analysis supported this model. In Study 2 measures of these same variables were administered to a group of undergraduate students. Eight items were selected from each measure (on the basis of item-total correlations) to form the Involuntary Subordination Questionnaire (ISQ). In Study 3 scores on the ISQ showed high levels of internal consistency and test-retest reliability in a sample of undergraduate students. Scores on the ISQ were significantly positively correlated with various neurotic personality styles and negatively correlated with variables indicating dominance or mastery. Involuntary subordination scores also significantly predicted change in social anxiety symptoms over 9 weeks. In Study 4 scores on the ISQ were examined in relation to nonverbal behaviors. In men, the ISQ was correlated with behaviors indicating a lack of confidence and submissiveness. Involuntary subordination appears to be a relatively stable trait with implications for personality, mood, and real-world behavior. PMID- 21280957 TI - An evaluation of the Brief Symptom Inventory-18 using item response theory: which items are most strongly related to psychological distress? AB - The psychometric structure of the Brief Symptom Inventory-18 (BSI-18; Derogatis, 2001) was investigated using Mokken scaling and parametric item response theory. Data of 487 outpatients, 266 students, and 207 prisoners were analyzed. Results of the Mokken analysis indicated that the BSI-18 formed a strong Mokken scale for outpatients and prisoners, indicating strong unidimensionality. For students, only the depression and anxiety items formed a medium Mokken scale. Parametric item response theory analyses showed that the best discriminating items came from the depression and anxiety subscales. PMID- 21280958 TI - Comparing factor structures of adolescent psychopathology. AB - Research on the structure of adolescent psychopathology can provide information on broad factors that underlie different forms of maladjustment in youths. Multiple studies from the literature on adult populations suggest that 2 factors, Internalizing and Externalizing, meaningfully comprise the factor structure of adult psychopathology (e.g., Krueger, 1999) and presumably represent broad vulnerability for co-occurring disorders. Though this research was partially inspired by early work with children and adolescents (e.g., Achenbach & Edelbrock, 1984), the role of substance use in these models of youth psychopathology has not been fully explored. Toward this goal, we recruited 223 youths (10-17 years of age, M = 14.2) from mental health agencies and the community. We found evidence for a 3-factor model of youth psychopathology, including Internalizing (depression, generalized anxiety), Externalizing (conduct disorder, attention deficit, oppositional defiant disorder), and Substance Use (alcohol and cannabis). The 3-factor model showed the best fit to the data relative to other factor models tested, including across subsamples of adolescents who differed on level of psychopathology (treatment vs. community samples). Implications for the structure of adolescent psychopathology, including important developmental considerations, are discussed. PMID- 21280959 TI - Virtual social environments as a tool for psychological assessment: dynamics of interaction with a virtual spouse. AB - Computer games are advocated as a promising tool bridging the gap between the controllability of a lab experiment and the mundane realism of a field experiment. At the same time, many authors stress the importance of observing real behavior instead of asking participants about possible or intended behaviors. In this article, the authors introduce an online virtual social environment, which is inhabited by autonomous agents including the virtual spouse of the participant. Participants can freely explore the virtual world and interact with any other inhabitant, allowing the expression of spontaneous and unprompted behavior. The authors investigated the usefulness of this game for the assessment of interactions with a virtual spouse and their relations to intimacy and autonomy motivation as well as relationship satisfaction with the real-life partner. Both the intimacy motive and the satisfaction with the real-world relationship showed significant correlations with aggregated in-game behavior, which shows that some sort of transference between the real world and the virtual world took place. In addition, a process analysis of interaction quality revealed that relationship satisfaction and intimacy motive had different effects on the initial status and the time course of the interaction quality. Implications for psychological assessment using virtual social environments are discussed. PMID- 21280960 TI - Test-taking behaviors in a neurocognitive assessment: associations with school age outcomes in a Finnish longitudinal follow-up. AB - Test-taking behaviors (i.e., task focus, maintenance of attention, and cooperation) affect children's cognitive test performance, and, thus, it is critical to take test-taking behavior into account when drawing conclusions and making recommendations. Prior studies have evaluated test-taking behaviors at the end of the assessment; the present study focused on the fluctuation of cooperation and attention during a neuropsychological assessment. We examined the attention and cooperation of 5-year-old children in a test-taking situation; the associations between these aspects of their test-taking behavior and the children's concurrent neurocognitive test performance, IQ, and parent-rated behavior; and the associations with their IQ, behavioral outcomes, and academic achievement at 8 years of age. The data (for 76 boys and 63 girls) were drawn from the Jyvaskyla Longitudinal Study of Dyslexia (Lyytinen et al., 2001, 2004). All the children were Caucasian and spoke Finnish as their native language. As a whole, the 5-year-old children showed high cooperation and attention, but a slight decrement in test-taking behavior toward the end of the session was rather common. Three subgroups of children with different levels of cooperation and attention were identified. Children in the subgroup with nonoptimal attention and cooperation showed decreasing neurocognitive test performance toward the end of the assessment session. They also showed more inattentive behavior 3 years later. The findings imply that the examiner's observations of waning attention and cooperation during the assessment session are highly relevant, as these provide stable and clinically meaningful information about the child's behavioral tendencies. PMID- 21280961 TI - Feeling the future: experimental evidence for anomalous retroactive influences on cognition and affect. AB - The term psi denotes anomalous processes of information or energy transfer that are currently unexplained in terms of known physical or biological mechanisms. Two variants of psi are precognition (conscious cognitive awareness) and premonition (affective apprehension) of a future event that could not otherwise be anticipated through any known inferential process. Precognition and premonition are themselves special cases of a more general phenomenon: the anomalous retroactive influence of some future event on an individual's current responses, whether those responses are conscious or nonconscious, cognitive or affective. This article reports 9 experiments, involving more than 1,000 participants, that test for retroactive influence by "time-reversing" well established psychological effects so that the individual's responses are obtained before the putatively causal stimulus events occur. Data are presented for 4 time reversed effects: precognitive approach to erotic stimuli and precognitive avoidance of negative stimuli; retroactive priming; retroactive habituation; and retroactive facilitation of recall. The mean effect size (d) in psi performance across all 9 experiments was 0.22, and all but one of the experiments yielded statistically significant results. The individual-difference variable of stimulus seeking, a component of extraversion, was significantly correlated with psi performance in 5 of the experiments, with participants who scored above the midpoint on a scale of stimulus seeking achieving a mean effect size of 0.43. Skepticism about psi, issues of replication, and theories of psi are also discussed. PMID- 21280962 TI - Don't hide your happiness! Positive emotion dissociation, social connectedness, and psychological functioning. AB - It is now clear that positive emotion leads to enhanced psychological functioning. What is less clear, however, is just why this is so. Drawing on a social-functional perspective, we argue that positive emotional behavior that accurately signals to others the individual's internal state will enhance social connectedness. Positive emotional behavior that does not accurately signal a person's experience--such as a smile that is not felt--may impede social connectedness and, in turn, psychological functioning. This perspective suggests that (a) the degree to which experience and behavior are dissociated during positive emotional episodes, over and above level of positive behavior, should predict worse psychological functioning and (b) the effect of dissociation should be mediated by social connectedness. To test these hypotheses, we conducted a short-term prospective longitudinal study, with a baseline assessment of depressive symptoms and well-being at Time 1. Six months later, at Time 2, we used a novel within-individual laboratory paradigm to measure the degree to which positive emotional behavior was dissociated from (vs. coherent with) a participant's positive emotional experience. We also assessed level of positive behavior and experience. Then, another 6 months later, we assessed social connectedness as a mediator and depressive symptoms and well-being as outcomes at Time 3. Even when controlling for baseline functioning and for level of positive emotion behavior and experience, we found that greater positive experience behavior dissociation at Time 2 predicted higher levels of depressive symptoms and lower levels of well-being at Time 3. As predicted, these associations were mediated by social connectedness. PMID- 21280963 TI - The moral emotions: a social-functionalist account of anger, disgust, and contempt. AB - Recent research has highlighted the important role of emotion in moral judgment and decision making (Greene, Sommerville, Nystrom, Darley, & Cohen, 2001; Haidt, 2001). What is less clear is whether distinctions should be drawn among specific moral emotions. Although some have argued for differences among anger, disgust, and contempt (Rozin, Lowery, Imada, & Haidt, 1999), others have suggested that these terms may describe a single undifferentiated emotional response to morally offensive behavior (Nabi, 2002). In this article, we take a social-functionalist perspective, which makes the prediction that these emotions should be differentiable both in antecedent appraisals and in consequent actions and judgments. Studies 1-3 tested and found support for our predictions concerning distinctions among antecedent appraisals, including (a) a more general role for disgust than has been previously been described, (b) an effect of self-relevance on anger but not other emotions, and (c) a role for contempt in judging incompetent actions. Studies 4 and 5 tested and found support for our specific predictions concerning functional outcomes, providing evidence that these emotions are associated with different consequences. Taken together, these studies support a social-functionalist account of anger, disgust, and contempt and lay the foundation for future research on the negative interpersonal emotions. PMID- 21280964 TI - Self-compassion and relationship maintenance: the moderating roles of conscientiousness and gender. AB - Should intimates respond to their interpersonal mistakes with self-criticism or with self-compassion? Although it is reasonable to expect self-compassion to benefit relationships by promoting self-esteem, it is also reasonable to expect self-compassion to hurt relationships by removing intimates' motivation to correct their interpersonal mistakes. Two correlational studies, 1 experiment, and 1 longitudinal study demonstrated that whether self-compassion helps or hurts relationships depends on the presence versus absence of dispositional sources of the motivation to correct interpersonal mistakes. Among men, the implications of self-compassion were moderated by conscientiousness. Among men high in conscientiousness, self-compassion was associated with greater motivation to correct interpersonal mistakes (Studies 1 and 3), observations of more constructive problem-solving behaviors (Study 2), reports of more accommodation (Study 3), and fewer declines in marital satisfaction that were mediated by decreases in interpersonal problem severity (Study 4); among men low in conscientiousness, self-compassion was associated with these outcomes in the opposite direction. Among women, in contrast, likely because women are inherently more motivated than men to preserve their relationships for cultural and/or biological reasons, self-compassion was never harmful to the relationship. Instead, women's self-compassion was positively associated with the motivation to correct their interpersonal mistakes (Study 1) and changes in relationship satisfaction (Study 4), regardless of conscientiousness. Accordingly, theoretical descriptions of the implications of self-promoting thoughts for relationships may be most complete to the extent that they consider the presence versus absence of other sources of the motivation to correct interpersonal mistakes. PMID- 21280965 TI - Why psychologists must change the way they analyze their data: the case of psi: comment on Bem (2011). AB - Does psi exist? D. J. Bem (2011) conducted 9 studies with over 1,000 participants in an attempt to demonstrate that future events retroactively affect people's responses. Here we discuss several limitations of Bem's experiments on psi; in particular, we show that the data analysis was partly exploratory and that one sided p values may overstate the statistical evidence against the null hypothesis. We reanalyze Bem's data with a default Bayesian t test and show that the evidence for psi is weak to nonexistent. We argue that in order to convince a skeptical audience of a controversial claim, one needs to conduct strictly confirmatory studies and analyze the results with statistical tests that are conservative rather than liberal. We conclude that Bem's p values do not indicate evidence in favor of precognition; instead, they indicate that experimental psychologists need to change the way they conduct their experiments and analyze their data. PMID- 21280966 TI - The evolution of intergroup bias: perceptions and attitudes in rhesus macaques. AB - Social psychologists have learned a great deal about the nature of intergroup conflict and the attitudinal and cognitive processes that enable it. Less is known about where these processes come from in the first place. In particular, do our strategies for dealing with other groups emerge in the absence of human specific experiences? One profitable way to answer this question has involved administering tests that are conceptual equivalents of those used with adult humans in other species, thereby exploring the continuity or discontinuity of psychological processes. We examined intergroup preferences in a nonhuman species, the rhesus macaque (Macaca mulatta). We found the first evidence that a nonhuman species automatically distinguishes the faces of members of its own social group from those in other groups and displays greater vigilance toward outgroup members (Experiments 1-3). In addition, we observed that macaques spontaneously associate novel objects with specific social groups and display greater vigilance to objects associated with outgroup members (Experiments 4-5). Finally, we developed a looking time procedure-the Looking Time Implicit Association Test, which resembles the Implicit Association Test (Greenwald & Banaji, 1995)-and we discovered that macaques, like humans, automatically evaluate ingroup members positively and outgroup members negatively (Experiments 6-7). These field studies represent the first controlled experiments to examine the presence of intergroup attitudes in a nonhuman species. As such, these studies suggest that the architecture of the mind that enables the formation of these biases may be rooted in phylogenetically ancient mechanisms. PMID- 21280967 TI - A two-process view of Facebook use and relatedness need-satisfaction: disconnection drives use, and connection rewards it. AB - Does using Facebook help people to meet their relatedness needs? Study 1 shows that more frequent Facebook usage paradoxically correlates with more relatedness satisfaction (connection) and more relatedness dissatisfaction (disconnection). Study 2 supports a 2-process explanation of this finding, showing that disconnection motivates greater usage as a coping strategy, whereas connection results from greater usage. Study 3 examines the effects of depriving participants of Facebook use for 48 hr. Further supporting the 2-process view, connection decreased, but disconnection was unaffected during the deprivation period; however, those who became more disconnected during the deprivation period engaged in more Facebook use during a 2nd, unconstrained 48-hr period, whereas changes in connection did not predict later use. In Study 4, participants set a Facebook reduction goal; initial disconnection interfered with and predicted worse performance in this goal. Implications for theories of psychological needs, behavioral motives, and adaptive coping are considered. PMID- 21280968 TI - Middle class and marginal? Socioeconomic status, stigma, and self-regulation at an elite university. AB - In four studies, the authors investigated the proposal that in the context of an elite university, individuals from relatively lower socioeconomic status (SES) backgrounds possess a stigmatized identity and, as such, experience (a) concerns regarding their academic fit and (b) self-regulatory depletion as a result of managing these concerns. Study 1, a correlational study, revealed the predicted associations between SES, concerns about academic fit, and self-regulatory strength. Results from Studies 2 and 3 suggested that self-presentation involving the academic domain is depleting for lower (but not higher) SES students: After a self-presentation task about academic achievement, lower SES students consumed more candy (Study 2) and exhibited poorer Stroop performance (Study 3) relative to their higher SES peers; in contrast, the groups did not differ after discussing a nonacademic topic (Study 3). Study 4 revealed the potential for eliminating the SES group difference in depletion via a social comparison manipulation. Taken together, these studies support the hypothesis that managing concerns about marginality can have deleterious consequences for self-regulatory resources. PMID- 21280969 TI - Editorial comment. PMID- 21280970 TI - Enantiomorphy through the looking glass: literacy effects on mirror-image discrimination. AB - To examine whether enantiomorphy (i.e., the ability to discriminate lateral mirror images) is influenced by the acquisition of a written system that incorporates mirrored letters (e.g., b and d), unschooled illiterate adults were compared with people reading the Latin alphabet, namely, both schooled literate adults and unschooled adults alphabetized in adulthood. In various sorting and same-different comparison tasks with nonlinguistic materials, illiterate participants displayed some sensitivity to enantiomorphic contrasts but performed far worse than all the other participant groups when the task required paying attention to such contrasts. The difficulties of illiterate participants were more severe with enantiomorphs than with rotations in the plane or shape contrasts. Learning a written system that incorporates enantiomorphic letters thus pushes the beginning reader to break the mirror invariance characteristic of the visual system, and this process generalizes beyond the realm of symbolic characters. PMID- 21280971 TI - Creating a sustainable and effective mental health workforce for Gippsland, Victoria: solutions and directions for strategic planning. AB - INTRODUCTION: The Gippsland region of Victoria, in common with other Australian rural and regional areas, is experiencing a shortage of qualified mental health professionals. Attracting mental health professionals to work in such areas is a major concern for service providers, policy-makers and rural/regional communities. Previous studies have focused on identifying factors contributing to the maldistribution of the health workforce, principally medical practitioners. Recent reviews have highlighted the strengths and weaknesses of evidence for the effectiveness of initiatives designed to address workforce shortages in underserved locations. The reported study sought the views of mental health organisation leaders from Gippsland to identify current approaches and potential solutions to the challenges of workforce recruitment, retention and training. A key goal of the study was to inform a strategic regional approach to the development of a more sustainable and effective mental health workforce. METHODS: Investigators conducted semi-structured individual interviews with 26 administrators, managers and senior clinicians from public and private sector mental health organisations throughout Gippsland. Thematic content analysis of the transcribed interviews identified current approaches and potential solutions to the recruiting, retaining and training problems in the region. RESULTS: The study categorised solutions as focusing on factors external or internal to organisations. Solutions external to organisations included efforts to enhance the pool of available workers, improve intra-sectoral collaboration and cross sectoral linkages, make funding more flexible, and to institute a contemporary curriculum and take innovative pedagogical approaches to training. Internal solutions included the need for strong leadership and quality organisational culture, flexible and adaptable approaches to meeting individual worker and community needs, promoting the organisation and local area and adopting models of care. Informants indicated that individual organisations are limited in their capacity to address recruitment, retention and training issues and highlighted the potential benefits of a regional mental health workforce recruitment, retention and training strategy. CONCLUSION: This study provides a unique insight into the creative approaches adopted by managers in Gippsland to recruit and retain mental health workers. It brings a new perspective to the literature due to the reflections of managers, grounded as they are in day-to-day work. PMID- 21280972 TI - Receipt of preventive counseling among reproductive-aged women in rural and urban communities. AB - INTRODUCTION: Preventive health interventions often occur less frequently among rural women compared to urban women. Preventive counseling is an important feature of comprehensive preventive healthcare provision, but geographic disparities in the receipt of preventive counseling services have not been fully described. In this study the framework of the behavioral model of healthcare utilization was employed to investigate the association between rurality and receiving preventive counseling. It was hypothesized that demographic differences in rural and urban communities, as well as differential healthcare resources, explain rural-urban healthcare disparities in preventive counseling. METHODS: Data were collected by telephone survey during 2004-2005 for 2002 participants aged 18-45 years in the Central Pennsylvania Women's Health Study. Measures of preventive counseling were based on US Preventive Services Task Force recommendations as of 2004. Multivariable models assessed the independent contribution of rurality to the receipt of counseling for smoking, alcohol/drug use, birth control, nutrition, weight management, and physical activity. Rurality was assessed using Rural-Urban Community Area Codes. All models controlled for variables that predispose individuals to use health services (age, race/ethnicity, educational level), variables that enable or impede healthcare access (having a usual healthcare provider, using an obstetrician-gynecologist, poverty, and continuous health insurance coverage) and need-based variables (health behaviors and indicators). RESULTS: In bivariate analysis, the rural population was older, had lower educational attainment, and was more likely to be White, non-Hispanic. Urban women tended to report seeing an obstetrician gynecologist more frequently, and engaged more frequently in binge drinking/drug use. Preventive counseling was low among both rural and urban women, and ranged from 12% of the population for alcohol/drug use counseling, to 37% for diet or nutrition counseling. The degree of rurality appeared to impact counseling, with women in small or isolated rural areas significantly less likely than urban women and women in large rural areas to receive counseling related to smoking, alcohol/drug use and birth control. Overall, rural women reported less counseling for alcohol/drug use, smoking, birth control, nutrition and physical activity. In multivariable analysis, rurality was independently associated with lack of preventive counseling for physical activity. However, adjusting for predisposing, enabling and need-based variables fully attenuated the effect of rurality in the remaining models. Younger age, higher educational attainment, and seeing any obstetrician-gynecologist were associated with receipt of counseling in several models. CONCLUSIONS: Most women do not receive recommended preventive counseling. While rural women are less likely than urban women to receive counseling, rurality generally was not independently associated with receipt of counseling once demographics, access to health care, and health behaviors and indicators were controlled. This suggests that both demographic differences between rural and urban communities as well as aspects of healthcare access govern rural-urban healthcare disparities in preventive counseling. These results speak to important targets for reducing urban-rural healthcare disparities in receiving preventive counseling, improving the health literacy of the rural population, educating rural healthcare providers about the need for preventive counseling, and the expansion of access to obstetrician-gynecologists in rural communities. PMID- 21280973 TI - Colorectal cancer screening among rural Appalachian residents with multiple morbidities. AB - INTRODUCTION: Colorectal cancer is the second leading cause of cancer deaths in the USA. Although early detection through screening has been shown to be effective in preventing colorectal cancer mortality, adherence to screening guidelines remains low. Among certain populations--namely those with lower socioeconomic status, a greater number of chronic conditions or multiple morbidity, and those living in rural locations-- colorectal cancer screening is particularly underused. This study explored the prevalence of such screening and explanations for how multiple chronic conditions might affect colorectal cancer screening among an especially vulnerable group of middle-aged and older adults. METHODS: In total, 41 participants were recruited aged 50-76 years with two or more chronic conditions, from three rural health clinics in Appalachian Kentucky, USA. Using semi-structured and structured questions and instruments, participants engaged in two interviews. RESULTS: Study results demonstrate colorectal cancer screening rates lower than state and national averages. In addition to commonly expressed barriers including unpleasant screening modality, lack of health insurance, and shortage of gastroenterologists to perform colonoscopy, participants described the ways in which multiple morbidities undermine screening. Barriers specific to multiple morbidity include competing demands from other conditions, such as financial pressures, physical limitations, and worries over regimen interference. CONCLUSION: The window of opportunity left open by more frequent visits to health care professionals should be used to patients' advantage, especially as people with multiple morbidity are living longer with their chronic conditions. Efforts must accelerate to establish clinical guidelines and practices incorporating both management of existing conditions and the prevention of additional future morbidity. PMID- 21280974 TI - Town-level comparisons may be an effective alternative in comparing rural and urban differences: a look at accidental traumatic brain injuries in North Texas children. AB - INTRODUCTION: Rural areas in the USA are generally poorer, more isolated, less populated, have older populations, and also unique work dynamics that fundamentally set them apart from urban areas. Additionally, funding and resources are limited in rural areas; a problem that may be exacerbated when looking specifically at town-level resources. One of the key problems in comparing US rural and urban areas, particularly at the county level, is that the resources available to individual towns within a particular county may not accurately reflect the resources available to the county as a whole. This leads to questions about the validity of county-level comparisons between rural and urban areas because of differences in town sizes and the resources availability at this level. The authors of this study attempted to assess this difference by analyzing data previously collected for a study examining pediatric traumatic brain injury among four levels of rurality: urban city, large town, small town, and isolated town. METHODS: This study employed Rural and Urban Commuting Area 2 (RUCA2) codes to determine if significant differences exist between small and large towns for pediatric traumatic brain injury. Patients were included in this study if they presented to Children's Medical Center Dallas with severe traumatic brain injury, and comparisons of injury severity and outcome were compared between small and large towns. Patient zip (postal) codes were collected and designated as either small or large town based on the corresponding RUCA2 code. RESULTS: A total of 444 patients were included in this study, with significant differences between large and small towns for Trauma Scores, Trauma Score and Injury Severity Score (TRISS) measures, and the total length of stay. CONCLUSION: This study has numerous limitations, yet it demonstrates that comparisons based on the RUCA code designations of large and small towns can be an effective means for understanding the differences at the town level, and also to better establish prevention strategies geared toward these differences. PMID- 21280975 TI - Effects of polysaccharides of the Euphoria Longan (Lour.) Steud on focal cerebral ischemia/reperfusion injury and its underlying mechanism. AB - OBJECTIVE: To investigate the effects of polysaccharides of the Euphoria Longan (Lour.) Steud on focal cerebral ischemia/reperfusion(I/R) injury in rats. METHODS: In this study, spectrophotometry was employed to observe the effects of polysaccharides of the Euphoria Longan (Lour.) Steud on [Formula: see text] and ?OH in?vitro. The operation was performed to induce the middle cerebral artery occlusion (MCAO) in rats. The influences of polysaccharides on the neurological function score, the brain water content, the infarct volume, activities of superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GSH-Px) and myeloperoxidase (MPO), the contents of malondialdehyde (MDA), the protein levels of Bcl-2 and Bax, the concentration of tumour necrosis factor-? (TNF-?) and interleukin-1? (IL-?) in brain tissue were measured. RESULTS: Compared with the I/R group, polysaccharides of the Euphoria Longan (Lour.) Steud could obviously reduce the neurological score, the infract volume, the brain water content, MDA content, MPO activity, TNF-? and IL-1? level, expression of Bax, and increase SOD, GSH, GSH-Px activity and expression of Bcl-2. CONCLUSION: The data suggest that polysaccharides of the Euphoria Longan (Lour.) Steud are capable of alleviating I/R injury by a mechanism that may involve decreasing oxidative stress. PMID- 21280976 TI - Sulphoraphane enhances aquaporin-4 expression and decreases spinal cord oedema following spinal cord injury. AB - BACKGROUND: Aquaporin-4 (AQP4) is a water channel protein and it is an important determinant of outcome after brain injury. Sulphoraphane (SFN) increases AQP4 levels with reduction of brain oedema at 3 days post-traumatic brain injury. However, little is known about the effect of SFN on AQP4 expression and oedema after spinal cord injury (SCI). METHODS AND PROCEDURES: The present study used a murine SCI model induced by compression injury. AQP4 protein level and mRNA level were detected by Western blot and by RT-PCR at 48 hours after SCI, respectively. In addition, immunohistochemical study was used to show AQP4 expression in the spinal cord segments and water content of the spinal cord segments were measured by wet?:?dry weight ratio. MAIN OUTCOMES AND RESULTS: This study shows that AQP4 level was decreased in the injured spinal cord segments at 48 hours following SCI. Post-injury administration of SFN increased AQP4 levels, which was accompanied by a significant reduction in spinal cord segment oedema at 48 hours post-injury. CONCLUSION: These findings suggest that the reduction of spinal cord oedema in response to SFN administration could be due, in part, to water clearance by AQP4 from the injured spinal cord segments. PMID- 21280977 TI - Evaluating the contribution of a neural component of ankle joint resistive torque in patients with stroke using a manual device. AB - PRIMARY OBJECTIVE: To investigate the methodology using a manual ankle joint resistive torque measurement device to evaluate the contribution of the neural component of ankle joint resistive torque in patients with stroke. RESEARCH DESIGN: Within-subject comparison to compare the ankle joint resistive torque between fast and slow stretching conditions. METHODS AND PROCEDURES: Ten patients with stroke participated in this study. The incremental ratio of ankle joint resistive torque at the ankle angular position of 5degrees dorsiflexion under the fast stretching condition in comparison to the slow one was calculated in each patient. MAIN OUTCOMES AND RESULTS: A significant increase (p<0.01) in the ankle joint resistive torque was demonstrated under the fast stretching condition in comparison to the slow one in all patients and the mean ankle joint resistive torque was 4.6 (SD=1.7) Nm under the slow stretching condition, while it was 8.4 (SD=4.1) Nm under the fast stretching condition at the ankle angular position of 5 degrees dorsiflexion. The incremental ratio ranged from 9.4-139.3% among the patients. CONCLUSIONS: The results of this study demonstrated the potential advantage of the device to evaluate the contribution of the neural component of ankle joint resistive torque. PMID- 21280978 TI - Post-traumatic stress symptoms in relatives in the first weeks after severe traumatic brain injury. AB - INTRODUCTION: Severe traumatic brain injury (STBI) can cause psychological stress in proxies in the long-term. This study assessed post-traumatic stress (PTS) symptoms in proxies of survivors of STBI in the short-term and investigated stress-associated factors. METHODS: Prospective cross-sectional study, conducted at three Swiss trauma centres over 1 year. Patient and proxy demographics, trauma data including Glasgow Coma Scale (GCS) and management data were collected. The proxies' PTS symptoms were assessed by applying the Impact of Event Scale-Revised (IES-R), once in the first month after the accident (median: 11 days). RESULTS: Sixty-nine proxies were included; 52 proxies were female (77.8%). Mean IES-R sum score for intrusions was 13.38 (SD=7.26), for avoidance 8.91 (SD=5.94), and for hyperarousal 9.07 (SD=6.75). Clinically significant PTS symptoms were observed in 36 proxies (52.2%); mean IES-R sum scores were significantly higher in women. IES R sub-scale values were inversely related with GCS at the scene of the accident and on hospital admission. CONCLUSIONS: More than half of proxies had clinically significant PTS symptoms shortly after their relative's accident. More severe PTS symptoms were found in women and in proxies of patients with poorer initial GCS scores. Further research into risk groups in the short- and long-term and the long-term impact on patients of PTS syndrome in proxies is warranted. PMID- 21280979 TI - Outcomes of participation objective, participation subjective (POPS) measure following traumatic brain injury. AB - PRIMARY OBJECTIVE: To investigate the participation of adults living with traumatic brain injury in regional and rural NSW as measured by the Participation Objective Participation Subjective (POPS) measure. RESEARCH DESIGN: A quantitative survey of a single cohort as the first of a two phase mixed methods study. METHODS AND PROCEDURES: One hundred and thirty-one adults with a TBI were recruited through eight rural brain injury rehabilitation programmes in NSW. These adults completed a range of survey instruments, including the POPS. MAIN OUTCOMES AND RESULTS: The POPS measure supported findings from other research that identified varying impacts of TBI. However, in contrast to other studies, there was no correlation between participation scores and age, gender, time since injury and severity of injury. CONCLUSIONS: The findings from this study suggest that the issue of participation of adults with TBI living in non-metropolitan areas needs to be further researched. PMID- 21280981 TI - Efficacy of plasma TGF-beta1 level in predicting therapeutic efficacy and prognosis in patients with advanced non-small cell lung cancer. AB - We hypothesized that serial assessment of TGF-beta1 during chemotherapy might predict therapeutic response and prognosis in non-small cell lung cancer (NSCLC) patients. Plasma TGF-beta1 levels were quantified before first, second, and third cycles of chemotherapy in 42 advanced NSCLC patients and correlated with therapeutic response. Plasma TGF-beta1 levels measured before first and second cycles of chemotherapy failed to predict response to therapy. The increased presence of TGF-beta1 measured before second and third cycles of chemotherapy was associated with poor survival. Estimation of plasma TGF-beta1 during the course of chemotherapy might not be a reliable biomarker for predicting therapeutic efficacy in NSCLC. PMID- 21280982 TI - Human beta-defensin-1, -2, and -3 exhibit opposite effects on oral squamous cell carcinoma cell proliferation. AB - The objective of this study was to investigate the impact of human beta-defensins (hBDs) on oral squamous cell carcinoma (OSCC) proliferation and hBD expression in vitro. BHY-OSCC cell lines were stimulated with hBD-1, -2, and -3. Proliferation of BHY cells was ascertained and hBD-mRNA expression was evaluated by real-time PCR. Proliferation of BHY cells decreased by 25% in response to hBD-1 stimulation but increased after stimulation with hBD-2 and -3. HBD-1 stimulation enhanced hBD 3 expression, whereas HBD-2 stimulation decreased early hBD-3 expression. HBD-3 stimulation enhanced hBD-1 expression. HBDs profoundly impact on OSCC proliferation and hBD expression in vitro. Therefore, hBD-1 might function as a tumor suppressor gene in OSCCs, while hBD-2 and -3 might be protooncogenes. PMID- 21280983 TI - Autologous transplantation of lentivector/acid ceramidase-transduced hematopoietic cells in nonhuman primates. AB - Farber disease is a rare lysosomal storage disorder (LSD) that manifests due to acid ceramidase (AC) deficiencies and ceramide accumulation. We present a preclinical gene therapy study for Farber disease employing a lentiviral vector (LV-huAC/huCD25) in three enzymatically normal nonhuman primates. Autologous, mobilized peripheral blood (PB) cells were transduced and infused into fully myelo-ablated recipients with tracking for at least 1 year. Outcomes were assessed by measuring the AC specific activity, ceramide levels, vector persistence/integration, and safety parameters. We observed no hematological, biochemical, radiological, or pathological abnormalities. Hematological recovery occurred by approximately 3 weeks. Vector persistence was observed in PB and bone marrow (BM) cells by qualitative and quantitative PCR. We did not observe any clonal proliferation of PB and BM cells. Importantly, AC-specific activity was detected above normal levels in PB and BM cells analyzed post-transplantation and in spleens and livers at the endpoint of the study. Decreases of ceramide in PB cells as well as in spleen and liver tissues were seen. We expect that this study will provide a roadmap for implementation of clinical gene therapy protocols targeting hematopoietic cells for Farber disease and other LSDs. PMID- 21280984 TI - Management of placenta praevia and accreta. AB - With the rising incidence of caesarean sections, the numbers of cases of placenta praevia accreta and its complications is continuing to increase. There is a paucity of information about the management of placenta praevia accreta. An Embase and MEDLINE search was performed using the keywords 'placenta praevia', 'placenta accreta', and 'placenta praevia and accreta', from 1978 to 2010. Further articles were identified by cross-referencing. In addition to the above information from the Royal College of Obstetricians and Gynaecologists Guideline on placenta praevia and placenta praevia accreta, RCOG Guideline No. 27 and the Confidential Enquiry into Maternal Deaths in the UK were searched. The review discusses the incidence, predisposing factors, pathogenesis, diagnosis, clinical implications and management options of this condition. It is concluded that a multidisciplinary team approach is essential to reduce neonatal and maternal morbidity and mortality. The mainstay of treatment is by caesarean hysterectomy, however in carefully selected cases, conservative options may be considered with caution. PMID- 21280985 TI - Heterotopic pregnancy. AB - Heterotopic pregnancy is a life-threatening condition. A recent case at our institution prompted a systematic review of the literature from 2005 to 2010. In the majority (71%) of cases reviewed, risk factors for a heterotopic pregnancy were present. However, in several instances (33%), previous sonographic reports of a normal intrauterine pregnancy gave false reassurance. These results highlight the complexity of diagnosis. In addition, our findings were compared with two previous reviews covering cases from 1971 to 2004. This comparison highlighted two important trends: first, the increasing role of ultrasound in the definitive diagnosis of a heterotopic pregnancy, and second, the development of conservative approaches to management. Medical knowledge and technology may be improving, but ultimately, even in the presence of a known intrauterine pregnancy, the simple dictum 'think ectopic' must not be forgotten. PMID- 21280986 TI - Conservative management of young patients with endometrial highly-differentiated adenocarcinoma. AB - Endometrial cancer is uncommon in young women. However, almost 5% of patients are younger than 40 years old. Progestins such as medroxyprogesterone acetate (MPA) and megestrol acetate (MA), have been used as a fertility-sparing approach in this group of patients, with different dose regimens of cyclic (14 days every month) or continuous therapy successfully used. According to the present data, the overall response rate was 73% in a median time of 4 months (range 1-15 months). Endometrial biopsy every 3 months was the common approach to evaluate the patient's response during the treatment. The relapse rate was 36% in a median follow-up time of 22 months (range 6-73 months). Overall, 40% of patients who responded to the treatment successfully, conceived. Half of the patients used assisted reproductive technology to achieve an immediate pregnancy. Although, there are no definite recommendations concerning the conservative management of young patients with early stage endometrial cancer, progestin agents may be used in a selected group of patients for fertility-sparing reasons. After childbearing is completed, hysterectomy remains the standard treatment. PMID- 21280987 TI - Improving essential obstetric and newborn care in resource-poor countries. AB - Skilled birth attendance (SBA) and essential obstetric care (EOC) are key strategies for reducing maternal and newborn mortality and morbidity globally. Lack of adequately trained competent staff is a key barrier to achieving this. We assessed the effectiveness of a new package of 'Life Saving Skills - Essential Obstetric and Newborn Care Training' (LSS-EOC and NC) designed specifically around the UN signal functions in seven countries in sub-Saharan Africa. Among 600 healthcare providers (nurse-midwives, doctors, clinical officers and specialists), knowledge about the diagnosis and management of complications of pregnancy and childbirth as well as newborn care significantly increased (p < 0.001). There was measurable improvement in skills (p < 0.001), and participants expressed a high level of satisfaction with the training. The training package was found to meet the needs of healthcare providers, increased awareness of the need for evidence-based care and encouraged teamwork. PMID- 21280988 TI - Poor agreement between operators on grading of the placenta. AB - Abnormal placental grading is associated with poor pregnancy outcome. The aim of this study was to measure intra- and interobserver variability in placental grading. Five expert sonographers independently graded 90 images on two occasions, each viewing separated by 1 week. A number of measures were employed to standardise assessment and minimise potential for variation: prior agreement was established between observers on the classifications for placental grading; a controlled viewing laboratory was used for all viewings; ambient lighting was optimal and monitors were calibrated to the GSDF standard. Kappa (kappa) analysis was used to measure observer agreement. Substantial variations between individuals' scores were observed. A mean kappa-value of 0.34 (range from 0.19 to 0.50) indicated fair interobserver agreement over the two occasions and only nine of the 90 images were graded the same by all five observers. Intraobserver agreement had a moderate mean kappa-value of 0.52, with individual comparisons ranging from 0.45 to 0.66. This study demonstrates that, despite standardised viewing conditions, Grannum grading of the placenta is not a reliable technique even among expert observers. The need for new methods to assess placental health is required and work is ongoing to develop 2D and 3D software-based methods. PMID- 21280989 TI - The effect of late pregnancy consumption of date fruit on labour and delivery. AB - We set out to investigate the effect of date fruit (Phoenix dactylifera) consumption on labour parameters and delivery outcomes. Between 1 February 2007 and 31 January 2008 at Jordan University of Science and Technology, a prospective study was carried out on 69 women who consumed six date fruits per day for 4 weeks prior to their estimated date of delivery, compared with 45 women who consumed none. There was no significant difference in gestational age, age and parity between the two groups. The women who consumed date fruit had significantly higher mean cervical dilatation upon admission compared with the non-date fruit consumers (3.52 cm vs 2.02 cm, p < 0.0005), and a significantly higher proportion of intact membranes (83% vs 60%, p = 0.007). Spontaneous labour occurred in 96% of those who consumed dates, compared with 79% women in the non date fruit consumers (p = 0.024). Use of prostin/oxytocin was significantly lower in women who consumed dates (28%), compared with the non-date fruit consumers (47%) (p = 0.036). The mean latent phase of the first stage of labour was shorter in women who consumed date fruit compared with the non-date fruit consumers (510 min vs 906 min, p = 0.044). It is concluded that the consumption of date fruit in the last 4 weeks before labour significantly reduced the need for induction and augmentation of labour, and produced a more favourable, but non-significant, delivery outcome. The results warrant a randomised controlled trial. PMID- 21280990 TI - Comparison of two policies for induction of labour postdates. AB - The objective of this study was to compare maternal and midwifery manpower effects of policies for induction of labour (IOL) postdates, using a retrospective cohort design, in a level two maternity unit in a district hospital in South-West England. Primary outcome measures included mode of delivery, admission-delivery interval, midwifery manpower use. Group I consisted of 124 women who underwent IOL at 40+10. Group II were 104 women who underwent IOL at 42 weeks' gestation and 123 women who laboured spontaneously between 40+10 and 42 weeks' gestation. The nulliparous women had a shorter admission-delivery interval when induction was planned for 42 weeks, compared with 40+10 (p = 0.003), and required less frequent use of syntocinon (p = 0.04) and of continuous fetal monitoring (p = 0.02). The caesarean rate was higher in Group I than in Group II (p = 0.04) for nulliparous women only. The earlier induction policy was associated with a higher midwifery manpower requirement for nulliparae (p = 0.002). For parous women, the only difference was the greater use of oxytocin in labour. There was no difference between the groups in duration of labour, analgesia, Apgar scores, admission to neonatal care and meconium aspiration. In conclusion, delaying planned induction by three days was associated with lower medicalisation of labour and manpower needs for nulliparous women. PMID- 21280991 TI - The retained placenta: historical and geographical rate variations. AB - In this study, we sought to explore the variation in reported rates of retained placenta around the world and over time in the UK. A systematic review of observational studies was performed to obtain retained placenta rates from around the world and annual hospital reports from the Royal College of Obstetricians and Gynaecologists archives were examined to obtain historical retained placenta rates. The data show that the median rate of retained placenta at 30 minutes was higher in developed countries (2.67% vs 1.46%, p < 0.02), as was the median manual removal rate (2.24% vs 0.45%, p < 0.001). In addition to this, there appears to have been a rise in rate of manual removal in the UK from a mean of 0.66% in the 1920s to 2.34% in the 1980s (p < 0.0001). PMID- 21280992 TI - Apgar scores in assessing morbidity of the second neonate of cephalic/non cephalic twins in different delivery modes. AB - Our study was undertaken to determine whether caesarean section for the second of cephalic/non-cephalic presenting twins may prevent or diminish neonatal morbidity. For this study, 482 cephalic/non-cephalic presenting twins admitted to our hospital were retrospectively evaluated. They were separated into two groups according to their delivery mode: vaginal or caesarean delivery. Records of Apgar score (<7) at 5 min, seizure occurrence, neonatal intensive care unit (NICU) admission and duration, need for mechanical ventilation and perinatal mortality of second twins were compared. Second fetuses' mortality rates of the two groups were similar. NICU admission rate and duration, seizure and mechanical ventilation necessity rates of second fetuses were similar for both groups. Only 5 min Apgar score rates of the vaginal group were lower than the caesarean group. Caesarean section for cephalic/non-cephalic presenting twins does not decrease morbidity scores but provides effective improvement on morbidity of second fetus, according to Apgar scores. PMID- 21280993 TI - Maternal and perinatal outcomes of uterine rupture in the Kassala Hospital, east Sudan: 2006-2009. AB - Medical files of patients with ruptured uterus during 2006-2009 at the Kassala Hospital, east Sudan were reviewed. Of 13,569 deliveries, there were 28 cases of ruptured uterus (two per 1,000 deliveries). The majority of these patients had parity >=5 (53.5%), were illiterate (82.1%), rural residence (75%) and unbooked (92.8%). The identified causes of ruptured uterus were: obstructed labour (50%), previous caesarean section (32.1%). Caesarean hysterectomy was carried out in (39.3%), repair in (32.2%) and repair with tubal ligation in (28.5%). There was 14.3% and 92.8% maternal and perinatal mortality, respectively. A total of 21.4% and 7.14% developed sepsis and vesicovaginal fistulae, respectively. PMID- 21280994 TI - Attitudes and practice of gynaecologists towards abortion in Northern Ireland. AB - Women from Northern Ireland (NI) have to travel to Britain and pay for their terminations as the Abortion Act (1967) does not apply in that part of the UK. This paper analyses the attitudes of gynaecologists. A questionnaire was posted in 2009 to all NHS gynaecologists in NI (43). One had retired. After three mailings, 37 replied; a response rate of 88% (37.42). We found that of these, 21 (57%) favoured a liberalisation of the law in NI. If all the non-responders were against liberalisation, then still half (21/42) would be in favour. A total of 35% (13/37) wanted unrestricted access in the 1st trimester, a more liberal position than allowed by the current law in Great Britain. A total of 29 (78%) were in favour of free abortions for women from NI, as is largely the case in England and Wales. A total of 19 (51%) were in favour of the abortion charities being licensed to carry out legal abortions in Northern Ireland but 38% were opposed to this proposal. PMID- 21280995 TI - Comparison of diagnostic accuracy of saline infusion sonohysterography, transvaginal sonography and hysteroscopy. AB - We aimed to compare the accuracy of transvaginal sonography (TVS), saline infusion sonohysterography (SIS) and hysteroscopy (HS) for uterine pathologies among infertile women. A total of 346 patients were selected for operative hysteroscopy, following SIS after TVS. SIS was performed with a Cook Soft 500 IVF catheter. Sensitivity, specificity, positive and negative predictive values (PPV, NPV) were calculated to compare the accuracy of TVS, SIS and hysteroscopy for uterine abnormalities. SIS showed a sensitivity of 87%, specificity of 100% and PPV of 100% for endometrial hyperplasia, and a sensitivity and NPV of 100% for polypoid lesions. For submucosal myoma SIS showed a sensitivity of 99% with PPV of 96%. Hysteroscopy had a sensitivity, specificity, PPV and NPV of 98%, 83%, 96% and 91%, respectively for overall uterine pathologies. Finally, SIS seems to be superior to TVS, for uterine pathologies, with respect to hysteroscopy as the gold standard. PMID- 21280996 TI - Patient disclosure of the use of complementary and alternative medicine to their obstetrician/gynaecologist. AB - The objective of the study was to determine the extent of complementary and alternative medicine use and the disclosure of that use by patients seeing an obstetrician/gynaecologist. Data from the National Health Interview Survey of the USA 2007 were reviewed. Of the 2,673 women seeing an obstetrician/gynaecologist 956 (35.8%) used at least one form of CAM. However, only 51.8% of the women using CAM disclosed that use to their physician. PMID- 21280997 TI - How can we reduce negative laparoscopies for pelvic pain? AB - Chronic pelvic pain is a common condition and the RCOG guideline provides an evidence-based framework for the initial assessment. This study investigated the adequacy and relevance of the initial assessment in patients who underwent elective laparoscopic procedure for pelvic pain. History-taking was found to be deficient and was unable to identify factors which may be related to the cause or perception of the pain. Only a small percentage benefitted from a therapeutic trial of hormonal and non-hormonal agents and referral to other specialities. Ultrasound and bimanual examination were both found to be of little value. Laparoscopy assisted in diagnosis in 45% of patients. A structured initial assessment and targeted selection of patients for laparoscopy would reduce the number of patients with normal findings and thus, it would reduce the number of women who suffer pain and isolation after a negative laparoscopy. PMID- 21280998 TI - New nomogram for safe laparoscopic entry to reduce vascular injury. AB - A nomogram is developed to determine the length of Veress needle that could be safely inserted to achieve pneumoperitoneum to reduce the risk of vascular injury during laparoscopic entry. Axial images of magnetic resonance imaging (MRI) were used to measure the vertical distance between umbilicus and retroperitoneal vessels (STR). This distance was correlated with body mass index and a nomogram was developed to exactly measure the safe distance for the length of Veress needle insertion. The fitted equation was STR (skin to rectus sheath) = 31.6 + 3.952 * BMI with adjusted R(2) = 94.5%. The abdominal cavity depth showed a correlation with adjusted R(2) = 84.2%. This showed a significant relation between body mass index and prediction of cavity depth. Using the mean regression line for STP (skin to peritoneum), a safe insertion distance was identified and a nomogram developed which can be used to objectively predict the depth of the peritoneal cavity. PMID- 21280999 TI - Ovarian artery clamp: initial experience with a new clamp to reduce bleeding at open myomectomy. AB - We studied the effect of novel ovarian artery clamps on intraoperative bleeding in 46 women undergoing open myomectomy for large fibroids. The clamps were applied medial to the ovaries to occlude uterine blood flow from the ovarian arteries without compressing the fallopian tubes, and were used in conjunction with a pericervical tourniquet. Myomectomy was completed successfully in all patients, and an average of 10 fibroids weighing 588 g were removed per patient. The clamps could be applied bilaterally in all but three cases. In the 45 women when at least one ovarian artery clamp was used, the intraoperative blood loss averaged 500 ml, which was comparable with historic data with conventional tourniquets. Ovarian artery clamps appear to be as effective as tourniquets applied to the infundibulopelvic ligaments in reducing bleeding at open myomectomy but have the advantage that they do not occlude ovarian perfusion or crush the fallopian tubes. PMID- 21281000 TI - Aplastic anaemia in pregnancy. PMID- 21281001 TI - Infective endocarditis affecting the pulmonary valves in pregnant intravenous drug users. PMID- 21281002 TI - Spontaneous pneumothorax-a rare complication of pregnancy. PMID- 21281003 TI - Antenatal uterine rupture in a pregnancy following microwave endometrial ablation. PMID- 21281004 TI - Uterine rupture following abdominal cerclage with prior classical caesarean section. PMID- 21281005 TI - Peripartum haemolytic uraemic syndrome complicating pregnancy. PMID- 21281006 TI - The use of vena cava filters in laparoscopic removal of the cervix after subtotal hysterectomy. PMID- 21281007 TI - Bladder perforation: a rare complication during diagnostic hysteroscopy. PMID- 21281008 TI - Femoral neuropathy after vaginal surgery: a complication of the lithotomy position. PMID- 21281009 TI - Imperforate hymen: a rare case of secondary amenorrhoea. PMID- 21281010 TI - A rare case report of chronic uterine inversion due to placental polyp. PMID- 21281011 TI - A case of ichthyosis uteri. PMID- 21281012 TI - Xanthogranulomatous salpingitis with enterobial appendicitis. PMID- 21281013 TI - Microscopic intravenous leiomyomatosis: an incidental finding at myomectomy. PMID- 21281014 TI - Bilateral malignant ovarian haemangiopericytoma. PMID- 21281015 TI - Metastatic placental site trophoblastic tumour successfully treated with hysterectomy and EMA/CO chemotherapy. PMID- 21281018 TI - Agathisflavone enhances retinoic acid-induced neurogenesis and its receptors alpha and beta in pluripotent stem cells. AB - Flavonoids have key functions in the regulation of multiple cellular processes; however, their effects have been poorly examined in pluripotent stem cells. Here, we tested the hypothesis that neurogenesis induced by all-trans retinoic acid (RA) is enhanced by agathisflavone (FAB, Caesalpinia pyramidalis Tull). Mouse embryonic stem (mES) cells and induced pluripotent stem (miPS) cells growing as embryoid bodies (EBs) for 4 days were treated with FAB (60 MUM) and/or RA (2 MUM) for additional 4 days. FAB did not interfere with the EB mitotic rate of mES cells, as evidenced by similar percentages of mitotic figures labeled by phospho histone H3 in control (3.4% +/- 0.4%) and FAB-treated groups (3.5% +/- 1.1%). Nevertheless, the biflavonoid reduced cell death in both control and RA-treated EBs from mES cells by almost 2-fold compared with untreated EBs. FAB was unable, by itself, to induce neuronal differentiation in EBs after 4 days of treatment. On the other hand, FAB enhanced neuronal differentiation induced by RA in both EBs of mES and miPS. FAB increased the percentage of nestin-labeled cells by 2.7 fold (mES) and 2.4 (miPS) and beta-tubulin III-positive cells by 2-fold (mES) and 2.7 (miPS) in comparison to RA-treated EBs only. FAB increased the expression of RA receptors alpha and beta in mES EBs, suggesting that the availability of RA receptors is limiting RA-induced neurogenesis in pluripotent stem cells. This is the first report to describe that naturally occurring biflavonoids regulate apoptosis and neuronal differentiation in pluripotent stem cells. PMID- 21281019 TI - Editorial decisions: what should we publish? PMID- 21281020 TI - The drive to improve efficiency in theatre: what are the implications for obstetric and gynaecology trainees? PMID- 21281021 TI - Insulin resistance and the long-term consequences of polycystic ovary syndrome. AB - In a significant number of women with the polycystic ovary syndrome there is impaired insulin metabolism with hypersecretion of insulin. Insulin resistance is defined as a diminution in the glucose response to a given amount of insulin. Insulin resistance has been implicated in the pathogenesis of many aspects of the syndrome. Hyperinsulinaemia leads to increased production of androgens resulting in anovulatory infertility. Women and particularly obese women with insulin resistance and the polycystic ovary syndrome have an increased risk of developing gestational diabetes and also type 2 diabetes and cardiovascular disease in later life. The women should be counselled about long-term health risks, and obese women with the polycystic ovary syndrome should be periodically screened. Lifestyle modification to reduce weight in obese women and treatment with insulin sensitising drugs such as metformin in women with glucose intolerance result in the improvement of some metabolic abnormalities and hyperandrogenic disorders with the consequent restoration of normal menstrual and ovulatory function in a significant number of women with polycystic ovaries. PMID- 21281022 TI - Transabdominal cervical cerclage in triplet pregnancies and risk of extreme prematurity and neonatal loss. AB - There are no reports indicating the effect of prophylactic transabdominal cerclage (TAC) on the prolongation of multifetal pregnancies. We report the use of TAC in triplets, which evolved over 20 years in one practice. A retrospective cohort study of triplet pregnancies was conducted. Obstetric and neonatal outcomes were compared among women who underwent a prophylactic TAC or transvaginal cerclage and no cerclage. Of the 141 women who delivered triplets, prophylactic TAC was associated with reduced incidence of extreme prematurity and improved incidence of neonatal/postnatal survival. With the exception of mode of conception, prepregnancy weight, and the use of home monitoring uterine activity monitor, procardia and terbutaline, no major differences were found in terms of patient characteristics and pregnancy and delivery management among the three groups. It was concluded that in triplet pregnancies, prophylactic placement of a TAC appears to lower the incidence of delivery before 28 weeks. PMID- 21281023 TI - Reduced infant birth weight in the North West of England consequent upon 'maternal exposure' to 7/7 terrorist attacks on central London. AB - The effect of media coverage of the London terrorist attacks on 7 July 2005 on pregnancy outcome in mothers living in the North Western region of England was assessed. Pregnant women exposed to media coverage of these attacks had infants with mean birth weight lowered by 16 g and increased risks of a small and very small for gestational age infant (odds ratio 1:10 and 1:09, respectively). This small, but significant reduction in birth weight may indicate excess glucocorticoid exposure within the fetus, which could contribute to fetal programming and an increased likelihood of disease in adult life. PMID- 21281024 TI - Unified communication to reach vulnerable mothers. AB - The feasibility of using a mobile text to reach vulnerable patient groups was assessed in this study. A total of 121 pregnant or postnatal women were randomly asked to complete a questionnaire. The questionnaire was given to them in the antenatal clinic, postnatal ward, antenatal ward or in the day assessment unit at St Thomas' Hospital, London. The forms were collected and analysed using an Excel database. The results of this survey show that mobile technology is readily available for 97% of the obstetric population. In mothers from vulnerable groups and in mothers from deprived areas, 61% possessed 3rd generation mobile technology. The majority of mothers surveyed wanted their care supplemented by the use of their mobile phones. PMID- 21281025 TI - Effects of body mass index on sleep patterns during pregnancy. AB - The purpose of this study was to profile sleep patterns during pregnancy according to body mass index (BMI) and to correlate labour outcomes with both BMI and hours sleep. Data were collected from 200 postpartum women detailing sleep characteristics before and during pregnancy. A validated sleep questionnaire was employed, which comprised of questions about sleep apnoea, snoring, subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication and daytime dysfunction. Descriptive analyses were used. With advancing gestation, the mean (SD) number of hours sleep per night declined: pre-pregnancy 8.1 (SD 1.4); 1st trimester 8.3 (SD 1.8); 2nd trimester 7.7 (SD 1.7) and 3rd trimester 6.7 (SD 2.2). In the 18.5-24.9 BMI group, there was a marked difference in hours sleep per night from pre-pregnancy to 1st (8.6 h, p = 0.007), 2nd (7.9 h, p = 0.023) and 3rd (6.4 h, p = 0.000) trimesters in primiparous women. In the 25-29.9 BMI group, there was a difference from pre-pregnancy to 3rd trimester (p = 0.000). These changes were not reflected in a clinically significant difference in birth weight or mode of delivery. PMID- 21281026 TI - Is the urine spot protein/creatinine ratio a valid diagnostic test for pre eclampsia? AB - The objective of this study was to assess the value of the spot protein/creatinine ratio as the diagnostic test for pre-eclampsia by correlating it to the 24 h urine protein. For the spot test, this study uses the cut-off value recognised by the International Society for the Study of Hypertension in Pregnancy (ISSHP). Ours was a correlational study made in the setting of the antenatal assessment unit/antenatal ward in a District General Hospital. Patients at >24 weeks' gestation with hypertension and >1+ proteinuria (n = 32) were included in the study. A 10 ml sample of urine was collected for the spot protein/creatinine ratio (PCR) before the 24 h collection was started. Spot PCR samples were stored at -18 degrees C until the end of the study period. The results of the spot PCR were correlated to 24 h results using Pearson's correlation coefficient. Main outcome measures were correlation coefficient, sensitivity, specificity, positive and negative predictive values. Correlation was significant (r(2) = 0.82). Sensitivity, 83%; specificity, 92%; positive likelihood ratio, 10.3; negative likelihood ratio, 0.18. The spot PCR correlates well to the 24 h urine protein. The new cut-off values recognised by the ISSHP are producing consistent results. The evidence in favour of the spot PCR needs to be reassessed by larger studies. PMID- 21281027 TI - Induction of labour in women with one previous caesarean section. AB - We conducted a postal survey of NHS obstetric consultants working in England regarding their own practice and views on induction of labour in women with one previous caesarean section. Out of 480 consultant obstetricians across England, 322 replied, giving a response rate of 67%. Our survey has revealed a wide variation in practice of consultants across England, regarding induction of labour at term or post-term in women with one previous caesarean section. Hence, we feel that there is a need for a national audit of induction of labour in women with one previous caesarean section, with uterine rupture following induction of labour in such women as an auditable standard. PMID- 21281028 TI - Comparison of intermittent and continuous epidural analgesia on delivery and progression of labour. AB - In this study, 205 nulliparous parturients were enrolled to receive either intermittent (n = 101) or continuous (n = 104) type of epidural analgesia in labour. The primary outcome was rate of caesarean deliveries, whereas secondary outcomes included rate of fundal pressure manoeuvres, duration of labour from application of analgesia, dose of anaesthetic and short-term maternal and neonatal outcome between two groups. Rate of caesarean deliveries was significantly increased in the continuous group (15/104 vs 5/101, p = 0.02), as well as rate of fundal pressure manoeuvres (24/104 vs 11/101, p = 0.02) and dose of fentanyl (100 [100-300] vs 187.5 [125-450] MUg, p < 0.001 and levobupivacaine (40 [40-60] vs 75 [50-90] ml, p < 0.001). Duration of labour from analgesia to delivery was not significantly different between the two groups (414 +/- 101 vs 432 +/- 94 min, p = 0.12). PMID- 21281029 TI - Obstetric hysterectomy: a review of cases over 16 years. AB - Emergency peripartum hysterectomy (EPH), is performed when life-threatening obstetric conditions occur. The authors attempt to assess the incidence of EPH as well as to investigate risk factors and patients' characteristics. A retrospective study of all cases of EPH performed at the 2nd Department of Obstetrics and Gynecology, Medical School of Athens University, from 1994 to 2009 has been conducted. Data were abstracted from individual medical charts and laboratory records. Among 16,182 deliveries, 15 EPH were performed (0.92 per 1,000 deliveries). Indication was uncontrollable haemorrhage due to placenta accreta (73.3%) or uterine atony (26.6%). Incidence of 1.54 EPHs per 1,000 caesarean sections and 0.51 per 1,000 vaginal deliveries, were noted. Morbidity rate was 46.6%. One (6.6%) mother died because of pulmonary embolism. In conclusion, peripartum hysterectomy is a severe but life-saving procedure. Caesarean section increases the risk of EPH. Obstetricians should always be prepared to confront this emergency situation. PMID- 21281030 TI - Characteristics and outcome of 102 fetuses with fetal cerebral ventriculomegaly: experience of a university hospital in Turkey. AB - The aim of this study was to evaluate the incidence of associated structural anomalies and the outcome of fetuses with ventriculomegaly. We retrospectively collected 102 cases of antenatally diagnosed ventriculomegaly examined between 2000 and 2008. Ventricular width measurements were 10-12 mm, 12.1-14.9 mm and >= 15 mm in 24.5%, 20.6% and 54.9% of the cases, respectively. Associated structural malformations were detected in 77.4% of the fetuses. Mortality rate of fetuses with associated malformations and isolated ventriculomegaly was 86.1% and 55.7%, respectively (p < 0.001). The mortality rate was significantly lower in mild (10 12 mm) than in moderate (12.1-14.9 mm) and severe (>= 15 mm) cases (p < 0.05). All of the fetuses with mild isolated ventriculomegaly were alive at >12 months of age, without morbidity. Our results suggest that the prognosis of fetuses with ventriculomegaly mainly depends on the aetiology and on the presence of associated abnormalities. Fetuses with mild isolated ventriculomegaly have a favourable outcome. PMID- 21281031 TI - Factors associated with psychological morbidity in mothers of pre-term infants: a study from Wesley Guild Hospital, Nigeria. AB - This was a cross-sectional prospective study of 57 mothers of pre-term infants consecutively recruited from the Neonatal Intensive Care Unit (NICU) of Wesley Guild Hospital, Ilesa, Nigeria, between April and August 2009. The mothers were screened for psychological morbidity using the General Health Questionnaire (GHQ 30), and the Hospital Anxiety and Depression Inventory (HADS). More than one third of these mothers (36.8%), showed high levels of psychological distress on the GHQ30, and 19.3% were cases of depression, whereas 12.3% were cases of anxiety on the HADS. Psychological morbidity and depression were related to both neonatal birth weight and gestational age. There was no association between either maternal age at birth, or parity with maternal depression and psychological morbidity. These results indicate that the detection and effective management of postnatal psychological morbidity in mothers of pre-term infants, should be given priority in the design of maternal and child health services in Nigeria. PMID- 21281032 TI - The success of 6-hour hospital discharge on patients having vaginal repair operations using a new conscious sedation technique. AB - Anterior and posterior repair are standard surgical techniques for treatment of vaginal prolapse. These procedures are performed traditionally under general anaesthetic or spinal anaesthetic and usually require overnight admission in the hospital. We describe our case series of 40 patients who underwent anterior (18/40), posterior (20/40) or combined repair (2/40) under local anaesthetic and conscious sedation (Remifentanyl). The majority (35/40) were performed in the day case surgery unit and 95% patients were discharged within 6 hours of the operation, with no complications. All the patients were satisfied with the anaesthetic technique. We concluded that our technique of vaginal repair avoids the risk of general and spinal anaesthetic. The majority of operations can be performed as day cases with good patient satisfaction and without increasing risks to the patients. This technique has potential significant financial saving for the hospitals. PMID- 21281033 TI - NovaSure endometrial ablation under local anaesthesia in an outpatient setting: An observational study. AB - The use of NovaSure under local anaesthesia (LA) has been described as part of efficacy trials, but its use in an outpatient setting has not previously been explored. This prospective study was conducted to determine feasibility and efficacy of NovaSure in the outpatient setting under LA. The study included all women with menorrhagia unresponsive to medical management and were agreeable for treatment under LA (n = 50). The mean duration of procedure was 100 s. A total of 47 (94%) patients were discharged home the same day. Simple analgesics controlled postoperative pain in 44 (88%) patients. Seven (14%) patients gave preference for general anaesthesia for future treatment. The mean pain scores at 30, 60 and 90 min were 4.18, 4.38 and 3.85, respectively on the visual analogue scale. At follow-up, the improvement in menstrual symptoms was seen in 47 (94%) and the satisfaction rate was 43 (86%) and 47 (94%) at 4 and 6 months, respectively. PMID- 21281034 TI - Streamlining outpatient urogynaecology: a novel approach. AB - With population ageing, service expansion in urogynaecology is a necessity. The aim of this study was to determine the feasibility of a nurse specialist-led triage clinic as a novel way of outpatient care provision. Review of the patient pathway through the service over a 15-month period demonstrated effective patient management with timely order of investigations and treatment initiation, improved continuity of care, a reduction in the volume of medical consultations and high patient satisfaction. In conclusion, specialist nurse clinics provide a sustainable method of service expansion, while simultaneously facilitating service transfer to the community in line with current healthcare policy. PMID- 21281035 TI - Long-acting reversible contraception (LARC) use among adolescent females in secondary institutions in Nnewi, Nigeria. AB - In recent times, long-acting reversible contraceptives (LARC) use among adolescent girls has received a great deal of attention in developed countries. However, in some developing countries like Nigeria, it has received little attention, despite the fact that unwanted pregnancies and unsafe abortions are high among adolescents. This paper presents the findings of a study conducted among 243 adolescent girls aged 10-19 years in 12 secondary schools in Nnewi, Nigeria. Of these, 81 (34.5%) were sexually active; 42 (17.9%) have heard of LARC and 25 (10.6%) have used LARC. The most common source of information about contraception was from friends (47.6%), while religious (25.7%) and cultural (21.4%) beliefs were the most common reasons for non-use of LARC. The acceptability rate for LARCs was high (95.8%). The authors argue that reproductive health services should focus on the delivery of adequate and accurate information on user-independent contraceptives to improve use among adolescent girls. PMID- 21281036 TI - Characterisation of transient benign hCG elevations in women following chemotherapy for GTT. AB - The occurrence of post-chemotherapy transient low level hCG elevations has been observed in a number of women treated for gestational trophoblastic tumours (GTT). The authors reviewed the records of patients treated at Charing Cross Hospital over the last 10 years and identified those with a benign rise in hCG. Stored serum samples were assayed for hCG, LH, FSH and oestradiol at varying points during patient management. The endocrine profile in patients experiencing benign hCG elevation is comparable with that seen in post-menopausal women, with low oestradiol, combined with greatly elevated LH and FSH levels. In contrast, women with genuine disease relapse as the cause of their post-chemotherapy hCG elevation had normal or only minor elevations of LH and FSH. These findings support the observation that a major rise in LH and FSH can be used as an indicator for benign pituitary hCG production in patients experiencing a low level rise in hCG levels following chemotherapy for GTT. PMID- 21281037 TI - Cervical cytology profile of infertility patients in Abakaliki, South-eastern Nigeria. AB - Cervical cancer is of public health importance in developing countries. High risk sexual behaviour is a risk factor. This cross-sectional study aimed at establishing the cervical cytology profile of infertile women in Abakaliki, Nigeria. It involved 200 infertility patients and 200 general gynaecological patients. They were interviewed with a structured questionnaire and screened for pre-malignant cervical changes. A total of 28 infertility patients (14.9%) and 34 general gynaecological patients (17.7%) had epithelial cell abnormalities. A total of 21 infertility patients had cytology positive for pre-malignant changes, comprising: seven with atypical squamous cells of undetermined significance (ASCUS) (3.7%); eight with a low-grade squamous intraepithelial lesion (LSIL) (4.3%); and six with a high-grade intraepithelial lesion (HSIL) (3.2%). There were 25 general gynaecological patients who had cytology positive for pre malignant changes, comprising: eight ASCUS (4.2%); seven LSIL (3.5%); and ten HSIL (5.2%). The distribution did not attain statistical significance. Infertility did not increase the risk of development of cervical pre-malignant changes. PMID- 21281038 TI - Pattern and chemosensitivity of ovarian cancer in patients with BRCA1/2 mutations. AB - Our study adds to the BRCAness theory that hereditary ovarian cancers with BRCA 1 or 2 mutations show better chemosensitivity when compared with sporadic ovarian cancers. PMID- 21281039 TI - A case of laparoscopic myomectomy performed during pregnancy for subserosal uterine myoma. PMID- 21281040 TI - Morbidly adherent placentation: conservative management is an acceptable option in selected cases. PMID- 21281041 TI - An uncommon compound umbilical cord knot. PMID- 21281042 TI - Pseudoaneurysm of the vaginal artery as a cause of postpartum haemorrhage [corrected]. PMID- 21281043 TI - Vulval haemangioma in an adolescent girl. PMID- 21281044 TI - Bilateral endometrioma of Bartholin glands accompanying ovarian endometrioma. PMID- 21281045 TI - A tale of a urethral diverticulum. PMID- 21281046 TI - Ormond's disease and vaginal varicosities. PMID- 21281047 TI - Wegener's granulomatosis presenting as intermenstrual bleeding. PMID- 21281048 TI - Group A streptococcus necrotising fasciitis from a levonorgestrel-containing intrauterine system ('Mirena' coil). PMID- 21281049 TI - Rare finding in a common procedure: unsuspected pregnancy during hysterosalpingography. PMID- 21281050 TI - An unusual case of surgical emphysema following TVT. PMID- 21281051 TI - Bladder cancer co-existing with ovarian cancer coincidentally detected by transvaginal ultrasonography. PMID- 21281052 TI - Malignant melanoma metastatic to ovary: a diagnostic dilemma. PMID- 21281053 TI - Small cell carcinoma of the ovary: hypercalcaemic type. PMID- 21281056 TI - Effect of location of glass fiber-reinforced composite reinforcement on the flexural properties of a maxillary complete denture in vitro. AB - Objective. To evaluate the effect of the location of glass fiber-reinforced composite (FRC) reinforcement on the flexural load at the proportional limit (FL PL) and the flexural deflection of a maxillary acrylic resin complete denture. Material and methods. Maxillary acrylic resin complete dentures strengthened with and without FRC reinforcement were tested. The polymerized FRC was embedded in the denture base resin in the doughy state and placed (1) under the ridge lap region, (2) in the anterior region, (3) in the middle region or (4) in the anterior and posterior regions. The FL-PL and flexural deflection value at the 100-N loading point of the reinforced maxillary denture specimens were tested. Results. All of the reinforced dentures had a higher FL-PL than the denture without reinforcement but the FL-PL values of all the dentures were not significantly different from each other. The efficiency of the FRC reinforcement compared to the unreinforced denture was 1.54-1.75 times greater. All of the reinforced dentures showed significantly lower deflection compared to the unreinforced denture, but the flexural deflections of all the dentures were not significantly different from each other. Conclusions. The location of the FRC reinforcement did not affect the fracture resistance of the maxillary acrylic resin complete denture. All of the reinforced dentures had higher FL-PL and lower flexural deflection than the denture without reinforcement. PMID- 21281057 TI - Combined electric acoustic stimulation with the PULSARCI(100) implant system using the FLEX(EAS) electrode array. AB - CONCLUSION: This study demonstrates that electric acoustic stimulation (EAS((r))) using the FLEX(EAS) electrode is a successful treatment method for preservation and stability of low frequency hearing, and results in significant improvements in speech perception. OBJECTIVES: Low frequency hearing preservation and stability following EAS surgery with the MED-EL PULSARCI(100) implant using the FLEX(EAS) electrode and a combined processor in a multicentre setting, and the efficacy and benefits of EAS over time were evaluated. METHODS: Eighteen subjects with normal to moderate hearing loss in the low frequencies and severe to profound hearing loss in the high frequencies were implanted with the FLEX(EAS) electrode. Implantation was performed by different surgeons at three participating centres using either the cochleostomy or the round window approach. Preoperatively, hearing was measured; a battery of speech perception tests and the subjective benefit questionnaire were administered. These tests were subsequently repeated: first at EAS fitting, which was due 3 months after surgery, and then again 3, 6 and 12 months after EAS fitting. RESULTS: Hearing could be preserved in all subjects. Speech understanding showed significant improvement in all tests over time with the EAS condition outperforming the cochlear implant-only condition at all intervals. These considerable effects were also reflected in the subjective benefit outcome. PMID- 21281058 TI - Speech recognition with BAHA simulator in subjects with acquired unilateral sensorineural hearing loss. AB - CONCLUSION: We question the justification for the cost of a surgically implanted device for the restoration of limited circumstances of audible communication, although we understand that the decision is taken depending on the social relevance of communication or personal criteria. OBJECTIVES: The purpose of this study was to evaluate the effect of the BAHA simulator (BAHAS) system in subjects with acquired unilateral sensorineural hearing loss. In particular we tested the changes of speech reception threshold (SRT) in relation to different speech source positions, with a background of diffuse noise. METHODS: The primary message consisting of lists of Italian sentences was delivered from a loudspeaker placed at horizontal azimuths of 0 degrees , 90 degrees , 180 degrees and 270 degrees ; the interference consisted of uncorrelated speech-shaped noise simultaneously delivered by four loudspeakers at a fixed intensity. The speech recognition tests were administered to 11 patients with BAHAS either on or off; hence each patient underwent 8 acoustic conditions (4 primary message directions * 2 BAHAS conditions). The SRT (50% correct responses) was measured by a simple 2 dB step adaptive procedure. Ten normal-hearing subjects served as the control group. RESULTS: Our data demonstrated that even for the acoustic condition where BAHAS should be more useful (i.e. lateral speech toward the impaired side), it was definitely ineffective in the study conditions. PMID- 21281059 TI - Age-related changes in apoptosis in rat hippocampus induced by oxidative stress. AB - Also known as programmed cell death, apoptosis is a sequence of events that leads to elimination of cells without releasing harmful substances into the surrounding area. Apoptosis may be induced by intracellular or extracellular signals. Certain apoptotic signals activate mitochondrial pro-apoptotic events and increase reactive oxygen species (ROS). Increased ROS production may lead to oxidative stress. The goal of our study was to characterize age-related changes in apoptosis induced by oxidative stress in the hippocampus. Rats 2, 7, 21 and 38 days old, and adult rats were used for our study. Hippocampal CA1, CA2, CA3 and dentate gyrus apoptosis, and hippocampal superoxide dismutase (SOD), glutathione peroxidase (GPx) enzyme activities and thiobarbituric acid reactive substances (TBARS) levels were measured. We found that numbers of hippocampal neurons were low in rats 2, 7 and 21 days old (CA1, p < 0.001; CA3, p < 0.05; gyrus dentatus, p < 0.001). The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) positive cell count was highest in the CA1 and dentate gyrus of 21-day-old rats. Among 21-day-old rats, the hippocampal TBARS levels and SOD enzyme activity were high, whereas GPx activity was low. These results demonstrate that the hippocampal CA1 and dentate gyrus of 21-day-old rats are more prone to damage by oxidative stress. PMID- 21281060 TI - Pseudallescheria/Scedosporium complex species identification by Matrix-Assisted Laser Desorption Ionization Time-Of-Flight Mass Spectrometry. AB - Because timely and accurate identification of members of the Pseudallescheria/ Scedosporium species complex (PSC) is clinically relevant, the objective of this investigation was to study the stability and influence of the main variable factors in the routine clinical laboratory to the potential use the Matrix Assisted Laser Desorption Ionization-Time-Of-Flight (MALDI-TOF MS) in the identification of these fungi. Twenty-two PSC reference strains, three clinical isolates, an alphaHCCA matrix, and an Autoflex I spectrometer with BioTyper software (Bruker) were employed in this study. Intra-and inter-specimen composite correlation indices for each MS spectrum as compared to a reference spectrum were computed. MS identification was stable after the fungi were subcultured over a 1 month period. While neither culture medium (Sabouraud vs. Malt extract) nor protein extraction methods (formic acid vs. trifluoroacetic acid) significantly influenced the quality of the MS identifications, they were considerably increased from day 3 to day 6 of incubation. MALDI-TOF MS can be used in the routine clinical laboratory in the identification of members of the complex provided that valid spectra libraries are developed. Although preliminary results are encouraging, further studies are warranted to demonstrate whether MS can distinguish the species that have recently been described using multilocus sequence analysis within P. boydii sl. and to validate its use in the routine clinical laboratory for identifying clinically relevant moulds. PMID- 21281061 TI - Phaeohyphomycosis caused by a plant pathogen, Corynespora cassiicola. AB - We report a case of subcutaneous phaeohyphomycosis caused by Corynespora cassiicola. Molecular identification of this pathogen on grasses confirms that it may be involved in human infection, as previously reported once in pre-molecular literature. In vitro antifungal susceptibility data of the strain are provided. The patient was successfully treated with oral terbinafine with topical povidone iodine in accordance with the results obtained through in vitro susceptibility testing. PMID- 21281062 TI - DPP-4 inhibition increases GIP and decreases GLP-1 incretin effects during intravenous glucose tolerance test in Wistar rats. AB - GIP metabolite [GIP (3-42)] and GLP-1 metabolite [GLP-1 (9-36) amide] have been reported to differ with regard to biological actions. Systemic DPP-4 inhibition can therefore reveal different actions of GIP and GLP-1. In catheter wearing Wistar rats, insulinotropic effects of equipotent doses of GIP (2.0 nmol/kg) and GLP-1 (7-36) amide (4.0 nmol/kg) and vehicle were tested in the absence/presence of DPP-4 inhibition. Blood glucose and insulin were frequently sampled. DPP-4 inhibitor was given at -20 min, the incretin at -5 min and the intravenous glucose tolerance test (0.4 g glucose/kg) commenced at 0 min. G-AUC and I-AUC, insulinogenic index and glucose efflux, were calculated from glucose and insulin curves. Systemic DPP-4 inhibition potentiated the acute GIP incretin effects: I AUC (115+/-34 vs. 153+/-39 ng.min/ml), increased the insulinogenic index (0.74+/ 0.24 vs. 0.99+/-0.26 ng/mmol), and improved glucose efflux (19.8+/-3.1 vs. 20.5+/ 5.0 min-1). The GLP-1 incretin effects were diminished: I-AUC (124+/-18 vs. 106+/ 38 ng.min/ml), the insulinogenic index was decreased (0.70+/-0.18 vs. 0.50+/-0.19 ng/mmol), and glucose efflux declined (14.9+/-3.1 vs. 11.1+/-3.7 min-1). GLP-1 and GIP differ remarkably in their glucoregulatory actions in healthy rats when DPP-4 is inhibited. These previously unrecognized actions of DPP-4 inhibitors could have implications for future use in humans. PMID- 21281065 TI - In vitro fluid dynamics of the Ahmed glaucoma valve modified with expanded polytetrafluoroethylene. AB - PURPOSE: Long-term intraocular pressure reduction by glaucoma drainage devices (GDDs) is often limited by the fibrotic capsule that forms around them. Prior work demonstrates that modifying a GDD with a porous membrane promotes a vascularized and more permeable capsule. This work examines the in vitro fluid dynamics of the Ahmed valve after enclosing the outflow tract with a porous membrane of expanded polytetrafluoroethylene (ePTFE). MATERIALS AND METHODS: The control and modified Ahmed implants (termed porous retrofitted implant with modified enclosure or PRIME-Ahmed) were submerged in saline and gelatin and perfused in a system that monitored flow (Q) and pressure (P). Flow rates of 1-50 MUl/min were applied and steady state pressure recorded. Resistance was calculated by dividing pressure by flow. RESULTS: Modifying the Ahmed valve implant outflow with expanded ePTFE increased pressure and resistance. Pressure at a flow of 2 MUl/min was increased in the PRIME-Ahmed (11.6 +/- 1.5 mm Hg) relative to the control implant (6.5 +/- 1.2 mm Hg). Resistance at a flow of 2 MUl/min was increased in the PRIME-Ahmed (5.8 +/- 0.8 mm Hg/MUl/min) when compared to the control implant (3.2 +/- 0.6 mm Hg/MUl/min). CONCLUSIONS: Modifying the outflow tract of the Ahmed valve with a porous membrane adds resistance that decreases with increasing flow. The Ahmed valve implant behaves as a variable resistor. It is partially open at low pressures and provides reduced resistance at physiologic flow rates. PMID- 21281064 TI - Effect of microtopographical cues on human keratocyte orientation and gene expression. AB - PURPOSE: To determine if microtopographical cues can influence the orientation and extracellular matrix production of human keratocytes in vitro. MATERIALS AND METHODS: Human keratocytes were cultured on grooved and ungrooved polycaprolactone films for up to 3 weeks. The cell morphology was examined using ordinary light microscopy, reflective microscopy, and scanning electron microscopy. The cells gene expression was examined using a GEArray Q series gene expression kit. RESULTS: Cells initially appeared to orientate in the direction of the grooves. Cells cultured on ungrooved films exhibited random orientations. For longer culture periods on grooved membranes, a second cell layer formed on top of the initial layer at an angle orientation to the initial layer. Analysis of mRNA showed that several genes involved in the production of integrins and matrix metalloproteinases were either up-regulated or down-regulated in the presence of the grooves. CONCLUSIONS: The introduction of microtopographical cues has been shown to influence the orientation of keratocytes and alter their gene expression. This pilot study reveals some important findings that can be used in the development of bioengineered corneas. PMID- 21281066 TI - Effect of avosentan (SPP-301) in porcine ciliary arteries. AB - PURPOSE: To investigate the vasoactive effect of ET(A)-endothelin receptor antagonists avosentan (SPP-301) and BQ-123 in isolated porcine ciliary arteries with and without endothelium. To investigate the effect of avosentan on the endothelin-1 induced contractions in comparison with BQ-123 and BQ-788 (ET(B) endothelin receptor antagonist) in isolated porcine ciliary arteries with and without endothelium. METHODS: Vessels were placed in a myograph system to measure isometric forces. In a first set of experiments, quiescent vessels were exposed, cumulatively, to increasing concentrations of avosentan and BQ-123 (10(-9) M-3 * 10(-6) M). In a second set of experiments, quiescent vessels were first incubated with avosentan (10(-6) M and 10(-8) M), BQ-123 (10(-6) M), and BQ-788 (10(-6) M), respectively. Then the vessels were exposed, cumulatively, to increasing concentrations of endothelin-1 (10(-12) M-3 * 10(-8) M). Each set of experiments was conducted in the vessels with and without endothelium. RESULTS: Cumulative concentrations of avosentan and BQ-123 had no vasoactive effect in quiescent vessels. Avosentan had a strong inhibitory effect on the endothelin-1-induced contractions. The inhibitory effect of 10(-6) M avosentan was significantly stronger than the effect of 10(-8) M avosentan. The effect of avosentan (10(-6) M) tended to be stronger than the effect of BQ-123 (10(-6) M). To a lesser extent, BQ-788 also had an inhibitory effect on the endothelin-1-induced contractions. CONCLUSIONS: Avosentan has a strong inhibitory effect on the endothelin-1-induced contractions. Blockade of ET receptors is potentially an attractive target in many eye diseases including glaucoma. Further studies are needed to evaluate the usefulness of endothelin blockers in ophthalmology. PMID- 21281067 TI - Evidence for a novel autosomal dominant retinitis pigmentosa linked to chromosome 1p22.1-q12 in a Chinese family. AB - PURPOSE: To identify the causative genetic locus in a Chinese autosomal dominant retinitis pigmentosa (adRP) family that contained seven affected members in three generations. METHODS: After clinical diagnosis and exclusion of all mapped genes and loci, the SLINK program was used to simulate the maximum logarithm of the likelihood ratio (LOD) score for a linkage study in this small family. A genome wide scan was performed using microsatellite markers at 10 cM intervals. Two point and multipoint LOD scores were calculated, and haplotypes were constructed. RESULTS: The H11 family clinical presentation included an early onset of night blindness, a progressive loss of the peripheral visual field, typical retinitis pigmentosa (RP) fundus changes, and a cataract complication. A maximum two-point LOD score of 2.54 (theta = 0) was found at markers D1S2739, D1S457, D1S187, D1S189, and D1S305, and multipoint linkage analysis yielded a maximum LOD score of 2.54 for marker D1S187. These LOD scores were the closest to the maximum simulated LOD score. Haplotype analysis revealed that this form of adRP segregates with a 38.25 cM region that spanned 50 Mb on chromosome 1p22.1-q12. CONCLUSIONS: Although this locus overlaps the RP19 locus caused by mutations in ABCA4 and the RP32 locus, both are inherited in an autosomal recessive mode rather than the autosomal dominant mode of inheritance found in the H11 family. The identification of this potential new locus for adRP further confirms the high level of heterogeneity for RP. PMID- 21281069 TI - Sarcoidosis presenting as imploding antrum syndrome. AB - We present a case of a male patient who presented with facial asymmetry and epiphora. A diagnosis of imploding antrum syndrome secondary to sarcoidosis was made on the basis of characteristic computerised tomography features, elevated serum ACE and histopathological findings. We suggest that chronic inflammation within the sinus cavities, due to sarcoid, had caused osteolysis of the sinus walls, subsequently leading to the typical presentation of imploding antrum syndrome. PMID- 21281068 TI - Endoscopic dacryocystorhinostomy in acute dacryocystitis: a multicenter case series. AB - OBJECTIVE: To present our experience of early endonasal DCR (endoDCR) in the treatment of acute dacryocystitis (AD). Methods. International multicenter non comparative retrospective study. RESULTS: Eighteen patients were identified. All were treated with antibiotics prior to surgery with a median of time from referral to endoDCR surgeon to surgery of 3 days (range 1-7). Surgery was performed using mechanical powered endoDCR (MENDCR) in 15/18 (83.3%) cases; mitomycin C was used in 5/18 (27.8%) and all cases underwent bicanalicular intubation. An increase in perioperative bleeding was noted in 5/18 (27.8%), causing interference in surgical technique in one (5.6%). Resolution of AD was seen in all cases, with no recurrences. 17/18 (94.4%) cases were free of epiphora at median follow-up of 12 months (range 2-36), with nasal endoscopy revealing free flow of fluorescein through the ostium in 17/18 (94.4%) of cases. The median total length of stay was 1 night (range 0-3). CONCLUSIONS: EndoDCR surgery performed early in AD led to rapid resolution of the condition in all cases and was associated with subsequent anatomical and functional success in 94.4% of cases. Early endoDCR surgery in the context of AD and the potential associated health economic benefits are worth further consideration and study. PMID- 21281063 TI - A novel thermodynamic treatment for meibomian gland dysfunction. AB - PURPOSE: To evaluate a novel thermodynamic treatment for obstructive meibomian gland dysfunction (MGD). MATERIALS AND METHODS: Fourteen adult subjects (10 females, 4 males, mean age = 54.2 +/- 9.6 yr) were recruited in a multi-center, feasibility clinical trial in Durham and Cary, North Carolina and Boston, Massachusetts. Inclusion criteria included: previous diagnosis of moderate to severe dry eye; dry eye symptoms for at least three months prior; daily topical lubricant use; and evidence of meibomian gland (MG) obstruction in the central five glands of both eyes lower eyelids. Exclusion criteria included: history of recent acute or chronic ocular inflammation or infection and lid surface abnormalities affecting lid function. The treatment: the device heats the palpebral surface of upper and lower eyelids while simultaneously applying graded pulsatile pressure to the outer eyelid for 12 min, thereby expressing the MGs during heating. One eye was randomly selected to undergo additional manual heated expression with another treatment device. RESULTS: The mean MG secretion score, tear break-up time, corneal staining score, number of MGs yielding liquid secretion and symptom scores all improved significantly from baseline to 1 week. This was maintained through the 3-month follow-up. There was no statistically significant difference in any outcome between the automated device treatment only and the additional heated manual expression. CONCLUSION: The combination of heat applied to the palpebral surface, while simultaneously expressing MGs during a single 12-minute treatment, was effective, in this feasibility study, in treating obstructive MG dysfunction and dry eye signs and symptoms for the 3-month study period. PMID- 21281070 TI - An unusual orbital blow-out fracture: a case report. AB - The complete dislocation of the orbital contents into the maxillary antrum as a result of trauma is an extremely rare event and requires immediate exploration and repositioning of the globe with reconstruction of the orbital floor. We present the case of a 10-year-old male who sustained trauma to the orbit and was initially suspected to have developed auto-evisceration. He underwent successful exploration and reconstruction of orbital floor with remarkable improvement. PMID- 21281071 TI - Orbital sarcoidosis treated with hydroxychloroquine. AB - We report a case of orbital sarcoidosis with extraocular muscle and orbital fat involvement that did not respond to oral corticosteroid treatment, but was successfully treated with oral hydroxychloroquine. There were no side effects or disease recurrence. To our knowledge, anti-malarial therapy for isolated orbital sarcoidosis has not been reported in the literature. PMID- 21281072 TI - Hyaluronic acid treatment for upper eyelid retraction after glaucoma filtering surgery. AB - A 51-year old female presented with upper lid retraction after glaucoma filtering surgery. After two surgical procedures to correct the retraction with only transient effect, she was finally treated with hyaluronic acid gel filling achieving good aesthetic and functional result. PMID- 21281073 TI - Metastatic mucinous adenocarcinoma of the orbit. AB - Metastatic mucinous adenocarcinoma in the orbit is extremely rare. We review the literature and report a case of metastatic mucinous adenocarcinoma of the orbit in a 37-year-old male with primary pancreatic adenocarcinoma. PMID- 21281074 TI - Entomophthoramycosis: a rare fungal orbital infection presenting with dacryocystitis. AB - We report a case of a rare fungal orbital infection in an infant presenting with dacryocystitis. The causative organism was Conidiobolus sp. of the order Entomophthorales. There is no standard treatment for entomophthoramycosis. Our patient responded well to combined antifungal therapy without aggressive surgical debridement. PMID- 21281075 TI - Primary Wegener's granulomatosis of the orbital apex with initial optic nerve infiltration. AB - Wegener's granulomatosis can involve the orbit and sometimes the optic nerve. This usually occurs as a result of contiguous spread from affected sinuses or extraocular muscles, or from a vasculitic posterior optic neuropathy. However, we present an unusual case of isolated orbital apex infiltrative disease in a patient with known Wegener's granulomatosis. This initially caused painless optic neuropathy and progressed to painful ophthalmoplegia and blindness. Optic nerve biopsy, performed to exclude methotrexate-induced lymphoma, confirmed optic nerve infiltration. The condition was refractory to high-dose pulsed methylprednisolone but the patient gained symptomatic relief from rituximab. Wegener's granulomatosis should be considered in cases of isolated posterior optic neuropathy, and close attention should be placed on imaging the orbital apex. PMID- 21281076 TI - Sarcoid-related dacryoadenitis following treatment with interferon alpha and ribavarin for hepatitis C. AB - Sarcoidosis is an increasingly well-recognised complication of interferon therapy for hepatitis C infection, primarily manifesting with cutaneous or pulmonary involvement. However, we present an unusual case of sarcoid-related dacryoadenitis in a 67-year-old Caucasian lady following such treatment. The literature relating to ophthalmic presentations of interferon-related sarcoidosis is reviewed, and the potential for confusion with interferon-induced thyroid- associated orbitopathy is discussed. PMID- 21281077 TI - Orbital granular cell tumor in a patient with Churg Strauss syndrome: the importance of biopsy. AB - A 65-year-old woman presented with a long standing, progressive exophthalmos of the right eye. Her medical history was significant for Churg Strauss syndrome, and was treated with immunosuppressive therapy. She had undergone two previous orbital biopsies showing inflammatory reactive lymphoid hyperplasia. A diagnosis of orbital inflammation in Churg-Strauss syndrome was suspected, and the immunosuppressive therapy was increased. Because of the lack of response to therapy, a further biopsy was performed, by lateral orbitotomy approach. Biopsy of the mass revealed a granular cell tumor composed of S-100 positive cells with an acidophilic granular cytoplasm and peripheral lymphocytic infiltration. A granular cell tumor, which is very rare in the orbit, should be considered in the differential diagnosis of orbital tumors, and if suspected, an excisional biopsy must be undertaken. Typical histopathological aspect of the granular cell tumor is characterized by the presence of S-100 positive closely packed polygonal cells with a granular cytoplasm. PMID- 21281078 TI - Diagnosis and management of mucoepidermoid carcinoma of the lacrimal duct. AB - Primary tumors of the lacrimal sac are rare, and mucoepidermoid carcinomas of the lacrimal sac have only been reported 13 times in the literature. We reported an intermediate-grade mucoepidermoid carcinoma that was managed with wide local excision, medial maxillectomy, and external beam radiotherapy, and the patient has remained disease-free for 7 years. Orbital exenteration had generally been recommended for these tumors, but newer, more conservative resections along with radiation therapy may be equally effective. PMID- 21281080 TI - Botulinum toxin for lower lid entropion correction. AB - This prospective clinical study was designed to evaluate the efficacy of botulinum toxin for temporary treatment of senile and congenital lower lid entropion. Seventeen patients with senile entropion and three children with congenital entropion were treated with botulinum toxin injection into the preseptal orbicularis muscle of lower lid. This resulted in transient relieve of the condition, which lasted for a period of 8-26 weeks. This technique is easy and effective for senile entropion as well as certain cases of congenital entropion. PMID- 21281081 TI - Surgical approaches to the orbital apex: comparison of endoscopic endonasal and transcranial approaches using a novel 3D endoscope. AB - INTRODUCTION: Extended endoscopic endonasal approaches are increasingly applied to treat a variety of orbital pathologies. We performed a cadaveric study, comparing the endonasal approach with a transcranial approach to the orbital apex, using a two-dimensional (2D) and novel three-dimensional (3D) endoscope. MATERIALS AND METHODS: Dissection was performed on two fresh cadaver heads using a novel 3D endoscope for the endonasal approach to the orbit and orbital apex. On the same heads, a fronto-orbito-zygomatic (FOZ) approach was performed to expose the orbital apex region. Anatomical boundaries and limitations of each exposure were noted. 2D and 3D images of the approaches and anatomical dissections were captured and recorded. RESULTS: The endonasal endoscopic approach achieved direct exposure to the inferior and medial aspects of the orbit. The FOZ approach, on the other hand, provided excellent access to the superior and lateral aspects of the orbit. Appreciation of the spatial relationships of the intracranial skull base anatomy was significantly improved using the 3D endoscope compared with the 2D endoscope. CONCLUSIONS: The endoscopic endonasal approach achieves direct exposure to the inferomedial aspect of the orbit and orbital apex, which is not exposed using the transcranial approach, hence the two approaches are complementary. 3D endoscopes augment the spatial orientation of extracranial and intracranial anatomical structures. This may improve patient's safety and hasten the learning curve for endoscopic approaches to the midline skull base. PMID- 21281079 TI - Two cases of drug-induced orbital inflammatory disease. AB - Orbital inflammatory disease (OID) includes all inflammatory processes affecting the orbit. Although several aetiologies are recognised, a cause may not be elucidated. We describe 2 cases in which drugs (hyaluronidase and zoledronic acid) were the cause of OID. In patients with a clinical picture of OID simulating an orbital cellulitis, the recent drug history should be considered as a possible aetiology, and treatment with steroids with or without a biopsy should be considered after an infection has been excluded. PMID- 21281083 TI - Delayed hypersensitivity reaction to Restylane (r) SubQ. AB - PURPOSE: To report on 4 patients who developed delayed hypersensitivity reactions to Restylane((r)) SubQ and their management. To our knowledge, no cases of delayed hypersensitivity to Restylane((r)) SubQ have been previously reported. METHODS: A retrospective case series of 4 patients who were treated with preperiosteal Restylane((r)) SubQ to their cheeks, for facial volume augmentation. All 4 patients were subsequently referred with delayed hypersensitivity reactions over a 4-month period. RESULTS: The hypersensitivity reactions occurred from 1 week to 4 months' post-cheek augmentation using Restylane((r)) SubQ. All patients had previously (and some since) been treated with other non-animal stabilized hyaluronic acid (NASHA) products without adverse effect. Hyaluronidase led to fast and effective resolution in all cases, although 2 of the patients required repeat treatment. CONCLUSION: Hyaluronidase was effective at treating the inflammatory reaction and breaking up the retained Restylane((r)) SubQ in all patients. Although Restylane((r)) SubQ should be avoided in these patients, in our experience this does not preclude them from using other similar NASHA products. PMID- 21281084 TI - Asian blepharoplasty--an overview. AB - Asian blepharoplasty has evolved over the years as greater understanding of the differences between the Asian and Caucasian eyelid anatomy has led to the development of modified techniques for upper lid blepharoplasty. The aim of Asian upper blepharoplasty is to create a pleasing and permanent upper lid crease. This article reviews the differences in the anatomy and the various techniques currently employed. PMID- 21281089 TI - Electrophysiological evidence for biased competition in V1 for fear expressions. AB - When multiple stimuli are concurrently displayed in the visual field, they must compete for neural representation at the processing expense of their contemporaries. This biased competition is thought to begin as early as primary visual cortex, and can be driven by salient low-level stimulus features. Stimuli important for an organism's survival, such as facial expressions signaling environmental threat, might be similarly prioritized at this early stage of visual processing. In the present study, we used ERP recordings from striate cortex to examine whether fear expressions can bias the competition for neural representation at the earliest stage of retinotopic visuo-cortical processing when in direct competition with concurrently presented visual information of neutral valence. We found that within 50 msec after stimulus onset, information processing in primary visual cortex is biased in favor of perceptual representations of fear at the expense of competing visual information (Experiment 1). Additional experiments confirmed that the facial display's emotional content rather than low-level features is responsible for this prioritization in V1 (Experiment 2), and that this competition is reliant on a face's upright canonical orientation (Experiment 3). These results suggest that complex stimuli important for an organism's survival can indeed be prioritized at the earliest stage of cortical processing at the expense of competing information, with competition possibly beginning before encoding in V1. PMID- 21281082 TI - Predictors of anatomical patency following primary endonasal dacryocystorhinostomy: a pilot study. AB - PURPOSE: To identify factors influencing early anatomical patency following primary endonasal dacryocystorhinostomy (DCR) for nasolacrimal obstruction. METHODS: A prospective study of 50 patients who underwent primary endonasal DCR for nasolacrimal obstruction was undertaken. Age, gender, dacryocystitis, endonasal access, clearance (bony clearance superiorly from the common canaliculus after bone removal), mobility (mobility of the flaps created from the lacrimal sac once opened), marsupialization (degree of reflection of the lacrimal sac following surgical opening) and a combined score (incorporating clearance, mobility and marsupialization) were examined. Outcomes were measured 10 weeks postoperatively by assessing anatomical patency via probe and syringe and modified functional endoscopic dye test. RESULTS: Using the Kendall's tau-beta test, there was a significant relationship between greater mobility and better outcome (p<.03) and greater marsupialization and better outcome (p=.03). A higher combined score (incorporating mobility, marsupialization and bony clearance) was also related to better outcome (p<.02). There was no significant relationship between outcome and age, gender, dacryocystitis, endonasal access or bony clearance. Overall, 47 patients (94%) had complete or partial patency at 10 weeks and 3 patients (6%) had complete nasolacrimal obstruction at 10 weeks. CONCLUSIONS: Greater flap mobility and greater lacrimal sac marsupialization in endonasal DCR are associated with better rates of early anatomical patency. A novel scoring system incorporating mobility, marsupialization and bony clearance also showed a significant relationship to early outcome, with higher scores being associated with better outcomes. These results may enable greater understanding of the perioperative features associated with better outcomes in endonasal DCR. PMID- 21281106 TI - Highlights from the February 2011 issue of DNA and Cell Biology. PMID- 21281094 TI - Childbearing, the desire to have children, and awareness about the impact of age on female fertility among Finnish university students. AB - OBJECTIVE: To describe Finnish university students' childbearing histories, desires concerning childbearing, and awareness regarding the impact of age on female fertility. METHODS: A national survey of Finnish university students in 2008. A questionnaire was sent to 9,967 Finnish undergraduate university students aged less than 35 years. Altogether, the questionnaire was answered by 1,864 men and 3,222 women. The overall response rate was 51% (42% for men and 59% for women). Students were asked about their number of children, desired childbearing, and awareness of the effect of age on female fertility. RESULTS: Of the respondents, 8.25% had children, and 94.0% wanted to have children in the future. Female students were more aware of the impact of age on female fertility than were male students. Over half of the men and approximately one-third of the women thought that the marked decrease in female fertility begins after the age of 45 years. CONCLUSIONS: A vast majority of Finnish university students wanted to have children in the future. Their awareness of the natural, age-related decline in female fertility was insufficient. Sexual health education in schools and health care personnel's family planning counselling, for both men and women, should include information about the age-related drop in fertility. PMID- 21281095 TI - Exposing oneself and one's partner to sexual risk-taking as perceived by young Swedish men who requested a Chlamydia test. AB - OBJECTIVES: To explore young men's perceptions of (i) the risk for themselves and their partners in connection with unprotected intercourse, and (ii) the main barriers to practising safe sex. METHODS: Qualitative latent content analysis of interviews involving 22 Swedish males aged 16-20, who requested a Chlamydia test. RESULTS: The main categories identified were: (1) Low perceived threat regarding sexual risk-taking - personal consequences in focus. Threats could be both immediate and distant with varying preventative strategies. The young men worried more about their personal consequences than about the consequences for their partner. They were confident that an unintended pregnancy would be terminated, leading to decreased motivation for sharing pregnancy-preventing practices with their partner. (2) Perceived barriers to practising safe sex. Main barriers to condom use were interference with spontaneity, pleasure reduction, fear of loosing one's erection, and embarrassment or distrust. Other obstacles were the girl's use of hormonal contraception, and difficulties in communicating about safe sex. CONCLUSION: The young men did not seem to worry about risks when having unprotected sex. To protect men's - and women's - sexual and reproductive health, efforts are needed to increase the former's contraceptive responsibilities and awareness of consequences related to unprotected sex. PMID- 21281093 TI - Working memory encoding delays top-down attention to visual cortex. AB - The encoding of information from one event into working memory can delay high level, central decision-making processes for subsequent events [e.g., Jolicoeur, P., & Dell'Acqua, R. The demonstration of short-term consolidation. Cognitive Psychology, 36, 138-202, 1998, doi:10.1006/cogp.1998.0684]. Working memory, however, is also believed to interfere with the deployment of top-down attention [de Fockert, J. W., Rees, G., Frith, C. D., & Lavie, N. The role of working memory in visual selective attention. Science, 291, 1803-1806, 2001, doi:10.1126/science.1056496]. It is, therefore, possible that, in addition to delaying central processes, the engagement of working memory encoding (WME) also postpones perceptual processing as well. Here, we tested this hypothesis with time-resolved fMRI by assessing whether WME serially postpones the action of top down attention on low-level sensory signals. In three experiments, participants viewed a skeletal rapid serial visual presentation sequence that contained two target items (T1 and T2) separated by either a short (550 msec) or long (1450 msec) SOA. During single-target runs, participants attended and responded only to T1, whereas in dual-target runs, participants attended and responded to both targets. To determine whether T1 processing delayed top-down attentional enhancement of T2, we examined T2 BOLD response in visual cortex by subtracting the single-task waveforms from the dual-task waveforms for each SOA. When the WME demands of T1 were high (Experiments 1 and 3), T2 BOLD response was delayed at the short SOA relative to the long SOA. This was not the case when T1 encoding demands were low (Experiment 2). We conclude that encoding of a stimulus into working memory delays the deployment of attention to subsequent target representations in visual cortex. PMID- 21281096 TI - Anti-ovulatory activity of H2 receptor blockers in albino rabbits--a preliminary study. AB - OBJECTIVE: To evaluate the anti-ovulatory activity of H(2) receptor blockers (ranitidine, famotidine and roxatidine) in albino rabbits considering the role of histamine in ovulation. METHOD: The drugs were orally administered once daily for three days to adult female rabbits weighing between 1.3-2.0 kg (four groups of three animals). The control group received the 1% weight/volume gum acacia suspension. Thirty minutes after the administration of the last dose, a freshly prepared 0.4 % solution of cupric acetate was administered to each animal intravenously via the marginal ear vein (4 mg/kg body weight) to induce ovulation. To assess ovulation, laparotomy was carried out 48 h after cupric acetate injection. The ovaries were exposed, bleeding points on each ovary were counted, and the ovaries and uteri were subjected to histopathological evaluation. RESULTS: Based on the number of bleeding points (ovulation sites) observed on the ovary, H(2) blockers showed varying degrees of anti-ovulatory activity. Roxatidine exerted the most pronounced activity. Histopathological observations of uterus and ovary confirmed the aforementioned observations. CONCLUSION: H(2) receptor blockers appeared to inhibit the cupric acetate-induced ovulation in albino rabbits. Our results seem to confirm the role of histamine in ovulation reported by other authors. PMID- 21281098 TI - Intrauterine contraceptives that do not fit well contribute to early discontinuation. AB - BACKGROUND: To shed additional light on various aspects of intrauterine contraception discussed recently in a comprehensive review article and on the continued development of frameless copper intrauterine devices (IUDs). CONTENT: An essential feature of intrauterine contraceptives is their long duration of action. However, this only applies in the absence of side effects. The importance of dimensional compatibility of the IUD or intrauterine system (IUS) with the uterine cavity should be stressed: IUD/IUS designs that fit will lead to high acceptability, a prerequisite with regard to continuation of use. Dimensional incompatibility, on the other hand, is a cause of cramping pain, erratic bleeding or menorrhagia, dislocation or expulsion and, as a result thereof, pregnancy. The size of the intrauterine foreign body, in relation to that of the uterine cavity, determines its acceptability and influences menstrual bleeding. Abnormal and heavy menstrual bleeding is an issue which has not been fully resolved. It is the most common cause of discontinuation of this contraceptive modality. The size of the IUD can be reduced without jeopardizing its effectiveness provided the effective copper surface is sufficiently large. CONCLUSION: Properly designed and fitting IUDs and IUSs are associated with fewer side effects and greater user satisfaction. This, in turn, could increase usage of intrauterine contraception and thus reduce further the number of unintented pregnancies and induced abortions. PMID- 21281091 TI - Effects of cooperating and conflicting prosody in spoken English garden path sentences: ERP evidence for the boundary deletion hypothesis. AB - In reading, a comma in the wrong place can cause more severe misunderstandings than the lack of a required comma. Here, we used ERPs to demonstrate that a similar effect holds for prosodic boundaries in spoken language. Participants judged the acceptability of temporarily ambiguous English "garden path" sentences whose prosodic boundaries were either in line or in conflict with the actual syntactic structure. Sentences with incongruent boundaries were accepted less than those with missing boundaries and elicited a stronger on-line brain response in ERPs (N400/P600 components). Our results support the notion that mentally deleting an overt prosodic boundary is more costly than postulating a new one and extend previous findings, suggesting an immediate role of prosody in sentence comprehension. Importantly, our study also provides new details on the profile and temporal dynamics of the closure positive shift (CPS), an ERP component assumed to reflect prosodic phrasing in speech and music in real time. We show that the CPS is reliably elicited at the onset of prosodic boundaries in English sentences and is preceded by negative components. Its early onset distinguishes the speech CPS in adults both from prosodic ERP correlates in infants and from the "music CPS" previously reported for trained musicians. PMID- 21281097 TI - Sexual risk-taking following relationship break-ups. AB - BACKGROUND: Changes in sexual behaviour over time have resulted in more frequent relationship break-ups, which carry specific sexual health challenges that we aim to explore in this study. STUDY DESIGN: The data were drawn from the French sexual behaviour survey, comprising a random sample of 4,798 women and 4,045 men aged 18-44 years. Logistic regression models were used to describe the associations between recent relationship break-ups and reported sexually transmitted infections and abortions over the same period, and being tested positive for Chlamydia at the time of the survey. RESULTS: Respondents who had experienced a break-up in the last five years (32% of women and 35% of men among respondents who were sexually active in the last five years) were more likely to report an abortion during the same time period (9% vs.5%, p < 0.001) and to be tested positive for Chlamydia at the time of interview (3% vs. 1%, p = 0.003), especially those aged 30-44. Women were less likely than men to have used a condom with a new partner after the separation (76% vs. 82%, p = 0.005), which suggests gender asymmetry in preventive issues following a break-up. CONCLUSIONS: This study shows that relationship dissolution is associated with higher sexual risk taking, especially among middle-aged adults. PMID- 21281092 TI - Perceptual and conceptual priming of environmental sounds. AB - It is still unknown whether sonic environments influence the processing of individual sounds in a similar way as discourse or sentence context influences the processing of individual words. One obstacle to answering this question has been the failure to dissociate perceptual (i.e., how similar are sonic environment and target sound?) and conceptual (i.e., how related are sonic environment and target?) priming effects. In this study, we dissociate these effects by creating prime-target pairs with a purely perceptual or both a perceptual and conceptual relationship. Perceptual prime-target pairs were derived from perceptual-conceptual pairs (i.e., meaningful environmental sounds) by shuffling the spectral composition of primes and targets so as to preserve their perceptual relationship while making them unrecognizable. Hearing both original and shuffled targets elicited a more positive N1/P2 complex in the ERP when targets were related to a preceding prime as compared with unrelated. Only related original targets reduced the N400 amplitude. Related shuffled targets tended to decrease the amplitude of a late temporo-parietal positivity. Taken together, these effects indicate that sonic environments influence first the perceptual and then the conceptual processing of individual sounds. Moreover, the influence on conceptual processing is comparable to the influence linguistic context has on the processing of individual words. PMID- 21281110 TI - Factors affecting survival among women with breast cancer in Hawaii. AB - BACKGROUND: Given previous reports of ethnic differences in breast cancer survival among Hawaii's population, we investigated the role of adherence to treatment standards, treatment toxicity, preexisting chronic conditions, and obesity in the survival of 382 prospectively studied breast cancer patients representing six ethnic groups. METHODS: Participants were recruited from several hospitals in Honolulu. Information on tumor characteristics and treatment was abstracted from medical records. Based on the Physicians Data Query (PDQ(r)), we assessed compliance with recommended treatment guidelines. Vital status and cause of death data were obtained through linkage with the Hawaii Tumor Registry. Cox proportional hazard models were used to compute hazard ratios for predictors of survival. RESULTS: After a median follow-up time of 13.2 +/- 3.7 years, 115 deaths had occurred, 43 from breast cancer and 72 from other causes. After adjustment, we observed only small differences in survival by ethnicity that were not statistically significant. In addition to advanced disease stage, obesity at diagnosis was a significant independent predictor of worse and receiving PDQ recommended treatment of better breast cancer-specific and all-cause survival. Developing high-grade toxicity was associated with worse breast cancer survival, whereas comorbidity and older age at diagnosis were associated with higher all cause mortality. Hormone receptor status, menopausal status, and type of health insurance were not associated with survival. CONCLUSIONS: These findings suggest that given access to healthcare, breast cancer patients experience similar survival rates. Although more information about mechanisms of action would be useful, it appears reasonable to recommend weight control to breast cancer survivors. PMID- 21281112 TI - Salicylic acid-dependent restriction of Tomato ringspot virus spread in tobacco is accompanied by a hypersensitive response, local RNA silencing, and moderate systemic resistance. AB - Tomato ringspot virus (ToRSV, a Nepovirus sp.) systemically infects many herbaceous plants. Viral RNA accumulates in symptomatic leaves and in young, asymptomatic leaves that emerge late in infection. Here, we show that systemic infection by ToRSV is restricted in tobacco. After an initial hypersensitive response in inoculated leaves, only a few plants showed limited systemic symptoms. Viral RNA did not usually accumulate to detectable levels in asymptomatic leaves. ToRSV-derived small-interfering RNAs and PR1a transcripts were only detected in tissues that contained viral RNA, indicating local induction of RNA silencing and salicylic acid (SA)-dependent defense responses. Lesion size and viral systemic spread were reduced with SA pretreatment but enhanced in NahG transgenic lines deficient in SA accumulation, suggesting that SA-dependent mechanisms play a key role in limiting ToRSV spread in tobacco. Restriction of virus infection was enhanced in transgenic lines expressing the P1 HC-Pro suppressor of silencing. Knocking down the SA-inducible RNA-dependent RNA polymerase 1 exacerbated the necrotic reaction but did not affect viral systemic spread. ToRSV-infected tobacco plants were susceptible to reinoculation by ToRSV or Tobacco mosaic virus, although a small reduction in lesion size was observed. This moderate systemic resistance suggests inefficient induction or spread of RNA silencing and systemic acquired resistance signal molecules. PMID- 21281111 TI - Alcohol consumption among HIV-infected women: impact on time to antiretroviral therapy and survival. AB - OBJECTIVE: Alcohol use is prevalent among HIV-infected people and is associated with lower antiretroviral adherence and high-risk sexual and injection behaviors. We sought to determine factors associated with alcohol use among HIV-infected women engaged in clinical care and if baseline alcohol use was associated with time to combination antiretroviral therapy (cART) and death in this population. METHODS: In an observational clinical cohort, alcohol consumption at the initial medical visit was examined and categorized as heavy, occasional, past, or no use. We used multinomial logistic regression to test preselected covariates and their association with baseline alcohol consumption. We then examined the association between alcohol use and time to cART and time to death using Kaplan-Meier statistics and Cox proportional hazards regression. RESULTS: Between 1997 and 2006, 1030 HIV-infected women enrolled in the cohort. Assessment of alcohol use revealed occasional and hazardous consumption in 29% and 17% of the cohort, respectively; 13% were past drinkers. In multivariate regression, heavy drinkers were more likely to be infected with hepatitis C than nondrinkers (relative risk ratios [RRR] 2.06, 95% confidence interval [CI] 1.29-3.44) and endorse current drug (RRR 3.51, 95% CI 2.09-5.91) and tobacco use (RRR 3.85 95% CI 1.81-8.19). Multivariable Cox regression adjusting for all clinical covariates demonstrated an increased mortality risk (hazard ratio [HR] 1.40, 95% CI 1.00-1.97, p < 0.05) among heavy drinkers compared to nondrinkers but no delays in cART initiation (1.04 95% CI 0.81-1.34) CONCLUSIONS: Among this cohort of HIV-infected women, heavy alcohol consumption was independently associated with earlier death. Baseline factors associated with heavy alcohol use included tobacco use, hepatitis C, and illicit drug use. Alcohol is a modifiable risk factor for adverse HIV-related outcomes. Providers should consistently screen for alcohol consumption and refer HIV-infected women with heavy alcohol use for treatment. PMID- 21281113 TI - Auxin signaling and transport promote susceptibility to the root-infecting fungal pathogen Fusarium oxysporum in Arabidopsis. AB - Fusarium oxysporum is a root-infecting fungal pathogen that causes wilt disease on a broad range of plant species, including the model plant Arabidopsis thaliana. Currently, very little is known about the molecular or physiological processes that are activated in the host during infection and the roles these processes play in resistance and susceptibility to F. oxysporum. In this study, we analyzed global gene expression profiles of F. oxysporum-infected Arabidopsis plants. Genes involved in jasmonate biosynthesis as well as jasmonate-dependent defense were coordinately induced by F. oxysporum. Similarly, tryptophan pathway genes, including those involved in both indole-glucosinolate and auxin biosynthesis, were upregulated in both the leaves and the roots of inoculated plants. Analysis of plants expressing the DR5:GUS construct suggested that root auxin homeostasis was altered during F. oxysporum infection. However, Arabidopsis mutants with altered auxin and tryptophan-derived metabolites such as indole glucosinolates and camalexin did not show an altered resistance to this pathogen. In contrast, several auxin-signaling mutants were more resistant to F. oxysporum. Chemical or genetic alteration of polar auxin transport also conferred increased pathogen resistance. Our results suggest that, similarly to many other pathogenic and nonpathogenic or beneficial soil organisms, F. oxysporum requires components of auxin signaling and transport to colonize the plant more effectively. Potential mechanisms of auxin signaling and transport-mediated F. oxysporum susceptibility are discussed. PMID- 21281114 TI - Exploring soil bacterial communities in different peanut-cropping sequences using multiple molecular approaches. AB - Soil bacterial communities have significant influence on soilborne plant pathogens and, thus, crop health. The present study focuses on ribotyping soil bacterial communities in different peanut-cropping sequences in Alabama. The objective was to identify changes in microbial assemblages in response to cropping sequences that can play a role in managing soilborne plant pathogens in peanut. Four peanut-cropping sequences were sampled at the Wiregrass Research Station, Headland, AL in 2006 and 2007, including continuous peanut, 4 years of bahiagrass followed by peanut, peanut-cotton, and peanut-corn-cotton. Soil sampling was done at early and mid-season and at harvest. Bacterial community structure was assessed using ribosomal intergenic spacer analysis (RISA) combined with 16S rRNA cloning and sequencing. RISA results indicated >70% dissimilarities among different cropping sequences. However, 90% similarities were noticed among replicated plots of the same cropping sequences. Cropping sequences and time of soil sampling had considerable effect on soil microbial community structure. Bahiagrass rotation with peanut was found to have the highest bacterial diversity, as indicated by a high Shannon Weaver Diversity index. Overall, higher bacterial diversity was observed with bahiagrass and corn rotations compared with continuous peanut. The bacterial divisions Proteobacteria, Acidobacteria, Firmicutes, Bacteroidetes, and Actinomycetes were the predominant bacterial phyla found in all peanut-cropping sequences. The Proteobacteria taxa in these soils were negatively correlated with the abundance of members of division Firmicutes but, conversely, had a significant positive correlation with Gemmatimonadetes taxa. The prevalence of the division Actinomycetes was negatively correlated with the relative abundance of members of division Verrucomicrobia. These results indicate complex interactions among soil bacteria that are important contributors to crop health. PMID- 21281118 TI - Representations and evolutionary operators for the scheduling of pump operations in water distribution networks. AB - Reducing the energy consumption of water distribution networks has never had more significance. The greatest energy savings can be obtained by carefully scheduling the operations of pumps. Schedules can be defined either implicitly, in terms of other elements of the network such as tank levels; or explicitly, by specifying the time during which each pump is on/off. The traditional representation of explicit schedules is a string of binary values with each bit representing pump on/off status during a particular time interval. In this paper, we formally define and analyze two new explicit representations based on time-controlled triggers, where the maximum number of pump switches is established beforehand and the schedule may contain fewer than the maximum number of switches. In these representations, a pump schedule is divided into a series of integers with each integer representing the number of hours for which a pump is active/inactive. This reduces the number of potential schedules compared to the binary representation, and allows the algorithm to operate on the feasible region of the search space. We propose evolutionary operators for these two new representations. The new representations and their corresponding operations are compared with the two most-used representations in pump scheduling, namely, binary representation and level-controlled triggers. A detailed statistical analysis of the results indicates which parameters have the greatest effect on the performance of evolutionary algorithms. The empirical results show that an evolutionary algorithm using the proposed representations is an improvement over the results obtained by a recent state of the art hybrid genetic algorithm for pump scheduling using level-controlled triggers. PMID- 21281115 TI - Biocontrol activity and primed systemic resistance by compost water extracts against anthracnoses of pepper and cucumber. AB - We investigated direct and indirect effects of compost water extracts (CWEs) from Iljuk-3, Iljuk-7, Shinong-8, and Shinong-9 for the control of anthracnoses caused by Colletotrichum coccodes on pepper and C. orbiculare on cucumber. All tested CWEs significantly (P < 0.05) inhibited in vitro conidial germination and appressorium formation of the fungal pathogens; however, DL-beta-amino-n-butyric acid (BABA) failed to inhibit the conidial development of the pathogens. Direct treatments of the CWEs and BABA on pepper and cucumber leaves at 1 and 3 days before or after inoculation significantly (P < 0.05) reduced anthracnose severities; Iljuk-3, Shinong-9, and BABA for pepper and Iljuk-7 for cucumber had more protective activities than curative activities. In addition, root treatment of CWEs suppressed anthracnoses on the plants by the pathogens; however, CWE treatment on lower leaves failed to reduce the diseases on the upper leaves of the plants. The CWE root treatments enhanced not only the expression of the pathogenesis-related (PR) genes CABPR1, CABGLU, CAChi2, CaPR-4, CAPO1, and CaPR 10 in pepper and PR1-1a, PR-2, PR-3, and APOX in cucumber but also the activity of beta-1,3-glucanase, chitinase, and peroxidase and the generation of hydrogen peroxide in pepper and cucumber under pathogen-inoculated conditions. However, the CWE treatments failed to induce the plant responses under pathogen-free conditions. These results indicated that the CWEs had direct effects, reducing anthracnoses by C. coccodes on pepper leaves and C. orbiculare on cucumber leaves through protective and curative effects. In addition, CWE root treatments could induce systemic resistance in the primed state against pathogens on plant leaves that enhanced PR gene expression, defense-related enzyme production, and hydrogen peroxide generation rapidly and effectively immediately after pathogen infection. Thus, the CWEs might suppress anthracnoses on leaves of both pepper and cucumber through primed (priming-mediated) systemic resistance. PMID- 21281119 TI - Multi-objective reliability-based optimization with stochastic metamodels. AB - This paper addresses continuous optimization problems with multiple objectives and parameter uncertainty defined by probability distributions. First, a reliability-based formulation is proposed, defining the nondeterministic Pareto set as the minimal solutions such that user-defined probabilities of nondominance and constraint satisfaction are guaranteed. The formulation can be incorporated with minor modifications in a multiobjective evolutionary algorithm (here: the nondominated sorting genetic algorithm-II). Then, in the perspective of applying the method to large-scale structural engineering problems--for which the computational effort devoted to the optimization algorithm itself is negligible in comparison with the simulation--the second part of the study is concerned with the need to reduce the number of function evaluations while avoiding modification of the simulation code. Therefore, nonintrusive stochastic metamodels are developed in two steps. First, for a given sampling of the deterministic variables, a preliminary decomposition of the random responses (objectives and constraints) is performed through polynomial chaos expansion (PCE), allowing a representation of the responses by a limited set of coefficients. Then, a metamodel is carried out by kriging interpolation of the PCE coefficients with respect to the deterministic variables. The method has been tested successfully on seven analytical test cases and on the 10-bar truss benchmark, demonstrating the potential of the proposed approach to provide reliability-based Pareto solutions at a reasonable computational cost. PMID- 21281126 TI - One method for objective adherence measurement in mind-body medicine. AB - OBJECTIVES: Home practice is frequently prescribed as part of mind-body medicine interventions, although rarely objectively measured. This brief methods report describes one method for objectively measuring home practice adherence using a custom monitoring software program. DESIGN: Methods for objectively measuring adherence were developed as part of a randomized controlled trial on the mechanisms of mindfulness meditation. SETTINGS/LOCATION: The study was conducted at Oregon Health & Science University, Portland, Oregon. SUBJECTS: The subjects comprised 11 combat veterans with post-traumatic stress disorder. INTERVENTIONS: The method used was mindfulness meditation. OUTCOME MEASURES: There were subjective and objective adherence measurements of mindfulness meditation home practice. RESULTS: The first iteration of objective adherence monitoring used an iPod device and had limitations in participant usage and correctly capturing data. In the second iteration, objective data were easily collected, uploaded, and viewed using the custom software application, iMINDr. Participants reported that iMINDr was straightforward to use, and they returned the monitoring units as directed. CONCLUSIONS: The iMINDr is an example of a simple objective adherence measurement system that may help mind-body researchers examine how home practice adherence may affect outcomes in future clinical trials. PMID- 21281122 TI - Follow-up study of complicated grief among parents eighteen months after a child's death in the pediatric intensive care unit. AB - OBJECTIVE: We previously demonstrated that parents whose children die in a pediatric intensive care unit (PICU) have a high level of complicated grief symptoms 6 months after the death. In this study, we investigate the change in the extent of complicated grief symptoms among these parents between 6 and 18 months postdeath and identify factors predicting improvement. METHODS: One hundred thirty-eight parents of 106 children completed surveys at 6 and 18 months. Surveys included the Inventory of Complicated Grief (ICG), measures of grief avoidance, attachment, caregiving and social support, and demographics. Multivariable analysis was performed using generalized estimating equations to identify characteristics independently associated with improvement in ICG score. RESULTS: ICG scores were 33.4 +/- 13.6 at 6 months and 28.0 +/- 13.5 at 18 months, representing an improvement in ICG score of 5.4 + 8.0 (95% confidence interval [CI] 4.1-6.8, p < 0.001). Variables independently associated with greater improvement in ICG score included traumatic death and greater grief avoidance. Variables independently associated with less improvement included being the biological parent and having more responsive caregiving. Parents with one or two surviving children had more improvement in ICG score than those with no surviving children whereas parents with three or more surviving children had less improvement. CONCLUSION: Complicated grief symptoms decrease among parents between 6 and 18 months after their child's death in the PICU; however, high symptom levels persists for some. Better understanding of the trajectory of complicated grief will allow parents at risk for persistent distress to receive professional support. PMID- 21281128 TI - T-oligos inhibit growth and induce apoptosis in human ovarian cancer cells. AB - Ovarian cancer remains a leading cause of death among women worldwide, and current treatment regimens for advanced disease are inadequate. Oligonucleotides with sequence homology to telomeres (called T-oligos) have been shown to mimic DNA damage responses in cells and induce cytotoxic effects in certain tumor cell lines. We studied the effects of 2 distinct 16 mer T-oligos in 4 human ovarian epithelial carcinoma cell lines. A T-oligo with perfect homology to the telomere overhang region demonstrated some cytotoxic activity in half of the cell lines. A G-rich T-oligo derivative showed more potency and broader cytotoxic activity in these lines than the parental T-oligo. Activation of apoptotic pathways in ovarian cancer cells by exposure to the T-oligo was demonstrated by multiple independent assays. T-oligo was shown to have additive, or more than additive, activity in combination with 2 different histone deacetylase drugs currently in clinical testing. T-oligos may therefore provide a new and tumor-targeted approach to ovarian cancers. PMID- 21281129 TI - The CTX-M conundrum: dissemination of plasmids and Escherichia coli clones. AB - The ongoing global spread and increased prevalence of CTX-M-type extended spectrum beta-lactamases in Enterobacteriaceae is of great concern. The successful distribution of CTX-M enzymes mainly involves Escherichia coli causing systemic as well as urinary tract infections in patients worldwide. CTX-M expression is often associated with coresistance that critically reduces treatments options. The mobilization of bla(CTX-M) genes from their original chromosomal position in various Kluyvera species has been facilitated by mobile genetic elements such as ISEcp1 or ISCR1. Molecular epidemiological studies have revealed a thriving linkage of bla(CTX-M) genes to conjugative plasmids and successful bacterial clones. Multireplicon FII plasmids are shown to carry the most widely distributed bla(CTX-M-15) across continents, paving the way for bla(CTX-M-15) into different genetic lineages of E. coli. Dissemination of virulent clones ST131-O25:H4-B2 and ST405-O102:H6-D is now being described worldwide. Importantly, CTX-M-producing strains are uncovering their ability of long-term gastrointestinal colonization often associated with travel to high prevalent areas. Thus, we are witnessing a global epidemic of bla(CTX-M)-encoding E. coli strains and plasmids, which require serious attention and efficient infection control measures. PMID- 21281131 TI - Efficient in silico assay of inhibitors of hepatitis C Virus RNA-dependent RNA polymerase by structure-based virtual screening and in vitro evaluation. AB - To identify a new protective or therapeutic intervention for hepatitis C virus (HCV) infection, we performed efficient structure-based virtual screening to identify novel inhibitory agents for HCV. To this end, we selected NS5B, an RNA dependent RNA polymerase (RdRp), as the target for the treatment of HCV infection. To decipher the dockable nature of various RdRp X-ray crystals, we docked the crystal ligand (inhibitor) to the crystal receptor (enzyme). The accuracy of regeneration of the crystal pose indicates the amenability of the RdRp binding pocket for structure-based virtual screening. We also utilized a consensus scoring scheme to reduce false positives, thereby ensuring efficient virtual screening. In this study, each molecule that ranked in the top 1% among all screening molecules gained 1 consensus point in a scoring function. Thus, after virtual screening of 57,177 chemicals from the Maybridge Screening collection, 14 molecules gained 8 points across 11 scoring functions. One of them, an isoxazole, showed significant dose-dependent inhibition of HCV RdRp activity and replication. In this study, we have developed a structure-based virtual screening method using HCV RdRp for efficient identification of novel inhibitors. PMID- 21281130 TI - A screen to identify small molecule inhibitors of protein-protein interactions in mycobacteria. AB - Despite extensive efforts in tuberculosis (TB) drug research, very few novel inhibitors have been discovered. This issue emphasizes the need for innovative methods to discover new anti-TB drugs. In this study, we established a new high throughput screen (HTS) platform technology that differs from traditional TB drug screens because it utilizes Mycobacterial-Protein Fragment Complementation (M PFC) to identify small molecule inhibitors of protein-protein interactions in mycobacteria. Several examples of protein-protein interactions were tested with M PFC to highlight the diversity of selectable drug targets that could be used for screening. These included interactions of essential regulators (IdeR dimerization), enzymatic complexes (LeuCD), secretory antigens (Cfp10-Esat6), and signaling pathways (DevR dimerization). The feasibility of M-PFC in a HTS platform setting was tested by performing a proof-of-concept quantitative HTS of 3,600 small molecule compounds on DevR-DevR interaction, which was chosen because of its strong implications in Mycobacterium tuberculosis persistence and the need for effective drugs against latent TB. The calculated Z'-factor was consistently >=0.8, indicating a robust and reproducible assay. Completion of the proof-of concept screen allowed for the identification of advantages and disadvantages in the current assay design, where improvements made will further pioneer M-PFC based applications in a large-scale HTS format. PMID- 21281165 TI - Evaluation of antibacterial activity of Australian basidiomycetous macrofungi using a high-throughput 96-well plate assay. AB - CONTEXT: The production of antimicrobial compounds by macrofungi is not unexpected because they have to compete with other organisms for survival in their natural hostile environment. Previous studies have indicated that macrofungi contain secondary metabolites with a range of pharmacological activities including antimicrobial agents. OBJECTIVE: To investigate macrofungi for antimicrobial activity due to the increasing need for new antimicrobials as a result of resistance in the bacterial community to existing treatments. MATERIALS AND METHODS: Forty-seven different specimens of macrofungi were collected across Queensland, Australia. Freeze-dried fruiting bodies were sequentially extracted with three solvents: water, ethanol, and hexane. These extracts were tested against representative Gram+ve, Staphylococcus aureus and Gram-ve, Escherichia coli bacteria. RESULTS AND DISCUSSION: Overall water and ethanol extracts were more effective against S. aureus than E. coli, whereas a small number of hexane extracts showed better results for their antimicrobial potential against E. coli at higher concentrations only. Encouraging results were found for a number of macrofungi in the genera Agaricus (Agaricaceae), Amanita (Amanitaceae), Boletus (Boletaceae), Cantharellus (Cantharellaceae), Fomitopsis (Fomitopsidaceae), Hohenbuehelia (Pleurotaceae), Lentinus (Polyporaceae), Ramaria (Gomphaceae), and Strobilomyces (Boletaceae) showing good growth inhibition of the pathogens tested. CONCLUSION: The present study establishes the antimicrobial potential of a sample of Australian macrofungi that can serve as potential candidates for the development of new antibiotics. PMID- 21281171 TI - Informatics in medical education. PMID- 21281172 TI - Standards for teaching in medical schools: double or nothing. PMID- 21281174 TI - BEME Guide No. 1: Best Evidence Medical Education. AB - There is a need to move from opinion-based education to evidence-based education. Best evidence medical education (BEME) is the implementation, by teachers in their practice, of methods and approaches to education based on the best evidence available. It involves a professional judgement by the teacher about his/her teaching taking into account a number of factors-the QUESTS dimensions. The Quality of the research evidence available-how reliable is the evidence? the Utility of the evidence-can the methods be transferred and adopted without modification, the Extent of the evidence, the Strength of the evidence, the Target or outcomes measured-how valid is the evidence? and the Setting or context how relevant is the evidence? The evidence available can be graded on each of the six dimensions. In the ideal situation the evidence is high on all six dimensions, but this is rarely found. Usually the evidence may be good in some respects, but poor in others.The teacher has to balance the different dimensions and come to a decision on a course of action based on his or her professional judgement.The QUESTS dimensions highlight a number of tensions with regard to the evidence in medical education: quality vs. relevance; quality vs. validity; and utility vs. the setting or context. The different dimensions reflect the nature of research and innovation. Best Evidence Medical Education encourages a culture or ethos in which decision making takes place in this context. PMID- 21281173 TI - AMEE Guide No. 14: Outcome-based education: Part 5-From competency to meta competency: a model for the specification of learning outcomes. AB - Increased attention is being paid to the specification of learning outcomes.This paper provides a framework based on the three-circle model: what the doctor should be able to do ('doing the right thing'), the approaches to doing it ('doing the thing right') and the development of the individual as a professional ('the right person doing it').Twelve learning outcomes are specified, and these are further subdivided.The different outcomes have been defined at an appropriate level of generality to allow adaptability to the phases of the curriculum, to the subject matter, to the instructional methodology and to the students' learning needs. Outcomes in each of the three areas have distinct underlying characteristics.They move from technical competences or intelligences to meta competences including academic, emotional, analytical, creative and personal intelligences. The Dundee outcome model offers an intuitive, user-friendly and transparent approach to communicating learning outcomes. It encourages a holistic and integrated approach to medical education and helps to avoid tension between vocational and academic perspectives.The framework can be easily adapted to local needs. It emphasizes the relevance and validity of outcomes to medical practice.The model is relevant to all phases of education and can facilitate the continuum between the different phases. It has the potential of facilitating a comparison between different training programmes in medicine and between different professions engaged in health care delivery. PMID- 21281175 TI - BEME Guide No. 2: Teaching and learning communication skills in medicine-a review with quality grading of articles. AB - A literature search for articles concerning communication skills teaching and learning in medicine was done.The search yielded 180 pertinent articles, which were quality graded into the three categories of high, medium and low quality, using established criteria. Only those of high and medium quality were used for the review, which thus is based on 31 randomized studies, 38 open effect studies and 14 descriptive studies. Communication skills can be taught in courses, are learnt, but are easily forgotten if not maintained by practice.The most effective point in time to learn these at medical school is probably during the clinical clerkships, but there is no study that has specifically addressed this question.After a short period of training, doctors can be effective as teachers.The teaching method should be experiential as it has been shown conclusively that instructional methods do not give the desired results.The contents of communication skills courses should primarily be problem defining.All students should have communication skills training since those with the lowest pre-course scores gain the most from such courses. Men are slower learners of communication skills than women, which should be taken into account by course organizers. As there is only one really long-term follow up into the residency phase of communication skills training at medical school, those who have done randomized studies in the field should if possible carry out further follow-up studies. PMID- 21281176 TI - Twelve tips on teaching basic surgical skills using simulation and multimedia. AB - SUMMARY All doctors need a core of basic surgical skills, whether or not they eventually specialize as surgeons. Mastering any skill requires sustained deliberate practice, usually over several years. Ideally this should start early in undergraduate training and be reinforced at intervals. Simulation is well established in medical education and is ideal for learning surgical techniques. Realistic simulated tissue models allow initial training to be detached from the stresses of clinical practice. Small-group workshops run by experienced tutors provide learner-centred teaching. Computer-aided learning encourages regular practice, in preparation for supervised clinical experience when the basics have been mastered. This article describes a five-stage approach to learning surgical procedures using the author's multimedia CD-ROM in combination with simulated tissue: (1) watching an animated graphic; (2) watching a clinical video; (3) watching a demonstration on a simulated tissue model; (4) doing the procedure on a model; (5) doing the procedure on a patient, under supervision. PMID- 21281177 TI - Student attitudes towards the goals of an inter-professional training ward. AB - For some years, a 14-day practice period in an inter-professional, integrated training ward has been a compulsory element for students in six programmes at the Faculty of Health Sciences (FHS) in Linkoping, Sweden.The main purposes of the training are to enable students to collaborate in teams and to understand the competences and skills of the other students, to recognize the needs of the patients and to practise and develop their own professional role. A process evaluation of the first year of this training ward focused on students' attitudes towards the goals of the integrated learning activity.Results show that students from all programmes, generally speaking, entered the training with high expectations and that these expectations changed very little, i.e.their expectations were satisfied.The ability to 'understand other competences and skills' had an impact as a result of the training and was the only goal showing a measurable change in a positive direction. As regards programmes, the student nurses were the most positive group. It seems that students representing caring professions, who will cooperate closely in the future, have the highest expectations of teamwork and development of their own professional role and that these expectations are satisfied. Students from medicine and the paramedical programmes were less positive regarding the goal of developing their own professional role. A possible goal conflict between teamwork and practising one's own professional role is discussed. PMID- 21281178 TI - An accident waiting to happen? A case for medical education. AB - Item 18 of the GMC's (1997) Duties of a Doctor advises new doctors: "You must protect patients when you believe that a colleague's performance or health is a threat to them". Recent incidents have highlighted serious failures in standards of care, particularly where clinical mistakes have been made and subsequently covered up. Through the medium of a short case study, this article illustrates how the patterns of behaviour that lead to such failures and cover-ups may have their roots in the early stages of medical education.We argue that a more effective system of education and support for medical students and junior doctors will engender a culture in which mistakes can be admitted and rectified immediately. This will enable incidents to be used actively as learning experiences, shaping good clinical practice for the future. The emerging documentation from the GMC and others indicates a commitment to planning and monitoring of educational activity, within the context of clinical goverance.We hope that this will lead to an educational environment in which the quality of both training and service delivery may be assured. PMID- 21281179 TI - Unexpected pathological findings in skills training and assessing skills. AB - This article draws attention to unexpected pathological findings encountered by students and teachers when examining one another and/or simulated patients in skills training and assessment sessions.Although no literature on the subject was found, it appears to be not uncommon for students and teachers to find abnormalities during skills training and assessment. It is important that both students and teachers should be aware of this possibility and students should be encouraged to disclose any unexpected findings. Teachers should be given guidelines on the appropriate course of action during teacher-training sessions and students should be informed of the possibility of finding abnormal pathology prior to their participation in skills training and assessment. PMID- 21281180 TI - The role and development needs of general practice tutors. PMID- 21281181 TI - Learning the process of research by using the scientific method. PMID- 21281182 TI - Comparison of ambulatory and inpatient experiences in five specialties. AB - This study compared medical student evaluations of ambulatory and inpatient components of third-year clerkships in internal medicine, obstetrics/gynaecology, paediatrics, psychiatry, and surgery. Seventy-two students completed evaluation questionnaires at the conclusion of each of five clerkships over 12 months. Although ambulatory and inpatient evaluations were comparable across all five specialties in several areas, ambulatory education was rated more favorably in scheduling, clear definition of student roles and responsibilities, appropriate supervision, timely and constructive feedback, being welcomed, and working in a non-threatening environment.Student feedback thus implied that ambulatory experiences were comparable to, or better than, inpatient experiences and suggests areas for improving clinical education in inpatient settings. PMID- 21281183 TI - Do you know? PMID- 21281185 TI - News for AMEE members. PMID- 21281186 TI - What's new in medical education: items of interest to medical educators. PMID- 21281187 TI - Jottings. PMID- 21281189 TI - Use of a meal challenge test to estimate peak postprandial triglyceride concentrations in dogs. AB - OBJECTIVE: To develop a standardized meal challenge test by assessing associations between food-withheld preprandial (ie, fasting) and postprandial triglyceride concentrations, determining the most appropriate sampling time to detect the peak concentration (highest postprandial concentration), and estimating reference intervals for fasting and postprandial concentrations in healthy dogs. ANIMALS: 12 lean healthy mixed-breed dogs. PROCEDURES: Dogs were fed a dry commercially available diet (fat, 31% metabolizable energy) for 3 weeks. After food was withheld for 23 to 24 hours, plasma triglyceride concentrations were measured 1 and 0.083 hours before and 1, 2, 3, 4, 5, 6, 9, and 12 hours after feeding of a standardized challenge meal (median amount eaten, 63 kcal/kg [127 kcal/kg0.75]). Correlation and agreement between concentrations at peak and other time points were assessed by use of correlation coefficients and Bland-Altman limits of agreement. Reference intervals were calculated by use of a robust method. RESULTS: Fasting and peak triglyceride concentrations were not closely associated. The highest concentration among samples obtained 2, 5, and 6 hours after meal consumption had closest agreement with peak concentration. In 5 of 12 dogs, concentrations 12 hours after eating were still significantly above baseline concentration (mean of each dog's fasting concentrations). CONCLUSIONS AND CLINICAL RELEVANCE: Fasting triglyceride concentration could not be used to accurately predict peak concentration. When estimating peak concentration, multiple samples should be collected 2, 5, and 6 hours after consumption of a standardized meal. Food may need to be withheld for > 12 hours when assessing fasting concentrations in healthy dogs. PMID- 21281190 TI - Assessment of five ELISAs for measurement of leptin concentrations in dogs. AB - OBJECTIVE: To evaluate 5 commercially available ELISAs for determination of leptin concentrations in serum samples from dogs. SAMPLE POPULATION: Serum samples from overweight-obese and thin-ideal weight clientowned dogs. PROCEDURES: Serum samples with high and low leptin concentrations (n = 7 samples each) were used for validation of the assays. Intra- and interassay precision, linearity under dilution, spiking recovery, and limit of quantification were determined. In addition, leptin concentrations in thin-ideal weight (n = 8) and overweight-obese (37) dogs were quantified. RESULTS: Use of 2 of the 5 ELISAs (A and B) revealed reactivity with canine leptin. Intra-and interassay coefficients of variation were < 6.1% and 76%, respectively, for assay A and 14.0% and 13.7%, respectively, for assay B. In assays A and B, dilutions of canine serum pools were used to determine linear regression equations. Recoveries were 77% to 101% for assay A and 67% to 125% for assay B. Significant differences in leptin concentrations between thin-ideal weight and overweight-obese dogs were detected only when analyzed with assay A. CONCLUSIONS AND CLINICAL RELEVANCE: Among 5 leptin ELISAs evaluated, a canine-specific leptin ELISA had adequate precision, linearity, and ability to discriminate between high and low leptin concentrations corresponding to overweight-obese and thin-ideal weight dogs, respectively. PMID- 21281192 TI - Evaluation of subcutaneous and oral administration of robenacoxib and meloxicam for the treatment of acute pain and inflammation associated with orthopedic surgery in dogs. AB - OBJECTIVE: To assess efficacy and tolerability of robenacoxib for control of pain and inflammation in dogs undergoing orthopedic surgery. ANIMALS: 140 client-owned dogs. PROCEDURES: A multicenter, prospective, randomized, blinded field trial was conducted to compare robenacoxib (97 dogs) and meloxicam (43 dogs). After randomization, each dog received an initial dose (robenacoxib, 2 mg/kg; meloxicam, 0.2 mg/kg) via SC injection before surgery and daily doses (robenacoxib, 1 to 2 mg/kg; meloxicam, 0.1 mg/kg) administered orally for up to 15 days after surgery. Efficacy was assessed by veterinarians and owners via numeric rating scales and visual analogue scales. Safety was assessed on the basis of reported adverse events, clinical signs, results of hematologic and biochemical analyses, and buccal mucosa bleeding times. RESULTS: Treatment groups were balanced with respect to baseline and demographic data. Both treatments provided similar adequate pain control, as assessed with a modified Glasgow pain scale as the primary end point and supported by secondary end points in evaluations conducted by veterinarians and owners. For the primary end point, the ratio of the reciprocal of the scores for robenacoxib to meloxicam was 1.16 (95% confidence interval, 0.98 to 1.37). No dogs required rescue analgesia. Both treatments were associated with only minor adverse events, which were not necessarily related to the administered treatments and did not affect mucosal bleeding times. CONCLUSIONS AND CLINICAL RELEVANCE: Robenacoxib provided efficacy and tolerability similar to those of meloxicam for the management of perioperative pain and inflammation in dogs undergoing orthopedic surgery. PMID- 21281191 TI - Refinement and initial validation of a multidimensional composite scale for use in assessing acute postoperative pain in cats. AB - OBJECTIVE: To refine and test construct validity and reliability of a composite pain scale for use in assessing acute postoperative pain in cats undergoing ovariohysterectomy. SAMPLE POPULATION: 40 cats that underwent ovariohysterectomy in a previous study. PROCEDURES: In a previous randomized, double-blind, placebo controlled study, a composite pain scale was developed to assess postoperative pain in cats that received a placebo or an analgesic (tramadol, vedaprofen, or tramadol-vedaprofen combination). In the present study, the scale was refined via item analysis (distribution frequency and occurrence), a nonparametric ANOVA, and item-to-total score correlation. Construct validity was assessed via factor analysis and known-groups discrimination, and reliability was measured by assessing internal consistency. RESULTS: Respiratory rate and respiratory pattern were rejected after item analysis. Factor analysis resulted in 5 dimensions (F1 [psychomotor change], posture, comfort, activity, mental status, and miscellaneous behaviors; F2 [protection of wound area], reaction to palpation of the surgical wound and palpation of the abdomen and flank; F3 [physiologic variables], systolic arterial blood pressure and appetite; F4 [vocal expression of pain], vocalization; and F5 [heart rate]). Internal consistency was excellent for the overall scale and for F1, F2, and F3; very good for F4; and unacceptable for F5. Except for heart rate, the identified factors and scale total score could be used to detect differences between the analgesic and placebo groups and differences among the analgesic treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Results provided initial evidence of construct validity and reliability of a multidimensional composite tool for use in assessing acute postoperative pain in cats undergoing ovariohysterectomy. PMID- 21281193 TI - Effects of transforming growth factor-beta3 and matrix metalloproteinase-3 on the pathogenesis of chronic mitral valvular disease in dogs. AB - OBJECTIVE: To investigate the roles of transforming growth factor-beta (TGF-beta) isoforms and matrix metalloproteinases (MMPs) in development of chronic mitral valvular disease (CMVD) in dogs. SAMPLE POPULATION: 12 mitral valve leaflets collected from cadavers of 5 clinically normal dogs and from 7 dogs with CMVD. PROCEDURES: Expression of TGF-beta isoforms 1, 2, and 3; MMPs 1, 2, 3, and 9; TGF beta receptor II (TbetaR-II); and alpha smooth muscle actin (alphaSMA) in mitral valves of dogs with CMVD was compared with that in mitral valves from clinically normal dogs. Additionally, responses of valvular interstitial cells (VICs) to TGF beta3, MMP-3, and angiotensin-converting enzyme inhibitor (ACEI) as a suppressor of TGF-beta3 were examined in vitro. RESULTS: Expression of TGF-beta3, TbetaR-II, alphaSMA, and MMP-3 was only detected in mitral valves of dogs with CMVD. Concentrations of alphaSMA and proteoglycans in cultured VICs were significantly increased following incubation with TGF-beta3; treatment with MMP-3 resulted in increased amounts of active and total TGF-beta3, and total TGF-beta3 in VICs was significantly decreased by incubation with ACEI. CONCLUSIONS AND CLINICAL RELEVANCE: Findings suggested that increased TGF-beta3 and MMP-3 contribute to the pathogenesis of valvular degeneration associated with CMVD. In addition, it is possible that the use of ACEI could effectively block pathological alterations in VICs associated with CMVD in vitro. Impact on Human Medicine-CMVD is associated with primary mitral valve prolapse and Marfan syndrome in humans. Results of the study reported here will help to elucidate the molecular mechanisms of CMVD in dogs and humans. PMID- 21281195 TI - Estimation of intrathoracic arterial diameter by means of computed tomographic angiography in Hispaniolan Amazon parrots. AB - OBJECTIVE: To establish a computed tomography (CT)-angiography protocol and measure the diameters of major arteries in parrots. ANIMALS: 13 Hispaniolan Amazon parrots (Amazona ventralis). PROCEDURES: 16-slice CT scanning was used to measure the apparent diameter of the ascending aorta, abdominal aorta, pulmonary arteries, and brachiocephalic trunk. Before scanning, all birds underwent ECG and echocardiographic assessment and were considered free of detectable cardiovascular diseases. Each bird was anesthetized, and a precontrast helical CT scan was performed. Peak aortic enhancement was established with a test bolus technique via dynamic axial CT scan over a predetermined single slice. An additional bolus of contrast medium was then injected, and a helical CT angiography scan was performed immediately afterward. Arterial diameter measurements were obtained by 2 observers via various windows before and after injection, and intra- and interobserver agreement was assessed. RESULTS: Reference limits were determined for arterial diameter measurements before and after contrast medium administration in pulmonary, mediastinal, and manual angiography windows. Ratios of vertebral body diameter to keel length were also calculated. Intraobserver agreement was high (concordance correlation coefficients >= 0.95); interobserver agreement was medium to high (intraclass correlation coefficients >= 0.65). CONCLUSIONS AND CLINICAL RELEVANCE: CT angiography was safe and is of potential diagnostic value in parrots. We recommend performing the angiography immediately after IV injection of 3 mL of iohexol/kg. Arterial diameter measurements at the described locations were reliable. PMID- 21281196 TI - Ultrasonographic characterization of the liver, caudal vena cava, portal vein, and gallbladder in goats. AB - OBJECTIVE: To characterize the localization, visible extent (ie, measurement of selected dimensions), and appearance of the liver, caudal vena cava, portal vein, and gallbladder during ultrasonography in healthy goats. ANIMALS: 27 female Saanen goats. PROCEDURES: A 5.0-MHz linear transducer was used to ultrasonographically examine the localization, visible extent of various dimensions, and appearance of the liver, caudal vena cava, portal vein, and gallbladder from the right side of each goat. RESULTS: Images of the liver were obtained in all goats. The dorsal margin of the liver extended in a cranioventral to caudodorsal direction parallel to the caudal margin of the lungs. The greatest visible extent of the liver was evident at the seventh and eighth intercostal spaces (mean value, 15.9 cm), and width was evident at the 10th intercostal space (mean value, 5.2 cm). The caudal vena cava had a triangular shape on cross section; the maximum width in cross section, circumference, and surface area ranged from 1.2 to 1.8 cm, 4.8 to 5.2 cm, and 0.8 to 1.1 cm2, respectively. The portal vein was round on cross section (diameter, 0.8 to 1.7 cm) with stellate ramifications into the liver parenchyma. The gallbladder was pear-shaped and variable in size; it extended beyond the ventral margin of the liver to a variable degree depending on the amount of bile. CONCLUSIONS AND CLINICAL RELEVANCE: Results provided information regarding the ultrasonographic appearance of the liver, caudal vena cava, portal vein, and gallbladder in healthy goats; these data may be useful during examination of goats with suspected liver disease. PMID- 21281194 TI - Comparison of five blood-typing methods for the feline AB blood group system. AB - Objective-To compare the ease of use and accuracy of 5 feline AB blood-typing methods: card agglutination (CARD), immunochromatographic cartridge (CHROM), gel based (GEL), and conventional slide (SLIDE) and tube (TUBE) agglutination assays. Sample Population-490 anticoagulated blood samples from sick and healthy cats submitted to the Transfusion or Clinical Laboratory at the Veterinary Hospital of the University of Pennsylvania. Procedures-Sample selection was purposely biased toward those from anemic, type B, or type AB cats or those with autoagglutination. All blood samples were tested by use of GEL, SLIDE, and TUBE methods. Fifty-eight samples were also tested by use of CARD and CHROM methods. The presence of alloantibodies in all cats expressing the B antigen as detected by use of any method was also assessed. Results-Compared with the historical gold standard TUBE method, good to excellent agreement was achieved with the other typing tests: CARD, 53 of 58 (91% agreement); CHROM, 55 of 58 (95%); GEL, 487 of 490 (99%); and SLIDE, 482 of 487 (99%; 3 samples were excluded because of autoagglutination). Four of the samples with discordant test results originated from cats with FeLV-related anemia. Conclusions and Clinical Relevance-Current laboratory and in-clinic methods provide simple and accurate typing for the feline AB blood group system with few discrepancies. Retyping after in-clinic typing with the GEL or TUBE laboratory methods is recommended to confirm any type B or AB cats. PMID- 21281197 TI - Evaluation of the cyclooxygenase selectivity of robenacoxib and its effect on recovery of ischemia-injured jejunal mucosa in horses. AB - OBJECTIVE: To determine the cyclooxygenase (COX) selectivity of robenacoxib and its effect on recovery of jejunal mucosa following ischemic injury in horses. ANIMALS: 12 healthy horses. PROCEDURES: Half the maximal inhibition (EC50) of robenacoxib for COX-1 and COX-2 activity was established in bloods samples from 6 horses via measurement of thromboxane B2 (TXB2) and prostaglandin E2 concentrations, respectively; COX selectivity was subsequently calculated. Six other horses were anesthetized, and ischemia was induced in the jejunum for 2 hours. Control and ischemia-injured mucosa were collected and incubated with Ringer's solution (control treatment), flunixin meglumine (2.7 * 10-5M), or robenacoxib (2.7 * 10-5M). Transepithelial electrical resistance and mannitol flux were measured over a 4-hour recovery period. Bathing solution TXB2 and prostaglandin E metabolite concentrations were measured to assess COX-1 and COX-2 function, respectively. RESULTS: The mean +/- SD EC50 value of robenacoxib for COX-1 and COX-2 was 11.46 +/- 4.46 MUM and 0.19 +/- 0.07 MUM, respectively, resulting in a COX selectivity ratio of 61.01. The transepithelial electrical resistance of ischemia-injured jejunum treated with flunixin meglumine was significantly lower than that of control and robenacoxib-treated tissues. A significant increase in concentrations of prostaglandin E metabolites and TXB2 was detected in control and robenacoxib-treated tissues but not flunixin meglumine-treated tissues. CONCLUSIONS AND CLINICAL RELEVANCE: Robenacoxib selectively inhibited COX-2 and allowed recovery of barrier function in ischemia injured equine jejunal tissue in vitro. PMID- 21281198 TI - Characterization of the temporal and spatial distribution and reproductive ratio of vesicular stomatitis outbreaks in Mexico in 2008. AB - OBJECTIVE: To characterize the temporal and spatial distribution and reproductive ratio of vesicular stomatitis (VS) outbreaks reported in Mexico in 2008. ANIMALS: Bovine herds in Mexico in which VS outbreaks were officially reported and confirmed from January 1 through December 31, 2008. PROCEDURES: The Poisson model of the space-time scan statistic was used to identify periods and geographical locations at highest risk for VS in Mexico in 2008. The herd reproductive ratio (R(h)) of the epidemic was computed by use of the doubling-time method. RESULTS: 1 significant space-time cluster of VS was detected in the state of Michoacan from September 4 through December 10, 2008. The temporal extent of the VS outbreaks and the value and pattern of decrease of the R(h) were different in the endemic zone of Tabasco and Chiapas, compared with findings in the region included in the space-time cluster. CONCLUSIONS AND CLINICAL RELEVANCE: The large number of VS outbreaks reported in Mexico in 2008 was associated with the spread of the disease from the endemic zone in southern Mexico to areas sporadically affected by the disease. Results suggested that implementation of a surveillance system in the endemic zone of Mexico aimed at early detection of changes in the value of R(h) and space-time clustering of the disease could help predict occurrence of future VS outbreaks originating from this endemic zone. This information will help prevent VS spread into regions of Mexico and neighboring countries that are only sporadically affected by the disease. PMID- 21281201 TI - Effect of feeding a high-protein diet following an 18-hour period of feed withholding on mammalian target of rapamycin-dependent signaling in skeletal muscle of mature horses. AB - OBJECTIVE: To determine the effect of refeeding following an 18-hour period of feed withholding on the phosphorylation of translation initiation factors in the skeletal muscle of mature horses. ANIMALS: 8 adult horses. PROCEDURES: Following an 18-hour period of feed withholding, horses either continued to have feed withheld (postabsorptive state) or were fed 2 g/kg of a high-protein feed (33% crude protein) at time 0 and 30 minutes (postprandial state). Blood samples were taken throughout the experimental period. At 90 minutes, a biopsy specimen was taken from the middle gluteal muscle to measure the phosphorylation of translation initiation factors and tissue amino acid concentrations. Plasma glucose, insulin, and amino acid concentrations were also measured. RESULTS: Horses in the postprandial state had significantly higher plasma insulin, glucose, and amino acid concentrations than did those in the postabsorptive state at the time of biopsy. Refeeding significantly increased the phosphorylation state of riboprotein S6 and eukaryotic initiation factor 4E binding protein 1. CONCLUSIONS AND CLINICAL RELEVANCE: In mature horses, feeding resulted in increased mammalian target of rapamycin signaling and the mechanism appeared to be independent of an increase in Akt phosphorylation at Ser473. Results indicate that adult horses may be able to increase rates of muscle protein synthesis in response to feeding and that dietary amino acids appear to be the main mediators of this effect. PMID- 21281199 TI - Evaluation of the effects of a commercially available Salmonella Newport siderophore receptor and porin protein vaccine on fecal shedding of Salmonella bacteria and health and performance of feedlot cattle. AB - OBJECTIVE: To evaluate effects of a Salmonella Newport siderophore receptor and porin protein (SRP) vaccine on cattle health and performance and on prevalence of fecal shedding of Salmonella bacteria in feedlot cattle. ANIMALS: 1,591 beef cattle. PROCEDURES: Cattle were randomly allocated within a replicate (n = 10 replicates [20 total pens]), administered 2 mL of a Salmonella Newport SRP vaccine (n = 795 cattle) or a placebo (796), and revaccinated approximately 21 days after the first administration. Health and performance data were recorded by trained feedlot personnel who were blinded to treatment. Fresh fecal samples (n = 25) were collected from pen floors on days 0, 60, and 120 and within 24 hours of cattle harvest and were subjected to selective Salmonella culture and serotyping by laboratory personnel who were blinded to treatment. Pen-level mixed models were used to analyze data. RESULTS: Significant differences in fecal prevalence of Salmonella bacteria or health and performance variables were not detected between vaccinated and control cattle. Salmonella bacteria were recovered from all 10 replicates, and cumulative prevalence estimates ranged from 1.5% to 22%. Overall prevalence of fecal shedding of Salmonella bacteria was 10.2% and 10.9% in vaccinated and control cattle, respectively. Overall morbidity risk was 34.8% for both vaccinated and control cattle. Overall mortality risks were 1.9% and 1.1% for vaccinated and control cattle, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: In this setting, administration of the Salmonella Newport SRP vaccine in feedlot cattle had no effect on fecal prevalence of Salmonella bacteria or cattle health and performance. PMID- 21281202 TI - Pharmacokinetics and antinociceptive effects of oral tramadol hydrochloride administration in Greyhounds. AB - OBJECTIVE: To determine the pharmacokinetics of tramadol, the active metabolite O desmethyltrcamadol, and the metabolites N-desmethyltramadol and N,O didesmethyltramadol after oral tramadol administration and to determine the antinociceptive effects of the drug in Greyhounds. ANIMALS: 6 healthy 2- to 3 year-old Greyhounds (3 male and 3 female), weighing 25.5 to 41.1 kg. PROCEDURES: A mean dose of 9.9 mg of tramadol HCl/kg was administered PO as whole tablets. Blood samples were obtained prior to and at various points after administration to measure plasma concentrations of tramadol and its metabolites via liquid chromatography with mass spectrometry. Antinociceptive effects were determined by measurement of pain-pressure thresholds with a von Frey device. RESULTS: Tramadol was well tolerated, and a significant increase in pain-pressure thresholds was evident 5 and 6 hours after administration. The mean maximum plasma concentrations of tramadol, O-desmethyltramadol, N-desmethyltramadol, and N,O didesmethyltramadol were 215.7, 5.7, 379.1, and 2372 ng/mL, respectively. The mean area-under-the-curve values for the compounds were 592, 16, 1,536, and 1,013 h.ng/mL, respectively. The terminal half-lives of the compounds were 1.1, 1.4, 2.3, and 3.6 hours, respectively. Tramadol was detected in urine 5 days, but not 7 days, after administration. CONCLUSIONS AND CLINICAL RELEVANCE: Oral tramadol administration yielded antinociceptive effects in Greyhounds, but plasma concentrations of tramadol and O-desmethyltramadol were lower than expected. Compared with the approved dose (100 mg, PO) in humans, a mean dose of 9.9 mg/kg, PO resulted in similar tramadol but lower O-desmethyltramadol plasma concentrations in Greyhounds. PMID- 21281203 TI - Evaluation of an extractionless high-performance liquid chromatography-tandem mass spectrometry method for detection and quantitation of rosiglitazone in canine plasma. AB - OBJECTIVE: To develop a simple extractionless method for detection of rosiglitazone in canine plasma and test the method in a pharmacokinetic study after oral administration of rosiglitazone in dogs. ANIMALS: 3 client-owned dogs with cancer. PROCEDURES: High-performance liquid chromatography-tandem mass spectrometry was performed on canine plasma. The 3 dogs with cancer in the pharmacokinetic study were assessed via physical examination and clinicopathologic evaluation and considered otherwise healthy. Food was withheld for 12 hours, and dogs were administered a single dose (4 mg/m2) of rosiglitazone. Plasma was collected at various times, processed, and analyzed for rosiglitazone. RESULTS: The developed method was robust and detected a minimum of 0.3 ng of rosiglitazone/mL. Mean +/- SD maximum plasma concentration was 205.2 +/ 79.1 ng/mL, which occurred at 3 +/- 1 hours, and mean +/- SD elimination half life was 1.4 +/- 0.4 hours. The area under the plasma rosiglitazone concentration versus-time curve varied widely among the 3 dogs (mean +/- SD, 652.2 +/- 351.3 ng/h/mL). CONCLUSIONS AND CLINICAL RELEVANCE: A simple extractionless method for detection of rosiglitazone in canine plasma was developed and was validated with excellent sensitivity, accuracy, precision, and recovery. The method enabled unambiguous evaluation and quantitation of rosiglitazone in canine plasma. This method will be useful for pharmacokinetic, bioavailability, or drug-drug interaction studies. Oral rosiglitazone administration was well tolerated in the dogs. PMID- 21281207 TI - Researching low-cost alternative treatments. PMID- 21281204 TI - Effects of preparation method, shear force, and exposure to collagen on release of growth factors from equine platelet-rich plasma. AB - OBJECTIVE: To test the hypotheses that preparation method, exposure to shear force, and exposure to collagen affect the release of growth factors from equine platelet-rich plasma (PRP). SAMPLE POPULATION: PRP obtained from 6 horses. PROCEDURES: PRP was prepared via 2 preparation methods (tube and automated) and subjected to 6 treatment conditions (resting, detergent, exposure to shear via 21 and 25-gauge needles, and exposure to collagen [10 and 20 MUg/mL]). Concentrations of platelet-derived growth factor, isoform BB (PDGF-BB); transforming growth factor beta, isoform 1 (TGFbeta1); and insulin-like growth factor, isoform 1 (IGF-1) were quantified by use of ELISAs. Statistical analysis was conducted via repeated-measures ANOVA. RESULTS: Platelet numbers were significantly higher in tube-prepared PRP than in automated-prepared PRP Growth factor concentrations did not differ significantly between preparation methods. Mean PDGF-BB concentration ranged from 134 to 7,157 pg/mL, mean TGFbeta1 concentration ranged from 1,153 to 22,677 pg/mL, and mean IGF-1 concentration ranged from 150 to 280 ng/mL. Shear force did not affect growth factor concentrations. Dose-dependent increases in PDGF-BB and TGFbeta1 were detected in response to collagen, but equalled only 10% of the estimated total platelet content. Concentrations of IGF-1 were not significantly different among treatments and negative or positive control treatments. Serum concentrations of PDGF-BB and TGFbeta1 exceeded concentrations in PRP for most treatment conditions. CONCLUSIONS AND CLINICAL RELEVANCE: Release of growth factors from equine PRP was negligible as a result of the injection process alone. Investigation of platelet-activation protocols is warranted to potentially enhance PRP treatment efficacy in horses. PMID- 21281208 TI - What is your diagnosis? Uterine adenocarcinoma. PMID- 21281209 TI - What is your diagnosis? Ectopic ureterocele. PMID- 21281210 TI - Pathology in practice. Extraskeletal chondroblastic osteosarcoma. PMID- 21281211 TI - Pathology in practice. Scuticociliatosis. PMID- 21281212 TI - Detecting statistical errors in veterinary research. PMID- 21281213 TI - Prevalence of infectious diseases in cats and dogs rescued following Hurricane Katrina. AB - OBJECTIVE: To determine the prevalence of infectious diseases of animal and zoonotic importance in cats and dogs rescued and transferred from the Gulf Coast region following Hurricane Katrina. DESIGN: Cross-sectional study. ANIMALS: 414 dogs and 56 cats rescued and transferred from the Gulf Coast region within 4 months after the hurricane. PROCEDURES: EDTA-anticoagulated blood and serum samples were tested via PCR and serologic assays for infectious diseases. RESULTS: In dogs, prevalence was highest for anti-West Nile virus (WNV) antibodies (218/390 [55.9%]), Dirofilaria immitis antigen (195/400 [48.8%]), anti Toxoplasma gondii antibodies (92/366 [25.1%]), and hemotropic mycoplasma DNA (40/345 [11.9%]). The DNA of Bartonella spp, Ehrlichia spp, or Babesia spp or anti-canine influenza virus antibodies were identified in < 2% of dogs. In cats, prevalence was highest for antibodies against Bartonella spp and DNA of Bartonella spp combined (49/55 [89.1 %]), anti-T gondii antibodies (13/55 [23.6%]), hemotropic mycoplasma DNA (5/47 [10.6%]), anti-WNV antibodies (5/48 [10.4%]), D immitis antigen (4/50 [8.0%]), and anti-FIV antibodies (4/56 [7.1%]). A total of 308 (74.4%) dogs and 52 (92.9%) cats had evidence of previous or current vector-borne infections. CONCLUSIONS AND CLINICAL RELEVANCE: Cats and dogs rescued from the disaster region had evidence of multiple infectious diseases. The dispersal of potentially infectious animals to other regions of North America where some infections were not typically found could have contributed to new geographic ranges for these organisms or to underdiagnosis in affected animals because of a low index of suspicion in regions with low disease prevalence. PMID- 21281215 TI - Efficacy of oral transmucosal and intravenous administration of buprenorphine before surgery for postoperative analgesia in dogs undergoing ovariohysterectomy. AB - OBJECTIVE: To compare the efficacy of preoperative administration of buprenorphine (via oral transmucosal [OTM] and IV routes) for postoperative analgesia in dogs undergoing ovariohysterectomy. DESIGN: Prospective, randomized, blinded study. ANIMALS: 18 dogs undergoing routine ovariohysterectomy. PROCEDURES: Dogs were allocated to 3 groups (6 dogs/group) and were assigned to receive buprenorphine (20 MUg/kg [9.09 MUg/lb], IV; a low dose [20 MUg/kg] via OTM administration [LOTM]; or a high dose [120 MUg/kg [54.54 MUg/lb] via OTM administration [HOTM]) immediately before anesthetic induction with propofol and maintenance with isoflurane for ovariohysterectomy. Postoperative pain was assessed by use of a dynamic interactive pain scale. Dogs were provided rescue analgesia when postoperative pain exceeded a predetermined threshold. Blood samples were collected, and liquid chromatography-electrospray ionization-tandem mass spectrometry was used to determine plasma concentrations of buprenorphine and its metabolites. Data were analyzed with an ANOVA. RESULTS: Body weight, surgical duration, propofol dose, isoflurane concentration, and cardiorespiratory variables did not differ significantly among treatment groups. Number of dogs requiring rescue analgesia did not differ significantly for the HOTM (1/6), IV (3/6), and LOTM (5/6) treatments. Similarly, mean +/- SEM duration of analgesia did not differ significantly for the HOTM (20.3 +/- 3.7 hours), IV (16.0 +/- 3.8 hours), and LOTM (7.3 +/- 3.3 hours) treatments. Plasma buprenorphine concentration was <= 0.60 ng/mL in 7 of 9 dogs requiring rescue analgesia. CONCLUSIONS AND CLINICAL RELEVANCE: Buprenorphine (HOTM) given immediately before anesthetic induction can be an alternative for postoperative pain management in dogs undergoing ovariohysterectomy. PMID- 21281216 TI - Trends in intake and outcome data for animal shelters in Colorado, 2000 to 2007. AB - OBJECTIVE: To measure trends in animal shelter intake and outcome data for dogs and cats in Colorado on a statewide, urban, and rural basis from 2000 through 2007. DESIGN: Retrospective cohort study. SAMPLE POPULATION: A group of 104 animal shelters and rescue organizations from Colorado representing 92% and 94% of statewide dog and cat intake, respectively, in 2007. PROCEDURES: Annual animal shelter data were analyzed for trends by use of linear regression analysis. Trends in urban and rural subgroups of shelters were compared by use of Student t tests. RESULTS: Statewide, the number of intakes/1,000 residents decreased by 10.8% for dogs during the 8-year study period, but increased by 19.9% for cats. There was no change in the dog euthanasia rate at 3.7/1,000 residents/y, but the rate for cats increased by 35.7% to 3.9/1,000 residents/y. There was no change in the statewide live release rate for dogs or cats, but there was a decrease of 12.6% for cats in the urban subgroup. CONCLUSIONS AND CLINICAL RELEVANCE: The trends suggested that the number of unwanted dogs in Colorado decreased during the study period, whereas the number of unwanted cats in animal shelters increased. There were clear differences in the trends in the urban and rural data, suggesting different needs in each type of community. At the current level of resource allocation, the shelter dynamics for dogs appeared to have reached equilibrium with respect to euthanasia. Transfers were increasingly being used within all regions of the state to optimize the chances of adoption. PMID- 21281217 TI - Comparison of oral administration of lomustine and prednisolone or prednisolone alone as treatment for granulomatous meningoencephalomyelitis or necrotizing encephalitis in dogs. AB - OBJECTIVE: To compare oral administration of lomustine and prednisolone with oral administration of prednisolone alone as treatment for granulomatous meningoencephalomyelitis (GME) or necrotizing encephalitis (NE) in dogs. DESIGN: Retrospective cohort study. ANIMALS: 25 dogs with GME and 18 dogs with NE (diagnosis confirmed in 8 and 5 dogs, respectively). PROCEDURES: Records of dogs with GME or NE were reviewed for results of initial neurologic assessments and clinicopathologic findings, treatment, follow-up clinicopathologic findings (for lomustine-treated dogs), and survival time. Dogs with GME or NE treated with lomustine and prednisolone were assigned to groups 1 (n = 14) and 3 (10), respectively; those treated with prednisolone alone were assigned to groups 2 (11) and 4 (8), respectively. RESULTS: Prednisolone was administered orally every 12 hours to all dogs. In groups 1 and 3, mean lomustine dosage was 60.3 mg/m2, PO, every 6 weeks. Median survival times in groups 1 through 4 were 457, 329, 323, and 91 days, respectively (no significant difference between groups 1 and 2 or between groups 3 and 4). Within the initial 12 months of treatment, median prednisolone dosage was reduced in all groups; dosage reduction in group 1 was significantly larger than that in group 2 at 6, 9, and 12 months. Combination treatment most frequently caused leukopenia, but had no significant effect on liver enzyme activities. CONCLUSIONS AND CLINICAL RELEVANCE: In dogs with GME and NE, oral administration of lomustine and prednisolone or prednisolone alone had similar efficacy. Inclusion of lomustine in the treatment regimen was generally tolerated well. PMID- 21281218 TI - Treatment and predictors of outcome in dogs with immune-mediated thrombocytopenia. AB - OBJECTIVE: To characterize the clinical course of disease and identify prognostic indicators for immune-mediated thrombocytopenia in dogs. DESIGN: Retrospective cohort study. ANIMALS: 73 dogs treated for immune-mediated thrombocytopenia at the Foster Hospital for Small Animals at the Tufts Cummings School of Veterinary Medicine and the Tufts Veterinary Emergency Treatment and Specialties Hospital. PROCEDURES: Medical records from the period of January 2002 through June 2008 were reviewed to identify dogs with a diagnosis of immune-mediated thrombocytopenia. Data collected included signalment, clinical signs, results of initial diagnostic tests, treatment, complications, and survival duration. RESULTS: Dog ages ranged from 5 months to 15 years (median, 8.1 years). Cocker Spaniels were overrepresented, compared with their distribution in the entire hospital population during the same period. Sixty-one of the 73 (84%) dogs survived to discharge. Seven (11 %) of those dogs were lost to follow-up. Five of the remaining 54 (9%) dogs had a relapse of the disease. The presence of melena or high BUN concentration at admission to the hospital was significantly correlated with a decreased probability of survival. CONCLUSIONS AND CLINICAL RELEVANCE: Immune-mediated thrombocytopenia is a serious yet treatable disease, which may have a lower rate of recurrence than previously reported. The presence of melena or high BUN concentration in the study suggested a poor prognosis for affected dogs. PMID- 21281219 TI - Suspected phenobarbital-induced pseudolymphoma in a cat. AB - CASE DESCRIPTION: A 4.5-year-old spayed female domestic shorthair cat was evaluated because of a generalized seizure disorder that developed after an anesthesia-related hypoxic event. CLINICAL FINDINGS: Following administration of phenobarbital, the seizures stopped but the cat developed severe generalized lymphadenopathy. Results of a CBC and serum biochemical analysis were unremarkable. Cytologic examination of the lymph nodes revealed a reactive lymphocyte population. Differential diagnoses included neoplasia and infection, but results of related diagnostic tests were all negative. TREATMENT AND OUTCOME: Treatment was changed from phenobarbital to levetiracetam. Ten days following discontinuation of phenobarbital, the lymph node enlargement resolved, and the cat remained free of seizures with levetiracetam as treatment. CLINICAL RELEVANCE: Pseudolymphoma and anticonvulsant hypersensitivity syndrome are recognized potential sequelae to anticonvulsant administration in humans. However, a pseudolymphoma-like reaction to anticonvulsants in veterinary species has not previously been reported. This case highlighted a potentially serious yet reversible sequela to phenobarbital treatment that may have been mistaken for more severe illness such as neoplasia. PMID- 21281220 TI - Evaluation of population health among bottlenose dolphins (Tursiops truncatus) at the United States Navy Marine Mammal Program. AB - OBJECTIVE: To evaluate health indicators for a population of bottlenose dolphins in the US Navy Marine Mammal Program (MMP) by use of data acquired from 1988 through 2007. DESIGN: Retrospective cohort study. ANIMALS: 167 bottlenose dolphins. PROCEDURES: The following indicators were used to evaluate the health of dolphins during the 20-year period: 5-year age structure, median survival age, annual survival rates, mortality rates, and neonatal and calf survival and mortality rates. Limitations of these population measurements as health indicators for dolphins were assessed. RESULTS: Crude mortality rates of dolphins for 1988 through 1992, 1993 through 1997, 1998 through 2002, and 2003 through 2007 were 3.1%, 4.7%, 3.6%, and 2.4%, respectively; during these same 4 study periods, median survival ages were 14.3, 14.4, 17.7, and 26.1 years, respectively, and mean survival rates were 0.98, 0.97, 0.97, and 0.99, respectively. From 1988 through 1997, 1998 through 2002, and 2003 through 2007, neonatal mortality rates were 4 of 16, 5 of 20, and 2 of 14 neonates, respectively. During these 3 study periods, mean annual survival rates for calves < 3 years old (excluding neonates that died at < 30 days old) were 0.97, 0.92, and 0.99, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Although there were limitations to the measurement of some health indicators, use of multiple methods indicated that the health of dolphins in the MMP population was comparable to, if not better than, that published for other dolphin populations. The MMP population of dolphins may provide useful reference values of health indicators for use in assessment of other managed dolphin populations. PMID- 21281222 TI - Applying genetic techniques to study remote shark fisheries in northeastern Madagascar. AB - BACKGROUND AND AIMS: The shark fisheries of Madagascar remain largely unstudied. Remoteness makes fisheries monitoring challenging while the high value of shark fins combined with the extreme poverty in Madagascar creates intensive pressure on shark resources. MATERIALS AND METHODS: We use DNA barcoding and species specific PCR assays to characterize shark fisheries in Antongil Bay in northeastern Madagascar. RESULTS: The 239 samples taken from individuals collected in 2001 and 2002 correspond to 19 species. The four most common species were Sphyrna lewini, Rhizoprionodon acutus, Carcharhinus brevipinna, and C. sorrah. Antongil Bay may be a breeding area for C. brevipinna, C. leucas, and S. lewini. CONCLUSION: Local names are generally not a useful proxy for monitoring the species harvested in the fishery. Conservation efforts should characterize species exploitation at present, create spatial and temporal fishing restrictions to protect endangered species, and restrict large mesh gillnets. PMID- 21281223 TI - Alterations in welding process voltage affect the generation of ultrafine particles, fume composition, and pulmonary toxicity. AB - The goal was to determine if increasing welding voltage changes the physico chemical properties of the fume and influences lung responses. Rats inhaled 40 mg/m3 (3 h/day * 3 days) of stainless steel (SS) welding fume generated at a standard voltage setting of 25 V (regular SS) or at a higher voltage (high voltage SS) of 30 V. Particle morphology, size and composition were characterized. Bronchoalveolar lavage was performed at different times after exposures to assess lung injury. Fumes collected from either of the welding conditions appeared as chain-like agglomerates of nanometer-sized primary particles. High voltage SS welding produced a greater number of ultrafine-sized particles. Fume generated by high voltage SS welding was higher in manganese. Pulmonary toxicity was more substantial and persisted longer after exposure to the regular SS fume. In summary, a modest raise in welding voltage affected fume size and elemental composition and altered the temporal lung toxicity profile. PMID- 21281224 TI - Random small interfering RNA library screen identifies siRNAs that induce human erythroleukemia cell differentiation. AB - Cancers are characterized by poor differentiation. Differentiation therapy is a strategy to alleviate malignant phenotypes by inducing cancer cell differentiation. Here we carried out a combinatorial high-throughput screen with a random siRNA library on human erythroleukemia K-562 cell differentiation. Two siRNAs screened from the library were validated to be able to induce erythroid differentiation to varying degrees, determined by CD235 and globin up-regulation, GATA-2 down-regulation, and cell growth inhibition. The screen we performed here is the first trial of screening cancer differentiation-inducing agents from a random siRNA library, demonstrating that a random siRNA library can be considered as a new resource in efforts to seek new therapeutic agents for cancers. As a random siRNA library has a broad coverage for the entire genome, including known/unknown genes and protein coding/non-coding sequences, screening using a random siRNA library can be expected to greatly augment the repertoire of therapeutic siRNAs for cancers. PMID- 21281225 TI - JAK2V617F mutation is associated with special alleles in essential thrombocythemia. AB - Janus kinase 2 mutation (JAK2V617F) has been identified in myeloproliferative neoplasms. Furthermore, special single nucleoside polymorphisms (SNPs) have been found to be associated with the JAK2V617F mutation. Therefore, the associations among JAK2V617F and special SNPs and the allelic location between them were investigated in patients with essential thrombocythemia (ET). A total of 61 patients with ET and 106 healthy individuals were enrolled. The PCR-RFLP method was applied to investigate the pattern of three SNPs, rs10974944, rs12343867, and rs12340895. Allele-specific PCR was used to examine the allelic location between rs10974944 and JAK2V617F. Among the patients with ET, 34 (55.7%, 34/61) were JAK2V617F positive (heterozygous) while the other 27 (44.3%, 27/61) were negative, and there were no MPLW515L/K mutations noted. The pattern of special SNPs in JAK2V617F(+) was significantly different from that in normal individuals (p <0.05), while there was no difference between JAK2V617F(-) patients and normal individuals. Allele-specific PCR showed high association of a cis-location between the special G-allele of rs10974944 and JAK2V617F(+). Based on this small numbered study, the results show the association between special SNPs and JAK2V617F mutation and a cis-location between the special G-allelic form of rs10974944 and the JAK2V617F mutation. These data highlight a close relationship between them in patients with ET. PMID- 21281226 TI - De novo acute myeloid leukemia with Philadelphia chromosome (BCR-ABL) and inversion 16 (CBFB-MYH11): report of two cases and review of the literature. PMID- 21281227 TI - Cyclin D1 positive diffuse large B-cell lymphoma is a post-germinal center-type lymphoma without alterations in the CCND1 gene locus. AB - The aims of this study were to analyze the incidence and morphology of cyclin D1+ DLBCL and cases of Richter transformation (RT), and to elucidate possible molecular mechanisms of cyclin D1 overexpression. Seventy-two cases of de novo DLBCL and 12 cases of RT were included in this study. Cyclin D1 positivity was found in 10/66 (15%) cases of unselected de novo DLBCL and in 2/11 (18%) cases of RT. Seven independently identified cases of cyclin D1+ DLBCL, including one RT, were added to the study. Centroblastic morphology was found in 17/19 (89%) cases of cyclin D1+, most with a post-germinal center phenotype (CD10-, BCL6+, MUM1+). No alterations in the CCND1 gene indicative for a translocation t(11;14) were identified by FISH. Analysis of the MYC locus yielded gene copy alterations in five cases and no disruption of the gene locus in any case, suggesting an alternative mechanism of cyclin D1 deregulation. PMID- 21281228 TI - Allogeneic hematopoietic cell transplant with fludarabine-based reduced-intensity conditioning as treatment for advanced chronic lymphocytic leukemia. PMID- 21281229 TI - Osteomalacia due to adult Fanconi syndrome in multiple myeloma. PMID- 21281230 TI - Physical and biophysical properties of proton tracks of energies 1 keV to 300 MeV in water. AB - PURPOSE: To investigate physical and biophysical properties of proton tracks 1 keV-300 MeV using Monte Carlo track structure methods. MATERIALS AND METHODS: We present model calculations for cross sections and methods for simulations of full slowing-down proton tracks. Protons and electrons were followed interaction-by interaction to cut-off energies, considering elastic scattering, ionisation, excitation, and charge-transfer. RESULTS: Model calculations are presented for singly differential and total cross sections, and path lengths and stopping powers as a measure of the code evaluation. Depth-dose distributions for 160 MeV protons are compared with experimental data. Frequencies of energy loss by electron interactions increase from ~ 3% for 10 keV to ~ 77% for 300 MeV protons, and electrons deposit >70% of the dose in 160 MeV tracks. From microdosimetry calculations, 1 MeV protons were found to be more effective than 5-300 MeV in energy depositions greater than 25, 50, and 500 eV in cylinders of diameters and lengths 2, 10, and 100 nm, respectively. For lower-energy depositions, higher energy protons are more effective. Decreasing the target size leads to the reduction of frequency- and dose-mean lineal energies for protons <1 MeV, and conversely for higher-energy protons. CONCLUSIONS: Descriptions of proton tracks at molecular levels facilitate investigations of track properties, energy loss, and microdosimetric parameters for radiation biophysics, radiation therapy, and space radiation research. PMID- 21281231 TI - A revival: radioimmunotherapy in mucosa associated lymphoid tissue lymphoma. PMID- 21281232 TI - Epidemiology of myelodysplastic syndromes: many questions remain. PMID- 21281233 TI - Asparaginase revisited. AB - Asparaginase is one of the main drugs used to treat acute lymphoblastic leukemia and certain non-Hodgkin lymphomas. The drug is a bacterial product, and this results in differences in activity, efficacy, and side effects among the various marketed products. Native products originate from either Escherichia coli or Erwinia chrysanthemi. Currently a new product, PEG-asparaginase, is on the market. Recombinant asparaginases will be entering the market in a few years, and development of the incorporation of asparaginase in erythrocytes is progressing. This article reviews the available data on the various asparaginases and current developments. Differences between the various preparations are discussed in relation to pharmacokinetics, i.e. the short half-life of Erwinia preparations and prolonged activity of PEG-asparaginase. Uncertainties in relation to antibody formation and batch related differences of the newer products are discussed. The adverse effects related to origin of a product, mode of action, and antibody formation are also discussed. PMID- 21281234 TI - Design issues in a randomized controlled trial of a pre-emptive versus empiric antifungal strategy for invasive aspergillosis in patients with high-risk hematologic malignancies. AB - Invasive aspergillosis (IA) is a major cause of mortality in patients with hematological malignancies, due largely to the inability of traditional culture and biopsy methods to make an early or accurate diagnosis. Diagnostic accuracy studies suggest that Aspergillus galactomannan (GM) enzyme immunoassay (ELISA) and Aspergillus PCR-based methods may overcome these limitations, but their impact on patient outcomes should be evaluated in a diagnostic randomized controlled trial (D-RCT). This article describes the methodology of a D-RCT which compares a new pre-emptive strategy (GM-ELISA- and Aspergillus PCR-driven antifungal therapy) with the standard fever-driven empiric antifungal treatment strategy. Issues including primary end-point and patient selection, duration of screening, choice of tests for the pre-emptive strategy, antifungal prophylaxis and bias control, which were considered in the design of the trial, are discussed. We suggest that the template presented herein is considered by researchers when evaluating the utility of new diagnostic tests (ClinicalTrials.gov number, NCT00163722). PMID- 21281235 TI - Lack of survival improvement in patients with peripheral T-cell lymphoma: a Surveillance, Epidemiology, and End Results analysis. AB - In patients with aggressive non-Hodgkin lymphomas (NHLs), T-cell lymphoma (TCL) confers a poor prognosis. Since rituximab has increased survival for patients with diffuse large B-cell lymphoma (DLBCL), we hypothesized that the difference in outcome by phenotype became more pronounced recently and evaluated these changes using the Surveillance, Epidemiology, and End Results (SEER) Program. Cases diagnosed in 1992-1997 (era 1) and 1998-2003 (era 2) were evaluated for outcomes according to immunophenotype and era. A total of 22,252 patients with DLBCL and 2222 with TCL were included. In both eras, patients with TCL were more likely to die from their disease than those with DLBCL. Death from NHL decreased significantly from era 1 to era 2 for all DLBCL patients grouped by age and stage but in none of the TCL groups. Improved outcomes for DLBCL after the introduction of rituximab-based therapies in 1997 have no counterpart in patients with TCL, pointing to the need for new therapies to treat TCL. PMID- 21281236 TI - Hypoxia-associated protein expression in primary central nervous system diffuse large B-cell lymphoma: does it predict prognosis? AB - Hypoxia-associated proteins are commonly expressed as a consequence of disturbances in microcirculation. However, the clinical relevance of the proteins has never been studied in primary central nervous system lymphoma (PCNSL). The expression of hypoxia-inducible factor 1alpha (HIF-1alpha) and its downstream proteins, vascular endothelial growth factor (VEGF) and glucose transporter 1 (GLUT-1), were evaluated in a central nervous system (CNS) lymphoma xenograft model and in human PCNSL tissue. In the CNS lymphoma xenograft model, the expression of HIF-1alpha, VEGF, and GLUT-1 co-localized in subsets of lymphoma cells adjacent to necrosis. In tumor specimens from 51 patients with PCNSL, positive HIF-1alpha staining was found in 26 patients (51.0%), positive VEGF in 30 (58.8%), and positive GLUT-1 in 17 (33.3%), and HIF-1alpha showed a significant correlation with VEGF (p < 0.05). However, no significant association was seen between hypoxia-associated protein positivity and unfavorable clinical characteristics. Thus, the results failed to show an association with shorter overall survival or time to progression, except that the percentage of lymphoma cells positive for GLUT-1 (>20%) was significantly associated with worse survival. In conclusion, hypoxia-associated proteins were expressed in PCNSL, suggesting a hypoxic microenvironment. However, the prognostic relevance of these proteins for PCNSL was not demonstrated in this study. PMID- 21281237 TI - Intermediate prognosis of 6q deletion in chronic lymphocytic leukemia. AB - Cytogenetic features have an important role in the definition of distinct disease subsets in CLL. The deletion of 6q is known to occur at a relatively low frequency in CLL, and the detailed analysis of hematologic and clinical features of patients with CLL with 6q deletion is limited. To verify the incidence and prognostic significance of 6q deletion in Chinese patients with CLL, fluorescence in situ hybridization (FISH) was used in 240 patients with CLL. del(6q23) was found in 18 patients (7.5%), and only five patients had deletion in 6q23 as the sole abnormality. Strong correlations between del(6q23) and clinical parameters were not found. A difference in terms of survival in patients with del(6q23) as compared with patients without this anomaly was not able to be demonstrated. However, a significant difference was found when comparing the del(6q23) group with the del(17p13) or del(11q22.3) group (p = 0.023), or isolated del(13q14) group (p = 0.019). Our findings place the del(6q23) cytogenetic subset of CLL in an intermediate prognosis position between patients with del(11q22.3) or del(17p13), and patients with isolated del(13q14). FISH probes to detect deletions of 6q might be useful in clinical practice in the work-up of patients with CLL. PMID- 21281238 TI - Baseline characteristics and predictors of outcome in patients with myelodysplastic syndromes living in Western Pennsylvania. AB - The myelodysplastic syndromes (MDS) are a collection of hematologic disorders that affect older adults, and whose baseline characteristics and risk factors for evolution to acute myeloid leukemia (AML) and death have not been completely defined. We analyzed a large unselected cohort of 214 patients with MDS from the University of Pittsburgh Network Cancer Registry in Western Pennsylvania. Patients' follow-up was 22 months, at the end of which 72.9% of patients were dead. Overall, the 36-month survival rate was 19.0% (95% CI: 14.0-24.5%); 22.4% (95% CI: 16.4-29.0%) for patients with lower-risk MDS; and 5.0% (95% CI: 0.1 14.8%) for patients with higher-risk MDS (p = 0.0007). During follow-up, 32.9% of the patients developed AML. Family history of cancer and having >=5% blasts at diagnosis were statistically significant predictors for progression to AML. A higher risk of death also was associated with age >70 years and previous diagnosis of another cancer. More than three cycles of chemotherapy sessions and a platelet count of >=50 * 10(3)/mm(3) were inversely associated with death. This study suggests the need to incorporate laboratory results such as percentage blasts and platelet counts as well as epidemiologic data on family history of cancer in future outcome studies on MDS. PMID- 21281239 TI - WAVE1 regulates P-glycoprotein expression via Ezrin in leukemia cells. AB - For children with acute myeloblastic leukemia (AML), multidrug resistance (MDR) reduces treatment effectiveness, and often leads to poor patient survival. While a number of factors have been described that affect MDR, the mechanisms underlying this effect remain unclear. In this study, the role of WAVE1 in MDR was investigated. Among 62 children with AML, high levels of WAVE1 were associated with poor patient outcomes. Proteomic techniques were used to identify novel WAVE1-interacting proteins from leukemia cells, one of which was the cytoskeleton regulator Ezrin. In leukemia cells, WAVE1 co-localized with both Ezrin and P-glycoprotein (P-gp), a critical regulator of the MDR phenotype. Overexpression of WAVE1 in K562 leukemia cells up-regulated P-gp and Ezrin, and reduced K562 cells' sensitivity to the chemotherapy drug adriamycin. The opposite effect was seen when WAVE1 expression was reduced via RNA interference. Critically, overexpression of WAVE1 in the absence of Ezrin did not affect P-gp levels or MDR. These data suggest that WAVE1 affects P-gp and MDR of leukemia cells through Ezrin. PMID- 21281240 TI - Allogeneic hematopoietic stem cell transplant after intravenous busulfan and fludarabine conditioning. PMID- 21281241 TI - Concomitant FIP1L1-PDGFRA fusion gene and T-cell clonality in a case of chronic eosinophilic leukemia with clonal evolution and an incomplete response to imatinib. PMID- 21281242 TI - An early computed tomography-guided antifungal treatment strategy is safe and efficacious in patients undergoing chemotherapy for high-risk acute leukemia. PMID- 21281244 TI - Effects of estradiol-drospirenone on ocular and nasal functions in postmenopausal women. AB - BACKGROUND: Hormones may have an impact on the incidence and course of dry-eye syndrome, and also nasal obstruction, especially in postmenopausal women. The aim of this study was to investigate the effects of drospirenone 2 mg + estradiol 1 mg (Angeliq(r), Bayer AG, Berlin, Germany) on ocular functions and nasal airflow in postmenopausal women. METHODS: Thirty-four postmenopausal women were recruited for the study. A questionnaire on ocular surface disease index (OSDI) was administered; after routine ophthalmologic examination, tear film break-up time (TBUT) and Schirmer tests were performed. Intraocular pressure was measured with a Goldmann applanation tonometer. Nasal airflow resistance values were measured using rhinomanometry. Participants were submitted to oral daily treatment with drospirenone 2 mg + estradiol 1 mg. The duration of the study was 6 months and the participants were studied in the basal condition and after 6 months of therapy. RESULTS: The OSDI score and intraocular pressure were significantly higher before treatment than after treatment (p<0.001); however, the results of the TBUT and Schimer test were significantly lower (p<0.05). Rhinomanometric values were better during drospirenone 2 mg + estradiol 1 mg therapy than those observed at baseline (p<0.001). CONCLUSIONS: Oral daily treatment with drospirenone 2 mg + estradiol 1 mg reduces the risks for ocular diseases and nasal obstruction in postmenopausal women. PMID- 21281245 TI - Antihyperglycemic activity and antioxidant role of Terminalia arjuna leaf in streptozotocin-induced diabetic rats. AB - CONTEXT: Terminalia arjuna Roxb. (Combretaceae), commonly known as Arjuna, is a large tree grown throughout the Indian peninsula and used traditionally for several medicinal purposes. OBJECTIVE: To evaluate antihyperglycemic and antioxidant role of methanol extract of T. arjuna leaf (META) in Wistar rats. MATERIALS AND METHODS: Hyperglycemia was induced in rats by single intraperitoneal injection of streptozotocin (STZ, 65 mg/kg body weight). Three days after STZ induction, the hyperglycemic rats were treated with META orally at the dose of 100 and 200 mg/kg body weight daily for 15 days. Glibenclamide (0.5 mg/kg, orally) was used as reference drug. The fasting blood glucose levels were measured on every fifth day during the 15-day treatment. Serum biochemical parameters such as serum glutamate pyruvate transaminase (SGPT), serum glutamate oxaloacetate transaminase (SGOT), alkaline phosphatase (ALP), cholesterol, and total protein were estimated. Antioxidant properties were assessed by estimating hepatic lipid peroxidation, reduced glutathione (GSH), and catalase (CAT). RESULTS AND DISCUSSION: META at the dose of 100 and 200 mg/kg orally significantly (P < 0.001) and dose-dependently reduced and normalized blood glucose levels as compared with that of STZ control group. Serum biochemical parameters were significantly (P < 0.001) restored toward normal levels in META treated rats as compared with STZ control. META treatment also significantly (P < 0.001) decreased lipid peroxidation and recovered GSH level and CAT activity toward normal as compared with STZ control. CONCLUSION: The present study infers that T. arjuna leaf demonstrated remarkable antihyperglycemic activity in STZ induced diabetic rats. The potential antihyperglycemic action is plausibly due to its underlying antioxidant role. PMID- 21281246 TI - Hypoglycemic activity of Erythrina variegata leaf in streptozotocin-induced diabetic rats. AB - CONTEXT: Erythrina variegata Linn. (Fabaceae), commonly known as Tiger's Claw, is a thorny deciduous tree grown in tropical and subtropical regions of Eastern Africa, Southern Asia, and Northern Australia. In India, its leaves are traditionally used for diabetes mellitus. OBJECTIVE: To evaluate the hypoglycemic activity of methanol extract of E. variegata leaf (MEEV) in streptozotocin (STZ) induced diabetic Wistar rats. MATERIALS AND METHODS: Hyperglycemia was induced in rats by single intraperitoneal injection of STZ (55 mg/kg body weight). Three days after STZ induction, the hyperglycemic rats were treated with MEEV orally at the doses of 300, 600, and 900 mg/kg body weight daily for 21 days. Glibenclamide (1 mg/kg, orally) was used as reference drug. The fasting blood glucose levels were measured on every 7th day during the 21 days of treatment. Serum biochemical parameters including lipid content were estimated. RESULTS AND DISCUSSION: MEEV at the doses of 300, 600, and 900 mg/kg orally significantly (P < 0.01) and dose dependently reduced and normalized blood glucose levels as compared to that of STZ control group; the dose 900 mg/kg being the most potent showing complete normalization of blood glucose levels. Serum biochemical parameters including lipid profile were significantly (P < 0.01) restored toward normal levels in META treated rats as compared to STZ control animals. CONCLUSION: This study concludes that E. variegata leaf demonstrated promising hypoglycemic action in STZ-induced diabetic rats substantiating its ethnomedicinal use. PMID- 21281247 TI - Cell line studies of glioblastoma and malignant glioma using a newly discovered prenylated chalcone. AB - CONTEXT: A newly discovered geranyl prenylated chalcone, semisynthesized from naturally occurring nymphaeol C, has the ability to inhibit the growth of CNS1 (glioblastoma) and 13-06 (malignant glioma) cells. A second-order regression model was established to predict the normalized cell viability of CNS1 and 13-06 cells. OBJECTIVE: The goal of this study is to evaluate the influence of prenylated chalcone on the glioblastoma and malignant glioma cell lines. For the first time, response surface methodology (RSM) has been introduced to perform a cell line study. MATERIALS AND METHODS: A newly discovered prenylated chalcone was used. This compound is a member of the flavonoid family and possesses a common phenylbenzopyrone structure. Two independent factors, including prenylated chalcone concentration and uptake time, were carefully evaluated by a 22 factorial design. RSM was introduced as a new method for CNS1 and 13-06 cell line studies. RESULTS: For CNS1 cells, the least inhibition uptake time was 20.7 h, and the least inhibition dose was 12.4 MUg/ml. For 13-06 cells, the best inhibition uptake time was 26.2 h, and the least inhibition dose was 12.0 MUg/ml. DISCUSSION AND CONCLUSION: The RSM model successfully predicted the normalized cell viability of CNS1 and 13-06 cells through the use of prenylated chalcone. The results obtained in this study will be useful for further studies on the use of prenylated chalcone. PMID- 21281248 TI - Evaluation of ethanol leaf extract of Ocimum sanctum in experimental models of anxiety and depression. AB - CONTEXT: Recent studies reveal the co-occurrence of both anxiety and depressive disorders in many clinical conditions, which has introduced the concept of mixed anxiety and depressive disorders (MADD). OBJECTIVE: The study evaluated the ethanol leaf extract of Ocimum sanctum (OS) Linn. (Labiatae), a prominent medicinal plant, against both anxiety and depressive disorder, to evaluate its potency in combating MADD. MATERIALS AND METHODS: Swiss albino mice weighing 20 25 g were used. Gross behavior was observed through Digiscan animal activity monitor. Depression was studied through tail suspension test (TST) and forced swim test (FST). Anxiety experiments included light dark test, elevated plus maze test, and holeboard test. Further, rotarod test was also used to study any defects in motor coordination. DISCUSSION AND CONCLUSION: OS at 200 mg/kg showed motor-depressant activity as evaluated with locomotor activity and stereotypy measures. OS at 50 mg/kg shortened the immobility time in the TST and FST, respectively, indicating a possible antidepressant activity. Further, a diminution in the anxiety response at a dose of 50 mg/kg, p.o. body weight was also observed against light dark, elevated plus maze, and holeboard tests, which signifies its antianxiety activity. No defects were observed in the motor coordination of the mice in the rotarod test. Thus, the OS extract shows antianxiety and antidepressant properties at the same dose and can be a potential therapeutic agent against mixed anxiety and depressive syndrome. PMID- 21281249 TI - Depsides isolated from the Sri Lankan lichen Parmotrema sp. exhibit selective Plk1 inhibitory activity. AB - CONTEXT: Mitotic kinase enzymes regulate critical stages of mitosis and are amenable to pharmacological inhibition. Since natural products have been a rich source of antimitotic inhibitors, we postulated that natural products would also provide effective inhibitors of mitotic kinases. OBJECTIVE: To explore unique marine and terrestrial natural product sources for new anticancer drug leads, we screened our natural product extract library for polo-like kinase-1 (Plk1) kinase inhibitors. MATERIALS AND METHODS: Extracts of the lichen Parmotrema sp. (Parmeliaceae) exhibited in vitro inhibitory activity. Bioassay-guided fractionation of the Parmotrema sp. extract led to the isolation of depside inhibitors. RESULTS: A new depside 1 has been isolated from the Sri Lankan lichen Parmotrema sp. along with the known metabolites 2 (beta-collatolic acid) and 3 (beta-alectoronic acid). The structure of depside 1 was elucidated by spectroscopic analysis. The three depsides 1-3 exhibited moderate inhibition of purified recombinant Plk1 kinase with IC50 of 2.8, 0.7, and 1.7 uM, respectively, at 1 uM ATP. Inhibitory activity was also observed at high concentrations of ATP, suggesting the potential for activity in a cellular environment. The depsides were also tested against a panel of 23 other recombinant kinases and were found to possess up to 30-fold selectivity toward Plk1. DISCUSSION AND CONCLUSION: These data suggest that the depsides 1-3 may serve as core structures that can be further explored as potential inhibitors of Plk1 and other kinases. PMID- 21281250 TI - Isolation and structure determination of a sesquiterpene lactone (vernodalinol) from Vernonia amygdalina extracts. AB - CONTEXT: Vernonia amygdalina Del. (VA; Asteraceae or Compositae) is a small tree growing throughout tropical Africa. It is widely used for food and medicinal purposes by local people. It was reported that it had several qualities, including anticancer activity. OBJECTIVE: A sesquiterpene lactone, vernodalinol, was isolated from VA leaves. The first reported source of vernodalinol was in 2009 from a different plant, only (1)H NMR spectrum and no detailed structural analysis were carried out. No whole spectroscopic data were provided. MATERIALS AND METHODS: VA dried leaves were extracted with 85% ethanol followed by further separation into four fractions by liquid-liquid extraction technique using various solvents: hexane, chloroform, and n-butanol. Vernodalinol was separated from the n-butanol fraction by column chromatography. The biological activity of vernodalinol was evaluated in estrogen receptor-positive (ER(+)) human breast carcinoma cells (MCF-7) in vitro. RESULTS: Results indicated that vernodalinol (25 and 50 MUg/mL) inhibited breast cancerous cell growth (DNA synthesis) by 34% (P < 0.025) and 40% (P < 0.025), respectively. It is reasonable to expect an LC(50) of 70-75 MUg/mL for vernodalinol in MCF-7 cells. DISCUSSION AND CONCLUSION: Vernodalinol structure was confirmed using a battery of spectroscopic methods, 1D and 2D NMR, high-resolution mass spectrometry (HR-MS), UV, IR, and X ray. These results suggest that vernodalinol, although it has some biological activity, is likely to work in concert with other ingredients responsible for the anticancer activity exhibited of VA. PMID- 21281251 TI - Pharmacological evaluation of aqueous extract of Althaea officinalis flower grown in Lebanon. AB - CONTEXT: Althaea officinalis Linn. (Malvaideae) flower is commonly used in folk medicine in Lebanon and neighboring countries. Although most of the studies have been conducted on the mucilage-rich roots, little is known about the flower. OBJECTIVE: This study investigates the potential role of aqueous extract of Althaea officinalis flower in lipemia, gastric ulcer, inflammation, and platelet aggregation using the rat model. MATERIAL AND METHODS: Blood lipid profile and liver function were assessed after 1 month of extract intake via drinking water. Anti-inflammatory activity was tested against acute and chronic inflammation induced by carrageenan and formalin, respectively. Antiulcer activity was evaluated using ethanol-induced gastric ulcer. Antiplatelet activity was investigated in vitro using the adenosine 5'-diphosphate (ADP)-induced platelet aggregation bioassay. RESULTS: The 50 mg/kg body weight dose resulted in significant increase in serum HDL cholesterol level with no effects on stool cholesterol and triacylglycerol. Increasing the dose to 500 mg/kg body weight caused a significant decrease in stool water content. No adverse effect on liver enzymes was observed. Significant anti-inflammatory (acute and chronic inflammation) and antiulcerogenic activities were observed at all used doses (50, 100, and 250 mg/kg body). Time-dependent inhibition of platelet aggregation was demonstrated at 500 ug/ml concentration. DISCUSSION AND CONCLUSION: The aqueous extract of Althaea officinalis flower demonstrated potential benefits in lipemia, inflammation, gastric ulcer, and platelet aggregation with no visible adverse effect. PMID- 21281254 TI - Threonine peptidases as drug targets against malaria. AB - INTRODUCTION: Malaria is caused by the intracellular parasite Plasmodium falciparum. Although numerous therapies are available to fight the disease, the number of pharmacophores is small, and constant development of novel therapies, especially with new targets, is desirable to fight developing resistance against presently prescribed drugs. AREAS COVERED: This review discusses research on plasmodial threonine peptidases along with recent advances in proteasome inhibitor development. EXPERT OPINION: While PfHslV is an attractive drug target in malaria, more investigation is required to clarify its functional role in the parasite. More efforts should also be invested in assessing the plasmodial proteasome as a drug target. The few papers investigating the effect of proteasome inhibitors on different stages of the life cycle point towards important roles not only during asexual, but also in hepatic and sexual stages, in humans and the mosquito. If this holds true, this is a key argument to further develop proteasome inhibitors for use against malaria. PMID- 21281255 TI - Increase of regulatory T cells in ileal mucosa of untreated pediatric Crohn's disease patients. AB - BACKGROUND: Inflammatory bowel disease (IBD) of pediatric and adult onset differs in several aspects although little knowledge exists about pathogenic disparity. Regulatory T cells (Tregs) characterized as CD4+CD25+Foxp3+ are modulators of gut homeostasis, but their role in human IBD remains unclear. OBJECTIVE: To evaluate the mucosal distribution of Foxp3+ and CD25+ cells in untreated pediatric IBD patients at the time of diagnosis. MATERIAL AND METHODS: Untreated pediatric (n = 14) and adult (n = 12) Crohn's disease (CD) patients were prospectively included together with age-matched symptomatic controls. Colonic and ileal mucosal biopsies collected at diagnosis were studied by immunohistochemistry for enumeration of T cells and for mucosal expression of Foxp3 and CD25. Multicolor immunofluorescence staining was performed in situ to phenotype Foxp3+ cells as Tregs and characterize the CD25+ cells. RESULTS: The density of mucosal T cells displayed only small variations, while that of Foxp3+ cells and CD25+ cells was increased in CD patients. Multicolor immunofluorescence showed that most CD25+ cells were macrophages. Interestingly, in the ileum of pediatric CD patients the density of Foxp3+ cells was significantly higher than in adult CD patients. Co expression of Foxp3 and CD25, as well as Foxp3 and CTLA-4, indicated that the Foxp3+ cells were Tregs. CONCLUSION: Mucosal numbers of Foxp3(+) Tregs and activated (CD25+) macrophages are elevated in both pediatric and adult ileal CD. The greater increase of ileal Foxp3+ Tregs in pediatric CD than in adult CD might contribute to the relatively less frequent phenotype of isolated ileal enteritis in CD children. PMID- 21281256 TI - Spinal cord injury therapies in humans: an overview of current clinical trials and their potential effects on intrinsic CNS macrophages. AB - INTRODUCTION: Macrophage activation is a hallmark of spinal cord injury (SCI) pathology. CNS macrophages, derived from resident microglia and blood monocytes, are ubiquitous throughout the injured spinal cord, and respond to signals in the lesion environment by changing their phenotype and function. Depending on their phenotype and activation status, macrophages may initiate secondary injury mechanisms and/or promote CNS regeneration and repair. AREAS COVERED: This review provides a comprehensive overview of current SCI clinical trials that are intended to promote neuroprotection, axon regeneration or cell replacement. None of these potential therapies were developed with the goal of influencing macrophage function; however, it is likely that each will have direct or indirect effects on CNS macrophages. The potential impact of each trial is discussed in the context of CNS macrophage biology. EXPERT OPINION: Activation of CNS macrophages is an inevitable consequence of traumatic SCI. Given that these cells are exquisitely sensitive to changes in microenvironment, any intervention that affects tissue integrity and/or the composition of the cellular milieu will undoubtedly affect CNS macrophages. Thus, it is important to understand how current clinical trials will affect intrinsic CNS macrophages. PMID- 21281257 TI - Development of simulated arthroscopic skills. AB - BACKGROUND AND PURPOSE: Previous studies have shown that there is a correlation between arthroscopic experience and performance on a virtual-reality (VR) unit. We analyzed the development inexperienced surgeons went through during VR training of shoulder arthroscopy. METHODS: 14 inexperienced surgeons from Silkeborg Regional Hospital were randomized into an intervention group and a control group. 7 experienced surgeons constituted another control group. All were tested twice on insightMIST-an advanced arthroscopic VR trainer-within a period of 6-15 days. The intervention group also received a 5-hour training program on the VR unit. RESULTS: The average time for the arthroscopy in the intervention group was reduced from 720 (SD 239) seconds to 223 (SD 114) seconds (p = 0.03 compared to the inexperienced control group). Distance travelled by the camera was reduced from 367 (SD 151) cm to 84 (SD 44) cm in the intervention group (p = 0.02 compared to the inexperienced control group). Depth of collisions was also significantly reduced, whereas distance travelled by the probe and number of collisions were improved in the intervention group, although not statistically significantly. INTERPRETATION: VR training is a possible way for young and inexperienced surgeons to achieve basic navigation skills necessary to perform arthroscopic surgery. Further studies regarding the transferability of the skills acquired on the VR unit to the operating theater are desirable. PMID- 21281258 TI - The role of bevacizumab in colorectal cancer: understanding its benefits and limitations. AB - INTRODUCTION: Angiogenesis is a key factor in the development of aberrant blood vessels required for malignant growth, invasion and progression. Inhibiting VEGF is by far the most clinically advanced anti-angiogenic target. Bevacizumab (BV), the only humanized mAb directed against VEGF, is approved for use in multiple tumor types after successful clinical trial results demonstrated benefits in progression-free survival and/or overall survival when combined with common cytotoxic chemotherapies. AREAS COVERED: The review focuses on the use of BV in colorectal cancer, discusses the clinical trial data supporting its increasing use and explores its limitations. Readers will gain a succinct description of the trial data demonstrating a modest survival benefit in metastatic colorectal cancer (mCRC) and the lack of benefit of BV when utilized in the adjuvant setting. A review of common BV toxicities and a discussion about possible BV resistance mechanisms are also provided. EXPERT OPINION: Although BV has demonstrated efficacy in mCRC, there is an urgent need to improve the understanding of its mechanism of action and the development of BV resistance. Furthermore, there is a need for delineating predictive markers of BV efficacy and toxicity. PMID- 21281259 TI - Validation of a 3D CT method for measurement of linear wear of acetabular cups. AB - BACKGROUND: We evaluated the accuracy and repeatability of a 3D method for polyethylene acetabular cup wear measurements using computed tomography (CT). We propose that the method be used for clinical in vivo assessment of wear in acetabular cups. MATERIAL AND METHODS: Ultra-high molecular weight polyethylene cups with a titanium mesh molded on the outside were subjected to wear using a hip simulator. Before and after wear, they were (1) imaged with a CT scanner using a phantom model device, (2) measured using a coordinate measurement machine (CMM), and (3) weighed. CMM was used as the reference method for measurement of femoral head penetration into the cup and for comparison with CT, and gravimetric measurements were used as a reference for both CT and CMM. Femoral head penetration and wear vector angle were studied. The head diameters were also measured with both CMM and CT. The repeatability of the method proposed was evaluated with two repeated measurements using different positions of the phantom in the CT scanner. RESULTS: The accuracy of the 3D CT method for evaluation of linear wear was 0.51 mm and the repeatability was 0.39 mm. Repeatability for wear vector angle was 17 degrees . INTERPRETATION: This study of metal-meshed hip simulated acetabular cups shows that CT has the capacity for reliable measurement of linear wear of acetabular cups at a clinically relevant level of accuracy. PMID- 21281260 TI - Surgery for skeletal metastases in lung cancer. AB - BACKGROUND AND PURPOSE: Most lung cancer patients with skeletal metastases have a short survival and it is difficult to identify those patients who will benefit from palliative surgery. We report complication and survival rates in a consecutive series of lung cancer patients who were operated for symptomatic skeletal metastases. METHODS: This study was based on data recorded in the Karolinska Skeletal Metastasis Register. The study period was 1987-2006. We identified 98 lung cancer patients (52 females). The median age at surgery was 62 (34-88) years. 78 lesions were located in the femur or spine. RESULTS: The median survival time after surgery was 3 (0-127) months. The cumulative 12-month survival after surgery was 13% (95% CI: 6-20). There was a difference between the survival after spinal surgery (2 months) and after extremity surgery (4 months) (p = 0.03). Complete pathological fracture in non-spinal metastases (50 patients) was an independent negative predictor of survival (hazard ratio (HR) = 1.8, 95% CI: 1-3). 16 of 31 patients with spinal metastases experienced a considerable improvement in their neurological function after surgery. The overall complication rate was 20%, including a reoperation rate of 15%. INTERPRETATION: Bone metastases and their subsequent surgical treatment in lung cancer patients are associated with high morbidity and mortality. Our findings will help to set appropriate expectations for these patients, their families, and surgeons. PMID- 21281261 TI - Platelet rich plasma therapies for sports muscle injuries: any evidence behind clinical practice? AB - INTRODUCTION: At present, no drugs are available to hasten restoration of muscle function after injury. Platelet-rich plasma (PRP) therapies may help athletes by promoting muscle regeneration. AREAS COVERED: This is a systematic review assessing the evidence base for PRP therapies in the management of muscle injuries. A computerized literature search, citation tracking and hand searching for original studies assessing the effect of PRP therapies on skeletal muscle cell biology, skeletal muscle repair, or regeneration in animals or humans was performed. No randomized trials have studied the merits of PRP injections for muscle healing. Clinical studies indicated that PRP therapies may enhance muscle repair after strain or contusion, and laboratory data indicated that they can enhance diverse aspects of myogenesis. However muscle injuries present a complicated picture that includes many components other than muscle cells, such as blood vessels, connective tissue and neural components. EXPERT OPINION: The field is relevant but under-researched. No PRP formulation has yet displayed proven solid evidence for the stimulation of healing and recovery after sports muscle injuries. Therefore, major issues, including standardization of formulations and application procedures, need to be addressed to inform clinical studies before recommending best practice guidelines. PMID- 21281262 TI - Wrist function recovers more rapidly after volar locked plating than after external fixation but the outcomes are similar after 1 year. AB - BACKGROUND AND PURPOSE: Promising results have been reported after volar locked plating of unstable dorsally displaced distal radius fractures. We investigated whether volar locked plating results in better patient-perceived, objective functional and radiographic outcomes compared to the less invasive external fixation. PATIENTS AND METHODS: 63 patients under 70 years of age, with an unstable extra-articular or non-comminuted intra-articular dorsally displaced distal radius fracture, were randomized to volar locked plating (n = 33) or bridging external fixation. Patient-perceived outcome was assessed with the Disability of the Arm, Shoulder, and Hand (DASH) questionnaire and the Patient Rated Wrist Evaluation (PRWE) questionnaire. RESULTS: At 3 and 6 months, the volar plate group had better DASH and PRWE scores but at 12 months the scores were similar. Objective function, measured as grip strength and range of movement, was superior in the volar plate group but the differences diminished and were small at 12 months. Axial length and volar tilt were retained slightly better in the volar plate group. INTERPRETATION: Volar plate fixation is more advantageous than external fixation, in the early rehabilitation period. PMID- 21281263 TI - Pseudoarthrosis repair after failed metatarsophalangeal 1 arthrodesis. PMID- 21281264 TI - Idiopathic and secondary osteonecrosis of the femoral head show different thrombophilic changes and normal or higher levels of platelet growth factors. AB - BACKGROUND AND PURPOSE: Thrombophilia represents a risk factor both for idiopathic and secondary osteonecrosis (ON). We evaluated whether clotting changes in idiopathic ON were different from corticosteroid-associated ON. As platelet-rich plasma has been proposed as an adjuvant in surgery, we also assessed whether platelet and serum growth factors were similar to those in healthy subjects. METHODS: 18 patients with idiopathic ON and 18 with corticosteroid-associated ON were compared with 44 controls for acquired and inherited thrombophilia. Platelet factor 4 (PF4), transforming growth factor beta1, platelet-derived growth factor-BB (PDGF-BB), and vascular endothelial growth factor were assayed in the supernatants of thrombin-activated platelets, in platelet lysates, and in serum from 14 ON patients and 10 controls. RESULTS: Idiopathic ON patients had higher plasminogen levels (median 118%) than controls (101%) (p = 0.02). Those with corticosteroid-associated ON had significantly higher D-dimer (333 ng/mL) and lower protein C levels (129%) than controls (164 ng/mL, p = 0.004; 160%, p = 0.02). The frequency of inherited thrombophilia was not different from the controls. No statistically significant differences were found between idiopathic and corticosteroid-associated ON. 20 of the 36 ON patients were smokers. (The controls were selected from smokers because nicotine favors hypercoagulability). ON patients had significantly higher serum PF4 levels (7,383 IU/mL) and PDGF-BB levels (3.1 ng/mL) than controls (4,697 IU/mL, p = 0.005; 2.2 ng/mL, p = 0.02). INTERPRETATION: Acquired hypercoagulability was common in both ON types, but the specific changes varied. The release of GF from platelets was not affected, providing a biological basis for platelet-rich plasma being used as an adjuvant in surgical treatment. PMID- 21281265 TI - Failed internal fixation. PMID- 21281266 TI - Overtreatment of cruciate ligament injuries. PMID- 21281268 TI - Characterization of CYP3A isozymes involved in the metabolism of domperidone: role of cytochrome b5 and inhibition by ketoconazole. AB - Previous studies have indicated that CYP3As are involved in the metabolism of the prokinetic agent domperidone.The objectives of our study were to characterize further the role of specific CYP3A isoforms in the metabolism of domperidone and to compare the kinetic parameters of domperidone to those of the CYP3A probe drug midazolam. Intrinsic clearance for the formation of domperidone major metabolite (5-hydroxydomperidone) was the highest with rCYP3A4 (0.4 mL/min/nmol CYP450) compared to rCYP3A5 (0.04 mL/min/nmol CYP450). The addition of cytochrome b5 to recombinant enzymes (rCYP3A4 or rCYP3A5) increased up to 6-fold the Vmax for the formation of 5-hydroxydomperidone. In contrast, much similar intrinsic clearance values for rCYP3A4 and rCYP3A5 were determined in the respective formation of either 1-hydroxmidazolam (1.28 and 1.57 mL/min/nmol CYP450) or 4 hydroxymidazolam(0.04 and 0.06 mL/min/nmol CYP450). Vmax for the formation of midazolam metabolites was increased to a lesser extent(1.5-3-fold) by the addition of cytochrome b5. Ketoconazole more potently inhibited CYP3A4 than CYP3A5 for both domperidone and midazolam. However, the addition of cytochrome b5 to the incubation mixture appeared to decrease the inhibitory potency of ketoconazole towards CYP3A4 for domperidone but not for midazolam. Our results indicate that CYP3A4 plays major role in the metabolism of domperidone. We demonstrated a modulatory role of cytochrome b5mostly for the metabolism of domperidone and confirmed selective inhibition of CYP3A4 over CYP3A5 by ketoconazole. Comparison of domperidone kinetic parameters to those of the CYP3A probe drug midazolam suggests that domperidone exhibits a much higher CYP3A4/CYP3A5 selectivity ratio than midazolam. PMID- 21281269 TI - N-Docosahexaenoylethanolamide promotes development of hippocampal neurons. AB - DHA (docosahexaenoic acid, C22:6,n-3) has been shown to promote neurite growth and synaptogenesis in embryonic hippocampal neurons, supporting the importance of DHA known for hippocampus-related learning and memory function. In the present study, we demonstrate that DHA metabolism to DEA (N-docosahexaenoylethanolamide) is a significant mechanism for hippocampal neuronal development, contributing to synaptic function. We found that a fatty acid amide hydrolase inhibitor URB597 potentiates DHA-induced neurite growth, synaptogenesis and synaptic protein expression. Active metabolism of DHA to DEA was observed in embryonic day 18 hippocampal neuronal cultures, which was increased further by URB597. Synthetic DEA promoted hippocampal neurite growth and synaptogenesis at substantially lower concentrations in comparison with DHA. DEA-treated neurons increased the expression of synapsins and glutamate receptor subunits and exhibited enhanced glutamatergic synaptic activity, as was the case for DHA. The DEA level in mouse fetal hippocampi was altered according to the maternal dietary supply of n-3 fatty acids, suggesting that DEA formation is a relevant in vivo process responding to the DHA status. In conclusion, DHA metabolism to DEA is a significant biochemical mechanism for neurite growth, synaptogenesis and synaptic protein expression, leading to enhanced glutamatergic synaptic function. The novel DEA-dependent mechanism offers a new molecular insight into hippocampal neurodevelopment and function. PMID- 21281270 TI - Cold sensitivity in rice (Oryza sativa L.) is strongly correlated with a naturally occurring I99V mutation in the multifunctional glutathione transferase isoenzyme GSTZ2. AB - GSTZs [Zeta class GSTs (glutathione transferases)] are multifunctional enzymes that belong to a highly conserved subfamily of soluble GSTs found in species ranging from fungi and plants to animals. GSTZs are known to function as MAAIs [MAA (maleylacetoacetate) isomerases], which play a role in tyrosine catabolism by catalysing the isomerization of MAA to FAA (fumarylacetoacetate). As tyrosine metabolism in plants differs from animals, the significance of GSTZ/MAAI is unclear. In rice (Oryza sativa L.), a major QTL (quantitative trait locus) for seedling cold tolerance has been fine mapped to a region containing the genes OsGSTZ1 and OsGSTZ2. Sequencing of tolerant (ssp. japonica cv. M-202) and sensitive (ssp. indica cv. IR50) cultivars revealed two SNPs (single nucleotide polymorphisms) in OsGSTZ2 that result in amino acid differences (I99V and N184I). Recombinant OsGSTZ2 containing the Val99 residue found in IR50 had significantly reduced activity on MAA and DCA (dichloroacetic acid), but the Ile184 residue had no effect. The distribution of the SNP (c.295A>G) among various rice accessions indicates a significant association with chilling sensitivity in rice seedlings. The results of the present study show that naturally occurring OsGSTZ2 isoforms differ in their enzymatic properties, which may contribute to the differential response to chilling stress generally exhibited by the two major rice subspecies. PMID- 21281271 TI - A comparison of association methods correcting for population stratification in case-control studies. AB - Population stratification is an important issue in case-control studies of disease-marker association. Failure to properly account for population structure can lead to spurious association or reduced power. In this article, we compare the performance of six methods correcting for population stratification in case control association studies. These methods include genomic control (GC), EIGENSTRAT, principal component-based logistic regression (PCA-L), LAPSTRUCT, ROADTRIPS, and EMMAX. We also include the uncorrected Armitage test for comparison. In the simulation studies, we consider a wide range of population structure models for unrelated samples, including admixture. Our simulation results suggest that PCA-L and LAPSTRUCT perform well over all the scenarios studied, whereas GC, ROADTRIPS, and EMMAX fail to correct for population structure at single nucleotide polymorphisms (SNPs) that show strong differentiation across ancestral populations. The Armitage test does not adjust for confounding due to stratification thus has inflated type I error. Among all correction methods, EMMAX has the greatest power, based on the population structure settings considered for samples with unrelated individuals. The three methods, EIGENSTRAT, PCA-L, and LAPSTRUCT, are comparable, and outperform both GC and ROADTRIPS in almost all situations. PMID- 21281272 TI - Doubly robust estimates for binary longitudinal data analysis with missing response and missing covariates. AB - Longitudinal studies often feature incomplete response and covariate data. Likelihood-based methods such as the expectation-maximization algorithm give consistent estimators for model parameters when data are missing at random (MAR) provided that the response model and the missing covariate model are correctly specified; however, we do not need to specify the missing data mechanism. An alternative method is the weighted estimating equation, which gives consistent estimators if the missing data and response models are correctly specified; however, we do not need to specify the distribution of the covariates that have missing values. In this article, we develop a doubly robust estimation method for longitudinal data with missing response and missing covariate when data are MAR. This method is appealing in that it can provide consistent estimators if either the missing data model or the missing covariate model is correctly specified. Simulation studies demonstrate that this method performs well in a variety of situations. PMID- 21281273 TI - Informative cluster sizes for subcluster-level covariates and weighted generalized estimating equations. AB - Williamson, Datta, and Satten's (2003, Biometrics 59, 36-42) cluster-weighted generalized estimating equations (CWGEEs) are effective in adjusting for bias due to informative cluster sizes for cluster-level covariates. We show that CWGEE may not perform well, however, for covariates that can take different values within a cluster if the numbers of observations at each covariate level are informative. On the other hand, inverse probability of treatment weighting accounts for informative treatment propensity but not for informative cluster size. Motivated by evaluating the effect of a binary exposure in presence of such types of informativeness, we propose several weighted GEE estimators, with weights related to the size of a cluster as well as the distribution of the binary exposure within the cluster. Choice of the weights depends on the population of interest and the nature of the exposure. Through simulation studies, we demonstrate the superior performance of the new estimators compared to existing estimators such as from GEE, CWGEE, and inverse probability of treatment-weighted GEE. We demonstrate the use of our method using an example examining covariate effects on the risk of dental caries among small children. PMID- 21281274 TI - Accounting for data errors discovered from an audit in multiple linear regression. AB - A data coordinating team performed onsite audits and discovered discrepancies between the data sent to the coordinating center and that recorded at sites. We present statistical methods for incorporating audit results into analyses. This can be thought of as a measurement error problem, where the distribution of errors is a mixture with a point mass at 0. If the error rate is nonzero, then even if the mean of the discrepancy between the reported and correct values of a predictor is 0, naive estimates of the association between two continuous variables will be biased. We consider scenarios where there are (1) errors in the predictor, (2) errors in the outcome, and (3) possibly correlated errors in the predictor and outcome. We show how to incorporate the error rate and magnitude, estimated from a random subset (the audited records), to compute unbiased estimates of association and proper confidence intervals. We then extend these results to multiple linear regression where multiple covariates may be incorrect in the database and the rate and magnitude of the errors may depend on study site. We study the finite sample properties of our estimators using simulations, discuss some practical considerations, and illustrate our methods with data from 2815 HIV-infected patients in Latin America, of whom 234 had their data audited using a sequential auditing plan. PMID- 21281275 TI - Kernel machine approach to testing the significance of multiple genetic markers for risk prediction. AB - There is growing evidence that genomic and proteomic research holds great potential for changing irrevocably the practice of medicine. The ability to identify important genomic and biological markers for risk assessment can have a great impact in public health from disease prevention, to detection, to treatment selection. However, the potentially large number of markers and the complexity in the relationship between the markers and the outcome of interest impose a grand challenge in developing accurate risk prediction models. The standard approach to identifying important markers often assesses the marginal effects of individual markers on a phenotype of interest. When multiple markers relate to the phenotype simultaneously via a complex structure, such a type of marginal analysis may not be effective. To overcome such difficulties, we employ a kernel machine Cox regression framework and propose an efficient score test to assess the overall effect of a set of markers, such as genes within a pathway or a network, on survival outcomes. The proposed test has the advantage of capturing the potentially nonlinear effects without explicitly specifying a particular nonlinear functional form. To approximate the null distribution of the score statistic, we propose a simple resampling procedure that can be easily implemented in practice. Numerical studies suggest that the test performs well with respect to both empirical size and power even when the number of variables in a gene set is not small compared to the sample size. PMID- 21281276 TI - Minimize the use of minimization with unequal allocation. AB - Minimization as an alternative to randomization is gaining popularity for small clinical trials. In response to critics' questions about the proper analysis of such a trial, proponents have argued that a rerandomization approach, akin to a permutation test with conventional randomization, can be used. However, they add that this computationally intensive approach is not necessary because its results are very similar to those of a t-test or test of proportions unless the sample size is very small. We show that minimization applied with unequal allocation causes problems that challenge this conventional wisdom. PMID- 21281277 TI - Modelling of cardiovascular response to graded orthostatic stress: role of capillary filtration. AB - BACKGROUND: Of the many possible factors that may contribute to orthostatic intolerance, the loss of circulating blood because of capillary filtration is one of the few that can explain the gradual decline of arterial pressure during stand tests. This study used a computer model to investigate the relative importance of haemodynamic parameters, including capillary filtration, as potential contributors to orthostatic intolerance. Simulated orthostatic tolerance times were compared to previous experiments combining head-up tilt and lower body negative pressure graded orthostatic stress, which provided haemodynamic data, in particular haematocrit measurements that allowed subject-specific modelling of capillary transport. MATERIALS AND METHODS: The cardiovascular system was simulated using a seven-compartment model with measured heart rate, stroke volume, total peripheral resistance, mean arterial pressure and haematocrit data for 12 subjects. Simulations were controlled by decreasing the total blood volume at the measured rates of capillary filtration until cerebral pressure dropped below a threshold for consciousness. Predicted times to syncope were compared to actual times to presyncope, and sensitivity of arterial pressure and cardiac output to independent system parameters were determined. RESULTS: There was no statistical difference in modelled times to syncope and actual times to presyncope. Both arterial pressure and cardiac output were most sensitive to total blood volume and least sensitive to caudal compliance parameters. CONCLUSIONS: The feasibility of subject-specific simulations of cardiovascular response to orthostatic stress was demonstrated, providing stronger evidence that capillary filtration is a prominent mechanism in causing orthostatic intolerance. These results may have clinical and spaceflight applications. PMID- 21281278 TI - Carotid intima media thickness is associated with plasma lipoprotein-associated phospholipase A2 mass in nondiabetic subjects but not in patients with type 2 diabetes. AB - BACKGROUND: A recent meta-analysis showed that both plasma lipoprotein-associated phospholipase A(2) (Lp-PLA(2) ) mass and activity independently predict cardiovascular events. Notably, Lp-PLA(2) activity but not mass was found to be a determinant of cardiovascular outcome in type 2 diabetes mellitus. We questioned whether relationships of carotid intima media thickness (IMT), a measure of subclinical atherosclerosis, with Lp-PLA(2) mass differ between diabetic and nondiabetic subjects. MATERIALS AND METHODS: Relationships of IMT with plasma Lp PLA(2) mass (turbidimetric immunoassay) were compared in 74 patients with type 2 diabetes and in 64 nondiabetic subjects. RESULTS: IMT was increased (P=0.016), but plasma Lp-PLA(2) mass was decreased in patients with diabetes compared to nondiabetic subjects (277+/-66 vs. 327+/-62MUgL(-1) , P<0.001). In nondiabetic subjects, IMT was correlated positively with Lp-PLA(2) (r=0.325, P<0.009); multiple linear regression analysis confirmed an independent association of IMT with Lp-PLA(2) (beta=0.192, P=0.048). In contrast, IMT was unrelated to Lp-PLA(2) in patients with diabetes (r=0.021, P=0.86), and the relationship of IMT with Lp PLA(2) was different in diabetic and control subjects (P<0.001). The relationship of Lp-PLA(2) with the total cholesterol/high-density lipoprotein (HDL) cholesterol ratio also differed between diabetic and nondiabetic subjects (P<0.001). CONCLUSIONS: Plasma Lp-PLA(2) may relate to early stages of atherosclerosis development. In diabetes mellitus, in contrast, the association of IMT with plasma Lp-PLA(2) mass is abolished, which could be partly ascribed to redistribution of Lp-PLA(2) mass from apolipoprotein B-containing lipoproteins towards HDL. These findings raise questions about the usefulness of plasma Lp PLA(2) mass measurement as a marker of subclinical atherosclerosis in type 2 diabetes mellitus. PMID- 21281279 TI - Iron stores are associated with asymptomatic atherosclerosis in healthy men of primary prevention. AB - BACKGROUND: The aim of our study was to assess the impact of increased iron stores on the presence of asymptomatic atherosclerosis in a cohort of healthy men. We anticipated that higher iron stores would be associated with higher soluble cluster of differentiation 163 (sCD163) concentrations, elevated markers of oxidative stress, inflammation and higher common carotid intima-media thickness, independently of traditional risk factors of atherosclerosis. METHODS: In this cross-sectional study that included 72 healthy men, we measured the ultrasonography of common carotid intima-media thickness (IACC), the ratio of plasma-circulating transferrin receptors concentration to plasma ferritin concentration, certain inflammatory and oxidative stress markers, insulin sensitivity, plasma lipids and markers of endothelial dysfunction. RESULTS: The plasma-circulating transferrin receptor concentration to plasma ferritin concentration ratio (TfR/F) showed significant association with IACC (r=-0.310, P=0.008 vs. r=0.295, P=0.012). Multivariate analysis confirmed that the correlation of TfR/F with IACC is independent of traditional risk factors of atherosclerosis. The TfR/F ratio correlated with other indicators of atherosclerotic process fibrinogen (r=-0.292, P=0.013), von Willebrand factor (vWf; r=0.284, P=0.017), sCD163 (r=0.239, P=0.043) and IL-8 (r=0.233, P=0.049). In multivariate analysis, TfR/F independently correlated with haemoglobin (beta= 0.220, P=0.047), fibrinogen (beta=-0.290, P=0.009), IL-8 (beta=0.227, P=0.039) and sCD163 (beta=0.244, P=0.025); however, when vWf was added, significant independent correlation was seen only with fibrinogen (beta=-0.301, P=0.007) and IL-8 (beta=0.219, P=0.047). In addition, we demonstrated the independent correlation of sCD163 with vWf (beta=0.240, P=0.040). CONCLUSIONS: Our study showed a clear association of body iron stores expressed by the TfR/F ratio with asymptomatic carotid atherosclerosis. TfR/F further exhibited an independent positive correlation with fibrinogen and a negative correlation with sCD163 and IL-8. PMID- 21281280 TI - Volume regulating hormone responses to repeated head-up tilt and lower body negative pressure. AB - BACKGROUND: We hypothesized the existence of different hormonal response patterns to repeated lower body negative pressure (LBNP) and head-up tilt (HUT) in healthy males. We compared hormonal, cardiovascular and plasma volume changes from rest to stress within- and between-LBNP and HUT applications. Hormones investigated included adrenocorticotropic hormone (ACTH), aldosterone, plasma renin activity (PRA), atrial natriuretic peptide (ANP) and arginine vasopressin (AVP). MATERIALS AND METHODS: Three sequential 30-min bouts of LBNP at -55mmHg (n=14) or 70 degrees HUT (n=9) were preceded by 30-min supine rest, and a 60-min supine rest followed the 3rd stimulus. RESULTS: Plasma renin activity increases above baseline, in relation to aldosterone, were larger with LBNP than with HUT. The 3rd HUT application resulted in a greater increase in aldosterone compared to LBNP. Mean arterial blood pressure was elevated significantly during 1st and 3rd HUT application. ACTH responses were highly correlated with those of aldosterone in both LBNP and HUT (r(2) =0.96). AVP responses, in contrast to ANP, to the three consecutive stress situations were not significantly different, both with LBNP and HUT. CONCLUSIONS: We speculate that the observed differences in blood pressure and hormonal responses to LBNP and HUT are caused by divergent effects of blood pooling in the splanchnic region, despite similar reductions in splanchnic perfusion. Apparently with repeated central hypovolaemia, especially by the 3rd application of stress, plasma aldosterone levels rise (along with ACTH), conceivably increasing its volume-guarding effect. PMID- 21281281 TI - The universality of nursing. PMID- 21281282 TI - Welcome to the first issue for 2011. PMID- 21281283 TI - When I'm sixty-four. PMID- 21281287 TI - How to talk to doctors--a guide for effective communication. AB - BACKGROUND: Nurses and doctors undertake segregated and distinct preparation for clinical practice, yet are expected to communicate effectively with each other in the workplace. Most healthcare facilities have policies relating to written communication, but guidelines for verbal communication, which is used most in times of uncertainty and urgency, are generally less regulated. Poor communication and communication overload are shown to have a direct correlation with patient outcomes, adverse events and stressors among healthcare professionals. We suggest a guide for more effective verbal communication between nurses and doctors. METHODS: We perform an integrated review of the extensive literature that identifies specific problems that contribute to ineffective communication between a doctor and nurse. We discuss these in five themes in the modern clinical context including intensification of workload, workforce mobility, differing perceptions, language use and heuristics. To combat these, we provide a four point practical guide to arm the nurse clinician with effective tools to ensure a satisfactory exchange of information in the context of patient advocacy. CONCLUSIONS: The guide assists in overcoming the discussed barriers by creating a premise for fostering communication, understanding each clinician's information needs in a mutually respectful manner, especially in the context of uncertainty. We recommend that a shared mental model regarding communication in health be adopted at tertiary institutions offering pre-registration nursing and medical training and techniques and be woven into respective curriculum design. PMID- 21281288 TI - Nursing research in three regions in China: a bibliometric study. AB - OBJECTIVE: To analyse scientific papers published by Chinese authors in nursing journals included in the Science Citation Index Expanded and compare the published scientific papers from mainland China (ML), Taiwan (TW) and Hong Kong (HK). METHODS: All articles published in 62 journals that were related to nursing originating from ML, TW and HK from 1999 to 2008 were retrieved from the PubMed and Institute for Scientific Information (ISI) Web of Knowledge database. The total number of articles published in nursing journals, impact factors and citation reports and articles were estimated for quantity and quality comparisons. RESULTS: The number of articles from the three regions increased significantly from 1999 to 2008. There were 1015 articles in total from the three regions: ML (48), HK (414) and TW (553) in PubMed. In the ISI Web of Knowledge database, TW derived the highest total citations (1755 citations from 500 articles), followed by HK (1316 citations from 347 articles) and ML (158 citations from 55 articles). HK had the highest average citations of 3.79, followed by TW (3.51) and then ML (2.87). DISCUSSION: The difference between the quantity and quality of nursing research articles published in ML, TW and HK is significant, although the gap appears to be narrowing. Long-term job stresses, low levels of education and language barriers are likely the main factors. ML, TW and HK have the same culture and ethnicity. We expect that ML will benefit significantly from increased exchanges with TW and HK in nursing research and education. We also speculate that TW and HK will benefit from exchanges because ML may have diverse nursing problems. PMID- 21281289 TI - Bibliometrics as politics: the case of emerging disciplines. AB - Academic nurses are increasingly turning to bibliometrics to assess the state and status of research publication in nursing in countries around the world. Early bibliometric studies were carried out by Cattell as part of a project to advance research in psychology in the early decades of the 20th century. There are some echoes in nursing's moves to increase its standing over the last 40 years. The interpretation of bibliometric studies can reveal embedded values about academic disciplinary activity and normative views of scientific work. Patterns of publishing by nurse academics appear increasingly to resemble those in biomedicine as a whole. PMID- 21281290 TI - Work/life balance and health: the Nurses and Midwives e-cohort Study. AB - BACKGROUND: Nursing and midwifery are demanding professions. Efforts to understand the health consequences and workforce needs of these professions are urgently needed. Using a novel electronic approach, the Nurses and Midwives e cohort Study (NMeS) aims to investigate longitudinally Australian and New Zealand nurses' and midwives' work/life balance and health. This paper describes NMeS participation; provides key baseline demographic, workforce and health indicators; compares these baseline descriptions with external norms; and assesses the feasibility of the electronic approach. METHODS: From 1 April 2006 to 31 March 2008, nurses in Australia and New Zealand, and midwives in Australia were invited to participate. Potential participants were directed to a purpose built NMeS Internet site, where study information was provided and consent sought. Once obtained, a range of standardized tools combined into one comprehensive electronic questionnaire was elicited. RESULTS: Overall, 7633 (2.3%) eligible nurses and midwives participated (6308 from Australia and 1325 from New Zealand) from a total pool of 334,400. Age, gender, occupational and health profiles were similar between countries and to national figures. However, some differences were noted; for instance, Queensland participants were over represented, while Victorian and South Australian participants were under represented, and 28.2% of Australians were in high strain positions compared with 18.8% of New Zealanders. CONCLUSIONS: Using an internationally novel web-based approach, a large cohort, which appears generally similar to population norms, has been established. Provided participant retention is adequate, the NMeS will provide insight into understanding the drivers of nurses' and midwives' workforce retention and work-related factors associated with their health. PMID- 21281291 TI - The relationship between incidence and report of medication errors and working conditions. AB - BACKGROUND: Medication errors are considered to be a serious threat to patients' safety. Efforts to detect and prevent these errors have increased considerably in recent years. AIM: To determine the incidence and reporting rate of medication errors as reported by Iranian nurses and their relationship with work conditions in hospitals under the authority of Iran University of Medical Sciences. METHODS: This descriptive-analytical study was carried out in six hospitals. Through a stratified multiple stage sampling, 300 nurses were selected. A researcher constructed, three-part, self-report questionnaire was used to collect data regarding the nurses' medication errors, medication error reports and their perceived working conditions during the previous 3 months. The data were processed using descriptive statistics and Kruskal-Wallis one-way analysis of variance. FINDINGS: The mean of medication errors that nurses recalled was 19.5, and the mean of error reporting was 1.3 cases during the previous 3 months. The relationship between error incidence and work conditions as perceived by nurses was statistically significant (df = 3, P <= 0.0001); however, there was no significant relationship between reporting the occurred error and nurses' perceived work conditions (df = 3, P <= 0.255). CONCLUSION AND IMPLICATIONS: The establishment of an efficient reporting system, documentation of errors and removal of obstacles to reporting may result in reduced frequency of medication errors. Considering the relationship between medication error incidence and working conditions, it seems that creating a work condition in which nurses feel more comfortable and decreasing work tensions may pave the way to preventing nursing errors. PMID- 21281292 TI - Signposting the causes of medication errors. AB - BACKGROUND: Medication errors are a universal problem, but the causes and solutions are uncertain. AIM: This commentary contextualizes an important paper describing the medication error problem in one hospital in Iran. EVALUATION: Medication errors may be an important link between poor employment conditions for nurses and less favourable patient outcomes. IMPLICATIONS: This paper, taken with other observational work, suggests that intervention studies to test strategies to reduce medication errors may be key to improving patient outcomes. PMID- 21281293 TI - MRSA--global threat and personal disaster: patients' experiences. AB - AIM: To ascertain and describe the patients' knowledge, perceptions and experiences of being methicillin-resistant Staphylococcus aureus (MRSA) positive. BACKGROUND: Antibiotic resistant bacteria are a serious global threat. MRSA can cause wound infection, pneumonia, septicaemia and mortality. This qualitative study has focused on patients' experiences of living with MRSA. METHODS: Fifteen patients with MRSA-infected wounds were interviewed. All data were transcribed verbatim and analysed according to content analysis. FINDINGS: Information about the MRSA diagnosis often caused a shock-like reaction. Patients' perception of being MRSA positive was stigmatizing as plague or leprosy; they felt dirty and felt that they were a severe threat to their environment. Fears of infecting someone else and being rejected were commonly expressed. The key findings emerged as a theme: Being exposed to others' shortcomings and being a threat to others' health. Three categories were identified: understanding and emotional reactions, treatment by the healthcare professionals and consequences and expectations. Gaps in both patient and staff knowledge of MRSA led to unnecessary misunderstandings, causing fear, social isolation and suffering. CONCLUSIONS: Living with MRSA can be extremely stressful for the patients. Knowledge and empathy from staff involved in their care is crucial to optimize patients' experiences. Staff education to meet patients' demand for information and prevent contamination is essential. PMID- 21281294 TI - Resilience among Japanese atomic bomb survivors. AB - AIM: The purpose of the study was to explore the experience of atomic bomb survivors from Hiroshima and Nagasaki. BACKGROUND: Never has the world experienced such extreme devastation as with the atomic bombings of Hiroshima and Nagasaki, Japan, in August 1945. Although significant quantitative research has been completed about the medical effects following radiation, the literature lacks qualitative exploration from a holistic health perspective. METHODS: This was a qualitative descriptive study, using methods of narrative analysis, oral history and ethnography. The sample for this research included eight individuals who were exposed to the atomic bombings in Japan and currently reside in the United States. FINDINGS: Findings provide insight to the resilience that the survivors exhibited immediately following the bomb, as well as throughout the 65 years following the event. From ethnographic data and interviews with survivors, a thematic structure was developed that depicts the essential elements of the atomic bomb experience. Two ways of being in the world followed the bombing: surviving and thriving, with resilience serving as a lever, allowing for fluid movement over time across the continuum. Individuals experiencing surviving exhibited anxiety about their personal and family members' health, expressed mistrust, and felt a stigma associated with being a survivor. For those who were thriving, peace activism, overcoming and forgiveness were typically displayed. CONCLUSION: Findings from this study add to the disaster nursing literature and highlight the role resilience plays in the atomic bomb survivors' life perspective. PMID- 21281295 TI - Context of sexual risk behaviour among abused ethnic minority adolescent women. AB - BACKGROUND: Evidence suggests that multiple influences on sexual behaviour of adolescents exist, ranging from relationships with significant others including sexual or physical abuse and childhood molestation to substances used prior to sex and environmental circumstances such as sex work. PURPOSE: This study aims to describe associations between childhood molestation and sexual risk behaviour. METHOD: African American and Mexican American adolescent women aged 14-18 years (n=562) with sexually transmitted infection (STI) or abuse histories and enrolled in a randomized controlled trial of behavioural interventions were interviewed via self-report concerning sexual risk behaviour, abuse and childhood molestation at study entry. RESULTS: Sexual (59%), physical (77%) and psychological (82%) abuse and childhood molestation (25%) were self-reported without differences by ethnicity. Adolescents reporting childhood molestation experienced more forms of sexual, physical and psychological abuse than others and higher incidences of STI. Fewer attended school; however, more had arrests, convictions, incarcerations and probations. Stressors including depression, running away, thoughts of death and suicide were highest for those reporting childhood molestation. Those reporting childhood molestation engaged in higher sexual risk behaviours than adolescents experiencing other forms of sexual or physical abuse (lifetime partners, bisexual relationships, anal and group sex, sex with friends with benefits, sex for money, concurrent partners, drug use including multiple substances, alcohol use and alcohol problems). These adolescents reported 'getting high' and having sex when out of control as reasons for sex with multiple partners. CONCLUSION: Interventions for abused adolescent women necessitate a focus on associations between childhood molestation and a multiplicity of sexual risk behaviours for prevention of abuse, substance use and sex work, STI/human immunodeficiency virus (HIV) and sequelae. PMID- 21281296 TI - Nurses' and nursing students' attitudes towards late abortions. AB - AIM: The aim of the present study is to compare the attitudes of nursing students and nurses working in maternity wards towards late abortions performed after the 16th week of pregnancy and to identify the factors influencing their attitudes. METHODS: A quantitative design was employed in this descriptive study, using two convenience samples: 100 nurses working in the maternity ward of a large hospital and 100 nursing students from a nursing school in Israel. The self-report questionnaire was specially designed for purposes of this study. FINDINGS: Results showed that the nurses had less prejudicial attitudes towards late abortions than the nursing students. Overall, the participants had a more positive attitude towards late abortions in the following cases: (1) risk of malformation or developmental disability, (2) pregnancy as a result of rape, and (3) danger to the life of the mother. There was a weak negative connection between the participants' number of children and their attitudes towards late abortions. In addition, there was a significant relationship found between the level of religious observance and attitudes towards late abortions, as negative attitudes increased with higher religious observance. Indeed, the level of religious observance was found to be the most significant predictor of the participants' attitudes towards late abortions. CONCLUSION: Differences in attitudes were found between nursing students and nurses providing care to patients undergoing late abortions. Their personal religious beliefs, as well as the reason for the abortion, were found to be influential in determining their attitudes. PMID- 21281297 TI - The Clinical Nurse Leader--new nursing role with global implications. AB - AIM: This paper describes the development of the Clinical Nurse Leader (CNL (c)) role and education, the CNL's impact and potential to improve quality globally. BACKGROUND: The need for clinical nurse leadership to improve the quality of health care systems while controlling costs is recognized in reports internationally. In the USA, a new nursing role, the CNL, was developed in response to such reports. CONCLUSION: CNLs are master's level nurse graduates (although not necessarily recruited from a nursing background) with the skills and knowledge to create change within complex systems and improve outcomes while they remain direct care providers. This innovative role can be adapted worldwide to improve the quality of health care systems. PMID- 21281298 TI - Facilitating the quality of care in a specialist Pacific ophthalmic nursing workforce. AB - BACKGROUND: Sufficient, appropriately trained health personnel need to be retained in the workforce, and their performance maintained, to achieve quality care. Mid-level ophthalmic personnel in Western Pacific Island Countries and Territories (WPICT) are no exception. AIM: The study aims to assess influences on the quality of care provided by specialist mid-level ophthalmic personnel in WPICT and devise strategies to train, retain and maintain performance of these personnel. METHODS: A situational assessment employed a checklist and semi structured interviews with specialist mid-level ophthalmic personnel, nursing bodies and Ministry of Health representatives from seven WPICT. A selective literature review guided strategies to address the issues identified. RESULTS: Appropriate training allows nurses to fulfill a mid-level role in WPICT as specialist ophthalmic nurses. Resources generally do not restrict practice. Nursing structures have generally failed to support professionalism: scope and conditions of service, clinical supervision, career structures, professional recognition and opportunities for continuing professional development are rudimentary. Ophthalmic nurses were dissatisfied with the lack of specialty recognition, career progression and salary increase. Regional and local strategies tailored to each country have been devised to establish sustainable processes for support. CONCLUSION: Salary was a major cause of dissatisfaction. It should be addressed along with professional recognition and related processes. Without professional support, specialist and advanced cadres within nursing may cease to exist, nurses' performance may be affected or they may leave. Specialist ophthalmic nursing, recognized, situated within and properly supported by nursing structures can provide a model for specialist clinical care for other specialties and in other countries. PMID- 21281299 TI - Characteristics associated with intent to stay among Quality Improvement nurses. AB - AIM: The study aims to investigate characteristics associated with intent to stay among Quality Improvement (QI) nurses in Korean hospitals. BACKGROUND: QI nurses have recently emerged as a new specialty area in the nursing profession in Korea. They have played a major role in coordinating and facilitating hospital-wide QI activities. However, their frequent turnover degrades the continuity of overall QI programmes and incurs additional costs in human resource management. METHODS: A cross-sectional questionnaire survey was administered to 123 QI nurses in 123 general hospitals. The collected data included their hospital and department characteristics, work demand, job satisfaction, organizational commitment and demographics. The response rate was 94.3% (n=116). Multiple logistic regression analysis was performed to determine the factors associated with intent to stay. FINDINGS: Only 32.8% intended to stay in their current job. Significant factors associated with intent to stay were affective commitment and work demands. QI nurses with a higher level of affective commitment were more likely to stay [odds ratios (OR)=2.50], whereas those with higher quantitative work demands in QI education and support were less likely to stay (OR=0.40). CONCLUSION: The findings indicated that intent to stay was closely associated with work environment characteristics. Efforts to enhance their affective commitment and support their workload management are needed to increase the retention of qualified and experienced QI nurses. PMID- 21281300 TI - A unit-coordinator system: an effective method of reducing inappropriate hospital stays. AB - BACKGROUND: Many hospitals would benefit from a reduction in the length of inpatient hospital stays; in this regard, nursing approaches require complementation to ensure optimized nursing care. Such action is particularly important in general hospitals in Korea, where the ratio of patients to nurses is more than 10:1. OBJECTIVES: This study aimed to determine the effectiveness of a unit-coordinator system in complementing primary nursing in general hospitals as a means of reducing inappropriate hospital stays. METHODS: The unit-coordinator system was implemented in seven wards in a hospital in Seoul for 8 weeks. The existing primary nursing system was maintained, and newly placed unit coordinators organized the activities within each ward. The numbers of early admissions and early discharges were determined by assessing the electronic administrative records of the hospital. Further, the number of patients who had undergone check-ups and chemotherapy on the day of admission was confirmed from the daily reports of each ward. The effect of the unit-coordinator system on nurse satisfaction was assessed through direct interviews. FINDINGS: Early discharge and early-admission numbers increased significantly after implementation of the unit-coordinator system. Early admission allowed check-ups and treatments to be performed on the day of admission. Thus, this system reduced the length of hospital stay by 1 day, and the total reduction of inappropriate hospital stays over the 8-week study period was 66 days. Further, the unit coordinator system also increased nurse satisfaction. CONCLUSION: The unit coordinator system is an effective method of complementing primary nursing and reducing inappropriate hospital stays. PMID- 21281301 TI - Confidence in competence: legislation and nursing in New Zealand. AB - AIM: This article aims to identify and discuss a variety of interpretations, myths and tensions that surround the requirements for demonstrating continuing competence under a new national regulatory regime, which is designed to promote confidence in professional nursing practice in New Zealand (NZ). BACKGROUND: The enactment of the Health Practitioners' Competence Assurance Act (HPCA) 2003 in NZ requires regulatory authorities to implement, administer and monitor systems to ensure that health practitioners registered in a specific scope of practice are competent. The Nursing Council of New Zealand (NCNZ) is the regulatory authority for nurses in NZ. While the onus for demonstrating and maintaining competence is clearly the responsibility of the individual nurse, since the enactment of the HPCA Act, the assessment and monitoring of that competence is the responsibility of the Nursing Council. Demonstration of competence to practise nursing begins during undergraduate nursing education. However, demonstration of continuing competence is a new legislative requirement for nurses in NZ. As a result of this new legislation the NCNZ implemented a mandatory process for the monitoring of the continuing competence of nurses. CONCLUSION: Definitions of continuing competence within legislation and health professional regulation across developed nations have strong similarities. The need for continuing competence frameworks is generally agreed by regulatory authorities to be necessary to protect the safety of the public. However, regulatory processes that monitor the maintenance, assessment and development of continuing competence in nursing practice need to be overt, structured and well communicated in order to engage nurses, promote confidence in professional practice and protect the health and safety of members of the public. PMID- 21281302 TI - Ethics, culture and nursing practice in Ghana. AB - OBJECTIVE: This paper describes how nurses in Ghana approach ethical problems. BACKGROUND: The International Council of Nurses' (ICN) Code for Nurses (2006) that serves as the model for professional code of ethics worldwide also acknowledges respect for healthy cultural values. Using the ICN's Code and universal ethical principles as a benchmark, a survey was conducted in 2009 to ascertain how nurses in Ghana respond to ethical and cultural issues in their practice. METHODS: The study was qualitative with 200 participant nurses. Data were obtained through anonymous self-administered questionnaires. Descriptive statistics were used to analyze the data. FINDINGS: Nurses' approaches to ethical problems in Ghana do not always meet expectations of the ICN Code for Nurses. They are also informed by local ethical practices related to the institutional setting and cultural environment in the country. While some cultural values complemented the ICN's Code and universal ethical principles, others conflicted with them. NURSING IMPLICATIONS: These data can assist nurses to provide culturally competent solutions to ethical dilemmas in their practice. Dynamic communication between nurses and patients/clients, intentional study of local cultural beliefs, and the development of ethics education will improve the conformity between universal ethical standards and local cultural values. PMID- 21281303 TI - Internationalising university schools of nursing in South Africa through a Community of Practice. AB - INTRODUCTION: International nursing experiences in higher education have traditionally enabled and continue to enable nurses to appreciate '...the richness of the nursing mosaic...and the realities of nursing in many different cultural contexts'. This article describes a case study of the Collaboration for Higher Education of Nurses and Midwives in Africa in terms of its success in internationalising the nursing schools involved. BACKGROUND: Different types of international contact have led to a limited pattern of internationalization in the universities of Southern Africa, which often places African academics in a secondary or dependent position. Opportunities for truly equal international partnerships have been limited. METHODS: A qualitative analysis of the views of participants from the consortium of universities was carried out based on the conceptual framework of communities of practice. FINDINGS: An effective community of practice had been established, focused on the major knowledge domain of nursing and midwifery in Africa, and sharing the perception that their work was empowering and collaborative. The community had established its own ways of working, and articulated major institutional and individual benefits. PMID- 21281304 TI - Lived experiences of internationally educated nurses in hospitals in the United States of America. AB - AIM: The overall goal of this study was to elicit and describe the lived experiences of internationally educated nurses (IENs) who work in a multi hospital medical centre in the urban USA. BACKGROUND: Since World War Two, US health care agencies have addressed the nursing shortage by hiring IENs. While other countries have produced substantial research findings about their IENs, much less research has been done about IENs in the USA. Findings from the limited US studies suggest that more research is needed and first-hand reports of lived experiences must be added. METHODS: Using a phenomenology of practice study design and Giorgi's principles of data analysis, narratives from the guided interviews with 20 new immigrant IENs who had migrated from the countries of the Philippines, Nigeria and India to the USA, were collected and studied for themes. FINDINGS AND DISCUSSION: Six themes that emerged from the stories of IENs together describe a trajectory of lived experiences that the IENs encountered during their adjustments to living and working in the USA. The emergent themes were dreams of a better life, a difficult journey, a shocking reality, rising above the challenges, feeling and doing better and ready to help others. Study findings are similar to studies done in other countries and highlight the needs of IENs. CONCLUSION: The study findings provide important first-hand insights from the subjective perspectives of the IENs in US hospitals and will guide recruitment and retention of a diverse nursing workforce. Findings will enrich orientation and transition programs for IENs as well as strengthen the cohesiveness of a diverse nursing workforce in the USA. PMID- 21281305 TI - Workplace violence against Iranian nurses working in emergency departments. AB - BACKGROUND: Nurses working in emergency departments (EDs) are in the most danger of workplace violence (WPV) because of the critical nature of the wards. AIMS: This study aimed to find the frequency and nature of physical and verbal WPV against Iranian nurses working in EDs. METHODS: A cross-sectional study was carried out using consensus sampling of 196 bachelor's degree nurses working in 11 EDs of teaching hospitals in Tehran, Iran. The data were collected through the adapted version of a self-administered questionnaire developed by the International Labor Office/International Council of Nurses/World Health Organization/Public Services International on WPV in the health sector. The gathered data were analysed using descriptive and inferential statistics. RESULTS: The participants were mostly (89.1%) female and their work experiences (63.2%) in nursing were between 1 and 5 years; 19.7% of the nurses had faced physical violence. All of the physical violence incidents were without-weapon; 91.6% of the participants experienced verbal abuse during the past year. Patients' relatives were the most common source of violence. Dissatisfaction was reported on the way the incidents were handled. CONCLUSION: It is believed that finding the pattern and nature of WPV is the first step to develop suitable strategies to deal with the issue. Establishing WPV management teams and enacting appropriate laws can improve workplace safety for nurses and patients' care quality. PMID- 21281306 TI - Empowerment and its effects on clinical nurses in central China. AB - BACKGROUND: Chinese healthcare institutions have undergone constant changes in recent years. A large number of research studies conducted on work-related factors revealed that nurses in China experienced a low level of job satisfaction and a high level of turnover intention. Empowerment is one of the most important concepts in nursing and is most relevant to the study of nursing professionals' job-related outcomes. AIM: The aim of this study was to test the Job Characteristics Model and the mediating role of structural empowerment on the relationships between the job characteristics and work-related outcomes among clinical nurses from central China. METHODS: Three self-reported questionnaires were administered to a sample of 238 clinical nurses from two hospitals in central China. The results were analyzed using descriptive statistics, Pearson's correlation analysis and multiple linear regressions. FINDINGS: Correlations were significant between job characteristics and job-related outcomes, and the estimated model on the effect of empowerment reduced the unique contribution of job characteristics on internal work motivation (from 17.2% to 13.0%) and general job satisfaction (from 13.4% to 10.1%), and eliminated the unique contribution of job characteristics on growth satisfaction (from 18.4% to 0%). CONCLUSIONS: The results supported the Job Characteristics Model in a nursing sample and empowerment mediated the impact of job characteristics on internal work motivation and general job satisfaction partially and on growth satisfaction completely. PMID- 21281307 TI - An RNA expression method for aging forensic hair samples. AB - A common limitation to most forensic trace evidence analysis is the ability to determine the time at which the evidence was deposited at the crime scene. This issue of timing is vitally important as it may not only reveal when the crime occurred, but could exclude potential suspects from the investigation. Using a reverse transcription quantitative polymerase chain reaction (RT-qPCR) assay, we monitored the relative expression ratio (RER) of two different RNA species (18S and beta-actin) in hair samples that were aged naturally over a period of 3 months. No gender or age-of-donor biases were observed, and results were linear up to 60 days. After 60 days, the results were more variable and gave unreliable estimates of time since deposition. Overall, the results presented in this paper suggest that the age of hair samples containing follicular tags can be approximated using a second-order polynomial, although with limitations: Age = 3.31RER(2) - 2.85RER - 0.54 (R(2) = 0.98). PMID- 21281308 TI - Sex determination from hand and foot dimensions in a North Indian population. AB - Hands and feet are often recovered from the site of natural as well as man-made disasters because of bomb blasts, train accidents, plane crashes, or mass homicides. This study is intended to establish standards for determination of sex from the dimensions of hands and feet in a North Indian population. The data for this study comprise 123 men and 123 women aged between 17 and 20 years from the "Rajput" population of Himachal Pradesh in North India. Four anthropometric measurements viz. hand length, hand breadth, foot length, and foot breadth have been taken on both sides of each subject following international anthropometric standards. The hand index (hand breadth/hand length * 100) and the foot index (foot breadth/foot length * 100) were calculated. Sectioning points and regression models are derived for the hand and foot dimensions and the derived indices. The hand and foot dimensions show a higher accuracy in sex determination by sectioning point analysis when compared to hand and foot index. Of the hand and the foot dimensions, hand breadth and foot breadth showed better accuracy in sex determination. Hand index and foot index remain poor sex discriminators in the study. PMID- 21281309 TI - Stimulation of bursting in pre-Botzinger neurons by Epac through calcium release and modulation of TRPM4 and K-ATP channels. AB - The exchange factor directly activated by cAMP (Epac) can couple cAMP production to the activation of particular membrane and cytoplasmic targets. Using patch clamp recordings and calcium imaging in organotypic brainstem slices, we examined the role of Epac in pre-Botzinger complex, an essential part of the respiratory network. The selective agonist 8-(4-chlorophenylthio)-2'-O-methyl-cAMP (8-pCPT) sensitized calcium mobilisation from inositol-1,4,5-trisphosphate-sensitive internal stores that stimulated TRPM4 (transient receptor potential cation channel, subfamily M, Melastatin) channels and potentiated the bursts of action potentials. 8-pCPT actions were abolished after inhibition of phospholipase C with U73122 and depletion of calcium stores with thapsigargin. Caffeine-sensitive release channels were not modulated by 8-pCPT. Epac inhibited ATP-sensitive K(+) channels that also led to the enhancement of bursting by 8-pCPT. Bursting activity, spontaneous calcium transients and activity of TRPM4 and ATP-sensitive K(+) channels were potentiated after brief exposures to bradykinin and incubation with wortmannin produced opposite effects that can be explained by changes in phosphatidylinositol 4,5-bisphosphate levels. 8-pCPT stimulated the respiratory motor output in functionally intact preparations and the effects of bradykinin and wortmannin were identical to those observed in organotypic slices. The data thus indicate a novel pathway of controlling bursting activity in pre-Botzinger complex neurons through Epac that can involved in reinforcement of the respiratory activity by cAMP. PMID- 21281310 TI - CCAAT/enhancer binding protein beta expression is increased in the brain during HIV-1-infection and contributes to regulation of astrocyte tissue inhibitor of metalloproteinase-1. AB - Human immunodeficiency virus (HIV)-1-associated neurocognitive disorders (HAND) associated with infection and activation of mononuclear phagocytes (MP) in the brain, occur late in disease. Infected/activated MP initiate neuroinflammation activating glial cells and ultimately disrupting neuronal function. Astrocytes secrete tissue inhibitor of metalloproteinase (TIMP)-1 in response to neural injury. Altered TIMP-1 levels are implicated in several CNS diseases. CCAAT enhancer-binding protein beta (C/EBPbeta), a transcription factor, is expressed in rodent brains in response to neuroinflammation, implicating it in Alzheimer's, Parkinson's, and HAND. Here, we report that C/EBPbeta mRNA levels are elevated and its isoforms differentially expressed in total brain tissue lysates of HIV-1 infected and HIV-1 encephalitis patients. In vitro, HAND-relevant stimuli additively induce C/EBPbeta nuclear expression in human astrocytes through 7 days of treatment. Over-expression of C/EBPbeta increases TIMP-1 promoter activity, mRNA, and protein levels in human astrocytes activated with interleukin-1beta. Knockdown of C/EBPbeta with siRNA decreases TIMP-1 mRNA and protein levels. These data suggest that C/EBPbeta isoforms are involved in complex regulation of astrocyte TIMP-1 production during HIV-1 infection; however, further studies are required to completely understand their role during disease progression. PMID- 21281311 TI - GalR2/3 mediates proliferative and trophic effects of galanin on postnatal hippocampal precursors. AB - Understanding how neural activity is functionally linked to the stem cell niche, is assuming ever increasing importance as hippocampal neurogenesis is shown to be important for modulating the behavioural responses to stress and for certain forms of learning and memory. Neuropeptides such as neuropeptide Y and vasoactive intestinal peptide have emerged as important mediators for signalling local interneuron activity to subgranular zone precursors, however, little is known regarding the effects of neuropeptides that are extrinsic modulators of hippocampal information processing. Here, we show that the galanin GalR2/3 agonist Gal2-11 is both trophic and proliferative for postnatal subgranular precursors and proliferating neuroblasts at 10 nM and is purely trophic at doses as low as 100 pM. We found no effect mediated via GalR1. As galanin is co released from noradrenergic and serotonergic projection neurons to the dentate gyrus, these findings support a direct effect of galanin on hippocampal neurogenesis, which may partly mediate its antidepressant effect via GalR2/3 receptors. PMID- 21281312 TI - Integrative analysis of metabolite and transcript abundance during the short-term response to saline and oxidative stress in the brown alga Ectocarpus siliculosus. AB - The model brown alga Ectocarpus siliculosus undergoes extensive transcriptomic changes in response to abiotic stress, many of them related to primary metabolism and particularly to amino acid biosynthesis and degradation. In this study we seek to improve our knowledge of the mechanisms underlying the stress tolerance of this alga, in particular with regard to compatible osmolytes, by examining the effects of these changes on metabolite concentrations. We performed extensive metabolic profiling (urea, amino acids, sugars, polyols, organic acids, fatty acids) of Ectocarpus samples subjected to short-term hyposaline, hypersaline and oxidative stress, and integrated the results with previously published transcriptomic data. The most pronounced changes in metabolite concentrations occurred under hypersaline stress: both mannitol and proline were accumulated, but their low final concentrations indicate that, in this stress condition, both compounds are not likely to significantly contribute to osmoregulation at the level of the entire cell. Urea and trehalose were not detected in any of our samples. We also observed a shift in fatty acid composition from n-3 to n-6 fatty acids under high salinities, and demonstrated the salt stress-induced accumulation of small amounts of gamma-aminobutyric acid (GABA). GABA could be synthesized in E. siliculosus through a salt stress-induced putrescine degradation pathway. PMID- 21281313 TI - 'Promising' therapies: neuroscience, clinical practice, and the treatment of psychopathy. AB - Neuroscientific research into mental health commands generous funding, suggesting neuroscience is understood by a variety of actors and institutions as having significant potential to enhance the therapeutic practices of psychiatrists. This article interrogates this 'therapeutic promise' of neuroscience through the case study of the psychiatric condition personality disorder. Specifically, the focus is on the promissory discourse of clinicians specialising in the management of two variants of personality disorder--antisocial personality disorder and psychopathy--and researchers investigating the neurobiology of these constructs. The article discusses the respondents' ambivalent expectations regarding the therapeutic promise of brain research, and shows how these are structured by understandings of the ontology of personality disorder. In turn, these ambivalences direct our attention to practical issues surrounding the potential of neuroscience to translate into and enhance clinical practice, as well as theoretical concerns revolving around the place and role of the biological within contemporary neuroscience, psychiatry and psychology. In sum, the necessity of large material and symbolic investments in neuroscience should, perhaps, be reflected upon more critically, and analytic encounters with this discipline must keep in mind it's at times surprising commitment to the realms of the social and the psychological. PMID- 21281314 TI - Shifting normalities: interactions of changing conceptions of a normal life and the normalisation of symptoms in rheumatoid arthritis. AB - Biographical disruption and related concepts have been widely applied in chronic illness. Different conceptualisations of normalisation have also been proposed in order to explain individuals' diverse responses to illness on their biography, but as yet, not clearly related to changing bodily experience or normalisation of symptoms. This article aims to examine the relevance of these concepts in rheumatoid arthritis (RA), an unpredictable autoinflammatory disease characterised by painful and swollen joints, disability, fatigue and joint damage. Interviews were conducted with 23 people living with RA, and analysed using Framework, to enable people's whole narratives and context to be considered. Six typologies of normality emerged from the data: disrupted; struggling to maintain; fluctuating; resetting; returning; and continuing normality. Multiple normalities were often present in individuals' narratives, with one normality typology usually dominating at the time of the interview. The typologies connect to several biographical concepts, and instances of 'biographical reinstatement' were also found, where participants described returning to normal life, through perceived effective medication rather than reconceptualisation of health. The concept of 'shifting normalities' is proposed, providing a dynamic explanatory model of chronic illness that captures the interaction of changing conceptions of a normal life and the normalisation of symptoms. PMID- 21281315 TI - Single site left ventricular pacing induced dyssynchrony and cardiomyopathy. AB - Single site left ventricular (LV) pacing in the absence of intrinsic ventricular activity can be as detrimental to LV function as right ventricular apical pacing. This report describes a patient with complete heart block who developed significant dyssynchrony and cardiomyopathy secondary to single site lateral LV pacing. The process was reversed by placement of a second anterior LV lead. PMID- 21281316 TI - Multiple interatrial electrical connection after heart transplantation. AB - A 62-year-old woman who underwent heart transplantation 6 years later presented a regular atrial tachycardia. Electrophysiologic evaluation showed an atrial arrhythmia in the recipient atrium with 2:1 conduction to the donor atrium, with a confusing electroanatomical map. With the suspect of alternant conduction through two different breakthroughs, the map was split in two concordant maps, corresponding to two connections that were successfully ablated. Later on, a third connection was detected and therefore ablated. PMID- 21281317 TI - Pulmonary vein isolation guided by real-time three-dimensional transesophageal echocardiography. AB - The present case illustrates pulmonary vein isolation guided by real-time three dimensional transesophageal echocardiography. This imaging modality allowed to navigate in a point-by-point fashion around pulmonary veins to assess both catheter location in relation to pulmonary vein ostia and stability of catheter tip. Also, it offered high-resolution visualization of a thickened, prominent tissue that surrounded the left upper pulmonary vein (the ligament of Marshall). The ability to visualize this anatomical structure along with intracardiac recording of electrical signals allowed to safely modulate in loco radiofrequency energy delivery, thus achieving electrical isolation of the pulmonary vein. PMID- 21281318 TI - Coronary sinus aneurysm and left ventricular-coronary sinus fistula. Implantation of CRT device. AB - We describe a 72-year-old man referred for implantation of a cardiac resynchronization therapy device who had previously undergone repeated operations to replace the mitral valve. Retrograde venography of the coronary sinus (CS) to implant the left ventricular (LV) pacing lead revealed aneurysmal dilatation of the CS with LV-CS fistula that hindered-but did not prevent-complete implantation of the system. PMID- 21281319 TI - Meta-analysis: the impact of diabetes mellitus on the immunological response to hepatitis B virus vaccine in dialysis patients. AB - BACKGROUND: Patients on maintenance dialysis typically show a suboptimal immune response to hepatitis B virus vaccine compared with the non-uraemic population. A variety of inherited or acquired factors have been implicated in this diminished response. It is well known that patients with diabetes mellitus have a compromised immune system, and diabetic nephropathy is an important cause of chronic kidney disease. However, the impact of diabetes mellitus on the immune response to HBV vaccine in patients receiving long-term dialysis remains unclear. AIM: To evaluate the influence of diabetes mellitus on the immune response to HBV vaccine in dialysis population by performing a systematic review of the literature with a meta-analysis of clinical studies. METHODS: We used the random effects model of DerSimonian and Laird with heterogeneity and sensitivity analyses. The end-point of interest was the rate of patients showing seroprotective antibody against hepatitis B surface antigen at completion of vaccine schedule in the diabetic vs. the nondiabetic dialysis individuals. RESULTS: We identified 12 studies involving 1002 unique patients on long-term dialysis. Aggregation of study results showed a significant decrease in response rates among the diabetic vs. the nondiabetic patients [pooled odds ratio=0.52 (95% CI 0.38-0.71)]. The P-value was 0.29 for our test of study heterogeneity. Stratified analysis in various subgroups of interest did not meaningfully change our results. CONCLUSIONS: Our meta-analysis showed a clear association between diabetes mellitus and impaired response to hepatitis B virus vaccine in individuals on long-term dialysis. Such a relationship is biologically plausible. Vaccination schedules with adapted vaccine doses and frequent serum testing for loss of immunity against hepatitis B virus should be considered in patients on maintenance dialysis with diabetes mellitus. PMID- 21281320 TI - Paediatric and Perinatal Epidemiology. In this issue. PMID- 21281321 TI - Foreign body injuries in children: need for a step forward against an old yet neglected epidemic. PMID- 21281322 TI - Uncovering the complex relationship between pre-eclampsia, preterm birth and cerebral palsy. AB - Pre-eclampsia is a leading cause of preterm birth, which is strongly associated with cerebral palsy (CP). However, there is controversy about whether pre eclampsia is associated with increased risk of CP. We evaluated the association between pre-eclampsia and CP in 122,476 mother-child pairs insured by the South Carolina Medicaid programme, with births between 1996 and 2002. Prenatal billing records were linked to the children's Medicaid billing records after birth until December 2008. The odds of CP were modelled using logistic regression with generalised estimating equations. There were 337 children (0.28%) diagnosed with CP by at least two different health care providers, and 4226 (3.5%) women were diagnosed with pre-eclampsia at least twice during pregnancy. Children whose mothers had pre-eclampsia were almost twice as likely to have CP compared with children of mothers without pre-eclampsia [odds ratio (OR)=1.94, 95% confidence interval (CI) 1.25, 2.97]. The association was only significant for pre-eclampsia diagnosed prior to 37 weeks' gestation. Full term (gestational age >= 37 weeks) infants whose mothers were diagnosed with pre-eclampsia prior to 37 weeks had increased odds of CP compared with full term children whose mothers did not have pre-eclampsia (OR=3.41, 95% CI 1.40, 8.31). Preterm infants whose mothers had pre eclampsia were at significantly increased risk of CP compared with full term infants whose mothers did not have pre-eclampsia (OR=5.88, 95% CI 3.40, 10.17). The greatest risk for CP was in preterm infants whose mothers did not have pre eclampsia (OR=8.12, 95% CI 6.49, 10.17 compared with full term infants without exposure to pre-eclampsia). We conclude that pre-eclampsia with onset before 37 weeks' gestation is a significant risk factor for CP. Some of the association is probably attributable to high risk of preterm birth because of early pre eclampsia, while a 'direct' effect of pre-eclampsia on fetal brain development also seems likely. PMID- 21281323 TI - Is there a direct effect of pre-eclampsia on cerebral palsy not through preterm birth? PMID- 21281324 TI - Risk of preterm delivery and hypertensive disorders of pregnancy in relation to maternal co-morbid mood and migraine disorders during pregnancy. AB - We evaluated the risks of preterm delivery and hypertensive disorders of pregnancy among pregnant women with mood and migraine disorders, using a cohort study of 3432 pregnant women. Maternal pre-pregnancy or early pregnancy (<20 weeks gestation) mood disorder and pre-pregnancy migraine diagnoses were ascertained from interview and medical record review. We fitted generalised linear models to derive risk ratios (RR) and 95% confidence intervals (CI) of preterm delivery and hypertensive disorders of pregnancy for women with isolated mood, isolated migraine and co-morbid mood-migraine disorders, respectively. Reported RR were adjusted for maternal age, race/ethnicity, marital status, parity, smoking status, chronic hypertension or pre-existing diabetes mellitus, and pre-pregnancy body mass index. Women without mood or migraine disorders were defined as the reference group. The risks for preterm delivery and hypertensive disorders of pregnancy were more consistently elevated among women with co-morbid mood-migraine disorders than among women with isolated mood or migraine disorder. Women with co-morbid disorders were almost twice as likely to deliver preterm (adjusted RR=1.87, 95% CI 1.05, 3.34) compared with the reference group. There was no clear evidence of increased risks of preterm delivery and its subtypes with isolated migraine disorder. Women with mood disorder had elevated risks of pre-eclampsia (adjusted RR=3.57, 95% CI 1.83, 6.99). Our results suggest an association between isolated migraine disorder and pregnancy-induced hypertension (adjusted RR=1.42, 95% CI 1.00, 2.01). This is the first study examining perinatal outcomes in women with co-morbid mood-migraine disorders. Pregnant women with a history of migraine may benefit from screening for depression during prenatal care and vigilant monitoring, especially for women with co-morbid mood and migraine disorders. PMID- 21281326 TI - Maternal reproductive history and the risk of isolated congenital malformations. AB - We examined the relationship between maternal reproductive history and the newborn's risk of isolated congenital malformations in a large case-control cohort from the Polish Registry of Congenital Malformations. Congenital malformations were classified into four categories: isolated congenital heart defects (n=1673), isolated cleft palate (n=255), cleft lip with or without cleft palate (n=448) and renal agenesis (n=103). The case groups were compared with a shared group of 2068 controls recruited in the same time period and geographic area. Multivariable logistic regression was used to assess the risk associated with maternal gravidity and of previous miscarriages after accounting for maternal age and other potential risk factors. In unadjusted analyses, maternal gravidity was significantly associated with increased risk of all four classes of congenital malformations. After adjustment, a significant association persisted for congenital heart defects [odds ratio (OR)=1.22, [95% confidence interval (CI) 1.09, 1.36], P=0.0007] and cleft lip with or without cleft palate (OR=1.21, [95% CI 1.09, 1.36], P=0.0005). A similar trend existed for isolated cleft palate (OR=1.18, [95% CI 1.02, 1.37], P=0.03). There was no appreciable increase in the risk of congenital malformations associated with a maternal history of miscarriages, but a trend for a protective effect on the occurrence of cleft lip with or without cleft palate was observed (OR=0.72, [95% CI 0.52, 0.99], P=0.045). Based on our data, maternal gravidity represents a significant risk factor for congenital heart defects and cleft lip with or without cleft palate in the newborn infant. Our data do not support an increase in risk because of past history of miscarriages. PMID- 21281325 TI - Association between selected folate pathway polymorphisms and nonsyndromic limb reduction defects: a case-parental analysis. AB - Inadequate folate status resulting from either genetic variation or nutritional deficiencies has been associated with an increased risk of congenital malformations including orofacial clefting, limb, cardiac and neural tube defects. Few epidemiological studies have examined the association between limb reduction defects (LRDs) and folate-related genetic polymorphisms other than MTHFR 677C->T. We conducted a case-parental analysis of 148 families who participated in the National Birth Defects Prevention Study to examine the association between nonsyndromic transverse and longitudinal LRDs with five single nucleotide polymorphisms (SNPs) in genes encoding enzymes in folate and methionine pathways. Log-linear Poisson regression, adapted for analysis of case parental data assuming an additive genetic model, was used to estimate genetic relative risks and 95% confidence intervals for the association between LRDs and each SNP. Among women who did not take multivitamin supplements, the MTHFR 677T variant acts via the offspring's genome to increase the risk of LRDs. No association between LRDs and any fetal SNP was found among women who used multivitamin supplements. These results suggest the possibility that initiating folic acid supplementation prior to pregnancy may reduce the risk of having a LRD affected pregnancy, especially in women whose offspring inherit one or two copies of the MTHFR 677T variant. PMID- 21281327 TI - Epidemiology and outcome of congenital diaphragmatic hernia: a 9-year experience. AB - The aim of this study was to report the birth prevalence and short-term outcome of congenital diaphragmatic hernia (CDH) in a large geographically defined population, and to assess the feasibility of performing a randomised control trial (RCT) in this population. Data were collected on all cases of CDH reported to the East Midlands and South Yorkshire Congenital Anomalies Register between 1997 and 2005. A total of 194 cases of CDH were identified from 547,025 births; a birth prevalence of 3.5/10,000. Overall 1-year survival was 42%. In total, 69% of cases resulted in a live birth, of these 61% survived to 1 year; 73% were diagnosed antenatally and 22% postnatally, with 1-year survivals 30% and 71%, respectively. A total of 54% were isolated cases and 46% associated with another anomaly, with more live births (80% vs. 56%) and better 1-year survival (62% vs. 19%) with isolated CDH. Overall, only 83 babies were born alive with an isolated CDH: the only group suitable for inclusion in a RCT. In conclusion, given the small numbers of live isolated CDH cases it is impossible that any network alone would be able to perform a valid RCT of treatments, highlighting the need for collaborative international trials to address this complex condition. PMID- 21281328 TI - Leptin levels in cord blood and anthropometric measures at birth: a systematic review and meta-analysis. AB - The role of intrauterine environment in the development of obesity is increasingly recognised. Adipokines and specifically leptin have been examined as potential biomarkers predicting early development of obesity. We conducted a systematic review and meta-analysis of the epidemiological evidence for the association between leptin levels in cord blood and anthropometric measurements at birth in healthy mother-newborn pairs. A PubMed search was performed between 1994 and 2009 and manual search of reference lists of retrieved articles. Forty four studies met the inclusion criteria set. All studies reported a positive correlation between leptin levels and birthweight. The combined correlation coefficient (r) was 0.46 [95%CI 0.43, 0.50]. Leptin levels explained 21% of variation in birthweight. Results were similar in males (r=0.55; 0.40, 0.68) and females (r=0.60; 0.50, 0.69), and between Caucasians (r=0.45; 0.39, 0.51) and eastern Asian populations (r=0.47; 0.37, 0.55). Statistically significant positive correlations were also found for birth length (r=0.29; 0.23, 0.34) and ponderal index (r=0.36; 0.31, 0.41). There was no indication of publication bias (Egger's test P-value=0.23). This meta-analysis shows a clear but moderate correlation between leptin levels in cord blood and birthweight that is observed in different population groups. PMID- 21281329 TI - Reliability of routine clinical measurements of neonatal circumferences and research measurements of neonatal skinfold thicknesses: findings from the Born in Bradford study. AB - Assessing neonatal size reliably is important for research and clinical practice. The aim of this study was to examine the reliability of routine clinical measurements of neonatal circumferences and of skinfold thicknesses assessed for research purposes. All measurements were undertaken on the same population of neonates born in a large maternity unit in Bradford, UK. Technical error of measurement (TEM), relative TEM and the coefficient of reliability are reported. Intra-observer TEMs for routine circumference measurements were all below 0.4 cm and were generally within +/- 2-times the mean. Inter-observer TEM ranged from 0.20 to 0.36 cm for head circumference, 0.19 to 0.39 cm for mid upper arm circumference and from 0.39 to 0.77 cm for abdominal circumference. Intra and inter-observer TEM for triceps skinfold thickness ranged from 0.22 to 0.35 mm and 0.15 to 0.54 mm, respectively. Subscapular skinfold thickness TEM values were 0.14 to 0.25 mm for intra-observer measurements and 0.17 to 0.63 mm for inter observer measurements. Relative TEM values for routine circumferences were all below 4.00% but varied between 2.88% and 14.23% for research skinfold measurements. Reliability was mostly between 80% and 99% for routine circumference measurements and >= 70% for most research skinfold measurements. Routine clinical measurements of neonatal circumferences are reliably assessed in Bradford. Assessing skinfolds in neonates has variable reliability, but on the whole is good. The greater intra-observer, compared with inter-observer, reliability for both sets of measurements highlights the importance of having a minimal number of assessors whenever possible. PMID- 21281330 TI - Living near agricultural pesticide applications and the risk of adverse reproductive outcomes: a review of the literature. AB - Over the last decade, there has been growing concern about the possible health effects, including a number of adverse reproductive outcomes, from pesticide exposure of people living near agricultural fields. This systematic review evaluates the current epidemiological evidence on the association between living near agricultural pesticide applications and adverse reproductive outcomes, including congenital malformations, stillbirth, intrauterine growth retardation (IUGR), low birthweight, preterm birth and miscarriage. We identified and reviewed 25 studies from a systematic search of the main scientific databases and other sources published in 1950-2007. Study methods and main results were summarised and tabulated according to the year of study, design and type of adverse reproductive outcome. The levels of evidence for reproductive toxicity in humans contributed by each study were assessed and the main limitations associated with these studies discussed. Residential proximity to agricultural pesticide applications may be an important source of ambient environmental exposure, but because of the underlying methodological difficulties, the strength of evidence for its relationship with adverse reproductive outcomes is generally weak and varied between outcomes. The evidence suggested an association for congenital malformations, but because of methodological limitations, such as poor exposure measurement and potentially inadequate control of confounding, a firm conclusion remains beyond reach. For the other outcomes (stillbirth, IUGR, low birthweight, preterm birth and miscarriage) the evidence for any associations was equivocal at best, but some leads warrant further investigation. Improved exposure assessment methods are needed to obtain a more reliable assessment of any risks. PMID- 21281331 TI - Developing a community-based neonatal care intervention: a health facility assessment to inform intervention design. AB - Community-based interventions are an important way of improving health in low income countries. A necessary prerequisite for the design of such interventions is an understanding of the local health system. This will inform intervention design, help ensure the community-intervention forms part of a continuum of care, and provide information about health system strengthening activities that may be necessary for success. Such formative research processes, however, are seldom reported in the literature. We present the results of a health facility assessment used in the design stage of Newhints, a community-based intervention to improve neonatal survival in rural Ghana. We illustrate the methodology, findings and how these were used to inform the design and implementation of Newhints. The assessment involved key informant interviews with staff members at seven health facilities within the study area, including a brief inventory of available drugs and equipment. The key informant interviews identified that practices and health promotion messages at the health facilities were not consistent with one of the key target behaviours of the Newhints intervention - thermal care through delayed infant bathing. Health workers were bathing neonates soon after delivery and also advising women to do the same, which is a potential cause of hypothermia for the newborn. We found that health centres other than large district hospitals were ill-equipped to treat serious complications of labour or illness in the newborn, which had implications for advice on health seeking behaviour within the intervention. As a result of the health facility assessment, it was deemed necessary to undertake both health worker training and sensitisation activities. We demonstrate that important information can be yielded from a relatively simple health facility assessment involving key informant interviews. PMID- 21281333 TI - Cardiopulmonary haemodynamics in lambs during induced capillary leakage immediately after preterm birth. AB - 1. Early postnatal events might play a critical role in the development of cardiorespiratory diseases of prematurity. Although the exact mechanism is unknown, capillary leakage resulting in increased interstitial fluid volume has been postulated to play a critical role. We investigated the effects of capillary leakage, induced by a volume load, on cardiopulmonary and systemic haemodynamics immediately after preterm delivery. 2. Fetal sheep were instrumented at 129 days gestation, delivered and ventilated. After 15 min, lambs in the volume load group received intravenous saline (50 mL/kg) infused over 10 min; control lambs received no infusion. At 30 min, lambs underwent a pulmonary challenge by increasing positive end-expiratory pressure (PEEP) by 2 cmH(2)O every 10 min to 10 cmH(2)O, with similar decrements back to baseline PEEP. Pulmonary blood flow (PBF) and arterial pressures were recorded in real-time and cardiovascular variables were measured by Doppler echocardiography. 3. Total protein concentration in the bronchoalveolar-lavage fluid was higher in volume load lambs compared with controls, and histological interstitial fluid retention was evident in volume load lambs, both indicative of capillary leak. PBF increased immediately after the volume load, but PBF, pulmonary and systemic arterial pressures, and oxygenation all deteriorated during the PEEP challenge compared with controls, coinciding with an increase in downstream pulmonary resistance. Three of six volume load lambs had pulmonary haemorrhage, which was not observed in control lambs. 4. Capillary leakage had moderate effects, but subsequent high levels of PEEP had significant negative effects on cardiopulmonary and respiratory function in preterm lambs. Capillary leakage might contribute to postnatal cardiopulmonary failure in preterm infants. PMID- 21281332 TI - Inter-generational continuity in periodontal health: findings from the Dunedin family history study. AB - OBJECTIVE: To determine whether parental periodontal disease history is a risk factor for periodontal disease in adult offspring. METHODS: Proband periodontal examination [combined attachment loss (CAL) at age 32, and incidence of CAL from ages 26 to 32] and interview data were collected during the age-32 assessments in the Dunedin Study. Parental data were also collected. The sample was divided into two familial-risk groups for periodontal disease (high- and low-risk) based on parents' self-reported periodontal disease. RESULTS: Periodontal risk analysis involved 625 proband-parent(s) groups. After controlling for confounding factors, the high-familial-risk periodontal group was more likely to have 1+ sites with 4+mm CAL [relative risk (RR) 1.45; 95% confidence interval (CI) 1.11-1.88], 2+ sites with 4+mm CAL (RR 1.45; 95% CI 1.03-2.05), 1+ sites with 5+mm CAL (RR 1.60; 95% CI 1.02-2.50), and 1+ sites with 3+mm incident CAL (RR 1.64; 95% CI 1.01 2.66) than the low-familial-risk group. Predictive validity was enhanced when information was available from both parents. CONCLUSIONS: Parents with poor periodontal health tend to have offspring with poor periodontal health. Family/parental history of oral health is a valid representation of the shared genetic and environmental factors that contribute to an individual's periodontal status, and may help to predict patient prognosis and preventive treatment need. PMID- 21281334 TI - Neuroendocrine-immune disorder in type 2 diabetic patients with retinopathy. AB - 1. Diabetes mellitus is usually accompanied by hyperactivity of the hypothalamus pituitary-adrenal (HPA) axis. Diabetic retinopathy is one of the most devastating complications in diabetes although little is known with regards to the HPA activity in type 2 diabetic patients (T2DM) with diabetic retinopathy. The present study was designed to evaluate the HPA axis activity in type 2 diabetic patients with diabetic retinopathy. 2. Diabetic retinopathy was examined by fluorescein fundus angiography (FFA) in 174 consecutive type 2 diabetic patients. Levels of / were measured using flow cytometry. Serum concentrations of interleukin (IL)-1beta, IL-6, tumour necrosis factor-alpha (TNF-alpha), adrenocorticotrophic hormone (ACTH) and cortisone were measured by radioimmunoassay. Plasma levels of monoamines norepinephrine (NE) and dopamine (DA) were assessed using high performance liquid chromatograph equipped with a fluorescence detection. Patients were grouped into the non-diabetic retinopathy (NDR), non-proliferating diabetic retinopathy (NPR) and proliferating diabetic retinopathy (PDR) categories. 3. Patients with PDR showed significantly less than those with NDR and NPR (P<0.05). No significant correlation was found in / and NK or severity of retinopathy among the three patient groups. There was no significant difference in serum IL-1beta, IL-6 and TNF-alpha levels among the different patient groups (P>0.05). The serum concentrations of ACTH and cortisone were lower in PDR patients than other groups. There was no significant difference in plasma concentrations of DA and NE among all three groups (P>0.05). 4. Our data suggest that HPA and immune dysfunction might play a role in the development and/or progression of PDR. PMID- 21281335 TI - The publication of Diabetes UK position statements and care recommendations. PMID- 21281337 TI - Hyperpigmentation and hypotonia in a 3-month-old infant. PMID- 21281338 TI - Reversible severe sensorineural hearing loss in a 7-year-old child. PMID- 21281339 TI - Neonatal trials need thousands, not hundreds, to change global practice. PMID- 21281342 TI - Successful repair of multiple muscular ventricular septal defects using a unique hybrid procedure. AB - The surgical management of multiple muscular ventricular septal defects (mVSDs) in the infant remains a challenging problem because of the presence of residual shunts and postoperative myocardial dysfunction. We present a case of successful repair of multiple mVSDs with a unique hybrid procedure combining both the perventricular closure and open surgical repair. PMID- 21281343 TI - Valve-sparing aortic root replacement after cocaine-induced acute ascending aortic dissection. AB - Cocaine-induced ascending aortic dissection is being recognized with increasing frequency. We present two cases of patients treated using valve-sparing aortic root replacement after cocaine-induced aortic root dissection. Valve-sparing aortic root replacement represents an alternative surgical technique that may be particularly well-suited toward this younger, noncompliant patient population. PMID- 21281344 TI - Is there a role for surgery in the management of giant B-cell right atrial lymphoma? AB - We describe a case of a giant right atrial large B-cell lymphoma treated with initial surgical excision followed by postoperative chemotherapy. The patient had no clinical evidence of recurrence through 87 months after her hospital discharge. To our knowledge, this is the first reported case of long-term survival following this method of disease management. The discussion reviews the current status of chemotherapy for cardiac lymphomas and the pros and cons of treatment option algorithms. PMID- 21281345 TI - Breed-specific polymyositis in Hungarian Vizsla dogs. PMID- 21281346 TI - Neurological causes of diaphragmatic paralysis in 11 alpacas (Vicugna pacos). AB - BACKGROUND: Diaphragmatic paralysis is a relatively uncommon medical condition in animals not reported in alpacas. OBJECTIVES: Describe the signalment, physical examination, diagnostic testing, clinical, and histopathologic findings related to diaphragmatic paralysis in alpacas. ANIMALS: Eleven alpacas with spontaneous diaphragmatic paralysis. METHODS: A retrospective study examined medical records from a 10-year period and identified 11 alpacas with confirmed diaphragmatic paralysis admitted to Washington State University and Colorado State University Veterinary Teaching Hospitals between September 2003 and October 2009. RESULTS: The 11 alpacas ranged in age from 2 to 12 months. Fluoroscopic imaging confirmed the presence of bilateral diaphragmatic paralysis in the 7 alpacas that were imaged. Arterial blood gas analyses showed hypercapnea, hypoxemia, and low oxygen saturation. Seven alpacas died or were euthanized between 2 and 60 days after onset of respiratory signs. Histopathologic examination of tissues found phrenic nerve degeneration in the 6 alpacas that were necropsied and additional long nerves examined demonstrated degeneration in 2 of these animals. Two animals had spinal cord lesions and 2 had diaphragm muscle abnormalities. No etiologic agent was identified in the alpacas. CONCLUSIONS AND CLINICAL IMPORTANCE: The etiology for diaphragmatic paralysis in these alpacas is unknown. A variety of medical treatments did not appear to alter the outcome. PMID- 21281347 TI - Clinical and histopathologic characterization of a central and peripheral axonopathy in Rouge-des-pres (Maine Anjou) calves. AB - BACKGROUND: Recently, a progressive pelvic limb ataxia and paraparesis leading invariably to recumbency has been reported in Rouge-des-pres calves. OBJECTIVES: To characterize the clinical and pathological findings of this newly reported disease and to investigate its potential causes. ANIMALS: Nine calves from 7 different farms were prospectively studied from initial diagnosis through postmortem examination. METHODS: Physical and neurological examinations, blood tests, cerebrospinal fluid (CSF) analysis, and myelographic examinations were performed. Neuropathology was carried out on both central and peripheral nervous systems. Copper deficiency and organophosphate intoxication also were investigated. Pedigrees were analyzed. RESULTS: Age of onset varied from 2 to 6 weeks. Initial signs included pelvic limb ataxia and paraparesis. The neurological signs systematically progressed, over a 1-3-month period, to severe pelvic limb and truncal ataxia along with moderate paraparesis, leading to permanent recumbency. Animals remained alert. Cranial nerve function was normal. Muscle atrophy was not observed and spinal reflexes were normal. Blood tests, CSF analysis, and myelographic examination did not identify any abnormality. Neuropathology indicated neuronal fiber degeneration particularly in the dorsolateral and ventromedial funiculi of the spinal cord and in the peripheral nerves. Degenerative lesions also were observed in lateral vestibular and thoracic nuclei. No environmental factors such as copper deficiency or organophosphate intoxication could be incriminated as the cause of this axonopathy. Pedigree analysis suggested an inherited defect. CONCLUSIONS AND CLINICAL IMPORTANCE: The first description of a central and peripheral axonopathy is reported in Rouge-des-pres calves. An inherited defect is highly suspected. PMID- 21281348 TI - Bronchoalveolar lavage fluid cytology and cytokine messenger ribonucleic Acid expression of racehorses with exercise intolerance and lower airway inflammation. AB - BACKGROUND: There is limited information relating bronchoalveolar lavage (BAL) cytology and cytokine messenger ribonucleic acid (mRNA) expression in racehorses with inflammatory airway disease (IAD). HYPOTHESIS AND OBJECTIVE: We hypothesize that cytokine expression in BAL cells would correlate with cytology. Thus, we evaluated the mRNA expression of selected cytokines in BAL cells in racehorses with exercise intolerance and lower airway inflammation. ANIMALS: Thirty-one client-owned Standardbred racehorses with exercise intolerance. METHODS: Prospective, observational study. Cells were obtained by BAL, and mRNA expression of interleukin (IL)-1beta, IL-4, IL-8, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma was determined by reverse transcription quantitative polymerase chain reaction (RT-qPCR). RESULTS: Nine horses had normal BAL cell differential cytology (Controls), while 22 horses had evidence of IAD based on BAL fluid cytology. Relative expressions of TNF-alpha/glyceraldehyde 3-phosphate dehydrogenase (GAPDH; 0.0092 +/- 0.010 versus 0.0045 +/- 0.005, P= .034), IL 4/GAPDH (0.001 +/- 0.002 versus 0.0003 +/- 0.0003, P= .029), and IFN-gamma/GAPDH (0.0027 +/- 0.003 versus 0.0009 +/- 0.001, P= .028) were greater in horses with IAD compared with controls. Furthermore, IL-4/GAPDH (0.001 +/- 0.002 versus 0.0002 +/- 0.0003, P < .0001) and IFN-gamma/GAPDH (0.003 +/- 0.003 versus 0.001 +/- 0.001, P= .002) mRNA expression was increased in horses with increased metachromatic cell counts compared with horses with normal metachromatic cell counts. Only the mRNA expression of IL-1beta/GAPDH (1.1 +/- 0.7 versus 0.3 +/- 0.3, P= .045) was increased with airway neutrophilia. CONCLUSIONS AND CLINICAL IMPORTANCE: Differences in gene expression were associated with the presence of IAD and with specific cell types present in airway secretions of Standardbred racehorses with poor performance. These findings suggest that different pathophysiological pathways are implicated in IAD. PMID- 21281349 TI - Effect of diets differing in fat content on chronic diarrhea in cats. AB - BACKGROUND: Fat-restricted diets have been advocated for dogs with diarrhea for many years. Recommendations for cats with diarrhea have varied between low-fat and high-fat diets, but there have been no published studies to support either recommendation. OBJECTIVES: The objective of this study was to compare the clinical responses of cats with chronic diarrhea to dietary management using either a high fat or a low fat, highly digestible diet. ANIMALS: Sixty pet cats with chronic diarrhea were recruited; 55 cats completed the study. METHODS: Randomized, double-blinded, controlled clinical trial. Upon completion of baseline measures, cats were fed 1 of 2 diets for 6 weeks, during which the owners recorded fecal scores daily using an illustrated fecal score chart ranging from 0 (very watery) to 100 (firm and dry). After 6 weeks, cats were reevaluated by the attending veterinarians. RESULTS: Fecal scores improved significantly, with 78.2% of cats improving by at least 25 points on the 100-point scale or having a final fecal score of at least 66. Over one third of the cats developed normal stools. There were no differences in clinical responses between the diets. Clinical improvement was noted within the 1st week, and maximized within 3 weeks. CONCLUSIONS AND CLINICAL IMPORTANCE: These results show that dietary management can be helpful in cats with chronic diarrhea, but dietary fat content does not appear to affect the outcome. Cats that do not respond within 3 weeks should be evaluated further. PMID- 21281350 TI - A truncated retrotransposon disrupts the GRM1 coding sequence in Coton de Tulear dogs with Bandera's neonatal ataxia. AB - BACKGROUND: Bandera's neonatal ataxia (BNAt) is an autosomal recessive cerebellar ataxia that affects members of the Coton de Tulear dog breed. OBJECTIVE: To identify the mutation that causes BNAt. ANIMALS: The study involved DNA from 112 Cotons de Tulear (including 15 puppies with signs of BNAt) and 87 DNA samples from dogs of 12 other breeds. METHODS: The BNAt locus was mapped with a genome wide association study (GWAS). The coding exons of positional candidate gene GRM1, which encodes metabotropic glutamate receptor 1, were polymerase chain reaction (PCR)-amplified and resequenced. A 3-primer PCR assay was used to genotype individual dogs for a truncated retrotransposon inserted into exon 8 of GRM1. RESULTS: The GWAS indicated that the BNAt locus was in a canine chromosome 1 region that contained candidate gene GRM1. Resequencing this gene from BNAt affected puppies indicated that exon 8 was interrupted by the insertion of a 5' truncated retrotransposon. All 15 BNAt-affected puppies were homozygous for the insert, whereas all other Cotons de Tulear were heterozygotes (n = 43) or homozygous (n = 54) for the ancestral allele. None of the 87 dogs from 12 other breeds had the insertion allele. CONCLUSIONS AND CLINICAL IMPORTANCE: BNAt is caused by a retrotransposon inserted into exon 8 of GRM1. A DNA test for the GRM1 retrotransposon insert can be used for genetic counseling and to confirm the diagnosis of BNAt. PMID- 21281351 TI - Serum free cortisol fraction in healthy and septic neonatal foals. AB - BACKGROUND: Relative cortisol insufficiency occurs in septic foals and impacts survival. Serum free (biologically available) cortisol concentration might be a better indicator of physiologic cortisol status than serum total cortisol concentration in foals. HYPOTHESES: In septic foals, (1) low free cortisol concentration correlates with disease severity and survival and (2) predicts disease severity and outcome better than total cortisol concentration. ANIMALS: Fifty-one septic foals; 11 healthy foals; 6 healthy horses. METHODS: In this prospective clinical study, foals meeting criteria for sepsis at admission were enrolled. University-owned animals served as healthy controls. Basal and cosyntropin-stimulated total cortisol concentration and percent free cortisol (% free cortisol) were determined by chemiluminescent immunoassay and ultrafiltration/ligand-binding methods, respectively. Group data were compared by ANOVA, Mann-Whitney U-tests, and receiver operator characteristic curves. Significance was set at P < .05. RESULTS: Basal % free cortisol was highest in healthy foals at birth (58 +/- 8% mean +/- SD), and was higher (P <= .004) in healthy foals of all ages (33 +/- 6 to 58 +/- 8%) than in adult horses (7 +/- 3%). Cosyntropin-stimulated total and free cortisol concentrations were lower (P <= .03) in foals with shock (total = 6.2 +/- 8.1 MUg/dL; free = 3.5 +/- 4.8 MUg/dL versus total = 10.8 +/- 6.0 MUg/dL; free = 6.9 +/- 3.3 MUg/dL in foals without shock) and in nonsurvivors (total = 3.8 +/- 6.9 MUg/dL; free = 1.9 +/- 3.9 MUg/dL versus total = 9.1 +/- 7.7 MUg/dL; free = 5.5 +/- 4.4 MUg/dL in survivors). Free cortisol was no better than total cortisol at predicting disease severity or outcome in septic foals. CONCLUSIONS AND CLINICAL IMPORTANCE: Serum free cortisol is impacted by age and illness in the horse. There is no advantage to measuring free over total cortisol in septic foals. PMID- 21281352 TI - Paraparesis caused by vertebral canal leishmaniotic granuloma in a dog. PMID- 21281353 TI - Comparison of signalment, clinicopathologic findings, histologic diagnosis, and prognosis in dogs with glomerular disease with or without nephrotic syndrome. AB - BACKGROUND: Nephrotic syndrome (NS) develops most commonly in people with glomerular diseases associated with marked albuminuria. Hypernatremia, hypertension, and progressive renal failure are more prevalent in nephrotic than nonnephrotic human patients. HYPOTHESIS/OBJECTIVES: Dogs with NS have higher serum cholesterol, triglyceride, and sodium concentrations, higher urine protein:creatinine ratios (UPC) and systolic blood pressure, and lower serum albumin concentrations than dogs with nonnephrotic glomerular disease (NNGD). NS is associated with membranous glomerulopathy and amyloidosis. Affected dogs are more likely to be azotemic and have shorter survival times. ANIMALS: Two hundred and thirty-four pet dogs (78 NS dogs, 156 NNGD dogs). METHODS: Multicenter retrospective case-control study comparing time-matched NS and NNGD dogs. NS was defined as the concurrent presence of hypoalbuminemia, hypercholesterolemia, proteinuria, and extravascular fluid accumulation. Signalment, clinicopathologic variables, histopathologic diagnoses, and survival time were compared between groups. RESULTS: Age, serum albumin, chloride, calcium, phosphate, creatinine, and cholesterol concentrations, and UPC differed significantly between NS and NNGD dogs. Both groups were equally likely to be azotemic at time of diagnosis, and NS was not associated with histologic diagnosis. Median survival was significantly shorter for NS (12.5 days) versus NNGD dogs (104.5 days). When subgrouped based on serum creatinine (< or >=1.5 mg/dL), survival of NS versus NNGD dogs was only significantly different in nonazotemic dogs (51 versus 605 days, respectively). CONCLUSIONS AND CLINICAL IMPORTANCE: Presence of NS is associated with poorer prognosis in dogs with nonazotemic glomerular disease. Preventing development of NS is warranted; however, specific interventions were not evaluated in this study. PMID- 21281354 TI - Comparison of water manometry to 2 commercial electronic pressure monitors for central venous pressure measurement in horses. AB - BACKGROUND: Central venous pressure (CVP) customarily has been measured in veterinary patients with water manometry. However, many institutions are now using stallside electronic monitors in both anesthesia and intensive care units for many aspects of patient monitoring. HYPOTHESIS: Electronic stall side monitoring devices will agree with water manometry for measurement of CVP in horses. ANIMALS: Ten healthy adult horses from the university research herd. METHODS: Central venous catheters were placed routinely, and measurements were obtained in triplicate with each of the 3 methods every 12 hours for 3 days. Data were analyzed by a Lin concordance correlation coefficient and modified Bland Altman limits of agreement, with all devices compared pairwise. RESULTS: Compared with water manometry, agreement (bias) of the Passport was -1.94 cmH2O (95% limits of agreement, -8.54 to 4.66 cmH2O) and of the Medtronic was -1.83 cmH2O (95% limits of agreement, -8.60 to 4.94 cmH2O). When compared with the Passport, agreement of the data obtained with the Medtronic was 0.27 cmH2O (95% limits of agreement, -4.39 to 4.93 cmH2O). CONCLUSIONS AND CLINICAL IMPORTANCE: These data show that both electronic monitors systematically provide measurements that are approximately 2 cmH2O lower than water manometry, but differences between the 2 electronic devices are small enough (< 0.5 cmH2O) to be considered clinically unimportant. This discrepancy should be taken into account when interpreting data obtained with these monitoring devices. PMID- 21281355 TI - Effect of parvoviral enteritis on plasma citrulline concentration in dogs. AB - BACKGROUND: Plasma citrulline concentration is a reliable marker of global enterocyte mass in humans and is markedly decreased in diffuse small intestinal diseases. However, the relationship between acute intestinal damage and plasma citrulline concentration in dogs has never been documented. HYPOTHESIS: That dogs with parvoviral enteritis have a lower plasma citrulline concentration than healthy dogs and that plasma citrulline concentration is a predictor of death in puppies with parvoviral enteritis. ANIMALS: Sixty-one dogs with spontaneous parvoviral enteritis and 14 healthy age-matched control dogs. METHODS: Observational cohort study. Plasma citrulline concentration was measured by liquid chromatography and tandem mass spectrometry in blood samples collected at admission and each day until death or discharge from the hospital. Parvovirus enteritis was confirmed by electron microscopy on a fecal sample. RESULTS: Median (interquartile range) plasma citrulline concentrations at admission were 2.8 MUmol/L (range: 0.3, 49.0; P < .001 versus controls) in survivors (n = 49), 2.1 MUmol/L (range: 0.5, 6.4, P < .001 versus controls) in nonsurvivors (n = 12) and 38.6 MUmol/L (range: 11.4, 96.1) in controls (n = 14), respectively. There was no significant difference in plasma citrulline concentration between survivors and nonsurvivors within the parvovirus-infected puppies, and plasma citrulline concentration was not significantly associated with outcome in parvoviral enteritis. There were no significant changes in plasma citrulline concentration over the 8-day follow-up period. CONCLUSION AND CLINICAL IMPORTANCE: Parvovirus enteritis is associated with a severe decrease in plasma citrulline concentration that does not appear to have any significant prognostic value. PMID- 21281356 TI - A comparison of drug-eluting stents versus bare metal stents in saphenous vein graft PCI outcomes: a meta-analysis. AB - AIMS: Studies demonstrate that percutaneous coronary intervention (PCI) with drug eluting stents (DES) is associated with reduced revascularization and major adverse cardiac events (MACE) rates compared to bare metal stents (BMS) in native coronary vessels. Optimal PCI treatment of saphenous vein graft (SVG) lesions remains unclear despite SVG procedures representing up to 10% of PCI cases. We therefore performed a meta-analysis to compare outcomes between BMS and DES in SVG PCI. METHODS AND RESULTS: A search (2004-2009) of MEDLINE and conference proceedings for all relevant studies comparing mortality and MACE outcomes in DES versus BMS in SVG PCI and meta-analysis of the data was performed. Twenty studies were identified from 2005 to 2009 enrolling a total of 5,296 patients. Meta analysis revealed a decrease in mortality associated with DES use, odds ratio (OR) 0.68; 95% confidence interval (CI) 0.53-0.88; P = 0.004. Similarly, MACE (OR 0.64; 95% CI 0.51-0.82; P < 0.001), total lesion revascularization (OR 0.60; 95% CI 0.43-0.83; P = 0.002), and total vessel revascularization (OR 0.57; 95% CI 0.41-0.80; P = 0.001) were significantly decreased in the patients in which DES were used compared to BMS. This reduction in mortality and MACE events associated with DES use appears to be limited to registry studies and not randomized controlled studies. CONCLUSIONS: Our meta-analysis suggests DES use to be safe in SVG PCI and associated with reduced mortality and MACE rates with reductions in revascularization also observed. PMID- 21281357 TI - Percutaneous closure of coronary artery fistulae in adults with intermediate term follow-up results. AB - OBJECTIVE: Percutaneous closure of coronary artery fistulae (CAF) has become an alternative method to surgery. But there are limited data about intermediate and long-term results. In this manuscript, we aimed to review our experience about the closure of CAF with several percutaneous methods in our center. METHODS: Seven patients who admitted to our hospital, either symptomatic or having complications attributable to CAF, were analyzed. The immediate closure results and clinical follow-up were reviewed. RESULTS: Five patients were male (71%) and mean age was 58.3 +/- 13.3 years. Five of the CAF were draining into pulmonary artery and 2 of them were draining into the right atrium. Closure of CAF was performed with coil embolization in 5 patients, detachable balloon in 1 patient, and a combination of coil embolization and glue in the remaining 1 patient. In the early follow-up, 1 patient had atrial fibrillation and 1 patient had chest pain immediately after the closure procedure; other patients discharged from hospital uneventfully. Intermediate term follow-up results (32-83 months; median, 54 months) revealed that the procedure was clinically successful in all of the patients, despite the complaint of chest pain in 3 patients and minimal flow in 1 of these patients. CONCLUSION: Percutaneous closure of CAF is feasible and safe in anatomically suitable vessels with good results at intermediate term follow up. PMID- 21281358 TI - Twelve-month outcomes after coronary stenting with the GenousTM bio-engineered R StentTM in diabetic patients from the e-HEALING registry. AB - OBJECTIVES: We compared 12-month outcomes, regarding ischemic events, repeat intervention, and ST, between diabetic and nondiabetic patients treated with the GenousTM EPC capturing R stentTM during routine nonurgent percutaneous coronary intervention (PCI) using data from the multicenter, prospective worldwide e HEALING registry. BACKGROUND: Diabetic patients have an increased risk for restenosis and stent thrombosis (ST). METHODS: In the 4,996 patient e-HEALING registry, 273 were insulin requiring diabetics (IRD), 963 were non-IRD (NIRD), and 3,703 were nondiabetics. The 12-month primary outcome was target vessel failure (TVF), defined as target vessel-related cardiac death or myocardial infarction (MI) and target vessel revascularization. Secondary outcomes were the composite of cardiac death, MI or target lesion revascularization (TLR), and individual outcomes including ST. Cumulative event rates were estimated with the Kaplan-Meier method and compared with a log-rank test. RESULTS: TVF rates were respectively 13.4% in IRD, 9.0% in NIRD, and 7.9% in nondiabetics (P < 0.01). This was mainly driven by a higher mortality hazard in IRD (P < 0.001) and NIRD (P = 0.07), compared with nondiabetics. TLR rates were comparable in NIRD and nondiabetics, but significantly higher in IRD (P = 0.04). No difference was observed in ST. CONCLUSION: The 1-year results of the Genous stent in a real world population of diabetics show higher TVF rates in diabetics compared with nondiabetics, mainly driven by a higher mortality hazard. IRD is associated with a significant higher TLR hazard. Definite or probable ST in all diabetic patients was comparable with nondiabetics. (J Interven Cardiol 2011;24:285-294). PMID- 21281359 TI - Re-canalization of peripheral chronic total occlusions using the BridgePoint Stingray re-entry device. AB - Percutaneous intervention of peripheral chronic total occlusions (CTO) is increasingly common, but Interventionalists still face significant barriers to successful treatment of CTO lesions in the coronary and peripheral anatomy. The greatest overall challenges are in crossing the CTO lesion and re-entering the true lumen from a successful subintimal crossing. We present a case report of a patient with a CTO of a lower extremity artery, in which treatment with a new, novel system was used to address both of these challenges. PMID- 21281360 TI - Chemistry in indoor environments: 20 years of research. AB - In the two decades since the first issue of Indoor Air, there have been over 250 peer-reviewed publications addressing chemical reactions among indoor pollutants. The present review has assembled and categorized these publications. It begins with a brief account of the state of our knowledge in 1991 regarding 'indoor chemistry', much of which came from corrosion and art conservation studies. It then outlines what we have learned in the period between 1991 and 2010 in the context of the major reference categories: gas-phase chemistry, surface chemistry, health effects and reviews/workshops. The indoor reactions that have received the greatest attention are those involving ozone-with terpenoids in the gas-phase as well as with the surfaces of common materials, furnishings, and the occupants themselves. It has become clear that surface reactions often have a larger impact on indoor settings than do gas-phase processes. This review concludes with a subjective list of major research needs going forward, including more information on the decomposition of common indoor pollutants, better understanding of how sorbed water influences surface reactions, and further identification of short-lived products of indoor chemistry. Arguably, the greatest need is for increased knowledge regarding the impact that indoor chemistry has on the health and comfort of building occupants. PRACTICAL IMPLICATIONS: Indoor chemistry changes the type and concentration of chemicals present in indoor environments. In the past, products of indoor chemistry were often overlooked, reflecting a focus on stable, relatively non-polar organic compounds coupled with the use of sampling and analytical methods that were unable to 'see' many of the products of such chemistry. Today, researchers who study indoor environments are more aware of the potential for chemistry to occur. Awareness is valuable, because it leads to the use of sampling methods and analytical tools that can detect changes in indoor environments resulting from chemical processes. This, in turn, leads to a more complete understanding of occupants' chemical exposures, potential links between these exposures and adverse health effects and, finally, steps that might be taken to mitigate these adverse effects. PMID- 21281361 TI - Age-related changes in skin mechanical properties: a quantitative evaluation of 120 female subjects. AB - BACKGROUND/PURPOSE: The most commonly used method to determine the mechanical ability of skin is the creep test using suction chamber devices. Until now, there is no scientific consensus upon which skin deformation parameters and which body sites are particularly suitable to describe age-related changes in human skin mechanics. The aim of this study was to find those mechanical skin parameters best representing influence of aging at five different body sites. METHODS: A total of 120 healthy women aged 18-65, divided into four similar age groups, were included in this study. The biomechanical properties of the skin were measured using the Cutometer(r) MPA 580 on five body sites: cheek, neck, cleavage, volar forearm and back of the hand. In order to analyze parameters referred to 1 mm skin thickness, we also used 20 MHz sonography (DUB 20). RESULTS: A high average correlation with age was found for the parameters U(a)/U(f), U(r)/U(e), U(r), U(r)/U(f) and U(a). Only low correlation with age was found for the parameters U(v)/U(e), U(f)-U(a), U(f5)/U(f), U(d)/U(f) and U(a5). The localizations cheek, forearm and neck showed the highest correlation with age, while cleavage showed only low correlation. CONCLUSION: According to the results of our study, we recommend the parameter ratio of elastic recovery to distensibility (U(r)/U(f) ) as well as the gross elasticity (U(a)/U(f)) for evaluation of aging effects on the mechanical properties of skin. Their high correlation with age makes them particularly applicable to represent the influence of aging onto skin mechanical properties. Most suitable localizations to evaluate skin aging are cheek, forearm and neck. PMID- 21281362 TI - T helper 1, 2 and 17 cell subsets in renal transplant patients with delayed graft function. AB - Ischemia-reperfusion injury (IRI) in kidney transplantation is the major cause of delayed graft function (DGF), an event associated with an increased risk of acute rejection. The aim of this study was to evaluate T helper (Th) cell phenotype in renal transplants with DGF. T-bet (Th1), GATA-3 (Th2) and IL-17 (Th17) protein expression was investigated in pretransplant biopsies, DGF and acute tubular damage (ATD) caused by calcineurin-inhibitor toxicity. Intracytofluorimetric analysis of IFN-gamma, IL-4 and IL-17 was performed to analyze Th1, Th2 and Th17 responses in peripheral blood mononuclear cells of recipients with early graft function (EGF) and DGF, before (T0) and 24 h after transplantation (T24). In pretransplant biopsies, T-bet(+) , GATA-3(+) and IL-17(+) cells were barely detectable. In DGF, T-bet(+) and IL-17(+) cells were significantly increased compared with pretransplant and ATD. More than 90% of T-bet(+) and less then 5% of IL-17(+) cells were CD4(+) . GATA-3(+) cells were increased to a lower extent. T-bet(+) /GATA-3(+) cell ratio was significantly higher in DGF. Peripheral CD4(+) IFN-gamma/IL-4 ratio was significantly decreased in DGF, while CD4(+) /IL-17(+) cells did not differ between T0 and T24 in DGF. Our data suggest that DGF is characterized by a prevalent Th1 phenotype within the graft. This event might represent a link between DGF and acute rejection. PMID- 21281363 TI - Twenty-four-hour ambulatory blood pressure measurement in clinical practice and research: a critical review of a technique in need of implementation. AB - This review presents evidence that ambulatory blood pressure measurement (ABPM) should be used more widely in clinical practice and hypertension research. The technique, which should be mandatory in trials of antihypertensive drugs, is not being used in all studies of antihypertensive drug efficacy. ABPM is also being under-used in outcome studies. The failure to implement ABPM in primary care and hypertension research is impeding patient management and scientific advancement. ABPM offers so many advantages in assessing the efficacy of blood pressure (BP) lowering drugs that it should be mandatory in pharmacological trials. Likewise, the technique provides a means of achieving BP control in clinical practice, which is essential if we are to halt the epidemic of the cardiovascular consequences of hypertension. However, if ABPM is to be implemented for these purposes, certain requirements will need to be fulfilled. These include the availability of accurate, patient-friendly and inexpensive devices; standardization of the presentation and plotting of data with summary statistics for day-to-day practice; provision of comprehensive data analysis for research; an interpretative report to facilitate use in busy clinical practice; a trend report to demonstrate efficacy or otherwise of treatment in clinical practice and online transmission of data to provide immediate real-time data analysis. The reasons why ABPM is not being implemented are reviewed, and proposals are made to make the technique more acceptable. PMID- 21281364 TI - The intracellular Arabidopsis COPT5 transport protein is required for photosynthetic electron transport under severe copper deficiency. AB - Copper is an essential micronutrient that functions as a redox cofactor in multiple plant processes, including photosynthesis. Arabidopsis thaliana possesses a conserved family of CTR-like high-affinity copper transport proteins denoted as COPT1-5. COPT1, the only family member that is functionally characterized, participates in plant copper acquisition. However, little is known about the function of the other Arabidopsis COPT proteins in the transport and distribution of copper. Here, we show that a functional fusion of COPT5 to the green fluorescent protein localizes in Arabidopsis cells to the prevacuolar compartment. Plants defective in COPT5 do not exhibit any significant phenotype under copper-sufficient conditions, but their growth is compromised under copper limitation. Under extreme copper deficiency, two independent copt5 knockout mutant lines exhibit severe defects in vegetative growth and root elongation, low chlorophyll content, and impairment in the photosynthetic electron transfer. All these phenotypes are rescued when the wild-type copy of the COPT5 gene is retransformed into a copt5 knockout line or when copper, but not other metals, are added to the medium. COPT5 is expressed in vascular tissues, with elevated levels in roots. Taken together, these results suggest that COPT5 plays an important role in the plant response to environmental copper scarcity, probably by remobilizing copper from prevacuolar vesicles, which could act as internal stores or recycling vesicles to provide the metal cofactor to key copper dependent processes such as photosynthesis. PMID- 21281365 TI - Dental caries status and salivary properties of asthmatic children and adolescents. AB - AIMS: This study aimed to investigate the dental caries status and salivary properties in 3- to 15-year-old children/adolescents. METHODS: The sample was split in two groups: asthma group (AG), composed of 65 patients who attended Public Health Service; asthma-free group (AFG), composed of 65 nonasthmatic children/adolescents recruited in two public schools. Stimulated salivary samples were collected for 3 min. Buffering capacity and pH were ascertained in each salivary sample. A single trained and calibrated examiner (kappa = 0.98) performed the dental caries examination according to WHO criteria. RESULTS: The AFG showed salivary flow rate (1.10 +/- 0.63 mL/min) higher (P = 0.002) than AG (0.80 +/- 0.50 mL/min). An inverse relationship was observed between asthma severity and salivary flow rate (Phi coefficient, rphi: 0.79, P = 0.0001). Children with moderate or severe asthma showed an increased risk for reduced salivary flow rate (OR: 17.15, P < 0.001). No association was observed between drug use frequency (P > 0.05) and drug type (P > 0.05) with salivary flow rate. Buffering capacity was similar in both groups. No significant differences were encountered in dental caries experience between AFG and AG groups. CONCLUSIONS: Although asthma can cause reduction in flow rate, the illness did not seem to influence dental caries experience in children with access to proper dental care. PMID- 21281366 TI - Factors associated with dental behaviour management problems in children aged 2-8 years in Beijing, China. AB - AIM: This study determined the prevalence of children's dental behaviour management problems (BMP) in our clinic, investigated the influence of non-dental and dental background variables on BMP, and analysed the predictive power of these variables. DESIGN: The study group included 209 children aged 2-8 years who received dental treatment. Interviews were conducted with accompanying guardians. Children's dental behaviour was rated by a modified Venham's clinical anxiety scale and a cooperative behaviour rating scale. Regression models were used to analyse behavioural and interview data and to calculate the power of background variables to predict children's dental behaviour. RESULTS: During the first treatment, 29.7% of children displayed BMP. Four variables were found to predict BMP in 87.9% of cases. The risk factors for BMP were younger age, negative guardian expectations of the child's behaviour during treatment, anxiety or shyness around strangers, and presence of toothache. Children aged 2.5-3.5 years who attended kindergarten showed better dental behaviour than those who did not. CONCLUSIONS: This study is the first to report BMP prevalence in mainland China. Our results indicate that a simple pre-treatment interview could provide data allowing the dentist to identify children with special dental behavioural needs. PMID- 21281367 TI - Listening to patients: the best way to improve the quality of cancer care and survivorship. PMID- 21281368 TI - Oral mucositis in head and neck cancer. AB - This module explores the risk factors, pathogenesis and development of oral mucositis. It considers the early diagnosis and accurate management of oral mucositis in head and cancer patients undergoing treatment. PMID- 21281369 TI - Functional connectivity in slow-wave sleep: identification of synchronous cortical activity during wakefulness and sleep using time series analysis of electroencephalographic data. AB - Sleep is a behavioral state ideal for studying functional connectivity because it minimizes many sources of between-subject variability that confound waking analyses. This is particularly important for potential connectivity studies in mental illness where cognitive ability, internal milieu and active psychotic symptoms can vary widely across subjects. We, therefore, sought to adapt techniques applied to magnetoencephalography for use in high-density electroencephalography (EEG), the gold-standard in brain-recording methods during sleep. Autoregressive integrative moving average modeling was used to reduce spurious correlations between recording sites (electrodes) in order to identify functional networks. We hypothesized that identified network characteristics would be similar to those found with magnetoencephalography, and would demonstrate sleep stage-related differences in a control population. We analysed 60-s segments of low-artifact data from seven healthy human subjects during wakefulness and sleep. EEG analysis of eyes-closed wakefulness revealed widespread nearest-neighbor positive synchronous interactions, similar to magnetoencephalography, though less consistent across subjects. Rapid eye movement sleep demonstrated positive synchronous interactions akin to wakefulness but weaker. Slow-wave sleep (SWS), instead, showed strong positive interactions in a large left fronto-temporal-parietal cluster markedly more consistent across subjects. Comparison of connectivity from early SWS to SWS from a later sleep cycle indicated sleep-related reduction in connectivity in this region. The consistency of functional connectivity during SWS within and across subjects suggests this may be a promising technique for comparing functional connectivity between mental illness and health. PMID- 21281370 TI - Understanding obesity research: making a difference in the obesity epidemic. PMID- 21281371 TI - Overweight and obesity: pharmacotherapeutic considerations. AB - PURPOSE: This article reviews current trends for using pharmacotherapy in combination with other weight loss modalities and offers points for consideration by clinicians in practice. DATA SOURCES: Selected evidence-based articles and government websites. CONCLUSIONS: Pharmacotherapy as a strategy for managing overweight, obese, and extremely obese individuals remains controversial. Risk versus benefit and overall safety of prescription drugs for weight loss management remains a primary focus for consideration among clinicians and a viable topic for evidence-based outcomes research. IMPLICATIONS FOR PRACTICE: Overweight and obesity are well accepted as critical risk factors and predictors of morbidity and mortality in individuals of all ages from childhood to senescence. In the United States, overweight and obesity exist in epidemic proportions. It is critical that primary care providers be knowledgeable about pharmacologic factors related to obesity. PMID- 21281372 TI - Parents' perceptions and attitudes on childhood obesity: a Q-methodology study. AB - PURPOSE: The purpose of this study was to investigate parents of young children for their perceptions on the causes of obesity, the impact of childhood obesity on health, and the barriers to successful prevention of childhood obesity. DATA SOURCES: The target population included parents who attended a clinic for their well-baby check-up. The study was conducted in two phases. Using Q-methodology, 33 parents were classified into two groups representing two viewpoints: "confident in delivering healthy nutrition" and "family physical activity focused." CONCLUSION: This work indicates that parents have varying foci on causation of obesity, and differ in focus on nutrition and physical activity. Most of the parents in this study were aware of healthy nutrition, and about one third of them believed in the benefits of physical activity for children and did not see being overweight or obese as a barrier to physical activity. The first group was confident in being able to deliver healthy nutrition to their family, and the second group was characterized by a focus on physical activity and its role in childhood obesity. Both groups agreed that exercising and sports are very important to a child's health status. IMPLICATIONS FOR PRACTICE: Nurse practitioners have a unique role in the health system and are one of the best facilitators to deliver health messages to the public; thus, they are able to educate parents and increase their awareness about the causes and consequences of childhood obesity. PMID- 21281373 TI - Implementing an evidence-based metabolic syndrome prevention and treatment program utilizing group visits. AB - PURPOSE: To develop and implement a pilot program designed as a shared medical group visit targeting metabolic syndrome prevention in two ethnically diverse patient populations. DATA SOURCES: The Cooperative Health Care Clinics (CHCC) module was utilized for group sessions to focus on interactive discussions following the L.E.A.R.N. format in order to encourage healthy lifestyle changes. Participants completed a pre- and postknowledge base test that encompassed information on healthy lifestyle changes in addition to disease processes associated with metabolic syndrome. Each didactic session was evaluated using mean +/- standard deviation for the knowledge tests. Analysis of variance was used in determining body mass index (BMI) and weight measured at weeks 1, 5, and 10. Participants completed a 5-point Likert scale satisfaction survey on week 10. Independent means t-test compared clinic results along with the Satterthwaite approximate t-test because of unequal sample sizes to evaluate differences in means. CONCLUSIONS: There were no significant statistical differences in mean weight or BMI on weeks 1 and 5. However, on week 10, there was a statistically significant difference for waist circumference in both clinics (p= .0466). Knowledge base improved in both clinics with a premean (0 score = 87 +/- 18) and postmean (0 score = 93 +/- 14). Both sites received high scores for patient satisfaction. IMPLICATIONS FOR PRACTICE: The shared medical group visits program implemented in both clinic sites demonstrated that this is an effective model in which to provide intensive patient education, foster peer support, and facilitate health-related behavioral changes. Peer support, self-management, and continuity appear to be important factors in behavior change and improved knowledge. PMID- 21281374 TI - An assessment of measures of body image, body attitude, acculturation, and weight status among Mexican American women. AB - PURPOSE: The purpose of this descriptive study was to establish the validity and reliability of the measurement of body image and body attitudes among Mexican American women. DATA SOURCES: Completed measures of height, weight, waist circumference, body mass index, acculturation, body image, and body attitude of 35 U.S.-born Mexican American women between the ages of 18 and 65 years of age. Also included were repeated measures of body image and body attitude and verbatim face-to-face interviews with 13 study participants. CONCLUSIONS: Most study participants were overweight; however, body image discrepancy (difference between perceived actual and ideal body image) did not increase as anticipated and was negatively related to body mass index; suggesting those participants' perceptions of ideal body image increased with increasing body size and was reliable. Body attitude subscale scores had varying relationships to weight status. IMPLICATIONS FOR PRACTICE: Further study is warranted examining why an acceptance of a greater body image occurs, potentially leading to a greater understanding of the influences of body image integration on health behaviors. Clinicians working with Mexican American women should consider weight reduction interventions that are based on an individual assessment of the perceptions of body image and body attitudes. PMID- 21281375 TI - Exercise and exercise intentions among obese and overweight individuals. AB - PURPOSE: To determine the relationship between exercise stage and decisional balance in overweight and obese individuals seeking advanced practice nurse (APN) care. DATA SOURCES: A convenience sample of 175 persons aged 40 or above with the values of body mass index (BMI) exceeding 25. CONCLUSIONS: One fourth of the respondents were considering beginning exercise within the next month; 23% had exercised regularly for more than 6 months and 39% indicated that they exercised regularly. Most respondents believed the pros of exercise outweighed the cons, and as the pros increased, so did the likelihood of exercising. IMPLICATIONS FOR PRACTICE: In approaching the subject of exercise among obese and overweight individuals it is important for the APN to understand behavioral change. Thus, it would be more fruitful to ask, "What would it take to move those who intend to begin exercising to the next stage?" For health behavior change to occur, the pros must be twice as numerous as the cons. In clinical practice, reviewing and adding to the pros of exercise as outlined by the patient might tip the decisional balance in favor of exercise. PMID- 21281376 TI - Body dissatisfaction in California adolescents. AB - PURPOSE: Factors that contribute to body dissatisfaction among adolescents from ethnically diverse California were examined to determine if the factors vary with gender and race. DATA SOURCES: Data from the 2005 California Health Interview Survey were used; 1807 White, Latino, and Asian American adolescents from 12 to 17 years old were included. CONCLUSIONS: Ordinal multiple logistic regression with gender and ethnicity controlled for revealed two major factors (high body mass index and poor/fair general health status) contribute to body dissatisfaction across gender and ethnicity in California adolescents. Other factors related to body dissatisfaction varied with ethnicity and gender. IMPLICATIONS FOR PRACTICE: Gender- and ethnicity-specific interventions to improve body image in adolescents must be developed. PMID- 21281377 TI - The relationship among registered nurses' weight status, weight loss regimens, and successful or unsuccessful weight loss. AB - PURPOSE: To investigate relationships between body mass index (BMI), personality type, weight loss regimens, and successful or unsuccessful weight loss. DATA SOURCES: Seven hundred and twenty-one registered nurses (RNs) were recruited from the American Academy of Nurse Practitioners, the membership of a nursing honor society, and RNs at a large state university. Participants completed the Myers Briggs Type Indicator (MBTI), a demographic survey (age, gender, height, weight, ethnicity, education status, disability, shift work hours, and prescription medication use), and questions related to their weight status, weight loss attempts, and motivation. CONCLUSIONS: RNs who had a lower BMI were more successful in losing weight than RNs who had a higher BMI. They were also more successful in their weight loss attempts if they did not use a diet regimen. IMPLICATIONS FOR PRACTICE: RNs who were successful in losing weight did not use a specified dietary regimen. PMID- 21281378 TI - Endovascular therapy for cardiac catheterization associated strokes. AB - BACKGROUND: Stroke is one of the most feared complications after cardiac catheterization. Endovascular treatment combining mechanical and pharmacological therapy has been reported as an effective treatment option in selected patients with acute stroke due to large-vessel occlusion. Little is known about safety and clinical outcome when this approach is utilized in cardiac catheterization associated strokes. METHODS AND RESULTS: We analyzed clinical and radiological characteristics and outcomes in the endovascular acute stroke treatment databases from two University Hospitals from July 2006 to December 2008 (Cleveland Clinic Foundation) and September 1999 and December 2008 (UPMC Presbyterian hospital), respectively. Of a total of 419 acute stroke interventions, 14 (3.34%) were identified as strokes during or immediately after cardiac catheterization. The mean age was 71 +/- 7 years; eight were women (57.1%). Mean National Institute of Health Stroke Scale was 17 (+/-7.6). Four patients underwent intravenous thrombolysis followed by intraarterial intervention. Median time to treatment was 240 minutes from last time seen normal (range 66-1,365 minutes). Seven patients (50%) had a favorable outcome (modified Rankin Scale [mRS]<= 2). In-patient mortality was 42%. CONCLUSION: In acute strokes following cardiac catheterization, multimodal endovascular therapy is safe and feasible and despite a high mortality is associated with a higher than expected rate of favorable outcomes compared to the natural history of the disease. Despite a significant proportion of patients developing symptoms in hospitals where neurointerventions are available, the median time to treatment was longer than expected. Future efforts should focus on faster implementation of recanalization therapies for this form of acute stroke. PMID- 21281379 TI - Magnetic resonance angiography of the circle of Willis in patients with symptomatic intracranial neuropathology: medicare LCD L25367(R4). AB - Patients with symptomatic intracranial neuropathology such as atherosclerotic occlusive disease or unruptured aneurysms face high risks for morbidity and mortality. Magnetic resonance angiography of the circle of Willis is an important tool used to detect and diagnose intracranial neuropathology; however, recent changes to the Medicare local coverage determinations for this procedure threaten to compromise the physician's ability to deliver this current standard of care. Physicians can assume an important role in advocating for this lifesaving procedure on behalf of this vulnerable patient population. PMID- 21281380 TI - Susceptibility-weighted imaging of the brain: current utility and potential applications. AB - BACKGROUND AND PURPOSE: Susceptibility-Weighted Imaging (SWI) is a relatively new magnetic resonance imaging (MRI) sequence relying on susceptibility differences between adjacent tissues to produce an image. It is extremely sensitive for detection of blood products (hemosiderin, ferritin), deoxygenated blood, calcium, iron, and small vein depiction. Little information is available in the literature to describe common findings seen using this imaging sequence. This article is an comprehensive review of appearances across the spectrum of brain pathology encountered in routine clinical practice. MATERIALS AND METHODS: A retrospective review of 400 MRI Brain examinations was performed by one fellowship trained Neuroradiologist with 5 years experience (SB) and one general radiologist (RR). Agreement was by consensus observing normal and pathological imaging features seen in SWI sequences. RESULTS: Results are presented as a comprehensive pictorial review highlighting the key imaging findings observed and new directions using SWI. CONCLUSION: SWI is an extremely useful adjunct to current MRI sequences of the brain and is advocated for inclusion into routine Neuroimaging protocols. PMID- 21281381 TI - Nonblinding, penetrating orbital injury with pontine and cerebellar involvement secondary to antenna trauma. AB - BACKGROUND AND PURPOSE: Traumatic pontine and cerebellar damage originating from ocular injury has been documented in the past; however, no report has been made about an orbital trauma causing injury to the pons and cerebellum with associated neurological symptoms while leaving the globe, visual pathway, and ocular controls intact. METHODS: Chart review of a single case of a traumatic antenna injury. RESULTS: A traumatic antenna injury that penetrated the orbit and injured the pons and cerebellum without involving the visual pathway and its controls. CONCLUSIONS: Pontine and cerebellar injury can occur from trauma that originated in the orbit and traveled posteriorly through the cranium without causing any overt damage to ocular structures but still causing other associated neurological problems. PMID- 21281382 TI - Therapeutic role of endothelial progenitor cells in inhibiting carotid artery neointimal hyperplasia. PMID- 21281383 TI - Acute stroke, catheter related venous thrombosis, and paradoxical cerebral embolism: report of two cases. AB - BACKGROUND: Patent foramen ovale (PFO) has been associated with cryptogenic stroke, particularly in young adults. However, the source of particles leading to cerebral embolism remains frequently unknown despite comprehensive evaluation. OBJECTIVE: To report and comment on therapeutic options for 2 patients with acute ischemic strokes, PFO, and venous access related thrombosis, sources of paradoxical embolism, from Boston Medical Center stroke database. CASE DESCRIPTIONS: Case 1. A 71-year-old man presented with brain magnetic resonance imaging (MRI) confirmed acute cerebellar infarction. Echocardiography showed a PFO and thrombotic material at the tip of a peripherally inserted central catheter (PICC) line in the superior vena cava (SVC) prolapsing into the right atrium (RA). Case 2. A 64-year-old woman with end-stage renal disease and PFO presented with brain MRI confirmed acute parietal lobe infarction. Three days prior to her stroke, she had thrombectomy and venoplasty of an arterio-venous (AV) dialysis graft followed by a post-thrombectomy fistulogram that showed persistent thrombotic material at the venous site. CONCLUSIONS: PFO associated with large venous access site thrombosis was the most likely mechanism of stroke in both cases. Local thrombosis at sites of large venous access may be an overlooked source of paradoxical embolism in patients with PFO as well as a preventable cause of stroke in critically ill patients. PMID- 21281384 TI - Surgical technique innovation for the excision of subungual glomus tumors. PMID- 21281385 TI - Persistence of nasolabial fold correction with a hyaluronic acid dermal filler with retreatment: results of an 18-month extension study. AB - BACKGROUND: An 18-month persistence study reported nasolabial fold (NLF) improvements using a small gel-particle hyaluronic acid (SGP-HA) dermal filler lasted up to 18 months after one retreatment. OBJECTIVE: [corrected] To evaluate the efficacy and persistence of SGP-HA for the correction of NLFs for up to 36 months. METHODS & MATERIALS: Subjects completing the 18-month persistence study were permitted to enroll in an 18-month extension trial. Most required second retreatments to achieve optimal correction of their NLFs. Subjects were followed for up to 36 months after their initial treatment. The primary efficacy measure was a 1-point improvement from baseline Wrinkle Severity Rating Scale (WSRS) score as determined by a blinded evaluator at different time points. RESULTS: The study enrolled 52 subjects. Forty subjects required a second retreatment for optimum NLF correction. Mean retreatment volume was less than 50% of the initial treatment volume. Twenty-six subjects completed the study. Blinded assessments revealed that 94% to 100% of subjects maintained WSRS scores of 1 point or more higher than baseline throughout the study. CONCLUSIONS: Participants in the 18 month extension of an 18-month SGP-HA persistence study continued to demonstrate improvement of NLFs up to 36 months after a second retreatment. The mean volume of SGP-HA required for optimum NLF correction decreased substantially with each retreatment. Subjects reported no treatment-related adverse events after the second retreatment. PMID- 21281386 TI - A case of cutaneous malignant mixed tumor treated with mohs micrographic surgery. PMID- 21281387 TI - Correlation among dermoscopy, confocal reflectance microscopy, and histologic features of melanoma and basal cell carcinoma collision tumor. PMID- 21281388 TI - Herpes zoster in the distribution of the trigeminal nerve after nonablative fractional photothermolysis of the face: report of 3 cases. PMID- 21281390 TI - Demoralization and remoralization: a review of these constructs in the healthcare literature. AB - Demoralization and remoralization: a review of these constructs in the healthcare literature Development of the constructs of demoralization and remoralization began in the psychiatric literature in the 1970s when a psychiatrist in the USA observed a pattern of characteristics in people referred to him for depression, which he believed, was not depression. These characteristics included hopelessness, helplessness, isolation, low self-esteem and despair. Such characteristics are often termed existential distress. Distinguishing between depression and the existential distress of demoralization is still central in the literature. This is important as successful responses to each condition differ. Research into these constructs has broadened and contributions now come from many different countries and multiple health disciplines, including nursing. This study presents a review and exploration of these constructs in the healthcare literature in an attempt to bring them to the attention of greater numbers of nurses. Facilitating remoralization requires time and sensitivity to people's personal narratives. Difficulty in achieving such a response in the present efficiency climate of many health institutions can lead to moral distress. PMID- 21281391 TI - Enhancing decolonization and knowledge transfer in nursing research with non western populations: examining the congruence between primary healthcare and postcolonial feminist approaches. AB - This article is a call for reflection from two distinct programs of research which converge on common interests pertaining to issues of health, social justice, and globalization. One of the authors has developed a research program related to the health and well-being of non-western populations, while the other author has expanded the field of Aboriginal and international research in Canada and abroad. Based on examples drawn from our respective programs of research, we suggest conciliating the philosophy of primary healthcare to postcolonial feminism for decolonizing research and enhancing knowledge transfer with non western populations. We contend that applying the theoretical and methodological strengths of these two approaches is a means to decolonize nursing research and to avoid western neocolonization. In conciliating primary health care and postcolonial feminism, the goal is to enhance the pragmatic relevance of postcolonial feminism to generate resistance through transformative research for achieving social justice. In tapping into the synergistic and complementary epistemological assumptions of the philosophy of primary health care and postcolonial 'feminisms', nurse researchers reinforce the anti-oppresive goals of postcolonial feminist research. Consequently, this approach may enhance both decolonization and knowledge transfer through strategies like photovoice. PMID- 21281392 TI - The good, the bad and the 'not so bad': reflecting on moral appraisal in practice. AB - The aim of this study is to facilitate reflection on the moral merit of practitioners in various contexts. Insight is gained from Aristotelian and Kantian accounts of moral character and an original framework for reflection is presented as an adjunct to ethical theory and principles considered when appraising others. In relation to states of character, there is an irreconcilable difference between Kantian (deontic) and Aristotelian (aretaic) conceptions of the nature of full virtue (excellence of character), but at the same time it can be argued that in relation to practice their approaches complement each other. It is also argued that in relation to caring for the vulnerable, Aristotle's conception of full virtue is more compelling than Kant's. On the other hand, Kant's notion of self-serving action is important in nursing and it therefore needs to be considered when reflecting on professional conduct. The conclusion reached is that Aristotelian and Kantian accounts of character appraisal should be used in a combined approach to moral appraisal. This approach draws on the accounts of both philosophers and offers valuable insight into moral character, professional conduct and, in a more formal setting, fitness to practise. PMID- 21281393 TI - Examining our privileges and oppressions: incorporating an intersectionality paradigm into nursing. AB - An intersectionality paradigm is a means by which nurses can attend to issues of oppression and privilege within their practice and profession. Intersectionality is introduced as an essential theory to help debunk the hegemony of the 'white, middle class' perspective that often directs nursing research, practice, and education. The values and benefits of using an intersectionality paradigm in nursing are shown through recent research done with Aboriginal women. These findings contribute to an increased understanding of the importance and necessity of attending to the power relations that dominate nursing care encounters and influence the way nurses provide care. By acknowledging and responding to the presence of privilege and oppression and the associated power dynamics within the therapeutic encounter, nursing can strive further in helping to alleviate social injustices and health disparities that arise from unequal power relations. PMID- 21281394 TI - Valued identities and deficit identities: Wellness Recovery Action Planning and self-management in mental health. AB - Wellness Recovery Action Planning (WRAP) is a self-management programme for people with mental illnesses developed by a mental health consumer, and rooted in the values of the 'recovery' movement. The WRAP is noteworthy for its construction of a health identity which is individualised, responsibilized, and grounded in an 'at risk' subjectivity; success with this programme requires development of an intensely focused health lifestyle. We draw on Bourdieu and Giddens to argue that what is being developed is a 'reflexive health habitus', which is not equally accessible to all social groups, and is in tension with WRAP's recovery-orientated aims. However, it is understandable that such a programme developed in mental health, because people with mental illness are highly stigmatized as 'a risk' and viewed as in need of risk management. By developing their own form of self-monitoring 'at risk' identity, mental health consumers are, paradoxically, able to construct themselves as ideal health citizens and no longer a risk, thus re-entering the moral community. We conclude by suggesting some changes to WRAP practice. PMID- 21281395 TI - Bringing ourselves into view: disclosure as epistemological and ontological production of a lesbian subject. AB - Using Gadamerian hermeneutics as a methodology and feminist philosophical thought as an analytical framework, this study explores understandings of experiences of disclosure of sexual orientation for older 'lesbian' women. The study draws on an interpretative inquiry in which participants theoretically align with sexual identity categories with both an ontological and an epistemological purpose and later move away from or even disassociate from the 'category' (of lesbian). Reflecting on these interpretations, that of the epistemological and the ontological production of a subject, we ask: What does it mean then to say I am a lesbian? This is where a tension exists: how is it that in spite of the incongruencies of what constitutes a lesbian, and the apparent ambiguity of people to name themselves, we continue to act (as health care providers and researchers) as if the category itself is meaningful and stable? A feminist lens provides an inroad to consider sexuality as practices, rather than as fixed identity; practices that are constituted within the discursive, social and material realities of a life as well as within political and ideological systems in which one resides. PMID- 21281396 TI - Relocating care: negotiating nursing skillmix in a mental health unit for older adults. AB - Mental health care in Australia in the last 20 years has moved from stand-alone psychiatric hospitals to general hospitals and the community. This paper reports an action research project exploring the experiences of nurses on an acute mental health unit for older adults staffed with a skillmix of mental health and general nurses, which recently transitioned from a psychiatric to a general hospital. The new service provides comprehensive health care, including the management of physical co-morbidity and a recovery orientation. Recovery acknowledges the role and rights of consumers and carers in planning and management of care, choice and individual strengths (Shepherd). The new ward received additional resources to establish the model of care, including a broader skillmix. The paper explores the dynamics of development of a new model of care and of bringing together staff with different professional orientations, cultures and priorities. Focus groups and interviews were conducted with 18 staff. Analysis resulted in three themes relating to the impact of competing goals and foci of care upon professional boundaries; competing organisational cultures and the impact of service change upon work practices. The findings are explored in relation to ideas about health care delivery associated with neoliberalism. PMID- 21281397 TI - An exploration of empowerment discourse within home-care nurses' accounts of practice. AB - In this study, we explore how client and family caregiver 'empowerment' is interpreted by home-care nurses talking about their practice with palliative (and to a lesser extent, non-palliative) clients and families. We draw on secondary analysis of qualitative data collected through in-person interviews with 27 home care nurses from a western Canadian health authority. First, we illustrate how the practice ideal of empowerment, in the sense of 'respecting autonomy and choices', can be understood as reflecting home-care nurses' needs to mitigate the emotional impact of feeling unable to effectively help palliative clients/families. Then, we illustrate how the practice ideal of empowerment, in the sense of 'promoting independence', can be understood to accomplish the need to shift responsibility for particular care tasks to clients and family members. Lastly, home-care nurses, talk about 'promoting choices' is also investigated. 'Choice' was framed narrowly with respect to allowing palliative clients and families to determine visit time and frequency. Findings are discussed in relation to the concept of 'responsibilization'. PMID- 21281398 TI - Reversing Kristeva's first instance of abjection: the formation of self reconsidered. AB - Psychoanalyst Julia Kristeva defines the theoretical concept of abjection as an unconscious defence mechanism used to protect the self against threats to one's subjectivity. Kristeva suggests that the first instance of abjection in an individual's life occurs when the child abjects the mother. However, the instance of abjection addressed within this paper is the reverse of this: the abjection of the child, with a disability, by the parent, and more broadly society. Using the contemporary example of prenatal testing, the authors explore how parents of children with disabilities may be influenced in abjecting the child. The implications of abjection of the child are then used to explore normalization, routinization of care and the development of standardized care practices within health-care. Prenatal screening practices and standardized care permeate medical obstetric care and social discourses regarding pregnancy and childbirth, thereby affecting not only healthcare professionals but also parents in their position as consumers of health-care. In a time when the focus of health-care is increasingly placed on disease prevention and broader medical and social discourses glorify normalcy and consistency, the unconscious abjection of those that do not fit within these standards must be identified and addressed. PMID- 21281399 TI - The Kangaroo Program at a Brazilian maternity hospital: the preterm/low-weight babies' health-care under examination. AB - The Kangaroo Program, originally developed in Colombia, was adopted as a public policy by the Brazilian Unified Health System (SUS) in 2000, in an effort to improve maternal and infant health in the country. This article aims to examine the Kangaroo Program as it is practiced and carried out at a maternity hospital in the northeastern Brazilian region. Through an institutional ethnographic approach, research demonstrates that the Kangaroo Program has been effective in saving lives and improving some of the infants' health outcomes. However, research also demonstrates that: (i) the socioeconomic profile of mothers in the Kangaroo Program, (ii) conflicting relationships between healthcare workers and users, and (iii) lack of socioeconomic and emotional support are impairing the adequate implementation of the program. Due to the low literacy level of most of these mothers, institutional power is used as a form of social control to keep mothers uninformed about the possibility of leaving the maternity wards. In a two tier health system, this controlling behavior is part of existing social inequities, as the Kangaroo Program is a choice in the private health system but tends to be mandatory at SUS maternity hospitals across Brazil. PMID- 21281400 TI - Ectopic expression of MECA-79 as a novel prognostic indicator in gastric cancer. AB - The aim of this study was to clarify the clinical implications of a unique carbohydrate determinant, MECA-79, in gastric cancer specimens and cells. Immunohistochemical analysis showed that 62 of 225 (27.6%) cases were defined as positive for MECA-79. MECA-79 expression was correlated with depth of invasion, venous invasion, TNM stage, and distant metastasis. In survival analyses, patients with MECA-79 expression had worse prognosis by the log-rank test. Multivariate analysis of the Cox proportional hazard model showed that MECA-79 expression was an independent factor of a worse cancer-specific survival. Among 11 gastric cancer cells, MECA-79 was observed in only MKN7 cells, which also expressed GlcNAc6ST-2 transcript. A knockdown of GlcNAc6ST-2 in MKN7 cells showed a markedly reduced expression of MECA-79, suggesting that GlcNAc-sulfation of MECA-79 is mainly synthesized by GlcNAc6ST-2. Furthermore, real-time RT-PCR analysis revealed that GlcNAc6ST-2 was significantly increased in cancer tissues compared with paired normal mucosa. In conclusion, the expression of MECA-79 could be a useful marker for the prognosis of gastric cancer. Our results might also provide novel perspectives on the biology of MECA-79 and GlcNAc6ST-2 in cancer progression and metastasis. PMID- 21281401 TI - HLA-A2-restricted glypican-3 peptide-specific CTL clones induced by peptide vaccine show high avidity and antigen-specific killing activity against tumor cells. AB - Glypican-3 (GPC3) is an onco-fetal antigen that is overexpressed in human hepatocellular carcinoma (HCC), and is only expressed in the placenta and embryonic liver among normal tissues. Previously, we identified an HLA-A2 restricted GPC3(144-152) (FVGEFFTDV) peptide that can induce GPC3-reactive CTLs without inducing autoimmunity in HLA-A2 transgenic mice. In this study, we carried out a phase I clinical trial of HLA-A2-restricted GPC3(144-152) peptide vaccine in 14 patients with advanced HCC. Immunological responses were analyzed by ex vivo gamma-interferon enzyme-linked immunospot assay. The frequency of GPC3(144-152) peptide-specific CTLs after vaccination (mean, 96; range, 5-441) was significantly larger than that before vaccination (mean, 6.5; range, 0-43) (P < 0.01). An increase in the GPC3(144-152) peptide-specific CTL frequency was observed in 12 (86%) of 14 patients after vaccination. Additionally, there was a significant correlation between the maximum value of GPC3(144-152) peptide specific CTLs after vaccination and the dose of the peptide injected (P = 0.0166, r = 0.665). Moreover, we established several GPC3(144-152) peptide-specific CTL clones from PBMCs of patients vaccinated with GPC3(144-152) peptide by single cell sorting using Dextramer and CD107a antibody. These CTL clones had high avidity (the recognition efficiency showing 50% cytotoxicity was 10(-10) or 10( 11) M) and could recognize HCC cell lines expressing GPC3 in an HLA-class I restricted manner. These results suggest that GPC3(144-152) peptide vaccine can induce high avidity CTLs capable of killing HCC cells expressing GPC3. This trial was registered with University Hospital Medical Information Network number 000001395. PMID- 21281402 TI - RNA aptamer against a cancer stem cell marker epithelial cell adhesion molecule. AB - The lack of a specific targeting strategy against cancer stem cells in current cancer treatment regimens is at least partly responsible for life-threatening cytotoxicity for patients undergoing traditional chemotherapy. An effective cancer stem cell targeting system is urgently required for the next generation of cancer medicine. Epithelial cell adhesion molecule (EpCAM) is overexpressed in most solid cancers and it has recently been identified as a cancer stem cell marker. In this study, we isolated a 40-base RNA aptamer that binds to EpCAM from a random oligonucleotide library using systematic evolution of ligands by exponential enrichment. The aptamer was further truncated to 19 bases. This 19-nt RNA aptamer interacts specifically with a number of live human cancer cells derived from breast, colorectal, and gastric cancers that express EpCAM, but not with those not expressing EpCAM, as analyzed using flow cytometry and confocal microscopy. The binding affinity of the EpCAM RNA aptamer to human cancer cells is approximately 55 nM. Importantly, this EpCAM RNA aptamer is efficiently internalized after binding to cell surface EpCAM. To our knowledge, this is the first RNA aptamer against a cancer stem cell surface marker being developed. Such cancer stem cell aptamers will greatly facilitate the development of novel targeted nanomedicine and molecular imaging agents for cancer theranostics. PMID- 21281403 TI - Oncogenic phosphatase Wip1 is a novel prognostic marker for lung adenocarcinoma patient survival. AB - DNA damage response pathways are important for maintaining genomic stability. The oncogenic phosphatase Wip1 plays a crucial role in DNA damage response by inhibiting several cell cycle proteins, including p53. Although Wip1 gene amplification has been reported in various primary tumors, including lung cancer, its biological significance for survival of primary lung tumor patients remains unclear. We investigated the expression of Wip1 in cancer epithelial cells immunohistochemically in 84 consecutive resected cases of lung adenocarcinoma. Increased Wip1 expression was observed in 54 (64.3%) of the 84 cases. Wip1 expression was found to be correlated significantly with two clinicopathological factors: gamma-H2AX expression, and invasion to the pulmonary vein. A univariate analysis and log-rank test indicated a significant association between Wip1 expression and lower overall survival rate (P = 0.019 and P = 0.0099, respectively). A multivariate analysis also indicated a statistically significant association between increased Wip1 expression and lower overall survival rate (hazard ratio, 4.3; P = 0.026). The Ki67 index level was higher in the Wip1 positive group than in the negative group (P < 0.04, Mann-Whitney U-test). Moreover, in a subgroup analysis of only stage I patients, increased Wip1 expression was also significantly associated with a lower overall survival rate (P = 0.023, log-rank test). These results indicate that the increased expression of Wip1 in cancer epithelial cells has significant value for tumor progression and the clinical prognosis of patients with primary lung adenocarcinoma. PMID- 21281404 TI - Caffeine and Parkinson's disease: are we getting our fix on risk-modifying gene environment interactions? PMID- 21281405 TI - Coffee, ADORA2A, and CYP1A2: the caffeine connection in Parkinson's disease. AB - BACKGROUND AND PURPOSE: In 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine animal models of Parkinson's disease (PD), caffeine protects neurons by blocking the adenosine receptor A2A (ADORA2A). Caffeine is primarily metabolized by cytochrome P450 1A2 (CYP1A2). Our objective was to examine whether ADORA2A and CYP1A2 polymorphisms are associated with PD risk or modify the caffeine-PD association. METHODS: Parkinson's Epidemiology and Genetic Associations Studies in the United States (PEGASUS) included five population-based case-control studies. One laboratory genotyped four ADORA2A and three CYP1A2 polymorphisms in 1325 PD cases and 1735 age- and sex-matched controls. Information regarding caffeine (coffee) consumption and other lifestyle factors came from structured in-person or telephone interviews. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression. RESULTS: Two ADORA2A polymorphisms were inversely associated with PD risk - rs71651683, a 5' variant (adjusted allelic OR = 0.51, 95% CI 0.33-0.80, permutation-adjusted P = 0.015) and rs5996696, a promoter region variant (adjusted OR for AC and CC genotypes compared with the AA wild-type genotype were 0.76 (95% CI 0.57-1.02) and 0.37 (95% CI 0.13-1.01), respectively (permutation-adjusted P for trend = 0.04). CYP1A2 polymorphisms were not associated with PD risk; however, the coffee-PD association was strongest among subjects homozygous for either variant allele rs762551 (P(interaction) = 0.05) or rs2470890 (P(interaction) = 0.04). CONCLUSION: In this consortium study, two ADORA2A polymorphisms were inversely associated with PD risk, but there was weak evidence of interaction with coffee consumption. In contrast, the coffee-PD association was strongest among slow metabolizers of caffeine who were homozygous carriers of the CYP1A2 polymorphisms. PMID- 21281406 TI - Trichuris and hookworm infections associated with anaemia during pregnancy. AB - OBJECTIVE: To assess the following associations between the second and third trimesters of pregnancy: (i) the intensity of soil-transmitted helminth (STH) infection and haemoglobin/anaemia, (ii) the effect of mebendazole treatment on the occurrence of STH infection, and (iii) the effect of mebendazole treatment on haemoglobin/anaemia. METHODS: Data originated from a trial of 1042 pregnant women recruited in their second trimester and followed to delivery. Baseline assessments included socio-demographic/health information from questionnaires, haemoglobin/anaemia from HemoCue ascertainment of fingerprick blood, and the presence and intensity of STH (Ascaris lumbricoides, hookworms and Trichuris trichiura) infections from Kato-Katz examination. All women were given iron supplements; half were randomly allocated to receive single dose 500 mg mebendazole, and half, placebo. Haemoglobin/anaemia and STH infection status were determined again in the third trimester of pregnancy. RESULTS: Complete information was available from 935 (89.7%) women. Mebendazole significantly reduced the prevalence and intensity of all three STH infections. Higher intensities of hookworm and Trichuris infections in the second trimester were associated with a higher risk of anaemia in the third trimester. Overall, women with moderate/heavy Trichuris infection were found to be at a higher risk of anaemia; the highest risk was observed among those with moderate/heavy hookworm co-infection (adjusted OR = 2.77; 95% CI: 1.26, 6.11). Mebendazole treatment did not reduce the risk of anaemia. CONCLUSION: Higher intensities of both Trichuris and hookworm infections are associated with anaemia in pregnancy. The importance of Trichuris infections during pregnancy requires renewed attention. PMID- 21281407 TI - Randomised, placebo-controlled trial to evaluate co-trimoxazole to reduce mortality and morbidity in HIV-infected post-natal women in Zambia (TOPAZ). AB - OBJECTIVE: To evaluate the role of prophylactic trimethoprim-sulfamethoxazole (co trimoxazole) antibacterial prophylaxis in reducing morbidity and mortality in HIV infected post-natal women in southern Africa. METHODS: Double-blind placebo controlled trial. HIV-infected women with WHO stage 2 or 3 HIV disease who had recently delivered in the Department of Obstetrics and Gynaecology at the University Teaching Hospital, Lusaka, Zambia were randomised to receive daily co trimoxazole (cotox) or matched placebo daily for the duration of the trial. Participants were followed up for a minimum of 1 year. Primary outcome measures were mortality from any cause or hospital admission and serious adverse events. RESULTS: Of 600 women randomised, follow-up information was available from 355 (180 cotox, 175 placebo) participants. Thirty-six (17 cotox, 19 placebo) women died during the trial, and another 11 (5 cotox, 6 placebo) were admitted to hospital. There was no significant difference in the combined event rates between the two treatment arms: HR = 0.82, 95% CI (0.46, 1.45), P = 0.49; morbidity was reduced over a range of symptoms. Secondary analyses of the outcome in babies indicated some evidence of reduced mortality in those whose mothers were allocated cotox. CONCLUSIONS: Follow-up rates were poor; there was no evidence that co-trimoxazole prophylaxis reduced mortality or hospital admission rates, although fewer symptoms were reported in the cotox arm. Cotox was safe and well tolerated. PMID- 21281408 TI - Beneficial effect of oral administration of Lactobacillus casei strain Shirota on insulin resistance in diet-induced obesity mice. AB - AIMS: This study aimed at determining whether oral administration of a probiotic strain, Lactobacillus casei strain Shirota (LcS), can improve insulin resistance, which is the underlying cause of obesity-associated metabolic abnormalities, in diet-induced obesity (DIO) mice. METHODS AND RESULTS: DIO mice were fed a high fat diet without or with 0.05% LcS for 4 weeks and then subjected to an insulin tolerance test (ITT) or oral glucose tolerance test (OGTT). Oral administration of LcS not only accelerated the reduction in plasma glucose levels during the ITT, but also reduced the elevation of plasma glucose levels during the OGTT. In addition, plasma levels of lipopolysaccharide-binding protein (LBP), which is a marker of endotoxaemia, were augmented in the murine models of obese DIO, ob/ob, db/db and KK-A(y) and compared to those of lean mice. LcS treatment suppressed the elevation of plasma LBP levels in DIO mice, but did not affect intra abdominal fat weight. CONCLUSIONS: LcS improves insulin resistance and glucose intolerance in DIO mice. The reduction in endotoxaemia, but not intra-abdominal fat, may contribute to the beneficial effects of LcS. SIGNIFICANCE AND IMPACT OF THE STUDY: This study suggests that LcS has the potential to prevent obesity associated metabolic abnormalities by improving insulin resistance. PMID- 21281409 TI - Biotechnological conversion of waste cooking olive oil into lipid-rich biomass using Aspergillus and Penicillium strains. AB - AIMS: In this study, we have investigated the biochemical behaviour of Aspergillus sp. (five strains) and Penicillium expansum (one strain) fungi cultivated on waste cooking olive oil. The production of lipid-rich biomass was the main target of the work. In parallel, the biosynthesis of other extracellular metabolites (organic acids) and enzyme (lipase) and the substrate fatty acid specificity of the strains were studied. METHODS AND RESULTS: Carbon-limited cultures were performed on waste oil, added in the growth medium at 15g l(-1) , and high biomass quantities were produced (up to c.18g l(-1) , conversion yield of c. 1.0 g of dry biomass formed per g of fat consumed or higher). Cellular lipids were accumulated in notable quantities in almost all cultures. Aspergillus sp. ATHUM 3482 accumulated lipid up to 64.0% (w/w) in dry fungal mass. In parallel, extracellular lipase activity was quantified, and it was revealed to be strain and fermentation time dependent, with a maximum quantity of 645 U ml(-1) being obtained by Aspergillus niger NRRL 363. Storage lipid content significantly decreased at the stationary growth phase. Some differences in the fatty acid composition of both cellular and residual lipids when compared with the initial substrate fat used were observed; in various cases, cellular lipids more saturated and enriched with arachidic acid were produced. Aspergillus strains produced oxalic acid up to 5.0 g l(-1) . CONCLUSIONS: Aspergillus and Penicillium strains are able to convert waste cooking olive oil into high-added-value products. SIGNIFICANCE AND IMPACT OF THE STUDY: Increasing fatty wastes amounts are annually produced. The current study provided an alternative way of biovalourization of these materials, by using them as substrates, to produce added-value compounds. PMID- 21281410 TI - Treating disordered speech and voice in Parkinson's disease online: a randomized controlled non-inferiority trial. AB - BACKGROUND: Telerehabilitation may be a feasible solution to the current problems faced by people with Parkinson's disease in accessing speech pathology services. AIM: To investigate the validity and reliability of online delivery of the Lee Silverman Voice Treatment (LSVT(r)) for the speech and voice disorder associated with Parkinson's disease. METHOD & PROCEDURES: Thirty-four participants with Parkinson's disease and mild-to-moderate hypokinetic dysarthria took part in the randomized controlled non-inferiority laboratory trial and received the LSVT(r) in either the online or the face-to-face environment. Online sessions were conducted via two personal computer-based videoconferencing systems with real time and store-and-forward capabilities operating on a 128 kbit/s Internet connection. Participants were assessed pre- and post-treatment on acoustic measures of mean vocal sound pressure level, phonation time, maximum fundamental frequency range, and perceptual measures of voice, articulatory precision and speech intelligibility. OUTCOMES & RESULTS: Non-inferiority of the online LSVT(r) modality was confirmed for the primary outcome measure of mean change in sound pressure level on a monologue task. Additionally, non-significant main effects for the LSVT(r) environment, dysarthria severity, and interaction effects were obtained for all outcomes measures. Significant improvements following the LSVT(r) were also noted on the majority of measures. The LSVT(r) was successfully delivered online, although some networking difficulties were encountered on a few occasions. High participant satisfaction was reported overall. CONCLUSIONS & IMPLICATIONS: Online treatment for hypokinetic dysarthria associated with Parkinson's disease appears to be clinically valid and reliable. Suggestions for future research are outlined. PMID- 21281411 TI - Adapting a receptive vocabulary test for preschool-aged Greek-speaking children. AB - BACKGROUND: Receptive vocabulary is an important measure for language evaluations. Therefore, norm-referenced receptive vocabulary tests are widely used in several languages. However, a receptive vocabulary test has not yet been normed for Modern Greek. AIMS: To adapt an American English vocabulary test, the Receptive One-Word Picture Vocabulary Test-II (ROWPVT-II), for Modern Greek for use with Greek-speaking preschool children. METHODS & PROCEDURES: The list of 170 English words on ROWPVT-II was adapted by (1) developing two lists (A and B) of Greek words that would match either the target English word or another concept corresponding to one of the pictured objects in the four-picture array; and (2) determining a developmental order for the chosen Greek words for preschool-aged children. For the first task, adult word frequency measures were used to select the words for the Greek wordlist. For the second task, 427 children, 225 boys and 202 girls, ranging in age from 2;0 years to 5;11 years, were recruited from urban and suburban areas of Greece. A pilot study of the two word lists was performed with the aim of comparing an equal number of list A and list B responses for each age group and deriving a new developmental list order. OUTCOMES & RESULTS: The relative difficulty of each Greek word item, that is, its accuracy score, was calculated by taking the average proportion of correct responses across ages for that word. Subsequently, the word accuracy scores in the two lists were compared via regression analysis, which yielded a highly significant relationship (R(2) = 0.97; p < 0.0001) and a few outlier pairs (via residuals). Further analysis used the original relative ranking order along with the derived ranking order from the average accuracy scores of the two lists in order to determine which word item from the two lists was a better fit. Finally, new starting levels (basals) were established for preschool ages. CONCLUSIONS & IMPLICATIONS: The revised word list can serve as the basis for adapting a receptive vocabulary test for Greek preschool-aged children. Further steps need to be taken when testing larger numbers of 2;0 to 5;11-year-old children on the revised word list for determination of norms. This effort will facilitate early identification and remediation of language disorders in Modern Greek-speaking children. PMID- 21281412 TI - Expecting a good quality of life in health: assessing people with diverse diseases and conditions using the WHOQOL-BREF. AB - BACKGROUND AND OBJECTIVES: Fulfilling patient expectations is central to defining a good quality of life (QoL) in health. The WHOQOL-BREF was developed using novel, person-centred methods and is a generic patient-reported outcomes measure (PROM). However, without robust psychometric performance, PROMs cannot be relied upon to assess individuals. This study investigated the WHOQOL-BREF (UK), with this use in mind. DESIGN: Cross sectional with nested repeated measures. SETTING AND PARTICIPANTS: Twenty-seven disease groups or health conditions and healthy people were recruited at 38 UK sites, in a wide range of settings (n = 4628). INTERVENTIONS: 'Treatment as usual'; new and alternative interventions. OUTCOME MEASURES: WHOQOL-BREF (UK); SF-36. RESULTS: Respondent burden was low, as acceptability and feasibility were high. Internal consistency was excellent (0.92) and test-retest reliability good. Distinctive QoL profiles were found for diverse conditions. Musculoskeletal, psychiatric and cardiovascular patients reported the poorest QoL and also improved most during treatment. Overall, QoL was good, and best for healthy groups, supporting discriminant validity. Compared with the SF-36, WHOQOL physical and psychological domains showed good concurrent validity, although social was weak. Small or moderate effect sizes confirmed responsiveness to change in specified domains for certain conditions and interventions. Age had a small impact on reporting QoL. DISCUSSION AND CONCLUSION: The WHOQOL-BREF is found to be a high quality patient-centred generic tool suited to individual assessment in clinics, for research, and audit. PMID- 21281413 TI - Innovation and participation for healthy public policy: the first National Health Assembly in Thailand. AB - AIM: This paper aims to describe and disseminate the process and initial outcomes of the first National Health Assembly (NHA) in Thailand, as an innovative example of health policy making. SETTING: The first NHA, held in December 2008 in Bangkok, brought together over 1500 people from government agencies, academia, civil society, health professionals and the private sector to discuss key health issues and produce resolutions to guide policy making. It adapted the approach used at the World Health Assembly of the World Health Organization. METHOD: Findings are derived from a literature review, document analysis, and the views and experiences of the authors, two of whom contributed to the organization of the NHA and two of whom were invited external observers. RESULTS: Fourteen agenda items were discussed and resolutions passed. Potential early impacts on policy making have included an increase in the 2010 public budget for Thailand's universal health coverage scheme as total public expenditure has decreased; cabinet endorsement of proposed Strategies for Universal Access to Medicines for Thai People; and establishment of National Commissions on Health Impact Assessment and Trade and Health. DISCUSSION: The NHA was successful in bringing together various actors and sectors involved in the social production of health, including groups often marginalized in policy making. It provides an innovative model of how governments may be able to increase public participation and intersectoral collaboration that could be adapted in other contexts. Significant challenges remain in ensuring full participation of interested groups and in implementing, and monitoring the impact of, the resolutions passed. PMID- 21281414 TI - Patients' experiences and views of an emergency and urgent care system. AB - BACKGROUND: Surveys of patients' experiences and views of health care usually focus on single services. During an unexpected episode of ill health, patients may make contact with different services and therefore experience care within an emergency and urgent care system. We developed the Urgent Care System Questionnaire and used it to describe patients' experiences and views of an emergency and urgent care system in England. METHODS: A market research company used quota sampling and random digit dialling to undertake a telephone survey of 1000 members of the general population in July 2007. RESULTS: 15% (151/1000) of the population reported using the emergency and urgent care system in the previous 3 months. Two thirds of users (68%, 98/145) contacted more than one service for their most recent event, with a mean of 2.0 services per event. Users entered the system through a range of services: the majority contacted a daytime GP in the first instance (59%, 85/145), and 12% (18/145) contacted either a 999 emergency ambulance or an emergency department. Satisfaction with all aspects of care diminished when four or more services had been contacted. CONCLUSIONS: This is the first study to describe patients' experiences and views of the emergency and urgent care system. The majority of patients experienced a system of care rather than single service care. There was an indication that longer pathways resulted in lower levels of patient satisfaction. Health care organisations can undertake similar surveys to identify problems with their system or to assess the impact of changes made to their system. PMID- 21281415 TI - Donor transmission of pineoblastoma in a two-yr-old male recipient of a multivisceral transplant: a case report. AB - Transplant-transmitted malignances are rare but devastating events. Primary brain tumors are the least common among reported donor-derived malignancies. We report a case of donor-transmitted pineoblastoma, a PNET, in a two-yr-old male recipient, who presented with a rapidly growing mass in the right mandible, four months after multiple visceral organ transplantation. The recipient had liver, pancreas, and small bowel transplants because of end-stage liver failure and short gut syndrome, which was secondary to large bowel resection for management of gastroschisis complicated by intestinal volvulus. The donor autopsy results became available seven wk after transplantation, which found a pineoblastoma with meningeal spread. Evaluation of eyes, adrenal glands, bone marrow, and other organs did not identify metastasis outside the CNS. A biopsy of the recipient's right mandibular mass revealed a malignant small round blue cell tumor with the immunohistochemistry profile of a PNET. Staging evaluation revealed the tumor in the right mandible with bone marrow involvement. Further investigation showed that recipient's tumor and donor's pineoblastoma shared the same immunophenotype and HLA type, suggesting the recipient's tumor is a donor-transmitted pineoblastoma. This is the first case report of donor-transmitted pineoblastoma post-organ transplant. PMID- 21281416 TI - "When I had my transplant, I became normal." Adolescent perspectives on life after kidney transplantation. AB - This study aimed to explore experiences and perspectives of adolescent kidney transplant recipients following kidney transplantation. We conducted 22 in-depth, face-to-face interviews with adolescent kidney transplant recipients (aged 12-19 yr) from five Australian pediatric transplant units. We analyzed the interview transcripts for descriptive and analytical themes. The overarching theme was achieving a sense of normality. Having the same opportunities and potential to achieve as other adolescents facilitated better adjustment, well-being and positive development after transplant. Five facilitators and five barriers to achieving a sense of normality were identified. The facilitators were developing their own identity, peer acceptance, making medications routine, freedom and energy, and support structures. The barriers included identity crisis, peer rejection, aversion to medications, lifestyle limitations, and fear and uncertainty. The adolescents felt more knowledge was needed on the technical, medical, and experiential aspects of transplantation and on pertinent issues such as alcohol, drugs, and substance use. Adolescent kidney transplant recipients value normality and have specific information needs about the effect of kidney transplantation on their physical appearance and the tolerance of drugs and alcohol. Novel approaches are needed to foster self-confidence and sense of normality and to provide comprehensive information on the patient journey following kidney transplantation. PMID- 21281417 TI - Bacterial contamination of organ graft preservation solution and infection after transplantation. AB - Infectious complications represent a major cause of morbidity and mortality in patients with organ transplantation. Contamination of preservation solution (PS) can lead to life-threatening complications in the recipients. For a 3-year period, we investigated the bacterial contamination of both PSs and graft fragments, recipient infections, and explored the link between them. In total 137 organs were transplanted, and 131 organ and perfusate cultures out of 426 tested (30.8%) gave a positive bacterial culture, mainly with coagulase-negative staphylococci. Overall, 80 recipients out of 137 (58.4%) had at least 1 infection during the 4-month post-graft surveillance period. Twelve recipients had an infection with the same bacterial species that was recovered in the corresponding graft. However, based on pulsed-field gel electrophoresis typing results, only 1 case was very likely cross-transmitted via the transplantation. PMID- 21281418 TI - Recurrent leishmaniasis in kidney transplant recipients: report of 2 cases and systematic review of the literature. AB - The characteristics of 8 episodes of leishmaniasis with atypical manifestations in 2 Italian kidney transplant recipients are analyzed and contextualized among those of 52 other episodes of leishmaniasis observed in 19 transplant recipients found through a systematic review of the international literature. In all the patients, the initial episode was visceral leishmaniasis, which was associated with mucocutaneous involvement in 2 cases. With the exception of 1 case of post kala-azar dermal leishmaniasis, 2 episodes of Leishmania endophthalmitis, and 3 episodes of mucocutaneous leishmaniasis, all the recurrences were characterized by visceral involvement. The potential role of polymerase chain reaction in monitoring the infection, the importance of a long follow-up, the potential benefit of chemoprophylaxis, and the therapeutic challenges are discussed. PMID- 21281419 TI - Abundance of introduced species at home predicts abundance away in herbaceous communities. AB - Many ecosystems worldwide are dominated by introduced plant species, leading to loss of biodiversity and ecosystem function. A common but rarely tested assumption is that these plants are more abundant in introduced vs. native communities, because ecological or evolutionary-based shifts in populations underlie invasion success. Here, data for 26 herbaceous species at 39 sites, within eight countries, revealed that species abundances were similar at native (home) and introduced (away) sites - grass species were generally abundant home and away, while forbs were low in abundance, but more abundant at home. Sites with six or more of these species had similar community abundance hierarchies, suggesting that suites of introduced species are assembling similarly on different continents. Overall, we found that substantial changes to populations are not necessarily a pre-condition for invasion success and that increases in species abundance are unusual. Instead, abundance at home predicts abundance away, a potentially useful additional criterion for biosecurity programmes. PMID- 21281420 TI - Regulatory exaptation of the catabolite repression protein (Crp)-cAMP system in Pseudomonas putida. AB - The genome of the soil bacterium Pseudomonas putida KT2440 encodes singular orthologues of genes crp (encoding the catabolite repression protein, Crp) and cyaA (adenylate cyclase) of Escherichia coli. The levels of cAMP formed by P. putida cells were below detection with a Dictyostelium biosensor in vivo. The cyaA(P. putida) gene was transcribed in vivo but failed to complement the lack of maltose consumption of a cyaA mutant of E. coli, thereby indicating that cyaA(P. putida) was poorly translated or rendered non-functional in the heterologous host. Yet, generation of cAMP by CyaA(P. putida) could be verified by expressing the cyaA(P. putida) gene in a hypersensitive E. coli strain. On the other hand, the crp(P. putida) gene restored the metabolic capacities of an equivalent crp mutant of E. coli, but not in a double crp/cyaA strain, suggesting that the ability to regulate such functions required cAMP. In order to clarify the breadth of the Crp/cAMP system in P. putida, crp and cyaA mutants were generated and passed through a battery of phenotypic tests for recognition of gross metabolic properties and stress-endurance abilities. These assays revealed that the loss of each gene led in most (but not all) cases to the same phenotypic behaviour, indicating a concerted functionality. Unexpectedly, none of the mutations affected the panel of carbon compounds that can be used by P. putida as growth substrates, the mutants being impaired only in the use of various dipeptides as N sources. Furthermore, the lack of crp or cyaA had little influence on the gross growth fingerprinting of the cells. The poor physiological profile of the Crp cAMP system of P. putida when compared with E. coli exposes a case of regulatory exaptation, i.e. the process through which a property evolved for a particular function is co-opted for a new use. PMID- 21281421 TI - Depicting more accurate pictures of protistan community complexity using pyrosequencing of hypervariable SSU rRNA gene regions. AB - Initial environmental pyrosequencing studies suggested highly complex protistan communities with phylotype richness decisively higher than previously estimated. However, recent studies on individual bacteria or artificial bacterial communities evidenced that pyrosequencing errors may skew our view of the true complexity of microbial communities. We pyrosequenced two diversity markers (hypervariable regions V4 and V9 of the small-subunit rDNA) of an intertidal protistan model community, using the Roche GS-FLX and the most recent GS-FLX Titanium sequencing systems. After pyrosequencing 24 reference sequences we obtained up to 2039 unique tags (from 3879 V4 GS-FLX Titanium reads), 77% of which were singletons. Even binning sequences that share 97% similarity still emulated a pseudodiversity exceeding the true complexity of the model community up to three times (V9 GS-FLX). Pyrosequencing error rates were higher for V4 fragments compared with the V9 domain and for the GS-FLX Titanium compared with the GS-FLX system. Furthermore, this experiment revealed that error rates are taxon-specific. As an outcome of this study we suggest a fast and efficient strategy to discriminate pyrosequencing signals from noise in order to more realistically depict the structure of protistan communities using simple tools that are implemented in standard tag data-processing pipelines. PMID- 21281422 TI - Molecular diversity and distribution of aromatic hydrocarbon-degrading anaerobes across a landfill leachate plume. AB - Natural attenuation of the mono-aromates benzene, toluene, ethylbenzene and xylene occurs under iron-reducing conditions in a leachate-contaminated aquifer near the Banisveld landfill, the Netherlands. The diversity of mono-aromate degrading microorganisms was studied by targeting functional genes encoding benzylsuccinate synthase alpha-subunit (bssA) and 6-oxocyclohex-1-ene-1-carbonyl CoA hydrolase (bamA). Sixty-four bssA and 188 bamA variants were sequenced from groundwater sampled along the pollution plume in 1999 and 2004. Species containing bssA sequences closest affiliated (> 91%) with the betaprotebacterium Georgfuchsia toluolica were the dominant alkylbenzene degraders (89% of bssA sequences). bssA genes were found at more than 10-fold lower copy numbers than bamA genes, of which only a small fraction (< 2%) was closely related to the genes of Georgfuchsia. bamA gene diversity was high and bamA-based community composition was primarily affected by dissolved organic carbon (DOC) and ferrous iron concentrations. bamA sequences closest related to Geobacteraceae were dominantly (43.2%) observed and the presence of Geobacteraceae-related bamA sequences was associated with DOC. Our results indicate a key role for specialized Georgfuchsia spp. in the degradation of alkylbenzenes, whereas Geobacteraceae are involved in degradation of aromatics other than toluene and xylene. PMID- 21281423 TI - Characterization of novel antibiotic resistance genes identified by functional metagenomics on soil samples. AB - The soil microbial community is highly complex and contains a high density of antibiotic-producing bacteria, making it a likely source of diverse antibiotic resistance determinants. We used functional metagenomics to search for antibiotic resistance genes in libraries generated from three different soil samples, containing 3.6 Gb of DNA in total. We identified 11 new antibiotic resistance genes: 3 conferring resistance to ampicillin, 2 to gentamicin, 2 to chloramphenicol and 4 to trimethoprim. One of the clones identified was a new trimethoprim resistance gene encoding a 26.8 kDa protein closely resembling unassigned reductases of the dihydrofolate reductase group. This protein, Tm8-3, conferred trimethoprim resistance in Escherichia coli and Sinorhizobium meliloti (gamma- and alpha-proteobacteria respectively). We demonstrated that this gene encoded an enzyme with dihydrofolate reductase activity, with kinetic constants similar to other type I and II dihydrofolate reductases (K(m) of 8.9 uM for NADPH and 3.7 uM for dihydrofolate and IC(50) of 20 uM for trimethoprim). This is the first description of a new type of reductase conferring resistance to trimethoprim. Our results indicate that soil bacteria display a high level of genetic diversity and are a reservoir of antibiotic resistance genes, supporting the use of this approach for the discovery of novel enzymes with unexpected activities unpredictable from their amino acid sequences. PMID- 21281424 TI - Pectin engineering to modify product quality in potato. AB - Although processed potato tuber texture is an important trait that influences consumer preference, a detailed understanding of tuber textural properties at the molecular level is lacking. Previous work has identified tuber pectin methyl esterase (PME) activity as a potential factor impacting on textural properties, and the expression of a gene encoding an isoform of PME (PEST1) was associated with cooked tuber textural properties. In this study, a transgenic approach was undertaken to investigate further the impact of the PEST1 gene. Antisense and over-expressing potato lines were generated. In over-expressing lines, tuber PME activity was enhanced by up to 2.3-fold; whereas in antisense lines, PME activity was decreased by up to 62%. PME isoform analysis indicated that the PEST1 gene encoded one isoform of PME. Analysis of cell walls from tubers from the over expressing lines indicated that the changes in PME activity resulted in a decrease in pectin methylation. Analysis of processed tuber texture demonstrated that the reduced level of pectin methylation in the over-expressing transgenic lines was associated with a firmer processed texture. Thus, there is a clear link between PME activity, pectin methylation and processed tuber textural properties. PMID- 21281426 TI - Hepatitis B re-activation with rituximab therapy: treat the patient not the disease. PMID- 21281425 TI - Expression of an immunogenic Ebola immune complex in Nicotiana benthamiana. AB - Filoviruses (Ebola and Marburg viruses) cause severe and often fatal haemorrhagic fever in humans and non-human primates. The US Centers for Disease Control identifies Ebola and Marburg viruses as 'category A' pathogens (defined as posing a risk to national security as bioterrorism agents), which has lead to a search for vaccines that could prevent the disease. Because the use of such vaccines would be in the service of public health, the cost of production is an important component of their development. The use of plant biotechnology is one possible way to cost-effectively produce subunit vaccines. In this work, a geminiviral replicon system was used to produce an Ebola immune complex (EIC) in Nicotiana benthamiana. Ebola glycoprotein (GP1) was fused at the C-terminus of the heavy chain of humanized 6D8 IgG monoclonal antibody, which specifically binds to a linear epitope on GP1. Co-expression of the GP1-heavy chain fusion and the 6D8 light chain using a geminiviral vector in leaves of N. benthamiana produced assembled immunoglobulin, which was purified by ammonium sulphate precipitation and protein G affinity chromatography. Immune complex formation was confirmed by assays to show that the recombinant protein bound the complement factor C1q. Size measurements of purified recombinant protein by dynamic light scattering and size exclusion chromatography also indicated complex formation. Subcutaneous immunization of BALB/C mice with purified EIC resulted in anti-Ebola virus antibody production at levels comparable to those obtained with a GP1 virus-like particle. These results show excellent potential for a plant-expressed EIC as a human vaccine. PMID- 21281427 TI - The dark side of sports: using steroids may harm your liver. PMID- 21281428 TI - Hepatocyte metabolic signalling pathways and regulation of hepatitis B virus expression. AB - Hepatitis B virus (HBV) is a small DNA virus responsible for significant morbidity and mortality worldwide. The liver, which is the main target organ for HBV infection, provides the virus with the machinery necessary for persistent infection and propagation, a process that might ultimately lead to severe liver pathologies such as chronic hepatitis, cirrhosis and liver cancer. HBV gene expression is regulated mainly at the transcriptional level by recruitment of a whole set of cellular transcription factors (TFs) and co-activators to support transcription. Over the years, many of these TFs were identified and interestingly enough most are associated with the body's nutritional state. These include the hepatocyte nuclear factors, forkhead Box O1, Farnesoid X receptor, cyclic-AMP response element-binding (CREB), CCAAT/enhancer-binding protein (C/EBP) and glucocorticoid receptor TFs and the transcription coactivator PPARgamma coactivator-1alpha. Consequently, HBV gene expression is linked to hepatic metabolic processes such as glucose and fat production and utilization as well as bile acids' production and secretion. Furthermore, recent evidence indicates that HBV actively interferes with some of these hepatic metabolic processes by manipulating key TFs, such as CREB and C/EBP, to meet its requirements. The discovery of the mechanisms by which HBV is controlled by the hepatic metabolic milieu may broaden our understanding of the unique regulation of HBV expression and may also explain the mechanisms by which HBV induces liver pathologies. The emerging principle of the intimate link between HBV and liver metabolism can be further exploited for host-targeted therapeutic strategies. PMID- 21281429 TI - Recurrence of non-viral liver disease after orthotopic liver transplantation. AB - Liver transplant remains the ultimate treatment for decompensated liver disease. However, many diseases do recur after orthotopic liver transplant, which may affect recipients' quality of life and survival rate. We performed a systematic review of relevant epidemiological studies available on Medline that provided information on the recurrence of non-viral hepatitis after orthotopic liver transplantation in adult patients published until August 2010. All data were compiled from either review articles or retrospective studies. Primary sclerosing cholangitis, primary biliary cirrhosis, autoimmune hepatitis, non-alcoholic steatohepatitis, alcoholic steatohepatitis and haemochromatosis can recur after liver transplantation. The rates for disease recurrence varied according to the indication for transplantation, and ranged from 7 to 50%. Although the survival rate of patients with liver disease has increased with the advent of liver transplantation and novel immunosuppressive protocols, recurrence of the primary liver disease remains a concern. The recurrence rates differ not only according to the cause of underlying liver disease but also vary within the indication for transplant. Further studies are needed to elucidate the risk factors for varied disease recurrence. PMID- 21281430 TI - Effect of mutant beta-catenin on liver growth homeostasis and hepatocarcinogenesis in transgenic mice. AB - BACKGROUND: Mutations in the Wnt signalling pathway molecule beta-catenin are associated with liver cancer. AIMS: Our aim was to confirm the effects of stabilized beta-catenin on liver growth, identify whether those effects were reversible and cell autonomous or non-cell autonomous and to model beta-catenin induced liver cancer in mice. METHODS: Using a liver-specific inducible promoter, we generated transgenic mice in which the expression of mutant beta-catenin can be induced or repressed within hepatocytes in mice of different ages. RESULTS: Similar to other models, the hepatic expression of mutant beta-catenin in our model beginning in utero or induced in quiescent adult liver resulted in a two fold liver enlargement and development of disease with a latency of 1-5 months, and mice displayed elevated blood ammonia and altered hepatic gene expression. Our model additionally allowed us to discover that molecular and phenotypic abnormalities were reversible following the inhibition of transgene expression. Hepatocyte transplant studies indicated that mutant beta-catenin could not increase the growth of transgene-expressing foci in either growth-permissive or restrictive hepatic environments, but still directly altered hepatocyte gene expression. Mice with continuous but focal transgene expression developed hepatic neoplasms after the age of 1 year. CONCLUSIONS: Our findings indicate that hepatocyte gene expression is directly affected by mutant beta-catenin in a cell autonomous manner. However, hepatomegaly associated with diffuse hepatocyte specific expression of mutant beta-catenin is secondary to liver functional alteration or non-cell autonomous. Both phenotypes are reversible. Nevertheless, some foci of transgene-expressing cells progressed to carcinoma, confirming the association of mutant beta-catenin with liver cancer. PMID- 21281431 TI - Arguments against toxic effects of chemotherapy on liver injury and regeneration in an experimental model of partial hepatectomy. AB - BACKGROUND: New chemotherapy regimens are increasingly used in metastatic colorectal cancer to the liver before surgery. Some clinical observations have suggested that chemotherapy may affect liver regeneration. AIMS: The aim of this study was to evaluate liver damage and liver regeneration after chemotherapy treatment in a model of partial hepatectomy. METHODS: C57BL/6 mice were repeatedly treated with intraperitoneal injections of either saline or different chemotherapy regimens including the drugs 5-fluorouracyl (5-FU), irinotecan, oxaliplatin, gemcitabine and combined treatments with 5-FU/irinotecan, 5 FU/oxaliplatin. A 70% partial hepatectomy was performed 1 week after the last injection. Ki-67 and PCNA immunohistochemistry were performed to assess liver regeneration, serum liver enzymes and histology analysis to evaluate injury. RESULTS: A variety of chemotherapeutic agents used at maximum tolerated doses compatible with survival affected body weight and blood cell levels. However, these regimens did not affect liver injury before and after hepatectomy nor did they impair liver regeneration. Liver histology showed no steatosis, fibrosis or inflammation before hepatectomy. We therefore tested whether chemotherapy in presence of diet-induced steatosis may trigger injury. Even under these conditions, we did not observe histological signs of inflammation or sinusoidal injury. CONCLUSIONS: Liver injury and liver regeneration are not impaired after neoadjuvant chemotherapy with 5-FU, irinotecan, oxaliplatin and gemcitabine in non-tumoural liver parenchyma. In addition, combined treatments disclose no adverse effects on liver regeneration. Chemotherapy alone induces no histological alterations even in the presence of steatosis. PMID- 21281432 TI - Differential expression of the anterior gradient protein-2 is a conserved feature during morphogenesis and carcinogenesis of the biliary tree. AB - BACKGROUND: The anterior gradient protein-2 (AGR2) is overexpressed in numerous tumours such as breast, prostate or pancreas carcinomas and recently reported in fibrolamellar hepatocellular carcinoma (HCC). AIMS: In the present study, we further describe AGR2 expression patterns all along the adult and fetal biliary tree and in cholangiocarcinomas. METHODS: Immunohistochemistry using anti-AGR2 antibodies was performed in adult and fetal livers, gallbladders as well as cholangiocarcinomas and HCCs. RESULTS: In adult and fetal liver, the tall epithelial cells covering the large bile ducts as well as gallbladder epithelial cells showed strong AGR2 staining. Hilar and extrahepatic cholangiocarcinomas, and a subset of intrahepatic cholangiocarcinomas, which displayed a morphological mucus-excreting feature, also displayed AGR2 expression. In contrast, AGR2 expression was not detected in typical HCCs. CONCLUSION: Our study shows that the differential expression of AGR2 is a phenotypic feature of the cholangiocytes covering different segments of the biliary tree. This pattern of expression is conserved during fetal and adult life, as well as during biliary carcinogenesis. PMID- 21281433 TI - Bone marrow mononuclear cell therapy for patients with cirrhosis: a Phase 1 study. AB - BACKGROUND: Bone marrow-derived cell therapy has been investigated in patients with severe liver disease. AIMS: To assess the feasibility, safety and cell kinetics of autologous bone marrow-derived mononuclear cells (BMMCs) infusion in cirrhotic patients. METHODS: BMMCs were isolated from autologous bone marrow and 10% of the cells were labelled with (99m)Tc-SnCl2. Whole body scintigraphy (WBS) was performed 3 and 24 h after infusion via the hepatic artery. Liver function and image were followed during 1 year. RESULTS: Eight patients received 2.0-15.0 * 108 cells. Three and 24-h WBS showed mean hepatic radiotracer retentions of 41 and 32% respectively. One case of dissection of the hepatic artery and one case of Tako-tsubo syndrome occurred as early complications. A patient developed a cutaneous immunomediated disorder and another patient developed hepatocellular carcinoma (HCC) 12 months after infusion. A reduction in bilirubin was shown at 1 week while serum albumin increased above baseline up to 1 month after infusion (P<0.05). CONCLUSIONS: BMMCs infusion is feasible and practical in a clinical setting. In vivo tracking of labelled cells demonstrated that the hepatic artery route successfully delivered BMMCs to the liver. The early improvement of laboratory indices of liver function should be interpreted with caution, because this study was not designed to evaluate efficacy. The median Model for End-Stage Liver Disease score had not deteriorated 1 year later. The occurrence of a graft versus-host disease-like phenomenon highlights the importance of sustained vigilance even when giving autologous cells. Controlled studies are needed to determine whether BMMCs infusion affects HCC development in cirrhosis. PMID- 21281434 TI - Enhanced efficacy of pegylated interferon alpha-2a over pegylated interferon and ribavirin in chronic hepatitis C genotype 4A randomized trial and quality of life analysis. AB - AIM: The therapy of chronic hepatitis C genotype 4 (HCV-4) has not been optimized yet. This randomized, prospective, parallel-group clinical trial compared the efficacy and safety of pegylated interferon alpha-2a (PEG-IFN alpha-2a) plus ribavirin and PEG-IFN alpha-2b plus ribavirin and assessed the health-related quality of life (HRQOL) in patients with chronic HCV-4. METHODS: Eligible patients with proven chronic HCV-4 were randomized to receive either a weekly dose of PEG-IFN alpha-2a (180 MUg) or PEG-IFN alpha-2b (1.5 MUg/kg) and a daily dose of ribavirin (1000-1200 mg) for 48 weeks with 24 weeks post-treatment follow up. The primary end point was sustained virological response (SVR) defined by undetectable HCV RNA 24 weeks after treatment. The Short form-36 Health Survey version 2 (SF-36v2) and the Chronic Liver Disease questionnaires (CLDQ) were assessed before, during and after therapy. RESULTS: The overall SVR rate of the entire cohort was 59.9%. The SVR rates were significantly higher in patients treated with PEG-IFN alpha-2a and ribavirin (Group A; n=109) compared with those treated with PEG-IFN alpha-2b and ribavirin (Group B; n=108, 70.6 vs. 54.6%, respectively; P=0.017). The relapse rates were 5.1% for PEG-IFN alpha-2a and 15.7% for PEG-IFN alpha-2b (P=0.0019). The SF-36v2 and CLDQ were low during therapy and improved significantly after therapy successful therapy. CONCLUSION: Pegylated interferon alpha-2a plus ribavirin was significantly more effective than PEG-IFN alpha-2b and ribavirin therapy in the treatment of chronic HCV-4 patients. The tolerability and adverse events were comparable between the two regimens. The HRQOL improved significantly after successful PEG-IFN alpha-2a plus ribavirin therapy. PMID- 21281435 TI - Association of PNPLA3 with non-alcoholic fatty liver disease in a minority cohort: the Insulin Resistance Atherosclerosis Family Study. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent condition, particularly among Hispanic Americans. A genetic variant in PNPLA3 (rs738409) has been identified as a strong predictor of hepatic fat content. AIMS: To confirm the association of this variant with NAFLD in two minority cohorts, Hispanic Americans and African Americans, in whom liver density was quantified by computed tomography (CT). METHODS: This analysis was conducted in the Insulin Resistance Atherosclerosis (IRAS) Family Study. Participants were recruited from the general community and included 843 Hispanic American and 371 African American adults aged 18-81 years. A single variant in PNPLA3 (rs738409) was genotyped. Liver density was calculated in Hounsfield Units from abdominal CT scans. RESULTS: Single nucleotide polymorphism (SNP) rs738409 was strongly associated with reduced liver density (i.e. NAFLD) in Hispanic Americans (1.18 * 10-9) and in African Americans (P=4.99 * 10-6). The association followed an additive genetic model with the G allele conferring risk. The allele was two times more common in Hispanic Americans than in African Americans (40 vs 19%), consistent with the greater prevalence of NAFLD in Hispanic Americans (24 vs 9%). The SNP explained 4.4 and 5.6% of the variance of the adjusted liver density outcome in Hispanic Americans and African Americans, respectively. CONCLUSIONS: We confirmed the association of a PNPLA3 variant with NAFLD in Hispanic Americans and African Americans, suggesting that PNPLA3 contributes to the variation in NAFLD across multiple ethnicities. This study adds to the growing evidence that some of the ethnic variation in NAFLD is genetic. PMID- 21281436 TI - Outcome predictors of cirrhotic patients with spontaneous bacterial empyema. AB - BACKGROUND: Spontaneous bacterial empyema (SBE) is a complication of cirrhotic patients in which a pre-existing pleural effusion becomes infected. This retrospective study was designed to investigate the bacteriology and outcome predictors of SBE in cirrhotic patients. METHODS: Medical records of cirrhotic patients treated in a tertiary care university hospital from December 2004 to December 2008 were retrospectively reviewed. RESULTS: Of 3390 cirrhotic patients seen during the study period, 81 cases of SBE were diagnosed. The incidence of SBE was 2.4% (81/3390) in cirrhotic patients and 16% (81/508) in patients with cirrhosis with hydrothorax. There were 46 monomicrobial infections found in 46 SBE patients. Aerobic Gram-negative organisms were the predominant pathogens (n=29, 63%), and Escherichia coli (n=9, 20%) was the most frequently isolated sole pathogen. The mortality rate of SBE was 38% (31/81). Univariate analysis showed that Child-Pugh score, model for end-stage liver disease (MELD)-Na score, concomitant bacteraemia, concomitant spontaneous bacterial peritonitis, initial intensive care unit (ICU) admission and initial antibiotic treatment failure were predictors of poor outcomes. Multivariate regression analysis demonstrated that the independent factors related to a poor outcome were initial ICU admission [odds ratio (OR): 4.318; 95% confidence interval 1CI) 1.09-17.03; P=0.037], MELD Na score (OR: 1.267; 95% CI 1.08-1.49; P=0.004) and initial antibiotic treatment failure (OR: 13.10; 95% CI 2.60-66.03). CONCLUSION: Spontaneous bacterial empyema in cirrhotic patients is a high mortality complication. The independent factors related to poor outcome are high MELD-Na score, initial ICU admission and initial antibiotic treatment failure. High MELD-Na score may be a useful mortality predictor of SBE in cirrhotic patients. PMID- 21281437 TI - Assessment of adrenal function in cirrhotic patients using concentration of serum free and salivary cortisol. AB - OBJECTIVE: Because over 90% of serum cortisol is bound to albumin and corticosteroid-binding globulin (CBG), changes in these proteins can affect measures of serum total cortisol levels in cirrhotics without altering serum-free and salivary cortisol concentrations. METHODS: We assessed basal (T0) and post synacthen (T60) serum total cortisol, serum-free and salivary cortisol in 125 consecutive cirrhotics (95 non-septic and 30 septic patients with a Child>8). RESULTS: Serum total cortisol levels significantly decreased from the Child A-C non-septic group, as did albumin and CBG levels, with a non-significant rise in serum-free cortisol concentrations. Non-septic patients with low albumin (<=25 g/L) or CBG levels (<=35 mg/L) had lower T0 serum total cortisol levels than patients with near-normal albumin (303.4 vs. 382.6 nmol/L; P=0.0035) or with normal CBG levels (289.9 vs. 441.4 nmol/L; P<0.0001), respectively, despite similar serum-free cortisol or salivary cortisol concentrations. Subnormal T60 serum total cortisol concentrations (<510.4 nmol/L) were measured in 7.2% of all patients (Child C: 14.5% vs. Child A and B: 0%; P=0.0013) but no patients exhibited symptoms suggesting adrenal insufficiency. Patients with or without subnormal T60 total cortisol had similar T0 salivary cortisol and serum-free cortisol concentrations. A trend was observed towards high serum-free cortisol concentrations and mortality in multivariate analysis. CONCLUSIONS: Serum total cortisol levels overestimated the prevalence of adrenal dysfunction in cirrhotics with end-stage liver disease. Since serum-free cortisol cannot be measured routinely, salivary cortisol testing could represent a useful approach but needs to be standardized. PMID- 21281438 TI - Chewing khat and chronic liver disease. PMID- 21281439 TI - A prospective non-randomised study to compare oral trauma from laryngoscope versus laryngeal mask insertion. AB - BACKGROUND: Prospective studies evaluating the incidence of dental injuries in anaesthesia are scarce or absent. The aim of this study was to compare the incidence of oral trauma in patients submitted to laryngoscopy and orotracheal intubation with those anaesthetized with a laryngeal mask. MATERIAL AND METHODS: This observational study was performed in the University Hospital, with blind evaluation. We evaluated 121 patients older than 18 years old who were submitted to elective surgery under general anaesthesia. Patients were excluded if they were pregnant, underwent surgery of the mouth or required nasal intubation. Laryngoscopy and orotracheal tube were used in 70 patients and laryngeal mask in 51. Twelve to 24 h before anaesthesia and after surgery, all patients underwent a detailed oral examination performed by an anaesthesiology and a senior dentist, both blind to anaesthetic management details. Injuries of the teeth were diagnosed based on WHO's classification system modified by Andreasen. RESULTS: Oral injuries were found in 84.1% of the patients after laryngoscopy and 19.6% after laryngeal mask insertion (P < 0.001). Corresponding values for teeth injuries were, respectively, 38.6% and 2.0% (P < 0.001). The great majority were enamel fractures of the maxillary incisors. This means that patients submitted to laryngoscopy had a significantly higher incidence of oral injuries compared with those having laryngeal mask insertion (unadjusted OR 21, 99; CI 0.95: 8.55 56.55). CONCLUSION: Minor oral trauma is significantly more frequent after endotracheal intubation than after use of the laryngeal mask. This is true for injuries of the teeth, inferior lip and tongue. Further studies are needed to evaluate on a long-term basis the clinical relevance of the dental injuries we found. PMID- 21281440 TI - Impact of traumatic dental injuries with unmet treatment need on daily life among Albanian adolescents: a case-control study. AB - BACKGROUND: Traumatic dental injuries (TDI) are common in children and adolescences. Neglected or inadequate treatment may lead to psychosocial distress during late adolescence. AIM: To investigate the potential impact of traumatic dental injuries (TDI) with unmet treatment need, on the quality of life of 16-19 year-olds in Tirana, Albania. MATERIAL AND METHODS: A case-control survey (1:2) was conducted in public high schools in Albania, comprising 95 subjects affected by TDI with unmet treatment need based on objective clinical signs. Controls (n = 190) with no history of TDI were matched by age, sex and belonging to the same school class and group of friends as the respective case. The Oral Impact on Daily Performances (OIDP) index was used to measure the impacts. DMFT, Community Periodontal Index and the Aesthetic Component of the Index of Orthodontic Treatment Need as well as social parameters were recorded. RESULTS: The response rate was 98%. Overall, the impact prevalence of OIDP was 88.4% among the cases, and 58.9% among the controls (P < 0.001). The most prevalent OIDP impact was 'smiling and showing teeth without embarrassment': cases had significantly higher values than controls (78.9% vs 31.6%). Multiple conditional logistic regression analysis was used to disclose the effect of TDI with unmet treatment need on quality of life by adjusting for possible confounders. Compared to the control group, TDI cases with unmet treatment need are at greater overall risk of impacts measured as OIDP, with an odds ratio of 3.9 (95% CI: 1.6-9.1). CONCLUSION: TDI with unmet treatment need in this sample of adolescents is associated with reduced OHRQoL. Compared to adolescents with no history of TDI, those affected by TDI with unmet treatment need are at greater risk of suffering impacts on OHRQoL in the form of OIDP. PMID- 21281441 TI - Horizontal root fractures in posterior teeth: a case series. AB - This case series describes observations of 12 patients who developed horizontal root fractures in non-endodontically treated teeth. Using clinical and radiographic examination, horizontal fractures were observed in eight maxillary first molars, one maxillary second molar, one mandibular first premolar and four mandibular second premolars. A total of 12 teeth had clinically intact crowns and 2 had carious. Eight fractures of maxillary molars occurred in the palatal roots, while one fracture was observed in the distobuccal root. Eleven patients experienced pain from the affected teeth during mastication. Within the limits of this case series, it was concluded that these fractures were related to; root morphology, damaging masticatory habits and excessive occlusal forces. PMID- 21281442 TI - Treatment of multiple traumatized anterior teeth associated with an alveolar bone fracture in a 15-year-old school boy: a 2.5-year follow up. AB - We report a case of multiple dental traumas in a 15-year-old school boy who was hit by a stone. Clinical examinations revealed the avulsion of teeth 21, 22, and 23, an uncomplicated crown fracture of tooth 41, and a complicated crown fracture (CCF) of teeth 11, 31, and 33. An alveolar bone fracture and a root fracture in the apical third of tooth 23 were as well noted on radiographs. The avulsed teeth were replanted and rigidly splinted after an extraoral dry time of 90 min. Endodontic treatments were performed on teeth with CCFs. The dental morphology was restored using polyethylene fiber-reinforced composite resin. Endodontic obturations were performed on replanted teeth after the arrest of external root resorptions by a long-term calcium hydroxide dressing. Esthetics and function were recovered with a 2.5-year follow-up period. PMID- 21281443 TI - A retrospective study of oral and maxillofacial injuries in Seremban Hospital, Malaysia. AB - INTRODUCTION: Aetiology of oral and maxillofacial injuries in this country includes motorvehicle accident (MVA), fall, industrial accidents and others. Among these causes, MVA accident is the predominant cause of injury in Malaysia. MATERIALS AND METHODS: A retrospective record review was carried out using hospital records of all patients who sustained oral and maxillofacial injury at the Department of Oral Surgery, Seremban Hospital, Negeri Sembilan, Malaysia between 1998 and 2002. Information related to demographics, aetiology of trauma, vehicles involved in collision, location of injuries and treatment modalities were reviewed. RESULTS: Two thousand nine hundred and eighty-six patients sustained oral and maxillofacial injuries. Of these patients, 79.2% were men and the remaining were women. Among all the races, Malays had the highest involvement (50.6%) followed by Indians (24.5%), Chinese (19.6%) and others (5.3%). There were statistically significant results on the association of aetiology and the ethnic groups, in the age group of 30 years or less and male gender (P < 0.001). The most common injury was the soft-tissue injury followed by dental and dentoalveolar injuries and bony fracture. Among all facial fractures, 66.3% were managed conservatively, 13% were treated surgically and 19.7% did not have any intervention. In relation to dental and dentoalveolar injuries, 64.8% had treatment in the form of splinting, restorations or dental extraction. The rest of the patients (35.2%) were referred to their dentists or did not have any active treatment at Seremban Hospital. CONCLUSION: Most of the dental and facial injuries in Seremban Hospital were caused by MVA and were predominantly managed using conservative methods. PMID- 21281444 TI - Conventional and digital radiography in vertical root fracture diagnosis: a comparison study. AB - BACKGROUND: Vertical root fractures (VRFs) can only be detected by radiography. In recent years, direct digital dental radiography (DDR) has become a substitute to film-based radiography. Purpose of this study was to compare accuracy and reliability of charge couple device (CCD)-based direct digital radiography with conventional radiography (CR) in VRF diagnosis. METHODS AND MATERIALS: In this in vitro study, 230 extracted single-rooted human teeth were endodontically instrumented. VRFs were performed experimentally in half of the samples. Each tooth was imaged using the paralleling technique with E-speed film and a CCD based digital image receptor. Two oral radiologists interpreted the images and repeated the procedure a month later with half of the samples. The accuracy, sensitivity, and specificity of each technique were determined. The reliability and degree of agreement were also determined by the means of Cohen's Kappa analysis. chi2 test was used to compare two observers' diagnosis, considering the location of fracture line. RESULTS: The accuracy of CR and DDR was 65% and 70% retrospectively. The sensitivity was 60% for CR, 61% for DDR and the specificity was 70% for CR, 78% for DDR, but the differences were not significant. The interobserver reliability was moderate for CR (K = 0.366, 95% CI) and fair for DDR (K = 0.538, 95% CI). CONCLUSION: No significant difference was seen between the two techniques. The specificity of DDR was slightly better than CR, and their accuracy and sensitivity showed small differences. PMID- 21281445 TI - Polymorphisms associated with normal memory variation also affect memory impairment in schizophrenia. AB - Neurocognitive dysfunction is a core feature of schizophrenia with particularly prominent deficits in verbal episodic memory. The molecular basis of this memory impairment is poorly understood and its relatedness to normal variation in memory performance is unclear. In this study, we explore, in a sample of cognitively impaired schizophrenia patients, the role of polymorphisms in seven genes recently reported to modulate episodic memory in normal subjects. Three polymorphisms (GRIN2B rs220599, GRM3 rs2189814 and PRKCA rs8074995) were associated with episodic verbal memory in both control and patients with cognitive deficit, but not in cognitively spared patients or the pooled schizophrenia sample. GRM3 and PRKCA acted in opposite directions in patients compared to controls, possibly reflecting an abnormal brain milieu and/or adverse environmental effects in schizophrenia. The encoded proteins balance glutamate signalling vs. excitotoxicity in complex interactions involving the excitatory amino acid transporter 2 (EAAT2), implicated in the dysfunctional glutamatergic signalling in schizophrenia. Double carrier status of the GRM3 and PRKCA minor alleles was associated with lower memory test scores and with increased risk of schizophrenia. Single nucleotide polymorphism (SNP) rs8074995 lies within the PRKCA region spanned by a rare haplotype associated with schizophrenia in a recent UK study and provides further evidence of PRKCA contribution to memory impairment and susceptibility to schizophrenia. Our study supports the utility of parsing the broad phenotype of schizophrenia into component cognitive endophenotypes that reduce heterogeneity and enable the capture of potentially important genetic associations. PMID- 21281446 TI - Modulation of F0F1-ATP synthase activity by cyclophilin D regulates matrix adenine nucleotide levels. AB - Cyclophilin D was recently shown to bind to and decrease the activity of F(0)F(1) ATP synthase in submitochondrial particles and permeabilized mitochondria [Giorgio V et al. (2009) J Biol Chem, 284, 33982-33988]. Cyclophilin D binding decreased both ATP synthesis and hydrolysis rates. In the present study, we reaffirm these findings by demonstrating that, in intact mouse liver mitochondria energized by ATP, the absence of cyclophilin D or the presence of cyclosporin A led to a decrease in the extent of uncoupler-induced depolarization. Accordingly, in substrate-energized mitochondria, an increase in F(0)F(1)-ATP synthase activity mediated by a relief of inhibition by cyclophilin D was evident in the form of slightly increased respiration rates during arsenolysis. However, the modulation of F(0)F(1)-ATP synthase by cyclophilin D did not increase the adenine nucleotide translocase (ANT)-mediated ATP efflux rate in energized mitochondria or the ATP influx rate in de-energized mitochondria. The lack of an effect of cyclophilin D on the ANT-mediated adenine nucleotide exchange rate was attributed to the ~ 2.2-fold lower flux control coefficient of the F(0)F(1)-ATP synthase than that of ANT, as deduced from measurements of adenine nucleotide flux rates in intact mitochondria. These findings were further supported by a recent kinetic model of the mitochondrial phosphorylation system, suggesting that an ~ 30% change in F(0)F(1)-ATP synthase activity in fully energized or fully de-energized mitochondria affects the ADP-ATP exchange rate mediated by the ANT in the range 1.38-1.7%. We conclude that, in mitochondria exhibiting intact inner membranes, the absence of cyclophilin D or the inhibition of its binding to F(0)F(1)-ATP synthase by cyclosporin A will affect only matrix adenine nucleotides levels. PMID- 21281447 TI - Oxylipins in fungi. AB - In nearly every living organism, metabolites derived from lipid peroxidation, the so-called oxylipins, are involved in regulating developmental processes as well as environmental responses. Among these bioactive lipids, the mammalian and plant oxylipins are the best characterized, and much information about their physiological role and biosynthetic pathways has accumulated during recent years. Although the occurrence of oxylipins and enzymes involved in their biosynthesis has been studied for nearly three decades, knowledge about fungal oxylipins is still scarce as compared with the situation in plants and mammals. However, the research performed so far has shown that the structural diversity of oxylipins produced by fungi is high and, furthermore, that the enzymes involved in oxylipin metabolism are diverse and often exhibit unusual catalytic activities. The aim of this review is to present a synopsis of the oxylipins identified so far in fungi and the enzymes involved in their biosynthesis. PMID- 21281448 TI - Sex determination and the control of Sox9 expression in mammals. AB - In mouse sex determination, the presence or absence of Sertoli cells in the developing gonad is essential for the decision to form either a testis or an ovary. The transcription factor SOX9 has emerged as the master regulator of Sertoli cell differentiation during testis development and thus the crucial gene to determine sex. It is the target of two sets of regulatory controls, one positive and one negative, where one set tries to gain dominance over the other in the early gonad and then to establish and maintain the activity or silence of Sox9 throughout life. The data reveal the importance of the positive regulatory loops to reinforce initial decisions, whereas the maintenance of the gonadal phenotype appears to rely on the active repression of the opposite pathway. PMID- 21281449 TI - Dmrt1 genes at the crossroads: a widespread and central class of sexual development factors in fish. AB - A plethora of corroborative genetic studies led to the view that, across the animal kingdom, the gene-regulatory cascades triggering sexual development bear little resemblance to each other. As a result, the common emerging picture is that the genes at the top of the cascade are not conserved, whereas the downstream genes have homologues in a much broader spectrum of species. Among these downstream effectors, a gene family involved in sex differentiation in organisms as phylogenetically divergent as corals, Caenorhabditis elegans, Drosophila, frogs, fish, birds and mammals is the dmrt gene family. Despite the attention that Dmrt1 factors have received, to date it has not been elucidated how Dmrt1s mediate their activities and putative downstream targets have yet to be characterized. However, a remarkable amount of descriptive expression data has been gathered in a large variety of fish, particularly with respect to early gonadal differentiation and sex change. This minireview aims at distilling the current knowledge of fish dmrt1s, in terms of expression and regulation. It is shown how gonadal identities correlate with dimorphic dmrt1 expression in gonochoristic and hermaphroditic fish species. It is also described how sex steroid hormones affect gonadal identity and dmrt1 expression. Emphasis is also given to recent findings dealing with transcriptional, post-transcriptional, post translational and functional regulations of the dmrt1a/dmrt1bY gene pair in medaka. PMID- 21281450 TI - A ZZ/ZW-type sex determination in Xenopus laevis. AB - Genetic sex-determining systems in vertebrates include two basic types of heterogamety, which are represented by the XX/XY and ZZ/ZW types. Both types occur among amphibian species. Little is known, however, about the molecular mechanisms underlying amphibian sex determination. Recently, a W-linked gene, DM W, was isolated as a paralog of DMRT1 in the African clawed frog Xenopus laevis, which has a female heterogametic ZZ/ZW-type sex-determining system. The DNA binding domain of DM-W shows high sequence identity with that of DMRT1, but DM-W does not contain a domain with homology to DMRT1's transactivation domain. Importantly, phenotypic analysis of transgenic individuals bearing a DM-W expression or -knockdown vector strongly suggested that DM-W acts as a female sex determining gene in this species. In this minireview, we briefly describe the sex determining systems in amphibians, discuss recent findings from the discovery of the DM-W gene in terms of its molecular evolution and its function in sex determination and ovary formation, and introduce a new model for the ZZ/ZW-type sex determination elicited by DM-W and DMRT1 in X. laevis. Finally, we discuss sex-determining systems and germ-cell development during vertebrate evolution, especially in view of a conserved role of DMRT1 in gonadal masculinization. PMID- 21281451 TI - Sex determination and sexual differentiation in the avian model. AB - The sex of birds is determined by the inheritance of sex chromosomes (ZZ male and ZW female). Genes carried on one or both of these sex chromosomes control sexual differentiation during embryonic life, producing testes in males (ZZ) and ovaries in females (ZW). This minireview summarizes our current understanding of avian sex determination and gonadal development. Most recently, it has been shown that sex is cell autonomous in birds. Evidence from gynandromorphic chickens (male on one side, female on the other) points to the likelihood that sex is determined directly in each cell of the body, independently of, or in addition to, hormonal signalling. Hence, sex-determining genes may operate not only in the gonads, to produce testes or ovaries, but also throughout cells of the body. In the chicken, as in other birds, the gonads develop into ovaries or testes during embryonic life, a process that must be triggered by sex-determining genes. This process involves the Z-linked DMRT1 gene. If DMRT1 gene activity is experimentally reduced, the gonads of male embryos (ZZ) are feminized, with ovarian-type structure, downregulation of male markers and activation of female markers. DMRT1 is currently the best candidate gene thought to regulate gonadal sex differentiation. However, if sex is cell autonomous, DMRT1 cannot be the master regulator, as its expression is confined to the urogenital system. Female development in the avian model appears to be shared with mammals; both the FOXL2 and RSPO1/WNT4 pathways are implicated in ovarian differentiation. PMID- 21281452 TI - Zebrafish physiology: big interest in a small fish. PMID- 21281453 TI - Oxygen gradients in the microcirculation. AB - Early in the last century August Krogh embarked on a series of seminal studies to understand the connection between tissue metabolism and mechanisms by which the cardiovascular system supplied oxygen to meet those needs. Krogh recognized that oxygen was supplied from blood to the tissues by passive diffusion and that the most likely site for oxygen exchange was the capillary network. Studies of tissue oxygen consumption and diffusion coefficient, coupled with anatomical studies of capillarity in various tissues, led him to formulate a model of oxygen diffusion from a single capillary. Fifty years after the publication of this work, new methods were developed which allowed the direct measurement of oxygen in and around microvessels. These direct measurements have confirmed the predictions by Krogh and have led to extensions of his ideas resulting in our current understanding of oxygenation within the microcirculation. Developments during the last 40 years are reviewed, including studies of oxygen gradients in arterioles, capillaries, venules, microvessel wall and surrounding tissue. These measurements were made possible by the development and use of new methods to investigate oxygen in the microcirculation, so mention is made of oxygen microelectrodes, microspectrophotometry of haemoglobin and phosphorescence quenching microscopy. Our understanding of oxygen transport from the perspective of the microcirculation has gone from a consideration of oxygen gradients in capillaries and tissue to the realization that oxygen has the ability to diffuse from any microvessel to another location under the conditions that there exists a large enough PO(2) gradient and that the permeability for oxygen along the intervening pathway is sufficient. PMID- 21281454 TI - Pregnancy protects against antiangiogenic and fibrogenic effects of angiotensin II in rat hearts. AB - AIM: To investigate the difference between physiological and pathological cardiac remodelling induced, respectively, by pregnancy and angiotensin (Ang) II, and to test the hypothesis that pregnancy protects against Ang II effects. METHODS: Female Wistar rats, pregnant (n = 12) and non-pregnant (n = 12), were implanted with mini-pumps containing saline (sham) or 150 ng kg(-1) min(-1) Ang II. Ten days later echocardiography and blood pressure measurement were performed. Expression of 22 genes was assessed using RT-PCR. Microscopic sections of LV were prepared to determine collagen content (Sirius Red staining), vessel density (beta-actin immunolabelling) and myocytes diameter (Toluidine Blue). RESULTS: Heart weight (HW) was increased in Ang II treated groups compared with their controls. Furthermore, HW of Ang II treated pregnant rats (1.0 +/- 0.03 g) was higher than that in non-pregnant sham (0.7 +/- 0.02 g), pregnant (0.8 +/- 0.01 g) and Ang II treated non-pregnant (0.8 +/- 0.02 g) rats. Relative LV wall thickness showed similar pattern. Aortic pressure was significantly increased in Ang II groups. Collagen content was increased in Ang II (4.0 +/- 0.5%) compared with sham (1.5 +/- 0.1%) but reduced again when treated rats were pregnant (2.8 +/- 0.4%). Vessel density was reduced by 47.8% after Ang II treatment in non-pregnant and by only 13.9% in pregnant rats. Gene expression analysis showed increased expression of atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), anykrin repeat domain-containing protein 1 (Ankrd-1), protein kinase C-alpha and delta and tumour suppressor gene TP53 (p53) in Ang II treated groups and upregulation of ANF, BNP and Ankrd-1 remained when pregnancy was combined with Ang II. Pregnancy reduced expression of: alpha-myosin heavy chain, tumour necrosis factor-alpha, p53, endothelial nitric oxide synthase and inducible nitric oxide synthase. CONCLUSION: Pregnancy seems to counteract the detrimental effects of Ang II on fibrosis and angiogenesis in heart. In addition, pregnancy and Ang II lead to partly opposite changes in the expression of some genes important for heart function. PMID- 21281455 TI - Serotonin, depression, and cardiovascular disease: sex-specific issues. AB - The comorbidity of cardiovascular disease (CVD) and depression/anxiety disorders is well established, but the mechanisms are not well understood. This paper will review the epidemiological and biological evidence for the role of depression in CVD, as well as the pathophysiological process underlying both depression and CVD. The focus will be on the roles of serotonin, platelets, and the immune system, with an emphasis on the relevance of sex differences in both depression/anxiety and CVD as they pertain to women. PMID- 21281456 TI - Obesity, insulin resistance and diabetes: sex differences and role of oestrogen receptors. AB - Obesity increases the risk of coronary artery disease through insulin resistance, diabetes, arterial hypertension and dyslipidemia. The prevalence of obesity has increased worldwide and is particularly high among middle-aged women and men. After menopause, women are at an increased risk to develop visceral obesity due to the loss of endogenous ovarian hormone production. Effects of oestrogens are classically mediated by the two nuclear oestrogen receptors (ERs) alpha and beta. In addition, more recent research has shown that the intracellular transmembrane G-protein-coupled oestrogen receptor (GPER) originally designated as GPR30 also mediates some of the actions attributed to oestrogens. Oestrogen and its receptors are important regulators of body weight and insulin sensitivity not only in women but also in men as demonstrated by ER mutations in rodents and humans. This article reviews the role of sex hormones and ERs in the context of obesity, insulin sensitivity and diabetes as well as the related clinical issues in women and men. PMID- 21281457 TI - Opposing effects of NaCl restriction and carbohydrate loading on urine volume in diabetic rats. AB - AIM: To test the effects of dietary NaCl and carbohydrate content on urine volume in diabetic rats. METHODS: Streptozotocin-induced diabetic rats were subjected to NaCl restriction using either a NaCl-deficient carbohydrate-rich synthetic diet (Altromin C1036) supplemented to contain 0.16% NaCl (C1036 + lowNaCl) or a modified normal cereal-based diet (Altromin 1320) containing 0.086% NaCl (lowNaCl 1320). Normal diet contained 0.2683% NaCl. RESULTS: Using the C1036 + lowNaCl diet, earlier reported paradoxical increases in water intake and urine volume of diabetic rats were reproduced. However, water intake and urine volume also increased in diabetic rats offered the synthetic C1036 diet supplemented with NaCl to normal levels. Using the lowNaCl-1320 diet, water intake and urine volume were markedly reduced. Highly significant correlations between urine volume and both osmotic output and urinary glucose excretion were found in diabetic rats on normal diet, but these correlations were absent in diabetic rats on synthetic diet, which showed higher urine volumes than expected from the correlations. In contrast, urine volume was significantly correlated with carbohydrate intake in diabetic rats, irrespective of the diet. CONCLUSIONS: (i) The synthetic diet dramatically increases the urine volume in STZ-DM rats irrespectively of NaCl content. (ii) Rats with STZ-DM on a normal diet show reduced water intake and urine volume in response to dietary NaCl restriction. (iii) A shift to high carbohydrate diet induces polyuria in STZ-DM rats. (iv) Urine volume in all STZ DM rats only shows correlation with dietary carbohydrate intake. (v) Glucose driven osmotic diuresis is unlikely to explain the carbohydrate-induced polyuria. PMID- 21281458 TI - On the function of the mammalian renal papilla and the peristalsis of the surrounding pelvis. AB - This is an informal personal review of the development over time of my ideas about the concentrating mechanism of the mammalian renal papilla. It had been observed that animals with a need to produce a concentrated urine have a long renal papilla. I saw the function of the long papilla in desert rodents as an elongation of the counter-current concentrating mechanism of the inner medulla. This model led me to overlook contrary evidence. For example, in many experiments, the final urine has a higher osmolality than that of the tissue at the tip of the papilla. In addition, we had observations of the peristalsis of the renal pelvis surrounding the papilla. The urine concentration falls if the peristalsis is stopped. I was wrong; together, these lines of evidence show that the renal papilla is not just an elongation of the inner medulla. We are left without a full explanation of the concentrating mechanism of the mammalian renal papilla. It is hoped that other researchers will tackle this interesting problem. PMID- 21281459 TI - The mining of toxin-like polypeptides from EST database by single residue distribution analysis. AB - BACKGROUND: Novel high throughput sequencing technologies require permanent development of bioinformatics data processing methods. Among them, rapid and reliable identification of encoded proteins plays a pivotal role. To search for particular protein families, the amino acid sequence motifs suitable for selective screening of nucleotide sequence databases may be used. In this work, we suggest a novel method for simplified representation of protein amino acid sequences named Single Residue Distribution Analysis, which is applicable both for homology search and database screening. RESULTS: Using the procedure developed, a search for amino acid sequence motifs in sea anemone polypeptides was performed, and 14 different motifs with broad and low specificity were discriminated. The adequacy of motifs for mining toxin-like sequences was confirmed by their ability to identify 100% toxin-like anemone polypeptides in the reference polypeptide database. The employment of novel motifs for the search of polypeptide toxins in Anemonia viridis EST dataset allowed us to identify 89 putative toxin precursors. The translated and modified ESTs were scanned using a special algorithm. In addition to direct comparison with the motifs developed, the putative signal peptides were predicted and homology with known structures was examined. CONCLUSIONS: The suggested method may be used to retrieve structures of interest from the EST databases using simple amino acid sequence motifs as templates. The efficiency of the procedure for directed search of polypeptides is higher than that of most currently used methods. Analysis of 39939 ESTs of sea anemone Anemonia viridis resulted in identification of five protein precursors of earlier described toxins, discovery of 43 novel polypeptide toxins, and prediction of 39 putative polypeptide toxin sequences. In addition, two precursors of novel peptides presumably displaying neuronal function were disclosed. PMID- 21281460 TI - Genetic affinities between the Yami tribe people of Orchid Island and the Philippine Islanders of the Batanes archipelago. AB - BACKGROUND: Yami and Ivatan islanders are Austronesian speakers from Orchid Island and the Batanes archipelago that are located between Taiwan and the Philippines. The paternal genealogies of the Yami tribe from 1962 monograph of Wei and Liu were compared with our dataset of non-recombining Y (NRY) chromosomes from the corresponding families. Then mitochondrial DNA polymorphism was also analyzed to determine the matrilineal relationships between Yami, Ivatan, and other East Asian populations. RESULTS: The family relationships inferred from the NRY Phylogeny suggested a low number of paternal founders and agreed with the genealogy of Wei and Liu (P < 0.01). Except for one Y short tandem repeat lineage (Y-STR), seen in two unrelated Yami families, no other Y-STR lineages were shared between villages, whereas mtDNA haplotypes were indiscriminately distributed throughout Orchid Island. The genetic affinity seen between Yami and Taiwanese aborigines or between Ivatan and the Philippine people was closer than that between Yami and Ivatan, suggesting that the Orchid islanders were colonized separately by their nearest neighbors and bred in isolation. However a northward gene flow to Orchid Island from the Philippines was suspected as Yami and Ivatan peoples both speak Western Malayo-Polynesian languages which are not spoken in Taiwan. Actually, only very little gene flow was observed between Yami and Ivatan or between Yami and the Philippines as indicated by the sharing of mtDNA haplogroup B4a1a4 and one O1a1* Y-STR lineage. CONCLUSIONS: The NRY and mtDNA genetic information among Yami tribe peoples fitted well the patrilocal society model proposed by Wei and Liu. In this proposal, there were likely few genetic exchanges among Yami and the Philippine people. Trading activities may have contributed to the diffusion of Malayo-Polynesian languages among them. Finally, artifacts dating 4,000 YBP, found on Orchid Island and indicating association with the Out of Taiwan hypothesis might be related to a pioneering stage of settlement, as most dating estimates inferred from DNA variation in our data set ranged between 100-3,000 YBP. PMID- 21281461 TI - A randomised controlled trial of a cognitive behavioural intervention for women who have menopausal symptoms following breast cancer treatment (MENOS 1): trial protocol. AB - BACKGROUND: This trial aims to evaluate the effectiveness of a group cognitive behavioural intervention to alleviate menopausal symptoms (hot flushes and night sweats) in women who have had breast cancer treatment. Hot flushes and night sweats are highly prevalent but challenging to treat in this population. Cognitive behaviour therapy has been found to reduce these symptoms in well women and results of an exploratory trial suggest that it might be effective for breast cancer patients. Two hypotheses are tested:Compared to usual care, group cognitive behavioural therapy will:1. Significantly reduce the problem rating and frequency of hot flushes and nights sweats after six weeks of treatment and at six months post-randomisation.2. Improve mood and quality of life after six weeks of treatment and at six months post-randomisation. METHODS/DESIGN: Ninety-six women who have completed their main treatment for breast cancer and who have been experiencing problematic hot flushes and night sweats for over two months are recruited into the trial from oncology and breast clinics in South East London. They are randomised to either six weekly group cognitive behavioural therapy (Group CBT) sessions or to usual care. Group CBT includes information and discussion about hot flushes and night sweats in the context of breast cancer, monitoring and modifying precipitants, relaxation and paced respiration, stress management, cognitive therapy for unhelpful thoughts and beliefs, managing sleep and night sweats and maintaining changes.Prior to randomisation women attend a clinical interview, undergo 24-hour sternal skin conductance monitoring, and complete questionnaire measures of hot flushes and night sweats, mood, quality of life, hot flush beliefs and behaviours, optimism and somatic amplification. Post treatment measures (sternal skin conductance and questionnaires) are collected six to eight weeks later and follow-up measures (questionnaires and a use of medical services measure) at six months post-randomisation. DISCUSSION: MENOS 1 is the first randomised controlled trial of cognitive behavioural therapy for hot flushes and night sweats that measures both self-reported and physiologically indexed symptoms. The results will inform future clinical practice by developing an evidence-based, non-medical treatment, which can be delivered by trained health professionals. TRIAL REGISTRATION: Current Controlled Trials ISRCTN13771934. PMID- 21281462 TI - Expression, secretion and surface display of a human alkaline phosphatase by the ciliate Tetrahymena thermophila. AB - BACKGROUND: Tetrahymena thermophila possesses many attributes that render it an attractive host for the expression of recombinant proteins. Surface proteins from the parasites Ichthyophthirius multifiliis and Plasmodium falciparum and avian influenza virus antigen H5N1 were displayed on the cell membrane of this ciliate. Furthermore, it has been demonstrated that T. thermophila is also able to produce a functional human DNase I. The present study investigates the heterologous expression of the functional human intestinal alkaline phosphatase (hiAP) using T. thermophila and thereby presents a powerful tool for the optimization of the ciliate-based expression system. RESULTS: Functional and full length human intestinal alkaline phosphatase was expressed by T. thermophila using a codon adapted gene containing the native signal-peptide and GPI (Glycosylphosphatidylinositol) anchor attachment signal. HiAP activity in the cell extract of transformants suggested that the hiAP gene was successfully expressed. Furthermore, it was demonstrated that the enzyme was modified with N glycosylation and localized on the surface membrane by the C-terminal GPI anchor. A C-terminally truncated version of hiAP lacking the GPI anchor signal peptide was secreted into the medium as an active enzyme. In a first approach to establish a high level expression system up to 14,000 U/liter were produced in a time frame of two days, which exceeds the production rate of other published expression systems for this enzyme. CONCLUSIONS: With the expression of hiAP, not only a protein of commercial interest could be produced, but also a reporter enzyme that offers the possibility to analyze T. thermophila genes that play a role in the regulation of protein secretion. Additionally, the fact that ciliates do not secrete an endogenous alkaline phosphatase provides the possibility to use the truncated hiAP as a reporter enzyme, allowing the quantification of measures that will be necessary for further optimization of the host strains and the fermentation processes. PMID- 21281463 TI - A randomized phase III trial of adjuvant chemotherapy with irinotecan, leucovorin and fluorouracil versus leucovorin and fluorouracil for stage II and III colon cancer: a Hellenic Cooperative Oncology Group study. AB - BACKGROUND: Colon cancer is a public health problem worldwide. Adjuvant chemotherapy after surgical resection for stage III colon cancer has been shown to improve both progression-free and overall survival, and is currently recommended as standard therapy. However, its value for patients with stage II disease remains controversial. When this study was designed 5-fluorouracil (5FU) plus leucovorin (LV) was standard adjuvant treatment for colon cancer. Irinotecan (CPT-11) is a topoisomerase I inhibitor with activity in metastatic disease. In this multicenter adjuvant phase III trial, we evaluated the addition of irinotecan to weekly 5FU plus LV in patients with stage II or III colon cancer. METHODS: The study included 873 eligible patients. The treatment consisted of weekly administration of irinotecan 80 mg/m2 intravenously (i.v.), LV 200 mg/m2 and 5FU 450 mg/m2 bolus (Arm A) versus LV 200 mg/m2 and 5FU 500 mg/m2 i.v. bolus (Arm B). In Arm A, treatments were administered weekly for four consecutive weeks, followed by a two-week rest, for a total of six cycles, while in Arm B treatments were administered weekly for six consecutive weeks, followed by a two week rest, for a total of four cycles. The primary end-point was disease-free survival (DFS) at three years. RESULTS: The probability of overall survival (OS) at three years was 0.88 for patients in Arm A and 0.86 for those in Arm B, while the five-year OS probability was 0.78 and 0.76 for patients in Arm A and Arm B, respectively (P = 0.436). Furthermore, the probability of DFS at three years was 0.78 and 0.76 for patients in Arm A and Arm B, respectively (P = 0.334). With the exception of leucopenia and neutropenia, which were higher in patients in Arm A, there were no significant differences in Grades 3 and 4 toxicities between the two regimens. The most frequently recorded Grade 3/4 toxicity was diarrhea in both treatment arms. CONCLUSIONS: Irinotecan added to weekly bolus 5FU plus LV did not result in improvement in disease-free or overall survival in stage II or III colon cancer, but did increase toxicity. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12610000148077. PMID- 21281464 TI - Patient preferences and treatment safety for uncomplicated vulvovaginal candidiasis in primary health care. AB - BACKGROUND: Vaginitis is a common complaint in primary care. In uncomplicated candidal vaginitis, there are no differences in effectiveness between oral or vaginal treatment. Some studies describe that the preferred treatment is the oral one, but a Cochrane's review points out inconsistencies associated with the report of the preferred way that limit the use of such data. Risk factors associated with recurrent vulvovaginal candidiasis still remain controversial. METHODS/DESIGN: This work describes a protocol of a multicentric prospective observational study with one year follow up, to describe the women's reasons and preferences to choose the way of administration (oral vs topical) in the treatment of not complicated candidal vaginitis. The number of women required is 765, they are chosen by consecutive sampling. All of whom are aged 16 and over with vaginal discharge and/or vaginal pruritus, diagnosed with not complicated vulvovaginitis in Primary Care in Madrid.The main outcome variable is the preferences of the patients in treatment choice; secondary outcome variables are time to symptoms relief and adverse reactions and the frequency of recurrent vulvovaginitis and the risk factors. In the statistical analysis, for the main objective will be descriptive for each of the variables, bivariant analysis and multivariate analysis (logistic regression).. The dependent variable being the type of treatment chosen (oral or topical) and the independent, the variables that after bivariant analysis, have been associated to the treatment preference. DISCUSSION: Clinical decisions, recommendations, and practice guidelines must not only attend to the best available evidence, but also to the values and preferences of the informed patient. PMID- 21281465 TI - Spatial distribution and characteristics of injecting drug users (IDU) in five Northeastern states of India. AB - BACKGROUND: Injecting drugs is the major driving force of human immunodeficiency virus (HIV) epidemic in Northeastern India. We have assessed the spatial distribution of locations where injecting drug users (IDU) congregate, as well as the risk behaviour and key characteristics of IDUs to develop new strategies strengthening intervention measures for HIV prevention in this region. METHODS: Locations of IDUs congregation for buying and injecting drugs were identified through Key Informants (KI). Verification of the location and its characteristics were confirmed through field visits. We also conducted semi-structured and structured interviews with IDUs to learn more about their injecting behaviour and other characteristics. RESULTS: Altogether, 2462 IDU locations were identified in 5 states. The number of IDU locations was found to be greater in the states bordering Myanmar. Private houses, parks, abandoned buildings, pharmacies, graveyards, and isolated places were the most frequently chosen place for injecting drugs. Many injecting locations were visited by IDUs of varying ages, of which about 10-20% of locations were for females. In some locations, female IDUs were also involved in sex work. Sharing of needle and syringes was reported in all the states by large proportion of IDUs, mainly with close friends. However, even sharing with strangers was not uncommon. Needle and syringes were mainly procured from pharmacies, drug peddlers and friends. Lack of access to free sterile needles and syringes, and inconsistent supplies from intervention programs, were often given as the cause of sharing or re-use of needles and syringes by IDUs. Most of the IDUs described a negative attitude of the community towards them. CONCLUSION: We highlight the injection of drugs as a problem in 5 Northeastern India states where this is the major driving force of an HIV epidemic. Also highlighted are the large numbers of females that are unrecognized as IDUs and the association between drug use and sex work. Understanding of risk behaviours and other key characteristics of IDUs in the region will help in strengthening harm reduction efforts that can prevent HIV transmission. PMID- 21281466 TI - EuropeaN Energy balance Research to prevent excessive weight Gain among Youth (ENERGY) project: Design and methodology of the ENERGY cross-sectional survey. AB - BACKGROUND: Obesity treatment is by large ineffective long term, and more emphasis on the prevention of excessive weight gain in childhood and adolescence is warranted. To inform energy balance related behaviour (EBRB) change interventions, insight in the potential personal, family and school environmental correlates of these behaviours is needed. Studies on such multilevel correlates of EBRB among schoolchildren in Europe are lacking. The ENERGY survey aims to (1) provide up-to-date prevalence rates of measured overweight, obesity, self reported engagement in EBRBs, and objective accelerometer-based assessment of physical activity and sedentary behaviour and blood-sample biomarkers of metabolic function in countries in different regions of Europe, (2) to identify personal, family and school environmental correlates of these EBRBs. This paper describes the design, methodology and protocol of the survey. METHOD/DESIGN: A school-based cross-sectional survey was carried out in 2010 in seven different European countries; Belgium, Greece, Hungary, the Netherlands, Norway, Slovenia, and Spain. The survey included measurements of anthropometrics, child, parent and school-staff questionnaires, and school observations to measure and assess outcomes (i.e. height, weight, and waist circumference), EBRBs and potential personal, family and school environmental correlates of these behaviours including the social-cultural, physical, political, and economic environmental factors. In addition, a selection of countries conducted accelerometer measurements to objectively assess physical activity and sedentary behaviour, and collected blood samples to assess several biomarkers of metabolic function. DISCUSSION: The ENERGY survey is a comprehensive cross-sectional study measuring anthropometrics and biomarkers as well as assessing a range of EBRBs and their potential correlates at the personal, family and school level, among 10-12 year old children in seven European countries. This study will result in a unique dataset, enabling cross country comparisons in overweight, obesity, risk behaviours for these conditions as well as the correlates of engagement in these risk behaviours. PMID- 21281467 TI - Persistent increase in cardiac troponin I in Fabry disease: a case report. AB - BACKGROUND: Hypertrophic cardiomyopathy is a frequent manifestation in Fabry disease (FD) - an X-linked lysosomal storage disorder caused by reduced activity of the enzyme alpha-galactosidase A. In FD an elevation of specific cardiac biomarkers, such as cardiac troponin I (cTNI) has been reported in case of clinical manifestation suggestive of myocardial ischemia. In diagnosing acute myocardial infarction cTNI is considered the most reliable parameter. CASE PRESENTATION: In the referred case we present a 59 years old female patient with the diagnosis of FD presenting with persistently increased cTNI level (lowest value 0.46 ng/ml, highest value 0.69 ng/ml; normal range <0.05 ng/ml) over a period of 5 months lacking cardiac clinical signs. Since renal insufficiency did not explain the degree of cTNI elevation, this was interpreted as a result of cardiac involvement in FD. Cardiac MRI showed marked left ventricular hypertrophy and focal late Gadolinium enhancement. CONCLUSIONS: Our case report demonstrates a persistent cTNI release in FD with cardiac involvement. Proving the persistence in a symptom free interval, it might be related to a direct damage of myocytes. In FD cTNI could serve as a beneficial long term parameter providing new perspectives for screening strategies. PMID- 21281468 TI - ChIPseqR: analysis of ChIP-seq experiments. AB - BACKGROUND: The use of high-throughput sequencing in combination with chromatin immunoprecipitation (ChIP-seq) has enabled the study of genome-wide protein binding at high resolution. While the amount of data generated from such experiments is steadily increasing, the methods available for their analysis remain limited. Although several algorithms for the analysis of ChIP-seq data have been published they focus almost exclusively on transcription factor studies and are usually not well suited for the analysis of other types of experiments. RESULTS: Here we present ChIPseqR, an algorithm for the analysis of nucleosome positioning and histone modification ChIP-seq experiments. The performance of this novel method is studied on short read sequencing data of Arabidopsis thaliana mononucleosomes as well as on simulated data. CONCLUSIONS: ChIPseqR is shown to improve sensitivity and spatial resolution over existing methods while maintaining high specificity. Further analysis of predicted nucleosomes reveals characteristic patterns in nucleosome sequences and placement. PMID- 21281469 TI - Effects of EpCAM overexpression on human breast cancer cell lines. AB - BACKGROUND: Recently, EpCAM has attracted major interest as a target for antibody and vaccine-based cancer immunotherapies. In breast cancer, the EpCAM antigen is overexpressed in 30-40% of all cases and this increased expression correlates with poor prognosis. The use of EpCAM-specific monoclonal antibodies is a promising treatment approach in these patients. METHODS: In order to explore molecular changes following EpCAM overexpression, we investigated changes of the transcriptome upon EpCAM gene expression in commercially available human breast cancer cells lines Hs578T and MDA-MB-231. To assess cell proliferation, a tetrazolium salt based assay was performed. A TCF/LEF Reporter Kit was used to measure the transcriptional activity of the Wnt/beta-catenin pathway. To evaluate the accumulation of beta-catenin in the nucleus, a subcellular fractionation assay was performed. RESULTS: For the first time we could show that expression profiling data of EpCAM transfected cell lines Hs578TEpCAM and MDA-MB-231EpCAM indicate an association of EpCAM overexpression with the downregulation of the Wnt signaling inhibitors SFRP1 and TCF7L2. Confirmation of increased Wnt signaling was provided by a TCF/LEF reporter kit and by the finding of the nuclear accumulation of beta-catenin for MDA-MB-231 EpCAM but not Hs578T EpCAM cells. In Hs578T cells, an increase of proliferation and chemosensitivity to Docetaxel was associated with EpCAM overexpression. CONCLUSIONS: These data show a cell type dependent modification of Wnt signaling components after EpCAM overexpression in breast cancer cell lines, which results in marginal functional changes. Further investigations on the interaction of EpCAM with SFRP1 and TCF7L2 and on additional factors, which may be causal for changes upon EpCAM overexpression, will help to characterize unique molecular properties of EpCAM positive breast cancer cells. PMID- 21281470 TI - An evaluation of access to health care services along the rural-urban continuum in Canada. AB - BACKGROUND: Studies comparing the access to health care of rural and urban populations have been contradictory and inconclusive. These studies are complicated by the influence of other factor which have been shown to be related to access and utilization. This study assesses the equity of access to health care services across the rural-urban continuum in Canada before and after taking other determinants of access into account. METHODS: This is a cross-sectional study of the population of the 10 provinces of Canada using data from the Canadian Community Health Survey (CCHS 2.1). Five different measures of access and utilization are compared across the continuum of rural-urban. Known determinants of utilization are taken into account according to Andersen's Health Behaviour Model (HBM); location of residence at the levels of province, health region, and community is also controlled for. RESULTS: This study found that residents of small cities not adjacent to major centres, had the highest reported utilisation rates of influenza vaccines and family physician services, were most likely to have a regular medical doctor, and were most likely to report unmet need. Among the rural categories there was a gradient with the most rural being least likely to have had a flu shot, use specialist physicians services, or have a regular medical doctor. Residents of the most urban centres were more likely to report using specialist physician services. Many of these differences are diminished or eliminated once other factors are accounted for. After adjusting for other factors those living in the most urban areas were more likely to have seen a specialist physician. Those in rural communities had a lower odds of receiving a flu shot and having a regular medical doctor. People residing in the most urban and most rural communities were less likely to have a regular medical doctor. Those in any of the rural categories were less likely to report unmet need. CONCLUSION: Inequities in access to care along the rural-urban continuum exist and can be masked when evaluation is done at a very large scale with gross indicators of rural-urban. Understanding the relationship between rural-urban and other determinants will help policy makers to target interventions appropriately: to specific demographic, provincial, community, or rural categories. PMID- 21281471 TI - Mobile phone use and stress, sleep disturbances, and symptoms of depression among young adults--a prospective cohort study. AB - BACKGROUND: Because of the quick development and widespread use of mobile phones, and their vast effect on communication and interactions, it is important to study possible negative health effects of mobile phone exposure. The overall aim of this study was to investigate whether there are associations between psychosocial aspects of mobile phone use and mental health symptoms in a prospective cohort of young adults. METHODS: The study group consisted of young adults 20-24 years old (n = 4156), who responded to a questionnaire at baseline and 1-year follow-up. Mobile phone exposure variables included frequency of use, but also more qualitative variables: demands on availability, perceived stressfulness of accessibility, being awakened at night by the mobile phone, and personal overuse of the mobile phone. Mental health outcomes included current stress, sleep disorders, and symptoms of depression. Prevalence ratios (PRs) were calculated for cross-sectional and prospective associations between exposure variables and mental health outcomes for men and women separately. RESULTS: There were cross sectional associations between high compared to low mobile phone use and stress, sleep disturbances, and symptoms of depression for the men and women. When excluding respondents reporting mental health symptoms at baseline, high mobile phone use was associated with sleep disturbances and symptoms of depression for the men and symptoms of depression for the women at 1-year follow-up. All qualitative variables had cross-sectional associations with mental health outcomes. In prospective analysis, overuse was associated with stress and sleep disturbances for women, and high accessibility stress was associated with stress, sleep disturbances, and symptoms of depression for both men and women. CONCLUSIONS: High frequency of mobile phone use at baseline was a risk factor for mental health outcomes at 1-year follow-up among the young adults. The risk for reporting mental health symptoms at follow-up was greatest among those who had perceived accessibility via mobile phones to be stressful. Public health prevention strategies focusing on attitudes could include information and advice, helping young adults to set limits for their own and others' accessibility. PMID- 21281472 TI - Modulation of sulfur metabolism enables efficient glucosinolate engineering. AB - BACKGROUND: Metabolic engineering in heterologous organisms is an attractive approach to achieve efficient production of valuable natural products. Glucosinolates represent a good example of such compounds as they are thought to be the cancer-preventive agents in cruciferous plants. We have recently demonstrated that it is feasible to engineer benzylglucosinolate (BGLS) in the non-cruciferous plant Nicotiana benthamiana by transient expression of five genes from Arabidopsis thaliana. In the same study, we showed that co-expression of a sixth Arabidopsis gene, gamma-glutamyl peptidase 1 (GGP1), resolved a metabolic bottleneck, thereby increasing BGLS accumulation. However, the accumulation did not reach the expected levels, leaving room for further optimization. RESULTS: To optimize heterologous glucosinolate production, we have in this study performed a comparative metabolite analysis of BGLS-producing N. benthamiana leaves in the presence or absence of GGP1. The analysis revealed that the increased BGLS levels in the presence of GGP1 were accompanied by a high accumulation of the last intermediate, desulfoBGLS, and a derivative thereof. This evidenced a bottleneck in the last step of the pathway, the transfer of sulfate from 3'-phosphoadenosine 5'-phosphosulfate (PAPS) to desulfoBGLS by the sulfotransferase AtSOT16. While substitution of AtSOT16 with alternative sulfotransferases did not alleviate the bottleneck, experiments with the three genes involved in the formation and recycling of PAPS showed that co-expression of adenosine 5'-phosphosulfate kinase 2 (APK2) alone reduced the accumulation of desulfoBGLS and its derivative by more than 98% and increased BGLS accumulation 16-fold. CONCLUSION: Adjusting sulfur metabolism by directing sulfur from primary to secondary metabolism leads to a remarkable improvement in BGLS accumulation and thereby represents an important step towards a clean and efficient production of glucosinolates in heterologous hosts. Our study emphasizes the importance of considering co-substrates and their biological nature in metabolic engineering projects. PMID- 21281473 TI - A multi-faceted intervention to implement guideline care and improve quality of care for older people who present to the emergency department with falls. AB - BACKGROUND: Guidelines recommend that older people should receive multi-factorial interventions following an injurious fall however there is limited evidence that this is routine practice. We aimed to improve the delivery of evidence based care to patients presenting to the Emergency Department (ED) following a fall. METHODS: A prospective before and after study was undertaken in the ED of a medium-sized hospital in Perth, Western Australia. Participants comprised 313 community-dwelling patients, aged 65 years and older, presenting to ED as a result of a fall. A multi-faceted strategy to change practice was implemented and included a referral pathway, audit and feedback and additional falls specialist staff. Key measures to show improvements comprised the proportion of patients reviewed by allied health, proportion of patients referred for guideline care, quality of care index, all determined by record extraction. RESULTS: Allied health staff increased the proportion of patients being reviewed from 62.7% in the before period to 89% after the intervention (P < 0.001). Before the intervention a referral for comprehensive guideline care occurred for only 6/177 (3.4%) of patients, afterwards for 28/136 (20.6%) (difference = 17.2%, 95% CI 11 23%). Average quality of care index (max score 100) increased from 18.6 (95% CI: 16.7-20.4) to 32.6 (28.6-36.6). CONCLUSIONS: A multi-faceted change strategy was associated with an improvement in allied health in ED prioritizing the review of ED fallers as well as subsequent referral for comprehensive geriatric care. The processes of multi-disciplinary care also improved, indicating improved care received by the patient. PMID- 21281474 TI - Anti-class a scavenger receptor autoantibodies from systemic lupus erythematosus patients impair phagocytic clearance of apoptotic cells by macrophages in vitro. AB - INTRODUCTION: Inadequate clearance of apoptotic cells by macrophages is one of the reasons for the breakdown of self-tolerance. Class A scavenger receptors, macrophage receptor with collagenous structure (MARCO) and scavenger receptor A (SR-A), which are expressed on macrophages, play important roles in the uptake of apoptotic cells. A previous study reported the presence of the anti-MARCO antibody in lupus-prone mice and systemic lupus erythematosus (SLE) patients. The purpose of this study was to investigate the prevalence of anti-class A scavenger receptor antibodies in patients with various autoimmune diseases, in particular SLE, and the functional implication of those autoantibodies in the phagocytic clearance of apoptotic cells by macrophages. METHODS: Purified recombinant scavenger receptor cysteine-rich (SRCR) polypeptide (ligand-binding domain of MARCO) and recombinant SR-A were used as antigens. By using enzyme-linked immunosorbent assay, the anti-SRCR and anti-SR-A antibodies were detected in the sera of untreated patients with SLE (n = 65), rheumatoid arthritis (n = 65), primary Sjogren syndrome (n = 25), and healthy blood donors (n = 85). The effect of IgG purified from SLE patients or healthy controls on the phagocytosis of apoptotic cells by macrophages was measured by the flow cytometry assay. RESULTS: Anti-SRCR antibodies were present in patients with SLE (18.5%) and rheumatoid arthritis (3.1%), but not in those with primary Sjogren syndrome. Anti-SR-A antibodies were present in patients with SLE (33.8%), rheumatoid arthritis (13.8%), and primary Sjogren syndrome (12.0%). IgG from SLE patients positive for anti-SRCR or anti-SR-A antibodies showed a higher inhibition rate on binding of apoptotic cells to macrophages than IgG from healthy controls (both P < 0.05). IgG from SLE patients positive for both anti-SRCR and anti-SR-A antibodies showed a significantly higher inhibition rate on ingestion of apoptotic by macrophages than IgG from healthy controls (P < 0.05). CONCLUSIONS: Our results indicated that autoantibodies to class A scavenger receptors might contribute to the breakdown of self-tolerance by impairing the clearance of apoptotic debris and play a role in the pathogenesis of autoimmune disease, especially in SLE. PMID- 21281475 TI - Diffusion patterns of new anti-diabetic drugs into hospitals in Taiwan: the case of thiazolidinediones for diabetes. AB - BACKGROUND: Diffusion of new drugs in the health care market affects patients' access to new treatment options and health care expenditures. We examined how a new drug class for diabetes mellitus, thiazolidinediones (TZDs), diffused in the health care market in Taiwan. METHODS: Assuming that monthly hospital prescriptions of TZDs could serve as a micro-market to perform drug penetration studies, we retrieved monthly TZD prescription data for 580 hospitals in Taiwan from Taiwan's National Health Insurance Research Database for the period between March 1, 2001 and December 31, 2005. Three diffusion parameters, time to adoption, speed of penetration (monthly growth on prescriptions), and peak penetration (maximum monthly prescription) were evaluated. Cox proportional hazards model and quantile regressions were estimated for analyses on the diffusion parameters. RESULTS: Prior hospital-level pharmaceutical prescription concentration significantly deterred the adoption of the new drug class (HR: 0.02, 95%CI = 0.01 to 0.04). Adoption of TZDs was slower in district hospitals (HR = 0.43, 95%CI = 0.24 to 0.75) than medical centers and faster in non-profit hospitals than public hospitals (HR = 1.79, 95%CI = 1.23 to 2.61). Quantile regression showed that penetration speed was associated with a hospital's prior anti-diabetic prescriptions (25%Q: 18.29; 50%Q: 25.57; 75%Q: 30.97). Higher peaks were found in hospitals that had adopted TZD early (25%Q: -40.33; 50%Q: -38.65; 75%Q: -32.29) and in hospitals in which the drugs penetrated more quickly (25%Q: 16.53; 50%Q: 24.91; 75%Q: 31.50). CONCLUSIONS: Medical centers began to prescribe TZDs earlier, and they prescribed more TZDs at a faster pace. The TZD diffusion patterns varied among hospitals depending accreditation level, ownership type, and prescription volume of Anti-diabetic drugs. PMID- 21281476 TI - Acceptability of the Distress Thermometer and Problem List to community-based telephone cancer helpline operators, and to cancer patients and carers. AB - BACKGROUND: Cancer can be a distressing experience for cancer patients and carers, impacting on psychological, social, physical and spiritual functioning. However, health professionals often fail to detect distress in their patients due to time constraints and a lack of experience. Also, with the focus on the patient, carer needs are often overlooked. This study investigated the acceptability of brief distress screening with the Distress Thermometer (DT) and Problem List (PL) to operators of a community-based telephone helpline, as well as to cancer patients and carers calling the service. METHODS: Operators (n = 18) monitored usage of the DT and PL with callers (cancer patients/carers, >18 years, and English-speaking) from September-December 2006 (n = 666). The DT is a single item, 11-point scale to rate level of distress. The associated PL identifies the cause of distress. RESULTS: The DT and PL were used on 90% of eligible callers, most providing valid responses. Benefits included having an objective, structured and consistent means for distress screening and triage to supportive care services. Reported challenges included apparent inappropriateness of the tools due to the nature of the call or level of caller distress, the DT numeric scale, and the level of operator training. CONCLUSIONS: We observed positive outcomes to using the DT and PL, although operators reported some challenges. Overcoming these challenges may improve distress screening particularly by less experienced clinicians, and further development of the PL items and DT scale may assist with administration. The DT and PL allow clinicians to direct/prioritise interventions or referrals, although ongoing training and support is critical in distress screening. PMID- 21281477 TI - Mannose-binding lectin does not explain the course and outcome of pregnancy in rheumatoid arthritis. AB - INTRODUCTION: Rheumatoid arthritis (RA) improves during pregnancy and flares after delivery. It has been hypothesized that high levels of the complement factor mannose-binding lectin (MBL) are associated with a favourable disease course of RA by facilitating the clearance of pathogenic immunoglobulin G (IgG) lacking galactose sugar moieties. During pregnancy, increased galactosylation of IgG and simultaneously increased MBL levels can be observed, with the latter being strictly related to maternal MBL genotypes. Therefore, increased MBL levels in concert with increased IgG galactosylation may be associated with pregnancy induced improvement of RA. The objective of this study was to investigate whether MBL genotypes are associated with changes in RA disease activity and with changes in IgG galactosylation during pregnancy and in the postpartum period. We also studied the association between MBL genotypes and pregnancy outcomes in RA. METHODS: Serum from 216 patients with RA and 31 healthy controls participating in the Pregnancy-induced Amelioration of Rheumatoid Arthritis (PARA) Study was collected before, during and after pregnancy. IgG galactosylation was determined by performing matrix-assisted laser desorption/ionization time of flight mass spectrometry. Disease activity was determined using the internationally recognized Disease Activity Score 28 (DAS28). MBL genotypes were determined. The pregnancy outcome measures studied were gestational age, birth weight, miscarriage and hypertensive disorders. RESULTS: No association was found between the MBL genotype groups and changes in RA disease activity (P = 0.89) or changes in IgG galactosylation (patients, P = 0.75, and controls, P = 0.54) during pregnancy and in the postpartum period. Furthermore, MBL genotype groups were not related to the studied pregnancy outcome measures. CONCLUSIONS: This study does not provide evidence for a role for MBL in the improvement of RA during pregnancy or for a role for MBL in pregnancy outcome. PMID- 21281478 TI - From causes to solutions--insights from lay knowledge about health inequalities. AB - BACKGROUND: This paper reports on a qualitative study of lay knowledge about health inequalities and solutions to address them. Social determinants of health are responsible for a large proportion of health inequalities (unequal levels of health status) and inequities (unfair access to health services and resources) within and between countries. Despite an expanding evidence base supporting action on social determinants, understanding of the impact of these determinants is not widespread and political will appears to be lacking. A small but growing body of research has explored how ordinary people theorise health inequalities and the implications for taking action. The findings are variable, however, in terms of an emphasis on structure versus individual agency and the relationship between being 'at risk' and acceptance of social/structural explanations. METHODS: This paper draws on findings from a qualitative study conducted in Adelaide, South Australia, to examine these questions. The study was an integral part of mixed-methods research on the links between urban location, social capital and health. It comprised 80 in-depth interviews with residents in four locations with contrasting socio-economic status. The respondents were asked about the cause of inequalities and actions that could be taken by governments to address them. RESULTS: Although generally willing to discuss health inequalities, many study participants tended to explain the latter in terms of individual behaviours and attitudes rather than social/structural conditions. Moreover, those who identified social/structural causes tended to emphasise individualized factors when describing typical pathways to health outcomes. This pattern appeared largely independent of participants' own experience of advantage or disadvantage, and was reinforced in discussion of strategies to address health inequalities. CONCLUSIONS: Despite the explicit emphasis on social/structural issues expressed in the study focus and framing of the research questions, participants did not display a high level of knowledge about the nature and causes of place-based health inequalities. By extending the scope of lay theorizing to include a focus on solutions, this study offers additional insights for public health. Specifically it suggests that a popular constituency for action on the social determinants of health is unlikely to eventuate from the current popular understandings of possible policy levers. PMID- 21281479 TI - Treatment patterns associated with Duloxetine and Venlafaxine use for Major Depressive Disorder. AB - BACKGROUND: Duloxetine and venlafaxine extended release (venlafaxine XR) are SNRIs indicated for the treatment of MDD. This study addresses whether duloxetine and venlafaxine XR are interchangeable in their patterns of use with patients who are depressed or are used more selectively based on treatment history, background characteristics, and presenting symptoms. METHODS: This was a retrospective analysis of an administrative insurance claims database. We studied patients in managed care with major depressive disorder (MDD) treated with duloxetine or venlafaxine XR. Predictors of treatment and cost were assessed using Chi-square and logistic regression analyses of demographics and past-year medication use and comorbidities. RESULTS: Patients with MDD treated with duloxetine (n = 9,641) versus venlafaxine XR (n = 8,514) tended to be older, slightly more likely to be female, and treated by a psychiatrist (P < 0.0001). In the prior year, more duloxetine patients (vs. venlafaxine XR) received >= 3 unique antidepressants (20.8% vs. 16.6%), >= 3 unique pain medications (25.5% vs. 15.6%), and had >= 8 unique diagnosed comorbid medical and psychiatric conditions (38.6% vs. 29.1%). The prior 6-month total health care costs were $1,731 higher for duloxetine than for venlafaxine XR and declined for both medications in the 6 months after treatment began. Logistic regression analysis revealed that 61% of duloxetine patients and 61% of venlafaxine XR patients were predictable from prior patient and treatment factors. CONCLUSIONS: Patients with MDD treated with duloxetine tended to have a more complex and costly antecedent clinical presentation compared with venlafaxine XR patients, suggesting that physicians do not use the medications interchangeably. PMID- 21281480 TI - Tumor-specific HMG-CoA reductase expression in primary premenopausal breast cancer predicts response to tamoxifen. AB - INTRODUCTION: We previously reported an association between tumor-specific 3 hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR) expression and a good prognosis in breast cancer. Here, the predictive value of HMG-CoAR expression in relation to tamoxifen response was examined. METHODS: HMG-CoAR protein and RNA expression was analyzed in a cell line model of tamoxifen resistance using western blotting and PCR. HMG-CoAR mRNA expression was examined in 155 tamoxifen treated breast tumors obtained from a previously published gene expression study (Cohort I). HMG-CoAR protein expression was examined in 422 stage II premenopausal breast cancer patients, who had previously participated in a randomized control trial comparing 2 years of tamoxifen with no systemic adjuvant treatment (Cohort II). Kaplan-Meier analysis and Cox proportional hazards modeling were used to estimate the risk of recurrence-free survival (RFS) and the effect of HMG-CoAR expression on tamoxifen response. RESULTS: HMG-CoAR protein and RNA expression were decreased in tamoxifen-resistant MCF7-LCC9 cells compared with their tamoxifen-sensitive parental cell line. HMG-CoAR mRNA expression was decreased in tumors that recurred following tamoxifen treatment (P < 0.001) and was an independent predictor of RFS in Cohort I (hazard ratio = 0.63, P = 0.009). In Cohort II, adjuvant tamoxifen increased RFS in HMG-CoAR-positive tumors (P = 0.008). Multivariate Cox regression analysis demonstrated that HMG-CoAR was an independent predictor of improved RFS in Cohort II (hazard ratio = 0.67, P = 0.010), and subset analysis revealed that this was maintained in estrogen receptor (ER)-positive patients (hazard ratio = 0.65, P = 0.029). Multivariate interaction analysis demonstrated a difference in tamoxifen efficacy relative to HMG-CoAR expression (P = 0.05). Analysis of tamoxifen response revealed that patients with ER-positive/HMG-CoAR tumors had a significant response to tamoxifen (P = 0.010) as well as patients with ER-positive or HMG-CoAR-positive tumors (P = 0.035). Stratification according to ER and HMG-CoAR status demonstrated that ER positive/HMG-CoAR-positive tumors had an improved RFS compared with ER positive/HMG-CoAR-negative tumors in the treatment arm (P = 0.033); this effect was lost in the control arm (P = 0.138), however, suggesting that HMG-CoAR predicts tamoxifen response. CONCLUSIONS: HMG-CoAR expression is a predictor of response to tamoxifen in both ER-positive and ER-negative disease. Premenopausal patients with tumors that express ER or HMG-CoAR respond to adjuvant tamoxifen. PMID- 21281481 TI - Detection of an antibody against Plasmodium vivax in residents of Gimpo-si, South Korea, using an indirect fluorescent antibody test. AB - BACKGROUND: First reemerged malaria case was reported in 1993 after two decades absent in South Korea. Thereafter, Plasmodium vivax spreads out near demilitarized zone (DMZ). This study investigated the prevalence of P. vivax after the malaria transmission season in Gimpo-si where adjacent to DMZ of South Korea. An indirect fluorescent antibody test (IFAT) was performed to evaluate anti-malaria antibodies in blood samples. METHODS: Microscopic examinations were performed to identify the presence of malaria parasites. Antibodies against P. vivax were detected using IFAT, and blood samples from antibody-positive cases were tested using a polymerase chain reaction (PCR) assay that detects malaria parasites. RESULTS: A total of 5,797 blood samples were collected from residents in Gimpo-si. The positivity rate by IFAT was 2.16% (n = 125). Yangchon-myeon (3.28%) had the highest positivity rate of the seven administrative districts tested. Positivity rates increased with age (P < 0.05). Sixteen of the IFAT positive samples (12.80%, n = 125) were positive for malaria DNA according to PCR. Blood samples with an antibody titer over 1:256 had high positivity rates in the PCR analysis (P < 0.05). CONCLUSIONS: These results indicate that antibody titers obtained using IFAT may provide useful information about the prevalence of P. vivax in low endemic areas and could be used to detect asymptomatic patients. Finding asymptomatic patients is important in eliminating vivax malaria in South Korea. PMID- 21281482 TI - nocoRNAc: characterization of non-coding RNAs in prokaryotes. AB - BACKGROUND: The interest in non-coding RNAs (ncRNAs) constantly rose during the past few years because of the wide spectrum of biological processes in which they are involved. This led to the discovery of numerous ncRNA genes across many species. However, for most organisms the non-coding transcriptome still remains unexplored to a great extent. Various experimental techniques for the identification of ncRNA transcripts are available, but as these methods are costly and time-consuming, there is a need for computational methods that allow the detection of functional RNAs in complete genomes in order to suggest elements for further experiments. Several programs for the genome-wide prediction of functional RNAs have been developed but most of them predict a genomic locus with no indication whether the element is transcribed or not. RESULTS: We present NOCORNAc, a program for the genome-wide prediction of ncRNA transcripts in bacteria. NOCORNAc incorporates various procedures for the detection of transcriptional features which are then integrated with functional ncRNA loci to determine the transcript coordinates. We applied RNAz and NOCORNAc to the genome of Streptomyces coelicolor and detected more than 800 putative ncRNA transcripts most of them located antisense to protein-coding regions. Using a custom design microarray we profiled the expression of about 400 of these elements and found more than 300 to be transcribed, 38 of them are predicted novel ncRNA genes in intergenic regions. The expression patterns of many ncRNAs are similarly complex as those of the protein-coding genes, in particular many antisense ncRNAs show a high expression correlation with their protein-coding partner. CONCLUSIONS: We have developed NOCORNAc, a framework that facilitates the automated characterization of functional ncRNAs. NOCORNAc increases the confidence of predicted ncRNA loci, especially if they contain transcribed ncRNAs. NOCORNAc is not restricted to intergenic regions, but it is applicable to the prediction of ncRNA transcripts in whole microbial genomes. The software as well as a user guide and example data is available at http://www.zbit.uni tuebingen.de/pas/nocornac.htm. PMID- 21281483 TI - Single-nucleotide polymorphisms and haplotype of CYP2E1 gene associated with systemic lupus erythematosus in Chinese population. AB - INTRODUCTION: Cytochrome P-450 2E1 (CYP2E1) is an important member of the CYP superfamily, which is involved in the metabolism and activation of many low molecular weight toxic compounds. We tried to investigate the possible association of CYP2E1 tag single nucleotide polymorphisms (SNPs) with susceptibility to systemic lupus erythematosus (SLE) in a Chinese Han population. METHODS: The coding and flanking regions of the CYP2E1 gene were scanned for polymorphisms and tag SNPs were selected. A two-stage case-control study was performed to genotype a total of 876 SLE patients and 680 geographically matched healthy controls (265 cases and 288 controls in stage I and 611 cases and 392 controls in stage II). SLE associations of alleles, genotypes and haplotypes were tested by age and sex adjusted logistic regression. The gene transcription quantitation was carried out for peripheral blood mononuclear cell (PBMC) samples from 120 healthy controls. RESULTS: Tag SNP rs2480256 was found significantly associated with SLE in both stages of the study. The "A" allele was associated with slightly higher risk (odds ratio (OR) = 1.165, 95% confidence interval (CI) 1.073 to 1.265, P = 2.75E-4) and "A/A" genotype carriers were with even higher SLE risk (OR = 1.464 95% CI 1.259 to 1.702, P = 7.48E-7). When combined with another tag SNP rs8192772, we identified haplotype "rs8192772-rs2480256/TA" over presented in SLE patients (OR 1.407, 95% CI 1.182 to 1.675, P = 0.0001) and haplotype "TG" over presented in the controls (OR 0.771, 95% CI 0.667 to 0.890, P = 0.0004). The gene transcription quantitation analysis further proved the dominant effect of rs2480256 as the "A/A" genotype showed highest transcription. CONCLUSIONS: Our results suggest the involvement of CYP2E1 as a susceptibility gene for SLE in the Chinese population. PMID- 21281484 TI - The iSBTc/SITC primer on tumor immunology and biological therapy of cancer: a summary of the 2010 program. AB - The Society for Immunotherapy of Cancer, SITC (formerly the International Society for Biological Therapy of Cancer, iSBTc), aims to improve cancer patient outcomes by advancing the science, development and application of biological therapy and immunotherapy. The society and its educational programs have become premier destinations for interaction and innovation in the cancer biologics community. For over a decade, the society has offered the Primer on Tumor Immunology and Biological Therapy of CancerTM in conjunction with its Annual Scientific Meeting. This report summarizes the 2010 Primer that took place October 1, 2010 in Washington, D.C. as part of the educational offerings associated with the society's 25th anniversary. The target audience was basic and clinical investigators from academia, industry and regulatory agencies, and included clinicians, post-doctoral fellows, students, and allied health professionals. Attendees were provided a review of basic immunology and educated on the current status and most recent advances in tumor immunology and clinical/translational cancer immunology. Ten prominent investigators presented on the following topics: innate immunity and inflammation; an overview of adaptive immunity; dendritic cells; tumor microenvironment; regulatory immune cells; immune monitoring; cytokines in cancer immunotherapy; immune modulating antibodies; cancer vaccines; and adoptive T cell therapy. Presentation slides, a Primer webinar and additional program information are available online on the society's website. PMID- 21281485 TI - Assessment of surfactant use in preterm infants as a marker of neonatal intensive care unit quality. AB - BACKGROUND: Proposed neonatal quality measures have included structural measures such as average daily census, and outcome measures such as mortality and rates of complications of prematurity. However, process measures have remained largely unexamined. The objective of this research was to examine variation in surfactant use as a possible process measure of neonatal quality. METHODS: We obtained data on infants 30 to 34 weeks gestation admitted with respiratory distress syndrome (RDS) within 48 hours of birth to 16 hospitals participating in the Pediatric Health Information Systems database from 2001-2006. Models were developed to describe hospital variation in surfactant use and identify patient and hospital predictors of use. Another cohort of all infants admitted within 24 hours of birth was used to obtain adjusted neonatal intensive care unit (NICU) mortality rates. To assess the construct validity of surfactant use as a quality metric, adjusted hospital rates of mortality and surfactant use were compared using Kendall's tau. RESULTS: Of 3,633 infants, 46% received surfactant. For individual hospitals, the adjusted odds of surfactant use varied from 2.2 times greater to 5.9 times less than the hospital with the median adjusted odds of surfactant use. Increased annual admissions of extremely low birth weight infants to the NICU were associated with greater surfactant use (OR 1.80, 95% CI 1.02-3.19). The correlation between adjusted hospital rates of surfactant use and in-hospital mortality was 0.37 (Kendall's tau p = 0.051). CONCLUSIONS: Though results were encouraging, efforts to examine surfactant use in infants with RDS as a process measure reflecting quality of care revealed significant challenges. Difficulties related to adequate measurement including defining RDS using administrative data, accounting for care received prior to transfer, and adjusting for severity of illness will need to be addressed to improve the utility of this measure. PMID- 21281486 TI - Perioperative cancer cell dissemination detected with a real-time RT-PCR assay for EpCAM is not associated with worse prognosis in pancreatic ductal adenocarcinoma. AB - BACKGROUND: Epithelial cell adhesion molecule (EpCAM) has been used as surrogate marker for the quantification of circulating tumour cells (CTC). Our aim was to prospectively study the value of a real-time RT-PCR assay for EpCAM detection in the peripheral blood and peritoneal cavity of patients undergoing pancreatectomy for pancreatic ductal adenocarcinoma (PDAC). METHODS: From 48 patients with PDAC (40 resectable, 8 unresectable) and 10 patients with chronic pancreatitis undergoing pancreatectomy 10 ml of venous blood was drawn preoperatively (PB) and postoperatively (POB, day 1 (D1B), day 7 (D7B) and after 6 weeks (6WB). Of all patients undergoing pancreatectomy, 40 ml peritoneal lavage fluid was taken preoperatively and postoperatively. A real-time RT-PCR assay (TaqMan, ABI Prism 7700) was developed for the detection of EpCAM mRNA. To discriminate between EpCAM-positive and negative samples a cut-off was applied. Median postoperative follow-up was 24.0 months (range: 0.7-41.3). RESULTS: PB was EpCAM-positive+ in 25% of patients versus 65% of patients in POB (p < 0.0001). EpCAM+ was noted at D1B, D7B and 6WB was found in 28.6%, 23.1% and 23.5% of patients respectively. Preoperative peritoneal lavage fluid was EpCAM+ in 10.3% versus 53.8% of patients postoperatively (p < 0.0001). At none of the time-points, an association was found between EpCAM positivity in blood and/or peritoneal cavity and cancer specific or disease-free survival. Also, no significant associations were found between clinicopathological variables and perioperative EpCAM positivity. CONCLUSIONS: Despite a significant increase in EpCAM counts in postoperative blood and peritoneal lavage fluid this was not associated with worse prognosis after pancreatectomy for PDAC. TRIAL REGISTRATION: Clinicaltrials.gov NCT00495924. PMID- 21281487 TI - A conceptual framework for interprofessional shared decision making in home care: protocol for a feasibility study. AB - BACKGROUND: Shared decision making (SDM) is fundamental to informed consent and client-centered care. So far, SDM frameworks have been limited to the client physician dyad, even though care is increasingly delivered by interprofessional (IP) teams. IP collaboration is especially essential in home care, one of health care's most rapidly growing areas. This study will assess whether it is possible to practice SDM in IP home care. METHODS/DESIGN: We will use a qualitative case study and a quantitative survey to capture the macro, meso and micro levels of stakeholders in home care. The case study will follow the knowledge-to-action process framework to evaluate the work of an IP home care team at a Quebec City health center. Sources of data will include one-on-one interviews with patients, family caregivers or surrogates and significant others, and administrators; a focus group of home care health professionals; organizational documents; and government policies and standards. The interview guide for the interviews and the focus group will explore current practices and clinical problems addressed in home care; factors that could influence the implementation of the proposed IP approach to SDM; the face and content validity of the approach; and interventions to facilitate the implementation and evaluation of the approach. The survey will ask 300 health professionals working in home care at the health center to complete a questionnaire based on the Theory of Planned Behaviour that measures their intentions to engage in an IP approach to SDM. We will use our analysis of the individual interviews, the focus group and the survey to elaborate a toolkit for implementing an IP approach to SDM in home care. Finally, we will conduct a pilot study in Alberta to assess the transferability of our findings. DISCUSSION: We believe that developing tools to implement IP SDM in home care is essential to strengthening Canada's healthcare system and furthering patient-centered care. This study will contribute to the evaluation of IP SDM delivery models in home care. It will also generate practical, policy-oriented knowledge regarding the barriers and facilitators likely to influence the practice of IP SDM in home care. PMID- 21281488 TI - In-vivo generation of bone via endochondral ossification by in-vitro chondrogenic priming of adult human and rat mesenchymal stem cells. AB - BACKGROUND: Bone grafts are required to repair large bone defects after tumour resection or large trauma. The availability of patients' own bone tissue that can be used for these procedures is limited. Thus far bone tissue engineering has not lead to an implant which could be used as alternative in bone replacement surgery. This is mainly due to problems of vascularisation of the implanted tissues leading to core necrosis and implant failure. Recently it was discovered that embryonic stem cells can form bone via the endochondral pathway, thereby turning in-vitro created cartilage into bone in-vivo. In this study we investigated the potential of human adult mesenchymal stem cells to form bone via the endochondral pathway. METHODS: MSCs were cultured for 28 days in chondrogenic, osteogenic or control medium prior to implantation. To further optimise this process we induced mineralisation in the chondrogenic constructs before implantation by changing to osteogenic medium during the last 7 days of culture. RESULTS: After 8 weeks of subcutaneous implantation in mice, bone and bone marrow formation was observed in 8 of 9 constructs cultured in chondrogenic medium. No bone was observed in any samples cultured in osteogenic medium. Switch to osteogenic medium for 7 days prevented formation of bone in-vivo. Addition of beta-glycerophosphate to chondrogenic medium during the last 7 days in culture induced mineralisation of the matrix and still enabled formation of bone and marrow in both human and rat MSC cultures. To determine whether bone was formed by the host or by the implanted tissue we used an immunocompetent transgenic rat model. Thereby we found that osteoblasts in the bone were almost entirely of host origin but the osteocytes are of both host and donor origin. CONCLUSIONS: The preliminary data presented in this manuscript demonstrates that chondrogenic priming of MSCs leads to bone formation in vivo using both human and rat cells. Furthermore, addition of beta-glycerophosphate to the chondrogenic medium did not hamper this process. Using transgenic animals we also demonstrated that both host and donor cells played a role in bone formation. In conclusion these data indicate that in-vitro chondrogenic differentiation of human MSCs could lead to an alternative and superior approach for bone tissue engineering. PMID- 21281489 TI - The nephrogenic potential of the transcription factors osr1, osr2, hnf1b, lhx1 and pax8 assessed in Xenopus animal caps. AB - BACKGROUND: The three distinct types of kidneys, pronephros, mesonephros and metanephros, develop consecutively in vertebrates. The earliest form of embryonic kidney, the pronephros, is derived from intermediate mesoderm and the first expressed genes localized in the pronephros anlage are the transcription factors osr1, osr2, hnf1b, lhx1 and pax8, here referred to as the early nephrogenic transcription factors. However, the pathway inducing nephrogenesis and the network of theses factors are poorly understood. Treatment of the undifferentiated animal pole explant (animal cap) of Xenopus with activin A and retinoic acid induces pronephros formation providing a powerful tool to analyze key molecular events in nephrogenesis. RESULTS: We have investigated the expression kinetics of the early nephrogenic transcription factors in activin A and retinoic acid treated animal caps and their potential to induce pronephric differentiation. In treated animal caps, expression of osr1, osr2, hnf1b and lhx1 are induced early, whereas pax8 expression occurs later implying an indirect activation. Activin A alone is able to induce osr2 and lhx1 after three hours treatment in animal caps while retinoic acid fails to induce any of these nephrogenic transcription factors. The early expression of the five transcription factors and their interference with pronephros development when overexpressed in embryos suggest that these factors potentially induce nephrogenesis upon expression in animal caps. But no pronephros development is achieved by either overexpression of OSR1, by HNF1B injection with activin A treatment, or the combined application of LHX1 and PAX8, although they influenced the expression of several early nephrogenic transcription factors in some cases. In an additional approach we could show that HNF1B induces several genes important in nephrogenesis and regulates lhx1 expression by an HNF1 binding site in the lhx1 promoter. CONCLUSIONS: The early nephrogenic transcription factors play an important role in nephrogenesis, but have no pronephros induction potential upon overexpression in animal caps. They activate transcriptional cascades that partially reflect the gene activation initiated by activin A and retinoic acid. Significantly, HNF1B activates the lhx1 promoter directly, thus extending the known activin A regulation of the lhx1 gene via an activin A responsive element. PMID- 21281490 TI - A neurological approach to biopsychosocial medicine: Lessons from irritable bowel syndrome. PMID- 21281491 TI - The reliability and validity of the Japanese version of the Levels of Emotional Awareness Scale (LEAS-J). AB - BACKGROUND: The Levels of Emotional Awareness Scale (LEAS) was developed to assess five levels of emotional awareness: bodily sensations, action tendencies, single emotions, blends of emotion, and combinations of blends. It is a paper and pencil performance questionnaire that presents 20 emotion-evoking scenes. We developed a Japanese version of the LEAS (LEAS-J), and its reliability and validity were examined. METHODS: The LEAS-J level was independently assessed by two researchers who scored each response according to the LEAS scoring manual. High inter-rater reliability and internal consistency were obtained for the LEAS J. Measures were socioeconomic status, LEAS-J, Toronto Alexithymia Scale-20 (TAS 20), Interpersonal Reactivity Index (IRI), and NEO Five-Factor Inventory (NEO FFI). TAS-20, IRI and NEO-FFI were the measures used to explore the construct validity of LEAS-J, as it was predicted that higher scores on the LEAS-J would be related to fewer alexithymic features, greater empathetic ability, and a greater sense of cooperation with others. Questionnaires were completed by 344 university students. RESULTS: The criterion-referenced validity was determined: a significant negative relationship was found with the externally-oriented thinking scores of TAS-20, and positive relationships were found with fantasy, perspective taking, and empathic concern on IRI and with extraversion, openness to experience, and agreeableness on NEO-FFI. CONCLUSIONS: Consistent with our expectations, the findings provide evidence that the LEAS-J has good reliability and validity. In addition, women had significantly higher scores than men on LEAS J, showing that the gender difference identified in the original LEAS was cross culturally consistent. PMID- 21281492 TI - Proximity of food retailers to schools and rates of overweight ninth grade students: an ecological study in California. AB - BACKGROUND: The prevalence of obesity and overweight in youth has increased dramatically since the 1980s, and some researchers hypothesize that increased consumption of low-nutrient, energy-dense foods is a key contributor. The potential importance of food retailers near schools has received increasing attention, but public health research and policy has focused primarily on fast food restaurants. Less is known about the relationship between overweight/obesity and other types of retailers. This study aims to investigate the potential associations between nearby 1) fast food restaurants, 2) convenience stores, and 3) supermarkets, and rates of overweight students in California schools. METHODS: We examined the rate of overweight ninth grade students in public schools in 2007 using linear regression. The percentage of overweight students per school was determined by a state required physical fitness test, with three different options for measuring individual body composition. Our key independent variables were the presence of three different types of retailers within 800 m network buffers of the schools. Additional independent variables included school ethnic, gender and socioeconomic composition, as well as urban/non-urban location. We obtained the data from the California Department of Education and ESRI, Inc. RESULTS: The presence of a convenience store within a 10-minute walking distance of a school was associated with a higher rate of overweight students than schools without nearby convenience stores, after controlling for all school-level variables in the regression (1.2%, 95% confidence interval 0.03, 2.36). Nearby fast food restaurants and supermarkets, however, were not associated with school rates of overweight students. CONCLUSIONS: Public health researchers and policy makers interested in the food environments outside schools should expand their recent focus on nearby fast food restaurants to include convenience stores, which may also be important sources of low-nutrient, energy-dense foods for students. PMID- 21281493 TI - RAIphy: phylogenetic classification of metagenomics samples using iterative refinement of relative abundance index profiles. AB - BACKGROUND: Computational analysis of metagenomes requires the taxonomical assignment of the genome contigs assembled from DNA reads of environmental samples. Because of the diverse nature of microbiomes, the length of the assemblies obtained can vary between a few hundred bp to a few hundred Kbp. Current taxonomic classification algorithms provide accurate classification for long contigs or for short fragments from organisms that have close relatives with annotated genomes. These are significant limitations for metagenome analysis because of the complexity of microbiomes and the paucity of existing annotated genomes. RESULTS: We propose a robust taxonomic classification method, RAIphy, that uses a novel sequence similarity metric with iterative refinement of taxonomic models and functions effectively without these limitations. We have tested RAIphy with synthetic metagenomics data ranging between 100 bp to 50 Kbp. Within a sequence read range of 100 bp-1000 bp, the sensitivity of RAIphy ranges between 38%-81% outperforming the currently popular composition-based methods for reads in this range. Comparison with computationally more intensive sequence similarity methods shows that RAIphy performs competitively while being significantly faster. The sensitivity-specificity characteristics for relatively longer contigs were compared with the PhyloPythia and TACOA algorithms. RAIphy performs better than these algorithms at varying clade-levels. For an acid mine drainage (AMD) metagenome, RAIphy was able to taxonomically bin the sequence read set more accurately than the currently available methods, Phymm and MEGAN, and more accurately in two out of three tests than the much more computationally intensive method, PhymmBL. CONCLUSIONS: With the introduction of the relative abundance index metric and an iterative classification method, we propose a taxonomic classification algorithm that performs competitively for a large range of DNA contig lengths assembled from metagenome data. Because of its speed, simplicity, and accuracy RAIphy can be successfully used in the binning process for a broad range of metagenomic data obtained from environmental samples. PMID- 21281494 TI - Acne vulgaris, probiotics and the gut-brain-skin axis - back to the future? AB - Over 70 years have passed since dermatologists John H. Stokes and Donald M. Pillsbury first proposed a gastrointestinal mechanism for the overlap between depression, anxiety and skin conditions such as acne. Stokes and Pillsbury hypothesized that emotional states might alter the normal intestinal microflora, increase intestinal permeability and contribute to systemic inflammation. Among the remedies advocated by Stokes and Pillsbury were Lactobacillus acidophilus cultures. Many aspects of this gut-brain-skin unifying theory have recently been validated. The ability of the gut microbiota and oral probiotics to influence systemic inflammation, oxidative stress, glycemic control, tissue lipid content and even mood itself, may have important implications in acne. The intestinal microflora may also provide a twist to the developing diet and acne research. Here we provide a historical perspective to the contemporary investigations and clinical implications of the gut-brain-skin connection in acne. PMID- 21281495 TI - Genetic variation in the genome-wide predicted estrogen response element-related sequences is associated with breast cancer development. AB - INTRODUCTION: Estrogen forms a complex with the estrogen receptor (ER) that binds to estrogen response elements (EREs) in the promoter region of estrogen responsive genes, regulates their transcription, and consequently mediates physiological or tumorigenic effects. Thus, sequence variants in EREs have the potential to affect the estrogen-ER-ERE interaction. In this study, we examined the hypothesis that genetic variations of EREs are associated with breast cancer development. METHODS: This case-control study involved 815 patients of Asian descent with incident breast cancer and 821 healthy female controls. A total of 13,737 ERE sites in the whole genome predicted by a genome-wide computational algorithm were blasted with single-nucleotide polymorphism (SNP) sequences. Twenty-one SNPs located within 2,000 bp upstream or within introns 1 and 2 of putative genes and with a minor allele frequency greater than 5% were identified and genotyped. Frequencies of SNPs were compared between cases and controls to identify SNPs associated with cancer susceptibility. RESULTS: A significant combined effect of rs12539530, an ERE SNP in intron 2 of NRCAM which codes for a cell adhesion molecule, and SNPs of ESR1, the gene coding for ER, on breast cancer risk was found. Interestingly, this combined effect was more significant in women who had experienced a longer period of lifetime estrogen exposure, supporting a hormonal etiology of this SNP in breast tumorigenesis. CONCLUSIONS: Our findings provide support for a role of genetic variation in ERE-ESR1 in determining susceptibility of breast cancer development. PMID- 21281496 TI - Health impact of US military service in a large population-based military cohort: findings of the Millennium Cohort Study, 2001-2008. AB - BACKGROUND: Combat-intense, lengthy, and multiple deployments in Iraq and Afghanistan have characterized the new millennium. The US military's all volunteer force has never been better trained and technologically equipped to engage enemy combatants in multiple theaters of operations. Nonetheless, concerns over potential lasting effects of deployment on long-term health continue to mount and are yet to be elucidated. This report outlines how findings from the first 7 years of the Millennium Cohort Study have helped to address health concerns related to military service including deployments. METHODS: The Millennium Cohort Study was designed in the late 1990s to address veteran and public concerns for the first time using prospectively collected health and behavioral data. RESULTS: Over 150,000 active-duty, reserve, and National Guard personnel from all service branches have enrolled, and more than 70% of the first 2 enrollment panels submitted at least 1 follow-up survey. Approximately half of the Cohort has deployed in support of operations in Iraq and Afghanistan. CONCLUSION: The Millennium Cohort Study is providing prospective data that will guide public health policymakers for years to come by exploring associations between military exposures and important health outcomes. Strategic studies aim to identify, reduce, and prevent adverse health outcomes that may be associated with military service, including those related to deployment. PMID- 21281497 TI - A nanocomplex that is both tumor cell-selective and cancer gene-specific for anaplastic large cell lymphoma. AB - BACKGROUND: Many in vitro studies have demonstrated that silencing of cancerous genes by siRNAs is a potential therapeutic approach for blocking tumor growth. However, siRNAs are not cell type-selective, cannot specifically target tumor cells, and therefore have limited in vivo application for siRNA-mediated gene therapy. RESULTS: In this study, we tested a functional RNA nanocomplex which exclusively targets and affects human anaplastic large cell lymphoma (ALCL) by taking advantage of the abnormal expression of CD30, a unique surface biomarker, and the anaplastic lymphoma kinase (ALK) gene in lymphoma cells. The nanocomplexes were formulated by incorporating both ALK siRNA and a RNA-based CD30 aptamer probe onto nano-sized polyethyleneimine-citrate carriers. To minimize potential cytotoxicity, the individual components of the nanocomplexes were used at sub-cytotoxic concentrations. Dynamic light scattering showed that formed nanocomplexes were ~140 nm in diameter and remained stable for more than 24 hours in culture medium. Cell binding assays revealed that CD30 aptamer probes selectively targeted nanocomplexes to ALCL cells, and confocal fluorescence microscopy confirmed intracellular delivery of the nanocomplex. Cell transfection analysis showed that nanocomplexes silenced genes in an ALCL cell type-selective fashion. Moreover, exposure of ALCL cells to nanocomplexes carrying both ALK siRNAs and CD30 RNA aptamers specifically silenced ALK gene expression, leading to growth arrest and apoptosis. CONCLUSIONS: Taken together, our findings indicate that this functional RNA nanocomplex is both tumor cell type-selective and cancer gene-specific for ALCL cells. PMID- 21281498 TI - Sequence similarity between the erythrocyte binding domain 1 of the Plasmodium vivax Duffy binding protein and the V3 loop of HIV-1 strain MN reveals binding residues for the Duffy Antigen Receptor for Chemokines. AB - BACKGROUND: The surface glycoprotein (SU, gp120) of the human immunodeficiency virus (HIV) must bind to a chemokine receptor, CCR5 or CXCR4, to invade CD4+ cells. Plasmodium vivax uses the Duffy Binding Protein (DBP) to bind the Duffy Antigen Receptor for Chemokines (DARC) and invade reticulocytes. RESULTS: Variable loop 3 (V3) of HIV-1 SU and domain 1 of the Plasmodium vivax DBP share a sequence similarity. The site of amino acid sequence similarity was necessary, but not sufficient, for DARC binding and contained a consensus heparin binding site essential for DARC binding. Both HIV-1 and P. vivax can be blocked from binding to their chemokine receptors by the chemokine, RANTES and its analog AOP RANTES. Site directed mutagenesis of the heparin binding motif in members of the DBP family, the P. knowlesi alpha, beta and gamma proteins abrogated their binding to erythrocytes. Positively charged residues within domain 1 are required for binding of P. vivax and P. knowlesi erythrocyte binding proteins. CONCLUSION: A heparin binding site motif in members of the DBP family may form part of a conserved erythrocyte receptor binding pocket. PMID- 21281499 TI - Gaussian graphical modeling reconstructs pathway reactions from high-throughput metabolomics data. AB - BACKGROUND: With the advent of high-throughput targeted metabolic profiling techniques, the question of how to interpret and analyze the resulting vast amount of data becomes more and more important. In this work we address the reconstruction of metabolic reactions from cross-sectional metabolomics data, that is without the requirement for time-resolved measurements or specific system perturbations. Previous studies in this area mainly focused on Pearson correlation coefficients, which however are generally incapable of distinguishing between direct and indirect metabolic interactions. RESULTS: In our new approach we propose the application of a Gaussian graphical model (GGM), an undirected probabilistic graphical model estimating the conditional dependence between variables. GGMs are based on partial correlation coefficients, that is pairwise Pearson correlation coefficients conditioned against the correlation with all other metabolites. We first demonstrate the general validity of the method and its advantages over regular correlation networks with computer-simulated reaction systems. Then we estimate a GGM on data from a large human population cohort, covering 1020 fasting blood serum samples with 151 quantified metabolites. The GGM is much sparser than the correlation network, shows a modular structure with respect to metabolite classes, and is stable to the choice of samples in the data set. On the example of human fatty acid metabolism, we demonstrate for the first time that high partial correlation coefficients generally correspond to known metabolic reactions. This feature is evaluated both manually by investigating specific pairs of high-scoring metabolites, and then systematically on a literature-curated model of fatty acid synthesis and degradation. Our method detects many known reactions along with possibly novel pathway interactions, representing candidates for further experimental examination. CONCLUSIONS: In summary, we demonstrate strong signatures of intracellular pathways in blood serum data, and provide a valuable tool for the unbiased reconstruction of metabolic reactions from large-scale metabolomics data sets. PMID- 21281500 TI - Associations between subspecialty fellowship interest and knowledge of internal medicine: a hypothesis-generating study of internal medicine residents. AB - BACKGROUND: Little is known about whether and how medical knowledge relates to interest in subspecialty fellowship training. The purpose of this study was to examine the relationships between residents' interest in subspecialty fellowship training and their knowledge of internal medicine (IM). METHODS: A questionnaire was emailed to 48 categorical postgraduate-year (PGY) two and three residents at a New York university-affiliated IM residency program in 2007 using the Survey Monkey online survey instrument. Overall and content area-specific percentile scores from the IM in-training examination (IM-ITE) for the same year was used to determine objective knowledge. RESULTS: Forty-five of 48 residents (response rate was 93.8%) completed the survey. Twenty-two (49%) were PG2 residents and 23(51%) were PGY3 residents. Sixty percent of respondents were male. Six (13%) residents were graduates of U.S. medical schools. Eight (18%) reported formal clinical training prior to starting internal medicine residency in the U.S. Of this latter group, 6 (75%) had training in IM and 6 (75) % reported a training length of 3 years or less. Thirty-seven of 45 (82%) residents had a subspecialty fellowship interest. Residents with a fellowship interest had a greater mean overall objective knowledge percentile score (56.44 vs. 31.67; p = 0.04) as well as greater mean percentile scores in all content areas of IM. The adjusted mean difference was statistically significant (p < 0.02) across three content areas. CONCLUSIONS: More than half of surveyed residents indicated interest in pursuing a subspecialty fellowship. Fellowship interest appears positively associated with general medical knowledge in this study population. Further work is needed to explore motivation and study patterns among internal medicine residents. PMID- 21281501 TI - Methodological criteria for the assessment of moderators in systematic reviews of randomised controlled trials: a consensus study. AB - BACKGROUND: Current methodological guidelines provide advice about the assessment of sub-group analysis within RCTs, but do not specify explicit criteria for assessment. Our objective was to provide researchers with a set of criteria that will facilitate the grading of evidence for moderators, in systematic reviews. METHOD: We developed a set of criteria from methodological manuscripts (n = 18) using snowballing technique, and electronic database searches. Criteria were reviewed by an international Delphi panel (n = 21), comprising authors who have published methodological papers in this area, and researchers who have been active in the study of sub-group analysis in RCTs. We used the Research ANd Development/University of California Los Angeles appropriateness method to assess consensus on the quantitative data. Free responses were coded for consensus and disagreement. In a subsequent round additional criteria were extracted from the Cochrane Reviewers' Handbook, and the process was repeated. RESULTS: The recommendations are that meta-analysts report both confirmatory and exploratory findings for sub-groups analysis. Confirmatory findings must only come from studies in which a specific theory/evidence based a-priori statement is made. Exploratory findings may be used to inform future/subsequent trials. However, for inclusion in the meta-analysis of moderators, the following additional criteria should be applied to each study: Baseline factors should be measured prior to randomisation, measurement of baseline factors should be of adequate reliability and validity, and a specific test of the interaction between baseline factors and interventions must be presented. CONCLUSIONS: There is consensus from a group of 21 international experts that methodological criteria to assess moderators within systematic reviews of RCTs is both timely and necessary. The consensus from the experts resulted in five criteria divided into two groups when synthesising evidence: confirmatory findings to support hypotheses about moderators and exploratory findings to inform future research. These recommendations are discussed in reference to previous recommendations for evaluating and reporting moderator studies. PMID- 21281502 TI - Update on the management of acute pharyngitis in children. AB - Streptococcal pharyngitis is a very common pathology in paediatric age all over the world. Nevertheless there isn't a joint agreement on the management of this condition. Some authors recommend to perform a microbiological investigation in suspected bacterial cases in order to treat the confirmed cases with antibiotics so to prevent suppurative complications and acute rheumatic fever. Differently, other authors consider pharyngitis, even streptococcal one, a benign, self limiting disease. Consequently they wouldn't routinely perform microbiological tests and, pointing to a judicious use of antibiotics, they would reserve antimicrobial treatment to well-selected cases. It has been calculated that the number of patients needed to treat to prevent one complication after upper respiratory tract infections (including sore throat), was over 4000. Even the use of the Centor score, in order to evaluate the risk of streptococcal infection, is under debate and the interpretation of the test results may vary considerably. Penicillin is considered all over the world as first line treatment, but oral amoxicillin is also accepted and, due to its better palatability, can be a suitable option. Macrolides should be reserved to the rare cases of proved allergy to beta-lactams. Cephalosporins can be used in patients allergic to penicillin (with the exception of type I hypersensibility) and have been also proposed to treat the relapses. PMID- 21281503 TI - Optimization of PCR conditions to amplify microsatellite loci in the bunchgrass lizard (Sceloporus slevini) genomic DNA. AB - BACKGROUND: Microsatellites, also called Simple Sequence Repeats (SSRs), repetitions of nucleotide motifs of 1-5 bases, are currently the markers of choice due to their abundant distribution in the genomes, and suitability for high-throughput analysis. A total of five different primer pairs were optimized for polymerase chain reaction (PCR) to amplify microsatellite loci in total genomic DNA of bunchgrass lizards (Sceloporus slevini) collected from three sites in southeastern Arizona; the Sonoita Plain, Chiricahua Mountains and Huachuca Mountains. FINDINGS: The primers used for current investigation were originally designed for the Eastern Fence Lizard (Sceloporus undulatus). Five primer pairs were selected based on annealing temperatures for optimizing the PCR conditions to amplify with bunchgrass lizards. Different concentrations of DNA and annealing temperature were optimized. While keeping other reagents constant, a DNA concentration, 37.5 ng in the final reaction volume and PCR conditions of an initial denaturation of 94 degrees C for five minutes, an annealing temperature of 55 degrees C and final extension of 72 degrees C for four minutes gave the best amplification for all the primer pairs. CONCLUSIONS: Modifying the standard protocol for annealing temperatures and final extension time increases the success of cross amplification of specific microsatellite loci in the bunchgrass lizard. A loading volume of 5 ul DNA at a concentration of 10 ng/ul and a 2% agarose for gel electrophoresis were observed the best for cross amplification of selected five primer pairs on bunch grass lizard. TRIAL REGISTRATION: The research was conducted with Arizona Game and Fish Department scientific collecting permits SP565256, SP657407 & SP749119 to Dr. Christian A d'Orgeix. PMID- 21281504 TI - Knowledge of ghostwriting and financial conflicts-of-interest reduces the perceived credibility of biomedical research. AB - BACKGROUND: While the impact of conflicts-of-interest (COI) is of increasing concern in academic medicine, there is little research on the reaction of practicing clinicians to the disclosure of such conflicts. We developed two research vignettes presenting a fictional antidepressant medication study, one in which the principal investigator had no COI and another in which there were multiple COI disclosed. We confirmed the face validity of the COI vignette through consultation with experts. Hospital-based clinicians were randomly assigned to read one of these two vignettes and then administered a credibility scale. FINDINGS: Perceived credibility ratings were much lower in the COI group, with a difference of 11.00 points (31.42%) on the credibility scale total as calculated through the Mann-Whitney U test (95% CI = 6.99 - 15.00, p < .001). Clinicians in the COI group were also less likely to recommend the antidepressant medication discussed in the vignette (Odds Ratio = 0.163, 95% CI = .03 = 0.875). CONCLUSIONS: In this study, increased disclosure of COI resulted in lower credibility ratings. PMID- 21281505 TI - Contribution of large genomic BRCA1 alterations to early-onset breast cancer selected for family history and tumour morphology: a report from The Breast Cancer Family Registry. AB - INTRODUCTION: Selecting women affected with breast cancer who are most likely to carry a germline mutation in BRCA1 and applying the most appropriate test methodology remains challenging for cancer genetics services. We sought to test the value of selecting women for BRCA1 mutation testing on the basis of family history and/or breast tumour morphology criteria as well as the value of testing for large genomic alterations in BRCA1. METHODS: We studied women participating in the Breast Cancer Family Registry (BCFR), recruited via population-based sampling, who had been diagnosed with breast cancer before the age of 40 years who had a strong family history of breast or ovarian cancer (n = 187) and/or a first primary breast tumour with morphological features consistent with carrying a BRCA1 germline mutation (n = 133; 37 met both criteria). An additional 184 women diagnosed before the age of 40 years who had a strong family history of breast or ovarian cancer and who were not known to carry a germline BRCA1 mutation were selected from among women who had been recruited into the BCFR from clinical genetics services. These 467 women had been screened for BRCA1 germline mutations, and we expanded this testing to include a screen for large genomic BRCA1 alterations using Multiplex Ligation-dependent Probe Amplification. RESULTS: Twelve large genomic BRCA1 alterations were identified, including 10 (4%) of the 283 women selected from among the population-based sample. In total, 18 (12%), 18 (19%) and 16 (43%) BRCA1 mutations were identified in the population based groups selected on the basis of family history only (n = 150), the group selected on the basis of tumour morphology only (n = 96) and meeting both criteria (n = 37), respectively. CONCLUSIONS: Large genomic alterations accounted for 19% of all BRCA1 mutations identified. This study emphasises the value of combining information about family history, age at diagnosis and tumour morphology when selecting women for germline BRCA1 mutation testing as well as including a screen for large genomic alterations. PMID- 21281506 TI - A unified framework for multi-locus association analysis of both common and rare variants. AB - BACKGROUND: Common, complex diseases are hypothesized to result from a combination of common and rare genetic variants. We developed a unified framework for the joint association testing of both types of variants. Within the framework, we developed a union-intersection test suitable for genome-wide analysis of single nucleotide polymorphisms (SNPs), candidate gene data, as well as medical sequencing data. The union-intersection test is a composite test of association of genotype frequencies and differential correlation among markers. RESULTS: We demonstrated by computer simulation that the false positive error rate was controlled at the expected level. We also demonstrated scenarios in which the multi-locus test was more powerful than traditional single marker analysis. To illustrate use of the union-intersection test with real data, we analyzed a publically available data set of 319,813 autosomal SNPs genotyped for 938 cases of Parkinson disease and 863 neurologically normal controls for which no genome-wide significant results were found by traditional single marker analysis. We also analyzed an independent follow-up sample of 183 cases and 248 controls for replication. CONCLUSIONS: We identified a single risk haplotype with a directionally consistent effect in both samples in the gene GAK, which is involved in clathrin-mediated membrane trafficking. We also found suggestive evidence that directionally inconsistent marginal effects from single marker analysis appeared to result from risk being driven by different haplotypes in the two samples for the genes SYN3 and NGLY1, which are involved in neurotransmitter release and proteasomal degradation, respectively. These results illustrate the utility of our unified framework for genome-wide association analysis of common, complex diseases. PMID- 21281507 TI - Dengue-2 structural proteins associate with human proteins to produce a coagulation and innate immune response biased interactome. AB - BACKGROUND: Dengue virus infection is a public health threat to hundreds of millions of individuals in the tropical regions of the globe. Although Dengue infection usually manifests itself in its mildest, though often debilitating clinical form, dengue fever, life-threatening complications commonly arise in the form of hemorrhagic shock and encephalitis. The etiological basis for the virus induced pathology in general, and the different clinical manifestations in particular, are not well understood. We reasoned that a detailed knowledge of the global biological processes affected by virus entry into a cell might help shed new light on this long-standing problem. METHODS: A bacterial two-hybrid screen using DENV2 structural proteins as bait was performed, and the results were used to feed a manually curated, global dengue-human protein interaction network. Gene ontology and pathway enrichment, along with network topology and microarray meta analysis, were used to generate hypothesis regarding dengue disease biology. RESULTS: Combining bioinformatic tools with two-hybrid technology, we screened human cDNA libraries to catalogue proteins physically interacting with the DENV2 virus structural proteins, Env, cap and PrM. We identified 31 interacting human proteins representing distinct biological processes that are closely related to the major clinical diagnostic feature of dengue infection: haemostatic imbalance. In addition, we found dengue-binding human proteins involved with additional key aspects, previously described as fundamental for virus entry into cells and the innate immune response to infection. Construction of a DENV2-human global protein interaction network revealed interesting biological properties suggested by simple network topology analysis. CONCLUSIONS: Our experimental strategy revealed that dengue structural proteins interact with human protein targets involved in the maintenance of blood coagulation and innate anti-viral response processes, and predicts that the interaction of dengue proteins with a proposed human protein interaction network produces a modified biological outcome that may be behind the hallmark pathologies of dengue infection. PMID- 21281508 TI - Prognostic value of circulating amino-terminal pro-C-type natriuretic peptide in critically ill patients. AB - INTRODUCTION: C-type natriuretic peptide (CNP) is a paracrine molecule which is mainly synthesized in the vasculature. High levels have been reported in sepsis, and CNP has been proposed as a biomarker predicting sepsis in traumatized patients. We aimed at evaluating the diagnostic and prognostic value of N terminal pro-CNP (NT-proCNP) for predicting sepsis, disease severity and mortality in critically ill medical patients. METHODS: 273 critically ill patients (197 patients with sepsis or septic shock, 76 without evidence of sepsis) and 43 healthy controls were consecutively included in a prospective clinical single-center non-interventional study at the Medical Intensive Care Unit, RWTH-University Aachen, Germany. Patients' outcome was followed for about 1 year. NT-proCNP serum concentrations were determined upon ICU admission, as well as in the mornings of day 3 and day 7 after admission. Intensive care treatment measures as well as routine and experimental laboratory parameters were recorded and analyzed. RESULTS: NT-proCNP serum concentrations upon admission to the ICU were elevated in critically ill patients as compared with healthy controls. Patients with sepsis had significantly higher NT-proCNP levels than non-sepsis patients. NT-proCNP was strongly associated with inflammatory parameters (i.e. C reactive protein, procalcitonin and TNF-alpha), biomarkers of organ dysfunction and clinical composite scores (APACHE-II, SOFA, SAPS2). NT-proCNP levels at admission and day 3 were found to be a strong predictive marker for ICU- and overall survival. Moreover, a decline of serum NT-proCNP after admission to the ICU was associated with reduced mortality. The predictive power of serum NT proCNP was similar to 'conventional' prognostic tools such as clinical scores. CONCLUSIONS: NT-proCNP is significantly elevated in critically ill patients, with highest levels in sepsis. Inflammation as well as organ function are strongly associated with NT-proCNP serum concentrations. Low initial NT-proCNP levels and a decline during initial treatment indicate a favourable ICU- and long-term outcome. PMID- 21281509 TI - The complete mitochondrial genome of an 11,450-year-old aurochsen (Bos primigenius) from Central Italy. AB - BACKGROUND: Bos primigenius, the aurochs, is the wild ancestor of modern cattle breeds and was formerly widespread across Eurasia and northern Africa. After a progressive decline, the species became extinct in 1627. The origin of modern taurine breeds in Europe is debated. Archaeological and early genetic evidence point to a single Near Eastern origin and a subsequent spread during the diffusion of herding and farming. More recent genetic data are instead compatible with local domestication events or at least some level of local introgression from the aurochs. Here we present the analysis of the complete mitochondrial genome of a pre-Neolithic Italian aurochs. RESULTS: In this study, we applied a combined strategy employing both multiplex PCR amplifications and 454 pyrosequencing technology to sequence the complete mitochondrial genome of an 11,450-year-old aurochs specimen from Central Italy. Phylogenetic analysis of the aurochs mtDNA genome supports the conclusions from previous studies of short mtDNA fragments--namely that Italian aurochsen were genetically very similar to modern cattle breeds, but highly divergent from the North-Central European aurochsen. CONCLUSIONS: Complete mitochondrial genome sequences are now available for several modern cattle and two pre-Neolithic mtDNA genomes from very different geographic areas. These data suggest that previously identified sub-groups within the widespread modern cattle mitochondrial T clade are polyphyletic, and they support the hypothesis that modern European breeds have multiple geographic origins. PMID- 21281510 TI - The transfer from survey (map-like) to route representations into Virtual Reality Mazes: effect of age and cerebral lesion. AB - BACKGROUND: To go from one place to another, we routinely generate internal representations of surrounding spaces, which can include egocentric (body centred) and allocentric (world-centred) coordinates, combined into route and survey representations.Recent studies have shown how both egocentric and allocentric representations exist in parallel and are joined to support behaviour according to the task.Our study investigated the transfer from survey (map-like) to route representations in healthy and brain-damaged subjects. The aim was two fold: first, to understand how this ability could change with age in a sample of healthy participants, aged from 40 to 71 years old; second, to investigate how it is affected after a brain lesion in a 8 patients' sample, with reference to specific neuropsychological frames. METHODS: Participants were first required to perform the paper and pencil version of eight mazes, then to translate the map like paths into egocentric routes, in order to find the right way into equivalent Virtual Reality (VR) mazes.Patients also underwent a comprehensive neuropsychological evaluation, including a specific investigation of some topographical orientation components. RESULTS: As regards the healthy sample, we found age-related deterioration in VR task performance. While education level and gender were not found to be related to performance, global cognitive level (Mini Mental State Examination), previous experience with computer and fluidity of navigation into the VR appeared to influence VR task results.Considering the clinical sample, there was a difficulty in performing the VR Maze task; executive functions and visuo-spatial abilities deficits appeared to be more relevant for predicting patients' results. CONCLUSIONS: Our study suggests the importance of developing tools aimed at investigating the survey to route transfer ability in both healthy elderly and clinical samples, since this skill seems high cognitive demanding and sensitive to cognitive decline.Human-computer interaction issues should be considered in employing new technologies, such as VR environments, with elderly subjects and neurological patients. PMID- 21281511 TI - Subtype specific genetic associations for juvenile idiopathic arthritis: ERAP1 with the enthesitis related arthritis subtype and IL23R with juvenile psoriatic arthritis. AB - INTRODUCTION: Juvenile idiopathic arthritis (JIA) is an umbrella term for all chronic childhood arthropathies and can be divided into seven subtypes. It includes the enthesitis related arthritis (ERA) subtype which displays symptoms similar to ankylosing spondylitis (AS) and juvenile-onset psoriatic arthritis which has similarities to psoriatic arthritis (PsA) and psoriasis (Ps). We, therefore, hypothesized that two well-established susceptibility loci for AS and Ps, ERAP1 and IL23R, could also confer susceptibility to these JIA subtypes. METHODS: Single nucleotide polymorphisms (SNPs) in ERAP1 (rs30187) and IL23R (rs11209026) were genotyped in JIA cases (n = 1,054) and healthy controls (n = 5,200). Genotype frequencies were compared between all JIA cases and controls using the Cochrane-Armitage trend test implemented in PLINK. Stratified analysis by ILAR subtype was performed. RESULTS: The ERA subtype showed strong association with ERAP1 SNP (P trend = 0.005). The IL23R SNP showed significant association in the PsA subtype (P trend = 0.04). The SNPs were not associated with JIA overall or with any other subtype. CONCLUSIONS: We present evidence for subtype specific association of the ERAP1 gene with ERA JIA and the IL23R gene with juvenile-onset PsA. The findings will require validation in independent JIA datasets. These results suggest distinct pathogenic pathways in these subtypes. PMID- 21281512 TI - Quantitative analysis of DNA methylation at all human imprinted regions reveals preservation of epigenetic stability in adult somatic tissue. AB - BACKGROUND: Genes subject to genomic imprinting are mono-allelically expressed in a parent-of-origin dependent manner. Each imprinted locus has at least one differentially methylated region (DMR) which has allele specific DNA methylation and contributes to imprinted gene expression. Once DMRs are established, they are potentially able to withstand normal genome reprogramming events that occur during cell differentiation and germ-line DMRs are stably maintained throughout development. These DMRs, in addition to being either maternally or paternally methylated, have differences in whether methylation was acquired in the germ-line or post fertilization and are present in a variety of genomic locations with different Cytosine-phosphate guanine (CpG) densities and CTCF binding capacities. We therefore examined the stability of maintenance of DNA methylation imprints and determined the normal baseline DNA methylation levels in several adult tissues for all imprinted genes. In order to do this, we first developed and validated 50 highly specific, quantitative DNA methylation pyrosequencing assays for the known DMRs associated with human imprinted genes. RESULTS: Remarkable stability of the DNA methylation imprint was observed in all germ-line DMRs and paternally methylated somatic DMRs (which maintained average methylation levels of between 35% - 65% in all somatic tissues, independent of gene expression). Maternally methylated somatic DMRs were found to have more variation with tissue specific methylation patterns. Most DMRs, however, showed some intra-individual variability for DNA methylation levels in peripheral blood, suggesting that more than one DMR needs to be examined in order to get an overall impression of the epigenetic stability in a tissue. The plasticity of DNA methylation at imprinted genes was examined in a panel of normal and cancer cell lines. All cell lines showed changes in DNA methylation, especially at the paternal germ-line and the somatic DMRs. CONCLUSIONS: Our validated pyrosequencing methylation assays can be widely used as a tool to investigate DNA methylation levels of imprinted genes in clinical samples. This first comprehensive analysis of normal methylation levels in adult somatic tissues at human imprinted regions confirm that, despite intra individual variability and tissue specific expression, imprinted genes faithfully maintain their DNA methylation in healthy adult tissue. DNA methylation levels of a selection of imprinted genes are, therefore, a valuable indicator for epigenetic stability. PMID- 21281513 TI - GC content around splice sites affects splicing through pre-mRNA secondary structures. AB - BACKGROUND: Alternative splicing increases protein diversity by generating multiple transcript isoforms from a single gene through different combinations of exons or through different selections of splice sites. It has been reported that RNA secondary structures are involved in alternative splicing. Here we perform a genomic study of RNA secondary structures around splice sites in humans (Homo sapiens), mice (Mus musculus), fruit flies (Drosophila melanogaster), and nematodes (Caenorhabditis elegans) to further investigate this phenomenon. RESULTS: We observe that GC content around splice sites is closely associated with the splice site usage in multiple species. RNA secondary structure is the possible explanation, because the structural stability difference among alternative splice sites, constitutive splice sites, and skipped splice sites can be explained by the GC content difference. Alternative splice sites tend to be GC enriched and exhibit more stable RNA secondary structures in all of the considered species. In humans and mice, splice sites of first exons and long exons tend to be GC-enriched and hence form more stable structures, indicating the special role of RNA secondary structures in promoter proximal splicing events and the splicing of long exons. In addition, GC-enriched exon-intron junctions tend to be overrepresented in tissue-specific alternative splice sites, indicating the functional consequence of the GC effect. Compared with regions far from splice sites and decoy splice sites, real splice sites are GC-enriched. We also found that the GC-content effect is much stronger than the nucleotide-order effect to form stable secondary structures. CONCLUSION: All of these results indicate that GC content is related to splice site usage and it may mediate the splicing process through RNA secondary structures. PMID- 21281514 TI - Evaluation of transduction efficiency in macrophage colony-stimulating factor differentiated human macrophages using HIV-1 based lentiviral vectors. AB - BACKGROUND: Monocyte-derived macrophages contribute to atherosclerotic plaque formation. Therefore, manipulating macrophage function could have significant therapeutic value. The objective of this study was to determine transduction efficiency of two HIV-based lentiviral vector configurations as delivery systems for the transduction of primary human blood monocyte-derived macrophages. RESULTS: Human blood monocytes were transduced using two VSV-G pseudotyped HIV-1 based lentiviral vectors containing EGFP expression driven by either native HIV LTR (VRX494) or EF1alpha promoters (VRX1090). Lentiviral vectors were added to cultured macrophages at different times and multiplicities of infection (MOI). Transduction efficiency was assessed using fluorescence microscopy and flow cytometry. Macrophages transduced between 2 and 120 hours after culturing showed the highest transduction efficiency at 2-hours transduction time. Subsequently, cells were transduced 2 hours after culturing at various vector concentrations (MOIs of 5, 10, 25 and 50) to determine the amount of lentiviral vector particles required to maximally transduce human monocyte-derived macrophages. On day 7, all transduced cultures showed EGFP-positive cells by microscopy. Flow cytometric analysis showed with all MOIs a peak shift corresponding to the presence of EGFP positive cells. For VRX494, transduction efficiency was maximal at an MOI of 25 to 50 and ranged between 58 and 67%. For VRX1090, transduction efficiency was maximal at an MOI of 10 and ranged between 80 and 90%. Thus, transductions performed with VRX1090 showed a higher number of EGFP-positive cells than VRX494. CONCLUSIONS: This report shows that VSV-G pseudotyped HIV-based lentiviral vectors can efficiently transduce human blood monocyte-derived macrophages early during differentiation using low particle numbers that do not interfere with differentiation of monocytes into macrophages. PMID- 21281515 TI - Travelling in time with networks: Revealing present day hybridization versus ancestral polymorphism between two species of brown algae, Fucus vesiculosus and F. spiralis. AB - BACKGROUND: Hybridization or divergence between sympatric sister species provides a natural laboratory to study speciation processes. The shared polymorphism in sister species may either be ancestral or derive from hybridization, and the accuracy of analytic methods used thus far to derive convincing evidence for the occurrence of present day hybridization is largely debated. RESULTS: Here we propose the application of network analysis to test for the occurrence of present day hybridization between the two species of brown algae Fucus spiralis and F. vesiculosus. Individual-centered networks were analyzed on the basis of microsatellite genotypes from North Africa to the Pacific American coast, through the North Atlantic. Two genetic distances integrating different time steps were used, the Rozenfeld (RD; based on alleles divergence) and the Shared Allele (SAD; based on alleles identity) distances. A diagnostic level of genotype divergence and clustering of individuals from each species was obtained through RD while screening for exchanges through putative hybridization was facilitated using SAD. Intermediate individuals linking both clusters on the RD network were those sampled at the limits of the sympatric zone in Northwest Iberia. CONCLUSION: These results suggesting rare hybridization were confirmed by simulation of hybrids and F2 with directed backcrosses. Comparison with the Bayesian method STRUCTURE confirmed the usefulness of both approaches and emphasized the reliability of network analysis to unravel and study hybridization. PMID- 21281516 TI - Novel human genetic variants associated with extrapulmonary tuberculosis: a pilot genome wide association study. AB - BACKGROUND: Approximately 5-10% of persons infected with M. tuberculosis develop tuberculosis, but the factors associated with disease progression are incompletely understood. Both linkage and association studies have identified human genetic variants associated with susceptibility to pulmonary tuberculosis, but few genetic studies have evaluated extrapulmonary disease. Because extrapulmonary and pulmonary tuberculosis likely have different underlying pathophysiology, identification of genetic mutations associated with extrapulmonary disease is important. FINDINGS: We performed a pilot genome-wide association study among 24 persons with previous extrapulmonary tuberculosis and well-characterized immune defects; 24 pulmonary tuberculosis patients and 57 patients with M. tuberculosis infection served as controls. The Affymetrix GeneChip Human Mapping Xba Array was used for genotyping; after careful quality control, genotypes at 44,175 single nucleotide polymorphisms (SNPs) were available for analysis. Eigenstrat quantified population stratification within our sample; logistic regression, using results of the Eigenstrat analysis as a covariate, identified significant associations between groups. Permutation testing controlled the family-wise error rate for each comparison between groups. Four SNPs were significantly associated with extrapulmonary tuberculosis compared to controls with M. tuberculosis infection; one (rs4893980) in the gene PDE11A, one (rs10488286) in KCND2, and one (rs2026414) in PCDH15; one was in chromosome 7 but not associated with a known gene. Two additional variants were significantly associated with extrapulmonary tuberculosis compared with pulmonary tuberculosis; one (rs340708) in the gene FAM135B and one in chromosome 13 but not associated with a known gene. The function of all four genes affects cell signaling and activity, including in the brain. CONCLUSIONS: In this pilot study, we identified 6 novel variants not previously known to be associated with extrapulmonary tuberculosis, including two SNPs more common in persons with extrapulmonary than pulmonary tuberculosis. This provides some support for the hypothesis that the pathogenesis and genetic predisposition to extrapulmonary tuberculosis differs from pulmonary tuberculosis. Further study of these novel SNPs, and more well powered genome-wide studies of extrapulmonary tuberculosis, is warranted. PMID- 21281517 TI - Different attitudes during breastfeeding consultations when infant formula was given: a phenomenographic approach. AB - BACKGROUND: WHO and UNICEF believe that both antenatal and maternity care organizations are in an excellent position to protect and, if necessary, reinstate a culture that promotes breastfeeding, and that they are responsible for doing so. In Sweden, the number of breastfeeding women has been decreasing annually since 1996. Thus the aim of this study is to identify, describe and analyze the attitude midwives have towards the mother, child and breastfeeding when infant formula is given. METHODS: From the theoretical standpoint of Buber's I-Thou and I-It concept, the different attitudes during breastfeeding consultations are interpreted. By using a phenomenographic approach based on 101 accounts of varying lengths from 39 midwives, different attitudes or approaches were identified. RESULTS: Four different approaches are distinguished in the breastfeeding consultation. The first is the family as a whole, the second is mother and child as separate and equal, the third views the mother as superior and the fourth views the child as superior. CONCLUSIONS: The approach of the midwife is related to how she defines the overall perspective of the mother-child relationship and how she looks upon her relationship to the mother-child dyad. Her approach varies depending on whether she meets the mother and child as a subject, similar to herself, or whether she sees one of them as an object. A midwife may also take an outside position, as an object, thus excluding a genuine relationship with the mother. The results also indicate that health care professionals focus on parts of the whole instead of maintaining a holistic perspective. PMID- 21281518 TI - Partial abdominal evisceration and intestinal autotransplantation to resect a mesenteric carcinoid tumor. AB - BACKGROUND: Midgut carcinoids are neuroendocrine tumors that commonly metastasize to the intestinal mesentery, where they predispose to intestinal obstruction, ischemia and/or congestion. Because of their location, many mesenteric carcinoid tumors are deemed unresectable due to the risk of uncontrollable bleeding and prolonged intestinal ischemia. CASE PRESENTATION: We report the case of a 60-year old male with a mesenteric carcinoid tumor obstructing his superior mesenteric vein, resulting in intestinal varices and severe recurrent GI bleeds. While his tumor was thought to be unresectable by conventional techniques, it was successfully resected using intestinal autotransplantation to safely gain access to the tumor. This case is the first described application of this technique to carcinoid tumors. CONCLUSIONS: Intestinal autotransplantation can be utilized to safely resect mesenteric carcinoid tumors from patients who were not previously thought to be surgical candidates. We review the literature concerning both carcinoid metastases to the intestinal mesentery and the use of intestinal autotransplantation to treat lesions involving the mesenteric root. PMID- 21281519 TI - RCT of a client-centred, caseworker-delivered smoking cessation intervention for a socially disadvantaged population. AB - BACKGROUND: Disadvantaged groups are an important target for smoking cessation intervention. Smoking rates are markedly higher among severely socially disadvantaged groups such as indigenous people, the homeless, people with a mental illness or drug and alcohol addiction, and the unemployed than in the general population. This proposal aims to evaluate the efficacy of a client centred, caseworker delivered cessation support intervention at increasing validated self reported smoking cessation rates in a socially disadvantaged population. METHODS/DESIGN: A block randomised controlled trial will be conducted. The setting will be a non-government organisation, Community Care Centre located in New South Wales, Australia which provides emergency relief and counselling services to predominantly government income assistance recipients. Eligible clients identified as smokers during a baseline touch screen computer survey will be recruited and randomised by a trained research assistant located in the waiting area. Allocation to intervention or control groups will be determined by time periods with clients randomised in one-week blocks. Intervention group clients will receive an intensive client-centred smoking cessation intervention offered by the caseworker over two face-to-face and two telephone contacts. There will be two primary outcome measures obtained at one, six, and 12 month follow-up: 1) 24-hour expired air CO validated self-reported smoking cessation and 2) 7-day self-reported smoking cessation. Continuous abstinence will also be measured at six and 12 months follow up. DISCUSSION: This study will generate new knowledge in an area where the current information regarding the most effective smoking cessation approaches with disadvantaged groups is limited. TRIAL REGISTRATION NUMBER: ISRCTN: ISRCTN85202510. PMID- 21281520 TI - Early identification and preventive care for elevated cardiovascular disease risk within a remote Australian Aboriginal primary health care service. AB - BACKGROUND: Cardiovascular disease (CVD) is the single greatest contributor to the gap in life expectancy between Indigenous and non-Indigenous Australians. Our objective is to determine if holistic CVD risk assessment, introduced as part of the new Aboriginal and Torres Strait Islander Adult Health Check (AHC), results in better identification of elevated CVD risk, improved delivery of preventive care for CVD and improvements in the CVD risk profile for Aboriginal adults in a remote community. METHODS: Interrupted time series study over six years in a remote primary health care (PHC) service involving Aboriginal adults identified with elevated CVD risk (N = 64). Several process and outcome measures were audited at 6 monthly intervals for three years prior to the AHC (the intervention) and three years following: (i) the proportion of guideline scheduled CVD preventive care services delivered, (ii) mean CVD medications prescribed and dispensed, (iii) mean PHC consultations, (iv) changes in participants' CVD risk factors and estimated absolute CVD risk and (v) mean number of CVD events and iatrogenic events. RESULTS: Twenty-five percent of AHC participants were identified as having elevated CVD risk. Of these, 84% had not been previously identified during routine care. Following the intervention, there were significant improvements in the recorded delivery of preventive care services for CVD (30% to 53%), and prescription of CVD related medications (28% to 89%) (P < 0.001). Amongst participants there was a 20% relative reduction in estimated absolute CVD risk (P = 0.004) following the intervention. However, there were no significant changes in the mean number of PHC consultations or mean number of CVD events or iatrogenic events. CONCLUSIONS: Holistic CVD risk assessment during an AHC can lead to better and earlier identification of elevated CVD risk, improvement in the recorded delivery of preventive care services for CVD, intensification of treatment for CVD, and improvements in participants' CVD risk profile. Further research is required on strategies to reorient and restructure PHC services to the care of chronic illness for Aboriginal peoples in remote areas for there to be substantial progress in decreasing excess CVD related mortality. PMID- 21281521 TI - Compliance with behavioral guidelines for diet, physical activity and sedentary behaviors is related to insulin resistance among overweight and obese youth. AB - BACKGROUND: Overweight and obesity are established risk factors for insulin resistance in youth. A number of behavioral recommendations have been publicized with the goal of improving glycemic control. However, there is limited information about whether meeting these behavioral recommendations actually reduces insulin resistance. FINDINGS: 92 youths 11 - 16 years with BMI >= 85% underwent oral glucose tolerance testing. HOMA-IR and AUCInsulin/AUCGlucose were calculated as measures of insulin resistance. Dietary and physical activity (PA) measures were performed. Assessments included whether or not participants met recommended levels of diet, PA and sedentary behaviors.62% youths met criteria for insulin resistance. 82% (75/92) met at least one behavioral recommendation. Participants who met >= 1 dietary, sedentary, or PA recommendations had significantly reduced insulin resistance as compared with youth who did not. This relationship remained significant in multivariate modeling of insulin resistance adjusting for age, sex, and BMI. CONCLUSIONS: Even relatively minor behavior change may reduce insulin resistance in youth at risk for diabetes. Our findings support the relevance of current behavioral interventions for glycemic control. TRIALS REGISTRATION: Clinical Trials #NCT00412165. PMID- 21281522 TI - Multivariate analysis of microarray data: differential expression and differential connection. AB - BACKGROUND: Typical analysis of microarray data ignores the correlation between gene expression values. In this paper we present a model for microarray data which specifically allows for correlation between genes. As a result we combine gene network ideas with linear models and differential expression. RESULTS: We use sparse inverse covariance matrices and their associated graphical representation to capture the notion of gene networks. An important issue in using these models is the identification of the pattern of zeroes in the inverse covariance matrix. The limitations of existing methods for doing this are discussed and we provide a workable solution for determining the zero pattern. We then consider a method for estimating the parameters in the inverse covariance matrix which is suitable for very high dimensional matrices. We also show how to construct multivariate tests of hypotheses. These overall multivariate tests can be broken down into two components, the first one being similar to tests for differential expression and the second involving the connections between genes. CONCLUSION: The methods in this paper enable the extraction of a wealth of information concerning the relationships between genes which can be conveniently represented in graphical form. Differentially expressed genes can be placed in the context of the gene network and places in the gene network where unusual or interesting patterns have emerged can be identified, leading to the formulation of hypotheses for future experimentation. PMID- 21281523 TI - Effects of bone morphogenic protein 4 (BMP4) and its inhibitor, Noggin, on in vitro maturation and culture of bovine preimplantation embryos. AB - BACKGROUND: BMP4 is a member of the transforming growth factor beta (TGFbeta) superfamily and Noggin is a potent BMP inhibitor that exerts its function by binding to BMPs preventing interactions with its receptors. The aim of this work was to investigate the role of BMP4 and Noggin, on oocytes in vitro maturation (m experiments) and embryos in vitro development (c experiments) of bovine. METHODS: For m experiments, COCs were collected from slaughterhouse ovaries and in vitro matured in TCM with 100 ng/ml of either BMP4 or Noggin. After 24 h, the nuclear stage of the oocytes was determined by staining with Hoechst 33342. In addition, RT-qPCR was performed on MII oocytes to study the relative concentration of ZAR1, GDF9, BAX, MATER and HSP70 transcripts. Treated oocytes were submitted to parthenogenic activation (PA) or in vitro fertilization (IVF) and cultured in CR2. For c experiments, non-treated matured oocytes were submitted to PA or IVF to generate embryos that were exposed to 100 ng/ml of BMP4 or Noggin in CR2 until day nine of culture. Cleavage, blastocyst and hatching rates, expression pattern of the transcription factor Oct-4 in blastocysts and embryo cell number at day two and nine post-activation or fertilization were evaluated. RESULTS: We found that Noggin, as BMP4, did not affect oocyte nuclear maturation. Noggin supplementation up-regulated the expression of HSP70 and MATER genes in matured oocytes. Moreover, BMP4 during maturation increased the proportion of Oct-4 positive cells in parthenogenic embryos. On the other hand, when Noggin was added to embryo culture medium, developmental rates of parthenogenic and in vitro fertilized embryos were reduced. However, BMP4 addition decreases the development only for in vitro fertilized embryos. BMP4 and Noggin during culture reduced the proportion of Oct-4-expressing cells. CONCLUSIONS: Our results show that BMP4 is implicated in bovine oocytes maturation and embryo development. Moreover, our findings demonstrate, for the first time, that a correct balance of BMP signaling is needed for proper pre-implantation development of bovine embryos. PMID- 21281524 TI - DeStripe: frequency-based algorithm for removing stripe noises from AFM images. AB - BACKGROUND: Atomic force microscopy (AFM) is a relatively recently developed technique that shows a promising impact in the field of structural biology and biophysics. It has been used to image the molecular surface of membrane proteins at a lateral resolution of one nanometer or less. An immediate obstacle of characterizing surface features in AFM images is stripe noise. To better interpret structures at a sub-domain level, pre-processing of AFM images for removing stripe noises is necessary. Noise removal can be performed in either spatial or frequency domain. However, denoising processing in the frequency domain is a better solution for preserving edge sharpness. RESULTS: We have developed a denoising protocol, called DeStripe, for AFM bio-molecular images that are contaminated with heavy and fine stripes. This program adopts a divide and-conquer approach by dividing the Fourier spectrum of the image into central and off-center regions for noisy pixels detection and intensity restoration; it is also applicable to other images interfered with high-density stripes such as those acquired by the scanning electron microscope. The denoising effect brought by DeStripe provides better visualization for image objects without introducing additional artifacts into the restored image. CONCLUSIONS: The DeStripe denoising effect on AFM images is illustrated in the present work. It allows extracting extended information from the topographic measurements and implicitly enhances the molecular features in the image. All the presented images were processed by DeStripe with the raw image as the only input without any requirement for other prior information. A web service, http://biodev.cea.fr/destripe, is available for running DeStripe. PMID- 21281525 TI - Modularity of gene-regulatory networks revealed in sea-star development. AB - Evidence that conserved developmental gene-regulatory networks can change as a unit during deutersostome evolution emerges from a study published in BMC Biology. This shows that genes consistently expressed in anterior brain patterning in hemichordates and chordates are expressed in a similar spatial pattern in another deuterostome, an asteroid echinoderm (sea star), but in a completely different developmental context (the animal-vegetal axis). This observation has implications for hypotheses on the type of development present in the deuterostome common ancestor. PMID- 21281526 TI - Dietary modulation of body composition and insulin sensitivity during catch-up growth in rats: effects of oils rich in n-6 or n-3 PUFA. AB - The present study investigates whether excessive fat accumulation and hyperinsulinaemia during catch-up growth on high-fat diets are altered by n-6 and n-3 PUFA derived from oils rich in either linoleic acid (LA), alpha-linolenic acid (ALA), arachidonic acid (AA) or DHA. It has been shown that, compared with food-restricted rats refed a high-fat (lard) diet low in PUFA, those refed isoenergetically on diets enriched in LA or ALA, independently of the n-6:n-3 ratio, show improved insulin sensitivity, lower fat mass and higher lean mass, the magnitude of which is related to the proportion of total PUFA precursors (LA+ALA) consumed. These relationships are best fitted by quadratic regression models (r2>0.8, P < 0.001), with threshold values for an impact on body composition corresponding to PUFA precursors contributing 25-30 % of energy intake. Isoenergetic refeeding on high-fat diets enriched in AA or DHA also led to improved body composition, with increases in lean mass as predicted by the quadratic model for PUFA precursors, but decreases in fat mass, which are disproportionately greater than predicted values; insulin sensitivity, however, was not improved. These findings pertaining to the impact of dietary intake of PUFA precursors (LA and ALA) and their elongated-desaturated products (AA and DHA), on body composition and insulin sensitivity, provide important insights into the search for diets aimed at counteracting the pathophysiological consequences of catch-up growth. In particular, diets enriched in essential fatty acids (LA and/or ALA) markedly improve insulin sensitivity and composition of weight regained, independently of the n-6:n-3 fatty acid ratio. PMID- 21281527 TI - In vitro assessment of praziquantel and a novel nanomaterial against protoscoleces of Echinococcus granulosus. AB - The present study describes the activity of a nanomaterial on protoscoleces of Echinococcus granulosus, which exhibited morphological changes and apoptosis. Apoptotic changes were deduced on the basis of effector caspase activation and nucleosomal laddering. Invaginated protoscoleces maintained in vitro became evaginated and had hooks, presumptive suckers and stalks. Degenerative changes of protoscoleces were evidenced after treatment with praziquantel and nano combination. Protoscoleces treated with praziquantel had distinct attestation of necrosis and nano-combination-treated protoscoleces had signatures of apoptosis. PMID- 21281528 TI - The epidemiology of soil-transmitted helminth and protozoan infections in south west Cameroon. AB - A cross-sectional study of the prevalence, intensity and effects of soil transmitted helminth and protozoan infections was undertaken among patients at the Buea Hospital Annex located in Buea sub-division of Cameroon. Stool samples from 356 subjects (174 males and 182 females) were collected and processed using standard concentration methods. Our results showed that 31.0% of subjects were infected with intestinal helminths and the prevalence was higher in females (32.4%) than in males (30.5%). A significantly higher prevalence was observed in rural (47.2%) than in urban areas (21.0%); significance < 0.1%. Prevalence was highest among those aged between 6 and 12 years (41.4%). The total prevalence of intestinal helminth infections were 19.3% for Ascaris lumbricoides, 14.0% for hookworm and 11.8% for Trichuris trichiura. The intensity of infection was unevenly distributed, with very heavy loads concentrated in a few individuals. Data also showed that 28.1% (100/356) of the subjects were infected with protozoans. Females showed a higher prevalence (28.6%; 52/182) than males (20.7%; 36/174). Also, there was a significantly higher prevalence in rural (34.0%; 49/144) than urban areas (18.4%; 39/212); significance < 0.1%. The age group 6-12 years again had a higher prevalence (37.1%; 26/70). The total prevalence of intestinal protozoans was: Entamoeba histolytica (24.4%), Entamoeba coli (11.2%) and Giardia lamblia (0.6%). These relatively heavy prevalences in patients may be reduced by appropriate medication and maintaining strict personal hygiene. Health education, clean water supply, good sewage management and a congenial environment will all help to minimize infection. PMID- 21281529 TI - Larval gryporhynchid tapeworms (Cestoda: Cyclophyllidea) of British freshwater fish, with a description of the pathology caused by Paradilepis scolecina. AB - Larvae of the cyclophyllidean tapeworms Paradilepis scolecina (Rudolphi, 1819), Neogryporhynchus cheilancristrotus (Wedl, 1855) and Valipora campylancristrota (Wedl, 1855), are described from British freshwater fish. The morphometrics of the rostellar hooks, infection characteristics and host ranges of these parasites from fisheries in England and Wales are presented. Difficulties in the detection, handling and identification of these tapeworms are highlighted, and may in part explain the paucity of records from Britain. Tissue digestion was shown to be a useful technique for the examination of these parasites, providing clear and consistent preparations of the rostellar hooks for measurement. The pathological changes caused by P. scolecina to the liver of wild tench, Tinca tinca, are detailed for the first time. Tapeworms located in the hepatic parenchyma and pancreatic tissues caused little pathological damage and invoked only mild inflammatory responses. The small size of these tapeworms and their encapsulation within host tissues appear to limit the severity of pathology, compared with parasites that insert their rostellum during attachment. PMID- 21281530 TI - Primary cervical tracheal monophasic synovial sarcoma confirmed by SYT-SSX gene rearrangement. AB - OBJECTIVE: To review the existing diagnostic modalities and treatment for primary tracheal synovial sarcoma, and to report a case of primary cervical synovial sarcoma arising in the trachea. DESIGN: Retrospective. SETTING: Head and neck surgery unit at a tertiary university centre. PATIENT: One case of primary cervical tracheal monophasic synovial sarcoma diagnosed by SYT-SSX gene rearrangement. INTERVENTION: This patient underwent surgical resection of the synovial sarcoma, together with tracheal resection and primary anastomosis assisted by laryngeal-releasing manoeuvres, without complication. MAIN OUTCOME MEASURES: Clinical, radiographical, pathological and surgical information were collected. RESULT: One year post-operatively, there was no evidence of recurrence. CONCLUSION: Synovial sarcoma arising in the trachea is very rare. Diagnosis is confirmed by demonstrating the SYT-SSX gene rearrangement. The first line treatment is surgery. PMID- 21281531 TI - Airway obstruction due to inflammatory myofibroblastic tumour of the posterior pharyngeal wall. AB - OBJECTIVE: We report a unique case of inflammatory myofibroblastic tumour of the posterior wall of the hypopharynx. METHOD: We present the patient's case history, management and histopathological findings. A literature review of all cases localised to the larynx or pharynx is provided and discussed. RESULTS: A 67-year old man presented with airway obstruction due to a spherical mass in the hypopharynx originating from the posterior pharyngeal wall. The tumour was resected. Histopathological examination revealed an inflammatory myofibroblastic tumour. We found only five previously reported cases with pharyngeal localisation. Further treatment of the patient is described. CONCLUSION: Inflammatory myofibroblastic tumour of the pharynx is extremely rare. It is regarded as a neoplastic tumour of intermediate biological potential. In cases with extrapulmonary localisation, the incidence of local recurrence can be as high as 25 per cent. Radical surgery is the treatment of choice; no adjuvant therapy is necessary. PMID- 21281532 TI - Dairy calcium intake modifies responsiveness of fat metabolism and blood lipids to a high-fat diet. AB - Intervention studies have demonstrated that saturated fat increases total and LDL cholesterol concentrations, and it is therefore recommended that the intake of high-fat dairy products be limited. However, observational studies have found an inverse relationship between the intake of dairy products and incidence of CVD. We aimed to study whether the Ca content of dairy products influences the effect of dairy fat on the lipid profile. The study had a randomised cross-over design. Subjects (n 9) were randomised to one of the sequence of four isoenergetic 10 d diets: low Ca and low fat (LC/LF: approximately 700 mg Ca/d, 25 % of energy (fat); high Ca and LF (HC/LF: approximately 2800 mg Ca/d, 25 % of energy fat); LC and high fat (LC/HF: approximately 700 mg Ca/d, 49 E% fat); or HC and HF (approximately 2800 mg Ca/d, 49 E% fat). Blood variables were measured before and after each diet period, and faeces and urine were collected at the end of each diet period. A two-way ANOVA was used to examine the effect of Ca and fat intake. Independent of Ca intake, the HF diet increased the concentrations of total (9 %; P < 0.0001), LDL (14 %; P < 0.0001)- and HDL (13 %; P = 0.0002)-cholesterol compared with the LF diet. However, independent of fat intake, the HC diet decreased the concentrations of total (4 %; P = 0.0051) and LDL-cholesterol (10 %; P < 0.0001) but not HDL-cholesterol compared with the LC diet. In addition, total:HDL-cholesterol was decreased (5 %; P = 0.0299), and HDL:LDL was increased (12 %; P = 0.0097) by the HC diet compared with the LC diet. Faecal fat excretion was increased by both the HC (P < 0.0001) and HF (P = 0.0052) diets. In conclusion, we observed that dairy Ca seems to partly counteract the raising effect of dairy fat on total and LDL-cholesterol, without reducing HDL cholesterol. PMID- 21281533 TI - Prevalence of GJB2-associated deafness and outcomes of cochlear implantation in Iran. AB - OBJECTIVES: To investigate the prevalence of mutations in the coding exon of the GJB2 gene in Iranian children with cochlear implants, and to compare the outcomes of auditory perception and speech production in cochlear-implanted children with and without GJB2 mutation. MATERIALS AND METHODS: One hundred and sixty-six prelingually deaf children who had undergone cochlear implantation at the Iranian Cochlear Implant Center, Tehran, were selected from a pool of 428 implanted children. The prevalence of GJB2 gene mutations was assessed using nested polymerase chain reaction and direct sequencing. To enable comparisons, we also identified 36 implanted children with non-GJB2 deafness. Patients' speech perception and speech production were assessed using the Categorization of Auditory Performance and Speech Intelligibility Rating scales. RESULTS: Thirty three of 166 probands (19.9 per cent) were found to have GJB2 deafness-causing allele variants and were diagnosed with DFNB1 deafness. Results also indicated a significant improvement in speech perception and production scores in both GJB2 and non-GJB2 patients over time. CONCLUSION: Children with GJB2-related deafness benefit from cochlear implantation to the same extent as those with non-GJB2 related deafness. PMID- 21281534 TI - Transoral laser microsurgery outcomes with early glottic cancer: the Dalhousie University experience. AB - OBJECTIVE: To report the results of transoral laser microsurgery for the treatment of early glottic cancer at our institution. DESIGN: Cohort study. Retrospective review of charts of patients diagnosed with tumour stage 1 or 2 (early stage; no nodes or metastases), previously untreated, primary glottic cancer, treated with transoral laser microsurgery at the Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada. The minimum follow-up period was two years. SETTING: Tertiary care head and neck cancer centre. PARTICIPANTS: Fifty-three patients treated between January 2002 and November 2007. OUTCOME MEASURE: Kaplan-Meier survival analysis for disease-free survival, overall survival and laryngectomy-free survival, at five years. RESULTS: The group comprised 46 men and seven women, with a mean age of 66 years (range 30-84 years). Mean follow up was 40 months (range 12-89 months). There were four cases of complications (7.5 per cent). Kaplan-Meier survival analysis revealed a five year disease-free survival (including salvage) of 96.2 per cent, a five-year overall survival (all causes) of 88.8 per cent and a five-year laryngectomy-free survival of 98.1 per cent. CONCLUSION: Transoral laser microsurgery is a safe and effective initial treatment for early laryngeal cancer, and has high rates of laryngeal preservation and disease-free survival. PMID- 21281535 TI - Short term effect of hubble-bubble smoking on voice. AB - OBJECTIVE: To investigate the short term effect of hubble-bubble smoking on voice. STUDY DESIGN: Prospective study. MATERIAL: Eighteen non-dysphonic subjects (seven men and 11 women) with a history of hubble-bubble smoking and no history of cigarette smoking underwent acoustic analysis and laryngeal video-stroboscopic examination before and 30 minutes after hubble-bubble smoking. RESULTS: On laryngeal video-stroboscopy, none of the subjects had vocal fold erythema either before or after smoking. Five patients had mild vocal fold oedema both before and after smoking. After smoking, there was a slight increase in the number of subjects with thick mucus between the vocal folds (six, vs four before smoking) and with vocal fold vessel dilation (two, vs one before smoking). Acoustic analysis indicated a drop in habitual pitch, fundamental frequency and voice turbulence index after smoking, and an increase in noise-to-harmonics ratio. CONCLUSION: Even 30 minutes of hubble-bubble smoking can cause a drop in vocal pitch and an increase in laryngeal secretions and vocal fold vasodilation. PMID- 21281536 TI - Novel method of intralesional cidofovir injection into laryngotracheal papillomata. AB - Laryngeal papillomatosis is characterised by multiple papillomata affecting the upper respiratory tract. This condition is difficult to treat due to its recurrent nature. Treatment often involves surgical debulking. A number of non surgical treatments have been reported. Intralesional cidofovir, a cytosine nucleoside analogue with antiviral activity, has been used in an attempt to manage the condition. We present a novel technique of administering cidofovir in a case of recurrent laryngotracheal papillomata. PMID- 21281537 TI - Three-dimensional analysis of high-resolution X-ray computed tomography data with Morpho+. AB - Three-dimensional (3D) analysis is an essential tool to obtain quantitative results from 3D datasets. Considerable progress has been made in 3D imaging techniques, resulting in a growing need for more flexible, complete analysis packages containing advanced algorithms. At the Centre for X-ray Tomography of the Ghent University (UGCT), research is being done on the improvement of both hardware and software for high-resolution X-ray computed tomography (CT). UGCT collaborates with research groups from different disciplines, each having specific needs. To meet these requirements the analysis software package, Morpho+, was developed in-house. Morpho+ contains an extensive set of high performance 3D operations to obtain object segmentation, separation, and parameterization (orientation, maximum opening, equivalent diameter, sphericity, connectivity, etc.), or to extract a 3D geometrical representation (surface mesh or skeleton) for further modeling. These algorithms have a relatively short processing time when analyzing large datasets. Additionally, Morpho+ is equipped with an interactive and intuitive user interface in which the results are visualized. The package allows scientists from various fields to obtain the necessary quantitative results when applying high-resolution X-ray CT as a research tool to the nondestructive investigation of the microstructure of materials. PMID- 21281538 TI - Application of electron backscatter diffraction techniques to quenched and partitioned steels. AB - Electron backscatter diffraction (EBSD) techniques were used to characterize "hot rolled" quenched and partitioned microstructures produced via Gleeble thermal simulations representing a hot-strip cooling practice for steel. In particular, EBSD was utilized to positively identify the morphology and location of retained austenite, to qualitatively distinguish martensite from ferrite, and in an attempt to identify transition carbides. Large pools of retained austenite and some thin films were accurately indexed; however, there was some disparity between austenite volume fractions measured by EBSD and those measured by X-ray diffraction. Due to similarities between the crystal structures of martensite and ferrite (body centered tetragonal versus body centered cubic, respectively), martensite could not be distinguished from ferrite by indexing of diffraction patterns; however, martensite could qualitatively be distinguished from ferrite by regions of low image quality based on the very high dislocation density of martensite. PMID- 21281539 TI - JNK2 participates in spindle assembly during mouse oocyte meiotic maturation. AB - It is well known that c-Jun N-terminal kinase (JNK) plays pivotal roles in various mitotic events, but its function in mammalian oocyte meiosis remains unknown. In this study, we found that no specific JNK2 signal was detected in germinal vesicle stage. JNK2 was associated with the spindles especially the spindle poles and cytoplasmic microtubule organizing centers at prometaphase I, metaphase I, and metaphase II stages. JNK2 became diffusely distributed and associated with the midbody at telophase I stage. Injection of myc-tagged JNK2alpha1 mRNA into oocytes also revealed its localization on spindle poles. The association of JNK2 with spindle poles was further confirmed by colocalization with the centrosomal proteins, gamma-tubulin and Plk1. Nocodazole treatment showed that JNK2 may interact with Plk1 to regulate the spindle assembly. Then we investigated the possible function of JNK2 by JNK2 antibody microinjection and JNK specific inhibitor SP600125 treatment. These two manipulations caused abnormal spindle formation and decreased the rate of first polar body (PB1) extrusion. In addition, inhibition of JNK2 resulted in impaired localization of Plk1. Taken together, our results suggest that JNK2 plays an important role in spindle assembly and PB1 extrusion during mouse oocyte meiotic maturation. PMID- 21281540 TI - Behavioural correlates of active commuting to school in Spanish adolescents: the AFINOS (Physical Activity as a Preventive Measure Against Overweight, Obesity, Infections, Allergies, and Cardiovascular Disease Risk Factors in Adolescents) study. AB - OBJECTIVE: To examine the associations between lifestyle factors and active commuting to school in Spanish adolescents. DESIGN: Cross-sectional study. Lifestyle factors (overall/extracurricular physical activity, television viewing, reading as a hobby, sleep duration, breakfast/fruit intake, smoking and alcohol intake) as well as mode and duration of commuting to school were self-reported. Active commuters were defined as those adolescents who walked or cycled to school. SETTING: Secondary schools in Madrid, Spain. SUBJECTS: Adolescents (n 2029) aged 13 to 17 years. RESULTS: Similar percentages of adolescent boys (57.6 %) and girls (56.1 %) were classified as active commuters to school (P = 0.491). The analysis showed that only adequate sleep duration (OR = 1.35, 95 % CI 1.11, 1.66; P = 0.003) and breakfast consumption (OR = 0.66, 95 % CI 0.49, 0.87; P = 0.004) were independently associated with active commuting to school. CONCLUSIONS: Only those behaviours that occur immediately before commuting to school (sleep and breakfast) are associated with active commuting in Spanish adolescents. PMID- 21281541 TI - Regional and socio-economic differences in food, nutrient and supplement intake in school-age children in Germany: results from the GINIplus and the LISAplus studies. AB - OBJECTIVE: To describe regional differences between eastern and western Germany with regard to food, nutrient and supplement intake in 9-12-year-old children, and analyse its association with parental education and equivalent income. DESIGN: Data were obtained from the 10-year follow-up of the two prospective birth cohort studies - GINIplus and LISAplus. Data on food consumption and supplement intake were collected using an FFQ, which had been designed for the specific study population. Information on parental educational level and equivalent income was derived from questionnaires. Logistic regression modelling was used to analyse the effect of parental education, equivalent income and region on food intake, after adjusting for potential confounders. SETTING: Germany. SUBJECTS: A total of 3435 children aged 9-12 years. RESULTS: Substantial regional differences in food intake were observed between eastern and western Germany. Intakes of bread, butter, eggs, pasta, vegetables/salad and fruit showed a significant direct relationship with the level of parental education after adjusting for potential confounders, whereas intakes of margarine, meat products, pizza, desserts and soft drinks were inversely associated with parental education. Equivalent income had a weaker influence on the child's food intake. CONCLUSIONS: Nutritional education programmes for school-age children should therefore account for regional differences and parental education. PMID- 21281543 TI - Information tracking and encoding in early L1: linguistic competence vs. cognitive limitations. AB - This study provides experimental evidence for preschool children's competence in basic information structure, with particular attention to the notions of topic and focus. It investigates their mastery of structural and definiteness distinctions to encode the information status of discourse referents, and seeks to distinguish linguistic competence from cognitive development as the source for children's 'errors'. Evidence comes from a story-telling experiment performed on 45 children acquiring French (between the ages of 2;6.22 and 5;6.15). The article demonstrates continuity between the child and adult systems of basic discourse representation. It further argues that children's definiteness errors are not due to a lack of knowledge of the adult rules of information encoding. Rather, such errors stem from cognitive limitations and from assuming a wider common ground than adults would. PMID- 21281544 TI - Micronutrient and anthropometric status indicators are associated with physical fitness in Colombian schoolchildren. AB - Poor physical fitness is associated with increased health-related risks in children. The association of nutritional status indicators and physical fitness in children residing in developing countries is not well characterised. We conducted a cross-sectional study among 1945 children of age 5-12 years in Bogota, Colombia, to assess whether anthropometric and micronutrient status indicators were associated with performance in the shuttle run and standing long jump tests. Stunted children scored significantly lower in the run (0.4 s; P = 0.0002) and jump (6 cm; boys only; P = 0.003) tests than non-stunted children, after adjustment for age and other factors. Children who were thin, overweight or obese ran slower than normal-weight children (P < 0.01). Lower jump scores were associated with overweight or obesity and greater arm fat area in boys only (P < 0.0001). Girls with low ferritin concentrations ran 0.6 s slower than girls with normal ferritin concentrations (P = 0.02). Erythrocyte folate concentrations were linearly related to higher run (P < 0.0001) and long jump scores (P = 0.0001). Boys with marginal or low vitamin B12 status had 4 cm lower long jump scores than children with normal status (P = 0.01). Suboptimal anthropometric and micronutrient status are related to poorer performance in fitness tests. The effects of improving nutritional status on physical fitness of children warrant investigation. PMID- 21281545 TI - Does the technique of interventional closure of perimembranous ventricular septal defect reduce the incidence of heart block? AB - OBJECTIVE: To describe the difficulties and differing techniques in the transcatheter placement of amplatz ventricular septal defect devices to close perimembranous ventricular septal defects and place these in the context of the expanding literature on ventricular septal defect catheter closure. BACKGROUND: Surgery remains the established first-line therapy for closure of haemodynamically significant perimembranous ventricular septal defects. Transcatheter techniques appeared to promise a possible alternative, obviating the need for cardiac surgery. However, significant technical and anatomical constraints coupled with ongoing reports of a high incidence of heart block have prevented these hopes from being realised to any significant extent. It is likely that there are important methodological reasons for the high complication rates observed. The potential advantages of transcatheter perimembranous ventricular septal defect closure over surgery warrant further exploration of differing transcatheter techniques. METHODS: Between August, 2004 and November, 2009, 21 patients had a perimembranous ventricular septal defect closed with transcatheter techniques. Of these, 14 were closed with a muscular amplatz ventricular septal defect device. The median age and weight at device placement were 8 years, ranging from 2 to 19 years, and 18.6 kilograms, ranging from 10 to 21 kilograms, respectively. RESULTS: There were 25 procedures performed on 23 patients using 21 amplatz ventricular septal defect devices. Median defect size on angiography was 7.8 millimetres, ranging from 4 to 14.3 millimetres, with a median device size of 8 millimetres, ranging from 4 to 18 millimetres, and a defect/device ratio of 1.1, with a range from 0.85 to 1.33. Median procedure time was 100 minutes, with a range from 38 to 235 minutes. Adverse events included device embolisation following haemolysis in one, and new aortic incompetence in another, but there were no cases of heart block. Median follow-up was 41.7 months, with a range from 2 to 71 months. CONCLUSIONS: Evaluating transcatheter closure of perimembranous ventricular septal defect using amplatz ventricular septal defect devices remains important, if a technically feasible method with low and acceptable complication rates is to be identified. Incidence of heart block may be minimised by avoiding oversized devices, using muscular devices, and accepting defeat if an appropriately selected device pulls through. Given the current transcatheter technologies, the closure of perimembranous ventricular septal defects should generally be performed in children when they weigh at least 10 kilograms. PMID- 21281542 TI - Pilot evaluation of the HELENA (Healthy Lifestyle in Europe by Nutrition in Adolescence) Food-O-Meter, a computer-tailored nutrition advice for adolescents: a study in six European cities. AB - OBJECTIVE: To investigate the feasibility and impact of the Food-O-Meter, an Internet-based computer-tailored nutrition intervention in adolescents. DESIGN: Participants in the intervention condition received the computer-tailored advice at baseline and at 1 month, those in the control condition received standardised advice. Effects were evaluated at 1 month (n 621) and at 3 months (n 558) using multi-level modelling. SETTING: Secondary schools in six European cities. Adolescents accessed the intervention in the school computer room under the supervision of teachers. SUBJECTS: Classes with students aged 12-17 years in the schools participating in the HELENA (Healthy Lifestyle in Europe by Nutrition in Adolescence) cross-sectional study were randomised into intervention and control schools. RESULTS: In most participating centres the intervention was feasible and generally well appreciated, especially by girls. Technical problems and lack of motivation of the teachers hindered implementation in some centres. Overweight adolescents had higher scores for reading and using the advice than normal weight adolescents. After 1 month adolescents receiving the standardised advice reported an increase in fat intake, while fat intake in the intervention condition was stable (F = 4.82, P < 0.05). After 3 months, there was a trend in the total group for an intervention effect of the tailored advice on fat intake (F = 2.80, P < 0.10). In the overweight group there was a clear positive effect (F = 5.76, P < 0.05). CONCLUSIONS: The Food-O-Meter should be developed further. The results were modest but clear for percentage energy from fat, specifically in the overweight group. Adaptations based on new research are needed to enhance the reliability and effectiveness of the intervention. PMID- 21281546 TI - Left ventricular dilatation late after arterial switch operation: usefulness of cardiac computed tomography to detect aorto-pulmonary collaterals. PMID- 21281547 TI - Longitudinal and spatial distribution of GP60 subtypes in human cryptosporidiosis cases in Ireland. AB - Within Europe, Ireland has one of the highest reported infection rates with the diarrhoeal protozoan pathogen Cryptosporidium. In this study 249 Cryptosporidium parvum isolates collected from Irish patients between 2000 and 2009 were subtyped by sequence analysis of the GP60 locus. A subsample of 127 isolates was also typed at the MS1 and ML1 loci. GP60 subtype IIaA18G3R1 was the predominant subtype in every year and every season throughout the country. Over the 10-year period there was no evidence that host immunity to the predominant subtype caused a shift in its prevalence. Length frequency distributions of the GP60 TCA/TCG repeats compiled from published data, showed distinct patterns for countries with predominantly zoonotic or anthroponotic transmission cycles, respectively. Although considered to be mostly affected by zoonotic cryptosporidiosis, the GP60 fragment length of Irish C. parvum isolates mirrored that of countries with predominantly human-to-human transmission, indicating more complex routes of infection between livestock and humans. Due to their homogeneity, ML1 and MS1 were not considered useful loci for subtyping C. parvum strains in Ireland. PMID- 21281548 TI - Children with specific language impairment in Finnish: the use of tense and agreement inflections. AB - Children with specific language impairment (SLI) vary widely in their ability to use tense/agreement inflections depending on the type of language being acquired, a fact that current accounts of SLI have tried to explain. Finnish provides an important test case for these accounts because: (1) verbs in the first and second person permit null subjects whereas verbs in the third person do not; and (2) tense and agreement inflections are agglutinating and thus one type of inflection can appear without the other. Probes were used to compare the verb inflection use of Finnish-speaking children with SLI, and both age-matched and younger typically developing children. The children with SLI were less accurate, and the pattern of their errors did not match predictions based on current accounts of SLI. It appears that children with SLI have difficulty learning complex verb inflection paradigms apart from any problem specific to tense and agreement. PMID- 21281549 TI - Shigellosis outbreak linked to canteen-food consumption in a public institution: a matched case-control study. AB - On 13 November 2009, the authorities of Flemish Brabant, Belgium, received an alert concerning a potential outbreak of Shigella sonnei at a public institution. A study was conducted to assess the extent, discover the source and to implement further measures. We performed a matched case-control study to test an association between shigellosis and canteen-food consumption. Water samples and food handlers' faecal samples were tested. The reference laboratory characterized the retrospectively collected Shigella specimens. We found 52 cases distributed over space (25/35 departments) and time (2 months). We found a matched odds ratio of 3.84 (95% confidence interval 1.02-14.44) for canteen-food consumption. A food handler had travelled to Morocco shortly before detection of the first laboratory confirmed case. Water samples and food handlers' faecal samples tested negative for Shigella. Confirmed cases presented PFGE profiles, highly similar to archived isolates from Morocco. Foodborne transmission associated with the canteen was strongly suspected. PMID- 21281550 TI - An overview of the epidemic of highly pathogenic H5N1 avian influenza virus in Egypt: epidemiology and control challenges. AB - Emergence of the highly pathogenic avian influenza (HPAI) H5N1 virus in Egypt in mid-February 2006 caused significant losses for the poultry industry and constituted a potential threat to public health. Since late 2007, there has been increasing evidence that stable lineages of H5N1 viruses are being established in chickens and humans in Egypt. The virus has been detected in wild, feral and zoo birds and recently was found in donkeys and pigs. Most of the outbreaks in poultry and humans occurred in the highly populated Nile delta. The temporal pattern of the virus has changed since 2009 with outbreaks now occurring in the warmer months of the year. Challenges to control of endemic disease in Egypt are discussed. For the foreseeable future, unless a global collaboration exists, HPAI H5N1 virus in Egypt will continue to compromise the poultry industry, endanger public health and pose a serious pandemic threat. PMID- 21281551 TI - Lead pipe scale analysis using broad-beam argon ion milling to elucidate drinking water corrosion. AB - Herein, we characterized lead pipe scale removed from a drinking water distribution system using argon ion beam etching and a variety of solids analysis approaches. Specifically, pipe scale cross sections and solids were analyzed using scanning electron microscopy, energy dispersive X-ray analysis, X-ray diffraction, and acid digestion followed by inductively coupled plasma mass spectrometry analyses. The pipe scale consisted of at least five layers that contained Pb(II) and Pb(IV) minerals, and magnesium, aluminum, manganese, iron, and silicon solids. The outer layer was enriched with crystalline amorphous manganese and iron, giving it a dark orange to red color. The middle layers consisted of hydrocerussite and plattnerite, and the bottom layer consisted primarily of litharge. Over the litharge layer, hydrocerussite crystals were grown vertically away from the pipe wall, which included formations of plattnerite. Significant amounts of trace contaminant vanadium, likely in the form of vanadinite, and copper accumulated in the scale as well. PMID- 21281552 TI - Influence of referral bias on the clinical characteristics of patients with Gram negative bloodstream infection. AB - Referral bias can influence the results of studies performed at tertiary-care centres. In this study, we evaluated demographic and microbiological factors that influenced referral of patients with Gram-negative bloodstream infection (BSI). We identified 2919 and 846 unique patients with Gram-negative BSI in a referral cohort of patients treated at Mayo Clinic Hospitals and a population-based cohort of Olmsted County, Minnesota, residents between 1 January 1998 and 31 December 2007, respectively. Multivariable logistic regression analysis was used to determine factors associated with referral. Elderly patients aged >=80 years with Gram-negative BSI were less likely to be referred than younger patients [odds ratio (OR) 0.43, 95% confidence intervals (CI) 0.30-0.62] as were females (OR 0.63, 95% CI 0.53-0.74). After adjusting for age and gender, bloodstream isolates of Escherichia coli (OR 0.50, 95% CI 0.43-0.58) and Proteus mirabilis (OR 0.49, 95% CI 0.30-0.82) were underrepresented in the referral cohort; and Pseudomonas aeruginosa (OR 2.26, 95% CI 1.70-3.06), Enterobacter cloacae (OR 2.31, 95% CI 1.53-3.66), Serratia marcescens (OR 2.34, 95% CI 1.33-4.52) and Stenotrophomonas maltophilia (OR 17.94, 95% CI 3.98-314.43) were overrepresented in the referral cohort. We demonstrated that demographic and microbiological characteristics of patients with Gram-negative BSI had an influence on referral patterns. These factors should be considered when interpreting results of investigations performed at tertiary-care centres. PMID- 21281553 TI - The transition to dementia--individual and family experiences of receiving a diagnosis: a review. AB - BACKGROUND: Consensus recommends early recognition of memory problems through multi-disciplinary assessment in memory clinics; however, little is known about the experiences of people accessing such services. The aim of this review was to synthesis empirical evidence on patient and carer experiences in the transition to dementia. METHODS: This review updates an earlier review (Bamford et al., 2004) on the topic of disclosure of the diagnosis of dementia. Key electronic databases were searched including OVID Medline, CINAHL, Web of Science, EMBASE, and Sociological Abstracts; this was supplemented by hand searching of reference lists and contact with experts in the field. Only papers published after 2003 were included. RESULTS: Of the 35 papers included in the review, only one study observed the process of disclosure and only two papers explored the effects on the person with dementia's health. The vast majority of people with dementia wished to know their diagnosis. The key challenges for the person with dementia were coming to terms with losses on multiple levels. Although there may be short term distress, the majority of people with dementia do not appear to experience long-term negative effects on their psychological health. For family carers, becoming the main decision-maker and adjusting to increased responsibility were common concerns. CONCLUSIONS: There is still little empirical research observing the process of diagnostic disclosure in dementia. Studies exploring the views of patients and their families suggest this should be an ongoing process with the provision of support and information tailored to individual needs. The term "Alzheimer's disease" appears to have more negative connotations than the word "dementia". PMID- 21281554 TI - Electron-beam-induced growth of TiO(2) nanostructures. AB - We report the evolution of titanium dioxide nanostructures when Au nanoparticles, supported on single crystal TiO(2) substrates, were heated under ~260 Pa of flowing O(2) in an environmental transmission electron microscope. Nanostructures with different morphologies were first observed around 500 degrees C. Our measurements show that temperature, oxygen pressure, and the electron beam control the nanostructure growth. We propose a reaction-controlled growth mechanism where mobile Ti atoms generated by the electron- beam-induced reduction of TiO(2) are preferentially reoxidized at the Au-TiO(2) interface. PMID- 21281555 TI - Improving precision in the quantification of cognition using the Montreal Cognitive Assessment and the Mini-Mental State Examination. AB - BACKGROUND: The Montreal Cognitive Assessment (MoCA) can be used to quantify cognitive ability in older persons undergoing screening for cognitive impairment. Although highly sensitive in detecting mild cognitive impairment, its measurement precision is weakest among persons with milder forms of impairment. We sought to overcome this limitation by integrating information from the Mini-Mental State Examination (MMSE) into the calculation of cognitive ability. METHODS: Data from 185 geriatric outpatients screened for cognitive impairment with the MoCA and the MMSE were Rasch analyzed to evaluate the extent to which the MMSE items improved measurement precision in the upper ability ranges of the population. RESULTS: Adding information from the MMSE resulted in a 13.8% (13.3-14.3%) reduction in measurement error, with significant improvements in all quartiles of patient ability. The addition of three-word repetition and recall, copy pentagons, repeat sentence, and write sentence improved measurement of cognition in the upper levels of ability. CONCLUSIONS: The algorithm presented here maximizes the yield of available clinical data while improving measurement of cognitive ability, which is particularly important for tracking changes over time in patients with milder levels of impairment. PMID- 21281556 TI - What is the quality of life in the oldest old? AB - BACKGROUND: Maintaining and improving quality of life has become a major focus in geriatric medicine, but the oldest old have received limited attention in clinical investigations. We aimed to investigate the relationship between self perceived and caregiver-perceived quality of life (QOL), cognitive functioning, and depressive symptoms in the oldest old. METHODS: This IRB-approved prospective study recruited community dwellers aged 90-99 years old. Collected data included neurological evaluation, DSM III-R criteria for dementia, Mini-Mental State Examination (MMSE), Dementia Rating Scale (DRS), Geriatric Depression Scale (GDS), Record of Independent Living (ROIL), and QOL assessment using the Linear Analogue Self Assessment (LASA). RESULTS: Data on 144 subjects (56 cognitively normal (normal), 13 mild cognitive impairment (MCI), 41 dementia (DEM), 34 dementia with stroke and parkinsonism (DEMSP)) over a three-year period were analyzed. Mean ages ranged from 93 to 94 years, and the majority were female with at least high school education. Overall functional ability was higher in groups without dementia (p < 0.0001). All subjects reported high overall QOL (range 6.76 8.3 out of 10), regardless of cognitive functioning. However, caregivers perceived the subjects' overall QOL to be lower with increasing severity of cognitive impairment (p < 0.0001). Lower GDS scores correlate with higher self perceived overall QOL (rho = -0.38, p < 0.0001). CONCLUSIONS: In our community sample of the oldest old, there was a fairly high level of overall QOL, whether or not cognitive impairment exists. Individuals perceive their QOL better than caregivers do, and the difference in subjects' and caregivers' perception is more pronounced for the groups with dementia. QOL is more strongly correlated with depressive symptoms than with dementia severity. PMID- 21281557 TI - Acute nicotine enhances strategy-based semantic processing in Parkinson's disease. AB - Nicotinic mechanisms may play a role in the cognitive deficits of Parkinson's disease (PD). Recently, on a cognitively demanding strategy-based priming task, nicotine selectively affected controlled semantic processing in young adult non smokers as reported by Holmes et al. (International Journal of Neuropsychopharmacology 11, 389-399, 2008). Such controlled semantic processing is compromised in PD. This study investigated the effects of acute transdermal nicotine on controlled semantic processing in non-smokers with PD (n = 10) and non-smoking matched controls (n = 16) using a strategy-based semantic priming paradigm. Transdermal nicotine patches (7 mg/24 h) were administered in a double blind, placebo-controlled, crossover design. Participants were instructed to expect target words from specified semantic categories based on the primes, while unexpected targets were also presented. Priming conditions included those concurring with trained expectations (expected-related and expected-unrelated), those which did not (unexpected-related and unexpected-unrelated), and neutral baseline conditions. Controls evidenced significant expectancy effects (i.e. reaction-time differences for expected vs. unexpected conditions) under both drug states. An expectancy effect was not evident for PD under placebo due to a lack of reaction-time slowing for unexpected conditions. However, under nicotine an expectancy effect was present for PD at a level comparable to controls. Overall the findings indicate that nicotine can improve impaired controlled semantic processing in PD possibly via enhanced expectancy or inhibitory mechanisms. PMID- 21281558 TI - A functional promoter polymorphism of neuronal nitric oxide synthase moderates prefrontal functioning in schizophrenia. AB - Cognitive deficits in tasks involving the prefrontal cortex such as working memory or verbal fluency are a key component of schizophrenia. This led to the hypofrontality hypothesis of schizophrenia, which is widely accepted even though molecular underpinnings are elusive. While disturbances of glutamatergic neurotransmission might play a role, other components have rarely been investigated. Recently, the promoter region of nitric oxide (NO) synthase-I (NOS I, encoded by the gene NOS1), impacting on prefrontal glutamate transmission, has repeatedly been associated with schizophrenia. We thus tested whether an associated schizophrenia risk variant (rs41279104), leading to reduced expression of the transcript, influences prefrontal brain functioning. Forty-three patients suffering from chronic schizophrenia and 44 controls were genotyped for NOS1 rs41279104 and investigated by means of functional near-infrared spectroscopy (fNIRS), while completing a working-memory task (2-back test) and a verbal fluency test (VFT). After matching for genotype, behavioural and brain activation data of 26 patients and 28 comparable controls were correlated to rs41279104. Healthy controls showed significant activation of large parts of the lateral prefrontal cortex during both tasks, whereas task-related changes in oxygenation were significantly reduced in patients. Schizophrenia patients also performed worse in both tasks. The NOS1 schizophrenia risk genotype rs41279104 AA/AG was associated with slower reaction time in the 2-back task, as well as with reduced right-hemispheric activation of the frontal cortex for VFT in patients only. Our fNIRS data extend previous studies suggesting disturbed prefrontal functioning in schizophrenia and suggest that genetic variation of NOS1 has a role in cognitive dysfunction, probably by mediating glutamatergic tone. PMID- 21281559 TI - Integrating molecular and morphological approaches for characterizing parasite cryptic species: implications for parasitology. AB - Herein we review theoretical and methodological considerations important for finding and delimiting cryptic species of parasites (species that are difficult to recognize using traditional systematic methods). Applications of molecular data in empirical investigations of cryptic species are discussed from an historical perspective, and we evaluate advantages and disadvantages of approaches that have been used to date. Developments concerning the theory and practice of species delimitation are emphasized because theory is critical to interpretation of data. The advantages and disadvantages of different molecular methodologies, including the number and kind of loci, are discussed relative to tree-based approaches for detecting and delimiting cryptic species. We conclude by discussing some implications that cryptic species have for research programmes in parasitology, emphasizing that careful attention to the theory and operational practices involved in finding, delimiting, and describing new species (including cryptic species) is essential, not only for fully characterizing parasite biodiversity and broader aspects of comparative biology such as systematics, evolution, ecology and biogeography, but to applied research efforts that strive to improve development and understanding of epidemiology, diagnostics, control and potential eradication of parasitic diseases. PMID- 21281560 TI - Dynamic regulation of dopamine and serotonin responses to salient stimuli during chronic haloperidol treatment. AB - Antipsychotic drugs are the clinical standard for the treatment of schizophrenia. Although these drugs work initially, many compliant patients relapse due to treatment failure. The known biomarkers can not sufficiently explain antipsychotic treatment failure. We, therefore, enquired how the dynamic responses of the neurotransmitters, dopamine and serotonin, change in relation to treatment action and failure. Rats received either short-term (2-6 d) or long term (12-14 d) treatment with haloperidol, which resembled human D2 receptor occupancy, using osmotic mini-pumps. Dopamine and serotonin basal levels and responses to novelty, appetitive food, and to an aversive tail pinch were measured in the prefrontal cortex, nucleus accumbens and caudate putamen using in vivo microdialysis, and the behaviour was recorded. Subsequently, we used in-vivo voltammetry to measure dopamine overflow in the nucleus accumbens. Haloperidol decreased dopamine, but not serotonin baseline levels in a time-dependent way. Salient stimuli induced dopamine and serotonin responses. Short-term haloperidol treatment attenuated the mesolimbic dopamine responses to aversive stimulation, while the responses to appetitive stimulation were largely preserved. After long term treatment, the initial response adaptations were reversed. Similar changes were also observed at the behavioural level. In-vivo voltammetry showed that nucleus accumbens dopamine adaptations and their reversal were mediated by changes in extracellular dopamine release. Chronic haloperidol treatment, which resembles human D2 receptor occupancy, modulates dopamine and behavioural responses to aversive and appetitive stimulation depending on the duration of treatment. Specific changes in dopamine response dynamics and their reversal may be a functional substrate of antipsychotic action and failure respectively. PMID- 21281561 TI - Aquaporin-4 deficiency exacerbates brain oxidative damage and memory deficits induced by long-term ovarian hormone deprivation and D-galactose injection. AB - Astrocyte dysfunction is implicated in pathogenesis of certain neurological disorders including Alzheimer's disease (AD). A growing body of evidence indicates that water channel aquaporin-4 (AQP4) is a potential molecular target for the regulation astrocyte function. Recently, we reported that AQP4 expression was increased in the hippocampus of an AD mouse model established by long-term ovarian hormone deprivation combined with D-galactose (D-gal) exposure. However, pathophysiological roles and mechanisms of AQP4 up-regulation remain unclear. To address this issue, age-matched female wild-type and AQP4 null mice underwent ovariectomy, followed by D-gal administration for 8 wk. AQP4 null mice showed more severe brain oxidative stress, spatial learning and memory deficits, and basal forebrain cholinergic impairment than the wild-type controls. Notably, AQP4 null hippocampus contained more prominent amyloid-beta production and loss of synapse-related proteins. These results suggested that ovariectomy and D-gal injection induced oxidative damage results in compensatory increases of AQP4 expression, and deficiency of AQP4 exacerbates brain oxidative stress and memory deficits. Therefore, regulation of astrocyte function by AQP4 may attenuate oxidative damage, offering a promising therapeutic strategy for AD. PMID- 21281562 TI - Animal grazing selectivity and plant chemistry issues impact on the potential of Rhagodia preissii as an anthelmintic shrub. AB - Rhagodia preissii had shown significant in vitro anthelmintic activity in a previous study, we examined the effect of including this shrub in the diet of sheep infected with Trichostrongylus colubriformis. Worm-infected merino wethers were grazed for 7 weeks on either R. preissii or annual pasture, and faecal egg counts (FECs) were conducted weekly. Plant material was collected weekly from eaten and uneaten plants, and analysed for levels of plant secondary metabolites (tannins, oxalates, saponins) and in vitro anthelmintic activity. While mean FECs were consistently lower in sheep grazing R. preissii compared to pasture (reductions of 20-74%), the differences were not significant. There was no relationship between grazing preference (eaten or uneaten) and in vitro anthelmintic activity of plant extracts. The levels of saponins and oxalates did not correlate with grazing preference or in vitro anthelmintic activity, while tannins were not responsible for the anthelmintic activity. While the identity of the grazing deterrent and in vitro anthelmintic compounds remain unknown, the presence of plants which were both highly preferred by the sheep and showed in vitro anthelmintic activity indicates a potential to develop the species as an anthelmintic shrub through selection of shrub populations dominated by such plants. PMID- 21281563 TI - Salivary secretions from the honeybee mite, Varroa destructor: effects on insect haemocytes and preliminary biochemical characterization. AB - INTRODUCTION: The ectoparasitic honey bee mite Varroa destructor feeds on the haemolymph of the honey bee, Apis mellifera, through a single puncture wound that does not heal but remains open for several days. It was hypothesized that factors in the varroa saliva are responsible for this aberrant wound healing. METHODS: An in vitro procedure was developed for collecting salivary gland secretions from V. destructor. Mites were incubated on balls of cotton wool soaked in a tissue culture medium (TC-100), and then induced to spit by topical application of an ethanolic pilocarpine solution. RESULTS: Elution of secretions from balls of cotton wool, followed by electrophoretic analysis by SDS-PAGE and electroblotting indicated the presence of at least 15 distinct protein bands, with molecular weights ranging from 130 kDa to <17 kDa. Serial titration of V. destructor salivary secretions in TC-100 followed by an 18-h incubation with haemocytes from the caterpillar, Lacanobia oleracea, indicated that the secretions damage the haemocytes and suppresses their ability to extend pseudopods and form aggregates. CONCLUSION: We suggest that these secretions facilitate the ability of V. destructor to feed repeatedly off their bee hosts by suppressing haemocyte mediated wound healing and plugging responses in the host. PMID- 21281564 TI - Palivizumab for immunoprophylaxis of respiratory syncytial virus (RSV) bronchiolitis in high-risk infants and young children: a systematic review and additional economic modelling of subgroup analyses. AB - BACKGROUND: Respiratory syncytial virus (RSV) is a seasonal infectious disease, with epidemics occurring annually from October to March in the UK. It is a very common infection in infants and young children and can lead to hospitalisation, particularly in those who are premature or who have chronic lung disease (CLD) or congenital heart disease (CHD). Palivizumab (Synagis(r), MedImmune) is a monoclonal antibody designed to provide passive immunity against RSV and thereby prevent or reduce the severity of RSV infection. It is licensed for the prevention of serious lower respiratory tract infection caused by RSV in children at high risk. While it is recognised that a policy of using palivizumab for all children who meet the licensed indication does not meet conventional UK standards of cost-effectiveness, most clinicians feel that its use is justified in some children. OBJECTIVES: To use systematic review evidence to estimate the cost effectiveness of immunoprophylaxis of RSV using palivizumab in different subgroups of children with or without CLD or CHD who are at high risk of serious morbidity from RSV infection. DATA SOURCES: A systematic review of the literature and an economic evaluation was carried out. The bibliographic databases included the Cochrane Library [Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA)] and five other databases, from inception to 2009. Research registries of ongoing trials including Current Controlled Trials metaRegister, Clinical Trials.gov and the National Institute for Health Research Clinical Research Network Portfolio were also searched. REVIEW METHODS: Searches were conducted for prognostic and hospitalisation studies covering 1950-2009 (the original report searches conducted in 2007 covering the period 1950-2007 were rerun in August 2009 to cover the period 2007-9) and the database of all references from the original report was sifted to find any relevant studies that may have been missed. The risk factors identified from the systematic review of included studies were analysed and synthesised using stata. The base-case decision tree model developed in the original HTA journal publication [Health Technol Assess 2008;12(36)] was used to derive the cost-effectiveness of immunoprophylaxis of RSV using palivizumab in different subgroups of pre-term infants and young children who are at high risk of serious morbidity from RSV infection. Cost-effective spectra of prophylaxis with palivizumab compared with no prophylaxis for children without CLD/CHD, children with CLD, children with acyanotic CHD and children with cyanotic CHD were derived. RESULTS: Thirteen studies were included in this analysis. Analysis of 16,128 subgroups showed that prophylaxis with palivizumab may be cost-effective [at a willingness-to-pay threshold of L30,000/quality adjusted life-year (QALY)] for some subgroups. For example, for children without CLD or CHD, the cost-effective subgroups included children under 6 weeks old at the start of the RSV season who had at least two other risk factors that were considered in this report and were born at 24 weeks gestational age (GA) or less, but did not include children who were > 9 months old at the start of the RSV season or had a GA of > 32 weeks. For children with CLD, the cost-effective subgroups included children < 6 months old at the start of the RSV season who were born at 28 weeks GA or less, but did not include children who were > 21 months old at the start of the RSV season. For children with acyanotic CHD, the cost-effective subgroups included children < 6 months old at the start of the RSV season who were born at 24 weeks GA or less, but did not include children who were > 21 months old at the start of the RSV season. For children with cyanotic CHD, the cost-effective subgroups included children < 6 weeks old at the start of the RSV season who were born at 24 weeks GA or less, but did not include children who were > 12 months old at the start of the RSV season. LIMITATIONS: The poor quality of the studies feeding numerical results into this analysis means that the true cost-effectiveness may vary considerably from that estimated here. There is a risk that the relatively high mathematical precision of the point estimates of cost-effectiveness may be quite inaccurate because of poor-quality inputs. CONCLUSIONS: Prophylaxis with palivizumab does not represent good value for money based on the current UK incremental cost-effectiveness ratio threshold of L30,000/QALY when used unselectively in children without CLD/CHD or children with CLD or CHD. This subgroup analysis showed that prophylaxis with palivizumab may be cost-effective (at a willingness-to-pay threshold of L30,000/QALY) for some subgroups. In summary, the cost-effective subgroups for children who had no CLD or CHD must contain at least two other risk factors apart from GA and birth age. The cost-effective subgroups for children who had CLD or CHD do not necessarily need to have any other risk factors. Future research should be directed towards conducting much larger, better powered and better reported studies to derive better estimates of the risk factor effect sizes. FUNDING: This report was funded by the HTA programme of the National Institute for Health Research. PMID- 21281565 TI - Oligomerization state of dynamin 2 in cell membranes using TIRF and number and brightness analysis. AB - Dynamin 2 is an ubiquitously expressed ~100 kDa GTPase involved in receptor mediated endocytosis, Golgi budding, and cytoskeletal reorganization. Dynamin molecules assemble around the necks of budding vesicles and constrict membranes in a GTP-dependent process, resulting in vesicle release. The oligomerization state of dynamin 2 in the membrane is still controversial. We investigated dynamin 2 within the plasma membrane of live cells using total internal reflection microscopy coupled with number and brightness analysis. Our results demonstrate that dynamin 2 is primarily tetrameric throughout the entire cell membrane, aside from punctate structures that may correspond to regions of membrane vesiculation. PMID- 21281566 TI - A simplified mass-transfer model for visual pigments in amphibian retinal-cone outer segments. AB - When radiolabeled precursors and autoradiography are used to investigate turnover of protein components in photoreceptive cone outer segments (COSs), the labeled components--primarily visual pigment molecules (opsins)--are diffusely distributed along the COS. To further assess this COS labeling pattern, we derive a simplified mass-transfer model for quantifying the contributions of advective and diffusive mechanisms to the distribution of opsins within COSs of the frog retina. Two opsin-containing regions of the COS are evaluated: the core axial array of disks and the plasmalemma. Numerical solutions of the mass-transfer model indicate three distinct stages of system evolution. In the first stage, plasmalemma diffusion is dominant. In the second stage, the plasmalemma density reaches a metastable state and transfer between the plasmalemma and disk region occurs, which is followed by an increase in density that is qualitatively similar for both regions. The final stage consists of both regions slowly evolving to the steady-state solution. Our results indicate that autoradiographic and cognate approaches for tracking labeled opsins in the COS cannot be effective methodologies for assessing new disk formation at the base of the COS. PMID- 21281567 TI - Continuum model of collective cell migration in wound healing and colony expansion. AB - Collective cell migration plays an important role during wound healing and embryo development. Although the exact mechanisms that coordinate such migration are still unknown, experimental studies of moving cell layers have shown that the primary interactions governing the motion of the layer are the force of lamellipodia, the adhesion of cells to the substrate, and the adhesion of cells to each other. Here, we derive a two-dimensional continuum mechanical model of cell-layer migration that is based on a novel assumption of elastic deformation of the layer and incorporates basic mechanical interactions of cells as well as cell proliferation and apoptosis. The evolution equations are solved numerically using a level set method. The model successfully reproduces data from two types of experiments: 1), the contraction of an enterocyte cell layer during wound healing; and 2), the expansion of a radially symmetric colony of MDCK cells, both in the edge migration velocity and in cell-layer density. In accord with experimental observations, and in contrast to reaction-diffusion models, this model predicts a partial wound closure if lamellipod formation is inhibited at the wound edge and gives implications of the effect of spatially restricted proliferation. PMID- 21281568 TI - Elimination of thermodynamically infeasible loops in steady-state metabolic models. AB - The constraint-based reconstruction and analysis (COBRA) framework has been widely used to study steady-state flux solutions in genome-scale metabolic networks. One shortcoming of current COBRA methods is the possible violation of the loop law in the computed steady-state flux solutions. The loop law is analogous to Kirchhoff's second law for electric circuits, and states that at steady state there can be no net flux around a closed network cycle. Although the consequences of the loop law have been known for years, it has been computationally difficult to work with. Therefore, the resulting loop-law constraints have been overlooked. Here, we present a general mixed integer programming approach called loopless COBRA (ll-COBRA), which can be used to eliminate all steady-state flux solutions that are incompatible with the loop law. We apply this approach to improve flux predictions on three common COBRA methods: flux balance analysis, flux variability analysis, and Monte Carlo sampling of the flux space. Moreover, we demonstrate that the imposition of loop law constraints with ll-COBRA improves the consistency of simulation results with experimental data. This method provides an additional constraint for many COBRA methods, enabling the acquisition of more realistic simulation results. PMID- 21281569 TI - Roles of subcellular Na+ channel distributions in the mechanism of cardiac conduction. AB - The gap junction and voltage-gated Na(+) channel play an important role in the action potential propagation. The purpose of this study was to elucidate the roles of subcellular Na(+) channel distribution in action potential propagation. To achieve this, we constructed the myocardial strand model, which can calculate the current via intercellular cleft (electric-field mechanism) together with gap junctional current (gap-junctional mechanism). We conducted simulations of action potential propagation in a myofiber model where cardiomyocytes were electrically coupled with gap junctions alone or with both the gap junctions and the electric field mechanism. Then we found that the action potential propagation was greatly affected by the subcellular distribution of Na(+) channels in the presence of the electric field mechanism. The presence of Na(+) channels in the lateral membrane was important to ensure the stability of propagation under conditions of reduced gap-junctional coupling. In the poorly coupled tissue with sufficient Na(+) channels in the lateral membrane, the slowing of action potential propagation resulted from the periodic and intermittent dysfunction of the electric field mechanism. The changes in the subcellular Na(+) channel distribution might be in part responsible for the homeostatic excitation propagation in the diseased heart. PMID- 21281570 TI - Direct detection of cellular adaptation to local cyclic stretching at the single cell level by atomic force microscopy. AB - The cellular response to external mechanical forces has important effects on numerous biological phenomena. The sequences of molecular events that underlie the observed changes in cellular properties have yet to be elucidated in detail. Here we have detected the responses of a cultured cell against locally applied cyclic stretching and compressive forces, after creating an artificial focal adhesion under a glass bead attached to the cantilever of an atomic force microscope. The cell tension initially increased in response to the tensile stress and then decreased within ~1 min as a result of viscoelastic properties of the cell. This relaxation was followed by a gradual increase in tension extending over several minutes. The slow recovery of tension ceased after several cycles of force application. This tension-recovering activity was inhibited when cells were treated with cytochalasin D, an inhibitor of actin polymerization, or with (-) blebbistatin, an inhibitor of myosin II ATPase activity, suggesting that the activity was driven by actin-myosin interaction. To our knowledge, this is the first quantitative analysis of cellular mechanical properties during the process of adaptation to locally applied cyclic external force. PMID- 21281571 TI - Sensing and modulation of invadopodia across a wide range of rigidities. AB - Recent studies have suggested that extracellular matrix rigidity regulates cancer invasiveness, including the formation of cellular invadopodial protrusions; however, the relevant mechanical range is unclear. Here, we used a combined analysis of tissue-derived model basement membrane (BM) and stromal matrices and synthetic materials to understand how substrate rigidity regulates invadopodia. Urinary bladder matrix-BM (UBM-BM) was found to be a rigid material with elastic moduli of 3-8 MPa, as measured by atomic force microscopy and low-strain tensile testing. Stromal elastic moduli were ~6-fold lower, indicating a more compliant material. Using synthetic substrates that span kPa-GPa moduli, we found a peak of invadopodia-associated extracellular matrix degradation centered around 30 kPa, which also corresponded to a peak in invadopodia/cell. Surprisingly, we observed another peak in invadopodia numbers at 2 GPa as well as gene expression changes that indicate cellular sensing of very high moduli. Based on the measured elastic moduli of model stroma and BM, we expected to find more invadopodia formation on the stroma, and this was verified on the stromal versus BM side of UBM-BM. These data suggest that cells can sense a wide range of rigidities, up into the GPa range. Furthermore, there is an optimal rigidity range for invadopodia activity that may be limited by BM rigidity. PMID- 21281572 TI - Cross-correlated fluctuation analysis reveals phosphorylation-regulated paxillin FAK complexes in nascent adhesions. AB - We used correlation methods to detect and quantify interactions between paxillin and focal adhesion kinase (FAK) in migrating cells. Cross-correlation raster-scan image correlation spectroscopy revealed that wild-type paxillin and the phosphorylation-inhibiting paxillin mutant Y31F-Y118F do not interact with FAK in the cytosol but a phosphomimetic mutant of paxillin, Y31E-Y118E, does. By extending cross-correlation number and brightness analysis to the total internal reflection fluorescence modality, we were able to show that tetramers of paxillin and FAK form complexes in nascent adhesions with a 1:1 stoichiometry ratio. The phosphomimetic mutations on paxillin increase the size of the complex and the assembly rate of nascent adhesions, suggesting that the physical molecular aggregation of paxillin and FAK regulates adhesion formation. In contrast, when phosphorylation is inhibited, the interaction decreases and the adhesions tend to elongate rather than turn over. These direct in vivo data show that the phosphorylation of paxillin is specific to adhesions and leads to localized complex formation with FAK to regulate the dynamics of nascent adhesions. PMID- 21281573 TI - Systematic heterogeneity of fractional vesicle pool sizes and release rates of hippocampal synapses. AB - Hippocampal neurons in tissue culture develop functional synapses that exhibit considerable variation in synaptic vesicle content (20-350 vesicles). We examined absolute and fractional parameters of synaptic vesicle exocytosis of individual synapses. Their correlation to vesicle content was determined by activity dependent discharge of FM-styryl dyes. At high frequency stimulation (30 Hz), synapses with large recycling pools released higher amounts of dye, but showed a lower fractional release compared to synapses that contained fewer vesicles. This effect gradually vanished at lower frequencies when stimulation was triggered at 20 Hz and 10 Hz, respectively. Live-cell antibody staining with anti synaptotagmin-1-cypHer 5, and overexpression of synaptopHluorin as well as photoconversion of FM 1-43 followed by electron microscopy, consolidated the findings obtained with FM-styryl dyes. We found that the readily releasable pool grew with a power function with a coefficient of 2/3, possibly indicating a synaptic volume/surface dependency. This observation could be explained by assigning the rate-limiting factor for vesicle exocytosis at high frequency stimulation to the available active zone surface that is proportionally smaller in synapses with larger volumes. PMID- 21281574 TI - Molecular dynamics studies of ion permeation in VDAC. AB - The voltage-dependent anion channel (VDAC) in the outer membrane of mitochondria serves an essential role in the transport of metabolites and electrolytes between the cell matrix and mitochondria. To examine its structure, dynamics, and the mechanisms underlying its electrophysiological properties, we performed a total of 1.77 MUs molecular dynamics simulations of human VDAC isoform 1 in DOPE/DOPC mixed bilayers in 1 M KCl solution with transmembrane potentials of 0, +/-25, +/ 50, +/-75, and +/-100 mV. The calculated conductance and ion selectivity are in good agreement with the experimental measurements. In addition, ion density distributions inside the channel reveal possible pathways for different ion species. Based on these observations, a mechanism underlying the anion selectivity is proposed; both ion species are transported across the channel, but the rate for K(+) is smaller than that for Cl(-) because of the attractive interactions between K(+) and residues on the channel wall. This difference leads to the anion selectivity of VDAC. PMID- 21281575 TI - Brownian dynamics simulations of ion transport through the VDAC. AB - It is important to gain a physical understanding of ion transport through the voltage-dependent anion channel (VDAC) because this channel provides primary permeation pathways for metabolites and electrolytes between the cytosol and mitochondria. We performed grand canonical Monte Carlo/Brownian dynamics (GCMC/BD) simulations to explore the ion transport properties of human VDAC isoform 1 (hVDAC1; PDB:2K4T) embedded in an implicit membrane. When the MD derived, space-dependent diffusion constant was used in the GCMC/BD simulations, the current-voltage characteristics and ion number profiles inside the pore showed excellent agreement with those calculated from all-atom molecular-dynamics (MD) simulations, thereby validating the GCMC/BD approach. Of the 20 NMR models of hVDAC1 currently available, the third one (NMR03) best reproduces both experimental single-channel conductance and ion selectivity (i.e., the reversal potential). In addition, detailed analyses of the ion trajectories, one dimensional multi-ion potential of mean force, and protein charge distribution reveal that electrostatic interactions play an important role in the channel structure and ion transport relationship. Finally, the GCMC/BD simulations of various mutants based on NMR03 show good agreement with experimental ion selectivity. The difference in ion selectivity between the wild-type and the mutants is the result of altered potential of mean force profiles that are dominated by the electrostatic interactions. PMID- 21281576 TI - Dual-mode phospholipid regulation of human inward rectifying potassium channels. AB - The lipid bilayer is a critical determinant of ion channel activity; however, efforts to define the lipid dependence of channel function have generally been limited to cellular expression systems in which the membrane composition cannot be fully controlled. We reconstituted purified human Kir2.1 and Kir2.2 channels into liposomes of defined composition to study their phospholipid dependence of activity using (86)Rb(+) flux and patch-clamp assays. Our results demonstrate that Kir2.1 and Kir2.2 have two distinct lipid requirements for activity: a specific requirement for phosphatidylinositol 4,5-bisphosphate (PIP(2)) and a nonspecific requirement for anionic phospholipids. Whereas we previously showed that PIP(2) increases the channel open probability, in this work we find that activation by POPG increases both the open probability and unitary conductance. Oleoyl CoA potently inhibits Kir2.1 by antagonizing the specific requirement for PIP(2), and EPC appears to antagonize activation by the nonspecific anionic requirement. Phosphatidylinositol phosphates can act on both lipid requirements, yielding variable and even opposite effects on Kir2.1 activity depending on the lipid background. Mutagenesis experiments point to the role of intracellular residues in activation by both PIP(2) and anionic phospholipids. In conclusion, we utilized purified proteins in defined lipid membranes to quantitatively determine the phospholipid requirements for human Kir channel activity. PMID- 21281577 TI - Comparative study of the energetics of ion permeation in Kv1.2 and KcsA potassium channels. AB - Biological ion channels rely on a multi-ion transport mechanism for fast yet selective permeation of ions. The crystal structure of the KcsA potassium channel provided the first microscopic picture of this process. A similar mechanism is assumed to operate in all potassium channels, but the validity of this assumption has not been well investigated. Here, we examine the energetics of ion permeation in Shaker Kv1.2 and KcsA channels, which exemplify the six-transmembrane voltage gated and two-transmembrane inward-rectifier channels. We study the feasibility of binding a third ion to the filter and the concerted motion of ions in the channel by constructing the potential of mean force for K(+) ions in various configurations. For both channels, we find that a pair of K(+) ions can move almost freely within the filter, but a relatively large free-energy barrier hinders the K(+) ion from stepping outside the filter. We discuss the effect of the CMAP dihedral energy correction that was recently incorporated into the CHARMM force field on ion permeation dynamics. PMID- 21281578 TI - Bending and puncturing the influenza lipid envelope. AB - Lysosomes, enveloped viruses, as well as synaptic and secretory vesicles are all examples of natural nanocontainers (diameter ~ 100 nm) which specifically rely on their lipid bilayer to protect and exchange their contents with the cell. We have applied methods primarily based on atomic force microscopy and finite element modeling that allow precise investigation of the mechanical properties of the influenza virus lipid envelope. The mechanical properties of small, spherical vesicles made from PR8 influenza lipids were probed by an atomic force microscopy tip applying forces up to 0.2 nN, which led to an elastic deformation up to 20%, on average. The liposome deformation was modeled using finite element methods to extract the lipid bilayer elastic properties. We found that influenza liposomes were softer than what would be expected for a gel phase bilayer and highly deformable: Consistent with previous suggestion that influenza lipids do not undergo a major phase transition, we observe that the stiffness of influenza liposomes increases gradually and weakly (within one order of magnitude) with temperature. Surprisingly, influenza liposomes were, in most cases, able to withstand wall-to-wall deformation, and forces >1 nN were generally required to puncture the influenza envelope, which is similar to viral protein shells. Hence, the choice of a highly flexible lipid envelope may provide as efficient a protection for a viral genome as a stiff protein shell. PMID- 21281579 TI - Meconium impairs pulmonary surfactant by a combined action of cholesterol and bile acids. AB - Mechanisms for meconium-induced inactivation of pulmonary surfactant as part of the meconium aspiration syndrome in newborn infants, to our knowledge, are not clearly understood. Here we have studied the biophysical mechanisms of how meconium affects surface activity of pulmonary surfactant and whether the membrane-perturbing effects of meconium can be mimicked by exposure of surfactant to a mixture of bile acids and cholesterol. Surface activity of pulmonary surfactant complexes purified from animal lungs was analyzed in the absence and in the presence of meconium in standard surface balances and in a captive bubble surfactometer. We have also evaluated accumulation of surfactant at the air liquid interface by what we believe to be a novel microtiter plate fluorescent assay, and the effect of meconium components on surfactant membrane fluidity using Laurdan fluorescence thermotropic profiles and differential scanning calorimetry thermograms. Rapid interfacial adsorption, low surface tension upon film compression, efficient film replenishment upon expansion, and thermotropic properties of surfactant complexes are all adversely affected by meconium, and, in a similar manner, they are affected by cholesterol/taurocholate mixtures but not by taurocholate alone. We conclude that inhibition of surfactant by meconium can be mimicked by a bile salt-promoted incorporation of excess cholesterol into surfactant complexes. These results highlight the potential pathogenic role of cholesterol-mobilizing agents as a crucial factor resulting in cholesterol induced alterations of structure and dynamics of surfactant membranes and films. PMID- 21281580 TI - Orientation and dynamics of synthetic transbilayer polypeptides containing GpATM dimerization motifs. AB - Deuterium NMR spectroscopy was used to study how the positioning of a dimerization motif within a transbilayer polypeptide influences its orientation and dynamics in bilayers. Three polypeptide variants comprising glycophorin A transmembrane (GpATM) dimerization motifs incorporated into lysine-terminated poly-leucine-alanine helices were mixed into 1-palmitoyl-2-oleoyl-sn-glycero-3 phosphatidylcholine multilamellar vesicles. The variants differed in orientation of the motif segment around the helix axis with respect to the peptide ends. Polypeptides were labeled with methyl-deuterated alanines at positions that were identically situated relative to the peptide ends (Ala-20 and Ala-22) and at two positions within the motif. An analysis of quadrupole splittings revealed similar tilts and orientations of the peptide ends for all three variants, suggesting that average orientations were dominated by interactions at the bilayer surface. For one variant, however, fast orientational fluctuations about the helix axis were significantly smaller. This may indicate some perturbation of peptide dynamics and conformation by interactions that are sensitive to the motif orientation relative to the peptide ends. For the variant that displayed distinct dynamics, one orientation consistent with observed splittings corresponded to the motif being situated such that its two glycines were particularly accessible to adjacent peptides. PMID- 21281581 TI - Orthovanadate and orthophosphate inhibit muscle force via two different pathways of the myosin ATPase cycle. AB - Measurements of the half-sarcomere stiffness during activation of skinned fibers from rabbit psoas (sarcomere length 2.5 MUm, temperature 12 degrees C) indicate that addition of 0.1 mM orthovanadate (Vi) to the solution produces a drop to ~1/2 in number of force-generating myosin motors, proportional to the drop in steady isometric force (T(0)), an effect similar to that produced by the addition of 10 mM phosphate (Pi). However, in contrast to Pi, Vi does not change the rate of isometric force development. The depression of T(0) in a series of activations in presence of Vi is consistent with an apparent second-order rate constant of ~1 * 10(3) M(-1) s(-1). The rate constant of T(0) recovery in a series of activations after removal of Vi is 3.5 * 10(-2) s(-1). These results, together with the finding in the literature that the ATPase rate is reduced by Vi in proportion to isometric force, are reproduced with a kinetic model of the acto myosin cross-bridge cycle where binding of Vi to the force-generating actomyosin ADP state induces detachment from actin to form a stable myosin-ADP-Vi complex that is not able to complete the hydrolysis cycle and reenters the cycle only via reattachment to actin upon activation in Vi-free solution. PMID- 21281582 TI - Anchoring nascent RNA to the DNA template could interfere with transcription. AB - During normal transcription, the nascent RNA product is released from the DNA template. However, in some cases, the RNA remains bound or can become reattached to the template DNA duplex (for example, through R-loop formation). We have analyzed the effect on transcription elongation of nascent RNA anchoring to the template DNA duplex. Because the RNA polymerase follows a helical path along DNA duplex during transcription, the anchoring would result in wrapping the nascent RNA around the DNA in the region between the anchoring point and the translocating polymerase. This wrapping would cause an unfavorable loss of conformation entropy of the nascent RNA. It consequently would create an apparent force to unwrap the RNA by disrupting either the transcription complex or the anchoring structure. We have estimated that this force would be comparable to those required to melt nucleic acid duplexes or to arrest transcription elongation in single-molecule experiments. We predict that this force would create negative supercoiling in the DNA duplex region between the anchoring point and the transcribing RNA polymerase: this can promote the formation of unusual DNA structures and facilitate RNA invasion into the DNA duplex. Potential biological consequences of these effects are discussed. PMID- 21281583 TI - Biphasic effects of insulin on islet amyloid polypeptide membrane disruption. AB - Type II diabetes, in its late stages, is often associated with the formation of extracellular islet amyloid deposits composed of islet amyloid polypeptide (IAPP or amylin). IAPP is stored before secretion at millimolar concentrations within secretory granules inside the beta-cells. Of interest, at these same concentrations in vitro, IAPP rapidly aggregates and forms fibrils, yet within secretory granules of healthy individuals, IAPP does not fibrillize. Insulin is also stored within the secretory granules before secretion, and has been shown in vitro to inhibit IAPP fibril formation. Because of insulin's inhibitory effect on IAPP fibrillization, it has been suggested that insulin may also inhibit IAPP mediated permeabilization of the beta-cell plasma membrane in vivo. We show that although insulin is effective at preventing fiber-dependent membrane disruption, it is not effective at stopping the initial phase of membrane disruption before fibrillogenesis, and does not prevent the formation of small IAPP oligomers on the membrane. These results suggest that insulin has a more complicated role in inhibiting IAPP fibrillogenesis, and that other factors, such as the low pH of the secretory granule, may also play a role. PMID- 21281584 TI - Accounting for protein-solvent contacts facilitates design of nonaggregating lattice proteins. AB - The folding specificity of proteins can be simulated using simplified structural models and knowledge-based pair-potentials. However, when the same models are used to simulate systems that contain many proteins, large aggregates tend to form. In other words, these models cannot account for the fact that folded, globular proteins are soluble. Here we show that knowledge-based pair-potentials, which include explicitly calculated energy terms between the solvent and each amino acid, enable the simulation of proteins that are much less aggregation prone in the folded state. Our analysis clarifies why including a solvent term improves the foldability. The aggregation for potentials without water is due to the unrealistically attractive interactions between polar residues, causing artificial clustering. When a water-based potential is used instead, polar residues prefer to interact with water; this leads to designed protein surfaces rich in polar residues and well-defined hydrophobic cores, as observed in real protein structures. We developed a simple knowledge-based method to calculate interactions between the solvent and amino acids. The method provides a starting point for modeling the folding and aggregation of soluble proteins. Analysis of our simple model suggests that inclusion of these solvent terms may also improve off-lattice potentials for protein simulation, design, and structure prediction. PMID- 21281585 TI - Mechanisms of protein-ligand association and its modulation by protein mutations. AB - Protein-ligand interactions are essential for nearly all biological processes, and yet the biophysical mechanism that enables potential binding partners to associate before specific binding occurs remains poorly understood. Fundamental questions include which factors influence the formation of protein-ligand encounter complexes, and whether designated association pathways exist. To address these questions, we developed a computational approach to systematically analyze the complete ensemble of association pathways. Here, we use this approach to study the binding of a phosphate ion to the Escherichia coli phosphate-binding protein. Various mutants of the protein are considered, and their effects on binding free-energy profiles, association rates, and association pathway distributions are quantified. The results reveal the existence of two anion attractors, i.e., regions that initially attract negatively charged particles and allow them to be efficiently screened for phosphate, which is subsequently specifically bound. Point mutations that affect the charge on these attractors modulate their attraction strength and speed up association to a factor of 10 of the diffusion limit, and thus change the association pathways of the phosphate ligand. It is demonstrated that a phosphate that prebinds to such an attractor neutralizes its attraction effect to the environment, making the simultaneous association of a second phosphate ion unlikely. This study suggests ways in which structural properties can be used to tune molecular association kinetics so as to optimize the efficiency of binding, and highlights the importance of kinetic properties. PMID- 21281586 TI - Evidence from solid-state NMR for nonhelical conformations in the transmembrane domain of the amyloid precursor protein. AB - The amyloid precursor protein (APP) is subject to proteolytic processing by gamma secretase within neuronal membranes, leading to Alzheimer's disease-associated beta-amyloid peptide production by cleavage near the midpoint of the single transmembrane (TM) segment of APP. Conformational properties of the TM segment may affect its susceptibility to gamma-secretase cleavage, but these properties have not been established definitively, especially in bilayer membranes with physiologically relevant lipid compositions. In this article, we report an investigation of the APP-TM conformation, using (13)C chemical shifts obtained with two-dimensional solid-state NMR spectroscopy as site-specific conformational probes. We find that the APP-TM conformation is not a simple alpha-helix, particularly at 37 degrees C in multilamellar vesicles with compositions that mimic the composition of neuronal cell membranes. Instead, we observe a mixture of helical and nonhelical conformations at the N- and C-termini and in the vicinity of the gamma-cleavage site. Conformational plasticity of the TM segment of APP may be an important factor in the gamma-secretase cleavage mechanism. PMID- 21281587 TI - All-atom molecular dynamics simulations reveal significant differences in interaction between antimycin and conserved amino acid residues in bovine and bacterial bc1 complexes. AB - Antimycin A is the most frequently used specific and powerful inhibitor of the mitochondrial respiratory chain. We used all-atom molecular dynamics (MD) simulations to study the dynamic aspects of the interaction of antimycin A with the Q(i) site of the bacterial and bovine bc(1) complexes embedded in a membrane. The MD simulations revealed considerable conformational flexibility of antimycin and significant mobility of antimycin, as a whole, inside the Q(i) pocket. We conclude that many of the differences in antimycin binding observed in high resolution x-ray structures may have a dynamic origin and result from fluctuations of protein and antimycin between multiple conformational states of similar energy separated by low activation barriers, as well as from the mobility of antimycin within the Q(i) pocket. The MD simulations also revealed a significant difference in interaction between antimycin and conserved amino acid residues in bovine and bacterial bc(1) complexes. The strong hydrogen bond between antimycin and conserved Asp-228 (bovine numeration) was observed to be frequently broken in the bacterial bc(1) complex and only rarely in the bovine bc(1) complex. In addition, the distances between antimycin and conserved His-201 and Lys-227 were consistently larger in the bacterial bc(1) complex. The observed differences could be responsible for a weaker interaction of antimycin with the bacterial bc(1) complex. PMID- 21281588 TI - Dimeric endophilin A2 stimulates assembly and GTPase activity of dynamin 2. AB - Endophilin, which participates in membrane vesiculation during receptor-mediated endocytosis, is a ~40 kDa SH3 domain-containing protein that binds to the proline/arginine-rich domain of dynamin, a ~100 kDa GTPase that is essential for endocytic membrane scission. It has been suggested that endophilin is monomeric in the cytoplasm and dimerizes only after it binds to membranes (or perhaps to dimers or tetramers of dynamin). To clarify this issue, we studied the oligomeric state of endophilin both in vitro using analytical ultracentrifugation and fluorescence anisotropy, and in living cells using two-photon fluorescence fluctuation spectroscopy. We analyzed the fluctuation data using the Q-analysis method, which allowed us to determine the intrinsic brightness of the labeled protein complexes and hence its aggregation state in the cytoplasmic regions of the cell. Although a relatively high K(d) (~5-15 MUM) was observed in vitro, the cell measurements indicate that endophilin is dimeric in the cytoplasm, even at submicromolar concentrations. We also demonstrate that endophilin significantly enhances the assembly of dynamin, and that this enhancement is proportional to the fraction of dimeric endophilin that is present. Moreover, there is correlation between the concentrations of endophilin that promote dynamin self assembly and those that stimulate dynamin GTPase activity. These findings support the view that endophilin-dynamin interactions play an important role in endocytosis. PMID- 21281589 TI - Effects of macromolecular crowding on the inhibition of virus assembly and virus cell receptor recognition. AB - Biological fluids contain a very high total concentration of macromolecules that leads to volume exclusion by one molecule to another. Theory and experiment have shown that this condition, termed macromolecular crowding, can have significant effects on molecular recognition. However, the influence of molecular crowding on recognition events involving virus particles, and their inhibition by antiviral compounds, is virtually unexplored. Among these processes, capsid self-assembly during viral morphogenesis and capsid-cell receptor recognition during virus entry into cells are receiving increasing attention as targets for the development of new antiviral drugs. In this study, we have analyzed the effect of macromolecular crowding on the inhibition of these two processes by peptides. Macromolecular crowding led to a significant reduction in the inhibitory activity of: 1), a capsid-binding peptide and a small capsid protein domain that interfere with assembly of the human immunodeficiency virus capsid, and 2), a RGD containing peptide able to block the interaction between foot-and-mouth disease virus and receptor molecules on the host cell membrane (in this case, the effect was dependent on the conditions used). The results, discussed in the light of macromolecular crowding theory, are relevant for a quantitative understanding of molecular recognition processes during virus infection and its inhibition. PMID- 21281590 TI - High-resolution conformation and backbone dynamics of a soluble aggregate of apomyoglobin119. AB - The structure and dynamics of soluble misfolded aggregates are poorly understood, despite their importance in protein science and disease. Water-soluble self associated species that do not become insoluble over time are invaluable tools for high-resolution conformational studies aimed at dissecting the determinants of self-association. Here, we characterize the soluble model aggregate apomyoglobin(119) (apoMb(119)), generated upon truncating the residues corresponding to the C-terminal helix of sperm whale apomyoglobin. The secondary structure and backbone dynamics of apoMb(119), determined by multidimensional NMR at pH 6.0, reveal the presence of an N-terminal slow-tumbling core and a highly disordered flexible C-terminus displaying residual helicity and large-amplitude backbone motions on the picosecond-to-nanosecond timescale. The backbone of the apoMb(119) aggregate assumes progressively increased mobility as residues get further removed from the nonpolar core and closer to the more hydrophilic C terminal end. This structural motif establishes a useful paradigm for the topology of soluble misfolded protein aggregates in aqueous solution in the absence of stabilizing additives. The partially helical and flexible C-terminus of apoMb(119)'s aggregate is in interesting contrast with the amyloid-related globulomers, which display dangling ends rich in beta-strand. Finally, we investigate how a molecular chaperone, the substrate-binding domain of DnaK, interferes with apoMb(119)'s aggregation. PMID- 21281591 TI - Molecular simulations of mutually exclusive folding in a two-domain protein switch. AB - A major challenge with testing designs of protein conformational switches is the need for experimental probes that can independently monitor their individual protein domains. One way to circumvent this issue is to use a molecular simulation approach in which each domain can be directly observed. Here we report what we believe to be the first molecular simulations of mutually exclusive folding in an engineered two-domain protein switch, providing a direct view of how folding of one protein drives unfolding of the other in a barnase-ubiquitin fusion protein. These simulations successfully capture the experimental effects of interdomain linker length and ligand binding on the extent of unfolding in the less stable domain. In addition, the effect of linker length on the potential for oligomerization, which eliminates switch activity, is in qualitative agreement with analytical ultracentrifugation experiments. We also perform what we believe to be the first study of protein unfolding via progressive localized compression. Finally, we are able to explore the kinetics of mutually exclusive folding by determining the effect of linker length on rates of unfolding and refolding of each protein domain. Our results demonstrate that molecular simulations can provide seemingly novel biological insights on the behavior of individual protein domains, thereby aiding in the rational design of bifunctional switches. PMID- 21281592 TI - Dilutional control of prothrombin activation at physiologically relevant shear rates. AB - The generation of proteolyzed prothrombin species by preassembled prothrombinase in phospholipid-coated glass capillaries was studied at physiologic shear rates (100-1000 s(-1)). The concentration of active thrombin species (alpha-thrombin and meizothrombin) reaches a steady state, which varies inversely with shear rate. When corrected for shear rate, steady-state levels of active thrombin species exhibit no variation and a Michaelis-Menten analysis reveals that chemistry of this reaction is invariant between open and closed systems; collectively, these data imply that variations with shear rate arise from dilutional effects. Significantly, the major products observed include nonreactive species arising from the loss of prothrombin's phospholipid binding domain (des F1 species). A numerical model developed to investigate the spatial and temporal distribution of active thrombin species within the capillary reasonably approximates the observed output of total thrombin species at different shears; it also predicts concentrations of active thrombin species in the wall region sufficient to account for observed levels of des FI species. The predominant feedback formation of nonreactive species and high levels of the primarily anticoagulant intermediate meizothrombin (~40% of total active thrombin species) may provide a mechanism to prevent thrombus propagation downstream of a site of thrombosis or hemorrhage. PMID- 21281593 TI - Fluctuation methods to study protein aggregation in live cells: concanavalin A oligomers formation. AB - Prefibrillar oligomers of proteins are suspected to be the primary pathogenic agents in several neurodegenerative diseases. A key approach for elucidating the pathogenic mechanisms is to probe the existence of oligomers directly in living cells. In this work, we were able to monitor the process of aggregation of Concanavalin A in live cells. We used number and brightness analysis, two-color cross number and brightness analysis, and Raster image correlation spectroscopy to obtain the number of molecules, aggregation state, and diffusion coefficient as a function of time and cell location. We observed that binding of Concanavalin A to the membrane and the formation of small aggregates paralleled cell morphology changes, indicating progressive cell compaction and death. Upon protein aggregation, we observed increased membrane water penetration as reported by Laurdan generalized polarization imaging. PMID- 21281594 TI - HU protein induces incoherent DNA persistence length. AB - HU is a highly conserved protein that is believed to play an important role in the architecture and dynamic compaction of bacterial DNA. Its ability to control DNA bending is crucial for functions such as transcription and replication. The effects of HU on the DNA structure have been studied so far mainly by single molecule methods that require us to apply stretching forces on the DNA and therefore may perturb the DNA-protein interaction. To overcome this hurdle, we study the effect of HU on the DNA structure without applying external forces by using an improved tethered particle motion method. By combining the results with DNA curvature analysis from atomic force microscopy measurements we find that the DNA consists of two different curvature distributions and the measured persistence length is determined by their interplay. As a result, the effective persistence length adopts a bimodal property that depends primarily on the HU concentration. The results can be explained according to a recently suggested model that distinguishes single protein binding from cooperative protein binding. PMID- 21281595 TI - Proposed correction to Feder's anomalous diffusion FRAP equations. PMID- 21281597 TI - Cloning and biochemical characterization of Staphylococcus aureus type IA DNA topoisomerase comprised of distinct five domains. AB - DNA topoisomerases play critical roles in regulating DNA topology and are essential enzymes for cell survival. In this study, a gene encoding type IA DNA topoisomerase was cloned from Staphylococcus aureus (S. aureus) sp. strain C-66, and the biochemical properties of recombinant enzyme was characterized. The nucleotide sequence analysis showed that the cloned gene contained an open reading frame (2070 bp) that could encode a polypeptide of 689 amino acids. The cloned gene actually produced 79.1 kDa functional enzyme (named Sau-TopoI) in Escherichia coli (E. coli). Sau-TopoI enzyme purified from E. coli showed ATP independent and Mg(2+)-dependent manners for relaxing negatively supercoiled DNA. The relaxation activity of Sau-TopoI was inhibited by camptothecin, but not by nalidixic acid and etoposide. Cleavage site mapping showed that the enzyme could preferentially bind to and cleave the sequence GGNN?CAT (N and ? represent any nucleotide and cleavage site, respectively). All these results suggest that the purified enzyme is type IA DNA topoisomerase. In addition, domain mapping analysis showed that the enzyme was composed of conserved four domains (I through IV), together with a variable C-terminal region containing a unique domain V. PMID- 21281598 TI - Secretion of three enzymes for fatty acid synthesis into mouse milk in association with fat globules, and rapid decrease of the secreted enzymes by treatment with rapamycin. AB - The mammary epithelium produces numerous lipid droplets during lactation and secretes them in plasma membrane-enclosed vesicles known as milk fat globules. The biogenesis of such fat globules is considered to provide a model for clarifying the mechanisms of lipogenesis in mammals. In the present study, we identified acetyl coenzyme A carboxylase, ATP citrate lyase, and fatty acid synthase in mouse milk. Fractionation of milk showed that these three enzymes were located predominantly in milk fat globules. The three enzymes were resistant to trypsin digestion without Triton X-100, indicating that they were not located on the outer surface of the globules and thus associated with the precursors of the globules before secretion. When a low dose of rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), was injected into lactating mice, the levels of the three enzymes in milk were decreased within 3h after injection. Since the protein levels of the three enzymes in tissues were not obviously altered by this short-term treatment, known transcriptional control by mTOR signaling was unlikely to account for this decrease in their levels in milk. Our findings suggest a new, putatively mTOR-dependent localization of the three enzymes for de novo lipogenesis. PMID- 21281599 TI - The E2-25K ubiquitin-associated (UBA) domain aids in polyubiquitin chain synthesis and linkage specificity. AB - E2-25K is an ubiquitin-conjugating enzyme with the ability to synthesize Lys48 linked polyubiquitin chains. E2-25K and its homologs represent the only known E2 enzymes which contain a C-terminal ubiquitin-associated (UBA) domain as well as the conserved catalytic ubiquitin-conjugating (UBC) domain. As an additional non covalent binding surface for ubiquitin, the UBA domain must provide some functional specialization. We mapped the protein-protein interface involved in the E2-25K UBA/ubiquitin complex by solution nuclear magnetic resonance (NMR) spectroscopy and subsequently modeled the structure of the complex. Domain-domain interactions between the E2-25K catalytic UBC domain and the UBA domain do not induce significant structural changes in the UBA domain or alter the affinity of the UBA domain for ubiquitin. We determined that one of the roles of the C terminal UBA domain, in the context of E2-25K, is to increase processivity in Lys48-linked polyubiquitin chain synthesis, possibly through increased binding to the ubiquitinated substrate. Additionally, we see evidence that the UBA domain directs specificity in polyubiquitin chain linkage. PMID- 21281600 TI - Artefacts in cell culture: alpha-Ketoglutarate can scavenge hydrogen peroxide generated by ascorbate and epigallocatechin gallate in cell culture media. AB - Ascorbate and several phenolic compounds readily oxidise in cell culture media to generate hydrogen peroxide. However, addition of alpha-ketoglutarate, which is known to be released by several cell types, decreased the levels of H(2)O(2), and the alpha-ketoglutarate was depleted and converted to succinate. These observations could account for previous reports of the protective effects of alpha-ketoglutarate in promoting the growth of cells in culture, and may contribute to explaining some of the variability in the literature in reported rates of H(2)O(2) production from autoxidisable compounds in cell culture systems. PMID- 21281601 TI - GCN5 regulates the activation of PI3K/Akt survival pathway in B cells exposed to oxidative stress via controlling gene expressions of Syk and Btk. AB - Histone acetyltransferase(s) (HATs) are involved in the acetylation of core histones, which is an important event for transcription regulation through alterations in the chromatin structure in eukaryotes. General control non depressible 5 (GCN5) was first identified as a global coactivator and transcription-related HAT. Here we report that GCN5 regulates the activation of phosphatidylinositol 3-kinase (PI3K)/acutely transforming retrovirus AKT8 in rodent T cell lymphoma (Akt) survival pathway in B cells exposed to oxidative stress via controlling gene expressions of spleen tyrosine kinase (Syk) and Bruton's tyrosine kinase (Btk). The GCN5-deficiency remarkably caused apoptotic cell death by treatment with exogenous hydrogen peroxide (H(2)O(2)) in chicken DT40 cells. In GCN5-deficient DT40 cells, gene expressions of Syk and Btk, which are involved in activation of PI3K/Akt survival pathway in DT40 cells exposed to exogenous H(2)O(2), were remarkably decreased compared with those in wild type DT40 cells. In addition, phosphorylation of Akt in H(2)O(2)-treated GCN5 deficient cells was remarkably suppressed as compared to that of DT40. Chromatin immunoprecipitation assay revealed that GCN5 binds to proximal 5'-upstream regions of Syk and Btk genes in vivo. These results suggest that GCN5 takes part in transcriptional regulations of the Syk and Btk genes, and plays a key role in epigenetic regulation of PI3K/Akt survival pathway in B cells exposed to reactive oxygen species such as H(2)O(2). PMID- 21281602 TI - Activation of H-Ras and Rac1 correlates with epidermal growth factor-induced invasion in Hs578T and MDA-MB-231 breast carcinoma cells. AB - There is considerable experimental evidence that hyperactive Ras proteins promote breast cancer growth and development including invasiveness, despite the low frequency of mutated forms of Ras in breast cancer. We have previously shown that H-Ras, but not N-Ras, induces an invasive phenotype mediated by small GTPase Rac1 in MCF10A human breast epithelial cells. Epidermal growth factor (EGF) plays an important role in aberrant growth and metastasis formation of many tumor types including breast cancer. The present study aims to investigate the correlation between EGF-induced invasiveness and Ras activation in four widely used breast cancer cell lines. Upon EGF stimulation, invasive abilities and H-Ras activation were significantly increased in Hs578T and MDA-MB-231 cell lines, but not in MDA MB-453 and T47D cell lines. Using small interfering RNA (siRNA) to target H-Ras, we showed a crucial role of H-Ras in the invasive phenotype induced by EGF in Hs578T and MDA-MB-231 cells. Moreover, siRNA-knockdown of Rac1 significantly inhibited the EGF-induced invasiveness in these cells. Taken together, this study characterized human breast cancer cell lines with regard to the relationship between H-Ras activation and the invasive phenotype induced by EGF. Our data demonstrate that the activation of H-Ras and the downstream molecule Rac1 correlates with EGF-induced breast cancer cell invasion, providing important information on the regulation of malignant progression in mammary carcinoma cells. PMID- 21281603 TI - Electron microscopic evidence for the myosin head lever arm mechanism in hydrated myosin filaments using the gas environmental chamber. AB - Muscle contraction results from an attachment-detachment cycle between the myosin heads extending from myosin filaments and the sites on actin filaments. The myosin head first attaches to actin together with the products of ATP hydrolysis, performs a power stroke associated with release of hydrolysis products, and detaches from actin upon binding with new ATP. The detached myosin head then hydrolyses ATP, and performs a recovery stroke to restore its initial position. The strokes have been suggested to result from rotation of the lever arm domain around the converter domain, while the catalytic domain remains rigid. To ascertain the validity of the lever arm hypothesis in muscle, we recorded ATP induced movement at different regions within individual myosin heads in hydrated myosin filaments, using the gas environmental chamber attached to the electron microscope. The myosin head were position-marked with gold particles using three different site-directed antibodies. The amplitude of ATP-induced movement at the actin binding site in the catalytic domain was similar to that at the boundary between the catalytic and converter domains, but was definitely larger than that at the regulatory light chain in the lever arm domain. These results are consistent with the myosin head lever arm mechanism in muscle contraction if some assumptions are made. PMID- 21281604 TI - A gain-of-function screen identifies wdb and lkb1 as lifespan-extending genes in Drosophila. AB - The insulin/insulin-like growth factor (IGF) and the target of rapamycin (TOR) signaling pathways are known to regulate lifespan in diverse organisms. However, only a limited number of genes involved in these pathways have been examined regarding their effects on lifespan. Through a gain-of-function screen in Drosophila, we found that overexpression of the wdb gene encoding a regulatory subunit of PP2A, and overexpression of the lkb1 gene encoding a serine/threonine kinase, reduced organ size and extended lifespan. Overexpression of wdb also reduced the level of phosphorylated AKT, while overexpression of lkb1 increased the level of phosphorylated AMPK and decreased the level of phosphorylated S6K. Taken together, our results suggest that wdb- and lkb1-dependent lifespan extension is mediated by downregulation of S6K, a downstream component of the insulin/IGF and TOR signaling pathways. PMID- 21281605 TI - Retrograde study of projections from the tuberomammillary nucleus to the mesopontine cholinergic complex in the rat. AB - The mesopontine cholinergic complex comprising the pedunculopontine (PPTg) and laterodorsal (LDTg) tegmental nuclei is a key component of ascending reticular activating system. The brainstem cholinergic nuclei are yet under the control of descending projections from hypothalamic arousal centers such as the hypocretinergic, lateral hypothalamus (LH), and the histaminergic, tuberomammillary nucleus (TMN). The present study was designed to determine the differential projection pattern as well as the laterality of descending TMN projections to the PPTg and LDTg. Our results showed that each TMN subdivision provided differential projections to the mesopontine complex. The majority of PPTg-projecting neurons were located in ventrolateral TMN mainly at its subpial border, whereas LDTg-projecting cells were in dorsomedial TMN with a few in the medial border of the ventrolateral subdivision. For both PPTg and LDTg cases, retrogradely labeled neurons were more pronounced in each TMN subdivision ipsilateral to the injection site. The light microscopic observation also indicated that hypocretinergic, terminal-like boutons formed close appositions to somata as well as proximal dendrites of PPTg- or LDTg-projecting TMN neurons. Taken together, the present observations suggested that each TMN subdivision provide differential projections to the mesopontine cholinergic complex and that the LH, via the TMN, provides indirect, descending projections to the complex as well. PMID- 21281606 TI - A clinically relevant model of perinatal global ischemic brain damage in rats. AB - We have designed a clinically relevant model of perinatal asphyxia providing intrapartum hypoxia in rats. On gestation day 22 SD rats were anesthetized and the uterine horns were exteriorized and placed in a water bath at 37 degrees C for up to 20min. After this, pups were delivered from the uterus and manually stimulated to initiate breathing in an incubator at 37 degrees C for 1 h in air. Brains were harvested and stained with cresyl violet, caspase-3, and TUNEL to detect morphological and apoptotic changes on postnatal days (PND) 1, 3, and 7. Separate cohorts were maintained until PND 50 and tested for learning and memory using Morris water maze (WM). Survival rate was decreased with longer hypoxic time, and 100% mortality was noted when hypoxia time was beyond 18min. Apoptosis was increased with the duration of hypoxia with neuronal loss and cell shrinkage in the CA1 of hippocampus. The time taken for the juveniles to locate the hidden platform during WM was increased in animals subjected to hypoxia. These data demonstrate that perinatal ischemic injury leads to neuronal death in the hippocampus and long-lasting cognitive dysfunction. This model mimics hypoxic ischemic encephalopathy in humans and may be appropriate for investigating therapeutic interventions. PMID- 21281607 TI - Altered spontaneous synaptic inhibition in an animal model of cerebral heterotopias. AB - We have investigated spontaneous synaptic transmission in hippocampal nodular heterotopias in rats exposed to methylazoxymethanol (MAM) in utero. Pregnant Wistar rats were injected with MAM at E16. Acute hippocampal slices were prepared from the rat pups P14 to P40. Whole-cell voltage-clamp recordings were made from visually identified neurons using IR-DIC video microscopy. Synaptic events were recorded from either heterotopic neurons in the CA1 region or "slice-matched" normotopic CA1 pyramidal neurons. Both the spontaneous inhibitory (sIPSC) and excitatory synaptic transmission (sEPSC) to the same neurons were recorded. We found a profound reduction in the frequency of sIPSCs in the heterotopic neurons vs. normotopic neurons. No significant differences in the frequency of sEPSCs were found. We also found a profound reduction in the frequency of spontaneous IPSCs in normotopic neurons following application of the GABA reuptake blocker, NO-711, even in the presence of a GABA(B) receptor antagonist (CGP 55845). Preferentially blocking extrasynaptic GABA(A) receptors caused an increased frequency of sIPSCs in the heterotopic neurons. Our data suggest that there is a predominant change in inhibitory synaptic transmission, as measured by changes in sIPSCs, with no change in excitatory synaptic transmission to heterotopic neurons in hippocampus of rats exposed to MAM in utero. We suggest that this change is caused by an increase in the extracellular concentration of GABA but is not mediated via activation of presynaptic GABA(B) receptors. Rather, we propose that the increased extracellular GABA concentration in the heterotopias dampens the activity in inhibitory neurons via activation of extrasynaptic GABA(A) receptors. PMID- 21281608 TI - The role of ASIC1a in neuroprotection elicited by quercetin in focal cerebral ischemia. AB - One of the major instigators to neuronal cell death and brain damage following cerebral ischemia is calcium dysregulation. The intracellular calcium overload resulting from glutamate excitotoxicity is considered a major determinant for neuronal loss during cerebral ischemia. Moreover, ASIC1a activation due to acidosis also promotes intracellular calcium overload during ischemic insult. Interestingly, ASIC1a was found to be inhibited by some flavonoids which carry an anti-inflammatory property particularly quercetin, which could be exploited in hypoxic conditions like cerebral ischemia. This encourages us to investigate the neuroprotective effect of quercetin besides its possible downstream signaling mechanism in focal cerebral ischemia. The treatment of quercetin 30min before ischemia and 4h after reperfusion shows significant protection from ischemic injury as noticed by reduction in cerebral infarct volume and neurobehavioral deficit. In addition to earlier calcium dependent rise in the levels of nitrite and MDA exhibited marked reduction (P<0.01) in their levels when given quercetin pretreatment in ischemic brain regions. The quercetin treatment also reduced the spectrin break down products (SBDP) caused by ischemic activation of calcium dependent protease calpain. In ex-vivo study, it was also observed that quercetin inhibited the acid mediated intracellular calcium levels in rat brain synaptoneurosomes. These studies suggest the neuroprotective role of quercetin in focal cerebral ischemia by regulation of ASIC1a. PMID- 21281609 TI - Distinct mechanisms underlie the regulation of body fluid balance by neurokinin B and angiotensin II in the rat brain. AB - Although central injections of either neurokinin B (NKB) or angiotensin II (ANGII) induce a pressor response, they show different involvements in fluid intake behaviors. The aim of the present study was to elucidate the mechanisms by which these two peptides regulate body fluid balance in rats. We demonstrate that intracerebroventricular injections of NKB (1nmol) and ANGII (0.1nmol) both induce pressor responses. However, only ANGII induced significant water intake and increased sodium preference. Co-injection of NKB suppressed the ANGII-induced sodium preference but did not affect the ANGII-induced water intake. Immunohistochemistry for c-Fos, a marker of neuronal activation, revealed that both NKB and ANGII increased neuronal activation in the circumventricular organs and the hypothalamic paraventricular and supraoptic nuclei. In contrast, only ANGII significantly increased c-Fos immunoreactivity in the paraventricular thalamic nucleus, the central amygdala (CeA) and the ventrolateral bed nucleus of the stria terminalis (BSTvl). Co-injection of NKB suppressed the ANGII-induced c Fos expression in the CeA and BSTvl. These results suggest that centrally injected NKB and ANGII lead to common cardiovascular responses by neuronal pathways through the circumventricular organs and hypothalamus but that they regulate fluid intake behaviors through different pathways. It is likely that the opposing effects of these two peptides on sodium preference can be explained by their differential actions in the CeA and BSTvl, both of which are inhibited by NKB and activated by ANGII. PMID- 21281610 TI - Effects of streptozotocin-induced diabetes on tau phosphorylation in the rat brain. AB - Brain protein kinase B (Akt) and glycogen synthase kinase-3 (GSK-3) activities are adaptable to changes of peripheral blood glucose level in vivo. GSK-3 phosphorylates microtube-associated protein tau at multiple sites, which can be antagonized by protein phosphatase-2A (PP-2A). The imbalance among these enzymes might have potential connections with diabetes mellitus (DM) and Alzheimer's disease (AD). In this study hyperglycemia rat DM model was achieved by streptozotocin (STZ) treatment. The phosphorylation of tau in the rat hippocampus was detected with specific antibodies. Insulin and Li(2)CO(3) administration were also employed to find out the regulatory efforts of the kinases. We observed that rat hippocampus tau was hyperphosphorylated at Ser(396)/Ser(404) (PHF-1 sites) in STZ-induced DM model, accompanied by lowered phosphorylation levels of Akt, GSK-3 and PP-2A. Lithium, a specific GSK-3 inhibitor, nearly reversed all phosphorylation of tau at above sites in 30days. Insulin administration restored the blood glucose level in DM rats but suppressed PP-2A activity, resulting in the PHF-1 sites of tau not being dephosphorylated. These findings strongly suggest that STZ-induced hyperglycemia may cause disorder of Akt/GSK-3/PP-2A regulations in rat brain and further lead to abnormal phosphorylation of hippocampus tau. PMID- 21281611 TI - Nonphosphorylated neurofilament protein is expressed by scattered neurons in the human vestibular brainstem. AB - Vestibular information is critical for the maintenance of balance and posture and for the control of eye movements. The eighth nerve carries vestibular information to four brainstem nuclei called the vestibular nuclear complex (VNC); these nuclei relay vestibular signals to several additional brainstem nuclei. The structure, connections, effects of lesions and neuronal response properties of the vestibular brainstem have been studied in many nonhuman species. The development of bipedal locomotion in humans mandates differences in the vestibular control of balance and suggests that there may also be differences in the organization of the human vestibular brainstem. While the four nuclei of the VNC are described in human, there is a lot of variability among reports in their borders and extent. Further, there are several nuclei described in the human brainstem that are not present in other species. We have been using immunohistochemistry to study the patterns of expression of several different proteins to define and compare the organization of the vestibular brainstem in animals and humans. We here describe the expression of nonphosphorylated neurofilament protein (NPNFP) in the human vestibular brainstem. As in the cat, NPNFP is expressed by scattered cells within multiple regions of the vestibular brainstem and in cranial nerve nuclei. NPNFP expression in other cortical and subcortical regions suggests that it is expressed by projection neurons. For vestibular brainstem, these may be vestibulospinal, vestibulo-oculomotor or vestibulocerebellar neurons. Studies of other brain regions suggest that brainstem neurons expressing NPNFP may be especially vulnerable in different neurological disorders including Alzheimer's disease or to alterations in sensory input. PMID- 21281612 TI - The role of the left inferior frontal gyrus in social perception: an rTMS study. AB - Perceiving and interpreting social information richness is something that humans do automatically whenever they engage in social interactions. Numerous studies have identified neural substrates, including mirror neurons that may enable such social perception. In this study, we temporarily disrupted activity in the left inferior frontal gyrus (LIFG) using repetitive transcranial magnetic stimulation (rTMS). We investigated whether this cortical region, that is hypothesized to include mirror neurons, plays a central role in social perception. The LIFG was stimulated in the experimental condition (n=18), the vertex was targeted in the control condition (n=19). Disrupting LIFG, but not vertex, increased reaction times during an emotion recognition task, and eliminated the suppression of the 8 12Hz EEG MU rhythm, postulated as an index of mirroring activity. The results of this study provide further evidence for the role of the human mirror neuron system (MNS) in social perception, and indicate that the MNS can be measured with EEG. PMID- 21281613 TI - Diabetes induces early transient changes in the content of vesicular transporters and no major effects in neurotransmitter release in hippocampus and retina. AB - Diabetes induces changes in neurotransmitter release in central nervous system, which depend on the type of neurotransmitter and region studied. In this study, we evaluated the effect of diabetes (two and eight weeks duration) on basal and evoked release of [(14)C]glutamate and [(3)H]GABA in hippocampal and retinal synaptosomes. We also analyzed the effect of diabetes on the protein content of vesicular glutamate and GABA transporters, VGluT-1, VGluT-2 and VGAT, and on the alpha(1A) subunit of P/Q type calcium channels, which are abundant in nerve terminals. The protein content of vesicular glutamate and GABA transporters, and of the alpha(1A) subunit, was differently affected by diabetes in hippocampal and retinal synaptosomes. The changes were more pronounced in the retina than in hippocampus. VGluT-1 and VGluT-2 content was not affected in hippocampus. Moreover, changes occurred early, at two weeks of diabetes, but after eight weeks almost no changes were detected, with the exception of VGAT in the retina. Regarding neurotransmitter release, no major changes were detected. After two weeks of diabetes, neurotransmitter release was similar to controls. After eight weeks of diabetes, the basal release of glutamate slightly increased in hippocampus and the evoked GABA release decreased in retina. In conclusion, diabetes induces early transient changes in the content of glutamate and/or GABA vesicular transporters, and on calcium channels subunit, in retinal or hippocampal synaptosomes, but only minor changes in the release of glutamate or GABA. These results point to the importance of diabetes-induced changes in neural tissues at the presynaptic level, which may underlie alterations in synaptic transmission, particularly if they become permanent during the later stages of the disease. PMID- 21281614 TI - Opioid receptor agonists reduce brain edema in stroke. AB - Cerebral edema is a leading cause of mortality in stroke patients. The purpose of this study was to assess a non-selective opioid receptor agonist, biphalin, in decreasing reducing brain edema formation using both in vitro and in vivo models of stroke. For the in situ model of ischemia, hippocampal slices were exposed to oxygen glucose deprivation (OGD) conditions and we observed that hippocampal water content was increased, compared to normoxia. Treatment with the mu agonist, Tyr-D-Ala', N-CH, -Phe4, Glyol-Enkephalin (DAMGO), delta opioid agonists, D pen(2), D-phe(5) enkephalin (DPDPE), and kappa agonist, U50 488, all significantly decreased brain slice water gain. Interestingly, the non-selective agonist, biphalin, exhibited a statistically significant (P<0.01) greater effect in decreasing water content in OGD-exposed hippocampal slices, compared with mu, delta, and kappa selective opioid agonists. Moreover, biphalin exhibited anti edematous effects in a dose responsive manner. The non-selective opioid antagonist, naloxone, returned the water content nearly back to original OGD values for all opioid agonist treatments, supporting that these effects were mediated by an opioid receptor pathway. Furthermore, biphalin significantly decreased edema (53%) and infarct (48%) ratios, and neuronal recovery from stroke, compared with the vehicle-treated groups in a 12h permanent middle cerebral artery occlusion (MCAO) model of focal ischemia. Biphalin also significantly decreased the cell volume increase in primary neuronal cells exposed to OGD condition. These data suggest that opioid receptor activation may provide neuroprotection during stroke and further investigations are needed in the development of novel opioid agonist as efficacious treatments for brain ischemia. PMID- 21281615 TI - Interactions of estradiol and NSAIDS on carrageenan-induced hyperalgesia. AB - How exogenous estrogen affects inflammatory responses is poorly understood despite the large numbers of women receiving estrogen-alone hormone therapy. The aim of this study was to determine if estradiol alters injury- or inflammation induced nociceptive responses after carrageenan administration in females and whether its effects are mediated through cyclo-oxygenase (COX) and prostaglandins (PG). To this end, paw withdrawal latencies and serum levels of PGE2 and PGD2 were measured in rats treated with estradiol (0, 10, 20, and 30%) and/or SC560 (COX-1 inhibitor) or NS398 (COX-2 inhibitor) after intraplantar carrageenan administration. Estradiol significantly increased withdrawal latencies before (baseline condition) and after carrageenan administration to one hindpaw. NS398 was anti-nociceptive only in carrageenan treated animals. SC560 increased withdrawal latencies in both paws at 1 and 5hours after carrageenan administration. Co-administration of estradiol and NS398, but not SC560, was additive except for a prolonged anti-nociceptive effects of estradiol combined with NS398. The anti-nociceptive effect extended beyond that observed with either drug or estradiol alone at the 5-hour time point. Estradiol had no significant effect on PGE2 serum levels, but both COX antagonists decreased them. Although neither estradiol nor the COX inhibitors alone had an effect on PGD2 serum levels, co-administration of NS398 and estradiol significantly elevated PGD2 levels. Taken together, our results suggest that estradiol is anti-nociceptive in the thermal test and reduces carrageenan-induced hyperalgesia. These effects are minimally altered through PG-mediated mechanisms. PMID- 21281616 TI - Clozapine and SCH 23390 prevent the spatial working memory disruption induced by Delta9-THC administration into the medial prefrontal cortex. AB - Marijuana (Cannabis sativa) is one of the most widely used illicit drugs in the world. Its use is associated with impairments in cognitive function. We previously reported that Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the primary psychoactive component of marijuana, impaired spatial working memory in the radial maze task when injected intracortically (IC) into the medial prefrontal cortex (mPFC) of rats. Here, we used this paradigm to evaluate the involvement of prefrontal dopamine receptors in working memory disruption induced by Delta(9)-THC. Intracortical pre-treatment of animals with either the D(1)- or D(2)-like dopamine receptor antagonists SCH 23390 or clozapine, respectively, significantly reduced the number of errors rats made in the radial maze following treatment with Delta(9)-THC also administered intracortically. These results were obtained in the absence of locomotor impairment, as evidenced by the time spent in each arm a rat visited. Our findings suggest that prefrontal dopamine receptors are involved in Delta(9)-THC-induced disruption of spatial working memory. This interaction between the cannabinoid system and dopamine release in the PFC contributes to new directions in research and to treatments for cognitive dysfunctions associated with drug abuse and dependence. PMID- 21281617 TI - Activation of the VIP/VPAC2 system induces reactive astrocytosis associated with increased expression of glutamate transporters. AB - Vasoactive intestinal peptide (VIP) is a pleiotropic neuropeptide that acts as a neuromodulator in the CNS. Recently, secretion of several functional molecules has been identified in VIP-stimulated astrocytes in vitro. However, the relationship between VIP and its specific receptors in neurological disorders remains unknown. To investigate the role of the VIP system under pathological conditions, we performed a cold injury on the right cerebrum of adult C57BL/6 mice and observed expression patterns for VIP and its receptor, VPAC2. Immunohistochemical studies revealed VPAC2 expression in reactive astrocytes around the core lesion by post-injury day 7, which then returned to contralateral levels at post-injury day 14. By contrast, VIP immunoreactivity was detected in activated microglial cells, suggesting that microglia-astrocyte interactions in the VIP/VPAC2 system are important for the tissue repair process. In primary cultured astrocytes stimulated with N6,2'-O-dibutyryladenosine 3',5'-cyclic monophosphate sodium salt (dbcAMP) to mimic reactive astrocytosis, VPAC2 mRNA expression was highly up-regulated compared to that of the other VIP receptors, PAC1 and VPAC1. VPAC2 activation by the selective VPAC2 agonist, Ro25-1553, induced reactive morphological and biochemical changes from a polygonal shape to a stellate shape in cultured astrocytes. Further, Ro25-1553 increased cell surface expression of the glutamate transporters GLAST and GLT-1, which can limit excitotoxic neuronal cell death. In summary, the transient expression of VPAC2 in reactive astrocytes and the up-regulation of functional glutamate transporters suggest that the VIP/VPAC2 system induces reactive astrocytosis and plays a key role in neuroprotection against excitotoxicity in neurological disorders. PMID- 21281618 TI - Gender-specific response of brain corticosteroid receptors to stress and fluoxetine. AB - Gender-related differences in dexamethasone binding to corticosteroid receptors (CR) and in glucocorticoid receptor (GR) protein level in the pituitary, hypothalamus, hippocampus and prefrontal cortex were studied before and after antidepressant fluoxetine administration to both unstressed and rats exposed to a chronic social isolation stress. Untreated males, in comparison to females, displayed higher hormone-binding capacity of both GR and mineralocorticoid receptor (MR) in the hippocampal cytosol, as well as higher GR protein level in the pituitary cytosol. In both genders, dexamethasone binding to MR exceeded that to GR. While fluoxetine treatment and social isolation had no effect on GR activity, the influence on MR was gender-specific. Fluoxetine facilitated MR hormone-binding only in females, increasing the MR/GR activity ratio. In contrast, after a 6-week isolation of males, MR binding capacity was diminished and MR/GR ratio inverted in favor of GR. In addition, fluoxetine induced elevation of cytosolic GR protein level in the pituitary and hypothalamus, the latter change being gender-specific. The results point to gender-related differences in the CRs functioning and suggest that both MR and GR may contribute to well-known sexual dimorphism in vulnerability to stress and stress-related disorders and in the outcome of antidepressant treatment. PMID- 21281619 TI - Electroencephalographic characterization of seizure activity in the synapsin I/II double knockout mouse. AB - We present a detailed comparison of the behavioral and electrophysiological development of seizure activity in mice genetically depleted of synapsin I and synapsin II (SynDKO mice), based on combined video and surface EEG recordings. SynDKO mice develop handling-induced epileptic seizures at the age of 2months. The seizures show a very regular behavioral pattern, where activity is initially dominated by truncal muscle contractions followed by various myoclonic elements. Whereas seizure behavior goes through clearly defined transitions, cortical activity as reflected by EEG recordings shows a more gradual development with respect to the emergence of different EEG components and the frequency of these components. No EEG pattern was seen to define a particular seizure behavior. However, myoclonic activity was characterized by more regular patterns of combined sharp waves and spikes. Where countable, the number of myoclonic jerks was significantly correlated to the number of such EEG complexes. Furthermore, some EEG recordings revealed epileptic regular discharges without clear behavioral seizure correlates. Our findings suggest that seizure behavior in SynDKO mice is not solely determined by cortical activity but rather reflects interplay between cortical activity and activity in other brain regions. PMID- 21281620 TI - Sex-dependent and region-specific changes in TrkB signaling in BDNF heterozygous mice. AB - Altered expression of neurotrophins may contribute to the pathogenesis of schizophrenia. Several studies suggest sex steroid hormones may be involved in the regulation of brain-derived neurotrophic factor (BDNF) signaling, as well as the symptoms of schizophrenia. This study aimed to identify sex differences in BDNF-TrkB signaling in the forebrain of wild type (WT) and BDNF heterozygous (+/ ) mice. Protein expression of neurotrophins and TrkB were measured by Western blot analysis in brain regions pertinent to schizophrenia, namely the frontal cortex, striatum, and dorsal (DHP) and ventral hippocampus (VHP). In both the frontal cortex and striatum, protein expression levels of phosphorylated TrkB (pTrkB) over total TrkB (pTrkB/TrkB) was significantly increased in male, but not female BDNF(+/-) mice, suggesting sex-specific changes in TrkB signaling. pTrkB/TrkB levels were also elevated in the DHP of both male and female BDNF(+/ ), while levels remained unchanged in the VHP, indicating region-specific changes in TrkB signaling. Sex-specific phosphorylation of TrkB corresponded with downstream changes in ERK2 phosphorylation in the frontal cortex and striatum. No sex-specific effects of genotype were found in the expression of TrkB ligands, BDNF and NT-4. However, a marked, region-specific increase in NT-4 expression was found in the striatum of both male and female BDNF(+/-) mice. In conclusion, there are complex sex- and region-specific changes in BDNF-TrkB signaling in BDNF(+/-) mice. These results provide new insight into sex-dependent BDNF signaling in forebrain regions and assist in understanding the role of neurotrophins in schizophrenia. PMID- 21281621 TI - Steroid degradation and two steroid-inducible enzymes in the marine bacterium H5. AB - Natural and synthetic steroid hormones excreted into the environment are potentially threatening the population dynamics of all kinds of animals and public health. We have previously isolated a steroid degrading bacterial strain (H5) from the Baltic Sea, at Kiel, Germany. 16S-rRNA analysis showed that bacterial strain H5 belongs to the genus Vibrio, family Vibrionaceae and class Gamma-Proteobacteria. Bacterial strain H5 can degrade steroids such as testosterone and estrogens, which was shown in this study by determining the (3)H labeled steroid retaining in the bacterial H5 culture medium at incubation times of 5 h and 20 h. Since 3alpha-hydroxysteroid dehydrogenase/carbonyl reductase (3alpha-HSD/CR) is a key enzyme in adaptive steroid degradation in Comamonas testosteroni (C. testosteroni), in previous investigations, a meta-genomic system with the 3alpha-HSD/CR gene as a positive control was established. By this meta genomic system, two estradiol inducible genes coding 3-ketosteroid-delta-1 dehydrogenase and carboxylesterase, respectively, which are involved in steroid degradation, were found in marine strain H5. In the present work, the 3 ketosteroid-delta-1-dehydrogenase and carboxylesterase genes were subcloned into plasmids pET38-12 and pET24-17, respectively. Overexpression in Escherichia coli (E. coli) strain BL21(DE3)pLysS cells resulted in corresponding proteins with an N-terminal His-tag sequence. After induction with isopropyl-beta-D thiogalactoside, 3-ketosteroid-delta-1-dehydrogenase and carboxylesterase were purified in one step using nickel-chelate chromatography. After protein determination, 3-ketosteroid-delta-1-dehydrogenase (0.48 mg/ml) and carboxylesterase (1.28 mg/ml) were used to prepare antibodies to determine steroid binding specificity in future research. In summary, we have shown that the marine strain H5 could metabolize steroids; have isolated two estradiol inducible genes from strain H5 chromosomal DNA, and purified the corresponding proteins for further research. The exact characterization and systematic classification of the marine steroid degrading bacterial strain H5 is envisaged. The strain might be used for the bioremediation of steroid contaminations in seawater. PMID- 21281622 TI - A new automated urine fentanyl immunoassay: technical performance and clinical utility for monitoring fentanyl compliance. AB - BACKGROUND: Opiate and other drugs of abuse screening assays have been available for many years, and successfully utilized for monitoring patient medication compliance and for detecting misuse. However, immunoassays designed to rapidly detect the highly potent synthetic opioid, fentanyl, have not been available. METHODS: We evaluated a new fentanyl homogeneous enzyme immunoassay (HEIA) (Immunalysis Corporation) for its ability to accurately detect fentanyl in 307 urine samples from patients prescribed chronic opioid therapy. Samples were screened by HEIA and confirmed by LC-MS/MS and ELISA for diagnostic comparison. HEIA precision and interference studies were performed. RESULTS: HEIA diagnostic sensitivity, specificity and accuracy were 97%, 99%, and 99%, respectively, in comparison with LC-MS/MS and ELISA. HEIA detected 37 of the 38 LC-MS/MS positive samples identified in our initial evaluation, including some that contained very low levels of fentanyl, <1 ng/ml (<3 fmol/l). HEIA showed minimal cross reactivity with other opioid analgesics and commonly encountered drugs. Interferences by common urine contaminants were negligible, but we observed considerable signal suppression in acidic samples (pH<4.0). CONCLUSIONS: The HEIA urine fentanyl assay allows for rapid and accurate fentanyl detection, illustrating its utility in monitoring fentanyl compliance and abuse. PMID- 21281623 TI - Six1 regulates Grem1 expression in the metanephric mesenchyme to initiate branching morphogenesis. AB - Urinary tract morphogenesis requires subdivision of the ureteric bud (UB) into the intra-renal collecting system and the extra-renal ureter, by responding to signals in its surrounding mesenchyme. BMP4 is a mesenchymal regulator promoting ureter development, while GREM1 is necessary to negatively regulate BMP4 activity to induce UB branching. However, the mechanisms that regulate the GREM1-BMP4 signaling are unknown. Previous studies have shown that Six1-deficient mice lack kidneys, but form ureters. Here, we show that the tip cells of Six1(-/-) UB fail to form an ampulla for branching. Instead, the UB elongates within Tbx18- and Bmp4-expressing mesenchyme. We find that the expression of Grem1 in the metanephric mesenchyme (MM) is Six1-dependent. Treatment of Six1(-/-) kidney rudiments with GREM1 protein restores ampulla formation and branching morphogenesis. Furthermore, we demonstrate that genetic reduction of BMP4 levels in Six1(-/-) (Six1(-/-); Bmp4(+/-)) embryos restores urinary tract morphogenesis and kidney formation. This study uncovers an essential function for Six1 in the MM as an upstream regulator of Grem1 in initiating branching morphogenesis. PMID- 21281624 TI - Growth-limiting role of endothelial cells in endoderm development. AB - Endoderm development is dependent on inductive signals from different structures in close vicinity, including the notochord, lateral plate mesoderm and endothelial cells. Recently, we demonstrated that a functional vascular system is necessary for proper pancreas development, and that sphingosine-1-phosphate (S1P) exhibits the traits of a blood vessel-derived molecule involved in early pancreas morphogenesis. To examine whether S1P(1)-signaling plays a more general role in endoderm development, S1P(1)-deficient mice were analyzed. S1P(1) ablation results in compromised growth of several foregut-derived organs, including the stomach, dorsal and ventral pancreas and liver. Within the developing pancreas the reduction in organ size was due to deficient proliferation of Pdx1(+) pancreatic progenitors, whereas endocrine cell differentiation was unaffected. Ablation of endothelial cells in vitro did not mimic the S1P(1) phenotype, instead, increased organ size and hyperbranching were observed. Consistent with a negative role for endothelial cells in endoderm organ expansion, excessive vasculature was discovered in S1P(1)-deficient embryos. Altogether, our results show that endothelial cell hyperplasia negatively influences organ development in several foregut-derived organs. PMID- 21281625 TI - Genistein effects on stromal cells determines epithelial proliferation in endometrial co-cultures. AB - BACKGROUND: Estrogen is the leading etiologic factor for endometrial cancer. Estrogen-induced proliferation of endometrial epithelial cells normally requires paracrine growth factors produced by stromal cells. Epidemiologic evidence indicates that dietary soy prevents endometrial cancer, and implicates the phytoestrogen genistein in this effect. However, results from previous studies are conflicting regarding the effects of genistein on hormone responsive cancers. METHODS: The effects of estrogen and genistein on proliferation of Ishikawa (IK) endometrial adenocarcinoma cells were examined in co-cultures of IK cells with endometrial stromal cells, recapitulating the heterotypic cell-to-cell interactions observed in vivo. The roles of estrogen receptor (ER)alpha and ERbeta were evaluated using ERalpha and ERbeta specific agonists. ER activation and cell proliferation in the IK epithelial cells were determined by alkaline phosphatase assay and Coulter counter enumeration, respectively. RESULTS: Both estrogen and genistein increased estrogen receptor-induced gene activity in IK cells over a range of concentrations. Estrogen alone but not genistein increased IK proliferation in co-cultures. When primed by estrogen treatment, increasing concentrations of genistein produced a biphasic effect on IK proliferation: nM concentrations inhibited estrogen-induced proliferation while MUM concentrations increased proliferation. Studies with an ERbeta-specific agonist produced similar results. Genistein did not influence the effects of estrogen on IK proliferation in monoculture. CONCLUSIONS: Our study indicates that nutritionally relevant concentrations (nM) of genistein inhibit the proliferative effects of estrogen on endometrial adenocarcinoma cells presumably through activation of stromal cell ERbeta. We believe that sub-micromolar concentrations of genistein may represent a novel adjuvant for endometrial cancer treatment and prevention. PMID- 21281626 TI - Eps8 involvement in neuregulin1-ErbB4 mediated migration in the neuronal progenitor cell line ST14A. AB - Stable expression of the tyrosine kinase receptor ErbB4 confers increased migratory behavior to the neuronal progenitor cell line ST14A, in response to neuregulin 1 (NRG1) stimulation. We used gene expression profiling analysis to identify transcriptional changes associated with higher migratory activity caused by the activation of a specific ErbB4 isoform, and found constitutive up regulation of the epidermal growth factor receptor pathway substrate 8 (Eps8), a multimodular regulator of actin dynamics. We confirmed the increase of Eps8, both at the mRNA and at the protein level, in stable clones expressing two different ErbB4 isoforms, both characterized by high migratory activity. Using Transwell assays and experimental manipulation of Eps8 expression level, we demonstrated that Eps8 synergizes with ErbB4 to increase both basal and ligand induced cell migration, whereas siRNA mediated Eps8 silencing strongly impairs cell motility and NRG1 induced actin cytoskeleton remodeling. By transient knockdown of Eps8 through in vivo siRNA electroporation, followed by explant primary cultures, we demonstrated that Eps8 down-regulation affects migration of normal neuronal precursors. In conclusion, our data demonstrate that Eps8 is a key regulator of motility of neuronal progenitor cells expressing ErbB4, both in basal conditions and in response to external motogenic cues. PMID- 21281627 TI - Differential epithelial and stromal protein profiles in keratoconus and normal human corneas. AB - The purpose of the study was to identify epithelial and stromal proteins that exhibit up- or down-regulation in keratoconus (KC) vs. normal human corneas. Because previous proteomic studies utilized whole human corneas or epithelium alone, thereby diluted the specificity of the proteome of each tissue, we selectively analyzed the epithelium and stromal proteins. Individual preparations of epithelial and stromal proteins from KC and age-matched normal corneas were analyzed by two independent methods, i.e., a shotgun proteomic using a Nano Electrospray Ionization Liquid Chromatography Tandem Mass Spectrometry [Nano-ESI LC-MS (MS)(2)] and two-dimensional-difference gel electrophoresis (2D-DIGE) coupled with mass spectrometric methods. The label-free Nano-ESI-LC-MS (MS)(2) method identified 104 epithelial and 44 stromal proteins from both normal and KC corneas, and also quantified relative changes in levels of selected proteins, in both the tissues using spectral counts in a proteomic dataset. Relative to normal corneal epithelial proteins, six KC epithelial proteins (lamin-A/C, keratin type I cytoskeletal 14, tubulin beta chain, heat shock cognate 71 kDa protein, keratin type I cytoskeletal 16 and protein S100-A4) exhibited up-regulation and five proteins (transketolase, pyruvate kinase, 14-3-3 sigma isoform, phosphoglycerate kinase 1, and NADPH dehydrogenase (quinone) 1) showed down-regulation. A similar relative analysis showed that three KC stromal proteins (decorin, vimentin and keratocan) were up-regulated and five stromal proteins (TGF-betaig h3 (Bigh3), serotransferrin, MAM domain-containing protein 2 and isoforms 2C2A of collagen alpha-2[VI] chain) were down-regulated. The 2D-DIGE-mass spectrometry followed by Decyder software analysis showed that relative to normal corneas, the KC corneal epithelium exhibited up-regulation of four proteins (serum albumin, keratin 5, L lactate dehydrogenase and annexin A8) and down-regulation of four proteins (FTH1 [Ferritin heavy chain protein 1], calpain small subunit 1, heat shock protein beta 1 and annexin A2). A similar relative analysis of stroma by this method also showed up-regulation of aldehyde dehydrogenase 3A1 (ALDH3A1), keratin 12, apolipoprotein A-IV precursor, haptoglobin precursor, prolipoprotein and lipoprotein Gln in KC corneas. Together, the results suggested that the Nano-ESI LC-MS(MS)(2) method was superior than the 2D-DIGE method as it identified a greater number of proteins with altered levels in KC corneas. Further, the epithelial and stromal structural proteins of KC corneas exhibited altered levels compared to normal corneas, suggesting that they are affected due to structural remodeling during KC development and progression. Additionally, because several epithelial and stromal enzymes exhibited up- or down-regulation in the KC corneas relative to normal corneas, the two layers of KC corneas were under metabolic stress to adjust their remodeling. PMID- 21281628 TI - Folate deficiency increases mtDNA and D-1 mtDNA deletion in aged brain of mice lacking uracil-DNA glycosylase. AB - Strong epidemiological and experimental evidence links folate deficiency and resultant hyperhomocysteinemia with cognitive decline and neurodegeneration. Here, we tested the hypothesis that uracil misincorporation contributes to mitochondrial pathology in aged brain following folate deprivation. In a 2 * 2 design, 14-month-old mice lacking uracil DNA glycosylase (Ung-/-) versus wild type controls were subjected to a folate-deficient versus a regular diet for six weeks. Folate-deficient feeding significantly enhanced mtDNA content and overall abundance of the D-1 mtDNA deletion in brain of Ung-/-, but not of wild-type mice. Independent of folate status, the frequency of the D-1 mtDNA deletion in mtDNA was significantly increased in Ung-/- mice. The rate of mitochondrial biogenesis as assessed at six weeks of the experimental diet by mRNA expression levels of transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator (PGC)-1alpha and of mitochondrial transcription factor A (Tfam) was not affected by either Ung-/- genotype or short-term folate deficiency. Similarly, citrate synthase (CS) activity in the brain did not differ across experimental groups. By contrast, independent of genotype, lactate dehydrogenase (LDH) activity was significantly reduced in folate-deficient animals. Our results suggest that impaired uracil excision repair causes an increase in mitochondrial mutagenesis in aged brain along with a compensatory increase in mtDNA content in response to low folate status. Folate deficiency may contribute to neurodegeneration via mtDNA damage. PMID- 21281630 TI - Differentiation of mesenchymal stem cells to support peripheral nerve regeneration in a rat model. AB - Mesenchymal stem cells (MSCs) support axon regeneration across artificial nerve bridges but their differentiative capacity and ability to promote nerve regeneration remains unclear. In this study, MSCs isolated from bone marrow of Sprague-Dawley rats were characterized by plastic adherence and pluripotency towards mesodermal lineages. Isolated undifferentiated MSCs (uMSCs) were stimulated towards a Schwann cell (SC) phenotype using specific growth factors, and cell marker analysis was performed to verify SC phenotype in vitro. Differentiation resulted in temporally dependent positive immunocytochemical staining for the SC markers, glial fibrillary acidic protein (GFAP), S100, and nerve growth factor receptor (NGFR), with maximal marker expression achieved after 6days of treatment with differentiation media. Quantitative analysis demonstrated that ~50% of differentiated MSCs (dMSCs) have a SC phenotype. Using an indirect co-culture system, we compared the ability of dorsal root ganglion (DRG) cells to extend neurites in indirect contact with uMSCs and dMSCs as compared to SCs. The mean values of the longest length of the DRG neurites were the same for the dMSCs and SCs and significantly higher than the uMSC and DRG mono-culture systems (p < 0.05). In vivo, compared to an empty conduit, dMSC seeded collagen nerve conduits resulted in a greater number of sciatic motoneurons regenerating axons through the conduit into the distal nerve stump. We conclude that bone marrow-derived MSCs differentiate into a SC-phenotype that expresses SC markers transiently and sufficiently to support limited neurite outgrowth in vitro and axonal regeneration equivalent to that of SCs in vitro and in vivo. The nerve autograft remains the most effective conduit for supporting regeneration across nerve gaps. PMID- 21281629 TI - Stress, stress hormones, and adult neurogenesis. AB - The dentate gyrus of the hippocampus continues to produce new neurons throughout adulthood. Adult neurogenesis has been linked to hippocampal function, including learning and memory, anxiety regulation and feedback of the stress response. It is thus not surprising that stress, which affects hippocampal function, also alters the production and survival of new neurons. Glucocorticoids, along with other neurochemicals, have been implicated in stress-induced impairment of adult neurogenesis. Paradoxically, increases in corticosterone levels are sometimes associated with enhanced adult neurogenesis in the dentate gyrus. In these circumstances, the factors that buffer against the suppressive influence of elevated glucocorticoids remain unknown; their discovery may provide clues to reversing pathological processes arising from chronic exposure to aversive stress. PMID- 21281631 TI - Effects of sex hormones on Alzheimer's disease-associated beta-amyloid oligomer formation in vitro. AB - The folding of amyloid beta-protein (Abeta) into oligomeric, protofibrillar, and fibrillar assemblies is hypothesized to be the key pathogenic event in Alzheimer's disease (AD), with oligomeric assemblies thought to be the most neurotoxic. Inhibitors of oligomer formation, therefore, could be valuable therapeutics for patients with AD. Epidemiological studies have indicated that estrogen therapy reduces the risk of developing AD in women. Here, we examined the effects of estrogen (estrone (E1), estradiol (E2), and estriol (E3)) and related sexual steroids (androstenedione (AND) and testosterone (TES)) on the in vitro oligomer formation of Abeta(1-40) and Abeta(1-42) using a method of photo induced cross-linking of unmodified proteins (PICUP) and electron microscopic studies. Estrogens (E1, E2, and E3) inhibited low-order Abeta oligomer formation, and among them, E3 had the strongest in vitro activity. Estrogen could be a potential therapeutic agent to prevent or delay AD progression, and further understanding of the fact that these very similar molecules have different anti oligomeric effects would contribute to the development of new agents. PMID- 21281632 TI - Transgenerational inheritance of stress pathology. AB - It is becoming increasingly evident that maternal exposure to adversity during pregnancy leads to life-long effects in offspring. While there appears to be some commonality in the effects of maternal stress on endocrine and behavioral outcomes in the first generation offspring, it is clear that effects are highly dependent on species, sex and age, as well as on the time in pregnancy when stress is experienced. Recent studies have identified that the effects of maternal stress are not confined to the first generation and that they can extend over multiple generations. These effects are also evident in humans. While our understanding of the potential mechanisms by which transgenerational programming of the stress response occurs remain largely undetermined, recent studies have begun to identify potential mechanisms of transfer. These include modified maternal adaptations to pregnancy, altered maternal behavior and transgenerational epigenetic programming. Such transgenerational programming of stress responses and pathologies has important societal consequences as it could provide a biological explanation for the generational persistence of human behaviors in populations exposed to adversity. PMID- 21281634 TI - Remyelination after olfactory ensheathing cell transplantation into diverse demyelinating environments. AB - Olfactory ensheathing cells (OECs) can remyelinate demyelinated spinal cord axons when transplanted into chemically induced demyelinated lesions. Cell transplantation is typically performed within a few days after lesion induction, i.e. during active demyelination when myelin debris, cytokine level increases and macrophage/microglia activation is extensive. Inflammatory signaling has been suggested to facilitate remyelination in cell transplant studies. In this review we discuss the migration and remyelination properties of OECs transplanted into various demyelinating lesion environments including conditions when inflammation is active and when it is largely subsided. While sharing many common properties, comparisons of the in vivo fate between OECs and SCs suggest unique properties of OECs as compared to SCs. A complicating factor in the assessment of experimental remyelination by transplantation of myelin-forming cells in general is the rapidity of endogenous myelin repair in most rodent models of demyelination. Alternative persistent demyelination models are discussed as potential tools to study both the competency of chronic demyelinated axons for remyelination and the remyelination potential of cells such as human progenitors that require longer times to mobilize and remyelinate axons. This article is part of a Special Issue entitled: Understanding olfactory ensheathing glia and their prospect for nervous system repair. PMID- 21281633 TI - Gene therapy approaches to enhancing plasticity and regeneration after spinal cord injury. AB - During the past decades, new insights into mechanisms that limit plasticity and functional recovery after spinal cord injury have spurred the development of novel approaches to enhance axonal regeneration and rearrangement of spared circuitry. Gene therapy may provide one means to address mechanisms that underlie the insufficient regenerative response of injured neurons and can also be used to identify factors important for axonal growth. Several genetic approaches aimed to modulate the environment of injured axons, for example by localized expression of growth factors, to enhance axonal sprouting and regeneration and to guide regenerating axons towards their target have been described. In addition, genetic modification of injured neurons via intraparenchymal injection, or via retrograde transport of viral vectors has been used to manipulate the intrinsic growth capacity of injured neurons. In this review we will summarize some of the progress and limitations of cell transplantation and gene therapy to enhance axonal bridging and regeneration across a lesion site, and to maximize the function, collateral sprouting and connectivity of spared axonal systems. PMID- 21281635 TI - Increased expression of three-repeat isoforms of tau contributes to tau pathology in a rat model of chronic type 2 diabetes. AB - The imbalance between three-repeat (3R) and four-repeat (4R) tau isoforms produced by the alternative splicing of tau exon 10 leads to neuronal instability and eventual neurodegeneration in tauopathy. However, the role of altered 3R/4R tau ratio in Alzheimer's disease (AD) remains controversial. It has been shown that the expression of 3R tau is modulated by peptide amyloid beta (Abeta) and that 3R tau levels increase with the progression of AD. The incidence of AD increases in patients with type 2 diabetes mellitus (T2DM), and the comorbidity of these disorders is closely associated with both aging and disease duration. To investigate whether changes in 3R and 4R tau isoforms are involved in AD pathology pertaining to age-related T2DM, the expression of tau isoforms and their relationship with AD-like tau pathology were examined in a spontaneous T2DM model using aged Otsuka Long-Evans Tokushima Fatty (OLETF) rats with obesity. An AD-like pathology consisting of increased aggregates in the neuronal cytoplasm and a loss of synaptic proteins was observed in these rats. The aggregates were reactive with a 3R tau-specific, but not 4R tau-specific, antibody. In contrast to 4R tau, the level of 3R tau profoundly increased and the proteins were prone to taking toxic phosphorylated and truncated forms. Taken together, these findings suggest that increased 3R tau may contribute to AD-like tau pathology in a chronic T2DM model. Thus, the restoration of normal 3R tau expression should be considered as an important therapeutic strategy in the treatment of AD. PMID- 21281636 TI - Stress and social isolation increase vulnerability to stroke. AB - Stress is a universal experience for living organisms. Under many circumstances activation of the hypothalamic-pituitary adrenal (HPA) axis is an adaptive response to stress. However, when stress or HPA activation is prolonged or its timing immediately precedes or coincides with an ongoing neurodegenerative process, the results can be deleterious. A causal relationship among stress, HPA axis activity, and stroke outcome exists. Stress is one of many potential triggers of ischemic stroke and sustained elevations in glucocorticoids compromise neuronal survival following an ischemic attack. Indeed, glucocorticoid exposure is a critical determinant of stroke outcome; prior exposure to stress and elevated peri-ischemic glucocorticoid concentrations are associated with poor outcome among stroke patients and in rodent models of cerebral ischemia. Likely, stress and glucocorticoid exposure exacerbate stroke by sensitizing the neuroimmune response to ischemia; stroke induces an upregulation of pro inflammatory cytokines which contributes to migration of leukocytes into cerebral tissue and neuronal death. Social isolation also appears to compromise stroke outcome through priming of the neuroimmune system. Among individuals who survive the stroke, residual inflammation is apt to further compromise quality of life via its effect on cognitive function and affect. A better understanding of the mechanisms through which stress and social environment modulate neuroimmune function could lead to improved treatment of stroke and other neurodegenerative diseases. PMID- 21281637 TI - Toxoplasma gondii: a bradyzoite-specific DnaK-tetratricopeptide repeat (DnaK-TPR) protein interacts with p23 co-chaperone protein. AB - The DnaK-tetratricopeptide repeat (DnaK-TPR) gene (ToxoDB ID, TGME49_002020) is expressed predominantly at the bradyzoite stage. DnaK-TPR protein has a heat shock protein (DnaK) and tetratricopeptide repeat (TPR) domains with amino acid sequence similarity to the counterparts of other organisms (40.2-43.7% to DnaK domain and 41.1-66.0% to TPR domain). These findings allowed us to infer that DnaK-TPR protein is important in the tachyzoite-to-bradyzoite development or maintenance of cyst structure although the function of this gene is still unknown. An immunofluorescence assay (IFA) revealed that DnaK-TPR protein was expressed in Toxoplasma gondii-encysted and in vitro-induced bradyzoites and distributed in the whole part of parasite cells. We conducted yeast two-hybrid screening to identify proteins interacting with DnaK-TPR protein, and demonstrated that DnaK-TPR protein interacts with p23 co-chaperone protein (Tgp23). It was expected that DnaK-TPR protein would have a function as a molecular chaperon in bradyzoite cells associated with Tgp23. Possible mechanisms for this gene are discussed. PMID- 21281638 TI - The DYW-E-PPR protein MEF14 is required for RNA editing at site matR-1895 in mitochondria of Arabidopsis thaliana. AB - We here identify the PPR protein MEF14 of the DYW subclass as a specific trans factor required for C to U editing of site matR-1895 by genetic mapping of an EMS induced editing mutant in Arabidopsis thaliana. The wild type Col MEF14 gene complements mutant protoplasts. A T-DNA insertion in the MEF14 gene abolishes detectable editing at the matR-1895 site. Lack of RNA editing at the matR-1895 site does not alter the level of mature and precursor nad1 mRNA molecules. Such RNA editing mutants can be used to analyse the function of genes like this maturase related reading frame in plant mitochondria. PMID- 21281639 TI - Arachidonic acid stimulates formation of a novel complex containing nucleolin and RhoA. AB - Arachidonic acid (AA) stimulates cell adhesion through a p38 mitogen activated protein kinase-mediated RhoA signaling pathway. Here we report that a proteomic screen following AA-treatment identified nucleolin, a multifunctional nucleolar protein, in a complex with the GTPase, RhoA, that also included the Rho kinase, ROCK. AA-stimulated cell adhesion was inhibited by expression of nucleolin targeted shRNA and formation of the multiprotein complex was blocked by expression of dominant-negative RhoA. AA-treatment also induced ROCK-dependent serine phosphorylation of nucleolin and translocation of nucleolin from the nucleus to the cytoplasm, where it appeared to co-localize with RhoA. These data suggest the existence of a new signaling pathway through which the location and post-translational state of nucleolin are modulated. PMID- 21281640 TI - Redox control of iron regulatory protein 2 stability. AB - Iron regulatory protein 2 (IRP2) is a critical switch for cellular and systemic iron homeostasis. In iron-deficient or hypoxic cells, IRP2 binds to mRNAs containing iron responsive elements (IREs) and regulates their expression. Iron promotes proteasomal degradation of IRP2 via the F-box protein FBXL5. Here, we explored the effects of oxygen and cellular redox status on IRP2 stability. We show that iron-dependent decay of tetracycline-inducible IRP2 proceeds efficiently under mild hypoxic conditions (3% oxygen) but is compromised in severe hypoxia (0.1% oxygen). A treatment of cells with exogenous H(2)O(2) protects IRP2 against iron and increases its IRE-binding activity. IRP2 is also stabilized during menadione-induced oxidative stress. These data demonstrate that the degradation of IRP2 in iron-replete cells is not only oxygen-dependent but also sensitive to redox perturbations. PMID- 21281641 TI - Histidine 416 of the periplasmic binding protein NikA is essential for nickel uptake in Escherichia coli. AB - Escherichia coli require nickel for the synthesis of [NiFe] hydrogenases under anaerobic growth conditions. Nickel import depends on the specific ABC transporter NikABCDE encoded by the nik operon, which deletion causes the complete abolition of hydrogenase activity. We have previously postulated that the periplasmic binding protein NikA binds a natural metallophore containing three carboxylate functions that coordinate a Ni(II) ion, the fourth ligand being His416, the only direct metal-protein contact, completing a square-planar coordination for the metal. The crystal structure of the H416I mutant showed no electron density corresponding to a metal-chelator complex. In vivo experiments indicate that the mutation causes a significant decrease in nickel uptake and hydrogenase activity. These results confirm the essential role of His416 in nickel transport by NikA. PMID- 21281642 TI - Intranasal administration of testosterone increased immobile-sniffing, exploratory behavior, motor behavior and grooming behavior in rats. AB - Currently, testosterone (T) replacement therapy is typically provided by oral medication, injectable T esters, surgically implanted T pellets, transdermal patches and gels. However, most of these methods of administration are still not ideal for targeting the central nervous system. Recently, therapeutic intranasal T administration (InT) has been considered as another option for delivering T to the brain. In the present study, the effects of 21-day InT treatment were assessed on open field behavior in gonadectomized (GDX) rats and intact rats. Subcutaneous injections of T at same dose were also tested in GDX rats. A total of 12 behavioral events were examined in GDX groups with or without T and in intact groups with or without InT. Significant decreases in open field activity were observed in rats after GDX without InT compared to sham-operated rats. The open field activity scores for most tests significantly increased with InT treatment in GDX rats and in intact rats compared with the corresponding GDX rats and intact rats. Intranasal administration of T improved the reduced behaviors resulted from T deficiency better than subcutaneous injection of T, demonstrating that T can be delivered to the brain by intranasal administration. Our results suggest that intranasal T delivery is an effective option for targeting the central nervous system. PMID- 21281643 TI - Sex difference and response to testosterone in gabaergic cells of the medial preoptic nucleus and ventral bed nuclei of the stria terminalis in gerbils. AB - The medial preoptic nucleus (MPN) and ventral bed nuclei of the stria terminalis (BST) are needed to maintain mating in sexually experienced male gerbils and rats. The gerbil ventral BST is also activated with mating, as assessed by Fos expression, as is the medial MPN (MPNm) of both species. In gerbils, many of those mating-activated cells contain glutamic acid decarboxylase (GAD), the enzyme that synthesizes gamma-aminobutyric acid (GABA). Some of those cells are projection neurons, but others may release GABA locally. Through actions in the medial preoptic area, GABA inhibits and testosterone (T) promotes male sex behavior. Thus, T may promote mating, in part, by decreasing GAD in MPNm or ventral BST cells. In rats, T increases GAD mRNA in the central MPN (MPNc), where MPN GABAergic cells are densest, but mating behavior does not change in sexually experienced males when the MPNc is ablated. Therefore, this study focused on the MPNm and ventral BST to ask whether their GABAergic cells respond to T or are sexually dimorphic. This was done by visualizing cells immunoreactive (IR) for GAD(67), an isoform found primarily in cell bodies, in male and female gerbils and in castrated males with and without T. At both sites, males had more GAD(67) IR cells than females, and T decreased GAD(67)-IR cell numbers in males. Thus, the MPNm and ventral BST have GABAergic cells that are sexually dimorphic and in which T decreases GAD, consistent with local effects of T and GABA on mating. PMID- 21281644 TI - A rapid method for assessment of natural killer cell function after multiple receptor crosslinking. AB - NK cell function is regulated by the integration of signals from activating and inhibitory receptors. We developed an assay to study the effect of co crosslinking NK cell receptors in pair-wise combinations without the need to purify NK cells. Monoclonal antibodies recognising inhibitory and activating receptors were coated to flat bottomed tissue culture plates and degranulation was measured within unfractionated, freshly isolated resting or cytokine activated peripheral blood mononuclear cells by flow cytometric analysis of CD107a expression. Measured degranulation responses were NK cell specific, since no expression of CD107a was induced in gated T cells. We detected enhancement of degranulation in response to combinations of antibodies against activating NK cell receptors, including CD16, NKG2D, NKp30 and NKp46 compared to each antibody when combined with an isotype matched control antibody. Co-crosslinking of NKG2A resulted in the inhibition of degranulation measured in response to anti-NKp30 or anti-NKp46 alone in both resting or cytokine pre-activated NK cells, but had no effect on CD16 or NKG2D mediated responses. Interferon gamma production was assayed by intracellular cytokine staining and in cell culture supernatants after receptor crosslinking. No IFN-gamma could be detected from resting NK cells after receptor crosslinking whereas the pattern of IFN-gamma production in cytokine pre activated NK cells reflected that observed for degranulation. We conclude that this assay is suitable for the analysis of the impact of NK cell receptor co crosslinking on multiple NK cell functions and has the potential for application to pathologic conditions where limited numbers of cells are available for study. PMID- 21281645 TI - Active sensing in a freely walking spider: look where to go. AB - The Central American hunting spider Cupiennius salei, like most other spiders, has eight eyes, one pair of principal eyes and three pairs of secondary eyes. The principal eyes and one pair of the secondary eyes have almost completely overlapping visual fields, and presumably differ in function. The retinae of the principal eyes can be moved independently by two pairs of eye muscles each, whereas the secondary eyes do not have such eye muscles. The behavioural relevance of retinal movements of freely moving spiders was investigated by a novel dual-channel telemetric registration of the eye muscle activities. Walking spiders shifted the ipsilateral retina with respect to the walking direction before, during and after a turning movement. The change in the direction of vision in the ipsilateral anterior median eye was highly correlated with the walking direction, regardless of the actual light conditions. The contralateral retina remained in its resting position. This indicates that Cupiennius salei shifts it visual field in the walking direction not only during but sometimes previous to an intended turn, and therefore "peers" actively into the direction it wants to turn. PMID- 21281646 TI - Characterisation of a nucleopolyhedrovirus and Spiroplasma sp. bacterium associated with outbreaking populations of the Antler moth Cerapteryx graminis. AB - A broad survey was undertaken to characterise microbes associated with larval outbreaks of the Antler moth Cerapteryx graminis in Cumbria, United Kingdom. A nucleopolyhedrovirus present in all sampled populations at <=5% prevalence, was characterised via restriction fragment length polymorphism and partial sequencing the Polyhedrin, Lef-8 and Lef-9 genes; indicating a previously uncharacterised species most closely related to Agrotis ipsilon NPV. A survey of the host associated bacterial community detected a species phylogenetically related to Spiroplasma sp., a male-killing phenotype previously isolated from Lepidoptera and Coleoptera, present at <63% prevalence in larvae. The implications of these associated microbes for host population dynamics are discussed. PMID- 21281647 TI - Structural asymmetry in a trimeric Na+/betaine symporter, BetP, from Corynebacterium glutamicum. AB - The Na(+)-coupled symporter BetP catalyzes the uptake of the compatible solute betaine in the soil bacterium Corynebacterium glutamicum. BetP also senses hyperosmotic stress and regulates its own activity in response to stress level. We determined a three-dimensional (3D) map (at 8 A in-plane resolution) of a constitutively active mutant of BetP in a C. glutamicum membrane environment by electron cryomicroscopy of two-dimensional crystals. The map shows that the constitutively active mutant, which lacks the C-terminal domain involved in osmosensing, is trimeric like wild-type BetP. Recently, we reported the X-ray crystal structure of BetP at 3.35 A, in which all three protomers displayed a substrate-occluded state. Rigid-body fitting of this trimeric structure to the 3D map identified the periplasmic and cytoplasmic sides of the membrane. Fitting of an X-ray monomer to the individual protomer maps allowed assignment of transmembrane helices and of the substrate pathway, and revealed differences in trimer architecture from the X-ray structure in the tilt angle of each protomer with respect to the membrane. The three protomer maps showed pronounced differences around the substrate pathway, suggesting three different conformations within the same trimer. Two of those protomer maps closely match those of the atomic structures of the outward-facing and inward-facing states of the hydantoin transporter Mhp1, suggesting that the BetP protomer conformations reflect key states of the transport cycle. Thus, the asymmetry in the two dimensional maps may reflect cooperativity of conformational changes within the BetP trimer, which potentially increases the rate of glycine betaine uptake. PMID- 21281648 TI - Joint evolution of specialization and dispersal in structured metapopulations. AB - We study the joint evolution of dispersal and specialization concerning resource usage in a mechanistically underpinned structured discrete-time metapopulation model. We show that dispersal significantly affects the evolution of specialization and that specialization is a key factor that determines the possibility of evolutionary branching in dispersal propensity. Allowing both dispersal propensity and specialization to evolve as a consequence of natural selection is necessary in order to understand the evolutionary dynamics. The joint evolution of dispersal and specialization forms a natural evolutionary path leading to the coexistence of generalists and specialists. We show that in this process, the number of different patch types and the resource distribution are essential. PMID- 21281649 TI - Track structures, DNA targets and radiation effects in the biophysical Monte Carlo simulation code PARTRAC. AB - This review describes the PARTRAC suite of comprehensive Monte Carlo simulation tools for calculations of track structures of a variety of ionizing radiation qualities and their biological effects. A multi-scale target model characterizes essential structures of the whole genomic DNA within human fibroblasts and lymphocytes in atomic resolution. Calculation methods and essential results are recapitulated regarding the physical, physico-chemical and chemical stage of track structure development of radiation damage induction. Recent model extension towards DNA repair processes extends the time dimension by about 12 orders of magnitude and paves the way for superior predictions of radiation risks. PMID- 21281650 TI - Factors affecting the frequency of micronuclei in asthmatic and healthy children from Ostrava. AB - A higher incidence of asthma is one of the serious problems confronting urban populations worldwide. The aim of the present study was to analyze the effect of age, gender, smoking, vitamin intake, genetic polymorphisms in genes related to the metabolic activation of polycyclic aromatic hydrocarbons (PAHs) and their detoxification and oxidative damage to DNA, lipids and proteins on the frequency of micronuclei (MN) in a group of 175 children (81 with bronchial asthma and 94 healthy controls) aged 6-15 years. The study group from the most polluted region of the Czech Republic, Ostrava, was followed in November 2008, when the mean concentration of benzo[a]pyrene (B[a]P) measured by stationary monitoring was 11.4+/-9.8ng/m(3). The results of cotinine analysis revealed active smoking in 15 children. The frequency of MN per 1000 binucleated cells (MN/1000 BNC), measured by automated image analysis, indicated a significant risk for smoking children with asthma in comparison with smoking control children (4.25+/-1.54 and 3.00+/ 0.77, respectively, p<0.05). Girls in the control group had 16% higher levels of MN in comparison with boys. Markers of oxidative damage to DNA, proteins and lipids were not associated with asthma in this study. Higher levels of MN were associated with increased levels of protein carbonyl groups. We conclude that smoking asthmatic children are at higher risk of DNA damage measured as the frequency of micronuclei in peripheral blood lymphocytes. PMID- 21281651 TI - Control of hippocampal theta rhythm by serotonin: role of 5-HT2c receptors. AB - The hippocampus plays an important role in learning and memory and has been implicated in a number of diseases, including epilepsy, anxiety and schizophrenia. A prominent feature of the hippocampal network is the capability to generate rhythmic oscillations. Serotonergic modulation is known to play an important role in the regulation of theta rhythm. 5-HT2c receptors represent a specific target of psychopharmacology and, in particular, the behavioral effects of the 5-HT2c receptor agonist mCPP have been thoroughly tested. The present study used this compound and the selective 5-HT2c receptor antagonist SB-242084 to elucidate the role of 5-HT2c receptors in the generation of hippocampal oscillations. Hippocampal EEG was recorded and the power in the theta frequency range was monitored in different behaviors in freely-moving rats and after brainstem stimulation in anesthetized animals. We found that in freely-moving rats, mCPP suppressed hippocampal theta rhythm and the effect was stronger during REM sleep than during waking theta states. Under urethane anesthesia, mCPP decreased the power for both spontaneous and elicited theta rhythm in a dose dependent manner and the 5-HT2c antagonist reversed this effect. The results of this study demonstrate that 5-HT2c receptors are important element of the serotonergic modulation of hippocampal theta oscillations and thus pharmacological interactions with these receptors can modulate physiological and pathological processes associated with limbic theta activity. PMID- 21281652 TI - Subchronic memantine administration on spatial learning, exploratory activity, and nest-building in an APP/PS1 mouse model of Alzheimer's disease. AB - Glutamate neurotoxicity has been proposed to be involved in Alzheimer pathogenesis, with clinical data supporting successful treatment with the NMDA receptor antagonist memantine. In the present study, the effects of subchronic memantine administration were assessed on spatial and non-spatial learning as well as exploratory activity and nest-building in APP/PS1 mutant mice. Memantine (10 mg/kg, i.p.) was better than placebo during the reversal phase of left-right discrimination, though equivalent to saline for Morris water maze and passive avoidance learning. The drug had no effect on non-learned behaviors in elevated plus-maze exploration and nest-building. These results support a specific action of the NMDA receptor antagonist on behavioral flexibility in mutant mice with amyloid pathology. PMID- 21281653 TI - Transcranial magnetic stimulation of medial prefrontal cortex modulates face expressions processing in a priming task. AB - The medial prefrontal cortex (mPFC) and the right somatosensory cortex (rSC) are known to be involved in emotion processing and face expression recognition, although the possibility of segregated circuits for specific emotions in these regions remains unclear. To investigate this issue, we used transcranial magnetic stimulation (TMS) together with a priming paradigm to modulate the activation state of the mPFC and the rSC during emotional expressions discrimination. This novel paradigm allows analyzing how TMS interacts with the ongoing activity of different neuronal populations following prime processing. Participants were asked to discriminate between angry and happy faces that were preceded by a congruent prime (a word expressing the same emotion), an incongruent prime (a word expressing the opposite emotion) or a neutral prime. In TMS trials, a single pulse was delivered over the mPFC, rSC or Vertex (control site) between prime and target presentation. TMS applied over the mPFC significantly affected the priming effect, by selectively increasing response latencies in congruent trials. This indicates that the mPFC contains different neural representations for angry and happy expressions. TMS over rSC did not significantly affect the priming effect, suggesting that rSC is not involved in processing verbal emotional stimuli. PMID- 21281654 TI - ERP evidence of a meaningfulness impact on visual global/local processing: when meaning captures attention. AB - Event-related potentials (ERPs) were recorded to investigate whether the meaningfulness of experimental stimuli impacted performances during global/local visual tasks. Participants were presented with compound stimuli, based on either meaningful letters, meaningful objects, or meaningless non-objects. The ERP recordings displayed typical early components, P1 and N1, evoked by task-related processes that affected global and local processes differently according to the meaningfulness of the stimuli. The effect of meaningfulness of the stimuli during global processing showed that P1 amplitudes were larger in response to objects and non-objects compared to letters, while letters and objects elicited larger N1 amplitudes than non-objects. Second, during local processing, the mean amplitudes of the ERPs recorded for object and letter stimuli were systematically smaller than the amplitudes recorded for non-object stimuli for both P1 and N1 components. In addition, object and letter stimuli elicited comparable mean ERP responses during local processing. These results are discussed in terms of the influences of both attentional and top-down identification processes. Taken together, these findings suggested that looking for meaning is crucial in the perception of visual scenes and that the meaningfulness nature of the stimuli should be taken into account in future studies. PMID- 21281655 TI - Identification of low and high frequency ranges for heart rate variability and blood pressure variability analyses using pharmacological autonomic blockade with atropine and propranolol in swine. AB - Understanding autonomic nervous system functioning, which mediates behavioral and physiological responses to stress, offers great potential for assessing farm animal stress and welfare. Evaluation of heart rate variability (HRV) and blood pressure variability (BPV), using time and frequency domain analyses may provide a sensitive and reliable measure of affective states and stress-mediated changes in sympathetic and parasympathetic tones. The aim of this research was to define low (LF) and high frequency (HF) power spectral ranges using pharmacological autonomic blockade, and to examine HRV and BPV parameter changes in response to atropine and propranolol in swine. Ten, 13-week old, barrows (n=6) and gilts (n=4) underwent surgery to place an intra-cardiac electrode and a blood pressure catheter attached to a biotelemetric transmitter; pigs had a 3-week recovery period prior to data collection. Each pig was subjected to administration of 4 intravenous (i.v.) drug treatments: a control treatment, 3 mL of saline, and 3 blockade treatments; 0.1 mg/kg of atropine, 1.0 mg/kg of propranolol, and .1 mg/kg of atropine together with 1.0 mg/kg of propranolol. All treatments were delivered by injection in the jugular vein with a minimum of 48 h between individual treatments. Behavior, ECG and blood pressure data were recorded continuously for a total of 1h, from 30 min pre-injection to 30 min post injection. For data analyses, two 512-beat intervals were selected for each treatment while the pig was lying and inactive. The first interval was selected from the pre-injection period (baseline), and the second was selected between 10 and 30 min post-injection. Time and frequency domain (power spectral density) analyses were performed on each data interval. Subsequent, LF and HF bands from the power spectral densities were defined based on general linear and regression analyses. The HRV and BPV were computed with a covariate (baseline) factorial analysis of treatment by sex interaction, and day of injection, with mixed models and Tukey's post-hoc tests. The best-fit range for LF was 0.0-0.09 Hz, and HF was 0.09-2.0 Hz (r2: 0.41 and 0.43, respectively). Propranolol and saline injections led to a greater overall total power and overall higher inter-beat interval, HF and LF power. Atropine led to a dominant sympathovagal balance of the cardiac activity in pigs. In addition, atropine led to an increase in LF power of both systolic and diastolic blood pressures in gilts suggesting vagal tone mediation of BPV. The understanding of autonomic regulation of HRV and BPV in domestic swine facilitates our ability to detect and quantify stress responses, and broadens its application in assessing farm animal welfare. PMID- 21281656 TI - The effect of narrowband 500 nm light on daytime sleep in humans. AB - Naps frequently take place during the daytime under some ambient light. People are commonly advised to wear eyeshades, or use black-out curtains while sleeping, as light is thought to inhibit sleep. Little is known, however, about how light during daytime sleep may affect the quality or architecture of that sleep. The present within-subjects design administered green narrowband light via light masks to 17 young adults (23.2 +/- 4.7 years) during four 90-minute afternoon naps. Subjects were exposed to each of four light conditions that approximate the intensity of 1) physiological darkness (~0 lx), 2) moonlight (~1 lx), 3) typical indoor lighting (~80 lx) and 4) indirect outdoor light (~6400 lx). All subjects were able to sleep in all lighting conditions, with no differences in sleep quality or architecture. Power analysis revealed sufficient power to detect meaningful differences. Sleep inertia measured upon waking showed a general effect of the nap, independent of condition. Although light has various alerting effects at night, 500 nm LED light presented via light mask does not appear to inhibit daytime sleep. The finding that this light had no effect on the ability of individuals to fall asleep or stay asleep during an afternoon nap may inform decisions regarding the use of the nap as a facilitator of schedule adjustment, and challenges the assumption of light as a barrier to napping. PMID- 21281657 TI - Oxysterol binding proteins (OSBPs) and their encoding genes in Arabidopsis and rice. AB - Cell wall deposition, biosynthesis of steroid hormones, and maintenance of membrane composition and integrity, are some of the crucial functions of sterols in plants. Followed by their synthesis in the endoplasmic reticulum, the sterols accumulate in the plasma membrane. The concept of sterol trafficking in plant cell is not well understood. The oxysterol binding proteins are implicated in sterol transport in non-plant systems. In the study, the oxysterol binding proteins in Arabidopsis and rice are described and classified. The Arabidopsis genome encodes 12 oxysterol binding proteins-related proteins (ORPs) as compared to 6 oxysterol binding proteins (OSBPs/ORPs) in rice. The protein alignment studies reveal that amino acid sequences for oxysterol binding proteins are relatively well conserved in Arabidopsis and rice. The rice OSBPs are classified based on their phylogenetic relationship with Arabidopsis ORPs. The sequence LOGO built on LOC_Os03g16690 indicated presence of fingerprint region of amino acids "EQVSHHPP" for Arabidopsis and rice OSBPs/ORPs. The organization of pleckstrin homology domain is identified in several OSBPs/ORPs in Arabidopsis and rice. The Arabidopsis oligonucleotide array data is explored to understand the expression patterns of ORPs under 17 different experimental conditions. The analysis showed the expression of ORPs in Arabidopsis is necessarily under the control of biotic stress, chemical, elicitor, hormone, light intensity, abiotic stress, and temperature conditions. The linear mean signal values for Arabidopsis ORPs revealed their relative expression patterns in different developmental stages. The genes for ORP3C and ORP3B are highly expressed in all developmental stages that were analyzed. The present study thus indicates crucial functional role of the individual members of this gene family in different environmental stress conditions. PMID- 21281658 TI - Probabilistic functional gene societies. AB - A cellular system may be viewed as a social network of genes. Genes work together to conduct physiological processes in the cells. Thus if we have a view of the functional association among genes, we may also be able to unravel the association between genotypes and phenotypes; the emergent properties of interactive activities of genes. We could have various points of view for a gene network. Perhaps the most common standpoints are protein-protein interaction networks (PPIN) and transcriptional regulatory networks (TRN). Here I introduce another type of view for the gene network; the probabilistic functional gene network (PFGN). A 'functional view' of association between genes enables us to have a holistic model of the gene society. A 'probabilistic view' makes the model of gene associations derived from noisy high-throughput data more robust. In addition, the dynamics of gene association may be presented in a single static network model by the probabilistic view. By combining the two modeling views, the probabilistic functional gene networks have been constructed for various organisms and proved to be highly useful in generating novel biological hypotheses not only for simple unicellular microbes, but also for highly complex multicellular animals and plants. PMID- 21281659 TI - A comparison of two cell regulatory models entailing high dimensional attractors representing phenotype. AB - Two models for mammalian cell regulation that invoke the concept of cellular phenotype represented by high dimensional dynamic attractor states are compared. In one model the attractors are derived from an experimentally determined genetic regulatory network (GRN) for the cell type. As the state space architecture within which the attractors are embedded is determined by the binding sites on proteins and the recognition sites on DNA the attractors can be described as "hard-wired" in the genome through the genomic DNA sequence. In the second model attractors arising from the interactions between active gene products (mainly proteins) and independent of the genomic sequence, are descended from a pre cellular state from which life originated. As this model is based on the cell as an open system the attractor acts as the interface between the cell and its environment. Environmental sources of stress can serve to trigger attractor and therefore phenotypic, transitions without entailing genotypic sequence changes. It is asserted that the evidence from cell and molecular biological research and logic, favours the second model. If correct there are important implications for understanding how environmental factors impact on evolution and may be implicated in hereditary and somatic disease. PMID- 21281660 TI - Gluteal adipose-tissue polyunsaturated fatty-acids profiles and depressive symptoms in obese adults with obstructive sleep apnea hypopnea syndrome: a cross sectional study. AB - Biomarkers of Polyunsaturated Fatty Acids (PUFAs) have been related to depressive symptoms in healthy adults. It is also known that depression is high prevalent in Obstructive Sleep Apnea Hypopnea Syndrome (OSAHS) and obesity. The aim of our study was to examine a possible association between PUFAs of the n-6 and n-3 families and depressive symptoms in obese OSAHS patients. Sixty three patients with OSAHS based on overnight attended polysomnography were included. Gluteal adipose tissue biopsies were performed in all participants. Fatty acids were analyzed by gas chromatography. Depressive symptoms were assessed by the Zung Self-rating Depression Scale. The majority of participants had grade II obesity (BMI: 36.2+/-4.3 kg/m(2)) and moderate to severe OSAHS. Mild depressive symptoms were found to affect 27.8% of the studied patients. No link between symptoms of depression and individual n-6 and/or n-3 PUFAs of gluteal adipose tissue was detected. However, multiple linear regression analysis showed a positive correlation between depressive symptoms and 20:3n-6/18:3n-6 ratio, and a negative association with age and n-6/n-3 ratio. The possible influence of OSAHS and obesity in depression development and the quiescent nature of gluteal adipose tissue may account for the absence of any significant relations between n-6 and/or n-3 PUFAs and depressive symptoms in our sample. The positive relationship between symptoms of depression and the particular fatty acid ratio probably indicates an increase in prostaglandins family although this needs further research. PMID- 21281661 TI - Tamoxifen effects on respiratory chain complexes and creatine kinase activities in an animal model of mania. AB - The present study aimed to investigate the effects of tamoxifen (TMX) on locomotor behavior and on the activities of mitochondrial respiratory chain complexes and creatine kinase (CK) in the brain of rats subjected to an animal model of mania induced by d-amphetamine (D-AMPH)-reversion and prevention protocols. The D-AMPH administration increased locomotor activity in saline treated rats under prevention and reversion treatment; furthermore, there was evident reduction in the locomotion in the D-amphetamine group treated with TMX. D-AMPH significantly decreased the activity of mitochondrial respiratory chain complexes in saline-treated rats in prefrontal cortex, hippocampus, striatum and amygdala in both prevention and reversion treatment. Depending on the cerebral area and evaluated complex, TMX was able to prevent and reverse this impairment. A decrease in CK activity was also verified in the brain of rats when D-AMPH was administrated in both experiments; the administration of TMX reversed but not prevented the decrease in CK activity induced by D-AMPH. The present study demonstrated that TMX reversed and prevented the alterations in behavioral and energy metabolism induced by D-AMPH (alterations were also observed in bipolar disorder), reinforcing the need for more studies about inhibitors of PKC as possible targets for new medications in the treatment of bipolar disorder. PMID- 21281662 TI - Fluoxetine prevents 8-OH-DPAT-induced hyperphagia in Fischer inbred rats. AB - Ovariectomized, Fischer rats were hormonally primed with 10 MUg estradiol benzoate and 50 MUg progesterone or were treated with the sesame seed oil vehicle. Food intake was measured 2 h and 24 h after treatment with 0.25 mg/kg of the 5-HT(1A) receptor agonist, (+/-)-8-hydroxy 2-(di-n-propylamino) tetralin (8 OH-DPAT), 5 mg/kg of the selective serotonin reuptake inhibitor, fluoxetine, or their combination. Consistent with prior studies, two hour food intake of rats given fluoxetine and 8-OH-DPAT did not differ from vehicle controls. 8-OH-DPAT induced hyperphagia, evident at 2 h, was blocked by co-treatment with fluoxetine. However, in contrast to prior studies, 5 mg/kg fluoxetine, alone, had only modest effects on food intake. Differences in our experimental protocols and/or the strain of rat may account for the lower anorectic response to fluoxetine. Nevertheless, the absence of a significant response to fluoxetine, alone, coupled with the drug's attenuation of the hyperphagic effect of 8-OH-DPAT, leads to the suggestion that the behavioral response to the combined treatment is more complex than that of simple additivity. Consistent with this suggestion, 24 h food intake of rats given 8-OH-DPAT and fluoxetine was lower than that of vehicle or 8-OH DPAT-treated rats. PMID- 21281663 TI - Degree of dependence influences the effect of smoking on cognitive flexibility. AB - Pre-frontal cortical (PFC) dysfunction has been put forward as the basis for development and maintenance of addiction. To explore this relationship, the present study investigated the effects of smoking on PFC-mediated cognitive flexibility and subjective states in low- (LD) and high-dependent (HD) smokers. Twenty-four LD and 24 HD smokers (Fagerstrom dependence scores <= 4 and >= 5, respectively) were randomly allocated to non-smoking or smoking condition (12 LD and 12 HD participants per condition). After abstaining from smoking for a minimum of two hours volunteers completed a battery of questionnaires [nicotine specific Visual Analogue Scales (Nic-VAS), Questionnaire of Smoking Urges (QSU) and Profile of Mood States (POMS)] at baseline [T1] and again after smoking one cigarette or remaining abstinent [T2]. Cognitive flexibility was evaluated at T2 using the Intra-Extra Dimensional Set-Shift test. The Rapid Visual Information Processing test was performed as a control nicotine-sensitive task at several time points during the experiment. Compared to LD smokers, HD smokers had higher salivary cotinine and breath CO levels at baseline and reported more craving (QSU) and felt less stimulated (Nic-VAS), vigorous, friendly and elated (POMS) throughout the experiment. Smoking increased Nic-VAS ratings of 'Buzzed' and 'Dizzy' and decreased craving in all participants. Smoking selectively impaired cognitive flexibility in HD smokers since HD smokers allocated to the smoking condition made significantly more errors with the intra-dimensional set-shift than their counterparts in the abstinent condition. No effect of smoking on RVIP test was observed, most likely due to the practice effect which was significant in both groups of smokers. The practice effect, however, was more pronounced in LD smokers. This study demonstrates that PFC-mediated cognitive effects of smoking as well as subjective reports vary according to the degree of nicotine dependence. PMID- 21281664 TI - The effects of physical activity on attention deficit hyperactivity disorder symptoms: the evidence. AB - Evidence supports the beneficial effects of physical activity (PA) on cognitive performance and suggests that effects might be particularly large for children. However, limited research has explored PA as a means of managing behavioral symptoms and improving cognitive performance of children with attention deficit hyperactivity disorder (ADHD). The etiology of ADHD and the putative mechanisms for the effects of PA on cognitive performance suggest that PA might be especially important for this population. OBJECTIVE: The purpose of this paper is to review the literature regarding the potential of PA for ADHD symptom management, particularly in regard to behavioral and cognitive symptoms. METHODS: Literature was reviewed for published and unpublished research specifically examining the effects of PA on cognitive and/or behavioral symptoms of ADHD. Additionally, potential mechanisms were addressed. RESULTS: Albeit limited, current research generally supports the potential for acute and chronic PA to mitigate ADHD symptoms. CONCLUSION: Given the generally supportive extant literature and the challenges that face children with ADHD, future research exploring the potential of PA with this population is advocated. PMID- 21281665 TI - Impact of short bouts of physical activity on attention-to-task in elementary school children. AB - OBJECTIVE: The study's objective was to describe the measurement of on-task behavior and review the research on the effects of short physical activity breaks on attention-to-task in elementary school students, with a particular focus on a promising approach to improving on-task behavior with short bouts of physical activity in the classroom setting. METHODS: Procedures to directly observe attention-to-task were detailed. Published studies that measured attention-to task in elementary school students following physical activity breaks were reviewed. RESULTS: Direct measurement of attention-to-task is intensive and demanding on observers. Previous research on attention-to-task following physical activity breaks is sparse. The limited evidence suggests a small to moderate improvement on attention-to-task following physical activity breaks (Effect Sizes typically ranged from 0.13 to 0.60). Teachers can be trained in a relatively short time to effectively lead classroom-based physical activities. Students who participated in classroom-based physical activities that incorporate academic concepts demonstrated significantly better improvements (+8.3%) in attention-to task than control group participants (-3.1%). CONCLUSIONS: Attention-to-task is a variable that directly relates to concerns of classroom teachers. The limited available research has demonstrated moderate to good evidence that physical activity during the school day improves attention-to-task in elementary school students. Because of the positive effects of physical activity on attention-to task, it is recommended that elementary school teachers consider implementing physical activity sessions throughout the school day in the form of recess and classroom-based physical activities. PMID- 21281666 TI - Classroom-based physical activity, cognition, and academic achievement. AB - BACKGROUND: There is increasing evidence for the association between physical activity, cardiovascular fitness, fatness, and cognitive function during childhood and adolescence. Evidence also suggests that these variables are linked to academic achievement. Classroom-based physical activity provides a viable approach to improve fitness, body mass index (BMI), cognitive function, and ultimately academic achievement. METHODS: Studies examining the relation between physical activity, fitness, fatness, cognitive function, and academic achievement are described. The results of a large-scale, longitudinal, cluster randomized trial to examine the impact of classroom based physical activity on body mass index and academic achievement will be presented. RESULTS: Overall, the data support the link between physical activity, cognitive function, and academic achievement. The role of physical activity in the classroom was also supported by the Physical Activity Across the Curriculum (PAAC) project. Physically active academic lessons of moderate intensity improved overall performance on a standardized test of academic achievement by 6% compared to a decrease of 1% for controls (p<0.02). Body mass index increased less from baseline to 3 years in students with greater than 75 minutes of PAAC lessons per week (1.8 BMI) compared to students with less than 75 minutes of PAAC per week (2.4 BMI), p<0.00. CONCLUSIONS: Future research examining the effects of physically active academic instruction is warranted. The impact of physically active academic lessons of greater intensity may provide larger benefits for body mass index and academic achievement. PMID- 21281667 TI - The combined effects of exercise and foods in preventing neurological and cognitive disorders. AB - OBJECTIVE: Exercise and select diets have important influences on health and plasticity of the nervous system, and the molecular mechanisms involved with these actions are starting to be elucidated. New evidence indicates that exercise, in combination with dietary factors, exerts its effects by affecting molecular events related to the management of energy metabolism and synaptic plasticity. METHODS: Published studies in animals and humans describing the effects of exercise and diets in brain plasticity and cognitive abilities are discussed. RESULTS: New evidence indicates that exercise and select diets exert their effects by affecting molecular events related to the management of energy metabolism and synaptic plasticity. An important instigator in the molecular machinery stimulated by exercise is brain-derived neurotrophic factor (BDNF), which acts at the interface of metabolism and plasticity. CONCLUSIONS: Recent studies show that selected dietary factors share similar mechanisms with exercise, and in some cases they can complement the action of exercise. Therefore, exercise and dietary management appear as a non-invasive and effective strategy to counteract neurological and cognitive disorders. PMID- 21281668 TI - Fitness, fatness, cognition, behavior, and academic achievement among overweight children: do cross-sectional associations correspond to exercise trial outcomes? AB - BACKGROUND: This study examined associations of fitness and fatness with cognitive processes, academic achievement, and behavior, independent of demographic factors, at the baseline of an exercise trial. METHODS: Overweight, sedentary but otherwise healthy 7-11 year olds (N=170) participated in a study of health, cognition and achievement in the Augusta, GA area from 2003-2006. Children underwent evaluations of fatness and fitness, psychological assessments of cognition and academic achievement, and behavior ratings by parents and teachers. Partial correlations examined associations of fitness and fatness with cognitive and achievement scores and behavior ratings, controlling for demographic factors. RESULTS: Fitness was associated with better cognition, achievement and behavior, and fatness with worse scores. Specifically, executive function, mathematics and reading achievement, and parent ratings of child behavior were related to fitness and fatness. Teacher ratings were related to fitness. CONCLUSION: These results extend prior studies by providing reliable, standardized measures of cognitive processes, achievement, and behavior in relation to detailed measures of fitness and fatness. However, cross-sectional associations do not necessarily indicate that improving one factor, such as fatness or fitness, will result in improvements in factors that were associated with it. Thus, randomized clinical trials are necessary to determine the effects of interventions. PMID- 21281669 TI - A review of chronic and acute physical activity participation on neuroelectric measures of brain health and cognition during childhood. AB - BACKGROUND: A growing body of research has detailed the beneficial relation of chronic participation in--and acute responses to--physical activity on aspects of cognition that underlie scholastic achievement. Here, we review the relevant neuroelectric findings on this beneficial relation in children, providing support for the influence of physical activity on specific cognitive processes that comprise academic performance. METHOD: A review of studies examining physical activity and neuroelectric concomitants of cognition during childhood is described. When applicable, research involving adult populations is also described to better inform on this relationship in children. RESULTS: Collectively, the data support a beneficial relation of chronic and acute participation in physical activity to brain health and cognition. The results suggest more effective allocation of cognitive processes involved in stimulus engagement and action monitoring during tasks requiring variable amounts of cognitive control in children. CONCLUSION: Physical activity may influence brain health and cognition in children, leading to enhanced scholastic performance and greater overall effective functioning across the lifespan. PMID- 21281670 TI - Ten Years of TAKE 10!((r)): Integrating physical activity with academic concepts in elementary school classrooms. AB - OBJECTIVE: Current literature supports the link between physical activity (PA) or fitness and a child's ability to achieve academically; however, little structured activity time is incorporated into elementary school classrooms. This paper explores the impact of a classroom-based PA program, TAKE 10!, and health academic integration through existing state and federal policy and programming. METHODS: Evidence from journal articles, published abstracts, and reports were examined to summarize the impact of TAKE 10! on student health and other outcomes. This paper reviews 10 years of TAKE 10! studies and makes recommendations for future research. RESULTS: Teachers are willing and able to implement classroom-based PA integrated with grade-specific lessons (4.2 days/wk). Children participating in the TAKE 10! program experience higher PA levels (13%>), reduced time-off-task (20.5%), and improved reading, math, spelling and composite scores (p<0.01). Furthermore, students achieved moderate energy expenditure levels (6.16 to 6.42 METs) and studies suggest that BMI may be positively impacted (decreases in BMI z score over 2 years [P<0.01]). CONCLUSION: TAKE 10! demonstrates that integrating movement with academics in elementary school classrooms is feasible, helps students focus on learning, and enables them to realize improved PA levels while also helping schools achieve wellness policies. PMID- 21281671 TI - FIT Kids: Time in target heart zone and cognitive performance. AB - OBJECTIVE: This present study examined time spent in the target heart zone (THZ) and its relationship to tasks requiring variable amounts of executive control function in prepubescent children participating in a 9-month randomized controlled physical activity program. METHODS: A sample of 59 participants performed the Stroop Color-Word Test and the Comprehensive Trail Making Test cognitive assessments. Heart rate data were collected during participation in the physical activity program using E600 heart rate monitors (Polar, Finland). RESULTS: There was a significant difference, F(1, 58)=7.44, p <.009, between males and females for relative VO2max, but not absolute (p=.69) or percent VO2max (p=.73). Regression analysis identified KBIT, age, and mean time above the THZ as significant predictors of performance in the Stroop Color-Word condition, F(1, 56)=5.21, p=.02. KBIT and mean time above the THZ were significant predictors for Trails B, F(1, 56)=7.60. CONCLUSIONS: These results suggest that heart rate, as a measure of physical activity intensity, should be closely monitored during research that is intended to make inferences about its effects on cognitive performance as participation in vigorous activities may have specific benefits over lower intensities among prepubescent children. PMID- 21281672 TI - Physically active academic lessons in elementary children. AB - BACKGROUND: Although schools are an ideal location to conduct interventions that target children, the emphasis on standardized testing makes it difficult to implement interventions that do not directly support academic instruction. In response, physically active academic lessons have been developed as a strategy to increase physical activity while also addressing core educational goals. Texas I CAN! is one incarnation of this approach. METHODS: We will review the on-going research on the impact of these active lessons on: teacher implementation, child step count, child attention control, and academic performance. RESULTS: The collected studies support the impact of physically active academic lessons on each area of interest. CONCLUSIONS: If these data can be replicated, it suggests that teachers might find these lessons of benefit to their primary role as educators, which should ease dissemination of these and other physically active lessons in elementary schools. PMID- 21281673 TI - Liver abscess due to non-O1 Vibrio cholerae in a cirrhotic patient with hepatocellular carcinoma. PMID- 21281674 TI - Follow up of cases of PVL-positive Staphylococcus aureus is not worthwhile. PMID- 21281675 TI - Disseminated tuberculosis following unrelated cord blood transplantation for refractory peripheral T-cell lymphoma: Clinical role of serum procalcitonin levels. PMID- 21281676 TI - C-Reactive protein levels but not CRP dynamics predict mortality in patients with pneumococcal pneumonia. PMID- 21281677 TI - OxLDL or TLR2-induced cytokine response is enhanced by oxLDL-independent novel domain on mouse CD36. AB - OxLDL binding to CD36 is shown to result in macrophage activation and foam cell formation that have been implicated in atherosclerosis. However, CD36 has also been shown to induce inflammatory response to other ligands besides oxLDL. During the course of blocking CD36 oxLDL binding function using anti CD36 antibodies, we have identified a novel domain of CD36 that triggers inflammatory response independent of oxLDL binding. OxLDL bound to the mouse reporter cell line RAW Blue induced TNF-alpha and RANTES mRNA and protein expression. Pretreatment of RAW-Blue cells with an anti-mCD36 mAb, JC63.1, an activating mCD36 mAb, surprisingly did not inhibit oxLDL-induced response. Further, binding of this antibody to CD36 alone induced a pro-inflammatory cytokine response in RAW-Blue cells as well as primary mouse macrophages. The induction of cytokine response was specific only to this antibody and was CD36-dependent, since CD36(-/-) macrophages failed to induce a similar response. The interaction of the antibody to CD36 led to activation of NF-kappaB and MAP kinase. Notably, a CD36 peptide blocked oxLDL-induced foam cell formation and macrophage activation. However, the activating mCD36 mAb induced macrophage activation was not inhibited by CD36 peptide. Further, activating mCD36 mAb enhanced oxLDL- or TLR2- or TLR4-mediated inflammatory responses. Collectively, our data provide evidence that activating mCD36 mAb binds to a domain different from the oxLDL-binding domain on mouse CD36, and suggest that interaction at this domain may contribute to oxLDL independent macrophage inflammatory responses that lead to chronic inflammatory diseases. PMID- 21281678 TI - How accurately can we detect Mycobacterium avium subsp. paratuberculosis infection? AB - Mycobacteria have thwarted detection by scientists for centuries. Mycobacterium paratuberculosis is one of the most fastidious of the Mycobacteriaceae, and has been implicated in both animal and human diseases. In domestic livestock, M. paratuberculosis has been associated with Johne's disease, which given its increasing incidence, is currently a cause for concern, due to the potential for M. paratuberculosis to enter our food chain. In addition, a tenuous link has been reported between M. paratuberculosis and Crohn's disease, however evidence to support this link is hampered by the lack of accurate methodologies for detection of M. paratuberculosis in humans. This review compares the sensitivity and specificity of traditional and more recent techniques to the culture and molecular detection of M. paratuberculosis. While serology and culture are popular choices for the livestock industry they have not produced useful data for human infection. Although the advent of molecular biology has enabled faster diagnosis of M. paratuberculosis in human infection, there is currently no gold standard such as culture on which to validate these findings. Even with DNA/RNA detection methods, there is the ever present issue of the genetic relatedness of M. paratuberculosis to other mycobacteria of the Mycobacterium avium complex, some of which also infect humans with very different pathological outcomes. Recent developments in this field include more rapid methods of M. paratuberculosis culture as well as the development of more accurate and sensitive PCR assays. The application of these techniques should offer a greater insight as to the role of M. paratuberculosis in human gastrointestinal diseases. PMID- 21281679 TI - RGD targeting hyaluronic acid coating system for PEI-PBLG polycation gene carriers. AB - Hyaluronic acid (HA), a natural anionic mucopolysaccharide, was used to coat polyethylenimine-poly(gamma-benzyl L-glutamate)/DNA (PEI-PBLG/DNA) complexes. HA was further modified by introducing RGD peptide with grafting density of one RGD in every 1.9 HA repeating units. HA can coat the cationic surface of PEI-PBLG/DNA complexes without destroying them even at high weight ratio of HA/PEI PBLG/DNA=40/10/1. Coating the complexes by HA and HA-RGD caused lower surface charges and little bigger size than the naked PEI-PBLG/DNA. HA/PEI-PBLG/DNA has little lower transfection efficiency compared with naked PEI-PBLG/DNA, while the transfection efficiency of HA-RGD/PEI-PBLG/DNA is 9.7 times of HA/PEI-PBLG/DNA for the RGD target bonding affinity to the receptors on the cell surface. HA coating on PEI-PBLG/DNA reduced the electrostatic binding affinity to the cells while the RGD binding affinity for integrin on HeLa cells can not only compensate the reduced binding affinity but also enhance the affinity for HA-RGD/PEI PBLG/DNA. RGD and RDG competition assay and lactate dehydrogenase (LDH) release studies further confirmed the specific target functions of RGD on HA. Cell viability measurements confirmed the high viability (above 70% viability) of the cells treated with HA-RGD and HA coated complex particles. These results would show that HA-RGD coated PEI-PBLG/DNA complexes have an attractive feature to a targeting in vivo non-viral gene delivery system. PMID- 21281680 TI - Dectin-1 targeting delivery of TNF-alpha antisense ODNs complexed with beta-1,3 glucan protects mice from LPS-induced hepatitis. AB - Antisense therapy, the first concept of oligonucleotide therapeutics, was proposed more than two decades ago. However, the lack of suitable delivering carriers continues to be a major obstacle to practical therapy. In this study, we present a novel complex consisting of beta-1,3-glucan and antisense oligonucleotide (AS-ODN) as a new candidate of the carriers. We used schizophyllan (SPG) as a beta-1,3-glucan and an AS-ODN sequence to suppress tumor necrosis factor alpha (TNF-alpha), where the AS-ODN has a (dA)(60) tail to induce complex with SPG. When the complexes were applied to peritoneal macrophages, they were incorporated into the cells via dectin-1 (a beta-1,3-glucan receptor expressed on antigen presenting cells) and suppressed lipopolysaccharide (LPS) induced TNF-alpha secretion. In-vivo, AS-ODN/SPG decreased the secretion of TNF alpha in serum and drastically reduced the inflammation of LPS-induced hepatitis. This new complex could overcome the long outstanding problem for antisense therapy because of its complexation ability, non-toxicity and high target specificity. PMID- 21281681 TI - Acute autochthonous hepatitis E in western patients with underlying chronic liver disease: a role for ribavirin? PMID- 21281682 TI - Role of mycophenolate mofetil in the treatment of autoimmune hepatitis. PMID- 21281683 TI - Genomic medicine reaches HCV-related liver transplantation: hopes and clinical and public health implications. PMID- 21281684 TI - No need for a large belly to have NASH. PMID- 21281685 TI - Aortic valve disease and treatment: the need for naturally engineered solutions. AB - The aortic valve regulates unidirectional flow of oxygenated blood to the myocardium and arterial system. The natural anatomical geometry and microstructural complexity ensures biomechanically and hemodynamically efficient function. The compliant cusps are populated with unique cell phenotypes that continually remodel tissue for long-term durability within an extremely demanding mechanical environment. Alteration from normal valve homeostasis arises from genetic and microenvironmental (mechanical) sources, which lead to congenital and/or premature structural degeneration. Aortic valve stenosis pathobiology shares some features of atherosclerosis, but its final calcification endpoint is distinct. Despite its broad and significant clinical significance, very little is known about the mechanisms of normal valve mechanobiology and mechanisms of disease. This is reflected in the paucity of predictive diagnostic tools, early stage interventional strategies, and stagnation in regenerative medicine innovation. Tissue engineering has unique potential for aortic valve disease therapy, but overcoming current design pitfalls will require even more multidisciplinary effort. This review summarizes the latest advancements in aortic valve research and highlights important future directions. PMID- 21281686 TI - Co-culture systems for vascularization--learning from nature. AB - The endothelial cell (EC) is practically ubiquitous in the human body and forms the inner cellular lining of the entire cardiovascular system. Following tissue injury, the microcirculation becomes the stage for both the inflammatory response and the subsequent healing reaction to restore physiological function to the damaged tissue. The advent of the multidisciplinary field of Regenerative Medicine (RegMed), of which Tissue Engineering (TE) and drug delivery using modern stimuli-responsive or interactive biomaterials are important components, has opened up new approaches to the acceleration of the healing response. A central and rate-limiting role in the latter is played by the process of vascularization or neovascularization, so that it is not surprising that in RegMed concepts have been developed for the drug- and gene-delivery of potent stimuli such as vascular-endothelial growth factor (VEGF) to promote neovessel development. However, not all of these novel materials can be tested in vivo, and in vitro co-culture model systems using human primary cells are being developed to pre-evaluate and determine which of the RegMed concepts exhibit the most promising potential for success after implantation. This review describes some of the growing number of in vitro co-cultures model systems that are being used to study cell-cell and cell-material interactions at the cellular and molecular levels to determine which materials are best suited to integrate into the host, promote a rapid vascularization and fit into the regenerative process without disturbing or slowing the normal healing steps. PMID- 21281687 TI - The effect of pre-exposure and recovery type on activity-based anorexia in rats. AB - Activity-based anorexia (ABA) occurs when there is limited access to food and an opportunity to engage in high levels of physical activity. While the ABA effect is well established, the distinct functions of exercise and food restriction in maintaining ABA have not been determined. The current study examined the effect of pre-exposure to a restricted feeding schedule and pre-exposure to a running wheel on the incidence of ABA in 36 rats. Access to food and the running wheel was also varied in the recovery phase of the study in order to establish the effect of these variables on recovery from ABA. Three adaptation conditions (pre exposed to food restriction, pre-exposed to wheel access and non-exposed) and two recovery conditions (wheel access and food restriction recovery) defined the six groups in the current study. Pre-exposure to food restriction was found to ameliorate the ABA effect during the anorexia phase while pre-exposure to wheel access exacerbated ABA. It was also found that subjects in the wheel access recovery condition gained more weight than the subjects in the food restriction recovery. In food restriction recovery, there was an interaction between the adaptation and recovery condition, with subjects that were pre-exposed to food restriction gaining the most weight. The results of the current study aid in understanding the distinct functions of food restriction and exercise in maintaining and recovering from ABA and have possible implications for the treatment of people diagnosed with some types of anorexia nervosa. PMID- 21281688 TI - Percutaneous penetration of 5-methoxypsoralen in rhesus monkeys. AB - OBJECTIVE AND DESIGN: 5-methoxypsoralen (bergapten) has been used in the treatment of psoriasis and vitiligo, and as a sun tanning accelerator. While low plasma concentrations have previously been detected, there is no data on its dermatopharmacokinetics. MATERIALS AND METHODS: Three rhesus monkeys were used as a model for human skin. [14C]-5-methoxypsoralen, as a parenteral excretion control, was injected in propylene glycol with an activity of 1.12 uCi/ml at a concentration of 80 mcg/ml and urine was collected at 4, 8, 12, 24h, and then daily for a total of 6 days. [14C]-5-methoxypsoralen was then applied topically in acetone with a dose of 1.19 mc (72 mcg) and urine was collected at 4 and 24h and then daily for a total of 7 days. The amount excreted was corrected for the previously determined parenteral excretion kinetics. RESULTS: Intramuscular [14C] 5-methoxypsoralen had an average of 71.87+/-7.77% of excretion and percutaneously applied [14C]-5-methoxypsoralen had an average of 58.4+/-11.8% of excretion. CONCLUSION: A high percentage of the administered 5-methoxypsoralen was absorbed. This provides a foundation of methodology to evaluate the efficacy of other delivery vehicles for 5-methoxypsoralen and serves as part of its dermatotoxic profile. PMID- 21281689 TI - Immunization of female BALB/c mice with Neospora cyclophilin and/or NcSRS2 elicits specific antibody response and prevents against challenge infection by Neospora caninum. AB - Neospora caninum is the causal agent of bovine neosporosis which results in high levels of abortion. The present study determined the protective efficacy of two Neospora antigens--Neospora cyclophilin (NcCyP) and NcSRS2. The ability of native NcCyP to upregulate mouse IFN-gamma was also confirmed in this study. Recombinant NcCyP or NcSRS2 were tested either alone or in combination and formulated with adjuvant ImmuMax-SR and CpG. Female BALB/c mice (n=15) of 10-12 weeks of age were immunized s.c. twice over a 2-week interval with vaccines containing either NcCyP (20 MUg/dose) alone, NcSRS2 (20 MUg/dose) alone, NcCyP plus NcSRS2, or non recombinant bacterial antigen (NR) in 2 separate trials. All mice were challenge infected 3 weeks following the booster immunization and necropsied 3 weeks after the challenge infection. Brain and serum were collected and Nc-specific DNA sequence in brain tissue and antibodies in serum were analyzed by PCR or ELISA/Western blotting. Results showed that mice vaccinated with rNcCyP, rNcSRS2, or both rNcCyP and rNcSRS2 responded with high levels of NcCyP or NcSRS2 specific antibodies. Overall, mice received vaccines formulated with either rNcCyP or rNcCyP and rNcSRS2 had a higher (p<0.01) percent protection when compared to the mock- or non-vaccinated mice. The group immunized with rNcSRS2 alone exhibited slightly lower levels of protection, which was higher (p<0.05) than that of the non-vaccinated group but did not differ (p=0.06) from that of the mock-vaccinated group. The results of the present study indicate that NcCyP is a highly efficacious vaccine candidate which may be useful in protection against Neospora infection. PMID- 21281690 TI - Pseudouridylation of 23S rRNA helix 69 promotes peptide release by release factor RF2 but not by release factor RF1. AB - Pseudouridine [Psi] is a frequent base modification in the ribosomal RNA [rRNA] and may be involved in the modulation of the conformational flexibility of rRNA helix-loop structures during protein synthesis. Helix 69 of 23S rRNA contains pseudouridines at the positions 1911, 1915 and 1917 which are formed by the helix 69-specific synthase RluD. The growth defect caused by the lack of RluD can be rescued by mutations in class I release factor RF2, indicating a role for helix 69 pseudouridines in translation termination. We investigated the role of helix 69 pseudouridines in peptide release by release factors RF1 and RF2 in an in vitro system consisting of purified components of the Escherichia coli translation apparatus. Lack of all three pseudouridines in helix 69 compromised the activity of RF2 about 3-fold but did not significantly affect the activity of RF1. Reintroduction of pseudouridines into helix 69 by RluD-treatment restored the activity of RF2 in peptide release. A Psi-to-C substitution at the 1917 position caused an increase in the dissociation rate of RF1 and RF2 from the postrelease ribosome. Our results indicate that the presence of all three pseudouridines in helix 69 stimulates peptide release by RF2 but has little effect on the activity of RF1. The interactions around the pseudouridine at the 1917 position appear to be most critical for a proper interaction of helix 69 with release factors. PMID- 21281691 TI - Prediction of mitochondrial proteins of malaria parasite using bi-profile Bayes feature extraction. AB - Mitochondrial proteins of Plasmodium falciparum are considered as attractive targets for anti-malarial drugs, but the experimental identification of these proteins is a difficult and time-consuming task. Computational prediction of mitochondrial proteins offers an alternative approach. However, the commonly used subcellular location prediction methods are unsuited for P. falciparum mitochondrial proteins whereas the organism and organelle-specific methods were constructed on the basis of a rather small dataset. In this study, a novel dataset termed PfM233, which included 108 mitochondrial and 125 non-mitochondrial proteins with sequence similarity below 25%, was established and the methods for predicting mitochondrial proteins of P. falciparum were described. Both bi profile Bayes and split amino acid composition were applied to extract the features from the N- and C-terminal sequences of these proteins, which were then used to construct two SVM based classifiers (PfMP-N25 and PfMP-30). Using PfM233 as the dataset, PfMP-N25 and PfMP-30 achieved accuracies (MCCs) of 90.13% (0.80) and 90.99% (0.82). When tested with the commonly used 40 mitochondrial proteins in PfM175 and the 108 mitochondrial proteins in PfM233, these two methods obviously outperformed the existing general, organelle-specific and organism and organelle-specific methods. PMID- 21281692 TI - Molecular and structural characterization of a surfactant-stable high-alkaline protease AprB with a novel structural feature unique to subtilisin family. AB - High-alkaline proteases are of great importance because of their proteolytic activity and stability under high-alkaline condition. We have previously isolated a new protease (AprB) which has potential industrial applications based on its high-alkaline adaptation. However, the molecular and structural basis for alkaline adaptation of this enzyme has not been fully elucidated. In the present study, AprB gene was cloned and expressed in the Bacillus subtilis WB600. This gene codes for a protein of 375 amino acids comprised with a 28-residual signal peptide, a 78-residual pro-peptide, and a 269-residual mature protein. The deduced amino acid sequence has the highest homology of 63.2% with that of the high-alkaline proteases. Recombinant AprB was purified and determined to be monomeric with molecular mass of 26.755kDa. The NH(2)-terminal sequence of the purified AprB was A-Q-S-I-P-W-G-I-E-R. This enzyme exhibited high catalytic efficiencies (K(cat)/K(m)) towards natural, modified, and synthesis substrates with optimal activity at 60 degrees C and pH 10. AprB was stable over a wide range of pH 5 to 11 and various surfactants, and could be activated by Mg(2+), Ca(2+) and Ba(2+). The structural properties of AprB, like a higher ratio of R/(R+K), a larger area of hydrophobic surface, increased number of ion pairs formed by Arg residue, and the exposure of Asp active residue on the surface, might be responsible for its alkaline adaptation. In contrast with members of subtilisin family, such as M-protease and subtilisin BPN', AprB harbored a high content of Glu and Asp residues, and a low content of Arg and Lys residues on the surface. Interestingly, these structural characters were similar with that of psychrophilic proteases, which suggested that these molecular factors were not restricted in the psychrophilic proteases, and therefore were not solely responsible for their cold-adaptation. Our results reveal a novel structural feature of AprB unique to subtilisin family and provide clues for its alkaline adaptation. PMID- 21281693 TI - Intensity dependence of auditory evoked potentials during light interference in migraine. AB - Migraine patients show interictally a strong intensity dependence of auditory evoked cortical potentials (IDAP) and a lack of habituation of evoked potentials. Photic drive on high-frequency flash stimulation is another well-known interictal feature in migraineurs, associated with alpha-rhythm hyper-synchronisation. We compared therefore the influence of light stimulation on IDAP in healthy volunteers (HV) and migraine patients. A continuous flash stimulation was delivered during the recording of auditory evoked potentials at suprathreshold increasing stimulation intensities. IDAP was measured as the amplitude/stimulus intensity function (ASF) slope. In HV, the ASF slope decreased during flash stimulation, whereas, on average, there was no significant change in migraineurs. A closer analysis of migraineurs disclosed two subgroups of patients with no detectable clinical differences: one, the largest, in which the ASF slope was normal at baseline, but increased during light stimulation, the other with an increased ASF slope at rest and a decrease during light interference. Visual sensory overload is able to increase IDAP in the majority of migraineurs, which contrasts with HV. We hypothesise that this could be due to hyper-synchronisation of the alpha rhythm because of photic drive and possibly thalamo-cortical dysfunction. A minority of migraineurs have, like HV, an IDAP reduction during light interference. They are, however, characterised, unlike most HV, by a high IDAP at baseline. Besides underscoring the pathophysiological heterogeneity of migraine, these results suggest that light interference might improve the phenotyping of migraine patients who have a normal IDAP in the resting condition. PMID- 21281694 TI - Face recognition in Asperger syndrome: a study on EEG spectral power changes. AB - EEG reactions in emotional face recognition were studied in five participants with Asperger syndrome (AS) and seven control subjects. Control subjects showed a spectral power increase following the stimulus onset in two time-frequency intervals-(1) 150-300ms in the 1-16Hz frequency range and (2) 300-650ms in the 1 8Hz range. Also, alpha/beta desynchronization occurred 400-1000ms after the stimulus onset with maximal amplitude in the posterior region. Theta synchronization (4-8Hz) was weaker in the AS group than in the control group, but beta2 desynchronization was stronger in the AS group. The results were interpreted in terms of automatic and voluntary control of perception. PMID- 21281695 TI - Brain-derived neurotrophic factor (BDNF) ameliorates the suppression of thyroid hormone-induced granule cell neurite extension by hexabromocyclododecane (HBCD). AB - Thyroid hormone (TH) plays an essential role in growth and differentiation of the central nervous system. Deficiency of TH during perinatal period results in abnormal brain development known as cretinism in human. We recently reported that an environmental chemical 1,2,5,6,9,10-alpha-hexabromocyclododecane (HBCD) suppressed TH receptor (TR)-mediated transcription. To examine the effect of HBCD on cerebellar granule cells, we used purified rat cerebellar granule cells in reaggregate culture. Low dose HBCD (10(-10)M) significantly suppressed TH-induced neurite extension of granule cell aggregate. To clarify further the mechanisms of such suppression, we added brain-derived neurotrophic factor (BDNF) into culture medium, since BDNF plays a critical role in promoting granule cell development and is regulated by TH. BDNF completely rescued HBCD-induced suppression of granule cell neurite extension in the presence of T3. These results indicate that HBCD may disrupt TH-mediated brain development at least in part due to a disruption of the T3 stimulated increase in BDNF and BDNF may possess ability to ameliorate the effect of HBCD in granule cells. PMID- 21281696 TI - Simultaneous absolute measures of glabrous skin hemodynamic and light-scattering change in response to formalin injection in rats. AB - Subcutaneous injection of formalin is a well-known model to study the nature of inflammatory pain. One of the cardinal signs of inflammation is redness, as a result of increased blood perfusion. We used an optical technology, light reflectance spectroscopy, to noninvasively obtain absolute measures of cutaneous hemodynamic components, including the concentrations of oxy- ([HbO]), deoxy- ([Hb]), total-hemoglobin ([HbT]), oxygen saturation (SO(2)), and the reduced light-scattering coefficient (MUs'). The objective is to assess the effect of formalin-induced skin inflammation on the aforementioned parameters. Six rats were injected with formalin (50 MUl, 3%) into left hind paw under pentobarbital anesthesia. Our results indicate prolonged increases in [HbO], [HbT], and SO(2) post injection only in the ipsilateral side. No statistically significant changes in [Hb] and MU(s)' occurred in either side. The arterial blood influx tends to be the major attribute of local hyperemia during inflammation. Thereby, [HbO] appears to be superior to [Hb] in measuring inflammation. In conclusion, the needle-probe-based light reflectance can be a feasible means to obtaining absolute measures of skin hemodynamic and light-scattering parameters when studying inflammatory pain. PMID- 21281697 TI - Sensory-motor interference abolishes repetition priming for observed actions, but not for action-related verbs. AB - Several studies on humans have shown a recruitment of the sensory-motor system in the perception of action-related visual and verbal material, suggesting that actions are represented through sensory-motor processes. To date, these studies have not disentangled whether such a recruitment is epiphenomenal or necessary to action representation. Here we took advantage of repetition priming as a tool to investigate the cognitive representation of actions, and systematically looked whether a concurrent motor or verbal task had a detrimental effect on this representation. In a first experiment participants discriminated images depicting meaningless and meaningful actions, while performing either a concurrent sensory motor or an articulatory suppression task. Images were classified as depicting a repeated or a new action, relative to the previous image in the trial series. We found a facilitation by repetition priming, that was unaffected by the articulatory task but was completely abolished by the sensory-motor task. In a second experiment, we investigated whether the sensory-motor system is also causally involved in processing action-related verbs. In this experiment actions were presented as written infinitive verbs rather than as images. The facilitation by repetition priming was again unaffected by the concurrent articulatory task, while the sensory-motor concurrent task, although reducing the facilitation, did not abolish it. Our data provide evidence that the sensory motor system is differentially involved during visual processing of actions and during processing of action-related verbs. Results are discussed within the theoretical frame of embodied cognition. PMID- 21281698 TI - Cross state-dependency of learning between WIN55, 212-2 and scopolamine in rat dorsal hippocampus. AB - In the current study, cross state-dependent learning between the cannabinoid CB1/CB2 receptor agonist WIN55, 212-2 (WIN) and muscarinic receptor antagonist scopolamine (SCO) in a step-through inhibitory avoidance task was investigated. All drugs were injected bilaterally into the dorsal hippocampus (intra-CA1) of rats. Data indicated that the immediate post-training administration of WIN (0.25 and 0.5MUg/rat) and SCO (2 and 4MUg/rat) decreased memory consolidation and induced amnesia. Moreover, the amnesia induced by the post-training injections of WIN (0.5MUg/rat) or SCO (2MUg/rat) was restored by either pre-test injections of WIN (0.25 and 0.5MUg/rat) or SCO (2 and 4MUg/rat). Furthermore, pre-test co administration of ineffective doses of WIN (0.1MUg/rat) with SCO (1MUg/rat) restored amnesia induced by the post-training injections of WIN (0.5MUg/rat) or SCO (2MUg/rat). In conclusion, the data strongly revealed a cross state-dependent learning between WIN and SCO in the rat dorsal hippocampus. PMID- 21281699 TI - Enhancement of sciatic nerve regeneration by adenovirus-mediated expression of dominant negative RhoA and Rac1. AB - It is known that Rho family small GTPases activate a number of signal transduction pathways involved in cell cycle progression, gene expression, and cell survival. These small G proteins play an important role in neuronal survival and axon regeneration in neural injury. In this study, we tested whether the activity of RhoA or Rac1 regulates neurite extension in dorsal root ganglia (DRGs) in vitro and nerve regeneration in injured sciatic nerves. Regeneration of neurites from explanted DRGs was accelerated by combined suppression of RhoA and Rac1 activity using adenoviruses expressing dominant negative (DN) forms of both RhoA and Rac1 (Ad-Rho/RacDN) in vitro. Rat sciatic nerves were cut and Ad Rho/RacDN was injected into the proximal stumps. After bridge grafting with chitosan mesh tubes, muscle evoked potentials induced by transcranial electrical stimulation were recorded eight weeks postoperatively. The terminal latencies were shorter in the Ad-Rho/RacDN group than in the control group. Histological analysis revealed extensive regrowth of neurofilament-positive and myelinated axons within the tubes in the group that received Ad-Rho/RacDN. These findings suggest that combined regulation of RhoA and Rac1 using DN adenoviral transgenic methods has the potential to modify injured peripheral nerve tissues directly. PMID- 21281700 TI - Motor cortex excitability in Alzheimer's disease: a transcranial magnetic stimulation follow-up study. AB - Transient cognitive and behavioral stabilization of patients with Alzheimer's disease (AD) is the main goal of acetylcholinesterase inhibitor (AChEI) therapy. Response to treatment is variable and it is usually assessed clinically via neuropsychological scales. Functional neuroimaging could ideally permit the objective evaluation of the topographic correlates of therapy on brain functioning, but is expensive and little available on a large scale. On the other hand, neurophysiological methods such as transcranial magnetic stimulation (TMS) could offer an alternative, low-cost and risk free tool of assessing response to treatment in AD. Previous TMS studies have demonstrated hyperexcitability and asymptomatic motor cortex reorganization in the early stages of AD in patients with normal motor function. The aim of this study was to compare motor cortex functionality in 10 AD patients before and after long-term AchEIs therapy in order to monitor potential drug-related changes in cortical excitability and organization. Examined parameters of motor cortex physiology were found to be unchanged in patients with stabilized cognitive performance during the therapy. TMS, along with clinical, neuropsychological, and neuroimaging data, could be an inexpensive measure of biological progression in AD and it might supplement traditional methods to assess the effects of therapy. PMID- 21281701 TI - Glutathione biochemistry in asthma. AB - BACKGROUND: Oxidative stress in an important hallmark of asthma and much research has therefore focused on the predominant antioxidant in the lungs, namely the tripeptide glutathione. MAJOR CONCLUSIONS: In lung samples of patients with asthma increased levels of glutathione are typically observed, which appear to relate to the level of pulmonary inflammation and are therefore regarded as an adaptive response to the associated oxidative stress. Also in blood samples increased total GSH levels have been reported, representing the systemic inflammatory component of the disease. In addition, a number of the antioxidant enzymes involved in the maintenance of the GSH/GSSG ratio as well as enzymes that utilize GSH have been found to be altered in the lungs and blood of asthmatics and will be summarized in this review. Very few studies have however linked enzymatic alterations to GSH levels or found that either of these correlated with disease severity. Some animal studies have started to investigate the pathophysiological role of GSH biochemistry in asthma and have yielded surprising results. Important in this respect is the physiological role of the GSH redox equilibrium in determining the outcome of immune responses, which could be deregulated in asthmatics and contribute to the disease. SCOPE OF REVIEW: Clinical data as well as animal and cell culture studies regarding these aspects of GSH in the context of asthma will be summarized and discussed in this review. This article is part of a Special Issue entitled: Biochemistry of Asthma. PMID- 21281702 TI - Interaction of berberine, palmatine, coralyne, and sanguinarine to quadruplex DNA: a comparative spectroscopic and calorimetric study. AB - BACKGROUND: Interaction of isoquinoline alkaloids berberine, palmatine, coralyne and sanguinarine with human telomeric quadruplex DNA, dAGGG(TTAGGG)(3), has been investigated and compared with ethidium. METHODS: Biophysical techniques such as absorption, fluorescence, circular dichroism, optical melting and microcalorimetry have been used. RESULTS: Absorption and fluorescence studies revealed noncooperative 1:1 binding for all the molecules. Coralyne showed highest affinity (10(6) M(-1)) and for others it was ~10(5) M(-1). The binding affinity varied as coralyne>sanguinarine>berberine>palmatine. Ethidium showed affinity close to sanguinarine. Comparative fluorescence quenching and polarization anisotropy of the emission spectra gave evidence for a stronger stacking interaction of coralyne and sanguinarine compared to berberine and palmatine. Circular dichroic spectral perturbations were similar in all the cases, but a strong induced circular dichroism for the bound molecules was observed only for coralyne and sanguinarine. The interaction of all the alkaloids was exothermic. Binding of coralyne and sanguinarine was predominantly enthalpy driven while that of berberine and palmatine was entropy driven. Heat capacity values of -169, -198, -105 and -95cal/molK, respectively, for coralyne, sanguinarine, berberine, and palmatine suggested significant differences in the hydrophobic contribution to the binding. CONCLUSIONS: This study presents a complete structural and thermodynamic profile of the binding of isoquinoline alkaloids with G-quadruplex. GENERAL SIGNIFICANCE: These results suggest strong and specific binding of these molecules to the G-quadruplex and highlight the differences in their structure in the interaction profile. PMID- 21281703 TI - Regulation of mucin secretion and inflammation in asthma: a role for MARCKS protein? AB - BACKGROUND: A major characteristic of asthmatic airways is an increase in mucin (the glycoprotein component of mucus) producing and secreting cells, which leads to increased mucin release that further clogs constricted airways and contributes markedly to airway obstruction and, in the most severe cases, to status asthmaticus. Asthmatic airways show both a hyperplasia and metaplasia of goblet cells, mucin-producing cells in the epithelium; hyperplasia refers to enhanced numbers of goblet cells in larger airways, while metaplasia refers to the appearance of these cells in smaller airways where they normally are not seen. With the number of mucin-producing and secreting cells increased, there is a coincident hypersecretion of mucin which characterizes asthma. On a cellular level, a major regulator of airway mucin secretion in both in vitro and in vivo studies has been shown to be MARCKS (myristoylated alanine-rich C kinase substrate) protein, a ubiquitous substrate of protein kinase C (PKC). GENERAL SIGNIFICANCE: In this review, properties of MARCKS and how the protein may regulate mucin secretion at a cellular level will be discussed. In addition, the roles of MARCKS in airway inflammation related to both influx of inflammatory cells into the lung and release of granules containing inflammatory mediators by these cells will be explored. This article is part of a Special Issue entitled: Biochemistry of Asthma. PMID- 21281704 TI - Phytocomplexes from liquorice (Glycyrrhiza glabra L.) leaves--chemical characterization and evaluation of their antioxidant, anti-genotoxic and anti inflammatory activity. AB - Three extracts of different polarities of Glycyrrhiza glabra L. leaves were characterized and evaluated for their antioxidant, anti-genotoxic and anti inflammatory activity. In total, thirty components have been identified and quantified through the use of liquid chromatography (LC) with ultraviolet-visible diode-array-detector (UV-vis-DAD) and mass spectrometry (MS). The main components belong to the polyphenols family, being flavonoid and dihydrostilbene derivatives. The extracts have been investigated for their antioxidant, anti genotoxic and anti-inflammatory activities, which are fundamental requirements of efficacious chemo-preventive agents. The ethyl acetate extract proved to be the most valuable, evidently for the conspicuous presence of several polyphenols, namely flavonoids and dihydrostilbenes. PMID- 21281705 TI - Inhibitory effects of flavonoids from Abelmoschus manihot flowers on triglyceride accumulation in 3T3-L1 adipocytes. AB - The 95% EtOH extract from the flowers of Abelmoschus manihot (L.) Medic showed inhibitory activity on TG accumulation in 3T3-L1 preadipocyte. Chemical studies on the active fraction led to the isolation of 14 flavonoids (1-14). To clarify the multi-mechanism of the isolates on preadipocyte differentiation, the levels of TG and FFA and the related role transcription factors (PPARgamma, CEBP/alpha, and ap2) expression were evaluated. At the concentration of 30 MUM, compounds 1-6 and 10-14 showed inhibitory activity on TG accumulation significantly in mature 3T3-L1 cells. 1, 2, 4-7, 9, 10, 13, and 14 reduced the level of FFA. At the molecular level, the mRNA expressions of PPARgamma, CEBP/alpha, and ap2 were down regulated by compounds 1, 5, 9, 12, 13; 1-8, 10-14; and 1-4, 6, 8-12, 14, respectively. The structure-activity relationships of the 14 flavonoids were also discussed. PMID- 21281706 TI - p,p'-Dichlorodiphenoxydichloroethylene induced apoptosis of Sertoli cells through oxidative stress-mediated p38 MAPK and mitochondrial pathway. AB - p,p'-DDE, the major metabolite of dichlorodiphenoxytrichloroethane (DDT), is a known persistent organic pollutant and male reproductive toxicant. However, the mechanism underlying its male reproductive toxicity remains limited. Our previous studies have demonstrated that p,p'-DDE could induce mitochondria-mediated apoptosis of cultured rat Sertoli cells. In the present study, we investigated mitogen-activated protein kinase pathways as well as other mitochondria-related molecules including Bax family members and cytochrome c. Results showed that p,p' DDE could induce oxidative stress-mediated p38 and JNK phosphorylation. In addition, elevated mRNA levels of cytochrome c and ratios of bax/bcl-w and bak/bcl-w were induced by p,p'-DDE treatment, which could be inhibited by RNA synthesis inhibitor (actinomycin D). p,p'-DDE-induced apoptosis was blocked by NAC (N-acetyl-L-cystein) preincubation and attenuated by pretreatment with p38 inhibitor (SB202190) or actinomycin D, but not with JNK inhibitor (SP600125). All of the findings suggested that oxidative stress-mediated p38 MAPK pathway and the balance between pro- and anti-apoptotic bax-gene family might play critical roles in p,p'-DDE-induced apoptosis. PMID- 21281708 TI - The effect of Nrf2 knockout on the constitutive expression of drug metabolizing enzymes and transporters in C57Bl/6 mice livers. AB - Previous reports have proposed a cross-talk between the nuclear factor erythroid 2 p45-related factor-2 (Nrf2)/antioxidant response element (ARE) and the aryl hydrocarbon receptor (AhR)/xenobiotic response element (XRE) signaling pathways. Therefore, the aim of the current study was to examine the level of phase I, phase II drug metabolizing enzymes (DMEs), and phase III transporters and their related transcription factors in the Nrf2 knockout model. Our results showed that phase II DMEs that are under the control of Nrf2 typified by NAD(P)H: quinone oxidoreductase 1 (Nqo1), and glutathione S-transferase (Gst) were significantly lower at the mRNA, protein, and catalytic activity levels in the livers of Nrf2 knockout mice compared to wild type. Furthermore, phase I cytochrome P450s (CYPs), Cyp1, and Cyp2b10 at mRNA, protein, and catalytic activity levels were significantly lower in the livers of Nrf2 knockout mice. Interestingly, our results showed that the transcription factors AhR, constitutive androstane receptor (CAR), and pregnane X receptor (PXR) at mRNA, and protein expression levels were significantly lower in the livers of Nrf2 knockout mice compared to wild type. Importantly, phase III drug transporters mRNA levels of the multiple drug resistance associated proteins (Mrp2 and Mrp3), and solute carrier organic anion transporters (Slco1a6 and Slco2b1) were significantly lower in the liver of Nrf2 knockout mice. Co-activators, Ncoa1, Ncoa2, and Ncoa3 mRNA levels were not altered while co-repressors, Ncor1 and Ncor2 were significantly lower in the livers of Nrf2 knockout mice. In conclusion, knockout of Nrf2 causes disruption to the coordination of phase I, phase II drug DMEs, and phase III drug transporters through altering the transcription factors controlling them. PMID- 21281707 TI - Complex distribution patterns of voltage-gated calcium channel alpha-subunits in the spiral ganglion. AB - As with other elements of the peripheral auditory system, spiral ganglion neurons display specializations that vary as a function of location along the tonotopic axis. Previous work has shown that voltage-gated K(+) channels and synaptic proteins show graded changes in their density that confers rapid responsiveness to neurons in the high frequency, basal region of the cochlea and slower, more maintained responsiveness to neurons in the low frequency, apical region of the cochlea. In order to understand how voltage-gated calcium channels (VGCCs) may contribute to these diverse phenotypes, we identified the VGCC alpha-subunits expressed in the ganglion, investigated aspects of Ca(2+)-dependent neuronal firing patterns, and mapped the intracellular and intercellular distributions of seven VGCC alpha-subunits in the spiral ganglion in vitro. Initial experiments with qRT-PCR showed that eight of the ten known VGCC alpha-subunits were expressed in the ganglion and electrophysiological analysis revealed firing patterns that were consistent with the presence of both LVA and HVA Ca(2+) channels. Moreover, we were able to study seven of the alpha-subunits with immunocytochemistry, and we found that all were present in spiral ganglion neurons, three of which were neuron-specific (Ca(V)1.3, Ca(V)2.2, and Ca(V)3.3). Further characterization of neuron-specific alpha-subunits showed that Ca(V)1.3 and Ca(V)3.3 were tonotopically-distributed, whereas Ca(V)2.2 was uniformly distributed in apical and basal neurons. Multiple VGCC alpha-subunits were also immunolocalized to Schwann cells, having distinct intracellular localizations, and, significantly, appearing to distinguish putative compact (Ca(V)2.3, Ca(V)3.1) from loose (Ca(V)1.2) myelin. Electrophysiological evaluation of spiral ganglion neurons in the presence of TEA revealed Ca(2+) plateau potentials with slopes that varied proportionately with the cochlear region from which neurons were isolated. Because afterhyperpolarizations were minimal or absent under these conditions, we hypothesize that differential density and/or kinetics of one or more of the VGCC alpha-subunits could account for observed tonotopic differences. These experiments have set the stage for defining the clear multiplicity of functional control in neurons and Schwann cells of the spiral ganglion. PMID- 21281709 TI - Insights into the molecular correlates modulating functional compensation between monogenic and polygenic disease gene duplicates in human. AB - Functional redundancy by gene duplication appears to be a common phenomenon in biological system and hence understanding its underlying mechanism deserves much attention. Here, we investigated the differences between functional compensation of monogenic and polygenic disease genes which are unexplored till date. We found that the competence of functional buffering varies in the order of non-disease genes>monogenic disease genes>polygenic disease genes. This fact has been explained by the sequence identity, expression profile similarity, shared interaction partners and cellular locations between duplicated pairs. Moreover, we observed an inverse relationship between backup capacity and the non synonymous substitution rate of disease and non-disease genes while the opposite trend is found for their corresponding paralogs. Logistic regression analysis among sequence identity, sharing of expression profile, interaction partners and cellular locations with backup capacity between duplicated pairs demonstrated that the sharing of expression profile is the most dominant regulator of backup capacity. PMID- 21281710 TI - No difference in antibody titers against xenotropic MLV related virus in prostate cancer cases and cancer-free controls. AB - New ELISA assays were developed to measure immunoreactivity for XMRV. Antibody titers were measured in a cohort of prostate cancer cases and cancer free controls from the central United States. No statistically significant differences were observed in immunoreactivity between cases and controls for either the XMRV env or the XMRV-gag antigen. PMID- 21281711 TI - UVB-induced DNA damage, generation of reactive oxygen species, and inflammation are effectively attenuated by the flavonoid luteolin in vitro and in vivo. AB - Ultraviolet (UV) radiation induces DNA damage, oxidative stress, and inflammatory processes in human keratinocytes resulting in skin inflammation, photoaging, and photocarcinogenesis. The flavonoid luteolin is one of the most potent antioxidative plant polyphenols. We investigated the UV protective and antioxidant properties of luteolin in human keratinocytes in vitro, ex vivo, and in vivo. Spectrophotometric measurements revealed extinction maxima of luteolin in the UVB and UVA range. UV transmission below 370 nm was <10%. In human skin, luteolin effectively reduced the formation of UVB-induced cyclobutane pyrimidine dimers. The free radical scavenging activity of luteolin was assessed in various cell-free and cell-based assays. In the cell-free DPPH assay the half-maximal effective concentration (EC50) of luteolin (12 MUg/ml) was comparable to those of Trolox (25 MUg/ml) and N-acetylcysteine (32 MUg/ml). In contrast, in the H2DCFDA assay performed with UVB-irradiated keratinocytes, luteolin (EC50 3 MUg/ml) was much more effective compared to Trolox (EC50 12 MUg/ml) and N-acetylcysteine (EC50 847 MUg/ml). Luteolin also inhibited both UVB-induced skin erythema and the upregulation of cyclooxygenase-2 and prostaglandin E2 production in human skin via interference with the MAPK pathway. These data suggest that luteolin may protect human skin from UVB-induced damage by a combination of UV-absorbing, DNA protective, antioxidant, and anti-inflammatory properties. PMID- 21281712 TI - S-allylmercapto-N-acetylcysteine up-regulates cellular glutathione and protects vascular endothelial cells from oxidative stress. AB - Oxidative stress and/or low cellular glutathione (GSH) levels are associated with the development and progression of numerous pathological conditions. Cells possess various antioxidant protection mechanisms, including GSH and phase II detoxifying enzymes. N-acetylcysteine (NAC) supplies cells with cysteine to increase GSH level but its efficacy is relatively low because of its limited tissue penetration. Allicin (diallyl thiosulfinate), a reactive sulfaorganic compound, increases cellular GSH and phase II detoxifying enzymes in vascular endothelial cells (EC). A novel compound was designed: S-allylmercapto-N acetylcysteine (ASSNAC), a conjugate of S-allyl mercaptan (a component of allicin) and NAC. Both ASSNAC and NAC increased cellular GSH of ECs, reaching a maximum of up to four- and threefold increase after exposure for 24 or 6 h at a concentration of 0.2 or 1 mM, respectively. ASSNAC induced nuclear translocation of the activated transcription factor Nrf2 and expression of phase II detoxifying enzymes. EC exposure to tBuOOH resulted in 75% cytotoxicity, and pretreatment of cultures with 0.2 mM ASSNAC or 2mM NAC reduced cytotoxicity to 20 and 42%, respectively. In conclusion, ASSNAC is superior to NAC in protecting cells from oxidative stress because of its ability to up-regulate both GSH and the expression of phase II detoxifying enzymes. PMID- 21281715 TI - The relationships between extent and microstructural properties of the midsagittal corpus callosum in human brain. AB - Recent quantitative analyses of the corpus callosum (CC) have tried to assess the interhemispheric connectivity. Based on histological results showing an expansion of callosal extent at the midsagittal plane, without fiber density alterations, callosal extent was interpreted as an index of interhemispheric connectivity. The microstructural properties of the CC have also been investigated extensively using diffusion tensor imaging, to assess interhemispheric connectivity. The relationships between axonal density and callosal extent need to be investigated to understand how these parameters reflect interhemispheric connectivity. We used a semi-automated CC segmentation scheme in T1-weighted magnetic resonance image and fractional anisotropy (FA) image, respectively. The parameterization method of the segmented CC was applied to 47 right-handed healthy adult subjects. The callosal extent and microstructural properties were measured using the callosal thickness and diffusion indices (FA, mean diffusivity, and axial and radial diffusivity), respectively. Our results revealed a correlation between callosal thickness and FA on the posterior body and isthmus of the CC, which suggests that these regions are more sensitive to fiber alterations than other regions. Based on this result, we suggest that both the extent of the CC and its microstructural properties should be considered together in the estimation of interhemispheric connectivity in healthy adult populations. PMID- 21281713 TI - Estradiol impairs response inhibition in young and middle-aged, but not old rats. AB - Estrogens have been shown to have a strong influence on such cognitive domains as spatial memory, response learning, and several tasks of executive function, including both working memory and attention. However, the effects of estrogens on inhibitory control and timing behavior, both important aspects of executive function, have received relatively little attention. We examined the effects of estradiol on inhibitory control and timing behavior using a differential reinforcement of low rates of responding (DRL) task. Ovariectomized young (3 month), middle-aged (12 month), and old (18 month) Long-Evans rats were implanted with Silastic implants containing 0, 5 or 10% 17beta-estradiol in cholesterol vehicle and were tested on a DRL task requiring them to wait 15s between lever presses to receive a food reinforcer. The ratio of reinforced to non-reinforced lever presses did not differ across age in the cholesterol vehicle group. Conversely, 17beta-estradiol impaired learning of the DRL task in young and middle-aged rats, but the learning of old rats was not impaired relative to vehicle controls following either 5% or 10% 17beta-estradiol treatment. Overall, old rats also made fewer lever presses than both the young and middle-aged rats. These results provide new evidence that estrogens impair inhibitory control, an important aspect of self regulation, and add to existing evidence that estrogens differentially affect cognition at different ages. PMID- 21281716 TI - Prefrontal pathways target excitatory and inhibitory systems in memory-related medial temporal cortices. AB - The anterior cingulate cortex (ACC), situated in the caudal part of the medial prefrontal cortex, is involved in monitoring on-going behavior pertaining to memory of previously learned outcomes. How ACC information interacts with the medial temporal lobe (MTL) memory system is not well understood. The present study used a multitiered approach to address two questions on the interactions between the ACC and the parahippocampal cortices in the rhesus monkey: (1) What are the presynaptic characteristics of ACC projections to the parahippocampal cortices? (2) What are the postsynaptic targets of the pathway and are there laminar differences in innervation of local excitatory and inhibitory systems? Labeled ACC terminations were quantified in parahippocampal areas TH and TF and a cluster analysis showed that boutons varied in size, with a population of small (<=0.97 MUm) and large (>0.97 MUm) terminations that were nearly evenly distributed in the upper and deep layers. Exhaustive sampling as well as unbiased stereological techniques independently showed that small and large boutons were about evenly distributed within cortical layers in the parahippocampal cortex. Synaptic analysis of the pathway, performed at the electron microscope (EM), showed that while most of the ACC projections formed synapses with excitatory neurons, a significant proportion (23%) targeted presumed inhibitory classes with a preference for parvalbumin (PV+) inhibitory neurons. These findings suggest synaptic mechanisms that may help integrate signals associated with attention and memory. PMID- 21281717 TI - Fast and robust extraction of hippocampus from MR images for diagnostics of Alzheimer's disease. AB - Assessment of temporal lobe atrophy from magnetic resonance images is a part of clinical guidelines for the diagnosis of prodromal Alzheimer's disease. As hippocampus is known to be among the first areas affected by the disease, fast and robust definition of hippocampus volume would be of great importance in the clinical decision making. We propose a method for computing automatically the volume of hippocampus using a modified multi-atlas segmentation framework, including an improved initialization of the framework and the correction of partial volume effect. The method produced a high similarity index, 0.87, and correlation coefficient, 0.94, with semi-automatically generated segmentations. When comparing hippocampus volumes extracted from 1.5T and 3T images, the absolute value of the difference was low: 3.2% of the volume. The correct classification rate for Alzheimer's disease and cognitively normal cases was about 80% while the accuracy 65% was obtained for classifying stable and progressive mild cognitive impairment cases. The method was evaluated in three cohorts consisting altogether about 1000 cases, the main emphasis being in the analysis of the ADNI cohort. The computation time of the method is about 2 minutes on a standard laptop computer. The results show a clear potential for applying the method in clinical practice. PMID- 21281718 TI - 24-month effect of smoking cessation on cognitive function and brain structure in later life. AB - BACKGROUND: Observational studies investigating the association between smoking, cognitive decline and dementia have produced conflicting results. We completed this trial to determine if smoking cessation decreases the progression of cognitive decline in later life. METHODS: We recruited older smokers (n=229) and never smokers (n=98) and invited smokers to join a smoking cessation trial. The primary outcome of interest was change in Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog) scores over 24 months. Secondary measures included the Logical Memory test and changes in gray matter density. Successful smoking cessation was defined as a minimum of 547 smoking free days during follow up. RESULTS: The ADAS-cog scores of unsuccessful quitters (UQ) increased (i.e., became worse) 1.1+/-0.3 and 1.2+/-0.4 points more than the scores of never smokers (NS) (p=0.001) and successful quitters (SQ) (p=0.006) respectively over the 24 months of follow up. Similarly, the scores of UQ declined (i.e., became worse) relative to NS on measures of immediate (p=0.004) and delayed recall (p=0.029). All analyses were adjusted for age, years of education, baseline cognitive performance, alcohol use, depression scores, and the presence of chronic respiratory disease. Thirty-six NS, 18 SQ and 48 UQ completed the imaging substudy. Compared with NS, UQ showed a disproportional loss of gray matter density in the right thalamus, right and left inferior semi-lunar lobule, as well as left superior and inferior parietal lobule over 24 months. SQ showed loss of gray matter compared with NS in the right middle and inferior occipital gyri, right and left culmen, and the left superior frontal gyrus. We did not find any brain regions in which UQ had lost more gray matter than SQ over 2 years. CONCLUSION: These results are consistent with the hypothesis that smoking causes cognitive decline and loss of gray matter tissue in the brain over time. PMID- 21281719 TI - Pattern-information analysis: from stimulus decoding to computational-model testing. AB - Pattern-information analysis has become an important new paradigm in functional imaging. Here I review and compare existing approaches with a focus on the question of what we can learn from them in terms of brain theory. The most popular and widespread method is stimulus decoding by response-pattern classification. This approach addresses the question whether activity patterns in a given region carry information about the stimulus category. Pattern classification uses generic models of the stimulus-response relationship that do not mimic brain information processing and treats the stimulus space as categorical-a simplification that is often helpful, but also limiting in terms of the questions that can be addressed. We can address the question whether representations are consistent across different stimulus sets or tasks by cross decoding, where the classifier is trained with one set of stimuli (or task) and tested with another. Beyond pattern classification, a major new direction is the integration of computational models of brain information processing into pattern information analysis. This approach enables us to address the question to what extent competing computational models are consistent with the stimulus representations in a brain region. Two methods that test computational models are voxel receptive-field modeling and representational similarity analysis. These methods sample the stimulus (or mental-state) space more richly, estimate a separate response pattern for each stimulus, and can generalize from the stimulus sample to a stimulus population. Computational models that mimic brain information processing predict responses from stimuli. The reverse transform can be modeled to reconstruct stimuli from responses. Stimulus reconstruction is a challenging feat of engineering, but the implications of the results for brain theory are not always clear. Exploratory pattern analyses complement the confirmatory approaches mentioned so far and can reveal strong, unexpected effects that might be missed when testing only a restricted set of predefined hypotheses. PMID- 21281720 TI - Human reversal learning under conditions of certain versus uncertain outcomes. AB - Reversal learning tasks assess behavioral flexibility by requiring subjects to switch from one learned response choice to a different response choice when task contingencies change. This requires both the processing of negative feedback once a learned response is no longer reinforced, and the capacity for flexible response selection. In 2-choice reversal learning tasks, subjects switch between only two responses. Multiple choice reversal learning is qualitatively different in that at reversal, it requires subjects to respond to non-reinforcement of a learned response by selecting a new response from among several alternatives that have uncertain consequences. While activity in brain regions responsible for processing unexpected negative feedback is known to increase in relation to the hedonic value of the reward itself, it is not known whether the uncertainty of reinforcement for future response choices also modulates these responses. In an fMRI study, 15 participants performed 2- and 4-choice reversal learning tasks. Upon reversal in both tasks, activation was observed in brain regions associated with processing changing reinforcement contingencies (midbrain, ventral striatum, insula), as well as in neocortical regions that support cognitive control and behavioral planning (prefrontal, premotor, posterior parietal, and anterior cingulate cortices). Activation in both systems was greater in the 4- than in the 2-choice task. Therefore, reinforcement uncertainty for future responses enhanced activity in brain systems that process performance feedback, as well as in areas supporting behavioral planning of future response choices. A mutually facilitative integration of responses in motivational and cognitive brain systems might enhance behavioral flexibility and decision making in conditions for which outcomes for future response choices are uncertain. PMID- 21281721 TI - Locally Linear Diffeomorphic Metric Embedding (LLDME) for surface-based anatomical shape modeling. AB - This paper presents the algorithm, Locally Linear Diffeomorphic Metric Embedding (LLDME), for constructing efficient and compact representations of surface-based brain shapes whose variations are characterized using Large Deformation Diffeomorphic Metric Mapping (LDDMM). Our hypothesis is that the shape variations in the infinite-dimensional diffeomorphic metric space can be captured by a low dimensional space. To do so, traditional Locally Linear Embedding (LLE) that reconstructs a data point from its neighbors in Euclidean space is extended to LLDME that requires interpolating a shape from its neighbors in the infinite dimensional diffeomorphic metric space. This is made possible through the conservation law of momentum derived from LDDMM. It indicates that initial momentum, a linear transformation of the initial velocity of diffeomorphic flows, at a fixed template shape determines the geodesic connecting the template to a subject's shape in the diffeomorphic metric space and becomes the shape signature of an individual subject. This leads to the compact linear representation of the nonlinear diffeomorphisms in terms of the initial momentum. Since the initial momentum is in a linear space, a shape can be approximated by a linear combination of its neighbors in the diffeomorphic metric space. In addition, we provide efficient computations for the metric distance between two shapes through the first order approximation of the geodesic using the initial momentum as well as for the reconstruction of a shape given its low-dimensional Euclidean coordinates using the geodesic shooting with the initial momentum as the initial condition. Experiments are performed on the hippocampal shapes of 302 normal subjects across the whole life span (18-94years). Compared with Principal Component Analysis and ISOMAP, LLDME provides the most compact and efficient representation of the age-related hippocampal shapes. Even though the hippocampal volumes among young adults are as variable as those in older adults, LLDME disentangles the hippocampal local shape variation from the hippocampal size and thus reveals the nonlinear relationship of the hippocampal morphometry with age. PMID- 21281722 TI - Whole brain diffeomorphic metric mapping via integration of sulcal and gyral curves, cortical surfaces, and images. AB - This paper introduces a novel large deformation diffeomorphic metric mapping algorithm for whole brain registration where sulcal and gyral curves, cortical surfaces, and intensity images are simultaneously carried from one subject to another through a flow of diffeomorphisms. To the best of our knowledge, this is the first time that the diffeomorphic metric from one brain to another is derived in a shape space of intensity images and point sets (such as curves and surfaces) in a unified manner. We describe the Euler-Lagrange equation associated with this algorithm with respect to momentum, a linear transformation of the velocity vector field of the diffeomorphic flow. The numerical implementation for solving this variational problem, which involves large-scale kernel convolution in an irregular grid, is made feasible by introducing a class of computationally friendly kernels. We apply this algorithm to align magnetic resonance brain data. Our whole brain mapping results show that our algorithm outperforms the image based LDDMM algorithm in terms of the mapping accuracy of gyral/sulcal curves, sulcal regions, and cortical and subcortical segmentation. Moreover, our algorithm provides better whole brain alignment than combined volumetric and surface registration (Postelnicu et al., 2009) and hierarchical attribute matching mechanism for elastic registration (HAMMER) (Shen and Davatzikos, 2002) in terms of cortical and subcortical volume segmentation. PMID- 21281723 TI - Evidence for conceptual combination in the left anterior temporal lobe. AB - Conceptual combination allows for the construction of an infinite number of complex ideas from a finite base. The anterior temporal lobes appear to be important for the process of conceptual combination. In a previous study (Baron et al., 2010) we showed that the neural representation of complex concepts (e.g., young man) in the left anterior temporal lobe is additive. Specifically, in that region, the representation of a complex concept can be predicted by the superimposition of the voxel-wise neural representations of its constituent concepts (e.g., young+man). However, this finding could be the result of phonological similarity or the simple co-activation of constituent concepts. Here we use concepts that are only related semantically: boy, girl, woman, man, female, male, child, and adult. The neural representation for each concept was evoked through a visual categorization task. Subsequent brain maps were then analyzed using a searchlight analysis meant to show areas of the cortex where multiplicative (as well as additive) conceptual combination occurred (e.g., areas in which activations for boy correlated with the product of the activations for male and child). Across all participants, the left anterior temporal lobe showed such an effect. PMID- 21281724 TI - Molecular phylogeny of the Calanoida (Crustacea: Copepoda). AB - The order Calanoida includes some of the most successful planktonic groups in both marine and freshwater environments. Due to the morphological complexity of the taxonomic characters in this group, subdivision and phylogenies have been complex and problematic. This study establishes a multi-gene molecular phylogeny of the calanoid copepods based upon small (18S) and large (28S) subunits of nuclear ribosomal RNA genes and mitochondrial encoded cytochrome b and cytochrome c oxidase subunit-I genes, including 29 families from 7 superfamilies of the order. This analysis is more comprehensive than earlier studies in terms of number of families, range of molecular markers, and breadth of taxonomic levels resolved. Patterns of divergence of ribosomal RNA genes are shown to be significantly heterogeneous among superfamilies, providing a likely explanation for disparate results of previous studies. The multi-gene phylogeny recovers a monophyletic Calanoida, as well as the superfamilies Augaptiloidea, Centropagoidea, Bathypontioidea, Eucalanoidea, Spinocalanoidea and Clausocalanoidea. The phylogeny largely agrees with previously-published morphological phylogenies, including e.g., enlargement of the Bathypontioidea to include the Fosshageniidae. PMID- 21281725 TI - Deep sequencing of GDF5 reveals the absence of rare variants at this important osteoarthritis susceptibility locus. AB - OBJECTIVE: The common single nucleotide polymorphism (SNP) rs143383 in the 5' untranslated region (5'UTR) of growth and differentiation factor 5 (GDF5) is strongly associated with osteoarthritis (OA) and influences GDF5 allelic expression in vitro and in the joint tissues of OA patients. This effect is modulated in cis by another common SNP, also located within the 5'UTR, whilst a common SNP in the 3'UTR influences allelic expression independent of rs143383. DNA variants can be common, rare or extremely rare/unique. To therefore enhance our understanding of the allelic architecture of this very important OA susceptibility locus we sequenced the gene for potentially functional and novel rare variants. METHOD: Using the Sanger method we sequenced GDF5 in 992 OA patients and 944 controls, with DNA changes identified by sequencing software. We encompassed the protein-coding region of the two GDF5 exons, both untranslated regions and approximately 100 bp of the proximal promoter of the gene. RESULTS: We detected 13 variants. Six were extremely rare with minor allele frequencies (MAFs) of <= 0.0006. One is in a predicted transcription factor binding site in the GDF5 promoter whilst two substitute conserved amino acids. The remaining seven variants were common and are previously known variants, with MAFs ranging from 0.025 to 0.39. There was a complete absence of variants with frequencies in between the extremely rare (n=6) and the common (n=7). CONCLUSIONS: This is the first report of the deep sequencing of an OA susceptibility locus. The absence of rare variants informs us that within the regions of the gene that we have sequenced GDF5 does not harbour any novel variants that are able to contribute, at a population level, to the OA association signal mediated by rs143383 nor does it harbour, at a population level, any novel variants that can influence OA susceptibility independent of rs143383. PMID- 21281726 TI - A systematic review of the association between radiographic and clinical osteoarthritis of hip and knee. AB - OBJECTIVE: There is ongoing debate on whether an association between radiographic and clinical osteoarthritis (OA) exists. We hypothesized that the inconsistency in the detection of an association might be caused by different definitions of OA, by different radiographic protocols, and by scoring methods for radiographic damage and symptoms. The goal of this study was to evaluate which methodological criteria are important to detect an association between radiographic and clinical OA of hip and knee. METHODS: A literature search was performed with the keywords 'OA', 'hip', 'knee', 'radiographic', and 'clinical' and results were screened for relevant studies. Quality criteria for study characteristics and methodology were developed. Studies were classified according to these criteria and the presence of an association between radiographic and clinical OA was scored. The importance of methodological quality and patient characteristics on the presence of an association was evaluated. RESULTS: The literature search resulted in 39 studies describing an association between radiographic and clinical OA. The frequency of an association between radiographic and clinical OA outcome measures diminished when less quality criteria were fulfilled. Specifically the criterion for standardized outcome measures appeared important in the detection of an association. The association was not influenced by patient characteristics. Only four studies were identified that fulfilled all quality criteria and in these studies an association was found for the knee joint and an inconsistent association was found for the hip joint. CONCLUSION: Methodological quality criteria are of importance to reveal an association between radiographic and clinical OA. PMID- 21281727 TI - Identification and characterization of putative osmosensors, HwSho1A and HwSho1B, from the extremely halotolerant black yeast Hortaea werneckii. AB - In Saccharomyces cerevisiae, the Sho1 protein is one of two potential osmosensors that can activate the kinase cascade of the HOG pathway in response to increased extracellular osmolarity. Two novel SHO1-like genes, HwSHO1A and HwSHO1B, have been cloned from the saltern-inhabiting, extremely halotolerant black yeast Hortaea werneckii. The HwSho1 protein isoforms are 93.8% identical in their amino acid sequences, and have a conserved SH3 domain. When the HwSHO1 genes were transferred into S. cerevisae cells lacking the SHO1 gene, both of the HwSho1 isoforms fully complemented the function of the native S. cerevisiae Sho1 protein. Through microscopic and biochemical validation, we demonstrate that in S. cerevisiae, both of the HwSho1 proteins have characteristic subcellular localizations similar to the S. cerevisiae Sho1 protein, and they can both activate the HOG pathway under conditions of osmotic stress. To a lower extent, crosstalk to the mating pathway expressing HwSho1 proteins is conserved in the PBS2 deleted S. cerevisiae strain. These data show that the HwSho1 proteins from H. werneckii are true functional homologs of the Sho1 protein of S. cerevisiae. PMID- 21281728 TI - Cataloging and profiling genes expressed in Lentinula edodes fruiting body by massive cDNA pyrosequencing and LongSAGE. AB - This study investigated the molecular mechanism of the fruiting body development and sporulation in the cap of the Shiitake mushroom, Lentinula edodes. Although there has been much research into L. edodes, there remain significant gaps in our knowledge of how the species reproduces. In order to provide molecular resources and to understand the molecular mechanism of the fruiting body development in basidiomycete comprehensively, we searched for the genes which are important for fruiting body development and sporulation in the cap of mature fruiting body of L. edodes by using the whole-genome approach. Massive cDNA pyrosequencing was used to generate >7000 sequence contigs from mature fruiting bodies. We used Gene Ontology to categorize the contigs to form the catalog of genes expressed at the stage of the mature fruiting body. We also assigned the contigs into the KEGG pathways. The catalog of expressed genes indicates that the mature fruiting bodies (1) sense the external environment, (2) transmit signals to express genes through regulatory systems, (3) produce many proteins, (4) degrade unwanted proteins, (5) perform extensive biosynthesis, (6) generate energy, (7) regulate the internal environment, (8) transport molecules, (9) carry out cell division, and (10) differentiate and develop. After establishing the catalog of expressed genes in L. edodes, we used the LongSAGE approach to analyze the expression levels of genes found in mature fruiting bodies before (FB) and after (FBS) spores appeared. Gene-expression patterns according to GO categories were similar in these two stages. We have also successfully identified genes differentially expressed in FB and FBS. Fold-changes in expression levels of selected genes based on LongSAGE tag counts were similar to those obtained by real-time RT-PCR. The consistency between real-time RT-PCR and LongSAGE results indicates reliability of the LongSAGE results. Overall, this study provides valuable information on the fruiting processes of L. edodes through a combination of massive cDNA pyrosequencing and LongSAGE sequencing, and the knowledge thereby obtained may provide insight into the improvement of the yield of commercially grown Shiitake mushrooms. PMID- 21281729 TI - A mutation in the Cc.ubc2 gene affects clamp cell morphogenesis as well as nuclear migration for dikaryosis in Coprinopsis cinerea. AB - The formation and proliferation of the dikaryon in the agaricomycete Coprinopsis cinerea is controlled by the mating type genes, A and B. The B genes, which encode pheromones and pheromone receptors, control nuclear migration for dikaryosis as well as the fusion of the clamp cell with the subterminal cell while the A genes, which encode two classes of homeodomain proteins, control conjugate nuclear division associated with clamp connection development. We characterized the mutant, B28, which was newly isolated as a strain that fails to form a primary hyphal knot, the first visible sign toward fruiting, from a homokaryotic fruiting strain after REMI mutagenesis. Detailed phenotypic analysis revealed that strain B28 exhibits, in addition to the fruiting defect, a defect in A-regulated clamp cell morphogenesis as well as a defect in B-regulated nuclear migration for dikaryosis. The mutant clamp cells are unique in that they continue growing like branches without fusing with the subterminal cells, in contrast to the unfused pseudoclamp which are normally formed in A-on B-off strains, providing evidence for the existence of an as yet unidentified mechanism for the growth suppression of the clamp cell. Molecular analysis revealed that the gene responsible for the phenotypes, designated Cc.ubc2, encodes a protein similar to Ubc2, an adaptor protein for filamentous growth, pheromone response and virulence in the smut fungus Ustilago maydis. In addition, western blot analysis demonstrated that the Cc.ubc2-1 mutation blocks phosphorylation of a presumptive MAP kinase. PMID- 21281730 TI - Up-regulation of arginase II contributes to pulmonary vascular endothelial cell dysfunction during experimental pulmonary embolism. AB - Pulmonary embolism (PE) causes pulmonary hypertension by mechanical obstruction and constriction of non-obstructed vasculature. We tested if experimental PE impairs pulmonary vascular endothelium-dependent dilation via activation of arginase II. Experimental PE was induced in male Sprague-Dawley rats by infusing 25 MUm microspheres in the right jugular vein, producing moderate pulmonary hypertension. Shams received vehicle injection. Pulmonary arterial rings were isolated after 18 h and isometric tensions were determined. Dilations were induced with acetylcholine, calcium ionophore A23187 or nitroglycerin (NTG) in pre-contracted rings (phenylephrine). Protein expression was assessed by Western blot and immunohistochemistry. Arginase activity was inhibited by intravenous infusion of N(w)-hydroxy-nor-l-arginine (nor-NOHA). l-Arginine supplementation was also given. Endothelium-dependent dilation responses were significantly reduced in PE vs. vehicle-treated animals (ACh: 50 +/- 9% vs. 93 +/- 3%; A23187: 19 +/- 7% vs. 85 +/- 7%, p < 0.05), while endothelium-independent dilations (NTG) were unchanged. Endothelial nitric oxide synthase (eNOS) protein content was unchanged by PE. Expression of arginase II increased 4.5-fold and immunohistochemistry revealed increased arginase II staining. Nor-NOHA treatment and l-arginine supplementation significantly improved pulmonary artery ring endothelium-dependent dilation in PE (ACh: 58 +/- 6% PE, 88 +/- 6% PE + nor-NOHA, 84 +/- 4% PE + l-arginine). Experimental PE impairs endothelium-dependent pulmonary artery dilation, while endothelium-independent dilation remains unchanged. The data support the conclusion that up-regulation of arginase II protein expression contributes to pulmonary artery endothelial dysfunction in this model of experimental PE. PMID- 21281731 TI - Adaptive haemoglobin gene control in Daphnia pulex at different oxygen and temperature conditions. AB - Hypoxia-induced haemoglobin (Hb) expression is a central regulatory mechanism in Daphnia in response to environmental hypoxia or warm temperatures. Changes in Hb concentration as well as Hb subunit composition, which modulate Hb oxygen affinity, guarantee the oxygen supply of tissues under these environmental conditions. Based on the sequenced D. pulex genome, Hb genes were related to the properties of haemolymph Hb, which included its concentration and oxygen affinity (both measured by spectrophotometry) as well as the Hb subunit composition (determined by 2-D gel electrophoresis and ESI-MS analysis). Permanent cultures of D. pulex acclimated to different oxygen conditions (normoxia and hypoxia) and temperatures (10 degrees C, 20 degrees C, and 24 degrees C), showed characteristic changes in Hb concentration, subunit composition and oxygen affinity. Several subunits (Hb4, Hb7, Hb8, and Hb10) were obviously responsible for changes in oxygen affinity including those, which carry a number of hypoxia responsive elements (HREs) upstream of the respective gene (hb4 and hb10). Analysing the effects of different oxygen- or temperature-acclimations on Hb subunit expression in D. pulex and D. magna on a common basis (Hb concentration or oxygen affinity) revealed a general pattern of oxygen and temperature effects on Hb, which implies that Hb quantity and quality are mostly influenced by the degree of tissue hypoxia. Differences between both species in the onset of hypoxia-induced differential Hb expression and Hb oxygen affinity, which are probably related to different HRE patterns and functionally important differences in the amino acid sequence of only a few subunits, cause a reduced ability of D. pulex to adjust Hb function to temperature changes in comparison to D. magna. PMID- 21281732 TI - Imbalanced dietary ascorbic acid alters molecular pathways involved in skeletogenesis of developing European sea bass (Dicentrarchus labrax). AB - The influence of dietary ascorbic acid (AA) on growth and morphogenesis during the larval development of European sea bass (Dicentrarchus labrax) was evaluated until 45days post hatching. Diets incorporated 0, 5, 15, 30, 50 or 400mg AA per kg diet to give AA-0, AA-5, AA-15, AA-30, AA-50 and AA-400 dietary treatments, respectively. Dietary AA levels lower than 15mg/kg reduced larval growth and survival was affected in specimens fed diets devoid of AA. Globally, disruption of the expression of genes involved in AA and calcium absorption in the intestine (SVCT-1, TRPV-6), skeletogenesis (BMP-4, IGF-1, RARgamma) and bone mineralization (VDRbeta, osteocalcin) were observed in groups fed doses lower and higher than 50mg AA/kg diet. Such disturbances detected at molecular level were associated with disruptions of the ossification process and the appearance of skeletal abnormalities. PMID- 21281734 TI - The contribution of ventricular apicobasal and transmural repolarization patterns to the development of the T wave body surface potentials in frogs (Rana temporaria) and pike (Esox lucius). AB - The study aimed at the simultaneous determination of the transmural and apicobasal differences in the repolarization timing and the comparison of the contributions of these two repolarization gradients to the development of the body surface T wave potentials in animals with the single heart ventricle (fishes and amphibians). Unipolar potentials were measured on the body surface, epicardium and in the intramural (subepicardial, Epi; midmyocardial; and subendocardial, Endo) ventricular layers of 9 pike and 8 frogs. Activation times, repolarization times and activation-recovery intervals were determined. A transmural gradient in repolarization durations in frogs (Endo>Epi, P<0.024) corresponds to the gradient in repolarization times. No significant transmural difference in repolarization duration is observed in pike that produces a repolarization sequence from Endo to Epi (Endo=85% maximal oxygen uptake; 20.7+/-9.8min). Individual post hoc calculation of TwPdi(c) was conducted (diaphragmatic contractility versus lung volume). Diaphragmatic fatigue (i.e. TwPdi reduction baseline/recovery >=10%) occurred in 9/11 subjects (82% "fatiguers"; baseline/recovery TwPdi(c) -16+/-13%, p<0.01). Fatiguers TwPdi(c) was: baseline: 2.99+/-0.40kPa, exercise-onset: 2.98+/-0.41kPa, initial third: 2.80+/-0.67kPa, second third: 2.54+/-0.55kPa, final third-task failure: 2.51+/-0.44kPa, recovery: 2.50+/-0.52kPa. Diaphragmatic contractility and lung volume (rest) were strongly related (r(2)=0.98, mean TwPdi(c) gradient 0.78kPa/l). To conclude, diaphragmatic contractility (lung volume corrected) decreases relatively early (initial two thirds) during exhaustive exercise and remains preserved towards task failure. This confirms previous assumptions postulating that respiratory performance is sustained without further fatigue of the primary inspiratory muscle. PMID- 21281745 TI - Inflammatory cytokine response to titanium chemical composition and nanoscale calcium phosphate surface modification. AB - Nanoscale surface modification of titanium dental implants with calcium phosphate (CaP) has been shown to achieve superior bone wound healing and osseointegration compared with smooth or microrough titanium surfaces alone. As bone healing has been shown to be influenced by the action of cytokines, this study examined whether changes in cytokine gene expression from RAW 264.7 cells cultured on commercially pure and titanium alloy (Ti-6Al-4V) microrough or nanoscale crystalline CaP-modified surfaces, may influence downstream events in bone wound healing and osseointegration. Whilst no significant difference in the attachment or proliferation of RAW 264.7 cells was observed, the nanoscale CaP-modified surface elicited a gene expression profile with marked down-regulation of a number of pro-inflammatory cytokines and chemokines. Inflammatory cytokine gene expression was further influenced by chemical composition, with lower levels of pro-inflammatory markers noted following exposure of the macrophage-like cells to titanium alloy (Ti-6Al-4V) compared with the commercially pure titanium surface. Down-regulation of pro-inflammatory cytokine gene expression (confirmed at the protein level for TNFalpha and CCL5), may thus facilitate the enhanced bone wound healing and osseointegration observed clinically with nanoscale calcium phosphate modified implant surfaces. PMID- 21281746 TI - Resection of liver metastases from breast cancer: towards a management guideline. AB - In selected patients with colorectal and neuroendocrine liver metastases, the outcome of liver resection is well established with 5-year survival rates ranging from 25% to 60%. However, the role of liver resection for non-colorectal non neuroendocrine (NCRCE) liver metastases has not been fully established. Liver metastases in breast cancer are common and a small number of those patients may be suitable for surgical resection. There have been some case series with low mortality and morbidity and prolonged survival after liver resection. We performed this review to evaluate the overall and disease free survival after liver resections for breast metastases. Extensive search of Pubmed, Medline, Cochrane database was performed and data was analysed. Although mostly case series with smaller number of patients, outcome has been comparable to colorectal liver metastases in selected group of patients with 5 years survival rate at the range of 20%-60% with main prognostic factors of being the absence of extrahepatic disease (in exception of isolated pulmonary and bony metastasis) and to achieve an R0 resection. PMID- 21281747 TI - Identification of novel alternative splicing variants of interferon regulatory factor 3. AB - Interferon regulatory factor 3 (IRF-3) plays a crucial role in host defense against viral and microbial infection as well as in cell growth regulation. IRF 3a is the only structurally and functionally characterized IRF-3 splicing variant and has been established to antagonize IRF-3 activity. Here, five novel splicing variants of IRF-3, referred to as IRF-3b, -3c, -3d, -3e, and -3f, were identified and shown to be generated by deletion of exons 2, 3, or 6 or some combination thereof. RT-PCR examination revealed that these novel splicing variants were more frequently expressed in human liver, esophagus, and cervical tumor tissues than in their normal counterparts. Additionally, electrophoretic mobility shift assay and subcellular localization showed only IRF-3 and IRF-3e were capable of binding the PRDI/III element of interferon-beta (IFNbeta) promoter in vitro and underwent cytoplasm-to-nucleus translocation following Poly(I:C) stimulation. Coimmunoprecipitation assay revealed that only IRF-3c (3f) of novel splicing variants associated with IRF-3 in vivo. Further luciferase assay showed IRF-3c (3f) and IRF-3e failed to transactivate PRDI/III-containing promoter but appeared to inhibit transactivation potential of IRF-3 to varying degrees. Taken together, our findings suggest novel splicing variants may function as negative modulators of IRF-3 and may be correlated with pathogenesis of human tumors. PMID- 21281748 TI - Pharmacology of bisphosphonates. AB - Four decades of preclinical and clinical research of the pharmacology of bisphosphonates have generated data and concepts that have considerably improved their clinical use. However, despite this progress several pharmacological aspects relevant to bisphosphonate action on bone are still incompletely understood. This is mainly due to the complex, unique pharmacological properties of bisphosphonates. We review here the pharmacokinetic and pharmacodynamic data of bisphosphonates that are relevant for their clinical application and for the potential choice of a given compound, focusing on uncertainties that still exist. PMID- 21281749 TI - Association of bone turnover markers and arterial stiffness in pre-dialysis chronic kidney disease (CKD). AB - Vascular calcification (VC) is highly prevalent in CKD and leads to increased vascular stiffness and cardiovascular disease (CVD). Non-traditional cardiovascular risk factors include abnormal bone turnover and/or dysregulation of the calcification inhibitors, although their relative contribution remains unclear. We investigated the association between bone turnover, the calcification inhibitors (matrix gla protein; MGP and Fetuin-A), and the phosphate regulating hormone; fibroblast growth factor-23 (FGF-23) and arterial stiffness in pre dialysis CKD patients. One hundred and forty-five patients with CKD stages 1-4 (74 M, 71 F) aged (mean [SD]) 53 [14] years were studied. Bone turnover markers (bone-specific alkaline phosphatase (BALP) and tartrate-resistant acid phosphatase (TRACP)) and MGP, Fetuin-A and FGF-23 were determined. BMD was measured at the lumbar spine (LS), femoral neck (FN), forearm (FARM) and total hip (TH). Arterial stiffness was assessed by contour analysis of digital volume pulse (SI(DVP)). There was a significant positive correlation between TRACP:BALP ratio and SI(DVP) ( r=0.19, p=0.023). Following multi-linear regression analysis, significant associations were seen between serum BALP (p=0.037), TRACP (p=0.009) and TRACP:BALP ratio (p=0.001) and SI(DVP) independently of traditional CVD risk factors. No significant relationship between SI(DVP) and MGP, Fetuin-A and FGF-23 was observed. A significant negative correlation was seen between BMD at the FARM and SI(DVP) in CKD stage 4 (r=-0.35, p=0.024). The association remained significant following correction for age, gender and cardiovascular risk factors (p=0.029). Our data suggest a link between imbalances in bone turnover and arterial stiffness in pre-dialysis CKD. Longitudinal studies are needed to evaluate the clinical usefulness of these bone turnover markers as predictors of CVD in CKD. PMID- 21281750 TI - A new animal model for implant-related infected non-unions after intramedullary fixation of the tibia in rats with fluorescent in situ hybridization of bacteria in bone infection. AB - There is no adequate animal model to mimic the difficult clinical situation of infected non-union of the tibia after intramedullary stabilization. The purpose was to establish an animal model of implant-related infected non-unions of the tibia in rats. Furthermore, it was evaluated if detection of bacteria by fluorescent in situ hybridisation (FISH) technique is possible in bone infection. 17 rats were used in which osteotomy of the midshaft tibia was performed and stabilized with an intramedullary device. Two groups were tested: group 1: contamination of the osteotomy site with 10(4) colony forming units (CFUs) of Staphylococcus aureus (11 animals), group 2: no bacterial contamination (6 animals). The animals were sacrificed after 42 days and bone healing and infection were assessed clinically, by X-ray, micro-CT, and microbiological methods including FISH technique using EUB and STAPHY probes. Histology and scanning electron microscopy (SEM) for biofilm formation were performed. All animals of the control group showed uneventful bone healing after 6 weeks without any signs of local infections. 10 of 11 (90.9%) animals of group 1 with bacterial contamination exhibited infected non-union formation with positive clinical, radiological and microbiological infection signs of the tibia but without any systemic infection signs. FISH technique was able to identify bacteria in the infected bone. All intramedullary implants from the infected animals showed positive biofilm formation in SEM. This work presents the first animal model for the induction of intramedullary device-related infected non-union in the tibia and detection of bacteria by FISH technique in infected bone. PMID- 21281751 TI - FOXO1 modulates osteoblast differentiation. AB - Forkhead box O1 (FOXO1) is upregulated during bone formation and in response to stimulation by bone morphogenetic proteins. Studies presented here examined the functional role of FOXO1 in a well defined culture system in which pre osteoblastic cells undergo terminal differentiation in vitro. Mineralizing cultures of MC3T3-E1 cells were examined with or without FOXO1 knockdown by RNAi. Normal cells show the upregulation of FOXO1 and RUNX2 DNA binding activity, alkaline phosphatase activity, and mRNA levels of FOXO1, RUNX2, type 1 collagen, osteocalcin and MMP13 during formation of mineralizing nodules. In FOXO1 depleted cells each of these measurements was significantly reduced compared to values in control cells transfected with scrambled siRNA (P<0.05). Depletion of FOXO1 also reduced the number of mineralized nodules formed. Moreover, chromatin immunoprecipitation assays revealed a direct interaction of FOXO1 with the RUNX2 promoter. Overexpression of FOXO1 reduced the MC3T3-E1 cell number and the number of PCNA positive cells with little effect on apoptosis. These findings indicate that FOXO1 plays an important role in promoting osteoblast differentiation and suppressing proliferation in differentiating cells. PMID- 21281752 TI - The role of myeloid receptors on murine plasmacytoid dendritic cells in induction of type I interferon. AB - This study tested the hypothesis that a set of predominantly myeloid restricted receptors (F4/80, CD36, Dectin-1, CD200 receptor and mannan binding lectins) and the broadly expressed CD200 played a role in a key function of plasmacytoid DC (pDC), virally induced type I interferon (IFN) production. The Dectin-1 ligands zymosan, glucan phosphate and the anti-Dectin-1 monoclonal antibody (mAb) 2A11 had no effect on influenza virus induced IFNalpha/beta production by murine splenic pDC. However, mannan, a broad blocking reagent against mannose specific receptors, inhibited IFNalpha/beta production by pDC in response to inactivated influenza virus. Moreover, viral glycoproteins (influenza virus haemagglutinin and HIV-1 gp120) stimulated IFNalpha/beta production by splenocytes in a mannan inhibitable manner, implicating the function of a lectin in glycoprotein induced IFN production. Lastly, the effect of CD200 on IFN induction was investigated. CD200 knock-out macrophages produced more IFNalpha than wild-type macrophages in response to polyI:C, a MyD88-independent stimulus, consistent with CD200's known inhibitory effect on myeloid cells. In contrast, blocking CD200 with an anti CD200 mAb resulted in reduced IFNalpha production by pDC-containing splenocytes in response to CpG and influenza virus (MyD88-dependent stimuli). This suggests there could be a differential effect of CD200 on MyD88 dependent and independent IFN induction pathways in pDC and macrophages. This study supports the hypothesis that a mannan-inhibitable lectin and CD200 are involved in virally induced type I IFN induction. PMID- 21281753 TI - Exercising the freedom to choose. PMID- 21281754 TI - AORN Congress: Bringing it home. PMID- 21281756 TI - Maintenance and repair of anesthesia machines. PMID- 21281757 TI - Electrosurgery not a likely culprit for this burn injury. PMID- 21281759 TI - Pressure ulcer prevention. PMID- 21281760 TI - A few minutes with Lyda C. Arevalo-Flechas. PMID- 21281765 TI - Anterior cruciate ligament reconstruction of the knee. AB - Anterior cruciate ligament (ACL) injuries affect more than 175,000 patients annually. Located in the center of the knee joint, the ACL is the major stabilizing ligament of the knee. If the ACL is injured, then the knee becomes unstable and can buckle when the person pivots. Surgeons can use autograft or allograft tissue to accomplish ACL reconstruction by using a single-bundle or double-bundle type of repair. The surgeon performs the reconstruction arthroscopically, using two ports and a small incision over the anteromedial surface of the tibia to facilitate passage of the graft and for distal fixation of the graft. Correct placement of the tibial and femoral tunnels is the most important technical aspect of the procedure. After reconstruction, the patient must undergo intense physical therapy starting one or two days after surgery. If diligent with physical therapy, then the patient can return to full activity as soon as four months after surgery. PMID- 21281766 TI - Surviving OR computerization. AB - In 2007, a steering committee at West Virginia University Hospitals, Morgantown, began a three-year, accelerated design, computer implementation project to institute an automated perioperative record. The process included budgeting, selecting a vendor, designing and building the system, educating perioperative staff members, implementing the system, and re-evaluating the system for upgrades. Important steps in designing and building the system included mapping patient care and documentation processes, assessing software and hardware needs, and creating a new preference card system and surgical scheduling system. Staff members were educated to use the new computer applications via contests, inservice programs, hands-on learning modules, and a preimplementation rehearsal. Role-based security ensures that staff members are granted access to the computer applications they need to perform the work defined by their scope of practice. Planning ensures that the computer system will be maintained and enhanced over time. PMID- 21281767 TI - Intraoperative monitoring technician: a new member of the surgical team. AB - As surgery needs have increased, the traditional surgical team has expanded to include personnel from radiology and perfusion services. A new surgical team member, the intraoperative monitoring technician, is needed to perform intraoperative monitoring during procedures that carry a higher risk of central and peripheral nerve injury. Including the intraoperative monitoring technician on the surgical team can create challenges, including surgical delays and anesthesia care considerations. When the surgical team members, including the surgeon, anesthesia care provider, and circulating nurse, understand and facilitate this new staff member's responsibilities, the technician is able to perform monitoring functions that promote the smooth flow of the surgical procedure and positive patient outcomes. PMID- 21281768 TI - Engaging undergraduate nursing students in perioperative research. AB - Actively engaging in perioperative research lays a framework for stimulating interest in future research possibilities and provides students and graduate nurses with challenges to keep them interested as their careers progress. In this article, former honors students and a faculty researcher share their perceptions of participating in perioperative research. The primary investigator must emphasize learning throughout the process, be available to the students, provide structured guidance, and clarify the goals and expectations of the research experience. The students gain a greater understanding of the research process, discover the dedication and ethical values that are required of the researcher, learn how theory becomes the underlying framework for the research, and discover how descriptive statistics can be used to help explain the study results. Involvement in applied research may encourage these students to continue to contribute to evidence-based practice when they are employed as nurses and thus improve patient care. PMID- 21281769 TI - Perioperative pharmacology: pharmacotherapeutics, pharmacokinetics, and pharmacodynamics. AB - Results of current research into perioperative medication errors have revealed that more than half of medication errors occur during the administration phase of the medication-use process. The administration phase is the point at which the medication and the patient intersect and the medication imposes its pharmacological effect. During this phase, the only safety net between the patient and the medication is the health care provider's attention and care when administering the medication. To help mitigate these errors, perioperative nurses must understand pharmacotherapeutics: the use of medications to prevent, treat, cure, or alleviate symptoms of disease. Pharmacotherapeutics incorporates pharmacokinetics (ie, what the body does to a medication after it enters the system) and pharmacodynamics (ie, how a medication acts on the body to achieve a desired therapeutic effect). PMID- 21281770 TI - Implementing safe computer practices. PMID- 21281771 TI - Information literacy: implications for perioperative nurses. AB - The concept of information literacy may be new to some perioperative nurses; however, embracing this concept will help nurses identify situations that necessitate gaining more information, locate and access information sources, evaluate and analyze data, and cite information in compliance with copyright and fair use laws. The culture of health care is continually changing as a result of new technology and new methods to improve patient care, and this creates an information explosion. Perioperative educators should add information literacy as a strategic goal for obtaining Magnet status because it is foundational to evidence-based practice. Administrators also should advocate to obtain resources that will enable nurses to access information that addresses current patient care issues. PMID- 21281772 TI - Preventing infection: collaboration between surgical team members and infection preventionists. PMID- 21281773 TI - Cultural competence and perioperative nursing practice in New Zealand. PMID- 21281776 TI - Mark my tooth. PMID- 21281778 TI - Activation-induced cytidine deaminase and aberrant germinal center selection in the development of humoral autoimmunities. AB - Humoral immunity, which is the branch of the immune system governed by B cells, protects the body from extracellular pathogens through the secretion of immunoglobulins. Given the unpredictability of exogenous antigens, B cells must be accommodating to numerous genetic alterations to mold immunoglobulin specificity to recognize offending pathogens. Abnormalities in this process leave the host susceptible to permanent pathological modifications and in particular humoral autoimmunities in which secreted immunoglobulins mistake host proteins as pathogenic targets. Underlying the development of self-reactive immunoglobulins is activation-induced cytidine deaminase (AID), a mutagenic enzyme responsible for modifying the specificity of B cells by producing point mutations at the immunoglobulin gene locus. Ideally, these mutations result in an increased affinity for exogenous antigens. However, in pathological scenarios, these mutations produce or enhance a B cell's ability to target the host. AID-induced mutations occur in the germinal center microenvironment of peripheral lymphoid tissue, where pathogenic B-cell clones must evade overwhelming selection pressures to be released systemically. Recent research has revealed numerous genes and pathways responsible for eliminating self-reactive clones within the germinal center. On the basis of these studies, this review aims to clarify the link between AID and the generation of pathogenic immunoglobulins. Furthermore, it describes the selective pressures that pathogenic B cells must bypass within the germinal center to secrete immunoglobulins that ultimately result in disease. PMID- 21281779 TI - Regulation of biliary proliferation by neuroendocrine factors: implications for the pathogenesis of cholestatic liver diseases. AB - The proliferation of cholangiocytes occurs during the progression of cholestatic liver diseases and is critical for the maintenance and/or restoration of biliary mass during bile duct damage. The ability of cholangiocytes to proliferate is important in many different human pathologic conditions. Recent studies have brought to light the concept that proliferating cholangiocytes serve as a unique neuroendocrine compartment in the liver. During extrahepatic cholestasis and other pathologic conditions that trigger ductular reaction, proliferating cholangiocytes acquire a neuroendocrine phenotype. Cholangiocytes have the capacity to secrete and respond to a variety of hormones, neuropeptides, and neurotransmitters, regulating their surrounding cell functions and proliferative activity. In this review, we discuss the regulation of cholangiocyte growth by neuroendocrine factors in animal models of cholestasis and liver injury, which includes a discussion of the acquisition of neuroendocrine phenotypes by proliferating cholangiocytes and how this relates to cholangiopathies. We also review what is currently known about the neuroendocrine phenotypes of cholangiocytes in human cholestatic liver diseases (ie, cholangiopathies) that are characterized by ductular reaction. PMID- 21281780 TI - TGF-beta sequestration by mesangial cell integrin alphavbeta8: A novel mechanism of glomerular endothelial cell regulation. PMID- 21281781 TI - Family portrait: renal progenitor of Bowman's capsule and its tubular brothers. PMID- 21281782 TI - Bone marrow-derived progenitor cells do not contribute to podocyte turnover in the puromycin aminoglycoside and renal ablation models in rats. AB - A key event in the progression of glomerular disease is podocyte loss that leads to focal and segmental glomerulosclerosis (FSGS). Because adult podocytes are postmitotic cells, podocyte replacement by bone marrow-derived progenitors could prevent podocytopenia and FSGS. This study uses double immunofluorescence for Wilms' tumor-1 and enhanced green fluorescent protein (eGFP) to examine whether an eGFP-positive bone marrow transplant can replace podocytes under normal circumstances and in 3 different rat models of FSGS: puromycin aminoglycoside nephropathy, subtotal nephrectomy, and uninephrectomy. Bone marrow engraftment was successful, with more than 70% eGFP-positive cells and virtually normal histologic findings. No bone marrow transplant-derived podocytes were found in four control rats after transplantation, in nine rats at up to 10 weeks after puromycin aminoglycoside nephropathy induction, in three rats 23 days after subtotal nephrectomy, and in six rats up to 21 days after uninephrectomy. A total of 2200 glomeruli with 14,474 podocytes were evaluated in all groups. Thus, podocyte replacement by bone marrow-derived cells does not contribute to podocyte turnover in rats, even in models of podocyte damage. This is in contrast to previous studies in mice, in which bone marrow-derived podocytes were found. Further studies will address this discrepancy, which could be explained by species differences or by predominant podocyte regeneration from a parietal epithelial cell niche. PMID- 21281783 TI - The development of cutaneous neurofibromas. AB - Cutaneous neurofibromas are the hallmarks of neurofibromatosis type 1 (NF1). They are composed of multiple cell types, and traditionally they are believed to arise from small nerve tributaries of the skin. A key finding in the context of this view has been that subpopulations of tumor Schwann cells harbor biallelic inactivation of the NF1 gene (NF1(-/-)). In the present study, our aim was to clarify further the pathogenesis of cutaneous neurofibromas. First, we detected cells expressing multipotency-associated biomarkers in cutaneous neurofibromas. Second, we developed a method for isolating and expanding multipotent neurofibroma-derived precursor cells (NFPs) from dissociated human cutaneous neurofibromas and used it to analyze their growth and differentiation potential. In analogy to solitary cells resident in neurofibromas, NFPs were found to express nestin and had the potential to differentiate to, at least, Schwann cells, neurons, epithelial cells, and adipocytes. Mutation analysis of the NFPs revealed that their genotype was NF1(+/-). The results led us to speculate that the development of cutaneous neurofibromas includes the recruitment of multipotent NF1(+/-) precursor cells. These cells may be derived from the multipotent cells of the hair roots, which often are intimately associated with microscopic neurofibromas. PMID- 21281784 TI - Reduced stathmin-1 expression in natural killer cells associated with spontaneous abortion. AB - Female CBA/J mice impregnated by male DBA/2J mice (CBA/J*DBA/2J matings) are prone to spontaneous abortion, although the reason for this is unclear. In this study, the stathmin-1 expression pattern was evaluated in uterine natural killer (uNK) cells purified from CBA/J*DBA/2J matings. Results were compared with those in a CBA/J*BALB/c control group that yields successful pregnancies. The mean +/- SD percentage of stathmin-1(+) cells in the CD49b(+) uNK cell population was lower in CBA/J*DBA/2J mice (0.7% +/- 0.4%) than in control CBA/J*BALB/c mice (4.9% +/- 1.5%, P < 0.01) using flow cytometry, and the intracellular stathmin-1 level in uNK cells was lower in CBA/J*DBA/2J mice than in control mice using Western blot analysis. Co-localization of lectin from Dolichos biflorus agglutinin (DBA-lectin) and stathmin-1 was confirmed using multivision immunohistochemical analysis. The frequency of stathmin-1(+)DBA-lectin(+) cells was lower in CBA/J*DBA/2J mice than in CBA/J*BALB/c mice. A similar trend in the frequency of stathmin-1(+)CD56(+) cells was seen in patients with unexplained spontaneous abortion compared with normal early pregnancy. A neutralizing antibody against stathmin-1 further increased the percentage of embryo loss in CBA/J*DBA/2J matings. These results provide evidence that stathmin-1 expression in uNK cells at the maternal-fetal interface may help modulate uNK cell function and may be beneficial for a successful pregnancy. PMID- 21281785 TI - Expression of hypoxic marker CA IX is regulated by site-specific DNA methylation and is associated with the histology of gastric cancer. AB - The hypoxic marker carbonic anhydrase (CA) IX has been recognized as a tumor associated protein and is essential for cancer development. However, because CA IX expression does not always correlate with hypoxia, its regulatory mechanism remains unclear. The objective of the present study was to clarify the role and regulation of CA IX expression in gastric cancer. The immunohistochemical expression of CA IX and hypoxia-inducible factor-1alpha was assessed in 77 patients with gastric cancer. A methylation-sensitive restriction enzyme method was used to quantify site-specific methylation at -74 bp in the CA9 promoter in tissue from patients with gastric cancer and in corresponding normal tissue. CA9 expression in cell lines was strongly dependent on methylation status but not hypoxic stimuli. In tissue from patients with gastric cancer, the quantity of methylation was significantly correlated with the protein expression (P = 0.003). Moreover, the methylation value was significantly lower in intestinal-type compared with diffuse-type cancer (P = 0.003). Compared with normal mucosa, intestinal-type cancer demonstrated significant hypomethylation, whereas diffuse type cancer exhibited hypermethylation. In conclusion, expression of CA IX in gastric cancer is predominantly regulated by methylation of a single CpG rather than by hypoxia. Furthermore, epigenetic alterations in CA9 differ between the intestinal and diffuse types of gastric cancer. PMID- 21281786 TI - Arachidonic acid pathway members PLA2G7, HPGD, EPHX2, and CYP4F8 identified as putative novel therapeutic targets in prostate cancer. AB - The arachidonic acid and prostaglandin pathway has been implicated in prostate carcinogenesis, but comprehensive studies of the individual members in this key pathway are lacking. Here, we first conducted a systematic bioinformatic study of the expression of 36 arachidonic acid pathway genes across 9783 human tissue samples. The results showed that the PLA2G7, HPGD, EPHX2, and CYP4F8 genes are highly expressed in prostate cancer. Functional studies using RNA interference in prostate cancer cells indicated that all four genes are also essential for cell growth and survival. Clinical validation confirmed high PLA2G7 expression, especially in ERG oncogene-positive prostate cancers, and its silencing sensitized ERG-positive prostate cancer cells to oxidative stress. HPGD was highly expressed in androgen receptor (AR)-overexpressing advanced tumors, as well as in metastatic prostate cancers. EPHX2 mRNA correlated with AR in primary prostate cancers, and its inhibition in vitro reduced AR signaling and potentiated the effect of antiandrogen flutamide in cultured prostate cancer cells. In summary, we identified four novel putative therapeutic targets with biomarker potential for different subtypes of prostate cancer. In addition, our results indicate that inhibition of these enzymes may be particularly powerful when combined with other treatments, such as androgen deprivation or induction of oxidative stress. PMID- 21281787 TI - Genome-wide expression analysis of Middle Eastern colorectal cancer reveals FOXM1 as a novel target for cancer therapy. AB - To identify genes potentially playing an important role in the progression of colorectal carcinoma (CRC), we screened global gene expression using cDNA expression array on 41 CRC tissue samples and 25 noncancerous colorectal tissue samples. Among the up-regulated genes, forkhead box M1 (FOXM1) has been shown to play a critical role in pathogenesis of various malignancies. Using immunohistochemistry on 448 Saudi CRC samples in tissue microarray format, FoxM1 protein overexpression was seen in 66% of CRC tissues and was significantly associated with poorly differentiated and highly proliferative tumors (P = 0.0200 and 0.0018, respectively). FoxM1 expression was also significantly associated with MMP-9 protein expression (P = 0.0002). In vitro data using CRC cell lines showed that inhibition of FoxM1 by thiostrepton resulted in inhibition of proliferation and induction of apoptosis in a dose-dependent manner. Overexpression of FoxM1 potentiated cell proliferation, cell transformation, and migration/invasion of CRC cells via up-regulation of FoxM1 target genes MMP2 and MMP9 and protected these cells from thiostrepton-mediated antiproliferative effects. Finally, in vivo, overexpression of FoxM1 promoted growth of CRC-cell line xenograft tumors in nude mice. Altogether, our data indicate that FoxM1 signaling contributes to aggressiveness in a subset of CRC and that the FOXM1 gene may serve as a useful molecular biomarker and potential therapeutic target. PMID- 21281788 TI - Phosphoproteomic analysis of signaling pathways in head and neck squamous cell carcinoma patient samples. AB - Molecular targeted therapy represents a promising new strategy for treating cancers because many small-molecule inhibitors targeting protein kinases have recently become available. Reverse-phase protein microarrays (RPPAs) are a useful platform for identifying dysregulated signaling pathways in tumors and can provide insight into patient-specific differences. In the present study, RPPAs were used to examine 60 protein end points (predominantly phosphoproteins) in matched tumor and nonmalignant biopsy specimens from 23 patients with head and neck squamous cell carcinoma to characterize the cancer phosphoproteome. RPPA identified 18 of 60 analytes globally elevated in tumors versus healthy tissue and 17 of 60 analytes that were decreased. The most significantly elevated analytes in tumor were checkpoint kinase (Chk) 1 serine 345 (S345), Chk 2 S33/35, eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) S65, protein kinase C (PKC) zeta/iota threonine 410/412 (T410/T412), LKB1 S334, inhibitor of kappaB alpha (IkappaB-alpha) S32, eukaryotic translation initiation factor 4E (eIF4E) S209, Smad2 S465/67, insulin receptor substrate 1 (IRS-1) S612, mitogen-activated ERK kinase 1/2 (MEK1/2) S217/221, and total PKC iota. To our knowledge, this is the first report of elevated PKC iota in head and neck squamous cell carcinoma that may have significance because PKC iota is an oncogene in several other tumor types, including lung cancer. The feasibility of using RPPA for developing theranostic tests to guide personalized therapy is discussed in the context of these data. PMID- 21281789 TI - Basigin/CD147 promotes renal fibrosis after unilateral ureteral obstruction. AB - Regardless of their primary causes, progressive renal fibrosis and tubular atrophy are the main predictors of progression to end-stage renal disease. Basigin/CD147 is a multifunctional molecule-it induces matrix metalloproteinases and hyaluronan, for example-and has been implicated in organ fibrosis. However, the relationship between basigin and organ fibrosis has been poorly studied. We investigated basigin's role in renal fibrosis using a unilateral ureteral obstruction model. Basigin-deficient mice (Bsg(-/-)) demonstrated significantly less fibrosis after surgery than Bsg(+/+) mice. Fewer macrophages had infiltrated in Bsg(-/-) kidneys. Consistent with these in vivo data, primary cultured tubular epithelial cells from Bsg(-/-) mice produced less matrix metalloproteinase and exhibited less motility on stimulation with transforming growth factor beta. Furthermore, Bsg(-/-) embryonic fibro blasts produced less hyaluronan and alpha smooth muscle actin after transforming growth factor beta stimulation. Together, these results demonstrate for the first time that basigin is a key regulator of renal fibrosis. Basigin could be a candidate target molecule for the prevention of organ fibrosis. PMID- 21281790 TI - The IL-27 receptor has biphasic effects in crescentic glomerulonephritis mediated through Th1 responses. AB - Despite its initially defined role as a T-helper type 1 cell (Th1)-inducing cytokine, interleukin-27 (IL-27) has complex roles in vivo. The role of IL-27 receptor (IL-27R) was defined in experimental crescentic glomerulonephritis induced by a foreign antigen, sheep globulin, which is planted in glomeruli. This lesion is dependent on a Th1 effector cellular response. Twenty-one days after the administration of sheep anti-mouse glomerular basement membrane antibody, wild-type mice developed histologic and functional inflammatory renal injury. Injury was attenuated in the absence of IL-27R alpha chain (IL-27Ralpha), the unique component of the IL-27R complex. In contrast to the attenuated renal injury on day 21, Il27ra(-/-) mice exhibited enhanced systemic immune responses, including Th1 responses, with increased IL-2-dependent interferon-gamma (IFN gamma) production. However, earlier in the development of the nephritogenic immune response, IFN-gamma production was decreased, with reduced early immune responses translating into attenuated renal injury. Having demonstrated decreased early Th1 systemic immune responses, followed by enhanced nephritogenic Th1 immune responses, renal injury was studied at later time points. On days 28 and 35 after injection of the nephritogenic antigen, renal injury was enhanced in Il27ra(-/-) mice compared with wild-type mice in an at least partially IFN-gamma dependent manner. In Th1-dependent autoinflammatory lesions, IL-27Ralpha has a biphasic role in vivo, initially pathogenic, but ultimately playing a protective role by regulating immune responses and attenuating disease. PMID- 21281791 TI - Administration of pigment epithelium-derived factor inhibits left ventricular remodeling and improves cardiac function in rats with acute myocardial infarction. AB - Oxidative stress and inflammation are involved in cardiac remodeling after acute myocardial infarction (AMI). We have found that pigment epithelium-derived factor (PEDF) inhibits vascular inflammation through its anti-oxidative properties. However, effects of PEDF on cardiac remodeling after AMI remain unknown. We investigated whether PEDF could inhibit left ventricular remodeling and improve cardiac function in rats with AMI. AMI was induced in 8-week-old Sprague-Dawley rats by ligation of the left ascending coronary artery. Rats were treated intravenously with vehicle or 10 MUg PEDF/100 g b.wt. every day for up to 2 weeks after AMI. Each rat was followed until 16 weeks of age. PEDF levels in infarcted areas and serum were significantly decreased at 1 week after AMI and remained low during the observational periods. PEDF administration inhibited apoptotic cell death and oxidative stress generation around the infarcted areas at 2 and 8 weeks after AMI. Further, PEDF injection suppressed cardiac fibrosis by reducing transforming growth factor-beta and type III collagen expression, improved left ventricular ejection fraction, ameliorated diastolic dysfunction, and inhibited the increase in left ventricular mass index at 8 weeks after AMI. The present study demonstrated that PEDF could inhibit tissue remodeling and improve cardiac function in AMI rats. Substitution of PEDF may be a novel therapeutic strategy for cardiac remodeling after AMI. PMID- 21281792 TI - Obliterative airway remodeling: molecular evidence for shared pathways in transplanted and native lungs. AB - Obliteration of the small airways is a largely unresolved challenge in pulmonary medicine. It represents either the irreversible cause of functional impairment or a morphologic disorder of limited importance in a multitude of diseases. Bronchiolitis obliterans is a key complication of lung transplantation. No predictive markers for the onset of obliterative remodeling are currently available. To further elucidate the molecular mechanisms of airway remodeling, compartment-specific expression patterns were analyzed in patients. For this purpose, remodeled and nonremodeled bronchioli were isolated from transplanted and nontransplanted lung explants using laser-assisted microdissection (n = 24). mRNA expression of 45 fibrosis-associated genes was measured using quantitative real-time RT-PCR. For 20 genes, protein expression was also analyzed by immunohistochemistry. Infiltrating cells were characterized at conventional histology and immunohistochemistry. Obliterative remodeling of the small airways in transplanted and nontransplanted lungs shared similar grades of chronic inflammation and pivotal fibrotic pathways such as transforming growth factor beta signaling and increased collagen expression. Bone morphogenetic protein and thrombospondin signaling, and also matrix metalloproteinases and tissue inhibitor of metalloproteinases, were primarily up-regulated in obliterative airway remodeling in nontransplanted lungs. In transplanted lungs, clinical remodeled bone morphogenetic protein but nonremodeled bronchioli were characterized by a concordant up-regulation of matrix metalloproteinase-9, RANTES, and tissue inhibitor of metalloproteinase-1. These distinct expression patterns warrant further investigation as potential markers of impending airway remodeling, especially for prospective longitudinal molecular profiling. PMID- 21281793 TI - Mesangial cell integrin alphavbeta8 provides glomerular endothelial cell cytoprotection by sequestering TGF-beta and regulating PECAM-1. AB - Integrins are heterodimeric receptors that regulate cell adhesion, migration, and apoptosis. Integrin alphavbeta8 is most abundantly expressed in kidney and brain, and its major ligand is latent transforming growth factor-beta (TGF-beta). Kidney alphavbeta8 localizes to mesangial cells, which appose glomerular endothelial cells and maintain glomerular capillary structure by mechanical and poorly understood paracrine mechanisms. To establish kidney alphavbeta8 function, mice with homozygous Itgb8 deletion (Itgb8(-/-)) were generated on outbred and C57BL/6 congenic backgrounds. Most Itgb8(-/-) mice died in utero, and surviving Itgb8(-/ ) mice failed to gain weight, and rarely survived beyond 6 weeks. A renal glomerular phenotype included azotemia and albuminuria, as well as increased platelet endothelial cell adhesion molecule-1 (PECAM-1) expression, which was surprisingly not associated with conventional functions, such as endothelial cell hyperplasia, hypertrophy, or perivascular inflammation. Itgb8(-/-) mesangial cells demonstrated reduced latent TGF-beta binding, resulting in bioactive TGF beta release, which stimulated glomerular endothelial cell apoptosis. Using PECAM 1 gain and loss of function strategies, we show that PECAM-1 provides endothelial cytoprotection against mesangial cell TGF-beta. These results clarify a singular mechanism of mesangial-to-endothelial cell cross-talk, whereby mesangial cell alphavbeta8 homeostatically arbitrates glomerular microvascular integrity by sequestering TGF-beta in its latent conformation. Under pathological conditions associated with decreased mesangial cell alphavbeta8 expression and TGF-beta secretion, compensatory PECAM-1 modulation facilitates glomerular endothelial cell survival. PMID- 21281794 TI - A quantitative approach to scar analysis. AB - Analysis of collagen architecture is essential to wound healing research. However, to date no consistent methodologies exist for quantitatively assessing dermal collagen architecture in scars. In this study, we developed a standardized approach for quantitative analysis of scar collagen morphology by confocal microscopy using fractal dimension and lacunarity analysis. Full-thickness wounds were created on adult mice, closed by primary intention, and harvested at 14 days after wounding for morphometrics and standard Fourier transform-based scar analysis as well as fractal dimension and lacunarity analysis. In addition, transmission electron microscopy was used to evaluate collagen ultrastructure. We demonstrated that fractal dimension and lacunarity analysis were superior to Fourier transform analysis in discriminating scar versus unwounded tissue in a wild-type mouse model. To fully test the robustness of this scar analysis approach, a fibromodulin-null mouse model that heals with increased scar was also used. Fractal dimension and lacunarity analysis effectively discriminated unwounded fibromodulin-null versus wild-type skin as well as healing fibromodulin null versus wild-type wounds, whereas Fourier transform analysis failed to do so. Furthermore, fractal dimension and lacunarity data also correlated well with transmission electron microscopy collagen ultrastructure analysis, adding to their validity. These results demonstrate that fractal dimension and lacunarity are more sensitive than Fourier transform analysis for quantification of scar morphology. PMID- 21281795 TI - Attenuation of the lysosomal death pathway by lysosomal cholesterol accumulation. AB - In the past decade, lysosomal membrane permeabilization (LMP) has emerged as a significant component of cell death signaling. The mechanisms by which lysosomal stability is regulated are not yet fully understood, but changes in the lysosomal membrane lipid composition have been suggested to be involved. Our aim was to investigate the importance of cholesterol in the regulation of lysosomal membrane permeability and its potential impact on apoptosis. Treatment of normal human fibroblasts with U18666A, an amphiphilic drug that inhibits cholesterol transport and causes accumulation of cholesterol in lysosomes, rescued cells from lysosome dependent cell death induced by the lysosomotropic detergent O-methyl-serine dodecylamide hydrochloride (MSDH), staurosporine (STS), or cisplatin. LMP was decreased by pretreating cells with U18666A, and there was a linear relationship between the cholesterol content of lysosomes and their resistance to permeabilization induced by MSDH. U18666A did not induce changes in expression or localization of 70-kDa heat shock proteins (Hsp70) or antiapoptotic Bcl-2 proteins known to protect the lysosomal membrane. Induction of autophagy also was excluded as a contributor to the protective mechanism. By using Chinese hamster ovary (CHO) cells with lysosomal cholesterol overload due to a mutation in the cholesterol transporting protein Niemann-Pick type C1 (NPC1), the relationship between lysosomal cholesterol accumulation and protection from lysosome-dependent cell death was confirmed. Cholesterol accumulation in lysosomes attenuates apoptosis by increasing lysosomal membrane stability. PMID- 21281796 TI - Mast cells are an essential component of human radiation proctitis and contribute to experimental colorectal damage in mice. AB - Radiation proctitis is characterized by mucosal inflammation followed by adverse chronic tissue remodeling and is associated with substantial morbidity and mortality. Mast cell hyperplasia has been associated with diseases characterized by pathological tissue remodeling and fibrosis. Rectal tissue from patients treated with radiotherapy shows mast cell hyperplasia and activation, suggesting that these cells play a role in the development of radiation-induced sequelae. To investigate the role of mast cells in radiation damage, experimental radiation proctitis was induced in a mast cell-deficient (W(sh)/W(sh)) mouse model. The colon and rectum of W(sh)/W(sh) and wild-type mice were exposed to 27-Gy single dose irradiation and studied after 2 and 14 weeks. Irradiated rodent rectum showed mast cell hyperplasia. W(sh)/W(sh) mice developed less acute and chronic rectal radiation damage than their control littermates. Tissue protection was associated with increased tissue neutrophil influx and expression of several inflammatory mediators immediately after radiation exposure. It was further demonstrated that mast cell chymase, tryptase, and histamine could change human muscularis propria smooth muscle cells into a migrating/proliferating and proinflammatory phenotype. These data show that mast cells have deleterious effects on both acute and chronic radiation proctitis, possibly by limiting acute tissue neutrophil influx and by favoring phenotypic orientation of smooth muscle cells, thus making them active participants in the radiation-induced inflammatory process and dystrophy of the rectal wall. PMID- 21281797 TI - DNA methylation suppresses expression of the urea cycle enzyme carbamoyl phosphate synthetase 1 (CPS1) in human hepatocellular carcinoma. AB - Carbamoyl phosphate synthetase 1 (CPS1) is a liver-specific, intramitochondrial, rate-limiting enzyme in the urea cycle. A previous study showed that CPS1 is the antigen for hepatocyte paraffin 1 antibody, a commonly used antibody in surgical pathology practice; and CPS1 expression appears to be down-regulated in liver cancer tissue and cell lines. The aim of this study is to understand how the CPS1 gene is regulated in liver carcinogenesis. In this report, we show that human hepatocellular carcinoma (HCC) cells do not express CPS1, whereas cultured human primary hepatocytes express abundant levels. In addition, CPS1 was silenced or down-regulated in liver tumor tissues compared with the matched noncancerous tissues. The expression of CPS1 in HCC cells was restored with a demethylation agent, 5-azacytidine. We show that two CpG dinucleotides, located near the transcription start site, and a CpG-rich region in the first intron were hypermethylated in HCC cells. The hypermethylation of the two CpG dinucleotides was also detected in HCC tumor tissues compared with noncancerous tissues. Further molecular analysis with mutagenesis indicated that the two CpG dinucleotides play a role in promoter activity of the CPS1 gene. In conclusion, our study demonstrates that DNA methylation is a key mechanism of silencing CPS1 expression in human HCC cells, and CPS1 gene hypermethylation of the two CpG dinucleotides is a potential biomarker for HCC. PMID- 21281798 TI - Serotonin activates dendritic cell function in the context of gut inflammation. AB - Mucosal inflammation in the gut is characterized by infiltration of innate and adaptive immune cells and by an alteration in serotonin-producing enterochromaffin cells. We investigated the role of serotonin in the function of dendritic cells (DCs) and sequential T-cell activation in relation to generation of gut inflammation. DCs isolated from tryptophan hydroxylase-1-deficient (TPH1( /-)) mice, which have reduced serotonin in the gut, and wild-type (TPH1(+/+)) mice with or without dextran sulfate sodium (DSS)-induced colitis were stimulated with lipopolysaccharide to assess interleukin-12 (IL-12) production. Isolated DCs from TPH1(+/+) and TPH1(-/-) mice were also cocultured with CD4(+) T cells of naive TPH1(+/+) mice to assess the role of serotonin in priming T cells. In addition, serotonin-pulsed DCs were transferred to TPH1(-/-) mice to assess the effect on DSS-induced colitis. Consistent with a reduced severity of colitis, DCs from DSS-induced TPH1(-/-) mice produced less IL-12 compared with the TPH1(+/+) mice. In vitro serotonin stimulation restored the cytokine production from TPH1( /-) DCs and adoptive transfer of serotonin-pulsed DCs into TPH1(-/-) up-regulated colitis. Furthermore, CD4(+) T cells primed by TPH1(-/-) DCs produce reduced the levels of IL-17 and interferon-gamma. This study provides novel information on serotonin-mediated immune signaling and promotion of interactions between innate and adaptive immune responses in the context of gut inflammation, which may ultimately lead to improved strategies to combat gut inflammatory disorders. PMID- 21281799 TI - Gastrin-releasing peptide signaling alters colon cancer invasiveness via heterochromatin protein 1Hsbeta. AB - Epithelial cells lining the adult colon do not normally express gastrin-releasing peptide (GRP) or its receptor (GRPR). In contrast, GRP/GRPR can be aberrantly expressed in colon cancer where they are associated with improved patient survival rates. However, the mechanism of action whereby these proteins mediate their beneficial effects is not known. Heterochromatin protein 1 is an epigenetic modifier of gene transcription for which three different isoforms exist in humans: HP1(Hsalpha), HP1(Hsbeta), and HP1(Hsgamma). In breast cancer and melanoma, respectively, HP1(Hsalpha) and HP1(Hsbeta) have been shown to modulate the aggressiveness of tumor cells in vivo. In contrast, the role of HP1 in colon cancer has not been elucidated, and a mechanism of regulating the expression of any HP1 isoform in any context has not yet been identified. In this article we demonstrate that abrogating GRP/GRPR signaling specifically down-regulates HP1(Hsbeta) expression and that inhibiting GRPR signaling, or ablating HP1(Hsbeta) expression, increases colon cancer cell invasiveness in vitro. These findings identify for the first time a signaling pathway regulating heterochromatin protein expression and suggest a mechanism whereby aberrantly expressed GRPR might alter the outcome of patients with colorectal cancer. PMID- 21281800 TI - UV-B radiation induces macrophage migration inhibitory factor-mediated melanogenesis through activation of protease-activated receptor-2 and stem cell factor in keratinocytes. AB - UV radiation indirectly regulates melanogenesis in melanocytes through a paracrine regulatory mechanism involving keratinocytes. Protease-activated receptor (PAR)-2 activation induces melanosome transfer by increasing phagocytosis of melanosomes by keratinocytes. This study demonstrated that macrophage migration inhibitory factor (MIF) stimulated PAR-2 expression in human keratinocytes. In addition, we showed that MIF stimulated stem cell factor (SCF) release in keratinocytes; however, MIF had no effect on the release of endothelin 1 or prostaglandin E2 in keratinocytes. In addition, MIF had no direct effect on melanin and tyrosinase synthesis in cultured human melanocytes. The effect of MIF on melanogenesis was also examined using a three-dimensional reconstituted human epidermal culture model, which is a novel, commercially available, cultured human epidermis containing functional melanocytes. Migration inhibitory factor induced an increase in melanin content in the epidermis after a 9-day culture period. Moreover, melanin synthesis induced by UV-B stimulation was significantly down regulated by anti-MIF antibody treatment. An in vivo study showed that the back skin of MIF transgenic mice had a higher melanin content than that of wild-type mice after 12 weeks of UV-B exposure. Therefore, MIF-mediated melanogenesis occurs mainly through the activation of PAR-2 and SCF expression in keratinocytes after exposure to UV-B radiation. PMID- 21281801 TI - Overexpression of pigment epithelium-derived factor inhibits retinal inflammation and neovascularization. AB - Pigment epithelium-derived factor (PEDF) is a serine proteinase inhibitor with antiangiogenic activities. To investigate whether PEDF overexpression has an impact on ocular neovascularization in vivo, we generated PEDF transgenic (PEDF Tg) mice that ubiquitously express human PEDF driven by the beta-actin promoter. The PEDF-Tg mice under normal conditions did not show any abnormalities in retinal histologic findings or visual function. In contrast, PEDF-Tg animals with oxygen-induced retinopathy (OIR) developed significantly less severe retinal neovascularization compared with wild-type (Wt) mice with OIR. In addition, PEDF Tg mice with OIR had significantly lower vascular leakage in the retina but higher occludin levels than the Wt mice with OIR, suggesting a protective effect on the blood-retinal barrier. Furthermore, retinal levels of proinflammatory factors were significantly lower in PEDF-Tg mice with OIR than in the Wt mice with OIR. In the laser-induced choroidal neovascularization (CNV) model, the CNV area was significantly smaller in the PEDF-Tg mice than in the Wt mice. Also, the laser burn-induced overexpression of proangiogenic and inflammatory factors was observed in the retina and retinal pigment epithelium of Wt mice but not in PEDF Tg mice. Taken together, these results suggest that overexpression of PEDF inhibits retinal inflammation and neovascularization in both the OIR and laser induced CNV models. The PEDF-Tg mice provide a useful model for studying the roles of angiogenic inhibitors in neovascular disorders such as diabetic retinopathy. PMID- 21281802 TI - Platelet-activating factor blockade inhibits the T-helper type 17 cell pathway and suppresses psoriasis-like skin disease in K5.hTGF-beta1 transgenic mice. AB - Platelet-activating factor (PAF), a potent biolipid mediator, is involved in a variety of cellular transduction pathways and plays a prominent role in inducing inflammation in different organs. We used K5.hTGF-beta1 transgenic mice, which exhibit an inflammatory skin disorder and molecular and cytokine abnormalities with strong similarities to human psoriasis, to study the pathogenic role of PAF. We found that injecting PAF into the skin of transgenic mice led to inflammation and accelerated manifestation of the psoriatic phenotype by a local effect. In contrast, injecting mice with PAF receptor antagonist PCA-4248 lowered the PAF level (most likely by depressing an autocrine loop) and neutrophil, CD68(+) cell (monocyte/macrophage), and CD3(+) T-cell accumulation in the skin and blocked progression of the psoriasis-like phenotype. This effect of PAF blockade was specific and similar to that of psoralen-UV-A and was paralleled by a decrease in abnormally elevated mRNA and/or protein levels of T-helper type 17 cell-related cytokines IL-17A, IL-17F, IL-23, IL-12A, and IL-6 and its transcription factor signal transducer and activator of transcription 3. In contrast, PCA-4248 treatment up-regulated mRNA levels of cyclooxygenase-2 and IL-10 in dorsal skin and release of IL-10 in serum and skin. Interfering with PAF may offer the opportunity to develop novel therapeutic strategies for inflammatory psoriasis and associated comorbidities, including metabolic syndrome and atherosclerosis, in which the IL-17 axis may be involved. PMID- 21281803 TI - Differential distribution and phenotype of decidual macrophages in preeclamptic versus control pregnancies. AB - Maternal immune tolerance of the semiallogeneic fetus is a complex phenomenon. Macrophages are an abundant cell population in the human decidua, and changes in distribution or phenotype may be involved in the development of preeclampsia. The aim of this study was to assess the distribution and phenotype of macrophages in preterm preeclamptic, preterm control, and term control placentas. Placentas of preterm preeclamptic (n = 6), preterm control (n = 5), and term control pregnancies (n = 6) were sequentially immunohistochemically stained for CD14, CD163, DC SIGN, and IL-10. The distributions of CD14(+), CD163(+), DC SIGN(+), IL 10(+), CD163(+)/CD14(+), DC SIGN(+)/CD14(+), and Flt-1/CD14(+) cells were determined by double staining and by digital image analysis of sequential photomicrographs. CD14 and CD163 expression increased significantly in preterm preeclamptic decidua basalis compared with preterm control pregnancies (P = 0.0006 and P = 0.034, respectively). IL-10 expression was significantly lower in the decidua parietalis of preterm preeclamptic pregnancies compared with preterm control pregnancies (P = 0.03). The CD163/CD14 ratio was significantly lower in the decidua basalis (P = 0.0293) and the DC SIGN/CD14 ratio was significantly higher in the decidua basalis (P < 0.0001) and parietalis (P < 0.0001) of preterm preeclamptic pregnancies compared with preterm control pregnancies. CD14(+) macrophages did express Flt-1. Alterations in distribution and phenotype of macrophages in the decidua of preterm preeclamptic pregnancies compared with control pregnancies may contribute to the pathogenesis of preeclampsia. PMID- 21281804 TI - IgG autoantibodies against desmocollin 3 in pemphigus sera induce loss of keratinocyte adhesion. AB - Pemphigus is considered an autoimmune bullous skin disorder associated with IgG against the desmosomal components, desmoglein 3 (Dsg3) and desmoglein 1 (Dsg1). This concept is supported by the in vitro and in vivo pathogenicity of anti Dsg3/Dsg1 IgG and the mucosal blistering phenotype of mice with a genetic deficiency of Dsg3. Mice deficient for another desmosomal adhesion molecule, desmocollin 3 (Dsc3), show a similar pemphigus phenotype, and we investigated the pathogenicity of Dsc3-reactive IgG autoantibodies that were identified previously in a subset of patients with atypical pemphigus. We here demonstrate that IgG against Dsc3 causes loss of adhesion of epidermal keratinocytes. Specifically, IgG against Dsc3 was purified from Dsc3-reactive pemphigus sera by affinity column chromatography using recombinant human Dsc3. Affinity purified IgG was functionally active and did not only react with recombinant Dsc3 but also with epidermis and cultured human keratinocytes. Moreover, Dsc3-reactive IgG induced loss of adhesion of epidermal keratinocytes in a dispase-based keratinocyte dissociation assay that was reversed on pre-adsorption with human Dsc3 but not Dsg3. These findings demonstrate that IgG autoantibodies against an additional component of the desmosomes, Dsc3, induce loss of keratinocyte adhesion and thus may contribute to blister formation in pemphigus. PMID- 21281805 TI - CD14 signaling reciprocally controls collagen deposition and turnover to regulate the development of lyme arthritis. AB - CD14 is a glycosylphosphatidylinositol-anchored protein expressed primarily on myeloid cells (eg, neutrophils, macrophages, and dendritic cells). CD14(-/-) mice infected with Borrelia burgdorferi, the causative agent of Lyme disease, produce more proinflammatory cytokines and present with greater disease and bacterial burden in infected tissues. Recently, we uncovered a novel mechanism whereby CD14(-/-) macrophages mount a hyperinflammatory response, resulting from their inability to be tolerized by B. burgdorferi. Paradoxically, CD14 deficiency is associated with greater bacterial burden despite the presence of highly activated neutrophils and macrophages and elevated levels of cytokines with potent antimicrobial activities. Killing and clearance of Borrelia, especially in the joints, depend on the recruitment of neutrophils. Neutrophils can migrate in response to chemotactic gradients established through the action of gelatinases (eg, matrix metalloproteinase 9), which degrade collagen components of the extracellular matrix to generate tripeptide fragments of proline-glycine-proline. Using a mouse model of Lyme arthritis, we demonstrate that CD14 deficiency leads to decreased activation of matrix metalloproteinase 9, reduced degradation of collagen, and diminished recruitment of neutrophils. This reduction in neutrophil numbers is associated with greater numbers of Borrelia in infected tissues. Variation in the efficiency of neutrophil-mediated clearance of B. burgdorferi may underlie differences in the severity of Lyme arthritis observed in the patient population and suggests avenues for development of adjunctive therapy designed to augment host immunity. PMID- 21281806 TI - IL-10-producing regulatory B10 cells inhibit intestinal injury in a mouse model. AB - B cells mediate multiple functions that influence immune and inflammatory responses. In mice, the addition of dextran sulfate sodium (DSS) to drinking water leads to immediate intestinal injury. Dextran sulfate sodium-induced intestinal injury serves as an experimental animal model for human ulcerative colitis. The contribution of B cells to DSS-induced intestinal injury is unclear. In this study, we show that DSS-induced intestinal injury was more severe in CD19 deficient (CD19(-/-)) mice than in wild-type mice. These inflammatory responses were negatively regulated by a unique IL-10-producing CD1d(hi)CD5(+) regulatory B cell subset (B10 cells) that was absent in CD19(-/-) mice and represented only 1% to 2% of splenic B220(+) cells in wild-type mice. Remarkably, adoptive transfer of these B10 cells from wild-type mice reduced inflammation in CD19(-/-) mice in an IL-10-dependent manner. These results demonstrate that IL-10 production from regulatory B10 cells regulates DSS-induced intestinal injury. These findings may provide new insights and therapeutic approaches for treating ulcerative colitis. PMID- 21281807 TI - Antigen presentation and MHC class II expression by human esophageal epithelial cells: role in eosinophilic esophagitis. AB - Professional antigen-presenting cells (APCs) play a crucial role in initiating immune responses. Under pathological conditions, epithelial cells at mucosal surfaces act as nonprofessional APCs, thereby regulating immune responses at the site of exposure. Epithelial cells in the esophagus may contribute to the pathogenesis of eosinophilic esophagitis (EoE) by presenting antigens on the major histocompatibility complex (MHC) class II. Our goal was to demonstrate the ability of esophageal epithelial cells to process and present antigens on the MHC class II system and to investigate the contribution of epithelial cell antigen presentation to EoE. Immunohistochemistry detected HLA-DR, CD80, and CD86 expression and enzyme-linked immunosorbent assay detected interferon-gamma (IFNgamma) in esophageal biopsies. Antigen presentation was studied using the human esophageal epithelial cell line HET-1A by reverse transcriptase-PCR, flow cytometry, and confocal microscopy. T helper cell lymphocyte proliferation was assessed by flow cytometry and IL-2 secretion. IFNgamma and MHC class II were increased in mucosa of patients with EoE. IFNgamma increased mRNA of HLA-DP, HLA DQ, HLA-DR, and CIITA in HET-1A cells. HET-1A engulfed cell debris and processed ovalbumin. HET-1A cells expressed HLA-DR after IFNgamma treatment. HET-1A stimulated T helper cell activation. In this study, we demonstrated the ability of esophageal epithelial cells to act as nonprofessional APCs in the presence of IFNgamma. Esophageal epithelial cell antigen presentation may contribute to the pathophysiology of eosinophilic esophagitis. PMID- 21281808 TI - Tenascin C induces epithelial-mesenchymal transition-like change accompanied by SRC activation and focal adhesion kinase phosphorylation in human breast cancer cells. AB - Tenascin C (TNC) is an extracellular matrix glycoprotein up-regulated in solid tumors. Higher TNC expression is shown in invading fronts of breast cancer, which correlates with poorer patient outcome. We examined whether TNC induces epithelial-mesenchymal transition (EMT) in breast cancer. Immunohistochemical analysis of invasive ductal carcinomas showed that TNC deposition was frequent in stroma with scattered cancer cells in peripheral margins of tumors. The addition of TNC to the medium of the MCF-7 breast cancer cells caused EMT-like change and delocalization of E-cadherin and beta-catenin from cell-cell contact. Although amounts of E-cadherin and beta-catenin were not changed after EMT in total lysates, they were increased in the Triton X-100-soluble fractions, indicating movement from the membrane into the cytosol. In wound healing assay, cells were scattered from wound edges and showed faster migration after TNC treatment. The EMT phenotype was correlated with SRC activation through phosphorylation at Y418 and phosphorylation of focal adhesion kinase (FAK) at Y861 and Y925 of SRC substrate sites. These phosphorylated proteins colocalized with alphav integrin positive adhesion plaques. A neutralizing antibody against alphav or a SRC kinase inhibitor blocked EMT. TNC could induce EMT-like change showing loss of intercellular adhesion and enhanced migration in breast cancer cells, associated with FAK phosphorylation by SRC; this may be responsible for the observed promotion of TNC in breast cancer invasion. PMID- 21281809 TI - Elastin degradation and vascular smooth muscle cell phenotype change precede cell loss and arterial medial calcification in a uremic mouse model of chronic kidney disease. AB - Arterial medial calcification (AMC), a hallmark of vascular disease in uremic patients, is highly correlated with serum phosphate levels and cardiovascular mortality. To determine the mechanisms of AMC, mice were made uremic by partial right-side renal ablation (week 0), followed by left-side nephrectomy at week 2. At 3 weeks, mice were switched to a high-phosphate diet, and various parameters of disease progression were examined over time. Serum phosphate, calcium, and fibroblast growth factor 23 (FGF-23) were up-regulated as early as week 4. Whereas serum phosphate and calcium levels declined to normal by 10 weeks, FGF-23 levels remained elevated through 16 weeks, consistent with an increased phosphate load. Elastin turnover and vascular smooth muscle cell (VSMC) phenotype change were early events, detected by week 4 and before AMC. Both AMC and VSMC loss were significantly elevated by week 8. Matrix metalloprotease 2 (MMP-2) and cathepsin S were present at baseline and were significantly elevated at weeks 8 and 12. In contrast, MMP-9 was not up-regulated until week 12. These findings over time suggest that VSMC phenotype change and VSMC loss (early phosphate-dependent events) may be necessary and sufficient to promote AMC in uremic mice fed a high phosphate diet, whereas elastin degradation might be necessary but is not sufficient to induce AMC (because elastin degradation occurred also in uremic mice on a normal-phosphate diet, but they did not develop AMC). PMID- 21281810 TI - A mouse model of beta-thalassemia shows a liver-specific down-regulation of Abcc6 expression. AB - beta-Thalassemia and pseudoxanthoma elasticum (PXE) are distinct genetic disorders. Yet, a dystrophic mineralization phenotype similar to PXE has frequently been associated with beta-thalassemia or sickle cell anemia patients of Mediterranean descent. These calcifications are clinically and structurally identical to inherited PXE. As we previously excluded the presence of PXE-causing mutations in the ABCC6 gene of beta-thalassemia patients with PXE manifestations, we hypothesized that a molecular mechanism independent of gene mutations either altered the ABCC6 gene expression or disrupted the biologic properties of its product in the liver or kidneys, which are the tissues with the highest levels of expression. To test this possibility, we investigated Abcc6 synthesis in the liver and kidneys of a beta-thalassemia mouse model (Hbb(th3/+)). We found a progressive liver-specific down-regulation of the Abcc6 gene expression and protein levels by quantitative PCR, Western blotting, and immunofluorescence. The levels of Abcc6 protein decreased significantly at 6 months of age and stabilized at 10 months and older ages at ~25% of the wild-type protein levels. We studied the transcriptional regulation of the Abcc6 gene in wild-type and Hbb(th3/+) mice, and we identified the erythroid transcription factor NF-E2 as the main cause of the transcriptional down-regulation using transcription factor arrays and chromatin immunoprecipitation. The Hbb(th3/+) mice did not develop spontaneous calcification as seen in the Abcc6(-/-) mice probably because the Abcc6 protein decrease occurred late in life and was probably insufficient to promote mineralization in the Hbb(th3/+) mouse C57BL/6J genetic background. Nevertheless, our result suggested that a similar decrease of ABCC6 expression occurs in the liver of beta-thalassemia patients and may be responsible for their frequent PXE-like manifestations. PMID- 21281811 TI - Inhibition of activin receptor type IIB increases strength and lifespan in myotubularin-deficient mice. AB - X-linked myotubular myopathy (XLMTM) is a congenital disorder caused by deficiency of the lipid phosphatase, myotubularin. Patients with XLMTM often have severe perinatal weakness that requires mechanical ventilation to prevent death from respiratory failure. Muscle biopsy specimens from patients with XLMTM exhibit small myofibers with central nuclei and central aggregations of organelles in many cells. It was postulated that therapeutically increasing muscle fiber size would cause symptomatic improvement in myotubularin deficiency. Recent studies have elucidated an important role for the activin-receptor type IIB (ActRIIB) in regulation of muscle growth and have demonstrated that ActRIIB inhibition results in significant muscle hypertrophy. To evaluate whether promoting muscle hypertrophy can attenuate symptoms resulting from myotubularin deficiency, the effect of ActRIIB-mFC treatment was determined in myotubularin deficient (Mtm1delta4) mice. Compared with wild-type mice, untreated Mtm1delta4 mice have decreased body weight, skeletal muscle hypotrophy, and reduced survival. Treatment of Mtm1delta4 mice with ActRIIB-mFC produced a 17% extension of lifespan, with transient increases in weight, forelimb grip strength, and myofiber size. Pathologic analysis of Mtm1delta4 mice during treatment revealed that ActRIIB-mFC produced marked hypertrophy restricted to type 2b myofibers, which suggests that oxidative fibers in Mtm1delta4 animals are incapable of a hypertrophic response in this setting. These results support ActRIIB-mFC as an effective treatment for the weakness observed in myotubularin deficiency. PMID- 21281812 TI - IL-21 and IL-21 receptor expression in lymphocytes and neurons in multiple sclerosis brain. AB - IL-17-producing CD4(+) T cells (Th-17) contribute to the pathogenesis of experimental autoimmune encephalomyelitis and are associated with active disease in multiple sclerosis (MS). In addition to IL-17, Th-17 cells can also express IL 21, IL-22, and IL-6 under Th-17-polarizing conditions (IL-6 and transforming growth factor-beta). In this study we investigated IL-21 and IL-21 receptor (IL 21R) expression in MS lesions by in situ hybridization and immunohistochemistry. We detected strongly IL-21(+) infiltrating cells predominantly in acute but also in chronic active white matter MS lesions in which IL-21 expression was restricted to CD4(+) cells. In contrast, IL-21R was much more broadly distributed on CD4(+), CD19(+), and CD8(+) lymphocytes but not major histocompatibility complex class-II(+) macrophages/microglia. Interestingly, in cortical areas we detected both IL-21 and IL-21R expression by neurons. These findings suggest role(s) for IL-21 in both the acute and chronic stages of MS via direct effects on T and B lymphocytes and, demonstrated for the first time, also on neurons. PMID- 21281813 TI - Accelerated human mutant tau aggregation by knocking out murine tau in a transgenic mouse model. AB - Many models of human tauopathies have been generated in mice by expression of a human mutant tau with maintained expression of mouse endogenous tau. Because murine tau might interfere with the toxic effects of human mutant tau, we generated a model in which a pathogenic human tau protein is expressed in the absence of wild-type tau protein, with the aim of facilitating the study of the pathogenic role of the mutant tau and to reproduce more faithfully a human tauopathy. The Tg30 line is a tau transgenic mouse model overexpressing human 1N4R double-mutant tau (P301S and G272V) that develops Alzheimer's disease-like neurofibrillary tangles in an age-dependent manner. By crossing Tg30 mice with mice invalidated for their endogenous tau gene, we obtained Tg30xtau(-/-) mice that express only exogenous human double-mutant 1N4R tau. Although Tg30xtau(-/-) mice express less tau protein compared with Tg30, they exhibit signs of decreased survival, increased proportion of sarkosyl-insoluble tau in the brain and in the spinal cord, increased number of Gallyas-positive neurofibrillary tangles in the hippocampus, increased number of inclusions in the spinal cord, and a more severe motor phenotype. Deletion of murine tau accelerated tau aggregation during aging of this mutant tau transgenic model, suggesting that murine tau could interfere with the development of tau pathology in transgenic models of human tauopathies. PMID- 21281814 TI - Ophthalmic pterygium: a stem cell disorder with premalignant features. AB - Pterygia are common ocular surface lesions thought to originate from limbal stem cells altered by chronic UV exposure. Traditionally regarded as a degenerative condition, pterygia also display tumor-like features, such as a propensity to invade normal tissue and high recurrence rates following resection, and may coexist with secondary premalignant lesions. This study was initiated to determine the rate of concurrent ocular surface diseases in patients with pterygia recruited from the practice of a single surgeon operating in a Sydney metropolitan hospital. One hundred pterygium specimens were histopathologically reviewed and selected cases were immunohistochemically assessed to confirm diagnosis. Along with previously documented typical features including epithelial proliferation, goblet cell hyperplasia, angiogenesis, inflammation, elastosis, stromal plaques, and Bowman's membrane dissolution, we identified five cases of ocular surface squamous neoplasia, six cases of primary acquired melanosis, two compound nevi (one suspect invasive melanoma), and one dermoid-like lesion. In 18 specimens, clusters of basal epithelial cells that coexpressed cytokeratin-15/-19 and p63-alpha were identified at the head of the pterygium, coinciding with clinical observation of Fuchs' flecks. Our data show that significant preneoplastic lesions may be associated with pterygium and that all excised pterygia should undergo histological examination. The presence of p63-alpha positive epithelial cell clusters supports the hypothesis that pterygia develop from limbal epithelial progenitors. PMID- 21281815 TI - Isolation and characterization of progenitor-like cells from human renal proximal tubules. AB - The tubules of the kidney display a remarkable capacity for self-renewal on damage. Whether this regeneration is mediated by dedifferentiating surviving cells or, as recently suggested, by stem cells has not been unequivocally settled. Herein, we demonstrate that aldehyde dehydrogenase (ALDH) activity may be used for isolation of cells with progenitor characteristics from adult human renal cortical tissue. Gene expression profiling of the isolated ALDH(high) and ALDH(low) cell fractions followed by immunohistochemical interrogation of renal tissues enabled us to delineate a tentative progenitor cell population scattered through the proximal tubules (PTs). These cells expressed CD24 and CD133, previously described markers for renal progenitors of Bowman's capsule. Furthermore, we show that the PT cells, and the glomerular progenitors, are positive for KRT7, KRT19, BCL2, and vimentin. In addition, tubular epithelium regenerating on acute tubular necrosis displayed long stretches of CD133(+)/VIM(+) cells, further substantiating that these cells may represent a progenitor cell population. Furthermore, a potential association of these progenitor cells with papillary renal cell carcinoma was discovered. Taken together, our data demonstrate the presence of a previously unappreciated subset of the PT cells that may be endowed with a more robust phenotype, allowing increased resistance to acute renal injury, enabling rapid repopulation of the tubules. PMID- 21281816 TI - Increased expression of P-glycoprotein is associated with doxorubicin chemoresistance in the metastatic 4T1 breast cancer model. AB - Development of drug resistance is one of the major causes of breast cancer treatment failure. The goal of this study was to understand the chemoresistance mechanism using the highly metastatic 4T1 breast cancer model, which emulates stage IV breast cancer in humans. The metastatic 4T1 breast cancer cell line treated with either doxorubicin or 5-FU showed a concentration-dependent reduced cell proliferation, with induced G2-phase growth arrest (doxorubicin) or G1-phase growth arrest (5-FU). Doxorubicin treatment partially suppressed the multiorgan metastasis of 4T1 breast cancer cells in the lung, heart, liver, and bone, compared with either 5-FU or cyclophosphamide. We isolated and characterized 4T1 breast cancer cells from doxorubicin-resistant metastatic tumors (cell line 4T1 R). Multiorgan metastasis of drug-resistant 4T1 breast tumors was totally resistant to doxorubicin treatment. Our results indicate that doxorubicin is localized exclusively in the cytoplasm of resistant 4T1 breast cancer cells and that it cannot reach the nucleus because of increased nuclear expression of P glycoprotein. Pretreatment of doxorubicin-resistant 4T1-R breast cancer cells with verapamil, a general inhibitor of P-glycoprotein, increased nuclear translocation of doxorubicin and cellular cytotoxicity. Thus, impaired nuclear translocation of doxorubicin due to increased expression of P-glycoprotein is associated with doxorubicin resistance of highly metastatic 4T1 breast cancer. PMID- 21281817 TI - Deregulation of E2-EPF ubiquitin carrier protein in papillary renal cell carcinoma. AB - Molecular pathways associated with pathogenesis of sporadic papillary renal cell carcinoma (PRCC), the second most common form of kidney cancer, are poorly understood. We analyzed primary tumor specimens from 35 PRCC patients treated by nephrectomy via gene expression analysis and tissue microarrays constructed from an additional 57 paraffin-embedded PRCC samples via immunohistochemistry. Gene products were validated and further studied by Western blot analyses using primary PRCC tumor samples and established renal cell carcinoma cell lines, and potential associations with pathologic variables and survival in 27 patients with follow-up information were determined. We show that the expression of E2-EPF ubiquitin carrier protein, which targets the principal negative regulator of hypoxia-inducible factor (HIF), von Hippel-Lindau protein, for proteasome dependent degradation, is markedly elevated in the majority of PRCC tumors exhibiting increased HIF1alpha expression, and is associated with poor prognosis. In addition, we identified multiple hypoxia-responsive elements within the E2-EPF promoter, and for the first time we demonstrated that E2-EPF is a hypoxia inducible gene directly regulated via HIF1. These findings reveal deregulation of the oxygen-sensing pathway impinging on the positive feedback mechanism of HIF1 mediated regulation of E2-EPF in PRCC. PMID- 21281818 TI - Gene expression patterns related to vascular invasion and aggressive features in endometrial cancer. AB - The presence of tumor cells entering vascular channels is a prognostic marker for many cancers, including endometrial carcinoma. Vascular invasion is considered to be an early step in the metastatic process and important for the progress of malignant tumors. Here, we investigated the gene expression patterns related to vascular involvement in 57 primary endometrial cancers, using DNA microarray and quantitative PCR techniques. A vascular invasion signature of 18 genes was significantly associated with patient survival and clinicopathological phenotype. Vascular involvement was also related to gene sets for epithelial-mesenchymal transition, wound response, endothelial cells, and vascular endothelial growth factor (VEGF) activity. With immunohistochemical validation, both collagen 8 and matrix metalloproteinase 3 (MMP3) were associated with vascular invasion, whereas ANGPTL4 and IL-8 were associated with patient survival. Our findings indicate that vascular involvement within primary tumors is associated with gene expression profiles related to angiogenesis and epithelial-mesenchymal transition. These data could contribute to an improved understanding of potential targets for metastatic spread and may provide clinically important information for better management of endometrial cancer. PMID- 21281819 TI - Suppression of prostate cancer cell rolling and adhesion to endothelium by 1alpha,25-dihydroxyvitamin D3. AB - Adhesion of circulating prostate cancer (PCa) cells to the microvascular endothelium is a critical step during cancer metastasis. To study PCa cell rolling and adhesion behavior, we developed a dynamic flow-based microtube system to mimic the microvascular environment. We found that PCa cell rolling capacity is mediated by E-selectin and can be enhanced by stromal cell-derived factor-1 under different wall shear stresses. Using this device, we tested if the chemopreventive agent, vitamin D, could interfere with PCa cell adhesion. We found that 1alpha,25-dihydroxyvitamin D(3) (1,25-VD), the bioactive form of vitamin D, reduced PCa cell rolling numbers and increased rolling velocities resulting in a significant decreased number of PCa cells adhering to the microtube. The inhibitory effects of 1,25-VD on PCa cell heterotypic adhesion were further confirmed using microvascular endothelial cells in a static condition. Furthermore, we demonstrated that 1,25-VD can increase E-cadherin expression in PCa cells and promote the homotypic cell-cell aggregation, which can then hinder PCa cell adhesion to the endothelium. Blocking E-cadherin with a neutralizing antibody can reverse 1,25-VD-mediated suppression of PCa cell adhesion to the endothelium. Taken together, our data revealed that 1,25-VD promoted PCa cell aggregation by increasing E-cadherin expression, thus interfering with circulating PCa cell adhesion to microvascular endothelial cells and potentially reducing their metastatic potential. PMID- 21281820 TI - Syntenic relationships between genomic profiles of fiber-induced murine and human malignant mesothelioma. AB - Malignant mesothelioma (MM) is an aggressive tumor with a poor prognosis mainly linked to past asbestos exposure. Murine models of MM based on fiber exposure have been developed to elucidate the mechanism of mesothelioma formation. Genomic alterations in murine MM have now been partially characterized. To gain insight into the pathophysiology of mesothelioma, 16 murine and 35 human mesotheliomas were characterized by array-comparative genomic hybridization and were screened for common genomic alterations. Alteration of the 9p21 human region, often by biallelic deletion, was the most frequent alteration in both species, in agreement with the CDKN2A/CDKN2B locus deletion in human disease and murine models. Other shared aberrations were losses of 1p36.3-p35 and 13q14-q33 and gains of 5p15.3-p13 regions. However, some differences were noted, such as absence of recurrent alterations in mouse regions corresponding to human chromosome 22. Comparison between altered recurrent regions in asbestos-exposed and non-asbestos-exposed patients showed a significant difference in the 14q11.2 q21 region, which was also lost in fiber-induced murine mesothelioma. A correlation was also demonstrated between genomic instability and tumorigenicity of human mesothelioma xenografts in nude mice. Overall, these data show similarities between murine and human disease, and contribute to the understanding of the influence of fibers in the pathogenesis of mesothelioma and validation of the murine model for preclinical testing. PMID- 21281821 TI - Rear polarization of the microtubule-organizing center in neointimal smooth muscle cells depends on PKCalpha, ARPC5, and RHAMM. AB - Directed migration of smooth muscle cells (SMCs) from the media to the intima in arteries occurs during atherosclerotic plaque formation and during restenosis after angioplasty or stent application. The polarized orientation of the microtubule-organizing center (MTOC) is a key determinant of this process, and we therefore investigated factors that regulate MTOC polarity in vascular SMCs. SMCs migrating in vivo from the medial to the intimal layer of the rat carotid artery following balloon catheter injury were rear polarized, with the MTOC located posterior of the nucleus. In tissue culture, migrating neointimal cells maintained rear polarization, whereas medial cells were front polarized. Using phosphoproteomic screening and mass spectrometry, we identified ARPC5 and RHAMM as protein kinase C (PKC)-phosphorylated proteins associated with rear polarization of the MTOC in neointimal SMCs. RNA silencing of ARPC5 and RHAMM, PKC inhibition, and transfection with a mutated nonphosphorylatable ARPC5 showed that these proteins regulate rear polarization by organizing the actin and microtubule cytoskeletons in neointimal SMCs. Both ARPC5 and RHAMM, in addition to PKC, were required for migration of neointimal SMCs. PMID- 21281822 TI - Targeting endothelium-pericyte cross talk by inhibiting VEGF receptor signaling attenuates kidney microvascular rarefaction and fibrosis. AB - Microvascular pericytes and perivascular fibroblasts have recently been identified as the source of scar-producing myofibroblasts that appear after injury of the kidney. We show that cross talk between pericytes and endothelial cells concomitantly dictates development of fibrosis and loss of microvasculature after injury. When either platelet-derived growth factor receptor (R)-beta signaling in pericytes or vascular endothelial growth factor (VEGF)R2 signaling in endothelial cells was blocked by circulating soluble receptor ectodomains, both fibrosis and capillary rarefaction were markedly attenuated during progressive kidney injury. Blockade of either receptor-mediated signaling pathway prevented pericyte differentiation and proliferation, but VEGFR2 blockade also attenuated recruitment of inflammatory macrophages throughout disease progression. Whereas injury down-regulated angiogenic VEGF164, the dys-angiogenic isomers VEGF120 and VEGF188 were up-regulated, suggesting that pericyte myofibroblast differentiation triggers endothelial loss by a switch in secretion of VEGF isomers. These findings link fibrogenesis inextricably with microvascular rarefaction for the first time, add new significance to fibrogenesis, and identify novel therapeutic targets. PMID- 21281823 TI - IGF-1 has plaque-stabilizing effects in atherosclerosis by altering vascular smooth muscle cell phenotype. AB - Insulin-like growth factor-1 (IGF-1) signaling is important for the maintenance of plaque stability in atherosclerosis due to its effects on vascular smooth muscle cell (vSMC) phenotype. To investigate this hypothesis, we studied the effects of the highly inflammatory milieu of the atherosclerotic plaque on IGF-1 signaling and stability-related phenotypic parameters of murine vSMCs in vitro, and the effects of IGF-1 supplementation on plaque phenotype in an atherosclerotic mouse model. M1-polarized, macrophage-conditioned medium inhibited IGF-1 signaling by ablating IGF-1 and increasing IGF-binding protein 3, increased vSMC apoptosis, and decreased proliferation. Expression of alpha-actin and col3a1 genes was strongly attenuated by macrophage-conditioned medium, whereas expression of matrix-degrading enzymes was increased. Importantly, all of these effects could be corrected by supplementation with IGF-1. In vivo, treatment with the stable IGF-1 analog Long R3 IGF-1 in apolipoprotein E knockout mice reduced stenosis and core size, and doubled cap/core ratio in early atherosclerosis. In advanced plaques, Long R3 IGF-1 increased the vSMC content of the plaque by more than twofold and significantly reduced the rate of intraplaque hemorrhage. We believe that IGF-1 in atherosclerotic plaques may have a role in preventing plaque instability, not only by modulating smooth muscle cell turnover, but also by altering smooth muscle cell phenotype. PMID- 21281824 TI - Identification of a mechanism underlying regulation of the anti-angiogenic forkhead transcription factor FoxO1 in cultured endothelial cells and ischemic muscle. AB - Chronic limb ischemia, a complication commonly observed in conjunction with cardiovascular disease, is characterized by insufficient neovascularization despite the up-regulation of pro-angiogenic mediators. One hypothesis is that ischemia induces inhibitory signals that circumvent the normal capillary growth response. FoxO transcription factors exert anti-proliferative and pro-apoptotic effects on many cell types. We studied the regulation of FoxO1 protein in ischemic rat skeletal muscle following iliac artery ligation and in cultured endothelial cells. We found that FoxO1 expression was increased in capillaries within ischemic muscles compared with those from rats that underwent a sham operation. This finding correlated with increased expression of p27(Kip1) and reduced expression of Cyclin D1. Phosphorylated Akt was reduced concurrently with the increase in FoxO1 protein. In skeletal muscle endothelial cells, nutrient stress as well as lack of shear stress stabilized FoxO1 protein, whereas shear stress induced FoxO1 degradation. Endogenous FoxO1 co-precipitated with the E3 ubiquitin ligase murine double minute-2 (Mdm2) in endothelial cells, and this interaction varied in direct relation to the extent of Akt and Mdm2 phosphorylation. Moreover, ischemic muscles had a decreased level of Mdm2 phosphorylation and a reduced interaction between Mdm2 and FoxO1. Our results provide novel evidence that the Akt-Mdm2 pathway acts to regulate endothelial cell FoxO1 expression and illustrate a potential mechanism underlying the pathophysiological up-regulation of FoxO1 under ischemic conditions. PMID- 21281827 TI - Asbestos and lung diseases: introduction and epidemiology. PMID- 21281828 TI - Asbestosis. PMID- 21281829 TI - Benign asbestos-related pleural disease. PMID- 21281830 TI - Mesothelioma. PMID- 21281831 TI - Asbestos and lung cancer. PMID- 21281832 TI - Preface. Prediabetes and diabetes prevention. PMID- 21281833 TI - Definition of prediabetes. AB - Diabetes evolves through prediabetes, defined as impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT). Subjects with IFG/IGT have an increased risk of developing diabetes and a higher prevalence of cardiovascular disease than normoglycemic individuals. However, there is considerable evidence that glucose levels lower than those meeting the current definition of prediabetes may also be associated with similar concerns, particularly in high-risk individuals in accordance with a continuous glycemic risk perspective. Therefore, an absolute definition of prediabetes may underestimate the implications and vastness of this disorder. Research should focus on these aspects to minimize the risk of developing a preventable condition. PMID- 21281834 TI - Epidemiology of prediabetes. AB - Identifying individuals at increased risk of developing diabetes has assumed increasing importance with the expansion of the evidence from clinical trials on the prevention or delay of type 2 diabetes using lifestyle modification and medication. The epidemiology of prediabetes depends on the diagnostic method used. Glucose measures defining impaired glucose tolerance and impaired fasting glucose levels identify about 10% of the adults to have prediabetes, whereas glycated hemoglobin-based criteria identify a significantly lower proportion of the population. Increasingly, multifactorial risk tools are being used and cut points set to identify approximately 15% of the population as being at high risk. PMID- 21281835 TI - Mechanisms of vascular complications in prediabetes. AB - Although the state of prediabetes is defined by its role as a diabetes risk factor, it also carries a significant risk of cardiovascular disease, independent of progression to diabetes. Typical diabetic microvascular complications also occur, albeit at low rates, in prediabetes. There is evidence that both glucose related and glucose-independent mechanisms contribute to these vascular complications. Effective preventive strategies will likely require control of glycemia, as well as other metabolic risk factors. This article reviews some of the proposed mechanisms for the vascular complications of the prediabetic state. PMID- 21281836 TI - Pathophysiology of prediabetes. AB - Prediabetes encompasses conventional diagnostic categories of impaired fasting glucose and impaired glucose tolerance but is a band of glucose concentrations and a temporal phase over a continuum extending from conventional normal glucose tolerance to overt type 2 diabetes. Insulin resistance and defective glucose sensing at the beta-cell are the central pathophysiologic determinants that together cause hyperglycemia. Regardless of the cellular origin of insulin resistance, excessive tissue fat utilization is a consistent metabolic mechanism. Although genetic influences affect beta-cell function, becoming overweight is the main acquired challenge to insulin action. The phenotype of prediabetes includes dyslipidemia and higher arterial blood pressure. PMID- 21281837 TI - Diagnosis of prediabetes. AB - A rational approach to diagnosing prediabetes is essential to identify those who would benefit from entering diabetes prevention programs. Impaired fasting glucose and impaired glucose tolerance are similar in relation to their ability to identify those at risk of diabetes or cardiovascular disease; however, because they identify different segments of the at-risk population, there is value in undertaking glucose tolerance testing to ensure that both conditions can be diagnosed. Simple noninvasive diabetes risk scores offer a valuable entry point in the diagnosis of prediabetes, enabling the identification of those who need blood testing. PMID- 21281838 TI - Diabetes prevention programs. AB - Primary prevention of type 2 diabetes is effective for curbing its epidemic. Lifestyle intervention has been found to be a highly effective, safe, and cost effective method for the prevention of diabetes in high-risk persons, the benefit of which can extend for many years. Among the pharmacologic agents studied for prevention of diabetes, metformin has been found to be the safest. Interventions using drugs are less preferred because the drugs' effects tend to dissipate after their use is stopped and adverse effects may also result. The major challenge is to translate current knowledge into prevention programs at the national level. PMID- 21281840 TI - Treatment recommendations for prediabetes. AB - A variety of definitions and diagnostic cutpoints have been promulgated for prediabetes without universal agreement. Professional organizations agree that current scientific evidence justifies intervention in high-risk populations for the delay or prevention of progression to diabetes. Lifestyle intervention is universally accepted as the primary intervention strategy. Secondary intervention is advocated in high-risk individuals or in the absence of a clinical response to lifestyle modification. PMID- 21281839 TI - The economics of diabetes prevention. AB - In the United States, the costs associated with diabetes mellitus are increasing. Although people with diabetes comprise less than 6% of the US population, approximately 1 in 5 health care dollars is spent caring for people with diabetes. Healthy lifestyle interventions for the general population and intensive lifestyle and medication interventions for high-risk individuals present opportunities for diabetes prevention. This article describes the costs associated with glucose intolerance and diabetes, the effect of glucose intolerance and diabetes on the quality of life, and the cost-effectiveness of screening and primary prevention interventions for diabetes prevention. PMID- 21281841 TI - Public health implications: translation into diabetes prevention initiatives- four-level public health concept. AB - Many countries are struggling to meet the health care needs of a rapidly growing number of individuals with common chronic illnesses, especially diabetes mellitus. Incorporating the evidence from prevention trials into clinical practice represents one of the major challenges for public health, and the medical community is still learning how this can best be achieved at a population level. A 4-level public health initiative has been initiated that provides guidance for establishing milestones and strategies for such a program. PMID- 21281842 TI - Glycemic status, metabolic syndrome, and cardiovascular risk in children. AB - The metabolic syndrome and adult manifestation of prediabetes and diabetes are major public health problems that begin in childhood. Prevention must be considered as a serious public health issue. Health education and health promotion of school children needs incorporation as a community effort. PMID- 21281843 TI - Preface: Pediatric and adolescent psychopharmacology: the past, the present, and the future. PMID- 21281844 TI - Point-counter-point: psychotherapy in the age of pharmacology. AB - The long-held view that medicine or therapy is an "art" is quickly becoming obsolete. To procure referrals and reimbursement, clinicians are being forced to be accountable (ie, use empirically supported, effective, reproducible, and efficient treatment interventions) by insurance companies, professional credentialing bodies, and their consumers. This article focuses on reviews of treatment interventions by scholars, researchers, clinicians, and study groups who have examined multiple databases of published studies and ongoing treatment protocols. Behavioral and cognitive-behavioral therapies were most often identified as well-established treatments for specific mental and behavioral health disorders in children and adolescents. Psychotherapy alone or in conjunction with pharmacotherapy can be powerful tools in helping youth manage or eliminate negative outcomes of mental and behavioral disorders. PMID- 21281845 TI - Principles of pharmacology. AB - An understanding of the basic principles of pharmacokinetics and pharmacodynamics of drugs is important in appropriate therapeutic use of various drugs. In simple terms, the effects of the body on the drug once it has entered the body has been referred to as pharmacokinetics, and it aims to provide a quantitative assessment of the main processes involved in biodisposition of the drug, including absorption, distribution, metabolism, and elimination. Pharmacodynamics concerns itself with the effects of the drug on the body and the main processes involved are the action of the drug on specific sites, especially the receptors. In addition, pharmacogenetics and pharmacogenomics evaluates the influence of genetics on drug response. This article reviews basic concepts of pharmacology applicable to psychotherapeutic agents used for the treatment of mental disorders of children and adolescents. PMID- 21281846 TI - Basic concepts of neurotransmission. AB - An understanding of synaptic neurotransmission is fundamental to the understanding of various neuropsychiatric symptoms and disorders. It is also essential to the discovery of pharmacologic agents that modulate neurotransmission to alleviate such symptoms and conditions. Various aspects of the process of neurotransmission and the synthesis, release, reuptake, or destruction are all potential events for action of therapeutic drugs. This article reviews the basic aspects of relevant neuroanatomy, neurotransmission, and major neurotransmitter systems. PMID- 21281847 TI - Herbal medicines in pediatric neuropsychiatry. AB - An increasing number of studies have evaluated the role of herbal supplements in pediatric disorders, but they have numerous limitations. This review provides an overview of herbal components, regulation of supplements, and importance of product quality assurance. Use of herbal supplements is discussed with reference to factors that influence use in the pediatric population. The remainder of the article discusses the use of St John's wort, melatonin, kava, valerian, eicosapentaenoic acid, and docosahexaenoic acid, focusing on indications, adverse effects, and drug interactions, and providing a limited efficacy review. Herbal supplements used for weight loss are also briefly discussed. PMID- 21281848 TI - Pharmacotherapy for anxiety disorders in children and adolescents. AB - Anxiety disorders comprise the most prevalent mental health disorders among children and adults. Psychotherapy and pharmacotherapy are effective in improving clinical impairments from anxiety disorders and maintaining these improvements. This article discusses how to obtain a suitable diagnosis for anxiety disorders in youth for implementing appropriate treatments, focusing on the evidence base for pharmacologic treatment. Clinical guidelines are discussed, including Food and Drug Administration indications and off-label use of medications, and considerations for special populations and youth with comorbidities are highlighted. Findings suggest moderate effectiveness of medication, particularly selective serotonin reuptake inhibitors, in the treatment of anxiety disorders in youth. PMID- 21281849 TI - Psychopharmacologic control of aggression and violence in children and adolescents. AB - Aggression in children and adolescents is commonly displayed in the community and is even more commonly seen in clinical settings. As symptoms of an underlying disorder, aggressive behaviors should be comprehensively evaluated, and developmental, medical, and substance-use disorders should be identified and treated. This article reviews the most common psychiatric conditions associated with aggression and suggests appropriate psychopharmacologic interventions. Tables with recommended agents for each psychiatric disorder, as well as dosing ranges for each agent, are included. PMID- 21281850 TI - Psychopharmacology of autistic spectrum disorders in children and adolescents. AB - This article provides an overview of the psychopharmacologic management of irritability, hyperactivity, and repetitive behaviors in children and adolescents with autism spectrum disorder. A review of the current literature on medications used to treat these conditions with emphasis on randomized controlled trials is presented. PMID- 21281851 TI - Pharmacotherapy for child and adolescent attention-deficit hyperactivity disorder. AB - Research in the past 2 decades showed that attention-deficit/hyperactivity disorder (ADHD) is a frequently occurring psychiatric disorder that causes considerable suffering to patients and their families. This article outlines current pharmacologic ADHD treatment options and focuses on their safety profile and efficacy. In addition, it addresses treatment selection, guidelines for monitoring treatment, and recent controversies in the field. PMID- 21281852 TI - Psychopharmacology of eating disorders in children and adolescents. AB - Eating disorders are serious psychiatric illnesses that often present during adolescence and young adulthood. They are associated with medical as well as psychological disturbances, and pediatricians play an important role in their identification, diagnosis, and management. There has been a paucity of treatment research that specifically focuses on children and adolescents with eating disorders. This article reviews the scientific evidence for the use of psychotropic medication in the treatment of children and adolescents with eating disorders. PMID- 21281853 TI - Pharmacotherapy for obese adolescents. AB - The pharmaceutical search to induce weight loss was precipitated by the United States Food and Drug Administration's (FDA) 1959 formal approval of phentermine for short-term weight loss despite limited research supporting its assertions of weight loss. In addition to sympathomimetic amine products like phentermine, other medications considered in this article include herbal products, sibutramine, orlistat, metformin, and rimonabant. The use of pharmacotherapy for morbidly obese adolescents should be part of a comprehensive weight-loss program that recommends diet, exercise, and behavioral modification. Side effects and the possibility of major adverse effects should be remembered when considering use of these products. PMID- 21281854 TI - Psychopharmacology of depression in children and adolescents. AB - Although much debate continues about the prevalence of depressive disorders in prepubertal children, depression clearly is common in adolescents, increasing rapidly throughout the teen years. All physicians who work with young patients must to be able to recognize and treat these disorders. This article provides a brief overview of depressive disorders in children and adolescence, including their clinical presentation, prevalence, etiology, course, and prognosis. Psychopharmacological treatment options are reviewed in detail, including practical information for medication management including patient education, making the decision to treat with medication, selection of specific medications, strategies for nonresponsive patients, and decisions about stopping medication. PMID- 21281855 TI - Psychopharmacology of pediatric bipolar disorders in children and adolescents. AB - Pediatric bipolar disorder (PBD) is a chronic and disabling illness often leading to serious disruption in the lives of children and adolescents with this condition. Until recently, methodologically stringent data to guide pharmacologic interventions in the youth were scarce. However, clinical trials conducted recently have expanded the existing evidence base, and new data are emerging rapidly. Recent studies have examined the use of lithium, anticonvulsants, and atypical antipsychotics for acute and long-term treatment of PBD. Despite these new advances, further placebo-controlled trials investigating the efficacy and safety of pharmacologic treatment strategies for young people with bipolar disorder are still needed. PMID- 21281856 TI - Cognitive-adaptive disabilities. AB - Cognitive-adaptive disabilities (CADs) are not frequently seen in the general pediatric setting. Yet, given the high rates of comorbidity in that population, they commonly demand a lot of time and effort on the part of clinicians. One aspect of comorbidity is the degree to which psychiatric disorders occur in children, adolescents, and young adults with CADs. This article reviews the epidemiology, associated psychopathology, and pharmacologic treatment of selected CADs. PMID- 21281857 TI - Psychopharmacology of schizophrenia in children and adolescents. AB - The past 5 five years have seen major advances in the diagnosis and treatment of schizophrenia in children and adolescents. This article, reviews the clinical and diagnostic characteristics of schizophrenia in youth with an eye toward recent findings. This article also provides a more extensive review and update of the psychopharmacology of early-onset schizophrenia. PMID- 21281858 TI - Management of nonpsychiatric medical conditions presenting with psychiatric manifestations. AB - There is a significant dilemma when underlying medical disorders present as psychiatric conditions. It is important to identify the medical condition because treatment and management strategies need to be directed to the presenting symptoms and also to the underlying medical condition for successful treatment of the patient. Some systemic disorders present with psychiatric manifestations more often than others. The pattern of psychiatric disturbance seen may be specific for a particular medical disorder but may also be varied. Many drug formulations and medications also may produce psychiatric presentations. This article considers the management of nonpsychiatric medical conditions presenting with psychiatric manifestations. PMID- 21281859 TI - Pharmacotherapy for substance abuse disorders in adolescence. AB - The public health effects of adolescent substance abuse disorders (SUD) reaches further than the immediate intoxicating effects. Medications play a limited role in the treatment of youth beyond addressing short-term symptoms but may improve longer-term outcomes for some patients. Given the potential devastating consequences of SUD, clinicians should become familiar with all available treatment options. This article reviews the pharmacotherapy for adolescent SUD to inform clinicians considering the use of this modality for selected groups of patients. PMID- 21281860 TI - Psychopharmacology of tic disorders in children and adolescents. AB - Tics in children and adolescents are a common occurrence; however, a small proportion of these disorders require pharmacologic interventions. Several limitations exist with the use of pharmacologic interventions, and hence, a more ideal multidisciplinary approach is recommenced, with emphasis on nonpharmacologic management for improved functioning, adaptation, and comorbidities. Mutual and realistic goals ensure a trustful and successful relationship between the clinician and patient. An individualized plan is recommended with the goal of limiting side effects and managing comorbid conditions as a priority before addressing the tics specifically. This article reviews medications used to treat tic disorders in children and adolescents. PMID- 21281861 TI - Pharmacology of sleep disorders in children and adolescents. AB - There is a high prevalence of sleep disorders in children and an apparent increasing need for pharmacologic management. However, because of the paucity of data available with regards to dosing, efficacy, tolerability, and safety profiles of medications as well as a lack of adequate well-designed clinical trials, medications are currently not approved for the pediatric population by the US Food and Drug Administration. There are no pharmacologic guidelines for the specific sleep disorders or the different pediatric age ranges. Additional research is needed for evidence-based pediatric sleep pharmacotherapy. This article reviews pediatric sleep disorders and the pharmacologic therapeutic options. PMID- 21281862 TI - Current and novel therapeutics in the treatment of systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a complex autoimmune disease with significant clinical heterogeneity. Recent advances in our understanding of the genetic, molecular, and cellular bases of autoimmune diseases and especially SLE have led to the application of novel and targeted treatments. Although many treatment modalities are effective in lupus-prone mice, the situation is more complex in human subjects. This article reviews the general approach to the therapy of SLE, focusing on current approved therapies and novel approaches that might be used in the future. PMID- 21281863 TI - Advances in basic and clinical immunology in 2010. AB - Reports in basic and clinical immunology in 2010 reflected the use of state-of the-art genetic and immunologic tools to characterize the pathogenesis of immunologic diseases and the development of novel therapies directed to these conditions. B-cell biology has been explained in greater detail, significantly with lessons from the genetic defects found in the humoral immunodeficiencies. Therapeutic mAbs are given for an increasing number of indications, such as anti CD20 antibodies or rituximab, which was initially developed for non-Hodgkin lymphomas and is currently used in diverse autoimmune and inflammatory disorders. The report of an infant with severe combined immunodeficiency (SCID) in Massachusetts detected by means of newborn screening and successfully treated with hematopoietic stem cell transplantation validated recent efforts toward newborn screening for SCID. Improvement of survival outcomes for patients with primary immunodeficiencies treated with hematopoietic stem cell transplantation was demonstrated in a large European cohort, with significant appreciation of the type of donor graft, particularly the use of HLA-matched unrelated donors for patients with non-SCID. Progress in cellular mechanisms of drug hypersensitivity included the characterization of nitroso-modified drug metabolites as potent T cell activators and the identification of the relocation of plasmacytoid dendritic cells from blood to skin as a potential risk factor for reactivation of viral disease. PMID- 21281864 TI - Advances in upper airway diseases and allergen immunotherapy. AB - The purpose of this review is to highlight recently published important articles on upper airway diseases and immunotherapy. We review articles on rhinitis, sinusitis, conjunctivitis, and immunotherapy. New insights into epidemiology, pathophysiology, diagnosis, and therapy are described for each of the above diseases. Regarding immunotherapy, we discuss numerous clinical trials on sublingual and subcutaneous immunotherapy, mechanisms of immunotherapy, safety, and use of modified allergens and biological agents for immunotherapy. PMID- 21281865 TI - Altered T-cell receptor signaling in the pathogenesis of allergic disease. AB - Mounting evidence from animal models has demonstrated that alterations in T-cell receptor (TCR) signaling alone can lead to dramatically skewed differentiation of naive T cells into T(H)2 cells, to T(H)2 effector functions, and to T(H)2-related diseases. There is significant potential relevance of these observations to human disease. Specifically, a number of immunodeficiencies associated with atopic disease might have atopy as a manifestation because of aberrant TCR signaling. It is therefore important to attempt to identify a role for defects in TCR signaling in the pathogenesis of common atopic diseases. PMID- 21281866 TI - Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. AB - It is increasingly clear that asthma is a complex disease made up of number of disease variants with different underlying pathophysiologies. Limited knowledge of the mechanisms of these disease subgroups is possibly the greatest obstacle in understanding the causes of asthma and improving treatment and can explain the failure to identify consistent genetic and environmental correlations to asthma. Here we describe a hypothesis whereby the asthma syndrome is divided into distinct disease entities with specific mechanisms, which we have called "asthma endotypes." An "endotype" is proposed to be a subtype of a condition defined by a distinct pathophysiological mechanism. Criteria for defining asthma endotypes on the basis of their phenotypes and putative pathophysiology are suggested. Using these criteria, we identify several proposed asthma endotypes and propose how these new definitions can be used in clinical study design and drug development to target existing and novel therapies to patients most likely to benefit. This PRACTALL (PRACtical ALLergy) consensus report was produced by experts from the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology. PMID- 21281868 TI - The burden of adult asthma in the United States: evidence from the Medical Expenditure Panel Survey. AB - BACKGROUND: It is important to have an accurate picture of the sources and extent of medical expenditures and productivity loss to understand the nature and scope of the burden of asthma in the United States (US). OBJECTIVE: The current study aims to provide recent nationally representative estimates of direct and productivity-related costs attributable to asthma in adults in the US. METHODS: The 2003 and 2005 Medical Expenditure Panel Surveys were used to estimate the effect of asthma on medical expenditures, use, productivity, and chronic comorbidity among adults (>= 18 years). Productivity-related outcome variables included employment, annual wages, missed work days, days spent sick in bed, and activity limitations. Multivariate regression was conducted, controlling for sociodemographics and comorbidity. RESULTS: Of 44,795 adults, 1,935 reported an encounter for asthma [corrected]. Compared with those without, subjects with asthma were significantly less likely to be employed (odds ratio, 0.78), spent 1.4 more days sick in bed annually, and were significantly more likely to have activity limitations or to be unable to work. Adults with asthma incurred an additional $1,907 (2008 US dollars) annually and experienced higher health care use and comorbidity. The total national medical expenditure attributable to adult asthma was $18 billion. Adults with asthma were more likely to be covered by Medicaid (30%) than the general adult population (10%). The largest contributors to medical expenditures for adults with asthma were prescription drugs, followed by inpatient hospitalizations and home health care. CONCLUSIONS: In recent national data adult asthma is associated with a significant deleterious effect on direct and indirect costs in the US. PMID- 21281869 TI - Effect of day care attendance on sensitization and atopic wheezing differs by Toll-like receptor 2 genotype in 2 population-based birth cohort studies. AB - BACKGROUND: Variation in the Toll-like receptor 2 gene (TLR2/-16934) is associated with allergic diseases among farmers' children but not among children not living on farms. OBJECTIVE: To test the hypothesis that the same genetic variant conferring protection in the farming environment is associated with reduced risk of developing allergic phenotypes among urban children attending day care in early life. METHODS: In 2 population-based birth cohorts (Manchester, United Kingdom, Manchester Asthma and Allergy Study [MAAS]; Tucson, Ariz, Tucson Infant Immune Study [IIS]), participants were recruited prenatally and followed prospectively (MAAS: 3, 5, 8 and 11 years; IIS: 1, 2, 3 and 5 years). We assessed allergic sensitization and atopic wheezing at each follow-up. RESULTS: A total of 727 children participated in Manchester and 263 in Tucson. We found no significant associations between TLR2/-16934 and sensitization and atopic wheeze in either cohort. However, a different pattern emerged when we explored the interaction between TLR2/-16934 and day care attendance on these outcomes. We found a significant interaction between day care and TLR2/-16934 on the development of sensitization in the longitudinal model in MAAS in that children carrying the T allele who attended day care were less likely to be sensitized than those who did not attend day care, whereas among AA homozygotes, the association tended to be in the opposite direction. In a longitudinal model in IIS, we found a significant interaction between day care attendance and TLR2/ 16934 on the development atopic wheezing. Significant interactions between TLR2/ 16934 and day care were maintained when adjusting for socioeconomic status. CONCLUSION: The effect of day care on sensitization and atopic wheezing may differ among children with different variants of the TLR2 gene. PMID- 21281870 TI - Effects of omalizumab on changes in pulmonary function induced by controlled cat room challenge. AB - BACKGROUND: Environmental exposure to cat allergen is common, and sensitization to cat allergens is strongly associated with asthma. OBJECTIVE: We sought to examine the efficacy of omalizumab in preventing acute bronchoconstriction induced by environmental exposure to cat allergen. METHODS: Patients with a history of cat allergen-induced asthma were randomized to treatment with omalizumab or placebo and exposed to cat allergen in a controlled chamber for up to 1 hour at baseline and after 16 weeks of treatment. The primary efficacy outcome was area under the curve for percentage decrease from prechallenge FEV(1) at week 16 for omalizumab-treated versus placebo-treated patients. FEV(1) was recorded before and every 10 minutes during the 1-hour challenge. Chest, nasal, and ocular symptoms were also monitored during cat chamber exposure as secondary end points. RESULTS: The area under the curve for percentage decrease in FEV(1) was 15.2% per hour for omalizumab-treated patients (n = 32) and 27.3% per hour for placebo-treated patients (n = 33), reflecting 44% less reduction in FEV(1) and a treatment difference of -12.1% per hour (P = .0009; 95% CI, -19.0 to -5.2). Compared with placebo-treated patients, omalizumab-treated patients were also able to tolerate longer allergen exposure (P = .0006) and demonstrated significant reductions from prechallenge values in their chest symptom score (P < .0001) and nasal-ocular symptom score (P = .0002). CONCLUSIONS: The severity of acute airway reactions and symptoms caused by controlled cat room exposure to allergens was significantly reduced by treatment with omalizumab. PMID- 21281871 TI - The Madison Avenue effect: how drug presentation style influences adherence and outcome in patients with asthma. AB - BACKGROUND: Little is known about how drug presentation influences medication adherence. OBJECTIVE: To examine the effect of an educational program aimed at increasing expectations of treatment benefit on medication adherence. METHODS: Data are analyzed from 99 participants who underwent electronic drug monitoring during the Trial of Asthma Patient Education, a randomized, placebo-controlled, multicenter trial. Participants with suboptimally controlled asthma were randomized to placebo or montelukast in conjunction with a presentation mode that was either neutral or designed to increase outcome expectancy. Adherence was monitored electronically over 4 weeks and was defined as >= 80% use of prescribed doses. Outcome expectancy, peak expiratory flow, prebronchodilator FEV1, asthma control (Juniper asthma control questionnaire), and asthma-related quality of life were assessed at baseline and at the 4-week follow-up. RESULTS: Average electronic medication adherence was 69.9%. There was a significant interaction between presentation mode and drug assignment, with participants in the enhanced/montelukast group having a higher change in outcome expectancy (Delta 2.1 points; P < .001) and better medication adherence (odds ratio, 4.0; 95% CI, 1.1-14.3) compared with those in the neutral/placebo group. There was no difference in asthma symptoms, quality of life, or clinical outcomes on the basis of presentation mode. Rather, increased outcome expectancy was associated with modest improvements in asthma symptoms after adjusting for presentation mode, drug assignment, and medication adherence. CONCLUSION: The use of an enhanced presentation aimed at increasing outcome expectancy may lead to improved medication adherence. PMID- 21281872 TI - Pollen metabolome analysis reveals adenosine as a major regulator of dendritic cell-primed T(H) cell responses. AB - BACKGROUND: Water-soluble components from pollen modulate dendritic cell (DC) functions, such as IL-12 secretion and 3'-5'-cyclic adenosine monophosphate (cAMP) signaling and migration, possibly contributing to the establishment of a T(H)2-dominated immune response against pollen. Because these effects could not solely be attributed to the previously identified pollen-associated lipid mediators, the pollen metabolome was analyzed for candidate immunomodulatory substances. OBJECTIVE: We sought to perform an analysis of the effect of pollen associated adenosine on DC function and T(H) cell differentiation. METHODS: Fractions of aqueous pollen extracts (APEs) were generated by means of ultrafiltration and were subjected simultaneously to biological tests and metabolome analysis (ultra-high-resolution mass spectrometry) and ultraperformance liquid chromatography. Effects of pollen-derived adenosine on monocyte-derived DC cAMP signaling, cytokine response, and capacity to differentiate T(H) cells were studied. RESULTS: The less than 3-kd fraction of APEs comprised thousands of substances, including adenosine in micromolar concentrations. Pollen-derived adenosine mediated A2 receptor-dependent induction of cAMP and inhibition of IL-12p70 in DCs. APEs digested with adenosine deaminase failed to mediate IL-12 inhibition. DCs of nonatopic donors exposed to APEs showed an adenosine-dependent reduced capacity to differentiate T(H)1 cells and an enhanced capacity to induce regulatory T cells and IL-10. DCs of atopic donors failed to induce IL-10 but instead induced IL-5 and IL-13. CONCLUSION: This study identifies adenosine out of thousands of metabolites as a potent immunoregulatory substance in pollen. It acts on the level of the DC, with differential effects in atopic and nonatopic donors. PMID- 21281873 TI - Impact of immunotherapy on blood dendritic cells in patients with Hymenoptera venom allergy. AB - BACKGROUND: Modulation of T-cell differentiation, which is controlled by dendritic cells (DCs), plays a crucial role in specific immunotherapy (SIT). However, the number and the characteristics of blood DCs before and during immunotherapy are unknown. OBJECTIVE: To analyze the number and the characteristics of blood DC subsets in patients with Hymenoptera venom allergy before and after initiation of SIT. METHODS: In this clinical trial (NCT00947908), blood myeloid and plasmacytoid DCs were analyzed in 20 patients with Hymenoptera venom allergy (bee or wasp venom) by using 4-color flow cytometry at 3 time points: directly before SIT, and 52 hours and 12 months after initiation of SIT. In addition, 20 age-matched and sex-matched controls were examined. RESULTS: In patients with Hymenoptera venom allergy, the number of plasmacytoid DCs before SIT was comparable to that of controls. Plasmacytoid DCs decreased markedly 52 hours after initiation of SIT and returned to control levels after 12 months of treatment. Myeloid DCs were elevated in patients with Hymenoptera venom allergy before, during, and after the first 12 months of SIT. In addition, there were changes in the expression of function-associated surface molecules on myeloid DCs (such as Fc gamma receptor 2 and Toll-like receptor 2) during SIT. CONCLUSION: Numbers of blood myeloid DCs are elevated in patients with Hymenoptera venom allergy, and there are specific changes in the expression of function-associated surface molecules on these cells during SIT. Numbers of plasmacytoid DCs in blood are profoundly but are only transiently decreased after initiation of SIT. PMID- 21281874 TI - Efficacy and safety of immunotherapy for allergies to Alternaria alternata in children. AB - BACKGROUND: The safety and efficacy of specific immunotherapy for mold allergy are not known in children and adolescents. OBJECTIVE: We evaluated the efficacy and safety of specific immunotherapy with a standardized allergen extract in a randomized, double-blind, placebo-controlled, 3-year prospective study of patients who were allergic to only Alternaria alternata. METHODS: Fifty children and adolescents (25 girls; 5-18 years of age) with A alternata-induced seasonal allergic rhinoconjunctivitis and/or bronchial asthma were randomly assigned to groups given treatment (Novo-Helisen Depot, A alternata 100%) or placebo. The primary end point was the combined symptom medication score. Secondary end points included safety, quality of life, and sensitivity to allergen-specific nasal challenge. RESULTS: Forty-five children completed the 3-year study. Although there was no significant change in year 1, the combined symptom medication score decreased in years 2 and 3 of the study (by 38.7% and 63.5%, respectively; P < .001 for each). The reduction in symptoms was associated with a significant improvement in quality of life (P < .05) and decrease in sensitivity after allergen-specific nasal challenge. Side effects were observed in 7 patients; the most common (edema at the site of injection) occurred after 11 injections. CONCLUSIONS: Allergen-specific immunotherapy with standardized A alternata extract reduces symptoms of asthma and rhinoconjunctivitis in children and adolescents without serious side effects. PMID- 21281875 TI - Long-term tolerance after allergen immunotherapy is accompanied by selective persistence of blocking antibodies. AB - BACKGROUND: Grass pollen immunotherapy for allergic rhinitis is a disease modifying treatment that results in long-term clinical tolerance lasting years after treatment discontinuation. Active treatment is associated with generation of inhibitory grass pollen-specific IgG antibodies capable of blocking allergen IgE interactions. OBJECTIVES: We sought to investigate the involvement of IgG associated inhibitory antibodies with long-term clinical tolerance after discontinuation of grass pollen immunotherapy. METHODS: We conducted a 4-year study in which patients who had moderate-to-severe allergic rhinitis underwent a randomized, double-blind, placebo-controlled discontinuation of subcutaneous grass pollen immunotherapy. All subjects received grass pollen immunotherapy injections for 2 years (n = 13), followed by a further 2 years of either active (n = 7) or placebo (n = 6) injections. Clinical outcomes included seasonal symptoms and use of rescue medication. Serum specimens were collected at baseline and after 2 and 4 years for quantification of allergen-specific IgG antibodies. Sera were also tested for IgG-dependent inhibitory bioactivity against IgE allergen binding in cellular assays by using flow cytometry and confocal microscopy to detect binding of IgE-grass pollen allergen complexes to B cells. RESULTS: Clinical improvement was maintained after 2 years of discontinuation. Although immunotherapy-induced grass pollen-specific IgG1 and IgG4 levels decreased to near-preimmunotherapy levels during discontinuation, inhibitory bioactivity of allergen-specific IgG antibodies was maintained unchanged. CONCLUSION: Grass pollen immunotherapy induces a subpopulation of allergen specific IgG antibodies with potent inhibitory activity against IgE that persists after treatment discontinuation and that could account for long-term clinical tolerance. PMID- 21281876 TI - Two new families with X-linked inhibitor of apoptosis deficiency and a review of all 26 published cases. PMID- 21281877 TI - Lack of pretreatment cost-effectiveness and side effects of omalizumab versus prednisone/montelukast on tolerability of immunotherapy. PMID- 21281879 TI - Forced expiratory flow between 25% and 75% of vital capacity may be a marker of bronchial impairment in allergic rhinitis. PMID- 21281882 TI - Positive deviance: a program for sustained improvement in hand hygiene compliance. AB - BACKGROUND: There is a paucity of data evaluating whether positive deviance (PD) can sustain improvement in hand hygiene compliance. METHODS: An observational study comparing the effect of PD on compliance with hand hygiene was conducted in two 20-bed step-down units (SDUs) at a private tertiary care hospital. In a 3 month baseline period (April-June 2008), hand hygiene counts were performed by electronic handwashing counters. Between July 1, 2008, and November 30, 2009, (East SDU) and between September 30, 2008, and December 2009 (West SDU), PD was applied in both units. RESULTS: There was more than a 2-fold difference in the number of alcohol gel aliquots dispensed per month from April 2008 (before PD) to November 2009 (last month in PD) in the East SDU. There was also a 2-fold difference in the number of alcohol gel aliquots dispensed per month from September 2008 (before PD) to December 2009 (last month in PD) in the West SDU. The difference in the rate of health care-associated infections (HAIs) between the baseline period and 2009 was statistically significant in the East SDU (5.8 vs 2.8 per 1,000 device-days; P = .008) and in the West SDU (3.7 vs 1.7 per 1,000 device-days; P = .023). CONCLUSIONS: PD was responsible for a sustained improvement in hand hygiene in the inpatient setting and was associated with a decrease in the incidence of device-associated HAIs. PMID- 21281883 TI - Hospital hand hygiene opportunities: where and when (HOW2)? The HOW2 Benchmark Study. AB - BACKGROUND: Measurement and monitoring of health care workers' hand hygiene compliance (i.e., actions/opportunities) is a key component of strategies to eliminate hospital-acquired infections. Little data exist on the expected number of hand hygiene opportunities (HHOs) in various hospital settings, however. The purpose of this study was to estimate HHOs in 2 types of hospitals--large teaching and small community--and 3 different clinical areas-medical-surgical intensive care units, general medical wards, and emergency departments. METHODS: HHO data were collected through direct observations using the World Health Organization's monitoring methodology. Estimates of HHOs were developed for 12 hour AM/PM shifts and 24-hour time frames. RESULTS: During 436.7 hours of observation, 6,640 HHOs were identified. Estimates of HHOs ranged from 30 to 179 per patient-day on inpatient wards and from 1.84 to 5.03 per bed-hour in emergency departments. Significant differences in HHOs were found between the 2 hospital types and among the 3 clinical areas. CONCLUSION: This study is the first to use the World Health Organization's data collection methodology to estimate HHOs in general medical wards and emergency departments. These data can be used as denominator estimates to calculate hand hygiene compliance rates when product utilization data are available. PMID- 21281884 TI - Cost of screening intensive care unit patients for methicillin-resistant Staphylococcus aureus in hospitals. AB - BACKGROUND: The objective of this study is to determine the costs per hospital admission of screening intensive care unit patients for methicillin-resistant Staphylococcus aureus (MRSA) and isolating those who are colonized. METHODS: Data on the costs of the intervention come from the Minneapolis Veterans Affairs Medical Center, a 279-bed teaching hospital and outpatient facility. A microcosting approach is used to determine the intervention costs for 3 different laboratory testing protocols. The costs of caring for MRSA-infected patients come from the experience of 241 Minneapolis Veterans Affairs Medical Center patients with MRSA infections in 2004 through 2006. The effectiveness of the intervention comes from the extant literature. To capture the effect of screening on reducing transmission of MRSA to other patients and its effect on costs, a Markov simulation model was employed. RESULTS: The intervention was cost saving compared with no intervention for all 3 laboratory processes evaluated and for all of the 1-way sensitivity analyses considered. CONCLUSION: Because of the high cost of caring for a MRSA patient, interventions that reduce the spread of infections such as screening intensive care unit patients upon admission studied here-are likely to pay for themselves. PMID- 21281885 TI - Prevalence of and risk factors for methicillin-resistant Staphylococcus aureus colonization and infection among infants at a level III neonatal intensive care unit. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a well-known nosocomial pathogen of neonatal intensive care unit (NICU) patients and can cause both serious infections in preterm neonates and prolonged MRSA outbreaks in NICUs. OBJECTIVES: Our objectives were to determine the prevalence of and identify risk factors for MRSA colonization and infection in the NICU and the impact of an active surveillance program on MRSA in the NICU. METHODS: We collected weekly nasal MRSA surveillance cultures on 2,048 infants admitted to NICU over 3 years. Data on these infants were collected retrospectively. Characteristics of MRSA colonized and infected infants were analyzed and compared. RESULTS: MRSA colonization was detected in 6.74% of infants, and MRSA infection occurred in 22% of those colonized. Using clinical cultures alone, only 41 (27.5%) of 149 MRSA affected infants were identified. The majority (75%) developed MRSA infection within 17 days of colonization. For every 10-day increment in NICU stay, the odds ratio of being infected and colonized with MRSA increased by 1.32 and 1.29, respectively. Colonization was significantly associated with longer NICU stay, low birth weight, low gestational age, and multiple gestation status. CONCLUSION: Colonization is a risk factor for infection with MRSA in NICUs. Clinical cultures underestimate MRSA affected infants in NICUs, whereas active surveillance cultures could detect MRSA affected infants earlier and limit nosocomial spread. PMID- 21281886 TI - An investigation of bacterial contamination on treatment table surfaces of chiropractors in private practice and attitudes and practices concerning table disinfection. AB - BACKGROUND: The attitudes and behaviors of chiropractors regarding table disinfection have not yet been investigated. The purpose of this study was to evaluate (1) the bacterial contaminants present on treatment tables in private chiropractic clinics, (2) the effectiveness of the paper barrier in preventing bacterial deposition, and (3) chiropractors' attitudes and practices regarding table disinfection. METHODS: Defined portions of treatment tables from 14 private clinics in Alberta, Canada were sampled for the presence of bacteria. Growth characteristics and 16S rRNA gene sequencing were used for bacterial identification. In addition, a 12-item survey was administered to southern Alberta chiropractors (n = 79; 81% response rate) inquiring about their attitudes and behaviors regarding table disinfection. RESULTS: Respondents favored the idea of table disinfection (84%), but only 62% had a routine disinfection protocol. Table sampling revealed the presence of a number of bacteria, including methicillin-resistant Staphylococcus aureus, which were recovered from 3 separate clinics. The paper covering on table headpieces was an effective barrier to bacteria. CONCLUSION: Chiropractors have a positive attitude regarding disinfection; however, the risk of infection from treatment tables remains. Modification of the positioning of facial piece paper may be indicated, along with increased emphasis on disinfection. PMID- 21281887 TI - Preventing infections in hemodialysis: an executive summary of the APIC Elimination Guide. AB - This article is an executive summary of the APIC Hemodialysis Infection Elimination Guide. Infection preventionists are encouraged to obtain the original, full-length APIC Elimination Guide for more thorough coverage of hemodialysis infection prevention. PMID- 21281888 TI - Hospitals learn their collective power: an isolation gown success story. AB - BACKGROUND: We describe an investigation and improvement project designed to provide comfortable, affordable, fluid-resistant isolation gowns in response to inadequate compliance with gown use. METHODS: Infection control and purchasing departments determined number of gowns used, cost/gown, and contract information for our laundry service. We investigated disposable gown options. During a conference call for a multihospital project, we learned that 4 local hospitals all used the same laundry service and that all were dissatisfied with the quality of the reusable gowns. The 4 hospitals resolved to meet with the hospital laundry service to negotiate as a group. In preparation, we both investigated laundry services in neighboring cities and reviewed Centers for Disease Control and Prevention and Occupational Safety and Health Administration isolation gown requirements. RESULTS: Confronted with its major customers acting collectively, the laundry service agreed to identify gowns by age, bring gowns to Occupational Safety and Health Administration compliance, mark grids so gowns could be removed after 75 washes, add 6,000 new gowns, and remove 6,000 old gowns. The cost increase was 3.75c/gown. After the changeover was complete, reports of fluid leaking through gowns stopped. We saved $187,000 by keeping reusable gowns. CONCLUSION: When we tried to provide comfortable, affordable, fluid-resistant isolation gowns, we encountered 2 barriers: our city had only 1 hospital laundry service, and disposable gowns were costly. We solved the problem through unusual collaboration: internal (Infection Control and Purchasing) and external (with otherwise competing hospitals). Collaboration and knowledge sharing led to accountability: the hospital to its staff and budget and the laundry service to the hospitals. PMID- 21281889 TI - Low rate of compliance with hand hygiene before glove use. PMID- 21281890 TI - Preventive behaviors for the H1N1 influenza epidemic. PMID- 21281891 TI - Catheter-related colonization or infection in critically ill patients: Is the number of simultaneous catheters a risk factor? PMID- 21281892 TI - IT network, distribution of health infection on infectious disease, and need for quality control on data. PMID- 21281895 TI - Ocular risks from orbital and periorbital radiation therapy: a critical review. PMID- 21281896 TI - Stereotactic radiotherapy of primary lung cancer and other targets: results of consultant meeting of the International Atomic Energy Agency. AB - To evaluate the current status of stereotactic body radiotherapy (SBRT) and identify both advantages and disadvantages of its use in developing countries, a meeting composed of consultants of the International Atomic Energy Agency was held in Vienna in November 2006. Owing to continuous developments in the field, the meeting was extended by subsequent discussions and correspondence (2007 2010), which led to the summary presented here. The advantages and disadvantages of SBRT expected to be encountered in developing countries were identified. The definitions, typical treatment courses, and clinical results were presented. Thereafter, minimal methodology/technology requirements for SBRT were evaluated. Finally, characteristics of SBRT for developing countries were recommended. Patients for SBRT should be carefully selected, because single high-dose radiotherapy may cause serious complications in some serial organs at risk. Clinical experiences have been reported in some populations of lung cancer, lung oligometastases, liver cancer, pancreas cancer, and kidney cancer. Despite the disadvantages expected to be experienced in developing countries, SBRT using fewer fractions may be useful in selected patients with various extracranial cancers with favorable outcome and low toxicity. PMID- 21281897 TI - Atlas-based segmentation improves consistency and decreases time required for contouring postoperative endometrial cancer nodal volumes. AB - PURPOSE: Accurate target delineation of the nodal volumes is essential for three dimensional conformal and intensity-modulated radiotherapy planning for endometrial cancer adjuvant therapy. We hypothesized that atlas-based segmentation ("autocontouring") would lead to time savings and more consistent contours among physicians. METHODS AND MATERIALS: A reference anatomy atlas was constructed using the data from 15 postoperative endometrial cancer patients by contouring the pelvic nodal clinical target volume on the simulation computed tomography scan according to the Radiation Therapy Oncology Group 0418 trial using commercially available software. On the simulation computed tomography scans from 10 additional endometrial cancer patients, the nodal clinical target volume autocontours were generated. Three radiation oncologists corrected the autocontours and delineated the manual nodal contours under timed conditions while unaware of the other contours. The time difference was determined, and the overlap of the contours was calculated using Dice's coefficient. RESULTS: For all physicians, manual contouring of the pelvic nodal target volumes and editing the autocontours required a mean+/-standard deviation of 32+/-9 vs. 23+/-7 minutes, respectively (p=.000001), a 26% time savings. For each physician, the time required to delineate the manual contours vs. correcting the autocontours was 30+/-3 vs. 21+/-5 min (p=.003), 39+/-12 vs. 30+/-5 min (p=.055), and 29+/-5 vs. 20+/-5 min (p=.0002). The mean overlap increased from manual contouring (0.77) to correcting the autocontours (0.79; p=.038). CONCLUSION: The results of our study have shown that autocontouring leads to increased consistency and time savings when contouring the nodal target volumes for adjuvant treatment of endometrial cancer, although the autocontours still required careful editing to ensure that the lymph nodes at risk of recurrence are properly included in the target volume. PMID- 21281898 TI - Response to "Urinary obstruction in prostate cancer patients from the Dutch trial (68 Gy vs. 78 Gy): relationships with local dose, acute effects, and baseline characteristics" (Int J Radiat Oncol Biol Phys 2010;78:19-25). PMID- 21281899 TI - Hippocampal-sparing whole-brain radiotherapy: a "how-to" technique using helical tomotherapy and linear accelerator-based intensity-modulated radiotherapy: in regard to Gondi v, et al. (Int j radiat oncol biol phys 2010;78:1244-1252). PMID- 21281900 TI - Citation and quotation errors: in regards to Qiu et al. (Int J Radiat Oncol Biol Phys 2010;78:288-296). PMID- 21281903 TI - Imaging primary lung cancers in mice to study radiation biology: in regard to Kirsch et al. (Int J Radiat Oncol Biol Phys 2010;76:973-977). PMID- 21281906 TI - Running a hybrid lab-perspectives of a physician and a sonographer. PMID- 21281907 TI - Hand-carried echocardiography in heart failure and heart failure risk population: a community based prospective study. AB - BACKGROUND: The basic reservation concerning the use of hand-carried echocardiographic devices by general practitioners has been a lack of data demonstrating that they would provide clinically important information on patients' outcomes. METHODS: One hundred seventy-five patients with heart failure and/or heart failure risk factors were selected from a general community outpatient clinic. They underwent simplified hand-carried echocardiography performed by an internist with basic echocardiographic experience and N-terminal pro-B-type natriuretic peptide measurements. Patients were followed for the occurrence of the combined end point, consisting of death or hospitalization for cardiovascular causes. RESULTS: Hand-carried echocardiographic results were abnormal in 90 patients (55%). During 48 +/- 7 months of follow-up, the combined end point occurred in 41 patients (25%). On multivariate analysis, only abnormal echocardiography (hazard ratio, 5.55; 95% confidence interval, 2.04-14.28; P = .0004) was an independent predictor of outcomes. CONCLUSIONS: Hand-carried echocardiographic examinations performed by an internist with basic echocardiographic training can provide important prognostic information, independent of N-terminal pro-B-type natriuretic peptide levels. PMID- 21281908 TI - Echocardiography at the point of care: an ultra sound future. PMID- 21281909 TI - Echocardiographic findings in stable outpatients with properly functioning HeartMate II left ventricular assist devices. AB - BACKGROUND: Continuous-flow left ventricular assist devices (LVADs) have become part of the standard of care for the treatment of advanced heart failure. However, knowledge of normal values for transthoracic echocardiographic examination and measurements in these patients are lacking. METHODS: All transthoracic echocardiographic examinations in 63 consecutive patients, performed 90 and 180 days after surgery with the implantation of a HeartMate II continuous-flow LVAD between February 2007 and January 2010, were retrospectively analyzed. All patients had to be outpatients at 3 and 6 months after surgery and considered stable on LVAD therapy (New York Heart Association class I or II and no need for inotropes, intravenous furosemide, or hospitalization). RESULTS: End diastolic and end-systolic diameters and left ventricular mass decreased considerably compared with baseline measurements before LVAD implantation. Mitral inflow deceleration time increased (188 +/- 70 vs 132.5 +/- 27 msec, P = .009) and left atrial volume (84.1 +/- 33 vs 141.7 +/- 62 mL, P = .003) and E/e' ratio decreased (20.3 +/- 9 vs 26 +/- 11, P = .01), all consistent with decreased left ventricular filling pressure. Estimated right ventricular (RV) and right atrial pressure decreased significantly (34.1 +/- 10 vs 51.7 +/- 14 mm Hg and 9.5 +/- 5 vs 14.4 +/- 5 mm Hg, respectively, P < .0001 for both). Quantitatively estimated RV function (P = .02), RV fractional area change (27.9 +/- 10% vs 37.4 +/- 10.9%, P < .0001), and the RV index of myocardial performance (0.32 +/- 0.1 vs 0.65 +/- 0.2 vs 0.32 +/- .01, P < .0001) improved, suggesting improved RV efficiency. LVAD therapy resulted in significant decreases in the severity of mitral regurgitation. Tricuspid regurgitation improved in patients who had concurrent tricuspid surgical correction and was unchanged otherwise. Aortic regurgitation severity increased 3 months after LVAD implantation. There were no significant differences in any of the echocardiographic parameters in the 6-month evaluation compared with the 3-month evaluation. CONCLUSIONS: This is the first report of selected typical echocardiographic values in a group of stable patients with normally functioning HeartMate II continuous-flow LVADs. A stable functioning continuous LVAD is associated with evidence of efficient unloading of the left ventricle, improved RV function, significant improvement in mitral regurgitation, improvement in tricuspid regurgitation only in patients undergoing repair, and increased aortic regurgitation. These normal data provide a basis for future echocardiographic studies after LVAD implantation. PMID- 21281910 TI - The dyssynchrony in predicting response to cardiac resynchronization therapy: a call for change. PMID- 21281911 TI - The role of three-dimensional echocardiography in the assessment of right ventricular dysfunction after a half marathon: comparison with cardiac magnetic resonance imaging. AB - BACKGROUND: Although marathon running is associated with transient right ventricular (RV) systolic dysfunction as detected by two-dimensional transthoracic echocardiography, quantitative assessment of the right ventricle is difficult because of its complex geometry. Little is known about the use of real time three-dimensional echocardiography (RT3DE) in the detection of cardiac dysfunction after a half marathon. The aim of this study was to assess the extent of RV dysfunction after the completion of a half marathon using cardiac biomarkers, RT3DE, and cardiac magnetic resonance imaging (CMR). METHODS: A prospective study was performed in 15 individuals in 2009 participating in the Manitoba Half Marathon. Cardiac biomarkers (myoglobin, creatine kinase-MB and cardiac troponin T) were assessed and RT3DE and CMR were performed 1 week before, immediately after, and 1 week after the race. RESULTS: At baseline, cardiac biomarkers and ventricular function were within normal limits. Immediately following the half marathon, all patients demonstrated elevated cardiac troponin T levels, with a median value of 0.37 ng/mL. RV ejection fraction, as assessed by RT3DE, decreased from 59 +/- 4% at baseline to 45 +/- 5% immediately following the race (P < .05). On CMR, RV end-diastolic volume increased after the half marathon, and the RV ejection fraction was reduced, at 47 +/- 5% compared with 60 +/- 2% at baseline (P < .05). There were strong linear correlations between RV ejection fraction assessed by RT3DE and CMR at baseline and after the half marathon (r = 0.69 and r = 0.87, P < .01, respectively). CONCLUSIONS: Compared with CMR, RT3DE is a feasible and reproducible method of assessing transient RV dysfunction in athletes completing a half marathon. PMID- 21281912 TI - Normal values for left ventricular volume in infants and young children by the echocardiographic subxiphoid five-sixth area by length (bullet) method. AB - BACKGROUND: Left ventricular (LV) end-diastolic volume (LVEDV) can be estimated by the formula (5/6) x area x length, or the "bullet" method. The aim of this study was to determine the range of normal LVEDV values in infants and young children (aged 0-3 years) by the subxiphoid bullet method. METHODS: Echocardiograms from 100 normal subjects aged <= 3 years were retrospectively analyzed. Subjects with systemic disease, abnormal body size, cardiovascular disease, or nondiagnostic subxiphoid images were excluded. Measurements of LV short-axis cross-sectional diastolic area at the midventricular level and LV length were made offline from subxiphoid images. LVEDV was indexed to body surface area (BSA) to the powers of 1.0 and 1.38. Relationships between indexing methods, age, and gender were explored. RESULTS: The median age was 0.98 years (range, 0-2.9 years), the median weight was 9.5 kg (range, 3.1-16.0 kg), and the median BSA was 0.45 m(2) (range, 0.21-0.66 m(2)). The mean LVEDV/BSA(1.38) was 70.4 +/- 9.1 mL/m(2.6), with an excellent correlation between LVEDV and BSA(1.38) (r = 0.96, P < .01). There was no residual relationship between LVEDV/BSA(1.38) and BSA (r = 0.06, P = NS) and no significant relationship between LVEDV/BSA(1.38) and age (r = 0.10, P = NS) or LVEDV/BSA(1.38) and gender. CONCLUSIONS: The normal range for LVEDV by the subxiphoid echocardiographic bullet method is reported for newborns, infants, and young children. LVEDV should be indexed to BSA(1.38), which is consistent with the known relationship between LV size and body size. In children aged <= 3 years, these data can be used to calculate Z scores for LVEDV by the subxiphoid bullet technique independent of age or gender. PMID- 21281913 TI - Imaging probes--Introduction. PMID- 21281914 TI - Journal of Shoulder and Elbow Surgery. Editorial. PMID- 21281915 TI - Radial head fracture: open reduction-internal fixation or prosthetic replacement. PMID- 21281916 TI - Controversies in the surgical treatment of distal biceps tendon ruptures: single versus double-incision repairs. PMID- 21281917 TI - A systematic review of the clinical outcomes of single row versus double row rotator cuff repairs. PMID- 21281918 TI - Superior labral tears: repair versus biceps tenodesis. PMID- 21281919 TI - Treatment options for massive rotator cuff tears. PMID- 21281920 TI - Glenohumeral arthritis in the young patient. PMID- 21281921 TI - Trends in glenoid component design in unconstrained shoulder arthroplasty. PMID- 21281922 TI - Proximal humeral fractures in younger patients: fixation techniques and arthroplasty. PMID- 21281923 TI - Arthroscopic management of the post-traumatic stiff elbow. PMID- 21281924 TI - Arthroscopic suprascapular nerve release: indications and technique. PMID- 21281925 TI - Approaches for elbow arthroplasty: how to handle the triceps. PMID- 21281926 TI - Distal humeral fractures: fixation versus arthroplasty. PMID- 21281927 TI - Why we should effectively treat malaria. PMID- 21281928 TI - Comparison of nodal positivity between SLNM vs conventional surgery in colon cancer patients with <12 and >=12 lymph nodes harvested. AB - BACKGROUND: Examination of >=12 lymph nodes (LNs) ensures accurate staging in colon cancer. The aim of this study was to compare nodal positivity between sentinel LN mapping (SLNM) and conventional surgery in patients with <12 and >=12 LNs harvested. METHODS: From 1993 to 2008, 407 and 380 patients with colon cancer underwent SLNM and conventional surgery, respectively. Total LNs harvested and nodal positivity were analyzed. Patients were grouped according to number of LNs harvested: 2 to 11, 12 to 25, or >25. RESULTS: The average numbers of LNs harvested in the groups with 2 to 11, 12 to 25, and >25 LNs harvested for SLNM and conventional surgery, respectively, were 8.3 and 7.1 (P < .0001), 17.2 and 16.5 (P = .09), and 34.2 and 32.1 (P = .40). Nodal positivity for SLNM and conventional surgery in the groups with <12 and >=12 LNs harvested was 42% and 29% (P = .01) and 50% and 36% (P = .003), respectively. Overall nodal positivity was 47% for SLNM and 32% for conventional surgery (P < .0001). When SLNM with 2 to 11 LNs was compared with conventional surgery with 12 to 25 LNs, nodal positivity was 42% versus 36% (P = .35). CONCLUSIONS: SLNM possessed higher nodal positivity compared with conventional surgery. SLNM is a valuable adjunct to accurate nodal staging in colon cancer. PMID- 21281929 TI - [Profile of tobacco use among the teachers of Sousse, Tunisia]. AB - OBJECTIVE: To examine the prevalence of tobacco use among the teachers in the region of Sousse (Tunisia) and to identify the factors, which determine this behavior. PATIENTS AND METHODS: It is a transactional study; using a self administered and pre-tested questionnaire to 800 teachers. RESULTS: The population being studied was made up of 739 teachers including 50.6% of professors. The sample was 35.4% male and the average age was of 45.3+/-8.1 years. The total prevalence of tobacco use was 17.8% (41.4% among men and 4.7% among women). Half of these teachers smoked in their school establishments and in the presence of their pupils. The multivariate analysis had made it possible to identify four factors, which determine the profile of tobacco use in our teachers; these factors were: the sex, the age, knowledge and attitudes. CONCLUSION: It's necessary to intervene with the teachers of the town of Sousse with specific trainings on the topic of the tobacco use and dispose their adapted tools which will be used in the educational programmes of tobacco use prevention in schools. PMID- 21281930 TI - Improving and analyzing signage within a healthcare setting. AB - Healthcare facilities are increasingly utilizing pictograms rather than text signs to help direct people. The purpose of this study was to analyze a wide variety of standardized healthcare pictograms and the effects of color contrasts and complexity for participants with both normal and impaired vision. Fifty (25 males, 25 females) participants completed a signage recognition questionnaire and identified pictograms while wearing vision simulators to represent specific visual impairment. The study showed that certain color contrasts, complexities and orientations can help or hinder comprehension of signage for people with and without visual impairment. High contrast signage with consistent pictograms involving human figures (not too detailed or too abstract) is most identifiable. Standardization of healthcare signage is recommended to speed up and aid the cognitive thought process in detecting signage and determining meaning. These fundamental signage principles are critical in producing an efficient, universal wayfinding system for healthcare facilities. PMID- 21281931 TI - Sodium butyrate induces the production of cyclooxygenases and prostaglandin E2 in ROS 17/2.8 osteoblastic cells. AB - OBJECTIVE: Sodium butyrate (butyric acid; BA) is a major metabolic by-product of the anaerobic periodontopathic bacteria present in subgingival plaque. We examined the effects of BA and/or indomethacin on cell proliferation, the expression of cyclooxygenases (COXs), prostaglandin (PG) receptors (EP1-4), extracellular matrix proteins, such as type I collagen and osteopontin, and PGE(2) production, using ROS17/2.8 cells as osteoblasts. METHODS: The rat clonal cell line ROS 17/2.8 was cultured with 0, 10(-5), 10(-4), and 10(-3)M BA in the presence or absence of 0.5 MUM indomethacin, for up to 7 days. The expression of COX-1, COX-2, EP1, EP2, EP3, EP4, type I collagen, and osteopontin was examined at the mRNA and protein levels using real-time PCR and Western blotting, respectively. The amount of PGE(2) in the culture medium was measured by ELISA. RESULTS: Proliferation of ROS 17/2.8 cells was not affected by the addition of BA. However, PGE(2) production and the expression of COX-1 and COX-2 increased with the addition of BA. In contrast, indomethacin, an inhibitor of COX, blocked the stimulatory effect of BA. Furthermore, EP2 expression increased with BA treatment, whereas EP1 expression was not affected and the expression of EP3 and EP4 was not detected. The addition of BA also increased the expression of type I collagen and osteopontin. Indomethacin blocked about 50% of the stimulatory effect of BA on type I collagen, whereas it did not block the effect on osteopontin. CONCLUSIONS: These results suggest that BA induces PGE(2) production by increasing the expression of COX-1 and COX-2 in osteoblasts, and that an autocrine action of the produced PGE(2), via EP1 or BA-induced EP2, is related to an increase in type I collagen expression by BA. PMID- 21281932 TI - Nonlinear model identification and adaptive model predictive control using neural networks. AB - This paper presents two new adaptive model predictive control algorithms, both consisting of an on-line process identification part and a predictive control part. Both parts are executed at each sampling instant. The predictive control part of the first algorithm is the Nonlinear Model Predictive Control strategy and the control part of the second algorithm is the Generalized Predictive Control strategy. In the identification parts of both algorithms the process model is approximated by a series-parallel neural network structure which is trained by a recursive least squares (ARLS) method. The two control algorithms have been applied to: 1) the temperature control of a fluidized bed furnace reactor (FBFR) of a pilot plant and 2) the auto-pilot control of an F-16 aircraft. The training and validation data of the neural network are obtained from the open-loop simulation of the FBFR and the nonlinear F-16 aircraft models. The identification and control simulation results show that the first algorithm outperforms the second one at the expense of extra computation time. PMID- 21281933 TI - An analytical method for PID controller tuning with specified gain and phase margins for integral plus time delay processes. AB - In this paper, an analytical method is proposed for proportional integral/proportional-derivative/proportional-integral-derivative (PI/PD/PID) controller tuning with specified gain and phase margins (GPMs) for integral plus time delay (IPTD) processes. Explicit formulas are also obtained for estimating the GPMs resulting from given PI/PD/PID controllers. The proposed method indicates a general form of the PID parameters and unifies a large number of existing rules as PI/PD/PID controller tuning with various GPM specifications. The GPMs realized by existing PID tuning rules are computed and documented as a reference for control engineers to tune the PID controllers. PMID- 21281934 TI - Controlled-cycle pulsed liquid-liquid chromatography. A modified version of Craig's counter-current distribution. AB - A new liquid-liquid chromatography technique developed from a combination of controlled-cycle operation and a pulsed-mixing technique is suggested and validated. The controlled-cycle pulsed liquid-liquid chromatography (CPLC) system operates without involving a centrifuge and consists, of a series of multistage units, and a method for imparting pulsation motion to the liquids inside the units (the pulsation cycle). This chromatography technique can be considered as an improved continuous form of Craig's counter-current distribution method, or, alternatively, as a form of droplet chromatography with the cycling mode of operation. The theoretical model has been designed to account for the effects of the basic parameters influencing the CPLC operation. The theoretical model's suitability was proved by direct comparison between the experimental and model responses. The CPLC devices containing 1, 2, 4 and 5 multistage columns (each column was divided into 26 stages) have been designed, fabricated and tested; experiments were conducted to test the chromatographic behavior of organic (monocarboxylic) and mineral acids. The mass transfer rate in the stages depends on the nature of both--phase and sample systems: the highest values were achieved in experiments with acetic acid by using the octane/water biphasic system, where an equilibrium concentration distribution between stationary and mobile phases in the stages was attained. The results obtained demonstrated the potential of the new technique for preparative and industrial scale separations. PMID- 21281935 TI - Electrokinetics of charged spherical colloidal particles taking into account the effect of ion size constraints. AB - The electrokinetic properties of suspended spherical particles are examined using a modified standard electrokinetic model, which takes into account the finite ion size and considers that the minimum approach distance of ions to the particle surface need not be equal to their effective radius in the bulk solution. We calculate the conductivity increment and the electrophoretic mobility and present a detailed interpretation of the obtained results, based on the analysis of the equilibrium and field-induced ion concentrations, as well as the convective fluid flow in the neighborhood of the particle surface. We show that when charge reversal takes place, the sign of the concentration polarization remains unchanged while the sign of the electrophoretic mobility only changes under favorable circumstances. PMID- 21281936 TI - Dual-deposition rates in colloid filtration caused by coupled heterogeneities in a colloidal population. AB - Colloidal deposition from an aqueous suspension, during its flow through saturated porous media, is of significance in many natural and man-made processes which lead to water purification. Colloid filtration theory (CFT), which was used to predict removal of homogeneous colloids, in the above systems, is based on a distance-invariant deposition rate. However, many authors over the past decade have reported data which suggest that more than one deposition rate is demonstrated by colloids naturally occurring in the environment on apparently homogeneous media. The observation of two or more deposition rates has been attributed to two modes of deposition as well to the possibility of heterogeneity in the colloidal population, in the recent literature. In this paper, we first examine the variation of liquid-phase concentration C(x) with distance, and find that only two distinct deposition rates are demonstrated by the data under multiple conditions. Since heterogeneity in the colloidal population is expected to produce continuous property variations and hence multiple deposition rates, the appearance of the above dual-deposition behavior is probed further. Depth wise zeta-potential and particle-size-distribution data reveal that there is a coupling of favorable properties (larger size with positive surface charge) in a section of the population along with a coupling of unfavorable properties in the rest. The above coupling is then confirmed by independent separation experiments. This paper experimentally demonstrates how coupling of two types of heterogeneities in a colloidal population can lead to the appearance of dual deposition rates while recognizing that the above may be one of the many possible causes for the appearance of dual-deposition rates. PMID- 21281937 TI - Adsorption of oligomers on the polymer-tethered surfaces. AB - A density functional study of adsorption of oligomers on weakly attractive surfaces modified with grafted chains is presented. The chain molecules are modeled as freely jointed tangent spheres. The segments interact via Lennard Jones (12-6) potentials. Two types of substrates are considered - a neutral surface and the Lennard-Jones (9,3) surface. The mechanism of adsorption is discussed. Depending on the system characteristics, the primary, secondary and ternary adsorption is found. The effects of selected factors on adsorption and separation of mixtures are analyzed. PMID- 21281938 TI - Displacement of liquid droplets on a surface by a shearing air flow. AB - The motion of droplets on surfaces is crucial to the performance of a wide range of processes; this study examines the initiation of droplet motion through a shearing mechanism generated here by a controlled air flow. Systematic experiments are carried out for a range of fluids and well defined surfaces. A model is postulated that balances surface tension forces at the contact line and the drag force due to the air motion. Experiments reveal that the critical velocity at which droplet motion is initiated depends on the contact angle and the droplet size. Visualizations highlight three modes of motion: (I) the droplet retains a footprint similar to that at the point of motion; (II) a tail exists at the rear of the droplet; (III) a trail remains behind the droplet (that can shed smaller droplets). The predictions of droplet initiation velocity are good for type I motion, in accordance with the assumptions inherent within the model. This model confirms the dominant physics associated with the initiation of droplet motion and provides a useful predictive expression. PMID- 21281939 TI - Fluorescence enhancement by heterostructure colloidal photonic crystals with dual stopbands. AB - In this work, we present a facile approach on the remarkable enhancement of fluorescent signal by heterostructure colloidal photonic crystals (PCs) with dual stopbands. The intensity of fluorescent medium on heterostructure PCs with dual stopbands overlapping the excitation wavelength and the emission wavelength of fluorescent medium can be up to 162-fold enhancement in comparison to that on the control sample. Otherwise, parameters of heterostructure PC films such as film thickness or stacking order have important effects on fluorescent signals. The method will be of great significance for developing the highly sensitive fluorescence-based detection. PMID- 21281940 TI - Biotinylated thermoresponsive core cross-linked nanoparticles via RAFT polymerization and "click" chemistry. AB - A straightforward approach to the synthesis of "clickable" thermoresponsive core cross-linked (CCL) nanoparticles was developed. This approach was based on reversible addition-fragmentation chain transfer (RAFT) radical cross-linking polymerization of styrene and divinylbenzene with azide-functionalized poly(N isopropylacrylamide) (PNIPAM-N(3)) as macro chain transfer agent in a selective solvent. Spherical nanoparticles with a diameter of 12nm were obtained after 24h polymerization. When the lyophilized CCL nanoparticles were dispersed in THF, spherical nanoparticles were observed, confirming the stability of CCL nanoparticles. The transmission electron microscopy (TEM) studies demonstrated that spherical nanoparticles and wormlike structure coexisted in the aqueous solution. The CCL nanoparticles have a lower critical solution temperature (LCST) at about 29.6 degrees C, a little lower than that of PNIPAM homopolymer. Biotin molecules were conjugated to the surface of CCL nanoparticles via "click" chemistry in aqueous media. After bioconjugation, the LCST shifted to 28.3 degrees C. The bioavailability of biotin to protein avidin was evaluated by a 4' hydroxyazobenzene-2-carboxylic acid/avidin (HABA/avidin) binding assay and TEM. PMID- 21281941 TI - Dispersion of carbon nanotubes by carbazole-tailed amphiphilic imidazolium ionic liquids in aqueous solutions. AB - Surfactants with a polycyclic aromatic moiety and a long hydrocarbon chain, carbazole-tailed amphiphilic imidazolium ionic liquids 1-[n-(N-carbazole)alkyl]-3 methylimidazolium bromide [CzC(n)MIm]Br (n=10 and 12), were designed to disperse carbon nanotubes (CNTs) in aqueous solutions. UV-vis-NIR spectra were performed to determine the dispersion of CNTs and the optimal concentration (C(opt)) of [CzC(n)MIm]Br. Compared with [C(n)MIm]Br, [CzC(n)MIm]Br was more effective with the smaller C(opt) and more individual CNTs, reflecting the effect of the carbazole moiety. The adsorption of [CzC(n)MIm]Br molecules on CNTs was investigated by zeta-potential, surface tension, fluorescence, and (1)H NMR. Having zeta-potentials higher than 15mV contributed to the long-term stability of aqueous CNT dispersions. The significant fluorescence quenching and the upfield shift of carbazole protons support the pi-pi stacking interaction between carbazole moieties and the pi-networks of CNTs. Meanwhile, the upfield shift of imidazolium protons indicates the cation-pi interaction between the imidazolium ions and the pi-networks of CNTs. PMID- 21281942 TI - Prolonging the lifetime and activity of silica immobilised Cyanidium caldarium. AB - Over the past few years the idea of living photosynthetic materials has advanced from concept to reality. This work outlines the improvements made in the immobilisation of the thermotolerant acidophile Cyanidium caldarium (Tilden) Geitler SAG 16.91 within porous and transparent silica gels with the view to targeting photochemical materials that can be used to mitigate rising CO(2) emissions. Our results suggest that the immobilised cells are autofluorescent for at least 75 days post encapsulation and can maintain a steady oxygen production rate over a similar timeframe corroborating the viability and physiological activity of silica immobilised C. caldarium. PMID- 21281943 TI - Recombinant factor VIIa affects anastomotic patency of vascular grafts in a rabbit model. AB - OBJECTIVE: Recombinant factor VIIa can decrease postoperative bleeding after cardiac surgery. However, the potential for recombinant factor VIIa to cause early vascular graft occlusion at the site of new vascular anastomoses has not been fully explored. We hypothesized that recombinant factor VIIa would cause a dose-dependent reduction in vascular graft patency in rabbits. METHODS: Reversed end-to-end interpositional vein grafts were sutured into the carotid artery of heparinized rabbits, and then recombinant factor VIIa (300 MUg/kg, 90 MUg/kg, or 20 MUg/kg intravenously) or placebo was administered (n = 16/group). Graft patency was assessed at 24 hours using a vascular ultrasound probe. Factor VII activity levels were measured using a prothrombin time-based assay. In different rabbits, the patency of venous end-to-side anastomoses and simple carotid arterial repairs was assessed (recombinant factor VIIa, 300 MUg/kg vs placebo, n = 8/group). Data were analyzed using Fisher's exact test, t tests, or analysis of variance. RESULTS: Physiologic variables (activated clotting time, hemoglobin, pH, Pao(2)) and vessel diameter were not different between groups. Vein graft patency was reduced (93.8%, 81.2%, 13.8%, and 6.3%) as factor VII activity levels increased (1.8 +/- 0.4, 4.4 +/- 2.1, 11.8 +/- 4.7, and 23.6 +/- 16.9 U/mL, respectively) with increasing doses of recombinant factor VIIa administered (0, 20, 90, and 300 MUg/kg, respectively, P < .05). Patency in the arterial repairs and end-to-side venous grafts was also reduced in recombinant factor VIIa-treated rabbits (P < .05 for both). CONCLUSIONS: This study suggests that recombinant factor VIIa is associated with a dose-dependent increase in fresh vascular graft occlusion. Higher doses of recombinant factor VIIa may be associated with increased thrombotic outcomes. PMID- 21281944 TI - An unusual cause of dyspnea in a patient with prior mitral valve annuloplasty and congestive heart failure. PMID- 21281945 TI - Hybrid thoracic endovascular aortic repair via right anterior minithoracotomy. AB - OBJECTIVE: Hybrid thoracic endovascular aortic repair (TEVAR) has expanded the surgical management of complex thoracic aneurysms. Aortic arch debranching generally requires a sternotomy. We describe our experience performing a right anterior minithoracotomy for hybrid TEVAR. METHOD: During a 3-year period, 7 patients (aged 76 +/- 15 years; 57% were male) with aortic arch aneurysms underwent hybrid TEVAR via a right anterior minithoracotomy. Of all with prior thoracic or abdominal aortic surgery, 4 had a prior sternotomy. All patients included in this series had an American Society of Anesthesiology score of 4 or greater. RESULTS: Repairs were performed via a 5-cm incision at the third to fourth intercostal space to access the ascending arch. A Satinsky clamp on the ascending aorta facilitated bypass with the 10-mm arm of a bifurcated 10/12-mm graft to the innominate artery or right common carotid artery (12-mm arm: endoprosthesis conduit). The remaining arch vessels were bypassed as needed; subsequently, a thoracic stent graft was deployed by the 12- or 14-mm arm. Primary technical success was 86% (6 patients); 1 patient required conversion to sternotomy secondary to bleeding. Complications included cerebrovascular accident in 2 patients (28%) and respiratory failure in 2 patients (28%). The average length of stay was 12 days with no wound infection. One death occurred during the 30-day period. CONCLUSIONS: Right anterior minithoracotomy is a compelling, less invasive technique for hybrid TEVAR. Further experience will be necessary to completely evaluate the merits of this approach. PMID- 21281946 TI - Primary pulmonary vein stenosis: the impact of sutureless repair on survival. AB - BACKGROUND: Primary pulmonary vein stenosis is often associated with relentless restenosis and early death. During the last 2 decades, we have developed a sutureless repair to improve prognosis. METHODS: Hospital records for patients undergoing repair of primary pulmonary vein stenosis from 1989 to 2008 were reviewed. Pulmonary vein stenosis was quantified with a pulmonary vein stenosis score. Survival was determined by Kaplan-Meier analysis. RESULTS: Twenty-three patients underwent surgical repair. Mean ages at diagnosis and index repair were 23.3 +/- 45.6 and 24.1 +/- 40.9 months, respectively. Systemic or suprasystemic pulmonary artery pressures were present in 13 of 18 patients (72%). Seven (31%) had single-ventricle circulation. A sutureless technique was used in 19 of 23 cases (83%). Other types of repair were used in 4 of 23 (17%). There were 11 recorded deaths (47%). Survivals were 64%, 47%, and 31% at 1, 5, and 10 years, respectively. Five patients (22%) required 1 reintervention. Surgical repair significantly reduced the total pulmonary vein stenosis score (5.6 +/- 2.10 before repair, 2.6 +/- 2.72 after repair, P = .0057). The preoperative pulmonary vein stenosis score was the only independent predictor of mortality (hazard ratio, 1.732; P < .01). A preoperative pulmonary vein stenosis score of greater than 4 was a poor prognostic indicator (area under the curve, 0.83). CONCLUSIONS: Mortality and restenosis rates remained high despite the adoption of a sutureless technique. A preoperative pulmonary vein stenosis score of greater than 4 was a strong predictor of poor prognosis. PMID- 21281947 TI - Effect of preoperative non-dialysis-dependent renal dysfunction on isolated aortic and mitral valve surgery: a propensity score analysis. AB - OBJECTIVE: Our objective was to examine whether preoperative non-dialysis dependent renal dysfunction is associated with operative mortality or morbidity in isolated valve surgery. METHODS: We reviewed consecutive patients undergoing isolated aortic (n = 2132) or mitral valve (n = 1664) surgery, between 1996 and 2009. Preoperative renal dysfunction was defined as preoperative estimated glomerular filtration rate < 60 mL/min without dialysis. Propensity score 1:1 matched samples were created, one for aortic (n = 626) and one for mitral (n = 526) valve surgery. RESULTS: The mean age was 70 +/- 9 and 65 +/- 10 years for the aortic and mitral groups, respectively. In the aortic cohort, patients with preoperative renal dysfunction had greater need for inotropes (39% vs 29%; P = .009), length of intensive care unit stay (27 vs 25 hours; P = .006), and duration of mechanical ventilation (8.2 vs 6.6 hours; P < .001). Operative mortality was 3.2% in the group with preoperative renal dysfunction and 2.2% in the group without preoperative renal dysfunction (P = .5). In the mitral cohort, patients with preoperative renal dysfunction had greater need for inotropes (47% vs 36%; P = .013), length of intensive care unit stay (40 vs 26 hours; P = .01), and duration of mechanical ventilation (7.2 vs 6.5 hours; P = .004). Operative mortality was 0% and 2.7% in the groups without and with preoperative renal dysfunction, respectively (P = .015). CONCLUSIONS: Preoperative renal dysfunction is associated with higher morbidity in both cohorts, and patients undergoing mitral valve surgery also experienced higher mortality. The impact of non dialysis-dependent preoperative renal dysfunction appears to be more pronounced in patients undergoing mitral valve surgery, potentially owing to their relative intolerance to volume overload. PMID- 21281948 TI - Impact of neoadjuvant chemoradiotherapy followed by surgical resection on node negative T3 and T4 non-small cell lung cancer. AB - OBJECTIVE: This study examined the impact of neoadjuvant chemotherapy and concurrent high-dose radiation therapy on survival in patients with node-negative T3 and T4 non-small cell lung cancer. METHODS: A total of 110 consecutive patients underwent surgical resection for invasive T3N0M0 (94 patients) and T4N0M0 (16 patients) non-small cell lung cancer between 1979 and 2008. Forty seven patients received neoadjuvant chemotherapy and concurrent high-dose (5940 cGy) radiation therapy before resection (Chemo-RT group). Sixty-three patients underwent surgical resection without receiving induction chemoradiotherapy (Surg group), of whom 21 received neoadjuvant radiation, 19 received adjuvant radiation, 17 received surgery alone, 2 received adjuvant chemotherapy, 2 received adjuvant chemoradiotherapy, and 2 received brachytherapy. Survival of the Chemo-RT and Surg groups was compared using both crude and adjusted Cox proportional hazards models. RESULTS: The 5-year, 10-year, and median survivals were 61%, 50%, and 90 months, respectively, in the Chemo-RT group versus 22%, 14%, and 22 months, respectively, in the Surg group. Subjects in the Surg group had an increased risk of death (hazard ratio, 2.60; 95% confidence interval, 1.62 4.18; P = .0001) compared with the Chemo-RT group. After adjustment for potential confounding variables of age, sex, tumor size, tumor location, type of operation, and decade of care, subjects in the Surg group remained at increased risk of death (hazard ratio, 2.81; 95% confidence interval, 1.45-5.44, P = .002) compared with the Chemo-RT group. CONCLUSIONS: Aggressive treatment of node-negative invasive T3 and T4 NSCLC with induction chemoradiotherapy may significantly prolong survival. This approach should be evaluated in a prospective multicenter national trial. PMID- 21281949 TI - WITHDRAWN: Transfemoral aortic valve-in-valve procedure with the new Edwards SAPIEN XT valve. AB - This article has been withdrawn at the request of the authors and Editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 21281950 TI - Neurologic complications after off-pump coronary artery bypass grafting with and without aortic manipulation: meta-analysis of 11,398 cases from 8 studies. AB - OBJECTIVE: Neurologic complications after coronary artery bypass grafting remain a concern. Off-pump coronary artery bypass grafting is a surgical strategy proposed to decrease this risk. Use of an off-pump anaortic technique, which leaves the ascending aorta untouched, may result in further reductions. This systematic review of all published evidence compares neurologic complications after anaortic off-pump coronary artery bypass grafting versus that with aortic manipulation. METHODS: PubMed and Embase were searched up to August 2008. Experts were contacted, and reference lists of retrieved articles were hand searched. The search process was not limited to English-language sources. Observational studies comparing standard off-pump coronary artery bypass grafting technique with anaortic technique were eligible for inclusion if they reported neurologic complications (stroke and transient ischemic attack). Meta-analysis was conducted to assess differences between groups with regard to neurologic complications. RESULTS: Electronic search identified 1428 abstracts, which resulted in retrieval and detailed review of 331 full-text articles. Eight observational studies reported neurologic complications in 5619 anaortic off-pump coronary artery bypass grafting cases and 5779 cases with aortic manipulation. Postsurgical neurologic complications were significantly lower in anaortic off-pump coronary artery bypass grafting cases (odds ratio, 0.46; 95% confidence interval, 0.29 0.72; I(2) = 0.8%; P = .0008). CONCLUSIONS: Avoidance of aortic manipulation during off-pump coronary artery bypass grafting decreases neurologic complications relative to standard technique in which the ascending aorta is manipulated. In patients at high risk for stroke or transient ischemic attack, we recommend avoidance of aortic manipulation during off-pump coronary artery bypass grafting. PMID- 21281951 TI - Durability of bioprosthetic valves in the pulmonary position: long-term follow-up of 181 implants in patients with congenital heart disease. AB - OBJECTIVES: Durability of bioprosthetic valves in the pulmonary position is not well defined. We examined the durability of bioprosthetic valves in the pulmonary position and risk factors associated with bioprosthetic pulmonary valve failure. METHODS: Between 1993 and 2004, 181 patients underwent pulmonary valve replacement using bioprostheses. Patients who underwent valved conduit or homograft implantation were excluded. Mean age was 14.2 +/- 9.8 years and median valve size was 23 mm (range, 19-27 mm). Types of bioprosthesis used were Hancock II (n = 83), Perimount (n = 53), Freestyle (n = 23), Carpentier-Edwards porcine valve (n = 18), and others (n = 4). RESULTS: There were 3 early and 7 late deaths. Follow-up completeness was 88.6% and mean follow-up duration was 7.3 +/- 2.9 years. Forty-three patients underwent redo pulmonary valve replacement. Overall freedom from redo pulmonary valve replacement at 5 and 10 years was 93.9% +/- 1.9% and 51.7% +/- 8.6%, respectively. Overall freedom from both valve failure and valve dysfunction at 5 and 10 years was 92.2% +/- 2.1% and 20.2% +/- 6.7%, respectively. In multivariable analysis, younger age at operation, diagnosis of pulmonary atresia with ventricular septal defect, and use of stentless valve were identified as risk factors for redo pulmonary valve replacement. CONCLUSIONS: Durability of bioprosthetic valves in the pulmonary position was suboptimal. Valve function was maintained stable until 5 years after operation. By 10 years, however, about 80% will require reoperation or manifest valve dysfunction. In our experience, the stentless valve was less durable than stented valves. PMID- 21281952 TI - Cell wall composition as a maize defense mechanism against corn borers. AB - European and Mediterranean corn borers are two of the most economically important insect pests of maize (Zea mays L.) in North America and southern Europe, respectively. Cell wall structure and composition were evaluated in pith and rind tissues of resistant and susceptible inbred lines as possible corn borer resistance traits. Composition of cell wall polysaccharides, lignin concentration and composition, and cell wall bound forms of hydroxycinnamic acids were measured. As expected, most of the cell wall components were found at higher concentrations in the rind than in the pith tissues, with the exception of galactose and total diferulate esters. Pith of resistant inbred lines had significantly higher concentrations of total cell wall material than susceptible inbred lines, indicating that the thickness of cell walls could be the initial barrier against corn borer larvae attack. Higher concentrations of cell wall xylose and 8-O-4-coupled diferulate were found in resistant inbreds. Stem tunneling by corn borers was negatively correlated with concentrations of total diferulates, 8-5-diferulate and p-coumarate esters. Higher total cell wall, xylose, and 8-coupled diferulates concentrations appear to be possible mechanisms of corn borer resistance. PMID- 21281953 TI - Acylated flavonol tri- and tetraglycosides in the flavonoid metabolome of Cladrastis kentukea (Leguminosae). AB - The foliar metabolome of Cladrastis kentukea (Leguminosae) contains a complex mixture of flavonoids including acylated derivatives of the 3-O-rhamnosyl(1 >2)[rhamnosyl(1->6)]-galactosides of kaempferol and quercetin and their 7-O rhamnosides, together with an array of non-acylated kaempferol and quercetin di-, tri- and tetraglycosides. Thirteen of the acylated flavonoids, 12 of which had not been reported previously, were characterised by spectroscopic and chemical methods. Eight of these were the four isomers of kaempferol 3-O-alpha-l rhamnopyranosyl(1->2)[alpha-l-rhamnopyranosyl(1->6)]-(3/4-O-E/Z-p-coumaroyl-beta d-galactopyranoside) and their 7-O-alpha-l-rhamnopyranosides, and three were isomers of quercetin 3-O-alpha-l-rhamnopyranosyl(1->2)[alpha-l-rhamnopyranosyl(1 >6)]-(3/4-O-E/Z-p-coumaroyl-beta-d-galactopyranoside) - the remaining 4Z isomer was identified by LC-UV-MS analysis of a crude extract. The final two acylated flavonoids characterised by NMR were the 3E and 4E isomers of kaempferol 3-O alpha-l-rhamnopyranosyl(1->2)[alpha-l-rhamnopyranosyl(1->6)]-(3/4-O-E-feruloyl beta-d-galactopyranoside)-7-O-alpha-l-rhamnopyranoside while the 3Z and 4Z isomers were again detected by LC-UV-MS. Using the observed fragmentation behaviour of the isolated compounds following a variety of MS experiments, a further 18 acylated flavonoids were given tentative structures by LC-MS analysis of a crude extract. Acylated flavonoids were absent from the flowers of C. kentukea, which contained an array of non-acylated kaempferol and quercetin glycosides. Immature fruits contained kaempferol 3-O-alpha-rhamnopyranosyl(1 >2)[alpha-rhamnopyranosyl(1->6)]-beta-galactopyranoside and its 7-O-alpha rhamnopyranoside as the major flavonoids with acylated flavonoids, different from those in the leaves, only present as minor constituents. The presence of acylated flavonoids distinguishes the foliar flavonoid metabolome of C. kentukea from that of a closely related legume, Styphnolobium japonicum, which contains a similar range of non-acylated flavonoids. PMID- 21281954 TI - Involvement of cyclophilin B in the replication of Japanese encephalitis virus. AB - Japanese encephalitis virus (JEV) is a mosquito-borne RNA virus that belongs to the Flaviviridae family. In this study, we have examined the effect of cyclosporin A (CsA) on the propagation of JEV. CsA exhibited potent anti-JEV activity in various mammalian cell lines through the inhibition of CypB. The propagation of JEV was impaired in the CypB-knockdown cells and this reduction was cancelled by the expression of wild-type but not of peptidylprolyl cis-trans isomerase (PPIase)-deficient CypB, indicating that PPIase activity of CypB is critical for JEV propagation. Infection of pseudotype viruses bearing JEV envelope proteins was not impaired by the knockdown of CypB, suggesting that CypB participates in the replication but not in the entry of JEV. CypB was colocalized and immunoprecipitated with JEV NS4A in infected cells. These results suggest that CypB plays a crucial role in the replication of JEV through an interaction with NS4A. PMID- 21281955 TI - Response of Holm oak (Quercus ilex subsp. ballota) and mastic shrub (Pistacia lentiscus L.) seedlings to high concentrations of Cd and Tl in the rhizosphere. AB - The impairment of root growth and photosynthetical functioning are the main impacts of trace elements on woody plant seedlings. In this work, we assessed the response of Holm oak (Quercusilex subsp. ballota) and mastic shrub (Pistacia lentiscus) seedlings to high concentrations of Cd and Tl in the rhizosphere. These are non-essential trace elements, with a potential high mobility in the soil-plant system. Seedlings of these species are frequently used in the afforestation of degraded soils in mining areas. Plants were exposed to different levels of Cd (20, 80 and 200 mg L(-1)) and Tl (2, 10 and 20 mg L(-1)) in a sand culture. Biomass allocation, growth rates, chlorophyll fluorescence and gas exchange were studied. Both metals affected root biomass. Cadmium produced an increase in the root mass ratio and a decrease in the specific leaf area of the plants in oak seedlings, while Tl did not provoke such response. Mastic plants were more sensitive to Tl and Cd than oak plants. Between elements, Tl provoked more severe toxic effects in the plants, affecting the antennae complexes and reaction centers of the photosystem II. Both elements decreased net assimilation rates (down to a 20% of the control plants) and stomatal conductance (5-10% of the values for the control plants). Cadmium was highly retained in the roots of both species, while Tl was highly translocated into the leaves. In general, Holm oak showed a higher tolerance for Cd than for Tl, and a higher resistance to both metals than mastic shrub, due to a high capacity for Cd retention at the root level. However, such accumulation in roots may induce water stress in the seedling exposed to Cd. PMID- 21281956 TI - Size distribution of polycyclic aromatic hydrocarbons in a roadway tunnel in Lisbon, Portugal. AB - Atmospheric aerosols of four aerodynamic size ranges were collected using high volume cascade impactors in an extremely busy roadway tunnel in Lisbon (Portugal). Dust deposited on the tunnel walls and guardrails was also collected. Average particle mass concentrations in the tunnel atmosphere were more than 30times higher than in the outside urban background air, revealing its origins almost exclusively from fresh vehicle emissions. Most of the aerosol mass was concentrated in submicrometer fractions (65%), and polycyclic aromatic hydrocarbons (PAH) were even more concentrated in the finer particles with an average of 84% of total PAH present in sizes smaller than 0.49MUm. The most abundant PAH were methylated phenanthrenes, fluoranthene and pyrene. About 46% of the total PAH mass was attributed to lower molecular weight compounds (two and three rings), suggesting a strong influence of diesel vehicle emissions on the production of local particulate PAH. The application of diagnostic ratios confirmed the relevance of this source of PAH in the tunnel ambient air. Deposited dust presented PAH profiles similar to the coarser aerosol size range, in agreement with the predominant origin of coarser aerosol particles from soil dust resuspension and vehicle wear products. PMID- 21281957 TI - Acute toxicity, biochemical and gene expression responses of the earthworm Eisenia fetida exposed to polycyclic musks. AB - AHTN (Tonalide) and HHCB (galaxolide) are recognized as ubiquitous contaminants in soil and have potential adverse impacts on soil organisms. The aim of this study is to investigate the effects of AHTN and HHCB on the earthworm (Eisenia fetida) as an important soil animal with attention to the acute toxicity, biochemical and transcriptional changes of representative antioxidant enzymatic (SOD, CAT) and stress-response gene (Hsp70). The 48 h-LC(50) value was 20.76 MUg cm(-2) for AHTN and 11.87 MUg cm(-2) for HHCB respectively in the acute lethal studies. The time-dependent elevation in the level of malondialdehyde (MDA) suggests that reactive oxygen species (ROS)-induced cellular oxidative injury of E. fetida might be one of the main toxic effects of AHTN and HHCB. SOD and CAT were both up-regulated at low exposure dose (0.6 MUg cm(-2) AHTN and 0.3 MUg cm( 2) HHCB) during 48 h testing period, which protected earthworms from oxidative stresses. However, the down-regulation of SOD and CAT after 48 h exposure to high dose contaminants might be caused by the extreme oxidative stress levels (maximum up-regulation 1.70-fold and 1.40-fold for MDA levels at 6.0 MUg cm(-2) AHTN and 3.0 MUg cm(-2) HHCB compared to the controls, respectively). The Hsp70 gene expression did not show variation during 48 h, except that it had a significant down-regulation (P<0.05) after 48 h of exposure to high doses of contaminants. These results showed that the dermal contact of AHTN and HHCB could result in pronounced biochemical and physiological responses to earthworms, and the transcriptional level changes in antioxidant genes could be potential molecular biomarkers for the stress of the pollutants. PMID- 21281958 TI - Characterization of a novel human mast cell line that responds to stem cell factor and expresses functional FcepsilonRI. AB - BACKGROUND: Studies of human mast cells (MCs) are constrained by the paucity of functional cell lines, the expense of maintaining MCs in culture, and technical complexities. OBJECTIVE: We derived and characterized a human MC line that arose spontaneously from a culture of nontransformed hematopoietic progenitor cells. METHODS: CD34(+) enriched mononuclear cells derived from a donor with aspirin exacerbated respiratory disease were cultured for 8 weeks with stem cell factor and IL-6 and with IL-3 for the first week only. The cells (termed LUVA cells) survived and proliferated without further addition of any growth factors and have been maintained in culture for approximately 2 years. RESULTS: LUVA cells possess metachromatic cytoplasmic granules that are immunoreactive for tryptase, cathepsin G, and carboxypeptidase A3. They express transcripts encoding FcepsilonRI, c-kit, chymase, tryptase, histidine decarboxylase, carboxypeptidase A3, and the type 1 receptor for cysteinyl leukotrienes. Flow cytometry confirmed uniform expression of FcepsilonRI, c-kit, and FcgammaRII. FcepsilonRI cross linkage induced the release of beta-hexosaminidase, prostaglandin D(2), thromboxane A(2), and macrophage inflammatory protein 1beta. Immortalization was not associated with either a known genomic mutation of c-kit in the donor or a somatic mutation of c-kit within the cells, and it was not associated with c-kit autophosphorylation. CONCLUSIONS: LUVA cells are an immortalized human MC line that can be maintained without stem cell factor and display high levels of normally signaling c-kit and FcepsilonRI. These cells will prove valuable for functional human MC studies. PMID- 21281959 TI - Sublingual immunotherapy for peanut allergy: clinical and immunologic evidence of desensitization. AB - BACKGROUND: There are no treatments currently available for peanut allergy. Sublingual immunotherapy (SLIT) is a novel approach to the treatment of peanut allergy. OBJECTIVE: We sought to investigate the safety, clinical effectiveness, and immunologic changes with SLIT in children with peanut allergy. METHODS: In this double-blind, placebo-controlled study subjects underwent 6 months of dose escalation and 6 months of maintenance dosing followed by a double-blind, placebo controlled food challenge. RESULTS: Eighteen children aged 1 to 11 years completed 12 months of dosing and the food challenge. Dosing side effects were primarily oropharyngeal and uncommonly required treatment. During the double blind, placebo-controlled food challenge, the treatment group safely ingested 20 times more peanut protein than the placebo group (median, 1,710 vs 85 mg; P = .011). Mechanistic studies demonstrated a decrease in skin prick test wheal size (P = .020) and decreased basophil responsiveness after stimulation with 10(-2) MUg/mL (P = .009) and 10(-3) MUg/mL (P = .009) of peanut. Peanut-specific IgE levels increased over the initial 4 months (P = .002) and then steadily decreased over the remaining 8 months (P = .003), whereas peanut-specific IgG4 levels increased during the 12 months (P = .014). Lastly, IL-5 levels decreased after 12 months (P = .015). No statistically significant changes were found in IL-13 levels, the percentage of regulatory T cells, or IL-10 and IFN-gamma production. CONCLUSION: Peanut SLIT is able to safely induce clinical desensitization in children with peanut allergy, with evidence of immunologic changes suggesting a significant change in the allergic response. Further study is required to determine whether continued peanut SLIT is able to induce long-term immune tolerance. PMID- 21281961 TI - Inhibition of differentiation, amplification, and function of human TH17 cells by intravenous immunoglobulin. AB - BACKGROUND: T(H)17 cells play a critical role in the pathogenesis of several autoimmune and allergic diseases. Intravenous immunoglobulin (IVIg), a therapeutic preparation of polyclonal IgG that is increasingly used in the treatment of diverse autoimmune and allergic diseases, might target T(H)17 cells to exert therapeutic effects. OBJECTIVE: We sought to examine whether IVIg interferes with the development and function of human T(H)17 cells. METHODS: T(H)17 cells were differentiated from naive human CD4(+) T cells in the presence of TGF-beta and IL-21. T(H)17 cells were amplified by stimulating memory CD4(+) T cells in the presence of IL-1beta and IL-6. The effect of IVIg was examined on the differentiation and amplification of T(H)17 cells, expression of the T(H)17 lineage-specific transcription factor retinoic acid-related orphan receptor C, secretion of T(H)17 effector cytokines, and phosphorylation of signal transducer and activator of transcription 3, a transcription factor that plays an important role in T(H)17 cell development and function. RESULTS: IVIg inhibits the differentiation and amplification of human T(H)17 cells, as well as the production of their effector cytokines IL-17A, IL-17F, IL-21, and CCL20. The inhibitory effects of IVIg on T(H)17 cells are F(ab')(2) dependent and involve interference with the expression of retinoic acid-related orphan receptor C and activation of signal transducer and activator of transcription 3. Also, IVIg significantly enhanced forkhead box protein 3-positive regulatory T cells among the memory CD4(+) T cells. CONCLUSION: These results reveal a novel mechanism of action of IVIg in achieving a therapeutic effect in autoimmune and allergic diseases, in which T(H)17 cells play a key modulatory role in sustaining the chronic inflammatory response. Our results also suggest a reciprocal regulation of T(H)17 and regulatory T-cell populations by IVIg. PMID- 21281962 TI - Supplementation with cow's milk at birth is not recommended. PMID- 21281963 TI - Interleukin-1 receptor-like 1 polymorphisms are associated with serum IL1RL1-a, eosinophils, and asthma in childhood. AB - BACKGROUND: IL-1 receptor-like 1 (IL1RL1) is a membrane receptor involved in T(H)2 inflammatory responses and eosinophilia. Single nucleotide polymorphisms (SNPs) in IL1RL1 have been associated with blood eosinophil counts in a genome wide association study and with asthma in family-based and case-control studies. OBJECTIVE: We assessed in the prospective birth cohort Prevention and Incidence of Asthma and Mite Allergy (PIAMA) whether IL1RL1 SNPs associate with levels of its soluble transcript IL1RL1 (IL1RL1-a) in serum, blood eosinophil counts, and asthma prevalence from birth to age 8 years, and whether IL1RL1-a serum levels associate with blood eosinophil counts. METHODS: Fifteen IL1RL1 SNPs were genotyped. Serum IL1RL1-a levels were measured in 2 independent subsets within PIAMA, at 4 and 8 years. Blood eosinophil counts were measured in 4-year-old children. RESULTS: In 2 independent subsets of children, 13 of 15 SNPs were associated with serum IL1RL1-a levels at ages 4 and 8 years with a consistent direction of effect for each allele. Rs11685480 allele A and rs1420102 allele A were significantly associated with lower numbers of blood eosinophils. In the total cohort, rs1041973 allele A was associated with a decreased risk of developing asthma (odds ratio, 0.70; 95% CI, 0.54-0.90). Rs1420101, recently identified in a genome-wide association study in the Icelandic population, was not associated with asthma in this study. IL1RL1-a levels were not associated with eosinophil counts. CONCLUSION: We demonstrate that IL1RL1 polymorphisms are associated with serum IL1RL1-a, blood eosinophils, and asthma in childhood. PMID- 21281964 TI - Application of primary haemocyte culture of Penaeus monodon in the assessment of cytotoxicity and genotoxicity of heavy metals and pesticides. AB - Lack of shrimp cell lines has hindered the study of pollutants which adversely affects shrimp health and its export value. In this context a primary haemocyte culture developed from Penaeus monodon was employed for assessing the cytotoxicity and genotoxicity of two heavy metal compounds, cadmium chloride and mercuric chloride and two organophosphate insecticides, malathion and monocrotophos. Using MTT assay 12 h IC(50) values calculated were 31.09 +/- 16.27 MUM and 5.52 +/- 1.16 MUM for cadmium chloride and mercuric chloride and 59.94 +/ 52.30 mg l(-1) and 186.76 +/- 77.00 mg l(-1) for malathion and monocrotophos respectively. Employing Comet assay, DNA damage inflicted by these pollutants on haemocytes were evaluated and the pollutants induced DNA damage in >60% of the cells. The study suggested that haemocyte culture could be used as a tool for quantifying cytotoxicity and genotoxicity of aquaculture drugs, management chemicals and pollutants. PMID- 21281965 TI - Review: A high capacity of the human placenta for genetic and epigenetic variation: implications for assessing pregnancy outcome. AB - Genetic and epigenetic studies of the human placenta can help to clarify the underlying mechanisms of placenta-associated diseases. However, such studies have also revealed a considerable degree of within- and between-placenta variability, which can be attributed to a variety of influences. We illustrate the inherent heterogeneity in the placenta using examples from two types of studies: 1) chromosomal mosaicism and 2) DNA methylation variation. We discuss the factors that may influence the distribution of variation and how, understanding the source of this variation is important for interpreting data used to investigate and predict clinical outcomes. PMID- 21281966 TI - Dual inhibition of the homologous recombinational repair and the nonhomologous end-joining repair pathways in chronic lymphocytic leukemia therapy. AB - Resistance to chlorambucil in chronic lymphocytic leukemia (CLL) has been associated with increased DNA repair. Specifically, inhibition of either c-abl, which modulates Rad51 directed homologous recombination or DNA-PK dependent nonhomologous end joining has been shown to sensitize primary CLL lymphocytes to chlorambucil. Here we report that inhibition of c-abl can result in a compensatory increase in DNA-PK and thus inhibition of both c-abl and DNA-PK optimally sensitizes CLL lymphocytes to chlorambucil. In this paper we report a drug-induced compensatory change between two DNA repair pathways with potential therapeutic implications in CLL therapy. PMID- 21281967 TI - High TRAIL-R3 expression on leukemic blasts is associated with poor outcome and induces apoptosis-resistance which can be overcome by targeting TRAIL-R2. AB - Activation of the TNF-related apoptosis-inducing ligand (TRAIL) pathway can induce apoptosis in a broad range of human cancer cells. Four membrane-bound receptors have been identified. TRAIL-R1 and TRAIL-R2 contain a functional death domain; TRAIL-R3 and TRAIL-R4 lack a functional death domain and function as decoy receptors. Flow-cytometric analysis revealed that acute myeloid leukemic (AML) blasts expressed significantly more pro-apoptotic receptors compared to normal blasts. However, about 20% of AML patients highly expressed decoy receptor TRAIL-R3, which was strongly correlated to a shortened overall survival. TRAIL-R3 expression was also high on CD34+/CD38- cells, the compartment that harbors the leukemia initiating stem cell. Expression levels of pro-apoptotic TRAIL receptors were not correlated to the susceptibility for soluble TRAIL, which was generally low (mean level of cell death induction 14%). Cell death could be enhanced by down-modulation of TRAIL-R3, confirming its decoy function on AML blasts. Bypassing of TRAIL-R3 by treatment with antibodies directly targeting TRAIL-R2 resulted in higher rates of induced cell death (max. 80%). In conclusion, AML blasts do express pro-apoptotic TRAIL receptors. However, co-expression of decoy receptor TRAIL-R3 results in significant shortened overall survival. AML blasts could be targeted by anti-TRAIL-R2 antibodies, yielding a new therapeutic option for AML patients. PMID- 21281968 TI - Inorganic arsenic alters expression of immune and stress response genes in activated primary human T lymphocytes. AB - Inorganic arsenic, a carcinogenic environmental contaminant, exerts immunosuppressive effects on human T lymphocytes. In particular, interleukin-2 (IL2) secretion and T cell proliferation are reduced when peripheral blood mononuclear cells (PBMC) from individuals chronically exposed to arsenic are stimulated ex vivo with lectins such as phytohemaglutinin (PHA). However, it is not clear whether the metalloid directly acts on T cells or blocks monocyte dependent accessory signals activated by PHA. We report that in vitro pre treatment of PBMC with sodium arsenite (NaAs) reduces IL2 secretion and T cell proliferation induced by PHA, but does not prevent expression of monocyte-derived cytokines (IL1, IL6, TNFalpha) functioning as lymphocyte-activating factors. In addition, we found that NaAs delays induction of IL2 and IL2 receptor alpha chain (IL2RA) mRNA levels in human primary isolated T cells activated by PHA. Kinetic analysis showed that NaAs pre-treatment first inhibits, but thereafter markedly increases, induction of IL2 and IL2RA mRNA when T cells are stimulated with PHA for 8 h and 72 h, respectively. We conducted whole genome microarray-based analysis of gene expression in primary T cell cultures derived from independent donors. NaAs systematically and significantly up-regulated a set of 35 genes, including several immune and stress genes, such as IL13, granulocyte-macrophage colony stimulating factor, lymphotoxin alpha and heme oxygenase-1 (HO-1). Up regulation of HO-1, a stress and immunosuppressive protein, was rapidly detectable, both in T cells and in PBMC treated with NaAs. Inhibition of the immunosuppressive activity of HO-1 in PBMC however failed to prevent NaAs dependent inhibition of T cell proliferation induced by PHA. Our findings demonstrate that, at least in vitro, inorganic arsenic acts directly on human T cells and impairs their activity, probably independently of HO-1 expression and monocyte-related accessory signals. PMID- 21281969 TI - Macrophages from chickens selected for high antibody response produced more nitric oxide and have greater phagocytic capacity. AB - Macrophages are fundamental cells of the innate immune system, which, through phagocytosis and nitric oxide production, eliminate pathogens. The aim of the present study was to determine if macrophages from chicken families divergently selected to high and low antibodies response differ in nitric oxide production and phagocytic capacity. Blood monocytes derived macrophages were activated with lipopolysaccharide and supernatant from chicken spleen lymphocytes cultured with Concanavalin A (containing chicken interferon). Nitric oxide production was evaluated in culture supernatants. Phagocytic capacity of activated and non activated macrophages was assayed using yeasts and IgY opsonized sheep red blood cells. Activated and non-activated macrophages from the high antibodies response family produced higher nitric oxide levels, internalized more yeast and significantly more opsonized sheep red blood cells than macrophages from the low antibodies response family. Moreover, activated macrophages became more elongated and widely spread. These findings indicate that macrophages from the high antibodies response family were more active suggesting that the differences in antibody response also depend on macrophage function. PMID- 21281970 TI - Osteomyelitis of the mandible in a group of 33 pediatric patients with congenital insensitivity to pain with anhidrosis. AB - OBJECTIVE: To determine the frequency of mandibular osteomyelitis (OM) in patients with congenital insensitivity to pain with anhidrosis (CIPA) and to relate its appearance to possible risk factors. METHODS: The records of 33 patients were reviewed for data concerning events of jaw OM, oral trauma, maxillofacial interventions, or OM of long bones. RESULTS: Eighteen percent of the patients had mandibular OM. Of the six patients, preceding oral laceration was documented in one and tooth extraction in two. Seventy percent of the patients had OM of the limbs, but only 15% overlapped, having both jaw and limb OM. Half of the patients with mandibular OM had also OM of the limbs during the following year. There seems to be a correlation between high frequency of limb OM (at least 5 events per patient) and appearance of mandibular OM. CONCLUSION: The incidence of mandibular OM is very high among patients with CIPA and can result in pathologic fracture and the need for open reduction and internal fixation. The reason for this phenomenon is presently not clear. Preventive and therapeutic strategy for CIPA patients should be undertaken to minimize this severe complication. PMID- 21281971 TI - Facial nerve lying lateral to ossicles in one case of congenital aural atresia. AB - An abnormal facial nerve (FN) course can be found in a significant number of patients with congenital aural atresia. However, the literature does not include any cases in which the tympanic portion of the FN was displaced lateral to ossicles. We report a unique case of unilateral congenital aural atresia with this rare FN displacement. A review of the existing literature and a discussion are also provided. PMID- 21281972 TI - Influence of lean and fat mass on bone mineral density (BMD) in postmenopausal women with osteoporosis. AB - Despite known positive association between body mass and bone mineral density (BMD), relative contribution of fat and lean tissue to BMD remains under debate. We aimed at investigating the effect of selected anthropometric parameters, including fat content and lean body mass (LBM) on BMD in postmenopausal, osteoporotic women with body mass index (BMI) > 20 kg/m(2). The study involved 92 never-treated women (mean age 69.5 +/- 7.3). L1-L4 and femoral neck (FN) BMD were measured by dual energy X-ray absorptiometry (DEXA). Absolute (kg) and relative (%) fat and LBM were assessed by means of electric bioimpedance method. We showed both FN and L1-L4 BMD were positively correlated with body mass, waist circumference (WC), hip circumference (HC) and LBM (kg). Fat content correlated with FN BMD (r = 0.36, p < 0.001). Regression analysis revealed the only predictor of L1-L4 BMD was LBM (R(2) = 0.18, p < 0.05), for FN--both LBM and fat (R(2) = 0.18, p < 0.05 and p < 0.001, respectively). Of the women, 44.5% were overweight, 18.4% obese. Obese women displayed the highest BMD. Both L1-L4 and FN BMD were higher in women with WC > 80 cm. In postmenopausal osteoporotic women with BMI > 20 kg/m(2) both fat and lean tissue might contribute to BMD. Positive association between body mass and BMD does not make obesity and osteoporosis mutually exclusive. PMID- 21281973 TI - HbA1c may not be a sensitive determinant of diabetic status in the elderly. AB - OBJECTIVE: American Diabetes Association (ADA) has recently recommended the use of glycated haemoglobin (HbA1c) to diagnose diabetes mellitus. We aim to determine if indeed this recommendation applies to the population in Singapore and whether it varies with age. METHOD: This is a cross sectional study of 90 patients without previous history of diabetes who underwent screening and had both oral glucose tolerance test (OGTT) and HbA1c done at the same time. These patients were stratified into 4 age groups. RESULT: We found that HbA1c of 6.2% is the best cut-off to diagnose diabetes using ROC curve analysis. At the specified HbA1c, the area under ROC curve (AUROC) reduces as age group increases suggesting that sensitivity and specificity of HbA1c as diagnostic marker reduces as age increases. CONCLUSION: HbA1c has a low sensitivity to diagnose diabetes in older Asian subjects and caution is required when using HbA1c in isolation. This raises the possibility that a different cut-off value for different age groups may be more appropriate. PMID- 21281974 TI - Greater hand-grip strength predicts a lower risk of developing type 2 diabetes over 10 years in leaner Japanese Americans. AB - AIMS: Much is known about body composition and type 2 diabetes risk but less about body function such as strength. We assessed whether hand-grip strength predicted incident diabetes. METHODS: We followed 394 nondiabetic Japanese American subjects (mean age 51.9) for the development of diabetes. We fit a logistic regression model to examine the association between hand-grip strength at baseline and type 2 diabetes risk over 10 years, adjusted for age, sex, and family history. RESULTS: A statistically significant (p = 0.008) and negative (coefficient -0.208) association was observed between hand-grip strength and diabetes risk that diminished at higher BMI levels. Adjusted ORs for a 10-pound hand-grip strength increase with BMI set at the 25th, 50th or 75th percentiles were 0.68, 0.79, and 0.98, respectively. CONCLUSIONS: Among leaner individuals, greater hand-grip strength was associated with lower risk of type 2 diabetes, suggesting it may be a useful marker of risk in this population. PMID- 21281975 TI - Tissue-specific differences in mitochondrial DNA content in type 2 diabetes. AB - BACKGROUND: To investigate whether the effect of hyperglycemia on mitochondrial DNA (mtDNA) content is tissue-specific. METHOD: We compared the mtDNA contents in leg muscle, blood vessel, and peripheral leucocytes in seventeen patients with type 2 diabetes (T2DM) with those of seven controls. We measured 8 hydroxydeoxyguanosine (8-OHdG) expression in the muscles and thiobarbituric acid reactive substance (TBARS) in sera to evaluate oxidative stress. Immunohistochemical detection of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC1-alpha), mitochondrial transcription factor A (Tfam), and apoptosis were performed in the muscle tissue. RESULTS: The mtDNA copy number was highest in muscle tissue, followed by blood vessel tissue, and lowest in leucocytes in both the diabetic and control subjects. The diabetic patients had less mtDNA content in the muscle than the controls (2.86+/-0.33 vs. 3.20+/-0.14, P=0.025), but more mtDNA content in the leucocytes (2.25+/-0.26 vs. 1.98+/-0.06, P=0.04). In both groups, there was a positive correlation between muscle tissue mtDNA content and the expression of 8-OHdG. Patients with T2DM had significantly increased 8-OHdG and TUNEL labeling index and non-significant increases in the expression of PGC1-alpha and Tfam. CONCLUSION: Oxidative stress stimulates mitochondrial biogenesis but induces a greater degree of apoptosis in diabetic patients, resulting in a decrease in muscle tissue mtDNA content. PMID- 21281976 TI - Commensal bacteria promote migration of mast cells into the intestine. AB - Mast cells differentiate from hematopoietic stem cells in the bone marrow and migrate via the circulation to peripheral tissues, where they play a pivotal role in induction of both innate and adaptive immune responses. In this study, the effect of intestinal commensal bacteria on the migration of mast cells into the intestine was investigated. Histochemical analyses showed that germ-free (GF) mice had lower mast cell densities in the small intestine than normal mice. It was also shown that GF mice had lower mast cell proportion out of lamina propria leukocytes in the small intestine and higher mast cell percentages in the blood than normal mice by flow cytometry. These results indicate that migration of mast cells from the blood to the intestine is promoted by intestinal commensal bacteria. In addition, MyD88-/- mice had lower densities of intestinal mast cells than CV mice, suggesting that the promotive effect of commensals is, at least in part, TLR-dependent. The ligands of CXC chemokine receptor 2 (CXCR2), which is critical for homing of mast cells to the intestine, were expressed higher in intestinal tissues and in intestinal epithelial cells (IECs) of normal mice than in those of GF or MyD88-/- mice. Collectively, it is suggested that commensals promote migration of mast cells into the intestine through the induction of CXCR2 ligands from IECs in a TLR-dependent manner. PMID- 21281977 TI - Regions of botulinum neurotoxin A light chain recognized by human anti-toxin antibodies from cervical dystonia patients immunoresistant to toxin treatment. The antigenic structure of the active toxin recognized by human antibodies. AB - This work was aimed at determining the BoNT/A L-chain antigenic regions recognized by blocking antibodies in human antisera from cervical dystonia patients who had become immunoresistant to BoNT/A treatment. Antisera from 28 immunoresistant patients were analyzed for binding to each of 32 overlapping synthetic peptides that spanned the entire L-chain. A mixture of the antisera showed that antibodies bound to three peptides, L11 (residues 141-159), L14 (183 201) and L18 (239-257). When mapped separately, the antibodies were bound only by a limited set of peptides. No peptide bound antibodies from all the patients and amounts of antibodies bound to a given peptide varied with the patient. Peptides L11, L14 and L18 were recognized predominantly. A small but significant number of patients had antibodies to peptides L27 (365-383) and L29 (379-397). Other peptides were recognized at very low and perhaps insignificant antibody levels by a minority (15% or less) of patients or had no detectable antibody with any of the sera. In the 3-dimensional structure, antibody-binding regions L11, L14 and L18 of the L-chain occupy surface areas and did not correlate with electrostatic potential, hydrophilicity/hydrophobicity, or temperature factor. These three antigenic regions reside in close proximity to the belt of the heavy chain. The regions L11 and L18 are accessible in both the free light chain and the holotoxin forms, while L14 appears to be less accessible in the holotoxin. Antibodies against these regions could prevent delivery of the L-chain into the neurons by inhibition of the translocation. PMID- 21281978 TI - Contact allergic response to dinitrochlorobenzene (DNCB) in rats: insight from sensitization phase. AB - Contact hypersensitivity (CHS) is a T-cell-mediated skin inflammatory reaction to cutaneous exposure to small sensitizing chemicals, haptens. Majority of CHS studies were conducted in mice and there is paucity of data in other experimental animals. In the present study, characteristics of contact hypersensitivity reaction to dinitrochlorobenzene (DNCB) were determined in Th1-prone Dark Agouti (DA) rats by evaluating sensitization phase as a function of time-dependent changes in draining lymph nodes (DLN). Apart from basic indices of DLN activity (cellularity and proliferation), the production of cytokines relevant for CHS induction, interleukin-6 (IL-6), interferon-gamma (IFN-gamma), interleukin-17 (IL 17) and interleukin-4 (IL-4) was analyzed. Anti-inflammatory cytokine interleukin 10 (IL-10) production by DLN cells was determined as well. Highest production of IL-6, IFN-gamma and IL-17 in sensitized animals was observed at day 3 after DNCB application, with a decrease at day 5. Increased messages for IFN-gamma and IL-17 were noted at this time point. In contrast to inflammatory cytokines, anti inflammatory cytokine interleukin-4 (IL-4) was undetectable during the entire sensitization phase. Differential pattern (IL-6 and IFN-gamma) and level (IFN gamma and IL-17) of inflammatory cytokine production was noted in sensitized Th2 prone Albino Oxford (AO) rats. Similarly to DA rats, no changes in IL-4 were noted in AO rats. Strain-dependent differences in inflammatory cytokine production seem to be based on anti-inflammatory cytokine interleukin-10 (IL-10). Production of IFN-gamma concomitantly with undetectable IL-4 in both strains classify rat CHS to DNCB as Th1/type 1 reaction. Detection of IL-17 in sensitized DLN cells points to the involvement of T(IL-17) cells in rat contact hypersensitivity. PMID- 21281979 TI - Does a Th1 over Th2 dominancy really exist in the early stages of Mycobacterium avium subspecies paratuberculosis infections? AB - The immune response of ruminants to Johne's disease has been long associated with a cell mediated immune (CMI) response in the early stages of infection with a switch to an antibody response later as the disease manifests. This study examines the immune response in sheep to Mycobacterium avium subspecies paratuberculosis (Map) infections, specifically the antigen-specific interferon gamma (IFN-gamma) and antibody responses as surrogates of T helper-1 (Th1) and Th2 immunity. The difference in IFN-gamma production between paucibacillary and multibacillary diseased animals was also examined. The results show that sheep are more likely to have a combined antibody and IFN-gamma response (seen in 50% of the animals) rather than a switch from an IFN-gamma to antibody response (39%). Multibacillary diseased animals were found to have a decrease in functional ability to produce IFN-gamma from cells stimulated with MAP-specific antigens and non-specific mitogens. This indicates that the immune responses to Map infections are more complex than thought, where both antibody and cellular immunity may play key roles in the early stages of disease manifestation or resistance. The loss of the cellular response in multibacillary animals may be an indication that the entire immune response is dysfunctional, with the cell mediated responses becoming affected first. PMID- 21281980 TI - Monocyte-derived macrophages matured under prolonged hypoxia transcriptionally up regulate HIF-1alpha mRNA. AB - This study tested the hypothesis that prolonged severe hypoxia during monocyte to macrophage differentiation results in macrophages with a pattern of gene expression and phenotype distinct from those maturing in normal oxygen levels. Macrophages accumulate in hypoxic and anoxic areas within pathological sites such as tumours, wounds, and arthritic joints, and have been proposed as vehicles for gene therapy delivery to such tissues. Several non-pathological tissues are also hypoxic. We therefore argue that differentiation from monocyte to macrophage in hypoxic conditions is a common occurrence. However, the effect of long term severe hypoxia on monocyte to macrophage differentiation has not been studied. Here, using primary human peripheral blood monocytes, we show that maturation for 5 days in 0.2% oxygen results in decreased phagocytosis, and decreased CD40 and CD206 expression. Chronic hypoxia induced much higher mRNA levels of the pro angiogenic cytokine, VEGF, in adherence-purified macrophages (27-fold), CD14 magnetic bead purified monocytes (90-fold), and PBMC (104-fold) compared to acute (24h) hypoxia (11, 17 and 9-fold, respectively). This suggests that macrophages may play an even greater role in angiogenesis than previously appreciated. Furthermore, chronic hypoxia resulted in up-regulation of HIF-1alpha mRNA, in all monocyte-derived macrophage types studied. Actinomycin D experiments indicate that the increases in HIF-1alpha mRNA were not due to increased mRNA stability. To our knowledge this is the first study demonstrating up-regulation of HIF 1alpha mRNA by hypoxia in macrophages. Taken together, the data support the hypothesis that hypoxia affects monocyte to macrophage maturation, resulting in a distinct gene expression pattern and phenotype. PMID- 21281981 TI - Interaction between immunoglobulin allotypes and NK receptor genes in diabetes post-hepatitis C virus infection. AB - Genetic interactions between natural killer (NK) cells immunoglobulin-like receptor (KIR) genes and immunoglobulin allotypes have been previously reported in type 2 diabetes mellitus (DM) patients. Puerto Rican Americans with a history of intravenous drug use who developed DM following HCV infection (n=32) were compared to individuals infected with HCV without diabetes (n=121) and to DM non infected individuals (n=95). Subjects were genotyped for KIRs and immunoglobulin allotypes. We found interactions of immunoglobulin allotypes KM3/KM3 with NK inhibitory receptors 2DL3/2DL3, 2DL1 in the absence of 2DS4 associated with susceptibility to DM in HCV infected individuals. These data suggest the possibility that a subset of patients with HCV could have an immune-mediated component contributing to the development of DM. PMID- 21281982 TI - The role of co-inhibitory signals in spontaneous tolerance of weakly mismatched transplants. AB - The immune system of female H-2(b) (C57BL/6) mice is a strong responder against the male minor-H antigen. However rejection or acceptance of such weakly mismatched grafts depends on the type of tissue transplanted. The mechanism responsible for such spontaneous graft acceptance, and its relationship to the natural mechanisms of tolerance of self antigens is unknown. Co-inhibitory molecules negatively regulate immune responses, and are important for self tolerance. We examined whether co-inhibitory molecules play a critical role in "spontaneous" allograft tolerance. Naive or donor sensitized diabetic female C57BL/6 (B6) wild type (WT), PD-1(-/-), and BTLA(-/-) mice were transplanted with freshly isolated syngeneic male islet grafts. The role of co-inhibitors during priming of anti-donor responses and graft challenge was also assessed using monoclonal antibodies targeting co-inhibitory receptors. Among the co-inhibitor (CTLA-4, PD-1) specific antibodies tested, only anti-PD-1 showed some potential to prevent spontaneous acceptance of male islet grafts. All BTLA(-/-) and almost all PD-1(-/-) recipients maintained the ability to spontaneously accept male islet grafts. While spontaneous graft acceptance in naive recipients was only weakly PD-1 dependent, tolerance induced by the accepted islets was found to be highly PD-1 dependent. Furthermore, spontaneous graft acceptance in pre sensitized recipients showed an absolute requirement for recipient PD-1 but not BTLA. Thus, the PD-1 pathway, involved in self tolerance, plays a critical role in spontaneous tolerance induced by weakly mismatched grafts in naive recipients and spontaneous graft acceptance in pre-sensitized recipients. PMID- 21281983 TI - Methylation pattern of IFN-gamma and IL-10 genes in periodontal tissues. AB - DNA methylation is characterized by the addition of methyl groups in cytosines within CpG islands. Unmethylated CpGs are related to transcriptionally active structure, whereas methylated CpG recruits methyl-binding proteins that promote chromatin compaction. DNA methylation can influence the expression of cytokines and affect the development of periodontal disease. OBJECTIVES: The purpose of the present study was to evaluate the methylation status of the interferon gamma (IFN gamma) and interleukin-10 (IL-10) genes in periodontal tissues. DESIGN: Methylation-specific polymerase chain reaction (MSP) and DNA sequencing analysis were used to verify the DNA methylation status of the IFN-gamma and IL-10 genes, respectively, in samples from subjects without periodontitis and individuals with chronic periodontitis. Histological sections stained by hematoxylin-eosin were used for histopathological evaluation of samples. RESULTS: The methylation status of the IFN-gamma and IL-10 genes was similar among the groups. Most of the samples were positive for IFN-gamma methylation. Only 11% of the periodontitis group showed unmethylated DNA. Considering the IL-10 gene, no unmethylated sample was observed. The profile of total or partial methylation was detected in CpGs evaluated. CONCLUSIONS: The results showed evidence that methylation of IFN-gamma and IL-10 genes is a usual feature on periodontal tissues. Further studies are needed to determine the functional relevance of these alterations. PMID- 21281984 TI - Use of HLA-DR*08032/E7 and HLA-DR*0818/E7 tetramers in tracking of epitope specific CD4+ T cells in active and convalescent tuberculosis patients compared with control donors. AB - Comparative tracking of tetramer-positive and epitope-specific CD4(+) T cells in blood and other tissues from tuberculosis (TB) patients during TB development and treatment using control donor samples is not well characterized. In this study, a novel HLA-DR-restricted peptide E7 from the ESAT-6 protein of Mycobacterium tuberculosis (MTB) was used to prepare modified HLA-DR*08032/E7 tetramer (tetramer 1) and HLA-DR*0818/E7 tetramer (tetramer 2) to monitor a series of samples from TB patients and control donors. Tetramer staining showed that (1) by direct staining of single sample and flow cytometric analyses, detection of tetramer-positive CD4(+) T cells ranged from 0.1% to 8.8% (median 0.67% in tetramer 1 and 0.5% in tetramer 2), 0.1 to 10.7% (0.74% and 0.71%), 0.02 to 2.2% (0.25% and 0.25%), 0.02 to 0.48% (0.2% and 0.2%) and most at under 0-0.2% (0.2% and 0.16%) in the initial pulmonary TB (PTB) patients' blood, pleural fluid (PLF) of initial tuberculous pleuritis patients, non-TB patients' blood, healthy donors' blood and umbilical cord blood, respectively; significantly higher levels of CD4(+) T cells were detected in samples of TB patients than in three control donor groups; (2) by direct staining of time point TB samples and flow cytometric analyses, along with TB symptom amendment at day 60, tetramer-positive CD4(+) T cells began to decrease, until after 90-120 days, reached and kept at a relatively low even normal level about at 0.03-0.3%; (3) by enrichment approach, at least 10-fold increased memory tetramer-positive CD4(+) T cells were seen; (4) by in situ staining, tetramer-positive, IFN-gamma-producing and/or TNF-alpha producing CD4(+) T cells in the lymph node and lung granuloma and cavernous tissues of TB patients could be determined. Therefore, by further increasing the sample size tested to confirm the specificity and sensitivity of tetrameric molecules, it should be possible to develop them for use as research and diagnostic reagents. PMID- 21281985 TI - Serum DPPIV activity and CD26 expression on lymphocytes in patients with benign or malignant breast tumors. AB - The aim of this work was to determine serum DPPIV activity as well as the percentage of CD26+ white blood cells and of CD26+ lymphocytes and the mean fluorescence intensity (MFI) of CD26 expression on lymphocytes in groups of patients with benign or malignant breast tumors and in healthy control people. Serum DPPIV activity was determined by colorimetric test, while CD26+ cells were counted using flow cytometer. Results of this study show that there is no statistically significant difference in serum DPPIV activity between examined groups of patients and healthy controls. However, two times higher frequency of patients with breast cancers had the enhanced DPPIV enzymatic activity in comparison to controls. Significant decrease in the percentage of CD26+ total white blood cells was found in the group of breast cancer patients and in patients with benign breast tumors compared to that found for healthy people. Although there was decrease in the percentage of lymphocytes in patients with breast tumors it was not statistically significant. The MFI of CD26 expression on these cells was significantly lower for cancer patients in comparison to healthy controls. In conclusion, this work showed the enhanced frequency of breast cancer patients with higher serum DPPIV activity. Decreased percentage of CD26+ white blood cells and decreased CD26 expression on lymphocytes are also characteristics of this group of patients. Determination of the clinical outcome of analyzed patients, 1 and 2 years after the surgical resection of the tumor, would clarify potential prognostic values of examined parameters for breast cancer. PMID- 21281986 TI - Macrophages in skin injury and repair. AB - After recruitment to the wound bed, monocytes differentiate into macrophages. Macrophages play a central role in all stages of wound healing and orchestrate the wound healing process. Their functional phenotype is dependent on the wound microenvironment, which changes during healing, hereby altering macrophage phenotype. During the early and short inflammatory phase macrophages exert pro inflammatory functions like antigen-presenting, phagocytosis and the production of inflammatory cytokines and growth factors that facilitate the wound healing process. As such, the phenotype of wound macrophages in this phase is probably the classically activated or the so-called M1 phenotype. During the proliferative phase, macrophages stimulate proliferation of connective, endothelial and epithelial tissue directly and indirectly. Especially fibroblasts, keratinocytes and endothelial cells are stimulated by macrophages during this phase to induce and complete ECM formation, reepithelialization and neovascularization. Subsequently, macrophages can change the composition of the ECM both during angiogenesis and in the remodelling phase by release of degrading enzymes and by synthesizing ECM molecules. This suggests an important role for alternatively activated macrophages in this phase of wound healing. Pathological functioning of macrophages in the wound healing process can result in derailed wound healing, like the formation of ulcers, chronic wounds, hypertrophic scars and keloids. However, the exact role of macrophages in these processes is still incompletely understood. For treating wound repair disorders more should be elucidated on the role of macrophages in these conditions, especially their functional phenotype, to find more therapeutic opportunities. This review summarizes macrophage function in skin injury repair, thereby providing more insight in macrophage function in wound healing and possible interventions in this process. PMID- 21281987 TI - [SPA-2: semiology for phenotyping AMD: atrophic AMD]. AB - PURPOSE: The determination of homogeneous subgroups of age-related macular degeneration (AMD) is necessary for clinical and genetic studies; therefore, the development of a simple, reproducible, and discriminating classification is essential. In this second part of our study (SPA-2), we evaluated a selected list of items for atrophic AMD based on color photographs of fundus, red-free frames, autofluorescence, fluorescein angiography, indocyanine angiography, and Spectral Domain OCT. METHODS: Ten items for atrophy were chosen from the literature and clinical experience. Twenty eyes of 20 patients with atrophic AMD were included. For each patient, the grid was completed by five independent, experienced readers from our reading center and by an expert. The Kappa coefficient was calculated for each item. RESULTS: The greatest agreement between observers was found for the item "presence of atrophy" (Kappa=1). The worst concordance was recorded for the item "size of atrophy" (Kappa=-0.0286+/-0.0769 to 0.1813+/-0.0835). CONCLUSION: The classification of atrophic AMD is complex and currently not very consensual, hence the need for a discriminant and reproducible classification grid. The evaluation of our grid for atrophic AMD shows satisfactory agreement between observers for the majority of the items. Some modifications are proposed to make it more discriminant and reproducible. PMID- 21281988 TI - American Academy of Dermatology evidence-based guideline development process: responding to new challenges and establishing transparency. AB - BACKGROUND: Evidence-based clinical guidelines are developed to educate and inform physicians about best practices in patient care, and assist providers in the application of treatments and technologies that can improve outcomes. Clinical guidelines also aid appeal of payment decisions; serve as the basis for quality measure development, appropriateness criteria, and maintenance of certification modules; and help identify areas for further clinical research. OBJECTIVE: For guidelines to serve dermatologists effectively in these diverse roles, they must be current, varied in clinical focus, and developed with a high degree of rigor that includes attention to potential conflicts of interest. METHOD: To address these needs and keep pace with advances in medicine, the American Academy of Dermatology (AAD) recently revised the evidence-based guideline development process. RESULTS: Key changes include development of a yearly needs assessment process to determine what guidelines are most needed, the development of focused guidelines that address rapidly evolving clinical topics, a formal method of vetting guidelines produced by other societies, and a scheduled reassessment of existing guidelines to ensure they provide current and practical information. The process for identifying and managing potential conflicts of interest was also revised and expanded to meet current expectations and evolving standards. LIMITATIONS: The impact of these changes to the AAD's guideline development process will not be fully realized for several years. CONCLUSIONS: These changes will help ensure the AAD will be able to provide its members with continued evidence-based guidance to support patient care across the scope of dermatologic practice. PMID- 21281989 TI - Coexistence of blaOXA-23 with armA and novel gyrA mutation in a pandrug-resistant Acinetobacter baumannii isolate from the blood of a patient with haematological disease in China. PMID- 21281990 TI - [Safety problems associated with using physical restraint devices on the elderly]. AB - The use of physical restraint devices on frail elderly could have significant negative consequences on their health. Apart from complications due to prolonged immobility, the use of this procedure is associated with other serious adverse effects which occur when a person is restricted in a position which carries a risk of asphyxiation. The devices most implicated in these incidents are bedrails, vests and restraining belts. Physical restraint could also be associated as much with the sudden death of patients, due to the stress that it causes, as with injuries from falling. This article presents the recommendations which experts, manufacturers and institutions dealing with the quality of health care have issued for the safest use of this procedure. It stresses the need for better training of professionals, as well as the importance of investigating the factors which can lead to accidents with the aim of preventing them. PMID- 21281991 TI - An application of two MIFs-based tools (Volsurf+ and Pentacle) to binary QSAR: the case of a palinurin-related data set of non-ATP competitive glycogen synthase kinase 3beta (GSK-3beta) inhibitors. AB - VolSurf+ and GRIND descriptors extract the information present in MIFs calculated by GRID: the first are simpler to interpret and generally applied to ADME-Tox topics, whereas the latter are more sophisticated and thus more suited for pharmacodynamics events. Here we present a study which compares binary QSAR models obtained with VolSurf+ descriptors and GRIND for a data set of non-ATP competitive GSK-3beta inhibitors chemically related to palinurin for which the biological activity is expressed in binary format. Results suggest not only that the simpler Volsurf+ descriptors are good enough to predict and chemically interpret the investigated phenomenon but also a bioactive conformation of palinurin which may guide future design of ATP non-competitive GSK-3 inhibitors. PMID- 21281992 TI - Synthesis, hypoxia-selective cytotoxicity of new 3-amino-1,2,4-benzotriazine-1,4 dioxide derivatives. AB - We reported the synthesis, hypoxic cytotoxic activities and selectivities of 18 new 3-(alkoxymethylamino)-1,2,4-benzotriazine 1,4-dioxides. The synthesized compounds were screened in vitro against 5 cell lines: K562, SMMC-7721, A549, PC 3 and KB in hypoxia and in normoxia. Some of them showed higher or similar cytotoxic activity when compared to tirapazamine. Physico-chemical study showed the positive correlation between hypoxic activity and lipophilicity within a certain range. Preliminary mechanism study on the potent derivatives 4b, 4l and 4m indicated that the cytotoxic activities of these compounds might be mediated by inducing apoptosis. PMID- 21281993 TI - [Diabetic amyotrophy: favorable outcome following corticosteroid therapy?]. AB - Diabetic amyotrophy or lombosacral radiculoplexus neuropathy is a rare complication associated with early-stage diabetes. Thigh pain, quadricipital amyotrophy, proximal weakness of lower limbs and weight loss are the main symptoms of the disease. As neurological damage is related to inflammatory microvasculitis, corticosteroid therapy may be considered as the first line therapy. We report a 54-year-old patient with type 2 diabetes affected with severe diabetic amyotrophy. Following intravenous corticosteroid therapy, the patient reported a rapid pain relief and gained muscle strength. PMID- 21281994 TI - A new immune-modulating diet enriched with whey-hydrolyzed peptide, fermented milk, and isomaltulose attenuates gut ischemia-reperfusion injury in mice. AB - BACKGROUND & AIMS: Gut ischemia-reperfusion (I/R) is considered an important mechanism underlying multiple organ failure after severe surgical insults. We previously demonstrated an enteral diet enriched with whey-hydrolyzed peptide, fermented milk, and isomaltulose to have anti-inflammatory effects in a concanavalin A-induced hepatitis model. Here, we investigated whether the immune modulating diet (IMD), could prevent systemic inflammation, thereby improving survival in a gut I/R model. METHODS: Mice were randomized into control enteral diet (n = 58) or IMD (n = 56) for 2 weeks' feeding. In experiment 1, 39 mice underwent 45 min of gut ischemia, and were sacrificed at 3 h after reperfusion to collect blood samples. Plasma IL-6 and glucose levels were measured. In experiment 2, 75 mice underwent 60 min of ischemia, and their survival was observed until 48 h. RESULTS: Plasma IL-6 and glucose levels of the IMD group were significantly lower than those of control mice. In association with these changes, the IMD improved survival rate at early time points (12 and 30 h) after gut I/R (p < 0.05, chi(2) test). CONCLUSIONS: Nutritional management with the IMD may be useful for preventing systemic inflammatory response after gut I/R. PMID- 21281995 TI - Which data base should we use for our literature analysis? Web of Science versus SCOPUS. PMID- 21281996 TI - Haemotopsis as a first sign of pulmonary venous stenosis secondary to radiofrequency ablation of atrial fibrillation. PMID- 21281997 TI - Massive transfusion strategy or massive confusion in trauma with massive and ongoing bleeding. PMID- 21281998 TI - Intensive insulin therapy in critically ill children: it is time for outlining a protocol. PMID- 21281999 TI - Biodegradation of phenanthrene using adapted microbial consortium isolated from petrochemical contaminated environment. AB - In developing countries like India, there are many industrial areas discharging effluent containing large amount of polyaromatic hydrocarbon (PAH) which causes hazardous effect on the soil-water environment. The objective of this study was to isolate and characterize high-efficiency PAH-degrading microbial consortium from 3 decade old petrochemical refinery field located in Nagpur, Maharashtra with history of PAH disposal. Based on biochemical tests and 16S rDNA gene sequence analysis the consortium was identified as Sphingobacterium sp., Bacillus cereus and a novel bacterium Achromobacter insolitus MHF ENV IV with effective phenanthrene-degrading ability. The biodegradation data of phenanthrene indicates about 100%, 56.9% and 25.8% degradation at the concentration of 100mg/l, 250 mg/l and 500 mg/l respectively within 14 days. The consortium and its monoculture isolates also utilized variety of other hydrocarbons for growth. To best of our knowledge this is the first time that Achromobacter insolitus has been reported to mineralize phenanthrene effectively. GC-MS analysis of phenanthrene degradation confirmed biodegradation by detection of intermediates like salicylaldehyde, salicylic acid and catechol. All the results indicated that the microbial consortium have a promising application in bioremediation of petrochemical contaminated environments and could be potentially useful for the study of PAH degradation and for bioremediation purposes. PMID- 21282000 TI - Kinetics and mechanism of arsenate removal by nanosized iron oxide-coated perlite. AB - This study discussed the adsorption kinetics of As(V) onto nanosized iron oxide coated perlite. The effects of pH, initial concentration of As(V) and common anions on the adsorption efficiency were also investigated. It was observed that a 100% As(V) adsorption was achieved at pH value of 4-8 from the initial concentration containing 1.0 mg-As(V)L(-1) and the adsorption percentage depended on the initial concentration; the phosphate and silicate ions would not interfere with the adsorption efficiency. Furthermore, nanosized iron oxide-coated perlite (IOCP) has been shown to be an effective adsorbent for the removal of arsenate from water. The adsorption kinetics were studied using pseudo-first- and pseudo second-order models, and the experimental data fitted well with the pseudo-second order model. Moreover, it suggests that the Langmuir isotherm is more adequate than the Freundlich isotherm in simulating the adsorption isotherm of As(V). The adsorption rate constant is 44.84 L mg(-1) and the maximum adsorption capacity is 0.39 mg g(-1). These findings indicate that the adsorption property of IOCP gives the compound a great potential for applications in environmental remediation. PMID- 21282001 TI - Biodegradation of beta-cypermethrin and 3-phenoxybenzoic acid by a novel Ochrobactrum lupini DG-S-01. AB - A newly isolated bacterium DG-S-01 from activated sludge utilized beta cypermethrin (beta-CP) and its major metabolite 3-phenoxybenzoic acid (3-PBA) as sole carbon and energy source for growth in mineral salt medium (MSM). Based on the morphology, physio-biochemical characteristics, and 16S rDNA sequence analysis, DG-S-01 was identified as Ochrobactrum lupini. DG-S-01 effectively degraded beta-CP with total inocula biomass A(590 nm) = 0.1-0.8, at 20-40 degrees C, pH 5-9, initial beta-CP 50-400 mg L(-1) and metabolized to yield 3-PBA leading to complete degradation. Andrews equation was used to describe the special degradation rate at different initial concentrations. Degradation rate parameters q(max), K(s) and K(i) were determined to be 1.14 d(-1), 52.06 mg L(-1) and 142.80 mg L(-1), respectively. Maximum degradation was observed at 30 degrees C and pH 7.0. Degradation of beta-CP was accelerated when MSM was supplemented with glucose, beef extract and yeast extract. Studies on biodegradation in liquid medium showed that over 90% of the initial dose of beta CP (50 mg L(-1)) was degraded under the optimal conditions within 5d. Moreover, the strain also degraded beta-cyfluthrin, fenpropathrin, cyhalothrin and deltamethrin. These results reveal that DG-S-01 may possess potential to be used in bioremediation of pyrethroid-contaminated environment. PMID- 21282002 TI - Phenanthrene and pyrene uptake by arbuscular mycorrhizal maize and their dissipation in soil. AB - Polycyclic aromatic hydrocarbons (PAHs) commonly found in soils can be degraded in rhizosphere, but may also be taken up by plants. The effects of arbuscular mycorrhizal (AM) fungi on uptake of phenanthrene (PHE) and pyrene (PYR) in maize and on their dissipation in soil were investigated using the three compartmentalized rhizoboxes. Inoculation of Glomus mosseae significantly (p<0.01) increased PHE and PYR concentrations in maize roots and significantly (p<0.05) enhanced PYR translocation from roots to stems in the soil treatments of the PHE+PYR spiked-soils added into the central compartment of the rhizoboxes. There was a significant (p<0.05) dissipation gradient of PHE and PYR observed away from the maize roots, with the highest dissipation rates recorded in rhizosphere zone in the central compartments of the rhizoboxes, followed by near rhizosphere zone and bulk soil zone in the outer compartments. However, G. mosseae only exerted minimal impacts on dissipation of PHE and PYR in the rhizosphere. The present study suggested that the hyphae and extraradical mycelium of AM fungi could play important roles in the uptake and translocation of PHE and PYR in plants. The present results indicated that there is a potential for the use of AM fungi and plant for remediating PAHs contaminated soils. PMID- 21282003 TI - Use of farming and agro-industrial wastes as versatile barriers in reducing pesticide leaching through soil columns. AB - Increased interest has been recently focused on assessing the influence of the addition of organic wastes related to movement of pesticides in soils of low organic matter (OM) content. This study reports the effect of two different amendments, animal manure (composted sheep manure) and agro-industrial waste (spent coffee grounds) on the mobility of 10 pesticides commonly used for pepper protection on a clay-loam soil (OM = 0.22%). The tested compounds were azoxystrobin, cyprodinil, fludioxonil, hexaconazole, kresoxim-methyl, pyrimethanil, tebuconazole, and triadimenol (fungicides), pirimicarb (insecticide), and propyzamide (herbicide). Breakthrough curves were obtained from disturbed soil columns. Cumulative curves obtained from unamended soil show a leaching of all pesticides although in different proportions (12-65% of the total mass of compound applied), showing triadimenol and pirimicarb the higher leachability. Significant correlation (r = 0.93, p<0.01) was found between the observed and bibliographical values of GUS index. The addition of the amendments used drastically reduced the movement of the studied pesticides. Only two pesticides were found in leachates from amended soils, pyrimethanil (<1%) for both, and pirimicarb (44%) in the soil amended with spent coffee grounds. A decrease in pesticide leaching was observed with the increase in dissolved organic matter (DOM) of leachates. The results obtained point to the interest in the use of organic wastes in reducing the pollution of groundwater by pesticide drainage. PMID- 21282004 TI - Sodium dodecyl sulfate coated alumina modified with a new Schiff's base as a uranyl ion selective adsorbent. AB - A simple and selective method was used for the preconcentration and determination of uranium(VI) by solid-phase extraction (SPE). In this method, a column of alumina modified with sodium dodecyl sulfate (SDS) and a new Schiff's base ligand was prepared for the preconcentration of trace uranyl(VI) from water samples. The uranium(VI) was completely eluted with HCl 2M and determined by a spectrophotometeric method with Arsenazo(III). The preconcentration steps were studied with regard to experimental parameters such as amount of extractant, type, volume and concentration of eluent, pH, flow rate of sample source and tolerance limit of diverse ions on the recovery of uranyl ion. A preconcentration factor more than 200 was achieved and the average recovery of uranyl(VI) was 99.5%. The relative standard deviation was 1.1% for 10 replicate determinations of uranyl(VI) ion in a solution with a concentration of 5 MUg mL(-1). This method was successfully used for the determination of spiked uranium in natural water samples. PMID- 21282005 TI - Facile synthesis of Ag nanoparticles supported on MWCNTs with favorable stability and their bactericidal properties. AB - Stable Ag nanoparticles supported on multi-walled carbon nanotubes (MWCNTs) have been successfully synthesized by calcinations of the complexes of Ag cation and acid-treated MWCNTs under sparging N(2). The nanocomposites are characterized in detail by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and UV-visible absorption spectroscopy. The results indicate that Ag nanoparticles are relatively homogeneously dispersed on the surface of MWCNTs. The bactericidal properties of Ag/MWCNT nanocomposites are investigated with disk diffusion assay on the suspension samples inoculated with Escherichia coli. The results show that Ag/MWCNTs-500 nanocomposites possess excellent bactericidal property because of their suitable particle size (15 nm). Moreover, Ag nanoparticles supported on MWCNTs are very stable for half a year. What is more, the bactericidal effect was enhanced obviously under solar irradiation. This is because MWCNTs can absorb near-infrared light to kill parts of bacteria. A possible formation mechanism is also proposed in this article. PMID- 21282006 TI - Increased wind-up to heat pain in women with a childhood history of functional abdominal pain. AB - Idiopathic or functional abdominal pain (FAP) is common in school-age children and typically reflects a functional gastrointestinal disorder (FGID). FGIDs in adults have been distinguished by enhanced responses of the central nervous system to pain stimuli, known as central sensitization. This study investigated whether adolescents and young adults with a history of pediatric FAP (n=144), compared with well control subjects (n=78), showed enhanced central sensitization demonstrated by greater temporal summation (wind-up) to brief, repetitive heat pulses. We also assessed the role of gender and trait anxiety in wind-up to heat pain. Women with a history of FAP showed greater wind-up to heat pain than men with a history of FAP (P<.05) and well control subjects of both genders (P<.05). Results were similar for FAP participants whose abdominal pain was ongoing at follow-up and those whose pain had resolved. Although anxiety was significantly higher in the FAP group compared with control subjects (P<.01) and in women compared with men (P<.05), anxiety did not explain the increased wind-up observed in women with a childhood history of FAP. Results suggest that women with a pediatric history of FAP may have a long-term vulnerability to pain associated with enhanced central nervous system responses to pain stimuli. Young women with a childhood history of functional abdominal pain may have a long-term vulnerability to pain that is associated with enhanced responses of the central nervous system to pain stimuli. PMID- 21282007 TI - Painful issues in head pain classification. PMID- 21282008 TI - Inflammation alters trafficking of extrasynaptic AMPA receptors in tonically firing lamina II neurons of the rat spinal dorsal horn. AB - Peripheral inflammation alters AMPA receptor (AMPAR) subunit trafficking and increases AMPAR Ca(2+) permeability at synapses of spinal dorsal horn neurons. However, it is unclear whether AMPAR trafficking at extrasynaptic sites of these neurons also changes under persistent inflammatory pain conditions. Using patch clamp recording combined with Ca(2+) imaging and cobalt staining, we found that, under normal conditions, an extrasynaptic pool of AMPARs in rat substantia gelatinosa (SG) neurons of spinal dorsal horn predominantly consists of GluR2 containing Ca(2+)-impermeable receptors. Maintenance of complete Freund's adjuvant (CFA)-induced inflammation was associated with a marked enhancement of AMPA-induced currents and [Ca(2+)](i) transients in SG neurons, while, as we previously showed, the amplitude of synaptically evoked AMPAR-mediated currents was not changed 24 h after CFA. These findings indicate that extrasynaptic AMPARs are upregulated and their Ca(2+) permeability increases dramatically. This increase occurred in SG neurons characterized by intrinsic tonic firing properties, but not in those exhibited strong adaptation. This increase was also accompanied by an inward rectification of AMPA-induced currents and enhancement of sensitivity to a highly selective Ca(2+)-permeable AMPAR blocker, IEM-1460. Electron microcopy and biochemical assays additionally showed an increase in the amount of GluR1 at extrasynaptic membranes in dorsal horn neurons 24h post-CFA. Taken together, our findings indicate that CFA-induced inflammation increases functional expression and proportion of extrasynaptic GluR1-containing Ca(2+) permeable AMPARs in tonically firing excitatory dorsal horn neurons, suggesting that the altered extrasynaptic AMPAR trafficking might participate in the maintenance of persistent inflammatory pain. PMID- 21282009 TI - Spinal methylene blue is hazardous. PMID- 21282011 TI - Leishmania chagasi infection in cats with dermatologic lesions from an endemic area of visceral leishmaniosis in Brazil. AB - Although dogs are considered the main domestic reservoirs for Visceral Leishmaniosis (VL), which is caused in the Americas by Leishmania chagasi, infected cats have also been recently found in endemic areas of several countries and became a public health concern. Accordingly, the purpose of this study was to evaluate cats with dermatologic lesions from an endemic area of VL and the natural infection of L. chagasi. A total of 55 cats were selected between April 2008 and November 2009 from two major animal shelters of Aracatuba, Southeastern Brazil. All cats underwent general and dermatologic examinations, followed by direct parasitological examination of lymphoid organs, immunosorbent assay (ELISA) and indirect immunofluorescence (IFAT). In addition, detection of amastigotes was performed by immunohistochemistry (IHC) in skin lesions of all cats. VL was diagnosed in 27/55 (49.1%) cats with dermatological problems. Amastigotes were found in lymphoid organs of 10/27 (37.0%) cats; serology of 14/27 (51.9%), 6/27 (22.2%) and 5/27 (18.5%) cats was positive for ELISA, IFAT and both, respectively. The IHC identified 9/27 (33.3%) cats; 5/27 (18.5%) were positive only for IHC and therefore increased the overall sensitivity. Specific FIV antibodies were found in 6/55 (10.9%) cats, of which 5/6 (83.3%) had leishmaniosis. Real time PCR followed by amplicon sequencing successfully confirmed L. chagasi infection. In conclusion, dermatological lesions in cats from endemic areas was highly associated to visceral leishmaniosis, and therefore skin IHC and differential diagnosis of LV should be always conducted in dermatological patients in such areas. PMID- 21282012 TI - Dextran glucosidase: a potential target of iminosugars in caries prevention. AB - It is well known that iminosugars are inhibitors of glycosyltransferases (GTFs) and glucosidases. Because of iminosugars' inhibitory effect on GTFs, scientists have made great effort to verify their roles in the prevention of caries. The inhibition of GTFs can reduce the synthesis of extracellular polysaccharides, especially the synthesis of water-insoluble alpha-1,3-linked glucan. Extracellular polysaccharides have a critical influence on the biofilm formation and virulence of the bacteria. However, another mechanism in which iminosugars can affect the biofilm is ignored. Extracellular polysaccharides are synthesized by bacteria via GTFs and modified by dextran glucosidase. Thus the authors propose that iminosugars be applied to caries prevention, which may involves in inhibiting the role of dextran glucosidase. The iminosugar can reduce glycosidases' hydrolysis of water-soluble alpha-1,6-linked glucan and raise the ration of alpha-1,6-linked glucan to alpha-1,3-linked glucan. As a result, it can change the components, structure and aqueous solubility of the biofilm extracellular polysaccharides, and finally reduce its cariogenicity. This will potentially decrease the incidence of dental caries, and improve the oral health. PMID- 21282013 TI - Early rerupture of cerebral arteriovenous malformations: beware the progressive hemispheric swelling. AB - While early rerupture of cerebral arteriovenous malformations (AVMs) may not be as rare as previously thought, its determinants and risk factors remain unknown. Impairment of the venous drainage of AVMs is a well known risk factor for rupture and has been linked with the development of perinidal cerebral edema. We propose that a significant proportion of early AVM reruptures are the result of post hemorrhagic venous drainage impairment, which may manifest as refractory perihematomal edema. To support this hypothesis, an illustrative case of early AVM rerupture occurring 3 weeks following intracranial hemorrhage and heralded by progressive perinidal and perihematomal edema is presented. This finding should be viewed as a marker for unstable lesions with a high risk of imminent rerupture and should thus prompt a rapid definitive treatment for the AVM. PMID- 21282014 TI - Do low testosterone levels contribute to the pathogenesis of asthma? AB - Asthma is a chronic inflammatory airway disorder that causes respiratory hypersensitivity and intermittent obstruction. Airway hyperresponsiveness to both specific and nonspecific stimuli is the hallmark of asthma. Although genetic susceptibility and airway inflammation are believed to play fundamental roles, etiology of asthma is unknown. In most cases, the treatment of asthma focuses on control of factors contributing to asthma severity and pharmacologic therapy including bronchodilator and anti-inflammatory agents. The prevalence of reported asthma is greater in prepubertal boys, with a change to a female predominance after puberty. Many epidemiological studies also suggest that women are at increased risk of developing adult-onset asthma and also suffer from more severe disease than men. This strongly suggests an important role for sex hormones in asthma. Previous articles provided us that, testosterone and/or its metabolites maintain the physiological balance of autoimmunity and protective immunity by preserving the number of regulatory cells. Testosterone is an immunosuppressant and is likely to be protective against immunological and inflammatory processes that trigger asthma. We hypothesized that the testosterone or selective androgen receptor modulators would have beneficial effects on asthma and could decrease the risk of asthmatic attacks. PMID- 21282015 TI - Cytokeratin 7 and cytokeratin 20 expression in colorectal adenocarcinomas. AB - Cytokeratin 7 (CK7) and cytokeratin 20 (CK20) are low molecular weight cytokeratins. The expressions of CK7 and CK20 have been studied in various primary and metastatic carcinomas. Their expression patterns may help to distinguish the site of origin of metastatic carcinomas. We investigated the expressions of CK7 and CK20 in 196 cases of colorectal carcinoma. Paraffin sections of 196 colonic adenocarcinomas were randomly selected, retrieved, and immunostained for CK7 and CK20 with a standard avidin-biotin complex method. CK7 was expressed in 34/196 (17.3%) and CK20 in 159/196 (81.1) cases of colorectal adenocarcinoma. CK7-/CK20+ had the greatest proportion (65.8%) in colorectal carcinomas. The CK7+/CK20+ immunophenotype was identified in 30/196 (15.3%), CK7 /CK20- in 33/196 (16.9%), and CK7+/CK20- in 4/196 (2%) colon adenocarcinomas. The CK7 and CK20 expression patterns were different in colorectal carcinomas according to histological grade, location of the tumor, and lymph node metastasis. CK20 positivity was more common in low grade carcinomas than in high grade carcinomas (85.1% versus 47.6%) and in rectal and sigmoid carcinomas than in proximal colon carcinomas (88.2% versus 63.2% and 88.9% versus 63.2%, respectively). Furthermore, CK7 expression was more common in tumors with lymph node metastasis than in non-metastatic tumors (25.3% versus 11%). In conclusion, a considerable number of colorectal carcinomas showed reactivity to CK7 (17.3%) or no reactivity to CK20 (18.9%). Therefore, CK7 positivity or CK20 negativity does not rule out a colorectal origin of metastatic carcinoma. PMID- 21282016 TI - Malignant granular cell tumor: a look into the diagnostic criteria. AB - Fanburg-Smith et al. classified granular cell tumors (GCTs) using six criteria with high Ki-67 and p53 in malignant cases. We aim to refine their classification and reproduce their immunohistochemical findings. We, first, classified our 48 cases according to Fanburg-Smith criteria (37 benign, seven atypical, and four malignant), and performed Ki-67 and p53 on a sample of tumors. Then, we reclassified them into 44 benign and four with uncertain malignant potential (GCT UMP) using only necrosis and/or mitoses. (1) According to Fanburg-Smith criteria: Malignant cases were significantly younger than benign and atypical ones; occurred predominantly in males; were significantly larger in size; and showed a higher Ki-67 expression but an insignificant difference in p53 staining. (2) Comparative findings: The four malignant cases according to Fanburg-Smith corresponded to our four cases with UMP. The seven atypical cases and our benign group shared similar means, except for age. None of these atypical cases recurred or metastasized. Despite its small number, our preliminary study showed similar selectivity of two more reproducible criteria (vs six) in the classification of cases of GCT with potential aggressive behavior, preserving a role for Ki-67 in difficult cases. However, metastases remain the sole definite criterion for malignancy. PMID- 21282017 TI - Glycogen-rich pleomorphic xanthoastrocytoma with clear-cell features: confirmatory report of a rare variant with implications for differential diagnosis. AB - Central nervous system space-occupying lesions with clear-cell features encompass a nosologically heterogeneous array, ranging from reactive histiocytic proliferations to neuroepithelial or meningothelial neoplasms of various grades and to metastases. In the face of such differential diagnostic breadth, recognizing cytoplasmic lucency as part of the morphological spectrum of some low grade gliomas will directly have an impact on patient care. We describe a prevailing clear-cell change in an epileptogenic left temporal pleomorphic xanthoastrocytoma surgically resected from a 36-year-old man. Mostly subarachnoid and focally calcified, the tumor was composed of fascicles of moderately atypical spindle cells with optically lucent cytoplasm that tended to intermingle with a desmoplastic mesh of reticulin fibers. Immunohistochemically, coexpression of S100 protein, vimentin, GFAP, and CD34 was noted. Conversely, neither punctate staining for EMA nor positivity for CD68 was seen. Mitotic activity was absent, and the MIB1 labeling index was 2-3% on average. Diastase-sensitive PAS-positive granula indicated clear-cell change to proceed from glycogen storage. Electron microscopy showed tumor cell cytoplasm to be largely obliterated by non-lysosomal bound pools of glycogen, while hardly any fat vacuole was encountered. Neither ependymal-derived organelles nor annular lamellae suggesting oligodendroglial differentiation were detected. The latter differential diagnosis was further invalidated by lack of codeletion of chromosomal regions 1p36 and 19q13 on molecular genetic testing. By significantly interfering with pattern recognition as an implicit approach in histopathology, clear-cell change in pleomorphic xanthoastrocytoma is likely to suspend its status as a "classic", and to prompt more deductive differential diagnostic strategies to exclude look-alikes, especially clear-cell ependymoma and oligodendroglioma. PMID- 21282018 TI - [The gynecologist and the melanoma: breast and endometrial metastases]. AB - Melanoma has an important metastatic potential and its incidence is greatly increasing. Even after many years of negative follow-up, gynecologists should be aware that a gynecological tumor might be a secondary location for a woman with a medical history of melanoma. Because of a poor prognosis and a reduced life expectancy, it is necessary to make a disease staging in order to offer a prompt diagnosis and a personalized strategy of treatment. Considering the increasing incidence of melanoma, gynecologists will face more frequently with this situation. PMID- 21282019 TI - Alcohol use and its consequences in South India: views from a marginalised tribal population. AB - BACKGROUND: Alcohol consumption in India is disproportionately higher among poorer and socially marginalised groups, notably Scheduled Tribes (STs). We lack an understanding of STs own views with regard to alcohol, which is important for implementing appropriate interventions. METHODS: This study was undertaken with the Paniyas (a previously enslaved ST) in a rural community in Kerala, South India. The study, nested in a participatory poverty and health assessment (PPHA). PPHA aims to enable marginalized groups to define, describe, analyze, and express their own perceptions through a combination of qualitative methods and participatory approaches (e.g. participatory mapping and ranking exercises). We worked with 5 Paniya colonies between January and June 2008. RESULTS: Alcohol is viewed as a problem among the Paniyas who reported that consumption is increasing, notably among younger men. Alcohol is easily available in licensed shops and is produced illicitly in some colonies. There is evidence that local employers are using alcohol to attract Paniyas for work. Male alcohol consumption is associated with a range of social and economic consequences that are rooted in historical oppression and social discrimination. CONCLUSION: Future research should examine the views of alcohol use among a variety of marginalised groups in developing countries and the different policy options available for these populations. In addition, there is a need for studies that untangle the potential linkages between both historical and current exploitation of marginalized populations and alcohol use. PMID- 21282020 TI - Multiple substance use among heroin-dependent patients before and during attendance at methadone maintenance treatment program, Yunnan, China. AB - BACKGROUND: Multiple substance use is a common problem among heroin users. This study aims to describe patterns of multiple substance use one year before and during attendance at methadone maintenance treatment (MMT) programs and associated variables of continued heroin use in MMT clinics in Yunnan, China. METHODS: The study was conducted among 168 heroin addicts who had received treatment for at least one year at two MMT clinics in Kunming city. A structured questionnaire, a medical record, and computer database were used to obtain history of substances use, significant clinical information, and treatment details, respectively. RESULTS: Heroin, tobacco, and alcohol were the most commonly used substances both before and during MMT. After one year in MMT, use of heroin, alcohol, tramadol, and triazolam significantly decreased whereas use of ephedrine increased. Simultaneous substance use was halved but the decrease was not statistically significant. The proportion of injecting users was reduced from 61% to 43%. History of heroin use in the preceding 6 months during MMT increased the odds of continued heroin use (OR=5.8, 95% CI=[2.9-11.3]). An average 10mg higher methadone dose increment was associated with a reduced odds of heroin use by 10%. CONCLUSION: MMT did not reduce the number of substances used, but the number of injecting heroin users after the first year of treatment decreased. Heroin use in the preceding 6 months during MMT treatment and lower methadone dose were associated with continued heroin use in MMT. PMID- 21282021 TI - Methodology for estimating endocranial capacity in a modern European population. AB - Various methods have been published in the literature to estimate endocranial capacity. These are based on mathematical equations using measurements made directly on the skull or indirectly from X-rays, by filling the skull with various materials, by endocasts both physical and virtual (using 3D CT-scan reconstructions). Each method has its advantages, limits and drawbacks. A useful method is one that is simple, time-efficient, cheap, and reproducible. For this study we estimated endocranial capacity by filling the skull with calibrated glass beads. We used a thorough protocol of tamping to ensure results reproducibility. Intra- and inter-observer trials showed no significant differences. The method was applied to 130 recent French (West European) skulls (65 males and 65 females). Sexual dimorphism was studied using logistic regression functions, discriminant analysis, and neural network. The best results were obtained using the neural network, built with two hidden nodes in the hidden layer and one output node, and trained with a steepest descent algorithm. Our tests show that there is obvious sexual dimorphism (p < 10(-5)) of the weight of the skulls (623.44 +/- 106.83 g in males; 548.07 +/- 94.57 in females), the weight of the glass beads used to fill the skulls (2379.83 +/- 228.92 g in males; 2095.95 +/- 145.49 in females), and endocranial capacity (1676.47 cm(3) +/- 161.26 in males; 1476.48 +/- 102.49 in females), but overlapping between sexes is quite significant. The average ECC in male (1676.5 cm(3)) and in female (1476.5 cm(3)) subjects is higher than those previously published, which deserves some discussion. PMID- 21282022 TI - Insects found on a human cadaver in central Italy including the blowfly Calliphora loewi (Diptera, Calliphoridae), a new species of forensic interest. AB - In the case of unidentified bodies the estimation of the period since death or of the season of death plays an important role to focus the attention on a reduced number of people among the ones reported missing. Forensic entomology can be one of the most important methods for these estimations, as occurred in this case. Flies are typically the first insects to colonize a dead body. The case reported here concerns the colonisation by insects of a male body in advanced decay found during the winter in Central Italy. This case is of particular interest as few data are available on the entomological evidence in the cold season. In particular, in this case we recovered Calliphora loewi (Calliphoridae), a species never collected before on dead bodies in Southern Europe. Larvae of the black soldier fly Hermetia illucens (Stratiomyidae), pupae and larvae belonging to genus Hydrothea (Muscidae), and Necrobia rufipes (Cleridae) specimens were also collected. The estimated PMI enabled identification of the cadaver, confirmed by DNA analysis. PMID- 21282023 TI - Acute encephalopathy with 2009 pandemic flu: comparison with seasonal flu. AB - To clarify the features of acute encephalopathy associated with 2009 pandemic flu. We identified 51 patients with acute encephalopathy with seasonal flu from the data base accumulated by Tokai Pediatric Neurology Society. We also collected 10 patients with acute encephalopathy with 2009 pandemic flu. The clinical course, laboratory data, neuroimaging findings, treatment, and the outcome of these patients were recruited using a structured research form. These data were compared between the two groups. The age was larger in the 2009 pandemic flu group (median, 109.5months) than in the seasonal flu group (median, 44months). There was no significant difference in other demographic data, neurologic symptoms, laboratory and neuroimaging findings, and treatment. Various degrees of neurologic sequelae including death were observed in 32% of the patients in the seasonal flu group, and in 50% in the 2009 pandemic flu groups. The analyses of patients with ages of 6years or older revealed that moderate or more severe sequelae were more frequent in patients with 2009 pandemic flu. Acute encephalopathy with 2009 pandemic flu occurred mainly among children with 6years of age or older, and the outcome was worse in this age group compared with acute encephalopathy with seasonal flu. PMID- 21282024 TI - [Sputum smear conversion during intensive TB treatment phase according to HIV status, in hospitalised patients in Togo]. AB - METHOD: We prospectively studied patients with pulmonary TB, with or without HIV 1 co-infection, from December 1, 2007 to December 1, 2008. Two groups of patients naive for TB and antiretroviral treatment (group A: 96 co-infected TB/HIV and group B: 171 TB infected but HIV negative) were selected randomly. The CD4 count was assessed according to HIV status, and all patients received RHEZ TB treatment for 2 months. Pulmonary smear was assessed at two weeks, four weeks, six weeks, and eight weeks. RESULT: Two hundred and sixty seven patients were treated (26.6% of admissions). The mean age was 34.62 +/- 11 years and the sex ratio was 1.3. A proportion of 35.75% patients were HIV co-infected with a median CD4 count at 157 cells per millimeter cube. The sputum smear conversion was obtained for more than 87.5% of patients in group A and 24.56% in group B at two weeks; 94% of patients in group A and 61.83% in group B at four weeks; 100% of patients in group A and 87.33% in group B at six weeks, and 100% of patients in group A and 96.77% in group B at eight weeks. P<0.05 at six weeks. CONCLUSION: HIV infected TB patients were more susceptible to treatment than TB/HIV infected patients in the first six weeks. PMID- 21282025 TI - Natural populations of lactic acid bacteria associated with silage fermentation as determined by phenotype, 16S ribosomal RNA and recA gene analysis. AB - One hundred and fifty-six strains isolated from corn (Zea mays L.), forage paddy rice (Oryza sativa L.), sorghum (Sorghum bicolor L.) and alfalfa (Medicago sativa L.) silages prepared on dairy farms were screened, of which 110 isolates were considered to be lactic acid bacteria (LAB) according to their Gram-positive and catalase-negative characteristics and, mainly, the lactic acid metabolic products. These isolates were divided into eight groups (A-H) based on the following properties: morphological and biochemical characteristics, gamma aminobutyric acid production capacity, and 16S rRNA gene sequences. They were identified as Weissella cibaria (36.4%), Weissella confusa (9.1%), Leuconostoc citreum (5.3%), Leuconostoc lactis (4.9%), Leuconostoc pseudomesenteroides (8.0%), Lactococcus lactis subsp. lactis (4.5%), Lactobacillus paraplantarum (4.5%) and Lactobacillus plantarum (27.3%). W. cibaria and W. confusa were mainly present in corn silages, and L. plantarum was dominant on sorghum and forage paddy rice silages, while L. pseudomesenteroides, L. plantarum and L. paraplantarum were the dominant species in alfalfa silage. The corn, sorghum and forage paddy rice silages were well preserved with lower pH values and ammonia-N concentrations, but had higher lactic acid content, while the alfalfa silage had relatively poor quality with higher pH values and ammonia-N concentrations, and lower lactic acid content. The present study confirmed the diversity of LAB species inhabiting silages. It showed that the differing natural populations of LAB on these silages might influence fermentation quality. These results will enable future research on the relationship between LAB species and silage fermentation quality, and will enhance the screening of appropriate inoculants aimed at improving such quality. PMID- 21282026 TI - Kinetics and mechanism of 2,3,5,4'-tetrahydroxystilbene-2-O-beta-d-glycoside (THSG) degradation in aqueous solutions. AB - The hydrolytic kinetics and degradation mechanism of 2,3,5,4' tetrahydroxystilbene-2-O-beta-d-glycoside (THSG) extracted from Radix Polygoni Multiflori (a commonly used official Chinese herbal Heshouwu), were investigated using reversed-phase high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS). The influences of pH (1.5-9.9), temperature (25-60 degrees C) and irradiation on the hydrolysis of THSG were studied in aqueous solutions. The results showed that the degradation of THSG was pH-, temperature- and irradiation-dependent and all followed first-order kinetics. The effect of temperature on the rate of THSG degradation was characterized using the Arrhenius equation. Maximum stability of THSG was found at pH 1.5 (t(0.5)=47.57 d). THSG was unstable in alkaline and irradiation conditions. The active energy (E(a)) of THSG degradation in aqueous solution at pH 6.8 (most frequently adopted extract solvent) under lucifugal and irradiation conditions was 47.7kJmol(-1) and 25.3kJmol(-1), respectively. Three hydrolytic products of THSG were identified by LC-MS. Cis-trans isomerism took place under irradiation, and hydrolysis took place in acid-base conditions. Moreover, further oxidation on aglycon occurred after hydrolytic cleavage of phenolic glycoside in acidic conditions. The possible hydrolytic pathways of THSG are proposed. PMID- 21282027 TI - Qualitative on-line profiling of ceramides and cerebrosides by high performance liquid chromatography coupled with electrospray ionization ion trap tandem mass spectrometry: the case of Dracontium loretense. AB - Ceramides and cerebrosides are key compounds in the metabolism of sphingolipids. Produced in response to a variety of apoptotic stimuli, these metabolites mediate either mitogenic or apoptotic responses, depending on cell type and nature of stimulus. Novel strategies using these selective targets for a therapeutic intervention, e.g. in cancer, cardiovascular and neurodegenerative diseases, and HIV, have been developed, along with anticancer approaches using controlled delivery of exogenous natural ceramides from ceramide-based liposomes. Thus, great is the need to find selective and sensitive analytical methods allowing a prompt detection of ceramides and cerebrosides in natural matrices. Here we report an analytical study carried out on the Amazonian plant Dracontium loretense, resulted in a preliminary analysis a rich source of this class of natural compounds. A handy, selective, and sensitive methodology based on high performance liquid chromatography coupled to electrospray negative ionization multistage ion trap mass spectrometry (HPLC-ESI/ITMS(n)) was developed. Analysis of fingerprint multistage mass spectra allowed the rapid identification of 3 major long-chain bases and their exact pairing with 11 different fatty acids and with carbohydrate headgroups. Thus, the structures of 21 ceramide and cerebroside species, among which 7 molecules never reported before, were unambiguously assigned. Results obtained in this study demonstrated that this analytical approach could provide a reliable and sensitive method to obtain the qualitative on-line profiling of ceramides and cerebrosides in new medicinal plant matrices. PMID- 21282028 TI - Characterization of a liposome-based formulation of oxaliplatin using capillary electrophoresis: encapsulation and leakage. AB - A capillary electrophoresis-based method to characterize a PEGylated liposomal drug formulation of the anti-cancer agent oxaliplatin was developed. Pharmaceutical characterization in terms of determination of the free and total oxaliplatin concentrations in the liposomal formulation was successfully performed allowing calculation of the percentage of encapsulated drug and encapsulation efficiency. The trapping efficiency was likewise calculated. The capillary electrophoresis method allowed liposome characterization in the intended formulation media (sucrose solution with low electrolyte concentration), and the attained results were consistent with inductively coupled plasma mass spectrometry measurements. Accelerated drug leakage studies were initiated by the sonication of the PEGylated formulation, using an ultrasound probe, subsequently the drug leakage was determined by capillary electrophoresis. The results obtained with the PEGylated liposomes demonstrate that capillary electrophoresis may be a useful tool for the characterization of liposomal drug formulations. PMID- 21282029 TI - Impact of patient obesity on the patient-provider relationship. AB - OBJECTIVE: Health professionals' weight bias may impair obese patients' interactions with providers. However, few studies have examined how negative provider attitudes affect the patient-provider relationship for obese patients. We hypothesized that higher patient body mass index (BMI) would be negatively associated with patient-provider relationship quality. METHODS: We analyzed data from the 2007 Health Tracking Household Survey. BMI was the independent variable, and patient-perceived quality of the patient-provider relationship was the outcome. We performed log-binominal regression analyses accounting for complex survey design to examine the association of BMI with the patient-provider relationship. RESULTS: Of the 15,197 adult survey respondents, the 6427 who answered the quality of care questions were eligible for analysis. Overall, 29% had a normal range BMI, 34% were overweight, and 37% were obese. We found few differences in ratings of the patient-provider relationship for overweight and obese respondents when compared to respondents with a normal range BMI. CONCLUSION: These unexpected findings may have occurred due to patients' inability to perceive providers' weight bias, measurement error in questionnaire items, or decreasing weight bias among health professionals. PRACTICE IMPLICATIONS: Patient's positive perceptions of providers may indicate promise for health professionals acting as motivators of behavior change in obese patients. PMID- 21282030 TI - Shared Decision Making Guidance Reminders in Practice (SDM-GRIP). AB - OBJECTIVE: Develop a system of practice tools and procedures to prompt shared decision making in primary care. SDM-GRIP (Shared Decision Making Guidance Reminders in Practice) was developed for suspected stable coronary artery disease (CAD), prior to the percutaneous coronary intervention (PCI) decision. METHODS: Program evaluation of SDM-GRIP components: Grand Rounds, provider training (communication skills and clinical evidence), decision aid (DA), patient group visit, encounter decision guide (EDG), SDM provider visit. RESULTS: Participation Physician training=73% (21/29); patient group visits=25% of patients with diagnosis of CAD contacted (43/168). SDM visits=16% (27/168). Among SDM visit pairs, 82% of responding providers reported using the EDG in SDM encounters. Patients valued the SDM-GRIP program, and wanted to discuss comparative effectiveness information with a cardiologist. SDM visits were routinely reimbursed. CONCLUSION: Program elements were well received and logistically feasible. However, recruitment to an extra educational group visit was low. Future implementation will move SDM-GRIP to the point of routine ordering of non emergent stress tests to retain pre-decision timing of PCI and to improve coordination of care, with SDM tools available across primary care and cardiology. PRACTICE IMPLICATIONS: Guidance prompts and provider training appear feasible. Implementation at stress testing requires further investigation. PMID- 21282031 TI - [TAP block and blocks of the abdominal wall]. AB - Since the revolution of ultrasound in regional anesthesia, new techniques have arisen. The "transversus abdominis plane" block or TAP block is one of them. The benefits of a TAP block for postoperative analgesia have been shown mostly after laparotomy. Because this block seems to be technically easy, many anesthesiologists have quickly adopted it. However, the TAP block presents some technical specificities and knowledge of the anatomy is required. This article reviews the anatomy of the abdominal wall, the different blocks, the indications, the complications, and highlights the many unanswered questions left. This review proposes a new vision of the abdominal wall blocks based on a new understanding of the anatomy of the abdominal wall associated with an ultrasound technique. PMID- 21282032 TI - [Ultrasound-guided bilateral paravertebral thoracic block in an obese patient]. PMID- 21282033 TI - [Knot in a thoracic epidural catheter]. AB - We report a case of impossible injection into a thoracic epidural catheter associated with a difficult withdrawal of this catheter after its introduction on the T3-T4 level. Thanks to a gentle and continuous traction, the catheter was finally successfully removed without being broken, but presented a simple knot at 13mm from its end. No neurological complication was observed later on. This complication happened during the introduction of the catheter at the thoracic level where anatomic conditions are less favorable for this kind of complication to happen than at the lumbar level. We have been probably confronted with a catheter taking an abnormal direction due to an anatomic structure. This case shows us that knots in an epidural catheter are also possible on the high thoracic level and that its ascent within the epidural space must happen without any resistance. PMID- 21282034 TI - [Cardiac biomarkers in perioperative risk stratification]. AB - OBJECTIVES: The field of new cardiac biomarkers has triggered physicians' enthusiasm because of their potential diagnostic and prognostic values for routine clinical practice in the surgical setting. The objective of the present article is to review the role of new cardiac biomarkers and their potential additive clinical value in predicting short- and long-term risk following cardiac and non-cardiac surgery. DATA SOURCES: A PubMed((r)) database research in English and French languages published until June 2010. Keywords were cardiac biomarkers, troponins, cardiac troponin I (cTnI), natriuretic peptides, B-type natriuretic peptide (BNP), C-reactive protein (CRP), multiple markers approach, risk stratification, clinical risk scores. DATA SYNTHESIS: Numerous publications deal with the diagnostic and prognostic values of new cardiac biomarkers in cardiac and non-cardiac surgical settings and provide an increasing evidence of their interest, validating different hierarchical steps which are mandatory before recommending a wide use of biomarkers for routine practice. Even if the first studies demonstrating an additional prognostic value of serum postoperative cTnI and/or preoperative BNP when compared with clinical predictive models are now available, we still lack data concerning an actual positive impact of new biomarkers measurements on clinical decision making or practice, as well as patient care and outcome. CONCLUSIONS: While use of new cardiac biomarkers in the perioperative period appears to be a simple and objective tool for risk stratification at the bedside, we still need to remain cautious concerning their additional clinical value on existing predictive models for routine practice. PMID- 21282035 TI - [Cricothyrotomy in emergency context: assessment of a cannot intubate cannot ventilate scenario]. AB - OBJECTIVE: The aim of this study was to assess airway management by emergency physicians in case of a simulated situation where intubation and ventilation were both impossible. STUDY DESIGN: Observational manikin study. METHODS: A manikin (Airman(r); Laerdal) allowing simulating difficult airway situations was used. The scenario assessed concerned a patient needing tracheal intubation for severe traumatic brain injury. The manikin was settled to make tracheal intubation under direct laryngoscopy impossible at the first attempt and to make facemask ventilation impossible after the second attempt. Manikin could initially be ventilated through the intubating laryngeal mask Airway (ILMA) but became impossible few seconds after its insertion. With impossible ventilation through the ILMA, arterial oxygen saturation decreased during 2 minutes before an hypoxic cardiac arrest occurred. Physicians could use classic laryngoscope with Macintosh blade, a Gum Elastic Bougie, an ILMA and a cricothyrotomy set. Adhesion to the national airway management algorithm was assessed. Time to cricothyroidotomy decision after ventilation through ILMA became impossible was measured. RESULTS: Twenty-five emergency physicians were assessed. For 14 of them, national expert conference algorithm was perfectly followed. For ten physicians, cricothyroidotomy decision was taken after hypoxic cardiac arrest occurred. CONCLUSION: Simulation with a manikin is useful to assess the adhesion rate to difficult intubation algorithms. Our study shows that the decision making process for cricothyrotomy is too often delayed as soon as ventilation became impossible and oxygenation compromized. PMID- 21282036 TI - [Respiratory distress during caesarean section under spinal anaesthesia]. PMID- 21282037 TI - [Splenic artery aneurysm rupture in late pregnancy: a case report and review of the literature]. AB - Haemorrhages during pregnancy may have a non-obstetrical origin, the pregnancy itself favoring some specific aetiologies because of pregnancy-related physiological modifications. These non-obstetrical haemorrhages are rare but are associated with a high maternal and foetal mortality. The prognosis depends on an early diagnosis and a multidisciplinary approach. We report the case of a patient who had a caesarean section for suspicion of acute foetal distress during which was found a large intraperitoneal bleeding due to rupture of an unknown splenic artery aneurysm. We discuss the principal causes of non-obstetrical intra abdominal bleeding, including subcapsular liver haematoma, rupture of uterine vessels and rupture of splenic artery aneurysm, with a specific focus on this last aetiology. PMID- 21282038 TI - Play, behaviour, language and social skills: the comparison of a play and a non play intervention within a specialist school setting. AB - The aim of the present study was to investigate the play, behaviour, language and social skills of children aged 5-8 years participating in a play intervention (based on the 'Learn to Play' program) compared to a group of children participating in traditional classroom activities within a specialist school over a six month period. Thirty-five children participated in the study, 19 participated in the play intervention group and 16 participated in the comparison group. Fourteen staff members at the special school were involved. A quasi experimental design was used with pre and post data collection. Children in the play intervention and the comparison group were assessed using the Child Initiated Pretend Play Assessment (play), Goal Attainment Scaling (behaviour), the Preschool Language Scale (language) and the Penn Interactive Peer Play Scale (social skills) at baseline and at follow up. Findings revealed that children participating in the play intervention showed a significant decrease in play deficits, became less socially disruptive and more socially connected with their peers. Both groups improved in their overall language skills and significantly improved in their goal attainment. This study supports the use of a play intervention in improving a child's play, behaviour, language and social skills. PMID- 21282039 TI - IL-2: a two-faced master regulator of autoimmunity. AB - CD4(+) T-cell (Th) cytokines provide important regulatory and effector functions of T-cells. Among them, IL-2 plays a unique role. IL-2 is required for the generation and maintenance of regulatory T-cells (Treg) to provide lifelong protection from autoimmune disease. Whether IL-2 is also required for autoimmune disease development is less clear as Il2(-/)(-) mice themselves spontaneously develop multi-organ inflammation (MOI). In this communication, we discuss evidence that support the thesis that IL-2 is required for the development of autoimmune response, although some aspects of autoimmune response are not regulated by IL-2. Potential IL-2-dependent mechanisms operating at specific stages of the inflammation process are presented. The interplays among Treg, IL 2, autoimmune response and adaptive immunity are discussed. Overall, available information indicates that IL-2 is a two-faced master regulator of autoimmunity: one to prevent autoimmunity while the other promotes autoimmune response. The latter is an unfortunate consequence of IL-2 function that is used to promote the adaptive immune response against foreign antigens and pathogens. PMID- 21282040 TI - Clinical-radiographic and histological evaluation of two hydroxyapatites in human extraction sockets: a pilot study. AB - After tooth extraction the healing process involves bone resorption and soft tissue contraction, events that can compromise the ideal implant placement with functional and aesthetic limitations. Following tooth extraction, a socket preservation technique can limit bone resorption. This study evaluated two different types of hydroxyapatite (HA) grafting materials placed into fresh extraction sockets, 6 months after tooth extraction, histologically, clinically and radiographically. Ten extraction sockets from 10 patients were divided in two groups: 5 sockets received a biomimetic HA and 5 received nanocrystalline HA. After 6 months, before implant placement, samples from the grafted area were harvested and evaluated clinically, radiographically and histologically. The percentages of bone, osteoid areas and residual material in the two groups were not statistically different. All samples showed great variability with extensive bone formation and total material resorption or amounts of osteoid tissue that filled the spaces between the residual material particles. The authors did not find any differences between biomimetic and nanocrystalline HA and assume that, within the limits of this study, both these materials could be applied into fresh extraction sockets to limit bone resorption. A control material and a much larger sample size are needed to confirm these findings. PMID- 21282041 TI - Influence of enzyme inducing antiepileptic drugs on the pharmacokinetics of levetiracetam in patients with epilepsy. AB - To assess whether levetiracetam elimination is influenced by enzyme inducing antiepileptic drugs (EIAEDs), serum levetiracetam levels were determined at frequent intervals after a single oral 1000mg dose in 15 subjects co-medicated with EIAEDs and 15 matched controls. The EIAED group showed a higher levetiracetam oral clearance (p=0.01) and a shorter half-life (p=0.02) than controls. Although the magnitude of interaction is relatively modest, it could have clinical significance for some patients. PMID- 21282042 TI - Olfactory deficits in deletion syndrome 22q11.2. PMID- 21282043 TI - Quercetin inhibits UV irradiation-induced inflammatory cytokine production in primary human keratinocytes by suppressing NF-kappaB pathway. AB - BACKGROUND: Topical flavonoids, such as quercetin, have been shown to reduce ultraviolet (UV) irradiation-mediated skin damage. However, the mechanisms and signaling pathways involved in this protective effect are not clear. UV irradiation leads to activation of two major signaling pathways, namely nuclear factor kappa B (NF-kappaB) and activator protein-1 (AP-1) pathways. Activation of NF-kappaB pathway by UV irradiation stimulates inflammatory cytokine expression, whereas activation of AP-1 pathway by UV irradiation promotes matrix metalloproteinase (MMP) production. Both pathways contribute to UV irradiation induced skin damage, such as photoaging and skin tumor formation. OBJECTIVE: To elucidate the underlying mechanism, we examined the effect of quercetin on UV irradiation induced activation of NF-kappaB and AP-1 pathways. METHODS: Primary human keratinocytes, the major skin cell type subjected to physiological solar UV irradiation, were used to study the effects of quercetin on UV irradiation induced signal transduction pathways. RESULTS: Quercetin decreased UV irradiation induced NF-kappaB DNA-binding by 80%. Consequently, quercetin suppressed UV irradiation-induced expression of inflammatory cytokines IL-1beta (~60%), IL-6 (~80%), IL-8 (~76%) and TNF-alpha (~69%). In contrast, quercetin had no effect on UV irradiation activation of three MAP kinases, ERK, JNK, or p38. Accordingly, induction of AP-1 target genes such as MMP-1 and MMP-3 by UV irradiation was not suppressed by quercetin. CONCLUSION: Our data indicate that the ability of quercetin to block UV irradiation-induced skin inflammation is mediated, at least in part, by its inhibitory effect on NF-kappaB activation and inflammatory cytokine production. PMID- 21282044 TI - CD98hc (SLC3A2) is a key regulator of keratinocyte adhesion. AB - BACKGROUND: Adhesion of keratinocytes is crucial for maintaining the integrity of the skin, as demonstrated by the number of dermatological disorders of genetic origin that are associated with a defect of basal keratinocyte adhesion. Integrins are the main component of the molecular networks involved in this phenomenon, but there are many others. In a recent description of proteins associated to caveolae at the plasma membrane of human basal epidermal cells, we demonstrated that CD98hc is localized with beta1 integrin. OBJECTIVES: We investigated the CD98hc proteins interactions and the role of CD98hc in keratinocyte adhesion. METHODS: CD98hc protein interaction was identified following co-immunoprecipitation and proteomic analysis using LTQ-FT mass spectrometer. Extinction of CD98hc gene expression using specific short hairpin RNA or over-expression of CD98hc lacking the beta1 integrin binding site was used to evaluate the role of this protein in keratinocyte fate. RESULTS: We show that CD98hc forms molecular complexes with beta1 and beta4 integrins in primary human keratinocytes and, using immunofluorescence, that these complexes are localized at the plasma membrane, in keeping with a role in adhesion. We confirmed that this protein is a key player of keratinocyte adhesion because in absence of interaction between CD98hc and integrins, beta1 integrin failed to translocate from the cytoplasm to the plasma membrane and keratinocytes expressed epidermal differentiation markers. CONCLUSIONS: All these data strongly suggested that CD98hc is involved in integrin trafficking and by consequence, in keratinocyte adhesion and differentiation. PMID- 21282045 TI - Biosorption of Cr(VI) ions from aqueous solutions: kinetics, equilibrium, thermodynamics and desorption studies. AB - Cr(VI) is a major water pollutant from industrial effluent whose concentration is to be reduced within the permissible limit. Present study reports a systematic evaluation of six different natural adsorbents for the removal of Cr(VI) from aqueous solutions in batch process. The adsorption kinetic data were best described by pseudo-second order model. The values of mass transfer coefficient for Cr(VI) adsorption indicated that the velocity of the adsorbate transport from the bulk to the solid phase was quite fast. The effective diffusivity of Cr(VI) removal for all the adsorbents were of the order of 10(-10) m(2)/s which suggested chemisorption of the process. The adsorption process was jointly controlled by film diffusion and intraparticle diffusion. Maximum monolayer adsorption capacities onto the natural adsorbents used were comparable to the other natural adsorbents used by other researchers. The thermodynamic studies and sorption energy calculation using Dubinin-Radushkevich isotherm model indicated that the adsorption processes were endothermic and chemical in nature. FT-IR studies were carried out to understand the type of functional groups responsible for Cr(VI) binding process. Desorption study was carried out with different concentration of NaOH solutions. Application study was carried out using electroplating industrial wastewater. PMID- 21282046 TI - Polymorphism of Paramecium pentaurelia (Ciliophora, Oligohymenophorea) strains revealed by rDNA and mtDNA sequences. AB - Paramecium pentaurelia is one of 15 known sibling species of the Paramecium aurelia complex. It is recognized as a species showing no intra-specific differentiation on the basis of molecular fingerprint analyses, whereas the majority of other species are polymorphic. This study aimed at assessing genetic polymorphism within P. pentaurelia including new strains recently found in Poland (originating from two water bodies, different years, seasons, and clones of one strain) as well as strains collected from distant habitats (USA, Europe, Asia), and strains representing other species of the complex. We compared two DNA fragments: partial sequences (349 bp) of the LSU rDNA and partial sequences (618 bp) of cytochrome B gene. A correlation between the geographical origin of the strains and the genetic characteristics of their genotypes was not observed. Different genotypes were found in Krakow in two types of water bodies (Opatkowice natural pond; Jordan's Park-artificial pond). Haplotype diversity within a single water body was not recorded. Likewise, seasonal haplotype differences between the strains within the artificial water body, as well as differences between clones originating from one strain, were not detected. The clustering of some strains belonging to different species was observed in the phylogenies. PMID- 21282047 TI - Ethanol induced adaptive changes in blood for the pathological and toxicological effects of chronic ethanol consumption in humans. AB - Alcohol consumption is associated with a number of toxicological changes in blood and the oxidant-antioxidant system. The present study was performed to investigate the alcohol induced toxicological, pathological changes in blood and an adaptive role of erythrocyte antioxidant system in chronic alcoholics. Human male volunteers aged 44+/-6 years with similar dietary habits were divided into two groups, namely non-alcoholic controls and chronic alcoholics. We measured hematological parameters, erythrocyte lipid peroxidation, NO production, erythrocyte antioxidant and liver function test enzyme activities. Alcoholics had increased erythrocyte nitric oxide levels and also elevated erythrocyte lipid malondialdehyde (MDA) concentrations. Strikingly, increments in reduced glutathione and markedly increased activities of certain antioxidant enzymes such as glutathione reductase (GR), superoxide dismutase (SOD), and another related enzyme G-6 phosphate dehydrogenase (G6-PDH) with no alterations in the activities of glutathione S-transferase (GST), glutathione peroxidase (GPx), and catalase (CAT) in chronic alcoholics were observed compared to controls. Furthermore, erythrocyte NO levels were positively correlated with lipid peroxidation, SOD, GSH, GR and G6PDH in chronic alcoholics. In addition, increased AST/ALT ratio and a significant increase in WBC and platelets were also noticed. Together, these results indicate that, antioxidants and defense enzymes appear to be rendering protection as a consequence of chronic adaptation in alcoholics. PMID- 21282048 TI - Toxicity of Moringa oleifera seed extract on some hematological and biochemical profiles in a freshwater fish, Cyprinus carpio. AB - The study was carried out to investigate the acute and sublethal toxicity of Moringa oleifera seed extract on hematological and biochemical variables of a freshwater fish Cyprinus carpio under laboratory conditions. The 96 h LC50 value of M. oleifera seed extract to the fish C. carpio was estimated by probit analysis method and was found to be 124.0 mg/L (with 95% confidence limits). For sublethal studies a non lethal dose of 1/10th of 96 h LC50 value (12.40 mg/L) was taken. During acute treatment (96 h), hematological variables like red blood cell count (RBC), hemoglobin (Hb), hematocrit (Hct), and mean corpuscular hemoglobin concentration (MCHC) were significantly (P<0.05) decreased in fish exposed to seed extract. However a significant (P<0.05) increase in white blood cell count (WBC), mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) value was observed in the exposed fish during above treatment period when compared to that of the control groups. Biochemical parameters such as plasma protein and glucose levels significantly declined in fish exposed to seed extract while a significant (P<0.05) increase in aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activity was observed. During sublethal treatment (12.40 mg/L), WBC count, MCV, MCH, plasma glucose, AST, ALT and ALP activities were gradually elevated (P<0.05) at the end of 7, 14, 21, 28 and 35th days in seed extract exposed fish, whereas plasma protein level declined. However, a biphasic trend was noticed in Hb, Hct, RBC and MCHC levels. This study may provide baseline information about the toxicity of M. oleifera seed extract to C. carpio and to establish safer limit in water purification. PMID- 21282049 TI - Abresham ameliorates dyslipidemia, hepatic steatosis and hypertension in high-fat diet fed rats by repressing oxidative stress, TNF-alpha and normalizing NO production. AB - This study was aimed to investigate whether standardized hydroalcoholic extract of abresham (AB) ameliorates dyslipidemia, hepatic steatosis and associated hypertension in rats fed with high-cholesterol/high-fat diet (HFD). HFD (55% calorie from fat and 2% cholesterol) were fed for 45 days to induce dyslipidemia, hepatic steatosis and associated hypertension. After confirmation of hypercholesterolemia (total cholesterol >150 mg/dl) on 30th day, different doses of AB (200-800 mg/kg/day) were administered for next 15 days. HFD administration for 45 days led to cardiometabolic syndrome characterized by significant increase in body weight, total cholesterol, triglyceride, low density lipoprotein cholesterol, TNF-alpha levels along with decrease in high density lipoprotein cholesterol and serum NO level. Furthermore, HFD resulted in significant increase in systolic arterial pressure, diastolic arterial pressure and mean arterial pressure. In addition, morphological studies revealed hepatic steatosis along with swelling of mitochondria and loss of cristae in hepatocyte and periarteritis in aorta. Treatment with AB for 15 days positively modulated the altered parameters in dose-dependent fashion, though maximum effect was seen at 800 mg/kg. These findings suggest that AB guard against cardiometabolic syndrome in HFD fed rats. It attenuates dyslipidemia, hepatic steatosis and associated hypertension by decreasing oxidative stress, TNF-alpha and normalizing NO production. PMID- 21282050 TI - Prognostic assessment in COPD: health related quality of life and the BODE index. AB - RATIONALE: COPD is a debilitating disease with increasing mortality worldwide. The BODE index evaluates disease severity and the St George's Respiratory Questionnaire (SGRQ) measures health status. OBJECTIVE: To identify the relationship between BODE index and the SGRQ and to test the predictive value of both tools against survival. METHODS: Open cohort study of 1398 COPD patients (85% male) followed for up to 10 years. MEASUREMENTS AND MAIN RESULTS: At the time of the inclusion, clinical data, forced spirometry and 6 min walking distance were determined and BODE index and SGRQ were calculated. Vital status and cause of death were documented at the end of follow-up. RESULTS: The cohort's mean of FEV1% predicted was 46 +/- 18%, BODE index was 3.6 +/- 2.5, and SGRQ% total score was 49 +/- 20. The SGRQ scores increased progressively as severity of COPD increased by BODE quartiles. The correlation between SGRQ and BODE index was good (r = 0.58, p < 0.0001). Both tests correlated with COPD survival (BODE = 0.4 vs. SGRQ = -0.20, p < 0.0001). The area under the curve (AUC) for the BODE index was 0.77 vs. 0.66 for the SGRQ % total score (p < 0.001). CONCLUSIONS: Health status as measured by SGRQ worsens with disease severity evaluated by the BODE index. Both tools predict mortality and provide complimentary information in the evaluation of patients with COPD. PMID- 21282051 TI - Nitrocellulose strip array assembled on superhydrophobic surface: an aqueous solution diffusion-localized platform for multianalyte immunogold staining assays. AB - In this paper, an aqueous solution diffusion-localized platform (ASDLP) for multianalyte immunogold staining assays has been developed for the first time by assembling nitrocellulose (NC) strips onto a superhydrophobic polycarbonate (PC) coating with a water contact angle (CA) up to 160 degrees . In the concept-of proof experiments, the ASDLP was used for colorimetric detection of a human IgG model antigen based on the gold-enhanced gold nanoparticle (AuNP) label amplification. The relative concentration of the analyte captured on NC was further quantified by measuring the intensity of staining result with the use of image analysis software. The comparison study demonstrates that the white superhydrophobic PC-based ASDLP can offer preferable advantages over the commonly adopted bulky piece of NC for immunogold staining assays, in terms of the localized antibody immobilization and reagent addition, the minimization of "coffee effect", uniformity of staining results, quantitative analysis and use efficiency of NC. Moreover, the high selectivity of a multiple antibodies immobilized NC strip array for multiple antigens in a single sample has been further demonstrated in the multianalyte immunogold staining assay experiments. PMID- 21282052 TI - The nuts and bolts of ring-translocase structure and mechanism. AB - Ring-shaped, oligomeric translocases are multisubunit enzymes that couple the hydrolysis of Nucleoside TriPhosphates (NTPs) to directed movement along extended biopolymer substrates. These motors help unwind nucleic acid duplexes, unfold protein chains, and shepherd nucleic acids between cellular and/or viral compartments. Substrates are translocated through a central pore formed by a circular array of catalytic subunits. Cycles of nucleotide binding, hydrolysis, and product release help reposition translocation loops in the pore to direct movement. How NTP turnover allosterically induces these conformational changes, and the extent of mechanistic divergence between motor families, remain outstanding problems. This review examines the current models for ring translocase function and highlights the fundamental gaps remaining in our understanding of these molecular machines. PMID- 21282053 TI - Improving anticancer activity and selectivity of camptothecin through conjugation with releasable substance P. AB - Substance P, an 11-residue neuropeptide, can be rapidly internalized through specific interaction with the neurokinin-1 receptor. Therefore, we designed and synthesized the substance P targeted camptothecin (CPT) conjugates via a releasable disulfide carbonate linker. All the conjugates exhibited comparable or stronger cytotoxicity to cancer cells that highly over-express neurokinin-1 receptor than free CPT. More importantly, the selectivity of conjugates was significantly improved compared with CPT. Our results indicated that these conjugates can be promising candidates for new chemotherapeutic drugs. In addition, increasing CPT loading or attachment of CPT to the C-terminal hexapeptide of substance P are useful strategies to enhance the therapeutic efficacy of substance P targeted conjugates. PMID- 21282054 TI - Scaffold oriented synthesis. Part 3: design, synthesis and biological evaluation of novel 5-substituted indazoles as potent and selective kinase inhibitors employing [2+3] cycloadditions. AB - We report the synthesis and biological evaluation of 5-substituted indazoles and amino indazoles as kinase inhibitors. The compounds were synthesized in a parallel synthesis fashion from readily available starting materials employing [2+3] cycloaddition reactions and were evaluated against a panel of kinase assays. Potent inhibitors were identified for numerous kinases such as Rock2, Gsk3beta, Aurora2 and Jak2. PMID- 21282055 TI - Pyrrolo[1,2-f]triazines as JAK2 inhibitors: achieving potency and selectivity for JAK2 over JAK3. AB - SAR studies of pyrrolo[1,2-f]triazines as JAK2 inhibitors is presented. Achieving JAK2 inhibition selectively over JAK3 is discussed. PMID- 21282056 TI - Enhancement of pancreatic lipase inhibitory activity of curcumin by radiolytic transformation. AB - The naturally occurring yellow dietary diarylheptanoid curcumin (1) was converted by gamma-ray to two new gamma-lactones, curculactones A (2) and B (3), as well as four known transformates, erythro-1-(3-methoxy-4-hydroxy-phenyl)-propan-1,2-diol (4), threo-1-(3-methoxy-4-hydroxy-phenyl)-propan-1,2-diol (5), vanillic acid (6), and vanillin (7). The structures of the two new gamma-lactone derivatives were elucidated on the basis of spectroscopic methods. The steroisomeric phenylpropanoids 4 and 5 exhibited significantly enhanced inhibitory activity against pancreatic lipase when compared to parent curcumin. PMID- 21282057 TI - Targeting bacterial biofilms: design of a terpenoid-like library as non-toxic anti-biofilm compounds. AB - A new class of anti-biofilm compounds possessing 1,4-disubstituted-(1H)-1,2,3 triazolic cores was designed. Their efficient synthesis was performed by means of click chemistry through 1,3-dipolar cycloadditions. Two compounds were found to act as specific anti-biofilm agents against a gram negative species. PMID- 21282058 TI - New imidazolidinedione derivatives as antimalarial agents. AB - A series of new N-alky- and N-alkoxy-imidazolidinediones was prepared and assessed for prophylactic and radical curative activities in mouse and Rhesus monkey models. New compounds are generally metabolically stable, weakly active in vitro against Plasmodium falciparum clones (D6 and W2) and in mice infected with Plasmodium berghei sporozoites. Representative compounds 8e and 9c showed good causal prophylactic activity in Rhesus monkeys dosed 30 mg/kg/day for 3 consecutive days by IM, delayed patency for 19-21 days and 54-86 days, respectively, as compared to the untreated control. By oral, 9c showed only marginal activity in causal prophylactic and radical curative tests at 50 mg/kg/day*3 and 30 mg/kg/day*7 plus chloroquine 10 mg/kg for 7 days, respectively. PMID- 21282059 TI - Kinetic and docking studies of phenol-based inhibitors of carbonic anhydrase isoforms I, II, IX and XII evidence a new binding mode within the enzyme active site. AB - Carbonic anhydrases (CAs, EC 4.2.1.1) are inhibited by sulfonamides, inorganic anions, phenols, coumarins (acting as prodrugs) and polyamines. A novel class of CA inhibitors (CAIs), interacting with the CA isozymes I, II (cytosolic) and IX, XII (transmembrane, tumor-associated) in a different manner, is reported here. Kinetic measurements allowed us to identify hydroxy-/methoxy-substituted benzoic acids as well as di-/tri-methoxy benzenes as submicromolar-low micromolar inhibitors of the four CA isozymes. Molecular docking studies of a set of such inhibitors within CA I and II allowed us to understand the inhibition mechanism. This new class of inhibitors binds differently compared to all other classes of inhibitors known to date: they were found between the phenol-binding site and the coumarin-binding site, filling thus the middle of the enzyme cavity. They exploit different interactions with amino acid residues and water molecules from the CA active site compared to other classes of inhibitors, offering the possibility to design CAIs with an interesting inhibition profile compared to the clinically used sulfonamides/sulfamates. PMID- 21282060 TI - Involvement of Deg5 protease in wounding-related disposal of PsbF apoprotein. AB - Deg5 is a serine-type protease peripherally attached to luminal side of thylakoid membrane. Given the lack of knowledge concerning its function homozygous T-DNA insertion line depleted in Deg5 was prepared to study the functional importance of this protease in Arabidopsis thaliana. deg5 mutants displayed a pleiotropic phenotype with regard to fourth whorl leaves of four-weeks old plants. The alterations involved an increased leaf area, reduced leaf thickness, reduced cross-sectional area of palisade mesophyll cells as well as changed chloroplast ultrastructure including lack of signs of entering the senescence phase (e.g. presence of much smaller plastoglobules) and the accumulation of large starch grains at the end of the dark period. It was shown that whereas PsbA, C and F apoproteins of photosystem II reaction center undergo an extensive disappearance in response to a set of brief stresses deg5 mutant was fully resistant to the disappearance of PsbF apoprotein which follows an exposition of leaves to wounding. Our results demonstrate that Deg5 is of seminal importance for normal plant development and degradation of PsbF which occurs following brief wounding. PMID- 21282061 TI - Prediction of regulatory interactions in Arabidopsis using gene-expression data and support vector machines. AB - Identification of regulatory relationships between transcription factors (TFs) and their targets is a central problem in post-genomic biology. In this paper, we apply an approach based on the support vector machine (SVM) and gene-expression data to predict the regulatory interactions in Arabidopsis. A set of 125 experimentally validated TF-target interactions and 750 negative regulatory gene pairs are collected as the training data. Their expression profiles data at 79 experimental conditions are fed to the SVM to perform the prediction. Through the jackknife cross-validation test, we find that the overall prediction accuracy of our approach achieves 88.68%. Our approach could help to widen the understanding of Arabidopsis gene regulatory scheme and may offer a cost-effective alternative to construct the gene regulatory network. PMID- 21282062 TI - In vitro effect of different Na+/K+ ratios on plasma membrane H+ -ATPase activity in maize and sugar beet shoot. AB - Plant growth is impaired primarily by osmotic stress in the first phase of salt stress, whereas Na+ toxicity affects the plant growth mainly in the second phase. Salinity leads to increased Na+/K+ ratio and thus displacement of K+ by Na+ in the plant cell. Relatively higher cytosolic Na+ concentrations may have an effect on the activity of plasma membrane (PM) H+ -ATPase. A decreased PM-H+ -ATPase activity could increase the apoplastic pH. This process could limit the cell-wall extensibility and thus reduce growth according to the acid growth theory. To compare the effect of Na+ on PM H+ -ATPase activity in salt-sensitive maize (Zea mays L.) and salt-resistant sugar beet (Beta vulgaris L.) shoot, PM vesicles were isolated from growing shoots of both species and ATPase activity was determined by assaying the P(i) released by hydrolysis of ATP. The H+ pumping activity was measured as the quenching of acridine-orange absorbance. An increased Na+/K+ ratio decreased the PM H+ -ATPase activity in vesicles of maize as well as of sugar beet shoots. Nevertheless, the detrimental effect of increased Na+/K+ ratio was more severe in salt-sensitive maize compared to salt-resistant sugar beet. At 25 mM Na+ concentration, hydrolytic activity was not affected in sugar beet. However, a significant decrease in hydrolytic activity was observed in maize at pH 7. In maize and sugar beet, reduction in active H+ flux was 20% and 5% at 25 mM Na+ concentration in the assay, respectively. The active H+ flux was decreased to 80% and 60%, when 100 mM K+ were substituted by 100mM Na+. We conclude that PM H+ -ATPases of salt-resistant sugar beet and maize shoot are sensitive to higher concentration of Na+. However, sugar beet PM-H+ -ATPases are relatively efficient and may have constitutive resistance against lower concentration (25 mM) of Na+ as compared to that of salt-sensitive maize. PMID- 21282063 TI - Long-term outcomes and prognostic factors of patients with surgically treated pulmonary carcinoid: our institutional experience with 104 patients. AB - OBJECTIVE: Pulmonary carcinoid tumors are rare low-grade malignant neoplasms and constitute 2-5% of all lung tumors. In this study, we aimed to determine the clinical presentations, types of surgery, long-term treatment outcomes and survival rates of patients diagnosed with carcinoid tumor treated surgically in our clinic. METHODS: Patients operated in our clinic between 1992 and 2008 with confirmed or suspected diagnoses of carcinoid tumors were included in our study. Patients' hospital records were retrospectively analyzed. RESULTS: A total of 104 patients (age 19-71 years, mean 44+/-13 years, 2 SD) with pathologically confirmed carcinoid tumor were analyzed. A total of 84 patients (81%) were diagnosed as typical and the remaining 20 (19%) being atypical carcinoid tumor. As many as 24 patients (23%) were asymptomatic. The most frequent symptom was recurrent respiratory infection (35%). The most used surgical procedures were lobectomy (47%) and bilobectomy (16%). Mean postoperative follow-up period was 72 months (6-190 months). No surgery related mortality was noticed. As many as 15 (14%) patients died during the follow-up period. Overall 5- and 10-year survival rates were 89% and 72%, respectively. For typical carcinoid tumors, the 5- and 10 year survival rates were 92% and 83%, and for atypical carcinoids 73% and 46%, respectively (p<0.001). CONCLUSIONS: In our study, we noticed histological subtype, stage of the disease and the type of surgery performed to be prognostic factors of carcinoid tumors. Atypical carcinoid tumors tend to be more metastatic and had worse prognosis when compared with typical carcinoid tumors. We conclude that surgery is the best treatment of choice for carcinoid tumors, especially parenchyma-sparing procedures, because of their good mid- and long-term survival rates. PMID- 21282064 TI - Outcome prediction in sepsis combined use of genetic polymorphisms - A study in Japanese population. AB - Genetic polymorphisms have recently been found to be related to clinical outcome in septic patients. The present study investigated to evaluate the influence of genetic polymorphisms in Japanese septic patients on clinical outcome and whether use of genetic polymorphisms as predictors would enable more accurate prediction of outcome. Effects of 16 genetic polymorphisms related to pro-inflammatory mediators and conventional demographic/clinical parameters (age, sex, past medical history, and APACHE II score) on ICU mortality as well as disease severity during ICU stay were examined in the septic patients (n=123) admitted to the ICU between October 2001 and November 2007 by multivariable logistic regression analysis. ICU mortality was significantly associated with TNF -308GA, IL1beta -31CT/TT, and APACHE II score. Receiver-operating characteristics (ROC) analysis demonstrated that, compared with APACHE II score alone (ROC-AUC=0.68), use of APACHE II score and two genetic parameters (TNF -308 and IL1beta -31) enabled more accurate prediction of ICU mortality (ROC-AUC=0.80). Significant association of two genetic polymorphisms, TNF -308 and IL1beta -31, with ICU mortality was observed in septic patients. In addition, combined use of these genetic parameters with APACHE II score may enable more accurate prediction of outcome in septic patients. PMID- 21282065 TI - Interpretation of elevated serum VEGF concentrations in patients with myocardial infarction. AB - Serum has been considered an unsuitable medium for measurements of circulating vascular endothelial growth factor (VEGF) since platelets release significant quantities of VEGF during clotting. Nevertheless, the assessment of platelet derived VEGF may be important in patients with acute coronary syndromes characterized by intraluminal thrombosis. The present study aimed at identifying the factors that impact on the interpretation of serum VEGF concentrations in patients with ST-elevation myocardial infarction (STEMI). VEGF was measured in 106 patients with STEMI and correlated with clinical and angiographic parameters. Serum VEGF levels were significantly higher in patients with STEMI than in healthy controls. Although the average number of platelets did not differ between the groups, the patients with STEMI, but not the controls, exhibited a significant correlation between serum VEGF levels and platelet counts. Stratification of patients according to different criteria revealed that VEGF concentrations were particularly elevated shortly (<3h) after the onset of chest pain in those patients who had occluding thrombi graded as large (3-4) on a TIMI scale. These data demonstrate that high levels of serum VEGF detected early in the course of STEMI may derive from activated platelets and may characterize patients with extensive intracoronary thrombosis. PMID- 21282066 TI - Cytokine gene polymorphisms are associated with markers of disease severity and prognosis in patients with idiopathic dilated cardiomyopathy. AB - AIMS: To identify potential genetic associations of five cytokine gene polymorphisms with disease severity and prognosis in patients with idiopathic dilated cardiomyopathy (DCM). METHODS AND RESULTS: Eighty patients with DCM were genotyped for transforming growth factor beta1 (TGF-beta1)+869 T/C (codon10 Leu >Pro), TGF-beta1 +915 G/C (codon25 Arg->Pro), interleukin (IL)-6 -174G/C, tumor necrosis factor-alpha (TNF-alpha) -308A/G, interferon-gamma (IFN-gamma) +874T/A, IL-10 -1082A/G, IL-10 -819T/C and IL-10 -592A/C gene polymorphisms. In homozygous TT patients for TGF-beta1 +869 T/C polymorphism mean VO(2) max was significantly higher than in CC homozygous patients (25.67+/-6.73ml/kg/min vs. 20.29+/-6.35 ml/kg/min, p = 0.046), which remained significant only for patients younger than 39 years old after adjusting for age and sex (p = 0.009). C carriers of TGF-beta1 +915 G/C polymorphism are 4.2 times more likely to be in a worse NYHA stage (III IV) than non C carriers [OR: 4.25, 95% CI (1.53-11.80), p = 0.006]. Patients GG homozygous for IL-6 -174G/C polymorphism presented greater left ventricle end systolic (p = 0.018) and end-diastolic (p = 0.04) diameters in comparison to the CC homozygous. The AA homozygote for IFN-gamma +874T/A polymorphism (p = 0.02) and the combination of the TGF-beta1 +869 T/C and TGF-beta1 +915 G/C genotypes were associated with adverse outcome (p = 0.014). CONCLUSION: Specific cytokine gene polymorphisms seem to be associated with worse prognosis as well as with measures of disease severity in DCM. PMID- 21282067 TI - Retrograde memory in cerebrovascular disease and Alzheimer's disease. AB - Retrograde memory is frequently tested in the mental status examination of patients with stroke or degenerative dementia. The goal of this experiment was to compare gradients of retrograde memory in patients without neurologic disease (n = 26), patients with cerebrovascular disease (n = 43), and patients with probable Alzheimer's disease (n = 27). Patients were asked to recall and then name photographs of the 6 most recent US presidents. The free recall of patients with both cerebrovascular disease and probable Alzheimer's disease formed an exaggeration of the normal forgetting curve seen in control patients, in that the most recent presidents were most likely to be remembered. For photo naming, control patients showed essentially no forgetting, whereas patients with cerebrovascular disease or Alzheimer's disease had substantial memory loss with no temporal gradient. Alzheimer's disease caused significantly worse retrograde memory loss than did cerebrovascular disease, despite the two groups' equivalence in global intellectual functioning. Consistent with the focal or multifocal nature of cerebrovascular disease, stepwise multiple regression of retrograde memory on neuropsychological testing indicated that producing names by free recall was predicted by aphasic deficits, and that photo naming was predicted by visuoperceptual deficits. In Alzheimer's disease, free recall was predicted primarily by deficits in verbal new learning, consistent with amnesia, whereas photo naming was predicted by loss of general knowledge, consistent with dementia. The results are consistent with the idea that free recall of names from the past is a form of episodic memory, whereas naming of famous faces from the past is a form of semantic memory. PMID- 21282068 TI - Therapeutic benefit of intravenous transplantation of mesenchymal stem cells after experimental subarachnoid hemorrhage in rats. AB - BACKGROUND: Subarachnoid hemorrhage (SAH) usually occurs when an aneurysm ruptures and bleeds into the subarachnoid space. However, no information is available regarding the therapeutic potency of transplanted mesenchymal stem cells (MSCs) for SAH. Therefore, our aim was to investigate whether MSC transplantation therapy may cause stem cell activation and improve neurologic functional recovery after induction of SAH. METHODS: Female rats were divided into 2 groups of SAH plus phosphate-buffered saline (PBS; control) and SAH plus MSCs (experimental). Both control and experimental groups received PBS or injection of 3 * 10(6) male rat MSCs labeled with bromodeoxyuridine (BrdU) into the tail vein 24 hours after SAH. All animals were killed 14 days after SAH. A behavioral test (Neurological Severity Score) was performed at 1, 7, and 14 days after SAH. Immunohistochemistry was used to identify MSCs and the cells derived from MSCs in brains with SAH. Terminal deoxynucleotidyltransferase mediated dUTP biotin nick-end labeling was used to identify apoptotic cells. RESULTS: Significant functional recovery (P < .05) was found in SAH animals infused with MSCs compared with other rats. Significantly more BrdU-positive cells were located in the parietal lobe of MSC-treated than in PBS-treated animals. MSCs were also seen to differentiate into glial cells (GFAP), neurons (Neu-N), and endothelial cells (vWF), thereby enhancing neuroplastic effects in the injured brain. Significantly fewer apoptotic cells were found in insulted cerebral tissue in SAH plus MSC rats when compared with other groups. CONCLUSIONS: Intravenously transplanted MSCs improve functional recovery, reduce apoptosis, and enhance neuroplastic effects after SAH in animal models. This is a promising novel procedure to repair central nervous system damage after SAH, and may provide a new way to induce plasticity in the injured brain cells. PMID- 21282069 TI - Interictal paroxysmal EEG abnormalities in childhood absence epilepsy. AB - The aim of this study is to analyze the graphic features and the clinical significance of the focal interictal paroxysmal abnormalities (FIPA) which can be found in the EEG of patients with typical absences, on the basis of 29 personal cases. The children (15 female; mean age at the first evaluation=8.2 years, range 4.8-14.3 years) were particularly selected, because they only showed absence seizures. In all subjects the ictal clinical and EEG features were typical for childhood absence epilepsy (CAE). The interictal EEG showed a normal background activity in all children and in 11 patients the presence of FIPA specially on frontal areas. The graphic aspects of FIPA and their spatial and temporal variability, often in the same subject, were in agreement with a functional form. Furthermore the excellent response to valproic acid and ethosuximide, with a complete seizure control also in the follow-up in 26 among 28 treated children, confirms the opinion that our cases are affected by a typical form of CAE. In conclusion FIPA probably are not uncommon in typical idiopathic CAE and their presence does not seem to change the benign prognosis. There is a relationship between our data and the experimental models proposed in the literature. PMID- 21282070 TI - Activation of AKT in feline mammary carcinoma: a new prognostic factor for feline mammary tumours. AB - The PI3K/AKT/PTEN pathway is involved in the pathogenesis of several human cancers. This study investigated the biological and prognostic value of PI3K/AKT/PTEN pathway dysregulation in feline mammary tumours. Expression of p AKT, HER2, PTEN and steroid receptors was assessed by immunohistochemistry (IHC) in 27 malignant and 12 benign mammary tumours from 39 female cats followed up over a 24-month period. Feline mammary carcinoma (FMC) cell lines were analyzed by Western blot and the feline AKT gene sequence was characterized. p-AKT expression statistically correlated with tumour malignancy, histological dedifferentiation and clinical recurrence. The animals with tumours expressing p AKT had a shorter disease-free period than those with p-AKT-negative tumours. AKT activation was associated with HER2 expression and PTEN down-regulation, as occurs in human breast cancer, and feline AKT sequencing showed high homology with the human AKT gene. No AKT activation was observed in relation to either oestrogen receptor alpha (ERalpha) or progesterone receptor expression. Taken together, these data offer an explanation for AKT signalling and its role in FMC pathogenesis and prognosis, shedding new light on similarities between feline mammary tumours and hormone-independent breast cancer. PMID- 21282071 TI - 'Omics' of natural products and redox biology. PMID- 21282072 TI - Biophysical probes of iron metabolism in cells and organelles. AB - In living systems, iron is found in many different structures, including Fe/S clusters, hemes and nonheme centers, and magnetically interacting aggregates. Understanding Fe metabolism and trafficking will require biophysical spectroscopic tools that can evaluate the types of Fe centers within entire cells and isolated organelles. Mossbauer spectroscopy will play an important role in such analyses, as it has perhaps the best combination of resolution, sensitivity, coverage, and quantifying abilities. Other spectroscopic techniques, with particular strengths, will be used in combination with Mossbauer, and results will be integrated to assess the 'ironome' of such complex samples. This integrative biophysical approach is illustrated by a discussion of iron trafficking in yeast cells. PMID- 21282073 TI - Early ictal face wiping in frontal lobe epilepsy. AB - We describe two patients with medication-resistant nonlesional mesial frontal lobe epilepsy and seizures that manifested with early face wiping prior to other motor phenomena. Ictal scalp monitoring either was nonlocalizing or involved the central regions. Intracranial monitoring demonstrated anterior mesial frontal ictal low-voltage gamma activity during the face wiping activity in both patients. Habitual seizures with the same clinical characteristics were induced during extraoperative functional mapping with stimulation of the same region. Ictal activation of mesial frontal regions can elicit early ictal face wiping activity, and this clinical sign may play a role in presurgical evaluation. PMID- 21282074 TI - Transforming cerebrospinal fluid Abeta42 measures into calculated Pittsburgh Compound B units of brain Abeta amyloid. AB - BACKGROUND: Positron-emission tomography (PET) imaging of amyloid with Pittsburgh Compound B (PIB) and Abeta42 levels in the cerebrospinal fluid (CSF Abeta42) demonstrate a highly significant inverse correlation. Both these techniques are presumed to measure brain Abeta amyloid load. The objectives of this study were to develop a method to transform CSF Abeta42 measures into calculated PIB measures (PIBcalc) of Abeta amyloid load, and to partially validate the method in an independent sample of subjects. METHODS: In all, 41 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) underwent PIB PET imaging and lumbar puncture (LP) at the same time. This sample, referred to as the "training" sample (nine cognitively normal subjects, 22 subjects with mild cognitive impairment, and 10 subjects with Alzheimer's disease), was used to develop a regression model by which CSF Abeta42 (with apolipoprotein E E4 carrier status as a covariate) was transformed into units of PIB PET (PIBcalc). An independent "supporting" sample of 362 ADNI subjects (105 cognitively normal subjects, 164 subjects with mild cognitive impairment, and 93 subjects with Alzheimer's disease) who underwent LP but not PIB PET imaging had their CSF Abeta42 values converted to PIBcalc. These values were compared with the overall PIB PET distribution found in the ADNI subjects (n=102). RESULTS: A linear regression model demonstrates good prediction of actual PIB PET from CSF Abeta42 measures obtained in the training sample (R(2)=0.77, P<.001). PIBcalc data (derived from CSF Abeta42) in the supporting sample of 362 ADNI subjects who underwent LP but not PIB PET imaging demonstrate group-wise distributions that are highly consistent with the larger ADNI PIB PET distribution and with published PIB PET imaging studies. CONCLUSION: Although the precise parameters of this model are specific for the ADNI sample, we conclude that CSF Abeta42 can be transformed into PIBcalc measures of Abeta amyloid load. Brain Abeta amyloid load can be ascertained at baseline in therapeutic or observational studies by either CSF or amyloid PET imaging and the data can be pooled using well-established multiple imputation techniques that account for the uncertainty in a CSF-based PIBcalc value. PMID- 21282075 TI - Confirmation of Essure placement using transvaginal ultrasound. AB - STUDY OBJECTIVE: To evaluate the protocol for confirmation of satisfactory Essure placement using transvaginal ultrasound. DESIGN: Prospective multicenter cohort study (Canadian Task Force classification II-2). SETTING: Outpatient departments of 4 teaching hospitals in the Netherlands. PATIENTS: Eleven hundred forty-five women who underwent hysteroscopic sterilization using the Essure device between March 2005 and December 2007. INTERVENTION: Transvaginal ultrasound examination 12 weeks after uncomplicated successful bilateral placement or as indicated according to the transvaginal ultrasound protocol after 4 weeks, and hysterosalpingography (HSG) at 12 weeks to confirm correct placement of the device after 3 months. MEASUREMENTS AND MAIN RESULTS: The rate of successful placement was 88.4% initially. In 164 women (15%), successful placement was confirmed at HSG according the protocol. In 9 patients (0.84%), incorrect position of the device was observed at HSG. The cumulative pregnancy rate after 18 months was 3.85 per thousand women. CONCLUSION: Transvaginal ultrasound should be the first diagnostic test used to confirm the adequacy of hysteroscopic Essure sterilization because it is minimally invasive, averts ionizing radiation, and does not decrease the effectiveness of the Essure procedure. PMID- 21282076 TI - Simultaneous bioanalysis of L-arginine, L-citrulline, and dimethylarginines by LC MS/MS. AB - PURPOSE: L-Arginine (ARG) is converted to nitric oxide (NO) and L-citrulline (CIT) by endothelial nitric oxide synthase which is competitively inhibited by asymmetric dimethylarginine (ADMA). We have developed a liquid chromatography mass spectrometric method for the simultaneous determination of endogenous ARG, labeled ARG (15N4-ARG), CIT, ADMA, and its inactive isomer, symmetric dimethylarginine (SDMA) in biological samples. METHODS: Concentrations of unlabeled ARG, 15N4-ARG, CIT, ADMA, and SDMA in EA.hy926 human endothelial cell lysate, cell incubation media, rat plasma or rat urine were measured by hydrophilic-interaction liquid chromatography electrospray tandem mass spectrometry. 13C6-ARG, D4-CIT and D7-ADMA were used as internal standards for ARG and 15N4-ARG, CIT, and dimethylarginines, respectively. RESULTS: The calibration curves of ARG, 15N4-ARG, CIT, ADMA, and SDMA were linear and independent of several sample matrices. Intra- and inter-day variabilities for the quantification of all the compounds were below 15% in quality control samples. Application of this method to determine the uptake as well as efflux of these compounds was illustrated through in vitro cell study by exposing human endothelial cells to 15N4-ARG, which allowed the observation of generation of 15N3-CIT and 15N3-ARG in the cell lyate. Use of these isotopes adds insights into the cellular handling of endogenous vs. exogenous ARG. Application of this method for rat plasma and rat urine assays was demonstrated after ARG oral supplementation in rats. CONCLUSION: An LC-MS/MS method was developed to quantify 6 ARG-related compounds simultaneously, utilizing 3 separate internal standards. This assay allows concurrent monitoring of uptake, efflux and metabolic processes when isotope-labeled ARG and CIT are measured, and can be applied for determination of these compounds in rat plasma and rat urine. PMID- 21282077 TI - Secondary shoulder reconstruction in patients with brachial plexus injuries. AB - Restoration of shoulder stability in post-traumatic plexopathy patients is very important because more distal functions depend on a stable and functioning shoulder. The purpose of this study is to present our experience with secondary surgeries in patients with devastating paralysis. Functional outcomes were analyzed in relation to age, severity score and type of reconstruction. The medical records of 55 post-traumatic plexopathy patients who underwent secondary shoulder reconstruction, by a single surgeon, between 1978 and 2006, were reviewed. 55 patients had 73 procedures, 44 for shoulder abduction and 29 for external rotation. 38 patients underwent secondary surgery to augment shoulder abduction. Trapezius advancement was performed in 14 patients, double free muscle transfer in 18, free latissimus dorsi in 4 and triceps muscle transfer in 2 patients. 26 patients had secondary procedures for enhancement of shoulder external rotation. Dynamic rerouting of latissimus dorsi and teres major was carried out in 18 patients and rotational humerus osteotomy in 11 patients. All patients had improvement of shoulder stability and function. Shoulder abduction reached 40.80 +/- 15.93 and external rotation at 24.28 +/- 17.90 degrees . Trapezius advancement yielded 41.81 +/- 9.02 degrees of abduction. Latissimus dorsi yielded stronger shoulder abduction than adductor longus. Rerouting of latissimus dorsi and teres major attained 22.33 +/- 20.31 degrees of dynamic external rotation while humerus osteotomy produced 26.87 +/- 10.32 of external rotation. Secondary procedures such as pedicle and free muscles transfers, tendon transfers, and rotational humerus osteotomy augment shoulder stability and function in patients with irreparable paralysis. PMID- 21282078 TI - Bracketing off population does not advance ethical reflection on EVCs: a reply to Kayser and Schneider. PMID- 21282079 TI - Genetic variation of 15 autosomal STR loci in various populations from southern Africa. PMID- 21282080 TI - Population genetics polymorphisms on 17 autosomal STRs from Chinese Bai ethnic minority group. PMID- 21282081 TI - Polly Arango: a remembrance. PMID- 21282082 TI - Caring for children with special needs: historical perspective. PMID- 21282083 TI - The APA and the rise of pediatric generalist network research. AB - The Academic Pediatric Association (APA, formerly the Ambulatory Pediatric Association) first encouraged multi-institutional collaborative research among its members over 30 years ago. Individual APA members subsequently went on to figure prominently in establishing formal research networks. These enduring collaborations have been established to conduct investigations in a variety of generalist contexts. At present, 4 generalist networks--Pediatric Research in Office Settings (PROS), the Pediatric Emergency Care Applied Research Network (PECARN), the COntinuity Research NETwork (CORNET), and Pediatric Research in Inpatient Settings (PRIS)--have a track record of extensive achievement in generating new knowledge aimed at improving the health and health care of children. This review details the history, accomplishments, and future directions of these networks and summarizes the common themes, strengths, challenges, and opportunities inherent in pediatric generalist network research. PMID- 21282084 TI - Integrity matters: recapturing the relevance of general academic pediatrics. PMID- 21282085 TI - Family-centered care. PMID- 21282086 TI - From my head and my heart: improving quality of care for children and youth with special health care needs. PMID- 21282087 TI - Coordination of Golgi functions by phosphatidylinositol 4-kinases. AB - Phosphatidylinositol 4-kinases (PI4Ks) regulate vesicle-mediated export from the Golgi apparatus via phosphatidylinositol 4-phosphate (PtdIns4P) binding effector proteins that control vesicle budding reactions and regulate membrane dynamics. Evidence has emerged from the characterization of Golgi PI4K effectors that vesicle budding and lipid dynamics are tightly coupled via a regulatory network that ensures that the appropriate membrane composition is established before a transport vesicle buds from the Golgi. An important hub of this network is protein kinase D, which regulates the activity of PI4K and several PtdIns4P effectors that control sphingolipid and sterol content of Golgi membranes. Other newly identified PtdIns4P effectors include Vps74/GOLPH3, a phospholipid flippase called Drs2 and Sec2, a Rab guanine nucleotide exchange factor (GEF). These effectors orchestrate membrane transformation events facilitating vesicle formation and targeting. In this review, we discuss how PtdIns4P signaling is integrated with membrane biosynthetic and vesicle budding machineries to potentially coordinate these crucial functions of the Golgi apparatus. PMID- 21282088 TI - Cannabis and skin diseases. AB - From time out of mind, man has grown hemp for both "industrial" and "recreational" use (it is then referred to as cannabis). Of course, cannabis has strong psychoactive properties and is one of the most commonly used "soft drugs" in the world. Clinicians should know the adverse effects on mucous membranes and on skin, which may sometimes entail an absolutely necessary stopping of consumption. Raynaud's phenomenon, as well as arteritis due to cannabis consumption may be extremely severe and result in worrying situations for both clinicians and patients. PMID- 21282089 TI - [The role of interval surgery in the treatment's strategy of advanced ovarian cancer]. AB - The extent of cytoreductive surgery and the amount of residual disease are among the most important factors impacting the survival of women with advanced ovarian cancer. Chronology of treatment is still debating. In the French standard treatment, primary surgery remains the cornerstone and interval surgery is an option. Neoadjuvant chemotherapy followed by surgery may reduce morbidity and mortality. Nevertheless the impact of this strategy on survival is still controversial. PMID- 21282090 TI - Leukocytoclastic vasculitis with eosinophilic infiltration in an HIV-positive patient. PMID- 21282091 TI - Clinical improvement of pityriasis rubra pilaris with antibiotic therapy. PMID- 21282092 TI - Oral erosive lichen planus and alopecia areata with Good's syndrome (thymoma with hypogammaglobulinemia). PMID- 21282093 TI - Pancytopaenia secondary to bone marrow dissemination of Merkel cell carcinoma in a patient with Waldenstrom macroglobulinaemia. PMID- 21282094 TI - Treatment of verruca vulgaris using the ultrasonic surgical aspirator. PMID- 21282095 TI - Lipedematous scalp with heterochromia of scalp hair in a boy. PMID- 21282096 TI - Flagellate pigmentation: a unique adverse effect of bleomycin therapy. PMID- 21282097 TI - [Sociological perspectives on the management of TB/HIV co-infection in Burkina Faso]. AB - In Burkina Faso, the management of TB/HIV co-infection presents a challenge for policy-makers and the health-care system, with its psychological, sociocultural and biomedical issues. The purpose of this paper is to describe the concerns caused by this co-infection and propose a management strategy for these patients. These findings result from a qualitative socio-anthropological study during a public health project in three health districts from 2006 to 2008 and from the observation of care practices in health centres. Patients face a double burden: the negative social image of both diseases and complicated difficult treatment. They deal with problems of social integration, with their social relations impaired by humiliation and marginalisation. The painful experience of daily doses of antiretroviral and anti-TB drugs creates bitterness against drugs, aggravated sometimes by apparently capricious care. In addition to economic insecurity, these chronically ill patients face social stigma and marginalisation, all damaging to their self-esteem. PMID- 21282098 TI - Wikipedia: a key tool for global public health promotion. AB - The Internet has become an important health information resource for patients and the general public. Wikipedia, a collaboratively written Web-based encyclopedia, has become the dominant online reference work. It is usually among the top results of search engine queries, including when medical information is sought. Since April 2004, editors have formed a group called WikiProject Medicine to coordinate and discuss the English-language Wikipedia's medical content. This paper, written by members of the WikiProject Medicine, discusses the intricacies, strengths, and weaknesses of Wikipedia as a source of health information and compares it with other medical wikis. Medical professionals, their societies, patient groups, and institutions can help improve Wikipedia's health-related entries. Several examples of partnerships already show that there is enthusiasm to strengthen Wikipedia's biomedical content. Given its unique global reach, we believe its possibilities for use as a tool for worldwide health promotion are underestimated. We invite the medical community to join in editing Wikipedia, with the goal of providing people with free access to reliable, understandable, and up-to-date health information. PMID- 21282100 TI - Tyrosine latching of a regulatory gate affords allosteric control of aromatic amino acid biosynthesis. AB - The first step of the shikimate pathway for aromatic amino acid biosynthesis is catalyzed by 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase (DAH7PS). Thermotoga maritima DAH7PS (TmaDAH7PS) is tetrameric, with monomer units comprised of a core catalytic (beta/alpha)(8) barrel and an N-terminal domain. This enzyme is inhibited strongly by tyrosine and to a lesser extent by the presence of phenylalanine. A truncated mutant of TmaDAH7PS lacking the N-terminal domain was catalytically more active and completely insensitive to tyrosine and phenylalanine, consistent with a role for this domain in allosteric inhibition. The structure of this protein was determined to 2.0 A. In contrast to the wild type enzyme, this enzyme is dimeric. Wild-type TmaDAH7PS was co-crystallized with tyrosine, and the structure of this complex was determined to a resolution of 2.35 A. Tyrosine was found to bind at the interface between two regulatory N terminal domains, formed from diagonally located monomers of the tetramer, revealing a major reorganization of the regulatory domain with respect to the barrel relative to unliganded enzyme. This significant conformational rearrangement observed in the crystal structures was also clearly evident from small angle X-ray scattering measurements recorded in the presence and absence of tyrosine. The closed conformation adopted by the protein on tyrosine binding impedes substrate entry into the neighboring barrel, revealing an unusual tyrosine-controlled gating mechanism for allosteric control of this enzyme. PMID- 21282101 TI - ChREBP mediates glucose repression of peroxisome proliferator-activated receptor alpha expression in pancreatic beta-cells. AB - Chronic exposure to elevated levels of glucose and fatty acids leads to dysfunction of pancreatic beta-cells by mechanisms that are only partly understood. The transcription factor peroxisome proliferator-activated receptor alpha (PPARalpha) is an important regulator of genes involved in fatty acid metabolism and has been shown to protect against lipid-induced beta-cell dysfunction. We and others have previously shown that expression of the PPARalpha gene in beta-cells is rapidly repressed by glucose. Here we show that the PPARalpha gene is transcribed from five alternative transcription start sites, resulting in three alternative first exons that are spliced to exon 2. Expression of all PPARalpha transcripts is repressed by glucose both in insulinoma cells and in isolated pancreatic islets. The observation that the dynamics of glucose repression of PPARalpha transcription are very similar to those of glucose activation of target genes by the carbohydrate response element-binding protein (ChREBP) prompted us to investigate the potential role of ChREBP in the regulation of PPARalpha expression. We show that a constitutively active ChREBP lacking the N-terminal domain efficiently represses PPARalpha expression in insulinoma cells and in rodent and human islets. In addition, we demonstrate that siRNA-mediated knockdown of ChREBP abrogates glucose repression of PPARalpha expression as well as induction of well established ChREBP target genes in insulinoma cells. In conclusion, this work shows that ChREBP is a critical and direct mediator of glucose repression of PPARalpha gene expression in pancreatic beta-cells, suggesting that ChREBP may be important for glucose suppression of the fatty acid oxidation capacity of beta-cells. PMID- 21282102 TI - Energy restriction-mimetic agents induce apoptosis in prostate cancer cells in part through epigenetic activation of KLF6 tumor suppressor gene expression. AB - Although energy restriction has been recognized as an important target for cancer prevention, the mechanism by which energy restriction-mimetic agents (ERMAs) mediate apoptosis remains unclear. By using a novel thiazolidinedione-derived ERMA, CG-12 (Wei, S., Kulp, S. K., and Chen, C. S. (2010) J. Biol. Chem. 285, 9780-9791), vis-a-vis 2-deoxyglucose and glucose deprivation, we obtain evidence that epigenetic activation of the tumor suppressor gene Kruppel-like factor 6 (KLF6) plays a role in ERMA-induced apoptosis in LNCaP prostate cancer cells. KLF6 regulates the expression of many proapoptotic genes, and shRNA-mediated KLF6 knockdown abrogated the ability of ERMAs to induce apoptosis. Chromatin immunoprecipitation analysis indicates that this KLF6 transcriptional activation was associated with increased histone H3 acetylation and histone H3 lysine 4 trimethylation occupancy at the promoter region. Several lines of evidence demonstrate that the enhancing effect of ERMAs on these active histone marks was mediated through transcriptional repression of histone deacetylases and H3 lysine 4 demethylases by down-regulating Sp1 expression. First, putative Sp1-binding elements are present in the promoters of the affected histone-modifying enzymes, and luciferase reporter assays indicate that site-directed mutagenesis of these Sp1 binding sites significantly diminished the promoter activities. Second, shRNA mediated knockdown of Sp1 mimicked the repressive effect of energy restriction on these histone-modifying enzymes. Third, ectopic Sp1 expression protected cells from the repressive effect of CG-12 on these histone-modifying enzymes, thereby abolishing the activation of KLF6 expression. Together, these findings underscore the intricate relationship between energy restriction and epigenetic regulation of tumor suppressor gene expression, which has therapeutic relevance to foster novel strategies for prostate cancer therapy. PMID- 21282103 TI - A genome-wide chromatin-associated nuclear peroxiredoxin from the malaria parasite Plasmodium falciparum. AB - Malaria parasites are subjected to high levels of oxidative stress during their development inside erythrocytes and the ability of the parasite to defend itself against this assault is critical to its survival. Therefore, Plasmodium possesses an effective antioxidant defense system that could potentially be used as a target for the development of inhibitor-based therapy. We have identified an unusual peroxiredoxin protein that localizes to the nucleus of Plasmodium falciparum and have renamed it PfnPrx (PF10_0268, earlier called MCP1). Our work reveals that PfnPrx has a broad specificity of substrate being able to utilize thioredoxin and glutaredoxin as reductants and having the ability to reduce simple and complex peroxides. Intriguingly, chromatin immunoprecipitation followed by deep sequencing reveals that the enzyme associates with chromatin in a genome-wide manner with a slight enrichment in coding regions. Our results represent the first description of a dedicated chromatin-associated peroxiredoxin and potentially represent an ingenious way by which the parasite can survive the highly oxidative environment within its human host. PMID- 21282104 TI - N-terminal glutamate to pyroglutamate conversion in vivo for human IgG2 antibodies. AB - Therapeutic proteins contain a large number of post-translational modifications, some of which could potentially impact their safety or efficacy. In one of these changes, pyroglutamate can form on the N terminus of the polypeptide chain. Both glutamine and glutamate at the N termini of recombinant monoclonal antibodies can cyclize spontaneously to pyroglutamate (pE) in vitro. Glutamate conversion to pyroglutamate occurs more slowly than from glutamine but has been observed under near physiological conditions. Here we investigated to what extent human IgG2 N terminal glutamate converts to pE in vivo. Pyroglutamate levels increased over time after injection into humans, with the rate of formation differing between polypeptide chains. These changes were replicated for the same antibodies in vitro under physiological pH and temperature conditions, indicating that the changes observed in vivo were due to chemical conversion not differential clearance. Differences in the conversion rates between the light chain and heavy chain on an antibody were eliminated by denaturing the protein, revealing that structural elements affect pE formation rates. By enzymatically releasing pE from endogenous antibodies isolated from human serum, we could estimate the naturally occurring levels of this post-translational modification. Together, these techniques and results can be used to predict the exposure of pE for therapeutic antibodies and to guide criticality assessments for this attribute. PMID- 21282105 TI - Minocycline suppresses activation of nuclear factor of activated T cells 1 (NFAT1) in human CD4+ T cells. AB - Minocycline is a tetracycline family antibiotic that has anti-inflammatory and immunomodulatory properties. These properties have shown promise in the treatment of conditions such as rheumatoid arthritis, Huntington disease, and multiple sclerosis. As lymphocyte activation is involved in the pathogenesis of many of these diseases, T cells are postulated to be a primary target in minocycline therapy. Previous studies have demonstrated attenuation of CD4(+) T cell activation by minocycline, but a specific mechanism has not been elucidated. In this study, we investigated the effect of minocycline on the activity of three key transcription factors regulating CD4(+) T cell activation: NF-kappaB, AP-1 (activator protein 1), and NFAT (nuclear factor of activated T) cells. Our data demonstrate that minocycline selectively impairs NFAT-mediated transcriptional activation, a result of increased phosphorylation and reduced nuclear translocation of the isoform NFAT1. Minocycline increased the activity of the NFAT kinase GSK3 and decreased intracellular Ca(2+) flux, both of which facilitate NFAT1 phosphorylation. These findings provide a novel mechanism for minocycline induced suppression of CD4(+) T cell activation and may better inform the application of minocycline as an immunomodulatory agent. PMID- 21282106 TI - Elevated miR-155 promotes inflammation in cystic fibrosis by driving hyperexpression of interleukin-8. AB - Cystic Fibrosis (CF) is characterized by a massive proinflammatory phenotype in the lung arising from profound expression of inflammatory genes, including interleukin-8 (IL-8). We have previously reported that IL-8 mRNA is stabilized in CF lung epithelial cells, resulting in concomitant hyperexpression of IL-8 protein. However, the mechanistic link between mutations in CFTR and acquisition of the proinflammatory phenotype in the CF airway has remained elusive. We hypothesized that specific microRNAs (miRNAs) might mediate this linkage. To identify the potential link, we screened an miRNA library for differential expression in DeltaF508-CFTR and wild type CFTR lung epithelial cell lines. Of 22 differentially and significantly expressed miRNAs, we found that expression of miR-155 was more than 5-fold elevated in CF IB3-1 lung epithelial cells in culture, compared with control IB3-1/S9 cells. Clinically, miR-155 was also highly expressed in CF lung epithelial cells and circulating CF neutrophils biopsied from CF patients. We report here that high levels of miR-155 specifically reduced levels of SHIP1, thereby promoting PI3K/Akt activation. However, overexpressing SHIP1 or inhibition of PI3K in CF cells suppressed IL-8 expression. Finally, we found that phospho-Akt levels were elevated in CF lung epithelial cells and were specifically lowered by either antagomir-155 or elevated expression of SHIP1. We therefore suggest that elevated miR-155 contributes to the proinflammatory expression of IL-8 in CF lung epithelial cells by lowering SHIP1 expression and thereby activating the PI3K/Akt signaling pathway. These data suggest that miR-155 may play an important role in the activation of IL-8-dependent inflammation in CF. PMID- 21282107 TI - Extracellular hepatitis C virus core protein activates STAT3 in human monocytes/macrophages/dendritic cells via an IL-6 autocrine pathway. AB - Hepatitis C virus (HCV) infection is highly efficient in the establishment of persistent infection, which leads to the development of chronic liver disease and hepatocellular carcinoma. Impaired T cell responses with reduced IFN-gamma production have been reported to be associated with persistent HCV infection. Extracellular HCV core is a viral factor known to cause HCV-induced T cell impairment via its suppressive effect on the activation and induction of pro inflammatory responses by antigen-presenting cells (APCs). The activation of STAT proteins has been reported to regulate the inflammatory responses and differentiation of APCs. To further characterize the molecular basis for the regulation of APC function by extracellular HCV core, we examined the ability of extracellular HCV core to activate STAT family members (STAT1, -2, -3, -5, and 6). In this study, we report the activation of STAT3 on human monocytes, macrophages, and dendritic cells following treatment with extracellular HCV core as well as treatment with a gC1qR agonistic monoclonal antibody. Importantly, HCV core-induced STAT3 activation is dependent on the activation of the PI3K/Akt pathway. In addition, the production of multifunctional cytokine IL-6 is essential for HCV core-induced STAT3 activation. These results suggest that HCV core-induced STAT3 activation plays a critical role in the alteration of inflammatory responses by APCs, leading to impaired anti-viral T cell responses during HCV infection. PMID- 21282108 TI - Time-resolved fluorescence resonance energy transfer (TR-FRET) to analyze the disruption of EGFR/HER2 dimers: a new method to evaluate the efficiency of targeted therapy using monoclonal antibodies. AB - In oncology, simultaneous inhibition of epidermal growth factor receptor (EGFR) and HER2 by monoclonal antibodies (mAbs) is an efficient therapeutic strategy but the underlying mechanisms are not fully understood. Here, we describe a time resolved fluorescence resonance energy transfer (TR-FRET) method to quantify EGFR/HER2 heterodimers on cell surface to shed some light on the mechanism of such therapies. First, we tested this antibody-based TR-FRET assay in NIH/3T3 cell lines that express EGFR and/or HER2 and in various tumor cell lines. Then, we used the antibody-based TR-FRET assay to evaluate in vitro the effect of different targeted therapies on EGFR/HER2 heterodimers in the ovarian carcinoma cell line SKOV-3. A simultaneous incubation with Cetuximab (anti-EGFR) and Trastuzumab (anti-HER2) disturbed EGFR/HER2 heterodimers resulting in a 72% reduction. Cetuximab, Trastuzumab or Pertuzumab (anti-HER2) alone induced a 48, 44, or 24% reduction, respectively. In contrast, the tyrosine kinase inhibitors Erlotinib and Lapatinib had very little effect on EGFR/HER2 dimers concentration. In vivo, the combination of Cetuximab and Trastuzumab showed a better therapeutic effect (median survival and percentage of tumor-free mice) than the single mAbs. These results suggest a correlation between the extent of the mAb-induced EGFR/HER2 heterodimer reduction and the efficacy of such mAbs in targeted therapies. In conclusion, quantifying EGFR/HER2 heterodimers using our antibody based TR-FRET assay may represent a useful method to predict the efficacy and explain the mechanisms of action of therapeutic mAbs, in addition to other commonly used techniques that focus on antibody-dependent cellular cytotoxicity, phosphorylation, and cell proliferation. PMID- 21282110 TI - Cellobiohydrolase hydrolyzes crystalline cellulose on hydrophobic faces. AB - Biodegradation of plant biomass is a slow process in nature, and hydrolysis of cellulose is also widely considered to be a rate-limiting step in the proposed industrial process of converting lignocellulosic materials to biofuels. It is generally known that a team of enzymes including endo- and exocellulases as well as cellobiases are required to act synergistically to hydrolyze cellulose to glucose. The detailed molecular mechanisms of these enzymes have yet to be convincingly elucidated. In this report, atomic force microscopy (AFM) is used to image in real-time the structural changes in Valonia cellulose crystals acted upon by the exocellulase cellobiohydrolase I (CBH I) from Trichoderma reesei. Under AFM, single enzyme molecules could be observed binding only to one face of the cellulose crystal, apparently the hydrophobic face. The surface roughness of cellulose began increasing after adding CBH I, and the overall size of cellulose crystals decreased during an 11-h period. Interestingly, this size reduction apparently occurred only in the width of the crystal, whereas the height remained relatively constant. In addition, the measured cross-section shape of cellulose crystal changed from asymmetric to nearly symmetric. These observed changes brought about by CBH I action may constitute the first direct visualization supporting the idea that the exocellulase selectively hydrolyzes the hydrophobic faces of cellulose. The limited accessibility of the hydrophobic faces in native cellulose may contribute significantly to the rate-limiting slowness of cellulose hydrolysis. PMID- 21282109 TI - MCM2-7 form double hexamers at licensed origins in Xenopus egg extract. AB - In late mitosis and G1, Mcm2-7 are assembled onto replication origins to license them for initiation in the upcoming S phase. After initiation, Mcm2-7 provide helicase activity to unwind DNA at the replication fork. Here we examine the structure of Mcm2-7 on chromatin in Xenopus egg extracts. We show that prior to replication initiation, Mcm2-7 is present at licensed replication origins in a complex with a molecular mass close to double that of the Mcm2-7 hexamer. This complex has approximately stoichiometric quantities of the 6 Mcm2-7 proteins and we conclude that it consists of a double heterohexamer. This provides a configuration potentially capable of initiating a pair of bidirectional replication forks in S phase. We also show that after initiation, Mcm2-7 associate with Cdc45 and GINS to form a relatively stable CMG (Cdc45-MCM-GINS) complex. The CMG proteins also associate less strongly with other replication proteins, consistent with the idea that a single CMG complex forms the core of the replisome. PMID- 21282111 TI - Control of secondary granule release in neutrophils by Ral GTPase. AB - Neutrophil (polymorphonuclear leukocyte; PMN) inflammatory functions, including cell adhesion, diapedesis, and phagocytosis, are dependent on the mobilization and release of various intracellular granules/vesicles. In this study, we found that treating PMN with damnacanthal, a Ras family GTPase inhibitor, resulted in a specific release of secondary granules but not primary or tertiary granules and caused dysregulation of PMN chemotactic transmigration and cell surface protein interactions. Analysis of the activities of Ras members identified Ral GTPase as a key regulator during PMN activation and degranulation. In particular, Ral was active in freshly isolated PMN, whereas chemoattractant stimulation induced a quick deactivation of Ral that correlated with PMN degranulation. Overexpression of a constitutively active Ral (Ral23V) in PMN inhibited chemoattractant-induced secondary granule release. By subcellular fractionation, we found that Ral, which was associated with the plasma membrane under the resting condition, was redistributed to secondary granules after chemoattractant stimulation. Blockage of cell endocytosis appeared to inhibit Ral translocation intracellularly. In conclusion, these results demonstrate that Ral is a critical regulator in PMN that specifically controls secondary granule release during PMN response to chemoattractant stimulation. PMID- 21282112 TI - Regulation of the mutually exclusive exons 8a and 8 in the CaV1.2 calcium channel transcript by polypyrimidine tract-binding protein. AB - CaV1.2 calcium channels play roles in diverse cellular processes such as gene regulation, muscle contraction, and membrane excitation and are diversified in their activity through extensive alternative splicing of the CaV1.2 mRNA. The mutually exclusive exons 8a and 8 encode alternate forms of transmembrane segment 6 (IS6) in channel domain 1. The human genetic disorder Timothy syndrome is caused by mutations in either of these two CaV1.2 exons, resulting in disrupted Ca(2+) homeostasis and severe pleiotropic disease phenotypes. The tissue-specific pattern of exon 8/8a splicing leads to differences in symptoms between patients with exon 8 or 8a mutations. Elucidating the mechanisms controlling the exon 8/8a splicing choice will be important in understanding the spectrum of defects associated with the disease. We found that the polypyrimidine tract-binding protein (PTB) mediates a switch from exon 8 to 8a splicing. PTB and its neuronal homolog, nPTB, are widely studied splicing regulators controlling large sets of alternative exons. During neuronal development, PTB expression is down-regulated with a concurrent increase in nPTB expression. Exon 8a is largely repressed in embryonic mouse brain but is progressively induced during neuronal differentiation as PTB is depleted. This splicing repression is mediated by the direct binding of PTB to sequence elements upstream of exon 8a. The nPTB protein is a weaker repressor of exon 8a, resulting in a shift in exon choice when nPTB replaces PTB in cells. These results provide mechanistic understanding of how these two exons, important for human disease, are controlled. PMID- 21282113 TI - NBA1/MERIT40 and BRE interaction is required for the integrity of two distinct deubiquitinating enzyme BRCC36-containing complexes. AB - BRCC36-deubiquitinating enzyme (DUB) forms two different complexes through interactions with two different adaptor proteins Abraxas and ABRO1 in cells. Abraxas mainly localizes in the nucleus, mediating the interaction of BRCC36 with BRCA1. ABRO1 is mainly localized in the cytoplasm. Because it lacks the BRCA1 interacting motif, the ABRO1 complex does not interact with BRCA1. Both BRCC36 containing complexes contain common components including BRE and NBA1/MERIT40. Here, we found that the two complexes are assembled in a similar manner and NBA1 and BRE interaction is critical for maintaining the integrity of both of the complexes. Knockdown of NBA1 or BRE leads to decreased levels of components of the two BRCC36-containing complexes. We provided evidence that NBA1 interacts with BRE through a C-terminal conserved motif of the NBA1 protein and a C terminal UEV domain of the BRE protein. Furthermore, the NBA1-BRE interaction is required for cellular resistance to ionizing irradiation and NBA1's role in recruiting BRCA1 to DNA damage sites. Together, these studies reveal critical interactions required for the formation and function of BRCC36-containing DUB complexes. PMID- 21282114 TI - Genetic evidence that intestinal Notch functions vary regionally and operate through a common mechanism of Math1 repression. AB - Notch signaling is active in many sites, and its diverse activities must require tissue-specific intermediaries, which are largely unknown. In the intestinal epithelium, Notch promotes crypt cell proliferation and inhibits goblet cell differentiation. Pharmacologic studies suggest that the latter effect occurs through the transcription factor Math1/Atoh1, which specifies all intestinal secretory cells. We tested this hypothesis using mouse mutants. Genetic loss of the Notch effector RBP-Jkappa alone increases all intestinal secretory lineages, with variation between proximal and distal gut segments. This secretory cell excess observed with RBP-Jkappa loss was blocked in the absence of Math1 in RBP Jkappa(Fl/Fl);Math1(Fl/Fl);Villin-Cre((ER-T2)) mice. Loss of both factors also restored progenitor replication, proving that Math1 is epistatic to Notch signaling in both secretory cell differentiation and crypt cell proliferation. Investigating mechanisms downstream of Math1, we found that expression of the known Notch effector protein Hes1 was predictably lost in RBP-Jkappa(-/-) mice but surprisingly recovered in RBP-Jkappa;Math1 compound conditional mutants. Furthermore, the cell cycle inhibitors p27(Kip1) and p57(Kip2) were selectively overexpressed in duodenal and ileal crypts, respectively, in RBP-Jkappa-deficient mice. Regional activation of these products was completely abrogated in the absence of Math1. Thus, all intestinal Notch effects channel through the tissue restricted factor Math1, which promotes secretory differentiation and cell cycle exit by regionally distinct mechanisms. Our data further suggest that, besides transmitting Notch signals, the transcription factor Hes1 acts downstream of Math1 to regulate expression of cell cycle inhibitors and intestinal crypt cell replication. PMID- 21282115 TI - Effects of histone acetylation by Piccolo NuA4 on the structure of a nucleosome and the interactions between two nucleosomes. AB - We characterized the effect of histone acetylation on the structure of a nucleosome and the interactions between two nucleosomes. In this study, nucleosomes reconstituted with the Selex "Widom 601" sequence were acetylated with the Piccolo NuA4 complex, which acetylates mainly H4 N-terminal tail lysine residues and some H2A/H3 N-terminal tail lysine residues. Upon the acetylation, we observed directional unwrapping of nucleosomal DNA that accompanies topology change of the DNA. Interactions between two nucleosomes in solution were also monitored to discover multiple transient dinucleosomal states that can be categorized to short-lived and long-lived (~1 s) states. The formation of dinucleosomes is strongly Mg(2+)-dependent, and unacetylated nucleosomes favor the formation of long-lived dinucleosomes 4-fold as much as the acetylated ones. These results suggest that the acetylation of histones by Piccolo NuA4 disturbs not only the structure of a nucleosome but also the interactions between two nucleosomes. Lastly, we suggest a structural model for a stable dinucleosomal state where the two nucleosomes are separated by ~2 nm face-to-face and rotated by 34 degrees with respect to each other. PMID- 21282116 TI - ACASI and face-to-face interviews yield inconsistent estimates of domestic violence among women in India: The Samata Health Study 2005-2009. AB - BACKGROUND: Audio computer-assisted self-interviews (ACASI) are increasingly used in health research to improve the accuracy of data on sensitive behaviors. However, evidence is limited on its use among low-income populations in countries like India and for measurement of sensitive issues such as domestic violence. METHOD: We compared reports of domestic violence and three less sensitive behaviors related to household decision making and spousal communication in ACASI and face-to-face interviews (FTFI) among 464 young married women enrolled in a longitudinal study of gender-based power and adverse health outcomes in low income communities in Bangalore, India. We used a test-retest design. At the 12 month study visit, we elicited responses from each participant through FTFI first, followed by ACASI. At the 24-month visit, we reversed the order, implementing ACASI first, followed by FTFI. Univariable log-linear regression models and kappa statistics were used to examine ACASI's effects on self-reports. RESULTS: Regression results showed significantly lower reporting in ACASI relative to FTFI at both visits, including for domestic violence (12-month risk ratio [RR] = 0.61, 95% CI = 0.52, 0.73; 24-month RR = 0.74, 95% CI = 0.62, 0.89). Response agreement between interview modes, calculated by kappa scores, was universally low, though highest for domestic violence (12-month kappa = 0.45; 24 month kappa = 0.48). Older age and greater educational attainment appeared associated with higher response agreement. CONCLUSIONS: Greater reporting in FTFI may be due to social desirability bias for the less sensitive questions and perceptions of therapeutic benefit for domestic violence. These results cast doubt on the appropriateness of using ACASI for measurement of sensitive behaviors in India. PMID- 21282117 TI - Childhood animal cruelty methods and their link to adult interpersonal violence. AB - Recent research has begun to establish a relationship between childhood acts of animal cruelty and later violence against humans. However, few studies have focused on the influence of animal cruelty methods on later interpersonal violence. In a replication of a study by Hensley and Tallichet (2009) and based on a sample of 180 inmates at medium- and maximum-security prisons in a Southern state, the present study examines the relationship between several retrospectively identified animal cruelty methods (drowned, hit, shot, kicked, choked, burned, and sex) and interpersonal violence committed against humans. Four out of 5 inmates reported hitting animals. Over one third of the sample chose to shoot or kick animals, while 1 in 5 had sex with them. Less then one fifth of the sample drowned or choked animals, while less than one sixth of the inmates burned animals. Regression analyses revealed that the age at which offenders began committing animal cruelty and having sex with animals were predictive of adult interpersonal violence. PMID- 21282118 TI - Domestic violence during pregnancy in India. AB - Domestic violence can result in many negative health consequences for women's health and well-being. Studies on domestic violence illustrate that abused women in various settings had increased health problems such as injury, chronic pain, gastrointestinal, and gynecological signs including sexually transmitted diseases, depression, and posttraumatic stress disorder. This article tries to understand the association between domestic violence and pregnancy outcomes and other health consequences. The study was carried out in all the six zones of India that is, northern, southern, eastern, western, central, and northeast zones. The study design was conceived as an analytical cross sectional study with multicenter approach. Multistage sampling and then probability proportion to size (PPS) sampling were done. A total of 18 states were taken for the study with a total sample of 14,507 married women and 14,108 married men. Married men were considered from the neighboring villages to understand men's perspective. To understand the situation, women were interviewed using semistructured questionnaire as well as qualitative data like FGD and case studies. The result shows that domestic violence occurs during pregnancy across six zones. The situations become worse for women if her husband or family perceived the pregnancy to be a female child and there is a demand for male child. It has major health implications in accessing and utilizing antenatal care and immunization. PMID- 21282119 TI - The decline in sexual assaults in men's prisons in New South Wales: a "systems" approach. AB - Male prison rape and sexual assaults remains a serious and sensitive issue in many countries. Human rights groups claim that sexual assaults among male prisoners have reached pandemic proportions and need to be stopped. Researchers for many years have studied the causes of male sexual assault in prison and offered numerous recommendations on its prevention. Few, however, have presented evidence for a decline in male prisoner sexual assaults and investigated the reasons for the decline. This article provides evidence from population-based surveys of a steady decrease in male prisoner sexual assaults in New South Wales (NSW) between 1996 and 2009. The authors conducted in-depth interviews with former and current inmates, and using a "systems" approach they discuss the complexity of sexual assaults in prison, incorporating a multiplicity of perspectives. In particular, they bring together different sources of data and discuss this in relation to changes in power structures and control in a modern prison, the attitudes of older and younger prisoners, the concept of "duty of care," introduction of prison drug programs, and prisoner attitudes toward gender and sexuality. In anthropology, the term "system" is used widely for describing sociocultural phenomena of a given society in a holistic manner without reducing the complexity of a given community. PMID- 21282120 TI - Characteristics of young children exposed to violence: the safe start demonstration project. AB - The Safe Start demonstration projects, funded by the Office of Juvenile Justice and Delinquency Prevention (OJJDP) under the first phase of the Safe Start initiative, are primarily designed to influence change at the systems or macrolevels to reduce the incidence of and impact of exposure to violence for children aged birth to 6 years; direct services are also provided to young children and their families who were exposed to violence. The data presented in this article come from 10 communities that submitted data regarding the characteristics of young children exposed to violence to OJJDP. These data represent families who are typically not represented in the databases of state child protective services programs but instead have been identified by domestic violence advocates, early care and education providers, family members, court personnel, police, and other social service personnel as families with young children in need of intervention due to violence exposure.The purpose of this article is to describe the characteristics of young children and their parents who seek help for psychosocial problems related to exposure to family and community violence. Results indicate that one quarter of the children and nearly half of their parents evidenced clinical levels of stress, suggesting the need to intervene at the family level as well as at the individual level when working with young children exposed to violence. The information presented, including the extent of exposure to violence, the multiple types of violence to which children are exposed, the impact of this exposure on young children and their families, and the multiple ways in which families exposed to violence come to the attention of service providers is useful for policy makers and service providers who are interested in breaking the cycle of violence by meeting the needs of the children exposed to violence and their families. PMID- 21282121 TI - Client violence and its negative impacts on work attitudes of child protection workers compared to community service workers. AB - This study investigated the prevalence of client violence toward child protection workers and its negative impacts on the work attitudes of those workers compared with community service workers in South Korea. This study is based on the assumption that child protection workers are more vulnerable to violence than are community service workers because of the unique characteristics of the roles they play. Results of the data, drawn from a sample of 413 child protection workers and community service workers, found that client violence was more prevalent against child protection workers and that the negative impacts of this violence on work attitudes were more clearly highlighted for child protection workers. Based on the results of this study, implications for preventing client violence and lessening its negative impacts on work attitudes of child protection workers were identified. PMID- 21282122 TI - Is childhood physical abuse associated with peptic ulcer disease? Findings from a population-based study. AB - This study investigated childhood physical abuse and ulcers in a regionally representative community sample. Age, race and sex were controlled for in addition to five clusters of potentially confounding factors: adverse childhood conditions, adult socioeconomic status, current health behaviors, current stress and marital status, and history of mood/anxiety disorders. Childhood physical abuse is associated with many negative physical and psychological adult health outcomes. Two recent studies demonstrate a potential link between childhood physical abuse and peptic ulcer disease in adulthood. The authors use regional data for the Canadian provinces of Manitoba and Saskatchewan from the 2005 Canadian Community Health Survey. Of the 13,069 respondents with complete data on abuse and ulcers, 7.3% (n = 1,020) report that they had been physically abused as a child by someone close to them and 3.0% (n = 493) report that they had been diagnosed with peptic ulcers by a health professional. The regional response rate is approximately 84%. Findings show that those reporting abuse had more than twice the prevalence of ulcers than did those not reporting abuse (6.6% vs. 2.7%). The fully adjusted odd ratio of peptic ulcers among those who had reported childhood physical abuse is 1.68 (95% CI = 1.22, 2.32). A significant and stable relationship between childhood physical abuse and peptic ulcers is found, even when taking into account five clusters of potentially confounding factors. Prospective studies that apply the biopsychosocial model are likely to be the most effective for identifying the pathways that connect childhood physical abuse and ulcer disease. PMID- 21282123 TI - Domestic violence and sexual assault service goal priorities. AB - We investigated agency directors' perspectives about how service goals should be prioritized for domestic violence and sexual assault service subtypes, including crisis, legal advocacy, medical advocacy, counseling, support group, and shelter services. A sample of 97 (94% response rate) North Carolina domestic violence and/or sexual assault agency directors completed a survey asking participants to rank the importance of service goals. Overall, participants considered emotional support provision to be a critical service goal priority across all service types. Social support and self-care service strategies were deemed less important. However, prioritization of other service goals varied depending on the service type. Statistically significant differences on service goal prioritization based on key agency characteristics were also examined, and agency characteristics were found to relate to differences in service goal prioritization. PMID- 21282124 TI - An examination of intimate partner violence and psychological stressors in adult abortion patients. AB - The purpose of this article is to describe an exploratory study examining the relationship between intimate partner violence and psychological stressors in a sample of 188 adult abortion patients. Results indicate the almost 15% of respondents report a history of abuse by the coconceiving partner. In addition, women who reported having had one or more past abortions were more likely to also report that the person involved in the current pregnancy had also emotionally abused them. Women reporting one type of partner abuse were significantly more likely to also report other types of abuse. Women reporting abuse were less likely to report informing their coconceiving partner of their appointment at the clinic, less likely to report that their partner contributed financially to the abortion cost, and more likely to report partner refusal to wear a condom. Women who reported emotional abuse were more likely to score higher on all but one of the psychological stressor scales. The implications of these findings are discussed. PMID- 21282125 TI - What attracts men who batter to their partners? An exploratory study. AB - Men who batter, because of particular personality traits and sense of entitlement, may select partners whom they perceive will be dependent on them, meet their emotional needs, or be "objects" of physical attractiveness. During treatment intake, 181 offenders responded to the question, "What attracted you to her (your partner)?" We explored whether men who mentioned their own needs or her physical traits would engage in more frequent and severe violence and would have specific forms of personality disorder dimensions or personality traits. Six categories of attraction, including "her physical traits" and "his needs," were derived from the men's responses. The results showed that men who focused on their partners' physical attractiveness were more likely to be violent after treatment. Men who cited their own needs for their attraction had higher scores on borderline personality, alcohol abuse, and psychotic thinking and lower scores on compulsive-conforming. PMID- 21282126 TI - Managing in the contemporary world: rape victims' and supporters' experiences of barriers within the police and the health care system in Tanzania. AB - Grounded theory guided the analysis of 30 in-depth interviews with raped women and community members who had supported raped women in their contact with the police and health care services in Tanzania. The aim of this study was to understand and conceptualize the experiences of the informants by creating a theoretical model focusing on barriers, strategies, and responses during the help seeking process. The results illustrate a process of managing in the contemporary world characterized as walking a path of anger and humiliation. The barriers are illustrated by painful experiences of realizing it's all about money, meeting unprofessionalism and irresponsibility, subjected to unreliable services, and by being caught in a messed-up system. Negotiating truths and knowing what to do capture the informants' coping strategies. The study indicates an urgent need for improvement in the formal procedures of handling rape cases, improved collaboration between the police and the health care system, as well as specific training for professionals to improve their communication and caring skills. PMID- 21282127 TI - Managing victim status in group therapy for men: a discourse analysis. AB - In contrast to the abundance of research on women victims, this article sheds light on the discourse of men who are self-identified as victims of their female partners' abuse. The purpose of this study was to investigate the most salient identity constructions and abuse conceptualizations among participants of group psychotherapy for men who have been abused in intimate, heterosexual partner relationships (i.e., Calgary Counselling Centre's 14-week group program titled "A Turn for the Better"). The men's identity work was examined using the methods and theoretical perspective of discourse analysis. Analysis of the talk demonstrated that the group agenda was to work through the ambiguity of abuse in the service of having the men identify themselves as victims. Thus, both the men and the group facilitators actively constructed "true victim" subject positions through their resistance to commonsense orientations of (a) "men as perpetrators" and (b) whether abuse consisted of more than physical violence. The therapeutic language of resistance was a common strategy used to manage victim status but also required further negotiation as it entailed a component of abuse (i.e., risked positioning the men as abusers rather than victims). The discussion focuses on how these findings may differ from the identity work present in women victim therapeutic groups. In addition, we note that it is difficult to uphold the victim-versus-perpetrator dichotomy in therapeutic discourse. PMID- 21282128 TI - Thirty-five years of end-of-life issues in US medical schools. AB - The objective of this study was to examine US medical school offerings on end-of life issues between 1975 and 2010. Data were obtained from a mailed survey to the US medical schools in 1975, 1980, 1985, 1990, 1995, 2000, 2005, and 2010. Survey response rates for the 8 points in time (in percentages) were 95, 96, 90, 90, 93, 92, 81, and 79, respectively. Between 1975 and 2010, the overall offerings in death and dying increased so that 100% of US medical schools, beginning in 2000, offered something on death and dying. A multidisciplinary-team approach continued over the 35-year period. Palliative care is offered to some extent in 99% of US medical schools today. Numerous end-of-life topics are currently covered in the curriculum. Increased attention to end-of-life issues in medical schools should enhance medical students' relationship with terminally ill patients and their families. PMID- 21282129 TI - The promise of presence. PMID- 21282130 TI - Colorectal cancer screening with odour material by canine scent detection. AB - OBJECTIVE: Early detection and early treatment are of vital importance to the successful treatment of various cancers. The development of a novel screening method that is as economical and non-invasive as the faecal occult blood test (FOBT) for early detection of colorectal cancer (CRC) is needed. A study was undertaken using canine scent detection to determine whether odour material can become an effective tool in CRC screening. DESIGN: Exhaled breath and watery stool samples were obtained from patients with CRC and from healthy controls prior to colonoscopy. Each test group consisted of one sample from a patient with CRC and four control samples from volunteers without cancer. These five samples were randomly and separately placed into five boxes. A Labrador retriever specially trained in scent detection of cancer and a handler cooperated in the tests. The dog first smelled a standard breath sample from a patient with CRC, then smelled each sample station and sat down in front of the station in which a cancer scent was detected. RESULTS: 33 and 37 groups of breath and watery stool samples, respectively, were tested. Among patients with CRC and controls, the sensitivity of canine scent detection of breath samples compared with conventional diagnosis by colonoscopy was 0.91 and the specificity was 0.99. The sensitivity of canine scent detection of stool samples was 0.97 and the specificity was 0.99. The accuracy of canine scent detection was high even for early cancer. Canine scent detection was not confounded by current smoking, benign colorectal disease or inflammatory disease. CONCLUSIONS: This study shows that a specific cancer scent does indeed exist and that cancer-specific chemical compounds may be circulating throughout the body. These odour materials may become effective tools in CRC screening. In the future, studies designed to identify cancer-specific volatile organic compounds will be important for the development of new methods for early detection of CRC. PMID- 21282131 TI - Enteric glial cells: new players in mucosal defence against bacteria? PMID- 21282132 TI - Attitudes to perinatal postmortem: parental views about research participation. AB - OBJECTIVE: To study parental attitudes to participating in questionnaire research about perinatal postmortem immediately after late miscarriage, stillbirth and termination for fetal abnormality. DESIGN: Prospective self-completion questionnaire. SETTING: UK fetal medicine and delivery unit. PATIENTS: 35 women and their partners after second or third trimester pregnancy loss, making decisions about having a postmortem. METHODS: Participants were asked to complete a questionnaire about postmortem decision-making which included questions about their attitudes to taking part in research. Prior to giving full approval for the study, the Research Ethics Committee (REC) requested feedback after 10 questionnaires had been returned. RESULTS: Responses from the first 10 participants were positive about the research and the REC allowed the study to continue. 31 questionnaires were received from parents of 17 babies (49% of those asked; 16 from mothers, 15 from fathers). Of the 22 participants who answered a question about the impact of participating in this research, 73% stated that completing the questionnaire had helped them feel better about the decision whether or not to consent to postmortem and none reported any adverse effect of completing the questionnaire. Additional comments made by 19 participants supported this finding. CONCLUSION: Research into this sensitive area of perinatal medicine where there is a poor outcome is possible and is indeed well received by many parents. RECs should not automatically take a negative stance towards studies of this type. PMID- 21282133 TI - Diverse patterns of longitudinal and radial dyssynchrony in patients with advanced systolic heart failure. AB - BACKGROUND: Little is known about the impact of QRS duration and aetiology of heart failure on the pattern of left ventricular long- and short-axis dyssynchrony. OBJECTIVE: To investigate the impact of QRS duration and aetiology of heart failure on the pattern of left ventricular long- and short-axis dyssynchrony using tissue Doppler imaging (TDI) and two-dimensional (2D) speckle tracking imaging. METHODS: 448 patients with heart failure (aged 65 +/- 12 years, 75% men) with ejection fraction <= 35% from two cardiac centres were examined for the occurrence of longitudinal dyssynchrony by TDI, and for radial dyssynchrony by 2D speckle tracking imaging. Region(s) of the latest mechanical contraction were also determined. RESULTS: Longitudinal dyssynchrony was identified in 263 (59%) patients and radial dyssynchrony in 185 (41%). 125 (28%) patients had both longitudinal and radial dyssynchrony, 138 (31%) had only longitudinal, 60 (13%) had only radial, and 124 (28%) had neither form of dyssynchrony. TDI showed that the single most delayed segment was the septal, lateral, anterior, inferior, anteroseptal and posterior wall in 12%, 27%, 12%, 19%, 7% and 13% of patients, respectively, while multisegmental delay occurred in 10% of patients. These figures were 10%, 8%, 5%, 10%, 12%, 14% and 41%, respectively, using 2D speckle tracking. When compared between patients with wide and narrow QRS complexes, both longitudinal (63% vs 53%) and radial (49% vs 36%) dyssynchrony parameters were more frequently positive in the wide QRS group defined by QRS duration >= 120 ms (both p < 0.05). When compared between non-ischaemic and ischaemic patients, the prevalence of longitudinal dyssynchrony was comparable (61% vs 57%, p = 0.467), while radial dyssynchrony was marginally more common in the non-ischaemic group (47% vs 37%, p = 0.049). However, the distributions of the most delayed segment between the subgroups were similar when assessed by the same echocardiographic method. CONCLUSION: In patients with advanced systolic heart failure, the patterns of longitudinal and radial dyssynchrony are heterogeneous, and mechanical dyssynchrony tends to be more prevalent in the wide QRS group and the non-ischaemic group. PMID- 21282134 TI - Coronary heart disease mortality trends in the Netherlands 1972-2007. AB - BACKGROUND: Coronary heart disease (CHD) mortality has steadily declined since the early 1970s in the Netherlands. However, in some Western countries the rate of decline in younger groups may be starting to plateau or even rise. OBJECTIVE: To examine trends in age-specific CHD mortality rates among Dutch adults from 1972 to 2007, with a particular focus on recent trends for the younger age groups METHODS: Data for all CHD deaths (1972-2007) in the Netherlands were grouped by year, sex, age. A joinpoint regression was fitted to each age-sex-group to detect points in time at which significant changes in the trends occur. For every time period, the linear slope of the trend, p value, observed number of deaths, CHD mortality rates and change in the CHD mortality rate were calculated. RESULTS: Between 1972 and 2007, the age-adjusted CHD mortality rates decreased overall by 76% in both men and women. In men (35-54 years), the change in CHD mortality rate in the period 1980-1993 was -0.53 but attenuated in period 1993 1999: -0.16. In women (35-54 years) the decline likewise attenuated to 0.44 in period 1979-1989: and -0.05 in period 1989-2000. After 1999-2000, CHD mortality rate further declined in both men (period 1999-2007: -0.46) and women (period 2000-2007: -0.38). CONCLUSIONS: Evidence from several Western countries suggests that among young adults (< 55 years), CHD mortality rates are levelling out. In this study, similar attenuation of the decline in CHD mortality among young adults in the Netherlands has been observed. Furthermore, this is the first study to observe a subsequent increase in the pace of decline after a period of flattening. In order to better explain these encouraging changes in CHD mortality rates, a detailed analysis of recent changes in cardiovascular risk factors and treatments is now urgently required. PMID- 21282135 TI - Pulmonary venous isolation for atrial fibrillation in severe systolic heart failure: more questions than answers? PMID- 21282136 TI - Transnational tobacco industry promotion of the cigarette gifting custom in China. AB - OBJECTIVE: To understand how British American Tobacco (BAT) and Philip Morris (PM) researched the role and popularity of cigarette gifting in forming relationships among Chinese customs and how they exploited the practice to promote their brands State Express 555 and Marlboro. METHODS: Searches and analysis of industry documents from the Legacy Tobacco Documents Library complemented by searches on LexisNexis Academic news, online search engines and information from the tobacco industry trade press. RESULTS: From 1980-1999, BAT and PM employed Chinese market research firms to gather consumer information about perceptions of foreign cigarettes and the companies discovered that cigarettes, especially prestigious ones, were gifted and smoked purposely for building relationships and social status in China. BAT and PM promoted their brands as gifts by enhancing cigarette cartons and promoting culturally themed packages, particularly during the gifting festivals of Chinese New Year and Mid Autumn Festival to tie their brands in to festival values such as warmth, friendship and celebration. They used similar marketing in Chinese communities outside China. CONCLUSIONS: BAT and PM tied their brands to Chinese cigarette gifting customs by appealing to social and cultural values of respect and personal honour. Decoupling cigarettes from their social significance in China and removing their appeal would probably reduce cigarette gifting and promote a decline in smoking. Tobacco control efforts in countermarketing, large graphic warnings and plain packaging to make cigarette packages less attractive as gifts could contribute to denormalising cigarette gifting. PMID- 21282137 TI - For peace and pain: the medical legitimisation of Afghanistan's poppy crop. AB - Since the overthrow of the Taliban in 2001, there has been an overall increase in illicit opium production in Afghanistan and mounting human losses. The United Nations has attributed 1 million human deaths to Afghan opiates over the past decade. As the war in Afghanistan nears a crucial mark, the NATO coalition forces and Afghan people can no longer afford the same ineffective counternarcotics strategy. This commentary proposes a strategic revision that reframes Afghanistan's poppy problem as an opportunity for global public health. Specifically, The Afghan poppy crop could be repurposed away from illicit drug production, and towards manufacturing licit opioid analgesics to address unmet needs for pain palliation, particularly for diseases such as HIV/AIDS and cancer in the developing world--that is, illegal opium could be converted into legal pain medicine, solving two problems at once. We present a supply-and-demand that illustrates how this useful exchange could be made, and discuss the political opposition that now stands in the way and perpetuates the unsatisfactory status quo in Afghanistan. PMID- 21282138 TI - Glossary: migration and health. AB - The literature on migration and health is quite heterogeneous in how migrants are labelled and how the relation between migration and health is conceptualised. A narrative review has been carried out. This glossary presents the most commonly used terms in the field of migration and health, along with synonyms and related concepts, and discusses the suitability of their use in epidemiological studies. The terminology used in migrant health is ambiguous in many cases. Studies on migrant health should avoid layman terms and strive to use internationally defined concepts. PMID- 21282139 TI - Heterogeneity in the association between socioeconomic position in early life and adult self-rated health in two birth cohorts of Spanish adults. AB - BACKGROUND: The purpose of this work was to evaluate the association between socioeconomic circumstances in early life and poor self-rated health in adulthood, and to determine whether this association varies depending on birth cohort. METHODS: Using data from the 2005 Living Conditions Survey carried out in a Spanish population sample, separate analyses were made for persons born between 1941 and 1959 who lived their childhood and adolescence in a period marked by absence of economic growth in Spain, and those born between 1960 and 1980. The authors estimated of the relation of financial difficulties in adolescence, occupation of father, education of father and education of mother with poor self reported health, adjusted for the measures of socioeconomic position in adulthood. Also evaluated was the possibility of interaction between early and adult socioeconomic position and the cumulative effect of low socioeconomic position across the life course. RESULTS: In the two cohorts, the presence of financial difficulties in adolescence showed an association with an increased risk of poor self-rated health; in contrast, the relation of occupation and education of parents with poor self-rated health varied depending on the birth cohort and gender of the study subjects. The effect of family financial situation was shown to accumulate over the life course, whereas the effect of socioeconomic position across the life course was heterogeneous when occupation and education of parents were used. CONCLUSION: The importance of financial difficulties in the household has probably not varied over time; in contrast, the heterogeneity of the findings regarding occupation and education of parents suggests that the importance of these indicators and, consequently, their aetiological pathways may differ depending on the gender and birth cohort of the study subjects. PMID- 21282140 TI - Reduced acute hospitalisation with the healthy housing programme. AB - BACKGROUND: This study investigated the impact of the Healthy Housing Programme in reducing acute hospitalisations in South Auckland, New Zealand. The programme involved house modifications to reduce overcrowding, insulation and ventilation improvements, and health and social service assessments, referrals and linkages. METHODS: An intervention evaluation was used. Participants in the programme were considered cases following their house's intervention and counterfactuals/controls prior to the intervention. Rigorous age-censoring was used to construct a case-counterfactual comparison. 9736 residents of 3410 homes were involved in the programme from September 2001 to December 2007. All lived in areas of relative deprivation (NZDep01=decile 10) and almost all self-identified as Pacific ethnic group. The main outcome measure was acute hospitalisation rates before, during and after a health and housing intervention. Hospital data were gathered from July 1999 to January 2009. RESULTS: In the post-intervention group, people aged 5-34 years had a HR of 0.77 (95% CI 0.70 to 0.85) for acute hospitalisations compared to the counterfactual (pre-intervention). For children aged 0-4 years the HR was 0.89 (95% CI 0.79 to 0.99); a non-significant increase occurred in adults aged 35 years plus. When the causes of hospitalisation were restricted to those related to housing, further falls in the HRs were seen: 0.88 (95% CI 0.74 to 1.05) for 0-4 year olds and 0.73 (95% CI 0.58 to 0.91) for 5-34 year olds. CONCLUSION: A package of care that addresses housing conditions that impact on health and improves access to health and social services is associated with a reduced acute hospitalisation rate for 0-34 year olds. PMID- 21282141 TI - Increasing absolute mortality disparities by education in Finland, Norway and Sweden, 1971-2000. AB - BACKGROUND AND OBJECTIVES: Studies on socioeconomic health disparities often suffer from a lack of uniform data and methodology. Using high quality, census linked data and sensible inequality measures, this study documents the changes in absolute and relative mortality differences by education in Finland, Norway and Sweden over the period 1971 to 2000. METHODS: The age-standardised mortality rates and the population exposures for three educational categories were computed from detailed data provided by the national statistical offices. Mortality disparities by education were assessed using two range measures (rate differences and rate ratios), and two Gini-like measures (the average inter-group difference (AID) and the Gini coefficient (G)). The formulae for the decomposition of the change in the AID into (1) the contribution of change in population composition by education, and (2) the contribution of mortality change were introduced. RESULTS: Mortality decreases were often greater for high than for medium and low education. Both relative and absolute mortality disparities tend to increase over time. The magnitude and timing of the increases in absolute disparities vary by country. Both the rate differences and the AIDs have increased since the 1970s in Norway and Sweden, and since the 1980s in Finland. The contributions of the changes in population composition to the total AID increase were substantial in all countries, and for both sexes. The mortality contributions were substantial for males in Norway and Sweden. CONCLUSIONS: The study reports increases in absolute mortality disparity, and its components. This trend needs to be further studied and addressed by policies. PMID- 21282142 TI - The effect of health promotion on diagnosis and management of diabetes. AB - BACKGROUND: Undiagnosed disease is one of the critical public health problems in the world. In 2002 South Korea introduced the nation's first comprehensive public health promotion policy, Health Plan 2010. The first phase of Health Plan 2010 started in 2002, promoting the early detection of diseases and preventive care and continued until 2005. METHODS: Using the 2001 and 2005 Korean National Health and Nutrition Examination Surveys that were fielded before and after the health promotion programme, this study investigated the changes in healthcare utilisation and its impacts on the prevalence of diagnosed and undiagnosed diabetes as well as good management of the disease. RESULTS: A significant increase in diabetes diagnoses has occurred during this time period, especially for those with low education and older age. It was found that, during this time period, the prevalence of undiagnosed diabetes was significantly reduced especially among older and less-educated Koreans, the principal targets of the programme. This health promotion was also found to have had significant positive effects on the good management of diabetes. CONCLUSIONS: The increase in preventive health care through medical check-ups among less-educated, older people suggests that the implementation of free medical check-ups for individual aged 40 years and older may have a positive impact on those who had not previously used preventive care. The positive experience in South Korea indicates that similarly designed public health campaigns in other countries have enormous potential for improving the detection and management of chronic disease. PMID- 21282143 TI - Decomposing socioeconomic inequality in self-rated health in Tehran. AB - BACKGROUND: Measuring the distribution of health is a part of assessing health system performance. This study aims to estimate health inequality between different socioeconomic groups and its determinants in Tehran, the capital of Iran. METHODS: Self-rated health (SRH) and demographic characteristics, including gender, age, marital status, educational years, and assets, were measured by structured interviews of 2464 residents of Tehran in 2008. A concentration index was calculated to measure health inequality by economic status. The association of potential determinants and SRH was assessed through multivariate logistic regression. The contribution to concentration index of level of education, marital status and other determining factors was assessed by decomposition. RESULTS: The mean age of respondents was 41.4 years (SD 17.7) and 49% of them were men. The mean score of SRH status was 3.72 (range: 1-5; SD 0.93). 282 respondents (11.5%) rated their health status as poor or very poor. The concentration index was -0.29 (SE 0.03; p<0.001). Age, marital status, level of education and household economic status were significantly associated with SRH in both the crude and adjusted analyses. The main contributors to inequality in SRH were economic status (47.8%), level of education (29.2%) and age (23.0%). CONCLUSIONS: Sub-optimal SRH was more in lower than in higher economic status. After controlling for age, the levels of education and household wealth have the greatest contributions to SRH inequality. PMID- 21282144 TI - Geographic remoteness, area-level socio-economic disadvantage and advanced breast cancer: a cross-sectional, multilevel study. AB - BACKGROUND: Reducing disparities in cancer outcomes is a major priority for cancer-control agencies. The authors examine the relationships between geographic remoteness, area disadvantage and risk of advanced breast cancer among women. METHODS: Multilevel models were used to assess the area- and individual-level contributions to the risk of advanced breast cancer among women aged 30-79 years diagnosed as having breast cancer in Queensland, Australia between 1997 and 2006 (n=18,658). RESULTS: Women who resided in the most socio-economically disadvantaged areas were significantly more likely (OR 1.21, 95% CI 1.07 to 1.37) than residents of the most advantaged areas to be diagnosed as having advanced breast cancer after adjustment for individual-level factors. When geographic remoteness and area-disadvantage (and all the individual-level factors) were simultaneously adjusted, the rates of advanced breast cancer were significantly higher for women residing in Outer Regional areas (OR 1.13, 95% CI 1.02 to 1.24) and those who lived in the most disadvantaged areas (OR 1.16, 95% CI 1.02 to 1.32). There was no statistically significant interaction between geographic remoteness and area disadvantage. CONCLUSIONS: A woman's risk of being diagnosed as having advanced breast cancer depends on where she lives, separate from the individual characteristics of the woman herself. Both the rurality and socio economic characteristics of the geographical area in which women lived were important. The socio-economic factors contributing to advanced breast cancer, existing in both urban and rural environments, need to be investigated. PMID- 21282145 TI - The Australian epidemic of cardiovascular mortality 1935-2005: effects of period and birth cohort. AB - BACKGROUND: This study investigates the period and birth cohort effects in cardiovascular disease (CVD) mortality in Australia, and assesses explanations related to contemporaneous effects of changes in risk factors (period effects) and influences of exposures earlier in life (cohort effects). METHODS: Australian mortality from diseases of the circulatory system (DoCS; International Classification of Diseases (ICD) 9th revision, chapter 7), were investigated by sex and 5-year age group (35-79 years) from 1935 to 2005 for: all DoCS, all DoCS less rheumatic heart disease (RHD) and stroke. Ischaemic heart disease (IHD; ICD9 410-4) trends from 1968 were also examined. The extent to which the Australian CVD epidemic was characterised by period effects or birth cohort effects was investigated by age and cohort-specific analyses of secular trends, and age period-cohort (APC) models. RESULTS: The CVD epidemic increased into the 1960s, with men one third higher than women, predominantly due to IHD. A sustained decline occurred in both sexes from 1970. Deduction of RHD from CVD steepened the ascent of the epidemic. Age-specific analyses of CVD mortality (less RHD) by period and cohort, and APC modelling, indicate that the rise and fall of the epidemic are period effects. CONCLUSION: The period epidemic of CVD mortality in Australia 1935-2005, consistent with international reports, supports the concurrent effects of changes in risk factors in adults on CVD mortality, and does not support effects of differential exposures by birth cohort, as would occur with changes in perinatal influences such as birth weight. Prevention of CVD mortality should focus on lowering risk factors in adults. PMID- 21282146 TI - An economic evaluation of setting up physical barriers in railway stations for preventing railway injury: evidence from Hong Kong. AB - BACKGROUND: Setting physical barriers, for example platform screen doors (PSDs), has been proven to be effective in preventing falls onto railway tracks, but its cost-effectiveness is not known. For economic evaluation of public health interventions, the importance of including non-health factors has been noted despite a lack of empirical studies. This study aimed to investigate the effectiveness and cost-effectiveness of PSDs, which are installed in part of the Hong Kong railway system, for preventing railway injuries. METHODS: Data on railway injuries from 1997 to 2007 were obtained from the railway operators. Poisson regression was used to examine the risk reduction. Two incremental cost effectiveness ratios (ICER) were calculated to assess the cost-effectiveness based on (1) disability-adjusted life years (DALYs) only and (2) DALYs with potential fare revenue and passengers' waiting time lost due to railway circulation collapse. RESULTS: The PSD installation has effectively reduced railway injuries (adjusted 5-year average percentage change: -68.8%, p<0.0001) with no apparent substitution effect to the other platforms observed. To be cost effective, the cost of gaining a healthy life year (ICER) should not exceed three times the per capita GDP (US$74,700). The PSD installation would only be cost effective if the loss of fare revenue and passengers' waiting time, in addition to DALY, were included (ICER: US$65,400), while the ICER based on DALY only would be US$77,900. CONCLUSION: The challenges of complexity for economic evaluation appear in many community-based health interventions. A more extensive perspective for exploring other outcome measurements and evaluation methods to reflect a fair and appropriate value of the intervention's cost-effectiveness is needed. PMID- 21282147 TI - Work, worklessness and the political economy of health inequalities. AB - This essay argues that work, and the socioeconomic class polarities it creates, plays a fundamental role in determining inequalities in the distribution of morbidity and mortality. This is by means of uneven exposure to physical hazards and psychosocial risks in the workplace, as well as by inequalities in exclusion from the labour market and the absence of paid work. Furthermore, this essay shows that the relationships between work, worklessness and health inequalities are influenced by the broader political and economic context in the form of welfare state regimes. This leads to the development of a model of the political economy of health inequalities, and how different types of public policy interventions can mitigate these relationships. This model is then applied to the case of work and worklessness. The essay concludes by arguing that politics matters in the aetiology of health inequalities. PMID- 21282148 TI - End-of-life treatment of potential organ donors: paradigm shifts in intensive and emergency care. PMID- 21282149 TI - The Anthropocene: a new epoch of geological time? AB - Anthropogenic changes to the Earth's climate, land, oceans and biosphere are now so great and so rapid that the concept of a new geological epoch defined by the action of humans, the Anthropocene, is widely and seriously debated. Questions of the scale, magnitude and significance of this environmental change, particularly in the context of the Earth's geological history, provide the basis for this Theme Issue. The Anthropocene, on current evidence, seems to show global change consistent with the suggestion that an epoch-scale boundary has been crossed within the last two centuries. PMID- 21282150 TI - The Anthropocene: conceptual and historical perspectives. AB - The human imprint on the global environment has now become so large and active that it rivals some of the great forces of Nature in its impact on the functioning of the Earth system. Although global-scale human influence on the environment has been recognized since the 1800s, the term Anthropocene, introduced about a decade ago, has only recently become widely, but informally, used in the global change research community. However, the term has yet to be accepted formally as a new geological epoch or era in Earth history. In this paper, we put forward the case for formally recognizing the Anthropocene as a new epoch in Earth history, arguing that the advent of the Industrial Revolution around 1800 provides a logical start date for the new epoch. We then explore recent trends in the evolution of the Anthropocene as humanity proceeds into the twenty-first century, focusing on the profound changes to our relationship with the rest of the living world and on early attempts and proposals for managing our relationship with the large geophysical cycles that drive the Earth's climate system. PMID- 21282151 TI - Emergent dynamics of the climate-economy system in the Anthropocene. AB - Global CO(2) emissions are understood to be the largest contributor to anthropogenic climate change, and have, to date, been highly correlated with economic output. However, there is likely to be a negative feedback between climate change and human wealth: economic growth is typically associated with an increase in CO(2) emissions and global warming, but the resulting climate change may lead to damages that suppress economic growth. This climate-economy feedback is assumed to be weak in standard climate change assessments. When the feedback is incorporated in a transparently simple model it reveals possible emergent behaviour in the coupled climate-economy system. Formulae are derived for the critical rates of growth of global CO(2) emissions that cause damped or long-term boom-bust oscillations in human wealth, thereby preventing a soft landing of the climate-economy system. On the basis of this model, historical rates of economic growth and decarbonization appear to put the climate-economy system in a potentially damaging oscillatory regime. PMID- 21282152 TI - Anthropogenic modification of the oceans. AB - Human activities are altering the ocean in many different ways. The surface ocean is warming and, as a result, it is becoming more stratified and sea level is rising. There is no clear evidence yet of a slowing in ocean circulation, although this is predicted for the future. As anthropogenic CO(2) permeates into the ocean, it is making sea water more acidic, to the detriment of surface corals and probably many other calcifiers. Once acidification reaches the deep ocean, it will become more corrosive to CaCO(3), leading to a considerable reduction in the amount of CaCO(3) accumulating on the deep seafloor. There will be a several thousand-year-long interruption to CaCO(3) sedimentation at many points on the seafloor. A curious feedback in the ocean, carbonate compensation, makes it more likely that global warming and sea-level rise will continue for many millennia after CO(2) emissions cease. PMID- 21282153 TI - The Anthropocene and the international law of the sea. AB - The current law of the sea provides a framework for various specific issues, but is incapable of responding adequately to the overall challenges facing humankind, now conceivably already living in the Anthropocene. The linkages between the development of the law of the sea and the current process towards formal recognition of an Anthropocene epoch are twofold. First, there is a linkage of origin. The ideological foundations of the law of the sea facilitated the emergence of forces that were to lead to the Industrial Revolution and, eventually, to levels of development entailing ever-greater human impacts on the Earth System. Second, there are linkages in interaction. Geological information has prompted key developments in the law of the sea since the introduction of the continental shelf concept in the mid-twentieth century. With the formalization of the Anthropocene epoch, geology might again act as a trigger for new developments needed in the law of the sea. This article explores those two aspects of linkages and examines prospects for further development of the law of the sea framework, through concepts such as the responsibility for the seas as well as those related to new approaches to global sustainability such as the 'planetary boundaries'. PMID- 21282154 TI - Societal responses to the Anthropocene. AB - This article discusses the societal responses to the Anthropocene. First we need to confront the effects of our own population proliferation in all its aspects; next to look again at economics and replace consumerism as a goal; then to work out new ways of generating energy; to manage and adapt to what is in effect climate destabilization; to give higher priority to conservation of the natural world; and last to create the necessary institutional means of coping with global problems in a world in which society is more integrated than ever before. PMID- 21282155 TI - Are there pre-Quaternary geological analogues for a future greenhouse warming? AB - Given the inherent uncertainties in predicting how climate and environments will respond to anthropogenic emissions of greenhouse gases, it would be beneficial to society if science could identify geological analogues to the human race's current grand climate experiment. This has been a focus of the geological and palaeoclimate communities over the last 30 years, with many scientific papers claiming that intervals in Earth history can be used as an analogue for future climate change. Using a coupled ocean-atmosphere modelling approach, we test this assertion for the most probable pre-Quaternary candidates of the last 100 million years: the Mid- and Late Cretaceous, the Palaeocene-Eocene Thermal Maximum (PETM), the Early Eocene, as well as warm intervals within the Miocene and Pliocene epochs. These intervals fail as true direct analogues since they either represent equilibrium climate states to a long-term CO(2) forcing--whereas anthropogenic emissions of greenhouse gases provide a progressive (transient) forcing on climate--or the sensitivity of the climate system itself to CO(2) was different. While no close geological analogue exists, past warm intervals in Earth history provide a unique opportunity to investigate processes that operated during warm (high CO(2)) climate states. Palaeoclimate and environmental reconstruction/modelling are facilitating the assessment and calculation of the response of global temperatures to increasing CO(2) concentrations in the longer term (multiple centuries); this is now referred to as the Earth System Sensitivity, which is critical in identifying CO(2) thresholds in the atmosphere that must not be crossed to avoid dangerous levels of climate change in the long term. Palaeoclimatology also provides a unique and independent way to evaluate the qualities of climate and Earth system models used to predict future climate. PMID- 21282156 TI - Sediment flux and the Anthropocene. AB - Data and computer simulations are reviewed to help better define the timing and magnitude of human influence on sediment flux--the Anthropocene epoch. Impacts on the Earth surface processes are not spatially or temporally homogeneous. Human influences on this sediment flux have a secondary effect on floodplain and delta plain functions and sediment dispersal into the coastal ocean. Human impact on sediment production began 3000 years ago but accelerated more widely 1000 years ago. By the sixteenth century, societies were already engineering their environment. Early twentieth century mechanization has led to global signals of increased sediment flux in most large rivers. By the 1950s, this sediment disturbance signal reversed for many rivers owing to the proliferation of dams, and sediment load reduction below pristine conditions is the dominant signal today. A delta subsidence signal began in the 1930s and is now a dominant signal in terms of sea level for many coastal environments, overwhelming even the global warming imprint on sea level. Humans have engineered how most water and sediment are discharged into the coastal ocean. Hyperpycnal flow events have become more common for some rivers, and less common for other rivers. Bottom trawling is now widespread, suggesting that even continental shelves have received a significant but as yet quantified Anthropocene impact. The Anthropocene attains the level of a geological climate event, such as that seen in the transition between the Pleistocene and the Holocene. PMID- 21282157 TI - Anthropocene streams and base-level controls from historic dams in the unglaciated mid-Atlantic region, USA. AB - Recently, widespread valley-bottom damming for water power was identified as a primary control on valley sedimentation in the mid-Atlantic US during the late seventeenth to early twentieth century. The timing of damming coincided with that of accelerated upland erosion during post-European settlement land-use change. In this paper, we examine the impact of local drops in base level on incision into historic reservoir sediment as thousands of ageing dams breach. Analysis of lidar and field data indicates that historic milldam building led to local base-level rises of 2-5 m (typical milldam height) and reduced valley slopes by half. Subsequent base-level fall with dam breaching led to an approximate doubling in slope, a significant base-level forcing. Case studies in forested, rural as well as agricultural and urban areas demonstrate that a breached dam can lead to stream incision, bank erosion and increased loads of suspended sediment, even with no change in land use. After dam breaching, key predictors of stream bank erosion include number of years since dam breach, proximity to a dam and dam height. One implication of this work is that conceptual models linking channel condition and sediment yield exclusively with modern upland land use are incomplete for valleys impacted by milldams. With no equivalent in the Holocene or late Pleistocene sedimentary record, modern incised stream-channel forms in the mid-Atlantic region represent a transient response to both base-level forcing and major changes in land use beginning centuries ago. Similar channel forms might also exist in other locales where historic milling was prevalent. PMID- 21282158 TI - Anthropogenic transformation of the terrestrial biosphere. AB - Human populations and their use of land have transformed most of the terrestrial biosphere into anthropogenic biomes (anthromes), causing a variety of novel ecological patterns and processes to emerge. To assess whether human populations and their use of land have directly altered the terrestrial biosphere sufficiently to indicate that the Earth system has entered a new geological epoch, spatially explicit global estimates of human populations and their use of land were analysed across the Holocene for their potential to induce irreversible novel transformation of the terrestrial biosphere. Human alteration of the terrestrial biosphere has been significant for more than 8000 years. However, only in the past century has the majority of the terrestrial biosphere been transformed into intensively used anthromes with predominantly novel anthropogenic ecological processes. At present, even were human populations to decline substantially or use of land become far more efficient, the current global extent, duration, type and intensity of human transformation of ecosystems have already irreversibly altered the terrestrial biosphere at levels sufficient to leave an unambiguous geological record differing substantially from that of the Holocene or any prior epoch. It remains to be seen whether the anthropogenic biosphere will be sustained and continue to evolve. PMID- 21282159 TI - Stratigraphy of the Anthropocene. AB - The Anthropocene, an informal term used to signal the impact of collective human activity on biological, physical and chemical processes on the Earth system, is assessed using stratigraphic criteria. It is complex in time, space and process, and may be considered in terms of the scale, relative timing, duration and novelty of its various phenomena. The lithostratigraphic signal includes both direct components, such as urban constructions and man-made deposits, and indirect ones, such as sediment flux changes. Already widespread, these are producing a significant 'event layer', locally with considerable long-term preservation potential. Chemostratigraphic signals include new organic compounds, but are likely to be dominated by the effects of CO(2) release, particularly via acidification in the marine realm, and man-made radionuclides. The sequence stratigraphic signal is negligible to date, but may become geologically significant over centennial/millennial time scales. The rapidly growing biostratigraphic signal includes geologically novel aspects (the scale of globally transferred species) and geologically will have permanent effects. PMID- 21282160 TI - Humans as major geological and geomorphological agents in the Anthropocene: the significance of artificial ground in Great Britain. AB - Since the first prehistoric people started to dig for stone to make implements, rather than pick up loose material, humans have modified the landscape through excavation of rock and soil, generation of waste and creation of artificial ground. In Great Britain over the past 200 years, people have excavated, moved and built up the equivalent of at least six times the volume of Ben Nevis. It is estimated that the worldwide deliberate annual shift of sediment by human activity is 57,000 Mt (million tonnes) and exceeds that of transport by rivers to the oceans (22,000 Mt) almost by a factor of three. Humans sculpt and transform the landscape through the physical modification of the shape and properties of the ground. As such, humans are geological and geomorphological agents and the dominant factor in landscape evolution through settlement and widespread industrialization and urbanization. The most significant impact of this has been since the onset of the Industrial Revolution in the eighteenth century, coincident with increased release of greenhouse gases to the atmosphere. The anthropogenic sedimentological record, therefore, provides a marker on which to characterize the Anthropocene. PMID- 21282161 TI - Chemical signatures of the Anthropocene in the Clyde estuary, UK: sediment-hosted Pb, (207/206)Pb, total petroleum hydrocarbon, polyaromatic hydrocarbon and polychlorinated biphenyl pollution records. AB - The sediment concentrations of total petroleum hydrocarbons (TPHs), polyaromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), Pb and (207/206)Pb isotope ratios were measured in seven cores from the middle Clyde estuary (Scotland, UK) with an aim of tracking the late Anthropocene. Concentrations of TPHs ranged from 34 to 4386 mg kg(-1), total PAHs from 19 to 16,163 MUg kg(-1) and total PCBs between less than 4.3 to 1217 MUg kg(-1). Inventories, distributions and isomeric ratios of the organic pollutants were used to reconstruct pollutant histories. Pre-Industrial Revolution and modern non-polluted sediments were characterized by low TPH and PAH values as well as high relative abundance of biogenic-sourced phenanthrene and naphthalene. The increasing industrialization of the Clyde gave rise to elevated PAH concentrations and PAH isomeric ratios characteristic of both grass/wood/coal and petroleum and combustion (specifically petroleum combustion). Overall, PAHs had the longest history of any of the organic contaminants. Increasing TPH concentrations and a concomitant decline in PAHs mirrored the lessening of coal use and increasing reliance on petroleum fuels from about the 1950s. Thereafter, declining hydrocarbon pollution was followed by the onset (1950s), peak (1965-1977) and decline (post-1980s) in total PCB concentrations. Lead concentrations ranged from 6 to 631 mg kg(-1), while (207/206)Pb isotope ratios spanned 0.838-0.876, indicative of various proportions of 'background', British ore/coal and Broken Hill type petrol/industrial lead. A chronology was established using published Pb isotope data for aerosol-derived Pb and applied to the cores. PMID- 21282162 TI - New directions in biological research on polarized light. Preface. PMID- 21282163 TI - New directions in the detection of polarized light. PMID- 21282165 TI - Patterns and properties of polarized light in air and water. AB - Natural sources of light are at best weakly polarized, but polarization of light is common in natural scenes in the atmosphere, on the surface of the Earth, and underwater. We review the current state of knowledge concerning how polarization and polarization patterns are formed in nature, emphasizing linearly polarized light. Scattering of sunlight or moonlight in the sky often forms a strongly polarized, stable and predictable pattern used by many animals for orientation and navigation throughout the day, at twilight, and on moonlit nights. By contrast, polarization of light in water, while visible in most directions of view, is generally much weaker. In air, the surfaces of natural objects often reflect partially polarized light, but such reflections are rarer underwater, and multiple-path scattering degrades such polarization within metres. Because polarization in both air and water is produced by scattering, visibility through such media can be enhanced using straightforward polarization-based methods of image recovery, and some living visual systems may use similar methods to improve vision in haze or underwater. Although circularly polarized light is rare in nature, it is produced by the surfaces of some animals, where it may be used in specialized systems of communication. PMID- 21282166 TI - The molecular basis of mechanisms underlying polarization vision. AB - The underlying mechanisms of polarization sensitivity (PS) have long remained elusive. For rhabdomeric photoreceptors, questions remain over the high levels of PS measured experimentally. In ciliary photoreceptors, and specifically cones, little direct evidence supports any type of mechanism. In order to promote a greater interest in these fundamental aspects of polarization vision, we examined a varied collection of studies linking membrane biochemistry, protein-protein interactions, molecular ordering and membrane phase behaviour. While initially these studies may seem unrelated to polarization vision, a common narrative emerges. A surprising amount of evidence exists demonstrating the importance of protein-protein interactions in both rhabdomeric and ciliary photoreceptors, indicating the possible long-range ordering of the opsin protein for increased PS. Moreover, we extend this direction by considering how such protein paracrystalline organization arises in all cell types from controlled membrane phase behaviour and propose a universal pathway for PS to occur in both rhabdomeric and cone photoreceptors. PMID- 21282167 TI - Inversion by P4: polarization-picture post-processing. AB - Polarization may be sensed by imaging modules. This is done in various engineering systems as well as in biological systems, specifically by insects and some marine species. However, polarization per pixel is usually not the direct variable of interest. Rather, polarization-related data serve as a cue for recovering task-specific scene information. How should polarization-picture post processing (P(4)) be done for the best scene understanding? Answering this question is not only helpful for advanced engineering (computer vision), but also to prompt hypotheses as to the processing occurring within biological systems. In various important cases, the answer is found by a principled expression of scene recovery as an inverse problem. Such an expression relies directly on a physics based model of effects in the scene. The model includes analysis that depends on the different polarization components, thus facilitating the use of these components during the inversion, in a proper, even if non-trivial, manner. We describe several examples for this approach. These include automatic removal of path radiance in haze or underwater, overcoming partial semireflections and visual reverberations; three-dimensional recovery and distance-adaptive denoising. The resulting inversion algorithms rely on signal-processing methods, such as independent component analysis, deconvolution and optimization. PMID- 21282168 TI - Underwater linear polarization: physical limitations to biological functions. AB - Polarization sensitivity is documented in a range of marine animals. The variety of tasks for which animals can use this sensitivity, and the range over which they do so, are confined by the visual systems of these animals and by the propagation of the polarization information in the aquatic environment. We examine the environmental physical constraints in an attempt to reveal the depth, range and other limitations to the use of polarization sensitivity by marine animals. In clear oceanic waters, navigation that is based on the polarization pattern of the sky appears to be limited to shallow waters, while solar-based navigation is possible down to 200-400 m. When combined with intensity difference, polarization sensitivity allows an increase in target detection range by 70-80% with an upper limit of 15 m for large-eyed animals. This distance will be significantly smaller for small animals, such as plankton, and in turbid waters. Polarization-contrast detection, which is relevant to object detection and communication, is strongly affected by water conditions and in clear waters its range limit may reach 15 m as well. We show that polarization sensitivity may also serve for target distance estimation, when examining point source bioluminescent objects in the photic mesopelagic depth range. PMID- 21282169 TI - Polarization sensitivity as a contrast enhancer in pelagic predators: lessons from in situ polarization imaging of transparent zooplankton. AB - Because light in the pelagic environment is partially polarized, it has been suggested that the polarization sensitivity found in certain pelagic species may serve to enhance the contrast of their transparent zooplankton prey. We examined its potential during cruises in the Gulf of Mexico and Atlantic Ocean and at a field station on the Great Barrier Reef. First, we collected various species of transparent zooplankton and micronekton and photographed them between crossed polarizers. Many groups, particularly the cephalopods, pelagic snails, salps and ctenophores, were found to have ciliary, muscular or connective tissues with striking birefringence. In situ polarization imagery of the same species showed that, while the degree of underwater polarization was fairly high (approx. 30% in horizontal lines of sight), tissue birefringence played little to no role in increasing visibility. This is most likely due to the low radiance of the horizontal background light when compared with the downwelling irradiance. In fact, the dominant radiance and polarization contrasts are due to unpolarized downwelling light that has been scattered from the animal viewed against the darker and polarized horizontal background light. We show that relatively simple algorithms can use this negative polarization contrast to increase visibility substantially. PMID- 21282170 TI - Navigation by light polarization in clear and turbid waters. AB - Certain terrestrial animals use sky polarization for navigation. Certain aquatic species have also been shown to orient according to a polarization stimulus, but the correlation between underwater polarization and Sun position and hence the ability to use underwater polarization as a compass for navigation is still under debate. To examine this issue, we use theoretical equations for per cent polarization and electric vector (e-vector) orientation that account for the position of the Sun, refraction at the air-water interface and Rayleigh single scattering. The polarization patterns predicted by these theoretical equations are compared with measurements conducted in clear and semi-turbid coastal sea waters at 2 m and 5 m depth over sea floors of 6 m and 28 m depth. We find that the per cent polarization is correlated with the Sun's elevation only in clear waters. We furthermore find that the maximum value of the e-vector orientation angle equals the angle of refraction only in clear waters, in the horizontal viewing direction, over the deeper sea floor. We conclude that navigation by use of underwater polarization is possible under restricted conditions, i.e. in clear waters, primarily near the horizontal viewing direction, and in locations where the sea floor has limited effects on the light's polarization. PMID- 21282171 TI - Central neural coding of sky polarization in insects. AB - Many animals rely on a sun compass for spatial orientation and long-range navigation. In addition to the Sun, insects also exploit the polarization pattern and chromatic gradient of the sky for estimating navigational directions. Analysis of polarization-vision pathways in locusts and crickets has shed first light on brain areas involved in sky compass orientation. Detection of sky polarization relies on specialized photoreceptor cells in a small dorsal rim area of the compound eye. Brain areas involved in polarization processing include parts of the lamina, medulla and lobula of the optic lobe and, in the central brain, the anterior optic tubercle, the lateral accessory lobe and the central complex. In the optic lobe, polarization sensitivity and contrast are enhanced through convergence and opponency. In the anterior optic tubercle, polarized light signals are integrated with information on the chromatic contrast of the sky. Tubercle neurons combine responses to the UV/green contrast and e-vector orientation of the sky and compensate for diurnal changes of the celestial polarization pattern associated with changes in solar elevation. In the central complex, a topographic representation of e-vector tunings underlies the columnar organization and suggests that this brain area serves as an internal compass coding for spatial directions. PMID- 21282172 TI - Polarization-based brightness discrimination in the foraging butterfly, Papilio xuthus. AB - The human eye is insensitive to the angular direction of the light e-vector, but several animal species have the ability to discriminate differently polarized lights. How the polarization is detected is often unclear, however. Egg-laying Papilio butterflies have been shown to see false colours when presented with differently polarized lights. Here we asked whether this also holds in foraging butterflies. After training individuals to feed on nectar in front of an unpolarized spectral light, we carried out three dual-choice tests, where the discrimination of (i) the spectral content, (ii) the light intensity, and (iii) the e-vector orientation were investigated. In the first test, the butterflies selected the trained spectrum irrespective of its intensity, and in the second test they chose the light with the higher intensity. The result of the e-vector discrimination test was very similar to that of the second test, suggesting that foraging butterflies discriminate differently polarized lights as differing in brightness rather than as differing in colour. Papilio butterflies are clearly able to use at least two modes of polarization vision depending on the behavioural context. PMID- 21282173 TI - How dim is dim? Precision of the celestial compass in moonlight and sunlight. AB - Prominent in the sky, but not visible to humans, is a pattern of polarized skylight formed around both the Sun and the Moon. Dung beetles are, at present, the only animal group known to use the much dimmer polarization pattern formed around the Moon as a compass cue for maintaining travel direction. However, the Moon is not visible every night and the intensity of the celestial polarization pattern gradually declines as the Moon wanes. Therefore, for nocturnal orientation on all moonlit nights, the absolute sensitivity of the dung beetle's polarization detector may limit the precision of this behaviour. To test this, we studied the straight-line foraging behaviour of the nocturnal ball-rolling dung beetle Scarabaeus satyrus to establish when the Moon is too dim--and the polarization pattern too weak--to provide a reliable cue for orientation. Our results show that celestial orientation is as accurate during crescent Moon as it is during full Moon. Moreover, this orientation accuracy is equal to that measured for diurnal species that orient under the 100 million times brighter polarization pattern formed around the Sun. This indicates that, in nocturnal species, the sensitivity of the optical polarization compass can be greatly increased without any loss of precision. PMID- 21282174 TI - Honeybee navigation: following routes using polarized-light cues. AB - While it is generally accepted that honeybees (Apis mellifera) are capable of using the pattern of polarized light in the sky to navigate to a food source, there is little or no direct behavioural evidence that they actually do so. We have examined whether bees can be trained to find their way through a maze composed of four interconnected tunnels, by using directional information provided by polarized light illumination from the ceilings of the tunnels. The results show that bees can learn this task, thus demonstrating directly, and for the first time, that bees are indeed capable of using the polarized-light information in the sky as a compass to steer their way to a food source. PMID- 21282175 TI - Polarized iridescence of the multilayered elytra of the Japanese jewel beetle, Chrysochroa fulgidissima. AB - The elytra of the Japanese jewel beetle Chrysochroa fulgidissima are metallic green with purple stripes. Scanning electron microscopy and atomic force microscopy demonstrated that the elytral surface is approximately flat. The accordingly specular green and purple areas have, with normal illumination, 100 150 nm broad reflectance bands, peaking at about 530 and 700 nm. The bands shift progressively towards shorter wavelengths with increasing oblique illumination, and the reflection then becomes highly polarized. Transmission electron microscopy revealed that the epicuticle of the green and purple areas consists of stacks of 16 and 12 layers, respectively. Assuming gradient refractive index values of the layers between 1.6 and 1.7 and applying the classical multilayer theory allowed modelling of the measured polarization- and angle-dependent reflectance spectra. The extreme polarized iridescence exhibited by the elytra of the jewel beetle may have a function in intraspecific recognition. PMID- 21282176 TI - The retinal topography of three species of coleoid cephalopod: significance for perception of polarized light. AB - The retinal topography of three species of coleoid cephalopod (one cuttlefish, one squid and one octopus) was investigated to examine and compare the structure, density and organization of the photoreceptors. The aim was to determine if there were areas of increased cell density and/or cell specialization that might be related to lifestyle or phylogeny. The orientation of photoreceptors around the curved surface of the retina was also mapped to reveal how the overall arrangement of cell microvilli might enable the perception of polarized light stimuli. It was found that all species possessed an increase in photoreceptor density in a horizontal streak approximately placed at the position of a potential horizon in the habitat. The overall arrangement of photoreceptor microvillar arrangements followed lines of latitude and longitude in a global projection that has been rotated by 90 degrees . This arrangement seems to map polarization sensitivities on the outside world in a vertical and horizontal grid. The potential significance of this and other retinal specializations is discussed in the context of phylogenetic and habitat differences between species. PMID- 21282177 TI - Behavioural relevance of polarization sensitivity as a target detection mechanism in cephalopods and fishes. AB - Aquatic habitats are rich in polarized patterns that could provide valuable information about the environment to an animal with a visual system sensitive to polarization of light. Both cephalopods and fishes have been shown to behaviourally respond to polarized light cues, suggesting that polarization sensitivity (PS) may play a role in improving target detection and/or navigation/orientation. However, while there is general agreement concerning the presence of PS in cephalopods and some fish species, its functional significance remains uncertain. Testing the role of PS in predator or prey detection seems an excellent paradigm with which to study the contribution of PS to the sensory assets of both groups, because such behaviours are critical to survival. We developed a novel experimental set-up to deliver computer-generated, controllable, polarized stimuli to free-swimming cephalopods and fishes with which we tested the behavioural relevance of PS using stimuli that evoke innate responses (such as an escape response from a looming stimulus and a pursuing behaviour of a small prey-like stimulus). We report consistent responses of cephalopods to looming stimuli presented in polarization and luminance contrast; however, none of the fishes tested responded to either the looming or the prey like stimuli when presented in polarization contrast. PMID- 21282178 TI - Teleost polarization vision: how it might work and what it might be good for. AB - In this review, we will discuss the recent literature on fish polarization vision and we will present a model on how the retina processes polarization signals. The model is based on a general retinal-processing scheme and will be compared with the available electrophysiological data on polarization processing in the retina. The results of this model will help illustrate the functional significance of polarization vision for both feeding behaviour and navigation. First, we examine the linkage between structure and function in polarization vision in general. PMID- 21282179 TI - An unsuccessful attempt to elicit orientation responses to linearly polarized light in hatchling loggerhead sea turtles (Caretta caretta). AB - Sea turtles undertake long migrations in the open ocean, during which they rely at least partly on magnetic cues for navigation. In principle, sensitivity to polarized light might be an additional sensory capability that aids navigation. Furthermore, polarization sensitivity has been linked to ultraviolet (UV) light perception which is present in sea turtles. Here, we tested the ability of hatchling loggerheads (Caretta caretta) to maintain a swimming direction in the presence of broad-spectrum polarized light. At the start of each trial, hatchling turtles, with their magnetic sense temporarily impaired by magnets, successfully established a steady course towards a light-emitting diode (LED) light source while the polarized light field was present. When the LED was removed, however, hatchlings failed to maintain a steady swimming direction, even though the polarized light field remained. Our results have failed to provide evidence for polarized light perception in young sea turtles and suggest that alternative cues guide the initial migration offshore. PMID- 21282180 TI - Behavioural and physiological mechanisms of polarized light sensitivity in birds. AB - Polarized light (PL) sensitivity is relatively well studied in a large number of invertebrates and some fish species, but in most other vertebrate classes, including birds, the behavioural and physiological mechanism of PL sensitivity remains one of the big mysteries in sensory biology. Many organisms use the skylight polarization pattern as part of a sun compass for orientation, navigation and in spatial orientation tasks. In birds, the available evidence for an involvement of the skylight polarization pattern in sun-compass orientation is very weak. Instead, cue-conflict and cue-calibration experiments have shown that the skylight polarization pattern near the horizon at sunrise and sunset provides birds with a seasonally and latitudinally independent compass calibration reference. Despite convincing evidence that birds use PL cues for orientation, direct experimental evidence for PL sensitivity is still lacking. Avian double cones have been proposed as putative PL receptors, but detailed anatomical and physiological evidence will be needed to conclusively describe the avian PL receptor. Intriguing parallels between the functional and physiological properties of PL reception and light-dependent magnetoreception could point to a common receptor system. PMID- 21282181 TI - On the trail of Vikings with polarized skylight: experimental study of the atmospheric optical prerequisites allowing polarimetric navigation by Viking seafarers. AB - Between AD 900 and AD 1200 Vikings, being able to navigate skillfully across the open sea, were the dominant seafarers of the North Atlantic. When the Sun was shining, geographical north could be determined with a special sundial. However, how the Vikings could have navigated in cloudy or foggy situations, when the Sun's disc was unusable, is still not fully known. A hypothesis was formulated in 1967, which suggested that under foggy or cloudy conditions, Vikings might have been able to determine the azimuth direction of the Sun with the help of skylight polarization, just like some insects. This hypothesis has been widely accepted and is regularly cited by researchers, even though an experimental basis, so far, has not been forthcoming. According to this theory, the Vikings could have determined the direction of the skylight polarization with the help of an enigmatic birefringent crystal, functioning as a linearly polarizing filter. Such a crystal is referred to as 'sunstone' in one of the Viking's sagas, but its exact nature is unknown. Although accepted by many, the hypothesis of polarimetric navigation by Vikings also has numerous sceptics. In this paper, we summarize the results of our own celestial polarization measurements and psychophysical laboratory experiments, in which we studied the atmospheric optical prerequisites of possible sky-polarimetric navigation in Tunisia, Finland, Hungary and the high Arctic. PMID- 21282182 TI - ISCB public policy statement on open access to scientific and technical research literature. PMID- 21282183 TI - Synergism between NOD-like receptors and Toll-like receptors in human B lymphocytes. PMID- 21282184 TI - Incident hepatitis C virus infection among US HIV-infected men enrolled in clinical trials. AB - BACKGROUND: Outbreaks of sexually transmitted hepatitis C virus (HCV) infection have been reported among human immunodeficiency virus (HIV)-infected men who have sex with men in Europe, Australia, and New York. Whether this is occurring across the United States is unknown. METHODS: We determined incidence of HCV infection during 1996-2008 among male participants of the AIDS Clinical Trial Group Longitudinal Linked Randomized Trials cohort, a long-term study of HIV-infected persons randomized into selected US-based clinical trials. We evaluated associations with self-reported injection drug use (IDU), time-varying CD4(+) cell count, and HIV RNA level with use of multivariate Poisson regression. No sexual or non-IDU risk factor data was available. RESULTS: A total of 1830 men had an initial negative HCV antibody test result and at least 1 subsequent HCV antibody test result, contributing >7000 person-years. At the time of the initial negative HCV antibody test result, 94% of men were receiving highly active antiretroviral therapy (HAART) and 6% reported current or prior IDU. Thirty-six seroconverted, with overall incidence of .51 cases per 100 person-years (95% confidence interval, .36-.70). Mean age at seroconversion was 46 years. Seroconversion was associated with IDU (25% of seroconverters reported IDU history vs 5% of nonseroconverters; P < .001), whereas 75% (n = 27) of seroconverters reported no IDU (incidence, 2.67 cases per 100 person-years among IDUs, .40 cases per 100 person-years among non-IDUs). Seroconversion was associated with HIV RNA level >400 copies/mL (44% at time of antibody positivity vs 21% at time of last negative antibody test result; P = .02) but not with CD4(+) cell count. CONCLUSIONS: Incident HCV infection occurs in HIV-infected men involved in US HIV therapeutic trials, primarily through nonparenteral means, despite engagement in care and HAART. HCV antibody development was not related to immune status but was associated with inadequate HIV suppression. At-risk HIV infected persons should have access to HCV surveillance. PMID- 21282185 TI - Patterns and characteristics of hepatitis C transmission clusters among HIV positive and HIV-negative individuals in the Australian trial in acute hepatitis C. AB - BACKGROUND: Injecting drug users remain the population at greatest risk of acquiring hepatitis C virus (HCV) infection, although a recent increase in cases of sexually transmitted HCV infection has been observed among human immunodeficiency virus (HIV)-infected individuals. The extent to which these separate epidemics overlap is unknown. METHODS: The Australian Trial in Acute Hepatitis C (ATAHC) enrolled 163 individuals (29% of whom were HIV infected) with recent HCV infection. E1/HVR1 sequences were used to construct phylogenetic trees demonstrating monophyletic clusters or pairs, and viral epidemic history and phylogeography were assessed using molecular clock analysis. Individual clusters were characterized by clinical and demographic characteristics. RESULTS: Transmission through injection drug use occurred for 73% of subjects, with sexual transmission occurring for 18% (92% of whom were HIV infected). Among 112 individuals with available E1/HVR1 sequences, 23 (20%) were infected with a strain of HCV identical to that of another subject, comprising 4 homologous clusters and 3 monophyletic pairs, the majority of which (78%) were HIV infected. Clusters contained individuals with both injection drug use-related and sex related acquisition, and in all clusters (except for 1 female HIV-uninfected pair), individuals identified as men who have sex with men, irrespective of HIV status. CONCLUSIONS: This large unique study of HIV-infected and HIV-uninfected individuals with recently acquired HCV infection demonstrates that clustering is common in the HIV-infected population and that it occurred almost invariably among men who have sex with men, irrespective of the actual mode of acquisition. These findings suggest the coexistence of both injection drug use and sexual risk behaviors for individuals in the same social networks and have implications for the development of public health messages. Clinical trial registration. NCT00192569. PMID- 21282186 TI - Functional analysis of BBS3 A89V that results in non-syndromic retinal degeneration. AB - Bardet-Biedl syndrome (BBS) is a syndromic form of retinal degeneration. Recently, homozygosity mapping with a consanguineous family with isolated retinitis pigmentosa identified a missense mutation in BBS3, a known BBS gene. The mutation in BBS3 encodes a single amino acid change at position 89 from alanine to valine. Since this amino acid is conserved in a wide range of vertebrates, we utilized the zebrafish model system to functionally characterize the BBS3 A89V mutation. Knockdown of bbs3 in zebrafish alters intracellular transport, a phenotype observed with knockdown of all BBS genes in the zebrafish, as well as visual impairment. Here, we find that BBS3 A89V is sufficient to rescue the transport delays induced by the loss of bbs3, indicating that this mutation does not affect the function of BBS3 as it relates to syndromic disease. BBS3L A89V, however, was unable to rescue vision impairment, highlighting a role for a specific amino acid within BBS3 that is necessary for visual function, but dispensable in other cell types. These data aid in our understanding of why patients with the BBS3 A89V missense mutation only present with isolated retinitis pigmentosa. PMID- 21282187 TI - Disruption of genomic neighbourhood at the imprinted IGF2-H19 locus in Beckwith Wiedemann syndrome and Silver-Russell syndrome. AB - Hyper- and hypomethylation at the IGF2-H19 imprinting control region (ICR) result in reciprocal changes in IGF2-H19 expression and the two contrasting growth disorders, Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS). DNA methylation of the ICR controls the reciprocal imprinting of IGF2 and H19 by preventing the binding of the insulator protein, CTCF. We here show that local changes in histone modifications and CTCF--cohesin binding at the ICR in BWS and SRS together with DNA methylation correlate with the higher order chromatin structure at the locus. In lymphoblastoid cells from control individuals, we found the repressive histone H3K9me3 and H4K20me3 marks associated with the methylated paternal ICR allele and the bivalent H3K4me2/H3K27me3 mark together with H3K9ac and CTCF--cohesin associated with the non-methylated maternal allele. In patient-derived cell lines, the mat/pat asymmetric distribution of these epigenetic marks was lost with H3K9me3 and H4K20me3 becoming biallelic in the BWS and H3K4me2, H3K27me3 and H3K9ac together with CTCF-cohesin becoming biallelic in the SRS. We further show that in BWS and SRS cells, there is opposing chromatin looping conformation mediated by CTCF--cohesin binding sites surrounding the locus. In normal cells, lack of CTCF--cohesin binding at the paternal ICR is associated with monoallelic interaction between two CTCF sites flanking the locus. CTCF--cohesin binding at the maternal ICR blocks this interaction by associating with the CTCF site downstream of the enhancers. The two alternative chromatin conformations are differently favoured in BWS and SRS likely predisposing the locus to the activation of IGF2 or H19, respectively. PMID- 21282188 TI - Mutations in PPIB (cyclophilin B) delay type I procollagen chain association and result in perinatal lethal to moderate osteogenesis imperfecta phenotypes. AB - Recessive mutations in the cartilage-associated protein (CRTAP), leucine proline enriched proteoglycan 1 (LEPRE1) and peptidyl prolyl cis-trans isomerase B (PPIB) genes result in phenotypes that range from lethal in the perinatal period to severe deforming osteogenesis imperfecta (OI). These genes encode CRTAP (encoded by CRTAP), prolyl 3-hydroxylase 1 (P3H1; encoded by LEPRE1) and cyclophilin B (CYPB; encoded by PPIB), which reside in the rough endoplasmic reticulum (RER) and can form a complex involved in prolyl 3-hydroxylation in type I procollagen. CYPB, a prolyl cis-trans isomerase, has been thought to drive the prolyl containing peptide bonds to the trans configuration needed for triple helix formation. Here, we describe mutations in PPIB identified in cells from three individuals with OI. Cultured dermal fibroblasts from the most severely affected infant make some overmodified type I procollagen molecules. Proalpha1(I) chains are slow to assemble into trimers, and abnormal procollagen molecules concentrate in the RER, and bind to protein disulfide isomerase (PDI) and prolyl 4 hydroxylase 1 (P4H1). These findings suggest that although CYPB plays a role in helix formation another effect is on folding of the C-terminal propeptide and trimer formation. The extent of procollagen accumulation and PDI/P4H1 binding differs among cells with mutations in PPIB, CRTAP and LEPRE1 with the greatest amount in PPIB-deficient cells and the least in LEPRE1-deficient cells. These findings suggest that prolyl cis-trans isomerase may be required to effectively fold the proline-rich regions of the C-terminal propeptide to allow proalpha chain association and suggest an order of action for CRTAP, P3H1 and CYPB in procollagen biosynthesis and pathogenesis of OI. PMID- 21282189 TI - A complex regulatory network of transcription factors critical for ocular development and disease. AB - The PITX2 'homeobox' and FOXC1 and FOXC2 'forkhead box' transcription factors are critical for eye development and cause human ocular diseases when mutated. We have identified biochemical and genetic links between these transcription factors and a transcriptional regulator protein PRKC apoptosis Wilms' tumor 1 regulator (PAWR) that we propose to functionally connect all these proteins in a common pathway critically involved in eye development. We discovered all binary physical interactions between FOXC1, PITX2, FOXC2 and PAWR. Importantly, PAWR modulates the abilities of PITX2, FOXC1 and FOXC2 to activate their genetic targets. Together with either FOXC1 or FOXC2, PAWR increases PITX2 activity. PAWR reduces PITX2 activity in the absence of FOXC1 or FOXC2. At the same time, PAWR also exerts different regulatory effects on different FOXC target sites. Furthermore, morpholino knockdown of pitx2, foxc1 and pawr in zebrafish indicate that PAWR, FOXC1 and PITX2 genetically interact, and are in the same developmental pathway. These data for the first time tie PITX2, FOXC1, FOXC2 and PAWR into a common regulatory pathway. We have therefore identified a functional link between three transcription factors, modulated by PAWR, which we propose underlies the similar ocular phenotypes and glaucoma pathology caused by mutations of these genes. PMID- 21282190 TI - Prevention of hepatitis C virus in injecting drug users: a narrow window of opportunity. PMID- 21282191 TI - Changes in blood-borne infection risk among injection drug users. AB - BACKGROUND: Population-level hepatitis C virus (HCV) infection incidence is a surrogate for community drug-related risk. METHODS: We characterized trends in human immunodeficiency virus (HIV) and HCV infection incidence and HCV infection prevalence among injection drug users (IDUs) recruited over 4 periods: 1988-1989, 1994-1995, 1998, and 2005-2008. We calculated HIV and HCV infection incidence within the first year of follow-up among IDUs whose test results were negative for these viruses at baseline (n = 2061 and n = 373, respectively). We used Poisson regression to compare trends across groups. RESULTS: HIV infection incidence declined significantly from 5.5 cases/100 person-years (py) in the 1988 1989 group to 2.0 cases/100 py in the 1994-1995 group to 0 cases/100 py in the 1998 and 2005-2008 groups. Concurrently, HCV infection incidence declined but remained robust (22.0 cases/100 py in the 1988-1989 cohort to 17.2 cases/100 py in the 1994-1995 cohort, 17.9 cases/100 py in the 1998 cohort, and 7.8 cases/100 py in the 2005-2008 cohort; P = .07). Likewise, HCV infection prevalence declined, but chiefly in younger IDUs. For persons aged <39 years, relative to the 1988-1989 cohort, all groups exhibited significant declines (adjusted prevalence ratio [PR] for the 2005-08 cohort, .73; 95% confidence interval [CI], .65-.81). However, for persons aged >= 39 years, only the 2005-2008 cohort exhibited declining prevalence compared with the 1988-1989 cohort (adjusted PR, .87; 95% CI, .77-.99). CONCLUSIONS: Although efforts to reduce blood-borne infection incidence have had impact, this work will need to be intensified for the most transmissible viruses, such as HCV. PMID- 21282192 TI - Phase 1 safety and immunogenicity testing of DNA and recombinant modified vaccinia Ankara vaccines expressing HIV-1 virus-like particles. AB - BACKGROUND: Recombinant DNA and modified vaccinia virus Ankara (rMVA) vaccines represent a promising approach to an HIV/AIDS vaccine. This Phase 1 clinical trial compared the safety and immunogenicity of a rMVA vaccine administered with and without DNA vaccine priming METHODS: GeoVax pGA2/JS7 DNA (D) and MVA/HIV62 (M) vaccines encode noninfectious virus-like particles. Intramuscular needle injections were used to deliver placebo, 2 doses of DNA followed by 2 doses of rMVA (DDMM), one dose of DNA followed by 2 doses of rMVA (DMM), or 3 doses of rMVA (MMM) to HIV-seronegative participants. RESULTS: Local and systemic symptoms were mild or moderate. Immune response rates for CD4 + and CD8 + T cells were highest in the DDMM group and lowest in the MMM group (77% vs 43% CD4 + and 42% vs 17% CD8 +). In contrast, response rates for Env binding and neutralizing Ab were highest in the MMM group. The DMM group had intermediate response rates. A 1/10th-dose DDMM regimen induced similar T cell but reduced Ab response rates compared with the full-dose DDMM. CONCLUSIONS: MVA62 was well tolerated and elicited different patterns of T cell and Ab responses when administered alone or in combination with the JS7 DNA vaccine. PMID- 21282193 TI - Sequential Rift Valley fever outbreaks in eastern Africa caused by multiple lineages of the virus. AB - BACKGROUND: During the Rift Valley fever (RVF) epidemic of 2006-2007 in eastern Africa, spatial mapping of the outbreaks across Kenya, Somalia, and Tanzania was performed and the RVF viruses were isolated and genetically characterized. METHODS: Following confirmation of the RVF epidemic in Kenya on 19 December 2006 and in Tanzania on 2 February 2007, teams were sent to the field for case finding. Human, livestock, and mosquito specimens were collected and viruses isolated. The World Health Organization response team in Kenya worked with the WHO's polio surveillance team inside Somalia to collect information and specimens from Somalia. RESULTS: Seven geographical foci that reported hundreds of livestock and >25 cases in humans between December 2006 and June 2007 were identified. The onset of RVF cases in each epidemic focus was preceded by heavy rainfall and flooding for at least 10 days. Full-length genome analysis of 16 RVF virus isolates recovered from humans, livestock, and mosquitoes in 5 of the 7 outbreak foci revealed 3 distinct lineages of the viruses within and across outbreak foci. CONCLUSION: The findings indicate that the sequential RVF epidemics in the region were caused by multiple lineages of the RVF virus, sometimes independently activated or introduced in distinct outbreak foci. PMID- 21282194 TI - Safety and immunogenicity of influenza A H5 subunit vaccines: effect of vaccine schedule and antigenic variant. AB - BACKGROUND: The current US national stockpile of influenza H5 vaccine was produced using the antigen from the strain A/Vietnam/1203/2004 (a clade 1 H5 virus). Recent H5 disease has been caused by antigenically divergent H5 viruses, including A/Indonesia/05/2005 (a clade 2 H5 virus). METHODS: The influence of schedule on the antibody response to 2 doses of H5 vaccines (one a clade 1 hemagglutinin protein [HA] vaccine and one a clade 2 HA vaccine) containing 90 MUg of antigen was evaluated in healthy adults 18-49 years of age. RESULTS: Two doses of vaccine were required to induce antibody titers >= 1:10 in most subjects. Accelerated schedules were immunogenic, and antibody developed after vaccinations on days 0 and 7, 0 and 14, and 0 and 28, with the day 0 and 7 schedule inducing lower titers than those induced with the other schedules. With mixed vaccine schedules of clade 1 followed by clade 2 vaccine administration, the first vaccination primed for a heterologous boost. The heterologous response was improved when the second vaccination was given 6 months after the first, compared with the response when the second vaccination was given after an interval of 1 month. CONCLUSIONS: An accelerated vaccine schedule of injections administered at days 0 and 14 was as immunogenic as a vaccine schedule of injections at days 0 and 28, but both schedules were inferior to a vaccine schedule of injections administered at 0 and 6 months for priming for heterologous vaccine boosting. Clinical Trial Registry Number: NCT00703053. PMID- 21282195 TI - Circulating red cell-derived microparticles in human malaria. AB - In patients with falciparum malaria, plasma concentrations of cell-derived microparticles correlate with disease severity. Using flow cytometry, we quantified red blood cell-derived microparticles (RMPs) in patients with malaria and identified the source and the factors associated with production. RMP concentrations were increased in patients with Plasmodium falciparum (n = 29; median, 457 RMPs/MUL [range, 13-4,342 RMPs/MUL]), Plasmodium vivax (n = 5; median, 409 RMPs/MUL [range, 281-503/MUL]), and Plasmodium malariae (n = 2; median, 163 RMPs/MUL [range, 127-200 RMPs/MUL]) compared with those in healthy subjects (n = 11; median, 8 RMPs/MUL [range, 3-166 RMPs/MUL]; P = .01). RMP concentrations were highest in patients with severe falciparum malaria (P = .01). Parasitized red cells produced >10 times more RMPs than did unparasitized cells, but the overall majority of RMPs still derived from uninfected red blood cells (URBCs). In cultures, RMP production increased as the parasites matured. Hemin and parasite products induced RMP production in URBCs, which was inhibited by N acetylcysteine, suggesting heme-mediated oxidative stress as a pathway for the generation of RMPs. PMID- 21282196 TI - Leishmania major attenuates host immunity by stimulating local indoleamine 2,3 dioxygenase expression. AB - Inflammation stimulates immunity but can create immune privilege in some settings. Here, we show that cutaneous Leishmania major infection stimulated expression of the immune regulatory enzyme indoleamine 2,3 dioxygenase (IDO) in local lymph nodes. Induced IDO attenuated the T cell stimulatory functions of dendritic cells and suppressed local T cell responses to exogenous and nominal parasite antigens. IDO ablation reduced local inflammation and parasite burdens, as did pharmacologic inhibition of IDO in mice with established infections. IDO ablation also enhanced local expression of proinflammatory cytokines and induced some CD4(+) T cells to express interleukin (IL) 17. These findings showed that IDO induced by L. major infection attenuated innate and adaptive immune responses. Thus, IDO acts as a molecular switch regulating host responses, and IDO inhibitor drugs are a potential new approach to enhance host immunity to established leishmania infections. PMID- 21282198 TI - Salvianolic acid B and tanshinone IIA attenuate myocardial ischemia injury in mice by NO production through multiple pathways. AB - OBJECTIVE: Salvia miltiorrhiza (Danshen) has been widely used for the treatment of cardiac and cerebrovascular disease throughout history. The objective of this study is to further elucidate the mechanisms underlying Danshen's cardiac protective effects to support its clinical evidence. METHODS: AND RESULTS: Salvianolic acid B (Sal B) and Tanshinone IIA (Tan IIA) are two of the major components in Danshen. We observed that Sal B and Tan IIA have cardioprotective effects in an in vivo myocardial infarction model of C57 mice, have vasodilator action in a ex vivo micro-artery system through the endothelial nitric oxide synthase (eNOS)/nitric oxide (NO) pathway and are involved in the regulation of the L-arginine/eNOS/NO pathways in human umbilical vein endothelial cells (HUVECs). Both Sal B and Tan IIA inhibited cardiac hypertrophy and infarction sizes and improved cardiac function at 4 weeks after induction of infarction. Furthermore, an eNOS inhibitor (L-NAME) obliterated the observed effects. Sal B and Tan IIA mediated vasodilatation in mice coronaries ex vivo, the effect of which was decreased with either L-NAME or PI3K inhibitor (LY294002). In addition, Sal B and Tan IIA-induced vasodilatation was observed ex vivo in the microvessels of eNOS-/- mice. Sal B and Tan IIA also stimulated eNOS phosphorylation in a concentration- and time-dependent manner in the HUVEC culture, which was diminished by LY294002. In addition, Sal B and Tan IIA were found to stimulate the phosphorylation of AMPK (Thr(172)) and Akt (Ser(473)), while compound C significantly decreased the phosphorylation of Akt (Ser(473)) mediated by both. Finally, Sal B and Tan IIA were found to increase NO production, induce [(3)H]-L arginine uptake and increase the CAT-1 and CAT-2B mRNA levels in HUVEC culture. CONCLUSIONS: These findings suggest that both Sal B and Tan IIA have cardioprotective function in certain levels through multiple targets related with NO production, such as eNOS phosphorylation, L-arginine uptake and CAT expression, which may have major clinical implications. PMID- 21282199 TI - A common polymorphism in the human aromatase gene alters the risk for polycystic ovary syndrome and modifies aromatase activity in vitro. AB - Aromatase is a key enzyme involved in estradiol and estrone biosynthesis. Given that polymorphisms of the CYP19A1 gene encoding aromatase have been correlated with plasma testosterone levels, CYP19A1 may therefore act as a genetic modifier of the hyperandrogenic phenotype of polycystic ovary syndrome (PCOS). However, no functional CYP19A1 polymorphisms that predict the risk of PCOS have been identified. We explored the role of CYP19A1 genetic variation in a large case control study involving 1078 samples, in which five common genetic polymorphisms were scored. Human embryonic kidney 293 cells were transiently transfected with a vector encoding either the CYP19A1 wild-type (WT) allele or an Arg(264)Cys variant to evaluate aromatase activity. Cells were cultured with androstenedione and estrone levels were measured using a specific ELISA. The Arg(264)Cys variant of CYP19A1 (rs700519) is associated with PCOS (P= 0.004, corrected P = 0.02). In this functional study, when cells were cultured in varying concentrations of androstenedione (100, 400 and 500 nM), transfection with the Arg(264)Cys variant resulted in increased conversion of androstenedione to estrogen when compared with transfection with the WT construct (P< 0.001). Our data suggest that the common missense polymorphism rs710059 is associated with susceptibility to PCOS and that the Arg(264)Cys variant may increase aromatase enzymatic activity. Overall, these findings imply that aromatase plays an important role in PCOS. PMID- 21282200 TI - Antithrombotic therapy after percutaneous coronary intervention in anticoagulated patients: a fine balance between thrombosis and bleeding. PMID- 21282201 TI - Carbohydrate-enriched diet impairs cardiac performance by decreasing the utilization of fatty acid and glucose. AB - AIMS: We hypothesized that a high-carbohydrate diet affects the cardiac performance by interfering in the metabolic steps involved in energy transfer in this organ. To verify this, we investigated the myocardial utilization of different substrates and contractile function in rats fed a high-carbohydrate diet, under normal flow and ischemia. METHODS: and RESULTS: Male Wistar rats were fed over 9 days with standard (39.5% carbohydrate, 8% fiber) or high-carbohydrate diet (58% carbohydrate) and, afterwards, their cardiac function was examined using isolated heart preparations. The high-carbohydrate diet decreased the activity of the lipoprotein lipase, utilization of fatty acids, expression of the gene of peroxisome proliferator-activated receptor alpha and its target enzymes. In addition, decreased GLUT4 mass, glucose uptake, glycogen content and glycolytic intermediates were also observed. High-carbohydrate hearts displayed weaker activation of the glycolytic pathway during ischemia, according to minor production of lactate, in relation to control hearts. The functional impairment caused by high-carbohydrate diet shown by the decrease in the ventricular systolic strength, +dT/dt and -dT/dt was, at least in part, due to the low availability of adenosine triphosphate (ATP). CONCLUSION: Our data suggest that a high-carbohydrate diet can damage myocardial contractile function by decreasing the cardiac utilization of glucose and fatty acids and, consequently, the ATP pool. PMID- 21282202 TI - Transesophageal echocardiographic appearance and magnetic resonance imaging of a rare congenital heart disease: Gerbode defect. PMID- 21282203 TI - Developmental adaptations to increased fetal nutrient demand in mouse genetic models of Igf2-mediated overgrowth. AB - The healthy development of the fetus depends on an optimal balance between fetal genetic drive for growth and the maternal ability to provide nutrients through the placenta. Nothing is known about fetal-placental signaling in response to increased fetal demand in the situation of overgrowth. Here, we examined this question using the H19(Delta13) mouse model, shown previously to result in elevated levels of Igf2. Fetal and placental weights in H19(Delta13) were increased by 23% and 45%, respectively, at E19, when compared with wild-type mice. Unexpectedly, we found that disproportionately large H19(Delta13) placentas transport 20-35% less (per gram placenta) glucose and system A amino acids and have similar reductions in passive permeability, despite a significantly greater surface area for nutrient exchange and theoretical diffusion capacity compared with wild-type mice. Expression of key transporter genes Slc2a3 and Slc38a4 was reduced by ~20%. Decreasing the overgrowth of the H19(Delta13) placenta by genetically reducing levels of Igf2P0 resulted in up-regulation of system A activity and maintenance of fetal overgrowth. Our results provide direct evidence that large placentas can modify their nutrient transfer capacity to regulate fetal nutrient acquisition. Our findings are indicative of fetal-placental signaling mechanisms that limit total demand for maternal nutrients. PMID- 21282204 TI - Pharmacological inhibition of myostatin suppresses systemic inflammation and muscle atrophy in mice with chronic kidney disease. AB - Chronic kidney disease (CKD) and several other catabolic conditions are characterized by increased circulating inflammatory cytokines, defects in IGF-1 signaling, abnormal muscle protein metabolism, and progressive muscle atrophy. In these conditions, no reliable treatments successfully block the development of muscle atrophy. In mice with CKD, we found a 2- to 3-fold increase in myostatin expression in muscle. Its pharmacological inhibition by subcutaneous injections of an anti-myostatin peptibody into CKD mice (IC(50) ~1.2 nM) reversed the loss of body weight (~5-7% increase in body mass) and muscle mass (~10% increase in muscle mass) and suppressed circulating inflammatory cytokines vs. results from CKD mice injected with PBS. Pharmacological myostatin inhibition also decreased the rate of protein degradation (16.38 +/- 1.29%; P<0.05), increased protein synthesis in extensor digitorum longus muscles (13.21 +/- 1.09%; P<0.05), markedly enhanced satellite cell function, and improved IGF-1 intracellular signaling. In cultured muscle cells, TNF-alpha increased myostatin expression via a NF-kappaB-dependent pathway, whereas muscle cells exposed to myostatin stimulated IL-6 production via p38 MAPK and MEK1 pathways. Because IL-6 stimulates muscle protein breakdown, we conclude that CKD increases myostatin through cytokine-activated pathways, leading to muscle atrophy. Myostatin antagonism might become a therapeutic strategy for improving muscle growth in CKD and other conditions with similar characteristics. PMID- 21282205 TI - A bioresponsive hydrogel tuned to chondrogenesis of human mesenchymal stem cells. AB - Cartilage tissue engineering aims to replace damaged or diseased tissue with a functional regenerate that restores joint function. Scaffolds are used to deliver cells and facilitate tissue development, but they can also interfere with the structural assembly of the cartilage matrix. Biodegradable scaffolds have been proposed as a means to improve matrix deposition and the biomechanical properties of neocartilage. The challenge is designing scaffolds with appropriate degradation rates, ideally such that scaffold degradation is proportional to matrix deposition. In this study, we developed a bioresponsive hydrogel with cell mediated degradation aligned to the chondrogenic differentiation of human mesenchymal stem cells (hMSCs). We identified matrix metalloproteinase 7 (MMP7) as an enzyme with a temporal expression pattern that corresponded with cartilage development. By embedding MMP7 peptide substrates within a poly(ethylene glycol) diacrylate backbone, we built MMP7-sensitive hydrogels with distinct degradation rates. When MMP7-sensitive scaffolds were compared with nondegradable scaffolds in vitro, photoencapsulated hMSCs produced neocartilage constructs with more extensive collagenous matrices, as demonstrated through immunohistochemistry and biochemical quantification of matrix molecules. Furthermore, these changes translated into an increased dynamic compressive modulus. This work presents a practical strategy for designing biomaterials uniquely tuned to individual biological processes. PMID- 21282206 TI - Novel expression of a functional glycine receptor chloride channel that attenuates contraction in airway smooth muscle. AB - Airway smooth muscle (ASM) contraction is an important component of the pathophysiology of asthma. Taurine, an agonist of glycine receptor chloride (GlyR Cl(-)) channels, was found to relax contracted ASM, which led us to question whether functional GlyR Cl(-) channels are expressed in ASM. Messenger RNA for beta (GLRB), alpha1 (GLRA1), alpha2 (GLRA2), and alpha4 (GLRA4) subunits were found in human (Homo sapiens) and guinea pig (Cavia porcellus) tracheal smooth muscle. Immunoblotting confirmed the protein expression of GLRA1 and GLRB subunits in ASM. Electrical activity of cultured human ASM cells was assessed using a fluorescent potentiometric dye and electrophysiological recordings. Glycine increased current and significantly increased fluorescence in a dose dependent manner. The GlyR Cl(-) channel antagonist strychnine significantly blocked the effects of glycine on potentiometric fluorescence in ASM cells. Guinea pig airway ring relaxation of ACh-induced contractions by isoproterenol was significantly left-shifted in the presence of glycine. This effect of glycine was blocked by pretreatment with the GlyR Cl(-) channel antagonist strychnine. Glycine treatment during tachykinin- and acetylcholine-induced contractions significantly decreased the maintenance of muscle force compared to control. GlyR Cl(-) channels are expressed on ASM and regulate smooth muscle force and offer a novel target for therapeutic relaxation of ASM. PMID- 21282207 TI - Hornerin is a component of the epidermal cornified cell envelopes. AB - A single-nucleotide polymorphism within the gene encoding hornerin (HRNR) has recently been linked with atopic dermatitis (AD) susceptibility. HRNR shares features with filaggrin, a key protein for keratinocyte differentiation, but conflicting reports have been published concerning its expression in the epidermis, and its role is still unknown. To analyze HRNR expression and function in the epidermis, anti-HRNR antibodies were produced and used in Western blot analysis and immunohistochemical, confocal, and immunoelectron microscopy analyses of human skin and of cornified cell envelopes purified from plantar stratum corneum. We also tested whether HRNR was a substrate of transglutaminases. In the epidermis, HRNR was detected at the periphery of keratohyalin granules in the upper granular layer and at the corneocyte periphery in the whole cornified layer. Detected in Western blot analysis as numerous bands, HRNR was relatively insoluble and only extracted from epidermis with urea and/or reducing agents. The presence of HRNR in the purified envelopes was confirmed by immunoelectron microscopy and by Western blot analysis after V8 protease digestion. HRNR was shown to be a substrate of transglutaminase 3. These data demonstrate that HRNR is a component of cornified cell envelopes of human epidermis. Its reduced expression in AD may contribute to the epidermal barrier defect observed in the disease. PMID- 21282208 TI - Crystal structure of 4-diphosphocytidyl-2-C-methyl-D-erythritol kinase (IspE) from Mycobacterium tuberculosis. AB - Isoprenoid precursors, which are a large group of natural products and play key roles in many biological pathways, can only be biosynthesized by the 2-C-methyl-d erythritol 4-phosphate pathway in Mycobacterium tuberculosis. The 4 diphosphocytidyl-2-C-methyl-d-erythritol kinase (IspE), which is an essential enzyme in the isoprenoid precursor biosynthesis pathway, catalyzes ATP-dependent phosphorylation of 4-diphosphocytidyl-2-C-methyl-d-erythritol (CDP-ME) to 4 diphosphocytidyl-2C-methyl-d-erythritol-2-phosphate and plays a crucial role in M. tuberculosis survival. Therefore, IspE is characterized as an attractive and potential target for antimicrobial drug discovery. However, no experimental structure of M. tuberculosis IspE has been reported, which has hindered our understanding of its structural details and mechanism of action. Here, we report the expression and purification of fully active full-length M. tuberculosis IspE and solve the high-resolution crystal structures of IspE alone and in complex with either the substrate CDP-ME or nonhydrolyzable ATP analog or ADP. The structures present a characteristic galactose/homoserine/mevalonate/phosphomevalonate kinase superfamily alpha/beta fold with a catalytic center located in a cleft between 2 domains and display clear substrate and ATP binding pockets. Our results also indicate distinct differences in ligand binding of M. tuberculosis IspE with other reported IspEs. Combined with the results of mutagenesis and enzymatic studies, our results provide useful information on the structural basis of IspE for future anti-M. tuberculosis drug discovery targeting this kinase. PMID- 21282209 TI - Wiki-science and Moliere's beast. PMID- 21282210 TI - Focus on vision: 3 decades of remarkable contributions to biology and medicine. AB - The FASEB Journal is a pillar among biomedical publications, contributing greatly by disseminating the results of vision research during its lifetime. Progress over this period has been remarkable. George Wald provided the first chemical understanding of the fundamental processes governing vision: the photoisomerization of 11-cis-retinal to all-trans-retinal and the enzymatic regeneration of this chromophore. Contributions of this extraordinary scientist set the stage for discoveries ranging from gross recording of various electrical responses to light to elucidation of signal transduction at a structural level, and from characterization of retinal diseases to successful treatments. PMID- 21282212 TI - Long term results of early active extension and passive flexion mobilization following one-stage tendon grafting for neglected injuries of the flexor digitorum profundus in children. AB - We retrospectively reviewed the long-term clinical outcomes of one-stage flexor tendon grafting for seven paediatric patients with isolated flexor digitorum profundus (FDP) tendon injuries in Zones 1 or 2. Free tendon grafts (one palmaris longus tendons and six plantaris tendons) were used for reconstruction by Pulvertaft's procedure. The ages of the patients at reconstruction ranged from 7 to 15 (mean 11) years. The time from injury to surgery ranged from three to 78 (mean 25) months. These patients were followed up from 2.5 to 21 years after surgery (mean 8.5 years). All cases were started on early active extension and passive flexion according to the modified Kleinert mobilization for postoperative rehabilitation. The mean active motion after surgery was 49 degrees (range 20-80 degrees ) for the DIP joints and 106 degrees (range 95-110 degrees ) for the PIP joints. The total active range of motion was on average 237 degrees (range 195 275 degrees ). Excellent results were achieved in five patients, good in one, and fair in one. Growth arrest of the distal phalanx was seen in one patient. One stage flexor tendon grafting in paediatric patients combined with early controlled mobilization can be used to reconstruct neglected isolated ruptures of the FDP tendon with satisfactory results. PMID- 21282213 TI - Finger zone II flexor tendon repair in children (5-10 years of age) using three 'figure of eight' sutures followed by immediate active mobilization. AB - For children between 5-10 years of age with zone II flexor tendon lacerations, the literature recommends a modified early mobilization programme under the supervision of a hand therapist but the fingers are immobilized between physiotherapy sessions. We report on a series of children between 5-10 years of age with flexor tendon lacerations (n = 54 fingers) in zone II repaired with a six-strand core suture (three separate 'figure of eight' sutures) and actively mobilized immediately after surgery similar to adult rehabilitation programmes with no immobilization between the physiotherapy sessions. The average follow-up for the study group was 13 months (range 7-25 months). There were no ruptures. The final outcome was excellent in 46 fingers (85%) and good in the remaining eight fingers (15%) using the Strickland-Glogovac criteria. PMID- 21282214 TI - The tension band principle and angular testing of extensor tendon repairs. AB - Extensor tendons in the finger are flat and not amenable to repair by core and epitendinous sutures. Mattress sutures and Kessler repairs without epitendinous stitching are often used for extensor tendon divisions in the fingers. Except when in full extension, the finger presents a series of curved surfaces (at each joint) to the tendon. It was hypothesized that extensor tendons are subject to the 'tension band' principle and that they might be amenable to repair by dorsal only epitendinous sutures. A Silfverskiold dorsal-only repair was compared with mattress and Kessler repairs in vitro on a curvilinear testing apparatus. The epitendinous technique was found to be significantly more resistant to gapping and rupture, as well as more resistant to deformation (i.e. stiffer) than the conventional techniques. PMID- 21282215 TI - Primary cup fixation with different designs of trapeziometacarpal total joint trapezium components: a radiostereometric analysis in a pig bone model. AB - High loosening rates of the trapezium components of trapeziometacarpal total joint prostheses have been reported. The purpose of this study was to compare the primary press fit fixation of two different, uncemented cup designs (MOTEC and Elektra) with the primary fixation of a cemented polyethylene cup (DLC) in a pig bone model. We did a push out test to measure the maximal load strength of the implants and a low-pressure cyclic loading test combined with radiostereometric analysis to measure the micromotion of the implants. There was no significant difference in fixation strength between the two uncemented screw cup designs or between the two uncemented screw cups and the cemented polyethylene cup. However, we found that threading of the bone before insertion of the Electra screw cup weakens the primary fixation strength of the implant. The results indicate that focus should be on the insertion technique as well as on the cup design of uncemented trapezium cup implants. Further studies of trapezium implant migration in a clinical setting are needed. PMID- 21282216 TI - A new plate for partial wrist fusions: results in midcarpal arthrodesis. AB - Partial wrist fusions are commonly performed for various degenerative conditions. In this series 30 wrists had a scaphoidectomy and midcarpal arthrodesis performed with a new plate. The most common indications were SLAC and SNAC wrists. In 24 cases a four-corner arthrodesis was done and in the other six the triquetrum was not included. Mean follow-up was 3 years. Mean flexion was 31 degrees and extension 35 degrees . Union was achieved in all wrists despite movement being commenced early. The plates proved straightforward to use, allowing some latitude in placement. This series confirms that scaphoidectomy and midcarpal arthrodesis is a useful salvage procedure and that these plates are suitable for that purpose. PMID- 21282217 TI - Re: Puna R, Poon P. The anatomy of the dorsal cutaneous branch of the ulnar nerve. J Hand Surg Eur. 2010, 35: 583-5. PMID- 21282218 TI - Intravenous pyogenic granuloma of the finger. PMID- 21282219 TI - Which instrument should we use to assess hand function after digital replantation? AB - The functional recovery of a replanted body part is as important as its viability. We compared four instruments frequently used for the evaluation of hand function after digital replantation. The functional results of 17 patients at least one year after replantation of a total digital amputation between 2004 and 2007 were evaluated according to the Tamai, Ipsen, Chen and Disabilities of the Arm, Shoulder and Hand questionnaires. Scores of each patient for each test were calculated and intra-individual comparisons were made. Correlation was significant at the 0.05 level (two tailed) for all tests. A high correlation (>0.71) was found between the Ipsen, Tamai and DASH tests. The Chen test had a moderate correlation with the other tests. We determined that Ipsen, Tamai and DASH tests have similar effectiveness in assessing hand function after replantation. PMID- 21282220 TI - The outcome of wrist surgery: what factors are important and how should they be reported? AB - A prospective longitudinal study was carried out on a cohort of 86 patients who had undergone surgery for diverse wrist conditions. Disabilities of Arm Shoulder and Hand questionnaire, a pain assessment, a wrist functional score, range of movement and grip strength measures were completed. The Mayo Clinic wrist score was also calculated. The World Health Organization International Classification of Function was used as a framework for analysis. The responsiveness of each outcome measure was calculated in terms of distribution- and anchor-based methods. Pain was the most important factor in determining outcome. Changes in objective measures were less important. The responsiveness of the various measures was similar except for the Mayo Clinic wrist score, which was less responsive than the others. Patient-completed measures currently in use are multidimensional. Classifying the content according to the International Classification of Function would clarify the effects of wrist surgery on the different aspects of health. PMID- 21282221 TI - The effects of growth and differentiation factor 5 on bone marrow stromal cell transplants in an in vitro tendon healing model. AB - The effects of growth differentiation factor-5 (GDF-5) and bone marrow stromal cells (BMSCs) on tendon healing were investigated under in vitro tissue culture conditions. BMSCs and GDF-5 placed in a collagen gel were interpositioned between the cut ends of dog flexor digitorum profundus tendons. The tendons were randomly assigned into four groups: 1) repaired tendon without gel; 2) repaired tendon with BMSC-seeded gel; 3) repaired tendon with GDF-5 gel without cells; and 4) repaired tendon with GDF-5 treated BMSC-seeded gel. At 2 and 4 weeks, the maximal strength of repaired tendons with GDF-5 treated BMSCs-seeded gel was significantly higher than in tendons without gel interposition. However, neither BMSCs nor GDF-5 alone significantly increased the maximal strength of healing tendons at 2 or 4 weeks. These results suggest that the combination of BMSCs and GDF-5 accelerates tendon healing, but either BMSCs or GDF-5 alone are not effective in this model. PMID- 21282222 TI - Treatment of bony mallet finger using a modified pull-out wire suture technique. PMID- 21282223 TI - Effects of topical corticosteroids on the sciatic nerve: an experimental study to adduce the safety in treating carpal tunnel syndrome. AB - Despite known detrimental effects on the blood flow and histology of nerves after intraneural corticosteroid injection, the neurotoxic effect of corticosteroids remains unclear. We investigated the effect of topical dexamethasone on nerve function. Two sponge strips soaked with dexamethasone at doses of 0.8, 1.6, and 3.2 mg were placed under and over the left sciatic nerve of adult Wistar rats for 30 minutes. Mixed-nerve-elicited somatosensory evoked potentials and dermatomal somatosensory evoked potentials were evaluated immediately and repeated together with functional tests and histology 2 weeks later. Evoked potential amplitude was dose-dependently lower and latency was prolonged in dexamethasone-treated sciatic nerves compared to controls. The suppression persisted with incomplete recovery for at least 4 hours, but differences between treated and control nerves were not significant after 2 weeks. Topical dexamethasone adversely affected neural conduction in a dose-dependent manner. Our results suggest that caution is required when using large doses of corticosteroid for injection of the carpal tunnel. PMID- 21282224 TI - Granular cell tumour arising in a digital nerve. PMID- 21282225 TI - Kirschner wire fixation for scaphoid fractures: an experimental study in synthetic bones. AB - We have studied the biomechanical stability in vitro of three different Kirschner (K) wire configurations in three types of simulated scaphoid waist fractures. The fractures were created with a saw in Sawbones models. There were three fracture patterns: perpendicular to the long axis of the scaphoid model; and 30 degrees and 20 degrees oblique to that. Two 1.2 mm. K-wires were used in each scaphoid. The three configurations were: parallel; 20 degrees oblique; and crossing. The oblique or crossing configurations of K-wires were the most stable depending on the fracture pattern. PMID- 21282226 TI - Flexor tendon fibroma as a cause of wrist triggering and carpal tunnel syndrome. PMID- 21282227 TI - Screw prominences related to palmar locking plating of distal radius. AB - Fixation of unstable distal radius fractures with palmar locking plates provides a stable reduction and early return of function, but complications arising from unrecognized dorsally prominent screws penetrating the extensor compartments are increasingly reported. Standard radiographs and fluoroscopy may not adequately visualize screw lengths, owing to the complex shape of the dorsum of the distal radius. We examined 46 distal radius fractures treated with palmar locking plates by ultrasound. Of the total 230 locking screws, 59 protruded from the dorsal cortical surface by 0.5 mm or more (range 0.5-6.1 mm). The first extensor compartment was violated by one screw, the second compartment by 22 screws, the third compartment by 15 screws, and the fourth compartment by 21 screws. Asymptomatic tenosynovitis was detected in four and symptomatic tenosynovitis in 14 of the 59 prominent screws. Ultrasound imaging may be useful in cases where intra-articular and/or comminuted fractures require distal plate placement and engagement of screws in the dorsal cortex. PMID- 21282254 TI - Differential effects of cortisol and 11-deoxycorticosterone on ion transport protein mRNA levels in gills of two euryhaline teleosts, Mozambique tilapia (Oreochromis mossambicus) and striped bass (Morone saxatilis). AB - The role of cortisol as the only corticosteroid in fish osmoregulation has recently been challenged with the discovery of a mineralocorticoid-like hormone, 11-deoxycorticosterone (DOC), and necessitates new studies of the endocrinology of osmoregulation in fish. Using an in vitro gill explant incubation approach, DOC-mediated regulation of selected osmoregulatory target genes in the gill was investigated and compared with that of cortisol in two euryhaline teleosts, Mozambique tilapia (Oreochromis mossambicus) and striped bass (Morone saxatilis). The effects were tested in gills from both fresh water (FW)- and seawater (SW) acclimated fish. Both cortisol and DOC caused an up-regulation of the Na(+),K(+) ATPase alpha1 subunit in SW-acclimated tilapia but had no effect in FW-acclimated fish. Cortisol conferred an increase in Na(+),K(+),2Cl(-) cotransporter (NKCC) isoform 1a transcript levels in FW- and SW-acclimated tilapia, whereas DOC had a stimulatory effect only in SW-acclimated fish. Cortisol had no effect on NKCC isoform 1b mRNA levels at both salinities, while DOC stimulated this isoform in SW-acclimated fish. In striped bass, cortisol conferred an up-regulation of Na(+),K(+)-ATPase alpha1 and NKCC transcript levels in FW- and SW-acclimated fish, whereas DOC resulted in down-regulation of these transcripts in FW acclimated fish. It was also found that both corticosteroids may rapidly (30 min) alter the mitogen-activated protein kinase signalling pathway in gill, inducing phosphorylation of extracellular signal-regulated kinase 1 (ERK1) and ERK2 in a salinity-dependent manner. The study shows a disparate organisation of corticosteroid signalling mechanisms involved in ion regulation in the two species and adds new evidence to a role of DOC as a mineralocorticoid hormone in teleosts. PMID- 21282255 TI - Excess of glucocorticoid induces myocardial remodeling and alteration of calcium signaling in cardiomyocytes. AB - Ventricular dysfunction is one of the important side effects of the anti inflammatory agent, glucocorticoid (GC). The present study was undertaken to examine whether abnormal calcium signaling is responsible for cardiac dysfunction due to an excess of GC hormone. The synthetic GC drug, dexamethasone (DEX), significantly (P<0.001, n=20) increased heart weight to body weight ratio, left ventricular remodeling, and fibrosis. The microarray analysis showed altered expression of several genes encoding calcium cycling/ion channel proteins in DEX treated rat heart. The altered expression of some of the genes was validated by real-time PCR and western blotting analyses. The expression of the L-type calcium channels and calsequestrin was increased, whereas sarcoendoplasmic reticulum calcium transport ATPase 2a (SERCA2a) and junctin mRNAs were significantly reduced in DEX-treated rat left ventricular tissues. In neonatal rat ventricular cardiomyocytes, DEX also increased the level of mRNAs of atrial- and brain natriuretic peptides, L-type calcium channels, and calsequestrin after 24 h of treatment, which were mostly restored by mifepristone. The caffeine-induced calcium release was prolonged by DEX compared to the sharp release in control cardiomyocytes. Taken together, these data show that impaired calcium kinetics may be responsible for cardiac malfunction by DEX. The results are important in understanding the pathophysiology of the heart in patients treated with excess GC. PMID- 21282256 TI - US adolescent nutrition, exercise, and screen time baseline levels prior to national recommendations. AB - Experts have recommended daily obesity prevention goals: >=5 fruits/vegetables, <2 hours of screen time, >1 hour of physical activity, and no sugar-sweetened beverages (5-2-1-0). The authors analyzed National Health and Nutrition Examination Survey data for 1999-2002 to determine the proportion of US adolescents (12-19 years) who would have met each goal prior to dissemination of the 5-2-1-0 recommendations. Merely 0.4% would have met all goals; 41% would have met none. Only 9% consumed >=5 fruits/vegetables, 27% reported <2 hours of screen time, 32% had >1 hour of physical activity, and 14% consumed no sugar-sweetened beverages per day. Demographic subgroups (eg, racial/ethnic minority and lower income) would have been even farther from meeting the goals. Clinicians are likely to encounter adolescents with nutrition, exercise, and screen time behaviors that are far from 5-2-1-0 goals, and can use these guidelines during clinical encounters to counsel adolescents regarding healthier lifestyles. PMID- 21282257 TI - Vancomycin dosing in obese pediatric patients. AB - BACKGROUND: Data are lacking to guide antimicrobial dosing for overweight children. The authors hypothesized that obese children would have increased vancomycin serum trough concentrations compared with nonobese children. METHODS: A matched study design was employed to compare retrospectively vancomycin trough concentrations. RESULTS: Among 24 matched pairs, obese patients received 14.1 +/- 1.5 mg per kilogram and nonobese children 14.9 +/- 0.9 mg per kilogram of vancomycin per kilogram of vancomycin (P = .03). There was a trend toward higher vancomycin serum concentrations in obese (6.9 +/- 4.30 MUg/mL) versus nonobese children (4.8 +/- 3.08 MUg/mL; P = .052). Mean half-life in obese patients was 2.9 +/- 0.29 hours and volume of distribution was 0.35 +/- 0.15 L/kg. CONCLUSIONS: Since obesity did not alter vancomycin trough concentrations, overweight children should receive vancomycin based on actual body weight. However, since vancomycin troughs were substantially lower than those recommended for adults, further studies of vancomycin metabolism in children are needed. PMID- 21282258 TI - Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study. AB - OBJECTIVES: To evaluate the individual risk factors composing the CHADS(2) (Congestive heart failure, Hypertension, Age >= 75 years, Diabetes, previous Stroke) score and the CHA(2)DS(2)-VASc (CHA(2)DS(2)-Vascular disease, Age 65-74 years, Sex category) score and to calculate the capability of the schemes to predict thromboembolism. DESIGN: Registry based cohort study. SETTING: Nationwide data on patients admitted to hospital with atrial fibrillation. Population All patients with atrial fibrillation not treated with vitamin K antagonists in Denmark in the period 1997-2006. MAIN OUTCOME MEASURES: Stroke and thromboembolism. RESULTS: Of 121,280 patients with non-valvular atrial fibrillation, 73,538 (60.6%) fulfilled the study inclusion criteria. In patients at "low risk" (score = 0), the rate of thromboembolism per 100 person years was 1.67 (95% confidence interval 1.47 to 1.89) with CHADS(2) and 0.78 (0.58 to 1.04) with CHA(2)DS(2)-VASc at one year's follow-up. In patients at "intermediate risk" (score = 1), this rate was 4.75 (4.45 to 5.07) with CHADS(2) and 2.01 (1.70 to 2.36) with CHA(2)DS(2)-VASc. The rate of thromboembolism depended on the individual risk factors composing the scores, and both schemes underestimated the risk associated with previous thromboembolic events. When patients were categorised into low, intermediate, and high risk groups, C statistics at 10 years' follow-up were 0.812 (0.796 to 0.827) with CHADS(2) and 0.888 (0.875 to 0.900) with CHA(2)DS(2)-VASc. CONCLUSIONS: The risk associated with a specific risk stratification score depended on the risk factors composing the score. CHA(2)DS(2)-VASc performed better than CHADS(2) in predicting patients at high risk, and those categorised as low risk by CHA(2)DS(2)-VASc were truly at low risk for thromboembolism. PMID- 21282259 TI - Anticoagulation in people with atrial fibrillation. PMID- 21282261 TI - "Dangerous" locum surgeon is struck off medical register. PMID- 21282262 TI - Impact of a statewide intensive care unit quality improvement initiative on hospital mortality and length of stay: retrospective comparative analysis. AB - OBJECTIVE: To evaluate whether implementation of the Michigan Keystone ICU project, a comprehensive statewide quality improvement initiative focused on reduction of infections, was associated with reductions in hospital mortality and length of stay for adults aged 65 or more admitted to intensive care units. DESIGN: Retrospective comparative study, using data from Medicare claims. SETTING: Michigan and Midwest region, United States. Population The study period (October 2001 to December 2006) spanned two years before the project was initiated to 22 months after its implementation. The study sample included hospital admissions for patients treated in 95 study hospitals in Michigan (238,937 total admissions) compared with 364 hospitals in the surrounding Midwest region (1,091,547 total admissions). MAIN OUTCOME MEASURES: Hospital mortality and length of hospital stay. RESULTS: The overall trajectory of mortality outcomes differed significantly between the two groups upon implementation of the project (Wald test chi(2) = 8.73, P = 0.033). Reductions in mortality were significantly greater for the study group than for the comparison group 1-12 months (odds ratio 0.83, 95% confidence interval 0.79 to 0.87 v 0.88, 0.85 to 0.90, P = 0.041) and 13-22 months (0.76, 0.72 to 0.81 v 0.84, 0.81 to 0.86, P = 0.007) after implementation of the project. The overall trajectory of length of stay did not differ significantly between the groups upon implementation of the project (Wald test chi(2) = 2.05, P = 0.560). Group differences in adjusted length of stay compared with baseline did not reach significance during implementation of the project (-0.45 days, 95% confidence interval -0.62 to -0.28 v -0.35, -0.52 to -0.19) or during post-implementation months 1-12 (-0.59, -0.80 to -0.37 v -0.42, -0.59 to -0.25) and 13-22 (-0.67, -0.91 to -0.43 v -0.54, -0.72 to -0.37). CONCLUSIONS: Implementation of the Keystone ICU project was associated with a significant decrease in hospital mortality in Michigan compared with the surrounding area. The project was not, however, sufficiently powered to show a significant difference in length of stay. PMID- 21282263 TI - FDA panel advice may require trials to prove safety of ECT. PMID- 21282265 TI - Hong Kong schoolchildren get training to detect dementia in elderly relatives. PMID- 21282266 TI - US Preventive Services Task Force vision screening recommendations. PMID- 21282267 TI - Vision screening for children 1 to 5 years of age: US Preventive Services Task Force Recommendation statement. AB - OBJECTIVE: The goal was to provide an update of the 2004 US Preventive Services Task Force (USPSTF) statement about screening for visual impairment in children <5 years of age. METHODS: The USPSTF examined evidence on the association of screening for visual impairment in children 1 to 5 years of age with improved health outcomes, the accuracy of risk factor assessment and screening tests, the effectiveness of early detection and treatment, and the harms of screening and treatment. RECOMMENDATION: The USPSTF recommends vision screening for all children at least once between the ages of 3 and 5 years, to detect the presence of amblyopia or its risk factors (grade B recommendation). The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of vision screening for children <3 years of age (I statement). PMID- 21282269 TI - Screening for visual impairment in children ages 1-5 years: update for the USPSTF. AB - CONTEXT: Screening could identify preschool-aged children with vision problems at a critical period of visual development and lead to treatments that could improve vision. OBJECTIVE: To determine the effectiveness of screening preschool-aged children for impaired visual acuity on health outcomes. METHODS: We searched Medline from 1950 to July 2009 and the Cochrane Library through the third quarter of 2009, reviewed reference lists, and consulted experts. We selected randomized trials and controlled observational studies on preschool vision screening and treatments, and studies of diagnostic accuracy of screening tests. One investigator abstracted relevant data, and a second investigator checked data abstraction and quality assessments. RESULTS: Direct evidence on the effectiveness of preschool vision screening for improving visual acuity or other clinical outcomes remains limited and does not adequately address whether screening is more effective than no screening. Regarding indirect evidence, a number of screening tests have utility for identification of preschool-aged children with vision problems. Diagnostic accuracy did not clearly differ for children stratified according to age, although testability rates were generally lower in children 1 to 3 years of age. Treatments for amblyopia or unilateral refractive error were associated with mild improvements in visual acuity compared with no treatment. No study has evaluated school performance or other functional outcomes. CONCLUSIONS: Although treatments for amblyopia or unilateral refractive error can improve vision in preschool-aged children and screening tests have utility for identifying vision problems, additional studies are needed to better understand the effects of screening compared with no screening. PMID- 21282273 TI - "Alzheimer's and baby boomers". Letter to the editor. PMID- 21282274 TI - Risk of cerebrovascular adverse events and death in elderly patients with dementia when treated with antipsychotic medications: a literature review of evidence. AB - Behavioral and Psychological Symptoms of Dementia (BPSD) are increasingly recognized as a major risk factor for caregiver burden, institutionalization, greater impairment in activities of daily living (ADLs), more rapid cognitive decline, and a poorer quality of life. BPSD contribute significantly to the direct and indirect costs of caring for patients with dementia even after adjusting for the severity of cognitive impairment and other co-morbidities. Research on these symptoms has indicated a complex interplay between the biological, psychological and social factors involved in the disease process. Although some psychotropic medications have shown modest efficacy in the treatment of these behaviors, their use has generated controversy due to increasing recognition of the side effects of these medications especially the antipsychotic medications. In this review, we examine the risk of cerebrovascular adverse events (CVAEs) and death with antipsychotic medications when used to treat elderly patients with dementia. PMID- 21282275 TI - Young children in early-onset Alzheimer's disease families: research gaps and emerging service needs. AB - Early-onset Alzheimer's disease (EOAD), defined as affecting those under age 65, afflicts between 200,000 and 500,000 people in the US. EOAD tends to be a fast progressing and aggressive form of AD. There is a beginning body of research exploring EOAD patients' experience and needs, as well as that of their primary family caregivers, often spouses. However, there has been very little written about the experience and needs of EOAD patients' children, who because of the early onset, and increasing postponement of childbearing, may be latency-aged or in their early teens. This paper reviews existing and related literature in this area, and illustrates the psychosocial impact on children using the case of a 50 year-old father diagnosed with AD and his 16 year-old daughter and 11 year-old son. The need for increased research and program development to address these children's needs is discussed. PMID- 21282276 TI - Dementia caregivers' responses to 2 Internet-based intervention programs. AB - PURPOSE: The aim of this study was to examine the impact on dementia caregivers' experienced stress and health status of 2 Internet-based intervention programs. DESIGN AND METHODS: Ninety-one dementia caregivers were given the choice of being involved in either an Internet-based chat support group or an Internet-based video conferencing support group. Pre-post outcome measures focused on distress, health status, social support, and service utilization. RESULTS: In contrast to the Chat Group, the Video Group showed significantly greater improvement in mental health status. Also, for the Video Group, improvements in self-efficacy, neuroticism, and social support were associated with lower stress response to coping with the care recipient's cognitive impairment and decline in function. IMPLICATIONS: The results show that, of 2 Internet-based intervention programs for dementia caregivers, the video conferencing intervention program was more effective in improving mental health status and improvement in personal characteristics were associated with lower caregiver stress response. PMID- 21282277 TI - Physical restraint use and falls in nursing homes: a comparison between residents with and without dementia. AB - AIMS: To estimate the use of different types of physical restraints and assess their associations to falls and injuries among residents with and without Alzheimer's disease (AD) or dementia in US nursing homes. METHODS: Data were from the 2004 National Nursing Home Survey. AD or dementia was identified using International Classification of Diseases, Ninth Revision (ICD-9) codes. Analyses were conducted with the Surveyfreq and Surveylogistic procedures in SAS v.9.1. RESULTS: Residents with either AD or dementia were more likely to be physically restrained (9.99% vs 3.91%, P < .001) and less likely to have bed rails (35.06% vs 38.43%, P < .001) than those residents without the disease. The use of trunk restraints was associated with higher risk for falls (adjusted odds ratio [AOR] = 1.66, P < .001) and fractures (AOR = 2.77, P < .01) among residents with the disease. The use of full bed rails was associated with lower risk for falls among residents with and without the disease (AOR = 0.67 and AOR = 0.72, Ps < .05, respectively). CONCLUSIONS: The use of a trunk restraint is associated with a higher risk for falls and fractures among residents with either AD or dementia. PMID- 21282278 TI - Association of the spatial layout of the home and ADL abilities among older adults with dementia. AB - We investigated the relationship between architectural space syntax measures describing the spatial layout of a home and activities of daily living (ADL) among people with dementia. We visited the homes of 82 participants in a dementia care comparative effectiveness clinical trial and measured the space syntax variables intelligibility and convexity along with several clinical variables, including ADLs. In regression models, we estimated the cross-sectional association between space syntax measures and ADLs. Higher convexity was associated with worse performance of basic but not instrumental ADLs (adjusted beta =19.2, P = .02). Intelligibility was not associated with ADLs. These results imply that enclosed rooms with a clearly legible meaning and function might be better memorized and associated with the spatial layout of the home resulting in better basic ADL performance. These results warrant further research on space syntax measures in the home environment of people with dementia, including longitudinal study, which we are pursuing. PMID- 21282279 TI - The driver with dementia: a survey of physician attitudes, knowledge, and practice. AB - BACKGROUND: One of the most difficult issues physicians must address when caring for persons with dementia is fitness to drive. The purpose of this project was to investigate the attitudes, knowledge, and practices of physicians toward drivers with dementia. METHODS: A questionnaire that obtained perspectives about and experiences with drivers' with dementia was mailed to physicians from North Carolina and South Carolina. RESULTS: The sample was comprised of 239 physicians who worked with persons with dementia. Respondents who were aware of the Physician's Guide to Assessing and Counseling Older Drivers, had a strong perceived role regarding driving, were older, and believed it was important to address driving were more likely to engage in driving discussions. CONCLUSIONS: Concerns associated with the driver with dementia have implications for not only patient care but also public safety. We recommend that all physicians be encouraged to address the issue and utilize existing educational materials. PMID- 21282280 TI - Impact of rivastigmine patch and capsules on activities of daily living in Alzheimer's disease. AB - BACKGROUND: Rivastigmine patches provide similar efficacy to rivastigmine capsules with a lower incidence of gastrointestinal side effects in patients with probable Alzheimer's disease (AD). METHODS: Post hoc analysis of a 24-week, prospective, international, randomized, double-blind, placebo- and active controlled trial. Patients (n = 892) with probable AD received rivastigmine transdermal patches (9.5 mg/24 hours [10 cm(2)]), rivastigmine capsules (6 mg twice daily), or placebo, and impact on activities of daily living (ADLs) was assessed utilizing 3 subscales: basic, high-level function, and autonomy. RESULTS: At week 24, both rivastigmine groups demonstrated significantly superior performance in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Total Score versus placebo (rivastigmine patch, P = .013; capsules, P = .039). Overall, both rivastigmine formulations provided benefits in ADL subscales. For basic ADLs, rivastigmine capsules performed significantly better than placebo (P = .012). For high-level function ADLs, rivastigmine patch performed better than placebo (P = .056). For autonomy ADLs, rivastigmine patch performed significantly better than placebo (P = .017). CONCLUSION: Rivastigmine patches and capsules provide significant effects in both total and subscale ADLs in patients with probable AD. PMID- 21282281 TI - Extrapyramidal signs in the primary progressive aphasias. AB - BACKGROUND: Extrapyramidal signs (EPS) may vary across 3 major subtypes of primary progressive aphasia (PPA): progressive nonfluent aphasia (PNFA), semantic dementia (SD), and progressive logopenic aphasia (PLA). METHODS: We reviewed initial neurological examinations from a clinical PPA cohort (PNFA = 49, SD = 26, PLA = 28) to determine the prevalence of specific categories of EPS. RESULTS: The presence of any EPS was more common in PNFA (38.8%) and PLA (35.7%) than in SD (3.8%). The PNFA group exhibited the highest prevalence of bradykinesia (PNFA: 22.4%, SD: 3.8%, PLA: 0.0%) and rigidity (PNFA: 30.6%, SD: 0.0%, PLA: 10.7%). Calculated positive likelihood ratios indicated bradykinesia (12.1) or rigidity (5.5) was more strongly associated with PNFA than other PPAs. CONCLUSION: These findings suggest that on initial presentation, specific EPS may help distinguish PPA subtypes when linguistic and/or neuroimaging profiles are indistinct. Moreover, EPS could represent a marker of underlying tauopathy, linking clinical presentation to neuropathology in PPA. PMID- 21282282 TI - Differential efficacy of three cycles of CMF followed by tamoxifen in patients with ER-positive and ER-negative tumors: long-term follow up on IBCSG Trial IX. AB - BACKGROUND: The benefit of adjuvant chemotherapy in postmenopausal patients with estrogen receptor (ER)-positive lymph node-negative breast cancer is being reassessed. PATIENTS AND METHODS: After stratification by ER status, 1669 postmenopausal patients with operable lymph node-negative breast cancer were randomly assigned to three 28-day courses of 'classical' CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy followed by tamoxifen for 57 months (CMF->tamoxifen) or to tamoxifen alone for 5 years. RESULTS: ERs were positive in 81% of tumors. At a median follow-up of 13.1 years, patients with ER-positive breast cancers did not benefit from CMF [13-year disease-free survival (DFS) 64% CMF->tamoxifen, 66% tamoxifen; P = 0.99], whereas CMF substantially improved the prognosis of patients with ER-negative breast cancer (13-year DFS 73% versus 57%, P = 0.001). Similarly, breast cancer-free interval (BCFI) was identical in the ER positive cohort but significantly improved by chemotherapy in the ER-negative cohort (13-year BCFI 80% versus 63%, P = 0.001). CMF had no influence on second nonbreast malignancies or deaths from other causes. CONCLUSION: CMF is not beneficial in postmenopausal patients with node-negative ER-positive breast cancer but is highly effective within the ER-negative cohort. In the future, other markers of chemotherapy response may define a subset of patients with ER positive tumors who may benefit from adjuvant chemotherapy. PMID- 21282283 TI - A clinical photogrammetric method to measure dental arch dimensions and mesio distal tooth size. AB - The aim of this research was to evaluate the reliability and validity of measurements obtained from clinical standardized occlusal photographs compared with dental cast measurements. This study comprised a consecutive sample of 16 patients (eight males and eight females, aged 15-24 years) in the permanent dentition without agenesis and/or tooth loss. A paired t-test and intraclass correlation coefficient (ICC) were used to examine validity and reliability. Both statistics were applied for intra- and inter-methods error analysis, at P < 0.05. Random error for the photogrammetric method (less than 0.48 mm) was similar to that for the dental cast measurements (less than 0.43 mm). ICC revealed excellent reliability for both methods (P < 0.01) and no significant difference for any variables, with the exception of upper inter-canine width obtained on the dental casts (P = 0.0038) and photogrammetry (P = 0.01). However, differences were less than 1 per cent of the mean inter-canine width. Inter-method analysis showed a significant correlation for all variables (P < 0.001), with good to excellent reliability (r = 0.66-0.93). A significant mean inter-method difference was consistently observed for the upper first molars (0.33 mm, P < 0.01). For the remaining teeth (left to right second premolars), the largest mean difference was approximately equal to the resolution of the human eye (0.2 mm or less). Minor differences (around 2 per cent of the mean) and an excellent ICC (0.75-0.93, P < 0.01) were observed for arch dimensions. Except for the mesio-distal width of the upper first molars, the recently developed photogrammetric method showed accuracy, validity, and reliability acceptable for clinical and scientific purposes. PMID- 21282284 TI - Skeletal, dentoalveolar, and soft tissue cephalometric measurements of Malay transfusion-dependent thalassaemia patients. AB - Thalassaemia is a public health problem in Malaysia. It is known to cause skeletal deformity. The purpose of this study was to compare the skeletal, dentoalveolar, and soft tissue features of Malay transfusion-dependent thalassaemia (TDT) patients with a Malay control group. Lateral cephalometric radiographs of 30 Malay (14 males and 16 females aged 6.4-21.8 years) TDT patients and 60 normal Malays matched for chronological age and gender were analysed and compared using an independent t-test. The TDT group showed a similar sagittal relationship to the control group but with a significantly increased (P < 0.01) mandibular plane inclination. They also showed a significantly shorter (P <= 0.001) mandibular body, ramus length, and posterior face height and consequently a smaller ratio of posterior to anterior face height (P < 0.01). The upper and lower lips were significantly procumbent (P < 0.001) in the TDT group together with a significantly smaller nasolabial angle (P < 0.05). Dentoalveolar measurements showed less proclined maxillary teeth in the TDT group compared with the controls (P < 0.05). The cephalometric features of Malay TDT patients were characterized by a mild Class II skeletal pattern, prominent vertical growth direction of the mandible, and protruded upper and lower lips. PMID- 21282287 TI - Synthesis, function and possible new avenues for erythropoietin. PMID- 21282286 TI - Intramyocardial administration of chimeric ephrinA1-Fc promotes tissue salvage following myocardial infarction in mice. AB - The purpose of this study was to investigate the role of intramyocardial administration of chimeric ephrinA1-Fc in modulating the extent of injury and inflammation in non reperfused myocardial infarction (MI). Our results show that intramyocardial injection of 6 MUg ephrinA1-Fc into the border zone immediately after permanent coronary artery ligation in B6129s mice resulted in 50% reduction of infarct size, 64% less necrosis, 35% less chamber dilatation and 32% less left ventricular free wall thinning at 4 days post-MI. In the infarct zone, Ly6G+ neutrophil density was 57% reduced and CD45+ leukocyte density was 21% reduced. Myocyte damage was also reduced in ephrinA1-Fc-treated hearts, as evidenced by 54% reduced serum cardiac troponin I. Further, we observed decreased cleaved PARP, increased BAG-1 protein expression, increased phosphorylated AKT/total AKT protein, and reduced NF-kappaB protein with ephrinA1-Fc administration, indicating improved cellular survival. Of the eight EphA receptors known to be expressed in mice (A1-A8), RT-PCR revealed that A1-A4, A6 and A7 were expressed in the uninjured adult myocardium. Expression of EphA1-A3 and EphA7 were significantly increased following MI while EphA6 expression decreased. Treatment with ephrinA1-Fc further increased EphA1 and EphA2 gene expression and resulted in a 2-fold increase in EphA4. Upregulation and combinatorial activation of these receptors may promote tissue survival. We have identified a novel, beneficial role for ephrinA1-Fc administration at the time of MI, and propose this as a promising new target for infarct salvage in non reperfused MI. More experiments are in progress to identify receptor-expressing cell types as well as the functional implications of receptor activation. PMID- 21282288 TI - The role of synaptobrevin1/VAMP1 in Ca2+-triggered neurotransmitter release at the mouse neuromuscular junction. AB - Synaptobrevin (Syb)/vesicle-associated membrane protein (VAMP) is a small, integral membrane protein of synaptic vesicles. Two homologous isoforms of synaptobrevin, Syb1/VAMP1 and Syb2/VAMP2, exhibit distinct but partially overlapping patterns of expression in adult mammalian neurons: Syb1 is predominantly expressed in the spinal cord, especially in motor neurons and motor nerve terminals of the neuromuscular junction (NMJ), whereas Syb2 is primarily expressed in central synapses in the brain. Whereas many studies have focused on the function of Syb2 in the brain, few studies have examined the role of Syb1. Here we report that Syb1 plays a critical role in neuromuscular synaptic transmission. A null mutation of Syb1 resulting from a spontaneous, nonsense mutation in mice significantly impairs the function, but not the structure, of the NMJ. In particular, both spontaneous and evoked synaptic activities in Syb1 mutant mice are reduced significantly relative to control mice. Short-term synaptic plasticity in Syb1-deficient NMJs is markedly altered: paired-pulse facilitation is significantly enhanced, suggesting a reduction in the initial release probability of synaptic vesicles. Furthermore, Syb1-deficient NMJs display a pronounced asynchrony in neurotransmitter release. These impairments are not due to an alteration of the size of the readily releasable pool of vesicles, but are attributable to reduced sensitivity and cooperativity to calcium (Ca2+) due to the absence of Syb1. Our findings demonstrate that Syb1 plays an essential, non-redundant role in Ca2+-triggered vesicle exocytosis at the mouse NMJ. PMID- 21282289 TI - Relaxation gating of the acetylcholine-activated inward rectifier K+ current is mediated by intrinsic voltage sensitivity of the muscarinic receptor. AB - Normal heart rate variability is critically dependent upon the G-protein-coupled, acetylcholine (ACh)-activated inward rectifier K+ current, I(KACh). A unique feature of I(KACh) is the so-called 'relaxation' gating property that contributes to increased current at hyperpolarized membrane potentials. I(KACh) relaxation refers to a slow decrease or increase in current magnitude with depolarization or hyperpolarization, respectively. The molecular mechanism underlying this perplexing gating behaviour remains unclear. Here, we consider a novel explanation for I(KACh) relaxation based upon the recent finding that G-protein coupled receptors (GPCRs) are intrinsically voltage sensitive and that the muscarinic agonists acetylcholine (ACh) and pilocarpine (Pilo) manifest opposite voltage-dependent I(KACh) modulation. We show that Pilo activation of I(KACh) displays relaxation characteristics opposite to that of ACh. We explain the opposite effects of ACh and Pilo using Markov models of I(KACh) that incorporate ligand-specific, voltage-dependent parameters. Based on experimental and computational findings, we propose a novel molecular mechanism to describe the enigmatic relaxation gating process: I(KACh) relaxation represents a voltage dependent change in agonist affinity as a consequence of a voltage-dependent conformational change in the muscarinic receptor. PMID- 21282290 TI - Erythropoietic and non-erythropoietic functions of erythropoietin in mouse models. AB - As the basic function of erythropoietin (Epo) is stimulation of red blood cell production, systemic overexpression of Epo results in erythrocytosis. The patho physiological consequences of chronically elevated red blood cell counts have been studied in Epo overexpressing mice. Genetically modified mice, however, have also played an important role in discovering multiple additional functions of Epo besides stimulating erythrocyte production. Non-erythropoietic functions of Epo are widespread and play a role in organogenesis during early embryonic development and in tissue protection in ischaemic diseases. Future work in the field will most likely focus on these additional functions of Epo, which have great clinical potential. PMID- 21282291 TI - Conformational changes in the M2 muscarinic receptor induced by membrane voltage and agonist binding. AB - The ability to sense transmembrane voltage is a central feature of many membrane proteins, most notably voltage-gated ion channels. Gating current measurements provide valuable information on protein conformational changes induced by voltage. The recent observation that muscarinic G-protein-coupled receptors (GPCRs) generate gating currents confirms their intrinsic capacity to sense the membrane electrical field. Here, we studied the effect of voltage on agonist activation of M2 muscarinic receptors (M2R) in atrial myocytes and how agonist binding alters M2R gating currents. Membrane depolarization decreased the potency of acetylcholine (ACh), but increased the potency and efficacy of pilocarpine (Pilo), as measured by ACh-activated K+ current, I(KACh). Voltage-induced conformational changes in M2R were modified in a ligand-selective manner: ACh reduced gating charge displacement while Pilo increased the amount of charge displaced. Thus, these ligands manifest opposite voltage-dependent I(KACh) modulation and exert opposite effects on M2R gating charge displacement. Finally, mutations in the putative ligand binding site perturbed the movement of the M2R voltage sensor. Our data suggest that changes in voltage induce conformational changes in the ligand binding site that alter the agonist-receptor interaction in a ligand-dependent manner. Voltage-dependent GPCR modulation has important implications for cellular signalling in excitable tissues. Gating current measurement allows for the tracking of subtle conformational changes in the receptor that accompany agonist binding and changes in membrane voltage. PMID- 21282292 TI - Ageing reduces the compensatory vasodilatation during hypoxic exercise: the role of nitric oxide. AB - We tested the hypotheses that (1) the compensatory vasodilatation in skeletal muscle during hypoxic exercise is attenuated in ageing humans and (2) local inhibition of nitric oxide (NO) synthesis in the forearm of ageing humans will have less impact on the compensatory dilatation during rhythmic exercise with hypoxia, due to a smaller compensatory dilator response. Eleven healthy older subjects (61 +/- 2 years) performed forearm exercise (10% and 20% of maximum) during saline infusion (control) and NO synthase inhibition (NG-monomethyl-L arginine; L-NMMA) under normoxic and normocapnic hypoxic (80% arterial O2 saturation) conditions. Forearm vascular conductance (FVC; ml min-1 (100 mmHg)-1) was calculated from forearm blood flow(ml min-1) and blood pressure (mmHg). To further examine the effects of ageing on the compensatory vasodilator response to hypoxic exercise we compared the difference in DeltaFVC (% change compared to respective normoxic exercise trial) between the older subjects (present study) and previously published data from an identical protocol in young subjects. During the control condition, the compensatory vasodilator response to hypoxia was similar between the old and young groups at 10% exercise (28 +/- 6% vs. 40 +/ 8%, P =0.11) but attenuated at 20% exercise (14 +/- 4% vs. 31 +/- 6%, P <0.05). L-NMMA during hypoxic exercise only blunted the compensatory vasodilator response in the young group (P <0.05). Our data suggest that ageing reduces the compensatory vasodilator response to hypoxic exercise via blunted NO signalling. PMID- 21282293 TI - Bayesian models for subgroup analysis in clinical trials. AB - BACKGROUND: In a pharmaceutical drug development setting, possible interactions between the treatment and particular baseline clinical or demographic factors are often of interest. However, the subgroup analysis required to investigate such associations remains controversial. Concerns with classical hypothesis testing approaches to the problem include low power, multiple testing, and the possibility of data dredging. PURPOSE: As an alternative to hypothesis testing, the use of shrinkage estimation techniques is investigated in the context of an exploratory post hoc subgroup analysis. A range of models that have been suggested in the literature are reviewed. Building on this, we explore a general modeling strategy, considering various options for shrinkage of effect estimates. This is applied to a case-study, in which evidence was available from seven-phase II-III clinical trials examining a novel therapy, and also to two artificial datasets with the same structure. METHODS: Emphasis is placed on hierarchical modeling techniques, adopted within a Bayesian framework using freely available software. A range of possible subgroup model structures are applied, each incorporating shrinkage estimation techniques. RESULTS: The investigation of the case-study showed little evidence of subgroup effects. Because inferences appeared to be consistent across a range of well-supported models, and model diagnostic checks showed no obvious problems, it seemed this conclusion was robust. It is reassuring that the structured shrinkage techniques appeared to work well in a situation where deeper inspection of the data suggested little evidence of subgroup effects. LIMITATIONS: The post hoc examination of subgroups should be seen as an exploratory analysis, used to help make better informed decisions regarding potential future studies examining specific subgroups. To a certain extent, the degree of understanding provided by such assessments will be limited by the quality and quantity of available data. CONCLUSIONS: In light of recent interest by health authorities into the use of subgroup analysis in the context of drug development, it appears that Bayesian approaches involving shrinkage techniques could play an important role in this area. Hopefully, the developments outlined here provide useful methodology for tackling such a problem, in-turn leading to better informed decisions regarding subgroups. PMID- 21282294 TI - Knowledge and attitude regarding mercury handling and disposal in students. AB - The present cross-sectional study was carried out in higher secondary schools of the science specialty in Ahmedabad. A total of 653 students (196 taught in English, 395 taught in Gujarati and 62 taught in Hindi) from seven schools were included. The interview technique was used for data collection using a predesigned questionnaire. A total of 457 (70%) were boys and 196 (30%) were girls. About two-thirds of the study participants had handled mercury at sometime in their life and home was the common place where it was handled. More than half of the Hindi-taught students did not know about its physical appearance. The majority of the Gujarati-taught students knew that mercury is harmful to health whereas one-third of the English- and Hindi-taught students considered mercury to be harmless. A total of 46% of the Gujarati-taught and 44% of the English-taught students had encountered spilled mercury at sometime in their life and 21.6% of English-taught and 25% of Hindi-taught students had either smelled or played with spilled mercury. More than two-thirds of the English- and Hindi-taught students recommended the usual cleaning method whereas 81.8% of Gujarati-taught students suggested a special method should be used for the disposal of spilled mercury. The majority of the students did not know whether mercury could be substituted by a harmless substance. PMID- 21282295 TI - Meningitis in Korean patients with systemic lupus erythematosus: analysis of demographics, clinical features and outcomes; experience from affiliated hospitals of the Catholic University of Korea. AB - Meningitis is a rare complication of systemic lupus erythematosus (SLE), potentially leading to a fatal outcome. The demographic, clinical, and laboratory features, and the outcomes of meningitis were evaluated in Korean patients with SLE. In a retrospective medical record review of 1420 SLE patients, 20 patients who had developed septic or aseptic meningitis were identified. In 11 patients, the causative microorganisms were identified ('septic meningitis'), and Cryptococcus neoformans was the major pathogen. The other nine patients were diagnosed with aseptic meningitis. The patients with septic meningitis were older than those with aseptic meningitis (p = 0.025) and displayed mental changes more often (p = 0.005). Leukocyte counts in the cerebrospinal fluid (CSF) were higher (p = 0.044) and the levels of CSF glucose were lower in the septic meningitis group (p = 0.036). Plasma leukocyte counts and neutrophil counts were higher in patients with septic meningitis (p = 0.037 and p = 0.020, respectively). Meningitis was observed in 1.4% of Korean patients with SLE and, in 55% of the meningitis patients, microorganisms were isolated and Cryptococcus neoformans was most commonly identified. Altered mental status, plasma leukocytosis, neutrophilia, and CSF pleocytosis and hypoglycemia were more prominent in patients with septic meningitis. PMID- 21282296 TI - Penile anthropometry in systemic lupus erythematosus patients. AB - The aim of this study was to evaluate penile anthropometry in systemic lupus erythematosus (SLE) patients compared with healthy controls and the possible relevant pubertal, clinical, hormonal and treatment factors that could influence penile dimensions. Twenty-five consecutive SLE patients were assessed by urological examination, sexual function, testicular ultrasound, hormones, sperm analysis, genetic analysis, clinical features and treatment. The control group included 25 age-matched healthy males. SLE patients had a lower median penis length and circumference [8 (7.5-10) vs. 10 (8-13) cm, p = 0.0001; 8 (7-10) vs. 10 (7-11) cm, p = 0.001; respectively], lower median testicular volume by right and left Prader [15 (10-25) vs. 20 (12-25) ml, p = 0.003; 15 (10-25) vs. 20 (12 25) ml, p = 0.006; respectively], higher median of follicle-stimulating hormone [5.8 (2.1-25) vs. 3.3 (1.9-9) IU/l, p = 0.002] and lower morning total testosterone levels (28% vs. 0%, p = 0.009) compared with controls. In spite of that, erectile dysfunction was not observed in patients or controls. Analyses of lupus patients revealed that the median penis circumference was lower in patients with disease onset before first ejaculation compared with those with disease onset after first ejaculation [7.8 (7-10) vs. 9.0 (7.5-10) cm, p = 0.026]. No differences were observed in the median penile anthropometry regarding sexual dysfunction (p = 0.610), lower morning total testosterone levels (p = 0.662), oligo/azoospermia (p = 0.705), SLE Disease Activity Index >= 4 (p = 0.562), Systemic Lupus International Collaborating Clinics/ACR Damage Index >= 1 (p = 0.478), prednisone cumulative dose (p = 0.789) and intravenous cyclophosphamide therapy (p = 0.754). Klinefelters syndrome (46XY/47XXY) was diagnosed in one (4%) SLE patient with decreased penile size whereas Y-chromosomal microdeletions was absent in all of them. In conclusion, we have identified reduced penile dimensions in SLE patients with no deleterious effect in erectile function. Disease onset before first ejaculation seems to affect penis development in pre pubertal lupus. PMID- 21282297 TI - Hypercalcaemia in systemic lupus erythematosus. AB - Hypercalcaemia is found in more than 90% of the cases of primitive hyperparathyroidism and malignancies. Rarely, D hypervitaminosis, sarcoidosis, other granulomatous diseases, some drugs, and endocrine diseases may be responsible. Nine patients with systemic lupus erythematosus (SLE) and hypercalcaemia, without evidence of primary hyperparathyroidism, have been previously described. Here we report the 10th patient with SLE and hypercalcaemia, along with a brief review of the literature. PMID- 21282298 TI - Evaluation of shunting flow differences in varied conditions in a simulated adult CPB model during normothermia. AB - BACKGROUND: It is well documented that lower pump flow during clinical cardiopulmonary bypass (CPB) procedures may be significantly detrimental to tissues and organs. The major cause of hypoperfusion is due to shunting flow existing in the closed CPB circuits. The purpose of this investigation was to evaluate various shunting flow conditions in a simulated adult CPB model under normothermia. MATERIALS AND METHODS: The pseudo adult patient undergoing CPB was established with an extracorporeal circuit. The pre-oxygenator flow, post-filter flow and purge line pressure were recorded. The temperature of the circuit was kept around 36 degrees C using a heat-cooler. The pseudo patient was subjected to five pump flow rates ranging from 3000 to 5000 ml/min (500 ml/min increments), and post-filter pressure was varied from 120-220 mmHg (20 mmHg increments) using a single, static roller pump. Four different shunting states were measured with two flowmeters. RESULTS: When the pump flow was constant, the percentage of shunting flow increased as the post-filter pressure increased in State 1. However, when the post-filter pressure was constant, the trend of the shunting flow was the opposite. Purge line pressure increased with the increase of the post-filter pressure at a constant pump flow rate in State 1. The shunting flow for State 2 was the largest of the four states. The shunting flow for State 3 was similar to State 4. CONCLUSION: During different states of shunt opening, varying degrees of blood flow were diverted away from the arterial line. Shunting of blood flow may, therefore, result in hypoperfusion in the patient. PMID- 21282299 TI - Isolated mucinous adrenal metastasis in a breast cancer patient. AB - Mucinous breast carcinoma (MBC) is a rare histological type of breast cancer and rarely associated with advanced disease. We report a case that had MBC with an isolated adrenal metastasis which was removed by laparoscopic adrenelectomy. This case is unique due to the unexpected metastasis of pure mucinous carcinoma developed after 4 years of hormone therapy. PMID- 21282300 TI - Vascularizing the heart. AB - As the developing heart grows and the chamber walls thicken, passive diffusion of oxygen and nutrients is replaced by a vascular plexus which remodels and expands to form a mature coronary vascular system. The coronary arteries and veins ensure the continued development of the heart and facilitate cardiac output with progression towards birth. Many aspects of coronary vessel development are surprisingly not well understood and recently there has been much debate surrounding both the developmental origin and tissue contribution of cardiovascular cells alongside the specific signals that determine their fate and function. What is clear is that an understanding of the cellular and molecular cues to vascularize the heart of the embryo has significant implications for adult heart disease and regeneration, as we move towards targeted cell-based therapies for neovascularization and coronary bypass engraftment. This review will focus on the proposed cellular origins for the coronary endothelium with due consideration to the pro-epicardial organ/epicardium, sinus venosus and endocardium as potential sources, and we will explore the outstanding questions and technical limitations with respect to accurate labelling and lineage tracing of the developing coronaries. We will briefly document canonical vascular signalling that induces vessels in the heart alongside a focus on the potential for developmental reprogramming and putative mechanisms underpinning venous vs. arterial cell fate. Finally, we will extrapolate directly from development to address adult maintenance of the coronaries, vascular homeostasis and remodelling in response to pathology, aligned with the potential for revascularizing the injured adult heart. PMID- 21282301 TI - Epigenetic control of tissue-type plasminogen activator synthesis in human endothelial cells. AB - AIMS: Tissue-type plasminogen activator (t-PA) is produced by endothelial cells (EC) and is responsible for the removal of intravascular fibrin deposits. We investigated whether expression of t-PA by EC is under epigenetic control. METHODS AND RESULTS: Methylation analysis of the proximal t-PA promoter revealed a stretch of unmethylated CpG dinucleotides from position -121 to +59, while upstream CpG dinucleotides were all methylated. In contrast, in human primary hepatocytes, which express t-PA at much lower levels than EC, the proximal promoter was partially methylated. Treatment of EC with the non-specific histone deacetylase (HDAC) inhibitors butyrate and trichostatin and with MS275, a specific inhibitor of class I HDAC, resulted in a time- and dose-dependent increase in t-PA expression. Garcinol and anacardic acid, inhibitors of the histone acetyl transferases CBP/p300 and PCAF, reduced basal and HDAC inhibitor induced t-PA expression, whereas curcumin, an inhibitor of CBP/p300 only, had no effect. We performed chromosome immunoprecipitation analysis of the t-PA promoter using antibodies specific for acetylated histone H3 or H4 and observed an increase in H3 acetylation of 10 +/- 3 and 44 +/- 14-fold in EC treated with trichostatin or MS275, respectively, and in H4 acetylation of 7.7 +/- 1.4 and 16 +/- 3-fold, respectively. CONCLUSION: The proximal t-PA promoter is unmethylated in human EC and partially methylated in human primary hepatocytes. Expression of t-PA by EC is repressed by HDACs in a mechanism that involves de-acetylation of histone H3 and H4. PMID- 21282302 TI - Haemodialysis catheters increase mortality as compared to arteriovenous accesses especially in elderly patients. AB - BACKGROUND: Catheter use has been associated with an increased mortality risk in haemodialysis patients. However, differences in the all-cause and cause-specific mortality risk between catheter use and arteriovenous access use in young and elderly haemodialysis patients have not yet been investigated. METHODS: In this prospective cohort study of 1109 incident haemodialysis patients from 38 centres in the Netherlands, hazard ratios (HRs) with 95% confidence intervals (95% CIs) were calculated for 2-year all-cause, infection-related and cardiovascular mortality in patients with a catheter as compared to patients with an arteriovenous access stratified for age (< 65 years and >= 65 years). RESULTS: Of the 1109 patients, 919 had an arteriovenous access and 190 had a catheter. The mortality rate was 76 per 1000 person-years in young patients with an arteriovenous access, 129 per 1000 person-years in young patients with a catheter, 222 per 1000 person-years in elderly patients with an arteriovenous access and 427 per 1000 person-years in elderly patients with a catheter. The adjusted HR was 3.15 (95% CI: 2.09-4.75) for elderly patients with a catheter as compared to young patients with an arteriovenous access. The adjusted HRs in elderly patients with a catheter as compared to elderly patients with an arteriovenous access were 1.54 (95% CI: 1.13-2.12) for all-cause mortality, 1.60 (95%: CI 0.62-4.19) for infection-related mortality and 1.67 (95% CI: 1.04-2.68) for cardiovascular mortality. CONCLUSIONS: Especially, elderly haemodialysis patients with a catheter have an increased all-cause, infection-related and cardiovascular mortality risk as compared to patients with an arteriovenous access. PMID- 21282303 TI - Suboptimal initiation of dialysis with and without early referral to a nephrologist. AB - BACKGROUND: Our objective was to examine patients who initiate renal replacement therapy (RRT) at 10 representative Canadian centers, characterize their initiation as inpatient or outpatient and describe their initial type of dialysis access, duration of pre-dialysis care and clinical status at the time of dialysis initiation. We also examined the impact of an optimal dialysis start (i.e. initiated as an outpatient with an arteriovenous fistula, arteriovenous graft or peritoneal dialysis catheter) on subsequent health outcomes. METHODS: Charts of consecutive incident RRT patients were identified from 1 July to 31 December 2006. Information was collected until 6 months after the initiation or until death, transplant or transfer. RESULTS: Three hundred and thirty-nine incident RRT patients were studied: 39.6% initiated as an inpatient; 54% started hemodialysis (HD) with a central venous catheter; 15.3% had <1 month predialysis care, while 64.6% had >1 year. Optimal starts occurred in 39.5% of patients. For HD patients, optimal starts occurred in 19.8%. Suboptimal starts were noted in patients referred <12 months prior to end-stage renal disease (44%) and in patients referred earlier (56%). The composite end point of death, transfusion or subsequent hospitalization was significantly reduced with an optimal start [hazard ratio 0.47 (95% confidence interval 0.32-0.68), P = 0.0001]. CONCLUSIONS: Suboptimal initiation of dialysis is common in patients referred early or late. The benefits of early referral are lost if dialysis is initiated suboptimally. There is a need to identify factors that lead to suboptimal initiation despite early referral. PMID- 21282305 TI - CMA hosts first town hall on health care transformation. PMID- 21282306 TI - Spontaneous regression of a lumbar disk herniation. PMID- 21282307 TI - Germany clambers aboard translational research bandwagon. PMID- 21282309 TI - Partnerships between health organizations and the food industry risk derailing public health nutrition. PMID- 21282310 TI - Navigating assisted death and end-of-life care. PMID- 21282311 TI - Sex in pregnancy. PMID- 21282312 TI - Bariatric surgery guidelines in need of revision, experts argue. PMID- 21282313 TI - Milk sharing: boon or biohazard? PMID- 21282314 TI - Patchwork regulations likely outcome of reproductive technologies ruling. PMID- 21282315 TI - Work ability in midlife as a predictor of mortality and disability in later life: a 28-year prospective follow-up study. AB - BACKGROUND: Poor work ability correlates with increased morbidity and early retirement from the workforce, but the association in old age is not known. We investigated work ability in midlife among white-collar and blue-collar employees as a predictor of mortality and disability 28 years later. METHODS: A total of 5971 occupationally active people aged 44-58 years participated in the Finnish Longitudinal Study of Municipal Employees (FLAME) in 1981. Perceived work ability relative to lifetime best was categorized as excellent, moderate or poor. In 2009, the ability to perform activities of daily living was assessed among 2879 respondents (71.0% of the survivors). Mortality data were available up to July 2009. RESULTS: At the 28-year follow-up, 1918 of the 5971 participants had died and 1403 had some form of disability. Rates of death per 1000 person-years among white-collar men were 7.7 for those with excellent work ability, 14.7 for those with moderate work ability and 23.5 for those with poor work ability. Among blue collar men, the corresponding rates were 15.5, 20.2 and 25.3. In women, rates ranged between 6.3 and 10.6 per 1000 person-years. The age-adjusted hazard ratios (HRs) for mortality were two to three times higher among blue-collar male employees with lower work ability than among white-collar male employees with excellent work ability in midlife (i.e., the reference group). The odds of death or disability at follow-up compared with white-collar workers with excellent work ability were highest among blue-collar employees with poor work ability in midlife (odds ratio [OR] 4.56, 95% confidence interval [CI] 2.82-7.37 for men; OR 3.37, 95% CI 2.28-4.98 for women). Among the survivors, similar but slightly lower risks of disability 28 years later were found. INTERPRETATION: Perceived poor work ability in midlife was associated with accelerated deterioration in health and functioning and remains evident after 28 years of follow-up. PMID- 21282316 TI - Cardiac resynchronization therapy: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Studies of cardiac resynchronization therapy in addition to an implantable cardioverter defibrillator in patients with mild to moderate congestive heart failure had not been shown to reduce mortality until the recent RAFT trial (Resynchronization/Defibrillation for Ambulatory Heart Failure Trial). We performed a meta-analysis including the RAFT trial to determine the effect of cardiac resynchronization therapy with or without an implantable defibrillator on mortality. METHODS: We searched electronic databases and other sources for reports of randomized trials using a parallel or crossover design. We included studies involving patients with heart failure receiving optimal medical therapy that compared cardiac resynchronization therapy with optimal medical therapy alone, or cardiac resynchronization therapy plus an implantable defibrillator with a standard implantable defibrillator. The primary outcome was mortality. The optimum information size was considered to assess the minimum amount of information required in the literature to reach reliable conclusions about cardiac resynchronization therapy. RESULTS: Of 3071 reports identified, 12 studies (n = 7538) were included in our meta-analysis. Compared with optimal medical therapy alone, cardiac resynchronization therapy plus optimal medical therapy significantly reduced mortality (relative risk [RR] 0.73, 95% confidence interval [CI] 0.62-0.85). Compared with an implantable defibrillator alone, cardiac resynchronization therapy plus an implantable defibrillator significantly reduced mortality (RR 0.83, 95% CI 0.72-0.96). This last finding remained significant among patients with New York Heart Association (NYHA) class I or II disease (RR 0.80, 95% CI 0.67-0.96) but not among those with class III or IV disease (RR 0.84, 95% CI 0.69-1.07). Analysis of the optimum information size showed that the sequential monitoring boundary was crossed, which suggests no need for further clinical trials. INTERPRETATION: The cumulative evidence is now conclusive that the addition of cardiac resynchronization to optimal medical therapy or defibrillator therapy significantly reduces mortality among patients with heart failure. PMID- 21282317 TI - The effects of age, memory performance, and callosal integrity on the neural correlates of successful associative encoding. AB - This functional magnetic resonance imaging study investigated the relationship between the neural correlates of associative memory encoding, callosal integrity, and memory performance in older adults. Thirty-six older and 18 young subjects were scanned while making relational judgments on word pairs. Neural correlates of successful encoding (subsequent memory effects) were identified by contrasting the activity elicited by study pairs that were correctly identified as having been studied together with the activity elicited by pairs wrongly judged to have come from different study trials. Subsequent memory effects common to the 2 age groups were identified in several regions, including left inferior frontal gyrus and bilateral hippocampus. Negative effects (greater activity for forgotten than for remembered items) in default network regions in young subjects were reversed in the older group, and the amount of reversal correlated negatively with memory performance. Additionally, older subjects' subsequent memory effects in right frontal cortex correlated positively with anterior callosal integrity and negatively with memory performance. It is suggested that recruitment of right frontal cortex during verbal memory encoding may reflect the engagement of processes that compensate only partially for age-related neural degradation. PMID- 21282318 TI - Association between functional connectivity hubs and brain networks. AB - Functional networks are usually accessed with "resting-state" functional magnetic resonance imaging using preselected "seeds" regions. Frequently, however, the selection of the seed locations is arbitrary. Recently, we proposed local functional connectivity density mapping (FCDM), an ultrafast data-driven to locate highly connected brain regions (functional hubs). Here, we used the functional hubs obtained from local FCDM to determine the functional networks of the resting state in 979 healthy subjects without a priori hypotheses on seed locations. In addition, we computed the global functional connectivity hubs. Seven networks covering 80% of the gray matter volume were identified. Four major cortical hubs (ventral precuneus/posterior cingulate, inferior parietal cortex, cuneus, and postcentral gyrus) were linked to 4 cortical networks (default mode, dorsal attention, visual, and somatosensory). Three subcortical networks were associated to the major subcortical hubs (cerebellum, thalamus, and amygdala). The networks differed in their resting activity and topology. The higher coupling and overlap of subcortical networks was associated to higher contribution of short-range functional connectivity in thalamus and cerebellum. Whereas cortical local FCD hubs were also hubs of long-range connectivity, which corroborates the key role of cortical hubs in network architecture, subcortical hubs had minimal long-range connectivity. The significant variability among functional networks may underlie their sensitivity/resilience to neuropathology. PMID- 21282319 TI - Nitric oxide signaling modulates synaptic transmission during early postnatal development. AB - Early gamma-aminobutyric acid mediated (GABAergic) synaptic transmission and correlated neuronal activity are fundamental to network formation; however, their regulation during early postnatal development is poorly understood. Nitric oxide (NO) is an important retrograde messenger at glutamatergic synapses, and it was recently shown to play an important role also at GABAergic synapses in the adult brain. The subcellular localization and network effect of this signaling pathway during early development are so far unexplored, but its disruption at this early age is known to lead to profound morphological and functional alterations. Here, we provide functional evidence--using whole-cell recording--that NO signaling modulates not only glutamatergic but also GABAergic synaptic transmission in the mouse hippocampus during the early postnatal period. We identified the precise subcellular localization of key elements of the underlying molecular cascade using immunohistochemistry at the light--and electron microscopic levels. As predicted by these morpho-functional data, multineuron calcium imaging in acute slices revealed that this NO-signaling machinery is involved also in the control of synchronous network activity patterns. We suggest that the retrograde NO signaling system is ideally suited to fulfill a general presynaptic regulatory role and may effectively fine-tune network activity during early postnatal development, while GABAergic transmission is still depolarizing. PMID- 21282320 TI - Eye movements help link different views in scene-selective cortex. AB - To explore visual scenes in the everyday world, we constantly move our eyes, yet most neural studies of scene processing are conducted with the eyes held fixated. Such prior work in humans suggests that the parahippocampal place area (PPA) represents scenes in a highly specific manner that can differentiate between different but overlapping views of a panoramic scene. Using functional magnetic resonance imaging (fMRI) adaptation to measure sensitivity to change, we asked how this specificity is affected when active eye movements across a stable scene generate retinotopically different views. The PPA adapted to successive views when subjects made a series of saccades across a stationary spatiotopic scene but not when the eyes remained fixed and a scene translated in the background, suggesting that active vision may provide important cues for the PPA to integrate different views over time as the "same." Adaptation was also robust when retinotopic information was preserved across views when the scene moved in tandem with the eyes. These data suggest that retinotopic physical similarity is fundamental, but the visual system may also utilize oculomotor cues and/or global spatiotopic information to generate more ecologically relevant representations of scenes across different views. PMID- 21282321 TI - Intrathecal baclofen in multiple sclerosis: too little, too late? AB - The majority of patients with multiple sclerosis (MS) have symptoms of spasticity that increasingly impair function as the disease progresses. With appropriate treatment, however, quality of life can be improved. Oral antispasticity medications are useful in managing mild spasticity but are frequently ineffective in controlling moderate to severe spasticity, because patients often cannot tolerate the adverse effects of increasing doses. Intrathecal baclofen (ITB) therapy can be an effective alternative to oral medications in patients who have a suboptimal response to oral medications or who cannot tolerate dose escalation or multidrug oral regimens. ITB therapy may be underutilized in the MS population because clinicians (a) are more focused on disease-modifying therapies rather than symptom control, (b) underestimate the impact of spasticity on quality of life, and (c) have concerns about the cost and safety of ITB therapy. Delivery of ITB therapy requires expertly trained staff and proper facilities for pump management. This article summarizes the findings and recommendations of an expert panel on the use of ITB therapy in the MS population and the role of the physician and comprehensive care team in patient selection, screening, and management. PMID- 21282322 TI - Genetic suppression analysis in novel vacuolar processing enzymes reveals their roles in controlling sugar accumulation in tomato fruits. AB - In plant cells, many vacuolar proteins are synthesized as precursors in the endoplasmic reticulum and are subsequently transported to the vacuole. These precursors are subject to post-translational modifications to allow the active mature forms to be produced. Vacuolar processing enzyme (VPE) has been identified as a family of cysteine proteases involved in protein maturation in the vacuole. In this study, novel VPE genes were isolated from tomato (Solanum lycopersicum), and they were designated SlVPE1-SlVPE5. Phylogenic analysis suggested that SlVPE1 and SlVPE2 were categorized as the seed coat type, SlVPE4 was categorized as the seed type, and both SlVPE3 and SlVPE5 were categorized as the vegetative type. Expression analysis demonstrated that these genes were expressed during fruit development, and that their expression profiles agreed with this classification. High VPE enzyme activity was observed during tomato fruit development; the enzyme activity was correlated with the SlVPE mRNA levels, indicating that the SlVPE encoded active VPE proteins. The total sugar content was higher in RNA interference (RNAi) lines compared with the control plants, suggesting negative roles for SlVPE in sugar accumulation. The quantitative expression analysis of each SlVPE gene in the RNAi lines suggested that the suppression of SlVPE5 probably had the strongest effect on the sugar accumulation observed. The suppression of SlVPE did not influence the total amino acid content, suggesting that the molecular targets of SlVPE were mainly involved in sugar accumulation. PMID- 21282324 TI - RanGAP is required for post-meiotic mitosis in female gametophyte development in Arabidopsis thaliana. AB - RanGAP is the GTPase-activating protein of the small GTPase Ran and is involved in nucleocytoplasmic transport in yeast and animals via the Ran cycle and in mitotic cell division. Arabidopsis thaliana has two copies of RanGAP, RanGAP1 and RanGAP2. To investigate the function of plant RanGAP, T-DNA insertional mutants were analysed. Arabidopsis plants with a null mutant of either RanGAP1 or RanGAP2 had no observable phenotype. Analysis of segregating progeny showed that double mutants in RanGAP1 and RanGAP2 are female gametophyte defective. Ovule clearing with differential interference contrast optics showed that mutant female gametophytes were arrested at interphase, predominantly after the first mitotic division following meiosis. In contrast, mutant pollen developed and functioned normally. These results show that the two RanGAPs are redundant and indispensable for female gametophyte development in Arabidopsis but dispensable for pollen development. Nuclear division arrest during a mitotic stage suggests a role for plant RanGAP in mitotic cell cycle progression during female gametophyte development. PMID- 21282323 TI - An arginine decarboxylase gene PtADC from Poncirus trifoliata confers abiotic stress tolerance and promotes primary root growth in Arabidopsis. AB - Arginine decarboxylase (ADC) is an important enzyme responsible for polyamine synthesis under stress conditions. In this study, the gene encoding ADC in Poncirus trifoliata (PtADC) was isolated and it existed as a single-copy member. Transcript levels of PtADC were up-regulated by low temperature and dehydration. Overexpression of PtADC in an Arabidopsis thaliana ADC mutant adc1-1 promoted putrescine synthesis in the transgenic line and the stomatal density was reverted to that in the wild type. The transgenic line showed enhanced resistance to high osmoticum, dehydration, long-term drought, and cold stress compared with the wild type and the mutant. The accumulation of reactive oxygen species (ROS) in the transgenic line was appreciably decreased under the stresses, but ROS scavenging capacity was compromised when the transgenic plants were treated with the ADC inhibitor D-arginine prior to stress treatment. In addition, the transgenic line had longer roots than the wild type and the mutant under both normal and stressful conditions, consistent with larger cell number and length of the root meristematic zone. Taken together, these results demonstrated that PtADC is involved in tolerance to multiple stresses, and its function may be due, at least partly, to efficient ROS elimination and to its influence on root growth conducive to drought tolerance. PMID- 21282325 TI - Growth at elevated ozone or elevated carbon dioxide concentration alters antioxidant capacity and response to acute oxidative stress in soybean (Glycine max). AB - Soybeans (Glycine max Merr.) were grown at elevated carbon dioxide concentration ([CO(2)]) or chronic elevated ozone concentration ([O(3)]; 90 ppb), and then exposed to an acute O(3) stress (200 ppb for 4 h) in order to test the hypothesis that the atmospheric environment alters the total antioxidant capacity of plants, and their capacity to respond to an acute oxidative stress. Total antioxidant metabolism, antioxidant enzyme activity, and antioxidant transcript abundance were characterized before, immediately after, and during recovery from the acute O(3) treatment. Growth at chronic elevated [O(3)] increased the total antioxidant capacity of plants, while growth at elevated [CO(2)] decreased the total antioxidant capacity. Changes in total antioxidant capacity were matched by changes in ascorbate content, but not phenolic content. The growth environment significantly altered the pattern of antioxidant transcript and enzyme response to the acute O(3) stress. Following the acute oxidative stress, there was an immediate transcriptional reprogramming that allowed for maintained or increased antioxidant enzyme activities in plants grown at elevated [O(3)]. Growth at elevated [CO(2)] appeared to increase the response of antioxidant enzymes to acute oxidative stress, but dampened and delayed the transcriptional response. These results provide evidence that the growth environment alters the antioxidant system, the immediate response to an acute oxidative stress, and the timing over which plants return to initial antioxidant levels. The results also indicate that future elevated [CO(2)] and [O(3)] will differentially affect the antioxidant system. PMID- 21282326 TI - Abscisic acid triggers whole-plant and fruit-specific mechanisms to increase fruit calcium uptake and prevent blossom end rot development in tomato fruit. AB - Calcium (Ca) uptake into fruit and leaves is dependent on xylemic water movement, and hence presumably driven by transpiration and growth. High leaf transpiration is thought to restrict Ca movement to low-transpiring tomato fruit, which may increase fruit susceptibility to the Ca-deficiency disorder, blossom end rot (BER). The objective of this study was to analyse the effect of reduced leaf transpiration in abscisic acid (ABA)-treated plants on fruit and leaf Ca uptake and BER development. Tomato cultivars Ace 55 (Vf) and AB2 were grown in a greenhouse environment under Ca-deficit conditions and plants were treated weekly after pollination with water (control) or 500 mg l(-1) ABA. BER incidence was completely prevented in the ABA-treated plants and reached values of 30-45% in the water-treated controls. ABA-treated plants had higher stem water potential, lower leaf stomatal conductance, and lower whole-plant water loss than water treated plants. ABA treatment increased total tissue and apoplastic water-soluble Ca concentrations in the fruit, and decreased Ca concentrations in leaves. In ABA treated plants, fruit had a higher number of Safranin-O-stained xylem vessels at early stages of growth and development. ABA treatment reduced the phloem/xylem ratio of fruit sap uptake. The results indicate that ABA prevents BER development by increasing fruit Ca uptake, possibly by a combination of whole-plant and fruit specific mechanisms. PMID- 21282327 TI - Characterization of a transport activity for long-chain peptides in barley mesophyll vacuoles. AB - The plant vacuole is the largest compartment in a fully expanded plant cell. While only very limited metabolic activity can be observed within the vacuole, the majority of the hydrolytic activities, including proteolytic activities reside in this organelle. Since it is assumed that protein degradation by the proteasome results in the production of peptides with a size of 3-30 amino acids, we were interested to show whether the tonoplast exhibits a transport activity, which could deliver these peptides into the vacuole for final degradation. It is shown here that isolated barley mesophyll vacuoles take up peptides of 9-27 amino acids in a strictly ATP-dependent manner. Uptake is inhibited by vanadate, but not by NH(+)(4), while GTP could partially substitute for ATP. The apparent affinity for the 9 amino acid peptide was 15 MUM, suggesting that peptides are efficiently transferred to the vacuole in vivo. Inhibition experiments showed that peptides with a chain length below 10 amino acids did not compete as efficiently as longer peptides for the uptake of the 9 amino acid peptide. Our results suggest that vacuoles contain at least one peptide transporter that belongs to the ABC-type transporters, which efficiently exports long-chain peptides from the cytosol into the vacuole for final degradation. PMID- 21282329 TI - Respiration and nitrogen assimilation: targeting mitochondria-associated metabolism as a means to enhance nitrogen use efficiency. AB - Considerable advances in our understanding of the control of mitochondrial metabolism and its interactions with nitrogen metabolism and associated carbon/nitrogen interactions have occurred in recent years, particularly highlighting important roles in cellular redox homeostasis. The tricarboxylic acid (TCA) cycle is a central metabolic hub for the interacting pathways of respiration, nitrogen assimilation, and photorespiration, with components that show considerable flexibility in relation to adaptations to the different functions of mitochondria in photosynthetic and non-photosynthetic cells. By comparison, the operation of the oxidative pentose phosphate pathway appears to represent a significant limitation to nitrogen assimilation in non-photosynthetic tissues. Valuable new insights have been gained concerning the roles of the different enzymes involved in the production of 2-oxoglutarate (2-OG) for ammonia assimilation, yielding an improved understanding of the crucial role of cellular energy balance as a broker of co-ordinate regulation. Taken together with new information on the mechanisms that co-ordinate the expression of genes involved in organellar functions, including energy metabolism, and the potential for exploiting the existing flexibility for NAD(P)H utilization in the respiratory electron transport chain to drive nitrogen assimilation, the evidence that mitochondrial metabolism and machinery are potential novel targets for the enhancement of nitrogen use efficiency (NUE) is explored. PMID- 21282328 TI - Overexpression of AtCSP4 affects late stages of embryo development in Arabidopsis. AB - Eukaryotic cold shock domain proteins are nucleic acid-binding proteins that are involved in transcription, translation via RNA chaperone activity, RNA editing, and DNA repair during tissue developmental processes and stress responses. Cold shock domain proteins have been functionally implicated in important developmental transitions, including embryogenesis, in both animals and plants. Arabidopsis thaliana cold shock domain protein 4 (AtCSP4) contains a well conserved cold shock domain (CSD) and glycine-rich motifs interspersed by two retroviral-like CCHC zinc fingers. AtCSP4 is expressed in all tissues but accumulates in reproductive tissues and those undergoing cell divisions. Overexpression of AtCSP4 reduces silique length and induces embryo lethality. Interestingly, a T-DNA insertion atcsp4 mutant does not exhibit any morphological abnormalities, suggesting that the related AtCSP2 gene is functionally redundant with AtCSP4. During silique development, AtCSP4 overexpression induced early browning and shrunken seed formation beginning with the late heart embryo stage. A 50% segregation ratio of the defective seed phenotype was consistent with the phenotype of endosperm development gene mutants. Transcripts of FUS3 and LEC1 genes, which regulate early embryo formation, were not altered in the AtCSP4 overexpression lines. On the other hand, MEA and FIS2 transcripts, which are involved in endosperm development, were affected by AtCSP4 overexpression. Additionally, AtCSP4 overexpression resulted in up-regulation of several MADS-box genes (AP1, CAL, AG, and SHP2) during early stages of silique development. Collectively, these data suggest that AtCSP4 plays an important role during the late stages of silique development by affecting the expression of several development-related genes. PMID- 21282330 TI - Distribution, biological activities, metabolism, and the conceivable function of cis-zeatin-type cytokinins in plants. AB - Cytokinins (CKs) are plant hormones affecting numerous developmental processes. Zeatin and its derivatives are the most important group of isoprenoid CKs. Zeatin occurs as two isomers: while trans-zeatin (transZ) was found to be a bioactive substance, cis-zeatin (cisZ) was reported to have a weak biological impact. Even though cisZ derivatives are abundant in various plant materials their biological role is still unknown. The comprehensive screen of land plants presented here suggests that cisZ-type CKs occur ubiquitously in the plant kingdom but their abundance might correlate with a strategy of life rather than with evolutionary complexity. Changing levels of transZ and cisZ during Arabidopsis ontogenesis show that levels of the two zeatin isomers can differ significantly during the life span of the plant, with cisZ-type CKs prevalent in the developmental stages associated with limited growth. A survey of the bioassays employed illustrates mild activity of cisZ and its derivatives. No cis<->trans isomerization, which would account for the effects of cisZ, was observed in tobacco cells and oat leaves. Differences in uptake between the two isomers resulting in distinct bioactivity have not been detected. In contrast, cisZ and transZ have a different metabolic fate in oat and tobacco. Analysis of a CK-degrading enzyme, cytokinin oxidase/dehydrogenase (CKX), reveals that Arabidopsis possesses two isoforms, AtCKX1 expressed in stages of active growth, and AtCKX7, both of which have the highest affinity for the cisZ isomer. Based on the present results, the conceivable function of cisZ-type CKs as delicate regulators of CK responses in plants under growth-limiting conditions is hypothesized. PMID- 21282331 TI - Regulation of nitrate assimilation in cyanobacteria. AB - Nitrate assimilation by cyanobacteria is inhibited by the presence of ammonium in the growth medium. Both nitrate uptake and transcription of the nitrate assimilatory genes are regulated. The major intracellular signal for the regulation is, however, not ammonium or glutamine, but 2-oxoglutarate (2-OG), whose concentration changes according to the change in cellular C/N balance. When nitrogen is limiting growth, accumulation of 2-OG activates the transcription factor NtcA to induce transcription of the nitrate assimilation genes. Ammonium inhibits transcription by quickly depleting the 2-OG pool through its metabolism via the glutamine synthetase/glutamate synthase cycle. The P(II) protein inhibits the ABC-type nitrate transporter, and also nitrate reductase in some strains, by an unknown mechanism(s) when the cellular 2-OG level is low. Upon nitrogen limitation, 2-OG binds to P(II) to prevent the protein from inhibiting nitrate assimilation. A pathway-specific transcriptional regulator NtcB activates the nitrate assimilation genes in response to nitrite, either added to the medium or generated intracellularly by nitrate reduction. It plays an important role in selective activation of the nitrate assimilation pathway during growth under a limited supply of nitrate. P(II) was recently shown to regulate the activity of NtcA negatively by binding to PipX, a small coactivator protein of NtcA. On the basis of accumulating genome information from a variety of cyanobacteria and the molecular genetic data obtained from the representative strains, common features and group- or species-specific characteristics of the response of cyanobacteria to nitrogen is summarized and discussed in terms of ecophysiological significance. PMID- 21282332 TI - PITX2c is expressed in the adult left atrium, and reducing Pitx2c expression promotes atrial fibrillation inducibility and complex changes in gene expression. AB - BACKGROUND: Intergenic variations on chromosome 4q25, close to the PITX2 transcription factor gene, are associated with atrial fibrillation (AF). We therefore tested whether adult hearts express PITX2 and whether variation in expression affects cardiac function. METHODS AND RESULTS: mRNA for PITX2 isoform c was expressed in left atria of human and mouse, with levels in right atrium and left and right ventricles being 100-fold lower. In mice heterozygous for Pitx2c (Pitx2c(+/-)), left atrial Pitx2c expression was 60% of wild-type and cardiac morphology and function were not altered, except for slightly elevated pulmonary flow velocity. Isolated Pitx2c(+/-) hearts were susceptible to AF during programmed stimulation. At short paced cycle lengths, atrial action potential durations were shorter in Pitx2c(+/-) than in wild-type. Perfusion with the beta receptor agonist orciprenaline abolished inducibility of AF and reduced the effect on action potential duration. Spontaneous heart rates, atrial conduction velocities, and activation patterns were not affected in Pitx2c(+/-) hearts, suggesting that action potential duration shortening caused wave length reduction and inducibility of AF. Expression array analyses comparing Pitx2c(+/-) with wild type, for left atrial and right atrial tissue separately, identified genes related to calcium ion binding, gap and tight junctions, ion channels, and melanogenesis as being affected by the reduced expression of Pitx2c. CONCLUSIONS: These findings demonstrate a physiological role for PITX2 in the adult heart and support the hypothesis that dysregulation of PITX2 expression can be responsible for susceptibility to AF. PMID- 21282333 TI - Heritability of early repolarization: a population-based study. AB - BACKGROUND: Early repolarization (ER), defined by J-point elevation in 12-lead ECG, was recently associated with increased risk for idiopathic ventricular fibrillation and cardiovascular mortality. The determinants of ER are unknown. We investigated its heritability in a large, family-based cohort. METHODS AND RESULTS: The study sample comprised 1877 individuals from 505 white nuclear families representative of the British general population. Standard 12-lead ECGs were evaluated for the presence of ER, defined as J-point elevation of >=0.1 mV in at least 2 adjacent inferior (II, III, and aVF) or anterolateral (I, aVL, and V(4) through V(6)) leads. Narrow sense heritability estimates were computed adjusting for age, age(2), and sex. The prevalence of ER was 7.7% (n=145) in the whole cohort, 5.9% (n=56) in parents, and 9.6% (n=89) in offspring. Heritability estimate for the presence of ER was calculated at h(2)=0.49 (standard error=0.14; P=2.7*10(-4)) and was higher when restricted to its presence in inferior leads (h(2)=0.61, standard error=0.18, P=4.3*10(-4)) or for the notching ER morphology (h(2)=0.81, standard error=0.19, P=2.4*10(-5)). Individuals with at least 1 affected parent had a 2.5-fold increased risk for presenting with ER on ECG (odds ratio, 2.54; 95% confidence interval, 1.33 to 4.84; P=0.005). Familial transmission was more frequent when the mother was affected (odds ratio, 3.84; 95% confidence interval, 1.41 to 10.43; P=0.008) than when the father was affected (odds ratio, 1.82; 95% confidence interval, 0.82 to 4.03; P=0.141), although this difference was not statistically significant (P=0.18). CONCLUSIONS: ER is a heritable phenotype. Offspring of ER-positive parents have a 2.5-fold increased risk of presenting with ER on their ECG. PMID- 21282334 TI - Can computationally designed protein sequences improve secondary structure prediction? AB - Computational sequence design methods are used to engineer proteins with desired properties such as increased thermal stability and novel function. In addition, these algorithms can be used to identify an envelope of sequences that may be compatible with a particular protein fold topology. In this regard, we hypothesized that sequence-property prediction, specifically secondary structure, could be significantly enhanced by using a large database of computationally designed sequences. We performed a large-scale test of this hypothesis with 6511 diverse protein domains and 50 designed sequences per domain. After analysis of the inherent accuracy of the designed sequences database, we realized that it was necessary to put constraints on what fraction of the native sequence should be allowed to change. With mutational constraints, accuracy was improved vs. no constraints, but the diversity of designed sequences, and hence effective size of the database, was moderately reduced. Overall, the best three-state prediction accuracy (Q(3)) that we achieved was nearly a percentage point improved over using a natural sequence database alone, well below the theoretical possibility for improvement of 8-10 percentage points. Furthermore, our nascent method was used to augment the state-of-the-art PSIPRED program by a percentage point. PMID- 21282335 TI - Outgrowth of drug-resistant carcinomas expressing markers of tumor aggression after long-term TbetaRI/II kinase inhibition with LY2109761. AB - TGF-beta is produced excessively by many solid tumors and can drive malignant progression through multiple effects on the tumor cell and microenvironment. TGF beta signaling pathway inhibitors have shown efficacy in preclinical models of metastatic cancer. Here, we investigated the effect of systemic LY2109761, a TGF beta type I/II receptor (TbetaRI/TbetaRII) kinase inhibitor, in both a tumor allograft model and the mouse skin model of de novo chemically induced carcinogenesis in vivo. Systemic LY2109761 administration disrupted tumor vascular architecture and reduced myofibroblast differentiation of E4 skin carcinoma cells in a tumor allograft. In the 7,12-dimethyl-benzanthracene plus phorbol myristate acetate-induced skin chemical carcinogenesis model, acute dosing of established naive primary carcinomas with LY2109761 (100 mg/kg) every 8 hours for 10 days (100 mg/kg) diminished phospho-Smad2 (P-Smad2) levels and marginally decreased the expression of inflammatory and invasive markers. Sustained exposure to LY2109761 (100 mg/kg/d) throughout the tumor outgrowth phase had no effect on carcinoma latency or incidence. However, molecular analysis of resultant carcinomas by microarray gene expression, Western blotting, and immunohistochemistry suggests that long-term LY2109761 exposure leads to the outgrowth of carcinomas with elevated P-Smad2 levels that do not respond to drug. This is the first description of acquired resistance to a small-molecule inhibitor of the TbetaRI/TbetaRII kinase. Resultant carcinomas were more aggressive and inflammatory in nature, with delocalized E-cadherin and elevated expression of Il23a, laminin V, and matrix metalloproteinases. Therefore, TGF beta inhibitors might be clinically useful for applications requiring acute administration, but long-term patient exposure to such drugs should be undertaken with caution. PMID- 21282336 TI - CARM1 is an important determinant of ERalpha-dependent breast cancer cell differentiation and proliferation in breast cancer cells. AB - Breast cancers with estrogen receptor alpha (ERalpha) expression are often more differentiated histologically than ERalpha-negative tumors, but the reasons for this difference are poorly understood. One possible explanation is that transcriptional cofactors associated with ERalpha determine the expression of genes which promote a more differentiated phenotype. In this study, we identify one such cofactor as coactivator-associated arginine methyltransferase 1 (CARM1), a unique coactivator of ERalpha that can simultaneously block cell proliferation and induce differentiation through global regulation of ERalpha-regulated genes. CARM1 was evidenced as an ERalpha coactivator in cell-based assays, gene expression microarrays, and mouse xenograft models. In human breast tumors, CARM1 expression positively correlated with ERalpha levels in ER-positive tumors but was inversely correlated with tumor grade. Our findings suggest that coexpression of CARM1 and ERalpha may provide a better biomarker of well-differentiated breast cancer. Furthermore, our findings define an important functional role of this histone arginine methyltransferase in reprogramming ERalpha-regulated cellular processes, implicating CARM1 as a putative epigenetic target in ER-positive breast cancers. PMID- 21282337 TI - Anti-IL-23 monoclonal antibody synergizes in combination with targeted therapies or IL-2 to suppress tumor growth and metastases. AB - Immunosuppressive barricades erected by tumors during the evolution of immune escape represent a major obstacle to many potentially effective cancer therapies and vaccines. We have shown that host interleukin (IL)-23 suppresses the innate immune response during carcinogenesis and metastasis, independently of effects on the proinflammatory cytokine IL-17A. Based on these findings, we envisioned that IL-23 neutralization might offer a promising strategy to modulate immunosuppression, particularly in combination with immunostimulatory agents. Here we show that by itself a neutralizing monoclonal antibody (mAb) to IL-23 suppressed early experimental lung metastases in the B16F10 mouse model of melanoma and also modestly inhibited the subcutaneous growth of primary tumors. These antitumor effects were respectively mediated by natural killer cells or CD8(+) T cells. More notably, combinatorial treatments of anti-IL-23 mAb with IL 2 or anti-erbB2 mAb significantly inhibited subcutaneous growth of established mammary carcinomas and suppressed established experimental and spontaneous lung metastases. Overall, our results suggest the potential of anti-human IL-23 mAbs to improve the immunostimulatory effects of IL-2 and trastuzumab in the current management of some advanced human cancers. PMID- 21282338 TI - Cancer immunotherapy using a bispecific NK receptor fusion protein that engages both T cells and tumor cells. AB - T-cell immunotherapy is a promising strategy to treat cancer, but its efficacy, complexity, and costs may pose challenges. In this study, we report the results of an investigation of a new approach to selectively activate a T-cell attack against tumor cells. The immunotherapeutic approach we developed utilizes a bifunctional fusion protein that binds tumor cells through NK (natural killer) activating receptor NKG2D and that recruits and stimulates T cells through an anti-CD3 single-chain variable fragment (scFv-NKG2D). In vitro, this scFv-NKG2D fusion protein engaged both T cells and tumor cells, stimulating T cells to produce IFN-gamma, and cytotoxicity against NKG2D ligand-positive tumor cells. In vivo, expression of scFv-NKG2D by NKG2D ligand-positive tumor cells reduced tumor burden and, in some cases, led to tumor-free survival. Administration of scFv NKG2D in vivo also promoted survival in a murine lymphoma model. Tumor-free mice were resistant to rechallenge with cognate tumor cells, suggesting that a host specific immunologic memory response had been generated. Host adaptive immunity including gammadelta T cells was required for scFv-NKG2D-mediated therapeutic efficacy. ScFv-NKG2D also inhibited the growth of NKG2D ligand-negative B16F10 tumors, reduced the percentage of myeloid-derived suppressor cells and regulatory T cells, and increased the infiltration of T cells, suggesting that scFv-NKG2D may target these immune suppressive cells. Together, these results establish scFv NKG2D as a promising biological fusion protein to induce effective antitumor immunity. PMID- 21282339 TI - The McCollough effect with plaids and gratings: evidence for a plaid-selective visual mechanism. AB - We investigate if adapting to colored plaids produces a McCollough effect on plaids or gratings and if adapting to colored gratings produces a McCollough effect on plaids. We find that the answer is unambiguously yes in all cases, though the strength of the effect differs significantly depending on the inducing and testing stimuli. Furthermore, we show that plaids and gratings can simultaneously support opposite color aftereffects, suggesting that plaids drive a population of cells that are not stimulated by the same component gratings in isolation. PMID- 21282340 TI - Exogenous and endogenous attention during perceptual learning differentially affect post-training target thresholds. AB - There is conflicting evidence in the literature regarding the role played by attention in perceptual learning. To further examine this issue, we independently manipulated exogenous and endogenous attention and measured the rate of perceptual learning of oriented Gabor patches presented in different quadrants of the visual field. In this way, we could track learning at attended, divided attended, and unattended locations. We also measured contrast thresholds of the Gabor patches before and after training. Our results showed that, for both exogenous and endogenous attention, accuracy in performing the orientation discrimination improved to a greater extent at attended than at unattended locations. Importantly, however, only exogenous attention resulted in improved contrast thresholds. These findings suggest that both exogenous and endogenous attention facilitate perceptual learning, but that these two types of attention may be mediated by different neural mechanisms. PMID- 21282341 TI - Visually guided pointing movements are driven by the salience map. AB - Visual salience maps are assumed to mediate target selection decisions in a motor unspecific manner; accordingly, modulations of salience influence yes/no target detection or left/right localization responses in manual key-press search tasks, as well as ocular or skeletal movements to the target. Although widely accepted, this core assumption is based on little psychophysical evidence. At least four modulations of salience are known to influence the speed of visual search for feature singletons: (i) feature contrast, (ii) cross-trial dimension sequence and (iii) semantic pre-cueing of the target dimension, and (iv) dimensional target redundancy. If salience guides also manual pointing movements, their initiation latencies (and durations) should be affected by the same four manipulations of salience. Four experiments, each examining one of these manipulations, revealed this to be the case. Thus, these effects are seen independently of the motor response required to signal the perceptual decision (e.g., directed manual pointing as well as simple yes/no detection responses). This supports the notion of a motor-unspecific salience map, which guides covert attention as well as overt eye and hand movements. PMID- 21282342 TI - Glucose monitoring after fruit peeling: pseudohyperglycemia when neglecting hand washing before fingertip blood sampling: wash your hands with tap water before you check blood glucose level. AB - OBJECTIVE: To examine whether hand contamination with fruit results in a false blood glucose (BG) reading using capillary fingertip blood sample. RESEARCH DESIGN AND METHODS: The study subjects were healthy volunteers with normal glucose tolerance test. Capillary BG samples were collected from the fingertip after peeling orange, grape, or kiwi fruit, followed by no action, washing hands with tap water, or rubbing the fingertip with an alcohol swab, then analyzed with glucose monitors. RESULTS: The BG levels measured after peeling any of the fruits, followed by washing hands, were similar to the control subjects (no fruit handling), but the levels after fruit peeling, followed by no washing, were abnormally and significantly high, even when the fingertip was cleaned once or five times with an alcohol swab before blood sampling. CONCLUSIONS: To avoid overestimation of blood glucose using portable monitors, the hands should be washed before monitoring capillary BG, especially after fruit has been handled. PMID- 21282343 TI - Effects of bilio-pancreatic diversion on diabetic complications: a 10-year follow up. AB - OBJECTIVE: The surgical option could represent a valid alternative to medical therapy in some diabetic patients. However, no data are available on long-term effects of metabolic surgery on diabetic complications. We aimed to determine whether patients with newly diagnosed type 2 diabetes who underwent bilio pancreatic diversion (BPD) had less micro- and macrovascular complications than those who received conventional therapy. RESEARCH DESIGN AND METHODS: This was an unblinded, case-controlled trial with 10-years' follow-up, conducted from July 1998 through October 2009 at the Day Hospital of Metabolic Diseases, Catholic University, Rome, Italy. A consecutive sample of 110 obese patients (BMI >35 kg/m(2)) with newly diagnosed type 2 diabetes was enrolled. The study was completed by 50 subjects. The main outcome measure was long-term effects (10 years) of BPD versus those associated with conventional therapy on microvascular outcome, micro- and macroalbuminuria, and glomerular filtration rate (GFR). Secondary measures included macrovascular outcomes, type 2 diabetes remission, glycated hemoglobin, and hyperlipidemia. RESULTS: Ten-year GFR variation was 45.7 +/- 18.8% in the medical arm and 13.6 +/- 24.5% in the surgical arm (P < 0.001). Ten-year hypercreatininemia prevalence was 39.3% in control subjects and 9% in BPD subjects (P = 0.001). After 10 years, all BPD subjects recovered from microalbuminuria, whereas microalbuminuria appeared or progressed to macroalbuminuria in control subjects. Three myocardial infarctions, determined by electrocardiogram, and one stroke occurred in control subjects. After the 10-year follow-up, coronary heart disease (CHD) probability was 0.22 +/- 0.10 and 0.05 +/ 0.04 in the medical and surgical groups, respectively (P < 0.001). Remission from type 2 diabetes was observed in all patients within 1 year of surgery. Surgical and medical subjects had lost 34.60 +/- 10.25 and 0.38 +/- 6.10% of initial weight at the 10-year follow-up (P < 0.001). CONCLUSIONS: Renal and cardiovascular complications were dramatically reduced in the surgical arm, indicating long-term benefits of BPD on diabetic complications, at least in the case of morbid obesity with decompensated type 2 diabetes. PMID- 21282344 TI - Microvascular perfusion abnormalities of the Thalamus in painful but not painless diabetic polyneuropathy: a clue to the pathogenesis of pain in type 1 diabetes. AB - OBJECTIVE: The pathogenesis of painful diabetic neuropathy (DN) remains undetermined, with both central and peripheral mechanisms implicated. This study investigates whether thalamic perfusion abnormalities occur in painful DN. RESEARCH DESIGN AND METHODS: Eighteen subjects with type 1 diabetes (no DN = 6, painful DN = 5, painless DN = 7) and six healthy volunteers (HV) were recruited. Microvascular perfusion characteristics (relative cerebral blood volume [rCBV], flow [rCBF], and transit time [tt(FM)]) of the thalamus and caudate nucleus were assessed using magnetic resonance perfusion imaging. The caudate nucleus was chosen to serve as an in vivo control region. RESULTS: Subjects with painful DN had significantly greater thalamic rCBV (means [SD]; painful DN, 228.7 [19.5]; no DN, 202.3 [25.8]; painless DN, 216.5 [65.5]; HV, 181.9 [51.7]; P = 0.04) and the longest tt(FM)(s) (painful DN, 38.4 [3.6]; no DN, 35.3 [13.2]; painless DN, 35.9 [13.7]; HV, 33.7 [14.9]; P = 0.07). There was no significant difference in markers of caudate nucleus perfusion. CONCLUSIONS: Painful DN is associated with increased thalamic vascularity. This may provide an important clue to the pathogenesis of pain in DN. PMID- 21282345 TI - Prediabetes and prehypertension in healthy adults are associated with low vitamin D levels. AB - OBJECTIVE: To determine whether modest elevations of fasting serum glucose (FSG) and resting blood pressure (BP) in healthy adults are associated with differential serum vitamin D concentrations. RESEARCH DESIGN AND METHODS: Disease free adults in the National Health and Nutrition Examination Survey 2001-2006 were assessed. Prediabetes (PreDM) and prehypertension (PreHTN) were diagnosed using American Diabetes Association and Seventh Report of the Joint National Committee on Prevention, Detection, and Treatment of High Blood Pressure criteria: FSG 100-125 mg/dL and systolic BP 120-139 mmHg and/or diastolic BP 80 89 mmHg. Logistic regression was used to assess the effects of low vitamin D levels on the odds for PreDM and PreHTN in asymptomatic adults (n = 1,711). RESULTS: The odds ratio for comorbid PreDM and PreHTN in Caucasian men (n = 898) and women (n = 813) was 2.41 (P < 0.0001) with vitamin D levels <= 76.3 versus >76.3 nmol/L after adjusting for age, sex, and BMI. CONCLUSIONS: This study strengthens the plausibility that low serum vitamin D levels elevate the risk for early-stage diabetes (PreDM) and hypertension (PreHTN). PMID- 21282346 TI - Ethnic differences in diabetes management in patients with and without comorbid medical conditions: a cross-sectional study. AB - OBJECTIVE: To examine ethnic disparities in diabetes management among patients with and without comorbid medical conditions after a period of sustained investment in quality improvement in the U.K. RESEARCH DESIGN AND METHODS: This cross-sectional study examined associations between ethnicity, comorbidity, and intermediate outcomes for mean A1C, total cholesterol, and blood pressure levels in 6,690 diabetes patients in South West London. RESULTS: The presence of >= 2 cardiovascular comorbidities was associated with similar blood pressure control among white and South Asian patients when compared with whites without comorbidity but with worse blood pressure control among black patients, with a mean difference in systolic blood pressure of +1.5, +1.4, and +6.2 mmHg, respectively. CONCLUSIONS: Despite major reforms to improve quality, disparities in blood pressure management have persisted in the U.K., particularly among patients with cardiovascular comorbidities. Policy makers should consider the potential impacts of quality initiatives on high-risk groups. PMID- 21282347 TI - Identification of Tat-SF1 cellular targets by exon array analysis reveals dual roles in transcription and splicing. AB - Tat specific factor 1 (Tat-SF1) interacts with components of both the transcription and splicing machineries and has been classified as a transcription splicing factor. Although its function as an HIV-1 dependency factor has been investigated, relatively little is known about the cellular functions of Tat-SF1. To identify target genes of Tat-SF1, we utilized a combination of RNAi and exon specific microarrays. These arrays, which survey genome-wide changes in transcript and individual exon levels, revealed 450 genes with transcript level changes upon Tat-SF1 depletion. Strikingly, 98% of these target genes were down regulated upon depletion, indicating that Tat-SF1 generally activates gene expression. We also identified 89 genes that showed differential exon level changes after Tat-SF1 depletion. The 89 genes showed evidence of many different types of alternative exon use consistent with the regulation of transcription initiation sites and RNA processing. Minimal overlap between genes with transcript-level and exon-level changes suggests that Tat-SF1 does not functionally couple transcription and splicing. Biological processes significantly enriched with transcript- and exon-level targets include the cell cycle and nucleic acid metabolism; the insulin signaling pathway was enriched with Tat-SF1 transcript-level targets but not exon-level targets. Additionally, a hexamer, ATGCCG, was over-represented in the promoter region of genes showing changes in transcription initiation upon Tat-SF1 depletion. This may represent a novel motif that Tat-SF1 recognizes during transcription. Together, these findings suggest that Tat-SF1 functions independently in transcription and splicing of cellular genes. PMID- 21282348 TI - A flexible linker region in Fip1 is needed for efficient mRNA polyadenylation. AB - Synthesis of the poly(A) tail of mRNA in Saccharomyces cerevisiae requires recruitment of the polymerase Pap1 to the 3' end of cleaved pre-mRNA. This is made possible by the tethering of Pap1 to the Cleavage/Polyadenylation Factor (CPF) by Fip1. We have recently reported that Fip1 is an unstructured protein in solution, and proposed that it might maintain this conformation as part of CPF, when bound to Pap1. However, the role that this feature of Fip1 plays in 3' end processing has not been investigated. We show here that Fip1 has a flexible linker in the middle of the protein, and that removal or replacement of the linker affects the efficiency of polyadenylation. However, the point of tethering is not crucial, as a fusion protein of Pap1 and Fip1 is fully functional in cells lacking genes encoding the essential individual proteins, and directly tethering Pap1 to RNA increases the rate of poly(A) addition. We also find that the linker region of Fip1 provides a platform for critical interactions with other parts of the processing machinery. Our results indicate that the Fip1 linker, through its flexibility and protein/protein interactions, allows Pap1 to reach the 3' end of the cleaved RNA and efficiently initiate poly(A) addition. PMID- 21282349 TI - Do nursing homes for older people have the support they need to provide end-of life care? A mixed methods enquiry in England. AB - Nursing homes are a common site of death, but older residents receive variable quality of end-of-life care. We used a mixed methods design to identify external influences on the quality of end-of-life care in nursing homes. Two qualitative case studies were conducted and a postal survey of 180 nursing homes surrounding the case study sites. In the case studies, qualitative interviews were held with seven members of nursing home staff and 10 external staff. Problems in accessing support for end-of-life care reported in the survey included variable support by general practitioners (GPs), reluctance among GPs to prescribe appropriate medication, lack of support from other agencies, lack of out of hours support, cost of syringe drivers and lack of access to training. Most care homes were implementing a care pathway. Those that were not rated their end-of-life care as in need of improvement or as average. The case studies suggest that critical factors in improving end-of-life care in nursing homes include developing clinical leadership, developing relationships with GPs, the support of 'key' external advocates and leverage of additional resources by adoption of care pathway tools. PMID- 21282350 TI - A unique exonic splicing mutation in the CYP17A1 gene as the cause for steroid 17{alpha}-hydroxylase deficiency. AB - BACKGROUND: 17alpha-Hydroxylase/17,20-lyase deficiency (17OHD) caused by a mutation in the CYP17A1 gene is characterized by hypertension, hypokalemia, and abnormal development of the genitalia. The majority of CYP17A1 mutations are located in the coding sequence, and several intronic splicing site mutations have been reported. OBJECTIVE: A 2.5-year-old girl with 46,XY disordered sex development exhibited a nearly normal basal cortisol level and reduced sexual steroids. This study is aimed to explore the molecular basis and analyze its possible influence on the phenotype of the patient. METHODS AND RESULTS: Mutation analysis revealed compound heterozygous CYP17A1 mutations, with c.985_987delinsAA in one allele and a synonymous substitution (c.1263G>A) in another allele. In vitro expression analysis of the allelic minigene showed that the novel nucleotide variation located in exon 8 induces a splicing signal, which results in an aberrant splicing of CYP17A1 mRNA and a missing portion of exon 8. The translation product includes the deletion of six or seven amino acids from residue position 415 without causing a frameshift. Consistent with the result of molecular modeling, functional studies in transiently transfected HEK-293T cells with the aberrantly spliced enzyme proteins showed that the deleted proteins completely abolished the enzyme activity. However, RT-PCR indicated the existence of a small fraction of normal, functionally intact enzyme, which may explain the partial masculinization of this patient. CONCLUSION: This is the first description of an exonic splicing mutation in CYP17A1 relevant to the 17OHD phenotype. It also demonstrates the importance of studying synonymous change in such patients with less severe phenotype. PMID- 21282351 TI - Receptor for advanced glycation end-products expression in subcutaneous adipose tissue is related to coronary artery disease. AB - OBJECTIVE: Obesity, a risk factor for coronary artery disease (CAD), is associated with inflammation and reactive oxygen species (ROS) production, while advanced glycation end-products, through their receptor (AGER or RAGE), play an important role on these processes. The aim of this study was to analyze the expression levels of RAGE, NADPH oxidase subunits, and catalase in adipose tissue in relation with CAD. DESIGN AND METHODS: Patients undergoing heart surgery were included in two groups: with and without CAD. Epicardial adipose tissue (EAT) and subcutaneous adipose tissue (SAT) biopsies were analyzed for gene expression by RT-quantitative PCR, immunohistochemistry, or western blot. RESULTS: RAGE mRNA and protein expression in SAT from patients with CAD was lower than in patients without CAD. However, there was no change in EAT from patients with or without CAD. P22-PHOX and RAGE gene expression were higher in EAT than in SAT, whereas catalase mRNA levels were lower. NADPH oxidase subunits and catalase mRNA expression were not influenced by CAD. Whereas NADPH oxidase-dependent oxidative response of SAT and EAT to lipid circulating levels could be different; glycemic levels were not related with the analyzed genes expression. CONCLUSIONS: This study demonstrates that RAGE expression in SAT, but not in EAT, is down-regulated in patients with CAD with respect to those without CAD. Although changes were not observed for NADPH oxidase subunits or catalase expression between CAD and non CAD patients, a possible relationship between ROS production and RAGE expression in adipose tissues cannot be ruled out. PMID- 21282352 TI - Serum vaspin levels in normal pregnancy in comparison with non-pregnant women. AB - OBJECTIVE: Pregnancy represents a state of insulin resistance (IR). Vaspin (SERPINA12) is a novel insulin-sensitizing adipokine that might be implicated in endogenous glucose regulation. However, its role in pregnancy and its circulating levels have not been adequately studied. We aimed to evaluate serum vaspin levels in pregnancy and their correlation with known markers of IR. DESIGN: A group of 106 women (age 27.9+/-0.4 years) at the 24-30th week of gestation (pregnancy group) and another 106 age-matched healthy non-pregnant controls (control group) were included in the study. METHODS: Serum glucose, insulin, vaspin, adiponectin, and lipid parameters were measured. The quantitative insulin sensitivity check index (QUICKI) was used as an insulin sensitivity index. RESULTS: Pregnant women had significantly higher body mass index (BMI), lipids, and serum insulin and lower serum glucose and vaspin levels than controls. Vaspin was positively correlated to adiponectin in both groups (P<0.001 and P<0.004 respectively) but was not correlated to BMI, serum insulin levels, or the QUICKI index in either group. Furthermore, vaspin was negatively correlated to lipid parameters (total cholesterol, triglycerides, and low-density lipoproteins) in the pregnant but not in the non-pregnant women. CONCLUSIONS: Vaspin cannot serve as a marker of IR in either pregnant or non-pregnant women, although it is significantly correlated with adiponectin. On the other hand, vaspin might be useful as a surrogate marker of lipid metabolism in pregnancy if confirmed by subsequent studies. PMID- 21282353 TI - Radiosensitization of head and neck squamous cell carcinoma by a SMAC-mimetic compound, SM-164, requires activation of caspases. AB - Chemoradiation is the treatment of choice for locally advanced head and neck squamous cell carcinoma (HNSCC). However, radioresistance, which contributes to local recurrence, remains a significant therapeutic problem. In this study, we characterized SM-164, a small second mitochondria-derived activator of caspase mimetic compound that promotes degradation of cellular inhibitor of apoptosis 1(cIAP-1; also known as baculoviral IAP repeat-containing protein 2, BIRC2) and releases active caspases from the X-linked inhibitor of apoptosis inhibitory binding as a radiosensitizing agent in HNSCC cells. We found that SM-164 at nanomolar concentrations induced radiosensitization in some HNSCC cell lines in a manner dependent on intrinsic sensitivity to caspase activation and apoptosis induction. Blockage of caspase activation via short interfering RNA knockdown or a pan-caspase inhibitor, z-VAD-fmk, largely abrogated SM-164 radiosensitization. On the other hand, the resistant lines with a high level of Bcl-2 that blocks caspase activation and apoptosis induction became sensitive to radiation on Bcl-2 knockdown. Mechanistic studies revealed that SM-164 radiosensitization in sensitive cells was associated with NF-kappaB activation and TNFalpha secretion, followed by activation of caspase-8 and -9, leading to enhanced apoptosis. Finally, SM-164 also radiosensitized human tumor xenograft while causing minimal toxicity. Thus, SM-164 is a potent radiosensitizer via a mechanism involving caspase activation and holds promise for future clinical development as a novel class of radiosensitizer for the treatment of a subset of head and neck cancer patients. PMID- 21282354 TI - Lipoprotein lipase links dietary fat to solid tumor cell proliferation. AB - Many types of cancer cells require a supply of fatty acids (FA) for growth and survival, and interrupting de novo FA synthesis in model systems causes potent anticancer effects. We hypothesized that, in addition to synthesis, cancer cells may obtain preformed, diet-derived FA by uptake from the bloodstream. This would require hydrolytic release of FA from triglyceride in circulating lipoprotein particles by the secreted enzyme lipoprotein lipase (LPL), and the expression of CD36, the channel for cellular FA uptake. We find that selected breast cancer and sarcoma cells express and secrete active LPL, and all express CD36. We further show that LPL, in the presence of triglyceride-rich lipoproteins, accelerates the growth of these cells. Providing LPL to prostate cancer cells, which express low levels of the enzyme, did not augment growth, but did prevent the cytotoxic effect of FA synthesis inhibition. Moreover, LPL knockdown inhibited HeLa cell growth. In contrast to the cell lines, immunohistochemical analysis confirmed the presence of LPL and CD36 in the majority of breast, liposarcoma, and prostate tumor tissues examined (n = 181). These findings suggest that, in addition to de novo lipogenesis, cancer cells can use LPL and CD36 to acquire FA from the circulation by lipolysis, and this can fuel their growth. Interfering with dietary fat intake, lipolysis, and/or FA uptake will be necessary to target the requirement of cancer cells for FA. PMID- 21282355 TI - Cancer-targeted BikDD gene therapy elicits protective antitumor immunity against lung cancer. AB - Targeted cancer-specific gene therapy is a promising strategy for treating metastatic lung cancer, which is a leading cause of lung cancer-related deaths. Previously, we developed a cancer-targeted gene therapy expression system with high tumor specificity and strong activity that selectively induced lung cancer cell killing without affecting normal cells in immunocompromised mice. Here, we found this cancer-targeted gene therapy, SV-BikDD, composed of the survivin promoter in the VP16-GAL4-WPRE integrated systemic amplifier system to drive the apoptotic gene BikDD, not only caused cytotoxic effects in cancer cells but also elicited a cancer-specific cytotoxic T lymphocyte response to synergistically increase the therapeutic effect and further develop an effective systemic antitumoral immunity against rechallenges of tumorigenic dose of parental tumor cells inoculated at distant sites in immunocompetent mice. In addition, this cancer-targeted gene therapy does not elicit an immune response against normal tissues, but CMV-BikDD treatment does. The therapeutic vector could also induce proinflammatory cytokines to activate innate immunity and provide some benefits in antitumor gene therapy. Thus, this study provides a promising strategy with benefit of antitumoral immune response worthy of further development in clinical trials for treating lung cancer via cancer-targeted gene therapy. PMID- 21282356 TI - Targeting sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2 by curcumin induces ER stress-associated apoptosis for treating human liposarcoma. AB - Human liposarcoma is the most common soft tissue sarcoma. There is no effective therapy so far except for surgery. In this study, we report for the first time that curcumin induces endoplasmic reticulum (ER) stress in human liposarcoma cells via interacting with sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase 2 (SERCA2). Curcumin dose-dependently inhibited the cell survival of human liposarcoma cell line SW872 cells, but did not affect that of human normal adipose-derived cells. Curcumin-mediated ER stress via inhibiting the activity of SERCA2 caused increasing expressions of CHOP and its transcription target death receptor 5 (TRAIL-R2), leading to a caspase-3 and caspase-8 cascade-dependent apoptosis in SW872 cells in vitro and in vivo. Moreover, 70% of human liposarcoma tissues showed an elevated SERCA2 expression compared with normal adipose tissues. Curcumin dose-dependently inhibited the activity of SERCA2, and the interaction of molecular docking and colocalization in ER of curcumin with SERCA2 were further observed. These findings suggest that curcumin may serve as a potent agent for curing human liposarcoma via targeting SERCA2. PMID- 21282357 TI - Rapamycin reverses splenomegaly and inhibits tumor development in a transgenic model of Epstein-Barr virus-related Burkitt's lymphoma. AB - Epstein-Barr virus (EBV) infection and latency has been associated with malignancies, including nasopharyngeal carcinoma and Burkitt's lymphoma. EBV encoded latent membrane protein 2A (LMP2A) is expressed in most EBV-associated malignancies and as such provides a therapeutic target. Burkitt's lymphoma is a hematopoietic cancer associated with the translocation of c-MYC to one of the immunoglobulin gene promoters leading to abnormally high expression of MYC and development of lymphoma. Our laboratory has developed a murine model of EBV associated Burkitt's lymphoma by crossing LMP2A transgenic mice with MYC transgenic mice. Since LMP2A has been shown to activate the PI3K/Akt/mTOR pathway, we tested the therapeutic efficacy of mTOR inhibitor rapamycin on the tumors and splenomegaly in these double transgenic mice (Tg6/lambda-MYC). We found that rapamycin reversed splenomegaly in Tg6/lambda-MYC mice prior to tumor formation by targeting B cells. In a tumor transfer model, we also found that rapamycin significantly decreased tumor growth, splenomegaly, and metastasis of tumor cells in the bone marrow of tumor recipients. Our data show that rapamycin may be a valuable candidate for the development of a treatment modality for EBV positive lymphomas, such as Burkitt's lymphoma, and more importantly, provides a basis to develop inhibitors that specifically target viral gene function in tumor cells that depend on LMP2A signaling for survival and/or growth. PMID- 21282358 TI - Increased sensitivity to thiopurines in methylthioadenosine phosphorylase-deleted cancers. AB - The thiopurines, 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG), are used in the treatment of leukemia. Incorporation of deoxythioguanosine nucleotides (dG(s)) into the DNA of thiopurine-treated cells causes cell death, but there is also evidence that thiopurine metabolites, particularly the 6-MP metabolite methylthioinosine monophosphate (MeTIMP), inhibit de novo purine synthesis (DNPS). The toxicity of DNPS inhibitors is influenced by methylthioadenosine phosphorylase (MTAP), a gene frequently deleted in cancers. Because the growth of MTAP-deleted tumor cells is dependent on DNPS or hypoxanthine salvage, we would predict such cells to show differential sensitivity to 6-MP and 6-TG. To test this hypothesis, sensitivity to 6-MP and 6-TG was compared in relation to MTAP status using cytotoxicity assays in two MTAP-deficient cell lines transfected to express MTAP: the T-cell acute lymphoblastic leukemic cell line, Jurkat, transfected with MTAP cDNA under the control of a tetracycline-inducible promoter, and a lung cancer cell line (A549-MTAP(-)) transfected to express MTAP constitutively (A549-MTAP(+)). Sensitivity to 6-MP or methyl mercaptopurine riboside, which is converted intracellularly to MeTIMP, was markedly higher in both cell lines under MTAP(-) conditions. Measurement of thiopurine metabolites support the hypothesis that DNPS inhibition is a major cause of cell death with 6 MP, whereas dG(s) incorporation is the main cause of cytotoxicity with 6-TG. These data suggest that thiopurines, particularly 6-MP, may be more effective in patients with deleted MTAP. PMID- 21282359 TI - Novel functions for mda-7/IL-24 and IL-24 delE5: regulation of differentiation of acute myeloid leukemic cells. AB - Characterizing genes associated with leukemic cell differentiation may provide help for understanding mechanisms on the leukemia differentiation. The aim of this study is to investigate whether the expression of melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) could be induced during leukemia differentiation and whether mda-7/IL-24 plays a role in leukemia differentiation. We showed that the expression of mda-7/IL-24 and IL-24 delE5, an mda-7/IL-24 splice variant, was induced in U937 and HL60 cells during 12-O tetradecanoylphorbol-13-acetate (TPA)-mediated monocytic differentiation. Activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway was required for their induction. Knockdown of mda-7/IL-24 and IL 24 delE5 resulted in significant inhibition of the monocytic differentiation induced by TPA. More importantly, ectopic overexpression of mda-7/IL-24 and IL-24 delE5 significantly induced U937 cells, HL60 cells, and blast cells from patients with acute myeloid leukemia-M5 to differentiate, whereas normal hematopoietic progenitors were not affected. Furthermore, the molecular effector associated with selective differentiation induction by mda-7/IL-24 and IL-24 delE5 may be reactive oxygen species (ROS), and the source of ROS generation was nicotinamide adenine dinucleotide phosphate oxidase. Taken together, our results reveal the mechanism by which TPA induces monocytic differentiation and show for the first time the specific differentiation-inducing effects of mda-7/IL-24 and IL-24 delE5 on human myeloid leukemic cells. PMID- 21282360 TI - GPR54 is a target for suppression of metastasis in endometrial cancer. AB - Invasion into deep myometrium and/or lymphovascular space is a well-known risk factor for endometrial cancer metastasis, resulting in poor prognosis. It is therefore clinically important to identify novel molecules that suppress tumor invasion. Reduced expression of the metastasis suppressor, kisspeptin (KISS1), and its endogenous receptor, GPR54, has been reported in several cancers, but the significance of the KISS1/GPR54 axis in endometrial cancer metastasis has not been clarified. Metastin-10 is the minimal bioactive sequence of genetic products of KISS1. Clinicopathological analysis of 92 endometrial cancers revealed overall survival is improved in cancers with high expression of GPR54 (P < 0.05) and that GPR54 expression is associated with known prognostic factors including FIGO stage, grade, and deep myometrial invasion. Through RNAi and microarray analyses, metastin-10 was predicted to suppress metastasis of GPR54-expressing endometrial cancers in vivo. Methylation analysis revealed GPR54 is epigenetically regulated. Metastin-GPR54 axis function was restored following treatment with the DNA hypomethylating agent 5-aza-DC. These data suggest that metastin-10 may be effective at inhibiting the metastatic spread of endometrial cancers in combination with demethylating agents to induce GPR54 expression. PMID- 21282361 TI - Inflammatory induction of human resistin causes insulin resistance in endotoxemic mice. AB - OBJECTIVE: Although adipocyte-derived murine resistin links insulin resistance to obesity, the role of human resistin, predominantly expressed in mononuclear cells and induced by inflammatory signals, remains unclear. Given the mounting evidence that obesity and type 2 diabetes are inflammatory diseases, we sought to determine the relationship between inflammatory increases in human resistin and insulin resistance. RESEARCH DESIGN AND METHODS: To investigate the role of human resistin on glucose homeostasis in inflammatory states, we generated mice lacking murine resistin but transgenic for a bacterial artificial chromosome containing human resistin (BAC-Retn), whose expression was similar to that in humans. The metabolic and molecular phenotypes of BAC-Retn mice were assessed after acute and chronic endotoxemia (i.e., exposure to inflammatory lipopolysaccharide). RESULTS: We found that BAC-Retn mice have circulating resistin levels within the normal human range, and similar to humans, lipopolysaccharide markedly increased serum resistin levels. Acute endotoxemia caused hypoglycemia in mice lacking murine resistin, and this was attenuated in BAC-Retn mice. In addition, BAC-Retn mice developed severe hepatic insulin resistance under chronic endotoxemia, accompanied by increased inflammatory responses in liver and skeletal muscle. CONCLUSIONS: These results strongly support the role of human resistin in the development of insulin resistance in inflammation. Thus, human resistin may link insulin resistance to inflammatory diseases such as obesity, type 2 diabetes, and atherosclerosis. PMID- 21282362 TI - Mendelian randomization studies do not support a role for raised circulating triglyceride levels influencing type 2 diabetes, glucose levels, or insulin resistance. AB - OBJECTIVE: The causal nature of associations between circulating triglycerides, insulin resistance, and type 2 diabetes is unclear. We aimed to use Mendelian randomization to test the hypothesis that raised circulating triglyceride levels causally influence the risk of type 2 diabetes and raise normal fasting glucose levels and hepatic insulin resistance. RESEARCH DESIGN AND METHODS: We tested 10 common genetic variants robustly associated with circulating triglyceride levels against the type 2 diabetes status in 5,637 case and 6,860 control subjects and four continuous outcomes (reflecting glycemia and hepatic insulin resistance) in 8,271 nondiabetic individuals from four studies. RESULTS: Individuals carrying greater numbers of triglyceride-raising alleles had increased circulating triglyceride levels (SD 0.59 [95% CI 0.52-0.65] difference between the 20% of individuals with the most alleles and the 20% with the fewest alleles). There was no evidence that the carriers of greater numbers of triglyceride-raising alleles were at increased risk of type 2 diabetes (per weighted allele odds ratio [OR] 0.99 [95% CI 0.97-1.01]; P = 0.26). In nondiabetic individuals, there was no evidence that carriers of greater numbers of triglyceride-raising alleles had increased fasting insulin levels (SD 0.00 per weighted allele [95% CI -0.01 to 0.02]; P = 0.72) or increased fasting glucose levels (0.00 [-0.01 to 0.01]; P = 0.88). Instrumental variable analyses confirmed that genetically raised circulating triglyceride levels were not associated with increased diabetes risk, fasting glucose, or fasting insulin and, for diabetes, showed a trend toward a protective association (OR per 1-SD increase in log(10) triglycerides: 0.61 [95% CI 0.45-0.83]; P = 0.002). CONCLUSIONS: Genetically raised circulating triglyceride levels do not increase the risk of type 2 diabetes or raise fasting glucose or fasting insulin levels in nondiabetic individuals. One explanation for our results is that raised circulating triglycerides are predominantly secondary to the diabetes disease process rather than causal. PMID- 21282363 TI - The ENPP1 Q121 variant predicts major cardiovascular events in high-risk individuals: evidence for interaction with obesity in diabetic patients. AB - OBJECTIVE: Insulin resistance (IR) and cardiovascular disease may share a common genetic background. We investigated the role of IR-associated ENPP1 K121Q polymorphism (rs1044498) on cardiovascular disease in high-risk individuals. RESEARCH DESIGN AND METHODS: A prospective study (average follow-up, 37 months) was conducted for major cardiovascular events (myocardial infarction [MI], stroke, cardiovascular death) from the Gargano Heart Study (GHS; n = 330 with type 2 diabetes and coronary artery disease), the Tor Vergata Atherosclerosis Study (TVAS; n = 141 who had MI), and the Cardiovascular Risk Extended Evaluation in Dialysis (CREED) database (n = 266 with end-stage renal disease). Age at MI was investigated in cross-sectional studies of 339 type 2 diabetic patients (n = 169 from Italy, n = 170 from the U.S.). RESULTS: Incidence of cardiovascular events per 100 person--years was 4.2 in GHS, 10.8 in TVAS, and 11.7 in CREED. Hazard ratios (HRs) for KQ+QQ versus individuals carrying the K121/K121 genotype (KK) individuals were 1.47 (95% CI 0.80-2.70) in GHS, 2.31 (95% CI 1.22-4.34) in TVAS, and 1.36 (95% CI 0.88-2.10) in CREED, and 1.56 (95% CI 1.15-2.12) in the three cohorts combined. In the 395 diabetic patients, the Q121 variant predicted cardiovascular events among obese but not among nonobese individuals (HR 5.94 vs. 0.62, P = 0.003 for interaction). A similar synergism was observed in cross sectional studies, with age at MI being 3 years younger in Q121 carriers than in KK homozygotes among obese but not among nonobese patients (P = 0.035 for interaction). CONCLUSIONS: The ENPP1 K121Q polymorphism is an independent predictor of major cardiovascular events in high-risk individuals. In type 2 diabetes, this effect is exacerbated by obesity. Future larger studies are needed to confirm our finding. PMID- 21282364 TI - Leucine deprivation increases hepatic insulin sensitivity via GCN2/mTOR/S6K1 and AMPK pathways. AB - OBJECTIVE: We have previously shown that serum insulin levels decrease threefold and blood glucose levels remain normal in mice fed a leucine-deficient diet, suggesting increased insulin sensitivity. The goal of the current study is to investigate this possibility and elucidate the underlying cellular mechanisms. RESEARCH DESIGN AND METHODS: Changes in metabolic parameters and expression of genes and proteins involved in regulation of insulin sensitivity were analyzed in mice, human HepG2 cells, and mouse primary hepatocytes under leucine deprivation. RESULTS: We show that leucine deprivation improves hepatic insulin sensitivity by sequentially activating general control nonderepressible (GCN)2 and decreasing mammalian target of rapamycin/S6K1 signaling. In addition, we show that activation of AMP-activated protein kinase also contributes to leucine deprivation-increased hepatic insulin sensitivity. Finally, we show that leucine deprivation improves insulin sensitivity under insulin-resistant conditions. CONCLUSIONS: This study describes mechanisms underlying increased hepatic insulin sensitivity under leucine deprivation. Furthermore, we demonstrate a novel function for GCN2 in the regulation of insulin sensitivity. These observations provide a rationale for short-term dietary restriction of leucine for the treatment of insulin resistance and associated metabolic diseases. PMID- 21282365 TI - Thyroid transcription factor-1 regulates feeding behavior via melanocortin pathway in the hypothalamus. AB - OBJECTIVE: alpha-Melanocyte-stimulating hormone (alpha-MSH) and agouti-related peptide (AgRP) control energy homeostasis by their opposing actions on melanocortin receptors (MC3/4R) in the hypothalamus. We previously reported that thyroid transcription factor-1 (TTF-1) controls feeding behavior in the hypothalamus. This study aims to identify the function of TTF-1 in the transcriptional regulation of AgRP and alpha-MSH synthesis for the control of feeding behavior. RESEARCH DESIGN AND METHODS: TTF-1 activity in AgRP and pro opiomelanocortin (POMC) transcription was examined using gel-shift and promoter assays and an in vivo model of TTF-1 synthesis inhibition by intracerebroventricular injection of an antisense (AS) oligodeoxynucleotide (ODN). Double immunohistochemistry was performed to colocalize TTF-1 and AgRP or alpha-MSH in the hypothalamic arcuate nucleus (ARC). To determine whether TTF-1 action on food intake is mediated through MC3/4R, we measured changes in food intake upon intracerebroventricular injection of MC3/4R antagonists (SHU9119 and AgRP) into rat brain preinjected with the AS ODN. RESULTS: TTF-1 stimulated AgRP but inhibited POMC transcription by binding to the promoters of these genes. TTF 1 was widely distributed in the hypothalamus, but we identified some cells coexpressing TTF-1 and AgRP or alpha-MSH in the ARC. In addition, intracerebroventricular administration of leptin decreased TTF-1 expression in the hypothalamus, and AS ODN-induced inhibition of TTF-1 expression decreased food intake and AgRP expression but increased alpha-MSH expression. Anorexia induced by the AS ODN was attenuated by the administration of MC3/4R antagonists. CONCLUSIONS: TTF-1 transcriptionally regulates synthesis of AgRP and alpha-MSH in the ARC and affects feeding behavior via the melanocortin pathway. PMID- 21282366 TI - Molecular mechanism by which AMP-activated protein kinase activation promotes glycogen accumulation in muscle. AB - OBJECTIVE: During energy stress, AMP-activated protein kinase (AMPK) promotes glucose transport and glycolysis for ATP production, while it is thought to inhibit anabolic glycogen synthesis by suppressing the activity of glycogen synthase (GS) to maintain the energy balance in muscle. Paradoxically, chronic activation of AMPK causes an increase in glycogen accumulation in skeletal and cardiac muscles, which in some cases is associated with cardiac dysfunction. The aim of this study was to elucidate the molecular mechanism by which AMPK activation promotes muscle glycogen accumulation. RESEARCH DESIGN AND METHODS: We recently generated knock-in mice in which wild-type muscle GS was replaced by a mutant (Arg582Ala) that could not be activated by glucose-6-phosphate (G6P), but possessed full catalytic activity and could still be activated normally by dephosphorylation. Muscles from GS knock-in or transgenic mice overexpressing a kinase dead (KD) AMPK were incubated with glucose tracers and the AMPK-activating compound 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) ex vivo. GS activity and glucose uptake and utilization (glycolysis and glycogen synthesis) were assessed. RESULTS: Even though AICAR caused a modest inactivation of GS, it stimulated muscle glycogen synthesis that was accompanied by increases in glucose transport and intracellular [G6P]. These effects of AICAR required the catalytic activity of AMPK. Strikingly, AICAR-induced glycogen synthesis was completely abolished in G6P-insensitive GS knock-in mice, although AICAR-stimulated AMPK activation, glucose transport, and total glucose utilization were normal. CONCLUSIONS: We provide genetic evidence that AMPK activation promotes muscle glycogen accumulation by allosteric activation of GS through an increase in glucose uptake and subsequent rise in cellular [G6P]. PMID- 21282367 TI - Physical exercise reduces circulating lipopolysaccharide and TLR4 activation and improves insulin signaling in tissues of DIO rats. AB - OBJECTIVE: Insulin resistance in diet-induced obesity (DIO) is associated with a chronic systemic low-grade inflammation, and Toll-like receptor 4 (TLR4) plays an important role in the link among insulin resistance, inflammation, and obesity. The current study aimed to analyze the effect of exercise on TLR4 expression and activation in obese rats and its consequences on insulin sensitivity and signaling. RESEARCH DESIGN AND METHODS: The effect of chronic and acute exercise was investigated on insulin sensitivity, insulin signaling, TLR4 activation, c Jun NH(2)-terminal kinase (JNK) and IkappaB kinase (IKKbeta) activity, and lipopolysaccharide (LPS) serum levels in tissues of DIO rats. RESULTS: The results showed that chronic exercise reduced TLR4 mRNA and protein expression in liver, muscle, and adipose tissue. However, both acute and chronic exercise blunted TLR4 signaling in these tissues, including a reduction in JNK and IKKbeta phosphorylation and IRS-1 serine 307 phosphorylation, and, in parallel, improved insulin-induced IR, IRS-1 tyrosine phosphorylation, and Akt serine phosphorylation, and reduced LPS serum levels. CONCLUSIONS: Our results show that physical exercise in DIO rats, both acute and chronic, induces an important suppression in the TLR4 signaling pathway in the liver, muscle, and adipose tissue, reduces LPS serum levels, and improves insulin signaling and sensitivity. These data provide considerable progress in our understanding of the molecular events that link physical exercise to an improvement in inflammation and insulin resistance. PMID- 21282368 TI - Serum vascular adhesion protein-1 predicts 10-year cardiovascular and cancer mortality in individuals with type 2 diabetes. AB - OBJECTIVE: Vascular adhesion protein-1 (VAP-1) participates in inflammation and catalyzes the breakdown of amines to produce aldehyde, hydrogen peroxide, and ammonia. Serum VAP-1 correlates positively with both acute hyperglycemia and diabetes. We conducted a cohort study to evaluate whether serum VAP-1 predicts 10 year survival in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: Between July 1996 and June 2003, we enrolled 661 type 2 diabetic subjects at National Taiwan University Hospital. Serum VAP-1 in the samples obtained at enrollment was measured by time-resolved immunofluorometric assay. The vital status of all subjects was ascertained by linking their data with computerized death certificates in Taiwan. RESULTS: The medium follow-up period was 10.4 years. Subjects with serum VAP-1 in the highest tertile had a hazard ratio (HR) of 2.19 (95% CI 1.17-4.11) for all-cause mortality adjusted for age, sex, smoking, history of cardiovascular disease, obesity, hypertension, hemoglobin A(1c), diabetes duration, total cholesterol, use of statins, abnormal ankle-brachial index, estimated glomerular filtration rate (eGFR), and proteinuria. The adjusted HRs for logarithmically transformed serum VAP-1 were 5.83 (95% CI 1.17-28.97) for cardiovascular mortality, 6.32 (95% CI 1.25-32.00) for mortality from cardiovascular and diabetic causes, and 17.24 (95% CI 4.57-65.07) for cancer mortality. There were four variables, including age, serum VAP-1, proteinuria, and eGFR, which could enhance mortality prediction significantly. CONCLUSIONS: Serum VAP-1 can predict 10-year all-cause mortality, cardiovascular mortality, and cancer mortality independently in type 2 diabetic subjects. Serum VAP-1 is a novel biomarker that improves risk prediction over and above established risk factors. PMID- 21282369 TI - Tubular injury in a rat model of type 2 diabetes is prevented by metformin: a possible role of HIF-1alpha expression and oxygen metabolism. AB - OBJECTIVE: Chronic hypoxia has been recognized as a key regulator in renal tubulointerstitial fibrosis, as seen in diabetic nephropathy, which is associated with the activation of hypoxia-inducible factor (HIF)-1alpha. We assess here the effects of the biguanide, metformin, on the expression of HIF-1alpha in diabetic nephropathy using renal proximal tubular cells and type 2 diabetic rats. RESEARCH DESIGN AND METHODS: We explored the effects of metformin on the expression of HIF 1alpha using human renal proximal tubular epithelial cells (HRPTECs). Male Zucker diabetic fatty (ZDF; Gmi-fa/fa) rats were treated from 9 to 39 weeks with metformin (250 mg ? kg(-1) ? day(-1)) or insulin. RESULTS: Metformin inhibited hypoxia-induced HIF-1alpha accumulation and the expression of HIF-1-targeted genes in HRPTECs. Although metformin activated the downstream pathways of AMP activated protein kinase (AMPK), neither the AMPK activator, AICAR, nor the mTOR inhibitor, rapamycin, suppressed hypoxia-induced HIF-1alpha expression. In addition, knockdown of AMPK-alpha did not abolish the inhibitory effects of metformin on HIF-1alpha expression. The proteasome inhibitor, MG-132, completely eradicated the suppression of hypoxia-induced HIF-1alpha accumulation by metformin. The inhibitors of mitochondrial respiration similarly suppressed hypoxia-induced HIF-1alpha expression. Metformin significantly decreased ATP production and oxygen consumption rates, which subsequently led to increased cellular oxygen tension. Finally, metformin, but not insulin, attenuated tubular HIF-1alpha expression and pimonidazole staining and ameliorated tubular injury in ZDF rats. CONCLUSIONS: Our data suggest that hypoxia-induced HIF-1alpha accumulation in diabetic nephropathy could be suppressed by the antidiabetes drug, metformin, through the repression of oxygen consumption. PMID- 21282370 TI - Polymerase I and transcript release factor regulates lipolysis via a phosphorylation-dependent mechanism. AB - OBJECTIVE: Polymerase I and transcript release factor (PTRF) is a protein highly expressed in adipose tissue and is an integral structural component of caveolae. Here, we report on a novel role of PTRF in lipid mobilization. RESEARCH DESIGN AND METHODS: PTRF expression was examined in different adipose depots of mice during fasting, refeeding, and after administration of catecholamines and insulin. Involvement of PTRF during lipolysis was studied upon PTRF knockdown and overexpression and mutation of PTRF phosphorylation sites in 3T3-L1 adipocytes. RESULTS: PTRF expression in mouse white adipose tissue (WAT) is regulated by nutritional status, increasing during fasting and decreasing to baseline after refeeding. Expression of PTRF also is hormonally regulated because treatment of mice with insulin leads to a decrease in expression, whereas isoproterenol increases expression in WAT. Manipulation of PTRF levels revealed a role of PTRF in lipolysis. Lentiviral-mediated knockdown of PTRF resulted in a marked attenuation of glycerol release in response to isoproterenol. Conversely, overexpressing PTRF enhanced isoproterenol-stimulated glycerol release. Mass spectrometric analysis revealed that PTRF is phosphorylated at multiple sites in WAT. Mutation of serine 42, threonine 304, or serine 368 to alanine reduced isoproterenol-stimulated glycerol release in 3T3-L1 adipocytes. CONCLUSIONS: Our study is the first direct demonstration for a novel adipose tissue-specific function of PTRF as a mediator of lipolysis and also shows that phosphorylation of PTRF is required for efficient fat mobilization. PMID- 21282371 TI - Increased expression of macrophage-inducible C-type lectin in adipose tissue of obese mice and humans. AB - OBJECTIVE: We have provided evidence that saturated fatty acids, which are released from adipocytes via macrophage-induced adipocyte lipolysis, serve as a naturally occurring ligand for the Toll-like receptor (TLR) 4 complex in macrophages, thereby aggravating obesity-induced adipose tissue inflammation. The aim of this study was to identify the molecule(s) activated in adipose tissue macrophages in obesity. RESEARCH DESIGN AND METHODS: We performed a cDNA microarray analysis of coculture of 3T3-L1 adipocytes and RAW264 macrophages. Cultured adipocytes and macrophages and the adipose tissue of obese mice and humans were used to examine mRNA and protein expression. RESULTS: We found that macrophage-inducible C-type lectin (Mincle; also called Clec4e and Clecsf9), a type II transmembrane C-type lectin, is induced selectively in macrophages during the interaction between adipocytes and macrophages. Treatment with palmitate, a major saturated fatty acid released from 3T3-L1 adipocytes, induced Mincle mRNA expression in macrophages at least partly through the TLR4/nuclear factor (NF) kappaB pathway. Mincle mRNA expression was increased in parallel with macrophage markers in the adipose tissue of obese mice and humans. The obesity-induced increase in Mincle mRNA expression was markedly attenuated in C3H/HeJ mice with defective TLR4 signaling relative to control C3H/HeN mice. Notably, Mincle mRNA was expressed in bone-marrow cell (BMC)-derived proinflammatory M1 macrophages rather than in BMC-derived anti-inflammatory M2 macrophages in vitro. CONCLUSIONS: Our data suggest that Mincle is induced in adipose tissue macrophages in obesity at least partly through the saturated fatty acid/TLR4/NF kappaB pathway, thereby suggesting its pathophysiologic role in obesity-induced adipose tissue inflammation. PMID- 21282372 TI - Factors contributing to formation of edema in volume overloaded continuous ambulatory peritoneal dialysis patients. AB - BACKGROUND: Volume control is critical for the success of peritoneal dialysis (PD) but dry weight in PD has been difficult to obtain. Edema free is, in general, accepted clinically as a target for volume control in PD patients. However, PD patients can be free of edema despite significant volume overload. The present study investigates the possible factors that influence the formation of pitting edema in volume-overloaded PD patients. METHODS: In this cross sectional study, patients' fluid status was evaluated by multifrequency bioelectrical impedance spectroscopy analysis. Values for overhydration were obtained. Patients with overhydration >= 2.0 kg were considered volume overloaded and were eligible for inclusion. From 1 March 2009 to 1 December 2009, a total of 96 patients on continuous ambulatory PD were included. Endothelial function was evaluated by flow-mediated dilatation (FMD). Other clinical indicators, such as blood pressure, dialysis adequacy, nutrition status, and biochemical parameters, were recorded. Patients were divided into 2 groups based on edema status: the edema group (n = 35 volume-overloaded patients with bilateral pitting edema) and the non-edema group (n = 61 volume-overloaded patients without bilateral pitting edema). RESULTS: Overhydration in the edema group was significantly higher than in the non-edema group (4.28 +/- 1.75 kg vs 3.12 +/- 0.81 kg, p < 0.001), whereas both FMD and serum albumin in the edema group were significantly lower than in the non-edema group (6.65% +/- 5.2% vs 10.3% +/- 5.1%, p = 0.001; 37.6 +/- 4.2 g/L vs 39.3 +/- 3.5 g/L, p = 0.047, respectively). Edema status (edema = 1, non edema = 0) was positively correlated with overhydration (r = 0.341, p < 0.001), gender (male = 1, female = 2: r = 0.184, p = 0.072), and total fluid removal (r = 0.188, p = 0.074) and negatively correlated with endothelial function, as assessed by FMD (r = -0.33, p = 0.001), and serum albumin (r = -0.18, p = 0.055). Logistic regression analysis showed that FMD [odds ratio (OR) 0.90, 95% confidence interval (CI) 0.81 - 0.99; p = 0.036], gender (male = 1, female = 2: OR 4.06, 95% CI 1.23 - 13.35; p = 0.021), overhydration (OR 3.06, 95% CI 1.53 - 6.13; p = 0.002), and serum albumin (OR 0.86, 95% CI 0.75 - 0.99; p = 0.035) were independent factors affecting the edema status of the study population. CONCLUSION: Our study showed that endothelial function (assessed by FMD), gender, serum albumin, and overhydration are independent determinants of edema status in PD patients. This may explain why some PD patients can maintain free of edema despite significant volume overload. PMID- 21282373 TI - In younger dialysis patients, automated peritoneal dialysis is associated with better long-term patient and technique survival than is continuous ambulatory peritoneal dialysis. AB - BACKGROUND: In the U.S. Renal Data System registry, technique and patient survival are similar with automated peritoneal dialysis (APD) and continuous ambulatory peritoneal dialysis (CAPD). The clinical outcomes of APD and CAPD in various age groups have not been clarified. OBJECTIVES: We investigated whether patient and technique survival are different for incident dialysis patients treated with APD or CAPD in two age groups. METHODS: Our retrospective study of prospectively collected data included 282 incident peritoneal dialysis (PD) patients (161 on APD, 121 on CAPD). Patients on PD for less than 3 months were excluded. The patients were divided into those less than 65 years of age and those 65 years of age or older. Overall mortality and technique failure were the primary endpoints of the study. Hazard ratios (HRs) for mortality and technique failure were calculated by the Cox proportional hazards model and were adjusted for age, sex, diabetes mellitus, initial peritoneal equilibration test (PET), weekly peritoneal and renal creatinine clearances, and PD caregiver (self or other). RESULTS: The characteristics and clinical data were not significantly different between patients on APD and CAPD, except for age and sex. The adjusted risk for overall mortality was not different between patients on APD and CAPD (HR: 0.72; 95% CI: 0.44 to 1.20; p = 0.207). The adjusted risk for technique failure was lower in APD patients than in CAPD patients (HR: 0.58; 95% CI: 0.34 to 0.98; p = 0.041). In patients less than 65 years of age, those on APD had a significantly lower risk of mortality (HR: 0.35; 95% CI: 0.16 to 0.75; p = 0.007) and technique failure (HR: 0.52; 95% CI: 0.28 to 0.95; p = 0.034) than did those on CAPD. In patients 65 years of age and older, those on APD had risks for mortality (HR: 1.14; 95% CI: 0.53 to 2.46; p = 0.730) and technique failure (HR: 0.51; 95% CI: 0.17 to 1.50; p = 0.220) that were similar to those of patients on CAPD. Nutrition status, including serum albumin and protein catabolic rate, was not significantly different between patients on APD and on CAPD, in either younger or older patients. CONCLUSIONS: Younger Chinese patients on APD have better patient and technique survival than do those on CAPD. However, there is a strong possibility that this benefit may be confounded or accounted for by baseline differences between the APD and CAPD populations. PMID- 21282374 TI - Human herpesvirus 6 infection in hemodialysis and peritoneal dialysis patients. AB - BACKGROUND: Human herpesvirus 6 (HHV-6) infection occurs worldwide and can be reactivated from latency during periods of immunosuppression, especially after organ transplantation. No previous study has evaluated the influence of dialysis type on HHV-6 infection. The aim of the present study was to determine the prevalence of HHV-6 antibodies in hemodialysis (HD) and peritoneal dialysis (PD) patients. METHODS: We studied 36 PD patients, 35 HD patients, and 20 healthy subjects, all with no history of organ transplantation. After systematic inquiries and a physical examination, blood was drawn for determination of biochemical parameters, cytomegalovirus immunoglobulin M (IgM) and immunoglobulin G (IgG), hepatitis B surface antigen, and the hepatitis C and human immunodeficiency virus antibodies. Titers of HHV-6 IgM and IgG antibodies were determined by ELISA. RESULTS: Titers for HHV-6 IgM antibody were positive in 9 HD patients (25.7%), 8 PD patients (22.2%), and 2 control subjects (10.0%, p > 0.05). More HD patients (20.0%) than PD patients (5.6%, p = 0.07) or control subjects (0.0%, p = 0.03) were positive for HHV-6 IgG antibody. In HD patients, HHV-6 IgG seropositivity and duration of dialysis were positively correlated (R = 0.33, p = 0.05). CONCLUSIONS: Infection with HHV-6 is not rare in PD and HD patients. In addition, HHV-6 IgG seropositivity was significantly higher in HD patients than in control subjects and approached significance when compared with seropositivity in PD patients. Moreover, in HD patients, HHV-6 IgG seropositivity correlated with duration on HD. These preliminary findings provide insight into the pre-transplantation period for patients and may aid our understanding of how to best protect patients against HHV-6 after transplantation. PMID- 21282375 TI - Relationship between drain volume/fill volume ratio and clinical outcomes associated with overfill complaints in peritoneal dialysis patients. AB - BACKGROUND: To better understand the spectrum of overfill reports and their corresponding clinical severity and etiology, we conducted a review of overfill reports from the Manufacturer and User Facility Device Experience (MAUDE) database, which is within the Food and Drug Administration (FDA) Web site (www.fda.gov). METHOD: We searched the MAUDE database for events related to overfill reports between 1 January 1995 and 31 December 2008 and recorded drain volume (DV)/fill volume (FV), or DV/FV, and clinical symptoms and signs associated with the overfill report. RESULTS: Among 462 MAUDE reports with a possible overfill event, 440 reports (95.2%) with a confirmed overfill event contained sufficient information to ascertain the clinical severity of the event. The number of reports with a clinical severity rating of minor, moderate, major, or death was 331, 71, 28, and 10, respectively. The median (range) DV/FV for a subgroup of 292 reports with a clinical severity rating of minor, moderate, major, or death was 1.63 (1.06 - 4.29), 1.71 (1.08 - 5.87), 2.14(1.64 - 2.61), and 2.50 (2.28 - 3.33), respectively. Insufficient drain accounted for a majority of overfill reports. CONCLUSION: Our analysis of reports from the MAUDE database suggests an association between DV/FV and clinical severity of the reported overfill event, as well as significant patient-to-patient variability with respect to intraperitoneal volume tolerance. PMID- 21282376 TI - Loss of residual renal function was not associated with glycemic control in patients on peritoneal dialysis. AB - BACKGROUND: Better glycemic control has been reported to slow the progression of nephropathy in predialysis diabetic patients. However, the relationship between glycemic control and residual renal function (RRF) in patients on peritoneal dialysis (PD) is uncertain. METHODS: 89 incident diabetic patients on PD were recruited from 5 centers. We measured glomerular filtration rate (GFR) and hemoglobin A1c (HbA1c) within 2 months (baseline) after the start of PD and at 6 and 12 months. GFR was calculated as the average of renal creatinine and urea clearances. We analyzed whether mean HbA1c was associated with change in GFR (DeltaGFR) over 1 year. RESULTS: During the first year of PD, DeltaGFR was -1.7 +/- 3.4 mL/min/1.73 m2 and was not affected by mean HbA1c. Acute hemodialysis before starting PD and mean arterial diastolic pressure were related to the decline of GFR in a multivariate analysis. CONCLUSION: Glycemic control was not associated with change in RRF in diabetic patients during the first year after starting PD. PMID- 21282377 TI - FBXW7 influences murine intestinal homeostasis and cancer, targeting Notch, Jun, and DEK for degradation. AB - The Fbxw7 (F-box/WD repeat-containing protein 7; also called CDC4, Sel10, Ago, and Fbw7) component of the SCF (Skp1/Cullin/F-box protein) E3 ubiquitin ligase complex acts as a tumor suppressor in several tissues and targets multiple transcriptional activators and protooncogenes for ubiquitin-mediated degradation. To understand Fbxw7 function in the murine intestine, in this study, we specifically deleted Fbxw7 in the murine gut using Villin-Cre (Fbxw7(DeltaG)). In wild-type mice, loss of Fbxw7 in the gut altered homeostasis of the intestinal epithelium, resulted in elevated Notch and c-Jun expression, and induced development of adenomas at 9-10 mo of age. In the context of APC (adenomatous polyposis coli) deficiency (Apc(Min/+) mice), loss of Fbxw7 accelerated intestinal tumorigenesis and death and promoted accumulation of beta-catenin in adenomas at late but not early time points. At early time points, Fbxw7 mutant tumors showed accumulation of the DEK protooncogene. DEK expression promoted cell division and altered splicing of tropomyosin (TPM) RNA, which may also influence cell proliferation. DEK accumulation and altered TPM RNA splicing were also detected in FBXW7 mutant human colorectal tumor tissues. Given their reduced lifespan and increased incidence of intestinal tumors, Apc(Min/+)Fbxw7(DeltaG) mice may be used for testing carcinogenicity and drug screening. PMID- 21282378 TI - The Wnt agonist R-spondin1 regulates systemic graft-versus-host disease by protecting intestinal stem cells. AB - Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation (BMT), and damage to the gastrointestinal (GI) tract plays a critical role in amplifying systemic disease. Intestinal stem cells (ISCs) play a pivotal role not only in physiological tissue renewal but also in regeneration of the intestinal epithelium after injury. In this study, we have discovered that pretransplant conditioning regimen damaged ISCs; however, the ISCs rapidly recovered and restored the normal architecture of the intestine. ISCs are targets of GVHD, and this process of ISC recovery was markedly inhibited with the development of GVHD. Injection of Wnt agonist R-spondin1 (R-Spo1) protected against ISC damage, enhanced restoration of injured intestinal epithelium, and inhibited subsequent inflammatory cytokine cascades. R-Spo1 ameliorated systemic GVHD after allogeneic BMT by a mechanism dependent on repair of conditioning induced GI tract injury. Our results demonstrate for the first time that ISC damage plays a central role in amplifying systemic GVHD; therefore, we propose ISC protection by R-Spo1 as a novel strategy to improve the outcome of allogeneic BMT. PMID- 21282379 TI - Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS). AB - Reactive oxygen species (ROS) have an established role in inflammation and host defense, as they kill intracellular bacteria and have been shown to activate the NLRP3 inflammasome. Here, we find that ROS generated by mitochondrial respiration are important for normal lipopolysaccharide (LPS)-driven production of several proinflammatory cytokines and for the enhanced responsiveness to LPS seen in cells from patients with tumor necrosis factor receptor-associated periodic syndrome (TRAPS), an autoinflammatory disorder caused by missense mutations in the type 1 TNF receptor (TNFR1). We find elevated baseline ROS in both mouse embryonic fibroblasts and human immune cells harboring TRAPS-associated TNFR1 mutations. A variety of antioxidants dampen LPS-induced MAPK phosphorylation and inflammatory cytokine production. However, gp91(phox) and p22(phox) reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits are dispensable for inflammatory cytokine production, indicating that NADPH oxidases are not the source of proinflammatory ROS. TNFR1 mutant cells exhibit altered mitochondrial function with enhanced oxidative capacity and mitochondrial ROS generation, and pharmacological blockade of mitochondrial ROS efficiently reduces inflammatory cytokine production after LPS stimulation in cells from TRAPS patients and healthy controls. These findings suggest that mitochondrial ROS may be a novel therapeutic target for TRAPS and other inflammatory diseases. PMID- 21282380 TI - Expression of the G-CSF receptor in monocytic cells is sufficient to mediate hematopoietic progenitor mobilization by G-CSF in mice. AB - Granulocyte colony-stimulating factor (G-CSF), the prototypical mobilizing cytokine, induces hematopoietic stem and progenitor cell (HSPC) mobilization from the bone marrow in a cell-nonautonomous fashion. This process is mediated, in part, through suppression of osteoblasts and disruption of CXCR4/CXCL12 signaling. The cellular targets of G-CSF that initiate the mobilization cascade have not been identified. We use mixed G-CSF receptor (G-CSFR)-deficient bone marrow chimeras to show that G-CSF-induced mobilization of HSPCs correlates poorly with the number of wild-type neutrophils. We generated transgenic mice in which expression of the G-CSFR is restricted to cells of the monocytic lineage. G CSF-induced HSPC mobilization, osteoblast suppression, and inhibition of CXCL12 expression in the bone marrow of these transgenic mice are intact, demonstrating that G-CSFR signals in monocytic cells are sufficient to induce HSPC mobilization. Moreover, G-CSF treatment of wild-type mice is associated with marked loss of monocytic cells in the bone marrow. Finally, we show that bone marrow macrophages produce factors that support the growth and/or survival of osteoblasts in vitro. Together, these data suggest a model in which G-CSFR signals in bone marrow monocytic cells inhibit the production of trophic factors required for osteoblast lineage cell maintenance, ultimately leading to HSPC mobilization. PMID- 21282381 TI - Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche. AB - Hematopoietic stem cells (HSCs) reside in specialized bone marrow (BM) niches regulated by the sympathetic nervous system (SNS). Here, we have examined whether mononuclear phagocytes modulate the HSC niche. We defined three populations of BM mononuclear phagocytes that include Gr-1(hi) monocytes (MOs), Gr-1(lo) MOs, and macrophages (MPhi) based on differential expression of Gr-1, CD115, F4/80, and CD169. Using MO and MPhi conditional depletion models, we found that reductions in BM mononuclear phagocytes led to reduced BM CXCL12 levels, the selective down regulation of HSC retention genes in Nestin(+) niche cells, and egress of HSCs/progenitors to the bloodstream. Furthermore, specific depletion of CD169(+) MPhi, which spares BM MOs, was sufficient to induce HSC/progenitor egress. MPhi depletion also enhanced mobilization induced by a CXCR4 antagonist or granulocyte colony-stimulating factor. These results highlight two antagonistic, tightly balanced pathways that regulate maintenance of HSCs/progenitors in the niche during homeostasis, in which MPhi cross talk with the Nestin(+) niche cell promotes retention, and in contrast, SNS signals enhance egress. Thus, strategies that target BM MPhi hold the potential to augment stem cell yields in patients that mobilize HSCs/progenitors poorly. PMID- 21282384 TI - Home dialysis in the new USA bundled payment plan: implications and impact. AB - On 1 January 2011, a new payment system for Medicare patients will be implemented in the United States. This new system bundles services previously charged separately and under a "fee for service" environment. The authors discuss the implications of this approach. Over the next several pages is a response by American physicians and dialysis innovators to a federal initiative to change the way dialysis is paid for in the United States. Peter Blake, the Editor-in-Chief of Peritoneal Dialysis International, invited Thomas Golper to articulate physicians' concerns with this new payment scheme. After the government of the USA closed its comment period over the new payment methodology, called "bundling," Golper sought out colleagues from diverse backgrounds and compiled this collective view of the situation. PMID- 21282385 TI - The bundle is coming! The bundle is coming! PMID- 21282386 TI - Peritoneal dialysis in Argentina. A nationwide study. PMID- 21282387 TI - Sterile peritonitis associated with the use of amino-acid solution in eight peritoneal dialysis patients. PMID- 21282388 TI - Double-dose icodextrin to increase ultrafiltration in PD patients with inadequate ultrafiltration. PMID- 21282389 TI - Suspension of ACE-I and ARB treatment is associated with acute increase in serum AGE levels in patients on peritoneal dialysis. PMID- 21282390 TI - Ceftriaxone-associated gallbladder pseudolithiasis in a PD patient. PMID- 21282391 TI - Lower urinary tract symptoms are frequent in dialysis patients. PMID- 21282392 TI - Sterile peritonitis associated with amino acid-containing dialysate--a single center experience in Norway. PMID- 21282393 TI - No change in small molecule transport with prolonged embedding of peritoneal dialysis catheters. PMID- 21282394 TI - Kocuria kristinae: an unusual cause of acute peritoneal dialysis-related infection. PMID- 21282396 TI - An unusual organism for CAPD-related peritonitis: Kocuria kristinae. PMID- 21282397 TI - A patient with amphotericin-resistant Curvularia lunata peritonitis. PMID- 21282398 TI - Voltage- and cold-dependent gating of single TRPM8 ion channels. AB - Transient receptor potential (TRP) channels play critical roles in cell signaling by coupling various environmental factors to changes in membrane potential that modulate calcium influx. TRP channels are typically activated in a polymodal manner, thus integrating multiple stimuli. Although much progress has been made, the underlying mechanisms of TRP channel activation are largely unknown. The TRPM8 cation channel has been extensively investigated as a major neuronal cold sensor but is also activated by voltage, calcium store depletion, and some lipids as well as by compounds that produce cooling sensations, such as menthol or icilin. Several models of TRPM8 activation have been proposed to explain the interaction between these diverse stimuli. However, a kinetic scheme is not yet available that can describe the detailed single-channel kinetics to gain further insight into the underlying gating mechanism. To work toward this goal, we investigated voltage-dependent single-channel gating in cell-attached patches at two different temperatures (20 and 30 degrees C) using HEK293 cells stably expressing TRPM8. Both membrane depolarization and cooling increased channel open probability (P(o)) mainly by decreasing the duration of closed intervals, with a smaller increase in the duration of open intervals. Maximum likelihood analysis of dwell times at both temperatures indicated gating in a minimum of five closed and two open states, and global fitting over a wide range of voltages identified a seven-state model that described the voltage dependence of P(o), the single channel kinetics, and the response of whole-cell currents to voltage ramps and steps. The major action of depolarization and cooling was to accelerate forward transitions between the same two sets of adjacent closed states. The seven-state model provides a general mechanism to account for TRPM8 activation by membrane depolarization at two temperatures and can serve as a starting point for further investigations of multimodal TRP activation. PMID- 21282399 TI - The long activations of alpha2 glycine channels can be described by a mechanism with reaction intermediates ("flip"). AB - The alpha2 glycine receptor (GlyR) subunit, abundant in embryonic neurons, is replaced by alpha1 in the adult nervous system. The single-channel activity of homomeric alpha2 channels differs from that of alpha1-containing GlyRs, as even at the lowest glycine concentration (20 uM), openings occurred in long (>300-ms) groups with high open probability (P(open); 0.96; cell-attached recordings, HEK expressed channels). Shut-time intervals within groups of openings were dominated by short shuttings of 5-10 us. The lack of concentration dependence in the groups of openings suggests that they represent single activations, separated by very long shut times at low concentrations. Several putative mechanisms were fitted by maximizing the likelihood of the entire sequence of open and shut times, with exact missed-events allowance (program hjcfit). Records obtained at several glycine concentrations were fitted simultaneously. The adequacy of the different schemes was judged by the accuracy with which they predicted not only single channel data but also the time course and concentration dependence of macroscopic responses elicited by rapid glycine applications to outside-out patches. The data were adequately described only with schemes incorporating a reaction intermediate in the activation, and the best was a flip mechanism with two binding sites and one open state. Fits with this mechanism showed that for alpha2 channels, the opening rate constant is very fast, ~130,000 s(-1), much as for alpha1beta GlyRs (the receptor in mature synapses), but the estimated true mean open time is 20 times longer (around 3 ms). The efficacy for the flipping step and the binding affinity were lower for alpha2 than for alpha1beta channels, but the overall efficacies were similar. As we previously showed for alpha1 homomeric receptors, in alpha2 glycine channels, maximum P(open) is achieved when fewer than all five of the putative binding sites in the pentamer are occupied by glycine. PMID- 21282400 TI - Non-vesicular transfer of membrane proteins from nanoparticles to lipid bilayers. AB - Discoidal lipoproteins are a novel class of nanoparticles for studying membrane proteins (MPs) in a soluble, native lipid environment, using assays that have not been traditionally applied to transmembrane proteins. Here, we report the successful delivery of an ion channel from these particles, called nanoscale apolipoprotein-bound bilayers (NABBs), to a distinct, continuous lipid bilayer that will allow both ensemble assays, made possible by the soluble NABB platform, and single-molecule assays, to be performed from the same biochemical preparation. We optimized the incorporation and verified the homogeneity of NABBs containing a prototypical potassium channel, KcsA. We also evaluated the transfer of KcsA from the NABBs to lipid bilayers using single-channel electrophysiology and found that the functional properties of the channel remained intact. NABBs containing KcsA were stable, homogeneous, and able to spontaneously deliver the channel to black lipid membranes without measurably affecting the electrical properties of the bilayer. Our results are the first to demonstrate the transfer of a MP from NABBs to a different lipid bilayer without involving vesicle fusion. PMID- 21282401 TI - Slob, a Slowpoke channel-binding protein, modulates synaptic transmission. AB - Modulation of ion channels by regulatory proteins within the same macromolecular complex is a well-accepted concept, but the physiological consequences of such modulation are not fully understood. Slowpoke (Slo), a potassium channel critical for action potential repolarization and transmitter release, is regulated by Slo channel-binding protein (Slob), a Drosophila melanogaster Slo (dSlo) binding partner. Slob modulates the voltage dependence of dSlo channel activation in vitro and exerts similar effects on the dSlo channel in Drosophila central nervous system neurons in vivo. In addition, Slob modulates action potential duration in these neurons. Here, we investigate further the functional consequences of the modulation of the dSlo channel by Slob in vivo, by examining larval neuromuscular synaptic transmission in flies in which Slob levels have been altered. In Slob-null flies generated through P-element mutagenesis, as well as in Slob knockdown flies generated by RNA interference (RNAi), we find an enhancement of synaptic transmission but no change in the properties of the postsynaptic muscle cell. Using targeted transgenic rescue and targeted expression of Slob-RNAi, we find that Slob expression in neurons (but not in the postsynaptic muscle cell) is critical for its effects on synaptic transmission. Furthermore, inhibition of dSlo channel activity abolishes these effects of Slob. These results suggest that presynaptic Slob, by regulating dSlo channel function, participates in the modulation of synaptic transmission. PMID- 21282402 TI - Determinants of coupled transport and uncoupled current by the electrogenic SLC26 transporters. AB - Members of the SLC26 family of anion transporters mediate the transport of diverse molecules ranging from halides to carboxylic acids and can function as coupled transporters or as channels. A unique feature of the two members of the family, Slc26a3 and Slc26a6, is that they can function as both obligate coupled and mediate an uncoupled current, in a channel-like mode, depending on the transported anion. To identify potential features that control the two modes of transport, we performed in silico modeling of Slc26a6, which suggested that the closest potential fold similarity of the Slc26a6 transmembrane domains is to the CLC transporters, despite their minimal sequence identity. Examining the predicted Slc26a6 fold identified a highly conserved glutamate (Glu(-); Slc26a6(E357)) with the predicted spatial orientation similar to that of the CLC ec1 E148, which determines coupled or uncoupled transport by CLC-ec1. This raised the question of whether the conserved Glu(-) in Slc26a6(E357) and Slc26a3(E367) have a role in the unique transport modes by these transporters. Reversing the Glu(-) charge in Slc26a3 and Slc26a6 resulted in the inhibition of all modes of transport. However, most notably, neutralizing the charge in Slc26a6(E357A) eliminated all forms of coupled transport without affecting the uncoupled current. The Slc26a3(E367A) mutation markedly reduced the coupled transport and converted the stoichiometry of the residual exchange from 2Cl(-)/1HCO(3)(-) to 1Cl(-)/1HCO(3)(-), while completely sparing the current. These findings suggest the possibility that similar structural motif may determine multiple functional modes of these transporters. PMID- 21282403 TI - MYB46 modulates disease susceptibility to Botrytis cinerea in Arabidopsis. AB - In this study, we show that the Arabidopsis (Arabidopsis thaliana) transcription factor MYB46, previously described to regulate secondary cell wall biosynthesis in the vascular tissue of the stem, is pivotal for mediating disease susceptibility to the fungal pathogen Botrytis cinerea. We identified MYB46 by its ability to bind to a new cis-element located in the 5' promoter region of the pathogen-induced Ep5C gene, which encodes a type III cell wall-bound peroxidase. We present genetic and molecular evidence indicating that MYB46 modulates the magnitude of Ep5C gene induction following pathogenic insults. Moreover, we demonstrate that different myb46 knockdown mutant plants exhibit increased disease resistance to B. cinerea, a phenotype that is accompanied by selective transcriptional reprogramming of a set of genes encoding cell wall proteins and enzymes, of which extracellular type III peroxidases are conspicuous. In essence, our results substantiate that defense-related signaling pathways and cell wall integrity are interconnected and that MYB46 likely functions as a disease susceptibility modulator to B. cinerea through the integration of cell wall remodeling and downstream activation of secondary lines of defense. PMID- 21282404 TI - Metabolic and transcriptomic phenotyping of inorganic carbon acclimation in the Cyanobacterium Synechococcus elongatus PCC 7942. AB - The amount of inorganic carbon is one of the main limiting environmental factors for photosynthetic organisms such as cyanobacteria. Using Synechococcus elongatus PCC 7942, we characterized metabolic and transcriptomic changes in cells that had been shifted from high to low CO(2) levels. Metabolic phenotyping indicated an activation of glycolysis, the oxidative pentose phosphate cycle, and glycolate metabolism at lowered CO(2) levels. The metabolic changes coincided with a general reprogramming of gene expression, which included not only increased transcription of inorganic carbon transporter genes but also genes for enzymes involved in glycolytic and photorespiratory metabolism. In contrast, the mRNA content for genes from nitrogen assimilatory pathways decreased. These observations indicated that cyanobacteria control the homeostasis of the carbon nitrogen ratio. Therefore, results obtained from the wild type were compared with the MP2 mutant of Synechococcus 7942, which is defective for the carbon-nitrogen ratio-regulating PII protein. Metabolites and genes linked to nitrogen assimilation were differentially regulated, whereas the changes in metabolite concentrations and gene expression for processes related to central carbon metabolism were mostly similar in mutant and wild-type cells after shifts to low CO(2) conditions. The PII signaling appears to down-regulate the nitrogen metabolism at lowered CO(2), whereas the specific shortage of inorganic carbon is recognized by different mechanisms. PMID- 21282405 TI - Apoplastic alkalinization is instrumental for the inhibition of cell elongation in the Arabidopsis root by the ethylene precursor 1-aminocyclopropane-1 carboxylic acid. AB - In Arabidopsis (Arabidopsis thaliana; Columbia-0) roots, the so-called zone of cell elongation comprises two clearly different domains: the transition zone, a postmeristematic region (approximately 200-450 MUm proximal of the root tip) with a low rate of elongation, and a fast elongation zone, the adjacent proximal region (450 MUm away from the root tip up to the first root hair) with a high rate of elongation. In this study, the surface pH was measured in both zones using the microelectrode ion flux estimation technique. The surface pH is highest in the apical part of the transition zone and is lowest at the basal part of the fast elongation zone. Fast cell elongation is inhibited within minutes by the ethylene precursor 1-aminocyclopropane-1-carboxylic acid; concomitantly, apoplastic alkalinization occurs in the affected root zone. Fusicoccin, an activator of the plasma membrane H(+)-ATPase, can partially rescue this inhibition of cell elongation, whereas the inhibitor N,N' dicyclohexylcarbodiimide does not further reduce the maximal cell length. Microelectrode ion flux estimation experiments with auxin mutants lead to the final conclusion that control of the activity state of plasma membrane H(+) ATPases is one of the mechanisms by which ethylene, via auxin, affects the final cell length in the root. PMID- 21282406 TI - Human pharmacokinetic prediction of UDP-glucuronosyltransferase substrates with an animal scale-up approach. AB - The aim of the current study was to evaluate the accuracy of allometric scaling methods for drugs metabolized by UDP-glucuronosyltransferases (UGTs), such as ketoprofen, imipramine, lorazepam, levofloxacin, zidovudine, diclofenac, furosemide, raloxifene, gemfibrozil, mycophenolic acid, indomethacin, and telmisartan. Human plasma clearance (CL) predictions were conducted from preclinical in vivo data by using multiple-species allometry with the rule of exponents and single-species allometric scaling (SSS) of mice, rats, monkeys, or dogs. Distribution volume at a steady state (V(ss)) was predicted by multiple species allometry or SSS of V(ss). Oral plasma clearance (CL(po)) was calculated under the assumption that F(a) * F(g) was equivalent across species. Each of the results was compared with the observed parameter calculated from the clinical data after intravenous or oral administration. Multiple-species allometry and SSS of mice, rats, and dogs resulted in a similar accuracy of CL and CL(po) predictions. Monkeys tended to provide the most accurate predictions of human CL and CL(po). The ability to predict the half-life, which was determined from CL and V(ss) predictions, was more accurate in SSS of rats and monkeys. The in vivo fraction metabolized by glucuronidation (f(m,UGT)) in bile duct-cannulated monkeys was relatively similar to that of humans compared with other animal species, which likely contributed to the highest accuracy of SSS prediction of monkeys. On the basis of the current results, monkeys would be more reliable than other animal species in predicting human pharmacokinetics and f(m,UGT) for drugs metabolized by UGTs. PMID- 21282407 TI - Differential impact of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) on axitinib brain accumulation and oral plasma pharmacokinetics. AB - The second-generation tyrosine kinase inhibitor and anticancer drug axitinib is a potent, orally active inhibitor of the vascular endothelial growth factor receptors 1, 2, and 3. Axitinib has clinical activity against solid tumors such as metastatic renal cell carcinoma and advanced pancreatic cancer. We studied axitinib transport using Madin-Darby canine kidney II cells overexpressing human ABCB1 or ABCG2 or murine Abcg2. Axitinib was a good substrate of ABCB1 and Abcg2, whereas transport activity by ABCG2 was moderate. These transporters may therefore contribute to axitinib resistance in tumor cells. Upon oral administration of axitinib, Abcg2(-/-) and Abcb1a/1b;Abcg2(-/-) mice displayed 1.7- and 1.8-fold increased axitinib areas under the plasma concentration-time curve from 0 to 4 compared with those of wild-type mice. Plasma concentrations in Abcb1a/1b(-/-) mice were not significantly increased. In contrast, relative brain accumulation of axitinib in Abcb1a/1b(-/-) and Abcb1a/1b;Abcg2(-/-) mice was, respectively, 6.8- and 13.9-fold higher than that in wild-type mice at 1 h and 4.9- and 20.7-fold at 4 h after axitinib administration. In Abcg2(-/-) mice, we found no significant differences in brain accumulation compared with those in wild-type mice. Thus, Abcb1 strongly restricts axitinib brain accumulation and completely compensates for the loss of Abcg2 at the blood-brain barrier, whereas Abcg2 can only partially take over Abcb1-mediated axitinib efflux. Hence, Abcg2 has a stronger impact on axitinib oral plasma pharmacokinetics, whereas Abcb1 is the more important transporter at the blood-brain barrier. These findings illustrate that in vitro transport data for ABCB1 and ABCG2 cannot always be simply extrapolated to the prediction of the relative impact of these transporters on oral availability versus brain penetration. PMID- 21282408 TI - Oxygen saturation profile in healthy preterm infants. AB - AIM: To establish a reference range for oxygen saturation (SpO(2)) in well preterm infants to guide home oxygen therapy using a pulse oximeter and Pulse Oximetry Data Analysis Software (PODS). METHODS: SpO(2) and heart-rate profiles of healthy preterm infants receiving mechanical ventilation for less than 6 h and supplemental oxygen for less than 48 h were monitored using a pulse oximeter. The stored data were downloaded from the monitor to a personal computer as individual files. Each infant's files of SpO(2) were subsequently displayed in graphic form, and a reference range was constructed using dedicated software, PODS. RESULTS: 43 infants were studied. The median value of all infants mean SpO(2) values was 95% (range 92-99%). The median duration of saturations less than 85% and between 85% and 90 % were 1% and 2% respectively. Using the study group median, 5th and 95th percentiles, a cumulative frequency curve of time against SpO(2) value was constructed (representing the reference range of SpO(2) profiles in healthy preterm infants). CONCLUSION: The SpO(2) reference range can be used as an easy and practical guide to compare SpO(2) profiles of infants on home oxygen therapy and guide their oxygen therapy. PMID- 21282409 TI - Natural antibodies against several pneumococcal virulence proteins in children during the pre-pneumococcal-vaccine era: the generation R study. AB - The currently available pneumococcal vaccines do not protect against all serotypes of Streptococcus pneumoniae. A shift toward nonvaccine serotypes causing colonization and invasive disease has occurred, and studies on protein based vaccines have been undertaken. We assessed the association between specific antibodies against pneumococcal virulence proteins and colonization and respiratory tract infections (RTIs). Additionally, we assessed the extent to which colonization induces a humoral immune response. Nasopharyngeal swabs collected from children at 1.5, 6, 14, and 24 months of age were cultured for pneumococcus. Serum samples were obtained at birth and at 6, 14, and 24 months (n = 57 children providing 177 serum samples). Data were collected prior to the pneumococcal vaccine era. IgG, IgA, and IgM levels against 17 pneumococcal protein vaccine candidates were measured using a bead-based flow cytometry technique (xMAP; Luminex Corporation). Information regarding RTIs was questionnaire derived. Levels of IgG against all proteins were high in cord blood, decreased in the first 6 months and increased again thereafter, in contrast to the course of IgA and IgM levels. Specific antibodies were induced upon colonization. Increased levels of IgG against BVH-3, NanA, and SP1003 at 6 months, NanA, PpmA, PsaA, SlrA, SP0189, and SP1003 at 14 months, and SlrA at 24 months were associated with a decreased number of RTIs in the third year of life but not with colonization. Maternal antipneumococcal antibodies did not protect against pneumococcal colonization and infection. Certain antibodies against pneumococcal virulence proteins, some of which are induced by colonization, are associated with a decreased number of RTIs in children. This should be taken into account in future pneumococcal vaccine studies. PMID- 21282410 TI - Antibodies contribute to effective vaccination against respiratory infection by type A Francisella tularensis strains. AB - Pneumonic tularemia is a life-threatening disease caused by inhalation of the highly infectious intracellular bacterium Francisella tularensis. The most serious form of the disease associated with the type A strains can be prevented in experimental animals through vaccination with the attenuated live vaccine strain (LVS). The protection is largely cell mediated, but the contribution of antibodies remains controversial. We addressed this issue in a series of passive immunization studies in Fischer 344 (F344) rats. Subcutaneous LVS vaccination induced a robust serum antibody response dominated by IgM, IgG2a, and IgG2b antibodies. Prophylactic administration of LVS immune serum or purified immune IgG reduced the severity and duration of disease in naive rats challenged intratracheally with a lethal dose of the virulent type A strain SCHU S4. The level of resistance increased with the volume of immune serum given, but the maximum survivable SCHU S4 challenge dose was at least 100-fold lower than that shown for LVS-vaccinated rats. Protection correlated with reduced systemic bacterial growth, less severe histopathology in the liver and spleen during the early phase of infection, and bacterial clearance by a T cell-dependent mechanism. Our results suggest that treatment with immune serum limited the sequelae associated with infection, thereby enabling a sterilizing T cell response to develop and resolve the infection. Thus, antibodies induced by LVS vaccination may contribute to the defense of F344 rats against respiratory infection by type A strains of F. tularensis. PMID- 21282411 TI - Murine immune response to a chronic Staphylococcus aureus biofilm infection. AB - Staphylococcus aureus has reemerged as an important human pathogen in recent decades. Although many infections caused by this microbial species persist through a biofilm mode of growth, little is known about how the host's adaptive immune system responds to these biofilm infections. In this study, S. aureus cells adhered to pins in culture and were subsequently inserted into the tibiae of C57BL/6 mice, with an infecting dose of 2 * 105 CFU. This model was utilized to determine local cytokine levels, antibody (Ab) function, and T cell populations at multiple time points throughout infection. Like human hosts, S. aureus implant infection was chronic and remained localized in 100% of C57BL/6 mice at a consistent level of approximately 10(7) CFU/gram bone tissue after day 7. This infection persisted locally for >49 days and was recalcitrant to clearance by the host immune response and antimicrobial therapy. Local inflammatory cytokines of the Th1 (interleukin-2 [IL-2], IL-12 p70, tumor necrosis factor alpha [TNF-alpha], and IL-1beta) and Th17 (IL-6 and IL-17) responses were upregulated throughout the infection, except IL-12 p70, which dwindled late in the infection. In addition, Th1 Ab subtypes against a biofilm antigen (SA0486) were upregulated early in the infection, while Th2 Abs and anti inflammatory regulatory T cells (Tregs) were not upregulated until later. These results indicate that early Th1 and Th17 inflammatory responses and downregulated Th2 and Treg responses occur during the development of a chronic biofilm implant infection. This unrestrained inflammatory response may cause tissue damage, thereby enabling S. aureus to attach and thrive in a biofilm mode of growth. PMID- 21282412 TI - An autotransporter protein from Orientia tsutsugamushi mediates adherence to nonphagocytic host cells. AB - Orientia tsutsugamushi, the causative agent of scrub typhus, is an obligate intracellular pathogen whose mechanism of cellular adhesion and invasion is poorly characterized. Bioinformatic analyses of two O. tsutsugamushi genomes revealed the presence of a group of genes that encode autotransporter proteins. In this study, we identified 10 autotransporter gene products and categorized them into five groups of orthologs (ScaA to ScaE) based on their sequence similarities. Sequence homology was highest between members of ScaC group, suggesting the functional conservation of bacterium-host interactions. ScaC was actively expressed on the surface of O. tsutsugamushi and induced antibody responses in scrub typhus patients. Experiments using microbeads conjugated to recombinant ScaC or a surrogate Escherichia coli expression system showed that ScaC was sufficient to mediate attachment to, but not invasion of, nonphagocytic mammalian cells. In addition, preincubation of host cells with recombinant ScaC significantly inhibited their interaction with O. tsutsugamushi. Finally, fibronectin was identified as a potential receptor for ScaC by using yeast two hybrid screening, and this was confirmed using a glutathione S-transferase (GST) pulldown assay. Taken together, these results demonstrate that ScaC is involved in the interaction of O. tsutsugamushi with mammalian host cells and suggest that ScaC may play a critical role in bacterial pathogenesis. PMID- 21282413 TI - The OspE-related proteins inhibit complement deposition and enhance serum resistance of Borrelia burgdorferi, the lyme disease spirochete. AB - Borrelia burgdorferi, the Lyme disease spirochete, binds the host complement inhibitors factor H (FH) and FH-like protein 1 (FHL-1). Binding of FH/FHL-1 by the B. burgdorferi proteins CspA and the OspE-related proteins is thought to enhance resistance to serum-mediated killing. While previous reports have shown that CspA confers serum resistance in B. burgdorferi, it is unclear whether the OspE-related proteins are relevant in B. burgdorferi serum resistance when OspE is expressed on the borrelial surface. To assess the role of the OspE-related proteins, we overexpressed them in a serum-sensitive CspA mutant strain. OspE overexpression enhanced serum resistance of the CspA-deficient organisms. Furthermore, FH was more efficiently bound to the B. burgdorferi surface when OspE was overexpressed. Deposition of complement components C3 and C5b-9 (the membrane attack complex), however, was reduced on the surface of the OspE overexpressing strain compared to that on the CspA mutant strain. These data demonstrate that OspE proteins expressed on the surface of B. burgdorferi bind FH and protect the organism from complement deposition and subsequent serum-mediated destruction. PMID- 21282414 TI - CD4+ T cells are not essential for control of early acute Cryptosporidium parvum infection in neonatal mice. AB - Cryptosporidiosis is an important diarrheal disease of humans and neonatal livestock caused by Cryptosporidium spp. that infect epithelial cells. Recovery from Cryptosporidium parvum infection in adult hosts involves CD4(+) T cells with a strong Th1 component, but mechanisms of immunity in neonates are not well characterized. In the present investigation with newborn mice, similar acute patterns of infection were obtained in C57BL/6 wild-type (WT) and T and B cell deficient Rag2(-/-) mice. In comparison with uninfected controls, the proportion of intestinal CD4(+) or CD8(+) T cells did not increase in infected WT mice during recovery from infection. Furthermore, infection in neonatal WT mice depleted of CD4(+) T cells was not exacerbated. Ten weeks after WT and Rag2(-/-) mice had been infected as neonates, no patent infections could be detected. Treatment at this stage with the immunosuppressive drug dexamethasone produced patent infections in Rag2(-/-) mice but not WT mice. Expression of inflammatory markers, including gamma interferon (IFN-gamma) and interleukin-12p40 (IL-12p40), was higher in neonatal WT mice than in Rag2(-/-) mice around the peak of infection, but IL-10 expression was also higher in WT mice. These results suggest that although CD4(+) T cells may be important for elimination of C. parvum, these cells are dispensable for controlling the early acute phase of infection in neonates. PMID- 21282415 TI - Regulatory mechanism for exfoliative toxin production in Staphylococcus aureus. AB - The exfoliative toxin (ET) is a major virulence factor of Staphylococcus aureus that causes bullous impetigo and its disseminated form, staphylococcal scalded skin syndrome (SSSS). ET selectively digests one of the intracellular adhesion molecules, desmoglein 1, of epidermal keratinocytes and causes blisters due to intraepidermal cell-cell dissociation. Most S. aureus strains that cause blistering disease produce either ETA or ETB. They are serologically distinct molecules, where ETA is encoded on a phage genome and ETB is enocded on a large plasmid. ETA-producing S. aureus strains are frequently isolated from impetigo patients, and ETB-producing S. aureus strains are isolated from SSSS. ET-induced blister formation can be reproduced with the neonatal mouse. To determine the regulatory mechanism of ET production, we investigated the role of the two component systems and global regulators for eta or etb expression in vitro and in vivo with the mouse model. Western blot and transcription analyses using a series of mutants demonstrate ETA production was downregulated by sigB, sarS, and sarA, while ETB production was downregulated by sigB and sarA but not by sarS. Production of both toxins is upregulated by saeRS, arlRS, and agrCA. Furthermore, by the in vivo neonatal mouse model, sigB and sarS but not sarA negatively regulate the exfoliation activity of the ETA-producing strain, while sarA negatively regulates the ETB-producing strain. In both strains, saeRS, arlRS, and agrCA positively regulate the exfoliation activity in vivo. The data illustrate similar but distinct regulatory mechanisms for ETA and ETB production in S. aureus in vitro as well as in vivo. PMID- 21282416 TI - Differential requirements for NAIP5 in activation of the NLRC4 inflammasome. AB - Inflammasomes are cytosolic multiprotein complexes that assemble in response to infectious or noxious stimuli and activate the CASPASE-1 protease. The inflammasome containing the nucleotide binding domain-leucine-rich repeat (NBD LRR) protein NLRC4 (interleukin-converting enzyme protease-activating factor [IPAF]) responds to the cytosolic presence of bacterial proteins such as flagellin or the inner rod component of bacterial type III secretion systems (e.g., Salmonella PrgJ). In some instances, such as infection with Legionella pneumophila, the activation of the NLRC4 inflammasome requires the presence of a second NBD-LRR protein, NAIP5. NAIP5 also is required for NLRC4 activation by the minimal C-terminal flagellin peptide, which is sufficient to activate NLRC4. However, NLRC4 activation is not always dependent upon NAIP5. In this report, we define the molecular requirements for NAIP5 in the activation of the NLRC4 inflammasome. We demonstrate that the N terminus of flagellin can relieve the requirement for NAIP5 during the activation of the NLRC4 inflammasome. We also demonstrate that NLRC4 responds to the Salmonella protein PrgJ independently of NAIP5. Our results indicate that NAIP5 regulates the apparent specificity of the NLRC4 inflammasome for distinct bacterial ligands. PMID- 21282417 TI - In Vivo leukocyte changes induced by Escherichia coli subtilase cytotoxin. AB - Subtilase cytotoxin (SubAB) is the prototype of a new family of AB(5) cytotoxins produced by Shiga-toxigenic Escherichia coli. Its cytotoxicity is due to its capacity to enter cells and specifically cleave the essential endoplasmic reticulum chaperone BiP. Previous studies have shown that intraperitoneal injection of mice with purified SubAB causes a pathology that overlaps with that seen in human cases of hemolytic-uremic syndrome, as well as dramatic splenic atrophy, suggesting that leukocytes are targeted. Here we investigated SubAB induced leukocyte changes in the peritoneal cavity, blood, and spleen. After intraperitoneal injection, SubAB bound peritoneal leukocytes (including T and B lymphocytes, neutrophils, and macrophages). SubAB elicited marked leukocytosis, which peaked at 24 h, and increased neutrophil activation in the blood and peritoneal cavity. It also induced a marked redistribution of leukocytes among the three compartments: increases in leukocyte subpopulations in the blood and peritoneal cavity coincided with a significant decline in splenic cells. SubAB treatment also elicited significant increases in the apoptosis rates of CD4(+) T cells, B lymphocytes, and macrophages. These findings indicate that apart from direct cytotoxic effects, SubAB interacts with cellular components of both the innate and the adaptive arm of the immune system, with potential consequences for disease pathogenesis. PMID- 21282418 TI - Identification of Vibrio cholerae type III secretion system effector proteins. AB - AM-19226 is a pathogenic O39 serogroup Vibrio cholerae strain that lacks the typical virulence factors for colonization (toxin-coregulated pilus [TCP]) and toxin production (cholera toxin [CT]) and instead encodes a type III secretion system (T3SS). The mechanism of pathogenesis is unknown, and few effector proteins have been identified. We therefore undertook a survey of the open reading frames (ORFs) within the ~49.7-kb T3SS genomic island to identify potential effector proteins. We identified 15 ORFs for their ability to inhibit growth when expressed in yeast and then used a beta-lactamase (TEM1) fusion reporter system to demonstrate that 11 proteins were bona fide effectors translocated into HeLa cells in vitro in a T3SS-dependent manner. One effector, which we named VopX (A33_1663), is conserved only in V. cholerae and Vibrio parahaemolyticus T3SS-positive strains and has not been previously studied. A vopX deletion reduces the ability of strain AM-19226 to colonize in vivo, and the bile-induced expression of a vopX-lacZ transcriptional fusion in vitro is regulated by the T3SS-encoded transcriptional regulators VttR(A) and VttR(B). An RLM1 yeast deletion strain rescued the growth inhibition induced by VopX expression, suggesting that VopX interacts with components of the cell wall integrity mitogen-activated protein kinase (MAPK) pathway. The collective results show that the V. cholerae T3SS encodes multiple effector proteins, one of which likely has novel activities that contribute to disease via interference with eukaryotic signaling pathways. PMID- 21282419 TI - Impact of the N348I mutation in HIV-1 reverse transcriptase on nonnucleoside reverse transcriptase inhibitor resistance in non-subtype B HIV-1. AB - We investigated the effect of N348I alone and with M184V on nonnucleoside reverse transcriptase inhibitor (NNRTI) drug susceptibility and replicative capacity in B and non-B HIV-1 isolates. N348I reduced the susceptibility to all NNRTI drugs across subtypes. The replication capacity of all viruses in a variety of cell lines was impaired by N348I. Interestingly, the N348I and M184V double mutation compensated for the reduced NNRTI drug susceptibility observed in the N348I single mutant and marginally improved viral replicative capacity. PMID- 21282420 TI - Frequency of voriconazole resistance in vitro among Spanish clinical isolates of Candida spp. According to breakpoints established by the Antifungal Subcommittee of the European Committee on Antimicrobial Susceptibility Testing. AB - A total of 4,226 Spanish clinical isolates of Candida spp. were analyzed to assess resistance to voriconazole according to breakpoints established by the European Committee for Antimicrobial Susceptibility Testing (where susceptibility [S] to voriconazole corresponds to a MIC of <= 0.12 mg/liter). Resistance was uncommon among Candida albicans (5%), C. parapsilosis (1.2%), and C. tropicalis (11%) isolates. Voriconazole MICs of >0.12 mg/liter were more frequent among Candida glabrata and C. krusei isolates. A significant percentage of voriconazole resistant strains came from oropharyngeal infections and exhibited high MICs of other azoles. PMID- 21282421 TI - Activity of the fluoroquinolone DC-159a in the initial and continuation phases of treatment of murine tuberculosis. AB - DC-159a is a new fluoroquinolone with more potent in vitro activity than available fluoroquinolones against both drug-susceptible and fluoroquinolone resistant Mycobacterium tuberculosis. Here, we report that DC-159a displays pharmacokinetics similar to those of moxifloxacin yet is more active than moxifloxacin during both the initial and continuation phases of treatment in a murine model. These results warrant further preclinical evaluation of DC-159a in selected drug combinations against drug-susceptible and fluoroquinolone-resistant tuberculosis. PMID- 21282422 TI - Further characterization of Bacillus subtilis antibiotic biosensors and their use for antibacterial mode-of-action studies. AB - We further examined the usefulness of previously reported Bacillus subtilis biosensors for antibacterial mode-of-action studies. The biosensors could not detect the tRNA synthetase inhibitors mupirocin, indolmycin, and borrelidin, some inhibitors of peptidoglycan synthesis, and most membrane-damaging agents. However, the biosensors confirmed the modes of action of several RNA polymerase inhibitors and DNA intercalators and provided new insights into the possible modes of action of ciprofloxacin, anhydrotetracycline, corralopyronin, 8 hydroxyquinoline, and juglone. PMID- 21282423 TI - Lacticin Q-mediated selective toxicity depending on physicochemical features of membrane components. AB - Lacticin Q, a lactococcal pore-forming bacteriocin, shows activity toward Gram positive bacteria but not Gram-negative bacteria. Lacticin Q did not induce permeability of the outer membrane of Gram-negative bacteria. Experiments using model membranes containing outer membrane components suggested that lacticin Q binds to the outer membrane of Gram-negative bacteria but is unable to penetrate it. The lack of activity of lacticin Q was attributed to physicochemical features of the outer membrane components. PMID- 21282424 TI - Predicting in vitro antibacterial efficacy across experimental designs with a semimechanistic pharmacokinetic-pharmacodynamic model. AB - We have previously described a general semimechanistic pharmacokinetic pharmacodynamic (PKPD) model that successfully characterized the time course of antibacterial effects seen in bacterial cultures when exposed to static concentrations of five antibacterial agents of different classes. In this PKPD model, the total bacterial population was divided into two subpopulations, one growing drug-susceptible population and one resting drug-insensitive population. The drug effect was included as an increase in the killing rate of the drug susceptible bacteria with a maximum-effect (E(max)) model. The aim of the present study was to evaluate the ability of this PKPD model to describe and predict data from in vitro experiments with dynamic concentration-time profiles. Dynamic time kill curve experiments were performed by using an in vitro kinetic system, where cultures of Streptococcus pyogenes were exposed to benzylpenicillin, cefuroxime, erythromycin, moxifloxacin, or vancomycin using different starting concentrations (2 and 16 times the MIC) and elimination conditions (human half-life, reduced half-life, and constant concentrations). The PKPD model was applied, and the observations for the static as well as dynamic experiments were compared to model predictions based on parameter estimation using (i) static data, (ii) dynamic data, and (iii) combined static and dynamic data. Differences in experimental settings between static and dynamic experiments did not affect the growth kinetics of the bacteria significantly. With parameter reestimation, the structure of our previously proposed PKPD model could well characterize the bacterial growth and killing kinetics when exposed to dynamic concentrations with different elimination rates of all five investigated antibiotics. Furthermore, the model with parameter estimates based on data from only the static time-kill curve experiments could predict the majority of the time-kill curves from the dynamic experiments reasonably well. Adding data from dynamic experiments in the estimation improved the model fit for cefuroxime and vancomycin, indicating some differences in sensitivity to experimental conditions among the antibiotics studied. PMID- 21282425 TI - Contribution of N-glucuronidation to efavirenz elimination in vivo in the basal and rifampin-induced metabolism of efavirenz. AB - In this study, the contribution of efavirenz N-glucuronidation to efavirenz elimination in vivo was assessed. In a two-period placebo-controlled crossover trial design, a single 600-mg oral dose of efavirenz was administered to healthy volunteers (n = 10) pretreated with placebo pills or 600 mg/day rifampin orally for 10 days. Urine and plasma concentrations of efavirenz and 8-hydroxyefavirenz were measured by the liquid chromatography-tandem mass spectrometry method after enzymatic hydrolysis with beta-glucuronidase (conjugated and unconjugated) and without enzymatic hydrolysis (unconjugated). Pharmacokinetic parameters of efavirenz within the placebo- or rifampin-treated group obtained after enzymatic hydrolysis did not show any statistically significant difference compared with those obtained without enzymatic hydrolysis (P > 0.05; paired t test, two tailed). The amount of efavirenz excreted over 12 h was significantly larger after enzymatic hydrolysis in both the placebo (P = 0.007) and rifampin (P = 0.0001) treatment groups, supporting the occurrence of direct N-glucuronidation of efavirenz, but the relevance of this finding is limited because the amount of efavirenz excreted as unchanged or conjugated in urine is less than 1% of the dose administered. In both the placebo- and rifampin-treated groups, plasma concentrations of 8-hydroxyefavirenz and the amount excreted over 12 h were significantly larger (P < 0.00001) after enzymatic hydrolysis than without enzymatic hydrolysis. These findings suggest that although the occurrence of direct efavirenz N-glucuronidation is supported by the urine data, the abundance of efavirenz N-glucuronide in plasma is negligible and that the contribution of the N-glucuronidation pathway to the overall clearance of efavirenz seems minimal. PMID- 21282426 TI - Mupirocin resistance in Staphylococcus aureus causing recurrent skin and soft tissue infections in children. AB - Staphylococcus aureus resistance to mupirocin is often caused by acquisition of a novel isoleucyl-tRNA synthetase encoded on the plasmid gene mupA. We tested S. aureus isolates from children at Texas Children's Hospital with recurrent skin and soft tissue infections for mupirocin resistance and mupA. Of 136 isolates, 20 were resistant to mupirocin (14.7%). Fifteen isolates (11%) carried mupA, and the gene was more common in methicillin-susceptible S. aureus (21.4%) than methicillin-resistant S. aureus (8.3%; P=0.03). Seven of 20 mupirocin-resistant isolates displayed clindamycin resistance. PMID- 21282427 TI - C-terminal amino acids of alpha-melanocyte-stimulating hormone are requisite for its antibacterial activity against Staphylococcus aureus. AB - Alpha-melanocyte-stimulating hormone (alpha-MSH) is an endogenous neuropeptide that is known for its anti-inflammatory and antipyretic activities. We recently demonstrated that alpha-MSH possesses staphylocidal activity and causes bacterial membrane damage. To understand the role of its amino acid sequences in the staphylocidal mechanism, in the present study we investigated the antimicrobial activities of different fragments of alpha-MSH, i.e., alpha-MSH(6-13), alpha MSH(11-13), and alpha-MSH(1-5), and compared them with that of the entire peptide. Our results showed that peptides containing the C-terminal region of alpha-MSH, namely, alpha-MSH(6-13) and alpha-MSH(11-13), efficiently killed >90% of both methicillin-sensitive and -resistant Staphylococcus aureus cells in the micromolar range and ~50% of these cells in the nanomolar range; their efficiency was comparable to that of the entire alpha-MSH, whereas the peptide containing the N-terminal region, alpha-MSH(1-5), was found to be ineffective against S. aureus. The antimicrobial activity of alpha-MSH and its C-terminal fragments was not affected by the presence of NaCl or even divalent cations such as Ca2+ and Mg2+. Similar to the case for the parent peptide, alpha-MSH(6-13) and alpha MSH(11-13) also depolarized and permeabilized Staphylococcus cells (~70 to 80% of the cells were depolarized and lysed after 2 h of peptide exposure at micromolar concentrations). Furthermore, scanning and transmission electron microscopy showed remarkable morphological and ultrastructural changes on S. aureus cell surface due to exposure to alpha-MSH-based peptides. Thus, our observations indicate that C-terminal fragments of alpha-MSH retain the antimicrobial activity of entire peptide and that their mechanism of action is similar to that of full length peptide. These observations are important and are critical in the rational design of alpha-MSH-based therapeutics with optimal efficacy. PMID- 21282428 TI - Selective inhibitors of methionyl-tRNA synthetase have potent activity against Trypanosoma brucei Infection in Mice. AB - Human African trypanosomiasis continues to be an important public health threat in extensive regions of sub-Saharan Africa. Treatment options for infected patients are unsatisfactory due to toxicity, difficult administration regimes, and poor efficacy of available drugs. The aminoacyl-tRNA synthetases were selected as attractive drug targets due to their essential roles in protein synthesis and cell survival. Comparative sequence analysis disclosed differences between the trypanosome and mammalian methionyl-tRNA synthetases (MetRSs) that suggested opportunities for selective inhibition using drug-like molecules. Experiments using RNA interference on the single MetRS of Trypanosoma brucei demonstrated that this gene product was essential for normal cell growth. Small molecules (diaryl diamines) similar to those shown to have potent activity on prokaryotic MetRS enzymes were synthesized and observed to have inhibitory activity on the T. brucei MetRS (50% inhibitory concentration, <50 nM) and on bloodstream forms of T. brucei cultures (50% effective concentration, as low as 4 nM). Twenty-one compounds had a close correlation between enzyme binding/inhibition and T. brucei growth inhibition, indicating that they were likely to be acting on the intended target. The compounds had minimal effects on mammalian cell growth at 20 MUM, demonstrating a wide therapeutic index. The most potent compound was tested in the murine model of trypanosomiasis and demonstrated profound parasite suppression and delayed mortality. A homology model of the T. brucei MetRS based on other MetRS structures was used to model binding of the lead diaryl diamine compounds. Future studies will focus on improving the pharmacological properties of the MetRS inhibitors. PMID- 21282429 TI - Use of pharmacokinetic and pharmacodynamic principles to determine optimal administration of daptomycin in patients receiving standardized thrice-weekly hemodialysis. AB - This study identified optimal daptomycin dosing for patients receiving thrice weekly hemodialysis (HD). Twelve adult patients on HD received daptomycin at 6 mg/kg of body weight intravenously (i.v.) one time; plasma and dialysate samples were collected over 3 days. A 2-compartment model with separate HD and non-HD clearance terms was fit to the data. A series of 9,999-subject Monte Carlo simulations (MCS) was performed to identify HD dosing schemes providing efficacy and toxicity profiles comparable to those obtained for MCS employing the daptomycin population pharmacokinetic (PK) model derived from patients in the Staphylococcus aureus bacteremia-infective endocarditis (SAB-IE) study. For efficacy, we selected the HD dosing scheme which generated an area-under-the curve (AUC) exposure profile comparable to that for the SAB-IE population model. For toxicity, we selected HD dosing schemes that minimized trough concentrations of >= 24.3 mg/liter. Separate HD dosing schemes were developed for each FDA approved regimen and for two weekly interdialytic periods (48 and 72 h). Administration of the same parent daptomycin dose intra-HD and post-HD resulted in AUC, maximum concentration of drug in serum (C(max)), and C(min) values most comparable to those for SAB-IE simulations for the 48-hour interdialytic period. In contrast, all candidate HD dosing schemes provided AUC(48-72) values that were at least 50% lower than the SAB-IE AUC(48-72) values. Increasing the parent dose by 50% provided more comparable AUC(48-72) values while maintaining acceptable C(min) values. Administration of the daptomycin parent dose intra-HD or post-HD was optimal for the 48-h interdialytic period. For the 72-h interdialytic period, clinicians should consider increasing the dose by 50% to achieve more comparable AUC(48-72) values. PMID- 21282430 TI - Intra- and extracellular activities of dicloxacillin and linezolid against a clinical Staphylococcus aureus strain with a small-colony-variant phenotype in an in vitro model of THP-1 macrophages and an in vivo mouse peritonitis model. AB - The small-colony-variant (SCV) phenotype of Staphylococcus aureus has been associated with difficult-to-treat infections, reduced antimicrobial susceptibility, and intracellular persistence. This study represents a detailed intra- and extracellular investigation of a clinical wild-type (WT) S. aureus strain and its counterpart with an SCV phenotype both in vitro and in vivo, using the THP-1 cell line model and the mouse peritonitis model, respectively. Bacteria of both phenotypes infected the mouse peritoneum intra- and extracellularly. The SCV phenotype was less virulent and showed distinct bacterial clearance, a reduced multiplication capacity, and a reduced internalization ability. However, some of the SCV-infected mice were still culture positive up to 96 h postinfection, and bacteria of this phenotype could spread to the mouse kidney and furthermore revert to the more virulent WT phenotype in both the mouse peritoneum and kidney. The SCV phenotype is therefore, despite reduced virulence, an important player in S. aureus pathogenesis. In the THP-1 cell line model, both dicloxacillin (DCX) and linezolid (LZD) reduced the intracellular inocula of bacteria of both phenotypes by approximately 1 to 1.5 log(10) in vitro, while DCX was considerably more effective against extracellular bacteria. In the mouse peritonitis model, DCX and LZD were also able to control both intra- and extracellular infections caused by either phenotype. Treatment with a single dose of DCX and LZD was, however, insufficient to clear the SCVs in the kidneys, and the risk of recurrent infection remained. This stresses the importance of an optimal dosing of the antibiotic when SCVs are present. PMID- 21282431 TI - Deciphering the mode of action of the synthetic antimicrobial peptide Bac8c. AB - Bac8c (RIWVIWRR-NH(2)) is an 8-amino-acid peptide derived from Bac2A (RLARIVVIRVAR-NH(2)), a C3A/C11A variant of the naturally occurring bovine peptide, bactenecin (also known as bovine dodecapeptide), the smallest peptide with activity against a range of pathogenic Gram-positive and Gram-negative bacteria, as well as yeast. The effects of Bac8c on Escherichia coli were examined by studying its bacteriostatic and bactericidal properties, demonstrating its effects on proton motive force generation, and visually analyzing (via transmission electron microscopy) its effects on cells at different concentrations, in order to probe the complexities of the mechanism of action of Bac8c. Results were consistent with a two-stage model for the Bac8c mode of action. At sublethal concentrations (3 MUg/ml), Bac8c addition resulted in transient membrane destabilization and metabolic imbalances, which appeared to be linked to inhibition of respiratory function. Although sublethal concentrations resulted in deleterious downstream events, such as methylglyoxal formation and free radical generation, native E. coli defense systems were sufficient for full recovery within 2 h. In contrast, at the minimal bactericidal concentration (6 MUg/ml), Bac8c substantially but incompletely depolarized the cytoplasmic membrane within 5 min and disrupted electron transport, which in turn resulted in partial membrane permeabilization and cell death. PMID- 21282432 TI - Intracellular nucleotide levels during coadministration of tenofovir disoproxil fumarate and didanosine in HIV-1-infected patients. AB - Studies were conducted to determine if there is a mechanistic basis for reports of suboptimal virologic responses and concerns regarding the safety of regimens containing the combination of tenofovir (TFV) disoproxil fumarate (TDF) and didanosine (ddI) by assessing the pharmacokinetic consequences of coadministration of these drugs on intracellular nucleotides. This was a prospective and longitudinal study in HIV-1-infected patients of adding either TDF or ddI to a stable antiretroviral regimen containing the other drug. Intracellular concentrations of the nucleotide analogs TFV diphosphate (TFV-DP) and ddATP and the endogenous purine nucleotides dATP and 2'-dGTP in peripheral blood mononuclear cells were measured. A total of 16 patients were enrolled into the two study arms and a study extension. Intracellular TFV-DP concentrations (median, 120 fmol/10(6) cells) and ddATP concentrations (range, 1.50 to 7.54 fmol/10(6) cells in two patients) were unaffected following addition of ddI or TDF to a stable regimen containing the other drug. While coadministration of ddI and TDF for 4 weeks did not appear to impact dATP or dGTP concentrations, cross sectional analysis suggested that extended therapy with ddI-containing regimens, irrespective of TDF coadministration, may decrease dATP and ddATP concentrations. Addition of TDF or ddI to a stable regimen including the other drug, in the context of ddI dose reduction, did not adversely affect the concentration of dATP, dGTP, TFV-DP, or ddATP. The association between longer-term ddI therapy and reduced intracellular nucleotide concentrations and this observation's implication for the efficacy and toxicity of ddI-containing regimens deserve further study. PMID- 21282433 TI - Effect of antibiotic treatment on the intestinal metabolome. AB - The importance of the mammalian intestinal microbiota to human health has been intensely studied over the past few years. It is now clear that the interactions between human hosts and their associated microbial communities need to be characterized in molecular detail if we are to truly understand human physiology. Additionally, the study of such host-microbe interactions is likely to provide us with new strategies to manipulate these complex systems to maintain or restore homeostasis in order to prevent or cure pathological states. Here, we describe the use of high-throughput metabolomics to shed light on the interactions between the intestinal microbiota and the host. We show that antibiotic treatment disrupts intestinal homeostasis and has a profound impact on the intestinal metabolome, affecting the levels of over 87% of all metabolites detected. Many metabolic pathways that are critical for host physiology were affected, including bile acid, eicosanoid, and steroid hormone synthesis. Dissecting the molecular mechanisms involved in the impact of beneficial microbes on some of these pathways will be instrumental in understanding the interplay between the host and its complex resident microbiota and may aid in the design of new therapeutic strategies that target these interactions. PMID- 21282434 TI - Pharmacokinetic properties of conventional and double-dose sulfadoxine pyrimethamine given as intermittent preventive treatment in infancy. AB - Intermittent preventive treatment in infancy (IPTi) entails routine administration of antimalarial treatment doses at specified times in at-risk infants. Sulfadoxine-pyrimethamine (SDX/PYR) is a combination that has been used as first-line IPTi. Because of limited pharmacokinetic data and suggestions that higher milligram/kilogram pediatric doses than recommended should be considered, we assessed SDX/PYR disposition, randomized to conventional (25/1.25 mg/kg of body weight) or double (50/2.5 mg/kg) dose, in 70 Papua New Guinean children aged 2 to 13 months. Blood samples were drawn at baseline, 28 days, and three time points randomly selected for each infant at 4 to 8 h or 2, 5, 7, 14, or 21 days. Plasma SDX, PYR, and N(4)-acetylsulfadoxine (NSX, the principal metabolite of SDX) were assayed by high-performance liquid chromatography (HPLC). Using population modeling incorporating hepatic maturation and cystatin C-based renal function, two-compartment models provided best fits for PYR and SDX/NSX plasma concentration profiles. The area under the plasma concentration-time curve from 0 h to infinity (AUC(0-infinity)) was greater with the double dose versus the conventional dose of PYR (4,915 versus 2,844 MUg/day/liter) and SDX (2,434 versus 1,460 mg/day/liter). There was a 32% reduction in SDX relative bioavailability with the double dose but no evidence of dose-dependent metabolism. Terminal elimination half-lives (15.6 days for PYR, 9.1 days for SDX) were longer than previously reported. Both doses were well tolerated without changes in hemoglobin or hepatorenal function. Five children in the conventional and three in the double-dose group developed malaria during follow-up. These data support the potential use of double-dose SDX/PYR in infancy, but further studies should examine the influence of hepatorenal maturation in very young infants. PMID- 21282435 TI - Positive impact of HIV-1 gag cleavage site mutations on the virological response to darunavir boosted with ritonavir. AB - We assessed the roles of baseline gag and gag-pol cleavage site mutations (CSM) on the virological outcome of a darunavir-based regimen in highly antiretroviral experienced patients. We showed the association, in multivariate analysis, between the A431V gag CSM and the virological response, defined as a reduction in plasma HIV-1 RNA to <50 copies/ml at month 3 (P = 0.028). Our results suggest that a specific gag CSM might have a role on protease inhibitor susceptibility in an inhibitor-specific manner. PMID- 21282436 TI - Evaluation of mitochondrial toxicity in Marmota himalayana treated with metacavir, a novel 2',3'-dideoxyguanosine prodrug for treatment of hepatitis B Virus. AB - Metacavir (PNA) is a novel synthetic nucleoside analogue for the treatment of hepatitis B virus (HBV). Our recent studies showed that PNA, a prodrug of 2',3' dideoxyguanosine (ddG), exhibited lower mitochondrial toxicity in long-term cultures of HepG2 cells. In the current study, we examined the long-term effects of PNA on mitochondrial toxicity in Marmota himalayana (Himalayan marmot). Himalayan marmots were treated daily with oral PNA (50 or 100 mg/kg), ziduvidine (AZT) (100 mg/kg), or water (control) for 90 days. PNA treatment did not alter the body weight or plasma lactate acid level. In livers from the animals treated with PNA at 100 mg/kg/day, histopathology showed mild steatosis or small focal liver cell necrosis. Electron microscopy also showed minor proliferation and partial mitochondrial swelling with crista reduction. Measurement of respiratory chain complex enzyme activity and mitochondrial DNA (mtDNA) content revealed no significant differences in skeletal muscle, liver, and kidney tissues between animals treated with PNA and controls. In contrast, in Himalayan marmots treated with AZT we observed delayed toxicity, including lactic acidosis, severe hepatic steatosis, obvious mitochondrial damage, and significant decreases in respiratory chain complex enzyme activity and mtDNA content. This is similar to the delayed toxicity syndrome observed previously in animals and humans. In summary, PNA treatment did not alter mitochondrial enzyme activity or mtDNA content. This suggests that PNA could pose a very low risk for adverse mitochondrion-related effects. However, long-term hepatotoxic effects of PNA were observed, and this indicates a need for continued monitoring of PNA-associated hepatotoxicity in clinical trials. PMID- 21282437 TI - Role of Klebsiella pneumoniae LamB Porin in antimicrobial resistance. AB - To investigate the contribution of LamB in Klebsiella pneumoniae antimicrobial resistance, we determined the MICs of various antibiotics and the frequency of mutation to increased cefoxitin or meropenem resistance of the strains CSUB10S (expressing only OmpK36), CSUB10R (lacking OmpK35 and OmpK36), and their derived isogenic insertion-duplication mutants deficient in LamB. Expression of LamB was indispensable in order for CSUB10S to lose OmpK36 and become resistant to cefoxitin, while in CSUB10R, LamB deficiency promoted increased resistance to carbapenem. PMID- 21282438 TI - Novel VIM metallo-beta-lactamase variant, VIM-24, from a Klebsiella pneumoniae isolate from Colombia. AB - We report the emergence of a novel VIM variant (VIM-24) in a Klebsiella pneumoniae isolate in Colombia. The isolate displays MICs for carbapenems below the resistance breakpoints, posing a real challenge for its detection. The blaVIM 24 gene was located within a class 1 integron carried on a large plasmid. Further studies are needed to clarify its epidemiological and clinical impact. PMID- 21282439 TI - In vivo efficacy of the novel aminoglycoside ACHN-490 in murine infection models. AB - Aminoglycosides are broad-spectrum antibiotics with particular clinical utility against life-threatening infections. As resistance to antibiotics, including aminoglycosides, continues to grow, there is a need for new and effective antimicrobial agents. ACHN-490 is a novel aminoglycoside in clinical development with activity against multidrug-resistant Gram-negative and select Gram-positive pathogens. Here we assess the in vivo efficacy of ACHN-490 against a variety of common pathogens in two murine models: the septicemia and neutropenic thigh models. When its activity against a gentamicin-susceptible strain of Escherichia coli was tested in the septicemia model, ACHN-490 improved 7-day survival with a dose-response profile similar to that of gentamicin, with 100% survival seen at doses of 1.6 mg/kg of body weight and above. In animals infected with a gentamicin-susceptible strain of Pseudomonas aeruginosa, treatment with either ACHN-490 or gentamicin led to 100% survival at doses of 16 mg/kg and above in the septicemia model. ACHN-490 was also effective in the neutropenic thigh model, reducing multidrug-resistant Enterobacteriaceae family and methicillin-resistant Staphylococcus aureus strains, as well as broadly susceptible strains, to static levels with dose-dependent activity. Against gentamicin-sensitive Enterobacteriaceae and methicillin-resistant S. aureus, the efficacy of ACHN-490 was comparable to that of gentamicin. However, gentamicin-resistant Enterobacteriaceae strains and those harboring the Klebsiella pneumoniae carbapenemase responded to ACHN-490 but not gentamicin, with static doses ranging from 12 mg/kg to 64 mg/kg for ACHN-490. These results suggest that ACHN-490 has the potential to become a clinically useful agent against drug-resistant pathogens, including Enterobacteriaceae, P. aeruginosa, and methicillin-resistant S. aureus, and support further development of this promising novel aminoglycoside. PMID- 21282440 TI - Chitosan augments photodynamic inactivation of gram-positive and gram-negative bacteria. AB - Antimicrobial photodynamic inactivation (PDI) was shown to be a promising treatment modality for microbial infections. This study explores the effect of chitosan, a polycationic biopolymer, in increasing the PDI efficacy against Gram positive bacteria, including Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, and methicillin-resistant S. aureus (MRSA), as well as the Gram-negative bacteria Pseudomonas aeruginosa and Acinetobacter baumannii. Chitosan at <0.1% was included in the antibacterial process either by coincubation with hematoporphyrin (Hp) and subjection to light exposure to induce the PDI effect or by addition after PDI and further incubation for 30 min. Under conditions in which Hp-PDI killed the microbe on a 2- to 4-log scale, treatment with chitosan at concentrations of as low as 0.025% for a further 30 min completely eradicated the bacteria (which were originally at ~10(8) CFU/ml). Similar results were also found with toluidine blue O (TBO)-mediated PDI in planktonic and biofilm cells. However, without PDI treatment, chitosan alone did not exert significant antimicrobial activity with 30 min of incubation, suggesting that the potentiated effect of chitosan worked after the bacterial damage induced by PDI. Further studies indicated that the potentiated PDI effect of chitosan was related to the level of PDI damage and the deacetylation level of the chitosan. These results indicate that the combination of PDI and chitosan is quite promising for eradicating microbial infections. PMID- 21282441 TI - Vancomycin bactericidal activity as a predictor of 30-day mortality in patients with methicillin-resistant Staphylococcus aureus bacteremia. PMID- 21282442 TI - In vitro pharmacodynamics of simulated pulmonary exposures of tigecycline alone and in combination against Klebsiella pneumoniae isolates producing a KPC carbapenemase. AB - Multidrug-resistant Klebsiella pneumoniae strains that produce a serine carbapenemase (KPC) are emerging worldwide, with few therapeutic options that retain consistent susceptibility. The objective of this study was to determine the effect of combination therapy with tigecycline versus tigecycline alone against KPC-producing isolates (KPC isolates). An in vitro pharmacodynamic model was used to simulate adult steady-state epithelial lining fluid concentrations of tigecycline (50 mg every 12 h) given alone and in combination with either meropenem (2 g by 3-hour infusion every 8 h) or rifampin (600 mg every 12 h). Five KPC isolates with various phenotypic profiles were exposed over 48 h. Time kill curves were constructed, and the areas under the bacterial killing and regrowth curves (AUBCs) were calculated. No regimens tested were able to maintain bactericidal reductions in CFU over 48 h. The AUBCs for tigecycline and meropenem monotherapies at 48 h ranged from 375.37 to 388.11 and from 348.62 to 383.83 (CFU h/ml), respectively. The combination of tigecycline plus meropenem significantly reduced the AUBCs at 24 and 48 h for isolates with tigecycline MICs of <= 2 MUg/ml and meropenem MICs of <= 16 MUg/ml (P < 0.001) but added no additional activity when the meropenem MIC was 64 MUg/ml (P = 0.5). Rifampin provided no additional reduction in CFU or AUBC over tigecycline alone (P = 0.837). The combination of tigecycline with high-dose, prolonged-infusion meropenem warrants further study as a potential treatment option for these multidrug-resistant organisms. PMID- 21282443 TI - Voriconazole-induced inhibition of the fungicidal activity of amphotericin B in Candida strains with reduced susceptibility to voriconazole: an effect not predicted by the MIC value alone. AB - An antagonistic effect of voriconazole on the fungicidal activity of sequential doses of amphotericin B has previously been demonstrated in Candida albicans strains susceptible to voriconazole. Because treatment failure and the need to switch to other antifungals are expected to occur more often in infections that are caused by resistant strains, it was of interest to study whether the antagonistic effect was still seen in Candida strains with reduced susceptibility to voriconazole. With the hypothesis that antagonism will not occur in voriconazole-resistant strains, C. albicans strains with characterized mechanisms of resistance against voriconazole, as well as Candida glabrata and Candida krusei strains with differences in their degrees of susceptibility to voriconazole were exposed to voriconazole or amphotericin B alone, to both drugs simultaneously, or to voriconazole followed by amphotericin B in an in vitro kinetic model. Amphotericin B administered alone or simultaneously with voriconazole resulted in fungicidal activity. When amphotericin B was administered after voriconazole, its activity was reduced (median reduction, 61%; range, 9 to 94%). Levels of voriconazole-dependent inhibition of amphotericin B activity differed significantly among the strains but were not correlated with the MIC values (correlation coefficient, -0.19; P = 0.65). Inhibition was found in C. albicans strains with increases in CDR1 and CDR2 expression but not in the strain with an increase in MDR1 expression. In summary, decreased susceptibility to voriconazole does not abolish voriconazole-dependent inhibition of the fungicidal activity of amphotericin B in voriconazole-resistant Candida strains. The degree of interaction could not be predicted by the MIC value alone. PMID- 21282444 TI - Pharmacokinetics of solithromycin (CEM-101) after single or multiple oral doses and effects of food on single-dose bioavailability in healthy adult subjects. AB - The pharmacokinetics of orally administered solithromycin (CEM-101), a novel fluoroketolide, were evaluated in healthy subjects in three phase 1 studies. In two randomized, double-blinded, placebo-controlled studies, escalating single oral doses of solithromycin (50 to 1,600 mg) or seven oral daily doses (200 to 600 mg) of solithromycin were administered. A third study evaluated the effects of food on the bioavailability of single oral doses (400 mg) of solithromycin. Following single doses, the median time to peak concentration (Tmax) ranged from 1.5 h to 6 h. The mean maximum measured plasma concentration (Cmax) ranged from 0.0223 MUg/ml to 19.647 MUg/ml, and the area under the concentration-versus-time curve from time zero to time t (AUC0-t) ranged from 0.0402 MUg.h/ml to 28.599 MUg.h/ml. There was no effect of high-fat food on the oral bioavailability of solithromycin. In the multiple-dose study, after 7 days, the mean maximum measured plasma solithromycin concentration at steady-state (Cmax,ss) ranged from 0.248 to 1.50 MUg/ml, and the area under the concentration-versus-time curve over the final dosing interval (AUCtau) ranged from 2.310 to 18.41 MUg.h/ml. These values indicate a greater than proportional increase in exposure at 200 and 400 mg but a proportional exposure at 600 mg. Median Tmax values remained constant between day 1 and day 7. Moderate accumulation ratios of solithromycin were observed after 7 days of dosing. All dose regimens of solithromycin were well tolerated, and no discontinuations due to an adverse event occurred. The human pharmacokinetic profile and tolerability of solithromycin, combined with its in vitro potency and efficacy in animal models against a broad spectrum of pathogens, support further development of solithromycin. PMID- 21282445 TI - Activity of ACHN-490 tested alone and in combination with other agents against Pseudomonas aeruginosa. AB - ACHN-490 was tested alone and in combination with cefepime, doripenem, imipenem, or piperacillin-tazobactam in a synergy time-kill analysis against 25 Pseudomonas aeruginosa strains with different resistance phenotypes. Each combination was synergistic against most isolates at 24 h, and antagonism was not observed. Combinations of ACHN-490 with cefepime, doripenem, imipenem, or piperacillin tazobactam yielded synergies in >=70% and >=80% of strains at 6 and 12 h, respectively, and in >=68% at 24 h. PMID- 21282446 TI - Genomic analysis of Acinetobacter baumannii A118 by comparison of optical maps: identification of structures related to its susceptibility phenotype. AB - Acinetobacter baumannii A118, a naturally competent clinical isolate, is unusually susceptible to several antibiotics. Comparison of the optical map of strain A118 with in silico-generated restriction maps of sequenced genomes and sequence analyses showed that the AbaR region, commonly found inserted within the comM gene in other isolates, is missing in strain A118, which could in part explain the susceptible phenotype exhibited by this isolate. These comparative studies also showed differences in regions where genes coding for functions that may be involved in drug resistance or susceptibility are located. Further sequencing demonstrated that cat and bla(ADC), named bla(ADC-55), are present but that a tet(A) gene usually found in other strains is not. In addition, carO and pbp2, which may play a role in susceptibility to carbapenems, are present in strain A118. These findings support the idea that A. baumannii strains possess multiple mechanisms that contribute to antibiotic resistance, and the presence of some of them is not sufficient for a resistant phenotype. The results shown here indicate that optical mapping is a useful tool for preliminary comparative genomic analysis. PMID- 21282447 TI - Dose-dependent activity of pyrazinamide in animal models of intracellular and extracellular tuberculosis infections. AB - Recent in vitro pharmacokinetic data suggest that the currently recommended dose of pyrazinamide may be suboptimal for killing intracellular bacilli in humans. We evaluated a range of pyrazinamide doses against intracellular and extracellular Mycobacterium tuberculosis in chronically infected mice and guinea pigs, respectively. Antibiotics were given five times weekly for 4 weeks beginning 28 days after infection. Human-equivalent doses of isoniazid reduced lung bacterial counts 10-fold in each species. Pyrazinamide given at 1/4 and 1/2 the human equivalent dose was minimally active, while human-equivalent doses reduced lung bacterial counts by ~1.0 log(10) in each species. Doubling the human-equivalent dose of pyrazinamide reduced the lung bacillary burden by 1.7 and 3.0 log(10) in mice and guinea pigs, respectively. As in humans and mice, pyrazinamide showed significant synergy with rifampin in guinea pigs. Clinical studies are warranted to investigate the sterilizing activity and tolerability of higher doses of pyrazinamide in combination tuberculosis regimens. PMID- 21282448 TI - Chromosome-encoded AmpC and CTX-M extended-spectrum beta-lactamases in clinical isolates of Proteus mirabilis from Korea. AB - Among 222 Proteus mirabilis clinical isolates collected from 17 hospitals in Korea in 2008, 28 (12.6%) and 8 (3.6%) isolates exhibited extended-spectrum beta lactamase (ESBL) and AmpC phenotypes, respectively. The most common type of ESBL gene identified by PCR and sequencing experiments was bla(CTX-M-14a) (n = 12). The bla(CTX-M-90) (n = 4), bla(CTX-M-15) (n = 3), bla(CTX-M-12) (n = 3), bla(CTX M-2) (n = 2), bla(CTX-M-14b) (n = 1), bla(TEM-52) (n = 5), and bla(SHV-12) (n = 1) genes were also detected. Eight isolates carried an AmpC beta-lactamase gene, such as bla(CMY-2) (n = 6) or bla(DHA-1) (n = 2). All bla genes encoding CTX-M-1- and CTX-M-9-type enzymes and all bla(CMY-2) genes were preceded by ISEcp1-like elements. The bla(CTX-M-2) gene found in two isolates was located on a complex class 1 integron. The bla(DHA-1) gene was preceded by a transcriptional regulator gene and was followed by phage shock protein genes. The bla(CTX-M) genes were located on the chromosome in 21 isolates. A plasmid location for the bla(CTX-M) gene was found in only four isolates: the bla(CTX-M-14a) gene was located on ~150 kbp IncA/C plasmids in three isolates and on a ~50-kbp IncN plasmid in one isolate. The bla(TEM-52) gene was located on ~50-kbp IncN plasmids in all five isolates. The AmpC beta-lactamase genes were located on the chromosome in seven of eight isolates; one isolate carried the bla(CMY-2) gene on a ~150-kbp IncA/C plasmid. Our results show that a chromosomal location of CTX-M ESBL and AmpC beta lactamase genes in P. mirabilis is no longer an unusual phenomenon in hospital environments. PMID- 21282449 TI - Differential phenotypic and genotypic characteristics of qnrS1-harboring plasmids carried by hospital and community commensal enterobacteria. AB - The qnrS1 gene induces reduced susceptibility to fluoroquinolones in enterobacteria. We investigated the structure, antimicrobial susceptibility phenotype, and antimicrobial resistance gene characteristics of qnrS1 plasmids from hospitalized patients and community controls in southern Vietnam. We found that the antimicrobial susceptibilities, resistance gene characteristics, and plasmid structures of qnrS1 plasmids from the hospital differed from those from the community. Our data imply that the characteristics of the two plasmid groups are indicative of distinct selective pressures in the differing environments. PMID- 21282450 TI - Novel HIV-1 protease inhibitors (PIs) containing a bicyclic P2 functional moiety, tetrahydropyrano-tetrahydrofuran, that are potent against multi-PI-resistant HIV 1 variants. AB - We identified GRL-1388 and -1398, potent nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) containing a bicyclic P2 functional moiety, tetrahydropyrano-tetrahydrofuran (Tp-THF). GRL-1388 was as potent as darunavir (DRV) against various drug-resistant HIV-1 laboratory strains with 50% effective concentration (EC(50)s) of 2.6 to 32.6 nM. GRL-1398 was significantly more potent against such variants than DRV with EC(50)s of 0.1 to 5.7 nM. GRL 1388 and -1398 were also potent against multiple-PI-resistant clinical HIV-1 variants ((CL)HIV-1(MDR)) with EC(50)s ranging from 2.7 to 21.3 nM and from 0.3 to 4.8 nM, respectively. A highly DRV-resistant HIV-1 variant selected in vitro remained susceptible to GRL-1398 with the EC(50) of 21.9 nM, while the EC(50) of DRV was 214.1 nM. When HIV-1(NL4-3) was selected with GRL-1398, four amino acid substitutions--leucine to phenylalanine at a position 10 (L10F), A28S, L33F, and M46I--emerged, ultimately enabling the virus to replicate in the presence of >1.0 MUM the compound beyond 57 weeks of selection. When a mixture of 10 different (CL)HIV-1(MDR) strains was selected, the emergence of resistant variants was more substantially delayed with GRL-1398 than with GRL-1388 and DRV. Modeling analyses revealed that GRL-1398 had greater overall hydrogen bonding and hydrophobic interactions than GRL-1388 and DRV and that GRL-1388 and -1398 had hydrogen bonding interactions with the main chain of the active-site amino acids (Asp29 and Asp30) of protease. The present findings warrant that GRL-1398 be further developed as a potential drug for treating individuals with HIV-1 infection. PMID- 21282451 TI - Development of an antivirulence drug against Streptococcus mutans: repression of biofilm formation, acid tolerance, and competence by a histidine kinase inhibitor, walkmycin C. AB - Two-component signal transduction systems (TCSs) in prokaryotes often regulate gene clusters that induce pathogenicity, and thus they have frequently been proposed as potential drug targets for attenuating the virulence of pathogens. The pathogenic potential of Streptococcus mutans, the major etiological pathogen of dental caries, is also regulated by its TCSs. The object of this study was to evaluate the effect of a histidine kinase (HK) inhibitor against two major virulence factors of S. mutans: biofilm formation and acid tolerance. Walkmycin C (WKM C), an HK inhibitor isolated from the screening of inhibitors against WalK HK in Bacillus subtilis, inhibited the in vitro autophosphorylation activity of three purified S. mutans HKs, i.e., VicK, CiaH, and LiaS. Although S. mutans does not have any essential HK but only an essential response regulator, VicR, WKM C showed an MIC of 6.25 MUg/ml. This inhibitory effect of WKM C suggests that blocking the autophosphorylation of multiple HKs may inhibit phosphotransfer to VicR from VicK and other HKs. When WKM C was added at sub-MIC levels, the cells formed abnormal biofilms and also showed a defect in competence. When the cells were pretreated with WKM C, an increase in acid sensitivity was observed. Our results show that WKM C represses two pathogenic phenotypes of S. mutans, indicating the possibility of developing histidine kinase inhibitors into antivirulence drugs. PMID- 21282452 TI - Klebsiella pneumoniae outer membrane porins OmpK35 and OmpK36 play roles in both antimicrobial resistance and virulence. AB - OmpK35 and OmpK36 are the major outer membrane porins of Klebsiella pneumoniae. In this study, a virulent clinical isolate was selected to study the role of these two porins in antimicrobial resistance and virulence. The single deletion of ompK36 (DeltaompK36) resulted in MIC shifts of cefazolin, cephalothin, and cefoxitin from susceptible to resistant, while the single deletion of ompK35 (DeltaompK35) had no significant effect. A double deletion of ompK35 and ompK36 (DeltaompK35/36) further increased these MICs to high-level resistance and led to 8- and 16-fold increases in the MICs of meropenem and cefepime, respectively. In contrast to the routine testing medium, which is of high osmolarity, susceptibility tests using low-osmolarity medium showed that the DeltaompK35 mutation resulted in a significant (>= 4-fold) increase in the MICs of cefazolin and ceftazidime, whereas a DeltaompK36 deletion conferred a significantly (4 fold) lower increase in the MIC of cefazolin. In the virulence assays, a significant (P < 0.05) defect in the growth rate was found only in the DeltaompK35/36 mutant, indicating the effect on metabolic fitness. A significant (P < 0.05) increase in susceptibility to neutrophil phagocytosis was observed in both DeltaompK36 and DeltaompK35/36 mutants. In a mouse peritonitis model, the DeltaompK35 mutant showed no change in virulence, and the DeltaompK36 mutant exhibited significantly (P < 0.01) lower virulence, whereas the DeltaompK35/36 mutant presented the highest 50% lethal dose of these strains. In conclusion, porin deficiency in K. pneumoniae could increase antimicrobial resistance but decrease virulence at the same time. PMID- 21282453 TI - Human immunodeficiency virus type 1 resistance or cross-resistance to nonnucleoside reverse transcriptase inhibitors currently under development as microbicides. AB - Microbicides based on nonnucleoside reverse transcriptase inhibitors (NNRTIs) are currently being developed to protect women from HIV acquisition through sexual contact. However, the large-scale introduction of these products raises two major concerns. First, when these microbicides are used by undiagnosed HIV-positive women, they could potentially select for viral resistance, which may compromise subsequent therapeutic options. Second, NNRTI-based microbicides that are inactive against NNRTI-resistant strains might promote the selective transmission of these viruses. In order to address these concerns, drug resistance was selected in vitro by the serial passage of three viral isolates from subtypes B and C and CRF02_AG (a circulating recombinant form) in activated peripheral blood mononuclear cells (PBMCs) under conditions of increasing concentrations of three NNRTIs (i.e., TMC120, UC781, and MIV-160) that are currently being developed as candidate microbicides. TMC120 and MIV-160 displayed a high genetic barrier to resistance development, whereas resistance to UC781 emerged rapidly, similarly to efavirenz and nevirapine. Phenotypically, the selected viruses appeared to be highly cross-resistant to current first-line therapeutic NNRTIs (i.e., delavirdine, nevirapine, and efavirenz), although they retained some susceptibility to the more recently developed NNRTIs lersivirine and etravirine. The ability of UC781, TMC120, and MIV-160 to inhibit the in vitro-selected NNRTI resistant viruses was also limited, although residual activity could be observed for the candidate microbicide NNRTI MIV-170. Interestingly, only four p2/p7/p1/p6/PR/RT/INT recombinant NNRTI-resistant viruses (i.e., TMC120-resistant VI829, EFV-resistant VI829, MIV-160-resistant VI829, and EFV-resistant MP568) showed impairments in replicative fitness. Overall, these in vitro analyses demonstrate that due to potential cross-resistance, the large-scale introduction of single-NNRTI-based microbicides should be considered with caution. PMID- 21282454 TI - Association of thymidylate synthase gene polymorphisms with stavudine triphosphate intracellular levels and lipodystrophy. AB - The antiviral activity and toxicity of stavudine (d4T) depend on its triphosphate metabolite, stavudine triphosphate (d4T-TP). Therefore, modifications in intracellular levels of d4T-TP may change the toxicity profile of stavudine. d4T TP intracellular levels in peripheral blood mononuclear cells were determined with a prominence liquid chromatograph connected to a triple-quadruple mass spectrometer. Polymorphisms in the thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), dihydrofolate reductase (DHFR), reduced folate carrier 1 (RFC1; SLC19A1), and cyclin D1 (CCND1) genes were determined by direct sequencing using an ABI Prism 3100 genetic analyzer or Fluidigm's Biomark system. The Mann-Whitney test, rank analysis of variance (with Bonferroni's adjusted post hoc comparisons), and logistic regression were used for the inferential analyses. Thirty-three stavudine-treated patients were enrolled in this cross-sectional study. d4T-TP intracellular levels were 11.50 fmol/10(6) cells (interquartile range [IQR] = 8.12 to 13.87 fmol/10(6) cells) in patients with a high-expression TS genotype (2/3G, 3C/3G, and 3G/3G), whereas in those with a low-expression TS genotype (2/2, 2/3C, and 3C/3C), they were 21.40 fmol/10(6) cells (IQR = 18.90 to 27.0 fmol/10(6) cells) (P < 0.0001). Polymorphisms in the MTHFR, DHFR, RFC1, and CCND1 genes did not influence the intracellular concentration of d4T-TP. d4T-TP levels were independently associated with the TS genotype (low versus high expression; odds ratio [OR] = 86.22; 95% confidence interval [CI] = 8.48 to nonestimable; P = 0.0023). The low expression TS genotype was associated with the development of HIV/highly active antiretroviral therapy-associated lypodystrophy syndrome (HALS) (OR = 14.0; 95% CI = 2.09 to 108.0; P = 0.0032). Our preliminary data show that polymorphisms in the thymidylate synthase gene are strongly associated with d4T-TP intracellular levels and with development of HALS. PMID- 21282455 TI - Successful treatment of Old World cutaneous leishmaniasis caused by Leishmania infantum with posaconazole. AB - Old World cutaneous leishmaniasis is a widespread and potentially disfiguring protozoal infection that is endemic in the Mediterranean basin, Africa, and parts of Asia. Human infection is caused by several species of Leishmania parasites, such as Leishmania infantum. Available systemic and topical treatments vary in efficacy and are often unjustified due to their toxicity. We report on a case that was treated with posaconazole, a drug typically considered an antifungal agent but which also targets specific metabolic pathways of the parasite. PMID- 21282456 TI - Role of VltAB, an ABC transporter complex, in viologen tolerance in Streptococcus mutans. AB - Streptococcus mutans, a Gram-positive organism, is the primary causative agent in the formation of dental caries in humans. To persist in the oral cavity, S. mutans must be able to tolerate rapid environmental fluctuations and exposure to various toxic chemicals. However, the mechanisms underlying the ability of this cariogenic pathogen to survive and proliferate under harsh environmental conditions remain largely unknown. Here, we wanted to understand the mechanisms by which S. mutans withstands exposure to methyl viologen (MV), a quaternary ammonium compound (QAC) that generates superoxide radicals in the cell. To elucidate the essential genes for MV tolerance, screening of ~3,500 mutants generated by ISS1 mutagenesis, revealed 15 MV-sensitive mutants. Among them, five and four independent insertions had occurred in SMU.905 and SMU.906 genes, respectively. These two genes are appeared to be organized in an operon and encode a putative ABC transporter complex; we designated the genes as vltA and vltB, for viologen transporter. To verify our results, vltA was deleted by using an antibiotic resistance marker; the mutant was just as sensitive to MV as the ISS1 insertion mutants. Furthermore, vltA and vltB mutants were also sensitive to other viologen compounds such as benzyl and ethyl viologens. Complementation assays were also carried out to confirm the role of VltA and VltB in viologen tolerance. Sensitivity to various drugs, including a wide range of QACs, was evaluated. It appears that a functional VltA is also required for full resistance toward acriflavin, ethidium bromide, and safranin; all are well-known QACs. These results indicate that VltA/B constitute a heterodimeric multidrug efflux pump of the ABC family. BLAST-P analysis suggests that homologs of VltA/B are widely present in streptococci, enterococci, and other important Gram-positive pathogens. PMID- 21282457 TI - Multilaboratory testing of two-drug combinations of antifungals against Candida albicans, Candida glabrata, and Candida parapsilosis. AB - There are few multilaboratory studies of antifungal combination testing to suggest a format for use in clinical laboratories. In the present study, eight laboratories tested quality control (QC) strain Candida parapsilosis ATCC 22019 and clinical isolates Candida albicans 20533.043, C. albicans 20464.007, Candida glabrata 20205.075, and C. parapsilosis 20580.070. The clinical isolates had relatively high azole and echinocandin MICs. A modified CLSI M27-A3 protocol was used, with 96-well custom-made plates containing checkerboard pairwise combinations of amphotericin B (AMB), anidulafungin (AND), caspofungin (CSP), micafungin (MCF), posaconazole (PSC), and voriconazole (VRC). The endpoints were scored visually and on a spectrophotometer or enzyme-linked immunosorbent assay (ELISA) reader for 50% growth reduction (50% inhibitory concentration [IC(50)]). Combination IC(50)s were used to calculate summation fractional inhibitory concentration indices (FICIs) (SigmaFIC) based on the Lowe additivity formula. The results revealed that the IC(50)s of all drug combinations were lower or equal to the IC(50) of individual drugs in the combination. A majority of the SigmaFIC values were indifferent (SigmaFIC = 0.51 to 2.0), but no antagonism was observed (SigmaFIC >= 4). Synergistic combinations (SigmaFIC <= 0.5) were found for AMB-PSC against C. glabrata and for AMB-AND and AMB-CSP against C. parapsilosis by both visual and spectrophotometric readings. Additional synergistic interactions were revealed by either of the two endpoints for AMB AND, AMB-CSP, AMB-MCF, AMB-PSC, AMB-VRC, AND-PSC, CSP-MCF, and CSP-PSC. The percent agreements among participating laboratories ranged from 37.5% (lowest) for AND-CSP and POS-VOR to 87.5% (highest) for AMB-MCF and AND-CSP. Median SigmaFIC values showed a wide dispersion, and interlaboratory agreements were less than 85% in most instances. Additional studies are needed to improve the interlaboratory reproducibility of antifungal combination testing. PMID- 21282458 TI - Screening measure for early detection of depressive symptoms: the depressive cognition scale. AB - Nearly 10% of American adults experience depressive symptoms each year. Negative thought patterns associated with risk for depression can be identified using a psychometrically sound measure, such as the Depressive Cognition Scale (DCS). However, no meaningful cutoff score has been established for the DCS. This study used a receiver operating characteristic (ROC) curve to establish a DCS cutoff score for risk for depression, using the Center for Epidemiological Studies Depression Scale (CES-D) as the gold standard measure. In a national nondepressed sample of 629 adults, the ROC showed that the DCS accurately discriminated between participants with and without serious depressive thinking in 80% of cases and established an optimum balance of sensitivity (73.9-76.6%) and specificity (69.0-75.3%) at a score of 7. Although findings indicate that the DCS may overidentify risk for clinical depression, the instrument is useful for screening and assessment, with possible initiation of psychological treatment to prevent clinical depression. PMID- 21282459 TI - Systematic review: process of forming academic service partnerships to reform clinical education. AB - The aim of our systematic review was to retrieve and integrate relevant evidence related to the process of formation and implementation of the academic-service partnership, with the aim of reforming the clinical education program. Despite a plethora of research evidence about implementing the academic- service partnership, no one to date has undertaken a robust systematic review about its process. An electronic search was performed to identify published studies between 1995 and 2008. Search strategies adapted from the University of York's Centre for Reviews and Dissemination were used. Fifteen papers were accepted based on the inclusion criteria and assessed for quality. Data were summarized thematically. Four main stages emerged: Mutual Potential Benefits, Moving From Being Competitors to Collaborators, Joint Practice, and Beneficial Outcomes. This study's findings can provide practical guidelines to steer partnership programs within the academic and clinical bodies, with the aim of providing a collaborative partnership approach to clinical education. PMID- 21282460 TI - Confidence in breastfeeding among pregnant women. AB - Little is known about prenatal breastfeeding confidence, although such knowledge is necessary for developing the content of counseling and tailoring it for individuals. The purpose of this study was to describe women's prenatal breastfeeding confidence and how their sociodemographic characteristics, breastfeeding knowledge, and attitudes relate to it. The electronic confidence scale was used in data collection, and 123 Finnish women filled in the questionnaire. The mean confidence score was 83.88 when the maximum possible score was 120. Confidence scores varied when parity, breastfeeding knowledge, and attitudes were involved. Variables regarding breastfeeding as difficult, regarding breastfeeding as exhausting, and parity explained 38.1% of the variation of the breastfeeding confidence scores. Pregnant women need information about managing potential breastfeeding problems and the physiology of breastfeeding. Interventions designed to promote breastfeeding confidence need to be focused on primiparas and women with a lack of breastfeeding knowledge. PMID- 21282461 TI - The death domain kinase RIP1 links the immunoregulatory CD40 receptor to apoptotic signaling in carcinomas. AB - CD40, a tumor necrosis factor (TNF) receptor family member, is widely recognized for its prominent role in the antitumor immune response. The immunostimulatory effects of CD40 ligation on malignant cells can be switched to apoptosis upon disruption of survival signals transduced by the binding of the adaptor protein TRAF6 to CD40. Apoptosis induction requires a TRAF2-interacting CD40 motif but is initiated within a cytosolic death-inducing signaling complex after mobilization of receptor-bound TRAF2 to the cytoplasm. We demonstrate that receptor interacting protein 1 (RIP1) is an integral component of this complex and is required for CD40 ligand-induced caspase-8 activation and tumor cell killing. Degradation of the RIP1 K63 ubiquitin ligases cIAP1/2 amplifies the CD40-mediated cytotoxic effect, whereas inhibition of CYLD, a RIP1 K63 deubiquitinating enzyme, reduces it. This two-step mechanism of apoptosis induction expands our appreciation of commonalities in apoptosis regulatory pathways across the TNF receptor superfamily and provides a telling example of how TNF family receptors usurp alternative programs to fulfill distinct cellular functions. PMID- 21282462 TI - The serine/threonine kinase Par1b regulates epithelial lumen polarity via IRSp53 mediated cell-ECM signaling. AB - The serine/threonine kinase Par1b promotes cell-cell adhesion and determines the polarity of the luminal domain in epithelial cells. In this study, we demonstrate that Par1b also regulates cell-extracellular matrix (ECM) signaling in kidney derived Madin-Darby canine kidney (MDCK) cells and identified the rho-guanosine triphosphatase adaptor and scaffolding protein IRSp53 as a Par1b substrate involved in this pathway. Par1b overexpression inhibits basal lamina formation, cell spreading, focal adhesion, stress fiber formation, and compaction, whereas Par1b depletion has the opposite effect. IRSp53 depletion mimics Par1b overexpression on cell-ECM signaling and lumen polarity but had no effect on adherens junction formation. Par1b directly phosphorylates IRSp53 on S366 in cell lysates and stimulates phosphorylation on S453/3/5 via an indirect mechanism. A Par1b phosphorylation-deficient IRSp53 mutant but not the wild-type protein efficiently rescues both the cell spreading and the lumen polarity defects in Par1b MDCK cells. Our data suggest a model in which Par1b phosphorylation prevents recruitment of IRSp53 effector proteins to its Src homology domain 3 by promoting 14-3-3 binding in the vicinity of that domain. PMID- 21282463 TI - Replication protein A safeguards genome integrity by controlling NER incision events. AB - Single-stranded DNA gaps that might arise by futile repair processes can lead to mutagenic events and challenge genome integrity. Nucleotide excision repair (NER) is an evolutionarily conserved repair mechanism, essential for removal of helix distorting DNA lesions. In the currently prevailing model, NER operates through coordinated assembly of repair factors into pre- and post-incision complexes; however, its regulation in vivo is poorly understood. Notably, the transition from dual incision to repair synthesis should be rigidly synchronized as it might lead to accumulation of unprocessed repair intermediates. We monitored NER regulatory events in vivo using sequential UV irradiations. Under conditions that allow incision yet prevent completion of repair synthesis or ligation, preincision factors can reassociate with new damage sites. In contrast, replication protein A remains at the incomplete NER sites and regulates a feedback loop from completion of DNA repair synthesis to subsequent damage recognition, independently of ATR signaling. Our data reveal an important function for replication protein A in averting further generation of DNA strand breaks that could lead to mutagenic and recombinogenic events. PMID- 21282464 TI - A novel role for BRCA1 in regulating breast cancer cell spreading and motility. AB - BRCA1 C-terminal (BRCT) domains in BRCA1 are essential for tumor suppressor function, though the underlying mechanisms remain unclear. We identified ezrin, radixin, and moesin as BRCA1 BRCT domain-interacting proteins. Ezrin-radixin moesin (ERM) and F-actin colocalized with BRCA1 at the plasma membrane (PM) of cancer cells, especially at leading edges and focal adhesion sites. In stably expressing cancer cells, high levels of enhanced green fluorescent protein (EGFP) BRCA1(1634-1863) acted as a dominant-negative factor, displacing endogenous BRCA1 from the PM. This led to delayed cell spreading, increased spontaneous motility, and irregular monolayer wound healing. MCF-7 cells (intact BRCA1) showed lower motility than HCC1937 cells (truncated BRCA1), but expression of EGFP-BRCA1(1634 1863) in MCF-7 increased motility. Conversely, full-length BRCA1 expression in HCC1937 decreased motility but only if the protein retained ubiquitin ligase activity. We conclude that full-length BRCA1 is important for complete tumor suppressor activity via interaction of its BRCT domains with ERM at the PM, controlling spreading and motility of cancer cells via ubiquitin ligase activity. PMID- 21282465 TI - The N-terminal coiled-coil of Ndel1 is a regulated scaffold that recruits LIS1 to dynein. AB - Ndel1 has been implicated in a variety of dynein-related processes, but its specific function is unclear. Here we describe an experimental approach to evaluate a role of Ndel1 in dynein-dependent microtubule self-organization using Ran-mediated asters in meiotic Xenopus egg extracts. We demonstrate that extracts depleted of Ndel1 are unable to form asters and that this defect can be rescued by the addition of recombinant N-terminal coiled-coil domain of Ndel1. Ndel1 dependent microtubule self-organization requires an interaction between Ndel1 and dynein, which is mediated by the dimerization fragment of the coiled-coil. Full rescue by the coiled-coil domain requires LIS1 binding, and increasing LIS1 concentration partly rescues aster formation, suggesting that Ndel1 is a recruitment factor for LIS1. The interactions between Ndel1 and its binding partners are positively regulated by phosphorylation of the unstructured C terminus. Together, our results provide important insights into how Ndel1 acts as a regulated scaffold to temporally and spatially regulate dynein. PMID- 21282466 TI - The full-of-bacteria gene is required for phagosome maturation during immune defense in Drosophila. AB - Arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome is a fatal recessive disorder caused by mutations in the VPS33B or VPS16B genes. Both encode homologues of the Vps33p and Vps16p subunits of the HOPS complex necessary for fusions of vacuoles in yeast. Here, we describe a mutation in the full-of bacteria (fob) gene, which encodes Drosophila Vps16B. Flies null for fob are homozygous viable and fertile. They exhibit, however, a defect in their immune defense that renders them hypersensitive to infections with nonpathogenic bacteria. fob hemocytes (fly macrophages) engulf bacteria but fail to digest them. Phagosomes undergo early steps of maturation and transition to a Rab7 positive stage, but do not mature to fully acidified phagolysosomes. This reflects a specific requirement of fob in the fusion of phagosomes with late endosomes/lysosomes. In contrast, cargo of autophagosomes as well as endosomes exhibit normal lysosomal delivery in fob cells. These findings suggest that defects in phagosome maturation may contribute to symptoms of ARC patients including recurring infections. PMID- 21282467 TI - Role of helix-loop-helix proteins during differentiation of erythroid cells. AB - Helix-loop-helix (HLH) proteins play a profound role in the process of development and cellular differentiation. Among the HLH proteins expressed in differentiating erythroid cells are the ubiquitous proteins Myc, USF1, USF2, and TFII-I, as well as the hematopoiesis-specific transcription factor Tal1/SCL. All of these HLH proteins exhibit distinct functions during the differentiation of erythroid cells. For example, Myc stimulates the proliferation of erythroid progenitor cells, while the USF proteins and Tal1 regulate genes that specify the differentiated phenotype. This minireview summarizes the known activities of Myc, USF, TFII-I, and Tal11/SCL and discusses how they may function sequentially, cooperatively, or antagonistically in regulating expression programs during the differentiation of erythroid cells. PMID- 21282468 TI - Requirement of c-Jun NH(2)-terminal kinase for Ras-initiated tumor formation. AB - The c-Jun NH(2)-terminal kinase (JNK) signal transduction pathway causes increased gene expression mediated, in part, by members of the activating transcription factor protein (AP1) group. JNK is therefore implicated in the regulation of cell growth and cancer. To test the role of JNK in Ras-induced tumor formation, we examined the effect of compound ablation of the ubiquitously expressed genes Jnk1 plus Jnk2. We report that JNK is required for Ras-induced transformation of p53-deficient primary cells in vitro. Moreover, JNK is required for lung tumor development caused by mutational activation of the endogenous KRas gene in vivo. Together, these data establish that JNK plays a key role in Ras induced tumorigenesis. PMID- 21282469 TI - Role of PTIP in class switch recombination and long-range chromatin interactions at the immunoglobulin heavy chain locus. AB - How distal transcriptional enhancer sequences interact with proximal promoters is poorly understood within the context of chromatin. In this report, we have used the immunoglobulin heavy chain locus to address the role of the PTIP protein in transcription regulation and class switch recombination in B cells, a process that depends on regulated transcription and DNA recombination via Pax5 and distal 3' enhancer sequences. We first show that PTIP is recruited to a Pax5 binding site to promote histone H3 lysine 4 (H3K4) methylation. Using a CD19-Cre driver strain, we deleted PTIP in mature B cells. Loss of PTIP inhibited class switch recombination by suppressing transcription and histone H3K4 methylation at the germ line transcript promoters. In the absence of PTIP, Pax5 binding to the promoter regions is reduced and long-range chromatin interactions between the distal enhancer at the 3' regulatory region and the germ line transcript promoters are not detected. We propose a model whereby PTIP stabilizes the Pax5 DNA interactions that promote chromatin looping and regulate transcriptional responses needed for class switch recombination. PMID- 21282470 TI - Cellular functions of Ufd2 and Ufd3 in proteasomal protein degradation depend on Cdc48 binding. AB - The chaperone-related AAA ATPase Cdc48 (p97/VCP in higher eukaryotes) segregates ubiquitylated proteins for subsequent degradation by the 26S proteasome or for nonproteolytic fates. The specific outcome of Cdc48 activity is controlled by the evolutionary conserved cofactors Ufd2 and Ufd3, which antagonistically regulate the substrates' ubiquitylation states. In contrast to the interaction of Ufd3 and Cdc48, the interaction between the ubiquitin chain elongating enzyme Ufd2 and Cdc48 has not been precisely mapped. Consequently, it is still unknown whether physiological functions of Ufd2 in fact require Cdc48 binding. Here, we show that Ufd2 binds to the C-terminal tail of Cdc48, unlike the human Ufd2 homologue E4B, which interacts with the N domain of p97. The binding sites for Ufd2 and Ufd3 on Cdc48 overlap and depend critically on the conserved residue Y834 but are not identical. Saccharomyces cerevisiae cdc48 mutants altered in residue Y834 or lacking the C-terminal tail are viable and exhibit normal growth. Importantly, however, loss of Ufd2 and Ufd3 binding in these mutants phenocopies defects of Deltaufd2 and Deltaufd3 mutants in the ubiquitin fusion degradation (UFD) and Ole1 fatty acid desaturase activation (OLE) pathways. These results indicate that key cellular functions of Ufd2 and Ufd3 in proteasomal protein degradation require their interaction with Cdc48. PMID- 21282471 TI - Chaperone-mediated autophagy at a glance. PMID- 21282472 TI - The choice in meiosis - defining the factors that influence crossover or non crossover formation. AB - Meiotic crossovers are essential for ensuring correct chromosome segregation as well as for creating new combinations of alleles for natural selection to take place. During meiosis, excess meiotic double-strand breaks (DSBs) are generated; a subset of these breaks are repaired to form crossovers, whereas the remainder are repaired as non-crossovers. What determines where meiotic DSBs are created and whether a crossover or non-crossover will be formed at any particular DSB remains largely unclear. Nevertheless, several recent papers have revealed important insights into the factors that control the decision between crossover and non-crossover formation in meiosis, including DNA elements that determine the positioning of meiotic DSBs, and the generation and processing of recombination intermediates. In this review, we focus on the factors that influence DSB positioning, the proteins required for the formation of recombination intermediates and how the processing of these structures generates either a crossover or non-crossover in various organisms. A discussion of crossover interference, assurance and homeostasis, which influence crossing over on a chromosome-wide and genome-wide scale - in addition to current models for the generation of interference - is also included. This Commentary aims to highlight recent advances in our understanding of the factors that promote or prevent meiotic crossing over. PMID- 21282473 TI - Isoaspartate-dependent molecular switches for integrin-ligand recognition. AB - Integrins are cell-adhesion receptors that mediate cell-extracellular-matrix (ECM) and cell-cell interactions by recognizing specific ligands. Recent studies have shown that the formation of isoaspartyl residues (isoAsp) in integrin ligands by asparagine deamidation or aspartate isomerization could represent a mechanism for the regulation of integrin-ligand recognition. This spontaneous post-translational modification, which might occur in aged proteins of the ECM, changes the length of the peptide bond and, in the case of asparagine, also of the charge. Although these changes typically have negative effects on protein function, recent studies suggested that isoAsp formation at certain Asn-Gly-Arg (NGR) sites in ECM proteins have a gain-of-function effect, because the resulting isoAsp-Gly-Arg (isoDGR) sequence can mimic Arg-Gly-Asp (RGD), a well-known integrin-binding motif. Substantial experimental evidence suggests that the NGR to-isoDGR transition can occur in vitro in natural proteins and in drugs containing this motif, thereby promoting integrin recognition and cell adhesion. In this Commentary, we review these studies and discuss the potential effects that isoAsp formation at NGR, DGR and RGD sites might have in the recognition of integrins by natural ligands and by drugs that contain these motifs, as well as their potential biological and pharmacological implications. PMID- 21282474 TI - Letter to the editor: "Assessment of flow-mediated dilation in humans: a methodological and physiological guideline". PMID- 21282476 TI - Safety techniques for percutaneous endoscopic gastrostomy tube placement in Pierre Robin Sequence. AB - Pierre Robin Sequence (PRS) is a craniofacial anomaly characterized by a triad of micrognathia, glossoptosis, and cleft palate. Infants with PRS frequently have feeding problems that may require supplemental nutrition through a nasogastric or gastrostomy tube. Very few published studies have illustrated the most appropriate method for securing an enteral feeding route in this patient population. One case report described a major complication leading to death from airway compromise following percutaneous endoscopic gastrostomy (PEG) tube placement. The authors describe a case of an infant with PRS who underwent successful PEG tube placement without complications, and they highlight certain techniques to improve procedure success and patient safety. PMID- 21282477 TI - Adding ROS quenchers to cold K+ cardioplegia reduces superoxide emission during 2 hour global cold cardiac ischemia. AB - We reported that the combination of reactive oxygen species (ROS) quenchers Mn(III) tetrakis (4-benzoic acid) porphyrin (MnTBAP), catalase, and glutathione (MCG) given before 2 hours cold ischemia better protected cardiac mitochondria against cold ischemia and warm reperfusion (IR)-induced damage than MnTBAP alone. Here, we hypothesize that high K(+) cardioplegia (CP) plus MCG would provide added protection of mitochondrial bioenergetics and cardiac function against IR injury. Using fluorescence spectrophotometry, we monitored redox balance, ie reduced nicotinamide adenine dinucleotide and flavin adenine dinucleotide (NADH/FAD), superoxide (O(2) (*-)), and mitochondrial Ca(2+) (m[Ca(2+)]) in the left ventricular free wall. Guinea pig isolated hearts were perfused with either Krebs Ringer's (KR) solution, CP, or CP + MCG, before and during 27 degrees C perfusion followed immediately by 2 hours of global ischemia at 27 degrees C. Drugs were washed out with KR at the onset of 2 hours 37 degrees C reperfusion. After 120 minutes warm reperfusion, myocardial infarction was lowest in the CP + MCG group and highest in the KR group. Developed left ventricular pressure recovery was similar in CP and CP + MCG and was better than in the KR group. O(2) (*-), m[Ca(2+)], and NADH/FAD were significantly different between the treatment and KR groups. O(2) (*-) was lower in CP + MCG than in the CP group. This study suggests that CP and ROS quenchers act in parallel to improve mitochondrial function and to provide protection against IR injury at 27 degrees C. PMID- 21282478 TI - Clcn4-2 genomic structure differs between the X locus in Mus spretus and the autosomal locus in Mus musculus: AT motif enrichment on the X. AB - In Mus spretus, the chloride channel 4 gene Clcn4-2 is X-linked and dosage compensated by X up-regulation and X inactivation, while in the closely related mouse species Mus musculus, Clcn4-2 has been translocated to chromosome 7. We sequenced Clcn4-2 in M. spretus and identified the breakpoints of the evolutionary translocation in the Mus lineage. Genetic and epigenetic differences were observed between the 5'ends of the autosomal and X-linked loci. Remarkably, Clcn4-2 introns have been truncated on chromosome 7 in M. musculus as compared with the X-linked loci from seven other eutherian mammals. Intron sequences specifically preserved in the X-linked loci were significantly enriched in AT rich oligomers. Genome-wide analyses showed an overall enrichment in AT motifs unique to the eutherian X (except for genes that escape X inactivation), suggesting a role for these motifs in regulation of the X chromosome. PMID- 21282479 TI - 84-year-old man with respiratory distress and abdominal distention. PMID- 21282480 TI - Susumu Tonegawa--Japan's first Nobel laureate in physiology or medicine. PMID- 21282481 TI - The calcareous lung. PMID- 21282482 TI - Introduction to the Symposium on Antimicrobial Therapy. PMID- 21282483 TI - Effect of abnormal fasting plasma glucose level on all-cause mortality in older patients with acute myocardial infarction: results from the Beijing Elderly Acute Myocardial Infarction Study (BEAMIS). AB - OBJECTIVE: To assess whether the relationship between abnormal fasting plasma glucose (FPG) levels and patient outcomes holds for both older men and older women with acute myocardial infarction (AMI). PATIENTS AND METHODS: From April 1, 2004, to October 31, 2006, a total of 2016 consecutive older patients (age >=65 years) presenting with AMI were screened. Of these patients, 1854 were consecutively enrolled in the study. Patients were categorized into 4 groups: the hypoglycemic group (FPG, <=90.0 mg/dL [to convert to mmol/L, multiply by 0.0555]; n=443, 23.9%), the euglycemic group (FPG, 90.1-126.0 mg/dL; n=812, 43.8%), the mildly hyperglycemic group (FPG, 126.1-162.0 mg/dL; n=308, 16.6%), and the severely hyperglycemic group (FPG, >=162.1 mg/dL; n=291, 15.7%). The primary outcomes were rates of in-hospital and 3-year mortality. RESULTS: Female patients were older and had a higher incidence of diabetes mellitus but lower rates of smoking and use of invasive therapy. Men tended to have a higher frequency of hypoglycemia, whereas women tended to have a higher frequency of hyperglycemia. No significant difference was found in in-hospital (10.9% vs 9.1%; P=.36) or 3 year (24.5% vs 24.5%; P=.99) mortality between male and female patients, and FPG associated mortality did not vary significantly by sex. CONCLUSION: An increased FPG level was associated with a relatively higher risk of in-hospital mortality in men but not in women. Nonetheless, increased and decreased FPG levels at admission could predict higher mortality rates regardless of sex. There was a striking U-shaped relationship between FPG levels and in-hospital and 3-year mortality. The effect of abnormal FPG level on outcomes among older patients with AMI did not vary significantly by sex. PMID- 21282484 TI - Comparison of body habitus in patients with pulmonary arterial hypertension enrolled in the Registry to Evaluate Early and Long-term PAH Disease Management with normative values from the National Health and Nutrition Examination Survey. AB - OBJECTIVE: To investigate the correlation between body mass index (BMI) and pulmonary artery systolic pressure in a large population of patients with pulmonary arterial hypertension (PAH). PATIENTS AND METHODS: The BMI of patients with group 1 PAH enrolled in the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) was compared with that of age- and sex-matched controls in the National Health and Nutrition Examination Survey (NHANES) to clarify whether obesity is linked with PAH. The diagnosis of PAH was defined in REVEAL by right-sided heart catheterization. Differences in BMI and the percentage of patients considered obese (BMI >=30) and underweight (BMI <18.5) in various subgroups of patients enrolled in REVEAL from March 30, 2006, through September 11, 2007, were determined. RESULTS: Mean BMI was no different for patients with PAH (n=2141) than for the NHANES normal comparison group; however, the proportion of obese and underweight patients was increased in patients with PAH. Subgroup analysis demonstrated that subgroups with idiopathic PAH and those with PAH associated with drugs and toxins had both higher BMI and percentage of obese patients, whereas 3 other subgroups (those with PAH associated with congenital heart disease, connective tissue disease, and human immunodeficiency virus) had lower mean BMI. CONCLUSION: Mean BMI of the REVEAL patients was the same as that of the NHANES normal comparison group; however, there were higher percentages of obese and underweight patients in REVEAL. This discrepancy can be explained by the balancing effect of more overweight and underweight patients in different PAH subgroups. The reason for the increased frequency of obesity in idiopathic PAH is unknown, and additional study is needed. PMID- 21282485 TI - Association of socioeconomic status with Breslow thickness and disease-free and overall survival in stage I-II primary cutaneous melanoma. AB - OBJECTIVE: To investigate the influence of socioeconomic status (SES) on Breslow thickness, disease-free survival, and overall survival in patients with stage I II primary cutaneous melanoma (PCM). PATIENTS AND METHODS: The study consists of all consecutive patients who were diagnosed as having PCM and were treated and followed up at our hospital between November 1, 1998, and July 31, 2009. Pathologic and sociodemographic characteristics of the patients were obtained. We categorized SES into 3 levels: low (manual employees and skilled/unskilled workers, including farmers, with primary education level), middle (nonmanual employees and clerks with middle education level), and high (professionals, executives, administrators, and entrepreneurs with tertiary education). RESULTS: A total of 1443 consecutive patients were evaluated. In a multivariate logistic regression analysis, sex (female vs male: odds ratio [OR], 1.37; 95% confidence interval [CI], 1.08-1.75), SES (high vs middle: OR, 1.27; 95% CI, 0.96-1.69; high vs low: OR, 1.73; 95% CI, 1.26-2.38), age (<60 vs >=60 years: OR, 1.35; 95% CI, 1.03-1.78), and family context (single vs living with relatives: OR, 1.37; 95% CI, 0.97-1.94) were the strongest correlates of Breslow thickness. Compared with high SES, the risk of melanoma-related death, adjusted for age and sex, was 7 times higher (hazard ratio, 7.44; 95% CI, 3.27-16.93) and almost 2 times higher (hazard ratio, 1.88; 95% CI, 1.04-3.39) in patients with low SES living alone or living with relatives, respectively. CONCLUSION: In patients with PCM, low SES is associated with thicker melanoma and a poorer clinical outcome. PMID- 21282486 TI - Blood storage duration and biochemical recurrence of cancer after radical prostatectomy. AB - OBJECTIVE: To test the hypothesis that perioperative transfusion of allogeneic and autologous red blood cells (RBCs) stored for a prolonged period speeds biochemical recurrence of prostate cancer after prostatectomy. PATIENTS AND METHODS: We evaluated biochemical prostate cancer recurrence in men who had undergone radical prostatectomy and perioperative blood transfusions from July 6, 1998, through December 27, 2007. Those who received allogeneic blood transfusions were assigned to nonoverlapping "younger," "middle," and "older" RBC storage duration groups. Those who received autologous RBC transfusions were analyzed using the maximum storage duration as the primary exposure. We evaluated the association between RBC storage duration and biochemical recurrence using multivariable Cox proportional hazards regression. RESULTS: A total of 405 patients received allogeneic transfusions. At 5 years, the biochemical recurrence free survival rate was 74%, 71%, and 76% for patients who received younger, middle, and older RBCs, respectively; our Cox model indicated no significant differences in biochemical recurrence rates between the groups (P=.82; Wald test). Among patients who received autologous transfusions (n=350), maximum RBC age was not significantly associated with biochemical cancer recurrence (P=.95). At 5 years, the biochemical recurrence-free survival rate was 85% and 81% for patients who received younger and older than 21-day-old RBCs, respectively. CONCLUSION: In patients undergoing radical prostatectomy who require RBC transfusion, recurrence risk does not appear to be independently associated with blood storage duration. PMID- 21282487 TI - The hand that gives the rose. AB - "Convocation of Thanks" is the annual ceremony commemorating the gift of body donation to the Mayo Clinic Bequest program in the Department of Anatomy, College of Medicine, Mayo Clinic in Rochester, MN. For 26 years, this ceremony of gratitude has given students, researchers, faculty, and family members an opportunity to reflect on the immeasurable value of these gifts. The authors describe the significance of ceremonies such as these in historical context and provide abridged transcripts of participants' speeches. PMID- 21282488 TI - 62-year-old woman with fever, dyspnea, pleuritic chest pain, and weight loss. PMID- 21282489 TI - General principles of antimicrobial therapy. AB - Antimicrobial agents are some of the most widely, and often injudiciously, used therapeutic drugs worldwide. Important considerations when prescribing antimicrobial therapy include obtaining an accurate diagnosis of infection; understanding the difference between empiric and definitive therapy; identifying opportunities to switch to narrow-spectrum, cost-effective oral agents for the shortest duration necessary; understanding drug characteristics that are peculiar to antimicrobial agents (such as pharmacodynamics and efficacy at the site of infection); accounting for host characteristics that influence antimicrobial activity; and in turn, recognizing the adverse effects of antimicrobial agents on the host. It is also important to understand the importance of antimicrobial stewardship, to know when to consult infectious disease specialists for guidance, and to be able to identify situations when antimicrobial therapy is not needed. By following these general principles, all practicing physicians should be able to use antimicrobial agents in a responsible manner that benefits both the individual patient and the community. PMID- 21282490 TI - beta-receptor antagonist cessation resulting in tako-tsubo cardiomyopathy in a man with quadriplegia. PMID- 21282491 TI - Proteomic analysis of coronary sinus serum reveals leucine-rich alpha2 glycoprotein as a novel biomarker of ventricular dysfunction and heart failure. AB - BACKGROUND: Heart failure (HF) prevention strategies require biomarkers that identify disease manifestation. Increases in B-type natriuretic peptide (BNP) correlate with increased risk of cardiovascular events and HF development. We hypothesize that coronary sinus serum from a high BNP hypertensive population reflects an active pathological process and can be used for biomarker exploration. Our aim was to discover differentially expressed disease-associated proteins that identify patients with ventricular dysfunction and HF. METHODS AND RESULTS: Coronary sinus serum from 11 asymptomatic, hypertensive patients underwent quantitative differential protein expression analysis by 2-dimensional difference gel electrophoresis. Proteins were identified using mass spectrometry and then studied by enzyme-linked immunosorbent assay in sera from 40 asymptomatic, hypertensive patients and 105 patients across the spectrum of ventricular dysfunction (32 asymptomatic left ventricular diastolic dysfunction, 26 diastolic HF, and 47 systolic HF patients). Leucine-rich alpha2-glycoprotein (LRG) was consistently overexpressed in high BNP serum. LRG levels correlate significantly with BNP in hypertensive, asymptomatic left ventricular diastolic dysfunction, diastolic HF, and systolic HF patient groups (P<=0.05). LRG levels were able to identify HF independent of BNP. LRG correlates with coronary sinus serum levels of tumor necrosis factor-alpha (P=0.009) and interleukin-6 (P=0.021). LRG is expressed in myocardial tissue and correlates with transforming growth factor-betaR1 (P<0.001) and alpha-smooth muscle actin (P=0.025) expression. CONCLUSIONS: LRG was identified as a serum biomarker that accurately identifies patients with HF. Multivariable modeling confirmed that LRG is a stronger identifier of HF than BNP and this is independent of age, sex, creatinine, ischemia, beta-blocker therapy, and BNP. PMID- 21282492 TI - Where do college students get health information? Believability and use of health information sources. AB - This study aims to identify predictors of use of health information sources among U.S. college students. For this purpose, the Spring 2006 American College Health Association-National College Health Assessment (ACHA-NCHA) database of 94,806 students at 117 colleges and universities was used. Univariate and multivariable analyses of survey data were conducted. The four most believable sources of health information as indicated by survey respondents were health center medical staff, health educators, faculty or coursework, and parents. Health center medical staff, health educators, and faculty or coursework were underutilized in relation to their perceived believability, whereas parents were both used and believed at high frequencies. In general, older students, females, full time students, and Black and Hispanic students were more likely to use information from one of the four health sources. However, there was considerable subgroup variability, especially in the use of parents as a health information source. The authors conclude that information on use and believability of health information sources can help colleges to design more effective health information campaigns. PMID- 21282493 TI - 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease. PMID- 21282494 TI - 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease: executive summary. PMID- 21282495 TI - Augmented expression and activity of extracellular matrix-degrading enzymes in regions of low endothelial shear stress colocalize with coronary atheromata with thin fibrous caps in pigs. AB - Background- The molecular mechanisms that determine the localized formation of thin-capped atheromata in the coronary arteries remain unknown. This study tested the hypothesis that low endothelial shear stress augments the expression of matrix-degrading proteases and thereby promotes the formation of thin-capped atheromata. Methods and Results- Intravascular ultrasound-based, geometrically correct 3-dimensional reconstruction of the coronary arteries of 12 swine was performed in vivo 23 weeks after initiation of diabetes mellitus and a hyperlipidemic diet. Local endothelial shear stress was calculated in plaque-free subsegments of interest (n=142) with computational fluid dynamics. At week 30, the coronary arteries (n=31) were harvested and the same subsegments were identified. The messenger RNA and protein expression and elastolytic activity of selected elastases and their endogenous inhibitors were assessed. Subsegments with low preceding endothelial shear stress at week 23 showed reduced endothelial coverage, enhanced lipid accumulation, and intense infiltration of activated inflammatory cells at week 30. These lesions showed increased expression of messenger RNAs encoding matrix metalloproteinase-2, -9, and -12, and cathepsins K and S relative to their endogenous inhibitors and increased elastolytic activity. Expression of these enzymes correlated positively with the severity of internal elastic lamina fragmentation. Thin-capped atheromata developed in regions with lower preceding endothelial shear stress and had reduced endothelial coverage, intense lipid and inflammatory cell accumulation, enhanced messenger RNA expression and elastolytic activity of MMPs and cathepsins, and severe internal elastic lamina fragmentation. Conclusions- Low endothelial shear stress induces endothelial discontinuity and accumulation of activated inflammatory cells, thereby augmenting the expression and activity of elastases in the intima and shifting the balance with their inhibitors toward matrix breakdown. Our results provide new insight into the mechanisms of regional formation of plaques with thin fibrous caps. PMID- 21282496 TI - Stopping aspirin before coronary artery surgery: between the devil and the deep blue sea. PMID- 21282497 TI - Inflammasome activation in reperfusion injury: friendly fire on myocardial infarction? PMID- 21282498 TI - Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury. AB - Background- Inflammation plays a key role in the pathophysiology of myocardial ischemia/reperfusion (I/R) injury; however, the mechanism by which myocardial I/R induces inflammation remains unclear. Recent evidence indicates that a sterile inflammatory response triggered by tissue damage is mediated through a multiple protein complex called the inflammasome. Therefore, we hypothesized that the inflammasome is an initial sensor for danger signal(s) in myocardial I/R injury. Methods and Results- We demonstrate that inflammasome activation in cardiac fibroblasts, but not in cardiomyocytes, is crucially involved in the initial inflammatory response after myocardial I/R injury. We found that inflammasomes are formed by I/R and that its subsequent activation of inflammasomes leads to interleukin-1beta production, resulting in inflammatory responses such as inflammatory cell infiltration and cytokine expression in the heart. In mice deficient for apoptosis-associated speck-like adaptor protein and caspase-1, these inflammatory responses and subsequent injuries, including infarct development and myocardial fibrosis and dysfunction, were markedly diminished. Bone marrow transplantation experiments with apoptosis-associated speck-like adaptor protein-deficient mice revealed that inflammasome activation in bone marrow cells and myocardial resident cells such as cardiomyocytes or cardiac fibroblasts plays an important role in myocardial I/R injury. In vitro experiments revealed that hypoxia/reoxygenation stimulated inflammasome activation in cardiac fibroblasts, but not in cardiomyocytes, and that hypoxia/reoxygenation-induced activation was mediated through reactive oxygen species production and potassium efflux. Conclusions- Our results demonstrate the molecular basis for the initial inflammatory response after I/R and suggest that the inflammasome is a potential novel therapeutic target for preventing myocardial I/R injury. PMID- 21282499 TI - Omega-3 fatty acids prevent pressure overload-induced cardiac fibrosis through activation of cyclic GMP/protein kinase G signaling in cardiac fibroblasts. AB - BACKGROUND: Omega-3 polyunsaturated fatty acids (eicosapentaenoic acid and docosahexaenoic acid) from fish oil ameliorate cardiovascular diseases. However, little is known about the effects of omega-3 polyunsaturated fatty acids on cardiac fibrosis, a major cause of diastolic dysfunction and heart failure. The present study assessed the effects of omega-3 polyunsaturated fatty acids on cardiac fibrosis. METHODS AND RESULTS: We assessed left ventricular fibrosis and pathology in mice subjected to transverse aortic constriction after the consumption of a fish oil or a control diet. In control mice, 4 weeks of transverse aortic constriction induced significant cardiac dysfunction, cardiac fibrosis, and cardiac fibroblast activation (proliferation and transformation into myofibroblasts). Dietary supplementation with fish oil prevented transverse aortic constriction-induced cardiac dysfunction and cardiac fibrosis and blocked cardiac fibroblast activation. In heart tissue, transverse aortic constriction increased active transforming growth factor-beta1 levels and phosphorylation of Smad2. In isolated adult mouse cardiac fibroblasts, transforming growth factor beta1 induced cardiac fibroblast transformation, proliferation, and collagen synthesis. Eicosapentaenoic acid and docosahexaenoic acid increased cyclic GMP levels and blocked cardiac fibroblast transformation, proliferation, and collagen synthesis. Eicosapentaenoic acid and docosahexaenoic acid blocked phospho-Smad2/3 nuclear translocation. DT3, a protein kinase G inhibitor, blocked the antifibrotic effects of eicosapentaenoic acid and docosahexaenoic acid. Eicosapentaenoic acid and docosahexaenoic acid increased phosphorylated endothelial nitric oxide synthase and endothelial nitric oxide synthase protein levels and nitric oxide production. CONCLUSION: Omega-3 fatty acids prevent cardiac fibrosis and cardiac dysfunction by blocking transforming growth factor beta1-induced phospho-Smad2/3 nuclear translocation through activation of the cyclic GMP/protein kinase G pathway in cardiac fibroblasts. PMID- 21282500 TI - Microsomal prostaglandin e2 synthase-1 modulates the response to vascular injury. AB - BACKGROUND: Microsomal (m) prostaglandin (PG) E2 synthase (S)-1 catalyzes the formation of PGE2 from PGH2, a cyclooxygenase product that is derived from arachidonic acid. Previous studies in mice suggest that targeting mPGES-1 may be less likely to cause hypertension or thrombosis than cyclooxygenase-2-selective inhibition or deletion in vivo. Indeed, deletion of mPGES-1 retards atherogenesis and angiotensin II-induced aortic aneurysm formation. The role of mPGES-1 in the response to vascular injury is unknown. METHODS AND RESULTS: Mice were subjected to wire injury of the femoral artery. Both neointimal area and vascular stenosis were significantly reduced 4 weeks after injury in mPGES-1 knockout mice compared with wild-type controls (65.6 +/- 5.7 versus 37.7 +/- 5.1 * 103 pixel area and 70.5 +/- 13.4% versus 47.7 +/- 17.4%, respectively; P < 0.01). Induction of tenascin-C, a proproliferative and promigratory extracellular matrix protein, after injury was attenuated in the knockouts. Consistent with in vivo rediversion of PG biosynthesis, mPGES-1-deleted vascular smooth muscle cells generated less PGE2 but more PGI2 and expressed reduced tenascin-C compared with wild-type cells. Both suppression of PGE2 and augmentation of PGI2 attenuate tenascin-C expression and vascular smooth muscle cell proliferation and migration in vitro. CONCLUSIONS: Deletion of mPGES-1 in mice attenuates neointimal hyperplasia after vascular injury, in part by regulating tenascin-C expression. This raises for consideration the therapeutic potential of mPGES-1 inhibitors as adjuvant therapy for percutaneous coronary intervention. PMID- 21282502 TI - Growth factor therapy and autologous lymph node transfer in lymphedema. AB - BACKGROUND: Lymphedema after surgery, infection, or radiation therapy is a common and often incurable problem. Application of lymphangiogenic growth factors has been shown to induce lymphangiogenesis and to reduce tissue edema. The therapeutic effect of autologous lymph node transfer combined with adenoviral growth factor expression was evaluated in a newly established porcine model of limb lymphedema. METHODS AND RESULTS: The lymphatic vasculature was destroyed within a 3-cm radius around an inguinal lymph node. Lymph node grafts and adenovirally (Ad) delivered vascular endothelial growth factor (VEGF)-C (n=5) or VEGF-D (n=9) were used to reconstruct the lymphatic network in the inguinal area; AdLacZ (beta-galactosidase; n=5) served as a control. Both growth factors induced robust growth of new lymphatic vessels in the defect area, and postoperative lymphatic drainage was significantly improved in the VEGF-C/D-treated pigs compared with controls. The structure of the transferred lymph nodes was best preserved in the VEGF-C-treated pigs. Interestingly, VEGF-D transiently increased accumulation of seroma fluid in the operated inguinal region postoperatively, whereas VEGF-C did not have this side effect. CONCLUSIONS: These results show that growth factor gene therapy coupled with lymph node transfer can be used to repair damaged lymphatic networks in a large animal model and provide a basis for future clinical trials of the treatment of lymphedema. PMID- 21282501 TI - Inhaled nitrite reverses hemolysis-induced pulmonary vasoconstriction in newborn lambs without blood participation. AB - BACKGROUND: Nitrite can be converted to nitric oxide (NO) by a number of different biochemical pathways. In newborn lambs, an aerosol of inhaled nitrite has been found to reduce pulmonary blood pressure, possibly acting via conversion to NO by reaction with intraerythrocytic deoxyhemoglobin. If so, the vasodilating effects of nitrite would be attenuated by free hemoglobin in plasma that would rapidly scavenge NO. METHODS AND RESULTS: Pulmonary vascular pressures and resistances to flow were measured in anesthetized newborn lambs. Plasma hemoglobin concentrations were then elevated, resulting in marked pulmonary hypertension. This effect was attenuated if infused hemoglobin was first oxidized to methemoglobin, which does not scavenge NO. These results further implicate NO as a tonic pulmonary vasodilator. Next, while free hemoglobin continued to be infused, the lambs were given inhaled NO gas (20 ppm), inhaled sodium nitrite aerosol (0.87 mol/L), or an intravascular nitrite infusion (3 mg/h bolus, 5 mg . kg-1 . h-1 infusion). Inhaled NO and inhaled nitrite aerosol both resulted in pulmonary vasodilation. Intravascular infusion of nitrite, however, did not. Increases in exhaled NO gas were observed in lambs while breathing the nitrite aerosol (~ 20 ppb NO) but not during intravascular infusion of nitrite. CONCLUSIONS: We conclude that the pulmonary vasodilating effect of inhaled nitrite results from its conversion to NO in airway and parenchymal lung tissue and is not dependent on reactions with deoxyhemoglobin in the pulmonary circulation. Inhaled nitrite aerosol remains a promising candidate to reduce pulmonary hypertension in clinical application. PMID- 21282503 TI - Effect of timing of chronic preoperative aspirin discontinuation on morbidity and mortality in coronary artery bypass surgery. AB - BACKGROUND: Aspirin (ASA) has been shown to reduce postoperative coronary artery bypass grafting (CABG) mortality and ischemic events; however, the timing of chronic ASA discontinuation before surgery is controversial because of concern about postoperative bleeding. We evaluated the effect of the timing of ASA discontinuation before CABG on major adverse cardiovascular outcomes and postoperative bleeding using the Cleveland Clinic Cardiovascular Information Registry database. METHODS AND RESULTS: At the Cleveland Clinic between January 1, 2002, and January 31, 2008, 4143 patients undergoing CABG were taking preoperative chronic ASA. Of these, 2298 discontinued ASA 6 or more days before surgery (early discontinuation), and 1845 took ASA within 5 days of the surgery (late use). Because of substantial differences between these 2 groups, propensity score analysis, and matching based on 31 variables were used for fair comparison of outcomes. This resulted in 1519 well-matched pairs of patients (73%). There was no significant difference between those with early discontinuation and late ASA use with regard to the composite outcome of in-hospital mortality, myocardial infarction, and stroke (1.7% versus 1.8%, P=0.80). Late use was associated with more intraoperative transfusions (23% versus 20%, P=0.03) and postoperative transfusions (30% versus 26%, P=0.009) but a similar number of reoperations for bleeding (3.4% versus 2.4% P=0.10). CONCLUSIONS: Among patients undergoing isolated CABG, late discontinuation of ASA resulted in no difference in postoperative cardiovascular outcomes; however, there was an increased transfusion requirement. Thus, we recommend weighing the risks and benefits of late ASA use in these patients. PMID- 21282504 TI - 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American Stroke Association, American Association of Neuroscience Nurses, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Congress of Neurological Surgeons, Society of Atherosclerosis Imaging and Prevention, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, Society for Vascular Medicine, and Society for Vascular Surgery. PMID- 21282505 TI - 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease: executive summary. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American Stroke Association, American Association of Neuroscience Nurses, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Congress of Neurological Surgeons, Society of Atherosclerosis Imaging and Prevention, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, Society for Vascular Medicine, and Society for Vascular Surgery. PMID- 21282506 TI - Individual genetic variations directly effect polarization of cytokine responses to superantigens associated with streptococcal sepsis: implications for customized patient care. AB - Host immunogenetic variations strongly influence the severity of group A streptococcus sepsis by modulating responses to streptococcal superantigens (Strep-SAgs). Although HLA-II-DR15/DQ6 alleles strongly protect against severe sepsis, HLA-II-DR14/DR7/DQ5 alleles significantly increase the risk for toxic shock syndrome. We found that, regardless of individual variations in TCR-Vbeta repertoires, the presentation of Strep-SAgs by the protective HLA-II-DR15/DQ6 alleles significantly attenuated proliferative responses to Strep-SAgs, whereas their presentation by the high-risk alleles augmented it. Importantly, HLA-II variations differentially polarized cytokine responses to Strep-SAgs: the presentation of Strep-SAgs by HLA-II-DR15/DQ6 alleles elicited significantly higher ratios of anti-inflammatory cytokines (e.g., IL-10) to proinflammatory cytokines (e.g., IFN-gamma) than did their presentation by the high-risk HLA-II alleles. Adding exogenous rIL-10 significantly attenuated responses to Strep-SAgs presented by the high-risk HLA-II alleles but did not completely block the response; instead, it reduced it to a level comparable to that seen when these superantigens were presented by the protective HLA-II alleles. Furthermore, adding neutralizing anti-IL-10 Abs augmented Strep-SAg responses in the presence of protective HLA-II alleles to the same level as (but no higher than) that seen when the superantigens were presented by the high-risk alleles. Our findings provide a molecular basis for the role of HLA-II allelic variations in modulating streptococcal sepsis outcomes and suggest the presence of an internal control mechanism that maintains superantigen responses within a defined range, which helps to eradicate the infection while attenuating pathological inflammatory responses that can inflict more harm than the infection itself. PMID- 21282507 TI - A common haplotype of the TNF receptor 2 gene modulates endotoxin tolerance. AB - Endotoxin tolerance is characterized by the suppression of further TNF release upon recurrent exposure to LPS. This phenomenon is proposed to act as a homeostatic mechanism preventing uncontrolled cytokine release such as that observed in bacterial sepsis. The regulatory mechanisms and interindividual variation of endotoxin tolerance induction in man remain poorly characterized. In this paper, we describe a genetic association study of variation in endotoxin tolerance among healthy individuals. We identify a common promoter haplotype in TNFRSF1B (encoding TNFR2) to be strongly associated with reduced tolerance to LPS (p = 5.82 * 10(-6)). This identified haplotype is associated with increased expression of TNFR2 (p = 4.9 * 10(-5)), and we find basal expression of TNFR2, irrespective of genotype and unlike TNFR1, is associated with secondary TNF release (p < 0.0001). Functional studies demonstrate a positive-feedback loop via TNFR2 of LPS-induced TNF release, confirming this previously unrecognized role for TNFR2 in the modulation of LPS response. PMID- 21282508 TI - TLR2 hypersensitivity of astrocytes as functional consequence of previous inflammatory episodes. AB - Precedent inflammatory episodes may drastically modify the function and reactivity of cells. We investigated whether priming of astrocytes by microglia derived cytokines alters their subsequent reaction to pathogen-associated danger signals not recognized in the quiescent state. Resting primary murine astrocytes expressed little TLR2, and neither the TLR2/6 ligand fibroblast-stimulating lipopeptide-1 (FSL1) nor the TLR1/2 ligand Pam(3)CysSK(4) (P3C) triggered NF kappaB translocation or IL-6 release. We made use of single-cell detection of NF kappaB translocation as easily detectable and sharply regulated upstream indicator of an inflammatory response or of c-Jun phosphorylation to measure restimulation events in astrocytes under varying conditions. Cells prestimulated with IL-1beta, with a TLR3 ligand, with a complete cytokine mix consisting of TNF alpha, IL-1beta, and IFN-gamma, or with media conditioned by activated microglia responded strongly to FSL1 or P3C stimulation, whereas the sensitivity of the NF kappaB response to other pattern recognition receptors was unchanged. This sensitization to TLR2 ligands was associated with an initial upregulation of TLR2, displayed a "memory" window of several days, and was largely independent of the length of prestimulation. The altered signaling led to altered function, as FSL1 or P3C triggered the release of IL-6, CCL-20, and CXCL-2 in primed cells, but not in resting astrocytes. These data confirmed the hypothesis that astrocytes exposed to activated microglia assume a different functional phenotype involving longer term TLR2 responsiveness, even after the initial stimulation by inflammatory mediators has ended. PMID- 21282509 TI - Conventional dendritic cells mount a type I IFN response against Candida spp. requiring novel phagosomal TLR7-mediated IFN-beta signaling. AB - Human fungal pathogens such as the dimorphic Candida albicans or the yeast-like Candida glabrata can cause systemic candidiasis of high mortality in immunocompromised individuals. Innate immune cells such as dendritic cells and macrophages establish the first line of defense against microbial pathogens and largely determine the outcome of infections. Among other cytokines, they produce type I IFNs (IFNs-I), which are important modulators of the host immune response. Whereas an IFN-I response is a hallmark immune response to bacteria and viruses, a function in fungal pathogenesis has remained unknown. In this study, we demonstrate a novel mechanism mediating a strong IFN-beta response in mouse conventional dendritic cells challenged by Candida spp., subsequently orchestrating IFN-alpha/beta receptor 1-dependent intracellular STAT1 activation and IFN regulatory factor (IRF) 7 expression. Interestingly, the initial IFN-beta release bypasses the TLR 4 and TLR2, the TLR adaptor Toll/IL-1R domain-containing adapter-inducing IFN-beta and the beta-glucan/phagocytic receptors dectin-1 and CD11b. Notably, Candida-induced IFN-beta release is strongly impaired by Src and Syk family kinase inhibitors and strictly requires completion of phagocytosis as well as phagosomal maturation. Strikingly, TLR7, MyD88, and IRF1 are essential for IFN-beta signaling. Furthermore, in a mouse model of disseminated candidiasis we show that IFN-I signaling promotes persistence of C. glabrata in the host. Our data uncover for the first time a pivotal role for endosomal TLR7 signaling in fungal pathogen recognition and highlight the importance of IFNs-I in modulating the host immune response to C. glabrata. PMID- 21282510 TI - Naive T cell repertoire skewing in HLA-A2 individuals by a specialized rearrangement mechanism results in public memory clonotypes. AB - How the naive T cell repertoire arises and forms the memory repertoire is still poorly understood. This relationship was analyzed by taking advantage of the focused TCR usage in HLA-A2-restricted CD8 memory T cell responses to influenza M1(58-66). We analyzed rearranged BV19 genes from CD8 single-positive thymocytes, a surrogate for the naive repertoire, from 10 HLA-A2 individuals. CDR3 amino acid sequences associated with response to influenza were observed at higher frequencies than expected by chance, an indicator of preselection. We propose that a rearrangement mechanism involving long P-nucleotide addition from the J2.7 region explains part of this increase. Special rearrangement mechanisms can result in identical T cells in different individuals, referred to as public responses. Indeed, the rearrangements utilizing long P nucleotide additions were commonly observed in the response to the M1(58-66) epitope in 30 HLA-A2 middle aged adults. Thus, in addition to negative and positive selection, special rearrangement mechanisms may influence the composition of the naive repertoire, resulting in more robust responses to a pathogen in some individuals. PMID- 21282511 TI - IL-6 trans-signaling system in intra-amniotic inflammation, preterm birth, and preterm premature rupture of the membranes. AB - Classic IL-6 signaling is conditioned by the transmembrane receptor (IL-6R) and homodimerization of gp130. During trans-signaling, IL-6 binds to soluble IL-6R (sIL-6R), enabling activation of cells expressing solely gp130. Soluble gp130 (sgp130) selectively inhibits IL-6 trans-signaling. To characterize amniotic fluid (AF) IL-6 trans-signaling molecules (IL-6, sIL-6R, sgp130) in normal gestations and pregnancies complicated by intra-amniotic inflammation (IAI), we studied 301 women during second trimester (n = 39), third trimester (n = 40), and preterm labor with intact (n = 131, 85 negative IAI and 46 positive IAI) or preterm premature rupture of membranes (PPROM; n = 91, 61 negative IAI and 30 positive IAI). ELISA, Western blotting, and real-time RT-PCR were used to investigate AF, placenta, and amniochorion for protein and mRNA expression of sIL 6R, sgp130, IL-6R, and gp130. Tissues were immunostained for IL-6R, gp130, CD15(+) (polymorphonuclear), and CD3(+) (T cell) inflammatory cells. The ability of sIL-6R and sgp130 to modulate basal and LPS-stimulated release of amniochorion matrix metalloprotease-9 was tested ex vivo. We showed that in physiologic gestations, AF sgp130 decreases toward term. AF IL-6 and sIL-6R were increased in IAI, whereas sgp130 was decreased in PPROM. Our results suggested that fetal membranes are the probable source of AF sIL-6R and sgp130. Immunohistochemistry and RT-PCR revealed increased IL-6R and decreased gp130 expression in amniochorion of women with IAI. Ex vivo, sIL-6R and LPS augmented amniochorion matrix metalloprotease-9 release, whereas sgp130 opposed this effect. We conclude that IL-6 trans-signaling molecules are physiologic constituents of the AF regulated by gestational age and inflammation. PPROM likely involves functional loss of sgp130. PMID- 21282512 TI - Induction and maintenance of IL-4 expression are regulated differently by the 3' enhancer in CD4 T cells. AB - IL-4 expression is known to be activated in CD4 T cells when they are differentiated to Th2 but not Th1 cells. However, CD4 T cells selected by MH class II-expressing thymocytes, named thymocyte-selected CD4 T cells (T-CD4 T cells), express IL-4 under both Th1 and Th2 conditions. In this study, we investigated molecular mechanisms by which IL-4 gene expression is regulated in T CD4 T cells. We found that T-CD4 T cells express IL-4 soon after selection in the thymus. Deficiency of DNase I hypersensitive (HS) sites HS5a and HS5 at the 3' enhancer region in the IL-4 gene decreased IL-4 production, but T-CD4 T cells were able to make IL-4 under the Th1-inducing condition. Consistent with this, IL 4 was expressed in Th1 differentiated T-CD4 T cells in the absence of recombination signal binding protein-J that interacts with HS5. When HS5 was examined separately from other endogenous regulatory elements using a reporter system, CD4 T cells that are selected by thymic epithelial cells cannot transcribe the IL-4 reporter gene with HS5 alone. However, HS5 was able to induce the expression of the IL-4 reporter gene in T-CD4 T cells. Interestingly, the Th1 differentiating signal led to deacetylation at HS5 of the IL-4 endogenous gene, whereas the Th2-inducing environment had no effect. Therefore, in T-CD4 T cells, HS5 plays an essential role during the induction phase of IL-4 expression, but the maintenance of IL-4 expression in Th1 cells requires additional regulatory elements. PMID- 21282513 TI - Molecular characterization of caveolin-1 in pigs infected with Haemophilus parasuis. AB - Caveolin-1 (Cav1) plays a critical role in the invasion of pathogenic microbes into host cells, yet little is known about porcine Cav1. In this study, we provide the molecular characterization of Cav1 in pigs following stimulation with LPS/polyinosinic-polycytidylic acid as well as during infection with Haemophilus parasuis. The porcine Cav1 gene is 35 kb long and is located at SSC18q21; two isoforms (Cav1-alpha and Cav1-beta) are produced by alternative splicing. Three point mutations were identified in the coding region of the gene, two of which were significantly associated with nine immunological parameters in Landrace pigs, including the Ab response against porcine reproductive and respiratory syndrome virus and lymphocyte counts. Promoter analysis indicated that NF-kappaB activates both Cav1 transcripts, but the forkhead gene family specifically regulates Cav1-beta in the pig. Porcine Cav1 is expressed ubiquitously, with Cav1 alpha more abundantly expressed than Cav1-beta in all tissues investigated. Basal expression levels of Cav1 in PBMCs are relatively similar across different pig breeds. LPS and polyinosinic-polycytidylic acid markedly induced the expression of Cav1 in porcine kidney-15 cells in vitro, likely through NF-kappaB activation. Pigs infected with H. parasuis exhibited decreased expression of Cav1, particularly in seriously impaired organs such as the brain. This study provides new evidence that supports the use of Cav1 as a potential diagnostic and genetic marker for disease resistance in animal breeding. In addition, our results suggest that Cav1 may be implicated in the pathogenesis of Glasser's disease, which is caused by H. parasuis. PMID- 21282514 TI - IL-17A and TNF-alpha exert synergistic effects on expression of CXCL5 by alveolar type II cells in vivo and in vitro. AB - CXCL5, a member of the CXC family of chemokines, contributes to neutrophil recruitment during lung inflammation, but its regulation is poorly understood. Because the T cell-derived cytokine IL-17A enhances host defense by triggering production of chemokines, particularly in combination with TNF-alpha, we hypothesized that IL-17A would enhance TNF-alpha-induced expression of CXCL5. Intratracheal coadministration of IL-17A and TNF-alpha in mice induced production of CXCL1, CXCL2, and CXCL5, which was associated with increased neutrophil influx in the lung at 8 and 24 h. The synergistic effects of TNF-alpha and IL17A were greatly attenuated in Cxcl5(-/-) mice at 24 h, but not 8 h, after exposure, a time when CXCL5 expression was at its peak in wild-type mice. Bone marrow chimeras produced using Cxcl5(-/-) donors and recipients demonstrated that lung resident cells were the source of CXCL5. Using differentiated alveolar epithelial type II (ATII) cells derived from human fetal lung, we found that IL-17A enhanced TNF-alpha-induced CXCL5 transcription and stabilized TNF-alpha-induced CXCL5 transcripts. Whereas expression of CXCL5 required activation of NF-kappaB, IL-17A did not increase TNF-alpha-induced NF-kappaB activation. Apical costimulation of IL-17A and TNF-alpha provoked apical secretion of CXCL5 by human ATII cells in a transwell system, whereas basolateral costimulation led to both apical and basolateral secretion of CXCL5. The observation that human ATII cells secrete CXCL5 in a polarized fashion may represent a mechanism to recruit neutrophils in host defense in a fashion that discriminates the site of initial injury. PMID- 21282515 TI - Role of two adaptor molecules SLP-76 and LAT in the PI3K signaling pathway in activated T cells. AB - Previously, we identified p85, a subunit of PI3K, as one of the molecules that interacts with the N-terminal region of Src homology 2 domain-containing leukocyte protein of 76 kDa (SLP-76). We also demonstrated that tyrosine phosphorylation either at the 113 and/or 128 position is sufficient for the association of SLP-76 with the Src homology 2 domain near the N terminus of p85. The present study further examines the role of the association of these two molecules on the activation of PI3K signaling cascade. Experiments were done to determine the role of SLP-76, either wild-type, tyrosine mutants, or membrane targeted forms of various SLP-76 constructs, on the membrane localization and phosphorylation of Akt, which is an event downstream of PI3K activation. Reconstitution studies with these various SLP-76 constructs in a Jurkat variant cell line that lacks SLP-76 or linker for activation of T cells (LAT) show that the activation of PI3K pathway following TCR ligation requires both SLP-76 and LAT adaptor proteins. The results suggest that SLP-76 associates with p85 after T cell activation and that LAT recruits this complex to the membrane, leading to Akt activation. PMID- 21282516 TI - Conformational melding permits a conserved binding geometry in TCR recognition of foreign and self molecular mimics. AB - Molecular mimicry between foreign and self Ags is a mechanism of TCR cross reactivity and is thought to contribute to the development of autoimmunity. The alphabeta TCR A6 recognizes the foreign Ag Tax from the human T cell leukemia virus-1 when presented by the class I MHC HLA-A2. In a possible link with the autoimmune disease human T cell leukemia virus-1-associated myelopathy/tropical spastic paraparesis, A6 also recognizes a self peptide from the neuronal protein HuD in the context of HLA-A2. We found in our study that the complexes of the HuD and Tax epitopes with HLA-A2 are close but imperfect structural mimics and that in contrast with other recent structures of TCRs with self Ags, A6 engages the HuD Ag with the same traditional binding mode used to engage Tax. Although peptide and MHC conformational changes are needed for recognition of HuD but not Tax and the difference of a single hydroxyl triggers an altered TCR loop conformation, TCR affinity toward HuD is still within the range believed to result in negative selection. Probing further, we found that the HuD-HLA-A2 complex is only weakly stable. Overall, these findings help clarify how molecular mimicry can drive self/nonself cross-reactivity and illustrate how low peptide MHC stability can permit the survival of T cells expressing self-reactive TCRs that nonetheless bind with a traditional binding mode. PMID- 21282517 TI - TCR mimic monoclonal antibodies induce apoptosis of tumor cells via immune effector-independent mechanisms. AB - mAbs that recognize peptides presented on the cell surface by MHC class I molecules are potential therapeutic agents for cancer therapy. We have previously demonstrated that these Abs, which we termed TCR mimic mAbs (TCRm), reduce tumor growth in models of breast carcinoma. However, mechanisms of TCRm-mediated tumor growth reduction remain largely unknown. In this study, we report that these Abs, in contrast to several mAbs used currently in the clinic, destroy tumor cells independently of immune effector mechanisms such as Ab-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). We found that TCRm-mediated apoptosis of tumor cells was associated with selective and specific binding of these Abs to peptide/HLA class I complexes, which triggered the activation of JNK and intrinsic caspase pathways. This signaling was accompanied by the release of mitochondrial cytochrome c and apoptosis-inducing factor. TCRm induced apoptosis in tumor cells was completely inhibited by soluble MHC tetramers loaded with relevant peptide as well as with inhibitors for JNK and caspases. Furthermore, mAbs targeting MHC class I, independent of the peptide bound by HLA, did not stimulate apoptosis, suggesting that the Ab-binding site on the MHC/peptide complex determines cytotoxicity. This study suggests the existence of mechanisms, in addition to ADCC and CDC, through which these therapeutic Abs destroy tumor cells. These mechanisms would appear to be of particular importance in severely immunocompromised patients with advanced neoplastic disease, since immune cell-mediated killing of tumor cells through ADCC and CDC is substantially limited in these individuals. PMID- 21282518 TI - Echo-guided pericardiocentesis: let the bubbles show the way. PMID- 21282519 TI - Letter by Fearon regarding article, "Primary coronary microvascular dysfunction: clinical presentation, pathophysiology, and management". PMID- 21282521 TI - Predicting benefit from revascularization in patients with ischemic heart failure: imaging of myocardial ischemia and viability. PMID- 21282520 TI - Cardiovascular molecular imaging: focus on clinical translation. PMID- 21282522 TI - Multisite infective endocarditis with mural vegetations in the right atrium and right ventricle. PMID- 21282524 TI - The pea GIGAS gene is a FLOWERING LOCUS T homolog necessary for graft transmissible specification of flowering but not for responsiveness to photoperiod. AB - Garden pea (Pisum sativum) was prominent in early studies investigating the genetic control of flowering and the role of mobile flowering signals. In view of recent evidence that genes in the FLOWERING LOCUS T (FT) family play an important role in generating mobile flowering signals, we isolated the FT gene family in pea and examined the regulation and function of its members. Comparison with Medicago truncatula and soybean (Glycine max) provides evidence of three ancient subclades (FTa, FTb, and FTc) likely to be common to most crop and model legumes. Pea FT genes show distinctly different expression patterns with respect to developmental timing, tissue specificity, and response to photoperiod and differ in their activity in transgenic Arabidopsis thaliana, suggesting they may have different functions. We show that the pea FTa1 gene corresponds to the GIGAS locus, which is essential for flowering under long-day conditions and promotes flowering under short-day conditions but is not required for photoperiod responsiveness. Grafting, expression, and double mutant analyses show that GIGAS/FTa1 regulates a mobile flowering stimulus but also provide clear evidence for a second mobile flowering stimulus that is correlated with expression of FTb2 in leaf tissue. These results suggest that induction of flowering by photoperiod in pea results from interactions among several members of a diversified FT family. PMID- 21282525 TI - Pollen semi-sterility1 encodes a kinesin-1-like protein important for male meiosis, anther dehiscence, and fertility in rice. AB - In flowering plants, male meiosis produces four microspores, which develop into pollen grains and are released by anther dehiscence to pollinate female gametophytes. The molecular and cellular mechanisms regulating male meiosis in rice (Oryza sativa) remain poorly understood. Here, we describe a rice pollen semi-sterility1 (pss1) mutant, which displays reduced spikelet fertility (~40%) primarily caused by reduced pollen viability (~50% viable), and defective anther dehiscence. Map-based molecular cloning revealed that PSS1 encodes a kinesin-1 like protein. PSS1 is broadly expressed in various organs, with highest expression in panicles. Furthermore, PSS1 expression is significantly upregulated during anther development and peaks during male meiosis. The PSS1-green fluorescent protein fusion is predominantly localized in the cytoplasm of rice protoplasts. Substitution of a conserved Arg (Arg-289) to His in the PSS1 motor domain nearly abolishes its microtubule-stimulated ATPase activity. Consistent with this, lagging chromosomes and chromosomal bridges were found at anaphase I and anaphase II of male meiosis in the pss1 mutant. Together, our results suggest that PSS1 defines a novel member of the kinesin-1 family essential for male meiotic chromosomal dynamics, male gametogenesis, and anther dehiscence in rice. PMID- 21282526 TI - The FRIGIDA complex activates transcription of FLC, a strong flowering repressor in Arabidopsis, by recruiting chromatin modification factors. AB - The flowering of Arabidopsis thaliana winter annuals is delayed until the subsequent spring by the strong floral repressor FLOWERING LOCUS C (FLC). FRIGIDA (FRI) activates the transcription of FLC, but the molecular mechanism remains elusive. The fri mutation causes early flowering with reduced FLC expression similar to frl1, fes1, suf4, and flx, which are mutants of FLC-specific regulators. Here, we report that FRI acts as a scaffold protein interacting with FRL1, FES1, SUF4, and FLX to form a transcription activator complex (FRI-C). Each component of FRI-C has a specialized function. SUF4 binds to a cis-element of the FLC promoter, FLX and FES1 have transcriptional activation potential, and FRL1 and FES1 stabilize the complex. FRI-C recruits a general transcription factor, a TAF14 homolog, and chromatin modification factors, the SWR1 complex and SET2 homolog. Complex formation was confirmed by the immunoprecipitation of FRI associated proteins followed by mass spectrometric analysis. Our results provide insight into how a specific transcription activator recruits chromatin modifiers to regulate a key flowering gene. PMID- 21282527 TI - Chilling of dormant buds hyperinduces FLOWERING LOCUS T and recruits GA-inducible 1,3-beta-glucanases to reopen signal conduits and release dormancy in Populus. AB - In trees, production of intercellular signals and accessibility of signal conduits jointly govern dormancy cycling at the shoot apex. We identified 10 putative cell wall 1,3-beta-glucanase genes (glucan hydrolase family 17 [GH17]) in Populus that could turn over 1,3-beta-glucan (callose) at pores and plasmodesmata (PD) and investigated their regulation in relation to FT and CENL1 expression. The 10 genes encode orthologs of Arabidopsis thaliana BG_ppap, a PD associated glycosylphosphatidylinositol (GPI) lipid-anchored protein, the Arabidopsis PD callose binding protein PDCB, and a birch (Betula pendula) putative lipid body (LB) protein. We found that these genes were differentially regulated by photoperiod, by chilling (5 degrees C), and by feeding of gibberellins GA(3) and GA(4). GA(3) feeding upregulated all LB-associated GH17s, whereas GA(4) upregulated most GH17s with a GPI anchor and/or callose binding motif, but only GA(4) induced true bud burst. Chilling upregulated a number of GA biosynthesis and signaling genes as well as FT, but not CENL1, while the reverse was true for both GA(3) and GA(4). Collectively, the results suggest a model for dormancy release in which chilling induces FT and both GPI lipid-anchored and GA(3)-inducible GH17s to reopen signaling conduits in the embryonic shoot. When temperatures rise, the reopened conduits enable movement of FT and CENL1 to their targets, where they drive bud burst, shoot elongation, and morphogenesis. PMID- 21282528 TI - Dose-response study of mobilisation and tactile stimulation therapy for the upper extremity early after stroke: a phase I trial. AB - BACKGROUND: Physical therapy doses may need to be higher than provided in current clinical practice, especially for patients with severe paresis. The authors aimed to find the most effective and feasible dose of Mobilisation and Tactile Stimulation (MTS), which includes joint and soft-tissue mobilization and passive or active-assisted movement to enhance voluntary muscle contraction. METHODS: This 2-center, randomized, controlled, observer-blinded feasibility trial compared conventional rehabilitation but no extra therapy (group 1) with conventional therapy plus 1 of 3 daily doses of MTS, up to 30 (group 2), 60 (group 3), or 120 (group 4) minutes for 14 days. The 76 participants had substantial paresis (Motricity Index [MI] < 61) a mean of 30 days (standard deviation [SD] = 20 days) after anterior circulation stroke. MTS was delivered using a standardized schedule of techniques (eg, sensory input, active-assisted movement). The primary outcome was the Motricity Index (MI) and secondary outcome was the Action Research Arm Test (ARAT) tested on day 16. Adverse events were monitored daily. RESULTS: No difference was found in the change in control group MI compared with each of the 3 intervention groups (P = .593) or in the ARAT. Mean actual daily treatment time for all MTS groups was less than expected. The attrition rate was 1.3%. No adverse events related to overuse occurred. CONCLUSION: The authors were not able to deliver a maximum dose of 120 minutes of daily therapy each day. The mean daily dose of MTS feasible for subsequent evaluation is between 37 and 66 minutes. PMID- 21282530 TI - Interaction proteomics analysis of polycomb proteins defines distinct PRC1 complexes in mammalian cells. AB - Polycomb group (PcG) proteins maintain transcriptional repression of hundreds of genes involved in development, signaling or cancer using chromatin-based epigenetic mechanisms. Biochemical studies in Drosophila have revealed that PcG proteins associate in at least two classes of protein complexes known as Polycomb repressive complexes 1 and 2 (PRC1 and PRC2). Drosophila core PRC1 is composed of four subunits, Polycomb (Pc), Sex combs extra (Sce), Polyhomeotic (Ph), and Posterior sex combs (Psc). Each of these proteins has multiple orthologs in vertebrates classified respectively as the CBX, RING1/RNF2, PHC, and BMI1/PCGF families. Mammalian genomes encode five CBX family members (CBX2, CBX4, CBX6, CBX7, and CBX8) that are believed to have distinct biological functions. Here, we applied a tandem affinity purification (TAP) approach coupled with tandem mass spectrometry (MS/MS) methodologies in order to identify interacting partners of CBX family proteins under the same experimental conditions. Our analysis identified with high confidence about 20 proteins co-eluted with CBX2 and CBX7 tagged proteins, about 40 with CBX4, and around 60 with CBX6 and CBX8. We provide evidences that the CBX family proteins are mutually exclusive and define distinct PRC1-like protein complexes. CBX proteins also interact with different efficiencies with the other PRC1 components. Among the novel CBX interacting partners, protein kinase 2 associates with all CBX-PRC1 protein complexes, whereas 14-3-3 proteins specifically bind to CBX4. 14-3-3 protein binding to CBX4 appears to modulate the interaction between CBX4 and the BMI1/PCGF components of PRC1, but has no effect on CBX4-RING1/RNF2 interaction. Finally, we suggest that differences in CBX protein interactions would account, at least in part, for distinct subnuclear localization of the CBX family members. PMID- 21282531 TI - Pre-enucleation chemotherapy for eyes severely affected by retinoblastoma masks risk of tumor extension and increases death from metastasis. AB - PURPOSE: Initial response of intraocular retinoblastoma to chemotherapy has encouraged primary chemotherapy instead of primary enucleation for eyes with clinical features suggesting high risk of extraocular extension or metastasis. Upfront enucleation of such high-risk eyes allows pathologic evaluation of extraocular extension, key to management with appropriate surveillance and adjuvant therapy. Does chemotherapy before enucleation mask histologic features of extraocular extension, potentially endangering the child's life by subsequent undertreatment? METHODS: We performed retrospective analysis of 100 eyes with advanced retinoblastoma enucleated with, or without, primary chemotherapy, in Beijing Tongren Hospital, retrospectively, from October 31, 2008. The extent of retinoblastoma invasion into optic nerve, uvea, and anterior chamber on histopathology was staged by pTNM classification. The treatment groups were compared for pathologic stage (Cochran-Armitage trend test) and disease-specific mortality (competing risks methods). RESULTS: Children who received chemotherapy before enucleation had lower pTNM stage than primarily enucleated children (P = .01). Five patients who received pre-enucleation chemotherapy died as a result of extension into brain or metastasis. No patients who had primary enucleation died. For children with group E eyes, disease-specific survival (DSS) was lower with pre-enucleation chemotherapy (n = 45) than with primary enucleation (n = 37; P = .01). Enucleation longer than 3 months after diagnosis was also associated with lower DSS (P < .001). CONCLUSION: Chemotherapy before enucleation of group E eyes with advanced retinoblastoma downstaged pathologic evidence of extraocular extension, and increased the risk of metastatic death from reduced surveillance and inappropriate management of high-risk disease, if enucleation was performed longer than 3 months after diagnosis. PMID- 21282532 TI - Carboplatin in clinical stage I seminoma: too much and too little at the same time. PMID- 21282533 TI - Neoadjuvant concurrent chemoradiation for advanced esthesioneuroblastoma: a case series and review of the literature. PMID- 21282534 TI - Was [18F]fluorodeoxyglucose positron emission tomography complete response after chemoradiotherapy defined as standardized uptake value(max-1 hour) <= 3 complete? PMID- 21282535 TI - Impact of pretransplantation minimal residual disease, as detected by multiparametric flow cytometry, on outcome of myeloablative hematopoietic cell transplantation for acute myeloid leukemia. AB - PURPOSE: Allogeneic hematopoietic cell transplantation (HCT) benefits many patients with acute myeloid leukemia (AML) in first remission. Hitherto, little attention has been given to the prognostic impact of pretransplantation minimal residual disease (MRD). PATIENTS AND METHODS: We retrospectively studied 99 consecutive patients receiving myeloablative HCT for AML in first morphologic remission. Ten-color multiparametric flow cytometry (MFC) was performed on bone marrow aspirates before HCT. MRD was identified as a cell population showing deviation from normal antigen expression patterns compared with normal or regenerating marrow. Any level of residual disease was considered MRD positive. RESULTS: Before HCT, 88 patients met morphologic criteria for complete remission (CR), whereas 11 had CR with incomplete blood count recovery (CRi). Twenty-four had MRD before HCT as determined by MFC. Two-year estimates of overall survival were 30.2% (range, 13.1% to 49.3%) and 76.6% (range, 64.4% to 85.1%) for MRD positive and MRD-negative patients; 2-year estimates of relapse were 64.9% (range, 42.0% to 80.6%) and 17.6% (range, 9.5% to 27.9%). After adjustment for all or a subset of cytogenetic risk, secondary disease, incomplete blood count recovery, and abnormal karyotype pre-HCT, MRD-positive HCT was associated with increased overall mortality (hazard ratio [HR], 4.05; 95% CI, 1.90 to 8.62; P < .001) and relapse (HR, 8.49; 95% CI, 3.67 to 19.65; P < .001) relative to MRD negative HCT. CONCLUSION: These data suggest that pre-HCT MRD is associated with increased risk of relapse and death after myeloablative HCT for AML in first morphologic CR, even after controlling for other risk factors. PMID- 21282536 TI - Supporting clinical practice decisions with real-time patient-reported outcomes. PMID- 21282537 TI - Vandetanib plus pemetrexed for the second-line treatment of advanced non-small cell lung cancer: a randomized, double-blind phase III trial. AB - PURPOSE: Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling. This randomized, placebo-controlled phase III study assessed the efficacy of vandetanib plus pemetrexed as second-line therapy in advanced non-small-cell lung cancer. PATIENTS AND METHODS: Patients (N = 534) were randomly assigned to receive vandetanib 100 mg/d plus pemetrexed 500 mg/m(2) every 21 days (n = 256) or placebo plus pemetrexed (n = 278). Progression-free survival (PFS) was the primary end point; overall survival, objective response rate, disease control rate, time to deterioration of symptoms, and safety were secondary assessments. RESULTS: There was no significant difference in PFS between treatment arms (hazard ratio [HR], 0.86; 97.58% CI, 0.69 to 1.06; P = .108). Overall survival was also not significantly different (HR, 0.86; 97.54% CI, 0.65 to 1.13; P = .219). Statistically significant improvements in objective response rate (19% v 8%; P < .001) and time to deterioration of symptoms (HR, 0.71; P = .0052; median, 18.1 weeks for vandetanib and 12.1 weeks for placebo) were observed in patients receiving vandetanib. Adding vandetanib to pemetrexed increased the incidence of some adverse events, including rash, diarrhea, and hypertension, while showing a reduced incidence of nausea, vomiting, anemia, fatigue, and asthenia with no reduction in the dose intensity of pemetrexed. CONCLUSION: This study did not meet the primary end point of statistically significant PFS prolongation with vandetanib plus pemetrexed versus placebo plus pemetrexed. The vandetanib combination showed a significantly higher objective response rate and a significant delay in the time to worsening of lung cancer symptoms versus the placebo arm as well as an acceptable safety profile in this patient population. PMID- 21282538 TI - Spontaneous tumor lysis syndrome presenting as acute renal failure in an adult with de novo aleukemic T-ALL: value of renal biopsy? PMID- 21282539 TI - Randomized trial of carboplatin versus radiotherapy for stage I seminoma: mature results on relapse and contralateral testis cancer rates in MRC TE19/EORTC 30982 study (ISRCTN27163214). AB - PURPOSE: Initial results of a randomized trial comparing carboplatin with radiotherapy (RT) as adjuvant treatment for stage I seminoma found carboplatin had a noninferior relapse-free rate (RFR) and had reduced contralateral germ cell tumors (GCTs) in the short-term. Updated results with a median follow-up of 6.5 years are now reported. PATIENTS AND METHODS: Random assignment was between RT and one infusion of carboplatin dosed at 7 * (glomerular filtration rate + 25) on the basis of EDTA (n = 357) and 90% of this dose if determined on the basis of creatinine clearance (n = 202). The trial was powered to exclude a doubling in RFRs assuming a 96-97% 2-year RFR after radiotherapy (hazard ratio [HR], approximately 2.0). RESULTS: Overall, 1,447 patients were randomly assigned in a 3-to-5 ratio (carboplatin, n = 573; RT, n = 904). RFRs at 5 years were 94.7% for carboplatin and 96.0% for RT (RT-C 90% CI, 0.7% to 3.5%; HR, 1.25; 90% CI, 0.83 to 1.89). One death as a result of seminoma (in RT arm) occurred. Patients receiving at least 99% of the 7 * AUC dose had a 5-year RFR of 96.1% (95% CI, 93.4% to 97.7%) compared with 92.6% (95% CI, 88.0% to 95.5%) in those who received lower doses (HR, 0.51; 95% CI, 0.24 to 1.07; P = .08). There was a clear reduction in the rate of contralateral GCTs (carboplatin, n = 2; RT, n = 15; HR, 0.22; 95% CI, 0.05 to 0.95; P = .03), and elevated pretreatment follicle stimulating hormone (FSH) levels (> 12 IU/L) was a strong predictor (HR, 8.57; 95% CI, 1.82 to 40.38). CONCLUSION: These updated results confirm the noninferiority of single dose carboplatin (at 7 * AUC dose) versus RT in terms of RFR and establish a statistically significant reduction in the medium term of risk of second GCT produced by this treatment. PMID- 21282540 TI - Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. AB - PURPOSE: In patients with myeloma, thalidomide significantly improves outcomes but increases the risk of thromboembolic events. In this randomized, open-label, multicenter trial, we compared aspirin (ASA) or fixed low-dose warfarin (WAR) versus low molecular weight heparin (LMWH) for preventing thromboembolism in patients with myeloma treated with thalidomide-based regimens. PATIENTS AND METHODS: A total of 667 patients with previously untreated myeloma who received thalidomide-containing regimens and had no clinical indication or contraindication for a specific antiplatelet or anticoagulant therapy were randomly assigned to receive ASA (100 mg/d), WAR (1.25 mg/d), or LMWH (enoxaparin 40 mg/d). A composite primary end point included serious thromboembolic events, acute cardiovascular events, or sudden deaths during the first 6 months of treatment. RESULTS: Of 659 analyzed patients, 43 (6.5%) had serious thromboembolic events, acute cardiovascular events, or sudden death during the first 6 months (6.4% in the ASA group, 8.2% in the WAR group, and 5.0% in the LMWH group). Compared with LMWH, the absolute differences were +1.3% (95% CI, 3.0% to 5.7%; P = .544) in the ASA group and +3.2% (95% CI, -1.5% to 7.8%; P = .183) in the WAR group. The risk of thromboembolism was 1.38 times higher in patients treated with thalidomide without bortezomib. Three major (0.5%) and 10 minor (1.5%) bleeding episodes were recorded. CONCLUSION: In patients with myeloma treated with thalidomide-based regimens, ASA and WAR showed similar efficacy in reducing serious thromboembolic events, acute cardiovascular events, and sudden deaths compared with LMWH, except in elderly patients where WAR showed less efficacy than LMWH. PMID- 21282541 TI - First-in-man study of CPX-351: a liposomal carrier containing cytarabine and daunorubicin in a fixed 5:1 molar ratio for the treatment of relapsed and refractory acute myeloid leukemia. AB - PURPOSE: This phase I dose-escalation trial was performed to determine the maximum-tolerated dose, dose-limiting toxicities, and pharmacokinetics of CPX 351. PATIENTS AND METHODS: CPX-351 induction was administered on days 1, 3, and 5 by 90-minute infusion to 48 relapsed or refractory patients with acute myeloid leukemia (AML) or high-risk myelodysplasia. Doses started at 3 units/m(2) with dose doublings in single-patient cohorts until a pharmacodynamic effect (treatment-related adverse events or reduction in bone marrow cellularity or blast count) was observed, followed by 33% escalations in three patient cohorts until dose-limiting toxicity (DLT) occurred. RESULTS: The maximum-tolerated dose was 101 units/m(2). DLTs consisted of hypertensive crisis, congestive heart failure, and prolonged cytopenias. Adverse events were consistent with cytarabine and daunorubicin treatment. Response occurred at doses as low as 32 units/m(2). Of 43 patients with AML, nine had complete response (CR) and one had CR with incomplete platelet recovery; of patients with acute lymphoblastic leukemia, one of three had CR. Eight CRs were achieved among the 31 patients with prior cytarabine and daunorubicin treatment. CR in AML occurred in five of 26 patients age >= 60 years and in five of 17 patients younger than age 60 years. Median half life was 31.1 hours (cytarabine) and 21.9 hours (daunorubicin), with both drugs and their metabolites detectable > 7 days after the last dose. The targeted 5:1 molar ratio was maintained at all dose levels for up to 24 hours. CONCLUSION: The recommended dose of CPX-351 for phase II study is 101 units/m(2). Further exploration of efficacy and safety is ongoing in phase II trials in newly diagnosed and first-relapse patients with AML. PMID- 21282542 TI - Phase III trial of vandetanib compared with erlotinib in patients with previously treated advanced non-small-cell lung cancer. AB - PURPOSE: Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling. This phase III study assessed the efficacy of vandetanib versus erlotinib in unselected patients with advanced non-small-cell lung cancer (NSCLC) after treatment failure with one to two prior cytotoxic chemotherapy regimens. PATIENTS AND METHODS: One thousand two hundred forty patients were randomly assigned to receive vandetanib 300 mg/d (n = 623) or erlotinib 150 mg/d (n = 617). The primary objective was to show superiority in progression-free survival (PFS) for vandetanib versus erlotinib. If the difference did not reach statistical significance for superiority, a noninferiority analysis was conducted. RESULTS: There was no significant improvement in PFS for patients treated with vandetanib versus erlotinib (hazard ratio [HR], 0.98; 95.22% CI, 0.87 to 1.10; P = .721); median PFS was 2.6 months for vandetanib and 2.0 months for erlotinib. There was also no significant difference for the secondary end points of overall survival (HR, 1.01; P = .830), objective response rate (both 12%), and time to deterioration of symptoms for pain (HR, 0.92; P = .289), dyspnea (HR, 1.07; P = .407), and cough (HR, 0.94; P = .455). Both agents showed equivalent PFS and overall survival in a preplanned noninferiority analysis. Adverse events (AEs; any grade) more frequent with vandetanib than erlotinib included diarrhea (50% v 38%, respectively) and hypertension (16% v 2%, respectively); rash was more frequent with erlotinib than vandetanib (38% v 28%, respectively). The overall incidence of grade >= 3 AEs was also higher with vandetanib than erlotinib (50% v 40%, respectively). CONCLUSION: In patients with previously treated advanced NSCLC, vandetanib showed antitumor activity but did not demonstrate an efficacy advantage compared with erlotinib. There was a higher incidence of some AEs with vandetanib. PMID- 21282543 TI - Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors. AB - PURPOSE: Resistance to chemotherapy-induced apoptosis represents a major obstacle to cancer control. Overexpression of Bcl-2 is seen in multiple tumor types and targeting Bcl-2 may provide therapeutic benefit. A phase I study of navitoclax, a novel inhibitor of Bcl-2 family proteins, was conducted to evaluate safety, pharmacokinetics, and preliminary efficacy in patients with solid tumors. PATIENTS AND METHODS: Patients enrolled to intermittent dosing cohorts received navitoclax on day -3, followed by dosing on days 1 to 14 of a 21-day cycle. Patients on continuous dosing received a 1-week lead-in dose of 150 mg followed by continuous daily administration. Blood samples were collected for pharmacokinetic analyses, biomarker analyses, and platelet monitoring. RESULTS: Forty-seven patients, including 29 with small-cell lung cancer (SCLC) or pulmonary carcinoid, were enrolled between 2007 and 2008, 35 on intermittent and 12 on continuous dosing cohorts. Primary toxicities included diarrhea (40%), nausea (34%), vomiting (36%), and fatigue (34%); most were grade 1 or 2. Dose- and schedule-dependent thrombocytopenia was seen in all patients. One patient with SCLC had a confirmed partial response lasting longer than 2 years, and eight patients with SCLC or carcinoid had stable disease (one remained on study for 13 months). Pro-gastrin releasing peptide (pro-GRP) was identified as a surrogate marker of Bcl-2 amplification and changes correlated with changes in tumor volume. CONCLUSION: Navitoclax is safe and well tolerated, with dose-dependent thrombocytopenia as the major adverse effect. Preliminary efficacy data are encouraging in SCLC. Efficacy in SCLC and the utility of pro-GRP as a marker of treatment response will be further evaluated in phase II studies. PMID- 21282544 TI - New agents and new end points for recurrent gliomas. PMID- 21282545 TI - Donor lymphocyte infusions modulate relapse risk in mixed chimeras and induce durable salvage in relapsed patients after T-cell-depleted allogeneic transplantation for Hodgkin's lymphoma. AB - PURPOSE: Reduced-intensity conditioning has minimized nonrelapse-related mortality rates after allogeneic transplantation in patients with Hodgkin's lymphoma, and relapse has now become the major cause for treatment failure. We aimed to assess the impact of donor lymphocyte infusions (DLIs) on relapse incidence when administered for mixed chimerism and their utility as salvage therapy when given for relapse. PATIENTS AND METHODS: This study reports the outcomes of 76 consecutive patients with multiply relapsed or refractory Hodgkin's lymphoma who underwent allogeneic transplantation that incorporated in vivo T-cell depletion. Forty-two patients had related donors and 34 had unrelated donors. DLIs were administered in a dose-escalating fashion to 22 patients for mixed chimerism (median time of first dose, 9 months post-transplantation) and to 24 patients for relapse. RESULTS: Three-year donor lymphocyte-related mortality was 7%, relating mainly to the induction of graft-versus-host disease. Nineteen (86%) of 22 patients receiving donor lymphocytes for mixed chimerism converted to full donor status. Four-year relapse incidence was 5% in these 22 patients compared with 43% in patients who remained relapse free but full donor chimeras at 9 months post-transplantation (P = .0071). Nineteen (79%) of 24 patients receiving donor lymphocytes for relapse responded (14 complete responses, five partial responses). Four-year overall survival from relapse was 59% in recipients of donor lymphocytes, contributing to a 4-year overall survival from transplantation of 64% and a 4-year current progression-free survival of 59% in all 76 patients. CONCLUSION: These data demonstrate the potential for allogeneic immunotherapy with donor lymphocytes both to reduce relapse risk and to induce durable antitumor responses in patients with Hodgkin's lymphoma after hematopoietic stem-cell transplantation that incorporates in vivo T-cell depletion. PMID- 21282546 TI - Automated symptom alerts reduce postoperative symptom severity after cancer surgery: a randomized controlled clinical trial. AB - PURPOSE: Patients receiving cancer-related thoracotomy are highly symptomatic in the first weeks after surgery. This study examined whether at-home symptom monitoring plus feedback to clinicians about severe symptoms contributes to more effective postoperative symptom control. PATIENTS AND METHODS: We enrolled 100 patients receiving thoracotomy for lung cancer or lung metastasis in a two-arm randomized controlled trial; 79 patients completed the study. After hospital discharge, patients rated symptoms twice weekly for 4 weeks via automated telephone calls. For intervention group patients, an e-mail alert was forwarded to the patient's clinical team for response if any of a subset of symptoms (pain, disturbed sleep, distress, shortness of breath, or constipation) reached a predetermined severity threshold. No alerts were generated for controls. Group differences in symptom threshold events were examined by generalized estimating equation modeling. RESULTS: The intervention group experienced greater reduction in symptom threshold events than did controls (19% v 8%, respectively) and a more rapid decline in symptom threshold events. The difference in average reduction in symptom interference between groups was -0.36 (SE, 0.078; P = .02). Clinicians responded to 84% of e-mail alerts. Both groups reported equally high satisfaction with the automated system and with postoperative symptom control. CONCLUSION: Frequent symptom monitoring with alerts to clinicians when symptoms became moderate or severe reduced symptom severity during the 4 weeks after thoracic surgery. Methods of automated symptom monitoring and triage may improve symptom control after major cancer surgery. These results should be confirmed in a larger study. PMID- 21282547 TI - Loss of Epstein-Barr virus-encoded RNA expression in cutaneous dissemination of natural killer/T-cell lymphoma. PMID- 21282548 TI - Enhancing patient-provider communication with the electronic self-report assessment for cancer: a randomized trial. AB - PURPOSE: Although patient-reported cancer symptoms and quality-of-life issues (SQLIs) have been promoted as essential to a comprehensive assessment, efficient and efficacious methods have not been widely tested in clinical settings. The purpose of this trial was to determine the effect of the Electronic Self-Report Assessment-Cancer (ESRA-C) on the likelihood of SQLIs discussed between clinicians and patients with cancer in ambulatory clinic visits. Secondary objectives included comparison of visit duration between groups and usefulness of the ESRA-C as reported by clinicians. PATIENTS AND METHODS: This randomized controlled trial was conducted in 660 patients with various cancer diagnoses and stages at two institutions of a comprehensive cancer center. Patient-reported SQLIs were automatically displayed on a graphical summary and provided to the clinical team before an on-treatment visit (n = 327); in the control group, no summary was provided (n = 333). SQLIs were scored for level of severity or distress. One on-treatment clinic visit was audio recorded for each participant and then scored for discussion of each SQLI. We hypothesized that problematic SQLIs would be discussed more often when the intervention was delivered to the clinicians. RESULTS: The likelihood of SQLIs being discussed differed by randomized group and depended on whether an SQLI was first reported as problematic (P = .032). Clinic visits were similar with regard to duration between groups, and clinicians reported the summary as useful. CONCLUSION: The ESRA-C is the first electronic self-report application to increase discussion of SQLIs in a US randomized clinical trial. PMID- 21282549 TI - Differences in sleep disturbance parameters between oncology outpatients and their family caregivers. AB - PURPOSE: This study compared the occurrence rates for and severity ratings of sleep disturbance in patient-family caregiver (FC) dyads. PATIENTS AND METHODS: In total, 102 dyads were recruited from two radiation therapy (RT) departments. Patients and their FCs completed the Pittsburgh Sleep Quality Index (PSQI) and the General Sleep Disturbance Scale (GSDS) and wore wrist actigraphs to obtain subjective and objective measures of the occurrence and severity of sleep disturbance at the initiation of RT. Match paired t tests were used to evaluate for dyadic differences. RESULTS: No differences were found in the occurrence of clinically significant levels of sleep disturbance between patients and their FCs that ranged between 40% and 50% using subjective and objective measures. Few differences were found in the severity of any of the sleep-wake parameters between patients and FCs using both the subjective and objective measures of sleep disturbance. CONCLUSION: The findings from this study suggest that patients with cancer and their FCs experience similar levels of sleep disturbance and that both groups could benefit from interventions that aim to promote restful sleep. In addition to routine and systematic assessment of sleep disturbance by oncology clinicians, interventions are needed that take into account the specific needs of the patient and the FC as well as the potential for partners' sleep patterns to influence one another. PMID- 21282550 TI - Demonstration of durable graft versus lymphoma effects in Hodgkin's lymphoma. PMID- 21282551 TI - Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. AB - PURPOSE: Adoptive immunotherapy using tumor-infiltrating lymphocytes represents an effective cancer treatment for patients with metastatic melanoma. The NY-ESO-1 cancer/testis antigen, which is expressed in 80% of patients with synovial cell sarcoma and approximately 25% of patients with melanoma and common epithelial tumors, represents an attractive target for immune-based therapies. The current trial was carried out to evaluate the ability of adoptively transferred autologous T cells transduced with a T-cell receptor (TCR) directed against NY ESO-1 to mediate tumor regression in patients with metastatic melanoma and synovial cell sarcoma. PATIENTS AND METHODS: A clinical trial was performed in patients with metastatic melanoma or metastatic synovial cell sarcoma refractory to all standard treatments. Patients with NY-ESO-1-positive tumors were treated with autologous TCR-transduced T cells plus 720,000 iU/kg of interleukin-2 to tolerance after preparative chemotherapy. Objective clinical responses were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: Objective clinical responses were observed in four of six patients with synovial cell sarcoma and five of 11 patients with melanoma bearing tumors expressing NY ESO-1. Two of 11 patients with melanoma demonstrated complete regressions that persisted after 1 year. A partial response lasting 18 months was observed in one patient with synovial cell sarcoma. CONCLUSION: These observations indicate that TCR-based gene therapies directed against NY-ESO-1 represent a new and effective therapeutic approach for patients with melanoma and synovial cell sarcoma. To our knowledge, this represents the first demonstration of the successful treatment of a nonmelanoma tumor using TCR-transduced T cells. PMID- 21282552 TI - Intratubular renin-angiotensin system in hypertension. PMID- 21282553 TI - Angiotensin II stimulates renin in inner medullary collecting duct cells via protein kinase C and independent of epithelial sodium channel and mineralocorticoid receptor activity. AB - Collecting duct (CD) renin is stimulated by angiotensin (Ang) II, providing a pathway for Ang I generation and further conversion to Ang II. Ang II stimulates the epithelial sodium channel via the Ang II type 1 receptor and increases mineralocorticoid receptor activity attributed to increased aldosterone release. Our objective was to determine whether CD renin augmentation is mediated directly by Ang II type 1 receptor or via the epithelial sodium channel and mineralocorticoid receptor. In vivo studies examined the effects of epithelial sodium channel blockade (amiloride; 5 mg/kg per day) on CD renin expression and urinary renin content in Ang II-infused rats (80 ng/min, 2 weeks). Ang II infusion increased systolic blood pressure, medullary renin mRNA, urinary renin content, and intrarenal Ang II levels. Amiloride cotreatment did not alter these responses despite a reduction in the rate of progression of systolic blood pressure. In primary cultures of inner medullary CD cells, renin mRNA and (pro)renin protein levels increased with Ang II (100 nmol/L), and candesartan (Ang II type 1 receptor antagonist) prevented this effect. Aldosterone (10(-10) to 10(-7) mol/L) with or without amiloride did not modify the upregulation of renin mRNA in Ang II-treated cells. However, inhibition of protein kinase C with calphostin C prevented the Ang II-mediated increases in renin mRNA and (pro)renin protein levels. Furthermore, protein kinase C activation with phorbol 12 myristate 13-acetate increased renin expression to the same extent as Ang II. These data indicate that an Ang II type 1 receptor-mediated increase in CD renin is induced directly by Ang II via the protein kinase C pathway and that this regulation is independent of mineralocorticoid receptor activation or epithelial sodium channel activity. PMID- 21282554 TI - Contribution of a nuclear factor-kappaB binding site to human angiotensinogen promoter activity in renal proximal tubular cells. AB - Intrarenal angiotensinogen (AGT) is expressed highly in renal proximal tubular cells (RPTCs) and contributes to the regulation of intrarenal angiotensin II levels. Inhibition of nuclear factor (NF)-kappaB suppressed human (h)AGT expression in human RPTCs. However, the presence and localization of an NF-kappaB binding site in the hAGT promoter region have not been determined. Therefore, this study was performed to demonstrate that an NF-kappaB binding site in the hAGT promoter region contributes to hAGT promoter activity in human RPTCs. The hAGT promoter region was cloned from -4358 to +122 and deletion analysis was performed. A possible NF-kappaB binding site was removed from the hAGT promoter region (M1) and mutated (M2). Human RPTCs were transfected, and hAGT promoter activity was determined by luciferase assay. The identity of DNA binding proteins from binding assays were determined by Western blot. Progressive 5'-end deletions demonstrated removal of a distal promoter element in hAGT_-2414/+122 reduced promoter activity (0.61 +/- 0.12, ratio to hAGT_-4358/+122). Inhibition of NF kappaB suppressed promoter activity in hAGT_-4358/+122 (0.51 +/- 0.14, ratio to control) and hAGT_-3681/+122 (0.48 +/- 0.06, ratio to control) but not in the construct without the NF-kappaB binding site. Promoter activity was reduced in the domain mutants M1 (0.57 +/- 0.08, ratio to hAGT_-4358/+122) and M2 (0.61 +/- 0.16, ratio to hAGT_-4358/+122). DNA binding levels of NF-kappaB protein were reduced in M1. These data demonstrate the functional importance of an NF-kappaB binding site in the hAGT promoter region, which contributes to hAGT promoter activity in human RPTCs. PMID- 21282555 TI - Addition of angiotensin II type 1 receptor blocker to CCR2 antagonist markedly attenuates crescentic glomerulonephritis. AB - The monocyte chemoattractant protein-1 (MCP-1)/CC-chemokine receptor 2 (CCR2) pathway plays a critical role in the development of antiglomerular basement membrane (anti-GBM) nephritis. We recently showed angiotensin II (Ang II) infusion in rats activated MCP-1 and transforming growth factor-beta1 (TGF beta1), which in turn induced macrophage infiltration of renal tissues. This study was performed to demonstrate that combination therapy with a CCR2 antagonist (CA) and an Ang II type 1 receptor blocker (ARB) ameliorated renal injury in the anti-GBM nephritis model. An anti-GBM nephritis rat model developed progressive proteinuria and glomerular crescent formation, accompanied by increased macrophage infiltration and glomerular expression of MCP-1, angiotensinogen, Ang II, and TGF-beta1. Treatment with CA alone or ARB alone moderately ameliorated kidney injury; however, the combination treatment with CA and ARB dramatically prevented proteinuria and markedly reduced glomerular crescent formation. The combination treatment also suppressed the induction of macrophage infiltration, MCP-1, angiotensinogen, Ang II, and TGF-beta1 and reversed the fibrotic change in the glomeruli. Next, primary cultured glomerular mesangial cells (MCs) stimulated by Ang II showed significant increases in MCP-1 and TGF-beta1 expression. Furthermore, cocultured model consisting of MCs, parietal epithelial cells, and macrophages showed an increase in Ang II-induced cell proliferation and collagen secretion. ARB treatment attenuated these augmentations. These data suggest that Ang II enhances glomerular crescent formation of anti-GBM nephritis. Moreover, our results demonstrate that inhibition of the MCP-1/CCR2 pathway with a combination of ARB effectively reduces renal injury in anti-GBM nephritis. PMID- 21282556 TI - Linking oxidative stress, the renin-angiotensin system, and hypertension. PMID- 21282557 TI - Stimulation of renin secretion by catecholamines is dependent on adenylyl cyclases 5 and 6. AB - The sympathetic nervous system stimulates renin release from juxtaglomerular cells via the beta-adrenoreceptor-cAMP pathway. Recent in vitro studies have suggested that the calcium-inhibited adenylyl cyclases (ACs) 5 and 6 possess key roles in the control of renin exocytosis. To investigate the relative contribution of AC5 and AC6 to the regulation of renin release in vivo we performed experiments using AC5 and AC6 knockout mice. Male AC5(-/-) mice exhibited normal plasma renin concentrations, renal renin synthesis (mRNA and renin content), urinary volume, and systolic blood pressure. In male AC6(-/-) mice, plasma renin concentration (AC6(-/-): 732 +/- 119; AC6 (+/+): 436 +/- 78 ng of angiotensin I per hour*mL(-1); P<0.05), and renin synthesis were stimulated associated with an increased excretion of dilute urine (1.55-fold; P<0.05) and reduced blood pressure (-10.6 mm Hg; P<0.001). Stimulation of plasma renin concentration by a single injection of the beta-adrenoreceptor agonist isoproterenol (10 mg/kg IP) was significantly attenuated in AC5(-/-) (male: -20%; female: -33%) compared with wild-type mice in vivo. The mitigation of the plasma renin concentration response to isoproterenol was even more pronounced in AC6(-/ ) (male: -63%; female: -50% versus AC6(+/+)). Similarly, the effects of isoproterenol, prostaglandin E2, and pituitary adenylyl cyclase-activating polypeptide on renin release from isolated perfused kidneys were attenuated to a higher extent in AC6(-/-) (-51% to -98% versus AC6(+/+)) than in AC5(-/-) (-31% to 46% versus AC5(+/+)). In conclusion, both AC5 and AC6 are involved in the stimulation of renin secretion in vivo, and AC6 is the dominant isoforms in this process. PMID- 21282558 TI - An oral formulation of angiotensin-(1-7) produces cardioprotective effects in infarcted and isoproterenol-treated rats. AB - In this study we evaluated the cardiac effects of a pharmaceutical formulation developed by including angiotensin (Ang)-(1-7) in hydroxypropyl beta-cyclodextrin (HPbetaCD), in normal, infarcted, and isoproterenol-treated rats. Myocardial infarction was produced by left coronary artery occlusion. Isoproterenol (2 mg/kg, IP) was administered daily for 7 days. Oral administration of HPbetaCD/Ang (1-7) started immediately before infarction or associated with the first dose of isoproterenol. After 7 days of treatment, the rats were euthanized, and the Langendorff technique was used to analyze cardiac function. In addition, heart function was chronically (15, 30, 50 days) analyzed by echocardiography. Cardiac sections were stained with hematoxylin/eosin and Masson trichrome to evaluate cardiac hypertrophy and damage, respectively. Pharmacokinetic studies showed that oral HPbetaCD/Ang-(1-7) administration significantly increased Ang-(1-7) on plasma whereas with the free peptide it was without effect. Oral administration of HPbetaCD/Ang-(1-7) (30 MUg/kg) significantly reduced the deleterious effects induced by myocardial infarction on systolic and diastolic tension, +/-dT/dt, perfusion pressure, and heart rate. Strikingly, a 50% reduction of the infarcted area was observed in HPbetaCD/Ang-(1-7)-treated rats. Furthermore, HPbetaCD/Ang (1-7) attenuated the heart function impairment and cardiac remodeling induced by isoproterenol. In infarcted rats chronically treated with HPbetaCD/Ang-(1-7), the reduction of ejection fraction and fractional shorting and the increase in systolic and diastolic left ventricular volumes observed in infarcted rats were attenuated. Altogether, these findings further confirm the cardioprotective effects of Ang-(1-7). More importantly, our data indicate that the HPbetaCD/Ang (1-7) is a feasible formulation for oral administration of Ang-(1-7), which can be used as a cardioprotective drug. PMID- 21282559 TI - Oxidative stress causes renal angiotensin II type 1 receptor upregulation, Na+/H+ exchanger 3 overstimulation, and hypertension. AB - Oxidative stress modulates angiotensin (Ang) II type 1 receptor (AT(1)R) expression and function. Ang II activates renal Na(+)/H(+) exchanger 3 (NHE3) to increase sodium reabsorption, but the mechanisms are still elusive. In addition, the upregulation of AT(1)R during oxidative stress could promote sodium retention and lead to an increase in blood pressure. Herein, we investigated the mechanism of Ang II-mediated, AT(1)R-dependent renal NHE3 regulation and effect of oxidative stress on AT(1)R signaling and development of hypertension. Male Sprague-Dawley rats received tap water (control) or 30 mmol/L of l-buthionine sulfoximine, an oxidant, with and without 1 mmol/L of Tempol, an antioxidant, for 3 weeks. l-Buthionine-sulfoximine-treated rats exhibited oxidative stress and high blood pressure. Incubation of renal proximal tubules with Ang II caused significantly higher NHE3 activation in l-buthionine-sulfoximine-treated rats compared with control. The activation of NHE3 was sensitive to AT(1)R blocker and inhibitors of phospholipase C, tyrosine kinase, janus kinase 2 (Jak2), Ca(2+) dependent calmodulin (CaM), and Ca(2+) chelator. Also, incubation of proximal tubules with Ang II caused Jak2-dependent CaM phosphorylation, which led to Jak2 CaM complex formation and increased Jak2-CaM interaction with NHE3. The activation of these signaling molecules was exaggerated in l-buthionine sulfoximine-treated rats, whereas Tempol normalized the AT(1)R signaling. In conclusion, Ang II activates renal proximal tubular NHE3 through novel pathways that involve phospholipase C and an increase in intracellular Ca(2+), Jak2, and CaM. In addition, oxidative stress exaggerates Ang II signaling, which leads to overstimulation of renal NHE3 and contributes to an increase in blood pressure. PMID- 21282560 TI - Effects of the angiotensin receptor blocker azilsartan medoxomil versus olmesartan and valsartan on ambulatory and clinic blood pressure in patients with stages 1 and 2 hypertension. AB - Azilsartan medoxomil is an angiotensin receptor blocker (ARB) being developed for hypertension treatment. To compare this ARB with others in the class, we studied the effects of 2 doses of azilsartan medoxomil, with valsartan 320 mg and olmesartan medoxomil (olmesartan) 40 mg, in a randomized, double-blind, placebo controlled trial using ambulatory blood pressure (BP) monitoring and clinic BP measurements. The primary efficacy end point was the change from baseline in 24 hour mean systolic BP. Hierarchical analysis testing for superiority over placebo was followed by noninferiority analysis and then superiority testing of azilsartan medoxomil (80 mg and then 40 mg) versus the comparator ARBs. For 1291 randomized patients, mean age was 56 years, 54% were men, and baseline 24-hour mean systolic BP was 145 mm Hg. Azilsartan medoxomil at 80 mg had superior efficacy to both valsartan at 320 mg and olmesartan at 40 mg: placebo-adjusted 24 hour systolic BP was lowered (-14.3 mm Hg) more than 320 mg of valsartan (-10.0 mm Hg; P<0.001) and 40 mg of olmesartan (-11.7 mm Hg; P=0.009). Azilsartan medoxomil at 40 mg was noninferior to 40 mg of olmesartan (difference: -1.4 mm Hg [95% CI: -3.3 to 0.5]). For clinic systolic BP, both doses of azilsartan medoxomil were superior to the comparator ARBs. Safety and tolerability were similar among the placebo and 4 active treatments. These data demonstrate that azilsartan medoxomil at its maximal dose has superior efficacy to both olmesartan and valsartan at their maximal, approved doses without increasing adverse events. Azilsartan medoxomil could provide higher rates of hypertension control within the ARB class. PMID- 21282561 TI - Hsd11b2 haploinsufficiency in mice causes salt sensitivity of blood pressure. AB - Salt sensitivity of blood pressure is an independent risk factor for cardiovascular morbidity. Mechanistically, abnormal mineralocorticoid action and subclinical renal impairment may blunt the natriuretic response to high sodium intake, causing blood pressure to rise. 11beta-Hydroxysteroid dehydrogenase type 2 (11betaHSD2) controls ligand access to the mineralocorticoid receptor, and ablation of the enzyme causes severe hypertension. Polymorphisms in HSD11B2 are associated with salt sensitivity of blood pressure in normotensives. In this study, we used mice heterozygote for a null mutation in Hsd11b2 (Hsd11b2(+/-)) to define the mechanisms linking reduced enzyme activity to salt sensitivity of blood pressure. A high-sodium diet caused a rapid and sustained increase in blood pressure in Hsd11b2(+/-) mice but not in wild-type littermates. During the adaptation to high-sodium diet, heterozygotes displayed impaired sodium excretion, a transient positive sodium balance, and hypokalemia. After 21 days of high-sodium feeding, Hsd11b2(+/-) mice had an increased heart weight. Mineralocorticoid receptor antagonism partially prevented the increase in heart weight but not the increase in blood pressure. Glucocorticoid receptor antagonism prevented the rise in blood pressure. In Hsd11b2(+/-) mice, high-sodium feeding caused suppression of aldosterone and a moderate but sustained increase in corticosterone. This study demonstrates an inverse relationship among 11betaHSD2 activity, heart weight, and blood pressure in a clinically important context. Reduced activity causes salt sensitivity of blood pressure, but this does not reflect illicit activation of mineralocorticoid receptors by glucocorticoids. Instead, we have identified a novel interaction among 11betaHSD2, dietary salt, and circulating glucocorticoids. PMID- 21282562 TI - Decreased cGMP level contributes to increased contraction in arteries from hypertensive rats: role of phosphodiesterase 1. AB - Recent evidence suggests that angiotensin II (Ang II) upregulates phosphodiesterase (PDE) 1A expression. We hypothesized that Ang II augmented PDE1 activation, decreasing the bioavailability of cyclic guanosine 3' 5' monophosphate (cGMP), and contributing to increased vascular contractility. Male Sprague-Dawley rats received mini-osmotic pumps with Ang II (60 ng.min(-1)) or saline for 14 days. Phenylephrine (PE)-induced contractions were increased in aorta (E(max)168% +/- 8% vs 136% +/- 4%) and small mesenteric arteries (SMA; E(max)170% +/- 6% vs 143% +/- 3%) from Ang II-infused rats compared to control. PDE1 inhibition with vinpocetine (10 MUmol/L) reduced PE-induced contraction in aortas from Ang II rats (E(max)94% +/- 12%) but not in controls (154% +/- 7%). Vinpocetine decreased the sensitivity to PE in SMA from Ang II rats compared to vehicle (-log of half maximal effective concentration 5.1 +/- 0.1 vs 5.9 +/- 0.06), but not in controls (6.0 +/- 0.03 vs 6.1 +/- 0.04). Sildenafil (10 MUmol/L), a PDE5 inhibitor, reduced PE-induced maximal contraction similarly in Ang II and control rats. Arteries were contracted with PE (1 MUmol/L), and concentration-dependent relaxation to vinpocetine and sildenafil was evaluated. Aortas from Ang II rats displayed increased relaxation to vinpocetine compared to control (E(max)82% +/- 12% vs 445 +/- 5%). SMA from Ang II rats showed greater sensitivity during vinpocetine-induced relaxation compared to control (-log of half maximal effective concentration 6.1 +/- 0.3 vs 5.3 +/- 0.1). No differences in sildenafil-induced relaxation were observed. PDE1A and PDE1C expressions in aorta and PDE1A expression in SMA were increased in Ang II rats. cGMP production, which is decreased in arteries from Ang II rats, was restored after PDE1 blockade. We conclude that PDE1 activation reduces cGMP bioavailability in arteries from Ang II, contributing to increased contractile responsiveness. PMID- 21282563 TI - Human papillomavirus testing in the prevention of cervical cancer. AB - Strong evidence now supports the adoption of cervical cancer prevention strategies that explicitly focus on persistent infection with the causal agent, human papillomavirus (HPV). To inform an evidence-based transition to a new public health approach for cervical cancer screening, we summarize the natural history and cervical carcinogenicity of HPV and discuss the promise and uncertainties of currently available screening methods. New HPV infections acquired at any age are virtually always benign, but persistent infections with one of approximately 12 carcinogenic HPV types explain virtually all cases of cervical cancer. In the absence of an overtly persistent HPV infection, the risk of cervical cancer is extremely low. Thus, HPV test results predict the risk of cervical cancer and its precursors (cervical intraepithelial neoplasia grade 3) better and longer than cytological or colposcopic abnormalities, which are signs of HPV infection. The logical and inevitable move to HPV-based cervical cancer prevention strategies will require longer screening intervals that will disrupt current gynecologic and cytology laboratory practices built on frequent screening. A major challenge will be implementing programs that do not overtreat HPV-positive women who do not have obvious long-term persistence of HPV or treatable lesions at the time of initial evaluation. The greatest potential for reduction in cervical cancer rates from HPV screening is in low-resource regions that can implement infrequent rounds of low-cost HPV testing and treatment. PMID- 21282564 TI - The role of lysyl oxidase in SRC-dependent proliferation and metastasis of colorectal cancer. AB - BACKGROUND: Emerging evidence implicates lysyl oxidase (LOX), an extracellular matrix-modifying enzyme, in promoting metastasis of solid tumors. We investigated whether LOX plays an important role in the metastasis of colorectal cancer (CRC). METHODS: We analyzed LOX expression in a patient CRC tissue microarray consisting of normal colon mucosa (n = 49), primary (n = 510), and metastatic (n = 198) tissues. LOX was overexpressed in CRC cell line SW480 (SW480+LOX), and the expression was knocked down in CRC cell line SW620 using LOX-specific short hairpin RNA (SW620+shLOX). Effect of LOX manipulation on three-dimensional cell proliferation and invasion was characterized in vitro. Effect of LOX manipulation on tumor proliferation and metastasis was investigated in a subcutaneous tumor mouse model (n = 3 mice per group) and in an intrasplenic metastatic mouse model (n = 3 mice per group). The mechanism of LOX-mediated effects via v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian) (SRC) was investigated using dasatinib, an inhibitor of SRC activation. All statistical tests were two-sided. RESULTS: Compared with normal colon tissue (n = 49), LOX expression was statistically significantly increased in tumor tissues (n = 510) of CRC patients (P < .001), and a greater increase was observed in metastatic tissue (n = 198). SW480+LOX cells showed a statistically significantly increased three-dimensional proliferation (P = .037) and invasion (P = .015), whereas SW620+shLOX cells showed reduced proliferation (P = .011) and invasion (P = .013) compared with controls. Subcutaneous tumor growth in mice was statistically significantly increased in SW480+LOX tumors (P = .036) and decreased in SW620+shLOX tumors (P = .048), and metastasis was statistically significantly increased in SW480+LOX tumors (P = .044) and decreased in SW620+shLOX tumors (SW620 control vs SW620+shLOX, mean = 1.0 luminescent signal, 95% confidence interval = 0.3 to 1.7 luminescent signal, vs mean = 0.3 luminescent signal, 95% confidence interval = 0.1 to 0.5 luminescent signal; P = .035) compared with controls. LOX-mediated effects on tumor progression were associated with SRC activation, and these effects were inhibited by dasatinib. CONCLUSIONS: LOX showed an important role in CRC cell proliferation and metastasis and was dependent on the activation of SRC. These results have the potential to identify patients with high SRC activity, who may benefit from dasatinib treatment. PMID- 21282565 TI - Integration of a spectral domain optical coherence tomography system into a surgical microscope for intraoperative imaging. AB - PURPOSE: To demonstrate an operating microscope-mounted spectral domain optical coherence tomography (MMOCT) system for human retinal and model surgery imaging. METHODS: A prototype MMOCT system was developed to interface directly with an ophthalmic surgical microscope, to allow SDOCT imaging during surgical viewing. Nonoperative MMOCT imaging was performed in an Institutional Review Board approved protocol in four healthy volunteers. The effect of surgical instrument materials on MMOCT imaging was evaluated while performing retinal surface, intraretinal, and subretinal maneuvers in cadaveric porcine eyes. The instruments included forceps, metallic and polyamide subretinal needles, and soft silicone tipped instruments, with and without diamond dusting. RESULTS: High-resolution images of the human retina were successfully obtained with the MMOCT system. The optical properties of surgical instruments affected the visualization of the instrument and the underlying retina. Metallic instruments (e.g., forceps and needles) showed high reflectivity with total shadowing below the instrument. Polyamide material had a moderate reflectivity with subtotal shadowing. Silicone instrumentation showed moderate reflectivity with minimal shadowing. Summed voxel projection MMOCT images provided clear visualization of the instruments, whereas the B-scans from the volume revealed details of the interactions between the tissues and the instrumentation (e.g., subretinal space cannulation, retinal elevation, or retinal holes). CONCLUSIONS: High-quality retinal imaging is feasible with an MMOCT system. Intraoperative imaging with model eyes provides high-resolution depth information including visualization of the instrument and intraoperative tissue manipulation. This study demonstrates a key component of an interactive platform that could provide enhanced information for the vitreoretinal surgeon. PMID- 21282566 TI - Anterior segment dysgenesis and early-onset glaucoma in nee mice with mutation of Sh3pxd2b. AB - PURPOSE: Mutations in SH3PXD2B cause Frank-Ter Haar syndrome, a rare condition characterized by congenital glaucoma, as well as craniofacial, skeletal, and cardiac anomalies. The nee strain of mice carries a spontaneously arising mutation in Sh3pxd2b. The purpose of this study was to test whether nee mice develop glaucoma. METHODS: Eyes of nee mutants and strain-matched controls were comparatively analyzed at multiple ages by slit lamp examination, intraocular pressure recording, and histologic analysis. Cross sections of the optic nerve were analyzed to confirm glaucomatous progression. RESULTS: Slit lamp examination showed that, from an early age, nee mice uniformly exhibited severe iridocorneal adhesions around the entire circumference of the eye. Presumably as a consequence of aqueous humor outflow blockage, they rapidly developed multiple indices of glaucoma. By 3 to 4 months of age, they exhibited high intraocular pressure (30.8 +/- 12.5 mm Hg; mean +/- SD), corneal opacity, and enlarged anterior chambers. Although histologic analyses at P17 did not reveal any indices of damage, similar analysis at 3 to 4 months of age revealed a course of progressive retinal ganglion cell loss, optic nerve head excavation, and axon loss. CONCLUSIONS: Eyes of nee mice exhibit anterior segment dysgenesis and early-onset glaucoma. Because SH3PXD2B is predicted to be a podosome adaptor protein, these findings implicate podosomes in normal development of the iridocorneal angle and the genes influencing podosomes as candidates in glaucoma. Because of the early-onset, high penetrance glaucoma, nee mice offer many potential advantages as a new mouse model of the disease. PMID- 21282567 TI - Opioid receptor activation: suppression of ischemia/reperfusion-induced production of TNF-alpha in the retina. AB - PURPOSE: The detrimental role of TNF-alpha in ischemia-induced tissue damage is known. The authors study examined whether opioid receptor activation alters TNF alpha levels in the postischemic retina. METHODS: Retinal ischemia was induced by raising the intraocular pressure above systolic blood pressure (155-160 mm Hg) for 45 minutes. Rats were pretreated with the opioid receptor agonist morphine (1 mg/kg; intraperitoneally) before injury. Selected animals were pretreated with the opioid antagonist naloxone (3 mg/kg; intraperitoneally). Human optic nerve head (ONH) astrocytes and rat microglial cells were treated with morphine (0.1-1 MUM) for 24 hours and then treated with 10 MUg/mL or 30 ng/mL lipopolysaccharide (LPS), respectively. TNF-alpha was measured by ELISA. Opioid receptor subtypes in astrocytes and microglia were determined by Western blot analysis. RESULTS: There was a time-dependent increase in TNF-alpha production; the maximum production occurred at 4 hours after ischemia and localized to the inner retinal regions. Ischemia-induced TNF-alpha production was significantly inhibited by morphine. In astrocytes and microglia, LPS triggered a robust increase in the release of TNF alpha, which was significantly inhibited (P < 0.05) by morphine. Naloxone reversed the morphine-induced suppression of TNF-alpha production in vivo and in vitro. Both ONH astrocytes and microglial cells expressed delta-, kappa-, and MU opioid receptor subtypes. CONCLUSIONS: These data provide evidence that the production of TNF-alpha after ischemia/reperfusion injury is an early event and that opioid receptor activation reduces the production of TNF-alpha. Immunohistochemistry data and in vitro studies provide evidence that ONH astrocytes and microglial cells are the primary sources for the TNF-alpha production under ischemic/inflammatory conditions. Activation of one or more opioid receptors can reduce ischemic/reperfusion injury by the suppression of TNF alpha production. PMID- 21282568 TI - Validation of the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) in age-related macular degeneration. AB - PURPOSE: Patient-reported measures of visual function are increasingly incorporated into clinical trials of new treatments for age-related macular degeneration (AMD). Limited information is available regarding the associations between distance visual acuity (VA), reading speed, or contrast sensitivity and the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) subscales judged relevant to these measures. This study's objective was to evaluate such associations along with questions on restricted activity days. METHODS: This cross-sectional study was conducted in patients with clinical diagnoses of neovascular AMD. Patient-reported outcome measures included the NEI VFQ-25 and restricted activity days. Clinical assessments included best-corrected visual acuity (BCVA), reading speed, and contrast sensitivity. The better-seeing eye was defined based on the BCVA of each patient. Psychometric properties of the NEI VFQ-25 were examined; analyses a priori focused on the Near Activities, Distance Activities, and Vision-Specific Dependency subscales. RESULTS: The final study group included 92 participants (mean age, 78 years). Cronbach's alpha for the subscales ranged from 0.67 to 0.92. The NEI VFQ-25 overall composite, Near Activities, Distance Activities, and Vision-Specific Dependency scores were correlated with BCVA (r = -0.48 to -0.54, all P < 0.0001), reading speed (r = 0.43 to 0.56, all P < 0.0001), and contrast sensitivity (r = -0.39 to -0.46, all P < 0.001) of the better-seeing eye and with restricted activity days (r = -0.52 to -0.55, all P < 0.0001). CONCLUSIONS: This study provides additional evidence supporting the validity of the NEI VFQ-25 in neovascular AMD patients by demonstrating correlations with a spectrum of vision measurements and a daily function measure. PMID- 21282569 TI - Role of miR-204 in the regulation of apoptosis, endoplasmic reticulum stress response, and inflammation in human trabecular meshwork cells. AB - PURPOSE: To investigate the biological functions of miR-204 in human trabecular meshwork (HTM) cells. METHODS: Changes in gene expression induced by miR-204 in HTM cells were evaluated by gene array analysis using arrays and confirmed by quantitative-PCR (Q-PCR). Direct targeting of miR-204 to 12 potential novel targets was confirmed using a luciferase system, and five of them were verified by Western blot analysis. Effects of miR-204 on apoptosis, cell viability, and accumulation of carbonylated proteins were evaluated in HTM cells treated with H(2)O(2). Induction of endoplasmic reticulum (ER) stress markers by tunicamycin was analyzed by Q-PCR, and expression of IL-8 and IL-11 was analyzed by ELISA. RESULTS: MiR-204 decreased the expression of multiple genes in HTM cells. Twelve genes (AP1S2, Bcl2l2, BIRC2, EDEM1, EZR, FZD1, M6PR, RAB22A, RAB40B, SERP1, TCF12, and TCF4) were validated as direct targets of miR-204. Downregulation of expressions at protein levels of Bcl2l2, BIRC2, EZR, M6PR, and SERP1 were confirmed by Western blot analysis. HTM cells transfected with miR-204 showed increased levels of apoptosis, decreased viability, increased accumulation of oxidized proteins after H(2)O(2) treatment, decreased induction of ER stress response markers, and reduced expression of inflammatory mediators IL-8 and IL 11. CONCLUSIONS: MiR-204 potentially plays an important role in the regulation of multiple functions in HTM cells including apoptosis, accumulation of damaged proteins, ER stress response, and expression of inflammatory mediators. PMID- 21282570 TI - Retinal nerve fiber layer normative classification by optical coherence tomography for prediction of future visual field loss. AB - PURPOSE: To evaluate the utility of baseline Stratus optical coherence tomography (OCT; Carl Zeiss Meditec, Dublin, CA) retinal nerve fiber layer (RNFL) normative classification in the prediction of future visual field (VF) loss. METHODS: Eighty-eight eyes with suspected glaucoma with abnormal RNFL classification by Stratus OCT were followed up for more than 4 years. VF conversion in three consecutive tests was assessed after baseline Stratus OCT and VF examination. Baseline intraocular pressure, VF global indices, OCT RNFL thickness, and number of abnormal OCT sectors were compared between VF converters (CG) and nonconverters (NCG). Positive and negative predictive values (PPV, NPV) of OCT sectors with abnormal classifications were calculated with respect to VF conversion. Hazard ratios (HRs) of various risk factors, including abnormal OCT classification, with respect to future VF conversion, were determined by use of the Cox proportional hazard model. RESULTS: Twenty-one (23.9%) eyes showed VF conversion during follow-up. Baseline OCT RNFL thickness was significantly lower and the number of abnormal OCT RNFL sectors significantly greater in CG than in NCG patients (P = 0.022 for both). The PPV and NPV of normative OCT RNFL classification was highest in the inferior quadrant (50%, 87.1%, respectively). Baseline VF mean deviation (MD) and the number of abnormal OCT RNFL sectors were both associated with future VF conversion (HR, 0.788 and 1.290, respectively). CONCLUSIONS: In patients with suspected glaucoma, an abnormal RNFL classification in the inferior area of the optic disc or an elevated number of abnormal RNFL sectors, as determined by Stratus OCT, were both associated with future VF conversion. PMID- 21282571 TI - Elasticity-dependent modulation of TGF-beta responses in human trabecular meshwork cells. AB - PURPOSE: To gain further insight into a possible role of biomechanical cues in glaucoma, the authors assessed the influence of extracellular matrix (ECM) elasticity on TGF-beta2-induced changes in trabecular meshwork (TM) cells. METHODS: Human TM cells derived from donor cornea rings were plated on rigid collagen-coated tissue culture plastic or polyacrylamide gels of different elasticity and treated with vehicle or TGF-beta2. Activation of Smad-2/3, ERK, and AKT signaling and expression of alpha-SMA and PAI-1 proteins were assessed by Western blot analysis. Subcellular localization of alpha-SMA was determined by confocal immunofluorescence microscopy. Transcription of collagen-I, -IV, and VI, alpha-SMA, PAI-1, fibronectin, fibrillin-1, cochlin, and MGP-1 was studied by RT-qPCR. The contribution of non-Smad signaling pathways to TGF-beta-induced alpha-SMA and PAI-1 expression was assessed using the small molecule inhibitors U0126 and LY294002. RESULTS: TGF-beta2-induced activation of Smad-2/3, ERK, and AKT signaling as well as expression of collagen-1, alpha-SMA, fibulin, and MGP-1 were attenuated with increasing elasticity. In contrast, TGF-beta2-induced collagen-6, fibronectin, PAI-1, and cochlin expression were enhanced on elastic substrates. The MEK-inhibitor U0126 blocked TGF-beta-induced PAI-1 expression, whereas alpha-SMA expression was enhanced. PI3K inhibition with LY294002 reduced alpha-SMA expression. CONCLUSIONS: ECM elasticity modulates TGF-beta-induced signaling and protein expression in human TM cells. Non-Smad signaling contributes to TGF-beta-induced alterations. Increasing ECM elasticity in vitro promotes protein expression patterns reminiscent of patterns reported in primary open-angle glaucoma. Therefore, changes in TM elasticity and mechanical load may have a significant role in primary open-angle glaucoma. PMID- 21282572 TI - Knockdown of the zebrafish ortholog of the retinitis pigmentosa 2 (RP2) gene results in retinal degeneration. AB - PURPOSE: The authors investigated the expression and function of the zebrafish ortholog of the retinitis pigmentosa 2 (RP2) gene. METHODS: Zebrafish RP2 (ZFRP2) cDNA was isolated from adult eye mRNA by reverse transcription-polymerase chain reaction (RT-PCR). Gene expression was examined by RT-PCR. The deduced peptide sequence was aligned with RP2 orthologues from different species. Translational suppression (knockdown) of zebrafish RP2 was carried out by antisense morpholino injection. The phenotype of ZFRP2 knockdown morphants was characterized by immunohistology and histology. Human wild-type and mutant RP2 mRNAs were coinjected with ZFRP2 morpholinos to test whether human RP2 mRNA could rescue ZFRP2 knockdown phenotypes. RESULTS: ZFRP2 encodes a protein of 376 amino acids containing an N-terminal tubulin folding cofactor C-like domain and a C-terminal nucleoside diphosphate kinase-like domain. It shares 63% to 65% amino acid identity with human, mouse and bovine RP2. RP2 is expressed at the earliest stages of zebrafish development and persists into adulthood. Knockdown of RP2 in zebrafish causes a curved body axis and small eye phenotype, associated with increased cell death throughout the retina. Human wild-type RP2 mRNA could rescue the body curvature phenotype of ZFRP2 morphants, and the eye size of the resultant morphants was significantly increased over that of morphants in which ZFRP2 had been depleted. CONCLUSIONS: Zebrafish RP2 is widely expressed throughout development. ZFRP2 knockdown caused retinal degeneration in zebrafish. Human RP2 could partially rescue the small eye phenotype of ZFRP2 morphants. PMID- 21282573 TI - Imaging lid-parallel conjunctival folds with OCT and comparing its grading with the slit lamp classification in dry eye patients and normal subjects. AB - PURPOSE: To visualize and describe the morphologic appearance of lid-parallel conjunctival folds (LIPCOFs) by using optical coherence tomography (OCT) and to relate it to dry eye signs and symptoms. METHODS: The LIPCOF grade, noninvasive tear film breakup time (NIBUT), lipid layer interference pattern, and dry eye symptoms were recorded in 17 normal subjects and 33 patients with dry eye. LIPCOFs were evaluated with a slit lamp and visualized by OCT. Three different algorithms for OCT were developed to grade LIPCOFs according to tear meniscus height or the covering tear film on the folds. RESULTS: The three OCT methods showed significant correlation with the slit lamp method (r = 0.470-0.473, P < 0.01). The OCT LIPCOF imaging methods were independent of NIBUT. The Dry Eye Questionnaire (DEQ) scores correlated with the height of the folds and the absence of tear film coverage of the folds (r = 0.574, P < 0.001 and r = -0.527, P < 0.001, respectively). The OCT LIPCOF grades correlated with the DEQ scores (r = 0.494, P < 0.001 and r = 0.310, P = 0.029, respectively). The slit lamp grade did not correlate with the DEQ scores in the whole population, but did in the normal group (r = 0.458, P = 0.024). The OCT LIPCOF grades showed inverse correlation with lipid pattern in the normal group (r = -0.422-0.481, P = 0.05); however, this association disappeared in the dry eye group. CONCLUSIONS: OCT enabled a noninvasive, high-resolution method of imaging, evaluating, and classifying LIPCOFs. These new classifications correlated well with the slit lamp grade and the DEQ scores, promising a new, more objective evaluation of dry eye. PMID- 21282574 TI - Functional imaging of human extraocular muscles in head tilt dependent hypertropia. AB - PURPOSE: Although alteration in hypertropia induced by head tilt is considered a clinical criterion for diagnosis of superior oblique (SO) palsy, the mechanism of this head-tilt-dependent hypertropia (HTDHT) is unclear. In this study, magnetic resonance imaging (MRI) was used to study extraocular muscle (EOM) responses to head tilt in HTDHT. METHODS: Orbital MRI was used to study 16 normal subjects and 22 subjects with HTDT, of whom 12 had unilateral SO atrophy and 10 had "masquerading" SO palsy with normal SO size. Sizes and paths of all EOMs were compared in 90 degrees roll tilts. RESULTS: Normal subjects exhibited the expected 3 degrees to 7 degrees physiologic extorsion of all four rectus pulleys in the orbit up-versus-down roll positions, corresponding to ocular counterrolling. In orbits with SO atrophy, the lateral (LR) and inferior rectus (IR) pulleys paradoxically intorted by approximately 2 degrees . Subjects with HTDHT but normal SO size exhibited reduced or reversed extorsion of the medial, superior, and LR pulleys, whereas pulley shift was normal in nonhypertropic fellow orbits in HTDHT. In normal subjects and in SO atrophy, the inferior oblique (IO) muscle contracted in the orbit up-versus-down roll position, but paradoxically relaxed in HTDHT without SO atrophy. CONCLUSIONS: The ipsilesional IR and LR pulleys shift abnormally during head tilt in HTDHT with SO atrophy. In HTDHT without SO atrophy, the ipsilesional MR, SO, and LR pulleys shift abnormally, and the IO relaxes paradoxically during head tilt. These widespread alterations in EOM pulling directions suggest that complex neural adjustments to the otolith-ocular reflexes mediate HTDHT. PMID- 21282575 TI - Chinese character recognition using simulated phosphene maps. AB - PURPOSE: A visual prosthetic device may produce phosphene maps in which individual phosphene characteristics can be altered. This study was an investigation of the ability of normally sighted subjects to recognize Chinese characters (CCs) after altering simulated phosphene maps. METHODS: Thirty volunteers with normal or corrected visual acuity of 20/20 were recruited. CC recognition accuracy and response time were investigated while one parameter was changed (distortion, pixel dropout percentage, pixel size variability, or pixel gray level) or different combinations of three parameters were used. Five hundred CCs consisting of 1 to 16 strokes were used for the character sets. RESULTS: CC recognition accuracy and response times respectively decreased and increased when distortion, dropout, and pixel size variability increased. Gray levels did not significantly affect the results, except when eight levels were used. To maintain an 80% accuracy rate, there should be a distortion index (k) of no more than 0.2 (irregularity), a pixel dropout of 20%, and a pixel size range of 1 to 16 mm (7 112 min arc). Only a combination of a k=0.1 distortion index, a dropout of 10%, and a pixel size range of 1.33 to 12 mm (9.3-84 min arc) achieved a goal of >=80% accuracy. CONCLUSIONS: Distortion, dropout percentage, and pixel size variability have a significant impact on pixelated CC recognition. Although at present the visual ability of prosthesis users is limited, it should be possible to extend this to CC recognition and reading in the future. The results will help visual prosthesis researchers determine the effects of altering phosphene maps and improve outcomes for patients. PMID- 21282576 TI - Increased neovascularization in mice lacking tissue inhibitor of metalloproteinases-3. AB - PURPOSE: Tissue inhibitor of metalloproteinases-3 (TIMP-3) is a matrix-bound inhibitor of matrix metalloproteinases (MMPs). The authors have previously determined a novel function of TIMP-3 to inhibit vascular endothelial growth factor (VEGF)-mediated angiogenesis. Here, the authors examined the in vivo angiogenic phenotype of ocular vessels in mice deficient in TIMP-3. METHODS: VEGF mediated corneal neovascularization and laser-induced choroidal neovascularization (CNV) were examined in TIMP-3-null mice. The effects of the absence of TIMP-3 on the phosphorylation status of the VEGF-receptor-2 (VEGFR-2) and the downstream signaling pathways were evaluated biochemically. In addition, the activation state of MMPs in the retina of TIMP-3-deficient mice was examined by in situ zymography. RESULTS: The results of these studies determine an accentuation of pathologic VEGF-mediated angiogenesis in the cornea and laser induced CNV in mice lacking TIMP-3. In the absence of the MMP inhibitor, pathophysiological changes were observed in the choroidal vasculature concomitantly with an increase in gelatinolytic activity. These results suggest that an imbalance of extracellular matrix homeostasis, together with a loss of an angiogenesis inhibitor, can prime vascular beds to be more responsive to an angiogenic stimulus. CONCLUSIONS: In light of the recent studies suggesting that genetic variants near TIMP-3 influence susceptibility to age-related macular degeneration, these results imply that TIMP-3 may regulate the development of the choroidal vasculature and is a likely contributor to increased susceptibility to choroidal neovascularization. PMID- 21282577 TI - Clusterin promotes corneal epithelial cell growth through upregulation of hepatocyte growth factor by mesenchymal cells in vitro. AB - PURPOSE: Although the cornea expresses high levels of clusterin (CLU), the role of CLU in the cornea is poorly understood. This study was performed to investigate the possible role of CLU in corneal epithelial homeostasis. METHODS: CLU was overexpressed in 3T3 cells by transfection of a vector encoding full length CLU (Clu-3T3). Colony-forming efficacy (CFE) was compared in mouse corneal cell line (TKE2) and human primary corneal/limbal epithelial cells that were cocultured with Clu-3T3 and mock-3T3. To determine whether feeder cells have a contact effect, cocultures without feeder-epithelium contact were also performed. Neutralizing antibody against CLU was used to assess the effects of secretory CLU in TKE2 cells cocultured with Clu-3T3 cells. The expression of growth factors associated with limbal stem/progenitor cell maintenance and growth were analyzed by RT-PCR and Western blot analysis. RESULTS: TKE2 cells cocultured with Clu-3T3 feeders showed higher CFE and were larger in colony size than TKE2 cells cocultured with mock-3T3 feeders. Increased CFE of TKE2 was observed without direct contact with Clu-3T3 cells, which was significantly blocked by treatment with CLU neutralizing antibody. Clu-3T3 cells expressed higher levels of HGF than mock-3T3 cells, which were significantly suppressed with anti-HGF neutralizing antibodies. Collectively, the promotion of colony-forming and cell proliferation by Clu-3T3 cells was partially mediated by the induction of HGF. CONCLUSIONS: Clusterin indirectly enhances the CFE of corneal/limbal epithelial cells by inducing the production of HGF by feeder cells, suggesting a role in epithelial mesenchymal interaction. PMID- 21282578 TI - Evaluation of retinal function and flicker light-induced retinal vascular response in normotensive patients with diabetes without retinopathy. AB - PURPOSE: To correlate retinal function with vascular response to flicker light in normotensive patients with diabetes without diabetic retinopathy (DR). METHODS: Twenty-eight normotensive patients with diabetes (11 with type 1, 17 with type 2) without DR and 28 sex- and age-matched healthy control subjects underwent color vision and contrast sensitivity testing, pattern, full-field, and multifocal electroretinography, and evaluation of the vascular response to flicker light with the dynamic vessel analyzer. RESULTS: In the patients with diabetes, electroretinogram (ERG) pattern responses, b-wave in the scotopic bright flash ERG, a-wave and b-wave in the photopic single-flash ERG, and oscillatory potential responses were significantly impaired compared with those in control subjects. Vascular response to flicker light was also impaired in patients with diabetes compared with controls. In the whole population, correlations were found between flicker light-induced arterial retinal vasodilation and the amplitude and implicit time of the N95 wave of pattern ERG (r = -0.27, P = 0.047 and r = -0.35, P = 0.008, respectively), the b-wave implicit time of rod ERG (r = -0.36; P = 0.01) and the oscillatory potentials (r = 0.4; P = 0.003), suggesting that impairment of the vascular response to flicker light may reflect inner retinal neural impairment. However, no correlation between these factors was found when only patients with diabetes were considered. CONCLUSIONS: In patients with diabetes, neural and neurovascular dysfunctions both precede the onset of clinically detectable DR. To which extent these abnormalities are related to each other remains to be determined. (ClinicalTrials.gov number, NCT00839150.) PMID- 21282580 TI - Genetic association with response to intravitreal ranibizumab in patients with neovascular AMD. AB - PURPOSE: Neovascular age-related macular degeneration (AMD) resulting in decreased central vision severely impairs affected individuals. Current standard treatment is an intravitreal anti-VEGF therapy (ranibizumab), but responses to treatment show large variability. Genetic factors that influence AMD and that affect the outcome of ranibizumab treatment were sought within a sample of Swiss patients. METHODS: Changes in visual acuity (VA) after initiation of anti-VEGF treatment were observed during 12 months, and percentiles of VA were calculated. Genotypes of polymorphisms in known AMD susceptibility loci (CFH, CFB, HTRA1, AMRS2, and VEGFA) as well as not yet reported AMD-associated genes (KDR, LRP5, and FZD4) were determined, and their frequencies were compared. RESULTS: Of the 309 eyes included in the study, 243 completed VA assessment. On average, 3.9 +/ 2.6 ranibizumab injections were administered. Based on the change in visual acuity, two responder groups were established: 63 eyes were assigned to the poor responders (<=25th percentile) and 63 eyes to the good responders (>=75th percentile). Individuals with genotype CC of p.Y402H in CFH had a decreased chance of positive treatment outcome compared with those with the CT and TT genotypes (P = 0.005 and P = 0.006). In this study, the genotype combination of AG at CFH with CT at FZD4 (SNP rs10898563) promised an increased chance of positive treatment outcome (P = 0.004). Furthermore, the association with the known genetic susceptibility loci CFH, HTRA1, and AMRS2 were confirmed, and a risk-conferring polymorphism in one new locus, LRP5, was identified. CONCLUSIONS: Genetic predisposition may account for the variability in response to anti-VEGF treatment. PMID- 21282579 TI - Progressive-addition lenses versus single-vision lenses for slowing progression of myopia in children with high accommodative lag and near esophoria. AB - PURPOSE: To determine whether progressive-addition lenses (PALs) relative to single-vision lenses (SVLs) slow the progression of low myopia in children with high accommodative lag and near esophoria. METHODS: One hundred eighteen children 8 to <12 years of age with spherical equivalent refraction (SER) from -0.75 to 2.50 D and near esophoria >=2 PD were enrolled in this double-masked multicenter randomized trial. A key additional eligibility criterion was high accommodative lag, initially defined as at least 0.50 D (accommodative response less than 2.50 D for a 3.00-D demand) and later restricted further to at least 1.00 D. One hundred four subjects had accommodative lag of at least 1.00 D, and 14 had lag between 0.50 and 0.99 D. The children were randomized to receive either PALs with a +2.00-D addition or standard SVLs. The clinicians performing the outcome testing, as well as the children and their families, were masked to treatment group. Follow-up visits occurred every 6 months for 3 years. At annual visits, refractive error was assessed in each eye by using cycloplegic autorefraction. The main outcome measure was change from baseline to 3 years in SER by cycloplegic autorefraction. RESULTS: The mean change in SER between baseline and the 3-year primary outcome visit was -0.87 D in the PAL group and -1.15 D in the SVL group, for a difference of 0.28 D (95% confidence interval [CI], 0.01-0.55D). CONCLUSIONS: The PALs used in this study were found to have a statistically but not clinically significant effect of slowing myopia progression in children with high accommodative lag and near esophoria. (ClinicalTrials.gov number, NCT00320593.). PMID- 21282581 TI - Bovine lactoferrin structures promoting corneal epithelial wound healing in vitro. AB - PURPOSE: To use an in vitro alkali-induced wound model to identify structures of bovine lactoferrin (BLF) that contribute to the promotion of human corneal epithelial healing. METHODS: BLF N-lobe and C-lobe were separated using limited proteolysis and purified by preparative chromatography. Isoforms of BLF were separated according to serine protease activity. Catalytic activities of isoforms and lobes were quantified by hydrolysis of a synthetic serine protease substrate. The promotion of healing by cognate moieties, lactoferricin-B, BLF isoforms, and BLF in various forms-iron-free, iron-saturated, deglycosylated, zwitterionic detergent exposed, chaotrope denatured, disulfide reduced-was assessed on alkali wounding of confluent monolayers of human corneal epithelial cells. RESULTS: The C-lobe of BLF (6.4-128 MUM) promoted greater wound healing than native-BLF or N lobe. BLF (12.8 MUM) promoted wound closure in an iron-free, iron-bound, or deglycosylated state or after exposure to zwitterionic detergent. Healing was not stimulated by chaotropically denatured or disulfide reduced BLF (12.8 MUM) or by lactoferricin-B (12.8 MUM). Proteolytically active BLF (0.6 MUM) promoted wound closure at a lower concentration than proteolytically inactive BLF (12 MUM). This proteolytic activity was localized to the N-lobe. CONCLUSIONS: The C-lobe is the primary promoter of BLF-stimulated corneal epithelial wound closure in vitro and is effective at concentrations >=6.4 MUM. Increased healing from BLF occurs with the native conformation and is unaffected by glycosylation or iron saturation. To a lesser extent, proteolytic activity of the N-lobe also improves healing rates. The BLF C-lobe may be a novel treatment for corneal lesions with delayed healing. PMID- 21282582 TI - Structural organization and expression pattern of the canine RPGRIP1 isoforms in retinal tissue. AB - PURPOSE: To examine the structure and expression of RPGRIP1 in dog retina. METHODS: Determination of the structural analysis and expression pattern of canine RPGRIP1 (cRPGRIP1) was based on cDNA amplification. Absolute quantification of the expression level of cRPGRIP1 splice variants was determined by qRT-PCR. Regulatory structures were examined by computational analysis of comparative genomics. RESULTS: cRPGRIP1 encompasses 25 exons that harbor a 3627 bp open reading frame (ORF) encoding a 1209-amino-acid (aa)-predicted protein. In addition to the main transcript, five full-length and several partial cRPGRIP1 isoforms were identified revealing four alternative 3'-terminal exons--24, 19a, 19c, and 19d--three of which could potentially produce C-terminally truncated proteins that lack the RPGR-interacting domain. A complex organization of the 5' UTR for the cRPGRIP1 splice products have been described, with a common promoter driving multiple isoforms, including four full-length transcripts using the 3' terminal exon 24. In addition, a potential alternative internal promoter was revealed to initiate at least two cRPGRIP1 splice variants sharing the same 3' terminal exon 19c. Transcription initiation sites were highly supported by conserved arrangements of cis-elements predicted in a bioinformatic analysis of orthologous RPGRIP1 promoter regions. CONCLUSIONS: The use of alternative transcription start and termination sites results in substantial heterogeneity of cRPGRIP1 transcripts, many of which are likely to have tissue-specific expression. The identified exon-intron structure of cRPGRIP1 isoforms provides a basis for evaluating the gene defects underlying inherited retinal disorders in dogs. PMID- 21282583 TI - Sclera-choroid-RPE transport of eight beta-blockers in human, bovine, porcine, rabbit, and rat models. AB - PURPOSE: To determine the influence of drug lipophilicity, ocular pigmentation, and species differences on transscleral solute transport. METHODS: The transport of eight beta-blockers across excised sclera/sclera-choroid-RPE (SCRPE) of albino rabbit, pigmented rabbit, human, porcine, and bovine eyes was determined over 6 hours. The ex vivo transscleral beta-blocker transport to the vitreous at the end of 6 hours was determined in euthanatized, pigmented Brown Norway rats. The thicknesses of the sclera and SCRPE and the melanin content in choroid-RPE (CRPE) were measured to determine whether species differences in drug transport can be explained on this basis. RESULTS: Solute lipophilicity inversely correlated with the SCRPE cumulative percentage of transport in all species (R(2) >= 0.80). The CRPE impeded the SCRPE transport of all beta-blockers (51%-64% resistance in the rabbits; 84%-99.8% in the bovine and porcine eyes) more than the sclera, with the impedance increasing with lipophilicity. SCRPE transport followed the trend albino rabbit > pigmented rabbit > human > porcine > bovine, and a cross-species comparison showed good Spearman's rho correlation (R(2) >= 0.85). Bovine (R(2) = 0.84), porcine (R(2) = 0.84), and human (R(2) = 0.71) SCRPE transport was more predictive than that in the rabbit models (R(2) = 0.60-0.61) of transscleral solute transport to the vitreous in rats. The CRPE concentrations were higher in pigmented rabbits than in albino rabbits. The melanin content of the CRPE exhibited the trend albino rabbit ? pigmented rabbit < porcine ~ bovine < rat. Normalization to scleral thickness abolished the species differences in scleral transport. Normalization to SCRPE thickness and melanin content significantly reduced species differences in SCRPE transport. CONCLUSIONS: Owing to the presence of pigment and drug binding, choroid-RPE is the principal barrier to transscleral beta-blocker transport, with the barrier being more significant for lipophilic beta-blockers. Although different in magnitude between species, sclera/SCRPE transport can be correlated between species. Tissue thickness accounts for the species differences in scleral transport. Differences in tissue thickness and melanin content largely account for the species differences in SCRPE transport. PMID- 21282584 TI - Resveratrol inhibits pathologic retinal neovascularization in Vldlr(-/-) mice. AB - PURPOSE: Macular telangiectasia (MacTel) is a vision-threatening retinal disease with unknown pathogenesis and no approved treatment. Very low-density lipoprotein receptor mutant mice (Vldlr(-/-)) exhibit critical features of MacTel such as retinal neovascularization and photoreceptor degeneration. In this study, the authors evaluate the therapeutic potential of resveratrol, a plant polyphenol, in Vldlr(-/-) mice as a model for MacTel. METHODS: Vldlr(-/-) and wild-type mice at postnatal day (P) 21 to P60 or P10 to P30 were treated orally with resveratrol. The number of neovascular lesions was evaluated on retinal flatmounts, and resveratrol effects on endothelial cells were assessed by Western blot for phosphorylated ERK1/2, aortic ring, and migration assays. Vegf and Gfap expression was evaluated in laser-capture microdissected retinal layers of angiogenic lesions and nonlesion areas from Vldlr(-/-) and wild-type retinas. RESULTS: From P15 onward, Vldlr(-/-) retinas develop vascular lesions associated with the local upregulation of Vegf in photoreceptors and Gfap in the inner retina. Oral resveratrol reduces lesion formation when administered either before or after disease onset. The reduction of vascular lesions in resveratrol-treated Vldlr(-/-) mice is associated with the suppression of retinal Vegf transcription. Resveratrol also reduces endothelial ERK1/2 signaling as well as the migration and proliferation of endothelial cells. Furthermore, a trend toward increased rhodopsin mRNA in Vldlr(-/-) retinas is observed. CONCLUSIONS: Oral administration of resveratrol is protective against retinal neovascular lesions in Vldlr(-/-) mice by inhibiting Vegf expression and angiogenic activation of retinal endothelial cells. These results suggest that resveratrol might be a safe and effective intervention for treating patients with MacTel. PMID- 21282585 TI - Clinical reasoning: a 54-year-old woman with transient episodes of headache and neurologic dysfunction. PMID- 21282586 TI - Clinical reasoning: a 10-month-old boy with myoclonic status epilepticus. PMID- 21282587 TI - Bevacizumab antiangiogenic therapy for glioblastoma. PMID- 21282588 TI - Zoster sine herpete: it would be rash to ignore it. PMID- 21282589 TI - Association of UV radiation with multiple sclerosis prevalence and sex ratio in France. AB - BACKGROUND: French farmers and their families constitute an informative population to study multiple sclerosis (MS) prevalence and related epidemiology. We carried out an ecological study to evaluate the association of MS prevalence and ultraviolet (UV) radiation, a candidate climatologic risk factor. METHODS: Mean annual and winter (December-March) UVB irradiation values were systematically compared to MS prevalence rates in corresponding regions of France. UVB data were obtained from the solar radiation database (SoDa) service and prevalence rates from previously published data on 2,667 MS cases registered with the national farmer health insurance system, Mutualite Sociale Agricole (MSA). Pearson correlation was used to examine the relationship of annual and winter UVB values with MS prevalence. Male and female prevalence were also analyzed separately. Linear regression was used to test for interaction of annual and winter UVB with sex in predicting MS prevalence. RESULTS: There was a strong association between MS prevalence and annual mean UVB irradiation (r = -0.80, p < 0.001) and average winter UVB (r = -0.87, p < 0.001). Both female (r = -0.76, p < 0.001) and male (r = -0.46, p = 0.032) prevalence rates were correlated with annual UVB. Regression modeling showed that the effect of UVB on prevalence rates differed by sex; the interaction effect was significant for both annual UVB (p = 0.003) and winter UVB (p = 0.002). CONCLUSIONS: The findings suggest that regional UVB radiation is predictive of corresponding MS prevalence rates and supports the hypothesis that sunlight exposure influences MS risk. The evidence also supports a potential role for gender-specific effects of UVB exposure. PMID- 21282590 TI - Patterns of progression in patients with recurrent glioblastoma treated with bevacizumab. AB - OBJECTIVE: We evaluated patterns of tumor progression in patients with recurrent glioblastoma who were treated with bevacizumab (BEV) alone or in combination with irinotecan (CPT-11) while participating in the BRAIN study. METHODS: An independent neuroradiologist reviewed MRI scans at baseline and progression in patients who received BEV (n = 85) or BEV+CPT-11 (n = 82) while on BRAIN. Tumor patterns were scored as local, distant, diffuse, or multifocal. Median progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier methods. Hazard ratios for PFS and OS were estimated using a Cox regression model. RESULTS: Twenty-eight percent of patients who participated in BRAIN had nonlocal disease at baseline (72% local disease). Sixty-seven (79%) patients treated with single-agent BEV and 57 (70%) patients treated with BEV+CPT 11 experienced disease progression while on BRAIN. Most patients in each treatment group did not have a change in the radiographic pattern of their tumor (i.e., "no shift") at the time of progression. The proportion of BEV patients with no shift (82%) was greater than that of BEV+CPT-11 patients (53%, chi(2) p = 0.0004), and a greater proportion of BEV+CPT-11 patients (39%) compared with BEV patients (16%) experienced local-to-diffuse tumor pattern at progression (chi(2) p = 0.002). Patients treated with BEV or BEV+CPT-11 who had local-to-local or local-to-diffuse progression patterns had similar efficacy outcomes, including objective response, PFS, and OS. CONCLUSIONS: Most patients treated with BEV or BEV+CPT-11 on BRAIN did not experience a change from baseline in radiographic characteristics of disease at the time of progression. PMID- 21282591 TI - A novel clinical syndrome revealing a deficiency of the muscarinic M3 receptor. AB - OBJECTIVES: No clinical disorders have been caused by dysfunction of any of the 5 subtypes (M1-M5) of muscarinic receptors. We present a patient with a novel clinical syndrome that we suggest results from a deficiency of the muscarinic M3 receptor. METHODS: We conducted a comprehensive workup of autonomic function. The patient's disorder was compared to the phenotypic features of male M3 knockout mice. M3 protein quantity was assessed by Western blot and radioligand binding in peripheral blood lymphocytes. Tests for autoantibodies and genetic abnormalities were performed. RESULTS: The disease pattern was characterized by disturbances in micturition, pupil constriction, body weight, and sudomotor function, with normal accommodation, gastrointestinal motility, salivation, and lacrimation, similar to features of male M3 knockout mice. M3 protein quantity was reduced. Genetic tests were unrevealing, but unspecific antinuclear antibodies were present. CONCLUSIONS: The presented clinical syndrome suggests a deficiency of the muscarinic M3 receptor. These results and future evaluation of patients with autonomic deficits may provide insights into the site and functional role of the muscarinic M3 receptor in humans. PMID- 21282592 TI - A cross-sectional study contrasting olfactory function in autonomic disorders. AB - OBJECTIVE: To compare odor identification function in patients with peripheral or central autonomic neurodegeneration and in patients with intact autonomic neurons but undetectable norepinephrine. METHODS: Olfactory function was evaluated with the University of Pennsylvania Smell Identification Test (UPSIT) in 12 patients with pure autonomic failure, 10 patients with multiple system atrophy, and 4 patients with dopamine beta-hydroxylase deficiency. Blood pressure and catecholamine data were also compared. RESULTS: Odor identification was significantly impaired in patients with pure autonomic failure relative to patients with multiple system atrophy or dopamine beta-hydroxylase deficiency. Out of 40 odors, the patients correctly identified mean (95% confidence interval) 19.2 (14.1 to 24.2), 34.4 (32.2 to 36.6), and 31.7 (29.4 to 34.1) (p < 0.001). The difference between patients with pure autonomic failure and those with multiple system atrophy or dopamine beta-hydroxylase deficiency persisted after adjustment for age (p = 0.001). Patients with pure autonomic failure also had a greater orthostatic fall in blood pressure and lower plasma norepinephrine levels than patients with multiple system atrophy. CONCLUSIONS: Olfactory function was relatively intact in patients with dopamine beta-hydroxylase deficiency, who have intact noradrenergic neurons but lack norepinephrine. Odor identification was impaired in pure autonomic failure but not in multiple system atrophy, suggesting that 1) peripheral noradrenergic innervation is important for olfactory identification but norepinephrine is not essential and 2) UPSIT may be useful in the differential diagnosis between these disorders. PMID- 21282593 TI - A retrospective review of X-linked Charcot-Marie-Tooth disease in childhood. AB - OBJECTIVE: X-linked Charcot-Marie-Tooth disease (CMTX) is infrequently diagnosed in childhood, and its clinical and neurophysiologic features are not well described. We reviewed clinical, neurophysiologic, and pathologic findings in 17 children with CMTX. METHODS: This was a retrospective review of children with CMTX from 2 tertiary pediatric hospitals. The diagnosis of CMTX was based on an identifiable connexin 32 mutation (CMTX1) or a consistent pedigree and neurophysiologic features in children without a connexin 32 mutation (CMTX other). RESULTS: Six boys and 2 girls from 8 kindreds had CMTX1, and 8 boys and 1 girl from 5 kindreds had other forms of CMTX (CMTX-other). Fifteen children, including males and carrier females, were symptomatic from infancy or early childhood (younger than 5 years). In addition to the typical Charcot-Marie-Tooth disease clinical phenotype, some patients had delayed motor development, sensorineural hearing loss, tremor, pathologic fractures, or transient CNS disturbances. Eleven children underwent nerve conduction studies. Median nerve motor nerve conduction velocities were in the intermediate to normal range (30-54 m/s) in all children older than 2 years. Axon loss, reflected by low-amplitude compound muscle action potentials, was present in all patients. A pattern of X linked dominant inheritance, with carrier females showing an abnormal neurologic or neurophysiologic examination, correlated with the presence of a connexin 32 mutation in all but 2 pedigrees. CONCLUSIONS: The clinical phenotype of CMTX is broader than previously reported. Onset in males and carrier females is most often in early childhood. Families with an X-linked dominant inheritance pattern are likely to have CMTX1. PMID- 21282594 TI - An algorithm for genetic testing of frontotemporal lobar degeneration. AB - OBJECTIVE: To derive an algorithm for genetic testing of patients with frontotemporal lobar degeneration (FTLD). METHODS: A literature search was performed to review the clinical and pathologic phenotypes and family history associated with each FTLD gene. RESULTS: Based on the literature review, an algorithm was developed to allow clinicians to use the clinical and neuroimaging phenotypes of the patient and the family history and autopsy information to decide whether or not genetic testing is warranted, and if so, the order for appropriate tests. CONCLUSIONS: Recent findings in genetics, pathology, and imaging allow clinicians to use the clinical presentation of the patient with FTLD to inform genetic testing decisions. PMID- 21282595 TI - Zoster sine herpete: virologic verification by detection of anti-VZV IgG antibody in CSF. PMID- 21282596 TI - Gerstmann-Straussler-Scheinker disease due to a novel prion protein gene mutation. PMID- 21282597 TI - An unusual cause of symptomatic tension-type headache: hypertrophic branchial myopathy. PMID- 21282598 TI - The case against confirmatory tests for determining brain death in adults. PMID- 21282599 TI - Nongenetic factors influence severity of episodic ataxia type 1 in monozygotic twins. PMID- 21282601 TI - Rare copy number variations in congenital heart disease patients identify unique genes in left-right patterning. AB - Dominant human genetic diseases that impair reproductive fitness and have high locus heterogeneity constitute a problem for gene discovery because the usual criterion of finding more mutations in specific genes than expected by chance may require extremely large populations. Heterotaxy (Htx), a congenital heart disease resulting from abnormalities in left-right (LR) body patterning, has features suggesting that many cases fall into this category. In this setting, appropriate model systems may provide a means to support implication of specific genes. By high-resolution genotyping of 262 Htx subjects and 991 controls, we identify a twofold excess of subjects with rare genic copy number variations in Htx (14.5% vs. 7.4%, P = 1.5 * 10(-4)). Although 7 of 45 Htx copy number variations were large chromosomal abnormalities, 38 smaller copy number variations altered a total of 61 genes, 22 of which had Xenopus orthologs. In situ hybridization identified 7 of these 22 genes with expression in the ciliated LR organizer (gastrocoel roof plate), a marked enrichment compared with 40 of 845 previously studied genes (sevenfold enrichment, P < 10(-6)). Morpholino knockdown in Xenopus of Htx candidates demonstrated that five (NEK2, ROCK2, TGFBR2, GALNT11, and NUP188) strongly disrupted both morphological LR development and expression of pitx2, a molecular marker of LR patterning. These effects were specific, because 0 of 13 control genes from rare Htx or control copy number variations produced significant LR abnormalities (P = 0.001). These findings identify genes not previously implicated in LR patterning. PMID- 21282602 TI - Polarity proteins Bem1 and Cdc24 are components of the filamentous fungal NADPH oxidase complex. AB - Regulated synthesis of reactive oxygen species (ROS) by membrane-bound fungal NADPH oxidases (Nox) plays a key role in fungal morphogenesis, growth, and development. Generation of reactive oxygen species (ROS) by the plant symbiotic fungus, Epichloe festucae, requires functional assembly of a multisubunit complex composed of NoxA, a regulatory component, NoxR, and the small GTPase RacA. However, the mechanism for assembly and activation of this complex at the plasma membrane is unknown. We found by yeast two-hybrid and coimmunoprecipitation assays that E. festucae NoxR interacts with homologs of the yeast polarity proteins, Bem1 and Cdc24, and that the Phox and Bem1 (PB1) protein domains found in these proteins are essential for these interactions. GFP fusions of BemA, Cdc24, and NoxR preferentially localized to actively growing hyphal tips and to septa. These proteins interact with each other in vivo at these same cellular sites as shown by bimolecular fluorescent complementation assays. The PB1 domain of NoxR is essential for localization to the hyphal tip. An E. festucae DeltabemA mutant was defective in hyphal morphogenesis and growth in culture and in planta. The changes in fungal growth in planta resulted in a defective symbiotic interaction phenotype. Our inability to isolate a Deltacdc24 mutant suggests this gene is essential. These results demonstrate that BemA and Cdc24 play a critical role in localizing NoxR protein to sites of fungal hyphal morphogenesis and growth. Our findings identify a potential shared ancestral link between the protein machinery required for fungal polarity establishment and the Nox complex controlling cellular differentiation. PMID- 21282603 TI - An extinct monkey from Haiti and the origins of the Greater Antillean primates. AB - A new extinct Late Quaternary platyrrhine from Haiti, Insulacebus toussaintiana, is described here from the most complete Caribbean subfossil primate dentition yet recorded, demonstrating the likely coexistence of two primate species on Hispaniola. Like other Caribbean platyrrhines, I. toussaintiana exhibits primitive features resembling early Middle Miocene Patagonian fossils, reflecting an early derivation before the Amazonian community of modern New World anthropoids was configured. This, in combination with the young age of the fossils, provides a unique opportunity to examine a different parallel radiation of platyrrhines that survived into modern times, but is only distantly related to extant mainland forms. Their ecological novelty is indicated by their unique dental proportions, and by their relatively large estimated body weights, possibly an island effect, which places the group in a size class not exploited by mainland South American monkeys. Several features tie the new species to the extinct Jamaican monkey Xenothrix mcgregori, perhaps providing additional evidence for an inter-Antillean clade. PMID- 21282604 TI - Unique inhibitory synapse with particularly rich endocannabinoid signaling machinery on pyramidal neurons in basal amygdaloid nucleus. AB - 2-Arachidonoylglycerol (2-AG) is the endocannabinoid that mediates retrograde suppression of synaptic transmission in the brain. 2-AG is synthesized in activated postsynaptic neurons by sn-1-specific diacylglycerol lipase (DGL), binds to presynaptic cannabinoid CB(1) receptors, suppresses neurotransmitter release, and is degraded mainly by monoacylglycerol lipase (MGL). In the basolateral amygdala complex, it has been demonstrated that CB(1) is particularly enriched in axon terminals of cholecystokinin (CCK)-positive GABAergic interneurons, induces short- and long-term depression at inhibitory synapses, and is involved in extinction of fear memory. Here, we clarified a unique molecular convergence of DGLalpha, CB(1), and MGL at specific inhibitory synapses in the basal nucleus (BA), but not lateral nucleus, of the basolateral amygdala. The synapses, termed invaginating synapses, consisted of conventional symmetrical contact and unique perisynaptic invagination of nerve terminals into perikarya. At invaginating synapses, DGLalpha was preferentially recruited to concave somatic membrane of postsynaptic pyramidal neurons, whereas invaginating presynaptic terminals highly expressed CB(1), MGL, and CCK. No such molecular convergence was seen for flat perisomatic synapses made by parvalbumin-positive interneurons. On the other hand, DGLalpha and CB(1) were expressed weakly at axospinous excitatory synapses. Consistent with these morphological data, thresholds for DGLalpha-mediated depolarization-induced retrograde suppression were much lower for inhibitory synapses than for excitatory synapses in BA pyramidal neurons. Moreover, depolarization-induced suppression was readily saturated for inhibition, but never for excitation. These findings suggest that perisomatic inhibition by invaginating synapses is a key target of 2-AG-mediated control of the excitability of BA pyramidal neurons. PMID- 21282605 TI - Agronomic phosphorus imbalances across the world's croplands. AB - Increased phosphorus (P) fertilizer use and livestock production has fundamentally altered the global P cycle. We calculated spatially explicit P balances for cropland soils at 0.5 degrees resolution based on the principal agronomic P inputs and outputs associated with production of 123 crops globally for the year 2000. Although agronomic inputs of P fertilizer (14.2 Tg of P.y(-1)) and manure (9.6 Tg of P.y(-1)) collectively exceeded P removal by harvested crops (12.3 Tg of P.y(-1)) at the global scale, P deficits covered almost 30% of the global cropland area. There was massive variation in the magnitudes of these P imbalances across most regions, particularly Europe and South America. High P fertilizer application relative to crop P use resulted in a greater proportion of the intense P surpluses (>13 kg of P.ha(-1).y(-1)) globally than manure P application. High P fertilizer application was also typically associated with areas of relatively low P-use efficiency. Although manure was an important driver of P surpluses in some locations with high livestock densities, P deficits were common in areas producing forage crops used as livestock feed. Resolving agronomic P imbalances may be possible with more efficient use of P fertilizers and more effective recycling of manure P. Such reforms are needed to increase global agricultural productivity while maintaining or improving freshwater quality. PMID- 21282606 TI - Nepsilon-lysine acetylation determines dissociation from GAP junctions and lateralization of connexin 43 in normal and dystrophic heart. AB - Wanting to explore the epigenetic basis of Duchenne cardiomyopathy, we found that global histone acetylase activity was abnormally elevated and the acetylase P300/CBP-associated factor (PCAF) coimmunoprecipitated with connexin 43 (Cx43), which was N(epsilon)-lysine acetylated and lateralized in mdx heart. This observation was paralleled by Cx43 dissociation from N-cadherin and zonula occludens 1, whereas pp60-c-Src association was unaltered. In vivo treatment of mdx with the pan-histone acetylase inhibitor anacardic acid significantly reduced Cx43 N(epsilon)-lysine acetylation and restored its association to GAP junctions (GJs) at intercalated discs. Noteworthy, in normal as well as mdx mice, the class IIa histone deacetylases 4 and 5 constitutively colocalized with Cx43 either at GJs or in the lateralized compartments. The class I histone deacetylase 3 was also part of the complex. Treatment of normal controls with the histone deacetylase pan-inhibitor suberoylanilide hydroxamic acid (MC1568) or the class IIa-selective inhibitor 3-{4-[3-(3-fluorophenyl)-3-oxo-1-propen-1-yl]-1-methyl-1H pyrrol-2-yl}-N-hydroxy-2-propenamide (MC1568) determined Cx43 hyperacetylation, dissociation from GJs, and distribution along the long axis of ventricular cardiomyocytes. Consistently, the histone acetylase activator pentadecylidenemalonate 1b (SPV106) hyperacetylated cardiac proteins, including Cx43, which assumed a lateralized position that partly reproduced the dystrophic phenotype. In the presence of suberoylanilide hydroxamic acid, cell to cell permeability was significantly diminished, which is in agreement with a Cx43 close conformation in the consequence of hyperacetylation. Additional experiments, performed with Cx43 acetylation mutants, revealed, for the acetylated form of the molecule, a significant reduction in plasma membrane localization and a tendency to nuclear accumulation. These results suggest that Cx43 N(epsilon)-lysine acetylation may have physiopathological consequences for cell to cell coupling and cardiac function. PMID- 21282607 TI - Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors. AB - The dense collagen network in tumors significantly reduces the penetration and efficacy of nanotherapeutics. We tested whether losartan--a clinically approved angiotensin II receptor antagonist with noted antifibrotic activity--can enhance the penetration and efficacy of nanomedicine. We found that losartan inhibited collagen I production by carcinoma-associated fibroblasts isolated from breast cancer biopsies. Additionally, it led to a dose-dependent reduction in stromal collagen in desmoplastic models of human breast, pancreatic, and skin tumors in mice. Furthermore, losartan improved the distribution and therapeutic efficacy of intratumorally injected oncolytic herpes simplex viruses. Finally, it also enhanced the efficacy of i.v. injected pegylated liposomal doxorubicin (Doxil). Thus, losartan has the potential to enhance the efficacy of nanotherapeutics in patients with desmoplastic tumors. PMID- 21282608 TI - Successful respiratory immunization with dry powder live-attenuated measles virus vaccine in rhesus macaques. AB - Measles remains an important cause of childhood mortality worldwide. Sustained high vaccination coverage is the key to preventing measles deaths. Because measles vaccine is delivered by injection, hurdles to high coverage include the need for trained medical personnel and a cold chain, waste of vaccine in multidose vials and risks associated with needle use and disposal. Respiratory vaccine delivery could lower these barriers and facilitate sustained high coverage. We developed a novel single unit dose, dry powder live-attenuated measles vaccine (MVDP) for respiratory delivery without reconstitution. We tested the immunogenicity and protective efficacy in rhesus macaques of one dose of MVDP delivered either with a mask or directly intranasal with two dry powder inhalers, PuffHaler and BD Solovent. MVDP induced robust measles virus (MeV)-specific humoral and T-cell responses, without adverse effects, which completely protected the macaques from infection with wild-type MeV more than one year later. Respiratory delivery of MVDP was safe and effective and could aid in measles control. PMID- 21282609 TI - Simple and elegant design of a virion egress structure in Archaea. AB - Some viruses of Archaea use an unusual egress mechanism that involves the formation of virus-associated pyramids (VAPs) on the host cell surface. At the end of the infection cycle, these structures open outward and create apertures through which mature virions escape from the cell. Here we describe in detail the structure and composition of VAPs formed by the Sulfolobus islandicus rod-shaped virus 2 (SIRV2) in cells of its hyperthermophilic archaeal host. We show that the VAPs are stable and autonomous assemblies that can be isolated from membranes of infected cells and purified without affecting their structure. The purified VAPs are heterogeneous in size, reflecting the dynamics of VAP development in a population of infected cells; however, they have a uniform geometry, consisting of seven isosceles triangular faces forming a baseless pyramid. Biochemical and immunoelectron microscopy analyses revealed that the 10-kDa P98 protein encoded by the SIRV2 virus is the sole component of the VAPs. The VAPs were produced in Sulfolobus acidocaldarius and Escherichia coli by heterologous expression of the SIRV2-P98 gene. The results confirm that P98 is the only constituent of the VAPs and demonstrate that no other viral protein is involved in the assembly of pyramids. P98 was able to produce stable structures under conditions ranging from moderate to extremely high temperatures (80 degrees C) and from neutral to extremely acidic pH (pH 2), demonstrating another remarkable property of this exceptional viral protein. PMID- 21282610 TI - Histone H4 Lys 20 monomethylation by histone methylase SET8 mediates Wnt target gene activation. AB - Histone methylation has an important role in transcriptional regulation. However, unlike H3K4 and H3K9 methylation, the role of H4K20 monomethylation (H4K20me-1) in transcriptional regulation remains unclear. Here, we show that Wnt3a specifically stimulates H4K20 monomethylation at the T cell factor (TCF)-binding element through the histone methylase SET8. Additionally, SET8 is crucial for activation of the Wnt reporter gene and target genes in both mammalian cells and zebrafish. Furthermore, SET8 interacts with lymphoid enhancing factor-1 (LEF1)/TCF4 directly, and this interaction is regulated by Wnt3a. Therefore, we conclude that SET8 is a Wnt signaling mediator and is recruited by LEF1/TCF4 to regulate the transcription of Wnt-activated genes, possibly through H4K20 monomethylation at the target gene promoters. Our findings also indicate that H4K20me-1 is a marker for gene transcription activation, at least in canonical Wnt signaling. PMID- 21282611 TI - MSI4/FVE interacts with CUL4-DDB1 and a PRC2-like complex to control epigenetic regulation of flowering time in Arabidopsis. AB - Flowering at the right time is crucial to ensure successful plant reproduction and seed yield and is dependent on both environmental and endogenous parameters. Among the different pathways that impinge on flowering, the autonomous pathway promotes floral transition independently of day length through the repression of the central flowering repressor flowering locus C (FLC). FLC blocks floral transition by repressing flowering time integrators such as flowering locus T (FT). MSI4/FVE is a key regulator of the autonomous pathway that reduces FLC expression. Here we report that the MSI4 protein is a DDB1 and CUL4-associated factor that represses FLC expression through its association with a CLF-Polycomb Repressive Complex 2 (PRC2) in Arabidopsis. Thus, the lack of MSI4 or decreased CUL4 activity reduces H3K27 trimethylation on FLC, but also on its downstream target FT, resulting in increased expression of both genes. Moreover, CUL4 interacts with FLC chromatin in an MSI4-dependant manner, and the interaction between MSI4 and CUL4-DDB1 is necessary for the epigenetic repression of FLC. Overall our work provides evidence for a unique functional interaction between the cullin-RING ubiquitin ligase (CUL4-DDB1(MSI4)) and a CLF-PRC2 complex in the regulation of flowering timing in Arabidopsis. PMID- 21282612 TI - Hundred years of genetic structure in a sediment revived diatom population. AB - This paper presents research on the genetic structure and diversity of populations of a common marine protist and their changes over time. The bloom forming diatom Skeletonema marinoi was used as a model organism. Strains were revived from anoxic discrete layers of a (210)Pb-dated sediment core accumulated over more than 100 y, corresponding to >40,000 diatom mitotic generations. The sediment core was sampled from the highly eutrophic Mariager Fjord in Denmark. The genetic structure of S. marinoi was examined using microsatellite markers, enabling exploration of changes through time and of the effect of environmental fluctuations. The results showed a stable population structure among and within the examined sediment layers, and a similar genetic structure has been maintained over thousands of generations. However, established populations from inside the fjord were highly differentiated from open-sea populations. Despite constant water exchange and influx of potential colonizers into the fjord, the populations do not mix. One fjord population, accumulated in 1980, was significantly differentiated from the other groups of strains isolated from the fjord. This differentiation could have resulted from the status of Mariager Fjord, which was considered hypereutrophic, around 1980. There was no significant genetic difference between pre- and posteutrophication groups of strains. Our data show that dispersal potential and generation time do not have a large impact on the genetic structuring of the populations investigated here. Instead, the environmental conditions, such as the extreme eutrophication of the Mariager Fjord, are deemed more important. PMID- 21282613 TI - Lethal Arg9Cys phospholamban mutation hinders Ca2+-ATPase regulation and phosphorylation by protein kinase A. AB - The regulatory interaction of phospholamban (PLN) with Ca(2+)-ATPase controls the uptake of calcium into the sarcoplasmic reticulum, modulating heart muscle contractility. A missense mutation in PLN cytoplasmic domain (R9C) triggers dilated cardiomyopathy in humans, leading to premature death. Using a combination of biochemical and biophysical techniques both in vitro and in live cells, we show that the R9C mutation increases the stability of the PLN pentameric assembly via disulfide bridge formation, preventing its binding to Ca(2+)-ATPase as well as phosphorylation by protein kinase A. These effects are enhanced under oxidizing conditions, suggesting that oxidative stress may exacerbate the cardiotoxic effects of the PLN(R9C) mutant. These results reveal a regulatory role of the PLN pentamer in calcium homeostasis, going beyond the previously hypothesized role of passive storage for active monomers. PMID- 21282614 TI - Entropic crystal-crystal transitions of Brownian squares. AB - When a monolayer of hard microscale square platelets, produced lithographically, is osmotically concentrated in a flat plane to raise the particle area fraction Phi(A), an order-order transition occurs between a hexagonal rotator crystal and a rhombic crystal. Strikingly, phases having fourfold symmetry are not observed at any Phi(A). The rhombic lattice angle alpha increases continuously with Phi(A), as the system maximizes its total rotational and translational entropy. A cage model, based on packing rotationally swept squares, or "squaroids," reasonably predicts the measured alpha(Phi(A)), indicating that rotational entropy and the square particle shape combine to produce the rhombic unit cell. PMID- 21282615 TI - Crystal structure of the synergistic antibiotic pair, lankamycin and lankacidin, in complex with the large ribosomal subunit. AB - The structures of the large ribosomal subunit of Deinococcus radiodurans (D50S) in complex with the antibiotic lankamycin (3.2 A) and a double antibiotic complex of lankamycin and lankacidin C (3.45 A) have been determined, in continuation of previous crystallographic studies on lankacidin-D50S complex. These two drugs have been previously reported to inhibit ribosomal function with mild synergistic effect. Lankamycin, a member of the macrolide family, binds in a similar manner to erythromycin. However, when in complex with lankacidin, lankamycin is located so that it can form interactions with lankacidin in the adjacent ribosomal binding site. When compared to the well-documented synergistic antibiotics, Streptogramins A and B, the pair of lankacidin and lankamycin bind in similar sites, the peptidyl transferase center and nascent peptide exit tunnel, respectively. Herein, we discuss the structural basis for antibiotic synergism and highlight the key factors involved in ribosomal inhibition. PMID- 21282616 TI - Magnetosome-like ferrimagnetic iron oxide nanocubes for highly sensitive MRI of single cells and transplanted pancreatic islets. AB - For ultrasensitive magnetic resonance imaging (MRI), magnetic nanoparticles with extremely high r2 relaxivity are strongly desired. Magnetosome-like nanoparticles were prepared by coating polyethylene glycol-phospholipid (PEG-phospholipid) onto ferrimagnetic iron oxide nanocubes (FIONs). FIONs exhibited a very high relaxivity (r2) of 324 mM(-1) s(-1), allowing efficient labeling of various kinds of cells. The magnetic resonance (MR) imaging of single cells labeled with FIONs is demonstrated not only in vitro but also in vivo. Pancreatic islet grafts and their rejection could be imaged using FIONs on a 1.5 T clinical MRI scanner. The strong contrast effect of FIONs enabled MR imaging of transplanted islets in small rodents as well as in large animals. Therefore, we expect that MR imaging of pancreatic islet grafts using FIONs has the potentials for clinical applications. Furthermore, FIONs will enable highly sensitive noninvasive assessment after cell transplantation. PMID- 21282617 TI - Chemical storage of hydrogen in few-layer graphene. AB - Birch reduction of few-layer graphene samples gives rise to hydrogenated samples containing up to 5 wt % of hydrogen. Spectroscopic studies reveal the presence of sp(3) C-H bonds in the hydrogenated graphenes. They, however, decompose readily on heating to 500 degrees C or on irradiation with UV or laser radiation releasing all the hydrogen, thereby demonstrating the possible use of few-layer graphene for chemical storage of hydrogen. First-principles calculations throw light on the mechanism of dehydrogenation that appears to involve a significant reconstruction and relaxation of the lattice. PMID- 21282618 TI - Substantial expression of mature elastin in arterial constructs. AB - Mature elastin synthesis is a key challenge in arterial tissue engineering. Most engineered vessels lack elastic fibers in the medial layer and those present are poorly organized. The objective of this study is to increase mature elastin synthesis in small-diameter arterial constructs. Adult primary baboon smooth muscle cells (SMCs) were seeded in the lumen of porous tubular scaffolds fabricated from a biodegradable elastomer, poly(glycerol sebacate) (PGS) and cultured in a pulsatile flow bioreactor for 3 wk. We tested the effect of pore sizes on construct properties by histological, biochemical, and mechanical evaluations. Histological analysis revealed circumferentially organized extracellular matrix proteins including elastin and the presence of multilayered SMCs expressing calponin and alpha-smooth muscle actin. Biochemical analysis demonstrated that the constructs contained mature elastin equivalent to 19% of the native arteries. Mechanical tests indicated that the constructs could withstand up to 200 mmHg burst pressure and exhibited compliance comparable to native arteries. These results show that nontransfected cells in PGS scaffolds in unsupplemented medium produced a substantial amount of mature elastin within 3 wk and the elastic fibers had similar orientation as those in native arteries. The 25-32 MUm pore size supported cell organization and elastin synthesis more than larger pore sizes. To our knowledge, there was no prior report of the synthesis of mature and organized elastin in arterial constructs without exogenous factors or viral transduction. PMID- 21282619 TI - Microworm optode sensors limit particle diffusion to enable in vivo measurements. AB - There have been a variety of nanoparticles created for in vivo uses ranging from gene and drug delivery to tumor imaging and physiological monitoring. The use of nanoparticles to measure physiological conditions while being fluorescently addressed through the skin provides an ideal method toward minimally invasive health monitoring. Here we create unique particles that have all the necessary physical characteristics to serve as in vivo reporters, but with minimized diffusion from the point of injection. These particles, called microworms, have a cylindrical shape coated with a biocompatible porous membrane that possesses a large surface-area-to-volume ratio while maintaining a large hydrodynamic radius. We use these microworms to create fluorescent sodium sensors for use as in vivo sodium concentration detectors after subcutaneous injection. However, the microworm concept has the potential to extend to the immobilization of other types of polymers for continuous physiological detection or delivery of molecules. PMID- 21282620 TI - XMAP215 polymerase activity is built by combining multiple tubulin-binding TOG domains and a basic lattice-binding region. AB - XMAP215/Dis1 family proteins positively regulate microtubule growth. Repeats at their N termini, called TOG domains, are important for this function. While TOG domains directly bind tubulin dimers, it is unclear how this interaction translates to polymerase activity. Understanding the functional roles of TOG domains is further complicated by the fact that the number of these domains present in the proteins of different species varies. Here, we take advantage of a recent crystal structure of the third TOG domain from Caenorhabditis elegans, Zyg9, and mutate key residues in each TOG domain of XMAP215 that are predicted to be important for interaction with the tubulin heterodimer. We determined the contributions of the individual TOG domains to microtubule growth. We show that the TOG domains are absolutely required to bind free tubulin and that the domains differentially contribute to XMAP215's overall affinity for free tubulin. The mutants' overall affinity for free tubulin correlates well with polymerase activity. Furthermore, we demonstrate that an additional basic region is important for targeting to the microtubule lattice and is critical for XMAP215 to function at physiological concentrations. Using this information, we have engineered a "bonsai" protein, with two TOG domains and a basic region, that has almost full polymerase activity. PMID- 21282621 TI - Thiol peroxidases mediate specific genome-wide regulation of gene expression in response to hydrogen peroxide. AB - Hydrogen peroxide is thought to regulate cellular processes by direct oxidation of numerous cellular proteins, whereas antioxidants, most notably thiol peroxidases, are thought to reduce peroxides and inhibit H(2)O(2) response. However, thiol peroxidases have also been implicated in activation of transcription factors and signaling. It remains unclear if these enzymes stimulate or inhibit redox regulation and whether this regulation is widespread or limited to a few cellular components. Herein, we found that Saccharomyces cerevisiae cells lacking all eight thiol peroxidases were viable and withstood redox stresses. They transcriptionally responded to various redox treatments, but were unable to activate and repress gene expression in response to H(2)O(2). Further studies involving redox transcription factors suggested that thiol peroxidases are major regulators of global gene expression in response to H(2)O(2). The data suggest that thiol peroxidases sense and transfer oxidative signals to the signaling proteins and regulate transcription, whereas a direct interaction between H(2)O(2) and other cellular proteins plays a secondary role. PMID- 21282622 TI - CAF-I-dependent control of degradation of the discontinuous strands during mismatch repair. AB - DNA mismatch repair (MMR) is a multifunctional process that promotes genetic stability and suppresses carcinogenesis. Correction of DNA replication errors is its major function. Despite the importance of MMR, its functioning in eukaryotes is not well understood. Here we report that human mismatch correction reactions in cell-free extracts occur during concomitant nick-dependent nucleosome assembly shaped by the replication histone chaperone CAF-I. Concomitant nucleosome assembly protects the discontinuous mismatch-containing strands from excessive degradation by MMR machinery. Such protection is also demonstrated in a defined purified system that supports both mismatch correction and CAF-I-dependent histone H3-H4 deposition reactions. In addition, we find that the mismatch recognition factor MutSalpha suppresses CAF-I-dependent histone H3-H4 deposition in a mismatch-dependent manner. We suggest that there is active crosstalk between MMR and replication-dependent nucleosome assembly during the correction of DNA replication errors and, as a result, the nascent mismatch-containing strands are degraded in a controlled manner. PMID- 21282623 TI - Real-time mapping of a hydrogen peroxide concentration profile across a polymicrobial bacterial biofilm using scanning electrochemical microscopy. AB - Quantitative detection of hydrogen peroxide in solution above a Streptococcus gordonii (Sg) bacterial biofilm was studied in real time by scanning electrochemical microscopy (SECM). The concentration of hydrogen peroxide was determined to be 0.7 mM to 1.6 mM in the presence of 10 mM glucose over a period of 2 to 8 h. The hydrogen peroxide production measured was higher near the biofilm surface in comparison to Sg grown planktonically. Differential hydrogen peroxide production was observed both by fluorometric as well as by SECM measurements. The interaction between two different species in a bacterial biofilm of Sg and Aggregatibacter actinomycetemcomitans (Aa) in terms of hydrogen peroxide production was also studied by SECM. One-directional y-scan SECM measurements showed the unique spatial mapping of hydrogen peroxide concentration across a mixed species biofilm and revealed that hydrogen peroxide concentration varies greatly dependent upon local species composition. PMID- 21282624 TI - Physical and economic consequences of climate change in Europe. AB - Quantitative estimates of the economic damages of climate change usually are based on aggregate relationships linking average temperature change to loss in gross domestic product (GDP). However, there is a clear need for further detail in the regional and sectoral dimensions of impact assessments to design and prioritize adaptation strategies. New developments in regional climate modeling and physical-impact modeling in Europe allow a better exploration of those dimensions. This article quantifies the potential consequences of climate change in Europe in four market impact categories (agriculture, river floods, coastal areas, and tourism) and one nonmarket impact (human health). The methodology integrates a set of coherent, high-resolution climate change projections and physical models into an economic modeling framework. We find that if the climate of the 2080s were to occur today, the annual loss in household welfare in the European Union (EU) resulting from the four market impacts would range between 0.2-1%. If the welfare loss is assumed to be constant over time, climate change may halve the EU's annual welfare growth. Scenarios with warmer temperatures and a higher rise in sea level result in more severe economic damage. However, the results show that there are large variations across European regions. Southern Europe, the British Isles, and Central Europe North appear most sensitive to climate change. Northern Europe, on the other hand, is the only region with net economic benefits, driven mainly by the positive effects on agriculture. Coastal systems, agriculture, and river flooding are the most important of the four market impacts assessed. PMID- 21282625 TI - Involvement of ryanodine receptors in neurotrophin-induced hippocampal synaptic plasticity and spatial memory formation. AB - Ryanodine receptors (RyR) amplify activity-dependent calcium influx via calcium induced calcium release. Calcium signals trigger postsynaptic pathways in hippocampal neurons that underlie synaptic plasticity, learning, and memory. Recent evidence supports a role of the RyR2 and RyR3 isoforms in these processes. Along with calcium signals, brain-derived neurotrophic factor (BDNF) is a key signaling molecule for hippocampal synaptic plasticity and spatial memory. Upon binding to specific TrkB receptors, BDNF initiates complex signaling pathways that modify synaptic structure and function. Here, we show that BDNF-induced remodeling of hippocampal dendritic spines required functional RyR. Additionally, incubation with BDNF enhanced the expression of RyR2, RyR3, and PKMzeta, an atypical protein kinase C isoform with key roles in hippocampal memory consolidation. Consistent with their increased RyR protein content, BDNF-treated neurons generated larger RyR-mediated calcium signals than controls. Selective inhibition of RyR-mediated calcium release with inhibitory ryanodine concentrations prevented the PKMzeta, RyR2, and RyR3 protein content enhancement induced by BDNF. Intrahippocampal injection of BDNF or training rats in a spatial memory task enhanced PKMzeta, RyR2, RyR3, and BDNF hippocampal protein content, while injection of ryanodine at concentrations that stimulate RyR-mediated calcium release improved spatial memory learning and enhanced memory consolidation. We propose that RyR-generated calcium signals are key features of the complex neuronal plasticity processes induced by BDNF, which include increased expression of RyR2, RyR3, and PKMzeta and the spine remodeling required for spatial memory formation. PMID- 21282626 TI - A closer look at the turtle's eyes. PMID- 21282627 TI - Population genomics and local adaptation in wild isolates of a model microbial eukaryote. AB - Elucidating the connection between genotype, phenotype, and adaptation in wild populations is fundamental to the study of evolutionary biology, yet it remains an elusive goal, particularly for microscopic taxa, which comprise the majority of life. Even for microbes that can be reliably found in the wild, defining the boundaries of their populations and discovering ecologically relevant phenotypes has proved extremely difficult. Here, we have circumvented these issues in the microbial eukaryote Neurospora crassa by using a "reverse-ecology" population genomic approach that is free of a priori assumptions about candidate adaptive alleles. We performed Illumina whole-transcriptome sequencing of 48 individuals to identify single nucleotide polymorphisms. From these data, we discovered two cryptic and recently diverged populations, one in the tropical Caribbean basin and the other endemic to subtropical Louisiana. We conducted high-resolution scans for chromosomal regions of extreme divergence between these populations and found two such genomic "islands." Through growth-rate assays, we found that the subtropical Louisiana population has a higher fitness at low temperature (10 degrees C) and that several of the genes within these distinct regions have functions related to the response to cold temperature. These results suggest the divergence islands may be the result of local adaptation to the 9 degrees C difference in average yearly minimum temperature between these two populations. Remarkably, another of the genes identified using this unbiased, whole-genome approach is the well-known circadian oscillator frequency, suggesting that the 2.4 degrees -10.6 degrees difference in latitude between the populations may be another important environmental parameter. PMID- 21282628 TI - Impaired theory of mind for moral judgment in high-functioning autism. AB - High-functioning autism (ASD) is characterized by real-life difficulties in social interaction; however, these individuals often succeed on laboratory tests that require an understanding of another person's beliefs and intentions. This paradox suggests a theory of mind (ToM) deficit in adults with ASD that has yet to be demonstrated in an experimental task eliciting ToM judgments. We tested whether ASD adults would show atypical moral judgments when they need to consider both the intentions (based on ToM) and outcomes of a person's actions. In experiment 1, ASD and neurotypical (NT) participants performed a ToM task designed to test false belief understanding. In experiment 2, the same ASD participants and a new group of NT participants judged the moral permissibility of actions, in a 2 (intention: neutral/negative) * 2 (outcome: neutral/negative) design. Though there was no difference between groups on the false belief task, there was a selective difference in the moral judgment task for judgments of accidental harms, but not neutral acts, attempted harms, or intentional harms. Unlike the NT group, which judged accidental harms less morally wrong than attempted harms, the ASD group did not reliably judge accidental and attempted harms as morally different. In judging accidental harms, ASD participants appeared to show an underreliance on information about a person's innocent intention and, as a direct result, an overreliance on the action's negative outcome. These findings reveal impairments in integrating mental state information (e.g., beliefs, intentions) for moral judgment. PMID- 21282629 TI - Antigen-independent signalosome of CARMA1, PKCtheta, and TNF receptor-associated factor 2 (TRAF2) determines NF-kappaB signaling in T cells. AB - NF-kappaB activation is essential for T-cell responses, and costimulatory molecules in the TNF receptor (TNFR) superfamily are viewed as a major source of this signal. Although the TNFR family recruits TNFR-associated factor (TRAF) molecules leading to IKKalpha/beta/gamma activation, it is not clear whether simple binding of TRAFs explains why they are such strong activators of NF-kappaB and so important for T-cell immunity. We now show that one TNFR family member, OX40 (CD134), after ligation by OX40L, assembles a unique complex that not only contains TRAF2, RIP, and IKKalpha/beta/gamma but also CARMA1, MALT1, BCL10, and PKC, molecules previously shown to regulate NF-kappaB activation through the T cell receptor (TCR). The OX40 signalosome is formed in membrane microdomains irrespective of TCR engagement, and strongly promotes NF-kappaB activation only if CARMA1 and PKC are recruited. This NF-kappaB signal allows effector/memory T cells to survive when antigen is no longer available. Thus, by recruiting TCR related intracellular molecules into the TRAF2 complex, OX40 provides the T cell with a high level of NF-kappaB activity needed for longevity. PMID- 21282630 TI - Differential electrophysiological response during rest, self-referential, and non self-referential tasks in human posteromedial cortex. AB - The electrophysiological basis for higher brain activity during rest and internally directed cognition within the human default mode network (DMN) remains largely unknown. Here we use intracranial recordings in the human posteromedial cortex (PMC), a core node within the DMN, during conditions of cued rest, autobiographical judgments, and arithmetic processing. We found a heterogeneous profile of PMC responses in functional, spatial, and temporal domains. Although the majority of PMC sites showed increased broad gamma band activity (30-180 Hz) during rest, some PMC sites, proximal to the retrosplenial cortex, responded selectively to autobiographical stimuli. However, no site responded to both conditions, even though they were located within the boundaries of the DMN identified with resting-state functional imaging and similarly deactivated during arithmetic processing. These findings, which provide electrophysiological evidence for heterogeneity within the core of the DMN, will have important implications for neuroimaging studies of the DMN. PMID- 21282631 TI - Draft genome of the globally widespread and invasive Argentine ant (Linepithema humile). AB - Ants are some of the most abundant and familiar animals on Earth, and they play vital roles in most terrestrial ecosystems. Although all ants are eusocial, and display a variety of complex and fascinating behaviors, few genomic resources exist for them. Here, we report the draft genome sequence of a particularly widespread and well-studied species, the invasive Argentine ant (Linepithema humile), which was accomplished using a combination of 454 (Roche) and Illumina sequencing and community-based funding rather than federal grant support. Manual annotation of >1,000 genes from a variety of different gene families and functional classes reveals unique features of the Argentine ant's biology, as well as similarities to Apis mellifera and Nasonia vitripennis. Distinctive features of the Argentine ant genome include remarkable expansions of gustatory (116 genes) and odorant receptors (367 genes), an abundance of cytochrome P450 genes (>110), lineage-specific expansions of yellow/major royal jelly proteins and desaturases, and complete CpG DNA methylation and RNAi toolkits. The Argentine ant genome contains fewer immune genes than Drosophila and Tribolium, which may reflect the prominent role played by behavioral and chemical suppression of pathogens. Analysis of the ratio of observed to expected CpG nucleotides for genes in the reproductive development and apoptosis pathways suggests higher levels of methylation than in the genome overall. The resources provided by this genome sequence will offer an abundance of tools for researchers seeking to illuminate the fascinating biology of this emerging model organism. PMID- 21282632 TI - Dishevelled is essential for neural connectivity and planar cell polarity in planarians. AB - The Wingless/Integrated (Wnt) signaling pathway controls multiple events during development and homeostasis. It comprises multiple branches, mainly classified according to their dependence on beta-catenin activation. The Wnt/beta-catenin branch is essential for the establishment of the embryonic anteroposterior (AP) body axis throughout the phylogenetic tree. It is also required for AP axis establishment during planarian regeneration. Wnt/beta-catenin-independent signaling encompasses several different pathways, of which the most extensively studied is the planar cell polarity (PCP) pathway, which is responsible for planar polarization of cell structures within an epithelial sheet. Dishevelled (Dvl) is the hub of Wnt signaling because it regulates and channels the Wnt signal into every branch. Here, we analyze the role of Schmidtea mediterranea Dvl homologs (Smed-dvl-1 and Smed-dvl-2) using gene silencing. We demonstrate that in addition to a role in AP axis specification, planarian Dvls are involved in at least two different beta-catenin-independent processes. First, they are essential for neural connectivity through Smed-wnt5 signaling. Second, Smed-dvl-2, together with the S. mediterranea homologs of Van-Gogh (Vang) and Diversin (Div), is required for apical positioning of the basal bodies of epithelial cells. These data represent evidence not only of the function of the PCP network in lophotrocozoans but of the involvement of the PCP core elements Vang and Div in apical positioning of the cilia. PMID- 21282633 TI - Hox gene Ultrabithorax regulates distinct sets of target genes at successive stages of Drosophila haltere morphogenesis. AB - Hox genes encode highly conserved transcription factors that regionalize the animal body axis by controlling complex developmental processes. Although they are known to operate in multiple cell types and at different stages, we are still missing the batteries of genes targeted by any one Hox gene over the course of a single developmental process to achieve a particular cell and organ morphology. The transformation of wings into halteres by the Hox gene Ultrabithorax (Ubx) in Drosophila melanogaster presents an excellent model system to study the Hox control of transcriptional networks during successive stages of appendage morphogenesis and cell differentiation. We have used an inducible misexpression system to switch on Ubx in the wing epithelium at successive stages during metamorphosis--in the larva, prepupa, and pupa. We have then used extensive microarray expression profiling and quantitative RT-PCR to identify the primary transcriptional responses to Ubx. We find that Ubx targets range from regulatory genes like transcription factors and signaling components to terminal differentiation genes affecting a broad repertoire of cell behaviors and metabolic reactions. Ubx up- and down-regulates hundreds of downstream genes at each stage, mostly in a subtle manner. Strikingly, our analysis reveals that Ubx target genes are largely distinct at different stages of appendage morphogenesis, suggesting extensive interactions between Hox genes and hormone-controlled regulatory networks to orchestrate complex genetic programs during metamorphosis. PMID- 21282634 TI - Gradual disintegration of the floral symmetry gene network is implicated in the evolution of a wind-pollination syndrome. AB - Angiosperms exhibit staggering diversity in floral form, and evolution of floral morphology is often correlated with changes in pollination syndrome. The showy, bilaterally symmetrical flowers of the model species Antirrhinum majus (Plantaginaceae) are highly specialized for bee pollination. In A. majus, Cycloidea (CYC), Dichotoma (DICH), Radialis (RAD), and Divaricata (DIV) specify the development of floral bilateral symmetry. However, it is unclear to what extent evolution of these genes has resulted in flower morphological divergence among closely related members of Plantaginaceae differing in pollination syndrome. We compared floral symmetry genes from insect-pollinated Digitalis purpurea, which has bilaterally symmetrical flowers, with those from closely related Aragoa abietina and wind-pollinated Plantago major, both of which have radially symmetrical flowers. We demonstrate that Plantago, but not Aragoa, species have lost a dorsally expressed CYC-like gene and downstream targets RAD and DIV. Furthermore, the single P. major CYC-like gene is expressed across all regions of the flower, similar to expression of its ortholog in closely related Veronica serpyllifolia. We propose that changes in the expression of duplicated CYC-like genes led to the evolution of radial flower symmetry in Aragoa/Plantago, and that further disintegration of the symmetry gene pathway resulted in the wind pollination syndrome of Plantago. This model underscores the potential importance of gene loss in the evolution of ecologically important traits. PMID- 21282635 TI - Signaling mechanisms in the restoration of impaired immune function due to diet induced obesity. AB - Our previous data have linked obesity with immune dysfunction. It is known that physical exercise with dietary control has beneficial effects on immune function and the comorbidities of obesity. However, the mechanisms underlying the improvement of immune function in obesity after physical exercise with dietary control remain unknown. Here we show that moderate daily exercise with dietary control restores the impaired cytokine responses in diet-induced obese (DIO) mice and improves the resolution of Porphyromonas gingivalis-induced periodontitis. This restoration of immune responses is related to the reduction of circulating free fatty acids (FFAs) and TNF. Both FFAs and TNF induce an Akt inhibitor, carboxyl-terminal modulator protein (CTMP). The expression of CTMP is also observed increased in bone marrow-derived macrophages (BMMPhi) from DIO mice and restored after moderate daily exercise with dietary control. Toll-like receptor 2 (TLR2), which increases CTMP induction by FFAs, is inhibited in BMMPhi from DIO mice or after either FFA or TNF treatment, but unexpectedly is not restored by moderate daily exercise with dietary control. Furthermore, BMMPhi from DIO mice display reduced histone H3 (Lys-9) acetylation and NF-kappaB recruitment to TNF, IL-10, and TLR2 promoters after P. gingivalis infection. However, moderate daily exercise with dietary control restores these defects at promoters for TNF and IL 10, but not for TLR2. Thus, metabolizing FFAs and TNF by moderate daily exercise with dietary control improves innate immune responses to infection in DIO mice via restoration of CTMP and chromatin modification. PMID- 21282636 TI - Normal gut microbiota modulates brain development and behavior. AB - Microbial colonization of mammals is an evolution-driven process that modulate host physiology, many of which are associated with immunity and nutrient intake. Here, we report that colonization by gut microbiota impacts mammalian brain development and subsequent adult behavior. Using measures of motor activity and anxiety-like behavior, we demonstrate that germ free (GF) mice display increased motor activity and reduced anxiety, compared with specific pathogen free (SPF) mice with a normal gut microbiota. This behavioral phenotype is associated with altered expression of genes known to be involved in second messenger pathways and synaptic long-term potentiation in brain regions implicated in motor control and anxiety-like behavior. GF mice exposed to gut microbiota early in life display similar characteristics as SPF mice, including reduced expression of PSD-95 and synaptophysin in the striatum. Hence, our results suggest that the microbial colonization process initiates signaling mechanisms that affect neuronal circuits involved in motor control and anxiety behavior. PMID- 21282637 TI - Mesodermal developmental gene Tbx15 impairs adipocyte differentiation and mitochondrial respiration. AB - Increased intraabdominal (visceral) fat is associated with a high risk of diabetes and metabolic syndrome. We have previously shown that the mesodermal developmental transcription factor Tbx15 is highly differentially expressed between visceral and subcutaneous (s.c.) fat in both humans and rodents, and in humans visceral fat Tbx15 expression is decreased in obesity. Here we show that, in mice, Tbx15 is 260-fold more highly expressed in s.c. preadipocytes than in epididymal preadipocytes. Overexpression of Tbx15 in 3T3-L1 preadipocytes impairs adipocyte differentiation and decreases triglyceride content. This defect in differentiation can be corrected by stimulating cells with the PPARgamma agonist rosiglitazone (Rosi). However, triglyceride accumulation remains decreased by ~50%, due to a decrease in basal lipogenic rate and increase in basal lipolytic rate. 3T3-L1 preadipocytes overexpressing Tbx15 also have a 15% reduction in mitochondrial mass and a 28% reduction in basal mitochondrial respiration (P = 0.004) and ATP turnover (P = 0.02), and a 45% (P = 0.003) reduction in mitochondrial respiratory capacity. Thus, differential expression of Tbx15 between fat depots plays an important role in the interdepot differences in adipocyte differentiation, triglyceride accumulation, and mitochondrial function that may contribute to the risk of diabetes and metabolic disease. PMID- 21282638 TI - Transgenic elimination of high-affinity antidepressant and cocaine sensitivity in the presynaptic serotonin transporter. AB - Serotonin [i.e., 5-hydroxytryptamine (5-HT)]-targeted antidepressants are in wide use for the treatment of mood disorders, although many patients do not show a response or experience unpleasant side effects. Psychostimulants, such as cocaine and 3,4-methylenedioxymethamphetamine (i.e., "ecstasy"), also impact 5-HT signaling. To help dissect the contribution of 5-HT signaling to the actions of these and other agents, we developed transgenic mice in which high-affinity recognition of multiple antidepressants and cocaine is eliminated. Our animals possess a modified copy of the 5-HT transporter (i.e., SERT, slc6a4) that bears a single amino acid substitution, I172M, proximal to the 5-HT binding site. Although the M172 substitution does not impact the recognition of 5-HT, this mutation disrupts high-affinity binding of many competitive antagonists in transfected cells. Here, we demonstrate that, in M172 knock-in mice, basal SERT protein levels, 5-HT transport rates, and 5-HT levels are normal. However, SERT M172 mice display a substantial loss of sensitivity to the selective 5-HT reuptake inhibitors fluoxetine and citalopram, as well as to cocaine. Through a series of biochemical, electrophysiological, and behavioral assays, we demonstrate the unique properties of this model and establish directly that SERT is the sole protein responsible for selective 5-HT reuptake inhibitor-mediated alterations in 5-HT clearance, in 5-HT1A autoreceptor modulation of raphe neuron firing, and in behaviors used to predict the utility of antidepressants. PMID- 21282639 TI - Grb-2-associated binder 1 (Gab1) regulates postnatal ischemic and VEGF-induced angiogenesis through the protein kinase A-endothelial NOS pathway. AB - The intracellular signaling mechanisms underlying postnatal angiogenesis are incompletely understood. Herein we show that Grb-2-associated binder 1 (Gab1) plays a critical role in ischemic and VEGF-induced angiogenesis. Endothelium specific Gab1 KO (EGKO) mice displayed impaired angiogenesis in the ischemic hindlimb despite normal induction of VEGF expression. Matrigel plugs with VEGF implanted in EGKO mice induced fewer capillaries than those in control mice. The vessels and endothelial cells (ECs) derived from EGKO mice were defective in vascular sprouting and tube formation induced by VEGF. Biochemical analyses revealed a substantial reduction of endothelial NOS (eNOS) activation in Gab1 deficient vessels and ECs following VEGF stimulation. Interestingly, the phosphorylation of Akt, an enzyme known to promote VEGF-induced eNOS activation, was increased in Gab1-deficient vessels and ECs whereas protein kinase A (PKA) activity was significantly decreased. Introduction of an active form of PKA rescued VEGF-induced eNOS activation and tube formation in EGKO ECs. Reexpression of WT or mutant Gab1 molecules in EGKO ECs revealed requirement of Gab1/Shp2 association for the activation of PKA and eNOS. Taken together, these results identify Gab1 as a critical upstream signaling component in VEGF-induced eNOS activation and tube formation, which is dependent on PKA. Of note, this pathway is conserved in primary human ECs for VEGF-induced eNOS activation and tube formation, suggesting considerable potential in treatment of human ischemic diseases. PMID- 21282640 TI - Widespread establishment and regulatory impact of Alu exons in human genes. AB - The Alu element has been a major source of new exons during primate evolution. Thousands of human genes contain spliced exons derived from Alu elements. However, identifying Alu exons that have acquired genuine biological functions remains a major challenge. We investigated the creation and establishment of Alu exons in human genes, using transcriptome profiles of human tissues generated by high-throughput RNA sequencing (RNA-Seq) combined with extensive RT-PCR analysis. More than 25% of Alu exons analyzed by RNA-Seq have estimated transcript inclusion levels of at least 50% in the human cerebellum, indicating widespread establishment of Alu exons in human genes. Genes encoding zinc finger transcription factors have significantly higher levels of Alu exonization. Importantly, Alu exons with high splicing activities are strongly enriched in the 5'-UTR, and two-thirds (10/15) of 5'-UTR Alu exons tested by luciferase reporter assays significantly alter mRNA translational efficiency. Mutational analysis reveals the specific molecular mechanisms by which newly created 5'-UTR Alu exons modulate translational efficiency, such as the creation or elongation of upstream ORFs that repress the translation of the primary ORFs. This study presents genomic evidence that a major functional consequence of Alu exonization is the lineage-specific evolution of translational regulation. Moreover, the preferential creation and establishment of Alu exons in zinc finger genes suggest that Alu exonization may have globally affected the evolution of primate and human transcriptomes by regulating the protein production of master transcriptional regulators in specific lineages. PMID- 21282641 TI - Angiogenic sprouting into neural tissue requires Gpr124, an orphan G protein coupled receptor. AB - The vasculature of the CNS is structurally and functionally distinct from that of other organ systems and is particularly prone to developmental abnormalities and hemorrhage. Although other embryonic tissues undergo primary vascularization, the developing nervous system is unique in that it is secondarily vascularized by sprouting angiogenesis from a surrounding perineural plexus. This sprouting angiogenesis requires the TGF-beta and Wnt pathways because ablation of these pathways results in aberrant sprouting and hemorrhage. We have genetically deleted Gpr124, a member of the large family of long N-terminal group B G protein coupled receptors, few members of which have identified ligands or well-defined biologic functions in mammals. We show that, in the developing CNS, Gpr124 is specifically expressed in the vasculature and is absolutely required for proper angiogenic sprouting into the developing neural tube. Embryos lacking Gpr124 exhibit vascular defects characterized by delayed vascular penetration, formation of pathological glomeruloid tufts within the CNS, and hemorrhage. In addition, they display defects in palate and lung development, two processes in which TGF beta and/or Wnt pathways also play important roles. We also show that TGF-beta stimulates Gpr124 expression, and ablation of Gpr124 results in perturbed TGF beta pathway activation, suggesting roles for Gpr124 in modulating TGF-beta signaling. These results represent a unique function attributed to a long N terminal group B-type G protein-coupled receptor in a mammalian system. PMID- 21282642 TI - Intramolecular proton shuttle supports not only catalytic but also noncatalytic function of carbonic anhydrase II. AB - Carbonic anhydrases (CAs) catalyze the reversible hydration of CO(2) to HCO(3)(-) and H(+). The rate-limiting step in this reaction is the shuttle of protons between the catalytic center of the enzyme and the bulk solution. In carbonic anhydrase II (CAII), the fastest and most wide-spread isoform, this H(+) shuttle is facilitated by the side chain of His64, whereas CA isoforms such as carbonic anhydrase III (CAIII), which lack such a shuttle, have only low catalytic activity in vitro. By using heterologous protein expression in Xenopus oocytes, we tested the role of this intramolecular H(+) shuttle on CA activity in an intact cell. The data revealed that CAIII, shown in vitro to have ~1,000-fold reduced activity as compared with CAII, displays significant catalytic activity in the intact cell. Furthermore, we tested the hypothesis that the H(+) shuttle in CAII itself can facilitate transport activity of the monocarboxylate transporters 1 and 4 (MCT1/4) independent of catalytic activity. Our results show that His64 is essential for the enhancement of lactate transport via MCT1/4, because a mutation of this residue to alanine (CAII-H64A) abolishes the CAII induced increase in MCT1/4 activity. However, injection of 4-methylimidazole, which acts as an exogenous H(+) donor/acceptor, can restore the ability of CAII H64A to enhance transport activity of MCT1/4. These findings support the hypothesis that the H(+) shuttle in CAII not only facilitates CAII catalytic activity but also can enhance activity of acid-/base-transporting proteins such as MCT1/4 in a direct, noncatalytic manner, possibly by acting as an "H(+) collecting antenna." PMID- 21282643 TI - Neural dysregulation of peripheral insulin action and blood pressure by brain endoplasmic reticulum stress. AB - Chronic endoplasmic reticulum (ER) stress was recently revealed to affect hypothalamic neuroendocrine pathways that regulate feeding and body weight. However, it remains unexplored whether brain ER stress could use a neural route to rapidly cause the peripheral disorders that underlie the development of type 2 diabetes (T2D) and the metabolic syndrome. Using a pharmacologic model that delivered ER stress inducer thapsigargin into the brain, this study demonstrated that a short-term brain ER stress over 3 d was sufficient to induce glucose intolerance, systemic and hepatic insulin resistance, and blood pressure (BP) increase. The collection of these changes was accompanied by elevated sympathetic tone and prevented by sympathetic suppression. Molecular studies revealed that acute induction of metabolic disorders via brain ER stress was abrogated by NF kappaB inhibition in the hypothalamus. Therapeutic experiments further revealed that acute inhibition of brain ER stress with tauroursodeoxycholic acid (TUDCA) partially reversed obesity-associated metabolic and blood pressure disorders. In conclusion, ER stress in the brain represents a mediator of the sympathetic disorders that underlie the development of insulin resistance syndrome and T2D. PMID- 21282644 TI - Signatures of murine B-cell development implicate Yy1 as a regulator of the germinal center-specific program. AB - We utilized gene expression profiling of a comprehensive panel of purified developmentally defined normal murine B cells to identify unique transcriptional signatures for each subset. To elucidate transcription factor activities that function in a stage-specific fashion, we used gene sets that share transcription factor targets and found that germinal center B cells had a robust enrichment of up-regulated and down-regulated signatures compared with the other B-cell subsets. Notably, we found Yy1 and its targets to be central regulators of the germinal center B (GCB)-specific transcriptional program with binding of Yy1 to select signature genes in GCB cells, and translation of the Yy1 signatures to human GCB cells. We then tested whether our newly generated, stage-specific transcriptional signatures could be used to link murine lymphoma models to stages of normal B-cell development. Although each of the molecularly defined murine lymphoma models conserved certain stage-specific features of normal B-cell development, there was a significant alteration of the normal differentiation signature following malignant transformation. These findings offer important tools and insights for elucidating differences between normal and malignant B cells. PMID- 21282645 TI - Role of social networks in shaping disease transmission during a community outbreak of 2009 H1N1 pandemic influenza. AB - Evaluating the impact of different social networks on the spread of respiratory diseases has been limited by a lack of detailed data on transmission outside the household setting as well as appropriate statistical methods. Here, from data collected during a H1N1 pandemic (pdm) influenza outbreak that started in an elementary school and spread in a semirural community in Pennsylvania, we quantify how transmission of influenza is affected by social networks. We set up a transmission model for which parameters are estimated from the data via Markov chain Monte Carlo sampling. Sitting next to a case or being the playmate of a case did not significantly increase the risk of infection; but the structuring of the school into classes and grades strongly affected spread. There was evidence that boys were more likely to transmit influenza to other boys than to girls (and vice versa), which mimicked the observed assortative mixing among playmates. We also investigated the presence of abnormally high transmission occurring on specific days of the outbreak. Late closure of the school (i.e., when 27% of students already had symptoms) had no significant impact on spread. School-aged individuals (6-18 y) facilitated the introduction and spread of influenza in households, but only about one in five cases aged >18 y was infected by a school aged household member. This analysis shows the extent to which clearly defined social networks affect influenza transmission, revealing strong between-place interactions with back-and-forth waves of transmission between the school, the community, and the household. PMID- 21282646 TI - Escherichia coli sister chromosome separation includes an abrupt global transition with concomitant release of late-splitting intersister snaps. AB - The basis for segregation of sister chromosomes in bacteria is not established. We show here that two discrete ~150-kb regions, both located early in the right replichore, exhibit prolonged juxtaposition of sister loci, for 20 and 30 min, respectively, after replication. Flanking regions, meanwhile, separate. Thus, the two identified regions comprise specialized late-splitting intersister connections or snaps. Sister snap loci separate simultaneously in both snap regions, concomitant with a major global nucleoid reorganization that results in emergence of a bilobed nucleoid morphology. Split snap loci move rapidly apart to a separation distance comparable with one-half the length of the nucleoid. Concomitantly, at already split positions, sister loci undergo further separation to a comparable distance. The overall consequence of these and other effects is that thus far replicated sister chromosomes become spatially separated (individualized) into the two nucleoid lobes, while the terminus region (and likely, all unreplicated portions of the chromosome) moves to midcell. These and other findings imply that segregation of Escherichia coli sister chromosomes is not a smooth continuous process but involves at least one and likely, two major global transition(s). The presented patterns further suggest that accumulation of internal intranucleoid forces and constraining of these forces by snaps play central roles in global chromosome dynamics. They are consistent with and supportive of our previous proposals that individualization of sisters in E. coli is driven primarily by internally generated pushing forces and is directly analogous to sister individualization at the prophase to prometaphase transition of the eukaryotic cell cycle. PMID- 21282647 TI - Neuroligin-4 is localized to glycinergic postsynapses and regulates inhibition in the retina. AB - Neuroligins (NL1-NL4) are postsynaptic adhesion proteins that control the maturation and function of synapses in the central nervous system (CNS). Loss-of function mutations in NL4 are linked to rare forms of monogenic heritable autism, but its localization and function are unknown. Using the retina as a model system, we show that NL4 is preferentially localized to glycinergic postsynapses and that the loss of NL4 is accompanied by a reduced number of glycine receptors mediating fast glycinergic transmission. Accordingly, NL4-deficient ganglion cells exhibit slower glycinergic miniature postsynaptic currents and subtle alterations in their stimulus-coding efficacy, and inhibition within the NL4 deficient retinal network is altered as assessed by electroretinogram recordings. These data indicate that NL4 shapes network activity and information processing in the retina by modulating glycinergic inhibition. Importantly, NL4 is also targeted to inhibitory synapses in other areas of the CNS, such as the thalamus, colliculi, brainstem, and spinal cord, and forms complexes with the inhibitory postsynapse proteins gephyrin and collybistin in vivo, indicating that NL4 is an important component of glycinergic postsynapses. PMID- 21282648 TI - Enhanced T-cell signaling in cells bearing linker for activation of T-cell (LAT) molecules resistant to ubiquitylation. AB - Linker for activation of T cells (LAT) plays a central role in T-cell activation by nucleating signaling complexes that are critical for the propagation of T-cell signals from the plasma membrane to the cellular interior. The role of phosphorylation and palmitoylation in LAT function has been well studied, but not much is known about other strategies by which the cell modulates LAT activity. We have focused on LAT ubiquitylation and have mapped the sites on which LAT is ubiquitylated. To elucidate the biological role of this process, we substituted LAT lysines with arginines. This resulted in a dramatic decrease in overall LAT ubiquitylation. Ubiquitylation-resistant mutants of LAT were internalized at rates comparable to wild-type LAT in a mechanism that required Cbl family proteins. However, these mutants displayed a defect in protein turnover rates. T cell signaling was elevated in cells reconstituted with LAT mutants resistant to ubiquitylation, indicating that inhibition of LAT ubiquitylation enhances T-cell potency. These results support LAT ubiquitylation as a molecular checkpoint for attenuation of T-cell signaling. PMID- 21282649 TI - Chimpanzees know that others make inferences. AB - If chimpanzees are faced with two opaque boards on a table, in the context of searching for a single piece of food, they do not choose the board lying flat (because if food was under there it would not be lying flat) but, rather, they choose the slanted one- presumably inferring that some unperceived food underneath is causing the slant. Here we demonstrate that chimpanzees know that other chimpanzees in the same situation will make a similar inference. In a back and-forth foraging game, when their competitor had chosen before them, chimpanzees tended to avoid the slanted board on the assumption that the competitor had already chosen it. Chimpanzees can determine the inferences that a conspecific is likely to make and then adjust their competitive strategies accordingly. PMID- 21282650 TI - Lactobacillus reuteri-produced cyclic dipeptides quench agr-mediated expression of toxic shock syndrome toxin-1 in staphylococci. AB - The production of the staphylococcal exotoxin toxic shock syndrome toxin-1 (TSST 1) by Staphylococcus aureus has been associated with essentially all cases of menstruation-associated toxic shock syndrome (TSS). In this work, we show that the human vaginal isolate Lactobacillus reuteri RC-14 produces small signaling molecules that are able to interfere with the staphylococcal quorum-sensing system agr, a key regulator of virulence genes, and repress the expression of TSST-1 in S. aureus MN8, a prototype of menstrual TSS S. aureus strains. Quantitative real-time PCR data showed that transcription from the Ptst promoter, as well as the P2 and P3 promoters of the agr system from all four agr subgroups of S. aureus, was strongly inhibited in response to growth with L. reuteri RC-14 cultural supernatant. Alterations in the transcriptional levels of two other virulence-associated regulators sarA and saeRS were also observed, indicating a potential overall influence of L. reuteri RC-14 signals on the production of virulence factors in S. aureus. S. aureus promoter-lux reporter strains were used to screen biochemically fractionated L. reuteri RC-14 supernatant, and the cyclic dipeptides cyclo(L-Phe-L-Pro) and cyclo(L-Tyr-L-Pro) were identified as the signaling molecules. The results from this work contribute to a better understanding of interspecies cell-to-cell communication between Lactobacillus and Staphylococcus, and provide a unique mechanism by which endogenous or probiotic strains may attenuate virulence factor production by bacterial pathogens. PMID- 21282651 TI - Draft genome of the red harvester ant Pogonomyrmex barbatus. AB - We report the draft genome sequence of the red harvester ant, Pogonomyrmex barbatus. The genome was sequenced using 454 pyrosequencing, and the current assembly and annotation were completed in less than 1 y. Analyses of conserved gene groups (more than 1,200 manually annotated genes to date) suggest a high quality assembly and annotation comparable to recently sequenced insect genomes using Sanger sequencing. The red harvester ant is a model for studying reproductive division of labor, phenotypic plasticity, and sociogenomics. Although the genome of P. barbatus is similar to other sequenced hymenopterans (Apis mellifera and Nasonia vitripennis) in GC content and compositional organization, and possesses a complete CpG methylation toolkit, its predicted genomic CpG content differs markedly from the other hymenopterans. Gene networks involved in generating key differences between the queen and worker castes (e.g., wings and ovaries) show signatures of increased methylation and suggest that ants and bees may have independently co-opted the same gene regulatory mechanisms for reproductive division of labor. Gene family expansions (e.g., 344 functional odorant receptors) and pseudogene accumulation in chemoreception and P450 genes compared with A. mellifera and N. vitripennis are consistent with major life history changes during the adaptive radiation of Pogonomyrmex spp., perhaps in parallel with the development of the North American deserts. PMID- 21282652 TI - Regulation of induced colonic inflammation by Lactobacillus acidophilus deficient in lipoteichoic acid. AB - Imbalance in the regulatory immune mechanisms that control intestinal cellular and bacterial homeostasis may lead to induction of the detrimental inflammatory signals characterized in humans as inflammatory bowel disease. Induction of proinflammatory cytokines (i.e., IL-12) induced by dendritic cells (DCs) expressing pattern recognition receptors may skew naive T cells to T helper 1 polarization, which is strongly implicated in mucosal autoimmunity. Recent studies show the ability of probiotic microbes to treat and prevent numerous intestinal disorders, including Clostridium difficile-induced colitis. To study the molecular mechanisms involved in the induction and repression of intestinal inflammation, the phosphoglycerol transferase gene that plays a key role in lipoteichoic acid (LTA) biosynthesis in Lactobacillus acidophilus NCFM (NCK56) was deleted. The data show that the L. acidophilus LTA-negative in LTA (NCK2025) not only down-regulated IL-12 and TNFalpha but also significantly enhanced IL-10 in DCs and controlled the regulation of costimulatory DC functions, resulting in their inability to induce CD4(+) T-cell activation. Moreover, treatment of mice with NCK2025 compared with NCK56 significantly mitigated dextran sulfate sodium and CD4(+)CD45RB(high)T cell-induced colitis and effectively ameliorated dextran sulfate sodium-established colitis through a mechanism that involves IL-10 and CD4(+)FoxP3(+) T regulatory cells to dampen exaggerated mucosal inflammation. Directed alteration of cell surface components of L. acidophilus NCFM establishes a potential strategy for the treatment of inflammatory intestinal disorders. PMID- 21282653 TI - Human endothelial cells generate Th17 and regulatory T cells under inflammatory conditions. AB - Organ transplantation represents a unique therapeutic option for irreparable organ dysfunction and rejection of transplants results from a breakdown in operational tolerance. Although endothelial cells (ECs) are the first target in graft rejection following kidney transplantation, their capacity to alloactivate and generate particular T lymphocyte subsets that could intervene in this process remains unknown. By using an experimental model of microvascular endothelium, we demonstrate that, under inflammatory conditions, human ECs induced proliferation of memory CD4(+)CD45RA(-) T cells and selectively amplified proinflammatory Th17 and suppressive CD45RA(-)HLA-DR(+)FoxP3(bright) regulatory CD4(+) T lymphocytes (Tregs). Although HLA-DR expression on resting microvascular ECs was sufficient to induce proliferation of memory CD4(+) T cells, Treg amplification was dependent on the interaction with CD54, highly expressed only under inflammatory conditions. Moreover, expansion of Th17 cells was dependent on IL-6 and STAT-3, and inhibition of either specifically impaired Th17, without altering Treg expansion. Collectively these data reveal that the HLA-DR(+) ECs regulate the local inflammatory allogeneic response, promoting either an IL-6/STAT-3-dependent Th17 response or a contact-CD54-dependent regulatory response according to the cytokine environment. Finally, these data open therapeutic perspectives in human organ transplantation based on targeting the IL-6/STAT-3 pathway and/or promoting CD54 dependent Treg proliferation. PMID- 21282654 TI - Serotonin reverts age-related capillarization and failure of regeneration in the liver through a VEGF-dependent pathway. AB - The function of the liver is well-preserved during the aging process, although some evidence suggests that liver regeneration might be impaired with advanced age. We observed a decreased ability of the liver to restore normal volume after partial hepatectomy in elderly mice, and we identified a pathway that rescued regeneration and was triggered by serotonin. 2,5-dimethoxy-4-iodoamphetamine (DOI), a serotonin receptor agonist, reversed the age-related pseudocapillarization of old liver and improved hepatosinusoidal blood flow. After hepatectomy, the open fenestrae were associated with a restored attachment of platelets to endothelium and the initiation of a normal regenerative response, including the up-regulation of essential growth mediators and serotonin receptors. In turn, hepatocyte proliferation recovered along with regain of liver volume and animal survival. DOI operates through the release of VEGF, and its effects could be blocked with anti-VEGF antibodies both in vitro and in vivo. These results suggest that pseudocapillarization in the aged acts as a barrier to liver regeneration. DOI breaks this restraint through an endothelium-dependent mechanism driven by VEGF. This pathway highlights a target for reversing the age associated decline in the capacity of the liver to regenerate. PMID- 21282655 TI - Genetic disassembly and combinatorial reassembly identify a minimal functional repertoire of type III effectors in Pseudomonas syringae. AB - The virulence of Pseudomonas syringae and many other proteobacterial pathogens is dependent on complex repertoires of effector proteins injected into host cells by type III secretion systems. The 28 well-expressed effector genes in the repertoire of the model pathogen P. syringae pv. tomato DC3000 were deleted to produce polymutant DC3000D28E. Growth of DC3000D28E in Nicotiana benthamiana was symptomless and 4 logs lower than that of DC3000DeltahopQ1-1, which causes disease in this model plant. DC3000D28E seemed functionally effectorless but otherwise WT in diagnostic phenotypes relevant to plant interactions (for example, ability to inject the AvrPto-Cya reporter into N. benthamiana). Various effector genes were integrated by homologous recombination into native loci or by a programmable or random in vivo assembly shuttle (PRIVAS) system into the exchangeable effector locus in the Hrp pathogenicity island of DC3000D28E. The latter method exploited dual adapters and recombination in yeast for efficient assembly of PCR products into programmed or random combinations of multiple effector genes. Native and PRIVAS-mediated integrations were combined to identify a minimal functional repertoire of eight effector genes that restored much of the virulence of DC3000DeltahopQ1-1 in N. benthamiana, revealing a hierarchy in effector function: AvrPtoB acts with priority in suppressing immunity, enabling other effectors to promote further growth (HopM1 and HopE1), chlorosis (HopG1), lesion formation (HopAM1-1), and near full growth and symptom production (AvrE, HopAA1-1, and/or HopN1 functioning synergistically with the previous effectors). DC3000D28E, the PRIVAS method, and minimal functional repertoires provide new resources for probing the plant immune system. PMID- 21282656 TI - Rab GTPase-Myo5B complexes control membrane recycling and epithelial polarization. AB - The Rab GTPases are the largest family of proteins regulating membrane traffic. Rab proteins form a nidus for the assembly of multiprotein complexes on distinct vesicle membranes to regulate particular membrane trafficking pathways. Recent investigations have demonstrated that Myosin Vb (Myo5B) is an effector for Rab8a, Rab10, and Rab11a, all of which are implicated in regulating different pathways for recycling of proteins to the plasma membrane. It remains unclear how specific interactions of Myo5B with individual Rab proteins can lead to specificity in the regulation of alternate trafficking pathways. We examined the relative contributions of Rab/Myo5B interactions with specific pathways using Myo5B mutants lacking binding to either Rab11a or Rab8a. Myo5B Q1300L and Y1307C mutations abolished Rab8a association, whereas Myo5B Y1714E and Q1748R mutations uncoupled association with Rab11a. Expression of Myo5B tails containing these mutants demonstrated that Rab11a, but not Rab8a, was required for recycling of transferrin in nonpolarized cells. In contrast, in polarized epithelial cyst cultures, Myo5B was required for apical membrane trafficking and de novo lumen formation, dependent on association with both Rab8a and Rab11a. These data demonstrate that different combinations of Rab GTPase association with Myo5B control distinct membrane trafficking pathways. PMID- 21282657 TI - Eradication of melanomas by targeted elimination of a minor subset of tumor cells. AB - Proceeding on the assumption that all cancer cells have equal malignant capacities, current regimens in cancer therapy attempt to eradicate all malignant cells of a tumor lesion. Using in vivo targeting of tumor cell subsets, we demonstrate that selective elimination of a definite, minor tumor cell subpopulation is particularly effective in eradicating established melanoma lesions irrespective of the bulk of cancer cells. Tumor cell subsets were specifically eliminated in a tumor lesion by adoptive transfer of engineered cytotoxic T cells redirected in an antigen-restricted manner via a chimeric antigen receptor. Targeted elimination of less than 2% of the tumor cells that coexpress high molecular weight melanoma-associated antigen (HMW-MAA) (melanoma associated chondroitin sulfate proteoglycan, MCSP) and CD20 lastingly eradicated melanoma lesions, whereas targeting of any random 10% tumor cell subset was not effective. Our data challenge the biological therapy and current drug development paradigms in the treatment of cancer. PMID- 21282658 TI - Aphid genome expression reveals host-symbiont cooperation in the production of amino acids. AB - The evolution of intimate symbiosis requires the coordination of gene expression and content between the distinct partner genomes; this coordination allows the fusion of capabilities of each organism into a single integrated metabolism. In aphids, the 10 essential amino acids are scarce in the phloem sap diet and are supplied by the obligate bacterial endosymbiont (Buchnera), which lives inside specialized cells called bacteriocytes. Although Buchnera's genome encodes most genes for essential amino acid biosynthesis, several genes in essential amino acid pathways are missing, as are most genes for production of nonessential amino acids. Additionally, it is unresolved whether the supply of nitrogen for amino acid biosynthesis is supplemented by recycling of waste ammonia. We compared pea aphid gene expression between bacteriocytes and other body tissues using RNA sequencing and pathway analysis and exploiting the genome sequences available for both partners. We found that 26 genes underlying amino acid biosynthesis were up regulated in bacteriocytes. Seven of these up-regulated genes fill the gaps of Buchnera's essential amino acid pathways. In addition, genes underlying five nonessential amino acid pathways lost from Buchnera are up-regulated in bacteriocytes. Finally, our results reveal that two genes, glutamine synthetase and glutamate synthase, which potentially work together in the incorporation of ammonium nitrogen into glutamate (GOGAT) cycle to assimilate ammonia into glutamate, are up-regulated in bacteriocytes. Thus, host gene expression and symbiont capabilities are closely integrated within bacteriocytes, which function as specialized organs of amino acid production. Furthermore, the GOGAT cycle may be a key source of nitrogen fueling the integrated amino acid metabolism of the aphid-Buchnera partnership. PMID- 21282659 TI - Expansions, contractions, and fragility of the spinocerebellar ataxia type 10 pentanucleotide repeat in yeast. AB - Spinocerebellar ataxia 10 (SCA10) is an autosomal dominant disease caused by large-scale expansions of the (ATTCT)(n) repeat within an intron of the human ATXN10 gene. In contrast to other expandable repeats, this pentanucleotide repeat does not form stable intra- or interstranded DNA structures, being a DNA unwinding element instead. We analyzed the instability of the (ATTCT)(n) repeat in a yeast experimental system, where its expansions led to inactivation of the URA3 reporter gene. The inactivation was due to a dramatic decrease in the mRNA levels owing to premature transcription termination and RNA polyadenylation at the repeat. The rates of expansions strongly increased with the repeat's length, mimicking genetic anticipation in human pedigrees. A first round of genetic analysis showed that a functional TOF1 gene precludes, whereas a functional RAD5 gene promotes, expansions of the (ATTCT)(n) repeat. We hypothesize that repeat expansions could occur upon fortuitous template switching during DNA replication. The rate of repeat contractions was elevated in the Tof1 knockout strain, but it was not affected by the RAD5 gene. Supporting the notion of replication irregularities, we found that (ATTCT)(n) repeats also cause length-dependent chromosomal fragility in yeast. Repeat-mediated fragility was also affected by the Tof1 and Rad5 proteins, being reduced in their absence. PMID- 21282660 TI - Histone code pathway involving H3 S28 phosphorylation and K27 acetylation activates transcription and antagonizes polycomb silencing. AB - Histone H3 phosphorylation is a critical step that couples signal transduction pathways to gene regulation. To specifically assess the transcriptional regulatory functions of H3 phosphorylation, we developed an in vivo targeting approach and found that the H3 kinase MSK1 is a direct and potent transcriptional activator. Targeting of this H3 kinase to the endogenous c-fos promoter is sufficient to activate its expression without the need of upstream signaling. Moreover, targeting MSK1 to the alpha-globin promoter induces H3 S28 phosphorylation and reactivates expression of this polycomb-silenced gene. Importantly, we discovered a mechanism whereby H3 S28 phosphorylation not only displaces binding of the polycomb-repressive complexes, but it also induces a methyl-acetylation switch of the adjacent K27 residue. Our findings show that signal transduction activation can directly regulate polycomb silencing through a specific histone code-mediated mechanism. PMID- 21282661 TI - Exercise training increases size of hippocampus and improves memory. AB - The hippocampus shrinks in late adulthood, leading to impaired memory and increased risk for dementia. Hippocampal and medial temporal lobe volumes are larger in higher-fit adults, and physical activity training increases hippocampal perfusion, but the extent to which aerobic exercise training can modify hippocampal volume in late adulthood remains unknown. Here we show, in a randomized controlled trial with 120 older adults, that aerobic exercise training increases the size of the anterior hippocampus, leading to improvements in spatial memory. Exercise training increased hippocampal volume by 2%, effectively reversing age-related loss in volume by 1 to 2 y. We also demonstrate that increased hippocampal volume is associated with greater serum levels of BDNF, a mediator of neurogenesis in the dentate gyrus. Hippocampal volume declined in the control group, but higher preintervention fitness partially attenuated the decline, suggesting that fitness protects against volume loss. Caudate nucleus and thalamus volumes were unaffected by the intervention. These theoretically important findings indicate that aerobic exercise training is effective at reversing hippocampal volume loss in late adulthood, which is accompanied by improved memory function. PMID- 21282662 TI - Use of OmpU porins for attachment and invasion of Crassostrea gigas immune cells by the oyster pathogen Vibrio splendidus. AB - OmpU porins are increasingly recognized as key determinants of pathogenic host Vibrio interactions. Although mechanisms remain incompletely understood, various species, including the human pathogen Vibrio cholera, require OmpU for host colonization and virulence. We have shown previously that OmpU is essential for virulence in the oyster pathogen Vibrio splendidus LGP32. Here, we showed that V. splendidus LGP32 invades the oyster immune cells, the hemocytes, through subversion of host-cell actin cytoskeleton. In this process, OmpU serves as an adhesin/invasin required for beta-integrin recognition and host cell invasion. Furthermore, the major protein of oyster plasma, the extracellular superoxide dismutase Cg-EcSOD, is used as an opsonin mediating the OmpU-promoted phagocytosis through its RGD sequence. Finally, the endocytosed bacteria were found to survive intracellularly, evading the host defense by preventing acidic vacuole formation and limiting reactive oxygen species production. We conclude that (i) V. splendidus is a facultative intracellular pathogen that manipulates host defense mechanisms to enter and survive in host immune cells, and (ii) that OmpU is a major determinant of host cell invasion in Vibrio species, used by V. splendidus LGP32 to attach and invade oyster hemocytes through opsonisation by the oyster plasma Cg-EcSOD. PMID- 21282663 TI - Distinct progenitors for B-1 and B-2 cells are present in adult mouse spleen. AB - Recent studies by Dorshkind, Yoder, and colleagues show that embryonic (E9) B cell progenitors located in the yolk sac and intraembryonic hemogenic endothelium before the initiation of circulation give rise to B-1 and marginal zone B cells but do not give rise to B-2 cells. In studies here, we confirm and extend these findings by showing that distinct progenitors for B-1 and B-2 cells are present in the adult spleen. Furthermore, we show that the splenic B-cell progenitor population (lin(-)CD19(+)/B220(lo/-)/CD43(-)) that gives rise to B-1 cells is likely to be heterogeneous because, in some recipients, it also gives rise to B cells expressing the marginal zone phenotype (B220(hi)IgM(hi)IgD(lo)CD21(hi)) and to some (CD19(-)CD5(hi)) T cells. In addition to the well-known function differences between B-1 and B-2, our studies demonstrate that substantial developmental differences separate these B-cell lineages. Thus, consistent with the known dependence of B-2 development on IL-7, all B-2 progenitors express IL 7R. However, >30% of the B-1 progenitors do not express this marker, enabling the known IL-7 independent development of B-1 cells in IL-7(-/-) mice. In addition, marker expression on cells in the early stages of the B-2 development pathway (CD19(-)/c-Kit(lo/-)/Sca-1(lo/-)) in adult bone marrow distinguish it from the early stages of B-1 development (CD19(hi)/c-Kit(+)/Sca-1(+)), which occur constitutively in neonates. In adults, in vivo inflammatory stimulation (LPS) triggers B-1 progenitors in spleen to expand and initiate development along this B-1 developmental pathway. PMID- 21282664 TI - Identification of an antithrombotic allosteric modulator that acts through helix 8 of PAR1. AB - G protein-coupled receptors (GPCRs) can assume multiple conformations and possess multiple binding sites. Whereas endogenous agonists acting at the orthosteric binding site stabilize the active receptor conformation, small molecules that act at nonorthosteric sites can stabilize alternative conformations. The large majority of these allosteric modulators associate with extracellular loops of GPCRs. The role of intracellular domains in mediating allosteric modulation is largely unknown. In screening a small-molecule library for inhibitors of platelet activation, we identified a family of compounds that modified PAR1-mediated granule secretion. The most potent inhibitory compound, termed JF5, also demonstrated noncompetitive inhibition of the alpha(2A)-adrenergic receptor. Aggregation studies using a battery of platelet GPCR agonists demonstrated that sensitivity to JF5 was limited to GPCRs that possessed a constrained eighth helix, as defined by a C-terminal palmitoylation site and interactions with TM7 and the i1 loop. Inhibition by JF5 was overcome in a PAR1 mutant in which the eighth helix was deleted, confirming a role for helix 8 in JF5 activity. Evaluation of downstream signaling showed that JF5 was selective with regard to G protein coupling, blocking signaling mediated by G(alphaq) but not G(alpha12). The compound inhibited thrombus formation in vivo following vascular injury with an IC(50) of ~1 mg/kg. These results indicate a role for helix 8 in conferring sensitivity to small molecules, and show that this sensitivity can be exploited to control platelet activation during thrombus formation. PMID- 21282666 TI - Top 10 tips for responding to reviewer and editor comments. PMID- 21282665 TI - The genome of the fire ant Solenopsis invicta. AB - Ants have evolved very complex societies and are key ecosystem members. Some ants, such as the fire ant Solenopsis invicta, are also major pests. Here, we present a draft genome of S. invicta, assembled from Roche 454 and Illumina sequencing reads obtained from a focal haploid male and his brothers. We used comparative genomic methods to obtain insight into the unique features of the S. invicta genome. For example, we found that this genome harbors four adjacent copies of vitellogenin. A phylogenetic analysis revealed that an ancestral vitellogenin gene first underwent a duplication that was followed by possibly independent duplications of each of the daughter vitellogenins. The vitellogenin genes have undergone subfunctionalization with queen- and worker-specific expression, possibly reflecting differential selection acting on the queen and worker castes. Additionally, we identified more than 400 putative olfactory receptors of which at least 297 are intact. This represents the largest repertoire reported so far in insects. S. invicta also harbors an expansion of a specific family of lipid-processing genes, two putative orthologs to the transformer/feminizer sex differentiation gene, a functional DNA methylation system, and a single putative telomerase ortholog. EST data indicate that this S. invicta telomerase ortholog has at least four spliceforms that differ in their use of two sets of mutually exclusive exons. Some of these and other unique aspects of the fire ant genome are likely linked to the complex social behavior of this species. PMID- 21282667 TI - The Mouse Tumor Biology Database (MTB): a central electronic resource for locating and integrating mouse tumor pathology data. AB - The Mouse Tumor Biology Database (MTB) is designed to provide an electronic data storage, search, and analysis system for information on mouse models of human cancer. The MTB includes data on tumor frequency and latency, strain, germ line, and somatic genetics, pathologic notations, and photomicrographs. The MTB collects data from the primary literature, other public databases, and direct submissions from the scientific community. The MTB is a community resource that provides integrated access to mouse tumor data from different scientific research areas and facilitates integration of molecular, genetic, and pathologic data. Current status of MTB, search capabilities, data types, and future enhancements are described in this article. PMID- 21282668 TI - Histological and immunohistochemical identification of atypical ductal mammary hyperplasia as a preneoplastic marker in dogs. AB - This study describes and evaluates the morphological and molecular relationship between canine mammary ductal hyperplasias with atypia and canine mammary neoplasias. Ductal hyperplasia was identified in association with malignant neoplasia in 56 of the 115 cases (48,8%), and although ductal hyperplasia without atypia was the type most frequently noted in the cases, most examples of hyperplasia with atypia were associated with mammary tumors. Estrogen receptor, E cadherin, and cytokeratins 1, 5, 10 and 14 (CK34bE12) expression was quite lower than in normal mammary tissue, and HER2 overexpression was absent in all proliferative cells of ductal hyperplasia. The Ki-67 expression, epidermal growth factor receptor and progesterone receptor expression appeared higher in those hyperplastic lesions analyzed than in normal mammary glands. These findings suggest that canine mammary atypical hyperplasia may play an important role in the process of malignant neoplastic transformation, with molecular alterations that are similar to precursor lesions reported in humans. PMID- 21282669 TI - Equine penile squamous cell carcinomas are associated with the presence of equine papillomavirus type 2 DNA sequences. AB - Forty cases of equine penile disease were screened with polymerase chain reaction for the presence of papillomaviral DNA. Cases consisted of 20 squamous cell carcinomas (average age of horse, 23.9 years) and 20 non-squamous cell carcinoma diseases (average age of horse, 13.3 years). All horses but one originated from the Northeastern United States. Breeds were not recorded. As based on MY09/MY11 consensus primers, DNA sequences from equine papillomavirus type 2 were amplified from 9 of 20 horses (45%) with penile squamous cell carcinoma and only 1 of 20 horses (5%) with non-squamous cell carcinoma penile disease. Equine papillomavirus type 2 DNA was the only papillomaviral DNA amplified from any of the 40 horses. Tissues from the 10 horses in which papillomaviral DNA was detected by polymerase chain reaction were also screened with in situ hybridization and immunohistochemistry. The presence of papillomavirus was demonstrated in a subset of these by in situ hybridization (6 of 10) and immunohistochemistry (1 of 10). This report describes a possible association between equine penile squamous cell carcinomas and equine papillomavirus type 2. This study is also the first report of equine papillomavirus type 2 infection in North American horses. PMID- 21282670 TI - A systematic review and meta-analysis of intravenous palonosetron in the prevention of chemotherapy-induced nausea and vomiting in adults. AB - OBJECTIVES: We performed a systematic review and meta-analysis to compare treatment effectiveness and adverse effects in cancer patients receiving chemotherapy with palonosetron to prevent chemotherapy-induced nausea and vomiting (CINV). METHODS: We identified randomized controlled clinical trials (RCT) comparing palonosetron with first-generation 5-HT3RA in the prevention of CINV in cancer patients. Meta-analyses were performed on homogeneous studies. Fixed or random-effects models were used to combine data. RESULTS: Eight eligible trials were identified, reporting outcomes on 3,592 patients. Meta-analyses showed statistically significant differences in favor of palonosetron compared with first-generation 5-HT3RA in prevention of acute CINV (p = .0003), delayed CINV (p < .00001), and overall phase of CINV (p < .00001). Subgroup analyses showed statistically significant differences in favor of both 0.25 mg and 0.75 mg of palonosetron in prevention of all phases of CINV. There were no statistically significant differences between 0.25 and 0.75 mg of palonosetron. Compared with the first-generation 5-HT3RA, 0.75 mg of palonosetron showed a statistically significant difference in the occurrence of constipation (p = .04). INTERPRETATION: The use of palonosetron should be considered an integral part of adjuvant therapy for prevention of the acute, delayed, and overall phases of CINV. The 0.25 mg intravenous palonosetron dose is as effective as the 0.75 mg intravenous palonosetron dose. However, 0.75 mg intravenous palonosetron causes constipation more frequently than the first-generation 5-HT3RA. PMID- 21282671 TI - Factors associated with response to methylphenidate in advanced cancer patients. AB - BACKGROUND: There has been increasing interest in the use of methylphenidate for cancer-related fatigue (CRF) in patients with advanced cancer. However, there is limited literature on the specific patient characteristics associated with response to methylphenidate. Our objective of this study was to identify the specific patient characteristics associated with response to methylphenidate and to compare day 1 response with day 8 response. METHODS: We retrospectively reviewed the records of patients in two prospective controlled clinical trials that we had conducted who had received methylphenidate for cancer-related fatigue. Baseline patient characteristics, symptoms (as assessed by the Edmonton Symptom Assessment System [ESAS] and Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F]), and response (change in fatigue) at the end of day 1 treatment were analyzed to determine their association with response to methylphenidate on day 8. RESULTS: A total of 82 patients with advanced cancer who received methylphenidate for CRF were included in our review. The median age was 55 years, 66% were female, 74% were white, and the most common cancer type was breast (37%). Fifty out of 82 patients (61%) responded to methylphenidate (>= 7 points in FACIT-F). The intensity of baseline fatigue positively correlated with the response to methylphenidate (p < .001). Change in fatigue in response to methylphenidate was not associated with intensity of baseline depression, anxiety, drowsiness, or daily opioid dose. Better improvement of fatigue after treatment on day 1 was associated with more improvement with fatigue on day 8 as assessed by FACIT-F (p = .0004) and ESAS (p = .0001). Day 1 response as a predictor of day 8 response had a sensitivity of 0.84, a positive predictive value of 0.67, and specificity of 0.6. CONCLUSIONS: Response to methylphenidate is associated with higher baseline fatigue but not with higher baseline depression or sedation. Additionally, day 1 improvement is highly sensitive as a predictor of long-term improvement. PMID- 21282672 TI - Evidence-based guidelines for the care and maintenance of complete dentures: a publication of the American College of Prosthodontists. AB - The current rates of edentulism have been estimated to be between 7 percent and 69 percent of the adult population internationally. In the United States, while the incidence of edentulism continues to decline, rapid population growth coupled with current economic conditions suggest that edentulism and conventional denture use will continue at current or higher numbers. Unfortunately, evidence-based guidelines for the care and maintenance of removable complete denture prostheses do not exist. In 2009, the American College of Prosthodontists (ACP) formed a task force to establish evidence-based guidelines for the care and maintenance of complete dentures. The task force comprised members of the ACP, the Academy of General Dentistry, the American Dental Association Council on Scientific Affairs, the American Dental Hygienists' Association, the National Association of Dental Laboratories and GlaxoSmithKline Consumer Healthcare. The review process included the assessment of over 300 abstracts and selection of over 100 articles meeting the inclusion criteria of this review. The task force reviewed synopses of the literature and formulated 15 evidence-based guidelines for denture care and maintenance. These guidelines were reviewed by clinical experts from the participating organizations and are being published in The Journal of the American Dental Association for widespread distribution to the dental community. These guidelines reflect the views of the task force. PMID- 21282673 TI - When good may not be good enough: the need for clinical performance measures in dentistry. PMID- 21282674 TI - Dentistry and autism. PMID- 21282675 TI - Asthma, dental caries and NOP. PMID- 21282676 TI - Periapical abscess. PMID- 21282677 TI - Cantilevered prostheses. PMID- 21282678 TI - A humbling recession. PMID- 21282679 TI - Behavioral and socioeconomic correlates of dental problem experience and patterns of health care-seeking. AB - BACKGROUND: To recognize and better understand barriers to dental care, the authors studied behavioral and socioeconomic factors specific to low-income and minority populations that contribute to patterns of professional health care seeking. METHODS: A stratified random sample of 27,002 Maryland households participated in a cross-sectional telephone survey. The authors targeted respondents who were low-income non-Hispanic white, non-Hispanic black or Hispanic who had experienced a dental problem or injury during the previous 12 months, as well as similar people with higher incomes for comparison. A total of 94.8 percent (401 of 423) of eligible people completed the survey. RESULTS: Logistic regression modeling (95 percent confidence interval) revealed that the respondents' race or ethnicity and sex were associated with the number of dental problems experienced during the previous 10 years, and that having a regular source of medical care and the type of dental problem experienced were associated with earlier health care-seeking. The first choice of treatment site (physician's office, emergency department or dentist's office) was associated with the respondents' income, pain level, number of problems experienced in the past 10 years and the degree to which their problem was a burden. CONCLUSIONS: The authors found that predisposing, enabling and need-based factors were associated with dental problem experience and patterns of professional health care service use. PMID- 21282680 TI - Angled implant abutments: a practical application of available knowledge. AB - BACKGROUND: When dental implants are not placed parallel to adjacent teeth or contiguous implants, the clinician can use angled abutments to achieve proper restorative contours. However, increased stresses on implants and bone have been associated with use of angled abutments. In this regard, there are unresolved issues concerning implant survival and potential prosthetic complications that can arise when angled abutments are used to align prosthetic positions. TYPES OF STUDIES REVIEWED: The authors searched the dental literature for clinical trials that appraised the survival rate and complications (biological and technical) associated with pros-theses that are supported by angled abutments. RESULTS: The results of photoelastic stress assessments, finite element analysis and strain gauge studies indicated that increased abutment angulations result in the placement of a greater amount of stress on prostheses and the surrounding bone than that associated with straight abutments. However, survival studies did not demonstrate a significant decrease of prostheses' longevity associated with angled abutments. Furthermore, there was no additional bone loss adjacent to implants that supported angled abutments compared with straight abutments, and angled abutments did not manifest an increased incidence of screw loosening. CLINICAL IMPLICATIONS: The use of angled abutments facilitates paralleling nonaligned implants, thereby making prosthesis fabrication easier. These abutments also can aid the clinician in avoiding anatomical structures when placing the implants. In addition, use of angled abutments can reduce treatment time, fees and the need to perform guided bone regeneration procedures. PMID- 21282681 TI - A summary of the update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association. AB - BACKGROUND: The purpose of this statement is to update the recommendations by the American Heart Association (AHA) for cardiovascular implantable electronic device (CIED) infections and their management, which were last published in 2003. METHODS AND RESULTS: The AHA commissioned this scientific statement to educate clinicians about CIED infections, provide explicit recommendations for the care of patients with suspected or established CIED infections and highlight areas of needed research. The recommendations in this statement reflect analyses of relevant literature, to include recent advances in our understanding of the epidemiology, risk factors, microbiology, management and prevention of CIED infections. CONCLUSION: There are no scientific data to support the use of antimicrobial prophylaxis for dental or other invasive procedures. CLINICAL IMPLICATIONS: The concerns about life-threatening drug reactions, the development of resistant strains of bacterial pathogens, medicolegal issues and cost to the health care system are, thus, avoided. PMID- 21282682 TI - Diet and prevention of oral cancer: strategies for clinical practice. AB - BACKGROUND: Oral health care professionals can play an important role in preventing oral cancer by performing oral mucosal examinations to detect pre cancerous changes and by educating patients about oral cancer prevention strategies, including dietary approaches. CONCLUSIONS: Current evidence supports a diet high in fruits, vegetables and plant-based foods for prevention of oral cancer. Dietary supplements-including vitamins and minerals-have not been shown to be effective as substitutes for a diet high in fruits and vegetables. CLINICAL IMPLICATIONS: In addition to discussing tobacco and alcohol use with patients (and, if relevant, betel nut and gutka consumption), as well as the risk of sexual transmission of human papillo-mavirus, clinicians should provide dietary advice for the prevention of oral cancer as part of routine patient education practices. PMID- 21282683 TI - The impact of comorbid conditions on treatment of temporomandibular disorders. PMID- 21282684 TI - Assessing the relationship between children's oral health status and that of their mothers. AB - BACKGROUND: The authors conducted a study to describe the relationship between the oral health of young children and that of their mothers. METHODS: Using data from the Third National Health and Nutrition Examination Survey and a related birth certificate-linked file, the authors compiled a sample of 1,184 mother/child pairs for children aged 2 through 6 years. The authors performed logistic and cumulative logistic regression analyses by using children's caries experience and untreated caries status as dependent variables. They evaluated the mothers' untreated caries status and tooth loss status along with other covariates, including age, race/ethnicity and poverty status. RESULTS: Children of mothers who had high levels of untreated caries were more than three times as likely (odds ratio [OR], 3.5; 95 percent confidence interval [CI], 2.0-6.2) to have higher levels of caries experience (treated or untreated dental caries) compared with children whose mothers had no untreated caries. A similar relationship was observed between mothers' tooth loss and caries experience among their children. The children of mothers with high levels of tooth loss were more than three times as likely (OR, 3.3; 95 percent CI, 1.8-6.4) to have higher levels of caries experience compared with children of mothers with no tooth loss; for mothers with moderate tooth loss, the OR was 2.3 (95 percent CI, 1.5-3.5). CONCLUSIONS: Mothers' oral health status is a strong predictor of the oral health status of their children. PMID- 21282685 TI - The effect of an antibacterial monomer on the antibacterial activity and mechanical properties of a pit-and-fissure sealant. AB - BACKGROUND: The authors incorporated an antibacterial monomer, methacryloxylethyl cetyl dimethyl ammonium chloride (DMAE-CB), into a commercial pit-and-fissure sealant to evaluate the monomer's antibacterial activity and mechanical properties. METHODS: The authors incorporated DMAE-CB at 1 percent by weight into a commercially available sealant (Helioseal, Ivoclar Vivadent, Schaan, Lichtenstein). The same sealant, Helioseal, without DMAE-CB served as a negative control. The authors used Helioseal F (Ivoclar Vivadent), containing a fluoride releasing resin, as a positive control. They determined effects of the cured sealants and their eluents on the growth of Streptococcus mutans by means of a film contact test and absorbance measurement, respectively. They measured and compared surface contact angle, degree of conversion, microhardness and microleakage. RESULTS: The authors found that in comparison with the negative control sealant, the cured sealant containing DMAE-CB had an inhibitory effect on the growth of S. mutans (P < .05), whereas the eluents of neither of these sealants showed any detectable antibacterial activity. The positive control also showed no detectable bactericidal activity. Moreover, there were no significant differences in the contact angle, degree of conversion, microhardness and microleakage between the DMAE-CB group and the negative control group (P > .05). CONCLUSIONS: The incorporation of DMAE-CB can provide sealant with contact antibacterial activity after polymerization by influencing the growth of S. mutans. The incorporation of small amounts of the monomer DMAE-CB showed no influence on the contact angle, degree of conversion, hardness and microleakage of the parental material. CLINICAL IMPLICATIONS: The results provided inference concerning the potential clinical performance of the sealant with antibacterial activity. PMID- 21282686 TI - Insufficient evidence that pulsed Nd:YAG laser treatment is superior to conventional nonsurgical therapy in the treatment of periodontal disease. PMID- 21282687 TI - Helping patients understand and accept the best treatment plans. PMID- 21282688 TI - When patients want to negotiate fees. PMID- 21282689 TI - What are the ethical issues regarding the use of honorary degrees and other nonacademic designations? PMID- 21282690 TI - Summaries for patients. High-value, cost-conscious health care. PMID- 21282691 TI - Summaries for patients. Radiology tests for patients with low back pain: high value health care advice from the American College of Physicians. PMID- 21282692 TI - In the clinic. The polycystic ovary syndrome. PMID- 21282693 TI - Effect of routine sterile gloving on contamination rates in blood culture: a cluster randomized trial. AB - BACKGROUND: Blood culture contamination leads to inappropriate or unnecessary antibiotic use. However, practical guidelines are inconsistent about the routine use of sterile gloving in collection of blood for culture. OBJECTIVE: To determine whether the routine use of sterile gloving before venipuncture reduces blood culture contamination rates. DESIGN: Cluster randomized, assessor-blinded, crossover trial (ClinicalTrials.gov registration number: NCT00973063). SETTING: Single-center trial involving medical wards and the intensive care unit. PARTICIPANTS: 64 interns in charge of collection of blood for culture were randomly assigned to routine-to-optional or optional-to-routine sterile gloving groups for 1854 adult patients who needed blood cultures. INTERVENTION: During routine sterile gloving, the interns wore sterile gloves every time before venipuncture, but during optional sterile gloving, sterile gloves were worn only if needed. MEASUREMENTS: Isolates from single positive blood cultures were classified as likely contaminant, possible contaminant, or true pathogen. Contamination rates were compared by using generalized mixed models. RESULTS: A total of 10 520 blood cultures were analyzed: 5265 from the routine sterile gloving period and 5255 from the optional sterile gloving period. When possible contaminants were included, the contamination rate was 0.6% in routine sterile gloving and 1.1% in optional sterile gloving (adjusted odds ratio, 0.57 [95% CI, 0.37 to 0.87]; P = 0.009). When only likely contaminants were included, the contamination rate was 0.5% in routine sterile gloving and 0.9% in optional sterile gloving (adjusted odds ratio, 0.51 [CI, 0.31 to 0.83]; P = 0.007). LIMITATION: Blood cultures from the emergency department, surgical wards, and pediatric wards were not assessed. CONCLUSION: Routine sterile gloving before venipuncture may reduce blood culture contamination. PMID- 21282694 TI - Racial differences in mortality among patients with acute ischemic stroke: an observational study. AB - BACKGROUND: Black patients are commonly believed to have higher stroke mortality. However, several recent studies have reported better survival in black patients with stroke. OBJECTIVE: To examine racial differences in stroke mortality and explore potential reasons for these differences. DESIGN: Observational cohort study. SETTING: 164 hospitals in New York. PARTICIPANTS: 5319 black and 18 340 white patients aged 18 years or older who were hospitalized with acute ischemic stroke between January 2005 and December 2006. MEASUREMENTS: Influence of race on mortality, examined by using propensity score analysis. Secondary outcomes were selected aspects of end-of-life treatment, use of tissue plasminogen activator, hospital spending, and length of stay. Patients were followed for mortality for 1 year after admission. RESULTS: Overall in-hospital mortality was lower for black patients than for white patients (5.0% vs. 7.4%; P < 0.001), as was all-cause mortality at 30 days (6.1% vs. 11.4%; P < 0.001) and 1 year (16.5% vs. 24.4%; P < 0.001). After propensity score adjustment, black race was independently associated with lower in-hospital mortality (odds ratio [OR], 0.77 [95% CI, 0.61 to 0.98]) and all-cause mortality up to 1 year (OR, 0.86 [CI, 0.77 to 0.96]). The adjusted hazard ratio was 0.87 (CI, 0.79 to 0.96). After adjustment for the probability of dying in the hospital, black patients with stroke were more likely to receive life-sustaining interventions (OR, 1.22 [CI, 1.09 to 1.38]) but less likely to be discharged to hospice (OR, 0.25 [CI, 0.14 to 0.46]). LIMITATIONS: The study used hospital administrative data that lacked a stroke severity measure. The study design precluded determination of causality. CONCLUSION: Among patients with acute ischemic stroke, black patients had lower mortality than white patients. This could be the result of differences in receipt of life sustaining interventions and end-of-life care. PMID- 21282695 TI - Hospital spending and inpatient mortality: evidence from California: an observational study. AB - BACKGROUND: Evidence shows that high Medicare spending is not associated with better health outcomes at a regional level and that high spending in hospitals is not associated with better process quality. The relationship between hospital spending and inpatient mortality is less well understood. OBJECTIVE: To determine the association between hospital spending and risk-adjusted inpatient mortality. DESIGN: Retrospective cohort study. SETTING: Database of discharge records from 1999 to 2008 for 208 California hospitals included in The Dartmouth Atlas of Health Care. PATIENTS: 2 545 352 patients hospitalized during 1999 to 2008 with 1 of 6 major medical conditions. MEASUREMENTS: Inpatient mortality rates among patients admitted to hospitals with varying levels of end-of-life hospital spending. RESULTS: For each of 6 diagnoses at admission-acute myocardial infarction, congestive heart failure, acute stroke, gastrointestinal hemorrhage, hip fracture, and pneumonia-patient admission to hig her-spending hospitals was associated with lower risk-adjusted inpatient mortality. During 1999 to 2003, for example, patients admitted with acute myocardial infarction to California hospitals in the highest quintile of hospital spending had lower inpatient mortality than did those admitted to hospitals in the lowest quintile (odds ratio, 0.862 [95% CI, 0.742 to 0.983]). Predicted inpatient deaths would increase by 1831 if all patients admitted with acute myocardial infarction were cared for in hospitals in the lowest quintile of spending rather than the highest. The association between hospital spending and inpatient mortality did not vary by region or hospital size. LIMITATION: Unobserved predictors of mortality create uncertainty about whether greater inpatient hospital spending leads to lower inpatient mortality. CONCLUSION: Hospitals that spend more have lower inpatient mortality for 6 common medical conditions. PMID- 21282696 TI - Recommended adult immunization schedule: United States, 2011. PMID- 21282697 TI - High-value, cost-conscious health care: concepts for clinicians to evaluate the benefits, harms, and costs of medical interventions. AB - Health care costs in the United States are increasing unsustainably, and further efforts to control costs are inevitable and essential. Efforts to control expenditures should focus on the value, in addition to the costs, of health care interventions. Whether an intervention provides high value depends on assessing whether its health benefits justify its costs. High-cost interventions may provide good value because they are highly beneficial; conversely, low-cost interventions may have little or no value if they provide little benefit. Thus, the challenge becomes determining how to slow the rate of increase in costs while preserving high-value, high-quality care. A first step is to decrease or eliminate care that provides no benefit and may even be harmful. A second step is to provide medical interventions that provide good value: medical benefits that are commensurate with their costs. This article discusses 3 key concepts for understanding how to assess the value of health care interventions. First, assessing the benefits, harms, and costs of an intervention is essential to understand whether it provides good value. Second, assessing the cost of an intervention should include not only the cost of the intervention itself but also any downstream costs that occur because the intervention was performed. Third, the incremental cost-effectiveness ratio estimates the additional cost required to obtain additional health benefits and provides a key measure of the value of a health care intervention. PMID- 21282698 TI - Diagnostic imaging for low back pain: advice for high-value health care from the American College of Physicians. AB - Diagnostic imaging is indicated for patients with low back pain only if they have severe progressive neurologic deficits or signs or symptoms that suggest a serious or specific underlying condition. In other patients, evidence indicates that routine imaging is not associated with clinically meaningful benefits but can lead to harms. Addressing inefficiencies in diagnostic testing could minimize potential harms to patients and have a large effect on use of resources by reducing both direct and downstream costs. In this area, more testing does not equate to better care. Implementing a selective approach to low back imaging, as suggested by the American College of Physicians and American Pain Society guideline on low back pain, would provide better care to patients, improve outcomes, and reduce costs. PMID- 21282699 TI - Behavioral counseling to prevent skin cancer: a systematic review for the U.S. Preventive Services Task Force. AB - BACKGROUND: More than 2 million cases of skin cancer are diagnosed annually in the United States, and melanoma incidence is increasing. PURPOSE: To assist the U.S. Preventive Services Task Force in updating its 2003 recommendation on behavioral counseling to prevent skin cancer. DATA SOURCES: Existing systematic reviews, database searches through February 2010, and outside experts. STUDY SELECTION: English-language, primary care-relevant counseling trials to promote sun-protective behaviors and studies examining the association between sun protective behaviors and skin cancer outcomes or potential adverse effects were included. DATA EXTRACTION: Each study was appraised by using design-specific quality criteria. Important study details were abstracted into evidence tables. DATA SYNTHESIS: 11 fair- or good-quality, randomized, controlled trials examined the counseling interventions' effect on sun-protective behaviors. In young women, appearance-focused behavioral interventions decrease indoor tanning and ultraviolet exposure. In young adolescents, computer support can decrease midday sun exposure and increase sunscreen use. Thirty-five mainly fair-quality observational studies examined the relationship between ultraviolet exposure or sunscreen use and skin cancer. Increasing intermittent sun exposure in childhood is associated with an increased risk for squamous cell carcinoma, basal cell carcinoma, and melanoma. Evidence suggests that regular or early use of indoor tanning may increase melanoma risk. On the basis of 1 fair-quality trial, regular sunscreen use can prevent squamous cell carcinoma, but it is yet unclear if it can prevent basal cell carcinoma or melanoma. LIMITATIONS: There are limited rigorous counseling trials. Observational studies are limited by the complexity of measuring ultraviolet exposure and sunscreen use, and inadequate adjustment for important confounders. CONCLUSION: Randomized, controlled trials suggest that primary care-relevant counseling can increase sun-protective behaviors and decrease indoor tanning. PMID- 21282700 TI - The sum of the parts is greater than the whole: reducing blood culture contamination. PMID- 21282701 TI - Immunization 2011: expanding coverage, enhancing protection. PMID- 21282702 TI - "Value for money": use with care. PMID- 21282703 TI - Good night, Irene. PMID- 21282704 TI - Preventing Alzheimer disease and cognitive decline. PMID- 21282705 TI - Preventing Alzheimer disease and cognitive decline. PMID- 21282706 TI - Quality of care in patients with chronic hepatitis C virus infection. PMID- 21282707 TI - Quality of care in patients with chronic hepatitis C virus infection. PMID- 21282708 TI - Animal, vegetable, or ... clinical trial? PMID- 21282709 TI - The molecular basis of sex: linking yeast to human. AB - Species-specific recognition between egg and sperm, a crucial event that marks the beginning of fertilization in multicellular organisms, mirrors the binding between haploid cells of opposite mating type in unicellular eukaryotes such as yeast. However, as implied by the lack of sequence similarity between sperm binding regions of invertebrate and vertebrate egg coat proteins, these interactions are thought to rely on completely different molecular entities. Here, we argue that these recognition systems are, in fact, related: despite being separated by 0.6-1 billion years of evolution, functionally essential domains of a mollusc sperm receptor and a yeast mating protein adopt the same 3D fold as egg zona pellucida proteins mediating the binding between gametes in humans. PMID- 21282710 TI - Embryonic exposure to the polybrominated diphenyl ether mixture, DE-71, affects testes and circulating testosterone concentrations in adult American kestrels (Falco sparverius). AB - Polybrominated diphenyl ethers (PBDEs) are additive flame retardants that are environmentally persistent and bioaccumulative. The developmental effects of in ovo exposure to environmentally relevant levels of the PBDE technical mixture, DE 71, on male reproductive physiology in captive American kestrels (Falco sparverius) was determined. Males were exposed in ovo by direct maternal transfer to DE-71 at three mean concentrations of 289 ng/g ww (low exposure), 1131 ng/g ww (high-exposure), or background levels of 3 ng/g ww (control). As adults, males were paired with unexposed females for breeding and, 1 year later, sacrificed for testes evaluation. While breeding, high-exposure males demonstrated a trend of reduced circulating testosterone levels when their female mate commenced egg laying when compared with controls (p = 0.056). No differences in circulating free T4 or T3 were detected. Sperm numbers were elevated on the perivitelline layer of the first egg of both high- and low-exposure males when compared with controls (p = 0.021). High-exposure males had a higher gonadosomatic index (p = 0.046) and heavier right testis than controls (p = 0.034) with a similar trend for their left testis (p = 0.055). High-exposure males had more seminiferous tubules containing lumen than controls (p = 0.030), and in proportion to the total number of tubules, low-exposure males had more tubules containing lumen than did controls (p = 0.016). Only high-exposure males had fewer than half of tubules containing final spermatids (43%). The results of the present study demonstrate that embryonic exposure to technical DE-71 affects the reproductive tract of adult male kestrels. PMID- 21282711 TI - Comparative genomic analysis of the Streptococcus dysgalactiae species group: gene content, molecular adaptation, and promoter evolution. AB - Comparative genomics of closely related bacterial species with different pathogenesis and host preference can provide a means of identifying the specifics of adaptive differences. Streptococcus dysgalactiae (SD) is comprised of two subspecies: S. dysgalactiae subsp. equisimilis is both a human commensal organism and a human pathogen, and S. dysgalactiae subsp. dysgalactiae is strictly an animal pathogen. Here, we present complete genome sequences for both taxa, with analyses involving other species of Streptococcus but focusing on adaptation in the SD species group. We found little evidence for enrichment in biochemical categories of genes carried by each SD strain, however, differences in the virulence gene repertoire were apparent. Some of the differences could be ascribed to prophage and integrative conjugative elements. We identified approximately 9% of the nonrecombinant core genome to be under positive selection, some of which involved known virulence factors in other bacteria. Analyses of proteomes by pooling data across genes, by biochemical category, clade, or branch, provided evidence for increased rates of evolution in several gene categories, as well as external branches of the tree. Promoters were primarily evolving under purifying selection but with certain categories of genes evolving faster. Many of these fast-evolving categories were the same as those associated with rapid evolution in proteins. Overall, these results suggest that adaptation to changing environments and new hosts in the SD species group has involved the acquisition of key virulence genes along with selection of orthologous protein-coding loci and operon promoters. PMID- 21282712 TI - Transposable element proliferation and genome expansion are rare in contemporary sunflower hybrid populations despite widespread transcriptional activity of LTR retrotransposons. AB - Hybridization is a natural phenomenon that has been linked in several organismal groups to transposable element derepression and copy number amplification. A noteworthy example involves three diploid annual sunflower species from North America that have arisen via ancient hybridization between the same two parental taxa, Helianthus annuus and H. petiolaris. The genomes of the hybrid species have undergone large-scale increases in genome size attributable to long terminal repeat (LTR) retrotransposon proliferation. The parental species that gave rise to the hybrid taxa are widely distributed, often sympatric, and contemporary hybridization between them is common. Natural H. annuus * H. petiolaris hybrid populations likely served as source populations from which the hybrid species arose and, as such, represent excellent natural experiments for examining the potential role of hybridization in transposable element derepression and proliferation in this group. In the current report, we examine multiple H. annuus * H. petiolaris hybrid populations for evidence of genome expansion, LTR retrotransposon copy number increases, and LTR retrotransposon transcriptional activity. We demonstrate that genome expansion and LTR retrotransposon proliferation are rare in contemporary hybrid populations, despite independent proliferation events that took place in the genomes of the ancient hybrid species. Interestingly, LTR retrotransposon lineages that proliferated in the hybrid species genomes remain transcriptionally active in hybrid and nonhybrid genotypes across the entire sampling area. The finding of transcriptional activity but not copy number increases in hybrid genotypes suggests that proliferation and genome expansion in contemporary hybrid populations may be mitigated by posttranscriptional mechanisms of repression. PMID- 21282714 TI - Deferiprone or deferasirox for cardiac siderosis in beta-thalassemia major. PMID- 21282716 TI - Voriconazole as secondary antifungal prophylaxis in stem cell transplant recipients. PMID- 21282717 TI - Clonal evolution in myelodysplastic syndromes with isolated del(5q): the importance of genetic monitoring. PMID- 21282718 TI - Myelodysplastic syndromes with bone marrow fibrosis. PMID- 21282719 TI - Pathophysiology of thrombosis in myeloproliferative neoplasms. PMID- 21282720 TI - Macrophages predict treatment outcome in Hodgkin's lymphoma. PMID- 21282721 TI - Mammary-specific inactivation of E-cadherin and p53 impairs functional gland development and leads to pleomorphic invasive lobular carcinoma in mice. AB - Breast cancer is the most common malignancy in women of the Western world. Even though a large percentage of breast cancer patients show pathological complete remission after standard treatment regimes, approximately 30-40% are non responsive and ultimately develop metastatic disease. To generate a good preclinical model of invasive breast cancer, we have taken a tissue-specific approach to somatically inactivate p53 and E-cadherin, the cardinal cell-cell adhesion receptor that is strongly associated with tumor invasiveness. In breast cancer, E-cadherin is found mutated or otherwise functionally silenced in invasive lobular carcinoma (ILC), which accounts for 10-15% of all breast cancers. We show that mammary-specific stochastic inactivation of conditional E cadherin and p53 results in impaired mammary gland function during pregnancy through the induction of anoikis resistance of mammary epithelium, resulting in loss of epithelial organization and a dysfunctional mammary gland. Moreover, combined inactivation of E-cadherin and p53 induced lactation-independent development of invasive and metastatic mammary carcinomas, which showed strong resemblance to human pleomorphic ILC. Dissemination patterns of mouse ILC mimic the human malignancy, showing metastasis to the gastrointestinal tract, peritoneum, lung, lymph nodes and bone. Our results confirm that loss of E cadherin contributes to both mammary tumor initiation and metastasis, and establish a preclinical mouse model of human ILC that can be used for the development of novel intervention strategies to treat invasive breast cancer. PMID- 21282722 TI - Defects in hepatic Notch signaling result in disruption of the communicating intrahepatic bile duct network in mice. AB - Abnormal Notch signaling in humans results in Alagille syndrome, a pleiotropic disease characterized by a paucity of intrahepatic bile ducts (IHBDs). It is not clear how IHBD paucity develops as a consequence of atypical Notch signaling, whether by a developmental lack of bile duct formation, a post-natal lack of branching and elongation or an inability to maintain formed ducts. Previous studies have focused on the role of Notch in IHBD development, and demonstrated a dosage requirement of Notch signaling for proper IHBD formation. In this study, we use resin casting and X-ray microtomography (microCT) analysis to address the role of Notch signaling in the maintenance of formed IHBDs upon chronic loss or gain of Notch function. Our data show that constitutive expression of the Notch1 intracellular domain in bi-potential hepatoblast progenitor cells (BHPCs) results in increased IHBD branches at post-natal day 60 (P60), which are maintained at P90 and P120. By contrast, loss of Notch signaling via BHPC-specific deletion of RBP-J (RBP KO), the DNA-binding partner for all Notch receptors, results in progressive loss of intact IHBD branches with age. Interestingly, in RBP KO mice, we observed a reduction in bile ducts per portal vein at P60; no further reduction had occurred at P120. Thus, bile duct structures are not lost with age; instead, we propose a model in which BHPC-specific loss of Notch signaling results in an initial developmental defect resulting in fewer bile ducts being formed, and in an acquired post-natal defect in the maintenance of intact IHBD architecture as a result of irresolvable cholestasis. Our studies reveal a previously unappreciated role for Notch signaling in the post-natal maintenance of an intact communicating IHBD structure, and suggest that liver defects observed in Alagille syndrome patients might be more complex than bile duct paucity. PMID- 21282723 TI - Progression of endometriosis to cancer: too MUCh FoxP3+ regulatory T-cell response? PMID- 21282725 TI - Do low-shrink composites reduce polymerization shrinkage effects? AB - Progress in polymer science has led to continuous reduction of polymerization shrinkage, exemplified by a new generation of "low-shrink composites". The common inference that shrinkage stress effects will be reduced in teeth restored with such restoratives with lower shrinkage was tested in extracted human premolars. Mesio-occluso-distal slot-shaped cavities were cut and restored with a conventional (SupremePlus) or low-shrink (RefleXions, Premise, Kalore, and LS) composite (N = 5). We digitized the coronal surfaces before and 10 min after restoration to determine cuspal deflection from the buccal and lingual volume change/area. We also determined the main properties involved (total shrinkage, post-gel shrinkage, degree of conversion, and elastic modulus), as well as microleakage, to verify adequate bonding. It was shown that, due to shrinkage stresses, buccal and lingual surfaces pulled inward after restoration (9-14 microns). Only Kalore and LS resulted in significantly lower tooth deformation (ANOVA/Student-Newman-Keuls post hoc, p = 0.05). The other two low-shrink composites, despite having the lowest and highest total shrinkage values, did not cause significant differences in cuspal deflection. Deflection seemed most related to the combination of post-gel shrinkage and elastic modulus. Therefore, even for significantly lower total shrinkage values, shrinkage stress is not necessarily reduced. PMID- 21282726 TI - Microgenomics of ameloblastoma. AB - Gene expression profiles of human ameloblastoma microdissected cells were characterized with the purpose of identifying genes and their protein products that could be targeted as diagnostic and prognostic markers as well as for potential therapeutic interventions. Five formalin-fixed, decalcified, paraffin embedded samples of ameloblastoma were subjected to laser capture microdissection, linear mRNA amplification, and hybridization to oligonucleotide human 41,000 RNA arrays and compared with universal human reference RNA, to determine the gene expression signature. Assessment of the data by Significance Analysis of Microarrays (SAM) and cluster analysis showed that 38 genes were highly expressed (two-fold increase) in all samples, while 41 genes were underexpressed (two-fold reduction). Elements of the sonic hedgehog pathway and Wingless type MMTV integration site family were validated by immunohistochemistry. We have identified the expression of multiple genes and protein products that could serve as potential diagnostic, prognostic, and therapeutic targets. PMID- 21282727 TI - Death after head injury: the 13 year outcome of a case control study. AB - BACKGROUND: Head injury is common, and the risk of subsequent disability and death is high. Increased risk of death years after injury might be explained by factors associated with, but not a consequence of, the head injury. This unique prospective study investigates mortality over 13 years after injury. METHODS: A cohort of n=767 with head injury was compared with two case control groups, matched for age, gender and deprivation, and in one control group, matched for duration of hospital admission following (non-head) injury. RESULTS: Two-fifths of the head injury cohort had died. The death rate (30.99 per 1000 per year) was much higher than in community controls (13.72 per 1000 per year). More than 1 year after injury, the death rate in younger (15-54 years) adults was much higher than in community controls (17.36 vs. 2.36 per 1000 per year) whereas in older adults the difference was more marginal (61.47 vs. 42.36). Death rate was elevated after mild and after more severe head injury, including in younger adults after mild head injury (14.82 per 1000 per year mild head injury vs. 2.21 community). Female gender and greater deprivation were not associated with increased death rates after head injury. Late after injury, deaths occurred from the same main causes as for the general population. CONCLUSION: Head injury is associated with increased vulnerability to death from a variety of causes for at least 13 years after hospital admission. There is a need to understand how head injury influences mortality, particularly in younger adults and after mild head injury. PMID- 21282728 TI - Cell death after high-LET irradiation in orthotopic human hepatocellular carcinoma in vivo. AB - Hepatocellular carcinoma (HCC) represents the sixth most common cancer worldwide and a major health problem since the choice of treatment is limited due to chemo- and radio-resistance. It was previously reported that high linear energy transfer (LET) radiation induced massive autophagic cell death in the human HCC SK-Hep1 cell line in vitro. This study analyzed the effects of high-LET radiation on the same HCC tumor model, orthotopically transplanted into nude mice. For this purpose, after surgical xenograft in the liver, animals were irradiated with fast neutrons and cell death occurring in the tumors was assessed with various techniques, including electron microscopy and probe-based confocal laser endomicroscopy. Results indicate that considerable autophagy and only limited apoptosis took place in the tumor xenografts after high-LET irradiation. These data confirm the previous in vitro results, suggesting that autophagy may act as a predominant mode of cell death in the efficacy of high-LET radiation. PMID- 21282729 TI - Review: Animal models of N-Methyl-N-nitrosourea-induced mammary cancer and retinal degeneration with special emphasis on therapeutic trials. AB - N-Methyl-N-nitrosourea (MNU) is a direct-acting alkylating agent that interacts with DNA. Accumulation of mutations may enhance cancer risk in target organs or cause cell death in susceptible tissues or cells when excessive DNA damage is not repaired. MNU targets various organs in a variety of animal species. MNU-induced carcinogenesis can be used as organ-specific animal models for human cancer, and MNU has been most extensively utilized for the induction of mammary cancer in rats. MNU-induced rat mammary tumors possess many similarities to those of human breast cancer, and the model is utilized for screening cancer modulators. MNU induced cell disruption is also seen in several organs and tissues, especially when MNU is applied before maturity. However, photoreceptor cells in adults are highly sensitive to MNU, which causes cell death due to apoptosis. MNU-induced photoreceptor apoptosis mimics human retinitis pigmentosa and can be used for studies of therapeutic intervention. In this review, the targets of MNU in various animal species are described, and special emphasis is given to therapeutic trials against MNU-induced mammary cancer and retinal degeneration in animal models. PMID- 21282730 TI - Comparative study of long- and short-pulsed electric fields for treating melanoma in an in vivo mouse model. AB - A mouse melanoma model was set up with green fluorescent protein (GFP) expression in vivo. With the same energy, long- (1 ms) and short- (300 ns) pulsed electric fields were delivered to two melanomas injected into the same mouse. The tumor growth and green fluorescence were followed up to compare the different treatment efficacy of long and short pulses. After two days post treatment, short pulse treated tumors showed a significantly lower tumor volume compared with long pulse treated tumors (n=8, p<0.05). On 8 experimental animals, a short nanosecond pulsed electric field (nsPEF) had lesser or delayed effects on GFP quenching and greater effects in reducing tumor size. Short pulses produced by nsPEFs can cause melanoma regression with less effect on the plasma membrane. PMID- 21282731 TI - Epicatechin administration leads to necrotic cell death of rat leukaemia promyelocytes in vivo. AB - BACKGROUND: (-)-Epicatechin (EC) induces oxidative DNA damage in HL-60 cells. The association between genotoxic and apoptotic/necrotic effects of EC was studied in rats with acute myeloid leukaemia. MATERIALS AND METHODS: Healthy and leukaemic rats were given EC by oral gavage at a dose of 40 mg/kg body weight for 22 consecutive days. Bone marrow cells were subjected to analysis of DNA damage by the comet assay and apoptosis by flow cytometry. RESULTS: EC significantly increased DNA strand breaks in bone marrow cells of leukaemic animals but it did not exert such an effect on healthy rats. EC action led to necrosis of leukaemia cells but it did not induce apoptosis of these cells in comparison to the controls. CONCLUSION: EC has genotoxic and necrotic effects which may have utility in anticancer therapy against acute myeloid leukaemia. PMID- 21282732 TI - Agaricus blazei Murill extract abrogates CCl4-induced liver injury in rats. AB - Agaricus blazei Murill (ABM) is enriched with polysaccharides, lipids, vitamins, fibers and minerals. Many studies have shown that ABM possesses immune-enhancing and anti-tumor effects. However, little is known about its protective effects on liver function. We employed carbon tetrachloride (CCl(4)) to induce hepatic fibrosis in a rat model to examine the protective effects of ABM on the liver in this study. The experiments included non-treatment control, CCl(4)-only control, and treatment with 200 mg and 2,000 mg of ABM extracts (per kilogram rat weight). All groups other than the non-treatment control were treated with intraperitoneal injections of CCl(4) twice a week. Experimental and control rats were tube-fed with experimental ABM extracts or double-distilled water, respectively, on the remaining four days each week. The whole experimental protocol lasted 8 weeks; blood and liver samples were collected for biochemical and tissue histochemical analysis. Plasma alanine aminotransferase and aspartate aminotransferase, and the activities of the anti-oxidative enzymes glutathione peroxidase, superoxide dismutase and catalase in the liver were measured. We found that high-dose ABM treatment reduced hepatic necrosis and fibrosis caused by CCl(4) in comparison with the CCl(4) control group. ALT and AST activities in the sera collected from ABM-treated rats were lower than those in the CCl(4) control rats. These results suggested that ABM extract was capable of either enhancing liver recovering from CCl(4) damage or attenuating CCl(4) toxicity. Results of anti-oxidative enzyme activity analysis showed no apparent differences among ABM-treated groups and CCl(4) control groups, indicating that removal of free radicals does not explain the protective/recovery effects observed in this study. PMID- 21282733 TI - Hormetic and UV-protective effects of azulene-related compounds. AB - BACKGROUND: We have previously reported a possible anti-inflammatory activity of azulene-, tropolone- and azulenequinone-related compounds. To further pursue the newly discovered biological activity of these compounds, five compounds that inhibited nitric oxide production by activated macrophages were investigated for their possible hormetic and anti-radiation effects. MATERIALS AND METHODS: Viable cell number of human oral normal cells (gingival fibroblast, pulp cell and periodontal ligament fibroblast) and three oral squamous cell carcinoma cell lines on treatment with various concentrations of each azulene-related compound was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Apoptosis induction was monitored by caspase-3 activation and DNA fragmentation. RESULTS: Among five compounds, only benzo[b]cyclohepta[e][1,4]thiazine slightly stimulated the growth of all three normal cell types, but not tumor cell lines, at concentrations slightly higher than cytotoxic concentrations. Using a newly established evaluation system for UV induced cellular damage, we found that this compound slightly but significantly protected the cells from UV-induced cellular injury, and its effect was synergistically enhanced by sodium ascorbate. CONCLUSION: These data suggest the possible application of benzo[b]cyclohepta[e][1,4]thiazine in UV protection therapy. PMID- 21282734 TI - Radical-scavenging activity of melatonin, either alone or in combination with vitamin E, ascorbate or 2-mercaptoethanol as co-antioxidants, using the induction period method. AB - BACKGROUND: Melatonin shows antioxidant/prooxidant activity but its mechanism of action remains unknown. MATERIALS AND METHODS: The radical-scavenging activity of melatonin and various melatonin/co-antioxidant mixtures in a 1:1 molar ratio was evaluated in terms of the length of the induction period (IP) for polymerization of methyl methacrylate (MMA), initiated by thermal decomposition of 2,2' azobisisobutyronitrile (AIBN) or by benzoyl peroxide (BPO) under nearly anaerobic conditions, which was monitored by differential scanning calorimetry (DSC). RESULTS: The observed IP (A) for a pinoline, L-ascorbyl 2,6-dibutyrate (ASDB), vitamin E (alpha-, beta-, gamma- or delta-T) or 2-mercaptoethanol (2ME) mixture was compared with the calculated total sum of IP (melatonin+each co-antioxidant) (B). For both the AIBN and BPO systems, the A/B for the melatonin/ASDB, beta-T, gamma-T or delta-T mixture was 0.3-0.7, whereas that for the melatonin/2ME mixture was approximately 1. For the AIBN system, the A/B for the melatonin/alpha T or pinoline mixture was 0.7-0.8. By contrast, for the BPO system, that for the melatonin/alpha-T or pinoline mixture was approximately 1. CONCLUSION: The prooxidant effect of the melatonin/ascorbate or vitamin E mixtures induced by radical-oxidizing activity may help to explain the anticancer activity of melatonin in biological systems. PMID- 21282735 TI - In vivo testing of 177Lu-labelled anti-PSMA antibody as a new radioimmunotherapeutic agent against prostate cancer. AB - AIM: The goal of the present study was to test the (177)Lu-labelled anti-PSMA monoclonal antibody 3/F11 ((177)Lu-DOTA-3/F11) as a new radioimmunotherapeutic agent in a prostate cancer SCID mouse xenograft model. MATERIALS AND METHODS: The mAb 3/F11 was (177)Lu labelled using 1,4,7,10-tetraazacyclododecane-1,4,7,10 tetraacetic acid (DOTA) as chelating agent. DOTA-3/F11 was tested for cell binding and serum immunoreactivity by flow cytometry. The biodistribution and the therapeutic efficacy of (177)Lu-DOTA-3/F11 in mice bearing PSMA-positive C4-2 prostate cancer xenografts were evaluated. RESULTS: 3/F11 and DOTA-3/F11 showed high and specific cell binding and similar serum half-lives of approximately seven days. Biodistribution studies revealed an increasing tumour uptake of (177)Lu DOTA-3/F11 over time with maximum tumour-to-muscle and tumour-to-blood ratios after 72 h. A single dose of 1 MBq (177)Lu-DOTA-3/F11 inhibited tumour growth and prolonged survival. CONCLUSION: This study indicated that (177)Lu-DOTA 3/F11 may be a suitable radioimmunotherapeutic agent for the treatment of prostate cancer. PMID- 21282736 TI - Bispecific oligonucleotides may induce interferon expression in LNCaP cells enhancing surface antigen expression: effect of intrastrand base pair complementarity. AB - Antisense oligonucleotides (oligos) have been employed against in vivo and in vitro prostate cancer models. Most oligos consist of a single mRNA binding site, targeting a single gene product or others sharing sequence homology. However, our lab has developed bispecifics directed towards two (including unrelated) proteins. Previously we have shown that mono- and bispecific oligos targeting BCL 2 significantly inhibit LNCaP cell growth. Employing reverse transcriptase polymerase chain reaction we found comparable suppression of expressed BCL-2. Computer models suggested that this activity could, in part, be enhanced by the formation of siRNA-like double-stranded regions, generated by intrastrand base pair complementarity. We hypothesize that these regions could be interferon inducers (like poly I:C) and enhance the expression of prostate specific cell surface antigens. The expression of cell surface prostate-specific membrane antigen (PSMA) and the secreted prostate-specific antigen (PSA) were candidates for evaluation. To test this theory, we evaluated the effects of mono- and bispecific oligos (with intrastrand complementarity), targeting BCL-2, upon the expression of non-targeted proteins PSMA, PSA and interferon-gamma (IFN-gamma) in LNCaP cells. Levels of mRNA encoding PSMA were significantly elevated following treatment with the bispecific oligos (directed against both BCL-2 and the epidermal growth factor receptor) but not by the monospecific directed solely against BCL-2. Furthermore, no differences were detected in mRNA levels encoding PSA following treatment with either mono- or bispecific forms. IFN-gamma expression was also significantly increased by the bispecific and not by the monospecific oligos, supporting the hypothesis of interferon induction. This suggests that prostate cells (including LNCaP) retain an endogenous interferon based antiviral defense mechanism (similar to that found in the testes) which is induced by double stranded oligos. Enhanced expression of cell surface differentiation antigens (such as PSMA) could increase targeting by cytotoxic T cells and potentiate prostate cancer vaccines directed against tumor-associated cell surface antigens. PMID- 21282737 TI - ALDH activity indicates increased tumorigenic cells, but not cancer stem cells, in prostate cancer cell lines. AB - BACKGROUND: Cancer stem cells (CSCs) have been shown to be a small stem cell-like cell population which appears to drive tumorigenesis, tumor recurrence and metastasis. Thus, identification and characterization of CSCs may be critical to defining effective anticancer therapies. In prostate cancer (PCa), the CD44(+) cell population appears to have stem cell-like properties including being tumorigenic. The enzyme aldehyde dehydrogenase (ALDH) has been found to identify hematopoietic stem cells and our aim was to determine the utility of ALDH activity and CD44 in identifying PCa stem cell-like cells in PCa cell lines. MATERIALS AND METHODS: LNCaP cells and PC-3 cells were sorted based on their expression of CD44 and ALDH activity. The cell populations were investigated using colony-forming assays, invasion assays, sphere formation experiments in a non-adherent environment and 3-D Matrigel matrix culture to observe the in vitro stem-cell like properties. Different sorted cell populations were injected subcutaneously into NOD/SCID mice to determine the corresponding tumorigenic capacities. RESULTS: ALDH(hi) CD44(+) cells exhibit a higher proliferative, clonogenic and metastatic capacity in vitro and demonstrate higher tumorigenicity capacity in vivo than did ALDH(lo) CD44(-) cells. The tumors recapitulated the population of the original cell line. However, ALDHlo CD44(-) cells were able to develop tumors, albeit with longer latency periods. CONCLUSION: ALDH activity and CD44 do not appear to identify PCa stem cells; however, they do indicate increased tumorigenic and metastatic potential, indicating their potential importance for further exploration. PMID- 21282738 TI - Role of amifostine on acute and late radiation nephrotoxicity: a histopathological study. AB - BACKGROUND: The present study was performed to determine the effect of amifostine in the prevention of radiation-induced acute and late period morphologic damages in rat kidney via light and electron microscopic examinations. MATERIALS AND METHODS: Control rats (n=6) received saline solution 30 min before sham irradiation; the radiotherapy alone group (n=12) received saline solution 30 min before irradiation (a single dose of 15 Gy, applied unilaterally to the kidney) and a final radiotherapy +amifostine group (n=12) received 200 mg/kg amifostine 30 min prior to irradiation. RESULTS: Microscopic examinations of irradiated kidneys revealed presence of glomerular tuft capsular adhesion, fusion of the foot processes and ballon-like cellular degeneration and loss of luminal brush border in tubules as early as eight weeks after irradiation. By 24 weeks post irradiation, these changes were advanced and associated with focal mesangiolysis, segmental sclerosis and focal tubular atrophy. In addition, local irradiation caused interstitial fibrotic lesions in the kidney. Pretreatment of amifostine markedly prevented these glomerular and tubular changes, and interstitial fibrotic lesions. CONCLUSION: This study suggests that amifostine pretreatment may contribute to prevention of radiation-induced acute and late nephrotoxicity. PMID- 21282739 TI - Geraniol rescues inflammation in cellular and animal models of mevalonate kinase deficiency. AB - BACKGROUND/AIM: The inhibition of the mevalonate pathway through genetic defects such as mevalonate kinase deficiency (MKD) or pharmacological drugs such as aminobisphosphonates causes a shortage of intermediate compounds, in particular geranylgeranyl-pyrophosphate (GGPP), which is associated with the consequent augmented IL-1beta release in monocytes. Considering that, due to its biochemical structure, isoprenoid geraniol enters the mevalonate pathway and may revert the genetic or pharmacological inhibition, the present study tested isoprenoid geraniol in cellular and animal MKD models obtained through the use of aminobisphosphonate pamidronate. MATERIALS AND METHODS: The effect of natural isoprenoid geraniol on bacterial induced-inflammation was evaluated in a monocytic cell line (Raw 264.7) and in Balb/c mice treated with pamidronate. RESULTS: Geraniol diminished the levels of inflammatory markers induced by pamidronate stimuli in vitro and in vivo. CONCLUSION: Geraniol may be proposed as a novel therapeutic approach for the orphan disease MKD, and may also be considered for the evaluation of possible inflammatory side-effects of aminobisphosphonates. PMID- 21282740 TI - Effect of CO2 laser irradiation on hormesis induction in cultured oral cells. AB - BACKGROUND: Many drugs (including toxicants) and radiation therapy have been reported to exert bi-phasic hormetic effects on cultured cells, but only when both the concentration and treatment time were optimal. Most previous studies have been carried out with multiple laser modalities other than CO(2) laser, and there has been no comparison of the hormetic response between normal and tumor cells. We investigated here whether CO(2) laser treatment induces hormesis in human gingival fibroblast (HGF) and oral squamous cell carcinoma (HSC-2) cells. MATERIALS AND METHODS: Cells were cultured for 24, 48 or 72 hours after exposure to various irradiation powers, and the viable cell number was determined by 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. RESULTS: CO(2) laser irradiation stimulated cell growth at low and inhibited it at high irradiation power. Among three dispatch modes, super pulse (SP)2 most effectively induced growth stimulation in HGF, at an irradiation dose slightly lower than that which induced cytotoxicity. Higher irradiation doses were comparably cytotoxic against both normal (HGF) and tumor (HSC-2) cells, reaching a plateau of cytotoxicity within 24 hours. CONCLUSION: Since both the range and magnitude of hormetic response in HGF cells were very narrow and small, it is crucial to establish the optimal conditions for hormesis induction for clinical application in dentistry. PMID- 21282741 TI - Increased in vivo efficacy of lenalidomide by addition of piroctone olamine. AB - BACKGROUND: It was recently confirmed that the antifungal agent ciclopirox olamine inhibits Wnt/beta catenin signaling in myeloma. Piroctone olamine (PO) has very similar chemical features to ciclopirox olamine. MATERIALS AND METHODS: This study investigated the antitumor effect of PO in vitro and in vivo in a murine myeloma model. RESULTS: PO demonstrated a major apoptotic activity in various human and murine myeloma and lymphoma cell lines, as well as in human primary cells. In vivo, tumor growth, as well as overall survival, was significantly reduced in mice treated with PO as compared to untreated mice. Interestingly, concerning tumor growth and survival of the animals, a significant additive effect was seen by the combination of lenalidomide plus PO as compared to single application. CONCLUSION: These results reveal a significant selective induction of apoptosis by PO and suggest a significant in vivo effect against myeloma. PMID- 21282742 TI - The length of peritoneal surgical manipulation correlates with serum CA 125 levels. AB - BACKGROUND: Peritoneal recovery after uncomplicated serum manipulation usually lasts 7 days and high values of serical CA 125 are measured following abdominal surgery. The aim of this study was to assess a possible correlation between peritoneal manipulation and serical CA 125 levels following abdominal surgery for benign diseases. PATIENTS AND METHODS: Twenty-eight patients with abdominal benign disease were operated on. They were pooled into three groups of low, intermediate and high peritoneal manipulation, according to the extent of laparotomy and length of surgical peritoneal manipulation. Venous blood samples (5 ml) were taken from each patient 24-48 hours before surgery, 12-24 hours after surgery and on the 4th and 7th postoperative day. CA 125 levels were quantified by microparticle enzyme immunoassay. RESULTS: After surgery, patients having high peritoneal manipulation showed significantly higher levels of CA 125 compared to the preoperative levels. In particular, the length of peritoneal manipulation was correlated with increasing levels of the marker (p<0.0001). CONCLUSION: Peritoneal manipulation was significantly correlated to serum CA 125 levels; therefore its role as marker of peritoneal surgical injury should be considered. PMID- 21282743 TI - Beck Depression Inventory (BDI) in patients with breast disease and breast cancer: a prospective case-control study. AB - BACKGROUND: In 1972, Beck introduced an inventory (BDI) for rapid screening of depression. The associations between the BDI and the risk of breast cancer (BC) are rarely considered together in prospective studies. PATIENTS AND METHODS: In an extension of the Kuopio Breast Cancer Study, 115 women with breast cancer symptoms were semi-structurally interviewed in-depth as well as asked to complete standardised questionnaires (Forsen, Spielberger, MADRS), and all study variables were obtained before any diagnostic procedures were carried out. BDI was used to evaluate the depression of the study participants. RESULTS: The clinical examinations and biopsies showed BC in 34 patients, benign breast disease (BBD) in 53 patients, and 28 individuals were shown to be healthy (HSS). There was a trend for the women with HSS to have less sadness (BDI mean score, 0.27) than those of the BC (BDI mean score, 0.56) and BBD groups (BDI mean score, 0.49). The HSS group tended to be less pessimistic (BDI mean score, 0.15) than the patients in the BC group (BDI mean score, 0.44) and in the BBD group (BDI mean score, 0.42). The HSS group also had less self-accusation (BDI mean score, 0.19) than the patients in the BC group (BDI mean score, 0.50) and the patients in the BBD group (BDI mean score, 0.62). The HSS group also reported less work inhibition and weight loss than the patients in the BC group and in the BBD group. The mean sum of the scores of BDI variables was significantly lower in the HSS group (BDI mean score, 7.1) than in the BC (BDI mean score, 8.4) or BBD groups (BDI mean score, 8.8). CONCLUSION: The results of this study do not support a specific link between BDI and breast cancer risk. However, the patients with BC and BBD tended to have an increased risk for depressive symptoms. PMID- 21282744 TI - Use of flashlamp-pumped pulsed dye laser in the treatment of superficial vascular malformations and ulcerated hemangiomas. AB - A retrospective study of 502 patients treated with tunable flashlamp pulsed dye laser for superficial vascular malformations (433), ulcerated hemangiomas (65) and postinvolutional redness (4) is presented. Patients were treated in the period from June 1997 to March 2006, with follow-up ranging from six months to four years. The age of the patients ranged from three months to 80 years. Correlation between clinical response and patients' age, location of lesion and number of treatments were evaluated in groups of superficial vascular malformations, whereas healing rates of the ulceration were assessed in a series of hemangiomas. The result were judged to be excellent in 51%, good in 39%, fair in 7% and poor in 3% of patients with vascular malformations. Excellent ultimate outcome confirmed the clinical efficacy of the use of the pulsed dye laser in the treatment of dermal vascular malformations, which also appears to have good prospects in the management of hemangioma complication. PMID- 21282745 TI - Unicystic ameloblastoma of the mandible. AB - The aim of this work was to describe a case of unicystic ameloblastoma located in the left posterior mandibular body and angle of a 14-year-old Caucasian male. The tumour was described at clinical and histological level; moreover, its histopathological phenotype was depicted. Finally, the problems of differential diagnosis with odontogenic or congenital cyst and the most appropriate therapeutic procedures are discussed. PMID- 21282746 TI - Technological improvements in the treatment of haemorrhoids and obstructed defaecation syndrome. AB - BACKGROUND: An evolution of CPH34 (CPH34 HV) for stapled transanal rectal resections was developed and tested to assess its safety and resection volume as compared to other staplers. MATERIALS AND METHODS: A total of 16 pigs were randomly assigned to rectal prolapsectomy with CPH34 HV (n=4), CPH34 (n=4), PPH03 33 (n=4), HEEA (n=2) and PPH-01 (n=2). Measures and histological structure of specimens were assessed; transrectal echotomography (ETG) was performed on the third postoperative day, hence pigs were autopsied. RESULTS: Significant differences of the volumes and weights of specimens were observed by type of stapler (p=0.0298 and p=0.0278, respectively) which were mainly due to CPH34 HV vs. PPH03-33 (p=0.0402 and p=0.0375, respectively). The average volumes were 17.1% lower for CPH34, 30.2% lower for HEEA, and 34.7% lower for PPH03-33 with respect to CPH34 HV. No significant increase of resection volume (7.5%) was observed between two PPH-01 units combined (two specimens together) vs. a single CPH34 HV unit. The highest percentage of muscularis propria was observed into the specimens collected with CPH34 HV and HEEA (50%). ETG detected three intra- and two extraparietal haematomata. CONCLUSION: The safety and higher volume of resection achievable with CPH34 HV correlated well with the specimen weight and percentage of muscularis propria. PMID- 21282747 TI - An easy method to highlight chief cells in gastric biopsies. AB - BACKGROUND: Hematoxylin and eosin (H&E) is not an optimal stain to discriminate chief cells from parietal cells in gastric biopsies MATERIALS AND METHODS: Fifteen sets of biopsies from the gastric corpus were consecutively stained with H&E and toluidine blue stains; chief cells stained deep blue with toluidine blue, thus contrasting with lightly-stained parietal cells. In well-oriented sections, the continuity of the chief cell zone was studied at * 4 magnification and its thickness in one field at * 10 magnification. RESULTS: Toluidine blue stained fundic sections that exhibited normal mucosa or chronic gastritis without glandular atrophy displayed a distinct deep-blue chief cell zone, intercalated between the lightly-stained parietal cells on top and the muscularis mucosae underneath (Group A). In chronic gastritis with focal glandular atrophy or focal intestinal metaplasia, at least one focally fragmented toluidine blue chief cell zone was seen (Group B). In one case with severe autoimmune gastritis and in a case with extensive intestinal metaplasia, an absence of toluidine blue chief cells zone was recorded in the entire section (Group C). CONCLUSION: This quick and easy staining method made it possible to group sections from the gastric corpus into those with a continuous chief cell zone, with fragmented or with an absent chief cell zone, modalities that seem to correlate with different stages of fundic mucosal inflammation. These preliminary results should be validated in a larger cohort of gastric biopsies from patients with various diseases affecting the corpus mucosa. PMID- 21282748 TI - Mid-trimester amniotic fluid interleukins (IL-1beta, IL-10 and IL-18) as possible predictors of preterm delivery. AB - AIM: Strong evidence implicates chronic intraamniotic inflammation in the etiology of preterm delivery. The purpose of this study was to determine whether amniotic fluid IL-1beta, IL-10 and IL-18 concentrations in women undergoing mid trimester amniocentesis can identify those at risk for preterm labor or preterm rupture of membranes. PATIENTS AND METHODS: A case-control study was conducted to compare mid-trimester concentrations of amniotic fluid IL-1beta, IL-10 and IL-18 in women delivering at term or preterm. Out of 362 women included in the study, 38 presented with preterm labor. Thirty-eight women with term delivery, matched for chronological and gestational age served as controls. Women with abnormal fetal karyotypes or major anomalies were excluded. IL-1beta, IL-10 and IL-18 concentrations were determined by ELISA. Conditional logistic regression was applied in the statistical analysis. RESULTS: IL-1beta was found to be positively and significantly associated with preterm delivery. Specifically, for every unit increase in IL-1beta, women were on average 7.2 (OR: 7.2, CI: 1.94-26.77, p=0.003) times more likely to deliver preterm. IL-18 levels as well as gender were significantly associated with preterm delivery. Specifically, for every unit increase in IL-18, women were on average 1% less likely to have a preterm delivery (OR: 0.99, CI: 0.98-0.99, p=0.04). On the other hand, IL-10 was not significantly associated with preterm delivery. CONCLUSION: Mid-trimester IL 1beta concentrations are positively associated with preterm delivery. Therefore, IL-1beta, determined on the occasion of mid-trimester amniocentesis could possibly serve as a marker of preterm delivery. In contrast, IL-10 and IL-18 concentrations are not elevated in mid-trimester amniotic fluid and probably cannot serve this purpose. PMID- 21282749 TI - The bone and joint decade 2000 to 2010. PMID- 21282750 TI - What are the radiological predictors of functional outcome following fractures of the distal radius? AB - The fracture most commonly treated by orthopaedic surgeons is that of the distal radius. However, as yet there is no consensus on what constitutes an 'acceptable' radiological position before or after treatment. This should be defined as the position that will predict good function in the majority of cases. In this paper we review the radiological indices that can be measured in fractures of the distal radius and try to identify potential predictors of functional outcome. In patients likely to have high functional demands, we recommend that the articular reconstruction be achieved with less than 2 mm of gap or step-off, the radius be restored to within 2 mm of its normal length, and that carpal alignment be restored. The ultimate aim of treatment is a pain-free, mobile wrist joint without functional limitation. PMID- 21282751 TI - Biodegradable antibiotic delivery systems. AB - Bacterial infection in orthopaedic surgery can be devastating, and is associated with significant morbidity and poor functional outcomes, which may be improved if high concentrations of antibiotics can be delivered locally over a prolonged period of time. The two most widely used methods of doing this involve antibiotic loaded polymethylmethacrylate or collagen fleece. The former is not biodegradable and is a surface upon which secondary bacterial infection may occur. Consequently, it has to be removed once treatment has finished. The latter has been used successfully as an adjunct to systemic antibiotics, but cannot effect a sustained release that would allow it to be used on its own, thereby avoiding systemic toxicity. This review explores the newer biodegradable carrier systems which are currently in the experimental phase of development and which may prove to be more effective in the treatment of osteomyelitis. PMID- 21282752 TI - A medium-term comparison of hybrid hip replacement and Birmingham hip resurfacing in active young patients. AB - We compared the medium-term clinical and radiological results of hybrid total hip replacement (THR) with metal-on-metal Birmingham hip resurfacing (BHR) in two groups of 54 young patients matched for age, gender, body mass index and pre operative levels of activity. The clinical outcome was assessed by the University of California, Los Angeles (UCLA) activity score, the Oxford Hip Score (OHS) and the EuroQol scores. Radiologically, all hips were assessed for migration and osteolysis, the hybrid THRs for polyethylene wear and the BHRs for a pedestal sign. The mean follow-up of the patients with a hybrid THR was ten years and for those with a BHR, nine years. Four patients with a hybrid THR and one with a BHR had died. In each group five were lost to follow-up. The revision rate of the hybrid THRs was 16.7% (9 of 54) and of the BHRs 9.3% (5 of 54) (p = 0.195). Radiographs of a further eight hybrid THRs demonstrated wear and osteolysis, and they await revision (p = 0.008). Of the unrevised BHRs 90% had radiological changes, of which approximately 50% had progressed over the previous four years. All hybrid THRs demonstrated linear polyethylene wear with a mean of 1.24 mm (0.06 to 3.03). The BHRs recorded superior OHS (p = 0.013), UCLA (p = 0.008), and EuroQol visual analogue scores (p = 0.009). After nine years, patients with BHRs remained more active and had a lower rate of revision than those with hybrid THRs. Both groups demonstrated progressive radiological changes at medium-term follow-up. PMID- 21282753 TI - Adverse reaction to metal debris following hip resurfacing: the influence of component type, orientation and volumetric wear. AB - We sought to establish the incidence of joint failure secondary to adverse reaction to metal debris (ARMD) following metal-on-metal hip resurfacing in a large, three surgeon, multicentre study involving 4226 hips with a follow-up of 10 to 142 months. Three implants were studied: the Articular Surface Replacement; the Birmingham Hip Resurfacing; and the Conserve Plus. Retrieved implants underwent analysis using a co-ordinate measuring machine to determine volumetric wear. There were 58 failures associated with ARMD. The median chromium and cobalt concentrations in the failed group were significantly higher than in the control group (p < 0.001). Survival analysis showed a failure rate in the patients with Articular Surface Replacement of 12.8% [corrected] at five years, compared with < 1% at five years for the Conserve Plus and 1.5% at ten years for the Birmingham Hip Resurfacing. Two ARMD patients had relatively low wear of the retrieved components. Increased wear from the metal-on-metal bearing surface was associated with an increased rate of failure secondary to ARMD. However, the extent of tissue destruction at revision surgery did not appear to be dose-related to the volumetric wear. PMID- 21282754 TI - Short- and long-term mortality following primary total hip replacement for osteoarthritis: a Danish nationwide epidemiological study. AB - We evaluated the short-term of 0 to 90 days and the longer term, up to 12.7 years, mortality for patients undergoing primary total hip replacement (THR) in Denmark in comparison to the general population. Through the Danish Hip Arthroplasty Registry we identified all primary THRs undertaken for osteoarthritis between 1 January 1995 and 31 December 2006. Each patient (n = 44 558) was matched at the time of surgery with three people from the general population (n = 133 674). We estimated mortality rates and mortality rate ratios with 95% confidence intervals for THR patients compared with the general population. There was a one-month period of increased mortality immediately after surgery among THR patients, but overall short-term mortality (0 to 90 days) was significantly lower (mortality rate ratio 0.8; 95% confidence interval 0.7 to 0.9). However, THR surgery was associated with increased short-term mortality in subjects under 60 years old, and among THR patients without comorbidity. Long term mortality was lower among THR patients than in controls (mortality rate ratio 0.7; 95% confidence interval 0.7 to 0.7). Overall, THR was associated with lower short- and long-term mortality among patients with osteoarthritis. Younger patients and patients without comorbidity before surgery may also experience increased mortality after THR surgery, although the absolute risk of death is small. PMID- 21282755 TI - Late peri-prosthetic femoral fracture as a major mode of failure in uncemented primary hip replacement. AB - Peri-prosthetic femoral fracture after total hip replacement (THR) is associated with a poor outcome and high mortality. However, little is known about its long term incidence after uncemented THR. We retrospectively reviewed a consecutive series of 326 patients (354 hips) who had received a CLS Spotorno replacement with an uncemented, straight, collarless tapered titanium stem between January 1985 and December 1989. The mean follow-up was 17 years (15 to 20). The occurrence of peri-prosthetic femoral fracture during follow-up was noted. Kaplan Meier survival analysis was used to estimate the cumulative incidence of fracture. At the last follow-up, 86 patients (89 hips) had died and eight patients (eight hips) had been lost to follow-up. A total of 14 fractures in 14 patients had occurred. In ten hips, the femoral component had to be revised and in four the fracture was treated by open reduction and internal fixation. The cumulative incidence of peri-prosthetic femoral fracture was 1.6% (95% confidence interval 0.7 to 3.8) at ten years and 4.5% (95% confidence interval 2.6 to 8.0) at 17 years after the primary THR. There was no association between the occurrence of fracture and gender or age at the time of the primary replacement. Our findings indicate that peri-prosthetic femoral fracture is a significant mode of failure in the long term after the insertion of an uncemented CLS Spotorno stem. Revision rates for this fracture rise in the second decade. Further research is required to investigate the risk factors involved in the occurrence of late peri-prosthetic femoral fracture after the implantation of any uncemented stem, and to assess possible methods of prevention. PMID- 21282756 TI - Morphological analysis of collapsed regions in osteonecrosis of the femoral head. AB - In order to investigate the mechanisms of collapse in osteonecrosis of the femoral head, we examined which part of the femoral head was the key point of a collapse and whether a collapsed region was associated with the size of the necrotic lesion. Using 30 consecutive surgically removed femoral heads we retrospectively analysed whole serial cut sections, specimen photographs, specimen radiographs and histological sections. In all of the femoral heads, collapse consistently involved a fracture at the lateral boundary of the necrotic lesion. Histologically, the fractures occurred at the junction between the thickened trabeculae of the reparative zone and the necrotic bone trabeculae. When the medial boundary of the necrotic lesion was located lateral to the fovea of the femoral head, 18 of 19 femoral heads collapsed in the subchondral region. By contrast, when the medial boundary was located medial to the fovea, collapse in the subchondral region was observed in four of 11 femoral heads (p = 0.0011). We found that collapse began at the lateral boundary of the necrotic lesion and that the size of the necrotic lesion seemed to contribute to its distribution. PMID- 21282757 TI - The effect of surface finish and interstitial fluid on the cement-in-cement interface in revision surgery of the hip. AB - The mechanical performance of the cement-in-cement interface in revision surgery has not been fully investigated. The quantitative effect posed by interstitial fluids and roughening of the primary mantle remains unclear. We have analysed the strength of the bilaminar cement-bone interface after exposure of the surface of the primary mantle to roughening and fluid interference. The end surfaces of cylindrical blocks of cement were machined smooth (Ra = 200 nm) or rough (Ra = 5 MUm) and exposed to either different volumes of water and carboxymethylcellulose (a bone-marrow equivalent) or left dry. Secondary blocks were cast against the modelled surface. Monoblocks of cement were used as a control group. The porosity of the samples was investigated using micro-CT. Samples were exposed to a single shearing force to failure. The mean failure load of the monoblock control was 5.63 kN (95% confidence interval (CI) 5.17 to 6.08) with an estimated shear strength of 36 MPa. When small volumes of any fluid or large volumes were used, the respective values fell between 4.66 kN and 4.84 kN with no significant difference irrespective of roughening (p > 0.05). Large volumes of carboxymethylcellulose significantly weakened the interface. Roughening in this group significantly increased the strength with failure loads of 2.80 kN (95% CI 2.37 to 3.21) compared with 0.86 kN (95% CI 0.43 to 1.27) in the smooth variant. Roughening of the primary mantle may not therefore be as crucial as has been previously thought in clinically relevant circumstances. PMID- 21282758 TI - Posterolateral corner injuries of the knee: a serious injury commonly missed. AB - We retrospectively reviewed the hospital records of 68 patients who had been referred with an injury to the posterolateral corner of the knee to a specialist knee surgeon between 2005 and 2009. These injuries were diagnosed based on a combination of clinical testing and imaging and arthroscopy when available. In all, 51 patients (75%) presented within 24 hours of their injury with a mean presentation at eight days (0 to 20) after the injury. A total of 63 patients (93%) had instability of the knee at presentation. There was a mean delay to the diagnosis of injury to the posterolateral corner of 30 months (0 to 420) from the time of injury. In all, the injuries in 49 patients (72%) were not identified at the time of the initial presentation, with the injury to the posterolateral corner only recognised in those patients who had severe multiple ligamentous injuries. The correct diagnosis, including injury to the posterolateral corner, had only been made in 34 patients (50%) at time of referral to a specialist knee clinic. MRI correctly identified 14 of 15 injuries when performed acutely (within 12 weeks of injury), but this was the case in only four of 15 patients in whom it was performed more than 12 weeks after the injury. Our study highlights a need for greater diligence in the examination and investigation of acute ligamentous injuries at the knee with symptoms of instability, in order to avoid failure to identify the true extent of the injury at the time when anatomical repair is most straightforward. PMID- 21282759 TI - Minimally invasive Oxford phase 3 unicompartmental knee replacement: results of 1000 cases. AB - This prospective study describes the outcome of the first 1000 phase 3 Oxford medial unicompartmental knee replacements (UKRs) implanted using a minimally invasive surgical approach for the recommended indications by two surgeons and followed up independently. The mean follow-up was 5.6 years (1 to 11) with 547 knees having a minimum follow-up of five years. At five years their mean Oxford knee score was 41.3 (sd 7.2), the mean American Knee Society Objective Score 86.4 (sd 13.4), mean American Knee Society Functional Score 86.1 (sd 16.6), mean Tegner activity score 2.8 (sd 1.1). For the entire cohort, the mean maximum flexion was 130 degrees at the time of final review. The incidence of implant related re-operations was 2.9%; of these 29 re-operations two were revisions requiring revision knee replacement components with stems and wedges, 17 were conversions to a primary total knee replacement, six were open reductions for dislocation of the bearing, three were secondary lateral UKRs and one was revision of a tibial component. The most common reason for further surgical intervention was progression of arthritis in the lateral compartment (0.9%), followed by dislocation of the bearing (0.6%) and revision for unexplained pain (0.6%). If all implant-related re-operations are considered failures, the ten year survival rate was 96% (95% confidence interval, 92.5 to 99.5). If only revisions requiring revision components are considered failures the ten-year survival rate is 99.8% (confidence interval 99 to 100). This is the largest published series of UKRs implanted through a minimally invasive surgical approach and with ten-year survival data. The survival rates are similar to those obtained with a standard open approach whereas the function is better. This demonstrates the effectiveness and safety of a minimally invasive surgical approach for implanting the Oxford UKR. PMID- 21282760 TI - Early metallosis-related failure after total knee replacement: a report of 15 cases. AB - Metallosis is a rare cause of failure after total knee replacement and has only previously been reported when there has been abnormal metal-on-metal contact. We describe 14 patients (15 knees) whose total knee replacement required revision for a new type of early failure caused by extensive metallosis. A modification of a cementless rotating platform implant, which had previously had excellent long term survival, had been used in each case. The change was in the form of a new porous-beaded surface on the femoral component to induce cementless fixation, which had been used successfully in the fixation of acetabular and tibial components. This modification appeared to have resulted in metallosis due to abrasive two-body wear. The component has subsequently been recalled and is no longer in use. The presentation, investigation, and findings at revision are described and a possible aetiology and its implications are discussed. PMID- 21282761 TI - A multicentre study of the long-term results of using a flat-back polyethylene glenoid component in shoulder replacement for primary osteoarthritis. AB - We report the long-term clinical and radiological outcomes of the Aequalis total shoulder replacement with a cemented all-polyethylene flat-back keeled glenoid component implanted for primary osteoarthritis between 1991 and 2003 in nine European centres. A total of 226 shoulders in 210 patients were retrospectively reviewed at a mean of 122.7 months (61 to 219) or at revision. Clinical outcome was assessed using the Constant score, patient satisfaction score and range of movement. Kaplan-Meier survivorship analysis was performed with glenoid revision for loosening and radiological glenoid loosening (SD) as endpoints. The Constant score was found to improve from a mean of 26.8 (SD 10.3) pre-operatively to 57.6 (SD 20.0) post-operatively (p < 0.001). Active forward flexion improved from a mean of 85.3 degrees (SD 27.4) pre-operatively to 125 degrees (SD 37.3) postoperatively (p < 0.001). External rotation improved from a mean of 7 degrees (SD 6.5) pre-operatively to 30.3 degrees (SD 21.8 degrees ) post-operatively (p < 0.001). Survivorship with revision of the glenoid component as the endpoint was 99.1% at five years, 94.5% at ten years and 79.4% at 15 years. Survivorship with radiological loosening as the endpoint was 99.1% at five years, 80.3% at ten years and 33.6% at 15 years. Younger patient age and the curettage technique for glenoid preparation correlated with loosening. The rate of glenoid revision and radiological loosening increased with duration of follow-up, but not until a follow-up of five years. Therefore, we recommend that future studies reporting radiological outcomes of new glenoid designs should report follow-up of at least five to ten years. PMID- 21282762 TI - Surgical treatment of spontaneous posterior interosseous nerve palsy: a retrospective study of 50 cases. AB - We have reviewed 38 surgically treated cases of spontaneous posterior interosseous nerve palsy in 38 patients with a mean age of 43 years (13 to 68) in order to identify clinical factors associated with its prognosis. Interfascicular neurolysis was performed at a mean of 13 months (1 to 187) after the onset of symptoms. The mean follow-up was 21 months (5.5 to 221). Medical Research Council muscle power of more than grade 4 was considered to be a good result. A further 12 cases in ten patients were treated conservatively and assessed similarly. Of the 30 cases treated surgically with available outcome data, the result of interfascicular neurolysis was significantly better in patients < 50 years old (younger group (18 nerves); good: 13 nerves (72%), poor: five nerves (28%)) than in cases > 50 years old (older group (12 nerves); good: one nerve (8%), poor: 11 nerves (92%)) (p < 0.001). A pre-operative period of less than seven months was also associated with a good result in the younger group (p = 0.01). The older group had a poor result regardless of the pre-operative delay. Our recommended therapeutic approach therefore is to perform interfascicular neurolysis if the patient is < 50 years of age, and the pre-operative delay is < seven months. If the patient is > 50 years of age with no sign of recovery for seven months, or in the younger group with a pre-operative delay of more than a year, we advise interfascicular neurolysis together with tendon transfer as the primary surgical procedure. PMID- 21282763 TI - Comminuted fractures of the radial head and neck: is fixation to the shaft necessary? AB - Mason type III fractures of the radial head are treated by open reduction and internal fixation, resection or prosthetic joint replacement. When internal fixation is performed, fixation of the radial head to the shaft is difficult and implant-related complications are common. Furthermore, problems of devascularisation of the radial head can result from fixation of the plate to the radial neck. In a small retrospective study, the treatment of Mason type III fractures with fixation of the radial neck in 13 cases (group 2) was compared with 12 cases where no fixation was performed (group 1). The mean clinical and radiological follow-up was four years (1 to 9). The Broberg-Morrey index showed excellent results in both groups. Degenerative radiological changes were seen more frequently in group 2, and removal of the implant was necessary in seven of 13 cases. Post-operative evaluation of these two different techniques revealed similar ranges of movement and functional scores. We propose that anatomical reconstruction of the radial head without metalwork fixation to the neck is preferable, and the outcome is the same as that achieved with the conventional technique. In addition degenerative changes of the elbow joint may develop less frequently, and implant removal is not necessary. PMID- 21282764 TI - Outcomes of acetabular fracture fixation with ten years' follow-up. AB - We report the outcome of 161 of 257 surgically fixed acetabular fractures. The operations were undertaken between 1989 and 1998 and the patients were followed for a minimum of ten years. Anthropometric data, fracture pattern, time to surgery, associated injuries, surgical approach, complications and outcome were recorded. Modified Merle D'Aubigne score and Matta radiological scoring systems were used as outcome measures. We observed simple fractures in 108 patients (42%) and associated fractures in 149 (58%). The result was excellent in 75 patients (47%), good in 41 (25%), fair in 12 (7%) and poor in 33 (20%). Poor prognostic factors included increasing age, delay to surgery, quality of reduction and some fracture patterns. Complications were common in the medium- to long-term and functional outcome was variable. The gold-standard treatment for displaced acetabular fractures remains open reduction and internal fixation performed in dedicated units by specialist surgeons as soon as possible. PMID- 21282765 TI - Biomechanical testing of a concept of posterior pelvic reconstruction in rotationally and vertically unstable fractures. AB - The purpose of this study was to assess the stability of a developmental pelvic reconstruction system which extends the concept of triangular osteosynthesis with fixation anterior to the lumbosacral pivot point. An unstable Tile type-C fracture, associated with a sacral transforaminal fracture, was created in synthetic pelves. The new concept was compared with three other constructs, including bilateral iliosacral screws, a tension band plate and a combined plate with screws. The pubic symphysis was plated in all cases. The pelvic ring was loaded to simulate single-stance posture in a cyclical manner until failure, defined as a displacement of 2 mm or 2 degrees . The screws were the weakest construct, failing with a load of 50 N after 400 cycles, with maximal translation in the craniocaudal axis of 12 mm. A tension band plate resisted greater load but failure occurred at 100 N, with maximal rotational displacement around the mediolateral axis of 2.3 degrees . The combination of a plate and screws led to an improvement in stability at the 100 N load level, but rotational failure still occurred around the mediolateral axis. The pelvic reconstruction system was the most stable construct, with a maximal displacement of 2.1 degrees of rotation around the mediolateral axis at a load of 500 N. PMID- 21282766 TI - Biomechanical comparison of interfragmentary compression in transverse fractures of the olecranon. AB - Compression and absolute stability are important in the management of intra articular fractures. We compared tension band wiring with plate fixation for the treatment of fractures of the olecranon by measuring compression within the fracture. Identical transverse fractures were created in models of the ulna. Tension band wires were applied to ten fractures and ten were fixed with Acumed plates. Compression was measured using a Tekscan force transducer within the fracture gap. Dynamic testing was carried out by reproducing cyclical contraction of the triceps of 20 N and of the brachialis of 10 N. Both methods were tested on each sample. Paired t-tests compared overall compression and compression at the articular side of the fracture. The mean compression for plating was 819 N (sd 602, 95% confidence interval (CI)) and for tension band wiring was 77 N (sd 19, 95% CI) (p = 0.039). The mean compression on the articular side of the fracture for plating was 343 N (sd 276, 95% CI) and for tension band wiring was 1 N (sd 2, 95% CI) (p = 0.038). During simulated movements, the mean compression was reduced in both groups, with tension band wiring at -14 N (sd 7) and for plating -173 N (sd 32). No increase in compression on the articular side was detected in the tension band wiring group. Pre-contoured plates provide significantly greater compression than tension bands in the treatment of transverse fractures of the olecranon, both over the whole fracture and specifically at the articular side of the fracture. In tension band wiring the overall compression was reduced and articular compression remained negligible during simulated contraction of the triceps, challenging the tension band principle. PMID- 21282767 TI - Is routine chemical thromboprophylaxis after total hip replacement really necessary in a Japanese population? AB - Prophylaxis against venous thromboembolism after elective total hip replacement is routinely recommended. Our preference has been to use mechanical prophylaxis without anticoagulant drugs. A randomised controlled trial was performed to evaluate whether the incidence of post-operative venous thromboembolism was reduced by using pharmacological anticoagulation with either fondaparinux or enoxaparin in addition to our prophylactic mechanical regimen. A total of 255 Japanese patients who underwent primary unilateral cementless total hip replacement were randomly assigned to one of three postoperative regimens, namely injection of placebo (saline), fondaparinux or enoxaparin. There were 85 patients in each group. All also received the same mechanical prophylaxis during and after the operation, regardless of their assigned group. The primary measurement of efficacy was the presence of a venous thromboembolic event by day 11, defined as deep-vein thrombosis detected by ultrasonography, documented symptomatic deep vein thrombosis or documented symptomatic pulmonary embolism. The duration of follow-up was 12 weeks. The rate of venous thromboembolism was 7.2% with the placebo, 7.1% with fondaparinux and 6.0% with enoxaparin (p = 0.95 for the comparison of all three groups). Our study confirmed the effectiveness and safety of mechanical thromboprophylaxis without the use of anticoagulant drugs after total hip replacement in Japanese patients. PMID- 21282768 TI - Combined pelvic osteotomy for the bipartite acetabulum in late developmental dysplasia of the hip: a ten-year prospective study. AB - In late developmental dysplasia of the hip in childhood, the deformed dysplastic acetabulum is malaligned and has lost its shape due to pressure from the subluxed femoral head. The outer part of the acetabulum involves the upper part of the original acetabulum, thereby giving a bipartite appearance. A clear edge separates the outer from inner part which represents the lower part of the original acetabulum and has no direct contact with the femoral head. Combined pelvic osteotomy (CPO) using a Lance acetabuloplasty with either a Salter or a Pemberton procedure restores the original shape and realigns the acetabulum. A total of 20 children (22 hips), with a mean age of 46 months (28 to 94) at primary operation underwent CPO with follow-up for between 12 and 132 months. In each case concentric stable reduction with good acetabular cover was achieved and maintained throughout the period of follow-up. PMID- 21282769 TI - Elastic intramedullary nailing of paediatric fractures of the forearm: a decade of experience in a teaching hospital in the United Kingdom. AB - We present the results of 90 consecutive children with displaced fractures of the forearm treated by elastic stable intramedullary nailing with a mean follow-up of 6.6 months (2.0 to 17.6). Eight (9%) had open fractures and 77 (86%) had sustained a fracture of both bones. The operations were performed by orthopaedic trainees in 78 patients (86%). All fractures healed at a mean of 2.9 months (1.1 to 8.7). There was one case of delayed union of an ulnar fracture. An excellent or good functional outcome was achieved in 76 patients (84%). There was no statistical difference detected when the grade of operating surgeon, age of the patient and the diaphyseal level of the fracture were correlated with the outcome. A limited open reduction was required in 40 fractures (44%). Complications included seven cases of problematic wounds, two transient palsies of the superficial radial nerve and one case each of malunion and a post operative compartment syndrome. At final follow-up, all children were pain-free and without limitation of sport and play activities. Our findings indicate that the functional outcome following paediatric fractures of the forearm treated by elastic stable intramedullary nailing is good, without the need for anatomical restoration of the radial bow. PMID- 21282770 TI - Gitelman's syndrome: a rare presentation mimicking cauda equina syndrome. AB - We describe a case of bilateral weakness of the lower limbs, sensory disturbance and intermittent urinary incontinence, secondary to untreated Gitelman's syndrome, in a 42-year-old female who was referred with presumed cauda equina syndrome. On examination, the power of both legs was uniformly reduced, and the perianal and lower-limb sensation was altered. However, MRI of the lumbar spine was normal. Measurements of serum and urinary potassium were low and blood gas analysis revealed metabolic alkalosis. Her symptoms resolved following potassium replacement. We emphasise the importance of measurement of the plasma and urinary levels of electrolytes in the investigation of patients with paralysis of the lower limbs and suggest that they, together with blood gas analysis, allow the exclusion of unusual causes of muscle weakness resulting from metabolic disorders such as metabolic alkalosis. PMID- 21282771 TI - Re-ossification of the pelvis following hemipelvectomy for trauma. AB - We present a patient who underwent delayed sub-periosteal hemipelvectomy for control of infection and to enable soft-tissue cover after trauma. At four months after amputation, clinical examination and radiographs demonstrated almost complete re-ossification of the hemipelvis. This has allowed the patient to regain sitting balance and to use a walking prosthesis designed for patients following disarticulation of the hip. After 14 months from injury, no perineal hernia has developed, and no dysfunction of pelvic organs is attributable to heterotopic bone formation or adhesions. The patient's mobility with a prosthesis is similar to that expected of a through-hip amputee. PMID- 21282772 TI - Luxatio erecta of the hip. AB - We present the case of a young male patient with inferior dislocation of the hip and postulate a possible mechanism for this extremely rare injury. PMID- 21282773 TI - Entrapment of the sciatic nerve following closed reduction of a dislocated revision total hip replacement. AB - Injury to the sciatic nerve following closed manipulation of a dislocated total hip replacement is rare. We present such a case in an elderly patient with partial recovery following exploration and release of the nerve. PMID- 21282774 TI - Hyperosmolarity protects chondrocytes from mechanical injury in human articular cartilage: an experimental report. AB - The aim of this study was to determine whether exposure of human articular cartilage to hyperosmotic saline (0.9%, 600 mOsm) reduces in situ chondrocyte death following a standardised mechanical injury produced by a scalpel cut compared with the same assault and exposure to normal saline (0.9%, 285 mOsm). Human cartilage explants were exposed to normal (control) and hyperosmotic 0.9% saline solutions for five minutes before the mechanical injury to allow in situ chondrocytes to respond to the altered osmotic environment, and incubated for a further 2.5 hours in the same solutions following the mechanical injury. Using confocal laser scanning microscopy, we identified a sixfold (p = 0.04) decrease in chondrocyte death following mechanical injury in the superficial zone of human articular cartilage exposed to hyperosmotic saline compared with normal saline. These data suggest that increasing the osmolarity of joint irrigation solutions used during open and arthroscopic articular surgery may reduce chondrocyte death from surgical injury and could promote integrative cartilage repair. PMID- 21282775 TI - Assisted suicide: why psychiatrists should engage in the debate. AB - There is an increasing appetite for a change in the law to allow assisted suicide. This editorial suggests that psychiatrists should engage in the debate because the issues at stake will affect us, and we are likely to have a significant part to play were the law to be changed. We suggest that there are three main areas where psychiatrists' expertise may be informative: (a) the extent to which safeguards to limit the availability of assisted dying to target groups can be applied safely and fairly, including to individuals with psychiatric disorders; (b) the complexities inherent in assessing mental capacity; and (c) the degree to which individuals adapt or change their desires, particularly in relation to suicidal behaviours. PMID- 21282776 TI - Questioning the 'neuroprotective' hypothesis: does drug treatment prevent brain damage in early psychosis or schizophrenia? AB - The idea that psychotic disorders are characterised by progressive neurodegeneration that can be reversed by drug treatment is used to justify early treatment of increasing numbers of mostly young people. I argue that there is little evidence to support the view that old- or new-generation antipsychotics are 'neuroprotective', and some evidence that the drugs themselves may be responsible for the decline in brain matter observed in some studies. PMID- 21282777 TI - The movement for global mental health. AB - The Movement for Global Mental Health is a coalition of individuals and institutions committed to collective actions that aim to close the treatment gap for people living with mental disorders worldwide, based on two fundamental principles: evidence on effective treatments and the human rights of people with mental disorders. PMID- 21282778 TI - Equity of access to psychological therapies. AB - Improving access to psychological treatments for common mental disorders is a priority in a number of countries worldwide. We consider the evidence presented by Harris et al on the Australian Better Access initiative, and discuss the challenges of delivering such intitiatives and evaluating their impact. PMID- 21282779 TI - Efficacy of mood stabilisers in the treatment of impulsive or repetitive aggression: systematic review and meta-analysis. AB - BACKGROUND: Individuals with repetitive or impulsive aggression in the absence of other disorders may be diagnosed with intermittent explosive disorder according to DSM-IV, but no such diagnostic category exists in ICD-10. Mood stabilisers are often used off-license for the treatment of aggression associated with a variety of psychiatric conditions, but their efficacy in these and in idiopathic aggression is not known. AIMS: To summarise and evaluate the evidence for the efficacy of mood stabilisers (anticonvulsants/lithium) in the treatment of impulsive or repetitive aggression in adults. METHOD: A meta-analysis of randomised controlled trials that compared a mood stabiliser with placebo in adults without intellectual disability, organic brain disorder or psychotic illness, identified as exhibiting repetitive or impulsive aggression. RESULTS: Ten eligible trials (489 participants) were identified A pooled analysis showed an overall significant reduction in the frequency/severity of aggressive behaviour (standardised mean difference (SMD) = -1.02, 95% CI -1.54 to -0.50), although heterogeneity was high (I(2) = 84.7%). When analysed by drug type, significant effects were found in the pooled analysis of three phenytoin trials (SMD = -1.34, 95% CI -2.16 to -0.52), one lithium trial (SMD = -0.81, 95% CI 1.35 to -0.28), and two oxcarbazepine/carbamazepine trials (SMD = -1.20, 95% CI 1.83 to -0.56). However, when the results of only those studies that had a low risk of bias were pooled (347 participants), there was no significant reduction in aggression (SMD = -0.28, 95% CI -0.73 to 0.17, I(2) = 71.4%). CONCLUSIONS: There is evidence that mood stabilisers as a group are significantly better than placebo in reducing aggressive behaviour, but not all mood stabilisers appear to share this effect. There is evidence of efficacy for carbamazepine/oxcarbazepine, phenytoin and lithium. Many studies, however, were at risk of bias and so further randomised controlled trials are recommended. PMID- 21282780 TI - Neuropathological correlates of late-life depression in older people. AB - BACKGROUND: Depression is common in old age and is associated with risk of dementia, but its neuropathological correlates in the community are unknown. AIMS: To investigate for the first time in a population-representative sample of people with no dementia the association between depression observed during life and neurofibrillary tangles, diffuse and neuritic plaques, Lewy bodies, brain atrophy and cerebrovascular disease found in the brain at post-mortem. METHOD: Out of 456 donations to a population-based study, 153 brains were selected where donors had no dementia measured in life. Alzheimer and vascular pathology measures, Lewy bodies and neuronal loss were compared between those with (n = 36) and without (n = 117) depression ascertained using a fully structured diagnostic interview during life. Brain areas examined included frontal, parietal, temporal and occipital cortical areas as well as the entorhinal cortex, hippocampus and brain-stem monoaminergic nuclei. RESULTS: Depression was significantly associated with the presence of subcortical Lewy bodies. No association was found between depression and cerebrovascular or Alzheimer pathology in cortical or subcortical areas, although depression was associated with neuronal loss in the hippocampus as well as in some of the subcortical structures investigated (nucleus basalis, substantia nigra, raphe nucleus). CONCLUSIONS: Late-life depression was associated with subcortical and hippocampal neuronal loss but not with cerebrovascular or Alzheimer pathology. PMID- 21282781 TI - Neuropsychological changes and treatment response in severe depression. AB - BACKGROUND: Impaired neuropsychological function and differences in facial emotion processing are features of major depression. Some aspects of these functions may change during treatment and may be useful in assessing treatment response, even at an early stage of treatment. AIMS: To examine early and later changes in neuropsychological functioning and facial emotion processing as potential markers of treatment response in major depression. METHOD: In total, 68 newly admitted in-patients with a primary diagnosis of major depression and 50 healthy controls completed an assessment, including mood ratings, neuropsychological measures and facial emotion processing measures at three time points (baseline, 10-14 days and 6 weeks). RESULTS: Pervasive neuropsychological impairment was evident at baseline in patients with depression compared with healthy controls. During 6 weeks of treatment, only simple reaction time, verbal working memory and the recognition of angry facial expressions showed differential change in those whose depression responded to treatment compared with treatment non-responders in the depression group. None of the measures showed a significant difference between treatment responders and non-responders at 10-14 days. CONCLUSIONS: Despite significant impairment in neuropsychological functioning in the depression group, most measures failed to differentiate between treatment responders and non-responders at 10-14 days or at 6 weeks. Simple reaction time, verbal working memory and recognition of angry facial expressions may be useful in assessing response in severe depression but probably not at an early stage. PMID- 21282782 TI - Quantifying the effect of early retirement on the wealth of individuals with depression or other mental illness. AB - BACKGROUND: In addition to the health burden caused by mental illnesses, these conditions contribute to economic disadvantage because of their impact on labour force participation. AIMS: To quantify the cost of lost savings and wealth to Australians aged 45-64 who retire from the labour force early because of depression or other mental illness. METHOD: Cross-sectional analysis of the base population of Health&WealthMOD, a microsimulation model built on data from the Australian Bureau of Statistics' Survey of Disability, Ageing and Carers and STINMOD, an income and savings microsimulation model. RESULTS: People who are not part of the labour force because of depression or other mental illness have 78% (95% CI 92.2-37.1) and 93% (95% CI 98.4-70.5) less wealth accumulated respectively, compared with people of the same age, gender and education who are in the labour force with no chronic health condition. People who are out of the labour force as a result of depression or other mental illness are also more likely to have the wealth that they do have in cash assets, rather than higher growth assets such as superannuation, home equity and other financial investments. CONCLUSIONS: This lower accumulated wealth is likely to result in lower living standards for these individuals in the future. This will compound the impact of their condition on their health and quality of life, and put a large financial burden on the state as a result of the need to provide financial assistance for these individuals. PMID- 21282783 TI - Life stress, 5-HTTLPR and mental disorder: findings from a 30-year longitudinal study. AB - BACKGROUND: Recent meta-analyses have raised concerns about the replicability of gene * environment interactions involving the serotonin transporter gene (5 HTTLPR) in moderating the associations between adverse life events and mental disorders. AIMS: To use data gathered over the course of a 30-year longitudinal study of a New Zealand birth cohort to test the hypothesis that the presence of short ('s') alleles of 5-HTTLPR are associated with an increased response to life stress. METHOD: Participants were 893 individuals from the Christchurch Health and Development Study who had complete data on: the 5-HTTLPR genotype; psychiatric disorders up to the age of 30; and exposure to childhood and adult adverse life events. RESULTS: A series of 104 regression models were fitted to four mental health outcomes (depressive symptoms, major depression, anxiety disorder and suicidal ideation) observed at ages 18, 21, 25 and 30 using 13 measures of life-course stress that spanned childhood and adult stressors. Both multiplicative and additive models were fitted to the data. No evidence was found that would support the hypothesis that 's' alleles of 5-HTTLPR are associated with increased responsivity to life stressors. CONCLUSIONS: The present findings add to the evidence suggesting that it is unlikely that there is a stable gene * environment interaction involving 5-HTTLPR, life stress and mental disorders. PMID- 21282784 TI - Coming home may hurt: risk factors for mental ill health in US reservists after deployment in Iraq. AB - BACKGROUND: Little research has been conducted on the factors that may explain the higher rates of mental health problems in United States National Guard soldiers who have deployed to the Iraq War. AIMS: To examine whether financial hardship, job loss, employer support and the effect of deployment absence on co workers were associated with depression and post-traumatic stress disorder (PTSD). METHOD: Cross-sectional data were obtained from 4034 National Guard soldiers at two time points. All measures were assessed by self-report. RESULTS: The four factors were associated with depression and PTSD, with variability based on outcome and time point. For example, job loss increased the odds of meeting criteria for depression at 3 and 12 months and for PTSD at 12 months; the negative effect of deployment absence on co-workers increased the likelihood of meeting criteria for PTSD, but not depression, at both time points. CONCLUSIONS: The findings demonstrate that National Guard soldiers have unique post-deployment social and material concerns that impair their mental health. PMID- 21282785 TI - Mental health of the non-heterosexual population of England. AB - BACKGROUND: There has been little research into the prevalence of mental health problems in lesbian, gay and bisexual (LGB) people in the UK with most work conducted in the USA. AIMS: To relate the prevalence of mental disorder, self harm and suicide attempts to sexual orientation in England, and to test whether psychiatric problems were associated with discrimination on grounds of sexuality. METHOD: The Adult Psychiatric Morbidity Survey 2007 (n = 7403) was representative of the population living in private UK households. Standardised questions provided demographic information. Neurotic symptoms, common mental disorders, probable psychosis, suicidality, alcohol and drug dependence and service utilisation were assessed. In addition, detailed information was obtained about aspects of sexual identity and perceived discrimination on these grounds. RESULTS: Self-reported identification as non-heterosexual (determined by both orientation and sexual partnership, separately) was associated with unhappiness, neurotic disorders overall, depressive episodes, generalised anxiety disorder, obsessive-compulsive disorder, phobic disorder, probable psychosis, suicidal thoughts and acts, self-harm and alcohol and drug dependence. Mental health related general practitioner consultations and community care service use over the previous year were also elevated. In the non-heterosexual group, discrimination on the grounds of sexual orientation predicted certain neurotic disorder outcomes, even after adjustment for potentially confounding demographic variables. CONCLUSIONS: This study corroborates international findings that people of non-heterosexual orientation report elevated levels of mental health problems and service usage, and it lends further support to the suggestion that perceived discrimination may act as a social stressor in the genesis of mental health problems in this population. PMID- 21282786 TI - Overcrowding in psychiatric wards and physical assaults on staff: data-linked longitudinal study. AB - BACKGROUND: Patient overcrowding and violent assaults by patients are two major problems in psychiatric healthcare. However, evidence of an association between overcrowding and aggressive behaviour among patients is mixed and limited to small-scale studies. AIMS: This study examined the association between ward overcrowding and violent physical assaults in acute-care psychiatric in-patient hospital wards. METHOD: Longitudinal study using ward-level monthly records of bed occupancy and staff reports of the timing of violent acts during a 5-month period in 90 in-patient wards in 13 acute psychiatric hospitals in Finland. In total 1098 employees (physicians, ward head nurses, registered nurses, licensed practical nurses) participated in the study. The outcome measure was staff reports of the timing of physical assaults on both themselves and ward property. RESULTS: We found that 46% of hospital staff were working in overcrowded wards, as indicated by >10 percentage units of excess bed occupancy, whereas only 30% of hospital personnel were working in a ward with no excess occupancy. An excess bed occupancy rate of >10 percentage units at the time of an event was associated with violent assaults towards employees (odds ratio (OR) = 1.72, 95% CI 1.05 2.80; OR = 3.04, 95% CI 1.51-6.13 in adult wards) after adjustment for confounding factors. No association was found with assaults on ward property (OR = 1.06, 95% CI 0.75-1.50). CONCLUSIONS: These findings suggest that patient overcrowding is highly prevalent in psychiatric hospitals and, importantly, may increase the risk of violence directed at staff. PMID- 21282787 TI - Is transference-focused psychotherapy really efficacious for borderline personality disorder? PMID- 21282788 TI - Continuing lack of evidence for the psychotic subtyping of PTSD. PMID- 21282789 TI - Ziprasidone and the relative risk of diabetes. PMID- 21282790 TI - The iceberg theory of NHS culture. PMID- 21282791 TI - An evolution of professionalism. PMID- 21282792 TI - Multi-detector computed tomography coronary angiography: the incidental lung findings. PMID- 21282793 TI - Treatments to die for. PMID- 21282794 TI - Multidisciplinary team-led management of acute Type B aortic dissection in the United Kingdom? PMID- 21282795 TI - The discovery of thyroid replacement therapy. Part 2: the critical 19th century. PMID- 21282796 TI - A co-productive health leadership model to support the liberation of the NHS. AB - Following the recent white paper - Equity and Excellence: Liberating the NHS - we need a 21st-century model of leadership in the NHS that re-focuses on the centrality of the relationship between clinicians and patients. This paper argues the case for co-productive 'Health Leadership' that can meet the challenges set by the current Big Society agenda, Darzi and Wanless, so that we achieve a sustainable, high quality NHS, fit for the 21st century. PMID- 21282798 TI - Pneumocephalus - a possible cause of post-spinal surgery confusion. PMID- 21282797 TI - A systematic review of lung-sparing extirpative surgery for pleural mesothelioma. AB - OBJECTIVES: There is a resurgence of interest in lung-sparing extirpative surgery for malignant pleural mesothelioma with recent reports of better survival and fewer adverse consequences than with extrapleural pneumonectomy. However, these operations are not well-characterized and to offer evidence-based clinical recommendations and to plan future trials a summary of what is already known is required. DESIGN: A formal literature search was performed and all recovered titles were sequentially sifted by title, abstract and full-text reading according to prespecified criteria. Papers were selected if they contained data relevant to the area of enquiry. Quantitative synthesis and textual analysis, appropriate to the material, were performed. SETTING: Follow-up studies of patients undergoing surgery for malignant pleural mesothelioma in specialist thoracic or cardiothoracic units. PARTICIPANTS: Among the operated patients described in these papers, a total of 1270 patients had undergone lung-sparing surgery for mesothelioma. RESULTS: There were no randomized trials or other forms of controlled studies. From 464 titles, 26 papers contained sufficient data on 1270 patients to be included in the systematic review. Operative descriptions for all series were extracted and tabulated and variation was found in the nature of surgery within and between series, and the degree of detail with which it was described. There was more operative detail in recent papers. All available numerical data were extracted, tabulated and summarized using quantitative methods. The average survival at 1, 2, 3, 4 and 5 years was 51%, 26%, 16%, 11% and 9%, respectively. There were no data on patients' performance status, symptomatic change, or other patient reported outcomes. CONCLUSIONS: In the absence of any form of control data, no conclusions can be drawn concerning survival differences or symptomatic benefits attributable to surgery. As mesothelioma surgery is restricted to a selected minority of patients who often have multiple therapies, future research will require controlled studies with explicit definitions of the clinical and surgical intent. PMID- 21282799 TI - Dora Colebrook and the evaluation of light therapy. PMID- 21282800 TI - A lasting legacy from Tony Blair? NHS culture change. PMID- 21282802 TI - Physicians promoting physical activity using pedometers and community partnerships: a real world trial. AB - BACKGROUND: Healthcare providers are a primary source of information on preventive health issues for patients. Further research related to physical activity (PA) promotion in the primary care setting is needed. OBJECTIVE: To explore the feasibility of a physician and community PA intervention using a pedometer for: increasing PA levels among inactive patients; enhancing relationships between physicians and community PA partners; and influencing the PA promotion habits of physicians. METHODS: A 6-week PA intervention was delivered to 152 inactive patients who were recruited in physician waiting rooms, counselled by their physicians, provided with a pedometer and referred to a community action site (CAS) at their local recreation centre for further support. PA was measured at baseline and follow-up using the International Physical Activity Questionnaire. Follow-up interviews were conducted with physicians and recreation representatives on the challenges and benefits associated with the intervention. RESULTS: Study patients significantly increased their PA (103% change in MET min/week). Physicians and recreation professionals were highly satisfied with the intervention and partnership. There were challenges to ongoing communication. Physicians reported increased awareness of the pedometer and community resources as supports for PA. CONCLUSION: A pedometer-based PA intervention delivered by physicians in partnership with a community PA stakeholder is feasible and warrants further research. Long-term maintenance of this intervention would require resources for pedometers, and ongoing contact and communication between the physicians and CAS to ensure availability of community supports. PMID- 21282804 TI - Titanium and gold nanoparticles in asthma: the bad and the ugly. PMID- 21282805 TI - The promise of electronic data capture in respiratory medicine. PMID- 21282806 TI - Daytime predictors of sleep-disordered breathing in neuromuscular patients to better schedule polysomnography. PMID- 21282807 TI - The case for inspiratory muscle training in COPD. For. PMID- 21282808 TI - The case against inspiratory muscle training in COPD. Against. PMID- 21282809 TI - Impact of inspiratory muscle training in patients with COPD: what is the evidence? AB - A meta-analysis including 32 randomised controlled trials on the effects of inspiratory muscle training (IMT) in chronic obstructive pulmonary disease (COPD) patients was performed. Overall and subgroup analyses with respect to training modality (strength or endurance training, added to general exercise training) and patient characteristics were performed. Significant improvements were found in maximal inspiratory muscle strength (P(I,max); +13 cmH2O), endurance time (+261 s), 6- or 12-min walking distance (+32 and +85 m respectively) and quality of life (+3.8 units). Dyspnoea was significantly reduced (Borg score -0.9 point; Transitional Dyspnoea Index +2.8 units). Endurance exercise capacity tended to improve, while no effects on maximal exercise capacity were found. Respiratory muscle endurance training revealed no significant effect on P(I,max), functional exercise capacity and dyspnoea. IMT added to a general exercise programme improved P(I,max) significantly, while functional exercise capacity tended to increase in patients with inspiratory muscle weakness (P(I,max) <60 cmH2O). IMT improves inspiratory muscle strength and endurance, functional exercise capacity, dyspnoea and quality of life. Inspiratory muscle endurance training was shown to be less effective than respiratory muscle strength training. In patients with inspiratory muscle weakness, the addition of IMT to a general exercise training program improved P(I,max) and tended to improve exercise performance. PMID- 21282810 TI - Circulating endothelial progenitor cells and chronic pulmonary diseases. AB - Circulating endothelial progenitor cells (EPCs) are bone marrow-derived cells that contribute to vascular healing and remodelling under physiological and pathological conditions. Although controversies exist regarding the definition and origin of EPCs, it has been widely demonstrated that they are involved in several diseases and that they have therapeutic implications. Chronic obstructive pulmonary disease (COPD) is characterised by airflow limitation that is not fully reversible, associated with abnormalities of airways (bronchitis) and parenchyma (emphysema), reduced exercise tolerance and systemic inflammation. Growing evidence has also suggested that endothelial dysfunction may play a role in COPD. Although it is not clear whether endothelial dysfunction represents a cause or a consequence of COPD, several studies have highlighted the importance of EPCs in this disease, suggesting that the bone marrow could be a novel target of COPD. The present review summarises the role of EPCs in pulmonary diseases, with particular emphasis on COPD. The aim is to improve understanding as to the possible role of EPCs in COPD pathophysiology. This may help in the identification of novel diagnostic and therapeutic tools in COPD. PMID- 21282811 TI - Subsequent COPD and lung cancer in patients with autoimmune disease. PMID- 21282812 TI - Clinical features of secondary pulmonary alveolar proteinosis: pre-mortem cases in Japan. PMID- 21282813 TI - Is NMR-based metabolomic analysis of exhaled breath condensate accurate? PMID- 21282814 TI - Hypercalcaemia in asymptomatic sarcoidosis unmasked by a vitamin D loading dose. PMID- 21282815 TI - Sitaxentan-related acute liver failure in a patient with pulmonary arterial hypertension. PMID- 21282816 TI - Liver toxicity of sitaxentan in pulmonary arterial hypertension. PMID- 21282817 TI - Dyspnoea: a prognostic marker for idiopathic pulmonary fibrosis. PMID- 21282820 TI - Effects of laparoscopic ovarian drilling in treating infertile anovulatory polycystic ovarian syndrome patients with and without metabolic syndrome. AB - OBJECTIVE: To compare the effects of laparoscopic ovarian drilling in treating infertile polycystic ovarian syndrome in patients with and without metabolic syndrome. DESIGN: Retrospective review. SETTING: A university-affiliated hospital in Hong Kong. PATIENTS: A total of 89 infertile anovulatory polycystic ovarian syndrome patients, who underwent laparoscopic ovarian drilling with completed metabolic screening and seen over a 5-year period from 2002 to 2007. MAIN OUTCOME MEASURES: The clinical, hormonal, and metabolic characteristics as well as spontaneous ovulation rates, reproductive outcomes, and diabetes risks during pregnancy observed after laparoscopic ovarian drilling. RESULTS: Approximately one fifth (21%) of polycystic ovarian syndrome patients had the metabolic syndrome. There were no differences in spontaneous ovulation rates (68% vs 61%, P=0.76), cumulative pregnancy rates (68% vs 61%, P=0.77), and diabetes risks during pregnancy (64% vs 42%, P=0.13) between patients with and without metabolic syndrome. CONCLUSION: Laparoscopic ovarian drilling was equally effective in inducing ovulation in polycystic ovarian syndrome patients with metabolic syndrome. Thus, patients with metabolic syndrome should not be precluded from laparoscopic ovarian drilling, which has the additional advantage of enabling full tubo-peritoneal assessment at the same time. PMID- 21282821 TI - Hepatocarcinogenesis of regenerative and dysplastic nodules in Chinese patients. AB - OBJECTIVES: To determine the development rate of hepatocellular carcinoma and survival of patients diagnosed to have regenerative, and low-grade and high-grade dysplastic liver nodules. DESIGN: Retrospective descriptive study. SETTING: Acute public hospital, Hong Kong. PATIENTS: Patients with non-malignant liver nodules confirmed by imaging-guided liver biopsy between January 1997 and December 2008. MAIN OUTCOME MEASURES: Rates of hepatocellular carcinoma development and survival. RESULTS: A total of 147 patients with non-malignant liver nodules were followed up over a median duration of 29 months. The initial histological diagnosis included regenerative nodules (n=74), low-grade dysplastic nodules (n=34), and high-grade dysplastic nodules (n=39). The respective cumulative hepatocellular carcinoma development rate during the first, second, third, and fourth year were 3%, 5%, 9% and 12% for simple regenerative nodules, 29%, 35%, 38% and 44% for low-grade dysplastic nodules, and 38%, 41%, 51% and 51% for high grade dysplastic nodules. The hepatocellular carcinoma development rate was highest in those with high-grade dysplastic nodules. Multivariate analysis showed that histological dysplastic changes were associated with increased alpha fetoprotein levels and advanced age, which were both independent predictors of hepatocellular carcinoma development. Histological dysplastic changes, male sex, advanced age, prolonged prothrombin time, and ultrasound appearances were independent predictors of mortality. CONCLUSION: The presence of dysplastic change in liver nodules increased the risk of hepatocellular carcinoma development and death. PMID- 21282822 TI - Total knee arthroplasty for primary knee osteoarthritis: changing pattern over the past 10 years. AB - OBJECTIVE: To review the epidemiology of total knee arthroplasty for primary osteoarthritis and the change of patient characteristics over the last decade. DESIGN: Retrospective review. SETTING: A tertiary referral centre for joint replacement surgery in a teaching hospital in Hong Kong. PATIENTS: All patients who underwent primary total knee arthroplasty for primary knee osteoarthritis from January 2000 to December 2009. RESULTS: In all, 1157 total knee arthroplasties (589 left and 568 right) were performed on 588 females and 162 males. The annual number of total knee arthroplasties increased from 91 in 2000 to 181 in 2009. The annual number of patients increased from 58 (46 female, 12 male) in 2000 to 159 (117 female, 42 male) in 2009. When compared yearly results, there were no significant changes in the preoperative Knee Society Knee Score, Knee Society Functional Assessment, and passive range of motion of these patients. However, there was a significant decreasing trend with regard to lower limb mechanical axis mal-alignment, from 15.1 degrees deviation from the neutral axis in 2000, to 14.8 degrees deviation in 2004, and then 12.9 degrees deviation in 2009 (mostly varus deformity). There was no difference between left knees and right knees, and between females and males. The mean age of the patients did not show significant change over the past decade, but the number and proportion of patients over 80 years old showed an increase from 4.8% (2000 to 2004) to 13.8% (2005 to 2009). On the other hand, the number and proportion of patients under the age of 60 years did not change. CONCLUSIONS: There was an increasing trend towards total knee arthroplasties, both in terms of number of operations and patients. The number of younger patients having total knee arthroplasty did not increase over the last 10 years, whereas the number of those older than 80 years increased significantly over that period. PMID- 21282823 TI - Clinical outcome of open and laparoscopic surgery in Dukes' B and C rectal cancer: experience from a regional hospital in Hong Kong. AB - OBJECTIVE: To compare the long-term outcome of open and laparoscopic surgery for Dukes' B and C rectal cancer in a regional hospital in Hong Kong. DESIGN: Retrospective study. SETTING: A regional hospital in Hong Kong. MAIN OUTCOME MEASURES: Survival and local recurrence rates. PATIENTS: Patients with Dukes' B and C rectal cancers underwent elective curative open or laparoscopic surgery during the period December 2000 to December 2006. RESULTS: A total of 222 patients (open surgery, n=133; laparoscopic surgery, n=89) were assessed. The overall 3- and 5-year survival rates for all patients were 72% and 58%, respectively. Local recurrence rates were similar in both groups. Laparoscopic group had better overall survival (P=0.014), however. The overall 3-year survival rates were 79% and 68% in the laparoscopic and open groups, respectively. The corresponding 5-year rates were 75% and 52%. Multivariate analysis also demonstrated that laparoscopic surgery was a significant independent factor for better survival. Chemotherapy, local recurrence, lymph node metastasis, and poorly differentiated tumour were significantly associated with survival. CONCLUSION: Laparoscopic surgery for Dukes' B and C rectal cancer was associated with more favourable survival than with open surgery. PMID- 21282824 TI - Robot-assisted versus standard laparoscopic partial nephrectomy: comparison of perioperative outcomes from a single institution. AB - OBJECTIVE: To evaluate the perioperative outcomes of robot-assisted laparoscopic partial nephrectomy and standard laparoscopic partial nephrectomy in a teaching hospital. DESIGN: Retrospective study. SETTING: Division of Urology, Department of Surgery, Queen Mary and Tung Wah hospitals, Hong Kong. PATIENTS: The first 10 consecutive patients who had robot-assisted laparoscopic partial nephrectomy for renal tumours between January 2008 and September 2009 with prospective data collection were evaluated. Their outcomes were compared with the last 10 consecutive patients in our database, who had standard laparoscopic partial nephrectomy between November 2004 and October 2007. MAIN OUTCOME MEASURES: Demographics, tumour characteristics, perioperative outcomes, renal function, and pathological outcomes. RESULTS: There were no differences between the groups with regard to age (63 vs 56 years; P=0.313) and tumour size (2.7 vs 2.8 cm; P=0.895). No significant difference was found between the two groups with respect to the operating room time (376 vs 361 min; P=0.722), estimated blood loss (329 vs 328 mL; P=0.994), and length of hospital stay (7 vs 14 days; P=0.213). A statistically significant shorter mean warm ischaemic time for the robot-assisted group was noted (31 vs 40 minutes; P=0.032). Respective renal functional outcomes as shown by the difference between day 0 and day 60 serum creatinine levels were comparable (+10 vs +7 mmol/L; P=0.605). In both groups, there were no intra operative complications or instances of surgical margin tumour involvement. Three patients endured postoperative complications in the standard laparoscopic group (a perinephric haematoma, urine leakage, and lymph leakage) compared with one in the robot-assisted group (a perinephric haematoma). These complications all resolved with conservative treatment. CONCLUSIONS: Robot-assisted laparoscopic partial nephrectomy is a technically feasible alternative to standard laparoscopic partial nephrectomy, and provides comparable results. Robot-assisted laparoscopic partial nephrectomy appears to offer the advantage of decreased warm ischaemic time. Longer follow-up is required to assess renal function and oncological outcomes. Further experience and randomised trials are necessary to compare robot-assisted with standard laparoscopic partial nephrectomy. PMID- 21282825 TI - Cross-clade immunogenicity and safety of an AS03A-adjuvanted prepandemic H5N1 influenza vaccine in Hong Kong. AB - OBJECTIVE: To present Hong Kong'Aispecific data from a large Asian population (also involving Thailand, Singapore, and Taiwan) on safety and manufacturing consistency across four AS03(A)-adjuvanted H5N1 vaccine formulations in terms of immune response against the A/Vietnam/1194/2004 strain. Immunogenicity against the heterologous A/Indonesia/05/2005 strain was also assessed. NCT Number: 00449670. DESIGN: Prospective, observer-blind study. SETTING: Out-patient clinic of a tertiary hospital in Hong Kong. PARTICIPANTS: A total of 360 subjects aged 18 to 60 years were randomised into six groups to receive two doses (21 days apart) of the study vaccine. INTERVENTIONS: One of the four adjuvanted formulations (3.75 microgram H5N1 haemagglutinin [HA]+AS03(A)) of the vaccine (H5N1-AS03(A)) or one of the two non-adjuvanted (3.75 microgram H5N1 [HA]) formulations of the vaccine (H5N1-DIL). MAIN OUTCOME MEASURES: Blood samples collected before vaccination and 21 days after each vaccine dose were analysed using haemagglutination-inhibition and neutralisation assays. Solicited, unsolicited, and serious adverse events were recorded. RESULTS: Manufacturing consistency across all four vaccine formulations was demonstrated. After two doses, the AS03(A)-adjuvanted prepandemic influenza vaccine demonstrated high seroprotection rates against the A/Vietnam/1194/2004 strain (95.8%) and good immunogenicity against the heterologous A/Indonesia/05/2005 strain (45.7%), as compared to the non-adjuvanted vaccine (4.6% and 1.5%, respectively). The seroconversion rates induced by the adjuvanted formulations in terms of viral neutralising antibodies against the two strains were much higher than those induced by the non-adjuvanted formulations. There were no safety concerns for any of the adjuvanted vaccine formulations. CONCLUSIONS: The AS03(A)-adjuvanted H5N1 prepandemic influenza vaccine demonstrated good immunogenicity and an acceptable safety profile in Hong Kong. PMID- 21282826 TI - Family medicine training in Hong Kong: similarities and differences between family and non-family doctors. AB - OBJECTIVE: To study the local medical profession's opinions on the training requirements for the specialty of family medicine. This was to serve as a reference for future planning of the health care system. DESIGN: Cross-sectional study. PARTICIPANTS AND SETTING: All registered doctors in Hong Kong. MAIN OUTCOME MEASURES: Doctors' ratings on the importance of vocational training, professional assessment, job nature, and experience to become suitably qualified as a family doctor, and their opinions on the length of necessary vocational training. RESULTS: A total of 2310 doctors (23% of doctors in the local register) responded. Professional assessment was mostly agreed as a qualification, followed by vocational training, clinical experience, and job nature. Over 70% agreed on a training period of 4 years or less. Non-family doctors were more likely to opt for professional assessment as the qualification and also opt for a longer training period. CONCLUSION: Vocational training was considered important as a qualification for the specialty of family medicine. The length of training was mostly agreed to be 4 years or less, not the 6 years currently required by the Hong Kong Academy of Medicine. The vocational training programme for family medicine might require re-examination. PMID- 21282827 TI - Laparoscopic sacrocolpopexy for the treatment of vaginal vault prolapse: with or without robotic assistance. AB - OBJECTIVE: To assess perioperative and medium-term outcome after laparoscopic sacrocolpopexy with or without robotic assistance for vaginal vault prolapse in a Hong Kong tertiary centre. DESIGN: Retrospective study. SETTING: An urogynaecology unit in Hong Kong. PATIENTS: All women who underwent laparoscopic sacrocolpopexy with or without robotic assistance for vaginal vault prolapse from March 2005 to May 2010. MAIN OUTCOME MEASURES: The perioperative and medium-term outcomes. RESULTS: A total of 36 women underwent the operation during the study period. The mean operating time was 205 minutes, mean blood loss was 144 mL. The median hospital stay was 4 days. Two women required early re-operation but recovered fully. In all, 35 women were followed up for 29 (standard deviation, 19) months. Three of them (9%) had a recurrence of stage II prolapse, but there was statistically significant improvement in the pelvic organ prolapse quantification assessment for all three compartments of the vagina, and the length of vagina was well preserved. There were no mesh exposure or erosions. The overall objective cure rate of 91% (32/35) was high, and 91% (32/35) were satisfied with the operative outcome. Stress incontinence and voiding difficulty were significantly reduced. CONCLUSION: Laparoscopic sacrocolpopexy for vaginal vault prolapse is safe, although complications arising from concomitant surgery should not be neglected. High rates of objective cures and patient satisfaction were achieved. There were no mesh exposure or erosions. Laparoscopic sacrocolpopexy should be considered an option for women with vaginal vault prolapse. PMID- 21282828 TI - Reversible posterior leukoencephalopathy syndrome in Chinese children induced by chemotherapy: a review of five cases. AB - This is a retrospective review of the clinico-radiological features and neurological outcomes of reversible posterior leukoencephalopathy syndrome episodes in Chinese cancer children receiving chemotherapy in a regional hospital in Hong Kong from 1998 to 2008. Five children (3 males and 2 females) with a mean age of 7 years were identified, four of whom had acute lymphoblastic leukaemia and one had a central nervous system germ cell tumour. Presenting symptoms included seizures (100%), altered mental function (100%), headache (40%), and visual disturbance (60%). The mean systolic blood pressure at presentation was 158 mm Hg. Approximately 80% had typical radiological features of reversible posterior leukoencephalopathy syndrome. All showed complete recovery after the acute stage, but one subsequently developed epilepsy. Two patients ultimately died of refractory malignant disease. Two others were followed up for a mean of 6 years, and remained neurologically normal. This report was the first case review documenting reversible posterior leukoencephalopathy syndrome in Chinese cancer children. The clinico-radiological features and neurological outcomes were similar to those reported in western series. Early recognition of the syndrome is important to facilitate appropriate treatment. The central nervous system damage may not be reversible and thus long-term follow-up is warranted. PMID- 21282829 TI - RYR1-related central core myopathy in a Chinese adolescent boy. AB - Central core myopathy is a rare, inherited neuromuscular disorder with a wide spectrum of phenotypic presentations. It is also considered an allelic disease of malignant hyperthermia. We report a case of central core myopathy in a Chinese adolescent boy presenting with atypical clinical features and a moderately elevated serum creatine kinase level. The diagnosis was made from the histopathological findings of central cores on muscle biopsy, and confirmed by the molecular genetic testing for the RYR1 gene mutation. This is the first case of central core myopathy confirmed by molecular study in our locality. PMID- 21282830 TI - Relapse of amoebic infection 10 years after the infection. AB - A 52-year-old man with schizophrenia, who had a history of amoebic liver abscess treated with combination antimicrobial agents, presented 10 years later with severe rectal bleeding. Diagnosis of amoebic colitis was confirmed by histological examination of endoscopic biopsy. Doctors treating patients with amoebic infection should be aware of the risk of eradication failure. Post treatment stool testing, preferably by antigen testing or polymerase chain reaction, should be performed after antimicrobial treatment. PMID- 21282831 TI - An uncommon adverse effect of levodopa withdrawal in a patient taking antipsychotic medication: neuroleptic malignant-like syndrome. AB - A patient with symptoms suggestive of neuroleptic malignant syndrome after levodopa withdrawal is described. The patient presented with persistent high fever, stupor, autonomic dysfunction, rigidity, and rhabdomyolysis. He was successfully treated with intravenous dantrolene, resumption of levodopa, and forced alkaline diuresis. Doctors should be aware of the risk of abrupt cessation of dopamine agonists. PMID- 21282832 TI - Refractory bulbar and respiratory dysfunction in a young Chinese woman with seronegative, muscle-specific tyrosine kinase antibody-positive myasthenia gravis: response to cyclophosphamide and rituximab treatment. AB - The use of cyclophosphamide and rituximab for patients with refractory myasthenia gravis has shown promising results. We report on a 31-year-old Chinese woman with acetylcholine receptor antibody-negative and muscle-specific tyrosine kinase antibody-positive generalised myasthenia gravis who had refractory bulbar dysfunction and respiratory failure despite immunosuppressive therapy and thymectomy, and partial and sustained responses to cyclophosphamide and rituximab treatment, respectively. Myasthenia crisis was diagnosed when she presented in the third trimester of pregnancy with dysphagia, bilateral ptosis, prominent fatigability, and respiratory failure. She required prolonged intensive care and non-invasive ventilatory support despite several courses of intravenous immunoglobulins and plasmapheresis. Pulse cyclophosphamide 500 mg/m(2) was given monthly for 4 consecutive months with a partial response. Rituximab 500 mg weekly was subsequently given for 4 weeks with a dramatic and sustained response. She remained symptom-free and assumed full maternal care at 1 year. To the authors' knowledge, this is the first report of a Chinese patient with refractory myasthenia gravis who responded to cyclophosphamide and rituximab. PMID- 21282833 TI - Posterior reversible encephalopathy syndrome with bevacizumab. PMID- 21282834 TI - Thrombolytic therapy for acute ischaemic stroke: is the hype justified? PMID- 21282835 TI - Thrombolytic treatment in acute stroke. PMID- 21282836 TI - The relationship between physical activity and executive function performance in children with attention-deficit hyperactivity disorder. AB - Children with attention-deficit hyperactivity disorder (AD/HD) consistently perform worse on executive function (EF) tasks relative to those without AD/HD. Physical activity has a small effect on cognition in children and may be particularly beneficial for children with AD/HD by impacting fundamental EF deficiencies that characterize this disorder. The purpose of this study was to explore the extent to which physical activity is associated with EF in children with AD/HD. Eighteen boys (M age = 10.61, SD = 1.50) with AD/HD were recruited to complete four EF tasks. Physical activity was measured with an accelerometer that provided daily minutes of moderate-to-vigorous intensity physical activity; this measure was a significant predictor of performance on the Tower of London planning task, adjusted R2 = .28, F(1, 16) = 7.61, p < .05, and was positively associated with other EF measures. These results suggest that higher physical activity is associated with better EF performance in AD/HD children. PMID- 21282837 TI - A multimethod examination of the relationship between coaching behavior and athletes' inherent self-talk. AB - The aim of the present research was to investigate the relationship between coaching behavior and athletes' inherent self-talk (ST). Three studies were conducted. The first study tested the construct validity of the Coaching Behavior Questionnaire (CBQ) in the Greek language, and provided support for its original factor structure. The second study examined the relationships between coaching behavior and athletes' ST in field, with two different samples. The results showed that supportive coaching behavior was positively related to positive ST (in one sample) and negatively related to negative ST (in both samples), whereas negative coaching behavior was negatively related to positive ST (in one sample) and positively related to negative ST (in both samples). Finally, the third study examined the relationships experimentally, to produce evidence regarding the direction of causality. The results showed that variations in coaching behavior affected participants' ST. Overall, the results of the present investigation provided considerable evidence regarding the links between coaching behavior and athletes' ST and suggested that coaches may have an impact on athletes' thoughts. PMID- 21282838 TI - The impact of an experiential education program on the self-perceptions and perceived social regard of physical education students. AB - This study investigated the effectiveness of an 8-month Team Building through Physical Challenges (TBPC; Glover & Midura, 1992) program on the self-perceptions and perceived social regard of middle school physical education students (N = 1802). Data were analyzed using multilevel analyses where midpoint and final evaluations were conducted separately. Results revealed that at the midpoint evaluation, students in the experimental and control conditions were not different on any of the subscales assessed. At the end of the program, students in the experimental condition, compared with those in the control condition, showed significantly higher scores on 6 of the 10 subscales assessed and the effect sizes were medium to very large. The findings support the effectiveness of the TBPC program in creating positive psychological outcomes for students in a field-based setting. PMID- 21282839 TI - On the same page in sporting dyads: does dissimilarity on 2 x 2 achievement goal constructs impair relationship functioning? AB - This study examined the extent to which 2 x 2 achievement goal constructs (Elliot, 1999) were associated with key relational perceptions (i.e., relationship commitment, relationship satisfaction) for members of athlete athlete dyads. Both members from 82 regional-level partnerships (mean age = 22.72, SD = 3.83) were recruited from a variety of dyadic sports (e.g., tennis, badminton, rowing). Actor-partner interdependence model analyses revealed that greater dissimilarity between partners on mastery-approach and performance approach goals was associated with lower commitment and satisfaction. Mastery goals displayed positive actor effects with respect to both relationship perceptions, whereas performance-avoidance goals were negatively related to commitment (i.e., actor and partner effects) and satisfaction (i.e., partner effect). These results indicate that achievement goal constructs may align with important interpersonal perceptions in athlete dyads. PMID- 21282840 TI - Perceptual-cognitive skills in offside decision making: expertise and training effects. AB - This two-experiment study aims to investigate the role of expertise in offside decision making (Experiment 1) and the effect of perceptual-cognitive training (Experiment 2). In Experiment 1, a video-based offside decision-making task followed by a frame recognition task demonstrated a bias toward flag errors and a forward memory shift for less-successful elite-standard assistant referees that is in line with the predictions from the flash-lag effect. In Experiment 2, an offside decision-making training program demonstrated a substantial progress from pre- to posttest for response accuracy, but not for accuracy of memory in the frame recognition task. In both experiments, no differences were found for visual scan patterns. First, these results suggest that less-successful elite-standard assistant referees are more affected by the flash-lag effect. Second, an off field perceptual-cognitive training program can help assistant referees to deal with the perceptual consequences of the flash-lag illusion and to readjust their decision-making process accordingly. PMID- 21282841 TI - Training of perceptual-cognitive skills in offside decision making. AB - This study investigates the effect of two off-field training formats to improve offside decision making. One group trained with video simulations and another with computer animations. Feedback after every offside situation allowed assistant referees to compensate for the consequences of the flash-lag effect and to improve their decision-making accuracy. First, response accuracy improved and flag errors decreased for both training groups implying that training interventions with feedback taught assistant referees to better deal with the flash-lag effect. Second, the results demonstrated no effect of format, although assistant referees rated video simulations higher for fidelity than computer animations. This implies that a cognitive correction to a perceptual effect can be learned also when the format does not correspond closely with the original perceptual situation. Off-field offside decision-making training should be considered as part of training because it is a considerable help to gain more experience and to improve overall decision-making performance. PMID- 21282842 TI - Longitudinal examination of the exercise and self-esteem model in middle-aged women. AB - This 2-year prospective study examined the exercise and self-esteem model in middle-aged women (N = 143) previously enrolled in a randomized controlled exercise trial. Across the 2-year period, increases in physical activity (PA) and self-efficacy and reductions in body mass index (BMI) were associated with improved subdomain self-perceptions relative to physical condition, and reductions in BMI were associated with improved subdomain self-perceptions relative to physical condition and body attractiveness. The effects of PA, self efficacy, and BMI on changes in physical self-worth and global self-esteem were mediated by changes in self-perceptions relative to physical condition and body attractiveness. The results of this longitudinal analysis support the hierarchical and multidimensional structure of self-esteem and indicate that middle-aged women can enhance how they perceive their condition and body attractiveness by continued participation in physical activity, increasing their self-efficacy, and maintaining healthy BMI levels. PMID- 21282843 TI - Passion, self-esteem, and the role of comparative performance evaluation. AB - Two studies were conducted to investigate the paradoxical behavior of obsessively passionate individuals: they tend to continue involvement in their passion activity despite reporting the activity as a source of ill-being. We suggested that elevated self-esteem in activity engagement could be one such persistence promoting factor. In Study 1, we found that obsessively passionate individuals reported lower levels of global self-esteem compared with harmoniously passionate individuals, whereas they reported similar levels of activity-related self esteem. We suggest that this indicates that obsessively passionate individuals try to compensate for low global self-esteem by utilizing self-esteem contingencies in their passion activity. Study 2 showed that activity-related self-esteem among obsessively passionate individuals was found to be strongly related to comparative performance evaluations, whereas no such relationship was found among harmoniously passionate individuals. We suggest that self-esteem contingencies related to comparative performance criteria represent a persistence promoting factor among obsessively passionate individuals. PMID- 21282844 TI - Universal accessibility of "accessible" fitness and recreational facilities for persons with mobility disabilities. AB - This study descriptively measured the universal accessibility of "accessible" fitness and recreational facilities for Ontarians living with mobility disabilities. The physical and social environments of 44 fitness and recreational facilities that identified as "accessible" were assessed using a modified version of the AIMFREE. None of the 44 facilities were completely accessible. Mean accessibility ratings ranged between 31 and 63 out of a possible 100. Overall, recreational facilities had higher accessibility scores than fitness centers, with significant differences found on professional support and training, entrance areas, and parking lot. A modest correlation was found between the availability of fitness programming and the overall accessibility of fitness-center specific facility areas. Overall, the physical and social environments of the 44 fitness and recreational facilities assessed were limited in their accessibility for persons with mobility disabilities. Future efforts should be directed at establishing and meeting universal accessibility guidelines for Canadian physical activity facilities. PMID- 21282845 TI - The fair use of lower-limb running prostheses: A Delphi study. AB - The purpose of this paper is to investigate the role of lower-limb running prostheses and stakeholders' perceptions of fairness in relation to their use in competitive disability sport. A Delphi study was conducted over three rounds to solicit expert opinion in a developing area of knowledge. High levels of consensus were obtained. The findings suggest that the prosthesis is defined as a piece of sporting equipment to restore athletes' function to enable them to take part in disability sport. In addition, the panel determined that the development of this technology should be considered to be integral to the sport's ethos. Crucially, prostheses technology should be monitored and have limits placed upon it to ensure fairness for both participants and stakeholders. PMID- 21282846 TI - Volunteer motivations at a National Special Olympics event. AB - Understanding the motivations for people to volunteer with the management and execution of major sporting events is important for the recruitment and retention of the volunteers. This research investigated volunteer motivations at the first National Special Olympics held in Ames, Iowa, USA in July 2006. A total of 289 participants completed the 28 item Special Event Volunteer Motivation Scale. The top motivations related to the purposive incentives of wanting to help make the event a success and to do something good for the community. Factor analysis revealed a five-factor model, with the altruistic factor (purposive) being the most important. A MANCOVA was also used to compare subjects using both gender and experience as independent variables. Small but significant differences in motivation were observed. PMID- 21282847 TI - Connecting through summer camp: Youth with visual impairments find a sense of community. AB - The social meaning of a one-week residential summer sports camp to young people with visual impairments is described. The experiences of 13 youths (7 females and 6 males) with visual impairments (3 B1, 1 B2, and 9 B3) between 9 and 15 years of age were gathered using the phenomenological methods of focus groups, conversational interviews, and field notes. The thematic analysis revealed three themes: connected, reaching out, and resisting and acquiescing. Experiences of group membership and shared emotional connection to others with visual impairments surfaced in a supportive sport context although resistance to others' assumptions of ability was evident. The theory of psychological sense of community (McMillan & Chivas, 1986) provided the conceptual framework for interpreting the findings. PMID- 21282848 TI - "What I wish you knew": Social barriers toward physical activity in youth with congenital heart disease (CHD). AB - Despite the benefits of physical activity for youth with congenital heart disease (CHD), most patients are inactive. Although literature has addressed medical and psychological barriers to participation, little is known about the social barriers that youth encounter. This qualitative study explored sociocultural barriers to physical activity from the perspective of 17 youth with CHD. The main theme, "what I wish you knew," was related to all other themes-youths' efforts to resolve "disclosure dilemmas," the barriers they encounter during physical education, and their struggle to understand themselves as normal. The participants' narratives illuminate the centrality of their sociocultural world to physical activity. The findings call on researchers and educators to attend to the social and cultural environments where these youth live and play. PMID- 21282849 TI - Dynamic and Contextual Information in HMM Modeling for Handwritten Word Recognition. AB - This study aims at building an efficient word recognition system resulting from the combination of three handwriting recognizers. The main component of this combined system is an HMM-based recognizer which considers dynamic and contextual information for a better modeling of writing units. For modeling the contextual units, a state-tying process based on decision tree clustering is introduced. Decision trees are built according to a set of expert-based questions on how characters are written. Questions are divided into global questions, yielding larger clusters, and precise questions, yielding smaller ones. Such clustering enables us to reduce the total number of models and Gaussians densities by 10. We then apply this modeling to the recognition of handwritten words. Experiments are conducted on three publicly available databases based on Latin or Arabic languages: Rimes, IAM, and OpenHart. The results obtained show that contextual information embedded with dynamic modeling significantly improves recognition. PMID- 21282850 TI - Unsupervised image categorization by hypergraph partition. AB - We present a framework for unsupervised image categorization in which images containing specific objects are taken as vertices in a hypergraph and the task of image clustering is formulated as the problem of hypergraph partition. First, a novel method is proposed to select the region of interest (ROI) of each image, and then hyperedges are constructed based on shape and appearance features extracted from the ROIs. Each vertex (image) and its k-nearest neighbors (based on shape or appearance descriptors) form two kinds of hyperedges. The weight of a hyperedge is computed as the sum of the pairwise affinities within the hyperedge. Through all of the hyperedges, not only the local grouping relationships among the images are described, but also the merits of the shape and appearance characteristics are integrated together to enhance the clustering performance. Finally, a generalized spectral clustering technique is used to solve the hypergraph partition problem. We compare the proposed method to several methods and its effectiveness is demonstrated by extensive experiments on three image databases. PMID- 21282851 TI - Multiple Object Tracking Using K-Shortest Paths Optimization. AB - Multi-object tracking can be achieved by detecting objects in individual frames and then linking detections across frames. Such an approach can be made very robust to the occasional detection failure: If an object is not detected in a frame but is in previous and following ones, a correct trajectory will nevertheless be produced. By contrast, a false-positive detection in a few frames will be ignored. However, when dealing with a multiple target problem, the linking step results in a difficult optimization problem in the space of all possible families of trajectories. This is usually dealt with by sampling or greedy search based on variants of Dynamic Programming which can easily miss the global optimum. In this paper, we show that reformulating that step as a constrained flow optimization results in a convex problem. We take advantage of its particular structure to solve it using the k-shortest paths algorithm, which is very fast. This new approach is far simpler formally and algorithmically than existing techniques and lets us demonstrate excellent performance in two very different contexts. PMID- 21282852 TI - Dynamic Refraction Stereo. AB - In this paper we consider the problem of reconstructing the 3D position and surface normal of points on an unknown, arbitrarily-shaped refractive surface. We show that two viewpoints are sufficient to solve this problem in the general case, even if the refractive index is unknown. The key requirements are 1) knowledge of a function that maps each point on the two image planes to a known 3D point that refracts to it, and 2) light is refracted only once. We apply this result to the problem of reconstructing the time-varying surface of a liquid from patterns placed below it. To do this, we introduce a novel "stereo matching" criterion called refractive disparity, appropriate for refractive scenes, and develop an optimization-based algorithm for individually reconstructing the position and normal of each point projecting to a pixel in the input views. Results on reconstructing a variety of complex, deforming liquid surfaces suggest that our technique can yield detailed reconstructions that capture the dynamic behavior of free-flowing liquids. PMID- 21282853 TI - On improving the efficiency of tensor voting. AB - This paper proposes two alternative formulations to reduce the high computational complexity of tensor voting, a robust perceptual grouping technique used to extract salient information from noisy data. The first scheme consists of numerical approximations of the votes, which have been derived from an in-depth analysis of the plate and ball voting processes. The second scheme simplifies the formulation while keeping the same perceptual meaning of the original tensor voting: The stick tensor voting and the stick component of the plate tensor voting must reinforce surfaceness, the plate components of both the plate and ball tensor voting must boost curveness, whereas junctionness must be strengthened by the ball component of the ball tensor voting. Two new parameters have been proposed for the second formulation in order to control the potentially conflictive influence of the stick component of the plate vote and the ball component of the ball vote. Results show that the proposed formulations can be used in applications where efficiency is an issue since they have a complexity of order O(1). Moreover, the second proposed formulation has been shown to be more appropriate than the original tensor voting for estimating saliencies by appropriately setting the two new parameters. PMID- 21282854 TI - Active Learning Based on Locally Linear Reconstruction. AB - We consider the active learning problem, which aims to select the most representative points. Out of many existing active learning techniques, optimum experimental design (OED) has received considerable attention recently. The typical OED criteria minimize the variance of the parameter estimates or predicted value. However, these methods see only global euclidean structure, while the local manifold structure is ignored. For example, I-optimal design selects those data points such that other data points can be best approximated by linear combinations of all the selected points. In this paper, we propose a novel active learning algorithm which takes into account the local structure of the data space. That is, each data point should be approximated by the linear combination of only its neighbors. Given the local reconstruction coefficients for every data point and the coordinates of the selected points, a transductive learning algorithm called Locally Linear Reconstruction (LLR) is proposed to reconstruct every other point. The most representative points are thus defined as those whose coordinates can be used to best reconstruct the whole data set. The sequential and convex optimization schemes are also introduced to solve the optimization problem. The experimental results have demonstrated the effectiveness of our proposed method. PMID- 21282855 TI - Hybrid Parallelism for Volume Rendering on Large-, Multi-, and Many-Core Systems. AB - With the computing industry trending toward multi- and many-core processors, we study how a standard visualization algorithm, raycasting volume rendering, can benefit from a hybrid parallelism approach. Hybrid parallelism provides the best of both worlds: using distributed-memory parallelism across a large numbers of nodes increases available FLOPs and memory, while exploiting shared-memory parallelism among the cores within each node ensures that each node performs its portion of the larger calculation as efficiently as possible. We demonstrate results from weak and strong scaling studies, at levels of concurrency ranging up to 216,000, and with data sets as large as 12.2 trillion cells. The greatest benefit from hybrid parallelism lies in the communication portion of the algorithm, the dominant cost at higher levels of concurrency. We show that reducing the number of participants with a hybrid approach significantly improves performance. PMID- 21282856 TI - Modified Dendrogram of Attribute Space for Multidimensional Transfer Function Design. AB - We introduce a modified dendrogram (MD) (with subtrees to represent clusters) and display it in 2D for multidimensional transfer function design. Such a transfer function for direct volume rendering employs a multidimensional space, termed attribute space. The MD reveals the hierarchical structure information of the attribute space. The user can design a transfer function in an intuitive and informative manner using the MD user interface in 2D instead of multidimensional space, where it is hard to ascertain the relationship of the space. In addition, we provide the capability to interactively modify the granularity of the MD. The coarse-grained MD primarily shows the global information of the attribute space while the fine-grained MD reveals the finer details, and the separation ability of the attribute space is completely preserved in the finest granularity. With this so called multigrained method, the user can efficiently create a transfer function using the coarse-grained MD, and then fine tune it with the fine-grained MDs. Our method is independent on the type of the attributes and supports arbitrary-dimension attribute space. PMID- 21282857 TI - Mesh-driven vector field clustering and visualization: an image-based approach. AB - Vector field visualization techniques have evolved very rapidly over the last two decades, however, visualizing vector fields on complex boundary surfaces from computational flow dynamics (CFD) still remains a challenging task. In part, this is due to the large, unstructured, adaptive resolution characteristics of the meshes used in the modeling and simulation process. Out of the wide variety of existing flow field visualization techniques, vector field clustering algorithms offer the advantage of capturing a detailed picture of important areas of the domain while presenting a simplified view of areas of less importance. This paper presents a novel, robust, automatic vector field clustering algorithm that produces intuitive and insightful images of vector fields on large, unstructured, adaptive resolution boundary meshes from CFD. Our bottom-up, hierarchical approach is the first to combine the properties of the underlying vector field and mesh into a unified error-driven representation. The motivation behind the approach is the fact that CFD engineers may increase the resolution of model meshes according to importance. The algorithm has several advantages. Clusters are generated automatically, no surface parameterization is required, and large meshes are processed efficiently. The most suggestive and important information contained in the meshes and vector fields is preserved while less important areas are simplified in the visualization. Users can interactively control the level of detail by adjusting a range of clustering distance measure parameters. We describe two data structures to accelerate the clustering process. We also introduce novel visualizations of clusters inspired by statistical methods. We apply our method to a series of synthetic and complex, real-world CFD meshes to demonstrate the clustering algorithm results. PMID- 21282858 TI - Drawing-Based Procedural Modeling of Chinese Architectures. AB - This paper presents a novel modeling framework to build 3D models of Chinese architectures from elevation drawing. Our algorithm integrates the capability of automatic drawing recognition with powerful procedural modeling to extract production rules from elevation drawing. First, different from the previous symbol-based floor plan recognition, based on the novel concept of repetitive pattern trees, small horizontal repetitive regions of the elevation drawing are clustered in a bottom-up manner to form architectural components with maximum repetition, which collectively serve as building blocks for 3D model generation. Second, to discover the global architectural structure and its components' interdependencies, the components are structured into a shape tree in a top-down subdivision manner and recognized hierarchically at each level of the shape tree based on Markov Random Fields (MRFs). Third, shape grammar rules can be derived to construct 3D semantic model and its possible variations with the help of a 3D component repository. The salient contribution lies in the novel integration of procedural modeling with elevation drawing, with a unique application to Chinese architectures. PMID- 21282859 TI - Visualization of High-Dimensional Point Clouds Using Their Density Distribution's Topology. AB - We present a novel method to visualize multidimensional point clouds. While conventional visualization techniques, like scatterplot matrices or parallel coordinates, have issues with either overplotting of entities or handling many dimensions, we abstract the data using topological methods before presenting it. We assume the input points to be samples of a random variable with a high dimensional probability distribution which we approximate using kernel density estimates on a suitably reconstructed mesh. From the resulting scalar field we extract the join tree and present it as a topological landscape, a visualization metaphor that utilizes the human capability of understanding natural terrains. In this landscape, dense clusters of points show up as hills. The nesting of hills indicates the nesting of clusters. We augment the landscape with the data points to allow selection and inspection of single points and point sets. We also present optimizations to make our algorithm applicable to large data sets and to allow interactive adaption of our visualization to the kernel window width used in the density estimation. PMID- 21282860 TI - Restoration of brick and stone relief from single rubbing images. AB - We present a two-level approach for height map estimation from single images, aiming at restoring brick and stone relief(BSR) from their rubbing images in a visually plausible manner. In our approach, the base relief of the low frequency component is estimated automatically with a partial differential equation (PDE) based mesh deformation scheme. A few vertices near the central area of the object region are selected and assigned with heights estimated by an erosion-based contour map. These vertices together with object boundary vertices, boundary normals as well as the partial differential properties of the mesh are taken as constraints to deform the mesh by minimizing a least-squares error functional. The high frequency detail is estimated directly from rubbing images automatically or optionally with minimal interactive processing. The final height map for a restored BSR is obtained by blending height maps of the base relief and high frequency detail. We demonstrate that our method can not only successfully restore several BSR maps from their rubbing images, but also restore some relief like surfaces from photographic images. PMID- 21282861 TI - Automatic construction of quad-based subdivision surfaces using Fitmaps. AB - We present an automatic method to produce a Catmull-Clark subdivision surface that fits a given input mesh. Its control mesh is coarse and adaptive, and it is obtained by simplifying an initial mesh at high resolution. Simplification occurs progressively via local operators and addresses both quality of surface and faithfulness to the input shape throughout the whole process. The method is robust and performs well on rather complex shapes. Displacement mapping or normal mapping can be applied to approximate the input shape arbitrarily well. PMID- 21282862 TI - Parameterized algorithmics for finding connected motifs in biological networks. AB - We study the NP-hard LIST-COLORED GRAPH MOTIF problem which, given an undirected list-colored graph G = (V, E) and a multiset M of colors, asks for maximum cardinality sets S ? V and M' ? M such that G[S] is connected and contains exactly (with respect to multiplicity) the colors in M'. LIST-COLORED GRAPH MOTIF has applications in the analysis of biological networks. We study LIST-COLORED GRAPH MOTIF with respect to three different parameterizations. For the parameters motif size |M| and solution size |S|, we present fixed-parameter algorithms, whereas for the parameter |V| - |M|, we show W[1]-hardness for general instances and achieve fixed-parameter tractability for a special case of LIST-COLORED GRAPH MOTIF. We implemented the fixed-parameter algorithms for parameters |M| and |S|, developed further speed-up heuristics for these algorithms, and applied them in the context of querying protein-interaction networks, demonstrating their usefulness for realistic instances. Furthermore, we show that extending the request for motif connectedness to stronger demands, such as biconnectedness or bridge-connectedness leads to W[1]-hard problems when the parameter is the motif size |M|. PMID- 21282863 TI - A consensus tree approach for reconstructing human evolutionary history and detecting population substructure. AB - The random accumulation of variations in the human genome over time implicitly encodes a history of how human populations have arisen, dispersed, and intermixed since we emerged as a species. Reconstructing that history is a challenging computational and statistical problem but has important applications both to basic research and to the discovery of genotype-phenotype correlations. We present a novel approach to inferring human evolutionary history from genetic variation data. We use the idea of consensus trees, a technique generally used to reconcile species trees from divergent gene trees, adapting it to the problem of finding robust relationships within a set of intraspecies phylogenies derived from local regions of the genome. Validation on both simulated and real data shows the method to be effective in recapitulating known true structure of the data closely matching our best current understanding of human evolutionary history. Additional comparison with results of leading methods for the problem of population substructure assignment verifies that our method provides comparable accuracy in identifying meaningful population subgroups in addition to inferring relationships among them. The consensus tree approach thus provides a promising new model for the robust inference of substructure and ancestry from large-scale genetic variation data. PMID- 21282864 TI - Metasample-based sparse representation for tumor classification. AB - A reliable and accurate identification of the type of tumors is crucial to the proper treatment of cancers. In recent years, it has been shown that sparse representation (SR) by l1-norm minimization is robust to noise, outliers and even incomplete measurements, and SR has been successfully used for classification. This paper presents a new SR-based method for tumor classification using gene expression data. A set of metasamples are extracted from the training samples, and then an input testing sample is represented as the linear combination of these metasamples by l1-regularized least square method. Classification is achieved by using a discriminating function defined on the representation coefficients. Since l1-norm minimization leads to a sparse solution, the proposed method is called metasample-based SR classification (MSRC). Extensive experiments on publicly available gene expression data sets show that MSRC is efficient for tumor classification, achieving higher accuracy than many existing representative schemes. PMID- 21282865 TI - SLIDER: a generic metaheuristic for the discovery of correlated motifs in protein protein interaction networks. AB - Correlated motif mining (cmm) is the problem of finding overrepresented pairs of patterns, called motifs, in sequences of interacting proteins. Algorithmic solutions for cmm thereby provide a computational method for predicting binding sites for protein interaction. In this paper, we adopt a motif-driven approach where the support of candidate motif pairs is evaluated in the network. We experimentally establish the superiority of the Chi-square-based support measure over other support measures. Furthermore, we obtain that cmm is an np-hard problem for a large class of support measures (including Chi-square) and reformulate the search for correlated motifs as a combinatorial optimization problem. We then present the generic metaheuristic slider which uses steepest ascent with a neighborhood function based on sliding motifs and employs the Chi square-based support measure. We show that slider outperforms existing motif driven cmm methods and scales to large protein-protein interaction networks. The slider-implementation and the data used in the experiments are available on http://bioinformatics.uhasselt.be. PMID- 21282866 TI - A novel knowledge-driven systems biology approach for phenotype prediction upon genetic intervention. AB - Deciphering the biological networks underlying complex phenotypic traits, e.g., human disease is undoubtedly crucial to understand the underlying molecular mechanisms and to develop effective therapeutics. Due to the network complexity and the relatively small number of available experiments, data-driven modeling is a great challenge for deducing the functions of genes/proteins in the network and in phenotype formation. We propose a novel knowledge-driven systems biology method that utilizes qualitative knowledge to construct a Dynamic Bayesian network (DBN) to represent the biological network underlying a specific phenotype. Edges in this network depict physical interactions between genes and/or proteins. A qualitative knowledge model first translates typical molecular interactions into constraints when resolving the DBN structure and parameters. Therefore, the uncertainty of the network is restricted to a subset of models which are consistent with the qualitative knowledge. All models satisfying the constraints are considered as candidates for the underlying network. These consistent models are used to perform quantitative inference. By in silico inference, we can predict phenotypic traits upon genetic interventions and perturbing in the network. We applied our method to analyze the puzzling mechanism of breast cancer cell proliferation network and we accurately predicted cancer cell growth rate upon manipulating (anti)cancerous marker genes/proteins. PMID- 21282867 TI - Fast exact algorithms for the closest string and substring problems with application to the planted (L, d)-motif model. AB - We present two parameterized algorithms for the closest string problem. The first runs in O(nL + nd . 17.97d) time for DNA strings and in O(nL + nd . 61.86d) time for protein strings, where n is the number of input strings, L is the length of each input string, and d is the given upper bound on the number of mismatches between the center string and each input string. The second runs in O(nL + nd . 13.92d) time for DNA strings and in O(nL + nd . 47.21d) time for protein strings. We then extend the first algorithm to a new parameterized algorithm for the closest substring problem that runs in O((n - 1)m2(L + d . 17.97d . m[log2(d+1)])) time for DNA strings and in O((n - 1)m2(L + d . 61.86d . m[log2(d+1)])) time for protein strings, where n is the number of input strings, L is the length of the center substring, L - 1 + m is the maximum length of a single input string, and d is the given upper bound on the number of mismatches between the center substring and at least one substring of each input string. All the algorithms significantly improve the previous bests. To verify experimentally the theoretical improvements in the time complexity, we implement our algorithm in C and apply the resulting program to the planted (L, d)-motif problem proposed by Pevzner and Sze in 2000. We compare our program with the previously best exact program for the problem, namely PMSPrune (designed by Davila et al. in 2007). Our experimental data show that our program runs faster for practical cases and also for several challenging cases. Our algorithm uses less memory too. PMID- 21282868 TI - The plexus model for the inference of ancestral multidomain proteins. AB - Interactions of protein domains control essential cellular processes. Thus, inferring the evolutionary histories of multidomain proteins in the context of their families can provide rewarding insights into protein function. However, methods to infer these histories are challenged by the complexity of macroevolutionary events. Here, we address this challenge by describing an algorithm that computes a novel network-like structure, called plexus, which represents the evolution of domains and their combinations. Finally, we demonstrate the performance of this algorithm with empirical data sets. PMID- 21282869 TI - Effects of transcutaneous electrical nerve stimulation and therapeutic exercise on quadriceps activation in people with tibiofemoral osteoarthritis. AB - STUDY DESIGN: Blinded, randomized controlled trial. OBJECTIVES: To determine if the combination of transcutaneous electrical nerve stimulation (TENS) set to a sensory level and therapeutic exercise would be more effective than the combination of placebo TENS and therapeutic exercises or therapeutic exercises only to increase quadriceps activation in individuals with tibiofemoral osteoarthritis. BACKGROUND: Quadriceps activation deficits are common in those with tibiofemoral osteoarthritis, and TENS has been reported to immediately increase quadriceps activation. Yet the long-term benefits of TENS for motor neuron activation have yet to be determined. METHODS: Thirty-six individuals with radiographically assessed tibiofemoral osteoarthritis were randomly assigned to the TENS and exercise, placebo and exercise, and exercise only groups. All participants completed a supervised 4-week lower extremity exercise program. TENS and placebo TENS were worn throughout the therapeutic exercise sessions, as well as during daily activities. Our primary outcome measures, quadriceps central activation ratio, and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) were evaluated at baseline and at 2 weeks and 4 weeks of the intervention. RESULTS: Quadriceps activation was significantly higher in the TENS with exercise group compared to the exercise only group at 2 weeks (0.94 +/- 0.04 versus 0.82 +/- 0.12, P<.05) and the placebo and exercise group at 4 weeks (0.94 +/- 0.06 versus 0.81 +/- 0.15, P<.05). WOMAC scores improved in all 3 groups over time, with no significant differences among groups. CONCLUSION: This study provides evidence that TENS applied in conjunction with therapeutic exercise and daily activities increases quadriceps activation in patients with tibiofemoral osteoarthritis and, while function improved for all participants, effects were greatest in the group treated with a combination of TENS and therapeutic exercises. LEVEL OF EVIDENCE: Therapy, level 1b-. PMID- 21282870 TI - Transplacental transmission of influenza virus: what do we know? PMID- 21282871 TI - Chronic disease burden in rural India attributable to diet, obesity, and tobacco use. PMID- 21282872 TI - Good news for women with antiphospholipid syndrome? PMID- 21282873 TI - Is cell therapy promising or lost in translation in patients with acute myocardial infarction? PMID- 21282874 TI - CAVI, a new parameter that detects arterial stiffness change after smoking. PMID- 21282875 TI - Transition from asymptomatic diastolic dysfunction to heart failure with preserved ejection fraction: roles of systolic function and ventricular distensibility. AB - BACKGROUND: Systolic abnormality, as well as diastolic dysfunction, is observed in patients with heart failure with preserved ejection fraction (HFPEF). However, the role of these 2 conditions in the transition from asymptomatic diastolic dysfunction to symptomatic heart failure remains unclear. We recently demonstrated that diastolic wall strain (DWS) inversely correlates to the myocardial stiffness constant. METHODS AND RESULTS: This study consisted of 127 subjects: 52 consecutive HFPEF patients (HFPEF group), 50 asymptomatic hypertensive patients with ejection fraction >=50% whose age, gender and left ventricular (LV) mass index matched those of the HFPEF group (HT group) and 25 normal volunteers (Normal group). The tissue Doppler-derived peak systolic and early diastolic velocities of the mitral annulus were significantly decreased in groups HFPEF and HT than in group Normal, but were not significantly different between groups HFPEF and HT. DWS was significantly lower in group HFPEF than in group HT. CONCLUSIONS: The transition from asymptomatic diastolic dysfunction stage to HFPEF stage is not attributed to progression of systolic abnormality, and exacerbation of LV distensibility rather than relaxation plays a crucial role in the development of HFPEF. PMID- 21282876 TI - Anatomical characteristics of myocardial bridge in patients with myocardial infarction by multi-detector computed tomography. AB - BACKGROUND: Recent development of multi-detector computed tomography (MDCT) has made the detection of myocardial bridge (MB) easier on the left anterior descending coronary artery (LAD). The LAD segment proximal to the MB is well known to be susceptible to atherosclerosis. Anatomical characteristics of MB on LAD in patients with myocardial infarction (MI) were examined by MDCT. METHODS AND RESULTS: Subjects were 43 MI patients who had MB in the LAD and comprised 2 groups: 14 with culprit lesions in the LAD proximal to MB (culprit group) and 29 without culprit lesions in the LAD (non-culprit group). MB length, MB thickness, and the distance from the orifice of left main trunk (LMT) to MB entrance were compared. Age and coronary risk factors showed no significant difference between the 2 groups. MB length (P=0.011), MB thickness (P=0.035), and index of the length multiplied by thickness of MB (P=0.031) were significantly greater in the culprit group. The distance from the orifice of the LMT to MB entrance was significantly shorter in the culprit group (P=0.006). CONCLUSIONS: Anatomical properties of MB, such as length and thickness of MB as well as MB location, are associated with the formation of culprit lesions of LAD proximal to MB in MI. PMID- 21282877 TI - Usefulness of POSSUM physiological score for the estimation of morbidity and mortality risk after elective abdominal aortic aneurysm repair in Japan. AB - BACKGROUND: The Physiological and Operative Severity Score for enUmeration of Mortality and morbidity (POSSUM), which consists of a physiological score (PS) and an operative severity score, is useful in determining the risk profile for patients with abdominal aortic aneurysms in Western countries, but no information is available on the use of this method in Japan. METHODS AND RESULTS: A retrospective cohort study involving 225 patients was performed, and the prognostic factors for morbidity and in-hospital mortality including POSSUM were investigated. The morbidity rate was 26%. On univariate analysis age, renal disease, hemoglobin, albumin, operation time, blood loss and PS were significantly different. On multivariate analysis PS was significantly different. Using receiver operating characteristic (ROC) analysis, PS had an area under the curve (AUC) of 0.712 and the best cut-off point was 18. The in-hospital mortality rate was 2.2%. On univariate analysis renal disease, albumin and PS were significantly different, and on multivariate analysis PS was significantly different. On ROC analysis PS had an AUC of 0.921 and the best cut-off point was 22. CONCLUSIONS: PS was the only independent risk factor for morbidity and in hospital mortality. Further studies may be required to develop a risk-scoring system. PMID- 21282878 TI - Characteristics of acrylic acid-modified temperature-responsive polymers and application as cement liquid. AB - To reduce the adverse effects of water on the mechanical properties and bonding durability of glass ionomer cements, experimental cements which used a temperature-responsive polymer as the cement liquid were prepared and evaluated in this study. Temperature-responsive copolymers were synthesized using radical polymerization with varying molar ratios of N-isopropylacrylamide (NIPAM) and acrylic acid (AA). It was found that copolymer synthesis with varying ratios of NIPAM and AA was able to modify the lower critical solution temperature to range between 27 and 42 degrees C. Bond strength of the cement prepared from AA/NIPAM copolymer containing 53 mol% AA was better than that prepared from polyacrylic acid (PAA) - the conventional cement liquid. However, compressive strength of the experimental cement was slightly lower than that of PAA cement. PMID- 21282879 TI - Influence of fatigue testing and cementation mode on the load-bearing capability of bovine incisors restored with crowns and FRC posts. AB - The aim of the study was to evaluate the influence of fatigue and cementation mode on the fracture behaviour of endodontically treated bovine incisors restored with fiber-reinforced-composite (FRC) posts and crowns. Forty-eight endodontically treated incisors were restored with FRC posts, composite build ups, and cast crowns. In 16 teeth, each of the posts were cemented conventionally with KetacCem (3M Espe) or adhesively with Panavia F (Kuraray) or RelyXUniCem (3M Espe). One-half of the specimens in each group were subjected to thermal cycling with 10,000 cycles at 5-55 degrees C and mechanical aging, loading the specimens in 1,200,000 cycles with 50 N. Fracture resistance was determined by loading the specimens until fracture at an angle of 45 degrees . The loading test showed that cementation mode and fatigue testing had an influence on the load bearing capability. Before fatigue testing no statistically significant differences between the different cementation modes could be detected. After fatigue testing, conventionally cemented FRC posts lead to statistically significant higher fracture loads compared to adhesively luted posts. Most specimens fractured in a favourable way, independent from the type of cementation. PMID- 21282880 TI - Synthesis of dimethacryloxy ethyl-1,1,6,6-tetrahydro-perfluorohexamethylene-1,6 dicarbamate as dental base monomers and the mechanical properties of the copolymers of the monomer and methyl methacrylate. AB - To recognize good mechanical properties and water-resistance of a dental resin, dimethacryloxyethyl-1,1,6,6-tetrahydro-perfluoro-hexamethylene-1,6-dicarbamate (FDMHD) was newly synthesized. FDMHD initially was a white powder with m.p. 98.5 99.5 degrees C. The copolymers of FDMHD and methyl methacrylate (MMA), FDMHD/MMA copolymers, were prepared to estimate the basic properties for dental resin materials. The compressive strength of FDMHD/MMA copolymers was almost the same compared with those of the copolymers of Bis-GMA or dimethacryloxyethyl hexamethylene-1,6-carbamate (DMHD) and MMA. The bending, tensile, diametral tensile, impact strength and toughness of FDMHD/MMA copolymers containing 10.4 mol% FDMHD were higher than those of Bis-GMA/MMA copolymer, and the water sorption of FDMHD/MMA copolymers was lower than those of DMHD/MMA copolymers. PMID- 21282881 TI - Comparison of the marginal fit of different coping materials and designs produced by computer aided manufacturing systems. AB - In this study, marginal adaptations of different copings fabricated with CAD/CAM or MAD/CAM were analysed. Celay and Zirkonzahn groups were fabricated by MAD/CAM, LAVA and DC-Zircon groups were fabricated by CAD/CAM. Casting metal copings were used as the control group. An implant abutment that was embedded in octagonal acrylic block was used to prepare the copings. Sixteen previously established points were marked and the measurements were performed with the stereomicroscope (at * 150). The marginal fit of the samples were evaluated by calculating the mean measurements of each 16 points. The statistical analysis was performed by Tukey multiple comparisons test at 95% confidence interval. The groups can be summarized as follows in terms of marginal gap, from the lowest to highest: LAVA (24.6 +/- 14.0 um)0.05). On ARI scores, the predominant ARI scores in Groups 1, 2, 3, and 5 were 4, 2, 5, and 4 respectively; in Group 4, they were 0 and 4. Results showed that some combinations of flowable composites and self-etching adhesives might not be suitable for orthodontic use due to their low shear bond strengths and high ARI scores -with the latter signaling the risk of damaging the enamel surface during debonding. PMID- 21282887 TI - Connexin 43 expression at an early stage in dog mandibles by beta-TCP. AB - beta-TCP was implanted into bone defects of dog mandibles, and gene expression profiles were examined using DNA microarray. An implant drill was used to make bone defects, and then beta-TCP was filled into bone defects. All specimens were taken out, total RNA was isolated, and levels were analyzed using Affymetrix GeneChip. Higher mRNA levels of connexin 43 (Cx43) and Cx45 were observed in beta TCP-implanted samples compared with controls. The enhancement of Cx43 and Cx45 by beta-TCP was confirmed by RT-PCR and real-time RT-PCR. Since Cx43 is known to express in bone-forming regions and is involved in osteogenesis through gap junctional intercellular bone-cell communication (GJIB), immunohistochemical staining was also examined and demonstrated Cx43 protein expression was increased in beta-TCP-implanted bone. Cx43 plays a role in osteogenesis through GJIB; therefore, the stimulation of Cx43 expression by beta-TCP might be a mechanism of accelerating wound healing and bone formation. PMID- 21282888 TI - Selected physical properties of a PEMA-based resin for possible use in a root canal filling material. AB - The purpose of this study was to examine the physical properties of PEMA-TA/HX based resins including 20 to 100% ethanol, for a root canal filling material. The values of the elastic modulus in the samples including ethanol were more than 250 MPa, being higher than the approximately 40 MPa of Gutte-percha (GP). The values of compressive strain in the samples increased in an ethanol concentration dependent manner. The weight of samples including ethanol decreased gradually. In the adhesiveness test, the values of PEMA-TA/HX-based resins including ethanol were significantly higher than that of GP (p<0.01). Cohesive fractures were observed in Super-Bond SEALER in the samples including ethanol except for 20%. The results suggest that the new PEMA-TA/HX-based resin cone in combination with resin-based sealer might facilitate "monoblock obturation". The new PEMA-TA/HX based resin cone developed in the present study may be effective root canal filling material for vertical root fractures. PMID- 21282889 TI - Basic evaluation on physical properties of experimental fluorinated soft lining materials. AB - The purpose of the present study was to compare the properties required for the clinical application of soft lining materials containing a fluorinated monomer versus that of conventional materials in an effort to develop a new soft lining material with long-term stable viscoelastic properties. Four soft lining materials were examined. Two experimental materials containing dodecafluoroheptyl methacrylate (SR12F) or tridecafluorooctyl methacrylate (SR13F) were prepared. Two commercial soft lining materials, one acrylic-based and one silicone rubber based, were selected as reference materials. Shore A hardness, viscoelastic properties, water sorption, solubility, and staining resistance were evaluated. The Shore A hardness and the displacements were analyzed with two-way analysis of variance (ANOVA) and Tukey's HSD test. The water sorption, the solubility and the color change were analyzed with one-way ANOVA and Tukey's HSD test. The significance level was set at 0.05. SR12F and SR13F showed greater viscous flow, low water sorption, low solubility, and good staining resistance compared to the commercial products. The results indicate that the soft lining materials containing fluorinated monomers might have a potentially long-term stable viscoelastic behavior. PMID- 21282890 TI - Flexural properties of three kinds of experimental fiber-reinforced composite posts. AB - The aim of this study was to estimate the flexural properties of three kinds of experimental fiber-reinforced composite (FRC) posts and to evaluate their potential use as posts. Experimental FRC posts were fabricated with glass, aramid, and UHMWP fibers. Commercial FRC posts were used for comparison. A three point bending test was performed at a crosshead speed of 1 mm/min. Experimental glass fiber posts showed significantly higher flexural strengths and moduli than aramid and UHMWP posts. Experimental UHMWP posts demonstrated superior toughness to the commercial posts. The glass fiber posts displayed stiff, strong and brittle features, while the UHMWP posts were flexible, weak and ductile. The flexural properties of the aramid posts fell between those of the glass and UHMWP posts. In conclusion, the glass fiber posts proved excellent in flexural strengths and moduli. However, the superior toughness of UHMWP fibers suggests the possibility of their use as posts in combination with glass fibers. PMID- 21282891 TI - Three-dimensional finite element analysis of posterior fiber-reinforced composite fixed partial denture Part 2: influence of fiber reinforcement on mesial and distal connectors. AB - The aim of this study was to evaluate the influence of connectors under two different loading conditions on displacement and stress distribution generated in isotropic hybrid composite fixed partial denture (C-FPD) and partially anisotropic fiber-reinforced hybrid composite fixed partial denture (FRC-FPD). To this end, two three-dimensional finite element (FE) models of three-unit FPD from mandibular second premolar to mandibular second molar - intended to replace the mandibular first molar - were developed. The two loading conditions employed were a vertical load of 629 N (applied to eight points on the occlusal surface) and a lateral load of 250 N (applied to three points of the pontic). The results suggested that the reinforcing fibers in FRC framework significantly improved the rigidity of the connectors against any twisting and bending moments induced by loading. Consequently, maximum principal stress and displacement generated in the connectors of FRC-FPD were significantly reduced because stresses generated by vertical and lateral loading were transferred to the reinforcing fibers. PMID- 21282892 TI - In vivo graft performance of an improved bone substitute composed of poor crystalline hydroxyapatite based biphasic calcium phosphate. AB - The ability to promote new bone formation of poor crystalline hydroxyapatite (PC HA) based biphasic calcium phosphate (BCP) bone substitutes were investigated. Various ratios of porous PC-HA/beta-TCP (70/30, 60/40, and 0/100) grafts were fabricated. SEM and XRD measurements were performed to study the morphology and crystalline structure. Cylindrical artificial bone defects (3 * 6 mm(2)) were produced in alveolar bone at premolars extraction site and then filled with sterilized bone grafts. Commercial MBCP and unfilled empty defect served as control groups. At 8 weeks postoperation, samples were harvested from each artificial defect site for histological analysis. New bone formation of all the PC-HA/beta-TCP groups was significantly greater than that of the empty control group (p<0.05), but without statistical difference from that of MBCP group. The degree of uniformity of new bone formation within defect region for PC-HA/beta TCP (60/40) was higher than that for MBCP. The PC-HA/beta-TCP grafts showed enhanced bone regenerations with a more even dispersion of new bone formation than the other materials without causing inflammation, suggesting that these materials may be an alternative choice for bone void fillers in dental applications. PMID- 21282893 TI - Fabrication of low-crystalline carbonate apatite foam bone replacement based on phase transformation of calcite foam. AB - Carbonate apatite (CO(3)Ap) foam may be an ideal bone substitute as it is sidelined to cancellous bone with respect to its chemical composition and structure. However, CO(3)Ap foam fabricated using alpha-tricalcium phosphate foam showed limited mechanical strength. In the present study, feasibility of the fabrication of calcite which could be a precursor of CO(3)Ap was studied. Calcite foam was successfully fabricated by the so-called "ceramic foam" method using calcium hydroxide coated polyurethane foam under CO(2)+O(2) atmosphere. Then the calcite foam was immersed in Na(2)HPO(4) aqueous solution for phase transformation based on dissolution-precipitation reaction. When CaO-free calcite foam was immersed in Na(2)HPO(4) solution, low-crystalline CO(3)Ap foam with 93 96% porosity and fully interconnected porous structure was fabricated. The compressive strength of the foam was 25.6 +/- 6 kPa. In light of these results, we concluded that the properties of the precursor foam were key factors for the fabrication of CO(3)Ap foams. PMID- 21282894 TI - Effect of dentin location and long-term water storage on bonding effectiveness of dentin adhesives. AB - Dentin is a variable substrate with properties that change considerable in a single surface. The purpose of this study was to evaluate the bonding effectiveness to these different dentin locations and evaluate these differences over time. After bonding procedures with five different adhesives, small micro tensile bond strength (uTBS) beams were prepared and dichotomously divided in 'center' and 'periphery' dentin specimens. After 1 week, 3, 6 and 12 months of water storage the uTBS of specimens of each group was determined, enabling a paired study design. The bond strengths of both etch&rinse adhesives were insensitive to regional variability. For the two-step self-etch adhesives, a marked increase in bond strengths was observed with increasing amount of intertubular dentin. Regional variability did not affect the long-term bonding effectiveness for any of the adhesives tested. In conclusion, only for the mild self-etch adhesives, uTBS to 'periphery' dentin was higher than for the 'center' specimens. PMID- 21282895 TI - Development of a multi-layered virtual tooth model for the haptic dental training system. AB - A virtual reality (VR) haptic dental training system could be a promising tool for future dental education. One major challenge is to develop a virtual tooth model which similarly reflected a real tooth having multiple layers with different mechanical hardness in each layer. The multi-layered virtual tooth model was successfully constructed in our virtual system. The constructed model allows us to feel tooth cutting which is similar to that with a real tooth. Through a cutting experiment by using the real tooth, a spring coefficient and a damping coefficient of a dental hard tissue were determined 0.8 N/mm and 1.79 Nsec/mm respectively. The feedback force smoothly altered when crossing the border of regions having different mechanical hardnesses. The constructed model introduced in this study could be a promising tool for acquiring dental hand skills in a virtual learning system. PMID- 21282896 TI - Effect of atorvastatin and etidronate combination therapy on regression of aortic atherosclerotic plaques evaluated by magnetic resonance imaging. AB - AIM: Although statins have been well documented to induce the regression of thoracic aortic plaques, a similar effect of statins on abdominal aortic plaques has not been observed.We aimed to explore whether a statin in combination with a bisphosphonate was effective in the regression of abdominal aortic plaques, which are more likely to be calcified. METHODS: Eighty-seven patients with hypercholesterolemia were assigned to the atorvastatin (ATR)+etidronate (ETD) group (n = 45) or ATR group (n = 42). A total of 98 thoracic and 107 abdominal aortic plaques were detected in the ATR+ETD group, and 86 thoracic and 102 abdominal plaques in the ATR group at baseline, as measured by magnetic resonance imaging (MRI). The primary endpoint was the change of maximal vessel wall thickness (Max-VWT) in atherosclerotic lesions after 1 year, as assessed by MRI. RESULTS: ATR+ETD and ATR groups reduced the low density lipoprotein cholesterol level (-42% and -43%, p < 0.001 vs. baseline for both groups), and Max-VWT in thoracic lesions (-15% and -14%, p < 0.001 vs. baseline for both groups). ATR+ETD group reduced Max-VWT in abdominal lesions (-14%, p < 0.001 vs. baseline), whereas ATR group did not (-1%, p =0.958 vs. baseline). CONCLUSION: The results suggest that ATR+ETD treatment for 12 months significantly reduces both thoracic and abdominal aortic plaques, while ATR treatment reduces only thoracic aortic plaques. PMID- 21282897 TI - Hydrogenophaga temperata sp. nov., a betaproteobacterium isolated from compost in Korea. AB - A Gram-negative, rod-shaped, non-spore-forming and motile bacterial strain TR7 01(T) was isolated from a compost soil in South Korea and subjected to a polyphasic taxonomic study. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain TR7-01(T) belonged to the genus Hydrogenophaga within the class Betaproteobacteria. Strain TR7-01(T) exhibited 16S rRNA gene sequence similarity values of 95.0-98.3% to members of the genus Hydrogenophaga: Hydrogenophaga bisanensis DSM12412(T) (98.3%), Hydrogenophaga flava DSM 619(T) (97.1%), Hydrogenophaga pseudoflava ATCC 33668(T) (96.8%), Hydrogenophaga intermedia S1(T) (96.4%), Hydrogenophaga atypica BSB 41.8(T) (95.8%), Hydrogenophaga defluvii BSB 9.5(T) (95.7%), Hydrogenophaga palleronii CCUG 20334(T) (95.6%), Hydrogenophaga caeni EMB71(T) (95.4%) and Hydrogenophaga taeniospiralis ATCC 49743(T) (95.0%). Chemotaxonomic data revealed that strain TR7-01(T) possesses ubiquinone Q-8, the G+C content was 69.9 mol%, and the predominant fatty acids were 16 : 1 omega7c/15 : 0 iso 2OH, 18 : 1 omega7c/omega9t/omega12t and C(16:0), all of which corroborated our assignment of the strain to the genus Hydrogenophaga. The results of DNA-DNA hybridization and physiological and biochemical tests clearly demonstrated that strain TR7-01(T) represents a distinct species. Based on these data, TR7-01(T) (= KCTC 12203(T) = DSM 18117(T)) should be classified as a novel Hydrogenophaga species, for which the name Hydrogenophaga temperata sp. nov. has been proposed. PMID- 21282898 TI - Mobilicoccus pelagius gen. nov., sp. nov. and Piscicoccus intestinalis gen. nov., sp. nov., two new members of the family Dermatophilaceae, and reclassification of Dermatophilus chelonae (Masters et al. 1995) as Austwickia chelonae gen. nov., comb. nov. AB - Two Gram-positive bacteria, designated strains Aji5-31(T) and Ngc37-23(T), were isolated from the intestinal tracts of fishes. 16S rRNA gene sequence analysis indicated that both strains were related to the members of the family Dermatophilaceae, with 95.6-96.9% 16S rRNA gene sequence similarities. The family Dermatophilaceae contains 2 genera and 3 species: Dermatophilus congolensis, Dermatophilus chelonae and Kineosphaera limosa. However, it has been suggested that the taxonomic position of D. chelonae should be reinvestigated using a polyphasic approach, because the chemotaxonomic characteristics are not known (Stackebrandt, 2006; Stackebrandt and Schumann, 2000). Our present study revealed that strains Aji5-31(T), Ngc37-23(T) and D. chelonae NBRC 105200(T) should be separated from the other members of the family Dermatophilaceae on the basis of the following characteristics: the predominant menaquinone of strain Aji5-31(T) is MK-8(H(2)), strain Ngc37-23(T) possesses iso- branched fatty acids as major components, and the menaquinone composition of D. chelonae is MK-8(H(4)), MK-8 and MK-8(H(2)) (5 : 3 : 2, respectively). On the basis of these distinctive phenotypic characteristics and phylogenetic analysis results, it is proposed that strains Aji5-31(T) and Ngc37-23(T) be classified as two novel genera and species of the family Dermatophilaceae. The names are Mobilicoccus pelagius gen. nov., sp. nov. and Piscicoccus intestinalis gen. nov., sp. nov., and the type strains are Aji5-31(T) (=NBRC 104925(T) =DSM 22762(T)) and Ngc37-23(T) (=NBRC 104926(T) =DSM 22761(T)), respectively. In addition, D. chelonae should be reassigned to a new genus of the family Dermatophilaceae with the name Austwickia chelonae gen. nov., comb. nov. PMID- 21282899 TI - Expression specificity of CBP1 is regulated by transcriptional repression during vegetative growth of Magnaporthe oryzae. AB - The rice blast fungus Magnaporthe oryzae produces appressoria during the infection of a host. In M. oryzae, the appressorium formation-related gene CBP1 (Chitin Binding Protein 1) is specifically expressed during the early stage of appressorium differentiation. The transcription factor CON7 activates CBP1 expression. However, many aspects of the regulation of CBP1 expression are still unknown. In this report, the CBP1 5' upstream region was analyzed using an egfp reporter. Deletion of the CBP1 5 ' upstream region caused derepression of reporter gene activity during vegetative growth. This result suggests that CBP1 expression is repressed during vegetative growth. The key 5 ' upstream sequences for CBP1 repression were examined. Furthermore, cis- and trans-acting elements of the negative regulatory region were investigated. Here, we discuss the transcriptional regulatory mechanism of CBP1. PMID- 21282900 TI - A new Barnettozyma species forming hat-shaped ascospores isolated from soil in Japan. AB - In the course of a study on yeast diversity in Japan, we isolated 331 yeast strains from natural substrates in Rishiri Island, which belongs to the subarctic zone. Among the isolates from soil, two strains produced hat-shaped ascorspores and showed that reproduction occurred by conjugation of a larger cell and a smaller one. We surveyed strains preserved in our culture collection, NBRC, and found one Barnettozyma strain; thus we examined these three strains. A phylogenetic tree based on the D1/D2 domain of 26S rDNA (D1/D2) shows that these strains are included in the Barnettozyma clade, but clearly separated from the known Barnettozyma and Candida species within the clade. This group is distinguishable from B. vustinii by the ability to assimilate sucrose and maltose, and from B. populi by the ability to ferment glucose and to assimilate L sorbose, sucrose, maltose, alpha-methyl-D-glucoside, and salicin. We propose that the group represent a new species, B. sucrosica sp. nov. (NBRC 105021(T)=CBS 11512(T), Mycobank no. MB515733). PMID- 21282901 TI - Morphology and protein composition of the mitochondrial nucleoids in yeast cells lacking Abf2p, a high mobility group protein. AB - To elucidate the role of Abf2p, a major mitochondrial DNA-binding protein in the yeast Saccharomyces cerevisiae, we examined the morphology of the mitochondrial nucleoids (mt-nucleoids) in an ABF2-deficient mutant (Deltaabf2) in vivo and in vitro by 4',6-diamidino-2-phenylindole (DAPI) staining. The mt-nucleoids appeared as diffuse structures with irregular-size in Deltaabf2 cells that were grown to log phase in YPG medium containing glycerol, in contrast to the strings-of-beads appearance of mt-nucleoids in wild-type cells. In addition, DAPI-fluorescence intensity of the mt-nucleoids transmitted to the bud was significantly lower in Deltaabf2 cells than in wild-type cells at log phase. However, the lack of Abf2p did not affect the morphology or segregation of mitochondria. The protein composition of the mt-nucleoids isolated from Deltaabf2 cells grown to stationary phase in YPG medium was very similar to that of the mt-nucleoids isolated from wild-type cells cultured under the same conditions, except for the lack of Abf2p. These results together suggested that in log-phase cells, the lack of Abf2p influences not only the morphology of mt-nucleoids but also their transmission into the bud. On the other hand, our result suggested that in stationary-phase cells, the lack of Abf2p does not significantly alter the protein composition of the mt-nucleoids. PMID- 21282902 TI - A multipathogen selective enrichment broth for simultaneous growth of Salmonella spp., Vibrio parahaemolyticus, and Vibrio cholerae. AB - A selective enrichment broth (SVV) was formulated to allow concurrent growth of Salmonella spp., V. parahaemolyticus, and V. cholerae. Potassium tellurite and sodium citrate were added as the inhibitors, while glucose, mannitol, anhydrous sodium sulfite and sodium pyruvate were employed as the growth-promoters. When mixed in equal or varied proportions, the target pathogens in SVV had a great accumulation (10(5)-10(8) CFU/ml) and effectively inhibited the growth of competitive microflora. In the artificially contaminated samples, a high recovery of these 3 target pathogens was obtained in SVV. Finally, Salmonella spp., V. parahaemolyticus, and V. cholerae were detected from 608 suspicious food samples by SVV with real-time PCR, and no false-positive or -negative results were reported. In summary, SVV has been shown to be a suitable broth for the simultaneous detection of the 3 pathogens by multipathogen detection on a single assay platform. PMID- 21282903 TI - Psychrosphaera saromensis gen. nov., sp. nov., within the family Pseudoalteromonadaceae, isolated from Lake Saroma, Japan. AB - Three Gram-negative, motile, coccoid- and ellipsoidal-shaped, non-pigmented, chemoheterotrophic bacteria, designated strains SA4-31, SA4-46 and SA4-48(T), were isolated from Lake Saroma in Japan and subjected to a polyphasic taxonomical study. 16S rRNA gene sequence analysis revealed that the novel isolates could be affiliated to the family Pseudoalteromonadaceae of the order Alteromonadales. The strains shared approximately 99.7-100% sequence similarity with each other and showed 89.5-93.2% similarity with members of the family Pseudoalteromonadaceae with validly published names. The DNA-DNA relatedness among the strains SA 4-31, SA 4-46 and SA 4-48(T) was higher than 80%, a value that is accepted as a phylogenetic definition of one species. The DNA G+C contents of the three strains were 38.7-39.6 mol%. The major isoprenoid quinone was Q-8 and C16:0, C16:1 omega7c, C18:1 omega7c and C12:1 3OH were the major fatty acids. Based on the evidence from the polyphasic taxonomical study, it was concluded that the three strains should be classified as representing a new genus and species of the family Pseudoalteromonadaceae, for which the name Psychrosphaera saromensis gen. nov., sp. nov. (type strain SA4-48(T) =NBRC 107123(T)= KCTC 23240(T)) is proposed. PMID- 21282904 TI - Conversion of squid pen by a novel strain Lactobacillus paracasei subsp. paracasei TKU010, and its application in antimicrobial and antioxidants activity. AB - TKU010 was isolated from infant vomited milk and identified as Lactobacillus paracasei subsp. paracasei. TKU010 had desirable properties concerning its ability to withstand adverse conditions in the gastrointestinal tract. The hydrolysate of casein enhanced the growth of TKU010 most obviously (17.20-18.25 OD(660)), followed by the hydrolysate of SPP (16.00-15.06 OD(660)). Incubating with SPP, both the culture supernatant of TKU010 on the first day and the fourth day showed inhibitory activities on E. coli BCRC13086, F. oxysporum BCRC32121 and A. fumigatus BCRC30099. TKU010 culture supernatant (1% SPP) incubated for 3 days has high antioxidant activity; the DPPH scavenging ability was 75% per ml. Thus, TKU010 could be preferably used as a starter to produce fermented milk with possibly interesting organoleptic properties. Besides, we have shown that squid pen wastes can be utilized to generate a high value-added product, and have revealed its hidden potential in the production of biocontrol agents and functional foods. PMID- 21282905 TI - Differential gene expression in response to copper in Acidithiobacillus ferrooxidans strains possessing dissimilar copper resistance. AB - Locus afe_0454 from Acidithiobacillus ferrooxidans (At.ferrooxidans) is annotated as related to copper resistance in The Institute for Genomic Research database. In our study, two At.ferrooxidans strains, 26(#) and DC, with different levels of copper ion resistance were isolated from acid mine drainages at two major copper mines in China, and their copper-resistance capacity was determined. The 26(#) strain had a copper-tolerance level of 0.22 mol/L, whereas the DC strain had a lower copper-tolerance level of 0.04 mol/L. The mutant 26(#) was generated from strain 26(#), and its copper-tolerance level was 0.25 mol/L. Using real-time quantitative reverse transcription polymerase chain reaction, differential expression of the afe_0454 gene during copper ion stress of these three strains was investigated. The results showed that the expression of afe_0454 was increased under copper ion stress, indicating that the afe_0454 gene is sensitive to copper levels. Furthermore, the afe_0454 gene expression ratio varied in the different copper-resistant strains. Gene expression was highest in the highest copper-resistant strain. The deduced amino acid sequence of the afe_0454 gene was 56.87% non-polar, indicating the AFE_0454 protein was hydrophobic. Searching with the AFE_0454 protein in The Institute for Genomic Research database showed that the structure of the copper resistance protein D (CopD), which transports copper ions outside of the cell, had the highest sequence identity (46%). Bioinformatics analysis showed that the AFE_0454 protein has eight transmembrane helixes and was predicted to be localized to the plasma membrane. These results strongly suggested that the AFE_0454 protein is likely a transmembrane protein and might be directly involved in copper ion resistance. PMID- 21282906 TI - Vibrio sagamiensis sp. nov., luminous marine bacteria isolated from sea water. PMID- 21282907 TI - Aliivibrio sifiae sp. nov., luminous marine bacteria isolated from seawater. PMID- 21282908 TI - Antioxidant properties and nutritional value of wheat straw bioprocessed by Phanerochaete chrysosporium and Daedalea flavida. PMID- 21282909 TI - [Usefulness and safety of propranolol injection into vein for acquisition of coronary multidetector-row computed tomography]. AB - BACKGROUND: A low heart rate (HR), associated with a prolonged slow filling phase (SF), is necessary to obtain a high quality coronary CT at a low radiation dose with conventional 64 multidetector-row computed tomography (MDCT). The purpose of our study was to confirm the safety of injecting propranolol (2-10 mg) into the vein for lowering heart rate in patients requiring MDCT and to document the effect of the drug on HR, PQ and SF. METHOD: Of 1290 consecutive patients who were initially considered for enrollment in the coronary MDCT study, 40 patients with atrial fibrillations, 3 with atrial flutters, and 13 with artificial pacemakers were excluded. Of the remaining 1234 patients (M/F=714/520), 331 had already taken an oral beta-blocker before the CT examination, and were included in the study. In patients with no contraindications, propranolol was aggressively injected (2-10 mg) into the vein to reduce the HR. RESULT: In patients not taking an oral beta blocker, 2 mg propranolol reduced the HR by -10+/-5 bpm and 10 mg, by -20+/-7 bpm. However, in patients taking an oral beta-blocker, the decrease in HR by propranolol was minimal (2 mg, -6+/-4 bpm; 10 mg, -10+/-6 bpm). Propranolol significantly prolonged the PQ interval (from 169+/-27 to 179+/-29 ms, P<0.0001), and SF (from 125+/-69 to 264+/-79 ms, P<0.0001). Adverse effects of propranolol injection were observed in only 3 [2 mild hypotension and 1 paroxysmal atrial fibrillation (recovered to sinus rhythm by DC counter shock)] of 3212 patients. All 3 patients became stable after 1 or 2 hours of rest and could return home. CONCLUSION: Propranolol injection was a relatively safe and useful method to reduce HR and prolong SF, necessary for obtaining high quality coronary MDCT with a low radiation dose. PMID- 21282910 TI - [Comparison of radiation dose reduction of prospective ECG-gated one beat scan using 320 area detector CT coronary angiography and prospective ECG-gated helical scan with high helical pitch (FlashScan) using 64 multidetector-row CT coronary angiography]. AB - BACKGROUND: A high radiation dose associated with 64 multidetector-row computed tomography (64-MDCT) is a major concern for physicians and patients alike. A new 320 row area detector computed tomography (ADCT) can obtain a view of the entire heart with one rotation (0.35 s) without requiring the helical method. As such, ADCT is expected to reduce the radiation dose. We studied image quality and radiation dose of ADCT compared to that of 64-MDCT in patients with a low heart rate (HR<=60). METHODS: Three hundred eighty-five consecutive patients underwent 64-MDCT and 379 patients, ADCT. Patients with an arrhythmia were excluded. Prospective ECG-gated helical scan with high HP (FlashScan) in 64 was used for MDCT and prospective ECG-gated conventional one beat scan, for 320-ADCT. Image quality was visually evaluated by an image quality score. Radiation dose was estimated by DLP (mGy?cm) for 64-MDCT and DLP.e (mGy?cm) for 320-ADCT. RESULTS: Radiation dose of 320-ADCT (208+/-48 mGy?cm) was significantly (P<0.0001) lower than that of 64-MDCT (484+/-112 mGy?cm), and image quality score of 320-ADCT (3.0+/-0.2) was significantly (P=0.0011) higher than that of 64-MDCT (2.9+/-0.4). Scan time of 320-ADCT (1.4+/-0.1 s) was also significantly (P<0.0001) shorter than that of 64-MDCT (6.8+/-0.6 s). CONCLUSIONS: 320-ADCT can achieve not only a reduction in radiation dose but also a superior image quality and shortening of scan time compared to 64-MDCT. PMID- 21282911 TI - [Shielding evaluation of lead-free board for diagnostic X-rays]. AB - For physical foundation data used in the shielding calculation of structural facilities such as a radiation room, there are air kerma transmissions concerning the thickness of shielding objects, and half value layers and tenth value layers concerning a greatly attenuated wide X-ray beam. Accordingly, we evaluated the above-mentioned items with a lead-free board, which is mixed sulfuric acid calcium and barium sulfate with equiponderance for the amount of sulfuric acid calcium included in the usual plasterboard. Permeability in NCRP Report 147 is expressed by 3 parameters, alpha, beta and gamma, and shielding objects x. It showed that it corresponds to the measurement point and permeability curve with parameters, alpha, beta and gamma obtained by nonlinear regression analysis. Furthermore, we calculated the half value layer and tenth value layer concerning the greatly attenuated wide X-ray beam. The evaluated lead-free board, used in this examination, is useful as the shielding material for the diagnosis X-ray and, moreover, the partition wall materials are hard enough, with a board that is even heavier than the usual plaster board. Besides, the use of lead-free materials is friendly to the general environment. PMID- 21282912 TI - [Evaluation of low-contrast resolution for liver image in digital phantom and clinical image]. AB - The high performance of multi detector-row computed tomography (MDCT), enables a flow dynamic study of the liver that can be carried out within 10 seconds per one phase. In addition, it has been possible to obtain a stable image quality by utilizing the auto exposure control system. However, no clear standard of minimal CT value differences and minimal tumor sizes for detecting liver tumors has ever been shown. In order to help in their standardization, we developed novel software to make an arbitrary digital phantom. The limit of space occupied lesion (SOL) detection in each image quality could be determined by a detection study using digital phantoms superimposed on liver CT images. As a result, the detection rate of simulated tumors was significantly different, in comparisons of different image qualities for the late arterial phase and in comparison between the late arterial and equilibrium phases for the same image quality. Our method could help standardize the scan conditions for performing a liver CT. PMID- 21282913 TI - [Evaluation of new methods for removing moire artifact of radiochromic film]. AB - An optical interference-pattern, a moire artifact, is produced during the film scanning process using a flatbed scanner. Images with moire artifacts include optical density fluctuations thereby leading to inaccuracy of measurement. In this study, we proposed two methods for removing moire artifacts from radiochromic film and compared dose response and profile as well as image resolution and size between our proposed methods versus the conventional process. The proposed methods could remove the artifacts without impairing dosimetric performance. It is expected that the proposed methods facilitate more accurate film dosimetry with reflective radiochromic films. PMID- 21282914 TI - [3 T MRI imaging methods in the study of contrast-enhanced Adamkiewicz Artery]. AB - Contrast enhanced magnetic resonance angiography (CE-MRA) is a common method for imaging the Adamkiewicz Artery (AKA). Test-bolus imaging methods have long been the mainstream, and recently, a time resolved technique (4D-MRA) is also reported. However, the current rates of detection for both are mixed, and the best method has not been established yet. For AKA, the present rate is 72% left, Th8~L1 91% that exists between, with a vessel diameter of 0.5 to 1.5 mm. Additionally, the AKA branch is known to have large individual differences, and thus, a wide range of high spatial resolution imaging. At our institution from January 2009, a 3 T system is installed, and 4D-MRA (time-resolved angiography with interleaved stochastic trajectories: TWIST) imaging became possible. TWIST is a sequence to balance the temporal resolution and spatial resolution, and is considered optimal for the imaging of AKA. In accordance with this idea, the first group of seven patients was imaged by TWIST, but in all cases, the results were not depicting AKA. In subsequent cases, the technique was changed to a 3D gradient echo sequence with a Bolus-tracking method (Care bolus), and good results were obtained. In conclusion, AKA TWIST was not thought to depict the relationship between specific parameters. When using TWIST for imaging AKA, we will need to find out why it was not visualized, by examining AKA with simulated vessel phantoms, TWIST and Care Bolus. Furthermore, we report on our visual evaluation of the Retrospective clinical pictures. PMID- 21282915 TI - [Comparison of FBP and ML-EM reconstruction used by simulation data; effect of the projection number for the SPECT image]. AB - PURPOSE: The influence of the numbers of projection of SPECT exerting on a re constructed image cannot be strictly evaluated by phantom studies. Therefore, we compared re-constructed images of the FBP method and the ML-EM method by using simulation data. METHODS: Simulation data was entered in the image processing software, and the projection data that changed the numbers of projection was made. Afterwards, reconstructed images of the FBP and the ML-EM methods were compared with respect to contrast, %COV, and the NMSE value. RESULT: When the numbers of projection of the FBP and the ML-EM method were decreased, all of the contrast, %COV, and the NMSE value were more deteriorated than that of the ideal image. Therefore, the image quality of SPECT improves with both FBP and ML-EM methods when there are many numbers of projection. Moreover, the FBP method was excellent in a cold contrast, and the ML-EM method was uniformly excellent. Therefore, an understanding of features and their inspection are effective for the selection of each image reconstruction method. PMID- 21282916 TI - [Optimization of balanced turbo field echo sequence for depicting pelvic venous plexuses]. AB - Evaluating the relation between the developing range and the extent of invasion of a malignant tumor around the pelvic venous plexus is an important index for making strategic therapeutic decisions. In this study, we tried to depict a venous plexus in the pelvis using Balanced Turbo Field Echo (B-TFE). At first, we used an original phantom (derived from one layer of lard and another of agar (0.1%Gd-DTPA, 0.9%NaCl), each 500 ml, and we changed the Start Up Echo (SUE); 0 30, SPAIR inversion delay time (delay time); 0-200 ms, shot interval (SI); 1150, 1500 ms and evaluated the degree of fat suppression in SNR, CNR (the air signal method). The fat suppression-effect was found to be high in delay time; 120 ms in SUE; 0, SI; 1150 ms and 160 ms in SUE; 0, SI; 1500 ms was different SUE>0 each delay time. As for the images of healthy volunteers (5 men and 5 women), after fixing optimum conditions, we evaluated the images visually, as assessed by two radiologists and two radiographers, comparing between SUE; 0-30 and SI; 1150 and 1500 ms. According to the visual evaluation, the fat suppression-effect was worse, more than with the delay time; 20. We judged the best image of the venous plexus in the pelvis as being at SUE; 10, SI; 1500 ms. We think that using the B TFE can help distinguish pelvic venous plexuses, by setting an optimum sequence. PMID- 21282917 TI - [JSRT Honorary Member "Mr. Akio Hayami" interviewed by Tsukasa Doi]. PMID- 21282918 TI - [Fundamental knowledge for computer-aided diagnosis: Feature analysis using R]. PMID- 21282919 TI - [Possibility of next generation technology for coronary CT angiography]. PMID- 21282920 TI - [Experience with a client-server type 3D image analysis system as a radiological technologist: Novel software and effective workflow]. PMID- 21282921 TI - [Contribution changes of the radiological process - Consideration of the medical technologist's role]. PMID- 21282922 TI - [Case research methodology: research in clinical cases]. PMID- 21282923 TI - [Software development of an image processing program for Mac]. PMID- 21282924 TI - [Information security management for health information systems]. PMID- 21282926 TI - [Absorbed dose to water reference dosimetry using various water-equivalent solid phantoms in high-energy photon and electron beams]. PMID- 21282927 TI - [Economic effect of maintenance contracts for medical equipment safety check on health care cost]. PMID- 21282928 TI - [Guideline for the anti-virus software in the image diagnosis workstations]. PMID- 21282929 TI - Biphasic tracheal relaxation induced by higenamine and nantenine from Nandina domestica Thunberg. AB - We compared the effects of the extract from fruits of Nandina domestica Thunberg (NDE) and its constituents, higenamine and nantenine, on contractile responses in isolated guinea-pig trachea. NDE (1 mg/ml) caused biphasic relaxation of the trachea precontracted with high-K(+) stimulation: the fast component was blocked by propranolol and mimicked by higenamine; and the slow was resistant to propranolol and mimicked by nantenine. Ca(2+)-induced contraction under high-K(+) stimulation was antagonized by nantenine or NDE + propranolol. These results suggest that NDE relaxes the trachea quickly through beta-adrenoceptor stimulation by higenamine and slowly through Ca(2+) antagonism by nantenine. PMID- 21282931 TI - Diazepam enhances production of diazepam-binding inhibitor (DBI), a negative saliva secretion regulator, localized in rat salivary gland. AB - Peripheral-type benzodiazepine receptor (PBR) and central-type benzodiazepine receptor (CBR) in salivary gland play a role in the inhibitory regulation of salivary secretion in rodents. Diazepam-binding inhibitor (DBI), an endogenous ligand for PBR, produces neurosteroids, which modulate CBR activity. In this study, we investigated the effect of repetitive administration of diazepam (DZP) on salivary secretion and expression of DBI mRNA and peptide. Moreover, mRNA expression of PBR and pituitary adenylate cyclase-activating polypeptide (PACAP), a transcriptional regulator for DBI promoter, was evaluated after repetitive administration of DZP. Repetitive administration, but not single administration, of 0.4 mg/kg DZP caused inhibition of salivary secretion and enhanced expression of DBI, PACAP, and PBR mRNA in rat salivary gland, with an increase in production of DBI peptide. These results suggest that repetitive administration of DZP stimulates DBI production, which may result in an increase in the suppressive effect of DZP on salivary secretion. PMID- 21282930 TI - Chronopharmacology of angiotensin II-receptor blockers in stroke-prone spontaneously hypertensive rats. AB - Protective effect of valsartan (Val), an angiotensin II (AII)-receptor blocker (ARB), against organ damage is reported to depend on the dosing time in hypertensive patients. Dosing-time-dependent effect of Val on survival of stroke prone spontaneously hypertensive rats (SHRSP) under a 12-h lighting cycle was examined. Val (4 mg/kg per day) and olmesartan medoxomil (OM) (1 mg/kg per day), another ARB with a slower dissociation from the AII receptor, were given once daily at 2, 8, 14, or 20 HALO (hours after lights on). Dosing-time-dependent differences in plasma drug concentrations and effect on blood pressure (BP) were also evaluated. Survival of SHRSP showed a dosing-time-dependent change during Val therapy, with a peak at 2 HALO and a trough at 14 HALO. OM equally prolonged survival in all groups. The BP-lowering effect persisted for more than 24 h after dosing of Val at 2 HALO and of OM at 2 and 14 HALO, but disappeared at 5.5-h after Val dosing at 14 HALO. Plasma concentrations of Val and OM were higher after dosing at 2 HALO than at 14 HALO. These results suggest that the chronopharmacological phenomenon of Val was partly due to the dosing-time dependent difference in plasma concentration and subsequent duration of the antihypertensive effect. Slower dissociation of OM from AII receptors might have blunted a potential dosing-time-dependent event. PMID- 21282932 TI - Protective effect of alpha-lipoic acid against arsenic trioxide-induced acute cardiac toxicity in rats. AB - The clinical use of arsenic trioxide (ATO) is often limited because of its adverse effects. We examined whether alpha-lipoic acid (LA) protects against the ATO-induced cardiac toxicity. In the chronic study, two of four rats suddenly died by the repeated dosing of ATO, whereas no deaths were observed in combination with LA. In the acute study, continuous ECG recording revealed that intravenous injection of ATO caused transient ST-T change, whereas pretreatment with LA abolished the ATO-induced ECG abnormality in all animals. These results suggest that LA protects against the ATO-induced acute cardiac toxicity and subsequent sudden death in rats. PMID- 21282933 TI - Functional analysis of human sodium-phosphate transporter 4 (NPT4/SLC17A3) polymorphisms. AB - We analyzed the functional properties of five nonsynonymous single nucleotide polymorphisms (SNPs) in the sodium-phosphate transporter NPT4 gene (SLC17A3) using the Xenopus oocyte expression system. NPT4 variants carrying SNP V257F, G279R, or P378L exhibited reduced transport of [(14)C]para-aminohippurate, [(3)H]bumetanide, [(3)H]estrone sulfate, and [(14)C]urate, when each variant clone was expressed in the plasma membrane of oocytes. This study suggests the possibility that the genetic variation of NPT4 contributes to inter-individual differences in disposition of anionic drugs such as diuretics as well as certain endogenous organic anions such as urate. PMID- 21282934 TI - Caspase-4 directly activates caspase-9 in endoplasmic reticulum stress-induced apoptosis in SH-SY5Y cells. AB - The present study investigated the function of caspase-4 in endoplasmic reticulum (ER) stress-induced apoptosis in human neuronal cell line SH-SY5Y. Tunicamycin, which is known to induce ER stress, activated both caspase-9 and caspase-4, and the activation of caspase-4 preceded that of caspase-9. The caspase-4 inhibitor LEVD-CHO suppressed both the apoptosis and caspase-9 activation. In addition, human recombinant active caspase-4 cleaved wild type and D330A mutant substituted Asp-330 for alanine of human recombinant procaspase-9, but did not cleave D315A mutant substituted Asp-315 for alanine. These results suggest that caspase-4 directly activates caspase-9 by the processing of procaspase-9 at Asp-315 in ER stress-induced neuronal apoptosis. PMID- 21282935 TI - Inhibitory effects of a tryptamine derivative on ultraviolet radiation-induced apoptosis in MC3T3-E1 mouse osteoblasts. AB - MS-IPA1 is a new synthetic compound that is synthesized from tryptamine. Recently, our group demonstrated that SST-VED-I-1, which has a similar chemical structure to MS-IPA1, inhibits starvation-induced apoptosis in osteoblasts. However, the effects of MS-IPA1 on apoptosis in osteoblasts have not yet been examined. Therefore, this study examined the effects of this compound on apoptosis in osteoblasts. In this study, MC3T3-E1 mouse osteoblasts were used and apoptosis was induced by ultraviolet radiation (UV). We investigated the effect of MS-IPA1 on apoptosis by analyzing caspase3/7 activity, translocation of phosphatidylserine (PS), and mRNA expression levels of Bcl-2 and Bax. In addition, it was investigated whether MS-IPA1 affects cell proliferation and cell cycle progression. We found that MS-IPA1 had no effect on cell proliferation or cell cycle progression. However, MS-IPA1 suppressed UV-induced cell death in a dose-dependent manner, which was accompanied with the inhibition of caspase activation and translocation of PS. Furthermore, after UV exposure, Bcl-2 expression was increased in the MS-IPA1-treated cells as compared to that in the vehicle-treated cells. In contrast, Bax expression was decreased in the MS-IPA1 treated cell as compared to that in the vehicle-treated cells. These results suggest that MS-IPA1 has an inhibitory effect on apoptosis in osteoblasts through a Bcl-2 family-dependent signaling pathway. PMID- 21282936 TI - Distribution of glycoproteins on feline testicular sperm, epididymal sperm and ejaculated sperm. AB - Glycoproteins (GPs) are known to be involved in the phenomenon of sperm maturation and capacitation. In the present study, we investigated the attachment of GPs on sperm cell membrane during the process of feline sperm maturation from testicular sperm to ejaculated sperm by using 8 FITC-labeled lectins. The results showed that 3 types of GPs were presented on testicular sperm and 7 on caput epididymal sperm. Corpus and cauda epididymal sperm and ejaculated sperm had GPs detected by 8 FITC-labeled lectins used in the present study. This study demonstrates the part of the characteristic of GPs that are present on the feline sperm cell membrane during the process of sperm maturation. PMID- 21282937 TI - Impaired long-term potentiation in the prefrontal cortex of Huntington's disease mouse models: rescue by D1 dopamine receptor activation. AB - BACKGROUND: The introduction of gene testing for Huntington's disease (HD) has enabled the neuropsychiatric and cognitive profiling of human gene carriers prior to the onset of overt motor and cognitive symptoms. Such studies reveal an early decline in working memory and executive function, altered EEG and a loss of striatal dopamine receptors. Working memory is processed in the prefrontal cortex and modulated by extrinsic dopaminergic inputs. OBJECTIVE: We sought to study excitatory synaptic function and plasticity in the medial prefrontal cortex of mouse models of HD. METHODS: We have used 2 mouse models of HD, carrying 89 and 116 CAG repeats (corresponding to a preclinical and symptomatic state, respectively) and performed electrophysiological field recording in coronal slices of the medial prefrontal cortex. RESULTS: We report that short-term synaptic plasticity and long-term potentiation (LTP) are impaired and that the severity of impairment is correlated with the size of the CAG repeat. Remarkably, the deficits in LTP and short-term plasticity are reversed in the presence of a D(1) dopamine receptor agonist (SKF38393). CONCLUSION: In a previous study, we demonstrated that a deficit in long-term depression (LTD) in the perirhinal cortex could also be reversed by a dopamine agonist. These and our current data indicate that inadequate dopaminergic modulation of cortical synaptic function is an early event in HD and may provide a route for the alleviation of cognitive dysfunction. PMID- 21282938 TI - Canine fucosidosis: a neuroprogressive disorder. AB - The lysosomal storage disease, canine fucosidosis, is caused by the absence of the lysosomal enzyme canine alpha-L-fucosidase with storage of undegraded fucose rich material in different organs. Canine fucosidosis is a severe, progressive, fatal neurological disease which results in death or euthanasia and is the only available animal model for this human disease. We analysed the progressive neuropathology from birth to severe clinical disease and related this to the clinical signs. At birth no vacuolation was observed in fucosidosis brain; however, a complex storage presence with vacuolation was well established by 4 months of age, before the clinical signs of motor dysfunction which occurred at 10-12 months of age. Purkinje cell loss, neuronal loss, gliosis, perivascular storage and demyelination accompanied disease progression. Increased vacuolation (15.3-fold increase compared to controls) coincided with advanced motor and mental deterioration in late-stage disease. Significant loss of myelin commenced early, with greatest impact in the cerebellum, and was severe in late disease (1.6- to 1.9-fold decrease) compared to controls (p < 0.05) contributing to clinical signs of motor and mental dysfunction. This detailed description and quantification of the CNS pathology in canine fucosidosis will inform monitoring of the onset, progression and response of this disease to therapy. PMID- 21282939 TI - Asthma masquerading as chronic obstructive pulmonary disease: a study of smokers fulfilling the GOLD definition of chronic obstructive pulmonary disease. AB - BACKGROUND: Irreversible airways obstruction in smokers is usually attributed to chronic obstructive pulmonary disease (COPD). We speculate that some of these are cases of asthma indistinguishable from COPD. OBJECTIVES: To determine the prevalence of asthma in a 'COPD' population and how to differentiate the two conditions. METHODS: This was a prospective observational study of smokers fulfilling the Global Initiative for Chronic Obstructive Lung Disease definition of COPD [mean post-salbutamol forced expiratory volume in 1 s (FEV1) 66.9% predicted]. They were classified into 4 groups, as follows: (1) inhaled corticosteroid (ICS)-responsive asthma, defined by normalization of spirometry upon ICS treatment; (2) irreversible asthma, defined as airway obstruction for 1 year and bronchial biopsy indicating asthma; (3) COPD, in the presence of bilateral panlobular emphysema with bullae on high-resolution computed tomography, hypercapneic respiratory failure or bronchial biopsy indicating COPD, and (4) unclassified airflow limitation (AFL). RESULTS: Eighty patients fulfilled the definition of COPD. The initial diagnosis was COPD in 57.5% and asthma in 42.5%. The final diagnosis was ICS-responsive asthma in 48 patients (60%), irreversible asthma in 8 (10%), COPD in 16 (20%) and unclassified AFL in 8 (10%). A normal transfer coefficient for carbon monoxide (KCO) and an FEV1 fluctuation >=18% during 1 year of follow-up distinguished irreversible asthma and COPD. Seven of the 8 patients with irreversible asthma had improved FEV1 at the end of 1 year (median 320 ml compared with -29 ml in COPD). Five out of the 8 unclassified AFL cases had normal KCO and a large improvement in FEV(1) suggestive of irreversible asthma. CONCLUSIONS: COPD, even in heavy smokers, includes cases of asthma. FEV1 fluctuation during 1 year is a novel concept which may distinguish irreversible asthma and COPD. PMID- 21282940 TI - Serological profiles of urate, paraoxonase-1, ferritin and lipid in Parkinson's disease: changes linked to disease progression. AB - BACKGROUND: Oxidative stress plays a role in the pathogenesis of neuronal death. Serum levels of urate or lipid were associated with the incidence of Parkinson's disease (PD). OBJECTIVE: We compared urate, paraoxonase-1 (PON1), iron, ferritin and lipid in sera of 119 PD patients and 120 healthy controls matched by age, sex and body mass index. We aimed to elucidate whether those serological data are correlated with disease progression. RESULTS: Mean age (SD) of PD patients was 73.4 (8.7) years. Mean Yahr stage (SD) was 3.2 (0.9). Mean disease duration (SD) was 6.9 (5.1) years. Mean dose of L-DOPA (SD) was 355 (157) mg/day. As compared to controls, serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), urate and PON1 activity were significantly reduced, and serum ferritin levels were significantly increased in male and female PD patients. Serum urate levels and PON1 activities were inversely related, and serum ferritin levels were correlated with Yahr stage and PD duration in men and women. Serum levels of TC and LDL-C were inversely related to Yahr stage or PD duration in female patients. CONCLUSIONS: Our studies indicated serological profiles of urate, PON1, ferritin, TC and LDL-C in PD patients. These serological changes were linked to PD progression. Metabolism of lipid, oxidant- and antioxidant-related substances may contribute to the pathogenesis and the progression of PD. PMID- 21282941 TI - Insights into the meiotic behavior and evolution of multiple sex chromosome systems in spiders. AB - A characteristic feature of spider karyotypes is the predominance of unusual multiple X chromosomes. To elucidate the evolution of spider sex chromosomes, their meiotic behavior was analyzed in 2 major clades of opisthothele spiders, namely, the entelegyne araneomorphs and the mygalomorphs. Our data support the predominance of X(1)X(2)0 systems in entelegynes, while rare X(1)X(2)X(3)X(4)0 systems were revealed in the tuberculote mygalomorphs. The spider species studied exhibited a considerable diversity of achiasmate sex chromosome pairing in male meiosis. The end-to-end pairing of sex chromosomes found in mygalomorphs was gradually replaced by the parallel attachment of sex chromosomes in entelegynes. The observed association of male X univalents with a centrosome at the first meiotic division may ensure the univalents' segregation. Spider meiotic sex chromosomes also showed other unique traits, namely, association with a chromosome pair in males and inactivation in females. Analysis of these traits supports the hypothesis that the multiple X chromosomes of spiders originated by duplications. In contrast to the homogametic sex of other animals, the homologous sex chromosomes of spider females were already paired at premeiotic interphase and were inactivated until prophase I. Furthermore, the sex chromosome pairs exhibited an end-to-end association during these stages. We suggest that the specific behavior of the female sex chromosomes may have evolved to avoid the negative effects of duplicated X chromosomes on female meiosis. The chromosome ends that ensure the association of sex chromosome pairs during meiosis may contain information for discriminating between homologous and homeologous X chromosomes and thus act to promote homologous pairing. The meiotic behavior of 4 X chromosome pairs in mygalomorph females, namely, the formation of 2 associations, each composed of 2 pairs with similar structure, suggests that the mygalomorph X(1)X(2)X(3)X(4)0 system originated by the duplication of the X(1)X(2)0 system via nondisjunctions or polyploidization. PMID- 21282942 TI - Aneuploidy in human spermatozoa. AB - We reviewed the frequency and distribution of disomy in spermatozoa obtained by multicolor-FISH analysis on decondensed sperm nuclei in (a) healthy men, (b) fathers of aneuploid offspring of paternal origin and (c) individuals with Klinefelter syndrome and XYY males. In series of healthy men, disomy per autosome is approximately 0.1% but may range from 0.03 (chromosome 8) to 0.47 (chromosome 22). The great majority of authors find that chromosome 21 (0.18%) and the sex chromosomes (0.27%) have significantly elevated frequencies of disomy although these findings are not universal. The total disomy in FISH studies is 2.26% and the estimated aneuploidy (2* disomy) is 4.5%, more than double that seen in sperm karyotypes (1.8%). Increased disomy levels of low orders of magnitude have been reported in spermatozoa of some normal men (stable variants) and in men who have fathered children with Down, Turner and Klinefelter syndromes. These findings suggest that men with a moderately elevated aneuploidy rate may be at a higher risk of fathering paternally derived aneuploid pregnancies. Among lifestyle factors, smoking, alcohol and caffeine have been studied extensively but the compounding effects of the 3 are difficult to separate because they are common lifestyle behaviors. Increases in sex chromosome abnormalities, some autosomal disomies, and in the number of diploid spermatozoa are general features in 47,XXY and 47,XYY males. Aneuploidy of the sex chromosomes is more frequent than aneuploidy of any of the autosomes not only in normal control individuals, but also in patients with sex chromosome abnormalities and fathers of paternally derived Klinefelter, Turner and Down syndromes. PMID- 21282943 TI - Extended cytogenetic maps of sheep chromosome 1 and their cattle and river buffalo homoeologues: comparison with the OAR1 RH map and human chromosomes 2, 3, 21 and 1q. AB - Cytogenetic maps are useful tools for several applications, such as the physical anchoring of linkage and RH maps or genome sequence contigs to specific chromosome regions or the analysis of chromosome rearrangements. Recently, a detailed RH map was reported in OAR1. In the present study, we selected 38 markers equally distributed in this RH map for identification of ovine genomic DNA clones within the ovine BAC library CHORI-243 using the virtual sheep genome browser and performed FISH mapping for both comparison of OAR1 and homoeologous chromosomes BBU1q-BBU6 and BTA1-BTA3 and considerably extending the cytogenetic maps of the involved species-specific chromosomes. Comparison of the resulting maps with human-identified homology with HSA2q, HSA3, HSA21 and HSA1q reveals complex chromosome rearrangements differentiating human and bovid chromosomes. In addition, we identified 2 new small human segments from HSA2q and HSA3q conserved in the telomeric regions of OAR1p and homoeologous chromosome regions of BTA3 and BBU6, and OAR1q, respectively. Evaluation of the present OAR1 cytogenetic map and the OAR1 RH map supports previous RH assignments with 2 main exceptions. The 2 loci BMS4011 and CL638002 occupy inverted positions in these 2 maps. PMID- 21282944 TI - An elevated estimated pulmonary arterial systolic pressure, whenever measured, is associated with excess mortality in adults with sickle cell disease. PMID- 21282945 TI - Selection of housekeeping genes for gene expression studies in a rat model of irinotecan-induced mucositis. AB - BACKGROUND/AIMS: Mucositis is the term used to describe damage caused by chemotherapy to mucous membranes of the alimentary tract. RT-PCR has recently been utilised to determine the molecular events that occur in mucositis. As this method relies on the use of a validated endogenous control, this study aims to validate commonly used housekeeping genes in an irinotecan-induced mucositis model. METHODS: Rats were administered irinotecan and sacrificed at different time points, in particular 1, 24, 72 and 144 h following treatment. Histopathological damage was assessed by haematoxylin and eosin staining. RT-PCR was used to evaluate the expression of 11 housekeeping genes. Expression stability was determined by the Normfinder program. Matrix metalloproteinase 2 was used as a target gene to validate the appropriateness of the top-ranking housekeeping gene. RESULTS: For normalisation to multiple housekeeping genes, the most stable combination across all time points in the jejunum was Ywhaz/UBC and in the colon UBC/beta-actin. SDHA and GAPDH were the most variable genes in the jejunum and colon where they were 4.4 and 3.2 fold upregulated following irinotecan, respectively. CONCLUSIONS: For normalisation of irinotecan-induced mucositis gene expression studies, a combination of Ywhaz/UBC and UBC/beta-actin should be used in the jejunum and colon, respectively. UBC is the most favourable if restricted to a single housekeeping gene across all time points. PMID- 21282946 TI - Higher incidence of Enterococcus faecium and ampicillin resistance among the gut commensal enterococci isolated following oral antibiotic therapy. PMID- 21282947 TI - Mycophenolic acid inhibits replication of Japanese encephalitis virus. AB - BACKGROUND: Japanese encephalitis is a major public health problem in several parts of Asia, particularly India, Nepal, Sri Lanka and Myanmar (Burma). Despite its public health implications, there are no effective antiviral drugs available. METHODS: The present study evaluated the effect of mycophenolic acid on Japanese encephalitis virus (JEV) using an in vitro cytopathic effect inhibition assay, plaque reduction assay and virus yield reduction assay, and its therapeutic potential was also assessed in vivo in a mouse model. RESULTS: Analysis of the results obtained in the in vitro and in vivo experiments suggests that mycophenolic acid has significant antiviral activity against JEV, with an IC(50) of 3.1 MUg/ml, a therapeutic index of 16 and a 75% protection against lethal challenge of JEV. CONCLUSION: The study concludes that this compound significantly inhibited the replication of JEV in vitro and protected mice in vivo. PMID- 21282948 TI - Reversal of multidrug resistance by guggulsterone in drug-resistant MCF-7 cell lines. AB - BACKGROUND: Multidrug resistance (MDR) presents a serious problem in cancer chemotherapy. Our previous studies have shown that the MDR of K562/DOX cells could be reversed by guggulsterone through inhibiting the function and expression of P-glycoprotein. The purpose of this study was to investigate the reversal effect of guggulsterone on MDR in drug-resistant MCF-7 cells and the parental MCF 7 cells. METHODS: MTT cytotoxicity assays, flow cytometry, and Western blot analysis were performed to investigate the antiproliferative effects of the combination of anticancer drugs with guggulsterone, to study the reversal of drug resistance and to examine the inhibitory effects on MRP1 expression. RESULTS: The results showed that co-administration of guggulsterone (10 MUM) resulted in a significant increase in chemosensitivity of MCF-7/DOX cells to doxorubicin, compared with doxorubicin treatment alone (p < 0.01). The fold reversal of 10 MUM guggulsterone (11.48) was comparable to that of 10 MUM verapamil (13.23). Rhodamine123 and doxorubicin accumulation in MCF-7/DOX cells was significantly enhanced after the incubation with guggulsterone (10 MUM), compared with untreated MCF-7/DOX cells (p < 0.01). When doxorubicin (10 MUM) was combined with guggulsterone (10 MUM), the mean apoptotic population of MCF-7/DOX cells was 24.91%. It was increased by 6.15 times, compared with doxorubicin (10 MUM) treatment alone. However, guggulsterone had little inhibitory effect on the expression of MRP1 proteins. CONCLUSION: Guggulsterone is a novel and potent MDR reversal agent with the potential to be an adjunctive agent for tumor chemotherapy. PMID- 21282949 TI - Too cold in winter or too hot in summer: it is never a good season for heart failure patients. PMID- 21282950 TI - The Montreal Cognitive Assessment and the mini-mental state examination as screening instruments for cognitive impairment: item analyses and threshold scores. AB - AIMS: To perform an item analysis of the Montreal Cognitive Assessment (MoCA) versus the Mini-Mental State Examination (MMSE) in the prediction of cognitive impairment, and to examine the characteristics of different MoCA threshold scores. METHODS: 135 subjects enrolled in a longitudinal clinicopathologic study were administered the MoCA by a single physician and the MMSE by a trained research assistant. Subjects were classified as cognitively impaired or cognitively normal based on independent neuropsychological testing. RESULTS: 89 subjects were found to be cognitively normal, and 46 cognitively impaired (20 with dementia, 26 with mild cognitive impairment). The MoCA was superior in both sensitivity and specificity to the MMSE, although not all MoCA tasks were of equal predictive value. A MoCA threshold score of 26 had a sensitivity of 98% and a specificity of 52% in this population. In a population with a 20% prevalence of cognitive impairment, a threshold of 24 was optimal (negative predictive value 96%, positive predictive value 47%). CONCLUSION: This analysis suggests the potential for creating an abbreviated MoCA. For screening in primary care, the MoCA threshold of 26 appears optimal. For testing in a memory disorders clinic, a lower threshold has better predictive value. PMID- 21282951 TI - Gastric atrophy and intestinal metaplasia before and after Helicobacter pylori eradication: a meta-analysis. AB - OBJECTIVE: Whether gastric atrophy (GA) and intestinal metaplasia (IM) are reversible after the eradication of Helicobacter pylori remains controversial. The purpose of this meta-analysis was to systematically review histological alterations in GA and IM by comparing histological scores before and after H. pylori eradication. METHODS: English-language articles in the medical literature containing information about the association between infection with H. pylori and gastric premalignant lesions (i.e. GA and IM) were identified by searching the Medline, PubMed, and EMBASE databases with suitable key words up to December 2009. Review Manager 4.2.8 was used for the meta-analysis. RESULTS: Twelve studies containing a total of 2,658 patients were included in the first meta analysis. Before treatment, 2,648 patients had antrum GA, 2,401 patients had corpus GA, 2,582 patients had antrum IM, and 2,460 patients had corpus IM. Comparing the histological alterations before and after H. pylori eradication, the pooled weighted mean difference (WMD) with 95% CI for antral GA was 0.12 (0.00-0.23), p = 0.06. For corpus GA, the pooled WMD was 0.32 (0.09-0.54), p = 0.006. For antral IM, the pooled WMD was 0.02 (-0.12-0.16), p = 0.76, and for corpus IM, the pooled WMD was -0.02 (-0.05-0.02), p = 0.42. CONCLUSION: Our study shows that eradication of H. pylori results in significant improvement in GA in the corpus but not in the antrum; it also does not improve gastric mucous IM. Consequently, all patients with GA in the corpus should be tested for H. pylori infection, and eradication therapy should be prescribed for H. pylori-positive patients in those with GA in corpus. PMID- 21282952 TI - Sorafenib therapy in patients with advanced hepatocellular carcinoma in advanced liver cirrhosis. AB - BACKGROUND AND AIM: Sorafenib has become the treatment standard for patients with advanced hepatocellular carcinoma (HCC). It is not clear whether patients with advanced liver function impairment (Child B) and patients undergoing additional locoregional therapy may tolerate treatment with sorafenib and benefit. We aimed to evaluate the tolerability and efficiency of sorafenib in patients with advanced HCC and different stages of liver cirrhosis, and in combination with locoregional therapy. METHODS: In 50 patients with advanced HCC treated with sorafenib tolerability and efficiency of the therapy with respect to stage of liver cirrhosis, existence of extrahepatic tumor spread, and additional locoregional therapy were evaluated. RESULTS: Fifty patients with advanced HCC were treated with sorafenib, and 13 received additional locoregional therapy. Tolerability of the systemic treatment was moderate in all patients, with no significant differences between the subgroups, while the median survival was better in patients with Child A than Child B cirrhosis. CONCLUSION: Tolerability and toxicity of a systemic treatment with sorafenib are moderate in patients with liver cirrhosis in Child A or B. Prospective randomized studies are required to evaluate the efficacy and tolerability of combined systemic and locoregional treatment approaches in patients with advanced HCC. PMID- 21282953 TI - Follow-up of children with celiac disease - lost in translation? AB - BACKGROUND: Celiac disease (CD) is a prevalent condition with a broad spectrum of presentations requiring a lifelong gluten-free diet (GFD). Our aims were to examine the presentation and adherence to a GFD as well as the adequacy of follow up of children diagnosed with CD at a tertiary referral center. METHODS: A retrospective electronic chart review of pediatric patients suspected of CD (n = 581) who were seen at our institute between January 1999 and December 2008 was performed. RESULTS: 387 children were diagnosed with CD (F/M ratio of 1.54, median age: 6.25 years). Presenting symptoms were iron deficiency anemia (n = 82, 34%), short stature (n = 59, 24.5%) and abdominal pain (n = 59, 24.5%). In 63 patients (16.3%) an associated autoimmune disease was recorded. Only 42.7% of the patients (165/387) had regular out-patient gastroenterologist visits; 22% (86/387) were followed by their primary care physician. Over 35% (136/387) were completely lost to follow-up. Negative serology on follow-up was present in 91% of the CD patients(150/165) followed at our center in comparison to 70% (60/86) in those followed up by their primary physician (p = 0.0002). CONCLUSIONS: At least in our referral center, follow-up of children diagnosed with CD is far from satisfactory. Initiatives aimed at improving adherence to regular follow-up are needed as this intervention is associated with a significant increase in patient compliance with a long-term GFD. PMID- 21282954 TI - Increase in body size is associated with an increased incidence of advanced adenomatous colon polyps in male veteran patients. AB - BACKGROUND/AIMS: Our aim was to determine how weight change influences the development of advanced adenomas. METHODS: We performed a retrospective study of patients with adenomatous polyps (APs) on an index colonoscopy, and who also had a follow-up colonoscopy 3-5 years later. APs were evaluated for advanced features (i.e. size >=1 cm in diameter and/or villous component and/or high-grade dysplasia). Patients were divided into 2 groups: those with no change or a reduction in their body mass index (BMI) during the interval between colonoscopies and those with an increase in BMI during the interval between colonoscopies. RESULTS: 925 patients with a history of APs were identified. Univariate analysis showed that patients with an increase in BMI had more advanced APs (28 vs. 23%, p = 0.04), and a larger mean AP size (8.0 vs. 6.8 mm, p = 0.03) than those with a no change or decreased BMI. Multiple logistic regression analysis revealed that a decrease in BMI between colonoscopies was associated with a significantly reduced risk of developing advanced APs (OR: 0.4, 95% CI: 0.37-0.5, p < 0.05). CONCLUSIONS: An increase in weight in male veterans appears to be strongly associated with the development of clinically advanced AP lesions, even after adjustment for other known polyp risk factors. PMID- 21282955 TI - Effect of oral prednisolone on esophageal stricture after complete circular endoscopic submucosal dissection for superficial esophageal squamous cell carcinoma: a case report. AB - A 74-year-old man with nausea underwent upper gastrointestinal endoscopy, and a 0 IIb type tumor was found in the middle thoracic esophagus. Histological examination with endoscopic biopsies revealed squamous cell carcinoma (SCC), and chromoendoscopy with iodine staining revealed that the superficial SCC involved nearly the entire circumference of the esophageal lumen. There were neither nodal nor distant metastases. Complete circular endoscopic submucosal dissection (ESD) was successfully achieved with tumor-free margins in an en bloc fashion. The histopathological examination confirmed a diagnosis of intramucosal invasive carcinoma limited to the lamina propria mucosae without angiolymphatic invasion. Oral prednisolone was started with 0.5 mg/kg daily on the 3rd post-ESD day, tapered gradually, and then discontinued 8 weeks later without adverse effects. There were no complaints of dysphagia following ESD. On follow-up endoscopy with iodine staining, which was scheduled at 1, 3 and 6 months after ESD, there was no postprocedural esophageal stricture, and neither recurrent nor metachronous lesions were found. Thus, the patient required no sessions of endoscopic balloon dilatation. At the last outpatient clinic visit 7 months after ESD, he remained well without dysphagia. Oral prednisolone administration may offer an effective therapeutic strategy to prevent the post-ESD esophageal stricture after complete circular ESD. PMID- 21282956 TI - Covered stent placement for duodenal obstruction in pancreatic cancer. PMID- 21282957 TI - European addiction research: a new editor, a new advisory board and intriguing perspectives. PMID- 21282958 TI - Perceptions of addictions as societal problems in Canada, sweden, Finland and st. Petersburg, Russia. AB - AIMS: This study reports on the relative gravity people attribute to various addictive behaviors with respect to other societal concerns in four northern populations with different history, social policy and treatment alternatives for addicted individuals. METHODS: Random population surveys were conducted in Canada, Sweden, Finland and St. Petersburg, Russia. In Finland and Sweden, the survey was conducted by mail, in Canada and St. Petersburg by phone. As a part of this survey, the respondents were asked to assess the gravity of various societal problems, some of which involved various addictive behaviors. The data were analyzed by descriptive statistical methods, factor analysis, contextual analysis and multiple regression analysis. RESULTS: Hard drugs, criminality and environmental issues belonged to the topmost problems in all data samples. Overall, Finns and Canadians appeared the least worried about various societal problems, Swedes seemed the most worried and St. Petersburgian views were the most polarized. Two factors were extracted from the combined data. Factor 1 covered criminal behavior and various addictions; it was named Threats to Safety factor. Factor 2 comprised social equality issues. The country context explained 12.5% of the variance of the safety factor and 7.9% of the equality factor. CONCLUSIONS: Despite some cultural variation in the gravity assessments, the central core of the social representation of addictive behaviors tends still to be linked with 'badness' since they were mainly grouped with various forms of criminal behavior in all these countries. PMID- 21282959 TI - Showered cortical infarctions and brain atrophy in Churg-Strauss syndrome. PMID- 21282960 TI - Sensitization with 7S globulins from peanut, hazelnut, soy or pea induces IgE with different biological activities which are modified by soy tolerance. AB - BACKGROUND: It is not known why some foods sensitizing via the gastrointestinal tract are prevalent allergenic foods and others are not. Eating habits, processing, and the food matrix have been suggested to influence the allergenicity of a given food. Factors related to protein structure, such as stability to digestion, have also been suggested. 7S globulins from peanut, hazelnut, soy, and pea were studied to determine whether related proteins would induce a similar sensitization when removed from their 'normal' matrix. METHODS: Brown Norway rats (soy tolerant or nontolerant) were immunized i.p. 3 times with 100 MUg purified peanut, hazelnut, soy, or pea 7S without adjuvant. Sera were analyzed for specific antibodies by different ELISAs (IgG1, IgG2a, and IgE), inhibition ELISA, and rat basophilic leukemia cell assay. RESULTS: The 4 related 7S globulins induced a response with an almost identical level of specific antibodies, but peanut 7S induced IgE of higher avidity than hazelnut and pea 7S which, again, had a higher avidity than IgE induced by soy 7S. Soy tolerance reduced the functionality of IgE without influencing antibody titers. CONCLUSIONS: Although the 4 7S globulins are structurally related allergens, they induce antibodies with different antigen-binding characteristics. Peanut 7S induces IgE of a higher avidity than hazelnut and pea 7S which, again, has a higher avidity than IgE induced by soy 7S. We also show that soy tolerance influences the function of antibodies to peanut 7S. These findings may help explain how antibodies of different clinical significances can develop in different individuals sensitized to the same allergen. PMID- 21282961 TI - Development of a sandwich ELISA to measure exposure to occupational cow hair allergens. AB - BACKGROUND: Cow hair and dander are important inducers of occupational allergies in cattle-exposed farmers. To estimate allergen exposure in farming environments, a sensitive enzyme immunoassay was developed to measure cow hair allergens. METHODS: A sandwich ELISA was developed using polyclonal rabbitantibodies against a mixture of hair extracts from different cattle breeds. To assess the specificity of the assay, extracts from other mammalian epithelia, mites, molds and grains were tested. To validate the new assay, cow hair allergens were measured in passive airborne dust samples from the stables and homes of farmers. Dust was collected with electrostatic dust fall collectors (EDCs). RESULTS: The sandwich ELISA was found to be very sensitive (detection limit: 0.1 ng/ml) and highly reproducible, demonstrating intra- and interassay coefficients of variation of 4 and 10%, respectively. The assay showed no reactivity with mites, molds and grains, but some cross-reactivity with other mammalian epithelia, with the strongest reaction with goat. Using EDCs for dust sampling, high concentrations of bovine allergens were measured in cow stables (4,760-559,400 MUg/m2). In addition, bovine allergens were detected in all areas of cattle farmer dwellings. A large variation was found between individual samples (0.3-900 MUg/m2) and significantly higher values were discovered in changing rooms. CONCLUSION: The ELISA developed for the detection of cow hair proteins is a useful tool for allergen quantification in occupational and home environments. Based on its low detection limit, this test is sensitive enough to detect allergens in passive airborne dust. PMID- 21282962 TI - Allergen-induced accumulation of CD68-,CD123+ dendritic cells in the nasal mucosa. AB - BACKGROUND: Dendritic cells are antigen-presenting cells central to the immune system. They activate and orchestrate the innate and the adaptive immune systems. This phenotypically diverse group can be further divided into 2 subsets, the CD11c+ myeloid dendritic cells (mDCs) and the CD123+ plasmacytoid dendritic cells (pDCs). The aim of the study was to investigate the effect of allergen exposure on dendritic cells in subjects with allergic rhinitis. METHODS: Atopic and non atopic subjects were challenged intranasally with birch or timothy allergen. Nasal biopsies were taken before and 24 h after challenge, and were, after CD68 exclusion, stained for expression of CD11c and CD123 to identify dendritic cell subsets. The effect of allergic mediators on CD68-,CD123+ cells was studied with flow cytometry analysis in peripheral blood. RESULTS: The amount of CD68-,CD123+ cells increased in the nasal sub-epithelium upon allergen challenge, whereas the number of CD68-,CD11c+ cells was unaffected. In vitro study of the effect of inflammatory mediators on pDC phenotype showed an increased activation in response TNF-alpha, IL-4 and CpG. Furthermore, TNF-alpha caused a higher activation among atopic than non-atopic subjects. CONCLUSIONS: An increased number of CD68-,CD123+ dendritic cells along with the positive pDC response following stimulation with inflammatory mediators suggest that the increased pDCs may be of an activated phenotype. It also suggests that the inflammatory response by pDCs to mediators such as TNF-alpha may be markedly higher in atopic subjects. These data support the notion of pDCs as important participants in allergic rhinitis. PMID- 21282963 TI - Obestatin: a new element for mineral metabolism and inflammation in patients on hemodialysis. AB - BACKGROUND: Obestatin plays a key role in the process of energy balance maintenance with an anorectic effect. The main aim of the study was to evaluate obestatin in uremic patients to determine whether it is correlated with nutritional and inflammatory status. METHODS: We studied plasma obestatin in uremic patients (n = 50) undergoing hemodialysis therapy and in healthy subjects. Plasma obestatin was measured using an ELISA kit. RESULTS: Obestatin levels in uremic patients were lower than in healthy subjects (p < 0.0001). Patients with a body mass index (BMI) >23 had lower obestatin levels than those with a BMI <23 (p = 0.001). After multivariate analysis, direct correlations were maintained between obestatin and high-sensitivity C-reactive protein (beta = 0.68, p < 0.0001) and total alkaline phosphatases (beta = 0.30, p = 0.03), while inverse correlations were found with iron (beta = -0.32, p = 0.002) and calcium phosphorous product (beta = -0.40, p = 0.001). CONCLUSIONS: Based on the present observational data, obestatin might be implicated in the inflammatory state and the disturbances of calcium/phosphate metabolism of hemodialysis patients. However, further studies are warranted to determine whether this hormone plays a key role in contributing to malnutrition and to the chronic inflammatory process. PMID- 21282964 TI - Nationwide population-based epidemiologic study of cryptococcal meningitis in Taiwan. AB - BACKGROUND: Little is known about the epidemiology of cryptococcal meningitis in Taiwan. The aim of this study was to conduct the first nationwide population based epidemiologic study of cryptococcal meningitis in Taiwan. METHODS: Cases of cryptococcal meningitis were identified from the annual hospitalization discharge claims of the National Health Insurance Research Database with the corresponding ICD-9 code 321.0 from January 2000 to December 2007. RESULTS: A total of 845 incident cases of cryptococcal meningitis were detected. Among them, 109 patients (12.9%) had human immunodeficiency virus (HIV) infection. The average incidence was 4.7 per million person-years. The incidence remarkably increased in the age group of 60-69 years, peaked in the age group of 70-79 years, and fell after the age of 80 years. The average incidence for men was 2.2-fold higher than that for women. The most common complication was obstructive hydrocephalus in 15.3% of the patients, followed by acute respiratory failure in 12.0% of the patients. CONCLUSION: This is the first population-based epidemiologic study of cryptococcal meningitis in Taiwan. The incidence was stable during the study period, and most cases were non-HIV related. PMID- 21282965 TI - Smokers with multiple sclerosis are more likely to report comorbid autoimmune diseases. AB - BACKGROUND/AIMS: Smoking is a risk factor for multiple sclerosis (MS) and autoimmune disease, and might explain an increased risk of comorbid autoimmune disease (CAD) in MS. We compared the risk of CAD in smokers and nonsmokers with MS. METHODS: Participants enrolled in the North American Research Committee on Multiple Sclerosis Registry reported their smoking status, the presence of CAD and the year of diagnosis. We used multivariable logistic regression to determine the independent association between smoking and CAD. We also compared the risk of developing a CAD in current smokers versus never-smokers who did not report any CAD at MS onset, using a proportional hazards model. RESULTS: Among 8,875 participants reporting comorbidities and smoking status, 1,649 (18.5%) reported a CAD. In a multivariable logistic model, ever-smokers had increased odds of reporting a CAD (odds ratio: 1.22; 95% CI: 1.08-1.38). Among the 7,830 participants without a CAD at onset of MS who reported their smoking status, including the age at which they started smoking, 3,035 (36.8%) currently smoked, while 3,805 (48.6%) never smoked. After adjustment, smokers had an increased risk of developing any autoimmune disease (hazard ratio: 1.23; 95% CI: 1.08-1.41) after MS onset. CONCLUSION: Smoking is associated with an increased risk of CAD in MS. PMID- 21282966 TI - Endothelin-1 and nitric oxide levels in patients with glaucoma. AB - AIMS: To investigate the levels of endothelin-1 (ET-1) and nitric oxide (NO) in the aqueous humor and plasma of human eyes with different types of glaucoma: primary open-angle glaucoma (POAG) and chronic closed-angle glaucoma (CCAG). METHODS: Patients were classified into 3 groups: group I comprised 35 patients with POAG, group II comprised 25 patients with CCAG, and 30 patients with senile cataract (group III) were used as a control group. Aqueous humor and corresponding plasma were analyzed for ET-1 and NO concentrations by enzyme linked immunosorbent assay. A Bonferroni correction for multiple comparisons was performed. RESULTS: There was no significant difference in plasma levels of either ET-1 or NO metabolites between the groups studied. ET-1 and NO were significantly elevated in the aqueous humor of patients with CCAG and POAG compared to the corresponding value in patients with cataract (p < 0.001). ET-1 and NO concentrations in the aqueous humor were more marked in CCAG than in POAG. NO levels were correlated with ET-1 in the aqueous humor of patients with glaucoma (p < 0.001). CONCLUSIONS: Increased concentrations of ET-1 and NO in aqueous humor may be useful with POAG and CCAG. In addition, ET-1 and NO may have useful metabolite levels in the aqueous humor of POAG and CCAG patients as a result of glaucoma damage and may not be a cause of it. PMID- 21282967 TI - In vitro biotransformation, in vivo efficacy and pharmacokinetics of antimalarial chalcones. AB - 4'-n-Butoxy-2,4-dimethoxy-chalcone (MBC) has been described as protecting mice from an otherwise lethal infection with Plasmodium yoelii when dosed orally at 50 mg/kg/dose, daily for 5 days. In contrast, we found that oral dosing of MBC at 640 mg/kg/dose, daily for 5 days, failed to extend the survivability of P. berghei-infected mice. The timing of compound administration and metabolic activation likely contribute to the outcome of efficacy testing in vivo. Microsomal digest of MBC yielded 4'-n-butoxy-4-hydroxy-2-methoxy-chalcone and 4' (1-hydroxy-n-butoxy)-2,4-dimethoxy-chalcone. We propose that the latter will hydrolyze in vivo to 4'-hydroxy-2,4-dimethoxy-chalcone, which has greater efficacy than MBC in our P. berghei-infected mouse model and was detected in plasma following oral dosing of mice with MBC. Pharmacokinetic parameters suggest that poor absorption, distribution, metabolism and excretion properties contribute to the limited in vivo efficacy observed for MBC and its analogs. PMID- 21282968 TI - Pharmacokinetics and tissue distribution of dual-targeting daunorubicin liposomes in mice. AB - BACKGROUND: To circumvent the problem of transporting anticancer drugs across the blood-brain barrier (BBB) to target brain tumors, we have previously developed dual-targeting daunorubicin liposomes modified with 4-aminophenyl-alpha-D-manno pyranoside and transferrin molecules. The objective of the present study was to evaluate the pharmacokinetics and distribution of daunorubicin after intravenous administration of dual-targeting daunorubicin liposomes. METHODS: We evaluated pharmacological parameters in normal KunMing mice. Drug concentrations in plasma, heart, spleen, lung, kidney and brain were measured using HPLC-UV. RESULTS: The plasma drug concentration-time profile of the daunorubicin dual-targeting liposomes decreased more slowly than free daunorubicin in the initial phase and maintained higher drug levels in the terminal phase, resulting in longer blood exposure to daunorubicin liposomes compared with the free drug. Daunorubicin levels were lower in heart tissue and significantly higher in brain tissue after administration of the dual-targeting liposomes compared with the free drug. Daunorubicin was detected at varying levels in the liver, spleen, lung and kidney tissues. CONCLUSION: Our results indicate that dual-targeting daunorubicin liposomes improve the daunorubicin blood circulation time and show an enhanced drug transport potential across the BBB. PMID- 21282969 TI - Paracetamol fails to positively modulate and directly activate chloride currents in human alpha1-glycine receptors. AB - Paracetamol (acetaminophen) is a widely used antipyretic and analgesic drug for mild or moderate pain states. As the primary site of action of paracetamol is still the subject of ongoing discussion, the focus of this study is the investigation of a potential mechanism which might contribute to its beneficial effects in the therapy of pain. Loss of inhibitory synaptic transmission within the dorsal horn of the spinal cord plays a key role in the development of pain following inflammation or nerve injury. Inhibitory postsynaptic transmission in the adult spinal cord involves mainly glycine. In this study we investigated the interaction of paracetamol with strychnine-sensitive alpha(1)-glycine receptors (alpha(1)-GlyR). alpha(1)-GlyR subunits transiently expressed in HEK-293 cells were studied using the whole-cell patch-clamp technique and a piezo-controlled liquid filament fast application system. Paracetamol fails to show a positive allosteric modulatory effect in low nano- to micromolar concentrations and lacks direct activation in micromolar concentrations at the alpha(1)-GlyR. Consequently, the analgesic actions of paracetamol leading to pain relief appear to be mediated via other mechanisms, but not via activation of spinal glycinergic pathways. PMID- 21282970 TI - Knockdown of ezrin via RNA interference suppresses Helicobacter pylori-enhanced invasion of gastric cancer cells. AB - BACKGROUND AND AIM: H. pylori interacts with gastric epithelial cells, which may activate signaling pathways important for gastric cancer invasion. Ezrin, a membrane cytoskeletal crosslinker protein, is well documented to regulate cell adhesion and cell motility. The aim of the present study was to determine whether ezrin is involved in H. pylori-induced cancer cell motility and invasion. METHODS: The VIL-2 of RNA interference plasmid vector and control plasmid vector were constructed. AGS (a human gastric adenocarcinoma cell line) cells were transfected by these plasmid vectors. The stable expression cell lines AGS(ezrin) was obtained by G418 resistance screening. The express levels of ezrin protein and the cellular invasive potential of four groups, including the AGS control, AGS(ezrin) control, AGS co-culture with H. pylori, AGS(ezrin) co-culture with H. pylori were detected. Meanwhile, the morphology, cell migration and adhesion were determined respectively. RESULTS: Co-culture with H. pylori stimulated AGS cell motility and invasion, up-regulated ezrin expression at the protein level and induced a Hummingbird phenotype. The silencing of ezrin expression suppressed the motility and invasion of gastric cancer cells and inversed the cell invasion phenotype and enhanced the ability for cell adhesion. CONCLUSION: Knockdown of ezrin by RNAi suppresses H. pylori-enhanced migration and invasion of gastric cancer cells. These findings indicate that ezrin may play a key role in the migration and invasion of gastric cancer cells, and thus may be a therapeutic target to prevent metastasis of gastric cancer promoted by H. pylori infection. PMID- 21282971 TI - A therapeutic peptide in lupus alters autophagic processes and stability of MHCII molecules in MRL/lpr B cells. AB - The P140 phosphopeptide encompassing residues 131-151 of the spliceosomal U1-70K snRNP protein displays protective properties in lupus patients and MRL/lpr mice. It increases peripheral blood lymphocyte apoptosis via a mechanism involving gammadelta T cells. After intravenous administration, P140 accumulates in the lungs and spleen. It binds both the HSC70/Hsp73 chaperone and MHC class II (MHCII) molecules, which colocalize in splenic MRL/lpr B cells. Expression of HSC70 and MHCII, which is increased in MRL/lpr splenic B cells, is diminished after P140 administration. P140 impairs refolding properties of HSC70 and alters expression of stable MHCII molecules in B lymphocytes. In MRL/lpr B cells, P140 increases the accumulation of the autophagy markers p62/SQSTM1 and LC3-II, consistent with a downregulation of autophagic flux. Our study reveals a very unique property of P140 peptide that alters the autophagy pathway leading to a defect of endogenous (auto)antigen processing in MRL/lpr antigen-presenting B cells and a decrease of T cell priming and signaling. PMID- 21282972 TI - Modeling gene associations for virulence classification of verocytotoxin producing E. coli (VTEC) from patients and beef. AB - An evaluation of 22 EHEC genes was carried out for virulence classification of VTEC. The data consisted of 116 patient isolates and 42 beef isolates. The symptoms among patients ranged from mild (diarrhea) to severe (bloody diarrhea and HUS). A cluster of genes-efa1, eae, ecf4, paa, and ureC-were more frequent in patient isolates than beef isolates. They also contributed to the classification of high virulence isolates compared with low virulence isolates. These genes may together constitute a general virulence factor, being also associated with well known virulence serogroups: O157, O26, O103, O111, O145, O121, and O118. In a regression model of patient versus beef isolates, the combined presence of efa1 and paa proved a particularly efficient indicator of patient isolates (OR: 32.9). In contrast, a single gene, vtx22 (subtype vtx2 of vtx2) was a relatively efficient predictor of high virulence among patient isolates (OR: 41.6), but not of virulence in general. Significant interaction effects observed between genes need to be addressed and clarified in future studies. PMID- 21282973 TI - Augmentation of tumor-specific immunity by upregulation of apoptotic melanoma cell calreticulin expression. PMID- 21282974 TI - Bortezomib treatment causes remission in a Ph+ALL patient and reveals FoxO as a theranostic marker. AB - BCR-ABL is a key mediator in the pathogenesis of all cases of chronic myelogenous leukemia (CML) and a subset of precursor B-acute lymphoblastic leukemia (Ph+ALL). Previous animal and cell-based studies have shown that the expression of members of the Forkhead family of tumor suppressors, including FoxO3, is suppressed in BCR-ABL-expressing cells. Furthermore, it has been reported that the proteasomal degradation pathway plays an important role in suppression of FoxO expression in BCR-ABL-transformed cells. In this study, a patient diagnosed with Ph+ALL and refractory to standard therapies was treated with a proteasome inhibitor (bortezomib)-based chemotherapy regimen. This treatment resulted in complete hematologic, cytogenetic and molecular remission with excellent performance status for > 4 years since her initial diagnosis. FoxO3 was not detectable within the blasts of this patient at diagnosis and was 'rescued' following treatment with bortezomib therapy, leading to her recovery. As a next step, in the attempt to propose FoXO3 as a therapeutic target and a theranostic marker, we further validated FoxO3 expression in human bone marrow biopsy samples. Human core biopsy samples of Ph+ALL and Ph-negative-negative ALL, along with uninvolved controls, revealed that FoxO3 down-regulation was specific to Ph+ALL. This study provides support that FoxO3 is a good biomarker for BCR-ABL-mediated leukemogenesis. Additionally, proteasomal inhibition by bortezomib may be a promising therapeutic option in Philadelphia-positive ALL, where FoxO3 is downregulated. PMID- 21282975 TI - Effectiveness of engineering the nontypeable Haemophilus influenzae antigen Omp26 as an S-layer fusion in bacterial ghosts as a mucosal vaccine delivery. AB - The potential of empty bacterial cell envelopes (ghosts) as a delivery system for mucosal immunization was assessed in a rat model and different routes of immunization were evaluated. Animals were mucosally immunized targeting either gut only or gut and lung mucosal sites with Escherichia coli ghosts harbouring the nontypeable Haemophilus influenzae (NTHi) antigen Omp26. Omp26 was expressed as either a part of an S-layer fusion or as a soluble protein in the periplasm. In the gut/lung regime two initial gut targeted inoculations with the ghosts were followed by an intratracheal (IT) boost with purified Omp26. The gut only immunization regime showed a moderate enhancement of bacterial clearance following pulmonary challenge whereas the gut/lung immunization regime resulted in significantly enhanced pulmonary clearance of NTHi. Both immunization regimes induced high levels of Omp26 specific antibodies in the serum of immunized rats, with higher levels in the groups that received the IT boost with purified Omp26. Analysis of IgG isotypes present in serum suggest that the immune response was predominantly of a T-helper1 type. Additionally, immunization induced a significant cellular immune response with lymphocytes from animals vaccinated using the gut/lung regime responding significantly to Omp26 when compared to control groups. The results of this study show that mucosal immunization with recombinant Omp26 in E. coli ghosts followed by a boost with purified Omp26 can induce a specific and protective immune response in a rodent model of acute lung infection. PMID- 21282976 TI - In vitro selected RNA aptamer recognizing glutathione induces ROS mediated apoptosis in the human breast cancer cell line MCF 7. AB - Glutathione (GSH) is an abundant natural tripeptide with antioxidant properties. Under different conditions, it can play protective as well as pathogenic roles. The redox state of the cell has an important role in the induction of apoptosis. Elevated level of glutathione in cancer cells provides resistance to a number of chemotherapeutic drugs. Inhibition of glutathione synthesis sensitizes the cells for apoptosis and enhances the activity of chemotherapeutic drugs. We have selected GSH-binding RNA aptamers by employing in vitro selection protocol SELEX. The Kd value of these aptamers with respect to GSH were determined by surface plasmon resonance (SPR) analysis and isocratic affinity chromatography. Two aptamers GSHapt 8.17 (class-III) and GSHapt 5.39 (class-IV) had Kd values of 4.18 and 4.89 x 10(-8) M, respectively and GSHapt class-I had a Kd value of 1.2 x 10( 6) M. CD spectra suggested conformational change in aptamers upon GSH binding. Cultured breast cancer cells (MCF7) responded to expression of GSH aptamers by accumulating ROS and undergoing morphological transition, nuclear condensation, and DNA fragmentation, with concurrent depletion of cellular GSH and activation of caspase 3 eventually leading to apoptosis. DTT and caspase-3 inhibitor partially rescued aptamer induced apoptosis. These aptamers exhibit high specificity to GSH over non specific competitor. The same aptamers did not induce apoptosis in 293T cells. The kinetic properties and pro-apoptotic effects suggest that glutathione-binding RNA aptamer could be developed into an effective anti cancer chemotherapeutic agent. PMID- 21282977 TI - HMGA1-dependent and independent 7SK RNA gene regulatory activity. AB - The small nuclear 7SK RNA negatively controls transcription by inactivating positive transcription elongation factor b (P-TEFb) and is an integral component of Tat-dependent and independent HIV-1 transcription initiation complexes. 7SK RNA has recently been shown to also directly control HMGA1 transcription activity. HMGA1 is a master regulator of gene expression and its deregulation is associated with virtually any type of human cancer. The degree of HMGA1 over expression thereby correlates with tumor malignancy and metastatic potential. 7SK snRNA directly interacts through its loop2 (7SK L2) with the first A/T-hook DNA binding motif of HMGA1. We have developed several 7SK L2 RNA chimera with the Epstein Barr Virus expressed RNA 2 (EBER2) to target HMGA1 function in transcription regulation. The efficiency of interfering with HMGA1 transcription activity by the chimeric 7SK L2-EBER2 fusions by large exceeds the efficiency of 7SK wild-type RNA due to the stronger EBER2 promoter activity. Furthermore, the 7SK L2-EBER2 chimera do not interfere with P-TEFb controlled transcription elongation or the formation of 7SK sn/hnRNPs. The comparison of the effects of wild-type 7SK RNA on cellular transcriptome dynamics with those induced by the two 7SK L2 mutants as well as the changes in gene expression following inhibition of HMGA1 allow the identification and characterization of HMGA1-dependent and independent effects of 7SK snRNA. We furthermore also present evidence for P-TEFb and HMGA1-independent 7SK RNA L2 regulatory activity. PMID- 21282978 TI - Deep-sequencing of human Argonaute-associated small RNAs provides insight into miRNA sorting and reveals Argonaute association with RNA fragments of diverse origin. AB - While several studies have focused on the relationship between individual miRNA loci or classes of small RNA with human Argonaute (AGO) proteins, a comprehensive, global analysis of the RNA content associating with different AGO proteins has yet to be performed. We have compared the content of deep sequenced RNA extracted from immunoprecipitation experiments with the AGO1, AGO2, and AGO3 proteins. Consistent with previous observations, sequence tags derived from miRNA loci globally associate in approximately equivalent amounts with AGO1, AGO2, and AGO3. Exceptions include miR-182, miR-222, and miR-223*, which could be coupled to processes targeting the loci for interaction with specific AGO proteins. A closer inspection of the data, however, supports the presence of an unusual sorting mechanism wherein a subset of miRNA loci give rise to distinct isomirs which preferentially associate with distinct AGO proteins in a significantly differential manner. We also identify the complete set of short RNA derived from non-miRNA sources including tRNA, snRNA, snoRNA, vRNA, and mRNA associating with the AGO proteins, many of which are predicted to play roles in post transcriptional gene silencing. We also observe enrichment of tags mapping to promoter regions of genes, suggesting that a fraction of the recently-identified promoter-associated small RNAs in humans could function through interaction with AGO proteins. Finally, we observe antisense miRNA transcripts are frequently present in low copy numbers across a range of diverse miRNA loci and these transcripts appear to associate with AGO proteins. PMID- 21282979 TI - Nop6, a component of 90S pre-ribosomal particles, is required for 40S ribosomal subunit biogenesis in Saccharomyces cerevisiae. AB - In Saccharomyces cerevisiae, ribosome biogenesis requires, in addition to rRNA and ribosomal proteins, a myriad of small nucleolar RNAs (snoRNAs) and over two hundred protein trans-acting factors. There are protein trans-acting factors predicted to participate in ribosome biogenesis that have not been so far characterized. Here, we report the functional analysis of the Nucleolar protein 6 (Nop6) in ribosome biogenesis. Our results show that Nop6 is needed for optimal 40S ribosomal subunit biogenesis. Deletion of NOP6 leads to an appropriate 20% reduction in 18S rRNA levels and therefore in 40S ribosomal subunits. This is due to mild inhibition of pre-rRNA processing at cleavage site A 2. Tandem affinity purification followed by mass spectrometry and northern blot analyses indicate that Nop6 is a component of 90S pre-ribosomal particles. rDNA chromatin immunoprecipitation experiments and analysis of the intracellular localisation of Nop6-eGFP after in vivo shut down of pre-rRNA transcription strongly suggest that Nop6 binds to the pre-rRNA early during transcription. Genetic data suggest that Nop6 and the snoRNA snR57 both interact similarly with the protein trans-acting factor Nep1. It has been proposed that snR57 and Nep1 participate in a pre-rRNA conformational switch that allows the proper assembly of 40S ribosomal protein S19. Our results strongly suggest that the role Nop6 might have in this conformational switch is independent of snR57. PMID- 21282980 TI - Processive RNA decay by the exosome: merits of a quantitative Bayesian sampling approach. AB - RNA exosomes are large multi-subunit protein complexes involved in controlled and processive 3' to 5' RNA degradation. Exosomes form large molecular chambers and harbor multiple nuclease sites as well as RNA binding regions. This makes a quantitative kinetic analysis of RNA degradation with reliable parameter and error estimates challenging. For instance, recent quantitative biochemical assays revealed that degradation speed and efficiency depend on various factors, such as the type of RNA binding caps and the RNA length. We propose the combination of a differential equation model with bayesian Markov Chain Monte Carlo (MCMC) sampling for a more robust and reliable analysis of such complex kinetic systems. Using the exosome as a paradigm, it is shown that conventional "best fit" approaches to parameter estimation are outperformed by the MCMC method. The parameter distribution returned by MCMC sampling allows for a reliable and meaningful comparison of the data from different time series. In the case of the exosome, we find that the cap structures of the exosome have a direct effect on the recruitment and degradation of RNA, and that these effects are RNA length dependent. The described approach can be widely applied to any processive reaction with a similar kinetics like the XRN1-dependent RNA degradation, RNA/DNA synthesis by polymerases, and protein synthesis by the ribosome. PMID- 21282981 TI - Bacterial aptamers that selectively bind glutamine. AB - The continued expansion of microbial sequence data has allowed for the detection of an increasing number of conserved RNA motifs by using comparative sequence analysis. Recently, we reported the discovery of two structured non-coding RNA motifs, called glnA and Downstream-peptide, that have similarity in sequence and secondary structure. In this report, we describe data demonstrating that representatives of both RNA motifs selectively bind the amino acid L-glutamine. These glutamine aptamers are found exclusively in cyanobacteria and marine metagenomic sequences, wherein several glnA RNA representatives reside upstream of genes involved in nitrogen metabolism. These motifs have genomic distributions that are consistent with a gene regulation function, suggesting they are components of glutamine-responsive riboswitches. Thus, our findings implicate glutamine as a regulator of cyanobacterial nitrogen metabolism pathways. Furthermore, our findings expand the collection of natural aptamer classes that bind amino acids to include glycine, lysine and glutamine. PMID- 21282982 TI - snRNA-specific role of SMN in trypanosome snRNP biogenesis in vivo. AB - Pre-mRNA splicing in trypanosomes requires the SMN-mediated assembly of small nuclear ribonucleoproteins (snRNPs). In contrast to higher eukaryotes, the cellular localization of snRNP biogenesis and the involvement of nuclear cytoplasmic trafficking in trypanosomes are controversial. By using RNAi knockdown of SMN in T. brucei to investigate its functional role in snRNP assembly, we found dramatic changes in the steady-state levels of snRNAs and snRNPs: The SL RNA accumulates, whereas U1, U4, and U5 snRNA levels decrease, and Sm core assembly in particular of the SL RNA is strongly reduced. In addition, SMN depletion blocks U4/U6 di-snRNP formation; the variant Sm core of the U2 snRNP, however, still forms efficiently after SMN knockdown. Concerning the longstanding question, whether nuclear-cytoplasmic trafficking is involved in trypanosomal snRNP biogenesis, fluorescence in situ hybridization (FISH) and immunofluorescence assays revealed that the SL RNA genes and transcripts colocalize with SMN. Remarkably, SMN silencing leads to a nucleoplasmic accumulation of both SL RNA and the Sm proteins. In sum, our data demonstrate an essential and snRNA-selective role of SMN in snRNP biogenesis in vivo and strongly argue for a nucleoplasmic Sm core assembly of the SL RNP. PMID- 21282983 TI - ARNold: a web tool for the prediction of Rho-independent transcription terminators. AB - Rho-independent termination is a major mechanism of transcriptional arrest in bacteria that controls both normal 3' termination and a wide array of regulatory attenuation events. Detecting Rho-independent terminators is an obliged step in the annotation of bacterial operons. Yet, while several efficient algorithms are available for this purpose, there is no freely available web site enabling a rapid scanning of raw genomic sequence for the presence of terminators. Here we implemented such a web server, which combines two published prediction algorithms, Erpin and RNAmotif, and performs nearly as well as more complex procedures while being accessible to the non specialist. The ARNold Web server is available at : http://rna.igmors.u-psud.fr/toolbox/arnold/ PMID- 21282984 TI - 3,3'-Diindolylmethane negatively regulates Cdc25A and induces a G2/M arrest by modulation of microRNA 21 in human breast cancer cells: retraction. PMID- 21282987 TI - Incidence, occurrence rate, and characteristics of suture-related corneal infections after penetrating keratoplasty. AB - PURPOSE: To report the incidence, occurrence rate, and characteristics of suture related infections after penetrating keratoplasty (PK). METHODS: Patients who underwent PK at our institution between January 1, 2002, and July 1, 2006, were cross-referenced with patients diagnosed with corneal infections between January 1, 2002, and July 1, 2007. All patient charts were reviewed retrospectively for occurrence of suture-related infections, duration of follow-up, and clinical characteristics. RESULTS: Of the 487 PKs performed in 412 patients, 22 eyes of 22 patients developed postoperative corneal infections. Of these, 5 eyes were identified as having suture-related graft infections, yielding an occurrence rate of 1.0%. The average follow-up was 3.46 years per PK, yielding an incidence of 2.96 infections per 1000 PK-years. The mean interval from surgery to infection was 8 months (range: 3-23 months). All culprit sutures were in the interpalpebral zone. No patients were using topical antibiotics at the time of infection, and all patients were using topical corticosteroid drops. Cultured organisms included Staphylococcus aureus (3 cases), coagulase-negative Staphylcoccus (1 case), and S. viridans (1 case). In 2 patients with isolated corneal involvement, topical moxifloxacin was initiated, and the patients responded favorably. In 3 patients with corneal infection and an associated hypopyon or endophthalmitis, vitreous biopsy, intravitreal injections of antibiotics, and fortified topical antibiotics were used. One patient required a repeat PK as a result of the infection. Two eyes eventually became phthisical. CONCLUSIONS: The rate of suture-related infections after PK may be lower than previously reported. In our patients, suture-related infections all occurred within the first 2 years after surgery, and some of them resulted in significant morbidity, underscoring the importance of patient identification of symptoms and early clinical recognition. PMID- 21282985 TI - MicroRNAs: redefining mechanisms in cardiac disease. AB - MicroRNAs (miRs) regulate protein expression by inhibiting translation of expressed mRNAs. Targeting by one or more miRs of multiple mRNA transcripts encoding proteins with common functions confers nodal control over cardiac development and stress response. Dynamic coregulation of miRs and their mRNA targets has complicated understanding their biology but also provides opportunities for clinical diagnostics and therapeutics. Here, the biology of miRs is reviewed as it relates to the cardiac system, recent findings are described that illuminate miR control of cardiac development and myofiber identity, and the clinical ramifications of miR expression profiling are illustrated. PMID- 21282988 TI - Interface blood after descemet stripping automated endothelial keratoplasty. AB - The authors report a case of a Descemet stripping automated endothelial keratoplasty that was complicated by intraoperative bleeding from the iridotomy site. Slit-lamp examination on postoperative day 1 revealed significant amount of retained blood at the donor-recipient interface and a best-corrected visual acuity (BCVA) of 20/400. The patient was managed with periodic observation and a topical fluoroquinolone and 1% prednisolone. By postoperative month 8, the interface had cleared, and the BCVA improved to 20/50. The patient remained with a clear cornea and stable BCVA of 20/50 at her most recent 1-year postoperative follow-up examination. Performing an intraoperative peripheral iridotomy to reduce the risk of air-associated pupillary block introduces the risk of its inherent complications, including intraoperative bleeding, retained blood cells at the interface, and delayed visual recovery. In this case, periodic observation and conservative management with topical steroids resulted in the resolution of the interface debris, associated keratitis, and improved postoperative visual acuity. PMID- 21282989 TI - UV-riboflavin cross-linking of the cornea in bullous keratopathy: appraising the rationale. PMID- 21282990 TI - The New Zealand National Eye Bank: survival and visual outcome 1 year after penetrating keratoplasty. AB - PURPOSE: To identify potential donor, recipient, surgical, and postoperative factors that may influence survival and visual outcome of penetrating keratoplasty (PKP). METHODS: As part of a prospective longitudinal study, the electronic records of the New Zealand National Eye Bank were analyzed for the 10 year period from 1994-2003. Both univariate and multivariate analysis was performed. RESULTS: During the study period, the New Zealand National Eye Bank supplied 1820 corneas for PKP and 1629 (90%) had 1-year follow-up data. Overall, the 1-year survival rate was 87% (n = 1429). Donor factors including age, donor source, cause of death, death-to-preservation interval, endothelial cell density, donor lens status, and storage duration, were not significantly associated with decreased survival. The leading cause of PKP failure was irreversible rejection (7%, n = 114). Independent risk factors identified for decreased PKP survival were: 1 or more episodes of reversible rejection, active inflammation at PKP, preexisting corneal vascularization, intraoperative complications, small graft size (<= 7.25 mm), large graft size (>= 8.5 mm), preoperative glaucoma, and a preoperative diagnosis of regraft or trauma. A best-corrected Snellen visual acuity of 6/12 or better was achieved in 60% of eyes [mean: 6/15 (logarithm of the minimum angle of resolution 0.40)]. Keratoconus and Fuchs endothelial dystrophy were the diagnoses with best survival and visual outcome, whereas, bullous keratopathy, trauma or noninfective keratitis were associated with poorer visual outcome. CONCLUSIONS: Several independent risk factors were identified that significantly influenced PKP first year survival outcome. This information is valuable to patients and surgeons with respect to determining prognosis and clinical decision making. PMID- 21282991 TI - Molecular detection of Bartonella henselae for the diagnosis of cat scratch disease and bacillary angiomatosis of the conjunctiva. AB - PURPOSE: The purpose of this study was to evaluate clinical cases of cat scratch disease (CSD) and bacillary angiomatosis involving the conjunctiva by special stains and transmission electron microscopy (TEM) and to compare these findings with the results from species-specific polymerase chain reaction (PCR) analysis of the same specimens. METHODS: Six potential cases of CSD and 2 possible cases of bacillary angiomatosis of the conjunctiva were analyzed by light microscopy, the Warthin-Starry technique, TEM, and PCR. DNA isolated from cultured Bartonella henselae, B. bacilliformis, B. quintana, and B. elizabethae were used as control templates for establishment of the PCR sensitivity and specificity. Cultured DNA was also used as appropriate positive controls during analysis of the clinical specimens. RESULTS: The histological studies, electron microscopy, and the PCR analysis confirmed the identification of the bacilli within the involved tissues. Furthermore, molecular diagnosis by PCR allowed for speciation of the infecting Bartonella organisms in 6 of the 8 cases and correlated with the histological findings. CONCLUSIONS: The PCR-based identification of Bartonella correlated well with the results of light microscopy and TEM and provided a simple and rapid method of diagnosis to the species level. The molecular analysis may prove to be beneficial in enhancing the current diagnostic techniques for CSD and bacillary angiomatosis. PMID- 21282992 TI - In vivo confocal microscopy in Terrien marginal corneal degeneration: a case report. AB - PURPOSE: To report an advanced case of Terrien marginal corneal degeneration (TMD) analyzed by means of confocal microscopy. METHODS: A 62-year-old woman with TMD underwent a routine ophthalmological examination and was evaluated for the disease by using in vivo laser scanning confocal microscopy with the Heidelberg Retina Tomograph 2 Rostock Cornea Module. RESULTS: The slit-lamp examination of the right eye showed an upper peripheral cornea thinning associated with a deposition of refractile yellow-white materials in the anterior stroma. Superficial radial vessels in the upper peripheral cornea were the only pathological findings of the left eye. Confocal microscopy of the right eye lesion showed deposition of hyperreflective material, and the stroma below presented a honeycomb-like pattern. Inflammatory cell infiltration, abnormal subbasal nerve plexus, epithelial basal membrane defects, irregular Bowman membrane, and the presence of activated keratocytes were observed in the cornea of both eyes. CONCLUSIONS: In vivo confocal microscopy can detect subtle corneal changes in an advanced case of TMD, which may be signs of subclinical inflammation. PMID- 21282993 TI - Effect of tacrolimus on chemokine production by corneal myofibroblasts via toll like receptors, compared with cyclosporine and dexamethasone. AB - PURPOSE: To investigate the effect of tacrolimus on chemokine production by corneal myofibroblasts compared with that of cyclosporine or dexamethasone. METHODS: We investigated the expression of FK506-binding protein 12, calcineurin, and nuclear factor of activated T cells in corneal myofibroblasts by immunocytochemistry and flow cytometry. Next, we investigated whether toll-like receptor 9 ligand, CpG-DNA, or toll-like receptor 3 ligand, poly (I:C), induced the production of chemokines such as interleukin (IL) 8, Gro-alpha, and IL-6 by corneal myofibroblasts using enzyme-linked immunosorbent assay. Finally, we assessed the effect of tacrolimus on the production of these chemokines compared with that of cyclosporine or dexamethasone. RESULTS: FK506-binding protein 12, calcineurin, and nuclear factor of activated T cells were constantly expressed by cultured corneal myofibroblasts. CpG DNA and poly (I:C) enhanced the production of IL-8, Gro-alpha, and IL-6 by corneal myofibroblasts. At a concentration 10 nM/L or higher, dexamethasone strongly inhibited the production of these chemokines. In contrast, cyclosporine concentrations of 10 ng/mL or more enhanced the production of these chemokines by cells stimulated with poly (I:C). On the other hand, tacrolimus (at 10 ng/mL or more) inhibited the production of these chemokines by corneal myofibroblasts stimulated with poly (I:C) but not with CpG DNA. CONCLUSIONS: These results suggest that tacrolimus and dexamethasone, but not cyclosporine, have a direct immunosuppressive effect on corneal myofibroblasts. Therefore, when inflammatory diseases of the ocular surface are treated by tacrolimus, especially in combination with steroids, caution with regard to the risk of corneal infection may be needed. PMID- 21282995 TI - Relation between total tear IgE and specific serum IgE in seasonal allergic conjunctivitis. AB - PURPOSE: Recently, a new commercial test for total tear immunoglobulin E (IgE), based on immunochromatography (Allerwatch), was developed. We examined the relation between the total IgE level in tears and specific serum IgE. METHODS: A prospective, nonrandomized, cross-sectional study was conducted in 35 patients with allergic conjunctivitis (allergic group), 30 age- and sex-matched healthy control subjects (control group), and 8 patients with epidemic keratoconjunctivitis. In all subjects, the total tear IgE score was determined with the Allerwatch test (0, 1, and 2), and serum levels of total IgE and specific IgE for 12 inhaled allergens were measured with the Phadezym PRIST and CAP-RAST systems, respectively. RESULTS: The total tear IgE-positive rate was significantly higher in the allergic group than in the control and epidemic keratoconjunctivitis groups (100.0% vs. 0.0% vs. 0.0%; P < 0.00001). In the allergic group, the total tear IgE score was significantly correlated with the log-transformed total serum IgE level (r = 0.61) and with the serum levels of IgE for cedar pollen (r = 0.35), house dust (r = 0.46), Dermatophagoides pteronyssinus (r = 0.49), and acarus (r = 0.36). Multivariate logistic regression analysis showed that the log-transformed total serum IgE level was the only significant predictor of the total tear IgE score (odds ratio = 1.85, P = 0.00008). CONCLUSIONS: The total tear IgE score, determined with the Allerwatch test, was correlated with the total and specific serum IgE levels. This rapid test is easy to perform, sensitive, and highly specific for the detection of ocular allergy on an outpatient basis. PMID- 21282996 TI - Short-term effects of overnight orthokeratology on corneal cell morphology and corneal thickness. AB - PURPOSE: To examine the morphological and biometric corneal changes produced over periods of 15 days and 1 month after overnight orthokeratology (OK). METHODS: Prospective, single-center, longitudinal trial. Twenty-seven right eyes of 27 subjects (group 1) with low to moderate myopia wore OK lenses for 1 month. Ten right eyes of 10 subjects (group 2) with emmetropia to low myopia who did not wear any type of contact lens served as controls. Corneal morphometric measurements were obtained in vivo using a confocal microscope to examine the central and midperipheral cornea. Thickness measurements in the peripheral cornea were obtained by optical coherence tomography. Changes in visual acuity, refractive error, and corneal topography were also analyzed. RESULTS: No significant changes in either endothelial cell or stromal cell density were observed after 1 month of OK. Basal epithelial cells were, however, significantly reduced (P < 0.01), and epithelial wing and superficial cells showed enhanced visibility (P < 0.05). Superficial cells increased in height and width, the width increase after 1 month being significant (P < 0.01). Epithelial thickness was significantly reduced in the central cornea and 2 mm around the center. Corneal pachymetry increased significantly in the band from 5 to 10 mm from the corneal apex (P < 0.01). CONCLUSIONS: OK lenses for myopia induce significant structural and optical changes particularly in the central epithelium after 15 days or 1 month of wear. The central corneal epithelium responds to OK wear by undergoing significant epithelial cell shape and size alterations with no effects, however, on the cells of the corneal endothelium or the corneal stroma. Peripheral corneal thickness increased with respect to baseline values. These findings suggest that the corneal epithelium is the principal structure affected by the mechanical forces exerted by the OK lenses. PMID- 21282997 TI - Early changes in morphology and intraocular pressure by size of clear corneal incision. AB - PURPOSE: We compared changes in morphology and intraocular pressure (IOP) induced by clear 2.2-mm and 3.0-mm corneal incisions in a cohort of patients with cataracts. METHODS: In 160 eyes (from 70 men and 90 women at the Ophthalmic Center of Sun Yat-sen University), optical coherence tomography and tonometry were performed at 1, 5, and 24 hours after cataract surgery. The main outcome measures were IOP, postoperative changes in Descemet membrane detachment (DMD), healing of the surgical incision, and inflammation of the anterior chamber. RESULTS: Five hours after surgery, patients with 2.2-mm and 3.0-mm incisions had lower IOPs (P < 0.017) as measured by noncontact tonometry, but the difference was significant only among patients with grade V cataracts (2.2 mm, 12.6 +/- 1.2 mm Hg; 3.0 mm, 14.5 +/- 0.9 mm Hg, P < 0.05). The incidence of endothelial gap at 24 hours after surgery was significantly higher in the 2.2-mm (50%) versus 3.0-mm (11.1%) group of patients with grade V cataracts (P < 0.05). The incidence of DMD at 5 hours was also significantly higher in the 2.2-mm group (75%) than in the 3.0-mm group (22.2%) only among patients with this grade (P < 0.05). CONCLUSIONS: Incision width made no difference among patients with grade I-IV lens nuclei; but among those with grade V, 3.0-mm incisions had significantly less endothelial gaping, less DMD, and higher mean IOPs. For these patients, smaller incisions may not be optimal, and eyes may be especially vulnerable within 5 hours of surgery. PMID- 21282998 TI - Microbiological evaluation of chronic blepharitis among Iranian veterans exposed to mustard gas: a case-controlled study. AB - PURPOSE: To evaluate the microbiological characteristics of eyelid margin flora in chronic blepharitis in mustard gas-exposed individuals and compare the results with those in age- and sex-matched unexposed people. METHODS: In this comparative case series, 289 patients with ocular manifestations of mustard gas exposure (case) were evaluated for signs of chronic blepharitis. Additionally, microbiological evaluation of eyelid margins was conducted in these patients and compared with results of 100 unexposed patients with chronic blepharitis (control). RESULTS: One-hundred fifty (52.0%) of 289 mustard gas casualties had signs of chronic blepharitis. Microbiological evaluation revealed higher isolation rates of Staphylococcus epidermidis (78%) and Staphylococcus aureus (57%) in the case in comparison to control group (P < 0.01). Moreover, S. aureus isolated from the cases exhibited greater resistance to common antibiotics compared with control group. Fungi were isolated more frequent in the case compared with controls (30% vs. 4%, P < 0.01), with Cladosporium and Candida species being most common in the case group. CONCLUSIONS: Exposure to mustard gas seems to alter the microbiological flora of the eyelid margin. Staphylococcus spp., including antibiotic-resistant strains, and fungi were more frequently isolated in these patients. The relationship between microbial culture results and the severity of ocular surface manifestations in mustard gas-injured cases warrant further investigation. PMID- 21282999 TI - Central corneal thickness measurements with Fourier-domain optical coherence tomography versus ultrasonic pachymetry and rotating Scheimpflug camera. AB - PURPOSE: To compare the accuracy and repeatability of Fourier-domain optical coherence tomography (FD-OCT) with ultrasonic pachymetry (USP) and a rotating Scheimpflug camera for measuring the central corneal thickness (CCT). METHODS: The CCT was measured in 30 subjects (30 normal corneas) by the same examiner using RTVue-100 FD-OCT with an anterior segment adaptor, Pentacam rotating Scheimpflug camera, and SP-2000 USP. Two examiners obtained one FD-OCT measurement from 10 eyes of 5 subjects to assess interexaminer reproducibility. RESULTS: The mean CCT (+/-SD) measured by FD-OCT, USP, and the Pentacam were 530 +/- 33, 544 +/- 34, and 552 +/- 35 MUm, respectively. Significant correlations were found between FD-OCT and USP (r = 0.97; P < 0.0001), FD-OCT and Pentacam (r = 0.97; P < 0.0001), and USP and Pentacam (r = 0.96; P < 0.0001). Pairwise comparisons showed that the FD-OCT CCT measurement was significantly thinner than those of the other 2 methods (P < 0.001 for all comparisons). Regarding intraexaminer repeatability, the intraclass correlation coefficients ranged between 0.97 and 0.98. There was high repeatability of the CCT measurements with all methods. FD-OCT also had high interexaminer reproducibility (intraclass correlation coefficient = 0.98). CONCLUSIONS: RTVue-100 FD-OCT may be a useful alternative for measuring the CCT; however, it significantly underestimates the CCT compared with the USP and the Pentacam with slight differences. Although highly correlated, the measurements are not directly interchangeable in clinical practice. PMID- 21283000 TI - Soluble triggering receptor expressed on myeloid cells-1 as an infection marker for patients with neutropenic fever. AB - OBJECTIVE: To assess the value of soluble triggering receptor expressed on myeloid cells-1 as a biomarker of infection in patients with neutropenic fever comparing with procalcitonin and C-reactive protein. DESIGN: Prospective, comparative, single-center study. SETTING: Hematology ward at a university hospital. SUBJECTS: Seventy-five patients with neutropenic fever after chemotherapy for their hematologic malignancies. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: A total of 137 episodes of neutropenic fever in 75 patients were classified into 75 episodes of documented infections and 62 low likelihood of infection. The level of soluble triggering receptor expressed on myeloid cells 1 was significantly elevated in the group of documented infection. The area under the receiver operating characteristic curve for the diagnosis of infection was 0.719 (95% confidence interval, 0.632-0.806; p < .0001) for soluble triggering receptor expressed on myeloid cells-1, which was larger than the values of 0.501 for procalcitonin (0.465-0.657; p = .218) and 0.491 for C-reactive protein (0.394 0.589, p = .858). The fitted marginal logistic regression model of all episodes contained two statistically significant predictors of infection: soluble triggering receptor expressed on myeloid cells-1 (per 1-pg/mL increase; odds ratio [OR], 1.0002; 95% CI, 1.0001-1.0003; p < .0001) and procalcitonin (per 1 ng/mL increase; OR, 1.0094; 95% CI, 1.0005-1.0184; p = .0002). In a diagnostic panel with soluble triggering receptor expressed on myeloid cells-1 and procalcitonin, the sensitivity and specificity were 88% and 48%, respectively. CONCLUSIONS: Soluble triggering receptor expressed on myeloid cells-1 is better than procalcitonin in the prediction of infection at the onset of neutropenic fever. By applying soluble triggering receptor expressed on myeloid cells-1 and procalcitonin together, low or high risk for infection can be defined at the onset of neutropenic fever. PMID- 21283001 TI - Diagnostic use of serum procalcitonin levels in pulmonary aspiration syndromes. AB - OBJECTIVE: To assess the predictive accuracy of serum procalcitonin in distinguishing bacterial aspiration pneumonia from aspiration pneumonitis. DESIGN: Prospective observational study. SETTING: Intensive care unit of a university-affiliated hospital. PATIENTS: Sixty-five consecutive patients admitted with pulmonary aspiration and seven control subjects intubated for airway protection. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Quantitative cultures from bronchoalveolar lavage fluid were conducted on all participants at the time of admission. Serial serum procalcitonin levels were measured on day 1 and day 3 using the procalcitonin enzyme-linked fluorescent assay. There were no differences in the median serum concentrations of procalcitonin between patients with positive bronchoalveolar lavage cultures (n = 32) and patients with negative bronchoalveolar lavage cultures (n = 33) on either day 1 or day 3 postadmission. The areas under the receiver operator characteristic curves were 0.59 (95% confidence interval, 0.47-0.72) and 0.63 (95% confidence interval, 0.5-0.75), respectively (p = .74). However, duration of mechanical ventilation and antibiotic therapy were shorter in those who had a decrease in their procalcitonin levels on day 3 from baseline compared with those who did not (6.7 +/- 7.1 days and 11.1 +/- 13.5 days, p = .03; and 8.2 +/- 2.6 days vs. 12.8 +/- 4.6 days; p < .001, respectively). Hospital mortality was associated with radiographic multilobar disease (adjusted odds ratio, 1.14; 95% confidence interval, 1.01-1.31; p = .04) and increasing procalcitonin levels (adjusted odds ratio, 5.63; 95% confidence interval, 1.56-20.29; p = .008). CONCLUSION: Serum procalcitonin levels had poor diagnostic value in separating bacterial aspiration pneumonia from aspiration pneumonitis based on quantitative bronchoalveolar lavage culture. However, serial measurements of serum procalcitonin may be helpful in predicting survival from pulmonary aspiration. PMID- 21283002 TI - Cinnamophilin offers prolonged neuroprotection against gray and white matter damage and improves functional and electrophysiological outcomes after transient focal cerebral ischemia. AB - OBJECTIVE: We have previously shown that cinnamophilin ([8R, 8'S]-4, 4'-dihydroxy 3, 3'-dimethoxy-7-oxo-8, 8'-neolignan) exhibited potent antioxidant, radical scavenging, and anti-inflammatory actions and reduced acute ischemic brain damage, even when it was given up to 6 hrs postinsult. Here, we characterized the long-lasting neuroprotection of cinnamophilin against gray and white matter damage and its beneficial effects on electrophysiological and functional outcomes in a model of stroke. DESIGN: Prospective laboratory animal study. SETTING: Research laboratory in a university teaching hospital. SUBJECTS: Adult male Sprague-Dawley rats (240-290 g). INTERVENTIONS: Under controlled conditions of normoxia, normocarbia, and normothermia, spontaneously breathing, halothane anesthetized (1.0-1.5%) rats were subjected to transient middle cerebral artery occlusion for 90 mins. Cinnamophilin (80 mg/kg) or vehicle was given intravenously at reperfusion onset. MEASUREMENTS AND MAIN RESULTS: Physiological parameters, including arterial blood gases and cortical blood perfusion, somatosensory-evoked potentials, and neurobehavioral outcomes, were serially examined. Animals were euthanized at 7 days or 21 days postinsult. Gray matter and white matter (axonal and myelin) damage were then evaluated by quantitative histopathology and immunohistochemistry against phosphorylated component-H neurofilaments and myelin basic protein, respectively. After the follow-up period of 7 and 21 days, our results showed that cinnamophilin significantly decreased gray matter damage by 31.6% and 34.9% (p < .05, respectively) without notable adverse effects. Additionally, cinnamophilin effectively reduced axonal and myelin damage by 46.3-68.6% (p < .05) and 25.2-28.1% (p < .05), respectively. Furthermore, cinnamophilin not only improved the ipsilateral field potentials (p < .05, respectively), but also reduced the severity of contralateral electrophysiological diaschisis (p < .05). Consequently, cinnamophilin improved sensorimotor outcomes up to 21 days postinsult (p < .05, respectively). CONCLUSIONS: Administration with cinnamophilin provides long-lasting neuroprotection against gray and white matter damage and improves functional and electrophysiological outcomes after ischemic stroke. The results suggest a need for further studies to characterize the potential of cinnamophilin in the field of ischemic stroke. PMID- 21283003 TI - The influence of genetic variation in surfactant protein B on severe lung injury in African American children. AB - OBJECTIVE: To determine whether genetic variations in the gene coding for surfactant protein B are associated with lung injury in African American children with community-acquired pneumonia. DESIGN: A prospective cohort genetic association study of lung injury in children with community-acquired pneumonia. SETTING: Two major tertiary care children's hospitals. SUBJECTS: African American children with community-acquired pneumonia (n = 395) either evaluated in the emergency department or admitted to the hospital. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Three hundred ninety-five African American children (14 days to 18 yrs of age) with community-acquired pneumonia were enrolled. Thirty-seven patients required mechanical ventilation and 26 of these were diagnosed with acute lung injury or acute respiratory distress syndrome. Genotyping was performed on seven linkage disequilibrium-tag single nucleotide polymorphisms in the surfactant protein B gene. Univariate analysis demonstrated two linkage disequilibrium-tag single nucleotide polymorphisms, rs1130866 (also known as SP-B + 1580 C/T) and rs3024793, were associated with the need for mechanical ventilation in African American children (p = .016 and p = .030, respectively). Multivariable analysis indicated that both of these single nucleotide polymorphisms are independently associated with need for mechanical ventilation (p = .040 and p = .012, respectively) as was rs7316 when its interaction with age was considered (p = .015). Multivariable analysis examining acute lung injury demonstrated a significant association of rs7316 with acute lung injury (p = .031). Haplotype analysis was also performed. Two haplotypes, GTGCGCG and ATATAAG, were associated with need for mechanical ventilation using either univariate (p = .041 and p = .043, respectively) or multivariable analysis (odds ratios of 2.62, p = .048, and 3.12, p = .033, respectively). CONCLUSIONS: Genetic variations in the gene coding for surfactant protein B are associated with more severe lung injury as indicated by the association of specific single nucleotide polymorphism genotypes and haplotypes with the need for mechanical ventilation in African American children with community-acquired pneumonia. PMID- 21283004 TI - Qualitative analysis of an intensive care unit family satisfaction survey. AB - OBJECTIVES: To describe the qualitative findings from a family satisfaction survey to identify and describe the themes that characterize family members' intensive care unit experiences. DESIGN: As part of a larger mixed-methods study to determine the relationship between organizational culture and family satisfaction in critical care, family members of eligible patients in intensive care units completed a Family Satisfaction Survey (FS-ICU 24), which included three open-ended questions about strengths and weaknesses of the intensive care unit based on the family members' experiences and perspectives. Responses to these questions were coded and analyzed to identify key themes. SETTING: Surveys were administered in 23 intensive care units from across Canada. PARTICIPANTS: Surveys were completed by family members of patients who were in the intensive care unit for >48 hrs and who had been visited by the family member at least once during their intensive care unit stay. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 1381 surveys were distributed and 880 responses were received. Intensive care unit experiences were found to be variable within and among intensive care units. Six themes emerged as central to respondents' satisfaction: quality of staff, overall quality of medical care, compassion and respect shown to the patient and family, communication with doctors, waiting room, and patient room. Within three themes, positive comments were more common than negative comments: quality of the staff (66% vs. 23%), overall quality of medical care provided (33% vs. 2%), and compassion and respect shown to the patient and family (29% vs. 12%). Within the other three themes, positive comments were less common than negative comments: communication with doctors (18% vs. 20%), waiting room (1% vs. 8%), and patient rooms (0.4% vs. 5%). CONCLUSIONS: The study provided improved understanding of why family members are satisfied or dissatisfied with particular elements of the intensive care unit and this knowledge can be used to modify intensive care units to better meet the physical and emotional needs of the families of intensive care unit patients. PMID- 21283005 TI - Multiparameter Intelligent Monitoring in Intensive Care II: a public-access intensive care unit database. AB - OBJECTIVE: We sought to develop an intensive care unit research database applying automated techniques to aggregate high-resolution diagnostic and therapeutic data from a large, diverse population of adult intensive care unit patients. This freely available database is intended to support epidemiologic research in critical care medicine and serve as a resource to evaluate new clinical decision support and monitoring algorithms. DESIGN: Data collection and retrospective analysis. SETTING: All adult intensive care units (medical intensive care unit, surgical intensive care unit, cardiac care unit, cardiac surgery recovery unit) at a tertiary care hospital. PATIENTS: Adult patients admitted to intensive care units between 2001 and 2007. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The Multiparameter Intelligent Monitoring in Intensive Care II (MIMIC-II) database consists of 25,328 intensive care unit stays. The investigators collected detailed information about intensive care unit patient stays, including laboratory data, therapeutic intervention profiles such as vasoactive medication drip rates and ventilator settings, nursing progress notes, discharge summaries, radiology reports, provider order entry data, International Classification of Diseases, 9th Revision codes, and, for a subset of patients, high-resolution vital sign trends and waveforms. Data were automatically deidentified to comply with Health Insurance Portability and Accountability Act standards and integrated with relational database software to create electronic intensive care unit records for each patient stay. The data were made freely available in February 2010 through the Internet along with a detailed user's guide and an assortment of data processing tools. The overall hospital mortality rate was 11.7%, which varied by critical care unit. The median intensive care unit length of stay was 2.2 days (interquartile range, 1.1-4.4 days). According to the primary International Classification of Diseases, 9th Revision codes, the following disease categories each comprised at least 5% of the case records: diseases of the circulatory system (39.1%); trauma (10.2%); diseases of the digestive system (9.7%); pulmonary diseases (9.0%); infectious diseases (7.0%); and neoplasms (6.8%). CONCLUSIONS: MIMIC-II documents a diverse and very large population of intensive care unit patient stays and contains comprehensive and detailed clinical data, including physiological waveforms and minute-by-minute trends for a subset of records. It establishes a new public-access resource for critical care research, supporting a diverse range of analytic studies spanning epidemiology, clinical decision-rule development, and electronic tool development. PMID- 21283006 TI - Comparing clinician ratings of the quality of palliative care in the intensive care unit. AB - OBJECTIVE: There are numerous challenges to successfully integrating palliative care in the intensive care unit. Our primary goal was to describe and compare the quality of palliative care delivered in an intensive care unit as rated by physicians and nurses working in that intensive care unit. DESIGN: Multisite study using self-report questionnaires. SETTING: Thirteen hospitals throughout the United States. PARTICIPANTS: Convenience sample of 188 physicians working in critical care (attending physicians, critical care fellows, resident physicians) and 289 critical care nurses. MEASUREMENTS AND MAIN RESULTS: Clinicians provided overall ratings of the care delivered by either nurses or physicians in their intensive care unit for each of seven domains of intensive care unit palliative care using a 0-10 scale (0 indicating the worst possible and 10 indicating the best possible care). Analyses included descriptive statistics to characterize measurement characteristics of the ten items, paired Wilcoxon tests comparing item ratings for the domain of symptom management with all other item ratings, and regression analyses assessing differences in ratings within and between clinical disciplines. We used p < .001 to denote statistical significance to address multiple comparisons. The ten items demonstrated good content validity with few missing responses or ceiling or floor effects. Items receiving the lowest ratings assessed spiritual support for families, emotional support for intensive care unit clinicians, and palliative-care education for intensive care unit clinicians. All but two items were rated significantly lower than the item assessing symptom management (p < .001). Nurses rated nursing care significantly higher (p < .001) than physicians rated physician care in five domains. In addition, although nurses and physicians gave comparable ratings to palliative care delivered by nurses, nurses' and physicians' ratings of physician care were significantly different with nurse ratings of this care lower than physician ratings on all but one domain. CONCLUSION: Our study supports the content validity of the ten overall rating items and supports the need for improvement in several aspects of palliative care, including spiritual support for families, emotional support for clinicians, and clinician education about palliative care in the intensive care unit. Furthermore, our findings provide some preliminary support for surveying intensive care unit clinicians as one way to assess the quality of palliative care in the intensive care unit. PMID- 21283007 TI - Beneficial association of beta-blocker therapy on recovery from severe acute heart failure treatment: data from the Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support trial. AB - OBJECTIVES: Beta-blocker therapy is recommended for most patients with chronic heart failure, although such therapy may be discontinued or reduced during hospitalizations. The aim is to determine whether beta-blocker use at study entry and/or at discharge has an impact on 31- and 180-day survival. DESIGN: Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support study was designed as a randomized, double-blind, active-controlled, multi-center study. SETTING: Multinational. PATIENTS: A total of 1,327 critically ill patients hospitalized with low-output heart failure in need of inotropic therapy. INTERVENTION: Levosimendan versus dobutamine. MEASUREMENTS: All-cause mortality at 31 and 180 days in patients who survived initial hospitalization with/without beta-blocker use at entry and/or at discharge. RESULTS: Patients on beta-blockers at entry and at discharge had significantly lower 31-day (p < .0001) and 180-day (p < .0001) mortality compared to patients without beta-blockers use at both time points. The association was robust when adjusted for age and co-morbidities (p = .006 at 31 days; p = .003 at 180 days). CONCLUSIONS: Those results strongly suggest, in severe acutely decompensated heart failure patients, admitted on beta blockers, to continue on them at discharge. PMID- 21283008 TI - The role of intestinal colonization with gram-negative bacteria as a source for intensive care unit-acquired bacteremia. AB - OBJECTIVE: Selective digestive tract decontamination aims to eradicate gram negative bacteria in both the intestinal tract and respiratory tract and is combined with a 4-day course of intravenous cefotaxime. Selective oropharyngeal decontamination only aims to eradicate respiratory tract colonization. In a recent study, selective digestive tract decontamination and selective oropharyngeal decontamination were associated with lower day-28 mortality, when compared to standard care. Furthermore, selective digestive tract decontamination was associated with a lower incidence of intensive care unit-acquired bacteremia caused by gram-negative bacteria. We quantified the role of intestinal tract carriage with gram-negative bacteria and intensive care unit-acquired gram negative bacteremia. DESIGN: Data from a cluster-randomized and a single-center observational study. SETTING: Intensive care unit in The Netherlands. PATIENTS: Patients with intensive care unit stay of >48 hrs that received selective digestive tract decontamination (n = 2,667), selective oropharyngeal decontamination (n = 2,166) or standard care (n = 1,945). INTERVENTIONS: Selective digestive tract decontamination or selective oropharyngeal decontamination. MEASUREMENTS AND MAIN RESULTS: Incidence densities (episodes/1000 days) of intensive care unit-acquired gram-negative bacteremia were 4.5, 3.0, and 1.4 during standard care, selective oropharyngeal decontamination, and selective digestive tract decontamination, respectively, and the daily risk for developing intensive care unit-acquired gram-negative bacteria bacteremia increased until days 36, 33, and 31 for selective digestive tract decontamination, standard care, and selective oropharyngeal decontamination and was always lowest during selective digestive tract decontamination. Rectal colonization with gram-negative bacteria was present in 26% and 71% of patient days during selective digestive tract decontamination and selective oropharyngeal decontamination, respectively (p < .01). Irrespective of interventions, incidence densities of intensive care unit-acquired gram-negative bacteremia was 4.5 during patient days with both intestinal and respiratory tract gram-negative bacteria carriage. These incidence densities reduced with 33% (to 3.1) during days with intestinal gram-negative bacteria carriage only and with another 45% (to 1.0) during days without gram-negative bacteria carriage at both sites. CONCLUSIONS: Respiratory tract decolonization was associated with a 33% and intestinal tract decolonization was associated with a 45% reduction in the occurrence of intensive care unit-acquired gram-negative bacteremia. PMID- 21283010 TI - Sex of the first-born and risk of preterm birth in the subsequent pregnancy. AB - BACKGROUND: Recent data suggest that the chance of successfully maintaining a pregnancy may be influenced by the sex of previously born children. We explored a possible relation between sex of the first-born infant and the risk of preterm birth in the second pregnancy. METHODS: Using data from the National Medical Birth Registries in Denmark 1980-2004 and Sweden 1980-2001, we selected all women whose first and second births were singleton and who had information on sex of first-born infant and gestational age for the second (Denmark, n = 393,686; Sweden, n = 603,282). Cox proportional hazards regression analysis was used to estimate the hazard ratio of preterm birth in the second pregnancy according to the sex of the first-born infant. RESULTS: Compared with women whose first baby was a girl, women with boys had an increased risk of preterm birth in a second pregnancy (hazard ratio = 1.10 [95% confidence interval = 1.07-1.13]). This result was consistent in the 2 populations. The association was not confounded by maternal age, interpregnancy interval, or sex of the second infant or by maternal characteristics that do not vary from one pregnancy to the next. CONCLUSIONS: Exposure to a male fetus may increase a woman's risk of preterm delivery in the next pregnancy. While the findings have no direct public health relevance, they may suggest new pathways by which preterm birth can occur. PMID- 21283011 TI - A grand challenge: providing benefits of clinical genetics to those in need. AB - Genetic research, techniques, and knowledge have rapidly expanded in the last two decades with the completion of the Human Genome Project and other major advances in discovery research and diagnostic technologies. Although these developments have obvious potential, they also raise significant challenges related to programs for the actual delivery of useful genetic testing and services. This challenge is particularly acute in rural and remote areas, where lack of access to genetic services is pervasive resulting in significant inequities in access and availability of services. Huntington disease, the classic example of an adult onset hereditary disorder, is used to illustrate this concern and highlight the imperative of exploring novel mechanisms to improve access to effective genetic services. The components of an effective and practical solution strategy are outlined, including the development of innovative delivery systems such as telemedicine, web-based education tools, and cost-reduction mechanisms. A proactive approach is essential to ensure the potential benefits, and availability of clinical genetics is realized by those in need rather than just those in reach. PMID- 21283009 TI - Use of risk reclassification with multiple biomarkers improves mortality prediction in acute lung injury. AB - OBJECTIVE: Multiple single biomarkers have been associated with poor outcomes in acute lung injury; however, no single biomarker has sufficient discriminating power to clearly indicate prognosis. Using both derivation and replication cohorts, we tested novel risk reclassification methods to determine whether measurement of multiple plasma biomarkers at the time of acute lung injury diagnosis would improve mortality prediction in acute lung injury. DESIGN: Analysis of plasma biomarker levels and prospectively collected clinical data from patients enrolled in two randomized controlled trials of ventilator therapy for acute lung injury. SETTING: Intensive care units of university hospitals participating in the National Institutes of Health Acute Respiratory Distress Syndrome Network. PATIENTS: Subjects enrolled in a trial of lower tidal volume ventilation (derivation cohort) and subjects enrolled in a trial of higher vs. lower positive end-expiratory pressure (replication cohort). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The plasma biomarkers were intercellular adhesion molecule-1, von Willebrand factor, interleukin-8, soluble tumor necrosis factor receptor-1, and surfactant protein-D. In the derivation cohort (n = 547), adding data on these biomarkers to clinical predictors (Acute Physiology and Chronic Health Evaluation III score) at the time of study enrollment improved the accuracy of risk prediction, as reflected by a net reclassification improvement of 22% (95% confidence interval 13% to 32%; p < .001). In the replication cohort (n = 500), the net reclassification improvement was 17% (95% confidence interval 7% to 26%; p < .001). A reduced set of three biomarkers (interleukin-8, soluble tumor necrosis factor receptor-1, and surfactant protein-D) had nearly equivalent prognostic value in both cohorts. CONCLUSIONS: When combined with clinical data, plasma biomarkers measured at the onset of acute lung injury can improve the accuracy of risk prediction. Combining three or more biomarkers may be useful for selecting a high-risk acute lung injury population for enrollment in clinical trials of novel therapies. PMID- 21283012 TI - Genetics and genomics education: the next generation. PMID- 21283013 TI - Viral suppression rates in salvage treatment with raltegravir improved with the administration of genotypic partially active or inactive nucleoside/tide reverse transcriptase inhibitors. AB - BACKGROUND: Nucleoside reverse transcriptase inhibitors (NRTIs) are often administered in salvage therapy even if genotypic resistance tests (GRTs) indicate high-level resistance, but little is known about the benefit of these additional NRTIs. METHODS: The effect of <2 compared with 2 NRTIs on viral suppression (HIV-1 RNA < 50 copies/mL) at week 24 was studied in salvage patients receiving raltegravir. Intent-to-treat and per-protocol analyses were performed; last observation carried forward imputation was used to deal with missing information. Logistic regressions were weighted to create a pseudopopulation in which the probability of receiving <2 and 2 NRTIs was unrelated to baseline factors predicting treatment response. RESULTS: One-hundred thirty patients were included, of whom 58.5% (n = 76) received <2 NRTIs. NRTIs were often replaced by other drug classes. Patients with 2 NRTIs received less additional drug classes compared with patients with <2 NRTIs [median (IQR): 1 (1-2) compared with 2 (1 2), P Wilcoxon < 0.001]. The activity of non-NRTI treatment components was lower in the 2 NRTIs group compared with the <2 NRTIs group [median (IQR) genotypic sensitivity score: 2 (1.5-2.5) compared with 2.5 (2-3), P Wilcoxon < 0.001]. The administration of <2 NRTIs was associated with a worse viral suppression rate at week 24. The odds ratios were 0.34 (95% confidence interval: 0.13 to 0.89, P = 0.027) and 0.19 (95% confidence interval: 0.05 to 0.79, P = 0.023) when performing the last observation carried forward and the per-protocol approach, respectively. CONCLUSIONS: Our findings showed that partially active or inactive NRTIs contribute to treatment response, and thus the use of 2 NRTIs in salvage regimens that include raltegravir seems warranted. PMID- 21283014 TI - HLA alleles are associated with altered risk for disease progression and central nervous system impairment of HIV-infected children. AB - OBJECTIVE: To examine the effects of human leukocyte antigen (HLA) alleles on HIV 1-related disease progression and central nervous system (CNS) impairment in children. DESIGN: Five hundred seventy-two HIV-1-infected children, identified as disease progressors or nonprogressors, were selected from PACTG P152 and P300 through a case-cohort sampling scheme. Study endpoints were HIV-1-related disease progression-free survival and time to CNS impairment. METHODS: DNA was genotyped for HLA alleles using a Luminex 100 platform. Weighted Kaplan-Meier methods, and Cox proportional hazards models were used to assess the effects of HLA alleles on study endpoints. RESULTS: Presence of the B-27 allele (n = 20) was associated with complete protection against disease progression and CNS impairment over the median follow-up of 26 months (P < 0.0001 for both). These findings held in multivariate analyses controlling for baseline covariates including race, gender, age, log HIV-1 RNA, CD4 lymphocyte count and percent, weight for age z score and treatment, and for other genotypes shown to affect HIV-1-related disease progression. Also, although the Cw-2 allele protected against disease progression [Hazard ratio (HR), 0.48; 95% confidence interval (CI): 0.28 to 0.81; P = 0.006], the A-24 allele was associated with more rapid CNS impairment (HR: 2.01; 95% CI: 1.04 to 3.88; P = 0.04). The HLA class II DQB1-2 allele was associated with a delayed disease progression (HR: 0.66; 95% CI: 0.47-0.92; P = 0.01) and CNS impairment (HR: 0.58; 95% CI: 0.36 to 0.93; P = 0.02). CONCLUSIONS: Presence of B 27, Cw-2, or DQB1-2 alleles was associated with delayed HIV-1 disease progression, while B-27, A-24, and DQB1-2 alleles were associated with altered progression to CNS impairment in children. PMID- 21283016 TI - Correlation between circulating HIV-1 RNA and broad HIV-1 neutralizing antibody activity. AB - OBJECTIVE: To examine the relationship between HIV-1 antigenic load (plasma RNA copies/mL) and broad HIV-1 neutralizing antibody activity. METHODS: Plasma from 120 HIV-1-infected patients, including HIV-1 natural viral suppressors (similar to elite controllers), was tested for neutralization against 15 Tier 1/Tier 2 HIV 1 pseudoviruses. Broad HIV-1 neutralizing antibody activity was confirmed with immunoglobulin G and heterlogous clade testing (18 pseudoviruses from Clades A, C, and CRF02_AG). Statistical analysis was performed to determine factors associated with broad HIV-1 neutralizing antibody activity. RESULTS: Ten individuals with broad HIV-1 neutralizing antibody activity were identified. These individuals had a median CD4 count of 589 cells per microliter (range 202 927), 1611 HIV-1 RNA copies per milliliter (range 110-8964), and 13 years since HIV diagnosis (range 1-22). There was a significant correlation between the presence of broadly neutralizing antibodies in those with HIV-1 RNA between 100 and 10,000 copies per milliliter compared with those <100 or >10,000 copies per milliliter (P = 0.0003 and 0.0245, respectively). Individuals with HIV-1 RNA 100 10,000 copies per milliliter had a higher number of Tier 2 viruses neutralized compared with the <100 or >10,000 copies per milliliter groups (P <= 0.0001 and P = 0.076, respectively). Male sex was associated with broad HIV-1 neutralizing antibody activity (P = 0.016). CONCLUSIONS: These results indicate that low but persistent HIV antigen expression correlates with broad HIV-1 neutralizing antibody activity. At higher levels of plasma viremia, neutralization titers were diminished. Conversely, at lower levels, there seems to be insufficient antigen stimulation to maintain high neutralization titers. These findings may have important implications in furthering the understanding of the humoral response to HIV infection. PMID- 21283017 TI - Atazanavir pharmacokinetics with and without tenofovir during pregnancy. AB - BACKGROUND: Few data are available describing atazanavir exposure during pregnancy, especially when used in combination with tenofovir, whose coadministration with atazanavir results in decreased atazanavir exposure. DESIGN: International Maternal Pediatric Adolescent AIDS Clinical Trials 1026 s is an ongoing, prospective, nonblinded study of antiretroviral pharmacokinetics in HIV-infected pregnant women that included 2 cohorts receiving atazanavir/ritonavir 300 mg/100 mg once daily, either with or without tenofovir. METHODS: Intensive steady-state 24-hour pharmacokinetic profiles were performed during the third trimester and at 6-12 weeks postpartum. Atazanavir was measured by reverse-phase high-performance liquid chromatography (detection limit 0.047 mcg/mL). Pharmacokinetic targets were the estimated 10th percentile atazanavir area under the concentration versus time curve [(AUC): 29.4 mcg . hr . mL-1] in nonpregnant historical controls (mean AUC = 57 mcg . hr . mL-1) and a trough concentration of 0.15 mcg/mL, the concentration target used in therapeutic drug monitoring programs. RESULTS: Median atazanavir AUC was reduced during the third trimester compared with postpartum for subjects not receiving tenofovir (41.9 vs. 57.9 mcg . hr . mL-1, P = 0.02) and for subjects receiving tenofovir (28.8 vs. 39.6 mcg . hr . mL-1, P = 0.04). During the third trimester, AUC was below the target in 33% (6 of 18) of women not receiving tenofovir and 55% (11 of 20) of women receiving tenofovir. Trough concentration was below the target in 6% (1 of 18) of women not receiving tenofovir and 15% (3 of 20) of women receiving tenofovir. The median (range) ratio of cord blood/maternal atazanavir concentration in 29-paired samples was 0.18 (0-0.45). CONCLUSIONS: Atazanavir exposure is reduced by pregnancy and by concomitant tenofovir use. A dose increase of atazanavir/ritonavir to 400 mg/100 mg may be necessary in pregnant women to ensure atazanavir exposure equivalent to that seen in nonpregnant adults. PMID- 21283018 TI - Pranlukast attenuates hydrogen peroxide-induced necrosis in endothelial cells by inhibiting oxygen reactive species-mediated collapse of mitochondrial membrane potential. AB - OBJECTIVE: Recently, we reported that pranlukast, an antagonist of cysteinyl leukotriene receptor 1, attenuates ischemic injury in endothelial cells by decreasing reactive oxygen species (ROS) production and inhibiting nuclear factor kappaB activation in a leukotriene-independent manner. In this study, we investigated the effect of pranlukast on oxidative stress injury induced by hydrogen peroxide (H2O2) in EA.hy926 cells, a human endothelial cell line, and the possible mechanisms. METHODS AND RESULTS: We found that H2O2 reduced cell viability and increased lactate dehydrogenase release in a concentration- and time-dependent manner. Necrosis was the main death mode, and the necrotic rate increased 32% after exposure to 220 MUM H2O2 for 4 hours. Pretreatment with pranlukast significantly ameliorated the reduced viability and the increased lactate dehydrogenase release and necrosis after exposure to H2O2. We next examined the mechanisms underlying the antinecrotic effects of pranlukast. The results showed that pranlukast attenuated excessive ROS production and ameliorated the reduced superoxide dismuase and glutathione peroxidase activity in EA.hy926 cells exposed to H2O2. Pranlukast also inhibited the collapse of mitochondrial membrane potential (MMP) induced by H2O2. Inhibition of ROS production by N-acetyl-l-cysteine, a powerful antioxidant, reduced MMP collapse and necrosis. Inhibition of MMP collapse by cyclosporine A, a mitochondrial permeability transition inhibitor, attenuated necrosis but failed to reduce ROS production. In addition, we found no expression of 5-lipoxygenase in EA.hy926 cells and zileuton, a 5-lipoxygenase inhibitor, did not affect the cellular injury induced by H2O2. CONCLUSION: Pranlukast protects endothelial cells from H2O2-induced necrosis by inhibiting ROS-mediated collapse of mitochondrial membrane potential, and this is leukotriene-independent. PMID- 21283019 TI - Cardiovascular changes during maturation and ageing in male and female spontaneously hypertensive rats. AB - BACKGROUND: Cardiovascular remodeling leading to heart failure is common in the elderly. Testing effective pharmacological treatment of human heart failure requires a suitable animal model that adequately mimics the human disease state. METHODS: This study has characterized the structural, functional, and electrical characteristics of the cardiovascular system throughout the lifespan in male and female spontaneously hypertensive rats (SHRs), a genetic model of chronic hypertension-induced cardiovascular remodeling, and age- and gender-matched normotensive controls, to determine whether ageing SHRs mimic the changes seen in ageing humans. RESULTS: Both the ageing male and female SHRs developed progressive hypertension, ventricular hypertrophy, left ventricular fibrosis, action potential prolongation without impaired glucose tolerance. Male SHRs from 15 months of age exhibited left ventricular wall thinning and chamber dilation, together with systolic and diastolic dysfunction and increased cardiac stiffness and increased erythrocyte superoxide production, which were not present in the female SHRs. CONCLUSION: Ageing male SHRs in contrast to the female SHRs, better mimic the chronic heart failure in humans produced by chronic hypertension. Ageing male SHRs could then be used to investigate proposed therapeutic interventions for chronic congestive heart failure in humans. PMID- 21283020 TI - Comparison of the in vivo hemodynamic effects of the antiarrhythmic agents vernakalant and flecainide in a rat hindlimb perfusion model. AB - A series of in vivo experiments were conducted to compare the hemodynamic actions of vernakalant (a novel, relatively atrial selective, antiarrhythmic drug) to flecainide after infusion into the peripheral vasculature. Anesthetized rats were surgically prepared to have an extracorporeal perfusion circuit whereby blood in the abdominal aorta (distal to the renal arteries) was diverted to a constant flow pump and returned to the abdominal aorta at the same level allowing measurement of hindlimb vascular resistance. The effects of cumulative, ascending doses of intravenous vernakalant and flecainide on vascular resistance, after arterial pressures, and heart rate were measured. Blood samples were drawn following each dose to determine drug plasma concentrations. Vernakalant had no significant vasomotor effects on peripheral or systemic vasculature. In contrast, flecainide decreased peripheral vascular resistance (15% at 0.8 MUg/mL) and systemic pressures (32% mean arterial pressure at 0.8 MUg/mL) in a dose-dependent manner. At therapeutic plasma concentrations, vernakalant (1 MUg/mL) had little effect on heart rate (-24 beats/min) or QRS intervals (+3.4 msec), whereas flecainide (0.8 MUg/mL) significantly decreased heart rate (55 beats/min) and increased QRS intervals (9.9 msec). In conclusion, vernakalant did not have negative hemodynamic effects at therapeutic plasma concentrations in a rat hindlimb perfusion model. PMID- 21283021 TI - Reduced antiarrhythmic efficacy of verapamil in isolated rat hearts in the presence of elevated extracellular calcium. AB - An isolated heart method that has been proposed to aid in ascertaining the involvement of L-type calcium channel blockade in the mechanism of action of novel antiarrhythmic drugs involves increasing the calcium concentration in the perfusion buffer. The purpose of this study was to determine the validity of this method using an established L-type calcium channel blocker, verapamil. Isolated rat hearts were perfused with normal calcium (1.4 mM) Krebs solution containing drug vehicle only, a normal calcium solution containing verapamil (300 nM), or a high calcium (2.8 mM) solution containing verapamil. The occurrence of ventricular fibrillation during a subsequent period of regional myocardial ischemia was monitored. The incidence of ventricular fibrillation was significantly reduced from 80% in controls to 20% by perfusion with verapamil in normal calcium Krebs solution (P < 0.05). Perfusion with the high calcium solution increased the incidence of ventricular fibrillation in the presence of verapamil to 40% (P > 0.05 versus controls). We conclude that the antiarrhythmic effect of verapamil in isolated hearts can be attenuated by increasing the calcium content of the perfusion solution, but a twofold increase in the calcium concentration failed to fully restore susceptibility to ventricular fibrillation to that observed in verapamil-free controls. PMID- 21283022 TI - Hydrogen sulfide: a novel signaling molecule in the vascular system. AB - Hydrogen sulfide (H2S) is an endogenous gasotransmitter produced in mammalian cells. It is responsible for physiological functions in many organs and systems, with attention focused mainly on the cardiovascular and nervous systems. In the vascular system, H2S produces biphasic effects in regulation of vascular tone. At lower concentrations, it induces vasoconstriction predominantly via decreasing cyclic adenosine monophosphate in smooth muscle cell and inhibiting the production and bioavailability of nitric oxide. At higher concentrations, it produces vasorelaxation mainly through opening of KATP channels and induction of intracellular acidification. Scavenging reactive oxygen species and elevation of cyclic guanosine monophosphate are also implicated in the vasorelaxant response. This review presents an overview of the current knowledge of H2S in the vascular system, with special emphasis and discussion on the involvement of various signaling pathways and ion channels based on current understanding and reported literature till date. PMID- 21283023 TI - Mitochondrial uncoupling agents trigger ventricular fibrillation in isolated rat hearts. AB - Sudden cardiac death resulting from ventricular fibrillation (VF) remains a major cause of mortality. The purpose of this study was to investigate the roles of loss of oxidative phosphorylation and activation of the mitochondrial ATP sensitive K+ channel and permeability transition pore in VF development during myocardial ischemia by using mitochondrial uncoupling agents (carbonyl cyanide m chlorophenylhydrazone and 2,4-dinitrophenol) and channel blockers (5 hydroxydecanoate and cyclosporine A) at concentrations that have been demonstrated to block the intended targets selectively. Isolated rat hearts (n = 8 per group) were perfused with 0.3 MUM carbonyl cyanide m-chlorophenylhydrazone, 100 MUM 2,4-dinitrophenol, 0.2 MUM cyclosporine A, 100 MUM 5-hydroxydecanoate, or vehicle solution and regional ischemia induced after 10 minutes. Carbonyl cyanide m-chlorophenylhydrazone and 2,4 dinitrophenol caused profound QT shortening and triggered VF in 100% of hearts before ischemia. During ischemia, neither cyclosporine A (88%) nor 5-hydroxydecanoate (100%) reduced VF incidence compared with control (100% VF). In separate hearts, carbonyl cyanide m chlorophenylhydrazone decreased tissue ATP content, and glibenclamide or glimepiride delayed the QT shortening and onset of VF triggered by carbonyl cyanide m-chlorophenylhydrazone. In conclusion, mitochondrial uncoupling agents trigger VF, likely as a result of ATP depletion with subsequent activation of sarcolemmal ATP-sensitive K+ currents. The mechanism of VF in ischemia does not involve activation of the mitochondrial ATP-sensitive K+ channel or permeability transition pore. PMID- 21283024 TI - Nebivolol: an endothelium-friendly selective beta1-adrenoceptor blocker. AB - Nebivolol is a highly selective beta1-adrenoceptor blocker, which also stimulates endothelial nitric oxide synthase and scavenges reactive oxygen species (ROS). These characteristics endow nebivolol, compared with conventional beta-blockers, with a favorable hemodynamic profile for the treatment of hypertension, chronic heart failure, and possibly other cardiovascular diseases. Nebivolol is a racemic mixture of d- and l-isomers. Its beta1-antagonistic properties reside primarily with d-nebivolol although both isomers are capable of increasing the release of NO from the endothelium after binding to beta2- or beta3-adrenergic receptors. The latter action results in vasodilatation and reduced vascular resistance. Nebivolol also scavenges ROS in a receptor-independent manner by direct interaction with free radicals. By scavenging ROS nebivolol not only reduces oxidant stress but also augments NO bioavailability. The endothelial nitric oxide synthase -stimulating and ROS scavenging effects of nebivolol act synergistically to provide cardiovascular protection in addition to its beta1-antagonistic action. PMID- 21283025 TI - Challenges in posthospital care: nurses as coaches for medication management. AB - The purpose of this study was to evaluate a transitional care intervention posthospital discharge for chronically ill medical patients managing complex medication regimens. This descriptive pilot study tested 2 interventions: telephone follow-up and a home visit. Registered nurses delivered the interventions with consulting pharmacist support. Findings included 62% more medication discrepancies discovered during home visit than detected by telephone interview. This brief intervention identified significant knowledge gaps in self management of discharge medications in the inner city population. PMID- 21283026 TI - Extraocular muscle enlargement as a paraneoplastic effect of breast carcinoma in a male patient. AB - The authors report a rare case of a male patient who was diagnosed with breast cancer following investigations for proptosis secondary to extraocular muscle enlargement. A 65-year-old man presented with complaints of double vision and proptosis. CT scan of the orbits showed bilateral superior rectus muscle enlargement. On further investigation, the patient was detected to have a right breast mass. Biopsy of the mass showed an intermediate-grade carcinoma in situ. The patient underwent a right radical mastectomy following which his proptosis and symptoms of double vision resolved. Repeat MRI scans showed reduction in the size of the superior rectus muscle after mastectomy. Extraocular muscle enlargement has not been previously identified as a paraneoplastic effect of breast carcinoma in a male patient. Extraocular muscle enlargement can be a presenting feature of malignancies, and an appropriate systemic workup for the occult primary when all other preliminary tests are negative should be considered. PMID- 21283027 TI - Consecutive conjunctivodacryocystorhinostomy instrumentation. PMID- 21283029 TI - Dedifferentiated adenoid cystic carcinoma of the lacrimal gland. AB - A rare variant of adenoid cystic carcinoma is the dedifferentiated sarcomatoid form, which has previously been reported in the hard and soft palate, maxillary sinus, submandibular glands, and nasal cavity. The authors report the first case of a dedifferentiated sarcomatoid adenoid cystic carcinoma occurring in the lacrimal gland, that of a 52-year-old man. The patient presented with a 4-month history of diplopia, decreased vision, and right upper eyelid swelling. Radiographic imaging showed a soft tissue mass in the extraconal compartment superolateral to the right eye. The patient subsequently underwent surgical debulking. Histologic examination of the tissue revealed classic cribiform adenoid cystic carcinoma and a sarcomatous component consisting of malignant spindle cells and fusiform cells arranged in whorls. Dedifferentiation is a well established phenomenon in salivary gland tumors that is associated with aggressive behavior and poor prognosis; however, the exact nature of such dedifferentiated neoplasms remains unclear. PMID- 21283030 TI - Cicatricial entropion following docetaxel (Taxotere) therapy. AB - We report eyelid margin changes in 3 patients after docetaxel treatment for breast cancer. These patients were referred to Cincinnati Eye Institute for eyelash abnormalities and/or epiphora and all had been treated with docetaxel in the near past. The ophthalmic complaints started soon after chemotherapy. All 3 cases showed varying degrees of palpebral mucosal inflammation and cicatricial changes leading to marginal entropion. The first patient exhibited very prominent eyelid margin inflammation and diffuse trichiasis without madarosis. The second patient had extensive madarosis and abnormally curved, thin eyelashes with punctal and canalicular obstruction. Her marginal entropion was most prominent at the medial lower eyelids. The last patient showed significant lash misdirection in a scattered distribution and patchy madarosis along with pseudomembranes blocking the puncta. All of these eyelid abnormalities occurred soon after docetaxel treatment for advanced breast cancer. Such changes in the absence of questioning for previous docetaxel use in history taking. PMID- 21283031 TI - Treatment of a lacrimal pneumocele with punctal plug insertion. AB - A 37-year-old man presented with symptoms of air and mucus reflux from the right medial canthus on blowing his nose. Examination showed crepitus in the region overlying the right lacrimal sac, and he was able to produce bubbles in his conjunctival lake on instillation of topical 2% fluorescein. Dacryoscintigraphy showed symmetrical slow passage of tracer from the lacrimal sac in the nasolacrimal duct indicating delay at the postsac level. Dacryocystography showed that the right lacrimal system contained round filling defects, suggesting the presence of soft tissue tumors. However, a CT scan showed an enlarged right lacrimal fossa with air in the nasolacrimal duct and no evidence of a mass. Following lower punctal plug occlusive canaliculoplasty on the right, using a preloaded silicone plug, the patient noted an immediate resolution of reflux symptoms. PMID- 21283033 TI - Outcome following surgery for contact lens-induced ptosis. AB - PURPOSE: To assess the outcome of surgery in patients with a history of contact lens wear. DESIGN: Retrospective, comparative interventional case series. METHODS: A total of 419 patients underwent ptosis surgery during a 1-year period (2005-2006) at Moorfields Eye Hospital. Those included in this study had a diagnosis of aponeurotic ptosis and history of contact lens wear. MAIN OUTCOME MEASURES: The outcome was considered a success if the following criteria were met: 1) a margin reflex distance of between 3 and 5 mm, 2) an interlid difference of 1 mm or less, and 3) absence of redo surgery. RESULTS: Thirty patients (7.2%) were identified with a history of contact lens wear and were matched against a control group of 46 patients. The mean margin-reflex distance at presentation was 0.5 +/- 2.4 mm. This equated to a ptosis graded as mild (>=1.5 mm) for 32% of patients, moderate (0.5-1.0 mm) for 29%, and severe (<=0.0 mm) for 39%, with similar proportions in the control group (36% mild, 39% moderate, and 25% severe). The power of the refractive correction (p < 0.005) and the age of the patient (p < 0.05) were directly related to increased severity of ptosis at presentation. The surgical outcome of the ptosis correction was successful in 72% of patients, which was significantly lower than in the control group (89%) (p < 0.005). CONCLUSIONS: The severity of contact lens-related ptosis was related to the degree of myopia and the age of the patient but not to the duration of contact lens wear. There was a higher level of failure and requirement for redo surgery in patients with contact lens-related ptosis compared with matched controls. PMID- 21283032 TI - Propranolol for the treatment of orbital infantile hemangiomas. AB - PURPOSE: To evaluate the treatment of orbital infantile hemangiomas with systemic (oral) propranolol. METHODS: This study was a retrospective observational case series of 5 infants who were diagnosed with orbital infantile hemangiomas between March and July of 2009. RESULTS: The average age at presentation was 3.1 months (3 weeks to 9 months). The patients received oral propranolol, with dosage varying among study centers. The patients were treated for an average of 7.1 months. Treatment of 5 infantile hemangioma patients with oral propranolol produced a significant reduction in the size of the hemangioma in 4 (80%) of the patients and a minimal improvement in one patient. No patient had significant adverse events during the treatment period. CONCLUSION: Oral propranolol may be an effective treatment for orbital infantile hemangiomas. PMID- 21283034 TI - A rare case of progressive ptosis caused by lacrimal gland oncocytoma. AB - The authors present a case of a healthy 61-year-old woman who presented with a 4 year history of progressive right upper eyelid ptosis. Excisional biopsy revealed malignant oncocytoma, an exceedingly rare tumor of the lacrimal gland. PMID- 21283035 TI - Nonablative 4-MHz dual radiofrequency wand rejuvenation treatment for periorbital rhytides and midface laxity. AB - PURPOSE: To evaluate the wrinkle-reducing effects of 4-MHz radiofrequency (RF) energy applied to human periorbital, frontal, and midface facial skin using clinical wrinkle grading, patient self-satisfaction survey, and limited histologic studies. METHODS: Thirty-two patients, ranging from 29 to 71 years of age with skin types varying from class I to class III using the Fitzpatrick Wrinkle Classification system, underwent 8 weekly treatment sessions of nonablative RF therapy on the periorbital, frontal, and midface regions and were subjected to follow up for 6 months after treatment. Pretreatment and post treatment evaluations were compared. Two female subjects gave informed consent for RF treatment for the right upper eyelid and no treatment for left upper eyelid. Specimens from both upper eyelids then underwent histologic examination using light and transmission electron microscopy. RESULTS: Pre- and post-RF treatment evaluation by 3 independent observers using the Fitzpatrick wrinkle classification system showed progressive improvements in wrinkle score at 1-, 3-, and 6-month intervals (p < 0.01). Self-evaluation of 32 patients using a 9-point rating scale after application of RF treatment also showed improving satisfaction (p < 0.01). The most commonly noted adverse reaction was transient erythema (62.5%) lasting from a few hours to a day. Transmission electron microscopy (25,000*) showed scattered diffuse changes in collagen fibril architecture with a shift from smaller-diameter collagen fibers in the untreated samples to larger diameter fibers in the treated samples and a loss of distinct fibril borders. CONCLUSIONS: Four-megahertz dual RF wand delivery rejuvenation treatment produces a reduction in periorbital and midface rhytides. PMID- 21283036 TI - Three-dimensional analysis of the vestibular end organs in relation to the stapes footplate and piston placement. AB - OBJECTIVE: Measurements of the proximity of the membranous labyrinth to the stapes footplate show considerable variation. Largely, such measurements have been from histologic sections of fixed temporal bones, which may be affected by shrinkage artifact and perspective distortion in the 2-dimensional plane. To overcome these problems, the present study undertook an analysis of the 3 dimensional (3D) architecture of the relationship of the stapes to the membranous labyrinth using high-resolution X-ray micro-computed tomography. METHODS: Eleven temporal bones were fixed with Karnovsky's fixative (known to minimize shrinkage), soaked in 2% osmium tetroxide, and scanned in a micro-computed tomography scanner. The otic capsule was intact to exclude sectioning artifact, and no alcohol was used to avoid tissue shrinkage. Measurements were taken in a vertical plane to provide distances from the utricle and saccule to the footplate, and 3D reconstruction of the spatial relationship of these structures was carried out. The relationship of these structures to a stapes piston also was studied. RESULTS: The safest area of piston placement was the central and inferior part of the footplate. This was safe up to 0.5 mm depth at all areas except posterosuperiorly where the utricular macula is, on average, only 0.61 mm away from the footplate. The angle of insertion of the piston also influences the end result. CONCLUSION: Two-dimensional information about vestibular end organ location should serve as a guideline only because the operative field is 3D, and the relationship of the piston to the vestibular labyrinth changes with the angle of placement. PMID- 21283037 TI - Assessment of electrode placement and audiological outcomes in bilateral cochlear implantation. AB - OBJECTIVE: The goal of this study was to use highly accurate nonrigid algorithms to locate the position of cochlear implant (CI) electrodes and correlate this with audiological performance. PATIENTS: After obtaining institutional review board approval, adult patients who had bilateral CIs were identified, and those with preoperative temporal bone computed tomographic scans were asked to return for a postintervention computed tomography. Sixteen adult patients agreed. Demographics, cause of deafness, length of auditory deprivation, and audiological performance were recorded. INTERVENTION: Using a nonrigid model of the shape variations of intracochlear anatomy, the location of the basilar membrane was specified in relationship to the electrode array. The number of electrodes within each compartment of the cochlea was correlated with hearing in noise and consonant-noun-consonant scores for the known confounding variable: length of deafness. MAIN OUTCOMES: Mann-Whitney U tests of differences were used to compare the hearing performance resulting from implants completely in the scala tympani (ST) versus those not completely in the ST. RESULTS: Of all implants, 62.5% were fully inserted in the ST; 34.4% were partially inserted into the ST and 3.1% was fully inserted in the scala vestibuli. Controlling for the known contributing variable of length of auditory deprivation, our results show that the location of electrodes in relationship to the scala is not predictive of audiological performance. CONCLUSION: We have assessed electrode placement and correlated it with audiological outcome. The presence of the electrodes solely in the ST was not predictive of outcome. We estimate that it would take analyzing data of thousands of CI patients before any valid correlations can be made. PMID- 21283038 TI - Pancreatic volume and endocrine and exocrine functions in patients with diabetes. AB - OBJECTIVE: Exocrine function has been described in patients with diabetes. We hypothetized that patients with exocrine dysfunction have pancreatic atrophy. METHODS: This is a cohort study of hospitalized patients. Thirty-five patients were selected after detection of impaired exocrine function in routine tests, and 17 patients were matched for age and body mass index to the previous cohort. The pancreatic volume was evaluated on sections of computed tomographic scans of the pancreas. Other investigations included a glucagon stimulation test and determination of fecal elastase-1 concentration and chymotrypsin activity. RESULTS: Fifty-two patients participated in this study, 24 with type 1 diabetes and 28 with type 2 diabetes. Duration of diabetes was 15 years (5-26 years; median [interquartile range]). The pancreatic volume, 42 cm (25-57 cm), was decreased in most patients. It did not differ in patients with type 1 diabetes compared with those with type 2 diabetes. It was decreased in patients treated with insulin and in those with low elastase-1 concentration or low chymotrypsin activity. In the multiple linear regression analysis, the pancreatic volume correlated with chymotrypsin activity and stimulated C-peptide. CONCLUSIONS: We have unraveled a link between 2 old observations in patients with diabetes: atrophy of the pancreas and exocrine deficiency. These observations give credence to the reality of the exocrine dysfunction in patients with diabetes. PMID- 21283039 TI - Relationship of serum pancreatic enzyme testing trends with the diagnosis of acute pancreatitis. AB - OBJECTIVE: The reasons for increasing incidence of acute pancreatitis (AP) are not completely understood. We hypothesized that the rate of serum pancreatic enzyme (PE) testing is increasing, and it correlates with AP diagnosis. METHODS: We retrieved electronic patient data for all emergency department visits at 2 University of Pittsburgh Medical Center hospitals (UPMC Presbyterian [PUH] from 1996 to 2005, N = 422,745; UPMC St Margaret Hospital [SMH] from 1999 to 2005, N = 202,171). We evaluated the trends for serum PE testing (amylase, lipase, or both) and correlated this with the proportion of visits resulting in an inpatient discharge diagnosis of AP. RESULTS: Serum PE testing increased significantly from 4.6% (95% CI, 4.4-4.9) in 1996 to 9.5% (95% CI, 9.3-9.7) in 2005. On multivariate modeling, the rates for serum PE testing were higher at SMH (vs PUH: OR, 1.53; 95% CI, 1.50-1.57), among females (vs males: OR, 1.30 [95% CI, 1.28-1.33]), and increased with age (OR, 1.06 [95% CI, 1.05-1.06] for each 10 years). The proportion of ED visits resulting in an inpatient discharge diagnosis of AP increased significantly during the study period and correlated highly with the rate of PE testing. CONCLUSIONS: The rate of serum PE testing is increasing. Increased serum PE testing may be contributing to the increase in the incidence of AP. PMID- 21283040 TI - Down-regulation of Bax-interacting factor 1 in human pancreatic ductal adenocarcinoma. AB - OBJECTIVE: Bax-interacting factor 1 (Bif-1) protein plays a critical role in apoptosis, mitochondrial morphogenesis, and autophagy, and its loss promotes tumorigenesis. The role of Bif-1 in pancreatic cancer has not been studied. METHODS: We determined Bif-1 expression in 82 human pancreatic ductal adenocarcinomas (PDCs) and in 82 nonmalignant pancreatic specimens (NMPs), using immunohistochemistry and tissue microarray. Bif-1 immunostain was semiquantitatively scored on a scale of 0 to 9. RESULTS: Bif-1 scores in NMP were either 6 or 9, with lower scores in only 19 (23.2%) of 82 NMPs. Low Bif-1 expression (score <6) was found in 37 (45.1%) of 82 PDCs, a proportion significantly greater than that found in NMP (P = 0.005). The expression of Bif-1 was twice as likely to be low in PDC as in NMP (relative risk = 1.95, 95% confidence interval, 1.23-3.09). Kaplan-Meier survival estimates showed no difference in survival between patients with low and high Bif-1 expression (P = 0.21, log-rank test). CONCLUSIONS: The expression of Bif-1 is downregulated in a subset of PDC. This novel finding is in agreement with the tumor suppressor function of Bif-1. The lack of association between Bif-1 expression and patient survival may be best explained by the complexity of carcinogenesis. PMID- 21283041 TI - Construction and validation of a prognostic index for patients with metastatic pancreatic adenocarcinoma. AB - OBJECTIVES: To identify prognostic factors in patients with metastatic pancreatic adenocarcinoma. METHODS: The relationship between patient characteristics and outcome was examined by multivariate regression analyses of data from 409 consecutive patients with metastatic pancreatic adenocarcinoma who had been treated with a gemcitabine-containing regimen, and we stratified the patients into 3 risk groups according to the number of prognostic factors they had for a poor outcome. A validation data set obtained from 145 patients who had been treated with agents other than gemcitabine was analyzed. The prognostic index was applied the each of the patients. RESULTS: The multivariate regression analyses revealed that the presence of pain, peritoneal dissemination, liver metastasis, and an elevated serum C-reactive protein value significantly contributed to a shorter survival time. The patients were stratified into 3 groups according to their number of risk factors, and their outcomes of the 3 groups were significantly different. When the prognostic index was applied to the validation data set, the respective outcomes of the 3 groups were found to be significantly differed from each other. CONCLUSIONS: Pain, peritoneal dissemination, liver metastasis, and an elevated serum C-reactive protein value are important prognostic factors for patients with metastatic pancreatic adenocarcinoma. PMID- 21283042 TI - Serratia marcescens outbreak in a neonatal intensive care unit related to the exit port of an oscillator. AB - OBJECTIVE: To interrupt transmission of Serratia marcescens colonization in a neonatal intensive care unit and determine the source of ongoing transmission. DESIGN: Multidisciplinary outbreak investigation and simulation of droplet generation by a high-frequency oscillator using fluorescent dye. SETTING: Level III neonatal intensive care unit. PATIENTS: Very low birth weight premature infants with respiratory failure. INTERVENTIONS: Infection control interventions, pulsed-field gel electrophoresis of isolates to determine relatedness, and construction of a scavenging system to capture the circuitry condensate expelled by the oscillator exit port. MEASUREMENTS AND MAIN RESULTS: Affected infants were housed in the same geographic site. Serratia marcescens isolates were indistinguishable or closely related using pulsed-field gel electrophoresis. Fluorescent droplet splatter from the circuitry, generated when no containment device covered the exit valve, was visible up to 49 in (107.8 cm) from the source. CONCLUSIONS: Implementation and adherence to infection control measures is essential to prevent transmission of opportunistic pathogens among ventilated infants. Oscillators can generate droplets that travel farther than 1 m from the source. PMID- 21283043 TI - Incidental sinusitis in a pediatric intensive care unit. AB - OBJECTIVE: Intubation is a risk factor for nosocomial sinusitis in adult intensive care patients. Sinusitis in intubated adults can be an occult cause of fever. In children, nasal intubation may increase the risk of sinusitis. No pediatric study has determined the frequency of nosocomial sinusitis in the pediatric intensive care unit setting. We hypothesized that within a subset of patients who had head computed tomography imaging 1) the incidental frequency of sinusitis in pediatric intensive care unit patients exceeds the frequency in non pediatric intensive care unit patients, 2) the frequency of sinusitis is greater in pediatric intensive care unit patients with a tube (nasotracheal, nasogastric, orotracheal, or orogastric) compared to those without a tube, and 3) nasal tubes confer an increased risk for sinusitis over oral tubes. DESIGN: Retrospective chart review. SETTING: Independent not-for-profit pediatric healthcare system. PATIENTS: Pediatric intensive care unit and non-pediatric intensive care unit (inpatients hospitalized on medical-surgical wards) patients referred for head computed tomography. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Computed tomography images were scored using the Lund-MacKay staging system. Sinusitis was defined as a Lund-MacKay score >=5. A total of 596 patients were studied, 395 (66.3%) in the pediatric intensive care unit. A total of 154 (44.3%) pediatric intensive care unit vs. 54 (26.9%) non-pediatric intensive care unit patients had sinusitis (p < .001). A total of 102 of 147 (69.4%) pediatric intensive care unit patients with a tube present had sinusitis vs. 73 of 248 (29.4%) patients without a tube present (p < .001). There was no difference in sinusitis based on tube location (p = .472). Of patients with sinusitis, 51.3% (81 of 158) compared to 39.4% (89 of 226) were febrile within 48 hrs of imaging (p = .021). A younger age or the presence of a tube increased the probability of sinusitis (p < .001). CONCLUSIONS: A total of 44.3% of our pediatric intensive care unit patients imaged for reasons other than evaluation for sinus disease had evidence of sinusitis, and 51.3% of these had fever. These findings raise the concern that sinusitis in pediatric intensive care unit patients is common and should be considered in the differential diagnosis of fever in pediatric intensive care unit patients. PMID- 21283044 TI - Catheter-associated bloodstream infection in the pediatric intensive care unit: a multidisciplinary approach. AB - BACKGROUND: Catheter-associated bloodstream infections have been reported to occur in 3% to 8% of all central venous catheters inserted and are the predominant cause of hospital-acquired infection in intensive care units. OBJECTIVE: Decreasing the pediatric intensive care unit rate of catheter associated bloodstream infections became a high priority in 2008 for all members of the intensive care unit team affiliated with central venous catheter insertion and maintenance. INTERVENTIONS: Through a series of multidisciplinary initiatives, the annual average catheter-associated bloodstream infection rate in the pediatric intensive care unit fell from 7.9 infections per 1000 central catheter days in 2007 to 1.3 infections per 1000 central catheter days in 2009, a decrease of 83%. We attribute this success to the implementation of several key interventions, adherence to published insertion and maintenance bundles, and collaboration among pediatric intensive care unit physicians and nurses in all aspects of central catheter care. MEASUREMENTS AND MAIN RESULTS: Statistically significant interventions included improvements to central venous catheter insertion practices, the development of a dedicated central catheter team, and regular collaborative discussion of central venous catheter necessity. In this 24 month period, this equates to 50 catheter-associated infections avoided, six potential deaths prevented, and an estimated cost savings of $1.45 million (based on $29,000 per infection). CONCLUSION: While implementation of these and other interventions has shown a positive impact, this project will continue into the future to assure sustainable successes and continued best practice improvements. PMID- 21283045 TI - Investigation into the effect of closed-system suctioning on the frequency of pediatric ventilator-associated pneumonia in a developing country. AB - OBJECTIVE: To investigate the effect of closed-system vs. open endotracheal suctioning on the frequency of ventilator-associated pneumonia and outcome in a pediatric intensive care unit in a developing country. DESIGN: Prospective observational and nonrandomized controlled clinical study. SETTING: A 20-bed pediatric intensive care unit in a tertiary pediatric hospital. PATIENTS: Infants and children mechanically ventilated for >24 hrs. INTERVENTION: : Pediatric intensive care unit suctioning systems were alternated monthly. An 8-month interim analysis was planned with a priori efficacy and futility study termination boundaries set at p < .006 and p > .52, respectively. MEASUREMENTS AND MAIN RESULTS: Demographic, clinical, and laboratory data were prospectively recorded. Ventilator-associated pneumonia was diagnosed using the Clinical Pulmonary Infection Score, and the results were confirmed retrospectively using Centers for Disease Control criteria. A total of 250 patients (median [interquartile range] age of 3.8 [1.2-15.0] months) in 263 pediatric intensive care unit admissions were included. Fifty-nine admissions developed ventilator associated pneumonia, with a calculated rate of 45.1 infections per 1000 ventilated days. There was no difference in characteristics or outcome between patients on closed-system suctioning (n = 83) and those on open endotracheal suctioning (n = 180). The frequencies of ventilator-associated pneumonia for patients on closed-system suctioning and open endotracheal suctioning were 20.5% and 23.3%, respectively (p = .6), reaching the a priori set limit of futility. Patients who developed ventilator-associated pneumonia spent a median (interquartile range) of 22 (13-37) and 11 (8-16) days in the hospital and pediatric intensive care unit, respectively, compared to 14.5 (10-24) and 6 (4-8) days for those without ventilator-associated pneumonia (p < .001). A 22% proportion of patients who developed ventilator-associated pneumonia died compared to 11.3% of those without ventilator-associated pneumonia (p = .03). Risk factors for ventilator-associated pneumonia identified on multiple logistic regression were duration of mechanical ventilation, transport out of the pediatric intensive care unit, and blood transfusion. CONCLUSION: Closed-system suctioning did not affect the frequency of ventilator-associated pneumonia or patient outcome in this setting. PMID- 21283046 TI - Randomized controlled trial of interrupted versus continuous sedative infusions in ventilated children. AB - OBJECTIVE: To compare daily interruption vs. continuous sedative infusions in mechanically ventilated children with respect to lengths of mechanical ventilation and intensive care unit stay. DESIGN: Prospective randomized controlled trial. SETTING: Pediatric intensive care unit of a tertiary care teaching and referral hospital. PATIENTS: One hundred two patients mechanically ventilated for >48 hrs. INTERVENTIONS: Patients were randomized to receive either continuous (group 1) or interrupted (group 2) sedative infusion (midazolam bolus of 0.1 mg/kg, followed by infusion, to achieve a Ramsay score of 3-4). Each patient in group 2 had daily interruption of infusion at 8:00 AM till he/she became fully awake (response to verbal commands) or so agitated/uncomfortable that he/she needed restarting of infusion (whichever was earlier) at a dose 50% less than the previous dose. Primary outcome variables were the lengths of mechanical ventilation and intensive care unit stay, while the number and percentage of days awake on sedative infusions, frequency of adverse events, and total dose of sedatives required were the secondary outcome variables. MEASUREMENTS AND MAIN RESULTS: Of the 102 patients included in the study, 56 were randomized into the continuous sedation protocol and 46 into the interrupted sedation protocol. Both were statistically similar with respect to demography, primary diagnosis, severity of illness score (Pediatric Risk of Mortality I and III), indication for mechanical ventilation, and initial ventilatory variables except that the patients under the interrupted arm had lower peak inspiratory pressure and positive end-expiratory pressure requirements at the start of ventilation (p = .002 and p = .028, respectively). The mean (SD) length of mechanical ventilation in the interrupted sedation protocol was significantly less than that in the continuous sedation protocol (7.0 +/- 4.8 days vs. 10.3 +/- 8.4 days; p = .021). Similarly, the difference in the median duration of pediatric intensive care unit stay was significantly less in the interrupted sedation as compared to the continuous sedation protocol (10.7 days vs. 14.0 days; p = .048). The mean total dose of midazolam and the total calculated cost of midazolam in the former were significantly less compared to those of the latter (7.1 +/- 4.7 mL vs. 10.9 +/- 6.9 mL, p = .002; 4827 +/- 5445 rupees vs. 13,865 +/- 25,338 rupees, p = .020). The frequencies of adverse events in both the groups were however similar. CONCLUSION: The length of mechanical ventilation, duration of intensive care unit stay, total dose of midazolam, and average calculated cost of the therapy were significantly reduced in the interrupted as compared to the continuous group of sedation. PMID- 21283047 TI - Cerebrospinal fluid characteristics of infants who present to the emergency department with fever: establishing normal values by week of age. AB - BACKGROUND This study describes differences in the values of cerebrospinal fluid (CSF) white blood cell (WBC), glucose, and protein counts in infants less than 60 days of age with fever who were not proven to have viral or bacterial meningitis. METHODS: Three independent retrospective medical record reviews were conducted using a population of infants less than 60 days of age who presented to the Emergency Department with fever. Full-term infants were included if a lumbar puncture was performed within 24 hours of admittance and bacterial or viral meningitis was not identified as the cause of fever. RESULTS: A total of 1091 infants were included and grouped by week of age. Significant trends were found for CSF WBC and CSF protein with the highest values observed during the first week of life. Mean for CSF WBC was 8.63 cells/mm for infants aged 0 to 1 week and decreased for each age group ending with infants 8 weeks of age having a mean of 2.22 cell/mm. For CSF protein, a similar trend was observed. No significant differences were found for CSF glucose. CONCLUSIONS: Significant differences exist for infants by week of age for CSF WBC and CSF protein. These values can be used to assist in interpreting laboratory findings and making management decisions for infants less than 60 days of age. PMID- 21283048 TI - Second-dose varicella vaccination coverage in children and adolescents in a managed care organization in California, 2006-2009. AB - We assessed trends of second-dose varicella-containing vaccine coverage among children and adolescents in Kaiser Permanente Southern California health plan since the Advisory Committee on Immunization Practices recommendation of 2-dose varicella vaccination in 2006. The overall second-dose coverage increased rapidly from 42.1% in 2007 to 74.6% in 2009. The increasing trend was observed in all strata defined by age and race/ethnicity, with the highest coverage among children aged 5 to 6 years old. However, non-Hispanic White race/ethnicity and living in a neighborhood with higher education level were inversely associated with the second-dose uptake. PMID- 21283049 TI - Candida species differ in their interactions with immature human gastrointestinal epithelial cells. AB - Life-threatening gastrointestinal (GI) diseases of prematurity are highly associated with systemic candidiasis. This implicates the premature GI tract as an important site for invasion by Candida. Invasive interactions of Candida spp. with immature enterocytes have heretofore not been analyzed. Using a primary immature human enterocyte line, we compared the ability of multiple isolates of different Candida spp. to penetrate, injure, and induce a cytokine response from host cells. Of all the Candida spp. analyzed, C. albicans had the greatest ability to penetrate and injure immature enterocytes and to elicit IL-8 release (p < 0.01). In addition, C. albicans was the only Candida spp. to form filamentous hyphae when in contact with immature enterocytes. Similarly, a C. albicans mutant with defective hyphal morphogenesis and invasiveness had attenuated cytotoxicity for immature enterocytes (p < 0.003). Thus, hyphal morphogenesis correlates with immature enterocyte penetration, injury, and inflammatory responses. Furthermore, variability in enterocyte injury was observed among hyphal-producing C. albicans strains, suggesting that individual organism genotypes also influence host-pathogen interactions. Overall, the finding that Candida spp. differed in their interactions with immature enterocytes implicates that individual spp. may use different pathogenesis mechanisms. PMID- 21283050 TI - Feasibility of long-term continuous EEG monitoring during the first days of life in preterm infants: an automated quantification of the EEG activity. AB - Long-term EEG monitoring (LTM) with several electrodes could be a useful tool for surveillance of the brain during the first critical days of life. This study aimed to assess the feasibility of multichannel LTM for automated analysis of EEG activity from d 1 to 3 using eight electrodes. Premature infants (GA <31 wk; n = 48) were continuously monitored for 3 d. EEG monitoring for a total of 3257 h was successfully performed. Total absolute band power (tABP) was calculated per second. Artifacts were removed visually or by an algorithm removing the highest 5, 10, 15, and 20% tABPs. NS difference was found between the trends of visually edited and 5% mathematically trimmed data. Two groups were compared (24 <= GA < 28 wk and 28 <= GA < 31 wk) using the median of tABP for all frequency bands per day. The results showed that tABP differed between groups. The changes of tABP d 1-3 were equal in both groups. Automatically assessed LTM confirms that the EEG activity depends on GA. However, it reveals that the early changes (d 1-3) are independent of GA. The study demonstrates the feasibility of multichannel LTM and the possibility of developing automated EEG analyses. PMID- 21283051 TI - End-tidal CO2 detection of an audible heart rate during neonatal cardiopulmonary resuscitation after asystole in asphyxiated piglets. AB - Even brief interruption of cardiac compressions significantly reduces critical coronary perfusion pressure during cardiopulmonary resuscitation (CPR). End-tidal CO2 (ETCO2) monitoring may provide a continuous noninvasive method of assessing return of spontaneous circulation (ROSC) without stopping to auscultate for heart rate (HR). However, the ETCO2 value that correlates with an audible HR is unknown. Our objective was to determine the threshold ETCO2 that is associated with ROSC after asphyxia-induced asystole. Neonatal swine (n = 46) were progressively asphyxiated until asystole occurred. Resuscitation followed current neonatal guidelines with initial ventilation with 100% O2 followed by cardiac compressions followed by epinephrine for continued asystole. HR was auscultated every 30 s, and ETCO2 was continuously recorded. A receiver operator curve was generated using the calculated sensitivity and specificity for various ETCO2 values, where a positive test was defined as the presence of HR >60 bpm by auscultation. An ETCO2 cut-off value of 14 mm Hg is the most sensitive ETCO2 value with the least false positives. When using ETCO2 to guide uninterrupted CPR in this model of asphyxia-induced asystole, auscultative confirmation of return of an adequate HR should be performed when ETCO2 >= 14 mm Hg is achieved. Correlation during human neonatal CPR needs further investigation. PMID- 21283052 TI - Functional lateralization of sensorimotor cortex in infants measured using multichannel near-infrared spectroscopy. AB - Multichannel near-infrared spectroscopy (MNIRS) was used for the functional imaging of the sensorimotor cortex of newborn infants during passive knee and elbow movement under sedated sleep. Contralateral knee and elbow movement caused a marked increase in the concentration of oxyhemoglobin ([oxyHb]) from the baseline values at site within the sensorimotor area in all infants. During ipsilateral knee and elbow movement, [oxyHb] showed smaller changes, equivalent to 64 +/- 23 and 66 +/- 28% of the changes that occurred with contralateral stimulation, respectively. The mean times corresponding to maximal changes in [oxyHb] were 16.1 +/- 3.3 s for contralateral knee movement and 17.9 +/- 5.7 s for contralateral elbow movement. No significant difference was noted between the mean latencies showing the maximal changes in [oxyHb] between contralateral and ipsilateral movement. There was a significant difference in the area and degree of response between the contralateral and ipsilateral movement. MNIRS could be a useful tool to understand the pathophysiology of the developing brain and monitor cortical responses in various clinical situations. PMID- 21283054 TI - Discordance for retinitis pigmentosa in two monozygotic twin pairs. AB - BACKGROUND: Retinitis pigmentosa (RP) is a group of genetically heterogeneous diseases with progressive degeneration of the retina. The condition can be inherited as an autosomal dominant, autosomal recessive, and X-linked trait. METHODS: We report on two female twin pairs. One twin of each pair is affected with RP, the other twin is unaffected, both clinically and functionally.Molecular analysis in both twins included zygosity determination, arrayed primer extension chip analysis for autosomal recessive and dominant RP, sequencing of the entire RPGR gene, and analysis of X-chromosome inactivation status. RESULTS: Both unrelated twin pairs were genetically identical. Of the potential pathogenetic mechanisms, skewed X-inactivation was excluded on leukocytes. Autosomal recessive RP and autosomal dominant RP arrayed primer extension chip analysis result was completely normal, excluding known mutations in known genes as the cause of disease in the affected twins. Sequencing excluded mutations in RPGR. A postzygotic recessive or dominant genetic mutation of an RP gene is not impossible. A postfertilization error as a potential cause of uniparental isodisomy is unlikely albeit not entirely impossible. CONCLUSION: The authors report on the second and third unrelated identical twin pair discordant for RP. The exact cause of the condition and the explanation of the clinical discordance remain elusive. PMID- 21283055 TI - Intravitreal ranibizumab for macular edema secondary to central retinal vein occlusion. AB - PURPOSE: To evaluate the safety and efficacy of intravitreal ranibizumab for macular edema secondary to central retinal vein occlusion. METHODS: Patients with macular edema secondary to perfused central retinal vein occlusion were enrolled in this ongoing, prospective, open-label study. Treatment was initiated with monthly intravitreal ranibizumab for 3 months. In the first year, additional injections were administered for edema in quarterly intervals as needed (PRN) for Cohort 1 (n = 10) and monthly PRN for Cohort 2 (n = 10). In the second year of treatments, all patients received monthly PRN treatment. Early Treatment Diabetic Retinopathy Study best-corrected visual acuity, central retinal thickness, fundus photographs, and fluorescein angiograms were evaluated, and the incidence and severity of adverse events were documented. RESULTS: Mean change in best corrected visual acuity and central retinal thickness improved during the induction phase in both groups. During the remainder of the first year for Cohort 1, initial gains were lost during quarterly treatment but returned with monthly PRN treatment in the second year. For Cohort 2, improvement in best-corrected visual acuity and central retinal thickness from the induction phase was maintained through Month 24. Nineteen of 20 patients experienced a reduction in intraretinal hemorrhage, optic nerve swelling, and/or venous diameter after treatment. One myocardial infarction, one cerebrovascular accident, and no serious ocular adverse events were reported. Iris neovascularization was developed in none of the eyes. CONCLUSION: Ranibizumab was well tolerated and associated with a greater reduction in macular edema and improvement in visual acuity in the monthly PRN regimen compared with quarterly treatment. Vision lost during the quarterly PRN injection intervals in the first year of Cohort 1 could be regained by switching to monthly PRN dosing. PMID- 21283056 TI - Endophthalmitis caused by Pseudomonas aeruginosa in Taiwan. AB - PURPOSE: To investigate the clinical settings, treatment given, and visual outcomes for eyes with Pseudomonas aeruginosa endophthalmitis in Taiwan. METHODS: This is a retrospective, noncomparative, consecutive case series. Medical records were reviewed in 72 eyes of 71 patients with culture-proven P. aeruginosa endophthalmitis between January 1997 and December 2007. RESULTS: The clinical settings included keratitis/scleritis (44.4%), cataract surgery (15.3%), penetrating keratoplasty (13.9%), endogenous source (12.5%), trauma (6.9%), penetrating keratoplasty with cataract surgery (2.8%), trabeculectomy with cataract surgery (1.4%), trabeculectomy (1.4%), and secondary implant (1.4%). Initial visual acuity ranged from counting fingers to no light perception. Final visual acuity was better than 5/200 in 6 of 72 eyes (8.3%), 4/200 to hand motions in 4 eyes (5.6%), and light perception to no light perception in 62 eyes (86.1%). In vitro testing, the susceptibility patterns of organisms isolated were as follows: ceftazidime (100%), cefepime (100%), aztreonam (100%), imipenem (99%), amikacin (94%), and gentamicin (86%). Five of 16 eyes (31.3%) that underwent primary or secondary pars plana vitrectomy with intravitreal antibiotics achieved a final visual acuity of 5/200 or better compared with 1 of 45 eyes (2.2%) treated with 1 or multiple vitreous tap(s) and intravitreal antibiotics (Fisher's exact test, P = 0.004). CONCLUSION: Despite early diagnosis and treatment with intravitreal antibiotics, visual acuity outcomes were generally poor. PMID- 21283057 TI - Hypothermia increases rebleeding during uncontrolled hemorrhage in the rat. AB - Trauma registers show that hypothermia (HT) is an independent risk factor for death during hemorrhagic shock, although experimental animal studies indicate that HT may be beneficial during these conditions. However, the animal models were not designed to detect the expected increase in bleeding caused by HT. In a new model for uncontrolled bleeding, 40 Sprague-Dawley rats were exposed to a standardized femoral artery injury and randomized to either normothermia or HT. Ketamine/midazolam was used to minimize hemodynamic changes due to the anesthesia. The hypothermic rats were cooled to 30 degrees C and rewarmed again at 90 min. The study period was 3 h. The incidence, onset time, duration, and volume of bleedings as well as hemodynamic and metabolic changes were recorded. There was no difference between groups with respect to the initial bleeding. Rebleedings occurred among 60% of the animals in both groups. Hypothermic rebleeders had more, larger, and longer rebleedings, resulting in a total rebleeding volume amounting to 41% of their estimated blood volume. The corresponding figure for the normothermic rebleeders was 3% (P < 0.001). Total rebleeding volume was significantly larger in the hypothermic group, even at body temperatures greater than 35 degrees C. We conclude that the risk of rebleeding from a femoral injury is greater in the presence of cooling and HT. The larger rebleeding volumes seen even at body temperatures greater than 35 degrees C indicate that factors other than temperature-induced coagulopathy also contributed to the increased hemorrhage. PMID- 21283058 TI - PUMA mediates the apoptotic signal of hypoxia/reoxygenation in cardiomyocytes through mitochondrial pathway. AB - P53 upregulated modulator of apoptosis (PUMA) plays an important role in mediating cell death. However, the role of PUMA in cardiomyocyte death induced by hypoxia/reoxygenation (H/R) and its molecular mechanism still remain enigmatic. Here, we used the in vitro model to elucidate the effects of PUMA on H/R-induced cardiomyocyte apoptosis as well as the underlying mechanisms. We reported that H/R could upregulate the expression of PUMA accompanied by the elevation of cardiomyocyte apoptosis. Interestingly, inhibition of endogenous PUMA expression by PUMA siRNA or p53 inhibitor repressed H/R-induced cardiomyocyte apoptosis. Furthermore, we found H/R stimulated the associations of PUMA apoptosis repressor with caspase recruitment domain (ARC) and consequently attenuated the associations of ARC with caspase 8, resulting in caspase 8 activation. Also, H/R stimulated cytochrome C release and caspase 3 activation. However, these stimulating effects of H/R disappeared upon knockdown of endogenous PUMA. Our data reveal that PUMA participates in H/R-triggered cardiomyocyte apoptosis by interfering with mitochondrial pathway. PMID- 21283059 TI - Circulating levels of peroxiredoxin 4 as a novel biomarker of oxidative stress in patients with sepsis. AB - Oxidative stress, a situation with increased reactive oxygen species production and/or decreased antioxidant defense mechanisms, is evident in the pathogenesis of sepsis. Peroxiredoxin 4 (Prx4) is a hydrogen peroxide degrading peroxidase recently found circulating in blood of septic patients and potentially reflecting an antioxidant system in imbalance. We studied Prx4 serum levels of 79 consecutively enrolled medical intensive care unit patients. The diagnostic and prognostic performance of Prx4 was compared with other biomarkers, the APACHE II score and the SOFA score. Median Prx4 serum levels gradually increased with disease severity in patients classified on admission as having systemic immune response syndrome (2.32 arbitrary [arb.] U/L), sepsis (5.02 arb. U/L), severe sepsis (11.7 arb. U/L), or septic shock (11.4 arb. U/L). A positive correlation was found with the severity score Acute Physiological and Chronic Health Evaluation II (r = 0.27, P < 0.05) and the organ failure score Sequential Organ Failure Assessment (r = 0.55, P < 0.0001). Peroxiredoxin 4 correlated with the sepsis marker procalcitonin (r = 0.61, P < 0.0001), the inflammatory markers C reactive protein (r = 0.65, P < 0.0001) and interleukin 6 (r = 0.62, P < 0.0001), and antioxidant blood compounds total bilirubin (r = 0.37, P < 0.001) and albumin (r = -0.54, P < 0.0001). Peroxiredoxin 4 distinguished noninfectious from infectious inflammatory response syndrome with an area under the receiver operating characteristic (ROC) curve of 0.82. [corrected] High Prx4 serum levels were associated with a poor prognosis of septic patients and revealed an area under the ROC curve of 0.76 in prediction of in-hospital mortality. In this study, elevated serum levels of the antioxidant Prx4 were associated with an increased disease severity and adverse outcome of critically ill patients with sepsis. Peroxiredoxin 4 may therefore be a helpful new biomarker for diagnosing, monitoring, and risk assessing these patients. The pathophysiological mechanisms behind the observed increase remain to be elucidated. PMID- 21283060 TI - Sublingual microcirculatory effects of enalaprilat in an ovine model of septic shock. AB - Severe sepsis is frequently associated with microcirculatory abnormalities despite seemingly adequate hemodynamic resuscitation. As increased serum angiotensin II levels may play a role in this dysfunction, we evaluated the microcirculatory effects of enalaprilat in an experimental model of septic shock. One hour after injection of 1.5 g/kg body weight of feces into the abdominal cavity, 16 adult female anesthetized, mechanically ventilated sheep were randomized to receive 2.5 mg enalaprilat or saline. When fluid-resistant hypotension (mean arterial pressure, <65 mmHg) developed, norepinephrine was given up to a maximal dose of 3 MUg.kg(-1).min(-1). The sublingual microcirculation was evaluated using sidestream dark-field videomicroscopy. A cutoff of 20 MUm was used to differentiate small and large vessels. Experiments were pursued until the sheep's spontaneous death or for a maximum of 30 h. There were progressive and significant reductions in the proportion of small perfused vessels and in the microvascular flow index for small vessels (both P < 0.01 for trend) during shock and the first 2 h of norepinephrine infusion in the placebo group, which were prevented by the administration of enalaprilat. There were no differences between treated and placebo groups in global hemodynamic variables, time to shock or median survival time (21.8 [18.6-28.8] vs. 22.9 [21.8-30.0] h; P = 0.45). However, oxygen exchange was worse (PaO2/FiO2 ratio, 224 [128-297] vs. 332 [187-450]; P < 0.05), and creatinine concentrations increased more in the treated group (from 0.51 [0.42-0.75] to 1.19 [0.64-1.50] mg.dL(-1); P = 0.04) than in the control group (from 0.55 [0.45-0.62] to 0.78 [0.46-1.78] mg.dL(-1); P = 0.12), Enalaprilat therefore prevented the worsening of sublingual microcirculatory variables in this fluid-resuscitated, hyperdynamic model of septic shock, without significant effect on arterial pressure, but with a possible deleterious effect on renal and lung function. PMID- 21283061 TI - Activation of hypoxia-inducible factor 1 in skeletal muscle cells after exposure to damaged muscle cell debris. AB - Skeletal muscle damage provokes complex repair mechanisms including recruitment of leukocytes as well as activation of myogenic precursor cells such as satellite cells. To study muscle cell repair mechanisms after muscle fiber damage, we used an in vitro model of scrape-injured myotubes. Exposing vital C2C12 myoblasts and myotubes to cell debris of damaged myotubes revealed mRNA upregulation of adrenomedullin (ADM), insulin-like growth factors 1 and 2, metallopeptidase 9, and monocyte chemoattractant protein11. When cell debris was treated with ultrasound, frozen in liquid nitrogen, or heat inactivated before addition to C2C12 cells, gene expression was drastically reduced or completely absent. Moreover, incubations of myoblasts with debris separated by transwell inserts indicated that direct cell contact is required for gene induction. Incubation with albumin and PolyIC ruled out that ADM induction by cell debris simply results from increased protein or nucleic acid concentrations in the supernatant. Because the genes, which were upregulated by cell debris, are potential target genes of hypoxia-inducible factor (HIF), cells were analyzed for HIF-1alpha expression. Western blot analysis showed accumulation of the alpha-subunit upon contact to cell debris. Knockdown of HIF-1alpha in C2C12 cells proved that activation of HIF-1 in response to cell debris was responsible for upregulating ADM and monocyte chemoattractant protein 1. Furthermore, by incubating cells on gas-permeable culture dishes, we excluded a reduced pericellular pO2 induced by cell debris as the cause for ADM upregulation. Our data suggest that damaged myofibers activate HIF-1 in neighboring myotubes and precursor myoblasts by direct contact, concomitantly upregulating factors necessary for angiogenesis, tissue regeneration, and phagocyte recruitment. PMID- 21283062 TI - Elaboration of gene expression-based clinical decision aids for kidney transplantation: where do we stand? AB - Successful kidney transplant management throughout the graft lifespan depends on adequate diagnosis (i.e., recognition of a particular type of graft rejection or injury) and prognosis (i.e., predicting future events or outcome). The currently used methods (mainly graft histology, immunosuppressive drug level monitoring, measurement of renal function, and DSA) have proven highly useful on a population level by indicating good or bad outcome, but are difficult to translate into meaningful tests for individual patients. There is thus a need for diagnostic and predictive tests that add value by being more informative to each patient, more powerful, addressing more specific questions or providing less invasive interventions. Gene expression profiling using microarrays or quantitative PCR has become a benchmark in research into novel and informative monitoring assays for transplantation. A wealth of gene expression studies are reported in the literature spanning two decades. There is now a need for clinical validation so that such tests can become standardized and approved for widespread integration into the standard of care to improve outcome for kidney transplant recipients. PMID- 21283063 TI - Vaccine-induced allo-HLA-reactive memory T cells in a kidney transplantation candidate. AB - BACKGROUND: Allo-human leukocyte antigen (HLA) reactivity by naturally acquired viral-specific memory T cells is common. However, the effect of successful vaccination on the alloreactive memory T-cell repertoire is unclear. We hypothesized that vaccination could specifically induce allo-HLA-reactive memory T cells. METHODS: A varicella-zoster virus (VZV) immediate early 62 (IE62) specific CD8 memory T-cell clone was single cell sorted from a VZV seronegative renal transplant candidate after response to live attenuated varicella vaccination. To analyze the allo-HLA reactivity, the VZV IE62-specific T-cell clone was tested against HLA-typed target cells and target cells transfected with HLA molecules, in both cytokine production and cytotoxicity assays. RESULTS: The varicella vaccine-induced VZV IE62-specific T-cell clone specifically produced interferon-gamma when stimulated with HLA-B*55:01-expressing Epstein-Barr virus transformed B cells and HLA-B*55:01-transfected K562 cells (single HLA antigen expressing cell line [SALs]) only. The clone also demonstrated specific cytolytic effector function against HLA-B*55:01 SALs and phytohemagglutinin blasts. Cytotoxicity assays using proximal tubular epithelial cell and human umbilical vein endothelial cell targets confirmed the kidney tissue specificity of the allo HLA-B*55:01 reactivity, and the relevance of the cross-reactivity to clinical kidney transplantation. The results also suggest that molecular mimicry, and not bystander proliferation, is the mechanism underlying vaccine-induced alloreactivity. CONCLUSIONS: Varicella vaccination generated a de novo alloreactive kidney cell-specific cytolytic effector memory T cell in a patient awaiting renal transplantation. Vaccination-induced alloreactivity may have important clinical implications, especially for vaccine timing and recipient monitoring. PMID- 21283064 TI - The impact of proteasome inhibition on alloantibody-producing plasma cells in vivo. AB - BACKGROUND: Donor specific alloantibody producing plasma cells (DSA-PCs) appear resistant to conventional immunosuppressive agents. This study aimed to determine the impact of pretransplant monotherapy with the proteasome inhibitor bortezomib on DSA-PCs in sensitized renal allograft candidates and to assess if DSA-PC depletion would enhance the efficacy of DSA removal using plasma exchange (PE). METHODS: Only patients with DSA levels considered too high to successfully undergo transplantation with PE alone were included in this study: i.e. those with a baseline B flow cytometric crossmatch (BFXM) >450 against a potential living donor.Four sensitized patients received 4 doses (1.3 mg/m/dose) of bortezomib and 4 received 16 doses. The number of DSA-PCs was determined pre and post-treatment using an ELISPOT assay. Five of these patients underwent post treatment PE and their response was compared to 8 highly-sensitized patients (BFXM >450) who underwent PE alone. RESULTS: When considering all 8 patients as one group, bortezomib treatment decreased DSA-PCs in the marrow (mean+/-SD=16.7+/ 14.5 DSA-PCs/ml pre-treatment vs. 6.2+/-3.6 DSA-PCs/ml after treatment, P=0.048). In the time frame of the study, bortezomib alone did not decrease serum DSA levels. However, five bortezomib treated patients underwent PE and showed a greater decease in DSA compared to the historical control group of 8 sensitized patients who underwent PE alone (mean decrease in BFXM channel shift=272.6+/-92.1 with bortezomib vs 95.4+/-72.2 in PE alone P=0.008). CONCLUSIONS: Bortezomib depletes DSA-PCs and appears to potentiate DSA removal by PE in sensitized renal transplant recipients. PMID- 21283065 TI - Pediatric kidney recipients with small capacity, defunctionalized urinary bladders receiving adult-sized kidney without prior bladder augmentation. AB - BACKGROUND: Children with small capacity, defunctionalized urinary bladders present unique operative challenges. Thus, traditional practice has included pretransplant bladder augmentation, but this has several adverse consequences. METHODS: A single-institutional, retrospective review from January 1, 2004 to December 31, 2008 was conducted. Twelve pediatric patients, whom had not undergone pretransplant bladder augmentation, did not have neurogenic bladders or require preoperative catheterization, and a small capacity defunctionalized bladders were included. All were managed by the same surgeon with a previously described ureteral implantation, and a 7F ureteral stent attached to a large diameter suprapubic catheter was removed in a joint manner without cystoscopy at 2 weeks. Data were collected on patient and graft survival, rejection episodes, urinary tract infection (UTI) requiring antibiotics, grade of vesicoureteral reflux, and posttransplant bladder capacity. RESULTS: One-year patient and graft survival rates were 100%. One patient experienced a clinical rejection episode, which was successfully treated. Five patients (41.7%) had a UTI requiring abx treatment within the first postoperative year, but at 1 year, all patients had sterile urinary tracts. After removal of suprapubic catheters and ureteral stents, all patients were able to void spontaneously. Seven patients had no posttransplant ureteral reflux, three had grade 1 reflux, and two had grade 3 reflux (both successfully treated). The average age estimated pretransplant bladder and 1 year posttransplant bladder capacity was 14.5% and 84% of expected, respectively. CONCLUSIONS: In pediatric end-stage renal disease patients with a small capacity defunctionalized bladder, it is reasonable to proceed with kidney transplantation without pretransplant bladder augmentation, thus avoiding an unnecessary surgery. PMID- 21283067 TI - Closed tracheal suction and fluid aspiration past the tracheal tube. Impact of tube cuff and airway pressure. AB - BACKGROUND: This study investigated the effect of different tube cuff types and airway pressures on fluid leakage past the tracheal tube cuff during suction with a closed tracheal suction system (CTSS). METHODS: Unlubricated high-volume, low pressure tracheal tube cuffs made from polyvinylchloride (PVC) and polyurethane (PU) with a size 7.5 mm internal diameter (ID) were placed in a 22 mm ID artificial trachea connected to a test lung and inflated to 25 or 50 cmH2O of cuff pressure. Positive pressure ventilation (PPV) with peak inspiratory pressures of 15, 20 or 25 cmH2O and positive end expiratory pressures (PEEP) of 5 or 10 cmH2O were used. A CTSS catheter (14 Fr) was attached to the tracheal tube and suction was performed for 5, 10, 15 or 20 s with 200 or 300 cmH2O of negative suction pressures. The volume of fluid leaking across the tube cuff at the end of the suction procedure was measured (mL), and the airway pressure was simultaneously recorded. Fluid leakage and airway pressures during different suction conditions were compared using a Kruskal Wallis test and Mann Whitney test (P<0.05). RESULTS: The airway pressure drop during suction was similar for both tube cuffs. The PU tube cuff resulted in significantly less fluid leakage (range 0.00-0.12 mL) than the PVC tube cuff (P<0.001). For the PVC tube cuff, fluid leakage at higher cuff pressures was significantly less (P<0.01).Varying PEEP and PIP did not change the fluid leakage or the drop in airway pressure. CONCLUSION: The use of PU tube cuffs and intermittent transient increases in cuff pressure during suction can effectively reduce fluid leakage past the tracheal tube during closed tracheal suctioning. PMID- 21283068 TI - Chest pain caused by tracheostomy tube malposition: the importance of choosing the right tube. AB - We describe a case of chest pain caused by tracheostomy tube malposition in a 65 year old woman with chronic respiratory failure due to chronic obstructive pulmonary disease. This report highlights the importance of the correct choice of tracheostomy tube devices for mechanically ventilated and/or spontaneously breathing patients. PMID- 21283069 TI - Neuraxial dimensions. PMID- 21283070 TI - No progression of Eschmann tube: case report. AB - A 74-year-old patient was submitted to urgent surgery for intestinal occlusion. After the induction of the anaesthesia, tracheal intubation failed since no progression of Eshmann tracheal tube introducer was possible. The ventilation was difficult and a laryngeal mask was inserted. After oxygenation, the tracheal tube with a rigid catheter was positioned. The larynx was visible but there was a spur that obstacled the progression of the Eshmann tracheal tube introducer. The spur derived from a previous tracheostomy. PMID- 21283071 TI - Perioperative management of proximal hip fractures in the elderly: the surgeon and the anesthesiologist. AB - The comprehensive management of proximal hip fractures in elderly patients requires dedicated and responsive teamwork. Elderly patients often present with several comorbidities and the immediate treatment of a fracture has to optimize both medical therapy and analgesic control in order to reduce surgical and anesthetic complications and to preserve as much cognitive functioning as possible. The elderly are uniquely exposed to complications related to bed rest, delirium and postoperative cognitive dysfunction (POCD), which appear to be independent factors of morbidity. Anesthetic management that includes good perioperative pain management can influence the patient's inflammatory response and possibly decrease the incidence of POCD. The best choice of surgical treatment depends on the type of fracture as well as the patient's age and medical condition. However, the type of anesthesia management, which includes neuraxial blocks, peripheral nerve blocks and/or general anesthesia, has to be tailored towards generated the best outcome. We present a review from a surgical and anesthetic perspective on the most common perioperative issues in proximal fracture repair. PMID- 21283074 TI - Law and medical ethics: in defense of reality. PMID- 21283076 TI - Use of hypothermia for traumatic brain injury: point of view. AB - Traumatic brain injury (TBI) is one of the major causes of disability in modern society. The World Health Organization has predicted that, by 2020, traffic accidents will represent the greatest burden of global disease and injury. Brain injury after trauma occurs in two stages. Primary injury is directly associated with the biomechanical effects of the trauma, whereas secondary injury occurs later and can be attributed to processes that develop within the brain. Currently, there is no consensus for the use of hypothermia in the treatment of secondary injury after TBI. Until the results of ongoing studies are published, maintaining normothermia and avoiding hyperthermia should be used in managing patient with TBI. PMID- 21283077 TI - Differential expression of c-Ret in motor neurons versus non-neuronal cells is linked to the pathogenesis of ALS. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by selective degeneration of motor neurons throughout the central nervous systems. Non-cell autonomous damage induced by glial cells is linked to the selective susceptibility of motor neurons in ALS, but the mechanisms underlying this phenomenon are not known. We found that the expression of non phosphorylated and phosphorylated forms (tyrosine (Tyr) residue 905, 1016, and 1062) of c-Ret, a member of the glial cell line-derived neurotrophic factor (GDNF) receptor, are altered in motor neurons of the lumbar spinal cord in ALS transgenic (G93A) mice and ALS (G93A) cell line models. Phosphorylated forms of c Ret were colocalized with neurofilament aggregates in motor neurons of ALS mice. Consistent with the in vivo data, levels of non-phosphorylated and phosphorylated c-Ret (Tyr 905, 1016, and 1062) were decreased by oxidative stress in motor neuronal cells (NSC-34). Non-phosphorylated and phosphorylated forms of c-Ret immunoreactivity were markedly elevated in active microglia of ALS mice. Our findings suggest that constitutive oxidative stress modulates c-Ret function, thereby reducing GDNF signaling in motor neurons. Furthermore, the induction of c Ret expression in microglia may contribute to non-cell autonomous cell death of motor neurons by available GDNF in ALS. PMID- 21283078 TI - Slug enhances invasion ability of pancreatic cancer cells through upregulation of matrix metalloproteinase-9 and actin cytoskeleton remodeling. AB - Slug, a member of the Snail family of transcription factors, has a crucial role in the regulation of epithelial-mesenchymal transition (EMT) by suppressing several epithelial markers and adhesion molecules, including E-cadherin. A recent study demonstrated that no relationship exists between Slug and E-cadherin in pancreatic cancer. Another study showed that in malignant mesothelioma effusions Slug was associated with matrix metalloproteinase (MMP) expression, but that there was no association with E-cadherin. F-ascin is an actin-bundling protein involved in filopodia assembly and cancer invasion and metastasis of multiple epithelial cancer types. In this study, we investigated Slug, E-cadherin, and MMP 9 expression using immunohistochemistry in 60 patients with pancreatic cancer and their correlation with carcinoma invasion and metastasis. Additionally, we observed the effects of Slug on invasion and metastasis in the pancreatic cancer cell line PANC-1. Alterations in Slug, MMP-9, and E-cadherin were determined by RT-PCR, western blot, and immunohistochemistry. Alterations in MMP-9 and F-actin cytoskeleton were determined by immunofluorescence staining, flow cytometry (FCM), or gelatin zymography. Slug, E-cadherin, and MMP-9 expression in pancreatic cancer was significantly associated with lymph node metastases and we found a significant correlation between Slug and MMP-9 expression; however, no significant correlation was observed between Slug and E-cadherin expression. Slug transfection significantly increased invasion and metastasis in PANC-1 cells and orthotopic tumor of mouse in vivo, and significantly upregulated and activated MMP-9; however, there was no effect on E-cadherin expression. Slug promoted the formation of lamelliopodia or filopodia in PANC-1 cells. The intracellular F actin and MMP-9 was increased and relocated to the front of the extending pseudopodia from the perinuclear pool in Slug-transfected PANC-1 cells. These results suggest that Slug promotes migration and invasion of PANC-1 cells, which may correlate with the reorganization of MMP-9 and remodeling of the F-actin cytoskeleton, but not with E-cadherin expression. PMID- 21283079 TI - Coronary vein infusion of multipotent stromal cells from bone marrow preserves cardiac function in swine ischemic cardiomyopathy via enhanced neovascularization. AB - Few reports have examined the effects of adult bone marrow multipotent stromal cells (MSCs) on large animals, and no useful method has been established for MSC implantation. In this study, we investigate the effects of MSC infusion from the coronary vein in a swine model of chronic myocardial infarction (MI). MI was induced in domestic swine by placing beads in the left coronary artery. Bone marrow cells were aspirated and then cultured to isolate the MSCs. At 4 weeks after MI, MSCs labeled with dye (n=8) or vehicle (n=5) were infused retrogradely from the anterior interventricular vein without any complications. Left ventriculography (LVG) was performed just before and at 4 weeks after cell infusion. The ejection fraction (EF) assessed by LVG significantly decreased from baseline up to a follow-up at 4 weeks in the control group (P<0.05), whereas the cardiac function was preserved in the MSC group. The difference in the EF between baseline and follow-up was significantly greater in the MSC group than in the control group (P<0.05). The MSC administration significantly promoted neovascularization in the border areas compared with the controls (P<0.0005), though it had no affect on cardiac fibrosis. A few MSCs expressed von Willebrand factor in a differentiation assay, but none of them expressed troponin T. In quantitative gene expression analysis, basic fibroblast growth factor and vascular endothelial growth factor (VEGF) levels were significantly higher in the MSC-treated hearts than in the controls (P<0.05, respectively). Immunohistochemical staining revealed VEGF production in the engrafted MSCs. In vitro experiment demonstrated that MSCs significantly stimulated endothelial capillary network formation compared with the VEGF protein (P<0.0001). MSC infusion via the coronary vein prevented the progression of cardiac dysfunction in chronic MI. This favorable effect appeared to derive not from cell differentiation, but from enhanced neovascularization by angiogenic factors secreted from the MSCs. PMID- 21283081 TI - Hemodynamic alterations associated with polycythemia and partial exchange transfusion. AB - Polycythemia hyperviscosity syndrome has been associated with multiple systemic effects. There is dearth of data on the effects of polycythemia on cardiac function. This case presents a newborn infant with symptomatic polycythemia in whom detailed myocardial function analysis for systolic and diastolic performance, as well as end-organ perfusion assessment was carried out using transthoracic echocardiography. Hemodynamic information in polycythemic infants before and after partial exchange could improve our understanding of the impact on myocardial performance. PMID- 21283082 TI - Congenital multiple pituitary hormone deficiency associated with hyperammonemia: a case report with a short review of the literature. AB - We herein report a case study of a female newborn with multiple pituitary hormone deficiencies who presented with generalized seizures, hypoglycemia and hyperammonemia at 18 h after birth. In addition, we review the association of hyperammonemia in neonates with multiple pituitary hormone deficiencies reported in the previous literature. This unrecognized association should be taken into account for the early diagnosis and treatment of these patients. PMID- 21283083 TI - Investigation of rare non-synonymous variants at ABCA13 in schizophrenia and bipolar disorder. PMID- 21283084 TI - The inv(3)(q21q26)/t(3;3)(q21;q26) is frequently accompanied by alterations of the RUNX1, KRAS and NRAS and NF1 genes and mediates adverse prognosis both in MDS and in AML: a study in 39 cases of MDS or AML. PMID- 21283085 TI - International spinal cord injury male sexual function basic data set. AB - OBJECTIVE: To create the International Spinal Cord Injury (SCI) Male Sexual Function Basic Data Set within the International SCI Data Sets. SETTING: An international working group. METHODS: The draft of the data set was developed by an international working group consisting of members appointed by the International Spinal Cord Society (ISCoS), the American Spinal Injury Association (ASIA) and a representative from the executive committee of the International SCI Standards and Data Sets. The data set was developed in an iterative process with review and comments by the members of the executive committee of the International SCI Standards and Data Sets, ISCoS scientific committee, ASIA Board and the ISCoS Council, as well as all the interested organizations and individuals. Next, the data set was posted for 2 months at the ISCoS and ASIA's websites for comments. ISCoS and ASIA approved the final version of the data set. To make the data set uniform, each variable and each response category within each variable have been specifically defined in a way that is designed to promote the collection and reporting of comparable minimal data. RESULTS: Variables included in the International SCI Male Sexual Function Basic Data Set are as follows: date of data collection, interest in discussing sexual issues, sexual issues unrelated to spinal cord lesion, sexual dysfunction related to spinal cord lesion, psychogenic erection, reflex erection, ejaculation and orgasmic function. Complete instructions for data collection, data sheet and training cases are available at the website of ISCoS (http://www.iscos.org.uk) and ASIA (http://www.asia-spinalinjury.org). PMID- 21283086 TI - Clinical concomitant benefits on pelvic floor dysfunctions after sacral neuromodulation in patients with incomplete spinal cord injury. AB - OBJECTIVES: To assess the concomitant clinical improvement in incomplete spinal cord injury patients (SCIPs) suffering from neurogenic bowel symptoms (NBSs), neurogenic lower urinary tract symptoms (NLUTSs) and neurogenic erectile dysfunction (NED) using sacral neuromodulation (SNM) for NBSs and NLUTSs. METHODS: Seventy-five SCIPs were selected. Before and during the follow-ups post SNM, NLUTSs and NBSs were detected mainly through specific diaries. Erectile function was assessed using the International Index of Erectile Function composed of 5 questions (IIEF5). Quality of life (QoL) was measured with the Short Form 36 Health Survey questionnaire (SF-36). During the first stage, in which a permanent electrode was inserted percutaneously into the third sacral foramina and stimulated using an external generator, patients with NBSs or NLUTSs were required to improve their symptoms by at least 50% compared with baseline before proceeding to the second stage in which the generator was placed in the patient's buttock. NED patients needed to increase their IIEF5 score by at least 25% compared with baseline (evaluated initially 3 months after the second stage) in order to continue follow-up. RESULTS: Fourteen out of 37 subjects who manifested two functional pelvic dysfunctions at baseline maintained notable clinical improvement in two pelvic functions (median follow-up >3 years). Six had non obstructive retention (NOR) and NED, six double incontinence, and two constipation with NOR. In the general and mental health domains of the SF-36, all patients improved their scores by at least 20% compared with baseline. CONCLUSIONS: SNM may be beneficial to selected incomplete SCIP with concomitant pelvic functional disturbances. PMID- 21283087 TI - Tests of association for rare variants: case control mutation screening. PMID- 21283088 TI - Developmental switches that hold the key to a revolution in crop biotechnology. PMID- 21283089 TI - Mutation: the perils of transcription. PMID- 21283090 TI - An accelerated pathway for targeted cancer therapies. AB - A well-defined pathway for the accelerated development and approval of targeted cancer therapies and companion diagnostics would reduce uncertainty, improve efficiency in development and provide an effective incentive for developers. PMID- 21283091 TI - 'Pharmers' hope for first plant drug harvest. PMID- 21283092 TI - 2010 FDA drug approvals. PMID- 21283093 TI - Trial watch: antibody-drug conjugate shows efficacy in lymphoma. PMID- 21283094 TI - Regulatory watch: FDA guidance on co-developing investigational drugs. PMID- 21283095 TI - Trial watch: phase III and submission failures: 2007-2010. PMID- 21283096 TI - Patent watch: Indian patent office rejects HIV drug formulation patent. PMID- 21283097 TI - An audience with Abraham Thomas. Interview by Asher Mullard. PMID- 21283098 TI - Hepatitis C--pipeline update. PMID- 21283099 TI - Tesamorelin. AB - In November 2010, tesamorelin (Egrifta; Theratechnologies/EMD Serono), a growth hormone-releasing factor analogue, was approved by the US Food and Drug Administration for the reduction of excess abdominal fat in HIV-infected patients with lipodystrophy. PMID- 21283100 TI - G protein-coupled receptors: Crystallizing how agonists bind. PMID- 21283101 TI - Cardiovascular disease: microRNA protects the heart. PMID- 21283102 TI - Cancer: Hope for smoking-associated lung cancer? PMID- 21283103 TI - Antivirals: Identifying adenoviral receptors. PMID- 21283104 TI - Cardiovascular drugs: a determinant of clopidogrel efficacy. PMID- 21283105 TI - Advances in the assessment and control of the effector functions of therapeutic antibodies. AB - The Fc (crystallizable fragment) region of therapeutic antibodies can have an important role in their safety and efficacy. Although much is known about the structure-activity relationship of antibodies and the factors that influence Fc effector functions, a process has not yet been defined to clearly delineate how Fc functionality should be assessed and controlled during antibody development and manufacturing. In this article, we summarize the current knowledge of antibody Fc functionality, provide a strategy for assessing the effector functions of different classes of therapeutic antibodies (including Fc fusion proteins) and propose a path for routine testing and controls for manufacturers of antibody products. PMID- 21283106 TI - Cardiotoxicity of kinase inhibitors: the prediction and translation of preclinical models to clinical outcomes. AB - Targeted therapeutics, particularly those that inhibit the activity of protein kinases that are mutated and/or overexpressed in cancer, have revolutionized the treatment of some cancers and improved survival rates in many others. Although these agents dominate drug development in cancer, significant toxicities, including cardiotoxicity, have emerged. In this Review, we examine the underlying mechanisms that result in on-target or off-target cardiotoxicities of small molecule kinase inhibitors. We also discuss how well the various preclinical safety models and strategies might predict clinical cardiotoxicity. It is hoped that a thorough understanding of the mechanisms underlying cardiotoxicity will lead to the development of safe, effective drugs and consequently, fewer costly surprises as agents progress through clinical trials. PMID- 21283107 TI - Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond. AB - Recent advances in our understanding of the pathogenesis of the Philadelphia chromosome-negative myeloproliferative neoplasms, polycythaemia vera, essential thrombocythaemia and myelofibrosis have led to the identification of the mutation V617F in Janus kinase (JAK) as a potential therapeutic target. This information has prompted the development of ATP-competitive JAK2 inhibitors. Therapy with JAK2 inhibitors may induce rapid and marked reductions in spleen size and can lead to remarkable improvements in constitutional symptoms and overall quality of life. Because JAKs are involved in the pathogenesis of inflammatory and immune mediated disorders, JAK inhibitors are also being tested in clinical trials in patients with rheumatoid arthritis and psoriasis, as well as for the treatment of other autoimmune diseases and for the prevention of allograft rejection. Preliminary results indicate that these agents hold great promise for the treatment of JAK-driven disorders. PMID- 21283109 TI - Antibody responses to glycolipid-borne carbohydrates require CD4+ T cells but not CD1 or NKT cells. AB - Naturally occurring anti-carbohydrate antibodies play a major role in both the innate and adaptive immune responses. To elicit an anti-carbohydrate immune response, glycoproteins can be processed to glycopeptides and presented by the classical antigen-presenting molecules, major histocompatibility complex (MHC) Class I and II. In contrast, much less is known about the mechanism(s) for anti carbohydrate responses to glycolipids, although it is generally considered that the CD1 family of cell surface proteins presents glycolipids to T cells or natural killer T (NKT) cells. Using model carbohydrate systems (isogloboside 3 and B blood group antigen), we examined the anti-carbohydrate response on glycolipids using both antibody neutralisation and knockout mouse-based experiments. These studies showed that CD4(+) T cells were required to generate antibodies to the carbohydrates expressed on glycolipids, and unexpectedly, these antibody responses were CD1d and NKT cell independent. They also did not require peptide help. These data provide new insight into glycolipid antigen recognition by the immune system and indicate the existence of a previously unrecognised population of glycolipid antigen-specific, CD1-independent, CD4(+) T cells. PMID- 21283108 TI - Emerging therapeutic opportunities for skeletal restoration. AB - Osteoporosis, a syndrome characterized by thin bones and fractures, has become more prevalent in both women and men. Established therapies for treating this disorder consist primarily of drugs that prevent bone loss, such as the bisphosphonates and selective oestrogen receptor modulators. Although these drugs have been shown to reduce fractures in randomized trials, there is an urgent need for treatments that could lower fracture risk further without additional adverse effects. The introduction of parathyroid hormone (teriparatide), which significantly increases bone mineral density, albeit for a relatively short duration, raised expectations that drugs that stimulate bone formation might cure osteoporosis. After outlining current approaches for treating osteoporosis, this Review focuses on emerging therapeutic opportunities for osteoporosis that are based on recent insights into skeletal physiology. Such novel strategies offer promise not only for reducing age-related bone loss and the associated risk of fractures but also for restoring bone mineral density to healthy levels. PMID- 21283110 TI - CD27-deficient mice show normal NK-cell differentiation but impaired function upon stimulation. AB - Natural killer (NK) cells are part of the first line defense against tumors, parasites and virus-infected cells. Therefore, factors that control NK-cell numbers and their function are important. CD27 is constitutively expressed on NK cells and its expression correlates with sequential phases in NK-cell development, discriminating phenotypically and functionally different subsets within the NK-cell population. Although CD27 has been described to have an important regulatory role in effector and memory T and B lymphocytes, its role in NK-cell biology remains to be addressed. In this study, we used CD27(-/-) mice to investigate the role of CD27 in NK-cell development and function, both during the resting state and upon stimulation. The results show that NK-cell numbers are not impaired in CD27(-/-) mice. Moreover, CD27(-/-) NK cells reach full phenotypic maturity, evidenced by normal expression of CD49b, CD43 and CD11b. Expression of activating receptors is unaltered, whereas expression of several inhibitory receptors is increased. Cytotoxicity and interferon-gamma production by NK cells from CD27(-/-) mice in the resting state are normal. However, upon in vivo anti CD40- or poly-I:C-mediated activation, or in vitro interleukin-15 priming plus anti-NKp46 stimulation, the absence of CD27 results in decreased cytolytic activity and cytokine production by spleen and liver NK cells. In conclusion, this study demonstrates that CD27 is dispensable for the development of functional NK cells. However, upon stimulation of NK cells, CD27 displays an important role in their activation and functionality. PMID- 21283111 TI - Warhead. PMID- 21283112 TI - What about 'information'? PMID- 21283113 TI - Genomes: the truth is in there. PMID- 21283114 TI - Genomes, race and health. Racial profiling in medicine might just be a stepping stone towards personalized health care. PMID- 21283115 TI - The health of European medical research. Attempts are under way to update EU regulations, with the aim of harmonizing clinical research across the continent. PMID- 21283117 TI - Reviewing refereeing. AB - Considered and critical assessment of a manuscript is essential to peer review and the publication process, but what makes a good referee report? We highlight the central elements of the ideal referee report. PMID- 21283116 TI - Signal processing in complex chemotaxis pathways. AB - Bacteria use chemotaxis to migrate towards environments that are better for growth. Chemoreceptors detect changes in attractant levels and signal through two component systems to control swimming direction. This basic pathway is conserved across all chemotactic bacteria and archaea; however, recent work combining systems biology and genome sequencing has started to elucidate the additional complexity of the process in many bacterial species. This article focuses on one of the best understood complex networks, which is found in Rhodobacter sphaeroides and integrates sensory data about the external environment and the metabolic state of the cell to produce a balanced response at the flagellar motor. PMID- 21283118 TI - RNA seeds nuclear bodies. AB - The interior of the eukaryotic cell nucleus is populated by a multitude of microscopic domains termed nuclear bodies. Despite having attracted much attention, how these compartments form and are maintained remained elusive. Now, two live-cell imaging studies provide compelling evidence that nascent RNAs can act as transiently immobilized scaffolds that recruit specific nuclear body proteins. PMID- 21283119 TI - Proclaiming fate in the early mouse embryo. AB - In the mouse embryo, the first differences between cells that result in distinct lineages have long been thought to arise only as a consequence of differential cell positioning at relatively late preimplantation stages. Differences in Oct4 transcription factor kinetics between cells at the 4-8-cell stage are now shown to be predictive of future lineages, providing further evidence for much earlier initiation of cell fate decisions. PMID- 21283123 TI - Metformin or thiazolidinedione therapy in PCOS? PMID- 21283124 TI - Vaptans for the treatment of hyponatremia. AB - The vaptans constitute a new class of pharmaceuticals developed for the treatment of the hypervolemic and euvolemic forms of hyponatremia. These agents are nonpeptide vasopressin antagonists that interfere with the antidiuretic effect of the hormone by competitively binding to V(2) receptors in the kidney. This blockade results in water diuresis (aquaresis) that, if not offset by increased fluid intake, reduces body water content and raises plasma sodium levels. Probably as a result of this rise in plasma sodium, thirst and plasma vasopressin concentration increase, potentionally limiting the effects of the vasopressin antagonists. Nonetheless, vaptans are particularly useful to treat hypervolemic hyponatremia associated with severe congestive heart failure or chronic liver failure, as the only other treatments currently available, such as fluid restriction and diuretics, are slow-acting and minimally effective. Vaptans are also useful for treating euvolemic hyponatremia associated with the syndrome of inappropriate antidiuretic hormone (SIADH), at least when it is chronic and/or minimally symptomatic. However, because their effects vary unpredictably from patient to patient, vaptans are less useful than hypertonic saline infusion in cases of acute, severe and symptomatic hyponatremia. Vaptan therapy is absolutely contraindicated in hypovolemic hyponatremia (in which total body water is reduced) and is ineffective in the vasopressin-independent form of inappropriate antidiuresis caused by constitutive activating mutations of V(2) receptors. PMID- 21283125 TI - Statins for secondary prevention: might less in fact be more? PMID- 21283126 TI - Combination therapy: hypoxia modification with radiotherapy for bladder cancer. PMID- 21283127 TI - Mitosis is not a key target of microtubule agents in patient tumors. AB - Mitosis-specific agents have, to date, not been clinically successful. By contrast, microtubule-targeting agents (MTAs) have a long record of success, usually attributed to the induction of mitotic arrest. Indeed, it was this success that led to the search for mitosis-specific inhibitors. We believe the clinical disappointment of mitosis-specific inhibitors stands as evidence that MTAs have been successful not only by interfering with mitosis but, more importantly, by disrupting essential interphase cellular mechanisms. In this Perspective we will review literature that supports a paradigm shift in how we think about one of our most widely used classes of chemotherapeutics-MTAs. We believe that the steady presence and constant physiological role of microtubules are responsible for the overall success of MTAs. While mitosis-specific inhibitors are effective on only a small fraction of the tumor mass (dividing cells), MTAs target tubulin, a protein that has crucial roles in both mitotic and non-mitotic cells. PMID- 21283128 TI - Hematology: curing CML with imatinib--a dream come true? PMID- 21283130 TI - Waste disposal in the endoplasmic reticulum, ROS production and plant salt stress response. PMID- 21283129 TI - Slit-Robo signaling induces malignant transformation through Hakai-mediated E cadherin degradation during colorectal epithelial cell carcinogenesis. AB - The Slit family of guidance cues binds to Roundabout (Robo) receptors and modulates cell migration. We report here that ectopic expression of Slit2 and Robo1 or recombinant Slit2 treatment of Robo1-expressing colorectal epithelial carcinoma cells recruited an ubiquitin ligase Hakai for E-cadherin (E-cad) ubiquitination and lysosomal degradation, epithelial-mesenchymal transition (EMT), and tumor growth and liver metastasis, which were rescued by knockdown of Hakai. In contrast, knockdown of endogenous Robo1 or specific blockade of Slit2 binding to Robo1 prevented E-cad degradation and reversed EMT, resulting in diminished tumor growth and liver metastasis. Ectopic expression of Robo1 also triggered a malignant transformation in Slit2-positive human embryonic kidney 293 cells. Importantly, the expression of Slit2 and Robo1 was significantly associated with an increased metastatic risk and poorer overall survival in colorectal carcinoma patients. We conclude that engagement of Robo1 by Slit2 induces malignant transformation through Hakai-mediated E-cad ubiquitination and lysosomal degradation during colorectal epithelial cell carcinogenesis. PMID- 21283131 TI - Association of telomere length with authentic pluripotency of ES/iPS cells. AB - Telomerase and telomeres are important for indefinite replication of stem cells. Recently, telomeres of somatic cells were found to be reprogrammed to elongate in induced pluripotent stem cells (iPSCs). The role of telomeres in developmental pluripotency in vivo of embryonic stem cells (ESCs) or iPSCs, however, has not been directly addressed. We show that ESCs with long telomeres exhibit authentic developmental pluripotency, as evidenced by generation of complete ESC pups as well as germline-competent chimeras, the most stringent tests available in rodents. ESCs with short telomeres show reduced teratoma formation and chimera production, and fail to generate complete ESC pups. Telomere lengths are highly correlated (r > 0.8) with the developmental pluripotency of ESCs. Short telomeres decrease the proliferative rate or capacity of ESCs, alter the expression of genes related to telomere epigenetics, down-regulate genes important for embryogenesis and disrupt germ cell differentiation. Moreover, iPSCs with longer telomeres generate chimeras with higher efficiency than those with short telomeres. Our data show that functional telomeres are essential for the developmental pluripotency of ESCs/iPSCs and suggest that telomere length may provide a valuable marker to evaluate stem cell pluripotency, particularly when the stringent tests are not feasible. PMID- 21283133 TI - Talking to histone: methylated RelA serves as a messenger. PMID- 21283132 TI - Genomic imprinting in mammals: its life cycle, molecular mechanisms and reprogramming. AB - Genomic imprinting, an epigenetic gene-marking phenomenon that occurs in the germline, leads to parental-origin-specific expression of a small subset of genes in mammals. Imprinting has a great impact on normal mammalian development, fetal growth, metabolism and adult behavior. The epigenetic imprints regarding the parental origin are established during male and female gametogenesis, passed to the zygote through fertilization, maintained throughout development and adult life, and erased in primordial germ cells before the new imprints are set. In this review, we focus on the recent discoveries on the mechanisms involved in the reprogramming and maintenance of the imprints. We also discuss the epigenetic changes that occur at imprinted loci in induced pluripotent stem cells. PMID- 21283134 TI - Mitochondrial ROS fuel the inflammasome. PMID- 21283135 TI - Chronic kidney disease: the CKD-EPI equation to estimate GFR-better alchemy? PMID- 21283136 TI - Sudden cardiac death in chronic kidney disease: epidemiology and prevention. AB - Annual cardiovascular mortality in patients with chronic kidney disease (CKD) is much higher than in the general population. The rate of sudden cardiac death increases as the stage of CKD increases and could be responsible for 60% of cardiac deaths in patients undergoing dialysis. In hemodialysis units treating patients with CKD, cardiac arrest occurs at a rate of seven arrests per 100,000 hemodialysis sessions. Important risk factors for sudden cardiac death in patients with CKD include hospitalization within the past 30 days, a drop of 30 mmHg in systolic blood pressure during hemodialysis, duration of life on hemodialysis, time since the previous dialysis session, and the presence of concomitant diabetes mellitus. As a result of the adverse cardiomyopathic and vasculopathic milieu in CKD, the occurrence of arrhythmias, conduction abnormalities, and sudden cardiac death could be exacerbated by electrolyte shifts, divalent ion abnormalities, diabetes, sympathetic overactivity, in addition to inflammation and perhaps iron deposition. Impaired baroreflex effectiveness and sensitivity, as well as obstructive sleep apnea, might also contribute to the risk of sudden death in CKD. The likelihood of survival following cardiac arrest is very low in dialysis patients. Primary and secondary prevention of cardiac arrest could reduce cardiovascular mortality in patients with CKD. Cardioverter-defibrillator implantation decreases the risk of sudden death in patients with CKD. The decision to implant a cardioverter-defibrillator should be influenced by the patient's age and stage of CKD. PMID- 21283137 TI - Transplantation: strength in numbers-predicting long-term transplant outcomes. PMID- 21283138 TI - Chronic viral hepatitis in kidney transplantation. AB - Chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection in potential kidney transplant candidates-once considered absolute contraindications to kidney transplantation-no longer creates overt barriers to transplantation. Advances in the medical management of HBV and HCV infection have created opportunities for a substantial number of patients to be effectively treated with antiviral therapy before transplantation. For HBV infection, a number of new drugs enable clearance of the virus with minimal adverse effects and drug resistance. Pretransplantation antiviral therapy is advisable for patients with HCV infection, but adverse effects are common and viral eradication remains challenging. Regardless of viral clearance, pretransplant patients without bridging fibrosis (as confirmed by liver biopsy) or clinical stigmata of cirrhosis should be considered for kidney transplantation as survival is superior when compared to treatment with dialysis, and progression of liver disease is unlikely. For patients with advanced liver disease, simultaneous liver-kidney transplantation is an important consideration. These treatment advances further increase the burden of organ donor shortage; however, organs from deceased donors with chronic HBV or HCV infection could be efficiently allocated to certain individuals with a viral infection of the same type to increase the pool of available transplant organs. PMID- 21283139 TI - Prenatal programming-effects on blood pressure and renal function. AB - Impaired intrauterine nephrogenesis-most clearly illustrated by low nephron number-is frequently associated with low birthweight and has been recognized as a powerful risk factor for renal disease; it increases the risks of low glomerular filtration rate, of more rapid progression of primary kidney disease, and of increased incidence of chronic kidney disease or end-stage renal disease. Another important consequence of impaired nephrogenesis is hypertension, which further amplifies the risk of onset and progression of kidney disease. Hypertension is associated with low nephron numbers in white individuals, but the association is not universal and is not seen in individuals of African origin. The derangement of intrauterine kidney development is an example of a more general principle that illustrates the paradigm of plasticity during development-that is, that transcription of the genetic code is modified by epigenetic factors (as has increasingly been documented). This Review outlines the concept of prenatal programming and, in particular, describes its role in kidney disease and hypertension. PMID- 21283140 TI - Comprehensive quantitative analysis of central carbon and amino-acid metabolism in Saccharomyces cerevisiae under multiple conditions by targeted proteomics. AB - Decades of biochemical research have identified most of the enzymes that catalyze metabolic reactions in the yeast Saccharomyces cerevisiae. The adaptation of metabolism to changing nutritional conditions, in contrast, is much less well understood. As an important stepping stone toward such understanding, we exploit the power of proteomics assays based on selected reaction monitoring (SRM) mass spectrometry to quantify abundance changes of the 228 proteins that constitute the central carbon and amino-acid metabolic network in the yeast Saccharomyces cerevisiae, at five different metabolic steady states. Overall, 90% of the targeted proteins, including families of isoenzymes, were consistently detected and quantified in each sample, generating a proteomic data set that represents a nutritionally perturbed biological system at high reproducibility. The data set is near comprehensive because we detect 95-99% of all proteins that are required under a given condition. Interpreted through flux balance modeling, the data indicate that S. cerevisiae retains proteins not necessarily used in a particular environment. Further, the data suggest differential functionality for several metabolic isoenzymes. PMID- 21283141 TI - Synthetic in vitro transcriptional oscillators. AB - The construction of synthetic biochemical circuits from simple components illuminates how complex behaviors can arise in chemistry and builds a foundation for future biological technologies. A simplified analog of genetic regulatory networks, in vitro transcriptional circuits, provides a modular platform for the systematic construction of arbitrary circuits and requires only two essential enzymes, bacteriophage T7 RNA polymerase and Escherichia coli ribonuclease H, to produce and degrade RNA signals. In this study, we design and experimentally demonstrate three transcriptional oscillators in vitro. First, a negative feedback oscillator comprising two switches, regulated by excitatory and inhibitory RNA signals, showed up to five complete cycles. To demonstrate modularity and to explore the design space further, a positive-feedback loop was added that modulates and extends the oscillatory regime. Finally, a three-switch ring oscillator was constructed and analyzed. Mathematical modeling guided the design process, identified experimental conditions likely to yield oscillations, and explained the system's robust response to interference by short degradation products. Synthetic transcriptional oscillators could prove valuable for systematic exploration of biochemical circuit design principles and for controlling nanoscale devices and orchestrating processes within artificial cells. PMID- 21283142 TI - Programming an in vitro DNA oscillator using a molecular networking strategy. AB - Living organisms perform and control complex behaviours by using webs of chemical reactions organized in precise networks. This powerful system concept, which is at the very core of biology, has recently become a new foundation for bioengineering. Remarkably, however, it is still extremely difficult to rationally create such network architectures in artificial, non-living and well controlled settings. We introduce here a method for such a purpose, on the basis of standard DNA biochemistry. This approach is demonstrated by assembling de novo an efficient chemical oscillator: we encode the wiring of the corresponding network in the sequence of small DNA templates and obtain the predicted dynamics. Our results show that the rational cascading of standard elements opens the possibility to implement complex behaviours in vitro. Because of the simple and well-controlled environment, the corresponding chemical network is easily amenable to quantitative mathematical analysis. These synthetic systems may thus accelerate our understanding of the underlying principles of biological dynamic modules. PMID- 21283143 TI - Substrate-dependent control of MAPK phosphorylation in vivo. AB - Phosphorylation of the mitogen-activated protein kinase (MAPK) is essential for its enzymatic activity and ability to control multiple substrates inside a cell. According to the current models, control of MAPK phosphorylation is independent of its substrates, which are viewed as mere sensors of MAPK activity. Contrary to this modular view of MAPK signaling, our studies in the Drosophila embryo demonstrate that substrates can regulate the level of MAPK phosphorylation in vivo. We demonstrate that a twofold change in the gene dosage of a single substrate can induce a significant change in the phosphorylation level of MAPK and in the conversion of other substrates. Our results support a model where substrates of MAPK counteract its dephosphorylation by phosphatases. Substrate dependent control of MAPK phosphorylation is a manifestation of a more general retroactive effect that should be intrinsic to all networks with covalent modification cycles. PMID- 21283144 TI - Sexual dimorphism of RA manifestations: genes, hormones and behavior. AB - Women are more likely than men to develop rheumatoid arthritis (RA), and recent data suggest that they also suffer greater disability than men with this disease. The reasons for these sexually dimorphic patterns of disease incidence and progression are unknown, but investigations into the underlying mechanisms could provide useful insights into RA pathogenesis and may also suggest new treatment approaches. The processes of sexual differentiation involve genetic input, gonadal hormone signaling and responses from target cells and tissues. Layered upon these processes are behavioral characteristics of males and females acquired as a result of their social context. Differences in disease presentation between the sexes could be the result of complex combinations of all these factors. Recent research suggests that the developmental processes of sexual differentiation might render women more susceptible than men to similar levels of immune or inflammatory burden by virtue of sex-specific differences in body composition and structure. PMID- 21283145 TI - Harnessing programmed cell death as a therapeutic strategy in rheumatic diseases. AB - Programmed cell death (PCD) is a key process in the regulation of immune cell development and peripheral immune homeostasis. Caspase-dependent apoptosis, as well as a number of alternative cell death mechanisms, account for immune cell PCD induced by cell-intrinsic and extrinsic pathways. In animal models, compelling evidence has emerged that genetic defects in PCD can result in autoimmune disease. Autoimmune disease can arise from single-gene mutations that affect PCD, and defective PCD has been observed in some tissues and cells from patients with rheumatic disease. Selectively inducing PCD in autoreactive B and T cells is very attractive as a therapeutic strategy because it offers the possibility of permanent elimination of these pathogenic cell subsets. In addition, the anti-inflammatory effects of apoptotic cells may add to the therapeutic benefit of induced PCD. Immune cell subsets vary widely in their sensitivity to specific inducers of cell death, and understanding these differences is key to predicting the outcome of inducing apoptosis for therapeutic means. Here, we review approaches that have been used to induce PCD in the treatment of autoimmune disease, and describe the prospects of bringing these experimental strategies into clinical practice. PMID- 21283146 TI - Long-lived autoreactive plasma cells drive persistent autoimmune inflammation. AB - Aberrant production of autoantibodies by inappropriately self-reactive plasma cells is an inherent characteristic of autoimmune diseases. Several therapeutic strategies aim to deplete the plasma cell pool, or to prevent maturation of B cells into plasma cells. However, accepted views of B-cell biology are changing; recent findings show that long-lived plasma cells refractory to immunosuppressants and B-cell depletion therapies contribute to the maintenance of humoral memory and, in autoimmunity, to autoreactive memory. As a consequence of their longevity and persistence, long-lived plasma cells can support chronic inflammatory processes in autoimmune diseases by continuously secreting pathogenic antibodies, and they can contribute to flares of symptoms. As long lived plasma cells are not sufficiently eliminated by current therapies, these findings are extremely relevant to the development of novel concepts for the treatment of autoimmune diseases. Thus, long-lived plasma cells appear to be a promising new therapeutic target. PMID- 21283147 TI - Pain, catastrophizing, and depression in the rheumatic diseases. AB - Persistent and disabling pain is the hallmark of osteoarthritis, rheumatoid arthritis, fibromyalgia, and various other rheumatologic conditions. However, disease severity (as measured by 'objective' indices such as those that employ radiography or serology) is only marginally related to patients' reports of pain severity, and pain-related presentation can differ widely between individuals with ostensibly similar conditions (for example, grade 4 osteoarthritis of the knee). Increasing evidence in support of the biopsychosocial model of pain suggests that cognitive and emotional processes are crucial contributors to inter individual differences in the perception and impact of pain. This Review describes the growing body of literature relating depression and catastrophizing to the experience of pain and pain-related sequelae across a number of rheumatic diseases. Depression and catastrophizing are consistently associated with the reported severity of pain, sensitivity to pain, physical disability, poor treatment outcomes, and inflammatory disease activity, and potentially with early mortality. A variety of pathways, from cognitive to behavioral to neurophysiological, seem to mediate these deleterious effects. Collectively, depression and catastrophizing are critically important variables in understanding the experience of pain in patients with rheumatologic disorders. Pain, depression, and catastrophizing might all be uniquely important therapeutic targets in the multimodal management of a range of such conditions. PMID- 21283148 TI - Patent foramen ovale: anatomy, outcomes, and closure. AB - Patent foramen ovale (PFO) is a normal fetal communication between the right and left atria that persists after birth. PFO is a common finding that occurs in 20 34% of the population, although its prevalence decreases with age. In most cases, a PFO poses no threat to health. However, some PFOs have the ability to open widely under certain hemodynamic conditions, which enables any bloodborne material, such as thrombi, air, or vasoactive substances, to pass from the venous to the arterial circulation, with the potential to cause a cerebrovascular event. PFO has been linked to several conditions, including cryptogenic stroke, migraine with aura, decompression illness, and systemic arterial embolism. However, the data that support PFO closure in these conditions are mostly from nonrandomized cohort series, and are often contradictory. In this Review, we discuss the existing data on PFO closure, including results of the first randomized, controlled trial comparing device closure of PFO with medical therapy for cryptogenic stroke, and we examine controversies in the literature as well as ongoing studies. We also focus on the anatomy of a PFO and how it impacts on the procedure of PFO closure with a percutaneous device. PMID- 21283150 TI - Enlightened self-interest. PMID- 21283149 TI - Lipid parameters for measuring risk of cardiovascular disease. AB - Besides measuring blood pressure and glucose levels, assessing the lipid spectrum is the method most commonly used to identify individuals at high risk of cardiovascular disease (CVD), as well as those who are likely to benefit most from lipid-lowering therapy. Although lowering LDL-cholesterol levels is the primary target of therapy in most clinical guidelines, accumulating evidence indicates that other lipoprotein-lipid measurements could provide a predictive value over and above that of LDL-cholesterol levels. For example, individuals treated with statins who achieve low LDL-cholesterol levels, but have high concentrations of either non-HDL cholesterol or apolipoprotein (apo) B, remain at increased cardiovascular risk. Similarly, individuals with low levels of either HDL cholesterol or apo A-I are also likely to experience cardiovascular events, despite having normal LDL-cholesterol levels. The residual cardiovascular risk, beyond that characterized by LDL-cholesterol levels alone, is exacerbated by physical inactivity and abdominal obesity, which are both increasingly prevalent risk factors for CVD. In this Review, we discuss the measurement of various lipoprotein-lipid parameters for the prediction of CVD risk, and their importance in identifying those patients who are likely to benefit from lipid-lowering therapy. The impact of recent studies on clinical guidelines is also considered. PMID- 21283151 TI - Ophthalmic medical personnel certification: the ultimate training tool. PMID- 21283153 TI - Fee splitting in ophthalmology. AB - Fee splitting and co-management are common practices in ophthalmology. These arrangements may conflict with the ethical principles governing the doctor patient relationship, may constitute professional misconduct, and at times, may be illegal. Implications and perceptions of these practices may vary between different cultures. Full disclosure to the patient may minimize the adverse effects of conflicts of interest that arise from these practices, and may thereby allow these practices to be deemed acceptable by some cultural morays, professional guidelines, or by law. Disclosure does not necessarily relieve the physician from a potential ethical compromise. This review examines the practice of fee splitting in ophthalmology, its legal implications, the policies or guidelines governing such arrangements, and the possible ethical ramifications. A comparative view between 3 countries, Canada, the United States, and Oman, was conducted; illustrating that even in disparate cultures, there may be some universality to the application of ethical principles. PMID- 21283154 TI - Survey on allied health personnel in Canadian ophthalmology: the scalpel for change. AB - OBJECTIVE: To determine the recruiting and training needs for ophthalmic medical personnel (OMP), assess the value of their certification, and compare the ophthalmic practice productivity and performance of non-certified and certified OMP, as rated by both ophthalmologists and OMP. DESIGN: Comparative analysis. PARTICIPANTS: One hundred and sixteen Canadian ophthalmologists and 98 OMP. METHODS: An invitation to complete an online survey on OMP recruitment, training, certification, and productivity performance in a clinical setting was sent to 1081 ophthalmologists and OMP. RESULTS: Fifteen percent of ophthalmologists and 31% of OMP completed the survey. Ophthalmologists (61%) reported difficulty hiring OMP; employee referrals was the best method (40%). Awareness of formal OMP training programs was high and 50% of respondents supported developing additional training programs; 55% of OMP were encouraged by their employers to obtain certification. Personal challenge and achievement (79%) and improved skills (71%) were the main reasons for OMP to obtain certification. The majority of OMP and ophthalmologists felt that certified OMP enhanced most practice productivity measures. Higher wages associated with certification were reported by 73% of respondents. CONCLUSIONS: Training of qualified OMP was identified as a need by ophthalmologists. Ophthalmic practices can increase their overall productivity by adding certified OMP to their staff. PMID- 21283155 TI - Antioxidant enzyme mRNA expression in conjunctival epithelium of healthy human subjects. AB - OBJECTIVE: To determine the profile, relative quantitation, and correlation of gene expression of the antioxidant enzymes copper-zinc superoxide dismutase (CuZn SOD), Mn-superoxide dismutase (Mn-SOD), extracellular superoxide dismutase (EC SOD), catalase (CAT), glutathione synthetase (GSS), and glutathione reductase (GSR) in conjunctival samples from healthy subjects. DESIGN: Descriptive study. PARTICIPANTS: Sixteen healthy donors (32 eyes) were included in this study. METHODS: Conventional and real-time polymerase chain reactions (PCR) were performed using total RNA isolated from conjunctival impression cytology taken from bulbar superior conjunctiva from both eyes. RESULTS: Products amplified by conventional PCR had only 1 band with the expected size for each target gene. Melt-curve analysis of real-time PCR products also identified a single amplified product for each gene. Log-transformed antioxidant enzyme mRNA expression levels, relative to glyceraldehyde-3-phosphate dehydrogenase expression (mean +/- standard error of the mean [SEM]), were CuZn-SOD, 1.52 +/- 0.13; Mn-SOD, 1.72 +/- 0.08; EC-SOD, 0.35 +/- 0.08; GSS, 2.43 +/- 0.20; GSR, 2.52 +/- 0.16; and CAT, 0.90 +/- 0.08. The mRNA levels for CuZn-SOD were strongly correlated with GSS, GSR, Mn-SOD, and EC-SOD. Similarly, the levels of mRNA of GSS and GSR were strongly correlated with each other and with Mn-SOD and EC-SOD. CONCLUSIONS: Normal human conjunctiva expresses the antioxidant enzymes genes CuZn-SOD, Mn SOD, EC-SOD, CAT, GSS, and GSR. The relative quantitation of these genes expressed in conjunctivas of normal eyes will allow further comparisons in pathological circumstances. Knowledge of correlated gene expression will provide a better understanding of the antioxidant balance in the ocular surface. PMID- 21283156 TI - Comparison of antibiotic-only and antibiotic-steroid combination treatment in corneal ulcer patients: double-blinded randomized clinical trial. AB - OBJECTIVE: To determine the benefit of early addition of corticosteroids to antibiotics in the treatment of corneal ulcers. DESIGN: Randomized clinical trial. PARTICIPANTS: Thirty eyes of 30 patients, over the age of 12 years, with bacterial corneal ulcer confirmed by culture. METHODS: Patients were randomized before enrollment; 15 were treated with gatifloxacin (Zymar) and a masked placebo and the other 15 were treated with gatifloxacin and masked dexamethasone 0.1% (Maxidex). Primary outcome was residual ulcer size at 10 weeks based on digital photographs. Secondary outcomes included residual ulcer area by clinician estimate, visual acuity, VF-14 score, and time to healing. RESULTS: All subjects (n = 30) demonstrated a reduction in ulcer size over the study period. There was no significant difference between the 2 groups in terms of the primary outcome. There was a significant difference between the 2 groups in 1 of the secondary outcomes. The mean residual ulcer size compared with the baseline by clinician estimate (slit-lamp) was -0.789 mm2 for the antibiotic-only group and -4.206 mm2 for the antibiotic-steroid group (p = 0.05). Among the other secondary outcomes there were no significant differences between the 2 groups. CONCLUSIONS: No benefit was demonstrated in our primary outcome for using steroids in combination with antibiotic therapy in treatment of corneal ulcers. This study suggests that the early addition of steroids to the antibiotic treatment of corneal ulcers does not seem to be harmful when employed in a closely monitored clinical setting. PMID- 21283157 TI - Management of pediatric choroidal neovascular membranes with intravitreal anti VEGF agents: a retrospective consecutive case series. AB - OBJECTIVE: To report the results of pediatric choroidal neovascular membranes (CNVMs) secondary to a variety of etiologies treated with intravitreal anti vascular endothelial growth factor (anti-VEGF) agents. DESIGN: Retrospective case series. PARTICIPANTS: Four pediatric patients at the Hosptial for Sick Children with CNVMs secondary to a variety of etiologies. METHODS: Each patient received multiple treatments with one of the following anti-VEGF agents: pegaptanib sodium, bevacizumab, or ranibizumab. Progress was monitored by clinical exam, optical coherence tomography (OCT), and fluorescein angiography. RESULTS: The mean age of our patients was 11.5 years (range, 8-15 years). Patients were followed for a mean of 10 months (range, 4-14 months). One patient was treated with pegaptanib sodium, 2 with bevacizumab, and 1 with ranibizumab. Following treatment, 1 patient showed an improvement and 3 showed stabilization of vision with reduction of fluid on clinical exam and OCT, and cessation of leakage on the fluorescein angiogram. Patients required 2-5 injections of the anti-VEGF agent. No ocular or systemic adverse events were observed in any of our treated patients. CONCLUSIONS: Anti-VEGF agents were effective in the treatment of pediatric CNVMs in this case series. However, we do not know how these results would have differed from other treatment modalities, including observation. We did not observe any adverse side effects; however, larger studies are required to document the safety of these medications in the pediatric population where normal angiogenesis is occurring. PMID- 21283158 TI - High-density silicone oil as an intraocular tamponade in complex retinal detachments. AB - OBJECTIVE: To evaluate the efficacy and safety of high-density silicone oil (HDSO) as an internal retinal tamponade after vitrectomy for complicated retinal detachment. DESIGN: Retrospective, non-randomized study. PARTICIPANTS: Forty-one eyes of 41 patients who were 5-73 years of age. METHODS: Medical records of patients with retinal detachment (RD) complicated with inferior proliferative vitreoretinopathy (PVR) requiring internal tamponade with HDSO were reviewed. Eyes with retinal vascular diseases and inflammatory diseases were excluded from the study. Follow-up examinations were scheduled at 1 week and 1, 3, 6, and 12 months after the initial surgery. RESULTS: Median value of follow-up was 8 months (range, 3-40 months). Twenty-five patients had rhegmatogenous RD with significant PVR and the remaining patients had complicated RD secondary to trauma. Preoperative visual acuity was 2.55 +/- 0.75 logMAR, which became 1.89 +/- 0.91 at the last follow-up visit (p < 0.05). Complications included increased intraocular pressure (9.7%), hypotony (2.4%), cataract (57.1%), silicone oil in anterior chamber (17%), persistent total corneal edema (7.3%), band keratopathy (7.3%), and significant inflammation (2.4%). Intraretinal or subretinal fibrosis was found in 12 eyes (29.2%). HDSO removal was performed after a mean period of 5.7 months (range, 3-34 months) in 34 patients. The anatomical success was 87.8%. CONCLUSIONS: The high anatomical success rate of 87.8% is a satisfactory result for these complicated RD cases. Subretinal proliferations and early emulsification limit the results. Further studies, with longer follow-ups and more patients, are needed to be conclusive. PMID- 21283159 TI - Virtual reality ophthalmic surgical simulation as a feasible training and assessment tool: results of a multicentre study. AB - OBJECTIVE: To compare performance on the Eyesi surgical simulator by users with different levels of experience in ophthalmology. DESIGN: Multicentre cross sectional study. PARTICIPANTS: Four medical students, 4 ophthalmic medical technologist trainees, 36 ophthalmology residents, 3 fellows, and 18 staff ophthalmologists. METHODS: Subjects were recruited at the 2007 Canadian Ophthalmological Society Meeting and in the departments of ophthalmology at the University of Toronto, University of Ottawa, and University of Western Ontario. Subjects performed a standardized 20-minute session on the Eyesi simulator. The protocol consisted of a practice trial in the anterior segment module, followed by 3 scored trials in the anterior forceps, antitremor, and capsulorhexis modules. RESULTS: In the forceps module, participants with greater experience achieved significantly higher total scores than those who were less experienced: staff ophthalmologists (Group D) = 67.9 (SD 18.4), senior residents and fellows (Group C) = 67.6 (SD 21.1), junior residents (Group B) = 52.9 (SD 29.4), medical students and ophthalmic medical technologist trainees (Group A) = 27.8 (SD 29.4) (p = 0.011), with lower total task time (p = 0.044) and fewer injuries to the cornea (p = 0.001) and lens (p = 0.026). In the antitremor module, subjects in Group D achieved significantly higher (p = 0.004) total scores (46.7, SD 21.6) than Groups C (45.8, SD 25.1), B (41.2, SD 29.4), and A (8.5, SD 9.2) with lower total task time (p = 0.005) and fewer errors (p = 0.003). In the capsulorhexis module there was also a positive correlation between experience and total scores achieved (p = 0.065). CONCLUSIONS: Subjects' level of training is a reliable predictor of their performance on the Eyesi anterior forceps and antitremor modules (p < 0.05), indicating the modules' construct validity. PMID- 21283160 TI - Effect of sleep deprivation on the performance of simulated anterior segment surgical skill. AB - OBJECTIVE: To measure the effect, using a computer simulator, of acute sleep deprivation on the performance of simulated anterior segment surgery skill. DESIGN: Prospective, non-randomized interventional study. PARTICIPANTS: Nine ophthalmology residents (3 residents each from post-graduate years 2, 3, and 4). METHODS: Nine ophthalmology residents were tested on the Eyesi surgical simulator on 3 occasions; pre-call or rested (>= 7 hours of sleep in previous 24 hours), post-work (8 hour work day and >= 7 hours sleep in previous 24 hours), and post call or sleep-deprived (< 3 hours sleep in previous 24 hours). Residents were tested using the Eyesi forceps module and antitremor module. Level of sleepiness was assessed using the Epworth Sleepiness Scale (ESS). Differences were compared using a 3-factor repeated-measure analysis of variance to account for multiple comparisons. RESULTS: Compared with pre-call and post-work, post-call residents had significantly less sleep in the previous 24 hours (p < 0.001) and were significantly sleepier when assessed using the ESS (p < 0.001). However, we detected no difference in technical performance using the antitremor module in pre-call (85 +/- 21 points), post-work (80 +/- 24 points), and post-call (81 +/- 27 points; p = 0.51) residents or using the forceps module in pre-call (99 +/- 1 points), post-work (98 +/- 4 points), and post-call (98 +/- 5 points; p = 0.11) residents. CONCLUSIONS: Acute sleep deprivation had no detectable impact on the performance of selected surgical task outcome measures when tested using the Eyesi surgical simulator. PMID- 21283161 TI - Analysis of the publication volume of Canadian ophthalmology departments from 2005 to 2009: a systematic review of the literature. AB - OBJECTIVE: To assess the publication volume of Canadian ophthalmology departments over a 5-year period, 2005-2009. DESIGN: Systematic review of the literature. METHODS: MEDLINE was searched for papers published from 2005 to 2009 where the designated affiliation corresponded to a Canadian ophthalmology department. The papers were sorted by year, university, and study design. A total impact score (the impact factor of the journal multiplied by the number of papers published in that journal per year) was also calculated for each university. RESULTS: In the 5 year period there was an increasing trend in the total number of published ophthalmology papers. The University of Toronto had the highest number of published papers (224), followed by the University of British Columbia (143) and McGill University (120). The Canadian Journal of Ophthalmology published the most papers, followed by Investigative Ophthalmology and Visual Science. The most frequent study design category was basic science research and a total of 11 different randomized controlled trials were retrieved. CONCLUSIONS: The publication volume of Canadian ophthalmology researchers increased significantly from 2005 to 2009 with larger institutions accounting for the majority of published papers. Like researchers in other countries, Canadian ophthalmology researchers preferred to publish in domestic journals. PMID- 21283162 TI - Academic screencasting: internet-based dissemination of ophthalmology grand rounds. AB - OBJECTIVE: To evaluate and compare the preferences and attitudes of Ontario ophthalmologists and ophthalmology residents toward screencasting as an educational tool with potential use for continuing medical education (CME) events. DESIGN: Cross-sectional study. PARTICIPANTS: Eighty of 256 participants completed the survey. METHODS: The surveys were sent to participants by email, with follow-up via telephone. Study participants were urban and rural Ontario ophthalmologists, registered with the Canadian Ophthalmological Society, and University of Toronto ophthalmology residents. Pre-recorded online presentations screencasts-were used as the main intervention. Online surveys were used to measure multiple variables evaluating the attitudes of the participants toward screencasting. This data was then used for further quantitative and qualitative analysis. RESULTS: Over 95% of participants replied favourably to the introduction and future utilization of screencasting for educational purposes. Rural ophthalmologists were the most enthusiastic about future events. Practising in rural Ontario was associated with a higher interest in live broadcasts than practising in urban centres (p < 0.02), an association supported by qualitative data. Qualitative analysis revealed geographic isolation, busy schedules, ease of use/access, and convenience to be the key factors contributing to interest in screencasting. CONCLUSIONS: Practising ophthalmologists and residents in Ontario are interested in academic online screencasting. Rural ophthalmologists were more interested in live lectures than their urban colleagues. More research is required to assess the potential of screencasting as a CME tool. PMID- 21283163 TI - Phacoviscocanalostomy in pseudoexfoliation glaucoma versus primary open-angle glaucoma. AB - OBJECTIVE: To compare the outcome of phacoviscocanalostomy in pseudoexfoliation glaucoma (PEXG) versus that in primary open-angle glaucoma (POAG). DESIGN: Prospective comparative study. PARTICIPANTS: Sixty eyes of 60 patients who underwent phacoviscocanalostomy for cataract and medically uncontrolled PEXG (30 eyes) or POAG (30 eyes). METHODS: Success rate was based on intraocular pressure (IOP) reduction and need for antiglaucoma medication. Visual acuity (VA) and complication rates were secondary outcomes. RESULTS: The mean follow-up was 19.7 months (range, 12-36 months). The mean IOP values in both groups were significantly less than the preoperative values at all postoperative intervals (p < 0.001). From 1 month onward, the decrease in IOP was more dramatic in PEXG eyes than in POAG eyes (p < 0.05). At last visit, the mean percentage of IOP reduction was 49.7% in the PEXG group and 30.9% in the POAG group. All study eyes required decreased antiglaucoma medications and showed improved VA postoperatively. Transient complications included Descemet's membrane microperforations, macroperforation, zonular dehiscence, and postoperative IOP spike. No eyes developed trabeculectomy-type bleb, hyphema, fibrin exudation, or bleb-related complications. CONCLUSIONS: Phacoviscocanalostomy achieved excellent IOP control and VA improvement in both PEXG and POAG groups. PEXG demonstrated greater IOP reduction and fewer postoperative medications than POAG. The complication rate was low and did not affect surgical outcome. Phacoviscocanalostomy can be an effective and safe surgical alternative to phacotrabeculectomy in both groups of patients. PMID- 21283164 TI - Keratoconus caused by eye rubbing in patients with Tourette Syndrome. AB - OBJECTIVE: To report the association between keratoconus and Tourette Syndrome (TS) and to reinforce that eye rubbing may be a causative factor for keratoconus. DESIGN: Observational case series. PARTICIPANTS: Three patients with TS who presented with clinical and topographic findings suggestive of asymmetric or unilateral keratoconus. METHODS: Evaluation of patients in a single clinical practice. RESULTS: Patients' histories revealed asymmetric or unilateral rubbing of the affected eye as a result of a TS tic. Other organic causes associated with keratoconus were absent in these patients. CONCLUSIONS: A possible association between TS and keratoconus exists with chronic eye rubbing being the suggested mechanism. Eye rubbing seems to be an important causative factor for keratoconus. PMID- 21283165 TI - Comparing performance of junior and senior ophthalmology residents on an intraocular surgical simulator. PMID- 21283166 TI - A macular smile. PMID- 21283167 TI - Differential effects of triamcinolone and bevacizumab in central retinal vein occlusion. PMID- 21283168 TI - New glaucoma diagnostic technologies: a systematic review of economic studies. PMID- 21283169 TI - Choroidal detachment after PASCAL photocoagulation. PMID- 21283170 TI - Presumed dengue-associated immune-mediated uveitis. PMID- 21283171 TI - Ocular perforation by an acupuncture needle. PMID- 21283173 TI - Influence of polarization mode competition on chaotic unpredictability of vertical-cavity surface-emitting lasers with polarization-rotated optical feedback. AB - The chaotic unpredictability of vertical-cavity surface-emitting lasers (VCSELs) with polarization-rotated optical feedback is evaluated quantitatively via the normalized permutation entropy H. The effect of polarization mode competition (PMC) is explored. For weak PMC, the H for X-polarization mode, Y-polarization mode, and total output are close to each other, while for strong PMC, the H for the total output is the highest one, which indicates that the permutation entropy is an effective tool for quantifying chaotic unpredictability of VCSELs and provides valuable information for choosing the proper chaotic carrier. PMID- 21283174 TI - High-repetition-rate sub-5-fs pulses with 12 GW peak power from fiber-amplifier pumped optical parametric chirped-pulse amplification. AB - An optical parametric chirped-pulse amplification system delivering pulses with more than 12 GW peak power is presented. Compression to sub-5 fs, 87 MUJ and 5.4 fs, 100 MUJ is realized at the 30 kHz repetition rate. A high-energy fiber chirped-pulse amplification system operating at 1 mJ pulse energy and nearly transform-limited pulses is used to achieve ultrabroadband amplification in two 2mm beta-barium borate crystals. Precise pulse shaping is used to compress the pulses to a few percentages of their transform limit. Assuming diffraction limited focusing (d<2 MUm), peak intensities as high as 10(18) W/cm(2) can be reached. PMID- 21283175 TI - 135 W average-power femtosecond pulses at 520 nm from a frequency-doubled fiber laser system. AB - We present a high-average-power femtosecond laser system at 520 nm central wavelength. The laser system delivers sub-500 fs pulses with 135 W average power at a pulse repetition rate of 5.25 MHz. Excellent beam quality is provided by high power fiber amplifiers and maintained during frequency doubling, resulting in a beam quality factor of M2<1.2. To our knowledge, the system presented here is the highest average power green laser source generating femtosecond pulses with diffraction-limited beam quality. PMID- 21283176 TI - Continuous-wave room-temperature operation of a 2.8 MUm GaSb-based semiconductor disk laser. AB - We demonstrate an optically pumped semiconductor disk laser based on the (AlGaIn)(AsSb) material system, which operates at an emission wavelength of 2.8 MUm. Up to 120 mW of output power were obtained in cw operation and more than 500 mW in pulsed mode. The performance of the present laser is discussed in comparison to shorter-wavelength semiconductor disk lasers based on the same materials system. PMID- 21283177 TI - Optical 60 degrees hybrid for demodulating six-level DPSK signal. AB - We propose and demonstrate an optical 60 degrees hybrid for demodulating optical signals with six-level DPSK modulation format. The proposed device consisting of a paired-interference 2?6MMI coupler, phase shifters, and 2?2MMI couplers with an asymmetric splitting ratio of 72?28 exhibited hexagonal phase response over a C band range. PMID- 21283178 TI - Single-pulse ultrafast laser imprinting of axial dot arrays in bulk glasses. AB - Ultrafast laser processing of bulk transparent materials can significantly gain flexibility when the number of machining spots is increased. We present a photoinscription regime in which an array of regular dots is generated before the region of main laser focus under single-pulse exposure in fused silica and borosilicate crown glass without any external spatial phase modulation. The specific position of the dots does not rely on nonlinear propagation effects but is mainly determined by beam truncation and is explained by a Fresnel propagation formalism taking into account beam apodization and linear wavefront distortions at the air/glass interface. The photoinscription regime is employed to generate a two-dimensional array of dots in fused silica. We show that an additional phase modulation renders flexible the pattern geometry. PMID- 21283179 TI - Condition for far-zone spectral isotropy of an electromagnetic light wave on weak scattering. AB - The far-zone spectral isotropy of an electromagnetic light wave on scattering has been discussed. It is shown that a sufficient condition for the far-zone spectral isotropy of an electromagnetic light wave on scattering can be expressed by the following two requirements: the two-point correlation function of the dielectric susceptibility of the scattering medium obeys the so-called scaling law, and the normalized spectrum of the incident light wave has the same distribution along the two perpendicular directions. PMID- 21283180 TI - Heterodyne interferometer scheme using a double pass in an acousto-optic modulator. AB - We introduce a heterodyne interferometer scheme utilizing the double-pass arrangement of the deflected beams of an acousto-optic modulator. To prove our new idea, the interferometer has been applied for measuring small amplitude vibrations. The output intermediate frequency signal from the interferometer is processed by using an I/Q demodulator. In theory, it can provide the quantum noise limited sensitivity, whereas, in our present Letter, the sensitivity of the phase measurement is limited by the resolution of the 16 bit A/D converter used for processing the I/Q signals. Details of our interferometer scheme are discussed. PMID- 21283181 TI - On beam propagation in anisotropic media: one-dimensional analysis. AB - We theoretically investigate light beam propagation in (1+1)D homogeneous anisotropic uniaxials where ordinary and extraordinary waves are decoupled, accounting for the vectorial character of the electromagnetic field and addressing the nonparaxial limit. PMID- 21283182 TI - Light scattering by wavelength-sized particles "dusted" with subwavelength-sized grains. AB - The numerically exact superposition T-matrix method is used to compute the scattering cross sections and the Stokes scattering matrix for polydisperse spherical particles covered with a large number of much smaller grains. We show that the optical effect of the presence of microscopic dust on the surfaces of wavelength-sized, weakly absorbing particles is much less significant than that of a major overall asphericity of the particle shape. PMID- 21283183 TI - Picosecond pulses from a cryogenically cooled, composite amplifier using Yb:YAG and Yb:GSAG. AB - A cryogenic Yb amplifier using two laser materials, Gd3Sc2Al3O12 and Y3Al5O12 (YAG), has been used to obtain 70 W average power at 5 kHz pulse repetition frequency; the output was compressed to 1.6 ps, compared with an input compressible to 1.4 ps. The gain broadening obtained by combining two media enables shorter pulses than using Yb:YAG alone but retains the power-scaling advantages of cryogenic Yb:YAG. PMID- 21283184 TI - Resonance cone formation in a curved cylindrically anisotropic metamaterial film. AB - Resonance cones, the regions where major power and high-intensity fields are concentrated, form with cylindrically anisotropic media when the permittivity tensor elements have opposite signs. The resonance cones inside a circular layer of cylindrically anisotropic material is shown to experience multiple internal reflections from the layer boundaries. We introduce a spectrometer class by exploiting the dispersive properties of a metal-insulator stack metamaterial. The cones can exhibit negative refraction at the interface of two such circular layers, leading to a far-field bilayer subwavelength imaging system with more flexibility in the material parameter and operating wavelength spaces. PMID- 21283185 TI - Improved sensitivity of intensity-modulated spectroscopy using correlative signal processing. AB - Frequency-modulation (FM) spectroscopy is known to be a sensitive spectroscopic technique capable of accurately measuring the frequency dependence of the absorption and index of refraction of narrow spectral features. The absorption and index of refraction are coupled by a form of the Kramers-Kronig (K-K) relations, and both components provide information about the spectral feature. In this Letter, we propose a processing technique based on fitting the data to a complex signal model derived from the K-K relation. By using this complex constraint and only processing a single quadrature, our model predicts significant improvement in the minimum detectable absorption compared with conventional FM spectroscopy. PMID- 21283186 TI - Redistribution of energy flow in a material due to damping. AB - The field lines of energy flow of the radiation emitted by a linear dipole in free space are straight lines, running radially outward from the source. When the dipole is embedded in a medium, the field lines are curves when the imaginary part of the relative permittivity is finite. It is shown that due to the damping in the material all radiation is emitted in directions perpendicular to the dipole axis, whereas for a dipole in free space the radiation is emitted in all directions except along the dipole axis. It is also shown that some field lines in the near field form semiloops. Energy flowing along these semiloops is absorbed by the material and does not contribute to the radiative power in the far field. PMID- 21283187 TI - Optimization of focusing of linearly polarized light. AB - We show that, by adding a pi-phase shift to one-half of a linearly polarized beam, the roles of the transversal and longitudinal field components of the focused beam are interchanged, resulting in better focusing of the longitudinal component in the direction perpendicular to the phase jump line. For this component the scheme produces a spot with FWHM >15% smaller than a spot generated with either linearly or radially polarized light for any NA. The scheme has a similar advantage when applied to circularly polarized light, and it holds for both a plane wave and a realistic case of a Gaussian incident beam. This technique may find applications when using recording media responsive to the longitudinal field only, particularly in read/write for optical storage where the resolution in one transverse dimension is most important. PMID- 21283188 TI - Coaxial fiber-optic chemical-sensing excitation-emission matrix fluorometer. AB - Great reductions in the overall size and complexity of high throughput multichannel UV-visible fluorometers were achieved by coupling a compact optical fiber array to compact dispersive transmission optics. The coaxial configuration centers on the insertion of a silica/silica optical fiber into the hollow region of a UV-fused silica capillary waveguide. The outer core delivers the maximum power of the narrow wavelength region of the excitation spectrum created by coupling a xenon arc discharge lamp to a compact spectrometer. The molecular fluorescence resulting from the interaction of light emitted at the distal end of the hollow waveguide and the sample matrix is received and transmitted to a CCD via a compact dispersive grating-prism (grism) optical assembly. A linear array of the coaxial optical fibers permits a full excitation-emission matrix spectrum of the analyte matrix to be projected onto the face of the CCD. The in situ identification and monitoring of polycyclic aromatic hydrocarbons was carried out for the initial application testing for this prototype. PMID- 21283189 TI - Structure of plasmonic aerogel and the breakdown of the effective medium approximation. AB - A method for making aerogel doped with gold nanoparticles (GNPs) produces a composite material with a well-defined localized surface plasmon resonance peak at 520 nm. The width of the extinction feature indicates the GNPs are well dispersed in the aerogel, making it suited to optical study. A simple effective medium approximation cannot explain the peak extinction wavelengths. The plasmonic field extends on a scale where aerogel cannot be considered isotropic, so a new model is required: a 5 nm glass coating on the GNPs models the extinction spectrum of the composite material, with air (aerogel), methanol (alcogel), or toluene filling the pores. PMID- 21283190 TI - 465 nm laser sources by intracavity frequency doubling using a 49-edge-emitters laser bar. AB - A compact blue laser was generated by intracavity frequency doubling based on quasi-phase-matched second-harmonic generation (SHG) in a MgO-doped periodically poled lithium niobate bulk crystal. A 49 single-transverse-mode edge-emitters laser bar with antireflective coating was used as a pump source. An optical output power of 1.2 W SHG of blue lights at 465 nm is generated at 45 A injection current, equivalent to an overall wall-plug efficiency of 1.33%. PMID- 21283191 TI - Four-dimensional flash trajectory imaging using time-delay-modulated range-gated viewing. AB - We present a four-dimensional flash trajectory imaging method to image object trajectories over time in three-dimensional space. In the method, time-delay modulated range-gated viewing with multiple exposures is presented so that the time evolution of object trajectories free from background interference is directly given without complicated image processing and the motion parameters of objects can be estimated. The method is demonstrated by a ball oscillating as a pendulum. PMID- 21283192 TI - Efficient high-power frequency doubling of distributed Bragg reflector tapered laser radiation in a periodically poled MgO-doped lithium niobate planar waveguide. AB - We report on efficient single-pass, high-power second-harmonic generation in a periodically poled MgO-doped LiNbO3 planar waveguide using a distributed Bragg reflector tapered diode laser as a pump source. A coupling efficiency into the planar waveguide of 73% was realized, and 1.07 W of visible laser light at 532 nm was generated. Corresponding optical and electro-optical conversion efficiencies of 26% and 8.4%, respectively, were achieved. Good agreement between the experimental data and the theoretical predictions was observed. PMID- 21283193 TI - Vectorial complex ray model and application to two-dimensional scattering of plane wave by a spheroidal particle. AB - A vectorial complex ray model is introduced to describe the scattering of a smooth surface object of arbitrary shape. In this model, all waves are considered as vectorial complex rays of four parameters: amplitude, phase, direction of propagation, and polarization. The ray direction and the wave divergence/convergence after each interaction of the wave with a dioptric surface as well as the phase shifts of each ray are determined by the vector Snell law and the wavefront equation according to the curvatures of the surfaces. The total scattered field is the superposition of the complex amplitude of all orders of the rays emergent from the object. Thanks to the simple representation of the wave, this model is very suitable for the description of the interaction of an arbitrary wave with an object of smooth surface and complex shape. The application of the model to two-dimensional scattering of a plane wave by a spheroid particle is presented as a demonstration. PMID- 21283194 TI - Frequency bandwidth of light focused through turbid media. AB - We study the effect of frequency detuning on light focused through turbid media. By shaping the wavefront of the incident beam light is focused through an opaque scattering layer. When detuning the laser we observe a gradual decrease of the focus intensity, while the position, size,and shape of the focus remain the same within experimental accuracy. The frequency dependence of the focus intensity follows a measured speckle correlation function. We support our experimental findings with calculations based on transport theory. Our results imply wavefront shaping methods can be generalized to allow focusing of optical pulses in turbid media. PMID- 21283195 TI - Reflection-type wavelength-selective infrared emitter using surface plasmon polaritons. AB - A reflection-type wavelength selective IR emitter is proposed. Surface plasmon polaritons (SPPs), which occur on metallic grating at a wavelength near the pitch of the structure, are used for controlling thermal emissions. An emission peak at a wavelength nearly equal to the period of the grating is observed. As for the other wavelength, which cannot couple with the SPPs, the IR power is confined by the reflectors including the grating. The emitter temperature increases, consuming lower input power with higher power efficiency. PMID- 21283196 TI - Resonance cones in cylindrically anisotropic metamaterials: a Green's function analysis. AB - A Green's function analysis for cylindrically anisotropic media is presented that can be used in the design of various metamaterial devices. The resonance cones, which describe the direction of power flow, result from the Green's function singularity when the permittivity tensor elements have opposite signs. Shadow and accessible regions for the source are also identified. PMID- 21283197 TI - Generation of broadly tunable sub-30-fs infrared pulses by four-wave optical parametric amplification. AB - We report on the generation of sub-30-fs near-IR light pulses by means of broadband four-wave parametric amplification in fused silica. This is achieved by frequency downconversion of visible broadband pulses provided by a commercial blue-pumped beta-barium borate crystal-based noncollinear optical parametric amplifier. The proposed method produces the IR idler pulses with energy up to ~20 MUJ and tunable in wavelength from 1 to 1.5 MUm. The shortest pulse duration is 17.6 fs, measured at 1.2 MUm. PMID- 21283198 TI - Light transmission properties of double-overlapped annular apertures. AB - We investigate the light transmission properties of double-overlapped annular apertures in a silver film with the three-dimensional finite-difference time domain method. It has been found that the transmission peaks are attributed to the localized surface plasmon resonance (LSPR) of nanocavities and the surface plasmon polaritons (SPPs) of the nanoparticles. The peaks of the LSPR are blueshifted when the overlapping distance is increased. Moreover, a Fano-type resonance appears in the transmitted spectral response with an appropriate overlapping distance, which is elucidated as the hybridization results of the SPPs of the nanoparticles. The number and position of the Fano resonance can be tuned through varying the overlapping distance and other geometric parameters. PMID- 21283199 TI - Principal modes in fiber amplifiers. AB - The dynamics of the state of polarization in multimode fiber amplifiers is presented. The experimental results reveal that although the state of polarizations at the output can vary over a large range when changing the temperatures of the fiber amplifiers, the variations are significantly reduced when resorting to the principal states of polarization in single-mode fiber amplifiers and principal modes in multimode fiber amplifiers. PMID- 21283200 TI - Convolution reconstruction algorithm for refraction-contrast computed tomography using a Laue-case analyzer for dark-field imaging. AB - We derive a reconstruction algorithm for refraction-contrast computed tomography (CT) using dark-field imaging (DFI) optics, which can extract refraction information by a single shot, from the ray equation in geometrical optics. The proposed algorithm is similar to the convolution reconstruction technique widely used in conventional CT. Thus, this algorithm can be implemented simply while also being fast and stable. To demonstrate its validity, we constructed the imaging system based on DFI optics composed of a transmission Laue-type angular analyzer at the vertical wiggler beamline BL-14C in KEK and performed a preliminary imaging experiment using a physical phantom to successfully obtain the DFI-CT image using the proposed algorithm. PMID- 21283201 TI - Correlated imaging in scattering media. AB - We demonstrate for the first time (to our knowledge) that an image with high quality can still be obtained in scattering media by applying the second-order correlation of illuminating light field. The effect of multiple scattering on the imaging quality is analyzed both theoretically and experimentally. Potential applications and methods to further improve the imaging quality in scattering media are also discussed. PMID- 21283202 TI - A quantitative approach to soliton instability. AB - We present an approach for instabilities of solitons that is based on the spectrum of a fourth-order linearized operator. Unlike the standard approach which is based on the slope (Vakhitov-Kolokolov) condition, this approach provides the quantitative value of the instability rate and the qualitative nature of the instability dynamics. PMID- 21283203 TI - WDM compatible and electrically tunable SPE-OCDMA system based on the temporal self-imaging effect. AB - A coding/decoding setup for a spectral phase encoding optical code-division multiple access (SPE-OCDMA) system has been developed. The proposal is based on the temporal self-imaging effect and the use of an easily tunable electro-optic phase modulator to achieve line-by-line coding of the transmitted signal, thus assuring compatibility with WDM techniques. Modulation of the code is performed at the same rate as the data, avoiding the use of high-bandwidth electro-optic modulators. As proof of concept of the technique, experimental results are presented for a back-to-back coder/decoder setup transmitting a 10 GHz unmodulated optical pulse train within an 80 GHz optical window and using 8-chip Hadamard codes. PMID- 21283204 TI - Tunable complex photonic chiral lattices by reconfigurable optical phase engineering. AB - We present a novel single-step fabrication approach, based on optical phase engineering, for tunable complex photonic chiral lattices of diverse geometries in a large area. By means of engineered reconfigurable phase patterns, we computationally simulate as well as experimentally investigate these complex structures. We show the generation of both periodic right- and left-handed chiral structures as well as photonic transversely quasi-crystallographic chiral structures. These complex chiral lattices are also demonstrated in a photorefractive material, and the lattice formation is analyzed by plane-wave guided imaging as well as diffraction pattern imaging. Furthermore, complex photonic chiral structures with engineered tunable relative phase shifts between adjacent spiral units realizable in a single step are explored and analyzed. PMID- 21283205 TI - Dynamic generation of Debye diffraction-limited multifocal arrays for direct laser printing nanofabrication. AB - We propose a Debye-theory-based iterative method to produce accurate phase patterns for generating highly uniform diffraction-limited multifocal arrays with a high-NA objective. It is shown that by using the Debye method, the uniformity of the diffraction-limited focal arrays can reach 99%, owing to the critical consideration of the depolarization effect associated with high-NA objectives. The generated phase patterns are implemented in fast dynamic laser printing nanofabrication for the generation of individually controlled high-quality microvoid arrays in a solid polymer material by a single exposure of a femtosecond laser beam. As a result of the high-quality multifocal arrays, functional three-dimensional photonic crystals possessing multiple stopgaps with suppression up to 80% in transmission spectra are demonstrated. PMID- 21283206 TI - Quadrant detector calibration for vortex beams. AB - This Letter reports an experimental and theoretical study of the response of a quadrant detector (QD) to an incident vortex beam, specifically a Laguerre Gaussian (LG) beam. We have found that the LG beam response depends on the vorticity index l. We compare LG beams with hard-ringed beams and find that at higher l values, the QD response to LG beams can be approximated by its response to hard-ringed beams. Our findings are important in view of the increasing interest in optical vortex beams. PMID- 21283207 TI - High-pressure and high-temperature characteristics of a Fabry-Perot interferometer based on photonic crystal fiber. AB - A fiber-optic Fabry-Perot interferometer was constructed by splicing a short length of photonic crystal fiber to a standard single-mode fiber. The photonic crystal fiber functions as a Fabry-Perot cavity and serves as a direct sensing probe without any additional components. Its pressure and temperature responses in the range of 0-40 MPa and 25 degrees C-700 degrees C were experimentally studied. The proposed sensor is easy to fabricate, potentially low-cost, and compact in size, which makes it very attractive for high-pressure and high temperature sensing applications. PMID- 21283208 TI - Experimental investigation of relative timing jitter in passively synchronized Q switched lasers. AB - Relative timing jitter between synchronized Q-switched lasers, or lack thereof, is important for stable sum-frequency generation. Experimental investigation of two passively synchronized lasers shows that the jitter is minimized when the free-running repetition rates of the two lasers are close to, but not exactly, matching. When the free-running repetition rates are matched, the jitter is significantly large. At the best operating point, the pulse-to-pulse period was 200 MUs, while the relative jitter between the two lasers was 9 ns. If the effect of the master laser's pulse-to-pulse jitter is removed, the residual timing jitter between the two lasers was 6 ns, which corresponds to the lower limit set by pump power fluctuations and noise from spontaneous emission. PMID- 21283209 TI - Real-time increase in depth of field of an uncooled thermal camera using several phase-mask technologies. AB - Imaging systems that combine a phase mask in the pupil and digital postprocessing may have better performance than conventional ones. We have built such a system to enhance the depth of field of an uncooled thermal camera. The phase masks are binary, their structures are optimized thanks to an image quality criterion, and they have been realized with three different technologies that give equivalent results. The deconvolution postprocessing is performed in real time with a graphics processing unit. A significant increase of the depth of field of a factor 3 has been obtained. PMID- 21283210 TI - Fabrication and characterization of high-quality-factor silicon nitride nanobeam cavities. AB - We present the fabrication and characterization of high-quality-factor (Q) Si3N4 photonic crystal nanobeam cavities at visible wavelengths for coupling to nitrogen-vacancy centers in a cavity QED system. Confocal microphotoluminescence analysis of the nanobeam cavities demonstrates quality factors up to Q ~ 55,000, which are limited by the resolution of our grating spectrometer. This is a 1 order-of-magnitude improvement over previous SiNx cavities at this important wavelength range. We also demonstrate coarse tuning of cavity resonances across 600-700 nm by lithographically scaling the size of fabricated devices. PMID- 21283211 TI - All-optical controllable trapping and transport of subwavelength particles on a tapered photonic crystal waveguide. AB - We propose that a tapered photonic crystal waveguide design can unify optical trapping and transport functionalities to advance the controllability of optical manipulation. Subwavelength particles can be trapped by a resonance-enhanced field and transported to a specified position along the waveguide on demand by varying the input wavelength. A simulated transport ability as high as 148 (transport distance/wavelength variation) is obtained by the waveguide with 0.1 degrees tilted angle. Stable trapping of a 50 nm polystyrene particle can be achieved with input power of 7 mW. We anticipate that this design would be beneficial for future life science research and optomechanical applications. PMID- 21283212 TI - Stimulated Brillouin scattering slow-light-based fiber-optic temperature sensor. AB - We propose and experimentally demonstrate a method for temperature sensing using stimulated Brillouin scattering (SBS)-based slow light. The approach relies on temperature dependence of the Brillouin frequency shift in a fiber, hence the time delay of an input probe pulse. By measuring the delay, temperature sensing can be realized. We achieve temperature measurement in a 100 m single-mode fiber (SMF) using a cw pump. The main temperature-sensing range is ~18 degrees C from the room temperature, limited by the SBS gain bandwidth. To apply the technique for measurement of a shorter fiber segment, a pulsed pump is used to introduce SBS slow light. Temperature sensing is achieved in a 2 m SMF with a main sensing range of around ~25 degrees C. The scheme is easily implemented, exhibits a relatively high temperature sensitivity with a resolution better than 1.0 degrees C, and is potentially applicable for distributed sensing. PMID- 21283213 TI - Grating-cavity continuous-wave optical parametric oscillators for high-resolution mid-infrared spectroscopy. AB - The use of grating as a spectral filter provides a simple way of improving wavelength tuning and stability of continuous-wave optical parametric oscillators (cw OPOs). In this paper, we discuss how to design and use such grating-cavity cw OPOs for high-resolution spectroscopy in the molecular fingerprint region at ~3MUm. The first design presented in the paper is based on a metal-coated diffraction grating, which produces fast and broad wavelength tuning and high wavelength stability. The second design uses a bulk Bragg grating for high optical power and good spectral purity. We report a new Bragg-grating OPO and demonstrate its use in a Doppler-free absorption spectroscopy of CH4 at ~3.22MUm. In addition, we describe a new balanced detection scheme, which can be used to improve the signal-to-noise ratio of absorption measurements if the measurement noise is limited by the intensity noise of the mid-infrared OPO. PMID- 21283214 TI - External cavity tunable quantum cascade lasers and their applications to trace gas monitoring. AB - Since the first quantum cascade laser (QCL) was demonstrated approximately 16 years ago, we have witnessed an explosion of interesting developments in QCL technology and QCL-based trace gas sensors. QCLs operate in the mid-IR region (3 24 MUm) and can directly access the rotational vibrational bands of most molecular species and, therefore, are ideally suited for trace gas detection with high specificity and sensitivity. These sensors have applications in a wide range of fields, including environmental monitoring, atmospheric chemistry, medical diagnostics, homeland security, detection of explosive compounds, and industrial process control, to name a few. Tunable external cavity (EC)-QCLs in particular offer narrow linewidths, wide ranges of tunability, and stable power outputs, which open up new possibilities for sensor development. These features allow for the simultaneous detection of multiple species and the study of large molecules, free radicals, ions, and reaction kinetics. In this article, we review the current status of EC-QCLs and sensor developments based on them and speculate on possible future developments. PMID- 21283215 TI - Automated broad tuning of difference frequency sources for spectroscopic studies. AB - Transmission spectroscopy over large spectral ranges (>100 cm(-1)) generally requires a reference measurement to be taken separately from the sample scan. The ratio of the two measurements (i.e., the transmittance) is therefore susceptible to baseline changes that occur between the recording of the two spectra. The origins of relatively strong baseline changes (?1%) of a difference-frequency generation-based laser spectrometer (tuning range 2900-3144 cm(-1), 150 MUW average power) were investigated and a method for minimizing them by improving reproducibility and reducing measurement time is presented. The new method was tested for a gas mixture and the sensitivity for broad absorption features was determined as 5*10(-3) minimum measurable absorbance for a total scan duration of 70 min. PMID- 21283217 TI - MHz-rate nitric oxide planar laser-induced fluorescence imaging in a Mach 10 hypersonic wind tunnel. AB - Nitric oxide planar laser-induced fluorescence (NO PLIF) imaging at repetition rates as high as 1 MHz is demonstrated in the NASA Langley 31 in. Mach 10 hypersonic wind tunnel. Approximately 200 time-correlated image sequences of between 10 and 20 individual frames were obtained over eight days of wind tunnel testing spanning two entries in March and September of 2009. The image sequences presented were obtained from the boundary layer of a 20 degrees flat plate model, in which transition was induced using a variety of different shaped protuberances, including a cylinder and a triangle. The high-speed image sequences captured a variety of laminar and transitional flow phenomena, ranging from mostly laminar flow, typically at a lower Reynolds number and/or in the near wall region of the model, to highly transitional flow in which the temporal evolution and progression of characteristic streak instabilities and/or corkscrew shaped vortices could be clearly identified. PMID- 21283218 TI - Validation of temperature imaging by H2O absorption spectroscopy using hyperspectral tomography in controlled experiments. AB - This paper describes a preliminary demonstration and validation of temperature imaging using hyperspectral H2O absorption tomography in controlled experiments. Fifteen wavelengths are monitored on each of 30 laser beams to reconstruct the temperature image in a 381 mm * 381 mm square room-temperature plane that contains a 102 mm * 102 mm square zone of lower or higher temperature. The hyperspectral tomography technique attempts to leverage multispectral information to enhance measurement fidelity. The experimental temperature images exhibit average accuracies of 2.3% or better, with pixel-by-pixel standard deviations of less than 1%. In addition, even when the internal zone is only 4 K cooler than the surroundings, its presence is still detectable; statistical analysis of the associated experimental image reveals a 98% confidence that the internal zone is in fact cooler than the surroundings. PMID- 21283219 TI - Gas-phase thermometry using delayed-probe-pulse picosecond coherent anti-Stokes Raman scattering spectra of H2. AB - We report the development and application of a simple theoretical model for extracting temperatures from picosecond-laser-based coherent anti-Stokes Raman scattering (CARS) spectra of H2 obtained using time-delayed probe pulses. This approach addresses the challenges associated with the effects of rotational-level dependent decay lifetimes on time-delayed probing for CARS thermometry. A simple procedure is presented for accurate temperature determination based on a Boltzmann distribution using delayed-probe-pulse vibrational CARS spectra of H2; this procedure requires measurement at only a select handful of probe-pulse delays and requires no assumptions about sample environment. PMID- 21283220 TI - Laser-induced incandescence measurements of soot in turbulent pool fires. AB - We present what we believe to be the first application of the laser-induced incandescence (LII) technique to large-scale fire testing. The construction of an LII instrument for fire measurements is presented in detail. Soot volume fraction imaging from 2 m diameter pool fires burning blended toluene/methanol liquid fuels is demonstrated along with a detailed report of measurement uncertainty in the challenging pool fire environment. Our LII instrument relies upon remotely located laser, optical, and detection systems and the insertion of water-cooled, fiber-bundle-coupled collection optics into the fire plume. Calibration of the instrument was performed using an ethylene/air laminar diffusion flame produced by a Santoro-type burner, which allowed for the extraction of absolute soot volume fractions from the LII images. Single-laser-shot two-dimensional images of the soot layer structure are presented with very high volumetric spatial resolution of the order of 10(-5) cm3. Probability density functions of the soot volume fraction fluctuations are constructed from the large LII image ensembles. The results illustrate a highly intermittent soot fluctuation field with potentially large macroscale soot structures and clipped soot probability densities. PMID- 21283221 TI - Laser-based diagnostics for the measurement of liquid water film thickness. AB - Three different diagnostic techniques are investigated for measurement of the thickness of liquid water films deposited on a transparent quartz plate. The methods are based on laser-induced fluorescence (LIF) from low concentrations of a dissolved tracer substance and spontaneous Raman scattering of liquid water, respectively, both excited with 266 nm of radiation, and diode laser absorption spectroscopy (DLAS) in the near-infrared spectral region. Signal intensities are calibrated using liquid layers of known thickness between 0 and 1000 MUm. When applied to evaporating liquid water films, the thickness values derived from the direct DLAS and Raman scattering measurements correlate well with each other as a function of time after the start of data recording, while the LIF signal derived thickness values decrease faster with time due to selective tracer evaporation from the liquid. The simultaneous application of the LIF with a tracer-free detection technique can serve as an in situ reference for quantitative film thickness measurements. PMID- 21283222 TI - Detecting localized trace species in air using radar resonance-enhanced multi photon ionization. AB - A microwave-scattering-based resonance-enhanced multi-photon ionization technique is used to detect molecular species such as NO, CO, Xe, and Ar in pure form, and for standoff detection of trace species in atmospheric pressure air. In this paper,the spectra, dynamics, and the detection limits of trace species in air are studied. We demonstrate 10 m scale standoff detection of NO, and show that the system has a linear response down to the parts in 10(9) NO levels in ambient air. PMID- 21283223 TI - Dual quantum cascade laser trace gas instrument with astigmatic Herriott cell at high pass number. AB - We have developed and demonstrated a high-sensitivity trace gas instrument employing two mid-infrared quantum cascade lasers and an astigmatic Herriott sample cell with up to a 240 m path length. Several aspects of astigmatic Herriott cell optics have been addressed to enable operation at a high pass number (up to 554), including aberrations and pattern selection to minimize interference fringes. The new instrument design, based on the 200 m cell, can measure various atmospheric trace gases, depending on the installed lasers, with multiple trace gases measured simultaneously. Demonstrated concentration noise levels (1 s average) are 40 parts per trillion [(ppt) 10(-12)] for formaldehyde, 10 ppt for carbonyl sulfide, 110 ppt for hydrogen peroxide (H2O2), and 180 ppt for nitrous acid (HONO). High-precision measurements of nitrous oxide and methane have been recorded at the same time as high-sensitivity measurements of HONO and H2O2. PMID- 21283224 TI - Ship wake detection by Raman lidar. AB - We carried out a remote study of ship wakes by optical methods. Both Mie and Raman scattering signals and their evolution were simultaneously recorded by gated detector (intensified CCD). The Mie scattering signal was detectable within 1 min after water disturbance by a high-speed boat. According to an approximation of experimental data, Raman signal fluctuations can be detected for a much longer time under the same conditions. We have demonstrated that Raman spectroscopy is substantially more sensitive to water perturbation compared to conventional acoustic (sonar) technique and can be used for ship wake detection and monitoring. PMID- 21283225 TI - Real-time monitoring of benzene, toluene, and p-xylene in a photoreaction chamber with a tunable mid-infrared laser and ultraviolet differential optical absorption spectroscopy. AB - We describe the implementation of a mid-infrared laser-based trace gas sensor with a photoreaction chamber, used for reproducing chemical transformations of benzene, toluene, and p-xylene (BTX) gases that may occur in the atmosphere. The system performance was assessed in the presence of photoreaction products including aerosol particles. A mid-infrared external cavity quantum cascade laser (EC-QCL)-tunable from 9.41-9.88 MUm (1012-1063 cm(-1))-was used to monitor gas phase concentrations of BTX simultaneously and in real time during chemical processing of these compounds with hydroxyl radicals in a photoreaction chamber. Results are compared to concurrent measurements using ultraviolet differential optical absorption spectroscopy (UV DOAS). The EC-QCL based system provides quantitation limits of approximately 200, 200, and 600 parts in 10(9) (ppb) for benzene, toluene, and p-xylene, respectively, which represents a significant improvement over our previous work with this laser system. Correspondingly, we observe the best agreement between the EC-QCL measurements and the UV DOAS measurements with benzene, followed by toluene, then p-xylene. Although BTX gas detection limits are not as low for the EC-QCL system as for UV DOAS, an unidentified by-product of the photoreactions was observed with the EC-QCL, but not with the UV DOAS system. PMID- 21283226 TI - Laser Applications to Chemical, Security, and Environmental Analysis: introduction to the feature issue. PMID- 21283227 TI - Improved reconstructions and generalized filtered back projection for optical projection tomography. AB - Optical projection tomography (OPT) is a noninvasive imaging technique that enables imaging of small specimens (<1 cm), such as organs or animals in early developmental stages. In this paper, we present a set of computational methods that can be applied to the acquired data sets in order to correct for (a) unknown background or illumination intensity distributions over the field of view, (b) intensity spikes in single CCD pixels (so-called "hot pixels"), and (c) refractive index mismatch between the media in which the specimens are embedded and the environment. We have tested these correction methods using a variety of samples and present results obtained from Parhyale hawaiensis embedded in glycerol and in sea water. Successful reconstructions of fluorescence and absorption OPT images have been obtained for weakly scattering specimens embedded in media with nonmatched refractive index, thus advancing OPT toward routine in vivo imaging. PMID- 21283228 TI - Miniaturized, high-power diode-pumped, Q-switched Nd:YAG laser oscillator amplifier. AB - A miniaturized, passively Q-switched Nd:YAG laser oscillator-power amplifier is reported, which is axially pumped by a compact, fiber-coupled, high-power, quasi cw diode laser module. The pumping intensity of the oscillator crystal can be adjusted independently of the pumping intensity of the amplifier. This ensures that the oscillator pulse enters the amplifier when its maximum population density is reached. Furthermore, pulse bursts can be generated with a definite, adjustable number of single pulses. Maximum pulse energies of 8.4 and 22 mJ were achieved for a single pulse and for a pulse burst, respectively, at a pumping power of 470 W. The pulse widths were 2 ns, whereas the beam quality corresponded to M2<1.5. The laser is appropriate for scaling the power to the 10 MW range. Operation by using a 100 m pumping fiber was demonstrated. PMID- 21283229 TI - Active illumination single-pixel camera based on compressive sensing. AB - We present an optical imaging system based on compressive sensing (CS) along with its principal mathematical aspects. Although CS is undergoing significant advances and empowering many discussions and applications throughout various fields, this article focuses on the analysis of a single-pixel camera. This work was the core for the development of a single-pixel camera approach based on active illumination. Therefore, the active illumination concept is described along with the experimental results, which were very encouraging toward the development of compressive-sensing-based cameras for various applications, such as pixel-level programmable gain imaging. PMID- 21283230 TI - Realization of integrated polarizer and color filters based on subwavelength metallic gratings using a hybrid numerical scheme. AB - This study realizes integrated polarizer and RGB (red, green, and blue) color filters using single- and multiple-layered subwavelength metallic grating structures. A hybrid numerical scheme based on the rigorous coupled-wave analysis method and a genetic algorithm is used to determine the optimal values of the grating period, filling factor, and grating thickness of three different grating structures, namely, a single-layer grating, a double-layer grating, and a double layer grating with a lateral shift. The optical performance of the various structures is evaluated and compared in terms of the transmission efficiency at the center wavelengths 700.0 nm, 546.1 nm, and 435.8 nm of red, green, and blue light, respectively, and the extinction ratio over the visible wavelength spectrum (380-780 nm). It is shown that the double-layer grating achieves a transmission efficiency of about 50% and an extinction ratio of around 60 dB. Thus, this grating structure provides a convenient and effective means of achieving the polarizing and filtering functions in LCD panels using a single device. PMID- 21283231 TI - Refractive index determination of transparent samples by noniterative phase retrieval. AB - We present a simple method to determine the refractive indices of transparent specimens. The refractive index of an object under investigation is received by evaluating the optical path difference introduced by the object, while taking into account geometric parameters. The optical path difference that corresponds to the phase distribution is obtained by a noninterferometric, noniterative phase retrieval method based on Green's functions. It will be shown that this technique is a highly accurate and quantitative method for refractive index determination. PMID- 21283232 TI - Material classification of nanoparticles by focused beam scattering. AB - Advanced science and technology frequently encounters the need to detect particles in the micrometer and nanometer range of a given composition. While the scattering process of light by small particles is well documented, most conventional analytic methods employ wide illumination of large ensembles of particles. With such an approach, no information can be obtained about single particles due to their weak interaction. In this paper, we show that single particles can be classified with respect to their material composition by analyzing the scattering pattern of a focused Gaussian beam. PMID- 21283233 TI - Comparison of laser-induced surface damage density measurements with small and large beams: toward representativeness. AB - Pulsed laser damage density measurements obtained with diverse facilities are difficult to compare, due to the interplay of numerous parameters, such as beam area and pulse geometry, which, in operational large beam conditions, are very different from laboratory measurements. This discrepancy could have a significant impact; if so, one could not even pretend that laser damage density control is a real measurement process. In this paper, this concern is addressed. Tests with large beams of centimeter size on a high-power laser facility have beam performed according to a parametric study and are compared to small beam laboratory tests. It is shown that laser damage densities obtained with large and small beams are equal, within calculated error bars. PMID- 21283234 TI - Lunar absorption spectrophotometer for measuring atmospheric water vapor. AB - A novel instrument has been designed to measure the nighttime atmospheric water vapor column abundance by near-infrared absorption spectrophotometry of the Moon. The instrument provides a simple, effective, portable, and inexpensive means of rapidly measuring the water vapor content along the lunar line of sight. Moreover, the instrument is relatively insensitive to the atmospheric model used and, thus, serves to provide an independent calibration for other measures of precipitable water vapor from both ground- and space-based platforms. PMID- 21283235 TI - Coupled-wave analysis of vector holograms. 2. Reflective gratings formed in photoanisotropic medium with uniaxial birefringence. AB - The diffraction properties of reflective anisotropic gratings, which can be recorded in photoanisotropic media with uniaxial birefringence by three dimensional vector holography, were characterized through the use of coupled-wave analysis (CWA). By investigating the perturbation of the dielectric tensor, we demonstrated that the gratings with sinusoidal distribution of the azimuthal angle of the optic axis diffract polarized light in which the ordinary and extraordinary components are converted for incident light. The polarization conversion was consistent with that calculated by a numerical method. In addition, it was shown that CWA enables highly accurate calculation of the diffraction efficiency with wavelength dispersion when the amplitude of the azimuthal angle is small. PMID- 21283236 TI - Phase-locked loop based on machine surface topography measurement using lensed fibers. AB - We present the phase-locked loop (PLL)-based metrology concept using lensed fibers for on-machine surface topography measurement. The shape of a single-mode fiber at the endface was designed using an ABCD matrix method, and two designed lensed fibers-the ball type and the tapered type-were fabricated, and the performance was evaluated, respectively. As a result, the interferometric fringe was not found in the case of the ball lensed fiber, but the machined surface could be measured by utilization of autofocusing and intensity methods. On the other hand, a very clear Fizeau interferometric fringe was observed in the case of the tapered lensed fiber. Its performance was compared with the results of the capacitance sensor and a commercially available white-light interferometer. We confirmed that PLL-based surface profile measurement using the tapered and ball lensed fibers can be applied for on-machine surface topography measurement applications. PMID- 21283237 TI - Sensitivity-enhanced high-temperature sensing using all-solid photonic bandgap fiber modal interference. AB - A wavelength-encoded interferometric high-temperature sensor based on an all solid photonic bandgap fiber (AS-PBF) is reported. It consists of a small piece of AS-PBF spliced core offset with standard single-mode fibers. Two core modes LP(01) and LP(11) are conveniently utilized as optical arms to form Mach-Zehnder type interference at both the first and the second photonic bandgaps, and the maximum extinction ratio exceeds 25 dB. Experimental and theoretical investigation of its response to temperature confirms that high temperatures up to 700 degrees C can be effectively sensed using such an AS-PBF interferometer, and benefiting from a large effective thermo-optic coefficient of fiber structure, the sensitivity can be significantly enhanced (71.5 pm/ degrees C at 600 degrees C). PMID- 21283238 TI - Laser guide star wavefront sensing for ground-layer adaptive optics on extremely large telescopes. AB - We propose ground-layer adaptive optics (GLAO) to improve the seeing on the 42 m European Extremely Large Telescope. Shack-Hartmann wavefront sensors (WFSs) with laser guide stars (LGSs) will experience significant spot elongation due to off axis observation. This spot elongation influences the design of the laser launch location, laser power, WFS detector, and centroiding algorithm for LGS GLAO on an extremely large telescope. We show, using end-to-end numerical simulations, that with a noise-weighted matrix-vector-multiply reconstructor, the performance in terms of 50% ensquared energy (EE) of the side and central launch of the lasers is equivalent, the matched filter and weighted center of gravity centroiding algorithms are the most promising, and approximately 10*10 undersampled pixels are optimal. Significant improvement in the 50% EE can be observed with a few tens of photons/subaperture/frame, and no significant gain is seen by adding more than 200 photons/subaperture/frame. The LGS GLAO is not particularly sensitive to the sodium profile present in the mesosphere nor to a short-timescale (less than 100 s) evolution of the sodium profile. The performance of LGS GLAO is, however, sensitive to the atmospheric turbulence profile. PMID- 21283239 TI - Low-repetition-rate, high-energy, twin-pulse, passively mode locked Yb3+-doped fiber laser. AB - We report an all-normal-dispersion, low-repetition-rate, high-energy, twin-pulse, passively mode locked ytterbium-doped fiber laser. The mode-locking mechanism of the laser is based on nonlinear polarization evolution and strong pulse shaping with a cascade long-period fiber grating bandpass filtering in a highly chirped pulse. The laser generates a highly stable twin-pulse group with 248 ps and 296 ps duration simultaneously and maximum pulse energy of 26.8 nJ-each pulse at a 2.5445 MHz repetition rate. Energy quantization is observed, which demonstrates the nonparabolic nature of these pulses. The laser can also work in third harmonic mode locking with 17.8 nJ energy (at a repetition rate of 7.65 MHz and pulse width of 780 ps). PMID- 21283240 TI - Mode coupling and output beam quality of 100-400 MUm core silica fibers. AB - Propagation and mode coupling within relatively short (~1-10 m) large core, nominally multimode, fibers are of interest in a number of applications. In this research, we have studied the output beam quality and mode coupling in various fibers with core diameters of 100-400 MUm and lengths of 2 m. Output beam quality (M2) and mode-coupling coefficients (D) have been studied for different clad dimensions, numerical apertures, and wavelengths. The mode-coupling coefficients have been determined based on modal power diffusion considerations. The results show that D scales approximately as the inverse square of the clad dimension and inverse square root of the wavelength. Output from a 2 m length fiber of 100 MUm core and 660 MUm clad fiber is close to single mode (M2=1.6), while output from a 200 MUm core and 745 MUm clad fiber also has high beam quality. PMID- 21283241 TI - Fast numerical method for electromagnetic scattering from an object above a large scale layered rough surface at large incident angle: vertical polarization. AB - A fast numerical method has been proposed in this paper for calculating the electromagnetic scattering from a perfectly electric conducting object above a two-layered dielectric rough surface. The focus in this study is large incidence. The parallel fast multipole method is combined with the method of moments for fast implementation of the scattering from this composite model. The biconjugate gradient method is adopted to solve the unsymmetrical matrix equation and parallelized. The simulating time and parallel speedup ratio with different processors are provided. Several numerical results are shown and analyzed to discuss the influences of the parameters of the rough surface, the object, and the intermediate medium on the bistatic scattering. PMID- 21283242 TI - Reducing the diffraction artifacts while implementing a phase function on a spatial light modulator. AB - Spatial light modulators are often used to implement phase modulation. Since they are pixelated, the phase function is usually approximated by a regularly sampled piecewise constant function, and the periodicity of the pixel sampling generates annoying diffraction peaks. We theoretically investigate two pixelation techniques: the isophase method and a new nonperiodic method derived from the Voronoi tessellation technique. We show that, for a suitable choice of parameters, the diffraction peaks disappear and are replaced by a smoothly varying halo. We illustrate the potential of these two techniques for implementing a lens function and wavefront correction. PMID- 21283243 TI - Yule-Nielsen based recto-verso color halftone transmittance prediction model. AB - The transmittance spectrum of halftone prints on paper is predicted thanks to a model inspired by the Yule-Nielsen modified spectral Neugebauer model used for reflectance predictions. This model is well adapted for strongly scattering printing supports and applicable to recto-verso prints. Model parameters are obtained by a few transmittance measurements of calibration patches printed on one side of the paper. The model was verified with recto-verso specimens printed by inkjet with classical and custom inks, at different halftone frequencies and on various types of paper. Predictions are as accurate as those obtained with a previously developed reflectance and transmittance prediction model relying on the multiple reflections of light between the paper and the print-air interfaces. Optimal n values are smaller in transmission mode compared with the reflection model. This indicates a smaller amount of lateral light propagation in the transmission mode. PMID- 21283244 TI - Interferometric measurement of laser heating in praseodymium-doped YAG crystal. AB - Temperature measurement is required for many applications but can be difficult in some cases. Laser heating or cooling studies demand accurate measurements of temperature changes. A Michelson interferometer configuration has been used to investigate laser heating in solids. An analytical formula was derived to estimate the temperature change from the fringe count by taking into account the temperature dependence of the sample length and refractive index. When 115 mW of a focused Ar+ laser beam (488 nm) passes through a Pr(3+)-doped YAG sample, its temperature increased by 11.7+/-1.0 K along the beam path due to nonradiative relaxation. The power dependence of the fringe count/movement was recorded. The temperature change was estimated by the interferometric method and is in agreement with that measured by a thermocouple. PMID- 21283245 TI - Integrated three-dimensional shape and reflection properties measurement system. AB - Creating accurate three-dimensional (3D) digitalized models of cultural heritage objects requires that information about surface geometry be integrated with measurements of other material properties like color and reflectance. Up until now, these measurements have been performed in laboratories using manually integrated (subjective) data analyses. We describe an out-of-laboratory bidirectional reflectance distribution function (BRDF) and 3D shape measurement system that implements shape and BRDF measurement in a single setup with BRDF uncertainty evaluation. The setup aligns spatial data with the angular reflectance distribution, yielding a better estimation of the surface's reflective properties by integrating these two modality measurements into one setup using a single detector. This approach provides a better picture of an object's intrinsic material features, which in turn produces a higher-quality digitalized model reconstruction. Furthermore, this system simplifies the data processing by combining structured light projection and photometric stereo. The results of our method of data analysis describe the diffusive and specular attributes corresponding to every measured geometric point and can be used to render intricate 3D models in an arbitrarily illuminated scene. PMID- 21283246 TI - Rolled edges and phasing of segmented telescopes. AB - To achieve the diffraction limit, the segments in a segmented telescope must be correctly aligned to a fraction of a wavelength. This alignment is performed via optical measurements using starlight. We investigate the piston degree of freedom or phasing of the segments and the impact of rolled segment edges on the accuracy of the optical alignment. Three models for edge profiles are developed and fit to data from optic manufacturers. These profiles are then used, along with a simplified model of a Shack-Hartmann optical sensor, to determine their impact on phasing accuracy. The results can help estimate the residual phasing error and set requirements on segment polishing. PMID- 21283247 TI - Phasing beams with different dispersions and application to the petawatt-class beamline at the National Ignition Facility. AB - In order to achieve the highest intensities possible with the short-pulse Advanced Radiographic Capability beamline at the National Ignition Facility (NIF), it will be necessary to phase the individual ARC apertures. This is made especially challenging because the design of ARC results in two laser beams with different dispersions sharing the same NIF aperture. The extent to which two beams with different dispersions can be phased with each other has been an open question. This paper presents results of an analysis showing that the different dispersion values that will be encountered by the shared-aperture beams will not preclude the phasing of the two beams. We also highlight a situation in which dispersion mismatch will prevent good phasing between apertures, and discuss the limits to which higher-order dispersion values may differ before the beams begin to dephase. PMID- 21283248 TI - Polarization-independent tunable spectral slicing filter in Ti:LiNbO3. AB - A two-port polarization-independent tunable spectral slicing filter at the 1530 nm wavelength regime is presented. The design utilizes an asymmetric interferometer with a sparse index grating along its arms. The sparse grating makes it possible to select equally spaced frequency channels from an incident WDM signal and to place nulls between them to coincide with the signal comb frequency. The number of selected channels and nulls between them depends on the number of coupling regions used in the sparse grating. The free spectral range depends on the spacing between the coupling regions. The Z-transform method is used to synthesize the filter and determine the spectral response. The operation of a device with six coupling regions is demonstrated, and good agreement with theoretical predictions is obtained. A 3 dB bandwidth of ~1 nm and thermal tuning over a range of ~13 nm are measured. PMID- 21283249 TI - Diffractive simultaneous bidirectional shearing interferometry using tailored spatially coherent light. AB - Measurements of wavefront deformations can be carried out with the help of lateral shearing interferometers. Here the focus is on a setup providing two shears along orthogonal directions simultaneously to generate the data needed for a reconstruction. We describe a diffractive solution using Ronchi phase gratings with a suppressed zeroth order for both the doubling of the wavefront under test and the bidirectional shearing unit. A series arrangement of the gratings offers an on-axis geometry, which minimizes the systematic errors of the test. For illumination, an extended incoherent monochromatic light source is used. High contrast fringes can be obtained by tailoring the degree of coherence via a periodic intensity distribution. PMID- 21283250 TI - Fabrication of ellipticity-controlled microlens arrays by controlling the parameters of the multiple-exposure two-beam interference technique. AB - We demonstrate a promising method for fabrication of plastic microlens arrays (MLAs) with a controllable ellipticity and structure, by using the combination of multiple-exposure two-beam interference and plastic replication techniques. Multiple exposures of a two-beam interference pattern with a wavelength of 442 nm into a thick positive photoresist (AZ-4620) were used to form different two dimensional periodic structures. Thanks to the developing effect of the positive photoresist, fabricated structures consisting of hemielliptical- or hemispherical shaped concave holes were obtained. By controlling the rotation angle between different exposures, both the shape and structure of the holes varied. By adjusting the dosage ratio between different exposures, the shape of the holes was modified while the structure of the holes was unchanged. The photoresist concave microstructures were then transferred to plastic MLAs by employing replication and embossing techniques. The fabricated MLAs were characterized by a scanning electron microscope and atomic force microscope measurements. We show that the ellipticity of the microlenses can be well controlled from 0 (hemispherical) to 0.96 (hemielliptical) by changing the rotation angle or dosage ratio between the two exposures. PMID- 21283251 TI - Statistical phase-shifting step estimation algorithm based on the continuous wavelet transform for high-resolution interferometry metrology. AB - We propose a statistical phase-shifting estimation algorithm for temporal phase shifting interferometry (PSI) based on the continuous wavelet transform (CWT). The proposed algorithm explores spatial information redundancy in the intraframe interferogram dataset using the phase recovery property on the power ridge of the CWT. Despite the errors introduced by the noise of the interferogram, the statistical part of the algorithm is utilized to give a sound estimation of the phase-shifting step. It also introduces the usage of directional statistics as the statistical model, which was validated, so as to offer a better estimation compared with other statistical models. The algorithm is implemented in computer codes, and the validations of the algorithm were performed on numerical simulated signals and actual phase-shifted moire interferograms. The major advantage of the proposed algorithm is that it imposes weaker conditions on the presumptions in the temporal PSI, which, under most circumstances, requires uniform and precalibrated phase-shifting steps. Compared with other existing deterministic estimation algorithms, the proposed algorithm estimates the phase-shifting step statistically. The proposed algorithm allows the temporal PSI to operate under dynamic loading conditions and arbitrary phase steps and also without precalibration of the phase shifter. The proposed method can serve as a benchmark method for comparing the accuracy of the different phase-step estimation methods. PMID- 21283252 TI - Effects of anisotropic diffractions on holographic polymer-dispersed liquid crystal gratings. AB - Volume gratings fabricated by interferometric exposure using composite materials composed of nematic liquid crystals (LC) and LC diacrylate monomers are discussed in the effects of diffraction properties on different grating formations, such as varying LC content ratios, film thicknesses, and the surface conditions composed of alignment layers and rubbing directions. Diffraction properties are experimentally investigated in the viewpoints of anisotropic diffraction and LC orientation. The polarization-azimuth dependence of diffraction efficiencies as functions of the incident polarization states shows the controllability of anisotropic diffractions based on the effects of different surface conditions. PMID- 21283253 TI - Dual-wavelength distributed feedback fiber laser based on double exposure and equivalent phase shift method. AB - A special sampling structure based on double exposure technology is proposed to achieve dual-wavelength lasing in the distributed feedback fiber laser. This structure is composed of two grating pitches in one sampling period, which could be realized by changing the fiber's length in the fabrication. Through employing an equivalent phase shift, only a submicrometer-level precision is required for precise phase control. Then a stable dual-wavelength laser with the spacing of 400 pm is obtained in the experiment successfully. The output power is 30.46 MUW and the sidemode suppression ratio is 46 dB under a pumped power of 146 mW. PMID- 21283254 TI - Expression of hsp90 alpha and hsp90 beta during Xenopus laevis embryonic development. AB - BACKGROUND: Members of the eukaryotic Hsp90 family function as important molecular chaperones in the assembly, folding and activation of cellular signaling in development. Two hsp90 genes, hsp90 and hsp90, have been identified in fish and homeothermic vertebrates but not in poikilothermic vertebrates. In the present study, the expression of hsp90 and hsp90 genes in Xenopus laevis, which is phylogenetically positioned between zebrafish and mammals, has been addressed. METHODS: Partial Xenopus hsp90 and hsp90 cDNA were identified and isolated using RT-PCR, and a full-length Xenopus hsp90 cDNA was isolated from an embryonic cDNA library. Northern-blot analysis was used to study the expression of hsp90 and hsp90 genes in total RNA of the embryos and in situ hybridization was used to compare the expression of these genes with that of hsp70 and MyoD genes in Xenopus embryogenesis. RESULTS: Northern-blot analysis revealed that the hsp90 gene was strongly expressed constitutively at all stages of embryogenesis, but weakly induced following the heat shock. In contrast, the hsp90 gene was weakly expressed in embryos at control temperature, but strongly up-regulated following heat shock. In situ hybridization results showed that hsp90 gene was observed predominantly in cells of the developing somite. Microscopic sections showed that hsp90 and MyoD mRNA are expressed in similar regions in somite and this pattern was distinct from that of hsp70 and hsp90. CONCLUSION: These data support the hypothesis that the presence of hsp90 and hsp90 genes is conserved among vertebrates, and these genes are differentially regulated in a tissue, stress, and development stage-specific manner. PMID- 21283255 TI - In vivo characterization of fusion protein comprising of A1 subunit of Shiga toxin and human GM-CSF: Assessment of its immunogenicity and toxicity. AB - BACKGROUND: Most cancer cells become resistant to anti-cancer agents. In the last few years, a new approach for targeted therapy of human cancer has been developed using immunotoxins which comprise both the cell targeting and the cell killing moieties. METHODS: In the present study, the recombinant Shiga toxin A1 subunit fused to human granulocyte-macrophage colony stimulating factor (A1-GM-CSF), previously produced in E. coli, was further characterized. RESULTS: The recombinant protein could cause 50% cytotoxicity and induced apoptosis in cells bearing GM-CSF receptors. The non-specific toxicity of the fusion protein was assessed in C57BL/6 and BALB/c mice. No mortality was observed in either group of mice, with different concentration of fusion protein. CONCLUSION: The lymphocyte proliferation assay, induction of specific IgG response and a mixed (Th1/Th2) response were observed only in BALB/c mice. The mixed response in BALB/c mice (Th1/Th2) could be explained on the basis of the two components of the fusion protein i.e. A1 and GM-CSF. PMID- 21283256 TI - Comparison of transplantation of bone marrow stromal cells (BMSC) and stem cell mobilization by granulocyte colony stimulating factor after traumatic brain injury in rat. AB - BACKGROUND: Recent clinical studies of treating traumatic brain injury (TBI) with autologous adult stem cells led us to compare effect of intravenous injection of bone marrow mesenchymal stem cells (BMSC) and bone marrow hematopoietic stem cell mobilization, induced by granulocyte colony stimulating factor (G-CSF), in rats with a cortical compact device. METHODS: Forty adult male Wistar rats were injured with controlled cortical impact device and divided randomly into four groups. The treatment groups were injected with 2 * 106 intravenous bone marrow stromal stem cell (n = 10) and also with subcutaneous G-CSF (n = 10) and sham operation group (n = 10) received PBS and "bromodeoxyuridine (Brdu)" alone, i.p. All injections were performed 1 day after injury into the tail veins of rats. All cells were labeled with Brdu before injection into the tail veins of rats. Functional neurological evaluation of animals was performed before and after injury using modified neurological severity scores (mNSS). Animals were sacrificed 42 days after TBI and brain sections were stained by Brdu immunohistochemistry. RESULTS: Statistically, significant improvement in functional outcome was observed in treatment groups compared with control group (P<0.01). mNSS showed no significant difference between the BMSC and G-CSF treated groups during the study period (end of the trial). Histological analyses showed that Brdu-labeled (MSC) were present in the lesion boundary zone at 42nd day in all injected animals. CONCLUSION: In our study, we found that administration of a bone marrow-stimulating factor (G-CSF) and BMSC in a TBI model provides functional benefits. PMID- 21283257 TI - Verifying of participation of nitric oxide in morphine place conditioning in the rat medial septum using nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d). AB - BACKGROUND: Role of nitric oxide (NO) in morphine-induced conditioned place preference (CPP) has already been proposed in the rat medial septum (MS), but no molecular evidence has been provided to clear this fact. METHODS: Effects of intraseptal injections of L-arginine and/or NG-nitro-L-arginine methyl ester (L NAME) on morphine place conditioning in Wistar rats were examined. Morphine (2.5 7.5 mg/kg) was injected s.c. using a three-day schedule of an unbiased place preference. All of the brain samples were examined histochemically by nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d), the main marker for NO activation. RESULTS: Morphine induced a significant CPP in the rats. Single injections of L-arginine or L-NAME (0.3, 1.0 and 3.0 ug/rat) did not induce CPP. In addition, co-administration of morphine (5.0 mg/kg) with L arginine or L-NAME (0.3, 1.0 and 3.0 ug/rat) did not affect morphine response. However, administration of L-arginine (0.3, 1.0 and 3.0 ug/rat) prior to morphine conditioning testing enhanced the expression of morphine response. Moreover, pre injection of L-NAME (0.3, 1.0 and 3.0 ug/rat) to L-arginine (0.3 ug/rat) did not reverse the response to the agent. The expression of NADPH-d was observed in the rat brain samples treated by L-arginine. A decreased expression of NADPH-d was also observed in rats pre-injected by L-NAME. CONCLUSION: This finding strongly suggests that NO system in the rat MS has an impact on the expression of morphine rewarding, and that the NO participates in place conditioning induced of morphine. PMID- 21283258 TI - Degradation of extracellular matrix molecules in interleukin-1alpha treated bovine nasal cartilage. AB - BACKGROUND: This work aimed to show and compare the degradation time of some of cartilage extracellular matrix components using an in vitro model for cartilage degradation induced by interleukin-1alpha. It is known that elucidation of molecular events under Interleukin-1alpha induction of bovine nasal cartilage could obtain useful data to understand more about involving mechanisms for tissue breakdown in joint disease. METHODS: The cartilage was taken from an adult bovine in a local slaughterhouse. After removing the whole perichondrium, the equal 2 mm diameter pieces of bovine nasal cartilage were punched out and cultured in Dulbecco's modified Eagle's medium DMEM with or without 10 ng/ml Interleukin 1alpha for 24 days. Each 3 days, the media were removed and exchanged by fresh media, and the removed media were stored in -20 degrees C. Sodium dodecyl sulphate/polyacrylamid-gel electrophoresis SDS-PAGE and Western-blot methods were used for analyzing the samples. RESULTS: The first fragment of fibromodulin (FM) was seen at day 6 and further fragments were appeared at day 18. Cartilage oligomeric matrix protein (COMP) releasing was as a successive pattern during culture period and the first fragment was found at day 6. Collagen IX fragments were seen at day 9 and in a progressive pattern until the end of the study. CONCLUSION: This study shows that FM and COMP could be considered as the suitable candidates for studying the mechanisms that participate in the cartilage degradations. PMID- 21283259 TI - Study of the intraplantar injection of lidocaine and morphine on pain perception and the influence of morphine dependence and withdrawal on lidocaine-induced analgesia in rats. AB - BACKGROUND: Morphine and lidocaine are known to influence the perception of pain. The present study sought to determine the influence of local administration of morphine on lidocaine-induced analgesia in morphine non-dependent (MND), morphine dependent (MD) and morphine withdrawal (MW) animals. METHODS: Adult male Wistar rats were divided into four groups: Control, MND, MD and MW rats. Lidocaine (0.5, 1 and 2%) and morphine (200, 400 and 800 ug) were injected in the plantar surface of the right paw. MD animals received chronic oral morphine (0.1, 0.2, 0.3 and 0.4 mg/ml in their drinking water) for 20 days. Twenty four hours before experiment, the animals in the MW group were deprived of morphine in their drinking water (physical dependence was observed by precipitating an abstinence syndrome with naloxone 2 mg/kg i.p.). Analgesia was assessed using hot-plate apparatus. RESULTS: Morphine (400 ug) and lidocaine (2%) produce local analgesia in MND group. In MND rats, non-analgesic doses of each drug (200 ug morphine and 1% lidocaine) were used in combination and produced analgesia. In MD animals, all doses of lidocaine produced analgesia, while in MW animals, it failed to produce analgesia. In this situation, local administration of morphine could eventually influence the analgesic effect of lidocaine. CONCLUSION: Opioid withdrawal is one of the most common problems in clinic. This study determined the analgesic effect of lidocaine in MW animals in which lidocaine had no analgesic effect. In this regard, local administration of morphine with combination of lidocaine could probably produce an effective analgesia. PMID- 21283260 TI - Effect of ovarian stimulation on the endometrial apoptosis at implantation period. AB - BACKGROUND: Apoptosis is a process that plays an important role during early stage of implantation. The aim of this study was to investigate the incidence of apoptosis in mice endometrium after ovarian stimulation at implantation period. METHODS: NMRI female mice were divided into two groups: 1) control group, which were rendered pseudopregnant by vaginal stimulation and 2) experimental group, which were stimulated using an intrapritoneal injection of 10 IU hMG followed by another injection of 10 IU hCG after 48 h. In the evening of the second injection, the mice were rendered pseudopregnant the same as control group. Samples were obtained from 1/3 middle part of uterine horns during implantation period. Apoptosis was assessed in two groups at implantation period using light and electron microscopic studies, TUNEL staining and semiquantitative RT-PCR. RESULTS: Our morphological and ultrastructural results showed apoptosis in both groups, while TUNEL analysis showed that the percentage of TUNEL-positive cells was higher in stimulated group than in the control group (P<=0.05). The expression of P53, Fas and FasL mRNA was similar in two groups but Bax and Bcl2 were much higher in control group than in the stimulated group (P<=0.05). The ratio of Bax/Bcl2 expression was much higher in stimulated group than in the control group (P<=0.05). CONCLUSION: The ovarian stimulation could change the expression of some apoptosis-related genes and enhance the incidence of endometrial apoptosis at implantation period; thus, it could affect on the implantation rate and endometrial receptivity. PMID- 21283261 TI - The effect of "Teucrium polium L." extracts on insulin release from in situ isolated perfused rat pancreas in a newly modified isolation method: the role of Ca2+ and K+ channels. AB - BACKGROUND: "Teucrium polium L." (TP) has been long recommended in Iranian folk medicine for its anti-diabetic activities. We attempt here to evaluate the effect of TP extract on insulin secretion in rat pancreas. METHODS: Rat pancreas was isolated in situ and perfused with Krebs solution containing low glucose (LG, 2.8 mM) or high glucose (HG, 16.7 mM) as perfusate. The aqueous extract (Aq. E) and methanolic extract (Met. E) of TP aerial parts and two partition fractions of Met. E were added to perfusate to evaluate insulin release. Diazoxide (DZX) and verapamil (VPM) were also used for assessing the probable mechanism of the effects. In each experimental group, the peak and baseline of insulin levels in effluent samples were compared. The GC/MS analysis was carried out to detect active ingredients in the extracts. RESULTS: Adding Met. E to the LG caused a significant increase (P<0.05) in insulin release from the basal level of 0.17 +/- 0.05 ug/l to a peak value of 3.94 +/- 1.29 ug/l. when Met. E was introduced to the HG, there was a further protracted stimulation of insulin release from 2.15 +/- 1.35 ug/l to 6.16 +/- 0.52 ug/l. Both DZX and VPM when added separately to the LG, led to inhibition of Met. E induced insulin secretion. The Aq. E and fractions had no significant effect on insulin secretion. Only in the Met. E, the component 5-hydroxy-4',7-dimethoxyflavone (apigenin-4',7-dimethylether) was detected. CONCLUSION: It can be concluded that the insulinotropic properties of TP extracts can be attributed to the presence of apigenin existing only in Met. E, but not in Aq. E and fractions. Moreover, certain types of K+ and Ca2+ channels take part in this effect. PMID- 21283262 TI - East Meets West: WONCA in Singapore. PMID- 21283263 TI - [Not Available]. PMID- 21283264 TI - [Not Available]. PMID- 21283265 TI - The cost of protection. PMID- 21283266 TI - Another lift for leg length inequality. PMID- 21283267 TI - Lend an Ear To Reader's Plea. PMID- 21283268 TI - Diagnosing impotence. AB - Although psychogenic factors have been thought to account for 95% of cases of impotence, current research indicates that organic factors may be present in about 50%. Investigation of impotence therefore involves a complete history and physical examination, psychological evaluation, an interview with the patient's partner, tests for serum testosterone level, urological assessment, and measurement of nocturnal penile tumescence. Referral to a sexual dysfunction clinic should take place if the etiology remains obscure. Above all, thoroughness of approach and empathy for the patients is paramount. PMID- 21283269 TI - What to Tell Patients About TURP. AB - All elective surgery causes patients anxiety. Operations near the genital tract are associated with even larger fears. Prostatic surgery can be as traumatic for a man as having a breast removed is for a woman.This tear-out sheet can be copied and distributed to patients booked for transurethral prostate surgery. It describes the problem and how it will be dealt with. Postoperative complications especially sexual ones-decrease when the surgery has been adequately explained to patients. As in other instances, communication is one of the best medicines we have. PMID- 21283270 TI - Common scrotal lesions. AB - Scrotal masses may be asymptomatic, discovered by patients or on routine examination, and include herniae, hydroceles, spermatoceles and primary tumors. Painful masses include infections, trauma, or torsion and may require prompt surgical intervention. This article reviews examination, diagnosis and accepted treatment for each situation, emphasizing documentation and prompt diagnosis. PMID- 21283271 TI - Complications of vasectomy. AB - Much anxiety has arisen about the longterm immunological and cardiovascular effects of vasectomy. Evidence to date for increased atherosclerosis is inconclusive, although immunological side effects such as sperm agglutination and immobilization occur in about 40% of vasectomized men. Although many psychosocial effects have been reported, the only problem the authors have encountered is refusal to return for postoperative sperm counts. Careful preparation and counselling are essential in preventing postoperative psychological effects. Postoperative complications are few and minor. The failure rate varies from 0.25 1.2%; patients should be warned of this. Reversal of the procedure is now possible; 40-60% of men who request reversal eventually become fathers. PMID- 21283272 TI - Investigation and management of male infertility. AB - Infertility is rarely due only to the male or female partner. Usually each partner's fertility is in some way diminished. Male infertility may be related to deficiencies in spermatogenesis or sperm transport. Accurate diagnosis can be achieved only by a careful evaluation including precise semen analyses and, where indicated, gonadotropin and other assays. Treatment may be specific for physical or endocrine deficits, but is often empirical. Factors other than the sperm count, such as emission of sperm mainly at the beginning of ejaculation, low seminal volume with good quality sperm, excessive seminal viscosity, pyospermia, and idiopathic oligospermia, may be responsible for infertility. These may respond to simple measures. Understanding and empathy for the infertile couple is of the utmost importance. PMID- 21283273 TI - Exercise prescription: principles and current limitations. AB - Exercise prescriptions must be both safe and effective, while maximizing patient compliance. Safety can be threatened by physical injury, cardiac emergencies and environmental hazards. Risk can be reduced by individualizing the prescription, although the stress ECG contributes little to the prevention of the exercise catastrophe. Effectiveness of a prescription must be gauged by development of aerobic power and muscular strength, reduction of obesity, improvement of flexibility and control of coronary risk factors. The variability of patient response limits the potential for accurate laboratory prescription of exercise; fine tuning must depend upon the patient's immediate reactions. PMID- 21283274 TI - What Would You Have Done? Responses to Dr. Shortt's Case. PMID- 21283275 TI - The follow up: an unhappy solution. PMID- 21283276 TI - [Not Available]. PMID- 21283277 TI - [Not Available]. PMID- 21283278 TI - How prevalent is obesity in Canada? PMID- 21283279 TI - College, Not AMA, Rules on Home Births. PMID- 21283280 TI - Can you treat obesity? PMID- 21283281 TI - Be careful what you say. PMID- 21283282 TI - Illness Following MMR Immunization in Indian and Non-Indian Children. AB - A cohort study was undertaken to see if the frequency of office reported illness during the three weeks after MMR immunization was greater among Indian children (N=127) compared to non-Indian children (N=81) attending a family practice centre. All children had been given HPV(77)DE(5) vaccine or RA 27/3 vaccine between ages 11 and 24 months. Illness after immunization was not related to frequency of attendance at the medical centre or weight at age 12 months. The overall illness rate for Indian children was almost twice the rate for non Indians. Indian children who were ill before immunization were more likely to be ill during the three week post-MMR period. No such relationship was noted among non-Indian children. This suggests that children with an established record of frequent illness are likely to experience an illness following MMR immunization. These results need to be confirmed by a prospective study. PMID- 21283283 TI - The family physician in the witness box. AB - The doctor appearing in court must learn a new language and be prepared to deal with the legal profession, which is quite different from his own. Adequate preparation for a court case can make it less confusing; this article gives guidelines for doctors occasionally called to give evidence, or who are accused of malpractice. Doctors called as witnesses must consult with lawyers early, to determine exactly what information the court wants and the form a report should take. Physicians should carefully study and summarize all their evidence in non technical language before a court appearance. By learning some legal language, they can also understand and adequately answer lawyers' questions. A physician accused of negligence must make no admissions before the case and have no contact with the plaintiff other than to formally acknowledge the charge. The Canadian Medical Protective Association should be contacted as soon as possible. PMID- 21283284 TI - The office of the coroner. AB - Society has always been concerned about deaths which do not result from natural causes. In Canada, provincial legislatures have met this concern with legislation known as the Coroners' Act in some provinces and as the Fatality Inquiries Act in others. While these statutes are not identical, their intent is the same: to ensure that all unusual deaths are fully investigated to determine their true cause. The coroner's or medical examiner's primary responsibility is to show the public how similar deaths may be avoided. PMID- 21283285 TI - Sex and the mentally retarded: is sterilization the answer? AB - The sexuality of the mentally handicapped concerns them, their parents, their family physicians and other health professionals. Parents need advice, and the well-informed family physician who has the family's trust is in a good position to give it. However, the physician must protect the rights and autonomy of the mentally handicapped patient concerning contraception, surgical sterilization and hysterectomy. Before recommending a method of contraception, the physician must identify any medical risks and be satisfied that the patient clearly understands risks and advantages. Sterilization as a method of contraception should never be considered unless the patient chooses it; involuntary sterilization can produce serious and significant psychological damage. The physician must give a detailed explanation to make sure the patient electing to be surgically sterilized understands the procedure and has fully consented without coercion. Hysterectomy should never be used as a method of sterilization. PMID- 21283286 TI - The legal relationship of doctor and hospital. AB - While doctors working in hospitals have usually been regarded as independent contractors, liable to the patient and for whom the hospital may not be held liable by the patient, some recent cases are beginning to change this assumption, especially where the case is an emergency giving the patient no choice of doctor but the one on duty at the time. These changes have particular implications for the insurance situation, since hospitals are entitled to sue someone on whose behalf they have been found vicariously negligent. As a condition of hospital privileges, they may require evidence of the doctor's insurance protection against legal action. PMID- 21283288 TI - Why become a coroner? AB - The coroners' system varies in different countries and provinces. In many provinces the family physician's broad medical background is the prime requisite for the position. While the duties are sometimes onerous and time consuming, the satisfaction of playing a key role in investigating deaths, and being able to effect major changes in public safety and wellbeing, provides the family physician coroner with a challenging alternative to an otherwise routine family practice. PMID- 21283287 TI - Giving and taking: the family doctor and organ transplantation. AB - Organ transplantation has moved from clinical experimentation to accepted procedure. The number of organs now required highlights the importance of ethical considerations of both donors and recipients. The role of the family physician spans public education, influence on hospitals to maximize the number of organs retrieved from brain dead patients, advice to patients with organ failure concerning the availability and effectiveness of organ transplantation, advice to bereaved families who may consent to organ donation, and advice to living donors. PMID- 21283289 TI - Do sports enthusiasts need to take extra iron? AB - Anyone engaging in regular, vigorous physical activity is likely to be concerned about maximum physical performance. Canadian Olympic athletes have been shown to have hemoglobin levels below normal, giving concern about reduced physical work capacity. This two-part article outlines the principles of 'sports anemia' for the physician, and describes the role of iron in simple terminology for the sports enthusiast. PMID- 21283291 TI - Starting a practice, eh? Take my advice. PMID- 21283290 TI - Toxic shock syndrome: diagnosing recurrence. AB - Toxic shock syndrome (TSS) is not easily recognized, despite explicit criteria for diagnosis. These include fever, rash, desquamation of palms and soles, and hypotension, plus involvement of up to seven other organ systems. The disease is associated with tampon use; Staphylococcus aureus is the most likely causative organism. Recurrence with menstruation is unique to this disease, although recurrences have been reported without the use of tampons and efforts to isolate Staphylococcus aureus from cultures may prove fruitless. In this case, a 27-year old woman experienced recurrences which could be diagnosed only by hindsight. All suspected cases should be reported to the Laboratory Centre for Disease Control in Ottawa so that a true picture of this disease may be obtained. PMID- 21283292 TI - [Not Available]. PMID- 21283293 TI - [Not Available]. PMID- 21283294 TI - Ortho-novum 1/50. PMID- 21283295 TI - Homosexuality seen as against word of god. PMID- 21283296 TI - Formaldehyde in insulation: villain or innocent bystander? AB - When urea formaldehyde foam insulation (UFFI) deteriorates, it produces an off gas mixture whose major constituent is formaldehyde. Most investigative studies of UFFI have concentrated on formaldehyde. Health concerns fall into three groups: irritant characteristics, allergenic capabilities and potential carcinogenicity. Except for the first of these, formaldehyde's hazard potential is not clear. The extent to which formaldehyde may be responsible for UFFI's evil reputation is explored in this paper but the degree to which either substance is a real threat to health still appears to open to debate. PMID- 21283297 TI - The ocean and occupational health. AB - With the increase in offshore industrial operations, more needs to be known about health and safety of workers in such industries. Some general principles of occupational health apply; some special situations, such as depth diving, demand special knowledge and facilities. Equipment used also brings its own hazards. This article outlines the scope of health and safety concerns for those physicians whose patients work on or in the ocean. PMID- 21283298 TI - A Family Physician's Guide to Sewage Sludge. AB - The potential environmental and personal health effects from the agricultural uses of domestic sewage sludge may increasingly require the guidance of the family physician, especially in farming communities. This article summarizes the potential health hazards and outlines the tripartite risk phenomenon-hazard identification, risk assessment, and social evaluation. For the agricultural use of dewatered sewage sludge, strict adherence to regulated procedures should not increase risk beyond that of agriculture generally. Confirmation by prospective epidemiological studies is recommended. PMID- 21283299 TI - [Not Available]. AB - Because we are concerned with the teaching of preventive medicine to residents in family medicine, we decided to implement a vaccination study to evaluate residents' efficacy in preventing infectious diseases. After collecting each patient's past history of infectious diseases and vaccination the residents completed the necessary vaccination according to protocol, over one year. We used the one-tail hypothesis test of proportion to verify significant differences in the proportion of patients not well immunized at the end of the study, compared with the beginning, for each vaccine studied. We found no statistically significant difference for vaccination against whooping cough, measles and mumps; there was a significant difference for vaccination against tetanus, diphtheria, polio and rubeola (P:0.01). PMID- 21283300 TI - [Not Available]. AB - With more women entering the labor market, concern about adverse effects of occupational exposure on reproductive health has been increasing. Of special importance are those agents which might cause birth defects and gene mutations. The fetus can be subject to chemical, biological, physical and ergonomic threats to its wellbeing. Most of the concern has been focused on the occupational dangers for pregnant women. However, the potential risks for the male reproductive system are being more widely recognized. PMID- 21283301 TI - Reprint filing: a profile-based solution. AB - A reprint filing system based on practice profiles can give family physicians easy access to relevant medical information. The use of the ICHPPC classification and some supplemental categories provides a more practical coding mechanism than organ systems, textbook chapter titles or even Index Medicus subject headings. The system can be simply maintained, updated and improved, but users must regularly weed out unused information, and read widely to keep the reprints current. PMID- 21283302 TI - The challenge of family medicine around the world in the 1980s. PMID- 21283303 TI - Status epilepticus: a plan for management. AB - Status epilepticus of the generalized tonic-clonic form is a serious, life threatening neurological emergency. Management must be swift and effective to protect the brain from anoxic damage and serious neurological sequelae. Most cases are due to withdrawal or non-compliance with anticonvulsant medication in known epileptics. Diazepam, phenytoin and phenobartital are effective in stopping these episodes. Other drugs may be effective in certain individuals, but most appear to work with 'hit or miss' effectiveness. Barbiturate anesthesia is an effective method of ending status epilepticus episodes when the primary agents have failed, and this step should be undertaken early in the management of resistant cases. PMID- 21283304 TI - Thigh pain in a ten-year-old boy. AB - The ability to obtain a good history is still an essential skill, but various unforeseen obstacles can mislead the physician. In the case described, a ten-year old boy was unable to give an accurate history without his parents present. Then, his parents seemed relatively unconcerned about some fairly dramatic symptoms. Finally, even after the full history was obtained, there was a further two-month delay in making the correct diagnosis because it was so unlikely in a ten-year old. PMID- 21283306 TI - Having the right answer. PMID- 21283305 TI - Two years of prelicensure training: observations from the alberta experience. AB - Alberta is the only jurisdiction in North America which requires two years of training between receipt of the MD degree and licensure to practice medicine. Definitive studies to evaluate the validity of this decision are contemplated, since the legislation is now seven years old. Although several different bodies support the concept of two years' training rather than one, they disagree over how those two years should be spent, and there remain several interested parties which are not convinced about the necessity for two years' training. This article examines the data from seven years experience. PMID- 21283307 TI - [Not Available]. PMID- 21283308 TI - [Not Available]. PMID- 21283309 TI - La certification en medecine d'urgence. PMID- 21283310 TI - Treating schizophrenia: the sooner the better. PMID- 21283311 TI - More balanced diet at scientific assemblies? PMID- 21283313 TI - Importance of neonatal herpes. PMID- 21283312 TI - Cost/Benefit of hemoccult test. PMID- 21283314 TI - Reinstate 3rd year of residency training. PMID- 21283315 TI - Delayed orthopedic diagnosis. PMID- 21283316 TI - How family physicians manage urinary tract infection in women. AB - Physicians vary in their approaches to urinary tract infections in females. We studied 198 women with symptoms suggesting urinary tract infection. Computer analysis failed to identify any clusters of symptoms, signs or significant historical data which would predict significant bacteriuria with acceptable accuracy. Routine culturing of all symptomatic women is not recommended. Risk factors causing complications of urinary tract infection are reviewed. PMID- 21283317 TI - Herpes genitalis in patients attending a clinic for sexually transmitted diseases. AB - In a prospective study of 210 patients attending a hospital-based sexually transmitted disease clinic, we documented the prevalence of genital herpes infection (GHI) and its association with gonococcal infection (GI). Herpes simplex virus type 2 was cultured from 58% of symptomatic patients and 0.5% of asymptomatic patients.The ratio of GI to GHI was 41:31 by clinical criteria. The laboratory-confirmed ratio was 41:18. These ratios are much higher than those normally used to estimate the caseload of GHI. PMID- 21283318 TI - Office management of stasis ulcer and stasis dermatitis. AB - Effective management of stasis ulcer, and the frequently coexisting stasis dermatitis, depends on correct diagnosis. Significant morbidity and disability result, often over a long period of time. The usual defect involved is incompetence of the intrinsic valves in either the superficial or deep veins. Treatment is geared towards correction of venous hypertension in the lower leg, clearing of secondary infection and inflammation, protection from further injury, and correction of predisposing factors. Treatment failure is usually due to non compliance, since many treatment methods are irksome. A simplified method, using the Unna paste boot, partly eliminates dependence on patient compliance. PMID- 21283319 TI - Use of calcium ion entry blockers in family practice. AB - Verapamil, nifedipine, and diltiazem are drugs which decrease intracellular calcium in cardiac muscle, smooth muscle, and nodal cardiac cells. Unlike B blockers, each drug acts at a different site on the cell membrane and has an important difference in overall action. Verapamil is used to treat angina, systemic hypertension, hypertrophic cardiomyopathy, and supraventricular and junctional tachyarrhythmias. Nifedipine is useful in angina, vasospastic disorders, and hypertension. A specific role for diltiazem is now being defined. PMID- 21283320 TI - Resistant hypertension: evaluation of the patient. AB - Resistant hypertension is a common and serious problem. Before major changes in management are undertaken, seven questions should be asked: 1. What is a realistic goal blood pressure? 2. Is the erect blood pressure below the goal? 3. Is the patient compliant? 4. Does the patient have 'office hypertension'? 5. Is the patient using medication which aggravates hypertension? 6. Are there confounding renal or cardiovascular responses to medication? 7. Has a secondary cause of hypertension been overlooked? Newer and more potent medications such as captopril and minoxidil should be recommended only after exploration of these questions and after careful clinical and laboratory evaluation. PMID- 21283321 TI - [Not Available]. AB - Raynaud's phenomenon can be idiopathic (Raynaud's disease) and is found in healthy individuals or secondary to various conditions. Our perception of Raynaud's phenomenon has made a clear progression, partly due to a more useful set of diagnostic criteria for those rheumatic inflammatory diseases which are autoimmune. When it is unilateral, a vascular cause is generally found. When it is bilateral, there is usually an association with a systemic disorder. Laboratory investigation should be undertaken only if the physical findings suggest it. The etiology of Raynaud's disease remains unknown. Medications proposed for its treatment are aimed at suppressing adrenergic neuronal activity of the sympathetic nervous system (reserpine, guanethidine, methyldopa) or suppressing alpha receptor activity (phenoxybenzamine, prazosin) or stimulating beta receptor activity (isoxsuprine, terbutaline). PMID- 21283322 TI - Vertebral-basilar insufficiency. AB - Vertebral-basilar ischemia can result in giddiness, transient ischemic attacks, and drop attacks. Management involves controlling blood pressure, getting the patient to stop smoking, controlling diabetes and/or hyperlipidemia, and instituting antiplatelet therapy. Several facets of this problem remain unexplained. PMID- 21283323 TI - Acute arterial emergencies. AB - The response of the primary care physician in the initial assessment and management of acute arterial injuries will often be the deciding factor in survival of life, limb or organ system. Most arterial emergencies occur as a result of trauma, disruption of vessel wall and/or occlusion of flow. The common clinical syndromes of acute arterial emergencies are injuries to and beyond the aorta, acute aortic dissection, ruptured aortic aneurysm, and thromboembolic occlusive arterial disease. The role of arteriography and the urgency of definitive surgical repair in acute arterial emergencies is summarized. PMID- 21283324 TI - Intermittent claudication: initial assessment and management. AB - An illustrative case history shows the presenting symptoms of intermittent claudication, revealing how clinical impression can lead the physician to suspect either a minor manifestation of progressive disease which will not affect the patient's health for some time to come, if he modifies his risk factors, or an early manifestation of a painful, progressive and fatal disease. Resolution of pain involves adaptation of recreational activity, reduction of smoking, and weight control. It must be established whether the claudication is persistent, or if intermittent, whether it interferes with the patient's daily functioning. A regular walking program will encourage collateral circulation. Bypass surgery should be considered if other methods fail to control the pain; percutaneous transluminal angioplasty is also a possibility. PMID- 21283325 TI - Prevention of pulmonary emboli in hospitalized patients. AB - The risk of pulmonary infarction in any hospitalized population is high. To decrease this dreaded complication, the high risk population must be identified. These are chiefly elderly patients with a history of previous DVTP, cancer, cardiac disease, trauma to a lower limb or a history of recent surgery. All methods of reducing venous stasis should be used, and most of these patients should be treated prophylactically with subcutaneous heparin. PMID- 21283326 TI - Spinal claudication. AB - Spinal claudication is due to marked narrowing of the spinal canal with resulting pressure on the cauda equina. The characteristic symptoms are variable discomfort in the back and legs, brought on by exercise and/or extension movements of the hips and low back. The neurological examination may be normal or may reveal dysfunction of one or more lumbosacral nerve roots. Myelography and, particularly, body CT scanning are definitive diagnostic procedures. Most patients respond satisfactorily to extensive surgical decompression. PMID- 21283328 TI - What Would You Have Done? Responses to Dr. McIlwain's Case. PMID- 21283327 TI - Leg length inequality. AB - Leg length inequality, a common abnormality, can cause musculoskeletal pain, scoliosis, and osteoarthritis of the hip. Seven percent of the asymptomatic population has a leg length inequality greater than 12 mm; the incidence is considerably higher (13%-22%) in individuals complaining of low back pain. Correction can usually be accomplished by shoe modification, and can result in dramatic relief of pain. Leg length inequality of more than half an inch is considered clinically significant. Leg length measurement should be routine in all patients complaining of low back pain, hip pain, and atypical flank and lower quadrant pain. Correction might prove very cost-effective. PMID- 21283329 TI - The follow up: a way down the middle. PMID- 21283330 TI - Delayed diagnosis: did the patient have a case? PMID- 21283331 TI - Interpersonal skills and the credibility of family medicine. AB - While the discipline of family medicine has thrived in the last decade, the training programs in family medicine are still the subject of controversy. Older family doctors see the programs as an attack on the way they practice, rather than on the way they were trained. Acceptance of general licensure after a one year rotating internship shows that the two year program has not yet been accorded recognition. The teaching of family medicine has always placed strong emphasis on interpersonal skills, and has therefore tended to be judged by its ability in this area. However, there is still a prevailing belief that these skills are inherent, not taught, and therefore not to be credited to the excellence of the teaching programs. There is also a prevailing belief that these skills are 'nice', but not essential. Evidence shows, however, that compliance is enhanced by physicians' interpersonal skills, and that there are definite strategies for acquiring such skills. The programs must find ways to convince the profession at large of these facts. PMID- 21283332 TI - The game of the name. PMID- 21283333 TI - Stress and the physician: a preventive approach. PMID- 21283334 TI - [Not Available]. PMID- 21283336 TI - Statistical alertness. PMID- 21283335 TI - [Not Available]. PMID- 21283337 TI - Vested interests in alcohol. PMID- 21283339 TI - Device report devised. PMID- 21283338 TI - Helping seniors deter drug interactions. PMID- 21283340 TI - Antifungal shows promise. PMID- 21283341 TI - Emergency medicine. PMID- 21283342 TI - Uncontrolled trials. PMID- 21283343 TI - Follow up of Stress Management Groups in Family Practice. AB - Ninety-six registrants (70 females, 26 males, mean age 36.4) were trained in seven standard autogenic training groups for management of stress-related disorders by a family physician in a community health centre. Comparisons were made before and after six training weeks, using the State-Trait Anxiety Inventory and a questionnaire about physical and psychological symptoms, drug, tobacco and alcohol use. As in a previous study, state and trait anxiety scores and symptoms related to stress were decreased in a majority of subjects. Effects were maintained in a subgroup followed for 12 months. Problems of data collection over time in clinical settings and of establishing the impact of health education measures are discussed. PMID- 21283344 TI - Twins in the family. AB - The birth of two babies has an enormous impact on a family. This article describes coping mechanisms for the first three years, emphasizing the babies' psychological and developmental tasks, the parents' abilities to handle these transitions, and the impact on siblings. Each baby needs to feel that it is 'the only one', each parent needs help, and each sibling still needs to feel 'special'. PMID- 21283345 TI - Employment and stress. AB - Tension and anxiety are part of the adventure of work. Management and labor are working closely to make the workplace safe and the job rewarding, but growing numbers of bureaucrats and societies cannot replace the family physician. Bureaucrats and regulations are ever-changing. The worker must know how to use emotions to advantage, and remain on the job from teens to retirement. Pain and stress need not produce the diseases of stress. 'Tough love' techniques, organized by labor-management teams, confining their interests to the individual's problems, will flourish and cut out the family physician unless he works closely with these successes. Family physicians are encouraged to join Boards of Trade and Safety Councils to gain experience in prevention. PMID- 21283346 TI - Helping patients manage stress. AB - Stress and worry are always a part of our patients' problems and frequently the sole cause of their symptoms. Ways of relieving anxiety in different types of patients are described, according to complexity and time required. The main principles are: adequate diagnosis; explanation of the stress symptom cycle; supportive reassurance; identification and reduction of stressors where possible, and varying degrees of personal development to bring patients' level of functioning and adjustment up to match his stresses. Objections and difficulties are discussed, together with benefits such as diminised use of anxiolytics; a healthier adjustment for the patient, and greater job satisfaction for the physician. PMID- 21283347 TI - Homosexuality: a review. AB - Homosexuality is a sexual preference which arouses a great deal of hostility, is surrounded by myths, and is often viewed as a disease. In separating fact from fantasy, family physicians will be better able to treat the approximately 10% of their patients who are homosexual. Recent studies show that homosexuals lead a variety of lifestyles, do not suffer from more psychiatric illness than do heterosexuals, but are susceptible to stresses induced by a hostile society. PMID- 21283348 TI - Psychological aspects of retirement. AB - Retirement is a normal phenomenon which is not a crisis for most people. However, those who have previously had difficulty coping with major life events may be expected to experience difficulties at this time of life. Some will experience mild symptoms of anxiety, as part of an adjustment reaction to late life. A minority will suffer a significant depressive reaction. In most of these cases, however, other significant life events and factors will have triggered breakdown. In the milder cases psychotherapy is the main treatment of choice, either individually or conjointly with the spouse. Antidepressant drugs and other physical treatments may have a part to play in some cases. PMID- 21283349 TI - Life stress and illness: a systems approach. AB - The link between stress and illness has been forged by researchers like Holmes and Rahe whose Social Readjustment Rating Scale can be used by family physicians to assess their patients' stress. The concept of stress has been clarified by the systems approach to illness. Stress and illness are embedded in a biopsychosocial matrix of several systems levels, each of which may be a source of stress as well as a support system. Stress is not the end result of a linear chain of causes and effects, but part of a feedback system in a community or family. The family is the major source of lifestyle and personality, the health belief system and modes of problem solving and coping, as well as of stress and support. The family physician can have a major role in educating the individual and family about stress and illness, and in altering the meaning of stress from catastrophe to challenge and source of growth. Anticipatory guidance for the normal crises of the life cycle and the crises of illness, loss and death can help prevent further family dysfunction and illness. PMID- 21283351 TI - Anorexia nervosa: a lifestyle disorder. AB - Anorexia nervosa is a real lifestyle disorder. The apparent increase in frequency has been linked to the change of position of women in society. If families have an important role to play in the maintenance of the drama, they also hold the key to its resolution. The family physician in early contact with the anorectic patient is in an important position to involve the family in therapy and maximize the chances of recovery. The steps required are reframing, preparing the family involved for family therapy, exploring the benefits of change, and follow up. PMID- 21283350 TI - Obesity in family practice: is treatment effective? AB - Obesity is a common condition which has important effects on health status and longevity. This review examines the efficacy of treatments for both moderate and severe obesity. A plan of treatment combining diet, exercise, and behavioral strategies is outlined. Surgery and its complications are reviewed. Eight management issues, including rate of weight loss, self-help groups, and fringe therapies, are presented. Management recommendations are based on a critical review of the weight loss literature. PMID- 21283352 TI - Relationship of social supports to health. AB - The research literature has produced mixed findings on the relationship of social supports to health. There is a clear relationship between mortality and lack of social support, a less clear but still strongly positive relationship between psychological symptoms and the lack of social support. In relation to physical symptoms, the findings are mixed: some studies show positive effects and others show none. Mutual help groups are an effective way of offering social support to a variety of target groups, whose needs cannot be met by the medical care system. PMID- 21283354 TI - What Would You Have Done? Responses to Dr. Slater's Case. PMID- 21283353 TI - Glycosylated hemoglobins: a review. AB - The glycosylated hemoglobins are becoming accepted as a measure of longterm glycemic control in diabetes mellitus. The present review discusses the biochemistry and clinical studies in diabetes which relate glycosylated hemoglobin to screening, control and development of longterm complications. Other causes of increased glycosylated hemoglobin are also discussed. PMID- 21283355 TI - The follow up: what really happened. PMID- 21283356 TI - Peer review-or sneer review? PMID- 21283358 TI - [Not Available]. PMID- 21283357 TI - [Not Available]. PMID- 21283359 TI - Runners and leg length. PMID- 21283360 TI - No more tidbits! PMID- 21283361 TI - Disgusted reader. PMID- 21283362 TI - Language in families. PMID- 21283363 TI - Jack the ripper strikes again. PMID- 21283364 TI - Can children be promiscuous? PMID- 21283366 TI - Natural family planning. PMID- 21283365 TI - Name games. PMID- 21283367 TI - Medication info. PMID- 21283369 TI - Short leg or long leg? PMID- 21283368 TI - Those who shall be nameless. PMID- 21283370 TI - Moving a private community family practice to a hospital-based teaching unit: patients' response. AB - Patients' response to the relocation of an established practice from the community to a hospital-based teaching unit was measured at the end of one year. Questionnaires were sent to a randomly selected group of adult patients, asking about their impressions of the new clinic or their reasons for switching practices. The major reason cited for changing practices was the change of geographic location, rather than the change from community to teaching practice. Although most patients had been seen by residents, ratings were unrelated to the number of residents or staff administering care. PMID- 21283371 TI - Well Baby Care: The Nurse's Job? AB - The traditional content of the well baby examination has changed to include more health screening, emotional support and educational input. It has been suggested that the well baby care should now be done by nurses. Fifty-five mothers surveyed at the University of Western Ontario indicated that for them, the nurse was as important a source of information as the doctor. In some cases, such as advice on the telephone, nurses scored higher than doctors; however, younger mothers appeared to view the nurse less positively than older mothers did. Experienced mothers viewed the nurse more positively than did first-time mothers. Results suggest that mothers' perceptions would be compatible with a new and expanded role in well baby care for the family practice nurse. PMID- 21283372 TI - Toenail avulsion. AB - Ingrown toenails are commonly seen in family practice, and are treated conservatively. If this does not resolve the condition, lateral wedge resection and permanent, partial nail bed ablation are necessary. Recurrence can be prevented by chemical cautery with 10% sodium hydroxide. Betadine packing reduces infection. PMID- 21283373 TI - Acne surgery. AB - Acne surgery consists of comedone extraction of non-inflamed lesions, triamcinolone acetate injections of some inflamed lesions, and extraction of milia. Prevention is a very important part of comedone treatment, especially avoidance of picking, moisturizers and harsh soaps. Instruments are also very important: even the finest may be too thick and may have to be filed down. Acne surgery is only an adjunct of good medical therapy. PMID- 21283374 TI - Screening for endometrial cancer. AB - Although population screening for cervical neoplasia is widely practiced, screening for endometrial neoplasia has only recently been considered. Before development of endometrial carcinoma, the endometrium undergoes progressive neoplastic alterations in a parallel fashion to the premalignant precursors of cervical carcinoma. Screening for endometrial carcinoma may be particularly appropriate because of the existence of a well defined, easily identifiable high risk group and tissue sampling techniques that are accurate, easy to perform, inexpensive, and well tolerated. Women at increased risk of endometrial carcinoma include: obese postmenopausal women, women on postmenopausal estrogen replacement therapy, premenopausal women with a history of anovulatory cycles (including women with polycystic ovarian disease) and women with hepatic cirrhosis. Using endometrial aspiration devices, screening for endometrial hyperplasia and carcinoma may be performed by any physician familiar with intrauterine contraceptive device insertion in the office. The impact of such routine screening of high risk women will be determined only after large screening studies have been accomplished. PMID- 21283375 TI - The skin punch biopsy. AB - The skin punch biopsy is a simple and safe office procedure which is a valuable aid in diagnosing many skin diseases. It can be performed in a few minutes and offers in most situations a very suitable histological specimen with a minimum amount of scarring and little or no pain or discomfort to the patient. The indications for skin biopsy, selection of a proper site and the technique are described. PMID- 21283376 TI - Intrauterine contraceptive devices. AB - Although the ideal contraceptive has not been found, intrauterine contraceptive devices offer distinct advantages and provide adequate contraception. Unfortunately, they have side-effects, complications and failures. Their use is contraindicated in pregnancy, abnormalities of the uterine cavity, uterine hypoplasia, infection and abnormal uterine bleeding. Patients who have had an ectopic pregnancy, who are prone to endocarditis, who have allergies to copper, or who are taking anticoagulants also should not use IUCDs, Insertion is best performed during menstruation, and the patient should be seen in follow up to assess placement and any side-effects, including cramps, bleeding, vaginal discharge, or discomfort during intercourse. Pregnancy may occur when the IUCD is in place, and prompt diagnosis is mandatory. Depending on the type of IUCD used, replacement time varies from one to three years. PMID- 21283377 TI - Insertion of an IUD. PMID- 21283378 TI - The aspir-gun: when to draw: the technique of aspiration biopsy. AB - Aspiration biopsy cytology or fine needle aspiration is a well-established, safe, highly reliable, inexpensive diagnostic procedure which must be distinguished from the more familiar 'needle biopsy'. The Aspir-Gun, a plastic syringe 'pistol', makes the technique simple enough for use in a solo practitioner's office. Since it is cheaper to send slides to referral centres than patients, it has a special screening value for doctors in isolated areas. Indications are discussed, with emphasis on those anatomic sites and palpable masses, which have practical application for the primary care physician. PMID- 21283379 TI - Coming next month-a lifestyles section. PMID- 21283380 TI - Post-traumatic aneurysms of the superficial temporal artery. AB - Aneurysms of the superficial temporal artery usually occur after trauma to the area and present as a pulsatile mass. This lesion should be considered in a differential diagnosis of all forehead and temporal masses, to prevent undue hemorrhage during excision. The recommended treatment is surgical, and may be safely performed under local anesthesia, provided proximal and distal control of the superficial temporal artery is obtained. Although a rare lesion, aneurysm of the superficial temporal artery must be considered in the management of forehead masses. PMID- 21283381 TI - Martial arts and ulnar nerve compression injuries. PMID- 21283382 TI - Silent speech: 'talking' with blissymbolics. PMID- 21283383 TI - What would you have done? A case of functional abdominal pain. AB - So many situations in family medicine will not fit the nice, neat formulae of history, physical, findings and treatment that are presented in traditional 'grand rounds'. Frequently, the most logical, or the most medically sensible course of action is not possible. The family physician is left negotiating a situation in which there is not necessarily a 'right' way to act, as in this case. Responses, with comments from the presenter of the case, will be published in upcoming issues. Readers are invited to submit similar cases from their own experience. PMID- 21283385 TI - Should children be steered towards sports suited to their body type? PMID- 21283384 TI - Family Medicine Residency: Does it Make a Difference? AB - The Canadian Medical Association instituted a Task Force on Primary Care to investigate methods of training for family practice, as a result of a debate at their 1981 General Council meeting in Halifax. The fact that this debate took place shows the continuing controversy over how family physicians should be trained for their role in the health care system. Since 50% of Canada's medical graduates are involved in this controversy, it is unfortunate if confusion exists. Potential residents are often concerned about the emphasis placed on psychosocial skills, and about the volume of practice in family practice units. Both of these concerns show a lack of knowledge about the true nature of family practice, which is very different from in-hospital training. Graduates should be encouraged to make their career choices based on quality of training, not eligibility to sit the CFPC's certification examination in family medicine. PMID- 21283386 TI - In absentia. PMID- 21283387 TI - [Not Available]. PMID- 21283388 TI - Reaction: july cover. PMID- 21283390 TI - History of impotence: significant omissions. PMID- 21283389 TI - A directory of cancer support services. PMID- 21283391 TI - More on nurses and well baby care. PMID- 21283392 TI - IUCD and Incidence Of Ectopic Pregnancy. PMID- 21283393 TI - Surgical care in small alberta communities. AB - A three-phase study was carried out in 1981 to determine the number of surgical procedures being done in Alberta communities with fewer than 10,000 inhabitants. Health insurance statistics grouped according to hospital and community size revealed that approximately 25% of physicians practicing in smaller communities did relatively uncomplicated major procedures, such as inguinal hernia repair. Those physicians who were surgically active tended to be versatile, carrying out procedures in several surgical disciplines. A questionnaire to individual hospitals revealed significant differences in procedural work between hospitals of similar size, serving similar populations. A second questionnaire showed that almost all rural hospitals, regardless of size, felt that the ability to monitor cardiac arrhythmias, provide physiotherapy and manage normal obstetrics was important and indicated that the importance of the ability to do surgical procedures varied according to the size of the hospital. The majority of physicians performing these procedures are not surgeons, and many of them will be retiring in the next ten years, so the training of their replacements becomes an important issue. While some consolidation of facilities will be inevitable, it should be combined with technological upgrading. PMID- 21283394 TI - Psychological evaluation of acute low back pain in hospital workers. AB - Personality, anxiety and depression were assessed in 62 hospital workers divided in three experimental groups: those with acute organic low back pain, those with acute functional low back pain, and asymptomatic control subjects. Results showed no statistical differences between groups in the evaluation of personality. Asymptomatic subjects had significantly lower scores for trait anxiety and depression than did patients suffering from low back pain. Patients with pain of organic origin were also more depressed than were patients with pain of functional origin. Anxiety and depression are two psychological variables which must be examined in acute back pain problems. Further studies should be conducted to develop more accurate psychological instruments to evaluate the large population of patients suffering from low back pain. PMID- 21283395 TI - Ultrasonography in the diagnosis of gallbladder disease. AB - Ultrasonography is the technique of choice in diagnosing gallbladder calculi. In the mid-1970s ultrasound was only accurate enough to use as an adjunct to oral cholecystography but refinements such as gray scale and real-time imaging mean that in experienced hands it has a sensitivity of 96% and a specificity of 93%. Sonography is also the test of choice in the initial evaluation of jaundiced patients. It is an excellent technique for distinguishing between obstructive and nonobstructive jaundice, although it is less accurate in demonstrating the cause of the obstruction. Ultrasound is painless and relatively inexpensive, and has several advantages over oral cholecystography; it doesn't depend on contrast material, causes no adverse reactions or side-effects, is safe during pregnancy, does not expose the patient to radiation, and is less time-consuming. PMID- 21283396 TI - [Not Available]. AB - Constipation is an important problem in older patients, who are often chronic users of laxatives. Dietary fiber is becoming more important in treating gastrointestinal disorders. In studying the drug profiles of 52 elderly patients in a chronic care unit, we found that a large percentage were taking laxatives. We therefore wanted to compare the effect of a diet enriched with bran to the effect of an emollient laxative, docusate sodium. Patients were divided into two groups. For the first three weeks, one group received a diet with 15 g/day natural wheat bran added, plus a placebo, and the other received 200 mg/day docusate sodium. In the second three weeks, the groups were switched to the other treatment. After the 42 days of the study, the number of stools per day per patient did not differ significantly, whether they had been taking bran or laxatives. Otherwise, transit times revealed that those who had taken bran had a more rapid transit time than those who had taken laxatives. These results show the efficacy of dietary fiber, particularly wheat bran, in prevention and correction of constipation in the elderly. PMID- 21283397 TI - High fiber diets: their role in gastrointestinal disorders. AB - High fiber diets may help prevent colon cancer and be used to treat constipation, diverticular disease, irritable bowel syndrome and Crohn's disease. Some research indicates that cholelithiasis, duodenal ulcers, hemorrhoids and hiatal hernias may be prevented or treated with dietary fiber. However, many claims about fiber's usefulness lack scientific validation. Physicians can help patients establish goals for the amount of fiber they eat and advise them to record their daily intake of fiber. Doctors can also help patients select high fiber foods which fit their lifestyles, warn of possible side effects such as gas, abdominal pain and malabsorption of some nutrients, and advise them to exercise and drink adequate amounts of fluid. Children can be encouraged to eat whole grain breads, high-fiber snacks and natural bran hidden in cooked cereals, cookies and ground meat recipes. The physician or dietician should follow up patients to ensure their continued compliance. PMID- 21283398 TI - Diarrhea. AB - The four major mechanisms of diarrhea are osmotic forces, secretory forces, exudation from a disrupted intestinal mucosa, and disturbed intestinal motility. In many illnesses, more than one mechanism produces diarrhea. The rotaviruses and the Norwalk viruses have recently been recognized as common causes of viral gastroenteritis. Also, the major cause of antibiotic-associated colitis is now known to be an overgrowth of Clostridium difficile. Campylobacter has also been identified as a common cause of acute bacterial diarrhea both abroad and in Canada. Most cases of travellers' diarrhea are caused by strains of Escherichia coli to which the traveller has little immunity. Most travellers who develop diarrhea benefit from treatment with diphenoxylate, loperamide or bismuth subsalicylate. The few patients who develop more severe, incapacitating diarrhea are candidates for treatment with trimethoprim-sulfamethoxazole. Antibiotics should not be used to prevent travellers' diarrhea, because antibiotic resistance is becoming a problem. PMID- 21283399 TI - Colonoscopy: perspectives for family physicians. AB - Fiber-optic endoscopy is an important investigation of the lower gastrointestinal tract, whether or not the radiologist has discovered a lesion. Colonoscopy affords a unique opportunity to visualize the entire colonic mucosa. At the same time, the physician can obtain biopsy specimens, remove polyps, and decompress volvuli. Most experienced endoscopists can reach the cecum in over 90% of patients. If colonoscopy is properly performed, it has a low risk of complications, such as perforation and bleeding. The few absolute contraindications include serious illnesses such as acute myocardial infarction and severe acute inflammatory bowel diseases. Family physicians referring patients for investigations of lower gastrointestinal problems should explain that colonoscopy is an adjunct to, not a replacement for, a barium enema examination. If possible they should find out what preparation the patient will require. PMID- 21283400 TI - Psychological aspects of recurrent abdominal pain. AB - Recurrent abdominal pain with no apparent organic cause is common in children. An investigation should be made for both psychological and organic causes. The initial assessment should include a detailed history of pain, a developmental history, a detailed family pain history, and history of any school, family or marital stress. A diary recording the parents' and child's observations of the child's pain may indicate its causes, ideas for management, and indicate whether it is improving. Specific treatment for psychological pain focuses on the underlying cause, removing it if possible. However, only non-specific treatment is possible when neither organic nor psychological causes can be found. The physician should discuss the diagnosis with parents and child and reassure them the pain is benign and self-limiting. He should also acknowledge the child's pain is real and encourage him to cope by taking part in as many of his normal activities as possible. PMID- 21283401 TI - Orthotics in sports shoes. AB - We are all born with a varying assortment of biomechanical discrepancies. Ordinarily these may be of no consequence, but to those who try to achieve excellence in a certain sport these discrepancies can spell the difference between success and failure. Some athletes may have to accept the fact that biomechanically the odds are against them ever becoming excellent and that intensive training may in fact be detrimental to their wellbeing. However, the majority can be helped with advice on proper shoe wear and orthotic correction. This article highlights the role of foot orthotics as indicated for various biomechanically-related problems commonly encountered in athletes. PMID- 21283402 TI - Rational Choice of Antiemetic Agents during Cancer Chemotherapy. AB - Nausea and vomiting are major limitations in cancer chemotherapy. Individual susceptibility to nausea varies enormously. There is no ideal antiemetic, but some work with some chemotherapeutic agents, and some are more effective in younger patients. This article describes a flexible, stepped approach using the phenothiazines, metoclopramide, cannabinoids, anticholinergics, antihistamines and others. PMID- 21283403 TI - Addicted Doctors: Responding to their Needs. AB - A better understanding of the problems of physicians who misuse alcohol and drugs has helped in the early recognition and treatment of a chemical dependence. Treatment programs, particularly those which recognize physicians' special needs, report high rates of recovery. Many addicted doctors' needs are related to their professional role. Their image often becomes an obstacle to treatment. Relationships with colleagues frequently make it difficult to get help. These special problems usually reflect negative attitudes and moralistic judgments which are unwarranted. The early recognition of a developing dependence is encouraged by informal programs of assistance and an advocacy role for the profession. PMID- 21283404 TI - Insurance medicine: introduction for the family physician. AB - Insurance companies request reports on patients' health to corroborate and clarify information on insurance application forms. Illegible or vague reports, or one that varies from the patient's understanding of his health, can result in patients being offered substandard policies at increased premiums. Reports, even if brief, must include known risk factors, disease history, and information on stability of medical conditions. PMID- 21283406 TI - A family physician, a sabbatical and psychiatry. PMID- 21283405 TI - Malignancy in the aged: two 'cures' of stomach cancer. AB - Two elderly patients with longstanding gastrointestinal symptoms were eventually diagnosed as having cancer of the stomach. Both were treated-one surgically, the other with chemotherapy. While they were 'cured' of the disease, they succumbed to the treatment. These cases raise questions of the approach to be taken to malignancy in the aged. PMID- 21283407 TI - [Not Available]. PMID- 21283409 TI - [Not Available]. PMID- 21283408 TI - [Not Available]. PMID- 21283410 TI - Missing links? PMID- 21283411 TI - Sitting in judgment. PMID- 21283412 TI - Doctors and torture. PMID- 21283413 TI - We're Sorry, Too. PMID- 21283415 TI - Differential Insurance Fees and the CMPA. PMID- 21283414 TI - Differential Insurance Fees and the CMPA. PMID- 21283416 TI - Differential Insurance Fees and the CMPA. PMID- 21283417 TI - Give a doc a bad name. PMID- 21283418 TI - Differential Insurance Fees and the CMPA. PMID- 21283419 TI - [Not Available]. PMID- 21283420 TI - When Patients Divorce: The Family Physician's Legal Position. AB - When divorce and family disintegration loom, the family physician is often the first outsider on the scene. The family physician may, indeed, have a critical role to play in handling the crisis; he may advise, refer to other professionals like therapists or lawyers, or appear in court as an expert witness. The physician must consider his legal position. Is reconciliation counselling confidential, privileged information? Can he recommend a lawyer for a patient? What is the physician's vulnerability as an expert witness in divorce and custody proceedings? Knowledge, understanding and skillful handling of the legal and human processes involved can limit family destruction and help maintain the physician/patient relationship. PMID- 21283421 TI - Respite care. AB - Respite care is a program of planned admissions to the hospital for short periods of time to give the caregiver and family a rest from caring for the disabled person at home. It complements day hospitals, day care and home care. The Assiniboine Centre, a 201-bed rehabilitation/extended care facility in Brandon, Manitoba, has a respite program for the elderly and for multihandicapped children and adults. Family physicians are in an ideal position to encourage families to use the respite program because they know the family background and relationships, the caregiver's mental and physical strengths and weaknesses and can identify problems before they become a crisis. PMID- 21283422 TI - Dying at home. AB - Terminal care at home should be more generally available, but is often not offered because hospital treatment is perceived as better, because active treatment is not stopped until it is too late to move the patient, because families do not have the necessary resources, or because they are not given the option. To help families cope, good contact with the hospital and the family physician is essential. The decision to stop active treatment must include the family physician's perspective. Family resources must be explored, without assumptions that higher socioeconomic conditions are good, and lower ones bad. Many families are afraid of the unknown, or not being able to cope. They can be helped by short, informative visits. Pain control is paramount, but communication between members of the health care team comes a close second. PMID- 21283423 TI - The cancer survivor. AB - Patients who have completed therapy for malignant disease face many problems, including the possibility and persistent fear of recurrent disease or a new malignancy. The side effects of therapy, including surgical scars, radiation effects or damage to physiological function may strongly influence patients' complete recovery. Depletion of financial resources or a lengthy interruption of employment may present serious difficulties, particularly if patients cannot function as well as before. They may also find it difficult to buy life insurance, or mistakenly believe that they are not eligible to receive insurance. Their attitudes may change; they may become bitter, angry, resentful and have problems relating to others. They may also need counselling for sexual problems caused by physical or psychological effects of the disease or treatment. The family physician is in a position to help cancer survivors adjust, because he has a particular insight into medical, social, psychological and financial factors affecting the patient. PMID- 21283424 TI - The troubled teenager. AB - Problems that may bring teenagers to the family physician's office include bizarre behavior such as drug or alcohol intoxication, psychosis, panic or anxiety attacks and stealing; being dangerous to themselves or to others; sexual emergencies including pregnancy, rape and incest; a crisis involving key people such as parents' divorce or illness; school phobia, and anxiety or other reactions to sickness, surgery or death. When evaluating troubled teens and their families, the physician should first see adolescents alone, so he is not biased by parents' complaints that prevent 'accused' teens from expressing themselves. An evaluation should end with the teenager and adults together so the physician can summarize what happened in the interview and give treatment plans. The doctor should anticipate that he will need extra time in counselling teens about their problems, because it is also important to inform, support and direct parents, teachers and counsellors. PMID- 21283425 TI - Drug use as a lifestyle in the 1980s. AB - Trends in use of alcohol, marijuana, stimulants, sleeping pills and tranquillizers are examined from a recent report of a household survey in Ontario. Alcohol and marijuana use seems to be leveling off since the previous survey in 1977, although episodes of problem drinking are increasing and daily marijuana use is now more frequent. There has been a significant decrease in the use of sleeping pills and tranquillizers by women and those over age 50. PMID- 21283426 TI - The impact of day care. AB - Children who attend day care centres have different behavioral characteristics than children cared for at home by parents. Several studies report that children who have attended day care are more aggressive, more physically active, less cooperative, interact more with their peers, and are slower in acquiring adults' cultural values than children cared for at home. While children from low risk families appear to gain no cognitive advantage from day care, those from high risk families or with developmental problems do. Problems with hearing, vision, development or behavior, and child abuse may be identified in a well organized centre. Early recognition of developmental problems may help ensure the child does not lack self-worth later on. PMID- 21283427 TI - Helping patients going through separation and divorce. AB - The family doctor plays a very important role in the life of the patient who is going through separation or divorce. Separation is a form of mourning. People go through the stages of grief, including surprise, anger, depression, and acceptance. The physician must anticipate a wide range of emotions including disbelief and shock, anger, fear, uncertainty and depression. 'Involved neutrality' is his most useful stance. It allows him to be inquiring, solicitous and concerned but to refrain from giving direct advice or from trying to slant the outcome of counselling sessions. Worthwhile intervention goals include promoting reconciliation; offering a forum in which couples can be sure that they understand where each stands and what each wants; assessing the need for individual therapy, and smoothing separation by providing a forum in which the couple focuses upon matter-of-fact arrangements. This can save the couple and their children anguish, and ultimately save them money by decreasing litigation. The physician can also advise separating parents to reassure their children they have a continuing commitment to parenting. PMID- 21283428 TI - Behavior problems in children: a family approach to assessment and management. AB - When parents bring a child with a behavior problem to the family physician, he should obtain from them a brief developmental history of the child, a relevant family history, a precise description of the child's behavioral problem and the parents' attempts to solve it. The physician should recognize the different family styles susceptible to maintaining a behavior problem. The physician can help the family anticipate changes in behavior appropriate for the child's age. He can help the parents to agree on what the problem is and how to solve it; to reinforce good behavior by rewarding it; to avoid paying attention to negative behavior and to include the child in discussions about his behavior problem. The physician can also help them to tackle easy problems first so they become confident enough to handle more difficult ones, and advise them to give adolescents responsibility for solving some of their own problems without 'bailing them out' if they fail to do so. Sometimes the family physician will have to refer families with complex problems for more intensive or expert guidance. Parents can also be referred to community parenting groups that will help them cope. PMID- 21283429 TI - Pre-ski season preparation: conditioning and equipment. AB - Skiing-either downhill or cross-country-is one of the most popular winter sports. Because the skiing season is short, a pre-ski conditioning program is particularly important to enhance enjoyment and minimize the risk of injury. Aerobic and anaerobic training and abdominal, quadriceps, and hamstring strength and flexibility drills are advised for those planning to downhill ski. Aerobic training and paraspinal, shoulder girdle, abdominal, quadriceps, hamstring, gastrocsoleus and anterior tibial strengths and flexibility drills are advised for cross-country skiers. An equipment check by a qualified technician is mandatory. Cants or skiboot orthotics are useful for skiers whose leg and/or foot alignment is abnormal. PMID- 21283430 TI - Premenstrual syndrome: a psychological overview. AB - This paper reviews the premenstrual syndrome (PMS) from a historical and psychological perspective. The physician must recognize that the premenstruum-the four days before the onset of the menses-is a 'high risk' phase for women. They may demonstrate somatic and psychological complaints such as irritability, aggression, tension, anxiety, depression, lethargy, insomnia, poor coordination and concentration. Psychological disturbances can range from self-deprecation and the feeling that 'everything is too much' to pronounced feelings of oppression and depression. Psychiatric patients may become even more disturbed at this time. Recent reviews on PMS have studied its etiology and its possible connection to hormone imbalance, but to date there is no complete explanation for the syndrome's psychological symptoms. The most promising treatments for the psychological symptoms of PMS are pyridoxine (although there are conflicting reports about it), antidepressants, benzodiazepines if anxiety and tension dominate, and ongoing psychotherapy for severe cases. PMID- 21283431 TI - Social implications of sexually transmitted diseases. AB - Changes in attitudes toward sexuality have contributed to the rise in incidence of sexually transmitted diseases. The persistence of social stigma towards STD acts as a barrier to treatment-seeking. The exaggerated threat of genital herpes has led to unnecessary suffering, anxiety and increased social stigma, but is unlikely to alter sexual behavior. A change in attitudes will be necessary if attempts to control the spread of STD are to be successful. PMID- 21283432 TI - The psychiatry of family practice: personality disorders part 1: the problem patient. AB - Part 1 of this two part article on personality disorders follows Voineskos et al's suggestion that "in the psychiatric training of medical students the focus should be primarily on teaching 'psychiatry of medicla practice' and much less on teaching 'specialty psychiatry'."(1) It is not a comprehensive phenomenological presentation of the subject, but an attempt to stimulate clinicians to consider aspects of the personalities of their patients-'psychiatric' or otherwise-in clinical assessment and management. It also attempts to integrate historically 'psychiatric' skills and concepts into family practice. Case histories are discussed with particular reference to the work of Michael Balint.(2). PMID- 21283433 TI - The psychiatry of family practice: personality disorders part 2: interviewing the patient. AB - Part 1 of this article, published on page 1942, encourages family doctors to consider their patients' personalities in clinical assessment and management. This section discusses patient interviewing, demonstrating how family physicians can listen for 'themes' in a patient's conversation that may hold clues to what is bothering him. It is also best to avoid giving a patient too much support in an attempt 'to make him feel better' because such support may also prevent him from making mature decisions. It is equally important generally to avoid giving specific advice, because it may prevent patients from taking responsibility for their own actions. The clinician can use his own feelings and reactions to the patient to better understand the patient's personality and problems. Consultation with a psychiatrist can help clarify the family physician's role in assisting a particular patient. Balint groups are recommended for family doctors who are interested in further developing their interviewing skills. PMID- 21283434 TI - Traumatic rupture of a papillary muscle of the mitral valve due to blunt thoracic trauma. AB - Traumatic injuries of the mitral valve are rare but life threatening complications of high speed motor vehicle accidents. The physician must recognize traumatic mitral valve injuries early and arrange for immediate surgical repair, because if the papillary muscle ruptures completely, florid congestive failure and pulmonary edema develop rapidly. The signs and symptoms of traumatic mitral valve injuries vary. In general, the patient complains of chest pain and is hypotensive, dyspneic and cyanosed. He may have a bruised anterior chest wall, fractured ribs, unstable sternum and a flail chest, but extensive and severe cardiac damage from blunt trauma can occur without external evidence of chest injury. Traumatic mitral valve injuries should be suspected in any patient who has a blunt chest injury when a previously undocumented systolic murmur is discovered along the lower left sternal border or apex of the heart. The patient's deterioration, and the development of symptoms and signs of congestive heart failure support the diagnosis. PMID- 21283435 TI - Teaching physical diagnosis in an ambulatory family medicine setting. AB - A method of teaching physical diagnosis to second year medical students in an ambulatory family practice setting is described. During tutorial sessions, the tutor demonstrated each step in the physical examination and the students practiced on him or on other students who acted the part of patients. In addition, some newly registered patients in the family practice unit volunteered to allow the students to practice history taking and physical examinations on them. The students then watched the staff physician examine the same patients immediately afterwards. Some of the advantages of teaching physical diagnosis in this way rather than in the traditional ward setting include an emphasis on the practical aspects of family practice; the opportunity for student 'examiners' to learn from the advice of student 'patients', and the likelihood that early exposure to family medicine units influences students to pick family medicine as a career. A possible disadvantage is that students are unlikely to see many patients with abnormal physical findings in the family practice unit. PMID- 21283437 TI - [Not Available]. PMID- 21283436 TI - Sexually transmitted diseases and the family physician. PMID- 21283438 TI - Family med. Training: a diverse specialty. PMID- 21283439 TI - Headache and the pill: more information is necessary. PMID- 21283440 TI - Family med. Training: a diverse specialty. PMID- 21283441 TI - Natural family planning: readers comment. PMID- 21283443 TI - Calculator inaccurate. PMID- 21283442 TI - Factitious facial pain. PMID- 21283444 TI - More on hemoccult. PMID- 21283445 TI - Contrived dilemma. PMID- 21283446 TI - An unusual ophthalmological case. PMID- 21283447 TI - Action of nifedipine in ischemic heart disease. AB - Nifedipine, a calcium channel blocking drug with vasodilating action in both systemic and coronary arterial beds, was administered to 79 patients with a variety of ischemic heart diseases. Forty-five variant angina patients given a mean daily dose of 78 mg experienced a reduction from 2.6 to 0.28 attacks per day (p<0.001), confirmed by in-hospital ergonovine testing (22 patients) and outpatient 24-hour Holter monitoring (28 patients). Twenty-one stable post-acute myocardial infarction patients given a single 20 mg oral dose showed a significant (p<0.001) decrease in mean arterial pressure and systemic vascular resistance, accompanied by a significant (p<0.01) increase in cardiac index and heart rate, most noticeable in the patients with the worst ventricular function. Symptoms were relieved in nine of 13 patients with class III and IV refractory angina pectoris when nifedipine 40-80 mg was added to nitrate and beta blocker therapy. Of angina patients, 40% experienced mild side effects, but only 3% were forced to stop therapy due to peripheral edema. No serious hemodynamic or electrocardiographic toxicity occurred. Precautions should be taken if hepatic enzyme abnormalities or reflex tachycardia develop which may worsen angina. Diltiazem and verapamil have different hemodynamic effect and can be used advantageously in some clinical circumstances. PMID- 21283448 TI - Factors associated with cigaret smoking in elementary school children. AB - A survey of 625 elementary school children in an urban area for substance use, specifically, cigarets, alcohol and drugs, and the social factors associated with such use, revealed 38 admitted smokers in this age range, strongly influenced by parents, siblings and peers who smoked. Cigaret use was also associated with drug and alcohol use. These findings corroborate those from studies of teenagers who smoke, showing that peer pressure is not the sole factor in starting to smoke, as several other studies have claimed. In elementary school children, smoking is rare enough to be considered an early indicator of social deviation. PMID- 21283449 TI - Diagnostic ultrasound in gynecologic diagnosis. AB - Diagnostic ultrasound is helpful in the assessment of many common gynecological conditions from early teens to the late postmenopause. Female pelvic anatomy and pathology are readily imaged through a distended urinary bladder. In gynecologic cancer, examination of peritoneal cavity, kidneys and liver can suggest metastatic spread, which aids tumor staging. PMID- 21283450 TI - The apgar in perspective. AB - The Apgar score is assigned to virtually every child born in a North American hospital. While it was originally proposed as a grading system for comparing the results of perinatal events, it has been used as a guide to resuscitation of the newborn, as well as an index of the infant's longer term morbidity. The Apgar score has undoubtedly focused attention on the neonate, but it is often improperly used as a statistical method and is not useful as a resuscitation guide or prognosticator. It should be viewed as a biostatistical tool, and used as such. PMID- 21283451 TI - The abnormal pap smear: a rationale for follow up. AB - Cervical intraepithelial neoplasia (CIN) is readily identifiable by cytology, so theoretically, most cases of invasive carcinoma should be preventable. Risk factors for carcinoma of the cervix are related to sexual activity, therefore screening should be similarly related. All women should have routine annual cytology as soon as they are sexually active. The high risk male partner should also be considered when taking a history. Those with moderately atypical smears or higher should be referred for further colposcopic evaluation. Good quality cytology will reduce the incidence of false negative smears. Some cases of CIN progress, some remain static, some regress. Colposcopy is valuable in assessing cervical changes; cone biopsy should be required only when colposcopy is inconclusive, or invasion is suspected. Sampling errors in cytology account for the majority of false negative results. PMID- 21283452 TI - [Not Available]. AB - The menopause is one of the clinical manifestations of the climacteric. It is a sure sign of diminishing ovarian function and the hormonal deficiency which stems from it. Premenopause is characterized by a progesterone insufficiency which manifests in menstrual irregularity and menometrorrhagia. Treatment with progesterone replacement alone is most often sufficient. Menopause is the cessation of menstruation, sometimes without other symptoms. Immediate postmenopause is the most difficult period to live through; symptoms arise from the disappearance of ovarian secretions and an estrogen/progesterone replacement is necessary. Late postmenopause is sometimes complicated by osteoporosis, which estrogen helps prevent, but calcium should be added for greater effect. It is preferable to prevent the harmful effects of the menopause rather than cure the pathological consequences. PMID- 21283453 TI - Dysfunctional uterine bleeding. AB - Dysfunctional uterine bleeding is most commonly associated with chronic anovulation. Early diagnosis of anovulation is important; the induction of regular withdrawal periods using a progestin such as Provera prevents the development of endometrial hyperplasia with the subsequent inevitable occurrence of a heavy, frightening vaginal bleed. The etiology of dysfunctional uterine bleeding occurring during ovulatory cycles is unknown and all medical therapies at present are necessarily experimental. Hysterectomy is probably the treatment of choice for women who have finished their childbearing career and in whom persisting menorrhagia during ovulatory cycles results in anemia. PMID- 21283454 TI - [Not Available]. AB - Oral contraceptives containing high doses of estrogen and progesterone have been associated with several harmful side effects. In contrast, the new low dose contraceptives, although effective, do not present the same risks; in fact their use seems beneficial in certain conditions. The female population was frightened during the 1970s: several patients stopped taking the pill following publication of articles in the non-medical press about the dangers of using the pill. The family physician must reassure the patient. The new low dose oral contraceptives are safe and effective. PMID- 21283455 TI - Cervical dysplasia. AB - Invasive squamous carcinoma of the cervix is preceded by a series of premalignant changes described as mild, moderate, or severe dysplasia, and carcinoma in situ. These premalignant states are identified by cervical cytology, diagnosed by colposcopy and if effectively treated, can prevent invasive squamous carcinoma of the cervix. Because of the apparent biological variation of the premalignant states, even the most aggressive cervical screening program cannot be expected to eliminate all invasive squamous cancer of the cervix. Optimal results of a cervical screening program will be achieved when all women under 35 years of age and sexually active have an annual cytological smear; the cytology is screened by a laboratory with high quality control; the patient's positive cytology is accurately assessed by an experienced colposcopist, and the premalignant lesion is effectively treated. PMID- 21283456 TI - Office Visits with Patients over 65 Years of Age: Do They Take More Time? AB - Office visits were timed for 952 patients seen in a family practice, comparing time required for patients aged 65 and over with time required for patients aged two to 65. Diagnoses were similar in both groups. No significant difference was found in time required. This may be due to familiarity with the patients and appropriate office design, or may mean that not enough time was spent with geriatric patients. However, since family medicine is inherently patient-centred and not disease-centred, good geriatric care should take no more time than care to other age groups. PMID- 21283458 TI - Laughter is the Best Medicine: An Interview with Norman Cousins. PMID- 21283457 TI - Comparison of Consultant Pediatricians in an Ontario Community with their Provincial Counterparts. AB - Pediatric practice in Canada reflects both the British (consultant) and American (primary care) forms of pediatric practice. Since primary care in Canada is provided mostly by family doctors, there have been concerns about manpower and costs of pediatric practice. It has been suggested that Canadian pediatricians would not be able to survive in consultant practice only. This article compares the practice profiles of three consultant pediatricians working in an Ontario community of 150,000, served by 82 family doctors, with the profiles of all other Ontario pediatricians. Although the services provided were quite different, there was little difference in the number of services rendered, and the total amounts billed. The authors conclude that while mixed pediatric practice is likely to continue for some time, Canada urgently needs to reassess manpower needs in this specialty, since the present laissez-faire system is resulting in too many pediatricians for the British method of practice, and too few for the American method. PMID- 21283459 TI - What would you have done? The isolated geriatric alcoholic. AB - So many situations in family medicine will not fit the nice, neat formulae of history, physical, findings and treatment that are presented in traditional 'grand rounds'. Frequently, the most logical, or the most medically sensible course of action is not possible. The family physician is left negotiating a situation in which there is not necessarily a 'right' way to act, as in this case. Responses, with comments from the presenter of the case, will be published in upcoming issues. Readers are invited to submit similar cases from their own experience. PMID- 21283460 TI - The impact of continuing education on the quality of patient care. AB - We randomly allocated family physicians meeting explicit entry criteria to experimental and control groups to determine whether CME affects the quality of patient care. The experimental group received educational packages, the control group did not. These educational packages were closely matched with explicit criteria used in the indicator condition-our method of measuring the quality of care. The indicator conditions were divided into elective, mandatory and hidden categories. We compared over 4,500 patient encounters, before and after the educational maneuver, with explicit clinical criteria in the indicator condition. These episodes of care were then classified according to quality of care. Though knowledge increased from the educational packages, overall quality of care improved very little. If the topics were elective, quality of care improved equally in both the experimental and control groups. When the topics were mandatory, quality of care provided by the experimental group improved (P < 0.05). Topics covered by the hidden indicator conditions showed no spillover effect. PMID- 21283461 TI - How many of your patients am I seeing? PMID- 21283463 TI - [Not Available]. PMID- 21283462 TI - Treating the Arthritic Patient: A Physician's Perspective. PMID- 21283464 TI - [Not Available]. PMID- 21283465 TI - Skinning the cat. PMID- 21283466 TI - The receiving end. PMID- 21283467 TI - Bendectin's Safety Record. PMID- 21283468 TI - Bendectin MFR's. Comments. PMID- 21283469 TI - [Not Available]. AB - Giardiasis has recently been added to the list of infectious diseases whose transmission is favoured by day care centers. This article discusses an epidemic that occurred in a Outremont day care center where the systematic search for parasites in the stool has identified 19 cases of Giardia lamblia in a group of 82 persons at risk, and three additional cases in their families. Sixty-eight percent of the identified cases were asymptomatic. The dissemination process throughout the day care center and the families strongly suggests a person to person transmission. The systematic treatment of all the known carriers seems to have controlled the epidemic. Given the epidemiological date available, control measures against Giardia lamblia in day care centers are recommended. PMID- 21283470 TI - Articular manifestations of systemic diseases. AB - Many systemic diseases present with articular manifestations. An understanding of the clinical, laboratory and radiological features of these diseases can lead to early diagnosis and appropriate therapy. This article describes the articular presentation and management of four generalized disorders: idiopathic hemachromatosis; sarcoidosis; hepatitis-B virus-induced arthritis, and polymyositis-dermatomyositis induced arthritis. PMID- 21283471 TI - Osteoporosis: an update on pathogenesis and treatment. AB - Both hormonal and nonhormonal factors appear to contribute to bone loss in osteoporosis. Decreased estrogen production, not enough calcium and too much protein, phosphorus and caffeine in the diet all have a probable effect. Aims of treatment include giving symptomatic relief, rehabilitation, arresting further bone loss, increasing the useful bone mass and restoring damaged skeletal architecture where possible. Current treatment includes ensuring that the patient avoids excess protein and caffeine and has adequate calcium in her diet. Estrogen therapy is still subject to debate, but does seem to prevent bone loss if initiated within three to five years of menopause. Much research is currently being done on sodium fluoride, the only agent that appears actually able to produce new bone. PMID- 21283472 TI - A review of non-steroidal anti-inflammatory drugs. AB - An increasing number of non-steroidal anti-inflammatory drugs (NSAIDs) is available for clinical use each year. This article reviews significant differences between NSAIDs currently available in Canada, and helps the clinician to evaluate new NSAIDs. While their mechanism of action and efficacy are similar, side effects and cost vary considerably from one agent to another. Because all NSAIDs can produce adverse effects, patients, especially if they are elderly, should be selected carefully for treatment with a particular agent. PMID- 21283473 TI - The rheumatoid hand and preventive surgery. AB - Preventive surgery in rheumatoid arthritis of the hand is aimed at avoiding or at least delaying deformity and disability and at alleviating symptoms, especially pain. This can be successfully accomplished only in the disease's early phases. The family physician is in a position to assess his rheumatoid patients and to develop a good sense of the disease's progression. He can therefore make timely referrals to a hand surgeon, before major deformity and disability are present and the optimum time for preventive surgery has passed. The common surgical procedures-including excision of rheumatoid nodules; release of nerve entrapments; tenosynovectomy; synovectomy, and resection and reconstruction of the ulnar head-are discussed, as are their indications. PMID- 21283474 TI - Common foot problems in the arthritic patient. AB - The various arthridities, particularly rheumatoid arthritis and osteoarthritis, are a significant cause of pain in the foot. Symptoms may be due mainly to arthritis, but also may be complicated and even initiated by abnormal biomechanics of the foot. This article discusses the various arthritidities osteoarthritis, rheumatoid arthritis, gout, psoriatic and non-specific arthritis and how they affect the foot. By initiating appropriate conservative or surgical treatment in the arthritic disease's early stages, family physicians can prevent serious deformities from developing in the foot. PMID- 21283475 TI - Current Concepts of Reiter's Syndrome. AB - Reiter's syndrome (RS) is a major rheumatic disease, which is frequently chronic, often difficult to treat, and can cause significant, longterm morbidity. To date, there is no specific diagnostic test for RS. Therefore diagnosis has to be made by clinical acumen. Because of the venereal origin of most cases of RS, urethritis and/or cervicitis are often found. If absent, a thorough search should be made for other extra-articular features, e.g., diarrhea, conjunctivitis and mucocutaneous lesions. The condition afflicts mainly young men, but is becoming increasingly more common in women and is seen even in children. The arthritis associated with RS usually is oligoarticular, asymmetrical and tends to involve the lower extremities. However, extra-articular manifestations may be absent. If they are, a positive HLA-B27 test may be helpful, because 65-80% of Caucasians who develop RS are positive for HLA-B27. PMID- 21283476 TI - [Not Available]. AB - Systemic lupus erythematosus (SLE) is a chronic inflammatory disease of the connective tissue, affecting many organs of the body. The cause of SLE remains unknown, but the results of recent immunologic research have enlighted the characteristics of this disease and have contributed to improve the prognosis over the years. The renal and central nervous system involvement, as well as infection, remain high in the list of mortality causes. The usual treatment includes acetylsalicylic acid (ASA), antimalarials and corticosteroids. Main factors known to induce SLE are: sun exposures, pregnancy, therapeutic abortion, infection and several drugs. PMID- 21283477 TI - Arthralgia in children. AB - Arthralgia is joint pain unaccompanied by obvious clinical signs of arthritis or trauma. In most children and adolescents, the affected joint is the knee, hip, ankle, or less commonly an arm joint. Causes of arthralgia include arthritis; systemic disease; tumor; infection; growing pains; transient synovitis of the hip; osteochondroses; ostochondritis dissecans; traction syndrome; chondromalacia of the patella and post-traumatic synovitis. Some pains can be diagnosed with confidence with history, examination, X-ray, and laboratory studies. Other pains are vague, but careful observation of wasting and gait analysis may allow the physician to make a diagnosis. PMID- 21283478 TI - 'Doctor, how can I lose weight?'. AB - Millions of Canadians are trying to lose weight. According to the Metropolitan Life Insurance Company's recently released height and weight tables, some of them don't need to lose weight from a health standpoint. For those who would benefit from weight loss, a good program includes a balanced, low fat, high fiber diet; exercise; behavior modification and moral support. Few of the popular books and self-help groups offer all these essential components. PMID- 21283479 TI - Tennis elbow. AB - Tennis elbow, or pain on the lateral side of the elbow, is a common condition. We have seen 67 patients with tennis elbow in the past five years. Of these, 53 (79.1%) found relief from pain with conservative treatment, which usually consisted of one or more injections of local anesthetic and steroid. Fourteen patients (20.9%) required surgery to lengthen the radial wrist extensors, which gave relief from pain to 93% of them. The family physician can provide conservative treatment. Only resistant cases need referral to an orthopedic surgeon for corrective surgery or for more complicated surgery, which involves resecting the lateral epicondyle and freeing the attachment of the extensor muscles at the elbow. PMID- 21283480 TI - Injecting joints and tendons with steroids. AB - The local intra-articular injection of cortisone compounds is a dependable method for giving patients relief from the pain and swelling of arthritic joints. Injecting the diseased synovium surrounding a joint or tendon sheath or lining a bursa is usually an easy procedure, and the first injection has few contraindications if it is done cautiously. Many clinicians therefore readily embark upon treating patients with steroid injections. However, problems, including post-injection flares, infections and hematomata may begin about 12 hours after an injection. Indications and contraindications for administering injections are therefore discussed, and limitations and precautionary measures are explained. PMID- 21283481 TI - The swollen knee. AB - Family physicians are often confronted by a patient with a swollen knee. It is important to realize that swelling is a sign, not a diagnosis. An organized clinical examination includes eliciting a detailed history; inspection (comparing the swollen knee to the other); palpation (testing for fluid, ligamental stability and meniscal injury). Such an examination, coupled with knowledge of the causes and effects of various knee effusions, allows the physicians to embark on a therapeutic and diagnostic treatment program. By understanding the consequences of the problem, the physician is already on his way to finding a solution that will be gratifying both to him and to his patient. Treatment may include early aspiration of the effusion and/or seeking a consultant's opinion. PMID- 21283482 TI - Wife battering. AB - Wife battering refers to violent acts-psychological, sexual and/or physical assault-by an assailant against his wife and/or partner made with the intent of controlling the partner by inducing fear and pain. This paper addresses a theory about battered women and some common myths about battering are explored in social and historical context. It makes some suggestions concerning the physician's responsibility. As battered women may not complain of having been beaten, family physicians must be able to recognize behavioral symptoms in violent families and identify patterns of injury. Appropriate intervention always involves protecting the victim from further injury by stopping the cycle of violence and offering to help victims regain control by learning new ways to respond and connect with appropriate community resources. PMID- 21283483 TI - The unwritten contract between physician and patient. AB - There is a basic understanding between the family physician and the family under his care. His responsibility is to provide medical care and to assist with emotional problems and conflicts which arise from time to time in a growing family. In return, the family is expected to acknowledge his good will and professional skill. Under ideal conditions, this should produce an atmosphere of mutual understanding and trust. However, the strength of the unwritten contract is tested when problems become complex, difficult, or even tragic. What are the physician's moral obligations then, and how binding is this contract? A case study illustrates how the physician might approach these issues. PMID- 21283485 TI - Should Nurses' Services be Insured? PMID- 21283484 TI - Contracting for trust in family practice obstetrics. AB - A case is presented, illustrating a problem faced by family physicians who practice obstetrics; women who present with lists of inflexible requirements for labor and delivery may be attempting to control a situation in which they feel a great deal of fear, and little trust for the physician. The physician who tries to deal with every item on the list, rather than to explore the meaning of the total presentation, risks establishing a contract that cannot be met-and attracting more demanding patients. It is better to offer to discuss the patient's fear and distrust; this is described as 'contracting for trust', and is a way to promote patient and doctor flexibility. PMID- 21283486 TI - Finland's National Health Service Revisited: A Personal View. PMID- 21283487 TI - [Not Available]. PMID- 21283488 TI - Problems of caring for dying patients at home. PMID- 21283489 TI - Damning daycare with faint praise. PMID- 21283490 TI - Incriminating Evidence About VDTs. PMID- 21283491 TI - Dawson prognosis was never challenged. PMID- 21283492 TI - A complication from treatment. PMID- 21283493 TI - Prenatal care in rural newfoundland: room for improvement? AB - A retrospective chart survey of prenatal care in a clinic in rural Newfoundland was done for 1978-1982. As measured by the date of first prenatal attendance and the total number of prenatal visits, those women who went to the rural clinic received significantly less prenatal care than some women who visited a physician in a larger town. The obstetric outcomes for women who went to the rural clinic equalled those for women who attended doctors in town. The outcomes from both the clinic and town equalled those in Newfoundland and the rest of Canada. The potential benefits of prenatal care are discussed and suggestions are made about how to improve patients' attendance at the clinic. PMID- 21283494 TI - The use of cimetidine in hospitalized patients. AB - Cimetidine is the most commonly prescribed drug in North America. A clinical review was conducted to identify physicians' prescribing habits. From September 1, 1981 to March 31, 1982, the charts were reviewed of 50 patients receiving cimetidine in an isolated coastal community hospital in British Columbia. It was discovered that physicians prescribed the drug for reasons approved by the Food and Drug Administration (FDA) only 14% of the time. The FDA guidelines approve cimetidine for duodenal ulcer, Zollinger-Ellison syndrome, and other hypersecretory states. A literature review was conducted, and guidelines on prescribing cimetidine were given to all members of the hospital's medical staff. PMID- 21283495 TI - A survey of adverse drug reactions in family practice. AB - In this study, 232 Canadian family physicians recorded suspected adverse drug reactions (SADRs) in their practices for five months. Patients' age and sex, the drug(s) implicated, type of reaction and any disability were recorded on a card and sent to a central coordinating office each week. The number of SADRs in clinical practice seems to be small. An estimated 300,000 patients were involved in the study, and a total of 314 suspected adverse drug reactions in 314 patients were reported. A proposal is made for a surveillance system for new drugs. Family physicians would monitor all patients taking a drug or group of drugs and matched controls. The status of patients and controls would be recorded regularly and any SADRs reported to a central coordinating centre. PMID- 21283496 TI - Holistic medicine in family practice. AB - During the twentieth century there have been great advances in medicine in the area of science and technology. At the same time, there has been a trend back to a more natural, humanistic approach to counteract patients' feelings of alienation. Holistic medicine approaches the physical, emotional, spiritual, and social aspects of a person as they relate to health and disease. It emphasizes prevention; concern for the environment and the food we eat; patient responsibility; using illness as a creative force to teach people to change; the 'physician, heal thyself' philosophy; and appropriate alternatives to orthodox medicine. Family medicine faces the challenge of integrating these humanistic concepts with science. PMID- 21283497 TI - Acupuncture: a useful treatment modality. AB - Scientists have established that acupuncture's effects have a neurophysiological explanation. The procedure can be used to relieve musculoskeletal and facial pain, to treat allergies, headache, anxiety and depression, and to help rehabilitate addicted patients. The response rate is high, especially in patients with musculoskeletal pain or headaches. Clinical outcomes in a large Toronto acupuncture practice have consistently shown that about 80% of patients respond to acupuncture. The incidence of complications and side effects is low. The anatomical approach to this procedure is easily learned and can be incorporated into family practice. Failure to achieve the expected results from acupuncture should raise suspicions that the working diagnosis is incorrect and lead to further investigation. PMID- 21283498 TI - Chinese herbalism. AB - Chinese herbalism dates back to 2852 B.C. More than 2,600 herbs and thousands of herbal formulae are used to treat illness. Classical theories of Chinese medicine are integrated with the Taoist philosophy, whereby the universe is composed of two basic forces: a positive one called yang, and a negative one called yin. Illness is thought to occur when there is too much yang (tonification) or too much yin (sedation) in the body and herbal medicines are therefore intended either to tonify or to sedate the body so that balance is restored. Since 1954, some Chinese herbal remedies have been scientifically analyzed and tested. Several have been proven effective in treating a variety of diseases and conditions. PMID- 21283499 TI - Can faith heal? AB - Belief in the healing power of faith is widespread, and is receiving new support because of the holistic health movement. However, reports of faith healing are uncommon and always involve changes in symptoms rather than in disease. Unanticipated remissions probably occur more frequently than they are reported, but often they may be ascribed to misdiagnosis or to the fact that disease progresses more slowly than expected or even regresses in some patients. When they are sick, patients are more likely to pray and to seek spiritual assistance, and such improvements in their health may thus seem to result from faith. Faith especially an uncritical acceptance of medical authority-sometimes has negative effects. Patients' unquestioning compliance is not trust; it is an abdication of personal responsibility. Physicians also must maintain a healthy skepticism so that they do not accept all medical explanations without questioning them. PMID- 21283500 TI - Food sensitivities. AB - Food sensitivities are a common but frequently unrecognized cause of chronic symptomatology in patients with known allergies. Food sensitivities often are not detected by skin testing. This article discusses the controversy surrounding the treatment of food sensitivities; the provocative sublingual and intradermal tests for sensitivities, and the importance of eliciting complete past and family histories from the allergic patient. Because patients with symptoms of food sensitivity are likely to visit their family doctor first, he should be the first to detect and treat them. Usually patients with a food sensitivity obtain relief from symptoms when the offending food(s) are excluded from their diet. PMID- 21283501 TI - Behavioral treatment for common childhood problems. AB - Parents often consult family physicians about child rearing, child development, and school-related problems. Behavioral treatment is one method of dealing with such concerns. It involves identifying problems with a child's behavior, working to resolve them by rewarding desirable behavior and withholding rewards for undesirable behavior, and evaluating the outcome. Before treatment begins, it is necessary to establish that the parents feel the child's behavior is a problem; that the child can voluntarily control the behavior; that at least one parent or primary caretaker can benefit from instruction in how to modify behavior, and that the behavior to be changed is not just one facet of a larger family problem. Both parents and physicians may find self-help books and printed handouts very useful. Referral to specialized services may be appropriate for complex or recalcitrant problems. PMID- 21283502 TI - Neurolinguistic programming: a systematic approach to change. AB - Neurolinguistic programming (NLP) integrates advances in cybernetics, psychophysiology, linguistics, and information services. It has been used in business, education, law, medicine and psychotherapy to alter people's responses to stimuli, so they are better able to regulate their environment and themselves. There are five steps to an effective NLP interaction. They include 1. establishing rapport; the therapist must match his verbal and non-verbal behaviors to the patient's, 2. gathering information about the patient's present problem and goals by noting his verbal patterns and non-verbal responses, 3. considering the impact that achieving the patient's goals will have on him, his work, family and friends, and retaining any positive aspects of his current situation, 4. helping the patient achieve his goals by using specific techniques to alter his responses to various stimuli, and 5. ensuring the altered responses achieved in therapy are integrated into the patient's daily life. NLP has been used to help patients with medical problems ranging from purely psychological to complex organic ones. PMID- 21283503 TI - The role of the family physician in smoking cessation. AB - Two studies conducted at the Ottawa Civic Hospital Family Medicine Centre indicate that physicians are unlikely to help patients quit smoking merely by discussing cessation strategies; only highly motivated smokers who have made three to five attempts already are likely to stop smoking for a year or more. Each attempt helps the smoker to better understand the difficulties he must overcome in order to quit. A four-step program is suggested to help physicians address the problem of smoking. This program includes educating and informing the public about the dangers of smoking and second hand smoke; discussing the relationship between smoking and illness with smokers to encourage them to try quitting; low intensity intervention (e.g., support and encouragement and other simple strategies) to encourage smokers who aren't highly motivated to make an attempt to quit; and high intensity intervention (e.g., several group sessions) for patients who are highly motivated. PMID- 21283504 TI - A computerized e book and data base for family practice. AB - A new computerized E Book and data base management system is under development at the discipline of family practice of Memorial University of Newfoundland. This system is capable of rapid analyses and produces detailed reports on morbidity indices and age-sex distributions of patients. Examples show how this system is being used to analyze the content of family practice, monitor and improve family practice resident learning experiences, improve patient care, and stimulate and facilitate family practice research. Future directions of this project are discussed. PMID- 21283505 TI - A shopping list of family doctors' services. AB - The College of Family Physicians of Canada's Committee on Patterns of Practice and Health Care Delivery conducted a study to find out how much work family physicians must do to make the average income reported in the CFPC's annual economic survey. The committee examined what each provincial health care plan paid for 20 common procedures performed by an average family doctor during a typical working day. The fees each provincial paying agency paid for every item are given for February 10, 1979; October 1, 1981, and October 1, 1982. Comparisons are made between the fees paid in the various provinces, and on the three dates chosen. Since 1979 the disparities between fees paid in the different provinces have been reduced. However, physicians practicing in the Maritimes still are paid less than their western colleagues for the same procedures. In general, the family doctor's time seems to be valued at about $16.86 an hour before taxes. PMID- 21283506 TI - Benzodiazepines: part of lifestyle in the 1980s. AB - Benzodiazepines are among the most widely used drugs in the world. Although there is a public perception that they are widely abused and dangerous, there is minimal evidence to support this suggestion. At the Ottawa Civic Hospital Family Medicine Centre, 3.4% of patients over 15 years old received a prescription for a benzodiazepine. Of this group, 5% received prescriptions for more than two benzodiazepine tablets a day during 1982. Of these 21 patients, five were likely to suffer significant withdrawal reactions. There has been a significant shift to short-acting benzodiazepines over four years to 80% from 16%. There has also been a 15% decline in prescriptions for benzodiazepines between 1978 and 1982. Because benzodiazepines are safe and effective, and appear to be used with care in treating anxiety, they should be accepted as useful drugs for controlling one of the most common symptoms seen in family practice. PMID- 21283507 TI - Fine-Tuning of Polymeric Resins and Their Interfaces with Amorphous Calcium Phosphate. A Strategy for Designing Effective Remineralizing Dental Composites. AB - For over a decade our group has been designing, preparing and evaluating bioactive, remineralizing composites based on amorphous calcium phosphate (ACP) fillers embedded in polymerized methacrylate resin matrices. In these studies a major focus has been on exploring structure-property relationships of the matrix phase of these composites on their anti-cariogenic potential. The main challenges were to gain a better understanding of polymer matrix/filler interfacial properties through controlling the surface properties of the fillers or through fine-tuning of the resin matrix. In this work, we describe the effect of chemical structure and composition of the resin matrices on some of the critical physicochemical properties of the copolymers and their ACP composites. Such structure-property studies are essential in formulating clinically effective products, and this knowledge base is likely to have strong impact on the future design of therapeutic materials, appropriate for mineral restoration in defective tooth structures. PMID- 21283508 TI - Symptomatic glenoid loosening complicating total shoulder arthroplasty. AB - Glenoid component loosening is one of the most common causes of failed total shoulder arthroplasty. Previous reports indicate that it is desirable to reimplant the glenoid component during revision shoulder arthroplasty. The purpose of our study was to retrospectively evaluate the satisfaction of patients undergoing glenoid revision (reimplantation or resection) following total shoulder replacement specifically for symptomatic glenoid loosening. Twenty-eight shoulders that developed symptomatic glenoid loosening following primary total shoulder arthroplasty were included in the study. Patients were retrospectively evaluated at a minimum of 2 years postoperatively. Patients either underwent resection followed by reimplantation of the glenoid component (13) or resection of the component with or without bone grafting (15). Each patient was evaluated with the UCLA Shoulder Scale and the Constant-Murley Shoulder Assessment. There were seven excellent, 13 good, five fair and three poor results on the UCLA score. Functional outcome scores trended higher in the reimplantation group but were not statistically significant. Both groups reported equal pain relief and satisfaction. Five out of 15 patients underwent arthroscopic resection of the glenoid, and these patients scored as well on the UCLA and Constant scores as the reimplantation group. When symptomatic glenoid loosening is the indication for revision total shoulder replacement, patients tend to achieve good to excellent results. Though functional scores were slightly higher in the reimplantation group, satisfaction was equally high in both groups. Resection, when indicated, should be performed arthroscopically as this improved functional outcome in our series. PMID- 21283509 TI - Nonoperative Management of Complete Lateral Elbow Ligamentous Disruption in an NFL Player: A Case Report. AB - Disruptions of the lateral soft tissue restraints of the elbow, including the lateral ulnar collateral ligament, are a well-recognized clinical entity which may result in chronic elbow instability. When symptomatic, most authors recommend surgery to reconstruct the LUCL. We report on a case of a professional football player who sustained complete disruption of the lateral collateral ligamentous complex from the lateral humeral epicondyle with extension of his injury into his common extensor origin. He was treated conservatively and returned to play after 4 weeks. Treatment algorithm and a review of the literature are discussed. PMID- 21283510 TI - Enhancement of vaccinia virus based oncolysis with histone deacetylase inhibitors. AB - Histone deacetylase inhibitors (HDI) dampen cellular innate immune response by decreasing interferon production and have been shown to increase the growth of vesicular stomatitis virus and HSV. As attenuated tumour-selective oncolytic vaccinia viruses (VV) are already undergoing clinical evaluation, the goal of this study is to determine whether HDI can also enhance the potency of these poxviruses in infection-resistant cancer cell lines. Multiple HDIs were tested and Trichostatin A (TSA) was found to potently enhance the spread and replication of a tumour selective vaccinia virus in several infection-resistant cancer cell lines. TSA significantly decreased the number of lung metastases in a syngeneic B16F10LacZ lung metastasis model yet did not increase the replication of vaccinia in normal tissues. The combination of TSA and VV increased survival of mice harbouring human HCT116 colon tumour xenografts as compared to mice treated with either agent alone. We conclude that TSA can selectively and effectively enhance the replication and spread of oncolytic vaccinia virus in cancer cells. PMID- 21283511 TI - Detecting cancer gene networks characterized by recurrent genomic alterations in a population. AB - High resolution, system-wide characterizations have demonstrated the capacity to identify genomic regions that undergo genomic aberrations. Such research efforts often aim at associating these regions with disease etiology and outcome. Identifying the corresponding biologic processes that are responsible for disease and its outcome remains challenging. Using novel analytic methods that utilize the structure of biologic networks, we are able to identify the specific networks that are highly significantly, nonrandomly altered by regions of copy number amplification observed in a systems-wide analysis. We demonstrate this method in breast cancer, where the state of a subset of the pathways identified through these regions is shown to be highly associated with disease survival and recurrence. PMID- 21283512 TI - Synonymous mutations in the core gene are linked to unusual serological profile in hepatitis C virus infection. AB - The biological role of the protein encoded by the alternative open reading frame (core+1/ARF) of the Hepatitis C virus (HCV) genome remains elusive, as does the significance of the production of corresponding antibodies in HCV infection. We investigated the prevalence of anti-core and anti-core+1/ARFP antibodies in HCV positive blood donors from Cambodia, using peptide and recombinant protein-based ELISAs. We detected unusual serological profiles in 3 out of 58 HCV positive plasma of genotype 1a. These patients were negative for anti-core antibodies by commercial and peptide-based assays using C-terminal fragments of core but reacted by Western Blot with full-length core protein. All three patients had high levels of anti-core+1/ARFP antibodies. Cloning of the cDNA that corresponds to the core-coding region from these sera resulted in the expression of both core and core+1/ARFP in mammalian cells. The core protein exhibited high amino-acid homology with a consensus HCV1a sequence. However, 10 identical synonymous mutations were found, and 7 were located in the aa(99-124) region of core. All mutations concerned the third base of a codon, and 5/10 represented a T>C mutation. Prediction analyses of the RNA secondary structure revealed conformational changes within the stem-loop region that contains the core+1/ARFP internal AUG initiator at position 85/87. Using the luciferase tagging approach, we showed that core+1/ARFP expression is more efficient from such a sequence than from the prototype HCV1a RNA. We provide additional evidence of the existence of core+1/ARFP in vivo and new data concerning expression of HCV core protein. We show that HCV patients who do not produce normal anti-core antibodies have unusually high levels of anti-core+1/ARFP and harbour several identical synonymous mutations in the core and core+1/ARFP coding region that result in major changes in predicted RNA structure. Such HCV variants may favour core+1/ARFP production during HCV infection. PMID- 21283513 TI - Estimating the quality of reprogrammed cells using ES cell differentiation expression patterns. AB - Somatic cells can be reprogrammed to a pluripotent state by over-expression of defined factors, and pluripotency has been confirmed by the tetraploid complementation assay. However, especially in human cells, estimating the quality of Induced Pluripotent Stem Cell(iPSC) is still difficult. Here, we present a novel supervised method for the assessment of the quality of iPSCs by estimating the gene expression profile using a 2-D "Differentiation-index coordinate", which consists of two "developing lines" that reflects the directions of ES cell differentiation and the changes of cell states during differentiation. By applying a novel liner model to describe the differentiation trajectory, we transformed the ES cell differentiation time-course expression profiles to linear "developing lines"; and use these lines to construct the 2-D "Differentiation index coordinate" of mouse and human. We compared the published gene expression profiles of iPSCs, ESCs and fibroblasts in mouse and human "Differentiation-index coordinate". Moreover, we defined the Distance index to indicate the qualities of iPS cells, which based on the projection distance of iPSCs-ESCs and iPSCs fibroblasts. The results indicated that the "Differentiation-index coordinate" can distinguish differentiation states of the different cells types. Furthermore, by applying this method to the analysis of expression profiles in the tetraploid complementation assay, we showed that the Distance index which reflected spatial distributions correlated the pluripotency of iPSCs. We also analyzed the significantly changed gene sets of "developing lines". The results suggest that the method presented here is not only suitable for the estimation of the quality of iPS cells based on expression profiles, but also is a new approach to analyze time-resolved experimental data. PMID- 21283514 TI - Optimizing tactics for use of the U.S. antiviral strategic national stockpile for pandemic influenza. AB - In 2009, public health agencies across the globe worked to mitigate the impact of the swine-origin influenza A (pH1N1) virus. These efforts included intensified surveillance, social distancing, hygiene measures, and the targeted use of antiviral medications to prevent infection (prophylaxis). In addition, aggressive antiviral treatment was recommended for certain patient subgroups to reduce the severity and duration of symptoms. To assist States and other localities meet these needs, the U.S. Government distributed a quarter of the antiviral medications in the Strategic National Stockpile within weeks of the pandemic's start. However, there are no quantitative models guiding the geo-temporal distribution of the remainder of the Stockpile in relation to pandemic spread or severity. We present a tactical optimization model for distributing this stockpile for treatment of infected cases during the early stages of a pandemic like 2009 pH1N1, prior to the wide availability of a strain-specific vaccine. Our optimization method efficiently searches large sets of intervention strategies applied to a stochastic network model of pandemic influenza transmission within and among U.S. cities. The resulting optimized strategies depend on the transmissability of the virus and postulated rates of antiviral uptake and wastage (through misallocation or loss). Our results suggest that an aggressive community-based antiviral treatment strategy involving early, widespread, pro rata distribution of antivirals to States can contribute to slowing the transmission of mildly transmissible strains, like pH1N1. For more highly transmissible strains, outcomes of antiviral use are more heavily impacted by choice of distribution intervals, quantities per shipment, and timing of shipments in relation to pandemic spread. This study supports previous modeling results suggesting that appropriate antiviral treatment may be an effective mitigation strategy during the early stages of future influenza pandemics, increasing the need for systematic efforts to optimize distribution strategies and provide tactical guidance for public health policy-makers. PMID- 21283515 TI - Genome-wide polymorphism and comparative analyses in the white-tailed deer (Odocoileus virginianus): a model for conservation genomics. AB - The white-tailed deer (Odocoileus virginianus) represents one of the most successful and widely distributed large mammal species within North America, yet very little nucleotide sequence information is available. We utilized massively parallel pyrosequencing of a reduced representation library (RRL) and a random shotgun library (RSL) to generate a complete mitochondrial genome sequence and identify a large number of putative single nucleotide polymorphisms (SNPs) distributed throughout the white-tailed deer nuclear and mitochondrial genomes. A SNP validation study designed to test specific classes of putative SNPs provides evidence for as many as 10,476 genome-wide SNPs in the current dataset. Based on cytogenetic evidence for homology between cow (Bos taurus) and white-tailed deer chromosomes, we demonstrate that a divergent genome may be used for estimating the relative distribution and density of de novo sequence contigs as well as putative SNPs for species without draft genome assemblies. Our approach demonstrates that bioinformatic tools developed for model or agriculturally important species may be leveraged to support next-generation research programs for species of biological, ecological and evolutionary importance. We also provide a functional annotation analysis for the de novo sequence contigs assembled from white-tailed deer pyrosequencing reads, a mitochondrial phylogeny involving 13,722 nucleotide positions for 10 unique species of Cervidae, and a median joining haplotype network as a putative representation of mitochondrial evolution in O. virginianus. The results of this study are expected to provide a detailed template enabling genome-wide sequence-based studies of threatened, endangered or conservationally important non-model organisms. PMID- 21283516 TI - An FPT approach for predicting protein localization from yeast genomic data. AB - Accurately predicting the localization of proteins is of paramount importance in the quest to determine their respective functions within the cellular compartment. Because of the continuous and rapid progress in the fields of genomics and proteomics, more data are available now than ever before. Coincidentally, data mining methods been developed and refined in order to handle this experimental windfall, thus allowing the scientific community to quantitatively address long-standing questions such as that of protein localization. Here, we develop a frequent pattern tree (FPT) approach to generate a minimum set of rules (mFPT) for predicting protein localization. We acquire a series of rules according to the features of yeast genomic data. The mFPT prediction accuracy is benchmarked against other commonly used methods such as Bayesian networks and logistic regression under various statistical measures. Our results show that mFPT gave better performance than other approaches in predicting protein localization. Meanwhile, setting 0.65 as the minimum hit-rate, we obtained 138 proteins that mFPT predicted differently than the simple naive bayesian method (SNB). In our analysis of these 138 proteins, we present novel predictions for the location for 17 proteins, which currently do not have any defined localization. These predictions can serve as putative annotations and should provide preliminary clues for experimentalists. We also compared our predictions against the eukaryotic subcellular localization database and related predictions by others on protein localization. Our method is quite generalized and can thus be applied to discover the underlying rules for protein-protein interactions, genomic interactions, and structure-function relationships, as well as those of other fields of research. PMID- 21283517 TI - A new highly conserved antibiotic sensing/resistance pathway in firmicutes involves an ABC transporter interplaying with a signal transduction system. AB - Signal transduction systems and ABC transporters often contribute jointly to adaptive bacterial responses to environmental changes. In Bacillus subtilis, three such pairs are involved in responses to antibiotics: BceRSAB, YvcPQRS and YxdJKLM. They are characterized by a histidine kinase belonging to the intramembrane sensing kinase family and by a translocator possessing an unusually large extracytoplasmic loop. It was established here using a phylogenomic approach that systems of this kind are specific but widespread in Firmicutes, where they originated. The present phylogenetic analyses brought to light a highly dynamic evolutionary history involving numerous horizontal gene transfers, duplications and lost events, leading to a great variety of Bce-like repertories in members of this bacterial phylum. Based on these phylogenetic analyses, it was proposed to subdivide the Bce-like modules into six well-defined subfamilies. Functional studies were performed on members of subfamily IV comprising BceRSAB from B. subtilis, the expression of which was found to require the signal transduction system as well as the ABC transporter itself. The present results suggest, for the members of this subfamily, the occurrence of interactions between one component of each partner, the kinase and the corresponding translocator. At functional and/or structural levels, bacitracin dependent expression of bceAB and bacitracin resistance processes require the presence of the BceB translocator loop. Some other members of subfamily IV were also found to participate in bacitracin resistance processes. Taken together our study suggests that this regulatory mechanism might constitute an important common antibiotic resistance mechanism in Firmicutes. [Supplemental material is available online at http://www.genome.org.]. PMID- 21283518 TI - Predicting functions of proteins in mouse based on weighted protein-protein interaction network and protein hybrid properties. AB - BACKGROUND: With the huge amount of uncharacterized protein sequences generated in the post-genomic age, it is highly desirable to develop effective computational methods for quickly and accurately predicting their functions. The information thus obtained would be very useful for both basic research and drug development in a timely manner. METHODOLOGY/PRINCIPAL FINDINGS: Although many efforts have been made in this regard, most of them were based on either sequence similarity or protein-protein interaction (PPI) information. However, the former often fails to work if a query protein has no or very little sequence similarity to any function-known proteins, while the latter had similar problem if the relevant PPI information is not available. In view of this, a new approach is proposed by hybridizing the PPI information and the biochemical/physicochemical features of protein sequences. The overall first-order success rates by the new predictor for the functions of mouse proteins on training set and test set were 69.1% and 70.2%, respectively, and the success rate covered by the results of the top-4 order from a total of 24 orders was 65.2%. CONCLUSIONS/SIGNIFICANCE: The results indicate that the new approach is quite promising that may open a new avenue or direction for addressing the difficult and complicated problem. PMID- 21283519 TI - Metabolic impact of adult-onset, isolated, growth hormone deficiency (AOiGHD) due to destruction of pituitary somatotropes. AB - Growth hormone (GH) inhibits fat accumulation and promotes protein accretion, therefore the fall in GH observed with weight gain and normal aging may contribute to metabolic dysfunction. To directly test this hypothesis a novel mouse model of adult onset-isolated GH deficiency (AOiGHD) was generated by cross breeding rat GH promoter-driven Cre recombinase mice (Cre) with inducible diphtheria toxin receptor mice (iDTR) and treating adult Cre(+/-),iDTR(+/-) offspring with DT to selectively destroy the somatotrope population of the anterior pituitary gland, leading to a reduction in circulating GH and IGF-I levels. DT-treated Cre(-/-),iDTR(+/-) mice were used as GH-intact controls. AOiGHD improved whole body insulin sensitivity in both low-fat and high-fat fed mice. Consistent with improved insulin sensitivity, indirect calorimetry revealed AOiGHD mice preferentially utilized carbohydrates for energy metabolism, as compared to GH-intact controls. In high-fat, but not low-fat fed AOiGHD mice, fat mass increased, hepatic lipids decreased and glucose clearance and insulin output were impaired. These results suggest the age-related decline in GH helps to preserve systemic insulin sensitivity, and in the context of moderate caloric intake, prevents the deterioration in metabolic function. However, in the context of excess caloric intake, low GH leads to impaired insulin output, and thereby could contribute to the development of diabetes. PMID- 21283520 TI - Temporal and tissue specific regulation of RP-associated splicing factor genes PRPF3, PRPF31 and PRPC8--implications in the pathogenesis of RP. AB - BACKGROUND: Genetic mutations in several ubiquitously expressed RNA splicing genes such as PRPF3, PRP31 and PRPC8, have been found to cause retina-specific diseases in humans. To understand this intriguing phenomenon, most studies have been focused on testing two major hypotheses. One hypothesis assumes that these mutations interrupt retina-specific interactions that are important for RNA splicing, implying that there are specific components in the retina interacting with these splicing factors. The second hypothesis suggests that these mutations have only a mild effect on the protein function and thus affect only the metabolically highly active cells such as retinal photoreceptors. METHODOLOGY/PRINCIPAL FINDINGS: We examined the second hypothesis using the PRPF3 gene as an example. We analyzed the spatial and temporal expression of the PRPF3 gene in mice and found that it is highly expressed in retinal cells relative to other tissues and its expression is developmentally regulated. In addition, we also found that PRP31 and PRPC8 as well as snRNAs are highly expressed in retinal cells. CONCLUSIONS/SIGNIFICANCE: Our data suggest that the retina requires a relatively high level of RNA splicing activity for optimal tissue-specific physiological function. Because the RP18 mutation has neither a debilitating nor acute effect on protein function, we suggest that retinal degeneration is the accumulative effect of decades of suboptimal RNA splicing due to the mildly impaired protein. PMID- 21283521 TI - Increased inducible nitric oxide synthase expression in organs is associated with a higher severity of H5N1 influenza virus infection. AB - BACKGROUND: The mechanisms of disease severity caused by H5N1 influenza virus infection remain somewhat unclear. Studies have indicated that a high viral load and an associated hyper inflammatory immune response are influential during the onset of infection. This dysregulated inflammatory response with increased levels of free radicals, such as nitric oxide (NO), appears likely to contribute to disease severity. However, enzymes of the nitric oxide synthase (NOS) family such as the inducible form of NOS (iNOS) generate NO, which serves as a potent anti viral molecule to combat infection in combination with acute phase proteins and cytokines. Nevertheless, excessive production of iNOS and subsequent high levels of NO during H5N1 infection may have negative effects, acting with other damaging oxidants to promote excessive inflammation or induce apoptosis. METHODOLOGY/PRINCIPAL FINDINGS: There are dramatic differences in the severity of disease between chickens and ducks following H5N1 influenza infection. Chickens show a high level of mortality and associated pathology, whilst ducks show relatively minor symptoms. It is not clear how this varying pathogenicty comes about, although it has been suggested that an overactive inflammatory immune response to infection in the chicken, compared to the duck response, may be to blame for the disparity in observed pathology. In this study, we identify and investigate iNOS gene expression in ducks and chickens during H5N1 influenza infection. Infected chickens show a marked increase in iNOS expression in a wide range of organs. Contrastingly, infected duck tissues have lower levels of tissue related iNOS expression. CONCLUSIONS/SIGNIFICANCE: The differences in iNOS expression levels observed between chickens and ducks during H5N1 avian influenza infection may be important in the inflammatory response that contributes to the pathology. Understanding the regulation of iNOS expression and its role during H5N1 influenza infection may provide insights for the development of new therapeutic strategies in the treatment of avian influenza infection. PMID- 21283522 TI - Revisiting the hetero-fertilization phenomenon in maize. AB - Development of a seed DNA-based genotyping system for marker-assisted selection (MAS) has provided a novel opportunity for understanding aberrant reproductive phenomena such as hetero-fertilization (HF) by observing the mismatch of endosperm and leaf genotypes in monocot species. In contrast to conventional approaches using specific morphological markers, this approach can be used for any population derived from diverse parental genotypes. A large-scale experiment was implemented using seven F(2) populations and four three-way cross populations, each with 534 to 1024 individuals. The frequency of HF within these populations ranged from 0.14% to 3.12%, with an average of 1.46%. The highest frequency of HF in both types of population was contributed by the pollen gametes. Using three-way crosses allowed, for the first time, detection of the HF contributed by maternal gametes, albeit at very low frequency (0.14%-0.65%). Four HF events identified from each of two F(2) populations were tested and confirmed using 1032 single nucleotide polymorphic markers. This analysis indicated that only 50% of polymorphic markers can detect a known HF event, and thus the real HF frequency can be inferred by doubling the estimate obtained from using only one polymorphic marker. As expected, 99% of the HF events can be detected by using seven independent markers in combination. Although seed DNA-based analysis may wrongly predict plant genotypes due to the mismatch of endosperm and leaf DNA caused by HF, the relatively low HF frequencies revealed with diverse germplasm in this study indicates that the effect on the accuracy of MAS is limited. In addition, comparative endosperm and leaf DNA analysis of specific genetic stocks could be useful for revealing the relationships among various aberrant fertilization phenomena including haploidy and apomixis. PMID- 21283523 TI - The sodium iodide symporter (NIS) and potential regulators in normal, benign and malignant human breast tissue. AB - INTRODUCTION: The presence, relevance and regulation of the Sodium Iodide Symporter (NIS) in human mammary tissue remains poorly understood. This study aimed to quantify relative expression of NIS and putative regulators in human breast tissue, with relationships observed further investigated in vitro. METHODS: Human breast tissue specimens (malignant n = 75, normal n = 15, fibroadenoma n = 10) were analysed by RQ-PCR targeting NIS, receptors for retinoic acid (RARalpha, RARbeta), oestrogen (ERalpha), thyroid hormones (THRalpha, THRbeta), and also phosphoinositide-3-kinase (PI3K). Breast cancer cells were treated with Retinoic acid (ATRA), Estradiol and Thyroxine individually and in combination followed by analysis of changes in NIS expression. RESULTS: The lowest levels of NIS were detected in normal tissue (Mean(SEM) 0.70(0.12) Log(10) Relative Quantity (RQ)) with significantly higher levels observed in fibroadenoma (1.69(0.21) Log(10)RQ, p<0.005) and malignant breast tissue (1.18(0.07) Log(10)RQ, p<0.05). Significant positive correlations were observed between human NIS and ERalpha (r = 0.22, p<0.05) and RARalpha (r = 0.29, p<0.005), with the strongest relationship observed between NIS and RARbeta (r = 0.38, p<0.0001). An inverse relationship between NIS and PI3K expression was also observed (r = 0.21, p<0.05). In vitro, ATRA, Estradiol and Thyroxine individually stimulated significant increases in NIS expression (range 6-16 fold), while ATRA and Thyroxine combined caused the greatest increase (range 16 26 fold). CONCLUSION: Although NIS expression is significantly higher in malignant compared to normal breast tissue, the highest level was detected in fibroadenoma. The data presented supports a role for retinoic acid and estradiol in mammary NIS regulation in vivo, and also highlights potential thyroidal regulation of mammary NIS mediated by thyroid hormones. PMID- 21283524 TI - Regulation of neutrophil senescence by microRNAs. AB - Neutrophils are rapidly recruited to sites of tissue injury or infection, where they protect against invading pathogens. Neutrophil functions are limited by a process of neutrophil senescence, which renders the cells unable to respond to chemoattractants, carry out respiratory burst, or degranulate. In parallel, aged neutrophils also undergo spontaneous apoptosis, which can be delayed by factors such as GMCSF. This is then followed by their subsequent removal by phagocytic cells such as macrophages, thereby preventing unwanted inflammation and tissue damage. Neutrophils translate mRNA to make new proteins that are important in maintaining functional longevity. We therefore hypothesised that neutrophil functions and lifespan might be regulated by microRNAs expressed within human neutrophils. Total RNA from highly purified neutrophils was prepared and subjected to microarray analysis using the Agilent human miRNA microarray V3. We found human neutrophils expressed a selected repertoire of 148 microRNAs and that 6 of these were significantly upregulated after a period of 4 hours in culture, at a time when the contribution of apoptosis is negligible. A list of predicted targets for these 6 microRNAs was generated from http://mirecords.biolead.org and compared to mRNA species downregulated over time, revealing 83 genes targeted by at least 2 out of the 6 regulated microRNAs. Pathway analysis of genes containing binding sites for these microRNAs identified the following pathways: chemokine and cytokine signalling, Ras pathway, and regulation of the actin cytoskeleton. Our data suggest that microRNAs may play a role in the regulation of neutrophil senescence and further suggest that manipulation of microRNAs might represent an area of future therapeutic interest for the treatment of inflammatory disease. PMID- 21283525 TI - A mouse dry eye model induced by topical administration of benzalkonium chloride. AB - PURPOSE: To develop a dry eye model of mouse induced by topical administration of benzalkonium chloride (BAC) and investigate the possible mechanisms. METHODS: BAC at concentration of 0.2% was applied to the mouse ocular surface for 7 days. Phenol red thread tear test, tear break-up time (BUT) test, corneal inflammatory index scoring, fluorescein and rose bengal test were performed to evaluate the toxic effects of BAC on the ocular surface. Global specimens were collected on day (D) 7 and labeled with a series of antibodies including cytokeratin 10 (K10) and mucin 5AC (MUC5AC). Apoptosis of ocular surface epithelium was evaluated by in situ terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Histologic analysis and transmission electron microscopy (TEM) were performed on D7. RESULTS: BAC at a concentration of 0.2% successfully induced a dry eye condition with decreased tear volume and BUTs, increased corneal fluorescein and rose bengal scores. The Inflammatory index was increased in accompaniment with higher tumor necrosis factor-alpha (TNF-alpha) expression and more inflammatory infiltration in the cornea. Immunolabeling revealed positive K10 expression in BAC-treated corneal epithelium and fewer MUC5AC-positive cells in the BAC-treated conjunctival fornix. TUNEL assay showed more apoptotic cells in the corneal basal epithelium. TEM showed that the size and intervals of the microvillis were both reduced in the corneal epithelium. CONCLUSIONS: Topical administration of 0.2% BAC in mouse induces changes resembling that of dry eye syndrome in humans, and thus, represents a novel model of dry eye. PMID- 21283526 TI - Using HSV-TK/GCV suicide gene therapy to inhibit lens epithelial cell proliferation for treatment of posterior capsular opacification. AB - PURPOSE: To establish a novel, targeted lentivirus-based HSV-tk (herpes simplex virus thymidine kinase)/GCV (ganciclovir) gene therapy system to inhibit lens epithelial cell proliferation for treatment of posterior capsular opacification (PCO) after cataract surgery. METHODS: An enhanced Cre recombinase (Cre/loxP) system with a lentiviral vector expressing Cre under the control of the lens specific promoter LEP503 (Lenti-LEP503-HSVtk-Cre [LTKCRE]) was constructed, as well as another lentiviral vector containing a switching unit. The latter vector contains a stuffer sequence encoding EGFP (Lenti-hPGK-Loxp-EGFP-pA-Loxp-HSVtk [PGFPTK]) with a functional polyadenylation signal between two loxP sites, followed by the herpes simplex virus thymidine kinase (HSV-tk) gene, both under the control of the human phosphoglycerate kinase (hPGK) promoter. Expression of the downstream gene (HSV-tk) is activated by co-expression of Cre. Human lens epithelial cells (HLECs) or retinal pigmental epithelial cells (RPECs) were co infected with LTKCRE and PGFPTK. The inhibitory effects on HLECs and RPECs infected by the enhanced specific lentiviral vector combination at the concentration of 20 ug/ml GCV were assayed and compared. RESULTS: The specific gene expression of Cre and HSV-tk in HLECs is activated by the LEP503 promoter. LTKCRE and PGFPTK co-infected HLECs, but not RPECs, expressed high levels of the HSV-tk protein. After 96 h of GCV treatment, the percentage of apoptotic HLECs infected by the enhanced specific lentiviral vector combination was 87.23%, whereas that of apoptotic RPECs was only 10.12%. Electron microscopy showed that GCV induced apoptosis and necrosis of the infected HLECs. CONCLUSIONS: The enhanced specific lentiviral vector combination selectively and effectively expressed HSV-tk in HLECs. A concentration of 20 ug/ml, GCV is effective against the proliferation of HLECs in vitro. This cell-type-specific gene therapy using a Cre/loxP lentivirus system may be a feasible treatment strategy to prevent PCO. PMID- 21283527 TI - Menadione degrades the optical quality and mitochondrial integrity of bovine crystalline lenses. AB - PURPOSE: The crystalline lens is a unique cellular organ that performs metabolic processes while maintaining transparency for optical functionality. Mitochondria play a role in providing cells with aerobic respiration necessary for these metabolic processes. Using menadione, a mitochondria-specific inhibitor of the quinone family, and bovine lenses in vitro, this study was undertaken to determine whether a relationship exists between mitochondrial function and optical function. METHODS: Bovine lenses were treated with 50 MUM, 200 MUM, 600 MUM, and 1,000 MUM menadione and lens optical function, assessed as optical quality, was observed over 9 days. Confocal micrographs of mitochondria in superficial secondary fiber cells were also analyzed in 50 MUM, 200 MUM, and 600 MUM menadione-treated lenses over 48 h. RESULTS: A decrease in lens optical quality was observed in a dose-dependent manner within 24 h for the 200 uM- (p=0.0422), 600 uM- (p<0.0001), and 1,000 MUM- (p<0.0001) treated lenses. No change in optical quality was observed for the 50 MUM-treated lenses. Analysis of confocal micrographs indicated a trend of shorter mitochondria for 200 MUM- and 600 uM-treated lenses with time and analysis of the distributions of mitochondrial lengths indicated a relative increase in the number of shorter mitochondria with higher doses of, and longer exposures to, menadione. CONCLUSIONS: The data show that menadione has a detrimental effect on mitochondrial integrity and this change is associated with degradation of optical quality, suggesting a possible link between mitochondrial function and optical function. PMID- 21283528 TI - HIGH-RESOLUTION EPR SPECTROSCOPY OF MO ENZYMES. SULFITE OXIDASES: STRUCTURAL AND FUNCTIONAL IMPLICATIONS. AB - Sulfite oxidases (SOs) are physiologically vital Mo-containing enzymes that occur in animals, plants, and bacteria and which catalyze the oxidation of sulfite to sulfate, the terminal reaction in the oxidative degradation of sulfur-containing compounds. X-ray structure determinations of SOs from several species show nearly identical coordination structures of the molybdenum active center, and a common catalytic mechanism has been proposed that involves the generation of a transient paramagnetic Mo(V) state through a series of coupled electron-proton transfer steps. This chapter describes the use of pulsed electron-nuclear double resonance (ENDOR) and electron spin echo envelope modulation (ESEEM) spectroscopic techniques to obtain information about the structure of this Mo(V) species from the hyperfine interactions (hfi) and nuclear quadrupole interactions (nqi) of nearby magnetic nuclei. Variable frequency instrumentation is essential to optimize the experimental conditions for measuring the couplings of different types of nuclei (e.g., (1)H, (2)H, (31)P, and (17)O). The theoretical background necessary for understanding the ESEEM and ENDOR spectra of the Mo(V) centers of SOs is outlined, and examples of the use of advanced pulsed EPR methods (RP ESEEM, HYSCORE, integrated four-pulse ESEEM) for structure determination are presented. The analysis of variable-frequency pulsed EPR data from SOs is aided by parallel studies of model compounds that contain key functional groups or that are isotopically labeled and thus provide benchmark data for enzymes. Enormous progress has been made on the use of high-resolution variable-frequency pulsed EPR methods to investigate the structures and mechanisms of SOs during the past ~15 years, and the future is bright for the continued development and application of this technology to SOs, other molybdenum enzymes, and other problems in metallobiochemistry. PMID- 21283529 TI - The n170 shows differential repetition effects for faces, objects, and orthographic stimuli. AB - Previous event-related potentials research has suggested that the N170 component has a larger amplitude to faces and words than to other stimuli, but it remains unclear whether it indexes the same cognitive processes for faces and for words. The present study investigated how category-level repetition effects on the N170 differ across stimulus categories. Faces, cars, words, and non-words were presented in homogeneous (1 category) or mixed blocks (2 intermixed categories). We found a significant repetition effect of N170 amplitude for successively presented faces and cars (in homogeneous blocks), but not for words and unpronounceable consonant strings, suggesting that the N170 indexes different underlying cognitive processes for objects (including faces) and orthographic stimuli. The N170 amplitude was significantly smaller when multiple faces or multiple cars were presented in a row than when these stimuli were preceded by a stimulus of a different category. Moreover, the large N170 repetition effect for faces may be important to consider when comparing the relative N170 amplitude for different stimulus categories. Indeed, a larger N170 deflection for faces than for other stimulus categories was observed only when stimuli were preceded by a stimulus of a different category (in mixed blocks), suggesting that an enhanced N170 to faces may be more reliably observed when faces are presented within the context of some non-face stimuli. PMID- 21283530 TI - The ethics of memory blunting: some initial thoughts. PMID- 21283531 TI - No need to Talk, I Know You: Familiarity Influences Early Multisensory Integration in a Songbird's Brain. AB - It is well known that visual information can affect auditory perception, as in the famous "McGurk effect," but little is known concerning the processes involved. To address this issue, we used the best-developed animal model to study language-related processes in the brain: songbirds. European starlings were exposed to audiovisual compared to auditory-only playback of conspecific songs, while electrophysiological recordings were made in their primary auditory area (Field L). The results show that the audiovisual condition modulated the auditory responses. Enhancement and suppression were both observed, depending on the stimulus familiarity. Seeing a familiar bird led to suppressed auditory responses while seeing an unfamiliar bird led to response enhancement, suggesting that unisensory perception may be enough if the stimulus is familiar while redundancy may be required for unfamiliar items. This is to our knowledge the first evidence that multisensory integration may occur in a low-level, putatively unisensory area of a non-mammalian vertebrate brain, and also that familiarity of the stimuli may influence modulation of auditory responses by vision. PMID- 21283532 TI - Pelvic Nerve Injury Causes a Rapid Decrease in Expression of Choline Acetyltransferase and Upregulation of c-Jun and ATF-3 in a Distinct Population of Sacral Preganglionic Neurons. AB - Autonomic regulation of the urogenital organs is impaired by injuries sustained during pelvic surgery or compression of lumbosacral spinal nerves (e.g., cauda equina syndrome). To understand the impact of injury on both sympathetic and parasympathetic components of this nerve supply, we performed an experimental surgical and immunohistochemical study on adult male rats, where the structure of this complex part of the nervous system has been well defined. We performed unilateral transection of pelvic or hypogastric nerves and analyzed relevant regions of lumbar and sacral spinal cord, up to 4 weeks after injury. Expression of c-Jun, the neuronal injury marker activating transcription factor-3 (ATF-3), and choline acetyltransferase (ChAT) were examined. We found little evidence for chemical or structural changes in substantial numbers of functionally related but uninjured spinal neurons (e.g., in sacral preganglionic neurons after hypogastric nerve injury), failing to support the concept of compensatory events. The effects of injury were greatest in sacral cord, ipsilateral to pelvic nerve transection. Here, around half of all preganglionic neurons expressed c-Jun within 1 week of injury, and substantial ATF-3 expression also occurred, especially in neurons with complete loss of ChAT-immunoreactivity. There did not appear to be any death of retrogradely labeled neurons, in contrast to axotomy studies performed on other regions of spinal cord or sacral ventral root avulsion models. Each of the effects we observed occurred in only a subpopulation of preganglionic neurons at that spinal level, raising the possibility that distinct functional subgroups have different susceptibility to trauma-induced degeneration and potentially different regenerative abilities. Identification of the cellular basis of these differences may provide insights into organ-specific strategies for attenuating degeneration or promoting regeneration of these circuits after trauma. PMID- 21283533 TI - Combined anterior-posterior surgery versus posterior surgery for thoracolumbar burst fractures: a systematic review of the literature. AB - STUDY DESIGN: A systematic quantitative review of the literature. OBJECTIVE: To compare combined anterior-posterior surgery versus posterior surgery for thoracolumbar fractures in order to identify better treatments. SUMMARY OF BACKGROUND DATA: Axial load of the anterior and middle column of the spine can lead to a burst fracture in the vertebral body. The management of thoracolumbar burst fractures remains controversial. The goals of operative treatment are fracture reduction, fixation and decompressing the neural canal. For this, different operative methods are developed, for instance, the posterior and the combined anterior-posterior approach. Recent systematic qualitative reviews comparing these methods are lacking. METHODS: We conducted an electronic search of MEDLINE, EMBASE, LILACS and the Cochrane Central Register for Controlled Trials. RESULTS: Five observational comparative studies and no randomized clinical trials comparing the combined anteriorposterior approach with the posterior approach were retrieved. The total enrollment of patients in these studies was 755 patients. The results were expressed as relative risk (RR) for dichotomous outcomes and weighted mean difference (WMD) for continuous outcomes with 95% confidence intervals (CI). CONCLUSIONS: A small significantly higher kyphotic correction and improvement of vertebral height (sagittal index) observed for the combined anterior-posterior group is cancelled out by more blood loss, longer operation time, longer hospital stay, higher costs and a possible higher intra- and postoperative complication rate requiring re-operation and the possibility of a worsened Hannover spine score. The surgeons' choices regarding the operative approach are biased: worse cases tended to undergo the combined anterior-posterior approach. PMID- 21283534 TI - Carteolol hydrochloride suppresses the generation of reactive oxygen species and rescues cell death after ultraviolet irradiation of cultured lens epithelial cells. AB - INTRODUCTION: Anti-oxidant activities of adrenergic beta-blockers are proposed in various organs. The aim of the present study was to investigate the effect of carteolol hydrochloride, an adrenergic beta-blocker, on the production of reactive oxygen species (ROS) and the viable cell number after ultraviolet irradiation of cultured lens epithelial cells (LECs). MATERIALS AND METHODOLOGY: Cultured LECs were exposed to 0, 10(-5), 10(-4), and 10(-3) M carteolol hydrochloride for 30 min followed by ultraviolet B (UVB) irradiation at intensity of 100, 200, or 400 mJ/cm(2). The amount of ROS in the LECs was measured using dichlorodihydrofluorescein at 30 min after exposure to UVB. In addition, the number of living LECs was counted at 15 h after exposure to UVB. RESULTS: Exposure to 10(-3) M carteolol hydrochloride significantly decreased the amount of ROS after exposure to UVB at intensities of 100, 200, and 400 mJ/cm(2). In addition, 10(-3) M carteolol hydrochloride significantly increased the viable cell number after exposure to UVB at 400 mJ/cm(2). However, 10(-4) and 10(-5)M carteolol hydrochloride had no significant effect on ROS or the viable cell number in LECs. DISCUSSIONS: Carteolol hydrochloride protects LECs against UVB irradiation by inhibiting the intracellular production of ROS. PMID- 21283535 TI - Flux balance analysis of ammonia assimilation network in E. coli predicts preferred regulation point. AB - Nitrogen assimilation is a critical biological process for the synthesis of biomolecules in Escherichia coli. The central ammonium assimilation network in E. coli converts carbon skeleton alpha-ketoglutarate and ammonium into glutamate and glutamine, which further serve as nitrogen donors for nitrogen metabolism in the cell. This reaction network involves three enzymes: glutamate dehydrogenase (GDH), glutamine synthetase (GS) and glutamate synthase (GOGAT). In minimal media, E. coli tries to maintain an optimal growth rate by regulating the activity of the enzymes to match the availability of the external ammonia. The molecular mechanism and the strategy of the regulation in this network have been the research topics for many investigators. In this paper, we develop a flux balance model for the nitrogen metabolism, taking into account of the cellular composition and biosynthetic requirements for nitrogen. The model agrees well with known experimental results. Specifically, it reproduces all the (15)N isotope labeling experiments in the wild type and the two mutant (DeltaGDH and DeltaGOGAT) strains of E. coli. Furthermore, the predicted catalytic activities of GDH, GS and GOGAT in different ammonium concentrations and growth rates for the wild type, DeltaGDH and DeltaGOGAT strains agree well with the enzyme concentrations obtained from western blots. Based on this flux balance model, we show that GS is the preferred regulation point among the three enzymes in the nitrogen assimilation network. Our analysis reveals the pattern of regulation in this central and highly regulated network, thus providing insights into the regulation strategy adopted by the bacteria. Our model and methods may also be useful in future investigations in this and other networks. PMID- 21283536 TI - Predicted impact of barriers to migration on the Serengeti wildebeest population. AB - The Serengeti wildebeest migration is a rare and spectacular example of a once common biological phenomenon. A proposed road project threatens to bisect the Serengeti ecosystem and its integrity. The precautionary principle dictates that we consider the possible consequences of a road completely disrupting the migration. We used an existing spatially-explicit simulation model of wildebeest movement and population dynamics to explore how placing a barrier to migration across the proposed route (thus creating two disjoint but mobile subpopulations) might affect the long-term size of the wildebeest population. Our simulation results suggest that a barrier to migration--even without causing habitat loss- could cause the wildebeest population to decline by about a third. The driver of this decline is the effect of habitat fragmentation (even without habitat loss) on the ability of wildebeest to effectively track temporal shifts in high-quality forage resources across the landscape. Given the important role of the wildebeest migration for a number of key ecological processes, these findings have potentially important ramifications for ecosystem biodiversity, structure, and function in the Serengeti. PMID- 21283537 TI - Mitochondria of the yeasts Saccharomyces cerevisiae and Kluyveromyces lactis contain nuclear rDNA-encoded proteins. AB - In eukaryotes, the nuclear ribosomal DNA (rDNA) is the source of the structural 18S, 5.8S and 25S rRNAs. In hemiascomycetous yeasts, the 25S rDNA sequence was described to lodge an antisense open reading frame (ORF) named TAR1 for Transcript Antisense to Ribosomal RNA. Here, we present the first immuno detection and sub-cellular localization of the authentic product of this atypical yeast gene. Using specific antibodies against the predicted amino-acid sequence of the Saccharomyces cerevisiae TAR1 product, we detected the endogenous Tar1p polypeptides in S. cerevisiae (Sc) and Kluyveromyces lactis (Kl) species and found that both proteins localize to mitochondria. Protease and carbonate treatments of purified mitochondria further revealed that endogenous Sc Tar1p protein sub-localizes in the inner membrane in a N(in)-C(out) topology. Plasmid versions of 5' end or 3' end truncated TAR1 ORF were used to demonstrate that neither the N-terminus nor the C-terminus of Sc Tar1p were required for its localization. Also, Tar1p is a presequence-less protein. Endogenous Sc Tar1p was found to be a low abundant protein, which is expressed in fermentable and non fermentable growth conditions. Endogenous Sc TAR1 transcripts were also found low abundant and consistently 5' flanking regions of TAR1 ORF exhibit modest promoter activity when assayed in a luciferase-reporter system. Using rapid amplification of cDNA ends (RACE) PCR, we also determined that endogenous Sc TAR1 transcripts possess heterogeneous 5' and 3' ends probably reflecting the complex expression of a gene embedded in actively transcribed rDNA sequence. Altogether, our results definitively ascertain that the antisense yeast gene TAR1 constitutes a functional transcription unit within the nuclear rDNA repeats. PMID- 21283538 TI - beta-Arrestin1 mediates the endocytosis and functions of macrophage migration inhibitory factor. AB - Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine, regulating inflammatory and immune responses. MIF binds to cell surface receptor CD74, resulting in both rapid and sustained ERK activation. It was reported that MIF-induced rapid ERK activation requires its co-receptor CD44. But the exact mechanism underlying sustained ERK activation is not well understood. In the current study, we described a detailed mechanism of MIF mediated sustained ERK activation. We found that beta-arrestin1, a scaffold protein involved in the activation of the MAPK cascade, interacts with CD74 upon MIF stimulation, resulting in CD74-mediated MIF endocytosis in a chlorpromazine (CPZ)-sensitive manner. beta-arrestin1 is also involved in endocytotic MIF signaling, leading to sustained ERK activation. Therefore beta-arrestin1 plays a central role in coupling MIF endocytosis to sustained ERK activation. PMID- 21283539 TI - Digit ratio, color polymorphism and egg testosterone in the Australian painted dragon. AB - Variation in exposure to sex hormones during early development contributes to phenotypic plasticity in vertebrate offspring. As a proposed marker for prenatal sex hormone exposure and because of their association with various physiological and behavioral characteristics, digit ratio and/or digit length have received notable interest within the field of evolutionary ecology. However, the validity of digit measures as a proxy of prenatal sex hormone exposure is controversial and only few studies have provided direct evidence for the link between digit development and prenatal sex hormones. Here, we report morph- and sex-specific variation in digit ratio in wild painted dragon lizards (Ctenophorus pictus). Lizards expressing a yellow bib have significantly larger third-to-fourth toe ratios (3D:4D) than lizards without a bib. Males have significantly smaller 3D:4D than females. Furthermore, we show that experimental elevation of yolk testosterone significantly increases 3D:4D in hatchling painted dragon lizards, but has no influence on hatchling size. Our results provide direct and indirect evidence for the involvement of prenatal sex steroids in digit development and it is suggested that digit ratio may be used as a biomarker for prenatal steroid exposure in this reptilian species. As such, digit ratio may provide a useful tool to study temporal or spatial differences in the proximate hormonal mechanisms modulating physiological and behavioural phenotypes. PMID- 21283540 TI - CCL25/CCR9 interactions regulate large intestinal inflammation in a murine model of acute colitis. AB - BACKGROUND AIMS: CCL25/CCR9 is a non-promiscuous chemokine/receptor pair and a key regulator of leukocyte migration to the small intestine. We investigated here whether CCL25/CCR9 interactions also play a role in the regulation of inflammatory responses in the large intestine. METHODS: Acute inflammation and recovery in wild-type (WT) and CCR9(-/-) mice was studied in a model of dextran sulfate sodium (DSS)-induced colitis. Distribution studies and phenotypic characterization of dendritic cell subsets and macrophage were performed by flow cytometry. Inflammatory bowel disease (IBD) scores were assessed and expression of inflammatory cytokines was studied at the mRNA and the protein level. RESULTS: CCL25 and CCR9 are both expressed in the large intestine and are upregulated during DSS colitis. CCR9(-/-) mice are more susceptible to DSS colitis than WT littermate controls as shown by higher mortality, increased IBD score and delayed recovery. During recovery, the CCR9(-/-) colonic mucosa is characterized by the accumulation of activated macrophages and elevated levels of Th1/Th17 inflammatory cytokines. Activated plasmacytoid dendritic cells (DCs) accumulate in mesenteric lymph nodes (MLNs) of CCR9(-/-) animals, altering the local ratio of DC subsets. Upon re-stimulation, T cells isolated from these MLNs secrete significantly higher levels of TNFalpha, IFNgamma, IL2, IL-6 and IL-17A while down modulating IL-10 production. CONCLUSIONS: Our results demonstrate that CCL25/CCR9 interactions regulate inflammatory immune responses in the large intestinal mucosa by balancing different subsets of dendritic cells. These findings have important implications for the use of CCR9-inhibitors in therapy of human IBD as they indicate a potential risk for patients with large intestinal inflammation. PMID- 21283541 TI - Discovery of porcine microRNAs in multiple tissues by a Solexa deep sequencing approach. AB - The domestic pig (Sus scrofa) is an important economic animal for meat production and as a suitable model organism for comparative genomics and biomedical studies. In an effort to gain further identification of miRNAs in the pig, we have applied the Illumina Solexa sequencing technology to carry out an in-depth analysis of the miRNA transcriptome in a pool of equal amounts of RNA from 16 different porcine tissues. From this data set, we identified 437 conserved and 86 candidate novel miRNA/miRNA* in the pig, corresponding to 329 miRNA genes. Compared with all the reported porcine miRNAs, the result showed that 112 conserved and 61 candidate novel porcine miRNA were first reported in this study. Further analysis revealed extensive sequence variations (isomiRs) of porcine miRNAs, including terminal isomiRs at both the 5' and 3' ends and nucleotide variants. Read counts of individual porcine miRNA spanned from a few reads to approximately 405541 reads, confirming the different level of expression of porcine miRNAs. Subsequently, the tissue expression patterns of 8 miRNAs were characterized by Northern blotting. The results showed that miR-145, miR-423-5p, miR-320, miR-26a, and miR-191 are ubiquitously expressed in diverse tissues, while miR-92, miR 200a, and miR-375 were selectively enriched and expressed in special tissues. Meanwhile, the expression of 8 novel porcine-specific miRNAs was validated by stem-loop RT-PCR, and one of these was detected by Northern blotting. Using the porcine miRNA array designed according to our Solexa results, 123 miRNAs were detected expression in porcine liver tissues. A total of 58 miRNAs showed differential expression between the Tongcheng (a Chinese indigenous fatty breed) and Large White pig breeds (a lean type pig). Taken together, our results add new information to existing data on porcine miRNAs and should be useful for investigating the biological functions of miRNAs in pig and other species. PMID- 21283542 TI - Programmable ligand detection system in plants through a synthetic signal transduction pathway. AB - BACKGROUND: There is an unmet need to monitor human and natural environments for substances that are intentionally or unintentionally introduced. A long-sought goal is to adapt plants to sense and respond to specific substances for use as environmental monitors. Computationally re-designed periplasmic binding proteins (PBPs) provide a means to design highly sensitive and specific ligand sensing capabilities in receptors. Input from these proteins can be linked to gene expression through histidine kinase (HK) mediated signaling. Components of HK signaling systems are evolutionarily conserved between bacteria and plants. We previously reported that in response to cytokinin-mediated HK activation in plants, the bacterial response regulator PhoB translocates to the nucleus and activates transcription. Also, we previously described a plant visual response system, the de-greening circuit, a threshold sensitive reporter system that produces a visual response which is remotely detectable and quantifiable. METHODOLOGY/PRINCIPAL FINDINGS: We describe assembly and function of a complete synthetic signal transduction pathway in plants that links input from computationally re-designed PBPs to a visual response. To sense extracellular ligands, we targeted the computational re-designed PBPs to the apoplast. PBPs bind the ligand and develop affinity for the extracellular domain of a chemotactic protein, Trg. We experimentally developed Trg fusions proteins, which bind the ligand-PBP complex, and activate intracellular PhoR, the HK cognate of PhoB. We then adapted Trg-PhoR fusions for function in plants showing that in the presence of an external ligand PhoB translocates to the nucleus and activates transcription. We linked this input to the de-greening circuit creating a detector plant. CONCLUSIONS/SIGNIFICANCE: Our system is modular and PBPs can theoretically be designed to bind most small molecules. Hence our system, with improvements, may allow plants to serve as a simple and inexpensive means to monitor human surroundings for substances such as pollutants, explosives, or chemical agents. PMID- 21283543 TI - Pre-procedural atorvastatin mobilizes endothelial progenitor cells: clues to the salutary effects of statins on healing of stented human arteries. AB - OBJECTIVES: Recent clinical trials suggest an LDL-independent superiority of intensive statin therapy in reducing target vessel revascularization and peri procedural myocardial infarctions in patients who undergo percutaneous coronary interventions (PCI). While animal studies demonstrate that statins mobilize endothelial progenitor cells (EPCs) which can enhance arterial repair and attenuate neointimal formation, the precise explanation for the clinical PCI benefits of high dose statin therapy remain elusive. Thus we serially assessed patients undergoing PCI to test the hypothesis that high dose Atorvastatin therapy initiated prior to PCI mobilizes EPCs that may be capable of enhancing arterial repair. METHODS AND RESULTS: Statin naive male patients undergoing angiography for stent placement were randomized to standard therapy without Atorvastatin (n = 10) or treatment with Atorvastatin 80 mg (n = 10) beginning three days prior to stent implantation. EPCs were defined by flow cytometry (e.g., surface marker profile of CD45dim/34+/133+/117+). As well, we also enumerated cultured angiogenic cells (CACs) by standard in vitro culture assay. While EPC levels did not fluctuate over time for the patients free of Atorvastatin, there was a 3.5-fold increase in EPC levels with high dose Atorvastatin beginning within 3 days of the first dose (and immediately pre-PCI) which persisted at 4 and 24 hours post-PCI (p<0.05). There was a similar rise in CAC levels as assessed by in vitro culture. CACs cultured in the presence of Atorvastatin failed to show augmented survival or VEGF secretion but displayed a 2-fold increase in adhesion to stent struts (p<0.05). CONCLUSIONS: High dose Atorvastatin therapy pre-PCI improves EPC number and CAC number and function in humans which may in part explain the benefit in clinical outcomes seen in patients undergoing coronary interventions. PMID- 21283544 TI - Role of Bcr1-activated genes Hwp1 and Hyr1 in Candida albicans oral mucosal biofilms and neutrophil evasion. AB - Candida albicans triggers recurrent infections of the oropharyngeal mucosa that result from biofilm growth. Prior studies have indicated that the transcription factor Bcr1 regulates biofilm formation in a catheter model, both in vitro and in vivo. We thus hypothesized that Bcr1 plays similar roles in the formation of oral mucosal biofilms and tested this hypothesis in a mouse model of oral infection. We found that a bcr1/bcr1 mutant did not form significant biofilm on the tongues of immunocompromised mice, in contrast to reference and reconstituted strains that formed pseudomembranes covering most of the tongue dorsal surface. Overexpression of HWP1, which specifies an epithelial adhesin that is under the transcriptional control of Bcr1, partly but significantly rescued the bcr1/bcr1 biofilm phenotype in vivo. Since HWP1 overexpression only partly reversed the biofilm phenotype, we investigated whether additional mechanisms, besides adhesin down-regulation, were responsible for the reduced virulence of this mutant. We discovered that the bcr1/bcr1 mutant was more susceptible to damage by human leukocytes when grown on plastic or on the surface of a human oral mucosa tissue analogue. Overexpression of HYR1, but not HWP1, significantly rescued this phenotype. Furthermore a hyr1/hyr1 mutant had significantly attenuated virulence in the mouse oral biofilm model of infection. These discoveries show that Bcr1 is critical for mucosal biofilm infection via regulation of epithelial cell adhesin and neutrophil function. PMID- 21283545 TI - Matrix-assisted laser desorption ionization-time of flight mass spectrometry for the identification of clinically relevant bacteria. AB - BACKGROUND: Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) allows rapid and reliable identification of microorganisms, particularly clinically important pathogens. METHODOLOGY/PRINCIPAL FINDINGS: We compared the identification efficiency of MALDI-TOF MS with that of Phoenix(r), API(r) and 16S ribosomal DNA sequence analysis on 1,019 strains obtained from routine diagnostics. Further, we determined the agreement of MALDI-TOF MS identifications as compared to 16S gene sequencing for additional 545 strains belonging to species of Enterococcus, Gardnerella, Staphylococcus, and Streptococcus. For 94.7% of the isolates MALDI TOF MS results were identical with those obtained with conventional systems. 16S sequencing confirmed MALDI-TOF MS identification in 63% of the discordant results. Agreement of identification of Gardnerella, Enterococcus, Streptococcus and Staphylococcus species between MALDI-TOF MS and traditional method was high (Crohn's kappa values: 0.9 to 0.93). CONCLUSIONS/SIGNIFICANCE: MALDI-TOF MS represents a rapid, reliable and cost-effective identification technique for clinically relevant bacteria. PMID- 21283546 TI - Flagellin delivery by Pseudomonas aeruginosa rhamnolipids induces the antimicrobial protein psoriasin in human skin. AB - The opportunistic pathogen Pseudomonas aeruginosa can cause severe infections in patients suffering from disruption or disorder of the skin barrier as in burns, chronic wounds, and after surgery. On healthy skin P. aeruginosa causes rarely infections. To gain insight into the interaction of the ubiquitous bacterium P. aeruginosa and healthy human skin, the induction of the antimicrobial protein psoriasin by P. aeruginosa grown on an ex vivo skin model was analyzed. We show that presence of the P. aeruginosa derived biosurfactant rhamnolipid was indispensable for flagellin-induced psoriasin expression in human skin, contrary to in vitro conditions. The importance of the bacterial virulence factor flagellin as the major inducing factor of psoriasin expression in skin was demonstrated by use of a flagellin-deficient mutant. Rhamnolipid mediated shuttle across the outer skin barrier was not restricted to flagellin since rhamnolipids enable psoriasin expression by the cytokines IL-17 and IL-22 after topical application on human skin. Rhamnolipid production was detected for several clinical strains and the formation of vesicles was observed under skin physiological conditions. In conclusion we demonstrate herein that rhamnolipids enable the induction of the antimicrobial protein psoriasin by flagellin in human skin without direct contact of bacteria and responding cells. Hereby, human skin might control the microflora to prevent colonization of unwanted microbes in the earliest steps before potential pathogens can develop strategies to subvert the immune response. PMID- 21283547 TI - Viruses associated with ovarian degeneration in Apis mellifera L. queens. AB - Queen fecundity is a critical issue for the health of honeybee (Apis mellifera L.) colonies, as she is the only reproductive female in the colony and responsible for the constant renewal of the worker bee population. Any factor affecting the queen's fecundity will stagnate colony development, increasing its susceptibility to opportunistic pathogens. We discovered a pathology affecting the ovaries, characterized by a yellow discoloration concentrated in the apex of the ovaries resulting from degenerative lesions in the follicles. In extreme cases, marked by intense discoloration, the majority of the ovarioles were affected and these cases were universally associated with egg-laying deficiencies in the queens. Microscopic examination of the degenerated follicles showed extensive paracrystal lattices of 30 nm icosahedral viral particles. A cDNA library from degenerated ovaries contained a high frequency of deformed wing virus (DWV) and Varroa destructor virus 1 (VDV-1) sequences, two common and closely related honeybee Iflaviruses. These could also be identified by in situ hybridization in various parts of the ovary. A large-scale survey for 10 distinct honeybee viruses showed that DWV and VDV-1 were by far the most prevalent honeybee viruses in queen populations, with distinctly higher prevalence in mated queens (100% and 67%, respectively for DWV and VDV-1) than in virgin queens (37% and 0%, respectively). Since very high viral titres could be recorded in the ovaries and abdomens of both functional and deficient queens, no significant correlation could be made between viral titre and ovarian degeneration or egg laying deficiency among the wider population of queens. Although our data suggest that DWV and VDV-1 have a role in extreme cases of ovarian degeneration, infection of the ovaries by these viruses does not necessarily result in ovarian degeneration, even at high titres, and additional factors are likely to be involved in this pathology. PMID- 21283548 TI - Comparative analysis of acid sphingomyelinase distribution in the CNS of rats and mice following intracerebroventricular delivery. AB - Niemann-Pick A (NPA) disease is a lysosomal storage disorder (LSD) caused by a deficiency in acid sphingomyelinase (ASM) activity. Previously, we reported that biochemical and functional abnormalities observed in ASM knockout (ASMKO) mice could be partially alleviated by intracerebroventricular (ICV) infusion of hASM. We now show that this route of delivery also results in widespread enzyme distribution throughout the rat brain and spinal cord. However, enzyme diffusion into CNS parenchyma did not occur in a linear dose-dependent fashion. Moreover, although the levels of hASM detected in the rat CNS were determined to be within the range shown to be therapeutic in ASMKO mice, the absolute amounts represented less than 1% of the total dose administered. Finally, our results also showed that similar levels of enzyme distribution are achieved across rodent species when the dose is normalized to CNS weight as opposed to whole body weight. Collectively, these data suggest that the efficacy observed following ICV delivery of hASM in ASMKO mice could be scaled to CNS of the rat. PMID- 21283549 TI - Isolation of a rickettsial pathogen from a non-hematophagous arthropod. AB - Rickettsial diversity is intriguing in that some species are transmissible to vertebrates, while others appear exclusive to invertebrate hosts. Of particular interest is Rickettsia felis, identifiable in both stored product insect pests and hematophagous disease vectors. To understand rickettsial survival tactics in, and probable movement between, both insect systems will explicate the determinants of rickettsial pathogenicity. Towards this objective, a population of Liposcelis bostrychophila, common booklice, was successfully used for rickettsial isolation in ISE6 (tick-derived cells). Rickettsiae were also observed in L. bostrychophila by electron microscopy and in paraffin sections of booklice by immunofluorescence assay using anti-R. felis polyclonal antibody. The isolate, designated R. felis strain LSU-Lb, resembles typical rickettsiae when examined by microscopy. Sequence analysis of portions of the Rickettsia specific 17-kDa antigen gene, citrate synthase (gltA) gene, rickettsial outer membrane protein A (ompA) gene, and the presence of the R. felis plasmid in the cell culture isolate confirmed the isolate as R. felis. Variable nucleotide sequences from the isolate were obtained for R. felis-specific pRF-associated putative tldD/pmbA. Expression of rickettsial outer membrane protein B (OmpB) was verified in R. felis (LSU-Lb) using a monoclonal antibody. Additionally, a quantitative real-time PCR assay was used to identify a significantly greater median rickettsial load in the booklice, compared to cat flea hosts. With the potential to manipulate arthropod host biology and infect vertebrate hosts, the dual nature of R. felis provides an excellent model for the study of rickettsial pathogenesis and transmission. In addition, this study is the first isolation of a rickettsial pathogen from a non-hematophagous arthropod. PMID- 21283550 TI - Identification of ligand binding sites of proteins using the Gaussian Network Model. AB - The nonlocal nature of the protein-ligand binding problem is investigated via the Gaussian Network Model with which the residues lying along interaction pathways in a protein and the residues at the binding site are predicted. The predictions of the binding site residues are verified by using several benchmark systems where the topology of the unbound protein and the bound protein-ligand complex are known. Predictions are made on the unbound protein. Agreement of results with the bound complexes indicates that the information for binding resides in the unbound protein. Cliques that consist of three or more residues that are far apart along the primary structure but are in contact in the folded structure are shown to be important determinants of the binding problem. Comparison with known structures shows that the predictive capability of the method is significant. PMID- 21283551 TI - Assessment of factors influencing morale in the elderly. AB - BACKGROUND: We examined the relationship between morale measured by the Philadelphia Geriatric Morale Scale (PGC) and disability, social support, religiosity, and personality traits. Instruments predicting morale were then tested against PGC domains. METHODS: The study utilized a cross-sectional survey with a multistage cluster sampling design. Instruments used were disability (disease burden; WHO Disability Score-II, WHODAS-II), social support (Duke Social Support Scale, DUSOCS; Lubben Social Network Scale, LSNS-6; Medical Outcomes Study Social Support Survey, MOS-SSS), religiosity (Revised Intrinsic-Extrinsic Religious Orientation Scale, I/E-R), and personality (Ten-Item Personality Inventory, TIPI). These were plotted as bar charts against PGC, resolved with one way ANOVA and Kruskal-Wallis tests, then corrected for multiple comparisons. This process was repeated with PGC domains. Contribution of factors was modeled using population attributable risk (PAR) and odds ratios. Effect of confounders such as gender, age, and ethnicity were checked using binary logistic regression. RESULTS: All instruments showed clear relationships with PGC, with WHODAS-II and DUSOCS performing well (ANOVA p<0.001). For PGC domains, attitude toward aging and lonely dissatisfaction trended together, while agitation did not. PAR, odds ratios, and Exp(beta) were disability (WHODAS-II: 28.5%, 3.8, 2.8), social support (DUSOCS: 28.0%, 3.4, 2.2), religiosity (I/E-R: 21.6%, 3.2, 2.1), and personality (TIPI: 27.9%, 3.6, 2.4). Combined PAR was 70.9%. CONCLUSIONS: Disability, social support, religiosity, and personality strongly influence morale in the elderly. WHODAS-II and DUSOCS perform best in measuring disability and social support respectively. PMID- 21283552 TI - A randomized trial to assess anti-HIV activity in female genital tract secretions and soluble mucosal immunity following application of 1% tenofovir gel. AB - BACKGROUND: Preclinical and early phase clinical microbicide studies have not consistently predicted the outcome of efficacy trials. To address this gap, candidate biomarkers of microbicide pharmacodynamics and safety were evaluated in a double-blind, placebo-controlled trial of tenofovir gel, the first microbicide to demonstrate significant protection against HIV acquisition. METHODS: 30 women were randomized to apply a single daily dose of tenofovir or placebo gel for 14 consecutive days. Anti-HIV activity was measured in cervicovaginal lavage (CVL) on Days 0, 3, 7, 14 and 21 by luciferase assay as a surrogate marker of pharmacodynamics. Endogenous activity against E. coli and HSV-2 and concentrations of immune mediators were quantified in CVL as candidate biomarkers of safety. Tenofovir levels were measured in CVL and blood. RESULTS: A significant increase in anti-HIV activity was detected in CVL from women who applied tenofovir gel compared to their endogenous anti-HIV activity in genital tract secretions on Day 0 and compared to activity in CVL from women in the placebo group. The activity correlated significantly with CVL concentration of tenofovir (r = 0.6, p<0.001) and fit a sigmoid E(max) pharmacodynamic model. Anti HIV activity in CVL from women who applied tenofovir persisted when virus was introduced in semen, whereas endogenous anti-HIV activity decreased. Tenofovir did not trigger an inflammatory response or induce sustained loss in endogenous antimicrobial activity or immune mediators. CONCLUSIONS: Tenofovir gel had no deleterious impact on soluble mucosal immunity. The increased anti-HIV activity in CVL, which persisted in the presence of semen and correlated with tenofovir concentration, is consistent with the efficacy observed in a recent clinical trial. These results promote quantified CVL anti-HIV activity as a surrogate of tissue pharmacodynamics and as a potential biomarker of adherence to product. This simple, feasible and inexpensive bioassay may promote the development of models more predictive of microbicide efficacy. TRIAL REGISTRATION: ClinicalTrials.gov NCT00594373. PMID- 21283553 TI - Recipient outcomes after ABO-incompatible liver transplantation: a systematic review and meta-analysis. AB - BACKGROUND: ABO-incompatible live transplantation (ILT) is not occasionally performed due to a relative high risk of graft failure. Knowledge of both graft and patient survival rate after ILT is essential for donor selection and therapeutic strategy. We systematically reviewed studies containing outcomes after ILT compared to that after ABO-compatible liver transplantation (CLT). METHODOLOGY/PRINCIPAL FINDINGS: We carried out a comprehensive search strategy on MEDLINE (1966-July 2010), EMBASE (1980-July 2010), Biosis Preview (1969-July 2010), Science Citation Index (1981-July 2010), Cochrane Database of Systematic Reviews (Cochrane Library, issue 7, 2010) and the National Institute of Health (July 2010). Two reviewers independently assessed the quality of each study and abstracted outcome data. Fourteen eligible studies were included which came from various medical centers all over the world. Meta-analysis results showed that no significantly statistical difference was found in pediatric graft survival rate, pediatric and adult patient survival rate between ILT and CLT group. In adult subgroup, the graft survival rate after ILT was significantly lower than that after CLT. The value of totally pooled OR was 0.64 (0.55, 0.74), 0.92 (0.62, 1.38) for graft survival rate and patient survival rate respectively. The whole complication incidence (including acute rejection and biliary complication) after ILT was higher than that after CLT, as the value of totally pooled OR was 3.02 (1.33, 6.85). Similarly, in acute rejection subgroup, the value of OR was 2.02 (1.01, 4.02). However, it was 4.08 (0.90, 18.51) in biliary complication subgroup. CONCLUSIONS/SIGNIFICANCE: In our view, pediatric ILT has not been a contraindication anymore due to a similar graft and patient survival rate between ILT and CLT group. Though adult graft survival rate is not so satisfactory, ILT is undoubtedly life-saving under exigent condition. Most studies included in our analysis are observational researches. Larger scale of researches and Randomized Control Studies are still needed. PMID- 21283554 TI - The allylic chalcogen effect in olefin metathesis. AB - Olefin metathesis has emerged as a powerful tool in organic synthesis. The activating effect of an allylic hydroxy group in metathesis has been known for more than 10 years, and many organic chemists have taken advantage of this positive influence for efficient synthesis of natural products. Recently, the discovery of the rate enhancement by allyl sulfides in aqueous cross-metathesis has allowed the first examples of such a reaction on proteins. This led to a new benchmark in substrate complexity for cross-metathesis and expanded the potential of olefin metathesis for other applications in chemical biology. The enhanced reactivity of allyl sulfide, along with earlier reports of a similar effect by allylic hydroxy groups, suggests that allyl chalcogens generally play an important role in modulating the rate of olefin metathesis. In this review, we discuss the effect of allylic chalcogens in olefin metathesis and highlight its most recent applications in synthetic chemistry and protein modifications. PMID- 21283555 TI - Visual tuning properties of genetically identified layer 2/3 neuronal types in the primary visual cortex of cre-transgenic mice. AB - The putative excitatory and inhibitory cell classes within the mouse primary visual cortex V1 have different functional properties as studied using recording microelectrode. Excitatory neurons show high selectivity for the orientation angle of moving gratings while the putative inhibitory neurons show poor selectivity. However, the study of selectivity of the genetically identified interneurons and their subtypes remain controversial. Here we use novel Cre driver and reporter mice to identify genetic subpopulations in vivo for two photon calcium dye imaging: Wfs1(+)/Gad1(-) mice that labels layer 2/3 excitatory cell population and Pvalb(+)/Gad1(+) mice that labels a genetic subpopulation of inhibitory neurons. The cells in both mice were identically labeled with a tdTomato protein, visible in vivo, using a Cre-reporter line. We found that the Wfs1(+) cells exhibited visual tuning properties comparable to the excitatory population, i.e., high selectivity and tuning to the angle, direction, and spatial frequency of oriented moving gratings. The functional tuning of Pvalb(+) neurons was consistent with previously reported narrow-spiking interneurons in microelectrode studies, exhibiting poorer selectivity than the excitatory neurons. This study demonstrates the utility of Cre-transgenic mouse technology in selective targeting of subpopulations of neurons and makes them amenable to structural, functional, and connectivity studies. PMID- 21283556 TI - Risk-sensitivity in sensorimotor control. AB - Recent advances in theoretical neuroscience suggest that motor control can be considered as a continuous decision-making process in which uncertainty plays a key role. Decision-makers can be risk-sensitive with respect to this uncertainty in that they may not only consider the average payoff of an outcome, but also consider the variability of the payoffs. Although such risk-sensitivity is a well established phenomenon in psychology and economics, it has been much less studied in motor control. In fact, leading theories of motor control, such as optimal feedback control, assume that motor behaviors can be explained as the optimization of a given expected payoff or cost. Here we review evidence that humans exhibit risk-sensitivity in their motor behaviors, thereby demonstrating sensitivity to the variability of "motor costs." Furthermore, we discuss how risk sensitivity can be incorporated into optimal feedback control models of motor control. We conclude that risk-sensitivity is an important concept in understanding individual motor behavior under uncertainty. PMID- 21283557 TI - Active touch during shrew prey capture. AB - Although somatosensation in multiple whisker systems has been studied in considerable detail, relatively little information is available regarding whisker usage and movement patterns during natural behaviors. The Etruscan shrew, one of the smallest mammals, relies heavily on its whisker system to detect and kill its highly mobile insect prey. Here, we tracked whisker and body motion during prey capture. We found that shrews made periodic whisker movements (whisking) with frequencies ranging from 12 to 17 Hz. We compared shrew and rat whisking and found that shrew whisking was smaller amplitude and higher frequency than rat whisking, but that the shrew and rat whisking cycle were similar in that the velocity was higher during retraction than protraction. We were able to identify four phases during the shrew hunting behavior: (i) an immobile phase often preceding hunting, (ii) a search phase upon the initiation of hunting, (iii) a contact phase defined by whisker-to-cricket contact, and (iv) an attack phase, characterized by a rapid head movement directed toward the cricket. During the searching phase, whisking was generally rhythmic and whiskers were protracted forward. After prey contact, whisking amplitude decreased and became more variable. The final strike was associated with an abrupt head movement toward the prey with high head acceleration. Prey capture proceeded extremely fast and we obtained evidence that shrews can initiate corrective maneuvers with a minimal latency <30 ms. While the shrew's rostrum is straight and elongated during most behaviors, we show for the first time that shrews bend their rostrum during the final strike and grip their prey with a parrot beak shaped snout. PMID- 21283558 TI - ROMP-Derived cyclooctene-based monolithic polymeric materials reinforced with inorganic nanoparticles for applications in tissue engineering. AB - Porous monolithic inorganic/polymeric hybrid materials have been prepared via ring-opening metathesis copolymerization starting from a highly polar monomer, i.e., cis-5-cyclooctene-trans-1,2-diol and a 7-oxanorborn-2-ene-derived cross linker in the presence of porogenic solvents and two types of inorganic nanoparticles (i.e., CaCO3 and calcium hydroxyapatite, respectively) using the third-generation Grubbs initiator RuCl2(Py)2(IMesH2)(CHPh). The physico-chemical properties of the monolithic materials, such as pore size distribution and microhardness were studied with regard to the nanoparticle type and content. Moreover, the reinforced monoliths were tested for the possible use as scaffold materials in tissue engineering, by carrying out cell cultivation experiments with human adipose tissue-derived stromal cells. PMID- 21283559 TI - Highly substituted benzannulated cyclooctanol derivatives by samarium diiodide induced cyclizations. AB - A series of gamma-oxo esters suitably substituted with various styrene subunits was subjected to samarium diiodide-induced 8-endo-trig cyclizations. Efficacy, regioselectivity and stereoselectivity of these reactions via samarium ketyls strongly depend on the substitution pattern of the attacked alkene moiety. The stereoselectivity of the protonation of the intermediate samariumorganyl is also influenced by the structural features of the substrates. This systematic study reveals that steric and electronic factors exhibited by the alkene and ketone subunits are of high importance for the outcome of these cyclization reactions leading to highly substituted benzannulated cyclooctanol derivatives. In exceptional cases, 7-exo-trig cyclizations to cycloheptanol derivatives have been observed. In examples with high steric hindrance the ketyl-aryl coupling can be a competing process. PMID- 21283560 TI - Anthracene appended pyridinium amide-urea conjugate in selective fluorometric sensing of L-N-acetylvaline salt. AB - A new anthracene labeled pyridinium amide-urea conjugate 1 has been designed and synthesized. The receptor shows a different fluorometric response with L-N acetylvaline and L-N-acetylalanine salts in CH3CN in contrast to the other salts of L-N-acetyl alpha-amino acids and (S)-alpha-hydroxy acids studied. Upon complexation of the tetrabutylammonium salt of L-N-acetylvaline, the emission of 1 increases accompanied by the formation of a new band at higher wavelength and this characteristic change distinguishes it from other anionic substrates studied. The binding interaction has been studied by 1H NMR, fluorescence and UV titration experiments. PMID- 21283561 TI - The catalytic performance of Ru-NHC alkylidene complexes: PCy3versus pyridine as the dissociating ligand. AB - The catalytic performance of NHC-ligated Ru-indenylidene or benzylidene complexes bearing a tricyclohexylphosphine or a pyridine ligand in ring closing metathesis (RCM), cross metathesis, and ring closing enyne metathesis (RCEYM) reactions is compared. While the PCy3 complexes perform significantly better in RCM and RCEYM reactions than the pyridine complex, all catalysts show similar activity in cross metathesis reactions. PMID- 21283562 TI - Bronsted acid-promoted azide-olefin [3 + 2] cycloadditions for the preparation of contiguous aminopolyols: The importance of disiloxane ring size to a diastereoselective, bidirectional approach to zwittermicin A. AB - We report the first study of substrate-controlled diastereoselection in a double [3 + 2] dipolar cycloaddition of benzyl azide with alpha,beta-unsaturated imides. Using a strong Bronsted acid (triflic acid) to activate the electron deficient imide pi-bond, high diastereoselection was observed provided that a 1,1,3,3 tetraisopropoxydisiloxanylidene group (TIPDS) is used to restrict the conformation of the central 1,3-anti diol. This development provides a basis for a stereocontrolled approach to the aminopolyol core of (-)-zwittermicin A using a bidirectional synthesis strategy. PMID- 21283563 TI - Intracellular trafficking of hyaluronic acid-chitosan oligomer-based nanoparticles in cultured human ocular surface cells. AB - PURPOSE: Nanoparticles are a promising alternative for ocular drug delivery, and our group has proposed that they are especially suited for ocular mucosal disorders. The goal of the present study was to determine which internalization pathway is used by cornea-derived and conjunctiva-derived cell lines to take up hyaluronic acid (HA)-chitosan oligomer (CSO)-based nanoparticles (HA-CSO NPs). We also determined if plasmids loaded onto the NPs reached the cell nucleus. METHODS: HA-CSO NPs were made of fluoresceinamine labeled HA and CSO by ionotropic gelation and were conjugated with a model plasmid DNA for secreted alkaline phosphatase. Human epithelial cell lines derived from the conjunctiva and the cornea were exposed to HA-CSO NPs for 1 h and the uptake was investigated in living cells by fluorescence microscopy. The influence of temperature and metabolic inhibition, the effect of blocking hyaluronan receptors, and the inhibition of main endocytic pathways were studied by fluorometry. Additionally, the metabolic pathways implicated in the degradation of HA-CSO NPs were evaluated by lysosome identification. RESULTS: There was intracellular localization of plasmid-loaded HACSO NPs in both corneal and conjunctival cells. The intracellular presence of NPs diminished with time. HA-CSO NP uptake was significantly reduced by inhibition of active transport at 4 degrees C and by sodium azide. Uptake was also inhibited by blocking hyaluronan receptors with anti-CD44 Hermes-1 antibody, by excess HA, and by filipin, an inhibitor of caveolin-dependent endocytosis. HA-CSO NPs had no effect on cell viability. The transfection efficiency of the model plasmid was significantly higher in NP treated cells than in controls. CONCLUSIONS: HA-CSO NPs were internalized by two different ocular surface cell lines by an active transport mechanism. The uptake was mediated by hyaluronan receptors through a caveolin-dependent endocytic pathway, yielding remarkable transfection efficiency. Most of HA-CSO NPs were metabolized within 48 h. This uptake did not compromise cell viability. These findings further support the potential use of HA-CSO NPs to deliver genetic material to the ocular surface. PMID- 21283564 TI - An autosomal dominant cataract locus mapped to 19q13-qter in a Chinese family. AB - PURPOSE: The aim of this study was to map the disease locus of autosomal dominant cataracts (ADC) in a Chinese family. METHODS: A four-generation family with multiple individuals affected by ADC was investigated. Genomic DNA was collected from 22 family members. A gene-scan at known candidate ADC loci was performed. To achieve fine-mapping we genotyped fourteen STR markers at the critical region of 19q. The two-point logarithm of odds (LOD) score was calculated using Linkage Software Package Version 5.1 for linkage analysis. The haplotype was constructed using Cyrillic software. RESULTS: Ten members of this Chinese family were affected by nuclear cataracts. Initially, linkage analysis revealed a significant LOD score of 3.82 at the STR marker D19S418. Subsequently, after refine-marker analysis, a maximum LOD score (Z(max)=4.25) was obtained at the D19S877 (theta=0). Haplotype analysis also confirmed the locus and further narrowed it down to a critical interval from the marker D19S924 to the 19qter. CONCLUSIONS: We have successfully mapped an ADC locus to 19q13-qter. Previous studies have identified three cataract loci on 19q; however, we found no overlap between the locus of this study and any of the previously identified loci. We therefore suggest that the 19q13-qter locus in this family is a new locus for ADC. PMID- 21283565 TI - Reliability and validity of the Ethiopian version of the hospital anxiety and depression scale (HADS) in HIV infected patients. AB - BACKGROUND: The hospital anxiety and depression scale (HADS) is a widely used instrument for evaluating psychological distress from anxiety and depression. HADS has not yet been validated in Ethiopia. The aim of this study was to evaluate the reliability and validity of the Amharic (Ethiopian language) version of HADs among HIV infected patients. METHODS: The translated scale was administered to 302 HIV/AIDS patients on follow up for and taking anti-retroviral treatment. Consistency assessment was conducted using Cronbach's alpha, test retest reliability using intra-class correlation coefficients (ICC). Construct validity was examined using principal components analysis (PCA). Parallel analysis, Kaiser's criterion and the scree test were used for factor extraction. RESULTS: The internal consistency was 0.78 for the anxiety, 0.76 for depression subscales and 0.87 for the full scale of HADS. The intra-class correlation coefficient (ICC) was 80%, 86%, and 84% for the anxiety and depression subscales, and total score respectively. PCA revealed a one dimensional scale. CONCLUSION: This preliminary validation study of the Ethiopian version of the HADs indicates that it has promising acceptability, reliability and validity. The adopted scale has a single underlying dimension as indicated by Razavi's model. The HADS can be used to examine psychological distress in HIV infected patients. Findings are discussed and recommendations made. PMID- 21283566 TI - beta-Elemene piperazine derivatives induce apoptosis in human leukemia cells through downregulation of c-FLIP and generation of ROS. AB - beta-Elemene is an active component of the herb medicine Curcuma Wenyujin with reported antitumor activity. To improve its antitumor ability, five novel piperazine derivatives of beta-elemene, 13-(3-methyl-1-piperazinyl)-beta-elemene (DX1), 13-(cis-3,5-dimethyl-1-piperazinyl)-beta-elemene (DX2), 13-(4-ethyl-1 piperazinyl)-beta-elemene (DX3), 13-(4-isopropyl-1-piperazinyl)-beta-elemene (DX4) and 13-piperazinyl-beta-elemene (DX5), were synthesized. The antiproliferative and apoptotic effects of these derivatives were determined in human leukemia HL-60, NB4, K562 and HP100-1 cells. DX1, DX2 and DX5, which contain a secondary amino moiety, were more active in inhibiting cell growth and in inducing apoptosis than DX3 and DX4. The apoptosis induction ability of DX1 was associated with the generation of hydrogen peroxide (H(2)O(2)), a decrease of mitochondrial membrane potential (MMP), and the activation of caspase-8. Pretreatment with the antioxidants N-acetylcysteine and catalase completely blocked DX1-induced H(2)O(2) production, but only partially its activation of caspase-8 and induction of apoptosis. HL-60 cells were more sensitive than its H(2)O(2)-resistant subclone HP100-1 cells to DX1-induced apoptosis. The activation of caspase-8 by these compounds was correlated with the decrease in the levels of cellular FLICE-inhibitory protein (c-FLIP). The proteasome inhibitor MG-132 augmented the decrease in c-FLIP levels and apoptosis induced by these derivatives. FADD- and caspase-8-deficient Jurkat subclones have a decreased response to DX1-induced apoptosis. Our data indicate that these novel beta-elemene piperazine derivatives induce apoptosis through the decrease in c FLIP levels and the production of H(2)O(2) which leads to activation of both death receptor- and mitochondrial-mediated apoptotic pathways. PMID- 21283567 TI - SLC11A1 (NRAMP1) polymorphisms and tuberculosis susceptibility: updated systematic review and meta-analysis. AB - BACKGROUND: Natural resistance associated macrophage protein 1 (NRAMP1), encoded by the SLC11A1 gene, has been described to regulate macrophage activation and be associated with infectious and autoimmune diseases. The relation between SLC11A1 polymorphisms and tuberculosis susceptibility has been studied in different populations. METHODS: We systematically reviewed published studies on SLC11A1 polymorphisms and tuberculosis susceptibility until September 15, 2010 and quantitatively summarized associations of the most widely studied polymorphisms using meta-analysis. RESULTS: In total, 36 eligible articles were included in this review. In Meta-analysis, significant associations were observed between tuberculosis risk and widely studied SLC11A1 polymorphisms with summarized odds ratio of 1.35 (95%CI, 1.17-1.54), 1.25 (95% CI, 1.04-1.50), 1.23 (95% CI, 1.04 1.44), 1.31 (95%CI, 1.08-1.59) for 3' UTR, D543N, INT4, and 5' (GT)n, respectively. Heterogeneity between studies was not pronounced, and the associations did not remarkably vary in the stratified analysis with respect to study population and study base. CONCLUSIONS: The association between SLC11A1 polymorphisms and tuberculosis susceptibility observed in our analyses supports the hypothesis that NRAMP1 might play an important role in the host defense to the development of tuberculosis. PMID- 21283568 TI - Microglial morphology and dynamic behavior is regulated by ionotropic glutamatergic and GABAergic neurotransmission. AB - PURPOSE: Microglia represent the primary resident immune cells in the CNS, and have been implicated in the pathology of neurodegenerative diseases. Under basal or "resting" conditions, microglia possess ramified morphologies and exhibit dynamic surveying movements in their processes. Despite the prominence of this phenomenon, the function and regulation of microglial morphology and dynamic behavior are incompletely understood. We investigate here whether and how neurotransmission regulates "resting" microglial morphology and behavior. METHODS: We employed an ex vivo mouse retinal explant system in which endogenous neurotransmission and dynamic microglial behavior are present. We utilized live cell time-lapse confocal imaging to study the morphology and behavior of GFP labeled retinal microglia in response to neurotransmitter agonists and antagonists. Patch clamp electrophysiology and immunohistochemical localization of glutamate receptors were also used to investigate direct-versus-indirect effects of neurotransmission by microglia. RESULTS: Retinal microglial morphology and dynamic behavior were not cell-autonomously regulated but are instead modulated by endogenous neurotransmission. Morphological parameters and process motility were differentially regulated by different modes of neurotransmission and were increased by ionotropic glutamatergic neurotransmission and decreased by ionotropic GABAergic neurotransmission. These neurotransmitter influences on retinal microglia were however unlikely to be directly mediated; local applications of neurotransmitters were unable to elicit electrical responses on microglia patch-clamp recordings and ionotropic glutamatergic receptors were not located on microglial cell bodies or processes by immunofluorescent labeling. Instead, these influences were mediated indirectly via extracellular ATP, released in response to glutamatergic neurotransmission through probenecid sensitive pannexin hemichannels. CONCLUSIONS: Our results demonstrate that neurotransmission plays an endogenous role in regulating the morphology and behavior of "resting" microglia in the retina. These findings illustrate a mode of constitutive signaling between the neural and immune compartments of the CNS through which immune cells may be regulated in concert with levels of neural activity. PMID- 21283569 TI - Comparative effectiveness of guidelines for the management of hyperlipidemia and hypertension for type 2 diabetes patients. AB - BACKGROUND: Several guidelines to reduce cardiovascular risk in diabetes patients exist in North America, Europe, and Australia. Their ability to achieve this goal efficiently is unclear. METHODS AND FINDINGS: Decision analysis was used to compare the efficiency and effectiveness of international contemporary guidelines for the management of hypertension and hyperlipidemia for patients aged 40-80 with type 2 diabetes. Measures of comparative effectiveness included the expected probability of a coronary or stroke event, incremental medication costs per event, and number-needed-to-treat (NNT) to prevent an event. All guidelines are equally effective, but they differ significantly in their medication costs. The range of NNT to prevent an event was small across guidelines (6.5-7.6 for males and 6.5-7.5 for females); a larger range of differences were observed for expected cost per event avoided (ranges, $117,269-$157,186 for males and $115,999 $163,775 for females). Australian and U.S. guidelines result in the highest and lowest expected costs, respectively. CONCLUSIONS: International guidelines based on the same evidence and seeking the same goal are similar in their effectiveness; however, there are large differences in expected medication costs. PMID- 21283570 TI - Serological response to the 2009 pandemic influenza A (H1N1) virus for disease diagnosis and estimating the infection rate in Thai population. AB - BACKGROUND: Individuals infected with the 2009 pandemic virus A(H1N1) developed serological response which can be measured by hemagglutination-inhibition (HI) and microneutralization (microNT) assays. METHODOLOGY/PRINCIPAL FINDINGS: MicroNT and HI assays for specific antibody to the 2009 pandemic virus were conducted in serum samples collected at the end of the first epidemic wave from various groups of Thai people: laboratory confirmed cases, blood donors and health care workers (HCW) in Bangkok and neighboring province, general population in the North and the South, as well as archival sera collected at pre- and post-vaccination from vaccinees who received influenza vaccine of the 2006 season. This study demonstrated that goose erythrocytes yielded comparable HI antibody titer as compared to turkey erythrocytes. In contrast to the standard protocol, our investigation found out the necessity to eliminate nonspecific inhibitor present in the test sera by receptor destroying enzyme (RDE) prior to performing microNT assay. The investigation in pre-pandemic serum samples showed that HI antibody was more specific to the 2009 pandemic virus than NT antibody. Based on data from pre-pandemic sera together with those from the laboratory confirmed cases, HI antibody titers >= 40 for adults and >= 20 for children could be used as the cut off level to differentiate between the individuals with or without past infection by the 2009 pandemic virus. CONCLUSIONS/SIGNIFICANCE: Based on the cut-off criteria, the infection rates of 7 and 12.8% were estimated in blood donors and HCW, respectively after the first wave of the 2009 influenza pandemic. Among general population, the infection rate of 58.6% was found in children versus 3.1% in adults. PMID- 21283571 TI - Replication of extended lifespan phenotype in mice with deletion of insulin receptor substrate 1. AB - We previously reported that global deletion of insulin receptor substrate protein 1 (Irs1) extends lifespan and increases resistance to several age-related pathologies in female mice. However, no effect on lifespan was observed in male Irs1 null mice. We suggested at the time that the lack of any effect in males might have been due to a sample size issue. While such lifespan studies are essential to our understanding of the aging process, they are generally based on survival curves derived from single experiments, primarily due to time and economic constraints. Consequently, the robustness of such findings as a basis for further investigation has been questioned. We have therefore measured lifespan in a second, separate cohort of Irs1 null female mice, and show that, consistent with our previous finding, global deletion of Irs1 significantly extends lifespan in female mice. In addition, an augmented and completed study demonstrates lifespan extension in male Irs1 null mice. Therefore, we show that reduced IRS1-dependent signalling is a robust mechanism through which mammalian lifespan can be modulated. PMID- 21283572 TI - Deficits in long-term recognition memory reveal dissociated subtypes in congenital prosopagnosia. AB - The study investigates long-term recognition memory in congenital prosopagnosia (CP), a lifelong impairment in face identification that is present from birth. Previous investigations of processing deficits in CP have mostly relied on short term recognition tests to estimate the scope and severity of individual deficits. We firstly report on a controlled test of long-term (one year) recognition memory for faces and objects conducted with a large group of participants with CP. Long term recognition memory is significantly impaired in eight CP participants (CPs). In all but one case, this deficit was selective to faces and didn't extend to intra-class recognition of object stimuli. In a test of famous face recognition, long-term recognition deficits were less pronounced, even after accounting for differences in media consumption between controls and CPs. Secondly, we combined test results on long-term and short-term recognition of faces and objects, and found a large heterogeneity in severity and scope of individual deficits. Analysis of the observed heterogeneity revealed a dissociation of CP into subtypes with a homogeneous phenotypical profile. Thirdly, we found that among CPs self-assessment of real-life difficulties, based on a standardized questionnaire, and experimentally assessed face recognition deficits are strongly correlated. Our results demonstrate that controlled tests of long-term recognition memory are needed to fully assess face recognition deficits in CP. Based on controlled and comprehensive experimental testing, CP can be dissociated into subtypes with a homogeneous phenotypical profile. The CP subtypes identified align with those found in prosopagnosia caused by cortical lesions; they can be interpreted with respect to a hierarchical neural system for face perception. PMID- 21283573 TI - Does foraging performance change with age in female little penguins (Eudyptula minor)? AB - Age-related changes in breeding performance are likely to be mediated through changes in parental foraging performance. We investigated the relationship of foraging performance with age in female little penguins at Phillip Island, Australia, during the guard phase of the 2005 breeding season. Foraging parameters were recorded with accelerometers for birds grouped into three age classes: (1) young, (2) middle age and (3) old females. We found the diving behaviour of middle-aged birds differed from young and old birds. The dive duration of middle age females was shorter than that of young and old birds while their dive effort (measure for dive and post-dive duration relation) was lower than that of young ones, suggesting middle-aged birds were in better physical condition than other ones. There was no difference in prey pursuit frequency or duration between age classes, but in the hunting tactic. Females pursued more prey around and after reaching the maximum depth of dives the more experienced they were (old > middle age > young), an energy saving hunting tactic by probably taking advantage of up-thrust momentum. We suggest middle age penguins forage better than young or old ones because good physical condition and foraging experience could act simultaneously. PMID- 21283574 TI - Biased but in doubt: conflict and decision confidence. AB - Human reasoning is often biased by intuitive heuristics. A central question is whether the bias results from a failure to detect that the intuitions conflict with traditional normative considerations or from a failure to discard the tempting intuitions. The present study addressed this unresolved debate by using people's decision confidence as a nonverbal index of conflict detection. Participants were asked to indicate how confident they were after solving classic base-rate (Experiment 1) and conjunction fallacy (Experiment 2) problems in which a cued intuitive response could be inconsistent or consistent with the traditional correct response. Results indicated that reasoners showed a clear confidence decrease when they gave an intuitive response that conflicted with the normative response. Contrary to popular belief, this establishes that people seem to acknowledge that their intuitive answers are not fully warranted. Experiment 3 established that younger reasoners did not yet show the confidence decrease, which points to the role of improved bias awareness in our reasoning development. Implications for the long standing debate on human rationality are discussed. PMID- 21283575 TI - Control strategies for endemic childhood scabies. AB - Human scabies is a major global public health issue, with an estimated 300 million cases per year worldwide. Prevalence rates are particularly high in many third-world regions and within various indigenous communities in developed countries. Infestation with Sarcoptes Scabiei is associated with group-A streptococcal pyoderma which in turn predisposes to rheumatic fever, acute glomerulonephritis and their respective long-term sequelae: rheumatic heart disease and chronic renal insufficiency. The documented difficulties inherent in achieving scabies control within affected communities have motivated us to develop a network-dependent Monte-Carlo model of the scabies contagion, with the dual aims of gaining insight into its dynamics, and in determining the effects of various treatment strategies. Here we show that scabies burden is adversely affected by increases in average network degree, prominent network clustering, and by a person-to-person transmissibility of greater magnitude. We demonstrate that creating a community-specific model allows for the determination of an effective treatment protocol that can satisfy any pre-defined target prevalence. We find frequent low-density treatment protocols are inherently advantageous in comparison with infrequent mass screening and treatment regimes: prevalence rates are lower when compared with protocols that administer the same number of treatments over a given time interval less frequently, and frequent low-density treatment protocols have economic, practical and public acceptance advantages that may facilitate their long-term implementation. This work demonstrates the importance of stochasticity, community structure and the heterogeneity of individuals in influencing the dynamics of the human scabies contagion, and provides a practical method for investigating the outcomes of various intervention strategies. PMID- 21283576 TI - An atlas of altered expression of deubiquitinating enzymes in human cancer. AB - BACKGROUND: Deubiquitinating enzymes (DUBs) are proteases that process ubiquitin (Ub) or ubiquitin-like gene products, remodel polyubiquitin(-like) chains on target proteins, and counteract protein ubiquitination exerted by E3 ubiquitin ligases. A wealth of studies has established the relevance of DUBs to the control of physiological processes whose subversion is known to cause cellular transformation, including cell cycle progression, DNA repair, endocytosis and signal transduction. Altered expression of DUBs might, therefore, subvert both the proteolytic and signaling functions of the Ub system. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we report the first comprehensive screening of DUB dysregulation in human cancers by in situ hybridization on tissue microarrays (ISH-TMA). ISH-TMA has proven to be a reliable methodology to conduct this kind of study, particularly because it allows the precise identification of the cellular origin of the signals. Thus, signals associated with the tumor component can be distinguished from those associated with the tumor microenvironment. Specimens derived from various normal and malignant tumor tissues were analyzed, and the "normal" samples were derived, whenever possible, from the same patients from whom tumors were obtained. Of the ~90 DUBs encoded by the human genome, 33 were found to be expressed in at least one of the analyzed tissues, of which 22 were altered in cancers. Selected DUBs were subjected to further validation, by analyzing their expression in large cohorts of tumor samples. This analysis unveiled significant correlations between DUB expression and relevant clinical and pathological parameters, which were in some cases indicative of aggressive disease. CONCLUSIONS/SIGNIFICANCE: The results presented here demonstrate that DUB dysregulation is a frequent event in cancer, and have implications for therapeutic approaches based on DUB inhibition. PMID- 21283577 TI - Sperm competition selects for sperm quantity and quality in the Australian Maluridae. AB - When ejaculates from rival males compete for fertilization, there is strong selection for sperm traits that enhance fertilization success. Sperm quantity is one such trait, and numerous studies have demonstrated a positive association between sperm competition and both testes size and the number of sperm available for copulations. Sperm competition is also thought to favor increases in sperm quality and changes in testicular morphology that lead to increased sperm production. However, in contrast to sperm quantity, these hypotheses have received considerably less empirical support and remain somewhat controversial. In a comparative study using the Australian Maluridae (fairy-wrens, emu-wrens, grasswrens), we tested whether increasing levels of sperm competition were associated with increases in both sperm quantity and quality, as well as an increase in the relative amount of seminiferous tubule tissue contained within the testes. After controlling for phylogeny, we found positive associations between sperm competition and sperm numbers, both in sperm reserves and in ejaculate samples. Additionally, as sperm competition level increased, the proportion of testicular spermatogenic tissue also increased, suggesting that sperm competition selects for greater sperm production per unit of testicular tissue. Finally, we also found that sperm competition level was positively associated with multiple sperm quality traits, including the proportion of motile sperm in ejaculates and the proportion of both viable and morphologically normal sperm in sperm reserves. These results suggest multiple ejaculate traits, as well as aspects of testicular morphology, have evolved in response to sperm competition in the Australian Maluridae. Furthermore, our findings emphasize the importance of post-copulatory sexual selection as an evolutionary force shaping macroevolutionary differences in sperm phenotype. PMID- 21283578 TI - An unexpected location of the arginine catabolic mobile element (ACME) in a USA300-related MRSA strain. AB - In methicillin resistant Staphylococcus aureus (MRSA), the arginine catabolic mobile element (ACME) was initially described in USA300 (t008-ST8) where it is located downstream of the staphylococcal cassette chromosome mec (SCCmec). A common health-care associated MRSA in Copenhagen, Denmark (t024-ST8) is clonally related to USA300 and is frequently PCR positive for the ACME specific arcA-gene. This study is the first to describe an ACME element upstream of the SCCmec in MRSA. By traditional SCCmec typing schemes, the SCCmec of t024-ST8 strain M1 carries SCCmec IVa, but full sequencing of the cassette revealed that the entire J3 region had no homology to published SCCmec IVa. Within the J3 region of M1 was a 1705 bp sequence only similar to a sequence in S. haemolyticus strain JCSC1435 and 2941 bps with no homology found in GenBank. In addition to the usual direct repeats (DR) at each extremity of SCCmec, M1 had two new DR between the orfX gene and the J3 region of the SCCmec. The region between the orfX DR (DR1) and DR2 contained the ccrAB4 genes. An ACME II-like element was located between DR2 and DR3. The entire 26,468 bp sequence between DR1 and DR3 was highly similar to parts of the ACME composite island of S. epidermidis strain ATCC12228. Sequencing of an ACME negative t024-ST8 strain (M299) showed that DR1 and the sequence between DR1 and DR3 was missing. The finding of a mobile ACME II-like element inserted downstream of orfX and upstream of SCCmec indicates a novel recombination between staphylococcal species. PMID- 21283579 TI - Mechanism of inhibition of enveloped virus membrane fusion by the antiviral drug arbidol. AB - The broad-spectrum antiviral arbidol (Arb) inhibits cell entry of enveloped viruses by blocking viral fusion with host cell membrane. To better understand Arb mechanism of action, we investigated its interactions with phospholipids and membrane peptides. We demonstrate that Arb associates with phospholipids in the micromolar range. NMR reveals that Arb interacts with the polar head-group of phospholipid at the membrane interface. Fluorescence studies of interactions between Arb and either tryptophan derivatives or membrane peptides reconstituted into liposomes show that Arb interacts with tryptophan in the micromolar range. Interestingly, apparent binding affinities between lipids and tryptophan residues are comparable with those of Arb IC50 of the hepatitis C virus (HCV) membrane fusion. Since tryptophan residues of membrane proteins are known to bind preferentially at the membrane interface, these data suggest that Arb could increase the strength of virus glycoprotein's interactions with the membrane, due to a dual binding mode involving aromatic residues and phospholipids. The resulting complexation would inhibit the expected viral glycoprotein conformational changes required during the fusion process. Our findings pave the way towards the design of new drugs exhibiting Arb-like interfacial membrane binding properties to inhibit early steps of virus entry, i.e., attractive targets to combat viral infection. PMID- 21283580 TI - Individualized and clinically derived stimuli activate limbic structures in depression: an fMRI study. AB - OBJECTIVES: In the search for neurobiological correlates of depression, a major finding is hyperactivity in limbic-paralimbic regions. However, results so far have been inconsistent, and the stimuli used are often unspecific to depression. This study explored hemodynamic responses of the brain in patients with depression while processing individualized and clinically derived stimuli. METHODS: Eighteen unmedicated patients with recurrent major depressive disorder and 17 never-depressed control subjects took part in standardized clinical interviews from which individualized formulations of core interpersonal dysfunction were derived. In the patient group such formulations reflected core themes relating to the onset and maintenance of depression. In controls, formulations reflected a major source of distress. This material was thereafter presented to subjects during functional magnetic resonance imaging (fMRI) assessment. RESULTS: Increased hemodynamic responses in the anterior cingulate cortex, medial frontal gyrus, fusiform gyrus and occipital lobe were observed in both patients and controls when viewing individualized stimuli. Relative to control subjects, patients with depression showed increased hemodynamic responses in limbic-paralimbic and subcortical regions (e.g. amygdala and basal ganglia) but no signal decrease in prefrontal regions. CONCLUSIONS: This study provides the first evidence that individualized stimuli derived from standardized clinical interviewing can lead to hemodynamic responses in regions associated with self referential and emotional processing in both groups and limbic-paralimbic and subcortical structures in individuals with depression. Although the regions with increased responses in patients have been previously reported, this study enhances the ecological value of fMRI findings by applying stimuli that are of personal relevance to each individual's depression. PMID- 21283581 TI - Non-overlapping functions for Pyk2 and FAK in osteoblasts during fluid shear stress-induced mechanotransduction. AB - Mechanotransduction, the process by which cells convert external mechanical stimuli such as fluid shear stress (FSS) into biochemical changes, plays a critical role in maintenance of the skeleton. We have proposed that mechanical stimulation by FSS across the surfaces of bone cells results in formation of unique signaling complexes called mechanosomes that are launched from sites of adhesion with the extracellular matrix and with other bone cells [1]. Deformation of adhesion complexes at the cell membrane ultimately results in alteration of target gene expression. Recently, we reported that focal adhesion kinase (FAK) functions as a part of a mechanosome complex that is required for FSS-induced mechanotransduction in bone cells. This study extends this work to examine the role of a second member of the FAK family of non-receptor protein tyrosine kinases, proline-rich tyrosine kinase 2 (Pyk2), and determine its role during osteoblast mechanotransduction. We use osteoblasts harvested from mice as our model system in this study and compared the contributions of Pyk2 and FAK during FSS induced mechanotransduction in osteoblasts. We exposed Pyk2(+/+) and Pyk2(-/ ) primary calvarial osteoblasts to short period of oscillatory fluid flow and analyzed downstream activation of ERK1/2, and expression of c-fos, cyclooxygenase 2 and osteopontin. Unlike FAK, Pyk2 was not required for fluid flow-induced mechanotransduction as there was no significant difference in the response of Pyk2(+/+) and Pyk2(-/-) osteoblasts to short periods of fluid flow (FF). In contrast, and as predicted, FAK(-/-) osteoblasts were unable to respond to FF. These data indicate that FAK and Pyk2 have distinct, non-redundant functions in launching mechanical signals during osteoblast mechanotransduction. Additionally, we compared two methods of generating FF in both cell types, oscillatory pump method and another orbital platform method. We determined that both methods of generating FF induced similar responses in both primary calvarial osteoblasts and immortalized calvarial osteoblasts. PMID- 21283582 TI - Candidate genes detected in transcriptome studies are strongly dependent on genetic background. AB - Whole genome transcriptomic studies can point to potential candidate genes for organismal traits. However, the importance of potential candidates is rarely followed up through functional studies and/or by comparing results across independent studies. We have analysed the overlap of candidate genes identified from studies of gene expression in Drosophila melanogaster using similar technical platforms. We found little overlap across studies between putative candidate genes for the same traits in the same sex. Instead there was a high degree of overlap between different traits and sexes within the same genetic backgrounds. Putative candidates found using transcriptomics therefore appear very sensitive to genetic background and this can mask or override effects of treatments. The functional importance of putative candidate genes emerging from transcriptome studies needs to be validated through additional experiments and in future studies we suggest a focus on the genes, networks and pathways affecting traits in a consistent manner across backgrounds. PMID- 21283583 TI - The functional consequences of mutualistic network architecture. AB - The architecture and properties of many complex networks play a significant role in the functioning of the systems they describe. Recently, complex network theory has been applied to ecological entities, like food webs or mutualistic plant animal interactions. Unfortunately, we still lack an accurate view of the relationship between the architecture and functioning of ecological networks. In this study we explore this link by building individual-based pollination networks from eight Erysimum mediohispanicum (Brassicaceae) populations. In these individual-based networks, each individual plant in a population was considered a node, and was connected by means of undirected links to conspecifics sharing pollinators. The architecture of these unipartite networks was described by means of nestedness, connectivity and transitivity. Network functioning was estimated by quantifying the performance of the population described by each network as the number of per-capita juvenile plants produced per population. We found a consistent relationship between the topology of the networks and their functioning, since variation across populations in the average per-capita production of juvenile plants was positively and significantly related with network nestedness, connectivity and clustering. Subtle changes in the composition of diverse pollinator assemblages can drive major consequences for plant population performance and local persistence through modifications in the structure of the inter-plant pollination networks. PMID- 21283584 TI - Determination of plasmid copy number reveals the total plasmid DNA amount is greater than the chromosomal DNA amount in Bacillus thuringiensis YBT-1520. AB - Bacillus thuringiensis is the most widely used bacterial bio-insecticide, and most insecticidal crystal protein-coding genes are located on plasmids. Most strains of B. thuringiensis harbor numerous diverse plasmids, although the plasmid copy numbers (PCNs) of all native plasmids in this host and the corresponding total plasmid DNA amount remains unknown. In this study, we determined the PCNs of 11 plasmids (ranging from 2 kb to 416 kb) in a sequenced B. thuringiensis subsp. kurstaki strain YBT-1520 using real-time qPCR. PCNs were found to range from 1.38 to 172, and were negatively correlated to plasmid size. The amount of total plasmid DNA (~8.7 Mbp) was 1.62-fold greater than the amount of chromosomal DNA (~5.4 Mbp) at the mid-exponential growth stage (OD(600) = 2.0) of the organism. Furthermore, we selected three plasmids with different sizes and replication mechanisms to determine the PCNs over the entire life cycle. We found that the PCNs dynamically shifted at different stages, reaching their maximum during the mid-exponential growth or stationary phases and remaining stable and close to their minimum after the prespore formation stage. The PCN of pBMB2062, which is the smallest plasmid (2062 bp) and has the highest PCN of those tested, varied in strain YBT-1520, HD-1, and HD-136 (172, 115, and 94, respectively). These findings provide insight into both the total plasmid DNA amount of B. thuringiensis and the strong ability of the species to harbor plasmids. PMID- 21283585 TI - Cold-water coral distributions in the drake passage area from towed camera observations--initial interpretations. AB - Seamounts are unique deep-sea features that create habitats thought to have high levels of endemic fauna, productive fisheries and benthic communities vulnerable to anthropogenic impacts. Many seamounts are isolated features, occurring in the high seas, where access is limited and thus biological data scarce. There are numerous seamounts within the Drake Passage (Southern Ocean), yet high winds, frequent storms and strong currents make seafloor sampling particularly difficult. As a result, few attempts to collect biological data have been made, leading to a paucity of information on benthic habitats or fauna in this area, particularly those on primarily hard-bottom seamounts and ridges. During a research cruise in 2008 six locations were examined (two on the Antarctic margin, one on the Shackleton Fracture Zone, and three on seamounts within the Drake Passage), using a towed camera with onboard instruments to measure conductivity, temperature, depth and turbidity. Dominant fauna and bottom type were categorized from 200 randomized photos from each location. Cold-water corals were present in high numbers in habitats both on the Antarctic margin and on the current swept seamounts of the Drake Passage, though the diversity of orders varied. Though the Scleractinia (hard corals) were abundant on the sedimented margin, they were poorly represented in the primarily hard-bottom areas of the central Drake Passage. The two seamount sites and the Shackleton Fracture Zone showed high numbers of stylasterid (lace) and alcyonacean (soft) corals, as well as large numbers of sponges. Though data are preliminary, the geological and environmental variability (particularly in temperature) between sample sites may be influencing cold-water coral biogeography in this region. Each area observed also showed little similarity in faunal diversity with other sites examined for this study within all phyla counted. This manuscript highlights how little is understood of these isolated features, particularly in Polar regions. PMID- 21283586 TI - Gating of a pH-sensitive K(2P) potassium channel by an electrostatic effect of basic sensor residues on the selectivity filter. AB - K(+) channels share common selectivity characteristics but exhibit a wide diversity in how they are gated open. Leak K(2P) K(+) channels TASK-2, TALK-1 and TALK-2 are gated open by extracellular alkalinization. The mechanism for this alkalinization-dependent gating has been proposed to be the neutralization of the side chain of a single arginine (lysine in TALK-2) residue near the pore of TASK 2, which occurs with the unusual pK(a) of 8.0. We now corroborate this hypothesis by transplanting the TASK-2 extracellular pH (pH(o)) sensor in the background of a pH(o)-insensitive TASK-3 channel, which leads to the restitution of pH(o) gating. Using a concatenated channel approach, we also demonstrate that for TASK 2 to open, pH(o) sensors must be neutralized in each of the two subunits forming these dimeric channels with no apparent cross-talk between the sensors. These results are consistent with adaptive biasing force analysis of K(+) permeation using a model selectivity filter in wild-type and mutated channels. The underlying free-energy profiles confirm that either a doubly or a singly charged pH(o) sensor is sufficient to abolish ion flow. Atomic detail of the associated mechanism reveals that, rather than a collapse of the pore, as proposed for other K(2P) channels gated at the selectivity filter, an increased height of the energetic barriers for ion translocation accounts for channel blockade at acid pH(o). Our data, therefore, strongly suggest that a cycle of protonation/deprotonation of pH(o)-sensing arginine 224 side chain gates the TASK 2 channel by electrostatically tuning the conformational stability of its selectivity filter. PMID- 21283587 TI - An investigation of racing performance and whip use by jockeys in thoroughbred races. AB - Concerns have been expressed concerning animal-welfare issues associated with whip use during Thoroughbred races. However, there have been no studies of relationships between performance and use of whips in Thoroughbred racing. Our aim was to describe whip use and the horses' performance during races, and to investigate associations between whip use and racing performance. Under the Australian Racing Board (ARB) rules, only horses that are in contention can be whipped, so we expected that whippings would be associated with superior performance, and those superior performances would be explained by an effect of whipping on horse velocities in the final 400 m of the race. We were also interested to determine whether performance in the latter sections of a race was associated with performance in the earlier sections of a race. Measurements of whip strikes and sectional times during each of the final three 200 metre (m) sections of five races were analysed. Jockeys in more advanced placings at the final 400 and 200 m positions in the races whipped their horses more frequently. Horses, on average, achieved highest speeds in the 600 to 400 m section when there was no whip use, and the increased whip use was most frequent in the final two 200 m sections when horses were fatigued. This increased whip use was not associated with significant variation in velocity as a predictor of superior placing at the finish. PMID- 21283588 TI - The DOCK protein sponge binds to ELMO and functions in Drosophila embryonic CNS development. AB - Cell morphogenesis, which requires rearrangement of the actin cytoskeleton, is essential to coordinate the development of tissues such as the musculature and nervous system during normal embryonic development. One class of signaling proteins that regulate actin cytoskeletal rearrangement is the evolutionarily conserved CDM (C. elegansCed-5, human DOCK180, DrosophilaMyoblast city, or Mbc) family of proteins, which function as unconventional guanine nucleotide exchange factors for the small GTPase Rac. This CDM-Rac protein complex is sufficient for Rac activation, but is enhanced upon the association of CDM proteins with the ELMO/Ced-12 family of proteins. We identified and characterized the role of Drosophila Sponge (Spg), the vertebrate DOCK3/DOCK4 counterpart as an ELMO interacting protein. Our analysis shows Spg mRNA and protein is expressed in the visceral musculature and developing nervous system, suggesting a role for Spg in later embryogenesis. As maternal null mutants of spg die early in development, we utilized genetic interaction analysis to uncover the role of Spg in central nervous system (CNS) development. Consistent with its role in ELMO-dependent pathways, we found genetic interactions with spg and elmo mutants exhibited aberrant axonal defects. In addition, our data suggests Ncad may be responsible for recruiting Spg to the membrane, possibly in CNS development. Our findings not only characterize the role of a new DOCK family member, but help to further understand the role of signaling downstream of N-cadherin in neuronal development. PMID- 21283589 TI - Insulin and glucagon regulate pancreatic alpha-cell proliferation. AB - Type 2 diabetes mellitus (T2DM) results from insulin resistance and beta-cell dysfunction, in the setting of hyperglucagonemia. Glucagon is a 29 amino acid peptide hormone, which is secreted from pancreatic alpha cells: excessively high circulating levels of glucagon lead to excessive hepatic glucose output. We investigated if alpha-cell numbers increase in T2DM and what factor (s) regulate alpha-cell turnover. Lepr(db)/Lepr(db) (db/db) mice were used as a T2DM model and alphaTC1 cells were used to study potential alpha-cell trophic factors. Here, we demonstrate that in db/db mice alpha-cell number and plasma glucagon levels increased as diabetes progressed. Insulin treatment (EC50 = 2 nM) of alpha cells significantly increased alpha-cell proliferation in a concentration-dependent manner compared to non-insulin-treated alpha cells. Insulin up-regulated alpha cell proliferation through the IR/IRS2/AKT/mTOR signaling pathway, and increased insulin-mediated proliferation was prevented by pretreatment with rapamycin, a specific mTOR inhibitor. GcgR antagonism resulted in reduced rates of cell proliferation in alphaTC1 cells. In addition, blockade of GcgRs in db/db mice improved glucose homeostasis, lessened alpha-cell proliferation, and increased intra-islet insulin content in beta cells in db/db mice. These studies illustrate that pancreatic alpha-cell proliferation increases as diabetes develops, resulting in elevated plasma glucagon levels, and both insulin and glucagon are trophic factors to alpha-cells. Our current findings suggest that new therapeutic strategies for the treatment of T2DM may include targeting alpha cells and glucagon. PMID- 21283590 TI - Isolation and genetic characteristics of human genotype 1 Japanese encephalitis virus, China, 2009. AB - BACKGROUND: Several studies have shown that the predominant genotype of Chinese Japanese encephalitis virus (JEV) is evolving from genotype 3 to genotype 1. However, in recent years, almost all genotype 1 isolates were from mosquitoes, and genotype 1 has been less associated with human disease than genotype 3. This study reports the isolation of human genotype 1 JEV and its genetic characteristics to provide additional insights into human JE pathogens that are currently circulating in China. METHODS AND RESULTS: In 2009, 31 cerebrospinal fluid samples were collected from patients living in Yunnan and Shanxi provinces and were used to inoculate Aedes albopictus C6/36 cells for virus isolation. The JEV strains were identified using immunofluorescent assays and the reverse transcription-polymerase chain reaction. Phylogenetic analyses based on the partial capsid/pre-membrane and full envelope (E) sequences were performed using Clustalx 1.8 software. Three JEV isolates were obtained from a 4-year-old girl and a 2-year-old boy living in Yunnan and an 82-year-old woman in Shanxi. The boy had been immunized with one dose of JE live attenuated vaccine. New isolates were grouped into genotype 1. Amino acid sequence for the viral E protein indicated 95% to 100% identity with each other and with other JEV strains. When compared with a consensus sequence of E protein, two amino acid substitutions were found: Ser(E-123)-Asn in the two Yunnan isolates and Lys(E-166)-Arg in the Shanxi isolate. CONCLUSIONS: Our findings indicate that the genotype 1 of JEV is causing human infections in China. Our observation of a previously vaccinated boy developing JE from genotype 1 virus infection also calls for more detailed studies, both in vitro and in vivo neutralization tests as well as active surveillance, to examine the possibility of a lack of complete protection conferred by the live attenuated JE vaccine against genotype 1 virus. PMID- 21283591 TI - Carotenoid supplementation positively affects the expression of a non-visual sexual signal. AB - Carotenoids are a class of pigments which are widely used by animals for the expression of yellow-to-red colour signals, such as bill or plumage colour. Since they also have been shown to promote immunocompetence and to function as antioxidants, many studies have investigated a potential allocation trade-off with respect to carotenoid-based signals within the context of sexual selection. Although an effect of carotenoids on non-visual (e.g. acoustic) signals involved in sexual selection has been hypothesized, this has to date not been investigated. First, we examined a potential effect of dietary carotenoid supplementation on overall song rate during the non-breeding season in captive male European starlings (Sturnus vulgaris). After only 3-7 days, we found a significant (body-mass independent) positive effect of carotenoid availability on overall song rate. Secondly, as a number of studies suggest that carotenoids could affect the modulation of sexual signals by plasma levels of the steroid hormone testosterone (T), we used the same birds to subsequently investigate whether carotenoid availability affects the increase in (nestbox-oriented) song rate induced by experimentally elevated plasma T levels. Our results suggest that carotenoids may enhance the positive effect of elevated plasma T levels on nestbox-oriented song rate. Moreover, while non-supplemented starlings responded to T-implantation with an increase in both overall song rate and nestbox-oriented song, carotenoid-supplemented starlings instead shifted song production towards (reproductively relevant) nestbox-oriented song, without increasing overall song rate. Given that song rate is an acoustic signal rather than a visual signal, our findings therefore indicate that the role of carotenoids in (sexual) signalling need not be dependent on their function as pigments. PMID- 21283592 TI - Hyperglycemic myocardial damage is mediated by proinflammatory cytokine: macrophage migration inhibitory factor. AB - BACKGROUND: Diabetes has been regarded as an inflammatory condition which is associated with left ventricular diastolic dysfunction (LVDD). The purpose of this study was to examine the expression levels of macrophage migration inhibitory factor (MIF) and G protein-coupled receptor kinase 2 (GRK2) in patients with early diabetic cardiomyopathy, and to investigate the mechanisms involved in MIF expression and GRK2 activation. METHODS: 83 patients in the age range of 30-64 years with type 2 diabetes and 30 matched healthy men were recruited. Left ventricular diastolic function was evaluated by cardiac Doppler echocardiography. Plasma MIF levels were determined by ELISA. To confirm the clinical observation, we also studied MIF expression in prediabetic rats with impaired glucose tolerance (IGT) and relationship between MIF and GRK2 expression in H9C2 cardiomyoblasts exposed to high glucose. RESULTS: Compared with healthy subjects, patients with diabetes have significantly increased levels of plasma MIF which was further increased in diabetic patients with Left ventricular diastolic dysfunction (LVDD). The increased plasma MIF levels in diabetic patients correlated with plasma glucose, glycosylated hemoglobin and urine albumin levels. We observed a significant number of TUNEL-positive cells in the myocardium of IGT-rats but not in the control rats. Moreover, we found higher MIF expression in the heart of IGT with cardiac dysfunction compared to that of the controls. In H9C2 cardiomyoblast cells, MIF and GRK2 expression was significantly increased in a glucose concentration-dependant manner. Furthermore, GRK2 expression was abolished by siRNA knockdown of MIF and by the inhibition of CXCR4 in H9C2 cells. CONCLUSIONS: Our findings indicate that hyperglycemia is a causal factor for increased levels of pro-inflammatory cytokine MIF which plays a role in the development of cardiomyopathy occurring in patients with type 2 diabetes. The elevated levels of MIF are associated with cardiac dysfunction in diabetic patients, and the MIF effects are mediated by GRK2. PMID- 21283593 TI - Transgenic biofortification of the starchy staple cassava (Manihot esculenta) generates a novel sink for protein. AB - Although calorie dense, the starchy, tuberous roots of cassava provide the lowest sources of dietary protein within the major staple food crops (Manihot esculenta Crantz). (Montagnac JA, Davis CR, Tanumihardjo SA. (2009) Compr Rev Food Sci Food Saf 8:181-194). Cassava was genetically modified to express zeolin, a nutritionally balanced storage protein under control of the patatin promoter. Transgenic plants accumulated zeolin within de novo protein bodies localized within the root storage tissues, resulting in total protein levels of 12.5% dry weight within this tissue, a fourfold increase compared to non-transgenic controls. No significant differences were seen for morphological or agronomic characteristics of transgenic and wild type plants in the greenhouse and field trials, but relative to controls, levels of cyanogenic compounds were reduced by up to 55% in both leaf and root tissues of transgenic plants. Data described here represent a proof of concept towards the potential transformation of cassava from a starchy staple, devoid of storage protein, to one capable of supplying inexpensive, plant-based proteins for food, feed and industrial applications. PMID- 21283594 TI - High fat diet prevents over-crowding induced decrease of sex ratio in mice. AB - Adaptive theory predicts that mothers would be advantaged by adjusting the sex ratio of their offspring in relation to their offspring's future reproductive success. In the present study, we tested the effect of housing mice under crowded condition on the sex ratio and whether the fat content of the diet has any influence on the outcome of pregnancies. Three-week-old mice were placed on the control diet (NFD) for 3 weeks. Thereafter the mice were allotted randomly to two groups of 7 cages each with 4, 6, 8, 10, 12, 14, and 16 mice in every cage to create increasing crowding gradient and fed either NFD or high fat diet (HFD). After 4 weeks, dams were bred and outcomes of pregnancy were analyzed. The average dam body weight (DBW) at conception, litter size (LS) and SR were significantly higher in HFD fed dams. Further, male biased litters declined with increasing crowding in NFD group but not in HFD. The LS and SR in NFD declined significantly with increasing crowding, whereas only LS was reduced in HFD group. We conclude that female mice housed under overcrowding conditions shift offspring SR in favor of daughters in consistent with the TW hypothesis and high fat diet reduces this influence of overcrowding. PMID- 21283595 TI - Coordinating changes in cell adhesion and phenotype during EMT-like processes in cancer. AB - Understanding the progression of a primary cancer to the metastatic stage has been the focus of extensive research for years. Commonly accepted concepts in this process (i.e., that of genetic instability and loss of normal cellular constraints on growth and motility) are well established. Other important paradigms, such as the necessary change from an epithelial cell phenotype displaying cell-cell adhesions to a singular and motile mesenchymal-like cell phenotype (possibly derived from a stem cell-like cell) via a process similar to epithelial to mesenchymal transition (EMT), are less well understood. In this review we will address studies linking EMT and cancer stem cells during cancer development and observations that are challenging these concepts. PMID- 21283596 TI - Proteomics in rheumatology: the dawn of a new era. AB - Most rheumatic autoimmune diseases are complex in terms of their genetic origins and underlying pathogenic processes. Non-hypothesis-driven scanning platforms are adding novel insights to our understanding of these multifactorial diseases. This review summarizes the handful of recent proteomic studies that have been executed using samples from patients with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, osteoarthritis, or Sjogren's syndrome. The candidate biomarkers that have been uncovered in the reviewed studies have potential applications in diagnosis, prognosis, and theranostics. Though we are at the infancy of the proteomics era in rheumatology, the limited number of molecules uncovered thus far already hold promise. Ongoing research in proteomics holds tremendous potential for shaping how rheumatic diseases are diagnosed, prognosticated, and managed clinically over the coming years. PMID- 21283597 TI - HIV-associated anal cancer. AB - HIV-associated anal carcinoma, a non-AIDS-defining cancer, is a human papillomavirus-associated malignancy with a spectrum of preinvasive changes. The standardized incidence ratio for anal cancer in patients with HIV/AIDS is 20-50. Algorithms for anal cancer screening include anal cytology followed by high resolution anoscopy for those with abnormal findings. Outpatient topical treatments for anal intraepithelial neoplasia include infrared coagulation therapy, trichloroacetic acid, and imiquimod. The development of cost-effective national screening programs for HIV-associated anal cancer remains a challenge. PMID- 21283598 TI - Inflammation as a target for improving health in chronic kidney disease. AB - Since the first reports in the late 1990s connecting elevated circulating levels of C-reactive protein in patients with end-stage renal disease with an atherogenic, wasted phenotype and poor outcome, more than 3600 publications related to the subject have appeared on the Medline bibliographic database. This reflects the exponential interest that this topic has evoked in the field of nephrology, and the possibility of treating this common uremic complication has been much discussed. Several small studies have implied that various nutritional and pharmacological treatment strategies have beneficial effects on surrogate markers of inflammation. However, no randomized controlled trials on anti inflammatory treatment have yet been performed to test the hypothesis that persistent low-grade inflammation contributes to uremic morbidity and mortality. PMID- 21283599 TI - The case for resequencing studies of Arabidopsis thaliana accessions: mining the dark matter of natural genetic variation. AB - Ultra-high-throughput sequencing (UHTS) techniques are evolving rapidly and may soon become an affordable and routine tool for sequencing plant DNA, even in smaller plant biology labs. Here we review recent insights into intraspecific genome variation gained from UHTS, which offers a glimpse of the rather unexpected levels of structural variability among Arabidopsis thaliana accessions. The challenges that will need to be addressed to efficiently assemble and exploit this information are also discussed. PMID- 21283600 TI - Closing in on the link between apoptosis and autophagy. AB - While there is a clear connection between apoptosis and autophagy, the mechanisms that regulate the interaction have been difficult to identify. The initial clue to the link was the observation that Bcl-2 was located at the endoplasmic reticulum (ER), where it could prevent some forms of apoptosis and also bind to the autophagy regulatory protein Beclin-1. However, both of these enigmatic observations have been united with the discovery of the nutrient-deprivation autophagy factor-1 (NAF-1) protein. As an ER-localized protein that enhances the interaction of Bcl-2 and Beclin-1 and that also binds to the pro-apoptotic protein Bik, NAF-1 is perfectly placed to be a central regulator of the switch between autophagy and apoptosis. PMID- 21283601 TI - Creating transplant tolerance by taming adverse intragraft innate immunity. AB - Certain forms of inflammation of an allograft are highly detrimental to the induction and maintenance of transplant tolerance as they foster stable commitment to graft-destructive, not graft-protective, forms of T-cell immunity. Hence, a reduction in adverse tissue inflammation may prove crucial in facilitating the induction and maintenance of a long-lasting state of transplant tolerance. PMID- 21283602 TI - Does GSK-3 provide a shortcut for PI3K activation of Wnt signalling? AB - Glycogen synthase kinase-3 (GSK-3) is a well-established downstream component of the phosphatidylinositol 3-kinase (PI3K) signalling pathway but is also a key enzyme in negatively regulating the canonical Wnt/beta-catenin signalling pathway. Several recent studies argue that PKB (protein kinase B)-mediated inhibition of GSK-3 leads to beta-catenin accumulation, but whether cross-talk actually exists between these two pathways is controversial. To elucidate the mechanisms of shared signalling components, further studies taking into account different components of the PI3K signalling pathway and different pools of GSK-3 or beta-catenin are required. PMID- 21283603 TI - A research agenda for malaria eradication: cross-cutting issues for eradication. AB - Discipline-specific Malaria Eradication Research Agenda (malERA) Consultative Groups have recognized several cross-cutting issues that must be addressed to prevent repetition of some of the mistakes of past malaria elimination campaigns in future programs. Integrated research is required to develop a decision-making framework for the switch from malaria control to elimination. Similarly, a strong economic case is needed for the very long-term financial support that is essential for elimination. Another cross-cutting priority is the development of improved measures of intensity of transmission, especially at low and nonrandom levels. Because sustained malaria elimination is dependent on a functioning health system, a further key cross-cutting research question is to determine how inputs for malaria can strengthen health systems, information systems, and overall health outcomes. Implementation of elimination programs must also be accompanied by capacity building and training to allow the assessment of the impact of new combinations of interventions, new roles for different individuals, and the operational research that is needed to facilitate program expansion. Finally, because community engagement, knowledge management, communication, political, and multisectoral support are critical but poorly understood success factors for malaria elimination, integrated research into these issues is vital. PMID- 21283604 TI - Using the Delphi technique to determine which outcomes to measure in clinical trials: recommendations for the future based on a systematic review of existing studies. PMID- 21283605 TI - A research agenda for malaria eradication: modeling. AB - Malaria modeling can inform policy and guide research for malaria elimination and eradication from local implementation to global policy. A research and development agenda for malaria modeling is proposed, to support operations and to enhance the broader eradication research agenda. Models are envisioned as an integral part of research, planning, and evaluation, and modelers should ideally be integrated into multidisciplinary teams to update the models iteratively, communicate their appropriate use, and serve the needs of other research scientists, public health specialists, and government officials. A competitive and collaborative framework will result in policy recommendations from multiple, independently derived models and model systems that share harmonized databases. As planned, modeling results will be produced in five priority areas: (1) strategic planning to determine where and when resources should be optimally allocated to achieve eradication; (2) management plans to minimize the evolution of drug and pesticide resistance; (3) impact assessments of new and needed tools to interrupt transmission; (4) technical feasibility assessments to determine appropriate combinations of tools, an associated set of target intervention coverage levels, and the expected timelines for achieving a set of goals in different socio-ecological settings and different health systems; and (5) operational feasibility assessments to weigh the economic costs, capital investments, and human resource capacities required. PMID- 21283606 TI - The influence of distance and level of care on delivery place in rural Zambia: a study of linked national data in a geographic information system. AB - BACKGROUND: Maternal and perinatal mortality could be reduced if all women delivered in settings where skilled attendants could provide emergency obstetric care (EmOC) if complications arise. Research on determinants of skilled attendance at delivery has focussed on household and individual factors, neglecting the influence of the health service environment, in part due to a lack of suitable data. The aim of this study was to quantify the effects of distance to care and level of care on women's use of health facilities for delivery in rural Zambia, and to compare their population impact to that of other important determinants. METHODS AND FINDINGS: Using a geographic information system (GIS), we linked national household data from the Zambian Demographic and Health Survey 2007 with national facility data from the Zambian Health Facility Census 2005 and calculated straight-line distances. Health facilities were classified by whether they provided comprehensive EmOC (CEmOC), basic EmOC (BEmOC), or limited or substandard services. Multivariable multilevel logistic regression analyses were performed to investigate the influence of distance to care and level of care on place of delivery (facility or home) for 3,682 rural births, controlling for a wide range of confounders. Only a third of rural Zambian births occurred at a health facility, and half of all births were to mothers living more than 25 km from a facility of BEmOC standard or better. As distance to the closest health facility doubled, the odds of facility delivery decreased by 29% (95% CI, 14% 40%). Independently, each step increase in level of care led to 26% higher odds of facility delivery (95% CI, 7%-48%). The population impact of poor geographic access to EmOC was at least of similar magnitude as that of low maternal education, household poverty, or lack of female autonomy. CONCLUSIONS: Lack of geographic access to emergency obstetric care is a key factor explaining why most rural deliveries in Zambia still occur at home without skilled care. Addressing geographic and quality barriers is crucial to increase service use and to lower maternal and perinatal mortality. Linking datasets using GIS has great potential for future research and can help overcome the neglect of health system factors in research and policy. Please see later in the article for the Editors' Summary. PMID- 21283607 TI - Nematodes go viral. PMID- 21283608 TI - Natural and experimental infection of Caenorhabditis nematodes by novel viruses related to nodaviruses. AB - An ideal model system to study antiviral immunity and host-pathogen co-evolution would combine a genetically tractable small animal with a virus capable of naturally infecting the host organism. The use of C. elegans as a model to define host-viral interactions has been limited by the lack of viruses known to infect nematodes. From wild isolates of C. elegans and C. briggsae with unusual morphological phenotypes in intestinal cells, we identified two novel RNA viruses distantly related to known nodaviruses, one infecting specifically C. elegans (Orsay virus), the other C. briggsae (Santeuil virus). Bleaching of embryos cured infected cultures demonstrating that the viruses are neither stably integrated in the host genome nor transmitted vertically. 0.2 um filtrates of the infected cultures could infect cured animals. Infected animals continuously maintained viral infection for 6 mo (~50 generations), demonstrating that natural cycles of horizontal virus transmission were faithfully recapitulated in laboratory culture. In addition to infecting the natural C. elegans isolate, Orsay virus readily infected laboratory C. elegans mutants defective in RNAi and yielded higher levels of viral RNA and infection symptoms as compared to infection of the corresponding wild-type N2 strain. These results demonstrated a clear role for RNAi in the defense against this virus. Furthermore, different wild C. elegans isolates displayed differential susceptibility to infection by Orsay virus, thereby affording genetic approaches to defining antiviral loci. This discovery establishes a bona fide viral infection system to explore the natural ecology of nematodes, host-pathogen co-evolution, the evolution of small RNA responses, and innate antiviral mechanisms. PMID- 21283609 TI - Clusters of temporal discordances reveal distinct embryonic patterning mechanisms in Drosophila and anopheles. AB - Evolutionary innovations can be driven by spatial and temporal changes in gene expression. Several such differences have been documented in the embryos of lower and higher Diptera. One example is the reduction of the ancient extraembryonic envelope composed of amnion and serosa as seen in mosquitoes to the single amnioserosa of fruit flies. We used transcriptional datasets collected during the embryonic development of the fruit fly, Drosophila melanogaster, and the malaria mosquito, Anopheles gambiae, to search for whole-genome changes in gene expression underlying differences in their respective embryonic morphologies. We found that many orthologous gene pairs could be clustered based on the presence of coincident discordances in their temporal expression profiles. One such cluster contained genes expressed specifically in the mosquito serosa. As shown previously, this cluster is re-deployed later in development at the time of cuticle synthesis. In addition, there is a striking difference in the temporal expression of a subset of maternal genes. Specifically, maternal transcripts that exhibit a sharp reduction at the time of the maternal-zygotic transition in Drosophila display sustained expression in the Anopheles embryo. We propose that gene clustering by local temporal discordance can be used for the de novo identification of the gene batteries underlying morphological diversity. PMID- 21283610 TI - Gender-associated genes in filarial nematodes are important for reproduction and potential intervention targets. AB - BACKGROUND: A better understanding of reproductive processes in parasitic nematodes may lead to development of new anthelmintics and control strategies for combating disabling and disfiguring neglected tropical diseases such as lymphatic filariasis and onchocerciasis. Transcriptomatic analysis has provided important new insights into mechanisms of reproduction and development in other invertebrates. We have performed the first genome-wide analysis of gender associated (GA) gene expression in a filarial nematode to improve understanding of key reproductive processes in these parasites. METHODOLOGY/PRINCIPAL FINDINGS: The Version 2 Filarial Microarray with 18,104 elements representing ~85% of the filarial genome was used to identify GA gene transcripts in adult Brugia malayi worms. Approximately 19% of 14,293 genes were identified as GA genes. Many GA genes have potential Caenorhabditis elegans homologues annotated as germline-, oogenesis-, spermatogenesis-, and early embryogenesis- enriched. The potential C. elegans homologues of the filarial GA genes have a higher frequency of severe RNAi phenotypes (such as lethal and sterility) than other C. elegans genes. Molecular functions and biological processes associated with GA genes were gender segregated. Peptidase, ligase, transferase, regulator activity for kinase and transcription, and rRNA and lipid binding were associated with female GA genes. In contrast, catalytic activity from kinase, ATP, and carbohydrate binding were associated with male GA genes. Cell cycle, transcription, translation, and biological regulation were increased in females, whereas metabolic processes of phosphate and carbohydrate metabolism, energy generation, and cell communication were increased in males. Significantly enriched pathways in females were associated with cell growth and protein synthesis, whereas metabolic pathways such as pentose phosphate and energy production pathways were enriched in males. There were also striking gender differences in environmental information processing and cell communication pathways. Many proteins encoded by GA genes are secreted by Brugia malayi, and these encode immunomodulatory molecules such as antioxidants and host cytokine mimics. Expression of many GA genes has been recently reported to be suppressed by tetracycline, which blocks reproduction in female Brugia malayi. Our localization of GA transcripts in filarial reproductive organs supports the hypothesis that these genes encode proteins involved in reproduction. CONCLUSIONS/SIGNIFICANCE: Genome-wide expression profiling coupled with a robust bioinformatics analysis has greatly expanded our understanding of the molecular biology of reproduction in filarial nematodes. This study has highlighted key molecules and pathways associated with reproductive and other biological processes and identified numerous potential candidates for rational drug design to target reproductive processes. PMID- 21283611 TI - The cholera pandemic, still with us after half a century: time to rethink. PMID- 21283612 TI - Muscle-sparing approach for recurrent hydatidosis of the thigh and psoas: report of a rare case. PMID- 21283613 TI - Evaluation of urine CCA assays for detection of Schistosoma mansoni infection in Western Kenya. AB - Although accurate assessment of the prevalence of Schistosoma mansoni is important for the design and evaluation of control programs, the most widely used tools for diagnosis are limited by suboptimal sensitivity, slow turn-around-time, or inability to distinguish current from former infections. Recently, two tests that detect circulating cathodic antigen (CCA) in urine of patients with schistosomiasis became commercially available. As part of a larger study on schistosomiasis prevalence in young children, we evaluated the performance and diagnostic accuracy of these tests--the carbon test strip designed for use in the laboratory and the cassette format test intended for field use. In comparison to 6 Kato-Katz exams, the carbon and cassette CCA tests had sensitivities of 88.4% and 94.2% and specificities of 70.9% and 59.4%, respectively. However, because of the known limitations of the Kato-Katz assay, we also utilized latent class analysis (LCA) incorporating the CCA, Kato-Katz, and schistosome-specific antibody results to determine their sensitivities and specificities. The laboratory-based CCA test had a sensitivity of 91.7% and a specificity of 89.4% by LCA while the cassette test had a sensitivity of 96.3% and a specificity of 74.7%. The intensity of the reaction in both urine CCA tests reflected stool egg burden and their performance was not affected by the presence of soil transmitted helminth infections. Our results suggest that urine-based assays for CCA may be valuable in screening for S. mansoni infections. PMID- 21283614 TI - The case for reactive mass oral cholera vaccinations. AB - INTRODUCTION: The outbreak of cholera in Zimbabwe intensified interest in the control and prevention of cholera. While there is agreement that safe water, sanitation, and personal hygiene are ideal for the long term control of cholera, there is controversy about the role of newer approaches such as oral cholera vaccines (OCVs). In October 2009 the Strategic Advisory Group of Experts advised the World Health Organization to consider reactive vaccination campaigns in response to large cholera outbreaks. To evaluate the potential benefit of this pivotal change in WHO policy, we used existing data from cholera outbreaks to simulate the number of cholera cases preventable by reactive mass vaccination. METHODS: Datasets of cholera outbreaks from three sites with varying cholera endemicity--Zimbabwe, Kolkata (India), and Zanzibar (Tanzania)--were analysed to estimate the number of cholera cases preventable under differing response times, vaccine coverage, and vaccine doses. FINDINGS: The large cholera outbreak in Zimbabwe started in mid August 2008 and by July 2009, 98,591 cholera cases had been reported with 4,288 deaths attributed to cholera. If a rapid response had taken place and half of the population had been vaccinated once the first 400 cases had occurred, as many as 34,900 (40%) cholera cases and 1,695 deaths (40%) could have been prevented. In the sites with endemic cholera, Kolkata and Zanzibar, a significant number of cases could have been prevented but the impact would have been less dramatic. A brisk response is required for outbreaks with the majority of cases occurring during the early weeks. Even a delayed response can save a substantial number of cases and deaths in long, drawn-out outbreaks. If circumstances prevent a rapid response there are good reasons to roll out cholera mass vaccination campaigns well into the outbreak. Once a substantial proportion of a population is vaccinated, outbreaks in subsequent years may be reduced if not prevented. A single dose vaccine would be of advantage in short, small outbreaks. CONCLUSIONS: We show that reactive vaccine use can prevent cholera cases and is a rational response to cholera outbreaks in endemic and non endemic settings. In large and long outbreaks a reactive vaccination with a two dose vaccine can prevent a substantial proportion of cases. To make mass vaccination campaigns successful, it would be essential to agree when to implement reactive vaccination campaigns and to have a dynamic and determined response team that is familiar with the logistic challenges on standby. Most importantly, the decision makers in donor and recipient countries have to be convinced of the benefit of reactive cholera vaccinations. PMID- 21283615 TI - Cystic echinococcosis in Spain: current situation and relevance for other endemic areas in Europe. AB - Cystic echinococcosis (CE) remains an important health problem in many regions of the world, both where no control measures have been implemented, and where control programs have been incompletely successful with ensuing re-emergence of the disease. In Spain, official data on CE show an increase in the proportion of intermediate hosts with CE during the last few years, and autochthonous pediatric patients have been reported, a sign of active local transmission of disease. A similar picture emerges from data reported to the European Food Safety Authority by other European countries. Nevertheless, several crucial aspects related to CE that would help better understand and control the disease have not been tackled appropriately, in particular the emergence of infection in specific geographical areas. In this respect, while some data are missing, other data are conflicting because they come from different databases. We review the current situation of CE in Spain compared with areas in which similar problems in the CE field exist, and offer recommendations on how to overcome those limitations. Specifically, we believe that the introduction of national registries for CE with online data entry, following the example set by the European Registry for Alveolar Echinococcosis, would help streamline data collection on CE by eliminating the need for evaluating and integrating data from multiple regions, by avoiding duplication of data from patients who access several different health facilities over time, and by providing much needed clinical and epidemiological data that are currently accessible only to clinicians. PMID- 21283616 TI - Use of oral cholera vaccines in an outbreak in Vietnam: a case control study. AB - BACKGROUND: Killed oral cholera vaccines (OCVs) are available but not used routinely for cholera control except in Vietnam, which produces its own vaccine. In 2007-2008, unprecedented cholera outbreaks occurred in the capital, Hanoi, prompting immunization in two districts. In an outbreak investigation, we assessed the effectiveness of killed OCV use after a cholera outbreak began. METHODOLOGY/PRINCIPAL FINDINGS: From 16 to 28 January 2008, vaccination campaigns with the Vietnamese killed OCV were held in two districts of Hanoi. No cholera cases were detected from 5 February to 4 March 2008, after which cases were again identified. Beginning 8 April 2008, residents of four districts of Hanoi admitted to one of five hospitals for acute diarrhea with onset after 5 March 2008 were recruited for a matched, hospital-based, case-control outbreak investigation. Cases were matched by hospital, admission date, district, gender, and age to controls admitted for non-diarrheal conditions. Subjects from the two vaccinated districts were evaluated to determine vaccine effectiveness. 54 case-control pairs from the vaccinated districts were included in the analysis. There were 8 (15%) and 16 (30%) vaccine recipients among cases and controls, respectively. The vaccine was 76% protective against cholera in this setting (95% CI 5% to 94%, P = 0.042) after adjusting for intake of dog meat or raw vegetables and not drinking boiled or bottled water most of the time. CONCLUSIONS/SIGNIFICANCE: This is the first study to explore the effectiveness of the reactive use of killed OCVs during a cholera outbreak. Our findings suggest that killed OCVs may have a role in controlling cholera outbreaks. PMID- 21283617 TI - 30 Year patterns of mortality in Tobago, West Indies, 1976-2005: impact of glucose intolerance and alcohol intake. AB - OBJECTIVES: To determine the main predictors of all-cause and cardiovascular (CV) mortality in a rural West Indian population in Plymouth, Tobago over 30 years. METHODS: Questionnaire survey for CV risk factors and alcohol consumption patterns administered at baseline in 1976 with 92.5% response rate. 831/832 patients were followed up until 2005 or death. RESULTS: Hypertension (>140/90 mm Hg) was prevalent in 48% of men and 44% of women, and 21% of men and 17% of women had diabetes. Evidence showed most predictors for all cause and cardiovascular mortality having the main effects at ages <60 years, (p-value for interaction<0.01) but no risk factors having sex-specific effects on mortality. The main predictors of all-cause mortality at age <60 years in the fully adjusted model were high sessional alcohol intake (hazard ratio (HR) 2.04, 95% CI 1.10 3.80), severe hypertension >160/95 mm Hg (HR 1.68, 95% CI 1.09-2.60), diabetes (HR 3.28, 95% CI 1.89-5.69), and BMI (HR 1.04, 95% CI 1.00-1.07). The main predictors of cardiovascular mortality were similar in the fully adjusted model: high sessional alcohol intake (HR 2.47 95% CI 1.10-5.57), severe hypertension (HR 2.78 95% CI 1.56-4.95), diabetes (HR 3.68 95% CI 1.77-7.67) and additionally LVH, (HR 5.54 95% CI 1.38-22.26), however BMI did not show independent effects. For men, high sessional alcohol intake explains 27% of all cause mortality, and 40% of cardiovascular mortality at age <60 yrs. In adults aged <60 years, the attributable risk fraction for IGT/Diabetes and all cause mortality and cardiovascular mortality is 28% in women vs. 11% in men, and 22% in women vs. 6% in men respectively. CONCLUSIONS: In this Afro-Caribbean population we found that a major proportion of deaths are attributable to high sessional alcohol intake (in males), diabetes, and hypertension and these risk factors primarily operate in those below 60 years. PMID- 21283618 TI - Late entry into HIV care: estimated impact on AIDS mortality rates in Brazil, 2003-2006. AB - BACKGROUND: Worldwide, a high proportion of HIV-infected individuals enter into HIV care late. Here, our objective was to estimate the impact that late entry into HIV care has had on AIDS mortality rates in Brazil. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed data from information systems regarding HIV-infected adults who sought treatment at public health care facilities in Brazil from 2003 to 2006. We initially estimated the prevalence of late entry into HIV care, as well as the probability of death in the first 12 months, the percentage of the risk of death attributable to late entry, and the number of avoidable deaths. We subsequently adjusted the annual AIDS mortality rate by excluding such deaths. Of the 115,369 patients evaluated, 50,358 (43.6%) had entered HIV care late, and 18,002 died in the first 12 months, representing a 16.5% probability of death in the first 12 months (95% CI: 16.3-16.7). By comparing patients who entered HIV care late with those who gained timely access, we found that the risk ratio for death was 49.5 (95% CI: 45.1-54.2). The percentage of the risk of death attributable to late entry was 95.5%, translating to 17,189 potentially avoidable deaths. Averting those deaths would have lowered the 2003-2006 AIDS mortality rate by 39.5%. Including asymptomatic patients with CD4(+) T cell counts >200 and <= 350 cells/mm(3) in the group who entered HIV care late increased this proportion by 1.8%. CONCLUSIONS/SIGNIFICANCE: In Brazil, antiretroviral drugs reduced AIDS mortality by 43%. Timely entry would reduce that rate by a similar proportion, as well as resulting in a 45.2% increase in the effectiveness of the program for HIV care. The World Health Organization recommendation that asymptomatic patients with CD4(+) T cell counts <= 350 cells/mm(3) be treated would not have a significant impact on this scenario. PMID- 21283619 TI - Site-specific integration and expression of an anti-malarial gene in transgenic Anopheles gambiae significantly reduces Plasmodium infections. AB - Diseases transmitted by mosquitoes have a devastating impact on global health and this is worsening due to difficulties with existing control measures and climate change. Genetically modified mosquitoes that are refractory to disease transmission are seen as having great potential in the delivery of novel control strategies. Historically the genetic modification of insects has relied upon transposable elements which have many limitations despite their successful use. To circumvent these limitations the Streptomyces phage phiC31 integrase system has been successfully adapted for site-specific transgene integration in insects. Here, we present the first site-specific transformation of Anopheles gambiae, the principal vector of human malaria. Mosquitoes were initially engineered to incorporate the phiC31 targeting site at a defined genomic location. A second phase of genetic modification then achieved site-specific integration of Vida3, a synthetic anti-malarial gene. Expression of Vida3, specifically in the midgut of bloodfed females, offered consistent and significant protection against Plasmodium yoelii nigeriensis, reducing average parasite intensity by 85%. Similar protection was observed against Plasmodium falciparum in some experiments, although protection was inconsistent. In the fight against malaria, it is imperative to establish a broad repertoire of both anti-malarial effector genes and tissue-specific promoters for their expression, enabling those offering maximum effect with minimum fitness cost to be identified. In the future, this technology will allow effective comparisons and informed choices to be made, potentially leading to complete transmission blockade. PMID- 21283620 TI - Sequencing and bioinformatics-based analyses of the microRNA transcriptome in hepatitis B-related hepatocellular carcinoma. AB - MicroRNAs (miRNAs) participate in crucial biological processes, and it is now evident that miRNA alterations are involved in the progression of human cancers. Recent studies on miRNA profiling performed with cloning suggest that sequencing is useful for the detection of novel miRNAs, modifications, and precise compositions and that miRNA expression levels calculated by clone count are reproducible. Here we focus on sequencing of miRNA to obtain a comprehensive profile and characterization of these transcriptomes as they relate to human liver. Sequencing using 454 sequencing and conventional cloning from 22 pair of HCC and adjacent normal liver (ANL) and 3 HCC cell lines identified reliable reads of more than 314000 miRNAs from HCC and more than 268000 from ANL for registered human miRNAs. Computational bioinformatics identified 7 novel miRNAs with high conservation, 15 novel opposite miRNAs, and 3 novel antisense miRNAs. Moreover sequencing can detect miRNA modifications including adenosine-to-inosine editing in miR-376 families. Expression profiling using clone count analysis was used to identify miRNAs that are expressed aberrantly in liver cancer including miR-122, miR-21, and miR-34a. Furthermore, sequencing-based miRNA clustering, but not individual miRNA, detects high risk patients who have high potentials for early tumor recurrence after liver surgery (P = 0.006), and which is the only significant variable among pathological and clinical and variables (P = 0,022). We believe that the combination of sequencing and bioinformatics will accelerate the discovery of novel miRNAs and biomarkers involved in human liver cancer. PMID- 21283621 TI - The cytoskeletal protein Ndel1 regulates dynamin 2 GTPase activity. AB - Cytoskeleton dynamics, membranes trafficking and positioning are essential for the proper functioning of any mammalian cell. The identification of the molecules and mechanisms that allow these cellular processes to interface is vital for understanding cell behaviors. Ndel1, the mammalian homolog of the Aspergillus nidulans NudE, organizes the cytoskeleton and regulates molecular motors, thereby impacting on the positioning of membranes. Hypothetically, Ndel1 can act in concert with enzymes controlling membrane trafficking (vesicle-mediated transport) per se, but this idea has never been investigated. We now report that a pool of Ndel1 associates directly with Dynamin 2 (Dyn2), a large cytosolic GTPase involved in the trafficking of the AMPA receptor subunit GluR1. In vitro, Ndel1 enhances Dyn2 GTPase activity in its unassembled and assembled forms, without promoting oligomerization of the enzyme. In cells, gain and loss of function of Ndel1 recapitulate the effects of overexpression of Dyn2 and Dyn2 dominant negative with reduced GTPase activity on the intracellular localization of GluR1, respectively, without affecting the stability of microtubules. Together, these results indicate that Ndel1 regulates Dyn2 GTPase activity and impacts GluR1-containing membranes distribution in a manner reminiscent of Dyn2. PMID- 21283622 TI - Brain cells in the avian 'prefrontal cortex' code for features of slot-machine like gambling. AB - Slot machines are the most common and addictive form of gambling. In the current study, we recorded from single neurons in the 'prefrontal cortex' of pigeons while they played a slot-machine-like task. We identified four categories of neurons that coded for different aspects of our slot-machine-like task. Reward Proximity neurons showed a linear increase in activity as the opportunity for a reward drew near. I-Won neurons fired only when the fourth stimulus of a winning (four-of-a-kind) combination was displayed. I-Lost neurons changed their firing rate at the presentation of the first nonidentical stimulus, that is, when it was apparent that no reward was forthcoming. Finally, Near-Miss neurons also changed their activity the moment it was recognized that a reward was no longer available, but more importantly, the activity level was related to whether the trial contained one, two, or three identical stimuli prior to the display of the nonidentical stimulus. These findings not only add to recent neurophysiological research employing simulated gambling paradigms, but also add to research addressing the functional correspondence between the avian NCL and primate PFC. PMID- 21283623 TI - Assessment of virally vectored autoimmunity as a biocontrol strategy for cane toads. AB - BACKGROUND: The cane toad, Bufo (Chaunus) marinus, is one of the most notorious vertebrate pests introduced into Australia over the last 200 years and, so far, efforts to identify a naturally occurring B. marinus-specific pathogen for use as a biological control agent have been unsuccessful. We explored an alternative approach that entailed genetically modifying a pathogen with broad host specificity so that it no longer caused disease, but carried a gene to disrupt the cane toad life cycle in a species specific manner. METHODOLOGY/PRINCIPAL FINDINGS: The adult beta globin gene was selected as the model gene for proof of concept of autoimmunity as a biocontrol method for cane toads. A previous report showed injection of bullfrog tadpoles with adult beta globin resulted in an alteration in the form of beta globin expressed in metamorphs as well as reduced survival. In B. marinus we established for the first time that the switch from tadpole to adult globin exists. The effect of injecting B. marinus tadpoles with purified recombinant adult globin protein was then assessed using behavioural (swim speed in tadpoles and jump length in metamorphs), developmental (time to metamorphosis, weight and length at various developmental stages, protein profile of adult globin) and genetic (adult globin mRNA levels) measures. However, we were unable to detect any differences between treated and control animals. Further, globin delivery using Bohle iridovirus, an Australian ranavirus isolate belonging to the Iridovirus family, did not reduce the survival of metamorphs or alter the form of beta globin expressed in metamorphs. CONCLUSIONS/SIGNIFICANCE: While we were able to show for the first time that the switch from tadpole to adult globin does occur in B. marinus, we were not able to induce autoimmunity and disrupt metamorphosis. The short development time of B. marinus tadpoles may preclude this approach. PMID- 21283624 TI - Contributions made by CDC25 phosphatases to proliferation of intestinal epithelial stem and progenitor cells. AB - The CDC25 protein phosphatases drive cell cycle advancement by activating cyclin dependent protein kinases (CDKs). Humans and mice encode three family members denoted CDC25A, -B and -C and genes encoding these family members can be disrupted individually with minimal phenotypic consequences in adult mice. However, adult mice globally deleted for all three phosphatases die within one week after Cdc25 disruption. A severe loss of absorptive villi due to a failure of crypt epithelial cells to proliferate was observed in the small intestines of these mice. Because the Cdc25s were globally deleted, the small intestinal phenotype and loss of animal viability could not be solely attributed to an intrinsic defect in the inability of small intestinal stem and progenitor cells to divide. Here, we report the consequences of deleting different combinations of Cdc25s specifically in intestinal epithelial cells. The phenotypes arising in these mice were then compared with those arising in mice globally deleted for the Cdc25s and in mice treated with irinotecan, a chemotherapeutic agent commonly used to treat colorectal cancer. We report that the phenotypes arising in mice globally deleted for the Cdc25s are due to the failure of small intestinal stem and progenitor cells to proliferate and that blocking cell division by inhibiting the cell cycle engine (through Cdc25 loss) versus by inducing DNA damage (via irinotecan) provokes a markedly different response of small intestinal epithelial cells. Finally, we demonstrate that CDC25A and CDC25B but not CDC25C compensate for each other to maintain the proliferative capacity of intestinal epithelial stem and progenitor cells. PMID- 21283625 TI - Mechanisms promoting the long-term persistence of a Wolbachia infection in a laboratory-adapted population of Drosophila melanogaster. AB - Intracellular bacteria of the genus Wolbachia are widespread endosymbionts across diverse insect taxa. Despite this prevalence, our understanding of how Wolbachia persists within populations is not well understood. Cytoplasmic incompatibility (CI) appears to be an important phenotype maintaining Wolbachia in many insects, but it is believed to be too weak to maintain Wolbachia in Drosophila melanogaster, suggesting that Wolbachia must also have other effects on this species. Here we estimate the net selective effect of Wolbachia on its host in a laboratory-adapted population of D. melanogaster, to determine the mechanisms leading to its persistence in the laboratory environment. We found i) no significant effects of Wolbachia infection on female egg-to-adult survival or adult fitness, ii) no reduced juvenile survival in males, iii) substantial levels of CI, and iv) a vertical transmission rate of Wolbachia higher than 99%. The fitness of cured females was, however, severely reduced (a decline of 37%) due to CI in offspring. Taken together these findings indicate that Wolbachia is maintained in our laboratory environment due to a combination of a nearly perfect transmission rate and substantial CI. Our results show that there would be strong selection against females losing their infection and producing progeny free from Wolbachia. PMID- 21283626 TI - MoVam7, a conserved SNARE involved in vacuole assembly, is required for growth, endocytosis, ROS accumulation, and pathogenesis of Magnaporthe oryzae. AB - Soluble NSF attachment protein receptor (SNARE) proteins play a central role in membrane fusion and vesicle transport of eukaryotic organisms including fungi. We previously identified MoSce22 as a homolog of Saccharomyces cerevisiae SNARE protein Sec22 to be involved in growth, stress resistance, and pathogenicity of Magnaporthe oryzae. Here, we provide evidences that MoVam7, an ortholog of S. cerevisiae SNARE protein Vam7, exerts conserved functions in vacuolar morphogenesis and functions in pathogenicity of M. oryzae. Staining with neutral red and FM4-64 revealed the presence of abnormal fragmented vacuoles and an absence of the Spitzenkorper body in the DeltaMovam7 mutant. The DeltaMovam7 mutant also exhibited reduced vegetative growth, poor conidiation, and failure to produce the infection structure appressorium. Additionally, treatments with cell wall perturbing agents indicated weakened cell walls and altered distributions of the cell wall component chitin. Furthermore, the DeltaMovam7 mutant showed a reduced accumulation of reactive oxygen species (ROS) in the hyphal apex and failed to cause diseases on the rice plant. In summary, our studies indicate that MoVam7, like MoSec22, is a component of the SNARE complex whose functions in vacuole assembly also underlies the growth, conidiation, appressorium formation, and pathogenicity of M. oryzae. Further studies of MoVam7, MoSec22, and additional members of the SNARE complex are likely to reveal critical mechanisms in vacuole formation and membrane trafficking that is linked to fungal pathogenicity. PMID- 21283627 TI - Unveiling the role of Dps in the organization of mycobacterial nucleoid. AB - In order to preserve genetic information in stress conditions, bacterial DNA is organized into higher order nucleoid structure. In this paper, with the help of Atomic Force Microscopy, we show the different structural changes in mycobacterial nucleoid at different points of growth in the presence of different concentrations of glucose in the medium. We also observe that in Mycobacterium smegmatis, two different Dps proteins (Dps1 and Dps2) promote two types of nucleoid organizations. At the late stationary phase, under low glucose availability, Dps1 binds to DNA to form a very stable toroid structure. On the other hand, under the same condition, Dps2-DNA complex forms an incompletely condensed toroid and finally forms a further stable coral reef structure in the presence of RNA. This coral reef structure is stable in high concentration of bivalent ion like Mg(2+). PMID- 21283628 TI - E2F1 regulates cellular growth by mTORC1 signaling. AB - During cell proliferation, growth must occur to maintain homeostatic cell size. Here we show that E2F1 is capable of inducing growth by regulating mTORC1 activity. The activation of cell growth and mTORC1 by E2F1 is dependent on both E2F1's ability to bind DNA and to regulate gene transcription, demonstrating that a gene induction expression program is required in this process. Unlike E2F1, E2F3 is unable to activate mTORC1, suggesting that growth activity could be restricted to individual E2F members. The effect of E2F1 on the activation of mTORC1 does not depend on Akt. Furthermore, over-expression of TSC2 does not interfere with the effect of E2F1, indicating that the E2F1-induced signal pathway can compensate for the inhibitory effect of TSC2 on Rheb. Immunolocalization studies demonstrate that E2F1 induces the translocation of mTORC1 to the late endosome vesicles, in a mechanism dependent of leucine. E2F1 and leucine, or insulin, together affect the activation of S6K stronger than alone suggesting that they are complementary in activating the signal pathway. From these studies, E2F1 emerges as a key protein that integrates cell division and growth, both of which are essential for cell proliferation. PMID- 21283629 TI - LZAP inhibits p38 MAPK (p38) phosphorylation and activity by facilitating p38 association with the wild-type p53 induced phosphatase 1 (WIP1). AB - LZAP (Cdk5rap3, C53) is a putative tumor suppressor that inhibits RelA, Chk1 and Chk2 and activates p53. LZAP is lost in a portion of human head and neck squamous cell carcinoma and experimental loss of LZAP expression is associated with enhanced invasion, xenograft tumor growth and angiogenesis. p38 MAPK can increase or decrease proliferation and cell death depending on cellular context. LZAP has no known enzymatic activity, implying that its biological functions are likely mediated by its protein-protein interactions. To gain further insight into LZAP activities, we searched for LZAP-associated proteins (LAPs). Here we show that the LZAP binds p38, alters p38 cellular localization, and inhibits basal and cytokine-stimulated p38 activity. Expression of LZAP inhibits p38 phosphorylation in a dose-dependent fashion while loss of LZAP enhances phosphorylation and activation with resultant phosphorylation of p38 downstream targets. Mechanistically, the ability of LZAP to alter p38 phosphorylation depended, at least partially, on the p38 phosphatase, Wip1. Expression of LZAP increased both LZAP and Wip1 binding to p38. Taken together, these data suggest that LZAP activity includes inhibition of p38 phosphorylation and activation. PMID- 21283630 TI - Improved survival, vascular differentiation and wound healing potential of stem cells co-cultured with endothelial cells. AB - In this study, we developed a methodology to improve the survival, vascular differentiation and regenerative potential of umbilical cord blood (UCB)-derived hematopoietic stem cells (CD34(+) cells), by co-culturing the stem cells in a 3D fibrin gel with CD34(+)-derived endothelial cells (ECs). ECs differentiated from CD34(+) cells appear to have superior angiogenic properties to fully differentiated ECs, such as human umbilical vein endothelial cells (HUVECs). Our results indicate that the pro-survival effect of CD34(+)-derived ECs on CD34(+) cells is mediated, at least in part, by bioactive factors released from ECs. This effect likely involves the secretion of novel cytokines, including interleukin-17 (IL-17) and interleukin-10 (IL-10), and the activation of the ERK 1/2 pathway in CD34(+) cells. We also show that the endothelial differentiation of CD34(+) cells in co-culture with CD34(+)-derived ECs is mediated by a combination of soluble and insoluble factors. The regenerative potential of this co-culture system was demonstrated in a chronic wound diabetic animal model. The co-transplantation of CD34(+) cells with CD34(+)-derived ECs improved the wound healing relatively to controls, by decreasing the inflammatory reaction and increasing the neovascularization of the wound. PMID- 21283631 TI - Vectors based on modified vaccinia Ankara expressing influenza H5N1 hemagglutinin induce substantial cross-clade protective immunity. AB - BACKGROUND: New highly pathogenic H5N1 influenza viruses are continuing to evolve with a potential threat for an influenza pandemic. So far, the H5N1 influenza viruses have not widely circulated in humans and therefore constitute a high risk for the non immune population. The aim of this study was to evaluate the cross protective potential of the hemagglutinins of five H5N1 strains of divergent clades using a live attenuated modified vaccinia Ankara (MVA) vector vaccine. METHODOLOGY/PRINCIPAL FINDINGS: The replication-deficient MVA virus was used to express influenza hemagglutinin (HA) proteins. Specifically, recombinant MVA viruses expressing the HA genes of the clade 1 virus A/Vietnam/1203/2004 (VN/1203), the clade 2.1.3 virus A/Indonesia/5/2005 (IN5/05), the clade 2.2 viruses A/turkey/Turkey/1/2005 (TT01/05) and A/chicken/Egypt/3/2006 (CE/06), and the clade 2.3.4 virus A/Anhui/1/2005 (AH1/05) were constructed. These experimental live vaccines were assessed in a lethal mouse model. Mice vaccinated with the VN/1203 hemagglutinin-expressing MVA induced excellent protection against all the above mentioned clades. Also mice vaccinated with the IN5/05 HA expressing MVA induced substantial protection against homologous and heterologous AH1/05 challenge. After vaccination with the CE/06 HA expressing MVA, mice were fully protected against clade 2.2 challenge and partially protected against challenge of other clades. Mice vaccinated with AH1/05 HA expressing MVA vectors were only partially protected against homologous and heterologous challenge. The live vaccines induced substantial amounts of neutralizing antibodies, mainly directed against the homologous challenge virus, and high levels of HA-specific IFN-gamma secreting CD4 and CD8 T-cells against epitopes conserved among the H5 clades and subclades. CONCLUSIONS/SIGNIFICANCE: The highest level of cross protection was induced by the HA derived from the VN/1203 strain, suggesting that pandemic H5 vaccines utilizing MVA vector technology, should be based on the VN/1203 hemagglutinin. Furthermore, the recombinant MVA-HA-VN, as characterized in the present study, would be a promising candidate for such a vaccine. PMID- 21283632 TI - The cost of sex: quantifying energetic investment in gamete production by males and females. AB - The relative energetic investment in reproduction between the sexes forms the basis of sexual selection and life history theories in evolutionary biology. It is often assumed that males invest considerably less in gametes than females, but quantifying the energetic cost of gamete production in both sexes has remained a difficult challenge. For a broad diversity of species (invertebrates, reptiles, amphibians, fishes, birds, and mammals), we compared the cost of gamete production between the sexes in terms of the investment in gonad tissue and the rate of gamete biomass production. Investment in gonad biomass was nearly proportional to body mass in both sexes, but gamete biomass production rate was approximately two to four orders of magnitude higher in females. In both males and females, gamete biomass production rate increased with organism mass as a power law, much like individual metabolic rate. This suggests that whole-organism energetics may act as a primary constraint on gamete production among species. Residual variation in sperm production rate was positively correlated with relative testes size. Together, these results suggest that understanding the heterogeneity in rates of gamete production among species requires joint consideration of the effects of gonad mass and metabolism. PMID- 21283633 TI - Diagnostic accuracy of real-time PCR assays targeting 16S rRNA and lipL32 genes for human leptospirosis in Thailand: a case-control study. AB - BACKGROUND: Rapid PCR-based tests for the diagnosis of leptospirosis can provide information that contributes towards early patient management, but these have not been adopted in Thailand. Here, we compare the diagnostic sensitivity and specificity of two real-time PCR assays targeting rrs or lipL32 for the diagnosis of leptospirosis in northeast Thailand. METHODS/PRINCIPAL FINDINGS: A case control study of 266 patients (133 cases of leptospirosis and 133 controls) was constructed to evaluate the diagnostic sensitivity and specificity (DSe & DSp) of both PCR assays. The median duration of illness prior to admission of cases was 4 days (IQR 2-5 days; range 1-12 days). DSe and DSp were determined using positive culture and/or microscopic agglutination test (MAT) as the gold standard. The DSe was higher for the rrs assay than the lipL32 assay (56%, (95% CI 47-64%) versus 43%, (95% CI 34-52%), p<0.001). No cases were positive for the lipL32 assay alone. There was borderline evidence to suggest that the DSp of the rrs assay was lower than the lipL32 assay (90% (95% CI 83-94%) versus 93%, (95%CI 88-97%), p = 0.06). Nine controls gave positive reactions for both assays and 5 controls gave a positive reaction for the rrs assay alone. The DSe of the rrs and lipL32 assays were high in the subgroup of 39 patients who were culture positive for Leptospira spp. (95% and 87%, respectively, p = 0.25). CONCLUSIONS/SIGNIFICANCE: Early detection of Leptospira using PCR is possible for more than half of patients presenting with leptospirosis and could contribute to individual patient care. PMID- 21283634 TI - Tumor suppression by RNA from C/EBPbeta 3'UTR through the inhibition of protein kinase Cepsilon activity. AB - BACKGROUND: Since the end of last century, RNAs from the 3'untranslated region (3'UTR) of several eukaryotic mRNAs have been found to exert tumor suppression activity when introduced into malignant cells independent of their whole mRNAs. In this study, we sought to determine the molecular mechanism of the tumor suppression activity of a short RNA from 3'UTR of C/EBPbeta mRNuAlpha (C/EBPbeta 3'UTR RNA) in human hepatocarcinoma cells SMMC-7721. METHODOLOGY/PRINCIPAL FINDINGS: By using Western blotting, immunocytochemistry, molecular beacon, confocal microscopy, protein kinase inhibitors and in vitro kinase assays, we found that, in the C/EBPbeta 3'UTR-transfectant cells of SMMC-7721, the overexpressed C/EBPbeta 3'UTR RNA induced reorganization of keratin 18 by binding to this keratin; that the C/EBPbeta 3'UTR RNA also reduced phosphorylation and expression of keratin 18; and that the enzyme responsible for phosphorylating keratin 18 is protein kinase Cepsilon. We then found that the C/EBPbeta 3'UTR RNA directly inhibited the phosphorylating activity of protein kinase Cepsilon; and that C/EBPbeta 3'UTR RNA specifically bound with the protein kinase Cepsilon keratin 18 conjugate. CONCLUSION/SIGNIFICANCE: Together, these facts suggest that the tumor suppression in SMMC-7721 by C/EBPbeta 3'UTR RNA is due to the inhibition of protein kinase Cepsilon activity through direct physical interaction between C/EBPbeta 3'UTR RNA and protein kinase Cepsilon. These facts indicate that the 3'UTR of some eukaryotic mRNAs may function as regulators for genes other than their own. PMID- 21283635 TI - Biophysical characterization of the olfactomedin domain of myocilin, an extracellular matrix protein implicated in inherited forms of glaucoma. AB - Myocilin is an eye protein found in the trabecular extracellular matrix (TEM), within the anatomic region that controls fluid flow. Variants of myocilin, localized to its olfactomedin (OLF) domain, have been linked to inherited forms of glaucoma, a disease associated with elevated intraocular pressure. OLF domains have also been implicated in psychiatric diseases and cancers by their involvement in signaling, neuronal growth, and development. However, molecular characterization of OLFs has been hampered by challenges in recombinant expression, a hurdle we have recently overcome for the myocilin OLF domain (myoc OLF). Here, we report the first detailed solution biophysical characterization of myoc-OLF to gain insight into its structure and function. Myoc-OLF is stable in the presence of glycosaminoglycans, as well as in a wide pH range in buffers with functional groups reminiscent of such glycosaminoglycans. Circular dichroism (CD) reveals significant beta-sheet and beta-turn secondary structure. Unexpectedly, the CD signature is reminiscent of alpha-chymotrypsin as well as another ocular protein family, the betagamma-crystallins. At neutral pH, intrinsic tryptophan fluorescence and CD melts indicate a highly cooperative transition with a melting temperature of ~55 degrees C. Limited proteolysis combined with mass spectrometry reveals that the compact core structural domain of OLF consists of approximately residues 238-461, which retains the single disulfide bond and is as stable as the full myoc-OLF construct. The data presented here inform new testable hypotheses for interactions with specific TEM components, and will assist in design of therapeutic agents for myocilin glaucoma. PMID- 21283636 TI - From L-dopa to dihydroxyphenylacetaldehyde: a toxic biochemical pathway plays a vital physiological function in insects. AB - One protein in Aedes aegypti, classified into the aromatic amino acid decarboxylase (AAAD) family based on extremely high sequence homology (~70%) with dopa decarboxylase (Ddc), was biochemically investigated. Our data revealed that this predicted AAAD protein use L-dopa as a substrate, as does Ddc, but it catalyzes the production of 3,4-dihydroxylphenylacetaldehyde (DHPAA) directly from L-dopa and apparently has nothing to do with the production of any aromatic amine. The protein is therefore named DHPAA synthase. This subsequently led to the identification of the same enzyme in Drosophila melanogaster, Anopheles gambiae and Culex quinquefasciatus by an initial prediction of putative DHPAA synthase based on sequence homology and subsequent verification of DHPAA synthase identity through protein expression and activity assays. DHPAA is highly toxic because its aldehyde group readily reacts with the primary amino groups of proteins, leading to protein crosslinking and inactivation. It has previously been demonstrated by several research groups that Drosophila DHPAA synthase was expressed in tissues that produce cuticle materials and apparent defects in regions of colorless, flexible cuticular structures have been observed in its gene mutants. The presence of free amino groups in proteins, the high reactivity of DHPAA with the free amino groups, and the genetically ascertained function of the Drosophila DHPAA synthase in the formation of colorless, flexible cuticle, when taken together, suggest that mosquito and Drosophila DHPAA synthases are involved in the formation of flexible cuticle through their reactive DHPAA mediated protein crosslinking reactions. Our data illustrate how a seemingly highly toxic pathway can serve for an important physiological function in insects. PMID- 21283637 TI - Evolutionary dynamics of the Ty3/gypsy LTR retrotransposons in the genome of Anopheles gambiae. AB - Ty3/gypsy elements represent one of the most abundant and diverse LTR retrotransposon (LTRr) groups in the Anopheles gambiae genome, but their evolutionary dynamics have not been explored in detail. Here, we conduct an in silico analysis of the distribution and abundance of the full complement of 1045 copies in the updated AgamP3 assembly. Chromosomal distribution of Ty3/gypsy elements is inversely related to arm length, with densities being greatest on the X, and greater on the short versus long arms of both autosomes. Taking into account the different heterochromatic and euchromatic compartments of the genome, our data suggest that the relative abundance of Ty3/gypsy LTRrs along each chromosome arm is determined mainly by the different proportions of heterochromatin, particularly pericentric heterochromatin, relative to total arm length. Additionally, the breakpoint regions of chromosomal inversion 2La appears to be a haven for LTRrs. These elements are underrepresented more than 7-fold in euchromatin, where 33% of the Ty3/gypsy copies are associated with genes. The euchromatin on chromosome 3R shows a faster turnover rate of Ty3/gypsy elements, characterized by a deficit of proviral sequences and the lowest average sequence divergence of any autosomal region analyzed in this study. This probably reflects a principal role of purifying selection against insertion for the preservation of longer conserved syntenyc blocks with adaptive importance located in 3R. Although some Ty3/gypsy LTRrs show evidence of recent activity, an important fraction are inactive remnants of relatively ancient insertions apparently subject to genetic drift. Consistent with these computational predictions, an analysis of the occupancy rate of putatively older insertions in natural populations suggested that the degenerate copies have been fixed across the species range in this mosquito, and also are shared with the sibling species Anopheles arabiensis. PMID- 21283638 TI - Population genetics of GYPB and association study between GYPB*S/s polymorphism and susceptibility to P. falciparum infection in the Brazilian Amazon. AB - BACKGROUND: Merozoites of Plasmodium falciparum invade through several pathways using different RBC receptors. Field isolates appear to use a greater variability of these receptors than laboratory isolates. Brazilian field isolates were shown to mostly utilize glycophorin A-independent invasion pathways via glycophorin B (GPB) and/or other receptors. The Brazilian population exhibits extensive polymorphism in blood group antigens, however, no studies have been done to relate the prevalence of the antigens that function as receptors for P. falciparum and the ability of the parasite to invade. Our study aimed to establish whether variation in the GYPB*S/s alleles influences susceptibility to infection with P. falciparum in the admixed population of Brazil. METHODS: Two groups of Brazilian Amazonians from Porto Velho were studied: P. falciparum infected individuals (cases); and uninfected individuals who were born and/or have lived in the same endemic region for over ten years, were exposed to infection but have not had malaria over the study period (controls). The GPB Ss phenotype and GYPB*S/s alleles were determined by standard methods. Sixty two Ancestry Informative Markers were genotyped on each individual to estimate admixture and control its potential effect on the association between frequency of GYPB*S and malaria infection. RESULTS: GYPB*S is associated with host susceptibility to infection with P. falciparum; GYPB*S/GYPB*S and GYPB*S/GYPB*s were significantly more prevalent in the in the P. falciparum infected individuals than in the controls (69.87% vs. 49.75%; P<0.02). Moreover, population genetics tests applied on the GYPB exon sequencing data suggest that natural selection shaped the observed pattern of nucleotide diversity. CONCLUSION: Epidemiological and evolutionary approaches suggest an important role for the GPB receptor in RBC invasion by P. falciparum in Brazilian Amazons. Moreover, an increased susceptibility to infection by this parasite is associated with the GPB S+ variant in this population. PMID- 21283639 TI - Sustained delivery of activated Rho GTPases and BDNF promotes axon growth in CSPG rich regions following spinal cord injury. AB - BACKGROUND: Spinal cord injury (SCI) often results in permanent functional loss. This physical trauma leads to secondary events, such as the deposition of inhibitory chondroitin sulfate proteoglycan (CSPG) within astroglial scar tissue at the lesion. METHODOLOGY/PRINCIPAL FINDINGS: We examined whether local delivery of constitutively active (CA) Rho GTPases, Cdc42 and Rac1 to the lesion site alleviated CSPG-mediated inhibition of regenerating axons. A dorsal over hemisection lesion was created in the rat spinal cord and the resulting cavity was conformally filled with an in situ gelling hydrogel combined with lipid microtubes that slowly released constitutively active (CA) Cdc42, Rac1, or Brain derived neurotrophic factor (BDNF). Treatment with BDNF, CA-Cdc42, or CA-Rac1 reduced the number of GFAP-positive astrocytes, as well as CSPG deposition, at the interface of the implanted hydrogel and host tissue. Neurofilament 160kDa positively stained axons traversed the glial scar extensively, entering the hydrogel-filled cavity in the treatments with BDNF and CA-Rho GTPases. The treated animals had a higher percentage of axons from the corticospinal tract that traversed the CSPG-rich regions located proximal to the lesion site. CONCLUSION: Local delivery of CA-Cdc42, CA-Rac1, and BDNF may have a significant therapeutic role in overcoming CSPG-mediated regenerative failure after SCI. PMID- 21283640 TI - Functional interaction between herpes simplex virus type 2 gD and HVEM transiently dampens local chemokine production after murine mucosal infection. AB - Herpes virus entry mediator (HVEM) is one of two principal receptors mediating herpes simplex virus (HSV) entry into murine and human cells. It functions naturally as an immune signaling co-receptor, and may participate in enhancing or repressing immune responses depending on the natural ligand used. To investigate whether engagement of HVEM by HSV affects the in vivo response to HSV infection, we generated recombinants of HSV-2(333) that expressed wild-type gD (HSV-2/gD) or mutant gD able to bind to nectin-1 (the other principal entry receptor) but not HVEM. Replication kinetics and yields of the recombinant strains on Vero cells were indistinguishable from those of wild-type HSV-2(333). After intravaginal inoculation with mutant or wild-type virus, adult female C57BL/6 mice developed vaginal lesions and mortality in similar proportions, and mucosal viral titers were similar or lower for mutant strains at different times. Relative to HSV 2/gD, percentages of HSV-specific CD8(+) T-cells were similar or only slightly reduced after infection with the mutant strain HSV-2/gD-Delta7-15, in all tissues up to 9 days after infection. Levels of HSV-specific CD4(+) T-cells five days after infection also did not differ after infection with either strain. Levels of the cytokine IL-6 and of the chemokines CXCL9, CXCL10, and CCL4 were significantly lower in vaginal washes one day after infection with HSV-2/gD compared with HSV-2/gD-Delta7-15. We conclude that the interaction of HSV gD with HVEM may alter early innate events in the murine immune response to infection, without significantly affecting acute mortality, morbidity, or initial T-cell responses after lethal challenge. PMID- 21283642 TI - Social requests and social affordances: how they affect the kinematics of motor sequences during interactions between conspecifics. AB - The present study aimed at determining whether and what factors affect the control of motor sequences related to interactions between conspecifics. Experiment 1 demonstrated that during interactions between conspecifics guided by the social intention of feeding, a social affordance was activated, which modified the kinematics of sequences constituted by reaching-grasping and placing. This was relative to the same sequence directed to an inanimate target. Experiments 2 and 4 suggested that the related-to-feeding social request emitted by the receiver (i.e. the request gesture of mouth opening) is prerequisite in order to activate a social affordance. Specifically, the two experiments showed that the social request to be fed activated a social affordance even when the sequences directed towards a conspecific were not finalized to feed. Experiment 3 showed that moving inside the peripersonal space of a conspecific, who did not produce any social request, marginally affected the sequence. Finally, experiments 5 and 6 indicated that the gaze of a conspecific is necessary to make a social request effective at activating a social affordance. Summing up, the results of the present study suggest that the control of motor sequences can be changed by the interaction between giver and receiver: the interaction is characterized by a social affordance that the giver activates on the basis of social requests produced by the receiver. The gaze of the receiver is a prerequisite to make a social request effective. PMID- 21283641 TI - Functional role of the polymorphic 647 T/C variant of ENT1 (SLC29A1) and its association with alcohol withdrawal seizures. AB - BACKGROUND: Adenosine is involved in several neurological and behavioral disorders including alcoholism. In cultured cell and animal studies, type 1 equilibrative nucleoside transporter (ENT1, slc29a1), which regulates adenosine levels, is known to regulate ethanol sensitivity and preference. Interestingly, in humans, the ENT1 (SLC29A1) gene contains a non-synonymous single nucleotide polymorphism (647 T/C; rs45573936) that might be involved in the functional change of ENT1. PRINCIPAL FINDINGS: Our functional analysis showed that prolonged ethanol exposure increased adenosine uptake activity of mutant cells (ENT1 216Thr) compared to wild-type (ENT1-216Ile) transfected cells, which might result in reduced extracellular adenosine levels. We found that mice lacking ENT1 displayed increased propensity to ethanol withdrawal seizures compared to wild type littermates. We further investigated a possible association of the 647C variant with alcoholism and the history of alcohol withdrawal seizures in subjects of European ancestry recruited from two independent sites. Analyses of the combined data set showed an association of the 647C variant and alcohol dependence with withdrawal seizures at the nominally significant level. CONCLUSIONS: Together with the functional data, our findings suggest a potential contribution of a genetic variant of ENT1 to the development of alcoholism with increased risk of alcohol withdrawal-induced seizures in humans. PMID- 21283643 TI - A rigidity-enhanced antimicrobial activity: a case for linear cationic alpha helical peptide HP(2-20) and its four analogues. AB - Linear cationic alpha-helical antimicrobial peptides are referred to as one of the most likely substitutes for common antibiotics, due to their relatively simple structures (<= 40 residues) and various antimicrobial activities against a wide range of pathogens. Of those, HP(2-20) was isolated from Helicobacter pylori ribosomal protein. To reveal a mechanical determinant that may mediate the antimicrobial activities, we examined the mechanical properties and structural stabilities of HP(2-20) and its four analogues of same chain length by steered molecular dynamics simulation. The results indicated the following: the resistance of H-bonds to the tensile extension mediated the early extensive stage; with the loss of H-bonds, the tensile force was dispensed to prompt the conformational phase transition; and Young's moduli (N/m(2)) of the peptides were about 4 ~ 8 * 10(9). These mechanical features were sensitive to the variation of the residue compositions. Furthermore, we found that the antimicrobial activity is rigidity-enhanced, that is, a harder peptide has stronger antimicrobial activity. It suggests that the molecular spring constant may be used to seek a new structure-activity relationship for different alpha-helical peptide groups. This exciting result was reasonably explained by a possible mechanical mechanism that regulates both the membrane pore formation and the peptide insertion. PMID- 21283644 TI - Genome-wide analysis of PDZ domain binding reveals inherent functional overlap within the PDZ interaction network. AB - Binding selectivity and cross-reactivity within one of the largest and most abundant interaction domain families, the PDZ family, has long been enigmatic. The complete human PDZ domain complement (the PDZome) consists of 267 domains and we applied here a Bayesian selectivity model to predict hundreds of human PDZ domain interactions, using target sequences of 22,997 non-redundant proteins. Subsequent analysis of these binding scores shows that PDZs can be divided into two genome-wide clusters that coincide well with the division between canonical class 1 and 2 PDZs. Within the class 1 PDZs we observed binding overlap at unprecedented levels, mediated by two residues at positions 1 and 5 of the second alpha-helix of the binding pocket. Eight PDZ domains were subsequently selected for experimental binding studies and to verify the basics of our predictions. Overall, the PDZ domain class 1 cross-reactivity identified here implies that auxiliary mechanisms must be in place to overcome this inherent functional overlap and to minimize cross-selectivity within the living cell. Indeed, when we superimpose PDZ domain binding affinities with gene ontologies, network topology data and the domain position within a PDZ superfamily protein, functional overlap is minimized and PDZ domains position optimally in the binding space. We therefore propose that PDZ domain selectivity is achieved through cellular context rather than inherent binding specificity. PMID- 21283647 TI - Imaging and clinical findings in patients with aberrant course of the cervical internal carotid arteries. AB - BACKGROUND AND PURPOSE: Aberrrant course of the cervical internal carotid arteries (ICAs) may result in submucosal masses in the posterior pharyngeal wall, may cause confusion at physical examination, may be symptomatic, and can be at risk of surgical injury. The aim of this report is to present the clinical and imaging characteristics associated with aberrant course of the cervical portion of the ICAs. METHODS: Imaging studies of 5.500 patients were prospectively selected from CT studies of the head and neck performed in a five years period, in which the course of the one or both ICAs at the level of the hypopharynx and oropharynx was assessed as aberrant by means of a proposed classification. We then reviewed the medical records to establish which symptoms were present and if these symptoms could be caused by these variations in the course of the ICAs. In selected cases, further studies including magnetic resonance (MR) imaging, MR angiography (MRA), or selective catheter angiography were obtained. RESULTS: In our restricted classification, we found 14 (0.2%) patients who met the cervical ICA aberrancy criteria. In all patients contrast enhanced CT or CT angiography was performed, 4 also have had MRI and MRA, and in two additional catheter angiograms were performed. Mean age was 62 years. Eight patients were male and seven were female. Four patients (28%) were considered to have clinical symptoms related to aberrant course of the ICAs. In most of the symptomatic patients both ICAs had aberrant courses. Overall, the course of the right ICA was aberrant in 43%, the left ICA in 14%, and both in 43%. In 50% of the cases the aberrancy of the artery was focal (localized to the oropharynx or laryngopharynx) and in the other 50% it involved the entire cervical course of the ICA. CONCLUSIONS: In most of our patients variations in the course of the cervical portion of the ICA involved the right side and were asymptomatic, except with regard to potential surgical risks. However, in about 25% of our patients these variations were thought to be the culprit of patient complaints, particularly oropharyngeal pulsatile sensation. Furthermore, extreme degrees of medialization of the ICAs resulted in progressive symptoms including hoarseness and upper respiratory distress. PMID- 21283646 TI - Neurobiological alterations induced by exercise and their impact on depressive disorders [corrected]. AB - BACKGROUND: The impact of physical activity on brain metabolic functions has been investigated in different studies and there is growing evidence that exercise can be used as a preventive and rehabilitative intervention in the treatment of depressive disorders. However, the exact neuronal mechanisms underlying the latter phenomenon have not been clearly elucidated. The present article summarises key results derived from studies that focussed on the neurobiological impact of exercise on brain metabolic functions associated with depressive disorders. Since major depressive disorder (MDD) is a life threatening disease it is of great significance to find reliable strategies to prevent or to cure this illness. Therefore, the aim of this paper is to review (1) the physiological relationship between physical activity and depressive disorders and (2) the potential neurobiological alterations induced by exercise that might lead to the relief of mental disorders like depression. METHODS: We searched electronic databases for literature concerning the relationship between exercise and depression from 1963 until 2009. RESULTS: The data suggests an association between physical inactivity and higher levels of depressive symptoms. Properly designed studies could show that exercise training can be as effective as antidepressive medications. CONCLUSION: The exact mechanisms how exercise affects the brain are not fully understood and the literature lacks of well designed studies concerning the effects of exercise training on depressive disorders. But the observed antidepressant actions of exercise are strong enough that it already can be used as an alternative to current medications in the treatment of depressive disorders. PMID- 21283648 TI - Symptom dimensions as predictors of clinical outcome, duration of hospitalization, and aggressive behaviours in acutely hospitalized patients with psychotic exacerbation. AB - In the present study we extract clusters of symptoms in acute hospitalized psychotic patients during a re-exacerbation phase, using factor analysis of BPRS E. We aim to investigate the relative contribution of each symptom dimension in predicting the severity of symptoms at discharge, the length of acute hospitalization, and the occurrence of aggressive behaviours during acute hospitalization. The data are drawn from a prospective, naturalistic, observational study of 183 patients with Psychotic Disorders consecutively admitted to a psychiatric ward, during a re-exacerbation phase. General symptomatology has been measured through BPRS-E at admission and at discharge. Statistical analyses include principal component analysis and multiple linear regression.We found symptoms of acute psychosis disorder to cluster together in four distinct domains, labelled "Excitement/Activation", "Positive symptoms", and "Negative symptoms", and "Depression/Anxiety". Excitement/activation was the dimension most associated with occurrence of aggressive behaviours and severity of psychopathological symptoms at discharge. The negative symptoms dimension, also, predicted the severity of symptoms at discharge. Positive and negative symptoms dimensions were both predictors of duration of hospitalization. The depressive dimension was significantly associated only to self-aggression. These data indicate that during acute hospitalization due to re-exacerbation of psychosis each symptom dimension has a specific impact on distinct measures of outcome. PMID- 21283649 TI - Modeling complex neuropsychiatric disease with induced pluripotent stem cells. AB - The study of neuropsychiatric diseases and the development of effective treatments have been limited by a lack of appropriate models. Induced pluripotent stem cells (iPSCs) represent a potentially limitless supply of patient-specific cells for the study of neuropsychiatric disorders. In this review, we will discuss the potential and limitations of iPSCs for the development of cell-based models of neuropsychiatric diseases and the identification of novel therapeutics. PMID- 21283650 TI - Nephrogenic systemic fibrosis. AB - Nephrogenic systemic fibrosis, initially called nephrogenic fibrosing dermopathy, has been strongly linked to exposure to gadolinium-based contrast media used in magnetic resonance imaging in patients with renal insufficiency. This review discusses recent advances in our understanding of the pathophysiology and clinical approach to patients with chronic kidney disease who require diagnostic imaging with gadolinium-based contrast media. PMID- 21283651 TI - Serrated polyps of the colon. AB - Until recently, colonic polyps were traditionally classified as either hyperplastic or adenomatous, and only the latter were believed to have the potential to progress to carcinoma. However, it is now appreciated that a subset of serrated polyps also appear to have malignant potential. Serrated polyps are a heterogeneous group of colon polyps that include hyperplastic polyps, sessile serrated adenomas (SSAs), traditional serrated adenomas, and mixed polyps. Insights into these polyps were derived, in part, from studies of patients with the hyperplastic polyposis syndrome. SSAs show a predilection for the right colon, have a distinct histology, and their molecular genetic profile has recently been linked to a pathway for colon tumorigenesis that is characterized by microsatellite instability. Based upon available evidence, it is recommended that patients with serrated adenomas undergo colonoscopic follow-up at the same frequency as for conventional adenomas. It is important that physicians are aware of serrated polyps, particularly serrated adenomas and their relationship to colon cancer, and their proper clinical management. PMID- 21283652 TI - Use of dexmedetomidine for pain control. AB - For many years, clonidine, an alpha2-adrenergic receptor (alpha2-AR) agonist, has been widely used as an analgesic adjuvant in perioperative conditions and pain therapy. Dexmedetomidine (DMET) is currently the most potent alpha2-AR agonist available and was first approved as a sedative agent for use in the intensive care unit. However, DMET has recently been investigated for its analgesic effects and has the potential to become an alternative to clonidine. PMID- 21283653 TI - Antigen presentation to B cells. AB - B cells are capable of mounting responses to a bewildering range of potentially pathogenic antigens through the production of high-affinity antibodies and the establishment of immunological memory. Thus, regulated B-cell activation is critical for protection against a variety of bacterial and viral infections, as well as cancers. Here, we discuss a number of recent imaging studies that have provided new insights into the variety of mechanisms by which B-cell activation is initiated in the lymph node in vivo. PMID- 21283654 TI - Recent advances in magnetic resonance imaging of prostate cancer. AB - This concise review attempts to highlight the recent advances in magnetic resonance imaging (MRI) in relation to all the different aspects of prostate cancer (PCa), and outlines future implications of MRI in the diagnosis, treatment, and surveillance of PCa. PMID- 21283655 TI - Validation of the ALS assay in adult patients with culture confirmed pulmonary tuberculosis. AB - BACKGROUND: We have earlier shown that Bacille Calmette-Guerin (BCG) vaccine specific IgG Antibodies in Lymphocyte Supernatant (ALS) can be used for diagnosis of active tuberculosis (TB) in adults and children. METHODOLOGY/PRINCIPAL FINDINGS: The ALS method was validated in a larger cohort (n = 212) of patients with suspicion of pulmonary TB using multiple antigens (BCG, LAM, TB15.3, TB51A, CFP10-ESAT6-A, CFP, CW) from Mycobacterium tuberculosis. The sensitivity and specificity of the ALS assay was calculated using non-TB patients as controls. The sensitivity and the specificity were highest with BCG vaccine (90% and 88% respectively) followed by LAM (89% and 87% respectively). Simultaneous assessment of multiple antigen-specific antibodies increased sensitivity (91%) and specificity (88%). Using higher lymphocyte count in smaller volume of culture media increased detection and reduced the assay duration to ~30 hrs. Twenty one patients with clinical findings strongly suggestive of TB finally diagnosed as non-TB patients were positive by the ALS assay, of which 9 (43%) were positive for 7 antigens and 19 (90%) for at least 3 antigens. CONCLUSIONS/SIGNIFICANCE: Our findings show that simultaneous detection of antigens improves the diagnostic potential of the ALS assay; the modified method increases sensitivity and can provide results in <48 hours, and enable detection of some cases of pulmonary TB that are not detectable by standard methods. PMID- 21283656 TI - A high throughput amenable Arabidopsis-P. aeruginosa system reveals a rewired regulatory module and the utility to identify potent anti-infectives. AB - We previously demonstrated that in a metasystem consisting of Arabidopsis seedlings growing in liquid medium (in 96 well plates) even microbes considered to be innocuous such as laboratory strains of E. coli and B. subtilis can cause potent damage to the host. We further posited that such environment-induced adaptations are brought about by 'system status changes' (rewiring of pre existing cellular signaling networks and components) of the host and the microbe, and that prolongation of such a situation could lead to the emergence of pathogenic states in real-life. Here, using this infection model, we show that the master regulator GacA of the human opportunistic pathogen P. aeruginosa (strain PA14) is dispensable for pathogenesis, as evidenced by three independent read-outs. The gene expression profile of the host after infection with wild type PA14 or the gacA mutant are also identical. GacA normally acts upstream of the quorum sensing regulatory circuit (that includes the regulator LasR) that controls a subset of virulence factors. Double mutants in gacA and lasR behave similar to the lasR mutant, as seen by abrogation of a characteristic cell type specific host cell damage caused by PA14 or the gacA mutant. This indicates that a previously unrecognized regulatory mechanism is operative under these conditions upstream of LasR. In addition, the detrimental effect of PA14 on Arabidopsis seedlings is resistant to high concentrations of the aminoglycoside antibiotic gentamicin. These data suggest that the Arabidopsis seedling infection system could be used to identify anti-infectives with potentially novel modes of action. PMID- 21283657 TI - Gallbladder cancer predisposition: a multigenic approach to DNA-repair, apoptotic and inflammatory pathway genes. AB - Gallbladder cancer (GBC) is a multifactorial disease with complex interplay between multiple genetic variants. We performed Classification and Regression Tree Analysis (CART) and Grade of Membership (GoM) analysis to identify combinations of alleles among the DNA repair, inflammatory and apoptotic pathway genetic variants in modifying the risk for GBC. We analyzed 16 polymorphisms in 8 genes involved in DNA repair, apoptotic and inflammatory pathways to find out combinations of genetic variants contributing to GBC risk. The genes included in the study were XRCC1, OGG1, ERCC2, MSH2, CASP8, TLR2, TLR4 and PTGS2. Single locus analysis by logistic regression showed association of MSH2 IVS1+9G>C (rs2303426), ERCC2 Asp312Asn (rs1799793), OGG1 Ser326Cys (rs1052133), OGG1 IVS4 15C>G (rs2072668), CASP8 -652 6N ins/del (rs3834129), PTGS2 -1195G>A (rs689466), PTGS2 -765G>C (rs20417), TLR4 Ex4+936C>T (rs4986791) and TLR2 -196 to -174del polymorphisms with GBC risk. The CART analysis revealed OGG1 Ser326Cys, and OGG1 IVS4-15C>G polymorphisms as the best polymorphic signature for discriminating between cases and controls. In the GoM analysis, the data was categorized into six sets representing risk for GBC with respect to the investigated polymorphisms. Sets I, II and III described low intrinsic risk (controls) characterized by multiple protective alleles while sets IV, V and VI represented high intrinsic risk groups (GBC cases) characterized by the presence of multiple risk alleles. The CART and GoM analyses also showed the importance of PTGS2 1195G>A polymorphism in susceptibility to GBC risk. In conclusion, the present multigenic approach can be used to define individual risk profiles for gallbladder cancer in North Indian population. PMID- 21283658 TI - Diet-induced obesity impairs endothelium-derived hyperpolarization via altered potassium channel signaling mechanisms. AB - BACKGROUND: The vascular endothelium plays a critical role in the control of blood flow. Altered endothelium-mediated vasodilator and vasoconstrictor mechanisms underlie key aspects of cardiovascular disease, including those in obesity. Whilst the mechanism of nitric oxide (NO)-mediated vasodilation has been extensively studied in obesity, little is known about the impact of obesity on vasodilation to the endothelium-derived hyperpolarization (EDH) mechanism; which predominates in smaller resistance vessels and is characterized in this study. METHODOLOGY/PRINCIPAL FINDINGS: Membrane potential, vessel diameter and luminal pressure were recorded in 4(th) order mesenteric arteries with pressure-induced myogenic tone, in control and diet-induced obese rats. Obesity, reflecting that of human dietary etiology, was induced with a cafeteria-style diet (~30 kJ, fat) over 16-20 weeks. Age and sexed matched controls received standard chow (~12 kJ, fat). Channel protein distribution, expression and vessel morphology were determined using immunohistochemistry, Western blotting and ultrastructural techniques. In control and obese rat vessels, acetylcholine-mediated EDH was abolished by small and intermediate conductance calcium-activated potassium channel (SK(Ca)/IK(Ca)) inhibition; with such activity being impaired in obesity. SK(Ca)-IK(Ca) activation with cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl pyrimidin-4-yl]-amine (CyPPA) and 1-ethyl-2-benzimidazolinone (1-EBIO), respectively, hyperpolarized and relaxed vessels from control and obese rats. IK(Ca)-mediated EDH contribution was increased in obesity, and associated with altered IK(Ca) distribution and elevated expression. In contrast, the SK(Ca) dependent-EDH component was reduced in obesity. Inward-rectifying potassium channel (K(ir)) and Na(+)/K(+)-ATPase inhibition by barium/ouabain, respectively, attenuated and abolished EDH in arteries from control and obese rats, respectively; reflecting differential K(ir) expression and distribution. Although changes in medial properties occurred, obesity had no effect on myoendothelial gap junction density. CONCLUSION/SIGNIFICANCE: In obese rats, vasodilation to EDH is impaired due to changes in the underlying potassium channel signaling mechanisms. Whilst myoendothelial gap junction density is unchanged in arteries of obese compared to control, increased IK(Ca) and Na(+)/K(+)-ATPase, and decreased K(ir) underlie changes in the EDH mechanism. PMID- 21283659 TI - Long tract of untranslated CAG repeats is deleterious in transgenic mice. AB - The most frequent trinucleotide repeat found in human disorders is the CAG sequence. Expansion of CAG repeats is mostly found in coding regions and is thought to cause diseases through a protein mechanism. Recently, expanded CAG repeats were shown to induce toxicity at the RNA level in Drosophila and C. elegans. These findings raise the possibility that CAG repeats may trigger RNA mediated pathogenesis in mammals. Here, we demonstrate that transgenic mice expressing EGFP transcripts with long CAG repeats in the 3' untranslated region develop pathogenic features. Expression of the transgene was directed to the muscle in order to compare the resulting phenotype to that caused by the CUG expansion, as occurs in myotonic dystrophy. Transgenic mice expressing 200, but not those expressing 0 or 23 CAG repeats, showed alterations in muscle morphology, histochemistry and electrophysiology, as well as abnormal behavioral phenotypes. Expression of the expanded CAG repeats in testes resulted in reduced fertility due to defective sperm motility. The production of EGFP protein was significantly reduced by the 200 CAG repeats, and no polyglutamine-containing product was detected, which argues against a protein mechanism. Moreover, nuclear RNA foci were detected for the long CAG repeats. These data support the notion that expanded CAG repeat RNA can cause deleterious effects in mammals. They also suggest the possible involvement of an RNA mechanism in human diseases with long CAG repeats. PMID- 21283660 TI - Effects of sleeve gastrectomy in neonatally streptozotocin-induced diabetic rats. AB - BACKGROUND: Sleeve gastrectomy (SG) has emerged recently as a stand-alone bariatric procedure to treat morbid obesity and enhance glucose homeostasis. The aim of the study was to evaluate its effects in neonatally streptozotocin (STZ) induced diabetic rats (n-STZ diabetic rats). METHODOLOGY AND PRINCIPAL FINDINGS: To induce diabetes, STZ (90 mg/kg) was administered intraperitoneally to 2-day old male pups. When 12 weeks old, diabetic rats were randomized into sleeve operation group (SLG, n = 6) and sham operation group (SOG, n = 6). Body weights were monitored weekly, and daily consumption of water and food were followed for eight consecutive weeks postoperatively. Serum glucose levels were measured periodically at the 4th and 8th week after surgery. Insulin, ghrelin, glucose dependent insulinotropic polypeptide (GIP) and Glucagon-like peptide-1 (GLP-1) levels were assayed at the end of the study. Our data showed that SLG rats exhibited significantly lower body weight gain in addition to reduced food and water intakes postoperatively compared to their sham-operation counterparts. However, resolution of diabetes was not observed in our study. Correspondingly, there were no significant differences between SOG rats and SLG rats in glucose metabolism-associated hormones, including insulin, GIP and GLP-1. In contrast, ghrelin level significantly decreased (P<0.01) in SLG group (58.01 +/- 3.75 pg/ml) after SG surgery compared to SOG group (76.36 +/- 3.51 pg/ml). CONCLUSIONS: These observations strongly suggest that SG is effective in controlling body weight. However, SG did not achieve resolution or improvement of diabetes in n-STZ diabetic rats. PMID- 21283661 TI - Evolutionary analyses of Staphylococcus aureus identify genetic relationships between nasal carriage and clinical isolates. AB - Nasal carriage of Staphylococcus aureus has long been hypothesized to be a major vector for the transmission of virulent strains throughout the community. To address this hypothesis, we have analyzed the relatedness between a cohort of nasal carriage strains and clinical isolates to understand better the genetic conformity therein. To assess the relatedness between nasal carriage and clinical isolates of S. aureus, a genetic association study was conducted using multilocus sequence typing (MLST) and typing of the hypervariable regions of clumping factor and fibronectin binding protein genes. At all loci analyzed, genetic associations between both nasal carriage and clinical isolates were observed. Computational analyses of MLST data indicate that nasal carriage and clinical isolates belong to the same genetic clusters (clades), despite differences in sequence type assignments. Genetic analyses of the hypervariable regions from the clumping factor and fibronectin binding protein genes revealed that not only do clinically relevant strains belong to identical genetic lineages as the nasal carriage isolates within our cohort, but they also exhibit 100% sequence similarity within these regions. The findings of this report indicate that strains of S. aureus being carried asymptomatically throughout the community via nasal colonization are genetically related to those responsible for high levels of morbidity and mortality. PMID- 21283665 TI - Structure-based mutational analysis of eIF4E in relation to sbm1 resistance to pea seed-borne mosaic virus in pea. AB - BACKGROUND: Pea encodes eukaryotic translation initiation factor eIF4E (eIF4E(S)), which supports the multiplication of Pea seed-borne mosaic virus (PSbMV). In common with hosts for other potyviruses, some pea lines contain a recessive allele (sbm1) encoding a mutant eIF4E (eIF4E(R)) that fails to interact functionally with the PSbMV avirulence protein, VPg, giving genetic resistance to infection. METHODOLOGY/PRINCIPAL FINDINGS: To study structure-function relationships between pea eIF4E and PSbMV VPg, we obtained an X-ray structure for eIF4E(S) bound to m(7)GTP. The crystallographic asymmetric unit contained eight independent copies of the protein, providing insights into the structurally conserved and flexible regions of eIF4E. To assess indirectly the importance of key residues in binding to VPg and/or m(7)GTP, an extensive range of point mutants in eIF4E was tested for their ability to complement PSbMV multiplication in resistant pea tissues and for complementation of protein translation, and hence growth, in an eIF4E-defective yeast strain conditionally dependent upon ectopic expression of eIF4E. The mutants also dissected individual contributions from polymorphisms present in eIF4E(R) and compared the impact of individual residues altered in orthologous resistance alleles from other crop species. The data showed that essential resistance determinants in eIF4E differed for different viruses although the critical region involved (possibly in VPg-binding) was conserved and partially overlapped with the m(7)GTP-binding region. This overlap resulted in coupled inhibition of virus multiplication and translation in the majority of cases, although the existence of a few mutants that uncoupled the two processes supported the view that the specific role of eIF4E in potyvirus infection may not be restricted to translation. CONCLUSIONS/SIGNIFICANCE: The work describes the most extensive structural analysis of eIF4E in relation to potyvirus resistance. In addition to defining functional domains within the eIF4E structure, we identified eIF4E alleles with the potential to convey novel virus resistance phenotypes. PMID- 21283666 TI - Crystal structure of the pyrazinamidase of Mycobacterium tuberculosis: insights into natural and acquired resistance to pyrazinamide. AB - Pyrazinamidase (PncA) activates the first-line antituberculous drug pyrazinamide into pyrazinoic acid. The crystal structure of the Mycobacterium tuberculosis PncA protein has been determined, showing significant differences in the substrate binding cavity when compared to the pyrazinamidases from Pyrococcus horikoshii and Acinetobacter baumanii. In M. tuberculosis, this region was found to hold a Fe(2+) ion coordinated by one aspartate and three histidines, one of them corresponding to His57 which is replaced by Asp in Mycobacterium bovis, a species naturally resistant to pyrazinamide. The binding cavity also contains a Cys138-Asp8-Lys96 motif evocating a cysteine-based catalytic mechanism. Mutants have been constructed and investigated by kinetic and thermal shift assays, highlighting the importance of protein folding and thermal stability in the pyrazinamidase activity. PMID- 21283667 TI - Structure and function of ABCG2-rich extracellular vesicles mediating multidrug resistance. AB - Multidrug resistance (MDR) is a major impediment to curative cancer chemotherapy. The ATP-Binding Cassette transporters ABCG2, ABCB1 and ABCC2 form a unique defense network against multiple structurally and functionally distinct chemotherapeutics, thereby resulting in MDR. Thus, deciphering novel mechanisms of MDR and their overcoming is a major goal of cancer research. Recently we have shown that overexpression of ABCG2 in the membrane of novel extracellular vesicles (EVs) in breast cancer cells results in mitoxantrone resistance due to its dramatic sequestration in EVs. However, nothing is known about EVs structure, biogenesis and their ability to concentrate multiple antitumor agents. To this end, we here found that EVs are structural and functional homologues of bile canaliculi, are apically localized, sealed structures reinforced by an actin based cytoskeleton and secluded from the extracellular milieu by the tight junction proteins occludin and ZO-1. Apart from ABCG2, ABCB1 and ABCC2 were also selectively targeted to the membrane of EVs. Moreover, Ezrin-Radixin-Moesin protein complex selectively localized to the border of the EVs membrane, suggesting a key role for the tethering of MDR pumps to the actin cytoskeleton. The ability of EVs to concentrate and sequester different antitumor drugs was also explored. Taking advantage of the endogenous fluorescence of anticancer drugs, we found that EVs-forming breast cancer cells display high level resistance to topotecan, imidazoacridinones and methotrexate via efficient intravesicular drug concentration hence sequestering them away from their cellular targets. Thus, we identified a new modality of anticancer drug compartmentalization and resistance in which multiple chemotherapeutics are actively pumped from the cytoplasm and highly concentrated within the lumen of EVs via a network of MDR transporters differentially targeted to the EVs membrane. We propose a composite model for the structure and function of MDR pump rich EVs in cancer cells and their ability to confer multiple anticancer drug resistance. PMID- 21283668 TI - Pathology of camel tuberculosis and molecular characterization of its causative agents in pastoral regions of Ethiopia. AB - A cross sectional study was conducted on 906 apparently healthy camels slaughtered at Akaki and Metehara abattoirs to investigate the pathology of camel tuberculosis (TB) and characterize its causative agents using postmortem examination, mycobacteriological culturing, and multiplex polymerase chain reaction (PCR), region of difference-4 (RD4)-based PCR and spoligotyping. The prevalence of camel TB was 10.04% (91/906) on the basis of pathology and it was significantly higher in females (chi(2) = 4.789; P = 0.029). The tropism of TB lesions was significantly different among the lymph nodes (chi(2) = 22.697; P = 0.002) and lung lobes (chi(2) = 17.901; P = 0.006). Mycobacterial growth was observed in 34% (31/91) of camels with grossly suspicious TB lesions. Upon further molecular characterization using multiplex PCR, 68% (21/31) of the colonies showed a positive signal for the genus Mycobacterium, of which two were confirmed Mycobacterium bovis (M. bovis) by RD4 deletion typing. Further characterization of the two M. bovis at strains level revealed that one of the strains was SB0133 while the other strain was new and had not been reported to the M. bovis database prior to this study. Hence, it has now been reported to the database, and designated as SB1953. In conclusion, the results of the present study have shown that the majority of camel TB lesions are caused by mycobacteria other than Mycobacterium tuberculosis complex. And hence further identification and characterization of these species would be useful towards the efforts made to control TB in camels. PMID- 21283669 TI - Killing of targets by CD8 T cells in the mouse spleen follows the law of mass action. AB - It has been difficult to correlate the quality of CD8 T cell responses with protection against viral infections. To investigate the relationship between efficacy and magnitude of T cell responses, we quantify the rate at which individual CD8 effector and memory T cells kill target cells in the mouse spleen. Using mathematical modeling, we analyze recent data on the loss of target cells pulsed with three different peptides from the mouse lymphocytic choriomeningitis virus (LCMV) in mouse spleens with varying numbers of epitope-specific CD8 T cells. We find that the killing of targets follows the law of mass-action, i.e., the death rate of individual target cells remains proportional to the frequency (or the total number) of specific CD8 T cells in the spleen despite the fact that effector cell densities and effector to target ratios vary about a 1000-fold. The killing rate of LCMV-specific CD8 T cells is largely independent of T cell specificity and differentiation stage. Our results thus allow one to calculate the critical T cell concentration at which growth of a virus with a given replication rate can be prevented from the start of infection by memory CD8 T cell response. PMID- 21283670 TI - Single-nucleotide polymorphisms in LPA explain most of the ancestry-specific variation in Lp(a) levels in African Americans. AB - Lipoprotein(a) (Lp(a)) is an important causal cardiovascular risk factor, with serum Lp(a) levels predicting atherosclerotic heart disease and genetic determinants of Lp(a) levels showing association with myocardial infarction. Lp(a) levels vary widely between populations, with African-derived populations having nearly 2-fold higher Lp(a) levels than European Americans. We investigated the genetic basis of this difference in 4464 African Americans from the Jackson Heart Study (JHS) using a panel of up to 1447 ancestry informative markers, allowing us to accurately estimate the African ancestry proportion of each individual at each position in the genome. In an unbiased genome-wide admixture scan for frequency-differentiated genetic determinants of Lp(a) level, we found a convincing peak (LOD = 13.6) at 6q25.3, which spans the LPA locus. Dense fine mapping of the LPA locus identified a number of strongly associated, common biallelic SNPs, a subset of which can account for up to 7% of the variation in Lp(a) level, as well as >70% of the African-European population differences in Lp(a) level. We replicated the association of the most strongly associated SNP, rs9457951 (p = 6 * 10(-22), 27% change in Lp(a) per allele, ~5% of Lp(a) variance explained in JHS), in 1,726 African Americans from the Dallas Heart Study and found an even stronger association after adjustment for the kringle(IV) repeat copy number. Despite the strong association with Lp(a) levels, we find no association of any LPA SNP with incident coronary heart disease in 3,225 African Americans from the Atherosclerosis Risk in Communities Study. PMID- 21283671 TI - Regulation of apoptotic mediators reveals dynamic responses to thermal stress in the reef building coral Acropora millepora. AB - BACKGROUND: Mass coral bleaching is increasing in scale and frequency across the world's coral reefs and is being driven primarily by increased levels of thermal stress arising from global warming. In order to understand the impacts of projected climate change upon corals reefs, it is important to elucidate the underlying cellular mechanisms that operate during coral bleaching and subsequent mortality. In this respect, increased apoptotic cell death activity is an important cellular process that is associated with the breakdown of the mutualistic symbiosis between the cnidarian host and their dinoflagellate symbionts. METHODOLOGY/PRINCIPAL FINDINGS: The PRESENT study reports the impacts of different stressors (colchicine and heat stress) on three phases of apoptosis: (i) the potential initiation by differential expression of Bcl-2 members, (ii) the execution of apoptotic events by activation of caspase 3-like proteases and (iii) and finally, the cell disposal indicated by DNA fragmentation in the reef building coral Acropora millepora. In corals incubated with colchicine, an increase in caspase 3-like activity and DNA fragmentation was associated with a relative down-regulation of Bcl-2, suggesting that the initiation of apoptosis may be mediated by the suppression of an anti-apoptotic mechanism. In contrast, in the early steps of heat stress, the induction of caspase-dependent apoptosis was related to a relative up-regulation of Bcl-2 consecutively followed by a delayed decrease in apoptosis activity. CONCLUSIONS/SIGNIFICANCE: In the light of these results, we propose a model of heat stress in coral hosts whereby increasing temperatures engage activation of caspase 3-dependent apoptosis in cells designated for termination, but also the onset of a delayed protective response involving overexpression of Bcl-2 in surviving cells. This mitigating response to thermal stress could conceivably be an important regulatory mechanism for cell survival in corals exposed to sudden environmental changes. PMID- 21283672 TI - Functional significance of vitamin D receptor FokI polymorphism in human breast cancer cells. AB - BACKGROUND: The FokI vitamin D receptor (VDR) polymorphism results in different translation initiation sites on VDR. In the VDRff variant, initiation of translation occurs at the first ATG site, giving rise to a full length VDR protein of 427 amino acids. Conversely, in the VDRFF variant, translation begins at the second ATG site, resulting in a truncated protein with three less amino acids. Epidemiological studies have paradoxically implicated this polymorphism with increased breast cancer risk. 1alpha,25 (OH)(2)D(3), the active metabolite of vitamin D, is known to inhibit cell proliferation, induce apoptosis and potentiate differentiation in human breast cancer cells. It is well documented that 1alpha,25 (OH)(2)D(3) downregulates estrogen receptor alpha expression and inhibits estrogen mediated signaling in these cells. The functional significance of the VDR FokI polymorphism in vitamin D action is undefined. METHODS/FINDINGS: To elucidate the functional role of FokI polymorphism in breast cancer, MCF-7 Vector, MCF-7-VDRff and MCF-7-VDRFF stable cell lines were established from parental MCF-7 cells as single-cell clones. In response to 1alpha,25 (OH)(2)D(3) treatments, cell growth was inhibited by 60% in VDRFF cells compared to 28% in VDRff cells. The induction of the vitamin D target gene CYP24A1 mRNA was 1.8 fold higher in VDRFF cells than in VDRff cells. Estrogen receptor-alpha protein expression was downregulated by 62% in VDRFF cells compared to 25% in VDRff cells. VDR protein stability was greater in MCF-7-VDRFF cells in the presence of cycloheximide. PCR array analyses of VDRff and VDRFF cells revealed increased basal expression levels of pro-inflammatory genes Cyclooxygenase-2, Interleukin-8 and Chemokine (C-C Motif) Ligand 2 in MCF-7-VDRff cells by 14, 52.7 and 5 fold, respectively. CONCLUSIONS/SIGNIFICANCE: These results suggest that a VDRff genotype may play a role in amplifying aggressive breast cancer, paving the way for understanding why some breast cancer cells respond inefficiently to vitamin D treatment. PMID- 21283673 TI - An investigation of a role for U2 snRNP spliceosomal components in regulating transcription. AB - There is mounting evidence to suggest that the synthesis of pre-mRNA transcripts and their subsequent splicing are coordinated events. Previous studies have implicated the mammalian spliceosomal U2 snRNP as having a novel role in stimulating transcriptional elongation in vitro through interactions with the elongation factors P-TEFb and Tat-SF1; however, the mechanism remains unknown [1]. These factors are conserved in Saccharomyces cerevisiae, a fact that suggests that a similar interaction may occur in yeast to stimulate transcriptional elongation in vivo. To address this possibility we have looked for evidence of a role for the yeast Tat-SF1 homolog, Cus2, and the U2 snRNA in regulating transcription. Specifically, we have performed a genetic analysis to look for functional interactions between Cus2 or U2 snRNA and the P-TEFb yeast homologs, the Bur1/2 and Ctk1/2/3 complexes. In addition, we have analyzed Cus2 deleted or -overexpressing cells and U2 snRNA mutant cells to determine if they show transcription-related phenotypes similar to those displayed by the P-TEFb homolog mutants. In no case have we been able to observe phenotypes consistent with a role for either spliceosomal factor in transcription elongation. Furthermore, we did not find evidence for physical interactions between the yeast U2 snRNP factors and the P-TEFb homologs. These results suggest that in vivo, S. cerevisiae do not exhibit functional or physical interactions similar to those exhibited by their mammalian counterparts in vitro. The significance of the difference between our in vivo findings and the previously published in vitro results remains unclear; however, we discuss the potential importance of other factors, including viral proteins, in mediating the mammalian interactions. PMID- 21283674 TI - The progression of liver fibrosis is related with overexpression of the miR-199 and 200 families. AB - BACKGROUND: Chronic hepatitis C (CH) can develop into liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Liver fibrosis and HCC development are strongly correlated, but there is no effective treatment against fibrosis because the critical mechanism of progression of liver fibrosis is not fully understood. microRNAs (miRNAs) are now essential to the molecular mechanisms of several biological processes. In order to clarify how the aberrant expression of miRNAs participates in development of the liver fibrosis, we analyzed the liver fibrosis in mouse liver fibrosis model and human clinical samples. METHODOLOGY: In a CCL(4)-induced mouse liver fibrosis model, we compared the miRNA expression profile from CCL(4) and olive oil administrated liver specimens on 4, 6, and 8 weeks. We also measured expression profiles of human miRNAs in the liver biopsy specimens from 105 CH type C patients without a history of anti-viral therapy. PRINCIPLE FINDINGS: Eleven mouse miRNAs were significantly elevated in progressed liver fibrosis relative to control. By using a large amount of human material in CH analysis, we determined the miRNA expression pattern according to the grade of liver fibrosis. We detected several human miRNAs whose expression levels were correlated with the degree of progression of liver fibrosis. In both the mouse and human studies, the expression levels of miR-199a, 199a*, 200a, and 200b were positively and significantly correlated to the progressed liver fibrosis. The expression level of fibrosis related genes in hepatic stellate cells (HSC), were significantly increased by overexpression of these miRNAs. CONCLUSION: Four miRNAs are tightly related to the grade of liver fibrosis in both human and mouse was shown. This information may uncover the critical mechanism of progression of liver fibrosis. miRNA expression profiling has potential for diagnostic and therapeutic applications. PMID- 21283675 TI - Production of inactivated influenza H5N1 vaccines from MDCK cells in serum-free medium. AB - BACKGROUND: Highly pathogenic influenza viruses pose a constant threat which could lead to a global pandemic. Vaccination remains the principal measure to reduce morbidity and mortality from such pandemics. The availability and surging demand for pandemic vaccines needs to be addressed in the preparedness plans. This study presents an improved high-yield manufacturing process for the inactivated influenza H5N1 vaccines using Madin-Darby canine kidney (MDCK) cells grown in a serum-free (SF) medium microcarrier cell culture system. PRINCIPAL FINDING: The current study has evaluated the performance of cell adaptation switched from serum-containing (SC) medium to several commercial SF media. The selected SF medium was further evaluated in various bioreactor culture systems for process scale-up evaluation. No significant difference was found in the cell growth in different sizes of bioreactors studied. In the 7.5 L bioreactor runs, the cell concentration reached to 2.3 * 10(6) cells/mL after 5 days. The maximum virus titers of 1024 Hemagglutinin (HA) units/50 uL and 7.1 +/- 0.3 * 10(8) pfu/mL were obtained after 3 days infection. The concentration of HA antigen as determined by SRID was found to be 14.1 ug/mL which was higher than those obtained from the SC medium. A mouse immunogenicity study showed that the formalin-inactivated purified SF vaccine candidate formulated with alum adjuvant could induce protective level of virus neutralization titers similar to those obtained from the SC medium. In addition, the H5N1 viruses produced from either SC or SF media showed the same antigenic reactivity with the NIBRG14 standard antisera. CONCLUSIONS: The advantages of this SF cell-based manufacturing process could reduce the animal serum contamination, the cost and lot-to-lot variation of SC medium production. This study provides useful information to manufacturers that are planning to use SF medium for cell-based influenza vaccine production. PMID- 21283676 TI - Hypermethylation of tumor suppressor genes involved in critical regulatory pathways for developing a blood-based test in breast cancer. AB - BACKGROUND: Aberrant DNA methylation patterns might be used as a biomarker for diagnosis and management of cancer patients. METHODS AND FINDINGS: To achieve a gene panel for developing a breast cancer blood-based test we quantitatively assessed the DNA methylation proportion of 248 CpG sites per sample (total of 31,248 sites in all analyzed samples) on 10 candidate genes (APC, BIN1, BMP6, BRCA1, CST6, ESR-b, GSTP1, P16, P21 and TIMP3). The number of 126 samples consisting of two different cohorts was used (first cohort: plasma samples from breast cancer patients and normal controls; second cohort: triple matched samples including cancerous tissue, matched normal tissue and serum samples). In the first cohort, circulating cell free methylated DNA of the 8 tumor suppressor genes (TSGs) was significantly higher in patients with breast cancer compared to normal controls (P<0.01). In the second cohort containing triple matched samples, seven genes showed concordant hypermethylated profile in tumor tissue and serum samples compared to normal tissue (P<0.05). Using eight genes as a panel to develop a blood-based test for breast cancer, a sensitivity and specificity of more than 90% could be achieved in distinguishing between tumor and normal samples. CONCLUSIONS: Our study suggests that the selected TSG panel combined with the high-throughput technology might be a useful tool to develop epigenetic based predictive and prognostic biomarker for breast cancer relying on pathologic methylation changes in tumor tissue, as well as in circulation. PMID- 21283677 TI - Differential neuroprotective activity of two different grape seed extracts. AB - Glutamate excitotoxicity is one of the major events that takes place during various neurotoxic injuries such as brain ischemia. We prepared grape seed extracts, from two different varieties, containing high amounts of polyphenols but little resveratrol. Their neuroprotective effects were investigated using primary culture of neonatal mouse hippocampal neurons treated with an excitotoxic concentration of glutamate. Koshu, a white, local variety of V. vinifera, alleviated the acute inactivation of Erk1/2 and dendrite retraction in cultured hippocampal neurons exposed to a toxic concentration of glutamate (1.0 ng/ml). By contrast, Muscat Bailey A, a red, hybrid variety (Muscat Humburg * Bailey), failed to show any neuroprotective effect. Unlike brain-derived neurotrophic factor and other neuroprotective cytokines, Koshu extract did not induce Akt phosphorylation. Koshu extract also augmented neuron survival rate 24 hours after glutamate toxicity. The comparison of polyphenols between the two samples by liquid chromatography/time-of-flight mass spectrometry demonstrated that Koshu had higher amounts of low molecular weight polyphenols along with several Koshu specific procyanidin oligomers. These data suggest the presence of high affinity molecular targets for polyphenols in hippocampal neurons, which induce neuroprotective effects in a manner different from BDNF, and the importance of low molecular weight polyphenols and/or procyanidin oligomers for neuroprotection. PMID- 21283678 TI - Highly pathogenic avian influenza (H5N1): pathways of exposure at the animal human interface, a systematic review. AB - BACKGROUND: The threat posed by highly pathogenic avian influenza A H5N1 viruses to humans remains significant, given the continued occurrence of sporadic human cases (499 human cases in 15 countries) with a high case fatality rate (approximately 60%), the endemicity in poultry populations in several countries, and the potential for reassortment with the newly emerging 2009 H1N1 pandemic strain. Therefore, we review risk factors for H5N1 infection in humans. METHODS AND FINDINGS: Several epidemiologic studies have evaluated the risk factors associated with increased risk of H5N1 infection among humans who were exposed to H5N1 viruses. Our review shows that most H5N1 cases are attributed to exposure to sick poultry. Most cases are sporadic, while occasional limited human-to-human transmission occurs. The most commonly identified factors associated with H5N1 virus infection included exposure through contact with infected blood or bodily fluids of infected poultry via food preparation practices; touching and caring for infected poultry; [corrected] exposure to H5N1 via swimming or bathing in potentially virus laden ponds; and exposure to H5N1 at live bird markets. CONCLUSIONS: Research has demonstrated that despite frequent and widespread contact with poultry, transmission of the H5N1 virus from poultry to humans is rare. Available research has identified several risk factors that may be associated with infection including close direct contact with poultry and transmission via the environment. However, several important data gaps remain that limit our understanding of the epidemiology of H5N1 in humans. Although infection in humans with H5N1 remains rare, human cases continue to be reported and H5N1 is now considered endemic among poultry in parts of Asia and in Egypt, providing opportunities for additional human infections and for the acquisition of virus mutations that may lead to more efficient spread among humans and other mammalian species. Collaboration between human and animal health sectors for surveillance, case investigation, virus sharing, and risk assessment is essential to monitor for potential changes in circulating H5N1 viruses and in the epidemiology of H5N1 in order to provide the best possible chance for effective mitigation of the impact of H5N1 in both poultry and humans. DISCLAIMER: The opinions expressed in this article are those of the authors and do not necessarily reflect those of the institutions or organizations with which they are affiliated. PMID- 21283679 TI - A sensitive assay for virus discovery in respiratory clinical samples. AB - In 5-40% of respiratory infections in children, the diagnostics remain negative, suggesting that the patients might be infected with a yet unknown pathogen. Virus discovery cDNA-AFLP (VIDISCA) is a virus discovery method based on recognition of restriction enzyme cleavage sites, ligation of adaptors and subsequent amplification by PCR. However, direct discovery of unknown pathogens in nasopharyngeal swabs is difficult due to the high concentration of ribosomal RNA (rRNA) that acts as competitor. In the current study we optimized VIDISCA by adjusting the reverse transcription enzymes and decreasing rRNA amplification in the reverse transcription, using hexamer oligonucleotides that do not anneal to rRNA. Residual cDNA synthesis on rRNA templates was further reduced with oligonucleotides that anneal to rRNA but can not be extended due to 3'-dideoxy-C6 modification. With these modifications >90% reduction of rRNA amplification was established. Further improvement of the VIDISCA sensitivity was obtained by high throughput sequencing (VIDISCA-454). Eighteen nasopharyngeal swabs were analysed, all containing known respiratory viruses. We could identify the proper virus in the majority of samples tested (11/18). The median load in the VIDISCA-454 positive samples was 7.2 E5 viral genome copies/ml (ranging from 1.4 E3-7.7 E6). Our results show that optimization of VIDISCA and subsequent high-throughput sequencing enhances sensitivity drastically and provides the opportunity to perform virus discovery directly in patient material. PMID- 21283680 TI - The effect of a DNA repair gene on cellular invasiveness: XRCC3 over-expression in breast cancer cells. AB - Over-expression of DNA repair genes has been associated with resistance to radiation and DNA-damage induced by chemotherapeutic agents such as cisplatin. More recently, based on the analysis of genome expression profiling, it was proposed that over-expression of DNA repair genes enhances the invasive behaviour of tumour cells. In this study we present experimental evidence utilizing functional assays to test this hypothesis. We assessed the effect of the DNA repair proteins known as X-ray complementing protein 3 (XRCC3) and RAD51, to the invasive behavior of the MCF-7 luminal epithelial-like and BT20 basal-like triple negative human breast cancer cell lines. We report that stable or transient over expression of XRCC3 but not RAD51 increased invasiveness in both cell lines in vitro. Moreover, XRCC3 over-expressing MCF-7 cells also showed a higher tumorigenesis in vivo and this phenotype was associated with increased activity of the metalloproteinase MMP-9 and the expression of known modulators of cell cell adhesion and metastasis such as CD44, ID-1, DDR1 and TFF1. Our results suggest that in addition to its' role in facilitating repair of DNA damage, XRCC3 affects invasiveness of breast cancer cell lines and the expression of genes associated with cell adhesion and invasion. PMID- 21283681 TI - Hepcidin is an antibacterial, stress-inducible peptide of the biliary system. AB - BACKGROUND/AIMS: Hepcidin (gene name HAMP), an IL-6-inducible acute phase peptide with antimicrobial properties, is the key negative regulator of iron metabolism. Liver is the primary source of HAMP synthesis, but it is also produced by other tissues such as kidney or heart and is found in body fluids such as urine or cerebrospinal fluid. While the role of hepcidin in biliary system is unknown, a recent study demonstrated that conditional gp130-knockout mice display diminished hepcidin levels and increased rate of biliary infections. METHODS: Expression and localization of HAMP in biliary system was analyzed by real time RT-PCR, in-situ hybridization, immunostaining and -blotting, while prohepcidin levels in human bile were determined by ELISA. RESULTS: Hepcidin was detected in mouse/human gallbladder and bile duct epithelia. Biliary HAMP is stress-inducible, in that it is increased in biliary cell lines upon IL-6 stimulation and in gallbladder mucosa of patients with acute cholecystitis. Hepcidin is also present in the bile and elevated prohepcidin levels were observed in bile of primary sclerosing cholangitis (PSC) patients with concurrent bacterial cholangitis compared to PSC subjects without bacterial infection (median values 22.3 vs. 8.9; p = 0.03). In PSC-cholangitis subjects, bile prohepcidin levels positively correlated with C reactive protein and bilirubin levels (r = 0.48 and r = 0.71, respectively). In vitro, hepcidin enhanced the antimicrobial capacity of human bile (p<0.05). CONCLUSION: Hepcidin is a stress-inducible peptide of the biliary epithelia and a potential marker of biliary stress. In the bile, hepcidin may serve local functions such as protection from bacterial infections. PMID- 21283682 TI - Standing genetic variation in contingency loci drives the rapid adaptation of Campylobacter jejuni to a novel host. AB - The genome of the food-borne pathogen Campylobacter jejuni contains multiple highly mutable sites, or contingency loci. It has been suggested that standing variation at these loci is a mechanism for rapid adaptation to a novel environment, but this phenomenon has not been shown experimentally. In previous work we showed that the virulence of C. jejuni NCTC11168 increased after serial passage through a C57BL/6 IL-10(-/-) mouse model of campylobacteriosis. Here we sought to determine the genetic basis of this adaptation during passage. Re sequencing of the 1.64 Mb genome to 200-500 X coverage allowed us to define variation in 23 contingency loci to an unprecedented depth both before and after in vivo adaptation. Mutations in the mouse-adapted C. jejuni were largely restricted to the homopolymeric tracts of thirteen contingency loci. These changes cause significant alterations in open reading frames of genes in surface structure biosynthesis loci and in genes with only putative functions. Several loci with open reading frame changes also had altered transcript abundance. The increase in specific phases of contingency loci during in vivo passage of C. jejuni, coupled with the observed virulence increase and the lack of other types of genetic changes, is the first experimental evidence that these variable regions play a significant role in C. jejuni adaptation and virulence in a novel host. PMID- 21283683 TI - It takes two-skilled recognition of objects engages lateral areas in both hemispheres. AB - Our object recognition abilities, a direct product of our experience with objects, are fine-tuned to perfection. Left temporal and lateral areas along the dorsal, action related stream, as well as left infero-temporal areas along the ventral, object related stream are engaged in object recognition. Here we show that expertise modulates the activity of dorsal areas in the recognition of man made objects with clearly specified functions. Expert chess players were faster than chess novices in identifying chess objects and their functional relations. Experts' advantage was domain-specific as there were no differences between groups in a control task featuring geometrical shapes. The pattern of eye movements supported the notion that experts' extensive knowledge about domain objects and their functions enabled superior recognition even when experts were not directly fixating the objects of interest. Functional magnetic resonance imaging (fMRI) related exclusively the areas along the dorsal stream to chess specific object recognition. Besides the commonly involved left temporal and parietal lateral brain areas, we found that only in experts homologous areas on the right hemisphere were also engaged in chess specific object recognition. Based on these results, we discuss whether skilled object recognition does not only involve a more efficient version of the processes found in non-skilled recognition, but also qualitatively different cognitive processes which engage additional brain areas. PMID- 21283684 TI - Positive feedbacks in seagrass ecosystems--evidence from large-scale empirical data. AB - Positive feedbacks cause a nonlinear response of ecosystems to environmental change and may even cause bistability. Even though the importance of feedback mechanisms has been demonstrated for many types of ecosystems, their identification and quantification is still difficult. Here, we investigated whether positive feedbacks between seagrasses and light conditions are likely in seagrass ecosystems dominated by the temperate seagrass Zostera marina. We applied a combination of multiple linear regression and structural equation modeling (SEM) on a dataset containing 83 sites scattered across Western Europe. Results confirmed that a positive feedback between sediment conditions, light conditions and seagrass density is likely to exist in seagrass ecosystems. This feedback indicated that seagrasses are able to trap and stabilize suspended sediments, which in turn improves water clarity and seagrass growth conditions. Furthermore, our analyses demonstrated that effects of eutrophication on light conditions, as indicated by surface water total nitrogen, were on average at least as important as sediment conditions. This suggests that in general, eutrophication might be the most important factor controlling seagrasses in sheltered estuaries, while the seagrass-sediment-light feedback is a dominant mechanism in more exposed areas. Our study demonstrates the potentials of SEM to identify and quantify positive feedbacks mechanisms for ecosystems and other complex systems. PMID- 21283685 TI - It takes two to tango: defining an essential second active site in pyridoxal 5' phosphate synthase. AB - The prevalent de novo biosynthetic pathway of vitamin B6 involves only two enzymes (Pdx1 and Pdx2) that form an ornate multisubunit complex functioning as a glutamine amidotransferase. The synthase subunit, Pdx1, utilizes ribose 5 phosphate and glyceraldehyde 3-phosphate, as well as ammonia derived from the glutaminase activity of Pdx2 to directly form the cofactor vitamer, pyridoxal 5' phosphate. Given the fact that a single enzyme performs the majority of the chemistry behind this reaction, a complicated mechanism is anticipated. Recently, the individual steps along the reaction co-ordinate are beginning to be unraveled. In particular, the binding of the pentose substrate and the first steps of the reaction have been elucidated but it is not known if the latter part of the chemistry, involving the triose sugar, takes place in the same or a disparate site. Here, we demonstrate through the use of enzyme assays, enzyme kinetics, and mutagenesis studies that indeed a second site is involved in binding the triose sugar and moreover, is the location of the final vitamin product, pyridoxal 5'-phosphate. Furthermore, we show that product release is triggered by the presence of a PLP-dependent enzyme. Finally, we provide evidence that a single arginine residue of the C terminus of Pdx1 is responsible for coordinating co-operativity in this elaborate protein machinery. PMID- 21283686 TI - Surface localization of glucosylceramide during Cryptococcus neoformans infection allows targeting as a potential antifungal. AB - Cryptococcus neoformans (Cn) is a significant human pathogen that, despite current treatments, continues to have a high morbidity rate especially in sub Saharan Africa. The need for more tolerable and specific therapies has been clearly shown. In the search for novel drug targets, the gene for glucosylceramide synthase (GCS1) was deleted in Cn, resulting in a strain (Deltagcs1) that does not produce glucosylceramide (GlcCer) and is avirulent in mouse models of infection. To understand the biology behind the connection between virulence and GlcCer, the production and localization of GlcCer must be characterized in conditions that are prohibitive to the growth of Deltagcs1 (neutral pH and high CO(2)). These prohibitive conditions are physiologically similar to those found in the extracellular spaces of the lung during infection. Here, using immunofluorescence, we have shown that GlcCer localization to the cell surface is significantly increased during growth in these conditions and during infection. We further seek to exploit this localization by treatment with Cerezyme (Cz), a recombinant enzyme that metabolizes GlcCer, as a potential treatment for Cn. Cz treatment was found to reduce the amount of GlcCer in vitro, in cultures, and in Cn cells inhabiting the mouse lung. Treatment with Cz induced a membrane integrity defect in wild type Cn cells similar to Deltagcs1. Cz treatment also reduced the in vitro growth of Cn in a dose and condition dependent manner. Finally, Cz treatment was shown to have a protective effect on survival in mice infected with Cn. Taken together, these studies have established the legitimacy of targeting the GlcCer and other related sphingolipid systems in the development of novel therapeutics. PMID- 21283687 TI - Osteopontin expression during early cerebral ischemia-reperfusion in rats: enhanced expression in the right cortex is suppressed by acetaminophen. AB - Osteopontin (OPN) is a pleiotropic protein implicated in various inflammatory responses including ischemia-reperfusion (I-R) injury. Two distinct forms of the protein have been identified: an extensively studied secreted form (sOPN) and a less-well-known intracellular form (iOPN). Studies have shown that increased OPN expression parallels the time course of macrophage infiltration into injured tissue, a late event in the development of cerebral infarcts. sOPN has been suggested to promote remodeling of the extracellular matrix in the brain; the function of iOPN may be to facilitate certain signal transduction processes. Here, we studied OPN expression in adult male Sprague-Dawley rats subjected to global forebrain I-R injury. We found iOPN in the cytoplasm of both cortices and the hippocampus, but unexpectedly only the right cortex exhibited a marked increase in the iOPN level after 45 min of reperfusion. Acetaminophen, a drug recently shown to decrease apoptotic incidence, caspase-9 activation, and mitochondrial dysfunction during global I-R, significantly inhibited the increase in iOPN protein in the right cortex, suggesting a role for iOPN in the response to I-R injury in the right cortex. PMID- 21283688 TI - Plxdc2 is a mitogen for neural progenitors. AB - The development of different brain regions involves the coordinated control of proliferation and cell fate specification along and across the neuraxis. Here, we identify Plxdc2 as a novel regulator of these processes, using in ovo electroporation and in vitro cultures of mammalian cells. Plxdc2 is a type I transmembrane protein with some homology to nidogen and to plexins. It is expressed in a highly discrete and dynamic pattern in the developing nervous system, with prominent expression in various patterning centres. In the chick neural tube, where Plxdc2 expression parallels that seen in the mouse, misexpression of Plxdc2 increases proliferation and alters patterns of neurogenesis, resulting in neural tube thickening at early stages. Expression of the Plxdc2 extracellular domain alone, which can be cleaved and shed in vivo, is sufficient for this activity, demonstrating a cell non-autonomous function. Induction of proliferation is also observed in cultured embryonic neuroepithelial cells (ENCs) derived from E9.5 mouse neural tube, which express a Plxdc2-binding activity. These experiments uncover a direct molecular activity of Plxdc2 in the control of proliferation, of relevance in understanding the role of this protein in various cancers, where its expression has been shown to be altered. They also implicate Plxdc2 as a novel component of the network of signalling molecules known to coordinate proliferation and differentiation in the developing nervous system. PMID- 21283689 TI - Glutathione transferase from Trichoderma virens enhances cadmium tolerance without enhancing its accumulation in transgenic Nicotiana tabacum. AB - BACKGROUND: Cadmium (Cd) is a major heavy metal pollutant which is highly toxic to plants and animals. Vast agricultural areas worldwide are contaminated with Cd. Plants take up Cd and through the food chain it reaches humans and causes toxicity. It is ideal to develop plants tolerant to Cd, without enhanced accumulation in the edible parts for human consumption. Glutathione transferases (GST) are a family of multifunctional enzymes known to have important roles in combating oxidative stresses induced by various heavy metals including Cd. Some GSTs are also known to function as glutathione peroxidases. Overexpression/heterologous expression of GSTs is expected to result in plants tolerant to heavy metals such as Cd. RESULTS: Here, we report cloning of a glutathione transferase gene from Trichoderma virens, a biocontrol fungus and introducing it into Nicotiana tabacum plants by Agrobacterium-mediated gene transfer. Transgenic nature of the plants was confirmed by Southern blot hybridization and expression by reverse transcription PCR. Transgene (TvGST) showed single gene Mendelian inheritance. When transgenic plants expressing TvGST gene were exposed to different concentrations of Cd, they were found to be more tolerant compared to wild type plants, with transgenic plants showing lower levels of lipid peroxidation. Levels of different antioxidant enzymes such as glutathione transferase, superoxide dismutase, ascorbate peroxidase, guiacol peroxidase and catalase showed enhanced levels in transgenic plants expressing TvGST compared to control plants, when exposed to Cd. Cadmium accumulation in the plant biomass in transgenic plants were similar or lower than wild-type plants. CONCLUSION: The results of the present study suggest that transgenic tobacco plants expressing a Trichoderma virens GST are more tolerant to Cd, without enhancing its accumulation in the plant biomass. It should be possible to extend the present results to crop plants for developing Cd tolerance and in limiting Cd availability in the food chain. PMID- 21283690 TI - Field of attention for instantaneous object recognition. AB - BACKGROUND: Instantaneous object discrimination and categorization are fundamental cognitive capacities performed with the guidance of visual attention. Visual attention enables selection of a salient object within a limited area of the visual field; we referred to as "field of attention" (FA). Though there is some evidence concerning the spatial extent of object recognition, the following questions still remain unknown: (a) how large is the FA for rapid object categorization, (b) how accuracy of attention is distributed over the FA, and (c) how fast complex objects can be categorized when presented against backgrounds formed by natural scenes. METHODOLOGY/PRINCIPAL FINDINGS: To answer these questions, we used a visual perceptual task in which subjects were asked to focus their attention on a point while being required to categorize briefly flashed (20 ms) photographs of natural scenes by indicating whether or not these contained an animal. By measuring the accuracy of categorization at different eccentricities from the fixation point, we were able to determine the spatial extent and the distribution of accuracy over the FA, as well as the speed of categorizing objects using stimulus onset asynchrony (SOA). Our results revealed that subjects are able to rapidly categorize complex natural images within about 0.1 s without eye movement, and showed that the FA for instantaneous image categorization covers a visual field extending 20 degrees * 24 degrees , and accuracy was highest (>90%) at the center of FA and declined with increasing eccentricity. CONCLUSIONS/SIGNIFICANCE: In conclusion, human beings are able to categorize complex natural images at a glance over a large extent of the visual field without eye movement. PMID- 21283691 TI - Analysis of DNA methylation in various swine tissues. AB - DNA methylation is known to play an important role in regulating gene expression during biological development and tissue differentiation in eukaryotes. In this study, we used the fluorescence-labeled methylation-sensitive amplified polymorphism (F-MSAP) method to assess the extent and pattern of cytosine methylation in muscle, heart, liver, spleen, lung, kidney and stomach from the swine strain Laiwu, and we also examined specific methylation patterns in the seven tissues. In total, 96,371 fragments, each representing a recognition site cleaved by either or both EcoRI + HpaII and EcoRI + MspI, the HpaII and MspI are isoschizomeric enzymes, were amplified using 16 pairs of selective primers. A total of 50,094 sites were found to be methylated at cytosines in seven tissues. The incidence of DNA methylation was approximately 53.99% in muscle, 51.24% in the heart, 50.18% in the liver, 53.31% in the spleen, 51.97% in the lung, 51.15% in the kidney and 53.39% in the stomach, as revealed by the incidence of differential digestion. Additionally, differences in DNA methylation levels imply that such variations may be related to specific gene expression during tissue differentiation, growth and development. Three types of bands were generated in the F-MSAP profile, the total numbers of these three types of bands in the seven tissues were 46,277, 24,801 and 25,293, respectively.In addition, different methylation patterns were observed in seven tissues from pig, and almost all of the methylation patterns detected by F-MSAP could be confirmed by Southern analysis using the isolated amplified fragments as probes. The results clearly demonstrated that the F-MSAP technique can be adapted for use in large-scale DNA methylation detection in the pig genome. PMID- 21283692 TI - Whole transcriptome sequencing reveals gene expression and splicing differences in brain regions affected by Alzheimer's disease. AB - Recent studies strongly indicate that aberrations in the control of gene expression might contribute to the initiation and progression of Alzheimer's disease (AD). In particular, alternative splicing has been suggested to play a role in spontaneous cases of AD. Previous transcriptome profiling of AD models and patient samples using microarrays delivered conflicting results. This study provides, for the first time, transcriptomic analysis for distinct regions of the AD brain using RNA-Seq next-generation sequencing technology. Illumina RNA-Seq analysis was used to survey transcriptome profiles from total brain, frontal and temporal lobe of healthy and AD post-mortem tissue. We quantified gene expression levels, splicing isoforms and alternative transcript start sites. Gene Ontology term enrichment analysis revealed an overrepresentation of genes associated with a neuron's cytological structure and synapse function in AD brain samples. Analysis of the temporal lobe with the Cufflinks tool revealed that transcriptional isoforms of the apolipoprotein E gene, APOE-001, -002 and -005, are under the control of different promoters in normal and AD brain tissue. We also observed differing expression levels of APOE-001 and -002 splice variants in the AD temporal lobe. Our results indicate that alternative splicing and promoter usage of the APOE gene in AD brain tissue might reflect the progression of neurodegeneration. PMID- 21283693 TI - Non-invasive predictors of human cortical bone mechanical properties: T(2) discriminated H NMR compared with high resolution X-ray. AB - Recent advancements in magnetic resonance imaging (MRI) have enabled clinical imaging of human cortical bone, providing a potentially powerful new means for assessing bone health with molecular-scale sensitivities unavailable to conventional X-ray-based diagnostics. To this end, (1)H nuclear magnetic resonance (NMR) and high-resolution X-ray signals from human cortical bone samples were correlated with mechanical properties of bone. Results showed that (1)H NMR signals were better predictors of yield stress, peak stress, and pre yield toughness than were the X-ray derived signals. These (1)H NMR signals can, in principle, be extracted from clinical MRI, thus offering the potential for improved clinical assessment of fracture risk. PMID- 21283694 TI - Curcumin alleviates matrix metalloproteinase-3 and -9 activities during eradication of Helicobacter pylori infection in cultured cells and mice. AB - Current therapy-regimens against Helicobacter pylori (Hp) infections have considerable failure rates and adverse side effects that urge the quest for an effective alternative therapy. We have shown that curcumin is capable of eradicating Hp-infection in mice. Here we examine the mechanism by which curcumin protects Hp infection in cultured cells and mice. Since, MMP-3 and -9 are inflammatory molecules associated to the pathogenesis of Hp-infection, we investigated the role of curcumin on inflammatory MMPs as well as proinflammatory molecules. Curcumin dose dependently suppressed MMP-3 and -9 expression in Hp infected human gastric epithelial (AGS) cells. Consistently, Hp-eradication by curcumin-therapy involved significant downregulation of MMP-3 and -9 activities and expression in both cytotoxic associated gene (cag)(+ve) and cag(-ve) Hp infected mouse gastric tissues. Moreover, we demonstrate that the conventional triple therapy (TT) alleviated MMP-3 and -9 activities less efficiently than curcumin and curcumin's action on MMPs was linked to decreased pro-inflammatory molecules and activator protein-1 activation in Hp-infected gastric tissues. Although both curcumin and TT were associated with MMP-3 and -9 downregulation during Hp-eradication, but unlike TT, curcumin enhanced peroxisome proliferator activated receptor-gamma and inhibitor of kappa B-alpha. These data indicate that curcumin-mediated healing of Hp-infection involves regulation of MMP-3 and -9 activities. PMID- 21283695 TI - Computational design of auxotrophy-dependent microbial biosensors for combinatorial metabolic engineering experiments. AB - Combinatorial approaches in metabolic engineering work by generating genetic diversity in a microbial population followed by screening for strains with improved phenotypes. One of the most common goals in this field is the generation of a high rate chemical producing strain. A major hurdle with this approach is that many chemicals do not have easy to recognize attributes, making their screening expensive and time consuming. To address this problem, it was previously suggested to use microbial biosensors to facilitate the detection and quantification of chemicals of interest. Here, we present novel computational methods to: (i) rationally design microbial biosensors for chemicals of interest based on substrate auxotrophy that would enable their high-throughput screening; (ii) predict engineering strategies for coupling the synthesis of a chemical of interest with the production of a proxy metabolite for which high-throughput screening is possible via a designed bio-sensor. The biosensor design method is validated based on known genetic modifications in an array of E. coli strains auxotrophic to various amino-acids. Predicted chemical production rates achievable via the biosensor-based approach are shown to potentially improve upon those predicted by current rational strain design approaches. (A Matlab implementation of the biosensor design method is available via http://www.cs.technion.ac.il/~tomersh/tools). PMID- 21283696 TI - Comparison of HIV-, HBV-, HCV- and co-infection prevalence between Chinese and Burmese intravenous drug users of the China-Myanmar border region. AB - BACKGROUND: Co-infection with HIV and HCV and/or HBV is highly prevalent in intravenous drug users (IDUs). Because of the proximity to the "Golden Triangle", HIV prevalence among the IDUs is very high in the China-Myanmar border region. However, there are few studies about co-infection with HIV and HCV and/or HBV, especially in the region that belongs to Myanmar. METHODS: 721 IDUs, including 403 Chinese and 318 Burmese, were investigated for their HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) serological status. Statistical analysis was performed to evaluate the differences of the epidemic situation between the Chinese IDUs and the Burmese IDUs. RESULTS: Among the Chinese IDUs and the Burmese IDUs, HCV infection was the most prevalent (69.0% vs 48.1%, P<0.001), followed by HBV (51.6% vs 43.1%, P<0.05) and HIV (33.7% vs 27.0%, P>0.05). Besides, there were more HIV-HBV co-infected IDUs (20.1% vs 11.3%, P<0.005), and HIV-HCV co-infected IDUs (31.8% vs 23.9%, P<0.05) in China than in Myanmar, as well as HIV-HBV-HCV triple infection (19.1% vs 10.4%, P<0.005). CONCLUSION: Co infection with HIV and HCV and/or HBV is highly prevalent among the IDUs in the China-Myanmar border region. The HIV epidemic appears to be in a downward trend, compared with previous reports. However, all infections were more prevalent among the Chinese IDUs than among the Burmese. PMID- 21283697 TI - Isolation and partial characterisation of a novel lectin from Aegle marmelos fruit and its effect on adherence and invasion of Shigellae to HT29 cells. AB - Lectins are a class of ubiquitous proteins/glycoproteins that are abundantly found in nature. Lectins have unique carbohydrate binding property and hence have been exploited as drugs against various infectious diseases. We have isolated one such novel lectin from the fruit pulp of Aegle marmelos. The isolated lectin was partially characterised and its effect against Shigella dysenteriae infection was evaluated. The isolated lectin was found to be a dimeric protein with N acetylgalactosamine, mannose and sialic acid binding specificity. The effect of Aegle marmelos fruit lectin on the adherence of Shigella dysenteriae to human colonic epithelial cells (HT29 cells) was evaluated by Enzyme Linked Immune Sorbent Assay and invasion was analysed. The protective nature of the Aegle marmelos fruit lectin was assessed by analyzing apoptosis through dual staining method. Aegle marmelos fruit lectin significantly inhibited hemagglutination activity of Shigella and its minimum inhibitory concentration is 0.625 ug/well. Further, at this concentration lectin inhibited Shigella dysenteriae adherence and invasion of HT29 cells and protects the HT29 cells from Shigella dysenteriae induced apoptosis. To conclude, isolated lectin dimeric protein with N acetylgalactosamine, Mannose and sialic acid binding specificity and inhibits adherence and invasion of Shigellae to HT29 cells thus, protects the host. PMID- 21283698 TI - Estimating the power of indirect comparisons: a simulation study. AB - BACKGROUND: Indirect comparisons are becoming increasingly popular for evaluating medical treatments that have not been compared head-to-head in randomized clinical trials (RCTs). While indirect methods have grown in popularity and acceptance, little is known about the fragility of confidence interval estimations and hypothesis testing relying on this method. METHODS: We present the findings of a simulation study that examined the fragility of indirect confidence interval estimation and hypothesis testing relying on the adjusted indirect method. FINDINGS: Our results suggest that, for the settings considered in this study, indirect confidence interval estimation suffers from under coverage while indirect hypothesis testing suffers from low power in the presence of moderate to large between-study heterogeneity. In addition, the risk of overestimation is large when the indirect comparison of interest relies on just one trial for one of the two direct comparisons. INTERPRETATION: Indirect comparisons typically suffer from low power. The risk of imprecision is increased when comparisons are unbalanced. PMID- 21283699 TI - Stimulus saliency modulates pre-attentive processing speed in human visual cortex. AB - The notion of a saliency-based processing architecture [1] underlying human vision is central to a number of current theories of visual selective attention [e.g., 2]. On this view, focal-attention is guided by an overall-saliency map of the scene, which integrates (sums) signals from pre-attentive sensory feature contrast computations (e.g., for color, motion, etc.). By linking the Posterior Contralateral Negativity (PCN) component to reaction time (RT) performance, we tested one specific prediction of such salience summation models: expedited shifts of focal-attention to targets with low, as compared to high, target distracter similarity. For two feature-dimensions (color and orientation), we observed decreasing RTs with increasing target saliency. Importantly, this pattern was systematically mirrored by the timing, as well as amplitude, of the PCN. This pattern demonstrates that visual saliency is a key determinant of the time it takes for focal-attention to be engaged onto the target item, even when it is just a feature singleton. PMID- 21283700 TI - Polymorphic allele of human IRGM1 is associated with susceptibility to tuberculosis in African Americans. AB - An ancestral polymorphic allele of the human autophagy-related gene IRGM1 is associated with altered gene expression and a genetic risk for Crohn's Disease (CD). We used the single nucleotide polymorphism rs10065172C/T as a marker of this polymorphic allele and genotyped 370 African American and 177 Caucasian tuberculosis (TB) cases and 180 African American and 110 Caucasian controls. Among African Americans, the TB cases were more likely to carry the CD-related T allele of rs10065172 (odds ratio of 1.54; 95% confidence interval, 1.17-2.02; P<0.01) compared to controls. Our finding suggests that this CD-related IRGM1 polymorphic allele is also associated with human susceptibility to TB disease among African Americans. PMID- 21283701 TI - Constitutive activation of the thyroid-stimulating hormone receptor (TSHR) by mutating Ile691 in the cytoplasmic tail segment. AB - BACKGROUND: Autosomal dominant non-autoimmune hyperthyroidism (ADNAH) is a rare genetic disorder of the endocrine system. Molecular genetic studies in ADNAH have revealed heterozygous germline mutations in the TSHR. To data, mutations leading to an increase in the constitutive activation of the TSHR have been described in the transmembrane segments, exoloops and cytoplasmic loop of TSHR. These mutations result in constitutive activation of the G(alphas)/cAMP or G(alphaq/11)/inositol phosphate (IP) pathways, which stimulate thyroid hormone production and thyroid proliferation. METHODOLOGY/PRINCIPAL FINDINGS: In a previous study, we reported a new TSHR mutation located in the C-terminal domain of TSHR, which results in a substitution of the conserved Ile(691) for Phe. In this study, to address the question of whether the I691F mutated receptor could be responsible for G(alphas)/cAMP or G(alphaq/11)/IP constitutive activity, wild type and TSHR mutants were expressed in COS-7 cells to determine cAMP constitutive activity and IP formation. Compared to the cell surface with expression of the A623V mutated receptor as positive control, the I691F mutated receptor showed a slight increase of cAMP accumulation. Furthermore, I691F resulted in constitutive activation of the G(alphaq/11)/IP signaling pathway. CONCLUSIONS/SIGNIFICANCE: Our results indicate that Ile(691) not only contributes to keeping TSHR inactive in the G(alphas)/cAMP pathways but also in the G(alphaq/11)/IP cascade. PMID- 21283702 TI - Disruption of the abdominal-B promoter tethering element results in a loss of long-range enhancer-directed Hox gene expression in Drosophila. AB - There are many examples within gene complexes of transcriptional enhancers interacting with only a subset of target promoters. A number of molecular mechanisms including promoter competition, insulators and chromatin looping are thought to play a role in regulating these interactions. At the Drosophila bithorax complex (BX-C), the IAB5 enhancer specifically drives gene expression only from the Abdominal-B (Abd-B) promoter, even though the enhancer and promoter are 55 kb apart and are separated by at least three insulators. In previous studies, we discovered that a 255 bp cis-regulatory module, the promoter tethering element (PTE), located 5' of the Abd-B transcriptional start site is able to tether IAB5 to the Abd-B promoter in transgenic embryo assays. In this study we examine the functional role of the PTE at the endogenous BX-C using transposon-mediated mutagenesis. Disruption of the PTE by P element insertion results in a loss of enhancer-directed Abd-B expression during embryonic development and a homeotic transformation of abdominal segments. A partial deletion of the PTE and neighboring upstream genomic sequences by imprecise excision of the P element also results in a similar loss of Abd-B expression in embryos. These results demonstrate that the PTE is an essential component of the regulatory network at the BX-C and is required in vivo to mediate specific long range enhancer-promoter interactions. PMID- 21283703 TI - Changes in present and future circulation types frequency in northwest Iberian Peninsula. AB - The aim of the work described herein was to study projection scenarios in order to find changes in the synoptic variability of the northwest Iberian Peninsula in the 21st century. To this end, we investigated the changes in the frequency of the different circulation types computed for the study area using three different models used in the IPCC 4(th) assessment report. The circulation types were computed using the procedure known as Lamb circulation types. The control simulation for the late 20th century was evaluated objectively from the results obtained using data from the NCEP/NCAR reanalysis, as to evaluate the ability of the model to reproduce the present climate. We have compared not only seasonal mean sea level pressure fields but also the mean seasonal frequency of circulation types. The results for the end of the 21st century show a decrease in the frequency of cyclonic, W, and SW circulation types in the spring and summer months. This trend also appears in the autumn, with a concomitant increase in the anticyclonic types. PMID- 21283704 TI - Modulation of the major paths of carbon in photorespiratory mutants of synechocystis. AB - BACKGROUND: Recent studies using transcript and metabolite profiles of wild-type and gene deletion mutants revealed that photorespiratory pathways are essential for the growth of Synechocystis sp. PCC 6803 under atmospheric conditions. Pool size changes of primary metabolites, such as glycine and glycolate, indicated a link to photorespiration. METHODOLOGY/PRINCIPAL FINDINGS: The (13)C labelling kinetics of primary metabolites were analysed in photoautotrophically grown cultures of Synechocystis sp. PCC 6803 by gas chromatography-mass spectrometry (GC-MS) to demonstrate the link with photorespiration. Cells pre-acclimated to high CO(2) (5%, HC) or limited CO(2) (0.035%, LC) conditions were pulse-labelled under very high (2% w/w) (13)C-NaHCO(3) (VHC) conditions followed by treatment with ambient (12)C at HC and LC conditions, respectively. The (13)C enrichment, relative changes in pool size, and (13)C flux of selected metabolites were evaluated. We demonstrate two major paths of CO(2) assimilation via Rubisco in Synechocystis, i.e., from 3PGA via PEP to aspartate, malate and citrate or, to a lesser extent, from 3PGA via glucose-6-phosphate to sucrose. The results reveal evidence of carbon channelling from 3PGA to the PEP pool. Furthermore, (13)C labelling of glycolate was observed under conditions thought to suppress photorespiration. Using the glycolate-accumulating DeltaglcD1 mutant, we demonstrate enhanced (13)C partitioning into the glycolate pool under conditions favouring photorespiration and enhanced (13)C partitioning into the glycine pool of the glycine-accumulating DeltagcvT mutant. Under LC conditions, the photorespiratory mutants DeltaglcD1 and DeltagcvT showed enhanced activity of the additional carbon-fixing PEP carboxylase pathway. CONCLUSIONS/SIGNIFICANCE: With our approach of non-steady-state (13)C labelling and analysis of metabolite pool sizes with respective (13)C enrichments, we identify the use and modulation of major pathways of carbon assimilation in Synechocystis in the presence of high and low inorganic carbon supplies. PMID- 21283705 TI - Structural basis of enzymatic activity for the ferulic acid decarboxylase (FADase) from Enterobacter sp. Px6-4. AB - Microbial ferulic acid decarboxylase (FADase) catalyzes the transformation of ferulic acid to 4-hydroxy-3-methoxystyrene (4-vinylguaiacol) via non-oxidative decarboxylation. Here we report the crystal structures of the Enterobacter sp. Px6-4 FADase and the enzyme in complex with substrate analogues. Our analyses revealed that FADase possessed a half-opened bottom beta-barrel with the catalytic pocket located between the middle of the core beta-barrel and the helical bottom. Its structure shared a high degree of similarity with members of the phenolic acid decarboxylase (PAD) superfamily. Structural analysis revealed that FADase catalyzed reactions by an "open-closed" mechanism involving a pocket of 8 * 8 * 15 A dimension on the surface of the enzyme. The active pocket could directly contact the solvent and allow the substrate to enter when induced by substrate analogues. Site-directed mutagenesis showed that the E134A mutation decreased the enzyme activity by more than 60%, and Y21A and Y27A mutations abolished the enzyme activity completely. The combined structural and mutagenesis results suggest that during decarboxylation of ferulic acid by FADase, Trp25 and Tyr27 are required for the entering and proper orientation of the substrate while Glu134 and Asn23 participate in proton transfer. PMID- 21283706 TI - A novel modular antigen delivery system for immuno targeting of human 6-sulfo LacNAc-positive blood dendritic cells (SlanDCs). AB - BACKGROUND: Previously, we identified a major myeloid-derived proinflammatory subpopulation of human blood dendritic cells which we termed slanDCs (e.g. Schakel et al. (2006) Immunity 24, 767-777). The slan epitope is an O-linked sugar modification (6-sulfo LacNAc, slan) of P-selectin glycoprotein ligand-1 (PSGL-1). As slanDCs can induce neoantigen-specific CD4+ T cells and tumor reactive CD8+ cytotoxic T cells, they appear as promising targets for an in vivo delivery of antigens for vaccination. However, tools for delivery of antigens to slanDCs were not available until now. Moreover, it is unknown whether or not antigens delivered via the slan epitope can be taken up, properly processed and presented by slanDCs to T cells. METHODOLOGY/PRINCIPAL FINDINGS: Single chain fragment variables were prepared from presently available decavalent monoclonal anti-slan IgM antibodies but failed to bind to slanDCs. Therefore, a novel multivalent anti-slanDC scaffold was developed which consists of two components: (i) a single chain bispecific recombinant diabody (scBsDb) that is directed on the one hand to the slan epitope and on the other hand to a novel peptide epitope tag, and (ii) modular (antigen-containing) linker peptides that are flanked at both their termini with at least one peptide epitope tag. Delivery of a Tetanus Toxin-derived antigen to slanDCs via such a scBsDb/antigen scaffold allowed us to recall autologous Tetanus-specific memory T cells. CONCLUSIONS/SIGNIFICANCE: In summary our data show that (i) the slan epitope can be used for delivery of antigens to this class of human-specific DCs, and (ii) antigens bound to the slan epitope can be taken up by slanDCs, processed and presented to T cells. Consequently, our novel modular scaffold system may be useful for the development of human vaccines. PMID- 21283707 TI - An extensive field survey combined with a phylogenetic analysis reveals rapid and widespread invasion of two alien whiteflies in China. AB - BACKGROUND: To understand the processes of invasions by alien insects is a pre requisite for improving management. The whitefly Bemisia tabaci is a cryptic species complex that contains some of the most invasive pests worldwide. However, extensive field data to show the geographic distribution of the members of this species complex as well as the invasion by some of its members are scarce. METHODOLOGY/PRINCIPAL FINDINGS: We used field surveys and published data to assess the current diversity and distribution of B. tabaci cryptic species in China and relate the indigenous members to other Asian and Australian members of the complex. The survey covered the 16 provinces where indigenous B. tabaci occur and extends this with published data for the whole of China. We used molecular markers to identify cryptic species. The evolutionary relationships between the different Asian B. tabaci were reconstructed using Bayesian methods. We show that whereas in the past the exotic invader Middle East-Asia Minor 1 was predominant across China, another newer invader Mediterranean is now the dominant species in the Yangtze River Valley and eastern coastal areas, and Middle East-Asia Minor 1 is now predominant only in the south and south eastern coastal areas. Based on mtCO1 we identified four new cryptic species, and in total we have recorded 13 indigenous and two invasive species from China. Diversity was highest in the southern and southeastern provinces and declined to north and west. Only the two invasive species were found in the northern part of the country where they occur primarily in protected cropping. By 2009, indigenous species were mainly found in remote mountainous areas and were mostly absent from extensive agricultural areas. CONCLUSIONS/SIGNIFICANCE: Invasions by some members of the whitefly B. tabaci species complex can be rapid and widespread, and indigenous species closely related to the invaders are replaced. PMID- 21283708 TI - Specific thiazolidinediones inhibit ovarian cancer cell line proliferation and cause cell cycle arrest in a PPARgamma independent manner. AB - BACKGROUND: Peroxisome Proliferator Activated Receptor gamma (PPARgamma) agonists, such as the thiazolinediones (TZDs), have been studied for their potential use as cancer therapeutic agents. We investigated the effect of four TZDs--Rosiglitazone (Rosi), Ciglitazone (CGZ), Troglitazone (TGZ), and Pioglitazone (Pio)--on ovarian cancer cell proliferation, PPARgamma expression and PPAR luciferase reporter activity. We explored whether TZDs act in a PPARgamma dependent or independent manner by utilizing molecular approaches to inhibit or overexpress PPARgamma activity. PRINCIPAL FINDINGS: Treatment with CGZ or TGZ for 24 hours decreased proliferation in three ovarian cancer cell lines, Ovcar3, CaOv3, and Skov3, whereas Rosi and Pio had no effect. This decrease in Ovcar3 cell proliferation was due to a higher fraction of cells in the G(0)/G(1) stage of the cell cycle. CGZ and TGZ treatment increased apoptosis after 4 hours of treatment but not after 8 or 12 hours. Treatment with TGZ or CGZ increased PPARgamma mRNA expression in Ovcar3 cells; however, protein levels were unchanged. Surprisingly, luciferase promoter assays revealed that none of the TZDs increased PPARgamma activity. Overexpression of wild type PPARgamma increased reporter activity. This was further augmented by TGZ, Rosi, and Pio indicating that these cells have the endogenous capacity to mediate PPARgamma transactivation. To determine whether PPARgamma mediates the TZD-induced decrease in proliferation, cells were treated with CGZ or TGZ in the absence or presence of a dominant negative (DN) or wild type overexpression PPARgamma construct. Neither vector changed the TZD-mediated cell proliferation suggesting this effect of TZDs on ovarian cancer cells may be PPARgamma independent. CONCLUSIONS: CGZ and TGZ cause a decrease in ovarian cancer cell proliferation that is PPARgamma independent. This concept is supported by the finding that a DN or overexpression of the wild type PPARgamma did not affect the changes in cell proliferation and cell cycle. PMID- 21283709 TI - Adventures in the enormous: a 1.8 million clone BAC library for the 21.7 Gb genome of loblolly pine. AB - Loblolly pine (LP; Pinus taeda L.) is the most economically important tree in the U.S. and a cornerstone species in southeastern forests. However, genomics research on LP and other conifers has lagged behind studies on flowering plants due, in part, to the large size of conifer genomes. As a means to accelerate conifer genome research, we constructed a BAC library for the LP genotype 7-56. The LP BAC library consists of 1,824,768 individually-archived clones making it the largest single BAC library constructed to date, has a mean insert size of 96 kb, and affords 7.6X coverage of the 21.7 Gb LP genome. To demonstrate the efficacy of the library in gene isolation, we screened macroarrays with overgos designed from a pine EST anchored on LP chromosome 10. A positive BAC was sequenced and found to contain the expected full-length target gene, several gene like regions, and both known and novel repeats. Macroarray analysis using the retrotransposon IFG-7 (the most abundant repeat in the sequenced BAC) as a probe indicates that IFG-7 is found in roughly 210,557 copies and constitutes about 5.8% or 1.26 Gb of LP nuclear DNA; this DNA quantity is eight times the Arabidopsis genome. In addition to its use in genome characterization and gene isolation as demonstrated herein, the BAC library should hasten whole genome sequencing of LP via next-generation sequencing strategies/technologies and facilitate improvement of trees through molecular breeding and genetic engineering. The library and associated products are distributed by the Clemson University Genomics Institute (www.genome.clemson.edu). PMID- 21283710 TI - The development of metabolomic sampling procedures for Pichia pastoris, and baseline metabolome data. AB - Metabolic profiling is increasingly being used to investigate a diverse range of biological questions. Due to the rapid turnover of intracellular metabolites it is important to have reliable, reproducible techniques for sampling and sample treatment. Through the use of non-targeted analytical techniques such as NMR and GC-MS we have performed a comprehensive quantitative investigation of sampling techniques for Pichia pastoris. It was clear that quenching metabolism using solutions based on the standard cold methanol protocol caused some metabolite losses from P. pastoris cells. However, these were at a low level, with the NMR results indicating metabolite increases in the quenching solution below 5% of their intracellular level for 75% of metabolites identified; while the GC-MS results suggest a slightly higher level with increases below 15% of their intracellular values. There were subtle differences between the four quenching solutions investigated but broadly, they all gave similar results. Total culture extraction of cells + broth using high cell density cultures typical of P. pastoris fermentations, was an efficient sampling technique for NMR analysis and provided a gold standard of intracellular metabolite levels; however, salts in the media affected the GC-MS analysis. Furthermore, there was no benefit in including an additional washing step in the quenching process, as the results were essentially identical to those obtained just by a single centrifugation step. We have identified the major high-concentration metabolites found in both the extra- and intracellular locations of P. pastoris cultures by NMR spectroscopy and GC-MS. This has provided us with a baseline metabolome for P. pastoris for future studies. The P. pastoris metabolome is significantly different from that of Saccharomyces cerevisiae, with the most notable difference being the production of high concentrations of arabitol by P. pastoris. PMID- 21283711 TI - Genetic deletion of laminin isoforms beta2 and gamma3 induces a reduction in Kir4.1 and aquaporin-4 expression and function in the retina. AB - BACKGROUND: Glial cells such as retinal Muller glial cells are involved in potassium ion and water homeostasis of the neural tissue. In these cells, inwardly rectifying potassium (Kir) channels and aquaporin-4 water channels play an important role in the process of spatial potassium buffering and water drainage. Moreover, Kir4.1 channels are involved in the maintenance of the negative Muller cell membrane potential. The subcellular distribution of Kir4.1 and aquaporin-4 channels appears to be maintained by interactions with extracellular and intracellular molecules. Laminins in the extracellular matrix, dystroglycan in the membrane, and dystrophins in the cytomatrix form a complex mediating the polarized expression of Kir4.1 and aquaporin-4 in Muller cells. METHODOLOGY/PRINCIPAL FINDINGS: The aim of the present study was to test the function of the beta2 and gamma3 containing laminins in murine Muller cells. We used knockout mice with genetic deletion of both beta2 and gamma3 laminin genes to assay the effects on Kir4.1 and aquaporin-4. We studied protein and mRNA expression by immunohistochemistry, Western Blot, and quantitative RT-PCR, respectively, and membrane currents of isolated cells by patch-clamp experiments. We found a down-regulation of mRNA and protein of Kir4.1 as well as of aquaporin 4 protein in laminin knockout mice. Moreover, Muller cells from laminin beta2 and gamma3 knockout mice had reduced Kir-mediated inward currents and their membrane potentials were more positive than those in age-matched wild-type mice. CONCLUSION: These findings demonstrate a strong impact of laminin beta2 and gamma3 subunits on the expression and function of both aquaporin-4 and Kir4.1, two important membrane proteins in Muller cells. PMID- 21283712 TI - Transcriptomic signatures of ash (Fraxinus spp.) phloem. AB - BACKGROUND: Ash (Fraxinus spp.) is a dominant tree species throughout urban and forested landscapes of North America (NA). The rapid invasion of NA by emerald ash borer (Agrilus planipennis), a wood-boring beetle endemic to Eastern Asia, has resulted in the death of millions of ash trees and threatens billions more. Larvae feed primarily on phloem tissue, which girdles and kills the tree. While NA ash species including black (F. nigra), green (F. pennsylvannica) and white (F. americana) are highly susceptible, the Asian species Manchurian ash (F. mandshurica) is resistant to A. planipennis perhaps due to their co-evolutionary history. Little is known about the molecular genetics of ash. Hence, we undertook a functional genomics approach to identify the repertoire of genes expressed in ash phloem. METHODOLOGY AND PRINCIPAL FINDINGS: Using 454 pyrosequencing we obtained 58,673 high quality ash sequences from pooled phloem samples of green, white, black, blue and Manchurian ash. Intriguingly, 45% of the deduced proteins were not significantly similar to any sequences in the GenBank non-redundant database. KEGG analysis of the ash sequences revealed a high occurrence of defense related genes. Expression analysis of early regulators potentially involved in plant defense (i.e. transcription factors, calcium dependent protein kinases and a lipoxygenase 3) revealed higher mRNA levels in resistant ash compared to susceptible ash species. Lastly, we predicted a total of 1,272 single nucleotide polymorphisms and 980 microsatellite loci, among which seven microsatellite loci showed polymorphism between different ash species. CONCLUSIONS AND SIGNIFICANCE: The current transcriptomic data provide an invaluable resource for understanding the genetic make-up of ash phloem, the target tissue of A. planipennis. These data along with future functional studies could lead to the identification/characterization of defense genes involved in resistance of ash to A. planipennis, and in future ash breeding programs for marker development. PMID- 21283713 TI - Noninvasive monitoring of placenta-specific transgene expression by bioluminescence imaging. AB - BACKGROUND: Placental dysfunction underlies numerous complications of pregnancy. A major obstacle to understanding the roles of potential mediators of placental pathology has been the absence of suitable methods for tissue-specific gene manipulation and sensitive assays for studying gene functions in the placentas of intact animals. We describe a sensitive and noninvasive method of repetitively tracking placenta-specific gene expression throughout pregnancy using lentivirus mediated transduction of optical reporter genes in mouse blastocysts. METHODOLOGY/PRINCIPAL FINDINGS: Zona-free blastocysts were incubated with lentivirus expressing firefly luciferase (Fluc) and Tomato fluorescent fusion protein for trophectoderm-specific infection and transplanted into day 3 pseudopregnant recipients (GD3). Animals were examined for Fluc expression by live bioluminescence imaging (BLI) at different points during pregnancy, and the placentas were examined for tomato expression in different cell types on GD18. In another set of experiments, blastocysts with maximum photon fluxes in the range of 2.0E+4 to 6.0E+4 p/s/cm(2)/sr were transferred. Fluc expression was detectable in all surrogate dams by day 5 of pregnancy by live imaging, and the signal increased dramatically thereafter each day until GD12, reaching a peak at GD16 and maintaining that level through GD18. All of the placentas, but none of the fetuses, analyzed on GD18 by BLI showed different degrees of Fluc expression. However, only placentas of dams transferred with selected blastocysts showed uniform photon distribution with no significant variability of photon intensity among placentas of the same litter. Tomato expression in the placentas was limited to only trophoblast cell lineages. CONCLUSIONS/SIGNIFICANCE: These results, for the first time, demonstrate the feasibility of selecting lentivirally-transduced blastocysts for uniform gene expression in all placentas of the same litter and early detection and quantitative analysis of gene expression throughout pregnancy by live BLI. This method may be useful for a wide range of applications involving trophoblast-specific gene manipulations in utero. PMID- 21283714 TI - Effects of non-thermal plasma on mammalian cells. AB - Thermal plasmas and lasers have been widely used in medicine to cut, ablate and cauterize tissues through heating; in contrast, non-thermal plasma produces no heat, so its effects can be selective. In order to exploit the potential for clinical applications, including wound healing, sterilization, blood coagulation, and cancer treatment, a mechanistic understanding of the interaction of non thermal plasma with living tissues is required. Using mammalian cells in culture, it is shown here that non-thermal plasma created by dielectric barrier discharge (DBD) has dose-dependent effects that range from increasing cell proliferation to inducing apoptosis. It is also shown that these effects are primarily due to formation of intracellular reactive oxygen species (ROS). We have utilized gamma H2AX to detect DNA damage induced by non-thermal plasma and found that it is initiated by production of active neutral species that most likely induce formation of organic peroxides in cell medium. Phosphorylation of H2AX following non-thermal plasma treatment is ATR dependent and ATM independent, suggesting that plasma treatment may lead to replication arrest or formation of single stranded DNA breaks; however, plasma does not lead to formation of bulky adducts/thymine dimers. PMID- 21283715 TI - The mammalian class 3 PI3K (PIK3C3) is required for early embryogenesis and cell proliferation. AB - The Pik3c3 gene encodes an 887 amino acid lipid kinase, phosphoinositide-3-kinase class 3 (PIK3C3). PIK3C3 is known to regulate various intracellular membrane trafficking events. However, little is known about its functions during early embryogenesis in mammals. To investigate the function of PIK3C3 in vivo, we generated Pik3c3 null mice. We show here that Pik3c3 heterozygous are normal and fertile. In contrast, Pik3c3 homozygous mutants are embryonic lethal and die between E7.5 and E8.5 of embryogenesis. Mutant embryos are poorly developed with no evidence of mesoderm formation, and suffer from severely reduced cell proliferations. Cell proliferation defect is also evident in vitro, where mutant blastocysts in culture fail to give rise to typical colonies formed by inner cell mass. Electron microscopic analysis revealed that epiblast cells in mutant embryos appear normal, whereas the visceral endoderm cells contain larger vesicles inside the lipid droplets. Finally, we provide evidence that mTOR signaling is drastically reduced in Pik3c3 null embryos, which could be a major contributor to the observed proliferation and embryogenesis defects. PMID- 21283716 TI - Social, clinical and microbiological differential characteristics of tuberculosis among immigrants in Spain. AB - BACKGROUND: To identify the differential tuberculosis (TB) characteristics within the immigrant population with respect to natives in Spain. METHODOLOGY/PRINCIPAL FINDINGS: A prospective cohort study design was implemented to examine the TB cases diagnosed and starting standard antituberculous treatment in Spain, between January 1st 2006 and March 31st 2007. A logistic regression analysis was performed to determine differential characteristics. 1,490 patients were included in the study population, 1,048 natives and 442 (29.7%) immigrants. According to the multivariate analysis, the following variables were significantly associated with immigrant TB cases: younger age (OR = 3.79; CI:2.16-6.62), living in group situation (OR = 7.61; CI:3.38-12.12), lower frequency of disabled (OR:0.08; CI:0.02-0.26) and retired (OR:0.21; CI:0.09-0.48) employment status, lower frequency of pulmonary disease presentation (OR = 0.47; CI:0.24-0.92), primary or emergency care admission (OR = 1.80; CI:1.05-3.06 and OR = 2.16; CI:1.36-3.45), drug resistance (OR = 1.86; CI:1.01-3.46), treatment default (OR:2.12; CI:1.18 3.81), lower frequency of alcohol and cigarette consumption (OR = 2.10; CI:1.42 3.11 and OR = 2.85; CI:2.10-3.87 respectively), more directly observed treatment (OR = 1.68; CI:1.04-2.69), and poor understanding of TB disease and its treatment (OR = 3.11; CI:1.86-5.20). The low percentage of primary MDR-TB in the native population (0.1% vs. 2.2% of immigrants) should be noted. CONCLUSIONS/SIGNIFICANCE: The differences show the need to introduce specific strategies in the management of TB within the immigrant population, including the improvement of social and work conditions. PMID- 21283717 TI - Plasmodium vivax tryptophan-rich antigen PvTRAg33.5 contains alpha helical structure and multidomain architecture. AB - Tryptophan-rich proteins from several malarial parasites have been identified where they play an important role in host-parasite interaction. Structural characterization of these proteins is needed to develop them as therapeutic targets. Here, we describe a novel Plasmodium vivax tryptophan-rich protein named PvTRAg33.5. It is expressed by blood stage(s) of the parasite and its gene contains two exons. The exon 1 encodes for a 23 amino acids long putative signal peptide which is likely to be cleaved off whereas the exon 2 encodes for the mature protein of 252 amino acids. The mature protein contains B-cell epitopes which were recognized by the human immune system during P.vivax infection. The PvTRAg33.5 contains 24 (9.5%) tryptophan residues and six motifs whose patterns were similar among tryptophan-rich proteins. The modeled structure of the PvTRAg33.5 consists of a multidomain architecture which is stabilized by the presence of large number of tryptophan residues. The recombinant PvTRAg33.5 showed predominantly alpha helical structure and alpha helix to beta sheet transition at pH below 4.5. Protein acquires an irreversible non-native state at temperature more than 50 degrees C at neutral pH. Its secondary and tertiary structures remain stable in the presence of 35% alcohol but these structures are destabilized at higher alcohol concentrations due to the disturbance of hydrophobic interactions between tryptophanyl residues. These structural changes in the protein might occur during its translocation to interact with other proteins at its final destination for biological function such as erythrocyte invasion. PMID- 21283718 TI - Genetic analysis of Hedgehog signaling in ventral body wall development and the onset of omphalocele formation. AB - BACKGROUND: An omphalocele is one of the major ventral body wall malformations and is characterized by abnormally herniated viscera from the body trunk. It has been frequently found to be associated with other structural malformations, such as genitourinary malformations and digit abnormalities. In spite of its clinical importance, the etiology of omphalocele formation is still controversial. Hedgehog (Hh) signaling is one of the essential growth factor signaling pathways involved in the formation of the limbs and urogenital system. However, the relationship between Hh signaling and ventral body wall formation remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: To gain insight into the roles of Hh signaling in ventral body wall formation and its malformation, we analyzed phenotypes of mouse mutants of Sonic hedgehog (Shh), GLI-Kruppel family member 3 (Gli3) and Aristaless-like homeobox 4 (Alx4). Introduction of additional Alx4(Lst) mutations into the Gli3(Xt/Xt) background resulted in various degrees of severe omphalocele and pubic diastasis. In addition, loss of a single Shh allele restored the omphalocele and pubic symphysis of Gli3(Xt/+); Alx4(Lst/Lst) embryos. We also observed ectopic Hh activity in the ventral body wall region of Gli3(Xt/Xt) embryos. Moreover, tamoxifen-inducible gain-of-function experiments to induce ectopic Hh signaling revealed Hh signal dose-dependent formation of omphaloceles. CONCLUSIONS/SIGNIFICANCE: We suggest that one of the possible causes of omphalocele and pubic diastasis is ectopically-induced Hh signaling. To our knowledge, this would be the first demonstration of the involvement of Hh signaling in ventral body wall malformation and the genetic rescue of omphalocele phenotypes. PMID- 21283719 TI - Facilitators and barriers to adopting robotic-assisted surgery: contextualizing the unified theory of acceptance and use of technology. AB - Robotic-assisted surgical techniques are not yet well established among surgeon practice groups beyond a few surgical subspecialties. To help identify the facilitators and barriers to their adoption, this belief-elicitation study contextualized and supplemented constructs of the unified theory of acceptance and use of technology (UTAUT) in robotic-assisted surgery. Semi-structured individual interviews were conducted with 21 surgeons comprising two groups: users and nonusers. The main facilitators to adoption were Perceived Usefulness and Facilitating Conditions among both users and nonusers, followed by Attitude Toward Using Technology among users and Extrinsic Motivation among nonusers. The three main barriers to adoption for both users and nonusers were Perceived Ease of Use and Complexity, Perceived Usefulness, and Perceived Behavioral Control. This study's findings can assist surgeons, hospital and medical school administrators, and other policy makers on the proper adoption of robotic assisted surgery and can guide future research on the development of theories and framing of hypotheses. PMID- 21283720 TI - The Hsc/Hsp70 co-chaperone network controls antigen aggregation and presentation during maturation of professional antigen presenting cells. AB - The maturation of mouse macrophages and dendritic cells involves the transient deposition of ubiquitylated proteins in the form of dendritic cell aggresome-like induced structures (DALIS). Transient DALIS formation was used here as a paradigm to study how mammalian cells influence the formation and disassembly of protein aggregates through alterations of their proteostasis machinery. Co-chaperones that modulate the interplay of Hsc70 and Hsp70 with the ubiquitin-proteasome system (UPS) and the autophagosome-lysosome pathway emerged as key regulators of this process. The chaperone-associated ubiquitin ligase CHIP and the ubiquitin domain protein BAG-1 are essential for DALIS formation in mouse macrophages and bone-marrow derived dendritic cells (BMDCs). CHIP also cooperates with BAG-3 and the autophagic ubiquitin adaptor p62 in the clearance of DALIS through chaperone assisted selective autophagy (CASA). On the other hand, the co-chaperone HspBP1 inhibits the activity of CHIP and thereby attenuates antigen sequestration. Through a modulation of DALIS formation CHIP, BAG-1 and HspBP1 alter MHC class I mediated antigen presentation in mouse BMDCs. Our data show that the Hsc/Hsp70 co chaperone network controls transient protein aggregation during maturation of professional antigen presenting cells and in this way regulates the immune response. Similar mechanisms may modulate the formation of aggresomes and aggresome-like induced structures (ALIS) in other mammalian cell types. PMID- 21283721 TI - The K153R polymorphism in the myostatin gene and muscle power phenotypes in young, non-athletic men. AB - The Lys(K)153Arg(R) polymorphism in exon 2 (rs1805086, 2379 A>G replacement) of the myostatin (MSTN) gene is a candidate to influence skeletal muscle phenotypes. We examined the association between the MSTN K153R polymorphism and 'explosive' leg power, assessed during sprint (30 m) and stationary jumping tests [squat (SJ) and counter-movement jumps (CMJ)] in non-athletic young adults (University students) [n = 281 (214 men); age: 21-32 years]. We also genotyped the MSTN exonic variants E164K (rs35781413), I225T, and P198A, yet no subject carried any of these variant MSTN alleles. As for the K153R polymorphism, we found only one woman with the KR genotype; thus, we presented the results only for men. The results of a one-way ANCOVA (with age, weight and height entered as covariates) showed that men with the KR genotype (n = 15) had a worse performance in vertical jumps compared with those with the KK genotype [SJ: vertical displacement of center of gravity (CG) of 35.17 +/- 1.42 vs. 39.06 +/- 0.39 cm, respectively, P = 0.009; CMJ: vertical displacement of CG of 36.44 +/- 1.50 vs. 40.63 +/- 0.41 cm, respectively, P = 0.008]. The results persisted after adjusting for multiple comparisons according to Bonferroni. Performance in 30 m sprint tests did however not differ by K153R genotypes. In summary, the MSTN K153R polymorphism is associated with the ability to produce 'peak' power during muscle contractions, as assessed with vertical jump tests, in young non-athletic men. Although more research is still needed, this genetic variation is among the numerous candidates to explain, alone or in combination with other polymorphisms, individual variations in muscle phenotypes. PMID- 21283722 TI - The CCCTC-binding factor (CTCF) of Drosophila contributes to the regulation of the ribosomal DNA and nucleolar stability. AB - In the repeat array of ribosomal DNA (rDNA), only about half of the genes are actively transcribed while the others are silenced. In arthropods, transposable elements interrupt a subset of genes, often inactivating transcription of those genes. Little is known about the establishment or separation of juxtaposed active and inactive chromatin domains, or preferential inactivation of transposable element interrupted genes, despite identity in promoter sequences. CTCF is a sequence-specific DNA binding protein which is thought to act as a transcriptional repressor, block enhancer-promoter communication, and delimit juxtaposed domains of active and inactive chromatin; one or more of these activities might contribute to the regulation of this repeated gene cluster. In support of this hypothesis, we show that the Drosophila nucleolus contains CTCF, which is bound to transposable element sequences within the rDNA. Reduction in CTCF gene activity results in nucleolar fragmentation and reduced rDNA silencing, as does disruption of poly-ADP-ribosylation thought to be necessary for CTCF nucleolar localization. Our data establish a role for CTCF as a component necessary for proper control of transposable element-laden rDNA transcription and nucleolar stability. PMID- 21283723 TI - Cell-to-cell transformation in Escherichia coli: a novel type of natural transformation involving cell-derived DNA and a putative promoting pheromone. AB - Escherichia coli is not assumed to be naturally transformable. However, several recent reports have shown that E. coli can express modest genetic competence in certain conditions that may arise in its environment. We have shown previously that spontaneous lateral transfer of non-conjugative plasmids occurs in a colony biofilm of mixed E. coli strains (a set of a donor strain harbouring a plasmid and a plasmid-free recipient strain). In this study, with high-frequency combinations of strains and a plasmid, we constructed the same lateral plasmid transfer system in liquid culture. Using this system, we demonstrated that this lateral plasmid transfer was DNase-sensitive, indicating that it is a kind of transformation in which DNase-accessible extracellular naked DNA is essential. However, this transformation did not occur with purified plasmid DNA and required a direct supply of plasmid from co-existing donor cells. Based on this feature, we have termed this transformation type as 'cell-to-cell transformation'. Analyses using medium conditioned with the high-frequency strain revealed that this strain released a certain factor(s) that promoted cell-to-cell transformation and arrested growth of the other strains. This factor is heat labile and protease-sensitive, and its roughly estimated molecular mass was between ~9 kDa and ~30 kDa, indicating that it is a polypeptide factor. Interestingly, this factor was effective even when the conditioned medium was diluted 10(-5)-10(-6), suggesting that it acts like a pheromone with high bioactivity. Based on these results, we propose that cell-to-cell transformation is a novel natural transformation mechanism in E. coli that requires cell-derived DNA and is promoted by a peptide pheromone. This is the first evidence that suggests the existence of a peptide pheromone-regulated transformation mechanism in E. coli and in Gram-negative bacteria. PMID- 21283724 TI - Truncation of the deubiquitinating domain of CYLD in myelomonocytic cells attenuates inflammatory responses. AB - The cylindromatosis tumor suppressor (CYLD) is a deubiquitinating enzyme that has been implicated in various aspects of adaptive and innate immune responses. Nevertheless, the role of CYLD in the function of specific types of immune cells remains elusive. In this report we have used conditional gene targeting in mice to address the role of the deubiquitinating activity of CYLD in the myelomonocytic lineage. Truncation of the deubiquitinating domain of CYLD specifically in myelomonocytic cells impaired the development of lethal LPS induced endotoxic shock and the accumulation of thioglycollate-elicited peritoneal macrophages. Our data establish CYLD as a regulator of monocyte macrophage activation in response to inflammatory stimuli and identify it as a potential target for therapeutic intervention in relevant inflammatory disorders in humans. PMID- 21283725 TI - The Ras-PI3K signaling pathway is involved in clathrin-independent endocytosis and the internalization of influenza viruses. AB - BACKGROUND: Influenza virus infection causes highly contagious, severe respiratory disorders and gives rise to thousands of deaths every year; however, the efficacy of currently approved defense strategies, including vaccines and neuraminidase inhibitors, is limited because the virus frequently acquires resistance via antigen drift and reassortment. It is therefore important to establish a novel, effective therapeutic strategy that is effective irrespective of viral subtype. METHODOLOGY/PRINCIPAL FINDINGS: Here, we identify the Ras phosphoinositide 3-kinase (PI3K) signaling pathway as a host-cell regulatory mechanism for influenza virus entry. The binding of Ras to PI3K is specifically involved in clathrin-independent endocytosis, endosomal maturation, and intracellular transport of viruses, which result in decreased infectious efficacy of different subtypes of influenza viruses in cells lacking the Ras-PI3K interaction. Moreover, influenza virus infection indeed triggered Ras activation and subsequent PI3K activation in early endosomes. CONCLUSIONS/SIGNIFICANCE: Taken together, these results demonstrate that the Ras-PI3K signaling axis acts as a host-oriented mechanism for viral internalization. Given that virus incorporation is a process conserved among virus subtypes and species, this signaling pathway may provide a target for potent, well-tolerated prophylactics and therapeutics against a broad range of viruses. PMID- 21283726 TI - The antioxidant protein peroxiredoxin 4 is epigenetically down regulated in acute promyelocytic leukemia. AB - The antioxidant peroxiredoxin (PRDX) protein family comprises 6 members, which are implicated in a variety of cellular responses, including growth factor signal transduction. PRDX4 resides in the endoplasmic reticulum (ER), where it locally controls oxidative stress by reducing H(2)O(2) levels. We recently provided evidence for a regulatory function of PRDX4 in signal transduction from a myeloid growth factor receptor, the granulocyte colony-stimulating factor receptor (G CSFR). Upon activation, the ligand-induced G-CSFR undergoes endocytosis and routes via the early endosomes where it physically interacts with ER-resident PRDX4. PRDX4 negatively regulates G-CSFR mediated signaling. Here, we investigated whether PRDX4 is affected in acute myeloid leukemia (AML); genomic alterations and expression levels of PRDX4 were investigated. We show that genomic abnormalities involving PRDX4 are rare in AML. However, we find a strong reduction in PRDX4 expression levels in acute promyelocytic leukemia (APL) compared to normal promyelocytes and different molecular subtypes of AML. Subsequently, the possible role of DNA methylation and histone modifications in silencing of PRDX4 in APLs was investigated. We show that the reduced expression is not due to methylation of the CpG island in the promoter region of PRDX4 but correlates with increased trimethylation of histone 3 lysine residue 27 (H3K27me3) and lysine residue 4 (H3K4me3) at the transcriptional start site (TSS) of PRDX4, indicative of a bivalent histone code involved in transcriptional silencing. These findings suggest that the control of G-CSF responses by the antioxidant protein PRDX4 may be perturbed in APL. PMID- 21283727 TI - Natural variation in decision-making behavior in Drosophila melanogaster. AB - There has been considerable recent interest in using Drosophila melanogaster to investigate the molecular basis of decision-making behavior. Deciding where to place eggs is likely one of the most important decisions for a female fly, as eggs are vulnerable and larvae have limited motility. Here, we show that many natural genotypes of D. melanogaster prefer to lay eggs near nutritious substrate, rather than in nutritious substrate. These preferences are highly polymorphic in both degree and direction, with considerable heritability (0.488) and evolvability.Relative preferences are modulated by the distance between options and the overall concentration of ethanol, suggesting Drosophila integrate many environmental factors when making oviposition decisions. As oviposition related decisions can be efficiently assessed by simply counting eggs, oviposition behavior is an excellent model for understanding information processing in insects. Associating natural genetic polymorphisms with decision making variation will shed light on the molecular basis of host choice behavior, the evolutionary maintenance of genetic variation, and the mechanistic nature of preference variation in general. PMID- 21283728 TI - Genetic variants of diabetes risk and incident cardiovascular events in chronic coronary artery disease. AB - OBJECTIVE: To determine whether information from genetic risk variants for diabetes is associated with cardiovascular events incidence. METHODS: From the about 30 known genes associated with diabetes, we genotyped single-nucleotide polymorphisms at the 10 loci most associated with type-2 diabetes in 425 subjects from the MASS-II Study, a randomized study in patients with multi-vessel coronary artery disease. The combined genetic information was evaluated by number of risk alleles for diabetes. Performance of genetic models relative to major cardiovascular events incidence was analyzed through Kaplan-Meier curve comparison and Cox Hazard Models and the discriminatory ability of models was assessed for cardiovascular events by calculating the area under the ROC curve. RESULTS: Genetic information was able to predict 5-year incidence of major cardiovascular events and overall-mortality in non-diabetic individuals, even after adjustment for potential confounders including fasting glycemia. Non diabetic individuals with high genetic risk had a similar incidence of events then diabetic individuals (cumulative hazard of 33.0 versus 35.1% of diabetic subjects). The addition of combined genetic information to clinical predictors significantly improved the AUC for cardiovascular events incidence (AUC = 0.641 versus 0.610). CONCLUSIONS: Combined information of genetic variants for diabetes risk is associated to major cardiovascular events incidence, including overall mortality, in non-diabetic individuals with coronary artery disease. CLINICAL TRIAL REGISTRATION INFORMATION: Medicine, Angioplasty, or Surgery Study (MASS II). Unique identifier: ISRCTN66068876 URL. PMID- 21283729 TI - Imaging of functional connectivity in the mouse brain. AB - Functional neuroimaging (e.g., with fMRI) has been difficult to perform in mice, making it challenging to translate between human fMRI studies and molecular and genetic mechanisms. A method to easily perform large-scale functional neuroimaging in mice would enable the discovery of functional correlates of genetic manipulations and bridge with mouse models of disease. To satisfy this need, we combined resting-state functional connectivity mapping with optical intrinsic signal imaging (fcOIS). We demonstrate functional connectivity in mice through highly detailed fcOIS mapping of resting-state networks across most of the cerebral cortex. Synthesis of multiple network connectivity patterns through iterative parcellation and clustering provides a comprehensive map of the functional neuroarchitecture and demonstrates identification of the major functional regions of the mouse cerebral cortex. The method relies on simple and relatively inexpensive camera-based equipment, does not require exogenous contrast agents and involves only reflection of the scalp (the skull remains intact) making it minimally invasive. In principle, fcOIS allows new paradigms linking human neuroscience with the power of molecular/genetic manipulations in mouse models. PMID- 21283730 TI - Differential expression of rubisco in sporophytes and gametophytes of some marine macroalgae. AB - Rubisco (ribulose-1, 5-bisphosphate carboxylase/oxygenase), a key enzyme of photosynthetic CO(2) fixation, is one of the most abundant proteins in both higher plants and algae. In this study, the differential expression of Rubisco in sporophytes and gametophytes of four seaweed species--Porphyra yezoensis, P. haitanensis, Bangia fuscopurpurea (Rhodophyte) and Laminaria japonica (Phaeophyceae)--was studied in terms of the levels of transcription, translation and enzyme activity. Results indicated that both the Rubisco content and the initial carboxylase activity were notably higher in algal gametophytes than in the sporophytes, which suggested that the Rubisco content and the initial carboxylase activity were related to the ploidy of the generations of the four algal species. PMID- 21283731 TI - FTO and MC4R gene variants are associated with obesity in polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility in women. It is also associated with metabolic disturbances that place women at increased risk for obesity and type 2 diabetes. There is strong evidence for familial clustering of PCOS and a genetic predisposition. However, the gene(s) responsible for the PCOS phenotypes have not been elucidated. This two-phase family-based and case-control genetic study was designed to address the question of whether SNPs identified as susceptibility loci for obesity in genome-wide association studies (GWAS) are also associated with PCOS and elevated BMI. Members of 439 families having at least one offspring with PCOS were genotyped for 15 SNPs previously shown to be associated with obesity. Linkage and association with PCOS was assessed using the transmission/disequilibrium test (TDT). These SNPs were also analyzed in an independent case-control study involving 395 women with PCOS and 176 healthy women with regular menstrual cycles. Only one of these 15 SNPs (rs2815752 in NEGR1) was found to have a nominally significant association with PCOS (chi(2) = 6.11, P = 0.013), but this association failed to replicate in the case-control study. While not associated with PCOS itself, five SNPs in FTO and two in MC4R were associated with BMI as assessed with a quantitative-TDT analysis, several of which replicated association with BMI in the case-control cohort. These findings demonstrate that certain SNPs associated with obesity contribute to elevated BMI in PCOS, but do not appear to play a major role in PCOS per se. These findings support the notion that PCOS phenotypes are a consequence of an oligogenic/polygenic mechanism. PMID- 21283732 TI - Natural plant sugar sources of Anopheles mosquitoes strongly impact malaria transmission potential. AB - An improved knowledge of mosquito life history could strengthen malaria vector control efforts that primarily focus on killing mosquitoes indoors using insecticide treated nets and indoor residual spraying. Natural sugar sources, usually floral nectars of plants, are a primary energy resource for adult mosquitoes but their role in regulating the dynamics of mosquito populations is unclear. To determine how the sugar availability impacts Anopheles sergentii populations, mark-release-recapture studies were conducted in two oases in Israel with either absence or presence of the local primary sugar source, flowering Acacia raddiana trees. Compared with population estimates from the sugar-rich oasis, An. sergentii in the sugar-poor oasis showed smaller population size (37,494 vs. 85,595), lower survival rates (0.72 vs. 0.93), and prolonged gonotrophic cycles (3.33 vs. 2.36 days). The estimated number of females older than the extrinsic incubation period of malaria (10 days) in the sugar rich site was 4 times greater than in the sugar poor site. Sugar feeding detected in mosquito guts in the sugar-rich site was significantly higher (73%) than in the sugar-poor site (48%). In contrast, plant tissue feeding (poor quality sugar source) in the sugar-rich habitat was much less (0.3%) than in the sugar-poor site (30%). More important, the estimated vectorial capacity, a standard measure of malaria transmission potential, was more than 250-fold higher in the sugar rich oasis than that in the sugar-poor site. Our results convincingly show that the availability of sugar sources in the local environment is a major determinant regulating the dynamics of mosquito populations and their vector potential, suggesting that control interventions targeting sugar-feeding mosquitoes pose a promising tactic for combating transmission of malaria parasites and other pathogens. PMID- 21283733 TI - Factors and Conditions that Influence the Implementation of Standardized Nursing Care Plans. AB - RATIONALE AND AIM: There is a lack of evidence about how to successfully implement standardized nursing care plans (SNCP) in various settings. The aim of this study was to use the "Promotion Action on Research Implementation in Health Services framework" (PARIHS) to explore important factors and conditions at hospital wards that had implemented SNCPs. METHOD: We employed a retrospective, cross-sectional design and recruited nurses from four units at a rural hospital and seven units at a university hospital in the western and southern region of Sweden where SNCPs had been implemented. Outcome was measured by means of a questionnaire based on the PARIHS-model. RESULT: In total, 137 nurses participated in the study. The main factors that had motivated the nurses to implement SNCPs were that they were easy to understand and follow as well as corresponding to organisational norms. The SNCPs were normally based on clinical experience, although research more frequently formed the basis of the SNCPs at the university hospital. Internal facilitators acted as important educators, who provided reminders to use the SNCP and feedback to the SNCP users. The patient experience was not considered valuable. Those who claimed that the implementation was successful were generally more positive in all measurable aspects. The use of SNCPs was rarely evaluated. CONCLUSIONS: Clinical experience was considered important by the nurses, while they attributed little value to the patient experiences. Successful implementation of research based SNCPs requires internal facilitators with knowledge of evidence-based nursing. PMID- 21283734 TI - Influence of receptor antagonists, local anesthetics, and denervation on microcirculation. AB - OBJECTIVE: Impaired microcirculation is one of the most important factors in delayed wound healing. The aim of the study was to investigate the influence of chemical and surgical interruption of sympathetic nerve fibers and alpha- and beta-receptors blockers on muscular microcirculation. METHODS: The experiment was performed on a standardized cremaster muscle model of male Wistar rats (n=51). Microcirculation was recorded via transillumination microscopy on each of the 4 test groups and in a control group before and after their respective treatments with one of the following: topical application of bupivacaine, metoprolol, phentolamine, or surgical denervation. The arteriolar diameter and functional capillary density (FCD) as parameter for tissue perfusion were assessed. RESULTS: The alpha-blocker phentolamine was the only agent that caused a significant dilation of the arteriolar diameter (76.6 +/- 6.9 vs 100.0 +/- 12.0 um). However, like bupivacaine, metoprolol, and the surgical sympathectomy, it did not improve FCD as a parameter for tissue perfusion. The strongest vasoconstriction (35.9 +/- 4.3 vs 28.6 +/- 4.0) and impairment of the FCD (10.0 +/- 0.7 vs 4.1 +/- 0.9) was induced by the beta-blocker metoprolol. CONCLUSIONS: This study shows that phentolamine could be an agent for dilating arteriolar diameter, but it did not improve FCD. Whereas the other agents, including sympathectomy, did not alter arteriolar diameter, the beta-blocker worsened both investigated parameters. Our results raise the question whether beta-blockers negatively influence microcirculation. Therefore, further studies are needed to investigate the potential adverse effects of beta-blockers on wound healing. PMID- 21283735 TI - Expression-based in silico screening of candidate therapeutic compounds for lung adenocarcinoma. AB - BACKGROUND: Lung adenocarcinom (AC) is the most common form of lung cancer. Currently, the number of medical options to deal with lung cancer is very limited. In this study, we aimed to investigate potential therapeutic compounds for lung adenocarcinoma based on integrative analysis. METHODOLOGY/PRINCIPAL FINDINGS: The candidate therapeutic compounds were identified in a two-step process. First, a meta-analysis of two published microarray data was conducted to obtain a list of 343 differentially expressed genes specific to lung AC. In the next step, expression profiles of these genes were used to query the Connectivity Map (C-MAP) database to identify a list of compounds whose treatment reverse expression direction in various cancer cells. Several compounds in the categories of HSP90 inhibitor, HDAC inhibitor, PPAR agonist, PI3K inhibitor, passed our screening to be the leading candidates. On top of the list, three HSP90 inhibitors, i.e. 17-AAG (also known as tanespimycin), monorden, and alvespimycin, showed significant negative enrichment scores. Cytotoxicity as well as effects on cell cycle regulation and apoptosis were evaluated experimentally in lung adenocarcinoma cell line (A549 or GLC-82) with or without treatment with 17-AAG. In vitro study demonstrated that 17-AAG alone or in combination with cisplatin (DDP) can significantly inhibit lung adenocarcinoma cell growth by inducing cell cycle arrest and apoptosis. CONCLUSIONS/SIGNIFICANCE: We have used an in silico screening to identify compounds for treating lung cancer. One such compound 17 AAG demonstrated its anti-lung AC activity by inhibiting cell growth and promoting apoptosis and cell cycle arrest. PMID- 21283736 TI - A new multidisciplinary home care telemedicine system to monitor stable chronic human immunodeficiency virus-infected patients: a randomized study. AB - BACKGROUND: Antiretroviral therapy has changed the natural history of human immunodeficiency virus (HIV) infection in developed countries, where it has become a chronic disease. This clinical scenario requires a new approach to simplify follow-up appointments and facilitate access to healthcare professionals. METHODOLOGY: We developed a new internet-based home care model covering the entire management of chronic HIV-infected patients. This was called Virtual Hospital. We report the results of a prospective randomised study performed over two years, comparing standard care received by HIV-infected patients with Virtual Hospital care. HIV-infected patients with access to a computer and broadband were randomised to be monitored either through Virtual Hospital (Arm I) or through standard care at the day hospital (Arm II). After one year of follow up, patients switched their care to the other arm. Virtual Hospital offered four main services: Virtual Consultations, Telepharmacy, Virtual Library and Virtual Community. A technical and clinical evaluation of Virtual Hospital was carried out. FINDINGS: Of the 83 randomised patients, 42 were monitored during the first year through Virtual Hospital (Arm I) and 41 through standard care (Arm II). Baseline characteristics of patients were similar in the two arms. The level of technical satisfaction with the virtual system was high: 85% of patients considered that Virtual Hospital improved their access to clinical data and they felt comfortable with the videoconference system. Neither clinical parameters [level of CD4+ T lymphocytes, proportion of patients with an undetectable level of viral load (p = 0.21) and compliance levels >90% (p = 0.58)] nor the evaluation of quality of life or psychological questionnaires changed significantly between the two types of care. CONCLUSIONS: Virtual Hospital is a feasible and safe tool for the multidisciplinary home care of chronic HIV patients. Telemedicine should be considered as an appropriate support service for the management of chronic HIV infection. TRIAL REGISTRATION: Clinical Trials.gov: NCT01117675. PMID- 21283737 TI - Detection of hepatocyte growth factor (HGF) ligand-c-MET receptor activation in formalin-fixed paraffin embedded specimens by a novel proximity assay. AB - Aberrant activation of membrane receptors frequently occurs in human carcinomas. Detection of phosphorylated receptors is commonly used as an indicator of receptor activation in formalin-fixed paraffin embedded (FFPE) tumor specimens. FFPE is a standard method of specimen preparation used in the histological analysis of solid tumors. Due to variability in FFPE preparations and the labile nature of protein phosphorylation, measurements of phospho-proteins are unreliable and create ambiguities in clinical interpretation. Here, we describe an alternative, novel approach to measure receptor activation by detecting and quantifying ligand-receptor complexes in FFPE specimens. We used hepatocyte growth factor (HGF)-c-MET as our model ligand-receptor system. HGF is the only known ligand of the c-MET tyrosine kinase receptor and HGF binding triggers c-MET phosphorylation. Novel antibody proximity-based assays were developed and used to detect and quantify total c-MET, total HGF, and HGF-c-MET ligand-receptor interactions in FFPE cell line and tumor tissue. In glioma cells, autocrine activation of c-MET by HGF-c-MET increased basal levels of c-MET phosphorylation at tyrosine (Tyr) 1003. Furthermore, HGF-c-MET activation in glioma cell lines was verified by Surface Protein-Protein Interaction by Crosslinking ELISA (SPPICE) assay in corresponding soluble cell lysates. Finally, we profiled levels ofc-MET, HGF, and HGF-c-MET complexes in FFPE specimens of human Non-Small Cell Lung Cancer (NSCLC), Gastric Cancer, Head and Neck Squamous Cell, and Head and Neck Non-Squamous Cell carcinomas. This report describes a novel approach for the detection and quantification of ligand-receptor interactions that can be widely applied to measure receptor activation in FFPE preclinical models and archived FFPE human tissue specimens. PMID- 21283738 TI - Hydrogen peroxide probes directed to different cellular compartments. AB - BACKGROUND: Controlled generation and removal of hydrogen peroxide play important roles in cellular redox homeostasis and signaling. We used a hydrogen peroxide biosensor HyPer, targeted to different compartments, to examine these processes in mammalian cells. PRINCIPAL FINDINGS: Reversible responses were observed to various redox perturbations and signaling events. HyPer expressed in HEK 293 cells was found to sense low micromolar levels of hydrogen peroxide. When targeted to various cellular compartments, HyPer occurred in the reduced state in the nucleus, cytosol, peroxisomes, mitochondrial intermembrane space and mitochondrial matrix, but low levels of the oxidized form of the biosensor were also observed in each of these compartments, consistent with a low peroxide tone in mammalian cells. In contrast, HyPer was mostly oxidized in the endoplasmic reticulum. Using this system, we characterized control of hydrogen peroxide in various cell systems, such as cells deficient in thioredoxin reductase, sulfhydryl oxidases or subjected to selenium deficiency. Generation of hydrogen peroxide could also be monitored in various compartments following signaling events. CONCLUSIONS: We found that HyPer can be used as a valuable tool to monitor hydrogen peroxide generated in different cellular compartments. The data also show that hydrogen peroxide generated in one compartment could translocate to other compartments. Our data provide information on compartmentalization, dynamics and homeostatic control of hydrogen peroxide in mammalian cells. PMID- 21283739 TI - BMP signaling modulates hepcidin expression in zebrafish embryos independent of hemojuvelin. AB - Hemojuvelin (Hjv), a member of the repulsive-guidance molecule (RGM) family, upregulates transcription of the iron regulatory hormone hepcidin by activating the bone morphogenetic protein (BMP) signaling pathway in mammalian cells. Mammalian models have identified furin, neogenin, and matriptase-2 as modifiers of Hjv's function. Using the zebrafish model, we evaluated the effects of hjv and its interacting proteins on hepcidin expression during embryonic development. We found that hjv is strongly expressed in the notochord and somites of the zebrafish embryo and that morpholino knockdown of hjv impaired the development of these structures. Knockdown of hjv or other hjv-related genes, including zebrafish orthologs of furin or neogenin, however, failed to decrease hepcidin expression relative to liver size. In contrast, overexpression of bmp2b or knockdown of matriptase-2 enhanced the intensity and extent of hepcidin expression in zebrafish embryos, but this occurred in an hjv-independent manner. Furthermore, we demonstrated that zebrafish hjv can activate the human hepcidin promoter and enhance BMP responsive gene expression in vitro, but is expressed at low levels in the zebrafish embryonic liver. Taken together, these data support an alternative mechanism for hepcidin regulation during zebrafish embryonic development, which is independent of hjv. PMID- 21283740 TI - Large-scale candidate gene analysis of HDL particle features. AB - BACKGROUND: HDL cholesterol (HDL-C) is an established marker of cardiovascular risk with significant genetic determination. However, HDL particles are not homogenous, and refined HDL phenotyping may improve insight into regulation of HDL metabolism. We therefore assessed HDL particles by NMR spectroscopy and conducted a large-scale candidate gene association analysis. METHODOLOGY/PRINCIPAL FINDINGS: We measured plasma HDL-C and determined mean HDL particle size and particle number by NMR spectroscopy in 2024 individuals from 512 British Caucasian families. Genotypes were 49,094 SNPs in >2,100 cardiometabolic candidate genes/loci as represented on the HumanCVD BeadChip version 2. False discovery rates (FDR) were calculated to account for multiple testing. Analyses on classical HDL-C revealed significant associations (FDR<0.05) only for CETP (cholesteryl ester transfer protein; lead SNP rs3764261: p = 5.6*10(-15)) and SGCD (sarcoglycan delta; rs6877118: p = 8.6*10(-6)). In contrast, analysis with HDL mean particle size yielded additional associations in LIPC (hepatic lipase; rs261332: p = 6.1*10(-9)), PLTP (phospholipid transfer protein, rs4810479: p = 1.7*10(-8)) and FBLN5 (fibulin-5; rs2246416: p = 6.2*10( 6)). The associations of SGCD and Fibulin-5 with HDL particle size could not be replicated in PROCARDIS (n = 3,078) and/or the Women's Genome Health Study (n = 23,170). CONCLUSIONS: We show that refined HDL phenotyping by NMR spectroscopy can detect known genes of HDL metabolism better than analyses on HDL-C. PMID- 21283741 TI - Heat-killed Trypanosoma cruzi induces acute cardiac damage and polyantigenic autoimmunity. AB - Chagas heart disease, caused by the protozoan parasite Trypanosoma cruzi, is a potentially fatal cardiomyopathy often associated with cardiac autoimmunity. T. cruzi infection induces the development of autoimmunity to a number of antigens via molecular mimicry and other mechanisms, but the genesis and pathogenic potential of this autoimmune response has not been fully elucidated. To determine whether exposure to T. cruzi antigens alone in the absence of active infection is sufficient to induce autoimmunity, we immunized A/J mice with heat-killed T. cruzi (HKTC) emulsified in complete Freund's adjuvant, and compared the resulting immune response to that induced by infection with live T. cruzi. We found that HKTC immunization is capable of inducing acute cardiac damage, as evidenced by elevated serum cardiac troponin I, and that this damage is associated with the generation of polyantigenic humoral and cell-mediated autoimmunity with similar antigen specificity to that induced by infection with T. cruzi. However, while significant and preferential production of Th1 and Th17-associated cytokines, accompanied by myocarditis, develops in T. cruzi-infected mice, HKTC-immunized mice produce lower levels of these cytokines, do not develop Th1-skewed immunity, and lack tissue inflammation. These results demonstrate that exposure to parasite antigen alone is sufficient to induce autoimmunity and cardiac damage, yet additional immune factors, including a dominant Th1/Th17 immune response, are likely required to induce cardiac inflammation. PMID- 21283742 TI - Forced notch signaling inhibits commissural axon outgrowth in the developing chick central nerve system. AB - BACKGROUND: A collection of in vitro evidence has demonstrated that Notch signaling plays a key role in the growth of neurites in differentiated neurons. However, the effects of Notch signaling on axon outgrowth in an in vivo condition remain largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: In this study, the neural tubes of HH10-11 chick embryos were in ovo electroporated with various Notch transgenes of activating or inhibiting Notch signaling, and then their effects on commissural axon outgrowth across the floor plate midline in the chick developing central nerve system were investigated. Our results showed that forced expression of Notch intracellular domain, constitutively active form of RBPJ, or full-length Hes1 in the rostral hindbrain, diencephalon and spinal cord at stage HH10-11 significantly inhibited commissural axon outgrowth. On the other hand, inhibition of Notch signaling by ectopically expressing a dominant-negative form of RBPJ promoted commissural axonal growth along the circumferential axis. Further results revealed that these Notch signaling-mediated axon outgrowth defects may be not due to the alteration of axon guidance since commissural axon marker TAG1 was present in the axons in floor plate midline, and also not result from the changes in cell fate determination of commissural neurons since the expression of postmitotic neuron marker Tuj1 and specific commissural markers TAG1 and Pax7 was unchanged. CONCLUSIONS/SIGNIFICANCE: We first used an in vivo system to provide evidence that forced Notch signaling negatively regulates commissural axon outgrowth. PMID- 21283743 TI - Reasons for ineligibility in phase 1 and 2A HIV vaccine clinical trials at Kenya AIDS vaccine initiative (KAVI), Kenya. AB - BACKGROUND: With the persistent challenges towards controlling the HIV epidemic, there is an ongoing need for research into HIV vaccines and drugs. Sub-Saharan African countries--worst affected by the HIV pandemic--have participated in the conduct of clinical trials for HIV vaccines. In Kenya, the Kenya AIDS Vaccine Initiative (KAVI) at the University of Nairobi has conducted HIV vaccine clinical trials since 2001. METHODOLOGY: Participants were recruited after an extensive informed consent process followed by screening to determine eligibility. Screening included an assessment of risk behavior, medical history and physical examination, and if clinically healthy, laboratory testing. In the absence of locally derived laboratory reference ranges, the ranges used in these trials were derived from populations in the West. PRINCIPAL FINDINGS: Two hundred eighty-one participants were screened between 2003 and 2006 for two clinical trials. Of these, 167 (59.4%) met the inclusion/exclusion criteria. Overall, laboratory abnormalities based on the non-indigenous laboratory references used were the most frequent reasons (61.4%) for ineligibility. Medical abnormalities contributed 30.7% of the total reasons for ineligibility. Based on the laboratory reference intervals now developed from East and Southern Africa, those ineligible due to laboratory abnormalities would have been 46.3%. Of the eligible participants, 18.6% declined enrollment. CONCLUSIONS: Participant recruitment for HIV vaccine clinical trials is a rigorous and time-consuming exercise. Over 61% of the screening exclusions in clinically healthy people were due to laboratory abnormalities. It is essential that laboratory reference ranges generated from local populations for laboratory values be used in the conduct of clinical trials to avoid unnecessary exclusion of willing participants and to avoid over reporting of adverse events for enrolled participants. TRIAL REGISTRATION: Protocol IAVI VRC V001 [1]. ClinicalTrials.gov NCT00124007 Protocol IAVI 010 [2](registration with ClincalTrials.gov is in progress) Protocols IAVI 002 and IAVI 004 are Phase 1 trials only mentioned in introductory paragraphs; details will not be reported. Registration was not required when they were conducted. PMID- 21283744 TI - Regulation of pacing strategy during athletic competition. AB - BACKGROUND: Athletic competition has been a source of interest to the scientific community for many years, as a surrogate of the limits of human ambulatory ability. One of the remarkable things about athletic competition is the observation that some athletes suddenly reduce their pace in the mid-portion of the race and drop back from their competitors. Alternatively, other athletes will perform great accelerations in mid-race (surges) or during the closing stages of the race (the endspurt). This observation fits well with recent evidence that muscular power output is regulated in an anticipatory way, designed to prevent unreasonably large homeostatic disturbances. PRINCIPAL FINDINGS: Here we demonstrate that a simple index, the product of the momentary Rating of Perceived Exertion (RPE) and the fraction of race distance remaining, the Hazard Score, defines the likelihood that athletes will change their velocity during simulated competitions; and may effectively represent the language used to allow anticipatory regulation of muscle power output. CONCLUSIONS: These data support the concept that the muscular power output during high intensity exercise performance is actively regulated in an anticipatory manner that accounts for both the momentary sensations the athlete is experiencing as well as the relative amount of a competition to be completed. PMID- 21283745 TI - Mitochondrial damage in the trabecular meshwork occurs only in primary open-angle glaucoma and in pseudoexfoliative glaucoma. AB - BACKGROUND: Open-angle glaucoma appears to be induced by the malfunction of the trabecular meshwork cells due to injury induced by oxidative damage and mitochondrial impairment. Here, we report that, in fact, we have detected mitochondrial damage only in primary open-angle glaucoma and pseudo-exfoliation glaucoma, among several glaucoma types compared. METHODOLOGY/PRINCIPAL FINDINGS: Mitochondrial damage was evaluated by analyzing the common mitochondrial DNA deletion by real-time PCR in trabecular meshwork specimens collected at surgery from glaucomatous patients and controls. Glaucomatous patients included 38 patients affected by various glaucoma types: primary open-angle, pigmented, juvenile, congenital, pseudoexfoliative, acute, neovascular, and chronic closed angle glaucoma. As control samples, we used 16 specimens collected from glaucoma free corneal donors. Only primary open-angle glaucoma (3.0-fold) and pseudoexfoliative glaucoma (6.3-fold) showed significant increases in the amount of mitochondrial DNA deletion. In all other cases, deletion was similar to controls. CONCLUSIONS/SIGNIFICANCE: despite the fact that the trabecular meshwork is the most important tissue in the physiopathology of aqueous humor outflow in all glaucoma types, the present study provides new information regarding basic physiopathology of this tissue: only in primary open-angle and pseudoexfoliative glaucomas oxidative damage arising from mitochondrial failure play a role in the functional decay of trabecular meshwork. PMID- 21283746 TI - Serum lipidomics meets cardiac magnetic resonance imaging: profiling of subjects at risk of dilated cardiomyopathy. AB - Dilated cardiomyopathy (DCM), characterized by left ventricular dilatation and systolic dysfunction, constitutes a significant cause for heart failure, sudden cardiac death or need for heart transplantation. Lamin A/C gene (LMNA) on chromosome 1p12 is the most significant disease gene causing DCM and has been reported to cause 7-9% of DCM leading to cardiac transplantation. We have previously performed cardiac magnetic resonance imaging (MRI) to LMNA carriers to describe the early phenotype. Clinically, early recognition of subjects at risk of developing DCM would be important but is often difficult. Thus we have earlier used the MRI findings of these LMNA carriers for creating a model by which LMNA carriers could be identified from the controls at an asymptomatic stage. Some LMNA mutations may cause lipodystrophy. To characterize possible effects of LMNA mutations on lipid profile, we set out to apply global serum lipidomics using Ultra Performance Liquid Chromatography coupled to mass spectrometry in the same LMNA carriers, DCM patients without LMNA mutation and controls. All DCM patients, with or without LMNA mutation, differed from controls in regard to distinct serum lipidomic profile dominated by diminished odd-chain triglycerides and lipid ratios related to desaturation. Furthermore, we introduce a novel approach to identify associations between the molecular lipids from serum and the MR images from the LMNA carriers. The association analysis using dependency network and regression approaches also helped us to obtain novel insights into how the affected lipids might relate to cardiac shape and volume changes. Our study provides a framework for linking serum derived molecular markers not only with clinical endpoints, but also with the more subtle intermediate phenotypes, as derived from medical imaging, of potential pathophysiological relevance. PMID- 21283747 TI - Risk factors for obesity: further evidence for stronger effects on overweight children and adolescents compared to normal-weight subjects. AB - BACKGROUND: We recently showed that in preschoolers risk factors for overweight show stronger associations with BMI in children with high BMI values. However, it is unclear whether these findings might also pertain to adolescents. METHODS: We extracted data on 3-10 year-old (n = 7,237) and 11-17 year-old (n = 5,986) children from a representative cross-sectional German health survey (KiGGS) conducted between 2003 and 2006 and calculated quantile regression models for each age group. We used z-scores of children's body mass index (BMI) as outcome variable and maternal BMI, maternal smoking in pregnancy, low parental socioeconomic status, exclusive formula-feeding and high TV viewing time as explanatory variables. RESULTS: In both age groups, the estimated effects of all risk factors except formula-feeding on BMI z-score were greatest for children with the highest BMI z-score. The median BMI z-score of 11-17 year-old children with high TV viewing time, for example, was 0.11 [95% CI: 0.03, 0.19] units higher than the median BMI z-score of teenage children with low TV viewing time. This risk factor was associated with an average difference of 0.18 [0.06, 0.30] units at the 90(th) percentile of BMI z-score and of 0.20 [0.07, 0.33] units at the 97(th) percentile. CONCLUSIONS: We confirmed that risk factors for childhood overweight are associated with greater shifts in the upper parts of the children's BMI distribution than in the middle and lower parts. These findings pertain also to teenagers and might possibly help to explain the secular shift in the upper BMI percentiles in children and adolescents. PMID- 21283748 TI - Activation of MyD88 signaling upon staphylococcal enterotoxin binding to MHC class II molecules. AB - Ligands binding to Toll-like receptor (TLR), interleukin 1 receptor (IL-1R), or IFN-gammaR1 are known to trigger MyD88-mediated signaling, which activates pro inflammatory cytokine responses. Recently we reported that staphylococcal enterotoxins (SEA or SEB), which bind to MHC class II molecules on APCs and cross link T cell receptors, activate MyD88- mediated pro-inflammatory cytokine responses. We also reported that MyD88(-/-) mice were resistant to SE- induced toxic shock and had reduced levels of serum cytokines. In this study, we investigated whether MHC class II- SE interaction by itself is sufficient to activate MyD88 in MHC class II(+) cells and induce downstream pro-inflammatory signaling and production of cytokines such as TNF-alpha and IL-1beta. Here we report that human monocytes treated with SEA, SEB, or anti-MHC class II monoclonal antibodies up regulated MyD88 expression, induced activation of NF-kB, and increased expression of IL-1R1 accessory protein, TNF-alpha and IL-1beta. MyD88 immunoprecipitated from cell extracts after SEB stimulation showed a greater proportion of MyD88 phosphorylation compared to unstimulated cells indicating that MyD88 was a component of intracellular signaling. MyD88 downstream proteins such as IRAK4 and TRAF6 were also up regulated in monocytes after SEB stimulation. In addition to monocytes, primary B cells up regulated MyD88 in response to SEA or SEB stimulation. Importantly, in contrast to primary B cells, MHC class II deficient T2 cells had no change of MyD88 after SEA or SEB stimulation, whereas MHC class II-independent activation of MyD88 was elicited by CpG or LPS. Collectively, these results demonstrate that MHC class II utilizes a MyD88-mediated signaling mechanism when in contact with ligands such as SEs to induce pro-inflammatory cytokines. PMID- 21283749 TI - Retrospective investigation of an influenza A/H1N1pdm outbreak in an Italian military ship cruising in the Mediterranean Sea, May-September 2009. AB - BACKGROUND: Clinical surveillance may have underestimated the real extent of the spread of the new strain of influenza A/H1N1, which surfaced in April 2009 originating the first influenza pandemic of the 21(st) century. Here we report a serological investigation on an influenza A/H1N1pdm outbreak in an Italian military ship while cruising in the Mediterranean Sea (May 24-September 6, 2009). METHODS: The contemporary presence of HAI and CF antibodies was used to retrospectively estimate the extent of influenza A/H1N1pdm spread across the crew members (median age: 29 years). FINDINGS: During the cruise, 2 crew members fulfilled the surveillance case definition for influenza, but only one was laboratory confirmed by influenza A/H1N1pdm-specific RT-PCR; 52 reported acute respiratory illness (ARI) episodes, and 183 reported no ARI episodes. Overall, among the 211 crew member for whom a valid serological result was available, 39.3% tested seropositive for influenza A/H1N1pdm. The proportion of seropositives was significantly associated with more crowded living quarters and tended to be higher in those aged <40 and in those reporting ARI or suspected/confirmed influenza A/H1N1pdm compared to the asymptomatic individuals. No association was found with previous seasonal influenza vaccination. CONCLUSIONS: These findings underline the risk for rapid spread of novel strains of influenza A in confined environment, such as military ships, where crowding, rigorous working environment, physiologic stress occur. The high proportion of asymptomatic infections in this ship-borne outbreak supports the concept that serological surveillance in such semi-closed communities is essential to appreciate the real extent of influenza A/H1N1pdm spread and can constitute, since the early stage of a pandemic, an useful model to predict the public health impact of pandemic influenza and to establish proportionate and effective countermeasures. PMID- 21283750 TI - Studies of the association of Arg72Pro of tumor suppressor protein p53 with type 2 diabetes in a combined analysis of 55,521 Europeans. AB - AIMS: A study of 222 candidate genes in type 2 diabetes reported association of variants in RAPGEF1, ENPP1, TP53, NRF1, SLC2A2, SLC2A4 and FOXC2 with type 2 diabetes in 4,805 Finnish individuals. We aimed to replicate these associations in a Danish case-control study and to substantiate any replicated associations in meta-analyses. Furthermore, we evaluated the impact on diabetes-related intermediate traits in a population-based sample of middle-aged Danes. METHODS: We genotyped nine lead variants in the seven genes in 4,973 glucose-tolerant and 3,612 type 2 diabetes Danish individuals. In meta-analyses we combined case control data from the DIAGRAM+ Consortium (n = 47,117) and the present genotyping results. The quantitative trait studies involved 5,882 treatment-naive individuals from the Danish Inter99 study. RESULTS: None of the nine investigated variants were significantly associated with type 2 diabetes in the Danish samples. However, for all nine variants the estimate of increase in type 2 diabetes risk was observed for the same allele as previously reported. In a meta analysis of published and online data including 55,521 Europeans the G-allele of rs1042522 in TP53 showed significant association with type 2 diabetes (OR = 1.06 95% CI 1.02-1.11, p = 0.0032). No substantial associations with diabetes-related intermediary phenotypes were found. CONCLUSION: The G-allele of TP53 rs1042522 is associated with an increased prevalence of type 2 diabetes in a combined analysis of 55,521 Europeans. PMID- 21283751 TI - Surveillance for Clostridium difficile infection: ICD-9 coding has poor sensitivity compared to laboratory diagnosis in hospital patients, Singapore. AB - INTRODUCTION: Clostridium difficile infection (CDI) is an increasingly recognized nosocomial infection in Singapore. Surveillance methods include laboratory reporting of Clostridium difficile toxin assays (CDTA) or use of International Classification of Diseases, 9(th) Revision (ICD-9) discharge code 008.45. Previous US studies showed good correlation between CDTA and ICD-9 codes. However, the use of ICD-9 codes for CDI surveillance has not been validated in other healthcare settings. METHODS: We compared CDI rates based on CDTA to ICD-9 codes for all discharges in 2007 from our hospital to determine sensitivity and specificity of ICD-9 codes. Demographic and hospitalization data were analyzed to determine predictors for missing ICD-9 codes. RESULTS: During 2007, there were 56,352 discharges. Of these, 268 tested CDTA-positive but only 133 were assigned the CDI ICD-9 code. A total of 141 discharges had the ICD-9 code; 8 were CDTA negative, the rest were CDTA-positive. Community-acquired CDI accounted for only 3.2% of cases. The sensitivity and specificity of ICD-9 codes compared to CDTA were 49.6% and 100% respectively. Concordance between CDTA and ICD-9 codes was 0.649 (p<.001). Comparing concordant patients (CDTA+/ICD9+) to discordant patients (CDTA+/ICD9-), concordant patients were more likely to be over 50 years of age (OR 3.49, 95% CI 1.66-7.34, p = .001) and have shorter time from admission to testing (OR 0.98, 95% CI 0.97-0.99, p = .009). DISCUSSION: Unlike previous studies in the US, ICD-9 codes substantially underestimate CDI in Singapore compared to microbiological data. Older patients with shorter time to testing were less likely to have missing ICD-9 codes. PMID- 21283752 TI - Consumer-resource dynamics: quantity, quality, and allocation. AB - BACKGROUND: The dominant paradigm for modeling the complexities of interacting populations and food webs is a system of coupled ordinary differential equations in which the state of each species, population, or functional trophic group is represented by an aggregated numbers-density or biomass-density variable. Here, using the metaphysiological approach to model consumer-resource interactions, we formulate a two-state paradigm that represents each population or group in a food web in terms of both its quantity and quality. METHODOLOGY AND PRINCIPAL FINDINGS: The formulation includes an allocation function controlling the relative proportion of extracted resources to increasing quantity versus elevating quality. Since lower quality individuals senescence more rapidly than higher quality individuals, an optimal allocation proportion exists and we derive an expression for how this proportion depends on population parameters that determine the senescence rate, the per-capita mortality rate, and the effects of these rates on the dynamics of the quality variable. We demonstrate that oscillations do not arise in our model from quantity-quality interactions alone, but require consumer-resource interactions across trophic levels that can be stabilized through judicious resource allocation strategies. Analysis and simulations provide compelling arguments for the necessity of populations to evolve quality-related dynamics in the form of maternal effects, storage or other appropriate structures. They also indicate that resource allocation switching between investments in abundance versus quality provide a powerful mechanism for promoting the stability of consumer-resource interactions in seasonally forcing environments. CONCLUSIONS/SIGNIFICANCE: Our simulations show that physiological inefficiencies associated with this switching can be favored by selection due to the diminished exposure of inefficient consumers to strong oscillations associated with the well-known paradox of enrichment. Also our results demonstrate how allocation switching can explain observed growth patterns in experimental microbial cultures and discuss how our formulation can address questions that cannot be answered using the quantity-only paradigms that currently predominate. PMID- 21283753 TI - Specific binding of the pathogenic prion isoform: development and characterization of a humanized single-chain variable antibody fragment. AB - Murine monoclonal antibody V5B2 which specifically recognizes the pathogenic form of the prion protein represents a potentially valuable tool in diagnostics or therapy of prion diseases. As murine antibodies elicit immune response in human, only modified forms can be used for therapeutic applications. We humanized a single-chain V5B2 antibody using variable domain resurfacing approach guided by computer modelling. Design based on sequence alignments and computer modelling resulted in a humanized version bearing 13 mutations compared to initial murine scFv. The humanized scFv was expressed in a dedicated bacterial system and purified by metal-affinity chromatography. Unaltered binding affinity to the original antigen was demonstrated by ELISA and maintained binding specificity was proved by Western blotting and immunohistochemistry. Since monoclonal antibodies against prion protein can antagonize prion propagation, humanized scFv specific for the pathogenic form of the prion protein might become a potential therapeutic reagent. PMID- 21283754 TI - Differential proteomic analysis of mammalian tissues using SILAM. AB - Differential expression of proteins between tissues underlies organ-specific functions. Under certain pathological conditions, this may also lead to tissue vulnerability. Furthermore, post-translational modifications exist between different cell types and pathological conditions. We employed SILAM (Stable Isotope Labeling in Mammals) combined with mass spectrometry to quantify the proteome between mammalian tissues. Using (15)N labeled rat tissue, we quantified 3742 phosphorylated peptides in nuclear extracts from liver and brain tissue. Analysis of the phosphorylation sites revealed tissue specific kinase motifs. Although these tissues are quite different in their composition and function, more than 500 protein identifications were common to both tissues. Specifically, we identified an up-regulation in the brain of the phosphoprotein, ZFHX1B, in which a genetic deletion causes the neurological disorder Mowat-Wilson syndrome. Finally, pathway analysis revealed distinct nuclear pathways enriched in each tissue. Our findings provide a valuable resource as a starting point for further understanding of tissue specific gene regulation and demonstrate SILAM as a useful strategy for the differential proteomic analysis of mammalian tissues. PMID- 21283755 TI - Hypoxia potentiates glioma-mediated immunosuppression. AB - Glioblastoma multiforme (GBM) is a lethal cancer that exerts potent immune suppression. Hypoxia is a predominant feature of GBM, but it is unclear to the degree in which tumor hypoxia contributes to this tumor-mediated immunosuppression. Utilizing GBM associated cancer stem cells (gCSCs) as a treatment resistant population that has been shown to inhibit both innate and adaptive immune responses, we compared immunosuppressive properties under both normoxic and hypoxic conditions. Functional immunosuppression was characterized based on production of immunosuppressive cytokines and chemokines, the inhibition of T cell proliferation and effector responses, induction of FoxP3+ regulatory T cells, effect on macrophage phagocytosis, and skewing to the immunosuppressive M2 phenotype. We found that hypoxia potentiated the gCSC-mediated inhibition of T cell proliferation and activation and especially the induction of FoxP3+T cells, and further inhibited macrophage phagocytosis compared to normoxia condition. These immunosuppressive hypoxic effects were mediated by signal transducer and activator of transcription 3 (STAT3) and its transcriptionally regulated products such as hypoxia inducible factor (HIF)-1alpha and vascular endothelial growth factor (VEGF). Inhibitors of STAT3 and HIF-1alpha down modulated the gCSCs' hypoxia-induced immunosuppressive effects. Thus, hypoxia further enhances GBM mediated immunosuppression, which can be reversed with therapeutic inhibition of STAT3 and HIF-1alpha and also helps to reconcile the disparate findings that immune therapeutic approaches can be used successfully in model systems but have yet to achieve generalized successful responses in the vast majority of GBM patients by demonstrating the importance of the tumor hypoxic environment. PMID- 21283756 TI - STK35L1 associates with nuclear actin and regulates cell cycle and migration of endothelial cells. AB - BACKGROUND: Migration and proliferation of vascular endothelial cells are essential for repair of injured endothelium and angiogenesis. Cyclins, cyclin dependent kinases (CDKs), and cyclin-dependent kinase inhibitors play an important role in vascular tissue injury and wound healing. Previous studies suggest a link between the cell cycle and cell migration: cells present in the G(1) phase have the highest potential to migrate. The molecular mechanism linking these two processes is not understood. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we explored the function of STK35L1, a novel Ser/Thr kinase, localized in the nucleus and nucleolus of endothelial cells. Molecular biological analysis identified a bipartite nuclear localization signal, and nucleolar localization sequences in the N-terminal part of STK35L1. Nuclear actin was identified as a novel binding partner of STK35L1. A class III PDZ binding domains motif was identified in STK35L1 that mediated its interaction with actin. Depletion of STK35L1 by siRNA lead to an accelerated G(1) to S phase transition after serum stimulation of endothelial cells indicating an inhibitory role of the kinase in G(1) to S phase progression. Cell cycle specific genes array analysis revealed that one gene was prominently downregulated (8.8 fold) in STK35L1 silenced cells: CDKN2A alpha transcript, which codes for p16(INK4a) leading to G(1) arrest by inhibition of CDK4/6. Moreover in endothelial cells seeded on Matrigel, STK35L1 expression was rapidly upregulated, and silencing of STK35L1 drastically inhibited endothelial sprouting that is required for angiogenesis. Furthermore, STK35L1 depletion profoundly impaired endothelial cell migration in two wound healing assays. CONCLUSION/SIGNIFICANCE: The results indicate that by regulating CDKN2A and inhibiting G1- to S-phase transition STK35L1 may act as a central kinase linking the cell cycle and migration of endothelial cells. The interaction of STK35L1 with nuclear actin might be critical in the regulation of these fundamental endothelial functions. PMID- 21283757 TI - The microbe-derived short chain fatty acid butyrate targets miRNA-dependent p21 gene expression in human colon cancer. AB - Colonic microbiota ferment non-absorbed dietary fiber to produce prodigious amounts of short chain fatty acids (SCFAs) that benefit the host through a myriad of metabolic, trophic, and chemopreventative effects. The chemopreventative effects of the SCFA butyrate are, in part, mediated through induction of p21 gene expression. In this study, we assessed the role of microRNA(miRNA) in butyrate's induction of p21 expression. The expression profiles of miRNAs in HCT-116 cells and in human sporadic colon cancers were assessed by microarray and quantitative PCR. Regulation of p21 gene expression by miR-106b was assessed by 3' UTR luciferase reporter assays and transfection of specific miRNA mimics. Butyrate changed the expression of 44 miRNAs in HCT-116 cells, many of which were aberrantly expressed in colon cancer tissues. Members of the miR-106b family were decreased in the former and increased in the latter. Butyrate-induced p21 protein expression was dampened by treatment with a miR-106b mimic. Mutated p21 3'UTR reporter constructs expressed in HCT-116 cells confirmed direct miR-106b targeting. Butyrate decreased HCT-116 proliferation, an effect reversed with the addition of the miR-106b mimic. We conclude that microbe-derived SCFAs regulate host gene expression involved in intestinal homeostasis as well as carcinogenesis through modulation of miRNAs. PMID- 21283758 TI - Male responses to conspecific advertisement signals in the field cricket Gryllus rubens (Orthoptera: Gryllidae). AB - In many species males aggregate and produce long-range advertisement signals to attract conspecific females. The majority of the receivers of these signals are probably other males most of the time, and male responses to competitors' signals can structure the spatial and temporal organization of the breeding aggregation and affect male mating tactics. I quantified male responses to a conspecific advertisement stimulus repeatedly over three age classes in Gryllus rubens (Orthoptera: Gryllidae) in order to estimate the type and frequency of male responses to the broadcast stimulus and to determine the factors affecting them. Factors tested included body size, wing dimorphism, age, and intensity of the broadcast stimulus. Overall, males employed acoustic response more often than positive phonotactic response. As males aged, the frequency of positive phonotactic response decreased but that of the acoustic response increased. That is, males may use positive phonotaxis in the early stages of their adult lives, possibly to find suitable calling sites or parasitize calling males, and then later in life switch to acoustic responses in response to conspecific advertisement signals. Males with smaller body size more frequently exhibited acoustic responses. This study suggests that individual variation, more than any factors measured, is critical for age-dependent male responses to conspecific advertisement signals. PMID- 21283759 TI - CD4+ T cell effects on CD8+ T cell location defined using bioluminescence. AB - T lymphocytes of the CD8+ class are critical in delivering cytotoxic function and in controlling viral and intracellular infections. These cells are "helped" by T lymphocytes of the CD4+ class, which facilitate their activation, clonal expansion, full differentiation and the persistence of memory. In this study we investigated the impact of CD4+ T cells on the location of CD8+ T cells, using antibody-mediated CD4+ T cell depletion and imaging the antigen-driven redistribution of bioluminescent CD8+ T cells in living mice. We documented that CD4+ T cells influence the biodistribution of CD8+ T cells, favoring their localization to abdominal lymph nodes. Flow cytometric analysis revealed that this was associated with an increase in the expression of specific integrins. The presence of CD4+ T cells at the time of initial CD8+ T cell activation also influences their biodistribution in the memory phase. Based on these results, we propose the model that one of the functions of CD4+ T cell "help" is to program the homing potential of CD8+ T cells. PMID- 21283760 TI - Fine mapping of the NRG1 Hirschsprung's disease locus. AB - The primary pathology of Hirschsprung's disease (HSCR, colon aganglionosis) is the absence of ganglia in variable lengths of the hindgut, resulting in functional obstruction. HSCR is attributed to a failure of migration of the enteric ganglion precursors along the developing gut. RET is a key regulator of the development of the enteric nervous system (ENS) and the major HSCR-causing gene. Yet the reduced penetrance of RET DNA HSCR-associated variants together with the phenotypic variability suggest the involvement of additional genes in the disease. Through a genome-wide association study, we uncovered a ~350 kb HSCR associated region encompassing part of the neuregulin-1 gene (NRG1). To identify the causal NRG1 variants contributing to HSCR, we genotyped 243 SNPs variants on 343 ethnic Chinese HSCR patients and 359 controls. Genotype analysis coupled with imputation narrowed down the HSCR-associated region to 21 kb, with four of the most associated SNPs (rs10088313, rs10094655, rs4624987, and rs3884552) mapping to the NRG1 promoter. We investigated whether there was correlation between the genotype at the rs10088313 locus and the amount of NRG1 expressed in human gut tissues (40 patients and 21 controls) and found differences in expression as a function of genotype. We also found significant differences in NRG1 expression levels between diseased and control individuals bearing the same rs10088313 risk genotype. This indicates that the effects of NRG1 common variants are likely to depend on other alleles or epigenetic factors present in the patients and would account for the variability in the genetic predisposition to HSCR. PMID- 21283761 TI - miR-K12-7-5p encoded by Kaposi's sarcoma-associated herpesvirus stabilizes the latent state by targeting viral ORF50/RTA. AB - Seventeen miRNAs encoded by Kaposi's sarcoma-associated herpesvirus (KSHV) have been identified and their functions have begun to be characterized. Among these miRNAs, we report here that miR-K12-7 directly targets the replication and transcription activator (RTA) encoded by open reading frame 50. We found that miR K12-7 targeted the RTA 3' untranslated region (RTA3'UTR) in a seed sequence dependent manner. miR-K12-7-5p derived from miR-K12-7 mediates the inhibition of RTA expression, and the mutation of the seed match site totally abrogated the inhibitory effect of miR-K12-7 on RTA3'UTR. The inhibition of RTA expression by miR-K12-7 was further confirmed in the latently KSHV-infected 293/Bac36 cell line through transient transfection of miR-K12-7 expression plasmid or specific inhibitor of miR-K12-7-5p, respectively. The transient transfection of miR-K12-7 into 293/Bac36 cells reduced RTA expression and the expression of the downstream early genes regulated by RTA, and also the production of progeny virus was significantly reduced after treatment with chemical inducers. Our study revealed that another miRNA, miR-K12-7-5p, targets the viral immediate early gene RTA and that this miRNA contributes to the maintenance of viral latency. PMID- 21283763 TI - Anatomy and taxonomic status of the chasmosaurine ceratopsid Nedoceratops hatcheri from the upper Cretaceous Lance Formation of Wyoming, U.S.A. AB - BACKGROUND: The validity of Nedoceratops hatcheri, a chasmosaurine ceratopsid dinosaur known from a single skull recovered in the Lance Formation of eastern Wyoming, U.S.A., has been debated for over a century. Some have argued that the taxon is an aberrant Triceratops, and most recently it was proposed that N. hatcheri represents an intermediate ontogenetic stage between "young adult" and "old adult" forms of a single taxon previously split into Triceratops and Torosaurus. METHODOLOGY/PRINCIPAL FINDINGS: The holotype skull of Nedoceratops hatcheri was reexamined in order to map reconstructed areas and compare the specimen with other ceratopsids. Although squamosal fenestrae are almost certainly not of taxonomic significance, some other features are unique to N. hatcheri. These include a nasal lacking a recognizable horn, nearly vertical postorbital horncores, and relatively small parietal fenestrae. Thus, N. hatcheri is tentatively considered valid, and closely related to Triceratops spp. The holotype of N. hatcheri probably represents an "old adult," based upon bone surface texture and the shape of the horns and epiossifications on the frill. In this study, Torosaurus is maintained as a genus distinct from Triceratops and Nedoceratops. Synonymy of the three genera as ontogenetic stages of a single taxon would require cranial changes otherwise unknown in ceratopsids, including additions of ossifications to the frill and repeated alternation of bone surface texture between juvenile and adult morphotypes. CONCLUSIONS/SIGNIFICANCE: Triceratops, Torosaurus, and likely Nedoceratops, are all distinct taxa, indicating that species richness for chasmosaurine ceratopsids in the Lance Formation just prior to the Cretaceous-Paleocene extinction was roughly equivalent to that earlier in the Cretaceous. PMID- 21283762 TI - Protein-protein interactions within late pre-40S ribosomes. AB - Ribosome assembly in eukaryotic organisms requires more than 200 assembly factors to facilitate and coordinate rRNA transcription, processing, and folding with the binding of the ribosomal proteins. Many of these assembly factors bind and dissociate at defined times giving rise to discrete assembly intermediates, some of which have been partially characterized with regards to their protein and RNA composition. Here, we have analyzed the protein-protein interactions between the seven assembly factors bound to late cytoplasmic pre-40S ribosomes using recombinant proteins in binding assays. Our data show that these factors form two modules: one comprising Enp1 and the export adaptor Ltv1 near the beak structure, and the second comprising the kinase Rio2, the nuclease Nob1, and a regulatory RNA binding protein Dim2/Pno1 on the front of the head. The GTPase-like Tsr1 and the universally conserved methylase Dim1 are also peripherally connected to this second module. Additionally, in an effort to further define the locations for these essential proteins, we have analyzed the interactions between these assembly factors and six ribosomal proteins: Rps0, Rps3, Rps5, Rps14, Rps15 and Rps29. Together, these results and previous RNA-protein crosslinking data allow us to propose a model for the binding sites of these seven assembly factors. Furthermore, our data show that the essential kinase Rio2 is located at the center of the pre-ribosomal particle and interacts, directly or indirectly, with every other assembly factor, as well as three ribosomal proteins required for cytoplasmic 40S maturation. These data suggest that Rio2 could play a central role in regulating cytoplasmic maturation steps. PMID- 21283764 TI - Age-related Toxoplasma gondii seroprevalence in Dutch wild boar inconsistent with lifelong persistence of antibodies. AB - Toxoplasma gondii is an important zoonotic pathogen that is best known as a cause of abortion or abnormalities in the newborn after primary infection during pregnancy. Our aim was to determine the prevalence of T. gondii in wild boar to investigate the possible role of their meat in human infection and to get an indication of the environmental contamination with T. gondii. The presence of anti-T. gondii antibodies was determined by in-house ELISA in 509 wild boar shot in 2002/2003 and 464 wild boar shot in 2007. Most of the boar originated from the "Roerstreek" (n = 673) or the "Veluwe" (n = 241). A binormal mixture model was fitted to the log-transformed optical density values for wild boar up to 20 months old to estimate the optimal cut-off value (-0.685) and accompanying sensitivity (90.6%) and specificity (93.6%). The overall seroprevalence was estimated at 24.4% (95% CI: 21.1-27.7%). The prevalence did not show variation between sampling years or regions, indicating a stable and homogeneous infection pressure from the environment. The relation between age and seroprevalence was studied in two stages. Firstly, seroprevalence by age group was determined by fitting the binary mixture model to 200 animals per age category. The prevalence showed a steep increase until approximately 10 months of age but stabilized at approximately 35% thereafter. Secondly, we fitted the age-dependent seroprevalence data to several SIR-type models, with seropositives as infected (I) and seronegatives as either susceptible (S) or resistant (R). A model with a recovery rate (SIS) was superior to a model without a recovery rate (SI). This finding is not consistent with the traditional view of lifelong persistence of T. gondii infections. The high seroprevalence suggests that eating undercooked wild boar meat may pose a risk of infection with T. gondii. PMID- 21283765 TI - MicroRNAs MiR-17, MiR-20a, and MiR-106b act in concert to modulate E2F activity on cell cycle arrest during neuronal lineage differentiation of USSC. AB - BACKGROUND: MicroRNAs are short (~22 nt) non-coding regulatory RNAs that control gene expression at the post-transcriptional level. Here the functional impact of microRNAs on cell cycle arrest during neuronal lineage differentiation of unrestricted somatic stem cells from human cord blood (USSC) was analyzed. METHODOLOGY/PRINCIPAL FINDINGS: Expression profiling revealed downregulation of microRNAs miR-17, -20a, and -106b in USSC differentiated into neuronal lineage but not in USSC differentiated into osteogenic lineage. Transfection experiments followed by Ki67 immunostainings demonstrated that each of these microRNAs was able to promote proliferation of native USSC and to prevent in part cell cycle arrest during neuronal lineage differentiation of USSC. Bioinformatic target gene predictions followed by experimental target gene validations revealed that miR 17, -20a, and -106b act in a common manner by downregulating an overlapping set of target genes mostly involved in regulation and execution of G(1)/S transition. Pro-proliferative target genes cyclinD1 (CCND1) and E2F1 as well as anti proliferative targets CDKN1A (p21), PTEN, RB1, RBL1 (p107), RBL2 (p130) were shown as common targets for miR-17, -20a, and -106b. Furthermore, these microRNAs also downregulate WEE1 which is involved in G(2)/M transition. Most strikingly, miR-17, -20a, and -106b were found to promote cell proliferation by increasing the intracellular activity of E2F transcription factors, despite the fact that miR-17, -20a, and -106b directly target the transcripts that encode for this protein family. CONCLUSIONS/SIGNIFICANCE: Mir-17, -20a, and -106b downregulate a common set of pro- and anti-proliferative target genes to impact cell cycle progression of USSC and increase intracellular activity of E2F transcription factors to govern G(1)/S transition. PMID- 21283766 TI - Functional and structural characteristics of tumor angiogenesis in lung cancers overexpressing different VEGF isoforms assessed by DCE- and SSCE-MRI. AB - The expressions of different vascular endothelial growth factor (VEGF) isoforms are associated with the degree of tumor invasiveness and the patient's prognosis in human cancers. We hypothesized that different VEGF isoforms can exert different effects on the functional and structural characteristics of tumor angiogenesis. We used dynamic contrast-enhanced MRI (DCE-MRI) and steady-state contrast-enhanced MRI (SSCE-MRI) to evaluate in vivo vascular functions (e.g., perfusion and permeability) and structural characteristics (e.g., vascular size and vessel density) of the tumor angiogenesis induced by different VEGF isoforms (VEGF121, VEGF165, and VEGF189) in a murine xenograft model of human lung cancer. Tumors overexpressing VEGF189 were larger than those overexpressing the other two VEGF isoforms. The K(trans) map obtained from DCE-MRI revealed that the perfusion and permeability functions of tumor microvessels was highest in both the rim and core regions of VEGF189-overexpressing tumors (p<0.001 for both tumor rim and core). The relative vessel density and relative vessel size indexes derived from SSCE-MRI revealed that VEGF189-overexpressing tumors had the smallest (p<0.05) and the most-dense (p<0.01) microvessels, which penetrated deeply from the tumor rim into the core, followed by the VEGF165-overepxressing tumor, whose microvessels were located mainly in the tumor rim. The lowest-density microvessels were found in the VEGF121-overexpressing tumor; these microvessels had a relatively large lumen and were found mainly in the tumor rim. We conclude that among the three VEGF isoforms evaluated, VEGF189 induces the most densely sprouting and smallest tumor microvessels with the highest in vivo perfusion and permeability functions. These characteristics of tumor microvessels may contribute to the reported adverse effects of VEGF189 overexpression on tumor progression, metastasis, and patient survival in several human cancers, including non-small cell lung cancer, and suggest that applying aggressive therapy may be necessary in human cancers in which VEGF189 is overexpressed. PMID- 21283767 TI - Regional differentiation of retinoic acid-induced human pluripotent embryonic carcinoma stem cell neurons. AB - The NTERA2 cl D1 (NT2) cell line, derived from human teratocarcinoma, exhibits similar properties as embryonic stem (ES) cells or very early neuroepithelial progenitors. NT2 cells can be induced to become postmitotic central nervous system neurons (NT2N) with retinoic acid. Although neurons derived from pluripotent cells, such as NT2N, have been characterized for their neurotransmitter phenotypes, their potential suitability as a donor source for neural transplantation also depends on their ability to respond to localized environmental cues from a specific region of the CNS. Therefore, our study aimed to characterize the regional transcription factors that define the rostocaudal and dorsoventral identity of NT2N derived from a monolayer differentiation paradigm using quantitative PCR (qPCR). Purified NT2N mainly expressed both GABAergic and glutamatergic phenotypes and were electrically active but did not form functional synapses. The presence of immature astrocytes and possible radial glial cells was noted. The NT2N expressed a regional transcription factor code consistent with forebrain, hindbrain and spinal cord neural progenitors but showed minimal expression of midbrain phenotypes. In the dorsoventral plane NT2N expressed both dorsal and ventral neural progenitors. Of major interest was that even under the influence of retinoic acid, a known caudalization factor, the NT2N population maintained a rostral phenotype subpopulation which expressed cortical regional transcription factors. It is proposed that understanding the regional differentiation bias of neurons derived from pluripotent stem cells will facilitate their successful integration into existing neuronal networks within the CNS. PMID- 21283768 TI - Chronic respiratory aeroallergen exposure in mice induces epithelial-mesenchymal transition in the large airways. AB - Chronic allergic asthma is characterized by Th2-polarized inflammation and leads to airway remodeling and fibrosis but the mechanisms involved are not clear. To determine whether epithelial-mesenchymal transition contributes to airway remodeling in asthma, we induced allergic airway inflammation in mice by intranasal administration of house dust mite (HDM) extract for up to 15 consecutive weeks. We report that respiratory exposure to HDM led to significant airway inflammation and thickening of the smooth muscle layer in the wall of the large airways. Transforming growth factor beta-1 (TGF-beta1) levels increased in mouse airways while epithelial cells lost expression of E-cadherin and occludin and gained expression of the mesenchymal proteins vimentin, alpha-smooth muscle actin (alpha-SMA) and pro-collagen I. We also observed increased expression and nuclear translocation of Snail1, a transcriptional repressor of E-cadherin and a potent inducer of EMT, in the airway epithelial cells of HDM-exposed mice. Furthermore, fate-mapping studies revealed migration of airway epithelial cells into the sub-epithelial regions of the airway wall. These results show the contribution of EMT to airway remodeling in chronic asthma-like inflammation and suggest that Th2-polarized airway inflammation can trigger invasion of epithelial cells into the subepithelial regions of the airway wall where they contribute to fibrosis, demonstrating a previously unknown plasticity of the airway epithelium in allergic airway disease. PMID- 21283769 TI - Suppression of osteosarcoma cell invasion by chemotherapy is mediated by urokinase plasminogen activator activity via up-regulation of EGR1. AB - BACKGROUND: The cellular and molecular mechanisms of tumour response following chemotherapy are largely unknown. We found that low dose anti-tumour agents up regulate early growth response 1 (EGR1) expression. EGR1 is a member of the immediate-early gene group of transcription factors which modulate transcription of multiple genes involved in cell proliferation, differentiation, and development. It has been reported that EGR1 act as either tumour promoting factor or suppressor. We therefore examined the expression and function of EGR1 in osteosarcoma. METHODS: We investigated the expression of EGR1 in human osteosarcoma cell lines and biopsy specimens. We next examined the expression of EGR1 following anti-tumour agents treatment. To examine the function of EGR1 in osteosarcoma, we assessed the tumour growth and invasion in vitro and in vivo. RESULTS: Real-time PCR revealed that EGR1 was down-regulated both in osteosarcoma cell lines and osteosarcoma patients' biopsy specimens. In addition, EGR1 was up regulated both in osteosarcoma patient' specimens and osteosarcoma cell lines following anti-tumour agent treatment. Although forced expression of EGR1 did not prevent osteosarcoma growth, forced expression of EGR1 prevented osteosarcoma cell invasion in vitro. In addition, forced expression of EGR1 promoted down regulation of urokinase plasminogen activator, urokinase receptor, and urokinase plasminogen activity. Xenograft mice models showed that forced expression of EGR1 prevents osteosarcoma cell migration into blood vessels. CONCLUSIONS: These findings suggest that although chemotherapy could not prevent osteosarcoma growth in chemotherapy-resistant patients, it did prevent osteosarcoma cell invasion by down-regulation of urokinase plasminogen activity via up-regulation of EGR1 during chemotherapy periods. PMID- 21283770 TI - ReCLIP (reversible cross-link immuno-precipitation): an efficient method for interrogation of labile protein complexes. AB - The difficulty of maintaining intact protein complexes while minimizing non specific background remains a significant limitation in proteomic studies. Labile interactions, such as the interaction between p120-catenin and the E-cadherin complex, are particularly challenging. Using the cadherin complex as a model system, we have developed a procedure for efficient recovery of otherwise labile protein-protein interactions. We have named the procedure "ReCLIP" (Reversible Cross-Link Immuno-Precipitation) to reflect the primary elements of the method. Using cell-permeable, thiol-cleavable crosslinkers, normally labile interactions (i.e. p120 and E-cadherin) are stabilized in situ prior to isolation. After immunoprecipitation, crosslinked binding partners are selectively released and all other components of the procedure (i.e. beads, antibody, and p120 itself) are discarded. The end result is extremely efficient recovery with exceptionally low background. ReCLIP therefore appears to provide an excellent alternative to currently available affinity-purification approaches, particularly for studies of labile complexes. PMID- 21283771 TI - Plastid DNA diversity is higher in the island endemic Guadalupe cypress than in the continental Tecate cypress. AB - BACKGROUND: Callitropsis guadalupensis (Guadalupe cypress) is endemic to Guadalupe Island, Mexico, where it is the dominant species of the only forest. The species has suffered declining numbers following the introduction of goats to the island over 150 years ago. Callitropsis guadalupensis is closely related to Callitropsis forbesii (Tecate cypress), distributed in small isolated populations in mainland Baja California and southern California. The objective of the present study was to compare the genetic diversity of the island endemic to the continental species. METHODOLOGY/PRINCIPAL FINDINGS: We measured genetic diversity in Callitropsis guadalupensis (n =54) from Guadalupe Island and in Callitropsis forbesii (n = 100) from five populations in mainland Baja California. The plastid DNA trnS-trnG spacer and the trnL-trnF region were chosen for characterization. Thirty-four haplotypes were observed, of which six were shared between both species. One of these haplotypes was also shared with three other species, Callitropsis lusitanica, Callitropsis montana, and Callitropsis stephensonii. Haplotype diversity (h) and nucleotide diversity (pi) were significantly higher for Callitropsis guadalupensis (h = 0.698, pi = 0.00071) than for Callitropsis forbesii (h = 0.337, pi = 0.00024). CONCLUSIONS/SIGNIFICANCE: Callitropsis guadalupensis shows no evidence of a founder effect or of a genetic bottleneck, and can be added to a growing list of insular species with higher genetic diversity than their mainland relatives. PMID- 21283772 TI - The mitochondrial genome of the legume Vigna radiata and the analysis of recombination across short mitochondrial repeats. AB - The mitochondrial genomes of seed plants are exceptionally fluid in size, structure, and sequence content, with the accumulation and activity of repetitive sequences underlying much of this variation. We report the first fully sequenced mitochondrial genome of a legume, Vigna radiata (mung bean), and show that despite its unexceptional size (401,262 nt), the genome is unusually depauperate in repetitive DNA and "promiscuous" sequences from the chloroplast and nuclear genomes. Although Vigna lacks the large, recombinationally active repeats typical of most other seed plants, a PCR survey of its modest repertoire of short (38-297 nt) repeats nevertheless revealed evidence for recombination across all of them. A set of novel control assays showed, however, that these results could instead reflect, in part or entirely, artifacts of PCR-mediated recombination. Consequently, we recommend that other methods, especially high-depth genome sequencing, be used instead of PCR to infer patterns of plant mitochondrial recombination. The average-sized but repeat- and feature-poor mitochondrial genome of Vigna makes it ever more difficult to generalize about the factors shaping the size and sequence content of plant mitochondrial genomes. PMID- 21283773 TI - HIV-1 enhancing effect of prostatic acid phosphatase peptides is reduced in human seminal plasma. AB - We recently reported that HIV-1 infection can be inhibited by innate antimicrobial components of human seminal plasma (SP). Conversely, naturally occurring peptidic fragments from the SP-derived prostatic acid phosphatase (PAP) have been reported to form amyloid fibrils called "SEVI" and enhance HIV-1 infection in vitro. In order to understand the biological consequence of this proviral effect, we extended these studies in the presence of human SP. PAP derived peptides were agitated to form SEVI and incubated in the presence or absence of SP. While PAP-derived peptides and SEVI alone were proviral, the presence of 1% SP ablated their proviral activity in several different anti-HIV-1 assays. The anti-HIV-1 activity of SP was concentration dependent and was reduced following filtration. Supraphysiological concentrations of PAP peptides and SEVI incubated with diluted SP were degraded within hours, with SP exhibiting proteolytic activity at dilutions as high as 1:200. Sub-physiological concentrations of two prominent proteases of SP, prostate-specific antigen (PSA) and matriptase, could degrade physiological and supraphysiological concentrations of PAP peptides and SEVI. While human SP is a complex biological fluid, containing both antiviral and proviral factors, our results suggest that PAP peptides and SEVI may be subject to naturally occurring proteolytic components capable of reducing their proviral activity. PMID- 21283774 TI - Risk, unexpected uncertainty, and estimation uncertainty: Bayesian learning in unstable settings. AB - Recently, evidence has emerged that humans approach learning using Bayesian updating rather than (model-free) reinforcement algorithms in a six-arm restless bandit problem. Here, we investigate what this implies for human appreciation of uncertainty. In our task, a Bayesian learner distinguishes three equally salient levels of uncertainty. First, the Bayesian perceives irreducible uncertainty or risk: even knowing the payoff probabilities of a given arm, the outcome remains uncertain. Second, there is (parameter) estimation uncertainty or ambiguity: payoff probabilities are unknown and need to be estimated. Third, the outcome probabilities of the arms change: the sudden jumps are referred to as unexpected uncertainty. We document how the three levels of uncertainty evolved during the course of our experiment and how it affected the learning rate. We then zoom in on estimation uncertainty, which has been suggested to be a driving force in exploration, in spite of evidence of widespread aversion to ambiguity. Our data corroborate the latter. We discuss neural evidence that foreshadowed the ability of humans to distinguish between the three levels of uncertainty. Finally, we investigate the boundaries of human capacity to implement Bayesian learning. We repeat the experiment with different instructions, reflecting varying levels of structural uncertainty. Under this fourth notion of uncertainty, choices were no better explained by Bayesian updating than by (model-free) reinforcement learning. Exit questionnaires revealed that participants remained unaware of the presence of unexpected uncertainty and failed to acquire the right model with which to implement Bayesian updating. PMID- 21283775 TI - PhylOTU: a high-throughput procedure quantifies microbial community diversity and resolves novel taxa from metagenomic data. AB - Microbial diversity is typically characterized by clustering ribosomal RNA (SSU rRNA) sequences into operational taxonomic units (OTUs). Targeted sequencing of environmental SSU-rRNA markers via PCR may fail to detect OTUs due to biases in priming and amplification. Analysis of shotgun sequenced environmental DNA, known as metagenomics, avoids amplification bias but generates fragmentary, non overlapping sequence reads that cannot be clustered by existing OTU-finding methods. To circumvent these limitations, we developed PhylOTU, a computational workflow that identifies OTUs from metagenomic SSU-rRNA sequence data through the use of phylogenetic principles and probabilistic sequence profiles. Using simulated metagenomic data, we quantified the accuracy with which PhylOTU clusters reads into OTUs. Comparisons of PCR and shotgun sequenced SSU-rRNA markers derived from the global open ocean revealed that while PCR libraries identify more OTUs per sequenced residue, metagenomic libraries recover a greater taxonomic diversity of OTUs. In addition, we discover novel species, genera and families in the metagenomic libraries, including OTUs from phyla missed by analysis of PCR sequences. Taken together, these results suggest that PhylOTU enables characterization of part of the biosphere currently hidden from PCR-based surveys of diversity? PMID- 21283776 TI - Is my network module preserved and reproducible? AB - In many applications, one is interested in determining which of the properties of a network module change across conditions. For example, to validate the existence of a module, it is desirable to show that it is reproducible (or preserved) in an independent test network. Here we study several types of network preservation statistics that do not require a module assignment in the test network. We distinguish network preservation statistics by the type of the underlying network. Some preservation statistics are defined for a general network (defined by an adjacency matrix) while others are only defined for a correlation network (constructed on the basis of pairwise correlations between numeric variables). Our applications show that the correlation structure facilitates the definition of particularly powerful module preservation statistics. We illustrate that evaluating module preservation is in general different from evaluating cluster preservation. We find that it is advantageous to aggregate multiple preservation statistics into summary preservation statistics. We illustrate the use of these methods in six gene co-expression network applications including 1) preservation of cholesterol biosynthesis pathway in mouse tissues, 2) comparison of human and chimpanzee brain networks, 3) preservation of selected KEGG pathways between human and chimpanzee brain networks, 4) sex differences in human cortical networks, 5) sex differences in mouse liver networks. While we find no evidence for sex specific modules in human cortical networks, we find that several human cortical modules are less preserved in chimpanzees. In particular, apoptosis genes are differentially co-expressed between humans and chimpanzees. Our simulation studies and applications show that module preservation statistics are useful for studying differences between the modular structure of networks. Data, R software and accompanying tutorials can be downloaded from the following webpage: http://www.genetics.ucla.edu/labs/horvath/CoexpressionNetwork/ModulePreservation. PMID- 21283777 TI - From spiking neuron models to linear-nonlinear models. AB - Neurons transform time-varying inputs into action potentials emitted stochastically at a time dependent rate. The mapping from current input to output firing rate is often represented with the help of phenomenological models such as the linear-nonlinear (LN) cascade, in which the output firing rate is estimated by applying to the input successively a linear temporal filter and a static non linear transformation. These simplified models leave out the biophysical details of action potential generation. It is not a priori clear to which extent the input-output mapping of biophysically more realistic, spiking neuron models can be reduced to a simple linear-nonlinear cascade. Here we investigate this question for the leaky integrate-and-fire (LIF), exponential integrate-and-fire (EIF) and conductance-based Wang-Buzsaki models in presence of background synaptic activity. We exploit available analytic results for these models to determine the corresponding linear filter and static non-linearity in a parameter free form. We show that the obtained functions are identical to the linear filter and static non-linearity determined using standard reverse correlation analysis. We then quantitatively compare the output of the corresponding linear-nonlinear cascade with numerical simulations of spiking neurons, systematically varying the parameters of input signal and background noise. We find that the LN cascade provides accurate estimates of the firing rates of spiking neurons in most of parameter space. For the EIF and Wang-Buzsaki models, we show that the LN cascade can be reduced to a firing rate model, the timescale of which we determine analytically. Finally we introduce an adaptive timescale rate model in which the timescale of the linear filter depends on the instantaneous firing rate. This model leads to highly accurate estimates of instantaneous firing rates. PMID- 21283778 TI - Theoretical analysis of the stress induced B-Z transition in superhelical DNA. AB - We present a method to calculate the propensities of regions within a DNA molecule to transition from B-form to Z-form under negative superhelical stresses. We use statistical mechanics to analyze the competition that occurs among all susceptible Z-forming regions at thermodynamic equilibrium in a superhelically stressed DNA of specified sequence. This method, which we call SIBZ, is similar to the SIDD algorithm that was previously developed to analyze superhelical duplex destabilization. A state of the system is determined by assigning to each base pair either the B- or the Z-conformation, accounting for the dinucleotide repeat unit of Z-DNA. The free energy of a state is comprised of the nucleation energy, the sequence-dependent B-Z transition energy, and the energy associated with the residual superhelicity remaining after the change of twist due to transition. Using this information, SIBZ calculates the equilibrium B-Z transition probability of each base pair in the sequence. This can be done at any physiologically reasonable level of negative superhelicity. We use SIBZ to analyze a variety of representative genomic DNA sequences. We show that the dominant Z-DNA forming regions in a sequence can compete in highly complex ways as the superhelicity level changes. Despite having no tunable parameters, the predictions of SIBZ agree precisely with experimental results, both for the onset of transition in plasmids containing introduced Z-forming sequences and for the locations of Z-forming regions in genomic sequences. We calculate the transition profiles of 5 kb regions taken from each of 12,841 mouse genes and centered on the transcription start site (TSS). We find a substantial increase in the frequency of Z-forming regions immediately upstream from the TSS. The approach developed here has the potential to illuminate the occurrence of Z-form regions in vivo, and the possible roles this transition may play in biological processes. PMID- 21283779 TI - Practical measures of integrated information for time-series data. AB - A recent measure of 'integrated information', Phi(DM), quantifies the extent to which a system generates more information than the sum of its parts as it transitions between states, possibly reflecting levels of consciousness generated by neural systems. However, Phi(DM) is defined only for discrete Markov systems, which are unusual in biology; as a result, Phi(DM) can rarely be measured in practice. Here, we describe two new measures, Phi(E) and Phi(AR), that overcome these limitations and are easy to apply to time-series data. We use simulations to demonstrate the in-practice applicability of our measures, and to explore their properties. Our results provide new opportunities for examining information integration in real and model systems and carry implications for relations between integrated information, consciousness, and other neurocognitive processes. However, our findings pose challenges for theories that ascribe physical meaning to the measured quantities. PMID- 21283780 TI - A computational and experimental study of the regulatory mechanisms of the complement system. AB - The complement system is key to innate immunity and its activation is necessary for the clearance of bacteria and apoptotic cells. However, insufficient or excessive complement activation will lead to immune-related diseases. It is so far unknown how the complement activity is up- or down- regulated and what the associated pathophysiological mechanisms are. To quantitatively understand the modulatory mechanisms of the complement system, we built a computational model involving the enhancement and suppression mechanisms that regulate complement activity. Our model consists of a large system of Ordinary Differential Equations (ODEs) accompanied by a dynamic Bayesian network as a probabilistic approximation of the ODE dynamics. Applying Bayesian inference techniques, this approximation was used to perform parameter estimation and sensitivity analysis. Our combined computational and experimental study showed that the antimicrobial response is sensitive to changes in pH and calcium levels, which determines the strength of the crosstalk between CRP and L-ficolin. Our study also revealed differential regulatory effects of C4BP. While C4BP delays but does not decrease the classical complement activation, it attenuates but does not significantly delay the lectin pathway activation. We also found that the major inhibitory role of C4BP is to facilitate the decay of C3 convertase. In summary, the present work elucidates the regulatory mechanisms of the complement system and demonstrates how the bio pathway machinery maintains the balance between activation and inhibition. The insights we have gained could contribute to the development of therapies targeting the complement system. PMID- 21283781 TI - Multiple plant surface signals are sensed by different mechanisms in the rice blast fungus for appressorium formation. AB - Surface recognition and penetration are among the most critical plant infection processes in foliar pathogens. In Magnaporthe oryzae, the Pmk1 MAP kinase regulates appressorium formation and penetration. Its orthologs also are known to be required for various plant infection processes in other phytopathogenic fungi. Although a number of upstream components of this important pathway have been characterized, the upstream sensors for surface signals have not been well characterized. Pmk1 is orthologous to Kss1 in yeast that functions downstream from Msb2 and Sho1 for filamentous growth. Because of the conserved nature of the Pmk1 and Kss1 pathways and reduced expression of MoMSB2 in the pmk1 mutant, in this study we functionally characterized the MoMSB2 and MoSHO1 genes. Whereas the Momsb2 mutant was significantly reduced in appressorium formation and virulence, the Mosho1 mutant was only slightly reduced. The Mosho1 Momsb2 double mutant rarely formed appressoria on artificial hydrophobic surfaces, had a reduced Pmk1 phosphorylation level, and was nonresponsive to cutin monomers. However, it still formed appressoria and caused rare, restricted lesions on rice leaves. On artificial hydrophilic surfaces, leaf surface waxes and primary alcohols-but not paraffin waxes and alkanes- stimulated appressorium formation in the Mosho1 Momsb2 mutant, but more efficiently in the Momsb2 mutant. Furthermore, expression of a dominant active MST7 allele partially suppressed the defects of the Momsb2 mutant. These results indicate that, besides surface hydrophobicity and cutin monomers, primary alcohols, a major component of epicuticular leaf waxes in grasses, are recognized by M. oryzae as signals for appressorium formation. Our data also suggest that MoMsb2 and MoSho1 may have overlapping functions in recognizing various surface signals for Pmk1 activation and appressorium formation. While MoMsb2 is critical for sensing surface hydrophobicity and cutin monomers, MoSho1 may play a more important role in recognizing rice leaf waxes. PMID- 21283782 TI - Application of a new method for GWAS in a related case/control sample with known pedigree structure: identification of new loci for nephrolithiasis. AB - In contrast to large GWA studies based on thousands of individuals and large meta analyses combining GWAS results, we analyzed a small case/control sample for uric acid nephrolithiasis. Our cohort of closely related individuals is derived from a small, genetically isolated village in Sardinia, with well-characterized genealogical data linking the extant population up to the 16(th) century. It is expected that the number of risk alleles involved in complex disorders is smaller in isolated founder populations than in more diverse populations, and the power to detect association with complex traits may be increased when related, homogeneous affected individuals are selected, as they are more likely to be enriched with and share specific risk variants than are unrelated, affected individuals from the general population. When related individuals are included in an association study, correlations among relatives must be accurately taken into account to ensure validity of the results. A recently proposed association method uses an empirical genotypic covariance matrix estimated from genome-screen data to allow for additional population structure and cryptic relatedness that may not be captured by the genealogical data. We apply the method to our data, and we also investigate the properties of the method, as well as other association methods, in our highly inbred population, as previous applications were to outbred samples. The more promising regions identified in our initial study in the genetic isolate were then further investigated in an independent sample collected from the Italian population. Among the loci that showed association in this study, we observed evidence of a possible involvement of the region encompassing the gene LRRC16A, already associated to serum uric acid levels in a large meta-analysis of 14 GWAS, suggesting that this locus might lead a pathway for uric acid metabolism that may be involved in gout as well as in nephrolithiasis. PMID- 21283783 TI - Genetic epidemiology of tuberculosis susceptibility: impact of study design. AB - Several candidate gene studies have provided evidence for a role of host genetics in susceptibility to tuberculosis (TB). However, the results of these studies have been very inconsistent, even within a study population. Here, we review the design of these studies from a genetic epidemiological perspective, illustrating important differences in phenotype definition in both cases and controls, consideration of latent M. tuberculosis infection versus active TB disease, population genetic factors such as population substructure and linkage disequilibrium, polymorphism selection, and potential global differences in M. tuberculosis strain. These considerable differences between studies should be accounted for when examining the current literature. Recommendations are made for future studies to further clarify the host genetics of TB. PMID- 21283784 TI - Comparative study between transcriptionally- and translationally-acting adenine riboswitches reveals key differences in riboswitch regulatory mechanisms. AB - Many bacterial mRNAs are regulated at the transcriptional or translational level by ligand-binding elements called riboswitches. Although they both bind adenine, the adenine riboswitches of Bacillus subtilis and Vibrio vulnificus differ by controlling transcription and translation, respectively. Here, we demonstrate that, beyond the obvious difference in transcriptional and translational modulation, both adenine riboswitches exhibit different ligand binding properties and appear to operate under different regulation regimes (kinetic versus thermodynamic). While the B. subtilis pbuE riboswitch fully depends on co transcriptional binding of adenine to function, the V. vulnificus add riboswitch can bind to adenine after transcription is completed and still perform translation regulation. Further investigation demonstrates that the rate of transcription is critical for the B. subtilis pbuE riboswitch to perform efficiently, which is in agreement with a co-transcriptional regulation. Our results suggest that the nature of gene regulation control, that is transcription or translation, may have a high importance in riboswitch regulatory mechanisms. PMID- 21283785 TI - Segregating variation in the polycomb group gene cramped alters the effect of temperature on multiple traits. AB - The phenotype produced by a given genotype can be strongly modulated by environmental conditions. Therefore, natural populations continuously adapt to environment heterogeneity to maintain optimal phenotypes. It generates a high genetic variation in environment-sensitive gene networks, which is thought to facilitate evolution. Here we analyze the chromatin regulator crm, identified as a candidate for adaptation of Drosophila melanogaster to northern latitudes. We show that crm contributes to environmental canalization. In particular, crm modulates the effect of temperature on a genomic region encoding Hedgehog and Wingless signaling effectors. crm affects this region through both constitutive heterochromatin and Polycomb silencing. Furthermore, we show that crm European and African natural variants shift the reaction norms of plastic traits. Interestingly, traits modulated by crm natural variants can differ markedly between Drosophila species, suggesting that temperature adaptation facilitates their evolution. PMID- 21283786 TI - Global analysis of the impact of environmental perturbation on cis-regulation of gene expression. AB - Genetic variants altering cis-regulation of normal gene expression (cis-eQTLs) have been extensively mapped in human cells and tissues, but the extent by which controlled, environmental perturbation influences cis-eQTLs is unclear. We carried out large-scale induction experiments using primary human bone cells derived from unrelated donors of Swedish origin treated with 18 different stimuli (7 treatments and 2 controls, each assessed at 2 time points). The treatments with the largest impact on the transcriptome, verified on two independent expression arrays, included BMP-2 (t = 2h), dexamethasone (DEX) (t = 24 h), and PGE2 (t = 24 h). Using these treatments and control, we performed expression profiling for 18,144 RefSeq transcripts on biological replicates of the complete study cohort of 113 individuals (n(total) = 782) and combined it with genome-wide SNP-genotyping data in order to map treatment-specific cis-eQTLs (defined as SNPs located within the gene +/- 250 kb). We found that 93% of cis-eQTLs at 1% FDR were observed in at least one additional treatment, and in fact, on average, only 1.4% of the cis-eQTLs were considered as treatment-specific at high confidence. The relative invariability of cis-regulation following perturbation was reiterated independently by genome-wide allelic expression tests where only a small proportion of variance could be attributed to treatment. Treatment-specific cis-regulatory effects were, however, 2- to 6-fold more abundant among differently expressed genes upon treatment. We further followed-up and validated the DEX-specific cis-regulation of the MYO6 and TNC loci and found top cis regulatory variants located 180 kb and 250 kb upstream of the transcription start sites, respectively. Our results suggest that, as opposed to tissue-specificity of cis-eQTLs, the interactions between cellular environment and cis-variants are relatively rare (~1.5%), but that detection of such specific interactions can be achieved by a combination of functional genomic approaches as described here. PMID- 21283787 TI - Selective C-Rel activation via Malt1 controls anti-fungal T(H)-17 immunity by dectin-1 and dectin-2. AB - C-type lectins dectin-1 and dectin-2 on dendritic cells elicit protective immunity against fungal infections through induction of T(H)1 and T(H)-17 cellular responses. Fungal recognition by dectin-1 on human dendritic cells engages the CARD9-Bcl10-Malt1 module to activate NF-kappaB. Here we demonstrate that Malt1 recruitment is pivotal to T(H)-17 immunity by selective activation of NF-kappaB subunit c-Rel, which induces expression of T(H)-17-polarizing cytokines IL-1beta and IL-23p19. Malt1 inhibition abrogates c-Rel activation and T(H)-17 immunity to Candida species. We found that Malt1-mediated activation of c-Rel is similarly essential to induction of T(H)-17-polarizing cytokines by dectin-2. Whereas dectin-1 activates all NF-kappaB subunits, dectin-2 selectively activates c-Rel, signifying a specialized T(H)-17-enhancing function for dectin-2 in anti fungal immunity by human dendritic cells. Thus, dectin-1 and dectin-2 control adaptive T(H)-17 immunity to fungi via Malt1-dependent activation of c-Rel. PMID- 21283788 TI - Imaging single retrovirus entry through alternative receptor isoforms and intermediates of virus-endosome fusion. AB - A large group of viruses rely on low pH to activate their fusion proteins that merge the viral envelope with an endosomal membrane, releasing the viral nucleocapsid. A critical barrier to understanding these events has been the lack of approaches to study virus-cell membrane fusion within acidic endosomes, the natural sites of virus nucleocapsid capsid entry into the cytosol. Here we have investigated these events using the highly tractable subgroup A avian sarcoma and leukosis virus envelope glycoprotein (EnvA)-TVA receptor system. Through labeling EnvA pseudotyped viruses with a pH-sensitive fluorescent marker, we imaged their entry into mildly acidic compartments. We found that cells expressing the transmembrane receptor (TVA950) internalized the virus much faster than those expressing the GPI-anchored receptor isoform (TVA800). Surprisingly, TVA800 did not accelerate virus uptake compared to cells lacking the receptor. Subsequent steps of virus entry were visualized by incorporating a small viral content marker that was released into the cytosol as a result of fusion. EnvA-dependent fusion with TVA800-expressing cells occurred shortly after endocytosis and delivery into acidic endosomes, whereas fusion of viruses internalized through TVA950 was delayed. In the latter case, a relatively stable hemifusion-like intermediate preceded the fusion pore opening. The apparent size and stability of nascent fusion pores depended on the TVA isoforms and their expression levels, with TVA950 supporting more robust pores and a higher efficiency of infection compared to TVA800. These results demonstrate that surface receptor density and the intracellular trafficking pathway used are important determinants of efficient EnvA-mediated membrane fusion, and suggest that early fusion intermediates play a critical role in establishing low pH-dependent virus entry from within acidic endosomes. PMID- 21283789 TI - Joint genetic analysis of gene expression data with inferred cellular phenotypes. AB - Even within a defined cell type, the expression level of a gene differs in individual samples. The effects of genotype, measured factors such as environmental conditions, and their interactions have been explored in recent studies. Methods have also been developed to identify unmeasured intermediate factors that coherently influence transcript levels of multiple genes. Here, we show how to bring these two approaches together and analyse genetic effects in the context of inferred determinants of gene expression. We use a sparse factor analysis model to infer hidden factors, which we treat as intermediate cellular phenotypes that in turn affect gene expression in a yeast dataset. We find that the inferred phenotypes are associated with locus genotypes and environmental conditions and can explain genetic associations to genes in trans. For the first time, we consider and find interactions between genotype and intermediate phenotypes inferred from gene expression levels, complementing and extending established results. PMID- 21283790 TI - The transposon-like Correia elements encode numerous strong promoters and provide a potential new mechanism for phase variation in the meningococcus. AB - Neisseria meningitidis is the primary causative agent of bacterial meningitis. The genome is rich in repetitive DNA and almost 2% is occupied by a diminutive transposon called the Correia element. Here we report a bioinformatic analysis defining eight subtypes of the element with four distinct types of ends. Transcriptional analysis, using PCR and a lacZ reporter system, revealed that two ends in particular encode strong promoters. The activity of the strongest promoter is dictated by a recurrent polymorphism (Y128) at the right end of the element. We highlight examples of elements that appear to drive transcription of adjacent genes and others that may express small non-coding RNAs. Pair-wise comparisons between three meningococcal genomes revealed that no more than two thirds of Correia elements maintain their subtype at any particular locus. This is due to recombinational class switching between elements in a single strain. Upon switching subtype, a new allele is available to spread through the population by natural transformation. This process may represent a hitherto unrecognized mechanism for phase variation in the meningococcus. We conclude that the strain-to-strain variability of the Correia elements, and the large number of strong promoters encoded by them, allows for potentially widespread effects within the population as a whole. By defining the strength of the promoters encoded by the eight subtypes of Correia ends, we provide a resource that allows the transcriptional effects of a particular subtype at a given locus to be predicted. PMID- 21283791 TI - Visfatin induces sickness responses in the brain. AB - BACKGROUND/OBJECTIVE: Visfatin, also known as nicotiamide phosphoribosyltransferase or pre-B cell colony enhancing factor, is a pro inflammatory cytokine whose serum level is increased in sepsis and cancer as well as in obesity. Here we report a pro-inflammatory role of visfatin in the brain, to mediate sickness responses including anorexia, hyperthermia and hypoactivity. METHODOLOGY: Rats were intracerebroventricularly (ICV) injected with visfatin, and changes in food intake, body weight, body temperature and locomotor activity were monitored. Real-time PCR was applied to determine the expressions of pro inflammatory cytokines, proopiomelanocortin (POMC) and prostaglandin-synthesizing enzymes in their brain. To determine the roles of cyclooxygenase (COX) and melanocortin in the visfatin action, rats were ICV-injected with visfatin with or without SHU9119, a melanocortin receptor antagonist, or indomethacin, a COX inhibitor, and their sickness behaviors were evaluated. PRINCIPAL FINDINGS: Administration of visfatin decreased food intake, body weight and locomotor activity and increased body temperature. Visfatin evoked significant increases in the levels of pro-inflammatory cytokines, prostaglandin-synthesizing enzymes and POMC, an anorexigenic neuropeptide. Indomethacin attenuated the effects of visfatin on hyperthermia and hypoactivity, but not anorexia. Further, SHU9119 blocked visfatin-induced anorexia but did not affect hyperthermia or hypoactivity. CONCLUSIONS: Visfatin induced sickness responses via regulation of COX and the melanocortin pathway in the brain. PMID- 21283792 TI - The shared preference niche of sympatric Asiatic black bears and sun bears in a tropical forest mosaic. AB - BACKGROUND: Ecologically similar species often coexist by partitioning use of habitats or resources. Such partitioning can occur through divergent or shared niches. We investigated overlap in habitat use and spatial co-occurrence by sympatric Asiatic black bears and sun bears in three habitats in Thailand, and thereby assessed which niche model best accounts for their coexistence. METHODS/PRINCIPAL FINDINGS: We used density of species-specific signs to assess habitat use. Signs of both bear species occurred in all three habitats, and on >60% of sampling transects. Both species fed mostly on fruit; insect feeding signs were uncommon, and were mostly from sun bears. Significant differences in habitat use occurred only in montane forest, the habitat in which fruit was most abundant; incidence of black bear sign there was six times higher than that of sun bears. Habitat use was similar between the two species in the other habitats, which comprised 85% of the area. Of 10 habitat attributes examined, fruiting tree density was the best predictor of occurrence for both species. Models that included interspecific competition (fresh foraging activity of the other species) were less supported than the top models without competition. CONCLUSIONS/SIGNIFICANCE: Bear species co-occurrence at both coarse and fine spatial scales and use of the same resources (fruit trees) indicated common niche preferences. However, their habitat use differed in ways expected from their physical differences: larger black bears dominated in the most fruit-rich habitat, and smaller sun bears used less-preferred insects. These results indicate broadly overlapping fundamental niches combined with asymmetric competition-features consistent with the concept of shared preference niches. This model of the niche has received little attention in ecology, but appears to be relatively common in nature. PMID- 21283793 TI - Evolutionary and structural features of the C2, V3 and C3 envelope regions underlying the differences in HIV-1 and HIV-2 biology and infection. AB - BACKGROUND: Unlike in HIV-1 infection, the majority of HIV-2 patients produce broadly reactive neutralizing antibodies, control viral replication and survive as elite controllers. The identification of the molecular, structural and evolutionary footprints underlying these very distinct immunological and clinical outcomes may lead to the development of new strategies for the prevention and treatment of HIV infection. METHODOLOGY/PRINCIPAL FINDINGS: We performed a side by-side molecular, evolutionary and structural comparison of the C2, V3 and C3 envelope regions from HIV-1 and HIV-2. These regions contain major antigenic targets and are important for receptor binding. In HIV-2, these regions also have immune modulatory properties. We found that these regions are significantly more variable in HIV-1 than in HIV-2. Within each virus, C3 is the most entropic region followed by either C2 (HIV-2) or V3 (HIV-1). The C3 region is well exposed in the HIV-2 envelope and is under strong diversifying selection suggesting that, like in HIV-1, it may harbour neutralizing epitopes. Notably, however, extreme diversification of C2 and C3 seems to be deleterious for HIV-2 and prevent its transmission. Computer modelling simulations showed that in HIV-2 the V3 loop is much less exposed than C2 and C3 and has a retractile conformation due to a physical interaction with both C2 and C3. The concealed and conserved nature of V3 in the HIV-2 is consistent with its lack of immunodominancy in vivo and with its role in preventing immune activation. In contrast, HIV-1 had an extended and accessible V3 loop that is consistent with its immunodominant and neutralizing nature. CONCLUSIONS/SIGNIFICANCE: We identify significant structural and functional constrains to the diversification and evolution of C2, V3 and C3 in the HIV-2 envelope but not in HIV-1. These studies highlight fundamental differences in the biology and infection of HIV-1 and HIV-2 and in their mode of interaction with the human immune system and may inform new vaccine and therapeutic interventions against these viruses. PMID- 21283794 TI - Dynamics of viral evolution and CTL responses in HIV-1 infection. AB - Improved understanding of the dynamics of host immune responses and viral evolution is critical for effective HIV-1 vaccine design. We comprehensively analyzed Cytotoxic T-lymphocyte (CTL)-viral epitope dynamics in an antiretroviral therapy-naive subject over the first four years of HIV-1 infection. We found that CTL responses developed sequentially and required constant antigenic stimulation for maintenance. CTL responses exerting strong selective pressure emerged early and led to rapid escape, proliferated rapidly and were predominant during acute/early infection. Although CTL responses to a few persistent epitopes developed over the first two months of infection, they proliferated slowly. As CTL epitopes were replaced by mutational variants, the corresponding responses immediately declined, most rapidly in the cases of strongly selected epitopes. CTL recognition of epitope variants, via cross-reactivity and de novo responses, was common throughout the period of study. Our data demonstrate that HIV-specific CTL responses, especially in the critical acute/early stage, were focused on regions that are prone to escape. Failure of CTL responses to strongly target functional or structurally critical regions of the virus, as well as the sequential cascade of CTL responses, followed closely by viral escape and decline of the corresponding responses, likely contribute to a lack of sustainable viral suppression. Focusing early and rapidly proliferating CTL on persistent epitopes may be essential for durable viral control in HIV-1 infection. PMID- 21283795 TI - Dissecting genetic networks underlying complex phenotypes: the theoretical framework. AB - Great progress has been made in genetic dissection of quantitative trait variation during the past two decades, but many studies still reveal only a small fraction of quantitative trait loci (QTLs), and epistasis remains elusive. We integrate contemporary knowledge of signal transduction pathways with principles of quantitative and population genetics to characterize genetic networks underlying complex traits, using a model founded upon one-way functional dependency of downstream genes on upstream regulators (the principle of hierarchy) and mutual functional dependency among related genes (functional genetic units, FGU). Both simulated and real data suggest that complementary epistasis contributes greatly to quantitative trait variation, and obscures the phenotypic effects of many 'downstream' loci in pathways. The mathematical relationships between the main effects and epistatic effects of genes acting at different levels of signaling pathways were established using the quantitative and population genetic parameters. Both loss of function and "co-adapted" gene complexes formed by multiple alleles with differentiated functions (effects) are predicted to be frequent types of allelic diversity at loci that contribute to the genetic variation of complex traits in populations. Downstream FGUs appear to be more vulnerable to loss of function than their upstream regulators, but this vulnerability is apparently compensated by different FGUs of similar functions. Other predictions from the model may account for puzzling results regarding responses to selection, genotype by environment interaction, and the genetic basis of heterosis. PMID- 21283796 TI - In vivo characterization of the homing endonuclease within the polB gene in the halophilic archaeon Haloferax volcanii. AB - Inteins are parasitic genetic elements, analogous to introns that excise themselves at the protein level by self-splicing, allowing the formation of functional non-disrupted proteins. Many inteins contain a homing endonuclease (HEN) gene, and rely on its activity for horizontal propagation. In the halophilic archaeon, Haloferax volcanii, the gene encoding DNA polymerase B (polB) contains an intein with an annotated but uncharacterized HEN. Here we examine the activity of the polB HEN in vivo, within its natural archaeal host. We show that this HEN is highly active, and able to insert the intein into both a chromosomal target and an extra-chromosomal plasmid target, by gene conversion. We also demonstrate that the frequency of its incorporation depends on the length of the flanking homologous sequences around the target site, reflecting its dependence on the homologous recombination machinery. Although several evolutionary models predict that the presence of an intein involves a change in the fitness of the host organism, our results show that a strain deleted for the intein sequence shows no significant changes in growth rate compared to the wild type. PMID- 21283797 TI - Identification of genes with allelic imbalance on 6p associated with nasopharyngeal carcinoma in southern Chinese. AB - Nasopharyngeal carcinoma (NPC) is a malignancy of epithelial origin. The etiology of NPC is complex and includes multiple genetic and environmental factors. We employed case-control analysis to study the association of chromosome 6p regions with NPC. In total, 360 subjects and 360 healthy controls were included, and 233 single nucleotide polymorphisms (SNPs) on 6p were examined. Significant single marker associations were found for SNPs rs2267633 (p = 4.49 * 10(-5)), rs2076483 (most significant, p = 3.36 * 10(-5)), and rs29230 (p=1.43 * 10(-4)). The highly associated genes were the gamma-amino butyric acid B receptor 1 (GABBR1), human leukocyte antigen (HLA-A), and HLA complex group 9 (HCG9). Haplotypic associations were found for haplotypes AAA (located within GABBR1, p-value = 6.46 * 10(-5)) and TT (located within HLA-A, p = 0.0014). Further investigation of the homozygous genotype frequencies between cases and controls suggested that micro-deletion regions occur in GABBR1 and neural precursor cell expressed developmentally down-regulated 9 (NEDD9). Quantitative real-time polymerase chain reaction (qPCR) using 11 pairs of NPC biopsy samples confirmed the significant decline in GABBR1 and NEDD9 mRNA expression in the cancer tissues compared to the adjacent non-tumor tissue (p<0.05). Our study demonstrates that multiple chromosome 6p susceptibility loci contribute to the risk of NPC, possibly though GABBR1 and NEDD9 loss of function. PMID- 21283798 TI - Bves modulates tight junction associated signaling. AB - Blood vessel epicardial substance (Bves) is a transmembrane adhesion protein that regulates tight junction (TJ) formation in a variety of epithelia. The role of TJs within epithelium extends beyond the mechanical properties. They have been shown to play a direct role in regulation of RhoA and ZONAB/DbpA, a y-box transcription factor. We hypothesize that Bves can modulate RhoA activation and ZONAB/DbpA activity through its regulatory effect on TJ formation. Immortalized human corneal epithelial (HCE) cells were stably transfected with Flag-tagged full length chicken Bves (w-Bves) or C-terminus truncated Bves (t-Bves). We found that stably transfected w-Bves and t-Bves were interacting with endogenous human Bves. However, interaction with t-Bves appeared to disrupt cell membrane localization of endogenous Bves and interaction with ZO-1. w-Bves cells exhibited increased TJ function reflected by increased trans-epithelial electrical resistance, while t-Bves cells lost TJ protein immunolocalization at cell-cell contacts and exhibited decreased trans-epithelial electrical resistance. In parental HCE and w-Bves cells ZONAB/DbpA and GEF-H1 were seen at cell borders in the same pattern as ZO-1. However, expression of t-Bves led to decreased membrane localization of both ZONAB/DbpA and GEF-H1. t-Bves cells had increased RhoA activity, as indicated by a significant 30% increase in FRET activity compared to parental HCE cells. ZONAB/DbpA transcriptional activity, assessed using a luciferase reporter probe, was increased in t-Bves cells. These studies demonstrate that Bves expression and localization can regulate RhoA and ZONAB/DbpA activity. PMID- 21283799 TI - Plasma membrane factor XIIIA transglutaminase activity regulates osteoblast matrix secretion and deposition by affecting microtubule dynamics. AB - Transglutaminase activity, arising potentially from transglutaminase 2 (TG2) and Factor XIIIA (FXIIIA), has been linked to osteoblast differentiation where it is required for type I collagen and fibronectin matrix deposition. In this study we have used an irreversible TG-inhibitor to 'block -and-track' enzyme(s) targeted during osteoblast differentiation. We show that the irreversible TG-inhibitor is highly potent in inhibiting osteoblast differentiation and mineralization and reduces secretion of both fibronectin and type I collagen and their release from the cell surface. Tracking of the dansyl probe by Western blotting and immunofluorescence microscopy demonstrated that the inhibitor targets plasma membrane-associated FXIIIA. TG2 appears not to contribute to crosslinking activity on the osteoblast surface. Inhibition of FXIIIA with NC9 resulted in defective secretory vesicle delivery to the plasma membrane which was attributable to a disorganized microtubule network and decreased microtubule association with the plasma membrane. NC9 inhibition of FXIIIA resulted in destabilization of microtubules as assessed by cellular Glu-tubulin levels. Furthermore, NC9 blocked modification of Glu-tubulin into 150 kDa high-molecular weight Glu-tubulin form which was specifically localized to the plasma membrane. FXIIIA enzyme and its crosslinking activity were colocalized with plasma membrane associated tubulin, and thus, it appears that FXIIIA crosslinking activity is directed towards stabilizing the interaction of microtubules with the plasma membrane. Our work provides the first mechanistic cues as to how transglutaminase activity could affect protein secretion and matrix deposition in osteoblasts and suggests a novel function for plasma membrane FXIIIA in microtubule dynamics. PMID- 21283800 TI - Optimizing optical flow cytometry for cell volume-based sorting and analysis. AB - Cell size is a defining characteristic central to cell function and ultimately to tissue architecture. The ability to sort cell subpopulations of different sizes would facilitate investigation at genomic and proteomic levels of mechanisms by which cells attain and maintain their size. Currently available cell sorters, however, cannot directly measure cell volume electronically, and it would therefore be desirable to know which of the optical measurements that can be made in such instruments provide the best estimate of volume. We investigated several different light scattering and fluorescence measurements in several different cell lines, sorting cell fractions from the high and low end of distributions, and measuring volume electronically to determine which sorting strategy yielded the best separated volume distributions. Since we found that different optical measurements were optimal for different cell lines, we suggest that following this procedure will enable other investigators to optimize their own cell sorters for volume-based separation of the cell types with which they work. PMID- 21283801 TI - Classifications for cesarean section: a systematic review. AB - BACKGROUND: Rising cesarean section (CS) rates are a major public health concern and cause worldwide debates. To propose and implement effective measures to reduce or increase CS rates where necessary requires an appropriate classification. Despite several existing CS classifications, there has not yet been a systematic review of these. This study aimed to 1) identify the main CS classifications used worldwide, 2) analyze advantages and deficiencies of each system. METHODS AND FINDINGS: Three electronic databases were searched for classifications published 1968-2008. Two reviewers independently assessed classifications using a form created based on items rated as important by international experts. Seven domains (ease, clarity, mutually exclusive categories, totally inclusive classification, prospective identification of categories, reproducibility, implementability) were assessed and graded. Classifications were tested in 12 hypothetical clinical case-scenarios. From a total of 2948 citations, 60 were selected for full-text evaluation and 27 classifications identified. Indications classifications present important limitations and their overall score ranged from 2-9 (maximum grade =14). Degree of urgency classifications also had several drawbacks (overall scores 6-9). Woman based classifications performed best (scores 5-14). Other types of classifications require data not routinely collected and may not be relevant in all settings (scores 3-8). CONCLUSIONS: This review and critical appraisal of CS classifications is a methodologically sound contribution to establish the basis for the appropriate monitoring and rational use of CS. Results suggest that women based classifications in general, and Robson's classification, in particular, would be in the best position to fulfill current international and local needs and that efforts to develop an internationally applicable CS classification would be most appropriately placed in building upon this classification. The use of a single CS classification will facilitate auditing, analyzing and comparing CS rates across different settings and help to create and implement effective strategies specifically targeted to optimize CS rates where necessary. PMID- 21283802 TI - Impact of KRAS, BRAF, PIK3CA mutations, PTEN, AREG, EREG expression and skin rash in >= 2 line cetuximab-based therapy of colorectal cancer patients. AB - BACKGROUND: To investigate the predictive significance of KRAS, BRAF, PIK3CA mutational status, AREG- EREG mRNA expression, PTEN protein expression and skin rash in metastatic colorectal cancer (mCRC) patients treated with cetuximab containing salvage chemotherapy. METHODS: Primary tumors from 112 mCRC patients were analyzed. The worst skin toxicity during treatment was recorded. RESULTS: KRAS, BRAF and PIK3CA mutations were present in 37 (33%), 8 (7.2%) and 11 (9.8%) cases, respectively, PTEN was lost in 21 (19.8%) cases, AREG and EREG were overexpressed in 48 (45%) and 51 (49%) cases. In the whole study population, time to tumor progression (TTP) and overall survival (OS) was significantly lower in patients with KRAS (p = 0.001 and p = 0.026, respectively) or BRAF (p = 0.001 and p<0.0001, respectively) mutant tumors, downregulation of AREG (p = 0.018 and p = 0.013, respectively) or EREG (p = 0.002 and p = 0.004, respectively) and grade 0 1 skin rash (p<0.0001 and p<0.0001, respectively). In KRAS wt patients TTP and OS was significantly lower in patients with BRAF (p = 0.0001 and p<0.0001, respectively) mutant tumors, downregulation of AREG (p = 0.021 and p = 0.004, respectively) or EREG (p = 0.0001 and p<0.0001, respectively) and grade 0-1 skin rash (p<0.0001 and p<0.0001, respectively). TTP was significantly lower in patients with PIK3CA mutations (p = 0.01) or lost PTEN (p = 0.002). Multivariate analysis revealed KRAS (Hazard Ratio [HR] 4.3, p<0.0001), BRAF mutation (HR: 5.1, p<0.0001), EREG low expression (HR: 1.6, p = 0.021) and absence of severe/moderate skin rash (HR: 4.0, p<0.0001) as independent prognostic factors for decreased TTP. Similarly, KRAS (HR 2.9, p = 0.01), BRAF mutation (HR: 3.0, p = 0.001), EREG low expression (HR: 1.7, p = 0.021), absence of severe/moderate skin rash (HR: 3.7, p<0.0001) and the presence of undifferantited tumours (HR: 2.2, p = 0.001) were revealed as independent prognostic factors for decreased OS. CONCLUSIONS: These results underscore that KRAS-BRAF mutations and EREG expression can be used as biomarkers to further select patients undergoing anti EGFR treatment. PMID- 21283803 TI - Phylogeny of Mycobacterium tuberculosis Beijing strains constructed from polymorphisms in genes involved in DNA replication, recombination and repair. AB - BACKGROUND: The Beijing family is a successful group of M. tuberculosis strains, often associated with drug resistance and widely distributed throughout the world. Polymorphic genetic markers have been used to type particular M. tuberculosis strains. We recently identified a group of polymorphic DNA repair replication and recombination (3R) genes. It was shown that evolution of M. tuberculosis complex strains can be studied using 3R SNPs and a high-resolution tool for strain discrimination was developed. Here we investigated the genetic diversity and propose a phylogeny for Beijing strains by analyzing polymorphisms in 3R genes. METHODOLOGY/PRINCIPAL FINDINGS: A group of 3R genes was sequenced in a collection of Beijing strains from different geographic origins. Sequence analysis and comparison with the ones of non-Beijing strains identified several SNPs. These SNPs were used to type a larger collection of Beijing strains and allowed identification of 26 different sequence types for which a phylogeny was constructed. Phylogenetic relationships established by sequence types were in agreement with evolutionary pathways suggested by other genetic markers, such as Large Sequence Polymorphisms (LSPs). A recent Beijing genotype (Bmyc10), which included 60% of strains from distinct parts of the world, appeared to be predominant. CONCLUSIONS/SIGNIFICANCE: We found SNPs in 3R genes associated with the Beijing family, which enabled discrimination of different groups and the proposal of a phylogeny. The Beijing family can be divided into different groups characterized by particular genetic polymorphisms that may reflect pathogenic features. These SNPs are new, potential genetic markers that may contribute to better understand the success of the Beijing family. PMID- 21283804 TI - Time course of gene expression profiling in the liver of experimental mice infected with Echinococcus multilocularis. AB - BACKGROUND: Alveolar echinococcosis (AE) is a severe chronic parasitic disease which behaves like a slow-growing liver cancer. Clinical observations suggest that the parasite, Echinococcus multilocularis (E. multilocularis) influences liver homeostasis and hepatic cell metabolism. However, this has never been analyzed during the time course of infection in the common model of secondary echinococcosis in experimental mice. METHODOLOGY/PRINCIPAL FINDINGS: Gene expression profiles were assessed using DNA microarray analysis, 1, 2, 3 and 6 months after injection of E. multilocularis metacestode in the liver of susceptible mice. Data were collected at different time points to monitor the dynamic behavior of gene expression. 557 differentially expressed genes were identified at one or more time points, including 351 up-regulated and 228 down regulated genes. Time-course analysis indicated, at the initial stage of E. multilocularis infection (month 1-2), that most of up-regulated pathways were related to immune processes and cell trafficking such as chemokine-, mitogen activated protein kinase (MAPK) signaling, and down-regulated pathways were related to xenobiotic metabolism; at the middle stage (month 3), MAPK signaling pathway was maintained and peroxisome proliferator-activated receptor (PPAR) signaling pathway emerged; at the late stage (month 6), most of up-regulated pathways were related to PPAR signaling pathway, complement and coagulation cascades, while down-regulated pathways were related to metabolism of xenobiotics by cytochrome P450. Quantitative RT-PCR analysis of a random selection of 19 genes confirmed the reliability of the microarray data. Immunohistochemistry analysis showed that proliferating cell nuclear antigen (PCNA) was increased in the liver of E. multilocularis infected mice from 2 months to 6 months. CONCLUSIONS: E. multilocularis metacestode definitely exerts a deep influence on liver homeostasis, by modifying a number of gene expression and metabolic pathways. It especially promotes hepatic cell proliferation, as evidenced by the increased PCNA constantly found in all the experimental time-points we studied and by an increased gene expression of key metabolic pathways. PMID- 21283805 TI - Co-administration of IL-1+IL-6+TNF-alpha with Mycobacterium tuberculosis infected macrophages vaccine induces better protective T cell memory than BCG. AB - BCG has been administered globally for more than 75 years, yet tuberculosis (TB) continues to kill more than 2 million people annually. Further, BCG protects childhood TB but is quite inefficient in adults. This indicates that BCG fails to induce long-term protection. Hence there is a need to explore alternative vaccination strategies that can stimulate enduring T cell memory response. Dendritic cell based vaccination has attained extensive popularity following their success in various malignancies. In our previous study, we have established a novel and unique vaccination strategy against Mycobacterium tuberculosis (M. tb) and Salmonella typhimurium by utilizing infected macrophages (IM). In short term experiments (30 days), substantial degree of protection was observed. However, remarkable difference was not observed in long-term studies (240 days) due to failure of the vaccine to generate long-lasting memory T cells. Hence, in the present study we employed T cell memory augmenting cytokines IL-1+IL-6+TNF alpha and IL-7+IL-15 for the induction of the enhancement of long-term protection by the vaccine. We co-administered the M. tb infected macrophages vaccine with IL 1+IL-6+TNF-alpha (IM-1.6.alpha) and IL-7+IL-15 (IM-7.15). The mice were then rested for a reasonably large period (240 days) to study the bona fide T cell memory response before exposing them to aerosolized M. tb. IM-1.6.alpha but not IM-7.15 significantly improved memory T cell response against M. tb, as evidenced by recall responses of memory T cells, expansion of both central as well as effector memory CD4 and CD8 T cell pools, elicitation of mainly Th1 memory response, reduction in the mycobacterial load and alleviated lung pathology. Importantly, the protection induced by IM-1.6.alpha was significantly better than BCG. Thus, this study demonstrates that not only antigen-pulsed DCs can be successfully employed as vaccines against cancer and infectious diseases but also macrophages infected with M. tb can be utilized with great efficacy especially in protection against TB. PMID- 21283806 TI - Lipid catabolism of invertebrate predator indicates widespread wetland ecosystem degradation. AB - Animals frequently undergo periods when they accumulate lipid reserves for subsequent energetically expensive activities, such as migration or breeding. During such periods, daily lipid-reserve dynamics (DLD) of sentinel species can quantify how landscape modifications affect function, health, and resilience of ecosystems. Aythya affinis (Eyton 1838; lesser scaup; diving duck) are macroinvertebrate predators; they migrate through an agriculturally dominated landscape in spring where they select wetlands with the greatest food density to refuel and accumulate lipid reserves for subsequent reproduction. We index DLD by measuring plasma-lipid metabolites of female scaup (n = 459) that were refueling at 75 spring migration stopover areas distributed across the upper Midwest, USA. We also indexed DLD for females (n = 44) refueling on a riverine site (Pool 19) south of our upper Midwest study area. We found that mean DLD estimates were significantly (P<0.05) less than zero in all ecophysiographic regions of the upper Midwest, and the greatest negative value was in the Iowa Prairie Pothole region (-31.6). Mean DLD was 16.8 at Pool 19 and was markedly greater than in any region of the upper Midwest. Our results indicate that females catabolized rather than stored lipid reserves throughout the upper Midwest. Moreover, levels of lipid catabolism are alarming, because scaup use the best quality wetlands available within a given stopover area. Accordingly, these results provide evidence of wetland ecosystem degradation across this large agricultural landscape and document affects that are carried-up through several trophic levels. Interestingly, storing of lipids by scaup at Pool 19 likely reflects similar ecosystem perturbations as observed in the upper Midwest because wetland drainage and agricultural runoff nutrifies the riverine habitat that scaup use at Pool 19. Finally, our results underscore how using this novel technique to monitor DLD, of a carefully selected sentinel species, can index ecosystem health at a landscape scale. PMID- 21283807 TI - Transient alteration of cellular redox buffering before irradiation triggers apoptosis in head and neck carcinoma stem and non-stem cells. AB - BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is an aggressive and recurrent malignancy owing to intrinsic radioresistance and lack of induction of apoptosis. The major focus of this work was to design a transient glutathione depleting strategy during the course of irradiation of HNSCC in order to overcome their radioresistance associated with redox adaptation. METHODOLOGY/PRINCIPAL FINDINGS: Treatment of SQ20B cells with dimethylfumarate (DMF), a GSH-depleting agent, and L-Buthionine sulfoximine (BSO), an inhibitor of GSH biosynthesis 4 h before a 10 Gy irradiation led to the lowering of the endogenous GSH content to less than 10% of that in control cells and to the triggering of radiation-induced apoptotic cell death. The sequence of biochemical events after GSH depletion and irradiation included ASK-1 followed by JNK activation which resulted in the triggering of the intrinsic apoptotic pathway through Bax translocation to mitochondria. CONCLUSIONS: This transient GSH depletion also triggered radiation induced cell death in SQ20B stem cells, a key event to overcome locoregional recurrence of HNSCC. Finally, our in vivo data highlight the relevance for further clinical trials of endogenous redox modulation to enhance the cytotoxic effects of radiotherapy. PMID- 21283808 TI - Novel quantitative real-time LCR for the sensitive detection of SNP frequencies in pooled DNA: method development, evaluation and application. AB - BACKGROUND: Single nucleotide polymorphisms (SNP) have proven to be powerful genetic markers for genetic applications in medicine, life science and agriculture. A variety of methods exist for SNP detection but few can quantify SNP frequencies when the mutated DNA molecules correspond to a small fraction of the wild-type DNA. Furthermore, there is no generally accepted gold standard for SNP quantification, and, in general, currently applied methods give inconsistent results in selected cohorts. In the present study we sought to develop a novel method for accurate detection and quantification of SNP in DNA pooled samples. METHODS: The development and evaluation of a novel Ligase Chain Reaction (LCR) protocol that uses a DNA-specific fluorescent dye to allow quantitative real-time analysis is described. Different reaction components and thermocycling parameters affecting the efficiency and specificity of LCR were examined. Several protocols, including gap-LCR modifications, were evaluated using plasmid standard and genomic DNA pools. A protocol of choice was identified and applied for the quantification of a polymorphism at codon 136 of the ovine PRNP gene that is associated with susceptibility to a transmissible spongiform encephalopathy in sheep. CONCLUSIONS: The real-time LCR protocol developed in the present study showed high sensitivity, accuracy, reproducibility and a wide dynamic range of SNP quantification in different DNA pools. The limits of detection and quantification of SNP frequencies were 0.085% and 0.35%, respectively. SIGNIFICANCE: The proposed real-time LCR protocol is applicable when sensitive detection and accurate quantification of low copy number mutations in DNA pools is needed. Examples include oncogenes and tumour suppressor genes, infectious diseases, pathogenic bacteria, fungal species, viral mutants, drug resistance resulting from point mutations, and genetically modified organisms in food. PMID- 21283810 TI - Up regulation of the maternal immune response in the placenta of cattle naturally infected with Neospora caninum. AB - Neospora caninum is an intracellular protozoan parasite which is a major cause of abortion in cattle worldwide. It forms persistent infections which recrudesce during pregnancy leading to foetal infection and in a proportion of cases, abortion. The mechanisms underlying abortion are not understood. In this study, recrudescence of a persistent infection in eight naturally infected cows occurred between 20 and 33 weeks of gestation. Animals were killed at the time of recrudescence and parasites were detected in the placentae and foetuses. An active maternal immune response consisting of an infiltration of CD4+ and CD8+ T cells and a 46-49 fold increase in interferon-gamma and interleukin-4 mRNA was detected. Other cytokines, notably interleukin-12 p40, interleukin-10 and tumour necrosis factor-alpha were also significantly increased and Major Histocompatibility Class II antigen was expressed on maternal and foetal epithelial and stromal fibroblastoid cells. Significantly, despite the presence of an active maternal immune response in the placenta, all the foetuses were alive at the time of maternal euthanasia. There was evidence of parasites within foetal tissues; their distribution was restricted to the central nervous system and skeletal muscle and their presence was associated with tissue necrosis and a non-suppurative inflammatory response involving lymphocytes and macrophages, irrespective of the gestational age of the foetus. Whilst an active maternal immune response to a pathogen in the placenta is generally considered to be damaging to the foetal trophoblast, our findings suggest that the presence of a parasite-induced maternal immune response in the placenta is not detrimental to foetal survival but may contribute to the control of placental parasitosis. PMID- 21283809 TI - Characterization of the deleted in autism 1 protein family: implications for studying cognitive disorders. AB - Autism spectrum disorders (ASDs) are a group of commonly occurring, highly heritable developmental disabilities. Human genes c3orf58 or Deleted In Autism-1 (DIA1) and cXorf36 or Deleted in Autism-1 Related (DIA1R) are implicated in ASD and mental retardation. Both gene products encode signal peptides for targeting to the secretory pathway. As evolutionary medicine has emerged as a key tool for understanding increasing numbers of human diseases, we have used an evolutionary approach to study DIA1 and DIA1R. We found DIA1 conserved from cnidarians to humans, indicating DIA1 evolution coincided with the development of the first primitive synapses. Nematodes lack a DIA1 homologue, indicating Caenorhabditis elegans is not suitable for studying all aspects of ASD etiology, while zebrafish encode two DIA1 paralogues. By contrast to DIA1, DIA1R was found exclusively in vertebrates, with an origin coinciding with the whole-genome duplication events occurring early in the vertebrate lineage, and the evolution of the more complex vertebrate nervous system. Strikingly, DIA1R was present in schooling fish but absent in fish that have adopted a more solitary lifestyle. An additional DIA1 related gene we named DIA1-Like (DIA1L), lacks a signal peptide and is restricted to the genomes of the echinoderm Strongylocentrotus purpuratus and cephalochordate Branchiostoma floridae. Evidence for remarkable DIA1L gene expansion was found in B. floridae. Amino acid alignments of DIA1 family gene products revealed a potential Golgi-retention motif and a number of conserved motifs with unknown function. Furthermore, a glycine and three cysteine residues were absolutely conserved in all DIA1-family proteins, indicating a critical role in protein structure and/or function. We have therefore identified a new metazoan protein family, the DIA1-family, and understanding the biological roles of DIA1 family members will have implications for our understanding of autism and mental retardation. PMID- 21283811 TI - Associations between APOE variants and metabolic traits and the impact of psychological stress. AB - OBJECTIVE: In a previous study, we observed that associations between APOE rs439401 and metabolic traits were moderated by chronic stress. Thus, in a population of stressed and non-stressed Danish men, we examined whether associations between APOE rs439401 and a panel of metabolic quantitative traits, all metabolic traits which may lead to T2D and CVD were moderated by psychological stress. METHODS: Obese young men (n = 475, BMI >= 31.0 kg/m(2)) and a randomly selected control group (n = 709) identified from a population of 141,800 men were re-examined in two surveys (S-46: mean age 46, S-49: mean age 49 years) where anthropometric and biochemical measures were available. Psychological stress factors were assessed by a self-administered 7-item questionnaire. Each item had the possible response categories "yes" and "no" and assessed familial problems and conflicts. Summing positive responses constituted a stress item score, which was then dichotomized into stressed and non-stressed. Logistic regression analysis, applying a recessive genetic model, was used to assess odds ratios (OR) of the associations between APOE rs439401 genotypes and adverse levels of metabolic traits. RESULTS: The APOE rs439401 TT-genotype associated positively with BMI (OR = 1.09 [1.01; 1.17]), waist circumference (OR = 1.09 [1.02; 1.17]) in stressed men at S-46. Positive associations were observed for fasting plasma glucose (OR = 1.42 [1.07; 1.87]), serum triglycerides (OR = 1.41 [1.05; 1.91]) and with fasting plasma insulin (OR = 1.48 [1.05; 2.08]) in stressed men at S-49. Rs439401 TT-genotype also associated positively with surrogate measures of insulin resistance (HOMA-IR; OR = 1.21 [1.03; 1.41]) and inversely with insulin sensitivity (Stumvoll index; OR = 0.90 [0.82; 0.99], BIGTT S(I); OR = 0.60 [0.43; 0.85]) in stressed men. No significant associations were observed in non-stressed men, albeit the estimates showed similar but weaker trends as in stressed men. CONCLUSION: The present results suggest that the APOE rs439401 TT-genotype is associated with an adverse metabolic profile in a population of psychologically stressed Danish men. PMID- 21283812 TI - Double dissociation of amygdala and hippocampal contributions to trace and delay fear conditioning. AB - A key finding in studies of the neurobiology of learning memory is that the amygdala is critically involved in Pavlovian fear conditioning. This is well established in delay-cued and contextual fear conditioning; however, surprisingly little is known of the role of the amygdala in trace conditioning. Trace fear conditioning, in which the CS and US are separated in time by a trace interval, requires the hippocampus and prefrontal cortex. It is possible that recruitment of cortical structures by trace conditioning alters the role of the amygdala compared to delay fear conditioning, where the CS and US overlap. To investigate this, we inactivated the amygdala of male C57BL/6 mice with GABA (A) agonist muscimol prior to 2-pairing trace or delay fear conditioning. Amygdala inactivation produced deficits in contextual and delay conditioning, but had no effect on trace conditioning. As controls, we demonstrate that dorsal hippocampal inactivation produced deficits in trace and contextual, but not delay fear conditioning. Further, pre- and post-training amygdala inactivation disrupted the contextual but the not cued component of trace conditioning, as did muscimol infusion prior to 1- or 4-pairing trace conditioning. These findings demonstrate that insertion of a temporal gap between the CS and US can generate amygdala independent fear conditioning. We discuss the implications of this surprising finding for current models of the neural circuitry involved in fear conditioning. PMID- 21283813 TI - "Biological geometry perception": visual discrimination of eccentricity is related to individual motor preferences. AB - BACKGROUND: In the continuum between a stroke and a circle including all possible ellipses, some eccentricities seem more "biologically preferred" than others by the motor system, probably because they imply less demanding coordination patterns. Based on the idea that biological motion perception relies on knowledge of the laws that govern the motor system, we investigated whether motorically preferential and non-preferential eccentricities are visually discriminated differently. In contrast with previous studies that were interested in the effect of kinematic/time features of movements on their visual perception, we focused on geometric/spatial features, and therefore used a static visual display. METHODOLOGY/PRINCIPAL FINDINGS: In a dual-task paradigm, participants visually discriminated 13 static ellipses of various eccentricities while performing a finger-thumb opposition sequence with either the dominant or the non-dominant hand. Our assumption was that because the movements used to trace ellipses are strongly lateralized, a motor task performed with the dominant hand should affect the simultaneous visual discrimination more strongly. We found that visual discrimination was not affected when the motor task was performed by the non dominant hand. Conversely, it was impaired when the motor task was performed with the dominant hand, but only for the ellipses that we defined as preferred by the motor system, based on an assessment of individual preferences during an independent graphomotor task. CONCLUSIONS/SIGNIFICANCE: Visual discrimination of ellipses depends on the state of the motor neural networks controlling the dominant hand, but only when their eccentricity is "biologically preferred". Importantly, this effect emerges on the basis of a static display, suggesting that what we call "biological geometry", i.e., geometric features resulting from preferential movements is relevant information for the visual processing of bidimensional shapes. PMID- 21283814 TI - Acidic extracellular pH promotes activation of integrin alpha(v)beta(3). AB - Acidic extracellular pH is characteristic of the cell microenvironment in several important physiological and pathological contexts. Although it is well established that acidic extracellular pH can have profound effects on processes such as cell adhesion and migration, the underlying molecular mechanisms are largely unknown. Integrin receptors physically connect cells to the extracellular matrix, and are thus likely to modulate cell responses to extracellular conditions. Here, we examine the role of acidic extracellular pH in regulating activation of integrin alpha(v)beta(3). Through computational molecular dynamics simulations, we find that acidic extracellular pH promotes opening of the alpha(v)beta(3) headpiece, indicating that acidic pH can thereby facilitate integrin activation. This prediction is consistent with our flow cytometry and atomic force microscope-mediated force spectroscopy assays of integrin alpha(v)beta(3) on live cells, which both demonstrate that acidic pH promotes activation at the intact cell surface. Finally, quantification of cell morphology and migration measurements shows that acidic extracellular pH affects cell behavior in a manner that is consistent with increased integrin activation. Taken together, these computational and experimental results suggest a new and complementary mechanism of integrin activation regulation, with associated implications for cell adhesion and migration in regions of altered pH that are relevant to wound healing and cancer. PMID- 21283815 TI - Improved malaria case management through the implementation of a health facility based sentinel site surveillance system in Uganda. AB - BACKGROUND: Heath facility-based sentinel site surveillance has been proposed as a means of monitoring trends in malaria morbidity but may also provide an opportunity to improve malaria case management. Here we described the impact of a sentinel site malaria surveillance system on promoting laboratory testing and rational antimalarial drug use. METHODOLOGY/PRINCIPAL FINDINGS: Sentinel site malaria surveillance was established at six health facilities in Uganda between September 2006 and January 2007. Data were collected from all patients presenting to the outpatient departments including demographics, laboratory results, diagnoses, and treatments prescribed. Between the start of surveillance and March 2010, a total 424,701 patients were seen of which 229,375 (54%) were suspected of having malaria. Comparing the first three months with the last three months of surveillance, the proportion of patients with suspected malaria who underwent diagnostic testing increased from 39% to 97% (p<0.001). The proportion of patients with an appropriate decision to prescribe antimalarial therapy (positive test result prescribed, negative test result not prescribed) increased from 64% to 95% (p<0.001). The proportion of patients appropriately prescribed antimalarial therapy who were prescribed the recommended first-line regimen artemether-lumefantrine increased from 48% to 69% (p<0.001). CONCLUSIONS/SIGNIFICANCE: The establishment of a sentinel site malaria surveillance system in Uganda achieved almost universal utilization of diagnostic testing in patients with suspected malaria and appropriate decisions to prescribed antimalarial based on test results. Less success was achieved in promoting prescribing practice for the recommended first-line therapy. This system could provide a model for improving malaria case management in other health facilities in Africa. PMID- 21283816 TI - Mucin secretion induced by titanium dioxide nanoparticles. AB - Nanoparticle (NP) exposure has been closely associated with the exacerbation and pathophysiology of many respiratory diseases such as Chronic Obstructive Pulmonary Disease (COPD) and asthma. Mucus hypersecretion and accumulation in the airway are major clinical manifestations commonly found in these diseases. Among a broad spectrum of NPs, titanium dioxide (TiO(2)), one of the PM10 components, is widely utilized in the nanoindustry for manufacturing and processing of various commercial products. Although TiO(2) NPs have been shown to induce cellular nanotoxicity and emphysema-like symptoms, whether TiO(2) NPs can directly induce mucus secretion from airway cells is currently unknown. Herein, we showed that TiO(2) NPs (<75 nm) can directly stimulate mucin secretion from human bronchial ChaGo-K1 epithelial cells via a Ca(2+) signaling mediated pathway. The amount of mucin secreted was quantified with enzyme-linked lectin assay (ELLA). The corresponding changes in cytosolic Ca(2+) concentration were monitored with Rhod-2, a fluorescent Ca(2+) dye. We found that TiO(2) NP-evoked mucin secretion was a function of increasing intracellular Ca(2+) concentration resulting from an extracellular Ca(2+) influx via membrane Ca(2+) channels and cytosolic ER Ca(2+) release. The calcium-induced calcium release (CICR) mechanism played a major role in further amplifying the intracellular Ca(2+) signal and in sustaining a cytosolic Ca(2+) increase. This study provides a potential mechanistic link between airborne NPs and the pathoetiology of pulmonary diseases involving mucus hypersecretion. PMID- 21283817 TI - Chronic CSE treatment induces the growth of normal oral keratinocytes via PDK2 upregulation, increased glycolysis and HIF1alpha stabilization. AB - BACKGROUND: Exposure to cigarette smoke is a major risk factor for head and neck squamous cell carcinoma (HNSCC). We have previously established a chronic cigarette smoke extract (CSE)-treated human oral normal keratinocyte model, demonstrating an elevated frequency of mitochondrial mutations in CSE treated cells. Using this model we further characterized the mechanism by which chronic CSE treatment induces increased cellular proliferation. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrate that chronic CSE treatment upregulates PDK2 expression, decreases PDH activity and thereby increases the glycolytic metabolites pyruvate and lactate. We also found that the chronic CSE treatment enhanced HIF1alpha accumulation through increased pyruvate and lactate production in a manner selectively reversible by ascorbate. Use of a HIF1alpha small molecule inhibitor blocked the growth induced by chronic CSE treatment in OKF6 cells. Furthermore, chronic CSE treatment was found to increase ROS (reactive oxygen species) production, and application of the ROS scavengers N-acetylcysteine abrogated the expression of PDK2 and HIF1alpha. Notably, treatment with dichloroacetate, a PDK2 inhibitor, also decreased the HIF1alpha expression as well as cell proliferation in chronic CSE treated OKF6 cells. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that chronic CSE treatment contribute to cell growth via increased ROS production through mitochondrial mutations, upregulation of PDK2, attenuating PDH activity thereby increasing glycolytic metabolites, resulting in HIF1alpha stabilization. This study suggests a role for chronic tobacco exposure in the development of aerobic glycolysis and normoxic HIFalpha activation as a part of HNSCC initiation. These data may provide insights into development of chemopreventive strategies for smoking related cancers. PMID- 21283818 TI - Lkb1 and Pten synergise to suppress mTOR-mediated tumorigenesis and epithelial mesenchymal transition in the mouse bladder. AB - The AKT/PI3K/mTOR pathway is frequently altered in a range of human tumours, including bladder cancer. Here we report the phenotype of mice characterised by deletion of two key players in mTOR regulation, Pten and Lkb1, in a range of tissues including the mouse urothelium. Despite widespread recombination within the range of epithelial tissues, the primary phenotype we observe is the rapid onset of bladder tumorigenesis, with median onset of approximately 100 days. Single deletion of either Pten or Lkb1 had no effect on bladder cell proliferation or tumour formation. However, simultaneous deletion of Lkb1 and Pten led to an upregulation of the mTOR pathway and the hypoxia marker GLUT1, increased bladder epithelial cell proliferation and ultimately tumorigenesis. Bladder tissue also exhibited characteristic features of epithelial-mesenchymal transition, with loss of the epithelial markers E-cadherin and the tight junction protein ZO-1, and increases in the mesenchymal marker vimentin as well as nuclear localization of epithelial-mesenchymal transition (EMT) regulator Snail. We show that these effects were all dependent upon mTOR activity, as rapamycin treatment blocked both EMT and tumorigenesis. Our data therefore establish clear synergy between Lkb1 and Pten in controlling the mTOR pathway within bladder epithelium, and show that loss of this control leads to the disturbance of epithelial structure, EMT and ultimately tumorigenesis. PMID- 21283819 TI - Pharyngeal lavage lymphocytosis in patients with obstructive sleep apnea: a preliminary observation. AB - BACKGROUND: Upper airway inflammation has been previously demonstrated in obstructive sleep apnea (OSA). However, investigation has been hampered by the necessity of invasive tissue biopsies. OBJECTIVE: To evaluate the pharyngeal lavage (PHAL) as a new tool to analyze mucosal inflammation in the pharynx of patients with sleep-related disordered breathing. PATIENTS AND METHODS: 36 patients with a diagnosis of OSA, 14 patients with heavy snorer syndrome (HS) or body position dependent OSA (bd-OSA), and 14 healthy volunteers underwent PHAL. Inflammatory cell counts were compared. RESULTS: Neutrophils were the predominant cells in PHAL in all groups (94.3% +/- 0.7%, 98.5% +/- 0.6%, 94.3% +/- 0.7%, and 96.2% +/- 1.4%). OSA patients had significantly increased numbers of lymphocytes (3.2% +/- 0.4%) compared to bd-OSA/HS and controls group (0.5% +/- 0.1% and 0.6% +/- 0.2%, respectively; P<0.05). Patients with moderate to severe OSA had significantly higher numbers of lymphocytes compared to patients with mild OSA (P<0.05). CONCLUSIONS: Data from this study suggest that PHAL is a feasible tool to investigate upper airway inflammation in OSA. In addition, PHAL demonstrates lymphocytic inflammation of the pharynx in OSA patients. Future studies are warranted to evaluate whether PHAL can be used to monitor disease and whether lymphocytic inflammation is affected by OSA treatment. PMID- 21283820 TI - Traffic air pollution and oxidized LDL. AB - BACKGROUND: Epidemiologic studies indirectly suggest that air pollution accelerates atherosclerosis. We hypothesized that individual exposure to particulate matter (PM) derived from fossil fuel would correlate with plasma concentrations of oxidized low-density lipoprotein (LDL), taken as a marker of atherosclerosis. We tested this hypothesis in patients with diabetes, who are at high risk for atherosclerosis. METHODOLOGY/PRINCIPAL FINDINGS: In a cross sectional study of non-smoking adult outpatients with diabetes we assessed individual chronic exposure to PM by measuring the area occupied by carbon in airway macrophages, collected by sputum induction and by determining the distance from the patient's residence to a major road, through geocoding. These exposure indices were regressed against plasma concentrations of oxidized LDL, von Willebrand factor and plasminogen activator inhibitor 1 (PAI-1). We could assess the carbon load of airway macrophages in 79 subjects (58 percent). Each doubling in the distance of residence from major roads was associated with a 0.027 um(2) decrease (95% confidence interval (CI): -0.048 to -0.0051) in the carbon load of airway macrophages. Independently from other covariates, we found that each increase of 0.25 um(2) [interquartile range (IQR)] in carbon load was associated with an increase of 7.3 U/L (95% CI: 1.3 to 13.3) in plasma oxidized LDL. Each doubling in distance of residence from major roads was associated with a decrease of -2.9 U/L (95% CI: -5.2 to -0.72) in oxidized LDL. Neither the carbon load of macrophages nor the distance from residence to major roads, were associated with plasma von Willebrand factor or PAI-1. CONCLUSIONS: The observed positive association, in a susceptible group of the general population, between plasma oxidized LDL levels and either the carbon load of airway macrophages or the proximity of the subject's residence to busy roads suggests a proatherogenic effect of traffic air pollution. PMID- 21283821 TI - The dynamic processing of CD46 intracellular domains provides a molecular rheostat for T cell activation. AB - BACKGROUND: Adequate termination of an immune response is as important as the induction of an appropriate response. CD46, a regulator of complement activity, promotes T cell activation and differentiation towards a regulatory Tr1 phenotype. This Tr1 differentiation pathway is defective in patients with MS, asthma and rheumatoid arthritis, underlying its importance in controlling T cell function and the need to understand its regulatory mechanisms. CD46 has two cytoplasmic tails, Cyt1 and Cyt2, derived from alternative splicing, which are co expressed in all nucleated human cells. The regulation of their expression and precise functions in regulating human T cell activation has not been fully elucidated. METHODOLOGY/PRINCIPAL FINDINGS: Here, we first report the novel role of CD46 in terminating T cell activation. Second, we demonstrate that its functions as an activator and inhibitor of T cell responses are mediated through the temporal processing of its cytoplasmic tails. Cyt1 processing is required to turn T cell activation on, while processing of Cyt2 switches T cell activation off, as demonstrated by proliferation, CD25 expression and cytokine secretion. Both tails require processing by Presenilin/gammaSecretase (P/gammaS) to exert these functions. This was confirmed by expressing wild-type Cyt1 and Cyt2 tails and uncleavable mutant tails in primary T cells. The role of CD46 tails was also demonstrated with T cells expressing CD19 ectodomain-CD46 C-Terminal Fragment (CTF) fusions, which allowed specific triggering of each tail individually. CONCLUSIONS/SIGNIFICANCE: We conclude that CD46 acts as a molecular rheostat to control human T cell activation through the regulation of processing of its cytoplasmic tails. PMID- 21283822 TI - Subinhibitory concentrations of perilla oil affect the expression of secreted virulence factor genes in Staphylococcus aureus. AB - BACKGROUND: The pathogenicity of staphylococcus aureus is dependent largely upon its ability to secrete a number of virulence factors, therefore, anti-virulence strategy to combat S. aureus-mediated infections is now gaining great interest. It is widely recognized that some plant essential oils could affect the production of staphylococcal exotoxins when used at subinhibitory concentrations. Perilla [Perilla frutescens (L.) Britton], a natural medicine found in eastern Asia, is primarily used as both a medicinal and culinary herb. Its essential oil (perilla oil) has been previously demonstrated to be active against S. aureus. However, there are no data on the influence of perilla oil on the production of S. aureus exotoxins. METHODOLOGY/PRINCIPAL FINDINGS: A broth microdilution method was used to determine the minimum inhibitory concentrations (MICs) of perilla oil against S. aureus strains. Hemolysis, tumour necrosis factor (TNF) release, Western blot, and real-time RT-PCR assays were performed to evaluate the effects of subinhibitory concentrations of perilla oil on exotoxins production in S. aureus. The data presented here show that perilla oil dose-dependently decreased the production of alpha-toxin, enterotoxins A and B (the major staphylococcal enterotoxins), and toxic shock syndrome toxin 1 (TSST-1) in both methicillin sensitive S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA). CONCLUSIONS/SIGNIFICANCE: The production of alpha-toxin, SEA, SEB, and TSST-1 in S. aureus was decreased by perilla oil. These data suggest that perilla oil may be useful for the treatment of S. aureus infections when used in combination with beta-lactam antibiotics, which can increase exotoxins production by S. aureus at subinhibitory concentrations. Furthermore, perilla oil could be rationally applied in food systems as a novel food preservative both to inhibit the growth of S. aureus and to repress the production of exotoxins, particularly staphylococcal enterotoxins. PMID- 21283823 TI - Multisensory stimulation can induce an illusion of larger belly size in immersive virtual reality. AB - BACKGROUND: Body change illusions have been of great interest in recent years for the understanding of how the brain represents the body. Appropriate multisensory stimulation can induce an illusion of ownership over a rubber or virtual arm, simple types of out-of-the-body experiences, and even ownership with respect to an alternate whole body. Here we use immersive virtual reality to investigate whether the illusion of a dramatic increase in belly size can be induced in males through (a) first person perspective position (b) synchronous visual-motor correlation between real and virtual arm movements, and (c) self-induced synchronous visual-tactile stimulation in the stomach area. METHODOLOGY: Twenty two participants entered into a virtual reality (VR) delivered through a stereo head-tracked wide field-of-view head-mounted display. They saw from a first person perspective a virtual body substituting their own that had an inflated belly. For four minutes they repeatedly prodded their real belly with a rod that had a virtual counterpart that they saw in the VR. There was a synchronous condition where their prodding movements were synchronous with what they felt and saw and an asynchronous condition where this was not the case. The experiment was repeated twice for each participant in counter-balanced order. Responses were measured by questionnaire, and also a comparison of before and after self estimates of belly size produced by direct visual manipulation of the virtual body seen from the first person perspective. CONCLUSIONS: The results show that first person perspective of a virtual body that substitutes for the own body in virtual reality, together with synchronous multisensory stimulation can temporarily produce changes in body representation towards the larger belly size. This was demonstrated by (a) questionnaire results, (b) the difference between the self-estimated belly size, judged from a first person perspective, after and before the experimental manipulation, and (c) significant positive correlations between these two measures. We discuss this result in the general context of body ownership illusions, and suggest applications including treatment for body size distortion illnesses. PMID- 21283824 TI - A genetic association study of single nucleotide polymorphisms in FGFR1OP2/wit3.0 and long-term atrophy of edentulous mandible. AB - BACKGROUND: After dental extraction, the external surface of alveolar bone undergoes resorption at various rates, and a group of patients develop excessive jawbone atrophy. Oral mucosa overlying the atrophied jawbone is unusually thin; therefore, we have hypothesized that excessive jawbone atrophy may be associated with abnormal oral mucosa contraction. FGFR1OP2/wit3.0, a cytoskeleton molecule initially identified in oral wound fibroblasts, has been shown to induce oral mucosa contraction after dental extraction. This study examined the genetic association between single nucleotide polymorphisms (SNPs) of FGFR1OP2/wit3.0 and excessive atrophy of edentulous mandible. METHODS AND FINDINGS: First, the expression of FGFR1OP2/wit3.0 was determined in gingival tissues of 8 subjects before and after dental extraction. In situ hybridization revealed that all subject increased FGFR1OP2/wit3.0 expression in the post-operative oral mucosa tissues; however, significantly high levels of FGFR1OP2/wit3.0 were observed in 3 out of 8 subjects. In a separate study, 20 long-term edentulous subjects (66.4 +/ 9.4 years) were recruited. Tag-SNPs in the FGFR1OP2/wit3.0 allele were determined by Taqman-based polymerase chain reaction. The mandibular bone height was determined following the American College of Prosthodontists (ACP) protocol. Subjects with minor allele of rs840869 or rs859024 were found in the highly atrophied group by the ACP classification (Chi square test, p = 0.0384 and p = 0.0565, respectively; Fisher's Exact, p= 0.0515 and p = 0.2604, respectively). The linear regression analysis indicated a suggestive association between rs859024 and the decreased bone heights (Mann-Whitney, p = 0.06). The average bone height of the subjects with rs840869 or rs859024 minor alleles (10.6 +/- 3.2 mm and 9.6 +/- 3.2 mm, respectively) was significantly smaller than that of those subjects with the major alleles (14.2 +/- 4.5 mm, p<0.05). CONCLUSIONS: The patients with the minor allele of rs840869 or rs859024 were associated with excessive atrophy of edentulous mandible. This study may provide the basis for a genetic marker identifying susceptible individuals to develop jawbone atrophy after dental extraction. PMID- 21283825 TI - Education modifies genetic and environmental influences on BMI. AB - Obesity is more common among the less educated, suggesting education-related environmental triggers. Such triggers may act differently dependent on genetic and environmental predisposition to obesity. In a Danish Twin Registry survey, 21,522 twins of same-sex pairs provided zygosity, height, weight, and education data. Body mass index (BMI = kg weight/ m height(2)) was used to measure degree of obesity. We used quantitative genetic modeling to examine how genetic and shared and nonshared environmental variance in BMI differed by level of education and to estimate how genetic and shared and nonshared environmental correlations between education and BMI differed by level of education, analyzing women and men separately. Correlations between education and BMI were -.13 in women, -.15 in men. High BMI's were less frequent among well-educated participants, generating less variance. In women, this was due to restriction of all forms of variance, overall by a factor of about 2. In men, genetic variance did not vary with education, but results for shared and nonshared environmental variance were similar to those for women. The contributions of the shared environment to the correlations between education and BMI were substantial among the well-educated, suggesting importance of familial environmental influences common to high education and lower BMI. Family influence was particularly important in linking high education and lower levels of obesity. PMID- 21283826 TI - Stabilization by fusion to the C-terminus of hyperthermophile Sulfolobus tokodaii RNase HI: a possibility of protein stabilization tag. AB - RNase HI from the hyperthermophile Sulfolobus tokodaii (Sto-RNase HI) is stabilized by its C-terminal residues. In this work, the stabilization effect of the Sto-RNase HI C-terminal residues was investigated in detail by thermodynamic measurements of the stability of variants lacking the disulfide bond (C58/145A), or the six C-terminal residues (DeltaC6) and by structural analysis of DeltaC6. The results showed that the C-terminal does not affect overall structure and stabilization is caused by local interactions of the C-terminal, suggesting that the C-terminal residues could be used as a "stabilization tag." The Sto-RNase HI C-terminal residues (-IGCIILT) were introduced as a tag on three proteins. Each chimeric protein was more stable than its wild-type protein. These results suggested the possibility of a simple stabilization technique using a stabilization tag such as Sto-RNase HI C-terminal residues. PMID- 21283827 TI - Stepwise release of biologically active HMGB1 during HSV-2 infection. AB - BACKGROUND: High mobility group box 1 protein (HMGB1) is a major endogenous danger signal that triggers inflammation and immunity during septic and aseptic stresses. HMGB1 recently emerged as a key soluble factor in the pathogenesis of various infectious diseases, but nothing is known of its behaviour during herpesvirus infection. We therefore investigated the dynamics and biological effects of HMGB1 during HSV-2 infection of epithelial HEC-1 cells. METHODOLOGY/PRINCIPAL FINDINGS: Despite a transcriptional shutdown of HMGB1 gene expression during infection, the intracellular pool of HMGB1 protein remained unaffected, indicating its remarkable stability. However, the dynamics of HMGB1 was deeply modified in infected cells. Whereas viral multiplication was concomitant with apoptosis and HMGB1 retention on chromatin, a subsequent release of HMGB1 was observed in response to HSV-2 mediated necrosis. Importantly, extracellular HMGB1 was biologically active. Indeed, HMGB1-containing supernatants from HSV-2 infected cells induced the migration of fibroblasts from murine or human origin, and reactivated HIV-1 from latently infected T lymphocytes. These effects were specifically linked to HMGB1 since they were blocked by glycyrrhizin or by a neutralizing anti-HMGB1 antibody, and were mediated through TLR2 and the receptor for Advanced Glycation End-products (RAGE). Finally, we show that genital HSV-2 active infections also promote HMGB1 release in vivo, strengthening the clinical relevance of our experimental data. CONCLUSIONS: These observations target HMGB1 as an important actor during HSV-2 genital infection, notably in the setting of HSV-HIV co-infection. PMID- 21283828 TI - Biomarkers of extracellular matrix metabolism (MMP-9 and TIMP-1) and risk of stroke, myocardial infarction, and cause-specific mortality: cohort study. AB - OBJECTIVE: Turnover of the extracellular matrix in all solid organs is governed mainly by a balance between the degrading matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). An altered extracellular matrix metabolism has been implicated in a variety of diseases. We investigated relations of serum levels of MMP-9 and TIMP-1 to mortality risk from an etiological perspective. DESIGN: The prospective Uppsala Longitudinal Study of Adult Men (ULSAM) cohort, followed from 1991-1995 for up to 18.1 years. A random population-based sample of 1,082 71-year-old men, no loss to follow-up. Endpoints were all-cause (n = 628), cardiovascular (n = 230), non-cardiovascular (n = 398) and cancer mortality (n = 178), and fatal or non-fatal myocardial infarction (n = 138) or stroke (n = 163). RESULTS: Serum MMP-9 and TIMP-1 levels were associated with risk of all-cause mortality (Cox proportional hazard ratio [HR] per standard deviation 1.10, 95% confidence interval [CI] 1.03-1.19; and 1.11, 1.02-1.20; respectively). TIMP-1 levels were mainly related to risks of cardiovascular mortality and stroke (HR per standard deviation 1.22, 95% CI 1.09-1.37; and 1.18, 1.04-1.35; respectively). All relations except those of TIMP-1 to stroke risk were attenuated by adjustment for cardiovascular disease risk factors. Relations in a subsample without cardiovascular disease or cancer were similar to those in the total sample. CONCLUSION: In this community-based cohort of elderly men, serum MMP-9 and TIMP-1 levels were related to mortality risk. An altered extracellular matrix metabolism may be involved in several detrimental pathways, and circulating MMP-9 or TIMP-1 levels may be relevant markers thereof. PMID- 21283829 TI - Genomewide analyses define different modes of transcriptional regulation by peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta). AB - Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors with essential functions in lipid, glucose and energy homeostasis, cell differentiation, inflammation and metabolic disorders, and represent important drug targets. PPARs heterodimerize with retinoid X receptors (RXRs) and can form transcriptional activator or repressor complexes at specific DNA elements (PPREs). It is believed that the decision between repression and activation is generally governed by a ligand-mediated switch. We have performed genomewide analyses of agonist-treated and PPARbeta/delta-depleted human myofibroblasts to test this hypothesis and to identify global principles of PPARbeta/delta-mediated gene regulation. Chromatin immunoprecipitation sequencing (ChIP-Seq) of PPARbeta/delta, H3K4me3 and RNA polymerase II enrichment sites combined with transcriptional profiling enabled the definition of 112 bona fide PPARbeta/delta target genes showing either of three distinct types of transcriptional response: (I) ligand-independent repression by PPARbeta/delta; (II) ligand-induced activation and/or derepression by PPARbeta/delta; and (III) ligand-independent activation by PPARbeta/delta. These data identify PPRE-mediated repression as a major mechanism of transcriptional regulation by PPARbeta/delta, but, unexpectedly, also show that only a subset of repressed genes are activated by a ligand-mediated switch. Our results also suggest that the type of transcriptional response by a given target gene is connected to the structure of its associated PPRE(s) and the biological function of its encoded protein. These observations have important implications for understanding the regulatory PPAR network and PPARbeta/delta ligand-based drugs. PMID- 21283830 TI - Transcriptomics of the bed bug (Cimex lectularius). AB - BACKGROUND: Bed bugs (Cimex lectularius) are blood-feeding insects poised to become one of the major pests in households throughout the United States. Resistance of C. lectularius to insecticides/pesticides is one factor thought to be involved in its sudden resurgence. Despite its high-impact status, scant knowledge exists at the genomic level for C. lectularius. Hence, we subjected the C. lectularius transcriptome to 454 pyrosequencing in order to identify potential genes involved in pesticide resistance. METHODOLOGY AND PRINCIPAL FINDINGS: Using 454 pyrosequencing, we obtained a total of 216,419 reads with 79,596,412 bp, which were assembled into 35,646 expressed sequence tags (3902 contigs and 31744 singletons). Nearly 85.9% of the C. lectularius sequences showed similarity to insect sequences, but 44.8% of the deduced proteins of C. lectularius did not show similarity with sequences in the GenBank non-redundant database. KEGG analysis revealed putative members of several detoxification pathways involved in pesticide resistance. Lamprin domains, Protein Kinase domains, Protein Tyrosine Kinase domains and cytochrome P450 domains were among the top Pfam domains predicted for the C. lectularius sequences. An initial assessment of putative defense genes, including a cytochrome P450 and a glutathione-S-transferase (GST), revealed high transcript levels for the cytochrome P450 (CYP9) in pesticide exposed versus pesticide-susceptible C. lectularius populations. A significant number of single nucleotide polymorphisms (296) and microsatellite loci (370) were predicted in the C. lectularius sequences. Furthermore, 59 putative sequences of Wolbachia were retrieved from the database. CONCLUSIONS: To our knowledge this is the first study to elucidate the genetic makeup of C. lectularius. This pyrosequencing effort provides clues to the identification of potential detoxification genes involved in pesticide resistance of C. lectularius and lays the foundation for future functional genomics studies. PMID- 21283831 TI - A day in the life of microcystis aeruginosa strain PCC 7806 as revealed by a transcriptomic analysis. AB - The cyanobacterium, Microcystis aeruginosa, is able to proliferate in a wide range of freshwater ecosystems and to produce many secondary metabolites that are a threat to human and animal health. The dynamic of this production and more globally the metabolism of this species is still poorly known. A DNA microarray based on the genome of M. aeruginosa PCC 7806 was constructed and used to study the dynamics of gene expression in this cyanobacterium during the light/dark cycle, because light is a critical factor for this species, like for other photosynthetic microorganisms. This first application of transcriptomics to a Microcystis species has revealed that more than 25% of the genes displayed significant changes in their transcript abundance during the light/dark cycle and in particular during the dark/light transition. The metabolism of M. aeruginosa is compartmentalized between the light period, during which carbon uptake, photosynthesis and the reductive pentose phosphate pathway lead to the synthesis of glycogen, and the dark period, during which glycogen degradation, the oxidative pentose phosphate pathway, the TCA branched pathway and ammonium uptake promote amino acid biosynthesis. We also show that the biosynthesis of secondary metabolites, such as microcystins, aeruginosin and cyanopeptolin, occur essentially during the light period, suggesting that these metabolites may interact with the diurnal part of the central metabolism. PMID- 21283832 TI - C2-O-sLeX glycoproteins are E-selectin ligands that regulate invasion of human colon and hepatic carcinoma cells. AB - Similar to mechanisms of recruitment of activated leukocytes to inflamed tissues, selectins mediate adhesion and extravasation of circulating cancer cells. Our objective was to determine whether sialyl Lewis X modified core 2 O-glycans (C2-O sLe(X)) present on colon and hepatic carcinoma cells promote their adhesion and invasion. We examined membrane expression of C2-O-sLe(X), selectin binding, invasion of human colon and hepatic carcinoma cell lines, and mRNA levels of alpha-2,3 fucosyltransferase (FucT-III) and core 2 beta-1,6 N acetylglucosaminyltransferase (C2GnT1) genes, necessary for C2-O-sLe(X) synthesis, by quantitative reverse-transcriptase (RT) PCR. Synthesis of core 2 branched O-glycans decorated by sLe(X) is dependent on C2GnT1 function and thus we determined enzyme activity of C2GnT1. The cell lines that expressed C2GnT1 and FucT-III mRNA by quantitative RT-PCR were highly positive for C2-O-sLe(X) by flow cytometry, and colon carcinoma cells possessed highly active C2GnT1 enzyme. Cells bound avidly to E-selection but not to P- and L-selectin. Gene knock-down of C2GnT1 in colon and hepatic carcinoma cells using short hairpin RNAs (shRNA) resulted in a 40-90% decrease in C2-O-sLe(X) and a 30-50% decrease in E-selectin binding compared to control cells. Invasion of hepatic and colon carcinoma cells containing C2GnT1 shRNA was significantly reduced compared to control cells in Matrigel assays and C2GnT1 activity was down-regulated in the latter cells. The sLe(X) epitope was predominantly distributed on core 2 O-glycans on colon and hepatic carcinoma cells. Our findings indicate that C2GnT1 gene expression and the resulting C2-O-sLe(X) carbohydrates produced mediate the adhesive and invasive behaviors of human carcinomas which may influence their metastatic potential. PMID- 21283834 TI - Angiogenin induces nitric oxide release independently from its RNase activity. AB - Nitric oxide (NO), a biological mediator involved in vascular physiology, was sensed electrochemically using a microelectrode array. Angiogenin was shown to trigger nitric oxide synthase (NOS) activity in human umbilical vein endothelial cells and embryonic stem cell derived endothelial cells independently from its RNase activity. PMID- 21283833 TI - The gene regulatory cascade linking proneural specification with differentiation in Drosophila sensory neurons. AB - In neurogenesis, neural cell fate specification is generally triggered by proneural transcription factors. Whilst the role of proneural factors in fate specification is well studied, the link between neural specification and the cellular pathways that ultimately must be activated to construct specialised neurons is usually obscure. High-resolution temporal profiling of gene expression reveals the events downstream of atonal proneural gene function during the development of Drosophila chordotonal (mechanosensory) neurons. Among other findings, this reveals the onset of expression of genes required for construction of the ciliary dendrite, a key specialisation of mechanosensory neurons. We determine that atonal activates this cellular differentiation pathway in several ways. Firstly, atonal directly regulates Rfx, a well-known highly conserved ciliogenesis transcriptional regulator. Unexpectedly, differences in Rfx regulation by proneural factors may underlie variations in ciliary dendrite specialisation in different sensory neuronal lineages. In contrast, fd3F encodes a novel forkhead family transcription factor that is exclusively expressed in differentiating chordotonal neurons. fd3F regulates genes required for specialized aspects of chordotonal dendrite physiology. In addition to these intermediate transcriptional regulators, we show that atonal directly regulates a novel gene, dilatory, that is directly associated with ciliogenesis during neuronal differentiation. Our analysis demonstrates how early cell fate specification factors can regulate structural and physiological differentiation of neuronal cell types. It also suggests a model for how subtype differentiation in different neuronal lineages may be regulated by different proneural factors. In addition, it provides a paradigm for how transcriptional regulation may modulate the ciliogenesis pathway to give rise to structurally and functionally specialised ciliary dendrites. PMID- 21283835 TI - Molecular recognition of ADP over ATP in aqueous solution by a polyammonium receptor containing a pyrimidine residue. AB - The synergistic action of the different binding groups of the polyfunctional HL receptor leads to the recognition of ADP over ATP in water, with a selectivity coefficient of up to 116, a phenomenon which is unprecedented in the context of synthetic receptors in water. The recognition is mostly due to the good matching between H(3)L(2+) and the protonated forms of ADP. PMID- 21283836 TI - Modulation of chiroptical properties by DNA-guided assembly of fluorenes. AB - The supramolecular organization of fluorene building blocks in a DNA scaffold is described. The molecular assembly into ordered pi-aggregates leads to distinct changes in the electronic properties. PMID- 21283837 TI - A facile direct anti-selective catalytic asymmetric Mannich reaction of aldehydes with preformed N-Boc and N-Cbz imines. AB - Anti-selective Mannich reactions of N-Boc and N-Cbz protected imines with unmodified aldehydes proceeded smoothly under the catalysis of a secondary amine thiourea catalyst, which led to high yields (70%-95%) and excellent enantioselectivity (up to 96 : 4 dr and >99% ee) under conventional organic synthetic operations. PMID- 21283838 TI - Anaerobic conditions to reduce oxidation of proteins and to accelerate the copper catalyzed "Click" reaction with a water-soluble bis(triazole) ligand. AB - Oxidation of protein (bovine albumin serum) by air still occurred under the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction conditions even in the presence of a Cu(I)-stabilizing tris(triazole) ligand. Anaerobic conditions not only avoided the oxidation of the protein, but also greatly accelerated the CuAAC reaction using a water-soluble bis(triazole) Cu(I) ligand. PMID- 21283839 TI - Transition metal catalysed ammonia-borane dehydrogenation in ionic liquids. AB - Significant advantages result from combining the disparate hydrogen release pathways for ammonia-borane (AB) dehydrogenation using ionic liquids (ILs) and transition metal catalysts. With the RuCl(2)(PMe(3))(4) catalyst precursor, AB dehydrogenation selectivity and extent are maximized in an IL with a moderately coordinating ethylsulfate anion. PMID- 21283840 TI - Visible emission characteristics from different defects of ZnS nanocrystals. AB - Various sized ZnS nanocrystals were prepared by treatment under H(2)S atmosphere. Resonance Raman spectra indicate that the electron-phonon coupling increases with increasing the size of ZnS. Surface and interfacial defects are formed during the treatment processes. Blue, green and orange emissions are observed for these ZnS. The blue emission (430 nm) from ZnS without treatment is attributed to surface states. ZnS sintered at 873 K displays orange luminescence (620 nm) while ZnS treated at 1173 K shows green emission (515 nm). The green luminescence is assigned to the electron transfer from sulfur vacancies to interstitial sulfur states, and the orange emission is caused by the recombination between interstitial zinc states and zinc vacancies. The lifetimes of the orange emission are much slower than that of the green luminescence and sensitively dependent on the treatment temperature. Controlling defect formation makes ZnS a potential material for photoelectrical applications. PMID- 21283841 TI - Highly efficient CdS/CdSe-sensitized solar cells controlled by the structural properties of compact porous TiO2 photoelectrodes. AB - At present, the photovoltaic performance of quantum dot-sensitized solar cells (QDSCs) is still much lower than conventional DSCs. Appropriate porous TiO(2) photoanodes for QDSCs need to be further investigated, and optimization of the nanoparticle-based photoanodes is highly desirable as well. In this article, the influence of the structural properties of various TiO(2) photoanodes on CdS/CdSe sensitized solar cells have been systematically studied. Quantitative analyses of light-harvesting efficiency (LHE) and electron-transfer yield (Phi(ET)) for the QDSCs are investigated for the first time. It is revealed that the LHE increases in the long wavelength region with the addition of large size TiO(2) particles to the transparent film. In the meantime, the balance between the light scattering and surface area also needs to be controlled, which can significantly restrain the dark current of the device. A double-layer photoanodic structure can give 4.92% of light-to-electricity conversion efficiency with a photoactive area of 0.15 cm(2). PMID- 21283842 TI - Calculation of isotropic Compton profiles with Gaussian basis sets. AB - In this paper we present an adaptive algorithm for calculating the isotropic Compton profile (ICP) for any type of Gaussian basis set. The ICP is a measure of the momentum density of electrons and it can be obtained from inelastic X-ray scattering experiments employing synchrotron radiation. We have performed calculations of the ICP for water and helium monomers and dimers using density functional theory, Hartree-Fock and post-Hartree-Fock methods, with Dunning-type ((d-)aug-)cc-p(C)VXZ basis sets. We have examined the convergence of the Compton profile as a function of the basis set and the level of theory used for the formation of the density matrix. We demonstrate that diffuse basis functions are of utmost importance to the calculation of Compton profiles. Basis sets of at least triple-zeta quality appended by diffuse functions should be used in Compton profile calculations in order to obtain sufficient convergence with regard to the current, experimentally feasible accuracy for systems consisting of light elements. PMID- 21283843 TI - A general halide-to-anion switch for imidazolium-based ionic liquids and oligocationic systems using anion exchange resins (A- form). AB - Further studies on the application of an AER (A(-) form) method broadened the anion exchange scope of representative ionic liquids and bis(imidazolium) systems. Depending on the hydrophobicity nature of the targeted imidazolium species and counteranions, different organic solvents were used to swap halides for assorted anions, proceeding in excellent to quantitative yields. PMID- 21283844 TI - Protonation of the oxygen axial ligand in galactose oxidase model compounds as seen with high resolution X-ray emission experiments and FEFF simulations. AB - X-ray Emission Spectroscopy (XES) crossover peaks were shown to be sensitive to the protonation state of solvent molecules in the Zn protein carbonic anhydrase and its model compounds. Here we extend such studies to galactose oxidase models i.e. Cu(ii) open d-shell systems, illustrating that XES combined with FEFF8 simulations reflect changes in the protonation state of the phenolate ligand for the copper center. PMID- 21283845 TI - Boosting theoretical zeolitic framework generation for the determination of new materials structures using GPU programming. AB - Evolutionary algorithms have proved to be efficient for solving complicated optimization problems. On the other hand, the many-core architecture in graphical cards "General Purpose Graphic Processing Unit" (GPGPU) offers one of the most attractive cost/performance ratio. Using such hardware, the manuscript shows how an efficiently implemented genetic algorithm with a simple fitness function allows boosting the determination of zeolite structures. A case study is presented. PMID- 21283846 TI - Framework-structured weak ferromagnets. AB - Framework-structured weak ferromagnets are new rising stars in molecule-based magnetic materials. The framework structures are powerful carriers for long-range ordering of spins. And weak ferromagnetism due to spin canting is an effective approach for magnets because of its frequent occurrence and desired spontaneous magnetization as long as the canting angle gamma is large enough. In this critical review, we provide an overview of the various framework-structured weak ferromagnets based on different grades of ligands (from mono-atom to three-atom like ligands). Particular emphasis is given to the relationships between structural features and the properties, rational employment of the ligands, and weak ferromagnetic strategies for molecule-based magnets with exciting properties and applications (273 references). PMID- 21283847 TI - Transition-metal catalyzed oxidative cross-coupling reactions to form C-C bonds involving organometallic reagents as nucleophiles. AB - Transition-metal-catalyzed coupling reactions have become a versatile tool for chemical bond formation. From the variation of the coupling partners, coupling reactions can be classified into three models: traditional coupling, reductive coupling and oxidative coupling. The oxidative coupling, which is different from the traditional coupling, occurs between two nucleophiles. This critical review focuses on transition-metal-catalyzed oxidative coupling reactions involving organometallic reagents as nucleophiles. Since the scope of the oxidative coupling is highly diversified, this paper only reviews the oxidative coupling reactions concerning C-C bond formation, including the coupling between organometal reagents and hydrocarbons as well as coupling between two organometal reagents. Since terminal alkynes are normally activated by metal salts and in situ form the alkynyl metal reagents in coupling reactions, they are directly considered as organometal reagents in this review. Intramolecular oxidative couplings and oxidative cyclizations are not included in this critical review. Moreover, there are many examples of oxidative coupling leading to the formation of functional materials, such as the oxidative polymerization of thiophenes. Since several reviews in these areas have been published they are not included in this review either (99 references). PMID- 21283848 TI - Proton transfer reactions and dynamics in protonated water clusters. AB - Proton transfer reactions and dynamics were theoretically studied using the hydrogen-bond (H-bond) complexes formed from H(3)O(+) and nH(2)O, n = 1-4, as model systems. The investigations began with searching for characteristics of transferring protons in the gas phase and continuum aqueous solution using DFT method at the B3LYP/TZVP level, followed by Born-Oppenheimer molecular dynamics (BOMD) simulations at 350 K. B3LYP/TZVP calculations revealed the threshold asymmetric O-H stretching frequencies (nu(OH)*) for the proton transfers in the Zundel complex (H(5)O) in the gas phase and continuum aqueous solution at 1984 and 1881 cm(-1), respectively. BOMD simulations suggested lower threshold frequencies (nu(OH,MD)* = 1917 and 1736 cm(-1), respectively), with two characteristic nu(OH,MD) being the IR spectral signatures of the transferring protons. The low-frequency band could be associated with the "oscillatory shuttling motion" and the high-frequency band with the "structural diffusion motion". These can be regarded as the spectroscopic evidences of the formations of the shared-proton structure (O...H(+)...O) and the H(3)O(+)-H(2)O contact structure (O-H(+)...O), respectively. Since the quasi-dynamic equilibrium between the Zundel and Eigen complexes was suggested to be the rate-determining step, in order to achieve an "ideal" maximum efficiency of proton transfer, a concerted reaction pathway should be taken. The most effective interconversion between the two proton states, the shared-proton structure and the H(3)O(+)-H(2)O contact structure, can be reflected from comparable intensities of the oscillatory shuttling and structural diffusion bands. The present results iterated the previous conclusions that static proton transfer potentials cannot provide complete description of the structural diffusion process and it is essential to incorporate thermal energy fluctuations and dynamics in the model calculations. PMID- 21283849 TI - Graphene nanosheet: synthesis, molecular engineering, thin film, hybrids, and energy and analytical applications. AB - The emergence of graphene nanosheet (GN, 2010 Nobel Prize for Physics) has recently opened up an exciting new field in the science and technology of two dimensional (2D) nanomaterials with continuously growing academic and technological impetus. GN exhibits unique electronic, optical, magnetic, thermal and mechanical properties arising from its strictly 2D structure and thus has many important technical applications. Actually, GN-based materials have enormous potential to rival or even surpass the performance of carbon nanotube-based counterparts, given that cheap, large-scale production and processing methods for high-quality GN become available. Therefore, the studies on GN in the aspects of chemistry, physical, materials, biology and interdisciplinary science have been in full flow in the past five years. In this critical review, from the viewpoint of chemistry and materials, we will cover recent significant advances in synthesis, molecular engineering, thin film, hybrids, and energy and analytical applications of the "star-material" GN together with discussion on its major challenges and opportunities for future GN research (315 references). PMID- 21283850 TI - Chemomechanics: chemical kinetics for multiscale phenomena. AB - The purpose of this critical review is to introduce the reader to an increasingly important class of phenomena: enormous changes in rates of simple chemical reactions within macromolecules as they are stretched by interactions with the environment. In these chemomechanical, or mechanochemical, phenomena the effect of the macromolecular environment can be visualized as a spring (harmonic or anharmonic) bridging and pulling apart a pair of atoms of the macromolecule. Being able to predict how the parameters of this spring affect the kinetics of the reactions occurring between the constrained atoms may create revolutionary opportunities for designing new reactions, molecules and materials that would capture large-scale deformations to drive useful chemistry or, conversely, that would propel autonomous micro- and nanomechanical devices by coupling them to the concerted motion of atoms that convert reactants into products. Although chemists have long studied and exploited coupling between molecular strain and reactivity in small molecules, a quantitative understanding of the relationship between large-scale (>50 nm) strain and localized reactivity presents unique conceptual and experimental challenges. Below we discuss both the phenomenology and the interpretive framework of chemomechanical phenomena (102 references). PMID- 21283851 TI - Hierarchical core/shell Fe3O4@SiO2@gamma-AlOOH@Au micro/nanoflowers for protein immobilization. AB - A facile synthesis of monodispersed microparticles composed of superparamagnetic Fe(3)O(4) cores, SiO(2) shell, hierarchical gamma-AlOOH periphery with Au nanoparticles is reported. These particles are found to be useful for protein immobilization and bear resemblance to daisy flowers, and are hereafter termed "nanoflowers". PMID- 21283852 TI - Rationally designed fluorescence 'turn-on' sensor for Cu2+. AB - A rationally designed, coumarin-based fluorescent sensor imino-coumarin (IC) displays high selectivity for Cu(2+) over a variety of competing metal ions in aqueous solution with a significant fluorescence increase. DFT/TDDFT calculations support that the fluorescence 'turn-on' of IC originates from blocking the electron transfer of the nitrogen lone pair upon complexation with Cu(2+). IC was successfully applied to microscopic imaging for detection of Cu(2+) in LLC-MK2 cells (in vitro) and several living organs (in vivo). PMID- 21283853 TI - Electronic structure and optical properties of monoclinic clinobisvanite BiVO4. AB - Monoclinic clinobisvanite bismuth vanadate is an important material with wide applications. However, its electronic structure and optical properties are still not thoroughly understood. Density functional theory calculations were adopted in the present work, to comprehend the band structure, density of states, and projected wave function of BiVO(4). In particular, we put more emphasis upon the intrinsic relationship between its structure and properties. Based on the calculated results, its molecular-orbital bonding structure was proposed. And a significant phenomenon of optical anisotropy was observed in the visible-light region. Furthermore, it was found that its slightly distorted crystal structure enhances the lone-pair impact of Bi 6s states, leading to the special optical properties and excellent photocatalytic activities. PMID- 21283854 TI - Information visualization techniques for sensing and biosensing. AB - The development of new methods and concepts to visualize massive amounts of data holds the promise to revolutionize the way scientific results are analyzed, especially when tasks such as classification and clustering are involved, as in the case of sensing and biosensing. In this paper we employ a suite of software tools, referred to as PEx-Sensors, through which projection techniques are used to analyze electrical impedance spectroscopy data in electronic tongues and related sensors. The possibility of treating high dimension datasets with PEx Sensors is advantageous because the whole impedance vs. frequency curves obtained with various sensing units and for a variety of samples can be analyzed at once. It will be shown that non-linear projection techniques such as Sammon's Mapping or IDMAP provide higher distinction ability than linear methods for sensor arrays containing units capable of molecular recognition, apparently because these techniques are able to capture the cooperative response owing to specific interactions between the sensing unit material and the analyte. In addition to allowing for a higher sensitivity and selectivity, the use of PEx-Sensors permits the identification of the major contributors for the distinguishing ability of sensing units and of the optimized frequency range. The latter will be illustrated with sensing units made with layer-by-layer (LbL) films to detect phytic acid, whose capacitance data were visualized with Parallel Coordinates. Significantly, the implementation of PEx-Sensors was conceived so as to handle any type of sensor based on any type of principle of detection, representing therefore a generic platform for treating large amounts of data for sensors and biosensors. PMID- 21283855 TI - Mn4-hinged bithiacalix[4]arenes accommodating fullerenes. AB - The calixarene-Mn(4)-calixarene dumbbell-like unit can accommodate different fullerenes with its changeable curved surfaces and the addition of fullerenes completely remodels the packing of the dumbbell units. PMID- 21283856 TI - Solvent induced molecular magnetic changes observed in single-crystal-to-single crystal transformation. AB - Single-crystal-to-single-crystal (SCSC) transformations have recently been found in some molecular magnets, which involve rearrangement or dynamic movement of molecular components of the crystals. Various stimuli such as guest removal, guest exchange, ligand exchange as well as redox reactions may induce SCSC transformations. To date, only a few molecular magnets are known to exhibit SCSC transformations, which often show high-dimensional robust structures. This review mainly focuses on magnetic complexes that are robust enough to experience SCSC transformations and show magnetic changes induced by solvents in due course. This contribution is organized according to the means of solvent treatment of molecular magnets, aiming at revealing magneto-structural correlation in such SCSC transformations. PMID- 21283857 TI - Syntheses and structures of the first terminal phosphanylphosphido complex of hafnium [Cp2Hf(Cl){eta(1)-(Me3Si)P-P(NEt2)2}] and the first zirconocene phosphanylphosphinidene dimer [Cp2Zr{MU(2)-P-P(NEt2)2}2ZrCp2]. AB - Reactions of (Et(2)N)(2)P-P(SiMe(3))Li with [Cp(2)MCl(2)] (M = Zr, Hf) in toluene or pentane yield the related terminal phosphanylphosphido complexes [Cp(2)M(Cl){eta(1)-(Me(3)Si)P-P(NEt(2))(2)}]. The solid state structure of [Cp(2)Hf(Cl){eta(1)-(Me(3)Si)P-P(NEt(2))(2)}] was established by single crystal X ray diffraction. The reaction of (Et(2)N)(2)P-P(SiMe(3))Li with [Cp(2)ZrCl(2)] in THF or DME solutions leads to the formation of deep red crystals of the first neutral diamagnetic zirconocene-phosphanylphosphinidene dimer [Cp(2)Zr{MU(2)-P P(NEt(2))(2)}(2)ZrCp(2)]. The molecular structure of this compound was confirmed by X-ray diffraction. The reactions of (R(2)N)(2)P-P(SiMe(3))Li with [CpZrCl(3)] yield the related tetraphosphetanes R(2)NP(MU(2)-PSiMe(3))(2)PNR(2), which apparently are formed as a result of a transfer of NR(2) groups from a P atom to the Zr atom. PMID- 21283858 TI - Synthesis, structural characterization and reactivity of aluminium complexes supported by benzotriazole phenoxide ligands: air-stable alumoxane as an efficient catalyst for ring-opening polymerization of L-lactide. AB - Aluminium complexes bearing sterically bulky benzotriazole-phenoxide ligands are synthesized and characterized structurally. The reaction of 2-(2H-benzotriazol-2 yl)-4,6-bis(1-methyl-1-phenylethyl)phenol ((CMe2Ph)BTP-H) or 2-(2H-benzotriazol-2 yl)-4,6-di-tert-butylphenol ((t-Bu)BTP-H) with AlMe(3) (1.2 molar equiv.) in toluene yields [((CMe2Ph)BTP)AlMe(2)] (1) or [((t-Bu)BTP)AlMe(2)] (2) as a four coordinated monomeric aluminium complex. Compound 1 reacts further with (CMe2Ph)BTP-H in a stoichiometric proportion, affording penta-coordinated monomeric aluminium methyl complex [((CMe2Ph)BTP)(2)AlMe] (3). Complex 3 is also obtained directly upon treatment of AlMe(3) with (CMe2Ph)BTP-H (two molar equiv.) in refluxing toluene in high yield. In the presence of H(2)O (half a molar equiv.), hydrolysis of 3 in a mixed solvent of THF and toluene at ambient temperature affords [{((CMe2Ph)BTP)(2)Al}(2)(MU-O)] (4), in which the oxo ligand acts as a chelating group linearly bridging two aluminium centers. Air-stable alumoxane 4 is an efficient catalyst for the ring-opening polymerization of L lactide (L-LA) in the presence of 9-anthracenemethanol (9-AnOH). Complex 4 catalyzes the polymerization of L-LA in a controlled manner, yielding PLLAs with the expected molecular weights and narrow polydispersity indices (PDIs). PMID- 21283859 TI - CoMn2O4 spinel from a MOF: synthesis, structure and magnetic studies. AB - A hydrothermal reaction of Mn(OAc)(2).4H(2)O, Co(OAc)(2).4H(2)O and 1,2,4 benzenetricarboxylic acid at 220 degrees C for 24 h gives rise to a mixed metal MOF compound, [CoMn(2){C(6)H(3)(COO)(3)}(2)], I. The structure is formed by the connectivity between octahedral CoO(6) and trigonal prism MnO(6) units connected through their vertices forming a Kagome layer, which are pillared by the trimellitate. Magnetic susceptibility studies on the MOF compound indicate a canted anti-ferromagnetic behavior, due to the large antisymmetric DM interaction between the M(2+) ions (M = Mn, Co). Thermal decomposition studies indicate that the MOF compound forms a tetragonal mixed-metal spinel phase, CoMn(2)O(4), with particle sizes in the nano regime at 400 degrees C. The particle size of the CoMn(2)O(4) can be controlled by varying the decomposition temperature of the parent MOF compound. Magnetic studies of the CoMn(2)O(4) compound suggests that the coercivity and the ferrimagnetic ordering temperatures are dependent on the particle size. PMID- 21283860 TI - A cyclometalated iridium(III) complex with enhanced phosphorescence emission in the solid state (EPESS): synthesis, characterization and its application in bioimaging. AB - Iridium(III) complexes with intense phosphorescence in solution have been widely applied in organic light-emitting diodes, chemosensors and bioimaging. However, little attention has been paid to iridium(III) complexes showing weak phosphorescence in solution and enhanced phosphorescence emission in the solid state (EPESS). In the present study, two beta-diketonate ligands with different degrees of conjugation, 1-phenyl-3-methyl-4-benzoyl-5-pyrazolone (HL1) and 1 phenyl-3-methyl-4-phenylacetyl-5-pyrazolone (HL2), have been synthesized to be used as ancillary ligands for two iridium(III) complexes, Ir(ppy)(2)(L1) and Ir(ppy)(2)(L2) (Hppy = 2-phenylpyridine). The two complexes have been characterized by single-crystal X-ray crystallography, (1)H NMR and elemental analysis. Interestingly, Ir(ppy)(2)(L1) is EPESS-active whereas Ir(ppy)(2)(L2) exhibits moderately intense emission both in solution and as a neat film, indicating that the degree of conjugation of the beta-diketone ligands determines the EPESS-activity. The single-crystal X-ray analysis has indicated that there are pi-pi interactions between the adjacent ppy ligands in Ir(ppy)(2)(L1) but not in Ir(ppy)(2)(L2). Finally, EPESS-active Ir(ppy)(2)(L1) has been successfully embedded in polymer nanoparticles and used as a luminescent label in bioimaging. PMID- 21283861 TI - Lanthanide-centered organic-inorganic hybrids through a functionalized aza-crown ether bridge: coordination bonding assembly, microstructure and multicolor luminescence. AB - This work focuses on the synthesis of a series of chemically bonded lanthanide/inorganic/organic hybrid materials (CE-15-Si-Ln, CE-16-Si-Ln, CE-18-Si Ln) containing a novel aza-crown ether organic component. The materials show red emission (Ln = Eu), green emission (Ln = Tb) and near-infrared (NIR) luminescence (Ln = Nd). Three functional molecular precursors (denoted as CE-15-Si, CE-16-Si, CE-18-Si) have been synthesized with two or three N-substituted pendant arms containing chelating groups which can not only fulfill the high coordination numbers of Ln(3+) ions but also form an inorganic Si-O-Si network with tetraethoxysilane (TEOS). The resulting amorphous materials exhibit regular uniform microstructures for the organic and the inorganic components which are covalently linked through Si-O bonds via a self-assembly process. These hybrids present strong luminescent intensities in red, green and NIR ranges by embedding selected Ln(3+) ions into the hybrid system, which may lead to potential applications in organic electroluminescence displays, light emitting devices, functional membranes or chemical/biomedical sensors. PMID- 21283862 TI - Highly active and tunable catalysts for O2 evolution from water based on mononuclear ruthenium(II) monoaquo complexes. AB - The catalytic activity of [Ru(tpy)(bpy)OH(2)](2+) (tpy = 2,2':6',2''-terpyridine and bpy = 2,2'-bipyridine) increased by a 4'-substituted ethoxy group on the tpy ligand by more than one order of magnitude to give 1.1 * 10(-1) s(-1) of catalyst turnover frequency, which is comparable with the hitherto-reported champion data. PMID- 21283863 TI - Microcystins and cyanobacteria trends in a 14 year monitoring of a temperate eutrophic reservoir (Aguieira, Portugal). AB - A monitoring program of cyanobacteria and cyanotoxins in the framework of the surveillance of the Water Treatment Plant efficiency of the municipality of Santa Comba Dao (Portugal) was conducted from 1994 until 2007. With these data we aimed to answer the question, are MCs produced evenly over the years in a single water body? Samples were taken by the local health authorities in the site of the Water treatment plant and analyzed for total phytoplankton, cyanobacteria and the hepatotoxic cyanotoxins microcystins (MCs). Apart from 1999 and 2000, cyanobacteria represented a high proportion of total phytoplankton, attaining during several months of the year more than 90% of total phytoplankton density. A total of 24 cyanobacteria species were identified and Microcystis aeruginosa, Anabaena flos-aquae and Aphanizomenon flos-aquae were the main potentially toxic cyanobacteria species present throughout the period. MC concentration varied between 0.3 ug MC-LR eq l-1 in October 98 and 87.0 ug MC-LR eq l-1 in September 2001. The evolution of the average cell quota does not reveal any especial trend, although in 2001 the quota was the highest but not significantly different from the other years. The threshold limit of 5000 cells per ml of Microcystis aeruginosa should be taken into consideration in monitoring programs because the 10,000 cells per ml proposed by several other national programs might not be enough to prevent human health risks. Due to high annual variation in MC cell quota, monitoring programs of cyanobacteria and MC should be extended in time, since short term studies do not provide us the data needed for a safe management of a water body used for human purposes. PMID- 21283864 TI - Towards a fast, high specific and reliable discrimination of bacteria on strain level by means of SERS in a microfluidic device. AB - The interest in a fast, high specific and reliable detection method for bacteria identification is increasing. We will show that the application of vibrational spectroscopy is feasible for the validation of bacteria in microfluidic devices. For this purpose, reproducible and specific spectral pattern as well as the establishment of large databases are essential for statistical analysis. Therefore, short recording times are beneficial concerning the time aspect of fast identification. We will demonstrate that the requirements can be fulfilled by measuring ultrasonic busted bacteria by means of microfluidic lab-on-a-chip based SERS. With the applied sample preparation, high specificity and reproducibility of the spectra are achieved. Taking advantage of the SERS enhancement, the spectral recording time is reduced to 1 s and a database of 11,200 spectra is established for a model system E. coli including nine different strains. The validation of the bacteria on strain level is achieved accomplishing SVM accuracies of 92%. Within this contribution the potential of our approach of bacterial identification for future application is discussed, focusing on the time-benefit and the combination with other microfluidic applications. PMID- 21283865 TI - Modelling the microtubule: towards a better understanding of short-chain fatty acid molecular pharmacology. AB - Systems biology combines experimental data with computational modelling to describe complex biological mechanisms and pathways. Short-chain fatty acids (SCFAs-chemopreventive compounds produced in the colon lumen) impair microtubule (MT) function in colon cancer cells by altering the relative expression of beta tubulin isotypes. The beta-tubulin isotype composition along MT fibres is believed to contribute to a "tubulin code" defining which microtubule-associated proteins (MAPs) and kinesins are recruited and the arrangement of tubulin post transcriptional modifications (PTMs) along the fibre, which in turn dictate many critical cellular functions. SCFAs drive acetylation of many proteins by virtue of being histone deacetylase inhibitors (HDACi's). Known acetyl-proteins include transcription factors and cytoplasmic cytoskeletal keratins as well as histones. Disruption of the MT cytoskeleton is a prime target of many cancer therapies including anti-microtubule drugs (AMD). This review focuses on SCFAs as HDACi's and how they might affect tubulin dynamics, modifications and isotypes. It discusses the evolution of mechanistic models that have helped improve understanding of tubulin-MT structure and dynamics and how to develop these models, combined with those describing transcription and the cell cycle, could provide hypotheses for how SCFAs disrupt cytoskeletal function. The review demonstrates how systems biology could offer potentially novel ideas for therapies in the prevention and treatment of cancers through the continued development and elaboration of such models. PMID- 21283866 TI - A metabolomics strategy for detecting protein-metabolite interactions to identify natural nuclear receptor ligands. AB - Nuclear receptors are ligand-regulated transcription factors that control a range of (patho)physiological processes. Lipids are the most common type of nuclear receptor ligands. Here, we utilize a metabolomics approach that detects protein metabolite interactions to identify endogenous peroxisome proliferator-activated receptor (PPAR) ligands from tissue and cell extracts. PMID- 21283867 TI - Metal and redox selectivity of protoporphyrin binding to the heme chaperone CcmE. AB - The interaction of heme with the heme chaperone CcmE is central to our understanding of cytochrome c maturation, a complex post-translational process involving at least eight proteins in many Gram-negative bacteria and plant mitochondria. We have shown previously that Escherichia coli CcmE can interact with heme non-covalently in vitro, before forming a novel covalent histidine-heme bond, in a redox-sensitive manner. The function of CcmE is to bind heme in the periplasm before transferring it to apocytochromes c. In the absence of structural information on the complex of CcmE and heme, we have further characterized it by examining the binding of the soluble domain of CcmE (CcmE') to protoporphyrins containing metals other than Fe, namely Zn-, Sn-, Co- and Mn protoporphyrin (PPIX). CcmE' demonstrated no affinity for the Zn- or Sn containing protoporphyrins and low affinity for Mn(ii)-PPIX. High-affinity, reversible binding was, however, observed for Co(iii)-PPIX, which was highly sensitive to oxidation state as demonstrated by release of the ligand from the chaperone on reduction; no binding to Co(ii)-PPIX was observed. The non-covalent complex of CcmE' and Co(iii)-PPIX was characterized by non-denaturing mass spectrometry. The implications of these observations for the in vivo function of CcmE are discussed. PMID- 21283868 TI - Organic solvent-induced controllable crystallization of the inorganic salt Na3[Au(SO3)2] into ultralong nanobelts and hierarchical microstructures of nanowires. AB - The present paper reports an organic solvent-induced controllable crystallization of a water-soluble inorganic salt Na(3)[Au(SO(3))(2)] into ultralong nanobelts and hierarchical microstructures of one-dimensional (1D) nanowires. It was found that the morphology of the resulting crystals can be fine tuned by simply varying the experimental parameters, such as the ratios of water to organic solvent and gold salt to organic solvent, as well as the type of organic solvent. PMID- 21283869 TI - Curcumin-loaded biodegradable polymeric micelles for colon cancer therapy in vitro and in vivo. AB - Curcumin is an effective and safe anticancer agent, but its hydrophobicity inhibits its clinical application. Nanotechnology provides an effective method to improve the water solubility of hydrophobic drug. In this work, curcumin was encapsulated into monomethoxy poly(ethylene glycol)-poly(epsilon-caprolactone) (MPEG-PCL) micelles through a single-step nano-precipitation method, creating curcumin-loaded MPEG-PCL (Cur/MPEG-PCL) micelles. These Cur/MPEG-PCL micelles were monodisperse (PDI = 0.097 +/- 0.011) with a mean particle size of 27.3 +/- 1.3 nm, good re-solubility after freeze-drying, an encapsulation efficiency of 99.16 +/- 1.02%, and drug loading of 12.95 +/- 0.15%. Moreover, these micelles were prepared by a simple and reproducible procedure, making them potentially suitable for scale-up. Curcumin was molecularly dispersed in the PCL core of MPEG PCL micelles, and could be slow-released in vitro. Encapsulation of curcumin in MPEG-PCL micelles improved the t(1/2) and AUC of curcumin in vivo. As well as free curcumin, Cur/MPEG-PCL micelles efficiently inhibited the angiogenesis on transgenic zebrafish model. In an alginate-encapsulated cancer cell assay, intravenous application of Cur/MPEG-PCL micelles more efficiently inhibited the tumor cell-induced angiogenesis in vivo than that of free curcumin. MPEG-PCL micelle-encapsulated curcumin maintained the cytotoxicity of curcumin on C-26 colon carcinoma cells in vitro. Intravenous application of Cur/MPEG-PCL micelle (25 mg kg(-1) curcumin) inhibited the growth of subcutaneous C-26 colon carcinoma in vivo (p < 0.01), and induced a stronger anticancer effect than that of free curcumin (p < 0.05). In conclusion, Cur/MPEG-PCL micelles are an excellent intravenously injectable aqueous formulation of curcumin; this formulation can inhibit the growth of colon carcinoma through inhibiting angiogenesis and directly killing cancer cells. PMID- 21283870 TI - Molecular level studies on binding modes of labeling molecules with polyalanine peptides. AB - In this work, the binding modes of typical labeling molecules (thioflavin T (ThT), Congo red (CR) and copper(II) phthalocyanine tetrasulfonic acid tetrasodium salt (PcCu(SO(3)Na)(4))) on pentaalanine, which is a model peptide segment of amyloid peptides, have been resolved at the molecular level by using scanning tunneling microscopy (STM). In the STM images, ThT molecules are predominantly adsorbed parallel to the peptide strands and two binding modes could be identified. It was found that ThT molecules are preferentially binding on top of the peptide strand, and the mode of intercalated between neighboring peptides also exists. The parallel binding mode of CR molecules can be observed with pentaalanine peptides. Besides the binding modes of labeling molecules, the CR and PcCu(SO(3)Na)(4) display different adsorption affinity with the pentaalanine peptides. The results could be beneficial for obtaining molecular level insight of the interactions between labeling molecules and peptides. PMID- 21283871 TI - Functionalization of methyl orange using cationic peptide amphiphile: colorimetric discrimination between ATP and ADP at pH 2.0. AB - A solvatochromic and non-fluorescent acid-base indicator, methyl orange (MO) was applied to colorimetric discrimination between adenosine triphosphate (ATP) and the corresponding diphosphate (ADP) at pH 2.0 in the presence of L-glutamic acid derived cationic peptide amphiphile 1. This method is based on the fact that the amphiphile 1 can prevent MO from protonation even at pH 2.0. No similar colour change was observed when ADP was added instead of ATP under the same conditions. The effect of the molecular structure of several peptide amphiphiles and dyes was also investigated. PMID- 21283872 TI - Hybrid bidentate phosphorus ligands in asymmetric catalysis: privileged ligand approach vs. combinatorial strategies. AB - In this perspective the development of chiral phosphorus ligands for asymmetric catalysis is discussed, with a special focus on hybrid bidentate phosphorus ligands, in particular phosphine-phosphoramidites. An attempt is made to compare privileged ligand and combinatorial approaches to ligand development--for which the class of phosphine-phosphoramidite ligands is well suited--highlighting differences, similarities and their complementary use. PMID- 21283873 TI - Flow synthesis of organic azides and the multistep synthesis of imines and amines using a new monolithic triphenylphosphine reagent. AB - Here we describe general flow processes for the synthesis of alkyl and aryl azides, and the development of a new monolithic triphenylphosphine reagent, which provides a convenient format for the use of this versatile reagent in flow. The utility of these new tools was demonstrated by their application to a flow Staudinger aza-Wittig reaction sequence. Finally, a multistep aza-Wittig, reduction and purification flow process was designed, allowing access to amine products in an automated fashion. PMID- 21283874 TI - A fully automated, multistep flow synthesis of 5-amino-4-cyano-1,2,3-triazoles. AB - Having demonstrated in the preceding publication the flow synthesis of aryl azides, we describe here a general protocol for the in-line purification of these versatile intermediates. As part of this investigation, we evaluated the use of ReactIR 45m as a tool for real-time detection of hazardous azide contaminants. This azide synthesis and purification process was then incorporated into a multistep flow sequence to generate a small collection of 5-amino-4-cyano-1,2,3 triazoles directly from aniline starting materials in a fully automated fashion. PMID- 21283875 TI - Synthesis and properties of MIDA boronate containing aromatic amino acids: new peptide building blocks. AB - Herein, we report the synthesis of novel phenylalanine and tyrosine derivatives containing a N-methyliminodiacetic acid boronate group. These compounds can be prepared enantiomerically pure, they are stable to column chromatography and they can be stored in air for two months without degradation occurring. This new class of boronate containing aromatic amino acids has potential applications in both peptide chemistry and natural product synthesis. PMID- 21283876 TI - Naphthalene proton sponges as hydride donors: diverse appearances of the tert amino-effect. AB - It has been shown that the 1-NMe(2) group in the 2-substituted 1,8 bis(dimethylamino)naphthalenes (proton sponges) can intramolecularly donate a hydride ion to an appropriate electron-accepting ortho-substituent such as diarylcarbenium ion, beta,beta'-dicyanovinyl or methyleneiminium group. This produces the 1-N(+)(Me)=CH(2) functionality and triggers a number of further transformations (tert-amino effect) including peri-cyclization, ortho-cyclization or hydrolytic demethylation. In each particular case, the course of the reaction is determined by the nature of the ortho-substituent and the most potent nucleophile presenting in the reaction mixture. For 2,7-disubstituted 1,8 bis(dimethylamino)naphthalenes, two types of tandem tert-amino effect with the involvement of both peri-NMe(2) groups have been registered. The conclusion was made that proton sponges are generally more active in the tert-amino reactions than the corresponding monodimethylaminoarenes. This is ascribed both to higher electron donor ability of proton sponges and markedly shortened distance between electrophilic C(alpha)-atom in the ortho-substituent and hydrogen atoms of the nearest NMe(2) group. Most conversions observed proceed in good to high yields and are useful for the preparation of derivatives of benzo[h]quinoline, quino[7,8:7',8']quinoline, 2,3-dihydroperimidine, N,N,N'-trimethyl-1,8 diaminonaphthalene and proton sponge itself. PMID- 21283877 TI - Efficient palladium-catalyzed asymmetric allylic alkylation of ketones and aldehydes. AB - Palladium-catalyzed asymmetric allylic alkylation of ketones, via enamines generated in situ as nucleophiles, were carried out smoothly with chiral metallocene-based P,N-ligands. Under the same conditions, however, reactions of aldehydes could hardly be observed. Subsequently, this obstacle was resolved by using chiral metallocene-based P,P-ligands. Both ketones and aldehydes afforded excellent enantioselectivities with up to 98% ee and 94% ee, respectively. PMID- 21283889 TI - Single particle tracking as a method to resolve differences in highly colocalized proteins. AB - Single particle tracking fluorescence microscopy was used to study two late endosomal proteins, Rab7 and LAMP1, that appear to be highly colocalized in static fluorescence microscopy images. Imaging these proteins simultaneously reveals that Rab7 and LAMP1 undergo periods of separation within the cell. Single particle tracking carried out during these periods of separation shows that Rab7 vesicles have greater velocities, but undergo less efficient transport than LAMP1 vesicles. This research demonstrates the use of single particle tracking as a tool to resolve functional differences in highly colocalized proteins in intact live cells. PMID- 21283890 TI - New directions in screen printed electroanalytical sensors: an overview of recent developments. AB - Screen printing is widely used to fabricate disposable and economical electrochemical sensors and has helped us to establish the route from 'lab-to market' for a plethora of sensors. We overview recent developments in the field where screen printed electrochemical sensors are utilised. Starting with their fundamental understanding, through to highlighting new developments in bulk metal and mediator modified electrodes, as well as novel advantageous electrode designs, we demonstrate the wide and diverse range of applications that sensors based on this fabrication approach have achieved. PMID- 21283891 TI - Ultrasensitive fluorescence-based methods for nucleic acid detection: towards amplification-free genetic analysis. AB - Real time PCR is the mainstay of current nucleic acid assays, underpinning applications in forensic science, point-of-care diagnostics and detection of bioterrorism agents. Despite its broad utility, the search for new tests continues, inspired by second and third generation DNA sequencing technologies and fuelled by progress in single molecule fluorescence spectroscopy, nanotechnology and microfabrication. These new methods promise the direct detection of nucleic acids without the need for enzymatic amplification. In this feature article, we provide a chemist's perspective on this multidisciplinary area, introducing the concepts of single molecule detection then focussing on the selection of labels and probe chemistry suitable for generating a signal detectable by ultrasensitive fluorescence spectroscopy. Finally, we discuss the further developments that are required to incorporate these detection platforms into integrated 'sample-in-answer-out' instruments, capable of detecting many target sequences in a matter of minutes. PMID- 21283892 TI - Magnetic-field-assisted assembly of CoFe layered double hydroxide ultrathin films with enhanced electrochemical behavior and magnetic anisotropy. AB - Magnetic films based on CoFe LDH nanoplatelets and porphyrin anions were fabricated by the layer-by-layer assembly technique with an assistance of an external magnetic field, which show enhanced electrochemical behavior and magnetic anisotropy. PMID- 21283893 TI - New insights on the Au(core)/Pt(shell) nanoparticle structure in the sub monolayer range: SERS as a surface analyzing tool. AB - Surface-enhanced Raman spectroscopy (SERS) was used as a powerful surface analyzing tool to investigate the core-shell structural evolution of Au@Pt nanoparticles, revealing the templating role of the underlying Au atoms on the nanoscale Pt-phase structure in the sub-monolayer range. PMID- 21283894 TI - Self-assembled polymers of silver(I) with a chiral diphosphine ligand. AB - Silver(I) salts, AgX, form self-assembled polymers with the chiral diphosphine ligand R,R-trans-C(6)H(10)(NHCO-2-C(6)H(4)PPh(2))(2), 1, of formula {Ag(2)X(2)(MU 1)}(n) and ring-opening polymerization of the trans chelate complex [Ag(1)]X has given the helical polymer [{Ag(MU-1)}(n)]X(n), when X = CF(3)SO(3). PMID- 21283895 TI - Variational response-function formulation of vibrational circular dichroism. AB - The atomic axial tensor (AAT) of vibrational circular dichroism is expressed as the frequency derivative at zero frequency of a linear response function for operators referencing a nuclear displacement and a magnetic field. This is used in the density matrix-based quasienergy derivative Lagrangian approach of Thorvaldsen et al. [J. Chem. Phys., 2008, 129, 214108] to express the AAT in a form where the need to solve response equations for the nuclear displacements is removed, significantly reducing the computation cost compared to existing formulations. The density matrix-based quasienergy derivative Lagrangian approach also allows us straightforwardly to use London atomic orbitals to remove the gauge-origin dependence and to account for the atomic orbitals' dependence on the nuclear coordinates. The formalism is entirely based on atomic-orbital density and integral matrices and therefore amenable to linear scaling for sufficiently sparse matrices and given a linearly scaling response solver. PMID- 21283896 TI - Towards large-scale, fully ab initio calculations of ionic liquids. AB - Ionic liquids have attracted a substantial amount of interest as replacement of traditional electrolytes in high efficiency electrochemical devices for generation and storage of energy due to their superior physical and chemical properties, especially low volatility and high electrochemical stability. For enhanced performance of the electrochemical devices ionic liquids are required to be highly conductive and low viscous. Long-range Coulomb and short-range dispersion interactions between ions affect physical and chemical properties of ionic liquids in a very complex way, thus preventing direct correlations to the chemical structure. Considering a vast combination of available cations and anions that can be used to synthesize ionic liquids, development of predictive theoretical approaches that allow for accurate tailoring of their physical properties has become crucial to further enhance the performance of electrochemical devices such as lithium batteries, fuel and solar cells. This perspective article gives a thorough overview of current theoretical approaches applied for studying thermodynamic (melting point and enthalpy of vapourisation) and transport (conductivity and viscosity) properties of ionic liquids, emphasizing their reliability and limitations. Strategies for improving predictive power and versatility of existing theoretical approaches are also outlined. PMID- 21283897 TI - Metal-carboxylate coordination polymers with redox-active moiety of tetrathiafulvalene (TTF). AB - Though numerous metal-organic frameworks or polymers have been reported, the organic building blocks are usually not redox-active. On the other hand, some mono-, di- or tri-nuclear compounds with tetrathiafulvalene (TTF) have been prepared, although little is known about the coordination polymers combined with paramagnetic metals and organic TTF ligands. We report herein a series of coordination polymers of copper(II) and manganese(II) with TTF dicarboxylate ligand (L). Compound 1, [CuL(2,2-bpy)](n), is a one-dimensional (1-D) coordination polymer with five-coordinated square-pyramidal Cu(II) centers. Mn(II) complex 2, [MnL(2,2-bpy)](n), also takes a 1-D structure, showing a double bridged mode by carboxylate groups. The 4,4-bipyridine compound 3, [MnL(4,4 bpy)(H(2)O)](n).CH(3)CN, takes a 2-D grid network. A zinc(II) compound 4, [ZnL(4,4-bpy)(H(2)O)](n).CH(3)CN, isomorphous structure with 3, is also presented. The electrochemical properties of the solid-state compounds were investigated by cyclic voltammetry using surface-modified electrodes. As usually observed in TTF derivatives, two sets of redox-waves were observed. The values of E(1/2)(1) of compounds 1-4 are in the order of 2(Mn) ~ 3(Mn) < 1(Cu) < 4(Zn), indicating that the metal coordination can affect the potential shift of the TTF ligand. Weak antiferromagnetic exchanges are observed for compounds 1, 2, and 3. PMID- 21283898 TI - Copper complex species within a fragment of the N-terminal repeat region in opossum PrP protein. AB - A spectroscopic (UV-Vis, CD and EPR), thermodynamic and voltammetric study of the copper(ii) complexes with the Ac-PHPGGSNWGQ-NH(2) polypeptide (L), a fragment of the opossum PrP protein N-terminal four-repeat region, was carried out in aqueous solution. It suggests the formation of a highly distorted [Cu(L)H(-2)] complex species in the neutral region, the stereochemistry of which is ascribable to a square base pyramid and a CuN(3)O(2) chromophore, resulting from the coordination of a histidine imidazole and two peptide nitrogen atoms and probably oxygen atoms from water molecules. At basic pH values a [Cu(L)H(-3)](-) species with a pseudo octahedral geometry was also obtained, with four nitrogen donor atoms in its equatorial plane, coming from the histidine residue and from peptidic nitrogen atoms. Interestingly, at pH values relatively higher than the neutrality, the coordination sphere of the copper complex in the [Cu(L)H(-2)] species changes its stereochemistry towards a pseudo-octahedron, as suggested by the change in the parallel copper hyperfine coupling constant of the EPR spectra at low temperature. A slight difference in the redox potentials between this two-faced [Cu(L)H(-2)] complex species seems to confirm this behaviour. Both potentiometric and spectroscopic data were compared with the analogous species obtained with the Ac-PHGGGWGQ-NH(2) peptide, belonging to the octarepeat domain of the human prion protein (hPrP) N-terminal region. The [Cu(L)H(-2)] species formed by the Ac PHPGGSNWGQ-NH(2) decapeptide, having a slightly lower stability, turned out to be less abundant and to exist within a narrow pH range. PMID- 21283899 TI - Studies towards the synthesis of the northern polyene of viridenomycin and synthesis of Z-double bond analogues. AB - Viridenomycin is a structurally challenging, potentially biologically valuable molecule which has yet to succumb to total synthesis. Its instability, perhaps particularly associated with the northern polyene may contribute to the difficulties of piecing this molecule together. The synthesis of northern polyene models, including potentially stabilised analogues incorporating benzene rings as Z-alkene replacements, have been prepared using an efficient series of cross coupling reactions. The resulting polyenes and polyene surrogates have been converted into tetraene ester and amide models of the viridenomycin system. These analogues have sufficient stability compared with the unsubstituted northern polyene analogue to be viable for future developing a strategy for the construction of viridenomycin and analogues. PMID- 21283900 TI - Wide-field lensless fluorescent microscopy using a tapered fiber-optic faceplate on a chip. AB - We demonstrate lensless fluorescent microscopy over a large field-of-view of ~60 mm(2) with a spatial resolution of <4 um. In this on-chip fluorescent imaging modality, the samples are placed on a fiber-optic faceplate that is tapered such that the density of the fiber-optic waveguides on the top facet is >5 fold larger than the bottom one. Placed on this tapered faceplate, the fluorescent samples are pumped from the side through a glass hemisphere interface. After excitation of the samples, the pump light is rejected through total internal reflection that occurs at the bottom facet of the sample substrate. The fluorescent emission from the sample is then collected by the smaller end of the tapered faceplate and is delivered to an opto-electronic sensor-array to be digitally sampled. Using a compressive sampling algorithm, we decode these raw lensfree images to validate the resolution (<4 um) of this on-chip fluorescent imaging platform using microparticles as well as labeled Giardia muris cysts. This wide-field lensfree fluorescent microscopy platform, being compact and high-throughput, might provide a valuable tool especially for cytometry, rare cell analysis (involving large area microfluidic systems) as well as for microarray imaging applications. PMID- 21283902 TI - Transannular dipolar cycloaddition as an approach towards the synthesis of the core ring system of the sarain alkaloids. AB - Intramolecular transannular dipolar cycloaddition was investigated as a key step in a synthetic approach to the core of the sarain alkaloids; although the use of an azomethine ylide was unsuccessful with the chosen aldehyde substrate, cycloaddition with a nitrone did give the alternative regioisomeric bridged cycloadduct. PMID- 21283901 TI - New eutectic ionic liquids for lipase activation and enzymatic preparation of biodiesel. AB - The enzymatic preparation of biodiesel has been hampered by the lack of suitable solvents with desirable properties such as high lipase compatibility, low cost, low viscosity, high biodegradability, and ease of product separation. Recent interest in using ionic liquids (ILs) as advanced reaction media has led to fast reaction rates and high yields in the enzymatic synthesis of biodiesel. However, conventional (i.e., cation-anion paired) ILs based on imidazolium and other quaternary ammonium salts remain too expensive for wide application at industrial scales. In this study, we report on newly-synthesized eutectic ILs derived from choline acetate or choline chloride coupled with biocompatible hydrogen-bond donors, such as glycerol. These eutectic solvents have favorable properties including low viscosity, high biodegradability, and excellent compatibility with Novozym((r)) 435, a commercial immobilized Candida antarctica lipase B. Furthermore, in a model biodiesel synthesis system, we demonstrate high reaction rates for the enzymatic transesterification of Miglyol((r)) oil 812 with methanol, catalyzed by Novozym((r)) 435 in choline acetate/glycerol (1:1.5 molar ratio). The high conversion (97%) of the triglyceride obtained within 3 h, under optimal conditions, suggests that these novel eutectic solvents warrant further exploration as potential media in the enzymatic production of biodiesel. PMID- 21283903 TI - 2,5-PRODAN: synthesis and properties. AB - The preparations of 1-(6-(dimethylamino)naphthalen-1-yl)propan-1-one (2,5-PRODAN, 2) and 7-(dimethylamino)-2,3-dihydrophenanthren-4(1H)-one 3 are described. The photophysical properties of these compounds are characterized and compared with those of PRODAN. Both compounds show solvatochromism that is similar in magnitude to PRODAN with a quantum yield that is nearly one order of magnitude smaller. Emission occurs from a locally excited (LE) state with charge-transfer character. There is no internal conversion to a different charge-transfer state as is seen in PRODAN. PMID- 21283905 TI - Potential energy surfaces for gas-surface reactions. AB - A method for constructing the potential energy surface for reactions of a molecule with the surface of cleaved non-conducting crystals is reported. The method uses systematic fragmentation to express the total potential in terms of potential energy surfaces which describe reactions of relatively small molecules in the gas phase. The approach is illustrated by an application to the reaction of hydrogen atoms with a hydrogen-terminated silicon(111) surface. PMID- 21283906 TI - Tunable symmetry and periodicity in binary supramolecular nanostructures. AB - We present a route to change the "compositional" order of highly crystalline binary layers comprising diindenoperylene and copper-phthalocyanines from two- to one-dimensional periodicity. This is achieved by exchanging fluorine with hydrogen atoms in the phthalocyanines, thereby reducing the C-F...H-C interactions and allowing the interplay of long-range electrostatic interactions in mesoscopic phases. Linear patterns are thus obtained, whose periodicity can be additionally tuned by an appropriate stoichiometry of the components. PMID- 21283904 TI - L-5F, an apolipoprotein A-I mimetic, inhibits tumor angiogenesis by suppressing VEGF/basic FGF signaling pathways. AB - We recently reported that apolipoprotein A-I (apoA-I) and apoA-I mimetic peptides inhibit tumor growth and improve survival in a mouse model of ovarian cancer. The current study was designed to examine whether inhibition of angiogenesis is one of the mechanisms for the observed anti-tumorigenic effects. The apoA-I mimetic peptide L-5F had no affect on proliferation and cell viability of human umbilical vascular endothelial cells (HUVECs) in the basal state; however, treatment with L 5F at 1, 3, and 10 MUg ml(-1), dose-dependently inhibited both vascular endothelial growth factor (VEGF)- and basic fibroblast growth factor (bFGF) induced proliferation, cell viability, migration, invasion and tube formation in HUVECs. L-5F inhibited VEGF- and bFGF-induced activation of their corresponding receptors, VEGFR2 and FGFR1, as well as downstream signaling pathways, including Akt and ERK1/2. MicroCT scanning and immunohistochemistry staining demonstrated that daily injection of L-5F (10 mg kg(-1)) decreased both the quantity and size of tumor vessels in mice. L-5F treated mice showed significantly reduced levels of VEGF in both tumor tissue and the circulation, which is consistent with in vitro data showing that L-5F inhibited production and secretion of VEGF from mouse and human ovarian cell lines in the absence and presence of exogenously added lysophosphatidic acid, a potent tumor promoter. In conclusion, our data that L-5F inhibits angiogenesis suggests that apoA-I mimetic peptides may serve as novel anti-angiogenesis agents for the treatment of angiogenesis-associated diseases, including cancer. PMID- 21283907 TI - A polyethylene oxide-functionalized self-organized alumina nanochannel array for an immunoprotection biofilter. AB - Nanochannel membranes have been fabricated for many biological and engineering applications. However, due to low-throughput process, high cost, unsuitable pore geometries, and low chemical/mechanical stability, we could not have obtained optimized nanochannel membranes for biomedical treatments as well as a novel building block for artificial cell membranes. Here, we report a PEO functionalized straight nanochannel array based on a self-organized porous alumina for a novel biofilter with antifouling, superior immunoprotection and high permeability of nutrients, which have excellent in vivo mechanical stability. Thus, our strategy may provide great advantages in novel membrane biotechnologies such as biofiltration, artificial cells, and drug delivery. PMID- 21283909 TI - Use of thermally annealed multilayer gold nanoparticle films in combination analysis of localized surface plasmon resonance sensing and MALDI mass spectrometry. AB - A self-assembled film of gold nanoparticles (AuNPs) with a raspberry-like morphology was prepared on a glass plate by the layer-by-layer thermal annealing of multilayer films of AuNPs. It was possible to control the morphology of the obtained films of AuNPs by changing the annealing temperature, duration of annealing, and number of layers. On investigating the plasmonic properties of these films, we found that AuNP films with a raspberry-like morphology yielded the highest refractive index unit, which is a critical parameter in localized surface plasmon resonance (LSPR) sensing, as compared to other types of AuNP films. Self-assembled AuNP films with a raspberry-like morphology were subsequently functionalized with 11-mercaptoundecanoic acid (MUA) to enable the binding of lysozyme to the MUA-modified Au surface. The superior limit of detection for the LSPR sensing of lysozyme in a buffer solution was found to be in the picomolar range (~10(-12) M). The high sensitivity observed in the region was attributed to the raspberry-like morphology, where the AuNPs were packed closely together, and the electromagnetic field confinement was most intense (i.e., at hot spots). The MUA-modified, self-assembled AuNP films with a raspberry-like morphology were finally used in the combination analysis of LSPR sensing and matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) for the selective detection and identification of lysozyme in human serum. PMID- 21283908 TI - A microfabricated electrical differential counter for the selective enumeration of CD4+ T lymphocytes. AB - We have developed a microfabricated biochip that enumerates CD4+ T lymphocytes from leukocyte populations obtained from human blood samples using electrical impedance sensing and immunoaffinity chromatography. T cell counts are found by obtaining the difference between the number of leukocytes before and after depleting CD4+ T cells with immobilized antibodies in a capture chamber. This differential counting technique has been validated to analyze physiological concentrations of leukocytes with an accuracy of ~9 cells per uL by passivating the capture chamber with bovine serum albumin. In addition, the counter provided T cell counts which correlated closely with an optical control (R(2) = 0.997) for CD4 cell concentrations ranging from approximately 100 to 700 cells per uL. We believe that this approach can be a promising method for bringing quantitative HIV/AIDS diagnostics to resource-poor regions in the world. PMID- 21283910 TI - The molecular nature of photovoltage losses in organic solar cells. AB - Since the inception of heterojunction organic photovoltaic research the organic/organic interface has been thought to play a crucial role in determining the magnitude of the open-circuit voltage. Yet, the task of defining the molecular properties dictating the photovoltage delivered by these devices, that employ mixed or neat layers of different organic molecules to convert incident photons to electricity, is still an active area of research. This will likely be a key step in designing the new materials required for improving future device efficiencies. With the intent to underscore the importance of considering both thermodynamic and kinetic factors, this article highlights recent progress in elucidating molecular characteristics dictating photovoltage losses in heterojunction organic photovoltaics. PMID- 21283911 TI - Access to 1,2-diketones by an unusual radical cascade. AB - An unusual radical fragmentation of an unstrained cyclohexane structure was observed leading to complex 1,2-diketones. PMID- 21283912 TI - Ferromagnetic spin-delocalized electron donors for multifunctional materials: pi conjugated benzotriazinyl radicals. AB - We have developed new synthetic methodology for benzotriazinyl radicals that exhibit spin delocalization, low oxidation potentials, and ferromagnetic interactions in the solid state via pi-pi interactions, making them promising candidates for multifunctional magnetic materials. PMID- 21283913 TI - Site-selective metal-coordination-based patterning of silane monolayers. AB - Herein, we report a method to pattern a derivatized nifedipine silane monolayer that aromatizes under UV irradiation. Using a functionalized SCS-Pd(II) pincer complex, we demonstrate that a strong metal-coordination complex between the aromatized nifedipine derivative and the pincer complex is formed. This methodology integrates SAM photolithography (top-down) and molecular recognition directed self-assembly (bottom-up) strategies to create simple and rapid synthesizable functional patterned surfaces. PMID- 21283914 TI - Non-telomeric activities of telomerase. AB - Recent results suggest that telomerase is involved in many more cellular processes than merely telomere elongation. These include telomere-independent anti-apoptotic, cytoprotective and pro-proliferative effects of telomerase or protection of mitochondrial DNA against oxidative stress. Telomerase also participates in DNA repair and its essential subunits, hTR and hTERT, are able to modulate independently the cell's response to DNA damage. Recent high throughput analyses of gene expression showed that hTERT expression modulates expression of about 300 genes, including genes involved in the regulation of cell cycle progression, proliferation and differentiation. Besides the well-known telomerase catalytic activity of RNA-dependent DNA polymerase, its RNA-dependent RNA polymerase activity was recently described in association with the RNA subunit of mitochondrial RNA processing endoribonuclease, thus suggesting involvement of telomerase in RNA interference processes. These recent discoveries open novel possibilities and entirely unexpected research perspectives, branching off from the mainstream telomere and telomerase research. PMID- 21283915 TI - Polymer supported synthesis of novel benzoxazole linked benzimidazoles under microwave conditions: in vitro evaluation of VEGFR-3 kinase inhibition activity. AB - An efficient soluble polymer-supported method has been developed for the parallel synthesis of substituted benzimidazole linked benzoxazoles using focused microwave irradiation. The key step involves the amidation of 4-hydroxy-3 nitrobenzoic acid with polymer-immobilized o-phenylenediamine. Application of mild acidic conditions promoted the ring closure to furnish the benzimidazole ring. After hydrogenation of the nitro-group to amine, the resulted polymer conjugates underwent efficient ring closure with various alkyl, aryl and heteroaryl isothiocyanates to generate the polymer-bound benzimidazolyl benzoxazoles. The polymer-bound compounds were finally cleaved from the support to furnish benzimidazole linked benzoxazole derivatives. The efficacy of the resultant angular bis-heterocyclic library was studied against vascular endothelial growth factor receptor (VEGFR-3). The preliminary screening of these novel compounds exhibits moderate to high inhibition (IC(50) = 0.56-1.42 MUM). This protocol provides an easy access to novel angular bis-heterocycles which have potential for the discovery of novel leads for targeted cancer therapeutics. PMID- 21283916 TI - Combined treatment for skin rejuvenation and soft-tissue augmentation of the aging face. AB - Multiple types of anti-aging treatments are required to address the various etiologies of facial aging. Soft-tissue augmentation provides a minimally invasive option for patients seeking to look younger. However, due to changes in facial skin, musculature, fat and bone, anti-aging treatment requires a multifaceted approach. Injectable fillers may be combined with neurotoxins to resolve superficial wrinkles and restore facial volume. These modalities may be used with laser resurfacing or chemical peels to address epidermal and superficial dermal problems. Combining injectable soft-tissue augmentation treatments allows clinicians and patients to take advantage of the benefits of each modality and to address the multiple effects of facial aging. This review is based on clinical experience and a MEDLINE search for articles about volume replacement and soft-tissue augmentation. It provides a rationale that supports the use of combination techniques/products for soft-tissue augmentation. PMID- 21283917 TI - Efficacy and tolerability of a new monophasic, double-crosslinked hyaluronic acid filler for correction of deep lines and wrinkles. AB - BACKGROUND: A monophasic, highly crosslinked hyaluronic acid dermal filler offers further treatment options for deep lines. OBJECTIVE: To investigate the efficacy and tolerability of Belotero. METHODS AND MATERIALS: A total of 149 patients received injections. Efficacy was assessed on the Wrinkle Severity Rating Scale (WSRS) and the Global Aesthetic Improvement Scale (GAIS). Adverse events were recorded at each evaluation session. RESULTS: Mean WSRS improved significantly (P<0.001) by 1.9 score points without any decline throughout the 12-week period. Improvement was found in 89.9 percent of patients on the (GAIS), 59.7 percent of whom were designated as very much/much improved. Investigator and patient satisfaction was stated in more than 90 percent of cases as excellent/good. Adverse events, exclusively localized to the injection area, occurred in 85.9 percent of patients immediately after injection and declined to 12.8 percent in week 2. None were serious. CONCLUSION: The findings indicate the benefit of the highly cross-linked, monophasic hyaluronic acid dermal filler, especially in the treatment of patients with deep and extremely deep folds. Overall, the filler appears to be well tolerated. This evaluation raised no major safety concerns. PMID- 21283918 TI - An open-label, pilot study to assess the effectiveness and safety of hyaluronic acid gel in the restoration of soft tissue fullness of the lips. AB - BACKGROUND: There have been few systematic investigations of the effectiveness, safety and tolerability of aesthetic lip augmentation using hyaluronic acid (HA) fillers. OBJECTIVES: Evaluate the effectiveness of small gel particle hyaluronic acid filler (Restylane Injectable Gel [SGP-HA]; Medicis Aesthetics Inc., Scottsdale, AZ) in lip augmentation using the Medicis Lip Fullness Scale (MLFS). Assess subjective improvement in lip appearance using the Global Aesthetic Improvement Scale (GAIS). PATIENTS, MATERIALS AND METHODS: Investigators treated 21 adults. The primary efficacy endpoint was an increase in lip fullness at least one grade on MLFS at eight weeks post-treatment. Adverse events were reported using patient diaries. RESULTS: Sixteen of 18 evaluable subjects (89%) had an improvement at least one grade on MLFS in both lips. MLFS and GAIS scores were consistent, suggesting clinically significant aesthetic improvement. Adverse effects were transient and mostly mild to moderate in severity. CONCLUSION: Lip augmentation with SGP-HA was well tolerated and resulted in clinically meaningful increases in lip fullness. PMID- 21283919 TI - The impact of natural sunlight exposure on the UVB-sun protection factor (UVB SPF) and UVA protection factor (UVA-PF) of a UVA/UVB SPF 50 sunscreen. AB - OBJECTIVE: To compare the functional stability of Cetaphil UVA/UVB Defense SPF 50 as measured by its ultraviolet B sun protection factor (UVB-SPF) and ultraviolet A protection factor (UVA-PF) values following exposure to natural sunlight versus the UVB-SPF and UVA-PF values of unexposed product. METHODS: These two randomized, controlled, evaluator-blinded, single-center trials were conducted according to the methods outlined in the 2007 Proposed Amendment to the Final Monograph, "Sunscreen Drug Products for Over-the-Counter Human Use." Sunscreen samples were applied to glass plates and exposed to ultraviolet radiation in the form of natural sunlight in four minimal erythemal doses (MED) ranging from 2-6 MED (42-36 mJ/cm2). Three test sites were identified on the back of each study subject. Exposed sunscreen (one of four doses), unexposed sunscreen, and a UVB SPF 15 control sunscreen were applied to the three test sites in a randomized fashion, followed by UV irradiation of incremental doses. Erythema and pigment darkening responses were assessed immediately following UV exposure and again 16 24 hours (erythema) or three to 24 hours (pigment darkening) after exposure. UVB SPF and UVA-PF values were calculated for the exposed and unexposed samples. RESULTS: The calculated UVB-SPF and UVA-PF values for all test samples (exposed and unexposed) were >50 and >9, respectively, which were greater than the stated UVB-SPF and UVA-PF values on the product label. No differences were observed between the exposed and unexposed samples in UVB-SPF or UVA-PF. CONCLUSION: The UVA and UVB protection using standard evaluation techniques of Cetaphil UVA/UVB Defense SPF 50 remains stable despite exposure of the sunscreen to natural sunlight containing UVB ranging from 2-16 MED (41-336 mJ/cm2) and coexistent UVA. PMID- 21283920 TI - A multi-center, open-label study to evaluate the safety and efficacy of a sequential treatment regimen of clobetasol propionate 0.05% spray followed by Calcitriol 3 mg/g ointment in the management of plaque psoriasis. AB - BACKGROUND: Psoriasis is a hyperproliferative and inflammatory skin disorder that affects roughly 2 percent of the worldwide population. Clobetasol propionate is the most common corticosteroid used to treat moderate-to-severe psoriasis but the potential for side effects limits its long-term use. Topical vitamin D, which is used to treat mild-to-moderate psoriasis, has been shown to be safe when used daily for up to 52 weeks. To date, very few studies exist evaluating the use of clobetasol propionate in a regimen with calcitriol to manage moderate-to-severe disease over time. OBJECTIVES: To evaluate the efficacy and assess safety of a regimen of sequential topical treatments with clobetasol propionate 0.05% spray for up to four weeks followed by calcitriol 3 MUg/g ointment for eight weeks in the management of moderate-to-severe plaque psoriasis. METHODS: This was a multi center, open-label study in subjects aged 18-80 years with moderate-to-severe plaque psoriasis at baseline. Subjects applied clobetasol propionate 0.05% spray twice daily for up to four weeks. At the end of four weeks, if the subject's overall disease severity (ODS) was assessed as clear, almost clear, mild or moderate, subjects started treatment with calcitriol 3 MUg/g ointment twice daily. Twice-daily treatment with calcitriol 3 MUg/g ointment continued for eight weeks (until week 12) or unless the subject's ODS was assessed as severe or returned to the baseline score, at which time it was discontinued. Subjects were evaluated at baseline and at weeks 2, 4, 8 and 12. RESULTS: Of the 305 subjects enrolled, 170 subjects completed the full 12-week study with no major protocol deviations and comprised the per-protocol (PP) study population. Treatment success, defined as at least one grade improvement in ODS at week 12 compared to baseline, was achieved in 84.1 percent of subjects. The percent body surface area affected (% BSA) decreased from 7.1 percent at baseline to 3.9 percent at week 12 (P<0.001). The sequential treatment regimen was well tolerated with no unexpected adverse events. Most reported adverse events and cutaneous irritations were mild in severity. CONCLUSIONS: The results of this study indicate that the 12-week regimen of clobetasol propionate 0.05% spray treatment for four weeks immediately followed by an eight-week treatment phase with calcitriol 3 MUg/g ointment is efficacious and safe for the management of moderate-to-severe plaque psoriasis. PMID- 21283921 TI - Complete clearance is sustained for at least 12 months after treatment of actinic keratoses of the face or balding scalp via daily dosing with imiquimod 3.75% or 2.5% cream. AB - OBJECTIVE: Assess long-term, sustained, complete clearance of actinic keratoses after treatment with imiquimod 3.75% or 2.5% cream using two two-week or three week cycles of daily dosing. METHODS: Adults with five to 20 baseline actinic keratoses who achieved complete clearance at the eight-week post-treatment visit in four phase 3 placebo-controlled treatment studies were followed for an additional 12 months. RESULTS: For imiquimod 3.75% and 2.5% cream, respectively, complete clearance was sustained for 12 months in 17/42 (40.5%) and 13/39 (33.3%) subjects from the two-week cycle studies, and in 23/48 (47.9%) and 16/37 (43.2%) subjects from the three-week cycle studies. There were no safety concerns during the follow-up. CONCLUSION: In subjects with a median of eight to nine baseline actinic keratoses who achieved complete clearance after treatment of the full face or balding scalp with topical imiquimod 3.75% cream, complete clearance of all lesions (baseline, recurrent or new) was sustained in >= 40 percent of subjects for at least 14 months after the last dose. Clinicaltrials.gov identifier NCT00668733. PMID- 21283922 TI - Effects of a novel formulation of fluocinonide 0.1% cream on skin barrier function in atopic dermatitis. AB - OBJECTIVE: To determine the effect a novel formulation of fluocinonide cream on skin barrier function in subjects with atopic dermatitis. DESIGN: The authors performed an open-label, investigator-blinded, side-by-side, controlled trial examining skin barrier function before and after a two-week course of a class I, super-potent topical steroid. SETTING: Outpatient university-based dermatology clinic in Portland, OR. SUBJECTS: Twenty-five subjects aged 12 or older with a diagnosis of moderate, severe, or very severe AD were recruited for this study. INTERVENTION: Fluocinonide 0.1% cream, a novel formulation of a class I super potent topical steroid was applied to all affected areas, except a control site, once daily for two weeks or until clear. The control target site was treated with the vehicle once daily. MAIN OUTCOME MEASURE(S): The study's primary outcome was change in skin barrier function as measured by basal transepidermal water loss (TEWL) in acute lesional skin from baseline as measured at two weeks. RESULTS: TEWL readings significantly decreased (reflecting improved barrier function) in both the active and control target sites. The active target site decreased 14.35+/-16 mg/cm2 per hour; 95 percent confidence interval, P<0.001. The control target site decreased 8.75+/-11.80 mg/cm2 per hour in 25 subjects; 95 percent confidence interval, P<0.001. Skin electrical capacitance also improved significantly, reflecting improved stratum corneum hydration with therapy. Pruritus, clinical severity, and quality of life scores all showed significant improvement by the end of the study. CONCLUSION: The authors have shown that short-term treatment with a novel formulation of 0.1% fluocinonide led to significantly improved barrier function as measured by basal TEWL in subjects with active moderate to severe AD. These data suggest short-term treatment with AD with a super-potent corticosteroid improves skin barrier function. PMID- 21283923 TI - The erbium micropeel: a prospective, randomized trial of the effects of two fluence settings on facial photoaging. AB - BACKGROUND: Recent studies have suggested that a series of low-energy, single pass ablative laser resurfacing micropeels can reduce photoaging with decreased downtime. This randomized, prospective single-blinded trial sought to determine the ideal settings of sequential erbium:yttrium-aluminum-garnet (Er:YAG) laser treatments that maximize efficacy and patient satisfaction. METHODS: Forty-six subjects with mild-to-moderate facial dyschromia and rhytides were evenly randomized to two Er:YAG treatment arms. Patients in the lower fluence (LF) (2.5 J/cm2) and higher fluence (HF) (3.8 J/cm2) groups each received three one-pass, full-face treatments one month apart. Patient and investigator assessments of rhytides, dyschromia and global appearance were performed at baseline and at four, eight and 20 weeks using a nominal scale from 1-4. Adverse events and patient satisfaction were also evaluated. RESULTS: Patient scores showed rhytid improvement only with HF treatments. Investigator scores at three months post treatment showed dyschromia was significantly improved in both study arms, with a 24 and 36 percent reduction for the LF and HF groups, respectively. Global appearance scores improved by 25 and 32 percent, respectively. A trend towards greater post-procedure erythema and time-to-erythema resolution was observed in the HF group. Mild peeling was the most common adverse event. Individuals who underwent LF treatments were more likely to pursue future treatments. CONCLUSION: Both settings resulted in moderate but significant improvement in dyschromia, although only HF treatment improved rhytides. The decreased downtime of LF treatments made this the preferred choice of patients. PMID- 21283925 TI - Disease and treatment burden of psoriasis: examining the impact of biologics. AB - Plaque psoriasis is a chronic, inflammatory skin disease that can be difficult to treat. Traditional systemic agents, topical agents, phototherapy and biologic therapies can be used for patients with psoriasis. The authors reviewed published results from a variety of sources in order to better understand the effects of psoriasis treatments on patient satisfaction, patient adherence, healthcare resource utilization and productivity. Patients with psoriasis consider many factors when evaluating therapies, including the time for the therapy to be effective, cosmetic issues common with topical therapies and travel to and from phototherapy centers. Satisfaction with and adherence to biologic therapies appears to be greater than for traditional therapies. Although biologic therapies are generally more expensive than are traditional, these agents may contribute to decreased healthcare utilization and increased productivity. PMID- 21283927 TI - Modified Tripier flap for lateral eyelid reconstructions. AB - Eyelid defects can present many reconstructive challenges to surgeons; it is essential to maintain the function of the eyelid while avoiding tension vectors on the free margin, which could result in eyelid retraction. Thus, local skin flaps are often the closure option of choice for defects of the lateral eyelid. The Tripier flap was the first innervated myocutaneous flap to be reported, and was used for lateral lower eyelid repairs. The Tripier flap is a transposition flap utilizing redundant tissue on the upper eyelid to repair defects of the lateral inferior eyelid. The authors describe Their technique for the single pedicle Tripier flap, which does not rely on the inclusion of orbicularis muscle or innervation. This modified Triper flap is a valuable addition to the reconstructive armamentarium of the dermatologic surgeon. PMID- 21283928 TI - Dermatologic rituximab dosing: treatment of refractory pemphigus vulgaris in an adolescent male. AB - Rituximab is a chimeric monoclonal antibody against CD20 that mediates B-cell depletion. It has been shown to be effective in a variety of autoimmune-related diseases, including pemphigus vulgaris. Most reports of pemphigus treatment utilize the weekly dosing regimen designed for the treatment of B-cell malignancy. The authors report a case of successful treatment of refractory pemphigus vulgaris in an adolescent male using three infusions of rituximab spread over a four-month period of time. The authors also discuss recent updates in rituximab's mechanism of action in autoimmune disease. Rituximab acts to destroy auto-reactive B-cells prior to their development into auto-antibody producing plasma cells. More recent reports have shown that rituximab also indirectly leads to a decrease of autoreactive CD4+ T cells via depletion of B cells that are necessary for antigen presentation. Monthly to bi-monthly rituximab infusion dosing may be a more appropriate dosing strategy for autoimmune disease that minimizes potential side effects while generating remission of disease. Dermatology continues to see an increase in use of medications designed for treatment of rheumatologic disease and malignancy. Additional studies should focus on the appropriate dosing of these medications for dermatologic conditions that limit the risk of adverse effects while preserving therapeutic benefit. PMID- 21283929 TI - Part III: cutaneous hypersensitivity during selective serotonin reuptake inhibitor therapy resulting in acquired cutis laxa. PMID- 21283930 TI - [Ferrous sulfate: acute poisoning with a frequent use drug]. AB - The iron is the main component of hemoglobin and is also part of myoglobin and enzymes. Its deficit is the most common cause of nutritional anemia in humans. The use of iron salts is very common in children, because they are indicated for prophylaxis and treatment of iron deficiency anemia. The availability in households and the emergence of flavored formulations that promote adherence to treatment, greatly assist in this type of poisoning. Usually, the overdose is considered a low hazard, because it is a mineral supplement added in many of the baby food. Iron in free state is able of producing toxicity, disrupting multiple cellular processes by catalyzing redox reactions with lipid peroxidation and free radical formation. We report a case of serious toxicity by iron salts, in which early intervention and management with specific chelator, allowed a favorable evolution. PMID- 21283931 TI - [The centenary of the Sociedad Argentina de Pediatria and their publications]. PMID- 21283932 TI - [Who takes scare of our children?]. PMID- 21283933 TI - [Accidental cannabis poisoning in children: report of four cases in a tertiary care center from southern Spain]. AB - INTRODUCTION: Cannabis is the most frequently consumed illicit substance in Spain. Pediatric accidental cannabis poisoning is an uncommon but life threatening intoxication. OBJECTIVE: To describe clinical findings, diagnosis and management of children with accidental cannabis poisoning in a tertiary care pediatric hospital. We report four patients with accidental cannabis poisoning. Clinical presentation included reduced level of consciousness, drowsiness, ataxia, tremble, apnea, hypotonia, and seizures. Tetrahydrocannabinol (THC) was detected by urine screening for cannabinoids and other toxic substances in all cases. The four patients were treated with supportive care. All cases recovered uneventfully and were discharged within 24 hours of admission. CONCLUSION: The possibility of cannabis poisoning should be considered in cases of unexplained acute onset of neurological findings in previously healthy children. PMID- 21283934 TI - [Drivers older than 16 years involved in fatal crashes]. PMID- 21283935 TI - [Familial hypomagnesemia, hypercalciuria with nephrocalcinosis syndrome: report of a case]. AB - Familial hypomagnesemia and hypercalciuria with nephrocalcinosis is a rare autosomal recessive disease characterized by renal calcium and magnesium wasting, evolving in the progressive decrease of renal function, eventually requiring kidney transplant. Clinical findings include urinary infection, polyuria, polydipsia, cramps, tremors, convulsions, among others; these, associated to ocular and/or auditive abnormalities. We present a 4 year-old female with the syndrome, which was manifested by typical signs and symptoms in daily practice: fever, abdominal pain, polyuria and polydipsia. These symptoms may defer the diagnosis of the syndrome. PMID- 21283936 TI - [Non-urgent emergency department visits at a children's hospital]. AB - INTRODUCTION: The primary function of an Emergency Department is to assist patients with acute conditions; however, many visits are for nonurgent reasons. The objectives of this study were to estimate the prevalence of nonurgent emergency department visits and to describe the reasons for them. POPULATION AND METHODS: Cross-sectional and descriptive study, conducted in a Pediatric Hospital. We included patients aged between 1 month and 18 years, who presented to the emergency department during the whole day, in working and non-working days. We defined as nonurgent visits those corresponding to level 5 in the Emergency Severity Index classification. RESULTS: We included 249 visits; 59% of which were nonurgent. The main reason referred was the difficulty to obtain an appointment in a primary care center (42.9%). Nonurgent visits were more frequent in working days (p= 0.007), conducted by caregivers living within 15 km of the hospital (p= 0.003) and those who used to visit the emergency department when they were children (p= 0.005). Patients with chronic diseases (p= 0.001), those who were referred by another professional (p= 0.002), and caregivers who lived without another adult in their home (p= 0.002) consulted less frequently for nonurgent reasons. CONCLUSION: Frequency of nonurgent visits was high. The main reason referred was the difficulty to obtain an appointment with a primary care centre. PMID- 21283937 TI - [Chance fracture missed by convencional CT: Presentation of a clinical course]. AB - INTRODUCTION: Bending-disruption fractures of the vertebral body are called Chance fracture. In some cases these fractures may not be noticeable with a CT scan. CLINICAL CASE: A 9 years-old boy suffered a frontal collision while traveling in the back seat of a car. The child was secured by the safetybelt, without a child car seat or elevator adapted to his height. He had abdominal skin lesions in the physical exploration compatible with a belt mark. Conventional thoraco- abdominal CT scan did not show any vertebral fracture. As the clinical suspicion persisted, lateral plain radiography of the lumbar column was performed showing a Chance fracture in L2, confirmed by MRI. CONCLUSION: Chance fracture is typically seen in children under 12 years less than 135 cm height and with injuries associated with the belt after a traffic accident. This type of fractures may go unnoticed in a conventional CT scan so clinical suspicion must lead us to further work-up. The MRI is the gold standard for the diagnosis. This case remarks the importance of the use of homologated elevated seat devices in older children. PMID- 21283938 TI - [Greeting modalities preferred by patients in pediatric ambulatory setting]. AB - INTRODUCTION: The greeting is the first form of verbal and nonverbal communication and is a valuable tool to support the physician-patient relationship. OBJECTIVE: Assess parents and children preferences on how they want pediatricians greet and address them. MATERIAL AND METHODS: Cross-sectional study. The population was persons accompanying patients (parents or guardians) between 1 month and 19 years old and patients older than 5 years old. A survey questionnaire was completed after the medical visit. RESULTS: A total of 419 surveys from patients' companions and 249 from pediatric patients were analyzed; 68% of the companions preferred the doctor addressed them by the first name, 67% liked to be greeted with a kiss on the cheek and 90% liked to be treated informally. Preferring to be greeted with a kiss on the cheek was associated in multivariate analysis with the companion was the mother, age younger than 39 years and longer time in knowing the pediatrician; 60% of the patients preferred to be addressed by their first name. CONCLUSIONS: In the outpatient setting patients companions and patients themselves prefer to be addressed by their name informally and be greeted with a kiss on the cheek. PMID- 21283939 TI - [Suicide attempt in under 15's: An experience in a Pediatric Emergency Depart]. AB - INTRODUCTION: Suicide attempt (SA) in under 15's is one of the most frequent reasons for psychiatric consultation faced by paediatricians working in urgency services. Uruguay is the country with the highest suicide rate in South America. Suicide is currently the fifth cause of death in 10 to 14 year olds (1.8/ 100,000) and ninth in the 5 to 9 age group (0.4/100,000). OBJECTIVES: To know the incidence of SA consultations in under 15's, the characteristics of their environment and methods used. MATERIAL AND METHODS: Descriptive and prospective epidemiological study in a paediatric urgency service between 01/07/08 and 30/06/09. RESULTS: A total of 145 patients were included. Mean age was 12 yrs. 7 m. A 77% were female. The triggering factors were: interpersonal conflicts (57%), affective losses (17%) and battering or sexual-abuse (11%). A 78% took medication. An 18% planned the SA. A 77% occurred at home. The life of 10% was at risk. One third had at least one previous SA. A 49% had a family history of psychiatric disorders, 28% of SA and 7% of suicide. Of the total 123 SA with pills, 101 were women (n 112) and 22 males (n 33) (p <0.05). Eight out of 15 under 10 year olds were male, and 25 out of 130 had more than 10 years of age (p <0.05). Among under 10's, 50% used a non-pharmacological method and this figure rose to 19% (p <0.05) in those with more than 10 years. An 88% rectified or regretted their action. Median length of hospital stay was 6 days. At the time of discharge, 99.5% did not present sequelae. CONCLUSIONS: SA incidence in under 15's is 2/1,000 consultations per year. The main profile is a female between 12 and 14 years of age that attempts suicide at home using medication, preferably benzodiacepines, following a discussion or affective loss, without life risk. Among those under 10 years, there is a significant predominance of males using non pharmacological methods. Verification of these behavioural patterns will enable the design of prevention strategies in the age group studied. PMID- 21283940 TI - [Effects of prenatal steroids in the development of necrotizing enterocolitis in Wistar rat neonates]. AB - INTRODUCTION: Necrotizing enterocolitis (NEC) is a frequent problem in preterm infants. Prenatal treatment with steroids proved to be effective for lung maturation and it is thought to have a protective effect on the immature bowel. OBJECTIVES: To study the effects of prenatal treatment with steroids at the onset, clinical course and histological pattern of NEC in an animal model. METHODS: Pregnant rats received treatment with intraperitoneal hydrocortisone (5 mg/kg) 24 and 48 hrs prior to the expected date of delivery (group S). Control pregnant rats were injected with normal saline, at the same timing (group P). After term delivery by cesarean section, both groups were kept in identical conditions in a neonatal incubator at 35oC, away from their mothers to prevent any exposure to breast milk. Pups were fed every three hours with neonatal formula via an orogastric tube. To further increase the susceptibility to NEC, pups were exposed to hypoxia followed by hypothermia three times a day for 72 hrs (H-H) or until development of clinical signs of NEC. At that point, each animal was anesthetized and euthanized. The intestine was fixed for histological analysis. Those animals which died before 72 hours were excluded to prevent false positive results in the histopathological exam. RESULTS: The clinical signs of NEC include oral intolerance, gastric residuals, respiratory distress, abdominal distension, wall erythema and hematochezia; 60% of animals in group P (n= 16) presented with at least one clinical sign, vs. 40% of pups in group S (n= 15). The onset of clinical signs and clinical course in group S was more benign than in group P. Mortality rate was 40% for pups in group P vs. 20% for group S (NS). Histological analysis indicated that 80% of the animals from group P showed signs of NEC, of which 50% reached grade 3-4 (maximum score of damage), whereas only 40% of the animals in group S presented with signs of NEC (p<0.05), all were of grade 0-1 (minimum histological damage). CONCLUSIONS: Prenatal treatment with steroids was effective for amelioration of the onset and clinical presentation in this model of experimental NEC. PMID- 21283941 TI - [Sun protection questionnaire in Buenos Aires adolescent athletes]. AB - INTRODUCTION: Excessive sun exposure is the major environmental factor in the development of skin cancer. Adolescents who play outdoor sports are highly exposed to ultraviolet rays, which will result in cumulative photodamage with a higher risk of developing skin cancer in adulthood. OBJECTIVES: 1) To evaluate sun protection habits in Buenos Aires adolescent athletes. 2) To identify the characteristics of those adolescents who have developed sunburns. PATIENTS AND METHODS: An observational descriptive cross-sectional study was carried out using a voluntary anonymous written and self-reported survey addressed to adolescent athletes aged 11 to 18 years, who participated in a competitive sporting activity. RESULTS: The study included 554 adolescents. The 26% reported to have taken sunscreen to the competition. The 5.2% reported to have used it on a routine basis during training, and the 6.1% while doing sports. The 45% of the adolescents referred that sun protection factor rating was not relevant to them. Males most frequently inclined to believe that a good suntan was synonymous of health and women believed that suntan was synonymous of beauty. Most adolescents (73%) had developed at least one sunburn in the previous summer. CONCLUSIONS: In this study, a low compliance with the use of sunscreen was observed in adolescent athletes, despite the high rates of sunburns they had had recently. Nowadays, sun protection campaigns addressed to this age group are urgently needed. PMID- 21283942 TI - [Communication in Pediatrics: children and adolescents, subjects of right]. AB - We will analyze the patient-family-doctor communication. We suggest that the healthcare professional consider girls and boys subjects of right, in order to generate conditions for dialogue. Letting them speak, be listened to, as well as informed, results essential for them to participate in the decision-making regarding their health. To do so, we will give rise to the need to reflect on self-representations about childhood. Likewise, we will consider doctor's communicative competences and the active role of every single member of this triad. PMID- 21283943 TI - [Nutritional factors on retinopathy of prematurity]. AB - Retinopathy of prematurity is a complication affecting very low birth weight infants; it is produced by numerous factors. We review nutritional and growth aspects associated with larger or lesser incidence and severity of retinopathy. This information would allow a better prediction of risk and, a clinical management to minimize visual damage. PMID- 21283944 TI - [Prebiotics in infant health]. AB - The composition of human milk is the main base for the development of infant formulas concerning its macronutrients and micronutrients contents and bioactive compounds. Technological advances in the composition of human milk have identified a great number of bioactive compounds such as prebiotics which are responsible for immunological protection and the prevention of different pathologies. In order to achieve similar benefits, they are part of the contents of infant formulas. PMID- 21283945 TI - [Full-text publication of abstracts presented at the 33th Argentinean pediatric meeting and non publication related factors]. AB - INTRODUCTION: There is no information about non publication of research presented at scientific meetings in Argentina. We analyzed the full-text publication rate of abstracts presented at the 33 degrees Argentinean Pediatric Congress (APC), time to achieve publication, and factors associated with publication or non publication. METHODS: Survey-based cross-sectional study, including authors of abstracts presented at the 33 degrees APC. The survey included age, gender, specialty and sub-specialty, professional area and reason of publication or non publication. RESULTS: We randomly selected 140/894 presented abstracts. Only 16 abstracts (11.4%) were subsequently published in full, requiring 27+/-15 months. There were no association between full-text publication and author's characteristics. "Oral presentations" were more likely to be subsequently published (p= 0.018). In non published abstracts, 95% were not submitted by the author, more frequently because of "lack of time" (35.9%). CONCLUSION: Only 11.4% of abstracts were subsequently published in full. Oral presentation was associated with a higher publication rate. Most frequent cause for non publication was non submission due to lack of time. PMID- 21283946 TI - [The choking game in adolescence, between experimentation and risk]. AB - In the last year there was happened a series of adolescent deaths in the province of Salta that might be related to a dangerous game known as "the choking game". It has been practiced over many years in different countries around the world and consists of provoking brain hypoxia for some seconds by different techniques to obtain an instant of ecstasy and pleasure. We consider relevant that health providers know about this practice and so be able to recognize through signs and symptoms when an adolescent might be playing this game. PMID- 21283947 TI - [Obtention of an antivenom against Phoneutria nigriventer (arachnida; ctenidae) venom]. AB - Envenomation by spiders of the genus Phoneutria ("banana spider") may be lethal, especially in children. The only available specific treatment is the use of antivenom, which is produced by only one laboratory in the world. In this study we report the development of an equine F (ab')2 experimental antivenom raised against the venom of Phoneutria nigriventer. The antivenom neutralized the venom of spiders from different regions of Argentina (Misiones and Jujuy), the development of envenomation symptoms in experimental animals was totally inhibited. These results show that local production of this type of antivenom is possible. Independence of production is important since international acquisition is always conditioned by the availability of stock surplus from the sole producer. PMID- 21283948 TI - [Eosinophilic gastroenteropathy: a pediatric series]. AB - Eosinophilic gastroenteropathy (EoG) is an uncommon disease characterized by eosinophilic infiltration of the gastrointestinal (GI) mucosa. A chart review was performed searching for patients diagnosed between 2000 and 2010. EoG was diagnosed based on mucosal infiltration of 20 or more eosinophils/HPF in upper GI tract and more than 60 eosinophils/HPF in lower GI tract. Ten patients [median age: 10 mo. (r 2 mo.- 10 yr.)], 9 males, were diagnosed. Four presented with severe protracted diarrhea and weight loss, 2/10 abdominal distention and weight loss and 4/10 protein-losing enteropathy. Exclusive elemental or hypoallergenic diets were administered depending on the age of presentation with remission achieved in 4/10. Six required methylprednisolone to induce remission, 5 are still on budesonide. Due to the emergence of many cases of EoG in the last decade, we should increase our level of suspicion. Multicenter studies could contribute to define the best therapeutic approach for these patients. PMID- 21283949 TI - [Tetralogy of Fallot]. PMID- 21283951 TI - [Guideline for management of tumor lysis syndrome]. AB - A right management of the tumor lysis syndrome is essential for the ongoing improvement in survival and treatment of patients with hematological malignancies. This guide establishes clinical and laboratory criteria for confirming diagnosis, states initial laboratory tests, enumerates risk factors based stratification criteria, and develops guidelines for prevention and treatment of the syndrome and its complications. PMID- 21283952 TI - Testosterone deficiency as a risk factor for cardiovascular disease. AB - Testosterone deficiency (TD) has become a frequently diagnosed condition in our current society with an obesity epidemic. Men diagnosed with TD often have co morbidities including metabolic syndrome. Challenging aspects in diagnosing and treating patients with TD include intra-individual variation of symptoms combined with lack of its correlation with serum levels of testosterone. Apart from sexual aspects including libido and erectile function, replacement therapy with testosterone might have beneficial metabolic effects, whereas untreated TD might increase cardiometabolic risk and disease. In this article, we review the cardiovascular and metabolic risks associated with TD, as well as risks and benefits of testosterone replacement therapy. We also provide insights into potential mechanisms of the association between cardiometabolic risks with TD (treated and untreated) and propose an individual treatment algorithm. PMID- 21283953 TI - Influence of methimazole and radioactive iodine treatment in the serum levels of the chemokine CXCL10 in hyperthyroid patients with Graves' disease. AB - The chemokine CXCL10 plays an important role in Graves' disease (GD); however, data regarding the effectiveness of therapy are contradictory. Serum CXCL10 levels in 31 hyperthyroid patients were measured before and after establishing euthyroidism: 16 newly diagnosed GD patients received methimazole (MMI), 15 relapsed GD patients were treated with radioactive iodine (RAI), and 18 healthy subjects served as a control group. Baseline serum CXCL10 levels were higher than in controls (MMI group 144.0 +/- 48.24, RAI group 156.3 +/- 71.81 and control 71.32 +/- 26.03 pg/ml; p < 0.01). In the MMI group, serum CXCL10 levels decreased following euthyroidism at 6 months (76.51 +/- 22.06 pg/ml; p < 0.01) and 12 (76.42 +/- 34.07 pg/ml; p < 0.01). In the RAI group, serum CXCL10 levels decreased after 3, 6, 9, and 12 months of RAI administration (82.37 +/- 55.01, 66.35 +/- 48.62, 68.76 +/- 28.87, and 74.94 +/- 49.74 pg/ml, respectively; p < 0.05). Elevated serum TRAb levels in the MMI group (33.15 +/- 30.84) decreased at 6 months (14.64 +/- 16.57 IU/l; p = 0.0070), whereas in the RAI group (44.61 +/- 60.66 IU/l) they increased to a peak level at 6 months (66.40 +/- 104.2 IU/l; p = 0.003), which was significantly higher than those of the MMI group, but were decreased at 12 months (28.91 +/- 35.13 IU/l). Serum CXCL10 levels correlated with FT3 (r = 0.48, p < 0.0001), FT4 (r = 0.47, p < 0.0001) and TRAb (r = 0.37, p = 0.0014). In conclusion, these data show a relationship between serum CXCL10 and GD activity and suggest that a more complex mechanism is involved in the generation of the thyroid auto-antibodies TPOAb and TRAb. PMID- 21283954 TI - Plant-based antimicrobial studies--methods and approaches to study the interaction between natural products. AB - The therapeutic value of synergistic interactions has been known since antiquity, and many different cultural healing systems still rely on this principle in the belief that combination therapy may enhance efficacy. This paper intends to provide an overview, from an antimicrobial perspective, on the research undertaken and interactive principles involved in pharmacognosy studies. Methods used to determine antimicrobial interactions include basic combination studies, the sum of the fractional inhibitory concentration index (SigmaFIC), isobole interpretations, and death kinetic (time-kill) assays. The various interactions are discussed with reference to molecules, different plant parts or fractions, different plant species, and combinations with nonbotanical antimicrobial agents. It is recommended for future development in the field of phytosynergy that consideration should be given to the selection criteria for the two inhibitors. A more conservative approach should be adopted when classifying synergy. When examining interactions in plant-based studies, antagonistic interactions should not be ignored. Combinations involving more than two test samples should be examined where applicable, and very importantly, the mechanism of action of synergistic interactions should be given precedence. It is encouraging to observe the upsurge in papers exploring the complex interactions of medicinal plants, and undoubtedly this will become increasingly important in our continued quest to understand the mechanism of action of phytotherapy. The scientific validation of efficacious antimicrobial combinations could lead to patentable entities making research in the field of phytosynergy not only academically rewarding but also commercially relevant. PMID- 21283955 TI - A new naphthoquinone isolated from the bulbs of Cipura paludosa and pharmacological activity of two main constituents. AB - Cipura paludosa (Iridaceae) is a plant that is distributed in the north region of Brazil. Its bulbs are used in folk medicine to treat inflammation and pain. Four naphthalene derivatives have been isolated from the bulbs of this plant. Three of them have been identified as the known naphthalene derivatives, eleutherine, iso eleutherine, and hongkonin. The structure of the fourth and new component was determined as 11-hydroxyeleutherine by extensive NMR study. In addition, the IN VIVO effect of the two major compounds, eleutherine and iso-eleutherine, was evaluated in carrageenan-induced hypernociception and inflammation in mice. Eleutherine and iso-eleutherine (1.04-34.92 umol/kg), dosed intraperitoneally (i.p.) or orally (p.o.), decreased the carrageenan-induced paw oedema (i.p. - inhibitions of 36 +/- 7 % and 58 +/- 14 %, respectively; p.o. - inhibitions of 36 +/- 7 % and 58 +/- 14 %, respectively). Iso-eleutherine, but not eleutherine, significantly reduced (inhibitions of 39 +/- 4 %) the plasma extravasation induced by intradermal (i.d.) injection of carrageenan. Likewise, eleutherine and iso-eleutherine (1.04-34.92 umol/kg, i.p. or p.o.) were also effective in preventing the carrageenan-induced hypernociceptive response (i.p. - inhibition of 59 +/- 4 % and 63 +/- 1 %, respectively; p.o. - inhibitions of 36 +/- 7 % and 58 +/- 14 %, respectively). It was also suggested that the anti-inflammatory and anti-hypernociceptive effects of eleutherine or iso-eleutherine partly depend on the interference with the synthesis or activity of mast cell products, kinins, cytokine, chemokines, prostanoids, or sympathetic amines. Our findings show that two major compounds of C. paludosa contain pharmacologically active constituents that possess antinociceptive and anti-inflammatory activity, justifying, at least in part, its popular therapeutic use for treating conditions associated with pain. PMID- 21283956 TI - Orientin-induced cardioprotection against reperfusion is associated with attenuation of mitochondrial permeability transition. AB - In this study, we provide new evidence that orientin from bamboo leaves (Phyllostachys nigra) protect H9c2 cardiomyocytes against ischemia/reperfusion (I/R) injury through the mitochondrial apoptotic pathway. A previous work has identified that orientin could protect myocardium against ischemia/reperfusion injury. Mitochondria are both critical determinants of cardioprotection and crucial targets of cardioprotective signaling. Their role during reperfusion is conspicuously critical because the conditions promote apoptosis through the mitochondrial pathway and necrosis though irreversible damage to mitochondria, which is in association with mitochondrial permeability transition (MPT). After myocardial ischemia, opening of the mPTP is a critical determinant of cell death. The relationship of orientin and mPTP in mediating reperfusion-induced cardiomyocytes injury is still elusive. Here, our results indicate that the protective effect of orientin in H9c2 cells subjected to I/R injury is associated with depression of the mPTP opening, resultant mitochondrial dysfunction, and apoptosis. Further investigation of cellular mechanisms revealed that these effects were associated with inhibition of reactive oxygen species (ROS) generation, repolarization of mitochondrial membrane potential (Deltapsi(m)), suppression of mitochondrial cytochrome C release, enhancement of the Bcl-2 level, and inhibition of Bax and Smac/DIABLO levels. Furthermore, these beneficial effects of orientin were blocked by the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin, and orientin could enhance Akt phosphorylation. In summary, we demonstrate that orientin protects H9c2 cardiomytocytes against I/R induced apoptosis by modulating the mPTP opening, and this role of orientin may involve the PI3K/Akt signaling pathway. PMID- 21283957 TI - Stent-free tubularized incised plate (TIP) repair of distal and mid-shaft hypospadias irrespective of age. AB - PURPOSE: Aim of this study was to report our experiences with tubularized incised plate (TIP) repair without placement of a postoperative urethral stent in 41 cases. PATIENTS AND METHODS: Since October 2005, we have performed TIP repair for distal penile hypospadias without using a postoperative urethral stent. A urethral stent is used intraoperatively for the tubularization of the neourethra and is removed at the end of the procedure. Follow-up included clinical examination and a structured telephone interview on parental satisfaction. RESULTS: The group included 41 boys, 60% with coronal or distal hypospadias and 40% with mid-shaft hypospadias (aged 6 months to 16 years, median: 3 years). In 7 cases, the prepuce was also reconstructed. There were 2 cases with fistula and one case of meatal stenosis. No glans dehiscence, severe bleeding, or wound infection was observed. No urinary retention requiring catheterization was observed, irrespective of age. All but one patient was discharged the day after surgery. Follow-up ranged from 8 to 48 months (average: 22 months). Most parents (87.5%) were satisfied or very satisfied. CONCLUSION: Based on our preliminary experiences, patient comfort and safety, parental satisfaction and the rate of complications seem to be promising with this technique. PMID- 21283958 TI - Prospective, randomized, controlled trial comparing a tissue adhesive (DermabondTM) with adhesive strips (Steri-StripsTM) for the closure of laparoscopic trocar wounds in children. AB - BACKGROUND: 4 methods are used in pediatric laparoscopic surgery to close trocar wounds. While tissue adhesives or adhesive strips have been shown to produce fewer wound complications and a better cosmetic result compared to trans- or only subcutaneous sutures, the choice of technique is still often based on the surgeon's personal experience. Thus, the objective of this trial was to assess the impact of tissue adhesives (DermabondTM) compared to adhesive strips (Steri StripTM) on potential complications of wound healing, wound pain, cosmetic outcome, and patient satisfaction after laparoscopic appendectomy in children. METHODS: 49 patients undergoing laparoscopic appendectomy were enrolled in this prospective randomized trial. In every patient, two 5-mm and one 10-mm port-site incision was closed either with DermabondTM or Steri-StripTM after placing subcuticular absorbable sutures (4-0 VicrylTM). Postoperative complications, pain, and patient satisfaction with scars were evaluated at follow-up on day 10 and day 90 after the operation using a questionnaire and a visual analogue scale (VAS). Photographs of scars taken on day 90 were evaluated on a VAS by 2 pediatric surgeons blinded to the closure method used. RESULTS: According to the surgeons' evaluation of the cosmetic outcome, a significant difference between the 2 groups with regard to the cosmetic score was found on day 90 of follow-up, favoring Steri-StripTM wound closure (p < 0.05). On day 10 and 90 there were no statistical differences between the 2 methods as regards the result of patient evaluations (p > 0.05). Only one wound infection (4%) was observed in the Steri StripTM group (n = 25) on day 10. At follow-up on day 90 two patients (9.1%) in the DermabondTM group and one (4.8%) in the Steri-stripTM group complained of wound pain (p = 0.52). CONCLUSIONS: Both tissue adhesives and adhesive strips are excellent "no needle" alternatives for the closure of laparoscopic port-site incisions in children. As regards cosmetic outcome, Steri-StripTM wound closure seems to be the most suitable and is also the less expensive technique. PMID- 21283959 TI - Dysphagia in adults operated on for esophageal atresia--use of a symptom score to evaluate correlated factors. AB - INTRODUCTION: Dysphagia is not unusual following repair of esophageal atresia (EA). The lack of a uniform definition has led to a variance when it comes to reporting the prevalence of dysphagia among patients operated on for EA. Our aim is to estimate the occurrence and degree of dysphagia, using a numerical score with its statistical versatility independent of a specific definition. The results are used to find early risk factors of dysphagia within this patient group. The results are also used to see whether we can find a correlation between dysphagia and symptoms of gastroesophageal reflux (GER) and quality of life (QoL). METHODS: 79 consecutive survivors operated on for EA in Gothenburg between 1968 and 1983 were located. Hospital charts were reviewed and patients received questionnaires on dysphagia, symptoms of GER and QoL. Dysphagia was measured by a numerical score, symptoms of GER were extracted using a predetermined questionnaire (GerdQ), and QoL was determined using the generic questionnaire SF 36. RESULTS: 73 patients (92.4%) returned the questionnaires. In order to make the study group as homogeneous as possible with regard to the malformation we choose to study the 63 patients representing the vast majority: those with Gross type C. 36 patients (57%) had symptoms of dysphagia to varying degrees. We did not find any aggravating factors in their hospital charts nor did we find any correlation to the most recent demographics. There was a significant difference in dysphagia scores when we compared Gross type C to the often more complex type A (p<0.05). We did not find any correlation to heartburn but a strong correlation to regurgitation with an OR of 2.8 (95% CI: 1.2-6.6). The QoL was good for this patient group, and we did not find any correlation between QoL and the dysphagia score. CONCLUSIONS: The dysphagia score provides easy-to-use results when it comes to evaluating the potential influence of dysphagia. Dysphagia is common within this patient group. Patients operated on for EA Gross type A seem to do worse when it comes to dysphagia. Regurgitation is associated with dysphagia, which could imply that GER is an aggravating factor. Further studies to support this finding will show whether there is a correlation between the dysphagia score and the results of 24-h pH-monitoring. If so, this could mean that treating GER might decrease dysphagia, at least in this patient group. PMID- 21283960 TI - Osmotic expanders in children: no filling--no control--no problem? AB - BACKGROUND: Self-filling, hydrogel-based osmotic tissue expanders have been successfully used for several years, mainly in adult patients. We wanted to test this novel device in pediatric plastic and reconstructive surgery. MATERIAL AND METHODS: Between November 2004 and September 2009, we implanted 53 osmotic tissue expanders following standard surgical principles in a total of 30 children and adolescents with burn scars, congenital nevi, alopecia, or foot deformities. RESULTS: All expanders reached their predicted volume within 6 weeks and 51 (96.2%) produced a sufficient amount of additional skin for the intended coverage of the defect. A serious infection precluding the planned reconstructive procedure occurred with 2 expanders (3.8%). Minor complications occurred at 6 implantation sites (11.4%), and consisted of small necrotic areas and perforations (n = 3) and minor infections (n = 3). These problems could be controlled and did not interfere with the subsequent plasty. The final results recorded at the last follow-up (mean: 21 months, range: 9-48 months) were rated as excellent in 25, good in 19, moderate in 6, and poor in 1 patient. CONCLUSION: This is apparently the largest pediatric series in which self-filling expanders have been used. The data obtained indicates that self-filling expanders can be safely and effectively used for various plastic, reconstructive and orthopedic procedures in children and adolescents. The fact that numerous painful and distressing filling sessions are obviated with these expanders is particularly beneficial for those children too young to understand and cooperate. Moreover, this approach minimizes the risk of infection and lowers costs. PMID- 21283961 TI - Prenatal differential diagnosis of congenital chloride diarrhea: the importance of a dilated fluid-filled rectum. PMID- 21283962 TI - Transverse testicular ectopia treated by transseptal contralateral transposition: case report. PMID- 21283963 TI - Is octreotide safe for the management of persistent hyperinsulinemic hypoglycemia of infancy? PMID- 21283965 TI - [Occurrence and relevance to health of persistent organic substances and phthalates in breast milk]. AB - The aim of this study is to give an overview of the concentrations of persistent organic pollutants like the polychlorinated dibenzo- P-dioxins (PCDD), polychlorinated dibenzofurans (PCDF), polychlorinated biphenyls (PCB), polybrominated diphenyl ether (PBDE), perfluorinated compounds (PFC) and of phthalates in breast milk. On the basis of median and 95 (th) percentile values an "average" and a "high" intake were calculated for a 3-month-old infant exclusively breast-fed. Moreover, the actual daily intake was compared with tolerable daily intakes (TDI) recommended by scientific institutions. On this basis, we found an "average" ("high") daily intake of 70 (140) pg TEQ/kg body weight (b. w.) for PCDD/F and dioxin-like PCB (dl-PCB), 10 (20) ng/kg b. w. for PFOS (perfluorooctanesulfonate), 20 (50) ng/kg b. w. for PFOA (perfluorooctanoate), 1.7 (7.5) ng/kg b. w. for BDE 47, and 0.6 (2.1) ng/kg b. w. for BDE 99. For di-2-ethylhexyl phthalate (DEHP) and di- N-butyl phthalate (DnBP) an "average" and "high" intake of 400 ng/kg b. w. and 2,000 ng/kg b. w. and of 100 and 500 ng/kg b.w. were assumed, respectively. For all of these substances we found a daily intake via breast milk below the TDI, established on a livelong basis. On contrary, the daily intake for the sum of the PCDD/F and dl-PCB considerably exceeded the recommended TDI value. Even with regard to the "high" daily intake values the share of PBDE, PFC, and phthalates on the TDI was only in the lower percentage. Scientific organisations assume that an exceeding of the PCDD/F and dl-PCB intake in relation to the TDI value is acceptable only on the basis of the still declining levels in breast milk and the fact that this high exposure only occurs during some months of the entire life when breast milk is consumed. On the basis of the recent exposure situation mothers can exclusively breast-feed their infants for 6 months without any hesitation. The well established health benefits for mothers and infants when exclusively breast feeding should be utilised. There is also no health concern if the mother decides to breast-feed the baby for longer than 6 months when the infant also receives additional food. PMID- 21283966 TI - For all health. PMID- 21283967 TI - [Prevalence of overweight and obesity in children and adolescents from 1977 to 2009 - examination of the school medical data of more than 94,000 school-age children in the city of Basel (Switzerland)]. AB - OBJECTIVES: A cross-sectional study over a period of 30 years was used to investigate the development of overweight and obesity in school children. Of particular interest is the question of whether the overweight epidemic is continuing to increase, as often postulated, or whether a stagnation point or the start of a reversal of the trend has already been reached. METHODS: School medical examinations take place at three school levels in the city of Basel. 94,004 student files from these examinations from the school years 1977/78 and 1978/79, as well as from 1989/90 to 2008/09, have been subjected to a secondary analysis. The overweight and obesity prevalences were calculated for eleven 2 year cohorts according to the standards of the International Obesity Taskforce IOTF. A more in-depth analysis followed, differentiated by school grade, gender and nationality. RESULTS: The percentage of overweight and obese children and young people has increased strongly in the last 3 decades. Whereas every 11th child was overweight 30 years ago (9.3%), it now amounts to every 5th child (20.9%). The proportion of obese children has increased from 1.2% to 5.4%. The large increase in overweight and obesity prevalences mainly took place in the 1990s. Since the millennium change, the number of overweight and obese school children among those examined has only increased slightly, or has at least no longer increased. This general development was observed in all school grades and was independent of gender and nationality, although foreign children are always twice as likely to be affected by overweight and obesity. The stabilisation can be seen at its earliest and the change in trend is clearest in the kindergarten, which could indicate a "year's cohort effect". CONCLUSIONS: The development over the last 10 years is welcome from a public health point of view. The continued high prevalence still represents a significant health problem, however, and the prevention efforts being made against the overweight epidemic must be further strengthened. PMID- 21283969 TI - Systemic sclerosis - a systematic overview: part 1 - disease characteristics and classification, pathophysiologic concepts, and recommendations for diagnosis and surveillance. AB - Due to its high association with Raynaud's phenomenon systemic sclerosis (SSc) is probably the most common connective tissue disease seen by vascular specialists. In part 1 of our systematic overview we summarize classification concepts of scleroderma disorders, the epidemiologic and genetic burden, the complex pathophysiologic background, and the clinical features and the stage-dependent capillary microscopic features of SSc. Furthermore, we address the diagnostic recommendations propagated by the German Network for Systemic Sclerosis and the Task Force for Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology, the European Respiratory Society, and the International Society of Heart and Lung Transplantation. PMID- 21283970 TI - Systemic sclerosis - a systematic overview: part 2 - immunosuppression, treatment of SSc-associated vasculopathy, and treatment of pulmonary arterial hypertension. AB - Here we give an overview over treatment recommendations propagated by the European League Against Rheumatism (EULAR), EULAR Scleroderma Trials and Research Group, the German Network for Systemic Sclerosis, the European Respiratory Society, and the International Society of Heart and Lung Transplantation. As response to immunosuppressant (IS) therapy is usually weaker in systematic sclerosis (SSc) compared to other connective tissue disorders IS should be considered with caution. To prevent scleroderma renal crisis steroid doses should not exceed 15 mg/d. The definitive role of a number of new immunosuppressant drugs and the effects of autologous stem cell transplantation in systemic clerosis (SSc) have to be elucidated. Prostanoids, especially iloprost, are widely used as intravenous formulas for the treatment of severe Raynaud's phenomenon (RP) and digital ulcers (DU). Calcium antagonists are of limited therapeutic value. Bosentan, an oral endothelin receptor antagonists (ETRA), was shown to prevent new DU, but failed to heal existing DU, while the oral phopshodiesterase inhibitor (PDI) Sildenafil reduces the occurrence of RP and might be effective in ulcer healing. Combination therapies of PDI with ETRA are currently evaluated. Therapy of pulmonary arterial hypertension (PAH) is usually started as oral monotherapy, frequently using an ETRA. When this first-line therapy is not tolerated ETRA is substituted by PDI. If treatment goals are not reached with monotherapy combinationtherapy is started, for example by adding a PDI to an existing ETRA. In general, treatment of PAH in patients with connective tissue disease follows the same algorithms as in idiopathic PAH. PMID- 21283971 TI - New aspects of paradoxical embolism. AB - Paradoxical emboli have their origin in the low-pressure venous system and can cause ischemic stroke or peripheral arterial embolism through a cardiac or pulmonary shunt. In most cases, a patent foramen ovale (PFO) is found. About 20 % of the population has a patent foramen ovale. This review gives insight into publications concerning the association between the presence of a patent foramen ovale and cryptogenic stroke; the association of PFO, coagulation disorders and stroke; and recurrence rates of stroke in patients with PFO. Diagnostic features are discussed, as are the different therapy modalities, taking existing national and international guidelines into account. Also, our own recommendations are given. In addition some new information on the potential improvement of migraine after PFO closure is discussed. It is widely accepted that the optimal therapy for the prevention of recurrent stroke in patients with PFO and cryptogenic stroke has not yet been found. Randomized, controlled clinical studies are ongoing in the United States and will give even more insight and answer open questions in the future. PMID- 21283972 TI - Aortic elastic properties are impaired in patients with Graves' ophtalmopathy. AB - BACKGROUND: Aortic elastic properties have been shown to be an important predictor of cardiovascular morbidity and mortality. Hyperthyroidism was shown to be an important cause of impaired aortic elastic properties both due to the direct effect of the thyroid hormones on the aorta and also due to modulating effects of thyroid hormones on the vascular renin angiotensin system. However, there is no study investigating the aortic elastic properties in Graves's patients who were euthyroid. The goal of the present study was to investigate the aortic elastic properties of patients with Graves' Ophtalmopathy (GO) who had been euthyroid for at least 3 months. PATIENTS AND METHODS: A cross-sectional study was performed on 47 GO patients and 27 controls. Aortic-diastolic and aortic-systolic diameters, aortic strain, aortic distensibility, and aortic stiffness indices were calculated from the diameter of the thoracic aorta as measured by transthoracic echocardiography. RESULTS: The aortic stiffness index was markedly increased (31 +/- 26 vs. 17 +/- 8.9; p = 0.015) and aortic strain was markedly reduced (20.3 +/- 10 % vs. 25.9 +/- 12 %; p = 0.046) in the GO group relative to the control group. Aortic distensibility was statistically significantly decreased in the GO group as compared to the control group (9.5 +/- 5.7 10(-3)/kPa vs. 13.5 +/- 7.1 10(-3)/kPa; p = 0.022). Weak correlations were detected between GO severity and aortic distensibility (r = -0.333, p = 0.011) as well as the aortic stiffness index (r = 0.266, p = 0.044). CONCLUSIONS: Aortic elastic properties were impaired in patients with GO. Therefore, patients with GO, especially those with severe manifestations of the condition, should be followed closely with regard to the occurrence of future cardiovascular events. PMID- 21283973 TI - Prevalence and characteristics of atherosclerosis and peripheral arterial disease in a Chinese population of Inner Mongolia. AB - BACKGROUND: To investigate the relationship between brachial ankle pulse wave velocity (BaPWV), radial augmentation index (radial AI), ankle-brachial index (ABI), and carotid intima-media thickness (carotid-IMT), and to study the prevalence and characteristics of atherosclerosis and peripheral arterial disease in a Chinese population of Inner Mongolia. PATIENTS AND METHODS: Participants were recruited from Inner Mongolia in China through cluster multistage and random sampling. BaPWV, radial AI, ABI, and carotid-IMT values were measured in each subject. RESULTS: A total of 1,236 participants from natural population of Inner Mongolia in China were included in this study. The average ABI value was 1.082 +/ 0.093. The average values of common carotid, internal carotid, and carotid artery bifurcation IMT were 0.70 +/- 0.21, 0.77 +/- 0.24, and 0.78 +/- 0.25 mm, respectively. The average value of BaPWV was 1450.5 +/- 301.5 cm/s. The average value of radial AI was 78.9 +/- 16.8 %. BaPWV, radial AI, and carotid-IMT values were positively correlated with ages significantly. BaPWV values were positively correlated with radial AI significantly. BaPWV values were positively correlated with values of common carotid, internal carotid, and carotid artery bifurcation IMT respectively. Radial AI values were positively correlated with the values of common carotid, internal carotid, and carotid artery bifurcation IMT respectively. A U-shaped relationship was observed that radial AI values were decreased at first and then increased as ABI values increased. CONCLUSIONS: The data suggests that BaPWV, radial AI, and carotid-IMT values are positively correlated with each other, and AI values are correlated with ABI values in a U shaped curve in a Chinese population of Inner Mongolia. PMID- 21283974 TI - Budd-Chiari syndrome with fresh inferior vena cava thrombosis: agitation thrombolysis and balloon dilation. AB - BACKGROUND: To evaluate retrospectively our initial clinical experience of agitation thrombolysis and balloon dilation in the treatment of Budd-Chiari syndrome (BCS) in patients with fresh inferior vena cava (IVC) thrombosis. PATIENTS AND METHODS: Between August 2004 and March 2009, a total of 12 BCS patients with fresh IVC thrombosis were treated with agitation thrombolysis and balloon dilation. Color Doppler ultrasound results, as well as mortality, morbidity, and the clinical outcomes were evaluated immediately after the treatment and at one week and 1, 3, 6, 12 months after the procedure and then annually thereafter. RESULTS: Agitation thrombolysis and balloon dilation were technically successful in all patients, without immediate procedural complications. The inferior vena cavagrams after the procedure demonstrated complete resolution of the IVC thrombi without pulmonary embolism and full patency of the obstructed IVC. Thirty-day mortality was nil. Clinical success was observed in all patients respectively one month after the procedure. As of February 2010, the mean (+/- SD) follow-up period for the color Doppler ultrasound procedure was 21.7 +/- 8.9 months (range, 12 - 32 months). All patients showed complete patency of the treated IVC without thrombosis, restenosis, or reobstruction, and all patients are alive with resolution of the symptoms at the time of this report. CONCLUSIONS: Our preliminary results suggest that agitation thrombolysis and balloon dilation may be a feasible approach for patients with BCS and fresh IVC thrombosis. However, larger studies are warranted to confirm these results. PMID- 21283975 TI - Giant coronary sinus and absent right superior vena cava. AB - Although persistent left superior vena cava (PLSVC) is rare, it is the most common thoracic venous anomaly. The prevalence of PLSVC is 0.3 % in a general population and 10 % in patients with congenital heart disease. Diagnosis of PLSVC is usually incidental during cardiovascular imaging or surgery. Although PLSVC is usually not associated with any negative hemodynamic effect, it is important to be aware of its existence, since it may cause problems in central venous catheterization, pacemaker implantation and cardiopulmonary bypass. The overall proportion of absent right superior vena cava in patients with PLSVC is approximately 20 %. If PLSVC is associated with absence of the right superior vena cava, the coronary sinus may become gigantic due to excessive inflow. Herein, we report a case of PLSVC complicated by the absence of a right superior vena cava resulting in a giant coronary sinus. PMID- 21283976 TI - Successful surgical management of a recurrent leiomyosarcoma of the inferior vena cava. AB - The leiomyosarcoma of the inferior vena cava (IVC) is a rare malignant tumour of the venous system. The recurrence of the tumour after previous initial surgical resection is common and occurs in more than half of the patients. Surgical resection of a local recurrence is poorly described in the literature and the available data are restricted to a small number of cases. We report the case of a 62 year old woman, who was referred to our vascular surgical unit for recurrence of a leiomyosarcoma of the inferior vena cava, 35 months after diagnosis and initial surgical treatment. We performed an extensive local resection and circumferencial replacement of the IVC. 18 months after the second operation and adjuvant radiotherapy, the patient is in a very good physical condition and CT scans show no evidence of tumour recurrence. PMID- 21283977 TI - Rupture prone aneurysm of the inferior mesenteric artery complicated by mid aortic syndrome with occluded celiac and superior mesenteric arteries. AB - We present the case of a 45-year-old male patient with a large aneurysm of the inferior mesenteric artery complicated by mid aortic syndrome with occlusion of the celiac trunk and superior mesenteric artery. The vascular pathology was detected by CT imaging after presentation and hospitalization with symptoms of acute cholecystitis. After resolve of the acute symptoms, the aneurysm was resected and the proximal inferior mesenteric artery interponated with a reversed saphenous vein bypass graft. Besides presenting this case we review the literature concerning the rare descriptions of inferior mesenteric artery aneurysms. PMID- 21283978 TI - Ultrasound guided thrombin injection of pseudoaneurysm of the radial artery after percutaneous coronary intervention. AB - Thrombin injection is frequently used to occlude iatrogenic pseudoaneurysms in larger vessels, but has never successfully been used in the radial artery location. Here we report the use of this treatment in a patient with radial artery pseudoaneurysm following coronary intervention. After Doppler sonographic visualization of the pseudoaneurysm cavity and its neck, an ultrasound-guided transcutaneous injection of thrombin was carried out. Immediately after the injection, the pseudoaneurysm was completely clotted and Doppler measurement confirmed the stop of blood flow. The result suggests that ultrasound-guided injection of thrombin into a radial artery pseudoaneurysm following coronary intervention is a feasible alternative to surgical intervention. PMID- 21283979 TI - Clinical significance of calcified carotid artery atheromas on orthopantomograms. PMID- 21283981 TI - Randomized clinical trial of endovenous laser ablation compared with conventional surgery for great saphenous varicose veins. AB - BACKGROUND: Endovenous laser ablation (EVLA) is a popular minimally invasive treatment for varicose veins. Surgical treatment, featuring junctional ligation and inversion stripping, has shown excellent clinical and cost effectiveness. The clinical effectiveness of both treatments was compared within a randomized trial. METHODS: Some 280 patients were randomized equally into groups receiving either surgery or EVLA. Participants had primary, symptomatic, unilateral venous insufficiency, with isolated saphenofemoral junction incompetence, leading to reflux into the great saphenous vein. Outcomes included: quality of life (QoL), Venous Clinical Severity Score (VCSS), pain scores and time taken to return to normal function. Owing to the nature of the procedures, blinding was not possible. RESULTS: Both groups had significant improvements in VCSS after treatment (P < 0.001), which resulted in improved disease-specific QoL (Aberdeen Varicose Vein Questionnaire, P < 0.001) and quality-adjusted life year (QALY) gain (P < 0.001). The pain and disability following surgery impaired normal function, with a significant decline in five of eight Short Form 36 (SF-36((r))) domains (P < 0.001 to P = 0.029). Periprocedural QoL was relatively preserved following EVLA, leading to a significant difference between the two treatments in pain scores (P < 0.001), six of eight SF-36((r)) domains (P = 0.004 to P = 0.049) and QALYs (P = 0.003). As a result, surgical patients took longer to return to work and normal activity (14 versus 4 days; P < 0.001). Complications were rare. CONCLUSION: EVLA was as effective as surgery for varicose veins, but had a less negative impact on early postintervention QoL. REGISTRATION NUMBER: NCT00759434 (http://www.clinicaltrials.gov). PMID- 21283982 TI - Pulmonary toxicity related to systemic treatment of nonsmall cell lung cancer. AB - Physicians who are responsible for the delivery of systemic treatment in lung cancer should be aware of the potential risk of drug-induced pulmonary toxicity (DIPT), because such toxicity may develop in the context of a multifactorial clinical condition. First, most patients with lung cancer may suffer from other non-neoplastic, smoking-related lung diseases, such as emphysema and chronic obstructive lung disease, which may generate pathologic changes in lung parenchyma. In addition, lung cancer itself may worsen the respiratory function, inducing atelectasis and lymphangitic carcinomatosis. The superimposed iatrogenic damage may lead to respiratory failure and, sometimes, death. The risk of DIPT from chemotherapeutic agents has been widely examined in the past; and, currently, the potential for lung toxicity has been extended by the introduction of molecular targeted therapies. Because there are no univocal criteria with which to recognize DIPT, the diagnosis often is made by exclusion; consequently, it is hard to establish an early diagnosis. The objective of this review was to describe the major DIPTs associated with antineoplastic agents against nonsmall cell lung cancer to help physicians with this difficult diagnostic challenge. PMID- 21283983 TI - Tissue binding affects the kinetics of theophylline diffusion through the stratum corneum barrier layer of skin. AB - New data sets on both (i) equilibrium theophylline (TH) partitioning/binding in stratum corneum and (ii) transient TH diffusion through human epidermis are explained by an extended partition-diffusion model with reversible binding. Data conform to a linear binding isotherm within the tested concentration range (0 2000 MUg/mL) with an equilibrium ratio of bound-to-free solute of approximately 1.4. The permeability coefficient for TH is 4.86 * 10(-5) cm/h, and the lag time is 20.1 h. Binding occurs as a slow process, significantly affecting the kinetics of dermal penetration. PMID- 21283984 TI - The pharmacokinetics and pharmacological effect of (S)-5-OH-DPAT following controlled delivery with transdermal iontophoresis. AB - The pharmacokinetic (PK) and pharmacodynamic (PD) properties of the active (S) enantiomer of the potent dopamine (DA) agonist 5-hydroxy-2-(N,N,-di-n propylamino)tetralin (5-OH-DPAT) were investigated in a novel anesthetized animal model. First, the relationship between current density, in vivo transport, and plasma profile was characterized. Second, the effect of the anesthetic mixture, transdermal iontophoresis, and blood sampling on the striatal DA release (PD end point) was investigated. Third, the PK-PD relationship following transdermal iontophoresis was investigated during a controlled reversible pharmacological response. Given that striatal DA levels are unaltered during experimental procedures, this rat model can be used to investigate the PK-PD relationship. The in vivo flux was linearly correlated with the current density, indicating that drug delivery can be titrated by the current density. Following transdermal iontophoresis and intravenous infusion, a strong reversible effect was observed. Compartmental modeling showed that the relationship between plasma concentration and biomarker response is best characterized by an effect compartment, rather than an indirect response model. In addition, covariate analysis suggested that the delivery rate can affect the PD efficiency. Finally, PK-PD analysis revealed that steady delivery rates are translated into continuous dopaminergic stimulation. This can be of benefit for reducing side effects in the symptomatic treatment of Parkinson's disease with 5-OH-DPAT. PMID- 21283985 TI - Mannitol delivery by vibrating mesh nebulisation for enhancing mucociliary clearance. AB - Mucociliary clearance is compromised by airway surface liquid dehydration in respiratory disease states such as cystic fibrosis. Rehydration by hyperosmolar agents such as nebulised hypertonic saline and dry powder mannitol has demonstrated in vivo safety and efficacy for restoring mucociliary function. Mannitol, delivered as a nebulised formulation for this purpose, has not been investigated as yet. The current study examines the feasibility of delivering such a formulation using recent vibrating mesh technology. Nebulisation was conducted using an Aeroneb Go(TM) vibrating mesh nebuliser, and aerosol size was assessed by laser diffraction. Cascade impaction coupled with mass assay by high performance liquid chromatography was used to confirm fluid uniformity and correlation with laser diffraction sizing. The following nebuliser formulations were prepared and aerosolised: deionised water, mannitol (150 mg/mL) aqueous solution, sodium chloride aqueous solution [0.2%, 1%, 3%, 5%, 7% (w/v)] and mannitol (150 mg/mL) in sodium chloride solution [0.2%, 1%, 3%, 7% (w/v)]. Mannitol aqueous solution was poorly nebulised, resulting in lengthy treatment times and large median droplet size. Addition of sodium chloride drastically improved nebuliser performance and aerosol characteristics. In vivo studies are necessary to confirm efficacy of nebulised mannitol. If substantiated, it could provide a pleasant-tasting alternative mucoactive agent with prolonged therapeutic action. PMID- 21283986 TI - Local drug delivery system: inhibition of inflammatory angiogenesis in a murine sponge model by dexamethasone-loaded polyurethane implants. AB - Implants are defined as controlled sustained release delivery systems of therapeutic agents incorporated or dispersed into a polymeric carrier. These systems can be implanted in specific organs and delivered by the therapeutic agents at the target site to treat various pathological processes. In the present study, the effects of dexamethasone-loaded polyurethane implants [PU ACT (dexamethasone acetate) implants] on inflammatory angiogenesis in a murine sponge model were investigated. PU ACT implants were inserted into nonbiocompatible sponges, used as a framework for fibrovascular tissue growth, and implanted into subcutaneous tissue located on the back of mice. After 7 days of implantation, the implant system was collected and processed for the assessment of hemoglobin (Hb; vascular index), myeloperoxidase (MPO), and N-acetyl-beta-D-glucosaminidase (NAG; inflammatory enzymes activities) and collagen content. ACT released from the polymeric implants provided a significant decrease in the neovascularization in the sponge (Hb content). PU ACT implants provided no effects on neutrophil infiltration (MPO activity) but macrophage recruitment was affected by the glucocorticoid delivered by implants (NAG activity). ACT released from implants was able to reduce the collagen deposition. The qualitative histological findings corroborated with the measured biochemical parameters. These local drug delivery systems derived from polyurethane efficiently modulated the key components of inflammation, angiogenesis, and fibrosis induced by sponge discs in an experimental animal model. PMID- 21283987 TI - Effect of cyclodextrin derivation and amorphous state of complex on accelerated degradation of ziprasidone. AB - Inclusion complexes of ziprasidone with several beta-cyclodextrins [beta-CDs; sulfobutylether-beta-cyclodextrins (SBEbetaCD), hydroxypropyl-beta-cyclodextrins (HPbetaCD), methyl-beta-cyclodextrins (MbetaCD), and carboxyethyl-beta cyclodextrins (CEbetaCD)] were prepared and solution stability was evaluated at elevated temperature. Solid-state stability was assessed by subjecting various CD complexes of ziprasidone, spray-dried dispersion (SDD), partially crystalline ziprasidone-SBEbetaCD salts, and the physical mixture of ziprasidone-SBEbetaCD to gamma-irradiation. Degradant I was formed by oxidation of ziprasidone, which upon aldol condensation with ziprasidone formed degradant II in both solution and solid states. In the solution state, CD complexes with electron-donating side chains, such as SBEbetaCD and CEbetaCD, produced the highest oxidative degradation followed by HPbetaCD with 6, 3, and 4 degrees of substitution. In the solid state, crystalline drug substance and physical mixture of crystalline drug SBEbetaCD showed very little to no degradation. In contrast, amorphous betaCD, MbetaCD, CEbetaCD, and SBEbetaCD complexes as well as the amorphous SDD exhibited greatest extent of oxidative degradation. Results suggest that electron-donating side chains of the derivatized CD interact with transition state of the oxidation reaction and catalyze drug degradation in solution, However, higher mobility in the amorphous state of CD-drug complexes promoted chemical instability of ziprasidone under accelerated conditions irrespective of the chemical nature of the side chain on CD. PMID- 21283988 TI - Permeation and systemic absorption of R- and S-baclofen across the nasal mucosa. AB - Baclofen, an antispasmodic agent that acts as a GABA(B) agonist, resembles phenylalanine in structure and has been reported to be a substrate of the large amino acid transporter 1 (LAT-1). The objective of this study was to investigate the absorption of baclofen across the nasal mucosa both in vitro and in vivo. Baclofen transport was measured across excised bovine olfactory and respiratory mucosae to investigate site-specific uptake of baclofen, and the intranasal bioavailability of R- and S-baclofen was determined in rats. Increasing flux with increasing baclofen donor concentration and the absence of polarized transport was observed in vitro, and similar distribution profiles were observed for both enantiomers following intranasal administration in rats. The absence of stereospecificity in nasal absorption indicates limited involvement of the amino acid or other transporters in the nasal absorption of baclofen. PMID- 21283989 TI - Preparation, characterisation and entrapment of a non-glycosidic threitol ceramide into liposomes for presentation to invariant natural killer T cells. AB - Dendritic cells (DCs) are able to present glycolipids to invariant natural killer T (iNKT) cells in vivo. Very few compounds have been found to stimulate iNKT cells, and of these, the best characterised is the glycolipid alpha galactosylceramide, which stimulates the production of large quantities of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4). However, alphaGalCer leads to overstimulation of iNKT cells. It has been demonstrated that the alphaGalCer analogue, threitol ceramide (ThrCer 2), successfully activates iNKT cells and overcomes the problematic iNKT cell activation-induced anergy. In this study, ThrCer 2 has been inserted into the bilayers of liposomes composed of a neutral lipid, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), or dimethyldioctadecylammonium bromide (DDA), a cationic lipid. Incorporation efficiencies of ThrCer within the liposomes was 96% for DSPC liposomes and 80% for DDA liposomes, with the vesicle size (large multilamellar vs. small unilamellar vesicles) making no significant difference. Langmuir-Blodgett studies suggest that both DSPC and DDA stack within the monolayer co-operatively with the ThrCer molecules with no condensing effect. In terms of cellular responses, IFN gamma secretion was higher for cells treated with small DDA liposomes compared with the other liposome formulations, suggesting that ThrCer encapsulation in this liposome formulation resulted in a higher uptake by DCs. PMID- 21283990 TI - Diffuse malignant peritoneal mesothelioma: systematic review of clinical management and biological research. AB - Diffuse malignant peritoneal mesothelioma (DMPM) is an uncommon and locally aggressive tumor with poor prognosis. Currently, no standard therapy is available. The biology of this disease is still poorly understood. We performed a systematic search of relevant studies on clinical management and biological research of DMPM. Trials were selected using a predetermined protocol. The current evidence suggests that cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy (PIC) results in improved survival. Biological understanding of DMPM is currently evolving. PMID- 21283991 TI - The concepts in poorly differentiated carcinoma of the thyroid: a review article. AB - Poorly differentiated carcinomas of the thyroid have evolved over the past half century into a specific entity in the classification of thyroid carcinomas. The need for a consensus diagnostic criteria has been stressed in view of the wide discrepancies and confusion among pathologists and clinicians. This review attempts to understand the concept, the evolution, clarity and validity of the concepts in poorly differentiated carcinomas of the thyroid. PMID- 21283992 TI - Diagnosis and treatment of hepatic angiomyolipoma. AB - BACKGROUND AND OBJECTIVE: Hepatic angiomyolipoma is more frequently encountered in clinical practice, its diagnosis is difficult, its treatment remains controversial. We review a single-center experience in the treatment of hepatic angiomyolipoma. METHOD: The clinical data of 79 patients with hepatic angiomyolipoma treated at the authors' institute between January 1992 and December 2006 were retrospectively reviewed. RESULTS: During a period of 15 years, a total of 79 patients with hepatic angiomyolipoma underwent liver resection at our hospital. There are 58 women and 21 men. The tumor size varied from 1 to 25 cm in diameter (6.1 +/- 4.08). Fifty-four patients (68%) were asymptomatic. Accurate preoperative diagnosis was made in 41 patients (52%). Tumors less than 6 cm in size were more frequently misdiagnosed. Spontaneous rupture occurred in one patient. One patient had tumor recurrence 6 years after the surgery, and died of the disease 1 year later. Symptom relief was achieved in 92% of the symptomatic patients. Median survival was 90 months (90.12 +/- 30.84). CONCLUSIONS: Hepatic angiomyolipoma poses a diagnostic challenge clinically and radiologically. Surgical resection is a safe and effective treatment option. It is important to realize the potential of malignant transformation and risk of rupture as life-threatening complications. PMID- 21283993 TI - Assessment of lymphatic drainage patterns and implications for the extent of neck dissection in head and neck melanoma patients. AB - BACKGROUND AND OBJECTIVES: The aim of this study is to evaluate lymphatic drainage with sentinel node location data in patients with head and neck cutaneous melanoma, and to determine the implications for the extent of therapeutic neck dissections. METHODS: Sixty-five patients with head and neck cutaneous melanoma without evidence of regional metastases at ultrasound guided fine needle aspiration cytology examination were included. Lymphatic drainage patterns were investigated using planar and dynamic lymphoscintigraphy, and SPECT/CT. Biopsy of sentinel nodes was guided by images and gamma probe. The incidence of discordant sentinel nodes was determined by comparing actual drainage patterns to "O'Briens map" and to the treatment guidelines of The Netherlands Cancer Institute. RESULTS: Sentinel node identification was successful in 98% of the patients. Fifteen patients (23%) were diagnosed with a tumor-positive sentinel node. Two sentinel node-negative patients (3%) developed a regional lymph node metastasis (false-negative ratio: 12%). Twenty-three percent of the harvested sentinel nodes were discordant according to "O'Brien's map," while 14% were discordant according to the treatment guidelines of The Netherlands Cancer Institute (P < 0.001). CONCLUSIONS: Almost a quarter of head and neck melanomas metastasize outside clinically predicted neck levels. Neck surgery guidelines of The Netherlands Cancer Institute provide for a smaller number of discordant sentinel nodes. PMID- 21283994 TI - Re-evaluating the impact of tumor size on survival following pancreaticoduodenectomy for pancreatic adenocarcinoma. AB - BACKGROUND AND OBJECTIVES: Following resection of pancreatic adenocarcinoma, tumor size has been considered a key prognostic feature; however, this remains controversial. We sought to examine the association of size with outcomes following resection of pancreatic adenocarcinoma. METHODS: Between 1970 and 2010, 1,697 patients with pancreatic adenocarcinoma at the Johns Hopkins Hospital underwent curative intent pancreaticoduodenectomy. Prognostic factors were identified by univariate and multivariate analyses. RESULTS: Of 1,697 patients, tumor size was <= 2 cm in 418 (24.6%) patients, 2-5 cm in 1,070 (63.1%) patients, and >= 5 cm in 209 (12.3%) patients. On univariate analyses, 5-year survival was inversely proportional to tumor size (<= 2 cm: 28.8% vs. 2-5 cm: 19.4% vs. >= 5 cm: 14.2%; P < 0.001). Size correlated with the risk of other adverse factors, with larger tumors being more likely to be associated with nodal disease and poor differentiation (both P < 0.05). On multivariate analysis, the 2 cm cut-off was not associated with survival, while nodal disease (HR = 1.59; P = 0.006) and poor differentiation (HR = 1.59; P = 0.04) remained predictive of outcome, regardless of size. CONCLUSION: The cut-off value of 2 cm is not independently associated with outcome, however, tumor size was strongly associated with the risk of other adverse prognostic factors. The effect of size on prognosis was largely attributable to these other biologic factors rather than tumor size itself. PMID- 21283995 TI - Sonographic diagnosis of tumor thrombus formation in the umbilical vein: a case report. AB - There are few reports of tumor thrombus formation in the umbilical vein. We report a case in which sonographic examination revealed tumor thrombus formation in the reopened umbilical vein in a patient with hepatic cirrhosis, primary liver cancer, and portal hypertension. PMID- 21283996 TI - Analysis of achilles tendon vascularity with second-generation contrast-enhanced ultrasound. AB - PURPOSE: To compare morphological, power Doppler, and contrast-enhanced ultrasound (CEUS) features of the Achilles tendon between asymptomatic athletes and athletes who had undergone surgical repair of a previous rupture. METHODS: Twenty-four athletes were divided in two groups (A and B). Group A included 14 patients with a median age of 32 years (range 27 to 47 years) who had undergone surgical repair for unilateral Achilles tendon rupture. Group B (control group) included 10 subjects with a median age of 34 years (range 27 to 40 years) with no previous or present history of tendinopathy. All patients were evaluated with ultrasound, power Doppler, and CEUS with second-generation contrast agent. We studied the uninjured Achilles tendon in athletes of group A and either the left or the right Achilles tendon of the athletes in group B. RESULTS: CEUS showed a significantly greater ability to detect a greater number of vascular spots within the uninjured tendon of group A compared to group B (<0.05). CONCLUSIONS: In athletes who had suffered a tear of an Achilles tendon, CEUS detected small vessels that were not identified by power Doppler ultrasound in the uninjured contralateral Achilles tendon. CEUS is useful to evaluate vascularity not detected by other imaging techniques. Vascularity in the uninjured tendon seems to be increased in patients who had a previous rupture. PMID- 21283997 TI - The influence of adult behaviors on child coping during venipuncture: a sequential analysis. AB - The aim of this exploratory study was to investigate the influences of adult behaviors on child coping behaviors during venipunctures (VPs) in an emergency department. Observations of children and adults from 66 VPs were coded using a modified version of the Child-Adult Medical Procedure Interaction Scale and analyzed using sequential analysis. Results showed adult reassurance behavior promoted child distress behaviors, such as crying, as well as nondistress behaviors, such as information seeking; adult distraction behaviors promoted children's distraction, control, and coping behaviors; and children frequently ignored adult behaviors. Findings suggest further exploration of children's internal strategies for coping, such as appraisal, and clarifying the role of adult reassurance in child coping behaviors. PMID- 21283998 TI - Role of age, sex, and race on cardiac and total mortality associated with Super Bowl wins and losses. AB - BACKGROUND: Total and cardiac mortality rates in Los Angeles County, California, increased after the 1980 Super Bowl loss (SBL), but there was an overall reduction in total mortality after the 1984 Super Bowl win (SBW). HYPOTHESIS: We hypothesized that age, sex, and race may have played a role in the Super Bowl related differences in death rates. METHODS: We compared mortality rates for SB related days with non-SB control days assessing differences in demographics. We ran regression models predicting daily death rates per 100,000 including SB variable versus non-SB control days for age, sex, race, and interactions for these covariates. RESULTS: After the SBL, daily death rates increased for both males and females. People aged >=65 years had a larger absolute increase in all cause mortality during the SBL days compared with those aged <65 years, with significant interaction between age and SBL-variable for all-cause and cardiac related mortality. Whites and Hispanics had increased death rates on SBL days. There were trends suggesting less death in older patients and females associated with the SBW. CONCLUSION: A SBL triggered increased deaths in both men and women and especially in older patients, whereas a SBW reduced death more in those aged >=65 years and in women. PMID- 21283999 TI - Composition-induced structural transitions in mixed Lennard-Jones clusters: global reparametrization and optimization. AB - As extended benchmarks to global cluster structure optimization methods, we provide a first systematic point of entry into the world of strongly mixed rare gas clusters. A new set of generalized Lennard-Jones pair potentials is generated for this purpose, by fitting them to high-end ab initio reference data. Employing these potentials in our genetic algorithm-based global structure optimization framework, we examined various systems from binary to quinary mixtures of atom types. A central result from this study is that the famous fcc structure for 38 atoms can survive for certain binary mixtures but appears to be prone to collapsing into the dominating icosahedral structure, which we observed upon introduction of one single atom of a ternary type. PMID- 21284000 TI - Consideration of data load time on modern processors for the Verlet table and linked-cell algorithms. AB - Neighbor search algorithms are widely used in molecular dynamics for the direct computation of short-range pairwise interatomic potentials. These algorithms are based on the Verlet table (VT) and linked-cell (LC) methods. It is widely believed that the VT is more efficient than the LC. The analysis of these methods shows that in case when the average number of interactions per particle is relatively large, or more specifically, the particle density rho and skin radius r(skin) meet the condition (4pi/6)rhor (skin)3/27 ? 1, which may be true for most simulations of liquids, the number of memory data load operations in the LC is much less than that in the VT. Because memory access on modern processors is a bottleneck, this advantage of the LC should be and was in fact used, and a code outperforming the VT by a factor of almost 2 was obtained. Some modifications of the VT were proposed to reduce its disadvantage concerning memory data loading. The key modifications included automated skin radius tuning during simulations and compression of the VT to minimize duplications of atom identifiers in its nearby rows. Although these modifications had improved the performance, the VT failed to regain the superiority over the LC. The methods were tested in the MOLKERN simulation software by using SIMD and multithreading. PMID- 21284001 TI - Bringing about matrix sparsity in linear-scaling electronic structure calculations. AB - The performance of linear-scaling electronic structure calculations depends critically on matrix sparsity. This article gives an overview of different strategies for removal of small matrix elements, with emphasis on schemes that allow for rigorous control of errors. In particular, a novel scheme is proposed that has significantly smaller computational overhead compared with the Euclidean norm-based truncation scheme of Rubensson et al. (J Comput Chem 2009, 30, 974) while still achieving the desired asymptotic behavior required for linear scaling. Small matrix elements are removed while ensuring that the Euclidean norm of the error matrix stays below a desired value, so that the resulting error in the occupied subspace can be controlled. The efficiency of the new scheme is investigated in benchmark calculations for water clusters including up to 6523 water molecules. Furthermore, the foundation of matrix sparsity is investigated. This includes a study of the decay of matrix element magnitude with distance between basis function centers for different molecular systems and different methods. The studied methods include Hartree-Fock and density functional theory using both pure and hybrid functionals. The relation between band gap and decay properties of the density matrix is also discussed. PMID- 21284002 TI - Sensitivity analysis and uncertainty calculation for dispersion corrected density functional theory. AB - The precision of binding energies and distances computed with dispersion corrected density functional theory (DFT-D) is investigated by propagation of uncertainties, yielding relative uncertainties of several percent. Sensitivity analysis is used to calculate the geometry-dependent relative importance of each input parameter for the dispersion correction. While DFT-Ds are exact at asymptotically large distances, their damping functions are shown to play a significant role in binding geometries. This is demonstrated in detail for the interlayer binding of graphite. The techniques presented allow practitioners to quickly compute error bars and to get an a posteriori estimate about the transferability of their results. They can also aid the development of future dispersion corrections. PMID- 21284003 TI - Analyzing the robustness of the MM/PBSA free energy calculation method: application to DNA conformational transitions. AB - The ability to predict and characterize free energy differences associated with conformational equilibria or the binding of biomolecules is vital to understanding the molecular basis of many important biological functions. As biological studies focus on larger molecular complexes and properties of the genome, proteome, and interactome, the development and characterization of efficient methods for calculating free energy becomes increasingly essential. The aim of this study is to examine the robustness of the end-point free energy method termed the molecular mechanics Poisson-Boltzmann solvent accessible surface area (MM/PBSA) method. Specifically, applications of MM/PBSA to the conformational equilibria of nucleic acid (NA) systems are explored. This is achieved by comparing A to B form DNA conformational free energy differences calculated using MM/PBSA with corresponding free energy differences determined with a more rigorous and time-consuming umbrella sampling algorithm. In addition, the robustness of NA MM/PBSA calculations is also evaluated in terms of the sensitivity towards the choice of force field and the choice of solvent model used during conformational sampling. MM/PBSA calculations of the free energy difference between A-form and B-form DNA are shown to be in very close agreement with the PMF result determined using an umbrella sampling approach. Further, it is found that the MM/PBSA conformational free energy differences were also in agreement using either the CHARMM or AMBER force field. The influence of ionic strength on conformational stability was particularly insensitive to the choice of force field. Finally, it is also shown that the use of a generalized Born implicit solvent during conformational sampling results in free energy estimates that deviate slightly from those obtained using explicitly solvated MD simulations in these NA systems. PMID- 21284004 TI - Electron localization function and electron localizability indicator applied to study the bonding in the peroxynitrous acid HOONO. AB - The ground-state electronic structure of peroxynitrous acid (HOONO) and its singlet biradicaloid form (HO...ONO) have been studied using topological analysis of the electron localization function (ELF), together with the electron localizability indicator (ELI-D), at the DFT (B3LYP, M05, M052X, and M06), CCSD, and CASSCF levels. Three isomers of HOONO (cis-cis, cis-perp, and trans-perp) have been considered. The results show that from all functionals applied, only B3LYP yields the correct geometrical structure. The ELF and ELI-D-topology of the O-O and central N-O bonds strongly depends on the wave function used for analysis. Calculations carried out at CAS (14,12)/aug-cc-pVTZ//CCSD(T)/aug-cc pVTZ level reveal two bonds of the charge-shift type: a protocovalent N?O bond with a basin population of 0.82-1.08e, and a more electron depleted O-O bond with a population of 0.66-0.71e. The most favorable dissociation channel (HOONO -> HO + ONO) corresponds to breaking of the most electron-deficient bond (O?O). In the case of cis- and trans-HO...ONO, the ELF, ELI-D, and electron density fields results demonstrate a closed-shell O...O interaction. The alpha-spin electrons are found mainly (0.64e) in the lone pairs of oxygen V(i) (= 1,2)(O) from the OH group. The beta-spin electrons are delocalized over the ONO group, with the largest concentration (0.34e) on the lone pair of nitrogen V(N). PMID- 21284005 TI - Conformational searching using a population-based incremental learning algorithm. AB - A new population-based incremental learning algorithm for conformational searching of molecules is presented. This algorithm is particularly effective at determining, by relatively small number of energy minimizations, global energy minima of large flexible molecules. The algorithm is also able to find a large set of low energy conformations of more rigid small molecules. The performance of the algorithm is relation to other algorithm is examined via the test molecules: C(18) H(38) , C(39)H(80) , cycloheptadecane and a set of five drug-like molecules. PMID- 21284006 TI - Theoretical investigation of novel carbazole-fluorene based D-pi-A conjugated organic dyes as dye-sensitizer in dye-sensitized solar cells (DSCs). AB - The ground state structure and frontier molecular orbital of newly synthesized carbazole-fluorene based D-pi-A organic dyes, CFP1A, CFP2A, CFP1CA, and CFP2CA, were theoretically investigated using density functional theory (DFT) at B3LYP/6 31G(d,p) level. These dye molecules have been constructed based on carbazole fluorene as the electron-donating moiety while introducing benzene units as pi spacer connected to different anchor groups, such as acrylic acid and cyanoacrylic acid, as acceptors. The electronic vertical excitation energies and absorption wavelength were carried out using time-dependent DFT (TD-DFT). Furthermore, the adsorptions of phenylacrylic acid and phenylcyanoacrylic acid on the TiO(2) anatase (101) surface were carried out by means of quantum-chemical periodic calculations employing periodic PBE functional with DNP basis set. The results promise that anchor dyes with strong withdrawing CN group have easier injected electron to the conduction band of semiconductor implying that CFP1CA and CFP2CA show better performance among four dyes. Additionally, the intramolecular charge transfers (ICT) from electron donor group to anchoring group of CFP1CA and CFP2CA have shown better performance. The calculated results provide the efficiency trend of our new dyes as CFP1CA ~ CFP2CA > CFP1A ~ CFP2A which are excellently agree with experimental observation. PMID- 21284007 TI - Extensive theoretical study on electronically excited states and predissociation mechanisms of sulfur monoxide including spin-orbit coupling. AB - The potential energy curves of the 69 Omega states generated from the 24 Lambda-S states of sulfur monoxide are calculated for the first time using the internally contracted multireference configuration interaction method with the Davidson correction and the entirely uncontracted aug-cc-pV5Z basis set. Spin-orbit coupling is taken into account by the state interaction approach with the full Breit-Pauli Hamiltonian. Very good agreement is achieved between our computed spectroscopic properties and the available experimental data. The transition properties of the B(3)Sigma(-) -X(3)Sigma(-) and (4)1-X0(+) transitions are predicted, and our computed Franck-Condon factors and radiative lifetimes match the experimental results very well. The predissociation mechanisms are investigated, and various new predissociation channels are located. We present a new interpretation on the breaking-off of the rotational levels of the B(3)Sigma( ) lower vibrational states observed in experiment, and propose that the predissociation is induced by the Coriolis coupling between the B(3)Sigma(-) rovibrational levels and the A(3)Pi state. Our calculations indicate that, at nu' = 9, the B(3)Sigma(-) state predissociates via the C(3)Pi state; around nu' = 14, three spin-orbit-induced predissociation pathways via (1)(5)Sigma(+) , (2)(5)Pi, and e(1)Pi would be open; around nu' = 17, the pathways via (2)(1)Sigma(+) , (2)(3)Sigma(+) and (2)(5)Sigma(+) would contribute. These satisfactorily explain the experimental results about the diffuseness of the B(3)Sigma(-) bands. Furthermore, various predissociation pathways of the C'(3)Pi state are predicted, through which the C'(3)Pi state could predissociate rapidly. PMID- 21284008 TI - Assessment of occupational exposure to extremely low frequency magnetic fields in hospital personnel. AB - It has been proposed that chronic exposure to extremely low frequency (ELF) magnetic fields (MF) in occupational environments could represent a risk factor for a number of disorders. Medical and technical workers in hospitals have been reported to be exposed to relatively strong ELF fields. The present work aims to characterize exposure to MF in the 5 Hz to 2 kHz frequency range in a large hospital through both instantaneous environmental measurements and personal monitoring of workers. The study was conducted in different working environments of a hospital with about 4400 employees, many of them working at two or more different work stations and consequently, exposed to MF levels that were expected to be unevenly distributed in space and time. The results indicate that: (1) The dominant frequency at the studied environments was 50 Hz (average 90.8 +/- 6% of the total B value); (2) The best descriptive information on a worker's exposure is obtained from personal monitoring of volunteer workers; (3) The arithmetic averages of exposure levels obtained from the monitoring ranged from 0.03 +/- 0.01 uT in nurses to 0.39 +/- 0.13 uT in physiotherapists; and (4) The description of the MF environment through spot measurements in the workplace, although coherent with the data from personal monitoring, might not adequately estimate MF exposure in some professional categories. PMID- 21284009 TI - Dielectric properties of human skin at an acupuncture point in the 50-75 GHz frequency range: a pilot study. AB - The reason for using acupuncture points as exposure sites in some applications of millimeter wave therapy has been unclear. Acupuncture points have been suspected to exhibit particular direct current (DC), low-frequency electrical and optical properties compared to surrounding skin. To assess if such a biophysical correlation could exist at millimeter wave frequencies used in the therapy, we investigated the dielectric properties of an acupuncture point on the forearm skin within the 50-75 GHz range. These properties were compared with those of a neighboring ipsilateral control area and a corresponding contralateral control area. The complex reflection coefficient at the end of an open-ended rectangular waveguide loaded with a Teflon plug was measured with a vector network analyzer. A suitable model of the aperture admittance was used to calculate the dielectric properties of the skin at the measured spots. Statistical analyses were conducted with an ANOVA to compare the three sites. From these analyses, the dielectric properties of the acupuncture site were found to be somewhat different from those of surrounding non-acupuncture sites from 50 to about 61 GHz, in the case of the real part of the complex permittivity. PMID- 21284010 TI - Endoplasmic reticulum dynamics in hippocampal dendritic spines induced by agonists of type I metabotropic glutamate but not by muscarinic acetylcholine receptors. AB - Neurons in the hippocampus exhibit subpopulations of dendritic spines that contain endoplasmic reticulum (ER). ER in spines is important for synaptic activity and its associated Ca(2+) signaling. The dynamic distribution of ER to spines is regulated by diacylglycerol and partly mediated by protein kinase C, metalloproteinases and gamma-secretase. In this study, we explored whether pharmacological activation of type I metabotropic glutamate receptors (mGluRs) and muscarinic acetylcholine receptors (mAChRs) known to activate phospholipase C would have any effect on spine ER content. We found that DHPG (100 MUM) but not carbachol (10 MUM) caused a reduction in the number of spines with ER. We further found that ER Ca(2+) depletion triggered by thapsigargin (200 nM) had no effect on ER localization in spines. PMID- 21284011 TI - Assessment of joint symmetry in arthritis. AB - We evaluate three methods for the assessment of symmetry in the joints affected by an arthritic disease. The first two methods, based on published methodology, are limited by their assumptions. We introduce a third method that enables a more comprehensive investigation. In common with previous methods, this method examines tabulations of observed data for evidence of symmetry. Expected values for the table cells are simulated under an assumption of independent joint disease, whilst allowing for differences between patients, and joint locations, in terms of their susceptibility to disease symptoms. Departures of observed from expected values are assessed via a Pearson-type goodness-of-fit test and are examined for consistency with symmetry. We illustrate the three methods using data on the damage accrued in the hand joints of patients registered at the University of Toronto Psoriatic Arthritis clinic. PMID- 21284012 TI - Modelling the rate of change in a longitudinal study with missing data, adjusting for contact attempts. AB - The Collaborative Ankle Support Trial (CAST) is a longitudinal trial of treatments for severe ankle sprains in which interest lies in the rate of improvement, the effectiveness of reminders and potentially informative missingness. A model is proposed for continuous longitudinal data with non ignorable or informative missingness, taking into account the nature of attempts made to contact initial non-responders. The model combines a non-linear mixed model for the outcome model with logistic regression models for the reminder processes. A sensitivity analysis is used to contrast this model with the traditional selection model, where we adjust for missingness by modelling the missingness process. The conclusions that recovery is slower, and less satisfactory with age and more rapid with below knee cast than with a tubular bandage do not alter materially across all models investigated. The results also suggest that phone calls are most effective in retrieving questionnaires. PMID- 21284013 TI - Effective reproduction numbers are commonly overestimated early in a disease outbreak. AB - Reproduction numbers estimated from disease incidence data can give public health authorities valuable information about the progression and likely size of a disease outbreak. Here, we show that methods for estimating effective reproduction numbers commonly give overestimates early in an outbreak. This is due to many factors including the nature of outbreaks that are used for estimation, incorrectly accounting for imported cases and outbreaks arising in subpopulations with higher transmission rates. Awareness of this bias is necessary to correctly interpret estimates from early disease outbreak data. PMID- 21284014 TI - Generalized method for adaptive randomization in clinical trials. AB - A flexible, generalized method of treatment allocation is proposed. The method uses a set of controlling parameters that enables the generic algorithm to produce a family of possible outcomes ranging from simple randomization to deterministic allocation. The method controls balance at stratum level, stratification level and overall without detriment to the predictability of the method. The paper lists the desirable characteristics of allocation methods and shows that the proposed method fulfils the majority and is easy to use in the clinical context, once the coding has been established. An explanation of the method for 2, 3 and 4 treatment group allocations is given. Simulations demonstrate the flexibility of the method. PMID- 21284015 TI - Evaluation metrics for biostatistical and epidemiological collaborations. AB - Increasing demands for evidence-based medicine and for the translation of biomedical research into individual and public health benefit have been accompanied by the proliferation of special units that offer expertise in biostatistics, epidemiology, and research design (BERD) within academic health centers. Objective metrics that can be used to evaluate, track, and improve the performance of these BERD units are critical to their successful establishment and sustainable future. To develop a set of reliable but versatile metrics that can be adapted easily to different environments and evolving needs, we consulted with members of BERD units from the consortium of academic health centers funded by the Clinical and Translational Science Award Program of the National Institutes of Health. Through a systematic process of consensus building and document drafting, we formulated metrics that covered the three identified domains of BERD practices: the development and maintenance of collaborations with clinical and translational science investigators, the application of BERD-related methods to clinical and translational research, and the discovery of novel BERD related methodologies. In this article, we describe the set of metrics and advocate their use for evaluating BERD practices. The routine application, comparison of findings across diverse BERD units, and ongoing refinement of the metrics will identify trends, facilitate meaningful changes, and ultimately enhance the contribution of BERD activities to biomedical research. PMID- 21284016 TI - Regression-assisted deconvolution. AB - We present a semi-parametric deconvolution estimator for the density function of a random variable biX that is measured with error, a common challenge in many epidemiological studies. Traditional deconvolution estimators rely only on assumptions about the distribution of X and the error in its measurement, and ignore information available in auxiliary variables. Our method assumes the availability of a covariate vector statistically related to X by a mean-variance function regression model, where regression errors are normally distributed and independent of the measurement errors. Simulations suggest that the estimator achieves a much lower integrated squared error than the observed-data kernel density estimator when models are correctly specified and the assumption of normal regression errors is met. We illustrate the method using anthropometric measurements of newborns to estimate the density function of newborn length. PMID- 21284017 TI - High irradiance laser ionization orthogonal time-of-flight mass spectrometry: a versatile tool for solid analysis. AB - This article reviews the development of and applications for high irradiance laser ionization orthogonal time-of-flight mass spectrometry (LI-O-TOFMS). LI-O TOFMS has solved the bottleneck problems in traditional high irradiance laser ionization mass spectrometry, which allows the instrument to acquire explicit spectra with high resolution. A buffer-gas-assisted ion source effectively reduces the kinetic energy of the ions and suppresses the multiply charged ion interference. The pulse train data acquisition technique was applied to reduce the spectrum interference from multiply charged ions and polyatomic ions according to the temporal profiles of different ion packets in the repelling region. Relatively high laser irradiance (>=10(10) W/cm(2)) is preferable for achieving uniform relative sensitivities for different elements in the samples of different matrices. LI-O-TOFMS has been used in the standardless, semiquantitative analysis of solids, which is proved to be a fast and convenient technique for solid sample analysis. By increasing the laser irradiance and reducing the buffer gas pressure, the determination of nonmetallic elements in solids can also be achieved without losing spectral explicity. Recent applications, such as elemental analysis of a single egg cell and acquiring elemental, fragmental, and molecular information of chemicals, were given to demonstrate the potential of the new technique. All of these results reveal that LI-O-TOFMS is an advanced tool in the elemental analysis of solids in terms of modern mass spectrometry. PMID- 21284018 TI - Morphological variation in the ear region of pleistocene elephantimorpha (Mammalia, Proboscidea) from central Texas. AB - A large sample of isolated elephantimorph petrosal bones was recovered from Pleistocene deposits in Friesenhahn Cave, Bexar County, Texas. Morphology of the middle and inner ear of the elephantimorphs is described and variation within the sample is identified. Observed variations occur in the stapedial ratio, morphology of the aquaeductus Fallopii, and connection of the crista interfenestralis to the tympanohyal on the posterior portion of the petrosal to form a foramen for passage of the stapedius muscle. The morphology of the aquaeductus Fallopii supports an ontogenetic explanation for some variation, and a sequence of ossification surrounding the aquaeductus Fallopii, from the anterior end of the canal to the posterior, is hypothesized. The stapedial ratio varies to a high degree across the sample, and such variation should be considered when the ratio is used in phylogenetic analyses. Within the inner ear, the absence of the secondary lamina suggests evolution of low-frequency hearing in extinct proboscideans, which is known for extant elephants. The morphology of the petrosals from Friesenhahn Cave is compared to published descriptions of the ear regions of other extinct proboscideans, and the distribution and evolution of morphologic characters are discussed. J. Morphol., 2011. (c) 2011 Wiley-Liss, Inc. PMID- 21284019 TI - Mesothelium of the murine allantois exhibits distinct regional properties. AB - The rodent allantois is thought to be unique amongst mammals in not having an endodermal component. Here, we have investigated the mesothelium, or outer surface, of murine umbilical precursor tissue, the allantois (~7.25-8.5 days postcoitum, dpc) to discover whether it exhibits the properties of an epithelium. A combination of morphology, challenge with biotinylated dextran amines (BDAs), and immunohistochemistry revealed that the mesothelium of the mouse allantois exhibits distinct regional properties. By headfold stages (~7.75-8.0 dpc), distal mesothelium was generally squamous in shape, and highly permeable to BDA challenge, whereas ventral proximal mesothelium, referred to as "ventral cuboidal mesothelium" (VCM) for the characteristic cuboidal shape of its cells, was relatively impermeable. Although "dorsal cuboidal mesothelium" (DCM) resembled the VCM in cell shape, its permeability to BDA was intermediate between the other two regions. Results of immunostaining for Zonula Occludens-1 (ZO-1) and Epithelial-cadherin (E-cadherin), together with transmission electron microscopy (TEM), suggested that impermeability in the VCM may be due to greater cellular contact area between cells and close packing rather than to maturity of tight junctions, the latter of which, by comparison with the visceral yolk sac, appeared to be rare or absent from the allantoic surface. Both VCM and DCM exhibited an ultrastructure more favorable for protein synthesis than did the distal squamous mesothelium; however, at most stages, VCM exhibited robust afadin (AF-6), whereas the DCM uniquely contained alpha-4-integrin. These observations demonstrate that the allantoic mesothelium is not a conventional epithelium but possesses regional ultrastructural, functional and molecular differences that may play important roles in the correct deployment of the umbilical cord and its associated vascular, hematopoietic, and other cell types. PMID- 21284020 TI - Elevation of serum c-reactive protein in patients with OAB and IC/BPS implies chronic inflammation in the urinary bladder. AB - AIMS: Chronic inflammation has been implicated in the development of overactive bladder (OAB) and interstitial cystitis/bladder pain syndrome (IC/BPS). An elevation of C-reactive protein (CRP) has been associated with chronic inflammation and lower urinary tract symptoms. This study aims to elucidate the association between CRP and OAB or IC/BPS. METHODS: Serum CRP and urinary nerve growth factor (NGF) levels were examined in 70 patients with OAB (n=22) or IC/BPS (n=48) and compared with 33 normal controls. Data of serum CRP and urinary NGF levels were compared among the controls, IC/PBS, and OAB. The Spearmen correlation analysis test and ANOVA (Kruskal-Wallis) test were used for statistical analysis with P<0.05 considered significant. RESULTS: Serum CRP levels were significantly higher in subjects with OAB (1.83 +/- 2.30 mg/L vs. 0.59 +/- 0.40 mg/L, P=0.012) or IC/BPS (1.76 +/- 3.56 mg/L vs. 0.59 +/- 0.40 mg/L, P=0.049) than in controls. No significant difference in CRP level was noted between patients with OAB and IC/BPS (P=0.43). In a subgroup analysis, patients of OAB wet had higher serum CRP level than that of OAB dry (2.95 +/- 3.08 mg/L vs. 0.90 +/- 0.52 mg/L); however, the difference did not reach statistical significance (P=0.34). The CRP between OAB wet and OAB patients with medical disease was not significantly different. There was no significant correlation between serum CRP and urinary NGF levels in the controls or patients with OAB or IC/BPS, except in the OAB patients with a CRP level >3 mg/L. CONCLUSIONS: Our data support the association between chronic inflammation of the urinary bladder in patients with OAB or IC/BPS. PMID- 21284021 TI - Incidence of stress urinary incontinence following vaginal repair of pelvic organ prolapse in objectively continent women. AB - OBJECTIVE: To estimate the incidence of stress urinary incontinence (SUI) following vaginal repair of pelvic organ prolapse (POP) in preoperatively continent women and to evaluate the impact of the problem. METHODS: Women were eligible if they had undergone vaginal repairs for any degree or type of POP with no anti-incontinence procedure between July 1, 2004 and June 30, 2006, and had been continent preoperatively, as defined by a negative cough stress test with or without reduction of prolapse. Demographic, preoperative, operative, and postoperative data were retrieved from hospital charts. The incidence of postoperative SUI (POSUI) and its quality of life (QoL) impact were assessed by mailed questionnaire. The POSUI endpoint was defined by the report of SUI symptoms on the mailed questionnaire and/or affirmation of postoperative treatment for SUI. RESULTS: Forty-two out of 100 respondents reported POSUI within the 2-year average follow-up period. Twelve of 37 symptomatic women (32%) were moderately or greatly bothered by their symptoms. The QoL impact score was generally low but was statistically greater in women with POSUI compared to those with no POSUI (13 vs. 3, P=0.0006). CONCLUSION: The risk of POSUI following vaginal repairs of POP may be higher than previously reported and approximately one-third of women are bothered by these symptoms. These findings deserve further investigation. PMID- 21284022 TI - Incontinence improves in older women after intensive pelvic floor muscle training: an assessor-blinded randomized controlled trial. AB - AIMS: To test the hypotheses that high intensity pelvic floor muscle training (PFMT) is effective in relief of stress urinary incontinence in community dwelling older women, and that intense PFMT improves stress urinary incontinence more than bladder training (BT) in this population. METHODS: A two-center, assessor-blinded randomized controlled trial of 20 weeks duration with two active intervention arms: PFMT and BT. Assessments and interventions were undertaken at two metropolitan tertiary hospitals. Participants were community dwelling women over 65 years of age with urodynamic stress incontinence. Primary outcome measure was urinary leakage during a cough stress test. Secondary outcome measures included symptoms and bother (ICIQ-UI SF), participant global perception of change, leakage episodes (7-day accident diary), degree of "bother" (VAS) and health related quality of life (AQoL). RESULTS: Eighty-three Caucasian women, 71.8 (SD 5.3) years participated in the study. Both groups improved over the intervention period; however, the PFMT group reported significantly lower amounts of leakage on the stress test [PFMT median 0.0 g, 95% CI: 0.2-0.9; BT median 0.3 g, 95% CI: 0.2-1.7, P=0.006], improved symptoms and bother [PFMT mean 5.9, 95% CI: 4.8-7.1; BT group mean 8.5, 95% CI: 7.1-9.9 and greater perception of change [PFMT 28 (73.6%); BT 12 (36.4%) (P=0.002)] after 5 months than the BT group. CONCLUSIONS: High intensity PFMT is effective in managing stress urinary incontinence and is more effective than BT in healthy older women. PMID- 21284023 TI - Urinary diaries: evidence for the development and validation of diary content, format, and duration. AB - AIMS: To review the published literature for evidence of urinary diary development and validation, in terms of diary format, content, and duration. To identify a fully validated urinary diary. METHODS: MEDLINE search to identify all published English literature to date regarding urinary diaries. The search terms used were: micturition chart, micturition diary, frequency volume chart, bladder chart, bladder diary, urinary chart, urinary diary, voiding chart, and voiding diary. Studies were reviewed to identify any descriptions of diary development and whether diary format, duration, or content had been subject to validity testing. RESULTS: One thousand four hundred sixty-three studies were identified using the described search terms. Of these 81 were deemed potentially relevant to the investigation and reviewed. Fourteen studies investigated optimum diary duration but only four described the development of a new diary tool. There is limited evidence regarding the validation of dairy content and format. No study describes the use of content, construct, or criterion validity as well as tests of reliability and responsiveness for diary development and validation. CONCLUSIONS: A validated urinary diary does not currently exist. A validated diary would provide an enhanced clinical tool, and, as with validated symptom questionnaires, would allow comparison between different research studies. PMID- 21284024 TI - Tadalafil for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia: pathophysiology and mechanism(s) of action. AB - BACKGROUND: The PDE5 inhibitor tadalafil is investigation for the treatment of lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BPH). Several clinical studies of tadalafil and other PDE5 inhibitors have reported significant symptom reduction but limited urinary flow rate improvement. This manuscript reviews the published literature describing the pathophysiology of male LUTS, with an emphasis on mechanisms that may be modulated or improved by phosphodiesterase type 5 (PDE5) inhibition. METHODS: Literature (through March 2010) was obtained via Medline searches and from the individual reviewers files. Articles were selected for review based on describing in vitro, preclinical, or clinical studies of pathological processes contributing to LUTS, or possible effects of PDE5 inhibition in the lower urinary tract. RESULTS: Major mechanisms contributing to LUTS include: reduced nitric oxide/cyclic guanosine monophosphate signaling; increased RhoA kinase pathway activity; autonomic overactivity; increased bladder afferent activity; and pelvic ischemia. Tadalafil and other PDE5 inhibitors have demonstrated beneficial effects on smooth muscle relaxation, smooth muscle and endothelial cell proliferation, nerve activity, and tissue perfusion that may impact LUTS in men. CONCLUSIONS: The pathophysiology of male LUTS is complex and not completely understood. LUTS may occur independently of BPH or secondary to BPH but in both cases involve obstructive or irritative mechanisms with substantial pathophysiological overlap. While the precise mechanism remains unclear, inhibition of PDE5 seems to have an effect on several pathways that may impact LUTS. PMID- 21284025 TI - Renal sympathetic nervous system hyperactivity in early streptozotocin-induced diabetic kidney disease. AB - AIM: We assessed the role of renal sympathetic nervous system in the deterioration of renal hemodynamic and excretory functions in rats with streptozotocin (STZ)-induced diabetic kidney disease (DKD). METHODS: Male Sprague Dawley (SD) rats were induced with diabetes mellitus (DM) using STZ (55 mg/kg, i.p.). The acute studies were conducted on denervated anesthetized rats 7 days after STZ administration. Two sets of experiments were performed: clearance experiments in which six 20-min urine and plasma collections were carried out to measure kidney function parameters, and hemodynamic experiments in which the renal nerves were electrically stimulated and responses in renal vascular resistance (RVR) and renal blood flow (RBF) were recorded. RESULTS: Renal denervation in STZ-induced diabetic rats produced higher fractional excretion of sodium (FE(Na) ) but lower plasma sodium (P(Na) ), glomerular filtration rate (GFR), and plasma creatinine (P(Cr) ) (all P<0.05 vs. innervated diabetic rats). In innervated diabetic rats, renal nerve stimulation (RNS) caused significant attenuation in the renal vasoconstrictor responses (all P<0.05 vs. innervated control). Renal denervation in diabetic rats significantly blunted these responses (all P<0.05 vs. innervated diabetic rats); however, they were significantly higher (all P<0.05) while compared to denervated control counterparts. CONCLUSIONS: The data demonstrate an early role for the renal sympathetic innervation in the pathogenesis of DKD. If the kidney is prevented from renal sympathetic nerve action renal functional parameters are markedly improved. The data further suggest an early enhancement in renal sensitivity to intrarenal norepinephrine (NE) upon the removal of renal sympathetic tone in STZ induced diabetic rats. PMID- 21284026 TI - Quality of life in elderly men with aging symptoms and lower urinary tract symptoms (LUTS). AB - AIMS: The aims of this study were to investigate quality of life (QoL) due to physical and psychological changes occurring in elderly men and to identify associated factors between lower urinary tract symptoms (LUTS) and aging male symptoms (ADAM). MATERIALS AND METHODS: This was a case-control study whereby 200 elderly men were recruited from the community and the Urology and Geriatrics ambulatories. Subjects were asked to fill out the Aging Male Symptoms Scale (AMS), World Health Organization Quality of Life-BREF and -OLD, and IPSS questionnaires. Participants were classified in two groups according to IPSS: group I (moderate to severe symptoms) and group II (mild symptoms). RESULTS: The AMS scale and both QoL questionnaires of group I showed significantly worse median scores in all parameters. The average somatic and sexual subscore was significantly higher in group I (P < 0.0005). The social and environmental domains presented the most significant differences (P < 0.0005) in both questionnaires, and the mean of the WHOQOL-OLD score was significantly lower in group I (P < 0.0005). CONCLUSIONS: Moderate to severe ADAM and LUTS impact significantly all parameters of HRQOL and generic QoL proposed by the WHO. There was correlation between severity of LUTS and severity of the following ADAM: depression, feeling burnt out, decline of feeling of general well-being, joint and body complaints, insomnia, weakness of muscles, feeling that the peak had passed, decrease of sexual performance, and decrease of morning erections. PMID- 21284027 TI - Brain response provoked by different bladder volumes: a near infrared spectroscopy study. AB - AIMS: In order to understand frontal lobe responses in bladder sensation in healthy subjects, we examined the cortical localization of response to the different bladder volumes. METHODS: Frontal blood flow was measured non invasively in 24 resting adults using multi-channel near infrared spectroscopy (NIRS). Changes in bladder volume were induced by infusing and releasing water from the bladder. Two states of bladder sensation have been induced, "first desire to void" and "strong desire to void. RESULTS: NIRS analysis revealed that cerebral responses to bladder sensation were associated with increased levels of oxy-hemoglobin in the bilateral frontal cortex. The responses became stronger in the state of strong desire to void at enlarged bladder volume (P < 0.01). These results indicate that bilateral frontal areas are involved in bladder perception related to increased urine volumes in adults. CONCLUSIONS: The dynamic changes in cerebral blood oxygenation were similar to those assessed in other methodologies such as f-MRI and PET. This result suggests that NIRS study might be available for investigating the mutual relationship between bladder and brain in patients suffering from neurological problems and urinary tract symptoms. PMID- 21284028 TI - The association of changes in opening detrusor pressure with the resolution of overactive bladder symptoms after repair of pelvic organ prolapse. AB - AIMS: To evaluate whether changes in opening detrusor pressure (ODP) are associated with resolution of overactive bladder symptoms in women undergoing surgical correction of pelvic organ prolapse. METHODS: Forty women with DO and OAB together with anterior wall prolapse who underwent a repair between 2003 and 2007 were studied. Each woman was assessed pre- and post-operatively with a clinical assessment and cystometry. Opening pressures were recorded pre- and post operatively for each patient by retrospective review of the pressure flow traces. Patients were divided into those who experienced resolution of OAB symptoms and those with persistent OAB symptoms. Wilcoxon matched pairs signed rank test was used to assess any change in opening pressures between these groups. RESULTS: Resolution of urgency with an anterior repair was associated with a significant fall in ODP from a mean of 27.9 to 11.7 cmH(2)O (P = 0.01). There was no significant pre-operative difference in ODP between women in whom urgency resolved and those in whom it did not. CONCLUSION: These results suggest that a fall in ODP is associated with resolution of urgency in women undergoing prolapse surgery. This may imply that decreased urethral resistance is of importance in symptom resolution. PMID- 21284029 TI - LacZ transgene expression in the subcutaneous Dunn/LM8 osteosarcoma mouse model allows for the identification of micrometastasis. AB - More effective treatment of patients with metastasizing osteosarcoma (OS) with a mean 5-year survival rate of <20% requires more detailed knowledge on the complex mechanisms of metastasis for the design of new drugs, which selectively target metastasizing cells. Moreover, novel diagnostic imaging technology for early detection of metastases is needed. Mouse models, which reproduce human metastasizing OS and allow visualization of single metastatic cells are instrumental for preclinical testing of new pharmaceuticals and diagnostic instruments. Here, the low metastatic Dunn cell line and its highly metastatic LM8 subline, both equipped with a constitutively expressed lacZ gene, were used to improve the well-established OS models in syngeneic C3H mice to achieve ex vivo visualization of single metastatic cells in affected organs by X-gal staining. These models, combined with a technique for in situ high quality lung tissue-maintaining perfusion revealed, as a novel finding, single metastasizing Dunn cells in lung and liver. Importantly, constitutive lacZ gene expression did not affect in vitro and in vivo tumorigenic and metastatic properties of Dunn and LM8 cells. Thus, these improved Dunn and LM8 OS mouse models will in the future serve as a benchmark for the development of new metastasis-targeting drugs and metastasis-imaging technology. PMID- 21284030 TI - Caffeine enhances osteoclast differentiation from bone marrow hematopoietic cells and reduces bone mineral density in growing rats. AB - Caffeine-containing beverage consumption has been associated with low bone mass and increased fracture risk in some, but not most, observational studies. The effects of caffeine on bone metabolism are still controversial. We investigated the effects of caffeine on the differentiation of bone progenitor cells and bone mineral density (BMD) by in vitro and in vivo experiments. Low-concentration caffeine (0.005-0.1 mM) did not affect the bone marrow cell viability and alkaline phosphatase activity during osteoblast differentiation from bone marrow stromal cells, but it effectively enhanced the osteoclastogenesis from bone marrow hematopoietic cells and the bone resorption activity by pit formation assay. Moreover, caffeine effectively enhanced the receptor activator of NF kappaB ligand (RANKL), but reduced the osteoprotegerin protein expressions in osteoblast MC3T3-E1 cells. Caffeine could also increase the cyclooxygenase-2 (COX 2) protein expression and prostaglandin (PG)E(2) production in cultured neonatal mouse calvariae. In animal study, BMD in lumbar vertebra, femur, or tibia was significantly lowered in growing rats supplemented with 0.2% caffeine in diets for 20 weeks compared with the control group. The calcium contents in tibia and femur of caffeine-treated rats were also lower than that in the control group. The osteoclastogenesis of bone marrow cells isolated from caffeine-treated rats was markedly enhanced as compared with the control group. Taken together, these results suggest that caffeine may reduce BMD in growing rats through the enhancement in osteoclastogenesis. Caffeine may possess the ability to enhance a COX-2/PGE(2) -regulated RANKL-mediated osteoclastogenesis. PMID- 21284031 TI - Mesenchymal stem cells and platelet lysate in fibrin or collagen scaffold promote non-cemented hip prosthesis integration. AB - The objective of this study was to evaluate whether mesenchymal stem cells (MSC) and platelet lysate (PL) seeded in a fibrin or collagen scaffold could improve the new bone (NB) formation around an uncemented hip prosthesis stem in a sheep model. In vitro expanded MSC were suspended in PL and either mixed with collagen or fibrin gel as delivery vehicle. The cell-gel composites were inserted inside the femoral canal, then the prosthesis was press-fit inserted inside the femur. Identical procedures were performed in a control group, but only the prosthesis was implanted. Histomorphometrical analysis performed 4 months after surgery indicated that the newly formed bone inside the medullary canal, between the inner cortex and the prosthetic stem, was significantly higher in the MSC-PL collagen group (mean 18.7 +/- 4.5%) and in the MSC-PL-fibrin group (mean 18.8 +/- 15.2%) when compared to the control group (mean 4.6 +/- 2.0%). There was a significantly higher bone-prosthesis contact in the MSC-PL-collagen group (mean 2.7 +/- 2.6%) and in the MSC-PL-fibrin group (mean 2.3 +/- 3.1%) compared to the control group (mean 0.2 +/- 0.1%). The results indicate that MSC and PL in a fibrin or collagen scaffold can promote NB formation around an uncemented hip prosthesis stem. PMID- 21284032 TI - Local application of VEGF compensates callus deficiency after acute soft tissue trauma--results using a limb-shortening distraction procedure in rabbit tibia. AB - Acute soft tissue trauma influences callus formation and fracture healing. Several studies showed a relationship between angiogenesis and bone formation during distraction osteogenesis. The purpose of this study was to investigate the influence of controlled release of vascular endothelial growth factor (VEGF) on callus formation in a limb-shortening distraction procedure after acute compartment syndrome. Acute soft tissue trauma with critical increased compartment pressure was generated in 22 rabbits, and the limb was shortened simulating fracture site debridement. In the test group (n=11), a VEGF-coated collagen matrix was locally applied around the fracture, while no collagen was applied in the control group (n=11). Following 10 days in limb shortening, a gradual distraction of 0.5 mm/12 h was performed using an external fixation device and followed up for 40 days. Osseous consolidation occurred in all animals. Average callus diameter (1.54 +/- 0.8 vs. 1.27 +/- 0.14 mm) and torsional strength (72% vs. 46% of normal) were significantly higher in the test versus the control group. Blood vessel formation increased with a significantly higher number of vessels (6.3 vs. 3.81/mm2 ) and larger cross-sectional area (>40 um, 90.5% vs. 86%) in the test versus control group. The results showed that locally applied VEGF stimulates fracture healing after acute soft tissue trauma and might be an option for fracture treatment in cases with severe soft tissue damage. PMID- 21284033 TI - Oxidative stress induces senescence in chondrocytes. AB - Cellular senescence is a program activated during diverse situations of cell stress. Chondrocytes differ from other somatic cells as articular cartilage is an avascular tissue. The effects of oxidative stress on chondrocytes are still unknown. Our studies were to investigate into the proliferation potential, cytological features and the telomere linked stress response system of human osteoarthritic chondrocytes, subjected to acute or prolonged oxidant challenge with hydrogen peroxide. Telomere length was measured using the telomere restriction fragment assay, gene expression was determined by RT-PCR. Sub-lethal doses of oxidative stress induced cell-cycle arrest, senescent-morphological features and senescence-associated beta-galactosidase positivity. Prolonged oxidative treatment had no effects on cell proliferation or morphology. Sub lethal and prolonged low doses of oxidative stress considerably accelerated telomere attrition. The effects of sub-lethal oxidative stress regarding proliferation and telomere biology were more distinct in senescent cells. Acute oxidant insult caused up-regulation of p21 expression to levels comparable to senescent cells. TRF2 protects telomere ends and showed elevated expression levels. SIRT1 and XRCC5 enable cells to cope with unfavorable growing conditions. Both were up-regulated after oxidant insult, but expression levels decreased in aging cells. Taken together, oxidative stress considerably accelerated telomere shortening and cellular aging in chondrocytes. Senescent cells showed a reduced tolerance to oxidative stress. PMID- 21284034 TI - Callus patterns in femoral lengthening over an intramedullary nail. AB - Our objectives were to evaluate callus patterns seen in femoral lengthening over an intramedullary nail by Li classification regarding shape and type and to predict the result while using the nail to reduce the external fixation period and its complications. Eight hundred digital radiographs of 15 patients with 15 segments of femur shortening who underwent femoral lengthening with a monolateral external fixator over an intramedullary nail were analyzed retrospectively by four observers. Each radiograph was studied for callus shape, feature type, and callus density using pixel values. The classification was tested for concurrence and reproducibility by interobserver studies and callus patterns were compared with treatment indices to evaluate how they correlated with the outcome. Mean length gained was 4.5 cm (range: 2-8 cm). External fixator index (EFI) was 21.68 days/cm. Average distraction consolidation index (DCI) was 48.49 days/cm. Fusiform callus was seen in three cases, cylindrical in seven, and lateral in five. The homogenous pathway had higher DCI (43.7) than the heterogeneous pathway (32.9), and mixed pathways making up the rest had a DCI of 50.1. Pixel value of callus showed gradual increase in density until 20-24 weeks, then density gradually fell for 8 weeks, again increased after 32 weeks, again gradually fell, and was comparable to adjacent normal bone by 44-48 weeks. Our results suggest that the Li classification can be satisfactorily applied to lengthening procedures over intramedullary nails. The radiologic pattern and pixel value of regenerate can be correlated with the clinical outcome and can be an aid of prognostic value for the surgeon. PMID- 21284035 TI - Quantifying and correcting for the winner's curse in quantitative-trait association studies. AB - Quantitative traits (QT) are an important focus of human genetic studies both because of interest in the traits themselves and because of their role as risk factors for many human diseases. For large-scale QT association studies including genome-wide association studies, investigators usually focus on genetic loci showing significant evidence for SNP-QT association, and genetic effect size tends to be overestimated as a consequence of the winner's curse. In this paper, we study the impact of the winner's curse on QT association studies in which the genetic effect size is parameterized as the slope in a linear regression model. We demonstrate by analytical calculation that the overestimation in the regression slope estimate decreases as power increases. To reduce the ascertainment bias, we propose a three-parameter maximum likelihood method and then simplify this to a one-parameter method by excluding nuisance parameters. We show that both methods reduce the bias when power to detect association is low or moderate, and that the one-parameter model generally results in smaller variance in the estimate. PMID- 21284036 TI - Phenotype harmonization and cross-study collaboration in GWAS consortia: the GENEVA experience. AB - Genome-wide association study (GWAS) consortia and collaborations formed to detect genetic loci for common phenotypes or investigate gene-environment (G*E) interactions are increasingly common. While these consortia effectively increase sample size, phenotype heterogeneity across studies represents a major obstacle that limits successful identification of these associations. Investigators are faced with the challenge of how to harmonize previously collected phenotype data obtained using different data collection instruments which cover topics in varying degrees of detail and over diverse time frames. This process has not been described in detail. We describe here some of the strategies and pitfalls associated with combining phenotype data from varying studies. Using the Gene Environment Association Studies (GENEVA) multi-site GWAS consortium as an example, this paper provides an illustration to guide GWAS consortia through the process of phenotype harmonization and describes key issues that arise when sharing data across disparate studies. GENEVA is unusual in the diversity of disease endpoints and so the issues it faces as its participating studies share data will be informative for many collaborations. Phenotype harmonization requires identifying common phenotypes, determining the feasibility of cross study analysis for each, preparing common definitions, and applying appropriate algorithms. Other issues to be considered include genotyping timeframes, coordination of parallel efforts by other collaborative groups, analytic approaches, and imputation of genotype data. GENEVA's harmonization efforts and policy of promoting data sharing and collaboration, not only within GENEVA but also with outside collaborations, can provide important guidance to ongoing and new consortia. PMID- 21284037 TI - Clinical problems in the hospitalized Parkinson's disease patient: systematic review. AB - The problems Parkinson's disease (PD) patients encounter when admitted to a hospital, are known to be numerous and serious. These problems have been inventoried through a systematic review of literature on reasons for emergency and hospital admissions in PD patients, problems encountered during hospitalization, and possible solutions for the encountered problems using the Pubmed database. PD patients are hospitalized in frequencies ranging from 7 to 28% per year. PD/parkinsonism patients are approximately one and a half times more frequently and generally 2 to 14 days longer hospitalized than non-PD patients. Acute events occurring during hospitalization were mainly urinary infection, confusion, and pressure ulcers. Medication errors were also frequent adverse events. During and after surgery PD patients had an increased incidence of infections, confusion, falls, and decubitus, and 31% of patients was dissatisfied in the way their PD was managed. There are only two studies on medication continuation during surgery and one analyzing the effect of an early postoperative neurologic consultation, and numerous case reports, and opinionated views and reviews including other substitutes for dopaminergic medication intraoperatively. In conclusion, most studies were retrospective on small numbers of patients. The major clinical problems are injuries, infections, poor control of PD, and complications of PD treatment. There are many (un-researched) proposals for improvement. A substantial number of PD patients' admissions might be prevented. There should be guidelines concerning the hospitalized PD patients, with accent on early neurological consultation and team work between different specialities, and incorporating nonoral dopaminergic replacement therapy when necessary. PMID- 21284038 TI - Reduced sympathetically driven heart rate variability during sleep in Parkinson's disease: a case-control polysomnography-based study. AB - OBJECTIVES: To study heart rate variability during nocturnal sleep in idiopathic Parkinson's disease. METHODS: Retrospective study, using part of the data set accumulated in an earlier study, in which polysomnography was performed in 35 idiopathic Parkinson's disease patients under their usual medication and in 35 non-idiopathic Parkinson's disease controls, matched for age, gender, and amount of apneas/hypopneas per hour. R-R intervals were calculated separately for non rapid eye movements and rapid eye movements sleep stages. R-R variability was analyzed for time and frequency domains. Selected variables considered were high frequency band (0.15-0.40 Hz) influenced by parasympathetic input and low frequency band (0.04-0.15 Hz) influenced by sympathetic input. Both frequency bands were considered in normalized units (low frequency and high frequency normalized units). Low frequency/high frequency ratio was calculated as an estimate of sympathicovagal balance. RESULTS: All respiratory and sleep stage characteristics were similar in both groups. Low frequency normalized unit was reduced in idiopathic Parkinson's disease patients, both for non-rapid eye movements and rapid eye movements sleep (P = 0.005). Low frequency/high frequency was smaller in idiopathic Parkinson's disease for both sleep portions (P = 0.02). CONCLUSIONS: Idiopathic Parkinson's disease patients show reduced sympathetic influence on heart rate variability in both non-rapid eye movements and rapid eye movements sleep stages. We speculate that these findings are a consequence of the postganglionic noradrenergic cardiac denervation found in idiopathic Parkinson's disease patients. PMID- 21284039 TI - Pathological gambling in patients with Parkinson's disease is associated with fronto-striatal disconnection: a path modeling analysis. AB - BACKGROUND: Pathological gambling may occur in Parkinson's disease (PD) as a complication of dopaminergic therapy. Neuroimaging studies have suggested an abnormal dopamine transmission within the reward system, but the changes in the neural network characterizing PD patients with pathological gambling have never been investigated. METHODS: Thirty PD patients (15 with active gambling and 15 matched controls, on-medication) and 15 healthy subjects underwent brain perfusion single photon emission tomography at rest. The severity of gambling was assessed using the South Oaks Gambling Scale. Covariance analysis was applied to identify brain regions whose activity was associated with gambling severity. These regions were used as volume-of-interest to identify functionally interconnected areas using voxel-wise covariance analysis. A path model was defined by means of effective connectivity analysis within the Structural Equation Modeling framework. RESULTS: Gambling severity in PD was associated with a dysfunction of the brain network implicated in decision making, risk processing, and response inhibition, including the ventrolateral prefrontal cortex, anterior (ACC) and posterior cingulate cortex, medial prefrontal cortex, insula and striatum. PD gamblers showed a disconnection between the ACC and the striatum, while this interaction was very robust in both control groups. DISCUSSION: ACC-striatal disconnection may underlie a specific impairment of shifting behaviors after negative outcomes, possibly explaining why PD gamblers use to perseverate into risktaking behaviors despite self-destructive consequences. PMID- 21284040 TI - Essential tremor and Parkinson's disease: lack of a link. AB - BACKGROUND: Essential tremor (ET) is a very common disorder and proving that there is a relationship to another common movement disorder, Parkinson's disease (PD), has been debated for years. METHODS: Review of the literature for links between ET and PD primarily focused on neuropathology as well as neurochemistry, epidemiology, genetics, olfactory function, and neuroimaging. RESULTS: While there may be some evidence to suggest an increase in occurrence of PD in people who were previously diagnosed with ET, neuropathologic studies of ET with similarly assessed control subjects do not find an increase in Lewy bodies in the ET group. Studies of incidental Lewy body disease do not find an increase in ET or action tremor compared to controls. ET subjects as a group do not have neurochemical changes that are found in PD, do not respond to medications used to treat PD, are not hyposmic as is found in PD, and neuroimaging studies do not find changes of PD when groups are compared. CONCLUSION: The overwhelming amount of evidence suggests that any link between ET and PD is coincidental and not biological. Prospective, longitudinal cohort studies with standardized clinical and biomarker assessments followed by neuropathologic confirmation are needed. PMID- 21284041 TI - Association of olfactory dysfunction and brain. Metabolism in Parkinson's disease. AB - Hyposmia is one of the cardinal early symptoms of Parkinson disease (PD). Accumulating clinical and pathological evidence suggests that dysfunction of the olfactory-related cortices may be responsible for the impaired olfactory processing observed in PD; however, there are no clear data showing a direct association between altered brain metabolism and hyposmia in PD. In this study, we evaluated brain glucose metabolism and smell-identification ability in 69 Japanese patients with nondemented PD. Olfactory function was assessed using the Odor Stick Identification Test for Japanese. The regional cerebral metabolic rate of glucose consumption at rest was measured using (18)F-fluorodeoxyglucose positron emission tomography and was analyzed using SPM-based group comparisons and the brain-behavior partial least-squares method. We found that olfactory dysfunction was closely related to cognitive dysfunction, including memory impairment. Moreover, brain-behavior partial least-squares analysis revealed that odor-identification performance was closely associated with broad cortical dysfunction, including dysfunction of the piriform cortex and amygdala. Our results suggest that the cognitive deficit in olfactory perception is an important aspect of hyposmia in PD and that this deficit is caused by altered brain metabolism in the amygdala and piriform cortex. PMID- 21284042 TI - Prevalence and risk factors for depression in older people in Xi'an China: a community-based study. AB - OBJECTIVE: To estimate the prevalence of depressive symptoms and to determine the impact of socio-demographic variables, chronic diseases and health-related events on depression in a community sample of older adults in Xi'an, Shaanxi Province. METHODS: Cross sectional, multistage community survey. A semi-structured questionnaire including socio-demographic characteristics, physical health, chronic diseases and health-related events was administered to 1587 older adults from eight communities. Depression was assessed using the 30-item Geriatric Depression Scale (GDS) with a threshold of <11/11+. Analysis was conducted using SPSS16.0 Complex Samples Logistic analysis procedure. RESULTS: The prevalence of depression was 27.0% (95% CI 24.7-29.2%). In a univariate analysis, the following variables were significantly associated with depression: female gender, low max income, coronary heart disease, suffering 3 or above chronic diseases and functional impairments, 4 adverse life events (financial problems, death of closely related person, unpleasantness experience and horrifying experience) and suffering 1 or above adverse life events. After adjustment for age and gender, odds ratios for depression were significantly higher for coronary heart disease, suffering 3 or above chronic diseases and functional impairments, adverse life event (financial problems, unpleasantness experience) and suffering 3 or above adverse life events. CONCLUSIONS: According to GDS estimates, 27.0% Chinese urban older adult had depression symptoms. In designing prevention programs, detection and management of older patients with depression should be a high priority in developing countries. PMID- 21284043 TI - Multivariate statistical identification of human bladder carcinomas using ambient ionization imaging mass spectrometry. AB - Diagnosis of human bladder cancer in untreated tissue sections is achieved by using imaging data from desorption electrospray ionization mass spectrometry (DESI-MS) combined with multivariate statistical analysis. We use the distinctive DESI-MS glycerophospholipid (GP) mass spectral profiles to visually characterize and formally classify twenty pairs (40 tissue samples) of human cancerous and adjacent normal bladder tissue samples. The individual ion images derived from the acquired profiles correlate with standard histological hematoxylin and eosin (H&E)-stained serial sections. The profiles allow us to classify the disease status of the tissue samples with high accuracy as judged by reference histological data. To achieve this, the data from the twenty pairs were divided into a training set and a validation set. Spectra from the tumor and normal regions of each of the tissue sections in the training set were used for orthogonal projection to latent structures (O-PLS) treated partial least-square discriminate analysis (PLS-DA). This predictive model was then validated by using the validation set and showed a 5% error rate for classification and a misclassification rate of 12%. It was also used to create synthetic images of the tissue sections showing pixel-by-pixel disease classification of the tissue and these data agreed well with the independent classification that uses histological data by a certified pathologist. This represents the first application of multivariate statistical methods for classification by ambient ionization although these methods have been applied previously to other MS imaging methods. The results are encouraging in terms of the development of a method that could be utilized in a clinical setting through visualization and diagnosis of intact tissue. PMID- 21284044 TI - Gold-nanoparticle-catalyzed synthesis of propargylamines: the traditional A3 multicomponent reaction performed as a two-step flow process. AB - The alkyne, aldehyde, amine A(3)-coupling reaction, a traditional multicomponent reaction (MCR), has been investigated as a two-step flow process. The implicated aminoalkylation reaction of phenylacetylene with appropriate aldimine intermediates was catalyzed by gold nanoparticles impregnated on alumina. The aldimine formation was catalyzed by Montmorillonite K10 beforehand. The performance of the process has been investigated with respect to different reaction regimes. Usually, the A(3)-multicomponent reaction is performed as a "one-pot" process. Diversity-oriented syntheses using MCRs often have the shortcoming that only low selectivity and low yields are achieved. We have used a flow-chemistry approach to perform the A(3)-MCR in a sequential manner. In this way, the reaction performance was significantly enhanced in terms of shortened reaction time, and the desired propargylamines were obtained in high yields. PMID- 21284045 TI - Dual-phase titanate/anatase with nitrogen doping for enhanced degradation of organic dye under visible light. PMID- 21284046 TI - One-dimensional end-to-end azide-bridged Mn(III) complexes incorporating alkali metal ions: slow magnetic relaxations and metamagnetism. AB - Three azide-bridged Mn(III) chains [Mn(3-MeOsalpn)(N(3))]?0.5 AClO(4) (A = Na (1), K (2), Rb (3); 3-MeOsalpn = N,N'-propylenebis(3-methoxysalicylideneiminato) dianion) incorporating alkali metal ions and perchlorate anions were systematically synthesized. The overall structure can be described as a one dimensional chain bridged by end-to-end azide ligands, although spatial arrangements of Jahn-Teller axes of Mn in 1 and 2 are different from that in 3. Relying on the alkali metal ions, magnetic properties are varied from a two-step phase transition (1) to metamagnetic transitions (2 and 3). In this system, spin canting definitely plays a central role in giving rise to the apparent slow magnetic relaxations in 1 and 2 because application of a high external magnetic field tends to destroy single-chain magnet (SCM) properties. Despite the existence of a long-range antiferromagnetic order at T(N) , slow magnetic relaxation is notably observed in 2, which likely emanates from the operative spin canting below T(N) . PMID- 21284047 TI - Micro-morphometrical assessment of the effect of Harpagophytum procumbens extract on articular cartilage in rabbits with experimental osteoarthritis using magnetic resonance imaging. AB - In vitro effects indicate a putative beneficial effect of Harpagophytum procumbens on cartilage turnover, however, in vivo protective effects on cartilage have yet to be demonstrated. A 7.1T MRI scanner was used to derive measurements of thickness, surface area and volume of the tibial condylar cartilage and to assess their precision (in the case of volume also accuracy) against the volumes of dissected cartilage measured by water displacement. Quantitative measurements were made in 16 rabbits, 6 months after unilateral medial meniscectomy and transection of the anterior cruciate ligament, after which eight of these were given a proprietary extract of Harpagophytum procumbens (HP). A semiquantitative MRI-based grading of the tibial cartilage was also compared with a 'macroscopic' grading based on direct visual inspection of dissected joints. The test-retest precision for MRI-based measurement was <=6.4%. MRI-based measurements correlated well with volumes of surgically resected cartilage (r = 0.97, pair-wise random difference 4.2%). The medial tibial cartilage thickness and volume were about 35% smaller in the operated knees than in the non-operated contralateral knees (p < 0.05). The findings suggest that MRI is a precise and accurate tool for evaluating cartilage in a rabbit model of OA. The difference between the intact and operated knee in thickness and volume of the medial tibial cartilage was slightly but not significantly smaller in the HP treated group than in the non-treated group. PMID- 21284048 TI - Prognostic factors in patients with high-risk locally advanced salivary gland cancers treated with surgery and postoperative radiotherapy. AB - BACKGROUND: This study was designed to identify the factors associated with the outcome after standard treatment with surgery and postoperative radiotherapy (RT) for locally advanced salivary gland cancers. METHODS: We conducted a retrospective review of patients with salivary gland cancers registered in the University of Pittsburgh databases from 1990 to 2006. RESULTS: A total of 74 patients were analyzed. Histologic types included salivary duct carcinoma, 24%; adenoid cystic carcinoma, 23%; and adenocarcinoma, 19%; N2, 39%; N0-1, 58%; and major salivary gland origin, 80%. With a median follow-up of 4.1 years, the 5 year recurrence-free survival (RFS) was 49%, and the 5-year overall survival (OS) was 55%. The 5-year local RFS was 76% and the 5-year distant RFS was 60%. Using Cox-regression analysis, advanced N classification (N2) was the only significant predictor of both RFS and OS. CONCLUSION: The long-term survival of patients with high-risk, locally advanced salivary gland cancers is unsatisfactory. Advanced nodal disease is strongly associated with patient outcome and should be considered as a stratification factor in future trials in locally advanced salivary gland cancers. PMID- 21284049 TI - Outcome of patients treated surgically for lymph node metastases from cutaneous squamous cell carcinoma of the head and neck. AB - BACKGROUND: There is a paucity of outcomes data for patients with lymph node metastasis from cutaneous squamous cell carcinoma of head and neck (SCCHN). METHODS: Patients from a tertiary care center with cutaneous SCCHN metastatic to parotid and or cervical lymph nodes were identified. Data were abstracted and analyzed using COX multivariate analysis. RESULTS: Fifty-one patients (47 men, and 4 women) with a median age of 73 years were identified. Eight patients (16%) had recurrent disease and 11 (22%) were immunosuppressed. Forty patients (71%) received adjuvant radiation therapy. Median overall survival was 23 months (range, 3-148 months). Recurrent disease was associated with higher risk of death (hazard ratio [HR], 2.7; 95% confidence interval [CI] 1.1-6.9) and radiation therapy with reduced risk (HR, 0.18; 95% CI, 0.06-0.54). CONCLUSION: Lymph node metastases from cutaneous SCCHN is associated with poor survival. PMID- 21284050 TI - Role of DNA methyltransferase 1 in pharyngeal cancer related to treatment resistance. AB - BACKGROUND: The purpose of the present study was to highlight the role of DNA methyltransferase 1 (DNMT1) and its potential for improving treatment and informing prognosis for pharyngeal cancer. METHODS: Human pharyngeal cancer cell lines FaDu and its derivative FaDu-C225-R were selected for cellular experiments. Furthermore, 95 pharyngeal cancer tissue specimens were analyzed by immunohistochemical staining. RESULTS: DNMT1 was over-expressed in pharyngeal cancer specimens and cells with activated interleukin (IL)-6 signaling. When DNMT1 activity was blocked, accelerated tumor growth and treatment resistance were overcome as demonstrated by cell culture and animal experiments. The reduction in DNMT1 was associated with increased apoptosis, cell cycle arrest, and augmented irradiation-induced free radical levels and DNA damage. Furthermore, positive staining for DNMT1 in clinical cancer specimens was significantly linked to lower rates of response to treatments and shorter survival of patients with pharyngeal cancer. CONCLUSION: DNMT1 may be a significant clinical predictor and a potential treatment strategy against head and neck cancer. PMID- 21284051 TI - Image-guided surgery in head and neck cancer: current practice and future directions of optical imaging. AB - A key aspect for the postoperative prognosis of patients with head and neck cancer is complete tumor resection. In current practice, the intraoperative assessment of the tumor-free margin is dependent on visual appearance and palpation of the tumor. Optical imaging has the potential of traversing the gap between radiology and surgery by providing real-time visualization of the tumor, thereby allowing for image-guided surgery. The use of the near-infrared light spectrum offers 2 essential advantages: increased tissue penetration of light and an increased signal-to-background ratio of contrast agents. In this review, the current practice and limitations of image-guided surgery by optical imaging using intrinsic fluorescence or contrast agents are described. Furthermore, we provide an overview of the various molecular contrast agents targeting specific hallmarks of cancer that have been used in other fields of oncologic surgery, and we describe perspectives on its future use in head and neck cancer surgery. PMID- 21284052 TI - Novel neoadjuvant immunotherapy regimen safety and survival in head and neck squamous cell cancer. AB - BACKGROUND: Cellular immune suppression is observed in head and neck squamous cell cancer (HNSCC) and contributes to poor prognosis. Restoration of immune homeostasis may require primary cell-derived cytokines at physiologic doses. An immunotherapy regimen containing a biologic, with multiple-active cytokine components, and administered with cytoxan, zinc, and indomethacin was developed to modulate cellular immunity. METHODS: Study methods were designed to determine the safety and efficacy of a 21-day neoadjuvant immunotherapy regimen in a phase 2 trial that enrolled 27 therapy-naive patients with stage II to IVa HNSCC. Methods included safety, clinical and radiologic tumor response, disease-free survival (DFS), overall survival (OS), and tumor lymphocytic infiltrate (LI) data collection. RESULTS: Acute toxicity was minimal. Patients completed neoadjuvant treatment without surgical delay. By independent radiographic review, 83% had stable disease during treatment. OS was 92%, 73%, and 69% at 12, 24, and 36 months, respectively. Histologic analysis suggested correlation between survival and tumor LI. CONCLUSION: Immunotherapy regimen was tolerated. Survival results are encouraging. PMID- 21284053 TI - Clinical and pathological determinants in tonsillar cancer. AB - BACKGROUND: The purpose of this study was to present the impact of clinicopathological factors on patient survival in tonsillar squamous cell carcinoma (SCC) that needs to be evaluated. METHOD: This study enrolled 86 patients with tonsillar SCC undergoing surgical resection. RESULTS: The cumulative 5-year disease-specific survival (DSS) rate for stages I, II, III, and IVa/b tumors was 100%, 91.7%, 100%, and 61.8%, respectively. Unfavorable cumulative 5-year DSS rates were significantly correlated with advanced T classification (p = .029), tumor thickness over 1 cm (p = .007), 3 or more positive neck lymph nodes (p < .001), and extracapsular spread (ECS; p = .002). Cox regression analysis revealed that the presence of 3 or more positive neck lymph nodes (p = .035) and the stage IVa/b (p = .022) were the independent predictors of the 5-year DSS. CONCLUSION: Patients with tonsillar SCC with stage IVa/b and metastasis to 3 or more lymph nodes have poorer clinical outcomes. Novel therapeutic strategies are necessary for these patients. PMID- 21284054 TI - Reirradiation with intensity-modulated radiotherapy in recurrent head and neck cancer. AB - BACKGROUND: In this retrospective investigation we analyzed outcome and toxicity after intensity-modulated reirradiation of recurrent head and neck cancer. METHODS: Thirty-eight patients with local recurrent head and neck cancer were evaluated. The median dose of initial radiotherapy was 61 Gy. Reirradiation was carried out with step-and-shoot intensity-modulated radiotherapy (median dose: 49 Gy). RESULTS: Median overall survival was 17 months, and the 1- and 2-year overall survival rates were 63% and 34%. The 1- and 2-year local control rates were 57% and 53%. Distant spread occurred in 34%, and reirradiation induced considerable late toxicity in 21% of the patients. Thirty-two percent showed increased xerostomia after reirradiation. The risk for xerostomia was significantly higher for cumulative mean doses of >=45 Gy to parotid glands. Considering median cumulative maximum doses of 53 Gy to the spinal cord and 63 Gy to the brainstem, no late toxicities were observed. CONCLUSIONS: Reirradiation with intensity-modulated radiotherapy in recurrent head and neck cancer is feasible with acceptable toxicity and yields encouraging rates of local control and overall survival. PMID- 21284055 TI - Epidermal growth factor receptor mutations in patients with oral cavity cancer in a betel nut chewing-prevalent area. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) mutations exist in patients with oral cavity squamous cell carcinoma (OSCC), but few data about mutation patterns with clinical outcomes were reported. METHODS: Fifty-six formalin-fixed paraffin-embedded tumor samples were obtained surgically from OSCC patients. Direct sequencing of EGFR was carried out using nested polymerase chain reaction. The relationship between EGFR status and clinical courses was analyzed. RESULTS: Two (3.56%) missense mutations (G857R; L862Q) in exon 20 were identified. Two types of silent mutation, A859A in exon 21 (1.79%) and Q787Q mutations in exon 20 (30.36%), were also found. No mutation was detected in exons 18 and 19. No significant difference in disease-free survival and locoregional control rate was shown between patients with and without Q787Q mutation. CONCLUSIONS: We identified a high frequency of Q787Q mutation and a less prevalent active EGFR mutation in OSCC patients in Taiwan where betel nut is commonly chewed. PMID- 21284056 TI - Transoral laser microsurgery as primary treatment for advanced-stage oropharyngeal cancer: a United States multicenter study. AB - BACKGROUND: Nonsurgical modalities are sometimes advocated as the standard of care for advanced oropharyngeal tumors. Oncologic and functional results have been modest. The aim of our study was to evaluate outcomes of a minimally invasive approach, using transoral laser microsurgery (TLM) as the primary treatment for advanced oropharyngeal carcinoma. METHODS: A prospectively assembled database of 204 patients with American Joint Committee on Cancer (AJCC) stages III and IV tonsil or tongue base cancer, treated primarily with TLM during 1996-2006 at 3 centers with minimum 2-year follow-up was analyzed. Survival, locoregional control, and swallowing status were recorded. RESULTS: Mean follow up was 49 months and 79.4% of patients were alive. Three-year overall survival, disease-specific survival, and disease-free survival were 86%, 88%, and 82%, respectively. Local control was 97%, and 87% of patients had normal swallowing or episodic dysphagia. CONCLUSIONS: TLM as a primary treatment for advanced oropharyngeal malignancy confers excellent survival and swallowing proficiency. PMID- 21284057 TI - Primacy of surgery in the management of mucoepidermoid carcinoma in children. AB - BACKGROUND: Epithelial salivary gland neoplasms are rare in children. Malignant tumors account for 30% to 50% of cases in the pediatric age group, with mucoepidermoid carcinoma as the most common histology. METHODS: A retrospective medical record review was conducted from 1953 to 2007 to identify patients with mucoepidermoid carcinoma at the age of 18 years or younger at the time of diagnosis. Forty-nine patients were identified. Their medical records were examined for presentation, treatment, pathologic features, and outcomes. RESULTS: Forty-nine pediatric patients with mucoepidermoid carcinoma were identified. The parotid gland (49%) and oral cavity (35%) were the most common subsites. Nodal metastasis was seen in 24% of patients. All patients underwent surgery, and 11 patients (22%) were treated with radiation therapy. The 5-year overall survival was 98%, the 10-year overall survival was 94%, and 10% of patients developed recurrence. CONCLUSION: Mucoepidermoid carcinoma in children carries a favorable prognosis and can be successfully treated with surgery alone in most cases. PMID- 21284058 TI - Marginal recurrences after selective targeting with intensity-modulated radiotherapy for oral tongue cancer. AB - BACKGROUND: No universal consensus of optimal radiation target coverage for oral tongue cancer exists, and there is wide variability in practice. Some centers use intensity-modulated radiotherapy (IMRT) to selectively target only certain regions at risk while sparing others; however, patterns of failure after such selective targeting are rarely reported. METHODS AND RESULTS: We critically examined the location of failure in 4 patients with stage III to IV oral tongue cancer who presented to our department with locoregional recurrence after receiving IMRT with selective radiation targeting at outside institutions. All 4 patients' cancer recurred marginally in regions that were not initially targeted, whereas the regions would have been targeted if comprehensive IMRT targeting had been used. The median time to recurrence was short (3.9 months; range, 1.2-10.1 months). CONCLUSION: This case series highlights the occurrence of marginal failures after selective targeting with IMRT for oral tongue cancer and cautions against this practice unless further supporting evidence becomes available. PMID- 21284062 TI - Mental disorders and traumatic injury. PMID- 21284064 TI - Informing the symptom profile of complicated grief. AB - BACKGROUND: Complicated Grief (CG) is under consideration as a new diagnosis in DSM5. We sought to add empirical support to the current dialogue by examining the commonly used Inventory of Complicated Grief (ICG) scale completed by 782 bereaved individuals. METHODS: We employed IRT analyses, factor analyses, and sensitivity and specificity analyses utilizing our full sample (n = 782), and also compared confirmed CG cases (n = 288) to noncases (n = 377). Confirmed CG cases were defined as individuals bereaved at least 6 months who were seeking care for CG, had an ICG >= 30, and received a structured clinical interview for CG by a certified clinician confirming CG as their primary illness. Noncases were bereaved individuals who did not present with CG as a primary complaint (including those with depression, bipolar disorder, anxiety disorders, and controls) and had an ICG<25. RESULTS: IRT analyses provided guidance about the most informative individual items and their association with CG severity. Factor analyses demonstrated a single factor solution when the full sample was considered, but within CG cases, six symptom clusters emerged: (1) yearning and preoccupation with the deceased, (2) anger and bitterness, (3) shock and disbelief, (4) estrangement from others, (5) hallucinations of the deceased, and (6) behavior change, including avoidance and proximity seeking. The presence of at least one symptom from three different symptom clusters optimized sensitivity (94.8%) and specificity (98.1%). CONCLUSIONS: These data, derived from a diverse and predominantly clinical help seeking population, add an important perspective to existing suggestions for DSM5 criteria for CG. PMID- 21284065 TI - Acceptance-based behavioral therapy for GAD: effects on outcomes from three theoretical models. AB - BACKGROUND: Although cognitive-behavioral therapy (CBT) is efficacious in the treatment of generalized anxiety disorder (GAD), many individuals remain symptomatic following treatment, indicating a need for further treatment development. As a result, many researchers have developed unique cognitive behavioral therapies that highlight specific targets for intervention. METHODS: The current study examined the effect of an acceptance-based behavioral therapy for GAD on the proposed targets for intervention highlighted in several theoretical models: emotion regulation difficulties, intolerance of uncertainty, and low perceptions of control. Clients were randomly assigned to immediate (n=15) or delayed (n=16) treatment. RESULTS: Individuals treated with the acceptance-based behavioral therapy reported significantly fewer difficulties in emotion regulation and fear of emotional responses, as well as greater tolerance of uncertainty and perceived control over anxiety than individuals in the waitlist control condition. In addition, these effects were maintained at 3- and 9-month follow-up assessments. CONCLUSIONS: The present study provides promising evidence that an acceptance-based behavioral therapy for GAD has significant effects on the unique targets of intervention highlighted in several prominent theoretical models of GAD. PMID- 21284063 TI - Complicated grief and related bereavement issues for DSM-5. AB - Bereavement is a severe stressor that typically incites painful and debilitating symptoms of acute grief that commonly progresses to restoration of a satisfactory, if changed, life. Normally, grief does not need clinical intervention. However, sometimes acute grief can gain a foothold and become a chronic debilitating condition called complicated grief. Moreover, the stress caused by bereavement, like other stressors, can increase the likelihood of onset or worsening of other physical or mental disorders. Hence, some bereaved people need to be diagnosed and treated. A clinician evaluating a bereaved person is at risk for both over-and under-diagnosis, either pathologizing a normal condition or neglecting to treat an impairing disorder. The authors of DSM IV focused primarily on the problem of over-diagnosis, and omitted complicated grief because of insufficient evidence. We revisit bereavement considerations in light of new research findings. This article focuses primarily on a discussion of possible inclusion of a new diagnosis and dimensional assessment of complicated grief. We also discuss modifications in the bereavement V code and refinement of bereavement exclusions in major depression and other disorders. PMID- 21284066 TI - Residual symptoms after remission of major depressive disorder with fluoxetine and risk of relapse. AB - BACKGROUND: Many patients with major depressive disorder (MDD) who achieve full remission after antidepressant treatment still have residual depressive symptoms. In this study, we assess the type and frequency of residual symptoms and their relationship to subsequent depressive relapses after remission of major depression with fluoxetine. METHOD: Five hundred seventy-six patients with MDD were openly treated with fluoxetine for 12 weeks. Those who responded underwent random assignment, under double-blind conditions, to continue taking fluoxetine or to switch to placebo for 52 weeks or until relapse. The presence of residual symptoms in patients who achieved remission at the end of the acute phase (N=203) was assessed using the 28-item Hamilton Depression Rating Scale. Survival analysis was used to examine the effect of residual symptoms on relapse in remitters. RESULTS: More than 90% of patients who met criteria for remission had at least one residual depressive symptom (median=4). The most common were sleep disturbances (insomnia 48.2%, hypersomnia 35.9%) and anxiety (52.7%). The most common individual symptom was middle insomnia (33.5%). No statistically or clinically significant differences in baseline variables were found between remitters with and without residual symptoms. The presence of residual symptoms, the presence of residual insomnia and the global number of residual symptoms did not predict relapse during the continuation phase of the study. CONCLUSION: The great majority of patients with remission of MDD after treatment with fluoxetine continue to experience selected residual depressive symptoms. The presence of residual symptoms is not significantly associated with an increased risk of relapse. PMID- 21284067 TI - Anger problems across the anxiety disorders: findings from a population-based study. AB - BACKGROUND: Previous research examining anger problems among the anxiety disorders has been limited by the use of nonrepresentative samples, univariate analyses, as well as low sample size. The current study examined the association between posttraumatic stress disorder (PTSD), panic disorder (PD), social anxiety disorder, specific phobia (SP), and generalized anxiety disorder (GAD) and anger experience and expression. We hypothesized that greater anger experience and expression would be associated with all anxiety disorders, but that it would be most consistently associated with PTSD and PD diagnoses, and that these relationships would remain significant after controlling for demographics (i.e. age, gender, ethnicity, marital status, and income) and comorbid disorders. METHODS: Participants included 5,692 (54% female) adults from the National Comorbidity Survey-Replication, a large, nationally representative survey. RESULTS: Our data suggest that there are unique relationships between multiple anxiety disorders and various indices of anger experience and expression that are not better accounted for by psychiatric comorbidity. Contrary to predictions, PTSD and PD were not consistently associated with anger experience and expression. CONCLUSIONS: Overall, these findings lend support to the emerging literature demonstrating a potentially important relationship between anxiety disorders and anger problems. PMID- 21284068 TI - Parent-child interaction therapy emotion development: a novel treatment for depression in preschool children. AB - BACKGROUND: Psychotherapies with known efficacy in adolescent depression have been adapted for prepubertal children; however, none have been empirically validated for use with depressed very young children. Due to the centrality of the parent-child relationship to the emotional well being of the young child, with caregiver support shown to mediate the risk for depression severity, we created an Emotional Development (ED) module to address emotion development impairments identified in preschool onset depression. The new module was integrated with an established intervention for preschool disruptive disorders, Parent Child Interaction Therapy (PCIT). Preliminary findings of an open trial of this novel intervention, PCIT-ED, with depressed preschool children are reported. METHODS: PCIT was adapted for the treatment of preschool depression by incorporating a novel emotional development module, focused on teaching the parent to facilitate the child's emotional development and enhance emotion regulation. Eight parent-child dyads with depressed preschoolers participated in 14 sessions of the treatment. Depression severity, internalizing and externalizing symptoms, functional impairment, and emotion recognition/discrimination were measured pre- and posttreatment. RESULTS: Depression severity scores significantly decreased with a large effect size (1.28). Internalizing and externalizing symptoms as well as functional impairment were also significantly decreased pre- to posttreatment. CONCLUSIONS: PCIT-ED seems to be a promising treatment for preschoolers with depression, and the large effect sizes observed in this open trial suggest early intervention may provide a window of opportunity for more effective treatment. A randomized controlled trial of PCIT-ED in preschool depression is currently underway. PMID- 21284069 TI - Third-person effects and direct-to-consumer advertisements for antidepressants. AB - BACKGROUND: This study examines the evidence for a third- person effect (TPE) in the reactions of individuals affected by depression to direct-to-consumer (DTC) advertisements for antidepressants. TPE predicts that people will perceive the self to be less vulnerable to such advertisements than others. Previous research has identified such an effect, but did so in general population surveys. Past Previous research has also found a link between depression and diminished self serving biases; whether this would be the case for TPE is unknown. METHODS: An online questionnaire was administered to 148 participants in an Internet depression support group to investigate their perceptions of the influence of direct-to-consumer (DTC) advertisements for antidepressants. RESULTS: Consistent with expectations derived from third-person effect TPE research, participants, although relatively neutral in their attitudes toward such advertisements, nevertheless perceived other individuals with depression as more influenced than themselves. Positive attitudes towards DTC advertisements and depressive symptoms at the time of the survey were each negatively associated with this third-person perception (TPE). CONCLUSIONS: Individuals who have been diagnosed with depression and who participated in an online depression support group believe that they are less vulnerable to the influence of DTC advertisements than the typical person with a history of depression. This is moderated by attitudes towards DTC advertisements as well as by depressive symptoms, each of which is associated with a weakened TPE. PMID- 21284070 TI - Approach and avoidance learning in obsessive-compulsive disorder. AB - BACKGROUND: Current neurobiological models of obsessive-compulsive disorder (OCD) propose a dysfunction of cortico-striato-thalamo-cortical circuits that leads to enhanced activity in frontal and striatal brain regions. In accordance with that, OCD patients show alterations in learning and flexible adaptation to changing task requirements. The purpose of this study was to examine feedback-based learning and to investigate whether learning from positive and negative feedback is differentially altered in OCD. METHODS: In this study, 18 OCD patients and 18 healthy comparison subjects conducted a probabilistic selection task. The task consisted of an acquisition and a test phase and allowed disentangling the extent of learning based on positive and negative feedback. RESULTS: Groups did not differ during probabilistic feedback learning in the acquisition phase. In the test phase, OCD patients showed a negative learning bias in contrast to comparison subjects who showed a positive learning bias. Patients were better at avoiding stimuli that were initially associated with negative outcomes than at approaching stimuli that were associated with positive feedbacks. This interaction was also found for reaction times in that patients were faster in avoiding negative and slower in approaching positive stimuli. CONCLUSION: Enhanced avoidance learning was found in OCD patients that points to exaggerated anticipation and avoidance of aversive outcomes. Further studies are required to investigate whether neurobiological mechanisms, such as dopaminergic signaling or outcome processing, in the orbitofrontal cortex relate to enhanced negative learning in OCD. PMID- 21284071 TI - Generalized Anxiety Disorder in youth: diagnostic considerations. AB - BACKGROUND: Generalized Anxiety Disorder (GAD) in youth is characterized by excessive worry across domains for >= 6 months, an inability to stop worrying, and at least one physiological symptom. This study examined the multiple domains that optimally distinguish (1) GAD youth from nonanxiety-disordered youth and (2) GAD youth from other anxiety-disordered youth. METHODS: Receiver operating characteristic analyses examined a sample of youth (N=180) aged 7-13 (M=10.10; 52% male), to determine optimal cut scores to distinguish GAD youth from (1) nonanxiety-disordered youth and (2) other anxiety-disordered youth. The diagnostic efficiency of worries and physiological symptoms was also examined. RESULTS: By parent report, three worries and four physiological symptoms had favorable cut scores, and several specific worries possessed high diagnostic efficiency. Children endorsed fewer GAD symptoms. CONCLUSIONS: Recommendations are made regarding the criteria for GAD in youth and interview sequencing of symptom queries. PMID- 21284072 TI - Towards polycyclic aromatic hydrocarbons with a singlet open-shell ground state. PMID- 21284073 TI - Sitagliptin manufacture: a compelling tale of green chemistry, process intensification, and industrial asymmetric catalysis. PMID- 21284074 TI - Finite element analysis in adjacent segment degeneration after lumbar fusion. AB - BACKGROUND: Adjacent segment degeneration (ASD) following lumbar fusion has been well documented in recent years. However, the pathogenesis of ASD is not clear. To investigate this issue, we established a finite element model of segments L2 L5, simulated a single-segment posterior fixation in L3-L4 and investigated the stress variation and the effects of the instrumented lumbar posterior fixation on adjacent levels. METHODS: Models A, B and C of L2-L5 multisegment finite element intact models were established. In model A, segment L3-L4 was not fixed and was without disc degeneration in the adjacent segment (L2-L3, L4-L5); in model B there was posterior pedicle fixation in segment L3-L4 without disc degeneration in the adjacent segment (L2-L3, L4-L5); in model C there was posterior pedicle fixation in segment L3-L4 with a degenerated disc in the adjacent segment (L2-L3, L4-L5). Four levels of axial pressure, 0.3, 0.5, 1.0 and 2.0 MPa, were compared between each model of the stress variation on the discs of the adjacent segment (L2-L3, L4-L5). RESULTS: The maximum principal stress mean value of disc L2-L3 under four pressures in model A was determined. The statistical results showed that stress was not significant difference in disc L2-L3 between models A and B, but there was a significant difference in disc L2-L3 between models A and C and a significant difference between each group in disc L4-L5 under four pressure conditions. CONCLUSIONS: The preoperative degeneration of the adjacent segment of the disc is a significant risk factor for ASD. PMID- 21284075 TI - An oral developmental neurotoxicity study of decabromodiphenyl ether (DecaBDE) in rats. AB - BACKGROUND: Decabromodiphenyl ether (DecaBDE; CASRN 1163-19-5) is a flame retardant used in a variety of manufactured products. A single oral dose of 20.1 mg/kg administered to mice on postnatal day 3 has been reported to alter motor activity at 2, 4, and 6 months of age. METHODS: To further evaluate these results, a developmental neurotoxicity study was conducted in the most commonly used species for studies of this type, the rat, according to international validated testing guidelines and Good Laboratory Practice Standards. DecaBDE was administered orally via gavage in corn oil to dams from gestation day 6 to weaning at doses of 0, 1, 10, 100, or 1,000 mg/kg/day. Standard measures of growth, development, and neurological endpoints were evaluated in the offspring. Motor activity was assessed at 2 months of age. Additional motor activity assessments were conducted at 4 and 6 months of age. Neuropathology and morphometry evaluations of the offspring were performed at weaning and adulthood. RESULTS: No treatment-related neurobehavioral changes were observed in detailed clinical observations, startle response, or learning and memory tests. No test substance-related changes were noted in motor activity assessments performed at 2, 4, or 6 months of age. Finally, no treatment-related neuropathological or morphometric alterations were found. CONCLUSIONS: Under the conditions of this study, the no-observed-adverse-effect level for developmental neurotoxicity of DecaBDE was 1,000 mg/kg/day, the highest dose tested. PMID- 21284076 TI - Pediatric oncologists' practices of prescribing selective serotonin reuptake inhibitors (SSRIs) for children and adolescents with cancer: a multi-site study. AB - OBJECTIVE: To survey pediatric oncologists regarding prescription of selective serotonin reuptake inhibitors (SSRIs) and related medications for the treatment of depression and anxiety disorders in children with cancer. Specifically, we sought to determine (a) how frequently pediatric oncologists prescribed SSRIs and what were the most commonly prescribed agents; (b) how decisions were made to prescribe, particularly whether mental health professionals were consulted; (c) how patients were monitored while on the agents; and (d) how the FDA black box warning has affected prescribing practices. METHOD: Oncologists from nine children's cancer centers (N = 151) from across the U.S. were surveyed, responding to either on-line or paper versions of a questionnaire developed for this study. RESULTS: A majority of oncologists (71%) reported prescribing SSRIs for their patients. Oncologists reported difficulties differentiating symptoms of depression from aspects of cancer treatment. Mental health practitioners are consulted occasionally but not routinely, and oncologists reported a need for increased mental health resources. Approximately half of oncologists (51%) reported that the FDA black box warning had not affected their practice. In addition, only 28% reported monitoring patients on SSRIs at FDA recommended intervals, and only 9% indicated assessing for suicidality. CONCLUSIONS: Prescription of SSRIs is a common practice of pediatric oncologists, often without consultation with mental health professionals. Post-prescription monitoring appears to be suboptimal, and does not follow FDA guidelines. PMID- 21284077 TI - The successful integration of research and care: how pediatric oncology became the subspecialty in which research defines the standard of care. AB - Pediatric oncology successfully embodies the integration of patient care with medical research. Several factors may explain this phenomenon. Specifically, the study of childhood leukemia provided scientists with principles by which they could approach other forms of cancer. Multicenter, cooperative group RCTs resulted in meaningful advances. Parents' often desperate hope for a cure, combined with clinician-investigators efforts to continually improve upon treatments resulted in important improvements in children's lives. Finally, the seemingly tolerant regulatory oversight of human subjects research in the early years of childhood cancer research paradoxically helped link research with care, thus solidifying this bond for years to come. PMID- 21284078 TI - Increasing diversity in pediatric hematology/oncology. AB - BACKGROUND: Diversity is necessary for the survival and success of both biological and social systems including societies. There is a lack of diversity, particularly the proportion of women and minorities in leadership positions, within medicine [Leadley. AAMC 2009. Steinecke and Terrell. Acad Med 2010;85:236 245]. In 2009 a group of ASPHO members recognized the need to support the career advancement of women and minority members. This article reports the results of a survey designed to characterize the comparative career pathway experience of women and minority ASPHO members. PROCEDURE: A group of ASPHO members modified a published Faculty Worklife survey [Pribbenow et al. High Educ Policy 2010;23:17 38] for use by Pediatric Hematologist-Oncologists (PHOs). A link to an online version of the survey was sent to all ASPHO members. RESULTS: Of 1,228 ASPHO members polled, 213 responded (17%). Women and minority PHOs reported less satisfaction than their counterparts on 70 of the 90 issues addressed in the survey including the hiring process, access to resources as well as integration and satisfaction with their organizations. Women also expressed greater dissatisfaction with issues of work-life balance, support for family obligations and personal health. CONCLUSIONS: The current literature suggests that there are significant disparities in career opportunities, compensation and satisfaction for women compared to men and minority compared to majority faculty in academic medicine [Nivet. J Vasc Surg 2010;51:53S-58S; Peterson et al. J Gen Intern Med 2004;19:259-265; DesRoches et al. Acad Med 2010;85:631-639; Castillo-Page. AAMC 2008]. Our data, derived from a survey of ASPHO members, suggests that this holds true for PHOs as well. PMID- 21284079 TI - Electrospinning and biocompatibility evaluation of biodegradable polyurethanes based on L-lysine diisocyanate and L-lysine chain extender. AB - A series of biodegradable polyurethanes (PUs) were synthesized using poly(epsilon caprolactone) diol (PCL) to react with L-lysine ethyl ester diisocyanate (LDI) chain extend with L-lysine ethyl ester (LEE) in solution of DMF. The structure was characterized by gel permeation chromatography, 1H-NMR, Fourier transform infrared, and DSC analyses. Mechanical property testing showed that their tensile strength rose with increasing the hard segment content with a maximum tensile strength of 34.43 +/- 1.73 MPa. The average mass loss for the hydrolytic degradation was only about 13 % in 56 days while this value for the enzymatic degradation was around 95 % in 30 days. The morphological and biomechanical characters of the tubular scaffolds electrospun from the as-prepared PUs were also examined. As the solution concentration was varied from 10 to 18% (w/v), the fiber diameter was progressively increased, and the scaffold tensile strength was enhanced from 2.82 +/- 0.16 MPa to 7.07 +/- 0.44 MPa, the suture retention strength from 2.48 +/- 0.33 to 8.38 +/- 0.35 N, and the burst pressure strength from 72 +/- 2 to 172 +/- 2 kPa, all higher than those of native blood vessels. At the same time, the L-929 mouse fibroblasts (L-929) and human umbilical vein endothelial cells were used in cytotoxicity and cell-adhesion evaluations toward the electrospun scaffolds. The level of toxicity is less than level 1, and cells were found to attach well to and remain viable on the scaffolds. PMID- 21284080 TI - A novel collagen/hydroxyapatite/poly(lactide-co-epsilon-caprolactone) biodegradable and bioactive 3D porous scaffold for bone regeneration. AB - The goal of this study was to design a nontoxic scaffold with both composition and microstructure suitable for bone engineering using collagen (Coll), hydroxyapatite (HA), and poly(lactide-co-epsilon-caprolactone) (PLCL). Mineralized type I Coll was produced by direct nucleation of HA particles inside self-assembled Coll fibers to obtain a Coll/HA complex, which was then added to dissolved PLCL (70:30) in 1,4-dioxane. A 3D porous Coll/HA/PLCL scaffold was subsequently produced through freeze-drying/lyophilization and salt-leaching procedures. The resulting Coll/HA/PLCL scaffold displayed a high uniform porosity and highly interconnected pores. X-ray photoelectron spectrometer and Fourier transform infrared analyses revealed the presence of both collagen and HA particles on the surface of the Coll/HA/PLCL scaffold. Proliferation assay, microscopic observations, and gene analysis with quantitative RT-PCR showed that osteoblast cells were able to attach, proliferate, and maintain an osteoblastlike phenotype when cultured on the Coll/HA/PLCL scaffold. In summary, we produced a nontoxic scaffold that contains natural polymers (Coll and HA) and synthetic polymer (PLCL). Through its chemical composition and porous morphology, this scaffold may be useful for osteoblast growth, differentiation, and bone tissue formation. PMID- 21284081 TI - Evaluation of chlorine containing cellulose-based chiral stationary phases for the LC enantioseparation of basic pharmaceuticals using polar non-aqueous mobile phases. AB - The discrimination ability of three cellulose-based chiral stationary phases (CSPs) was evaluated towards the enantiomers of basic drugs, using ACN as the main solvent in polar organic mobile phases. The study was focused on CSPs containing cellulose tris(3-chloro-4-methylphenylcarbamate) (3-Cl-4-MePC), cellulose tris(4-chloro-3-methylphenylcarbamate) (4-Cl-3-MePC) or cellulose tris(3,5-dichlorophenylcarbamate) (3,5-diClPC) as the chiral selector. The behaviour of these CSPs was studied systematically in order to investigate the influence of the presence and position of the chlorine substituents on the phenylcarbamate moieties on the retention and resolution of the enantiomers. The evaluation was made with three different generic mobile phases, namely ACN/0.1%DEA/0.1% TFA (DEA, diethylamine), ACN/0.1%DEA/0.2% FA and ACN/0.1%DEA/0.2%AcA, deduced from the previous study. The nature of the acidic additive and of the chiral selector was found to be particularly important for the retention and enantioresolution of these basic compounds. High-resolution values could be obtained for most studied enantiomers with these CSPs, clearly demonstrating the interest of using them in combination with polar organic mobile phases. However, significant differences in enantioresolution between the CSPs have been observed for many compounds, indicating that these phases seem to be quite complementary. PMID- 21284082 TI - UHPLC-TOFMS coupled with chemometric method as a powerful technique for rapid exploring of differentiating components between two Ziziphus species. AB - To rapidly explore the differentiating components and the potential chemical markers for discrimination between those Chinese medicinal herbs with similar chemical characteristics, an ultra-high-performance liquid chromatography (UHPLC) TOFMS coupled with multivariate statistical analysis method was proposed and validated by using two Ziziphus species (Z. jujuba and Z. jujuba var. spinosa) as the model herbs. After the samples were analyzed using UHPLC-TOFMS, the data sets of retention time (RT)-m/z pairs, ion intensities and sample codes were further processed with orthogonal partial least squared discriminant analysis (OPLS-DA) to holistically compare the difference between the fruits of these two Ziziphus species, and to generate an S-plot. Those compounds correlating to the points at the two ends of "S" were regarded as the most differentiating components between these two kinds of samples. By comparing the mass/UV spectra and retention times with those of reference compounds, these components were finally characterized as zizyberenalic acid, palmitoleic acid, oleic acid, pomonic acid and rutin, and these compounds would be the potential chemical markers for discrimination of these jujube products. The results suggested that this newly established approach could be used to rapidly determine the subtle differences and explore the potential chemical markers for differentiation within the herbs with similar chemical ingredients. PMID- 21284083 TI - Determination of nitroanilines in hair dye using polymer monolith microextraction coupled with HPLC. AB - In this study, a novel method for the determination of nitroanilines in hair dye samples has been developed based on poly(methacrylic acid-co-ethylene glycol dimethacrylate) monolith microextraction (PMME) and high-performance liquid chromatography (HPLC) analysis. Four nitroanilines, p-nitroaniline (PNAL), m nitroaniline (MNAL), o-nitroaniline (ONAL), and 2,4-dinitroaniline (DNAL), are studied as representatives. To obtain optimum extraction efficiency, several experimental parameters including sample flow rate, sample volume, sample pH, and eluent flow rate have been investigated. Under the optimal experimental conditions, the linear regression coefficients of the standard curves are greater than 0.9990. The limits of detection for p-nitroaniline, m-nitroaniline, o nitroaniline, and 2,4-dinitroaniline are 0.012, 0.008, 0.018, and 0.005 MUg/mL, respectively. The intraday and interday relative standard deviations are less than 3.1 and 5.4%, respectively. The proposed method is simple, rapid, sensitive, and competent when used for the determination of nitroanilines in hair dye samples and the accuracy is assessed through recovery experiments. PMID- 21284090 TI - Protective effect of resveratrol on acute lung injury induced by lipopolysaccharide in mice. AB - Resveratrol, a phytoalexin found in a range of plant products, may exert a variety of pharmacological activities. In this study, we investigated the effect of resveratrol on acute lung injury (ALI) induced by lipopolysaccharide (LPS) in vivo, and we found that the pretreatment with resveratrol can effectively protect mice against LPS-induced ALI. Mice were pretreated with 1 mg/kg resveratrol for 3 days before challenging with a dose of 15 mg/kg LPS. The histological result showed that resveratrol can suppress the edema, inflammatory cell infiltration, and alveolar structure damage of lungs in ALI mice, and a decrease in the lung W/D ratio was also observed in mice with resveratrol pretreatment. Additionally, resveratrol markedly decreased the production of inflammatory cytokines, including IL-1beta and MIP-1alpha and prevented the release of nitric oxide (NO) through inhibiting the expression of inducible NO synthase in lung tissues. Furthermore, the pretreatment with resveratrol suppressed the nuclear translocation of NF-kappaB in lung tissues, which may be partly responsible for its effect on the ALI. In conclusion, the results presented here may suggest resveratrol as a potential therapeutic agent for treating ALI in the future. PMID- 21284091 TI - Age-related changes of the oligodendrocytes in rat subcortical white matter. AB - The age-related changes, of the oligodendrocytes in rat subcortical white matter, were investigated in this study. The oligodendrocytes in subcortical white matter were labeled with anti-2',3'-cyclic nucleotide 3'-phosphodiesterase antibody (anti-CNPase antibody, a specific marker of oligodendrocytes). The total number of CNPase(+) cells was estimated with an unbiased stereological technique, the optical fractionator. In this study, we found that the total number of CNPase(+) cells in the young male rats and aged male rats was 14.4 +/- 1.2 * 10(6) and 9.0 +/- 1.0 * 10(6) , respectively. The total number of the CNPase(+) cells in the subcortical white matter of aged rats was significantly decreased by 37.5% when compared to young male rats. This study demonstrated that there was an aged related decrease of the oligodendrocytes in subcortical white matter. PMID- 21284092 TI - Ultrastructural and immunohistochemical analysis of intestinal myofibroblasts during the early organogenesis of the human small intestine. AB - Intestinal myofibroblasts (IMFs), also known as pericryptal fibroblasts, are found at the basement membrane of the intestinal epithelium. They are characterized by well-developed endoplasmic reticulum, cytoplasmic fibers, and fibrous extensions called fibronexi. IMFs have structural features in common both with fibroblasts and smooth cells. Vimentin, desmin, and alpha-smooth-muscle actin (alpha-SM) are markers commonly used to discriminate between IMFs and smooth muscle cells. Immunohistochemical studies have shown that, when alpha-SM and vimentin are positive in both IMFs and smooth muscle cells, desmin is negative in IMFs but positive in smooth muscle cells. In the adult intestine, IMFs play an important role in various functions, especially in tissue repair and scar formation during wound healing. In the embryonic intestine, however, wound healing does not occur, and to date, no studies have investigated the first appearance and subsequent evolution of IMFs. In this study, we have examined the human small intestine in embryos at 7, 9, and 11 weeks of development by ultrastructural and immunohistochemical analysis to shed light on the formation of IMFs during these early phases of organogenesis. At 7 weeks, the embryonic mesenchymal cells are similar to proto-myofibroblasts and may be the precursors of the IMFs detected at 9 weeks and more abundantly at 11 weeks by immunohistochemistry. These IMFs seem to mediate information flow between the epithelium and the mesenchyme and thus contribute to the development of the small intestine. PMID- 21284093 TI - Comparative morphological configuration of the cardiac nervous system in lorises and galagos (infraorder Lorisiformes, Strepsirrhini, primates) with evolutionary perspective. AB - The detailed systematic morphology and comparative anatomy of the autonomic cardiac nervous system (ACNS) with its surrounding structures were examined in 14 sides of 7 Lorisiformes species (lorises and galagos) to consider its evolutionary differences and similarities to others in the primate lineage. Our detailed descriptions clarified that (1) a family-dependent morphology of the ACNS does not exist although several variations are recognized as common variation in Lorisiformes, (2) the morphology of the ACNS in Lorisiformes is almost consistent regardless of the number of presacral vertebrae and cardiac positions, and (3) the ACNS morphology in Lorisiformes is extremely different from that in New and Old World monkeys, gibbons, and human, specifically in a narrower contribution of the superior cervical ganglion to the spinal cervical nerves, the caudal position and organization of the cervicothoracic ganglion, and the narrower origins of the sympathetic cardiac nerves, although all parasympathetic vagal cardiac branches are consistently present among the primates. Based on these detailed findings, the systematic and evolutionary morphologies of the ACNS are discussed and compared with our previous works. These results suggest the primate ACNS preserves its evolutionary history without modification and specialization by its functional adaptation as seen in the somatic system. PMID- 21284094 TI - Exogenous material in the inner ear of the adult Port Jackson shark, Heterodontus portusjacksoni (Elasmbranchii). AB - Previous studies have suggested that the inner ear of some benthic species of elasmobranchs contain only exogenous material within their otoconial organs, a unique feature within vertebrates. However, these examinations have not accounted for the possibility of otoconial degeneration or used modern experimental methods to identify the materials present. Both of these issues are addressed in this study using inner ear samples from the adult Port Jackson shark, Heterodontus portusjacksoni. A comparison of the otoconial mass in fixed specimens over short and medium time scales reveals that over those timescales the degeneration of calcium carbonate-based otoconia does not occur and confirms that calcium carbonate-based otoconia are not found within the otoconial organs of H. portusjacksoni. Additionally, microanalysis of the chemical composition and ultrastructure of the otoconial mass using energy dispersive X-ray microanalysis and scanning electron microscopy confirms that the entire otoconial mass is comprised of exogenous silicon dioxide particles, bound within a carbon matrix. This exogenous material is suggested to play an equivalent role to the otoconia found in other species of elasmobranchs, and allows both hearing and vestibular control to occur in benthic sharks that spend their lives foraging within a sandy substrate. PMID- 21284095 TI - Diagnostic yield of nasal scrape biopsies in primary ciliary dyskinesia: a multicenter experience. AB - Examination of ciliary ultrastructure remains the cornerstone diagnostic test for primary ciliary dyskinesia (PCD), a disease of abnormal ciliary structure and/or function. Obtaining a biopsy with sufficient interpretable cilia and producing quality transmission electron micrographs (TEM) is challenging. Methods for processing tissues for optimal preservation of axonemal structures are not standardized. This study describes our experience using a standard operating procedure (SOP) for collecting nasal scrape biopsies and processing TEMs in a centralized laboratory. We enrolled patients with suspected PCD at research sites of the Genetic Disorders of Mucociliary Clearance Consortium. Biopsies were performed according to a SOP whereby curettes were used to scrape the inferior surface of the inferior turbinate, with samples placed in fixative. Specimens were shipped to a central laboratory where TEMs were prepared and blindly reviewed. Four hundred forty-eight specimens were obtained from 107 young children (0-5 years), 189 older children (5-18 years), and 152 adults (> 18 years), and 88% were adequate for formal interpretation. The proportion of adequate specimens was higher in adults than in children. Fifty percent of the adequate TEMs showed normal ciliary ultrastructure, 39% showed hallmark ultrastructural changes of PCD, and 11% had indeterminate findings. Among specimens without clearly normal ultrastructure, 72% had defects of the outer and/or inner dynein arms (IDA), while 7% had central apparatus defects with or without IDA defects. In summary, nasal scrape biopsies can be performed in the outpatient setting and yield interpretable samples, when performed by individuals with adequate training and experience according to an SOP. PMID- 21284096 TI - Seasonal variability of sleep-disordered breathing in children. AB - INTRODUCTION: Snoring and sleep-disordered breathing (SDB) are frequent pediatric conditions. Although allergies and respiratory viruses have been pathophysiologically implicated in these conditions, their seasonal distribution has not been examined. METHODS: The records of all children participating in a prospective, cross-sectional community-based research study that included a questionnaire on snoring frequency and loudness and an overnight sleep study were retrospectively assessed for seasonal patterns based on the day the children were evaluated. RESULTS: A total of 1,051 children were included with a mean age of 7 years. There were no seasonal differences in the number of children evaluated or in their demographic characteristics. However, the odds of increased snoring frequency and loudness were significantly higher in spring and summer and lowest in fall (P < 0.001). However, the mean AHI was highest and the nadir SaO(2) was lowest in winter and spring compared to summer and fall (P < 0.001 and P < 0.03, respectively). CONCLUSION: Snoring and the severity of SDB exhibit distinct and essentially non-overlapping patterns of seasonal variation, with peaks in spring summer for snoring and peaks in winter-spring for SDB severity. These findings suggest that both seasonal viral and allergen burdens may contribute to SDB severity and may prompt differing clinical referral patterns throughout the year. PMID- 21284097 TI - Pulmonary outcome of Alport syndrome with familial diffuse esophageal leiomyomatosis. AB - X-linked Alport syndrome is associated in some families with diffuse leiomyomatosis. We describe herein, the pulmonary complications and outcome of three family members (mother, daughter, and son). The three underwent esophagectomy at different ages (22 years, three years, and 15 months respectively). Their current forced expiratory volume in the first second (FEV1) ranged from 33% in the mother to 60% in the daughter and 97% in the son. It is suggested that earlier intervention may lead to improved pulmonary function tests. PMID- 21284098 TI - Surgery and the relapse rate of malaria. PMID- 21284099 TI - Vinesthene anaesthesia for repair of hare-lip and cleft palate. PMID- 21284100 TI - A case of polyneuritis due to gold. PMID- 21284101 TI - A case of myiasis due to warble-fly larvae. PMID- 21284102 TI - Vitamin C nutrition in north-east England. PMID- 21284103 TI - Gangrenous enteric intussusception in adolescence. PMID- 21284104 TI - Heterospecific pregnancy as a possible cause of erythroblastosis foetalis. PMID- 21284105 TI - Psychological reactions in war-blinded. PMID- 21284106 TI - Teeth of 5-year-old London school-children; second study; a comparison between 1929, 1943, and 1945. PMID- 21284107 TI - A case of Addison's disease successfully treated by a graft. PMID- 21284109 TI - Pathogenicity of Group C (Lancefield) haemolytic streptococcus. PMID- 21284110 TI - Chemical warfare experiment using human subjects. PMID- 21284113 TI - Imprisonment under the Japanese. PMID- 21284114 TI - The blood group Rh; a review of the antigenic structure and serological reactions of the Rh subtypes. PMID- 21284115 TI - The receptivity of cervical mucus to spermatozoa. PMID- 21284116 TI - Acute osteomyelitis of lumbar spine in an adult. PMID- 21284117 TI - Nicotinamide deficiency after oral administration of penicillin. PMID- 21284118 TI - Work of the Government Lymph Establishment, July, 1898 to June 1946. PMID- 21284121 TI - The blood group Rh; clinical applications in transfusion therapy and in haemolytic disease of the newborn. PMID- 21284122 TI - The fenestration operation for otosclerosis. PMID- 21284123 TI - Pituitary hypothyroidism with impaired renal function. PMID- 21284124 TI - Incidence of ulcer in haematemesis. PMID- 21284128 TI - [Minutes of the 29th meeting of the European Society for Therapeutic Radiology and Oncology (Estro), Barcelona (Spain), 12-16 September 2010]. PMID- 21284129 TI - Presidential address. Life on the river of science. PMID- 21284130 TI - Is blunted heart rate decrease at night associated with prevalent organ damage in essential hypertension? AB - AIM: The association between a blunted decrease in day-night heart rate and subclinical organ damage has not been investigated earlier in human hypertension. Therefore, we assessed such an association in a cohort of 658 untreated essential hypertensive patients. METHODS: All patients underwent procedures including cardiac and carotid ultrasonography, 24-h urine collection for microalbuminuria, ambulatory blood pressure monitoring with simultaneous assessment of heart rate over two 24-h periods within 4 weeks. Nondipping heart rate was defined as a mean heart rate reduction at night lower than 10% compared with daytime values. RESULTS: A reproducible nocturnal dipping (heart rate decrease >10% in both the ambulatory blood pressure monitoring periods) and nondipping profile was found in 513 (78%) and 76 patients (12%), respectively; 69 hypertensive patients (10%) had a variable dipping profile. The three groups did not differ with regard to age, sex, body size, metabolic variables, office and ambulatory blood pressures, left ventricular mass, carotid intima-media thickness, carotid plaque and microalbuminuria. In a univariate analysis, the decrease in nocturnal heart rate did not correlate with any parameter of subclinical organ damage. CONCLUSION: Our findings from a cross-sectional study do not support the view that a flattened heart rate circadian rhythm is related to a prevalent organ damage in essential hypertension and that this altered pattern is a marker for subclinical cardiovascular disease. The prognostic significance of this finding should be defined by prospective studies. PMID- 21284131 TI - Augmentation of central arterial pressure in adult patients after coarctation repair. AB - OBJECTIVES: Arterial hypertension and its complications are associated with an increased morbidity and mortality in patients after aortic coarctation (CoA) repair. It is debatable whether early surgery can prevent it. Residual stenosis of descending aorta (AoD) and stiffness in the precoarctation region supposedly lead to hypertension. The aim of this study was to evaluate aortic pulse-wave parameters in adult patients after CoA repair and to determine the influence of residual stenosis and age at operation on their values. METHODS: Eighty-five patients underwent CoA repair (53 males; aged 34.6+/-10.3 years, age at operation: 10.9+/-8.2 years). The control group consisted of 30 individuals (18 males; aged 33.6+/-8.2 years). Augmentation pressure (AP), augmentation index (AI), aortic pulse pressure (APP), and pulse-wave velocity (PWV) were measured with applanation tonometry method. RESULTS: Normotensive patients after CoA repair (47/55%) had higher values of AP (7.3+/-4.6 vs. 4.4+/-3.6 mmHg; P=0.002), AI (18.6+/-10.4 vs. 13.5+/-4.3%; P=0.03), APP (39.6+/-8.8 vs. 35.1+/-9.8; P=0.00001), and PWV (6.8+/-1.2 vs. 5.4+/-0.9 m/s; P=0.003) than controls. Forty six patients presented signs of recoarctation. No significant differences in the systolic blood pressure and diastolic blood pressure, AI and PWV were found between AoD(+) and AoD(-) but AoD(+) had significantly higher APP (46.7+/-13.8 vs. 38.3+/-6.9; P=0.001) and AP (10.5+/-6.9 vs. 7.5+/-4.1; P=0.02). Significant correlations were found between current age and APP, AP, and AI. No significant correlations were found between central parameters and the age at operation. CONCLUSION: Normotensive patients after CoA repair have elevated central parameters, related to the residual AoD gradient, regardless of the age at operation. Even early repair cannot prevent progressive vascular impairment in CoA. PMID- 21284132 TI - Interarm differences in blood pressure should be determined by measuring both arms simultaneously with an automatic oscillometric device. AB - OBJECTIVE: To compare two methods for screening interarm difference (IAD) of blood pressure. MATERIAL AND METHODS: This study compared two methods for double arm measurements: (i) conventional measurement (CM) and (ii) simultaneous automatic measurement (SAM). A total of 118 patients with two or more cardiovascular risk factors and a mean age of 59+/-17 years were referred to two internal clinics. CM was taken with a validated aneroid manometer in sitting position on the right and left arm subsequently and vice versa. SAM was taken three times in sitting position using a validated automatic oscillometric device equipped with two cuffs for simultaneous double-arm measurements. RESULTS: The average absolute IAD of the conventional systolic value (4.9 mmHg) was significantly higher than the average absolute IAD of the SAM pressures averaged from two (3.7 mmHg; P<0.03) and three measurements (3.8 mmHg; P<0.05). The standard deviations of IADs were significantly higher (P<0.05) for the conventional systolic and diastolic measurements (4.1/3.1 mmHg) than for SAM averaged from two and three (3.0/2.3 and 3.2/2.6 mmHg, respectively) measurements. Differences of more than 20 mmHg for systolic pressure and/or 10 mmHg for diastolic pressures averaged from two CMs, two SAMs, and three SAMs were seen in 10 (9%), four (3%), and six (5%) patients, respectively. CONCLUSION: SAM provides smaller and more reproducible IADs than CM and therefore, most likely better estimates a patient's true IAD. PMID- 21284133 TI - ISPOR 4th Asia-Pacific Conference. Abstracts. PMID- 21284134 TI - A comparative study of bone mineral density between premenopausal women with hyperthyroidism and healthy premenopausal women. AB - OBJECTIVE: To compare bone mineral density (BMD) of the lumbar spine (L1-L4), total hip (TH), and femoral neck (FN) analyzed by Dual Energy X-ray Absorptiometry (DXA) in premenopausal women with hyperthyroidism and in healthy premenopausal women. MATERIAL AND METHOD: Cross-sectional study included 49 premenopausal women with hyperthyroidism and 49 healthy premenopausal women. Age, weight and body mass index (BMI) were comparable in both groups. All subjects had a BMD measurement by DXA in the region of L1-L4, TH and FN and the unpaired t test was used to analyze. RESULTS: The mean BMD of premenopausal women with hyperthyroidism at L1-L4, TH and FN was 0.928, 0.838 and 0.774 g/cm2, which were lower than those of healthy premenopausal women; 0.991, 0.917 and 0.832 g/cm2 respectively (p-value is less than 0.05). Time interval that had elapsed for active hyperthyroidism was not associated with the decrease of BMD at L1-L4, TH and FN in hyperthyroid women. CONCLUSION: The BMD of L1-L4, TH and FN in premenopausal women with hyperthyroidism were significantly lower than those of healthy premenopausal women. Therefore, overt hyperthyroidism could be associated with bone loss and may be a risk factor for the development of osteoporosis. However, time interval of active hyperthyroidism was not related to the decrease of BMD in hyperthyroid women. PMID- 21284135 TI - Developing thai economic model to study cost-effectiveness of switching to bupropion compared to combination with bupropion after the failure of an SSRI for major depressive disorder. AB - OBJECTIVE: To present an economic model and cost-effectiveness estimates of switching to bupropion compared to combination with bupropion after failure of an SSRI for major depressive disorder (MDD). MATERIAL AND METHOD: An economic model was developed to simulate the transitions of Thai outpatients with nonpsychotic MDD who had no remission or could not tolerate the SSRI citalopram and received either sustained-release bupropion monotherapy as switching strategy or sustained release bupropion plus citalopram as combination strategy. Clinical data were obtained form 2 trials of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. The four event probabilities: remission rates, rates of non-remission, discontinuation rates due to intolerance, and incidence of serious adverse events were estimated. Direct costs included drug cost, hospitalizations, and electroconvulsive therapy (ECT). The primary outcome considered in the model was a remission of symptoms. Outputs were measured in terms of costs per remission and costs per quality-adjusted life-years (QALYs). RESULTS: In the base-case analysis, the total direct costs with a bupropion switch were 22,937 THB per remission and 29,346 THB per remission with a bupropion combination. Compared with combination option, switching to bupropion also had lower total cost per QALY (28,672 THB vs. 36,682 THB) and had cost saving of 21.8%. The incremental cost-effectiveness of the combination regimen compared with the switching regimen was 6,409 THB per remission gained and 8,011 THB per QALY gained. In a sensitivity analysis, combination strategy dominated switching strategy if the value of the transitional probability of remission changed to a value of greater than 0.547. CONCLUSION: The economic model indicated that treatment of MDD patients who fail to achieve remission from an SSRI with a switch to bupropion is a cost-effectiveness treatment option compared with a combination of SSRI with bupropion. PMID- 21284136 TI - The cost-effectiveness of aripiprazole as adjunctive therapy in major depressive disorder: Thai economic model. AB - BACKGROUND: Aripiprazole is the first atypical antipsychotic approved for adjunctive treatment to antidepressant therapy in patients with major depressive disorder (MDD). The current study aims to present an economic model and cost effectiveness estimates for aripiprazole compared with placebo as adjunctive therapy to antidepressant treatment in patients with MDD who showed an incomplete response to a prospective 8-week trial of antidepressant therapy. MATERIAL AND METHOD: An economic model of MDD treatment was developed to estimate the clinical and economic outcomes in Thai patients. Efficacy data were derived from a pooled analysis of two studies. A cost-effectiveness analysis was constructed in simulate the impact of treatment outcomes and costs over a 6-week time horizon. The primary outcome of the model was remission of symptoms. Quality-adjusted life year (QALYs) was the secondary outcome. The event probabilities were used to derive the transitional probability used in the model and to calculate the weighted cost of each treatment outcome. Only direct costs were considered. One way sensitivity analysis was performed to test the sensitivity of the model outputs. RESULTS: Treatment with aripiprazole came at the total costs per remission of 30,970 Baht while treatment with placebo came at the total costs per remission of 28,409 Baht. Placebo had lower total costs per QALY than aripiprazole (35,511 Baht vs. 38,713 Baht). The incremental cost-effectiveness ratio (ICER) of augmentation with aripiprazole compared with placebo was 2,561 Baht per remission gained and 3,201 Baht per QALY gained. Aripiprazole dominated placebo if the value of transitional probability of remission changed to a value of greater than 0.348 from the base-case value of 0.257. Aripiprazole was more cost-effective than placebo as adjunctive therapy if the unit cost of aripiprazole is more than 48.9% discount. CONCLUSIONS: Adjunctive aripiprazole is not more cost-effective than adjunctive placebo in Thai patients with MDD who showed an inadequate response to at least one prospective antidepressant therapy. Remission rates and unit cost are the key parameters involving the cost effectiveness of aripiprazole. PMID- 21284137 TI - Oral health status, dental caries risk factors of the children of public kindergarten and schools in Phranakornsriayudhya, Thailand. AB - BACKGROUND: Dental caries remains a public health problem even though it is preventable. There are several risk factors that relate to dental caries, especially in children in suburban and rural areas, where they normally receive their first dental examination in primary schools by teachers or health care personnel. Their oral health depends primarily on their parents' awareness. OBJECTIVE: To identify prevalence and severity of dental caries and their risk factors among children in public education centers in Phranakornsriayudhya, Thailand. MATERIAL AND METHOD: A cross-sectional total study was conducted among children attending public education centers in Koh-Rean Subdistrict, Phranakornsriayudhya District, Phranakornsriayudhya Province, Thailand including a day care center, 2 kindergartens and 2 elementary schools, during the academic year of 2005. All children were invited to attend a dental health survey including general oral examination and a face to face interview for the participants' parents as well as children attending grade 1-6. Standardized questionnaires were used to identify the participants' oral health care behaviors. RESULTS: There were 157 (99.4%) from 158 children aged 2-12 years participated in the survey, 152 (96.8%) students had dental caries. The prevalence of dental caries among pre-school children was 95.4%. The overall average Decay Missing Filling for primary teeth (dmft) was 7.4 (+/- 4.6) and the overall average Decay Missing Filling for permanent teeth (DMFT) was 3.7 (+/- 1.8). The dmft among pre-school children was 9.1 (+/- 5.2). The prevalence of gingivitis was 95.5%. The independence risk factors for dental caries for primary teeth were brushing under supervision of teacher when compared with the parents (Odds ratio = 12.1 (95% CI, 2.6-55.4)), and not brushing after breakfast (Odds ratio = 3.7 (95% CI, 1.1-12.1). There were no significant risk factors of dental caries for permanent teeth. CONCLUSION: A relatively high prevalence of dental caries was observed among children in suburban area in Thailand, especially in early childhood. It was shown that having the parents supervising their tooth brushing and having tooth brushing after breakfast may protect the dental caries for primary teeth. The public health interventions among this population are therefore urgently needed. PMID- 21284138 TI - Impact of new practice guideline to prevent catheter-related blood stream infection (CRBSI): experience at the Pediatric Intensive Care Unit of Phramongkutklao Hospital. AB - OBJECTIVE: To demonstrate the incidence of catheter-related blood stream infection (CRBSI) of patients in the pediatric intensive care unit (PICU) after implementing the new guideline to prevent CRBSI. METHODS: All patients who were admitted to PICU at Phramongkutklao Hospital between January and December 2006 and had central venous catheter (CVC) inserted from the operation room before admission or CVC placed in the PICU were included in a cohort study with longitudinal assessment of an overall catheter care policy targeted at the reduction of vascular access infection. The guideline included five key components (hand hygiene, maximal barrier precautions, povidine skin antiseptic, optimal catheter site selection, daily review of line necessity with prompt removal of unnecessary lines) called "central line bundle". All nursing staffs in the PICU were asked to attend an educational meeting in order to review the scientific data on vascular access insertion, device use and care. Data regarding age, underlying disease, location of insertion, duration, and complication were recorded. RESULTS: A total of 61 patients were recruited. Average duration of catheterization was 8.7 days. Complications were found in 8 cases (13.1%). Hematoma was the most common complication (6.6%) followed by infection (3.3%). Rate of CRBSI was reduced from 2.6 per 1000 catheter days to 2.4 per 1000 catheter days after implementing the new practice guideline. CONCLUSION: Rate of CRBSI was reduced after implementing the new "central line bundle" guideline to prevent CRBSI. PMID- 21284139 TI - Herbal medicine: affecting factors and prevalence of use among Thai population in Bangkok. AB - BACKGROUND: Remarkable growth in use of herbal medicines has recently been noted. In Thailand, eight items of herbal medicines with single composition are currently placed on the National List of Essential Medicines (EM). This study was to clarify the actual state of factors affecting the usage and knowledge of these herbal medicines, as the study concerning with these aspects was infrequently performed. MATERIAL AND METHOD: A descriptive and cross-sectional research was conducted by using self-administered questionnaires. Six hundred and thirty-one subjects were randomly sampling and the data were analyzed by the Statistic Package for the Social Sciences software program. RESULTS: The finding revealed that 28.6% of total subjects had experienced on herbal medicine treatment, especially eight items listed in EM. The elderly and government officers usually purchased the drugs from hospital and drugstore, while housewife purchased them from supermarket. Subjects with positive attitude towards herbal medicine use usually were government officers. Almost all of herbal medicines were well-known about their indications by less than 55% of total subjects. Among all well-known indications, the relief of gastric distress by Zingiber officinale was the most well-known one (73.2%). On the other hand, high percentage of media exposure (55 70%) was found in majority of the subjects which indicated that media was more likely to influence consumer's knowledge and behavior. CONCLUSION: Only 28.6% of total subjects had experienced on herbal medicines listed in EM, despite of high percentage of media exposure. Therefore, the providing proper information of herbal medicines on various medias and integrated education about herbal medicine in medical curricula could effectively help increase appropriate drug use and consumers' safety. PMID- 21284140 TI - A survey of metabolic syndrome and its components in Thai medical cadets. AB - OBJECTIVES: To determine the prevalence of the metabolic syndrome (MS) and its components in Thai medical cadets. MATERIAL AND METHOD: The study was conducted at Phramongkutklao College of Medicine. Ninety six participants (78 men and 18 women) were the healthy medical cadets class 34 who firstly enrolled as the second year medical students in the academic year 2008. Data on anthropometry, blood pressure and blood studies were collected. The MS was defined using the age specific NCEP ATP III criteria with a modified waist circumference by WHO. RESULTS: The prevalence of the MS in the second year Thai medical students was 1.04%. The high percentage of MS components was attributed to low HDL-cholesterol and high blood pressure. In addition, the prevalence rates of one and two abnormalities of MS components were 31.25% and 8.33%, respectively. Overweight and obesity were found at the percentage of 21.88 and 15.62, respectively and significantly more prevalent among men than among women. CONCLUSION: This study shows that the metabolic syndrome exists among second year medical cadets with the prevalence of 1.04%. This group is under the military rules and regulations. Though the prevalence of MS among this group is not high, the study reveals that the prevalence of one abnormality of MS components is very high up to 31.25%. These findings call for attention for developing appropriate intervention programs for early detection and promotion of proper health behaviors and lifestyles. These programs may help to decrease the incidence and morbidity associated with cardiovascular disease and diabetes in Thai young adults. PMID- 21284141 TI - Forward for ICCP2009 issue of Biopolymers peptide science. PMID- 21284142 TI - [The Campaign Program for Prostate Integrated Research]. PMID- 21284143 TI - [Insulin pump with glucose sensor in type 1 diabetes. But the artificial pancreas is still far off]. PMID- 21284144 TI - [THz-ultraviolet spectra of KDP crystal]. AB - THz time domain spectrum of KH2PO4 crystal in the range from 0.2 to 1.6 THz, the far-infrared spectrum in the range from 50-4000 cm(-1), and ultraviolet-visible infrared spectrum in the range from 200-2000 nm were measured at the room temperature. The energy band gap Eg of KH2PO4 Crystal is 5.91 eV. There is a wide band of the phonon absorption in the KDP crystal. The values of the absorption coefficient are 35-80 cm(-1) in the range from 0.2 to 205.5 THz. The end of the low frequency of the optical phonon model is smaller than 0.2 THz. The highest frequency upsilonLO of the longitudinal optical phonon model LO is about 205.5 THz, and the force constant K of H-O ionic chemical bond stretch vibration from the omegaLO was calculated to be 13.13 N x cm(-1). PMID- 21284145 TI - [Influence of humidity on characteristic of laser-induced soil plasmas]. AB - The soil samples at six different humidities were prepared for studying the influence of soil humidity on laser-induced plasmas. By analyzing the characteristic spectral lines of Pb with the wavelength of 405.78 nm, it was demonstrated that the intensities of spectral line, SNR and RSD are linearly inversely proportional to the soil humidity. Under the approximation of local thermal equilibrium, by analyzing the characteristic spectral lines of Fe within the wavelength range of 400 to 440 nm, the temperature of plasmas was obtained by means of the two-dimensional Boltzmann plane. The experimental results show that the plasma temperature monotonously changes from 11 800 to 7 800 K and the electron density monotonously changes from 3.3 x 10(6) cm(-3) to 2.8 x 10(6) cm( 3), when the humidity increases from 0 to 20%. PMID- 21284146 TI - [Simulation of image multi-spectrum using field measured endmember spectrum]. AB - The characteristic of landscape spectrum is the basic of application of remote sensing and plays an important role in quantitative analysis of remote sensing. However, in spectrum-based application of remote sensing, because the difference of measuring scale and instrument resolution yield serious error in spectral curve and reflectance for the same landscape, there exists difficulty in quantitative retrieval of special information extraction of remote sensing. Firstly, the imaging simulation principles of the optics image was described and proposed A method using field measured endmember spectrum with higher spectrum resolutions to simulate spectrum of Multi-spectrum images with lower spectrum resolution was proposed. In the present paper, the authors take the delta oasis of Weigan and Kuqa rivers ocated in the North of Tarim Basin as study area, and choose vegetation and soil as study object. At first, we accomplished the simulation from field measured endmember for multi-spectrum by using the spectral response function of AVNIR-2, and found the large correlation between simulated multi-spectrum and pixel spectrum of AVNIR-2 by using the statistical analyse. Finally, the authors set up the linear model to accomplish the quantitative transformation from edmember scale to pixel scale. The result of this study has the realistic meaning for the quantitative application of remote sensing. PMID- 21284147 TI - [Investigation on the gas temperature of a plasma jet at atmospheric pressure by emission spectrum]. AB - A plasma jet of a dielectric barrier discharge in coaxial electrode was used to produce plasma plume in atmospheric pressure argon. Spatially and temporally resolved measurement was carried out by photomultiplier tubes. The light emission signals both from the dielectric barrier discharge and from the plasma plume were analyzed. Furthermore, emission spectrum from the plasma plume was collected by high-resolution optical spectrometer. The emission spectra of OH (A 2sigma + --> X2 II, 307.7-308.9 nm) and the first negative band of N2+ (B2 sigma u+ --> X2 IIg+, 390-391.6 nm) were used to estimate the rotational temperature of the plasma plume by fitting the experimental spectra to the simulated spectra. The rotational temperature obtained is about 443 K by fitting the emission spectrum from the OH, and that from the first negative band of N2+ is about 450 K. The rotational temperatures obtained by the two method are consistent within 5% error band. The gas temperature of the plasma plume at atmospheric pressure was obtained because rotational temperature equals to gas temperature approximately in gas discharge at atmospheric pressure. Results show that gas temperature increases with increasing the applied voltage. PMID- 21284148 TI - [Study on removing the lamp spectrum structure in differential optical absorption spectroscopy]. AB - Differential optical absorption spectroscopy (DOAS) technique has been used to measure trace gases in the atmosphere by their strongly structured absorption of radiation in the UV and visible spectral range, and nowadays this technique has been widely utilized to measure trace polluted gases in the atmosphere e.g. SO2, NO2, O3, HCHO, etc. However, there exists lamp (xenon lamp or deuteriumlamp) spectrum structure in the measured band (300-700 nm) of the absorption spectra of atmosphere, which badly impacts on precision of retrieving the concentration of trace gases in the atmosphere. People home and abroad generally employ two ways to handle this problem, one is segmenting band retrieving method, another is remedial retrieving method. In the present paper, a new retrieving method to deal with this trouble is introduced. The authors used moving-window average smoothing method to obtain the slow part of the absorption spectra of atmosphere, then achieved the lamp (xenon lamp in the paper) spectrum structure in the measured band of the absorption spectra of atmosphere. The authors analyzed and retrieved the measured spectrum of the atmosphere, and the result is better than the forenamed ways. Chi-square of residuum is 2.995 x 10(-4), and this method was proved to be able to avoid shortcoming of choosing narrowband and disadvantage of discovering the new component of atmosphere in retrieving the concentration of air pollutants and measuring the air pollutants. PMID- 21284149 TI - [Research on monitoring mechanical wear state based on oil spectrum multi dimensional time series model]. AB - A new method using oil atomic spectrometric analysis technology to monitor the mechanical wear state was proposed. Multi-dimensional time series model of oil atomic spectrometric data of running-in period was treated as the standard model. Residues remained after new data were processed by the standard model. The residues variance matrix was selected as the features of the corresponding wear state. Then, high dimensional feature vectors were reduced through the principal component analysis and the first three principal components were extracted to represent the wear state. Euclidean distance was computed for feature vectors to classify the testing samples. Thus, the mechanical wear state was identified correctly. The wear state of a specified track vehicle engine was effectively identified, which verified the validity of the proposed method. Experimental results showed that introducing the multi-dimensional time series model to oil spectrometric analysis can fuse the spectrum data and improve the accuracy of monitoring mechanical wear state. PMID- 21284150 TI - [Up-conversion luminescent materials of Y2O3: RE(RE=Er or Er/Yb) prepared by sol gel combustion synthesis]. AB - Y2O3 powders doped with rare-earth ions were synthesized by sol-gel combustion synthesis. Effects of different calcinating temperatures, Er+ doping concentration and Yb3+ doping concentration were investigated. It was shown that the single well crystallized Y2O3 powders could be obtained at 800 degrees C; as the calcinating temperature increased, the crystallinity and upconversion luminescence intensity were higher; the particle size was uniform around 1 microm at 900 degrees C; when Er3+ doping concentration was 1 mol%, the green upconversion luminescence intensity reached the maximum, but for red upconversion luminescence, when Er3+ doping concentration was 4 mol%, its luminescence intensity reached the maximum; as the ratio of Yb3+ to Er3+ was 4:1, the green emission intensity reached the maximum, while the red emission intensity was always increasing as Yb3+ doping concentration increased. PMID- 21284151 TI - [Study on thulium oxide nanoparticles modulating electro-optics characteristics of polymer dispersed liquid crystals]. AB - By adding the thulium oxide nanoparticles (NP) of Gd2 O3 and Eu2O3 and Nd2O3 to polymer dispersed liquid crystals (PDLC), and the transmittances of PDLC and NP PDLC changing with voltage in visible light was tested, and the thulium oxide modulation for PDLC was studied. The results show that transmittance of Gd2O3-NP PDLC decreases with increasing voltage when the voltage is less than 10 V. The relaxation phenomenon of the sample appears at 15 V, and its transmittance curve fluctuates slightly around that at 10 V. The transmittance of Gd2O3-NP-PDLC increases rapidly at 20 V, and its filter phenomenon emerges. And the transmittance of Eu2O3-NP-PDLC decreases with increasing voltage, but the decrease is only slight. And the transmittance of Nd2O3-NP-PDLC changes with voltage insignificantly. PMID- 21284152 TI - [Detecting leaf and twig temperature of some trees by using thermography]. AB - Noninvasive detection of temperature with thermography from natural things has been used in many fields and it was attempted to detect the temperature for leaves and branches of trees in the present paper. Leaf and twig temperatures were monitored during the increasing process of temperature under the direct sunshine heating. The difference of specific heat and latent heat from leaves and twigs caused by different water content and transpiration capacity were measured. Not only the leaf temperature, scorch and branch dieback were detected, but the transpiration cooling fail of sweetgum (Liquidambar styraciflua L.) leaves was successfully measured by using thermography. In this study, the local water stress characteristics on sweetgum leaves from specially designed vein severing became special materials for studying the leaf temperature or transpiration failure. The temperature gradient on severed leaf made the thermo image taking easy, with less systematical error. Direct comparison between non-severed lobes and vein-severed lobes on the same leaf lamina makes it more comparable. According to thermography analysis, significant high temperature area was observed and there existed the consistence between high temperature area and the reddened leaf lamina. PMID- 21284153 TI - [A frequency selection method of NIR spectroscopy for discrimination of maize seed varieties]. AB - A frequency selection method of NIR spectroscopy was proposed in the present paper for discrimination of maize seed varieties. A criterion function was defined to evaluate the discriminative ability of NIR spectroscopy at different frequencies, and then features of maize seed varieties were extracted accordingly for further processing. By eliminating correlation between features at different frequencies, the selected features are guaranteed to contain as much information of inter-variety difference as possible. Also, features with larger variances are preferred to suppress the impact of noise. Experiment results demonstrate that our frequency selection method can achieve high recognition rate with less spectroscopy features than traditional methods. Specifically, a recognition rate as high as 94.16% can be attained with NIR spectroscopy with only 30 frequencies. Simulation results show that recognition rate of NIR spectroscopy at selected frequencies is stable with small disturbance of frequencies, which verifies the robustness of the authors' method. PMID- 21284154 TI - [Studies on the characters and microstructure of enzyme and octenyl succinic anhydride modified starch]. AB - Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), UV-Vis spectra, laser nano size detector (LNSD) and scanning electron microscope (SEM) were employed to analyze the characters and structure of enzyme and octenyl succinic anhydride modified starch. The results indicated that the enzymatic starch reacted with octenyl succinic anhydride, bringing only octenyl succinic anhydride groups but not any other groups. The esterification of enzymatic starch only took place in amorphous region, but had no effect on the crystal form of starch granule. The clarity of EOSS increased with the increase in substitution degree. The particle size of oil emulsion made by EOSS was fine and well distributed, meaning that the emulsion has excellent emulsibility and emulsifying stability. The embedding of oil encapsulated with EOSS is fine. It can be concluded that the properties of EOSS is excellent, and can be used as emulsifier and wall material of microcapsule. PMID- 21284155 TI - [Research on zinc content in leaf of Olinda Valencia orange using visible near infrared spectroscopy model]. AB - Olinda valencia orange leaves dry powder-like were taken as sample, and chemical analysis combined with technology of visible near-infrared spectroscopy (Vis/NIRS) was used, through the treatment process of second derivative spectrum of samples of the original spectrum and denoising (Noise). Meanwhile, method of partial least squares (PLS) and cross-validation were used to establish maths model of Zn concentration which applying band combination composited by 400-500 and 1201-1300 nm of characteristic wavelength band. The coefficient of establishing models is 0.9975, while the coefficient of correlation coefficient of prediction is 0.9920. The root mean square error of prediction (RMSEP) of cross-validation is 0.5868. Therefore, the means using visible near-infrared spectroscopy (Vis/NIRS) and the methods of cross-validation and PLS to establish the spectral correction model reflecting the Zn content in leaves and characteristic wavelength bands can detect the Zn content in citrus leaves quantitatively and quickly. PMID- 21284156 TI - [Near-infrared spectrum quantitative analysis model based on principal components selected by elastic net]. AB - Elastic net is an improvement of the least-squares method by introducing in L1 and L2 penalties, and it has the advantages of the variable selection. The quantitative analysis model build by Elastic net can improve the prediction accuracy. Using 89 wheat samples as the experiment material, the spectrum principal components of the samples were selected by Elastic net. The analysis model was established for the near-infrared spectrum and the wheat's protein content, and the feasibility of using Elastic net to establish the quantitative analysis model was confirmed. In experiment, the 89 wheat samples were randomly divided into two groups, with 60 samples being the model set and 29 samples being the prediction set. The 60 samples were used to build analysis model to predict the protein contents of the 29 samples, and correlation coefficient (R) of the predicted value and chemistry observed value was 0. 984 9, with the mean relative error being 2.48%. To further investigate the feasibility and stability of the model, the 89 samples were randomly selected five times, with 60 samples to be model set and 29 samples to be prediction set. The five groups of principal components which were selected by Elastic net for building model were basically consistent, and compared with the PCR and PLS method, the model prediction accuracies were all better than PCR and similar with PLS. In view of the fact that Elastic net can realize the variable selection and the model has good prediction, it was shown that Elastic net is suitable method for building chemometrics quantitative analysis model. PMID- 21284157 TI - [Quantitative analysis of the content of deltamethrin in agrochemicals by near infrared, attenuated total reflectance infrared and raman spectroscopy]. AB - The method of near-infrared, attenuated total reflectance infrared and Raman spectroscopy was used for the rapid determination of the content of deltamethrin in agrochemicals. The quantitative models were established by PLS (partial least squares) method and optimized. The independent validation sets were used to evaluate the model accuracy. The determination coefficient R2 and RMSECV of the near-infrared model and mid-infrared model were 0.9999, 0.022 and 0.9996 and 0.056, respectively. The accuracy of both was similar. The determination coefficient R2 and RMSECV of Raman were 0. 996 7 and 0.172, which exhibits the lower accuracy. The result indicated that near-infrared, mid-infrared and Raman spectroscopy can be applied to the rapid determination of the content of the active ingredients precisely, which has an important significance in the on-line determination, analysis on site in the enterprise and the rapid quantitative analysis of agrichemicals in the department of quality monitoring. PMID- 21284158 TI - [Identification of fungal strain by Fourier transform infrared spectroscopy and cluster analysis]. AB - Fourier transform attenuated total reflection infrared spectroscopy (FTIR-ATR) has been a novel technical procedure to identify and classify microorganisms in recent years. In the present study, Fourier transform infrared spectroscopy(FTIR) in combination with an attenuated total reflection (ATR) unit were used to discriminate important plant-destroying fungi. Mycelia of 17 fungal strains belonging to 14 different species were grown on potato dextrose agar (PDA) plants and subjected to FTIR-ATR measurements. High-resolution and well-reproducibility infrared spectra were obtained, and significant spectral differences among these strains were observed in the wavenumber regions of 1800-1485 cm(-1), 1485-1185 cm(-1), and 1185-900 cm(-1). According to the characteristic bands in these regions, cluster analysis was executed to classify the FTIR spectra. The result showed that different fungal strains could be identified correctly, demonstrating the high potential of FTIR-ATR as a tool for fungal strain identification and classification. The method is rapid, inexpensive and reproducible, and requires minimum sample preparation. PMID- 21284159 TI - [Rapid identification of microorganisms based on Fourier transform near infrared spectroscopy]. AB - Fourier transform-near infrared (FT-NIR) spectra of microorganisms reflect the overall molecular composition of the sample. The spectra were specific and can serve as spectroscopic fingerprints that enable highly accurate identification of microorganisms. Bacterial powders of one yeast and five bacteria strains were prepared to collect FT-NIR spectra. FT-NIR measurements were done using a diffuse reflection-integrating sphere. Reduction of data was performed by principal component analysis (PCA) and two identification models based on linear discriminant analysis (LDA) and artificial neural network (ANN) were established to identify bacterial strains. The reproducibility of the method was proved to be excellent (D(yly2) : 1.61 +/- 1.05-10.97 +/- 6. 65) and high identification accuracy was achieved in both the LDA model (Accuracy rate: 100%) and the ANN model (Average relative error: 5.75%). FT-NIR spectroscopy combined with multivariate statistical analysis (MSA) may provide a novel answer to the fields which need for rapid microbial identification and it will have great prospect in industry. PMID- 21284160 TI - [Measurement of cooking loss and tenderness of fresh pork using visible/near infrared spectroscopy]. AB - Cooking loss and tenderness are important quality characteristics of fresh pork. To find a rapid, non-destructive and non-contaminated method to measure them, visible/near infrared spectroscopy was proposed for measurement of cooking loss and tenderness of vacuum-packed pork loin. The acquired raw spectra were pretreated by Savisky-Golay smoothing, second derivative and MSC, respectively using the software of Unscrambler 9.6. A total of 104 samples were used in the experiment. The samples were divided into calibration set and validation set. The calibration set was used to set up calibration model and then the model was adopted to predict the samples of validation set. The partial least square regression (PLSR) was used to build calibration model. The results show that the correlation coefficient for cooking loss and shear force are 0.81 and 0.78 respectively. It is feasible and effective that measure cooking loss and shear force of vacuum-packed fresh pork loin using visible/near infrared spectroscopy in interactance mode. PMID- 21284161 TI - [Research on fast discrimination between Panax ginseng and Panax quinque folium based on near infrared spectroscopy]. AB - Near infrared spectroscopy combined with pattern recognition techniques were applied to develop a method of fast and nondestructive discrimination between Chinese ginseng and American ginseng. A total of 90 representative ginseng samples including root, fiber and powder were collected. NIR spectra of the samples were obtained directly with wrapped polyethylene packing film. MSC and first derivative were performed after the elimination of notable packing film absorbance in raw spectra. Then the informative wave bands were chosen by moving window partial least-squares regression method. PLS-DA, PCA-DA and SVM discrimination models were founded and their results were compared. SVM was proven to be the most effective method with 100% accurate identification rate for validation set. It indicates that the method founded is precise and convenient and can be practically used in practice for quality control and fast screening of raw herb materials. PMID- 21284162 TI - [Discrimination of varieties of tablets using near-infrared spectroscopy by wavelet clustering]. AB - A dataset of 310 samples of tablet were obtained by using near infrared spectroscopy (NIR) technique, and then the NIR data were used to discriminate the four types of tablets with three scales. Wavelet clustering algorithm, a new unsupervised method, which applied a classical clustering strategy on the suitably chosen subset of wavelet coefficients, was introduced to improve the clustering performance. The optimal wavelet decomposition and wavelet coefficients partition were determined according to the index of discriminant accuracy. The total accuracy rates for laboratory-scale, pilot-scale and full scale tablets samples were 100%, 100% and 99.2%, respectively, with only one sample misclassified. The overall results indicated that the wavelet clustering was an effective way for the discrimination analysis. NIR combined with wavelet clustering method is surely much more rapid and easier to use, and offers a feasible solution to the quality control of pharmaceutical tablet products. PMID- 21284163 TI - [Rapid detection of dichlorvos in chlorpyrifos by mid-infrared and near-infrared spectroscopy]. AB - In the present study, the content of dichlorvos in chlorpyrifos was rapidly determined by mid-infrared and near-infrared spectroscopy. The quantitative models were established by partial least squares (PLS) method and optimized. The independent validation sets and 7 test samples were used to evaluate the model accuracy. The results showed that mid-infrared and near-infrared spectroscopy can accurately determine the content of dichlorvos in chlorpyrifos. The RMSEC (the root mean square error of calibration) of the mid-infrared model and near infrared model was 0.013 and 0.020, respectively. R2 (determination coefficient) both were 1.000. For 7 test samples, RMSEP before model recalibration is 0.22 (MIRS) and 0.09 (NIRS). The adaptability of the near-infrared model was much better and model updating was unnecessary. To sum up, MIR and NIR are both rapid and easy-operation method with simple pretreatment. PMID- 21284164 TI - [Infrared spectrum analysis of SF6 and SF6 decomposition]. AB - Pressured SF6 gas is widely used in GIS for electrical insulation as well as for are extinction. And a chemical way for detecting the SF6 and its byproducts is a powerful diagnosis method for GIS. The present paper analyzes the decomposition of insulated gas of GIS (mostly SF6) in three cases with infrared spectrometer. As a result, it was found that the content of S2F10 can be used to decide whether spark or arc discharge leads to the fall down of GIS; CF4 can be used for judging the insulation grade of GIS. Besides, the gas leakage of the GIS should be concerned in the long lifetime of GIS. Finally, it is supposed that a data base containing the history of results from the gas diagnostics for each piece of equipment should be created for future maintenance activities. PMID- 21284165 TI - [Progress in quality analysis of honey by infrared spectroscopy]. AB - The detection of the quality of honey and the differentiation of adulteration are very important for quality and safety assurance. Traditionally used chemical methods were expensive and complicated, therefore they are not suitable for the requirement of wide-scale detection. In the past decade, the detection technology of honey developed with a trend of fast and high throughput detection. Spectroscopy has the fast and non-contact characteristic, and was widely used in petrifaction. This technology also has the potential for application in honey analysis. In the present study, the progress in quantitative and qualitative analysis of honey by near infrared spectroscopy (NIR) and mid infrared spectroscopy (MIR) is reviewed. The application of this two spectroscopy methods to honey detection refers to several aspects, such as quality control analysis, determination of botanical origin, determination of geographical origin and detection of adulteration. The detailed information of the detection of honey by NIR and MIR spectroscopy was analyzed, containing detection principle, technology path, accuracy, influence factors, and the development trend. PMID- 21284166 TI - [Quantum chemistry ab initio calculation study on microstructure and raman spectra of phosphosilicates]. AB - Quantum chemistry ab initio calculation was applied to study the hyperfine structure of ternary alkali phosphosilicates. Restricted Hartree-Fock method (RHF) with the basis sets of 6-31G(d) was employed to optimize geometric structure and calculate Raman spectra of a series of phosphosilicates model cluster structural units. Stress index of tetrahedron (SIT) was introduced to describe and classify the microstructure of ternary alkali phosphosilicates in order to investigate the effect of phosphorus-oxygen tetrahedron on the micro environment of silicon-oxygen tetrahedron. It was suggested that the calculated vibrational wavenumbers of symmetric stretching vibration of non-bridging oxygen (NBO) depend not only on the species of the silicon-oxygen tetrahedron, which was called primary structure units, but also on the linkage of the neighboring tetrahedron and ring types. The phosphorus-oxygen tetrahedron exhibits regulative ability of bond angle and conductive ability of stress, so that the vibrational wavenumbers of silicon-oxygen tetrahedron are insensitive to the bond angle. It demonstrated that vibrational wavenumbers of NBO stretching vibration in the high frequency range show linear relationship with the value of SIT. PMID- 21284167 TI - [Surfaced-enhanced Raman spectroscopic study on single living human nasopharyngeal carcinoma cells incubated with colloidal gold]. AB - The surface-enhanced Raman scattering (SERS) spectroscopy and normal Raman spectroscopy of single living human nasopharyngeal carcinoma cells(CNE-1) were tested and analyzed by gold nanoparticles incubation into cells. Six obvious Raman bands (718, 1001, 1123, 1336, 1446 and 1660 cm(-1)) were observed in the normal Raman spectroscopy of living CNE-1 cells. The characteristic Raman bands in the SERS spectra of living cells were tentatively assigned. Colloidal gold particles that were introduced inside cells result in strongly enhanced Raman signals of the native chemical constituents of the cells, and over twenty SERS Raman bands were observed in the SERS spectroscopy of living CNE-1 cells. The Raman lines of 1026, 1097, 1336 and 1585 cm(-1) were assigned to vibrations of the DNA backbone, which confirms that some gold nanoparticles were able to enter the nucleus. The results showed that, based on colloidal gold, the SERS spectroscopy might provide a sensitive and structurally selective detecting method for native chemicals inside a cell, such as DNA and phenylalanine. PMID- 21284168 TI - [Raman spectra and its application of graphite enclaves in nephrite-jades in Xiuyan, Liaoning]. AB - Xiuyan, Liaoning was an important locality of jade material of the Red Mountain Culture in the Neolithic Age in Chinese history where there are two types of raw material of nephrite jades, namely gravel nephrite jade (Hemo Yu in Chinese) and old nephrite jade (Lao Yu in Chinese). In the present paper, Laser Raman spectrum technique was applied to analyze the graphite enclaves in the nephrite jades of the two types of materials. The results show that the graphite enclaves in the two types of jades have different characteristics of Raman spectra, indicating that they probably were formed under different geological conditions, or originated from different ore-forming periods or were exploited from different section of ore body. Hence, laser Raman spectrum technique could be used as a supplementary measure for nondestructive detection to determine the occurrence of jades. PMID- 21284169 TI - [Raman spectroscopy analysis of impact of UV radiation on linoleic acid oxidation]. AB - The authors studied on self oxidation of linoleic acid and the effect of UV irradiation on oxidation of linoleic by Raman spectroscopy. The result reflects that:the intensity of 1 266 cm' which stands for ==CH olenic hydrogen in-plane bend is diminished, and it disappeared at 72 hours after the oxidation beginning. That indicates that double bond was lost or reduced. upsilon(C==C) and the carboxylic acid C==O vibrations are lies in 1 658 cm(-1). The intensity of 1 658 cm(-1) was increased in the beginning and decreased then. At the initial stage in the reaction, rearrangement of carbon chains and the formation of carboxylic acids caused the increasing. Later in the reaction, carboxyl of linoleic acid reacted with the generated hydroxy acids, hydroxy aldehyde. So it decreased. UV irradiation accelerated the oxidation reaction starting, increased the speed of the oxidation reaction. All the result shows that the changes of Raman spectroscopy indicate the changes of bulky group in fatty acid oxidation process and the effect of UV irradiation. It provides an effective research tool for the mechanism of lipid peroxidation reaction. PMID- 21284170 TI - [Fast recognition of gasoline brands based on the Raman spectroscopy]. AB - A novel method for fast recognition of gasoline brands based on the Raman spectroscopy is presented. A classification model on the basis of product gasoline samples with known brands was established. The detailed modeling process includes measurement and pretreatment of Raman spectra of these samples, principal component analysis (PCA) to obtain loading vectors and score vectors of all known samples, and calculating each average score vector for all of the samples with the same brand. For a gasoline sample with unknown brand, first measure and preprocess its Raman spectrum with the same pretreatment algorithm, then calculate its score vector on the above loading vectors and its distances to the average score vectors for different brands, and finally determine the brand of the unknown sample by the minimum distance. For 45 product gasoline samples from different refinery, experimental results show that there are significant distances between different brands in the principal component space, and the above classification model can decide the brand of unknown gasoline samples rapidly and accurately. PMID- 21284171 TI - [Laser Raman and infrared spectrum analysis of low-density lipoproteins purified from hen egg yolk]. AB - During the experiment, diversified proteins were separated from hen egg yolk by ammonium sulphate rapid fractionation, and pure LDL was obtained after filtrating through Sephadex G-200 chromatography. After the qualitative detection of SDS PAGE, the authors discovered that LDL consists of five major apoprotein. The Raman and infrared spectrum showed CH2 asymmetric stretching and symmetric stretching mode. However, the authors found C==O stretching vibrations of protein peptide bonds and N+ (CH3)3 asymmetric stretching vibration from the choline group in phospholipids. Laser Raman and infrared spectrum analysis of LDL provided useful information for studying their structure. PMID- 21284172 TI - [Fast analysis of benzene concentration in gasoline based on low-resolution dispersive Raman spectroscopy]. AB - In order to fast analyze the benzene concentration in gasoline, a new measure method based on low-resolution dispersive Raman spectroscopy is proposed. There exist strong measurement noise and fluorescence background in dispersive Raman spectra, so the present paper applies the Savitzky-Golay smoothing filter to remove the measurement noise and uses iterative polynomial curve-fitting to reduce the fluorescence background. Based on ridge regression, principal component regression and partial least squares algorithm, three calibration models of the benzene concentration in gasoline are built and validated by a set of gasoline samples from a refinery. Experimental results show that their repeatability and reproducibility can satisfy the accuracy requirement specified by the standards SH/T0713-2002, regardless of applying what kind of calibration models. In addition to its low cost, small size, convenience to use and so on, the fast measure method based on low-resolution dispersive Raman spectroscopy can be widely applied to the routine analysis. PMID- 21284173 TI - [Application of Raman spectroscopy technique to food quality and safety determination]. AB - With the merits of doing without sample pretreatment, easy operation, short response time and high sensitivity, Raman spectroscopy technique can acquire samples' physical chemistry and the deep structure information. It has been widely applied in petrol chemical, biomedicine, geoarchaeology, criminal justice, gem identification, etc. Raman spectroscopy has good application prospect in food quality and safety determination, for its spectra are not extremely sensitive to polar materials such as water. The detection principle, classification and the system composition of Raman spectroscopy technique were introduced briefly. The latest research progress in food constituent analysis and pesticide residue determination by Raman spectroscopy was reviewed. Finally, its key technologies for food quality and safety determination were pointed out and the future research was prospected. PMID- 21284174 TI - [Fluorescence lifetime measurement based on different pump waveform]. AB - The present paper analyzes the different pump wave theory under the fluorescence decay law, and presents a different pump wave measured fluorescence lifetime of the new method-double-pulse detection method, namely the use of pump pulse and probe pulse for the fluorescence decay methods to measure fluorescence lifetime. By measuring the sample neodymium glass and Cr:ZnSe crystal fluorescence lifetime, results showed that: using this method can be achieved under different pump wave in visible and near-infrared to the mid-infrared laser medium of the fluorescence lifetime measurement. Therefore, using the measurement method can be convenient and effective to avoid seeking samples by deconvolution for fluorescence lifetime with the cumbersome process of measuring laser medium at different pump wave under the fluorescence lifetime with a reference value. PMID- 21284175 TI - [Diagnosis of cucumber diseases and insect pests by fluorescence spectroscopy technology based on PCA-sVM]. AB - The diagnosis model of the cucumber diseases and insect pests was established by laser-induced chlorophyll fluorescence (LICF) spectroscopy technology combined with support vector machines (SVM) algorithm in the present research. This model would be used to realize the fast and exact diagnosis of the cucumber diseases and insect pests. The noise of original spectrum was reduced by three methods, including Savitzky-Golay smoothing (SG), Savitzky-Golay smoothing combined with fast Fourier transform (FFT) and Savitzy-Golay smoothing combined with first derivative transform (FDT). According to the accumulative reliabilities (AR) seven principal components (PCs) were selected to replace the complex spectral data. The one hundred fifty samples were randomly separated into the calibration set and the validation set. Support vector machines (SVM) algorithm with four kinds of kernel functions was used to establish diagnosis models of the cucumber diseases and insect pests based on the calibration set, then these models were applied to the diagnosis of the validation set. According to the best diagnosis accuracy of cross-validation method in calibration set, the parameters of four kinds of kernel function models were optimized, and the capabilities of SVM with different kernel function were compared. Results showed that SVM with the ploy kernel function had the best identification capabilities and the accuracy was 98. 3% after the original spectrum noise was reduced by SG+FDT+ PCA. This research indicated that the method of PCA-SVM had a good identification effect and could realize rapid diagnosis of the cucumber diseases and insect pests as a new method. PMID- 21284176 TI - [Estimation of forest canopy chlorophyll content based on PROSPECT and SAIL models]. AB - The forest canopy chlorophyll content directly reflects the health and stress of forest. The accurate estimation of the forest canopy chlorophyll content is a significant foundation for researching forest ecosystem cycle models. In the present paper, the inversion of the forest canopy chlorophyll content was based on PROSPECT and SAIL models from the physical mechanism angle. First, leaf spectrum and canopy spectrum were simulated by PROSPECT and SAIL models respectively. And leaf chlorophyll content look-up-table was established for leaf chlorophyll content retrieval. Then leaf chlorophyll content was converted into canopy chlorophyll content by Leaf Area Index (LAD). Finally, canopy chlorophyll content was estimated from Hyperion image. The results indicated that the main effect bands of chlorophyll content were 400-900 nm, the simulation of leaf and canopy spectrum by PROSPECT and SAIL models fit better with the measured spectrum with 7.06% and 16.49% relative error respectively, the RMSE of LAI inversion was 0. 542 6 and the forest canopy chlorophyll content was estimated better by PROSPECT and SAIL models with precision = 77.02%. PMID- 21284177 TI - [Research on spectral data feature extraction based on wavelet decomposition]. AB - Reflectance spectral curve reveals the unique physical characteristic of different materials. Through spectral match and recognition, different materials could be distinguished. Because of the great amount of spectral data and the ambiguous absorption feature of original spectral curve, feature extraction of reflectance spectral curve is one of the essential techniques in hyper-spectral image classification and recognition. Using wavelet decomposition technique, the present paper proposes a new spectral feature extraction algorithm to compress data amount while reserve spectral feature selectively. Through selecting the appropriate decomposition level by measuring the objective absorption feature frequency, the original signal would be projected into a new feature space with less data amount and more obvious objective feature than the original one. The experiments show that the method proposed can reduce the spectrum dimensions effectively and improve the recognition precision with the spectrum matching. PMID- 21284178 TI - [Analysis of spectral response of vegetation leaf biochemical components]. AB - Based on the leaf spectra data measured with LOPEX'93, the authors analyzed the relationship between leaf spectra and leaf biochemical components including leaf chlorophyll and leaf water content. It was showed that leaf chlorophyll was highly correlated with the second derivation of leaf reflectance at wavelengths 700, 670, 600, 500, 490, 440, and 410 nm; similarly, it was also showed that leaf water content was highly correlated with the continuum removed leaf reflectance at wavelengths 2350, 2180, 2130, 2120, 1870, and 1820 nm, which correspond to the absorption features of water in shortwave infrared bands. In addition, the authors found that ND (Normalized Difference) has a higher response to chlorophyll than other spectral indexes and the correlation coefficient is 0.618; Ratio975 has a very high response to water content and the correlation coefficient is up to 0.996. Based on the above evidences, the authors built a model to retrieve leaf chlorophyll and leaf water content through ground measured leaf spectra data and the simulated leaf chlorophyll and leaf water content are very accurate as compared to the ground measurements. PMID- 21284179 TI - [Alteration mineral mapping method based on statistical analysis of field measured spectra]. AB - The present paper presents a new alteration mineral mapping method based on statistical analysis of field measured spectra. First of all, this method processes a cluster of measurement data of spectra of field samples, in order to distinguish different sample area from the overall types. Second, the results of the clustering of different mineral alterations established their respective discriminant functions. Thus, mapping major alteration type accords with the clustered reference spectra by given remote sensing images. Finally mapping further alteration types was based on the discriminant function of second step, which leads to final alteration map. This method takes full account of the different combination of alteration types, as well as the regional differences of alterations, and the establishment of the discriminant function for alteration minerals is more scientific. Moreover, the authors accessed the reliability of mapping to a certain extent. The method was applied to a study area of Baogutu in Xinjiang Province, which represents a good result. PMID- 21284180 TI - [A principal components selection method based on the modified randomization test for avoiding over-fit and under-fit in spectra calibration]. AB - More or less principal components often give an over-fit or under-fit quantitative calibration model. In order to avoid over-fit or under-fit in spectra calibration, a principal components selection method based on a modified randomization test is proposed. Three near infrared spectra experiments (the complexity of the sample components in each experiment is increasing by degrees) are introduced in this paper for evaluating the proposed method. The method is compared with the cross-validation method. And the spectra model complexity of how to affect the prediction performance of calibration is discussed. Then the adaptability of this modified randomization test to the uncertainty complex spectra model is also discussed. The results indicate that the proposed method has no process of leaving some samples out like cross-validation does, and all the training samples are considered when selecting principal components, so the problem of over-fit or under-fit can be avoided, which is benefit to improve prediction performance of calibration in spectral analysis. And the modified randomization test method is different with the commonly used randomization test that a simplified criterion is introduced here and it is easy to implement. With the proposed method, the authors can have a visualized and interactive process when selecting principal components. For these three experiments, 4, 5 and 8 selected principal components are employed in calibration respectively and the prediction result is the best for the independent external prediction sets. It is also implied that the proposed method is adaptable to the complex samples with more variables and little samples. PMID- 21284181 TI - [Spectroscopic study on the conformational change of silk fibroin in methanol water mixtures]. AB - A combinational study of circular dichroism, intrinsic fluorescence of protein and exogenous fluorescence probe of ANS was made to investigate the conformational change of silk fibroin in methanol-water mixtures as well as the mechanism. The spectral results showed that small hydrophobic regions were formed in silk fibroin in methanol-water mixtures at the concentration lower than 30% (V/V) via hydrophobic interaction, which was decreased at higher methanol content due to a structural transition of silk fibroin from random coil to beta-sheet. The conformational change of silk fibroin was found to be of a close relationship with the microstructure of the solvent and to be determined by the interaction between the peptide unit of silk fibroin and the cluster of the mixed solvent. Methanol-water mixture at low concentration had little effect on the solvation of the peptide unit and the conformation of silk fibroin, as a consequence of the fact that the inherent water structure was conserved. The transition from the tetrahedral-like water structure to the chain-like methanol structure, due to the increasing concentration of methanol, induced the conformational change of silk fibroin to eliminate the contact of peptide unit with the solvent molecular. PMID- 21284182 TI - [Spectroscopy study of binding mechanisms and molecular recognition of class specific molecularly imprinted polymer beads]. AB - A novel class-specific molecularly imprinted polymer (MIP) beads for sulfonylurea herbicides was synthesized by precipitation polymerization using chlorsulfuron as the template molecule, 2-(diethylamino) ethyl methacrylate (DEAEMA) as the functional monomer, and trimethylolpropane trimethacrylate (TRIM) as the cross linker. The mechanisms of recognition of MIP beads to the template molecule were evaluated by UV-spectrum and FTIR in the choosing and optimizing polymerization system experiment. The results showed that MIP beads contained the group which could interact with template molecule and its analogue by the hydrogen bonding specifically. PMID- 21284183 TI - [Algorithm of inland water retrieval based on spectral matching]. AB - This present paper presents a new inversion method of inland water based on spectral matching. First step of this method is using the known water surface measured hyperspectral and the absorption coefficient of each component, and obtaining backscattering coefficient of suspended matter with bio-optical model. The second step is calculation of the spectral reflectance of water bodies based on bio-optical model, through the cross-combination of inherent optical property of water components (chlorophyll, suspended matter, yellow substance), in order to create a look-up table of Rrs that corresponds to all combinations of water component. The third step is changing the look-up table data into MODIS spectral data using MODIS channel response function. The final study examined the applicability of the look-up table using the Hyperspectral and MODIS bands spectra, based on the minimum distance principle, to find the best matched spectra, thus it has found corresponding concentrations of three components. The average relative error of chlorophyll and suspended matter is 38.6% and 28% respectively. Optical properties of water components interfere with each other because of the complexity of inland water bodies, resulting in difficulty to extract the feature band for statistical model, and while it is hard for bio optical model inversion method to solve the unstable problem of special inherent optical property with the seasons and regional issues, the method of this paper would have the advantages of bio-optical model, while eliminating instability of special inherent optical property, so it is a good approach to inland water retrieval. PMID- 21284184 TI - [Monitoring canopy nitrogen status in winter wheat of growth anaphase with hyperspectral remote sensing]. AB - Biomass, leaf area index (LAI) and nitrogen status are important parameters for indicating crop growth potential and photosynthetic productivity in wheat. Nondestructive, quick assessment of leaf dry weight, LAI and nitrogen content is necessary for nitrogen nutrition diagnosis and cultural regulation in wheat production. In order to establish the monitoring model of nitrogen richness in winter wheat of growth anaphase, studying the relationship between the nitrogen richness (NR) containing nitrogen density, LAI and leaf dry weight and the difference of hyperspectral reflectance rates (deltaR), we conducted a comparable experiment with five winter wheat varieties under nitrogen application level of 0, 100, 200 and 400 kg x N x ha(-1). The results indicated the NRs of the different varieties of winter wheat leaves increased with increasing growth stage while in the different nitrogen levels it was sequenced as: NO>N3>N1>N2. Twelve vegetation indices were compared with corresponding NR. The NR had significantly negative correlation to TCARI and VD672 in those vegetation indices, and their correlations (r) arrived at 0.870 and 0.855, respectively. The coefficients of determination (R2) of two models were 0.757 and 0.731 by erecting model with the two indexes and NR Root mean square error (RMSE), relative error (RE) and determination coefficient between measured and estimated NR were employed to test the model reliability and predicting accuracy. Accuracy rates of the models based on TCARI and VD672 achieved 84.56% and 80.13%. The overall results suggested that leaf nitrogen status of growth anaphase in winter wheat has stable relationships with some vegetation indexes, especially index of TCARI and VD672. PMID- 21284185 TI - [Review of monitoring soil water content using hyperspectral remote sensing]. AB - Soil water content is a key parameter in monitoring drought. In recent years, a lot of work has been done on monitoring soil water content based on hyperspectral remotely sensed data both at home and abroad. In the present review, theories, advantages and disadvantages of the monitoring methods using different bands are introduced first. Then the unique advantages, as well as the problems, of the monitoring method with the aid of hyperspectral remote sensing are analyzed. In addition, the impact of soil water content on soil reflectance spectrum and the difference between values at different wavelengths are summarized. This review lists and summarizes the quantitative relationships between soil water content and soil reflectance obtained through analyzing the physical mechanism as well as through statistical way. The key points, advantages and disadvantages of each model are also analyzed and evaluated. Then, the problems in experimental study are pointed out, and the corresponding solutions are proposed. At the same time, the feasibility of removing vegetation effect is discussed, when monitoring soil water content using hyperspectral remote sensing. Finally, the future research trend is prospected. PMID- 21284186 TI - [Application of hyperspectral imaging technology to objective diagnosis of TCM syndrome]. AB - Hyperspectral imaging technology is expected as a breakthrough to resolve the lack of objective indicators on the diagnosis of TCM syndrome because of its high sensitivity and including abundant information of the images and spectra. In view of fuzzy and complicated mappings between tongue and syndrome, aiming at the defects of the acquisition methods of tongue information and its processing mode which extracts the features by fragmenting the integrative information, a new idea is proposed that the specific spectral indices pool be extracted after acquiring the hyperspectral data cube of tongue by hyperspectral imaging technology and associating it as a whole because of the overlapping mixing of these characteristic information with syndrome in black-box mode by means of intergration of various linear and nonlinear data mining algorithms. The mechanisms of etiological factor and pathogenesis are analyzed from all angles by synthesis of specific spectral indices pool, clinical physiological and biochemical indicators and TCM indicators. Then a new mode of objective diagnosis for syndromes can be found. PMID- 21284187 TI - [Review on label-free optical bio-sensing technology based on whisper-gallery mode]. AB - Optical biosensors are becoming an important tool for drug research and life science, and the label-free optical biosensor based on whisper-gallery-mode (WGM) is reviewed in the present paper. The WGM-based sensors are categorized into three types according to the microcavity structure. The biosensor using microsphere got extensive research because of high quality factor, and its response to protein, virus, and bacteria had been studied. The models based on single photon resonant state and perturbation theory were established. The biosensor using microdisk was proposed early since it can make use of mature lithography technology; however, the quality factor was increased greatly only after the thermal reflow process was introduced and single molecule measurement was then realized. The biosensor using microring has simpler mode structure and materials such as polymer, silicon nitride and silicon-on-insulator had been used for sensor fabrication. As a 3-dimension expansion, sensor using microtube can combine the optical channel and fluidic channel, which attracting more and more attention. PMID- 21284188 TI - [Study on the characteristic UV absorption parameters of dissolved organic matter extracted from chicken manure during composting]. AB - The characteristic parameters obtained from UV-Visible spectra of dissolved organic matter (DOM) during composting were studied in the present paper. The results showed that, during composting progress, the non-humic substances were translated into humus substances, and the aromatization, humification degree and molecular weight of the humus substances increased, while the fatty chains linked with the benzene ring structure were cleavaged into carbonyl, carboxyl and other functional groups. The correlation analysis showed that, when DOM concentration (DOC) from all samples was the same, the specific ultraviolet absorbance values at 254 and 280 nm (SUVA254 and SUVA280, respectively), and the area of a spectrum obtained from 226 to 400 nm (A(226-400)) showed significant positive correlation, furthermore, they were all significantly negatively correlated with the concentration of DOM (DOC), but the correlation between A(226-400) and DOC was the best; The ratio between the absorbance value at 253 nm and that at 203 nm (E253/E203) was significantly correlative with SUVA254, SUVA280 and A 226-400, though the correlation between E253/E203 and DOC was not as good as the other three characteristic parameters; The ratio between the absorbance value at 250 nm and that at 365 nm (E250/E365) and the ratio between the absorbance value at 465 nm and that at 665 nm(E250/E365) were not correlated with the other parameters. The results showed that, the stability of DOM extracted from chicken manure increased during composting, and the complex ability between DOM and heavy metals enhanced as well; A(226-400) reflects the changes of compost maturity best in all UV-Visible spectral absorption parameters studied in this paper. PMID- 21284189 TI - [Investigation of polarization characteristics of soil surface with low vegetation cover and different soil moisture]. AB - Compared with the spectral detection method, polarization detection could obtain more information of the target. For example, the polarization detection could be applied to interpret the refractive index and the surface roughness of the object, or retrieve the soil moisture, etc. Polarization detection provides a new approach to quantitative retrieval of soil moisture, and this is very important in agriculture, hydrology, meteorology and ecology. The polarization characteristics of soil surface with low vegetation cover,which is a example of mixed pixel in remote sensing, were researched with experiments, and the relationship between the polarization characteristics and soil moisture was also explored. The results showed that the polarization characteristics of soil surface with low vegetation cover are mainly determined by the area of bare soil, and are strongly relevant with the soil moisture. For the results of experiments in this paper, the IDOLP of soil surface with low vegetation cover increased with increasing soil moisture when the viewing angle of instrument was between 20 degree and 60 degree, while the incident angle of light source was fixed at 40 degree. This paper offered a new method to retrieve moisture content of soil with low vegetation cover. PMID- 21284190 TI - [Study on spectrum characteristics of cotton leaf and its estimating with remote sensing under aphid stress]. AB - The spectrum and physical-chemical parameters were measured on cotton leaves infected by aphid with different severity levels (SL) at main cotton growth periods. Meanwhile, the reflectance and physical-chemical parameters of cotton leaves infected by aphid were analyzed and compared in different cotton growth periods and varieties. The sensitivity wave bands of cotton leaves infected by aphid were confirmed, and the estimating models of leaves infected by aphid were established. The results showed that there was a significant difference in the spectrum and physical-chemical parameters of cotton leaves infected by aphid. The thickness, water and Chl. b increased, while Chla, Chl. a+b and Cars content decreased in leaves infected by aphid. Besides, in visible region, the reflectance of cotton leaves infected by aphid has shown going up first and then down in different cotton growth periods and varieties with increasing of SL. However, in NIR region, it has shown discrepancy in varieties. The 434-727 and 648 nm can be used as sensitive and optimal aphid-band for cotton leaves. Estimation models for leaves infected by aphid were all in significant correlation. Among all the models, the model of (R1 589-R648)/ (R1 589+R648) had the best estimation precision, RE was the smallest (0.128), and it was commended as best models to estimate SL of leaves infected by aphid. The study provides an experimental reference for monitoring spectrum of cotton infected by aphid with remote sensing in large areas. PMID- 21284191 TI - [Overview on monitoring crop biomass with remote sensing]. AB - Crop biomass is one of the key indicators not only in crop condition monitoring, but also in crop production estimation. With the development of 3S technology, it is feasible to estimate crop biomass at large scales with remote sensing. In the present paper, the researches on crop biomass estimation models with remote sensing were reviewed, and the methods of crop biomass estimation were classified into six categories according to their differences in data source and methodology. The advantages and deficiencies of each method were discussed and analyzed. Finally, the paper presents the prospect of the methods of crop biomass estimation. PMID- 21284192 TI - [The canopy and leaf spectral characteristics and nutrition diagnosis of tomato in greenhouse]. AB - A green house experiment was conducted to research the characteristics of tomato canopy spectral reflectance and leaf spectral reflectance under different nutrition treatments, and the relationships between spectral reflectance and the water content, chlorophyll content, as well as nitrogen content were analyzed. Substrate cultivation method was used to grow the plants. The substrate was made from a mixture of peat and vermiculite. Test area was prepared for four levels of nutrition to form nutritional stress. There were 12 seedlings under each nutritional condition and a total of 48 seedlings were planted for the experiment. The canopy reflectance and leaf reflectance were measured by an ASD handheld spectroradiometer and a FT-NIR spectrometer respectively. It was observed that the trend of tomato canopy reflectance was similar to each others. There was a reflection peak at about 550 nm, and the reflectance in the visible light region was lower than that in near-infrared region. The results of analysis also indicated that under different nutrient conditions, canopy spectral reflectance characteristics of tomato took on disciplinary change. At near infrared bands, the reflectance gradually increased with adding nutrition, while reduced at visible light bands. The leaf spectral reflectance characteristics at near-infrared bands had the similar change with the canopy reflectance. There were four sensitive wavelengths of water at near-infrared bands: about 980, 1450, 1 930, and 2 210 nm, and the results of single linear regression (SLR) and multi linear regression (MLR) indicated that the reflectance at these sensitive wavelengths could be used to estimate the water content in tomato leaves. R2 were 0.5903 and 0.7437 respectively. NDCI as one of the most important spectral parameter was calculated by the spectral reflectance of 530 and 760 nm, and the result indicated that there existed a good correlation between NDCI and the nitrogen content, with R2 = 0.7511. Meanwhile, red edge inflection points were analyzed under four nutrition treatments based on the first derivative of canopy spectral reflectance. The analysis results illustrated that red edge inflection position moved to direction of red light (long wavelength) with the nutrition supply. PMID- 21284193 TI - [Spectroscopic properties of Er3+ : Ba0.65Sr0.35TiO nanopowders]. AB - Ba0.65Sr0.35TiO2 (BST) nanopowders doped with Er3+ were prepared by sol-gel method. The absorption spectrum and photoluminescence (PL) spectrum of Er3+ : BST nanopowders was measured at room temperature. Based on the Judd-Ofelt theory, the intensity parameters of Er3+ in BST nanopowders were determined, omega2 = 0.993 x 10(-20) cm2, omega4 = 1.665 x 10(-20) cm2 and omega = 0.540 x 10(-20) cm2, and then the values of the line strengths, radiative transition probabilities and branching ratios of Er3+ were calculated. According to the PL spectrum, the emission bands centered at about 522, 545, 654 and 851 nm corresponding to 2H(11/2)-->4S(3/2-->4I(15/2), 4F(9/2)-->4I(15/2), and 4S(3/2-->4I(13/2) transition were observed, and the emission properties were also discussed. The results show that the Er3+ : BST nanomaterials are prospective candidates for applications in new photoelectric devices. PMID- 21284194 TI - [Analysis on urban vegetations reflectance characteristics in Shanghai]. AB - The spectral features of ground objects are not only the brief contents of mechanism of remote sensing, but also the important basis in remote sensing application. As one of main components of terrestrial ecosystems, urban forest plays a key role in maintaining urban ecosystem balance. In the present paper, the authors adopted FieldSpec 3 portable spectroscope made by American ASD Company, and investigated or examined some spots in the Kangjian park of Shanghai, China. The spectra of euonymus japonicus L. cv, hypericum monogynum, sabina chinensis, ophiopogon japonicus, viburnum awabuki, and buxus sinica were measured. According to the actual conditions, the authors analyzed the data noise characteristic of the spectrum and got rid of the noise with Savitzky Golay method. Meanwhile, differential spectrum technology was used to remove the environmental background influence. Then the authors analyzed their features and variation of these spectral curves from the vegetation canopy and leaf level respectively. The research on spectral reflectance characteristics for urban vegetations is very significant. And the result of this research can be used for the study of physical chemistry performances of urban vegetation, remote sensing retrieval, vegetation classification, vegetation survey and environmental monitoring in urban area. PMID- 21284195 TI - [Resonance scattering spectral detection of trace K+ by aptamer-modified nanogold probe]. AB - In pH 7.0 Na2HPO4-NaH2PO4 buffer solution, nanogold particles interacted with the aptamer to form a stable aptamer-nanogold complex that was not aggregation by NaCl. At 80 degrees C, K+ and aptamer folded to form a stable G-quadruplex that released nanogold particles, the uncombined nanogold particles aggregated to large nanogold clusters that caused the increase in resonance scattering (RS) intensity at 563 nm in high concentration of NaCl, and the laser scattering showed that the average diameter was 120 nm. In the present paper, the resonance scattering spectral characteristics of K+ -ssDNA1-Au, K+ -ssDNA2-Au and K+ aptamer-Au systems were investigated, and the structural changes of aptamer were studied by circular dichroism spectral technology. Effects of pH value, NaCl concentration, nanogold concentration, aptamer concentration, and the reactation temperature and time on the resonance scattering intensity were considered in detail. The influence of coexistent substances on the determination of K+ was investigated, result showed that the common heavy metal ions such as Cu2+, Mg2+, Pb2+, Ca2+, Al3+, Zn2+ and Fe3+ do not interfere with the determination, and the method has good selectivity. Under the conditions selected, a 0. 67-3 350 micromol x L(-1) K+ can be detected by the aptamer-nanogold RS assay, with a detection limit of 0.3 micromol x L(-1) K+, regression equation deltaI = 0.167c 0.7, and a coefficient of 0.9932. The method was used for analysis of K+ in serum sample with the results consistent with the ion-selective electrode method. PMID- 21284196 TI - [The production of hydroxyl radical in HRP-NADH-H2O/O2 systems and its application in chlorobenzene removal]. AB - The mechanism of radical generation in HRP-NADH-O2/H2O2 systems and state-change of horseradish peroxidase (HRP) was investigated by using ESR and UV measurements, and the novel enzyme-coenzymatic systems were performed to degrade chlorobenzene as a non-phenolic persistent organic pollutants. The UV results showed that compound III was produced from HRP oxidized by hydrogen peroxide with the catalysis of NADH, which would generate hydroxyl radical. The ESR results demonstrated the production of *OH and O2-. in enzyme-coenzymatic system in the presence of O2 or H2O2 with DMPO and POBN as spin-trappers, respectively. In HRP NADH-H2O2 system, compound III was the main state of HRP in the initial 10 min, and then converted to HRP with generating hydroxyl radical; and after the addition of oxygen, the production of hydroxyl radical was promoted rapidly, as 4 times as that of the system in absence of oxygen. The addition of SOD(Zn-Cu) decreased the production of hydroxyl radical significantly, resulting from that SOD eliminated O2 reduction to O2-. by NADH and then inhibited *OH formation. The results showed that NADH could improve by about 20% enzyme activity of HRP for phenol removal. The removal of chlorobenzene with HRP-NADH-H2O2 and HRP-NADH-H2O2 O2 systems reached 24.6% and 48.2%, respectively, which was much higher than that with traditional enzymatic system (1.42%), showing a promising prospect in proposal PMID- 21284197 TI - [Synthesis, characterization and relaxivity of DTPA double alkyl esters heterocyclic gadolinium(III) complexes]. AB - The DTPA ligand modified by heterocyclic compound and linked through double alkyl ester covalent bond was synthesized by acylation reaction between diethylenetriamine pentaacetic (DTPA) bisanhydride and a novel heterocyclic compound. The corresponding paramagnetic Gd(III) complex was gained by the reaction of the DTPA ligand with GdCl3.6H2O. The structure of the ligand and its Gd(III) complex was characterized by elemental analysis, FTIR and 1H NMR, and the longitudinal relaxivity (R1) was measured. Besides, the magnetic resonance imaging of the new Gd(III) complex in vitro was studied. The result suggested that the stability of the complex was well, and when the Gd(III) quantity was identical, the R1 of the Gd(III) complex (5.12 mmol x L(-1) x s(-1)) was higher than the clinical magnetic resonance imaging contrast agent Gd-DTPA (3.64 mmol x L(-1). PMID- 21284198 TI - [Diagnosis and analysis of high power YAG laser and MAG arc hybrid source with spectral information]. AB - High power YAG laser and MAG are hybrid source is a promising material processing heat source for future industry application Diagnosis of the plasma state is critical for better understanding of the coupling effect, application of the source and optimization of the hybrid parameters. Through establishing a hollow probe spectral collecting system, Avaspec-Ft-2 high speed digital spectrometer was applied for collecting the spectral information of hybrid are plasma. The hollow probe scans the plasma body to acquire the spatial distribution of the YAG laser-MAG hybrid are spectrum. The radiation intensity in specific spectral zone was acquired for analysis of the radiation variation when the laser beam was hybrid with the MAG arc. High speed photo was also applied for comparison of the plasma with and without laser beam coupling. Furthermore, line spectra of Fe I were selected for calculating the electronic temperature of the hybrid plasma with Boltzmann plot method. The results show that energy of the hybrid plasma focused on the weld plate with high intensity and wider acting zone. The electronic temperature increased in the center of the hybrid plasma. PMID- 21284199 TI - [Measurement and analysis of copper in soil using laser-induced breakdown spectroscopy]. AB - The present paper analyzed the characteristics of laser-induced breakdown spectroscopy (LIBS) of metal element Cu in soil using the Nd:YAG (wavelength: 1064 nm) laser as the excitation source, where the spectral signals were detected by the highly resolved and wide spectral echelle spectrograph and intensified charge coupled device (ICCD). The time evolution of the characteristic spectral line of Cu was obtained by changing the delay time of ICCD at the same concentration and the gate of ICCD with wavelength of 329. 396 nm of Cu as the characteristic spectral line, from which the best delay time 1.1 micros was found. By measuring the intensities of the characteristic spectral line with different Cu concentrations, it was demonstrated that the intensities of the spectral line increased with the concentration of Cu under the condition of low concentration From the results the LIBS calibration curve of Cu was obtained, and by fitting calculation the detection limit of Cu in soil at 13. 36 microg x g(-1) was obtained. PMID- 21284200 TI - [Determination of trace BrO3- and Br- in Chinese patent drugs, waters and beverages by ion chromatography coupled with inductively coupled plasma mass spectrometry]. AB - In the present study, a method for determination of BrO3- and Br- using ion chromatograghy coupling with inductively coupled plasma mass spectrometry (IC-ICP MS) was developed. BrO3- and Br- were separated on a Hamilton PRP X-100 (150 x 4.1 mm, 10 microm) column guarding with a On-guard II RP (4 x 50 mm) column with 10 mmol x L(-1) NH4NO3 eluent solution at 2 mL x min(-1). By using 200 microL sample loop, the detection limits for BrO3- and Br were 0.35 and 0.36 microg x L( 1), respectively. BrO3- had good linearity in the range 4.8-160.0 ng x L(-1). The standard solution linear equation was y = 250.31x-45.43, and R2 = 0.9999. Br had good linearity in the range 4.2-140.0 ng x L(-1). The standard solution linear equation was y = 186.84x-127.10, and R2 = 0.9994. Recoveries of spiked samples were 98.9%-109.5% and 97.4%-106.1%, respectively. The samples included various kinds of Chinese patent drugs, waters, and beverages. Among them, 14 bottled drinking waters and 2 kinds of tap waters were found containing BrO-, while other samples were under BrO3- detection limit. Br- was detected in all samples. PMID- 21284201 TI - [Determining the content of trace element in Potentilla parvifolia Fisch at different altitudes]. AB - Determining the content of Ca, Fe, Mn, Zn, Cu and Mg in Potentilla parvifolia Fisch by atomic absorption spectrometry was studied. Recovery and RSD of the method is 98.3%-103.2% and 1.21%-3.01% respectively, and the method is rapid and precise. The order of the content in Potentilla parvifolia Fisch is Mg>Ca>Fe>Mn>Zn>Cu. There is not a relation between altitude and content. The mean of the content of Mg, Ca and Fe is 5079.641, 2760.188 and 1070.297 mg * kg(-1) respectively. The result of Potentilla parvifolia Fisch can provide theoretical basis for medicine research. PMID- 21284202 TI - [Development of ceramic standard samples used for X-ray fluorescence spectrometric analysis]. AB - The preparation of 17 kinds of ceramic standard samples (CSS) is introduced briefly in the present paper, and the experimental results of the sintered CSS by using EPMA and XRF are discussed in detail. The conclusions can be mainlydrawn that the CSS, which have high density, low water absorption and good homogeneity of element distribution, have similar phase structure (or matrix) to the bodies of ancient ceramics, and perfectly meet the requirements of being used as ceramic standard samples. This set of CSS are expected to play an important role in x-ray fluorescence spectrometric quantitative analysis of Na2O, MgO, Al2O3, SiO2, K2O, CaO, TiO2 and Fe2O3 in the body of ancient ceramics and can provide accurate and reliable data for study and identification of ancient ceramics. PMID- 21284203 TI - [HJ1A/HSI radiometric calibration and spectrum response function sensitivity analysis]. AB - Hyper spectrum imager (HSI) loaded on HJ-1A satellite is Chinese first spaceborne hyperspectrum sensor. Since the HSI has no spectrum response function of all channels, the usually used calibration method-reflectance based method has been modified, and a new calibration method is proposed, in which the spectrum response function is neglected. Based on the calibration experiment data of Dunhuang in Aug., 2009, the HSI sensor was calibrated on orbit. The different kinds of spectrum response were constructed based on the formula, and the errors of calibration results with different spectrum response function were analyzed. The results show, expecting for the channels of water vapor and oxygen absorption channel, the influence of spectrum response function in other channel is less than 3%, and the calibration result based on new calibration method can satisfy the application requirement. PMID- 21284204 TI - [Analysis and experimental verification of SNR for a far ultraviolet imaging spectrograph in 115-180 nm]. AB - An 115-180 nm far ultraviolet limb imaging spectrograph prototype was developed for the detection of the ionosphere. For the particularity of the wavelength band in far ultraviolet, the signals accepted by the instrument are very weak. So the sensitivity and signal-noise-ratio (SNR) are two important performance parameters for the spectrograph. In the present paper, based on the signal statistical detection theory and the threshold detection theory, a method for calculation of the sensitivity and SNR has been proposed. Firstly, the probabilities of the accepted signals and system noises were analyzed. Secondly, the mathematical expressions of sensitivity and SNR of the instrument were deduced by introducing the detection probability factor and the false alarm rate factor. Based on the calculation of the sensitivity and the intensity of the particles radiation wavelengths, it was found that the sensitivity can meet the need of the detection. Finally, the SNR of the instrument were analyzed by using the method, and the coherent experiment was built to prove the results. The error of theoretic calculation and experimental results can be accepted. It indicates that the SNR analysis method is feasible. PMID- 21284205 TI - [Development of transient pyrometer based on multi-spectral radiation technology]. AB - In modern dynamics system, the radiant temperature of the flame, which caused by the transient plasma stimulated by high-energy-level electromagnetism field, takes an important role in the description of the flying object's status as well as cauterization of the trajectory. Due to its extremely high temperature and transient process, the radiant temperature of the flame can hardly be measured through contracted ways, either static ways such as traditional pyrophotometer or CCD arrays. In the present paper, the authors bring forward a novel pyrophotometer based on classical theory of Planck's law (blackbody radiation law) and multi-channel spectrums radiation method. With this new type pyrophotometer, any spectrum can be selected out from the wavelength of 300 to 860 nm within 2 ns. Also, the application of high-definition diffraction grating and fibers can'ensure the accuracy of selected spectrum. The results through a serial of experiments by using this theory as well as high-speed photodetector indicate that this method is valid and accurate for the measurement of the object's surface's radiant temperature. PMID- 21284206 TI - [Arms racing between human beings and pathogens: NDM-1 and superbugs]. AB - Throughout human history, pandemic bacterial diseases such as the plague and tuberculosis have posed an enormous threat to human beings. The discovery of antibiotics has provided us with powerful arsenal for the defense against bacterial infections. However, bacteria are acquiring more and more resistance genes to shield off antibiotics through mutation and horizontal gene transfer. Therefore, novel antibiotics must be produced and the arms race between bacterial pathogens and antibiotics is becoming increasingly intense. Recently, researchers have found that plasmids carrying a new metallo-beta-lactamase gene, blaNDM-1, and many other antibiotics resistance genes can easily spread through bacterial populations and confer recipient stains resistance to nearly all of the current antibiotics. It is a threat to the human health and a great challenge for our medical science, which we are facing. We need to find new ways to fight and win this arms racing. PMID- 21284207 TI - [Fermentation production of microbial catalase and its application in textile industry]. AB - Microbial catalase is an important industrial enzyme that catalyzes the decomposition of hydrogen peroxide to water and oxygen. This enzyme has great potential of application in food, textile and pharmaceutical industries. The production of microbial catalase has been significantly improved thanks to advances in bioprocess engineering and genetic engineering. In this paper, we review the progresses in fermentation production of microbial catalase and its application in textile industry. Among these progresses, we will highlight strain isolation, substrate and environment optimization, enzyme induction, construction of engineering strains and application process optimization. Meanwhile, we also address future research trends for microbial catalase production and its application in textile industry. Molecular modification (site-directed mutagenesis and directed revolution) will endue catalase with high pH and temperature stabilities. Improvement of catalase production, based on the understanding of induction mechanism and the process control of recombinant stain fermentation, will further accelerate the application of catalase in textile industry. PMID- 21284208 TI - [Plant-specific type III polyketide synthase superfamily: gene structure, function and metabolites]. AB - Plant-specific type III polyketide synthase (PKS) produces a variety of plant secondary metabolites with notable structural diversity and biological activity. So far 14 plant-specific type III PKS have been identified according to their enzymatic products, and the corresponding genes have been cloned and characterized. The differences among the various PKS are mainly in their substrate specificities, the number of their condensation reactions, and the type of ring closure of their products. However, numerous studies have revealed the common features among the plant-specific type III PKS, which include sequence homology, similar gene structure, conserved amino acid residues in the reaction center, enzymatic characteristics and reaction mechanism. We briefly reviewed 14 plant-specific type III PKS to better understand genetic and metabolic engineering of plant-specific type III PKS. PMID- 21284209 TI - [Cloning of delta8-fatty acid desaturase gene from Euglena gracilis and its expression in Saccharomyces cerevisiae]. AB - Delta8 desaturase pathway, different from common delta6 desaturase pathway, is an alternate pathway of polyunsaturated fatty acids biosynthesis. Delta8-fatty acid desaturase is one of the key enzymes in delta8 desaturase pathway. Two specific fragments were separately cloned from genomic DNA and cDNA of Euglena gracilis by PCR with the primers designed according to the reported sequence. Comparison of the genomic and cDNA sequences revealed that there wasn't intron in this delta8 fatty acid desaturase gene. This gene has an open reading frame of 1 266 bp that encodes 421 amino acids. It is 6 bp longer than the reported gene sequence, and also showed certain difference from the reported sequence in the N-terminal. The recombinant expression plasmid pYEFD by subcloning delta8-fatty acid desaturase gene into the yeast-E. coli shuttle vector pYES2.0 was constructed and was transformed into the defective mutant INVSc1 of Saccharomyces cerevisiae by electrotransformation. The resulting strain YD8 harboring plasmid pYEFD was selected and was cultured in the induction medium with exogenous substrates omega6-eicosadienoic acid and omega3-eicosatrienoic acid for the expression of delta8-fatty acid desaturase gene. The results indicated that high level expressed As-fatty acid desaturase could convert omega6-eicosadienoic acid and omega3-eicosatrienoic acid to dihomo-gamma-linolenic acid and eicosatetraenoic acid with substrate conversion ratio 31.2% and 46.3%, respectively. PMID- 21284210 TI - [Effects of different neutralizing agents on succinate production by Actinobacillus succinogenes NJ113]. AB - Different neutralizing agents were used as pH controller to investigate their effects on the growth and succinic acid production of Actinobacillus succinogenes NJ113. The fermentation results showed that Ca(OH)2, CaCO3 and NH4OH were not suitable for succinic acid production by A. succinogenes NJ113 because of their negative effects on cell growth. When Na-base was used, cells would flocculate and lump, and due to the sodium ion concentration reaching to a high level, OD660 dropped sharply after 12 h of fermentation. Mg-base was better because there was no significant inhibition by magnesium ion. Two combined neutralizing agents were used to maintain pH level, one with NaOH and Mg(OH)2 while the other with Na2CO3 and Mg(OH)2. The optimum ratios of the combined neutralizing agents were both 1:1 (g:g) when using 100 g/L glucose. When NaOH and Mg(OH)2 were chosen with the ratio of 1:1(g:g), 69.8 g/L of the succinic acid and 74.5% of the yield was obtained. PMID- 21284211 TI - [Enhancing 2-keto-L-gulonic acid production under hyperosmotic stress by adding sucrose]. AB - This study aimed to further enhance 2-keto-L-gulonic acid (2-KLG) production efficiency. A strategy for enhancing Ketogulonigenium vulgare growth and 2-KLG production by improving B. megaterium growth with sucrose was developed based on the time course of osmolality during 2-KLG industrial scale fermentation and effects of osmolality on cells growth and 2-KLG production. Results showed that the accumulation of 2-KLG and the feeding of alkaline matter led to an osmolality rise of 832 mOsmol/kg in the culture broth. High osmotic stress (1 250 mOsmol/kg) made the growth ofB. megaterium and K. vulgare decreased 15.4% and 31.7%, respectively, and consequently the titer and productivity of 2-KLG reduced 67.5% and 69.3%, respectively. When supplement sucrose under high osmotic condition (1 250 mOsmol/kg), B. megaterium growth was significantly improved, with the result that 2-KLG production was increased 87%. Furthermore, by applying this sucrose addition strategy further to batch fermentation in 3 L fermentor, the productivity of 2-KLG increased 10.4%, and the duration of fermentation declined 10.8%. The results presented here provide a potential strategy for enhancing the target metabolites produced by mixed strains at environmental stress. PMID- 21284212 TI - [Reuse of recombinant Escherichia coli to produce succinic acid by bioconversion]. AB - The possibility of reusing Escherichia coli cells from the broth for succinic acid production was investigated. Using succinic acid yield and productivity as criterion, we investigated the effects of cell concentration, initial glucose concentration, different neutralizers on the bioconversion. The results revealed that E. coli could convert glucose to succinic acid in a water solution of glucose and a neutralizer. According to the results, the optimal condition was as follows: the cell concentration was 50 (OD600), glucose concentration was 40 g/L and neutralizer was MgCO3. Under the optimum conditions, we carried out the consecutive batch bioconversion in 7 L fermenter. Succinic acid yield reached 91% with the productivity of 3.22 g/(L x h) for the first conversion. For the second conversion, succinic acid yield reached 86% with productivity of 2.04 g/(L x h). Furthermore, we achieved a high mass yield above 83% with the productivity of 1.82 g/(L x h) for the third bioconversion. PMID- 21284213 TI - [Essential expression and inducible synthesis polymorphism of chitinase in Bacillus thuringiensis]. AB - Chitinases were produced by a lot of microorganisms. Chitinase gene expression in most of the chitinase producing bacteria was inducible by chitin. Low levels of chitinase were observed in the presence of glucose. To date, however, the regulation of such chitinase gene in Bacillus thuringiensis had not been well studied. In this paper, all 77 Bacillus thuringiensis strains were grown in the medium with or without chitin. We measured quantitatively the chitinase activity of the cultures. Moreover, we investigated the suppressive effect of glucose on chitinase of 4 strains. Also we studied the relationship between chitin induction and glucose suppression on chitinase. This investigation demonstrated that all tested B. thuringiensis strains could produce chitinase without chitin. After induction, the chitinolytic activity of 31 tested strains had no obvious response to the inducer, whereas 44 stains increased in different degree. Among these strains, most of them did not markedly increase the levels of chitinase, and many stains simultaneously displayed the expression mode of inducible and constitutive. The glucose inhibited the inductive effect of chitin, but it could not inhibit the basal expression of chitinase. Two strains No. 38 and No. 75 belonged to different expression types. But we just found several different bases in the regulatory region of chitinase genes chiA and chiB from them. PMID- 21284214 TI - [Spatiotemporal expression patterns of three vernalization genes in wheat]. AB - To identify spatiotemporal expression patterns of vernalization genes in common wheat, we analyzed expression characteristics of several vernalization genes (VRN1, VRN2 and VRN3) in the wheat cultivars 'Chinese spring' and 'Luohan 2' by RT-PCR. The VRN1 gene was expressed at different levels in the leaves and roots at the 3-leaf stage, stems, flag leaves at the grain-filling stage, anthers, ovules, and developing seeds in 'Chinese spring'. Expression of VRN1 increased before flowering date, then decreased after flowering time. Expression of VRN1 was not detected in dry seeds or seeds germination. Expression patterns of VRN1 in 'Luohan 2' were similar to those in 'Chinese spring', except that it was not expressed in roots or in the leaves at the 3-leaf stage in 'Luohan 2'. Expression of VRN2 was only detected in the leaves at the 3-leaf stage and in the embryo buds during seeds germination. The Spatiotemporal expression of VRN3 was similar to that of VRN1, except that VRN3 was not expressed in roots. These results improved our understanding of the molecular regulation of vernalization genes in common wheat. PMID- 21284215 TI - [Regulation pattern of the FRUITFULL (FUL) gene of Arabidopsis thaliana]. AB - FRUITFULL (FUL) is an MADS box gene that functions early in controlling flowering time, meristem identity and cauline leaf morphology and later in carpel and fruit development in Arabidopsis thaliana. In order to clarify the regulation of FUL expression the upstream regulatory region, -2148 bp - +96 bp and the first intron of the FUL gene were cloned, and vectors with a series of deletion of FUL promoter, and the ones fused with the first intron were constructed. Vectors harboring the fusion of cis-acting elements with the constitutive promoters of TUBULIN and ACTIN were also constructed. Beta-Glucuronidase activity assays of the transgenic Arabidopsis plants showed that two cis-elements were involved in the repression of FUL expression, with one of the two being probably the binding site of the transcriptional factor AP1. And the two CArG boxes played a important role in FUL initiation particularly. Furthermore, the first intron of FUL was shown to participate in the development of carpel and stamen as an enhancer. PMID- 21284216 TI - [Cloning and expression of a single human immunoglobulin heavy-chain variable domain with vascular endothelial growth factor binding activity]. AB - In the application of therapeutic antibodies, large molecular weight of antibodies is always a problem that prevents them from penetrating into tissues or binding to antigenic determinants. To overcome this problem, we investigated the function of the heavy chain variable domain of a monoclonal anti-VEGF human IgM antibody derived from the Five-Feature Translocus Mice. We cloned the cDNA of the heavy chain variable domain, which was then inserted into pET28a vector and expressed in Escherichia coli. After purification and renaturation of the denatured recombinant protein, we obtained a 16 kDa antibody fragment, which is named as rhVVH. By immunoassaying its VEGF-binding capability in vitro, we proved that rhVVH retains this activity as the complete IgM. Importantly, rhVVH is shown to inhibit the HUVEC cell proliferation in a concentration-dependent manner. Our results indicate that the single heavy chain variable domain might inherit part of the biological function of the complete IgM antibody, which provided a valuable potential in further research on antibody miniaturisation. PMID- 21284217 TI - [Expression and crystallographic studies of a fungal immunomodulatory protein LZ 8 from a medicinal fungus Ganoderma lucidum]. AB - LZ-8 protein, isolated from a well known Chinese traditional medicinal fungus Ganoderma lucidum, is the first member of fungal immunomodulatory protein, members of which have been isolated from a variety of medicinal and edible mushrooms in the last two decades. The protein plays a multifunctional and important role in modulating immune system. In this report, in order to get LZ-8 protein crystals, the LZ-8 gene was expressed and purified by affinity chromatography, gel filtration chromatography and anion exchange chromatography subsequently. The protein was then crystallized using the hanging-drop vapour diffusion method. The LZ-8 crystals were obtained and the phase information was calculated by X-ray diffraction. The resolution of LZ-8 crystals is 3.2A. This study will provide an insight into the structure of fungal immunomodulatory proteins. PMID- 21284218 TI - [Construction and identification of recombinant lentiviral vector of hNoc4L gene]. AB - Formation and nuclear export of pre-ribosomes requires many nucleolar complexes, hNoc4L which contains a conserved Noc doman is a homolog of nucleolar complex associated 4 (S. cerevisiae), but its function is completely unclear. Here, we successfully got the recombinant lentiviral vector p113.7-EF1-hNoc4L-Flag by replacing the U6 promoter in p113.7 with EF1alpha promoter, and then inserted hNoc4L to down-stream of the EF1alpha prompter. We determined the transduction efficiency in different mammalian cell lines based on lentiviral packaging system. Subsequently, we analyzed the immunogenicity of the recombinant lentivirus and stable expression of hNoc4L in RAW264.7 cells. The results showed that the recombinant lentivirus characterized a high transduction efficiency, long-term expression and low immunogenicity. Therefore, we pave the way for further identification of the biological activity of hNoc4L protein during ribosome biogenesis in mammalian. PMID- 21284219 TI - [Purification and characterization of recombinant human lactoferrin expressed in a cattle mammary bioreactor]. AB - Novel ion exchange adsorbents were synthesized by immobilizing sulfopropyl derivative onto homemade highly cross-linked agarose beads. The effects of different ligand densities (from 0.05 to 0.24 mol/L) on static and dynamic adsorption of the adsorbents were investigated using lysozyme as a model protein. Based on these results, rHLF was purified from the transgenic milk by our SP media. 1 mL high density (0.24 mol/L) adsorbent could handle 50 mL rHLF containing milk. The mass recovery of rHLF was 86.5% and the purity was 98.5%. CD spectra demonstrated that the native structure of rHLF was not affected in the purification process. The biological functions of the purified rHLF, including iron binding, releasing and antimicrobial activities were then investigated. The results showed that rHLF had comparable iron binding and releasing activity to that of native HLF. 5 g/L concentration of rHLF significantly inhibited the growth of Escherichia coli. These studies lay a solid foundation for the wide application of our self-prepared ion exchange adsorbents in protein purification. PMID- 21284220 TI - [Effect of affinity medium and solution conditions on endotoxin removal from protein solutions]. AB - Endotoxin removal is essential for the safety of biological products. To remove endotoxin efficiently, we used polymyxin B (PMB) affinity adsorbent to remove endotoxin from protein solutions by static adsorption. We studied the effects of spacer length and ligand density of the affinity adsorbent, pH, salt type and concentration, protein type and concentration, endotoxin concentration, and additive on endotoxin removal and protein recovery. Endotoxin content and protein concentration were determined by test and Lowry assay respectively. The results showed that PMB affinity adsorbent had high capacity, high adsorption speed, high removal efficiency and good reusability. In addition, ligand density, pH, salt concentration and the isoelectric point and hydrophobicity of protein all had remarkable influence on the endotoxin removal. Under the optimal conditions, the recoveries of hemoglobin, human serum albumin and lysozyme were 87.2%, 73.4% and 97.3%, respectively, and the corresponding endotoxin removal rates 99.8%, 97.9% and 99.7%, respectively. This study illustrated the effects of solution conditions on the efficiency of endotoxin removal and protein recovery, and would provide useful reference for the efficient removal of endotoxin from biological products. PMID- 21284221 TI - [Congenital cyst and fistula of the face and neck]. AB - The authors propose an update on cervicofacial congenital cysts and fistulas' symptomatology. Embryological data, epidemiology and clinical manifestations are described. A reminder of the therapeutic principles is proposed as well as the evolution of these congenital pathologies, which may or may not involve the branchial system. branchial. PMID- 21284222 TI - [Resorption of cartilage grafts in rhinoplasty: fundamental basis]. AB - Resorption of the autologous cartilage graft of the nasal dorsum is a problem which concerns all rhinoplasticians. Their rate of resorption is estimated between 20 to 30% of the graft volume and can occur with no means of prevention from the side of the surgeon. The goal of this article is to highlight, through a short review of the literature, the current data regarding the composition of the septal cartilage, its healing process and the progress made in cartilaginous tissue engineering to adapt our surgical technique. Cartilaginous tissue engineering does not yet have the abilities to provide a replacement septal cartilage with the same molecular composition, the same mechanical properties and devoid of volume loss after implantation and in spite of a certain progress, autologous cartilage grafts are still making the headlines. However to avoid the resorption of the latter and to preserve their volume, it seems necessary to avoid crushing them so as not to compromise chondrocyte viability and proliferation. Cutting-out millimeter-length dices seems more adapted to preserve cellular viability but remains insufficient because of the low healing capacities of the cartilage. Diced-cartilage wrapped with connective tissue seems an elegant and efficient solution over the long run to safeguard their volume and to harmonize contours and irregularities of the dorsum. PMID- 21284223 TI - [Advantages of combined therapies in cosmetic medicine for the treatment of face aging: botulinum toxin, fillers and mesotherapy]. AB - Non surgical cosmetic medicine procedures for the face are developing considerably, as they deliver good results using simple, non invasive, atraumatic and reproducible techniques. Aesthetic mesotherapy, also known as anti-aging mesotherapy, uses intra-dermal injections of a nutritive and moisturizing solution to improve brightness, skin hydration and tonus, and also smooth out superficial wrinkles. Subcutaneous filler injections enable to fill wrinkles and folds; by using high density products it is also able to provide genuine facial volumetric reconstruction. Finally, botulinum toxin acts by reducing certain muscle contractions to smooth out expression lines and folds induced by facial dynamics. In this article, we explore the concept of combined therapy and describe our experience associating anti-aging mesotherapy (NCTF-135HA, Filorga, Paris, France), hyaluronic acid based fillers (X-HA3 and X-HA-Volume, Filorga, Paris, France) and botulinum toxin (Vistabel, Allergan, Irvine CA, USA). A therapy combining anti-aging mesotherapy, botulinum toxin and filler injections, offers full treatment of the 3 biological levels of the covering tissues. This non-invasive therapeutic strategy brings patient satisfaction through a global approach to facial aging. PMID- 21284224 TI - [Termino-terminal hypoglossofacial anastomosis, indications, results]. AB - OBJECTIVES: Retrospective study about the indications and the results of the end to-end hypoglossofacial anastomosis (AHF tt). MATERIALS AND METHODS: Between 2004 and 2010, 38 patients were able to benefit from an AHF tt. It was about 13 men and 25 women. The mean age was of 40 years and the average deadline of coverage after facial paralysis was of 21.3 months. The etiology of the paralysis was in 47.7% of the cases a surgery for vestibular schwannoma and in 18% of the cases, of the facial nerve schwannoma. Besides the AHF tt, a golden weight was put to 6 of our patients. A specific and premature speech therapy remediation was realized at our all patient's. RESULTS: The beginning of recovery was spread out between 3 and 9 months. The final result was a grade III HB (37%) and IV HB (60%). Only a case of grade VHB was observed. The complications often reported by the AHF tt were very widely decreased by the specific reeducation. CONCLUSION: AHF tt is a particularly reliable technique, for rehabilitation of facial palsy, when the peripheral branches are intact and it, for the deadline 4-years-old subordinate except particular cases. PMID- 21284225 TI - [Importance of a molding nasolabial flap in the reconstruction of mobile nose defects, a review of 25 cases]. AB - INTRODUCTION: Mobile nose reconstruction, because of its location, its anatomy and its functional role is a surgical challenge. We describe throughout this article the surgical technique and the importance of the nasolabial flap in a single-step procedure for repairing mobile nose defects. MATERIALS AND METHODS: We present 25 cases of mobile nose defects secondary to an oncologic etiology, affecting the supratip, the alar margin and the columella. Patients benefited from a superiorly pedicled molding nasolabial flap harvested in a one-step procedure under local anesthesia. RESULT: Aesthetic result of each repair was evaluated according to 5 criteria and was considered as very satisfactory by the surgeons. No complication such as necrosis or infection was recorded. DISCUSSION: A molding nasolabial flap allows optimum repair of the mobile nose. It represents reliability, elasticity at the price of minimal scarring. We find it an important tool in the therapeutic armamentarium in patients with tissue loss in mobile nose. PMID- 21284226 TI - [A new look on septoplasties: an anatomo-clinical study and surgical procedures of the 4 main septoplasties]. AB - The aim of a nasal septum surgery is functional and aesthetic aims. With a semiologic study the authors analyse four kinds of septoplasties which allows to correct the main septal deviations: erndoscopic septoplasty for posterior nasal obstruction, Cottle's septoplasty for septum's luxation and deviation on the premaxilla area, septoplasty with spreader grafts for dorsum cartilage deviations, extracorporeal septoplasty with a new septum cartilage frame for the complex deviations. The authors emphasize on the help given by videoendoscopy during the surgical procedures. PMID- 21284227 TI - [The nasal framework in rhinoplasty and its dimensions: the importance of a third element]. AB - INTRODUCTION: Reconstructing a crooked nose has been a challenge. Reshaping a nose reducing or improving its profile may be followed by irregularities and functional troubles. The principles of the extracorporeal septoplasty were launched in the 50's, consisting of the treatment of the septal framework outside the nose. Thus, it is replaced and fixed inside the nose. Dorsal irregularity or low projection may be overcome with a dorsal onlay graft. OBJECTIVE: To describe an evolution of extracorporeal rhinoseptoplasty based on a three-dimensional reshaping of the nasal framework, and its average dimensions. PATIENTS AND METHODS: Data of patients presenting nasal obstruction related to septal deviation and operated by the proposed technique were collected prospectively. The dimensions of the framework were measured during the surgery. RESULTS: 25 patients were operated from February to September 2010. Fifteen (60%) cases were related to previous trauma or surgery. The other 40% (N=10) were primary, claiming mainly a reduction rhinoplasty. A closed approach was used for all but one (4%). In 12% (N=3) of the patients no lateral osteotomies were performed after opening the bony roof. Tip surgery was performed in 32% (N=8). CONCLUSIONS: The principles of the "three-dimensional framework technique" are globally reproducible independently of the amount of residual septal cartilage. We believe that our technique assures more stability to the framework and offers a better regularity of the nasal dorsum, eliminating the need of an open approach if other manoeuvres requiring it are not associated. PMID- 21284228 TI - [Plastic surgery indications for the repair of nasal tip and nasal alae defects]. AB - Analyze methods of reconstruction of non-transfixing and transfixing loss of substance of the nasal tip and nasal ala. We would like to share the attitude guiding our selecting of the different methods to rehabilitate this mobile and functional portion of the nose. We retrospectively studied 32 cases of defects of the tip and ala treated between 2007 and 2009. There were 26 basal cell carcinomas, 5 squamous cell carcinomas and 1 melanoma. The minimum postoperative follow-up was one year. For reconstruction we used local flaps: medial dorsal flap, bilobed flap, transverse island flap and regional flaps: fronto-glabellar flap, forehead flap, nasolabial flap. In this study we analyzed the aesthetic and functional result achieved at the nasal orifice. We also studied the histopathological reports regarding safety tissue margins, both in depth and peripherally. Most of the defects of the tip and the alae of less than 1 cm were repaired by local flaps; bilobed or transverse island flaps. For the median region, the Rintala mid-dorsal flap appears to give better results. Tissue losses greater than 1 cm often required the use of a fronto-glabellar flap that allowed delivery of more tissue with less scarring at the donor site. The nasolabial flap may have the disadvantage of removing the crease and sometimes a certain thickness at the arc of rotation, which might require further thinning at a later stage. For transfixing loss of substance, we must repair all the layers: skin, cartilage and mucosa. The forehead flap with respect to the principles of the aesthetic subunits of the nose is the flap of choice. We stress on the importance of ample resection with adequate safety margins peripherally and in depth. PMID- 21284229 TI - [Enlarged marginal incision in rhinoplasty: an anatomic and clinic study]. AB - OBJECTIVE: This study is an evaluation of technical feasibility and clinical results of the wide marginal rhinoplasty. MATERIALS AND METHODS: A wide marginal approach has been used in remodeling and positioning cartilage grafts in 13 cadavers. The clinical study was focused on 20 patients with aesthetics indications and no functional need. The practise was a work on the dorsum, the tip, resections of alar and cartilage graft positioning. We investigated the feasibility of different procedures, quality of exposure and we have identified the problems and incidents of dissection. In additional a subjective evaluation of patient satisfaction and a 6 to 15 months photographic follow up were performed. RESULTS: The operative incidents and problems were similar in anatomic and clinical study. Our study found an excellent technical feasibility with an easy job in the lateral areas and more difficult in median area. CONCLUSION: Wide marginal approach in rhinoplasty doesn't substitute open rhinoplasty but can be used in specific indications. PMID- 21284230 TI - [Contribution to the anatomical and surgical study of the infra orbital area. Clinical applications to the tear trough area]. AB - OBJECTIVES: To define the anatomy of the infra orbital area and assess the possible connections with the facial morphotypes identifying the tears trough. To deduce therapeutic proposition concerning the management of this area in aesthetic medicine or surgery. METHODS: Anatomic dissections of 10 fresh specimens not frozen and not formalin. Dissection layer by layer from skin to bones paying special attention to the infra orbital superficial muscles and the distribution of subcutaneous fat. RESULTS: In this study, it was precised the existence of zygomaticus superficialis and levator genae muscles whose variations in the connections with the orbicularis oculi muscle is probably the origin of the diversity of human facial expression. On the other hand, the tear trough seems to depend on different distributions of the anatomical complex formed by these muscles with the subcutaneous fat and skin that covers it. An anatomical classification into three muscle types has been proposed. CONCLUSION: The main variations between individual facial expression are related to a different muscular anatomy from one subject to another. The myological classical anatomic description, too stereotyped, can not explain those differences. The classification proposed by the authors can differentiate the facial morphotypes in the infra orbital area and offer therapeutic solutions. PMID- 21284231 TI - [Orbital decompression in Grave's ophtalmopathy]. AB - Graves disease orbitopathy is a complex progressive inflammatory disease. Medical treatment remains in all cases the proposed treatment of choice. Surgical treatment by bone decompression can be considered as an emergency mainly in cases of optic neuropathy or ocular hypertension not being controlled medically or in post-traumatic exophthalmos stage. Emergency bone decompression eliminates compression or stretching of the optic nerve allowing visual recovery. The uncontrolled ocular hypertension will benefit from decompression. The normalization of intraocular pressure may be obtained by this surgery or if needed by the use of postoperative antiglaucoma drops or even filtration surgery. In all operated cases, the IOP was normalized with an average decrease of 7.71 mmHg and a cessation of eye drops in 3/7 cases. Regarding sequelae, our therapeutic strategy involves consecutively surgery of the orbit, extraocular muscles and eyelids. The orbital expansion gives excellent results on the cosmetic level and facilitates the implementation of subsequent actions. PMID- 21284232 TI - [Blepharoplasty and upper eyelid malposition]. AB - Upper eyelid blepharoplasties are sometimes performed for functional purposes, but more often for cosmetic reasons. Upper eyelid malpositions, such as ptosis or lid retraction, are frequent and of varying causes. It is not rare for patients to present upper lid malposition, with or without functional consequences, associated with myocutaneous excess. Both functional and cosmetic outcomes are important. This article explores the etiologies of these pathologies and current surgical procedures. Furthermore we will discuss the advantages of combined procedures and different approaches to treat these concomitant pathologies. PMID- 21284233 TI - [Technique of upper blepharoplasty in the ageing hollow eye: fragment of orbicular muscle of eyelids]. AB - OBJECTIVE: The purpose of this article is to describe an original surgical technique allowing to treat the hollow eye. TECHNIQUE: Realization of an upper fragment of circular muscle of eyelids turned on itself during a upper blepharoplasty with fat autograft. CONCLUSION: The hollow eye is filled durably in the time. This surgical technique is simple, easily reproducible. The harmonization of outlines and the trophicity are preserved, which gives a much more natural aspect. PMID- 21284234 TI - [Cosmetic radiofrequency]. AB - Cosmetic radio frequency uses an electric current of high frequency that generates heat through the subcutaneous tissues enough to break the collagen fibers and allow synthesis of a neo-collagen. It permits cutaneous resurfacing, improving the tone and quality of the skin (wrinkles and enlarged pores), and delicately reshaping facial volumes. The principle of a type Ellman monopolar radiofrequency at a rate of 4 MHz Pelleve, Surgitron Dual RF S 5 is described. Its use inclines more towards anti-aging and natural rejuvenation of the face, neck and neckline. It may be associated with other rejuvenation techniques such as fillers and botulinum toxin within certain time limits. PMID- 21284235 TI - [Rejuvenation of the eye: combined techniques]. AB - To show that adjuvant techniques to traditional blepharoplasty: Fat graft, phototherapy, radiofrequency must be offered in combination with cosmetic eyelid surgery for rejuvenation and embellishment of the orbital and peri-orbital regions. PMID- 21284236 TI - Using the latest genome sequencing technologies to develop new carrier and prenatal genetic tests. Interview by Orla Smith. PMID- 21284237 TI - Food crises, food regimes and food movements: rumblings of reform or tides of transformation? AB - This article addresses the potential for food movements to bring about substantive changes to the current global food system. After describing the current corporate food regime, we apply Karl Polanyi's 'double-movement' thesis on capitalism to explain the regime's trends of neoliberalism and reform. Using the global food crisis as a point of departure, we introduce a comparative analytical framework for different political and social trends within the corporate food regime and global food movements, characterizing them as 'Neoliberal', 'Reformist', 'Progressive', and 'Radical', respectively, and describe each trend based on its discourse, model, and key actors, approach to the food crisis, and key documents. After a discussion of class, political permeability, and tensions within the food movements, we suggest that the current food crisis offers opportunities for strategic alliances between Progressive and Radical trends within the food movement. We conclude that while the food crisis has brought a retrenchment of neoliberalization and weak calls for reform, the worldwide growth of food movements directly and indirectly challenge the legitimacy and hegemony of the corporate food regime. Regime change will require sustained pressure from a strong global food movement, built on durable alliances between Progressive and Radical trends. PMID- 21284238 TI - The Campesino-to-Campesino agroecology movement of ANAP in Cuba: social process methodology in the construction of sustainable peasant agriculture and food sovereignty. AB - Agroecology has played a key role in helping Cuba survive the crisis caused by the collapse of the socialist bloc in Europe and the tightening of the US trade embargo. Cuban peasants have been able to boost food production without scarce and expensive imported agricultural chemicals by first substituting more ecological inputs for the no longer available imports, and then by making a transition to more agroecologically integrated and diverse farming systems. This was possible not so much because appropriate alternatives were made available, but rather because of the Campesino-a-Campesino (CAC) social process methodology that the National Association of Small Farmers (ANAP) used to build a grassroots agroecology movement. This paper was produced in a 'self-study' process spearheaded by ANAP and La Via Campesina, the international agrarian movement of which ANAP is a member. In it we document and analyze the history of the Campesino-to-Campesino Agroecology Movement (MACAC), and the significantly increased contribution of peasants to national food production in Cuba that was brought about, at least in part, due to this movement. Our key findings are (i) the spread of agroecology was rapid and successful largely due to the social process methodology and social movement dynamics, (ii) farming practices evolved over time and contributed to significantly increased relative and absolute production by the peasant sector, and (iii) those practices resulted in additional benefits including resilience to climate change. PMID- 21284239 TI - 2010 Frechette Awards. PMID- 21284240 TI - Abstracts of the Global Congress of Minimally Invasive Gynecology, the 37th Annual Meeting of the AAGL. October 28-November 1, 2008. Las Vegas, Nevada, USA. PMID- 21284241 TI - Moving toward point-of-care? PMID- 21284242 TI - In the service of humankind. Interview by Kristie Nybo. PMID- 21284243 TI - Back to school. PMID- 21284244 TI - [Abstracts of the 28th Congress of the International Association of French speaking Dermatologists. February 2-5, 2011. Chamonix, France]. PMID- 21284245 TI - Dentin hypersensitivity: the effects of an arginine-calcium carbonate and fluoride desensitizing dentifrice. PMID- 21284246 TI - Recent advances in dentin hypersensitivity: clinically proven treatments for instant and lasting sensitivity relief. AB - PURPOSE: To provide a brief overview of the diagnosis, epidemiology, etiology and clinical management of dentin hypersensitivity, to discuss technical approaches to relieve sensitivity, with special emphasis on dentin tubule occlusion and the clinical evidence for efficacy of desensitizing toothpastes based upon this approach, and to summarize the science behind a new dentifrice technology, based upon arginine and calcium carbonate, and the clinical evidence which proves that it delivers both instant and lasting relief of dentin hypersensitivity. RESULTS: Clinical studies have shown that a new toothpaste, containing arginine and calcium carbonate (known as Pro-Argin technology) with 1450 ppm fluoride, offers clinically proven instant and lasting relief of dentin hypersensitivity. Three 8 week clinical studies have shown that this new toothpaste provides statistically significantly superior efficacy in reducing sensitivity to market leading desensitizing toothpastes containing 2% potassium ion. Importantly, three further clinical studies have shown that a single direct topical application of toothpaste to sensitive teeth, using a fingertip or cotton swab followed by 1 minute of massage, resulted in instant relief of dentin hypersensitivity and that the relief was maintained with subsequent twice-daily brushing. Mechanism of action studies have shown that this technology physically seals dentin tubules with a plug that contains arginine, calcium carbonate and phosphate. This plug, which is resistant to normal pulpal pressures and to acid challenge, effectively reduces dentin fluid flow and thereby relieves sensitivity. A new whitening variant of this desensitizing toothpaste, containing the Pro-Argin technology, fluoride and a high cleaning calcium carbonate system, has now been clinically and scientifically validated. This toothpaste works by the same mechanism of action as its non-whitening counterpart and is clinically proven to provide both instant and lasting relief of sensitivity, while providing proven efficacy in removal of extrinsic stains. No difference in desensitizing efficacy was observed between the whitening and non-whitening versions. PMID- 21284247 TI - Mode of action studies on a new desensitizing dentifrice containing 8.0% arginine, a high cleaning calcium carbonate system and 1450 ppm fluoride. AB - PURPOSE: To ascertain the mode of action of a new Pro-Argin formula desensitizing dentifrice with a gentle whitening benefit containing 8.0% arginine, a high cleaning calcium carbonate system and sodium monofluorophosphate, utilizing a range of state-of-the-art surface techniques. METHODS: Confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM) were used to assess tubule occlusion. Electron spectroscopy for chemical analysis (ESCA) was used to identify the composition of the occlusive material. CLSM was also used to identify the location of the arginine within the occluded dentin tubule and to demonstrate the resistance of the occlusion to an acid challenge. RESULTS: The CLSM and SEM studies demonstrated that the arginine-calcium carbonate technology in this new Pro-Argin formula sensitivity dentifrice was highly effective in occluding dentin tubules. ESCA showed that the dentin surface deposit contained high levels of calcium, phosphorous, oxygen and carbonate. CLSM also confirmed that the arginine incorporated into the dentin plug, and the dentin plug resisted an acid challenge. PMID- 21284248 TI - Instant dentin hypersensitivity relief of a new desensitizing dentifrice containing 8.0% arginine, a high cleaning calcium carbonate system and 1450 ppm fluoride: a 3-day clinical study in Chengdu, China. AB - PURPOSE: To compare, with a double-blind, randomized, parallel-design clinical study, the hypersensitivity efficacy of a new Pro-Argin formula dentifrice containing 8.0% arginine, a high cleaning calcium carbonate system and 1450 ppm fluoride to a previously validated Pro-Argin formula dentifrice containing 8.0% arginine, calcium carbonate and 1450 ppm fluoride, and to a control toothpaste containing calcium carbonate and 1450 ppm fluoride, instantly after a single direct topical self-application using a fingertip, and after subsequent brushing for 3 days. METHODS: Qualifying subjects from the Chengdu, China area who presented two hypersensitive teeth with a tactile score of 10 to 50 grams, and an air blast score of 2 or 3, participated in this study. The first phase of the study consisted of a single topical application of the assigned product directly onto the hypersensitive surface of each of the two hypersensitive teeth. Study subjects applied a pea-size amount of their toothpaste onto the hypersensitive surface and massaged for 1 minute. The second phase of the study consisted of twice-daily at-home brushing with the toothpaste for 3 days. RESULTS: All one hundred and twenty-two (122) subjects complied with the study protocol and completed the study. There was good balance among the three groups at baseline. The mean tactile sensitivity scores for the new Pro-Argin formula dentifrice, the previously validated Pro-Argin formula dentifrice, and the control dentifrice were at baseline 14.88, 14.76 and 14.38, and after direct application were 28.90, 29.02 and 15.88, and after 3 days of brushing were 34.51, 33.41 and 16.00, respectively. The mean air blast scores at baseline were 2.11, 2.12 and 2.15, and after direct application were 1.21, 1.18 and 2.06, and after 3 days of brushing were 0.80, 0.83 and 1.93, respectively. Immediately after direct application and after 3 days of brushing, for both the tactile and air blast sensitivity scores, the differences between the two dentifrices containing 8.0% arginine and the control were statistically significant. There were no statistically significant differences between the two 8.0% arginine dentifrices immediately after direct application and after 3 days of brushing. PMID- 21284249 TI - Dentin hypersensitivity reduction of a new toothpaste containing 8.0% arginine and 1450 ppm fluoride: an 8-week clinical study on Chinese adults. AB - PURPOSE: To present the results of an 8-week dentin hypersensitivity clinical study in which the efficacy of a new Pro-Argin formula toothpaste, with gentle whitening benefits, containing 8.0% arginine, a high cleaning calcium carbonate system, and 1450 ppm fluoride as sodium monofluorophosphate (MFP) was compared to that of a commercial Pro-Argin formula toothpaste containing 8.0% arginine, calcium carbonate, and 1450 ppm fluoride as MFP and a negative control toothpaste containing calcium carbonate and 1450 ppm fluoride as MFP. METHODS: An 8-week clinical study, with 121 subjects, was conducted in Chengdu, Sichuan, China, using a double-blind, stratified, three-treatment design. Tactile and air blast sensitivity assessments were used to compare the efficacy of the three products. RESULTS: This clinical study demonstrated that the new Pro-Argin formula toothpaste provided a significant reduction in dentin hypersensitivity when used over a period of 8 weeks. The study also showed that the new toothpaste provided significantly greater reductions (P < 0.05) in dentin hypersensitivity in response to tactile (64.4%, 71.1%, and 61.0%) and air blast (40.7%, 58.8%, and 74.4%) stimuli than the negative control toothpaste containing 1450 ppm fluoride after 2, 4, and 8 weeks of product use, respectively. The results for the new toothpaste did not differ significantly from those of the positive control toothpaste at all time points in the study. PMID- 21284250 TI - Extrinsic stain removal efficacy of a new desensitizing dentifrice containing 8.0% arginine, calcium carbonate and 1450 ppm fluoride. AB - PURPOSE: To evaluate the extrinsic stain removal efficacy of a new Pro-Argin formula whitening dentifrice containing 8.0% arginine, a high cleaning calcium carbonate and 1450 ppm fluoride, as monofluorophosphate, after brushing twice daily for 4 and 8 weeks. METHODS: At the baseline visit, 92 adult subjects were stratified based on their Lobene Stain Index scores and randomized into two treatment groups; one using the new Pro-Argin formula whitening dentifrice (test group) and the other using the original Pro-Argin formula dentifrice (control group). Subjects were instructed to brush twice daily for the duration of the study. Tooth stain evaluations were conducted as stain area and stain intensity according to the Lobene Stain Index. RESULTS: All 92 enrolled subjects complied with the protocol and completed the 8-week study. Baseline scores demonstrated no significant differences between the two treatment groups for the evaluated area and intensity parameters of stain (P > 0.05). At both the 4- and 8-week post-use evaluations, subjects brushing with the test dentifrice demonstrated significant reductions for all stain parameters versus the control (P < 0.05). Relative to the control group, the test group demonstrated reductions in mean stain intensity scores of 9.7% and 17.9% at the 4- and 8-week evaluations, respectively. Corresponding reductions in mean stain area scores for the test group relative to the control were 11.7% and 20.8% at the 4- and 8-week evaluations, respectively. (Am JDent 2010;23 Sp Is A:36A-40A). PMID- 21284251 TI - Hepatic extraskeletal chondroblastic osteosarcoma with unusual angioinvasion of the caudal vena cava in a dog. AB - Extraskeletal osteosarcomas are rare malignant mesenchymal neoplasms that are able to directly produce osteoid, without requiring a cartilage template. The extraskeletal localization indicates that these neoplasms are not associated with pre-existing skeletal elements or periosteum. We describe the gross and histological findings of a 4-year-old male Rottweiler that presented with an extraskeletal chondroblastic osteosarcoma (also known as osteosarcoma of the chondroblastic subtype) originating from the liver and extending into the lumen of the caudal vena cava, passing through the right atrium and terminating in the right ventricle of the heart immediately below the pulmonary valve. In the liver, predominantly fusiform cells grew in loosely packed streams and whorls. In the vena cava, the neoplasm was multilobular with polygonal neoplastic cells scattered within lacunae in a chondroid matrix. In the cardiac lumen, neoplastic cells produced osteoid that showed multifocal mineralization. Immunohistochemical staining showed no cytokeratin and variable S-100 protein and vimentin immunoreactivity. To the best of our knowledge, this is the first report of a chondroblastic osteosarcoma arising in the liver and showing such extensive and unusual extension into the vasculature. PMID- 21284252 TI - Delivery of nanoparticulate drug delivery systems via the intravenous route for cancer gene therapy. AB - While the systemic route of administration enables therapeutic genes to spread through the bloodstream and access target cells, it is a challenge to achieve this. Several studies demonstrate that systemic administration of therapeutic genes or other nucleic acid-based constructs such as siRNA to solid tumors as well as cancer metastases are better with nanoparticulate systems compared to administration of free (uncomplexed) nucleic acids. Nanoparticle-based nucleic acid delivery systems might be more pertinent, due to the several privileges in terms of enhanced tissue penetrability, improved cellular uptake and to a lesser extent, targeted gene delivery to the cells of interest provided targeting ligands are used. Systemic delivery of nanoplexes has already been reported with different nanoparticles containing DNA via various routes of administration. The goal of the present article is to review the current state of intravenous delivery of nanoparticles for gene therapy of cancer. PMID- 21284253 TI - Evaluation of different preparation methods for a preservative free triamcinolone acetonide preparation for intravitreal administration: a validated stability indicating HPLC-method. AB - Intravitreally applied triamcinolone acetonide (TA) is used to treat a variety of macular diseases. Commercially available products of TA are mainly intended for intramuscular application and contain benzyl alcohol (BA) as a bacteriostatic preservative. Since this agent damages ocular tissues, different methods such as filtration techniques and centrifugation are usually used to eliminate BA from commercial products (40 mg/mL TA, 9.9 mg/mL BA). In this study, we evaluated these methods in regard to their ability to eliminate benzyl alcohol and to guarantee standard doses of triamcinolone acetonide. A new formulation without BA (TA 40 mg/mL) was developped according to the following criteria: autoclavability, stability, and suitability for intravitreal use. For QA/QC evaluation a new rapid and simple HPLC procedure (C18 RP column, mobile phase consisting of methanol-water, 48:52, v/v) to quantify the respective compounds was developed and validated according to ICH guidelines. The HPLC method was proven to be selective, linear, precise and accurate. Analysis of preparations based on commercial products undergoing different filtration techniques showed variable results: TA concentrations of 22-80% of the declared amount were found, and BA content was not reduced to safe levels (up to 39% of initial content remained). Centrifugation methods decreased the concentration of the preservative adequately, however agglomerated TA crystals were observed, leading to irreproducible and deviating particle sizes that are potentially harmful with ocular use. The newly developed preservative free formulation (TA 40 mg/mL) delivered uniform doses of TA, revealed no drug loss during forced light exposure and was proven to be stable, sterile and bacterial endotoxin free after autoclaving and after storage for three months,. The new formulation may offer an alternative for the in-house production of intravitreally applicable TA preparations in hospital pharmacies and should enhance medication safety. PMID- 21284254 TI - Comparative evaluation of in vitro parameters of tamoxifen citrate loaded poly(lactide-co-glycolide), poly(epsilon-caprolactone) and chitosan nanoparticles. AB - Tamoxifen (TAM), the clinical choice for the antiestrogen treatment of advanced or metastatic breast cancer, was formulated in nanoparticulate carrier systems in the form of poly(lactide-co-glycolide) (PLGA), poly-epsilon-caprolactone (PCL) and chitosan (CS) nanoparticles. The PLGA and PCL nanoparticles were prepared by a nanoprecipitation technique whereas the CS nanoparticles were prepared by the ionic gelation method. Mean particle sizes were under 260 nm for PLGA and PCL nanoparticles and around 400 nm for CS nanoparticles. Polydispersity indices were less than 0.4 for all formulations. Zeta potential values were positive for TAM loaded nanoparticles because of the positive charge of the drug. Drug loading values were significantly higher for PCL nanoparticles when compared to PLGA and CS nanoparticles. All nanoparticle formulations exhibited controlled release properties. These results indicate that TAM loaded PLGA, PCL and CS nanoparticles may provide promising carrier systems for tumor targeting. PMID- 21284255 TI - Lumichrome complexation by cyclodextrins: influence of pharmaceutical excipients. AB - Complexation of the model drug lumichrome by 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD), the most widely used cyclodextrin derivative in pharmaceutical preparations, was investigated in this study. The influence of frequently used pharmaceutical excipients, i.e. alcohols (ethanol, glycerol, propylene glycol), buffers (phosphate, citrate) and tonicity modulators (NaCl, MgCl2) was evaluated by phase solubility, absorption and fluorescence emission spectra and fluorescence lifetime studies. Further, complex formation constants and fluorescence quantum yields were calculated. The formation of a 1:1 complex was indicated by phase solubility studies. The shape of the absorption and emission spectra for lumichrome was nearly independent of dissolution medium. The intensity of the absorption peak was slightly decreasing by the addition of HPbetaCD, which indicates formation of an inclusion complex of lumichrome in the ground state. The intensity of the fluorescence emission peak (i.e. fluorescence quantum yield) was also steadily decreasing by the increase in HPbetaCD concentration. Monoexponential fluorescence decay was obtained in the absence of cyclodextrin. In the presence of cyclodextrin, bi-exponential decays were observed in all aqueous vehicles with the exception of plain water or samples containing salts. The longest decay time corresponds to the lifetime of free (uncomplexed) lumichrome, while the shortest decay time was attributed to the excited state of the complexed alloxazine form of lumichrome. The selected excipients influence the complexation constant and the lumichrome excited state deactivation pathways to various extents. PMID- 21284256 TI - smartCrystal combination technology--scale up from lab to pilot scale and long term stability. AB - The production of nanocrystals was scaled up from lab scale (20 g) to pilot scale (3 kg), scale up factor 150. The flavonoid apigenin was used as model compound, with potential for pharma, cosmetic and nutraceutical products. Lab scale production was performed by high pressure homogenization (HPH), pilot scale by applying the smartCrystal combination technology (CT), combining pearl milling and a subsequent HPH (1 cycle, 300 bar). The obtained particle sizes were compared on the basis of photon correlation spectroscopy (PCS), laser diffractometry (LD) and light microscopy. The results showed, that assessment of successful scale up depends on the characterization method used, e.g., PCS covering only a part of the particle size range (3 nm-3 microm) of the population, or LD the full size distribution. Long-term stability was predicted on zeta potential (ZP) measurements. Lab and pilot scale possessed sufficiently high ZP values (> 30 mV) for a stable dispersion, but the ZP values were different (5-7 mV). This was explained by differences in the Stern/Nernst potential of the nanocrystals, potentially due to different levels in the crystals where they break in a high energy process (HPH) versus a low energy size reduction (pearl mill). Independent on the production method and batch size, the nanosuspensions proved to be physically stable for 6 months at storage temperatures 4 degrees C, room temperature and 40 degrees C. PMID- 21284257 TI - Microparticles containing lemongrass volatile oil: preparation, characterization and thermal stability. AB - Lemongrass volatile oil (LVO) is an important ingredient in cosmetics, presenting antimicrobial properties, in particular antifungal activity, and it is a promising raw material for the development of pharmaceutical products. However, its volatility and susceptibility to degradation are the major drawbacks for the use of Cymbopogon citratus oil in pharmaceutical compounding. Thus, the aim of this work was to develop and to characterize microparticles containing this oil viewing the stabilization of LVO. Two techniques of preparation were evaluated; spray drying and precipitation, and two encapsulation materials, beta cyclodextrin (beta-CD) and hydroxypropyl-beta-cyclodextrin (HP-beta-CD) were tested. The microparticles were characterized in terms of content of water, yield, percentage of inclusion, infrared spectroscopy. Morphology was evaluated by scanning electronic microscopy. Studies of stability were also conducted. The content of citral (neral and geranial), major component of the oil, present in microparticles was assayed by a validated HPLC method. The percentage of inclusion of LVO into the microparticles was 56-60% and 26-29% using beta-CD and HP-beta-CD, respectively. The results showed that the use of the beta-CD as encapsulant material was more efficient. Additionally, an increased inclusion of lemongrass oil was observed with the precipitation technique. PMID- 21284258 TI - Influence of different generations of poly(propylene imine) dendrimers on human erythrocytes. AB - The unique characteristics of dendrimers make them attractive candidates as drug carriers. However, the toxicity associated with dendrimers is a basic hurdle in their biomedical application. To ensure development of dendrimer based safe and effective delivery systems, the effect of dendrimers on human erythrocytes (RBCs) must be studied. The present study explores the toxicological behavior of different generations of poly(propylene imine) dendrimers on human RBCs. Plain fifth generation PPI dendrimers (1 mg/mL) showed approximately 6.39% hemolysis which was an indication of their suitability in drug delivery. The study was conducted on all generations from 0.5 to 5.0 G of PPI dendrimers. PMID- 21284259 TI - In vitro silencing effect of chitosan nanoplexes containing siRNA expressing vector targeting VEGF in breast cancer cell lines. AB - Small interferring RNA (siRNA) is a powerful tool for controlling cellular processes of gene silencing at post-transcriptional level due to its high sequence-specific inhibition efficiency. The aim of this study is to compare silencing effect of chitosan/shVEGF (shRNA-expressing plasmid DNA targeting vascular endothelial growth factor-A (VEGF-A)) nanoplexes between four different cell lines, two of which are MCF-7 and MDA-MB435 breast cancer cell lines. Nanoplexes were prepared using different concentrations. The morphological and physicochemical characterization were made and silencing activity of appropriate formulations were investigated in vitro. As a result of in vitro transfection studies made in different cell lines with nanoplexes in the different ratios, the highest gene inhibition (60%) was measured in MCF-7 after transfection while the lowest gene inhibition (29%) was observed in MDA-MB435. This work suggests that RNA interference has potential to be applied to delivery system studies and to the angiogenesis treatment. PMID- 21284260 TI - Inhibitory effect of (E)-1,2-di(3,5-dimethoxyphenyl)ethene on 3T3-L1 adiopocyte differentiation. AB - Resveratrol (trans-3,5,4'-trihydroxystilbene) is a phytoalexin found in diverse plant species, including grapes and peanuts. The antioxidant, anticancer, and cardioprotective properties of resveratrol have been well-characterized. The anti obesity effect of resveratrol has also been demonstrated in previous studies. In this study, we evaluated the effects of a resveratrol analogue, (E)-1,2-di(3,5 dimethoxyphenyl)ethene, on adipocyte differentiation using 3T3-L1 cells. According to our results, the tested analogue potently inhibits the differentiation of 3T3-L1 adipocyte to a greater degree than resveratrol. Moreover, (E)-1,2-di(3,5-dimethoxyphenyl)ethene strongly downregulated the expression of fatty acid metabolism-related proteins such as fatty acid synthase and acetyl-CoA carboxylase. These results point to the potential of (E)-1,2 di(3,5-dimethoxyphenyl)ethene as an obesity prevention agent. PMID- 21284261 TI - Topical effects of roflumilast on 1-chloro-2,4-dinitrobenzene-induced atopic dermatitis-like skin lesions in NC/Nga mice. AB - Phosphodiesterase-4 (PDE-4) inhibitors have a wide range of anti-inflammatory and immunomodulatory activities. Here we examined the effects of roflumilast, a well known PDE-4 inhibitor, on 1-chloro-2,4-dinitrobenzene (DNCB)-induced atopic dermatitis-like lesions. Roflumilast inhibited DNCB-stimulated IL-1alpha secretion in HaCaT cells, and reduced ear thickness and lymph node weights in BALB/c mice sensitized with DNCB. Topical application of roflumilast to DNCB induced atopic dermatitis-like skin lesions of NC/Nga mice ameliorated intensity scores and dorsal skin thickness, in parallel with reduced tissue IL-1beta levels and epidermal hyperplasia. On the other hand, no effect on IgE and IL-4 was observed upon roflumilast treatment. Taken together, roflumilast showed beneficial effects against DNCB-induced atopic dermatitis. PMID- 21284262 TI - Tyrosinase inhibitory activities of cinnamic acid analogues. AB - The aim of this study was to show how tyrosinase inhibitory activity is correlated with the structure of cinnamic acid derivatives. We synthesized cinnamic acid derivatives, and investigated their tyrosinase inhibitory and DPPH radical scavenging activities. The results show that reduction of C=C double bonds and the substituent group of cinnamic acid derivatives have an effect on antioxidant activity and tyrosinase inhibitory activity. Among these compounds, compounds 2, 6 and 6a showed a potent tyrosinase inhibitory activity with IC50 (50% inhibitory concentration) values of 115.6 microM, 114.9 microM and 195.7 microM, respectively. The results obtained provide a useful clue for the design and development of new tyrosinase inhibitors. PMID- 21284263 TI - Strong inhibitory effect of medroxyprogesterone acetate (MPA) on UDP glucuronosyltransferase (UGT) 2B7 might induce drug-drug interactions. AB - The aim of the present study was to investigate the inhibitory effects of medroxyprogesterone acetate (MPA) on four important UGT isoforms (UGT1A1, 1A6, 1A9 and 2B7). 4-methylumbelliferone (4-MU) was used as a nonselective substrate, and recombinant UGT isoforms were utilized as an enzyme source. The results showed that MPA exhibited inhibitory effects on UGT2B7 (IC50 = 29.3 +/- 1.5 microM), with a negligible influence on other UGT isoforms. The results obtained from Lineweaver-Burk and Dixon plots showed that MPA competitively inhibited UGT2B7. The Ki value was calculated to be 7.2 microM. Based on the concentration of MPA in human liver, the magnitude of in vivo drug-drug interaction (DDI) was predicted. The [I]/Ki value was calculated to be 0.31, which suggested that DDIs might occur when MPA was co-administered with drugs which mainly undergo UGT2B7 mediated metabolism. PMID- 21284264 TI - Recombinant Microcystis viridis lectin as a potential anticancer agent. AB - MVL (Microcystis viridis lectin), a glycoprotein originally isolated from freshwater blue-green algae Microcystis viridis, has been reported to have potent anti-HIV activity. However, the objective of this study was to evaluate the anticancer activity of recombinant MVL (R-MVL). MTT assay was used to evaluate the in vitro anticancer activity of R-MVL, and the results show that the IC50 for HT-29, HepG2, SGC-7901 and SK-OV-3 were 40.20, 42.67, 49.87, and 53.40 microg/ml, respectively. Our data, for the first time, demonstrated that R-MVL exhibits potential anticancer activity, and open new therapeutic possibilities for the use of R-MVL as anti-cancer agent. PMID- 21284265 TI - Localizing the wandering uterus. PMID- 21284266 TI - A terrible spirit hath taken him. PMID- 21284267 TI - Non-AIDS defining cancers. PMID- 21284268 TI - Do race and ethnicity predict survival in metastatic non-small cell lung cancer? PMID- 21284269 TI - Primary care concerns in breast cancer patients. PMID- 21284270 TI - Why does Rhode Island have the greatest incidence of bladder cancer in the United States? PMID- 21284271 TI - The evolving role of histology in the treatment of non-small cell lung cancer. PMID- 21284272 TI - A new low for an old high: neutropenia induced by levamisole-adulterated cocaine. PMID- 21284273 TI - Nutrition recommendations for the independent-living older person. PMID- 21284275 TI - From catheters to cathedrals. PMID- 21284274 TI - Prepregnancy obesity and birth defects in Rhode Island. PMID- 21284276 TI - Genital emergencies for the dermatologist. PMID- 21284277 TI - What is your diagnosis? Bowenoid papulosis. PMID- 21284278 TI - What's eating you? Oriental rat flea (Xenopsylla cheopis). PMID- 21284279 TI - Non-dermatitis herpetiformis gluten-sensitive dermatitis: a personal account of an unrecognized entity. PMID- 21284280 TI - Pediatric molluscum contagiosum: reflections on the last challenging poxvirus infection, Part 2. AB - Molluscum contagiosum (MC) is a common dermatologic infection that usually affects school-aged children, sexually active young adults, and immunocompromised individuals. It is a benign and self-limiting disease, with most cases undergoing spontaneous resolution within 6 to 9 months. However, a more severe and prolonged course is associated with immunosuppression or atopic dermatitis. Treatment is recommended because of the high rate of associated symptoms, risk for transmissibility, and cosmetic or social concerns. Therapeutic modalities are subdivided into 3 types: destructive, immunomodulatory, and antiviral. We review the advantages and disadvantages of various agents and discuss combination therapy. PMID- 21284281 TI - Generalized acanthosis nigricans related to type B insulin resistance syndrome: a case report. AB - Acanthosis nigricans (AN) is a cutaneous marker for many underlying states such as endocrine abnormality, obesity, certain drugs, and malignancy. Generalized AN is a rare condition and is commonly seen in adults with an underlying malignancy. The type B insulin resistance syndrome, a rare autoimmune disorder, is caused by the autoantibodies to the insulin receptor. Patients typically present with hyperglycemia but also may present with hypoglycemia. We report a rare case of a 36-year-old man with generalized AN and type B insulin resistance syndrome with hypoglycemia. PMID- 21284282 TI - Green staining of clothing: a signal for pseudomonal infection. AB - Anticonvulsant hypersensitivity syndrome (AHS) is a nondose-related idiosyncratic reaction to aromatic antiepileptic drugs and is a cause of drug discontinuation. Pseudomonas aeruginosa is a gram-negative bacillus that can produce infections in many different organs, including the skin and soft tissue. We report a patient with erythroderma and AHS who developed a pseudomonal infection. Green staining of the underwear served as a diagnostic clue for severe P aeruginosa infection that had developed because of a local flexural skin infection that spread due to a damaged skin barrier. Inspection of the patient's clothes may give information about any exudate from the skin and should be done routinely as part of the physical examination. PMID- 21284283 TI - Randomized tolerability analysis of clindamycin phosphate 1.2%-tretinoin 0.025% gel used with benzoyl peroxide wash 4% for acne vulgaris. AB - The multiple etiologic factors involved in acne vulgaris make the use of several medications necessary to treat the condition. Use of a fixed combination of clindamycin phosphate 1.2% and tretinoin 0.025% in conjunction with a benzoyl peroxide (BPO) wash 4% targets several pathologic factors simultaneously and mitigates the potential for clindamycin-induced Propionibacterium acnes-resistant strains. New formulations may allow such regimens to be effectively used without overly reduced tolerability resulting from the irritation potential of tretinoin and BPO. This randomized, single-blind study investigated the local tolerability, irritation potential, and safety of an aqueous-based gel (clindamycin phosphate 7.2%-tretinoin 0.025% [CT gel]) when used in conjunction with a BPO wash 4% in participants with mild to moderate acne vulgaris. Participants applied the CT gel once daily in the evening for 4 weeks in conjunction with once-daily morning use of either BPO wash 4% or nonmedicated soap-free cleanser lotion (SFC). Local tolerability and irritation potential were assessed by participants and investigators using separate 6-point scales. The frequency and severity of dryness, scaling, erythema, burning/stinging, and itching increased during the first week of treatment in both treatment arms but decreased thereafter. Local tolerability reactions were slightly more frequent in the CT gel + BPO wash group versus the CT gel + SFC group at week 1 but were generally mild and improved within 1 to 2 weeks. In conclusion, therapy with CT gel + BPO wash appears safe and well-tolerated in participants with mild to moderate acne vulgaris. PMID- 21284284 TI - Environmental occurrences, behavior, fate, and ecological effects of nanomaterials: an introduction to the special series. AB - The release of engineered nanomaterials (ENMs) into the biosphere will increase as industries find new and useful ways to utilize these materials. Scientists and engineers are beginning to assess the material properties that determine the fate, transport, and effects of ENMs; however, the potential impacts of released ENMs on organisms, ecosystems, and human health remain largely unknown. This special collection of four review papers and four technical papers identifies many key and emerging knowledge gaps regarding the interactions between nanomaterials and ecosystems. These critical knowledge gaps include the form, route, and mass of nanomaterials entering the environment; the transformations and ultimate fate of nanomaterials in the environment; the transport, distribution, and bioavailability of nanomaterials in environmental media; and the organismal responses to nanomaterial exposure and effects of nanomaterial inputs, on ecological communities and biogeochemical processes at relevant environmental concentrations and forms. This introductory section summarizes the state of knowledge and emerging areas of research needs identified within the special collection. Despite recent progress in understanding the transport, transformations, and fate of ENMs in model environments and organisms, there remains a large need for fundamental information regarding releases, distribution, transformations and persistence, and bioavailability of nanomaterials. Moreover, fate, transport, bioaccumulation, and ecological impacts research is needed using environmentally relevant concentrations and forms of ENMs in real field materials and with a broader range of organisms. PMID- 21284285 TI - The release of nanosilver from consumer products used in the home. AB - Nanosilver has become one of the most widely used nanomaterials in consumer products because of its antimicrobial properties. Public concern over the potential adverse effects of nanosilver's environmental release has prompted discussion of federal regulation. In this paper, we assess several classes of consumer products for their silver content and potential to release nanosilver into water, air, or soil. Silver was quantified in a shirt, a medical mask and cloth, toothpaste, shampoo, detergent, a towel, a toy teddy bear, and two humidifiers. Silver concentrations ranged from 1.4 to 270,000 microg Ag g product(-1). Products were washed in 500 mL of tap water to assess the potential release of silver into aqueous environmental matrices (wastewater, surface water, saliva, etc.). Silver was released in quantities up to 45 microg Ag g product( 1), and size fractions were both larger and smaller than 100 nm. Scanning electron microscopy confirmed the presence of nanoparticle silver in most products as well as in the wash water samples. Four products were subjected to a toxicity characterization leaching procedure to assess the release of silver in a landfill. The medical cloth released an amount of silver comparable to the toxicity characterization limit. This paper presents methodologies that can be used to quantify and characterize silver and other nanomaterials in consumer products. The quantities of silver in consumer products can in turn be used to estimate real-world human and environmental exposure levels. PMID- 21284286 TI - The role of atmospheric transformations in determining environmental impacts of carbonaceous nanoparticles. AB - In studies that have explored the potential environmental impacts of manufactured nanomaterials, the atmosphere has largely been viewed as an inert setting that acts merely as a route for inhalation exposure. Manufactured nanomaterials will enter the atmosphere during production, use, and disposal, and rather than simply being transported, airborne nanoparticles are in fact subject to physical and chemical transformations that could modify their fate, transport, bioavailability, and toxicity once they deposit to aqueous and terrestrial ecosystems. The objective of this paper is to review the factors affecting carbonaceous nanomaterials' behavior in the environment and to show that atmospheric transformations, often overlooked, have the potential to alter nanoparticles' physical and chemical properties and thus influence their environmental fate and impact. Atmospheric processing of naturally occurring and incidental nanoparticles takes place through coagulation, condensation, and oxidation; these phenomena are expected to affect manufactured nanoparticles as well. It is likely that carbonaceous nanomaterials in the atmosphere will be oxidized, effectively functionalizing them. By influencing size, shape, and surface chemistry, atmospheric transformations have the potential to affect a variety of nanoparticle-environment interactions, including solubility, interaction with natural surfactants, deposition to porous media, and ecotoxicity. Potential directions for future research are suggested to address the current lack of information surrounding atmospheric transformations of engineered nanomaterials. PMID- 21284287 TI - Fate and transport of engineered nanomaterials in the environment. AB - With the fast development of nanotechnology, engineered nanomaterials (ENMs) will inevitably be introduced into the various environment. Increasing studies showed the toxiccity of various ENMs, which raises concerns over their fate and transport in the environment. This review focuses on advances in the research on environmental transport and fate of ENMs. Aggregation and suspension behaviors of ENMs determining their fate and transport in aqueous environment are discussed, with emphasis on the influencing factors, including natural colloids, natural organic matter, pH, and ionic strength. Studies on the transport of ENMs in porous media and its influencing factors are reviewed, and transformation and organismcleansing, as two fate routes of ENMs in the environment, are addressed. Future research directions and outlook in the environmental transport and fate of ENMs are also presented. PMID- 21284288 TI - Nanoparticle aggregation: challenges to understanding transport and reactivity in the environment. AB - Unique forms of manufactured nanomaterials, nanoparticles, and their suspensions are rapidly being created by manipulating properties such as shape, size, structure, and chemical composition and through incorporation of surface coatings. Although these properties make nanomaterial development interesting for new applications, they also challenge the ability of colloid science to understand nanoparticle aggregation in the environment and the subsequent effects on nanomaterial transport and reactivity. This review briefly covers aggregation theory focusing on Derjaguin-Landau-Verwey-Overbeak (DLVO)-based models most commonly used to describe the thermodynamic interactions between two particles in a suspension. A discussion of the challenges to DLVO posed by the properties of nanomaterials follows, along with examples from the literature. Examples from the literature highlighting the importance ofaggregation effects on transport and reactivity and risk of nanoparticles in the environment are discussed. PMID- 21284289 TI - Transport and retention of fullerene nanoparticles in natural soils. AB - Commercial production and use of fullerene (C60) nanomaterials will inevitably lead to their release into the environment, where knowledge of C60 fate and transport is limited. In this study, a series of one-dimensional column experiments was conducted to assess the transport and retention of nanoscale fullerene aggregates (nC60) in water-saturated soils. Under the experimental conditions, complete retention of nC60 was observed in columns (2.5 cm inside diameter x 11 cm length) packed with Appling or Webster soil, which contain 0.75 and 3.33% organic carbon by weight, respectively. When the volume of aqueous nC60 suspension (approximately 4.5 mg L(-1)) applied to Appling soil was increased from 5 to 65 pore volumes, the travel distance increased from 3 to 8 cm, and the retention capacity approached a limiting value of 130 microg g(-1), although nC60 was not detected in the column effluent. The addition of 20 mg C L(-1) Suwannee River humic acid to the influent suspension increased the nC60 transport in Appling soil but did not resul in breakthrough. Attempts to simulate the experimental data using clean-bed filtration theory were not satisfactory, yielding retention profiles that failed to match observed data. Subsequent incorporation of a limiting retention capacity expression into the mathematical model resulted in accurate predictions of the measured nC60 retention profiles and transport behavior. The sizable retention capacities observed in this study suggest that transport of nC60 is limited in relatively fine-textured soils containing appreciable amounts of clay minerals and organic matter, with substantial accumulation of nC60 aggregates near the point of release. PMID- 21284290 TI - Association of quantum dot nanoparticles with Pseudomonas aeruginosa biofilm. AB - Quantum dots (QDs) of two different surface chemistries (carboxyl [COOH] and polyethylene glycol [PEG] modified) were utilized to determine the impact of surface functionality on QD mobility and distribution in Pseudomonas aeruginosa PAO1 biofilms. Confocal laser scanning microscopy was utilized to evaluate QD association with biofilm components (proteins, cells, and polysaccharides). Quantum dots did not preferentially associate with cell surfaces compared but did colocalize with extracellular proteins in the biofilm matrix. Neither PEG nor COOH QDs were found to be internalized by individual bacterial cells. Neither QD functionality nor flow rate of QD application (0.3 mL min(-1) or 3.0 mL min(-1)) resulted in a marked difference in QD association with P. aeruginosa biofilms. However, center of density determinations indicated COOH QDs could more easily penetrate the biofilm matrix by diffusion than PEG QDs. Biofilms with PEG QDs associated had rougher polysaccharide layers and rougher cell distribution than biofilms with COOH QDs. This work suggests natural biofilms may serve as deposition locations in natural and engineered environmental systems, and biofilm structural parameters may change based on exposure to nanomaterials of varied physical characteristics. PMID- 21284291 TI - Effects of particle size on chemical speciation and bioavailability of copper to earthworms (Eisenia fetida) exposed to copper nanoparticles. AB - To investigate the role of particle size on the oxidation, bioavailability, and adverse effects of manufactured Cu nanoparticles (NPs) in soils, we exposed the earthworm Eisenia ferida to a series of concentrations of commercially produced NPs labeled as 20- to 40-nm or < 100-nm Cu in artificial soil media. Effects on growth, mortality, reproduction, and expression of a variety of genes associated with metal homeostasis, general stress, and oxidative stress were measured. We also used X-ray absorption spectroscopy and scanning X-ray fluorescence microscopy to characterize changes in chemical speciation and spatial distribution of the NPs in soil media and earthworm tissues. Exposure concentrations of Cu NPs up to 65 mg kg(-1) caused no adverse effects on ecologically relevant endpoints. Increases in metallothionein expression occurred at concentrations exceeding 20 mg kg(-1) of Cu NPs and concentrations exceeding 10 mg kg(-1) of CuSO4. Based on the relationship of Cu tissue concentration to metallothionein expression level and the spatial distribution and chemical speciation of Cu in the tissues, we conclude that Cu ions and oxidized Cu NPs were taken up by the earthworms. This study suggests that oxidized Cu NPs may enter food chains from soil but that adverse effects in earthworms are likely to occur only at relatively high concentrations (> 65 mg Cu kg(-1) soil). PMID- 21284292 TI - An ecological perspective on nanomaterial impacts in the environment. AB - Growing concerns over the potential for unintended, adverse consequences of engineered nanoparticles (ENPs) in the environment have generated new research initiatives focused on understanding the ecological effects of ENPs. Almost nothing is currently known about the fate and transport of ENPs in environmental waters, soils, and sediments or about the biological impacts of ENPs in natural environments, and the bulk of modern nanotoxicogical research is focused on highly controlled laboratory studies with single species in simple media. In this paper, we provide an ecological perspective on the current state of knowledge regarding the likely environmental impacts of nanomaterials and propose a strategy for making rapid progress in new research in ecological nanoscience. PMID- 21284293 TI - Distributions of median nutrient and chlorophyll concentrations across the Red River Basin, USA. AB - Acquisition and compilation of water-quality data for an 11-yr time period (1996 2006) from 589 stream and river stations were conducted to support nutrient criteria development for the multistate Red River Basin shared by Arkansas, Louisiana, New Mexico, Oklahoma, and Texas. Ten water-quality parameters were collected from six data sources (USGS, Arkansas Department of Environmental Quality, Louisiana Department of Environmental Quality, Oklahoma Conservation Commission, Oklahoma Water Resources Board, and Texas Commission on Environmental Quality), and an additional 13 parameters were acquired from at least one source. Median concentrations of water-quality parameters were calculated at each individual station and frequency distributions (minimum, 10th, 25th, 50th, 75th, 90th percentiles, and maximum) of the median concentrations were calculated. Across the Red River Basin, median values for total nitrogen (TN), total phosphorus (TP), and sestonic chlorophyll-a (chl-a) ranged from < 0.02 to 20.2 mg L(-1), < 0.01 to 6.66 mg L(-1), and 0.10 to 262 microg L(-1), respectively. Overall, the 25th percentiles of TN data specific to the Red River Basin were generally similar to the USEPA-recommended ecoregion nutrient criteria of 0.31 to 0.88 mg L(-1), whereas median TP and chl-a data specific to the Red River Basin showed 25th percentiles higher than the USEPA-recommended criteria (0.010-0.067 mg TP L(-1); 0.93-3.00 microg chl-a L(-1)). The unique location of the Red River Basin in the south-central United States places it near the boundaries of several aggregate ecoregions; therefore, the development of ecoregion nutrient criteria likely requires using data specific to the Red River Basin, as shown in these analyses. This study provided basin-specific frequency distribution of median concentrations of water-quality parameters as the first step to support states in developing nutrient criteria to protect designated uses in the multijurisdictional Red River Basin. PMID- 21284294 TI - Analysis of air pollution from swine production by using air dispersion model and GIS in Quebec. AB - Swine production, the second most important contributor to Quebec's agricultural revenue, faces many problems. Intensive piggeries, with up to 599 animal units, are used to raise finishing pigs for slaughter. Among the great number of gaseous species emitted to the atmospheric environment from livestock buildings and manure storage units is NH3, which is one of the most important and most offensive with respect to human health. Under appropriate meteorological and topographical conditions, gaseous contaminants can spread and cause a public nuisance--up to a 1-km radius around the farm. To mitigate these effects, the Quebec Government adopted regulations that set minimum buffer distances to be observed by any expansion of an existing or new pig farm. The objectives of this study were (i) to assess the efficiency of the current buffer distance prescriptions in Quebec in mitigating effects of air pollution from swine units and (ii) to identify potential areas for establishing pig farm operations that will not be offensive to people. The air dispersion American Meteorological Society/Environmental Protection Agency Regulatory Model (AERMOD) with receptors distributed at 1.6 km around each source was used first, followed by a spatial geographic information system (GIS) model. Results from the dispersion model showed that the highest hourly concentration with a 99.5% compliance frequency for a single farm was 3078.1 microg/m3 and exceeded the NH3 odor criterion hourly standard set by the Quebec Government at 183.4 microg/m3. Thus, for public safety, densely populated areas like housing developments must be located >1300 m from a pig farm. This distance is in the range of setback distances (723 to 1447 m) obtained by using abacuses defined in the L'Erable Regional County Municipality. That is why we can say the current rules established by the Quebec Government, if rigorously applied, can prevent odor nuisance, due to NH3 emission, from swine farms. In the spatial model, buffer zones were established around houses, roads, waterways, and drinking water intakes. By combining layers of information in the ArcGIS Model Builder, potential areas in which pig farms can be installed, without public odor nuisance, were identified. PMID- 21284295 TI - The effect of biofuel production on swine farm methane and ammonia emissions. AB - Methane (CH) and ammonia (NH3) are emitted to the atmosphere during anaerobic processing of organic matter, and both gases have detrimental environmental effects. Methane conversion to biofuel production has been suggested to reduce CH4 emissions from animal manure processing systems. The purpose of this research is to evaluate the change in CH4 and NH3 emissions in an animal feeding operation due to biofuel production from the animal manure. Gas emissions were measured from swine farms differing only in their manure-management treatment systems (conventional vs. biofuel). By removing organic matter (i.e., carbon) from the biofuel farms' manure-processing lagoons, average annual CH4 emissions were decreased by 47% compared with the conventional farm. This represents a net 44% decrease in global warming potential (CO2 equivalent) by gases emitted from the biofuel farms compared with conventional farms. However, because of the reduction of methanogenesis and its reduced effect on the chemical conversion of ammonium (NH4+) to dinitrogen (N2) gas, NH3 emissions in the biofuel farms increased by 46% over the conventional farms. These studies show that what is considered an environmentally friendly technology had mixed results and that all components of a system should be studied when making changes to existing systems. PMID- 21284296 TI - Effect of electrokinetics on the bioaccessibility of polycyclic aromatic hydrocarbons in polluted soils. AB - Bioaccessibility is one of the most relevant aspects to be considered in the restoration of soils using biological technologies. Polycyclic aromatic hydrocarbons (PAH) usually have residual fractions that are resistant to biodegradation at the end of the biological treatment. In some situations, these residual concentrations could still be above legal standards. Here, we propose that the available knowledge about electroremediation technologies could be applied to enhance bioremediation of soils polluted with PAH. The main objective of this study was to show that a previous electrokinetic treatment could reduce the PAH residual fractions when the soil is subsequently treated by means of a bioremediation process. The approach involved the electrokinetic treatment of PAH polluted soils at a potential drop of 0.9 to 1.1 V/cm and the subsequent estimations of bioaccessibility of residual PAHs after slurry-phase biodegradation. Bioaccessibility of PAH in two creosote-polluted soils (clay and loamy sand, total PAH content averaging 300 mg/kg) previously treated with an electric field in the presence of nonionic surfactant Brij 35 was often higher than in untreated controls. For example, total PAH content remaining in clay soil after bioremediation was only 62.65 +/- 4.26 mg/kg, whereas a 7-d electrokinetic pretreatment had, under the same conditions, a residual concentration of 29.24 +/ 1.88 mg/kg after bioremediation. Control treatments without surfactant indicated that the electrokinetic treatment increased bioaccessibility of PAHs. A different manner of electric field implementation (continuous current vs. current reversals) did not induce changes in PAH bioaccessibility. We suggest that this hybrid technology may be useful in certain bioremediation scenarios, such as soils rich in clay and black carbon, which show limited success due to bioavailability restrictions, as well as in highly heterogeneous soils. PMID- 21284297 TI - Evaluation of PCR-based quantification techniques to estimate the abundance of atrazine chlorohydrolase gene atzA in rhizosphere soils. AB - There are many challenges in the accurate quantification of bacterial genes, such as the atrazine-degrading enzyme antA from Pseudomonas sp. strain ADP, from soil samples. We compared four quantitative methods for enumeration of atrazine degrading bacteria in rhizosphere environments and utilized the optimal probe based real-time polymerase chain reaction (PCR)-based method in an ongoing bioremediation experiment to monitor atzA copy number over time. We compared three quantitative PCR (qPCR) based methods--quantitative competitive PCR and two real-time qPCR methods--to traditional dilution-plate counting techniques. The optimal real-time qPCR assay was then used to monitor atzA copy number over time in the robust atrazine-degrading Pseudomonas sp. strain ADP-spiked rhizosphere environment. The use of sensitive and reliable probe-based real-time qPCRs for the enumeration of bacterial catabolic genes allows for their detection from soil samples and monitoring of potential degradative populations over time. The addition of arrazine-biodegrading bacteria into arrazine-contaminated sites to remove entrapped atrazine is a promising approach for mitigating atrazine pollution and its metabolites. The methodology contained herein will allow for optimal monitoring of atzA in rhizosphere soil with or without the addition of biodegradative Pseudomonas sp. strain ADP of bacteria. PMID- 21284298 TI - Perennial filter strips reduce nitrate levels in soil and shallow groundwater after grassland-to-cropland conversion. AB - Many croplands planted to perennial grasses under the Conservation Reserve Program are being returned to crop production, and with potential consequences for water quality. The objective of this study was to quantify the impact of grassland-to-cropland conversion on nitrate-nitrogen (NO3-N) concentrations in soil and shallow groundwater and to assess the potential for perennial filter strips (PFS) to mitigate increases in NO3-N levels. The study, conducted at the Neal Smith National Wildlife Refuge (NSNWR) in central Iowa, consisted of a balanced incomplete block design with 12 watersheds and four watershed-scale treatments having different proportions and topographic positions of PFS planted in native prairie grasses: 100% rowcrop, 10% PFS (toeslope position), 10% PFS (distributed on toe and as contour strips), and 20 PFS (distributed on toe and as contour strips). All treatments were established in fall 2006 on watersheds that were under bromegrass (Bromus L.) cover for at least 10 yr. Nonperennial areas were maintained under a no-till 2-yr corn (Zea mays L.)--soybean [Glycine max. (L.) Merr.] rotation since spring 2007. Suction lysimeter and shallow groundwater wells located at upslope and toeslope positions were sampled monthly during the growing season to determine NO3-N concentration from 2005 to 2008. The results indicated significant increases in NO3-N concentration in soil and groundwater following grassland-to-cropland conversion. Nitrate-nitrogen levels in the vadose zone and groundwater under PFS were lower compared with 100% cropland, with the most significant differences occurring at the toeslope position. During the years following conversion, PFS mitigated increases in subsurface nitrate, but long term monitoring is needed to observe and understand the full response to land-use conversion. PMID- 21284299 TI - Multiscale effects of management, environmental conditions, and land use on nitrate leaching in dairy farms. AB - Nitrate leaching in intensive grassland- and silage maize-based dairy farming systems on sandy soil is a main environmental concern. Here, statistical relationships are presented between management practices and environmental conditions and nitrate concentration in shallow groundwater (0.8 m depth) at farm, field, and point scales in The Netherlands, based on data collected in a participatory approach over a 7-yr period at one experimental and eight pilot commercial dairy farms on sandy soil. Farm milk production ranged from 10 to 24 Mg ha(-1). Soil and hydrological characteristics were derived from surveys and weather conditions from meteorological stations. Statistical analyses were performed with multiple regression models. Mean nitrate concentration at farm scale decreased from 79 mg L(-1) in 1999 to 63 in 2006, with average nitrate concentration in groundwater decreasing under grassland but increasing under maize land over the monitoring period. The effects of management practices on nitrate concentration varied with spatial scale. At farm scale, nitrogen surplus, grazing intensity, and the relative areas of grassland and maize land significantly contributed to explaining the variance in nitrate concentration in groundwater. Mean nitrate concentration was negatively correlated to the concentration of dissolved organic carbon in the shallow groundwater. At field scale, management practices and soil, hydrological, and climatic conditions significantly contributed to explaining the variance in nitrate concentration in groundwater under grassland and maize land. We conclude that, on these intensive dairy farms, additional measures are needed to comply with the European Union water quality standard in groundwater of 50 mg nitrate L(-1). The most promising measures are omitting fertilization of catch crops and reducing fertilization levels of first-year maize in the rotation. PMID- 21284300 TI - Risk assessment of aquifer storage transfer and recovery with urban stormwater for producing water of a potable quality. AB - The objective of the Parafield Aquifer Storage Transfer and Recovery research project in South Australia is to determine whether stormwater from an urban catchment that is treated in a constructed wetland and stored in an initially brackish aquifer before recovery can meet potable water standards. The water produced by the stormwater harvesting system, which included a constructed wetland, was found to be near potable quality. Parameters exceeding the drinking water guidelines before recharge included small numbers of fecal indicator bacteria and elevated iron concentrations and associated color. This is the first reported study of a managed aquifer recharge (MAR) scheme to be assessed following the Australian guidelines for MAR. A comprehensive staged approach to assess the risks to human health and the environment of this project has been undertaken, with 12 hazards being assessed. A quantitative microbial risk assessment undertaken on the water recovered from the aquifer indicated that the residual risks posed by the pathogenic hazards were acceptable if further supplementary treatment was included. Residual risks from organic chemicals were also assessed to be low based on an intensive monitoring program. Elevated iron concentrations in the recovered water exceeded the potable water guidelines. Iron concentrations increased after underground storage but would be acceptable after postrecovery aeration treatment. Arsenic concentrations in the recovered water continuously met the guideline concentrations acceptable for potable water supplies. However, the elevated concentration of arsenic in native groundwater and its presence in aquifer minerals suggest that the continuing acceptable residual risk from arsenic requires further evaluation. PMID- 21284301 TI - Implications of cation exchange on clay release and colloid-facilitated transport in porous media. AB - Column experiments were conducted to study chemical factors that influence the release of clay (kaolinite and quartz minerals) from saturated Ottawa sand of different sizes (710,360, and 240 microm). A relatively minor enhancement of clay release occurred when the pH was increased (5.8 to 10) or the ionic strength (IS) was decreased to deionized (DI) water. In contrast, clay release was dramatically enhanced when monovalent Na+ was exchanged for multivalent cations (e.g., Ca2+ and Mg2+) on the clay and sand and then the solution IS was reduced to DI water. This solution chemistry sequence decreased the adhesive force acting on the clay as a result of an increase in the magnitude of the clay and sand zeta potential with cation exchange, and expansion of the double layer thickness with a decrease in IS to DI water. The amount of clay release was directly dependent on the Na+ concentration of the exchanging solution and on the initial clay content of the sand (0.026-0.054% of the total mass). These results clearly demonstrated the importance of the order and magnitude of the solution chemistry sequence on clay release. Column results and scanning electron microscope (SEM) images also indicated that the clay was reversibly retained on the sand, despite predictions of irreversible interaction in the primary minimum. One plausible explanation is that adsorbed cations increased the separation distance between the clay-solid interfaces as a result of repulsive hydration forces. A cleaning procedure was subsequently developed to remove clay via cation exchange and IS reduction; SEM images demonstrated the effectiveness of this approach. The transport of Cu2+ was then shown to be dramatically enhanced by an order of magnitude in peak concentration by adsorption on clays that were released following cation exchange and IS reduction. PMID- 21284302 TI - Copper lability in soils subjected to intermittent submergence. AB - Reducing conditions in soils can have significant influences on the availability of nutrient and toxic metals, through their remobilization, their release through reductive dissolution of oxide phases, and from the formation of precipitates. In the literature, contrasting results are reported on the effects of temporary waterlogging conditions on the availability of metals. In the present study, changes in the "labile" or "potentially available" pool of copper (Cu) in soils as a consequence of up to three intermittent soil submergence cycles was investigated using isotopic dilution. The soils (an Oxisol and an Inceprisol) selected were amended in the field with both biosolids-Cu and salt-Cu. Intermittent soil submergence was found to have a significant effect on the lability of Cu in soils, with E(total) values generally increasing in all the treatments with the different submergence cycles, the highest lability of Cu observed in the Cu-salt treatment. The presence of nonexchangeable colloidal forms of Cu, influenced by treatments and submergence cycles, was also reported. PMID- 21284303 TI - Effects of wood bark and fertilizer amendment on trace element mobility in mine soils, Broken Hill, Australia: implications for mined land reclamation. AB - Soil amendments can immobilize metals in soils, reducing the risks of metal exposure and associated impacts to flora, fauna and human health. In this study, soil amendments were compared, based on "closed system" water extracts, for reducing metal mobility in metal-contaminated soil from the Broken Hill mining center, Australia. Phosphatefertilizer (bovine bone meal, superphosphate, triple superphosphate, potassium orthophosphate) and pine bark (Pinus radiata) were applied to two soils (BH1, BH2) contaminated with mining waste. Both soils had near neutral to alkaline pH values, were sulfide- or sulfate-rich, and contained metal and metalloid at concentrations that pose high environmental risks (e.g., Pb = 1.25 wt% and 0.55 wt%, Zn = 0.71 wt% and 0.47 wt% for BH1 and BH2, respectively). The addition of fertilizers and/or pine bark to both soil types increased water extractable metals and metalloids concentrations (As, Cd, Cu, Fe, Mn, Pb, Sb, Zn) compared with nonamended soils. One or more of the elements As, Cd, Cu, Mn, Pb, and Zn increased significantly in extracts of a range of different soil+pine bark and soil+fertilizer+piner+pine bark tests in response to increased pine bark doses. By contrast, Fe and Sb concentrations in extracts did not change significantly with pine bark addition. Solution pH was decreased by phosphate fertilizers (except for bovine bone meal) and pine bark, and pine bark enhanced dissolved organic carbon. At least in the short-term, the application of phosphate fertilizers and pine bark proved to be an ineffective method for controlling metal and metalloid mobility in soils that contain admixtures of polymetallic, polymineralic mine wastes. PMID- 21284304 TI - Precipitation changes impact stream discharge, nitrate-nitrogen load more than agricultural management changes. AB - Nitrate-N losses to surface waters in the Upper Midwest of the Untied States have increased in recent decades, contributing to hypoxia in the Gulf of Mexico. This paper investigates whether increasing nitrate-N export from cropland in the Upper Midwest since the late 1960s results from changes in land use or climate. The Agricultural Drainage and Pesticide Transport (ADAPT) Model simulated current and historical agricultural systems under past and recent wet climate for Seven Mile Creek in Minnesota. Simulations were run with management and climate for three distinctly different periods--namely, 1965 to 1969, 1976 to 1980, and 1999 to 2003 (wettest period). Results showed discharge and nitrate-N losses responded more to changes in climate than management. The wetter period (1999-2003) caused a simulated 70% increase in discharge under 1960s-era management compared with that period's observed climate and a simulated 51% increase in discharge under 1970s-era management compared with the 1976 to 1980 climate. The recent, wetter climate also produced a 62% increase in nitrate-N losses for 1960s-era management compared with the actual climate and a 137% increase in nitrate-N losses for 1978 management conditions compared with actual 1970s climate. Had recent climate been in place and stable since 1965, agricultural changes would have decreased discharge by 6.4% through the late 1970s and then by another 21.1% under modern management but would have increased nitrate-N losses by 184% through the late 1970s and then decreased nitrate-N losses by 13.5% between 1978 and 2001. Management changes that were important drivers included increasing N-fertilizer rates, increases in corn acreage, and increases in crop yield. But the most important factor driving increased nitrate-N losses from agriculture since the 1970s was an increasingly wetter climate. PMID- 21284305 TI - Sequential accelerated solvent extraction of polycyclic aromatic hydrocarbons with different solvents: performance and implication. AB - Sixteen USEPA priority polycyclic aromatic hydrocarbons (PAHs) extracted by Soxhlet extraction (S-PAHs) with dichloromethane and routine accelerated solvent extraction (A-PAHs) with 1:1 toluene/methanol, respectively, were investigated in 24 soil samples from two cities in the center of the Pearl River Delta, South China. Polycyclic aromatic hydrocarbons, methylphenanthrene and perylene, in two soils, two sediments, and an immature oil shale were also sequentially extracted by accelerated solvent extraction (ASE) with each of four different organic solvents for three times. The A-PAHs' concentrations are 2.41 times the S-PAHs' concentrations. For sequential three ASEs, PAHs in the first extract account for 56 to 67% of their total concentrations in the sequential three extractions and toluene displays the best extraction performance among the four solvents. Diagnostic ratios of PAHs in Soxhlet extraction, routine ASE, and sequential ASE with each solvent for a given sample are very similar, suggesting their identical petrogenic and pyrogenic sources in the soils and sediments. But the PAH ratios for the shale have an obvious petrogenic origin. The perylene/5-ring PAH ratios indicate a diagenetic source, especially in the shale and sediments. The correlation analysis shows that A-PAHs/S-PAHs is better associated with the contents of total organic carbon (TOC) than those of black carbon (BC). The above results indicate the significant petrogenic origin of PAHs and the important effect of organic matter on their extraction and distribution in the investigated field soils/sediments. PMID- 21284306 TI - Occurrence of arsenic and phosphorus in ditch flow from litter-amended soils and barn areas. AB - Little is known about the fate of arsenic (As) in land-applied litter from chickens that have been fed roxarsone, an organic feed additive containing As. This study seeks to elucidate the transfer of As in runoff from ditch-drained soils of the poultry-producing region of the Delmarva Peninsula by tracking As and phosphorus (P) export from seven drainage ditches over two water-years (1 July 2005 to 30 June 2007). Annual losses of As from ditches ranged from 0.004 to 0.071 kg ha(-1) while P losses ranged from 0.33 to 18.56 kg ha(-1), with the largest loads associated with a litter storage shed that served as a point source. Event-based As and P losses in ditch flow fluctuated by a factor of 162 and 1882, respectively. The two elements were correlated in flow from the ditch draining a litter storage shed (r = 0.99), and in sediment extracts in soils near the litter shed (r = 0.73), pointing to similar behavior under point source conditions. Indeed, As and P exhibited similar behavior within storms for all ditches, characterized by relatively high initial concentrations subject to rapid concentration declines before peak flow, consistent with dilution of a finite source. However, As and P concentrations varied significantly between ditches and showed considerable temporal variability within ditches, with no clear seasonal trends or associations with current management strategies. The results suggest that similar management strategies might be effective for As and P point sources, but that field management practices geared toward controlling nonpoint source P losses may not readily transfer to the control of As losses. PMID- 21284307 TI - Phytoestrogens and mycotoxins in Iowa streams: an examination of underinvestigated compounds in agricultural basins. AB - This study provides the first broad-scale investigation on the spatial and temporal occurrence of phytoestrogens and mycotoxins in streams in the United States. Fifteen stream sites across Iowa were sampled five times throughout the 2008 growing season to capture a range of climatic and crop-growth conditions. Basin size upstream from sampling sites ranged from 7 km2 to > 836,000 km2. Atrazine (herbicide) also was measured in all samples as a frame-of-reference agriculturally derived contaminant. Target compounds were frequently detected in stream samples: atrazine (100%), formononetin (80%), equol (45%), deoxynivalenol (43%), daidzein (32%), biochanin A (23%), zearalenone (13%), and genistein (11%). The nearly ubiquitous detection of formononetin (isoflavone) suggests a widespread agricultural source, as one would expect with the intense row crop and livestock production present across Iowa. Conversely, the less spatially widespread detections of deoxynivalenol (mycotoxin) suggest a more variable source due to the required combination of proper host and proper temperature and moisture conditions necessary to promote Fusarium spp. infections. Although atrazine concentrations commonly exceeded 100 ng L(-1) (42/75 measurements), only deoxynivalenol (6/56 measurements) had concentrations that occasionally exceeded this level. Temporal patterns in concentrations varied substantially between atrazine, formononetin, and deoxynivalenol, as one would expect for contaminants with different source inputs and processes of formation and degradation. The greatest phytoestrogen and mycotoxin concentrations were observed during spring snowmelt conditions. Phytoestrogens and mycotoxins were detected at all sampling sites regardless of basin size. The ecotoxicological effects from long-term, low level exposures to phytoestrogens and mycotoxins or complex chemicals mixtures including these compounds that commonly rake place in surface water are poorly understood and have yet to be systematically investigated in environmental studies. PMID- 21284308 TI - Determining sources of dissolved organic carbon and disinfection byproduct precursors to the McKenzie River, Oregon. AB - This study was conducted to determine the main sources of dissolved organic carbon (DOC) and disinfection byproduct (DBP) precursors to the McKenzie River, Oregon (USA). Water samples collected from the mainstem, tributaries, and reservoir outflows were analyzed for DOC concentration and DBP formation potentials (trihalomethanes [THMFPs] and haloacetic acids [HAAFPs]). In addition, optical properties (absorbance and fluorescence) of dissolved organic matter (DOM) were measured to provide insight into DOM composition and assess whether optical properties are useful proxies for DOC and DBP precursor concentrations. Optical properties indicative of composition suggest that DOM in the McKenzie River mainstem was primarily allochthonous--derived from soils and plant material in the upstream watershed. Downstream tributaries had higher DOC concentrations than mainstem sites (1.6 +/- 0.4 vs. 0.7 +/- 0.3 mg L(-1)) but comprised < 5% ofmainstem flows and had minimal effect on overall DBP precursor loads. Water exiting two large upstream reservoirs also had higher DOC concentrations than the mainstem site upstream of the reservoirs, but optical data did not support in situ algal production as a source of the added DOC during the study. Results suggest that the first major rain event in the fall contributes DOM with high DBP precursor content. Although there was interference in the absorbance spectra in downstream tributary samples, fluorescence data were strongly correlated to DOC concentration (R2 = 0.98), THMFP (R2 = 0.98), and HAAFP (R2 = 0.96). These results highlight the value of using optical measurements for identifying the concentration and sources of DBP precursors in watersheds, which will help drinking water utilities improve source water monitoring and management programs. PMID- 21284309 TI - Phosphorus concentrations, loads, and sources within the Illinois River drainage area, northwest Arkansas, 1997-2008. AB - In the Ozark Highlands and across the United States, effluent phosphorus (P) sources often have a profound impact on water column concentrations and riverine transport. This study evaluated (i) annual P loads at the Illinois River at Arkansas Highway 59 from calendar year 1997 through 2008, (ii) the relative contribution of effluent P sources to annual riverine P transport, (iii) longitudinal gradients in water column P concentrations downstream from several wastewater treatment plant effluent discharges, and (iv) changes in monthly P loads over the last decade. This study showed that annual P loads have ranged from 64,000 kg to over 426,000 kg and that P transport was positively correlated to hydrology (i.e., the amount of water delivered downstream). The relative contribution of P inputs from municipal facilities has decreased from 40% of the annual P load at the Illinois River at Arkansas Highway 59 to < 15% in recent years. Elevated P concentrations during base flow conditions were traced 45 river km upstream to one municipal effluent discharge, but all effluent discharges influenced P concentrations in the receiving streams. Most important, flow adjusted monthly P loads showed two distinct trends over time. Flow-adjusted loads significantly increased from 1997 through 2002 and significantly decreased from 2002 through 2008. The concentrations and transport of P within the Illinois River drainage area are significantly decreasing from all the watershed management changes that have occurred, and monitoring should continue to determine if this decrease continues at the same rate over the next several years. PMID- 21284310 TI - Modeling phosphorus transport in an agricultural watershed using the WEPP model. AB - The Water Erosion Prediction Project (WEPP) model has been tested for its ability to predict soil erosion, runoff, and sediment delivery over a wide range of conditions and scales for both hillslopes and watersheds. Since its release in 1995, there has been considerable interest in adding a chemical transport element to it. Total phosphorus (TP) loss at the watershed outlet was simulated as the product of TP in the soil, amount of sediment at the watershed outlet, and an enrichment ratio (ER) factor. WEPP can be coupled with a simple algorithm to simulate phosphorus transport bound to sediment at the watershed outlet. The objective of this work was to incorporate and test the ability of WEPP in estimatingTP loss with sediment at the small watershed scale. Two approaches were examined. One approach (P-EER) estimated ER according to an empirical relationship; the other approach used the ER calculated by WEPP (P-WER).The data used for model performance test were obtained from two side-by-side watersheds monitored between 1976 and 1980. The watershed sizes were 5.05 and 6.37 ha, and each was in a corn (Zea mays L.)-soybean [Glycine max (L.) Merr.] rotation. Measured and simulated results were compared for the period April to October in each year. There was no statistical difference between the mean measured and simulated TP loss. The Nash-Sutcliffe coefficient was 0.80 and 0.78 for the P-EER and P-WER methods, respectively. It was critical for both methods that WEPP adequately represent the biggest sediment yield events because sediment is the main driver for TP loss so that the model can adequately simulate TP losses bound to sediment. The P-WER method is recommended because it does not require use of empirical parameters to estimate TP loss at the watershed outlet. PMID- 21284311 TI - Nontarget deposition and losses of chlorothalonil in irrigation runoff water from a commercial foliage plant nursery. AB - Commercial foliage plant production requires the use of pesticides for controlling pests and pathogens that can reduce aesthetic qualities of crops, rendering them unwanted by consumers. Chlorothalonil is a common, broad-spectrum, foliar fungicide used for protecting plants from a variety of fungal diseases. This fungicide may also be acutely toxic to nontarget aquatic organisms due to its mode of action. This study evaluated the amount of chlorothalonil deposited on nontarget ground surfaces during normal sprayer applications at a commercial nursery using Teflon targets. One day following application, irrigation runoff events were initiated and runoff water samples were collected and analyzed for chlorothalonil. Discharge volumes were also measured to allow estimation of the total mass of chlorothalonil discharged during each event. Results indicated that 9.8 to 53.6% of the active ingredient applied landed on nontarget ground surfaces depending on plant size, spacing, and row lengths (short rows sprayed from one side vs. longer rows sprayed from both ends). On an entire production-area scale, 29.2% of the active ingredient applied was deposited on ground surfaces. Of the total nontarget deposition, 0.25 to 0.53% was detected in runoff water discharged from the production area. Concentrations ranged from 1.2 to 500 microg/L during the first runoff events following application. PMID- 21284312 TI - Effect of varying the phosphorus content of dairy cow diets on losses of phosphorus in overland flow following surface applications of manure. AB - The increasing use of concentrate feedstuffs within Northern Ireland dairy systems has resulted in significant farm gate phosphorus (P) surpluses, and these have contributed to increased soil P levels and risk of P loss to overland flow. However, the P content of feed concentrates can be lowered without compromising animal performance. This study focuses on P losses from grassland and evaluates how adjusting the P content of manure impacts on the P composition and concentration in overland flow. Dairy cows were offered diets containing 5.3 to 3.0 g P kg(-1) dry matter (DM) and produced manures with a range of P contents. Manure was applied at a rate of 50 m3 ha(-1) to 0.5-m2 grassland plots, and simulated rainfall (40 mm h(-1)) was applied repeatedly 2, 9, 28, and 49 d after during the summer, winter, and spring. Decreasing the P content in the diet, from the highest to the lowest P treatment (43%), produced a proportionately greater reduction in manure TP content (63%), but reductions were not exclusively in the water-soluble fraction. Following surface applications of manure, P concentrations in overland flow increased in all seasons (P < or = 0.001), while the greatest impact of varying the manure P content was most evident during the first simulated overland flow event. When diet P content was reduced from 5.4 to 3.0 g P kg(-1) DM, a statistically significant reduction in runoff P concentration was observed in all seasons. Elevated P concentrations in overland flow were observed for 28 d in spring and 9 d in summer and winter. The large drop in P concentrations between simulated rainfall events on Day 2 and Day 9 suggests that increasing the time interval between manure application and the generation of overland flow has a greater impact on P losses than does varying the dietary P content. PMID- 21284313 TI - Transport of sulfadiazine in undisturbed soil columns: effects of flow rate, input concentration and pulse duration. AB - Antibiotics reach soils via spreading of manure or sewage sludge. Knowledge on the transport behavior of antibiotics in soils is needed to assess their environmental fate. The effect of flow rate and applied mass, i.e., input concentration and pulse duration, on the transport of 14C-sulfadiazine (SDZ; 4 aminoN-pyrimidin-2-yl-benzenesulfonamide) was investigated with soil column experiments and numerical studies. Sulfadiazine was applied in pulses (6.8, 68 or 306 h) under steady-state (0.051 and 0.21 cm h(-1)) and intermittent flow conditions and at two input concentrations (0.57 and 5.7 mg L(-1)). Breakthrough curves (BTCs) of 14C were measured and for one experiment concentrations of SDZ, and its transformation products 4-(2-iminopyrimidin-1(2H)-yl)aniline (An-SDZ) and N(1)-2-(4-hydroxypyrimidinyl)benzenesulfanilamide (4-OH-SDZ) were determined. After finalizing the leaching experiments, 14C was quantified in different slices of the columns. A lower flow rate led to remarkably lower eluted masses compared with the higher flow rates. All BTCs could be described well using a three-site attachment-detachment model for which a common set of parameters was determined. However, the BTC obtained with the high input concentration was slightly better described with a two-site isotherm-based model. The prediction of the concentration profiles was good with both model concepts. The fitted sorption capacities decreased in the order SDZ > 4-OH-SDZ > An-SDZ. Overall, the experiments reveal the presence of similar mechanisms characterizing SDZ transport. The dependence of model performance on concentration implies that although the three-site attachment-detachment model is appropriate to predict the transport of SDZ in soil columns, not all relevant processes are adequately captured. PMID- 21284314 TI - Assessment of a reclamation cover system for phosphogypsum stacks in Central Alberta, Canada. AB - Phosphogypsum (PG), a byproduct of the phosphate fertilizer industry, was produced and stockpiled at the Agrium Fort Saskatchewan facility from 1965 to 1991. Upon decommissioning, the outer slopes of the PG stacks were reclaimed by applying 15 cm of topsoil and planting a non-native seed mix. Physical, chemical, and hydrologic evaluations of the cover system confirmed that plants were successfully growing in various soil capping depths and were often rooting more than 200 mm into the PG. Percolation past the substrate into PG during a typical storm event was low (< 10 mm), and runoff from the stacks was negligible. Runoff quality met most guidelines, but some parameters, including fluoride, were up to 18 times higher than provincial or federal guidelines for soil and water quality. However, the cover system, when applied appropriately, does meet basic reclamation objectives. The exceedances are found in areas where the cover system has been compromised by erosion or mixing or in areas where the cover system has not been fully applied, such as roads or the inner basin. In areas where the cover system has been applied successfully, basic reclamation requirements are met. PMID- 21284315 TI - Characterization and dispersion modeling of odors from a piggery facility. AB - Piggeries are known for their nuisance odors, creating problems for workers and nearby residents. Chemical substances that contribute to these odors include sulfurous organic compounds, hydrogen sulfide, phenols and indoles, ammonia, volatile amines, and volatile fatty acids. In this work, daily mean concentrations of ammonia (NH3) and hydrogen sulfide (H2S) were measured by hand held devices. Measurements were taken in several places within the facility (farrowing to finishing rooms). Hydrogen sulfide concentration was found to be 40 to 50 times higher than the human odor threshold value in the nursery and fattening room, resulting in strong nuisance odors. Ammonia concentrations ranged from 2 to 18 mL m(-3) and also contributed to the total odor nuisance. Emission data from various chambers of the pig farm were used with the dispersion model AERMOD to determine the odor nuisance caused due to the presence of H2S and NH3 to receptors at various distances from the facility. Because just a few seconds of exposure can cause an odor nuisance, a "peak-to-mean" ratio was used to predict the maximum odor concentrations. Several scenarios were examined using the modified AERMOD program, taking into account the complex terrain around the pig farm. PMID- 21284316 TI - Phosphorus speciation in sequentially extracted agro-industrial by-products: evidence from X-ray absorption near edge structure spectroscopy. AB - The phosphorus (P) in agro-industrial by-products--a potential source of freshwater eutrophication but also a valuable fertilizer--needs to be speciated to evaluate its fate in the environment. We investigated to what extent X-ray absorption near edge structure (XANES) spectroscopy at the P K- and L2.3-edges reflected differences in sequentially extracted filter cakes from sugarcane (Saccharum officinarum L.) (FIC) and niger seed (Guizotia abyssinica Cass.; NIC) processing industry in Ethiopia. The P fractionation removed more labile (54%) and H2SO4-P (28%) from FIC than from NIC (18% labile, 12% H2SO4-P). For the FIC residues after each extraction step, linear combination (LC) fitting of P K-edge spectra provided evidence for the enrichment of Ca-P after the NaOH-extraction and its almost complete removal after the H2SO4-treatment. The LC-fitting was unsuccessful for the NIC samples, likely because of the predominance of organic P compounds. The different proportions of Ca-P compounds between FIC (large) and NIC (small) were more distinctive in L2-than in the K-edge XANES spectra. In conclusion, the added value of complementary P K- and L2.3-edge XANES was clearly demonstrated, and the P fractionation and speciation results together justify using FIC and NIC as soil amendments in the tropics. PMID- 21284318 TI - Quantifying nitrogen process rates in a constructed wetland using natural abundance stable isotope signatures and stable isotope amendment experiments. AB - This study describes the spatial variability in nitrogen (N) transformation within a constructed wetland (CW) treating domestic effluent. Nitrogen cycling within the CW was driven by settlement and mineralization of particulate organic nitrogen and uptake of NO3-. The concentration of NO3- was found to decrease, as the delta15N-NO3- signature increased, as water flowed through the CW, allowing denitrification rates to be estimated on the basis of the degree of fractionation of delta15N-NO3-. Estimates of denitrification hinged on the determination of a net isotope effect (eta), which was influenced byprocesses that enrich or deplete 15NO3- (e.g., nitrification), as well as the rate constants associated with the different processes involved in denitrification (i.e., diffusion and enzyme activity). The influence of nitrification on eta was quantified; however, it remained unclear how eta varied due to variability in denitrification rate constants. A series of stable isotope amendment experiments was used to further constrain the value of eta and calculate rates of denitrification, and nitrification, within the wetland. The maximum calculated rate of denitrification was 956 +/- 187 micromol N m(-2) h(-1), and the maximum rate of nitrification was 182 +/- 28.9 micromol N m(-2) h(-1). Uptake of NO3- was quantitatively more important than denitrification throughoutthe wetland. Rates of N cycling varied spatially within thewetland, with denitrification dominating in the downstream deoxygenated region of the wetland. Studies that use fractionation of N to derive rate estimates must exercise caution when interpreting the net isotope effect. We suggest a sampling procedure for future natural abundance studies that may help improve the accuracy of N cycling rate estimates. PMID- 21284317 TI - Pathogens and indicators in United States Class B biosolids: national and historic distributions. AB - This paper reports on a major study of the incidence of indicator organisms and pathogens found within Class B biosolids within 21 samplings from 18 wastewater treatment plants across the United States. This is the first major study of its kind since the promulgation of the USEPA Part 503 Rule in 1993, and includes samples before and after the Part 503 Rule was promulgated. National distributions collected between 2005 and 2008 show that the incidence of bacterial and viral pathogens in Class B mesophilic, anaerobically digested biosolids were generally low with the exception of adenoviruses, which were more prevalent than enteric viruses. No Ascaris ova were detected in any sample. In contrast, indicator organism numbers were uniformly high, regardless of whether they were bacteria (fecal coliforms) or viruses (phage). Indicators were not correlated with pathogen loads. Historic distributions were collected between 1988 and 2006 at one location in Tucson, AZ. By comparing data collected before and after 1993, the influence of the USEPA Part 503 Rule on indicator and pathogen levels within Class B biosolids can be inferred. In general, the bacterial indicators total and fecal coliforms decreased from the 1980s to present. Enteric virus concentrations after 1993 are much lower than those reported in other studies in the 1980s, although our values from 1988 to 1993 are not significantly different from our values obtained from 1994 to 2006. Presumably this is due to better and more consistent treatment of the wastewater, illustrating that the Part 503 Rule has been effective in reducing public exposure to pathogens relative to 17 yr ago. The percent reduction of both indicators and pathogens during anaerobic mesophilic digestion was between 94 and 99% for all organisms, illustrating that such treatment is effective in reducing pathogen loads. PMID- 21284319 TI - Selenium stable isotope investigation into selenium biogeochemical cycling in a lacustrine environment: Sweitzer Lake, Colorado. AB - We present a comprehensive set of Se concentration and isotope ratio data collected over a 3-yr period from dissolved, sediment-hosted, and organically bound Se in a Se-contaminated lake and littoral wetland. Median isotope ratios of these various pools of Se spanned a narrow isotopic range (delta80/76Se(SRM 3149)) = 1.14-2.40 per thousand). Selenium (VI) reduction in the sediments is an important process in this system, but its isotopic impact is muted by the lack of direct contact between surface waters and reduction sites within sediments. This indicates that using Se isotope data as an indicator of microbial or abiotic Se oxyanion reduction is not effective in this or other similar systems. Isotopic data suggest that most Se(IV) in the lake originates from oxidation of organically bound Se rather than directly through Se(VI) reduction. Mobilization of Se(VI) from bedrock involves only a slight isotopic shift. Temporally constant isotopic differences observed in Se(VI) from two catchment areas suggest the potential for tracing Se(VI) from different source areas. Phytoplankton isotope ratios are close to those of the water, with a small depletion in heavy isotopes (0.56 per thousand). Fish tissues nearly match the phytoplankton, being only slightly depleted in the heavier isotopes. This suggests the potential for Se isotopes as migration indicators. Volatile, presumably methylated Se was isotopically very close to median values for phytoplankton and macrophytes, indicating a lack of isotopic fractionation during methylation. PMID- 21284320 TI - Broad-host-range plasmids in treated wastewater effluent and receiving streams. AB - The occurrence of broad-host-range (BHR) plasmid amplicons belonging to incompatibility (Inc) groups IncA/C, IncN, IncP, and IncW in two wastewater treatment plant (WWTP) effluents and effluent-receiving streams in Northwest Arkansas, Mud Creek and Spring Creek, was determined. Community DNA captured on filter membranes and plasmid DNA extracted from antibiotic-resistant Escherichia coli isolated from Mud Creek was used for polymerase chain reaction at amplification of partial gene sequences specific to BHR plasmids. IncP plasmid amplicons were detected in effluent and downstream sites in both streams, while IncN and IncW plasmid amplicons were detected in Spring Creek in effluent and downstream but not upstream. IncA/C plasmid amplicons, in contrast, were detected at all sites, including upstream in most samples in Spring Creek and in one sample from Mud Creek. One IncP and two IncN were the only BHR plasmid amplicons found in 85 screened antibiotic-resistant E. coli isolates, and were detected only in isolates from effluent and downstream samples. Broad-host-range plasmids frequently carry antibiotic-resistance genes and can facilitate horizontal transfer of those genes. While BHR plasmids have been detected in WWTPs, WWTPs do not target these genetic elements for destruction. This study indicates that BHR plasmids are in WWTP effluent and are introducing BHR plasmids into streams. Additionally, species other than E. coli may be better targets as indicator bacteria for future studies of the impact of treated effluent on environmental dissemination of BHR plasmids. PMID- 21284321 TI - The low-dose ACTH and high dose ACTH test biology is not mathematics. PMID- 21284322 TI - The low-dose ACTH test does not identify mild insufficiency of the hypothalamnic pituitary-adrenal axis in children with inadequate stress response. AB - OBJECTIVE: To investigate retrospectively the sensitivity of published cortisol cut-off points of the low-dose ACTH test (LDAT) in children with proven mild hypothalamic-pituitary-adrenal (HPA) axis insufficiency. PATIENTS AND METHODS: The HPA axis of 11 pediatric patients (age range: 5.5-14.5 yr) with established mild HPA axis insufficiency was reinvestigated with the LDAT. The sensitivity of the LDAT was calculated on the basis of published stimulated cortisol cut-off points. RESULTS: The LDAT showed both a significantly higher cortisol peak and a greater cortisol rise compared with the ITT (both P < 0.01). The LDAT yielded a low sensitivity of 9-55% using published cortisol cut-off points as references. CONCLUSION: Using published cortisol cut-off points, the LDAT showed a poor sensitivity to detect mild HPA axis insufficiency. We cannot recommend the use of the LDAT as a screening test of HPA axis impairment in such children. PMID- 21284323 TI - Smith-Lemli-Opitz syndrome: autopsy with new morphological findings. PMID- 21284324 TI - Common skeletal growth retardation disorders resulting from abnormalities within the mesenchymal stem cells reservoirs in the epiphyseal organs pertaining to the long bones. AB - Among the objectives in writing the current chapter were the curiosity and the interest in allocating the sites and routes of migration of the reservoirs of the mesenchymal precartilaginous stem cells of the developing limbs in health and in disease. We chose to emphasize the events believed to initiate in these regions of stem cells, which may lead to growth retardation disorders. Thus, this narrow niche touches an enlarged scope of developmental biology angles and fields. The enclosed coverage sheds light on part of the musculoskeletal system, skeletogenesis, organogenesis of mobile structures and organs, the limbs, joints and digits (arthrology). It appears that the key role of the cartilage-bone regions is their responsibility to replenish the physis with committed chondrocytes, during the developmental, maturation and puberty periods. We shall start by outlining the framework of normal limb formation, the modalities, signals and the agents participating in this biological creation and regulation, illustrating potential sites that might deviate from normal development during the growth periods. PMID- 21284325 TI - Disorders of sexual development: an overview of 18 years experience in the pediatric Endocrinology Department of Ankara University. AB - INTRODUCTION: Disorders of sexual development (DSD) occur when the appearance of the internal and/or external genitalia is at variance with normal development for either sex. We reviewed the characteristics of patients with DSD. PATIENTS: Two hundred and eight children aged from newborn to 19 years with DSD from 1990 to 2008. RESULTS: 46,XY DSD (52.4%) was more common than 46,XX DSD (34.6%) and gonadal differentiation disorders (12.99%). Thirty-six (33.02%) patients were diagnosed with androgen resistance syndrome, 41 (37.61%) had 5alpha-reductase deficiency, 23 (21.10%) had testosterone synthesis disorders. Congenital adrenal hyperplasia was the most frequent underlying cause of 46,XX DSD. CONCLUSION: There are many difficult aspects in the diagnosis and management of DSD. Gender assessment teams of endocrine centers need a multidisciplinary approach for the diagnosis, medical and surgical treatment, genetic counseling, and psychosocial support of these patients. PMID- 21284326 TI - Cognitive profile, parental education and BMI in children: reflections on common neuroendrocrinobiological roots. AB - Overweight and obesity may be associated with cognitive problems and both may share "neuroendocrinobiological roots" in common cerebral areas. We investigated intellectual performances and a possible "specific cognitive profile" in overweight/obese children. A cross-sectional study was conducted on 898 school children (6 to 13 years) attending primary schools. Wechsler Intelligence Scale for Children-revised (WISC-R) revealed significant differences in performance intelligence quotient (PIQ) scores between body mass index (BMI) subgroups (p < 0.01). Regression analysis identified BMI as the only variable significantly related to PIQ (p < 0.05). Gender (p < 0.05) and parental educational score (p < 0.001) were significantly related to verbal intelligence quotient (VIQ). Parental educational score was the only factor significantly related to total intelligence quotient (TIQ) (p < 0.05). Parental education seems to play a major role in TIQ and VIQ; a lower PIQ score is clearly related to a higher BMI. A routine neurocognitive assessment in overweight/obese children is recommended. Finally, we have added some reflections on common neuroendocrinobiological roots. PMID- 21284327 TI - The relationship between abdominal aortic intima-media thickness and lipid profile in neonates born to mothers with preeclampsia. AB - Neonates born to mothers with preeclampsia are known to be associated with lipid alterations that might increase the risk for cardiovascular disease in adult life. The aim of this study was to investigate the effect of preeclampsia on lipid metabolism, aortic intimamedia thickness (aIMT) and subsequent atherogenic risk in newborn infants. Aortic intima-media thickness was measured in 60 neonates of mothers with preeclampsia (group I; 30 neonates of mothers with preeclampsia and group II; 30 neonates of mothers with severe preeclampsia) and 30 healthy neonates (group III). Maternal and cord serum lipid profiles were determined in all groups. Mean abdominal aIMT measurements were higher in the neonates born to mothers with preeclampsia (group I; 0.36 +/- 0.03 mm and group II; 0.36 +/- 0.04 mm) compared with the control group (group III; 0.33 +/- 0.03 mm, p = 0.006). Serum triglyceride levels were significantly higher in the neonates born to mothers with preeclampsia (group I; 39.2 +/- 42.0 mg/dl and group II; 39.5 +/- 56.5 mg/dl) compared with the control group (group III; 14.9 +/- 18.8 mg/dl, p = 0,039). Serum HDL cholesterol levels were significantly lower in the neonates born to mothers with preeclampsia (group I; 17.3 +/- 12.3 mg/dl and group II; 17.1 +/- 12.8 mg/dl) compared with the control group (group III; 27.6 +/- 13.0 mg/dl, p = 0.002). In conclusion; neonates of mothers with preeclampsia have significantly higher aIMT with lipid alterations. This may play a role in the pathogenesis of atherosclerosis in adult life. PMID- 21284328 TI - Clinical presentation and autoimmune characteristics of very young children at the onset of type 1 diabetes mellitus. AB - The aim of our study was to identify factors that are related to a more aggressive beta-cell destruction in children at presentation of type 1 diabetes mellitus (T1D). We analyzed age, HbAlc, pH, bicarbonate, IAA, IA2, GADA, C peptide of 290 consecutive patients with T1D at onset. Seventy-three (25.2%) were younger than 4 years; 217 (74.8%) were aged 4-18 years. Younger patients had lower C peptide, pH and bicarbonate than older ones. Age at T1D onset was negatively related to IAA titers (r: -0.3404, p < 0.001), positively related to IA2 titers (r: 0.1249, p: 0.03) and to C peptide (r: 0.42, p: < 0.001). Multivariable linear regression showed that C peptide was negatively related to HbA1c and positively related to age, pH at admission and IAA titers. T1D in very young children is characterized by a more extensive beta-cell destruction, and younger age at onset is related to a more severe decompensation. PMID- 21284329 TI - Identification of two novel chromosome regions associated with isolated growth hormone deficiency. AB - The goal of this study was to identify novel candidate genes that may cause or predispose to growth hormone (GH) deficiency. DNA samples from 45 individuals with isolated GH deficiency were assessed using oligonucleotide microarray comparative genomic hybridization. Five individuals with previously unreported copy number variants were identified. Two of the five individuals were hemizygous for regions already known to cause GH deficiency (chromosomes 22q11.21 and 15q26.3). The remaining three individuals had copy number changes involving two novel chromosome regions. One individual had a homozygous deletion of a 2.2 Mb region of 13q33.1 that contains a single gene: integrin, beta-like 1 (ITGBL1). The remaining two individuals had duplications of 4.7 Mb on chromosome 20q13.13. This region includes eight genes not previously identified as copy number variants. These genes are ARFGEF2, CSE1L, DDX27, ZNFX1, C20orf199, SNORD12, KCNB1, and PTGIS. Thus, further investigations into these potential candidate genes are necessary. PMID- 21284330 TI - Pericardial effusion in severe hypothyroidism in children. AB - Pleural and pericardial effusion is a rare complication of severe hypothyroidism in children but can be present in 10 to 30% of adults. Most pediatric cases have been in children with Down syndrome. In this report, six cases of pericardial effusion in children with severe hypothyroidism with and without trisomy 21 are presented. In all patients, the pericardial effusion was managed successfully without pericardiocentesis. The effusions resolved completely in 2 to 12 months after initiation of thyroxin replacement. In conclusion, hypothyroidism should be considered in any child with unexplained pericardial or pleural effusions. Early recognition and treatment with thyroid hormone replacement could eliminate the need for unnecessary diagnostic procedures and invasive treatment measures and reduce the risk of progression to cardiac tamponade. PMID- 21284331 TI - Effect of gluten-free diet on growth and glycemic control in children with type 1 diabetes and asymptomatic celiac disease. AB - We aimed to evaluate the effects of a gluten-free diet on growth and glycemic control in children with type 1 diabetes mellitus (DM) and asymptomatic, biopsy proven celiac disease (CD). Each case of CD was compared to two children with DM and no CD. We studied weight, height, and hemoglobin A1c (HgbAlc) up to 12 months pre- and post- CD diagnosis in 29 cases and 58 controls. The change in body mass index (deltaBMI Z-score) over 2 years was significantly higher in CD cases vs. controls (mean +/- SD 0.33 +/- 0.74 vs. +/- 0.08 +/- 0.46; p = 0.023). However, BMI Z-score did not change in CD patients diagnosed with DM for > 1 year. Mean HgbA1c was similar between groups throughout the study. In conclusion, children with asymptomatic CD and DM do not have significant changes in BMI, height Z score or metabolic control 1 year post-diagnosis. PMID- 21284332 TI - Rathke's cleft cysts in children and adolescents: association with female puberty. AB - There are few pediatric data regarding manifestations and outcomes of Rathke's cleft cysts (RCC). We retrospectively reviewed 13 cases treated at Massachusetts General Hospital over 10 years. Age at presentation was 12-17 years, except for one 7-year-old who presented with sexual precocity. There was a female preponderance [11 females, 2 males, p = 0.01], and all were pubertal at diagnosis. Common features at presentation were headaches (11/13), endocrine abnormalities (5/13) and visual disturbances (2/13). Four patients underwent transsphenoidal surgery. Symptoms improved in all but one, in whom headaches persisted. Recurrent growth in one patient was treated successfully by excision. For conservatively treated patients, cyst size was unchanged over follow-up (6 months-5 years). Female preponderance and pubertal presentation suggest a possible link between sex hormones and RCC pathogenesis. Although estrogen and progesterone receptor immunostaining was negative in the cyst lining, estrogen receptor immunostaining was positive in adjacent pituitary cells. Further investigations regarding this issue are warranted. PMID- 21284333 TI - Graves' disease in a Down's syndrome patient. AB - Thyroid dysfunction in patients with Down's syndrome is well known. Although the majority of children with Down's syndrome appear to have normal thyroid function, however, hypothyroidism is commonly seen. The presence of hyperthyroidism is rare. The etiology is believed to be autoimmune. We report a patient with Down syndrome and Graves' disease who responded well to antithyroid drugs. The rarity of this association, especially in a child younger than eight years of age, has prompted us to report this case. PMID- 21284334 TI - Subcutaneous fat necrosis and hypercalcemia following therapeutic hypothermia--a patient report and review of the literature. AB - Subcutaneous fat necrosis (SCFN) of the newborn is an uncommon dermatologic disorder characterized by firm, palpable subcutaneous nodules or plaques with or without erythema. Despite its benign course, SCFN may become complicated by extracutaneous manifestations. Hypercalcemia is considered a rare complication, but it is potentially fatal if unrecognized. During the last several years therapeutic hypothermia (TH) became an essential new therapeutic modality for severe neonatal asphyxia. We report a neonate who presented with SCFN and hypercalcemia following hypothermia therapy for hypoxic ischemic encephalopathy (HIE) and provide a review of the contemporary literature on the topic. We believe that this is important since the use of TH is rapidly increasing, and therefore, the possible side effects including SCFN and hypercalcemia may also become more prevalent. This prompts the need for awareness by treating physicians for this complication. PMID- 21284335 TI - Patient reports: Two novel frameshift mutations in the SOX9 gene in two patients with campomelic dysplasia who showed long-term survival. AB - Campomelic dysplasia (CD) is a rare and usually fatal congenital skeletal disorder with respiratory failure. The SOX9 gene has been cloned as a candidate gene for CD. Here, we report the cases of 2 Japanese patients with CD who have survived for over 5 years. Molecular investigations revealed novel frameshift mutations in SOX9 in these patients; a single G insertion in 1 allele at nucleotide 261 (261-262insG) and a single C insertion in 1 allele at nucleotide 888 (888-889insC). The predicted protein of 261-262insG may lack more than 80% composition of the normal SOX9 protein, including the SRY high mobility group (HMG) domain and the transactivation (TA) domain; the predicted protein of 888 889insC may not contain the normal TA domain. Although it has been reported that most patients with CD die during the neonatal period, our patients have survived for a long time, despite putative severely impaired SOX9 proteins. PMID- 21284336 TI - Leydig cell tumour revealed by bilateral gynecomastia in a 15-year-old adolescent: a patient report. AB - Pubertal gynecomastia is common, and may affect up to 70% adolescents boys. Its course is spontaneously benign with resolution occurring by age 18 years. Although the exact physio-pathological mechanism remains unknown, it is thought to result from hormonal imbalance between estrogens and testosterone at puberty. Association with Leydig cell tumour is more common in adults, so that scrotal ultrasound is part of routine work up. A 15-years-old boy with Leydig cell tumour revealed by bilateral gynecomastia is reported. Diagnosing this condition requires high level of suspicion, we suggest that clinicians always do a testicular examination on adolescents especially if they have gynecomastia, scrotal ultrasound may be performed in boys aged > or =14 years with gynecomastia that measures > or =4 cm, should there be any doubt. PMID- 21284337 TI - 21-hydroxylase autoantibody-negative Addison's disease in a 5-year-old boy with adrenal crisis and type 1 diabetes mellitus. AB - Patients with type 1 diabetes mellitus (T1DM) have an increased risk of other autoimmune disorders. The combination of Addison's disease with T1DM and/or autoimmune thyroid disease is known as autoimmune polyendocrinopathy type 2 (APS 2). 21-hydroxylase autoantibody (21OHAb) is considered as a valuable marker for identifying patients with autoimmune Addison's disease (AD); however, it is not available in some countries. Here we present a 5-year-old boy with newly diagnosed T1DM, who developed AD with adrenal crisis within only six months, and after 1-year treatment, the test of 21OHAb was negative. This was a rare and the first APS-2 case in Taiwan, because APS-2 affects female adults more often, but not boys. At diagnosis of T1DM, we suggest that checking diurnal cortisol and adrenocorticotropic hormone levels as a baseline evaluations, and if it is available, checking 21OHAb as well. If there is subtle evidence of AD, such as unexplained hypoglycemia or unreasonably reduced insulin requirements, adrenal functions must be studied as soon as possible, even in the 21OHAb-negative T1DM patients. Even if nothing is abnormal, the patient still needs an annual measurement. PMID- 21284338 TI - Neonatal diabetes due to neonatal hemochromatosis. PMID- 21284339 TI - Quercetin in combination with vitamins (C and E) improves oxidative stress and renal injury in cadmium intoxicated rats. AB - BACKGROUND AND OBJECTIVES: The aim of the present study was to determine if the combination therapy of quercetin along with vitamins (C and E) has any advantage over the cadmium (Cd) induced oxidative stress and renal injury in rats. They were analysed serum and urinary markers of renal damage (urea, uric acid, creatinine and creatinine clearance), renal oxidative stress indices (thio barbituric acid reactive substances: TBARS, lipid hydroperoxides (LOOH) and protein carbonyls (PC), renal non-enzymatic [reduced glutathione (GSH), total sulphydryl groups (TSH)], vitamin-C and vitamin-E, enzymatic [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), glutathione-s transferase, GST)], glutathione metabolizing enzymes [glutathione reductase (GR) and glucose-6-phosphate dehydrogenase, (G6PD)] and histological changes in kidney. RESULTS: Cd intoxication significantly (P > 0.05) increased the levels of serum nephritic markers (urea, uric acid, creatinine) and significantly (P > 0.05) reduced the urea, uric acid and creatinine in urine and serum creatinine clearance. It also significantly (P > 0.05) increased renal oxidative stress markers and significantly (P > 0.05) decreased renal non-enzymatic and enzymatic antioxidants status and severely increased the histo-pathological changes when compared to normal control rats. Cd intoxicated rats pre-treated with quercetin (QE) alone and QE along with vitamin-C (VC) and vitamin-E (VE) significantly ameliorated Cd induced anomalies in renal biochemical and histological indices. CONCLUSION: The ameliorative effect against Cd intoxication was much pronounced in rats treated with QE along with vitamins C and E. PMID- 21284340 TI - Piscicidal activity of leaf and bark extract of Thevetia peruviana plant and their biochemical stress response on fish metabolism. AB - OBJECTIVES: The leaf and bark of Thevetia peruviana (Family: Apocynaceae) plant was administered for 24 h to the freshwater fish Catla catla (Hamilton) to evaluate their piscicidal activity in laboratory and cemented pond condition. MATERIALS AND METHODS AND RESULTS: The LC0 values of lef and bark extracts of different solvents (i.e., acetone, diethyl ether, ethyl alcohol, chloroform and carbon tetrachloride) of this plant to fish Catla catla were determined. The LC50 values of acetone leaf extract of Thevetia peruviana plant is 88.80 mg/L (24h) in laboratory condition and 529.38 mg/L (24h) in cemented pond condition; acetone bark extract of this plant is 99.43 mg/L (24h) in laboratory condition and 591.78 mg/L (24h) in cemented pond condition against freshwater fish Catla catla. Similar trend was also observed in case of other solvent (i.e., diethyl ether, ethyl alcohol, chloroform and carbon tetrachloride) of leaf and bark extracts of Thevetia peruviana plant against freshwater fish Catla catla in laboratory and cemented pond conditions. The acetone leaf and bark extract of this plant was very effective in comparison to other solvent extract in both the conditions. So, the biochemical analysis is taken only acetone leaf and bark extract of Thevetia peruviana plant in laboratory condition. CONCLUSIONS: Exposure of sub-lethal doses (40% and 80% of LC,) of acetone leaf and bark extract of this plant over 24 h caused significant (P < 0.05) alterations in total protein, free amino acids, DNA & RNA, protease and acid and alkaline phosphatase activity in muscle, liver and gonadal tissues of fish Catla catla in laboratory condition. PMID- 21284341 TI - Larvicidal activity of some plant extracts to larvae of the mosquito Culex quinquefasciatus (Say 1823). AB - OBJECTIVES AND METHODS: Searching for potent plant larvicides, crude aqueous extract of the latex of Uschar (Calotropis procera) and Labakh (Ficus benghalensis) were tested against the fourth instar larvae of the lymphatic filariasis vector Culex quinquefasciatus (Diptera: Culicidae) using the conventional methods recommended by the WHO. Likewise, the toxicity level of Malathion was tested. The dose/response mortality relationship was statistically determined using double transformation regression analysis. The 24-hour LC50 of the test agents was taken as a measure of its acute toxicity. The 24-hour LC50 of Malathion to the larvae was 2.2693 mg/L. The most potent plant extract was the latex of Uschar which killed 50% of the larval population at a concentration of 0.0062% (V/V). RESULTS: The 24-hour LC50 of Labakh latex was 0.4796% (V/V). A range of concentration extending between 0.0195 and 10% (W/V) of the Labakh fruits (figs) produced more or less the same % of mortality (25%). CONCLUSION: Since the latex of the plants tested are hazardous to man and his animals, it is recommended that these extract must be used in bodies of water not accessible to man or animals such as pit latrines and septic tanks. PMID- 21284342 TI - Decreased renal mRNA expression of TRPM6 is associated with hypomagnesemia in C57BL/6 asthmatic mice. AB - BACKGROUND AND OBJECTIVES: Hypomagnesemia has been reported up to 40% in asthma patients, and a relationship between hypomagnesemia and asthma severity has been previously characterized. However, the mechanism for hypomagnesemia in asthma patients is not clear. Transient receptor potential melastatin 6 (TRPM6) is a newly identified channel that is involved in active epithelial magnesium transport, and downregulation of TRPM6 in the kidney was related to reduced Mg2+ reabsorption in mouse model. The aim of the study was to investigate whether plasma and erythrocyte magnesium levels were correlated with renal expression of TRPM6 mRNA in C57BL/6 asthmatic mice. MATERIALS AND METHODS: 48 healthy C57BL/6 mice were randomly divided into asthmatic group and control group with 24 mice in each group. Each group were randomly taken out 8 mice at 1d, 21d, 34d to detect plasma Mg2+, intracellular Mg2+ and renal TRPM6 mRNA expressions. RESULTS: There were no significant difference in plasma Mg2+, intracellular Mg2+ and TRPM6 mRNA expression of renal tissues between asthmatic group and control group at 1d. However, plasma Mg2+ and intracellular Mg2+ as well as TRPM6 mRNA of renal tissues in asthmatic group were significantly lower than that of control group at 21d and at 34d. Both plasma Mg2+ and intracellular Mg2+ were positively correlated with TRPM6 mRNA expression in the renal tissues. CONCLUSION: This study indicates that the consistently reduced expression of TRPM6 mRNA may play a role in the pathogenesis of hypomagnesemia in C57BL/6 asthmatic mice. PMID- 21284343 TI - A randomized double-blind clinical trial with two different doses of arginine enhanced enteral nutrition in postsurgical cancer patients. AB - OBJECTIVES: Patients with head and neck cancer undergoing surgery have a high incidence of postoperative complications. The aim of our study was to investigate whether postoperative nutrition of head and neck cancer patients, using an enteral high dose of arginine (20 g per day) vs a medium dose (12.3 g per day) could improve nutritional variables as well as clinical outcome. MATERIAL AND METHODS: A population of 115 patients with oral and laryngeal cancer was enrolled. At surgery patients were randomly allocated to two groups: group I (58 patients) received an enteral diet supplements with a high dose of arginine (20 g per day) and group II (57 patients) received an isocaloric, isonitrogenous enteral formula with a medium dose of arginine (12.3 g per day). RESULTS: Gastrointestinal tolerance (diarrhea) of both formulas was good (3.44% group I and 3.51% group II: ns). The postoperative infections complications were similar in both groups (8.6% group I and 12.2% group II: ns). Fistula was less frequent in enriched nutrition group (3.4% group I and 10.5% group II: p = 0.006). The length of postoperative stay was similar in both groups (27.2 +/- 17.8 days in group I vs 25.7 +/- 18.8 days in group II: ns). CONCLUSIONS: Enriched arginine formula improves fistula wound complications in postoperative head and neck cancer patients. Our results suggest that these patients could benefit from a high dose of arginine enhanced enteral formula. PMID- 21284344 TI - Androgen insensitivity syndrome (or Morris syndrome) and other associated pathologies. AB - BACKGROUND: The androgen insensitivity syndrome (AIS) is a disease connected with the inactivation of AR due to a mutation that inactivate male sexual differentiation, and causes a spectrum of phenotypic anomalies having as a common aspect the loss of reproductive characteristics. PATIENTS: In this paper the clinical, endocrinological and molecular features of three patients are reported. The first case concerns a 17 years old patient, the second an infant suffering from inguinal hernia that has been surgically corrected when he was 3 months old and finally the third case concerns a 57 years old woman. RESULTS: All the subjects had a common primary amenorrhea and a following pelvic echography highlighted the absence of internal genital organs and the presence of a dead-end vagina. All the patients are characterized by a normal male karyotype and present on the short arm of the Y chromosome the SRY gene. Moreover, FISH revealed the presence of androgen receptor gene on the X chromosome and the SRY gene on the Y one. The automatic sequencing of the genes for the androgen receptor (AR) shows that each subject has a mutation in the gene for the androgen receptor (AR). These mutations are associated with complete androgen insensivity syndrome (CAIS). All the cases of study exhibited a negative family history for CAIS. CONCLUSION: This study confirms the need to perform a pelvic examination by means of echography in pre-pubertal and pubertal age to highlight the normality of the internal genitalia (uterus and ovaries). If a primary amenorrhea is checked, the karyotyping is compulsory. If a Morris's syndrome is suspected, it is of critical importance to find the rudimentary male gonads (by means of MRI, pelvic echography, laparoscopy) and surgically remove them to prevent the onset of malignancies (teratoblastoma, gonadoblastoma). Once the considered disease has been identified, a continuous psychological help can be considered useful for the patient and the family. PMID- 21284345 TI - Oxidative stress and enzymatic antioxidant status in rheumatoid arthritis: a case control study. AB - BACKGROUND AND OBJECTIVES: Rheumatoid arthritis (RA) is a chronic multisystem disease of unknown cause. Formation of reactive oxygen species and lipid peroxides as a result of disease activity may play an important role. Oxidative stress and decreased antioxidant status are the hallmarks in patients of RA as observed in recent years. The objectives of the study was to determine oxidative stress by measuring malondialdehyde and enzymatic antioxidant status by estimating superoxide dismutase and glutathione reductase in patients of RA and then comparing with healthy individuals. MATERIALS AND METHODS: The present study comprises of 40 RA cases who were clinically diagnosed and confirmed by laboratory tests, attending KLE Society's Dr. Prabhakar Kore Hospital and Research Centre, Belgaum. Southern India attached to J. N. Medical College. between September 2007 to August 2008. All the patients were in the age group of 40-60 years including both the sexes. Biochemical parameters like malondialdehyde, enzymatic antioxidants like superoxide dismutase and glutathione reductase were estimated in cases (40) and controls (40). RESULTS: The mean level of blood malondialdehyde (in nmol/ml) in controls was 6.19 +/- 0.96 and 11.48 +/- 0.76 in cases. The mean level of superoxide dismutase (IU/g of Hb) in controls was 948.32 +/- 99.88 and 443.68 +/- 111.69 in the cases. The mean glutathione reductase level (in IU/g of Hb) in controls was 8.91 +/- 1.04 and 2.96 +/- 0.79 in the cases. CONCLUSIONS: This study revealed that there was an increased oxidative stress and a decreased antioxidant defense in patients with rheumatoid arthritis. PMID- 21284346 TI - Cardiac resynchronization therapy: could a numerical simulator be a useful tool in order to predict the response of the biventricular pacemaker synchronization? AB - BACKGROUND AND OBJECTIVES: Cardiac resynchronization therapy (CRT) can be considered as an established therapy for patients with moderate or severe heart failure (HF), depressed systolic function and a wide QRS complex. Biventricular stimulation through the CRT is applied at patients with an intra and/or inter ventricular conduction delay. The goal of this technique is to resynchronize contraction between and within ventricles. A numerical model of the cardiovascular system, together with the numerical model of the biventricular pacemaker (BPM), can be an useful tool to study the better synchronization of the BPM in order to reduce the inter-ventricular and/or intra-ventricular conduction delay. SUBJECTS AND METHODS: Within a group of patients which were representative of the most common disease etiologies of heart failure, seven patients, affected by dilated cardiomyopathy undergoing CRT with BPM, were studied and simulated using the numerical model of the cardiovascular system CARDIOSIM. The patients were submitted to echocardiographic evaluation (with pulsate Doppler and tissue Doppler imaging) and electrocardiography evaluation in order to evaluate intra ventricular and/or inter-ventricular dyssynchrony. These evaluations were made three times: the first one before BPM implantation, the second and the third one respectively within seven days and six months after BPM implantation. Also haemodynamic parameters were measured. Using the software simulator, the pathological conditions before CRT, within seven days and within six months since CRT were reproduced for each patients in order to evaluate the following haemodynamic parameters: the end-systolic and end-diastolic left ventricular volume, the systolic pulmonary arterial pressure, the systolic, diastolic and mean aortic blood pressure and the ejection fraction. Also the trend of the left ventricular elastance was studied for each patient in order to evaluate the benefits produced by the CRT. RESULTS: The results obtained by means the numerical simulator were in good agreement with clinical data measured on the patients. For each patient also the evolution of the left ventricular elastance was in accordance with the literature data. CONCLUSION: The cardiovascular numerical model seems to be a useful tool to study the synchronization of the BPM in order to reduce the inter-ventricular and/or intra-ventricular conduction delay and to reproduce the condition of a patient. PMID- 21284347 TI - Efficacy and safety of bowel cleansing solutions for colonoscopy: a prospective observational study. AB - BACKGROUND: The most critical factor determining the quality of colonoscopy results is the extent of bowel cleansing. AIM: This observational post-marketing study evaluated the efficacy, acceptability and safety of a range of the most commonly used bowel cleansing solutions in routine clinical practice. PATIENTS: Patients undergoing diagnostic, preventive or follow-up colonoscopy were recruited from 7 centres in Italy, Spain and Greece. METHODS: Quality of bowel preparation was assessed on a 5-point scale and included evaluation of visible bowel surface area and the amount and consistency of residual fluid. Patients evaluated ease of use and palatability. RESULTS: A total of 437 patients took part. Klean-Prep, the most commonly used preparation in this evaluation, achieved the highest score for quality of bowel cleansing and was rated as good or excellent in 72.0% of patients. In dosage-compliant patients, Klean-Prep showed better results in comparison to Fleet Phosphosoda (p < 0.05) in the maximum bowel level reached in the intestine during colonoscopy examinations. All of the bowel cleansing solutions were well tolerated. CONCLUSION: The polyethylene glycol based preparations provided the most adequate cleansing and, of these, Klean-Prep provided the highest "good" or "excellent" level of bowel preparation. PMID- 21284348 TI - Rhinocerebral mucormycosis: an update. AB - BACKGROUND AND OBJECTIVES: Mucormycoses are a group of invasive infections caused by filamentous fungi of the Mucoraceae family, with the rhinocerebral form of the disease being the most common in large case series. In the present paper we review the characteristics of the rhinocerebral form of the disease. EVIDENCE AND INFORMATION SOURCES: The present review is based on the analysis of the current literature on rhinocerebral mucormycosis. STATE OF THE ART: Rhinocerebral mucormycosis is associated with immunocompromised patient state, haemochromatosis, desferrioxamine therapy and prolonged corticosteroid therapy. Uncontrolled diabetes and increased serum iron are regarded as the two leading predisposing factors for the development of the disease. Currently, treatment for the disease is based on three main principles; rapid reversal of underlying predisposing factors, antifungal therapy with amphotericin B and timely surgical intervention. PERSPECTIVES: Antifungal drugs of the azole group and new iron chelating agents--deferasirox, deferiprone--have been supported as alternative options to amphotericin B or as salvage therapy. CONCLUSIONS: Rhinocerebral mucormycosis requires a high level of awareness if early diagnosis and treatment is to be achieved. Large scale evaluation of arising treatment options is a mandatory course of action in the future research of the disease. PMID- 21284349 TI - Rare malignant tumors of the scalp: a report of four cases, their treatment and a review of the literature. AB - BACKGROUND AND OBJECTIVES: Malignant tumors occurring in the scalp are not common and when asymptomatic or small in size, may be covered by hair and neglected by the patient, leading to a potential risk of delay in detection and resulting in poorer outcomes. MATERIALS AND METHODS: In our Departments in the last five years more than 200 malignant tumors of the scalp have been operated on. In this article we take into consideration four rare malignant tumours of the scalp taken from this study: a giant recurrent sebaceous carcinoma, a lung cancer metastatic lesion, a malignant melanoma and a breast cancer metastasis. RESULTS: The four patients with rare malignant tumours have been operated with good results. DISCUSSION: These four cases represent an important lesson for the plastic surgeon to learn: in the case of the presence of unusual, ulcerated/pigmented lesion of the scalp or in the case of alopecia we must consider the possibility of a tumour. PMID- 21284350 TI - First characterization of bla(VIM-11) cassette-containing integron in metallo beta-lactamase producing Pseudomonas aeruginosa in Malaysia. PMID- 21284351 TI - Improving outcomes in early-stage breast cancer. AB - Early-stage breast cancer is a prevalent malignancy that continues to cause a significant number of cancer-related deaths each year. Current evidence points to suboptimal care in patients with early-stage breast cancer, especially with regard to physician use of guideline-recommended care. Such appropriate treatment regimens as breast-conserving therapy and adjuvant therapy (including radiation therapy, chemotherapy, and hormonal therapy) are underutilized in this patient population. Critical steps toward optimizing the appropriate treatment of early stage breast cancer and providing the most significant benefits for patients include increasing awareness of potential barriers and developing strategies to overcome them. Improved communication, increased proactive behavior in terms of emerging data, and promotion of clinical trial participation may additionally improve outcomes in this patient population. This review incorporates pertinent oncology literature in a comprehensive overview of early-stage breast cancer treatment, including a review of existing guidelines, race and age disparities, and communication strategies for oncologists. The focus is on appropriate, evidence-based treatment of this patient population. PMID- 21284352 TI - It's official...but not infallible. PMID- 21284353 TI - Icatibant. Attacks of hereditary angioedema: continue to use C1 esterase inhibitor. AB - Hereditary angioedema is a severe genetic disorder due to C1 esterase inhibitor deficiency, which leads to an excess of bradykinin. It is characterised by attacks of subcutaneous or mucosal oedema, which can carry a risk of asphyxiation if the larynx is involved. The first-choice symptomatic treatment for attacks is intravenous C1 esterase inhibitor administration. Tranexamic acid is sometimes used. Icatibant, a decapeptide bradykinin B2 receptor antagonist, is now authorised in the European Union for use in this situation. We found no trials comparing icatibant versus C1 esterase inhibitor. The two principal clinical trials were both comparative trials, one versus tranexamic acid (74 patients), and the other versus placebo (56 patients). No mortality data were reported in either trial. Icatibant seemed to be more effective than tranexamic acid in relieving symptoms and also yielded a higher response rate. However, these positive results were not confirmed in the placebo-controlled trial. Both trials suffer from several biases, ruling out firm conclusions on the efficacy of icatibant, the trials were underpowered, some criteria were difficult to measure, the blinding was incomplete, and tranexamic acid was given at a lower dose than that recommended. The main adverse effects of icatibant are reactions at the injection site, which occur in almost all patients. A potential risk of cardiac disorders (especially angina) needs to be investigated. Subcutaneous administration of icatibant requires a large volume of solution (3 ml). In practice, in the absence of head-to-head comparisons, it remains to be shown whether or not icatibant has a better risk-benefit balance than C1 esterase inhibitor. Due to inconsistencies between the results and numerous biases in the two main clinical trials, the evidence supporting the efficacy of icatibant is weak. C1 esterase inhibitor remains the first-choice treatment for patients with acute attacks of hereditary angioedema. PMID- 21284354 TI - First-line raltegravir. No evidence of comparative effectiveness. AB - First-line treatment for HIV infection consists of a combination of antiretroviral drugs, specifically including a non-nucleoside reverse transcriptase inhibitor or an HIV protease inhibitor, usually boosted with ritonavir. Raltegravir, the only commercially available HIV integrase inhibitor, marketed since 2007 in the European Union, was initially reserved for patients with multiple treatment failure. It is now authorised for first-line use. Clinical evaluation of first-line raltegravir therapy is based on a comparative double-blind "non-inferiority" trial comparing raltegravir + tenofovir + emtricitabine versus efavirenz + tenofovir + emtricitabine in 566 patients. After 48 weeks, about 84% of the patients in the two arms had undetectable viral load. There are no trials versus other first-line combinations. The adverse effect profile of raltegravir is poorly documented. In the trial comparing raltegravir + tenofovir + emtricitabine with efavirenz + tenofovir+ emtricitabine, adverse effects of the two regimens were generally comparable. In practice, given the lack of firm evidence that raltegravir is a therapeutic improvement over existing first-line regimens, it is better to continue to reserve its use for patients with multiple treatment failure. Many satisfactory first-line combinations have been in use for several years. PMID- 21284355 TI - INN common stem: -azoline. PMID- 21284356 TI - Fentanyl intranasal. Breakthrough cancer pain: unsafe packaging. AB - There is no firm evidence that intranasal fentanyl is more effective than buccal fentanyl. The packaging is not entirely safe, thus exposing patients and others to major risks. PMID- 21284357 TI - Maraviroc first-line therapy for HIV infection. Too risky. AB - First-line treatment for HIV infection currently comprises a combination of antiretroviral drugs, including a non-nucleoside reverse transcriptase inhibitor such as efavirenz, or one or two protease inhibitors.The choice is based on the results of initial clinical trials of antiretroviral drugs with morbidity and mortality endpoints, and, since the 1990s, on trials with surrogate markers (viral load and the CD4+ T lymphocyte count). Maraviroc is the only CCR5 antagonist currently on the market. Drugs belonging to this class are designed to prevent HIV entry into CD4 T lymphocytes. Maraviroc is reserved for patients with multiple treatment failure, but has also been proposed for first-line treatment. Clinical evaluation of maraviroc in first-line treatment is limited to a single comparative trial designed to show the virological and immunological "non inferiority" of the maraviroc + zidovudine + lamivudine combination versus efavirenz + zidovudine + lamivudine, after 96 weeks of treatment, in 721 patients with CCR5-tropic HIV strains. A more sensitive version of the test used to determine CCR5 tropism became available during the trial, leading to the exclusion of 107 patients who were infected by strains capable of using other coreceptors. This trial fails to answer important questions regarding the adverse effects of maraviroc, such as hepatotoxicity, infections, cancer, and cardiovascular disorders. Tests used to identify exclusively CCR5-tropic HIV strains are difficult to implement and their results are unreliable. This means that some patients in whom maraviroc will not be effective may receive this drug, and will thus be at risk of developing viral resistance to other drugs in their antiretroviral regimen. In practice, first-line use of maraviroc is imprudent, as it depends on a test of uncertain reliability. Furthermore, there is no evidence to suggest that maraviroc combination therapy has a better risk-benefit balance than regimens with well-documented and long established efficacy. PMID- 21284358 TI - Immunoallergic adverse effects of fluindione. AB - Bleeding is the main adverse effect of all vitamin K antagonists. Fluindione, an indanedione derivative, can also have serious immunoallergic adverse effects. Several hypersensitivity reactions affecting various organ systems have been reported in detail in patients taking fluindione, mainly cutaneous, hepatic or renal disorders, often associated with fever. Cases of isolated kidney and liver damage have also been reported. Fluindione has been linked to cases of acute generalised exanthematic pustulosis. An immunoallergic mechanism is suspected, based on several factors, including the involvement of several organs, the types of damage, the chronological sequence of events, outcome after fluindione withdrawal, and cases of positive rechallenge. About a hundred reports of non haemorrhagic adverse effects attributed to fluindione were recorded in the French pharmacovigilance database during the course of a single year (July 2008 to June 2009). In practice, when anticoagulant therapy with a vitamin K antagonist is needed, it is better to use warfarin, the best-assessed oral anticoagulant. If fluindione is nonetheless prescribed, the patient must not only be taught how to manage vitamin K antagonist therapy but also how to recognise signs of hypersensitivity. PMID- 21284359 TI - Painful chronic ulceration linked with nicorandil: the vagina too. AB - Nicorandil is an antiangina drug with minor efficacy, which is known to cause painful ulceration of the gastrointestinal tract (from mouth to anus), and possibly the cornea. According to one detailed case report, a large, very painful, chronic vaginal ulceration only healed after permanent discontinuation of nicorandil. Prior to that, it had led to the patient undergoing hysterectomy and vaginal wall surgery that were ineffective. In practice, we must stop exposing patients unnecessarily to nicorandil. PMID- 21284360 TI - Aspirin and primary cardiovascular prevention. Uncertain balance between benefits and risks. AB - Most individuals with no pre-existing cardiovascular disease have a low risk of experiencing arterial thrombosis. Using the standard Prescrire methodology, we reviewed the literature on the risk-benefit balance of aspirin in the primary prevention of cardiovascular events. In the general population, a meta-analysis in 95 456 persons suggests that aspirin has no effect on either total or cardiovascular mortality. Aspirin may slightly reduce the risk of stroke in women and myocardial infarction in men, but it increases the risk of bleeding. It is unclear whether the benefits outweigh the risks. Aspirin does not reduce mortality in the elderly. in one trial, aspirin reduced the risk of ischaemic stroke and myocardial infarction in women aged 65 and over. However, the risk of cerebral haemorrhage associated with aspirin increases with age. Therefore, the risk-benefit balance of aspirin in primary cardiovascular prevention in the elderly is uncertain. Aspirin is more beneficial in patients with cardiovascular risk factors, but the bleeding risk is sometimes higher too. In clinical trials, aspirin did not reduce either total or cardiovascular mortality in hypertensive or diabetic patients. In contrast, it reduced the risk of myocardial infarction in hypertensive patients and diabetic men. Aspirin did not prevent cardiovascular events in smokers, and has not been assessed in patients with hypercholesterolaemia. In practice, the risks outweigh the benefits when aspirin is used to prevent a first thrombotic event in people at low risk. When the cardiovascular risk is higher than in the general population, for example in patients with risk factors, the weak preventive effects of aspirin on myocardial infarction and ischaemic stroke may outweigh the small extra risk of bleeding. The possible value of aspirin for cardiovascular prevention should be discussed with each individual patient. In general, it is preferable to recommend measures with a proven impact on mortality, such as dietary changes, smoking cessation, or drug therapy for patients with risk factors. PMID- 21284361 TI - Buruli ulcer. A disabling infection. AB - Buruli ulcers result from an initial skin infection that often leads to extensive tissue necrosis. The causative agent is Mycobacterium ulcerans, a bacterium prevalent in humid, rural tropical areas. Several thousand people are infected each year, especially in Africa, where Buruli ulcers are a source of major disability. A combination of oral rifampicin and injectable streptomycin is effective. Surgical treatment and functional rehabilitation are often necessary. Diagnostic tests suitable for use in primary care settings are needed, along with well-tolerated, effective oral treatments. PMID- 21284362 TI - Confusing French guidelines on the management of agitation in confused elderly patients. PMID- 21284363 TI - Stable angina: role of ivabradine unchanged between 2006 and 2010. PMID- 21284364 TI - Ulipristal and postcoital contraception. PMID- 21284365 TI - In vivo measurement of humeral elevation angles and exposure using a triaxial accelerometer. AB - OBJECTIVE: The aim of this study was to measure the capability of a triaxial accelerometer (Virtual Corset) to collect humeral elevation angles and exposure parameters in a simulated occupational environment. BACKGROUND: There is a need for an economical ambulatory device to estimate elevation angles and exposure parameters in occupational groups. METHOD: A magnetic tracking device was used to assess the ability of the Virtual Corset to evaluate humeral elevation angles and identify exposure parameters with in vivo dynamic conditions for 16 female dental hygienists. RESULTS: Significant differences were found for the reaching task with the Virtual Corset, underestimating the means of the average humeral elevation angle by 10 degrees and the means for the range of the humeral elevation by 4 degrees. Furthermore, significant differences were found for the exposure parameters with the Virtual Corset, overestimating the jerk by 4% and underestimating the percentage time above 40 degrees and 60 degrees by 9% and 4%, respectively. However, the Virtual Corset was able to identify similar kinematics patterns and exposure data when compared with a magnetic tracking device. CONCLUSION: The outcomes of the study suggest that the Virtual Corset may be useful for data collection during a dental hygienist workday. Professions that have similar patterns of angular velocity and acceleration and humeral range of elevation as the dental hygienist flossing technique may benefit from the use of the Virtual Corset. APPLICATION: This study provides evidence that the Virtual Corset can be used to reconstruct humeral elevation angles and identify exposure parameters in some tasks of dental hygienists. PMID- 21284366 TI - Understanding negative impacts of perceived cognitive load on job learning effectiveness: a social capital solution. AB - OBJECTIVE: This study proposes a model explaining how social capital helps ease excessively required mental effort. BACKGROUND: Although organizational researchers have studied both social capital and cognitive load, no prior research has critically examined the role of social capital in improving individuals' mental load and effort and consequently enhancing job learning effectiveness. METHOD: This study surveys participants made up of professionals in Taiwan's information technology industry. It measures the constructs with the use of 5-point Likert-type scale items modified from existing literature. The survey data were analyzed with the use of structural equation modeling. RESULTS: Job learning effectiveness is negatively influenced by role ambiguity and role conflict. Time pressure has a positive influence on role ambiguity and role conflict Although the relationship between task complexity and role ambiguity is insignificant, task complexity has a positive influence on role conflict. Because the relationship between network ties and role conflict is insignificant, trust has a negative influence on role conflict. Last, shared vision has a negative influence on role ambiguity. CONCLUSION: This study provides an example of how social capital can be applied as a useful remedy to ease the negative impact of perceived cognitive load on job learning effectiveness. APPLICATION: The negative relationship between shared vision and role ambiguity suggests that a shared vision helps in disseminating organizationally common goals and directions among employees to alleviate individuals' mental efforts in dealing with the ambiguity of their job roles. A firm's management team should take actions to decrease role conflict by strengthening trust among employees. PMID- 21284367 TI - Comparison of anthropometry of U.S. electric utility field-workers with North American general populations. AB - OBJECTIVE: The primary purpose of this study was to determine whether conventional anthropometric databases of the U.S. general population are applicable to the population of U.S. electric utility field-workers. BACKGROUND: On the basis of anecdotal observations, field-workers for electric power utilities were thought to be generally taller and larger than the general population. However, there were no anthropometric data available on this population, and it was not known whether the conventional anthropometric databases could be used to design for this population. METHOD: For this study, 3 standing and II sitting anthropometric measurements were taken from 187 male field-workers from three electric power utilities located in the upper Midwest of the United States and Southern California. The mean and percentile anthropometric data from field-workers were compared with seven well-known conventional anthropometric databases for North American males (United States, Canada, and Mexico). RESULTS: In general, the male field-workers were taller and heavier than the people in the reference databases for U.S. males. The field-workers were up to 2.3 cm taller and 10 kg to 18 kg heavier than the averages of the reference databases. CONCLUSION: This study was justified, as it showed that the conventional anthropometric databases of the general population underestimated the size of electric utility field-workers, particularly with respect to weight. APPLICATION: When designing vehicles and tools for electric utility field workers, designers and ergonomists should consider the population being designed for and the data from this study to maximize safety, minimize risk of injuries, and optimize performance. PMID- 21284368 TI - The role of working memory in supporting drivers' situation awareness for surrounding traffic. AB - OBJECTIVE: To link working memory to driver situational awareness (SA) for surrounding traffic. BACKGROUND: Operating a motor vehicle is a complex activity that requires drivers to maintain a high level of SA. Working memory has been conceptually linked to SA; however, the roles of working memory subsystems in supporting driver SA is unclear. METHOD: Participants drove a simulated vehicle and monitored surrounding traffic while concurrently performing either visuospatial- or phonological-load tasks. Drivers' SA was indexed as the ability to recall the positions of the surrounding traffic relative to their own vehicle at the end of each trial. RESULTS: In Experiment I, a visuospatial task interfered with drivers' ability to recall the positions of traffic located in front of their vehicle. In contrast, a phonological task interfered with drivers' ability to recall the positions of traffic located behind their vehicle. Experiment 2 confirmed and extended the findings of Experiment I with the use of different visuospatial- and phonological-load tasks. CONCLUSION: Visuospatial and phonological codes play a role in supporting driver SA for traffic located in the forward view and the rear view, respectively. APPLICATION: Drivers' SA for surrounding vehicles is disrupted by concurrent performance on secondary tasks. The development and implementation of new in-cabin communication, navigation, and informational technologies needs to be done with the knowledge that components of drivers' working memory capacity may be exceeded, thereby compromising driving safety. PMID- 21284369 TI - Common peroneal and tibial nerve paralysis secondary to herpes zoster infection: a case report. AB - BACKGROUND: The usual presentation of herpes zoster (HZ) is a self-limiting vesicular rash, often accompanied by post-herpetic neuralgia. However, HZ can give rise to other complications, that have unusual presentations and serious sequelae like segmental motor paralysis of the limbs that is a relatively rare complication. CASE: A 68-year-old man presented with foot drop on the right side had a history of HZ infection on and around the knee and the popliteal fossa. He was treated with acyclovir by a dermatologist and 10 days after the inital symptoms he developed weakness on the right ankle and on the muscles distal to the knee. In a few days foot drop has developed and he was unable to walk without help. Three months later he was admitted to the neurology out patient clinic. On his electrophysiological examination common peroneal nerve could not be stimulated on the right side. The distal latency of the tibial nerve has prolonged, CMAP amplitude has diminished and the nerve conduction velocity has slowed down. Latency of the sural nerve has prolonged with a small SNAP amplitude and a slow nerve conduction velocity on the right side. Electromyography revealed denervation on the muscles inervated by tibialis anterior and common peroneal nerves distal to the knee. CONCLUSION: The double mononeuropathy of the tibial and common peroneal nerves secondary to HZ was not found in the published data. HZ should be considered as a possible cause of the paralysis of peripheral nerves and more attention should be paid to it. PMID- 21284370 TI - Influence of gender on the EMG signal of the quadriceps femoris muscles and performance in high-intensity short-term exercise. AB - The aim of this study was to investigate the influence of gender on the EMG signal of the muscles of the quadriceps femoris and the physical performance in high-intensity, short-term exercise. Fourteen volunteers (7 men = 29.1 +/- 2.8 years and 7 women = 22.6 +/- 2.9 years) performed a Wingate Test (WT) with a load of 7.5% of body mass. The variables analyzed during the WT were the Relative Peak Power (W.Kg(-1)) (RPP), Relative Mean Power (W.Kg(-1)) (RMP), Fatigue Index (%) (FI) and Peak Power Instant (s) (PPI). EMG signals of the superficial muscles of the quadriceps femoris (QF) from the right leg: rectus femoris (RF), vastus lateralis (VL) and vastus medialis (VM) were analyzed through root mean square (RMS) values and the normalized median frequency (MNF) determined using the Fast Fourier Transform (FFT). The RPP and the RMP were significantly higher in men when compared to women (9.99 +/- 0.96 vs. 7.66 +/- 1.00 W.kg(-1); 7.23 +/- 0.49 vs. 5.65 +/- 0.61 W.kg(1), P < 0.05; respectively). No significant difference between genders was found on RMS and NMF during WT (P > 0.05). Although RPP and RMP were influenced by gender, the RMS and the NMF of the superficial muscles of the QF did not show the same behavior, suggesting that other mechanisms, not related to motor unit recruitment and speed of nervous stimuli in the muscle fiber may be associated to the lower performance of women in high-intensity, short-term exercise. PMID- 21284371 TI - Activity and asymmetry index of masticatory muscles in women with and without dysfunction temporomandibular. AB - PURPOSE: [corrected] Compare the symmetry of the activity and masticatory muscles in individuals with TMD and asymptomatic. METHODS: The study included 50 women, while 31 had temporomandibular disorders (TMD) and 19 were asymptomatic (control group), aged between 19 and 40 years. The volunteers were subjected to clinical examination of the diagnostic criteria in research with TMD (RDC/TMD) with the aim of diagnosing volunteers with or without TMD, and evaluate the electromyographic activity of the right temporalis muscle (TR) and left (TL), right masseter (MR) and left (ML), in situations of rest, isometric contraction of the muscles of the jaw elevators. We obtained the rates of activity and asymmetry in each situation and for the collection and TMD control groups. RESULTS: For the index of activity for the rest there was significant difference (p = 0.0008) between the control group and the TMD group, with predominance of temporal muscle, was not observed difference between groups for the index of activity during the isometric contraction (p = 0.1069). For the index of asymmetry no difference between groups during rest, for the masseter muscles (p = 0.4182) and the temporal (p = 0.7614), and also during the isometry for both masseter muscles (p = 0.8691) and for time (p = 0.6643). CONCLUSIONS: The control group showed prevalence of TMD and temporal muscle during rest, which did not occur in the isometry, and no difference for the index of asymmetry between the groups for the masseter and temporal muscles. PMID- 21284372 TI - Scientific basis for learning transfer from movements to urinary bladder functions for bladder repair in human patients with CNS injury. AB - Coordination Dynamics Therapy (CDT) has been shown to be able to partly repair CNS injury. The repair is based on a movement-based re-learning theory which requires at least three levels of description: the movement or pattern (and anamnesis) level, the collective variable level, and the neuron level. Upon CDT not only the actually performed movement pattern itself is repaired, but the entire dynamics of CNS organization is improved, which is the theoretical basis for (re-) learning transfer. The transfer of learning for repair from jumping on springboard and exercising on a special CDT and recording device to urinary bladder functions is investigated at the neuron level. At the movement or pattern level, the improvement of central nervous system (CNS) functioning in human patients can be seen (or partly measured) by the improvement of the performance of the pattern. At the collective variable level, coordination tendencies can be measured by the so-called 'coordination dynamics' before, during and after treatment. At the neuron level, re-learning can additionally be assessed by surface electromyography (sEMG) as alterations of single motor unit firings and motor programs. But to express the ongoing interaction between the numerous neural, muscular, and metabolic elements involved in perception and action, it is relevant to inquire how the individual afferent and efferent neurons adjust their phase and frequency coordination to other neurons to satisfy learning task requirements. With the single-nerve fibre action potential recording method it was possible to measure that distributed single neurons communicate by phase and frequency coordination. It is shown that this timed firing of neurons is getting impaired upon injury and has to be improved by learning The stability of phase and frequency coordination among afferent and efferent neuron firings can be related to pattern stability. The stability of phase and frequency coordination at the neuron level can therefore be assessed integratively at the (non-invasive) collective variable level by the arrhythmicity of turning (coordination dynamics) when a patient is exercising on a special CDT device. Upon jumping on springboard and exercising on the special CDT device, the intertwined neuronal networks, subserving movements (somatic) and urinary bladder functions (autonomic and somatic) in the sacral spinal cord, are synchronously activated and entrained to give rise to learning transfer from movements to bladder functions. Jumping on springboard and other movements primarily repair the pattern dynamics, whereas the exactly coordinated performed movements, performed on the special CDT device for turning, primarily improve the preciseness of the timed firing of neurons. The synchronous learning of perceptuomotor and perceptuobladder functioning from a dynamical perspective (giving rise to learning transfer) can be understood at the neuron level. Especially the activated phase and frequency coordination upon natural stimulation under physiologic and pathophysiologic conditions among a and gamma-motoneurons, muscle spindle afferents, touch and pain afferents, and urinary bladder stretch and tension receptor afferents in the human sacral spinal cord make understandable that somatic and parasympathetic functions are integrated in their functioning and give rise to learning transfer from movements to bladder functions. The power of this human treatment research project lies in the unit of theory, diagnostic/measurement, and praxis, namely that CNS injury can partly be repaired, including urinary bladder functions, and the repair can partly be understood even at the neuron level of description in human. PMID- 21284374 TI - TiO(2)/LiCl-based nanostructured thin film for humidity sensor applications. AB - A simple and straightforward method of depositing nanostructured thin films, based on LiCl-doped TiO(2), on glass and LiNbO(3) sensor substrates is demonstrated. A spin-coating technique is employed to transfer a polymer-assisted precursor solution onto substrate surfaces, followed by annealing at 520 degrees C to remove organic components and drive nanostructure formation. The sensor material obtained consists of coin-shaped nanoparticles several hundred nanometers in diameter and less than 50 nm thick. The average thickness of the film was estimated by atomic force microscopy (AFM) to be 140 nm. Humidity sensing properties of the nanostructured material and sensor response times were studied using conductometric and surface acoustic wave (SAW) sensor techniques, revealing reversible signals with good reproducibility and fast response times of about 0.75 s. The applicability of this nanostructured film for construction of rapid humidity sensors was demonstrated. Compared with known complex and expensive methods of synthesizing sophisticated nanostructures for sensor applications, such as physical vapor deposition (PVD) and chemical vapor deposition (CVD), this work presents a relatively simple and inexpensive technique to produce SAW humidity sensor devices with competitive performance characteristics. PMID- 21284373 TI - Nucleotide composition-linked divergence of vertebrate core promoter architecture. AB - Transcription initiation involves the recruitment of basal transcription factors to the core promoter. A variety of core promoter elements exists; however for most of these motifs, the distribution across species is unknown. Here we report on the comparison of human and amphibian promoter sequences. We have used oligo capping in combination with deep sequencing to determine transcription start sites in Xenopus tropicalis. To systematically predict regulatory elements, we have developed a de novo motif finding pipeline using an ensemble of computational tools. A comprehensive comparison of human and amphibian promoter sequences revealed both similarities and differences in core promoter architecture. Some of the differences stem from a highly divergent nucleotide composition of Xenopus and human promoters. Whereas the distribution of some core promoter motifs is conserved independently of species-specific nucleotide bias, the frequency of another class of motifs correlates with the single nucleotide frequencies. This class includes the well-known TATA box and SP1 motifs, which are more abundant in Xenopus and human promoters, respectively. While these motifs are enriched above the local nucleotide background in both organisms, their frequency varies in step with this background. These differences are likely adaptive as these motifs can recruit TFIID to either CpG island or sharply initiating promoters. Our results highlight both the conserved and diverged aspects of vertebrate transcription, most notably showing co-opted motif usage to recruit the transcriptional machinery to promoters with diverging nucleotide composition. This shows how sweeping changes in nucleotide composition are compatible with highly conserved mechanisms of transcription initiation. PMID- 21284375 TI - Dressing plasmons in particle-in-cavity architectures. AB - Placing metallic nanoparticles inside cavities, rather than in dimers, greatly improves their plasmonic response. Such particle-in-cavity (PIC) hybrid architectures are shown to produce extremely strong field enhancement at the particle-cavity junctions, arising from the cascaded focusing of large optical cross sections into small gaps. These simply constructed PIC structures produce the strongest field enhancement for coupled nanoparticles, up to 90% stronger than for a dimer. The coupling is found to follow a universal power law with particle-surface separation, both for field enhancements and resonant wavelength shifts. Significantly enhanced Raman signals are experimentally observed for molecules adsorbed in such PIC structures, in quantitive agreement with theoretical calculations. PIC architectures may have important implications in many applications, such as reliable single molecule sensing and light harvesting in plasmonic photovoltaic devices. PMID- 21284376 TI - Study on the transesterification of methyl aryl phosphorothioates in methanol promoted by Cd(II), Mn(II), and a synthetic Pd(II) complex. AB - Methanol solutions containing Cd(II), Mn(II), and a palladacycle, (dimethanol bis(N,N-dimethylbenzylamine-2C,N)palladium(II) (3), are shown to promote the methanolytic transesterification of O-methyl O-4-nitrophenyl phosphorothioate (2b) at 25 degrees C with impressive rate accelerations of 10(6)-10(11) over the background methoxide promoted reaction. A detailed mechanistic investigation of the methanolytic cleavage of 2a-d having various leaving group aryl substitutions, and particularly the 4-nitrophenyl derivative (2b), catalyzed by Pd-complex 3 is presented. Plots of k(obs) versus palladacycle [3] demonstrate strong saturation binding to form 2b:3. Numerical fits of the kinetic data to a universal binding equation provide binding constants, K(b), and first order catalytic rate constants for the methanolysis reaction of the 2b:3 complex (k(cat)) which, when corrected for buffer effects, give corrected (k(cat)(corr)) rate constants. A sigmoidal shaped plot of log(k(cat)(corr)) versus (s)(s)pH (in methanol) for the cleavage of 2b displays a broad (s)(s)pH independent region from 5.6 <= (s)(s)pH <= 10 with a k(minimum) = (1.45 +/- 0.24) * 10(-2) s(-1) and a [lyoxide] dependent wing plateauing above a kinetically determined (s)(s)pK(a) of 12.71 +/- 0.17 to give a k(maximum) = 7.1 +/- 1.7 s(-1). Bronsted plots were constructed for reaction of 2a-d at (s)(s)pH 8.7 and 14.1, corresponding to reaction in the midpoints of the low and high (s)(s)pH plateaus. The Bronsted coefficients (beta(LG)) are computed as -0.01 +/- 0.03 and -0.86 +/- 0.004 at low and high (s)(s)pH, respectively. In the low (s)(s)pH plateau, and under conditions of saturating 3, a solvent deuterium kinetic isotope effect of k(H)/k(D) = 1.17 +/- 0.08 is observed; activation parameters (DeltaH(Pd)(++) = 14.0 +/- 0.6 kcal/mol and DeltaS(Pd)(++)= -20 +/- 2 cal/mol.K) were obtained for the 3-catalyzed cleavage reaction of 2b. Possible mechanisms are discussed for the reactions catalyzed by 3 at low and high sspH. This catalytic system is shown to promote the methanolytic cleavage of O,O-dimethyl phosphorothioate in CD3OD, producing (CD3O)2P?O(S(-)) with a half time for reaction of 34 min. PMID- 21284377 TI - Mesoporous biocompatible and acid-degradable magnetic colloidal nanocrystal clusters with sustainable stability and high hydrophobic drug loading capacity. AB - Fabrication of magnetic particles (MPs) with high magnetization and large surface area simultaneously is critical for the application of MPs in bioseparation and drug delivery but remains a challenge. In this article, we describe an unprecedented approach to synthesize mesoporous magnetic colloidal nanocrystal clusters (MCNCs) stabilized by poly(gamma-glutamic acid) (PGA) with high magnetization, large surface area (136 m(2)/g) and pore volume (0.57 cm(3)/g), excellent colloidal stability, prominent biocompatibility, and acid degradability. This result provides the important step toward the construction of a new family of MCNCs and demonstrates its capacity in a "magnetic motor" drug delivery system. Here, as an example, we explore the applicability of as-prepared mesoporous MCNCs as hydrophobic drug delivery vehicles (paclitaxel as model drug), and the resultant loading capacity is as high as 35.0 wt %. The antitumor efficacy measured by MTT assay is significantly enhanced, compared with free drugs. Thus, combined with their inherent high magnetization, the mesoporous MCNCs pave the way for applying magnetic targeting drug carriers in antitumor therapeutics. PMID- 21284378 TI - A DFT study of the ambiphilic nature of arylpalladium species in intramolecular cyclization reactions. AB - The remarkable structure-dependent reactivity observed in the cyclization of (2 haloanilino)-ketones with Pd-catalysts has been studied computationally within the density functional theory framework. The experimental reaction products ratio may be explained through the formation of a common palladaaminocyclobutane intermediate which can undergo a nucleophilic addition reaction and/or an enolate alpha-arilation process. The evolution of this metallacycle to the final products depends on two factors, the length of the tether joining the amino and the carbonyl groups, and the electronic nature of the substituent directly attached to the nitrogen atom. Thus, shorter chains (2 CH(2)) facilitate the nucleophic addition reaction by approximating the reactive aryl and Pd-coordinated carbonyl groups whereas longer chains (3 CH(2)) favor the enolate alpha-arylation proccess. For electron-withdrawing groups attached to the aniline nitrogen atom, the nucleophilic addition pathway becomes slightly disfavored, mainly due to the electron-withdrawing effect of the CO(2)Me group which avoids the delocation of the LP in the pi-system, thus decreasing the nucleophilicity of the reactive arylic carbon atom. In contrast, the enolate alpha-arylation reaction is facilitated by the CO(2)Me group. This is translated into a small computed barrier energy difference of these competitive reaction pathways which should lead to a mixture of reaction products as experimentally found. PMID- 21284379 TI - Investigation of the mechanism of formation of a thiolate-ligated Fe(III)-OOH. AB - Kinetic studies aimed at determining the most probable mechanism for the proton dependent [Fe(II)(S(Me2)N(4)(tren))](+) (1) promoted reduction of superoxide via a thiolate-ligated hydroperoxo intermediate [Fe(III)(S(Me2)N(4)(tren))(OOH)](+) (2) are described. Rate laws are derived for three proposed mechanisms, and it is shown that they should conceivably be distinguishable by kinetics. For weak proton donors with pK(a(HA)) > pK(a(HO(2))) rates are shown to correlate with proton donor pK(a), and display first-order dependence on iron, and half-order dependence on superoxide and proton donor HA. Proton donors acidic enough to convert O(2)(-) to HO(2) (in tetrahydrofuran, THF), that is, those with pK(a(HA)) < pK(a(HO(2))), are shown to display first-order dependence on both superoxide and iron, and rates which are independent of proton donor concentration. Relative pK(a) values were determined in THF by measuring equilibrium ion pair acidity constants using established methods. Rates of hydroperoxo 2 formation displays no apparent deuterium isotope effect, and bases, such as methoxide, are shown to inhibit the formation of 2. Rate constants for p-substituted phenols are shown to correlate linearly with the Hammett substituent constants sigma(-). Activation parameters ((DeltaH(++) = 2.8 kcal/mol, DeltaS(++) = -31 eu) are shown to be consistent with a low-barrier associative mechanism that does not involve extensive bond cleavage. Together, these data are shown to be most consistent with a mechanism involving the addition of HO(2) to 1 with concomitant oxidation of the metal ion, and reduction of superoxide (an "oxidative addition" of sorts), in the rate-determining step. Activation parameters for MeOH- (DeltaH(++) = 13.2 kcal/mol and DeltaS(++) = -24.3 eu), and acetic acid- (DeltaH(++) = 8.3 kcal/mol and DeltaS(++) = -34 eu) promoted release of H(2)O(2) to afford solvent-bound [Fe(III)(S(Me2)N(4)(tren))(OMe)](+) (3) and [Fe(III)(S(Me2)N(4)(tren))(O(H)Me)](+) (4), respectively, are shown to be more consistent with a reaction involving rate-limiting protonation of an Fe(III)-OOH, than with one involving rate-limiting O-O bond cleavage. The observed deuterium isotope effect (k(H)/k(D) = 3.1) is also consistent with this mechanism. PMID- 21284380 TI - Reactions of copper(II)-phenol systems with O2: models for TPQ biosynthesis in copper amine oxidases. AB - Copper(II) complexes supported by a series of phenol-containing bis(pyridin-2 ylmethyl)amine N(3) ligands (denoted as L(o)H, L(m)H, and L(p)H) have been synthesized, and their O(2) reactivity has been examined in detail to gain mechanistic insights into the biosynthesis of the TPQ cofactor (2,4,5 trihydroxyphenylalaninequinone, TOPA quinone) in copper-containing amine oxidases. The copper(II) complex of L(o)H (ortho-phenol derivative) involves a direct phenolate to copper(II) coordination and exhibits almost no reactivity toward O(2) at 60 degrees C in CH(3)OH. On the other hand, the copper(II) complex of L(m)H (meta-phenol derivative), which does not involve direct coordinative interaction between the phenol moiety and the copper(II) ion, reacts with O(2) in the presence of triethylamine as a base to give a methoxy substituted para-quinone derivative under the same conditions. The product structure has been established by detailed nuclear magnetic resonance (NMR), infrared (IR) spectroscopy, and electrospray ionization-mass spectroscopy (ESI MS) (including (18)O-labeling experiment) analyses. Density functional theory predicts that the reaction involves (i) intramolecular electron transfer from the deprotonated phenol (phenolate) to copper(II) to generate a copper(I)-phenoxyl radical; (ii) the addition of O(2) to this intermediate, resulting in an end-on copper(II) superoxide; (iii) electrophilic substitution of the phenolic radical to give a copper(II)-alkylperoxo intermediate; (iv) O-O bond cleavage concomitant with a proton migration, giving a para-quinone derivative; and (v) Michael addition of methoxide from copper(II) to the para-quinone ring and subsequent O(2) oxidation. This reaction sequence is similar to that proposed for the biosynthetic pathway leading to the TPQ cofactor in the enzymatic system. The generated para-quinone derivative can act as a turnover catalyst for aerobic oxidation of benzylamine to N-benzylidene benzylamine. Another type of copper(II) phenol complex with an L(p)H ligand (para-phenol derivative) also reacts with O(2) under the same experimental conditions. However, the product of this reaction is a keto-alcohol derivative, the structure of which is qualitatively different from that of the cofactor. These results unambiguously demonstrate that the steric relationship between the phenol moiety and the supported copper(II) ion is decisive in the conversion of active-site tyrosine residues to the TPQ cofactor. PMID- 21284381 TI - Antiproliferative lactams and spiroenone from adlay bran in human breast cancer cell lines. AB - Two new lactams, coixspirolactam D (1) and coixspirolactam E (2), and a new spiroenone, coixspiroenone (3), together with seven known compounds, coixspirolactam A (4), coixspirolactam B (5), coixspirolactam C (6), coixlactam (7), coixol (8), ethyl dioxindole-3-acetate (9), and isoindol-1-one (10), and two neolignans, zhepiresionol (11) and ficusal (12), were isolated from the bioactive subfraction of adlay bran ethanolic extract (ABE). Compounds 9 and 10 are the first isolates from natural resources. The structures of new compounds were identified by spectroscopic methods, including infrared (IR) spectrum, 1D and 2D nuclear magnetic resonance (NMR), and mass spectrum (MS). All of the isolated compounds were tested for antiproliferative effects on MCF-7, MDA-MB-231, and T 47D cells. Results showed that compounds 1, 3, 4, 6, and 7 at 50 MUM significantly inhibited MCF-7 cell proliferation by 30.2, 19.2, 21.0, 13.5, and 32.4%, respectively; compounds 2, 4, and 7 significantly inhibited T-47D cells at 50 MUM by 20.7, 24.8, and 28.9%; and compounds 1, 2, and 12 significantly inhibited MDA-MB-231 cells at 50 MUM by 47.4, 25.3, and 69.3%, respectively. In conclusion, ABE has antiproliferative activities, and this effect is partially related to the presence of lactams and spiroenone. PMID- 21284382 TI - Field fluxes and speciation of arsines emanating from soils. AB - The biogeochemical cycle of arsenic (As) has been extensively studied over the past decades because As is an environmentally ubiquitous, nonthreshold carcinogen, which is often elevated in drinking water and food. It has been known for over a century that micro-organisms can volatilize inorganic As salts to arsines (arsine AsH(3), mono-, di-, and trimethylarsines, MeAsH(2), Me(2)AsH, and TMAs, respectively), but this part of the As cycle, with the exception of geothermal environs, has been almost entirely neglected because of a lack of suited field measurement approaches. Here, a validated, robust, and low-level field-deployable method employing arsine chemotrapping was used to quantify and qualify arsines emanating from soil surfaces in the field. Up to 240 mg/ha/y arsines was released from low-level polluted paddy soils (11.3 +/- 0.9 mg/kg As), primarily as TMAs, whereas arsine flux below method detection limit was measured from a highly contaminated mine spoil (1359 +/- 212 mg/kg As), indicating that soil chemistry is vital in understanding this phenomenon. In microcosm studies, we could show that under reducing conditions, induced by organic matter (OM) amendment, a range of soils varied in their properties, from natural upland peats to highly impacted mine-spoils, could all volatilize arsines. Volatilization rates from 0.5 to 70 MUg/kg/y were measured, and AsH(3), MeAsH(2), Me(2)AsH, and TMAs were all identified. Addition of methylated oxidated pentavalent As, namely monomethylarsonic acid (MMAA) and dimethylarsinic acid (DMAA), to soil resulted in elevated yearly rates of volatilization with up to 3.5% of the total As volatilized, suggesting that the initial conversion of inorganic As to MMAA limits the rate of arsine and methylarsines production by soils. The nature of OM amendment altered volatilization quantitatively and qualitatively, and total arsines release from soil showed correlation between the quantity of As and the concentration of dissolved organic carbon (DOC) in the soil porewater. The global flux of arsines emanating from soils was estimated and placed in the context of As atmospheric inputs, with arsines contributing from 0.9 to 2.6% of the global budget. PMID- 21284383 TI - Analysis of veterinary drugs and metabolites in milk using quadrupole time-of flight liquid chromatography-mass spectrometry. AB - A quadrupole time-of-flight (Q-TOF) liquid chromatography-mass spectrometry (LC MS) method was developed to analyze veterinary drug residues in milk. Milk samples were extracted with acetonitrile. A molecular weight cutoff filter was the only cleanup step in the procedure. Initially, a set of target compounds (including representative sulfonamides, tetracyclines, beta-lactams, and macrolides) was used for validation. Screening of residues was accomplished by collecting TOF (MS(1)) data and comparing the accurate mass and retention times of found compounds to a database containing information for veterinary drugs. The residues included in the study could be detected in samples fortified at the levels of concern with this procedure 97% of the time. Although the method was intended to be qualitative, an evaluation of the MS data indicated a linear response and acceptable recoveries for a majority of target compounds. In addition, MS/MS data were also generated for the [M + H](+) ions. Product ions for each compound were identified, and their mass accuracy was compared to theoretical values. Finally, incurred milk samples from cows dosed with veterinary drugs, including sulfamethazine, flunixin, cephapirin, or enrofloxacin, were analyzed with Q-TOF LC-MS. In addition to monitoring for the parent residues, several metabolites were detected in these samples by TOF. Proposed identification of these residues could be made by evaluating the MS and MS/MS data. For example, several plausible metabolites of enrofloxacin, some not previously observed in milk, are reported in this study. PMID- 21284384 TI - Effect of black raspberry ( Rubus occidentalis L.) extract variation conditioned by cultivar, production site, and fruit maturity stage on colon cancer cell proliferation. AB - Black raspberries have been shown to inhibit multiple stages of oral, esophageal, and colon cancer. The objective of this study was to evaluate how black raspberry extract variability conditioned by horticultural factors affected the antiproliferative activity of 75 black raspberry extracts using an in vitro colon cancer cell model. HT-29 cells grown in 96-well plates were treated with freeze dried extracts at 0.6 and 1.2 mg of extract/mL of medium. Percent cell growth inhibition for each concentration of the extracts was determined using the sulforhodamine B assay. All extracts significantly inhibited the growth of HT-29 colon cancer cells in a dose-dependent manner. Cell proliferation was significantly influenced by cultivar, production site, and stage of maturity. The lack of correlation between growth inhibition and extract total phenolic and total monomeric anthocyanin assays suggested horticultural parameters influence bioactivity in a complex manner. PMID- 21284385 TI - Antitumor agents. 284. New desmosdumotin B analogues with bicyclic B-ring as cytotoxic and antitubulin agents. AB - We previously reported that the biological activity of analogues of desmosdumotin B (1) was dramatically changed depending on the B-ring system. A naphthalene B ring analogue 3 exerted potent in vitro activity against a diverse panel of human tumor cell lines with GI(50) values of 0.8-2.1 MUM. In contrast, 1 analogues with a phenyl B-ring showed unique selective activity against P-glycoprotein (P-gp) overexpressing multidrug resistant cell line. We have now prepared and evaluated 1 analogues with bicyclic or tricyclic aromatic B-ring systems as in vitro inhibitors of human cancer cell line proliferation. Among all synthesized derivatives, 21 with a benzo[b]thiophenyl B-ring was highly active, with GI(50) values of 0.06-0.16 MUM, and this activity was not influenced by overexpression of P-gp. Furthermore, 21 inhibited tubulin assembly in vitro with an IC(50) value of 2.0 MUM and colchicine binding by 78% as well as cellular microtubule polymerization and spindle formation. PMID- 21284386 TI - Synthesis and biological evaluation of orally active prodrugs of indomethacin. AB - Synthesis and biological evaluation of orally active prodrugs (1a-d) of indomethacin are described. Prodrugs 1a-c showed a similar degree of anti inflammatory activity, and prodrug 1d was found to be less potent than the parent drug indomethacin (1). Ulcer index (UI) data indicated that 1a (UI = 19), 1c (UI = 0), and 1d (UI = 0) were substantially less ulcerogenic and 1b (UI = 62) was more ulcerogenic than parent drug 1 (UI = 47). These prodrugs demonstrated good stability at acidic and basic pH and found to be more lipophilic than parent drug compound 1, indicated by partition coefficients measured in octanol-buffer system at pH 7.4 and 3.0. On the basis of in vivo studies, 1a and 1c compounds were selected for metabolic stability in rat liver microsome (RLM) and rat plasma (RP), and both were found to be enzymatically labile. Prodrugs 1a and 1c emerged as potent anti-inflammatory agents with a lesser potential for ulcer than the parent drug indomethacin. PMID- 21284387 TI - Metabolic adaptations in a H2 producing heterocyst-forming cyanobacterium: potentials and implications for biological engineering. AB - Nostoc punctiforme ATCC 29133 is a photoautotrophic cyanobacterium with the ability to fix atmospheric nitrogen and photoproduce hydrogen through the enzyme nitrogenase. The H(2) produced is reoxidized by an uptake hydrogenase. Inactivation of the uptake hydrogenase in N. punctiforme leads to increased H(2) release but unchanged rates of N(2) fixation, indicating redirected metabolism. System-wide understanding of the mechanisms of this metabolic redirection was obtained using complementary quantitative proteomic approaches, at both the filament and the heterocyst level. Of the total 1070 identified and quantified proteins, 239 were differentially expressed in the uptake hydrogenase mutant (NHM5) as compared to wild type. Our results indicate that the inactivation of uptake hydrogenase in N. punctiforme changes the overall metabolic equilibrium, affecting both oxygen reduction mechanisms in heterocysts as well as processes providing reducing equivalents for metabolic functions such as N(2) fixation. We identify specific metabolic processes used by NHM5 to maintain a high rate of N(2) fixation, and thereby potential targets for further improvement of nitrogenase based H(2) photogeneration. These targets include, but are not limited to, components of the oxygen scavenging capacity and cell envelope of heterocysts and proteins directly or indirectly involved in reduced carbon transport from vegetative cells to heterocysts. PMID- 21284388 TI - Large shift and small broadening of Br2 valence band upon dimer formation with H2O: an ab initio study. AB - Valence electronic excitation spectra are calculated for the H(2)O...Br(2) complex using highly correlated ab initio potentials for both the ground and the valence electronic excited states and a 2-D approximation for vibrational motion. Due to the strong interaction between the O-Br and the Br-Br stretching motions, inclusion of these vibrations is the minimum necessary for the spectrum calculation. A basis set calculation is performed to determine the vibrational wave functions for the ground electronic state and a wave packet simulation is conducted for the nuclear dynamics on the excited state surfaces. The effects of both the spin-orbit interaction and temperature on the spectra are explored. The interaction of Br(2) with a single water molecule induces nearly as large a shift in the spectrum as is observed for an aqueous solution. In contrast, complex formation has a remarkably small effect on the T = 0 K width of the valence bands due to the fast dissociation of the dihalogen bond upon excitation. We therefore conclude that the widths of the spectra in aqueous solution are mostly due to inhomogeneous broadening. PMID- 21284389 TI - Nanoscale chemical composition analysis using peptides targeting inorganic materials. AB - Chemical composition analysis by scanning probe microscopy (SPM) in water is a method whose introduction has been long-awaited. Here we propose a simple method for performing chemical composition analyses of solid surfaces in water using atomic force microscopes (AFMs) with probes functionalized with peptides targeting inorganic materials. In this work, bicompositional surfaces of gold and titanium oxide were scanned with AFM probes modified with the titanium-binding peptide (TBP). We found that surface chemical composition clearly appeared as contrast in the mapping images of adhesion forces with nanometer-scale resolution. In this Article, we further discuss appropriate designs of the AFM probes and appropriate imaging conditions for the chemical composition analysis based on the results of force measurements of the single TBP-titanium bond. PMID- 21284390 TI - Water-dispersible iron oxide magnetic nanoparticles with versatile surface functionalities. AB - We report a simple one-pot strategy to prepare surface-function-alized, water dispersible iron oxide nanoparticles. Small organic molecules that have desired functional groups such as amines, carboxylics, and thiols are chosen as capping agents and are injected into the reaction medium at the end of the synthesis. A diversity of functionalities are effectively introduced onto the surface of the nanoparticles with a minimal consumption of solvents and chemical resources by simply switching the capping ligand to form the ligand shell. The resulting nanocrystals are quasi-spherical and narrowly size-distributed. Energy-dispersive X-ray analysis and Fourier transform infrared spectroscopy studies suggest a successful surface modification of iron oxide nanoparticles with selected functionalities. The colloidal stabilities are characterized by dynamic light scattering and zeta potential measurements. The results imply that functionalized nanoparticles are very stable and mostly present as individual units in buffer solutions. The pedant functional groups of the capping ligand molecules are very reactive, and their availabilities are investigated by covalently linking fluorescent dyes to the nanoparticles through the cross-linking of 1-ethyl-3-(3 dimethylaminopropyl)carbodiimide hydrochloride. The quenched quantum yield and shortened lifetime of the dyes strongly indicate a direct bonding between the functional group of the nanoparticles and the fluorescent molecules. PMID- 21284391 TI - Neutron reflectometry of quaternary gemini surfactants as a function of alkyl chain length: anomalies arising from ion association and premicellar aggregation. AB - We have measured the structure and properties of a series of dicationic quaternary ammonium compounds alpha,omega-bis(N-alkyl dimethyl ammonium)hexane halides (Cn-C6-Cn) for values of the alkyl chain length n of 8, 9, 10, 11, 12, and 16, and a series of alpha,omega-bis(N-alkyl dimethyl ammonium)diethylether halides (Cn-C2OC2-Cn) for values of n of 8, 12, and 16, as well as C8-C12-C8 and C12-C10-C12 at the air/water interface. Although the critical micelle concentration (CMC) in the two series decreases in the normal way, that is, logarithmically, with increasing chain length, the limiting surface tension at the CMC and the limiting area per molecule both increase with chain length, in the opposite direction from comparable single chain surfactants. The structures of the surface layers, which were determined by neutron reflectometry, indicate that the anomalous behavior of the surface tension and area are probably caused by poor packing of the gemini side chains between adjacent molecules. Comparison of the directly determined surface coverage using neutron reflectometry and the apparent coverage determined by application of the Gibbs equation to surface tension data gives an experimental measurement of the prefactor in the Gibbs equation, which should be 3 for these geminis. It was found to vary from about 3 for the two C16 geminis down to about 1.5 for the two C8 geminis. We have devised a simple quantitative model that explains this variation and earlier observations that the Gibbs prefactor for C12-Cn-C12 (n varying from 3 to 12) is around 2. The model is consistent with the conductivity, NMR, and fluorescence measurements of other authors. This model shows that both dimerization and ion association are required to explain the surface tension behavior of cationic gemini bromide surfactants and that, in many cases, the prefactor itself varies with concentration. PMID- 21284392 TI - Surface structures and electrochemical activities of Pt overlayers on Ir nanoparticles. AB - Pt overlayers were deposited on carbon-supported Ir nanoparticles with various coverages. Structural and electrochemical characterizations were performed using transmission electron microscopy (TEM), X-ray diffraction, high-resolution powder diffraction (HRPD), X-ray photoelectron spectroscopy (XPS), X-ray absorption near edge spectroscopy (XANES), cyclic voltammetry (CV), CO stripping voltammetry, and N2O reduction. The surface of Ir nanoparticles was covered with Pt overlayers with thickness varying from the submonolayer scale to more than two monolayers. Surface analyses such as CV and CO stripping voltammetry indicated that the Pt overlayers were uniformly deposited on the Ir nanoparticles, and the resultant Pt overlayers exhibited gradual changes in surface characteristics toward the Pt surface as the surface coverage increased. The distinct CO stripping characteristics and the enhanced Pt utilization affected electrocatalytic activities for methanol oxidation. The electrochemical stability of the Pt overlayer was compared with a commercial carbon-supported Pt catalyst by conducting a potential cycling experiment. PMID- 21284393 TI - A bulk water-dependent desolvation energy model for analyzing the effects of secondary solutes on biological equilibria. AB - A new phenomenological model for interpreting the effects of solutes on biological equilibria is presented. The model attributes changes in equilibria to differences in the desolvation energy of the reacting species that, in turn, reflect changes in the free energy of the bulk water upon addition of secondary solutes. The desolvation approach differs notably from that of other solute models by treating the free energy of bulk water as a variable and by not ascribing the observed shifts in reaction equilibria to accumulation or depletion of solutes next to the surfaces of the reacting species. On the contrary, the partitioning of solutes is viewed as a manifestation of the different subpopulations of water that arise in response to the surface boundary conditions. A thermodynamic framework consistent with the proposed model is used to derive a relationship for a specific reaction, an aqueous solubility equilibrium, in two or more solutions. The resulting equation reconciles some potential issues with the transfer free energy model of Tanford. Application of the desolvation energy model to the analysis of a two-state protein folding equilibrium is discussed and contrasted to the application of two other solute models developed by Timasheff and by Parsegian. Future tabulation of solvation energies and bulk water energies may allow biophysical chemists to confirm the mechanism by which secondary solutes influence binding and conformational equilibria and may provide a common ground on which experimentalists and theoreticians can compare and evaluate their results. PMID- 21284394 TI - Enantioselective conjugate addition nitro-Mannich reactions: solvent controlled synthesis of acyclic anti- and syn-beta-nitroamines with three contiguous stereocenters. AB - We report an enantioselective conjugate addition nitro-Mannich reaction protocol which combines dialkylzinc, aromatic nitro alkene and imine to form two C-C bonds and three contiguous stereocenters in one reaction vessel. Absolute stereochemistry was controlled from the initial 1,4-addition of dialkylzinc to aromatic nitroalkenes by known copper-chiral ligand catalysts. The choice of solvent dictated the formation of either the syn,anti or syn,syn diastereoisomers, two of the four possible diastereoisomers. The syn,syn isomer is a rare example of a syn-selective nitro-Mannich reaction. The diastereoselectivity is dependent upon the presence or not of Zn(O(2)CCF(3))(2) in the reaction mixture and empirical transition state models are proposed to account for the observed stereochemical course of the two reaction conditions. The extent of enantioselectivity and structural diversity of the process is limited by current methodology for the catalytic asymmetric addition of dialkylzincs to nitrostyrenes. The synthetically versatile products are the most complex beta-nitro amines prepared using the nitro-Mannich reaction and are formed in high yield and enantioselectivity. PMID- 21284395 TI - Genome mining in streptomyces. Discovery of an unprecedented P450-catalyzed oxidative rearrangement that is the final step in the biosynthesis of pentalenolactone. AB - The penM and pntM genes from the pentalenolactone biosynthetic gene clusters of Streptomyces exfoliatus UC5319 and Streptomyces arenae TU469 were predicted to encode orthologous cytochrome P450s, CYP161C3 and CYP161C2, responsible for the final step in the biosynthesis of the sesquiterpenoid antibiotic pentalenolactone (1). Synthetic genes optimized for expression in Escherichia coli were used to obtain recombinant PenM and PntM, each carrying an N-terminal His(6)-tag. Both proteins showed typical reduced-CO UV maxima at 450 nm, and each bound the predicted substrate, pentalenolactone F (4), with K(D) values of 153 +/- 14 and 126 +/- 11 MUM for PenM and PntM, respectively, as determined by UV shift titrations. PenM and PntM both catalyzed the oxidative rearrangement of 4 to 1 when incubated in the presence of NADPH, spinach ferredoxin, ferredoxin reductase, and O(2). The steady-state kinetic parameters were k(cat) = 10.5 +/- 1.7 min(-1) and K(m) = 340 +/- 100 MUM 4 for PenM and k(cat) = 8.8 +/- 0.9 min( 1) and K(m) = 430 +/- 100 MUM 4 for PntM. The in vivo function of both gene products was confirmed by the finding that the corresponding deletion mutants S. exfoliatus/DeltapenM ZD22 and S. arenae/DeltapntM ZD23 no longer produced pentalenolactone but accumulated the precursor pentalenolactone F. Complementation of each deletion mutant with either penM or pntM restored production of antibiotic 1. Pentalenolactone was also produced by an engineered strain of Streptomyces avermitilis that had been complemented with pntE, pntD, and either pntM or penM, as well as the S. avermitilis electron-transport genes for ferredoxin and ferrodoxin reductase, fdxD and fprD. PMID- 21284396 TI - Oriented attachment growth of quantum-sized CdS nanorods by direct thermolysis of single-source precursor. AB - Quantum-sized CdS nanorods were synthesized by direct thermal decomposition of a single-source precursor in a monosurfactant system. The CdS nanorods were uniform, had high crystallinity, and exhibited strong quantum confinement effect. The nanorod growth was controlled by an oriented attachment mechanism, and the morphology was determined by the competition between dipole attraction and steric repulsion of nanodots. Increasing precursor concentration and prolonging reaction time were favorable for the formation of CdS nanorods. PMID- 21284397 TI - Strong silica monoliths with large mesopores prepared using agarose gel templates. AB - Mesoporous silica pellets with controllable shape and pore size were prepared using agarose gel templates. Robust (compressive strength of 3.3-25.1 MPa), crack free silica monoliths have been produced with large mesopores (14-23 nm), high surface areas (410-540 m(2) g(-1)), and large pore volumes (1.1-1.2 cm(3) g(-1)). The synthesis was achieved by infusing preformed agarose gels with tetraethyl orthosilicate and the nonpolar condensation catalyst tetrabutyl ammonium fluoride. The infiltrated gels were transferred to water to initiate hydrolysis and condensation of the silica precursor. Fluoride catalyzed the gelation of silica in a matter of minutes; hence, the oxide maintained the shape of the agarose pellet. The mesopore size could be modified by altering the weight percent of agarose gel used. The method employed here is simple and reproducible. As these materials have such large mesopore dimensions, they could be used as hard templates or could be specifically functionalized for use in environmental remediation, as environmentally responsive materials, biocatalysts, or catalysts. PMID- 21284398 TI - Photothermally enhanced drug delivery by ultrasmall multifunctional FeCo/graphitic shell nanocrystals. AB - FeCo/graphitic carbon shell (FeCo/GC) nanocrystals (~4-5 nm in diameter) with ultrahigh magnetization are synthesized, functionalized, and developed into multifunctional biocompatible materials. We demonstrate the ability of this material to serve as an integrated system for combined drug delivery, near infrared (NIR) photothermal therapy, and magnetic resonance imaging (MRI) in vitro. We show highly efficient loading of doxorubicin (DOX) by pi-stacking on the graphitic shell to afford FeCo/GC-DOX complexes and pH sensitive DOX release from the particles. We observe enhanced intracellular drug delivery by FeCo/GC DOX under 20 min of NIR laser (808 nm) induced hyperthermia to 43 degrees C, resulting in a significant increase of FeCo/GC-DOX toxicity toward breast cancer cells. The synergistic cancer cell killing by FeCo/GC-DOX drug delivery under photothermal heating is due to a ~two-fold enhancement of cancer cell uptake of FeCo/GC-DOX complex and the increased DOX toxicity under the 43 degrees C hyperthermic condition. The combination of synergistic NIR photothermally enhanced drug delivery and MRI with the FeCo/GC nanocrystals could lead to a powerful multimodal system for biomedical detection and therapy. PMID- 21284399 TI - Wide control of proton conductivity in porous coordination polymers. AB - The proton conductivities of the porous coordination polymers M(OH)(bdc-R) [H(2)bdc = 1,4-benzenedicarboxylic acid; M = Al, Fe; R = H, NH(2), OH, (COOH)(2)] were investigated under humid conditions. Good correlations among pK(a), proton conductivity, and activation energy were observed. Fe(OH)(bdc-(COOH)(2)), having carboxy group and the lowest pK(a), showed the highest proton conductivity and the lowest activation energy in this system. This is the first example in which proton conductivity has been widely controlled by substitution of ligand functional groups in an isostructural series. PMID- 21284400 TI - Preparative scale synthesis of the biaryl core of anacetrapib via a ruthenium catalyzed direct arylation reaction: unexpected effect of solvent impurity on the arylation reaction. AB - In this report, we disclose our findings regarding the remarkable effect of a low level impurity found in the solvent used for a ruthenium-catalyzed direct arylation reaction. This discovery allowed for the development of a robust and high-yield arylation protocol that was demonstrated on a multikilogram scale using carboxylate as the cocatalyst. Finally, a practical, scalable, and chromatography-free synthesis of the biaryl core of Anacetrapib is described. PMID- 21284401 TI - Growth and characterization of ternary AlGaN alloy nanocones across the entire composition range. AB - AlGaN ternary alloys have unique properties suitable for numerous applications due to their tunable direct band gap from 3.4 to 6.2 eV by changing the composition. Herein we report a convenient chemical vapor deposition growth of the quasi-aligned Al(x)Ga(1-x)N alloy nanocones over the entire composition range. The nanocones were grown on Si substrates in large area by the reactions between GaCl(3), AlCl(3) vapors, and NH(3) gas under moderate temperature around 700 degrees C. The as-prepared wurtzite Al(x)Ga(1-x)N nanocones have single crystalline structure preferentially growing along the c-axis, with homogeneous composition distribution, as revealed by the characterizations of electron microscopy, X-ray diffraction, energy-dispersive X-ray spectroscopy, and selected area electron diffraction. The continuous composition tunability is also demonstrated by the progressive evolutions of the band edge emission in cathodoluminescence and the turn-on and threshold fields in field emission measurements. The successful preparation of Al(x)Ga(1-x)N nanocones provides the new possibility for the further development of advanced nano- and opto-electronic devices. PMID- 21284402 TI - Mechanically activated molecular switch through single-molecule pulling. AB - We investigate a prototypical single-molecule switch marrying force spectroscopy and molecular electronics far from the thermodynamic limit. We use molecular dynamics to simulate a conducting atomic force microscope mechanically manipulating a molecule bound to a surface between a folded state and an unfolded state while monitoring the conductance. Both the complexity and the unique phenomenology of single-molecule experiments are evident in this system. As the molecule unfolds/refolds, the average conductance reversibly changes over 3 orders of magnitude; however, throughout the simulation the transmission fluctuates considerably, illustrating the need for statistical sampling in these systems. We predict that emergent single-molecule signatures will still be evident with conductance blinking, correlated with force blinking, being observable in a region of dynamic bistability. Finally, we illustrate some of the structure-function relationships in this system, mapping the dominant interactions in the molecule for mediating charge transport throughout the pulling simulation. PMID- 21284403 TI - Theoretical studies on the interactions and interferences of HIV-1 glycoprotein gp120 and its coreceptor CCR5. AB - The interaction between the HIV gp120 protein and coreceptor CCR5 or CXCR4 of the host cell is critical in mediating the HIV entry process. A model for the CCR5 gp120 complex has been developed. In the model, the N-terminus of CCR5 binds to three discontinuous domains of gp120, including the fourth conserved (C4) region, beta19/beta20 connecting loop, and V3 loop. The second extra-cellular loop (ECL2) of CCR5 also interacts with the crown part of the gp120 V3 loop. The bindings of the three CCR5 antagonists, maraviroc, aplaviroc, and vicriviroc, to the trans membrane domain of CCR5 have been modeled. The bindings are found to affect the conformation of the ECL2 domain, which in turn drives the N-terminus of CCR5 to an altered state. Aplaviroc is more hydrophilic than maraviroc and vicriviroc, and its binding is more interfered by solvent, resulting in a quite different effect to the structure of CCR5 compared with those of the other two molecules. The above results are in accord with experimental observations and provide a structural basis for further design of CCR5 antagonists. PMID- 21284404 TI - Identification of small-molecule inhibitors against human leukocyte antigen-death receptor 4 (HLA-DR4) through a comprehensive strategy. AB - Rheumatoid arthritis (RA) is an autoimmune disease mediated by T-lymphocytes and associated with the human leukocyte antigen-death receptor 4 (HLA-DR4). The HLA DR4 protein selectively interacts with the antigenic peptides on the cell surface and presents them to the T cell receptor (TCR) on CD4+ T cells. The HLA-DR4 antigen-TCR complex initiates the autoimmune response and eventually causes the chronic inflammation within patients bodies. To inhibit HLA-DR4-restricted T cell activation, an ideal approach is to discover non-T cell stimulating substrates that specifically bind to HLA-DR4. In this paper, a comprehensive structure-based design strategy involved de novo design approach, pharmacophore search, and dock method was presented and applied to "simplify" the known binding peptide ligand of HLA-DR4 and identified specific small-molecule inhibitors for HLA-DR4. The designed three-step strategy successfully identified five nonpeptide ligands with novel scaffolds from a chemical library containing 4 * 10(6) commercially available compounds within a tolerable computing time. The identified five chemicals, BAS-0219606, T0506-2494, 6436645, 3S-71981, and KM 11073, are all non T cell stimulators and are able to significantly inhibit HLA-DR4-restricted T cell activation induced by type II collagen (CII) 263-272 peptide. IC(50) for the best two potentials, BAS-0219606 and T0506-2494, was 31 and 17 MUM, respectively, which is equivalent or better than the known peptide ligands. It is hopeful that they can be used as effective therapeutic means for further treatment of RA patients. In addition, the comprehensive strategy presented in this paper exhibited itself to be an effective flow line from peptide ligands to small molecule inhibitors and will have applications to other targets. PMID- 21284405 TI - Schizoaffective disorder: a review of current research themes and pharmacological management. AB - Despite a clear recognition of the existence of patients with co-morbid psychotic and mood symptoms, many studies conclude that schizoaffective disorder as a distinct diagnosis does not exist. Regardless of one's opinion on schizoaffective disorder, psychiatrists remain dependent on phenomenological descriptions for diagnosing psychiatric disorders, and these phenomenological criteria are also used for clinical trial entry. On the other hand, many psychiatrists prescribe for specific target symptoms and do not always rigidly follow diagnostic systems and, moreover, there have been very few trials that have specifically studied schizoaffective disorder. Despite recent intriguing work in epidemiology, genetics, neurocognition and electrophysiology, the diagnosis of schizoaffective disorder remains controversial. Taken together, these studies suggest that even if schizoaffective disorder exists as a separate diagnosis, it may not be useful clinically due to considerable variation in the general use of this term. It is possible that diagnostic criteria in the future will include genetic, imaging and electrophysiological components, and that this will allow for better differentiation of disease states among the heterogeneous pool of patients currently believed to have schizophrenia, schizoaffective disorder or bipolar disorder. Although it is likely that most, if not all, antipsychotics are effective for schizoaffective disorder, given recent regulatory approval of a specific antipsychotic agent for the acute treatment of schizoaffective disorder, greater attention is now being focused on the entity of schizoaffective disorder and potential treatment decisions. However, based on the limited extant evidence, it is not yet possible to make definitive treatment recommendations for schizoaffective disorder. Additional clinical trials that include other antipsychotics, mood stabilizers and antidepressants are desirable and necessary before clear and comprehensive evidence-based treatment recommendations can be made. PMID- 21284406 TI - Different doses of palonosetron for the prevention of postoperative nausea and vomiting in children undergoing strabismus surgery. AB - BACKGROUND: Postoperative vomiting is a common complication after strabismus surgery in children. The serotonin 5-HT(3) receptor antagonists have proven to be a particularly valuable addition to the armamentarium against postoperative nausea and vomiting (PONV). Palonosetron is a second-generation 5-HT(3) receptor antagonist that has recently been approved for prophylaxis against PONV. OBJECTIVE: The aim of this study was to evaluate the efficacy of different doses of palonosetron for the prevention of PONV in children undergoing strabismus surgery. PATIENTS AND METHOD: A total of 150 children who were classified with an American Society of Anesthesiologists physical status of I, were aged between 2 and 12 years, and were undergoing strabismus surgery under general anesthesia were enrolled in the study. A random numbers table was used to assign each child to receive palonosetron 0.5, 1.0, or 1.5 MUg/kg (n = 50 in each group). All episodes of PONV at the intervals of 0-2, 2-6, 6-24, and 24-48 hours were evaluated using a numeric scoring system for PONV. A p-value of <0.05 was considered statistically significant. RESULTS: The percentage of children with PONV during 0-48 hours after anesthesia was 24% with palonosetron 0.5 or 1.0 MUg/kg, and 20% with palonosetron 1.5 MUg/kg. There was no statistically significant difference between the study groups with respect to the number of children with PONV scores of 1, 2, or 3 during 0-48 hours after anesthesia. There was no statistically significant difference between the study groups with respect to the number of children with postoperative vomiting during all time periods after anesthesia. The percentage of children aged >6 years with postoperative nausea during 0-48 hours after anesthesia was 8.6%, 18.2%, and 15.4% with palonosetron 0.5, 1.0, or 1.5 MUg/kg, respectively, but there was no statistically significant difference between the study groups. CONCLUSION: Palonosetron doses of 0.5, 1.0, and 1.5 MUg/kg are recommended for further evaluation, as they appear to be the effective doses for the prevention of PONV following strabismus surgery in children. PMID- 21284407 TI - Efficacy and safety of the Betamethasone valerate 0.1% plaster in mild-to moderate chronic plaque psoriasis: a randomized, parallel-group, active controlled, phase III study. AB - BACKGROUND: Corticosteroids are a versatile option for the treatment of mild-to moderate psoriasis due to their availability in a wide range of potencies and formulations. Occlusion of the corticosteroid is a widely accepted procedure to enhance the penetration of the medication, thereby improving its effectiveness. Betamethasone valerate (BMV) is a moderately potent corticosteroid that is available as a cream, ointment, and lotion. A ready-to-use occlusive dressing, which provides a continuous sustained release of BMV, has been developed for the treatment of psoriasis. OBJECTIVE: To evaluate the efficacy and safety of a new BMV 0.1% plaster compared with a BMV 0.1% cream in patients with mild-to-moderate chronic plaque psoriasis. METHODS: This was a prospective, randomized, assessor blind, parallel-group, active-controlled, multicenter, phase III study. Eligible outpatients (aged >=18 years) with a diagnosis of stable, chronic plaque psoriasis vulgaris with two to four plaques on extensor surfaces of limbs were randomized to receive BMV 0.1% plaster or BMV 0.1% cream for 3-5 weeks; patients with resolution of target plaques then entered a 3-month, treatment-free, follow up period. The number of patients showing clearing of plaques (remission) at 3 weeks (primary endpoint) and at 5 weeks was independently evaluated from digitized images of target plaques by two blinded assessors, and also assessed by the investigator and patient. Additional endpoints were (i) change from baseline in target plaque size and in Psoriasis Global Assessment (PGA) score, as evaluated by the blinded assessors, investigator, and patient; (ii) change from baseline in symptom (itching, soreness) severity; (iii) treatment satisfaction and ease of use; (iv) clearing and relapse during the follow-up period; and (v) adverse events (AEs). RESULTS: Patients (n = 231) were screened and randomized to treatment with BMV 0.1% plaster (n = 116) and BMV 0.1% cream (n = 115). Significantly more patients achieved clearing after 3 weeks' treatment with BMV plaster than with BMV cream (Cochran-Mantel-Haenszel test, p < 0.001); this difference was maintained at 5 weeks. The total plaque area decreased to a larger extent for the BMV plaster group compared with the BMV cream group (analysis of covariance [ANCOVA] model, p = 0.017 at week 5). PGA scores were significantly lower after 3 and 5 weeks' treatment with BMV plaster (ANCOVA model, all p <= 0.016 vs BMV cream). Both treatments reduced itching and soreness to a similar degree, and the incidences of relapse during the follow-up period were comparable between treatment groups. There were no significant differences in AEs between treatment groups. CONCLUSIONS: BMV 0.1% plaster is more efficacious than BMV 0.1% cream in the treatment of patients with mild-to-moderate chronic plaque psoriasis in a clinical setting resembling daily clinical practice. PMID- 21284408 TI - Consensus features of CP-MLR and GA in modeling HIV-1 RT inhibitory activity of 4 benzyl/benzoylpyridin-2-one analogues. AB - The HIV-1 reverse transcriptase (RT) inhibitory activity of benzyl/benzoylpyridinones is modeled with molecular features identified in combinatorial protocol in multiple linear regression (CP-MLR) and genetic algorithm (GA). Among the features, nDB and LogP are found to be the most influential descriptors to modulate the activity. Although the coefficient of nDB suggested in favor of benzylpyridinones skeleton, the coefficient of LogP suggested the favorability of hydrophilic nature in compounds for better activity. The partial least squares analysis of the descriptors common to CP-MLR and GA has displayed their predictivity over the total descriptors identified in both the approaches. The back-propagation artificial neural networks model from the five most significant common descriptors (nDB, T(O..O), MATS8e, LogP, and BELp4) has explained 93.2% variance in the HIV-1 RT activity of the training set compounds and showed a test set r(2) of 0.89. The results suggest that the descriptors have the ability to identify the patterns in the compounds to predict potential analogues. PMID- 21284409 TI - Topological, hydrophobicity, and other descriptors on alpha-glucosidase inhibition: a QSAR study on xanthone derivatives. AB - Quantitative structure activity relationship analysis was performed on a series of xanthone derivatives to establish the structural features required for alpha glucosidase inhibitory activity. The computational and statistical analysis was performed with V life MDS (Molecular Design Suite) and Statistica software. The selected models show significant predictive power, stability, and reliability in terms of cross-validated correlation coefficient (Q(2)(cv) > 0.74 and Q(2)(test) > 0.5) and other validation parameters. The results show that the SaaaC count, MMFF_6 and dipole moment are mainly contributed for the activity along with the hydrophobicity descriptors. It describes that heteroatoms (oxygen atom connected with carbon atom) in the molecules are favourable for alpha-glucosidase inhibitory activity. The E-state count descriptor suggests that when carbon atoms connected with three aromatic bonds and hydrogen or other atoms are favourable for the activity. The SAHA and SAMH descriptors show that the hydrophilic area in the molecule is important for the activity while high hydrophilicity is unfavourable for the activity. This study concluded that hydrophilic, polar and/or electron negative groups, which are responsible for hydrogen bonding and interaction with the enzyme for favourable activity. PMID- 21284415 TI - The effectiveness of a sex education program facilitating social skills for people with intellectual disability in Japan. AB - BACKGROUND: Sex education should include social skills, such as those that allow individuals to relate, socialize, and communicate with others, to assist people with intellectual disability (ID) to live life fully in the community. OBJECTIVES: We administered and investigated the effects of a program involving 8 interactive sex education sessions that were aimed at improving the social skills of people with ID. METHODS: Participants were 17 people with ID and 17 control group participants in Japan. The evaluation was conducted with a questionnaire based on KiSS-18 (Kikuchi's Scale of Social Skills: 18 items; Kikuchi, 2007 ). RESULTS: The score of KiSS-18 in the experimental group was 55.4 +/- 12.9 before the administration of the program, as compared to a mean of 61.8 +/- 13.2 after the program. A significant increase was identified. There was no significant difference between the first and second average score in the control group. CONCLUSION: The sex education program involving social skills training for people with ID had significant effects. PMID- 21284426 TI - Transdermal absorption enhancement of gel containing elastic niosomes loaded with gallic acid from Terminalia chebula galls. AB - OBJECTIVES: To investigate transdermal absorption enhancement of gel containing elastic niosomes loaded with gallic acid in the semipurified fraction isolated from Terminalia chebula Retz. (Combretaceae) galls. MATERIALS AND METHODS: Nonelastic and elastic niosomes loaded with gallic acid in pure form or in the semipurified fraction were developed. Rat skin permeation by vertical Franz diffusion cells of gallic acid from various gel formulations containing elastic niosomes loaded with gallic acid or the semipurified fraction was performed. RESULTS: Elastic and nonelastic niosomes loaded with gallic acid or the semipurified fraction exhibited the mixture of unilamellar and multilamellar structures with negative zeta potential values and in the size range of 200-400 nm. Both loaded elastic and nonelastic niosomes showed good physical and chemical stability for 3 months. The percentages remaining of gallic acid in nonelastic were slightly higher than in elastic niosomes. Both elastic and nonelastic niosomes retarded rat skin permeation of the loaded pure gallic acid, while enhanced the loaded gallic acid in the semipurified fraction. However, elastic niosomes exhibited higher percentages of gallic acid through rat skin than the nonelastic niosomes. DISCUSSION AND CONCLUSION: This study has demonstrated the potential of niosomes, especially elastic niosomes, for the enhancement of chemical stability and rat skin transdermal absorption of gallic acid in the semipurified fraction from T. chebula galls, which will be beneficial for topical antiaging application. PMID- 21284429 TI - A proposed histopathologic classification, scoring, and grading system for renal amyloidosis. PMID- 21284430 TI - Pathologists as leaders, innovators, and devoted physicians: special section on pathology in resource-poor nations. PMID- 21284431 TI - Pathology against the odds. PMID- 21284432 TI - Pathologists overseas: coordinating volunteer pathology services for 19 years. AB - Pathologists Overseas is a nonprofit organization that has been coordinating the efforts of volunteer pathologists and technologists for 19 years to improve and provide affordable pathology services to underserved patients worldwide. This is accomplished by aiding and establishing pathology laboratories, providing diagnostic pathology services, and training local physicians as pathologists. Projects have been completed or are currently active in Kenya, Eritrea, Madagascar, Ghana, Nepal, Bhutan, Peru, El Salvador, and St Lucia. The main challenge is finding enough volunteers to provide uninterrupted service to maintain a project. Our goal is to build on these experiences and continue to both support existing and establish more pathology laboratories worldwide. PMID- 21284433 TI - The face of pathology in Afghanistan in 2006-2007. AB - The current state of the practice of pathology in Afghanistan is described on the basis of visits made by the author to a nongovernmental organization hospital in Kabul, for 6 months between October 2006 and March 2007, and a second visit for 6 weeks at the end of 2007. PMID- 21284434 TI - Pathology services in developing countries-the West African experience. AB - CONTEXT: Histopathology, like other branches of medicine in West Africa, has suffered largely from economic, political, social, and infrastructural problems, becoming a shadow of the top quality that had been obtained in the past. To address the prevailing problems, one needs to attempt defining them. OBJECTIVE: The existing structure of training and practice are discussed, highlighting the author's perception of the problems and suggesting practical ways to address these while identifying potential roles for North American pathology organizations. DESIGN: The author's past and ongoing association with pathology practice in Nigeria forms the basis for this review. RESULTS: Pathology practice is largely restricted to academic medical centers. The largest of academic centers each accession around 4000 or fewer surgical specimens per year to train 9 to 12 residents. Histopathology largely uses hematoxylin-eosin routine stains, sometimes with histochemistry but rarely immunohistochemistry. Pathologists depend largely on their skills in morphology (with its limitations) to classify and subclassify tumors on routine stains, including soft tissue and hematolymphoid malignancies. Immunofluorescence, intraoperative frozen section diagnosis, electronic laboratory system, and gross and microscopic imaging facilities are generally not available for clinical use. CONCLUSION: The existing facilities and infrastructure can be augmented with provision of material and professional assistance from other pathology associations in more developed countries and should, among other things, focus on supplementing residency education. Virtual residency programs, short-visit observerships, development of simple but practical laboratory information systems, and closer ties with pathologists in these countries are some of the suggested steps in achieving this goal. PMID- 21284435 TI - Practice of forensic medicine and pathology in Sri Lanka. AB - The practice of forensic medicine and pathology in Sri Lanka is based on the British model. Medical students during their third and fourth years receive approximately 50 hours of lectures and tutorials in forensic medicine and pathology and then undergo an examination. After completing an internship, these doctors are sent to various hospitals throughout Sri Lanka where they may be asked to perform medicolegal examinations on victims and suspects in rape cases, persons suspected of being under the influence of drugs and/or alcohol, and, injured live patients. As well, they may be asked to perform medicolegal autopsies. Depending upon their experience, some medical officers may be designated as judicial medical officers and appointed full time to do medicolegal work. Up until 1980, judicial medical officers with at least 2 years of work experience were allowed to obtain their postgraduate qualifications in the United Kingdom. However, since 1981 and the establishment of its own Postgraduate Institute of Medicine in Colombo, Sri Lanka, medical officers are offered 2 postgraduate programs in forensic medicine and pathology, a diploma in legal medicine and a doctorate in medicine (forensic medicine). After completing the doctorate in forensic medicine, doctors are allowed to train abroad for a further year in an approved center. Upon return they can then be appointed as consultant judicial medical officers. The practice of forensic medicine and pathology in Sri Lanka is unique and vibrant. However, due to the country's prevailing civil war, the practice of forensic medicine and pathology is suboptimal. PMID- 21284436 TI - Pathology practice in a resource-poor setting: Mwanza, Tanzania. AB - Practicing pathology in a resource-poor setting presents many challenges that are unfamiliar to pathologists in developed countries. Typically, the number of pathologists in a resource-poor country is small, even as a percentage of the total medical workforce. Although pathology should play a central role in the delivery of appropriate health care to the patient, this role is often hidden and not well recognized by patients, clinical colleagues, or other stakeholders, such as administrators and politicians. The public tends to think of the pathologist as the "Doctor of the Dead." The financial rewards are also small. Consequently, it is difficult to recruit physicians into pathology. The lack of human and material resources allocated to pathology leads inevitably to a large gap in health care for many patients, with an unmeasured negative effect, at both the individual and societal levels. Correct management of the patient, even when available, is not administered because of the lack of pathologic information. Surgery may be performed without the benefit of preoperative or postoperative pathologic confirmation of the diagnosis, let alone identification of important prognostic information. The pathologist plays a key role as an educator in developing countries to medical students, allied health professionals, and medical colleagues and is, therefore, called upon to provide many hours of teaching. The pathologist is uniquely qualified to provide knowledge and understanding regarding the diseases in the region where he or she practices. Although many of these challenges are universal, they are perhaps nowhere more acute than in resource-poor settings. PMID- 21284437 TI - Breast carcinoma in Uganda: microscopic study and receptor profile of 45 cases. AB - CONTEXT: Histologic and receptor data on breast carcinoma in Uganda are scarce. Estrogen receptor status is not routinely available. Breast cancer blocks from Uganda were studied in Montreal, Canada, and clinical correlations subsequently discussed in Kampala, Uganda. OBJECTIVE: To correlate histologic features (tumor type, histologic grade), receptor profile (estrogen receptor, progesterone receptor, and HER2/neu), and age in Ugandan women. DESIGN: Pathology reports for 2000-2004 from Nsambya Hospital, reporting invasive breast carcinoma, provided 45 microscopically confirmed cases. RESULTS: Seventy-three percent of patients were 50 years or younger. Histologic types were invasive ductal carcinoma (78%) and "good" prognosis types (11%). Overall 40% were grade 3, but 48% of invasive ductal carcinomas were grade 3. Estrogen receptor was positive in 60% overall and in 51% of invasive ductal carcinomas. HER2/neu was overexpressed in 11%; 36% were "triple" negative (estrogen receptor, progesterone receptor, HER2/neu negative). CONCLUSIONS: Breast carcinoma in Ugandan women presents at a younger age and is histologically and by receptor profile more aggressive than carcinoma in Caucasian women. PMID- 21284438 TI - Cytopathology including fine-needle aspiration in sub-Saharan Africa: a Cameroon experience. AB - CONTEXT: Surgical pathology is unavailable in most of sub-Saharan Africa because of equipment costs and lack of expertise. Cytopathology is an inexpensive and reliable alternative. OBJECTIVE: To explore the utility of cytopathology in a rural hospital setting in Africa. DESIGN: A cytopathologist and a pathology resident from Calgary, Alberta, Canada, went to Cameroon to provide a cytopathology service at the Banso Baptist Hospital. Both performed the fine needle aspiration procedures. Direct smears were fixed in alcohol and stained with hematoxylin-eosin. Surgical specimens subsequently obtained from the patients were processed and reported at Calgary Laboratory Services, Canada. The histopathologic diagnoses were the gold standard for determining the accuracy of the cytologic diagnoses. RESULTS: Fifty-nine patients were examined during a 5 week period, 33 females (56%) and 26 males (44%). Sixteen (27%) were known to be HIV positive. Forty-four fine-needle aspiration procedures were performed for 43 patients (73%). The cost of each procedure was approximately US $10. Head and neck and breast were the sites most frequently sampled for aspirates. Cervical smears from 5 patients were also assessed, as were 8 fluid specimens and 2 touch preparations of prostatic core biopsies. The most frequent diagnoses for malignancy were carcinoma and lymphoma. Tuberculous lymphadenitis was diagnosed in 6 patients, 4 of whom were HIV positive. Surgical specimens were received from 18 patients (30%). Cytohistologic and clinicopathologic correlation revealed 1 false-positive (1.6%) and 1 false-negative (1.6%) diagnosis. CONCLUSION: Cytopathology is a reliable alternative for tissue diagnosis in low-resource settings. PMID- 21284439 TI - Field histology: Point-of-care microscopic technique. AB - CONTEXT: Standard histology services in geographically remote areas are often not available or have long turn-around time, resulting in delayed diagnosis or inappropriate treatment due to incomplete diagnostic data. The use of rapid tissue processing and a portable microtome technique may offer timely, point-of care histologic diagnosis to patients in a low resources setting, such as medical missions. OBJECTIVE: To present an alternative to the conventional histologic processing that will permit point-of-care histopathology service. DESIGN: A total of 21 tissue samples from a variety of sites were collected and subjected to a protocol of rapid manual tissue processing, lightweight portable field microtome sectioning, and hematoxylin-eosin staining. The histologic preparations were evaluated for diagnostic quality. The scoring of the preparations was based on completeness and uniformity of the sections, integrity of architectural features, cytologic detail, staining quality, and overall adequacy for diagnosis. RESULTS: Diagnostic quality microscopic slides were obtained from each of the 21 samples that included lesions of the skin, uterus, colon, and breast. The average preparation time, including routine hematoxylin-eosin staining, was 1.5 hours. CONCLUSIONS: We validated a point-of-care field histology technique that will be useful in settings of low resources, such as medical missions. Actual field testing of the procedure with special staining for fungi and acid-fast bacilli is the next step in the validation of the methodology. PMID- 21284440 TI - The future of telepathology for the developing world. AB - Physician shortages are acute in developing countries, where disease burden is the greatest and resources for health care are very limited. A lack of pathologists in these countries has lead to delays in diagnosis and misdiagnoses that adversely affect patient care and survival. The introduction of telepathology into countries with limited resources for health care is but one of multiple approaches that can be used to alleviate the problem. Telepathology is the electronic transmission of digital images that can be used for education and diagnostic consultation. A basic system consists of a microscope with a mounted digital camera linked to a computer. The ability to produce histologic slides, to repair and maintain equipment, and to provide training are also needed for the successful use of this technology. iPath is a Web-based, open platform, software application which was developed at the University of Basel, Switzerland, for telepathology and which brings together pathologists from around the world to provide telepathology support for diagnostic consultation and provides education to centers with limited resources. The use of virtual-slide technology to provide a digital image of an entire glass slide is another technology for diagnostic consultation and pathology education. This technology requires more costly resources to support it, which may limit its utility in many areas. Telepathology can generate collections of digital images and virtual slides needed for training indigenous pathologists in their countries to become self-sufficient. Thus, the long-term goal of this technology is to improve patient care and survival. PMID- 21284441 TI - Virtual surgical pathology in underdeveloped countries: The Zambia Project. AB - Only 1 surgical pathology laboratory is available in Zambia, a country with a population of 12 million people. Since 2004 the Italian association of pathologists Patologi Oltre Frontiera has been working to create a virtual laboratory through the use of telemedicine. The project has involved staining histologic preparations on site, with the interpretation of imaged slides performed abroad through telepathology. Starting in April 2007, all surgical specimens obtained in Mtendere Mission Hospital, Chirundu, Zambia, were submitted for microscopic examination through whole-slide scans. Two independent Italian pathologists evaluated the cases by means of satellite connection and the final diagnoses were sent to Zambian clinicians via the internet. This article describes the spectrum of diagnoses made via telepathology for the Zambian population. Also, we analyze the concordant and discordant data between this telepathology method and traditional microscopy in a developing country. Moreover, we provide possible solutions for providing pathology services in other underdeveloped countries. PMID- 21284442 TI - Malaria in Malawi: inside a research autopsy study of pediatric cerebral malaria. AB - CONTEXT: Malaria is still a major cause of death in sub-Saharan Africa. OBJECTIVES: To describe my participation as a pathologist in a research autopsy study in Malawi and to examine retinal pathologic findings in cerebral malaria and correlate them with those in the brain. To describe the challenges of conducting a research study in sub-Saharan Africa and the personal and scientific benefits resulting from this. DESIGN: Children with coma are admitted to the pediatric research ward, classified according to the clinical definition of severe malaria or another cause of coma, evaluated, and treated systematically. The eyes are examined by indirect ophthalmoscopy after dilatation. If a child dies and permission is given, a standardized autopsy is carried out. The patients' condition is then reclassified pathologically. RESULTS: Ninety autopsies have been completed, with the cause of death confirmed as cerebral malaria in 64 cases (71.1%). These patients showed heavy parasite sequestration and often extravascular pathologic findings in the brain, retina, gastrointestinal tract, and subcutaneous fat. Clinical and pathologic findings in the retina correlated with those in the brain, and ophthalmoscopy has become a useful tool in the diagnosis and prognosis of children with cerebral malaria. Twenty-eight percent of patients clinically classified as having cerebral malaria showed another cause of death and no malarial pathologic process or retinopathy. CONCLUSIONS: The human, financial, and transportation resources and organization required for this autopsy project are substantial. The scientific benefits are now becoming evident after sufficient autopsies have been completed for detailed comparisons. Personal benefits include the opportunity to work and travel in an African setting and to develop collaborations world-wide. PMID- 21284443 TI - External quality assurance of antithrombin, protein C, and protein s assays: results of the College of American Pathologists proficiency testing program in thrombophilia. AB - CONTEXT: Hereditary and acquired deficiencies of antithrombin (AT), protein C (PC), and protein S (PS) are risk factors for venous thromboembolism. Proper diagnosis requires high-quality assays for these proteins. OBJECTIVE: To determine the accuracy and interlaboratory precision of AT, PC, and PS assays used by laboratories participating in the United States College of American Pathologists proficiency testing program in thrombophilia and to grade the performance of laboratories. DESIGN: Standardized normal plasma with assigned analyte values was sent in 2 separate challenges to participating laboratories. Participants measured AT, PC, and PS levels using local methods. RESULTS: When compared with the assigned values for the international standard, the order of assay accuracy from highest to lowest was AT activity, PC antigen, AT antigen, total PS antigen, PC activity, PS activity, and free PS antigen (range of assay bias, 2.6%-8.8%). The order of assay precision from highest to lowest was PC activity, AT activity, AT antigen, total PS antigen, PS activity, free PS antigen, and PC antigen (range of assay coefficient of variation, 6.1%-20.0%). Most testing events (87.8%) could be graded as pass or fail using a target range of +/-3 standard deviations from the method-specific mean. The pass rate was 98.2% for all AT, PC, and PS testing events combined. CONCLUSIONS: Accuracy and precision were higher for AT assays and lower for PC and PS assays. It was feasible to grade individual laboratory performance. PMID- 21284444 TI - Observer variability in the interpretation of HER2/neu immunohistochemical expression with unaided and computer-aided digital microscopy. AB - CONTEXT: Observer variability in digital microscopy and the effect of computer aided digital microscopy are underexamined areas in need of further research, considering the increasing use and future role of digital imaging in pathology. A reduction in observer variability using computer aids could enhance the statistical power of studies designed to determine the utility of new biomarkers and accelerate their incorporation in clinical practice. OBJECTIVES: To quantify interobserver and intraobserver variability in immunohistochemical analysis of HER2/neu with digital microscopy and computer-aided digital microscopy, and to test the hypothesis that observer agreement in the quantitative assessment of HER2/neu immunohistochemical expression is increased with the use of computer aided microscopy. DESIGN: A set of 335 digital microscopy images extracted from 64 breast cancer tissue slides stained with a HER2 antibody, were read by 14 observers in 2 reading modes: the unaided mode and the computer-aided mode. In the unaided mode, HER2 images were displayed on a calibrated color monitor with no other information, whereas in the computer-aided mode, observers were shown a HER2 image along with a corresponding feature plot showing computer-extracted values of membrane staining intensity and membrane completeness for the particular image under examination and, at the same time, mean feature values of the different HER2 categories. In both modes, observers were asked to provide a continuous score of HER2 expression. RESULTS: Agreement analysis performed on the output of the study showed significant improvement in both interobserver and intraobserver agreement when the computer-aided reading mode was used to evaluate preselected image fields. CONCLUSION: The role of computer-aided digital microscopy in reducing observer variability in immunohistochemistry is promising. PMID- 21284445 TI - Cardiac troponin T measured with a highly sensitive assay for diagnosis and monitoring of heart injury in chronic Chagas disease. AB - CONTEXT: Chronic Chagas disease (15 million patients; annual incidence, 40, 000 patients; annual mortality, 12 ,500 patients) is the most serious parasitic disease in Latin America. Between 10 and 30 years after infection, 30% of patients with Chagas disease develop heart injury, which is the main reason for its high mortality. Consequently, frequent cardiac diagnostics are required for patients with Chagas disease. OBJECTIVE: To minimize time-intensive and cost intensive diagnostics, such as electrocardiography, echocardiography, and radiologic imaging, we tested the effect of measuring serum cardiac troponin T (cTnT) with a highly sensitive assay. To indicate the pathophysiologic background for cTnT release in Chagas heart injury, inflammation markers, such as C-reactive protein and interleukin 6, were measured in parallel. DESIGN: Serum cTnT was measured in 26 healthy subjects and in 179 patients with chronic Chagas disease who were asymptomatic (indeterminate stage, n = 86), who were suffering from cardiomyopathy with or without megacolon (n = 71), or who were suffering from megacolon exclusively (n = 22). RESULTS: Serum cTnT was significantly higher in patients with cardiomyopathy with or without megacolon than in healthy subjects, asymptomatic subjects, and patients with megacolon, and the cTnT value was correlated with the severity of the cardiomyopathy. The lower limit of detection for the highly sensitive assay (3 ng/L) was best at distinguishing patients with, and without, heart injury. C-reactive protein and interleukin 6 were found to parallel cTnT changes in both the different Chagas groups and the cardiomyopathy groups separated by disease severity. CONCLUSIONS: Highly sensitive cTnT measurement has the potential to contribute to diagnosis and monitoring of heart injury in patients with chronic Chagas disease. The highly sensitive assay of cTnT release seems to be related to Chagas heart disease-specific inflammation. PMID- 21284446 TI - The Movat pentachrome stain as a means of identifying microcrystalline cellulose among other particulates found in lung tissue. AB - CONTEXT: Microcrystalline cellulose (MCC) is extensively used as a filler material in pharmaceutical tablets. When injected intravenously in aqueous tablet suspensions, MCC may contribute to embolic pulmonary hypertension and be identified histologically in lung tissue samples. In this study, we evaluated a modified Russell Movat pentachrome stain (MMPS) as a means of recognizing MCC and distinguishing it from other birefringent crystals in lung specimens. OBJECTIVE: To study the staining properties of MCC versus other crystalline materials using the MMPS stain. DESIGN: Archival, formalin-fixed, paraffin-embedded lung specimens that contained birefringent crystals, including MCC (3 cases of intravenous drug abuse), talc (2 cases of intravenous drug abuse, 1 talc pleurodesis), mixed silicates (1 case of silicate pneumoconiosis), and calcium oxalate (1 case of aspergillosis from Aspergillus niger infection), were evaluated with MMPS. Crystal identification was confirmed by morphology, other histochemical stains, infrared spectroscopy (1 case), and cellulose controls. RESULTS: The MMPS stained the MCC bright yellow in tissue and control specimens. Talc stained light greenish-blue; mixed silicates appeared either greenish-blue or unstained. Oxalate crystals stained sea-green. Crospovidone, a nonbirefringent tablet filler substance, stained yellow to dark green with MMPS and was easily distinguished from MCC. Starch granules were unstained by MMPS. CONCLUSIONS: The MMPS is an excellent method for the histochemical identification of MCC in tissue and its separation from other birefringent crystals with which MCC might be confused. The MMPS is especially useful in the evaluation of pulmonary foreign body embolization in cases of suspected intravenous substance abuse. PMID- 21284447 TI - Advances in microscopy techniques. AB - CONTEXT: Advances in microscopy enable visualization of a broad range of new morphologic features. OBJECTIVE: To review and illustrate advances in microscopy with relevance to pathologists. DATA SOURCES: Literature review and new observations. RESULTS: Fluorescence microscopy enables multiantigen detection; allows novel optical-sectioning techniques, with some advantages compared to paraffin sectioning; and permits live-cell imaging. Live-cell imaging allows pathologists to move from a period when all diagnostic expertise was reliant on interpreting static images to a period when cellular dynamics can play a role in diagnosis. New techniques have bypassed by about 100-fold what had long been believed to be a limit to the resolution of light microscopy. Fluorescence resonance energy transfer (FRET) appears capable of visualizing diagnostically relevant molecular events in living or fixed cells that are immeasurable by other molecular techniques. We describe applications of 2-photon microscopy, FRET, structured illumination, and the subdiffraction techniques of near-field microscopy, photoactivated localization microscopy, stochastic optical reconstruction microscopy, and stimulated emission depletion microscopy. CONCLUSION: New microscopy techniques present opportunities for pathologists to develop improved diagnostic tests. PMID- 21284448 TI - Pancreatic mucinous cystic neoplasm of the main pancreatic duct. AB - Mucinous cystic neoplasm and intraductal papillary mucinous neoplasm are 2 types of cystic pancreatic mucinous tumors, each with its own distinct clinicopathologic features and pathogenetic mechanisms. We report here an unusual pancreatic mucinous neoplasm with features of both a mucinous cystic neoplasm and an intraductal papillary mucinous neoplasm in a 40-year-old woman who underwent total pancreatectomy. The endoscopic retrograde cholangiopancreatogram and gross examination demonstrated a mucin-producing intraductal neoplasm involving the length of the main pancreatic duct, typical of main duct intraductal papillary mucinous neoplasm, but histology of the main duct showed involvement by a biphasic tumor composed of columnar epithelium overlying ovarian-type stroma, characteristic of a mucinous cystic neoplasm. Immunohistochemistry confirmed that the stromal cells expressed estrogen and progesterone receptors, inhibin, and calretinin. Pancreatic mucinous cystic neoplasm involving the entire main pancreatic duct has not, to our knowledge, been previously reported. PMID- 21284449 TI - Epithelioid angiosarcoma: a brief diagnostic review and differential diagnosis. AB - Epithelioid angiosarcoma is a highly aggressive endothelial cell malignancy, most commonly arising in the deep soft tissues, but a variety of primary sites, including the adrenals, thyroid, skin, and bone, are encountered. On hematoxylin eosin-stained sections, the pathologist encounters sheets of large, mildly to moderately pleomorphic epithelioid cells, with abundant eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli. Obvious vasoformative foci may not be present, creating confusion with metastatic carcinomas, malignant mesothelioma, melanoma, anaplastic lymphoma, epithelioid peripheral nerve sheath malignancies, and epithelioid sarcoma. Moreover, malignancies with apparent vascular differentiation must be distinguished from less aggressive vascular neoplasms, including epithelioid hemangioendothelioma. Given the range of clinical presentation, the diversity of primary sites, and the nonspecific initial histopathologic appearance, here we review the histologic findings and immunohistochemical profiles of epithelioid angiosarcoma and neoplasms in its differential diagnosis. PMID- 21284450 TI - Deep brain stimulation for the treatment of drug-refractory epilepsy in a patient with a hypothalamic hamartoma. Case report. AB - Hypothalamic hamartomas (HHs) are developmental malformations associated with a range of neurological problems, including intractable seizures. There is increasing evidence of the epileptogenicity of the hamartoma and of the inhomogeneous distribution of the epileptic abnormalities within the malformation. The management strategy for treatment and results differ according to the insertion plane and the extension of the malformation into the hypothalamus. Cases characterized by extensive involvement of the hypothalamus are particularly challenging. The authors describe the case of a patient with drug-resistant epilepsy and a large hypothalamic hamartoma with an extensive area of attachment. The patient underwent implantation of 2 deep brain electrodes. The intraoperative recording showed a synchronous interictal epileptic discharge in the left temporal lobe and on the left side of the lesion. The patient was treated with chronic high-frequency stimulation. No side effects due to the stimulation were reported. At 18 months' follow-up, a reduction in complex partial seizure frequency was reported, but no significant reduction in overall seizure frequency was noticed (p = 0.14, t-test). The authors report on neurophysiological studies of the relationship between HH and epilepsy, and also discuss the literature on chronic high-frequency stimulation, including its rationale and the results of chronic stimulation of various targets for the treatment of drug-resistant epilepsy due to HH. PMID- 21284451 TI - Long-term outcome after emergency resection of hypothalamic hamartomas for status gelasticus. AB - OBJECT: Gelastic seizures are epileptic events characterized by bouts of laughter. They are rare and mostly associated with hypothalamic hamartomas (HHs). Status gelasticus, a rare form of status epilepticus, is defined as a prolonged cluster of gelastic seizures (> 20-30 minutes) without necessarily involving loss of awareness between seizures. Emergency resection of the hamartoma is highly effective in these situations and should be considered as early as possible. The authors retrospectively reviewed their surgical cases to document the success, complications, and long-term follow-up after emergency resection of HHs for status gelasticus. METHODS: The authors report on a retrospective case series from a single tertiary care center. Three patients who presented with status gelasticus underwent emergency resection of HHs. Demographic details, seizure history, medical treatment, and postoperative follow-up data were evaluated. Long term follow-up (minimum 2 years) data were obtained either from the last clinic visit notes or via telephone and e-mail contacts. The institutional review board at St. Joseph's Hospital approved this study. RESULTS: In the last 7 years, of 157 patients who underwent HH resection, the resection was performed on an emergency basis for status gelasticus in 3 cases. At emergency surgery, these 3 patients ranged in age from 9 months to 3.5 years. All of the patients were boys. Delalande and Fohlen Type II, III, and IV lesions were present in the 3 patients. Surgical approaches for resection of HH included an orbitozygomatic, transcallosal anterior interforniceal approach and endoscopic resection. Status gelasticus was terminated following emergency surgery in all cases, and 1 patient was seizure free. Postsurgical complications included, in 1 case, a small right thalamic infarct with mild transient left hemiparesis, which completely resolved within 2 days. Within 2 years of their original surgery, 2 patients underwent further elective surgeries (endoscopic resection and radiosurgery for persistent symptomatic seizures). Follow-up since their most recent surgery ranged from 8 months to 2 years. Two patients were seizure free and 1 patient had greater than 50% reduction in seizures. CONCLUSIONS: Status gelasticus associated with HHs can be successfully terminated by emergency resection of the HH. Long-term follow-up in the present series suggests good seizure freedom results or at least greater than 50% reduction in seizures, although repeat operations were necessary. PMID- 21284452 TI - Syndrome of alternating hypernatremia and hyponatremia after hypothalamic hamartoma surgery. AB - OBJECT: In this paper, the authors' goal was to describe the occurrence of alternating hypernatremia and hyponatremia in pediatric patients who underwent resection of hypothalamic hamartomas (HHs) for epilepsy. Hypernatremia in patients after pituitary or hypothalamic surgery can be caused by diabetes insipidus (DI), whereas hyponatremia can occur due to a syndrome of inappropriate antidiuretic hormone, cerebral salt wasting, or excessive administration of desmopressin (DDAVP). The triphasic response after surgery in the pituitary region can also explain variations in sodium parameters in such cases. METHODS: One hundred fifty-three patients with HH who underwent surgery were enrolled in a prospective study to monitor outcomes. Of these, 4 patients (2.6%) were noted to experience dramatic alterations in serum sodium values. The medical records of these patients were identified and evaluated. RESULTS: Patients' ages at surgery ranged from 1.2 to 6.0 years. All patients were girls. Two patients had Delalande Type IV lesions (of 16 total Type IV lesions surgically treated) and 2 had Type III lesions (of 39 total Type III lesions). All patients had a history of gelastic seizures refractory to medication. Seizure frequency ranged from 3 to 300 per day. After surgery, all patients experienced hypernatremia and hyponatremia. The largest fluctuation in serum sodium concentration during hospitalization in a single patient was 53 mEq/L (range 123-176 mEq/L). The mean absolute difference in maximum and minimum sodium values was 38.2 mEq/L. All patients exhibited an initial period of immediate DI (independent of treatment) after surgery followed by a period of hyponatremia (independent of treatment), with a minimum value occurring between postoperative Days 5 and 8. All patients then returned to a hypernatremic state of DI, and 3 patients still require DDAVP for DI management. A second occurrence of hyponatremia lasting several days without DDAVP administration occurred in 2 patients during their hospitalization between periods of hypernatremia. One patient stabilized in the normal range of sodium values prior to discharge from rehabilitation without the need for further intervention. At last follow-up, 3 patients are seizure-free. CONCLUSIONS: Severe instability of sodium homeostasis with hypernatremia and hyponatremia is seen in up to 2.6% of children undergoing open resection of HH. This risk appears to be related to HH type, with a higher risk for Types III (2 [5.1%] of 39) and IV (2 [12.5%] of 16) lesions. Here, the authors describe alternating episodes of hypernatremia and hyponatremia in the postoperative period following HH surgery. Management of this entity requires careful serial assessment of volume status and urine concentration and will often require alternating salt replacement therapy with DDAVP administration. PMID- 21284453 TI - Giant solid-cystic hypothalamic hamartoma. Case report. AB - Hypothalamic hamartomas are rare lesions for which different classification schemes have been proposed. The authors report on an exceptionally large solid cystic hamartoma that led to hydrocephalus, precocious puberty, and intractable gelastic seizures. They discuss potential mechanisms of the development of hypothalamic hamartomas. PMID- 21284454 TI - Egas Moniz (1874-1955) and the "invention" of modern psychosurgery: a historical and ethical reanalysis under special consideration of Portuguese original sources. AB - The Portuguese neurologist Egas Moniz (1874-1955) is often regarded as the founder of psychosurgery. He performed the first prefrontal leukotomy in 1935 about 75 years ago-with the help of neurosurgeon Almeida Lima (1903-1985) [corrected]. In contrast to the psychosurgical interventions performed by the Swiss psychiatrist Gottlieb Burckhardt (1836-1907), Moniz's interventions on the white brain substance caught great attention worldwide. As a matter of fact, it was this repercussion that led to the award of the Nobel Prize for Medicine in 1949, an award that is still highly controversial today. The goal of the present article is to reconstruct the historical background of the first leukotomies, the tangible expert debate since 1935 on the indication and legitimacy of these interventions, and their contemporary and recent (ethical) evaluation. Special focus will be set on the original Portuguese literature, which has been given too little attention thus far in the English-language literature. PMID- 21284455 TI - Preoperative and postoperative developmental attainment in patients with sagittal synostosis: 5-year follow-up. AB - OBJECT: The object of this study was to clarify whether improved developmental attainment following surgical correction of sagittal synostosis (SS), previously identified at initial postoperative assessment, is maintained at longer-term follow-up at 5 years of age. METHODS: The study involved 32 children with SS who underwent corrective surgery at a mean (+/- SD) age of 8.5 +/- 7.25 months (range 2.8-39.9 months). All the children were assessed preoperatively, at 7 months postoperatively, and at 5 years of age, using the Griffiths Mental Development Scales. A control group consisted of 23 children with SS who had received developmental assessment on 2 or more occasions without surgical intervention (8 of these children had had follow-up at 5 years of age). RESULTS: The data indicated that, prior to surgical correction, children with SS had poorer Gross Locomotor function than other areas of development and that, following surgical intervention, the deficit resolved (even where there was severe developmental delay). The results further showed that improvement in Gross Locomotor function observed at 7 months postoperatively was further improved upon by 5 years of age. The same was true for their overall General Quotient, even in those children exhibiting severe developmental delay. Lesser improvements across time were shown for other skill areas. The children with SS who did not undergo surgery did not show any improvement in development, and in fact a deterioration in fine locomotor control was identified in these patients. CONCLUSIONS: The results of this study suggest that corrective surgery for SS has a positive early impact on development, which is maintained and improved upon by 5 years of age, and that this surgery therefore offers more than simply a cosmetic improvement. Furthermore, the results suggest that not operating on children with SS means not only that this opportunity for developmental gain is missed, but that it may also cause an actual deterioration in developmental attainment. PMID- 21284456 TI - Factors affecting survival of infants with myelomeningocele in southeastern Uganda. AB - OBJECT: The survival of infants treated for myelomeningocele (MM) and hydrocephalus in Uganda is unknown. This study investigated 5-year survival and the factors that influenced death in these patients. METHODS: All 140 children from 16 contiguous districts in southeastern Uganda presenting to CURE Children's Hospital of Uganda for repair of MM prior to 6 months of age between December 2000 and December 2004 comprised the study cohort. Nine patients died within 1 month (6.4% operative mortality) and were excluded from further analysis. Sixty seven (51%) required treatment for hydrocephalus. Survival status could not be determined for 3 patients (2%). Circumstances of death were ascertained by hospital record or interview. The Kaplan-Meier method was used for survival analysis. Association between survival and district of origin, age at MM closure, MM lesion level, presence of hydrocephalus, and method of hydrocephalus treatment were investigated. RESULTS: The median follow-up was 86 months. Seventy-three children (56%) were alive at the time of the study, and 81 (63%) had survived more than 5 years. The under-5 mortality rate was 37% (2.5 times greater than the general population). Only 4 deaths appeared directly related to hydrocephalus or MM. There was no significant association between survival and age at MM closure, MM lesion level, presence of hydrocephalus, or its method of treatment. Mortality was lower, approaching that for their unaffected peers, in districts with community-based rehabilitation programs (p = 0.001). CONCLUSIONS: Community-based support following surgical interventions for MM and hydrocephalus appears essential to the continued survival of these children in Africa. PMID- 21284457 TI - Variability among pediatric neurosurgeons in the threshold for ventricular shunting in asymptomatic children with hydrocephalus. AB - OBJECT: The thresholds for shunting CSF in children with asymptomatic hydrocephalus are unclear; there are neither guidelines nor sufficient research to determine what degree of hydrocephalus should be treated. The authors hypothesize that 1) pediatric neurosurgeons currently have high thresholds for recommending treatment for these children, but 2) there is significant variability among these treatment thresholds. METHODS: The authors surveyed attendees of the Joint Pediatric Neurosurgery Section meeting in Spokane, Washington, in December 2008, regarding their treatment thresholds for 22 clinical scenarios. Each participant was provided an illustration of 5 imaging studies (3 slices each) showing progressively larger ventricles. For each scenario, respondents were asked to indicate the minimum ventricular size they would treat, if any. Responses were quantified from 1 to 6 from smaller to larger, with 6 being no treatment, and a mean theoretical treated ventricular size (MTTVS) was calculated for each scenario. RESULTS: Respondents were relatively conservative in recommending treatment, with MTTVSs of 3.7-6.0; in 13 scenarios, the MTTVS was greater than 5.0 (larger than the largest presented ventricular size). For scenarios in which a mean frontooccipital ratio could be calculated, the value ranged from 0.55 to 0.67 (moderate to severe hydrocephalus). Although there were clear majority responses for each scenario, there was also significant variability. There were no patterns of association with the respondent's age, training, board certification, or type or location of practice. CONCLUSIONS: This study demonstrates that pediatric neurosurgeons' thresholds for treating asymptomatic children with hydrocephalus are generally high, but there is also significant variability. PMID- 21284458 TI - Use of the ETV Success Score to explain the variation in reported endoscopic third ventriculostomy success rates among published case series of childhood hydrocephalus. AB - OBJECT: Published case series of endoscopic third ventriculostomy (ETV) for childhood hydrocephalus have reported widely varying success rates. The authors recently developed and internally validated the ETV Success Score (ETVSS); this is a simplified means of predicting the 6-month success rate of ETV for a child with hydrocephalus, based on age, etiology of hydrocephalus, and presence of a previous shunt. The authors hypothesized that the ETVSS would be able to predict with reasonable accuracy the actual ETV success rate reported among published case series. METHODS: A literature search was performed to identify published pediatric ETV papers that contained enough information with which to calculate an aggregate, mean predicted ETVSS for the cohort. This was then compared with the actual ETV success rate in the cohort. Data were extracted independently in triplicate, including by 2 individuals who were not involved with the development of the ETVSS. RESULTS: Fifteen papers reporting on 322 patients were included. Interrater reliability was very high in determining the predicted ETVSS (intraclass correlation coefficient 0.99). The predicted ETVSS for each paper agreed strongly with the actual ETV success rate reported in each paper (reliability intraclass correlation coefficient 0.81). There was no significant difference in the magnitude of the predicted ETVSS and the actual ETV success (p = 0.98, paired t-test). In a linear regression model, the predicted ETVSS explained 62% of the variation in actual ETV success. When the entire cohort was combined and analyzed together, the overall mean predicted ETVSS was 57.9%, which was nearly identical to the actual ETV success rate of 59.2%. CONCLUSIONS: The ETVSS closely predicts the actual ETV success rate reported in selected papers published over the last 20 years and explains much of the variation. PMID- 21284459 TI - Analysis of the risk of shunt failure or infection related to cerebrospinal fluid cell count, protein level, and glucose levels in low-birth-weight premature infants with posthemorrhagic hydrocephalus. AB - OBJECT: Premature, low-birth-weight infants with posthemorrhagic hydrocephalus have a high risk of shunt obstruction and infection. Established risk factors for shunt failure include grade of the hemorrhage and age at shunt insertion. There is anecdotal evidence that the amount of red blood cells or protein levels in the CSF may affect shunt performance. However, this has not been analyzed specifically for this cohort of high-risk patients. Therefore, the authors performed this study to examine whether any statistical relationship exists between the CSF constituents and the rate of shunt malfunction or infection in this population. METHODS: A retrospective cohort study was performed on premature infants born at Riley Hospital for Children from 2000 to 2009. Inclusion criteria were a CSF sample analyzed within 2 weeks prior to shunt insertion, low birth weight (< 1500 grams), prematurity (birth prior to 37 weeks estimated gestational age), and shunt insertion for posthemorrhagic hydrocephalus. Data points included the gestational age at birth and shunt insertion, weight at birth and shunt insertion, history of CNS infection prior to shunt insertion, shunt failure, shunt infection, and the levels of red blood cells, white blood cells, protein, and glucose in the CSF. Statistical analysis was performed to determine any association between shunt outcome and the CSF parameters. RESULTS: Fifty-eight patients met the study entry criteria. Ten patients (17.2%) had primary shunt failure within 3 months of insertion. Nine patients (15.5%) had shunt infection within 3 months. A previous CNS infection prior to shunt insertion was a statistical risk factor for shunt failure (p = 0.0290) but not for shunt infection. There was no statistical relationship between shunt malfunction or infection and the CSF levels of red blood cells, white blood cells, protein, or glucose before shunt insertion. CONCLUSIONS: Low-birth-weight premature infants with posthemorrhagic hydrocephalus have a high rate of shunt failure and infection. The authors did not find any association of shunt failure or infection with CSF cell count, protein level, or glucose level. Therefore, it may not be useful to base the timing of shunt insertion on CSF parameters. PMID- 21284460 TI - Fourth ventriculostomy: an alternative treatment for hydrocephalus due to atresia of the Magendie and Luschka foramina. AB - Atresia of the foramina of Magendie and Luschka is a rare cause of obstructive hydrocephalus. Although this condition has been classically treated by CSF shunting, recent treatments have also included endoscopic third ventriculostomy. In the present study, the authors present the case of a patient with hydrocephalus in whom an alternative method was used following a CSF shunt malfunction. A young female patient in whom a shunt was placed during the patient's 1st year of life was faring well until she was 8 years old. She was admitted to the emergency department 5 times with signs of CSF shunt malfunction. Each time, the CT scan showed a slight dilation of the lateral and third ventricles and a large increase in the size of the fourth ventricle. In comparison, ventricles were smaller in a previous imaging study obtained when the patient was asymptomatic. Magnetic resonance imaging showed the same slight dilation of all the ventricles and a significant increase in the fourth ventricle. There was no aqueductal stenosis. An important enlargement of both lateral recesses of the fourth ventricle suggested the possibility of an atresia of the foramina. The foramen of Monro and the width of the third ventricle would not allow the passage of an endoscope. The decision was made to open those foramina endoscopically through the fourth ventricle. After induction of general anesthesia, with the patient in the prone position, a bur hole was made in the left paramedian and suboccipital region. The endoscope was introduced underneath the cerebellar hemisphere. The authors were then able to distinguish the floor of the fourth ventricle and other anatomical landmarks. Navigation through the lateral recesses allowed them to see the fine membranes closing the foramina. These membranes were opened with a monopolar cautery as a blunt instrument. The orifice was then enlarged with a 3 Fr Fogarty catheter. The authors also opened a bulging thin membrane located at the foramen of Magendie. During the postoperative period, the authors observed a marked improvement in the state of the patient's alertness as well as a disappearance of her headaches and cessation of vomiting. In addition, the patient's gait ataxia improved slowly. Six-month postoperative MR imaging demonstrated an unequivocal reduction in the size of the fourth ventricle. The patient was still doing well 36 months after the surgery. Endoscopic fourth ventriculostomy, the opening of the 3 foramina of the fourth ventricle, may be an alternative treatment in cases in which these structures are congenitally closed. PMID- 21284461 TI - Endoscopic fenestration of a cerebellopontine angle arachnoid cyst resulting in complete recovery from sensorineural hearing loss and facial nerve palsy. AB - Cerebellopontine angle arachnoid cysts are usually asymptomatic, but are frequently found incidentally because of increased use of neuroimaging. Nevertheless, as these cysts enlarge, they may compress surrounding structures and cause neurological symptoms. Patients may present with vague, nonspecific symptoms such as headache, nausea, vomiting, and vertigo. Cranial nerve palsies, including sensorineural hearing loss and facial weakness, although rare, have also been reported in association with posterior fossa arachnoid cysts. Although surgery for these entities is controversial, arachnoid cysts can be treated surgically with open craniotomy for cyst removal, fenestration into adjacent arachnoid spaces, shunting of cyst contents, or endoscopic fenestration. Reversal of sensorineural hearing loss following open craniotomy treatment has been described in the literature in only 1 adult and 1 pediatric case. Improvement in facial weakness has also been reported after open craniotomy and arachnoid cyst fenestration. The authors report the first case of complete recovery from sensorineural hearing loss and facial weakness following endoscopic fenestration in a patient with a cerebellopontine angle arachnoid cyst. PMID- 21284462 TI - Endoscopy-assisted removal of periorbital inclusion cysts in children. AB - OBJECT: Surgical treatment for periorbital inclusion cysts typically involves a brow, pterional, or partial bicoronal scalp incision for sufficient exposure. The authors have recently employed an endoscopy-assisted technique as an alternative approach intended to minimize the length of the skin incision and avoid scarring in the brow. METHODS: Children having typical clinical findings of a dermoid cyst located on the hairless forehead were selected to undergo endoscopy-assisted cyst removal. For suspected intradiploic lesions, MR imaging was used to assess osseous involvement. After induction of general anesthesia, a 1-2-cm curvilinear incision was made posterior to the hairline. A 30 degrees -angled endoscope (4 mm) was then used for dissection in the subgaleal compartment. Subgaleal dissection was followed by a circumferential periosteal incision in which the authors used an angled needle-tip unipolar cautery. For lesions within the diploe, a high-speed air drill was used to expose the lesion. Complete removal was accomplished with curettage of either the skull or dural surface. RESULTS: Eight patients (5-33 months of age) underwent outpatient endoscopic resection. Seven cysts were extracranial, and 1 cyst extended through the inner table. In all patients complete excision of the cyst was achieved. There was negligible blood loss, no dural violation, and no postoperative infection. There have been no recurrences at a mean follow-up of 15 months. CONCLUSIONS: Endoscopy-assisted resection of inclusion cysts of the scalp and calvaria is a safe and effective surgical approach. The technique results in negligible incisions with less apparent scarring compared with previously described incisions. This limited access technique does not appear to be associated with a higher incidence of cyst recurrence. PMID- 21284464 TI - Giant glioependymal cyst in an infant. AB - The authors report the case of an infant with a giant glioependymal cyst. Although it has been suggested that these cysts originate from the tela choroidea, their origin remains controversial. This 35-month-old girl with truncal ataxia was referred to the authors' hospital. Magnetic resonance imaging revealed a giant cystic mass extending from the anterior to the posterior cranial fossa. Hydrocephalus was caused by obstruction of the sylvian aqueduct. Endoscopic fenestration of the cyst wall was performed. Histochemical and immunohistochemical staining identified the lesion as a glioependymal cyst. Magnetic resonance imaging performed 8 months later suggested that the cyst originated from the tela choroidea. At 5-year follow-up, there was no tumor recurrence and she had fully recovered. The origin of glioependymal cysts is discussed, and the authors suggest that their origin is the tela choroidea. PMID- 21284463 TI - Use of T2 signal intensity of cerebellar neoplasms in pediatric patients to guide preoperative staging of the neuraxis. AB - OBJECT: The question of whether to obtain routine or selective preoperative imaging of the neuraxis in pediatric patients with cerebellar neoplasms remains a controversial topic. Staging of the neuraxis is generally considered beneficial in patients with neoplasms associated with an elevated risk of leptomeningeal dissemination (LD). When these studies are obtained preoperatively, there is a decrease in the number of false-positive images related to debris in the immediate postoperative period. Additionally, knowledge of the extent of spread has the potential to affect the risk/benefit analysis of aggressive resection. Although the majority of pediatric neurosurgeons surveyed choose to obtain selective preoperative imaging of the neuraxis in cases of cerebellar neoplasms "with findings suggestive of high-grade pathology," an evidence-based protocol in the literature is lacking. The goal of this study was to assess radiological characteristics of tumors with an elevated risk of LD and identify a method to help guide preoperative imaging of the neuraxis. METHODS: The authors first reviewed the literature to gain an appreciation of the risk of LD of pediatric cerebellar neoplasms based on underlying histopathology and/or grade. Available evidence indicates preoperative imaging of the neuraxis in patients with Grade I tumors to be of questionable utility. In contrast, evidence suggested that preoperative imaging of the neuraxis in patients with Grades II-IV neoplasms was clinically warranted. The authors then evaluated an extensive base of neuroradiological literature to identify possible MR imaging and/or CT findings with the potential to differentiate Grade I from higher-grade neoplasms in pediatric patients. They analyzed the preoperative radiological findings in 50 pediatric patients who had undergone craniotomy for resection of cerebellar neoplasms at Vanderbilt Children's Hospital since 2003 with reference to 7 chosen radiological criteria. Logistic regression models were fit using radiological features to determine the best predictors of Grades II-IV tumors. Receiver operating characteristic methods were used to identify diagnostic properties of the best predictors. RESULTS: The relative T2 signal intensity (RT2SI), an indirect measure of the water content of the solid component of the tumor, was best able to identify neoplasms with an elevated risk of LD. An RT2SI value of 0.71 was selected by the authors as the best operating point on the curve. Of the 31 neoplasms retrospectively designated as hypointense T2-weighted lesions (RT2SI <= 0.71), 30 (97%) were Grade II or higher. All medulloblastomas, ependymomas, and high-grade (Grades III and IV) neoplasms were hypointense T2-weighted lesions. Of the 19 T2-weighted hyperintense neoplasms (RT2SI > 0.71), 16 (84%) were Grade I and 3 were Grade II. CONCLUSIONS: Measurement of the RT2SI can help predict Grade II-IV tumors at an elevated risk of leptomeningeal spread and guide staging of the neuraxis. Pediatric patients with cerebellar neoplasms found to have an RT2SI of less than or equal to 0.71 are recommended for neuraxis imaging prior to surgery. PMID- 21284465 TI - Extratemporal, nonlesional epilepsy in children: postsurgical clinical and neurocognitive outcomes. AB - OBJECT: Patients undergoing epilepsy surgery without evidence of a lesion on MR imaging and without a temporal source for seizure onset generally have less favorable outcomes than patients with structural lesions or temporal onset. However, many of these patients are viable candidates for invasive monitoring and subsequent resection or multiple subpial transections (MSTs). The purpose of this study was to evaluate the surgical treatment of pediatric patients with extratemporal, nonlesional epilepsy in order to better understand the clinical and neuropsychological outcomes expected in this patient group. METHODS: Forty three pediatric patients with negative results on MR imaging and lateralized, extratemporal findings on electroencephalography underwent invasive monitoring with grid and/or strip electrodes. Thirty-three subsequently had resection of an epileptogenic focus and/or MSTs. RESULTS: Outcome was classified as Engel class I or II in 54.5% of the patients who underwent resection/MSTs and Engel class III or IV in 45.5%. Use of MSTs was associated with poor outcome. Neuropsychological evaluation showed significant improvement in immediate auditory attention following surgery and revealed several significant results on subgroup analysis. Complications occurred in 14% of patients (a 7% rate per procedure). Ten patients (23%) underwent invasive monitoring without proceeding to therapeutic surgery because no epileptogenic region was amenable to resection. Neuropsychological outcomes were generally stable. CONCLUSIONS: Patients with extratemporal, nonlesional seizures are viable candidates for invasive monitoring with grid/strip electrodes, and good outcomes can be obtained with resective surgery. The use of MSTs may correlate with worse outcome. This study also provides additional data to assist in counseling patients on the risks of negative invasive monitoring, deficits resulting from resection/MSTs, and possible operative complications. PMID- 21284466 TI - Corpus callosotomy in multistage epilepsy surgery in the pediatric population. AB - OBJECT: The object of this study was to evaluate surgical outcome in a select group of patients with medically refractory epilepsy who had undergone corpus callosotomy combined with bilateral subdural electroencephalography (EEG) electrode placement as the initial step in multistage epilepsy surgery. METHODS: A retrospective chart review of 18 children (ages 3.5-18 years) with medically refractory symptomatic generalized or localization-related epilepsy was undertaken. A corpus callosotomy with subdural bihemispheric EEG electrode placement was performed as the initial step in multistage epilepsy surgery. All of the patients had tonic and atonic seizures; 6 patients also experienced complex partial seizures. All of the patients had frequent generalized epileptiform discharges as well as multifocal independent epileptiform discharges on surface EEG monitoring. Most of the patients (94%) had either normal (44%) MR imaging studies of the brain or bihemispheric abnormalities (50%). One patient had a suspected unilateral lesion (prominent sylvian fissure). RESULTS: Of the 18 patients who underwent corpus callosotomy and placement of subdural strips and grids, 12 progressed to further resection based on localizing data obtained during invasive EEG monitoring. The mean patient age was 10.9 years. The duration of invasive monitoring ranged from 3 to 14 days, and the follow-up ranged from 6 to 70 months (mean 35 months). Six (50%) of the 12 patients who had undergone resection had an excellent outcome (Engel Class I or II). There were no permanent neurological deficits or deaths. CONCLUSIONS: The addition of invasive monitoring for patients undergoing corpus callosotomy for medically refractory epilepsy may lead to the localization of surgically amenable seizure foci, targeted resections, and improved seizure outcomes in a select group of patients typically believed to be candidates for palliative surgery alone. PMID- 21284467 TI - Delayed development of os odontoideum after traumatic cervical injury: support for a vascular etiology. AB - A previously healthy 2-year-old girl sustained a C1-2 ligamentous injury after a motor vehicle accident and underwent successful halo immobilization, with postimmobilization images showing good cervical alignment. At the time, plain radiography, CT scanning, and MR imaging showed a normal odontoid. Four years later, however, the patient was found to have an os odontoideum, evident on plain radiography and CT imaging. At the 10-year follow-up, the os odontoideum had not been surgically repaired, and the child had mild hypermobility. This is the first documented case in the modern imaging era of delayed os odontoideum formation after definitive CT scanning showed no fracture. As such, this suggests that os odontoideum may result from traumatic vascular interruption in the developing spine, with resulting osseous remodeling leading to an os odontoideum. This case argues against the congenital etiology of os odontoideum, as well as the strict posttraumatic theory whereby a trauma-induced odontoid fracture leads to osseous remodeling and subsequent development of an os odontoideum. PMID- 21284468 TI - Spinal epidural abscess in a neonate. AB - Spinal epidural abscess constitutes a neurosurgical emergency in which early diagnosis and prompt decompression are necessary to avoid permanent cord damage. This entity is rare in premature infants and neonates in whom diagnosis can be challenging. The authors present a case of a premature twin neonate who developed an epidural abscess with complete paraparesis after coagulase-negative Staphylococcus epidermidis bacteremia that was treated with a single-level flavotomy and catheter irrigation. PMID- 21284469 TI - Presentation and progression of a disc cyst in a pediatric patient. AB - Disc cysts are rare intraspinal extradural lesions that communicate with the intervertebral disc and can mimic the symptoms of acute lumbar disc herniation. Initially reported in the Japanese-language literature as a new entity (discal cyst), there are few documented cases in North America, and only 1 prior case in the pediatric population. The authors present the case of a 16-year-old girl with an intervertebral disc cyst causing lumbar radiculopathy that progressed despite conservative treatment. All medical records, imaging studies, intraoperative findings, and pertinent literature were reviewed. Serial preoperative MR imaging revealed enlargement of the intraspinal cyst at the L4-5 level, resulting in compression of the right L-5 nerve root. Enlargement of the cyst occurred over a 4-month period despite conservative treatment with physical therapy and corticosteroid injections. Microsurgical discectomy and excision of the cyst resulted in complete resolution of the preoperative radiculopathy. An intervertebral disc cyst is a rare entity in the adult population and exceedingly rare in the pediatric population but should remain in the differential diagnosis of any intraspinal extradural mass. The authors hypothesize that there exists a spectrum of this entity that may not be responsive to conservative therapy. Cyst excision alone or in conjunction with microsurgical discectomy is safe and effective in treating radiculopathy caused by disc cysts. PMID- 21284470 TI - Posttraumatic subgaleal and orbital hematoma due to factor XIII deficiency. AB - The authors report on a 6-year-old boy who presented with a tense subgaleal hematoma and proptosis 2 weeks after a minor head injury that were successfully managed by continuous closed-system drainage and blood transfusion. At evaluation he was found to have a transient mild factor XIII deficiency. PMID- 21284471 TI - Craniosynostosis. PMID- 21284473 TI - Erratum. Predicting who will benefit from endoscopic third ventriculostomy compared with shunt insertion in childhood hydrocephalus using the ETV Success Score. Clinical article. PMID- 21284474 TI - Fear of hypoglycemia in type 1 diabetes managed by continuous subcutaneous insulin infusion: is it associated with poor glycemic control? AB - BACKGROUND: We surveyed the extent of fear of hypoglycemia in people with type 1 diabetes treated by continuous subcutaneous insulin infusion (CSII) and tested the hypothesis that suboptimal glycemic control during CSII is related to fear of hypoglycemia. METHODS: We audited nonpregnant type 1 diabetes patients attending an Insulin Pump Clinic with at least 6 months' duration of CSII. In 104 eligible subjects, fear of hypoglycemia was assessed by questionnaire; 75 responded. RESULTS: The median duration of CSII was 5 years (range, 1-29 years). Poor glycemic control (hemoglobin A1c [HbA1c] >= 8.5%; mean +/- SD, 9.1 +/- 1.0%) was present in 27%, and this group had more men than a good-control group with HbA1c < 7.0% (43% vs. 11%). Substantial fear of hypoglycemia (score > 50%) occurred in 27% of subjects, but fear of hypoglycemia was not correlated with HbA1c. The only significant correlates of fear of hypoglycemia were accumulated episodes of severe hypoglycemia (r = 0.48, P < 0.001) and rate of hypoglycemia on CSII (r = 0.48, P < 0.001). The HbA1c on CSII was correlated with multiple daily injection (MDI) HbA1c (r = 0.66, P < 0.001) and the change in HbA1c (r = 0.63, P < 0.001). CONCLUSIONS: Fear of hypoglycemia is not correlated with, and is unlikely to be a major determinant of, HbA1c on CSII. Other factors (such as HbA1c on MDI and adherence to insulin pump procedures) are likely to be more important. Nevertheless, substantial fear of hypoglycemia is present in many CSII-treated people and may adversely affect quality of life and psychological well-being. PMID- 21284475 TI - Use of integrated real-time continuous glucose monitoring/insulin pump system in children and adolescents with type 1 diabetes: a 3-year follow-up study. AB - BACKGROUND: Insulin pumps and real-time continuous glucose monitoring devices have recently been combined into the sensor-augmented pump (SAP) system. The objective of this study was the evaluation of the clinical use of SAP in a large series of children with type 1 diabetes using insulin pump therapy. METHODS: A questionnaire was administered in all pediatric diabetologic centers in Italy; data were analyzed only regarding patients 18 years old or younger and using SAP for 6 months or more. RESULTS: Among all patients using an insulin pump, 129 (13.5 +/- 3.8 years old, with a disease duration of 6.3 +/- 3.4 years) have been using SAP for 1.4 +/- 0.7 years. Four hundred ninety-three patients (12.9 +/- 3.4 years old, with a disease duration of 6.2 +/- 3.3 years) using conventional insulin pump therapy for 1.7 +/- 0.5 years have been evaluated as the control group. After 0.5-3 years of using SAP or conventional insulin pump therapy, glycosylated hemoglobin significantly improved (8.0 +/- 1.5% vs. 7.4 +/- 0.8% [P = 0.002] and 8.0 +/- 1.6% vs. 7.7 +/- 1.1% [P = 0.006], respectively); the improvement was higher with SAP (P = 0.005). Insulin requirement showed a significant decrease only in SAP patients (0.88 +/- 0.25 vs. 0.7 +/- 0.23 U/kg/day, P = 0.003). Body mass index did not change during the observation period. No diabetic ketoacidosis episodes were observed during the follow-up, and severe hypoglycemia significantly decreased in SAP patients (P = 0.04). CONCLUSIONS: The increased availability of continuous glucose sensors is likely to have a significant impact on pediatric diabetes therapy and education in the near future. In daily settings, patients using SAP can achieve a better control than patients using conventional insulin pump. PMID- 21284476 TI - An algorithm guiding patient responses to real-time-continuous glucose monitoring improves quality of life. AB - OBJECTIVE: This study evaluated the impact on quality of life (QoL) of an algorithm guiding the responses of continuous subcutaneous insulin infusion (CSII)-treated type 1 diabetes (T1D) patients using real-time (RT)-continuous glucose monitoring (CGM). RESEARCH DESIGN AND METHODS: Sixty CSII-treated T1D participants (13-70 years old, glycosylated hemoglobin [HbA1c] <= 9.5%), including adult and adolescent subgroups, were randomized in age-, gender-, and HbA1c-matched pairs. Phase 1 was an open 16-week multicenter randomized controlled trial; Group A received CSII/RT-CGM with the algorithm, and Group B received CSII/RT-CGM without algorithm. Phase 2 was the 16-32-week follow-up study; Group A returned to usual care (CSII without RT-CGM), and Group B was provided with algorithm at 16 weeks. QoL was assessed by DQOL (adults) and DQOLY (adolescents) questionnaires at baseline, 16 weeks, and 32 weeks. Higher scores (range 1-5) indicate poorer QoL. Analysis was by analysis of variance (between group for baseline-16 weeks) and paired two-tailed t tests (within group for baseline and 32 weeks) with significance at P < 0.05. RESULTS: Withdrawals left 28 of 30 patients in Group A and 27 of 30 patients in Group B at 32 weeks. In Phase 1, QoL in Group A (2.16 [0.44] baseline to 1.86 [0.40] at 16 weeks) improved compared with Group B (2.03 [0.47] to 2.03 [0.50]) (P = 0.002). Change in QoL correlated with changes in HbA1c (R = 0.36; P = 0.007). In Phase 2, Group A QoL was better at 32 weeks compared with baseline (2.16 [0.44] vs. 2.02 [0.43]) (P = 0.04) but was not in Group B (2.03 [0.47] vs. 1.99 [0.51]) (P = not significant). CONCLUSIONS: An algorithm guiding CSII-treated T1D responses to RT CGM improved QoL, which persisted post-RT-CGM withdrawal. Algorithm provision at RT-CGM initiation was required to benefit QoL. PMID- 21284477 TI - A new index to optimally design and compare continuous glucose monitoring glucose prediction algorithms. AB - BACKGROUND: Continuous glucose monitoring (CGM) data can be exploited to prevent hypo-/hyperglycemic events in real time by forecasting future glucose levels. In the last few years, several glucose prediction algorithms have been proposed, but how to compare them (e.g., methods based on polynomial rather than autoregressive time-series models) and even how to determine the optimal parameter set for a given method (e.g., prediction horizon and forgetting) are open problems. METHODS: A new index, J, is proposed to optimally design a prediction algorithm by taking into account two key components: the regularity of the predicted profile and the time gained thanks to prediction. Effectiveness of J is compared with previously proposed criteria such as the root mean square error (RMSE) and continuous glucose-error grid analysis (CG-EGA) on 20 Menarini (Florence, Italy) Glucoday(r) CGM data sets. RESULTS: For a given prediction algorithm, the new index J is able to suggest a more consistent and better parameter set (e.g., prediction horizon and forgetting factor of choice) than RMSE and CG-EGA. In addition, the minimization of J can reliably be used as a selection criterion in comparing different prediction methods. CONCLUSIONS: The new index can be used to compare different prediction strategies and to optimally design their parameters. PMID- 21284478 TI - Conversion from intravenous insulin to subcutaneous insulin after cardiovascular surgery: transition to target study. AB - BACKGROUND: No study of transition from intravenous to subcutaneous insulin after cardiac surgery with dose based on percentage of intravenous total daily insulin (TDI) has reported a clearly superior regimen for achieving target blood glucose. We compared three first-dose transition strategies for insulin glargine: two based on TDI alone and one that also took body weight into account. METHODS: Mostly obese, type 1 and type 2 diabetes patients (n = 223) undergoing cardiac surgery were randomized to receive insulin glargine subcutaneously at 60% or 80% of TDI or in a dose based on TDI and body weight. RESULTS: Transition to subcutaneous insulin occurred 27.4 +/- 6.6 h after surgery. Over the study period, mean proportion of blood glucose values within target range (80-140 mg/dL) were 0.34 +/- 0.24, 0.35 +/- 0.24, and 0.36 +/- 0.22 in the 60% TDI, 80% TDI, and weight-based groups, respectively. This difference was not significant. Significantly more insulin corrections were needed in the 60% TDI group than in the weight-based group. There was only one incidence of hypoglycemia (blood glucose < 40 mg/dL). CONCLUSIONS: No subcutaneous insulin regimen implemented approximately 1 day after cardiac surgery showed significantly better control of blood glucose over the 3-day study period. Further studies are needed to determine optimal formulae for effecting an early transition to subcutaneous insulin after cardiac surgery or whether it is preferable and/or necessary to continue intravenous insulin therapy for an additional period of time. PMID- 21284479 TI - Prediction of glucose concentration in post-cardiothoracic surgery patients using continuous glucose monitoring. AB - OBJECTIVE: This study evaluated the predictive capability of simple linear extrapolation of continuous glucose data in postsurgical patients undergoing intensive care. METHODS: Twenty patients, both with or without an established diagnosis of diabetes mellitus, scheduled to undergo cardiothoracic surgery were included. Glucose was continuously monitored in the intensive care unit with a microdialysis-based subcutaneous glucose monitoring system. The prediction horizon (PH) with respect to a given glucose reading was calculated by extrapolating the linear trend of the glucose signal and subjected to both analytical and clinical assessment (by calculation of the average duration of consecutive positive and negative glucose signal trends, the root mean squared error [RMSE], and by insulin titration error grid [ITEG] analysis, respectively). RESULTS: In total, 609 h of continuous glucose data from 17 patients were analyzed. The average duration of consecutive positive and negative glucose signal trends was 7.97 (3.99-19.98) min (median, interquartile range). An increase in the RMSE of 0.5 mmol/L (9 mg/dL) was associated with a PH of 37 min. A strong increase in the number of data points in the unacceptable violation zone of the ITEG was associated with a PH of approximately 20 min. CONCLUSIONS: Our data provide evidence that simple linear extrapolation of glucose trend information obtained by continuous glucose monitoring can be used to predict the course of glycemia in critically ill patients for up to 20-30 min. This "glimpse into the future" can be used to proactively prevent the occurrence of adverse events. PMID- 21284480 TI - Neural network-based real-time prediction of glucose in patients with insulin dependent diabetes. AB - BACKGROUND: Continuous glucose monitoring (CGM) technologies report measurements of interstitial glucose concentration every 5 min. CGM technologies have the potential to be utilized for prediction of prospective glucose concentrations with subsequent optimization of glycemic control. This article outlines a feed forward neural network model (NNM) utilized for real-time prediction of glucose. METHODS: A feed-forward NNM was designed for real-time prediction of glucose in patients with diabetes implementing a prediction horizon of 75 min. Inputs to the NNM included CGM values, insulin dosages, metered glucose values, nutritional intake, lifestyle, and emotional factors. Performance of the NNM was assessed in 10 patients not included in the model training set. RESULTS: The NNM had a root mean squared error of 43.9 mg/dL and a mean absolute difference percentage of 22.1. The NNM routinely overestimates hypoglycemic extremes, which can be attributed to the limited number of hypoglycemic reactions in the model training set. The model predicts 88.6% of normal glucose concentrations (> 70 and < 180 mg/dL), 72.6% of hyperglycemia (>= 180 mg/dL), and 2.1% of hypoglycemia (<= 70 mg/dL). Clarke Error Grid Analysis of model predictions indicated that 92.3% of predictions could be regarded as clinically acceptable and not leading to adverse therapeutic direction. Of these predicted values, 62.3% and 30.0% were located within Zones A and B, respectively, of the error grid. CONCLUSIONS: Real-time prediction of glucose via the proposed NNM may provide a means of intelligent therapeutic guidance and direction. PMID- 21284481 TI - Effect of exenatide on inflammatory and oxidative stress markers in patients with type 2 diabetes mellitus. AB - AIM: This study was designed to determine the effect of exenatide on inflammatory and oxidative stress markers in type 2 diabetes mellitus (T2DM) patients who were suboptimally controlled with metformin and/or sulfonylurea. SUBJECTS AND METHODS: Twenty-three patients with T2DM with inadequate glucose control were randomly divided into two groups: exenatide group (E group) (12 patients, 5 MUg b.d. * 4 weeks followed by 10 MUg b.d. * 12 weeks) and placebo group (P group) (11 patients). Glycosylated hemoglobin (HbA1c), the seven-point glucose profile, daily mean glucose, and glycemic excursion were determined. The effects of exenatide on 8-iso-prostaglandin F2alpha (PGF2alpha), monocyte chemoattractant protein-1 (MCP-1), and high-sensitivity C-reactive protein (hs-CRP) were investigated. RESULTS: Exenatide treatment reduced body weight and body mass index (BMI) and improved HbA1c, the seven-point glucose profile, and daily mean glucose compared with placebo (P < 0.05). Limited glycemic excursion was found in the E group compared with the P group (P < 0.05), including a smaller SD and postprandial glucose excursion. In addition, the oxidative stress maker PGF2alpha was significantly reduced by exenatide treatment (P < 0.05). The inflammatory markers hs-CRP and MCP-1 were also significantly reduced in the E group compared with the P group (P < 0.05). PGF2alpha was significantly correlated with glycemic excursion (P < 0.05), whereas MCP-1 was significantly correlated with body weight, BMI, glycemic excursion, and HbA1c (P < 0.05 for all). CONCLUSIONS: Exenatide treatment reduced patient body weight and BMI, improved HbA1c and the seven-point glucose profile, reduced daily mean glucose, limited glycemic excursion, and reduced oxidative stress and inflammatory markers in patients of T2DM having inadequate glucose control. PMID- 21284482 TI - Increased liver fat content and unfavorable glucose profiles in subjects without diabetes. AB - BACKGROUND: Liver fat content (LFC) in subjects without diabetes may be correlated with adverse glucose profiles. METHODS: LFC was measured by (1)H magnetic resonance spectroscopy in 47 healthy subjects, 35 of whom also completed continuous glucose monitoring (CGM) studies. Subjects were divided into two groups according to LFC, and between-group comparisons of glucose profiles were made. RESULTS: The median LFC value was 3.8% (interquartile range, 2.4-7.6%), and 29.8% of the subjects had LFC values >= 5.5%. LFC was positively correlated with triglyceride, aspartate aminotransferase, gamma-glutamyltransferase, fasting C peptide, fasting insulin, insulin concentration at 120 min, area under the time concentration curve for insulin, and change in insulin from 0 to 30 min, homeostatic model assessment of insulin resistance, fasting plasma glucose, nocturnal mean blood glucose concentration (MBG) (all P < 0.05). The 35 CGM profiles revealed that nocturnal MBG was higher in subjects with LFC >= 3.8% (P < 0.05). In subjects with LFC >= 5.5%, both diurnal and nocturnal MBG values were elevated compared with subjects with lower LFC (P < 0.05). LFC was the strongest predictive factor of nocturnal MBG. CONCLUSIONS: Even modestly elevated LFC was associated with unfavorable glucose profiles in subjects without diabetes. PMID- 21284483 TI - Genetic variants in peroxisome proliferator-activated receptor-gamma and retinoid X receptor-alpha gene and type 2 diabetes risk: a case-control study of a Chinese Han population. AB - BACKGROUND: The serum levels of adiponectin are paradoxically decreased in obesity and may play important roles in the development of type 2 diabetes mellitus (T2DM). Potentially functional polymorphisms in the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and retinoid X receptor-alpha (RXR-alpha) genes may alter T2DM risks by increasing the human adiponectin promoter activity in cells. Therefore, we hypothesized that single nucleotide polymorphisms (SNPs) in PPAR-gamma and RXR-alpha were associated with risk of T2DM. To test this hypothesis, three potentially functional SNPs of PPAR-gamma and four of RXR-alpha with a minor allele frequency of >= 0.05 in the Chinese Han population were identified from the National Center for Biotechnology Information dbSNPs database to evaluate their association with T2DM. METHODS: Polymerase chain reaction-restriction fragment length polymorphism was performed to test the genotypes in T2DM patients (n = 540) and normal controls (n = 604). RESULTS: The variant genotypes rs2920502CC, rs3856806CT, rs3856806CT/TT, and rs4240711AG/GG were associated with T2DM. Furthermore, the prevalences of haplotype GTC and CTG in PPAR-gamma and GTAC in RXR-alpha were less frequent in cases (17.1%, 2.6%, and 2.4%, respectively) than in controls (22.3%, 3.8%, and 6.6%, respectively), whereas GTGT in RXR-alpha was more frequent in cases (6.9%) than in controls (4.4%) (P < 0.05 for both two-sided chi(2) test and thousand times permutation tests). Patients with genotype CT/TT of rs3856806 and genotype AG/GG of rs4240711 had higher levels of serum adiponectin than those with the genotype CC and genotype AA (P = 0.026 and 0.021, respectively). Model X2 X5 X6 X7 (rs3856806, rs3132291, rs4240711, and rs4842194) was the best model with the highest test balanced accuracy (0.5764) (cross-validation consistency = 10/10) in the multifactor dimensionality reduction method. CONCLUSIONS: The PPAR-gamma and RXR alpha gene variants associated with the development of T2DM in this study must be investigated in a larger population to reveal any potential effects on metabolism. PMID- 21284484 TI - Dermal factors influencing measurement of skin autofluorescence. AB - BACKGROUND: Skin autofluorescence (SAF) is a noninvasive marker of accumulation of advanced glycation end products. It predicts cardiovascular complications and mortality in diabetes and renal failure. We assessed the influence of potential common confounders in SAF measurement, by determining the effects of endogenous and exogenous local dermal changes by body creams, hyperemia, vasoconstriction, and hydration. METHODS: SAF was measured before and after local administration of body lotion, day cream, sunscreen, or self-browning cream and after attempts to remove these effects with alcohol swabs and washing. SAF was measured before and during three hyperemia maneuvers: vasoconstriction and on a dry and wet skin. RESULTS: The body lotion increased SAF by 18%. Day cream, sunscreen, and self browning cream gave an increase of >100%. Except for body lotion, subsequent cleaning with alcohol swabs and washing with soap did not return SAF to baseline values. The effect of self-browning cream persisted for 2 weeks and that of sunscreen for 4 days. Hyperemia caused by a hot bath, capsicum cream, or postocclusive reactive hyperemia gave a decrease in SAF of, respectively, 18%, 22%, and 2.3%. Vasoconstriction caused by immersing the arm in cold water gave a 10% increase. Hydration state did not influence SAF. CONCLUSIONS: Measurement of SAF is strongly affected by several skin creams. This effect was often not fully corrected by alcohol swabs and washing with soap and may persist for many days. Marked hyperemia and vasoconstriction also influence SAF. We advise avoiding these potential error sources. PMID- 21284485 TI - Protocol errors may lead to incorrect conclusions. PMID- 21284487 TI - Organization patterns of the AGFG genes: an evolutionary study. AB - A number of proteins which are needed for the building of new immunodeficiency virus type 1 virions can only be translated from unspliced virus-derived pre mRNAs. These unspliced mRNAs are shuttled through the nuclear pores reaching the cytosol when bound to the viral protein Rev. However, as a cellular co-factor Rev requires a Rev-binding protein of the AGFG family (nucleoporin-related Arf-GAP domain and FG repeats-containing proteins). In this article we address the evolution of the AGFGs by analyzing the first section of the coding mRNAs. This contains a "core module" which can be traced from Drosophilae to fish, amphibia, birds, and mammals, including man. In the subfamily of AGFG1 molecules the estimated conservation from Drosophilae to primates is 67% (with limited gaps). In some Drosophilae the core module is preceded by a long stretch of more than 300 coding nucleotides, but this additional module is absent in other Drosophilae and in all AGFG1s of other species. The AGFG2 molecules emerged later in evolution, possibly deriving from a duplication of AGFG1s. AGFG2s, present in mammals only, exhibit an additional module of about 50 coding nucleotides ahead of the core module, which is significantly less conserved (54%, with more remarkable gaps). This additional module does not seem to have homologies with the additional module of Drosophilae nor with the precoding section of AGFG1s. Interestingly, in birds a highly re-edited form of the AGFG1 core module (Gallus gallus, Galliformes) coexists with a typical form of the AGFG1 core module (Taeniopygia guttata, Passeriformes). PMID- 21284488 TI - Enhancement of the immunogenicity of DNA replicon vaccine of Clostridium botulinum neurotoxin serotype A by GM-CSF gene adjuvant. AB - Granulocyte-macrophage clony-stimulating factor (GM-CSF) is an attractive adjuvant for a DNA vaccine on account of its ability to recruit antigen presenting cells to the site of antigen synthesis as well as stimulate the maturation of dendritic cells.This study evaluated the utility of GM-CSF as a plasmid DNA replicon vaccine adjuvants for botulinum neurotoxin serotype A (BoNT/A) in mouse model. In balb/c mice that received the plasmid DNA replicon vaccines derived from Semliki Forest virus (SFV) carrying the Hc gene of BoNT/A (AHc), both antibody and lymphoproliferative response specific to AHc were induced, the immunogenicity was enhanced by co-delivery or coexpress of the GM CSF gene. In particular, when AHc and GM-CSF were coexpressed within the SFV based DNA vaccine, the anti-AHc antibody titers and survival rates of immunized mice after challenged with BoNT/A were significantly increased, and further enhanced by coimmunization with aluminum phosphate adjuvant. PMID- 21284489 TI - Attenuation of oxidative stress by allylpyrocatechol in synovial cellular infiltrate of patients with Rheumatoid Arthritis. AB - Free radicals are involved in the pathogenesis of Rheumatoid arthritis, a systemic autoimmune disorder characterized by unchecked synovial inflammation. Allylpyrocatechol, a phytoconstituent of Piper betle leaves, has potent anti inflammatory activity and this study evaluated its anti-oxidant effect on the synovial infiltrate of patients with Rheumatoid arthritis. The ex vivo effect of allylpyrocatechol upon generation of reactive oxygen species in neutrophils, macrophages and lymphocytes was measured by flow cytometry using dichlorodihydrofluorescein diacetate, wherein it significantly decreased basal levels as also scavenged phorbol myristate acetate generated reactive oxygen species. Furthermore, its effect on generation of superoxide and hydroxyl radicals produced within infiltrated neutrophils was measured by cytochrome c and deoxyribose assay, respectively. Allylpyrocatechol significantly scavenged superoxide and hydroxyl radicals in infiltrated neutrophils. The effect of allylpyrocatechol on nitric oxide was measured in macrophages using 4,5 diaminofluorescein diacetate by flow cytometry wherein it decreased production of nitric oxide in infiltrated macrophages, which correlated with its in vitro nitric oxide scavenging activity. Taken together, this ex vivo study has established that allylpyrocatechol has potent scavenging activity and could be considered as an add-on therapy in the treatment of inflammation-associated disorders like Rheumatoid Arthritis. PMID- 21284490 TI - Modulation of NF-kappaB and FOXOs by baicalein attenuates the radiation-induced inflammatory process in mouse kidney. AB - The bioactive flavonoid baicalein has been shown to have radioprotective activity, although the molecular mechanism is poorly understood in vivo. C57BL/6 mice were irradiated with X-rays (15 Gy) with and without baicalein treatment (5 mg/kg/day). Irradiation groups showed an increase of NF-kappaB-mediated inflammatory factors with oxidative damage and showed inactivation of FOXO and its target genes, catalase and SOD. However, baicalein suppressed radiation induced inflammatory response by negatively regulating NF-kappaB and up regulating FOXO activation and catalase and SOD activities. Furthermore, baicalein inhibited radiation-induced phosphorylation of MAPKs and Akt, which are the upstream kinases of NF-kappaB and FOXOs. Based on these findings, it is concluded that baicalein has a radioprotective effect against NF-kappaB-mediated inflammatory response through MAPKs and the Akt pathway, which is accompanied by the protective effects on FOXO and its target genes, catalase and SOD. Thus, these findings provide new insights into the molecular mechanism underlying the radioprotective role of baicalein in mice. PMID- 21284491 TI - Pregnancy outcome in patients with fibromyalgia syndrome. AB - OBJECTIVE: To investigate pregnancy outcome of patients with fibromyalgia syndrome (FMS). METHODS: A retrospective cohort study comparing pregnancies of women with and without FMS was conducted. Multivariable logistic regression models was performed to control for confounders RESULTS: Deliveries of 112 women with FMS were compared with a control group of 487 deliveries of women without FMS. Parturients with FMS had higher rates of intrauterine growth restriction (IUGR; 7.1% vs. 1.0%, p = 0.001), recurrent abortions (9.8% vs. 1.8%, p < 0.001), gestational diabetes mellitus (14.3% vs. 7%, p = 0.012), and polyhydramnios (12.5% vs. 1.6%, p < 0.001). These patients had lower rates of preterm deliveries (PTD; 6.3% vs. 16.7%, p = 0.018). No significant differences were noted between the groups regarding the rates of cesarean deliveries (CD) (15.2% vs. 21.2%, p = 0.149) and perinatal outcomes such as low Apgar scores (<7) at 1 and 5 min (4.5% vs. 6.7%, p = 0.292 and 1.2% vs. 0.6%, p = 0.372; respectively). Using two multiple logistic regression models, the positive association between FMS and IUGR (adjusted OR = 4.1, 95% CI 1.2-13.2; p = 0.02) and the negative association with PTD (OR = 0.3, 95% CI 0.2-0.6; p = 0.001) remained significant. CONCLUSION: FMS is an independent risk factor for intrauterine growth restriction. Nevertheless, it is associated with lower rates of preterm deliveries. PMID- 21284492 TI - Hydrogen sulfide inhibits the spontaneous and oxytocin-induced contractility of human pregnant myometrium. AB - Hydrogen sulfide (H(2)S) is a novel endogenous gaseous signaling transmitter in mammalian tissues including smooth muscle tissues. We investigated the effect of sodium hydrosulfide (NaHS), a H(2)S donor, on the contractility of isolated human myometrium strips from term pregnant women who were undergoing labor. Cumulative effects of NaHS on spontaneous and oxytocin-induced contractility were evaluated by using isometric tension recordings. NaHS (0.1 MUM-1 mM) concentration dependently inhibited spontaneous contractility of laboring myometrium, with a decrease in amplitude and frequency. NaHS (0.1 MUM-1 mM) decreased the frequency but not the amplitude of oxytocin (1 MUM)-induced contractions. NaHS-induced relaxation could be prevented by pretreatment with glibenclamide, an inhibitor of K(+)(ATP) channels. Thus, NaHS evokes relaxation of human pregnant myometrium, suggesting a possible role of H(2)S during human pregnancy. PMID- 21284493 TI - Incomplete inhibition of platelet function as assessed by the platelet function analyzer (PFA-100) identifies a subset of cardiovascular patients with high residual platelet response while on aspirin. AB - Sixty-six patients with a history of ischemic events (myocardial infarction, unstable angina, or stroke) on chronic aspirin therapy were studied by different platelet function tests: 37 patients had suffered a recurrent event while on aspirin and 29 were without recurrences. Based on results from light transmission aggregometry (LTA) induced by arachidonic acid (AA) and serum TxB(2) both COX-1 dependent methods, only one patient could be identified as aspirin "resistant". However, when methods only partially-dependent on platelet COX-1 activity were considered, the prevalence of aspirin non-responders ranged, according to the different tests, from 0 to 52%. No difference was observed between patients with recurrences and those without. Among patients with recurrent events, those with an incomplete inhibition of platelet function, as assessed by the PFA-100, had significantly higher residual serum TxB(2) (2.4 +/- 2.4 ng/mL vs 0.4 +/- 0.1 ng/mL, p = 0.03), residual LTA-AA (9.2 +/- 10.6% vs 2.0 +/- 1.6%, p = 0.008), LTA Coll (49.3 +/- 14.6% vs 10.2 +/- 8.3%, p = 0.007) and LTA-ADP (50.9 +/- 16.2% vs 34.3 +/- 11.0%, p = 0.04). In conclusion, laboratory tests solely exploring the AA-mediated pathway of platelet function, while being the most appropriate to detect the effect of aspirin on its pharmacologic target (platelet COX-1), may fail to reveal the functional interactions between minimal residual TxA(2) and additional stimuli or primers potentially leading to aspirin-insensitive platelet aggregation. High residual platelet response in platelet function tests only partially dependent on COX-1 may reveal a condition of persistent platelet reactivity in a subset of aspirin-treated patients characterizing them as a subgroup at higher vascular risk. PMID- 21284495 TI - A marked decline in the incidence of renal replacement therapy for amyloidosis associated with inflammatory rheumatic diseases - data from nationwide registries in Finland. AB - Risk for amyloidosis in rheumatic diseases is associated with a long-lasting inflammation. To assess possible changes in the incidence of terminal uraemia due to amyloidosis associated with rheumatic diseases on a nationwide basis, we scrutinised the files of the Finnish Registry for Kidney Diseases for patients suffering from amyloidosis associated with rheumatoid arthritis (RA), ankylosing spondylitis (AS) or juvenile idiopathic arthritis (JIA) over the period 1995 2008. The registry has an estimated 97-99% coverage of all patients accepted for renal replacement therapy (RRT) in the country. Data on the consumption of antirheumatic drugs were collected from two sources: the Social Insurance Institution's Drug Reimbursement Register, and the Sales Register of the National Agency for Medicines from the above period. Altogether 264 cases were identified. Two hundred twenty-nine of them had RA, 15 AS and 20 JIA. When the total annual number of new admissions to RRT varied between 20 and 37 at the end of 1990s, it was under half of that from 2002 onwards. Over this period, the number of users of low-dose methotrexate (MTX) has increased 3.6-fold, the drug being the most frequently used disease modifying anti-rheumatic drug in Finland. The present nationwide series is the first to show that the incidence of end-stage renal disease due to amyloidosis associated with rheumatic diseases is decreasing. An obvious reason for this is intensive anti-rheumatic drug therapy. PMID- 21284496 TI - Nutritional characteristics of proteins from the volva and pileus in cultivated mushroom Dictyophora rubrovolvata. AB - Dictyophora rubrovolvata is one of the commercially important mushroom species in China. However, its volva and pileus account for about 65% of the whole mushroom (by fresh weight), and most of them are dumped without utilization. To effectively utilize the waste, the present study determined their proximate composition and investigated the nutritional characteristics of their proteins via the analysis of amino acid composition and protein fractionation. The results showed that the volva and pileus were rich in protein with 26.74% and 15.55% (dry basis), respectively. Predicted protein efficiency ratio values of proteins of the volva and pileus were 2.8 and 2.2, and the amino acid scores were 96 and 85.The albumin was the highest fraction both in the volva and pileus, accounting for 69.52% and 27.91% of the crude protein. The protein quality of the volva was therefore higher than that of the pileus. The volva might be developed as resource of high-quality vegetable-base protein. PMID- 21284497 TI - Oral preexposure anti-HIV prophylaxis for high-risk U.S. populations: current considerations in light of new findings. AB - This article reviews the status of current research evaluating oral preexposure prophylaxis (PrEP) for prevention of HIV infection in high-risk populations. In animal model studies, the use of antiretrovirals has been shown to be effective in preventing HIV acquisition. Early-phase PrEP studies have established safety in humans. Currently, more than 20,000 men and women will soon be enrolled in studies of oral or topical chemoprophylaxis, testing a variety of drug delivery methods including tenofovir disoproxil fumarate (TDF) gel applied vaginally or rectally, as well as oral PrEP using TDF by itself or coformulated with emtricitabine (FTC). The largest global PrEP trial in men who have sex with men (MSM), known as iPrEx has demonstrated that oral chemoprophylaxis can decrease HIV incidence in this population. Although TDF/FTC PrEP was generally well tolerated, side effects such as nausea, as well as mild and reversible renal abnormalities were increased among the men who received active medication, suggesting that PrEP users will need ongoing PrEP clinical monitoring. The prophylactic benefits of TDF/FTC were substantially attenuated by nonadherence, indicating that effective PrEP implementation programs will need to focus on this behavioral variable, in addition to safer sex counseling. This article considers biological, policy, and practical implications of large-scale oral PrEP implementation. PMID- 21284498 TI - Continuity of HIV-related medical care, New York City, 2005-2009: Do patients who initiate care stay in care? AB - In this era of effective antiretroviral therapy, early diagnosis of HIV and timely linkage to and retention in care are vital to survival and quality of life. Federal guidelines recommend regular monitoring of HIV-related laboratory parameters and initiation of antiretroviral treatment at specified thresholds. We used routinely reported laboratory data to measure intervals between visits by New York City residents newly diagnosed with HIV July 1 to September 30, 2005, and initiating care within 3 months of diagnosis. We measured regular care (>=1 visit every 6 months) and retention in care (last visit <=6 months before close of analysis) through June 30, 2009. Patients were followed for 45-48 months. Seventy-seven percent (650/842) of patients initiated care within 3 months of diagnosis; 609 (93.7%) made at least one subsequent visit; 45.4% had regular care. Risk factors for not receiving regular care included age 13-24 versus 50+ (adjusted odds ratio [AOR] 3.0, 95% confidence interval [CI] 1.5, 6.0), black race (AOR 2.0, 95% CI 1.4,2.8), eligibility for antiretroviral treatment (AOR 1.5, 95% CI 1.1, 2.2), and injection drug use (IDU; AOR = 2.7. 95% CI 1.0, 7.1). In a time-to-event analysis, risk factors for loss to care were age 13-24 versus 50+ at diagnosis (adjusted hazard ratio [AHR] 1.9, 95% CI 1.1, 3.4), non-hospital site of care (AHR 1.4, 95% CI 1.0, 2.0) and early stage (non-AIDS) disease (AHR 1.4, 95% CI 1.0, 2.0). The analysis demonstrates how mandated reporting of HIV related laboratory tests provides surveillance systems with the capacity to monitor utilization of care, identify deficits, and evaluate progress in programs designed to facilitate retention in care. PMID- 21284504 TI - Can environmental and socioeconomic factors explain the recent emergence of Rift Valley fever in Yemen, 2000-2001? AB - Rift Valley fever (RVF) is a major vector-borne zoonosis first identified on the African continent in the early 1900s. In 2000, RVF was reported for the first time in Yemen. In this study, we provide a descriptive analysis of the period 1999-2007 in Yemen, taking into account the environmental and socioeconomic factors likely to have been involved in the emergence of RVF in the country. We characterize each year in the study period by the environmental conditions (linked to vegetation indexes), the festival calendar, and economic data. We then use a principal component analysis to synthesize the different variables, assess whether the year 2000 was atypical compared with other years in the study period, and, if that was the case, in what respect. Our results show that 2000 presented above-normal vegetation index values, which reflect important precipitation, for both the two rainy seasons (the first between March and May; the second between July and October). These environmental conditions, ones favorable to mosquito vector populations, coincided that year with a late (March) starting date of the Eid al-Kabeer festival, which corresponds to a period with high host (cattle, sheep, goats) densities. According to these criteria, 2000 was an atypical year. These conclusions suggest that it is important to consider social variables in addition to environmental ones when assessing the risk of RVF emergence. PMID- 21284505 TI - Comparison of goldmann applanation tonometer, noncontact tonometer, and TonoPen XL for intraocular pressure measurement in different types of glaucomatous, ocular hypertensive, and normal eyes. AB - PURPOSE: To compare intraocular pressure (IOP) measurements by Goldmann applanation tonometer (GAT), noncontact tonometer (NCT), and TonoPen XL in glaucomatous, ocular hypertensive (OHT), and normal eyes, all with various central corneal thickness (CCT). METHODS: In 508 subjects, IOP was measured by three different tonometers: GAT, NCT, and TonoPen. CCT was also measured. RESULTS: There was a statistically significant difference between IOP measurements made using the three different tonometers (RMANOVA, P < 0.0001). Both NCT/GAT and TonoPen/GAT differences were significantly associated with age, CCT, IOP, and glaucoma diagnosis (multiple regression analysis, all P <= 0.05). CCT and IOP had the greatest effect on IOP measurement variance by different tonometers. IOP measurements made by NCT were consistently higher than those made by GAT; this difference increased both with IOP and CCT levels, but decreased with age and OHT. In addition, TonoPen overestimated the GAT in the eyes of subjects with OHT. CONCLUSION: IOP measurement differences between the three tonometers are affected by age, type of glaucoma, and especially CCT and IOP levels. PMID- 21284506 TI - VEGF as a biomarker for metastatic uveal melanoma in humans. AB - PURPOSE: High levels of serum VEGF have been reported in many types of cancers, especially in the metastatic stage. The aim of this study was to examine the potential of VEGF serum level as a tumor marker for metastases in uveal melanoma (UM) patients. MATERIALS AND METHODS: Levels of serum VEGF were analyzed by ELISA for 23 UM patients (none of whom developed metastases within 5 years from diagnosis) at the time of diagnosis, soon after treatment, and 3 years later, and compared with serum VEGF levels of 39 metastatic patients, 58 10-year disease free (10yDF) patients, and 23 healthy subjects. VEGF ratios were calculated per patient between diagnosis and after treatment, and between diagnosis and 3 years later. Matched pairs univariate analysis was performed for 17 metastatic patients for whom sera were available from before and after the diagnosis of metastases. Patients were followed biannually with liver ultrasonography and liver function tests for the presence of metastases. RESULTS: The inter-patient VEGF level range was large (e.g., the range for the metastatic patients was 46-1892 pg/ml). The mean +/- SD levels for the control, 10yDF, and metastatic groups were: 329.65 +/- 190.0, 407.66 +/- 261.9 and 453.52 +/- 270.2, respectively (p = 0.2456). The mean VEGF level ratio from after treatment to diagnosis was 1.08 (p = 0. 0024), and the ratio from 3 years after diagnosis to diagnosis was 1.53 (p = 0.0009). The mean +/- SE post/premetastatic levels ratio was 1.35 +/- 0.21 (p = 0.0595). CONCLUSIONS: Serum VEGF increased significantly after metastases developed. However, the wide inter-patient variance precludes the use of any cut-off level to determine the metastatic status of an individual patient based on a single VEGF serum level. An increase in VEGF on serial measurements may indicate the development of metastases. Further investigation is warranted to assess VEGF's value as a predictive marker for metastatic disease. PMID- 21284509 TI - Applications of microcalorimetry in the antibacterial activity evaluation of various Rhizoma coptidis. AB - CONTEXT: Various Rhizoma coptidis are commonly used in clinical applications due to their strong antibacterial effect. OBJECTIVE: The antibacterial effect of various R. coptidis were evaluated by microcalorimetry together with statistical analysis. MATERIALS AND METHODS: The dried roots of Coptis chinensis Franch, Coptis deltoidea C.Y. Cheng et Hsiao, and Coptis teeta Wall (Ranunculaceae) were identified by Prof. Xiao-He Xiao. The herbs were tested using thermal activity monitor (TAM) air isothermal microcalorimeter, ampoule mode, to evaluate the biological activity. The dynamic energy metabolism information about the Staphylococcus aureus growth at 37 degrees C was analyzed with principal component analysis. RESULTS: From the principle component analysis on quantitative parameters, the action of various R. coptidis on S. aureus growth at 37 degrees C could be easily evaluated by analyzing the change of values of the two main parameters: the growth rate constant of first stage (k(1)) and the maximum heat rating of the first stage (P(1)). And the results of paired t-test show that there were no notable differences between inhibitory ratios calculated with k(1) and that of P(1). Using microdilution method, the minimal inhibitory concentrations (MIC) of C. chinensis, C. deltoidea, and C. teeta were detected, and they were 77.8 +/- 2, 116.6 +/- 4, 93.3 +/- 2 MUg/mL, respectively. DISCUSSION AND CONCLUSION: This work provided a useful method for the evaluation of antibacterial activity of various R. coptidis. PMID- 21284510 TI - Bioassay-guided isolation of antioxidant agents with analgesic properties from flowers of Tagetes patula. AB - CONTEXT: Tagetes patula L. is one of the French marigold group of the Asteraceae family. It is recognized in folklore for its medicinal and pesticidal properties. OBJECTIVE: In search of more effective, but non-toxic compounds with antioxidative potential led to the bioassay guided isolation studies on the extracts of T. patula. MATERIALS AND METHODS: The bioassay on Tagetes patula flowers were carried out guided by in vitro antioxidant activity using DPPH assay. A minor but proven plant constituent methyl protocatechuate (1) was isolated by column chromatography, while patuletin (2) and patulitrin (3) obtained in bulk by employing solvent partition of methanol extract. Derivatization of patuletin into benzoyl, cinnamoyl and methyl was conducted to establish the structure activity relationship (SAR). Analgesic activity of compound 2 was evaluated using acetic acid-induced writhing test and hot-plate test in mice. The toxicity of methanol extract and compound 2 were also determined. RESULTS: Polar extracts, fractions and phases demonstrated better antioxidant activity. The synthetic methyl protocatechuate (1) showed IC(50) value of 2.8 +/- 0.2 MUg/mL, whereas patuletin (2) (IC(50) = 4.3 +/- 0.25 ug/mL) was comparable to quercetin and rutin but significantly better than patulitrin (3) (IC(50) = 10.17 +/- 1.16 ug/mL). Toxicity test for the methanol extract and compound 2 did not elicit any behavioral changes or cause mortality in mice. Compound 2 also demonstrated mild analgesic property. DISCUSSION AND CONCLUSION: These findings demonstrate that the plant polar extracts and fractions possess significant antioxidant property with non-toxic effect. Compound 1 is a genuine plant constituent of T. patula. PMID- 21284512 TI - Rickettsia felis and Bartonella henselae in fleas from Lebanon. AB - A total of 155 fleas collected in 2009 in Lebanon from 16 cats (104 Ctenocephalides felis specimens, 1 C. canis specimen) and 2 dogs (50 C. canis specimens) were tested for the presence of Rickettsia spp. and Bartonella spp. using molecular methods, including real-time quantitative polymerase chain reaction (PCR), regular PCR, and sequencing of amplified PCR products. Rickettsia felis, the agent of the emerging flea-borne spotted fever in humans, was identified in 17 (16%) C. felis cat fleas. Bartonella henselae, an agent of cat scratch disease, was identified in three (2.9%) C. felis. Our results emphasize the potential risk of these emerging flea-borne infections in Lebanon. PMID- 21284513 TI - Laparoscopic pyeloplasty for ureteropelvic junction obstruction in children. AB - PURPOSE: To examine our experience of laparoscopic pyeloplasty for the treatment of ureteropelvic junction obstruction (UPJO) in the pediatric population. METHODS: From November 2001 to June 2009, 112 patients underwent transperitoneal laparoscopic pyeloplasty for the treatment of symptomatic or radiographic UPJO. Data were collected retrospectively. Patients were followed at regular intervals with imaging and symptom assessment. Failure was defined as inability to complete the intended procedure, persistent flank pain, radiographic evidence of obstruction, or the need for definitive adjunctive procedures. RESULTS: Mean patient age was 9.4 years (0.2-20.5 years), and follow-up was available on all 112 patients with a mean duration of 15.3 months (0.6-84.5 months). There was one open conversion in the series. Mean operative time was 254 minutes (102-525 minutes). There was one minor intraoperative complication reported (0.8%). There were 12 (10.8%) postoperative complications; most were relatively minor with complete resolution and without long-term sequelae. Postoperative ultrasonography has been performed in 102 patients, with 99 (97%) patients demonstrating improvement of the UPJO. Three patients (3%) continued to have symptomatic and/or radiographic evidence of obstruction that necessitated the need for adjunctive procedures, which included laser endopyelotomy in 2 patients, and a re-do open pyeloplasty in 1 patient. Of those cases that were completed laparoscopicaly, the overall success rate was 97.2%. CONCLUSIONS: Laparoscopic pyeloplasty for UPJO in the pediatric population is technically challenging; however, with experience, one can expect excellent success rates comparable to open pyeloplasty, with minor complications with reasonable operative times. PMID- 21284514 TI - Genetic evidence of hantavirus infections in wild rodents from northwestern Colombia. AB - This report builds on recent serological evidence for the presence of hantavirus in northern Colombia by providing sequence-specific and phylogenetic data of hantavirus infections in wild rodents. From August 2007 to August 2008, 354 rodent specimens representing four families were collected in the northwestern Antioquia region of Colombia. Antibodies reactive to Sin Nombre virus and Maciel virus antigens by IgG enzyme-linked immunosorbent assay were found in 15 of 109 (14%) Cherries cane rats (Zygodontomys cherriei), the only sigmodontinae rodents captured. Lung tissue samples from 11 of the 15 seropositive rodents were RT polymerase chain reaction positive for hantavirus RNA, using primers for the S and M genome segments. Eight of these amplicons were sequenced and phylogenetic analyses indicated RNA of a hantavirus closely related to Calabazo virus, previously found in Panama. This is the first report of the genetic characterization of a hantavirus in rodents in Colombia. PMID- 21284515 TI - Overcoming technical difficulties with single-port access laparoscopic surgery in gynecology: using conventional laparoscopic instruments. AB - AIM: The aim of this report was to investigate ways to overcome technical difficulties of the single-port access (SPA) laparoscopic surgery using conventional laparoscopic instruments in gynecology. METHODS: We performed 140 cases of SPA total laparoscopic hysterectomy for benign gynecologic diseases and 40 cases of two-port access laparoscopic surgery for gynecologic cancers. The conventional laparoscopic instruments, including a 45-cm-long, 5-mm-diameter, 30 degree-angled laparoscope, a 90-degree light cable adaptor, a curved instrument, and nonbulky trocars, and intracorporeal suturing and tying technique were used. RESULTS: All operations were laparoscopically completed with no conversion to conventional laparoscopy or laparotomy. We obtained tolerable surgical outcomes with these instruments. CONCLUSIONS: As the technical difficulties have been overcome, the SPA laparoscopic surgery will be a more and more widespread procedure in the gynecologic field with only minimal skin incision. PMID- 21284516 TI - Use of the Habib 4 * radiofrequency-assisted bipolar hemostatic device to avoid warm ischemia in select large partial nephrectomies: description and video of technique. AB - OBJECTIVES: The Habib 4 * radiofrequency-assisted bipolar hemostatic device (AngioDynamics) was used during select open partial nephrectomies to minimize blood loss and prevent warm renal ischemia. The article and video demonstrate this novel technique for partial nephrectomies in select renal masses. METHODS: Patients with large renal tumors requiring partial nephrectomy where avoidance of warm ischemia was deemed imperative underwent open partial nephrectomy at our institution utilizing the Habib 4 * radiofrequency ablation device to avoid prolonged warm ischemia time and prevent blood loss. RESULTS: We have used the device successfully in 4 partial nephrectomies (2 patients with solitary kidneys, 2 patients with bilateral large masses). The mean age was 65 years. Mean tumor size was 6.4 cm. All tumors were located either in the upper pole or lower pole of the kidney. Mean hospital stay was 4.6 days. No patient received an intraoperative blood transfusion. Two patients required long-term ureteral stenting and surgical drainage for urine leakage. CONCLUSIONS: Bipolar radiofrequency ablation offers avoidance of hilar clamping in carefully selected large partial nehrectomies. PMID- 21284517 TI - Minimally invasive approach to pancreatic necrosectomy. AB - BACKGROUND: Conventional open surgery for infected pancreatic necrosis is associated with significant surgical morbidity, that is, wound complications, facial dehiscence, and intestinal fistulae. In recent years, there has been interest in attempting to reduce this surgical morbidity by adopting a number of minimally invasive approaches. METHODS: Fifteen patients with pancreatic necrosis underwent pancreatic necrosectomy by minimally invasive surgery (11 men, 4 women; age group: 25-64 years, mean age: 46 years). Apache II scores ranged from 5 to 14. Pancreatic necrosectomy was performed by laparoscopic transperitoneal approach in 12 patients (transmesocolic, 4 patients; transgastrocolic, 6 patients; and gastrohepatic omentum, 2 patients), by retroperitoneal approach in 2 patients, and by a combination of methods in 1 patient (endoscopic transgastric drainage followed by laparoscopic intracavity necrosectomy). Relook laparoscopy was done in 5 patients to assess for residual necrosis. RESULTS: All the patients tolerated the procedure well, and there was no mortality. Two of them had pancreatic fistula, which eventually responded to conservative treatment. Three patients were converted to open necrosectomy because of bleeding or difficulty to access the area of necrosis. The mean operating time was 120 +/- 10 minutes. There were no postoperative complications related to the procedure itself, such as major wound infections, intestinal fistulae, or postoperative hemorrhage. Postoperative computed tomographic scans confirmed adequacy of debridement. The average length of hospital stay after surgery was 14 days. CONCLUSIONS: Minimally invasive necrosectomy is technically feasible and a body of evidence now suggests that acceptable outcomes can be achieved. There are no comparisons of results available, either with open surgery or among different minimally invasive techniques. PMID- 21284518 TI - Bile duct injuries during pediatric laparoscopic cholecystectomy: a national perspective. AB - BACKGROUND: Though rare, bile duct injuries (BDI) during laparoscopic cholecystectomy (LC) represent a major potential complication with significant associated morbidity. The objectives of this study were to (1) assess the national use of LC and incidence of BDI over time in the pediatric surgical population, (2) measure the added resource utilization burden associated with BDI, and (3) identify patient and hospital factors associated with BDI. METHODS: All patients 0 to 20 years of age undergoing cholecystectomy were identified in the Kids' Inpatients Database from 1997 to 2006. National rates of LC use and BDI as well as overall costs were assessed using weighted estimates. Factors associated with BDI were analyzed with a logistic regression model. RESULTS: Of 31,653 patients undergoing cholecystectomy, 28,243 (89.2%) underwent LC. Over time, the proportion of LC has risen from 81% in 1997 to 91% in 2006 (P < .001). Of patients undergoing LC, 0.44% had BDI with no significant change of BDI rate over time. Length of stay was 6.1 days for patients with BDI compared to 3.3 days for those without injury (P < .001). BDI patients had median costs of US $9550 as compared to US $6030 for non-BDI patients (P < .001). After taking patient, hospital, and disease-specific factors into consideration, BDI was more common in patients 5 years of age or less, nonwhite patients, and in patients admitted under an elective setting (all P < .01). CONCLUSIONS: With increasing LC use, BDI remains a rare yet resource intense complication in children. Age, race, and admission related factors are associated with BDI and may provide guidance toward improving outcomes. PMID- 21284519 TI - Competitive edge of laparoscopic appendectomy versus open appendectomy: a subgroup comparison analysis. AB - BACKGROUND: With the advances in laparoscopic instruments and surgical techniques, the use of laparoscopic appendectomy (LA) has been increasing rapidly in recent years. In this retrospective analysis, we aimed to determine the competitive edge of LA versus open appendectomy (OA) in different settings of disease complexity, gender, and age difference. METHODS: A retrospective analysis of the patients diagnosed with acute appendicitis at Changhua and Chang-Bing Show Chwan Memorial Hospitals from January 1, 2004 to December 31, 2009 was conducted. Trend and indication of OA and LA were recorded, combined with a comparison of medical costs, complication rates, wound infection rates, and hospital stays in different settings of disease complexity, gender, and age group. RESULTS: A total of 1366 appendicitis patients were enrolled, and the rate of LA use increased rapidly, from 8.1% in 2004 to 90.3% in 2009. The increased use of LA was seen in both the uncomplicated and complicated appendicitis patients and in both gender and age groups (pediatric, adult, and elderly). Compared with OA, LA was associated with a lower complication rate (9.5% versus 5.8%; P = .013), a lower wound infection rate (8.6% versus 4.2%; P = .001), and a shorter hospital stay (4.60 +/- 3.64 versus 4.06 +/- 1.84 days; P = .001), but a higher mean cost (32,670 +/- 28,568 versus 37,567 +/- 12,064 New Taiwan dollars). In the subgroup analysis, the patients with complicated appendicitis, female patients, and pediatric and elderly patients benefited from a reduced hospital stay. LA is about 15% more expensive than OA. CONCLUSIONS: LA is as safe and effective as OA in many settings of appendicitis and may be selectively advantageous in patients with complicated appendicitis and in elderly subgroups. PMID- 21284520 TI - Twisting of distal ileum around end ileostomy: is it a specific complication after laparoscopic subtotal colectomy? AB - Ulcerative colitis affects 1 in 1000 people in Western cultures. In acute colitis, up to 40% of cases require surgical intervention. In suitable patients laparoscopic subtotal colectomy has become the standard of care. This case series demonstrates the hitherto unreported complication of twisting of an end ileostomy after laparoscopic subtotal colectomy. Each of the cases shared a young age and a slow postoperative recovery. The fact that the ileostomies remained intact after an open approach indicates that the laparoscopic approach (and its limitations) must be at least partly responsible for the initial morbidity in these cases. Limited literature means we can only speculate as to the reason for twisted ileostomy. Apart from the above stated reason, it may be that the minimally invasive approach causes fewer intraperitoneal adhesions than an open approach due to reduced bowel handling, allowing the small bowel to move more freely within the abdomen causing twisting. Numerous studies have applauded the use of minimally invasive colonic resection in cases of inflammatory bowel disease; however, great care must be taken to avoid this specific complication occurring when using a laparoscopic approach. PMID- 21284521 TI - Cystic echinococcosis in Romania: the pediatric approach. AB - Cystic echinococcosis (CE) has represented a leading parasitic disease in Romania since 1862 when the first case was detected. Following the extremely high number of human and animal cases registered in 1995, Romania was framed in the forefront of Europe and among the first countries worldwide. This review aims to overview and analyze important data concerning CE in Romania from a pediatric point of view. To fulfill these goals, we focused on information provided by major epidemiological studies and rare/unusual case presentations. CE represents a serious concern for both public health services and the society, mainly because of prolonged hospitalization and convalescence periods. Moreover, the situation is much more problematic in children because physical, psychical, or intellectual impairments may impact negatively on their developmental and educational progress. The management of the disease consumes considerable healthcare resources estimated at about 1500-2000 United States Dollar (USD) for each uncomplicated case and approximately double for the complicated ones. A systematic analysis of data framed important epidemiological characteristics that may be useful when assessing individuals at risk: children (0-19 years old) represented 22.1% of the total number of cases, patients aged 13 years were most frequently affected (p < 0.0001), male patients and rural inhabitants predominated (p = 0.01 and p < 0.0001, respectively), and pulmonary involvement was detected most frequently (p < 0.0001). Considering the immense burden of this disease in Romania, emphasis should be given to the wide-scale implementation of effective prophylactic measures toward its eradication. Among them, education of the population plays an important role and should begin in early childhood. PMID- 21284522 TI - Prevalence and carrier status of leptospirosis in smallholder dairy cattle and peridomestic rodents in Kandy, Sri Lanka. AB - Leptospirosis is an important bacterial zoonotic disease globally and one of the notifiable diseases in Sri Lanka. Other than human leptospirosis, little information is available on leptospirosis in domestic and feral animals in Sri Lanka. Thus, this study attempted to determine the prevalence and carrier status of leptospirosis in smallholder dairy cattle and peridomestic rodents to understand the impact of the disease on public health in Kandy, Sri Lanka. Cattle and rodent samples were collected from the Yatinuwara and Udunuwara divisional secretaries in Kandy. Serum samples were analyzed for the presence of antileptospiral antibodies using microscopic agglutination test. DNA was extracted from cattle urine and rodent kidney tissue samples, in which polymerase chain reaction was carried out to detect the Leptospira flaB gene. The cattle in 19 (38.8%) of the 49 farms harbored antileptospiral antibodies. Out of 113 cattle serum samples, 23 (20.3%) were positive; 17 (73.9%) and 6 (26.1%) reacted with serogroups Sejroe and Hebdomadis, respectively. Out of the 74 rodent samples, 13 (17.5%) were positive; 8 (61.5%) and 4 (30.8%) had reactions to serogroups Javanica and Icterohaemorrhagiae, respectively. Leptospiral DNA was detected in one cattle urine sample and identified as Leptospira interrogans. This study revealed a high prevalence of leptospirosis in cattle and rodents in Kandy. These animals were infected with a wide array of leptospiral serogroups, which are consistent with the research findings observed in humans in Kandy. Overall, serological data indicate that relative to rodents, cattle may be a more significant reservoir for human transmission and a greater source of potential risk to local agricultural communities. PMID- 21284523 TI - Replication of the primary dog kidney-53 dengue 2 virus vaccine candidate in Aedes aegypti is modulated by a mutation in the 5' untranslated region and amino acid substitutions in nonstructural proteins 1 and 3. AB - Previous studies have demonstrated reduced replication of the cell culture adapted Dengue-2 virus (DENV-2) vaccine candidate, primary dog kidney (PDK)-53, compared with the parental DENV-2 strain, 16681, in C6/36 cells. Various DENV-2 mutants incorporating PDK-53 substitutions singly and in combination into the 16681 genetic backbone were used to identify the genetic basis for impaired replication of the vaccine candidate in vitro in Aedes aegypti cell culture (Aag2 cells) as well as the reduced in vivo infectivity and transmissibility within Ae. aegypti infected by intrathoracic inoculation. 5' untranslated region (UTR-c57t) and nonstructural protein 1 (NS1-G53D) mutations were required to completely attenuate in vitro replication. In contrast, incorporation of the PDK-53-specific NS3-250V mutation into the 16681 virus resulted in reduced replication in mosquitoes but had no effect on in vitro replication. Further, reversion of the PDK-53 NS3-250 site to that of the wild-type 16681 virus (NS3-V250E) failed to increase either in vitro or in vivo replication. Intrathoracic inoculation of Ae. aegypti with mutants containing the PDK-53 NS1 substitution exhibited in vivo replication indistinguishable from the parental PDK-53 virus, implicating this mutation as the dominant determinant for impaired mosquito replication of the PDK 53 candidate; however, further attenuation of in vivo replication was magnified in mutants including the additional 5'UTR-c57t mutation. PMID- 21284524 TI - Comparative analysis of the new chronic kidney disease epidemiology collaboration and the modification of diet in renal disease equations for estimation of glomerular filtration rate in HIV type 1-infected subjects. AB - Recently, a new Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula was presented as a better alternative to the modification of diet in renal disease (MDRD) formula for GFR estimation (eGFR) in patients with relatively well-preserved kidney function. The main objective of our study was to compare the eGFR results arrived by the new CKD-EPI to the older MDRD equation in antiretroviral (ARV)-naive and ARV-treated HIV-1-infected patients. The study was performed in 287 adult HIV-1-infected patients and was an evaluation comparing eGFR results based on age, gender, race, and serum creatinine. The biggest difference in estimated glomerular filtration rate (eGFR) measured by the two formulas was seen in ARV-naive men with well-preserved kidney function (p = 0.001). Moreover, we found a significant negative correlation between mean difference in eGFR measured by the two equations and the age of the studied subjects (r = -0.37, p < 0.001). No correlation was observed between mean difference in eGFR and HIV viral load (r = -0.15, p = 0.2). Independent of the equation used, a significant decrease of eGFR in ARV-treated in comparison to ARV untreated HIV-1-infected patients was seen (p < 0.001). In conclusion, in HIV-1 infected subjects, especially in ARV-naive men with well-preserved kidney function, eGFR measured by MDRD and CKD-EPI formulas varies strongly following the method used. Such discrepancies may be important in everyday clinical practice and must be confirmed by additional studies using GFR measured with a reference method. PMID- 21284525 TI - Short communication: immunogenicity of an inactivated influenza vaccine and postvaccination influenza surveillance in HIV-infected and noninfected children and adolescents. AB - Individuals infected with HIV are at higher risk for severe cases of seasonal influenza infection and should receive annual doses of vaccine. Our objectives were to evaluate the immunogenicity of an influenza vaccine in 37 HIV-infected patients (HIV group) compared to 29 uninfected individuals (control group) and to carry out a clinical and virological surveillance of influenza during a 6-month follow-up. Both groups received the vaccine recommended for the southern hemisphere in 2008. Antibody responses to antigens H1N1, H3N2, and B were measured in blood samples at vaccination (T0) and after 1 month (T1). Influenza surveillance was performed by weekly telephone calls for a follow-up period of 6 months. Nasal washes were taken from subjects with respiratory symptoms. The direct immunofluorescence assay in house polymerase chain reaction (PCR) and real time PCR were used for the detection of different respiratory viruses. The median age of the participants was 13.3 years (sd = 2.2) and 12.1 years (sd = 1.3) for the HIV group and control group, respectively. One month after vaccination (T1), both groups showed significant increases in the antibody geometric mean titers (GMTs) for all antigens. However, healthy controls showed higher values for antigens A/H1N1 and A/H3N2 (p = 0.002 and 0.001, respectively). There was a higher increase in the percentage of HIV-uninfected subjects with protective A/H1N1 antibodies (96.6%) compared to HIV-infected vaccinees (67.6%) at T1 (p = 0.004). Rhinovirus (27.7%) and coronavirus (22.5%) were the most prevalent agents identified in HIV-infected individuals. In the control group, the viruses most frequently found were rhinovirus (24.2%) and adenovirus (21.2%). The seroprotection rate for the H1N1 antigen was higher in the control group, which also showed a greater increase in GMTs for H1N1 and H3N2 antigens after immunization. Viral agents were identified in 39/60 (65%) episodes of respiratory infections from the HIV-infected group and in 17/32 episodes (53.1%) from the control group (p = 0.273). PMID- 21284526 TI - Prostate cancer mortality in Taiwanese men: increasing age-standardized trend in general population and increased risk in diabetic men. AB - BACKGROUND: To evaluate the trend of prostate cancer mortality in Taiwanese general population and the association between diabetes and prostate cancer mortality. MATERIALS AND METHODS: In the general population during 1995-2006, the trends of prostate cancer mortality were evaluated, followed by calculation of age-specific mortality rates for age 40-64, 65-74, and >= 75 years. A cohort of 102,651 diabetic men aged >= 40 years recruited in 1995-1998 was followed prospectively. RESULTS: The trends of crude and age-standardized mortality from prostate cancer in the general population increased significantly (P < 0.0001). In the general population, 7,966 men aged >= 40 years died of prostate cancer, and aging was associated with increased risk. Age-specific prostate cancer mortality suggested significantly increasing trend for ages 65-74 and >= 75 years. A total of 321 diabetic men died of prostate cancer (crude mortality rate 41.9/100,000 person-years). Mortality rate ratios (95% confidence interval) showed higher risk of prostate cancer mortality in the diabetic patients, with magnitude increased with decreasing age: 1.55 (1.29-1.86), 2.68 (2.29-3.13), and 6.84 (5.34-8.75) for age >= 75, 65-74, and 40-64 years, respectively. CONCLUSIONS: Prostate cancer mortality in the Taiwanese general population is increasing. Diabetic patients have a higher risk of prostate cancer mortality, which is more remarkable with decreasing age. PMID- 21284527 TI - Vascular endothelial growth factors in retinal and choroidal neovascular diseases. AB - Angiogenesis, or neovascularization, refers to development of new vessels from pre-existing vasculature. Retinal and choroidal neovascularization leads to oedema, haemorrhages, and fibrosis, causing visual impairment and blindness. In multiple studies, vascular endothelial growth factor (VEGF) has been shown to be the most important factor in ocular angiogenesis. Recently discovered anti-VEGF treatments have revolutionized the therapy of neovascular diseases in the eye. These agents have been shown not just to stop the angiogenic process and maintain visual acuity but also improve vision in a great proportion of patients at least during a 2-year follow-up. However, there are also problems with these agents and their delivery regimens, and new therapeutic strategies are needed. This review summarizes the most important growth factors participating in the angiogenic process in the retina and the choroid, diseases where angiogenesis plays the most devastating part causing visual impairment, as well as current antiangiogenic treatments for these diseases. PMID- 21284528 TI - Oxidative stress and endothelial dysfunction: therapeutic implications. AB - In a previous issue of Annals of Medicine, we presented evidence in support of the concept that an abnormally increased production of reactive oxygen species plays a central role in the genesis and progression of cardiovascular disease. While a number of preclinical lines of evidence support this concept, and despite the results of many studies suggesting a beneficial impact of antioxidant drugs on endothelial function, large clinical trials have failed to demonstrate a benefit of antioxidants on cardiovascular outcomes. Studies exploring the possibility that classical antioxidants such as vitamin C, vitamin E, selenium, or folic acid may improve the prognosis of patients with cardiac disease have substantially reported neutral-and occasionally negative-results. In contrast, medications such as statins, ACE inhibitors, certain beta-blockers, or angiotensin I receptor blockers, which possess indirect 'ancillary' antioxidant properties, have been associated with beneficial effects in both preclinical studies and large clinical trials. The reasons for the failure of the 'direct' approach to antioxidant therapy, and for the success of the therapy with these drugs, are discussed in the present review. PMID- 21284529 TI - Chlamydia trachomatis infections of the female genital tract: state of the art. AB - Chlamydia trachomatis (CT) is the most common bacterial cause of sexually transmitted infections. CT infections are strongly associated with risk-taking behavior. Recommendations for testing have been implemented in many countries. The effectiveness of the screening programs has been questioned since chlamydia rates have increased. However, the complication rates including pelvic inflammatory disease, tubal factor infertility, and tubal pregnancy have been decreasing, which is good news. The complication rates associated with CT infection have clearly been over-estimated. Genetic predisposition and host immune response play important roles in the pathogenesis of long-term complications. CT plays a co-factor role in the development of cervical neoplasia caused by high-risk human papillomavirus (HPV) types. The evidence linking CT and other adverse pregnancy outcomes is weak. The current nucleic acid amplification tests perform well. A new genetic variant of CT was discovered in Sweden but has only rarely been detected elsewhere. Single-dose azithromycin remains effective against CT. Secondary prevention by screening is still the most important intervention to limit the adverse effects of CT on reproductive health. PMID- 21284530 TI - Autoinflammatory diseases and cardiovascular manifestations. AB - Abstract A host of clinical scenarios can be depicted in hereditary autoinflammatory diseases, and the cardiovascular system can also be involved especially in familial Mediterranean fever (FMF), caused by mutations in the MEFV gene, and tumour necrosis factor receptor-associated periodic syndrome (TRAPS), caused by mutations in the TNFRSF1A gene. Pericardial diseases are the most represented cardiovascular abnormalities, though the role of MEFV and TNFRSF1A in the initiation of heart involvement has not been demonstrated formally and will be discussed herein. PMID- 21284531 TI - Risk of asthma and autoimmune diseases and related conditions in patients hospitalized for obesity. AB - BACKGROUND: Although there are putative mechanistic links between obesity and autoimmune diseases, obesity is not considered a risk factor for most autoimmune diseases. METHODS: Using the nation-wide Hospital Discharge Register we defined a cohort of 29,665 patients hospitalized for obesity since year 1964. The patients were followed for hospitalization for any of 34 autoimmune or related conditions through year 2007. Standardized incidence ratios (SIRs) were calculated for autoimmune diseases in obese individuals compared to those who had not been hospitalized for obesity. RESULTS: Among 22 immune diseases diagnosed after hospitalization for obesity and in at least 5 patients, the overall SIR was 2.05. Of the individual diseases studied, the risk of 16 was significantly increased; none displayed a decreased risk. Psoriasis (4.54) and Behcet's disease (4.49) exhibited the highest risks, followed by Hashimoto's disease/hypothyroidism (4.12) and asthma (3.39). Small but significant increases in SIRs were also noted for the common autoimmune diseases Graves's disease/hyperthyroidism (1.28) and rheumatoid arthritis (1.37). CONCLUSIONS: The present population of obese individuals, subsequently diagnosed with a number of autoimmune diseases and related conditions, was hospitalized at a relatively young age. Further studies are needed to describe the morbidity in the obese population at large. PMID- 21284532 TI - Setting up TRAPS. AB - Tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is a dominantly inherited autoinflammatory disease caused by heterozygous mutations in the TNFRSF1A gene encoding for the TNF receptor 1 (TNFR1). TRAPS is a multi faceted and heterogeneous disease which commonly manifests as recurrent episodes of high fever accompanied by abdominal pain, pleurisy, migratory rash, and myalgia. Disease attacks occur spontaneously or may be elicited by minor triggers. Because of a vigorous and sustained acute-phase response it may be complicated by systemic AA amyloidosis. Therapeutically interleukin-1 blockade seems even more promising than TNF blockade. Studies on the pathogenesis of TRAPS have shown TNFalpha-dependent cellular signalling to be defective, an enigmatic finding considering the hyperinflammatory phenotype of the disease. Several studies indicate that most mutated receptors never reach the cell surface but are misfolded and trapped in the endoplasmic reticulum, where they may elicit an intracellular inflammatory response, and thus lead to constitutional expression of proinflammatory cytokines. The aim of this review is to describe the current understanding of the pathogenesis of TRAPS by integrating recent clinical and laboratory data. PMID- 21284533 TI - Metabolic syndrome in childhood and increased arterial stiffness in adulthood: the Cardiovascular Risk In Young Finns Study. AB - OBJECTIVE. We conducted the present study to examine the associations of two different paediatric metabolic syndrome (MetS) definitions and recovery from childhood MetS with arterial pulse wave velocity (PWV), an index of arterial stiffness, measured in adulthood. METHODS. A total of 945 subjects participated in the base-line study in 1986 (then aged 9-18 years) and the adult follow-up in 2007 (then aged 30-39 years). Cardiovascular risk factor data were available at both base-line and follow-up. In the follow-up study, arterial PWV was measured using a whole-body impedance cardiography device. RESULTS. Subjects suffering from MetS in childhood (prevalence 11.1%-14.1%) had higher arterial PWV after 21 year follow-up when compared with those not afflicted by the syndrome in childhood (P < 0.007). An increasing number of the MetS components in childhood were associated with increased PWV in adulthood (P for trend = 0.005). Subjects who recovered from the MetS during the 21-year follow-up period had lower PWV than those with persistent MetS (P < 0.001). CONCLUSION. MetS in childhood predicted increased arterial stiffness in adulthood, and recovery from childhood MetS was associated with decreased arterial PWV in adulthood. The current results emphasize the importance of the prevention and controlling of MetS risk factors both in childhood and adulthood. PMID- 21284534 TI - Microvascular mural cell functionality of human embryonic stem cell-derived mesenchymal cells. AB - Microvascular mural or perivascular cells are required for the stabilization and maturation of the remodeling vasculature. However, much less is known about their biology and function compared to large vessel smooth muscle cells. We have developed lines of multipotent mesenchymal cells from human embryonic stem cells (hES-MC); we hypothesize that these can function as perivascular mural cells. Here we show that the derived cells do not form teratomas in SCID mice and independently derived lines show similar patterns of gene expression by microarray analysis. When exposed to platelet-derived growth factor-BB, the platelet-derived growth factor receptor beta is activated and hES-MC migrate in response to a gradient. We also show that in a serum-free medium, transforming growth factor beta1 (TGFbeta1) induces robust expression of multiple contractile proteins (alpha smooth muscle actin, smooth muscle myosin heavy chain, smooth muscle 22alpha, and calponin). TGFbeta1 signaling is mediated through the TGFbetaR1/Alk5 pathway as demonstrated by inhibition of alpha smooth muscle actin expression by treatment of the Alk5-specific inhibitor SB525334 and stable retroviral expression of the Alk5 dominant negative (K232R). Coculture of human umbilical vein endothelial cell (HUVEC) with hES-MC maintains network integrity compared to HUVEC alone in three-dimensional collagen I-fibronectin by paracrine signaling. Using high-resolution laser confocal microscopy, we show that hES-MC also make direct contact with HUVEC. This demonstrates that hESC-derived mesenchymal cells possess the molecular machinery expected in a perivascular progenitor cells and can play a functional role in stabilizing EC networks in in vitro three-dimensional culture. PMID- 21284535 TI - Antiplasmodial activity of New Caledonia and Vanuatu traditional medicines. AB - CONTEXT: With the emergence of strains multiresistant to antimalarial drugs, the search for new active molecules remains a priority. Ethnopharmacology appears to be a good method of selection in such investigations. OBJECTIVE: The aim of this research work is to select plants used in Melanesian traditional medicine, in New Caledonia and Vanuatu, which should be a promising source for the isolation of new antimalarial drugs. MATERIALS AND METHODS: Forty-seven plant extracts belonging to 12 families, traditionally used by the Melanesian people or belonging to an antimalarial known genus, were screened in vitro for antimalarial activity on Plasmodium falciparum chloroquine (CQ)-resistant (FcB1) and CQ sensitive (HB3) strains. They were also tested for their inhibitory effects on a protein kinase (Pfnek) and their cytotoxicity on human breast adenocarcinoma (MCF7) cells. RESULTS: Among all extracts, four displayed strong in vitro activities against P. falciparum: Gardenia urvillei Montrouzier, Scleria polycarpa Boeckeler, Terminalia catappa L. and Acronychia laevis J.R. & J.G. Forster, the latter being also toxic on MCF7 cells. Except for the extracts of S. polycarpa, all others that were active on P. falciparum, also possess an inhibitory effect on Pfnek. DISCUSSION AND CONCLUSION: These results confirm that ethnopharmacology is an excellent approach for such investigations. The two countries considered clearly present advantages in the field. Indeed, local populations keep their traditional knowledge alive, and their flora is exceptionally rich. In New Caledonia, the high endemicity rate (74%) ranks the island as one of the world's biodiversity hotspots. As a consequence, chances to discover new active natural compounds are also high. PMID- 21284536 TI - Hepatoprotective and antioxidant activities of Tamarix nilotica flowers. AB - CONTEXT: Tamarix nilotica (Ehrenb.) Bunge (Tamaricaceae) is used in the Egyptian traditional medicine as an antiseptic agent. This plant has been known since pharaonic times and has been mentioned in medical papyri to expel fever, relieve headache, to draw out inflammation, and as an aphrodisiac. No scientific study is available about the biological effect of this plant. OBJECTIVE: This study aimed to evaluate the hydro-alcoholic extract (80%) of T. nilotica flowers for hepatoprotective and antioxidant activities. MATERIALS AND METHODS: Hepatoprotective activity was assessed using carbon tetrachloride-induced hepatic injury in rats by monitoring biochemical parameters. Antioxidant activity was evaluated in alloxan-induced diabetic rats. Biochemical markers of hepatic damage such as serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase (ALP), and tissue glutathione were determined in all groups. RESULTS AND CONCLUSION: Carbon tetrachloride (5 mL/kg body weight) enhanced the SGOT, SGPT, and ALP levels. There was a marked reduction in tissue glutathione level in diabetic rats. The hydro-alcoholic extract of T. nilotica (100 mg/kg body weight) ameliorated the adverse effects of carbon tetrachloride and returned the altered levels of biochemical markers near to the normal levels. PMID- 21284537 TI - Regulation of CD1, Ki-67, PCNA mRNA expression, and Akt activation in estrogen responsive human breast adenocarcinoma cell line, MCF-7 cells, by griffonianone C, an isoflavone derived from Millettia griffoniana. AB - CONTEXT: Millettia griffoniana Baill. (Fabaceae), which contains isoflavonoids like griffonianone C (Griff C), is commonly used in the folk medicine in Cameroon to treat various ailments. Possible health benefits of Griff C which include alleviation of menopausal symptoms, limitation of bone resorption, and lowering of the risks of cancer and cardiovascular diseases attracted our interest. OBJECTIVE: The effects of Griff C on the regulation of the expression of proliferation markers such as proliferating cell nuclear antigen (PCNA), cyclin D1 (CD1) and Ki-67 are investigated here. Its role in apoptosis or cell survival, through the phosphatidylinositol 3 kinase-Akt (PI3K-Akt) signaling pathway is further studied. MATERIALS AND METHODS: Semiquantitative real-time PCR was performed to analyze the effects of Griff C on gene expression in MCF-7 cells. Western blot analysis was used to assess the role of Griff C on the expression of phosphorylated Akt in MCF-7 cells. RESULTS: Griff C induced a 4.84-fold increase in the expression of Ki-67 mRNA at the concentration of 10(-8) M and a 3.90-fold increase of CD1 mRNA at 10(-7) M. Griff C slightly increased the phosphorylation of Akt at its serine 473 residue. Akt phosphorylation was inhibited by the PI3K inhibitor, LY294002, but not by the specific estrogen receptor antagonist, fulvestrant. DISCUSSION AND CONCLUSION: These findings suggest that Griff C can modulate proliferation of MCF-7 cells. Our results also suggest that Griff C can affect the PI3K-related signaling pathway. Thus, Griff C may exert part of its low proliferative and antiapoptotic effects by a nongenomic mode of action. PMID- 21284538 TI - Antioxidant and anticholinesterase activities of eleven edible plants. AB - CONTEXT: Consumers have become more interested in beneficial effects of vegetables, fruits, and tea to protect their health. OBJECTIVE: The antioxidant potential and anticholinesterase activity of eleven edible plants were investigated. MATERIAL AND METHODS: The dichloromethane, ethanol and water extracts prepared from celery [Apium graveolens L. (Umbelliferae)], Jerusalem artichoke [Helianthus tuberosus L. (Compositae)], spinach [Spinacia oleracea L. (Chenopodiaceae)], chard [Beta vulgaris L. var. cicla (Chenopodiaceae)], purslane [Portulaca oleracea L. (Portulacaceae)], ispit, or borage [Trachystemon orientale (L.) G. Don (Boraginaceae)], garden rocket [Eruca sativa Mill. (Brassicaceae)], red cabbage [Brassica oleracea L. var. capitata f. rubra DC. (Cruciferae)], lime flower [Tilia tomentosa Moench (Tiliaceae)], cinnamon [Cinnamomum cassia Presl. (Lauraceae)], and rosehip [Rosa canina L. (Rosaceae)], were tested to determine their antioxidant and anticholinesterase activities by using CUPRAC (cupric reducing antioxidant capacity) and Ellman methods, respectively, for the first time. RESULTS: As a result, the dichloromethane, ethanol and water extracts of cinnamon showed the best antioxidant effect among the extracts of the tested plants. The ethanol extract of cinnamon exhibited 63.02% inhibition against acetylcholinesterase and 85.11% inhibition against butyrylcholinesterase (BChE) at 200 ug/mL concentration while the dichloromethane extract of garden rocket possessed the highest inhibition (91.27%) against BChE among all the tested extracts. DISCUSSION AND CONCLUSION: This study indicated that the ethanol extract of cinnamon may be a new potential resource of natural antioxidant and anticholinesterase compounds. PMID- 21284539 TI - Chemical composition and mosquito larvicidal activities of Salvia essential oils. AB - CONTEXT: Vector control is facing a threat due to the emergence of resistance to synthetic insecticides. In this context, essential oils have received much attention as potentially useful bioactive compounds against insects. Therefore, our present study aimed to evaluate the efficacy of essential oils from the aerial parts of Salvia elegans Vahl, Salvia dorisiana Standl., Salvia splendens Sello ex J.A. Schult Blue Ribbon, and S. splendens Sello ex J.A. Schult Scarlet Sage Red (Lamiaceae) against the fourth instar larvae of Aedes albopictus Skuse (Diptera: Culicidae). OBJECTIVE: The mosquito larvicidal activities of the essential oils and chemical composition of four taxa of Salvia are investigated in this article for the first time. MATERIALS AND METHODS: Chemical compositions of essential oils obtained from four taxa of Salvia were analyzed by gas chromatography-mass spectrometry (GC-MS), GC-FID, and the effects of essential oils on fourth instar larvae of A. albopictus were investigated. RESULTS: The main components identified from each Salvia essential oils were as follows: spathulenol (38.73%) and caryophyllene (10.32%) from S. elegans; ledol (45.8%) and 4,4'-[(p-phenylene)diisopropylidene]diphenol (17.38%) from S. dorisiana; beta cubebene (22.9%), and caryophyllene (12.99%) from S. splendens Blue Ribbon; phytol (41.46%) and cyclooctasulfur (24.88%) from S. splendens Scarlet Sage Red. The essential oils of S. elegans and S. splendens Blue Ribbon had excellent inhibitory larvicidal effect against A. albopictus larvae, and their LC(50) values in 24 h were 46.4 ppm (LC(90) = 121.8 ppm) and 59.2 ppm (LC(90) = 133.0 ppm), respectively. DISCUSSION AND CONCLUSION: These findings demonstrate that the essential oils of these Salvia species could be considered as the powerful candidates to bring about useful botanicals so as to prevent the resurgence of mosquito vectors. PMID- 21284540 TI - Chondrogenesis from human placenta-derived mesenchymal stem cells in three dimensional scaffolds for cartilage tissue engineering. AB - Human placenta-derived mesenchymal stem cells (hPMSCs) represent a promising source of stem cells. The application of hPMSCs in cartilage tissue engineering, however, was less reported. In this study, hPMSCs were grown in a three dimensional (3D) environment for cartilage tissue formation in vitro. To select proper scaffolds for 3D culture of mesenchymal stem cells (MSCs), rat adipose derived MSCs were initially employed to optimize the composition and condition of the 3D environment. The suitability of a poly(D,L-lactide-co-glycolide) (PLGA) precision scaffold previously developed for seeding and culture of primary chondrocytes was tested for MSCs. It was established that MSCs had to be embedded in alginate gel before seeded in the PLGA precision scaffold for cartilage-like tissue formation. The inclusion of nano-sized calcium-deficient hydroxyapatite (nCDHA) and/or a recombinant protein containing arginine-glycine-aspartate (RGD) into the alginate gel enhanced the chondrogenesis for both rat adipose-derived MSCs and hPMSCs. The amount of extracellular matrix such as glycosaminoglycan and type II collagen accumulated during a period of 21 days was found to be the greatest for hPMSCs embedded in the alginate/nCDHA/RGD gel and injected and cultivated in the precision scaffold. Also, histological analyses revealed the lacunae formation and extracellular matrix production from the seeded hPMSCs. Comparing human bone marrow-derived MSCs (hBMSCs) and hPMSCs grown in the previous composite scaffolds, the secretion of glycosaminoglycan was twice as higher for hPMSCs as that for hBMSCs. It was concluded that the alginate/nCDHA/RGD mixed gel in the aforementioned system could provide a 3D environment for the chondrogenesis of hPMSCs, and the PLGA precision scaffold could provide the dimensional stability of the whole construct. This study also suggested that hPMSCs, when grown in a suitable scaffold, may be a good source of stem cells for building up the tissue-engineered cartilage. PMID- 21284541 TI - Push-pull osmotic pump for zero order delivery of lithium carbonate: development and in vitro characterization. AB - Lithium carbonate, a drug with narrow therapeutic index, needs therapeutic drug monitoring and dose adjustment to maintain lithium level within the therapeutic window. Conventional formulations of lithium carbonate exhibit immediate drug release causing swing/fluctuations in the plasma concentration of lithium, consequently leading to unfavorable side-effects and make dose adjustment difficult. The push-pull osmotic pump has been developed for zero order delivery of lithium carbonate for a period of 24 h. The effect of various formulation variables on bilayer core tablet and its semi permeable coating along with orifice diameter have been investigated and optimized for desired drug release profile. Drug release was found to be inversely proportional to the membrane thickness but directly related to the amount of pore formers in the semipermeable membrane. Images from a scanning electron microscope confirmed the presence of pores in the semipermeable membrane which facilitated the required water penetration. No distortion or change in orifice shape was noticed prior to and after the dissolution study. Drug release from the developed formulation was found to be independent of pH, agitation intensity and agitation mode but depended on osmotic pressure of dissolution media. PMID- 21284542 TI - Evaluation of the tumor targeting of a FAPalpha-based doxorubicin prodrug. AB - Fibroblast activation protein-alpha (FAPalpha) is a tumor-associated antigen uniquely expressed by reactive stromal fibroblasts in the majority of human epithelial tumors. FAPalpha also possesses both post-prolyl peptidase and endopeptidase activities. Consequently, FAPalpha is increasingly considered as a potential pan-tumor target for designing tumor-targeted prodrugs. We previously conjugated Doxorubicin (Dox) with a FAPalpha-specific dipeptide (Z-Gly-Pro) to develop a FAPalpha-targeting prodrug of Dox (FTPD). The aim of current work was to validate the tumor targeting of this targeted-delivery strategy. The results demonstrated that FTPD could effectually release Dox upon the hydrolysis of FAPalpha as well as the incubation with tumor homogenate of FAPalpha-positive tumor (4T1 tumor), while it was highly stable in mouse plasma and a variety of tissue homogenates including heart, liver, and so on. And the FAPalpha-cleaved FTPD exhibited significantly higher cytotoxicity against 4T1 cells in vitro than the uncatalyzed prodrug. Additionally, FTPD produced similar antitumor efficacy in 4T1 tumor-bearing mice to free Dox without obvious cardiotoxic effect. Moreover, subsequent study indicated that the accumulation of FTPD reduced significantly in the heart compared to free Dox. These findings suggest that such FAPalpha-based prodrug strategy is promising to achieve targeted delivery of antitumor agents. PMID- 21284543 TI - The effect of MS14 on innate and cellular immune responses in BALB/c mice. AB - MS14 is an Iranian natural preparation of herbal-marine source with no obvious toxicity in oral administration, which possesses anti-inflammatory and immunomodulatory effects. In this study, the effect of oral administration of MS14 on nitric oxide (NO) production of peritoneal macrophages and lymphocyte Th1 cytokines and delayed-type hypersensitivity (DTH) test in BALB/c mice were investigated. Peritoneal macrophages were cultured and NO production was measured by Griess method. Viability of macrophages was assayed by MTT (3-(4,5-dimethy-2 lthiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) test. Interleukin-2 (IL-2) and INFgamma levels in supernatant of spleen lymphocytes culture were assayed by enzyme-linked immunosorbent assay kit. For DTH test the mice were immunized with sheep red blood cell and DTH was measured 24 h after the last immunization of mice. NO production of macrophages has been diminished significantly in MS14 treated group (about 40%) at the presence or absence of stimulators. Macrophage viability had no significant alteration after MS14 administration. However, interferon-gamma production of lymphocytes was significantly decreased in MS14 group both at the absence or presence of concanavalin A (ConA; about 50%); IL-2 production declined about 20% at the presence of ConA. In comparison with the control group, MS14 had no statistically significant effect on DTH test. The results have pointed that MS14 may have immunomodulatory potentials at least through its decreasing effect on NO production of macrophages and level of Th1 cytokine pattern. PMID- 21284544 TI - Caries risk and periodontitis in patients with coronary artery disease. AB - BACKGROUND: There is considerable variation in studies on the oral health of patients with coronary artery disease (CAD). The aims of this investigation are to study the caries risk profile using the Cariogram computer program and the periodontal disease severity in patients with CAD. METHODS: A total of 127 participants (54 test and 73 control) were included. Participants were asked about their general health and daily habits. Clinical examinations, radiographs, and salivary sampling were performed. Cariologic data were entered into the computer program for risk-profile illustration. The onset of CAD conditions was also documented. RESULTS: Compared with controls, participants with CAD consumed less sugar, used fluoride toothpaste less frequently, and had significantly less favorable periodontal parameters (P <0.005). Generally, differences in cariologic parameters between the two groups were not significant. Significantly more participants with CAD exhibited low salivary-secretion rates than controls. The actual chance (percentage) of avoiding new cavities according to the Cariogram was low in the test and control groups (31% and 40%, respectively; P <0.05). Only gingival recession was correlated with the onset of CAD. CONCLUSIONS: Test and control groups had a relatively high caries risk. More severe periodontal disease was observed in participants with CAD. PMID- 21284545 TI - Autologous platelet-rich fibrin in the treatment of mandibular degree II furcation defects: a randomized clinical trial. AB - BACKGROUND: Platelet-rich fibrin (PRF), an intimate assembly of cytokines, glycan chains, and structural glycoproteins enmeshed within a slowly polymerized fibrin network, has the potential to accelerate soft and hard tissue healing. This double-masked randomized study is designed to evaluate the effectiveness of autologous PRF in the treatment of mandibular degree II furcation defects compared with open flap debridement (OFD). METHODS: Using a split-mouth design, 18 patients with 36 mandibular degree II furcation defects were randomly allotted and treated either with autologous PRF and OFD or OFD. Plaque index, sulcus bleeding index, probing depth, relative vertical and horizontal clinical attachment level, gingival marginal level, and radiographic bone defect were recorded at baseline and 9 months postoperatively. Comparison between indices between the test and control groups was performed using the paired t test except for plaque index and sulcus bleeding index data, which used the chi(2) test. RESULTS: All clinical and radiographic parameters showed statistically significant improvement at the sites treated with PRF and OFD compared to those with OFD alone. CONCLUSION: Within the limitation of this study, significant improvement with autologous PRF implies its role as a regenerative material in the treatment of furcation defects. PMID- 21284546 TI - The accuracy of identifying the greater palatine neurovascular bundle: a cadaver study. AB - BACKGROUND: The palate is a common site for harvesting subepithelial connective tissue grafts (SCTG). The size of SCTG that can be harvested is dictated by the position of the greater palatine neurovascular bundle (GPB). The aims of this cadaver study are to assess the accuracy of predicting the location of the GPB on study models and to evaluate anatomic factors that might influence the predictability. METHODS: Eleven fully dentate or partially edentulous maxillary cadavers were used. Study models were fabricated after the greater palatine foramen was identified. The GPB was recognized after dissection, from which the distance to the cemento-enamel junction of the first molar and premolar was measured. Eight periodontists and twelve periodontal residents were asked to estimate the location of the GPB on the study models and the same measurements were taken. Comparisons of the estimated and true GPB position were performed. The correlation between the palatal vault height and the variability of detecting the GPB was investigated. RESULTS: The most frequent greater palatine foramen location was between the second and third molars (66.6%). For most cases, there was an underestimation of the location of the GPB up to 4 mm. The interexaminer variability was positively correlated with the vault height. CONCLUSIONS: The estimated location of the GPB was commonly closer to the cemento-enamel junction of posterior teeth. Agreement on the location of the GPB was lowered with the presence of high palatal vaults. The results of this study could assist clinicians in planning the location for harvesting SCTG on the hard palate. PMID- 21284547 TI - Oral impact on daily performance, personality traits, and compliance in periodontal maintenance therapy. AB - BACKGROUND: To our knowledge, the association between personality traits and oral health impacts on daily activities among patients under periodontal maintenance was not previously evaluated. The present study aims to determine the oral health impacts among regular- and erratic-complier patients and their correlations with personality traits by means of the oral impacts on daily performance (OIDP) and the neuroticism extraversion openness five-factor inventory (NEO FFI-R) instruments. METHODS: A total of 58 regular and 58 erratic compliers matched by sex, diabetes, and smoking were recruited from a cohort of 238 participants under periodontal maintenance. Periodontal examinations and questionnaire applications were performed in recalls during a 3-year interval. The influence of variables of interest on the OIDP was evaluated through univariate and multivariate linear regression analyses. RESULTS: The periodontal status of regular compliers was significantly better than that of erratic compliers. Erratic compliers presented higher OIDP scores (36.34 +/- 6.64) compared to regular compliers (30.45 +/- 7.72). Higher scores of neuroticism and conscientiousness (R(2) = 68%; P <0.001) were associated with higher OIDP scores among regular compliers, whereas among erratic compliers, lower scores of neuroticism, higher openness, and extraversion (R(2) = 77%; P = 0.001) were associated with higher OIDP scores. CONCLUSION: Personality traits, mainly neuroticism, showed significant influences on OIDP among patients under periodontal maintenance. PMID- 21284548 TI - A clinical and histologic evaluation of gingival fibroblasts seeding on a chitosan-based scaffold and its effect on the width of keratinized gingiva in dogs. AB - BACKGROUND: Finding biocompatible matrix materials capable of enhancing the procedures of gingival augmentation is a major concern in periodontal research. This has prompted the investigation of a safe grafting technique by means of synthetic or natural polymers. The objective of this study is to examine the effect of a gingival fibroblast cultured on a naturally derived (i.e., chitosan based) scaffold on the width of keratinized gingiva in dogs. METHODS: Gingival fibroblasts were cultured from a small portion of hard palates of five dogs. A bilayered chitosan scaffold was seeded with the gingival fibroblasts and transferred to dogs. Surgery was performed bilaterally, and the regions were randomly divided into two groups: chitosan only (control site) and chitosan + fibroblast (test site). Periodontal parameters, including probing depth and width of keratinized and attached gingiva, were measured at baseline and 3 months after surgery. A histologic evaluation was also performed on the healed grafted sites. RESULTS: Comparison of width of keratinized and attached gingiva in control and test sites showed that the mean width of keratinized and attached gingiva increased in each group after surgery. However, the difference between control and test groups was not statistically significant. Concerning the existence of the keratinized epithelium, exocytosis, and epithelium thickness, no significant difference was observed in test and control sites. The difference was significant in relation to rete ridge formation. CONCLUSION: The tissue-engineered graft consisting of chitosan + fibroblast was applied to gingival augmentation procedures and generated keratinized tissue without any complications usually associated with donor-site surgery. PMID- 21284549 TI - Clinical and patient-centered outcomes after minimally invasive non-surgical or surgical approaches for the treatment of intrabony defects: a randomized clinical trial. AB - BACKGROUND: The present study aims to compare the performance of minimally invasive non-surgical and surgical approaches for the therapy of intrabony defects. METHODS: Twenty-nine patients who presented with intrabony defects were randomly assigned to: 1) a minimally invasive non-surgical technique (MINST) group, or 2) minimally invasive surgical technique (MIST) group. The chair time of each therapeutic procedure was calculated. The probing depth (PD), position of the gingival margin (PGM) and relative clinical attachment level (RCAL) were evaluated at 3 and 6 months after treatments. The patient perception of discomfort/pain experienced during and after therapy and patient satisfaction regarding treatments were also evaluated. RESULTS: Significant PD reductions, RCAL gains, and no changes in the PGM were obtained at 3 and 6 months in MINST and MIST groups (P <0.05). No differences were observed between groups at any time points (P >0.05). Patient-oriented outcomes did not demonstrate differences between therapeutic approaches (P >0.05). Significant higher chair times were required in the MIST group than in the MINST group (P <0.05). CONCLUSIONS: Minimally invasive non-surgical and surgical approaches were successfully used for the treatment of intrabony defects and achieved periodontal health in association with negligible morbidity and suitable patient satisfaction. However, non-surgical therapeutic modality presented an advantage in terms of a reduction of treatment chair time. PMID- 21284550 TI - Cytokines and bone-related factors in systemically healthy patients with chronic periodontitis and patients with type 2 diabetes and chronic periodontitis. AB - BACKGROUND: This study compares the levels of cytokines and bone-related factors in the gingival crevicular fluid (GCF) of systemically healthy patients with chronic periodontitis (CP); and better-controlled, and poorly controlled patients with type 2 diabetes and CP. METHODS: Thirty-seven patients with type 2 diabetes and CP and 20 systemically healthy patients with CP were enrolled in this study. The patients with diabetes mellitus were categorized as better-controlled (n = 17; HbA(1c) levels <=8%) or poorly controlled (n = 20; glycated hemoglobin values >8%). Levels of tumor necrosis factor-alpha, interleukin (IL)-4, interferon (IFN) gamma, IL-23, IL-17, soluble receptor activator of nuclear factor-kappa B ligand (sRANKL), and osteoprotegerin (OPG) in GCF of diseased sites were analyzed by enzyme-linked immunosorbent assay. RESULTS: Type 2 diabetes mellitus, as a whole, upregulates the levels of OPG, sRANKL, IFN-gamma, IL-17, and IL-23 and downregulates the production of IL-4 in sites with CP (P <0.05). Better controlled individuals exhibited the highest levels of IFN-gamma, whereas poorly controlled patients presented the highest levels of IL-17 (P <0.05). There were no differences in the levels of tumor necrosis factor-alpha, OPG, and IL-23 among systemically healthy, better-controlled, and poorly controlled patients with diabetes (P >0.05). CONCLUSIONS: Increased levels of proinflammatory cytokines and RANKL were observed in the GCF of patients with type 2 diabetes with CP, compared to patients without diabetes. In addition, poor or good glycemic status seems to modulate osteo-immunoinflammatory mediators in a different manner. PMID- 21284551 TI - Periodontal Status of Adults With Systemic Sclerosis: Case-Control Study. AB - Background: Systemic sclerosis (SSc) is a systemic autoimmune disease that affects connective tissue in the skin, blood vessels and major organs of the body. This project aimed to compare the periodontal status of dentate Hong Kong Chinese with and without SSc. Methods: Thirty-six non-smoking adults with SSc (35 women; 50.6 ? 11.7 years, free from Sjogren's syndrome) attending a teaching hospital were age- and sex-matched to systemically healthy controls attending a dental hospital. Both groups had similar demographic characteristics but a lower proportion of SSc patients were working or studying (p < 0.05). Twenty-three (32.0%) of all participants were regular dental attendees. Orthopantomogram rediograph were taken. Participants were surveyed and periodontally examined. Results: Both groups had a similar number of erupted teeth, proportion of sites with detectable plaque, and mean full-mouth probing attachment level, whereas controls had less bleeding on probing (BOP(%), 49.3 ? 22.6 vs. 78.4 ? 19.6; p < 0.001) and a shallower mean full-mouth probing pocket depth (PPD(mm), 1.92 ? 0.44 vs. 2.52 ? 0.58; p < 0.001). Radiographically, SSc patients had wider periodontal ligament spaces. (PDL (mm), 0.36 ? 0.06 vs. 0.33 ? 0.03, p < 0.01) Conclusion: Hong Kong Chinese SSc adults seem to exhibit higher levels of periodontal inflammation and wider radiographic PDL spaces than age- and sex- matched controls. Future studies are warranted to further investigate any associations between these periodontal features and SSc. PMID- 21284552 TI - Hard and soft tissue changes after crestal and subcrestal immediate implant placement. AB - BACKGROUND: The purpose of this study is to assess the influence of the placement level of implants with a laser-microtextured collar design on the outcomes of crestal bone and soft tissue levels. In addition, we assessed the vertical and horizontal defect fill and identified factors that influenced clinical outcomes of immediate implant placement. METHODS: Twenty-four patients, each with a hopeless tooth (anterior or premolar region), were recruited to receive dental implants. Patients were randomly assigned to have the implant placed at the palatal crest or 1 mm subcrestally. Clinical parameters including the keratinized gingival (KG) width, KG thickness, horizontal defect depth (HDD), facial and interproximal marginal bone levels (MBLs), facial threads exposed, tissue-implant horizontal distance, gingival index (GI), and plaque index (PI) were assessed at baseline and 4 months after surgery. In addition, soft tissue profile measurements including the papilla index, papilla height (PH), and gingival level (GL) were assessed after crown placement at 6 and 12 months post-surgery. RESULTS: The overall 4-month implant success rate was 95.8% (one implant failed). A total of 20 of 24 patients completed the study. At baseline, there were no significant differences between crestal and subcrestal groups in all clinical parameters except for the facial MBL (P = 0.035). At 4 months, the subcrestal group had significantly more tissue thickness gain (keratinized tissue) than the crestal group compared to baseline. Other clinical parameters (papilla index, PH, GL, PI, and GI) showed no significant differences between groups at any time. A facial plate thickness <=1.5 mm and HDD >=2 mm were strongly correlated with the facial marginal bone loss. A facial plate thickness <=2 mm and HDD >=3 were strongly correlated with horizontal dimensional changes. CONCLUSIONS: The use of immediate implants was a predictable surgical approach (96% survival rate), and the level of placement did not influence horizontal and vertical bone and soft tissue changes. This study suggests that a thick facial plate, small gaps, and premolar sites were more favorable for successful implant clinical outcomes in immediate implant placement. PMID- 21284554 TI - Factors influencing the periodontal referral process. AB - BACKGROUND: General dental practitioners (GPs) assess the periodontal status of patients and make decisions to treat patients or refer them to a periodontist. There is little information available regarding this process. The purpose of this study is to identify significant factors that GPs consider important in selecting a particular periodontist. The findings were compared and contrasted with responses of periodontists to gain perspectives from both groups involved in the referral process. METHODS: Data from an online cross-sectional survey of GPs (n = 533) and periodontists (n = 533) who practice in the southeastern region of the United States (from the databases of the American Dental Association and American Academy of Periodontology member directories) were obtained. RESULTS: The specialist's clinical skill was identified as the most important factor influencing periodontal referrals by GPs, whereas periodontists identified a previous positive experience between a GP and periodontist as the most important factor. In a descending order of importance, the top three rating averages (rated out of five) by GPs were clinical skill (4.84), a previous positive experience between a GP and periodontist (4.57), and communication (4.52). The top three factors of periodontists were a previous positive experience between a GP and periodontist (4.66), communication (4.40), and the likelihood of a good patient and periodontist rapport (4.29). CONCLUSIONS: The periodontist's clinical skill was chosen by GPs as the primary factor influencing the referral decisions of GPs. Periodontists perceived a previous positive experience between the GP and periodontist as the most influential factor. Further studies are required to gain more insight into the referral process. PMID- 21284553 TI - Cell- and gene-based therapeutic strategies for periodontal regenerative medicine. AB - Inflammatory periodontal diseases are a leading cause of tooth loss and are linked to multiple systemic conditions, such as cardiovascular disease and stroke. Reconstruction of the support and function of affected tooth-supporting tissues represents an important therapeutic endpoint for periodontal regenerative medicine. An improved understanding of periodontal biology coupled with current advances in scaffolding matrices has introduced novel treatments that use cell and gene therapy to enhance periodontal tissue reconstruction and its biomechanical integration. Cell and gene delivery technologies have the potential to overcome limitations associated with existing periodontal therapies, and may provide a new direction in sustainable inflammation control and more predictable tissue regeneration of supporting alveolar bone, periodontal ligament, and cementum. This review provides clinicians with the current status of these early stage and emerging cell- and gene-based therapeutics in periodontal regenerative medicine, and introduces their future application in clinical periodontal treatment. The paper concludes with prospects on the application of cell and gene tissue engineering technologies for reconstructive periodontology. PMID- 21284555 TI - Three-dimensional topography of synthetic scaffolds induces elastin synthesis by human coronary artery smooth muscle cells. AB - Due to the important structural and signaling roles of elastin in vascular stability, engineered human vascular tissues must incorporate elastin. However, despite considerable progress toward engineering of elastin-containing vascular tissues from animal cells, currently engineered vascular tissues using human cells largely lack elastin. In this study, we evaluated the effect of scaffold topography (two dimensional [2D] vs. three dimensional [3D]) on elastogenesis in adult human coronary artery smooth muscle cells (HCASMCs). We report that elastin gene expression by HCASMCs was increased by twofold after 4 days of culture in porous 3D polyurethane scaffolds. Transforming growth factor beta1 (TGF-beta1) further increased elastin gene expression in 3D cultures but not in 2D cultures. To evaluate if gene expression is translated into elastin synthesis, both 2D and 3D cultures were analyzed using Western blots. We show that only HCASMCs in 3D scaffolds produced elastin, suggesting that scaffold geometry itself is an important cue for elastogenesis. Moreover, TGF-beta1 enhanced elastin synthesis in 3D, but had no effect on cells grown on 2D surfaces. TGF-beta1, known to induce vascular smooth muscle cells (VSMC) differentiation, upregulated contractile VSMC marker proteins smooth muscle-alpha-actin and calponin in cells on 2D surfaces. Interestingly, in 3D scaffolds, TGF-beta1 failed to upregulate these differentiation marker proteins for at least 7 days, but did so in cells cultured for 14 days, whereas elastin synthesis was not affected. To our knowledge this study is the first to successfully demonstrate that adult human VSMC can produce elastin when seeded on 3D scaffolds and to directly compare the effect of scaffold topography on elastin synthesis. Knowledge about the conditions required to regulate the phenotype of human VSMCs is paramount to engineer elastin-containing autologous human vascular substitutes. PMID- 21284556 TI - Regulatory T-cell as orchestra leader in immunosuppression process of multiple sclerosis. AB - Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system characterized by perivascular inflammation and demyelination and loss of neurologic function. In this disease and its experimental model (experimental autoimmune encephalomyelitis, EAE), axonal and neuronal loss is thought to play a key role in irreversible loss of function and disability. Regarding the evident role of autoreactive T-cells (particularly Th1 and Th17 cells) in pathophysiology of MS, it might be assumed that the regulatory T-cells (Tregs) can control initiation and progression of disease and even treat it. The frequency, function and properties of various subsets of Tregs including natural Tregs (nTregs), IL-10 producing type 1 Tregs (Tr1 cells), transforming growth factor-beta producing Th3 cells, CD8(+) Tregs, and natural killer like T regulatory cells in MS and its model EAE, have been investigated in several experimental studies. In this review, we intend to submit the comprehensive information about the immunobiology of various subsets of Tregs and their roles and function in immunopathophysiology of MS and its animal model, EAE. PMID- 21284557 TI - Sustained release spherical agglomerates of polymethacrylates containing mefenamic acid: in vitro release, micromeritic properties and histological studies. AB - Mefenamic acid (MA) spherical agglomerates (SAs) were prepared with various polymethacrylates having different permeability characteristics (Eudragit RS 100, Eudragit RL 100 and Eudragit L 100) and also with combination of Eudragit RS 100 and Eudragit L 100 in different ratios. SAs were prepared by spherical crystallization method using ethanol/dichloromethane solvent (crystallization) system. The influence of various formulation factors on the encapsulation efficiency, as in vitro drug release, and micromeritic properties was investigated. Target release profile of MA was also drawn. The yields of preparation and the encapsulation efficiencies were high for all formulations. The shape and surface characteristics of SAs were observed by a scanning electron microscope. The particle sizes are in the range of 0.219 +/- 0.1 to 0.482 +/- 0.25 mm (mean +/- confidence interval t(95%)). In addition, histological studies showed that the administration of MA in SAs containing Eudragit RS/L provided a distinct tissue protection in the stomach and duodenum. Differential scanning calorimetry and X-ray diffraction of powder studies showed that MA particles crystallized in the presence of polymethacrylates did not undergo structural modifications. PMID- 21284558 TI - Engineering ear constructs with a composite scaffold to maintain dimensions. AB - Engineered cartilage composed of a patient's own cells can become a feasible option for auricular reconstruction. However, distortion and shrinkage of ear shaped constructs during scaffold degradation and neocartilage maturation in vivo have hindered the field. Scaffolds made of synthetic polymers often generate degradation products that cause an inflammatory reaction and negatively affect neocartilage formation in vivo. Porous collagen, a natural material, is a promising candidate; however, it cannot withstand the contractile forces exerted by skin and surrounding tissue during normal wound healing. We hypothesised that a permanent support in the form of a coiled wire embedded into a porous collagen scaffold will maintain the construct's size and ear-specific shape. Half-sized human adult ear-shaped fibrous collagen scaffolds with and without embedded coiled titanium wire were seeded with sheep auricular chondrocytes, cultured in vitro for up to 2 weeks, and implanted subcutaneously on the backs of nude mice. After 6 weeks, the dimensional changes in all implants with wire support were minimal (2.0% in length and 4.1% in width), whereas significant reduction in size occurred in the constructs without embedded wire (14.4% in length and 16.5% in width). No gross distortion occurred over the in vivo study period. There were no adverse effects on neocartilage formation from the embedded wire. Histologically, mature neocartilage extracellular matrix was observed throughout all implants. The amount of DNA, glycosaminoglycan, and hydroxyproline in the engineered cartilage were similar to that of native sheep ear cartilage. The embedded wire support was essential for avoiding shrinkage of the ear-shaped porous collagen constructs. PMID- 21284559 TI - Selective inhibition of dipeptidyl peptidase 4 by targeting a substrate-specific secondary binding site. AB - Dipeptidyl peptidase 4/CD26 (DP4) is a multifunctional serine protease liberating dipeptide from the N-terminus of (oligo)peptides which can modulate the activity of these peptides. The enzyme is involved in physiological processes such as blood glucose homeostasis and immune response. DP4 substrate specificity is characterized in detail using synthetic dipeptide derivatives. The specificity constant k(cat)/K(m) strongly depends on the amino acid in P1-position for proline, alanine, glycine and serine with 5.0 x 105 M-1 s-1, 1.8 x 104 M-1 s-1, 3.6 x 102 M-1 s-1, 1.1 x 102 M-1 s-1, respectively. By contrast, kinetic investigation of larger peptide substrates yields a different pattern. The specific activity of DP4 for neuropeptide Y (NPY) cleavage comprising a proline in P1-position is the same range as the k(cat)/K(m) values of NPY derivatives containing alanine or serine in P1-position with 4 x 105 M-1 s-1, 9.5 x 105 M-1 s 1 and 2.1 x 105 M-1 s-1, respectively. The proposed existence of an additional binding region outside the catalytic center is supported by measurements of peptide substrates with extended chain length. This 'secondary' binding site interaction depends on the amino acid sequence in P4'-P8'-position. Interactions with this binding site could be specifically blocked for substrates of the GRF/glucagon peptide family. By contrast, substrates not belonging to this peptide family and dipeptide derivative substrates that only bind to the catalytic center of DP4 were not inhibited. This more selective inhibition approach allows, for the first time, to distinguish between substrate families by substrate-discriminating inhibitors. PMID- 21284560 TI - Decreased mechanical properties of heart valve tissue constructs cultured in platelet lysate as compared to fetal bovine serum. AB - In autologous heart valve tissue engineering, there is an ongoing search for alternatives of fetal bovine serum (FBS). Human platelet-lysate (PL) might be a promising substitute. In the present article, we aimed to examine the tissue formation, functionality, and mechanical properties of engineered three dimensional tissue constructs cultured in PL as a substitute for FBS. Our results show that tissue constructs that were cultured in PL and FBS produce similar amounts of collagen, glycosoaminoglycans, and collagen crosslinks, and that the cellular phenotype remains unchanged. Nevertheless, mechanical testing showed that the ultimate tensile strength in PL constructs was on average approximately three times lower as compared to FBS (0.25 vs. 0.74 MPa, respectively, p<0.01), and also the elastic modulus was almost three times lower (1.33 MPa of PL constructs vs. 3.94 MPa of FBS constructs, p<0.01). Additional tests indicated that this difference might be explained by different collagen fiber architecture possibly due to increased production of matrix-degrading proteases by cells cultured in PL. In summary, our results indicate that PL is not preferred for the culture of strong heart valve tissue constructs. PMID- 21284561 TI - Effects of peer-mediated instruction to teach use of speech-generating devices to students with autism in social game routines. AB - Supporting social interactions between students with autism spectrum disorders (ASDs) and their typically developing peers presents many challenges. The purpose of this study was to investigate the effects of a peer-mediated intervention designed to teach two students with ASD to use speech-generating devices (SGDs) to engage in interactions with peers in a social context at school. Six peer confederates (three from each student with ASD's general education classroom) were taught to support SGD use during game activities. A multiple baseline design was used to examine the relationship between peer-mediated instruction and an increase in total communicative acts (CAs) by the two students with ASD. Results provide evidence that the confederates acquired the skills needed to support SGD use by students with ASD. The results also suggest that the intervention was effective at increasing total appropriate CAs by students with ASD. In addition, social validity ratings by all of the confederates were positive. Results are discussed regarding educational implications, limitations, and future research. PMID- 21284562 TI - Teamwork in AAC: examining clinical perceptions. AB - This study examines Prescription Review (PR), a model of teamwork practiced in Augmentative and Alternative Communication (AAC) centres in Ontario, Canada. PR is a process in which teams make decisions about AAC system recommendations. For this study, 92 out of 141 professionals working on AAC teams completed questionnaires measuring the benefits of PR. Findings suggest that PR is beneficial in the areas of learning, providing quality services, team support, and decision making. Participants reported satisfaction with the quality of treatment plan, the PR results, and process. Perceptions of PR were related to size of the teams, participants' years of experience, and the range of experience on teams. This study supports PR and highlights the importance of healthy working relationships. PMID- 21284563 TI - Reconstructing the voice of an individual following laryngectomy. AB - This case study describes the generation of a synthetic voice resembling that of an individual before she underwent a laryngectomy. Recordings of this person (6-7 min) speaking prior to the operation were used to create the voice. Synthesis was based on statistical speech models and this method allows models pre-trained on many speakers to be adapted to resemble an individual voice. The results of a listening test in which participants were asked to judge the similarity of the synthetic voice to the pre-operation (target) voice are reported. Members of the patient's family were asked to make a similar judgment. These experiments show that, for most listeners, the voice is quite convincing despite the low quality and small quantity of adaptation data. PMID- 21284564 TI - Treatment of non-healing wounds with autologous bone marrow cells, platelets, fibrin glue and collagen matrix. AB - BACKGROUND AIMS: Recalcitrant diabetic wounds are not responsive to the most common treatments. Bone marrow-derived stem cell transplantation is used for the healing of chronic lower extremity wounds. METHODS: We report on the treatment of eight patients with aggressive, refractory diabetic wounds. The marrow-derived cells were injected/applied topically into the wound along with platelets, fibrin glue and bone marrow-impregnated collagen matrix. RESULTS: Four weeks after treatment, the wound was completely closed in three patients and significantly reduced in the remaining five patients. CONCLUSIONS: Our study suggests that the combination of the components mentioned can be used safely in order to synergize the effect of chronic wound healing. PMID- 21284565 TI - Association of parvovirus B19 infection with acute icteric hepatitis in adults. AB - Infection by human parvovirus B19 is widespread and can be associated with a wide range of different pathologies and clinical manifestations. However, parvovirus B19 infection associated with hepatitis or hepatic dysfunction in adults is rarely reported. We describe two cases of acute icteric hepatitis associated with parvovirus B19 infection in adults. PMID- 21284566 TI - Is sarcoidosis a rickettsiosis? An archival study. AB - BACKGROUND: Based on earlier research, Rickettsia helvetica could possibly be involved in the pathogenesis of sarcoidosis. Rickettsiae are transmitted to humans by a tick vector, Ixodes ricinus; this tick is highly prevalent in Northern Europe. We aimed to investigate the association between evidence of rickettsiae and sarcoidosis in histological samples. METHODS: We included formalin-fixed, paraffin-embedded mediastinal lymph node biopsies from 52 ethnic Danish patients with sarcoidosis and compared these with 50 biopsies from ethnic Danish patients with mediastinal lymphadenopathy of other causes. Samples were analysed for: (1) rickettsial DNA by real-time polymerase chain reaction (PCR) and (2) rickettsial rDNA (ribosomal DNA) by a specific fluorescence in situ hybridization technique (FISH). RESULTS: Rickettsia was not detected in biopsies by real-time PCR and/or FISH analyses. CONCLUSION: Our results do not support the hypothesis that Rickettsia is involved in the pathogenesis of sarcoidosis. PMID- 21284567 TI - Development of a colloidal gold-based immunochromatographic test strip for the rapid, on-site detection of Pseudomonas aeruginosa in clinical samples. AB - BACKGROUND: Current procedures for the detection of Pseudomonas aeruginosa require sophisticated equipment, skilled technicians, and a great deal of time. Immunochromatography assays (ICA) are simple and rapid diagnostic procedures that can be performed and interpreted on the spot or at the bedside without a machine. METHODS: We developed a rapid, 1-step immunochromatographic test strip that is well suited to the on-site detection of P. aeruginosa with high sensitivity and specificity. In brief, a monoclonal antibody targeting the outer membrane protein F (OprF) of P. aeruginosa, 3C3B5, was conjugated to colloidal gold and used as a detection antibody. An OprF polyclonal antibody was developed as the capture antibody. Eighty-three clinical samples were examined for P. aeruginosa by rapid 1-step ICA and compared with Multiplex-polymerase chain reaction (M-PCR). RESULTS: The detection limit of this method is 5 * 10(5) CFU/ml for P. aeruginosa and 10 ng/ml for the OprF protein. The immunochromatographic strip test demonstrated a slightly lower sensitivity (84.8%), but a similar specificity (100%), to multi-PCR, which is an accurate method for the detection of P. aeruginosa in the laboratory. We observed no cross-reactivity with non-P. aeruginosa bacterial microbes. The detection of P. aeruginosa by the ICA strip can be completed within 5-10 min and is at least 10-fold faster than M-PCR. CONCLUSIONS: The ICA test strip developed in this study has proved to be a rapid, simple, effective and economical method for the detection of P. aeruginosa infection in clinical samples. To our knowledge, this is the first report of an ICA method being used to detect P. aeruginosa. PMID- 21284568 TI - Cryptococcal osteomyelitis of the skull. AB - An otherwise healthy 65-year-old male from a rural area presented with a 1-month old non-tender scalp mass. He had a history of being stuck with a stone in the parietal region a year earlier but hadn't developed any complications. Needle aspiration of the mass revealed numerous yeast cells, which were confirmed to be Cryptoccus neoformans. This case describes a rare presentation of C. neoformans infection in a human immunodeficiency virus (HIV)-negative patient. Moreover, while osteomyelitis due to Cryptococcus is generally preceded by fungemia, in the present case it was caused by direct inoculation of the etiologic agent. We review 11 similar cases published since 1983 in which most of the patients developed an insidious mass in their scalps with osteolytic lesions as seen on X ray and all were HIV-negative. Nine of the eleven patients in these cases had good recovery after surgical debridement and treatment with amphotericin B, flucytocise and/or fluconazole. The remaining two patients died during hospitalization. Cryptococcal osteomyelitis should be part of a differential diagnosis when confronted with an insidious growing mass or abscess of unclear origin in the scalp. PMID- 21284569 TI - Systemic nocardiosis caused by Nocardia concava in China. AB - A 42-year-old man with polychondritis and a 2-year history of using low-dose prednisone and other immunosuppressive drugs was admitted to our hospital due to persistent high fever of 10 days duration. A strain of Nocardia was twice isolated from his blood and subsequently identified to be N. concava. The patient was initially treated with sulphadiazine sodium, vancomycin and imipenema for 7 days but the symptoms persisted. Consequently, the regimen was changed to sulphadiazine sodium, ciprofloxacin and amikacin sulfate based on the antibiotic susceptibility tests of the Nocardia isolate. The fever disappeared and the patient's condition improved after 10 days of this treatment to the extent that he was discharged. However, 7 days later, the patient's condition deteriorated and he died due to multiple organ failure. This is the first report of N. concava causing systemic nocardiosis in China. PMID- 21284570 TI - Responses of the bacterial community to chronic gamma radiation in a rice paddy ecosystem. AB - PURPOSE: Public concern about radiation protection of the environment and non human species is increasing. The potential impact of chronic gamma radiation on the bacterial community in a rice paddy ecosystem was investigated. MATERIALS AND METHODS: Paddy field microcosm samples were continuously exposed at a dose rate of 1 Gy day(-1) for five days after which the bacterial community structures in them were compared with those of unirradiated control samples by denaturing gradient gel electrophoresis (DGGE) of the 16S ribosomal ribonucleic acid (rRNA) gene. Dissolved ions in ponding waters of the microcosm samples were determined by ion chromatography. RESULTS: The DGGE band profiles were clearly different between the control and exposure samples. Sequencing of selected DGGE bands revealed that a specific species of the genus Clostridium and of the genus Massilia were grown under radiation exposure. Additionally, the concentrations of sulphate ion in the ponding water of the microcosm samples increased under radiation exposure. Concentrations of Na(+), Ca(2+), and F(-) inversely decreased. CONCLUSIONS: The data presented suggest that chronic gamma radiation affects the bacterial community structure and material cycles in the rice paddy ecosystem. PMID- 21284571 TI - Current immunosuppressive treatment after kidney transplantation. AB - INTRODUCTION: Since 1995, several immunosuppressive drugs have entered the field of organ transplantation: tacrolimus, mycophenolate and the mTOR-inhibitors. Now treating physicians have a choice. AREAS COVERED: The authors review the important studies on immunosuppressive drugs used at present after kidney transplantation, published in the last three decades. This review also discusses the available evidence for selecting one of the calcineurin inhibitors, antiproliferative agents and induction therapy. Interesting new drugs are discussed briefly. EXPERT OPINION: Calcineurin inhibitors (CNIs) are considered, especially in de novo transplantation, to be the most effective maintenance drugs to prevent acute rejection. Combining CNI with mycophenolate or an mTOR-inhibitor has made it possible to reduce CNI dose and diminish nephrotoxicity. Uniform treatment regimes according to guidelines are useful but should leave room for adjustment to the needs of individual patients. Longer follow-up studies are needed to decide on the optimal maintenance treatment. PMID- 21284573 TI - Common pathogenic mechanisms and pathways in the development of COPD and lung cancer. AB - INTRODUCTION: Lung cancer and COPD commonly coexist in smokers, and the presence of COPD increases the risk of developing lung cancer. In addition to smoking cessation and preventing smoking initiation, understanding the shared mechanisms of these smoking-related lung diseases is critical, in order to develop new methods of prevention, diagnosis and treatment of lung cancer and COPD. AREAS COVERED: This review discusses the common mechanisms for susceptibility to lung cancer and COPD, which in addition to cigarette smoke, may involve inflammation, epithelial-mesenchymal transition, abnormal repair, oxidative stress, and cell proliferation. Furthermore, we discuss the underlying genomic and epigenomic changes (single nucleotide polymorphisms (SNPs), copy number variation, promoter hypermethylation and microRNAs) that are likely to alter biological pathways, leading to susceptibility to lung cancer and COPD (e.g., altered nicotine receptor biology). EXPERT OPINION: Strategies to study genomics, epigenomics and gene-environment interaction will yield greater insight into the shared pathogenesis of lung cancer and COPD, leading to new diagnostic and therapeutic modalities. PMID- 21284574 TI - History of cryptorchidism and ejaculate volume as simple predictors for the presence of testicular sperm. AB - Testicular volume, hormones, and growth factors are used as predictors of finding motile testicular sperm in azoospermic men. In this study, the possible predictive value of very simple parameters such as systematic history, clinical examination, and determination of ejaculate volume have been evaluated. Two hundred and sixty-two consecutive non-vasectomized men with azoospermia/aspermia were evaluated by systematic history, clinical examination, ultrasonography of the scrotal content, and hormonal and genetic analyses. Hormonal analyses included, as a minimum, determination of follicular stimulating hormone (FSH), luteinizing hormone (LH), and testosterone, while genetic analyses included karyotyping and examination for cystic fibrosis transmembrane conductance regulator (CFTR) mutations and Y microdeletions. In seventy-six cases (29%) genetics was the most likely cause of azoospermia. For men with at least one CFTR mutation, motile sperm could be detected in 100% of 13 men with congenital bilateral absence of vasa deferentia (VD) but only in 44% of 18 with present VD. Ejaculate volumes were significantly lower (2.3 mL versus 3.6 mL) in 81 men with motile testicular sperm detected compared to 111 men without detectable motile sperm (p < 0.001; Student's t-test), and the difference was still significant after exclusion of men carrying a CFTR mutation. Based on the present data, an ejaculate volume of 2.5 mL was considered a useful threshold value. Furthermore, an inhomogeneous histological pattern with maturation of sperm in small islands isolated in tissue showing Sertoli cell only (SCO) pattern seems characteristic for men with a history of cryptorchidism (negative predictive value: 95%). In addition to FSH, testicular volume, and other endocrine factors, it is important to consider that very simple factors such as ejaculate volume and presence or absence of VD in men with CFTR mutations might be used as predictors according to the chance of finding motile testicular sperm. Evidence for a strong association between a history of cryptorchidism and an inhomogeneous histological pattern with maturation of sperm in islands in tissue presenting SCO pattern might indicate that multiple TESEs should be considered in men with a history of cryptorchidism. PMID- 21284575 TI - Re-evaluation of in vitro dissolution techniques for supersaturating drug delivery systems. AB - Conventional dissolution testing using high-performance liquid chromatography (HPLC) analysis was evaluated against fiber optic dissolution method for studying supersaturable drug delivery systems. Two self-microemulsifying (SME) formulations of albendazole (ABZ) (15 mg/capsule and 5 mg/capsule) were prepared. Dissolution study was performed in medium with pH 1.2, 4.5, 6.8 and 7.4. Samples were analyzed simultaneously by HPLC and online fiber optic dissolution system. For 15 mg/capsule formulation, the profiles obtained using HPLC data showed almost 80-100% releases at pH 4.5, 6.8 and 7.4, whereas fiber optic data showed less than 40% release at the end of 60 min. The observed precipitation was due to pH-dependent solubility of ABZ in water and data analysis revealed a supersaturation phenomenon. This difference in release profiles was due to the presence of oil and water phase in the dissolution sample that upon dilution with high organic mobile phase resulted in quantification of the total drug and not the dissolved drug. The 5 mg/capsule formulation showed no difference in release profiles between methods as the concentration was under the saturation solubility. These results pointed out a considerable error in the development of a complex SME formulation, and use of fiber optic dissolution method was found beneficial. PMID- 21284576 TI - Key considerations for optimization of formulation and melt-extrusion process parameters for developing thermosensitive compound. AB - The melt-extrusion process is currently applied in the pharmaceutical field in the manufacturing of a variety of dosage forms and formulations, including solid dispersions. Though this technology is considered efficient and continuous, there are potential challenges of which, additional thermal degradation of drug substance because heat stress and shear forces are of a primary concern. This paper attempts to understand the impact of thermal and/or mechanical components of the melt-extrusion process on the stability of a thermosensitive drug substance during scale-up. The overall degradation profile of the drug substance was correlated with the various physical changes made to the extruder as well as the process temperature. The results suggested that the degradation profile of a thermosensitive drug substance could be controlled by proper design of screw assemblies and by optimization of screw rotations per minute, process temperature, and feed rate during development and scale-up. PMID- 21284577 TI - Advances in orodispersible films for drug delivery. AB - INTRODUCTION: Orodispersible films for oral delivery are gaining popularity. Whereas breath-fresheners and over-the-counter products have already become quite common in the US, the first prescription drug films were introduced into the EU and US markets only very recently. Already considered as a unique Rx (prescription drug) dosage form by the FDA (oral soluble film), such products are not substitutable by conventional oral dosage forms. The official term defined by the European Medicines Agency is orodispersible film (ODF). AREAS COVERED: This review gives an overview on the benefits of ODFs, typical excipients and products already available on the market. ODFs are defined and differentiated from other films and dosage forms. Possible manufacturing methods are described. As ODFs are not yet listed in one of the pharmacopoeias, possible methods for characterization and quality control are discussed. Required characteristics, advantages and disadvantages are elaborated. Biopharmaceutical considerations are provided because such films can also be used to enhance bioavailability of a drug. EXPERT OPINION: The magnitude of variants of ODF technology and the advantages over conventional dosage forms promise more applications and more marketed products with ODFs in the near future. Therefore, the authorities have to publish a monograph for ODFs as soon as possible to standardize characterization methods and quality specifications. PMID- 21284578 TI - Effects of process parameters on solid self-microemulsifying particles in a laboratory scale fluid bed. AB - The purpose of this study was to select the critical process parameters of the fluid bed processes impacting the quality attribute of a solid self microemulsifying (SME) system of albendazole (ABZ). A fractional factorial design (2(4-1)) with four parameters (spray rate, inlet air temperature, inlet air flow, and atomization air pressure) was created by MINITAB software. Batches were manufactured in a laboratory top-spray fluid bed at 625-g scale. Loss on drying (LOD) samples were taken throughout each batch to build the entire moisture profiles. All dried granulation were sieved using mesh 20 and analyzed for particle size distribution (PSD), morphology, density, and flow. It was found that as spray rate increased, sauter-mean diameter (D(s)) also increased. The effect of inlet air temperature on the peak moisture which is directly related to the mean particle size was found to be significant. There were two-way interactions between studied process parameters. The main effects of inlet air flow rate and atomization air pressure could not be found as the data were inconclusive. The partial least square (PLS) regression model was found significant (P < 0.01) and predictive for optimization. This study established a design space for the parameters for solid SME manufacturing process. PMID- 21284579 TI - Association between T lymphocyte sub-sets apoptosis and peripheral blood mononuclear cells oxidative stress in systemic lupus erythematosus. AB - Increased oxidative stress and lymphocyte apoptosis are a hallmark of the autoimmune disease systemic lupus erythematosus (SLE). However, the association between oxidative stress and T lymphocytes apoptosis has still to be elucidated in SLE. In order to appraise the interaction between oxidative stress and T lymphocyte apoptosis with the severity of disease, oxidative stress profile and T lymphocytes apoptosis were studied. Increased levels of ROS, MDA and CD4(+) lymphocyte apoptosis were positively associated with disease activity while decreased levels of GSH and percentage expression of CD4(+) lymphocyte were negatively associated with disease activity. The decrease in intracellular levels of GSH was negatively associated with T lymphocyte, CD4(+) lymphocyte, CD8(+) lymphocyte apoptosis and intracellular caspase-3 expression. The present study suggests that increased T lymphocyte sub-sets apoptosis may be mediated by decreased intracellular glutathione concentration and severity of disease might be enhanced together by over-production of ROS in SLE. PMID- 21284580 TI - Cilostazol and atherogenic dyslipidemia: a clinically relevant effect? AB - INTRODUCTION: Cilostazol is a reversible, selective inhibitor of PDE3A able to significantly improve walking distance in patients with intermittent claudication. However, beyond its antiplatelet and vasodilator properties, cilostazol seems to have significant effects on atherogenic dyslipidemia. AREAS COVERED: The effects of cilostazol on plasma lipids, lipoproteins, apolipoproteins and postprandial lipemia are reviewed. A literature search (using Medline and Scopus) was performed up to 24 October 2010. The authors also manually reviewed the references of selected articles for any pertinent material. EXPERT OPINION: Cilostazol is able to significantly lower plasma triglyceride levels, with a concomitant increase in high-density lipoprotein (HDL) cholesterol concentrations. Additional effects on pro-atherogenic lipoproteins and apolipoproteins include those on remnant-like particles, HDL subclasses, apolipoprotein B and postprandial lipemia. Cilostazol can improve the pro atherogenic lipid profile in patients with peripheral arterial disease or type 2 diabetes. Further studies are needed to establish whether cilostazol treatment exerts clinically relevant effects on atherogenic dyslipidemia in high-risk patients. PMID- 21284582 TI - Side effects of chemotherapy in musculoskeletal oncology. AB - With recent advances in medical and orthopedic oncology, radiation therapy and single- or multiple-agent perioperative chemotherapy are currently applied as an essential part of the multidisciplinary treatment to improve disease-free and overall survival of patients with primary and metastatic bone and soft tissue tumors. However, these treatments have led to unwanted complications. A better understanding of the effects of various antineoplastic agents on bone, soft tissue, and organs may provide the basis for the more efficacious use of antiproliferative drugs when fracture healing or allograft incorporation is required. This knowledge may also provide a rationale for concurrent treatment with drugs that protect against or compensate for adverse effects in osseous repair resulting from chemotherapy. PMID- 21284583 TI - Right ventricular outflow tract pacing: an alternative, safe, and effective pacing site. AB - The right ventricular apex (RVA) has traditionally been preferred for the insertion of permanent cardiac pacemaker leads because of vast experience with their use, their ease of implantation, and the stability of passive fixation leads in the RVA trabeculae. However, prolonged RVA pacing is associated with progressive left ventricular dysfunction due to dysynchronous ventricular activation, and often results in substantial functional, hemodynamic, electrical, and structural changes, as previously demonstrated in many studies. Only in recent years has interest in the use of alternate pacing sites developed. The right ventricular outflow tract (RVOT) is now the preferred site of pacing because of potential advantages such as ease of application, better hemodynamics, synchronous activation, fewer myocardial perfusion defects, and a narrower QRS complex compared with RVA pacing. This review article comprehensively discusses this novel technique in terms of its beneficial effects, long-term safety, and performance measures compared with RVA pacing, and as an alternative method for biventricular pacing. PMID- 21284584 TI - Preface: Retrieval analysis of implanted medical devices. PMID- 21284585 TI - Technique to quantify subsurface cracks in retrieved polyethylene components using micro-CT. AB - No current method to study delamination and subsurface cracking in polyethylene joint replacement components provides accurate, nondestructive, and quantitative measurements. A technique to study damage both at and below the surface could be of great benefit. We report the development of a micro-CT technique to nondestructively examine and quantify subsurface cracking in retrieved polyethylene tibial inserts. Five severely delaminated inserts and two never implanted inserts were obtained from our institution's implant retrieval library and scanned with micro-CT. The insert subsurface was examined for cracks, and their location and widths were measured using a digital line tool. Subsurface cracks were readily apparent only in the images of the delaminated inserts. Cracks ran horizontally, just below the articular and back-side surfaces, and vertically at the center and lateral edges of the inserts and at the tibial post. Cracks ranged from 0.12 to 6.01 mm below the surface, with widths of 0.06-0.97 mm. Micro-CT can nondestructively visualize and quantify subsurface cracks. This is an enhancement to its previously reported use to quantify surface deviations from wear. Micro-CT is well suited for longitudinal pin-on-disk and wear simulator trials, in addition to studies of retrieved components. PMID- 21284586 TI - Effects of hydroxyapatite on titanium foam as a bone ingrowth surface in acetabular shells: a canine study. AB - This study investigated a highly porous titanium foam with and without a PeriApetite coating as an alternative surface for implant fixation. Twelve mongrel canines received staged total hip replacements under International Animal Care and Use Committee (IACUC) approval from our institution. Animals were randomly placed in three- or six-month groups for sacrifice. Seventeen total hips were available for evaluation. The area and depth of ingrowth was measured by SEM. At three months, PeriApetite Ti foam had 37% more depth and almost 10% more bone ingrowth. Both groups were found not to be different at the six-month mark with over 36% of ingrowth calculated on SEM. The results prove not only that titanium foam is a viable ingrowth surface but also that PA coating can enhance the time to bony incorporation. PMID- 21284587 TI - Evidence that in vivo wear damage alters kinematics and contact stresses in a total knee replacement. AB - Polyethylene wear after a total knee arthroplasty is inevitable. The effects of the wear particles on the surrounding soft tissue causing inflammatory responses and eventual aseptic loosening are well documented, but the biomechanical changes from polyethylene wear have been less understood. This study investigated how wear from a retrieved polyethylene insert from a total knee arthroplasty changed the kinematics and contact stresses. A cruciate-retaining total knee implant (Natural-Knee, Intermedics Orthopedics, Inc., Austin, Texas) was retrieved from a donor program. The polyethylene insert was then scanned and modeled. KneeSIM (LifeMOD/KneeSIM, San Clemente, California) was used to simulate one cycle of gait of three second duration (100% of cycle). A threefold increase in contact stress as well as resulting kinematic changes were seen when the model was used to compare the retrieved versus a modeled off-the-shelf new polyethylene insert. Total knee designs should take into account the wear patterns that result from years of use and how they may affect the biomechanics of the knee long term. PMID- 21284588 TI - Regional measurements of surface deviation volume in worn polyethylene joint replacement components. AB - Total joint replacements can be subject to the loss of polyethylene material due to wear, leading to osteolysis and decreased implant longevity. Micro-computed tomography (micro-CT) techniques have recently been developed to calculate 3D surface deviations in worn implant components. We describe a micro-CT technique to measure the volume of the surface deviations (volume of wear plus creep) within a specific region or compartment, and report its repeatability and reproducibility. Six worn polyethylene tibial inserts were scanned using a laboratory micro-CT scanner and subsequently reconstructed at 50 MUm voxel spacing. A previously developed custom software application was used to quantify the 3D surface deviations between the worn tibial inserts and an unworn reference geometry. Three observers (two trained and one expert) used new custom software to manually outline the localized regions of surface deviation (three times for each of the worn inserts) and calculate the volume of the deviations. The overall intraobserver variability in the surface deviation volumes was 3.6% medially and 1.1% laterally. The overall interobserver variability was 4.8% medially and 1.7% laterally. Placement of points in outlining the region of deviation contributed the greatest variability to the measurements. Repeatability and reproducibility of the volume measurements are similar to measurements of total (nonregional) wear volume including a previous micro-CT technique (10%), fluid displacement (4.8%), and radiographic measurements (15.7%). The principles of this technique can likely be used to measure regional wear and creep volume in knee and hip joint replacement components from wear simulator, pin-on-disk, and retrieval studies. PMID- 21284589 TI - Assessment of the damage in retrieved patellar components. AB - Patellofemoral complications are cited as a leading cause for revision surgery following total knee arthroplasty. Despite widespread clinical use, the decision to resurface the patella, or not, is controversial and remains surgeon dependent. Damage to the patellar component can lead to revision surgery; however, little work exists investigating the damage they sustain in vivo. Twenty-four retrieved patellar components were assessed for damage. There was a wide variation in wear scar morphology, although the mean wear scar area spanned mediolaterally in a band across the articular surface and was 364.32+/-64.7 mm2 in area. Maximum linear penetration was located in the lateral region of the articular surface. Assessment of damage mode grading indicated that it was more severe in the lateral quadrant, although the method's lack of consideration of the chronological progression of wear creates uncertainty over this finding. Volume change ranged from -1.3 to -45.16 mm3/year, and maximum penetration was in the lateral region. Damage to the patellar component of knee replacement has been shown to be significant. The number of components in the study was too small to determine a difference in damage in all-polyethylene and metal-backed designs; however, the volume loss of all-polyethylene patellae was found to be significant. PMID- 21284590 TI - Patellar button wear patterns in well-functioning total knee arthroplasty retrievals. AB - One of the common reasons for early revision or poor outcome in total knee arthroplasty is due to patellar maltracking, loosening, or pain. The analysis of how the patellofemoral mechanism operates and wears in vivo has not been a focus of many retrieval studies. This paper describes the wear pattern observed on patellar buttons from well-functioning TKA specimens that were harvested as part of a donor program. The attempt was to describe the variations in wear patterns to see if any commonalities existed that may predict a well-functioning patellofemoral mechanism after TKA. PMID- 21284591 TI - Human postmortem device retrieval and analysis--orthopaedic, cardiovascular, and dental systems. AB - On the basis of decades of analyzing implant devices, tissues, and clinical records from revision surgical explants (called device failure), studies now include postmortem donors and in situ conditions (called success). A key issue has been information exchange from an interdisciplinary team where basic physical and biological studies complement details of the clinical conditions for each device. Overall, the summary information has shown that most revisions were based on factors associated with the patient health, disease, and compliance, with few outcomes directly correlated with technology and device-specific factors. However, because of the large numbers of devices implanted annually (millions), any sampling that reveals adverse circumstances could result in a high level of importance and the need for additional studies of this type. Experience from prior retrieval and analysis demonstrates significant value where peer reviewed results from investigations have altered the discipline and have improved the quality and longevity of health care associated with implanted devices. This report summarizes completed and ongoing studies of cardiovascular, dental, and orthopaedic systems. Endovascular stents from autopsies showed damage including fretting and corrosion from overlapping and intersecting conditions, plus some corrosion and element transfers to tissues from individual stents. Studies are proposed to increase numbers to evaluate clinical significance. Dental implants from postmortem donors that functioned more than 10 years provided evaluations of cobalt alloy devices and calcium phosphate bone graft substitutes originally investigated in the 1970s. Tissue integration and stability correlated with data from prior laboratory in vitro and in vivo investigations. Studies of articulation and fixation from orthopaedic total joint arthroplasties showed some limitations related to surface changes of YTZ zirconia, specific damage due to implantation procedures, which led to modified instrumentation and techniques, and several examples of conditions leading to longer-term device-to-bone fixation. These types of multidisciplinary studies are continuing. PMID- 21284592 TI - A tribute to Richard F. Edlich, MD, PhD. AB - Richard F. Edlich was a Ford Foundation Scholar who gained early admission to Lafayette College at age 15. Three years later, he was accepted as an early admission student to New York University School of Medicine, where he received his medical degree. He completed a general surgery residency at the University of Minnesota Health Sciences Center under the guidance of his mentor, Dr. Owen H. Wangensteen, who is recognized as one of the twentieth century's greatest teachers of surgery.1 During his eight-year surgical residency, Dr. Edlich also received his PhD. He completed his plastic surgery residency at the University of Virginia Health Science Center in 1973. He commenced his teaching career at the University of Virginia in 1973, beginning as Assistant Professor and eventually becoming Distinguished Professor of Plastic Surgery and Professor of Biomedical Engineering. PMID- 21284593 TI - The evolution of emergency medicine. AB - In this manuscript, I will outline three specific evolutionary achievements in the delivery of emergency and trauma care, followed by caveats on what prevents an emergency and trauma system from achieving optimal goals and maintaining them. First, I will review the emergence of the specialty of emergency medicine under the guidance of Dr. James Mills, and outline the steps he took to establish the specialty in acute care hospitals. Second, I will discuss the heroic career of Dr. R Adams Cowley, a cardiothoracic surgeon who took some of the principles of cardiac resuscitation and surgery and rapid military evacuation of the wounded from the battlefield, and applied them to the resuscitation and transport of the severely injured trauma patient to a fully prepared and equipped trauma center, and also created an organized approach to trauma care in Maryland. Third, I will provide an overview of the subsequent development of a comprehensive emergency medical system in the Commonwealth of Virginia. Finally, I will emphasize what prevents good public health policy regarding emergency medical and trauma care, and some of the changes that must be made to ensure that the Commonwealth of Virginia and other states provide optimal care for their citizens through their emergency medical care and trauma systems. PMID- 21284594 TI - Postexposure prophylaxis for deadly bloodborne viral infections. AB - The purpose of this report is to discuss management of operating room personnel who have had occupational exposure to blood and other body fluids that might contain hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), and human T-cell lymphotropic virus type I (HTLV-I). HBV postexposure prophylaxis includes starting hepatitis B vaccine series in any susceptible unvaccinated operating room personnel who sustain an exposure to blood or body fluid during surgery. Postexposure prophylaxis with hepatitis B immune globulin (HBIG) is an important consideration after determining the hepatitis B antigen status of the patient. Ideally, all operating room personnel should be vaccinated with hepatitis B vaccine before they pursue their career in surgery. Immune globulin and antiviral agents (eg, interferon with or without ribavirin) should not be used for postexposure prophylaxis of operating room personnel exposed to patients with HCV; rather, follow-up HCV testing should be initiated to determine if infection develops. Postexposure prophylaxis for HIV involves a basic four-week regimen of two drugs (zidovudine and lamivudine; lamivudine and stavudine; or didanosine and stavudine) for most exposures. An expanded regimen that includes a third drug must be considered for HIV exposures that pose an increased risk for transmission. When developing a postexposure prophylaxis regimen, it is helpful to contact the National Clinicians' Postexposure Prophylaxis Hotline, (888) 448-4911. Prevention should be a major consideration in postexposure prophylaxis with the use of the double-glove hole indication system by all operating room personnel. PMID- 21284595 TI - Reducing accidental injuries during surgery. AB - All surgical healthcare professionals and their patients should be aware of exposure to blood from individuals infected with potentially transmissible disease. The site that was most susceptible to sharp injuries was the index finger of the surgeon's hand. It is also important to note that needles cause the vast majority of sharp injuries. During the last two decades, there have been two revolutionary advances in preventing accidental needlestick injuries during surgery that include the development of blunt tapering point needles as well as the double-glove hole indication systems. During the innovative development of blunt taper point needles, a glove manufacturer, Molnlycke, Inc., devised non latex and latex double-glove hole puncture indication systems that are being used throughout the world. The reliability of these double-glove hole indication systems in detecting holes in the outer glove has been reliably documented by scientific studies that are published in peer-reviewed journals. On the basis of these extensive quantitative studies, the authors recommended that the double glove hole indication system be used in all operative procedures to prevent the transmission of deadly bloodborne viral infections. PMID- 21284596 TI - Scientific basis for the selection of surgical staples and tissue adhesives for closure of skin wounds. AB - During the last four decades, there have been revolutionary advances in the development of skin staples as well as tissue adhesives. One of the purposes of this collective review is to provide an overview of recent advances in the development of metal and absorbable skin staples and tissue adhesives. In addition, we will provide technical considerations in the use of metal and absorbable skin staples and tissue adhesives during surgery. On the basis of extensive experimental studies, we would recommend the AutosutureTM Multifire PremiumTM metal skin stapler. During a surgical operation, the rotating head of this skin stapler can have its skin stapling cartridge removed once for additional stapling. The revolutionary InsorbTM subcuticular skin stapler is designed to combine the cosmetic result of absorbable sutures with the rapid closure times associated with metal skin staplers, while eliminating the need for metal staple removal postoperatively. The InsorbTM absorbable staple is composed of a copolymer that is predominantly polylactide, which is absorbed over a period of a few months. The superior performance of the InsorbTM absorbable staple has been confirmed by experimental and clinical studies. In the last 20 years, surgeons have become increasingly interested in replacing sutures by means of adhesive bonds in the closure of surgical wounds. A recent collective review of clinical studies done with tissue adhesive has recommended that there is a need for well-designed randomized, controlled trials comparing tissue adhesives and alternate methods of closure, especially in patients whose health may interfere with wound healing. PMID- 21284597 TI - Wound closure sutures and needles: a new perspective. AB - Ideally, the choice of the suture material should be based on the biological interaction of the materials employed, the tissue configuration, and the biomechanical properties of the wound. Measurements of the in vivo degradation of sutures separate them into two general classes: absorbable and nonabsorbable sutures. The nonabsorbable sutures and absorbable sutures are classified according to their origin. When considering an absorbable suture's tensile strength in vivo, we recommend that the manufacturer provides specific recommendations of its holding strength, rather than the percentage retained of its initial tensile strength. The newest advance in nonabsorbable sutures is polybutester suture, which is a block copolymer that contains butylene terephthalate (84%) and polytetramethylene ether glycol terephthalate (16%). The expanded polytetrafluoroethylene (ePTFE) suture has been expanded to produce a porous microstructure that is approximately 50% air by volume. The clinical performance of polybutester suture has been enhanced by coating its surface with a unique absorbable polymer. A search for a synthetic substitute for absorbable collagen sutures led to the development of the POLYSORBTM sutures that can reliably approximate tissues with a low risk for infection. The latest innovation in the development of monofilament absorbable sutures has been in the rapidly absorbing CAPROSYNTM suture. A new high-nickel stainless steel, SURGALLOYTM, has been used recently to manufacture surgical needles. Biomechanical performance studies of cutting edge needles made of S45500 stainless steel alloy and SURGALLOYTM stainless steel demonstrated that needles made of SURGALLOYTM had superior performance characteristics over those made of S45500. PMID- 21284598 TI - Scientific basis for the selection of skin closure techniques. AB - This scientific article was designed to teach the individual reader the scientific basis for suture and needle selection as well as to illustrate the appropriate surgical techniques involved in wound repair of skin incisions. Because the US Food and Drug Administration permits 1.5% of the sterile surgical gloves to have holes, the operating room personnel should wear sterile surgical double-glove hole indication systems that detect holes in the outer glove. From the surgeon's point of view, the rate of gain of strength of the skin wound is a key determinant of many decisions including when the suture can be removed, the level of patient activity, and the selection of the incision. Important considerations in wound closure are type of suture and mechanical performance, in vivo and in vitro. Measurements of the in vivo degradation of sutures separate them into two general classes, absorbable and nonabsorbable. Sutures that undergo rapid degradation in tissues, losing their tensile strength within 60 days, are considered absorbable. Those that maintain their tensile strength for longer than 60 days are considered nonabsorbable. For skin closure with nonabsorbable suture, we favor the use of the polybutester suture that is coated with an absorbable polymer, VASCUFILTM. When absorbable sutures are used for a dermal skin closure, the synthetic monofilament MAXONTM is recommended. Absorption of the suture is complete between 90 and 110 days. In either case, we would recommend that the suture be attached by a sewage attachment to a SURGALLOYTM reverse cutting stainless steel suture. Continuous percutaneous suture closure has definite, distinct advantages over interrupted suture closure. Although continuous dermal wound closure is technically more challenging for the surgeon than interrupted dermal suture closure, it has become an important wound closure technique. A monofilament absorbable synthetic MAXONTM attached to a reverse cutting edge SURGALLOYTM stainless steel needle is ideally suited for continuous dermal skin suture closure. PMID- 21284599 TI - Scientific basis for the selection of vascular closure techniques. AB - If this educational program heightens the surgeon's, resident's, and student's interest in the biology of vascular wound closure and infection, the long years occupied in our search for improved methods of wound management would more than fulfill our expectations. As with any master surgeon, he/she must understand the tools of his/her profession. This linkage between a surgeon and surgical equipment is a closed kinematic chain in which the surgeon's power is converted into finely coordinated movements that result in vascular wound closure with the least possible scar and without infection. The description of wound repair of blood vessels will be confined to arterial surgery in which the surgeon attempts to establish a new non-wettable intima and to reestablish a strong elastic muscular media. Repair of vessel wall wounds is encountered in arteriotomy for vascular access as well as in artery-to-artery anastomoses. In both circumstances, wound repair is primarily at the suture line. The surgical needles of SynetureTM are produced from stainless steel alloys, which have excellent resistance to corrosion. A new high-nickel stainless steel, SURGALLOY TM, has been used recently by SynetureTM to manufacture surgical needles. We prefer a polybutester monofilament suture whose surface is coated with an absorbable polymer. This absorbable coating of the VASCUFILTM monofilament sutures markedly reduces its drag forces in vascular tissue. The surgeon can practice using these sutures in femoral arteriotomies in animals. PMID- 21284603 TI - ATR (ataxia telangiectasia mutated- and Rad3-related kinase) is activated by mild hypothermia in mammalian cells and subsequently activates p53. AB - In vitro cultured mammalian cells respond to mild hypothermia (27-33 degrees C) by attenuating cellular processes and slowing and arresting the cell cycle. The slowing of the cell cycle at the upper range (31-33 degrees C) and its complete arrest at the lower range (27-28 degrees C) of mild hypothermia is effected by the activation of p53 and subsequent expression of p21. However, the mechanism by which cold is perceived in mammalian cells with the subsequent activation of p53 has remained undetermined. In the present paper, we report that the exposure of Chinese-hamster ovary-K1 cells to mildly hypothermic conditions activates the ATR (ataxia telangiectasia mutated- and Rad3-related kinase)-p53-p21 signalling pathway and is thus a key pathway involved in p53 activation upon mild hypothermia. In addition, we show that although p38MAPK (p38 mitogen-activated protein kinase) is also involved in activation of p53 upon mild hypothermia, this is probably the result of activation of p38MAPK by ATR. Furthermore, we show that cold-induced changes in cell membrane lipid composition are correlated with the activation of the ATR-p53-p21 pathway. Therefore we provide the first mechanistic detail of cell sensing and signalling upon mild hypothermia in mammalian cells leading to p53 and p21 activation, which is known to lead to cell cycle arrest. PMID- 21284604 TI - The progesterone receptor as a transcription factor regulates phospholipase D1 expression through independent activation of protein kinase A and Ras during 8-Br cAMP-induced decidualization in human endometrial stromal cells. AB - Decidualization is a biological and morphological process occurring in hES (human endometrial stromal) cells. Previously, we reported that PLD1 (phospholipase D1) plays an important role in cAMP-induced decidualization of hES cells. In the present study, we focused on how PLD1 expression is up-regulated during decidualization. Treatment with PKA (protein kinase A) inhibitors (Rp-cAMP or H89) or a Ras inhibitor (manumycin) partially inhibited PLD1 expression and decidua formation in response to cAMP treatment. Interestingly, dual inhibition of PKA and Ras completely inhibited PLD1 expression and cAMP-induced decidualization. These results suggest that PLD1 expression during decidualization is controlled additively by PKA and Ras. The use of inhibitors showed that extracellular-signal-regulated kinase, a downstream effector of Ras, was required for PLD activation and the morphological changes during decidualization, but not for the increase in PLD1 protein. Next, to investigate the regulator of the PLD1 gene at the transcriptional level, a promoter assay using deletion mutants of the PLD1 promoter was performed; the result indicated that PR (progesterone receptor) was a possible regulator of the PLD1 gene. In addition, chromatin immunoprecipitation assays on the PLD1 promoter identified PR as a transcription factor for PLD1 expression during 8-Br-cAMP-induced decidualization. Taken together, our findings demonstrate that PKA and Ras are novel regulators of PLD1 expression and also identify PR as a transcription factor for PLD1 expression during the decidualization of hES cells. PMID- 21284605 TI - Knockdown of T-cell intracellular antigens triggers cell proliferation, invasion and tumour growth. AB - TIA (T-cell intracellular antigen) proteins function as DNA/RNA trans-acting regulators to expand transcriptome and proteome diversity in mammals. In the present paper we report that the stable silencing of TIA1 and/or TIAR/TIAL1 (TIA1 related/like protein 1) expression in HeLa cells enhances cell proliferation, anchorage-dependent and -independent growth and invasion. HeLa cells lacking TIA1 and/or TIAR generate larger and faster-growing epithelial tumours with high rates of proliferation and angiogenesis in nude mice xenografts. Protein array analysis of a collection of human tumours shows that TIA1 and TIAR protein expression is down-regulated in a subset of epithelial tumours relative to normal tissues. Our results suggest a link between the epigenetic control exerted by TIA proteins and the transcriptional and post-transcriptional regulation of a subset of specific genes involved in tumour progression. Taken together, these results are consistent with a role for TIA proteins as growth/tumour-suppressor genes. PMID- 21284606 TI - Putative Arabidopsis homologues of metazoan coiled-coil cytoskeletal proteins. AB - The Arabidopsis thaliana genome encodes about 386 proteins with coiled-coil domains of at least 50 amino acids in length. In mammalian systems, many coiled coil proteins are part of various cytoskeletal networks including intermediate filament protein, actin-binding proteins and MAP (microtubule-associated proteins). Immunological evidence suggests that some of these cytoskeletal proteins, such as lamins, keratins and tropomyosins, may be conserved in Arabidopsis. However, coiled-coil proteins are of low complexity, and thus, traditional sequence comparison algorithms, such as BLAST may not detect homologies. Here, we use the PROPSEARCH algorithm to detect putative coiled-coil cytoskeletal protein homologues in Arabidopsis. This approach reveals putative intermediate filament protein homologues of filensin, lamin and keratin; putative actin-binding homologues of ERM (ezrin/radixin/moesin), periplakin, utrophin, tropomyosin and paramyosin, and putative MAP homologues of restin/CLIP-170 (cytoplasmic linker protein-170). We suggest that the AtFPP (Arabiopsis thaliana filament-like plant protein) and AtMAP70 (Arabidopsis microtubule-associated protein 70) families of coiled-coil proteins may, in fact, be related to lamins and function as intermediate filament proteins. PMID- 21284607 TI - Migraine in patients with eating disorders: a study using a sister-pair comparison design. AB - OBJECTIVE: To evaluate the relationship between migraine and eating disorders by applying a special study design. BACKGROUND: To date, only a few studies have assessed eating disorders and eating behavior in patients with migraine. METHODS: The distinctive feature of this design is the comparison of sister pairs with one sister suffering from an eating disorder according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition and the other being free of such disease. RESULTS: We investigated 120 female patients with a median age of 24 years (interquartile range 20-31) as well as their non-eating-disordered sisters with a median age of 24 (20-31) years. Headache was diagnosed according to the International Classification of Headache Disorders, Second Edition. Thirteen sister pairs were concordant for the presence of migraine, 67 were concordant for the absence of migraine and 40 were discordant. Among the latter, 21 patients and 19 controls had migraine. The prevalence of migraine was virtually identical in patients (28%) and controls (27%). CONCLUSION: This clinic-based controlled study using a sister-pair comparison design showed no evidence of an increased prevalence of migraine among patients with eating disorder. PMID- 21284608 TI - Characteristics of the first 1000 headaches in an outpatient headache clinic registry. AB - OBJECTIVE: To analyze the incidence and characteristics of the first 1000 headaches in an outpatient clinic. BACKGROUND: Headache is a common cause of medical consultation, both in primary care and in specialist neurology outpatient clinics. The International Classification of Headache Disorders, 2nd Edition (ICHD-II), enables headaches to be classified in a precise and reproducible manner. METHODS: In January 2008, an outpatient headache clinic was set up in Hospital Clinico Universitario, a tertiary hospital in Valladolid, Spain. Headaches were classified prospectively in accordance with ICHD-II criteria. In each case we recorded age and sex, duration of headache, ancillary tests required, and previous symptomatic or prophylactic therapies. RESULTS: In January 2010, the registry included 1000 headaches in 682 patients. The women/men ratio was 2.46/1 and the mean age of the patients was 43.19 +/- 17.1 years (range: 14 94 years). Patients were referred from primary care (53.4%), general neurology clinics (36.6%), and other specialist clinics (9%). The headaches were grouped (ICHD-II classification) as follows: group 1 (Migraine), 51.4%; group 2 (Tension type headache), 16%; group 3 (Trigeminal autonomic cephalalgias), 2.6%; group 4 (Other primary headaches) and group 13 (Cranial neuralgias), 3.4%. The diagnostic criteria of chronic migraine were satisfied in 8.5% of migraines. Regarding secondary headaches, 1.1% of all cases were included in group 5 (Headaches attributed to trauma) and 8.3% in group 8 (Headaches attributed to a substance or its withdrawal). Only 3.4% of headaches were classified in group 14 (Unspecified or not elsewhere classified), and 5.2% were included in the groups listed in the ICHD-II research appendix. CONCLUSION: This registry outlines the characteristics of patients seen in an outpatient headache clinic in a tertiary hospital; our results are similar to those previously reported for this type of outpatient clinic. Migraine was the most common diagnosis. Most headaches can be classified using ICHD-II criteria. PMID- 21284609 TI - Cluster headache--acute and prophylactic therapy. AB - Cluster headache (CH) pain is the most severe of the primary headache syndromes. It is characterized by periodic attacks of strictly unilateral pain associated with ipsilateral cranial autonomic symptoms. The majority of patients have episodic CH, with cluster periods that typically occur in a circannual rhythm, while 10% suffer from the chronic form, with no significant remissions between cluster periods. Sumatriptan injection or oxygen inhalation is the first-line therapy for acute CH attacks, with the majority of patients responding to either treatment. The calcium channel blocker verapamil is the drug of choice for CH prevention. Other drugs that may be used for this purpose include lithium carbonate, topiramate, valproic acid, gabapentin, and baclofen. Transitional prophylaxis, most commonly using corticosteroids, helps to control the attacks at the beginning of a cluster period. Peripheral neural blockade is effective for short-term pain control. Recently, the therapeutic options for refractory CH patients have expanded with the emergence of both peripheral (mostly occipital nerve) and central (hypothalamic) neurostimulation. With the emergence of these novel treatments, the role of ablative surgery in CH has declined. PMID- 21284610 TI - Zonisamide for migraine prophylaxis in topiramate-intolerant patients: an observational study. AB - BACKGROUND: Zonisamide, a sulfonamide analog, is an antiepileptic drug with mechanisms of action similar to topiramate. Because of its pharmacodynamic and pharmacokinetics profiles, zonisamide is also potentially suitable for migraine prevention. METHODS: Tolerability and effectiveness of zonisamide for migraine prophylaxis in patients with a good response to topiramate, but interrupting it for intolerable side effects, were evaluated in 34 patients. After a 1-month period of wash-out, patients were treated with zonisamide (up to a 100 mg/day dosage) for 6 consecutive months. RESULTS: Zonisamide was well tolerated, only 4 (12%) patients reported transient and tolerable side effects. Mean number of days with headache per month was reduced from 14.9 +/- 5.3 during the wash-out period to 2.5 +/- 0.6 after 6 months of zonisamide (P < .001). We observed a significant reduction in headache severity and disability, as assessed by visual analog scale and migraine disability assessment scale. Finally, when compared with the 1-month period prior to starting zonisamide, a reduced use of analgesics was recorded at the end of the follow-up. CONCLUSION: Our findings support the use of zonisamide as an alternative therapy for migraine prevention in patients with good response, but poor tolerance to topiramate. PMID- 21284611 TI - Migraine and fibromyalgia. PMID- 21284612 TI - Hemicrania continua changed to chronic paroxysmal hemicrania after treatment with cyclooxygenase-2 inhibitor. AB - Remission of hemicrania continua (HC) and transformation from HC to chronic paroxysmal hemicrania (CPH) are unusual. We report a patient with left-sided HC who, after a period of remission, presented as CPH. The continuous HC headache disappeared completely after initiating treatment with cyclooxygenase (COX)-2 inhibitor, but reappeared on the same side after 14 months remission with paroxysmal, frequent, intense and short-lasting headache attacks accompanied by ipsilateral cranial autonomic symptoms. This happened shortly after the treatment was discontinued because of withdrawal of the COX-2 inhibitor from the market. The response to indomethacin was prompt, and the patient became completely free from her paroxysmal headache with a dose of 50 mg 2 times daily. This case questions a possible modification effect on the course of HC by use of COX-2 inhibitor, as well as further supporting that some aspects of the pathophysiology of HC may resemble those of CPH, and may argue for common biological mechanisms in HC and CPH. PMID- 21284613 TI - Effective symptomatic medication should be available in prophylactic trials in cluster headache. PMID- 21284614 TI - Response to: Migraine and vertigo: a marriage of convenience? PMID- 21284615 TI - The headache of the day of awe--no more? PMID- 21284616 TI - Refractory headache definition. PMID- 21284618 TI - Teaching case: migraine and pupil dilation. PMID- 21284619 TI - The law of unintended consequences? PMID- 21284620 TI - The role of cardiovascular screening in headache patients. AB - There have been associations demonstrated between migraine and ischemic stroke and heart disease. Additionally, headache patients have increased cardiovascular risk factors. This article reviews available data supporting these concerns and answers the following questions: 1) Does the association between migraine and cardiovascular disease warrant cardiovascular screening tests in migraine sufferers? There is enough observational data to conclude that migraine with aura is a risk factor for cardiovascular disease. With the available data, we cannot recommend any additional cardiovascular screening tests for migraine patients. 2) Are there specific risk modification approaches for headache patients? As there is no data to suggest that migraine is a modifiable risk factor, no additional cardiovascular interventions beyond the standard practice of treating modifiable risk factors are suggested for migraine sufferers. 3) What is the appropriate screening for patients who may be candidates for triptans or tricyclic antidepressants? We support screening headache patients by obtaining a history of prior cardiovascular disease and traditional cardiovascular disease risk factors. We have found no data to suggest that any non-invasive cardiovascular screening test will identify a population of migraine sufferers at high risk for cardiovascular events following triptan use. Due to the increased risk of cardiovascular toxicity, ECGs should be considered prior to initiating tricyclic antidepressants in patients with preexisting cardiovascular disease. PMID- 21284621 TI - Evaluation for secondary causes of headache: the role of blood and urine testing. AB - Most patients presenting for evaluation of headache meet diagnostic criteria for a benign, primary headache disorder based on history and physical examination findings alone. No further testing is needed in such cases. Additional diagnostic evaluation is needed in cases that do not meet criteria for a primary headache disorder or which are associated with unusual or worrisome features. This article will review secondary causes of headache listed in the International Classification of Headache Disorders-II in which blood and urine testing might aid in diagnosis. We offer recommendations for diagnostic evaluation when these disorders are suspected causes of headache. PMID- 21284622 TI - The diagnostic evaluation of secondary headache disorders. PMID- 21284624 TI - Determinants of reproductive success in dominant pairs of clownfish: a boosted regression tree analysis. AB - 1. Central questions of behavioural and evolutionary ecology are what factors influence the reproductive success of dominant breeders and subordinate nonbreeders within animal societies? A complete understanding of any society requires that these questions be answered for all individuals. 2. The clown anemonefish, Amphiprion percula, forms simple societies that live in close association with sea anemones, Heteractis magnifica. Here, we use data from a well-studied population of A. percula to determine the major predictors of reproductive success of dominant pairs in this species. 3. We analyse the effect of multiple predictors on four components of reproductive success, using a relatively new technique from the field of statistical learning: boosted regression trees (BRTs). BRTs have the potential to model complex relationships in ways that give powerful insight. 4. We show that the reproductive success of dominant pairs is unrelated to the presence, number or phenotype of nonbreeders. This is consistent with the observation that nonbreeders do not help or hinder breeders in any way, confirming and extending the results of a previous study. 5. Primarily, reproductive success is negatively related to male growth and positively related to breeding experience. It is likely that these effects are interrelated because males that grow a lot have little breeding experience. These effects are indicative of a trade-off between male growth and parental investment. 6. Secondarily, reproductive success is positively related to female growth and size. In this population, female size is positively related to group size and anemone size, also. These positive correlations among traits likely are caused by variation in site quality and are suggestive of a silver-spoon effect. 7. Noteworthily, whereas reproductive success is positively related to female size, it is unrelated to male size. This observation provides support for the size advantage hypothesis for sex change: both individuals maximize their reproductive success when the larger individual adopts the female tactic. 8. This study provides the most complete picture to date of the factors that predict the reproductive success of dominant pairs of clown anemonefish and illustrates the utility of BRTs for analysis of complex behavioural and evolutionary ecology data. PMID- 21284625 TI - Ethical justification for the use and treatment of fishes in research: an update. PMID- 21284626 TI - Behavioural syndromes in fishes: a review with implications for ecology and fisheries management. AB - This review examines the contribution of research on fishes to the growing field of behavioural syndromes. Current knowledge of behavioural syndromes in fishes is reviewed with respect to five main axes of animal personality: (1) shyness boldness, (2) exploration-avoidance, (3) activity, (4) aggressiveness and (5) sociability. Compared with other taxa, research on fishes has played a leading role in describing the shy-bold personality axis and has made innovative contributions to the study of the sociability dimension by incorporating social network theory. Fishes are virtually the only major taxon in which behavioural correlations have been compared between populations. This research has guided the field in examining how variation in selection regime may shape personality. Recent research on fishes has also made important strides in understanding genetic and neuroendocrine bases for behavioural syndromes using approaches involving artificial selection, genetic mapping, candidate gene and functional genomics. This work has illustrated consistent individual variation in highly complex neuroendocrine and gene expression pathways. In contrast, relatively little work on fishes has examined the ontogenetic stability of behavioural syndromes or their fitness consequences. Finally, adopting a behavioural syndrome framework in fisheries management issues including artificial propagation, habitat restoration and invasive species, may promote restoration success. Few studies, however, have examined the ecological relevance of behavioural syndromes in the field. Knowledge of how behavioural syndromes play out in the wild will be crucial to incorporating such a framework into management practices. PMID- 21284627 TI - Does diurnal temperature variability affect growth in juvenile Atlantic salmon Salmo salar? AB - This study investigated the effects of diurnal temperature variability (>7 degrees C) on the growth of 1+ year Atlantic salmon Salmo salar. Experimental manipulation of water temperature was used to simulate: (1) constant and (2) naturally varying thermal regimes with similar daily mean values. Data from two replicates of four treatments (two thermal and two feeding regimes) were collected over 6 months corresponding to the main spring to summer growth period. Fish growth was assessed at fortnightly intervals. Small but significant differences in mean fork length (L(F) ) and mass were observed between temperature treatments, with smaller, lighter fish under the variable temperature regime. The effects of temperature regime on growth were independent of food ration. At termination of the experiment, the median L(F) and mass of fish exposed to the variable temperature regime were estimated, respectively, to be 2. 6 and 8. 0% less than those under the constant regime. Given the relatively small differences in growth attributable to variable temperature regime in these experiments, it is suggested that mean daily temperatures are adequate to inform juvenile growth models for field-based studies. PMID- 21284628 TI - Foraging, bioenergetic and predation constraints on diel vertical migration: field observations and modelling of reverse migration by young-of-the-year herring Clupea harengus. AB - Diel vertical migration (DVM) of young-of-the-year (YOY) herring Clupea harengus and one of their major predators, pikeperch Sander lucioperca, was examined using bottom-mounted hydroacoustics in Himmerfjarden, a brackish bay of the Baltic Sea, in summer. In contrast to previous studies on DVM of C. harengus aggregated across size and age classes, YOY C. harengus showed a reverse DVM trajectory, deeper at night and, on average, shallower during the day. This pattern was observed consistently on five acoustic sampling occasions in 3 years and was corroborated by two out of three trawl surveys. Large acoustic targets (target strength >-33 dB, probably piscivorous S. lucioperca >45 cm) showed a classic DVM trajectory, shallow at night and deeper during the day. Variability in YOY C. harengus vertical distribution peaked at dawn and dusk, and their vertical distribution at midday was distinctly bimodal. This reverse DVM pattern was consistent with bioenergetic model predictions for YOY C. harengus which have rapid gut evacuation rates and do not feed at night. Reverse DVM also resulted in low spatial overlap with predators. PMID- 21284629 TI - Genetic evidence for a single stock of the deep-sea teleost Beryx decadactylus in the North Atlantic Ocean as inferred from mtDNA control region analysis. AB - Mitochondrial control region sequences of 141 alfonsino Beryx decadactylus sampled off the coast of South Carolina were compared with 164 sequences from B. decadactylus collected in the Azores for inferring population structure and demographic history of this deep-water teleost in the North Atlantic Ocean. Analysis of molecular variance showed that 100% of the genetic variation was found within populations, indicating an absence of population structure (Phi(ST) = -0. 003). Neutrality tests and mismatch distribution analyses of pooled sequences suggested that B. decadactylus in the North Atlantic Ocean have undergone population expansion. These results may indicate that transatlantic gene flow occurs, possibly through passive drift of larvae or adult migration. The potential of a shared stock between the eastern and western North Atlantic Ocean will need to be considered if a directed fishery for B. decadactylus were to develop in the U.S.A. PMID- 21284630 TI - Community structure of soft sediment pool fishes in Moreton Bay, Australia. AB - A survey of soft sediment tide pools was conducted to assess the occupation and assemblage of fishes on three different intertidal shores in Moreton Bay, Australia, between January and December 2009. Tide-pool volume ranged from 0. 30 to 29. 75 l and varied significantly between months and sites. A total of 1364 individuals representing 15 species and nine families of fishes were observed. At Dunwich, fish assemblages were dominated by the sand goby Favonigobius lentiginosus (89%) and whiting, Sillago spp. (10%). At Manly, the gobies Favonigobius exquisitus (37%), Pseudogobius sp. (31%) and the blenny Omobranchus punctatus (19%) dominated the shores while at Godwin Beach, F. lentiginosus (15%), F. exquisitus (45%) and Sillago spp. (25%) were the most abundant species. The mean +/-s.e. density of fishes ranged from 0. 29 +/- 0. 13 to 5. 04 +/- 1. 74 fishes l(-1) and abundance of fish correlated with pool volume. Juveniles (75%) dominated assemblages suggesting that soft sediment pools may act as nurseries. The persistent and recurrent fish assemblages found in soft sediment tide pools in Moreton Bay suggest that these shores are behaving more like a tropical than a temperate climate shore, as there was no significant difference of fish abundances between seasons. PMID- 21284631 TI - Using data from an encounter sampler to model fish dispersal. AB - A method to estimate speed of free-ranging fishes using a passive sampling device is described and illustrated with data from the Everglades, U.S.A. Catch per unit effort (CPUE) from minnow traps embedded in drift fences was treated as an encounter rate and used to estimate speed, when combined with an independent estimate of density obtained by use of throw traps that enclose 1 m(2) of marsh habitat. Underwater video was used to evaluate capture efficiency and species specific bias of minnow traps and two sampling studies were used to estimate trap saturation and diel-movement patterns; these results were used to optimize sampling and derive correction factors to adjust species-specific encounter rates for bias and capture efficiency. Sailfin mollies Poecilia latipinna displayed a high frequency of escape from traps, whereas eastern mosquitofish Gambusia holbrooki were most likely to avoid a trap once they encountered it; dollar sunfish Lepomis marginatus were least likely to avoid the trap once they encountered it or to escape once they were captured. Length of sampling and time of day affected CPUE; fishes generally had a very low retention rate over a 24 h sample time and only the Everglades pygmy sunfish Elassoma evergladei were commonly captured at night. Dispersal speed of fishes in the Florida Everglades, U.S.A., was shown to vary seasonally and among species, ranging from 0. 05 to 0. 15 m s(-1) for small poeciliids and fundulids to 0. 1 to 1. 8 m s(-1) for L. marginatus. Speed was generally highest late in the wet season and lowest in the dry season, possibly tied to dispersal behaviours linked to finding and remaining in dry-season refuges. These speed estimates can be used to estimate the diffusive movement rate, which is commonly employed in spatial ecological models. PMID- 21284632 TI - You are what you eat, whenever or wherever you eat it: an integrative analysis of fish food habits in Canadian and U.S.A. waters. AB - The degree to which fish diet differs by season and area, particularly over broad scales, was examined for the first time in temperate, contiguous north-west Atlantic Ocean waters by comparing food habit data for 10 species of fishes collected concurrently during the spring and autumn surveys in the U.S.A. (Gulf of Maine proper and Georges Bank) and in the summer survey in Canada (western Scotian Shelf and Bay of Fundy). For most species, there was a general concurrence among the three seasons and four areas: summer diets had the same dominant prey items as spring and autumn diets. Although a suite of multivariate analyses did elucidate some differences in specific proportions of the diet for these species across seasons and areas, the main prey did not substantially change for most of these species. These results suggest that there are (1) minimal differences in diet across season for these species at these taxonomic resolutions, (2) there are minimal differences in diet geographically for these species and (3) differences across species, as expected, are important. Many fisheries ecosystem and multispecies models are dependent on food habit data, where resolving seasonal and spatial differences in diet remains an important consideration; however, the present work implies that amalgamated estimates of diet from seasonal surveys may be a reasonable approach when no finer seasonal resolution exists, as long as due diligence is exercised. PMID- 21284633 TI - Food selection of Coregonus lavaretus in a brackish water ecosystem. AB - This study examined how variability in the abundance and biomass structure of benthic invertebrates affected the feeding choice of the whitefish Coregonus lavaretus on a hard bottom habitat of the brackish Baltic Sea. In general, crustaceans such as Idotea balthica and Gammarus spp. were preferred over molluscs. Although being the most numerous taxon in the invertebrate samples, Mytilus trossulus was the lowest ranking in C. lavaretus food preference. The availability of benthic invertebrate prey set the dietary range of fish but the selectivity largely described fish feeding within this range. There was no clear link between fish predation and the dominance structure of benthic invertebrate communities, suggesting that species composition, abundance and biomass of invertebrate species had no impact on the feeding selectivity of the fish. Thus, while fish predation may not affect the dominant species within a benthic community, due to strong selectivity fish may impose strong pressure on some rarer but highly preferred invertebrate prey species. PMID- 21284634 TI - Effects of training on functional variables of muscles in reared Atlantic salmon Salmo salar smolts: connection to downstream migration pattern. AB - The relative amount of muscle contraction regulating dihydropyridine and ryanodine receptors in the swimming muscles of trained reared Atlantic salmon Salmo salar smolts was compared with those of untrained and wild smolts. After an optimized 2 week training period, i.e. swimming with a velocity of 1.5 body lengths per second for 6 h per day, the level of both receptors was significantly higher in the muscles of trained S. salar than in the untrained ones before they were released into the natural environment. This difference persisted after downstream migration in the river. The highest level of receptors was observed in wild S. salar. Swimming performance was also higher in trained fish compared to untrained ones. Furthermore, swimming performance was positively associated with the level of receptors in both red and white muscle types. Downstream migration after release into the wild was significantly slower in trained smolts than in untrained fish. This indicates that trained smolts were most probably swimming harder against the current in the river than untrained smolts. The possible advantages for a slower migration in the river are discussed. This study shows that the prerequisites for effective contraction of the swimming muscles are better met in trained S. salar compared to untrained fish, and the muscles of trained smolts more closely resemble those of wild smolts. The results also imply that the capacity of untrained, reared smolts to swim against the current is not equal to that of their trained or wild counterparts which affects the downstream migration pattern of S. salar smolts. PMID- 21284635 TI - Allometric growth and reproductive biology traits of pikeperch Sander lucioperca at the southern edge of its range. AB - This study describes some biological traits (allometric relationship, reproductive biology and condition factor) of pikeperch Sander lucioperca at the southern edge of its range. Data were compiled from field studies between January 1997 and January 2009 in three Tunisian reservoirs. Overall, 1497 fish were caught, from which 1308 specimens were sampled and dissected. Sexually undetermined, male and female fish from the different sites exhibited similar allometric growth, expressed through the equation M(T) = 5 * 10(-6) L(T) (3.06) , where M(T) is the total mass and L(T) is the total length. The exponent value is slightly but significantly greater than 3, indicating positive allometric growth. Sex ratio (males:females) was 47:53 but remained balanced only up to 55 cm L(T) and changed with increasing size towards female dominance. Spawning occurred in March and early April according to the changes in female size-adjusted gonad mass or corresponding gonado-somatic index (I(G) ) values. Thermal conditions seemed favourable in February, but March corresponded to the period of equal day and night lengths and the switch towards longer days in terms of photoperiod. Changes in both size-adjusted M(T) or Fulton's condition factor and size-adjusted liver mass or hepato-somatic index (I(H) ) were clearly associated with reproduction. Reserves were consumed during spring in association with spawning efforts. Nevertheless, the delay before the reconstitution of reserves seemed relatively long (from early spring to late summer) although both thermal and trophic conditions could be considered favourable for active feeding of the fish. PMID- 21284636 TI - Prolonged feed deprivation does not permanently compromise digestive function in migrating European glass eels Anguilla anguilla. AB - The effects of prolonged feed deprivation (40 days at 18 degrees C) and re feeding (30 days) on body mass, growth and the activity of selected pancreatic and intestinal enzymes were evaluated in migrating European glass eels Anguilla anguilla by comparison with a control group fed to satiation with hake Merluccius merluccius roe for the duration of the experiment. Feed deprivation resulted in mass loss and a reduction in digestive function, as revealed by a decrease in the total and specific activities of pancreatic (trypsin and alpha-amylase) and intestinal brush border (alkaline phosphatase and leucine aminopeptidase) enzymes. The total activity of intestinal brush border enzymes diminished after 5 days of feed deprivation, whereas that of pancreatic enzymes did not decrease until 10 days, indicating that the intestine is more sensitive to feed deprivation than the pancreas. Re-feeding A. anguilla that were starved for 40 days resulted in compensatory growth, with specific growth rates that were 2.6 times higher than the control group. This compensatory growth was associated with the recovery of trypsin and intestinal brush border enzyme activities, which were restored to control levels within 5 days of re-feeding. The ability to maintain pancreatic enzyme activity during 40 days of feed deprivation, and rapidly recover capacity for protein digestion upon re-feeding, would enable A. anguilla at this glass eel stage to withstand periods without food but rapidly provide amino acids for protein synthesis and growth when suitable food was available. PMID- 21284637 TI - Increased exposure to predators increases both exploration and activity level in Brachyrhaphis episcopi. AB - Two temperament traits, tendency to explore and activity level, were measured in a tropical poeciliid fish, the Panamanian bishop Brachyrhaphis episcopi. Open field arena tests were used to quantify how predation pressure shapes activity levels and exploratory behaviours. Fish behaviour differed between high and low predation populations. Fish that experienced higher levels of predation were both more explorative and more active. There were also some individual differences within populations; fish varied in their levels of exploration and activity in a novel open arena, but these differences were not related to sex or size. Together with previous studies on this species, these results indicate that there is a behavioural syndrome associated with predation pressure. Fish from high-predation populations are bolder, more explorative and more active than those from low predation populations. PMID- 21284638 TI - The genetic architecture of embryonic developmental rate and genetic covariation with age at maturation in rainbow trout Oncorhynchus mykiss. AB - The genetic architecture underlying variation in embryonic developmental rate (DR) and genetic covariation with age of maturation (MAT) was investigated in rainbow trout Oncorhynchus mykiss. Highly significant additive parental effects and more limited evidence of epistatic effects on progeny hatching time were detected in three diallel sets of families. Genome scans with an average of 142 microsatellite loci from all 29 linkage groups in two families detected significant quantitative trait loci (QTL) for developmental rate on RT-8 and RT 30 with genome-wide and chromosome-wide effects, respectively. The QTL on linkage group RT-8 explained 23.7% of the phenotypic variation and supports results from previous studies. The co-localization of QTL for both DR and MAT to several linkage groups and the observation that alleles associated with faster developmental rate were found significantly more often in early maturing rather than typical and later maturing male ancestors supports the hypothesis of genetic covariation between DR and MAT. The maturation background and schedule of additional sires, however, did not have a consistent association with their progeny hatching times, suggesting that other genetic, environmental and physiological effects contribute to variation in these life-history traits. PMID- 21284639 TI - Does river of origin influence the early marine migratory performance of Salmo salar? AB - The early marine migratory behaviour of two populations of hatchery-reared Atlantic salmon Salmo salar was compared in a common-garden experiment. Post smolts from a river in a long fjord (Laerdal River, 144 km from the open coastline, n = 79) and a short fjord (Flekke River, 20 km from the open coastline, n = 80) in western Norway were tagged with acoustic transmitters and released during the spring of 2005 and 2006 in the inner part of the Hardangerfjord system (Opo River mouth, 179 km from the open coastline). The migratory behaviour of the tagged fish was monitored by acoustic listening stations in the fjord system up to 167 km from the release site. The Laerdal fish began migrating before the Flekke fish and had higher progression rates in the middle part of the fjord system. A greater number of Laerdal fish was detected along the most direct migratory route and in the outermost part of the Hardangerfjord system, which is indicative of a higher survival. The results from this study demonstrate differences in early marine migratory behaviour between S. salar from two different stocks and suggest that the distance a S. salar population travels to reach the open coastline may influence its early marine migratory behaviour and performance. The selective pressures of marine predation and arrival time at feeding areas in the ocean may be stronger for stocks with a longer inshore migration, creating more efficient migrants over time. PMID- 21284640 TI - Is there genetic variation in the response to competition intensity in juvenile brown trout Salmo trutta? AB - Effects of intraspecific competition intensities on the relative performance (growth and movement) of juvenile brown trout Salmo trutta originating from nine different families were tested in tank experiments and in semi-natural streams. Both growth and movement differed consistently among families, indicating genetic variation in these traits. There were no significant interaction effects, however, between the intensity of competition and family origin on performance in either of the two experimental systems. Thus, genetic variation in response to competition intensity appeared to be limited in the population from which the juveniles used in this experiment originate. PMID- 21284641 TI - Early infection of discus Symphysodon aequifasciatus altricial larvae by Sciadicleithrum variabilum (Monogenea). AB - The occurrence of Sciadicleithrum variabilum on the gills of discus Symphysodon aequifasciatus larvae 7 days after hatching is reported for the first time. This suggests that altricial larvae are susceptible to Monogenea following gill differentiation and before complete yolk resorption. PMID- 21284642 TI - The effect of stimulation frequency on the transmural ventricular monophasic action potential in yellowfin tuna Thunnus albacares. AB - Monophasic action potentials (MAPs) were recorded from the spongy and compact layers of the yellowfin tuna Thunnus albacares ventricle as stimulation frequency was increased. MAP duration decreased with increase in stimulation frequency in both the spongy and compact myocardial layers, but no significant difference in MAP duration was observed between the layers. PMID- 21284643 TI - Use it and lose it: lipofuscin accumulation in the midbrain of a coral reef fish. AB - Lipofuscin, an autofluorescent biomarker of physiological wear-and-tear, was concentrated in those areas of a fish's midbrain responsible for visual performance, suggesting a potentially strong link between physiological specialization, ecological adaptation and senescence. PMID- 21284644 TI - An alternative approach for the measurement of trimethylamine oxide in body fluid samples of elasmobranchs. AB - The present study examined an alternative approach to the measurement of trimethylamine oxide (TMAO) in body fluids of an elasmobranch, the little skate Leucoraja erinacea. Using ion exchange chromatography, the values measured compared favourably with values from the same samples measured using a recognized and frequently published spectrophotometric technique. PMID- 21284645 TI - Exploring the effect of microsatellite size homoplasy on reconstruction of phylogenetic relationships of picote splitfin Zoogoneticus quitzeoensis. AB - This study explores the effects of microsatellite size homoplasies on the reconstruction of phylogenetic relationships and estimates of population parameters as the fixation index (F(ST) ) using as a case study a truncated microsatellite from the picote splitfin Zoogoneticus quitzeoensis. The results suggest that the use of imperfect microsatellites may have only a minor effect in phylogenetic and population studies. PMID- 21284646 TI - Female Maylandia zebra prefer victorious males. AB - Females of a widespread species of the rock-dwelling haplochromine cichlids of Lake Malawi, Maylandia zebra, show preference for males that successfully evict intruding males from their territory. This behaviour, experimentally induced by the investigators in a laboratory setting, was also preferred over males that were not permitted to interact with any other individual. PMID- 21284648 TI - Regulation of jasmonate metabolism and activation of systemic signaling in Solanum nigrum: COI1 and JAR4 play overlapping yet distinct roles. AB - * Jasmonates are ubiquitous messengers in land plants essential for the activation of defense responses. However, their signaling properties, accumulation and metabolism vary substantially among species. Solanum nigrum is a wild Solanaceous species developed as a model to study defense responses. * Solanum nigrum plants transformed to silence the expression of key genes in jasmonate production (SnLOX3), conjugation (SnJAR4) and perception (SnCOI1) were generated to analyze the function of these genes in jasmonate accumulation and metabolism (studied by a combination of LC-MS/MS and (13) C-isotope labeling methods) and in signaling [studied by the systemic elicitation of leucine aminopeptidase (LAP) activity]. * In contrast with the early single jasmonic acid (JA) burst induced by wounding in wild-type (WT) plants, elicitation with insect oral secretions induced a later, second burst that was essential for the induction of systemic LAP activity, as demonstrated by ablation experiments. This induction was dependent on SnLOX3 and SnCOI1, but not on SnJAR4. In addition, the local accumulation of JA-glucose and JA-isoleucine was dependent on SnCOI1, whereas the accumulation of hydroxylated jasmonates was dependent on both SnCOI1 and SnJAR4. * The results demonstrate that SnLOX3, SnCOI1 and SnJAR4 have overlapping yet distinct roles in jasmonate signaling, differentially controlling jasmonate metabolism and the production of a systemic signal. PMID- 21284649 TI - Interpreting tree responses to thinning and fertilization using tree-ring stable isotopes. AB - * Carbon sequestration has focused renewed interest in understanding how forest management affects forest carbon gain over timescales of decades, and yet details of the physiological mechanisms over decades are often lacking for understanding long-term growth responses to management. * Here, we examined tree-ring growth patterns and stable isotopes of cellulose (delta(13)C(cell) and delta(18)O(cell)) in a thinning and fertilization controlled experiment where growth increased substantially in response to treatments to elucidate physiological data and to test the dual isotope approach for uses in other locations. * delta(13)C(cell) and delta(18)O(cell) results indicated that fertilization caused an increase in intrinsic water-use efficiency through increases in photosynthesis (A) for the first 3 yr. The combination treatment caused a much larger increase in A and water-use efficiency. Only the thinning treatments showed consistent significant increases in delta(18)O(cell) above controls. Changes in canopy microclimate are the likely drivers for delta(18)O(cell) increases with decreases in relative humidity and increases in leaf temperature associated with thinning being the most probable causes. * Tree-ring isotopic records, particularly delta(13)C(cell), remain a viable way to reconstruct long-term physiological mechanisms affecting tree carbon gain in response to management and climate fluctuations. PMID- 21284650 TI - Treatment of mast cells with carbon dioxide suppresses degranulation via a novel mechanism involving repression of increased intracellular calcium levels. AB - BACKGROUND: Intranasal noninhaled delivery of carbon dioxide (CO2) is efficacious in the symptomatic treatment of seasonal allergic rhinitis. The goal of this study was to determine whether and how 100% CO2 inhibits mast cell degranulation, thereby possibly contributing to the reduction of symptoms in seasonal allergic rhinitis. METHODS: Peritoneal mast cells isolated from rats and labelled with sulforhodamine-B (SFRM-B) were used to determine whether CO2 treatment could block mast cell degranulation and histamine release in response to 48/80. In addition, the effect of CO2 on intracellular calcium levels in unstimulated and stimulated mast cells was determined by fluorescent microscopy. RESULTS: Treatment with 48/80 caused >90% of mast cells containing SFRM-B to degranulate, resulting in a marked decrease in the fluorescent intensity within the mast cells, and simultaneously causing a significant increase in histamine release. Significantly, the stimulatory effect of 48/80 on fluorescent intensity and histamine levels was greatly inhibited (>95%) to near control levels by pretreatment with 100% CO2. Treatment with 48/80 also caused a robust transient increase in intracellular calcium, whereas pretreatment with CO2 repressed the increase in calcium (>70%) in response to 48/80. CONCLUSIONS: Results from this study provide the first evidence of a unique regulatory mechanism by which CO2 inhibits mast cell degranulation and histamine release by repressing stimulated increases in intracellular calcium. Thus, our data provide a plausible explanation for the reported therapeutic benefit of noninhaled intranasal delivery of 100% CO2 to treat allergic rhinitis. PMID- 21284651 TI - Decline of antibodies in XLA infant: when to start IVIG. PMID- 21284652 TI - A case report of breastfeeding anaphylaxis: successful prophylaxis with oral antihistamines. PMID- 21284653 TI - Eosinophilic panniculitis triggered by intramuscular penicillin and occupational setting. PMID- 21284654 TI - Neuropeptide blood levels correlate with mast cell load in patients with mastocytosis. AB - BACKGROUND: Mastocytosis is characterized by abnormal growth and accumulation of mast cells (MCs) in different organs. MCs have been shown to express receptors for neuropeptides. Furthermore, neuropeptides can activate MCs inducing cytokine production and MC mediator release, which further contribute to MC chemotaxis and stimulate the release of vasoactive peptides from sensory nerves. Thus, a contribution of neuropeptides to mastocytosis seems highly conceivable, but has not been investigated sufficiently yet. This study aimed to analyse blood levels of the neuropeptides substance P (SP), somatostatin (SST), vasoactive intestinal peptide (VIP), calcitonine gene--related peptide (CGRP) and expression of the SP receptor NK-1R in the skin of patients with mastocytosis (n = 46) compared to healthy controls (n = 69). METHODS: Substance P, SST, VIP and CGRP plasma levels were analysed by ELISA, serum tryptase levels with the UniCAP System and NK-1R expression in the skin by immunohistochemistry. RESULTS: Plasma levels of SP (P < 0.0001), SST, (P = 0.007), VIP (P < 0.0001) and CGRP (P = 0.003) were significantly increased in patients with mastocytosis compared to controls. Tryptase serum levels correlated significantly with neuropeptide levels, implying a link between MC load and neuropeptide blood levels in mastocytosis. NK-1R was expressed on the majority of MCs, and NK-1R-positive cells were increased in lesional mastocytosis skin compared to control skin (P = 0.01). CONCLUSIONS: Elevated blood levels of the neuropeptides SP, SST, VIP and CGRP correlate with MC load and together with an increased expression of NK-1R in the skin of patients with mastocytosis indicate a role of neuropeptides in the pathophysiology of mastocytosis. PMID- 21284655 TI - PARP-1: a new player in the asthma field? PMID- 21284656 TI - Preparation and characterization of carnauba wax nanostructured lipid carriers containing benzophenone-3. AB - Nanostructured lipid carriers (NLCs) are potential active delivery systems based on mixtures of solid lipids and liquid oil. In this paper, aqueous dispersions of NLCs were prepared by a hot high-pressure homogenization technique using carnauba wax as the solid lipid and isodecyl oleate as the liquid oil. The preparation and stability parameters of benzophenone-3-loaded NLCs have been investigated concerning particle size, zeta potential and loading capacity to encapsulate benzophenone-3, a molecular sunscreen. The current investigation illustrates the effect of the composition of the lipid mixture on the entrapment efficiency, in vitro release and stability of benzophenone-3-loaded in these NLCs. A loading capacity of approximately 5% of benzophenone-3 (m(BZ-3) /m(lipids) ) was characteristic of these systems. PMID- 21284657 TI - Characterizing the composition of underarm and forearm skin using confocal raman spectroscopy. AB - Many studies have reported differences in skin composition as a function of body site and age. However, rarely has axilla (underarm) skin been included in these studies. This report highlights the results of a clinical study where confocal Raman spectroscopy was used to assess the differences between underarm and volar forearm skin. In the reported study, the concentration of natural moisturizing factor (NMF), urea, lactic acid, cholesterol, trans urocanic acid (t-UCA) and ceramide 3 (N-octadecanoyl-phytosphingosine) was evaluated as a function of depth, body site (underarm vs. forearm) and age. Two age groups of women were included: (i) between 20 and 30 years and (ii) older than 55 years (post menopause). The levels of cholesterol, ceramide 3 and lactic acid were highest in the underarm regardless of the age group whereas the forearm contained higher amounts of NMF. Ceramide 3, urea and lactic acid were significantly lower for women 55 years or older in the underarm. No age-related differences were detected within the forearm site.. PMID- 21284658 TI - ESR study of photoinduced free radicals by visible light in hair and the effects of ascorbic acid (vitamin C). AB - The ESR spectra of melanin's free radicals in natural black and red hair have been investigated. It is shown that the ESR spectrum of black hair is slightly asymmetric singlet with g=2.0037 and DeltaH=0.5 mTl. The ESR spectrum of red hair with g=2.0053 differs from the spectrum of black hair. Using the method of saturation was shown that ESR spectrum of red hair represents a superposition of two signals: a singlet, relating to the black hair, and a triplet from red hair's pheomelanin. Under the influence of visible light (blue with lambda(max) =450 nm, green with lambda(max) =510 nm and red with lambda(max) =650 nm) in both types of hair (black and red), the photoinduced free radicals appear, which indicates an increase in the intensity of already existing ESR spectrum of hair. It should be noted that the ESR spectra of red hair from various donors are different. The antioxidant ascorbic acid (vitamin C) has the different effect on the photoinduced free radicals. In particular, in the case of black hair, the concentration of photoinduced free radicals is slightly reduced, whereas in red hair, the disappearance of the triplet in the spectrum is observed, and at the same time, the spectrum becomes a singlet, the intensity of which increases sharply. It is assumed that the antioxidants, effective for black hair, may be ineffective for red hair and vice versa. Therefore, in each, specific case is necessary to investigate the effectiveness of an antioxidant separately. PMID- 21284659 TI - Lifting properties of the alkamide fraction from the fruit husks of Zanthoxylum bungeanum. AB - The fruits of various Zanthoxylum species are used as a spice in the Chinese and Japanese cuisine because of their delicate flavour and tingling properties. The lipophilic hydroxyalkamides hydroxy alpha- and beta-sanshools (1a,b) have been identified as the tingling principles of these plants, and previous studies have validated a sanshool-rich lipophilic extract from the fruit husks of Z. bungeanum Maxim. (Zanthalene (r) ) as an anti-itching cosmetic ingredient. Because tingling is a sort of 'paralytic pungency', and Zanthalene (r) potently inhibits synaptic transmission, we have investigated its capacity to relax subcutaneous muscles and act as a topical lifting agent for wrinkles. An anti-wrinkles extract rich in spilanthol (2), a lipophilic alkamide having sensory properties similar to those of Zanthalene (r) , was used as a reference. Short-term (lifting effect) and long term (anti-wrinkle) improvements of skin roughness parameters were evaluated by both objectives' and subjectives' measurements. An immediate 'lifting' effect was observed with the sanshool-rich lipophilic extract, at dosages at which the reference alkamide extract was inactive in the objective assays. Limited desensitization after repeated application and good overall tolerability were observed, although a modest long-term anti-wrinkle effect was shown by both products. Taken together, these observations validate the use of sanshool-rich lipophilic extracts as an efficacious, immediate-action lifting agent, and exemplify the relevance of sensory observations to foster the development of innovative cosmetic ingredients. PMID- 21284660 TI - Benefit of a topical slimming cream in conjunction with dietary advice. AB - The aim of this study was to determine how worthwhile it would be to combine a newly developed topical slimming product with customized dietary habits not based on calorie restriction, so as to improve the cellulite appearance of the skin. At the beginning of the study, a nutritionist recorded the dietary habits of each participant and gave recommendations to each of them according to their food consumption. The chosen methodology was a right/left comparison, one thigh and hip being treated with the new topical slimming product and the other one left untreated to serve as a random control. Objective evaluations were performed by blind assessors. Control of food intake improved the cellulite score after 4 weeks when compared with the base value, but this reduction was significantly greater and earlier on the treated side than on the untreated side, indicating an objective additional benefit derived from the new slimming cream. This result corroborated the slimming effect assessed by measurement in centimetres of the circumference of the upper thighs and the reconstructed volume of the thigh between two fixed horizontal slices. Furthermore, skin tonicity, a major component of cellulite visibility, was also significantly improved on the treated side after only 2 weeks. This new topical cream thus enhances the benefit of a dietetic control for the treatment of the visible aspect of cellulite on the skin. PMID- 21284661 TI - Relation between facial morphology, personality and the functions of facial make up in women. AB - Our external appearance plays a key role in everyday life's social interactions. Hence, taking care of our appearance allows us to adjust and protect ourselves, as well as communicate emotional disposition (i.e. sympathy or aversion) and social information (i.e. values, status). However, some discrete body parts or characteristics appear to be more salient than others in contributing to global body image. For example, authors showed that facial attractiveness is one of the best predictors of overall physical attractiveness and represent one of the primary factors influencing global self-esteem. Make-up is therefore ought to play a major influence in these parameters. Moreover, in a previous study whose subject was to explain the reasons that motivate women to make-up, we showed a high implication of specific psychological traits in correlation with two make-up functions (i.e. psycho-behavioural profiles 'Seduction' and 'Camouflage'; group S and group C, respectively). The purpose of this study was to assess the possible relation between our two psycho-behavioural profiles and some morphological parameters know to be involved in facial attraction (i.e. facial asymmetry and skin visual quality). First of all, our study revealed for women from the group C a greater asymmetry of the lower face (i.e. mouth area) that could be related to a possible larger amount of negative emotional experiences. Concerning make-up behaviour, women from the group S more extensively manipulated their relative facial attractiveness, by using a large range of colours, but also through a significantly longer make-up process used to adjust their visual asymmetry and therefore increase their potential of attractiveness. On the overall, our results suggest that make-up is used differentially, according to stable psychological profiles of women, to manipulate specific visual/morphological facial features involved in attractiveness. PMID- 21284662 TI - Sex difference in human fingertip recognition of micron-level randomness as unpleasant. AB - We investigated sex difference in evaluation, using the human fingertip, of the tactile impressions of three different micron-scale patterns laser-engraved on plastic plates. There were two ordered (periodical) patterns consisting of ripples on a scale of a few micrometres and one pseudo-random (non-periodical) pattern; these patterns were considered to mimic the surface geometry of healthy and damaged human hair, respectively. In the first experiment, 10 women and 10 men ran a fingertip over each surface and determined which of the three plates felt most unpleasant. All 10 female participants reported the random pattern, but not the ordered patterns, as unpleasant, whereas the majority of the male participants did not. In the second experiment, 9 of 10 female participants continued to report the pseudo-random pattern as unpleasant even after their fingertip had been coated with a collodion membrane. In the third experiment, participants were asked to evaluate the magnitude of the tactile impression for each pattern. The results again indicated that female participants tend to report a greater magnitude of unpleasantness than male participants. Our findings indicate that the female participants could readily detect microgeometric surface characteristics and that they evaluated the random pattern as more unpleasant. Possible physical and perceptual mechanisms involved are discussed. PMID- 21284663 TI - Standardized extract of Syzygium aqueum: a safe cosmetic ingredient. AB - Syzygium aqueum, a species in the Myrtaceae family, commonly called the water jambu is native to Malaysia and Indonesia. It is well documented as a medicinal plant, and various parts of the tree have been used in traditional medicine, for instance as an antibiotic. In this study, we show S. aqueum leaf extracts to have a significant composition of phenolic compounds, protective activity against free radicals as well as low pro-oxidant capability. Its ethanolic extract, in particular, is characterized by its excellent radical scavenging activity of EC(50) of 133 MUg mL(-1) 1,1-diphenyl-2-picryl-hydrazyl (DPPH), 65 MUg mL(-1) 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) and 71 MUg mL(-1) (Galvinoxyl), low pro-oxidant capabilities and a phenolic content of 585-670 mg GAE g(-1) extract. The extract also displayed other activities, deeming it an ideal cosmetic ingredient. A substantial tyrosinase inhibition activity with an IC(50) of about 60 MUg mL(-1) was observed. In addition, the extract was also found to have anti-cellulite activity tested for its ability to cause 98% activation of lipolysis of adipocytes (fat cells) at a concentration of 25 MUg mL(-1). In addition, the extract was not cytotoxic to Vero cell lines up to a concentration of 600 MUg mL(-1). Although various parts of this plant have been used in traditional medicine, this is the first time it has been shown to have cosmeceutical properties. Therefore, the use of this extract, alone or in combination with other active principles, is of interest to the cosmetic industry. PMID- 21284665 TI - Dendritic cells in alcoholic liver injury and fibrosis. AB - Alcohol consumption impairs the development of innate and adaptive immune responses, however the exact mechanism by which alcohol leads to immune defects remains to be established. Dendritic cells (DCs) form a heterogeneous population of hematopoietic cells that are present in all tissues including the liver. DC are initially described playing a key role in the induction of innate and adaptive immune response against specific antigens. In our presentation, we discussed few new aspects of DC development, critical assessment of DC in non lymphoid organs and the impact of alcohol consumption on DC function. Understanding the mechanism by which DC modulate liver function after alcohol consumption may help uncover novel therapeutic strategies for the treatment of these conditions. PMID- 21284666 TI - The unfolding web of innate immune dysregulation in alcoholic liver injury. AB - Inflammatory cell and cytokine cascade activation is present in humans with alcoholic liver disease as well as in animal models of alcohol-induced liver damage. Gut-derived lipopolysaccharide (LPS), a ligand of the Toll-like receptor 4 (TLR4), plays a central role in triggering and maintaining activation of Kupffer cells in alcoholic hepatitis. In this mini-review, we describe molecular mechanisms that lead to increased inflammatory cell activation by alcohol and LPS and discuss the mechanism for activation in alcohol-exposed macrophages. In alcohol-induced liver disease we discuss the role of MyD88-independent but IRF3 mediated TLR4 signaling in alcohol-related liver inflammation and liver damage. PMID- 21284667 TI - Molecular mechanisms of alcoholic liver disease: innate immunity and cytokines. AB - Alcohol consumption is a predominant etiological factor in the pathogenesis of chronic liver diseases worldwide, causing fatty liver, alcoholic hepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma. In the past few decades, significant progress has been made in our understanding of the molecular mechanisms underlying alcoholic liver injury. Activation of innate immunity components such as Kupffer cells, LPS/TLR4, and complements in response to alcohol exposure plays a key role in the development and progression of alcoholic liver disease (ALD). LPS activation of Kupffer cells also produces IL-6 and IL-10 that may play a protective role in ameliorating ALD. IL-6 activates signal transducer and activator of transcription 3 (STAT3) in hepatocytes and sinusoidal endothelial cells, while IL-10 activates STAT3 in Kupffer cells/macrophages, subsequently protecting against ALD. In addition, alcohol consumption also inhibits some components of innate immunity such as natural killer (NK) cells, a type of cells that play key roles in anti-viral, anti-tumor, and anti-fibrotic defenses in the liver. Ethanol inhibition of NK cells likely contributes significantly to the pathogenesis of ALD. Understanding the roles of innate immunity and cytokines in alcoholic liver injury may provide insight into novel therapeutic targets in the treatment of alcoholic liver disease. PMID- 21284668 TI - Models and mechanisms of fibrosis resolution. AB - Liver fibrosis and its end stage, cirrhosis, represent the final common pathway of virtually all chronic liver diseases. As our understanding of the pathogenesis of liver fibrosis has progressed, it has become evident that the liver provides a useful generic model of inflammation and repair, demonstrating interplay between the epithelial, inflammatory, myofibroblast and extracellular matrix components of the mammalian wound healing response. In this review, the paradigm that liver fibrosis is a potentially reversible process-demonstrating both fibrosis (scarring) and resolution with remodeling and restitution of normal or near normal tissue architecture-will be explored. The remarkable progress in unraveling the complexities of liver fibrosis has been due to developments in technologies including the isolation of discrete liver cell populations which have facilitated studies of their behavior in tissue culture and in vivo. More recently, animal models that mimic chronic liver diseases have been established. These models are tractable and can be applied in gene knockout and transgenic mice. This article will highlight recent studies that reveal key mechanisms mediating the regression of liver fibrosis which have derived from the use of such complementary animal and human model systems and describe how our greater understanding of this dynamic process is likely to inform the development of directed and effective anti-fibrotic approaches. PMID- 21284669 TI - Genetics of liver injury and fibrosis. AB - Genetic risk factors play critical roles in liver injury and fibrosis, since both initiation and progression of chronic liver diseases differ between individuals challenged by identical environmental factors. Recently genomewide association studies have identified specific novel risk genes for (non-alcoholic) fatty liver disease (adiponutrin), viral hepatitis (interleukin 28B), and chronic cholestatic diseases (interleukin 12). Here, we summarize these studies and provide an inventory of the susceptibility genes. In the future, risk assessment of complex liver diseases might be based on polygenic risk scores or even gene networks. Complimentary to study in humans, experimental crosses of inbred mouse strains contribute to the genetic dissection of gene-gene interaction and gene environment interactions. The results of these genomewide studies in mice and men might open new avenues for the prevention and treatment of chronic liver injury and the regression of liver fibrosis. PMID- 21284670 TI - Management of alcoholic liver disease: an update. AB - Treatment of alcoholic liver disease is for the most part based on the stage of the disease and the pathogenic event that is being targeted. The primary treatment modalities that are considered in the treatment of alcoholic liver disease include abstinence, agents that suppress inflammation, anticytokine therapy, nutritional support, modifiers of alcohol metabolism, anti-oxidants, and inhibitors of hepatic fibrosis. Future therapeutic options include exploration of new pathways such as the patatin-like phospholipase domain containing 3 protein (PNPLA-3). PMID- 21284671 TI - Acetaldehyde burst protection of ADH1B*2 against alcoholism: an additional hormesis protection against esophageal cancers following alcohol consumption? AB - This account of recent work presented at the 4th International Symposium on Alcohol Pancreatitis and Cirrhosis reports animal studies aimed at determining the role of the "acetaldehyde burst," generated shortly upon ethanol intake, as the mechanism of protection against alcoholism conferred by the ADH1B*2 polymorphism. Literature studies discussed suggest an additional role of the acetaldehyde burst on the paradoxical (hormesis) protection of the ADH1B*2 polymorphism against esophageal cancers in alcoholics. PMID- 21284672 TI - The hepatocarcinogenic effect of methionine and choline deficient diets: an adaptation to the Warburg effect? AB - Normal differentiated hepatocytes primarily metabolize methionine, via homocysteine synthesis, through the transsulfuration pathway. In addition to glutathione, this pathway produces alpha-ketobutyrate that is further metabolized in the mitochondria. It is only under low methionine conditions that differentiated hepatocytes predominantly regenerate methionine from homocysteine. In contrast, proliferating hepatocytes and liver cancer cells regenerate methionine from homocysteine regardless of the availability of methionine. Here we propose that this less efficient metabolism of methionine in proliferating hepatocytes and cancer cells is an adaptation to the "Warburg effect" that is, to the well known phenomenon that cancer cells rely on aerobic glycolysis instead of oxidative phosphorylation to generate energy. The observation that knockout mice with impaired S-adenosylmethionine (SAMe) synthesis (the first step in methionine metabolism) or catabolism spontaneously develop fatty liver and hepatocellular carcinoma, together with the observation that SAMe administration induces apoptosis in hepatoma cells and prevents liver cancer support this hypothesis. PMID- 21284673 TI - Alcoholic liver disease and malnutrition. AB - Malnutrition, both protein energy malnutrition (PEM) and deficiencies in individual nutrients, is a frequent complication of alcoholic liver disease (ALD). Severity of malnutrition correlates with severity of ALD. Malnutrition also occurs in patients with cirrhosis due to etiologies other than alcohol. The mechanisms for malnutrition are multifactorial, and malnutrition frequently worsens in the hospital due to fasting for procedures and metabolic complications of liver disease, such as hepatic encephalopathy. Aggressive nutritional support is indicated in inpatients with ALD, and patients often need to be fed through an enteral feeding tube to achieve protein and calorie goals. Enteral nutritional support clearly improves nutrition status and may improve clinical outcome. Moreover, late-night snacks in outpatient cirrhotics improve nutritional status and lean body mass. Thus, with no FDA-approved therapy for ALD, careful nutritional intervention should be considered as frontline therapy. PMID- 21284674 TI - Drinks like a fish: using zebrafish to understand alcoholic liver disease. AB - Steatosis is the most common consequence of acute alcohol abuse, such as occurs during a drinking binge. Acute alcohol induced steatosis may predispose to more severe hepatic disease. We have developed a model of alcoholic liver disease (ALD) in zebrafish larvae to provide a system in which the genes and pathways that contribute to steatosis can be rapidly identified. Zebrafish larvae represent an attractive vertebrate model for studying acute ALD because they possess the pathways to metabolize alcohol, the liver is mature by 4 days post fertilization (dpf), and alcohol can be simply added to their water. Exposing 4 dpf zebrafish larvae to 2% ethanol (EtOH) for 32 hours achieves ~80 mM intracellular EtOH and upregulation of hepatic cyp2e1, sod, and bip, indicating that EtOH is metabolized and provokes oxidative stress. EtOH-treated larvae develop ALD as demonstrated by hepatomegaly and steatosis. Increased lipogenesis driven by the sterol response element binding protein (SREBP) transcription factors is essential for steatosis associated with chronic alcohol ingestion but it has not been determined if the same pathway is essential for steatosis following a drinking binge. We report that several Srebp target genes are induced in the liver of zebrafish exposed to EtOH. We used fish which harbor a mutation in the gene encoding the membrane bound transcription factor protease 1 (mbtps1; also called site-1 protease) and embryos in which the Srebp cleavage activating protein (scap) is knocked down to determine the requirement of this pathway in acute ALD. We find that both means of blocking Srebp activation prevents steatosis in response to 2% EtOH. Moreover, this is accompanied by the failure to activate several Srebp target genes in response to alcohol. We conclude that Srebps are required for steatosis in response to acute alcohol exposure. Moreover, these data highlight the utility of zebrafish as a useful new vertebrate model to study ALD. PMID- 21284676 TI - Alcohol and HCV infection: biological process. PMID- 21284675 TI - Investigating the pathobiology of alcoholic pancreatitis. AB - Alcohol abuse is one of the most common causes of pancreatitis. The risk of developing alcohol-induced pancreatitis is related to the amount and duration of drinking. However, only a small portion of heavy drinkers develop disease, indicating that other factors (genetic, environmental, or dietary) contribute to disease initiation. Epidemiologic studies suggest roles for cigarette smoking and dietary factors in the development of alcoholic pancreatitis. The mechanisms underlying alcoholic pancreatitis are starting to be understood. Studies from animal models reveal that alcohol sensitizes the pancreas to key pathobiologic processes that are involved in pancreatitis. Current studies are focussed on the mechanisms responsible for the sensitizing effect of alcohol; recent findings reveal disordering of key cellular organelles including endoplasmic reticulum, mitochondria, and lysosomes. As our understanding of alcohol's effects continue to advance to the level of molecular mechanisms, insights into potential therapeutic strategies will emerge providing opportunities for clinical benefit. PMID- 21284680 TI - Oversight, oversight, oversight. PMID- 21284679 TI - Effect of nitrate, acetate, and hydrogen on native perchlorate-reducing microbial communities and their activity in vadose soil. AB - The effect of nitrate, acetate, and hydrogen on native perchlorate-reducing bacteria (PRB) was examined by conducting microcosm tests using vadose soil collected from a perchlorate-contaminated site. The rate of perchlorate reduction was enhanced by hydrogen amendment and inhibited by acetate amendment, compared with unamendment. Nitrate was reduced before perchlorate in all amendments. In hydrogen-amended and unamended soils, nitrate delayed perchlorate reduction, suggesting that the PRB preferentially use nitrate as an electron acceptor. In contrast, nitrate eliminated the inhibitory effect of acetate amendment on perchlorate reduction and increased the rate and the extent, possibly because the preceding nitrate reduction/denitrification decreased the acetate concentration that was inhibitory to the native PRB. In hydrogen-amended and unamended soils, perchlorate reductase gene (pcrA) copies, representing PRB densities, increased with either perchlorate or nitrate reduction, suggesting that either perchlorate or nitrate stimulates the growth of the PRB. In contrast, in acetate-amended soil pcrA increased only when perchlorate was depleted: a large portion of the PRB may have not utilized nitrate in this amendment. Nitrate addition did not alter the distribution of the dominant pcrA clones in hydrogen-amended soil, likely because of the functional redundancy of PRB as nitrate-reducers/denitrifiers, whereas acetate selected different pcrA clones from those with hydrogen amendment. PMID- 21284681 TI - New and highly efficient methodology for screening high-yield strains of cytotoxic deacetylmycoepoxydiene (DAM). AB - AIMS: To establish a highly efficient methodology for screening high yield strains of cytotoxic deacetylmycoepoxydiene (DAM), to meet the need of research on its mechanism of anti-tumor properties and in vivo toxicity studies. METHODS AND RESULTS: A simple, sensitive, and highly repetitive screening procedure 'Antimicrobial-TLC-HPLC' (ATH) was established for the rapid obtaining of high yielding DAM mutants to replace the time and labor intensive anti-tumor activity assay (MTT). With this ATH method, four highly yielding DAM mutants were selected out of 5000 total mutants, one of which, M4-143, showed yields of more than 300 times (250.3 mg l(-1) ) that of the parent strain A123. CONCLUSIONS: The ATH method developed in this work has proven to be both economical and highly efficient with the screening of 1200 mutants in a one week time period, thusly shortening the expenditure of time and labor, without missing a single high-yield mutant. Due to these characteristics, it is superior to other HTS screening methods described in earlier literature. The mutant M4-143 has a good genetic stability and can be used for further research. SIGNIFICANCE AND IMPACT OF THE STUDY: This ATH screening method is not only perfect for screening high-yield DAM mutants, but also, it is suitable to screen the strain libraries for those strains that have the ability to produce natural metabolites with antitumor activity. PMID- 21284682 TI - Quantitative links between arsenic exposure and influenza A (H1N1) infection associated lung function exacerbations risk. AB - The objective of this study was to link arsenic exposure and influenza A (H1N1) infection-induced respiratory effects to assess the impact of arsenic contaminated drinking water on exacerbation risk of A (H1N1)-associated lung function. The homogeneous Poisson process was used to approximate the related processes between arsenic exposure and influenza-associated lung function exacerbation risk. We found that (i) estimated arsenic-induced forced expiratory volume in 1 second (FEV(1) ) reducing rates ranged from 0.116 to 0.179 mL/MUg for age 15-85 years, (ii) estimated arsenic-induced A (H1N1) viral load increasing rate was 0.5 mL/MUg, (iii) estimated A (H1N1) virus-induced FEV(1) reducing rate was 0.10 mL/logTCID50, and (iv) the relationship between arsenic exposure and A (H1N1)-associated respiratory symptoms scores (RSS) can be described by a Hill model. Here we showed that maximum RSS at day 2 postinfection for Taiwan, West Bengal (India), and the United States were estimated to be in the severe range of 0.83, 0.89, and 0.81, respectively, indicating that chronic arsenic exposure and A (H1N1) infection together are most likely to pose potential exacerbations risk of lung function, although a 50% probability of lung function exacerbations risk induced by arsenic and influenza infection was within the mild and moderate ranges of RSS at day 1 and 2 postinfection. We concluded that avoidance of drinking arsenic-containing water could significantly reduce influenza respiratory illness and that need will become increasingly urgent as the novel H1N1 pandemic influenza virus infects people worldwide. PMID- 21284683 TI - Institutionalized ignorance as a precondition for rational risk expertise. AB - The present case study seeks to explain the conditions for experts' rational risk perception by analyzing the institutional contexts that constitute a field of food safety expertise in Denmark. The study highlights the role of risk reporting and how contextual factors affect risk reporting from the lowest organizational level, where concrete risks occur, to the highest organizational level, where the body of professional risk expertise is situated. The article emphasizes the role of knowledge, responsibility, loyalty, and trust as risk-attenuation factors and concludes by suggesting that the preconditions for the expert's rationality may rather be a lack of risk-specific knowledge due to poor risk reporting than a superior level of risk knowledge. PMID- 21284684 TI - Using a familiar risk comparison within a risk ladder to improve risk understanding by low numerates: a study of visual attention. AB - Previous experimental research provides evidence that a familiar risk comparison within a risk ladder is understood by low- and high-numerate individuals. It especially helps low numerates to better evaluate risk. In the present study, an eye tracker was used to capture individuals' visual attention to a familiar risk comparison, such as the risk associated with smoking. Two parameters of information processing-efficiency and level-were derived from visual attention. A random sample of participants from the general population (N= 68) interpreted a given risk level with the help of the risk ladder. Numeracy was negatively correlated with overall visual attention on the risk ladder (r(s) =-0.28, p= 0.01), indicating that the lower the numeracy, the more the time spent looking at the whole risk ladder. Numeracy was positively correlated with the efficiency of processing relevant frequency (r(s) = 0.34, p < 0.001) and relevant textual information (r(s) = 0.34, p < 0.001), but not with the efficiency of processing relevant comparative information and numerical information. There was a significant negative correlation between numeracy and the level of processing of relevant comparative risk information (r(s) =-0.21, p < 0.01), indicating that low numerates processed the comparative risk information more deeply than the high numerates. There was no correlation between numeracy and perceived risk. These results add to previous experimental research, indicating that the smoking risk comparison was crucial for low numerates to evaluate and understand risk. Furthermore, the eye-tracker method is promising for studying information processing and improving risk communication formats. PMID- 21284685 TI - NFKBIL1 confers resistance to experimental autoimmune arthritis through the regulation of dendritic cell functions. AB - We and others have reported that human NF-kappaB inhibitor-like-1 (NFKBIL1) was a putative susceptible gene for autoimmune diseases such as rheumatoid arthritis (RA). However, its precise role in the pathogenesis of RA is still largely unknown. In this study, we generated transgenic mice expressing human NFKBIL1 (NFKBIL1-Tg) and examined whether NFKBIL1 plays some role(s) in the development of autoimmune arthritis. In both a collagen-induced arthritis model and a collagen antibody-induced arthritis model, NFKBIL1-Tg mice showed resistance to arthritis compared to control mice, indicating that the gene product of NFKBIL1 was involved in the control of thusly induced arthritis. Total spleen cells of NFKBIL1-Tg mouse showed decreased proliferation to mitogenic stimuli, consistent with its resistance to arthritis. Unexpectedly, purified T cells of NFKBIL1-Tg mouse showed increased proliferation and cytokine production. This apparent discrepancy was accounted for by the impaired functions of antigen-presenting cells of NFKBIL1-Tg mouse; both T/B cell-depleted spleen cells and bone marrow derived dendritic cells of the Tg mouse induced less prominent proliferation and IL-2 production of T cells. Furthermore, dendritic cells (DCs) derived from NFKBIL1-Tg mouse showed lower expression of co-stimulatory molecules and decreased production of inflammatory cytokines when they were activated by lipopolysaccharide. Taken together, these results indicated that NFKBIL1 affected the pathogenesis of RA at least in part through the regulation of DC functions. PMID- 21284687 TI - Glucosamine improved atopic dermatitis-like skin lesions in NC/Nga mice by inhibition of Th2 cell development. AB - Dysregulated Th subset responses, characterized by Th2-dominant allergic inflammation, are thought to be central to the pathogenesis of atopic dermatitis (AD). Glucosamine has been shown to have immunosuppressive properties, but its effect on AD has not been examined. In this study, the immunoregulatory effects of glucosamine, using dermatophagoides farinae (Df)-induced AD-like skin lesions in NC/Nga mice, were investigated. The clinical scores were reduced significantly by the treatment with glucosamine at 10 and 20 mg/day. Histological analysis of the skin also revealed that treatment of glucosamine at 10 and 20 mg/day significantly reduced the inflammatory cellular infiltrate, including mast cells and eosinophils. The levels of serum IgE and Th2 cytokines in spleen cells were reduced, whereas no significant change was detected in IFN-gamma, a Th1 cytokine. To determine the mechanism associated with inhibition of the Th2 immune response, the effects of glucosamine on the selective differentiation pathway of the Th subset in vitro was examined in NC/Nga mice. The results showed that glucosamine suppressed the differentiation of naive CD4(+) T cells to Th2 cells in vitro. On the basis of in vivo and in vitro results of the NC/Nga mice, the immunobiological effects of glucosamine on peripheral blood mononuclear cells from patients with AD were examined. The production of Th2 cytokines, such as IL 4 and IL-5, was significantly decreased after in vitro administration of glucosamine, which suggest that glucosamine might be a useful immunomodulatory agent for the treatment of human AD. PMID- 21284688 TI - Patient-related risk factors for tooth loss in aggressive periodontitis after active periodontal therapy. AB - OBJECTIVES: Evaluation of patient-related risk factors contributing to tooth loss and recurrence of periodontitis 10.5 years after initial therapy in patients with aggressive periodontitis (AgP). MATERIAL AND METHODS: Eighty-four of 174 patients were included. Re-examination consisted of patient's history, clinical examination and test for interleukin (IL)-1 composite genotype. Patients' charts were searched for regularity of maintenance and initial diagnosis. Statistical analysis was performed using Poisson and logistical regression analysis. RESULTS: The responder rate was 48%. Thirteen of 84 patients presented a localized AgP, 68 were females and 29 smoked. One hundred and thirteen teeth out of 2154 were lost after therapy (1.34 teeth/patient). Age (p=0.0018), absence of IL-1 composite genotype (p=0.0091) and educational status (p=0.0085) were identified as statistically significant risk factors for tooth loss. Twenty patients exhibited recurrence of periodontitis at re-examination. Smoking (p=0.0034) and mean Gingival Bleeding Index (GBI) (p=0.0239) contributed significantly to recurrence of disease. No patient participating regularly in supportive periodontal therapy (SPT) showed disease recurrence. CONCLUSION: Age, absence of IL-1 composite genotype and low social status are detected as risk factors for tooth loss. Smoking and high mean GBI are associated with an increased risk for recurrence of periodontitis, whereas regular SPT acts as a protective factor. PMID- 21284686 TI - IgE sequences in individuals living in an area of endemic parasitism show little mutational evidence of antigen selection. AB - Patterns of somatic mutation in IgE genes from allergic individuals have been a focus of study for many years, but IgE sequences have never been reported from parasitized individuals. To study the role of antigen selection in the evolution of the anti-parasite response, we therefore generated 118 IgE sequences from donors living in Papua New Guinea (PNG), an area of endemic parasitism. For comparison, we also generated IgG1, IgG2, IgG3 and IgG4 sequences from these donors, as well as IgG1 sequences from Australian donors. IgE sequences had, on average, 23.0 mutations. PNG IgG sequences had average mutation levels that varied from 17.7 (IgG3) to 27.1 (IgG4). Mean mutation levels correlated significantly with the position of their genes in the constant region gene locus (IgG3 < IgG1 < IgG2 < IgG4). Interestingly, given the heavy, life-long antigen burden experienced by PNG villagers, average mutation levels in IgG sequences were little different to that seen in Australian IgG1 sequences (19.2). Patterns of mutation provide clear evidence of antigen selection in many IgG sequences. The percentage of IgG sequences that showed significant accumulations of replacement mutations in the complementarity determining regions ranged from 22% of IgG3 sequences to 39% of IgG2 sequences. By contrast, only 12% of IgE sequences had such evidence of antigen selection, and this was significantly less than in PNG IgG1, IgG2 and IgG4 subclass sequences (P < 0.01). The anti-parasite IgE response therefore has the reduced evidence of antigen selection that has previously been reported in studies of IgE sequences from allergic individuals. PMID- 21284689 TI - Stimulants of Toll-like receptors 2 and 4 are elevated in saliva of periodontitis patients compared with healthy subjects. AB - AIM: Because the absorption of stimulants of Toll-like receptor (TLR)2 and TLR4 from the gastrointestinal tract into the circulation has been proposed to promote the development of atherosclerosis and insulin resistance, we aimed to quantify the abundance of stimulants of TLR2 and TLR4 in human saliva. METHODS: A recently developed bioassay based upon measurement of NF-kappaB activation in TLR deficient human embryonic kidney (HEK)-293 cells transfected with human TLR2 or TLR4 and calibrated with synthetic bacterial lipopeptide (Pam(3) CSK(4) ) or Escherichia coli lipopolysaccharide (LPS), was used to establish the normal range of TLR stimulants in saliva of 20 healthy subjects and 20 subjects with periodontal disease. RESULTS: Median soluble stimulants of TLR2 and TLR4 were significantly higher in saliva of periodontitis patients compared with saliva of healthy subjects; 3450 versus 77 ng/ml Pam(3) CSK(4) equivalents (p<0.0001) and 138 versus 7 ng/ml LPS equivalents, respectively (p<0.0001). Salivary TLR stimulant levels remained relatively stable in healthy subjects over several days. Six strains of oral Gram-negative bacteria, including Tannerella forsythensis, Lysobacter enzymogenes, Prevotella intermedia, Prevotella oris and Porphyromonas gingivalis, from a panel of nine examined did not stimulate TLR4 dependent signalling. CONCLUSIONS: Elevated salivary TLR stimulants may represent a novel mechanism by which periodontitis increases the risk of developing cardiovascular disease and insulin resistance. PMID- 21284690 TI - Manometric evaluation of oral function with a hand-held balloon probe. AB - Tongue pressure measured with a disposable hand-held balloon probe has been used for assessing tongue function; however, no diagnostic standard for assessing other oral functions exists currently. In this study, to develop a method for multifactorial manometric evaluation of oral functions, 20 men and 20 women (21 32 years of age) were instructed to apply 7-s maximal voluntary muscular effort on a hand-held balloon probe placed against the anterior and lateral parts of the palate, buccal surface of the molars on the habitual chewing side and labial surface of the anterior teeth for measuring anterior and posterior tongue, cheek and lip pressures (LPs), respectively. Intra-session reproducibility was determined by three repeated measurements, and associations between the obtained and the conventional data on oral diadochokinesis were tested. The men exhibited higher values of all the pressure types. Further, both genders showed a positive correlation between anterior and posterior tongue pressures (PTPs) (P < 0.05), but only the women exhibited positive correlations between anterior tongue and cheek pressures, cheek and PTPs, anterior tongue and LPs, and cheek and LPs (P < 0.05). No statistically significant correlation was found between the pressures and the number of syllabic articulations, except between LP and the number of /pa/ articulations in the women (r = 0.524, P < 0.05). In conclusion, the balloon probe method enables objective manometric evaluation of oral functions and could be an effective tool for clinical epidemiological studies and evidence-based decision-making in nursing care. PMID- 21284691 TI - Dual blockade of the renin-angiotensin system with angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). PMID- 21284692 TI - Methods in pharmacology: measurement of cardiac output. AB - Many methods of cardiac output measurement have been developed, but the number of methods useful for human pharmacological studies is limited. The 'holy grail' for the measurement of cardiac output would be a method that is accurate, precise, operator independent, fast responding, non-invasive, continuous, easy to use, cheap and safe. This method does not exist today. In this review on cardiac output methods used in pharmacology, the Fick principle, indicator dilution techniques, arterial pulse contour analysis, ultrasound and bio-impedance are reviewed. PMID- 21284694 TI - Clinical pharmacology of analgesic medicines in older people: impact of frailty and cognitive impairment. AB - Pain is highly prevalent in frail older people who often have multiple co morbidities and multiple medicines. Rational prescribing of analgesics in frail older people is complex due to heterogeneity in drug disposition, comorbid medical conditions, polypharmacy and variability in analgesic response in this population. A critical issue in managing older people with pain is the need for judicious choice of analgesics based on a comprehensive medical and medication history. Care is needed in the selection of analgesic medicine to avoid drug-drug or drug-disease interactions. People living with dementia and cognitive impairment have suboptimal pain relief which in part may be related to altered pharmacodynamics of analgesics and challenges in the systematic assessment of pain intensity in this patient group. In the absence of rigorously controlled trials in frail older people and those with cognitive impairment a pharmacologically-guided approach can be used to optimize pain management which requires a systematic understanding of the pharmacokinetics and pharmacodynamics of analgesics in frail older people with or without changes in cognition. PMID- 21284696 TI - Metformin for olanzapine-induced weight gain: a systematic review and meta analysis. AB - Olanzapine is an atypical antipsychotic that is useful in schizophrenia and bipolar affective disorder, but its use is associated with troublesome weight gain and metabolic syndrome. A variety of pharmacological agents has been studied in the efforts to reverse weight gain induced by olanzapine, but current evidence is insufficient to support any particular pharmacological approach. We conducted a systematic review and meta-analysis of randomized controlled trials of metformin for the treatment of olanzapine-induced weight gain. Systematic review of the literature revealed 12 studies that had assessed metformin for antipsychotic-induced weight gain. Of these, four studies (n= 105) met the review inclusion criteria and were included in the final analysis. Meta-analysis was performed to see the effect size of the treatment on body weight, waist circumference and body-mass index (BMI). Weighted mean difference (WMD) for body weight was 5.02 (95% CI 3.93, 6.10) kg lower with metformin as compared with placebo at 12 weeks. For waist circumference, the test for heterogeneity was significant (P= 0.00002, I(2) = 85.1%). Therefore, a random effects model was used to calculate WMD, which was 1.42 (95% CI 0.29, 3.13) cm lower with metformin as compared with placebo at 12 weeks. For BMI, WMD was 1.82 (95% CI 1.44, 2.19) kg m(-2) lower with metformin as compared with placebo at 12 weeks. Existing data suggest that short term modest weight loss is possible with metformin in patients with olanzapine-induced weight gain. PMID- 21284693 TI - Functional biomarkers for the acute effects of alcohol on the central nervous system in healthy volunteers. AB - The central nervous system (CNS) effects of acute alcohol administration have been frequently assessed. Such studies often use a wide range of methods to study each of these effects. Unfortunately, the sensitivity of these tests has not completely been ascertained. A literature search was performed to recognize the most useful tests (or biomarkers) for identifying the acute CNS effects of alcohol in healthy volunteers. All tests were grouped in clusters and functional domains. Afterwards, the effect of alcohol administration on these tests was scored as improvement, impairment or as no effect. Furthermore, dose-response relationships were established. A total number of 218 studies, describing 342 different tests (or test variants) were evaluated. Alcohol affected a wide range of CNS domains. Divided attention, focused attention, visuo-motor control and scales of feeling high and of subjective drug effects were identified as the most sensitive functional biomarkers for the acute CNS effects of alcohol. The large number of CNS tests that are used to determine the effects of alcohol interferes with the identification of the most sensitive ones and of drug-response relationships. Our results may be helpful in selecting rational biomarkers for studies investigating the acute CNS effects of alcohol or for future alcohol- interaction studies. PMID- 21284695 TI - Diabetes mellitus and Alzheimer's disease: shared pathology and treatment? AB - Epidemiological and basic science evidence suggest a possible shared pathophysiology between type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD). It has even been hypothesized that AD might be 'type 3 diabetes'. The present review summarizes some of the evidence for the possible link, putative biochemical pathways and ongoing clinical trials of antidiabetic drugs in AD patients. The primary and review literature were searched for articles published in peer-reviewed sources that were related to a putative connection between T2DM and AD. In addition, public sources of clinical trials were searched for the relevant information regarding the testing of antidiabetic drugs in AD patients. The evidence for a connection between T2DM and AD is based upon a variety of diverse studies, but definitive biochemical mechanisms remain unknown. Additional study is needed to prove the existence or the extent of a link between T2DM and AD, but sufficient evidence exists to warrant further study. Presently, AD patients might benefit from treatment with pharmacotherapy currently used to treat T2DM and clinical trials of such therapy are currently underway. PMID- 21284697 TI - Transcutaneous nicotine does not prevent postoperative nausea and vomiting: a randomized controlled trial. AB - AIMS: There is empirical evidence that smokers are less likely to suffer from postoperative nausea and vomiting (PONV). We sought to investigate whether transcutaneus nicotine prevents PONV. METHODS: Non-smokers receiving general anaesthesia for surgery were randomly allocated to Nicotinell Patch 10cm(2) (TTS 10), containing 17.5mg of nicotine (average delivery rate, 7mg 24h(-1) ) or matching placebo patch. Patches were applied 1h before surgery and were left in situ until 24h after surgery (or until the first PONV symptoms occurred). RESULTS: We randomized 90 patients (45 nicotine, 45 placebo). In the post anaesthetic care unit, the incidence of nausea was 22.2% with nicotine and 24.4% with placebo (P= 0.80), and the incidence of vomiting was 20.0% with nicotine and 17.8% with placebo (P= 0.78). Cumulative 24h incidence of nausea was 42.2% with nicotine and 40.0% with placebo (P= 0.83), and of vomiting was 31.1% with nicotine and 28.9% with placebo (P= 0.81). PONV episodes tended to occur earlier in the nicotine group. Postoperative headache occurred in 17.8% of patients treated with nicotine and in 15.6% with placebo (P= 0.49). More patients receiving nicotine reported a low quality of sleep during the first postoperative night (26.7% vs. 6.8% with placebo; P= 0.01). CONCLUSIONS: Non-smokers receiving a prophylactic nicotine patch had a similar incidence of PONV during the first 24h and tended to develop PONV symptoms earlier compared with controls. They had a significantly increased risk of insomnia during the first postoperative night. PMID- 21284698 TI - Population pharmacokinetic model and Bayesian estimator for two tacrolimus formulations--twice daily Prograf and once daily Advagraf. AB - AIM: To investigate the differences in the pharmacokinetics of Prograf and the prolonged release formulation Advagraf and to develop a Bayesian estimator to estimate tacrolimus inter-dose area under the curve (AUC) in renal transplant patients receiving either Prograf or Advagraf. METHODS: Tacrolimus concentration time profiles were collected, in adult renal transplant recipients, at weeks 1 and 2, and at months 1, 3 and 6 post-transplantation from 32 Prograf treated patients, and one profile was collected from 41 Advagraf patients more than 12 months post-transplantation. Population pharmacokinetic (popPK) parameters were estimated using nonmem. In a second step, the popPK model was used to develop a single Bayesian estimator for the two tacrolimus formulations. RESULTS: A two compartment model with Erlang absorption (n= 3) and first-order elimination best described the data. In Advagraf patients, a bimodal distribution was observed for the absorption rate constant (K(tr) ): one group with a K(tr) similar to that of Prograf treated patients and the other group with a slower absorption. A mixture model for K(tr) was tested to describe this bimodal distribution. However, the data were best described by the nonmixture model including covariates (cytochrome P450 3A5, haematocrit and drug formulation). Using this model and tacrolimus concentrations measured at 0, 1 and 3h post-dose, the Bayesian estimator could estimate tacrolimus AUC accurately (bias = 0.1%) and with good precision (8.6%). CONCLUSIONS: The single Bayesian estimator developed yields good predictive performance for estimation of individual tacrolimus inter-dose AUC in Prograf and Advagraf treated patients and is suitable for clinical practice. PMID- 21284699 TI - Riluzole pharmacokinetics in young patients with spinal muscular atrophy. AB - AIMS: The objective of the present study was to assess the pharmacokinetics of riluzole in patients with spinal muscular atrophy (SMA). METHODS: Fourteen patients were enrolled in an open-label, nonrandomized and repeat-dose pharmacokinetic study. All participants were assigned to receive 50mg riluzole orally for 5 days. Riluzole plasma concentrations were determined from samples obtained at day 5. RESULTS: The pharmacokinetic analysis demonstrated that a dose of 50mg once a day was sufficient to obtain a daily total exposure [AUC(0,24h)=2257ng ml(-1) h] which was comparable with results obtained in adult healthy volunteers or ALS patients in whom a dose of 50mg twice a day is recommended. The pharmacokinetic simulation demonstrated that the administration of 50mg twice a day could result in higher concentrations, hence reduced safety margin. CONCLUSION: The dose of 50mg once a day was chosen for the clinical trial evaluating the efficacy of riluzole in SMA patients. PMID- 21284700 TI - The effect of rectal ozone on the portal vein oxygenation and pharmacokinetics of propranolol in liver cirrhosis (a preliminary human study). AB - AIM: The aim of this study was to investigate the effect of rectal ozone on portal vein oxygenation and the pharmacokinetic changes of propranolol in patients with liver cirrhosis. METHODS: Fifteen patients with liver cirrhosis were included They were given a fixed oral dose of propranolol 80mg on the morning of day 1 after overnight fasting. Blood samples were collected at fixed time intervals for 24h. Patients were given 12 sessions of rectal ozone of 300ml of 40% ozone/oxygen mixture. On day 14 another oral dose of 80mg propranolol was given and blood samples were collected as on day 1. Plasma concentrations of propranolol were measured by HPLC. Portal vein oxygen tension and saturation were measured before and after rectal ozone. RESULTS: Plasma concentrations of propranolol were reduced after ozone therapy with pronounced decreases in the maximum plasma concentration and the area under the plasma concentration-time curve. The changes were consistent with a decrease in propranolol bioavailability. There was a decrease in the elimination half-life and mean residence time. Portal vein oxygenation significantly increased after rectal ozone. CONCLUSIONS: The changes in the pharmacokinetics of propranolol probably reflect an increase in the rate and extent of its metabolism resulting from improved portal vein oxygenation attributable to the ozone therapy. The present work highlights that ozone can be an alternative medical measure to improve portal vein oxygenation in liver cirrhosis. PMID- 21284701 TI - Integrated analysis of preclinical data to support the design of the first in man study of LY2181308, a second generation antisense oligonucleotide. AB - AIMS: To predict the concentration and target inhibition profiles of the survivin inhibitor antisense oligonucleotide LY2181308 in humans. METHODS: An indirect pharmacokinetic/pharmacodynamic (PK/PD) model was built to predict the inhibition of survivin mRNA and protein in humans following LY2181308 dosing. Plasma and tissue PK data from cynomolgus monkeys were analyzed by non-linear mixed effect modelling techniques. Human PK parameters were predicted using allometric scaling. Assumptions about the pharmacodynamic parameters were made based upon the target and tumour growth inhibition data from mouse xenograft models. This enabled the prediction of the clinical PK/PD profiles. RESULTS: Following a 750 mg dose, LY2181308 tumour concentrations ranging from 18.8 to 54ugg(-1) were predicted to lead to 50 to 90% target inhibition. In humans, LY2181308 tumour concentrations fro 13.9 to 52.8ugg(-1) (n=4, LY2181308 750mg) were observed associated with a median survivin mRNA and protein inhibition of 20%+/-34 (SD) (n=9) and 23%+/-63 (SD) (n=10), respectively. The human PK parameters were adequately estimated: central V(d) , 4.09 l (90% CI, 3.6, 4.95), distribution clearances, 2.54 (2.36, 2.71), 0.0608 (0.033, 0.6) and 1.67 (1.07, 2.00)lh(-1) , peripheral V(d) s, 25 900 (19 070, 37 200), 0.936 (0.745, 2.07) and 2.51 (1.01, 2.922)l, mean elimination clearance 23.1lh(-1) (5.6, 33.4) and mean terminal half life, 32.7 days (range 22-52 days). CONCLUSION: The model reasonably predicted LY2181308 PK in humans. Overall, the integration of preclinical PK/PD data enabled to appropriately predict dose and dosing regimen of LY2181308 in humans with pharmacologically relevant survivin inhibition achieved at 750mg. PMID- 21284702 TI - Evaluation of pharmacokinetic parameters and dipeptidyl peptidase-4 inhibition following single doses of sitagliptin in healthy, young Japanese males. AB - AIMS: Sitagliptin is a selective inhibitor of dipeptidyl peptidase-4 (DPP-4) used to treat type 2 diabetes. The present aim was to evaluate pharmacokinetic (PK), pharmacodynamic (PD) and safety characteristics of sitagliptin following single doses in healthy, young Japanese males. METHODS: In this alternating two-panel, randomized, controlled double-blind study, six healthy Japanese male subjects (aged 20-46 years) in each panel received single oral doses of 5-400mg sitagliptin and two received placebo. Plasma and urine drug concentrations were measured from 0-48h post dose and plasma DPP-4 inhibition from 0-24h post dose. The results were compared with historical data from young, healthy non-Japanese males. RESULTS: Plasma concentrations of sitagliptin increased approximately in proportion to dose; maximum concentrations occurred 2-6h post-dose. The mean apparent terminal half-life for plasma sitagliptin was 9-14h, with the half-life slightly decreasing as the dose increased. The mean dose fraction excreted unchanged in the urine was 0.73-1.00. Ingestion of a traditional Japanese breakfast prior to dosing had only a minor effect on PK parameters. After correction for dilution and competition effects during assay, doses of sitagliptin >=50mg resulted in weighted average DPP-4 inhibition from 0-24h post dose >94% (without correction, >78%). No clinically meaningful differences in PK and DPP-4 inhibition parameters were found between Japanese and non-Japanese subjects. Sitagliptin was generally well tolerated and there were no serious adverse experiences or episodes of hypoglycaemia. CONCLUSIONS: The PK and PD findings from this study are consistent with once daily dosing of sitagliptin in Japanese patients with type 2 diabetes. PMID- 21284703 TI - Equilibrative nucleoside transporter 1 genotype, cytidine deaminase activity and age predict gemcitabine plasma clearance in patients with solid tumours. AB - AIM: Gemcitabine (GEM) enters normal and tumour cells via concentrative (CNT) and equilibrative nucleoside transporters (ENT) and is subsequently deaminated to the inactive difluorodeoxyurine (dFdU) by cytidine deaminase (CDA). The aim of our study was to ascertain whether the nucleoside transporter genotype and the CDA activity phenotype can predict total GEM plasma clearance. METHODS: Forty-seven patients received GEM 1000-1250mgm(-2) i.v. over 30min. Plasma concentrations of GEM and dFdU were measured and individual pharmacokinetic profiles were determined. CDA activity was measured ex vivo in plasma samples. The two most common hENT1 and hCNT1 polymorphisms were determined from genomic DNA. RESULTS: Multivariate analysis revealed that GEM plasma clearance (CL) was positively correlated with the end of infusion dFdU : GEM ratio (P < 0.0001), which is a marker of in vivo CDA activity. The ENT1 genotype characterized by high transport capacity (G/G) and age were inversely correlated with CL (P= 0.027 and 0.048, respectively). A strong correlation was found between end of infusion GEM concentration and area under the concentration-time curve from time 0 to infinity (AUC(0,infinity)) (r(2) = 0.77). CONCLUSIONS: Our results confirm the role of CDA and age on the interindividual variability of GEM CL and show the contribution of the hENT1 genotype for the first time. PMID- 21284704 TI - Kava, the anxiolytic herb: back to basics to prevent liver injury? AB - The use of the anxiolytic herb kava has caused toxic liver injury in Western countries and economic problems in South Pacific Islands due to tthe regulatory ban on kava. This analysis shows poor quality of kava raw material as a cause for its toxicity and suggests preventative measures by going back to the traditional use of kava for the sake of the patients and the South Pacific economy. PMID- 21284706 TI - Trends in co-prescribing of angiotensin converting enzyme inhibitors and angiotensin receptor blockers in Ireland. AB - AIMS: (i) To examine the trends in co-prescribing of angiotensin converting enzyme inhibitor (ACEI) and angiotensin-II receptor blocker (ARB) therapy and (ii) to examine the influence of major clinical trials (CALM, COOPERATE, VALIANT and ONTARGET) on co-prescribing. METHODS: The Irish HSE-Primary Care Reimbursement Services database was used to identify patients >=16 years old co prescribed ACEIs and ARBs between January 2000 and April 2009 (n= 266 554 prescriptions). The rate of prescribing per 1000 general medical services (GMS) scheme population was calculated for each month. Patients with diabetes, hypertension, heart failure and ischaemic heart disease were also identified by prescribing of certain medications. A linear trend test was used to examine prescribing trends. Logistic regression was used to examine prescribing according to patient characteristics. The effects of the major trials on prescribing were examined using segmented regression analysis for 12 months pre- and post-trials. RESULTS: There was a significant linear trend in overall ACEI and ARB co prescribing over the study period (P < 0.001). Rate of co-prescribing in January 2000 and April 2009 was 0.16 and 5.72, per 1000 eligible population, respectively. Those 45-64 years old (OR = 2.88, 95% confidence interval (CI) 2.71, 3.06) and >=65 years (OR = 2.52, 95% CI 2.36, 2.68) were more likely to receive dual therapy compared with those <45 years old. Those with hypertension (OR = 8.85, 95% CI 8.45, 9.27), diabetes (OR = 4.10, 95% CI 3.97, 4.23) and heart failure (OR = 1.78, 95% CI 1.72, 1.84) were more likely to receive dual therapy compared with the general population. Significant increases in prescribing were observed only after the CALM (P= 0.03) and VALIANT (P= 0.007) trials. CONCLUSION: Increased co-prescribing of ACEIs and ARBs was observed in Ireland during 2000 09. Prescribing patterns did not appear to be affected by results from major trials. PMID- 21284705 TI - Medication details documented on hospital discharge: cross-sectional observational study of factors associated with medication non-reconciliation. AB - AIMS: Movement into or out of hospital is a vulnerable period for medication safety. Reconciling the medication a patient is using before admission with the medication prescribed on discharge, and documenting any changes (medication reconciliation) is recommended to improve safety. The aims of the study were to investigate the factors contributing to medication reconciliation on discharge, and identify the prevalence of non-reconciliation. METHODS: The study was a cross sectional, observational survey using consecutive discharges from purposively selected services in two acute public hospitals in Ireland. Medication reconciliation, potential for harm and unplanned re-admission were investigated. RESULTS: Medication non-reconciliation was identified in 50% of 1245 inpatient episodes, involving 16% of 9569 medications. The majority of non-reconciled episodes had potential to result in moderate (63%) or severe (2%) harm. Handwritten rather than computerized discharges (adjusted odds ratio (adjusted OR) 1.60, 95% CI 1.11, 2.99), increasing number of medications (adjusted OR 1.26, 95% CI 1.21, 1.31) or chronic illness (adjusted OR 2.08, 95% CI 1.33, 3.24) were associated with non-reconciliation. Omission of endocrine, central nervous system and nutrition and blood drugs was more likely on discharge, whilst omission on admission and throughout inpatient care, without documentation, was more likely for obstetric, gynaecology and urinary tract (OGU) or respiratory drugs. Documentation in the discharge communication that medication was intentionally stopped during inpatient care was less likely for cardiovascular, musculoskeletal and OGU drugs. Errors involving the dose were most likely for respiratory drugs. CONCLUSIONS: The findings inform strategies to facilitate medication reconciliation on discharge from acute hospital care. PMID- 21284707 TI - Improving the quality of drug research or simply increasing its cost? An evidence based study of the cost for data monitoring in clinical trials. AB - AIM: Procedures for verification of data from clinical studies are intended to maintain reliability for clinical trial results. Guidelines or legislations relating to clinical data management are of limited value and no study has yet demonstrated its effectiveness. METHOD: Sponsor queries and dual entry procedures from one CRO on three different phase I trials are analysed on content, impact and cost. RESULT: In this study, sponsor queries and dual entry procedures proved time and cost inefficient in detecting data discrepancies. CONCLUSION: We advocate a more evidence-based approach for enhancing data integrity throughout the process of clinical data management. PMID- 21284708 TI - An alternative view of the role of clinical pharmacology. PMID- 21284709 TI - Japan lags behind the UK in neurological drug approvals. PMID- 21284711 TI - Partial edentulism and removable partial denture design in a dental school population: a survey in Greece. AB - OBJECTIVES: To investigate the pattern of partial edentulism and the most frequent designs of cobalt-chromium removable partial dentures (RPDs), constructed at the Dental School of Athens, Greece. METHODS AND MATERIALS: Five hundred and fifty-three patients, between 42 and 81 years old, mostly males, treated by undergraduate dental students, were included. The survey was based on visual evaluation of master casts and work authorisation to dental technicians. Aspects examined were: Kennedy Classification, modification areas, major connectors, clasping, placement of rest seats and indirect retention. RESULTS: Kennedy Class I was the most common encountered in the maxilla (50.5%) and in the mandible (70%). The most frequent major connectors were the lingual bar (92.6%) and the U-shaped palatal strap (54%). The most common clasp was the Roach (69.2%) in Class I and Class II. In Class III and IV, the most common was the occlusally approaching clasp (55% and 70%). The most frequent location of the rest was mesial of abutment teeth. On the average, 39.5% of Class I RPDs and 58.6% of Class II RPDs had indirect retainers. CONCLUSION: A combination of the two major philosophies of RPD design (biomechanical and hygienic) was evident in the RPDs examined in our study. PMID- 21284712 TI - Examination of denture-cleaning methods based on the quantity of microorganisms adhering to a denture. AB - OBJECTIVES: To investigate effective denture-cleaning methods, we examined the relationships between the quantity of microorganisms adhering to dentures and the use of a denture brush and the frequency of use of a denture cleanser. SUBJECTS AND METHODS: Denture plaque was collected from the mucosal surface of the examined dentures, which were 142 and 80 upper and lower complete dentures, respectively, worn by 96 outpatients (mean age: 71.9 years) of a university hospital and 41 nursing home residents (mean age: 84.8 years). The collected microorganisms were counted in terms of isolated representative colonies that were cultured and identified using standard methods. The use of a denture brush, the frequency of use, and the type and soaking time of denture cleansers as denture-cleaning methods were surveyed. RESULTS: The quantity of microorganisms was significantly lower in dentures of denture brush users than in those of non users in the outpatients (p < 0.01, Mann-Whitney U test). The quantity of microorganisms was significantly lower in the dentures of outpatients who used a denture cleanser daily or 3-4 times a week than in those who used one once or less per month and in the dentures of nursing home residents who used one daily than in those who used one at other frequencies (p < 0.05, Kruskal-Wallis test, followed by Dunn's Multiple Comparison test). CONCLUSION: Within the limitations of this study, it was concluded that the use of a denture brush and daily use of denture cleanser should be recommended to complete dentures wearers as denture cleaning methods that effectively reduce the quantity of microorganisms adhering to dentures. PMID- 21284713 TI - Effect of water storage and heat treatment on the cytotoxicity of soft liners. AB - OBJECTIVE: To evaluate the effect of water storage time on the cytotoxicity of soft liners. METHODS: Sample discs of soft liners Dentusoft, Dentuflex, Trusoft, Ufi-Gel-P and denture base acrylic resin Lucitone-550 were prepared and divided into four groups: GN: No treatment, G24: Stored in water at 37 degrees C for 24 h; G48: Stored in water at 37 degrees C for 48 h, GHW: Immersed in water at 55 degrees C for 10 min. To analyse the cytotoxic effect, three samples of each group were placed in tubes with Dubelcco's Modified Eagle Mediums and incubated at 37 degrees C for 24 h. During this period, the toxic substances were leached to the culture medium. The cytotoxicity was analysed quantitatively by the incorporation of radioactivity (3)H-thymidine checking the number of viable cells (synthesis of DNA). The data were statistically analysed using two-way anova and Tukey's honestly significant difference tests (alpha = 0.05). RESULTS: Treatments did not reduce the cytotoxicity effect of the soft liners (p > 0.05). It was found that Ufi-Gel-P had a non-cytotoxic effect, Trusoft had a slightly cytotoxic effect, Dentuflex had a moderated cytotoxic effect, Dentusoft alternated between slightly and non-cytotoxic effect, and Lucitone-550 had non-cytotoxic effect when stored in water for 48 h. CONCLUSION: The effect of water storage and the heat treatment did not reduce the cytotoxicity of the soft liners. PMID- 21284714 TI - Cognitive and linguistic abnormalities in benign childhood epilepsy with centrotemporal spikes. AB - AIM: To assess the cognitive function and language ability in children with benign partial epilepsy with centrotemporal spikes. METHODS: Twenty-five patients with benign partial epilepsy with centrotemporal spikes were included. They were divided into two subgroups. Group I: 10 patients with rolandic focus who were not treated. Group II: 15 patients with rolandic focus receiving treatment. A third Group of 12 healthy subjects have been studied. All children underwent standardized neuropsychological testing: electroencephalogram recording, Wechsler Intelligence Scale for Children-revised, Peabody Picture Vocabulary Test-III (PPVT-III) and Boston Naming Test (BNT), both during active disease (T1) and 2 years after recovery from epilepsy (T2). RESULTS: At T1 evaluation, no significant differences in group I and II patients about general intelligence, when compared with controls, were found. Group I and II patients were impaired with respect to controls in the receptive and expressive vocabulary evaluated with PCVT-III and BNT, respectively. At T2 evaluation, group I and II patients showed a normalization of the language abnormalities. CONCLUSION: Deficits of speech-related abilities can be detected in children with this type of epilepsy: these dysfunctions seem to be independent of the effects of antiepileptic treatment and are reversible after remission of epilepsy. PMID- 21284715 TI - Incidence and predisposing factors for severe disease in previously healthy term infants experiencing their first episode of bronchiolitis. AB - AIM: To determine the incidence and predisposing factors for severe bronchiolitis in previously healthy term infants <12 months of age experiencing their first episode of bronchiolitis. METHODS: Epidemiological, clinical and virological data were prospectively collected. Severity was assessed by the need for ventilatory support. RESULTS: Of the 310 infants enrolled, 16 (5.1%) presented with severe bronchiolitis requiring ventilatory support (11 since admission). Compared with infants with less severe bronchiolitis, infants with severe disease presented with lower birth weight, gestational age, postnatal weight and postnatal age, and were more likely to be born by cesarian section. C-reactive protein positive results (>0.8 mg/dL) and pulmonary consolidation on chest X-ray were more common among infants with severe disease. Severity was independently associated with younger age on admission <30 days, respiratory syncytial virus (RSV) infection and lymphocyte counts < 3200/MUL. No significant differences were found between epidemiologic variables. CONCLUSIONS: Severe bronchiolitis is uncommon in previously healthy term infants <12 months of age and when present develops soon after disease onset. Severity is predicted by young age and RSV carriage, whereas epidemiologic variables seem less likely to intervene. PMID- 21284716 TI - Testosterone and the child (0-12 years) with Klinefelter syndrome (47XXY): a review. AB - AIM: To review the evidence base for providing testosterone therapy in the infant and prepubertal child with Klinefelter syndrome (KS). METHODS: Major databases were searched to identify articles that addressed the role of testosterone in the development of the male foetus with and without KS and that characterized testicular function in infants with KS. RESULTS: Infants with KS have been shown to have an increased frequency of clinical features consistent with deficient testosterone production. However, there are conflicting results regarding whether testosterone levels are low or normal. No direct data address the outcome of therapy in the prepubertal child. CONCLUSION: There is an absence of data that directly address the risks and benefits of testosterone therapy in prepubertal children with KS outside of the entity of microphallus. At this time, there is no other documented benefit for testosterone therapy in these children. PMID- 21284717 TI - Children with screening-detected coeliac disease show increased levels of nitric oxide products in urine. AB - AIM: Increased concentration of nitric oxide (NO) metabolites, nitrite and nitrate, in the urine is a strong indication of ongoing small intestinal inflammation, which is a hallmark of the enteropathy of coeliac disease (CD). It has previously been shown that children with symptomatic, untreated CD have increased levels of NO oxidation products in their urine. The aim of this study was to investigate whether screening-detected, asymptomatic coeliac children display the same urinary nitrite/nitrate pattern. METHODS: In a multicenter screening study, serum samples were collected from 7208 12-year-old children without previously diagnosed CD. Sera were analysed for anti-human tissue transglutaminase (tTG) of isotype IgA. Small bowel biopsy was performed in antibody-positive children, yielding 153 new cases of CD. In the screening detected individuals, the sum of nitrite and nitrate concentrations in the urine was analysed and used as an indicator of NO production. For comparison, 73 children with untreated, symptomatic CD were studied. RESULTS: The nitrite/nitrate levels in children with screening-detected CD and those with untreated symptomatic CD did not differ significantly. Both groups had significantly increased urinary nitrite/nitrate concentrations compared to the children with normal small bowel biopsy (p < 0.001). CONCLUSION: Children with screening-detected CD have increased production of NO just as children with untreated symptomatic CD. High NO metabolite levels in the urine may indicate a pathogenetic feature of CD and be a marker of major clinical importance. PMID- 21284718 TI - Monitoring of protein catabolism in neonates and young infants post-cardiac surgery. AB - AIMS: To evaluate cell catabolism by balance of nitrogen and phosphate, and creatinine excretion in children post-cardiac surgery; to establish protein and energy requirements to minimize catabolism; and to assess nutritional therapy by following these parameters and serial anthropometric measurements. METHODS: A prospective observational study of children with congenital heart disease undergoing cardiac surgery. Blood samples and 24-h urine collections were obtained postoperatively for creatinine measurement and nitrogen and phosphate balance. Anthropometric measurements (weight, mid-arm muscle circumference and triceps skinfold thickness) were obtained preoperatively and at paediatric intensive care unit and hospital discharge. RESULTS: Eleven children were studied for 3-10 postoperative days. Anabolism was associated with higher protein and energy intakes compared to catabolism (1.1 vs. 0.1 g/kg/day and 54 vs. 17 kcal/kg/day, respectively). On days with anabolism, phosphate balance was greater compared with that on days with catabolism. Daily creatinine excretion did not correlate with protein balance. Anthropometric measurements did not change significantly over time. CONCLUSIONS: Children with congenital heart disease undergoing cardiac surgery achieved anabolism with >55 kcal/kg/day and >1 g/kg/day of protein. Balance of phosphate was useful to monitor cell breakdown. Anthropometric measurements were not valuable to evaluate nutritional therapy in this population. PMID- 21284719 TI - Neurological complications and pandemic influenza A (H1N1) virus infection. AB - AIM: To report on a different clinical course of pandemic influenza A (H1N1) infection among children who were neurologically impaired before the acute onset of the disease, in comparison with children who were neurologically intact. METHODS: In a period of 6 months, six children with neurological complications associated with pandemic A (H1N1) infection were identified in a single institution paediatric emergency room. The children suffered from seizures or altered mental status during pandemic A (H1N1) infection. All children underwent extensive clinical and laboratory assessment. Three children were neurologically impaired before the acute onset of the H1N1 infection. The other three were neurologically intact before the acute viral infection. RESULTS: In all six patients, pandemic influenza A (H1N1) viral RNA was detected in nasopharyngeal specimens but none in the cerebrospinal fluid. Five children fully recovered or returned to baseline at discharge. The clinical course of the disease and recovery were different between the children who were neurologically impaired before the acute viral infection and those who were neurologically intact. CONCLUSIONS: It is possible that children with various neurological conditions are in a higher risk to develop further neurological complications during pandemic influenza A (H1N1) infection. PMID- 21284720 TI - Indomethacin prophylaxis revisited: changing practice and supportive evidence. AB - Important short-term intermediate outcomes such as patent ductus arteriosus (PDA), severe intraventricular haemorrhage, surgical ligation of PDA and serious pulmonary haemorrhage correlate with worse neurosensory outcomes in extreme low birth weight infants. Indomethacin prophylaxis has been shown to significantly prevent such outcomes. However, this positive effect did not translate into neither prevention of bronchopulmonary dysplasia nor long-term neurosensory outcome. The indomethacin prophylaxis story is indeed a puzzling one to neonatal practitioners. We present a summary of evidence and possible explanations to the lack of appreciated long-term effect of indomethacin prophylaxis. As the trial of indomethacin prophylaxis for preterms trial is a major contributor to current evidence, a detailed critical analysis of its methodology is presented. Methodological concerns such as the use of a composite outcome, statistical power, anticipated side effects of indomethacin prophylaxis and lack of predictive validity of cognitive delay measurements are presented. CONCLUSION: Conclusive evidence of indomethacin prophylaxis use in extreme low birth weight infants is still lacking. Future research should put more emphasis on parental preferences, synergistic effect of indomethacin prophylaxis and fluid restriction and early targeted approach to PDA management. PMID- 21284721 TI - A case of neonatal intrapericardial teratoma. Clinical and pathological findings. AB - AIM: It is of general agreement that complete surgical removal after birth of intrapericardial fetal teratomas is needed, because of the risk of severe cardiovascular and respiratory distress, related to the mass size, location and secondary pericardial effusion. Histological examination generally shows mature aspect of cells and tissues. METHODS: We present a case of grade II immature pericardial teratoma, diagnosed in utero and completely removed after birth. RESULTS: Even surgical removal was complete, histological aspects raised the need of long follow-up with serial alpha-fetoprotein determinations. CONCLUSION: A neonatal grade II immature pericardial teratoma was completely removed after birth. The follow-up of the patient, until 10 months of life, was good with no recurrence of the disease. PMID- 21284722 TI - Low-dose thiazide diuretics in children with idiopathic renal hypercalciuria. AB - AIM: To evaluate the therapeutic effect of hydrochlorothiazide in idiopathic renal hypercalciuria. METHODS: We retrospectively analysed the data of 28 children (6.0+/-4.1 years, M:F=19:9) diagnosed as having idiopathic renal hypercalciuria from the years 1991 to 2008. The dose of hydrochlorothiazide was initially 0.5 mg/kg/day and gradually increased to achieve the appropriate hypocalciuric effect (urinary calcium/creatinine<0.2 mg/mg) in some unresponsive patients. RESULTS: Twenty-two patients (79%) had gross haematuria, 6 (21%) microscopic haematuria, 2 left flank pain, 6 (21%) urolithiasis and 9 (32%) urinary tract infection at the diagnosis of hypercalciuria. The low doses (0.5 mg/kg/day) of hydrochlorothiazide reduced urinary calcium excretion in 25 patients (89%) and 3 (11%) required the increased doses (1-2 mg/kg/day). Haematuria and urolithiasis gradually resolved in accordance with the improvement of hypercalciuria. Nineteen patients (68%) maintaining hypocalciuria during hydrochlorothiazide therapy were discontinued after 12.5+/-5.3 months of treatment. Eleven of the 19 patients maintained normocalciuria, while 8 showed increased urinary calcium excretion at 2.9+/-2.3 months after treatment was stopped, requiring thiazide retreatment. CONCLUSION: Our results suggest that low dose (0.5 mg/kg/day) of hydrochlorothiazide may be safe and effective in controlling renal hypercalciuria in children. PMID- 21284723 TI - Health-related quality of life of Estonian adolescents: reliability and validity of the PedsQLTM 4.0 Generic Core Scales in Estonia. AB - AIM: The main aim of this study was to examine the reliability and validity of the Pediatric Quality of Life InventoryTM 4.0 (PedsQLTM 4.0) Generic Core Scales among Estonian adolescents. Gender differences in health-related quality of life (HRQoL) were also investigated. METHODS: The 654 adolescents (309 boys and 345 girls) aged 13-14 years (M age = 13.57 years, SD = 0.62) completed Estonian version of the PedsQLTM 4.0. RESULTS: Results of the confirmatory factor analysis for a five-factor model of the Estonian version of PedsQLTM 4.0 approached the criteria of acceptable fit after setting error covariance to be free between some of the items within physical health, emotional functioning and social functioning subscales. Cronbach's alpha coefficients exceeded the minimum criterion of 0.70 for all subscales except for days missed from school because of illness subscale. With regard to gender differences, consistent with previous studies, girls reported lower level on total score of HRQoL as well as its aspects of physical health, emotional functioning and psychosocial health. CONCLUSION: The present study revealed that after some modifications, the PedsQLTM 4.0 could be considered as suitable instrument to measure HRQoL among Estonian adolescents. PMID- 21284724 TI - Issues and influences on sexual violence within the adolescent population. PMID- 21284725 TI - The sexual safety of adolescents. AB - In this article, the authors review issues that affect the sexual safety of adolescents. First and foremost, these issues include risks for unintended pregnancy and sexually transmitted infections. Clinicians also need to understand other critical issues that affect sexual safety. These include adolescent dating patterns, decision making, communication and negotiation skills, social and environmental influences, and risks related to violence. Suggestions for clinical interventions to promote sexual safety are discussed. PMID- 21284726 TI - Media and technology in adolescent sexual education and safety. AB - Media play an important role in the lives of adolescents, providing them with opportunities for education and socialization. Media content is increasingly permeated with violence and sexual references that can be highly influential as adolescents continue the developmental process. Providing patient education is one of the cornerstones of nursing practice, and nurses are ideally suited to affect adolescent and parental education about the sexual and violent content of media. PMID- 21284727 TI - Sex trafficking and the exploitation of adolescents. AB - Human trafficking affects a surprisingly large number of adolescents around the globe. Women and girls make up the majority of sex trafficking victims. Nurses must be aware of sex trafficking as a form of sexual violence in the adolescent population. Nurses can play a role in identifying, intervening, and advocating for victims of human trafficking as they currently do for patients that are the victims of other types of violent crimes. PMID- 21284728 TI - Toward a management framework for networks of protected areas in the face of climate change. AB - Networks of sites of high importance for conservation of biological diversity are a cornerstone of current conservation strategies but are fixed in space and time. As climate change progresses, substantial shifts in species' ranges may transform the ecological community that can be supported at a given site. Thus, some species in an existing network may not be protected in the future or may be protected only if they can move to sites that in future provide suitable conditions. We developed an approach to determine appropriate climate-change adaptation strategies for individual sites within a network that was based on projections of future changes in the relative proportions of emigrants (species for which a site becomes climatically unsuitable), colonists (species for which a site becomes climatically suitable), and persistent species (species able to remain within a site despite the climatic change). Our approach also identifies key regions where additions to a network could enhance its future effectiveness. Using the sub-Saharan African Important Bird Area (IBA) network as a case study, we found that appropriate conservation strategies for individual sites varied widely across sub-Saharan Africa, and key regions where new sites could help increase network robustness varied in space and time. Although these results highlight the potential difficulties within any planning framework that seeks to address climate-change adaptation needs, they demonstrate that such planning frameworks are necessary, if current conservation strategies are to be adapted effectively, and feasible, if applied judiciously. PMID- 21284729 TI - Effects of road networks on bird populations. AB - One potential contributor to the worldwide decline of bird populations is the increasing prevalence of roads, which have several negative effects on birds and other vertebrates. We synthesized the results of studies and reviews that explore the effects of roads on birds with an emphasis on paved roads. The well-known direct effects of roads on birds include habitat loss and fragmentation, vehicle caused mortality, pollution, and poisoning. Nevertheless, indirect effects may exert a greater influence on bird populations. These effects include noise, artificial light, barriers to movement, and edges associated with roads. Moreover, indirect and direct effects may act synergistically to cause decreases in population density and species richness. Of the many effects of roads, it appears that road mortality and traffic noise may have the most substantial effects on birds relative to other effects and taxonomic groups. Potential measures for mitigating the detrimental effects of roads include noise-reduction strategies and changes to roadway lighting and vegetation and traffic flow. Road networks and traffic volumes are projected to increase in many countries around the world. Increasing habitat loss and fragmentation and predicted species distribution shifts due to climate change are likely to compound the overall effects of roads on birds. PMID- 21284730 TI - Population viability analysis with species occurrence data from museum collections. AB - The most comprehensive data on many species come from scientific collections. Thus, we developed a method of population viability analysis (PVA) in which this type of occurrence data can be used. In contrast to classical PVA, our approach accounts for the inherent observation error in occurrence data and allows the estimation of the population parameters needed for viability analysis. We tested the sensitivity of the approach to spatial resolution of the data, length of the time series, sampling effort, and detection probability with simulated data and conducted PVAs for common, rare, and threatened species. We compared the results of these PVAs with results of standard method PVAs in which observation error is ignored. Our method provided realistic estimates of population growth terms and quasi-extinction risk in cases in which the standard method without observation error could not. For low values of any of the sampling variables we tested, precision decreased, and in some cases biased estimates resulted. The results of our PVAs with the example species were consistent with information in the literature on these species. Our approach may facilitate PVA for a wide range of species of conservation concern for which demographic data are lacking but occurrence data are readily available. PMID- 21284731 TI - Understanding and estimating effective population size for practical application in marine species management. AB - Effective population size (N(e)) determines the strength of genetic drift in a population and has long been recognized as an important parameter for evaluating conservation status and threats to genetic health of populations. Specifically, an estimate of N(e) is crucial to management because it integrates genetic effects with the life history of the species, allowing for predictions of a population's current and future viability. Nevertheless, compared with ecological and demographic parameters, N(e) has had limited influence on species management, beyond its application in very small populations. Recent developments have substantially improved N(e) estimation; however, some obstacles remain for the practical application of N(e) estimates. For example, the need to define the spatial and temporal scale of measurement makes the concept complex and sometimes difficult to interpret. We reviewed approaches to estimation of N(e) over both long-term and contemporary time frames, clarifying their interpretations with respect to local populations and the global metapopulation. We describe multiple experimental factors affecting robustness of contemporary N(e) estimates and suggest that different sampling designs can be combined to compare largely independent measures of N(e) for improved confidence in the result. Large populations with moderate gene flow pose the greatest challenges to robust estimation of contemporary N(e) and require careful consideration of sampling and analysis to minimize estimator bias. We emphasize the practical utility of estimating N(e) by highlighting its relevance to the adaptive potential of a population and describing applications in management of marine populations, where the focus is not always on critically endangered populations. Two cases discussed include the mechanisms generating N(e) estimates many orders of magnitude lower than census N in harvested marine fishes and the predicted reduction in N(e) from hatchery-based population supplementation. PMID- 21284732 TI - Investigating and managing the rapid emergence of white-nose syndrome, a novel, fatal, infectious disease of hibernating bats. AB - White-nose syndrome (WNS) is a fatal disease of bats that hibernate. The etiologic agent of WNS is the fungus Geomyces destructans, which infects the skin and wing membranes. Over 1 million bats in six species in eastern North America have died from WNS since 2006, and as a result several species of bats may become endangered or extinct. Information is lacking on the pathogenesis of G. destructans and WNS, WNS transmission and maintenance, individual and site factors that contribute to the probability of an outbreak of WNS, and spatial dynamics of WNS spread in North America. We considered how descriptive and analytical epidemiology could be used to fill these information gaps, including a four-step (modified) outbreak investigation, application of a set of criteria (Hill's) for assessing causation, compartment models of disease dynamics, and spatial modeling. We cataloged and critiqued adaptive-management options that have been either previously proposed for WNS or were helpful in addressing other emerging diseases of wild animals. These include an ongoing program of prospective surveillance of bats and hibernacula for WNS, treatment of individual bats, increasing population resistance to WNS (through vaccines, immunomodulators, or other methods), improving probability of survival from starvation and dehydration associated with WNS, modifying hibernacula environments to eliminate G. destructans, culling individuals or populations, controlling anthropogenic spread of WNS, conserving genetic diversity of bats, and educating the public about bats and bat conservation issues associated with WNS. PMID- 21284733 TI - Gene expression of transcription factor NFATc1 in periodontal diseases. AB - Periodontitis is a disease of infectious aetiology that causes inflammatory destruction of the tooth-supporting tissues. Activated T cells are central to the pathogenesis of the disease, by producing receptor activator of nuclear factor kappaB (NF-kappaB) ligand (RANKL) that stimulates bone resorption. Antigenic activation of T cells is regulated by the induction of transcription factor nuclear factor of activated T cells, cytoplasmic 1 (NFATc1). There is as yet no information on the potential involvement of NFATc1 in periodontal diseases. This study aimed to investigate NFATc1 gene expression levels in periodontal diseases, and analyse the potential correlation with RANKL expression and clinical periodontal parameters. In this cross-sectional study, gingival tissue biopsies were obtained from healthy (n = 10) and periodontally diseased (n = 58) sites. NFATc1 and RANKL gene expression levels in these samples were analysed by quantitative real-time polymerase chain reaction. Compared with healthy subjects, patients with gingivitis, chronic and aggressive periodontitis, exhibited higher NFATc1 expression, which proved to be statistically significant in the periodontitis groups. NFATc1 and RANKL expression levels strongly correlated with each other, and with clinical periodontal parameters. The increased expression of NFATc1 in periodontitis denotes a role for this transcription factor in the pathogenesis of the disease. PMID- 21284734 TI - Immune clearance gastric carcinoma cells in ascites by activating caspase-9 induced apoptosis. AB - Floating gastric adenocarcinoma cells in ascitic fluid are the main cause of peritoneal dissemination. Activation of apoptosis is an important mechanism by which tumor cells are eliminated by the immune surveillance system. Hence, we examined caspase-9 expression and the apoptosis in gastric adenocarcinoma cells in ascitic fluid using immunohistochemistry, real-time polymerase chain reaction and in situ cell death detection kits, flow cytometry. The results revealed strong expression of caspase-9 in 58.49% (31/53) malignant cells and a relatively weak expression of caspase-9 in 41.51% (22/53) malignant cells. The proportion of apoptotic cells in 31 malignant cases with strong caspase-9 expression (35.14 +/- 3.42)% was significantly higher than that in 22 malignant cases with relatively weak caspase-9 expression (17.29 +/- 7.62)% or in mesothelial cells (10.76 +/- 4.21%; p < 0.05). Kaplan-Meier survival curves demonstrated that the patients with low caspase-9 expression showed significantly shorter survival (p < 0.05) than those with high caspase-9 expression. These findings suggest that immune clearance gastric carcinoma cells in ascites activated by caspase-9 helped to improve the prognosis of patients with gastric cancer. PMID- 21284735 TI - Clinicopathologic characteristics and steroid response of IgM nephropathy in children presenting with idiopathic nephrotic syndrome. AB - There is no detailed information on clinical and immunopathologic features of immunoglobulin M nephropathy (IgMN) in children with idiopathic nephrotic syndrome (INS) in Pakistan. We reviewed our native renal biopsies over 15 years (July 1995-July 2010) and identified 135 cases of IgMN in nephrotic children (<=17 years). Their demographic, clinical and immunopathologic data were retrieved from biopsy reports and case notes. Mean age of this cohort was 7.6 +/- 4.2 years. Males were 92 (68.1%) and females were 43 (31.9%). Steroid-dependent NS was seen in 88 (65.2%) cases and steroid-resistant NS in 47 (34.2%). Hematuria was found in 42 cases (31.2%) and hypertension in 27 (19.5%). The most common morphologic change was glomerular mesangial proliferation, found in 89 (65.9%) biopsies. Minor changes were seen in 46 (34.1%) cases and focal segmental glomerulosclerosis (FSGS) in 37 (27.4%). Immunofluorescence microscopy showed diffuse mesangial positivity of IgM in all cases. C3 and C1q were found in 72 (53.3%) and 40 (29.7%) cases, respectively. Our results show that IgMN is a fairly common cause of INS in children in Pakistan. It shows a spectrum of morphologic changes ranging from minor changes to FSGS. PMID- 21284736 TI - Helicobacter pylori induces malignant transformation of gastric epithelial cells in vitro. AB - Epidemiologic studies have demonstrated that Helicobacter pylori infection is associated with increased risk for the development of gastric cancer. Animal studies have also shown that H. pylori infection leads to gastric carcinogenesis, especially intestinal phenotypes. However, no in vitro study has been carried out for cell transformation induced by H. pylori. The present study aimed to investigate whether 'chronic'H. pylori infection induces gastric epithelial cell transformation, and elucidate the underlying mechanisms of transformation induced by H. pylori. The immortalized 'normal' gastric epithelial cell line, GES-1, was co-cultured for 45 days with H. pylori strains B975 and L301. The cell proliferation was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay, Ki-67 antigen, and colony formation assay. The cell transformation was determined by observing cell morphology and measuring the expression of E-cadherin, beta-catenin, and transcription factor-4 (TCF-4) at both protein and mRNA levels. H. pylori induced morphologic changes in GES-1 cells and significantly increased the proliferation of GES-1 cells. Moreover, H. pylori up-regulated the expression of beta-catenin and TCF-4, and also induced the nuclear accumulation of beta-catenin. In addition, the diffusive gastric cancer-related gene, E-cadherin, was up-regulated at the protein level, but down regulated at the mRNA level. H. pylori infection is capable of inducing GES-1 transformation to present with the characteristics of intestinal-type gastric cancers in vitro, likely through the beta-catenin/TCF-4 signaling pathway. PMID- 21284737 TI - Evaluation of three swab transport systems for the maintenance of clinically important bacteria in simulated mono- and polymicrobial samples. AB - In this study, three swab transport systems were evaluated: M40 Transystem, Amies broth with a relatively new type of swab (both Copan Diagnostics, Corona, CA, USA), and SSI transportmedium (Statens Serum Institut, Copenhagen Denmark). The CLSI M40-A standard procedures and 11 culture collection strains were used. The transport systems were tested at room temperature for holding times of 0, 24, and 48 h, and both mono- and polymicrobial samples were included. After 24 h of simulated transportation, all systems were able to maintain the viability of all organisms tested. SSI transportmedium exhibited the lowest maintaining ability, whereas the two Copan systems were the most growth-promoting system. In polymicrobial samples, this latter feature was a problem. At 48 h, no transport system could maintain the viability of all strains, and the recovery rates differed depending on organism and device. The species most difficult to recover in all the three systems was Neisseria gonorrhoeae. When selecting a swab transport system, consideration must be given to the sample type, the conditions that prevail locally, and the performance in the clinical setting. PMID- 21284738 TI - Prevalence of human papillomavirus genotypes in cytologic abnormalities from unvaccinated women living in north-western Spain. AB - Cervical cancer and its precursors low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL) are associated with infection by human papillomavirus (HPV), in particular HPV 16 and 18. The distribution of the HPV genotype varies with the severity of cervical disease, age and the geographic location of the patients. We report the results of a population study carried out in a region of north-western (NW) Spain aimed at determining the prevalence of single and multiple infections by 35 types of HPV using low-density microarrays for 113 cases with negative for intraepithelial lesions or malignancies; 588 with atypical squamous cells of undetermined significance (ASCUS)/LSIL; 183 with HSIL; and seven cases of squamous cell carcinomas. Of the 891 patients analysed, 50.2% had single infections and 49.8% had multiple HPV infections. In women aged below 30 years, there was a predominance of multiple infections (p = 0.027). ASCUS/LSIL was associated with multiple and HSIL with single infections (p = 0.025). We observed significant increases in the percentage of infections due to a high-risk (HR) type of HPV when the severity of the cytological lesion increased (p = 0.001). No relationship was found between greater aggressiveness in the cytological diagnosis and a higher number of HPV types involved in multiple infections. The five most frequent genotypes were HPV 16 (26.3%), 53 (18.2%), 51 (17.3%), 6 (14.8%) and 66 (13.1%). The prevalence of HPV 16, 33 and 58 increased significantly from ACUS/LSIL to HSIL and the prevalence of HPV 51, 53 and 66 decreased. HPV 16 was the only genotype that showed a significant increase in prevalence when the severity of the cytological disease increased in single infections (p = 0.0001). The implementation of bivalent prophylactic vaccination could potentially lead to prevention in 32% of the population included in the study - in at least a quarter of patients with ACUS/LSIL (26.7%), and in half of HSIL (50.2%). PMID- 21284739 TI - Tumor of fibroblastic reticular cells of lymph node coincidental with an undifferentiated endometrial stromal sarcoma. Report of a case with distinctive immunophenotype and Kikuchi-like necro-inflammatory response. PMID- 21284740 TI - Co-existence of cerebral infection with Rhinocladiella mackenziei and primary central nervous system lymphoma in a HIV-negative patient. PMID- 21284741 TI - The prevalence of bacterial vaginosis and aerobic vaginitis in young Finish women. PMID- 21284743 TI - Expression of the non-neuronal cholinergic system in rat liver. PMID- 21284744 TI - A comparative genomic map for Caulanthus amplexicaulis and related species (Brassicaceae). AB - Adaptation to environment is the cornerstone of ecological genetics. The subject of this study is a wild relative of the sequenced and annotated model plant species, Arabidopsis thaliana. Caulanthus amplexicaulis var. barbarae lives on serpentine soils, known for high concentrations of heavy metals and low concentrations of essential plant macronutrients, and provides a compelling example of an organism's adaptation to environment. We constructed an F(2) linkage map, using a cross to the nonserpentine sister taxon, C. amplexicaulis var. amplexicaulis. C. amplexicaulis is a member of a highly diverse set of taxa (within the tribe Thelypodieae), described here as the 'Streptanthoid Complex' that are adapted to a broad range of environments, yet share a common n = 14 chromosome number and likely arose by a recent radiation. The linkage map consists of 97 polymorphic microsatellite markers, and 40 exon-primed intron crossing markers based on A. thaliana exon sequences and Brassica ESTs. The map covers 14 linkage groups and has a total length of 1513 cM. Both the patterns of marker segregation and the comparative map indicate that C. amplexicaulis is a diploid organism with a compact genome. All exon-primed intron-crossing markers, and an unexpectedly large number of microsatellite markers (83%), had significant similarity to the A. thaliana genome, facilitating the development of a comparative genome map. As a proof of principle, we used the comparative map to identify candidate genes underlying differences in sepal colour between the two parent taxa. We demonstrate that the genomic tools developed here will be portable throughout the Streptanthoid Complex. PMID- 21284745 TI - Melatonin and cancer: current knowledge and its application to oral cavity tumours. AB - BACKGROUND: Melatonin (MLT) is a molecule secreted by the pineal gland in cyclical periods. In mammals, MLT is involved in physiological processes, such as sleep/wake regulation in the circadian cycle. It has antioxidant and anti inflammatory properties, functions as an immunomodulator, and stimulates bone metabolism. MLT is also involved in tumour processes in breast, prostate, liver, and bone cancers, among others, and in oral cavity tumours like epidermoid carcinoma. We are gradually increasing our knowledge of the underlying mechanism of MLT action in the aforementioned tumour processes, in which MT1, MT2, MT3, and RZR receptors appear to play a highly important role. These receptors belong to a large family of G-protein-coupled transmembrane receptors, some of which have been linked to melatonin's anticancer action, to tumour growth, and to prognosis. The objective of this article is to provide a clear review of research into the range of MLT functions, focusing specifically on MT receptors. We aim to contribute interesting, new approaches to research into oral cavity tumours. METHODS: An extensive review of the research literature was conducted using PubMed, Science Direct, ISI Web of Knowledge, and the Cochrane base. RESULTS: This study highlights the growing importance of MLT in the prognosis and treatment of certain tumours, including epidermoid carcinoma in the oral cavity. Moreover, it opens up a highly original, encouraging line of research in the field of tumours. CONCLUSIONS: MLT contributes to protecting the oral cavity from tissue damage caused by receptor action. Experimental evidence suggests that it may be useful in the treatment and prognosis of tumour processes in the oral cavity. PMID- 21284747 TI - Dyskeratosis congenita: a combined immunodeficiency with broad clinical spectrum- a single-center pediatric experience. AB - BACKGROUND: Dyskeratosis Congenita (DKC) is a syndrome characterized by immunodeficiency, bone marrow failure, somatic abnormalities, and cancer predisposition resulting from defective telomere maintenance. The immunologic features of DKC remain under diagnosed and under treated despite the fact that immunodeficiency is a major cause of premature mortality in DKC. METHODS: This study undertook a retrospective review of 7 DKC patients diagnosed at the Children's Hospital of Philadelphia. In parallel, we reviewed previously reported immunologic findings in DKC patients. RESULTS: Immunologic abnormalities (lymphopenia, low B-cell numbers, hypogammaglobulinemia, and decreased T-cell function) were the most frequent laboratory findings at initial presentation, preceding the development of significant anemia or thrombocytopenia. Recurrent sinopulmonary or opportunistic infections were present in 6/7 patients. Infant onset patients had more severe immunologic and somatic features (particularly severe enteropathy). CONCLUSION: In DKC, development of immunologic abnormalities can precede bone marrow failure, highlighting the importance of proper immunodeficiency management to minimize morbidity and premature mortality in this disease. PMID- 21284746 TI - Sensitization profiles to purified plant food allergens among pediatric patients with allergy to banana. AB - Banana fruit allergy is well known, but neither immunoglobulin E recognition patterns to purified plant food allergens nor true prevalences of putative banana allergens have been established. This study aimed to characterize beta-1,3 glucanase and thaumatin-like protein (TLP) as banana allergens, testing them, together with other plant food allergens, in 51 children with allergic reactions after banana ingestion and both positive specific IgE and skin prick test (SPT) to banana. Banana beta-1,3-glucanase and TLP were isolated and characterized. Both banana allergens, together with kiwifruit TLP Act d 2, avocado class I chitinase Pers a 1, palm pollen profilin Pho d 2 and peach fruit lipid transfer protein (LTP) Pru p 3, were tested by in vitro and in vivo assays. Banana beta 1,3-glucanase (Mus a 5) was glycosylated, whereas banana TLP (Mus a 4) was not, in contrast with its homologous kiwi allergen Act d 2. Specific IgE to both banana allergens, as well as to peach Pru p 3, was found in over 70% of sera from banana-allergic children, and Mus a 4 and Pru p 3 provoked positive SPT responses in 6 of the 12 tested patients, whereas Mus a 5 in only one of them. Both peptidic epitopes and cross-reactive carbohydrate determinants were involved in the IgE-binding to Mus a 5, whereas cross-reactivity between Mus a 4 and Act d 2 was only based on common IgE protein epitopes. Profilin Pho d 2 elicited a relevant proportion of positive responses on in vitro (41%) and in vivo (58%) tests. Therefore, Mus a 4 and LTP behave as major banana allergens in the study population, and profilin seems to be also a relevant allergen. Mus a 5 is an equivocal allergenic protein, showing high IgE-binding to its attached complex glycan, and low in vivo potency. PMID- 21284748 TI - Real-life epidemiology of food allergy testing in Finnish children. AB - BACKGROUND: The cumulative incidence of parental-reported symptoms of food allergy (FA) during the first years of life is estimated to exceed 30%. However, the occurrence and determinants of FA testing in a general child population have remained unknown. METHODS: The study population comprised all 5920 children aged 0-4 yr in the province of South Karelia, Finland, identified from the nationwide population register. The study included a questionnaire survey and a retrospective collection of FA test results (skin prick tests, IgE antibodies, or open food challenges) from the patient records of the entire study population. The questionnaire and patient record data were linked together on an individual basis with the parents' permission. RESULTS: A total of 5849 FA tests had been performed on 961 children. By the age of 4 yr, the cumulative incidence of FA testing was 18% for any food item; 17% for essential items (milk, egg, cereals) and 9% for other food items. Essential food items had been tested in 90% of children who reportedly had a physician-diagnosed FA for these. The incidence of testing was 30% higher in boys than in girls and twofold higher among the offspring whose either or both parents reportedly had some allergic manifestation. CONCLUSIONS: A large proportion of children are subjected to FA testing in their early years. This result shows the need to evaluate the financial burden of FA testing and to improve current testing practices. PMID- 21284749 TI - Primary peripheral PNET/Ewing's sarcoma arising in the meninges, confirmed by the presence of the rare translocation t(21;22) (q22;q12). AB - Peripheral primitive neuroectodermal tumor/Ewing's sarcoma (ES) (pPNET/ES) of intracranial origin are very rare. These tumors are characterized by specific translocations involving a gene on chromosome 22q12, the most common being t(11;22) (q24;q12). We report a case of 37-year-old man with pPNET/ES arising in the meninges and bearing the rare translocation t(21;22) (q22;q12). The tumor was composed of sheets and nests of monotonous small cells with round to oval nuclei, finely dispersed chromatin, small nucleolus and scant cytoplasm. We discuss the importance of the differential diagnosis with central primitive neuroectodermal tumors (cPNET). PMID- 21284750 TI - A glioblastoma arising from the attached region where a meningioma had been totally removed. AB - The co-occurrence of different histological tumors in the nervous system is rare and is mainly associated with phakomatoses or radiation exposure. A 72-year-old man underwent surgery for a frontal convexity meningioma. Four years after the surgery, a new lesion was detected in the attached region where the meningioma had been removed. The second tumor exhibited a high degree of cellularity, atypical mitosis, pseudo-palisading and microvascular proliferation, and was immunohistologically positive for GFAP and was diagnosed as a glioblastoma. Wild type isocitrate dehydrogenase 1 was found in the second specimen. A genetic analysis using comparative genomic hybridization showed a DNA copy number loss on 1p35, 9pter-21, 10, 11q23, 13q, 14q, 20q, 22q and a gain on 7 in the second specimen. Although the mechanism responsible for the consecutive occurrence of meningioma and glioblastoma has not been elucidated, five hypotheses are feasible: (i) the lesions occurred incidentally; (ii) a low-grade astrocytoma present at the time of the first operation transformed into a high-grade glioma during the next 4 years; (iii) radiation received during the endovascular treatment induced glioblastoma; (iv) a brain scar created at the time of the first operation for meningioma led to the occurrence of a glioblastoma; and (v) the previous meningioma affected the surrounding glial cells, causing neoplastic transformation. PMID- 21284751 TI - Optineurin in neurodegenerative diseases. AB - Optineurin is a gene associated with normal tension glaucoma and primary open angle glaucoma, one of the major causes of irreversible bilateral blindness. Recently, mutations in the gene encoding optineurin were found in patients with amyotrophic lateral sclerosis (ALS). Immunohistochemical analysis showed aggregation of optineurin in skein-like inclusions and round hyaline inclusions in the spinal cord, suggesting that optineurin appears to be a more general marker for ALS. However, our detailed examinations demonstrated that optineurin was found not only in ALS-associated pathological structures, but also in ubiquitin-positive intraneuronal inclusions in ALS with dementia, basophilic inclusions in the basophilic type of ALS, neurofibrillary tangles and dystrophic neurites in Alzheimer's disease, Lewy bodies and Lewy neurites in Parkinson's disease, ballooned neurons in Creutzfeldt-Jakob disease, glial cytoplasmic inclusions in multiple system atrophy, and Pick bodies in Pick disease. With respect to optineurin-positive basophilic inclusions, these structures showed variable immunoreactivities for ubiquitin; some structures were obviously ubiquitin-positive, while others were negative for the protein, suggesting that optineurin expression was not always associated with the expression of ubiquitin. This study indicates that optineurin is widely distributed in neurodegenerative conditions; however, its significance is obscure. PMID- 21284752 TI - Accumulation of histone deacetylase 6, an aggresome-related protein, is specific to Lewy bodies and glial cytoplasmic inclusions. AB - Histone deacetylase 6 (HDAC6) plays a crucial role in aggresome formation, resulting in the clearance of misfolded proteins. Previous studies have shown that HDAC6 is concentrated in Lewy bodies (LBs) in Parkinson's disease (PD) and dementia with LBs (DLB) (Cell 115: 727-738, 2003). We performed immunohistochemical and ultrastructural investigations on the brains of patients with various neurodegenerative disorders. Anti-HDAC6 antibody faintly immunostained the cytoplasm of neuronal and glial cells in control subjects. In PD and DLB, almost all of the cortical, brainstem-type and peripheral LBs were intensely immunolabeled with anti-HDAC6. In multiple system atrophy (MSA), the vast majority of glial cytoplasmic inclusions (GCIs) were also positive for HDAC6. Immunoelectron microscopy revealed that the reaction product was localized to the filamentous structures in LBs and GCIs. Various neuronal and glial inclusions in neurodegenerative disorders other than LB disease and MSA were HDAC6-negative. These findings suggest that accumulation of HDAC6 is specific to alpha-synucleinopathy and that both LBs and GCIs may represent cytoprotective responses to sequester toxic proteins. PMID- 21284753 TI - Auxin stimulates DWARF4 expression and brassinosteroid biosynthesis in Arabidopsis. AB - Brassinosteroids (BRs) are growth-promoting steroidal hormones. Despite the importance of BRs in plant biology, the signal that initiates BR biosynthesis remains unknown. Among the enzymes involved in BR biosynthesis in Arabidopsis (Arabidopsis thaliana), DWARF4 catalyzes the rate-determining step. Through both the histochemical analysis of DWF4pro:GUS plants and the direct measurement of endogenous BR content, we discovered that BR biosynthesis is stimulated by auxin. When DWF4pro:GUS was subjected to auxin dose-response tests and a time-course analysis, GUS activity started to increase at an auxin concentration of 10 nm, rising noticeably after 1 h of auxin treatment. In addition, the analysis of the DWF4pro:GUS line in BR- and auxin-mutant backgrounds revealed that the induction by auxin requires auxin-signaling pathways but not BRs, which implies that auxin signaling directly controls BR biosynthesis. Furthermore, chromatin immunoprecipitation assays confirmed that auxin inhibits the binding of the transcriptional repressor, BZR1, to the DWF4 promoter. A microarray analysis that was designed to examine the transcriptomes after treatment with auxin alone or auxin plus brassinazole (a BR biosynthetic inhibitor) revealed that genes previously characterized as being auxin responsive are not properly regulated when BR biosynthesis is disrupted by brassinazole. Therefore, our results support the idea that auxin regulates BR biosynthesis, and that auxin thus relies on synthesized BRs for some of its growth-promoting effects in Arabidopsis. PMID- 21284754 TI - VASCULAR-RELATED NAC-DOMAIN7 directly regulates the expression of a broad range of genes for xylem vessel formation. AB - The Arabidopsis thaliana NAC domain transcription factor, VASCULAR-RELATED NAC DOMAIN7 (VND7), acts as a key regulator of xylem vessel differentiation. In order to identify direct target genes of VND7, we performed global transcriptome analysis using Arabidopsis transgenic lines in which VND7 activity could be induced post-translationally. This analysis identified 63 putative direct target genes of VND7, which encode a broad range of proteins, such as transcription factors, IRREGULAR XYLEM proteins and proteolytic enzymes, known to be closely associated with xylem vessel formation. Recombinant VND7 protein binds to several promoter sequences present in candidate direct target genes: specifically, in the promoter of XYLEM CYSTEINE PEPTIDASE1, two distinct regions were demonstrated to be responsible for VND7 binding. We also found that expression of VND7 restores secondary cell wall formation in the fiber cells of inflorescence stems of nst1 nst3 double mutants, as well as expression of NAC SECONDARY WALL THICKENING PROMOTING FACTOR3 (NST3, however, the vessel-type secondary wall deposition was observed only as a result of VND7 expression. These findings indicated that VND7 upregulates, directly and/or indirectly, many genes involved in a wide range of processes in xylem vessel differentiation, and that its target genes are partially different from those of NSTs. PMID- 21284755 TI - Role of aromatic aldehyde synthase in wounding/herbivory response and flower scent production in different Arabidopsis ecotypes. AB - Aromatic L-amino acid decarboxylases (AADCs) are key enzymes operating at the interface between primary and secondary metabolism. The Arabidopsis thaliana genome contains two genes, At2g20340 and At4g28680, encoding pyridoxal 5' phosphate-dependent AADCs with high homology to the recently identified Petunia hybrida phenylacetaldehyde synthase involved in floral scent production. The At4g28680 gene product was recently biochemically characterized as an L-tyrosine decarboxylase (AtTYDC), whereas the function of the other gene product remains unknown. The biochemical and functional characterization of the At2g20340 gene product revealed that it is an aromatic aldehyde synthase (AtAAS), which catalyzes the conversion of phenylalanine and 3,4-dihydroxy-L-phenylalanine to phenylacetaldehyde and dopaldehyde, respectively. AtAAS knock-down and transgenic AtAAS RNA interference (RNAi) lines show significant reduction in phenylacetaldehyde levels and an increase in phenylalanine, indicating that AtAAS is responsible for phenylacetaldehyde formation in planta. In A. thaliana ecotype Columbia (Col-0), AtAAS expression was highest in leaves, and was induced by methyl jasmonate treatment and wounding. Pieris rapae larvae feeding on Col-0 leaves resulted in increased phenylacetaldehyde emission, suggesting that the emitted aldehyde has a defensive activity against attacking herbivores. In the ecotypes Sei-0 and Di-G, which emit phenylacetaldehyde as a predominant flower volatile, the highest expression of AtAAS was found in flowers and RNAi AtAAS silencing led to a reduction of phenylacetaldehyde formation in this organ. In contrast to ecotype Col-0, no phenylacetaldehyde accumulation was observed in Sei 0 upon wounding, suggesting that AtAAS and subsequently phenylacetaldehyde contribute to pollinator attraction in this ecotype. PMID- 21284756 TI - Ehd3, encoding a plant homeodomain finger-containing protein, is a critical promoter of rice flowering. AB - Oryza sativa (rice) flowers in response to photoperiod, and is a facultative short-day (SD) plant. Under SD conditions, flowering is promoted through the activation of FT-like genes (rice florigens) by Heading date 1 (Hd1, a rice CONSTANS homolog) and Early heading date 1 (Ehd1, with no ortholog in the Arabidopsis genome). On the other hand, under long-day (LD) conditions, flowering is delayed by the repressive function of Hd1 on FT-like genes and by downregulation of Ehd1 by the flowering repressor Ghd7 - a unique pathway in rice. We report here that an early heading date 3 (ehd3) mutant flowered later than wild-type plants, particularly under LD conditions, regardless of the Hd1 deficient background. Map-based cloning revealed that Ehd3 encodes a nuclear protein that contains a putative transcriptional regulator with two plant homeodomain (PHD) finger motifs. To identify the role of Ehd3 within the gene regulatory network for rice flowering, we compared the transcript levels of genes related to rice flowering in wild-type plants and ehd3 mutants. Increased transcription of Ghd7 under LD conditions and reduced transcription of downstream Ehd1 and FT-like genes in the ehd3 mutants suggested that Ehd3 normally functions as an LD downregulator of Ghd7 in floral induction. Furthermore, Ehd3 ghd7 plants flowered earlier and show higher Ehd1 transcript levels than ehd3 ghd7 plants, suggesting a Ghd7-independent role of Ehd3 in the upregulation of Ehd1. Our results demonstrate that the PHD-finger gene Ehd3 acts as a promoter in the unique genetic pathway responsible for photoperiodic flowering in rice. PMID- 21284757 TI - Improved protein-binding microarrays for the identification of DNA-binding specificities of transcription factors. AB - Transcriptional regulation depends on the specificity of transcription factors (TFs) recognizing cis regulatory sequences in the promoters of target genes. Current knowledge about DNA-binding specificities of TFs is based mostly on low- to medium-throughput methodologies, revealing DNA motifs bound by a TF with high affinity. These strategies are time-consuming and often fail to identify DNA motifs recognized by a TF with lower affinity but retaining biological relevance. Here we report on the development of a protein-binding microarray (PBM11) containing all possible double-stranded 11-mers for the determination of DNA binding specificities of TFs. The large number of sequences in the PBM11 allows accurate and high-throughput quantification of TF-binding sites, outperforming previous methods. We applied this tool to determine binding site specificities of two Arabidopsis TFs, MYC2 and ERF1, rendering the G-box and the GCC-box, respectively, as their highest-affinity binding sites. In addition, we identified variants of the G-box recognized by MYC2 with high and medium affinity, whereas ERF1 only recognized GCC variants with low affinity, indicating that ERF1 binding to DNA has stricter base requirements than MYC2. Analysis of transcriptomic data revealed that high- and medium-affinity binding sites have biological significance, probably representing relevant cis-acting elements in vivo. Comparison of promoter sequences with putative orthologs from closely related species demonstrated a high degree of conservation of all the identified DNA elements. The combination of PBM11, transcriptomic data and phylogenomic footprinting provides a straightforward method for the prediction of biologically active cis-elements, and thus for identification of in vivo DNA targets of TFs. PMID- 21284758 TI - Three-dimensional FEA of effects of two dowel-and-core approaches and effects of canal flaring on stress distribution in endodontically treated teeth. AB - PURPOSE: The aim of this 3D finite element analysis (FEA) was to assess stress distribution and levels in endodontically treated teeth restored with two dowel and-core systems with differing root canal configurations. MATERIALS AND METHODS: Four 3D finite element models of a laser-digitalized maxillary central incisor embedded in alveolar bone were created. Internal morphology data and mechanical properties of the materials were obtained from the literature. Models included a (1) sound tooth (control) versus an endodontically treated maxillary central incisor with a crown ferrule preparation with two restorative approaches of a ceramic crown over a (2) gold alloy dowel-and-core or (3) glass-fiber dowels with composite cores (4) the latter with a flared root canal. A 100 N static load was applied in the center of the palatal surface at a 45 degrees angle, and the stress distribution pattern was analyzed using ANSYS((r)) software. RESULTS: In Model 1 (control), maximum stresses occurred at the coronal third of the buccal (2.32 * 10(7) Pa) and palatal aspects of dentin. The stress peak value of the model (2.45 * 10(7) Pa) occurred on the palatal aspect of the enamel at the level of the cementoenamel junction. With the insertion of dowels with thin cement layers (Models 2 and 3), stress concentrations in radicular dentin decreased, while they increased in the dowel/cement/dentin interface. These models exhibited the greatest stress peak values in the incisal margin of the gold alloy core (18.9 * 10(7) Pa) and in the cement layer (4.7 * 10(7) Pa). In Model 4, stress peak value was observed in the porcelain crown (4.62 * 10(7) Pa), and there was no stress concentration inside the cement layer. CONCLUSIONS: Within the limits of this study, the results suggest that the use of dowels and cements with mechanical properties similar to those of dentin, and an increased cement layer thickness, results in mechanical behavior similar to the physiological behavior of a sound tooth. PMID- 21284759 TI - Revisiting tooth preservation in prosthodontic therapy. AB - Dental implants have been established as long-term supports for tooth replacements, and they have profoundly altered treatment concepts of traditional prosthodontics. The use of teeth as prosthetic abutments is revisited relative to implants as predictable support mechanisms for fixed and removable prostheses. The purpose of this review is to appraise tooth preservation in a different manner while considering implants as additional and even preferred support mechanisms for dental prostheses. Data reviewed in this article include a comparison of implants and traditional prostheses and their effects on abutment teeth, the use of periodontally and endodontically compromised teeth as abutments, and prosthetic complications potentially created by healthy remaining teeth. The evidence presented suggests that the longstanding objective of tooth preservation during prosthetic treatment be appended to include the use of dental implants for fixed/removable prostheses, and to avoid or remove teeth presenting as liabilities that diminish the overall prognosis. Patients are not well served if they are faced with biologic, economic, and psychological burdens associated with ongoing revisions of dental rehabilitations using natural teeth. Dentists must use all means available to carefully evaluate remaining teeth to determine if they benefit or impair proposed prosthetic outcomes. PMID- 21284760 TI - Impression materials in fixed prosthodontics: influence of choice on clinical procedure. AB - The purpose of this article is to review impression materials used for fabricating fixed restorations in dentistry. Their compositions, properties, advantages, and disadvantages are presented and compared. How these properties influence clinical decisions is also described. This review helps the clinician choose which material is more suitable for a specific case. A broad search of the published literature was performed using Medline to identify pertinent current articles. Textbooks, the Internet, and manufacturers' literature were also used to supplement this information. It is limited to impression materials used in fixed prosthodontics. The review gives basic knowledge of ideal impression material properties and discusses traditional and, primarily, more recently developed products, such as polyethers, poly(vinyl siloxane), polysulfides, and condensation silicone materials. Clear advantages and disadvantages for these impression materials are provided along with the role that compositional variations have on the outcome of the impression. This should enable clinicians and technicians to easily identify the important physical properties of each type of impression material and their primary clinical indications. PMID- 21284761 TI - Pilot evaluation of four experimental conditioning treatments to improve the bond strength between resin cement and Y-TZP ceramic. AB - PURPOSE: This study evaluated the bond strength between resin cement and Y-TZP ceramic (Yttrium-stabilized Tetragonal Zirconia Polycrystalline) submitted to different surface conditionings. MATERIALS AND METHODS: Fifty Y-TZP ceramic discs (O= 10 mm) were allocated into five groups: Gr1 (control)-no conditioning; Gr2 tribochemical silica coating (30-MUm SiO(2)) before sintering; Gr3-air abrasion with 50-MUm Al(2)O(3) before sintering; Gr4-air abrasion with 110-MU Al(2)O(3) before sintering; Gr5 - air abrasion with 50-MUm Al(2)O(3) after sintering. After specimen preparation, cylinders of composite resin were prepared and immediately cemented onto the ceramic. A shear test was performed. RESULTS: One-way ANOVA indicated a statistically significant difference among the groups (p= 0.0019). The mean shear bond strengths (MPa) were: Gr1 = 4.7 +/- 0.8,(b) Gr2 = 4.6 +/- 0.9,(b) Gr3 = 6.4 +/- 1.0,(a) Gr4 = 6.5 +/- 1.8,(a) Gr5 = 6 +/- 1.3(ab) (same superscript letter indicates statistical similarity). Adhesive fracture between the ceramic and resin cement was the most common failure. No complete cohesive fracture at the ceramic or composite cylinders was noted. CONCLUSION: Within the limitations of this study, additional surface treatment with air abrasion before and after sintering provided a significant increase in bond strength. Tribochemical silica coating before sintering was not effective as a surface treatment. PMID- 21284762 TI - Durability of resin cement bond to aluminium oxide and zirconia ceramics after air abrasion and laser treatment. AB - PURPOSE: The erbium laser has been introduced for cutting enamel and dentin and may have an application in the surface modification of high-strength aluminum oxide and zirconia ceramics. The aim of this study was to evaluate the durability of the bond of conventional dual-cured resin cements to Procera Al(2)O(3) and zirconium oxide ceramics after surface treatment with air abrasion and erbium laser. MATERIALS AND METHODS: One hundred twenty Al(2)O(3) and 120 zirconia specimens measuring 3 * 3 * 0.7 mm(3) were divided equally into three groups, and their surfaces treated as follows: either untreated (controls), air abraded with Al(2)O(3) particles, or erbium-laser-treated at a power setting of 200 mJ. The surface of each specimen was then primed and bonded with one of two dual-cured resin cements (either SCP-100 Ceramic Primer and NAC-100 or Monobond S and Variolink II) using a 1-mm thick Tygon tube mold with a 0.75-mm internal bore diameter. After 24 hours and 6 months of water storage at 37 degrees C, a microshear bond strength test was performed at a crosshead speed of 1 mm/min. Surface morphology was examined using a confocal microscope, and failure modes were observed using an optical microscope. The data were analyzed using the Kaplan-Meier nonparametric survival analysis. RESULTS: In the case of zirconia, air abrasion and Erbium:yttrium-aluminum-garnet (Er:YAG) laser treatment of the ceramic surface resulted in a significant reduction in the bond strengths of both resin cements after 6 months water storage; however, when the zirconia surface was left untreated, the SCP-100/NAC-100 group did not significantly reduce in bond strength. In the case of alumina, no treatment, air abrasion and Er:YAG laser treatment of the surface led to no significant reduction in the bond strengths of the three SCP-100/NAC-100 groups after 6 months water storage, whereas all three Monobond S/Variolink II groups showed a significant reduction. CONCLUSION: Er:YAG laser treatment of the zirconia surface did not result in a durable resin cement/ceramic bond; however, a durable bond between a conventional dual-cured resin cement and Procera All Ceram and Procera All Zirkon was formed using a ceramic primer containing the phosphate monomer, MDP, without any additional surface treatment. PMID- 21284764 TI - Salese to buffer saliva in elderly patients with xerostomia: a pilot study. AB - PURPOSE: The objective of this study was to compare the pH of saliva from xerostomic patients before and after the use of Salese lozenges (Nuvora Inc., Santa Clara, CA). MATERIALS AND METHODS: After IRB approval, ten subjects were selected to participate in this pilot study to evaluate the efficacy of Salese. The inclusion criteria were patients on multiple medications who demonstrated xerostomia and acidic salivary pH. Saliva was collected from the patients at baseline and after the use of Salese at selected intervals up to 120 minutes. The pH of the collected saliva was measured, and the data were analyzed using an ANOVA. RESULTS: Use of Salese lozenges showed a shift toward a more neutral pH in the first half hour. The pH remained at the same level after the primary shift for at least 2 hours. CONCLUSIONS: This pilot study indicates that patients suffering with xerostomia can use Salese lozenges for at least 10-30 minutes to induce a salivary pH shift to a more neutral level. More research should be performed to investigate the buffering capacity of Salese lozenges. PMID- 21284763 TI - Effect of accelerated aging on permanent deformation and tensile bond strength of autopolymerizing soft denture liners. AB - PURPOSE: The aim of this study was to evaluate the effect of different accelerated aging times on permanent deformation and tensile bond strength of two soft chairside liners, acrylic resin (T) and silicone (MS) based. MATERIALS AND METHODS: Different specimens were made for each test of each reliner. The specimens (n = 10) were submitted to accelerated aging for 2, 4, 8, 16, 32, and 64 cycles. Tensile bond strength testing was performed at a crosshead speed of 5 mm/min and permanent deformation with a compressive load of 750 gf. Data were submitted to Mann-Whitney test to compare the materials at different times, and Kruskal-Wallis and Dunn tests were used for comparing aging intervals within a given reliner. RESULTS: MS presented a lower percentage of permanent deformation (p < 0.0001) and higher tensile bond strength (p < 0.0001) than T in all time intervals and was not affected by the accelerated aging process, which reduced the permanent deformation and increased tensile bond strength of T (p < 0.05). CONCLUSION: MS presented lower permanent deformation and higher tensile bond strength than T. Although T presented changes in those properties after accelerated aging, both materials might be suited for long-term use. PMID- 21284765 TI - A multidisciplinary approach to the management of a subgingivally fractured tooth: a clinical report. AB - Anterior tooth fracture is the most common type of trauma occurring to the dental tissues. Teeth fracturing at or below the gingival level usually have a poor prognosis, with extraction of the tooth being the most probable outcome. Clinical crown lengthening followed by prosthetic rehabilitation is a promising approach toward such cases. The clinical report presented here explains in detail the various treatment modalities available for such cases with special emphasis on orthodontic extrusion/forced eruption. PMID- 21284766 TI - A novel oncoprotein Pirh2: rising from the shadow of MDM2. AB - Pirh2 (p53-induced RING-H2) is an E3 ubiquitin ligase that can target p53 for degradation and thereby repress a diverse group of biological activities regulated by p53. Notably, Pirh2, rather than MDM2, is the primary degrader of active p53 under conditions of DNA damage. Moreover, Pirh2 is highly expressed in multiple cancer cell lines regardless of p53 status. Recent research has shown that Pirh2 is involved in many signalling pathways related to the genesis and evolution of cancer. This review aims to summarize a comprehensive picture of the role of Pirh2 in cellular processes and its significance to tumorigenesis. Furthermore, this review focuses on its potential role as a cancer therapeutic target. PMID- 21284767 TI - Chronic immune-related demyelinating neuropathies. AB - In recent years many important advances have been made in the knowledge of the mechanisms that may produce peripheral nerve damage. Data in the literature indicate that in some chronic demyelinating neuropathy autoantibodies against myelin antigens may play a pathogenic role. The pathogenic role of T cells, cytokines, complement, and class II molecules has also been studied. Identification of specific immune-related demyelinating polyneuropathies provides clues to future therapeutic approaches. This paper focuses on the chronic inflammatory demyelinating polyneuropathy, chronic demyelinating neuropathies associated with monoclonal gammapathies of undetermined significance, and multifocal motor neuropathy, and reviews their clinical, patophysiological and immunological features. PMID- 21284768 TI - Sleep-related breathing disorders in the Shy-Drager syndrome. Observations on investigation and management. AB - We report on 18 patients with the Shy-Drager syndrome who were referred for assessment of a sleep-related breathing disorder. The main symptoms of snoring, apnoea, stridor and daytime hypersomnolence were detailed and vocal cord movement graded by laryngoscopy as normal, mild weakness of abduction or near paralysis of vocal cord movement Sleep studies involving oximetry and observations were performed. Obstructive and central apnoeas were detected in six patients. Many patients with near paralysis of vocal cord abduction had normal sleep studies. Successful management strategies of obstructive cases included CPAP, nasal surgery and tracheostomy or arytenoidectomy alone or in combination. Sleep related breathing disorders in the Shy-Drager syndrome may involve significant nocturnal desaturation; investigation with suitable medical or surgical treatment should be employed in these patients. PMID- 21284769 TI - AIDS dementia complex: incidence, clinical profile and impact of zidovudine treatment*. AB - This study aimed to determine the incidence of AIDS dementia complex (ADC), the clinical data which distinguish it from other neurological complications of HIV infection, and the impact of zidovudine (AZT) therapy on the appearance and course of this condition. Data on the neurological complications of HIV patients treated at a community hospital from 1988 to 1992 were collected prospectively. Out of 500 AIDS patients treated at the hospital, there were 142 patients with neurological complications, with an average of 1.42 complications/patient There were 23 patients diagnosed as having ADC; with an estimated incidence of 4.6%, it was the most frequent neurological complication, after cerebral toxoplasmosis. Age was higher in patients with ADC as first manifestation of AIDS with respect to ADC patients with previous AIDS diagnosed. Compared with the group of patients suffering from other neurological complications, patients with ADC showed significant differences in several biological markers of progression to AIDS, such as hemoglobin, hematocrit, global lymphocyte count, serum beta2 microglobulin and serum IgA. CD4 count was similar in both groups. Ten ADC patients had been treated previously with AZT. Dementia continued progressing in seven of these patients and remained stable in three. Of the other 13 cases not treated previously with the drug, eight received AZT therapy, and a favourable response was obtained in three patients (p = 0.068). ADC represents a major neurological complication in AIDS patients. AZT therapy may delay the appearance of ADC, but not prevent it. A trend towards a favourable response to AZT was observed in ADC patients who had not been treated with it previously. PMID- 21284770 TI - Mini-Mental State Examination: a normative study in Italian elderly population. AB - The Mini-Mental State Examination (MMSE), a brief test to assess cognitive status, is heavily influenced by age and education. It was administered to 1019 elderly subjects (aged 65-89 years) living in three different Italian cities. A statistical non-linear regression model was built up in order to obtain adjustment coefficients to reduce the influence of demographic variables on the MMSE raw scores. Age and educational level were significantly and independently associated with the MMSE score. Results of a multiple linear regression with transformation of age and education provided adjustment coefficients of the MMSE raw scores. Data from this study will ameliorate the overall reliability of MMSE as a screening test for cognitive impairment in elderly people. PMID- 21284771 TI - Auditory hallucinosis in brainstem lesions and musical hallucination in deafness. Analogies and differences. AB - Auditory hallucinations are found at the cross-roads of otological, neurological and psychiatric practice. They are generally considered to be the manifestation of psychosis, delirium tremens and chronic alcoholism, toxic states, hemispheric (predominantly temporal lobe) involvement, brainstem disorders or acquired peripheral (acoustic nerve, cochlea or middle-ear) deafness. Auditory hallucinosis in one case of brainstem lesion and musical hallucinations in two cases associated with acquired peripheral deafness are presented. Analogies and differences, pathophysiology and review of the literature are discussed. PMID- 21284772 TI - Increased use of target cues during visuo-motor tracking in Parkinson's disease. AB - The effect of temporarily suppressing the visual display of either the target or actual movement trajectory upon the accuracy of visuo-motor tracking was studied in patients with Parkinson's disease (PD) and healthy subjects. Subjects made wrist movements to superimpose a movement cursor upon a target cursor on a VDU screen. The tracking of slow ramp and sinewave target waveforms was investigated. Trials involving the three conditions of visual suppression, namely, target suppressed (TS), movement suppressed (MS) and non-suppressed (NS) were ordered randomly. In TS and MS trials, respectively, the target or movement cursor disappeared from the subject's view for a 4 s period whilst in NS trials both the target and movement cursors were continuously present. Prior to experimental trials, subjects initially practised a series of NS movements. Tracking errors were analysed by ANOVA for group, suppression condition and waveform effects. The tracking performance of the PD patients, during each form of suppression condition, was worse than that of healthy subjects. Both TS and MS elicited significant reductions in accuracy across groups and waveforms. TS induced a more pronounced impairment of tracking accuracy in the PD group than in the control group suggesting that parkinsonians exhibit an abnormally increased reliance upon visual information of the required trajectory during the present visuo-motor tracking tasks. By contrast, there was no between-group effect of MS in these tasks, suggesting that PD patients show a comparable dependence upon visual feedback of their own movements to that shown by controls. PMID- 21284773 TI - Objective assessment of foot strike in Parkinson's disease*. AB - We assessed the nature of foot strike and the potential effect of acute levodopa dosing in Parkinsonian patients with mild to severe fluctuations of motor performances in comparison with healthy volunteers. Forty-eight patients were enrolled in the study and compared with 33 age and gender matched controls. Each patient was assessed by a computerized electropodographic system before levodopa dosing and 1 and 2-h after intake of a standard fasting morning dose of levodopa plus benserazide. Twelve foot strikes (six right, six left) were analysed per patient. The controls underwent three repeated examinations at 1-h intervals. Patients' motor response to acute levodopa dosing was evaluated at fixed times by a battery of motor tests. Foot strike dynamics differed between patients and controls: in particular, first ground contact of the foot was significantly shifted from heel to forefoot in patients compared to controls. The forward shift in footprint during walking was more marked on the more affected body side but was unrelated to the severity and duration of Parkinsonism and unresponsive to levodopa dosing. Tapping and walking tests were overall responsive to acute levodopa intake. The system seemed suitable to detect irregular patterns of foot strike even at the early stages of Parkinsonism, when lower limb disorder was not clinically overt, and might be useful in the search for clinical markers of Parkinsonian gait. PMID- 21284774 TI - The peak time difference of time-density curve in intravenous digital subtraction angiography correlates to an asymmetric cerebral blood flow as determined by positron emission tomography. AB - A time-density curve study in contrast media transit is theoretically possible to evaluate an asymmetric cerebral perfusion. In this study, we confirmed the correlation between the peak time difference in a regional time-density curve and the asymmetry of cerebral blood flow using positron emission tomography (PET). Five patients with a unilateral occlusion of the carotid or middle cerebral artery underwent intravenous digital subtraction angiography and PET on two successive days. We placed four pairs of regions of interest as appropriate in each study, and obtained the peak time of a regional time-density curve, regional cerebral vascular blood flow (rCVBF) and regional cerebral blood flow (rCBF). We obtained a significant linear correlation between the right-to-left difference of peak time and the difference of 1/rCVBF (r = 0.85, p < 0.001). The peak time difference also showed good correlation to the absolute difference of rCBF (r = 0.84, p < 0.001). A time-density curve study can detect the asymmetry of rCBF, and may be used to evaluate unilateral ischemic damages. PMID- 21284775 TI - Dynamics of mRNA expression of interferon-gamma, interleukin 4 and transforming growth factor beta1 in sciatic nerves and lymphoid organs in experimental allergic neuritis. AB - Experimental allergic neuritis (EAN) is a T cell mediated inflammatory demyelinating disorder of the peripheral nervous system (PNS) and an animal model of the Guillain-Barre syndrome. Cytokines including interferon-gamma (IFN-gamma) have previously been shown to be upmodulated in lymphoid organs and assumed to be involved in the pathogenesis of EAN. Cytokines in the target organ for autoaggressive immunity in EAN, the PNS, could be pivotal for the development of EAN. By adopting in situ hybridization, we studied mRNA expression of the T helper 1 (Th1) cell associated IFN-gamma, the Th2 cell related interleukin-4 (IL 4) and the immune response down-regulating TGF-beta1 in the sciatic nerve and, in parallel, in the lymph nodes and the spleen over the course of EAN actively induced by immunization with bovine peripheral nerve myelin (BPM) and Freund's complete adjuvant. The dynamics of IFN-gamma mRNA expression in the sciatic nerve followed approximately the clinical course of EAN with peak values around day 14 post immunization (p.i.), whereas IFN-gamma was transcribed earlier in the spleen and lymph nodes with maximum on day 7 p.i. In contrast, transcription of IL-4 was only slightly enhanced in EAN, with minor fluctuations in the sciatic nerve peaking on days 11 and 28 p.i. In the lymph nodes, the highest numbers of TGF beta mRNA positive cells were observed during the clinical improvement of EAN. The data argue for a major proinflammatory role for IFN-gamma, and a disease down regulating function for TGF-beta at the target site in EAN. PMID- 21284776 TI - IgG subclasses and their intrathecal synthesis in patients with amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis may be an autoimmune disease. In this paper IgG subclasses levels in the CSF and sera and their intrathecal synthesis were studied. IgG subclasses levels were determined by ELISA method using monoclonal antibodies against human IgG subclasses, secondary biotinylated antibody and avidin-biotin-peroxidase complex. There was statistically significant elevation of IgG1 and IgG3 subclasses in the CSF of ALS patients. In sera of patients with ALS, IgG2 level was diminished, but there was no statistical difference in other IgG subclasses. IgG1 and IgG3 indices were elevated in patients with ALS, detecting synthesis of these subclasses in the CNS. General IgG index value did not differ from the control value. The results support the concept that autoimmune mechanisms may play a role in the pathogenesis of ALS. PMID- 21284777 TI - The influence of EMG-initiated electrical muscle stimulation on motor recovery of the centrally paretic hand. AB - The present study compares the effect of EMG-initiated electrical stimulation of hand extensors and flexors with the influence of a standardized repetitive training of the hand that had been proven to ameliorate arm and hand function significantly. Twenty hemiparetic stroke patients participated in the study. Following a 2 week baseline phase in which conventional inpatient occupational and physiotherapy was applied, all patients received EMG-initiated electrical muscle stimulation twice daily during 20 min periods followed by a third phase with a standardized repetitive training of the hand. Both training procedures were conducted in addition to conventional occupational and physiotherapy. Grip strength, peak force of isometric hand extensions as well as peak acceleration of isotonic hand extensions were measured as indicators of motor performance. Spasticity of hand flexors was assessed by means of the modified Ashworth scale. Motor capacity of the affected arm was scored by means of the Rivermead motor assessment, arm section. Contrary to usual occupational and physiotherapy, both the EMG-initiated stimulation and the repetitive training are appropriate to improve all biomechanical and functional parameters significantly whereas no difference in the efficacy of both methods could be detected. The functional significance of frequent active repetition of identifcal movements and the role of time-locked afferent information about the unfolding movement for motor learning and recovery are discussed. PMID- 21284778 TI - Occlusive hydrocephalus complicating tuberous sclerosis: report of two cases. AB - Two patients-6 and 14 years old-with tuberous sclerosis are presented. Both developed a subependymal giant cell astrocytoma from nodules located near to the foramen of Monro. They caused obstruction of the cerebrospinal fluid pathways. Signs of raised intracranial pressure were detected in both patients, and one of them had also developed infantile spasm-Blitz-Nick-Salaam seizures. Cutaneous stigmata being characteristic for this entity were observed in both cases, but their mental development was unaffected. Diagnosis was based on computed tomography. Angiography did not reveal pathological vessels. The tumours were completely excised through transcallosal exposure in both cases. The patients have been symptom-free during the follow-up time of 1 and 2 years. Although the incidence of malignant transformation of tuberous sclerosis is less than 15% the disease generally has a poor prognosis which can be ascribed to sudden increase of intracranial pressure caused by obstruction of cerebrospinal fluid pathways by paraventricular tumours. However, regular follow-up of paraventricular nodules and maintenance of patency of cerebrospinal fluid pathways by microsurgical methods in patients suffering from mild cerebral disorders offers a better chance of survival. PMID- 21284779 TI - Primary position upbeat nystagmus reversed with carbamazepine. AB - A 16-year old girl presented with primary position upbeat nystagmus (PPUN). MRI showed a small lesion at the perihypoglossal nuclei of the dorsal medulla oblongata. The case was diagnosed as a demyelinating disease for its response to prednisone, and the nystagmus decreased after administration of carbamazepine. Primary position upbeat nystagmus might be caused by an abnormal firing of neurons in the nuclei resulting in a tonic imbalance of vertical gaze. Also this is the first report to confirm the attenuation of PPUN by carbamazepine. PMID- 21284780 TI - Delayed somatosensory conduction in acute painful neuropathy of diabetes. AB - We examined the peripheral-central sensory conduction by using somatosensory evoked potential (SEP) in a 48 year old diabetic patient with acute painful neuropathy. The sural, ulnar and median sensory nerve conduction and SEP elicited by wrist stimulation showed no abnormalities, nevertheless, the tibial nerve SEP revealed absent spinal N19 and a remarkable delay of the cortical arrival time. These findings suggest involvement of the dorsal roots or the dorsal column in the acute painful neuropathy of diabetes. PMID- 21284781 TI - Acute meningo-encephalitis in pregnancy-a problem of differential diagnosis. AB - Two cases of Coxsackie B viral meningo-encephalitis in pregnant women are described. Both patients recovered well and delivered healthy babies, but because of delay in establishing the aetiology of their infections both mothers, and one child, received acyclovir therapy. The differential diagnosis of non-pyogenic meningo-encephalitis in late pregnancy can present particular problems: clinicians caring for such women should remain aware of the potential for enteroviral infection in their patients, and take appropriate action to prevent cross-infection in neonatal units. PMID- 21284782 TI - Recurrence of absence seizures induced by a low dose of amitriptyline: a case report. AB - We report a case of recurrence of absence seizures possibly induced by low doses of amitriptyline. A patient with juvenile absence epilepsy on chronic valproic acid monotherapy and seizure-free for a period of 6 years experienced a recurrence of absence seizures on starting a headache prophylaxis with a low dose of amitriptyline (0.3 mg/kg). Seizures disappeared immediately after the addition of ethosuximide to antiepileptic therapy in spite of continuing amitriptyline. After stopping amitriptyline (3 months later) ethosuximide was also stopped and the patient remained, as before, seizure-free on valproic acid monotherapy. PMID- 21284783 TI - Antioxidative properties of aspirin: dose dependence and clinical implications. PMID- 21284784 TI - Cerebral paradoxical embolism in a patient infected by human immunodeficiency virus; TO THE EDITOR. PMID- 21284785 TI - Pick complex and Pick's disease: the nosology of frontal lobe dementia, primary progressive aphasia, and corticobasal ganglionic degeneration. PMID- 21284787 TI - Travel grants. PMID- 21284786 TI - Pick complex: too simple?; Commentary on "Pick complex and Pick's disease: the nosology of frontal lobe dementia, primary progressive aphasia, and corticobasal ganglionic degeneration" by A. Kertesz*. PMID- 21284789 TI - Injury mortality in rural South Africa 2000-2007: rates and associated factors. AB - OBJECTIVE: To estimate injury mortality rates in a rural population in KwaZulu Natal, South Africa and to identify socio-demographic risk factors associated with adult injury-related deaths. METHODS: The study used population-based mortality data collected by a demographic surveillance system on all resident and non-resident members of 11,000 households. Deaths and person-years of observation (pyo) were aggregated for individuals between 01 January 2000 and 31 December 2007. Cause of death was determined by verbal autopsy, coded using ICD-10 and further categorised using global burden of disease categories. Socio-demographic risk factors associated with injuries were examined using regression analyses. RESULTS: We analysed data on 133,483 individuals with 717,584.6 person-years of observation (pyo) and 11,467 deaths. Of deaths, 8.9% were because of injury related causes; 11% occurred in children <15 years old. Homicide, road traffic injuries and suicide were the major causes. The estimated crude injury mortality rate was 142.4 (134.0, 151.4)/100,000 pyo; 116.9 (108.1, 126.5)/100,000 pyo among residents and 216.8 (196.5, 239.2)/100,000 pyo among non-residents. In multivariable analyses, the differences between residents and non-residents remained but were no longer significant for women. In men and women, full-time employment was significantly associated with lower mortality [adjusted rate ratios 0.6 (0.4, 0.9); 0.4 (0.2, 0.9)]; in men, higher asset ownership was independently associated with increased mortality [adjusted rate ratio 1.5 (1.1, 1.9)]. CONCLUSIONS: Reducing the high levels of injury-related mortality in South Africa requires intersectoral primary prevention efforts that redress the root causes of violent and accidental deaths: social inequality, poverty and alcohol abuse. PMID- 21284790 TI - Comparative clinical- and cost-effectiveness of candesartan and losartan in the management of hypertension and heart failure: a systematic review, meta- and cost utility analysis. AB - The UK National Health Service (NHS) currently spends in excess of L250 million per annum on angiotensin II receptor blockers (ARBs) for the treatment of hypertension and heart failure; with candesartan currently dominating the market. With the recent introduction of generic losartan, we set out to directly compare the branded market leader to its now cheaper alternative. The primary objectives were to compare the blood pressure (BP) lowering efficacy and cardiovascular outcomes of candesartan and losartan in the treatment of essential hypertension and chronic heart failure, respectively. The secondary objective was to model their comparative incremental cost-effectiveness in a UK NHS setting. The Cochrane Central Register of Controlled Trials (Cochrane Library 2009, issue 2), which contains the Hypertension and Heart Group's specialist register, Medline (1950-February 2010), and Embase (1980-February 2010) were included in the search strategy. Selection criteria were randomised studies of candesartan versus losartan in adults (> 18 years). The main outcome measures were as follows: Hypertension: mean change from baseline in trough (24 h postdose) systolic and diastolic BP. Heart failure: composite of cardiovascular death and hospital admission for management of heart failure. Two reviewers applied inclusion criteria, assessed trial quality, and extracted data. Eight (three of which met inclusion criteria) and zero trials compared candesartan directly with losartan in the treatment of hypertension and heart failure, respectively. A between treatment difference of -1.96 mmHg [95% confidence interval (CI) -2.40 to -1.51] for trough diastolic BP and -3.00 mmHg (95% CI -3.79 to -2.22) for trough systolic BP in favour of candesartan was observed. Based on this differential, a 10-year Markov model estimates the cost per quality-adjusted life-year gained to exceed L40,000 for using candesartan in place of generic losartan. Candesartan reduces BP to a slightly greater extent when compared with losartan, however, such difference is unlikely to be cost-effective based on current acquisition costs, perceived NHS affordability thresholds and use of combination regimens. We could find no robust evidence supporting the superiority of candesartan over losartan in the treatment of heart failure. We therefore recommend using generic losartan as the ARB of choice which could save the UK NHS approximately L200 million per annum in drug costs. PMID- 21284791 TI - Easy money? Health cost savings resulting from the switch from a branded drug to a low-cost generic drug in the same class. PMID- 21284792 TI - Waste not, want not: free money, moral hazard and value-based prescribing. PMID- 21284793 TI - The role of sacral nerve stimulation in treating faecal incontinence and refractory constipation. Editorial. PMID- 21284794 TI - Fifteen years of sacral nerve stimulation: from an open procedure to a minimally invasive technique. AB - AIM: This historical review describes the development of InterStimTM therapy from an open procedure to a minimally invasive technique for the treatment of pelvic floor disorders. The latest technological and surgical evaluations of sacral nerve stimulation (SNS) are presented with their impact on the therapy's success and safety. METHOD: A search for relevant literature on SNS in the PubMed database was carried out for this review, which focuses on technical modifications and related clinical outcomes. RESULTS: InterStimTM therapy for faecal incontinence was introduced in Europe in 1995. Since its introduction, technical improvements in devices and leads have progressed SNS from an open one stage procedure to a minimally invasive two-stage technique. A smaller neurostimulator and particularly the new tined lead allow InterStimTM therapy to be performed under local anaesthesia and in an outpatient setting. Additionally, the use of the self-anchoring tined lead has reduced the number of technical failures and improved the test phase significantly, from 60% to 80%. The new smaller-in-size neurostimulator facilitates the implant procedure and further improves patient comfort. CONCLUSION: By using new technical achievements over the past 15 years, InterStimTM therapy has become a highly effective and safe procedure for selected patients with faecal incontinence. PMID- 21284795 TI - The influence of sacral nerve stimulation on anorectal dysfunction. AB - AIM: Sacral nerve stimulation (SNS) has become an established option in the management of defaecatory disorders. There are many data on the end-organ effects of SNS, but limited consensus on its mechanism of action. The objective of this review was to determine the effect of sacral nerve stimulation (SNS) on anorectal function. METHOD: Systematic literature review of the effect of sacral nerve stimulation (SNS) on anorectal function. RESULTS: There was significant heterogeneity of data pertaining to the effects of SNS on anorectal function, with no consistent change in physiological measures identified. Most data supported a mixed mechanism of action on anal motor and rectal sensory functioning. CONCLUSION: To date, conflicting data exist on the mechanism of action of SNS as determined by end-organ changes in anorectal physiology. Nevertheless, the data as they stand best support a mixed mechanism of action on anal motor and rectal sensory functions. PMID- 21284796 TI - Sacral nerve stimulation for faecal incontinence: its role in the treatment algorithm. AB - AIM: Indications for sacral nerve stimulation (SNS) for faecal incontinence have expanded over the last decade. This report aims to determine the clinical outcome of the current use of SNS in the treatment of faecal incontinence. Its objective is also to review the most recent role of SNS in patients with anal sphincter lesions. METHOD: The literature was searched using Medline and Cochrane databases. The search was restricted to publications in English. For the analysis, studies with <25 patients were excluded. For SNS in patients with sphincter defects, all papers were included. RESULTS: Thirteen publications on the clinical outcome of SNS were included. Nine papers were identified reporting the application of SNS in patients with a morphological sphincter lesion. The most common outcome measures of clinical efficacy were frequency of incontinence using the Cleveland Clinic Incontinence Score. All studies demonstrated highly improved function across all outcome measures and improvement was statistically significant in all. Outcomes remain stable at long-term follow up. In patients with sphincteric gaps ranging from 17 to 180 degrees , SNS was clinically effective at short-term follow up. The size of the gap appears to have no impact on outcome. CONCLUSION: SNS has evolved to become a clinical efficient therapy applicable across a wide spectrum of causes of faecal incontinence with reproducible results. SNS can be considered to be an essential part of the current surgical treatment algorithm for faecal incontinence. PMID- 21284797 TI - The role of sacral neuromodulation in double incontinence. AB - AIM: Urinary and faecal incontinence are common conditions that are frequently associated. When conservative treatments fail, sacral nerve modulation (SNM) is considered to be a first-line treatment for patients with urge urinary incontinence and for patients with faecal incontinence. This article aims to determine the effect of SNM on the treatment of double incontinence (i.e. urinary and faecal incontinence). METHOD: We searched for relevant articles in MEDLINE, PubMed and Embase, and for reviews in the Cochrane database. Articles were restricted to the English language. RESULTS: Only a few studies have studied the efficacy of SNM for double incontinence and in a limited number of patients. Between 30% and 100% of patients with double incontinence experience improvement in urinary and faecal incontinence at medium-term follow up. CONCLUSION: Further prospective trials are needed to determine which patients with combined problems will benefit from SNM at a long-term follow up. PMID- 21284798 TI - Status of sacral neuromodulation for refractory constipation. AB - AIM: This review article aims to provide a brief update on the current data on and position of sacral neuromodulation (SNM) in the specialized management of refractory idiopathic constipation. METHOD: Published evidence from PubMed and our own unpublished data on SNM treatment for refractory idiopathic constipation were used for this evaluation. RESULTS: Seven studies were found in PubMed that covered this topic. The main focus was on the most recently published multicentre nonrandomized European trial. Summary data from our unpublished study on constipation in children are also included. CONCLUSIONS: The use of SNM in the treatment of idiopathic constipation is still in its early phase and while the available efficacy and safety data are limited, they show promising results. As there are few alternatives for this difficult patient group, it is worth offering a percutaneous nerve evaluation (PNE) test, which is known to be a good predictor of postimplant treatment success. PMID- 21284799 TI - Future indications for sacral nerve stimulation. AB - AIM: The aim of this article was to determine the effect of sacral nerve stimulation (SNS) on the treatment of faecal incontinence, constipation, irritable bowel syndrome, mixed urinary and bowel disorders, spinal injury and neurodegenerative disease, pain syndromes, and sexual dysfunction. METHOD: A Medline search was performed including the keywords and/or MeSH headings of 'sacral nerve stimulation', 'neuromodulation', 'artificial pacemaker', 'faecal incontinence', 'constipation' and 'anal pain'. Further studies were identified by cross-referencing from relevant articles and by appraisal of recent peer-reviewed conference abstracts and proceedings. RESULTS: SNS has been used for the treatment of urinary, bowel and sexual dysfunction, as well as pain resulting from such disorders, and dysfunction arising from nerve injury and degenerative disease. There is a paucity of high quality evidence to support the use of SNS for the majority of novel indications at present. CONCLUSION: Good quality prospective, cross-over studies are required to determine the true benefits of SNS. Further research into patient selection, operative technique and stimulation parameters for existing indications will ensure a place for SNS in the future treatment algorithm of functional pelvic floor disorders. PMID- 21284800 TI - Cytokinin-mediated source/sink modifications improve drought tolerance and increase grain yield in rice under water-stress. AB - Drought is the major environmental factor limiting crop productivity worldwide. We hypothesized that it is possible to enhance drought tolerance by delaying stress-induced senescence through the stress-induced synthesis of cytokinins in crop-plants. We generated transgenic rice (Oryza sativa) plants expressing an isopentenyltransferase (IPT) gene driven by P(SARK) , a stress- and maturation induced promoter. Plants were tested for drought tolerance at two yield-sensitive developmental stages: pre- and post-anthesis. Under both treatments, the transgenic rice plants exhibited delayed response to stress with significantly higher grain yield (GY) when compared to wild-type plants. Gene expression analysis revealed a significant shift in expression of hormone-associated genes in the transgenic plants. During water-stress (WS), P(SARK)::IPT plants displayed increased expression of brassinosteroid-related genes and repression of jasmonate related genes. Changes in hormone homeostasis were associated with resource(s) mobilization during stress. The transgenic plants displayed differential expression of genes encoding enzymes associated with hormone synthesis and hormone-regulated pathways. These changes and associated hormonal crosstalk resulted in the modification of source/sink relationships and a stronger sink capacity of the P(SARK)::IPT plants during WS. As a result, the transgenic plants had higher GY with improved quality (nutrients and starch content). PMID- 21284801 TI - Single intravenous administration of TB-402 for the prophylaxis of venous thromboembolism after total knee replacement: a dose-escalating, randomized, controlled trial. AB - BACKGROUND: TB-402 is a novel anticoagulant monoclonal antibody with a prolonged antithrombotic effect resulting from its partial factor (F)VIII inhibition and long half-life. We evaluated the efficacy and safety of a single administration of TB-402 for the prevention of venous thromboembolism (VTE) after total knee replacement (TKR). PATIENTS AND METHODS: This was a phase II, dose-escalating, randomized, enoxaparin-controlled, open-label study. Patients were post operatively assigned to a single dose of TB-402 (0.3, 0.6 or 1.2 mg kg(-1)) or enoxaparin 40 mg for at least 10 days (n = 75 per group; 3:1 TB-402 to enoxaparin). The primary efficacy outcome was total VTE defined as asymptomatic deep vein thrombosis (DVT) detected by bilateral venography and symptomatic VTE by day 7 to 11. The principal safety outcome was the incidence of major bleeding and clinically relevant non-major bleeding. RESULTS: Total VTE was lower in all TB-402 groups compared with enoxaparin: 16.7%(95% CI 9.8-26.9), 23.9%(95% CI 15.3 35.3), 24.1%(95% CI 16.0-34.5) and 39.0%(95% CI 28.8-50.1) for TB-402 0.3, 0.6, 1.2 mg kg(-1) and enoxaparin, respectively (P = 0.003 for TB-402 0.3 mg kg(-1) vs. enoxaparin). The incidence of total VTE in the pooled TB-402 groups was 21.6% (95%CI 16.6-27.5), an absolute risk reduction vs. enoxaparin of 17.4% (95% CI 5.2 29.6). Major or clinically relevant non-major bleeding was observed in 3/75(4.0%), 4/74(5.4%), 7/87(8.0%) and 3/79(3.8%) patients for TB-402 0.3, 0.6, 1.2 mg kg(-1) and enoxaparin, respectively. CONCLUSIONS: TB-402, as a single post operative administration, was associated with a lower rate of VTE in all doses tested, compared with enoxaparin. The incidence of major and clinically relevant non-major bleeding was similar to enoxaparin 40 mg for TB-402 0.3 and 0.6 mg kg( 1). PMID- 21284802 TI - Serum osteoprotegerin is a predictor for incident cardiovascular disease and mortality in a general population: the Tromso Study. AB - BACKGROUND: Osteoprotegerin (OPG) concentration in serum is associated with the presence and severity of atherosclerosis. OBJECTIVE: To investigate the association between serum osteoprotegerin and the risk of a future myocardial infarction, ischemic stroke and mortality in a general population. PATIENTS/METHODS: OPG was measured in serum collected from 6265 subjects recruited from a general population without a prior myocardial infarction and ischemic stroke (the Tromso Study). Incident myocardial infarction, ischemic stroke and mortality were registered during follow-up. Cox regression models were used to estimate crude and adjusted hazard ratios and 95% confidence intervals (HR; 95% CI). RESULTS: There were 575 myocardial infarctions, 284 ischemic strokes and 824 deaths (146 deaths as a result of ischemic heart disease, 78 deaths because of stroke and 600 deaths due to other causes) in the cohort during a median of 10.6 years of follow-up. Serum OPG (per SD [1.13 ng mL(-1)] increase in OPG) was associated with an increased risk of a myocardial infarction (1.20; 1.11-1.31), ischemic stroke (1.32; 1.18-1.47), total mortality (1.34; 1.26-1.42), death because of ischemic heart disease, (1.35; 1.18-1.54), stroke (1.44; 1.19 1.75) and non-vascular causes (1.31; 1.22-1.41) after adjustment for age, gender, current smoking, systolic blood pressure, body mass index, high density lipoprotein cholesterol, total cholesterol, creatinine, high sensitivity C reactive protein (CRP) and diabetes mellitus or HbA1c > 6.1%. No association was detected between OPG and incident hemorrhagic stroke (1.02; 0.73-1.43). CONCLUSIONS: Serum OPG was associated with future risk of myocardial infarction, ischemic stroke, total mortality, mortality of ischemic heart disease, stroke and of non-vascular causes independent of traditional cardiovascular risk factors. PMID- 21284803 TI - Current standards in the diagnostics and therapy of hair diseases - hair consultation. AB - Hair and scalp diseases present an extensive diagnostic and therapeutic task. Treating them is often a challenge for the physician in daily practice. Unclear diagnoses, chronic conditions with long-lasting therapies and the uncertainty of the patient may often lead to unsatisfying situations for both the patient as well as the doctor. The complaints can be divided into (1) hair loss, (2) increased hair growth and (3) abnormal hair quality. A structured history and the objectification of the clinical findings with the help of standardized diagnostic methods and score systems or classifications enable a diagnosis in most patients already at the first visit. Moreover, such structured processes strengthen the treatment satisfaction and compliance of both the patient and the therapist. In the meantime, diagnostic measures and clinical practice guidelines are available for the most common hair disorders. Expertise in basic psychosomatic care and an empathetic approach to the fears and concerns as well as practical advice for the daily contact with hair disorders should be integrated as separate elements in the management of hair diseases; in most cases they are gratefully welcomed by the patients. The aim of this article is to provide the physician with a guideline for the structured management of a hair patient. An overview of recent new developments and the currently available clinical practice guidelines for diagnosis and therapy of hair disorders is presented. PMID- 21284804 TI - Structural and functional aspects of unique type IV secretory components in the Helicobacter pylori cag-pathogenicity island. AB - Helicobacter pylori cytotoxin-associated gene-pathogenicity island (cagPAI) is responsible for the secretion of the CagA effector through a type IV secretion system (T4SS) apparatus, as well as of peptidoglycan and possibly other not yet identified factors. Twenty-nine different polypeptide chains are encoded by this cluster of genes, although only some of them show a significant similarity with the constitutive elements of well characterized secretion systems from other bacteria. The other cagPAI components represent almost unique proteins in this scenario. The majority of the T4SS include approximately fifteen components, taking into account either the transmembrane complex subunits, ATPases or substrate factors. The composition of the cagPAI is very complex: it includes proteins most likely involved at different levels in the pilus assembly, stabilization and processing of secreted substrate, as well as regulatory particles possibly involved in the control of the entire apparatus. Despite recent findings with respect to components that play a role in the interaction with the host cell, the function of several cagPAI proteins remains unclear or unknown. This is particularly true for those that represent unique members with no clear similarity to those of other T4SS and no obvious evidence of involvement in the secretion of CagA or induction of pro-inflammatory responses. We summarize what is known about these accessory components, both from a molecular and structural point of view, as well as their putative physiological role. PMID- 21284805 TI - Acceleration of disulfide-coupled protein folding using glutathione derivatives. AB - Protein folding occurs simultaneously with disulfide bond formation. In general, the in vitro folding of proteins containing disulfide bond(s) is carried out in the presence of redox reagents, such as glutathione, to permit native disulfide pairing to occur. It is well known that the formation of a disulfide bond and the correct tertiary structure of a target protein are strongly affected by the redox reagent used. However, little is known concerning the role of each amino acid residue of the redox reagent, such as glutathione. Therefore, we prepared glutathione derivatives - glutamyl-cysteinyl-arginine (ECR) and arginyl-cysteinyl glycine (RCG) - and examined their ability to facilitate protein folding using lysozyme and prouroguanylin as model proteins. When the reduced and oxidized forms of RCG were used, folding recovery was greater than that for a typical glutathione redox system. This was particularly true when high protein concentrations were employed, whereas folding recovery using ECR was similar to that of the glutathione redox system. Kinetic analyses of the oxidative folding of prouroguanylin revealed that the folding velocity (K(RCG) = 3.69 * 10(-3) s( 1)) using reduced RCG/oxidized RCG was approximately threefold higher than that using reduced glutathione/oxidized glutathione. In addition, folding experiments using only the oxidized form of RCG or glutathione indicated that prouroguanylin was converted to the native conformation more efficiently in the case of RCG, compared with glutathione. The findings indicate that a positively charged redox molecule is preferred to accelerate disulfide-exchange reactions and that the RCG system is effective in mediating the formation of native disulfide bonds in proteins. PMID- 21284806 TI - Silintaphin-1--interaction with silicatein during structure-guiding bio-silica formation. AB - Silicateins are unique enzymes of sponges (phylum Porifera) that template and catalyze the polymerization of nanoscale silicate to siliceous skeletal elements. These multifunctional spicules are often elaborately shaped, with complex symmetries. They carry an axial proteinaceous filament, consisting of silicatein and the scaffold protein silintaphin-1, which guides silica deposition and subsequent spicular morphogenesis. In vivo, the synthesis of the axial filament very likely proceeds in three steps: (a) assembly of silicatein monomers to form one pentamer; (b) assembly of pentamers to form fractal-like structures; and finally (c) assembly of fractal-like structures to form filaments. The present study was aimed at exploring the effect of self-assembled complexes of silicatein and silintaphin-1 on biosilica synthesis in vitro. Hence, in a comparative approach, recombinant silicatein and recombinant silintaphin-1 were used at different stoichiometric ratios to form axial filaments and to synthesize biosilica. Whereas recombinant silicatein-alpha reaggregates to randomly organized structures, coincubation of silicatein-alpha and silintaphin-1 (molecular ratio 4 : 1) resulted in synthetic filaments via fractal-like patterned self-assemblies, as observed by electron microscopy. Concurrently, owing to the concerted action of both proteins, the enzymatic activity of silicatein-alpha strongly increased by 5.3-fold (with the substrate tetraethyl orthosilicate), leading to significantly enhanced synthesis of biosilica. These results indicate that silicatein-alpha-mediated biosilicification depends on the concomitant presence of silicatein-alpha and silintaphin-1. Accordingly, silintaphin-1 might not only enhance the enzymatic activity of silicatein-alpha, but also accelerate the nonenzymatic polycondensation of the silica product before releasing the fully synthesized biosiliceous polymer. PMID- 21284807 TI - Developing academic paediatric emergency medicine in Australia and New Zealand. PMID- 21284808 TI - A stand against drug company advertising. PMID- 21284809 TI - A systematic review: The role and impact of the physician assistant in the emergency department. AB - This systematic review describes the role and impact of physician assistants (PAs) in the ED. It includes reports of surveys, retrospective and prospective studies as well as guidelines and reviews. Seven hundred and twelve studies were identified of which only 66 were included, and many of these studies were limited by methodological quality. Generally the use of PAs in the ED is modest with 13 18% of US EDs having PAs although academic medical centres report PA use in 65 68% of EDs. The evidence indicates that PAs are reliable in assessing certain medical complaints and performing procedures, and are well accepted by ED staff and patients alike. There is limited evidence as to whether PAs improve ED flow or are cost-effective. Future studies on work processes, cost-effectiveness, unfamiliar patients' willingness to be treated by non-physician providers, and ED physicians' acceptability of PAs are needed to inform and guide the integration of PAs into EDs. PMID- 21284810 TI - Management of cardiac arrest following poisoning. AB - Toxic cardiac arrest is an uncommon manifestation of poisoning. Patients might benefit from resuscitative measures that are over and above those recommended in standard ACLS resuscitation guidelines. Extraordinary resuscitative measures might include the use of toxin-specific antidotes, prolonged CPR and/or other measures to bypass the poisoned myocardium (such as extra-corporeal membrane oxygenation). Treating medical staff should seek expert advice from a toxicologist or from their Poisons Information Centre network (Australia 13 11 26; New Zealand 0800 764 766) at the earliest opportunity when managing patients with cardiac arrest or intractable shock from known or suspected poisoning. Ideally, toxicological expertise should be sought before the withdrawal of active treatment in cardiac arrest or shock from known or suspected poisoning. PMID- 21284811 TI - No effect of time of day at presentation to the emergency department on the outcome of patients who are admitted to the intensive care unit. AB - OBJECTIVES: To determine if an association exists between the time of day when a patient presents to ED and their outcome for those admitted directly to the ICU. METHODS: We performed a retrospective cohort study on all patients admitted to the ICU directly from the ED from 1 July 2006 to 30 June 2008, using data from the ED and ICU databases in a single institution. Comparisons of mortality, length of stay in the ED, ICU, hospital and time on a ventilator were made based on the time of presentation. RESULTS: A total of 400 patients were admitted to ICU from the ED. There was no evidence of a difference in mortality between those presenting between midnight and 8 am, 8 am and 4 pm or 4 pm and midnight (23.2%, 22.8%, 19.5%, respectively, P= 0.71), or for those presenting during office hours (8 am-4 pm Monday to Friday) or outside office hours (26.1% and 20.2%, respectively, P= 0.23). There were no differences in time on a ventilator, or length of stay in ED, intensive care and hospital. CONCLUSIONS: The time of day patients arrive at the ED has no association with length of stay in ED, intensive care or hospital, time on the ventilator, or mortality for those who are admitted to the ICU. PMID- 21284812 TI - Sick leave in the emergency department: staff attitudes and the impact of job designation and psychosocial work conditions. AB - AIM: To examine patterns of, and attitudes to, sick leave taken by ED and other hospital staff and to compare ED doctor and nurse psychosocial work conditions. METHODS: This was an observational study in a tertiary referral ED. An audit of sick leave taken over a 2-year period (2007-2008) by all ED, general medicine (GM) and pharmacy pay groups was undertaken. This was followed by a cross sectional survey of ED staff. It evaluated attitudes towards sick leave and used the Karasek's Job Content Questionnaire to assess psychosocial work conditions. RESULTS: Overall, sick leave taken by the various staff groups differed significantly (P < 0.01). The ED and GM nurse rates (6.0% and 5.9%, respectively) were approximately twice that of pharmacists (3.3%) and ED allied health staff (3.1%) and more than three times that of all doctor groups (range 1.3-1.9%). ED registrars and nurses tended to take more leave on Monday/Tuesday and Thursday/Friday, respectively. These groups also tended to take more leave in winter/early summer and autumn/spring, respectively. In total, 147 (93.0%, 95% CI 87.6-96.0) ED staff rarely/never took sick leave without being sick. However, 15 (9.5%, 95% CI 5.6-15.5) often/very often took sick leave because of work stress. Compared with ED nurses, ED doctors had significantly more job insecurity and supervisor support but less psychological job demand (P < 0.05). CONCLUSIONS: Emergency department staff generally report healthy psychosocial work conditions. However, the high rate of ED nurse sick leave might be related to their considerable psychological job demand and perceived lack of supervisor support. PMID- 21284813 TI - Emergency department knowledge management in the age of Web 2.0: evaluation of a new concept. AB - OBJECTIVE: The objective of the present study was to describe the implementation of an organizational learning model and evaluate the effectiveness and usability of an application used to facilitate it in an ED setting. METHODS: This was an implementation case study and technology evaluation. The organizational learning model was implemented using an online Web 2.0 collaborative learning application developed by the investigating team. Online use was tracked over a 9-month period. At the end of the study period, a usability assessment was conducted as well as a semistructured interview of participants to assess perceptions of usefulness and effect on learning capacity in the ED. RESULTS: Over a period of 9 months, a total of 54 individual sites from 74 eligible staff members were created within a specific web domain. There were 251 registered users including users outside the ED, who accessed learning materials within these sites 7494 times. The majority of staff members interviewed agreed or strongly agreed that the collaborative learning application had improved learning capacity within this ED (88%, 95% CI 74-94%). CONCLUSION: We demonstrate the implementation of an organizational learning model based on independent online sites networking together within an organization. This appears to be both usable and acceptable to staff members working in a large ED as a means of knowledge management. PMID- 21284814 TI - Scapular manipulation for reduction of anterior shoulder dislocation without analgesia: results of a prospective study. AB - OBJECTIVES: To the best of knowledge, this was the first study of scapular manipulation technique (SMT) in Asia. We conducted this prospective study to report our experiences of reducing anterior shoulder dislocation by SMT without analgesia in a large study group in Iran. METHODS: Scapular manipulation technique was applied to 111 patients presenting with anterior shoulder dislocation to the ED of the largest teaching hospital in north-east of Iran between January 2009 and January 2010. Reduction was performed without medication and if unsuccessful, the second attempt was carried out with i.v. injection of midazolam. We also evaluated the pain experienced by the patients immediately after reduction attempt. RESULTS: The study consisted of 112 dislocations (one patient had bilateral dislocation). We achieved a success rate of 87.5% without medication at the first attempt and 97.3% overall. In total, 98.2% of dislocations were reduced in less than 1 min. The success rate was significantly lower in the presence of greater tuberosity fractures and also in late presentations (>6 h after trauma). We showed a success rate of 100% in recurrent dislocations. Some 81.1% of the patients reported no pain or mild pain. No complications were observed. CONCLUSION: The results of our study showed that SMT even without medication is a safe, rapid and relatively painless technique in reducing anterior shoulder dislocation in the ED that might reduce medical resource utilization and can be cost-effective. PMID- 21284815 TI - Using 0.45% saline solution and a modified dosing regimen for infusing N acetylcysteine in children with paracetamol poisoning. AB - INTRODUCTION: N-acetylcysteine (NAC) administration is recommended to all patients judged to be at risk of developing hepatotoxicity following paracetamol overdose. However, it has been shown that standard i.v. dosing can cause symptomatic hyponatraemia in children. We describe a case series using 0.45% NaCl plus 5% dextrose for infusing i.v. NAC in children with paracetamol poisoning. CASE SERIES: A retrospective review of medical records of patients treated with NAC using 0.45% saline plus 5% dextrose, and a novel two-stage dosing regimen between January 2003 and July 2006 were undertaken. RESULTS: A total of 40 patients (20 male and 20 female) who received NAC in 0.45% sodium chloride (NaCl) with 5% dextrose were identified. Mean age was 9 years 6 months (95% CI 4 years 4 months to 15 years 1 month) and the range 3 months to 17 years. All patients had NAC infused in a two-stage infusion regimen (150 mg/kg bolus over 1 h followed by a continuous infusion of 10 mg/kg/h for 20 h). The serum sodium was measured in all 40 patients with a mean of 140 (range of 133 to 152 mmol/L). Repeat sodium was measured in 35 cases, with a mean of 140 mmol/L (range from 134 to 149 mmol/L). CONCLUSION: These findings support the use of saline-containing solutions to administer NAC as an alternative to 5% dextrose, and suggest that a two-stage infusion regimen should be further investigated with prospective studies. PMID- 21284816 TI - Comparison of visual analogue and Likert scales in evaluation of an emergency department bedside teaching programme. AB - The present study compares visual analogue scale (VAS) to Likert-type scale (LTS) instruments in evaluating perceptions of an ED bedside clinical teaching programme. A prospective study was conducted in the ED of an urban, adult tertiary hospital. Prospective pairing occurred of a teaching consultant and registrar who were relatively quarantined from normal clinical duties. Registrars received 3 months of the teaching intervention, and 3 months without the intervention in a cross-over fashion. Evaluation questionnaires were completed using both the LTS and 100 mm horizontal VAS for each question. Correlation between VAS and LTS gave a measure of validity, and test-retest stability and internal consistency gave measures of reliability. Registrar perceptions of the teaching programme were positive, but no differences were found between the pre- and post-intervention groups. The test-retest reliabilities (intraclass correlation coefficient) for the questionnaires were 0.51 and 0.54 for the VAS, and 0.58 and 0.58 for the LTS. Cronbach's alpha varied between 0.79 and 0.91 for the VAS, and 0.79 and 0.81 for the LTS. Correlations between the two methods varied from 0.35 to 0.94 for each question. A linear regression equation describing the relationship approximated VAS = 19.5 * LTS-9 with overall r= 0.89. An ED bedside teaching programme is perceived to be a beneficial educational intervention. The VAS is a reliable and valid alternative to the LTS for educational evaluation and might provide advantages in educational measurement. Further research into the significance of extreme values and educationally important changes in scores is required. PMID- 21284817 TI - The Emergency Medicine Capacity Assessment Study: perceived resource requirements to support a major increase in intern numbers in Australian emergency departments. AB - INTRODUCTION: A 70% increase in graduating interns is projected in Australia from 2007 to 2012. Emergency medicine is a key term in the intern year. There is little information on the preparedness of EDs for this increase, and what resources will be required. METHODS: Semistructured telephone interview to senior and junior ED medical staff nationwide with graded responses using a Likert scale or ordinal multi-category scales to enable quantitative analysis. RESULTS: 36 of 37 targeted hospitals were surveyed. 95 of 233 (40.1%) potential interviews were completed, including 61/61 (100%) of ED Directors. Communications systems and human resource adjustments were felt to be critical, including more supervisory staff and more time dedicated for senior medical staff to supervise. Thematic analysis confirmed the priorities were staffing and infrastructure requirements. DISCUSSION: We recommend attention to ED communications infrastructure, an increase in rostered supervisory time for senior ED medical staff, and the provision of additional ED medical educators to teach interns. PMID- 21284818 TI - Emergency Department Workforce Models: What the literature can tell us. AB - The present study looks at what the literature can tell us about examples of innovative ED staffing. Numerous medical databases, journals specific to emergency care, and key government agency sites were searched to obtain Australian and relevant international literature between 1995 and the present. Studies which discussed appropriate staffing arrangements in the EDs were assessed with preference given to those which gathered evidence about the staff mix. There is little literature available which looks at the entire staffing profile of an ED and assesses its effectiveness. The few papers that do exist conclude that senior staffing, matching peak staffing levels with peak patient demand, having appropriately skilled staff mixes and designing the staff profile based upon individual hospital needs produces the most effective outcomes. Although there are some lessons to be learnt from the success of the staffing of various teams, and the introduction of new roles in the EDs, there are still significant gaps within the literature. There is a need for assessment of the effectiveness of various ED-wide staffing profiles (rather than just individual teams within an ED). PMID- 21284819 TI - Acute compartment syndrome of the thigh following minor trauma in a patient on dual anti-platelet therapy. AB - Acute compartment syndrome of the thigh is a rare surgical emergency. It is usually associated with high energy trauma and concomitant femoral fracture. We present the case of a 54 year old man who developed acute compartment syndrome of the thigh following a low energy traumatic hamstring tear. Background anti platelet therapy and hospital prescribed anticoagulants were likely contributors to this pathology. We describe these factors and discuss the issues associated with assessment of minor trauma in the anti-coagulated patient. PMID- 21284820 TI - 'Mass allergy': acute scombroid poisoning in a deployed Australian Defence Force health facility. AB - On the last night of disaster relief operations in Sumatra, Indonesia, a mass casualty event occurred that involved deployed Australian Defence Force personnel. Symptoms of acute urticaria, angioedema, wheeze and gastrointestinal upset were experienced to varying degrees by 16% of the deployed element. The present report describes a presumed scombroid poisoning cluster and demonstrates the difficulties of operating in a deployed environment, the confusion that might be associated with evolving non-kinetic mass casualties, and provides a learning opportunity for an unusual mass casualty incident. PMID- 21284821 TI - Erythema multiforme major due to occupational exposure to the herbicides alachlor and butachlor. AB - Alachlor and butachlor are commonly used chloroacetanilide herbicides. They are cytotoxic, but there have been rare reported cases of alachlor or butachlor induced erythema multiforme major. We report the case of a 38-year-old farmer with erythema multiforme major due to the occupational exposure to alachlor/butachlor. The patient presented to the ED because of itching. Confluent erythematous to violaceous maculopatches with bullae and erosions were seen on the trunk, both upper extremities and both lower extremities. He had no relevant past or family history of a similar skin disease. He had used alachlor/butachlor for 3 days before he developed the itch. We performed a skin incisional biopsy and found diffuse hydropic degeneration with many necrotic keratinocytes in the epidermis and mild to moderate superficial perivascular lymphocytic infiltrate admixed with neutrophils and eosinophils in the upper dermis. These results confirmed the diagnosis of erythema multiforme major. The patient was admitted and received systemic and topical steroids. After 18 days, most lesions had healed, and he was discharged. PMID- 21284822 TI - Is it worth emergency departments recording information about alcohol-related assault occurring in inner-city, late-night entertainment precincts? PMID- 21284823 TI - Updated 2010 Consolidated Standards of Reporting Trials guidelines and selective reporting of clinical trial outcomes: In response to Babl and Davidson. PMID- 21284824 TI - Improving emergency department access by using a regional dashboard for ambulance diversion. PMID- 21284825 TI - A room of one's own. PMID- 21284826 TI - Lue TF, Zeineh SJ, Scmidt RA and Tanagho EA--Neuroanatomy of penile erection: its relevance to iatrogenic impotence. 1984. PMID- 21284828 TI - ISSM public policy: premature ejaculation. PMID- 21284829 TI - Impact of hypertension, aging, and antihypertensive treatment on the morphology of the pudendal artery. AB - INTRODUCTION: Aging and hypertension increase the risk of erectile dysfunction (ED) and cardiovascular disease. Arterial insufficiency is likely a primary factor in hypertension-related ED. Given the dominance of internal pudendal arteries in controlling penile vascular resistance, pathological changes in this vessel would be critical for inducing ED in aged hypertensives. AIM: We assessed the age-related impact of hypertension and its treatment on erectile function and pudendal artery structure in young and old spontaneously hypertensive rats (SHRs). METHODS: Erectile responses were monitored in 15- and 77-week-old SHR and Wistar Kyoto (WKY) rats using apomorphine (80 mg/kg). At sacrifice, the vasculature was perfusion-fixed and aorta, renal, mesenteric, and internal pudendal arteries assessed morphometrically using light and electron microscopy. A separate group of 15-week SHR were treated with enalapril and hydrochlorothiazide (30 mg/kg/day, 2 weeks) followed by 2 weeks off treatment, after which the same vessels were assessed morphometrically. Arterial pressures were determined using radiotelemetry. MAIN OUTCOMES MEASURED: Erectile function, vessel morphology (lumen diameter, wall thickness, cross-sectional area, extracellular matrix [ECM]) and arterial pressure. RESULTS: Erectile responses were similar in young SHR and WKY (1.7 +/- 0.80 vs. 1.4 +/- 0.85) but declined significantly in aged SHR (0.3 +/- 0.49). Vascular aging in SHR was associated with striking pudendal remodeling, characterized by marked neointimal proliferation and disruptions of the internal elastic lamina. This remodeling involved thickening of the medial layer (35 +/- 6.0 um vs. 81 +/- 3.5 um, P < 0.01), decreased lumen diameter (282 +/- 6.3 um vs. 250 +/- 12.4 um, P < 0.05) and increased ECM (10 +/- 2.0 um2 vs. 26 +/- 10.6 um2, P < 0.001). In old pudendals, there were significantly more round synthetic smooth muscle cells bordering the intima and in the neointima. Antihypertensive treatment decreased the wall:lumen ratio in young SHR pudendal arteries (-17%). CONCLUSIONS: Vascular aging in SHR with ED involved distinctive pathogenic remodeling in the internal pudendal artery. In young SHR, brief antihypertensive therapy was able to regress this abnormal morphology. PMID- 21284830 TI - First pharmacophore model of CCR3 receptor antagonists and its homology model assisted, stepwise virtual screening. AB - CCR3, a G protein-coupled receptor, plays a central role in allergic inflammation and is an important drug target for inflammatory diseases. To understand the structure-function relationship of CCR3 receptor, different computational techniques were employed, which mainly include: (i) homology modeling of CCR3 receptor, (ii) 3D-quantitative pharmacophore model of CCR3 antagonists, (iii) virtual screening of small compound databases, and (iv) finally, molecular docking at the binding site of the CCR3 receptor homology model. Pharmacophore model was developed for the first time, on a training data set of 22 CCR3 antagonists, using CATALYST HypoRefine program. Best hypothesis (Hypo1) has three different chemical features: two hydrogen-bond acceptors, one hydrophobic, and one ring aromatic. Hypo1 model was further validated using (i) 87 test set CCR3 antagonists, (ii) Cat Scramble randomization technique, and (iii) Decoy data set. Molecular docking studies were performed on modeled CCR3 receptor using 303 virtually screened hits, obtained from small compound database virtual screening. Finally, five hits were identified as potential leads against CCR3 receptor, which exhibited good estimated activities, favorable binding interactions, and high docking scores. These studies provided useful information on the structurally vital residues of CCR3 receptor involved in the antagonist binding, and their unexplored potential for the future development of potent CCR3 receptor antagonists. PMID- 21284831 TI - Evaluation of schistocyte monitoring after haematopoietic stem cell transplantation. AB - INTRODUCTION: Observation of schistocytes on the peripheral blood following haematopoietic stem cell transplantation (SCT) is a common finding. As their presence is not specific to the onset of SCT-related thrombotic microangiopathy, we evaluated the interest of schistocyte measurement twice a week during the entire follow-up of 195 patients undergoing SCT, particularly focussing on the 125 allogeneic SCT. METHODS: Schistocytes were strickly defined as triangular-, crescent- or helmet-shaped red blood cells according to consensus standards and were checked blindly under the microscope and with computer image analysis. RESULTS: Mean schistocyte percentage was 0.7% (+/-0.5%, reference value <=0.5). High schistocyte percentage was observed after allografts (0.79%) when compared to autologous SCT (0.47, P < 0.001). All but one patients undergoing allogenic SCT had schistocytes >=0.6%. Conversely, significant schistocytosis was observed in 20% of the autologous SCT. Initial diagnosis [chronic myelocytic leukaemia, acute lymphoblastic leukaemia (ALL)], high-risk status, unrelated transplant and conditioning regimen including total body irradiation influenced higher schistocyte percentage (~0.9%). Significant rise in the schistocyte percentage was observed during acute/chronic graft-versus-host disease, veno-occlusive disease (VOD), cholestatic hepatitis, haemorrhagic cystitis (HC) and pulmonary complications. Multivariate analysis showed a significant association between thrombotic microangiopathy (TM), renal impairment and delayed thrombopaenia after day 50, and schistocyte >1.2%. SCT-TM grade >=2 occurred in nine patients. A marked rise in schistocyte >4.5% was observed, which was not reached during the other SCT-related complications. Children with ALL, undergoing unrelated allogeneic SCT, with early acute graft-versus-host disease refractory to steroids were prone to present SCT-TM, associated with VOD, interstitial pneumopathy and HC, resulting in a high mortality rate (six of seven patients). Our data confirmed that schistocytosis was common after SCT. Mild percentages were likely concomitant with extensive endothelial damage but higher percentage should have prompted to a close monitoring with SCT-TM investigation. CONCLUSION: In our experience, systematic schistocyte count after HSCT proved to be useful: the occurrence of an increased percentage was a surrogate marker for complications even if unspecific for TM. PMID- 21284832 TI - Detection of dengue-4 virus in pune, western india after an absence of 30 years- its association with two severe cases. AB - BACKGROUND: Difference in severity of dengue outbreaks has been related to virus serotype, genotype and clades within genotypes. Till the 1980 s, India and Sri Lanka reported low number of dengue hemorrhagic fever (DHF) cases despite circulation of all four serotypes of dengue virus (DENV). Since the 1990 s the occurrence of DHF has increased. The increase has been attributed to changes in virus lineage especially with regard to DENV-2 and DENV-3. DENV-1 has been associated with dengue fever (DF) outbreaks and DENV-4 reports have been rare. The emergence of DENV-4 was reported recently in 2003 in Delhi and in 2007 in Hyderabad. The last report of DENV-4 from Maharashtra was in 1975 from Amalner. RESULTS: We report on the detection of DENV-4 in Pune, Maharashtra after an absence of almost 30 years. Two cases were detected in 2009-10, serotyped by multiplex reverse transcriptase polymerase chain reaction (RT-PCR). Both the cases were recorded as severe dengue (Category 3) requiring intensive care unit (ICU) level of treatment. Depending on the hemagglutination inhibiting (HI) antibody titres the 2009 case was characterized as a primary infection and the 2010 case as a secondary infection. Both the cases presented plasma leakage and neither showed any kind of haemorrhage. The 2009 case survived while the 2010 case was fatal. An isolate was obtained from the 2009 case. Based on envelope (E) gene sequence analysis, the virus belonged to genotype I of DENV-4, and clustered with isolates from India and Sri Lanka and was distant from the isolates from Thailand. The nucleotide and amino acid diversity of the E gene of the Indian isolates increased from 1996 to 2007 to 2009 in context of the E gene sequences of other isolates belonging to genotype I. CONCLUSION: The increasing diversity in the circulating DENV-4 calls for close monitoring of the DENV-4 serotype. PMID- 21284833 TI - Adiponectin levels and expression of adiponectin receptors in isolated monocytes from overweight patients with coronary artery disease. AB - BACKGROUND: Adiponectin has insulin-sensitizing and anti-atherosclerotic effects, partly mediated through its action on monocytes. We aimed to determine adiponectin levels and expression of its receptors (AdipoR1 and AdipoR2) in peripheral monocytes from overweight and obese patients with coronary artery disease (CAD). METHODS: Fifty-five overweight/obese patients, suspected for CAD, underwent coronary angiography: 31 were classified as CAD patients (stenosis >= 50% in at least one main vessel) and 24 as nonCAD. Quantitative RT-PCR and flow cytometry were used for determining mRNA and protein surface expression of adiponectin receptors in peripheral monocytes. A high sensitivity multiplex assay (xMAP technology) was used for the determination of plasma adiponectin and interleukin-10 (IL-10) secreted levels. RESULTS: Plasma adiponectin levels were decreased in CAD compared to nonCAD patients (10.9 +/- 3.1 vs. 13.8 +/- 5.8 MUg/ml respectively, p = 0.033). In multivariable analysis, Matsuda index was the sole independent determinant of adiponectin levels. AdipoR1 and AdipoR2 protein levels were decreased in monocytes from CAD compared to nonCAD patients (59.5 +/- 24.9 vs. 80 +/- 46 and 70.7 +/- 39 vs. 95.6 +/- 47.8 Mean Fluorescence Intensity Arbitrary Units respectively, p < 0.05). No significant differences were observed concerning the mRNA levels of the adiponectin receptors between CAD and nonCAD patients. AdipoR2 protein levels were positively correlated with plasma adiponectin and Matsuda index (r = 0.36 and 0.31 respectively, p < 0.05 for both). Furthermore, basal as well as adiponectin-induced IL-10 release was reduced in monocyte-derived macrophages from CAD compared to nonCAD subjects. CONCLUSIONS: Overweight patients with CAD compared to those without CAD, had decreased plasma adiponectin levels, as well as decreased surface expression of adiponectin receptors in peripheral monocytes. This fact together with the reduced adiponectin-induced IL-10 secretion from CAD macrophages could explain to a certain extent, an impaired atheroprotective action of adiponectin. PMID- 21284834 TI - General lack of global dosage compensation in ZZ/ZW systems? Broadening the perspective with RNA-seq. AB - BACKGROUND: Species with heteromorphic sex chromosomes face the challenge of large-scale imbalance in gene dose. Microarray-based studies in several independent male heterogametic XX/XY systems suggest that dosage compensation mechanisms are in place to mitigate the detrimental effects of gene dose differences. However, recent genomic research on female heterogametic ZZ/ZW systems has generated surprising results. In two bird species and one lepidopteran no evidence for a global dosage compensating mechanism has been found. The recent advent of massively parallel RNA sequencing now opens up the possibility to gauge the generality of this observation with a broader phylogenetic sampling. It further allows assessing the validity of microarray based inference on dosage compensation with a novel technology. RESULTS: We here exemplify this approach using massively parallel sequencing on barcoded individuals of a bird species, the European crow (Corvus corone), where previously no genetic resources were available. Testing for Z-linkage with quantitative PCR (qPCR,) we first establish that orthology with distantly related species (chicken, zebra finch) can be used as a good predictor for chromosomal affiliation of a gene. We then use a digital measure of gene expression (RNA-seq) on brain transcriptome and confirm a global lack of dosage compensation on the Z chromosome. RNA-seq estimates of male-to-female (m:f) expression difference on the Z compare well to previous microarray-based estimates in birds and lepidopterans. The data further lends support that an up-regulation of female Z linked genes conveys partial compensation and suggest a relationship between sex bias and absolute expression level of a gene. Correlation of sex-biased gene expression on the Z chromosome across all three bird species further suggests that the degree of compensation has been partly conserved across 100 million years of avian evolution. CONCLUSIONS: This work demonstrates that the study of dosage compensation has become amenable to species where previously no genetic resources were available. Massively parallele transcriptome sequencing allows re assessing the degree of dosage compensation with a novel tool in well-studies species and, in addition, gain valuable insights into the generality of mechanisms across independent taxonomic group for both the XX/XY and ZZ/ZW system. PMID- 21284835 TI - Phred-Phrap package to analyses tools: a pipeline to facilitate population genetics re-sequencing studies. AB - BACKGROUND: Targeted re-sequencing is one of the most powerful and widely used strategies for population genetics studies because it allows an unbiased screening for variation that is suitable for a wide variety of organisms. Examples of studies that require re-sequencing data are evolutionary inferences, epidemiological studies designed to capture rare polymorphisms responsible for complex traits and screenings for mutations in families and small populations with high incidences of specific genetic diseases. Despite the advent of next generation sequencing technologies, Sanger sequencing is still the most popular approach in population genetics studies because of the widespread availability of automatic sequencers based on capillary electrophoresis and because it is still less prone to sequencing errors, which is critical in population genetics studies. Two popular software applications for re-sequencing studies are Phred Phrap-Consed-Polyphred, which performs base calling, alignment, graphical edition and genotype calling and DNAsp, which performs a set of population genetics analyses. These independent tools are the start and end points of basic analyses. In between the use of these tools, there is a set of basic but error-prone tasks to be performed with re-sequencing data. RESULTS: In order to assist with these intermediate tasks, we developed a pipeline that facilitates data handling typical of re-sequencing studies. Our pipeline: (1) consolidates different outputs produced by distinct Phred-Phrap-Consed contigs sharing a reference sequence; (2) checks for genotyping inconsistencies; (3) reformats genotyping data produced by Polyphred into a matrix of genotypes with individuals as rows and segregating sites as columns; (4) prepares input files for haplotype inferences using the popular software PHASE; and (5) handles PHASE output files that contain only polymorphic sites to reconstruct the inferred haplotypes including polymorphic and monomorphic sites as required by population genetics software for re-sequencing data such as DNAsp. CONCLUSION: We tested the pipeline in re-sequencing studies of haploid and diploid data in humans, plants, animals and microorganisms and observed that it allowed a substantial decrease in the time required for sequencing analyses, as well as being a more controlled process that eliminates several classes of error that may occur when handling datasets. The pipeline is also useful for investigators using other tools for sequencing and population genetics analyses. PMID- 21284836 TI - MM-ChIP enables integrative analysis of cross-platform and between-laboratory ChIP-chip or ChIP-seq data. AB - The ChIP-chip and ChIP-seq techniques enable genome-wide mapping of in vivo protein-DNA interactions and chromatin states. The cross-platform and between laboratory variation poses a challenge to the comparison and integration of results from different ChIP experiments. We describe a novel method, MM-ChIP, which integrates information from cross-platform and between-laboratory ChIP-chip or ChIP-seq datasets. It improves both the sensitivity and the specificity of detecting ChIP-enriched regions, and is a useful meta-analysis tool for driving discoveries from multiple data sources. PMID- 21284837 TI - The relationship between various measures of obesity and arterial stiffness in morbidly obese patients. AB - BACKGROUND: Obesity is associated with increased risk of cardiovascular disease. Arterial stiffness assessed by carotid femoral pulse wave velocity (PWV) is an independent predictor of cardiovascular morbidity and mortality. We aimed to investigate how various measures of body composition affect arterial stiffness. METHODS: This is an analysis of cross-sectional baseline data from a controlled clinical trial addressing changes in arterial stiffness after either surgery or lifestyle intervention in a population of morbidly obese patients. High-fidelity applanation tonometry (Millar, Sphygmocor) was used to measure pulse wave velocity (PWV). Carotid femoral PWV is a direct measure of arterial stiffness and is considered to be the gold standard method. The Inbody 720 Body Composition Analyzer was used for bioelectrical impedance analysis (BIA). Spearman's correlation, independent samples t-test, chi-square tests, Fisher's exact test and multiple linear regression analyses were used as statistical methods. RESULTS: A total of 133 patients (79 women), with a mean (SD) age of 43 (11) years were included in the study. Men had a significantly higher prevalence of obesity related comorbidities and significantly higher PWV, 9.1 (2.0) m/s vs. 8.1 (1.8) m/s, p = 0.003, than women. In the female group, PWV was positively correlated with WC, WHtR, BMI and visceral fat area. In the male group, PWV was negatively correlated with BMI. Multiple linear regression analysis showed that increasing BMI, WC, WHtR, visceral fat area and fat mass were independently associated with higher PWV in women, but not in men, after adjustment for age, hypertension and type 2 diabetes. CONCLUSION: Most measures of general and abdominal obesity were predictors of arterial stiffness in female morbidly obese patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00626964. PMID- 21284838 TI - A randomised trial of a psychosocial intervention for cancer patients integrated into routine care: the PROMPT study (promoting optimal outcomes in mood through tailored psychosocial therapies). AB - BACKGROUND: Despite evidence that up to 35% of patients with cancer experience significant distress, access to effective psychosocial care is limited by lack of systematic approaches to assessment, a paucity of psychosocial services, and patient reluctance to accept treatment either because of perceived stigma or difficulties with access to specialist psycho-oncology services due to isolation or disease burden. This paper presents an overview of a randomised study to evaluate the effectiveness of a brief tailored psychosocial Intervention delivered by health professionals in cancer care who undergo focused training and participate in clinical supervision. METHODS/DESIGN: Health professionals from the disciplines of nursing, occupational therapy, speech pathology, dietetics, physiotherapy or radiation therapy will participate in training to deliver the psychosocial Intervention focusing on core concepts of supportive-expressive, cognitive and dignity-conserving care. Health professional training will consist of completion of a self-directed manual and participation in a skills development session. Participating health professionals will be supported through structured clinical supervision whilst delivering the Intervention. In the stepped wedge design each of the 5 participating clinical sites will be allocated in random order from Control condition to Training then delivery of the Intervention. A total of 600 patients will be recruited across all sites. Based on level of distress or risk factors eligible patients will receive up to 4 sessions, each of up to 30 minutes in length, delivered face-to-face or by telephone. Participants will be assessed at baseline and 10-week follow-up. Patient outcome measures include anxiety and depression, quality of life, unmet psychological and supportive care needs. Health professional measures include psychological morbidity, stress and burnout. Process evaluation will be conducted to assess perceptions of participation in the study and the factors that may promote translation of learning into practice. DISCUSSION: This study will provide important information about the effectiveness of a brief tailored psychological Intervention for patients with cancer and the potential to prevent development of significant distress in patients considered at risk. It will yield data about the feasibility of this model of care in routine clinical practice and identify enablers and barriers to its systematic implementation in cancer settings. TRIAL REGISTRATION: ACTRN12610000448044. PMID- 21284839 TI - The demise of the United Kingdom's forensic science service (FSS): loss of world leading engine of innovation and development in the forensic sciences. PMID- 21284840 TI - Long-term follow-up after en bloc resection and reconstruction of a solitary paraganglioma metastasis in the first lumbar vertebral body: a case report. AB - INTRODUCTION: Paragangliomas are rare tumors that originate from the autonomic nervous system-associated paraganglia. They metastasize infrequently. Malignancy can only be demonstrated by the presence of chromaffin tissue at sites where it usually is not present, such as bone, lung or liver, or local recurrence after total resection of a primary mass. Paragangliomas within the central nervous system are usually intradural near the conus medullaris. The metastatic spread of a retroperitoneal paraganglioma to a vertebral body is extremely rare, and there are only a few cases reported in the literature. CASE PRESENTATION: We report the case of a 16-year-old Caucasian girl who had undergone resection of a retroperitoneal paraganglioma that measured 15 * 11.5 * 9.5 cm. After further staging, a solitary metastatic paraganglioma was detected in the first lumbar vertebral body. After initial chemotherapy, marginal en bloc resection and reconstruction were performed followed by radiotherapy. Histologic examination of the specimen revealed that the tumor cells did not show any response to preoperative chemotherapy, which is in line with a few other reports in the literature. Ten years after operative treatment, the patient is free of complaints, very satisfied with the result and without signs of local recurrence or distant metastases. CONCLUSION: We recommend en bloc spondylectomy and local radiotherapy in the treatment of solitary spinal metastatic paragangliomas. PMID- 21284841 TI - Elementary, my dear Cameron. PMID- 21284842 TI - No evidence for transmission of SIVwrc from western red colobus monkeys (Piliocolobus badius badius) to wild West African chimpanzees (Pan troglodytes verus) despite high exposure through hunting. AB - BACKGROUND: Simian Immunodeficiency Viruses (SIVs) are the precursors of Human Immunodeficiency Viruses (HIVs) which have led to the worldwide HIV/AIDS pandemic. By studying SIVs in wild primates we can better understand the circulation of these viruses in their natural hosts and habitat, and perhaps identify factors that influence susceptibility and transmission within and between various host species. We investigated the SIV status of wild West African chimpanzees (Pan troglodytes verus) which frequently hunt and consume the western red colobus monkey (Piliocolobus badius badius), a species known to be infected to a high percentage with its specific SIV strain (SIVwrc). RESULTS: Blood and plasma samples from 32 wild chimpanzees were tested with INNO-LIA HIV I/II Score kit to detect cross-reactive antibodies to HIV antigens. Twenty-three of the samples were also tested for antibodies to 43 specific SIV and HIV lineages, including SIVwrc. Tissue samples from all but two chimpanzees were tested for SIV by PCRs using generic SIV primers that detect all known primate lentiviruses as well as primers designed to specifically detect SIVwrc. Seventeen of the chimpanzees showed varying degrees of cross-reactivity to the HIV specific antigens in the INNO-LIA test; however no sample had antibodies to SIV or HIV strain- and lineage-specific antigens in the Luminex test. No SIV DNA was found in any of the samples. CONCLUSIONS: We could not detect any conclusive trace of SIV infection from the red colobus monkeys in the chimpanzees, despite high exposure to this virus through frequent hunting. The results of our study raise interesting questions regarding the host-parasite relationship of SIVwrc and wild chimpanzees in their natural habitat. PMID- 21284843 TI - Obsessionality & compulsivity: a phenomenology of obsessive-compulsive disorder. AB - Progress in psychiatry depends on accurate definitions of disorders. As long as there are no known biologic markers available that are highly specific for a particular psychiatric disorder, clinical practice as well as scientific research is forced to appeal to clinical symptoms. Currently, the nosology of obsessive compulsive disorder is being reconsidered in view of the publication of DSM-V. Since our diagnostic entities are often simplifications of the complicated clinical profile of patients, definitions of psychiatric disorders are imprecise and always indeterminate. This urges researchers and clinicians to constantly think and rethink well-established definitions that in psychiatry are at risk of being fossilised. In this paper, we offer an alternative view to the current definition of obsessive-compulsive disorder from a phenomenological perspective. TRANSLATION: This article is translated from Dutch, originally published in [Handbook Obsessive-compulsive disorders, Damiaan Denys, Femke de Geus (Eds.), (2007). De Tijdstroom uitgeverij BV, Utrecht. ISBN13: 9789058980878.]. PMID- 21284844 TI - NKCC1 controls GABAergic signaling and neuroblast migration in the postnatal forebrain. AB - From an early postnatal period and throughout life there is a continuous production of olfactory bulb (OB) interneurons originating from neuronal precursors in the subventricular zone. To reach the OB circuits, immature neuroblasts migrate along the rostral migratory stream (RMS). In the present study, we employed cultured postnatal mouse forebrain slices and used lentiviral vectors to label neuronal precursors with GFP and to manipulate the expression levels of the Na-K-2Cl cotransporter NKCC1. We investigated the role of this Cl- transporter in different stages of postnatal neurogenesis, including neuroblast migration and integration in the OB networks once they have reached the granule cell layer (GCL). We report that NKCC1 activity is necessary for maintaining normal migratory speed. Both pharmacological and genetic manipulations revealed that NKCC1 maintains high [Cl-]i and regulates the resting membrane potential of migratory neuroblasts whilst its functional expression is strongly reduced at the time cells reach the GCL. As in other developing systems, NKCC1 shapes GABAA dependent signaling in the RMS neuroblasts. Also, we show that NKCC1 controls the migration of neuroblasts in the RMS. The present study indeed indicates that the latter effect results from a novel action of NKCC1 on the resting membrane potential, which is independent of GABAA-dependent signaling. All in all, our findings show that early stages of the postnatal recruitment of OB interneurons rely on precise, orchestrated mechanisms that depend on multiple actions of NKCC1. PMID- 21284845 TI - The chromatin remodeling factor Bap55 functions through the TIP60 complex to regulate olfactory projection neuron dendrite targeting. AB - BACKGROUND: The Drosophila olfactory system exhibits very precise and stereotyped wiring that is specified predominantly by genetic programming. Dendrites of olfactory projection neurons (PNs) pattern the developing antennal lobe before olfactory receptor neuron axon arrival, indicating an intrinsic wiring mechanism for PN dendrites. These wiring decisions are likely determined through a transcriptional program. RESULTS: We find that loss of Brahma associated protein 55 kD (Bap55) results in a highly specific PN mistargeting phenotype. In Bap55 mutants, PNs that normally target to the DL1 glomerulus mistarget to the DA4l glomerulus with 100% penetrance. Loss of Bap55 also causes derepression of a GAL4 whose expression is normally restricted to a small subset of PNs. Bap55 is a member of both the Brahma (BRM) and the Tat interactive protein 60 kD (TIP60) ATP dependent chromatin remodeling complexes. The Bap55 mutant phenotype is partially recapitulated by Domino and Enhancer of Polycomb mutants, members of the TIP60 complex. However, distinct phenotypes are seen in Brahma and Snf5-related 1 mutants, members of the BRM complex. The Bap55 mutant phenotype can be rescued by postmitotic expression of Bap55, or its human homologs BAF53a and BAF53b. CONCLUSIONS: Our results suggest that Bap55 functions through the TIP60 chromatin remodeling complex to regulate dendrite wiring specificity in PNs. The specificity of the mutant phenotypes suggests a position for the TIP60 complex at the top of a regulatory hierarchy that orchestrates dendrite targeting decisions. PMID- 21284846 TI - Insm1 promotes the transition of olfactory progenitors from apical and proliferative to basal, terminally dividing and neuronogenic. AB - BACKGROUND: Insm1 is a zinc-finger transcription factor transiently expressed throughout the developing nervous system in late progenitors and nascent neurons. Insm1 is also highly expressed in medulloblastomas and other neuroendocrine tumors. RESULTS: We generated mice lacking the Insm1 gene and used them to elucidate its role in neurogenic proliferation of the embryonic olfactory epithelium. We found that deletion of Insm1 results in more apical cells and fewer nascent and mature neurons. In the embryonic olfactory epithelium of Insm1 mutants we detect fewer basal progenitors, which produce neurons, and more apical progenitors, which at this stage produce additional progenitors. Furthermore, in the mutants we detect fewer progenitors expressing NEUROD1, a marker of terminally dividing, neuronogenic (neuron-producing) progenitors (immediate neuronal precursors), and more progenitors expressing ASCL1, a marker of the transit amplifying progenitors that migrate from the apical to the basal edges of the epithelium while dividing to generate the terminal, neuronogenic progenitors. Finally, with timed administration of nucleoside analogs we demonstrate that the Insm1 mutants contain fewer terminally dividing progenitors at embryonic day 12.5. CONCLUSIONS: Altogether, these results suggest a role for Insm1 in promoting the transition of progenitors from apical and proliferative to basal, terminal and neuronogenic. This role appears partially conserved with that of its nematode ortholog, egl-46. The similar effects of Insm1 deletion on progenitors of embryonic olfactory epithelium and cortex point to striking parallels in the development of these neuroepithelia, and particularly between the basal progenitors of olfactory epithelium and the subventricular zone progenitors of cortex. PMID- 21284847 TI - Local knowledge, pattern and diversity of use of Sclerocarya birrea. AB - BACKGROUND: Growing interest is on food tree species in general, and particularly indigenous fruit tree species in developing countries since they are inherent to most tropical landscapes and serve the dual function of local livelihood support and biodiversity conservation. It is therefore relevant to assess the level of integration of these species in local cultures and the factors affecting them. This study aims at assessing knowledge and uses of Sclerocarya birrea subsp. birrea and factors affecting the use values within and between communities. METHODS: This study combines quantitative and qualitative ethnobotanical approaches to investigate uses and factors affecting the use value of S. birrea subsp. birrea. Nine group discussions as well as 161 individual interviews were held in the dry and typical Sudanian zones. Seven different ethnic groups were involved and the survey focused on local uses and perception of factors affecting the dynamics of S. birrea. RESULTS: The species has a multitude of uses; all organs are used for more than 20 different purposes. The study highlights how gender, local availability, ethnicity and community location interact to influence the utilization value of the species. People living in drier areas with high occurrence of the S. birrea use it more than those living in wetter areas with low occurrence. While domestic and subsistence uses do not appear to threaten the species, carving, clearing and drought stand out as the major causes of its decline. CONCLUSIONS: Many factors and their interactions influence the use pattern of the species within and between communities. When compared to the level of exploitation of S. birrea subsp. caffra in southern Africa, the subspecies birrea is at this point relatively underutilized. A high commercial potential exists due to its simple propagation ability and makes it an interesting agroforestry resource. PMID- 21284848 TI - Late-life coronary heart disease mortality of Finnish war veterans in the TAMRISK study, a 28-year follow-up. AB - BACKGROUND: Wartime stress has been associated with increased late-life mortality of all causes of death. We evaluated whether wounded Finnish World War II veterans who were alive at the age of 55 have increased long-term coronary heart disease (CHD) mortality. METHODS: Health survey data were recorded in 1980 from 667 men, aged 55 years. Of them 102 had been wounded or injured in action during 1939-1945. The remaining participants served as the comparison group. The death certificates during a 28-year follow-up were obtained from the national statistics centre. Statistical comparisons were done by Cox proportional hazard regression model. RESULTS: There were altogether 140 deaths from CHD. In men who had been wounded or injured in action the crude CHD mortality rate per 10,000 population was 2843, while in the comparison group the corresponding figure was 1961. Men who had been wounded or injured in action were 1.7 times (95% CI 1.1 2.5; p = 0.01) more likely to die from CHD than the comparison group. CONCLUSIONS: Physical trauma at young adulthood may extend to lifelong effects on health. This study suggests that being physically wounded or injured in war may lead to increased CHD mortality in late adulthood in a Finnish population. PMID- 21284849 TI - Developing an electronic health record (EHR) for methadone treatment recording and decision support. AB - BACKGROUND: In this paper, we give an overview of methadone treatment in Ireland and outline the rationale for designing an electronic health record (EHR) with extensibility, interoperability and decision support functionality. Incorporating several international standards, a conceptual model applying a problem orientated approach in a hierarchical structure has been proposed for building the EHR. METHODS: A set of archetypes has been designed in line with the current best practice and clinical guidelines which guide the information-gathering process. A web-based data entry system has been implemented, incorporating elements of the paper-based prescription form, while at the same time facilitating the decision support function. RESULTS: The use of archetypes was found to capture the ever changing requirements in the healthcare domain and externalises them in constrained data structures. The solution is extensible enabling the EHR to cover medicine management in general as per the programme of the HRB Centre for Primary Care Research. CONCLUSIONS: The data collected via this Irish system can be aggregated into a larger dataset, if necessary, for analysis and evidence gathering, since we adopted the openEHR standard. It will be later extended to include the functionalities of prescribing drugs other than methadone along with the research agenda at the HRB Centre for Primary Care Research in Ireland. PMID- 21284850 TI - Analysis of electric moments of RNA-binding proteins: implications for mechanism and prediction. AB - BACKGROUND: Protein-RNA interactions play important role in many biological processes such as gene regulation, replication, protein synthesis and virus assembly. Although many structures of various types of protein-RNA complexes have been determined, the mechanism of protein-RNA recognition remains elusive. We have earlier shown that the simplest electrostatic properties viz. charge, dipole and quadrupole moments, calculated from backbone atomic coordinates of proteins are biased relative to other proteins, and these quantities can be used to identify DNA-binding proteins. Closely related, RNA-binding proteins are investigated in this study. In particular, discrimination between various types of RNA-binding proteins, evolutionary conservation of these bulk electrostatic features and effect of conformational changes by complex formation are investigated. Basic binding mechanism of a putative RNA-binding protein (HI1333 from Haemophilus influenza) is suggested as a potential application of this study. RESULTS: We found that similar to DNA-binding proteins (DBPs), RNA-binding proteins (RBPs) also show significantly higher values of electric moments. However, higher moments in RBPs are found to strongly depend on their functional class: proteins binding to ribosomal RNA (rRNA) constitute the only class with all three of the properties (charge, dipole and quadrupole moments) being higher than control proteins. Neural networks were trained using leave-one-out cross validation to predict RBPs from control data as well as pair-wise classification capacity between proteins binding to various RNA types. RBPs and control proteins reached up to 78% accuracy measured by the area under the ROC curve. Proteins binding to rRNA are found to be best distinguished (AUC = 79%). Changes in dipole and quadrupole moments between unbound and bound structures were small and these properties are found to be robust under complex formation. CONCLUSIONS: Bulk electric moments of proteins considered here provide insights into target recognition by RNA-binding proteins, as well as ability to recognize one type of RBP from others. These results help in understanding the mechanism of protein-RNA recognition, and identifying RNA-binding proteins. PMID- 21284851 TI - The role of codon selection in regulation of translation efficiency deduced from synthetic libraries. AB - BACKGROUND: Translation efficiency is affected by a diversity of parameters, including secondary structure of the transcript and its codon usage. Here we examine the effects of codon usage on translation efficiency by re-analysis of previously constructed synthetic expression libraries in Escherichia coli. RESULTS: We define the region in a gene that takes the longest time to translate as the bottleneck. We found that localization of the bottleneck at the beginning of a transcript promoted a high level of expression, especially if the computed dwell time of the ribosome within this region was sufficiently long. The location and translation time of the bottleneck were not correlated with the cost of expression, approximated by the fitness of the host cell, yet utilization of specific codons was. Particularly, enhanced usage of the codons UCA and CAU was correlated with increased cost of production, potentially due to sequestration of their corresponding rare tRNAs. CONCLUSIONS: The distribution of codons along the genes appears to affect translation efficiency, consistent with analysis of natural genes. This study demonstrates how synthetic biology complements bioinformatics by providing a set-up for well controlled experiments in biology. PMID- 21284852 TI - Myostatin-2 gene structure and polymorphism of the promoter and first intron in the marine fish Sparus aurata: evidence for DNA duplications and/or translocations. AB - BACKGROUND: Myostatin (MSTN) is a member of the transforming growth factor-beta superfamily that functions as a negative regulator of skeletal muscle development and growth in mammals. Fish express at least two genes for MSTN: MSTN-1 and MSTN 2. To date, MSTN-2 promoters have been cloned only from salmonids and zebrafish. RESULTS: Here we described the cloning and sequence analysis of MSTN-2 gene and its 5' flanking region in the marine fish Sparus aurata (saMSTN-2). We demonstrate the existence of three alleles of the promoter and three alleles of the first intron. Sequence comparison of the promoter region in the three alleles revealed that although the sequences of the first 1050 bp upstream of the translation start site are almost identical in the three alleles, a substantial sequence divergence is seen further upstream. Careful sequence analysis of the region upstream of the first 1050 bp in the three alleles identified several elements that appear to be repeated in some or all sequences, at different positions. This suggests that the promoter region of saMSTN-2 has been subjected to various chromosomal rearrangements during the course of evolution, reflecting either insertion or deletion events. Screening of several genomic DNA collections indicated differences in allele frequency, with allele 'b' being the most abundant, followed by allele 'c', whereas allele 'a' is relatively rare. Sequence analysis of saMSTN-2 gene also revealed polymorphism in the first intron, identifying three alleles. The length difference in alleles '1R' and '2R' of the first intron is due to the presence of one or two copies of a repeated block of approximately 150 bp, located at the 5' end of the first intron. The third allele, '4R', has an additional insertion of 323 bp located 116 bp upstream of the 3' end of the first intron. Analysis of several DNA collections showed that the '2R' allele is the most common, followed by the '4R' allele, whereas the '1R' allele is relatively rare. Progeny analysis of a full-sib family showed a Mendelian mode of inheritance of the two genetic loci. No clear association was found between the two genetic markers and growth rate. CONCLUSION: These results show for the first time a substantial degree of polymorphism in both the promoter and first intron of MSTN-2 gene in a perciform fish species which points to chromosomal rearrangements that took place during evolution. PMID- 21284853 TI - Complete genome sequence of a serotype 11A, ST62 Streptococcus pneumoniae invasive isolate. AB - BACKGROUND: Streptococcus pneumoniae is an important human pathogen representing a major cause of morbidity and mortality worldwide. We sequenced the genome of a serotype 11A, ST62 S. pneumoniae invasive isolate (AP200), that was erythromycin resistant due to the presence of the erm(TR) determinant, and carried out analysis of the genome organization and comparison with other pneumococcal genomes. RESULTS: The genome sequence of S. pneumoniae AP200 is 2,130,580 base pair in length. The genome carries 2216 coding sequences (CDS), 56 tRNA, and 12 rRNA genes. Of the CDSs, 72.9% have a predicted biological known function. AP200 contains the pilus islet 2 and, although its phenotype corresponds to serotype 11A, it contains an 11D capsular locus. Chromosomal rearrangements resulting from a large inversion across the replication axis, and horizontal gene transfer events were observed. The chromosomal inversion is likely implicated in the rebalance of the chromosomal architecture affected by the insertions of two large exogenous elements, the erm(TR)-carrying Tn1806 and a functional prophage designated phiSpn_200. Tn1806 is 52,457 bp in size and comprises 49 ORFs. Comparative analysis of Tn1806 revealed the presence of a similar genetic element or part of it in related species such as Streptococcus pyogenes and also in the anaerobic species Finegoldia magna, Anaerococcus prevotii and Clostridium difficile. The genome of phiSpn_200 is 35,989 bp in size and is organized in 47 ORFs grouped into five functional modules. Prophages similar to phiSpn_200 were found in pneumococci and in other streptococcal species, showing a high degree of exchange of functional modules. phiSpn_200 viral particles have morphologic characteristics typical of the Siphoviridae family and are capable of infecting a pneumococcal recipient strain. CONCLUSIONS: The sequence of S. pneumoniae AP200 chromosome revealed a dynamic genome, characterized by chromosomal rearrangements and horizontal gene transfers. The overall diversity of AP200 is driven mainly by the presence of the exogenous elements Tn1806 and phiSpn_200 that show large gene exchanges with other genetic elements of different bacterial species. These genetic elements likely provide AP200 with additional genes, such as those conferring antibiotic-resistance, promoting its adaptation to the environment. PMID- 21284854 TI - Unsuspected pulmonary alveolar proteinosis in a patient with acquired immunodeficiency syndrome: a case report. AB - INTRODUCTION: Diffuse lung infiltrates are a common finding in patients with acquired immunodeficiency syndrome and causes range from infectious processes to malignancies or interstitial lung diseases. Pulmonary alveolar proteinosis is a rare pulmonary disorder rarely reported in patients infected with human immunodeficiency virus. Secondary pulmonary alveolar proteinosis is associated with conditions involving functional impairment or reduced numbers of alveolar macrophages. It can be caused by hematologic malignancies, inhalation of toxic dust, fumes or gases, infectious or pharmacologic immunosuppression, or lysinuric protein intolerance. CASE PRESENTATION: A 42-year-old African American man infected with human immunodeficiency virus was admitted with chronic respiratory symptoms and diffuse pulmonary infiltrates. Chest computed tomography revealed bilateral spontaneous pneumothoraces, for which he required bilateral chest tubes. Initial laboratory investigations did not reveal any contributory conditions. Histological examination of a lung biopsy taken during video-assisted thoracoscopy showed pulmonary alveolar proteinosis concurrent with cytomegalovirus pneumonitis. After ganciclovir treatment, our patient showed radiologic and clinical improvement. CONCLUSION: The differential diagnosis for patients with immunosuppression and lung infiltrates requires extensive investigations. As pulmonary alveolar proteinosis is rare, the diagnosis can be easily missed. Our case highlights the importance of invasive investigations and histology in the management of patients infected with human immunodeficiency virus and pulmonary disease who do not respond to empiric therapy. PMID- 21284855 TI - SUMO-1 regulates the conformational dynamics of thymine-DNA Glycosylase regulatory domain and competes with its DNA binding activity. AB - BACKGROUND: The human thymine-DNA glycosylase (TDG) plays a dual role in base excision repair of G:U/T mismatches and in transcription. Regulation of TDG activity by SUMO-1 conjugation was shown to act on both functions. Furthermore, TDG can interact with SUMO-1 in a non-covalent manner. RESULTS: Using NMR spectroscopy we have determined distinct conformational changes in TDG upon either covalent sumoylation on lysine 330 or intermolecular SUMO-1 binding through a unique SUMO-binding motif (SBM) localized in the C-terminal region of TDG. The non-covalent SUMO-1 binding induces a conformational change of the TDG amino-terminal regulatory domain (RD). Such conformational dynamics do not exist with covalent SUMO-1 attachment and could potentially play a broader role in the regulation of TDG functions for instance during transcription. Both covalent and non-covalent processes activate TDG G:U repair similarly. Surprisingly, despite a dissociation of the SBM/SUMO-1 complex in presence of a DNA substrate, SUMO-1 preserves its ability to stimulate TDG activity indicating that the non-covalent interactions are not directly involved in the regulation of TDG activity. SUMO-1 instead acts, as demonstrated here, indirectly by competing with the regulatory domain of TDG for DNA binding. CONCLUSIONS: SUMO-1 increases the enzymatic turnover of TDG by overcoming the product-inhibition of TDG on apurinic sites. The mechanism involves a competitive DNA binding activity of SUMO-1 towards the regulatory domain of TDG. This mechanism might be a general feature of SUMO-1 regulation of other DNA-bound factors such as transcription regulatory proteins. PMID- 21284856 TI - Cooperative interaction of CTGF and TGF-beta in animal models of fibrotic disease. AB - BACKGROUND: Connective tissue growth factor (CTGF) is widely thought to promote the development of fibrosis in collaboration with transforming growth factor (TGF)-beta; however, most of the evidence for its involvement comes from correlative and culture-based studies. In this study, the importance of CTGF in tissue fibrosis was directly examined in three murine models of fibrotic disease: a novel model of multiorgan fibrosis induced by repeated intraperitoneal injections of CTGF and TGF-beta2; the unilateral ureteral obstruction (UUO) renal fibrosis model; and an intratracheal bleomycin instillation model of pulmonary fibrosis. RESULTS: Intraperitoneal coadministration of CTGF and TGF-beta2 elicited a profound fibrotic response that was inhibited by the human anti-CTGF antibody FG-3019, as indicated by the ability of FG-3019 to ameliorate the histologic signs of fibrosis and reduce the otherwise increased hydroxyproline:proline (Hyp:Pro) ratios by 25% in kidney (P < 0.05), 30% in liver (P < 0.01) and 63% in lung (P < 0.05). Moreover, administration of either cytokine alone failed to elicit a fibrotic response, thus demonstrating that CTGF is both necessary and sufficient to initiate fibrosis in the presence of TGF-beta and vice versa. In keeping with this requirement for CTGF function in fibrosis, FG-3019 also reduced the renal Hyp:Pro response up to 20% after UUO (P < 0.05). In bleomycin-injured animals, a similar trend towards a FG-3019 treatment effect was observed (38% reduction in total lung Hyp, P = 0.056). Thus, FG-3019 antibody treatment consistently reduced excessive collagen deposition and the pathologic severity of fibrosis in all models. CONCLUSION: Cooperative interactions between CTGF and TGF-beta signaling are required to elicit overt tissue fibrosis. This interdependence and the observed anti-fibrotic effects of FG-3019 indicate that anti-CTGF therapy may provide therapeutic benefit in different forms of fibroproliferative disease. PMID- 21284857 TI - Developing the practice context to enable more effective pain management with older people: an action research approach. AB - BACKGROUND: This paper, which draws upon an Emancipatory Action Research (EAR) approach, unearths how the complexities of context influence the realities of nursing practice. While the intention of the project was to identify and change factors in the practice context that inhibit effective person-centred pain management practices with older people (65 years or older), reflective critical engagement with the findings identified that enhancing pain management practices with older people was dependent on cultural change in the unit as a whole. METHODS: An EAR approach was utilised. The project was undertaken in a surgical unit that conducted complex abdominal surgery. Eighty-five percent (n = 48) of nursing staff participated in the two-year project (05/NIR02/107). Data were obtained through the use of facilitated critical reflection with nursing staff. RESULTS: Three key themes (psychological safety, leadership, oppression) and four subthemes (power, horizontal violence, distorted perceptions, autonomy) were found to influence the way in which effective nursing practice was realised. Within the theme of 'context,' effective leadership and the creation of a psychologically safe environment were key elements in the enhancement of all aspects of nursing practice. CONCLUSIONS: Whilst other research has identified the importance of 'practice context' and models and frameworks are emerging to address this issue, the theme of 'psychological safety' has been given little attention in the knowledge translation/implementation literature. Within the principles of EAR, facilitated reflective sessions were found to create 'psychologically safe spaces' that supported practitioners to develop effective person-centred nursing practices in complex clinical environments. PMID- 21284858 TI - Characterisation of two quorum sensing systems in the endophytic Serratia plymuthica strain G3: differential control of motility and biofilm formation according to life-style. AB - BACKGROUND: N-acylhomoserine lactone (AHL)-based quorum sensing (QS) systems have been described in many plant-associated Gram-negative bacteria to control certain beneficial phenotypic traits, such as production of biocontrol factors and plant growth promotion. However, the role of AHL-mediated signalling in the endophytic strains of plant-associated Serratia is still poorly understood. An endophytic Serratia sp. G3 with biocontrol potential and high levels of AHL signal production was isolated from the stems of wheat and the role of QS in this isolate was determined. RESULTS: Strain G3 classified as Serratia plymuthica based on 16S rRNA was subjected to phylogenetic analysis. Using primers to conserved sequences of luxIR homologues from the Serratia genus, splIR and spsIR from the chromosome of strain G3 were cloned and sequenced. AHL profiles from strain G3 and Escherichia coli DH5alpha expressing splI or spsI from recombinant plasmids were identified by liquid chromatography-tandem mass spectrometry. This revealed that the most abundant AHL signals produced by SplI in E. coli were N-3 oxo-hexanoylhomoserine lactone (3-oxo-C6-HSL), N-3-oxo-heptanoylhomoserine lactone (3-oxo-C7-HSL), N-3-hydroxy-hexanoylhomoserine lactone (3-hydroxy-C6 HSL), N-hexanoylhomoserine lactone (C6-HSL), and N-heptanoyl homoserine lactone (C7-HSL); whereas SpsI was primarily responsible for the synthesis of N butyrylhomoserine lactone (C4-HSL) and N-pentanoylhomoserine lactone (C5-HSL). Furthermore, a quorum quenching analysis by heterologous expression of the Bacillus A24 AiiA lactonase in strain G3 enabled the identification of the AHL regulated biocontrol-related traits. Depletion of AHLs with this lactonase resulted in altered adhesion and biofilm formation using a microtiter plate assay and flow cells coupled with confocal laser scanning microscopy respectively. This was different from the closely related S. plymuthica strains HRO-C48 and RVH1, where biofilm formation for both strains is AHL-independent. In addition, QS in G3 positively regulated antifungal activity, production of exoenzymes, but negatively regulated production of indol-3-acetic acid (IAA), which is in agreement with previous reports in strain HRO-C48. However, in contrast to HRO C48, swimming motility was not controlled by AHL-mediated QS. CONCLUSIONS: This is the first report of the characterisation of two AHL-based quorum sensing systems in the same isolate of the genus Serratia. Our results show that the QS network is involved in the global regulation of biocontrol-related traits in the endophytic strain G3. However, although free-living and endophytic S. plymuthica share some conservation on QS phenotypic regulation, the control of motility and biofilm formation seems to be strain-specific and possible linked to the life style of this organism. PMID- 21284859 TI - Accurate inference of shoot biomass from high-throughput images of cereal plants. AB - With the establishment of advanced technology facilities for high throughput plant phenotyping, the problem of estimating plant biomass of individual plants from their two dimensional images is becoming increasingly important. The approach predominantly cited in literature is to estimate the biomass of a plant as a linear function of the projected shoot area of plants in the images. However, the estimation error from this model, which is solely a function of projected shoot area, is large, prohibiting accurate estimation of the biomass of plants, particularly for the salt-stressed plants. In this paper, we propose a method based on plant specific weight for improving the accuracy of the linear model and reducing the estimation bias (the difference between actual shoot dry weight and the value of the shoot dry weight estimated with a predictive model). For the proposed method in this study, we modeled the plant shoot dry weight as a function of plant area and plant age. The data used for developing our model and comparing the results with the linear model were collected from a completely randomized block design experiment. A total of 320 plants from two bread wheat varieties were grown in a supported hydroponics system in a greenhouse. The plants were exposed to two levels of hydroponic salt treatments (NaCl at 0 and 100 mM) for 6 weeks. Five harvests were carried out. Each time 64 randomly selected plants were imaged and then harvested to measure the shoot fresh weight and shoot dry weight. The results of statistical analysis showed that with our proposed method, most of the observed variance can be explained, and moreover only a small difference between actual and estimated shoot dry weight was obtained. The low estimation bias indicates that our proposed method can be used to estimate biomass of individual plants regardless of what variety the plant is and what salt treatment has been applied. We validated this model on an independent set of barley data. The technique presented in this paper may extend to other plants and types of stresses. PMID- 21284860 TI - Sodium selectivity of Reissner's membrane epithelial cells. AB - BACKGROUND: Sodium absorption by Reissner's membrane is thought to contribute to the homeostasis of the volume of cochlear endolymph. It was previously shown that the absorptive transepithelial current was blocked by amiloride and benzamil. The most commonly-observed target of these drugs is the epithelial sodium channel (ENaC), which is composed of the three subunits alpha-,beta- and gamma-ENaC. However, other less-selective cation channels have also been observed to be sensitive to benzamil and amiloride. The aim of this study was to determine whether Reissner's membrane epithelial cells could support parasensory K+ absorption via amiloride- and benzamil-sensitive electrogenic pathways. RESULTS: We determined the molecular and functional expression of candidate cation channels with gene array (GEO GSE6196), RT-PCR, and whole-cell patch clamp. Transcript expression analysis of Reissner's membrane detected no amiloride sensitive acid-sensing ion channels (ASIC1a, ASIC2a, ASIC2b) nor amiloride sensitive cyclic-nucleotide gated channels (CNGA1, CNGA2, CNGA4, CNGB3). By contrast, alpha-,beta- and gamma-ENaC were all previously reported as present in Reissner's membrane. The selectivity of the benzamil-sensitive cation currents was observed in whole-cell patch clamp recordings under Cl--free conditions where cations were the only permeant species. The currents were carried by Na+ but not K+, and the permeability of Li+ was greater than that of Na+ in Reissner's membrane. Complete replacement of bath Na+ with the inpermeable cation NMDG+ led to the same inward current as with benzamil in a Na+ bath. CONCLUSIONS: These results are consistent with the amiloride/benzamil-sensitive absorptive flux of Reissner's membrane mediated by a highly Na+-selective channel that has several key characteristics in common with alphabetagamma-ENaC. The amiloride-sensitive pathway therefore absorbs only Na+ in this epithelium and does not provide a parasensory K+ efflux route from scala media. PMID- 21284861 TI - The development and geometry of shape change in Arabidopsis thaliana cotyledon pavement cells. AB - BACKGROUND: The leaf epidermis is an important architectural control element that influences the growth properties of underlying tissues and the overall form of the organ. In dicots, interdigitated pavement cells are the building blocks of the tissue, and their morphogenesis includes the assembly of specialized cell walls that surround the apical, basal, and lateral (anticlinal) cell surfaces. The microtubule and actin cytoskeletons are highly polarized along the cortex of the anticlinal wall; however, the relationships between these arrays and cell morphogenesis are unclear. RESULTS: We developed new quantitative tools to compare population-level growth statistics with time-lapse imaging of cotyledon pavement cells in an intact tissue. The analysis revealed alternating waves of lobe initiation and a phase of lateral isotropic expansion that persisted for days. During lateral isotropic diffuse growth, microtubule organization varied greatly between cell surfaces. Parallel microtubule bundles were distributed unevenly along the anticlinal surface, with subsets marking stable cortical domains at cell indentations and others clearly populating the cortex within convex cell protrusions. CONCLUSIONS: Pavement cell morphogenesis is discontinuous, and includes punctuated phases of lobe initiation and lateral isotropic expansion. In the epidermis, lateral isotropic growth is independent of pavement cell size and shape. Cortical microtubules along the upper cell surface and stable cortical patches of anticlinal microtubules may coordinate the growth behaviors of orthogonal cell walls. This work illustrates the importance of directly linking protein localization data to the growth behavior of leaf epidermal cells. PMID- 21284862 TI - Evolutionary history of the OmpR/IIIA family of signal transduction two component systems in Lactobacillaceae and Leuconostocaceae. AB - BACKGROUND: Two component systems (TCS) are signal transduction pathways which typically consist of a sensor histidine kinase (HK) and a response regulator (RR). In this study, we have analyzed the evolution of TCS of the OmpR/IIIA family in Lactobacillaceae and Leuconostocaceae, two families belonging to the group of lactic acid bacteria (LAB). LAB colonize nutrient-rich environments such as foodstuffs, plant materials and the gastrointestinal tract of animals thus driving the study of this group of both basic and applied interest. RESULTS: The genomes of 19 strains belonging to 16 different species have been analyzed. The number of TCS encoded by the strains considered in this study varied between 4 in Lactobacillus helveticus and 17 in Lactobacillus casei. The OmpR/IIIA family was the most prevalent in Lactobacillaceae accounting for 71% of the TCS present in this group. The phylogenetic analysis shows that no new TCS of this family has recently evolved in these Lactobacillaceae by either lineage-specific gene expansion or domain shuffling. Furthermore, no clear evidence of non-orthologous replacements of either RR or HK partners has been obtained, thus indicating that coevolution of cognate RR and HKs has been prevalent in Lactobacillaceae. CONCLUSIONS: The results obtained suggest that vertical inheritance of TCS present in the last common ancestor and lineage-specific gene losses appear as the main evolutionary forces involved in their evolution in Lactobacillaceae, although some HGT events cannot be ruled out. This would agree with the genomic analyses of Lactobacillales which show that gene losses have been a major trend in the evolution of this group. PMID- 21284863 TI - FlaME: Flash Molecular Editor - a 2D structure input tool for the web. AB - BACKGROUND: So far, there have been no Flash-based web tools available for chemical structure input. The authors herein present a feasibility study, aiming at the development of a compact and easy-to-use 2D structure editor, using Adobe's Flash technology and its programming language, ActionScript. As a reference model application from the Java world, we selected the Java Molecular Editor (JME). In this feasibility study, we made an attempt to realize a subset of JME's functionality in the Flash Molecular Editor (FlaME) utility. These basic capabilities are: structure input, editing and depiction of single molecules, data import and export in molfile format. IMPLEMENTATION: The result of molecular diagram sketching in FlaME is accessible in V2000 molfile format. By integrating the molecular editor into a web page, its communication with the HTML elements on this page is established using the two JavaScript functions, getMol() and setMol(). In addition, structures can be copied to the system clipboard. CONCLUSION: A first attempt was made to create a compact single-file application for 2D molecular structure input/editing on the web, based on Flash technology. With the application examples presented in this article, it could be demonstrated that the Flash methods are principally well-suited to provide the requisite communication between the Flash object (application) and the HTML elements on a web page, using JavaScript functions. PMID- 21284864 TI - Tobacco use, exposure to secondhand smoke, and cessation counseling among medical students: cross-country data from the Global Health Professions Student Survey (GHPSS), 2005-2008. AB - BACKGROUND: GHPSS is a school-based survey that collects self-administered data from students in regular classroom settings. GHPSS produces representative data at the national or city level in each country. This study aims to investigate the prevalence of tobacco use, exposure to secondhand smoke, and cessation counseling among medical students using the GHPSS data. METHODS: The Global Health Professions Student Survey (GHPSS) was conducted among 3rd year medical students in 47 countries and the Gaza Strip/West Bank from 2005-2008 to determine the prevalence of tobacco use and amount of formal training in cessation counseling. RESULTS: In 26 of the 48 sites, over 20% of the students currently smoked cigarettes, with males having higher rates than females in 37 sites. Over 70% of students reported having been exposed to secondhand smoke in public places in 29 of 48 sites. The majority of students recognized that they are role models in society (over 80% in 42 of 48 sites), believed they should receive training on counseling patients to quit using tobacco (over 80% in 41 of 48 sites), but few reported receiving formal training (less than 40% in 46 of 48 sites). CONCLUSION: Tobacco control efforts must discourage tobacco use among health professionals, promote smoke free workplaces, and implement programs that train medical students in effective cessation-counseling techniques. PMID- 21284865 TI - Variability in school closure decisions in response to 2009 H1N1: a qualitative systems improvement analysis. AB - BACKGROUND: School closure was employed as a non-pharmaceutical intervention against pandemic 2009 H1N1, particularly during the first wave. More than 700 schools in the United States were closed. However, closure decisions reflected significant variation in rationales, decision triggers, and authority for closure. This variability presents the opportunity for improved efficiency and decision-making. METHODS: We identified media reports relating to school closure as a response to 2009 H1N1 by monitoring high-profile sources and searching Lexis Nexis and Google news alerts, and reviewed reports for key themes. News stories were supplemented by observing conference calls and meetings with health department and school officials, and by discussions with decision-makers and community members. RESULTS: There was significant variation in the stated goal of closure decision, including limiting community spread of the virus, protecting particularly vulnerable students, and responding to staff shortages or student absenteeism. Because the goal of closure is relevant to its timing, nature, and duration, unclear rationales for closure can challenge its effectiveness. There was also significant variation in the decision-making authority to close schools in different jurisdictions, which, in some instances, was reflected in open disagreement between school and public health officials. Finally, decision-makers did not appear to expect the level of scientific uncertainty encountered early in the pandemic, and they often expressed significant frustration over changing CDC guidance. CONCLUSIONS: The use of school closure as a public health response to epidemic disease can be improved by ensuring that officials clarify the goals of closure and tailor closure decisions to those goals. Additionally, authority to close schools should be clarified in advance, and decision-makers should expect to encounter uncertainty disease emergencies unfold and plan accordingly. PMID- 21284866 TI - DoBo: Protein domain boundary prediction by integrating evolutionary signals and machine learning. AB - BACKGROUND: Accurate identification of protein domain boundaries is useful for protein structure determination and prediction. However, predicting protein domain boundaries from a sequence is still very challenging and largely unsolved. RESULTS: We developed a new method to integrate the classification power of machine learning with evolutionary signals embedded in protein families in order to improve protein domain boundary prediction. The method first extracts putative domain boundary signals from a multiple sequence alignment between a query sequence and its homologs. The putative sites are then classified and scored by support vector machines in conjunction with input features such as sequence profiles, secondary structures, solvent accessibilities around the sites and their positions. The method was evaluated on a domain benchmark by 10-fold cross validation and 60% of true domain boundaries can be recalled at a precision of 60%. The trade-off between the precision and recall can be adjusted according to specific needs by using different decision thresholds on the domain boundary scores assigned by the support vector machines. CONCLUSIONS: The good prediction accuracy and the flexibility of selecting domain boundary sites at different precision and recall values make our method a useful tool for protein structure determination and modelling. The method is available at http://sysbio.rnet.missouri.edu/dobo/. PMID- 21284867 TI - Digital stereophotogrammetry based on circular markers and zooming cameras: evaluation of a method for 3D analysis of small motions in orthopaedic research. AB - BACKGROUND: Orthopaedic research projects focusing on small displacements in a small measurement volume require a radiation free, three dimensional motion analysis system. A stereophotogrammetrical motion analysis system can track wireless, small, light-weight markers attached to the objects. Thereby the disturbance of the measured objects through the marker tracking can be kept at minimum. The purpose of this study was to develop and evaluate a non-position fixed compact motion analysis system configured for a small measurement volume and able to zoom while tracking small round flat markers in respect to a fiducial marker which was used for the camera pose estimation. METHODS: The system consisted of two web cameras and the fiducial marker placed in front of them. The markers to track were black circles on a white background. The algorithm to detect a centre of the projected circle on the image plane was described and applied. In order to evaluate the accuracy (mean measurement error) and precision (standard deviation of the measurement error) of the optical measurement system, two experiments were performed: 1) inter-marker distance measurement and 2) marker displacement measurement. RESULTS: The first experiment of the 10 mm distances measurement showed a total accuracy of 0.0086 mm and precision of +/- 0.1002 mm. In the second experiment, translations from 0.5 mm to 5 mm were measured with total accuracy of 0.0038 mm and precision of +/- 0.0461 mm. The rotations of 2.25 degrees amount were measured with the entire accuracy of 0.058 degrees and the precision was of +/- 0.172 degrees . CONCLUSIONS: The description of the non-proprietary measurement device with very good levels of accuracy and precision may provide opportunities for new, cost effective applications of stereophotogrammetrical analysis in musculoskeletal research projects, focusing on kinematics of small displacements in a small measurement volume. PMID- 21284868 TI - Retroperitoneal liposarcomas: the experience of a tertiary Asian center. AB - BACKGROUND: Liposarcoma is the single most common soft tissue sarcoma in the retroperitoneum. MATERIALS AND METHODS: A retrospective review of patients with primary retroperitoneal liposarcoma treated between June 1990 and June 2005 were conducted to evaluate the clinical results of resection for retroperitoneal liposarcomas (RPLS) and the prognostic factors for disease recurrence and patient survival in an Asian population. RESULTS: Twenty-one patients operated on for curative intent (12 Males, 9 Females; mean age: 52.4 years) were evaluated. Of these, 13 presented with tumors that were well differentiated (61.9%), 4 (19.0%) with myxoid/round cell, 3 (14.3%) with dedifferentiated and 1(4.8%) with pleomorphic morphology. The median tumor burden was 36 cm (9-83). Median follow up time was 62 months. There was no peri-operative mortality and morbidity occurred in 6(28.6%) patients. Surgical margins were involved in 10(47.6%) patients. Resection of contiguous organs was required in 15(71.4%) to achieve gross surgical margins. Eleven out of the 21(52%) of the patients had recurrence of the tumor. Median disease-free survival was 19 months and the overall 3- and 5 year survival rate was 87% and 49% respectively. CONCLUSION: An aggressive surgical approach in both primary and recurrent RPLS in our institution is associated with 3- and 5-year survival rate of 87% and 49% respectively. Contiguous organ resection is often required to achieve local control. PMID- 21284869 TI - Gastrointestinal stromal tumors: correlation between symptoms at presentation, tumor location and prognostic factors in 47 consecutive patients. AB - BACKGROUND: Gastrointestinal stromal tumors (GIST) are mesenchymal tumors of the gastrointestinal tract, usually kit-positive, that are believed to originate from interstitial cell of Cajal, or their related stem cells. The most common clinical presentation of these tumors is gastrointestinal bleeding, otherwise they may cause intestinal obstruction, abdominal pain, a palpable mass, or can be incidentally detected during surgery or endoscopic/radiological procedures. Prognosis is related to the size of the tumor and to the mitotic rate; other prognostic factors are tumor location, tumor resection margins, tumor rupture, and c-kit mutation that may interfere with molecular target therapy efficacy. AIM: Primary aim of this study was to report our experience regarding GIST patients, correlating symptoms at presentation with tumor localization and risk factors. PATIENTS AND METHODS: 47 consecutive patients undergone to surgical resection for GISTs were enrolled in a prospective study from December 1999 to March 2009. Patient's clinical and pathological features were collected and analysed. RESULTS: The most common symptom was abdominal pain. Bleeding in the digestive tract and abdominal pain were more frequent in gastric GISTs (58% and 61%); acute abdominal symptoms were more frequent in jejunal and ileal GISTs (40% and 60%), p < 0.05. We reported a mild correlation between the mitotic rate index and symptoms at presentation (p 0.074): this correlation was stronger if GISTs causing "acute abdominal symptoms" were compared with GISTs causing "abdominal pain" as main symptom (p 0.039) and with "incidental" GISTs (p 0.022).We observed an higher prevalence of symptomatic patients in the "high risk/malignant group" of both the Fletcher's and Miettines's classification (p < 0.05). CONCLUSION: According with our findings symptoms correlate to tumor location, to class risk criteria as mitotic index and risk classifications, however we cannot conclude that symptoms are per se predictive of survival or patient's outcome. PMID- 21284870 TI - Activation of beta-catenin and Akt pathways by Twist are critical for the maintenance of EMT associated cancer stem cell-like characters. AB - BACKGROUND: Epithelial-mesenchymal transition (EMT) not only confers tumor cells with a distinct advantage for metastatic dissemination, but also it provides those cells with cancer stem cell-like characters for proliferation and drug resistance. However, the molecular mechanism for maintenance of these stem cell like traits remains unclear. METHODS: In this study, we induced EMT in breast cancer MCF7 and cervical cancer Hela cells with expression of Twist, a key transcriptional factor of EMT. The morphological changes associated with EMT were analyzed by immunofluorescent staining and Western blotting. The stem cell-like traits associated with EMT were determined by tumorsphere-formation and expression of ALDH1 and CD44 in these cells. The activation of beta-catenin and Akt pathways was examined by Western blotting and luciferase assays. RESULTS: We found that expression of Twist induced a morphological change associated with EMT. We also found that the cancer stem cell-like traits, such as tumorsphere formation, expression of ALDH1 and CD44, were significantly elevated in Twist overexpressing cells. Interestingly, we showed that beta-catenin and Akt pathways were activated in these Twist-overexpressing cells. Activation of beta-catenin correlated with the expression of CD44. Knockdown of beta-catenin expression and inhibition of the Akt pathway greatly suppressed the expression of CD44. CONCLUSIONS: Our results indicate that activation of beta-catenin and Akt pathways are required for the sustention of EMT-associated stem cell-like traits. PMID- 21284871 TI - Dynamic summarization of bibliographic-based data. AB - BACKGROUND: Traditional information retrieval techniques typically return excessive output when directed at large bibliographic databases. Natural Language Processing applications strive to extract salient content from the excessive data. Semantic MEDLINE, a National Library of Medicine (NLM) natural language processing application, highlights relevant information in PubMed data. However, Semantic MEDLINE implements manually coded schemas, accommodating few information needs. Currently, there are only five such schemas, while many more would be needed to realistically accommodate all potential users. The aim of this project was to develop and evaluate a statistical algorithm that automatically identifies relevant bibliographic data; the new algorithm could be incorporated into a dynamic schema to accommodate various information needs in Semantic MEDLINE, and eliminate the need for multiple schemas. METHODS: We developed a flexible algorithm named Combo that combines three statistical metrics, the Kullback Leibler Divergence (KLD), Riloff's RlogF metric (RlogF), and a new metric called PredScal, to automatically identify salient data in bibliographic text. We downloaded citations from a PubMed search query addressing the genetic etiology of bladder cancer. The citations were processed with SemRep, an NLM rule-based application that produces semantic predications. SemRep output was processed by Combo, in addition to the standard Semantic MEDLINE genetics schema and independently by the two individual KLD and RlogF metrics. We evaluated each summarization method using an existing reference standard within the task-based context of genetic database curation. RESULTS: Combo asserted 74 genetic entities implicated in bladder cancer development, whereas the traditional schema asserted 10 genetic entities; the KLD and RlogF metrics individually asserted 77 and 69 genetic entities, respectively. Combo achieved 61% recall and 81% precision, with an F-score of 0.69. The traditional schema achieved 23% recall and 100% precision, with an F-score of 0.37. The KLD metric achieved 61% recall, 70% precision, with an F-score of 0.65. The RlogF metric achieved 61% recall, 72% precision, with an F-score of 0.66. CONCLUSIONS: Semantic MEDLINE summarization using the new Combo algorithm outperformed a conventional summarization schema in a genetic database curation task. It potentially could streamline information acquisition for other needs without having to hand-build multiple saliency schemas. PMID- 21284872 TI - Deciphering the shape and deformation of secondary structures through local conformation analysis. AB - BACKGROUND: Protein deformation has been extensively analysed through global methods based on RMSD, torsion angles and Principal Components Analysis calculations. Here we use a local approach, able to distinguish among the different backbone conformations within loops, alpha-helices and beta-strands, to address the question of secondary structures' shape variation within proteins and deformation at interface upon complexation. RESULTS: Using a structural alphabet, we translated the 3 D structures of large sets of protein-protein complexes into sequences of structural letters. The shape of the secondary structures can be assessed by the structural letters that modeled them in the structural sequences. The distribution analysis of the structural letters in the three protein compartments (surface, core and interface) reveals that secondary structures tend to adopt preferential conformations that differ among the compartments. The local description of secondary structures highlights that curved conformations are preferred on the surface while straight ones are preferred in the core. Interfaces display a mixture of local conformations either preferred in core or surface. The analysis of the structural letters transition occurring between protein-bound and unbound conformations shows that the deformation of secondary structure is tightly linked to the compartment preference of the local conformations. CONCLUSION: The conformation of secondary structures can be further analysed and detailed thanks to a structural alphabet which allows a better description of protein surface, core and interface in terms of secondary structures' shape and deformation. Induced-fit modification tendencies described here should be valuable information to identify and characterize regions under strong structural constraints for functional reasons. PMID- 21284873 TI - Exome localization of complex disease association signals. AB - BACKGROUND: Genome-wide association studies (GWAS) of common diseases have had a tremendous impact on genetic research over the last five years; the field is now moving from microarray-based technology towards next-generation sequencing. To evaluate the potential of association studies for complex diseases based on exome sequencing we analysed the distribution of association signal with respect to protein-coding genes based on GWAS data for seven diseases from the Wellcome Trust Case Control Consortium. RESULTS: We find significant concentration of association signal in exons and genes for Crohn's Disease, Type 1 Diabetes and Bipolar Disorder, but also observe enrichment from up to 40 kilobases upstream to 40 kilobases downstream of protein-coding genes for Crohn's Disease and Type 1 Diabetes; the exact extent of the distribution is disease dependent. CONCLUSIONS: Our work suggests that exome sequencing may be a feasible approach to find genetic variation associated with complex disease. Extending the exome sequencing to include flanking regions therefore promises further improvement of covering disease-relevant variants. PMID- 21284874 TI - An efficient record linkage scheme using graphical analysis for identifier error detection. AB - BACKGROUND: Integration of information on individuals (record linkage) is a key problem in healthcare delivery, epidemiology, and "business intelligence" applications. It is now common to be required to link very large numbers of records, often containing various combinations of theoretically unique identifiers, such as NHS numbers, which are both incomplete and error-prone. METHODS: We describe a two-step record linkage algorithm in which identifiers with high cardinality are identified or generated, and used to perform an initial exact match based linkage. Subsequently, the resulting clusters are studied and, if appropriate, partitioned using a graph based algorithm detecting erroneous identifiers. RESULTS: The system was used to cluster over 250 million health records from five data sources within a large UK hospital group. Linkage, which was completed in about 30 minutes, yielded 3.6 million clusters of which about 99.8% contain, with high likelihood, records from one patient. Although computationally efficient, the algorithm's requirement for exact matching of at least one identifier of each record to another for cluster formation may be a limitation in some databases containing records of low identifier quality. CONCLUSIONS: The technique described offers a simple, fast and highly efficient two-step method for large scale initial linkage for records commonly found in the UK's National Health Service. PMID- 21284875 TI - A functional and transcriptomic analysis of NET1 bioactivity in gastric cancer. AB - BACKGROUND: NET1, a RhoA guanine exchange factor, is up-regulated in gastric cancer (GC) tissue and drives the invasive phenotype of this disease. In this study, we aimed to determine the role of NET1 in GC by monitoring the proliferation, motility and invasion of GC cells in which NET1 has been stably knocked down. Additionally, we aimed to determine NET1-dependent transcriptomic events that occur in GC. METHODS: An in vitro model of stable knockdown of NET1 was achieved in AGS human gastric adenocarcinoma cells via lentiviral mediated transduction of short-hairpin (sh) RNA targeting NET1. Knockdown was assessed using quantitative PCR. Cell proliferation was assessed using an MTS assay and cell migration was assessed using a wound healing scratch assay. Cell invasion was assessed using a transwell matrigel invasion assay. Gene expression profiles were examined using affymetrix oligonucleotide U133A expression arrays. A student's t test was used to determine changes of statistical significance. RESULTS: GC cells were transduced with NET1 shRNA resulting in a 97% reduction in NET1 mRNA (p < 0.0001). NET1 knockdown significantly reduced the invasion and migration of GC cells by 94% (p < 0.05) and 24% (p < 0.001) respectively, while cell proliferation was not significantly altered following NET1 knockdown. Microarray analysis was performed on non-target and knockdown cell lines, treated with and without 10 MUM lysophosphatidic acid (LPA) allowing us to identify NET1 dependent, LPA-dependent and NET1-mediated LPA-induced gene transcription. Differential gene expression was confirmed by quantitative PCR. Shortlisted NET1 dependent genes included STAT1, TSPAN1, TGFBi and CCL5 all of which were downregulatd upon NET1 downregulation. Shortlisted LPA-dependent genes included EGFR and PPARD where EGFR was upregulated and PPARD was downregulated upon LPA stimulation. Shortlisted NET1 and LPA dependent genes included IGFR1 and PIP5K3. These LPA induced genes were downregulated in NET1 knockdown cells. CONCLUSIONS: NET1 plays an important role in GC cell migration and invasion, key aspects of GC progression. Furthermore, the gene expression profile further elucidates the molecular mechanisms underpinning NET1-mediated aggressive GC cell behaviour. PMID- 21284876 TI - A regulatory network of two galectins mediates the earliest steps of avian limb skeletal morphogenesis. AB - BACKGROUND: The skeletal elements of vertebrate embryonic limbs are prefigured by rod- and spot-like condensations of precartilage mesenchymal cells. The formation of these condensations depends on cell-matrix and cell-cell interactions, but how they are initiated and patterned is as yet unresolved. RESULTS: Here we provide evidence that galectins, beta-galactoside-binding lectins with beta-sandwich folding, play fundamental roles in these processes. We show that among the five chicken galectin (CG) genes, two, CG-1A, and CG-8, are markedly elevated in expression at prospective sites of condensation in vitro and in vivo, with their protein products appearing earlier in development than any previously described marker. The two molecules enhance one another's gene expression but have opposite effects on condensation formation and cartilage development in vivo and in vitro: CG-1A, a non-covalent homodimer, promotes this process, while the tandem-repeat type CG-8 antagonizes it. Correspondingly, knockdown of CG-1A inhibits the formation of skeletal elements while knockdown of CG-8 enhances it. The apparent paradox of mutual activation at the gene expression level coupled with antagonistic roles in skeletogenesis is resolved by analysis of the direct effect of the proteins on precartilage cells. Specifically, CG-1A causes their aggregation, whereas CG-8, which has no adhesive function of its own, blocks this effect. The developmental appearance and regulation of the unknown cell surface moieties ("ligands") to which CG-1A and CG-8 bind were indicative of specific cognate- and cross-regulatory interactions. CONCLUSION: Our findings indicate that CG-1A and CG-8 constitute a multiscale network that is a major mediator, earlier-acting than any previously described, of the formation and patterning of precartilage mesenchymal condensations in the developing limb. This network functions autonomously of limb bud signaling centers or other limb bud positional cues. PMID- 21284877 TI - End-stage renal disease preceded by rapid declines in kidney function: a case series. AB - BACKGROUND: Few studies have defined alternate pathways by which chronic kidney disease (CKD) patients transition into end-stage renal disease (ESRD). METHODS: We studied all consecutive patients initiated on maintenance hemodialysis or peritoneal dialysis over several years at two dialysis units in Northern California. Rapid decline in kidney function was considered to have occurred if a patient was documented to have estimated GFR > 30 ml/min/1.73 m2 within three months prior to the initiation of chronic dialysis. RESULTS: We found that 8 out of 105 incident chronic dialysis patients one dialysis unit (7.6%; 95% confidence interval 3.4-14.5%) and 9 out of 71 incident patients at another (12.7%, 95% CI 6.0%-22.7%) suffered rapid decline in kidney function that was the immediate precipitant for the need for permanent renal replacement therapy. All these patients started hemodialysis and all relied on catheters for vascular access. Documentation submitted to United States Renal Data System did not fully reflect the health status of these patients during their "pre-ESRD" period. CONCLUSIONS: A sizeable minority of ESRD cases are preceded by rapid declines in kidney function. The importance of these periods of rapid decline may have been under appreciated in prior studies of the natural history of CKD and ESRD. PMID- 21284878 TI - Sparse PrP(Sc) accumulation in the placentas of goats with naturally acquired scrapie. AB - BACKGROUND: Domestic goats (Capra hircus) are a natural and experimental host of scrapie and bovine spongiform encephalopathy, the transmissible spongiform encephalopathies (TSE) of sheep and cattle. Goats are also susceptible to experimental infection with the agents of TSEs of deer and elk (chronic wasting disease) and humans (Creutzfeldt Jakob disease). Distribution of PrPSc, the abnormal prion protein, is similar in the tissues of scrapie-infected sheep and goats but no data are available on the potential shedding of the agent through the placenta, the presumed route of transmission of ovine scrapie. We describe the sparse accumulation of PrPSc in the placentas of goats with naturally acquired classical scrapie in comparison to field cases of classical ovine scrapie. RESULTS: PrPSc was detected in the shed placentas from a sample of U.S. goats with naturally occurring scrapie, diagnosed by antemortem lymphoid tissue biopsy or identified as high risk progeny of infected dams. PrPSc accumulation patterns in the intact placentome and western blot banding was similar in the caprine and ovine samples. However, levels of PrPSc estimated from ELISA and immunohistochemistry assays were generally lower in goats than in sheep, although wide variation was noted in both species. CONCLUSIONS: PrPSc accumulates in the shed placentas of goats with naturally acquired scrapie. Although these levels were low in most caprine samples, the caprine placenta may contribute to prion contamination of kidding facilities and transmission to co-housed sheep or goats. PMID- 21284879 TI - Alumina-on-alumina total hip replacement for femoral neck fracture in healthy patients. AB - BACKGROUND: Total hip replacement is considered the best option for treatment of displaced intracapsular fractures of the femoral neck (FFN). The size of the femoral head is an important factor that influences the outcome of a total hip arthroplasty (THA): implants with a 28 mm femoral head are more prone to dislocate than implants with a 32 mm head. Obviously, a large head coupled to a polyethylene inlay can lead to more wear, osteolysis and failure of the implant. Ceramic induces less friction and minimal wear even with larger heads. METHODS: A total of 35 THAs were performed for displaced intracapsular FFN, using a 32 mm alumina-alumina coupling. RESULTS: At a mean follow-up of 80 months, 33 have been clinically and radiologically reviewed. None of the implants needed revision for any reason, none of the cups were considered to have failed, no dislocations nor breakage of the ceramic components were recorded. One anatomic cementless stem was radiologically loose. CONCLUSIONS: On the basis of our experience, we suggest that ceramic-on-ceramic coupling offers minimal friction and wear even with large heads. PMID- 21284880 TI - Evaluation of the safety of C-spine clearance by paramedics: design and methodology. AB - BACKGROUND: Canadian Emergency Medical Services annually transport 1.3 million patients with potential neck injuries to local emergency departments. Less than 1% of those patients have a c-spine fracture and even less (0.5%) have a spinal cord injury. Most injuries occur before the arrival of paramedics, not during transport to the hospital, yet most patients are transported in ambulances immobilized. They stay fully immobilized until a bed is available, or until physician assessment and/or X-rays are complete. The prolonged immobilization is often unnecessary and adds to the burden of already overtaxed emergency medical services systems and crowded emergency departments. METHODS/DESIGN: The goal of this study is to evaluate the safety and potential impact of an active strategy that allows paramedics to assess very low-risk trauma patients using a validated clinical decision rule, the Canadian C-Spine Rule, in order to determine the need for immobilization during transport to the emergency department.This cohort study will be conducted in Ottawa, Canada with one emergency medical service. Paramedics with this service participated in an earlier validation study of the Canadian C-Spine Rule. Three thousand consecutive, alert, stable adult trauma patients with a potential c-spine injury will be enrolled in the study and evaluated using the Canadian C-Spine Rule to determine the need for immobilization. The outcomes that will be assessed include measures of safety (numbers of missed fractures and serious adverse outcomes), measures of clinical impact (proportion of patients transported without immobilization, key time intervals) and performance of the Rule. DISCUSSION: Approximately 40% of all very low-risk trauma patients could be transported safely, without c-spine immobilization, if paramedics were empowered to make clinical decisions using the Canadian C-Spine Rule. This safety study is an essential step before allowing all paramedics across Canada to selectively immobilize trauma victims before transport. Once safety and potential impact are established, we intend to implement a multi-centre study to study actual impact. PMID- 21284881 TI - Mechanisms of confluence-dependent expression of CD26 in colon cancer cell lines. AB - BACKGROUND: CD26 (dipeptidyl peptidase IV, DPPIV) is a 110 kDa surface glycoprotein expressed in most normal tissues, and is a potential novel therapeutic target for selected cancers. Our work evaluates the mechanism involved in confluence-dependent CD26 expression in colon cancer. METHODS: Colon adenocarcinoma cells were grown to confluence, and expression of CD26 and transcription factors implicated in its regulation was confirmed by immunofluorescence and Western blotting. Real-time PCR was also performed to evaluate CD26 upregulation at the transcriptional level. The influence of c-Myc on CD26 expression during different growth conditions was further evaluated following transient transfection of a c-Myc-expressing plasmid and a c-Myc specific siRNA. RESULTS: We found that the colon cancer cell lines HCT-116 and HCT-15 exhibited a confluence-dependent increase in CD26 mRNA and protein, associated with decreased expression of c-Myc, increased USF-1 and Cdx 2 levels, and unchanged HNF-1alpha expression. Meanwhile, ectopic expression of c-Myc in both cell lines led to decreased CD26 expression. In contrast, transfection of a siRNA targeted to Cdx2 resulted in decreased CD26 level. Importantly, culturing of cells in serum-depleted media, but not acidic conditions, upregulated CD26. While HIF-1alpha level also increased when cells were cultured in serum-depleted media, its expression was required but not sufficient for CD26 upregulation. CONCLUSIONS: CD26 mRNA and protein levels increase in a confluence-dependent manner in colon carcinoma cell lines, with c-Myc acting as a repressor and Cdx2 acting as an enhancer of CD26 expression. The enhanced expression of CD26 in serum-depleted media and a requirement for HIF-1alpha suggest a role for nutrients or growth factors in the regulation of CD26 protein expression. PMID- 21284882 TI - Corticosteroid-induced spinal epidural lipomatosis in the pediatric age group: report of a new case and updated analysis of the literature. AB - Spinal epidural lipomatosis is a rare complication of chronic corticosteroid treatment. We report a new pediatric case and an analysis of this and 19 pediatric cases identified in the international literature. The youngest of these combined 20 patients was 5 years old when lipomatosis was diagnosed. Lipomatosis manifested after a mean of 1.3 (+/- 1.5) years (SD) (median, 0.8 years; range, 3 weeks - 6.5 years) of corticosteroid treatment. The corticosteroid dose at the time of presentation of the lipomatosis ranged widely, between 5 and 80 mg of prednisone/day. Back pain was the most common presenting symptom. Imaging revealed that lipomatosis almost always involved the thoracic spine, extending into the lumbosacral region in a subset of patients. Predominantly lumbosacral involvement was documented in only two cases. Although a neurological deficit at presentation was documented in about half of the cases, surgical decompression was not performed in the cases reported after 1996. Instead, reducing the corticosteroid dose (sometimes combined with dietary restriction to mobilize fat) sufficed to induce remission. In summary, pediatric spinal epidural lipomatosis remains a potentially serious untoward effect of corticosteroid treatment, which, if recognized in a timely manner, can have a good outcome with conservative treatment. PMID- 21284883 TI - Pullout strength of pedicle screws with cement augmentation in severe osteoporosis: a comparative study between cannulated screws with cement injection and solid screws with cement pre-filling. AB - BACKGROUND: Pedicle screws with PMMA cement augmentation have been shown to significantly improve the fixation strength in a severely osteoporotic spine. However, the efficacy of screw fixation for different cement augmentation techniques, namely solid screws with retrograde cement pre-filling versus cannulated screws with cement injection through perforation, remains unknown. This study aimed to determine the difference in pullout strength between conical and cylindrical screws based on the aforementioned cement augmentation techniques. The potential loss of fixation upon partial screw removal after screw insertion was also examined. METHOD: The Taguchi method with an L8 array was employed to determine the significance of design factors. Conical and cylindrical pedicle screws with solid or cannulated designs were installed using two different screw augmentation techniques: solid screws with retrograde cement pre filling and cannulated screws with cement injection through perforation. Uniform synthetic bones (test block) simulating severe osteoporosis were used to provide a platform for each screw design and cement augmentation technique. Pedicle screws at full insertion and after a 360-degree back-out from full insertion were then tested for axial pullout failure using a mechanical testing machine. RESULTS: The results revealed the following 1) Regardless of the screw outer geometry (conical or cylindrical), solid screws with retrograde cement pre filling exhibited significantly higher pullout strength than did cannulated screws with cement injection through perforation (p = 0.0129 for conical screws; p = 0.005 for cylindrical screws). 2) For a given cement augmentation technique (screws without cement augmentation, cannulated screws with cement injection or solid screws with cement pre-filling), no significant difference in pullout strength was found between conical and cylindrical screws (p >0.05). 3) Cement infiltration into the open cell of the test block led to the formation of a cement/bone composite structure. Observations of the failed specimens indicated that failure occurred at the composite/bone interface, whereas the composite remained well bonded to the screws. This result implies that the screw/composite interfacial strength was much higher than the composite/bone interfacial strength. 4) The back-out of the screw by 360 degrees from full insertion did not decrease the pullout strength in any of the studied cases. 5) Generally, larger standard deviations were found for the screw back-out cases, implying that the results of full insertion cases are more repeatable than those of the back-out cases. CONCLUSIONS: Solid screws with retrograde cement pre-filling offer improved initial fixation strength when compared to that of cannulated screws with cement injection through perforation for both the conically and cylindrically shaped screw. Our results also suggest that the fixation screws can be backed out by 360 degrees for intra-operative adjustment without the loss of fixation strength. PMID- 21284884 TI - Purification and biochemical characterization of a secreted group IIA chicken intestinal phospholipase A2. AB - BACKGROUND: Secretory phospholipase A2 group IIA (IIA PLA2) is a protein shown to be highly expressed in the intestine of mammals. However, no study was reported in birds. RESULTS: Chicken intestinal group IIA phospholipase A2 (ChPLA2-IIA) was obtained after an acidic treatment (pH.3.0), precipitation by ammonium sulphate, followed by sequential column chromatographies on Sephadex G-50 and mono-S ion exchanger. The enzyme was found to be a monomeric protein with a molecular mass of around 14 kDa. The purified enzyme showed a substrate preference for phosphatidylethanolamine and phosphatidylglycerol, and didn't hydrolyse phosphatidylcholine. Under optimal assay conditions, in the presence of 10 mM NaTDC and 10 mM CaCl2, a specific activity of 160 U.mg-1 for purified ChPLA2-IIA was measured using egg yolk as substrate. The fifteen NH2-terminal amino acid residues of ChPLA2-IIA were sequenced and showed a close homology with known intestinal secreted phospholipases A2. The gene encoding the mature ChPLA2-IIA was cloned and sequenced. To further investigate structure-activity relationship, a 3D model of ChPLA2-IIA was built using the human intestinal phospholipase A2 structure as template. CONCLUSION: ChPLA2-IIA was purified to homogeneity using only two chromatographic colomns. Sequence analysis of the cloned cDNA indicates that the enzyme is highly basic with a pI of 9.0 and has a high degree of homology with mammalian intestinal PLA2-IIA. PMID- 21284885 TI - Gaseous emissions during concurrent combustion of biomass and non-recyclable municipal solid waste. AB - BACKGROUND: Biomass and municipal solid waste offer sustainable sources of energy; for example to meet heat and electricity demand in the form of combined cooling, heat and power. Combustion of biomass has a lesser impact than solid fossil fuels (e.g. coal) upon gas pollutant emissions, whilst energy recovery from municipal solid waste is a beneficial component of an integrated, sustainable waste management programme. Concurrent combustion of these fuels using a fluidised bed combustor may be a successful method of overcoming some of the disadvantages of biomass (high fuel supply and distribution costs, combustion characteristics) and characteristics of municipal solid waste (heterogeneous content, conflict with materials recycling). It should be considered that combustion of municipal solid waste may be a financially attractive disposal route if a 'gate fee' value exists for accepting waste for combustion, which will reduce the net cost of utilising relatively more expensive biomass fuels. RESULTS: Emissions of nitrogen monoxide and sulphur dioxide for combustion of biomass are suppressed after substitution of biomass for municipal solid waste materials as the input fuel mixture. Interactions between these and other pollutants such as hydrogen chloride, nitrous oxide and carbon monoxide indicate complex, competing reactions occur between intermediates of these compounds to determine final resultant emissions. CONCLUSIONS: Fluidised bed concurrent combustion is an appropriate technique to exploit biomass and municipal solid waste resources, without the use of fossil fuels. The addition of municipal solid waste to biomass combustion has the effect of reducing emissions of some gaseous pollutants. PMID- 21284886 TI - Wildlife translocation: the conservation implications of pathogen exposure and genetic heterozygosity. AB - BACKGROUND: A key challenge for conservation biologists is to determine the most appropriate demographic and genetic management strategies for wildlife populations threatened by disease. We explored this topic by examining whether genetic background and previous pathogen exposure influenced survival of translocated animals when captive-bred and free-ranging bighorn sheep (Ovis canadensis) were used to re-establish a population that had been extirpated in the San Andres Mountains in New Mexico, USA. RESULTS: Although the free-ranging source population had significantly higher multi-locus heterozygosity at 30 microsatellite loci than the captive bred animals, neither source population nor genetic background significantly influenced survival or cause of death. The presence of antibodies to a respiratory virus known to cause pneumonia was associated with increased survival, but there was no correlation between genetic heterozygosity and the presence of antibodies to this virus. CONCLUSIONS: Although genetic theory predicts otherwise, increased heterozygosity was not associated with increased fitness (survival) among translocated animals. While heterosis or genetic rescue effects may occur in F1 and later generations as the two source populations interbreed, we conclude that previous pathogen exposure was a more important marker than genetic heterozygosity for predicting survival of translocated animals. Every wildlife translocation is an experiment, and whenever possible, translocations should be designed and evaluated to test hypotheses that will further improve our understanding of how pathogen exposure and genetic variability influence fitness. PMID- 21284887 TI - 'The difference in determinants of Chlamydia trachomatis and Mycoplasma genitalium in a sample of young Australian women'. AB - BACKGROUND: Differences in the determinants of Chlamydia trachomatis ('chlamydia') and Mycoplasma genitalium (MG) genital infection in women are not well understood. METHODS: A cohort study of 16 to 25 year old Australian women recruited from primary health care clinics, aimed to determine chlamydia and MG prevalence and incidence. Vaginal swabs collected at recruitment were used to measure chlamydia and MG prevalence, organism-load and chlamydia-serovar a cross sectional analysis undertaken on the baseline results is presented here. RESULTS: Of 1116 participants, chlamydia prevalence was 4.9% (95% CI: 2.9, 7.0) (n = 55) and MG prevalence was 2.4% (95% CI: 1.5, 3.3) (n = 27). Differences in the determinants were found - chlamydia not MG, was associated with younger age [AOR:0.9 (95% CI: 0.8, 1.0)] and recent antibiotic use [AOR:0.4 (95% CI: 0.2, 1.0)], and MG not chlamydia was associated with symptoms [AOR:2.1 (95% CI: 1.1, 4.0)]. Having two or more partners in last 12 months was more strongly associated with chlamydia [AOR:6.4 (95% CI: 3.6, 11.3)] than MG [AOR:2.2 (95% CI: 1.0, 4.6)] but unprotected sex with three or more partners was less strongly associated with chlamydia [AOR:3.1 (95%CI: 1.0, 9.5)] than MG [AOR:16.6 (95%CI: 2.0, 138.0)]. Median organism load for MG was 100 times lower (5.7 * 104/swab) than chlamydia (5.6 * 106/swab) (p < 0.01) and not associated with age or symptoms for chlamydia or MG. CONCLUSIONS: These results demonstrate significant chlamydia and MG prevalence in Australian women, and suggest that the differences in strengths of association between numbers of sexual partners and unprotected sex and chlamydia and MG might be due to differences in the transmission dynamics between these infections. PMID- 21284888 TI - Pathogenesis, diagnosis and management of primary melanoma of the colon. AB - BACKGROUND: Melanomas within the alimentary tract are usually metastatic in origin. On the other hand, primary melanomas of the gastrointestinal tract are relatively uncommon. There are several published reports of melanomas occurring in the esophagus, stomach, small bowel, and anorectum. The occurrence of primary melanoma of the colon has, however, only been rarely reported. The optimum modus operandi for the management of primary colonic melanoma remains nebulous due to the limited number of reports in literature. METHODS: A comprehensive search of Medline, Cochrane and Highwire was performed using the following keywords: 'melanoma', 'malignant melanoma', 'primary melanoma', 'colon', 'gastrointestinal tract', 'alimentary tract', 'digestive tract', and 'large bowel'. All patients with primary melanoma localized to the colon were included in the review. Patients with metastatic melanomas to the gastrointestinal (GI) tract and primary melanomas localized to the GI tract in anatomic locations other than colon were excluded. RESULTS: There have been only 12 reported cases of primary melanoma of the colon to date. The average age of patients on presentation was 60.4 years without any significant gender predilection. Right colon (33%) and cecum (33%) were the most common sites for the occurrence of primary colonic melanoma while abdominal pain (58%) and weight loss (50%) were the most common presenting complaints. Colonoscopy is the most reliable diagnostic investigation and offers the additional advantage of obtaining tissue for diagnosis. S-100 and HMB-45 are highly sensitive and specific for the diagnosis of this malignancy. For primary colonic melanomas that have not metastasized to any distant parts of the body, surgical resection with wide margins appears to be the treatment of choice. Although the management was individualized in every case, most of the authors preferred traditional hemicolectomy as the favored surgical approach. Chemotherapeutic agents including interferons, cytokines, biological agents and radiation therapy for brain metastases have been reported as adjuvant and palliative options while considering malignant melanomas in general. The average recurrence-free interval was 2.59 years. Nine of the 12 reports documented follow up in their patients. Two of these 9 (22.2%) patients died. CONCLUSIONS: Primary melanoma of the colon is a rare clinical entity. Whenever a seemingly primary melanoma is detected in an atypical location such as the colon, it is prudent to conduct a thorough clinical investigation to consider the possibility of metastatic disease. Further studies are needed to document the long term follow up, survival advantage and safety of the management approaches employed in patients with primary colonic melanoma. Based on current data, surgical resection appears to be appropriate management for primary colonic melanomas; unless the disease has metastasized to distant sites where surgery may have a limited palliative role. PMID- 21284889 TI - Factors associated with exclusive breastfeeding among infants under six months of age in peninsular malaysia. AB - BACKGROUND: Breastfeeding is accepted as the natural form of infant feeding. For mothers to be able to breastfeed exclusively to the recommended six months, it is important to understand the factors that influence exclusive breastfeeding. The aim of the study was to identify factors associated with exclusive breastfeeding in Peninsular Malaysia. METHODS: This was a cross-sectional study involving 682 mother-infant pairs with infants up to six months attending maternal and child health section of the government health clinics in Klang, Malaysia. Data were collected by face-to-face interviews using a pre-tested structured questionnaire over 4 months in 2006. Data on breastfeeding were based on practice in the previous one month period. Logistic regression was used to assess the independent association between the independent variables and exclusive breastfeeding adjusting for infant age. RESULTS: The prevalence of exclusive breastfeeding among mothers with infants aged between one and six months was 43.1% (95% CI: 39.4, 46.8). In the multivariate model exclusive breastfeeding was positively associated with rural residence, Malay mothers, non-working and non-smoking mothers, multiparous mothers, term infants, mothers with husbands who support breastfeeding and mothers who practice bed-sharing. CONCLUSIONS: Interventions that seek to increase exclusive breastfeeding should focus on women who are at risk of early discontinuation of breastfeeding. PMID- 21284890 TI - Gene ontology based transfer learning for protein subcellular localization. AB - BACKGROUND: Prediction of protein subcellular localization generally involves many complex factors, and using only one or two aspects of data information may not tell the true story. For this reason, some recent predictive models are deliberately designed to integrate multiple heterogeneous data sources for exploiting multi-aspect protein feature information. Gene ontology, hereinafter referred to as GO, uses a controlled vocabulary to depict biological molecules or gene products in terms of biological process, molecular function and cellular component. With the rapid expansion of annotated protein sequences, gene ontology has become a general protein feature that can be used to construct predictive models in computational biology. Existing models generally either concatenated the GO terms into a flat binary vector or applied majority-vote based ensemble learning for protein subcellular localization, both of which can not estimate the individual discriminative abilities of the three aspects of gene ontology. RESULTS: In this paper, we propose a Gene Ontology Based Transfer Learning Model (GO-TLM) for large-scale protein subcellular localization. The model transfers the signature-based homologous GO terms to the target proteins, and further constructs a reliable learning system to reduce the adverse affect of the potential false GO terms that are resulted from evolutionary divergence. We derive three GO kernels from the three aspects of gene ontology to measure the GO similarity of two proteins, and derive two other spectrum kernels to measure the similarity of two protein sequences. We use simple non-parametric cross validation to explicitly weigh the discriminative abilities of the five kernels, such that the time & space computational complexities are greatly reduced when compared to the complicated semi-definite programming and semi-indefinite linear programming. The five kernels are then linearly merged into one single kernel for protein subcellular localization. We evaluate GO-TLM performance against three baseline models: MultiLoc, MultiLoc-GO and Euk-mPLoc on the benchmark datasets the baseline models adopted. 5-fold cross validation experiments show that GO-TLM achieves substantial accuracy improvement against the baseline models: 80.38% against model Euk-mPLoc 67.40% with 12.98% substantial increase; 96.65% and 96.27% against model MultiLoc-GO 89.60% and 89.60%, with 7.05% and 6.67% accuracy increase on dataset MultiLoc plant and dataset MultiLoc animal, respectively; 97.14%, 95.90% and 96.85% against model MultiLoc-GO 83.70%, 90.10% and 85.70%, with accuracy increase 13.44%, 5.8% and 11.15% on dataset BaCelLoc plant, dataset BaCelLoc fungi and dataset BaCelLoc animal respectively. For BaCelLoc independent sets, GO-TLM achieves 81.25%, 80.45% and 79.46% on dataset BaCelLoc plant holdout, dataset BaCelLoc plant holdout and dataset BaCelLoc animal holdout, respectively, as compared against baseline model MultiLoc-GO 76%, 60.00% and 73.00%, with accuracy increase 5.25%, 20.45% and 6.46%, respectively. CONCLUSIONS: Since direct homology-based GO term transfer may be prone to introducing noise and outliers to the target protein, we design an explicitly weighted kernel learning system (called Gene Ontology Based Transfer Learning Model, GO-TLM) to transfer to the target protein the known knowledge about related homologous proteins, which can reduce the risk of outliers and share knowledge between homologous proteins, and thus achieve better predictive performance for protein subcellular localization. Cross validation and independent test experimental results show that the homology-based GO term transfer and explicitly weighing the GO kernels substantially improve the prediction performance. PMID- 21284891 TI - Kinetics of non-structural protein 1, IgM and IgG antibodies in dengue type 1 primary infection. AB - BACKGROUND: Early and accurate diagnosis of dengue infection is essential for control of disease outbreaks. Recently, the dengue virus non-structural antigen 1 (NS1), a conserved and secreted glycoprotein, has been used as a marker for early diagnosis of dengue with convenience and cost-effectiveness. Serological tests of dengue IgM and IgG antibodies are still the most widely used for diagnosis of dengue. In order to assess combined diagnostic value of these tests, we study the kinetic profiles of circulating NS1, dengue IgM and IgG antibodies over the course of the disease by using an in-house dengue type 1 (DENV1) specific NS1 capture ELISA and the commercial Panbio Dengue IgM and IgG capture ELISAs. RESULTS: A panel of 313 acute-and early convalescent-phase serum specimens from 140 DENV1 primary infected patients during an outbreak of dengue in Guangzhou, China, in 2006 were studied. Dengue NS1 presented high levels in acute-phase serum samples. It was detectable as early as day 1 of illness, and up to 14 day after onset. The sensitivity of NS1 detection was ranged from 81.8% to 91.1% with samples taken during the first 7 days. Anti-dengue IgM antibody was detectable on the third day of onset with the positive rate of 42.9%, and rapidly increasing to 100% by day 8 of illness. Anti-dengue IgG antibody was detectable on the fifth day of onset with low level at the first week of onset, and slowly increasing to 100% by day 15 of illness. Combining the results of NS1 and IgM antibody detection allowed positive diagnosis in 96.9%-100% for samples taken after day 3 of onset. CONCLUSIONS: Dengue NS1 detection might shorten the window period by first few days of illness. A combination of dengue NS1 antigen and IgM antibody testing facilitates enhanced diagnosis rates. The procedures should be suitable for developing countries where dengue is endemic. PMID- 21284892 TI - Comparative genomic and transcriptomic analysis revealed genetic characteristics related to solvent formation and xylose utilization in Clostridium acetobutylicum EA 2018. AB - BACKGROUND: Clostridium acetobutylicum, a gram-positive and spore-forming anaerobe, is a major strain for the fermentative production of acetone, butanol and ethanol. But a previously isolated hyper-butanol producing strain C. acetobutylicum EA 2018 does not produce spores and has greater capability of solvent production, especially for butanol, than the type strain C. acetobutylicum ATCC 824. RESULTS: Complete genome of C. acetobutylicum EA 2018 was sequenced using Roche 454 pyrosequencing. Genomic comparison with ATCC 824 identified many variations which may contribute to the hyper-butanol producing characteristics in the EA 2018 strain, including a total of 46 deletion sites and 26 insertion sites. In addition, transcriptomic profiling of gene expression in EA 2018 relative to that of ATCC824 revealed expression-level changes of several key genes related to solvent formation. For example, spo0A and adhEII have higher expression level, and most of the acid formation related genes have lower expression level in EA 2018. Interestingly, the results also showed that the variation in CEA_G2622 (CAC2613 in ATCC 824), a putative transcriptional regulator involved in xylose utilization, might accelerate utilization of substrate xylose. CONCLUSIONS: Comparative analysis of C. acetobutylicum hyper butanol producing strain EA 2018 and type strain ATCC 824 at both genomic and transcriptomic levels, for the first time, provides molecular-level understanding of non-sporulation, higher solvent production and enhanced xylose utilization in the mutant EA 2018. The information could be valuable for further genetic modification of C. acetobutylicum for more effective butanol production. PMID- 21284893 TI - RH knowledge and service utilization among unmarried rural-to-urban migrants in three major cities, China. AB - BACKGROUND: Large numbers of unmarried migrants are on the continuous move from rural-to-urban areas within China mainland, meanwhile their Reproductive Health (RH) is underserved when it is compared with the present urban RH policies. The purpose of this study is to investigate the RH knowledge and the utilization of RH services among unmarried migrants. METHODS: A cross-section survey was performed in three cities in China-Shenzhen, Guangzhou and Wuhan. A total of 3,450 rural-to-urban unmarried migrants were chosen according to a purposive sampling method. Around 3,412 (male: 1,680, female: 1,732) were qualified for this study. A face-to-face structured questionnaire survey was used, which focused on the knowledge concerning "fertility, contraception and STD/AIDS," as well as RH service utilization. RESULTS: Among unmarried migrants the RH knowledge about pregnancy-fertilization (29.4%) and contraception (9.1%) was at its lowest level. Around 21% of unmarried migrants had pre-marital sexual experience and almost half (47.4%) never used condoms during sexual intercourse. The most obtained RH services was about STD/AIDS health education (female: 49.6%, male: 50.2%) and free prophylactic use of contraceptives and/or condoms (female: 42.5%, male: 48.3%). As for accessing RH checkup services it was at its lowest level among females (16.1%). Those who migrated to Shenzhen (OR = 0.64) and Guangzhou (OR = 0.53) obtained few RH consultations compared to those in Wuhan. The white collar workers received more RH consultations and checkup services than the blue collar workers (all group P < 0.01). CONCLUSION: RH knowledge and the utilization of RH services amongst unmarried migrants remain insufficient in the three studied major cities. This study reveals the important gaps in the RH services' delivery, and highlights the requirements for tailored interventions, including further research, to address more effectively the demands and the needs of the unmarried migrant populations. PMID- 21284894 TI - Faecal calprotectin concentrations in apparently healthy children aged 0-12 years in urban Kampala, Uganda: a community-based survey. AB - BACKGROUND: Calprotectin is a calcium and zinc binding protein, abundant in neutrophils and is extremely stable in faeces. Faecal calprotectin is used as a non-specific marker for gastrointestinal inflammation. It has a good diagnostic precision to distinguish between irritable bowel syndrome and inflammatory bowel disease. Studies have established normal concentrations in healthy children; all these studies have been performed in high-income countries. The objective of this study was to determine the concentration of faecal calprotectin in apparently healthy children aged 0-12 years in urban Kampala, Uganda. METHOD: We tested 302 apparently healthy children aged, age 0-12 years (162 female, 140 male) in urban Kampala, Uganda. The children were recruited consecutively by door-to-door visits. Faecal calprotectin was analyzed using a quantitative enzyme-linked immunosorbent assay. Faeces were also tested for Helicobacter pylori (H. pylori) antigen, for growth of enteropathogens and microscopy was performed to assess protozoa and helminths. A short standardized interview with socio-demographic information and medical history was obtained to assess health status of the children. RESULTS: In the different age groups the median faecal calprotectin concentrations were 249 mg/kg in 0 < 1 year (n = 54), 75 mg/kg in 1 < 4 years (n = 89) and 28 mg/kg in 4 < 12 years (n = 159). There was no significant difference in faecal calprotectin concentrations and education of female caretaker, wealth index, gender, habits of using mosquito nets, being colonized with H. pylori or having other pathogens in the stool. CONCLUSION: Concentrations of faecal calprotectin among healthy children, living in urban Ugandan, a low-income country, are comparable to those in healthy children living in high-income countries. In children older than 4 years, the faecal calprotectin concentration is low. In healthy infants faecal calprotectin is high. The suggested cut-off concentrations in the literature can be used in apparently healthy Ugandan children. This finding also shows that healthy children living under poor circumstances do not have a constant inflammation in the gut. We see an opportunity to use this relatively inexpensive test for further understanding and investigations of gut inflammation in children living in low-income countries. PMID- 21284896 TI - 16th international charles heidelberger symposium on cancer research coimbra, portugal. 26-28 september 2010. Abstracts. PMID- 21284895 TI - An update on targeted gene repair in mammalian cells: methods and mechanisms. AB - Transfer of full-length genes including regulatory elements has been the preferred gene therapy strategy for clinical applications. However, with significant drawbacks emerging, targeted gene alteration (TGA) has recently become a promising alternative to this method. By means of TGA, endogenous DNA repair pathways of the cell are activated leading to specific genetic correction of single-base mutations in the genome. This strategy can be implemented using single-stranded oligodeoxyribonucleotides (ssODNs), small DNA fragments (SDFs), triplex-forming oligonucleotides (TFOs), adeno-associated virus vectors (AAVs) and zinc-finger nucleases (ZFNs). Despite difficulties in the use of TGA, including lack of knowledge on the repair mechanisms stimulated by the individual methods, the field holds great promise for the future. The objective of this review is to summarize and evaluate the different methods that exist within this particular area of human gene therapy research. PMID- 21284897 TI - Society of Chiropodists and Podiatrists Annual Conference 2010 Bournemouth, UK. 21-23 October 2010. Abstracts. PMID- 21284898 TI - Introducing the issue on "differential use of CCR5 versus CXCR4 by HIV-1. Pathogenic, translational and clinical open questions". PMID- 21284899 TI - Conformational HIV-1 envelope on particulate structures: a tool for chemokine coreceptor binding studies. AB - The human immunodeficiency virus type 1 (HIV-1) external envelope glycoprotein gp120 presents conserved binding sites for binding to the primary virus receptor CD4 as well as the major HIV chemokine coreceptors, CCR5 and CXCR4. Concerted efforts are underway to understand the specific interactions between gp120 and coreceptors as well as their contribution to the subsequent membrane fusion process. The present review summarizes the current knowledge on this biological aspect, which represents one of the key and essential points of the HIV-host cell interplay and HIV life cycle. The relevance of conformational HIV-1 Envelope proteins presented on Virus-like Particles for appropriate assessment of this molecular interaction, is also discussed. PMID- 21284900 TI - HIV-1 co-receptor usage: influence on mother-to-child transmission and pediatric infection. AB - Viral CCR5 usage is not a predictive marker of mother to child transmission (MTCT) of HIV-1. CXCR4-using viral variants are little represented in pregnant women, have an increased although not significant risk of transmission and can be eventually also detected in the neonates. Genetic polymorphisms are more frequently of relevance in the child than in the mother. However, specific tissues as the placenta or the intestine, which are involved in the prevalent routes of infection in MTCT, may play an important role of selective barriers. The virus phenotype of the infected children, like that of adults, can evolve from R5 to CXCR4-using phenotype or remain R5 despite clinical progression to overt immune deficiency. The refined classification of R5 viruses into R5(narrow) and R5(broad) resolves the enigma of the R5 phenotype being associated with the state of immune deficiency. Studies are needed to address more in specific the relevance of these factors in HIV-1 MTCT and pediatric infection of non-B subtypes. PMID- 21284901 TI - HIV-1 envelope, integrins and co-receptor use in mucosal transmission of HIV. AB - It is well established that HIV-1 infection typically involves an interaction between the viral envelope protein gp120/41 and the CD4 molecule followed by a second interaction with a chemokine receptor, usually CCR5 or CXCR4. In the early stages of an HIV-1 infection CCR5 using viruses (R5 viruses) predominate. In some viral subtypes there is a propensity to switch to CXCR4 usage (X4 viruses). The receptor switch occurs in ~ 40% of the infected individuals and is associated with faster disease progression. This holds for subtypes B and D, but occurs less frequently in subtypes A and C. There are several hypotheses to explain the preferential transmission of R5 viruses and the mechanisms that lead to switching of co-receptor usage; however, there is no definitive explanation for either. One important consideration regarding transmission is that signaling by R5 gp120 may facilitate transmission of R5 viruses by inducing a permissive environment for HIV replication. In the case of sexual transmission, infection by HIV requires the virus to breach the mucosal barrier to gain access to the immune cell targets that it infects; however, the immediate events that follow HIV exposure at genital mucosal sites are not well understood. Upon transmission, the HIV quasispecies that is replicating in an infected donor contracts through a "genetic bottleneck", and often infection results from a single infectious event. Many details surrounding this initial infection remain unresolved. In mucosal tissues, CD4(+) T cells express high levels of CCR5, and a subset of these CD4(+)/CCR5(high) cells express the integrin alpha4beta7, the gut homing receptor. CD4(+)/CCR5(high)/ alpha4beta7(high) T cells are highly susceptible to infection by HIV-1 and are ideal targets for an efficient productive infection at the point of transmission. In this context we have demonstrated that the HIV-1 envelope protein gp120 binds to alpha4beta7 on CD4(+) T cells. On CD4(+)/CCR5(high)/ alpha4beta7(high) T cells, alpha4beta7 is closely associated with CD4 and CCR5. Furthermore, alpha4beta7 is ~3 times the size of CD4 on the cell surface, that makes it a prominent receptor for an efficient virus capture. gp120-alpha4beta7 interactions mediate the activation of the adhesion-associated integrin LFA-1. LFA-1 facilitates the formation of virological synapses and cell to-cell spread of HIV-1. gp120 binding to alpha4beta7 is mediated by a tripeptide located in the V1/V2 domain of gp120. Of note, the V1/V2 domain of gp120 has been linked to variations in transmission fitness among viral isolates raising the intriguing possibility that gp120-alpha4beta7 interactions may be linked to transmission fitness. Although many details remain unresolved, we hypothesize that gp120-alpha4beta7 interactions play an important role in the very early events following sexual transmission of HIV and may have important implication in the design of vaccine strategies for the prevention of acquisition of HIV infection. PMID- 21284902 TI - R5X4 HIV-1 coreceptor use in primary target cells: implications for coreceptor entry blocking strategies. AB - Entry coreceptor use by HIV-1 plays a pivotal role in viral transmission, pathogenesis and disease progression. In many HIV-1 infected individuals, there is an expansion in coreceptor use from CCR5 to include CXCR4, which is associated with accelerated disease progression. While targeting HIV-1 envelope interactions with coreceptor during viral entry is an appealing approach to combat the virus, the methods of determining coreceptor use and the changes in coreceptor use that can occur during disease progression are important factors that may complicate the use of therapies targeting this stage of HIV-1 replication. Indicator cells are typically used to determine coreceptor use by HIV-1 in vitro, but the coreceptors used on these cells can differ from those used on primary cell targets. V3 based genetic sequence algorithms are another method used to predict coreceptor use by HIV-1 strains. However, these algorithms were developed to predict coreceptor use in cell lines and not primary cells and, furthermore, are not highly accurate for some classes of viruses. This article focuses on R5X4 HIV 1, the earliest CXCR4-using variants, reviewing the pattern of coreceptor use on primary CD4+ lymphocytes and macrophages, the relationship between primary cell coreceptor use and the two principal approaches to coreceptor analysis (genetic prediction and indicator cell phenotyping), and the implications of primary cell coreceptor use by these strains for treatment with a new class of small molecule antagonists that inhibit CCR5-mediated entry. These are important questions to consider given the development of new CCR5 blocking therapies and the prognosis associated with CXCR4 use. PMID- 21284903 TI - Natural anti-CCR5 antibodies in HIV-infection and -exposure. AB - Natural antibodies constitute a first-line of defence against pathogens; they may also play other roles in immune regulation and homeostasis, through their ability to bind host antigens, surface molecules and receptors. Natural anti-CCR5 antibodies can be decisive in preventing HIV infection in mucosal tissues and offer prompt and effective protection just at major sites of virus entry. Among natural anti-CCR5 antibodies, IgG and IgA to the ECL1 domain have been shown to block HIV effectively and durably without causing harm to the host. Their biological properties and their uncommon generation in subsets of HIV-infected and HIV-exposed individuals (so called ESN) will be introduced and discussed, with the aim at exploiting their potential in therapy and prevention. PMID- 21284904 TI - Clinical significance of HIV-1 coreceptor usage. AB - The identification of phenotypically distinct HIV-1 variants with different prevalence during the progression of the disease has been one of the earliest discoveries in HIV-1 biology, but its relevance to AIDS pathogenesis remains only partially understood. The physiological basis for the phenotypic variability of HIV-1 was elucidated with the discovery of distinct coreceptors employed by the virus to infect susceptible cells. The role of the viral phenotype in the variable clinical course and treatment outcome of HIV-1 infection has been extensively investigated over the past two decades. In this review, we summarize the major findings on the clinical significance of the HIV-1 coreceptor usage. PMID- 21284906 TI - Coreceptor use in nonhuman primate models of HIV infection. AB - SIV or SHIV infection of nonhuman primates (NHP) has been used to investigate the impact of coreceptor usage on the composition and dynamics of the CD4+ T cell compartment, mechanisms of disease induction and development of clinical syndrome. As the entire course of infection can be followed, with frequent access to tissue compartments, infection of rhesus macaques with CCR5-tropic SHIVs further allows for study of HIV-1 coreceptor switch after intravenous and mucosal inoculation, with longitudinal and systemic analysis to determine the timing, anatomical sites and cause for the change in envelope glycoprotein and coreceptor preference. Here, we review our current understanding of coreceptor use in NHPs and their impact on the pathobiological characteristics of the infection, and discuss recent advances in NHP studies to uncover the underlying selective pressures for the change in coreceptor preference in vivo. PMID- 21284905 TI - Selective transmission of R5 HIV-1 variants: where is the gatekeeper? AB - To enter target cells HIV-1 uses CD4 and a coreceptor. In vivo the coreceptor function is provided either by CCR5 (for R5) or CXCR4 (for X4 HIV-1). Although both R5 and X4 HIV-1 variants are present in body fluids (semen, blood, cervicovaginal and rectal secretions), R5 HIV-1 appears to transmit infection and dominates early stages of HIV disease. Moreover, recent sequence analysis of virus in acute infection shows that, in the majority of cases of transmission, infection is initiated by a single virus. Therefore, the existence of a "gatekeeper" that selects R5 over X4 HIV-1 and that operates among R5 HIV-1 variants has been suggested. In the present review we consider various routes of HIV-transmission and discuss potential gatekeeping mechanisms associated with each of these routes. Although many mechanisms have been identified none of them explains the almost perfect selection of R5 over X4 in HIV-1 transmission. We suggest that instead of one strong gatekeeper there are multiple functional gatekeepers and that their superimposition is sufficient to protect against X4 HIV-1 infection and potentially select among R5 HIV-1 variants. In conclusion, we propose that the principle of multiple barriers is more general and not restricted to protection against X4 HIV-1 but rather can be applied to other phenomena when one factor has a selective advantage over the other(s). In the case of gatekeepers for HIV-1 transmission, the task is to identify them and to decipher their molecular mechanisms. Knowledge of the gatekeepers' localization and function may enable us to enhance existing barriers against R5 transmission and to erect the new ones against all HIV-1 variants. PMID- 21284907 TI - Asymmetric HIV-1 co-receptor use and replication in CD4(+) T lymphocytes. AB - Susceptibility to infection by the human immunodeficiency virus type-1 (HIV-1), both in vitro and in vivo, requires the interaction between its envelope (Env) glycoprotein gp120 Env and the primary receptor (R), CD4, and Co-R, either CCR5 or CXCR4, members of the chemokine receptor family. CCR5-dependent (R5) viruses are responsible for both inter-individual transmission and for sustaining the viral pandemics, while CXCR4-using viruses, usually dualtropic R5X4, emerge in ca. 50% of individuals only in the late, immunologically suppressed stage of disease. The hypothesis that such a major biological asymmetry is explained exclusively by the availability of cells expressing CCR5 or CXCR4 is challenged by several evidences. In this regard, binding of the HIV-1 gp120 Env to the entry R complex, i.e. CD4 and a chemokine R, leads to two major events: virion-cell membrane fusion and a cascade of cell signaling. While the fusion/entry process has been well defined, the role of R/Co-R signaling in the HIV-1 life cycle has been less characterized. Indeed, depending on the cellular model studied, the capacity of HIV-1 to trigger a flow of events favoring either its own latency or replication remains a debated issue. In this article, we will review the major findings related to the role of HIV R/Co-R signaling in the steps following viral entry and leading to viral spreading in CD4(+) T lymphocytes. PMID- 21284908 TI - Clinical use of CCR5 inhibitors in HIV and beyond. AB - Since the discovery of CCR5 as a coreceptor for HIV entry, there has been interest in blockade of the receptor for treatment and prevention of HIV infection. Although several CCR5 antagonists have been evaluated in clinical trials, only maraviroc has been approved for clinical use in the treatment of HIV infected patients. The efficacy, safety and resistance profile of CCR5 antagonists with a focus on maraviroc are reviewed here along with their usage in special and emerging clinical situations. Despite being approved for use since 2007, the optimal use of maraviroc has yet to be well-defined in HIV and potentially in other diseases. Maraviroc and other CCR5 antagonists have the potential for use in a variety of other clinical situations such as the prevention of HIV transmission, intensification of HIV treatment and prevention of rejection in organ transplantation. The use of CCR5 antagonists may be potentiated by other agents such as rapamycin which downregulate CCR5 receptors thus decreasing CCR5 density. There may even be a role for their use in combination with other entry inhibitors. However, clinical use of CCR5 antagonists may have negative consequences in diseases such as West Nile and Tick borne encephalitis virus infections. In summary, CCR5 antagonists have great therapeutic potential in the treatment and prevention of HIV as well as future use in novel situations such as organ transplantation. Their optimal use either alone or in combination with other agents will be defined by further investigation. PMID- 21284909 TI - Development and use of FFQ among adults in diverse settings across the globe. AB - In nutritional epidemiology, development of valid dietary assessment instruments specific to populations in diverse settings is of paramount importance. Such instruments are essential when trying to characterise dietary patterns and intake, investigate diet-disease associations, inform and evaluate nutrition interventions, assess nutrient-gene interactions, conduct cross-country comparison studies and monitor nutrition transitions. The FFQ is a relatively inexpensive tool for measuring long-term dietary intake for large populations and for allowing researchers to track dietary changes over time. However, FFQ must be population specific to capture the local diet and available foods. Collecting 24 h dietary recalls and utilising community feedback to build the FFQ ensures that a culturally appropriate instrument is developed. This article presents several examples describing FFQ development and utilisation in different settings globally. In the Canadian Arctic, FFQ were developed and utilised to inform and evaluate a community-based intervention programme, characterise the diet and track dietary changes occurring among Inuit and Inuvialuit, populations experiencing rising rates of chronic disease and likely to be extremely vulnerable to the potential effects of climate change. Another example is an FFQ developed to assess sodium intake and evaluate a sodium reduction trial in a high risk population in Barbados. An example is provided from Brazil, where an FFQ was developed to assess associations between diet, heterocyclic aromatic amines and colorectal adenoma among Japanese Brazilians and to conduct cross-country comparisons. These and other case studies highlight the diversity in dietary intake between populations and the need for FFQ to be developed to capture this diversity. PMID- 21284910 TI - Prey sex pheromone as kairomone for a new group of predators (Coleoptera: Dasytidae, Aplocnemus spp.) of pine bast scales. AB - During the last decades, an increasing number of predators were found to use specific prey pheromones as chemical cues. Beyond its ecological relevance, this knowledge has practical applications on insect conservation and pest control. In this study, we present first evidence that two species of the family Dasytidae (Coleoptera) Aplocnemus brevis Rosenhauer and A. raymondi Sainte-Claire Deville use the sex pheromone of the pine bast scale Matsucoccus feytaudi Ducasse (Hemiptera: Matsucoccidae) as kairomone to locate this prey. The feeding habits and biology of Aplocnemus species are practically unknown. In the laboratory, the adults of Aplocnemus sp. accepted M. feytaudi egg masses as food source as well as other diets. Females represented more than 90% of Aplocnemus sp. attracted to the pheromone lures. We believe that females use this olfactory cue to locate suitable places for oviposition and that larvae are the predators of Matsucoccus. This study further demonstrates that the response to the kairomone elicited short prey searching times, about 23% of the individuals appeared less than 12 min after lure exposure, being consistent with the hypothesis of prey specialization. Habitat and geographical distribution predict an ancestral association of A. brevis with M. feytaudi and of A. raymondi with M. pini. Nevertheless, a recent prey shift of A. raymondi to the invasive M. feytaudi in Corsica is in progress. PMID- 21284911 TI - First detection of Babesia occultans in Hyalomma ticks from Tunisia. AB - Descriptions of Babesia occultans have previously been restricted to sub-Saharan Africa. Here, we report the finding, for the first time, of this low or non pathogenic bovine Babesia species in Tunisia, northern Africa. B. occultans DNA was detected by molecular methods in Hyalomma marginatum unfed ticks collected in 3 bioclimatic regions of Tunisia. The near-full-length 18S rRNA gene was sequenced and compared with related sequences retrieved from GenBank. Phylogenetic analysis indicated that other sequences deposited as Babesia sp. could also correspond to B. occultans, suggesting that this species may have a wide distribution in Mediterranean and Asiatic regions, and not only in sub Saharan Africa as previously described. A B. occultans-specific Reverse Line Blot (RLB) oligonucleotide probe was designed for future epidemiological studies that would help to clarify this possibility. PMID- 21284912 TI - Emotional face processing and flat affect in schizophrenia: functional and structural neural correlates. AB - BACKGROUND: There is a general consensus in the literature that schizophrenia causes difficulties with facial emotion perception and discrimination. Functional brain imaging studies have observed reduced limbic activity during facial emotion perception but few studies have examined the relation to flat affect severity. METHOD: A total of 26 people with schizophrenia and 26 healthy controls took part in this event-related functional magnetic resonance imaging study. Sad, happy and neutral faces were presented in a pseudo-random order and participants indicated the gender of the face presented. Manual segmentation of the amygdala was performed on a structural T1 image. RESULTS: Both the schizophrenia group and the healthy control group rated the emotional valence of facial expressions similarly. Both groups exhibited increased brain activity during the perception of emotional faces relative to neutral ones in multiple brain regions, including multiple prefrontal regions bilaterally, the right amygdala, right cingulate cortex and cuneus. Group comparisons, however, revealed increased activity in the healthy group in the anterior cingulate, right parahippocampal gyrus and multiple visual areas. In schizophrenia, the severity of flat affect correlated significantly with neural activity in several brain areas including the amygdala and parahippocampal region bilaterally. CONCLUSIONS: These results suggest that many of the brain regions involved in emotional face perception, including the amygdala, are equally recruited in both schizophrenia and controls, but flat affect can also moderate activity in some other brain regions, notably in the left amygdala and parahippocampal gyrus bilaterally. There were no significant group differences in the volume of the amygdala. PMID- 21284913 TI - Interaction effects of subjective memory impairment and ApoE4 genotype on episodic memory and hippocampal volume. AB - BACKGROUND: The apolipoprotein E4 allele (ApoE4) is an established genetic risk factor for Alzheimer's disease (AD). However, its effects on cognitive performance and brain structure in healthy individuals are complex. We investigated the effect of ApoE4 on cognitive performance and medial temporal lobe volumetric measures in cognitively unimpaired young elderly with and without subjective memory impairment (SMI), which is an at-risk condition for dementia.MethodAltogether, 40 individuals with SMI and 62 without were tested on episodic memory and on tasks of speed and executive function. All participants were ApoE genotyped. 21 subjects with SMI and 47 without received additional structural magnetic resonance imaging. Volumetric measures of the hippocampus, the entorhinal cortex and the amygdala were obtained manually. RESULTS: In the SMI group, ApoE4 carriers performed worse on the episodic memory (p=0.049) and showed smaller left hippocampal volumes (p=0.030). In the individuals without SMI, the ApoE4 carriers performed better on episodic memory (p=0.018) and had larger right hippocampal volumes (p=0.039). The interaction of group (SMI/no SMI) and ApoE genotype was significant for episodic memory (p=0.005) and right and left hippocampal volumes (p=0.042; p=0.035). There were no within-group differences or interaction effects on speed and executive function composite measures or other volumetric measures. CONCLUSIONS: The negative effect of ApoE4 on episodic memory and hippocampal volume in SMI supports SMI as a prodromal condition of AD. The positive effects of ApoE4 in subjects without SMI adds to a number of reports on positive ApoE4 effects in young and very old individuals. PMID- 21284914 TI - Asymmetry of salivary cortisol and alpha-amylase responses to psychosocial stress in anorexia nervosa but not in bulimia nervosa. AB - BACKGROUND: The stress response involves the activation of the hypothalamic pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). As a role for stress in determining of the onset and the natural course of eating disorders (EDs) has been proposed, the study of the psychobiology of the stress response in patients with anorexia nervosa (AN) and bulimia nervosa (BN) should be helpful in understanding the pathophysiology of these disorders. The two neurobiological components of the stress response can be easily explored in humans by the measurement of salivary cortisol and alpha-amylase response to a stressor. Therefore, we assessed salivary cortisol and alpha-amylase responses to the Trier Social Stress Test (TSST) in symptomatic patients with AN and BN compared to healthy controls. METHOD: Seven AN women, eight BN women and eight age-matched healthy females underwent the TSST between 1530 and 1700 h. Salivary cortisol and alpha-amylase levels were measured by an enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared to healthy women, AN patients showed a normal cortisol response to the TSST, although this occurred at significantly increased hormone levels, and an almost complete absence of response of alpha-amylase. BN women, however, exhibited enhanced pre-stress levels of salivary alpha-amylase but a normal response of the enzyme and cortisol to the TSST. CONCLUSIONS: These findings demonstrate, for the first time, the occurrence of an asymmetry between the HPA axis and SNS components of the stress response in the acute phase of AN but not in BN. The pathophysiological significance of this asymmetry remains to be determined. PMID- 21284915 TI - Haemoglobin A1c, fasting glucose and future risk of elevated depressive symptoms over 2 years of follow-up in the English Longitudinal Study of Ageing. AB - BACKGROUND: The cross-sectional association between impaired glucose/diabetes and depression is inconsistent. We examined the longitudinal associations between diabetes, indicators of glucose metabolism and depressive symptoms over 2 years of follow-up. METHOD: Participants were 4338 men and women from the English Longitudinal Study of Ageing, a prospective study of community-dwelling older adults [aged 62.9 (s.d.=9.0) years, 45.2% men]. Depressive symptoms were assessed at baseline and after 2 years of follow-up using the eight-item Centre of Epidemiological Studies--Depression (CES-D) scale. Glycated haemoglobin (HbA1c) levels, fasting glucose and other biological and behavioural risk factors were also assessed at baseline. RESULTS: Approximately 11.5% of the sample were categorized with elevated depressive symptoms at follow-up (a score >= 4 on the CES-D). There was an association between HbA1c and depressive symptoms at follow up [per unit increase, odds ratio (OR) 1.17, 95% confidence interval (CI) 1.03 1.33] after adjustment for age and baseline CES-D. Cross-sectionally, the probability of depressive symptoms increased with increasing HbA1c levels until the value of 8.0% after which there was a plateau [p(curve)=0.03]. Compared with those with normal fasting glucose, participants with diabetes (confirmed through self-report or elevated fasting blood glucose) at baseline had an elevated risk of depressive symptoms at follow-up (OR 1.52, 95% CI 1.01-2.30) after adjusting for depressive symptoms at baseline, behavioural and sociodemographic variables, adiposity and inflammation. CONCLUSIONS: These data suggest that poor glucose metabolism and diabetes are risk factors for future depression in older adults. There was no evidence of a U-shaped association. PMID- 21284916 TI - In utero exposure to virus infections and the risk of developing anorexia nervosa. AB - BACKGROUND: The study aims to explore, using indirect ecological measures of exposure, the role of viral infections in the development of anorexia nervosa (AN). METHOD: The cohort of participants consisted of all female subjects born in the Veneto region in the period between 1970 and 1984, and residing in the urban and suburban area of Padua (27,682 female subjects in an area of 424 km2). The main outcome measure was the diagnosis of AN resulting from the Public Mental Health Database, the Register of Hospital Admissions, and the Register of the Eating Disorders Unit (n=402, 1.4%). The number of cases of rubella, chickenpox, influenza and measles was ascertained for each month for the 15-year period. RESULTS: Exposures during the sixth month of pregnancy to the peaks of chickenpox [odds ratio (OR) 1.6, 95% confidence interval (CI) 1.2-2.0] and rubella infections (OR 1.5, 95% CI 1.1-2.0) were significantly associated with an increased risk of developing AN, even after controlling for socio-economic status, urbanization and month of birth. We found weak evidence of a season-of birth bias. CONCLUSIONS: In utero exposure to viral infection could be a risk factor for developing AN. We need further epidemiological and serological studies to confirm this hypothesis. PMID- 21284917 TI - Combined analysis of grey matter voxel-based morphometry and white matter tract based spatial statistics in late-life bipolar disorder. AB - BACKGROUND: Previous magnetic resonance imaging (MRI) studies in young patients with bipolar disorder indicated the presence of grey matter concentration changes as well as microstructural alterations in white matter in various neocortical areas and the corpus callosum. Whether these structural changes are also present in elderly patients with bipolar disorder with long-lasting clinical evolution remains unclear. METHODS: We performed a prospective MRI study of consecutive elderly, euthymic patients with bipolar disorder and healthy, elderly controls. We conducted a voxel-based morphometry (VBM) analysis and a tract-based spatial statistics (TBSS) analysis to assess fractional anisotropy and longitudinal, radial and mean diffusivity derived by diffusion tensor imaging (DTI). RESULTS: We included 19 patients with bipolar disorder and 47 controls in our study. Fractional anisotropy was the most sensitive DTI marker and decreased significantly in the ventral part of the corpus callosum in patients with bipolar disorder. Longitudinal, radial and mean diffusivity showed no significant between group differences. Grey matter concentration was reduced in patients with bipolar disorder in the right anterior insula, head of the caudate nucleus, nucleus accumbens, ventral putamen and frontal orbital cortex. Conversely, there was no grey matter concentration or fractional anisotropy increase in any brain region in patients with bipolar disorder compared with controls. LIMITATIONS: The major limitation of our study is the small number of patients with bipolar disorder. CONCLUSION: Our data document the concomitant presence of grey matter concentration decreases in the anterior limbic areas and the reduced fibre tract coherence in the corpus callosum of elderly patients with long-lasting bipolar disorder. PMID- 21284921 TI - Letter to the editor. Virological analysis of fatal influenza cases in the United Kingdom during the early wave of influenza in winter 2010/11. PMID- 21284922 TI - Pandemic influenza A(H1N1) 2009: molecular characterisation and duration of viral shedding in intensive care patients in Bordeaux, south-west France, May 2009 to January 2010. AB - From May 2009 to January 2010, the Virology Laboratory at the University Hospital of Bordeaux received more than 4,000 nasopharyngeal samples from the Aquitaine region (south-west France) for the diagnosis of pandemic influenza A(H1N1)2009. Eighty-three infected patients deteriorated and were admitted to intensive care units. Our study focused on 24 of these patients. Positivity for influenza A(H1N1)2009 was monitored by realtime PCR and duration of viral shedding was determined. The first available sample of each patient was analysed for bacterial, fungal and viral co-infection. We observed six bacterial (or bacterial/fungal) co-infections and one viral co-infection with respiratory syncytial virus. The samples were analysed for the presence of the neuraminidase H275Y (N1 numbering) mutation, which confers resistance to oseltamivir, by realtime PCR of the neuraminidase gene. No H275Y mutation was observed in any of the viral strains screened in this study. In parallel, a fragment of the haemagglutinin gene encoding amino acid residues 173 to 362 was sequenced to detect mutations that had been reported to increase the severity of the disease. Two patients were infected by strains bearing the D222G (H3 numbering) mutation. The viral shedding of A(H1N1)2009 in this study ranged from four to 28 days with a median of 11 days. PMID- 21284923 TI - Usefulness of porA sequencing in distinguishing sporadic and linked cases of serogroup B invasive meningococcal disease in Suffolk, United Kingdom, December 2009 to January 2010. AB - A cluster of three fatal cases of invasive meningococcal disease due to Neisseria meningitidis serogroup Bin a town in Suffolk, United Kingdom, during December 2009 to January 2010 was reported to the local Health Protection Unit. This paper describes the investigation undertaken to identify any potential epidemiological links among the cases, to determine if this was an outbreak and to consider whether to implement community-wide interventions and control measures. Case epidemiological information in addition to serogroup and genosubtyping (porA gene sequencing) data of the infecting organism was gathered on all cases in this reported cluster. Genosubtyping was also retrospectively requested for all serogroup B cases confirmed in Suffolk during 2009. Extensive investigation failed to establish an epidemiological link among the cluster of fatal cases of serogroup B invasive meningococcal disease in Suffolk. By demonstrating a number of distinct strains, the genosubtyping of isolates proved to be useful in the public health management of this incident by serving to exclude a community outbreak and preventing unnecessary mass chemoprophylaxis. PMID- 21284924 TI - Cases of community-acquired meticillin-resistant Staphylococcus aureus in an asylum seekers centre in Germany, November 2010. AB - In an asylum seeker centre in Schleswig-Holstein, a resident was diagnosed with furuncle caused by a Panton-Valentine leukocidine (PVL)-positive community acquired meticillin-resistant Staphylococcus aureus (CA-MRSA). As a result of active case finding, 232 of 427 persons (54% of all residents) were screened for MRSA and two further PVL-positive CA-MRSA cases were identified PMID- 21284925 TI - BioVyon Protein A, an alternative solid-phase affinity matrix for chromatin immunoprecipitation. AB - Chromatin immunoprecipitation (ChIP) is an important technique in the study of DNA/protein interactions. The ChIP procedure, however, has limitations in that it is lengthy, can be inconsistent, and is prone to nonspecific binding of DNA and proteins to the bead-based solid-phase matrices that are often used for the immunoprecipitation step. In this investigation, we examined the utility of a new matrix for ChIP assays, BioVyon Protein A, a solid support based on porous polyethylene. In ChIP experiments carried out using two antibodies and seven DNA loci, the performance of BioVyon Protein A was significantly better, with a greater percentage of DNA pull-down in all of the assays tested compared with bead-based matrices, Protein A Sepharose, and Dynabeads Protein A. Furthermore, the rigid porous disc format within a column made the BioVyon matrix much easier to use with fewer steps and less equipment requirements, resulting in a significant reduction in the time taken to process the ChIP samples. In summary, BioVyon Protein A provides a column-based assay method for ChIP and other immunoprecipitation-based procedures; the rigid porous structure of BioVyon enables a fast and robust protocol with higher ChIP enrichment ratios. PMID- 21284926 TI - A colorimetric assay for determination of residual detergent levels in reconstituted membrane protein preparations. AB - Simple and robust methods for the quantification of residual detergent in purified membrane proteins are not readily available. In this article, solubilization of precipitated dye by detergent is shown to be a facile method for the quantification of residual levels of octaethylene-glycol-mono(n dodecyl)ether in virosomal influenza vaccine. Dye solubilization starts in the critical micellar concentration range. The method is more sensitive than an existing assay and is highly accurate and precise. The method is applicable to other detergents as well. This method of residual detergent quantification is simple and straightforward and is a useful tool for quality control of subunit vaccines. PMID- 21284927 TI - An enzyme-linked assay for the rapid quantification of microRNAs based on the viral suppressor of RNA silencing protein p19. AB - MicroRNAs (miRNAs) are endogenous posttranscriptional regulators found in all metazoa and play crucial roles in virtually all cellular processes. Their aberrant expression has been linked to several diseased states; therefore, techniques capable of sensitive and specific profiling of the miRNA milieu will have significant application in prognostics, diagnostics, and therapeutics. Here we present a method for rapid quantification of miRNA levels using p19, a tombusvirus-encoded suppressor of RNA interference with sequence-independent and size-selective affinity toward 19-bp RNA duplexes. We present a surface plasmon resonance (SPR)-based miRNA sensing method where RNA probes are immobilized on gold surfaces demonstrating p19's utility in recognition of miRNA-bound probes. This allows detection of miRNAs in the low nanomolar range. To increase the sensitivity, a bead-based enzyme immunoassay was performed, and this technique displays a lower detection limit of 1fmol and a linear dynamic range from 1pmol to 1fmol. PMID- 21284928 TI - Qualitative and quantitative thrombin analysis in serum using aptamers and gold nanoparticles through progressive dilution. AB - It has been a long-standing challenge in bioassay using aptamers and gold nanoparticles to detect disease-related proteins and other substance directly in complex biological samples such as serum. Here we propose a progressive dilution (PD) method to achieve simultaneous qualitative and quantitative analysis of proteins in blood serum without pretreatment of the sample. Above the detection limit, PD has unlimited dynamic range. We demonstrate the PD strategy through the detection of thrombin in fetal bovine serum using the quenching of fluorescence by gold nanoparticles. PMID- 21284929 TI - Positive selection vector using the KillerRed gene. AB - Plasmid pZK18S is a novel positive selection vector containing the genetically encoded photosensitizer KillerRed as the selection marker. When transformed into host cells (lacI(q) or lacI(+)), the common medical surgical light is sufficient to activate phototoxicity of KillerRed. Thus, only the recombinants with disrupted reading frame of KillerRed genes finally allow forming viable colonies. Because lethality of KillerRed relies on light irradiation, no special host and culture medium are required to amplify and prepare pZK18S vector in larger quantities. The pZK18S was reliable and highly efficient for constructing the serial analysis of gene expression (SAGE) library. PMID- 21284930 TI - Specific berenil-DNA interactions: an approach for separation of plasmid isoforms by pseudo-affinity chromatography. AB - Small molecules, like some antibiotics and anticancer agents that bind DNA with high specificity, can represent a relevant alternative as ligands in affinity processes for plasmid DNA (pDNA) purification. In the current study, pDNA binding affinities of berberine, berenil, kanamycin, and neomycin were evaluated by a competitive displacement assay with ethidium bromide using a fluorimetric titration technique. The binding between pDNA and ethidium bromide was tested in different buffer conditions, varying the type and the salt concentration, and was performed in both the absence and presence of the studied compounds. The results showed that the minor groove binder berenil has the higher pDNA binding constant. Chromatographic experiments using a derivatized column with berenil as ligand showed a total retention of pDNA using 1.3M ammonium sulfate in eluent buffer. A selective separation of supercoiled and open circular isoforms was achieved by further decreasing the salt concentration to 0.6M and then to 0M. These results suggest a promising application of berenil as ligand for specific purification of pDNA supercoiled isoform by pseudo-affinity chromatography. PMID- 21284931 TI - Glyceraldehyde-3-phosphate dehydrogenase is a reliable internal control in Western blot analysis of leukocyte subpopulations from children. AB - To study differences in the development of immunity, leukocytes from cord blood are often compared with those from adult peripheral blood. Western blot analysis is a common method for detecting proteins. In this study, we investigated the reliability of using different housekeeping proteins (beta-actin, beta-tubulin, and glyceraldehyde-3-phosphate dehydrogenase [GAPDH]) as internal controls for different leukocyte subpopulations from infants, children, and adults. Our results showed that the expression levels of beta-actin and beta-tubulin were much lower in cord blood leukocytes than in adult leukocytes, and this expression pattern persisted in children up to 3 years old. Further study revealed that the beta-actin expression level in newborns was especially lower in CD14-positive monocytes. However, cord blood and adult peripheral blood monocytes had similar expression levels of beta-actin messenger RNA (mRNA). Further experiments showed that posttranslational regulation was responsible for the low beta-actin expression level in neonatal monocytes. Thus, researchers should carefully assess the appropriate use of housekeeping gene-encoded proteins as internal standards to normalize samples for comparisons of different leukocyte populations from subjects of different ages. In this study, we determined that GAPDH was a more reliable internal control than others in Western blot analysis for comparing the development of immunity among infants, children, and adults. PMID- 21284932 TI - Limiting the sedimentation coefficient for sedimentation velocity data analysis: partial boundary modeling and g(s) approaches revisited. AB - Brown and coworkers (Eur. Biophys. J. 38 (2009) 1079-1099) introduced partial boundary modeling (PBM) to simplify sedimentation velocity data analysis by excluding species outside the range of interest (e.g., aggregates, impurities) via restricting the sedimentation coefficient range being fitted. They strongly criticized the alternate approach of fitting g(s) distributions using similar range limits, arguing that (i) it produces "nonoptimal fits in the original data space" and (ii) the g(s) data transformations lead to gross underestimates of the parameter confidence intervals. It is shown here that neither of those criticisms is valid. These two approaches are not truly fitting the same data or in equivalent ways; thus, they should not actually give the same best-fit parameters. The confidence limits for g(s) fits derived using F statistics, bootstrap, or a new Monte Carlo algorithm are in good agreement and show no evidence for significant statistical distortion. Here 15 g(s) measurements on monoclonal antibody samples gave monomer mass estimates with experimental standard deviations of less than 1%, close to the confidence limit estimates. Tests on both real and simulated data help to clarify the strengths and drawbacks of both approaches. New algorithms for computing g(s) and a scan-differencing approach for PBM are introduced. PMID- 21284934 TI - Active transport of contact allergens in human monocyte-derived dendritic cells is mediated by multidrug resistance related proteins. AB - The multidrug resistance related proteins (MRPs) function as efflux transporters of a variety of large organic anions or their conjugates. In recent studies we demonstrated that antigen-presenting cells express a specific pattern of MRPs. MRP-mediated efflux activity of human monocyte-derived dendritic cells (moDCs) was analyzed using an in vitro transport assay. The efflux transport of radiolabeled contact allergens was inhibited using the specific MRP inhibitor indomethacin. Treatment with indomethacin increased intracellular concentration of [3H] eugenol and [3H] isoeugenol in moDCs. In addition by using MRP1 expressing inside-out membrane vesicles we revealed that the transport of eugenol is mediated by MRP1. Human DCs were employed to assess the sensitizing potential of contact allergens and alters their cytokine gene expression profile. Hence, to survey the functionality of indomethacin after stimulation with contact allergens IL-8 and TRIM16 regulation was measured by a DC-based in vitro assay. Incubation with isoeugenol after pre-treatment with indomethacin leads to increased IL-8 and TRIM16 gene expression. These results strongly support the functional role of MRPs in the active efflux of contact allergens also in antigen-presenting cells like moDCs, a novel mechanism which could possibly play a role in the pathogenesis of contact allergy. PMID- 21284933 TI - Myosin light chain kinase and the role of myosin light chain phosphorylation in skeletal muscle. AB - Skeletal muscle myosin light chain kinase (skMLCK) is a dedicated Ca(2+)/calmodulin-dependent serine-threonine protein kinase that phosphorylates the regulatory light chain (RLC) of sarcomeric myosin. It is expressed from the MYLK2 gene specifically in skeletal muscle fibers with most abundance in fast contracting muscles. Biochemically, activation occurs with Ca(2+) binding to calmodulin forming a (Ca(2+))(4)*calmodulin complex sufficient for activation with a diffusion limited, stoichiometric binding and displacement of a regulatory segment from skMLCK catalytic core. The N-terminal sequence of RLC then extends through the exposed catalytic cleft for Ser15 phosphorylation. Removal of Ca(2+) results in the slow dissociation of calmodulin and inactivation of skMLCK. Combined biochemical properties provide unique features for the physiological responsiveness of RLC phosphorylation, including (1) rapid activation of MLCK by Ca(2+)/calmodulin, (2) limiting kinase activity so phosphorylation is slower than contraction, (3) slow MLCK inactivation after relaxation and (4) much greater kinase activity relative to myosin light chain phosphatase (MLCP). SkMLCK phosphorylation of myosin RLC modulates mechanical aspects of vertebrate skeletal muscle function. In permeabilized skeletal muscle fibers, phosphorylation mediated alterations in myosin structure increase the rate of force-generation by myosin cross bridges to increase Ca(2+)-sensitivity of the contractile apparatus. Stimulation-induced increases in RLC phosphorylation in intact muscle produces isometric and concentric force potentiation to enhance dynamic aspects of muscle work and power in unfatigued or fatigued muscle. Moreover, RLC phosphorylation mediated enhancements may interact with neural strategies for human skeletal muscle activation to ameliorate either central or peripheral aspects of fatigue. PMID- 21284935 TI - Alterations of the C-terminal end do not affect in vitro or in vivo activity of surfactant protein C analogs. AB - The secondary structure, orientation and hydrogen/deuterium exchange of SP-C33, a surfactant protein C analog, in 1,2-dipalmitoyl-sn-glycero-3-phosphocholine/egg phosphatidylglycerol (8:2, wt./wt.) bilayers, was studied by attenuated total reflection Fourier transform infrared spectroscopy. This showed a transmembrane alpha-helix, in which about 55% of the amide hydrogens do not exchange for up to 20 h. Moreover, C-terminally modified SP-C33, either truncated after position 30, or having the methionine at position 31 exchanged for either lysine or isoleucine, showed the same secondary structure and orientation. The different peptides, suspended in 1,2-dipalmitoyl-sn-glycero-3-phosphocholine/1-palmitoyl-2 oleoyl-sn-glycero-3-phosphoglycerol 68:31 (wt./wt.), were tested for surfactant activity in vitro in a captive bubble surfactometer and in vivo in an animal model of respiratory distress syndrome using premature rabbit fetuses. All preparations showed similar surface activity in the captive bubble surfactometer. Also, in the rabbit model, all preparations performed equally well and significantly better than non-treated controls, both regarding tidal volumes and lung gas volumes. Thus, truncation or residue replacements in the C-terminal part of SP-C33 do not seem to affect membrane association or surfactant activity. PMID- 21284936 TI - Correlation of C4ST-1 and ChGn-2 expression with chondroitin sulfate chain elongation in atherosclerosis. AB - Subendothelial retention of lipoproteins by proteoglycans (PGs) is the initiating event in atherosclerosis. The elongation of chondroitin sulfate (CS) chains is associated with increased low-density lipoprotein (LDL) binding and progression of atherosclerosis. Recently, it has been shown that 2 Golgi enzymes, chondroitin 4-O-sulfotransferase-1 (C4ST-1) and chondroitin N-acetylgalactosaminyltransferase 2 (ChGn-2), play a critical role in CS chain elongation. However, the roles of C4ST-1 and ChGn-2 during the progression of atherosclerosis are not known. The aim of this study was to analyze the expression of C4ST-1 and ChGn-2 in atherosclerotic lesions in vivo and determine whether their expression correlated with CS chain elongation. Low-density lipoprotein receptor knockout (LDLr KO) mice were fed a western diet for 2, 4, and 8weeks to stimulate development of atherosclerosis. The binding of LDL and CS PG in this mouse model was confirmed by chondroitinase ABC (ChABC) digestion and apolipoprotein B (apo B) staining. Gel filtration analysis revealed that the CS chains began to elongate as early as 2weeks after beginning a western diet and continued as the atherosclerosis progressed. Furthermore, quantitative real-time polymerase chain reaction (qRT PCR) showed that the mRNA levels of C4ST-1 and ChGn-2 increased after 8weeks of this diet. In contrast, the mRNA levels of their homologs, C4ST-2 and ChGn-1, were unchanged. In addition, immunohistochemical analysis demonstrated that the expression of C4ST-1 and ChGn-2 appeared to have similar site-specific patterns and coincided with biglycan expression at the aortic root. Our results suggested that C4ST-1 and ChGn-2 may be involved in the elongation of CS chains in the arterial wall during the progression of atherosclerosis. Therefore, modulating their expression and activity might be a novel therapeutic strategy for atherosclerosis. PMID- 21284937 TI - Neuronal targeting, internalization, and biological activity of a recombinant atoxic derivative of botulinum neurotoxin A. AB - Non-toxic derivatives of botulinum neurotoxin A (BoNT/A) have potential use as neuron-targeting delivery vehicles, and as reagents to study intracellular trafficking. We have designed and expressed an atoxic derivative of BoNT/A (BoNT/A ad) as a full-length 150 kDa molecule consisting of a 50 kDa light chain (LC) and a 100 kDa heavy chain (HC) joined by a disulfide bond and rendered atoxic through the introduction of metalloprotease-inactivating point mutations in the light chain. Studies in neuronal cultures demonstrated that BoNT/A ad cannot cleave synaptosomal-associated protein 25 (SNAP25), the substrate of wt BoNT/A, and that it effectively competes with wt BoNT/A for binding to endogenous neuronal receptors. In vitro and in vivo studies indicate accumulation of BoNT/A ad at the neuromuscular junction of the mouse diaphragm. Immunoprecipitation studies indicate that the LC of BoNT/A ad forms a complex with SNAP25 present in the neuronal cytosolic fraction, demonstrating that the atoxic LC retains the SNAP25 binding capability of the wt toxin. Toxicity of BoNT/A ad was found to be reduced approximately 100,000-fold relative to wt BoNT/A. PMID- 21284938 TI - Icilin induces G1 arrest through activating JNK and p38 kinase in a TRPM8 independent manner. AB - Aberrant regulation of cell cycle confers a limitless replicative potential, which is a hallmark of cancer. Currently, the compounds targeting the cell cycle are undergoing cancer clinical trials. In this study, we demonstrated that icilin, a cooling compound, induces G1 arrest in PC-3 prostate cancer cells without cell death. Icilin modulated the expression level of various cell cycle regulators at transcription or post-translational levels. In addition, icilin activated JNK and p38 kinase pathways, but not ERK. Both JNK and p38 kinases cooperatively mediated icilin-induced G1 arrest, which was rescued by pharmacologic inhibition of these kinases. The action of icilin on G1 arrest was unrelated to the activation of TRPM8 calcium channel. Our findings suggest that icilin is a valuable chemical probe for future investigation aiming at delineating the molecular mechanisms of cell cycle regulation in prostate cancer. PMID- 21284939 TI - The cyanobacterium Synechocystis sp. PCC 6803 is able to express an active [FeFe] hydrogenase without additional maturation proteins. AB - [FeFe]-hydrogenases have been claimed as the most promising catalysts of hydrogen bioproduction and several efforts have been accomplished to express and purify them. However, previous attemps to obtain a functional recombinant [FeFe] hydrogenase in heterologous systems such as Escherichia coli failed due to the lack of the specific maturation proteins driving the assembly of its complex active site. The unique exception is that of [FeFe]-hydrogenase from Clostridium pasteurianum that has been expressed in active form in the cyanobacterium Synechococcus PCC 7942, which holds a bidirectional [NiFe]-hydrogenase with a well characterized maturation system, suggesting that the latter is flexible enough to drive the synthesis of a [FeFe]-enzyme. However, the capability of cyanobacteria to correctly fold a [FeFe]-hydrogenase in the absence of its auxiliary maturation proteins is a debated question. In this work, we expressed the [FeFe]-hydrogenase from Chlamydomonas reinhardtii as an active enzyme in the cyanobacterium Synechocystis sp. PCC 6803. Our results, using a different experimental system, confirm that cyanobacteria are able to express a functional [FeFe]-hydrogenase even in the absence of additional chaperones. PMID- 21284940 TI - Onset and dynamic expression of S100 proteins in the olfactory organ and the lateral line system in zebrafish development. AB - In the zebrafish olfactory epithelium, three morphologically distinct olfactory neurons express different marker proteins. We utilize this feature to access developmental dynamics of one of the neuron types, the crypt cells, to determine whether they are differentiated at a stage similar to other olfactory neurons. Immunohistochemical studies using an S100 antibody that specifically recognizes crypt cells showed that S100-positive cells appear in olfactory rosettes as early as at 2day postfertilization (dpf). However, some of the rosettes did not have any S100-positive cells until 4 dpf. The number of S100-positive cells in individual rosettes increased steadily over the next 3days before it decreased significantly. There were 7.8 S100-positive cells per rosettes on average in larvae at 7 dpf. The number reduced to 2.2 at 9 dpf. A recovery to a pre reduction level was detected in 12 dpf larvae. We also observed S100-positive cells in neuromasts of the lateral line system in 2 dpf larvae, suggesting that the crypt cells and sensory cells in the neuromasts have similar onsets of differentiation. Our data have provided a time line of differentiation of crypt cells in development of the olfactory system and demonstrated that this type of cell is differentiated at a stage similar to ciliated and microvillous olfactory neurons. A nonlinear growth trajectory of the crypt cell population in the first nine days of zebrafish development implicates a possible functional significance of crypt cells in early life stages of zebrafish. PMID- 21284941 TI - Nitric oxide-mediated neuronal functional recovery in hypoxic-ischemic brain damaged rats subjected to electrical stimulation. AB - The present study investigated the role of neuronal nitric oxide synthase (nNOS)/nitric oxide (NO) system in the pathophysiologic regulation of hypoxic ischemic brain damage (HIBD) in baby rats subjected to electrical stimulation (ES). The motor function, NO concentration in cortex, and protein expressions of nNOS were examined after 14 sessions of ES. Results showed that NO levels in cortex significantly increased 24h after hypoxia-ischemia than sham. ES could improve motor functions in HIBD rats and spontaneously decrease nNOS/NO system. In conclusion, the nNOS/NO pathway might play a critical role as mediator of neuronal recovery in HIBD rats after undergoing ES treatment. PMID- 21284942 TI - Differential roles of ERK, JNK and p38 MAPK in pain-related spatial and temporal enhancement of synaptic responses in the hippocampal formation of rats: multi electrode array recordings. AB - It is known that chronic pain affects various higher brain functions including perception, emotion, cognition, and memory. However, few studies have been performed to examine pain-induced synaptic plastic changes in the hippocampal formation (HF), an important region subserving affective-motivational component of pain. Our previous study has revealed a strong impact of peripheral persistent nociception on synaptic connection, transmission and function in the HF of rats, in both temporal and spatial domains, by using a newly developed MED64 multichannel recording system. However, the underlying signaling mechanisms for this pain-related spatial and temporal plasticity are still less understood. As an initial investigation, the present study attempted to examine potential different roles of the mitogen-activated protein kinase (MAPK) members in mediating this plastic phenomenon. By virtue of the three well-known MAPK inhibitors targeting extracellular signal-regulated kinase (ERK), p38 MAPK and c Jun N-terminal kinase (JNK), respectively, in combination with the well established MED64 multisite recording system, we found that pharmacological inhibition of the ERK- and JNK-mediated signaling pathway, at the plateau phase of the long-term potentiation (LTP), significantly decreased pain-enhanced LTP maintenance whereas similar blockade of p38 MAPK pathway dramatically further increased the potentiation. Regarding the spatial magnification of pain, ERK and p38 MAPK seemed to play opposing roles, with the former positively involved and the latter negatively involved, without any detectable effect of the JNK signaling pathway. Together, these results suggest differential roles of the specific members of the MAPK family in mediating pain-associated spatial and temporal plasticity in the HF, which are in good agreement with previous observations. In addition, a possible mechanistic separation between spatial and temporal magnification of pain is also indicated in this study. PMID- 21284943 TI - Protective effects of Mg-CUD against D-galactosamine-induced hepatotoxicity in rats. AB - This study examined the protective effects of magnesium chenoursodeoxycholic acid (Mg-CUD), a magnesium trihydrate salt of chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA), against D-galactosamine (D-GalN)-induced liver injury. Hepatotoxicity was induced by intraperitoneal injection of D-GalN (700mg/kg) and Mg-CUD (15.625, 31.25 and 62.5mg/kg) was administered orally once a day for 2weeks and 6h after D-GalN injection. Significant increases in the level of serum alanine aminotransferase activity and lipid peroxidation were attenuated by Mg-CUD 24h after D-GalN treatment. Hepatic glutathione/oxidized glutathione ratio was decreased, and this decrease was attenuated by Mg-CUD. Mg CUD attenuated the increase in the levels of serum tumor necrosis factor (TNF) alpha and interleukin (IL)-6, while it augmented the increase in serum IL-10 level and heme oxygenase (HO)-1 protein expression. Mg-CUD attenuated increased levels of TNF-alpha, IL-6, and IL-1beta mRNA expression. Increased levels of IL 10 and HO-1 mRNA expression were augmented by Mg-CUD. The increased nuclear level of nuclear factor-kappaB (NF-kappaB) and decreased cytosolic level of Inhibitory kappaB-alpha protein were attenuated by Mg-CUD. Nuclear phosphorylated c-Jun (p-c Jun) level showed a significant increase and this increase was attenuated by Mg CUD. Our results suggest that Mg-CUD ameliorates D-GalN-induced acute hepatitis and that this protection is likely due to its anti-oxidative and anti inflammatory activities, and inhibition of NF-kappaB nuclear translocation and nuclear p-c-Jun expression. PMID- 21284944 TI - Unique action of sodium tanshinone II-A sulfonate (DS-201) on the Ca(2+) dependent BK(Ca) activation in mouse cerebral arterial smooth muscle cells. AB - Sodium tanshinone II-A sulfonate (DS-201) is a water-soluble derivative of tanshinone IIA, a main active constituent of Salvia miltiorrhiza which has been used for treatments of cardio- and cerebro-vascular diseases. DS-201 activates large conductance Ca(2+)-sensitive K(+) channels (BK(Ca)) in arterial smooth muscle cells, and reduces the vascular tone. Here we investigated the effect of DS-201 on the BK(Ca) channel kinetics by analyzing single channel currents. Smooth muscle cells were freshly isolated from mouse cerebral arteries. Single channel currents of BK(Ca) were recorded by patch clamp. DS-201 increased the total open probability (NPo) of BK(Ca) in a concentration-dependent manner. But this action required intracellular Ca(2+), and the effect depended on the Ca(2+) concentration ([Ca(2+)](free)). DS-201 activated BK(Ca) with the half maximal effective concentration (EC(50)) of 111.5MUM at 0.01MUM [Ca(2+)](free), and 68.5MUM at 0.1MUM [Ca(2+)](free.) The effect of DS-201 on NPo was particularly strong in the range of [Ca(2+)](free) between 0.1 and 1MUM. Analysis of the channel kinetics revealed that DS-201 had only the effect on the channel closing without affecting the channel opening, which was a striking contrast to the effect of [Ca(2+)](free), that is characterized by changing the channel opening without changing the channel closing. DS-201 may be bound to the open state of BK(Ca), and have an inhibitory effect on the transition from the open to closed state. By this way DS-201 may enhance the activity of BK(Ca), and exhibit a strong vasodilating effect against vasoconstriction in the range of [Ca(2+)](free) between 0.1 and 1MUM. PMID- 21284945 TI - Proteomic insights into chronic anthracycline cardiotoxicity. AB - Chronic anthracycline cardiotoxicity is a feared complication of cancer chemotherapy. However, despite several decades of primarily hypothesis-driven research, the molecular basis of this phenomenon remains poorly understood. The aim of this study was to obtain integrative molecular insights into chronic anthracycline cardiotoxicity and the resulting heart failure. Cardiotoxicity was induced in rabbits (daunorubicin 3mg/kg, weekly, 10weeks) and changes in the left ventricular proteome were analyzed by 2D-DIGE. The protein spots with significant changes (p<0.01, >1.5-fold) were identified using MALDI-TOF/TOF. Key data were corroborated by immunohistochemistry, qRT-PCR and enzyme activity determination and compared with functional, morphological and biochemical data. The most important alterations were found in mitochondria - especially in proteins crucial for oxidative phosphorylation, energy channeling, antioxidant defense and mitochondrial stress. Furthermore, the intermediate filament desmin, which interacts with mitochondria, was determined to be distinctly up-regulated and disorganized in its expression pattern. Interestingly, the latter changes reflected the intensity of toxic damage in whole hearts as well as in individual cells. In addition, a marked drop in myosin light chain isoforms, activation of proteolytic machinery (including the proteasome system), increased abundance of chaperones and proteins involved in chaperone-mediated autophagy, membrane repair as well as apoptosis were found. In addition, dramatic changes in proteins of basement membrane and extracellular matrix were documented. In conclusion, for the first time, the complex proteomic signature of chronic anthracycline cardiotoxicity was revealed which enhances our understanding of the basis for this phenomenon and it may enhance efforts in targeting its reduction. PMID- 21284946 TI - Zinc-finger protein 90 negatively regulates neuron-restrictive silencer factor mediated transcriptional repression of fetal cardiac genes. AB - Neuron-restrictive silencer factor (NRSF) is a zinc-finger transcription factor that binds to specific DNA sequences (NRSE) to repress transcription. By down regulating the transcription of its target genes, NRSF contributes to the regulation of various biological processes, including neuronal differentiation, carcinogenesis and cardiovascular homeostasis. We previously reported that NRSF regulates expression of the cardiac fetal gene program, and that attenuation of NRSF-mediated repression contributes to genetic remodeling in hearts under pathological conditions. The precise molecular mechanisms and signaling pathways via which NRSF activity is regulated in pathological conditions of the heart remain unclear, however. In this study, to search for regulators of NRSF, we carried out yeast two-hybrid screening using NRSF as bait and identified zinc finger protein (Zfp) 90 as a novel NRSF-binding protein. NRSF and Zfp90 colocalized in the nucleus, with the zinc-finger DNA-binding domain of the former specifically interacting with the latter. Zfp90 inhibited the repressor activity of NRSF by inhibiting its binding to DNA, thereby derepressing transcription of NRSF-target genes. Knockdown of Zfp90 by siRNA led to reduced expression of NRSF target fetal cardiac genes, atrial and brain natriuretic peptide genes, and conversely, overexpression of Zfp90 in ventricular myocardium resulted in significant increases in the expression of these genes. Notably, expression of Zfp90 mRNA was significantly upregulated in mouse and human hearts with chronic heart failure. Collectively, these results suggest that Zfp90 functions as a negative regulator of NRSF and contributes to genetic remodeling during the development of cardiac dysfunction. PMID- 21284947 TI - Deprivation of MKK7 in cardiomyocytes provokes heart failure in mice when exposed to pressure overload. AB - There is little doubt that members of mitogen-activated protein kinase (MAPK) families play key roles in the transition from adaptive hypertrophic remodeling to heart failure. Mitogen-activated protein kinase kinase 7 (MKK7) is a critical component of stress-activated MAP kinase signaling pathway. The role of MKK7 plays in mediating cardiac remodeling in response to load stress has yet to be defined. Herein, we investigate the role of MKK7 in regulating cardiac remodeling in response to pressure overload. We generated and examined the phenotype of mice with cardiomyocyte-specific deletion of the mkk7 gene (MKK7(cko)). Following one week of pressure overload, MKK7(cko) mice exhibited characteristic phenotypes of heart failure evidenced by deterioration in ventricular function and pulmonary congestion. Cell death assays revealed an increased prevalence of cardiomyocyte apoptosis in the MKK7(cko) heart, in which elevated p53 levels and attenuated expression of manganese superoxide dismutase (MnSOD) were found. Moreover, extensive interstitial fibrosis was discovered in the knockout heart likely attributable to upregulation of transforming growth factor beta (TGF-beta) signaling. These results reveal an essential role of MKK7 in cardiomyocytes for protecting the heart from hypertrophic insults thereby preventing the transition to heart failure. PMID- 21284948 TI - Role of the androgen receptor CAG repeat polymorphism in prostate cancer, and spinal and bulbar muscular atrophy. AB - Androgens are involved in the development of several tissues, including prostate, skeletal muscle, bone marrow, hair follicles, and brain. Most of the biological effects of the androgens are mediated through an intracellular transcription factor, the androgen receptor (AR) at the level of gene regulation. Several types of mutations in the AR gene have been linked to endocrine dysfunctions. The expansion of CAG codon repeat, coding for a polyglutamine (PolyQ) tract in the N terminal domain is one such mutation. The polyQ chain length impacts AR's ability to interact with critical coregulators, which in turn modulates its transcriptional efficacy. Pathologic manifestations of variations in polyQ chain length have been associated with prostate cancer susceptibility, and the Spinal and Bulbar Muscular Atrophy (SBMA), a neurodegenerative disease. In this review article, we discuss multiple aspects of the role of polyQ chain length in the actions of the AR, their importance in prostate cancer development and progression, and SBMA with an aim to understand the underlying mechanisms involved in these diseases, which can be targeted for future therapeutic approaches. PMID- 21284949 TI - Hepatitis C virus resistance to protease inhibitors. AB - Recent advances in molecular biology have led to the development of novel small molecules that target specific viral proteins of the hepatitis C virus (HCV) life cycle. These drugs, collectively termed directly acting antivirals (DAA) against HCV, include a range of non-structural (NS) 3/NS4A protease, NS5B polymerase, and NS5A inhibitors at various stages of clinical development. The rapid replication rate of HCV, along with the low fidelity of its polymerase, gives rise to generations of mutations throughout the viral genome resulting in remarkable sequence variation in the HCV population, known as a quasispecies. The efficacy of DAAs is limited by the presence of those mutations that give rise to amino acid substitutions within the targeted protein, and that affect the viral sensitivity to these compounds. Thus, due to the high genetic variability of HCV, variants with reduced susceptibility to DAA can occur naturally even before treatment begins, but usually at low levels. Not surprisingly then, these changes are selected in patients either breaking through or not responding to potent DAA treatment. In vitro or in vivo, six major position mutations in the NS3 HCV protease (36, 54, 155, 156, 168, and 170) have now been reported associated with different levels of resistance. The amino acid composition at several of the drug resistance sites can vary between the HCV genotypes/subtypes, resulting in different consensus amino acids leading to a reduction in replicative fitness as well as reduced DAA sensitivity. Different amino acid diversity profiles for HCV genotypes/subtypes suggest differences in the position/type of immune escape and drug resistance mutations. Also, different pathways of resistance profiles based on the chemical scaffold (linear or macrocyclic) of the protease inhibitors have been described. This review first describes how resistance to a protease inhibitor can develop and then provides an overview of the mechanism of how particular mutations confer varying levels of resistance to protease inhibitor, which have been identified and characterized using both genotypic and phenotypic tools. Future potential therapeutic strategies to assist patients who do develop resistance to protease inhibitors are also outlined. The challenge developing new HCV protease inhibitors should take into consideration not only the antiviral potency of the drugs, the occurrence and importance of side effects, the frequency of oral administration, but also the resistance profiles of these agents. PMID- 21284950 TI - Gastric distention induced functional magnetic resonance signal changes in the rodent brain. AB - Investigating the localization of gastric sensation within the brain is important for understanding the neural correlates of satiety. Previous rodent studies have identified the brain-stem and hypothalamus as key mediators of gastric distention induced satiation. Although, recent blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) studies in humans have identified a role for higher cortico-limbic structures in mediating the satiation effects of gastric distention, the role of these regions in rodents remains to be characterized. We determined the effects of gastric distention on global spatio temporal BOLD fMRI signal changes in the rodent brain. Brain images were acquired with a high resolution 9.4 T magnet during gastric distention with continuous monitoring of blood pressure in adult male Sprague Dawley rats (n=8-10). Distention of the stomach with an intragastric balloon, at rates which mimicked the rate of consumption and emptying of a mixed nutrient liquid meal, resulted in robust reduction in food intake and increase in blood pressure. Gastric distention increased BOLD fMRI activity within homeostatic regions such as the hypothalamus and nucleus tractus solitarius, as well as non homeostatic regions including the hippocampus, amygdala, thalamus, cerebellum and the cortex (cingulate, insular, motor and sensory cortices). Further, the increase in BOLD fMRI activity following distention was strongly correlated to an increase in blood pressure. These results indicate that gastric distention, mimicking the rate of intake and emptying of a liquid meal, increases BOLD fMRI activity in both homeostatic and non homeostatic brain circuits which regulate food intake, and that these BOLD fMRI signal changes may in part be attributable to transient increases in blood pressure. PMID- 21284952 TI - Stimulus-specific adaptation and its dynamics in the inferior colliculus of rat. AB - Stimulus specific adaptation (SSA) is known as a decrease of neuronal response to stimuli that are commonly presented than those rarely occurred. Previous studies have shown that SSA occurs at different levels of auditory pathway, from inferior colliculus (IC), auditory thalamus to auditory cortex (AC). In this study, we further investigated the properties of SSA in rat IC using oddball paradigm. We found that SSA existed even at a lower repetition rate (1 Hz), besides at relatively higher rates (>=2 Hz) shown in previous studies. We also analyzed the temporal dynamics of adaptation to the entire stimulus sequence. Global and local components were found in the response process. These components include a long term adaptation during the entire oddball sequence, a short-term increase of responses to common stimuli after rare ones and the effects of stimulus history on current response. By fitting a linear model regarding stimulus local history and global probability, we found both of them affect IC neuronal responses. Our study further supports the existence of SSA in IC and provides detailed properties of the neural processing of novelty detection at midbrain level. PMID- 21284951 TI - Ultrastructure, synaptic organization, and molecular components of bushy cell networks in the anteroventral cochlear nucleus of the rhesus monkey. AB - Bushy cells (BCs) process auditory information in the ventral cochlear nucleus (VCN). Yet, most neuroanatomical findings come from studies in cats and rodents, and the ultrastructural morphological features of BCs in humans and higher nonhuman primates are unknown. In this study, we combined histological, immunocytochemical, and ultrastructural methods to examine the morphology and synaptic organization of BCs in the rhesus monkey VCN. We observed that BCs were organized in a complex neural network that appears to interconnect the cells. The fine structure of BC somata and dendrites, as well as their synaptic inputs, are similar to those in other mammals. We found that BCs received numerous endbulb like VGLUT1- and VGLUT2-immunopositive endings. In addition, they expressed glutamate AMPA (GluR2/3 and GluR4), NMDA (NR1), delta1/2 receptor subunits, and the alpha1 subunit of the glycine receptor. These receptor types and subunits mediate fast excitatory synaptic transmission from the cochlea and inhibitory neurotransmission from noncochlear inputs. Parvalbumin immunostaining and semithin sections showed that BC dendrites are oriented toward neighboring BC somas to form neuronal clusters. Within the cluster, the incoming inputs established multiple, divergent synaptic contacts. Thus, BCs were connected by specialized dendrosomatic and somasomatic membrane junctions. Our results indicate that the cytoarchitectural organization of BCs is well conserved between primates and other mammalian species. PMID- 21284953 TI - Protein synthesis in dorsal hippocampus supports the drug tolerance induced by prior elevated plus-maze experience. AB - Tolerance to the anxiolytic-like effect of drugs may develop because of a memory derived from prior experience in certain apparatuses such as the elevated plus maze (EPM). Activity in basolateral amygdala was shown to be required for consolidating this knowledge. The dorsal hippocampus (DH) is also implicated in long-term memory consolidation, a process relying on new protein synthesis. It is unknown, however, whether the DH protein synthesis disruption would prevent the phenomenon rendering animals unresponsive to benzodiazepines in the EPM retest. To address this, we bilaterally infused the protein synthesis inhibitor anisomycin (ANI) into the rat DH 0, 3 or 6 h after, or 15 min before, the EPM test. DH infusion of ANI (80 MUg) around the time of EPM testing preserved the anxiolysis of the midazolam (MDZ; 0.5 mg/kg, i.p.) in rats retested in the EPM 24 h later, suggesting that information consolidated by DH protein synthesis impacts on the subsequent animal's responsiveness to this drug. To examine whether impaired memory acquisition could also contribute to the prevention of MDZ tolerance seen in EPM-experienced animals infused with ANI before testing, the EPM retest was performed 3 h after testing to coincide with the temporal window in which short-term memory remains, for the reason that this process does not require protein synthesis for its formation. The pretest DH anisomycin infusion's ability to prevent the MDZ tolerance on retesting was now missing. This result confirms a specific action of the ANI on memory consolidation. We also found that rats express further avoidance to open-arms in the EPM retest. However, neither pretest nor posttest DH ANI infusion interfered with this pattern of results exhibited by EPM-experienced rats. PMID- 21284954 TI - Quinpirole-induced sensitization to noisy/sparse periodic input: temporal synchronization as a component of obsessive-compulsive disorder. AB - Quinpirole-sensitized rats were tested on a discrete-trials 40-s peak-interval procedure using lever pressing as the instrumental response. Although there was no evidence of rhythmical activity in lever pressing, periodic output was observed in a secondary response (food-cup entries) during the inter-trial interval following the delivery of reinforcement on fixed-interval trials, but not during unreinforced probe trials. This repetitive pattern of behavior with a 40-s period points to the primacy of reinforcement as a time marker and an increased tendency to synchronize to noisy and sparse periodic input as a result of reduced inhibitory control in cortico-striatal circuits following chronic quinpirole administration. Parallels between quinpirole-induced rhythmical behavior and the repetitive motor habits frequently observed in obsessive compulsive disorder are discussed. PMID- 21284955 TI - A comparative study of glycerin fatty acid ester and magnesium stearate on the dissolution of acetaminophen tablets using the analysis of available surface area. AB - To study the effect of glycerin fatty acid ester (Poem TR-FB) concentrations on the dissolution rate of acetaminophen (APAP), the dissolution and disintegration behaviors of APAP tablets formulated using various lubricants were examined. The change over time in the available surface area of APAP (S(t)), which is in direct contact with solvent, was also analyzed using these dissolution data. In the dissolution tests, a retarded dissolution of APAP was not observed with TR-FB, whereas magnesium stearate (Mg-St), which is widely used as a lubricant, retarded the dissolution. However, no significant difference in the disintegration time between the two lubricants was observed. With regard to the time course of the S(t), Mg-St at 0.1% gave a maximum surface area value at 9.19 min (peak time); however, the profiles for APAP with Mg-St at greater than 0.5% showed downward curvature indicating a gradual decrease in surface area over time. Conversely, with TR-FB, even when its concentration was increased, the S(t) profile for APAP had a maximum value that was more than twice that of APAP with that of 0.5-3.0% of Mg-St. Scanning electron microscopy (SEM) observations showed that the differences in the dissolution rate and S(t) patterns between Mg-St and TR-FB could be explained by differences in extensibility deriving from their morphology. Therefore, it was concluded that TR-FB does not cause retardation of drug dissolution and may prove to be a superior alternative lubricant to Mg-St. PMID- 21284956 TI - Integrity characterization of myoglobin released from poly(epsilon-caprolactone) microspheres using two analytical methods: UV/Vis spectrometry and conductometric bi-enzymatic biosensor. AB - Myoglobin (Mb)-loaded poly(epsilon-caprolactone) (PCL) microparticles were prepared by multiple emulsion with solvent extraction/evaporation method under more or less deleterious operating conditions. The protein integrity was monitored using both UV/Vis absorbance ratio method at specific wavelengths and a conductometric bi-enzymatic biosensor based on proteinase K and pronase. Under standard operating conditions, Mb remained in native conformation, while different degrees of protein denaturation were observed by changing the encapsulation conditions. It was shown that solvent elimination under reduced pressure and in a lower extent addition of a higher molecular weight PCL led to protein alteration. In the first case, the loss of protein integrity can be attributed to residual solvent entrapped in particles whose solidification was accelerated. In the second case, denaturation may be explained by an increase in the protein exposure time at water/organic solvent interface due to an increase in organic phase viscosity. PMID- 21284957 TI - High-level expression of soluble form of mouse natural killer cell receptor NKR P1C(B6) in Escherichia coli. AB - Mouse NKR-P1C(B6) receptor corresponding to NK1.1 alloantigen is one of the most widespread surface markers of mouse NK and NKT cells in C57BL/6 mice detected by monoclonal antibody PK136. Although functional studies revealed the ability of this receptor to activate both natural killing and production of cytokines upon antibody crosslinking, the ligand for NKR-P1C(B6) remains unknown. In order to initiate ligand identification, structural studies, and epitope mapping experiments, we developed a simple and efficient expression and purification protocol allowing to produce large amounts of pure soluble monomeric mouse NKR P1C(B6). Our protein encompassed approximately half of the stalk region and the entire C-terminal globular ligand binding domain. The identity of protein that was devoid of N-terminal initiation methionine and had all three expected disulfides closed was confirmed using high resolution ion cyclotron resonance mass spectrometry. Protein produced into inclusion bodies in Escherichia coli was efficiently refolded into a unique three dimensional structure as confirmed by NMR using (1)H-(15)N-HSQC spectra of uniformly labeled protein. The exceptional purity of the protein should allow its crystallization and detailed structural investigations, and is a prerequisite for its use as a probe in ligand identification and antibody epitope mapping experiments. PMID- 21284958 TI - Leveraging health social networking communities in translational research. AB - Health social networking communities are emerging resources for translational research. We have designed and implemented a framework called HyGen, which combines Semantic Web technologies, graph algorithms and user profiling to discover and prioritize novel associations across disciplines. This manuscript focuses on the key strategies developed to overcome the challenges in handling patient-generated content in Health social networking communities. Heuristic and quantitative evaluations were carried out in colorectal cancer. The results demonstrate the potential of our approach to bridge silos and to identify hidden links among clinical observations, drugs, genes and diseases. In Amyotrophic Lateral Sclerosis case studies, HyGen has identified 15 of the 20 published disease genes. Additionally, HyGen has highlighted new candidates for future investigations, as well as a scientifically meaningful connection between riluzole and alcohol abuse. PMID- 21284959 TI - Organic/inorganic hybrid network structure nanocomposite scaffolds based on grafted chitosan for tissue engineering. AB - We describe the first study of structure-processing-property relationship in organic/inorganic hybrid network structure nanocomposite scaffolds based on grafted chitosan for bone tissue engineering. Chitosan was first grafted with propylene oxide to form hydroxypropylated chitosan, which was subsequently linked with ethylene glycol functionalized nanohydroxyapatite to form an organic/inorganic network structure. The resulting scaffold was characterized by a highly porous structure and significantly superior physico-chemical, mechanical and biological properties compared to pure chitosan. The scaffolds exhibited high modulus, controlled swelling behavior and reduced water uptake, but the water retention ability was similar to pure chitosan scaffold. MTT assay studies confirmed the non-cytotoxic nature of the scaffolds and enabled degradation products to be analyzed. The nanocomposite scaffolds were biocompatible and supported adhesion, spreading, proliferation and viability of osteoblasts cells. Furthermore, the cells were able to infiltrate and colonize into the pores of the scaffolds and establish cell-cell interactions. The study suggests that hydroxypropylation of chitosan and forming a network structure with a nano inorganic constituent is a promising approach for enhancing physico-chemical, functional and biological properties for utilization in bone tissue engineering applications. PMID- 21284961 TI - Discussion: 'cost-effectiveness of induced labor' by Kaimal et al. PMID- 21284960 TI - Exposed hydroxyapatite particles on the surface of photo-crosslinked nanocomposites for promoting MC3T3 cell proliferation and differentiation. AB - We present a systematic study for investigating the role of exposed hydroxyapatite (HA) nanoparticles in influencing surface characteristics and mouse pre-osteoblastic MC3T3-E1 cell behavior using nanocomposites prepared by photo-crosslinking poly(epsilon-caprolactone) diacrylate (PCLDA) with HA. PCLDA530 and PCLDA2000 synthesized from poly(epsilon-caprolactone) diol precursors with nominal molecular weights of 530 and 2000 g mol(-1) were used as the polymer matrices. Crosslinked PCLDA530 was amorphous while crosslinked PCLDA2000 was semi-crystalline. Crosslinked PCLDA/HA composites with different compositions of HA (10%, 20% and 30%) as well as crosslinked PCLDAs were characterized in terms of their composition-dependent physicochemical properties. The tensile, compressive and shear moduli were greatly enhanced by incorporating HA nanoparticles with the polymer matrices. The disk surfaces of original crosslinked PCLDA/HA nanocomposites were removed by cutting using a blade to expose HA nanoparticles that were embedded in the polymer substrates. The composition of HA was much higher on the cut surface, particularly in semi crystalline crosslinked PCLDA2000/HA nanocomposites. The surface characteristics of original and cut crosslinked PCLDA/HA nanocomposites were compared and correlated with cell behavior on these nanocomposites. MC3T3-E1 cell attachment, proliferation and differentiation were significantly enhanced when the HA composition was increased in original crosslinked PCLDA/HA nanocomposites due to more bioactive HA, higher surface stiffness and rougher topography. More exposed HA on the surface of cut semi-crystalline PCLDA2000/HA nanocomposites resulted in improved hydrophilicity and significantly better MC3T3 cell attachment, proliferation and differentiation compared with the original surfaces. This study suggests that HA nanoparticles may not be fully exploited in polymer/HA nanocomposites where the top polymer surface covers the particles. The removal of this polymer layer can generate more desirable surfaces and osteoconductivity for bone repair and regeneration. PMID- 21284962 TI - Does treatment of premature labor with terbutaline increase the risk of autism spectrum disorders? PMID- 21284963 TI - Metaanalysis and labor inhibition therapy. PMID- 21284964 TI - Effect of a comprehensive obstetric patient safety program on compensation payments and sentinel events. AB - Our objective was to describe a comprehensive obstetric patient safety program and its effect on reducing compensation payments and sentinel adverse events. From 2003 to 2009, we implemented a comprehensive obstetric patient safety program at our institution with multiple integrated components. To evaluate its effect on compensation payments and sentinel events, we gathered data on compensation payments and sentinel events retrospectively from 2003, when the program was initiated, through 2009. Average yearly compensation payments decreased from $27,591,610 between 2003-2006 to $2,550,136 between 2007-2009, sentinel events decreased from 5 in 2000 to none in 2008 and 2009. Instituting a comprehensive obstetric patient safety program decreased compensation payments and sentinel events resulting in immediate and significant savings. PMID- 21284965 TI - Obesity and pregnancy: clinical management of the obese gravida. AB - In recent years, the prevalence of obesity in the United States has risen dramatically, especially among women of reproductive age. Research that has specifically evaluated pregnancy outcomes among obese parturients has allowed for a better understanding of the myriad adverse perinatal complications that are observed with significantly greater frequency in the obese pregnant population. The antepartum, intrapartum, intraoperative, postoperative, and postpartum periods are all times in which the obese pregnant woman is at greater risk for adverse maternal-fetal outcomes, compared with her ideal bodyweight counterpart. Comorbid medical conditions that commonly are associated with obesity further accentuate perinatal risks. All obese pregnant women should be counseled regarding these risks, and strategies should be used to improve perinatal outcome whenever possible. Obese women of reproductive age ideally should be counseled before conception and advised to achieve ideal bodyweight before pregnancy. PMID- 21284966 TI - Utility of dilation and curettage in the diagnosis of pregnancy of unknown location. AB - OBJECTIVE: We sought to determine utility of uterine evacuation for diagnosis of nonviable pregnancy of unknown location (PUL). STUDY DESIGN: We conducted a cohort study to assess the prevalence of ectopic pregnancy (EP), overall, and stratified by presenting signs and symptoms in women with a nonviable PUL. RESULTS: Of the 173 women, 66 (38%) had miscarriage (spontaneous abortion [SAB]) and 107 (62%) had EP. When initial human chorionic gonadotropin (hCG) was <2000 mIU/mL, the odds of an EP were greater (odds ratio, 4.32; 95% confidence interval, 2.04-9.12). Demographic factors, obstetric history, and clinical presentation were not useful in distinguishing between EP and SAB. Pre-evacuation hCG increase had strong trend association with EP (odds ratio, 2.14; 95% confidence interval, 0.98-4.68). A >30% fall in postcurettage hCG was suggestive, but was not a diagnostic indicator of SAB. CONCLUSION: Uterine evacuation is a useful diagnostic aid for women with nonviable PUL. Nondiagnostic ultrasound findings and absolute and serial hCG values are associated with, but do not accurately predict final diagnosis. PMID- 21284967 TI - Nifedipine in the management of preterm labor: a systematic review and metaanalysis. AB - OBJECTIVE: To determine the efficacy and safety of nifedipine as a tocolytic agent in women with preterm labor. STUDY DESIGN: A systematic review and metaanalysis of randomized controlled trials. RESULTS: Twenty-six trials (2179 women) were included. Nifedipine was associated with a significant reduction in the risk of delivery within 7 days of initiation of treatment and before 34 weeks' gestation, respiratory distress syndrome, necrotizing enterocolitis, intraventricular hemorrhage, neonatal jaundice, and admission to the neonatal intensive care unit when compared with beta2-adrenergic-receptor agonists. There was no difference between nifedipine and magnesium sulfate in tocolytic efficacy. Nifedipine was associated with significantly fewer maternal adverse events than beta2-adrenergic-receptor agonists and magnesium sulfate. Maintenance nifedipine tocolysis was ineffective in prolonging gestation or improving neonatal outcomes when compared with placebo or no treatment. CONCLUSION: Nifedipine is superior to beta2-adrenergic-receptor agonists and magnesium sulfate for tocolysis in women with preterm labor. PMID- 21284968 TI - Regression of high-grade cervical intraepithelial neoplasia with TG4001 targeted immunotherapy. AB - OBJECTIVE: We sought to evaluate the safety and efficacy of TG4001 in patients with human papillomavirus (HPV) 16-related cervical intraepithelial neoplasia (CIN) 2/3 at 6 and 12 months. STUDY DESIGN: In all, 21 patients with HPV 16 related CIN 2/3 received 3 weekly subcutaneous injections of TG4001. Regression of the CIN 2/3 lesion and the clearance of HPV 16 infection were monitored by cytology, colposcopy, and HPV DNA/messenger RNA (mRNA) detection. A clinical response was defined by no CIN 2/3 found on conization, or no conization performed because not suspected at cytology or colposcopy. RESULTS: Ten patients (48%) were evaluated as clinical responders at month 6. Nine patients experienced an improvement of their HPV 16 infection, by mRNA +/- DNA eradication. HPV 16 mRNA clearance was associated with CIN 2/3 cytologic and colposcopic regression in 7 of 10 patients. At month 12, 7 of 8 patients without conization reported neither suspicion of CIN 2/3 relapse nor HPV 16 infection. The remaining patient was lost to follow-up. CONCLUSION: These promising data warrant further development of TG4001 in CIN 2/3 treatment. PMID- 21284970 TI - Amniotic fluid levels of glial fibrillary acidic protein in fetal rats with retinoic acid induced myelomeningocele: a potential marker for spinal cord injury. AB - OBJECTIVE: The objective of this study was to determine whether amniotic fluid levels of glial acidic fibrillary protein (GFAP) would reflect myelomeningocele related neurodegeneration in the rat model of retinoic acid-induced myelomeningocele, which is a model that is very similar to human myelomeningocele and develops the entire spectrum of disease severity including features of the Chiari II malformation. STUDY DESIGN: Time-dated (embryonic day 10) pregnant Sprague-Dawley rats were gavage fed 60 mg/kg/bodyweight retinoic acid that had been dissolved in olive oil or olive oil alone. Myelomeningocele, retinoic acid exposed no myelomeningocele, and control fetuses were harvested at specific time points throughout gestation. A standard set of pinching tests was performed to interrogate the sensorimotor reflex arc of hindpaws and tails. Amniotic fluid GFAP levels were analyzed by standard enzyme-linked immunosorbent assay techniques. RESULTS: Amniotic fluid-GFAP levels were similar between groups at embryonic days 14, 16, and 18, respectively. Compared with control fetuses, amniotic fluid GFAP levels were significantly increased in myelomeningocele fetuses at embryonic days 20 and 22 (P < .001). Defect size (P < .001), presence of clubfoot deformity (P = .0004), and absence of sensorimotor function (P < .01) at embryonic day 22 correlated with amniotic fluid-GFAP levels. CONCLUSION: Amniotic fluid-GFAP levels appear to correlate with spinal cord injury as gestation proceeds in fetal rats with myelomeningocele. PMID- 21284972 TI - Breath-taking: a chronic cough in a pregnant patient had a surprising origin. PMID- 21284969 TI - A molecular signature of an arrest of descent in human parturition. AB - OBJECTIVE: This study was undertaken to identify the molecular basis of an arrest of descent. STUDY DESIGN: Human myometrium was obtained from women in term labor (TL; n = 29) and arrest of descent (AODes; n = 21). Gene expression was characterized using Illumina HumanHT-12 microarrays. A moderated Student t test and false discovery rate adjustment were applied for analysis. Confirmatory quantitative reverse transcription-polymerase chain reaction and immunoblot were performed in an independent sample set. RESULTS: Four hundred genes were differentially expressed between women with an AODes compared with those with TL. Gene Ontology analysis indicated enrichment of biological processes and molecular functions related to inflammation and muscle function. Impacted pathways included inflammation and the actin cytoskeleton. Overexpression of hypoxia inducible factor-1a, interleukin -6, and prostaglandin-endoperoxide synthase 2 in AODes was confirmed. CONCLUSION: We have identified a stereotypic pattern of gene expression in the myometrium of women with an arrest of descent. This represents the first study examining the molecular basis of an arrest of descent using a genome-wide approach. PMID- 21284973 TI - Functional mouse genomics. Introduction. PMID- 21284975 TI - You are what your dad ate. AB - Maternal nutrition and metabolism are critical determinants of adult offspring health. Recent reports describe adverse offspring outcomes associated with the father's diet, indicating nongenetic inheritance of paternal experience. Determining underlying mechanisms may require reconsideration of our understanding of the heritability of epigenetic states. PMID- 21284976 TI - Can dietary nitrates enhance the efficiency of mitochondria? AB - A decline in mitochondrial function occurs in many conditions. A report in this issue of Cell Metabolism (Larsen et al., 2011) shows that dietary inorganic nitrates enhance muscle mitochondrial efficiency. It is an attractive hypothesis that dietary changes enhance energy efficiency, but its potential application depends on long-term studies investigating net benefits versus adverse effects. PMID- 21284977 TI - AMPK-dependent phosphorylation of ULK1 induces autophagy. AB - AMP-activated protein kinase (AMPK) is a highly conserved cellular energy sensor that plays a central role in metabolic homeostasis. A recent study in Science (Egan et al., 2011) identifies ULK1 as a substrate for AMPK phosphorylation, a modification required for selective autophagy of mitochondria and cell survival during starvation. PMID- 21284978 TI - Autonomic MC sets the metabolic tone. AB - The CNS melanocortin (MC) and the autonomic nervous (ANS) system represent key regulators of energy homeostasis. In this issue, Rossi et al. (2011) dissect metabolic functions of MC4 receptors based on anatomic localization within the ANS by re-expressing MC4R subpopulations in cholinergic or brainstem neurons of MC4R-KO mice. PMID- 21284979 TI - Adiponectin receptor signaling: a new layer to the current model. AB - Adiponectin and its receptors, AdipoR1 and AdipoR2, regulate glucose and fatty acid metabolism partly via activation of AMP-activated protein kinase (AMPK). Recent work in Nature Medicine (Holland et al., 2011) suggests that adiponectin stimulates ceramidase activity through AdipoR1 and AdipoR2, an activity potentially involved in promoting cell survival. PMID- 21284980 TI - Crosstalk between components of circadian and metabolic cycles in mammals. AB - In mammals, most metabolic processes are influenced by biological clocks and feeding rhythms. The mechanisms that couple metabolism to circadian oscillators are just emerging. NAD-dependent enzymes (e.g., Sirtuins and poly[ADP-ribose] polymerases), redox- and/or temperature-dependent transcription factors (e.g., CLOCK, NPAS2, and HSF1), nutrient-sensing transcriptional regulatory proteins (e.g., CREB-CBP-CRCT2, FOXO-p300, nuclear receptors, PGC-1, and SP1 family members) and protein kinases (e.g., AMPK), are plausible candidates for conveying a cell's metabolic state to the core clock circuitry. The intertwining between these acute regulators and circadian clock components is so tight that the discrimination between metabolic and circadian oscillations may be somewhat arbitrary. PMID- 21284981 TI - The Drosophila estrogen-related receptor directs a metabolic switch that supports developmental growth. AB - Metabolism must be coordinated with development to provide the appropriate energetic needs for each stage in the life cycle. Little is known, however, about how this temporal control is achieved. Here, we show that the Drosophila ortholog of the estrogen-related receptor (ERR) family of nuclear receptors directs a critical metabolic transition during development. dERR mutants die as larvae with low ATP levels and elevated levels of circulating sugars. The expression of active dERR protein in mid-embryogenesis triggers a coordinate switch in gene expression that drives a metabolic program normally associated with proliferating cells, supporting the dramatic growth that occurs during larval development. This study shows that dERR plays a central role in carbohydrate metabolism, demonstrates that a proliferative metabolic program is used in normal developmental growth, and provides a molecular context to understand the close association between mammalian ERR family members and cancer. PMID- 21284982 TI - Dietary inorganic nitrate improves mitochondrial efficiency in humans. AB - Nitrate, an inorganic anion abundant in vegetables, is converted in vivo to bioactive nitrogen oxides including NO. We recently demonstrated that dietary nitrate reduces oxygen cost during physical exercise, but the mechanism remains unknown. In a double-blind crossover trial we studied the effects of a dietary intervention with inorganic nitrate on basal mitochondrial function and whole body oxygen consumption in healthy volunteers. Skeletal muscle mitochondria harvested after nitrate supplementation displayed an improvement in oxidative phosphorylation efficiency (P/O ratio) and a decrease in state 4 respiration with and without atractyloside and respiration without adenylates. The improved mitochondrial P/O ratio correlated to the reduction in oxygen cost during exercise. Mechanistically, nitrate reduced the expression of ATP/ADP translocase, a protein involved in proton conductance. We conclude that dietary nitrate has profound effects on basal mitochondrial function. These findings may have implications for exercise physiology- and lifestyle-related disorders that involve dysfunctional mitochondria. PMID- 21284983 TI - The unfolded protein response mediates adaptation to exercise in skeletal muscle through a PGC-1alpha/ATF6alpha complex. AB - Exercise has been shown to be effective for treating obesity and type 2 diabetes. However, the molecular mechanisms for adaptation to exercise training are not fully understood. Endoplasmic reticulum (ER) stress has been linked to metabolic dysfunction. Here we show that the unfolded protein response (UPR), an adaptive response pathway that maintains ER homeostasis upon luminal stress, is activated in skeletal muscle during exercise and adapts skeletal muscle to exercise training. The transcriptional coactivator PGC-1alpha, which regulates several exercise-associated aspects of skeletal muscle function, mediates the UPR in myotubes and skeletal muscle through coactivation of ATF6alpha. Efficient recovery from acute exercise is compromised in ATF6alpha(-/-) mice. Blocking ER stress-related cell death via deletion of CHOP partially rescues the exercise intolerance phenotype in muscle-specific PGC-1alpha KO mice. These findings suggest that modulation of the UPR through PGC1alpha represents an alternative avenue to improve skeletal muscle function and achieve metabolic benefits. PMID- 21284984 TI - Crosstalk between glucocorticoid receptor and nutritional sensor mTOR in skeletal muscle. AB - Maintenance of skeletal muscle mass relies on the dynamic balance between anabolic and catabolic processes and is important for motility, systemic energy homeostasis, and viability. We identified direct target genes of the glucocorticoid receptor (GR) in skeletal muscle, i.e., REDD1 and KLF15. As well as REDD1, KLF15 inhibits mTOR activity, but via a distinct mechanism involving BCAT2 gene activation. Moreover, KLF15 upregulates the expression of the E3 ubiquitin ligases atrogin-1 and MuRF1 genes and negatively modulates myofiber size. Thus, GR is a liaison involving a variety of downstream molecular cascades toward muscle atrophy. Notably, mTOR activation inhibits GR transcription function and efficiently counteracts the catabolic processes provoked by glucocorticoids. This mutually exclusive crosstalk between GR and mTOR, a highly coordinated interaction between the catabolic hormone signal and the anabolic machinery, may be a rational mechanism for fine-tuning of muscle volume and a potential therapeutic target for muscle wasting. PMID- 21284985 TI - Brain insulin controls adipose tissue lipolysis and lipogenesis. AB - White adipose tissue (WAT) dysfunction plays a key role in the pathogenesis of type 2 diabetes (DM2). Unrestrained WAT lipolysis results in increased fatty acid release, leading to insulin resistance and lipotoxicity, while impaired de novo lipogenesis in WAT decreases the synthesis of insulin-sensitizing fatty acid species like palmitoleate. Here, we show that insulin infused into the mediobasal hypothalamus (MBH) of Sprague-Dawley rats increases WAT lipogenic protein expression, inactivates hormone-sensitive lipase (Hsl), and suppresses lipolysis. Conversely, mice that lack the neuronal insulin receptor exhibit unrestrained lipolysis and decreased de novo lipogenesis in WAT. Thus, brain and, in particular, hypothalamic insulin action play a pivotal role in WAT functionality. PMID- 21284986 TI - Melanocortin-4 receptors expressed by cholinergic neurons regulate energy balance and glucose homeostasis. AB - Melanocortin-4 receptor (MC4R) mutations cause dysregulation of energy balance and hyperinsulinemia. We have used mouse models to study the physiological roles of extrahypothalamic MC4Rs. Re-expression of MC4Rs in cholinergic neurons (ChAT Cre, loxTB MC4R mice) modestly reduced body weight gain without altering food intake and was sufficient to normalize energy expenditure and attenuate hyperglycemia and hyperinsulinemia. In contrast, restoration of MC4R expression in brainstem neurons including those in the dorsal motor nucleus of the vagus (Phox2b-Cre, loxTB MC4R mice) was sufficient to attenuate hyperinsulinemia, while the hyperglycemia and energy balance were not normalized. Additionally, hepatic insulin action and insulin-mediated suppression of hepatic glucose production were improved in ChAT-Cre, loxTB MC4R mice. These findings suggest that MC4Rs expressed by cholinergic neurons regulate energy expenditure and hepatic glucose production. Our results also provide further evidence of the dissociation in pathways mediating the effects of melanocortins on energy balance and glucose homeostasis. PMID- 21284987 TI - Amino acid-dependent activation of liver estrogen receptor alpha integrates metabolic and reproductive functions via IGF-1. AB - Throughout evolution, organisms have devised strategies to limit fertility in case of prolonged starvation. In mammals, the liver plays a central role in the orchestration of mechanisms allowing for the maintenance of energy homeostasis. We here demonstrate that dietary amino acids regulate the transcriptional activity of hepatic estrogen receptor alpha (ERalpha) through an mTOR-dependent mechanism. As a result of ERalpha activation, hepatic IGF-1 mRNA and blood IGF-1 are increased. Conversely, calorie restriction or selective ablation of ERalpha in the liver decrease blood IGF-1 to levels inadequate for the correct proliferation of the lumen epithelium in the uterus and the progression of the estrous cycle. We propose that the liver acts as critical mediator of energetic and reproductive functions responsible for the blockade of the estrous cycle in case of protein scarcity. Our findings may provide novel insights to understand the cause of selected forms of infertility and metabolic alterations in women after menopause. PMID- 21284988 TI - Amino acid signaling to mTOR mediated by inositol polyphosphate multikinase. AB - mTOR complex 1 (mTORC1; mammalian target of rapamycin [mTOR] in complex with raptor) is a key regulator of protein synthesis and cell growth in response to nutrient amino acids. Here we report that inositol polyphosphate multikinase (IPMK), which possesses both inositol phosphate kinase and lipid kinase activities, regulates amino acid signaling to mTORC1. This regulation is independent of IPMK's catalytic function, instead reflecting its binding with mTOR and raptor, which maintains the mTOR-raptor association. Thus, IPMK appears to be a physiologic mTOR cofactor, serving as a determinant of mTORC1 stability and amino acid-induced mTOR signaling. Substances that block IPMK-mTORC1 binding may afford therapeutic benefit in nutrient amino acid-regulated conditions such as obesity and diabetes. PMID- 21284989 TI - Molecular annotation of integrative feeding neural circuits. AB - The identity of higher-order neurons and circuits playing an associative role to control feeding is unknown. We injected pseudorabies virus, a retrograde tracer, into masseter muscle, salivary gland, and tongue of BAC-transgenic mice expressing GFP in specific neural populations and identified several CNS regions that project multisynaptically to the periphery. MCH and orexin neurons were identified in the lateral hypothalamus, and Nurr1 and Cnr1 in the amygdala and insular/rhinal cortices. Cholera toxin beta tracing showed that insular Nurr1(+) and Cnr1(+) neurons project to the amygdala or lateral hypothalamus, respectively. Finally, we show that cortical Cnr1(+) neurons show increased Cnr1 mRNA and c-Fos expression after fasting, consistent with a possible role for Cnr1(+) neurons in feeding. Overall, these studies define a general approach for identifying specific molecular markers for neurons in complex neural circuits. These markers now provide a means for functional studies of specific neuronal populations in feeding or other complex behaviors. PMID- 21284990 TI - A comparison of daily total locomotor activity between the lactation and the dry period in dairy cattle. AB - The objective of this study was to investigate the influence of farming management on the total locomotor activity (TLA) behaviour in dairy cattle. We recorded 24h/day TLA in five not pregnant Holstein Friesian cows during parts of the lactation and dry periods, by means of an activity monitoring system (Actiwatch mini(r)) for seven days in each period. During mild lactation (period 1) animals were milked and fed twice a day. During the dry (period 2) they were kept to graze all day. In both periods hay and water were available ad libitum. Differences between the photophase and the scotophase were evaluated with a Student t-test. One-way repeated measure ANOVA was used to determine a statistical significant effect of time. A trigonometric statistical model was used to describe the main rhythmic parameters: mean level, amplitude, acrophase and robustness of rhythm. Our results showed a circadian rhythm of daily TLA in both periods, with different percentages of robustness, and acrophase in the middle of the photophase. The different patterns of activity in the two periods were attributed to the management practise during milking period. These results could be taken in consideration during farming management for the evaluation of such systems used in livestock, with respect to production and welfare. PMID- 21284991 TI - Mechanism of translation initiation by Dicistroviridae IGR IRESs. AB - The Dicistroviridae is a growing virus family characterized by a dicistronic genome, wherein each open reading frame (ORF) is translated from an independent internal ribosome entry site (IRES). The 5' IRES that translates the first open reading frame (ORF1) is similar to the picornaviral IRESs. However the second IRES, referred to as the intergenic region (IGR) IRES, - translates ORF2 by and uses an unusual mechanism of initiating protein synthesis. It folds into a compact RNA structure that can bind directly to 40S ribosomal subunits and form 80S complexes to initiate translation in the absence of any initiation factors. Despite its unusual mechanism, the IGR IRES has proven to be an elegant model for elucidating initiation mechanisms employed by IRESs, as well as making it a powerful research tool with diverse applications. PMID- 21284993 TI - Carry-over of dietary organochlorine pesticides, PCDD/Fs, PCBs, and brominated flame retardants to Atlantic salmon (Salmo salar L.) fillets. AB - Information on carry-over of contaminants from feed to animal food products is essential for appropriate human risk assessment of feed contaminants. The carry over of potentially hazardous persistent organic pollutants (POPs) from feed to fillet was assessed in consumption sized Atlantic salmon (Salmo salar). Relative carry-over (defined as the fraction of a certain dietary POP retained in the fillet) was assessed in a controlled feeding trial, which provided fillet retention of dietary organochlorine pesticides (OCPs), dioxins (PCDD/Fs), polychlorinated biphenyls (PCBs), and brominated flame retardants (BFRs). Highest retention was found for OCPs, BFRs and PCBs (31-58%), and the lowest retentions were observed for PCDD/Fs congeners (10-34%). National monitoring data on commercial fish feed and farmed Atlantic salmon on the Norwegian market were used to provide commercially relevant feed-to-fillet transfer factors (calculated as fillet POP level divided by feed POP level), which ranged from 0.4 to 0.5, which is a factor 5-10 times higher than reported for terrestrial meat products. For the OCP with one of the highest relative carry-over, toxaphene, uptake and elimination kinetics were established. Model simulations that are based on the uptake and elimination kinetics gave predicted levels that were in agreement with the measured values. Application of the model to the current EU upper limit for toxaphene in feed (50 MUg kg(-1)) gave maximum fillet levels of 22 MUg kg(-1), which exceeds the estimated permissible level (21 MUg kg(-1)) for toxaphene in fish food samples in Norway. PMID- 21284992 TI - HIV reservoirs and latency models. AB - The main impediment to a cure for HIV is the existence of long-lasting treatment resistant viral reservoirs. In this review, we discuss what is currently known about reservoirs, including their formation and maintenance, while focusing on latently infected CD4+ T cells. In addition, we compare several different in vivo and in vitro models of latency. We comment on how each model may reflect the properties of reservoirs in vivo, especially with regard to cell phenotype, since recent studies demonstrate that multiple CD4+ T cell subsets contribute to HIV reservoirs and that with HAART and disease progression the relative contribution of different subsets may change. Finally, we focus on the direct infection of resting CD4+ T cells as a source of reservoir formation and as a model of latency, since recent results help explain the misconception that resting CD4+ T cells appeared to be resistant to HIV in vitro. PMID- 21284994 TI - "Letter to editor" in lieu of article published below in Gynecol Oncolo. 2010 Oct;119(1):136-9. ctla-4 gene variations in southern Iranian patients with cervical cancer. PMID- 21284995 TI - Three cases of vaginal radical trachelectomy during pregnancy. PMID- 21284996 TI - Increased circulating hepatocyte growth factor (HGF): a marker of epithelial ovarian cancer and an indicator of poor prognosis. AB - OBJECTIVE: Hepatocyte growth factor (HGF) has been described to be increased in different cancers. In the present study we wanted to investigate whether HGF in serum can distinguish between benign and malignant ovarian tumors, and whether serum HGF levels can predict the outcome in patients with ovarian carcinomas. METHODS: We included 123 consecutive patients appointed for laparotomy due to a pelvic mass. Preoperative levels of serum cancer antigen 125 (CA 125), HGF and HGF activator (HGFA) were quantified with immunological methods. We performed immunohistochemical analyses of HGFalpha, HGFbeta and the receptor c-Met. Five year survival of patients with advanced disease (stage III and stage IV) was analyzed with the Kaplan-Meier method. RESULTS: Sixty patients had ovarian carcinomas, 23 borderline tumors, and 40 benign ovarian tumors. Patients with ovarian carcinomas had significantly higher preoperative HGF and CA 125 serum levels than patients with benign ovarian tumors, and borderline tumors. Patients with borderline tumors had significantly higher CA 125 values than benign cases. A combination of CA 125 and HGF increased the specificity in predicting carcinoma. We observed abundant HGFalpha, HGFbeta and c-Met expressions in all ovarian tumors. Patients with advanced disease and preoperative serum HGF values >=2SD above reference value had a shorter disease-free survival than patients with advanced disease and serum HGF <2SD above reference value. CONCLUSIONS: HGF in serum is an indicator of ovarian carcinoma in women with a pelvic mass, and of a poor prognosis in advanced ovarian cancer. PMID- 21284997 TI - Differences in valvular and vascular cell responses to strain in osteogenic media. AB - Calcification is the primary cause of failure of bioprosthetic and tissue engineered vascular and valvular grafts. We used tissue-engineered collagen gels containing human aortic smooth muscle cells (HASMC) and human aortic valvular interstitial cells (HAVIC) as a model to investigate cell-mediated differences in early markers of calcification. The HASMCs and HAVICs were isolated from non sclerotic human tissues. After 21 days of culture in either regular or osteogenic media with or without 10% cyclic strain at 1 Hz, the collagen gels were assessed for DNA content, collagen I, matrix metalloproteinase (MMP)-2 and glycosaminoglycan (GAG) content. The collagen gels containing HASMCs contained significantly greater amounts of collagen I and GAG compared to HAVICs. Although strain increased MMP-2 activity for both cell types, this trend was significant (p <= 0.05) only for HAVICs. Cultured gels were also assessed for osteogenic markers calcium content, alkaline phosphatase (ALP), and Runx2 and were present at greater amounts in gels containing HASMCs than HAVICs. Calcium content, Runx2 expression, and ALP activity were also modulated by mechanical strain. The results indicate that cell-mediated differences exist between the vascular and valvular calcification processes. Further investigation is necessary for improved understanding and to detect biomarkers for early detection or prevention of these diseases. PMID- 21284998 TI - The grossly invisible and generally ignored lymphatics of the mammalian heart. AB - It is well known that interference with the lymphatic drainage of various bodily organs predisposes to the development of inflammation, infection and the laying down of fibrous tissue. Based on the animal experimental studies and limited observations in man that are presented the hypothesis is offered that the cardiac lymphatic system plays an integral role in the etiology and evolution of the pathology of various human conditions and diseases. PMID- 21284999 TI - Isocitrate dehydrogenase mutations may be a protective mechanism in glioma patients. AB - Gliomas are the most common human brain tumours and can be classified into four grades based on clinical and pathological criteria. A recent cancer genome sequencing project revealed that more than 70% of low-grade gliomas bear mutations in one of two NAD(+)-dependent isocitrate dehydrogenase enzymes, namely, IDH1 and IDH2. Based on the findings that glioma-derived mutations in IDH1 can inhibit the catalytic activity of the enzyme, induce HIF-1alpha, and can produce 2-hydroxyglutarate, two research groups speculated that the IDH mutations may contribute to the promotion of tumorigenesis in gliomas. However, they cannot fully explain the phenomenon that patients harbouring such mutations usually have better outcomes than those with the wild-type IDH genes. This fact leads us to hypothesize that the IDH mutations are not the origin of gliomas but a subsequent protective mechanism that interferes with the metabolism of the tumour cells, making these cells fragile and susceptible to cell death. This process finally helps patients who harbour such IDH mutations to survive. Therefore, contrary to the proposals of other researchers, we speculate that any interventions that correct the impaired function of the mutant IDHs, such as the use of cell permeable alpha-ketoglutarate derivatives, may not cure gliomas and may even worsen the disease. PMID- 21285000 TI - Strategies for localisation of impalpable breast lesions. AB - With advances in the sensitivity of mammographic screening and the broader population of women screened via national programmes. More than 50% of all new breast cancers in the United Kingdom are screen-detected and of the 11,110 invasive breast cancers (78.7 per cent of all UK cancers) detected in the year 2007-2008, 5814 (52.3 per cent) measured 15 mm or less in diameter and were deemed clinically non-palpable. For excision of non-palpable lesions, localisation techniques are currently largely limited to wire-guided localisation with the associated risks of migration, transection and scheduling conflicts. In this review we will describe the current gold-standard of wire-guided localisation (WGL), its associated merits and limitations before reporting on the data available for Radioguided Occult Lesion Localisation (ROLL) and Radiolabeled Seed Localisation (RSL) trials. PMID- 21285001 TI - Best medical intervention for arterial disease or wishful thinking. PMID- 21285003 TI - Hypoalgesic effect of a passive accessory mobilisation technique in patients with lateral ankle pain. AB - A randomised, double blind, repeated measures study was conducted to investigate the initial effects of an accessory mobilisation technique applied to the ankle joint in 13 patients with a unilateral sub-acute ankle supination injury. Ankle dorsiflexion range of motion, pressure pain threshold, visual analogue scale rating of pain during functional activity and ankle functional scores were assessed before and after application of treatment, manual contact control and no contact control conditions. There were significant improvements in ankle dorsiflexion range of motion (p = 0.000) and pressure pain threshold (p = 0.000) during the treatment condition. However no significant effects were observed for the other measures. These findings demonstrate that mobilisation of the ankle joint can produce an initial hypoalgesic effect and an improvement in ankle dorsiflexion range of motion. PMID- 21285004 TI - Novel screening system for protein-protein interactions by bimolecular fluorescence complementation in Saccharomyces cerevisiae. AB - For high-throughput screening of protein-protein interactions, we have developed a novel yeast screening system using Bimolecular fluorescence complementation (BiFC). Two yeast plasmids, in which genes of heterodimerized peptides LZA and LZB were each fused with those of non-fluorescent half fragments of Kusabira Green mutant (mKG2), were transformed into a- and alpha-type yeast, respectively. Mating of them gave a library, which was screened by following green fluorescence resulted from LZA-LZB interaction. The method showed potential ability to detect the positive clones from a model library, in which green-fluorescent and non fluorescent yeast was mixed in a ratio of 1:675. PMID- 21285005 TI - Evidence for a modulatory effect of IL-10 on both Th1 and Th2 cytokine production: the role of the environment. AB - Allergic and other immune-mediated diseases are complex disease states determined by interplay between host genetics and environmental factors. Environmental changes such as fewer infections and reduced exposure to microbial products have been suggested to have led to insufficient regulation of Th1 and Th2 immune responses, causing an increased incidence of inflammatory diseases. The objective of the present study was to investigate the effect of poor living environmental conditions on mitogen-induced production of cytokines (Th1 and Th2) by peripheral blood leukocytes in children living in urban Brazil and investigate the role of IL-10 in modifying this effect. Our data showed that the proportion of children producing Th1 and Th2 cytokines was lower among those with poor living conditions and that this finding was stronger in children producing IL-10. These results provide a possible biologic explanation for the temporal trends of increasing risk of inflammatory diseases observed in populations living in affluent countries. PMID- 21285006 TI - Detectable expression of IL-35 in CD4+ T cells from peripheral blood of chronic hepatitis B patients. AB - Epstein-Barr virus-induced gene 3 (Ebi3) and the p35 subunit of IL-12 have been reported to form a heterodimeric cytokine, named IL-35, in human and mouse. In mice, IL-35 has been shown to be constitutively expressed by CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) and suggested to contribute to their suppressive activity. However, human CD4(+)CD25(+)Foxp3(+) Tregs do not constitutively express detectable amounts of IL-35 in both mRNA and protein levels. Circulating CD4(+)CD25(+) Treg frequency of chronic Hepatitis B patients significantly correlates with serum viral load. In this study, we investigated whether IL-35 expression could be detected in CD4(+) T cells from peripheral blood of chronic Hepatitis B patients. Using both RT-PCR and immunoprecipitation plus Western blot analysis, we demonstrated that IL-35 expression could be detected in the CD4(+) T cells from peripheral blood of Chronic Hepatitis B patients. PMID- 21285008 TI - Heat effects are unique: mortality risk depends on heat wave, community characteristics. PMID- 21285009 TI - Global estimate of SHS burden. PMID- 21285010 TI - Avoiding health pitfalls of home energy-efficiency retrofits. PMID- 21285011 TI - Does the smoke ever really clear? Thirdhand smoke exposure raises new concerns. PMID- 21285012 TI - Acrolein and neuro disorders. PMID- 21285013 TI - Beastly beauty products: exposure to inorganic mercury in skin-lightening creams. PMID- 21285014 TI - Thyroid hormone understanding branches out: insights into PBDE impacts on brain development. PMID- 21285015 TI - A second look at sea lice. PMID- 21285017 TI - [Preoperative and intraoperative risk factors affecting mortality after heart transplantation: a single-center experience]. AB - OBJECTIVE: We retrospectively analyzed case records to identify risk factors for mortality in heart transplant recipients in our center. METHODS: Data of 123 patients (mean age 40.6+/-14 years and 97 male) transplanted from February 1998 to April 2009 were studied and analyzed. Pre- and intra-operative variables of the 73 patients who survived (Group 1, mean age 39.1+/-14.6, 58 male) and 50 patients who died (Group 2, mean age 42.6+/-12.9, 39 male) were compared. For statistical analysis Student t, Mann-Whitney U and Chi-square tests were used. Logistic regression analysis was used to determine independent risk factors for mortality and survival analysis was accomplished using Kaplan-Meier analysis. RESULTS: Overall mortality in the entire population was 40.6% (50/123). Actuarial survival was 74%, 65%, 51% and 31% at 1, 2, 5 and 10 years respectively. Major causes of death after heart transplantation were infections (30%), right ventricular failure (18%), rejection (12%) and sudden cardiac death (12%). Total ischemic time was 176.7+/-63.3 minutes (range 90-410 minutes). The total cardiopulmonary by-pass (CPB) time (114.3+/-27.7 vs 126.9+/-42.1 min, p=0.05), pre-operative creatinine clearance (81.0+/-31.5 vs 67.2+/-33.0 ml/min, p=0.02), urea (45.2+/-18.6 vs 57.8+/-35.2 mg/dl, p=0.02), and creatinine (1.01+/-0.25 vs 1.17+/-0.36 mg/dl, p=0.05) were significantly different between survivors and non survivors. Group 2 patients had higher transpulmonary gradient (TPG) (9.21+/-5.16 vs 12.50+/-8.26 mmHg, p=0.02) as compared with group 1 patients. Logistic regression analysis revealed that preoperative creatinine clearance (OR 0.989, 95% CI 0.973-1.005, p=0.044), creatinine level (OR 2.028, 95% CI 0.288-14.301, p=0.027), total CPB time (OR 1.013, 95% CI 1.000-1.027, p=0.036), and TPG (OR 1.113, 95% CI 0.992 1.249, p=0.045) were the independent predictors of mortality. CONCLUSION: Our data showed that TPG, total CPB time, pre-transplant renal dysfunction are pre-operative and intra-operative risk factors for mortality after heart transplantation. PMID- 21285018 TI - [Relation of asymmetric dimethylarginine levels with conventional risk score systems in the healthy subjects with positive family history for coronary artery disease]. AB - OBJECTIVE: Coronary artery disease is the most common cause of death in Turkey and the world. Asymmetric dimethylarginine is the major inhibitor of nitric oxide synthesis in humans. It has been shown that increased levels of asymmetric dimethylarginine is associated with endothelial dysfunction and increased atherogenesis. In this study, we aimed to investigate whether asymmetric dimethylarginine level is related with conventional risk score systems in subjects who had family history of coronary artery disease. METHODS: Fifty two subjects within 20-40 years old of whom first degree relatives had myocardial infarction at young ages and 26 age and sex matched control subjects were included in this cross-sectional observational study. Frequency of diabetes, hyperlipidemia, smoking and serum levels of homocysteine, high-sensitive C reactive protein (hsCRP) and asymmetric dimethylarginine were compared between risk group and control subjects. Relation of asymmetric dimethylarginine level with Framingham and TEKHARF risk scores was also compared. Chi-square and Mann Whitney U tests were used to compare categorical and continuous variables, respectively. RESULTS: Fasting serum glucose, triglyceride, high-density lipoprotein, diastolic blood pressure, waist circumference and TEKHARF scores were increased in the subjects who had family history of myocardial infarction. Total cholesterol, low-density lipoprotein, hsCRP, homocysteine, creatinine and Framingham risk score were similar in studied groups . Asymmetric dimethylarginine levels were 0.1 umol/L higher in the risk group; however this difference could not reach significance (0.7+/-0.1 umol/l vs 0.8+/-0.1 umol/l; p=0.061). CONCLUSION: Measurement of serum asymmetric dimethylarginine levels did not reveal utility in defining conventional coronary artery disease risk score systems in cases that had positive family history. Larger studies including patients with different risk tertiles are needed. PMID- 21285019 TI - [Effects of patient education and counseling about life style on quality of life in patients with coronary artery disease]. AB - OBJECTIVE: The aim of this study is to investigate the effects of patient education and counseling intervention success on quality of life (QoL) in patients with coronary artery disease patients. METHODS: Sample of this study included 82 (80.3%) of total 102 patients diagnosed with coronary artery disease. Patients were older than 18 age and they had no perception and communication problems. QoL was measured by means of the Short Form-36 (SF-36) and then subscale scores were calculated in before getting the education and counseling intervention. Subject of education and counseling intervention consists of healthy nutrition, physical activity, maintaining healthy body weight, smoking and alcohol quit issues. After educations and counseling intervention three months later, Short Form-36 was administered. One way analyses of variance for repeated measures (ANOVAR), Chi-square significance test, t-test and nonparametric tests (Wilcoxon sign and Kruskal Wallis Variance) were used to compare demographic and clinic characteristic values of the patient's groups. RESULTS: After education and counseling intervention, SF 36 QoL points, mean exercise duration and number of patients with well -adjusted diet program increased, and diastolic blood pressure decreased (p<0.05 for all). However, mean body mass index, mean number of cigarettes and alcohol drinks per day, systolic blood pressure, lipid levels did not significantly change after education and counseling intervention. CONCLUSION: Education and counseling intervention in patients with coronary artery disease was accompanied by improvement in physical activity, increase in diet compliance level, significantly reduction of diastolic blood pressure and positive increasing trend in 8 scales of SF-36 quality of life scale. PMID- 21285020 TI - [A comparison of pulmonary function, peripheral and respiratory muscle strength and functional capacity in the heart failure patients with different functional classes]. AB - OBJECTIVE: This cross-sectional, observational study was planned to compare pulmonary function, respiratory and peripheral muscle strength, and functional capacity in different functional classes of heart failure patients. METHODS: Thirty-four heart failure patients, in New York Heart Association (NYHA) Class II and III (68.59+/-9.84 years, left ventricular ejection fraction (LVEF) =34.24+/ 7.59%) were included. Class II and III patients' pulmonary function was assessed using spirometry, respiratory muscle strength using a mouth pressure device, functional capacity using six minute walk test (6MWT), quadriceps femoris and biceps brachii muscle strength were evaluated using a hand-held dynamometer, and variables were compared. Student t, Chi-square, Mann-Whitney U tests, and Spearman correlation coefficients were used for statistical analysis. RESULTS: There were no statistically significant differences in pulmonary function and respiratory muscle strength between the two groups (p>0.05). The 6MWT distance (328.35+/-101.56 m; vs. 480.05+/-104.19 m) quadriceps femoris (218.83+/-63.62 N; vs. 290.69+/-115.53 N) and biceps brachii (164.22+/-44.78 N; vs. 219.19+/-49.37 N) muscle strength of Class III patients were significantly lower than of Class II patients (p<0.05 for all). The NYHA classification system was significantly correlated with measured and predicted 6MWT distance (r=-0.59, r=-0.65, respectively), biceps brachii muscle strength (r=-0.46, r=-0.40, respectively), and % quadriceps femoris muscle strength (r=-0.43) (p<0.05). CONCLUSION: Functional capacity and peripheral muscle strength decrease as the illness progresses in heart failure. Pulmonary function and respiratory muscle strength are preserved. The NYHA classification system is a reliable method in the detection of changes in functional capacity and peripheral muscle strength. Changes in functional capacity and peripheral muscle strength are consistent with the NYHA classification system. PMID- 21285021 TI - The effects of zoledronic acid on neointimal hyperplasia: a rabbit carotid anastomosis model. AB - OBJECTIVE: The aim of the present study was to investigate the effect of zoledronic acid (ZA), as a matrix metalloproteinase inhibitor, on neointimal hyperplasia in rabbit carotid anastomosis model. METHODS: New Zealand male rabbits were divided into two groups as placebo and treatment groups in this experimental study. After anesthesia, the right carotid artery of each rabbit was end-to-end anastomosed with an 8/0 polypropylene suture. Left carotid artery was kept as control without any operation. Placebo group (n=6) received phosphate buffered saline (PBS) (0.5mL/kg/day/s.c.) for 28 days postoperatively, whereas ZA group (n=6) received ZA (100 ug/kg/day/s.c.) for the same period. After sacrification, the anastomosed and control arteries were isolated. Morphometric and immunohistochemical examinations were performed. Statistical analyses of morphometric and immunohistochemical data were performed using two-way ANOVA and Chi-square test respectively. RESULTS: In PBS group, vascular injury in the anastomosed artery significantly increased the intimal area (anastomosed: 112.51+/-61.18 um(2)*1000 vs. control: 22.62+/-4.26 um(2)*1000, p<0.01) and intima/media index (anastomosed: 0.347+/-0.29 vs. control: 0.075+/-0.01, p<0.05) compared to control artery. ZA significantly reduced the intimal area (39.29+/ 18.21 um(2)*1000 , p<0.01) and intima/media index (0.112+/-0.07, p<0.05) compared to PBS group. Additionally, alpha-smooth muscle actin immunopositivity was found significantly decreased in anastomosed arteries from ZA group (ZA: 2.33+/-0.52 vs. PBS: 3.50+/-0.5, p<0.05). Moreover, intensive gelatinase (MMP-2 and MMP-9) immunoreactivities were clearly seen in anastomosed arteries compared to control arteries from PBS group. ZA apparently decreased immunopositivities for gelatinases in anastomosed arteries. CONCLUSION: ZA might be a promising agent for prevention of neointimal hyperplasia, which is the most significant cause of graft failures in late postoperative period. PMID- 21285022 TI - Quantitative trait prediction based on genetic marker-array data, a simulation study. AB - MOTIVATION: Using simulation studies for quantitative trait loci (QTL), we evaluate the prediction quality of regression models that include as covariates single-nucleotide polymorphism (SNP) genetic markers which did not achieve genome wide significance in the original genome-wide association study, but were among the SNPs with the smallest P-value for the selected association test. We compare the results of such regression models to the standard approach which is to include only SNPs that achieve genome-wide significance. Using mean square prediction error as the model metric, our simulation results suggest that by using the coefficient of determination (R(2)) value as a guideline to increase or reduce the number of SNPs included in the regression model, we can achieve better prediction quality than the standard approach. However, important parameters such as trait heritability, the approximate number of QTLs, etc. have to be determined from previous studies or have to be estimated accurately. PMID- 21285023 TI - High on altitude: new attitudes toward human cerebral blood flow regulation and altitude acclimatization. PMID- 21285024 TI - In pursuit of the glycogen-[Ca2+] connection. PMID- 21285025 TI - Do 'fibroblast-like cells' intercede during enteric inhibitory motor neurotransmission in gastrointestinal smooth muscles? PMID- 21285026 TI - The cardiovascular mighty mini-ruler. PMID- 21285027 TI - Oxygen's double-edged sword: balancing muscle O2 supply and use during exercise. PMID- 21285028 TI - 'Brute force' vs. 'gentle taps' in the control of unstable loads. PMID- 21285029 TI - Exhaled nitric oxide and spirometry in respiratory health surveillance. AB - BACKGROUND: Exposure to pollutants in bakeries and hairdressing salons can cause airway syndromes varying from bronchial irritation to asthma. Workplace respiratory health surveillance aims to identify possible cases requiring further investigation. AIMS: To compare the performance of fractional exhaled nitric oxide (FE(NO)) and spirometry for health surveillance of apprentice bakers (ABs) and apprentice hairdressers (AHDs). Determinants of FE(NO) were also identified. METHODS: Symptoms and physician-diagnosed asthma were evaluated by questionnaire. FE(NO) was measured and spirometry was carried out. Subjects with elevated FE(NO) (FE(NO) > upper limit normal), airway obstruction [forced expiratory volume in 1 s (FEV(1))/forced vital capacity (FVC) < 95th percentile] and atopy (history of allergies) were identified. RESULTS: A total of 126 apprentices (59 ABs and 67 AHDs) participated. Twenty-nine (23%) apprentices had abnormal tests: 4 had associated high FE(NO) and airway obstruction, while 25 had either high FE(NO) (n = 15) or airway obstruction (n = 10) alone. Compared with ABs (n = 16), AHDs (n = 13) had more asthma (38 versus 0%; P < 0.05) and atopy (62 versus 6%; P < 0.05). There was no difference in symptoms, smoking FE(NO) or airways obstruction. Among 97 subjects with normal tests, no differences existed between ABs (n = 53) and AHDs (n = 44). Average FE(NO) was increased in atopic non-smokers compared with atopic smokers and non-atopic subjects (P < 0.05). Smoking, a history of allergies, FEV(1)/FVC % observed and respiratory symptoms were the main determinants of FE(NO). CONCLUSIONS: FE(NO) and spirometry were not overlapping dimensions in ABs and hairdressers, each test contributing unique information on the physiological status of the respiratory system. FE(NO) may provide added information on airway inflammation not provided by spirometry. PMID- 21285030 TI - Occupational asthma in professional cleaning work: a clinical study. AB - BACKGROUND: Several epidemiological studies have reported an increased risk of asthma among professional cleaners. To date, however, no analysis of large patient series from clinic of occupational medicine has been published. AIMS: To describe the cases of occupational asthma (OA) diagnosed at the Finnish Institute of Occupational Health (FIOH) during the period 1994-2004 in workers employed in professional cleaning work. METHODS: OA was diagnosed according to patient history, lung function examinations and specific challenge tests with measurements of the forced expiratory volume in 1 second and peak expiratory flow values. RESULTS: Our series comprised 20 patients, all female, with a mean age of 48.8 years (range 27-60 years). The mean duration of cleaning work before the onset of the respiratory symptoms was 14.3 years (range 1-36 years), and the mean duration of cleaning work before the FIOH examinations was 18.6 years (range 3-38 years). OA was triggered by chemicals in 9 cases (45%) and by moulds in 11 cases (55%). The chemicals were cleaning chemicals (wax-removing substances containing ethanolamines in five cases and a cleaning agent containing chloramine-T in one case) and chemicals used in the industrial processes at workplaces (three cases). Of the moulds, the most frequently associated with OA was Aspergillus fumigatus (nine cases). CONCLUSIONS: OA was attributed not only to cleaning chemicals but also to other chemicals used in work environments. Moulds are presented as a new cause of OA in cleaners. PMID- 21285031 TI - Quantifying the phylodynamic forces driving papillomavirus evolution. AB - The associations between pathogens and their hosts are complex and can result from a variety of evolutionary processes including codivergence, lateral transfer, or duplication. Papillomaviruses (PVs) are double-stranded DNA viruses ubiquitously present in mammals and are a suitable target for rigorous statistical tests of potential virus-host codivergence. We analyze the evolutionary dynamics of PV diversification by comparing robust phylogenies of PVs and their respective hosts using different statistical approaches to assess topological and branch-length congruence. Mammalian PVs segregated into four diverse major clades that overlapped to varying degrees in terms of their mammalian host lineages. The hypothesis that PVs and hosts evolved independently was globally rejected (P = 0.0001), although only 90 of 207 virus-host associations (43%) were significant in individual tests. Virus-host codivergence accounted roughly for one-third of the evolutionary events required to reconcile PV-host evolutionary histories. When virus-host associations were analyzed locally within each of the four viral clades, numerous independent topological congruencies were identified that were incompatible with respect to the global trees. These results support an evolutionary scenario in which early PV radiation was followed by independent codivergence between viruses within each of the major clades and their hosts. Moreover, heterogeneous groups of closely related PVs infecting non-related hosts suggest several interspecies transmission events. Our results argue thus for the importance of alternative events in PV evolution, in contrast to the prevailing opinion that these viruses show a high degree of host specificity and codivergence. PMID- 21285033 TI - Persistent toe walking in autism. AB - The records of 954 ambulatory children presenting for initial evaluation to a university developmental pediatrician were reviewed for the prevalence of persistent toe walking and associated tight heel cords. The incidence of persistent toe walking (20.1%) and tight heel cords (12.0%) were found to be higher in 324 children with an autistic spectrum disorder but lower (10.0%/3.0%) in 30 children with Asperger syndrome. These results confirm the previously reported high incidence of toe walking in children with autism and with language disorders and also raise the possibility of a secondary orthopedic deformity that can complicate long-term management of these patients. PMID- 21285032 TI - Neutral evolution of robustness in Drosophila microRNA precursors. AB - Mutational robustness describes the extent to which a phenotype remains unchanged in the face of mutations. Theory predicts that the strength of direct selection for mutational robustness is at most the magnitude of the rate of deleterious mutation. As far as nucleic acid sequences are concerned, only long sequences in organisms with high deleterious mutation rates and large population sizes are expected to evolve mutational robustness. Surprisingly, recent studies have concluded that molecules that meet none of these conditions--the microRNA precursors (pre-miRNAs) of multicellular eukaryotes--show signs of selection for mutational and/or environmental robustness. To resolve the apparent disagreement between theory and these studies, we have reconstructed the evolutionary history of Drosophila pre-miRNAs and compared the robustness of each sequence to that of its reconstructed ancestor. In addition, we "replayed the tape" of pre-miRNA evolution via simulation under different evolutionary assumptions and compared these alternative histories with the actual one. We found that Drosophila pre miRNAs have evolved under strong purifying selection against changes in secondary structure. Contrary to earlier claims, there is no evidence that these RNAs have been shaped by either direct or congruent selection for any kind of robustness. Instead, the high robustness of Drosophila pre-miRNAs appears to be mostly intrinsic and likely a consequence of selection for functional structures. PMID- 21285034 TI - Comparison of structural magnetic resonance imaging and development in toddlers born very low birth weight and full-term. AB - Research suggests that regional structural differences can be associated with the neurodevelopmental impairments faced by children born very low birth weight. However, most studies have used magnetic resonance imaging (MRI) during the neonatal period or during adolescence. The current study used structural MRI to examine relationships between regional volume differences in toddlers (18-22 months adjusted age) born very low birth weight (n = 16) and full-term (n = 10) and neurodevelopmental outcomes, including cognition, language, and early executive functioning. Compared with the full-term group, the very low birth weight group had larger third ventricles and smaller cerebral white matter, thalamus, hippocampus, cerebellum white matter, and anterior cingulate volume. Additionally, a significant interaction was found between language and early executive function scores and cerebral white matter volumes between groups, suggesting that young children born very low birth weight can have different trajectories in the growth and development of overall brain structure. PMID- 21285035 TI - Prenatal brain disruption in molybdenum cofactor deficiency. AB - Molybdenum cofactor deficiency is a rare autosomal recessive disorder that may present during the neonatal period with intractable seizures and be mistaken for ischemic encephalopathy. We describe a patient whose prenatal sonography at 35 weeks' gestation revealed diffuse brain damage with multiple subcortical cavities, ventriculomegaly, dysgenesis of the corpus callosum, and a hypoplastic cerebellum with an enlarged cisterna magna. Magnetic resonance imaging (MRI) later revealed brain atrophy, and multicystic encephalomalacia with hypoplastic vermis and cerebellum. Neurological examination at 10 months showed microcephaly, profound mental retardation, and spasticity. Uric acid was low, and taurine and xanthine were increased in the urine. A sulfite test was positive. The diagnosis of molybdenum cofactor deficiency was made. Sulfite oxidase activity in fibroblasts was undetectable. The patient was found to be homozygous for the 251 418del in the MOCS1 gene. This is the first description of the prenatal development of severe brain disruption in molybdenum cofactor deficiency. PMID- 21285036 TI - Carpal tunnel syndrome secondary to ganglion cyst in a child. AB - Carpal tunnel syndrome is uncommon in children and is associated with an underlying etiology in the majority of cases. The diagnosis of the condition in childhood is dependent on a high degree of clinical suspicion, careful clinical examination, and judicious use of confirmatory investigations. The authors report a novel cause of carpal tunnel syndrome in a child, and discuss the investigation and management strategies in childhood carpal tunnel syndrome. PMID- 21285037 TI - Optic nerve enlargement in Krabbe disease: a pathophysiologic and clinical perspective. AB - Krabbe disease is an infantile-onset progressive leukodystrophy. The classic presentation includes excessive irritability, muscle hypertonicity, developmental delay, failure to thrive, peripheral neuropathy, seizures, and optic nerve atrophy. The authors report a rare case of optic nerve enlargement early in infantile Krabbe disease. Their case demonstrates proximal prechiasmatic enlargement of the nerves. They discuss the pathophysiological and clinical correlation of optic nerve enlargement in Krabbe disease and in other disorders. Although Krabbe disease does not feature in initial differential of optic nerve enlargement in children, its inclusion and early identification facilitate a timely diagnosis of this rapidly progressive fatal disease. PMID- 21285038 TI - Invited commentary. PMID- 21285039 TI - Resolution of headache and papilledema in idiopathic intracranial hypertension associated with inhibition of Na+-K+-2Cl- cotransport. AB - Medical treatment of idiopathic intracranial hypertension is often ineffective. Cerebrospinal fluid diversion or optic nerve sheath fenestration is employed when medical therapy fails. Here, we describe a case of a 13-year-old girl with idiopathic intracranial hypertension refractory to long-term trials of acetazolamide and furosemide at maximally tolerated doses. After declining surgical intervention despite progression of her visual symptoms, a trial of bumetanide (0.25 mg daily) monotherapy was successful in resolution of the patient's symptoms. These results suggest bumetanide could be effective in the treatment of idiopathic intracranial hypertension, perhaps by restoring the balance between cerebrospinal fluid formation and absorption and/or by altering the volume or ionic composition of the brain's extracellular fluid compartment. PMID- 21285040 TI - A novel MECP2 change in an indian boy with variant rett phenotype and congenital blindness: implications for genetic counseling and prenatal diagnosis. AB - Mutations in MECP2 gene are the primary cause of Rett syndrome, a neurodevelopmental disorder that primarily affects girls, and affect 90% to 95% patients with classical Rett syndrome. MECP2 mutations, once thought to be lethal in males, now present a broad spectrum of clinical manifestations in males. This article reports a family with a 9-year-old boy with Rett-like phenotype and congenital blindness, who inherited a novel MECP2 variant (p.P430S) from his asymptomatic mother. The variant was also identified in the asymptomatic maternal grandfather and maternal aunts of the proband, ruling out the possibility that the p.P430S was involved in the phenotype. Findings of the study suggest that a careful evaluation of the pathogenic nature of MECP2 variants identified in males be conducted before proposing genetic counseling or prenatal diagnosis to the family and that the interference of other factors like modifier genes, environment, epigenetics, and mosaicism be taken into account. PMID- 21285041 TI - Fetal exposure to alcohol, developmental brain anomaly, and vitamin a deficiency: a case report. AB - Prenatal alcohol exposure is a cause of congenital brain malformations such as hydrocephalus; however, a complete mechanism accounting for this phenomenon has yet to be discovered. We report a case of a newborn who was exposed to alcohol throughout pregnancy and presented with low serum vitamin A and hydrocephalus. To our knowledge, the connection between prenatal ethanol exposure, vitamin A deficiency, and a developmental brain anomaly has never been described in humans before. A possible mechanism may be mediated by disruption of the homeostasis of vitamin A, an important morphogen in the developing nervous system. This, in turn, compromises the activity of the floor plate, a structure in charge of polarization and midline formation in the neural tube. We conclude that vitamin A screening and supplementation might be recommended for newborns of mothers who ingested ethanol during pregnancy. PMID- 21285043 TI - Correspondence on ''experience with hyperphenylalaninemia in a developing country: unusual clinical manifestations and a novel gene mutation''. PMID- 21285044 TI - Correspondence on ''functional magnetic resonance imaging activation of the brain in children: real acupoint versus sham acupoint''. PMID- 21285047 TI - Review: delirium in the elderly: a comprehensive review. AB - Delirium is a common neuropsychiatric syndrome in the elderly characterized by concurrent impairments in cognition and behaviors. The etiologies for delirium are often multifactorial and are due to underlying medical illnesses and/or due to medication effect. The diagnosis of delirium is often missed in elderly patients and this condition may be mislabeled as depression or dementia. Untreated, delirium can have devastating consequences in the elderly with high rates of morbidity and mortality. Available evidence indicates that early detection, reduction of risk factors, and better management of this condition can decrease its morbidity rates. In this review, we discuss the etiology, neurobiology, diagnosis, prevention, and treatments for this potentially lethal condition in the elderly. PMID- 21285048 TI - Exploring the role of cognitive reserve in early-onset dementia. AB - AIM: Cognitive reserve (CR) is important in protecting the brain from injury and has not been investigated in people with early-onset dementia (EOD). METHODS: A retrospective case control study of 44 patients with dementia onset prior to 65 years of age: Alzheimer's disease (AD) = 23; frontotemporal dementia (FTD) = 21. Groups were matched for age, education, Mini-Mental State Examination (MMSE), premorbid IQ, sex and APOE epsilon4 genotype. Years of formal education were used as a marker of CR. Relationships between education and neuropsychological data was examined using linear regression analyses. RESULTS: There were no demographic differences between the AD and FTD groups. Significant associations were found between education and attention, working memory and visuospatial abilities. There was an effect of CR for the EOD group and selective effects in FTD and AD. CONCLUSION: Our findings suggest CR is operational in patients with FTD and AD. PMID- 21285049 TI - Could vitamins be helpful to patients with sleep apnea? PMID- 21285050 TI - Long-term oxygen therapy: still not preventing the blues. PMID- 21285051 TI - Optimal antithrombotic therapy in patients receiving long-term oral anticoagulation requiring percutaneous coronary intervention: "triple therapy" or "triple threat". PMID- 21285052 TI - "My advice is . . .": beneficent or veiled paternalism. PMID- 21285053 TI - "Triple therapy" rather than "triple threat": a meta-analysis of the two antithrombotic regimens after stent implantation in patients receiving long-term oral anticoagulant treatment. AB - BACKGROUND: An increasing number of patients with an indication for long-term oral anticoagulation (OAC) have undergone percutaneous coronary intervention with stent implantation (PCI-s). However, the optimal antithrombotic treatment for these patients is currently unknown. The purpose of this study was to characterize the benefits and risks of triple antithrombotic therapy (combined aspirin, clopidogrel, and OAC) after stent implantation in patients under long term OAC treatment compared with dual antiplatelet therapy (combined aspirin and clopidogrel). METHODS: The study consisted of clinical controlled trials with >= 3 months of follow-up that compared triple antithrombotic therapy with dual antiplatelet therapy after stent implantation in patients undergoing long-term OAC treatment. RESULTS: Nine clinical trials included 1,996 participants. The meta-analysis was feasible because the grouping criterion was similar. The meta analysis of the prevention of a major adverse cardiovascular event shows triple antithrombotic therapy to be more efficacious than dual antiplatelet therapy (OR, 0.60; 95% CI, 0.42-0.86; P = .005). There was a significant reduction in all cause mortality with triple antithrombotic therapy compared with dual antiplatelet therapy. The meta-analysis of major bleeding in the first 6 months during follow-up shows significantly more events with triple antithrombotic therapy (OR, 2.12; 95% CI, 1.05-4.29; P = .04). CONCLUSIONS: Based on our analysis, triple antithrombotic therapy is substantially more efficacious in reducing the occurrence of cardiovascular events and mortality in PCI-s patients with an indication for long-term OAC, compared with dual antiplatelet therapy. Although triple therapy predisposes patients to an increased risk of bleeding, especially major bleeding, it is the better choice for patients with a low bleeding risk. PMID- 21285054 TI - Pulmonary complications of lung transplantation. AB - Lung transplantation is an effective treatment option for select patients with a variety of end-stage lung diseases. Although transplant can significantly improve the quality of life and prolong survival, a myriad of pulmonary complications may result in significant morbidity and limit long-term survival. The recognition and early treatment of these complications is important for optimizing outcomes. This article provides an overview and update of the pulmonary complications that may be commonly encountered by pulmonologists caring for these patients. PMID- 21285055 TI - Small airway disease in asthma and COPD: clinical implications. AB - Asthma and COPD have a high personal, societal, and economic impact. Both diseases are characterized by airway obstruction and an inflammatory process. The inflammatory process affects the whole respiratory tract, from central to peripheral airways that are <2 mm in internal diameter, the so-called small airways. There is an increased interest in small airway disease, and some new insights have been gained about the contribution of these small airways to the clinical expression of asthma and COPD, as reviewed in this article. Newly developed devices enable drugs to target the small airways, and this may have implications for treatment of patients with asthma, particularly those not responding to large-particle inhaled corticosteroids or those with uncontrollable asthma. The first studies in COPD are promising, and results from new studies are eagerly awaited. PMID- 21285056 TI - Shaping patients' decisions. AB - Many physicians struggle to strike an acceptable balance between respecting patient autonomy and guiding patients' decisions toward what is in their best interests based on their expressed values and long-term goals. Over the past 40 years, the ethical principle of respect for autonomy has gained primacy in Western medicine, but judgments about the appropriate dose of influence on patient decisions have been clouded by misconceptions about patient autonomy. In this article, we consider three such misconceptions with the goal of helping physicians to optimally promote their patients' interests. PMID- 21285057 TI - Long-term oxygen therapy. AB - This article provides an overview of the status of long-term oxygen therapy (LTOT). In the United States, payment cutbacks are occurring as a result of congressionally mandated competitive bidding and capped rental programs. These Medicare programs are discussed. These legislative and regulatory changes may result in reduced patient access to appropriate oxygen-delivery systems that meet medical needs, including optimal ambulation. Prescribing LTOT is addressed in this article, as is the need for adequate patient education. The importance of appropriate monitoring and reassessment is presented. The use of an LTOT collaborative care model is discussed. Although the new intermittent flow oxygen delivery systems have potential benefits, there is consensus that each patient should be tested on the specific device because of variability in delivery and patient response. Feasible locations for patient education and monitoring are identified. PMID- 21285058 TI - Transtracheal oxygen therapy. AB - Transtracheal oxygen therapy (TTO) has been used for long-term oxygen therapy for nearly 30 years. Numerous investigators have explored the potential benefits of TTO. Those results are reviewed in this article. TTO is best viewed not as a catheter but as a program for care. This article discusses patient selection for TTO. Publications evaluating complications are reviewed. In the past, a modified Seldinger technique (MST) was used for the creation of the tracheocutaneous fistula. The rather long program required for tract maturation with MST was labor intensive and required substantial patient education and monitoring, particularly during the immature tract phase. Minor complications were not infrequent. More recently, the Lipkin method has been used to create a surgical tract under conscious sedation with topical anesthesia. The procedure is safe and well tolerated. Transtracheal oxygen is initiated the day following the procedure. Similarly, the tract matures in 7 to 10 days rather than the 6 to 8 weeks with MST. More rapid healing time and superior tract characteristics substantially reduce complications. The TTO program tailored for the Lipkin procedure is shortened, streamlined, and much less labor-intensive. Optimal outcomes with the TTO program require a committed pulmonologist, respiratory therapist, nurse, and surgeon (for the Lipkin procedure). This article discusses new directions in the use of transtracheal gas delivery, including the management of obstructive sleep apnea. Preliminary investigations regarding transtracheal augmented ventilation are presented. These include nocturnal use in severe chronic lung disease and liberation from prolonged mechanical ventilation. PMID- 21285059 TI - Polymyositis associated with severe interstitial lung disease: remission after three doses of IV immunoglobulin. AB - Interstitial lung disease associated with polymyositis/dermatomyositis (ILD PM/DM) often confers a poor prognosis, and optimal treatment of this condition is not well defined. This report describes a 63-year-old man with severe ILD-PM/DM who presented with 5 months of progressive dyspnea and weakness. He had an initial carbon-monoxide-diffusing capacity of 35% predicted and a creatine kinase level of 2,112 U/L. After three monthly doses of immunoglobulin at 2 gm/kg IV, he has sustained clinical remission for > 2 years. IV immunoglobulin has not previously been studied as a first-line agent for rheumatologic diseases, and it is currently used as a salvage therapy. However, if IV immunoglobulin is capable of inducing sustained remission after brief use as a treatment, as demonstrated in this patient, especially in the setting of significant pulmonary involvement, then it merits further consideration for investigation as a first-line therapeutic agent. PMID- 21285060 TI - Orthodeoxia platypnea syndrome in a patient with lipomatous hypertrophy of the interatrial septum due to long-term steroid use. AB - We describe an unusual case of orthodeoxia platypnea syndrome exacerbated by right ventricular inflow obstruction due to iatrogenic steroid-induced adipose deposition in cardiac tissues. A 68-year-old man on long-term prednisone therapy for eosinophilic pneumonia presented with progressive dyspnea worsened by bending forward. By using pulse oximetry, he was noted to have positional hypoxemia. Transthoracic echocardiogram demonstrated normal right-sided pressures but severe right to left shunting through a patent foramen ovale. Transesophageal echocardiogram showed a large patent foramen ovale, severe lipomatous hypertrophy of the interatrial septum, and massive adipose deposition in the pericardium causing compression of the right ventricular inflow tract. The patient underwent percutaneous closure of the patent foramen ovale, which resulted in the resolution of symptoms and hypoxemia. This case is unique because long-term steroid use resulted in reverse Lutembacher physiology and clinical orthodeoxia platypnea syndrome by inducing lipomatous hypertrophy of the interatrial septum and compression of the right atrium. PMID- 21285061 TI - Genome-wide association studies of sleep disorders. AB - Sleep disorders tend to be complex diseases, with multiple genes and environmental factors interacting to contribute to phenotypes. Our understanding of the genetic underpinnings of sleep disorders has benefited from recent genome wide association studies (GWAS). We review principles underlying GWAS and discuss recent GWAS for restless legs syndrome and narcolepsy. These studies have identified four gene variants associated with restless legs syndrome (BTBD9, MEIS1, MAP2K5/LBXCOR1, and PTPRD) and two variants associated with narcolepsy (one in the T-cell receptor alpha locus and another between CPT1B and CHKB). These discoveries have opened new lines of research to understand the pathophysiology of these disorders. In addition to GWAS, we expect that new technologies, such as next-generation sequencing, and continued use of animal models will provide important contributions to our understanding of the genetic basis of sleep disorders. PMID- 21285062 TI - Fleeting alveolar infiltrates and reversed halo sign in patients with breast cancer treated with tangential beam irradiation. PMID- 21285063 TI - A 49-year-old smoker with a lung mass and diffuse bone pain. PMID- 21285064 TI - Chest pain and progressive shortness of breath in a 60-year-old woman following liver transplantation. PMID- 21285065 TI - The dilemma of albuterol dosing for acute asthma exacerbations in pediatric patients. PMID- 21285066 TI - Pneumonia and mortality beyond hospital discharge in elderly patients. PMID- 21285067 TI - Alternative therapy: cupping for asthma. PMID- 21285068 TI - Autonomy. PMID- 21285069 TI - Complications of talc poudrage in the United States. PMID- 21285070 TI - Low cytomegalovirus viremia prevalence in a general intensive care population. PMID- 21285071 TI - Low-dose tissue plasminogen activator in pulmonary embolism: benefit remains unclear. PMID- 21285072 TI - Primary prevention of stroke: blood pressure, lipids, and heart failure. AB - Stroke contributes significantly to morbidity, mortality, and disability worldwide. Despite the successes accomplished in the acute treatment and rehabilitation of stroke, the global burden of this disease can only be tackled with co-ordinated approaches for primary prevention. Stroke is a heterogeneous disease and the contribution of individual risk factors to its occurrence estimated by population attributable risk differs from coronary heart disease. Here, we review evidence to demonstrate the prominent role of elevated blood pressure (BP) and heart disease on risk of stroke, while the influence of lipids on stroke is less clear; we also demonstrate that stroke is an important complication of heart failure. Current approaches to primary preventive action emphasize the need to target the absolute risk of cardiovascular diseases rather than individual risk factors. Lifestyle interventions serve as a basis for primary prevention of cardiovascular diseases. It is estimated that 70% of strokes are potentially preventable by lifestyle modification but prospective evidence is needed to support these hypotheses derived from epidemiological studies. Different strategies for drug interventions in primary prevention are discussed, including the polypill strategy. Additional measures are needed for the primary prevention of stroke which focus on BP, chronic heart failure, and possibly lipids. PMID- 21285073 TI - Implantation of nitinol self-expanding carotid stent to release circumflex artery compression caused by mitral valve prosthesis. PMID- 21285074 TI - Left ventricular non-compaction revisited: a distinct phenotype with genetic heterogeneity? AB - Non-compaction of the left ventricular myocardium (LVNC) has gained increasing recognition during the last 25 years. There is a morphological trait of the myocardial structure with a spectrum from normal variants to the pathological phenotype of LVNC, which reflects the embryogenic structure of the human heart due to an arrest in the compaction process during the first trimester. It must be cautioned not to overdiagnose LVNC: the morphological spectrum of trabeculations, from normal variants to pathological trabeculations with the morphological feature of LVNC must be carefully considered. The classical triad of complications are heart failure, arrhythmias, including sudden cardiac death, and systemic embolic events. Non-compaction of the left ventricular myocardium can occur in isolation or in association with congenital heart defects (CHDs), genetic syndromes, and neuromuscular disorders among others. The clinical spectrum is wide and the outcome is more favourable than in previously described populations with a negative selection bias. Familial occurrence is frequent with autosomal dominant and X-linked transmissions. Different mutations in sarcomere protein genes were identified and there seems to be a shared molecular aetiology of different cardiomyopathic phenotypes, including LVNC, hypertrophic and dilated cardiomyopathies. Thus, genetic heterogeneity, with an overlap of different phenotypes, and the variability of hereditary patterns, raise the questions whether there is a morphological trait from dilated/hypertrophic cardiomyopathy to LVNC and what are the triggers and modifiers to develop either dilated, hypertrophic cardiomyopathy, or LVNC in patients with the same mutation. The variety in clinical presentation, the genetic heterogeneity, and the phenotype of the first transgenetic animal model of an LVNC-associated mutation question the hypothesis that LVNC be a distinct cardiomyopathy: it seems to be rather a distinct phenotype or phenotypic, morphological expression of different underlying diseases than a distinct cardiomyopathy. PMID- 21285076 TI - The percutaneous approach to mitral valve repair. PMID- 21285075 TI - Dietary alpha-linolenic acid diminishes experimental atherogenesis and restricts T cell-driven inflammation. AB - AIMS: Epidemiological studies report an inverse association between plant-derived dietary alpha-linolenic acid (ALA) and cardiovascular events. However, little is known about the mechanism of this protection. We assessed the cellular and molecular mechanisms of dietary ALA (flaxseed) on atherosclerosis in a mouse model. METHODS AND RESULTS: Eight-week-old male apolipoprotein E knockout (ApoE( /-)) mice were fed a 0.21 % (w/w) cholesterol diet for 16 weeks containing either a high ALA [7.3 % (w/w); n = 10] or low ALA content [0.03 % (w/w); n = 10]. Bioavailability, chain elongation, and fatty acid metabolism were measured by gas chromatography of tissue lysates and urine. Plaques were assessed using immunohistochemistry. T cell proliferation was investigated in primary murine CD3 positive lymphocytes. T cell differentiation and activation was assessed by expression analyses of interferon-gamma, interleukin-4, and tumour necrosis factor alpha (TNFalpha) using quantitative PCR and ELISA. Dietary ALA increased aortic tissue levels of ALA as well as of the n-3 long chain fatty acids (LC n-3 FA) eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid. The high ALA diet reduced plaque area by 50% and decreased plaque T cell content as well as expression of vascular cell adhesion molecule-1 and TNFalpha. Both dietary ALA and direct ALA exposure restricted T cell proliferation, differentiation, and inflammatory activity. Dietary ALA shifted prostaglandin and isoprostane formation towards 3-series compounds, potentially contributing to the atheroprotective effects of ALA. CONCLUSION: Dietary ALA diminishes experimental atherogenesis and restricts T cell-driven inflammation, thus providing the proof of-principle that plant-derived ALA may provide a valuable alternative to marine LC n-3 FA. PMID- 21285078 TI - Finger lysis: osteomyelitis or cyst? PMID- 21285079 TI - Massive nodular pseudoangiomatous stromal hyperplasia (PASH) of the breast arising simultaneously in the axilla and vulva. AB - The authors describe a 52-year-old woman with a history of bilateral mastectomies for macromastia caused by massive nodular pseudoangiomatous stromal hyperplasia (PASH), who presented with 2 large growths in her left axilla and groin. These masses had been increasing in size for nearly a year. When excised, the axillary mass had dimensions of 14.0 * 14.0 * 5.5 cm(3) and weighed 664 g. The groin mass was slightly smaller at 14.5 * 11.0 * 5.0 cm(3) and 518 g. Microscopic examination of both masses revealed breast tissue expanded by a hyalinized stroma with prominent slit-like pseudovascular spaces, consistent with PASH. Small incidental foci of PASH are common findings in breast excisions; however, large nodular foci are rare. Furthermore, nodular foci in accessory breast tissue are exceedingly rarer and can raise clinical concerns for malignancy. Histopathologically, PASH can be mistaken for low-grade angiosarcoma. To the authors' knowledge, the present case appears to be the first description of multiple simultaneous foci of massive nodular PASH arising in accessory breast tissue. PMID- 21285080 TI - Psychopathy: early and recent clinical observations and the law. PMID- 21285081 TI - Critical involvement of the thalamus and precuneus during restoration of consciousness with physostigmine in humans during propofol anaesthesia: a positron emission tomography study. AB - BACKGROUND: Functional brain imaging offers a way to investigate how general anaesthetics impair consciousness. However, functional imaging changes may result from drug effects unrelated to hypnosis. Establishing a causal link with loss of consciousness is thus difficult. METHODS: To identify changes of neuronal activity functionally linked to the level of consciousness, physostigmine was used to restore consciousness without changing the anaesthetic concentration in 11 subjects anaesthetized with propofol. Eight subjects (responders) regained consciousness after physostigmine and three did not (non-responders). Positron emission tomography was used to measure regional cerebral blood flow (rCBF); during baseline (awake), after anaesthesia-induced loss of consciousness, after physostigmine administration, and recovery. In addition to subtraction analyses, we used conjunction analysis in the responders to identify changes common to the baseline-anaesthesia and physostigmine-anaesthesia contrasts. RESULTS: Complete data were available for seven subjects (four responders and three non responders). The analyses revealed that unconsciousness was associated with rCBF decreases in the thalamus and precuneus. Restoration of consciousness by physostigmine was associated with rCBF increases in these same structures, with the strongest effect in the thalamus. CONCLUSIONS: The results provide strong evidence that reductions in rCBF in the thalamus and precuneus are functionally related to propofol-induced unconsciousness independently of any non-specific effects of propofol. These observations confirm that the thalamus and precuneus are key elements to understand how general anaesthetics cause unconsciousness and how patients wake up from anaesthesia. Furthermore, they are consistent with the notion that anaesthetic-induced unconsciousness is associated with reduced cholinergic activation. PMID- 21285082 TI - Paracetamol and selective and non-selective non-steroidal anti-inflammatory drugs for the reduction in morphine-related side-effects after major surgery: a systematic review. AB - Non-opioid analgesics, paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), or cyclo-oxygenase 2 (COX-2) inhibitors are often given along with morphine as part of multimodal analgesia after major surgery. We have undertaken a systematic review and a mixed treatment comparison (MTC) analysis in order to determine explicitly which class of non-opioid analgesic, paracetamol, NSAIDs, or COX-2 inhibitors is the most effective in reducing morphine consumption and morphine-related adverse effects. Sixty relevant studies were identified. The MTC found that when paracetamol, NSAIDs, or COX-2 inhibitors were added to patient controlled analgesia (PCA) morphine, there was a statistically significant reduction in morphine consumption: paracetamol [mean difference (MD) -6.34 mg; 95% credibility interval (CrI) -9.02, -3.65], NSAIDs (MD -10.18; 95% CrI -11.65, 8.72), and COX-2 inhibitors (MD -10.92; 95% CrI -12.77, -9.08). There was a significant reduction in nausea and postoperative nausea and vomiting with NSAIDs compared with placebo (odds ratio 0.70; 95% CrI 0.53, 0.88) but not for paracetamol or COX-2 inhibitors, nor for NSAIDs compared with paracetamol or COX 2 inhibitors. There was no statistically significant difference in sedation between any intervention and comparator. On the basis of six trials (n=695), 2.4% of participants receiving an NSAID experienced surgical-related bleeding compared with 0.4% with placebo. The MTC found that there is a decrease in 24 h morphine consumption when paracetamol, NSAID, or COX-2 inhibitors are given in addition to PCA morphine after surgery, with no clear difference between them. Similarly, the benefits in terms of reduction in morphine-related adverse effects do not strongly favour one of the three non-opioid analgesics. PMID- 21285083 TI - Impaired glucose metabolism in Japanese patients with acromegaly is restored after successful pituitary surgery if pancreatic {beta}-cell function is preserved. AB - OBJECTIVE: Impaired glucose metabolism is common in acromegaly, but it is not clear how glucose metabolism is impaired or what predicts its restoration after cure of the disease. To identify factors involved in the impairment of glucose metabolism in acromegaly, we evaluated clinical parameters before and immediately after surgical cure of the disease. DESIGN AND METHODS: We retrospectively analyzed clinical data of 92 consecutive Japanese patients with acromegaly who underwent successful pituitary surgery. Patients who had received medical therapy for acromegaly or insulin treatment for diabetes were excluded. We evaluated insulin resistance (IR) and pancreatic beta-cell function in addition to GH and IGF1 levels before and after surgery. Results In this study of Japanese patients with acromegaly, average body mass index (BMI) was 23.4, and no patient had a BMI>30. IR was involved in the impairment of glucose metabolism, which was restored upon surgical cure of acromegaly if beta-cell function was preserved. Insufficient beta-cell function did not improve after normalization of GH/IGF1 and was associated with impaired glucose metabolism before and after surgery. RESULTS: of receiver operating characteristic analysis of preoperative clinical parameters suggest that insulinogenic index (IGI) >0.50 best predicts restoration of normal glucose metabolism upon cure of acromegaly in Japanese patients. CONCLUSIONS: IR impairs glucose metabolism in acromegaly. Once beta-cell function is impaired, abnormal glucose metabolism persists even after cure of acromegaly. IGI>0.50 indicates that beta-cell function is preserved in non-obese Japanese patients with acromegaly. PMID- 21285084 TI - Elevated LH predicts ischaemic heart disease events in older men: the Health in Men Study. AB - CONTEXT: Hypogonadism in men is associated with insulin resistance, elevations in pro-inflammatory cytokines and fibrinogen, and an atherogenic lipid profile. However, it is uncertain whether the age-related decline in testosterone is associated with ischaemic heart disease (IHD) events. OBJECTIVE: To determine whether testosterone and its associated hormones, sex hormone-binding globulin (SHBG) and LH, predict IHD events in older men. DESIGN: Prospective cohort study. METHODS: Between 2001 and 2004, 3637 community-dwelling men aged 70-88 years underwent a clinical assessment of cardiovascular risk factors and biochemical assessment of testosterone, SHBG and LH. Free testosterone was calculated using mass action equations. Participants were followed until December 2008 using electronic record linkage to capture IHD events (hospital admission or death). RESULTS: Mean follow-up was 5.1 years. During this period, 618 men (17.0%; 95% confidence interval (CI) 15.8, 18.3%) experienced an event, of which 160 were fatal. Men with higher baseline total or free testosterone levels experienced fewer IHD events (hazard ratio (HR)=0.89; 95% CI 0.82, 0.97 and HR=0.86; 95% CI 0.79, 0.94 for each one s.d. increase in total and free testosterone respectively). These associations were maintained after adjustment for age and waist:hip ratio but did not persist after adjustment for prevalent IHD or other cardiovascular risk factors. SHBG was not associated with IHD events. In contrast, higher LH levels were associated with reduced event-free survival in both univariate (HR=1.15; 95% CI 1.08, 1.22) and adjusted analyses (HR=1.08; 95% CI 1.01, 1.15). CONCLUSIONS: Dysregulation of the hypothalamic-pituitary-gonadal axis may be a risk factor for IHD. Further studies of men with either elevated LH or low testosterone are warranted. PMID- 21285085 TI - Inpatient care in the 21st century: we need more evidence. PMID- 21285087 TI - The Jail Inreach Project: linking homeless inmates who have mental illness with community health services. AB - The Jail Inreach Project is a health care-based intensive case management "inreach" program that engages incarcerated persons from the homeless population who have behavioral health disorders (mental illness, substance use disorder, or both) in establishing a plan for specific postrelease services. The Jail Inreach Project aims to provide continuity of care and integrate this highly marginalized subpopulation of homeless persons into primary and behavioral health care systems by establishing patient-centered health homes. The use of integrated primary and behavioral health models in conjunction with provisions for immediate access to and continuity of care upon release is emerging as a best practice in combating the rapid cycling of this vulnerable population between streets and shelters, emergency centers, and the county jail. Preliminary results indicate that more than half of the persons referred to the program remained successfully linked with services postrelease, whereas slightly less than one-third who engaged in services while incarcerated did not retain linkage on release. PMID- 21285088 TI - Mental health services in 42 low- and middle-income countries: a WHO-AIMS cross national analysis. AB - OBJECTIVE: The authors describe characteristics and capacities of mental health systems in low- and middle-income countries. METHODS: The World Health Organization Assessment Instrument for Mental Health Systems was used to assess services in 42 countries (13 low-, 24 lower-middle, and five upper-middle income). RESULTS: Of 36 countries with a mental health plan, 90% include the goal of developing community services. However, inpatient facilities are the main service providers, with less than one community contact (.70) for each inpatient day. Mental hospitals consume 80% of mental health budgets, and outpatient care is limited. CONCLUSIONS: Mental health services in participating countries are limited and often hospital based. PMID- 21285089 TI - Personal accounts: Making art, exploring madness. PMID- 21285090 TI - Effect of insurance parity on substance abuse treatment. AB - OBJECTIVE: This study examined the impact of insurance parity on the use, cost, and quality of substance abuse treatment. METHODS: The authors compared substance abuse treatment spending and utilization from 1999 to 2002 for continuously enrolled beneficiaries covered by Federal Employees Health Benefit (FEHB) plans, which require parity coverage of mental health and substance use disorders, with spending and utilization among beneficiaries in a matched set of health plans without parity coverage. Logistic regression models estimated the probability of any substance abuse service use. Conditional on use, linear models estimated total and out-of-pocket spending. Logistic regression models for three quality indicators for substance abuse treatment were also estimated: identification of adult enrollees with a new substance abuse diagnosis, treatment initiation, and treatment engagement. Difference-in-difference estimates were computed as (postparity - preparity) differences in outcomes in plans without parity subtracted from those in FEHB plans. RESULTS: There were no significant differences between FEHB and non-FEHB plans in rates of change in average utilization of substance abuse services. Conditional on service utilization, the rate of substance abuse treatment out-of-pocket spending declined significantly in the FEHB plans compared with the non-FEHB plans (mean difference=-$101.09, 95% confidence interval [CI]=-$198.06 to -$4.12), whereas changes in total plan spending per user did not differ significantly. With parity, more patients had new diagnoses of a substance use disorder (difference-in-difference risk=.10%, CI=.02% to .19%). No statistically significant differences were found for rates of initiation and engagement in substance abuse treatment. CONCLUSIONS: Findings suggest that for continuously enrolled populations, providing parity of substance abuse treatment coverage improved insurance protection but had little impact on utilization, costs for plans, or quality of care. PMID- 21285091 TI - Mental health-related beliefs as a barrier to service use for military personnel and veterans: a review. AB - OBJECTIVE: Although military personnel are at high risk of mental health problems, research findings indicate that many military personnel and veterans do not seek needed mental health care. Thus it is critical to identify factors that interfere with the use of mental health services for this population, and where possible, intervene to reduce barriers to care. The overarching goal of this review was to examine what is known with regard to concerns about public stigma and personal beliefs about mental illness and mental health treatment as potential barriers to service use in military and veteran populations and to provide recommendations for future research on this topic. METHODS: Fifteen empirical articles on mental health beliefs and service use were identified via a review of the military and veteran literature included in PsycINFO and PubMed databases. RESULTS: Although results suggest that mental health beliefs may be an important predictor of service use for this population, several gaps were identified in the current literature. Limitations include a lack of attention to the association between mental health beliefs and service use, a limited focus on personal beliefs about mental illness and mental health treatment, and the application of measures of mental health beliefs with questionable or undocumented psychometric properties. CONCLUSIONS: Studies that attend to these important issues and that examine mental health beliefs in the broader context within which decisions about seeking health care are made can be used to best target resources to engage military personnel and veterans in health care. PMID- 21285092 TI - Factors associated with use of psychiatrists and nonpsychiatrist providers by ESEMeD respondents in six European countries. AB - OBJECTIVE: This study analyzed use of services from psychiatrists and other mental health professionals (psychologists, psychotherapists, counselors, and social workers) in six European countries. METHODS: Data were from respondents (N=8,796) to the European Study of the Epidemiology of Mental Disorders (ESEMeD), a cross-sectional survey (2001-2003) of a representative sample of noninstitutionalized adults in Belgium, France, Germany, Italy, the Netherlands, and Spain that was conducted via computer-assisted interviews with the Composite International Diagnostic Interview, version 3.0. RESULTS: Twenty-three percent of respondents reported lifetime use of any professional for mental health problems, and 60% consulted a mental health provider. Among these, 56% used a psychiatrist and 68% used a nonpsychiatrist provider. Factors associated with use of psychiatrists only were being retired or unemployed, having 12 or fewer years of education, living in France or Spain, having a severe disorder, and using psychotropic medication. Factors associated with use of nonpsychiatrist providers only were living in the Netherlands or Germany, never being married, and having an anxiety disorder. CONCLUSIONS: The findings suggest that there is no simple model of associations between mental health care system and patterns of service use. System characteristics, such as practitioner-population ratios, levels of practitioner availability, and gatekeeping and reimbursement policies, affect patterns of use of mental health providers. Recent British and Australian plans could be used as models for better allocation of services in some ESEMeD countries. PMID- 21285093 TI - Use of primary and specialized mental health care for a major depressive episode in Spain by ESEMeD respondents. AB - OBJECTIVE: This study described use of services for a major depressive episode and determined factors associated with use in Spain, a country with universal access to care and a relatively low prevalence of depression. METHODS: Data were from the European Study of the Epidemiology of Mental Disorders (ESEMeD). ESEMeD Spain was a cross-sectional, general population survey conducted with a representative sample of noninstitutionalized adults (N=5,473). The Composite International Diagnostic Interview was used, and 12-month use of services for a major depressive episode, types of services used, and receipt of minimally adequate treatment were assessed. RESULTS: Among the 247 respondents with a major depressive episode in the past 12 months, 59% reported any use of past-year services for their disorder; of this group, 76% reported receipt of any active treatment (from a health care or mental health professional). Among respondents with severe depression, 31% used no services. A higher likelihood of service use was found among those who were unemployed or too disabled to work (OR=4.9, CI=1.3 19), who had moderate depression symptoms (OR=3.2, CI=1.1-9.0), and who had one mental disorder comorbid with depression (OR=2.9, CI=1.2-7.0) or two or more such comorbid disorders (OR=4.1, CI=1.9-8.9). In the active treatment group, only 31.2% received treatment that was minimally adequate. CONCLUSIONS: There is a need in Spain to increase use of services for a major depressive episode, especially among certain population groups, such as women, and to improve adequacy of treatments. The role of specific factors, such as availability of services and of professionals, deserves further research. PMID- 21285094 TI - One-year follow-up of collaborative depression care for low-income, predominantly Hispanic patients with cancer. AB - OBJECTIVE: This study assessed longer-term outcomes of low-income patients with cancer (predominantly female and Hispanic) after treatment in a collaborative model of depression care or in enhanced usual care. METHODS: The randomized controlled trial, conducted in safety-net oncology clinics, recruited 472 patients with major depression symptoms. Patients randomly assigned to a 12-month intervention (a depression care manager and psychiatrist provided problem-solving therapy, antidepressants, and symptom monitoring and relapse prevention) or enhanced usual care (control group) were interviewed at 18 and 24 months after enrollment. RESULTS: At 24 months, 46% of patients in the intervention group and 32% in the control group had a >=50% decrease in depression score over baseline (odds ratio=2.09, 95% confidence interval=1.13-3.86; p=.02); intervention patients had significantly better social (p=.03) and functional (p=.01) well being. Treatment receipt among intervention patients declined (72%, 21%, and 18% at 12, 18, and 24 months, respectively); few control group patients reported treatment receipt (10%, 6%, and 13%, respectively). Significant differences in receipt of counseling or antidepressants disappeared at 24 months. Depression recurrence was similar between groups (intervention, 36%; control, 39%). Among patients with depression recurrence, intervention patients were more likely to receive treatment after 12 months (34% versus 10%; p=.03). At 24 months, attrition (262 patients, 56%) did not vary by group; 22% were deceased, 20% declined further participation, and 14% could not be located. CONCLUSIONS: Collaborative care reduced depression symptoms and enhanced quality of life; however, results call for ongoing depression symptom monitoring and treatment for low-income cancer survivors. PMID- 21285095 TI - Does active substance use at housing entry impair outcomes in supported housing for chronically homeless persons? AB - OBJECTIVE: Recent clinical and policy trends have favored low-demand housing (provision of housing not contingent on alcohol and drug abstinence) in assisting chronically homeless people. This study compared housing, clinical, and service use outcomes of participants with high levels of substance use at time of housing entry and those who reported no substance use. METHODS: Participants in the outcome evaluation of the 11-site Collaborative Initiative on Chronic Homelessness (N=756), who were housed within 12 months of program entry and received an assessment at time of housing and at least one follow-up (N=694, 92%), were classified as either high-frequency substance users (>15 days of using alcohol or >15 days of using marijuana or any other illicit drugs in the past 30 days; N=120, 16%) or abstainers (no days of use; N=290, 38%) on entry into supported community housing. An intermediate group reporting from one to 15 days of use (N=284, 38%) was excluded from the analysis. Mixed-model multivariate regression adjusted outcome findings for baseline group differences. RESULTS: During a 24-month follow-up, the number of days housed increased dramatically for both groups, with no significant differences. High-frequency substance users maintained higher, though declining, rates of substance use throughout follow-up compared with abstainers. High-frequency users continued to have more frequent or more severe psychiatric symptoms than the abstainers. Total health costs declined for both groups over time. CONCLUSIONS: Active-use substance users were successfully housed on the basis of a low-demand model. Compared with abstainers, users maintained the higher rates of substance use and poorer mental health outcomes that were observed at housing entry but without relative worsening. PMID- 21285096 TI - Capitation of public mental health services in Colorado: a five-year follow-up of system-level effects. AB - OBJECTIVE: Capitated Medicaid mental health programs have reduced costs over the short term by lowering the utilization of high-cost inpatient services. This study examined the five-year effects of capitated financing in community mental health centers (CMHCs) by comparing not-for-profit with for-profit programs. METHODS: Data were from the Medicaid billing system in Colorado for the precapitation year (1994) and a shadow billing system for the postcapitation years (1995-1999). In a panel design, a random-effect approach estimated the impact of two financing systems on service utilization and cost while adjusting for all the covariates. RESULTS: Consistent with predictions, in both the for profit and the not-for-profit CMHCs, relative to the precapitation year, there were significant reductions in each postcapitation year in high-cost treatments (inpatient treatment) for all but one comparison (not-for-profit CMHCs in 1999). Also consistent with predictions, the for-profit programs realized significant reductions in cost per user for both outpatient services and total services. In the not-for-profit programs, there were no significant changes in cost per user for total services; a significant reduction in cost per user for outpatient services was found only in the first two years, 1995 and 1996). CONCLUSIONS: The evidence suggests that different strategies were used by the not-for-profit and for-profit programs to control expenditures and utilization and that the for profit programs were more successful in reducing cost per user. PMID- 21285097 TI - Association between prior authorization for medications and health service use by Medicaid patients with bipolar disorder. AB - OBJECTIVE: This study examined the association between a Medicaid prior authorization policy for second-generation antipsychotic and anticonvulsant agents and medication discontinuation and health service use by patients with bipolar disorder. METHODS: A pre-post design with a historical comparison group was used to analyze Maine Medicaid and Medicare claims data. A total of 946 newly treated patients were identified during the eight-month policy (July 2003 February 2004), and a comparison group of 1,014 was identified from the prepolicy period (July 2002-February 2003). Patients were stratified by number of visits to community mental health centers (CMHCs) before medication initiation (proxy for illness severity): CMHC attenders, at least two visits; nonattenders, fewer than two. Changes in rates of medication discontinuation and outpatient, emergency room, and hospital visits were estimated. RESULTS: Compared with nonattenders, at baseline CMHC attenders had substantially higher rates of comorbid mental disorders and use of medications and health services. The policy was associated with increased medication discontinuation among attenders and nonattenders, reductions in mental health visits after discontinuation among attenders (-.64 per patient per month; p<.05), and increases in emergency room visits after discontinuation among nonattenders (.16 per patient per month; p<.05). During the eight-month policy period, the policy had no detectable impact on hospitalization risk. CONCLUSIONS: The prior-authorization policy was associated with increased medication discontinuation and subsequent changes in health service use. Although small, these unintended effects raise concerns about quality of care for a group of vulnerable patients. Long-term consequences of prior-authorization policies on patient outcomes warrant further investigation. PMID- 21285098 TI - The effect of community mental health services on hospitalization rates in Virginia. AB - OBJECTIVE: This study examined the relationship between the availability of mental health outpatient services provided by 40 publicly funded community service boards (CSBs) and the use of inpatient mental health treatment among Medicaid recipients. METHODS: Three-year data were obtained for Medicaid recipients aged 18-64 from the Medicaid claims database for the Commonwealth of Virginia. Medicaid recipients who had a mental disorder diagnosis and who had received at least one community mental health service were included in the sample. A multivariate regression model was used for the analyses. RESULTS: Of the 11,107 individuals included, 27% had schizophrenia-related disorders and 32% had affective psychoses; 60% were white and 37% were black; and the average age was 40.1+/-13.1 years. In this sample, greater use of outpatient mental health services, but not greater variety of services available, was correlated with fewer inpatient hospital days for mental health treatment (-1.0+/-.2 days of hospitalization). CONCLUSIONS: Virginia's CSBs provide a range of outpatient mental health services that are designed to enable individuals to remain in their community. The availability of community-based mental health services was correlated with lower rates of inpatient hospitalization for mental illness. More research, however, is needed to establish causality and to determine which services are most effective at reducing the need for inpatient care. PMID- 21285099 TI - The impact of realigning a tertiary psychiatric hospital in British Columbia on other institutional sectors. AB - OBJECTIVE: Deinstitutionalization is an ongoing process, as many jurisdictions continue to struggle with redesigning their psychiatric systems. Historically, reducing psychiatric beds and closing hospitals have resulted in deleterious outcomes for people with severe and persistent mental illness. More recent evidence suggests that careful implementation of deinstitutionalization policies can thwart potential adverse consequences and may even foster favorable outcomes. This study evaluated the extent to which the recent devolution of the only tertiary psychiatric hospital in British Columbia resulted in a direct shift of individuals to other institutional sectors, such as criminal justice and health sectors. METHODS: Admission rates to general hospitals, continuing care facilities, correctional institutions, and forensic psychiatric facilities were compared among two patient groups: those discharged before the realignment of the tertiary psychiatric hospital system (prerealignment cohort) (N=164) and those discharged after initiation of the system reforms (postrealignment cohort) (N=171). RESULTS: Most of the patients in the postrealignment cohort have remained in the tertiary care settings to which they were originally discharged. For patients in the postrealignment cohort, contact with other institutional sectors was rare and shorter in duration than it was for patients in the prerealignment cohort. CONCLUSIONS: This study provides preliminary evidence that recent efforts to realign British Columbia's provincial tertiary psychiatric hospital system have not resulted in a significant shift of the relocated patients to institutions in other sectors. PMID- 21285100 TI - Inpatient psychiatric care in the 21st century: the need for reform. AB - Driven by financial pressures, the sole focus of psychiatric inpatient treatment has become safety and crisis stabilization. Data are lacking on outcomes of ultrashort-stay hospitalizations; however, such stays may diminish opportunities for a sustained recovery. In the absence of an evidence base to guide clinicians and policy makers, mental health professionals have an ethical obligation to promote what they consider to be best practice. This Open Forum focuses on the need to reconsider the current model of inpatient hospitalization in order to maximize positive outcomes and emphasize appropriate transition to the community and less intensive levels of care. A model of care is presented based on rapid formulation of diagnosis, goals, and treatment modalities before treatment begins. Three phases are described--assessment, implementation, and resolution- with specific principles to guide length-of-stay decisions and requirements for staffing. PMID- 21285101 TI - A comparison of participant information elicited by service user and non-service user researchers. AB - OBJECTIVE: The study examined whether data collected by researchers who were service users differed from data collected by non-service user researchers in a study that measured perceived coercion. METHODS: Over two years, 548 inpatients in England were interviewed during their first week of compulsory admission to a psychiatric bed at three regional mental health provider settings. Each site had one service user researcher and one nonuser researcher. The dependent variables were two measures of perceived coercion. Service users disclosed their status, including past hospitalization, to 93 of the 242 (38%) patients they interviewed. RESULTS: No differences were found on either variable between the three researcher categories (nondisclosed user, disclosed user, and nonuser researcher). An interaction with site was noted, and possible interpretations of this finding are discussed. CONCLUSIONS: Further research is needed to determine the conditions under which service user researchers obtain information that differs from that obtained by nonuser researchers. PMID- 21285102 TI - BREATHE: a pilot study of a one-day retreat to reduce burnout among mental health professionals. AB - OBJECTIVE: Staff burnout is a frequent problem for mental health providers and may be associated with negative outcomes for providers, consumers, and organizations. This study tested an intervention to reduce staff burnout. METHODS: Community mental health providers were invited to participate in a day long training session to learn methods to reduce burnout. A Web-based survey was given at time of registration, before the intervention, and again six weeks later. RESULTS: Eighty-four providers participated in the training, and follow-up data were available for 74. Six weeks after the day-long training, staff reported significant decreases in emotional exhaustion and depersonalization and significant increases in positive views toward consumers. There were no significant changes in providers' sense of personal accomplishment, job satisfaction, or intention to leave their position. Ninety-one percent of the staff reported the training to be helpful. CONCLUSIONS: This brief intervention is feasible, is acceptable to staff, and may improve burnout and staff attitudes. PMID- 21285103 TI - Valproate prescription prevalence among women of childbearing age. AB - OBJECTIVE: Valproate is associated with polycystic ovary syndrome as well as congenital malformations and developmental delays of infants who were prenatally exposed. The frequency of valproate use for mental health conditions among women of childbearing age was determined. METHODS: Using New York State Medicaid claims for persons with psychiatric disorders, 40,526 individuals with active prescriptions for mood stabilizers (non-antipsychotic) on May 1, 2009, were identified. Chi square tests were used to compare valproate use among women of childbearing age with similarly aged men and older women. RESULTS: Valproate was the most commonly prescribed agent for young women (23.4%). Men were more likely than women, and older women more likely than younger women, to take valproate. CONCLUSIONS: Over 20% of childbearing-aged women receiving mood stabilizers were treated with valproate, although increasing data on the reproductive toxicity of this agent compel consideration of other non-antipsychotic mood stabilizers as first-line choices. PMID- 21285104 TI - Universal or indicated screening in primary care? PMID- 21285105 TI - Societal stigma and suicide prevention. PMID- 21285107 TI - Race, mental illness, and premature mortality: double jeopardy? PMID- 21285109 TI - Deprivation of liberty and the Mental Capacity Act 2005. PMID- 21285110 TI - Health outcomes in economic evaluation: who should value health? AB - The valuation of health states is an integral part of economic evaluation studies. The source of these valuations (general public vs. patients) is surrounded by controversy. Health state values generated by the general public are often different compared with those of patients. General public values may not account for adaptation of the patients; patients' values potentially incorporate self-interest. Decisions on the appropriate source of health values ultimately depend on the specific decision-making context and objectives of the evaluation. Differences in valuations and implications for decision-making should be explicitly addressed. Further research should systematically identify circumstances in which public and patients' valuations diverge. There appears ground for development of methods that allow the simultaneous incorporation of patients and public preferences. Existing literature which discusses the issues around the health state valuation is summarized. PMID- 21285111 TI - Workplace monitoring of mixed neutron-photon radiation fields and its contribution to external dosimetry. AB - Workplace monitoring is a common procedure for determining measures for routine radiation protection in a particular working environment. For mixed radiation fields consisting of neutrons and photons, it is of increased importance because it contributes to the improved accuracy of individual monitoring. An example is the determination of field-specific correction factors, which can be applied to the readings of personal dosemeters. This paper explains the general problems associated with individual dosimetry of neutron radiation, and describes the various options for workplace monitoring. These options cover a range from the elaborate field characterisation using transport calculations or spectrometers to the simpler approach using area monitors. Examples are given for workplaces in nuclear industry, at particle accelerators and at flight altitudes. PMID- 21285112 TI - Reliability and confirmatory factor analysis of the arabic version of the University of Rhode Island Change Assessment (URICA). AB - AIM: To develop an Arabic version of the University of Rhode Island Change Assessment (URICA), and to examine its internal reliability and factor structure. METHODS: Participants were 175 substance abuse/dependent male patients recruited from Al-Amal Hospital of Substance Abuse in Dammam, Saudi Arabia. The URICA was administered to all subjects by two experienced psychologists working at the detoxification and rehabilitation units. RESULTS: All subscales showed good internal reliability and factorial validity. Coefficient alphas for each of the four scales of the URICA (precontemplation, contemplation, action and maintenance) revealed that each scale has adequate and acceptable internal consistency (ranging between 0.76 and 0.89). The correlation coefficients between all subscales confirmed the expected prediction in that scores for adjacent stages of changes showed significantly higher correlations than the scale scores for nonadjacent stages. Confirmatory factor analysis revealed an adequate to reasonable fit to the intended subscales and replicated the four-factor model of the original work. CONCLUSION: The Arabic version of the URICA has shown encouraging psychometric properties, supporting the validity and reliability of the four factors of the scale. The implications of these findings, and recommendation for future research, are described. PMID- 21285113 TI - Ethanol predominantly constricts pre-sinusoids of isolated perfused livers of rat, guinea pig and mouse. AB - AIMS: Ethanol constricts hepatic vessels of isolated perfused livers of rats, but not dogs. However, it is not known whether ethanol constricts or dilates the hepatic vessels in other species such as guinea pigs and mice. In addition, the sites of hepatic venoconstriction induced by ethanol were not known in rat livers. We therefore studied the effects of ethanol on the segmental hepatic vascular resistance and liver weight of mice, rats and guinea pigs. METHODS: The isolated livers were portally perfused with diluted blood at constant flow. The sinusoidal pressure was measured by the double occlusion method and was used to determine the pre- and post-sinusoidal resistance. The change of liver weight was also measured. Ethanol was administered cumulatively into the perfusate to gain clinically relevant concentrations of 1-300 mM. RESULTS: Ethanol dose dependently caused predominant pre-sinusoidal constriction in livers of all three species. When compared with the livers of the guinea pigs and rats, the mouse livers were the weakest in response. Dose-dependent decreases in liver weight and bile flow accompanied predominant pre-sinusoidal constriction in guinea pigs and rats. CONCLUSION: Ethanol predominantly constricts pre-sinusoids in rat, guinea pig and mouse livers, although the mouse liver response was much weaker. Ethanol-induced pre-sinusoidal constriction is accompanied by reduction of liver blood volume in guinea pigs and rats. PMID- 21285114 TI - An investigation of the inflammatory cytokine and chemokine network in systemic sclerosis. AB - OBJECTIVES: Systemic sclerosis (SSc) is characterised by vasculopathy, an aberrantly activated immune system and excessive extracellular matrix deposition. Inflammatory chemokines control migration of cells to sites of tissue damage; their removal from inflamed sites is essential for resolution of the inflammatory response. The atypical chemokine receptor D6 has a critical role in this physiological balance. To explore potential deregulation of this system in SSc, inflammatory chemokine and D6 expression were compared with that in healthy controls (HC). METHODS: Serum levels of inflammatory mediators were assessed by luminex analysis. Peripheral blood mononuclear cells (PBMCs) were used in molecular and immunocytochemical analysis. Platelet-rich plasma was collected and assessed by western blotting for D6 expression levels. Sex-matched HC were used for comparison. RESULTS: 72 patients with SSc and 30 HC were enrolled in the study. The chemokines MCP-1/CCL2, MIP-1alpha/CCL3, MIP-1beta/CCL4 and IL-8/CXCL8 were significantly increased in patients with SSc, regardless of disease subtype and phase. Quantitative PCR analysis revealed a significant 10-fold upregulation of D6 transcripts in patients with SSc compared with controls, and this was paralleled by increased D6 protein expression in the PBMCs of patients with SSc. Platelet lysates also showed strong D6 expression in patients with SSc but not in controls. Importantly, high levels of D6 expression correlated with reduced levels of its ligands in serum. CONCLUSIONS: Inflammatory chemokines and the regulatory receptor D6 are significantly upregulated in SSc and high D6 levels are associated with lower systemic chemokine levels, indicating that some patients control systemic chemokine levels using D6. These results suggest that chemokines may represent a therapeutic target in SSc. PMID- 21285115 TI - Risk factors for a first thrombotic event in antiphospholipid antibody carriers: a prospective multicentre follow-up study. AB - OBJECTIVES: To assess risk factors for a first thrombotic event in confirmed antiphospholipid (aPL) antibody carriers and to evaluate the efficacy of prophylactic treatments. METHODS: Inclusion criteria were age 18-65 years, no history of thrombosis and two consecutive positive aPL results. Demographic, laboratory and clinical parameters were collected at enrolment, once a year during the follow-up and at the time of the thrombotic event, whenever that occurred. RESULTS: 258 subjects were prospectively observed between October 2004 and October 2008. The mean +/- SD follow-up was 35.0 +/- 11.9 months (range 1 48). A first thrombotic event (9 venous, 4 arterial and 1 transient ischaemic attack) occurred in 14 subjects (5.4%, annual incidence rate 1.86%). Hypertension and lupus anticoagulant (LA) were significantly predictive of thrombosis (both at p<0.05) and thromboprophylaxis was significantly protective during high-risk periods (p<0.05) according to univariate analysis. Hypertension and LA were identified by multivariate logistic regression analysis as independent risk factors for thrombosis (HR 3.8, 95% CI 1.3 to 11.1, p<0.05, and HR 3.9, 95% CI 1.1 to 14, p<0.05, respectively). CONCLUSIONS: Hypertension and LA are independent risk factors for thrombosis in aPL carriers. Thromboprophylaxis in these subjects should probably be limited to high-risk situations. PMID- 21285116 TI - The influence of systemic glucocorticoid therapy upon the risk of non-serious infection in older patients with rheumatoid arthritis: a nested case-control study. AB - BACKGROUND: Glucocorticoid therapy is strongly associated with an elevated risk of serious infections in patients with rheumatoid arthritis (RA). The association between glucocorticoids and common non-serious infections (NSI) is not well studied. METHODS: A cohort of 16 207 patients with RA aged over 65 years was assembled using administrative data from Quebec. Glucocorticoid and disease modifying antirheumatic drug (DMARD) therapy were identified from drug dispensing records. NSI cases were defined as first occurrence of a community physician billing code for infection or community-dispensed anti-infectives. A nested case control analysis was performed considering drugs dispensed within 45 days of the index date, adjusting for age, sex, markers of disease severity, DMARD and comorbidity. RESULTS: For 13 634 subjects, a NSI occurred during 28 695 person years of follow-up, generating an incidence rate of 47.5/100 person-years. The crude rate of NSI in glucocorticoid-exposed and unexposed person time was 52.4 and 38.8/100 person-years, respectively. Glucocorticoid therapy was associated with an adjusted RR of 1.20 (95% CI 1.15 to 1.25). A dose response was seen, the adjusted RR increasing from 1.10 (<5 mg prednisolone/day) to 1.85 for doses greater than 20 mg/day. All glucocorticoid risk estimates (including <5 mg/day) were higher than that seen for methotrexate (adjusted RR 1.00; 0.95 to 1.04). CONCLUSION: Glucocorticoid therapy is associated with an increased risk of NSI. The magnitude of risk increases with dose, and is higher than that seen with methotrexate, although residual confounding may exist. While the RR is low at 1.20, the absolute risk is high with one additional infection seen for every 13 patients treated with glucocorticoids for 1 year. PMID- 21285117 TI - Performance of the 2010 ACR/EULAR criteria for rheumatoid arthritis: comparison with 1987 ACR criteria in a very early synovitis cohort. AB - OBJECTIVE: Early identification of patients with rheumatoid arthritis (RA) is essential to allow the prompt institution of therapy. The 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria, which replace the 1987 classification criteria, have been developed to facilitate such identification in patients with newly presenting inflammatory arthritis. This study therefore assesses the performance of these new criteria in patients with early synovitis. METHODS: Data were analysed from patients with synovitis seen within 3 months of the onset of inflammatory arthritis. Patients were followed for 18 months to determine outcomes, and data on the cumulative fulfilment of 2010 and 1987 criteria and therapy were recorded. RESULTS: 265 patients were included in the study. 60 had alternative diagnoses at baseline. Of the remaining 205 patients, 20% fulfilled both 1987 and 2010 criteria, 3% fulfilled only 1987 criteria and 22% fulfilled only 2010 criteria at baseline. The 2010 criteria, when applied at baseline, detected more patients who eventually required disease-modifying antirheumatic drugs (DMARD) (65 (62%) vs 40 (38%); p<0.001), especially methotrexate (50 (68%) vs 31 (42%); p<0.01), within the first 18 months. However, more patients whose disease eventually resolved without ever requiring DMARD were classified at baseline as RA according to the 2010 criteria than with the 1987 criteria (16 (8%) vs 5 (2%); p=0.01). CONCLUSION: The 2010 ACR/EULAR criteria allow more rapid identification of patients requiring methotrexate compared with the 1987 ACR criteria when applied at baseline. However, overdiagnosis is an important issue to consider if these criteria are to be used in very early disease. PMID- 21285118 TI - EUSTAR biobanking: recommendations for the collection, storage and distribution of biospecimens in scleroderma research. AB - The European League Against Rheumatism Scleroderma Trials and Research Group (EUSTAR) has established an online database with clinical data of currently more than 8200 patients with systemic sclerosis (SSc). In addition to clinical research, EUSTAR fosters biomolecular studies to develop novel biomarkers and therapies for SSc. High-quality biospecimens are the basis for successful biomolecular studies. The EUSTAR biobanking group has therefore developed recommendations to standardise the collection, storage and distribution of SSc biospecimens at EUSTAR centres. These recommendations consider the scientific challenges associated with biomolecular research in SSc and the organisational requirements of EUSTAR. They were approved by the EUSTAR executive committee as well as the EUSTAR board. Once they become effective, these recommendations will be the basis for international EUSTAR studies with large numbers of SSc biospecimens. These recommendations might also be followed by other SSc consortia to enable exchange of biosamples between different SSc initiatives and might serve as a template for biobanking initiatives in other rheumatic diseases. PMID- 21285119 TI - When a workforce strategy won't work: critique on current policy direction in England, UK. PMID- 21285120 TI - Carer satisfaction with telephone consultations in a community intellectual disability unit. AB - This paper reports on a survey of carer satisfaction with telephone consultations with doctors in a community service for people with intellectual disability (also known as learning disability in the UK health services). A 10-item anonymized carer satisfaction questionnaire was sent out following telephone consultations over a 4 week period with questions about suitability, effectiveness, efficiency and appropriateness of telephone consultations. Out of 13 questionnaires sent, 11 were returned. There was a high level of satisfaction with accessibility, effectiveness and suitability. Similar numbers felt that telephone consultations were an efficient use of time. However more than one-third of carers said they would have preferred a face-to-face consultation with the doctor. Telephone consultations, although routine practice in psychiatry, need further research to establish them as a viable alternative to face-to-face consultations. PMID- 21285121 TI - Individual, life events, family and socio-economic factors associated with young people with intellectual disability and with and without behavioural/emotional problems. AB - The aim of this study was to compare a range of individual, life events, family and socio-economic factors associated with young people with intellectual disabilities and with and without behavioural/emotional problems. Teachers in 16 schools in one region of the UK completed a postal questionnaire on 249 young people with intellectual disabilities aged between 11 and 19 years. There were two groups: 155 young people with behavioural/emotional issues, and 94 without. Using a binary logistic regression analysis, a number of individual, life events, family and socio-economic risk factors were found to be significantly associated with emotional/behavioural problems. The results are discussed alongside findings from other studies. The importance of a multidimensional assessment is highlighted, as well as the interdependent nature of the risk factors. PMID- 21285122 TI - Community-based day-care services for people with intellectual disabilities in Georgia: a step towards their social integration. AB - This article discusses the role of community-based day-care services in the lives of adults with intellectual disabilities in the Republic of Georgia. The study explores the impact of this service on users' social-adaptive skills, social life and sense of happiness, comparing service users and a matched comparison group. A mixed-methods approach was used to assess the influence of day-care-centre services on social adaptation and integration. Results indicated that the level of social-adaptive skills was higher for day-care-centre participants than for the comparison group along several key dimensions. Similarly, the level of social integration was higher for the day-care-centre group, although the two groups did not differ significantly on reported happiness. The findings from this study revealed that day-care-centre participants with intellectual disabilities enjoyed a greater degree of social interaction and socializing opportunities than their non-participant peers. PMID- 21285123 TI - Non-verbal communication between nurses and people with an intellectual disability: a review of the literature. AB - This article critically synthesizes current literature regarding communication between nurses and people with an intellectual disability who communicate non verbally. The unique context of communication between the intellectual disability nurse and people with intellectual disability and the review aims and strategies are outlined. Communication as a concept is explored in depth. Communication between the intellectual disability nurse and the person with an intellectual disability is then comprehensively examined in light of existing literature. Issues including knowledge of the person with intellectual disability, mismatch of communication ability, and knowledge of communication arose as predominant themes. A critical review of the importance of communication in nursing practice follows. The paucity of literature relating to intellectual disability nursing and non-verbal communication clearly indicates a need for research. PMID- 21285124 TI - The impact of social policy on changes in professional practice within learning disability services: different standards for children and adults? A two-part examination: Part 1. The policy foundations: from welfare markets to Valuing People, personalization and Baby P. AB - This is the first of two articles examining links between policy developments and changes in professional practice within learning disability services in England, focusing upon emergent differences between children's and adult provision. The article focuses on the evolving tension around policy directions and managerialism/professionalism, with the latter as a set of practices driving services, particularly following the 1988 Griffiths Report but referring also to its antecedents. Implications of this development are examined to highlight a difference in emphasis between the credibility and professional status of the workforce in children's, as opposed to adult, services for people with learning disabilities. A historical narrative demonstrates a continuum from the policies of Thatcherism to those of New Labour, underpinned by the assertion that normalization ideas have shaped both social policy and professional directions. The origins of current policy initiatives covering the last 20 years are explored, showing the consequences of a developing gap between professional inputs for children's and adult services. PMID- 21285125 TI - Efficacy and safety of losartan in children with Alport syndrome--results from a subgroup analysis of a prospective, randomized, placebo- or amlodipine-controlled trial. AB - BACKGROUND: No prospective, randomized, double-blind trials of angiotensin converting enzyme inhibitors or angiotensin receptor blockers have previously been reported in adults or children with proteinuria secondary to Alport syndrome. METHODS: This 12-week, double-blind multinational study investigated the effects of losartan 0.7-1.4 mg/kg/day compared with placebo (normotensive patients) or amlodipine 0.1-0.2 mg/kg/day up to 5 mg/day (hypertensive patients) on proteinuria [early morning-void urinary protein/creatinine ratio (UPr/Cr), baseline >= 34 mg/mmol] in 30 children of up to 17 years of age with Alport syndrome. RESULTS: Twelve weeks of treatment with losartan significantly reduced proteinuria compared with placebo/amlodipine: losartan -14.7 mg/mmol (interquartile range -49.7 to -5.7 mg/mmol) or 31.6% reduction using a mixed model approach versus placebo/amlodipine 2.3 mg/mmol (-26.0 to 18.1 mg/mmol), P = 0.01 or 2.3% increase using a mixed model approach. Adverse event incidence was low and comparable between losartan and placebo/amlodipine groups. CONCLUSIONS: Losartan significantly lowered proteinuria and was well tolerated after 12 weeks of treatment in children aged 1-17 years with proteinuria secondary to Alport syndrome with or without hypertension, a population that has not previously been rigorously studied. PMID- 21285126 TI - Clinical characteristics of potential kidney donors with asymptomatic kidney stones. AB - BACKGROUND: Patients with symptomatic kidney stones are characterized by older age, male gender, white race, hypertension, obesity, metabolic syndrome and chronic kidney disease. Whether these characteristics differ in patients with asymptomatic kidney stones is unknown. METHODS: All potential kidney donors who underwent protocol computed tomography angiograms/urograms (2000-08) at the Mayo Clinic were identified. Renal abnormalities, including kidney stones, were assessed radiographically. Comorbidities, including past symptomatic kidney stones, were abstracted from the medical record. Characteristics of persons with and without radiographic stones were compared. Stone burden among persons with and without past symptomatic stones was compared. RESULTS: Among 1957 potential kidney donors, 3% had past symptomatic stones and 11% had radiographic stones (10% had only asymptomatic radiographic stones). Asymptomatic stone formers were more likely to be of white race, have low urine volumes and have radiographic findings of renal parenchymal thinning, focal renal scarring, medullary sponge kidney and polycystic kidney disease. Asymptomatic stone formers were not characterized by older age, male gender, hypertension, obesity, metabolic syndrome, abnormal kidney function, hyperuricemia, hypercalcemia or hypophosphatemia. Among persons with radiographic stones, those with past symptomatic stones had a slightly higher number of stones (mean 2.7 versus 2.4; P = 0.04), but a much greater diameter for the largest stone (mean 4.8 versus 1.6 mm; P < 0.001). CONCLUSIONS: Asymptomatic kidney stone formers have different demographic characteristics and many lack the comorbidities that have been described in persons with symptomatic kidney stones. These findings suggest that different pathophysiologic mechanisms could be involved in asymptomatic stone formation versus symptomatic stone passage. PMID- 21285127 TI - Thrombophilic factors in Stage V chronic kidney disease patients are largely corrected by renal transplantation. AB - BACKGROUND: The aim of our study was to evaluate the prevalence of acquired thrombophilic factors in Stage V chronic kidney disease (CKD) patients according to dialysis modality, the rate of correction of these factors 1 month after renal transplantation and their impact on cardiovascular or thromboembolic events at 1 year. METHODS: Three hundred and ten patients were prospectively screened for seven thrombophilic factors at transplantation; 215 of them were also assayed 1 month after. All the patients received prophylactic acetylsalicylic acid, started before transplantation. RESULTS: The prevalence of thrombophilic factors was significantly higher in patients under dialysis (n = 289) than in patients not yet on dialysis (n = 21) (74 versus 52.4%; P = 0.03) but was similar in haemodialysis and peritoneal dialysis patients (74.2 versus 73.2%). One month after transplantation, the global prevalence of thrombophilic factors had dropped from 74.4 to 44.7% (P < 0.001). Most thrombophilic factors had disappeared after transplantation: antithrombin deficiency: 13.5 versus 0.9%; P < 0.001, protein C deficiency: 12.1 versus 1.9%; P < 0.001, protein S deficiency: 3.7 versus 1.4%; P = 0.1, lupus anticoagulant: 37.7 versus 8.4%; P < 0.001 and antiphospholipid antibodies: 29.3 versus 12.6%; P < 0.001. The prevalence of activated protein C resistance, which reflects inherited factor V (FV) Leiden, was unchanged (1.9%), while the prevalence of elevated factor VIIIc increased from 20.9 to 30.7%, P < 0.001. The incidence of cardiovascular or thromboembolic events 1 year after transplantation was similar in patients with more than or equal to one thrombophilic factor at 1 month (5.2%) versus thrombophilic-free patients (6.7%). CONCLUSION: Acquired thrombophilic factors are highly prevalent among Stage V CKD patients. Most thrombophilic factors are corrected 1 month after transplantation. PMID- 21285128 TI - Early short-term imatinib treatment is sufficient to prevent the development of chronic allograft nephropathy. AB - BACKGROUND: Chronic allograft nephropathy (CAN), now defined as interstitial fibrosis and tubular atrophy not otherwise specified, is a near universal finding in kidney grafts by the end of the first decade posttransplantation. Platelet derived growth factor (PDGF) is a major mitogen mediating mesenchymal cell proliferation in CAN. Here, we investigated whether early short-term PDGF inhibition with imatinib could prevent CAN. METHODS: Kidney transplantations were performed from Dark-Agouti (DA) to Wistar-Furth (WF) rats and syngenic controls were done between DA rats. Allografts were immunosuppressed with cyclosporine. One group was also treated with imatinib for the first 30 days after transplantation. Serum creatinine levels were measured once a week. Grafts were harvested 90 days after transplantation. RESULTS: In control allografts, moderate to intense chronic changes were seen, whereas in syngenic grafts, no changes were seen. The early imatinib treatment prevented the development of CAN significantly compared to control allografts. Only few histological changes were seen. Fibrogenic growth factor ligand and receptor induction as well as inflammatory cell response was significantly inhibited by imatinib. Creatinine values of imatinib-treated allografts were also significantly lower compared to controls. CONCLUSIONS: We show that short-term imatinib treatment is sufficient to prevent CAN significantly, indicating that early PDGF induction has an important role in the pathogenesis of CAN. Here, we provide preclinical work that will need to be confirmed in patients with CAN. PMID- 21285129 TI - Short-term increase of glucose concentration in PDS results in extensive removal and high glycation level of vital proteins during continuous ambulatory peritoneal dialysis. AB - BACKGROUND: The effect of clearance of so-called middle- and high-molecular weight proteins on clinical outcome of patients treated by peritoneal dialysis is still a matter of debate. In our present study, we investigated the impact of short-time alteration of the glucose concentration and the osmolarity of the peritoneal dialysis solution (PDS) on protein removal. METHODS: Peritoneal dialysis liquids (PDL) were collected from 19 well-characterized continuous ambulatory peritoneal dialysis (CAPD) patients treated with two types of PDS: Baxter (n = 10) and Fresenius (n = 9). The patients were treated with two different glucose concentration of each PDS in 4-h cycles. The depletion of the six interfering high-abundant proteins from the PDL samples was performed with the Multiple Affinity Removal LC Column-Human 6. The resulting protein fractions were analysed by 2D gel electrophoresis, differential in gel electrophoresis, mass spectrometry and 2D western blot. RESULTS: Proteomics investigation of the PDL fractions after depletion allowed the identification of 198 polypeptides of 424 excised spots. These polypeptides equates to 48 non-redundant proteins. Comparative analyses of 2D gel electrophoresis protein pattern revealed a clear correlation between protein removal and PDS glucose concentration and osmolarity. An increase for 4 h in the PDS osmolarity (with 43-51 mosmol/L) resulted qualitatively in 18-23% more protein removal in PDL. Moreover, 2D western blot analyses of the protein glycation pattern showed that the short-time increase in PDS glucose concentration (45-50 mM) resulted in significant alteration of the advanced glycosylation end products (AGEs) pattern. CONCLUSIONS: The data presented in this study demonstrate a clear correlation between the short-time changes in glucose concentration and osmolarity of the PDS, and the augmentation of the protein removal and the appearance of AGEs during CAPD. PMID- 21285130 TI - Mortality and renal function decline among a community-based Chinese population with normal or mildly impaired renal function. AB - BACKGROUND: Longitudinal studies of the mortality and renal outcomes among the population with an estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m(2) and among the elderly are limited, especially in developing countries. METHODS: This prospective cohort study included 1563 residents aged 59.5 +/- 9.4 years from an urban district of Beijing, China. All participants had an eGFR >30 mL/min/1.73 m(2). Urinary albumin-to-creatinine ratio and eGFR were assessed at baseline, and their relation with mortality and renal function decline after a 4 year follow-up were analyzed. RESULTS: During 4 years (6142 person-years) of follow-up, 59 deaths occurred (9.6 per 1000 person-years). After adjusting for potential confounders, albuminuria was associated with increased risk of mortality, with an odds ratio (OR) of 3.09 [95% confidence interval (CI) 1.53 6.26]. Altogether 183 patients (12.3%) developed renal function decline, with a median change of eGFR of -20.0 mL/min/1.73 m(2). Presence of albuminuria was significantly associated renal function decline, with an OR of 1.79 (95% CI 1.02 3.15). Plasma uric acid (OR = 1.25/59 MUmol/L increase, 95% CI 1.10-1.43) and age (OR = 1.35/5 years increase, 95% CI 1.22-1.50) was also independently associated with renal function decline. Baseline eGFR was not significantly associated with either mortality or renal function decline in our analysis. CONCLUSIONS: Compared with eGFR, albuminuria is a strong independent predictor for both mortality and renal function decline among a Chinese population with normal or mildly impaired renal function. Furthermore, plasma uric acid level and age are also independently associated with renal function decline and therefore may be used for identifying patients at higher risk of chronic kidney disease progression. PMID- 21285131 TI - Risk variables associated with the outcome of kidney recipients >70 years of age in the new millennium. AB - BACKGROUND: New and more potent immunosuppressive protocols have markedly reduced the occurrence of rejections following organ transplantation. Accordingly, survival of elderly kidney transplant recipients has been substantially improved in the new millennium. The present study was performed to identify variables associated with the outcome of kidney transplant recipients >70 years of age in the modern era. METHODS: A single center retrospective study was performed, evaluating clinical and survival data from all patients >70 years of age receiving their first kidney transplant between 2000 and 2005. Survival data were analyzed using Cox proportional hazard models and the Kaplan-Meier method. RESULTS: During the time period, 160 recipients >70 years of age received their first transplant. The following factors were negatively associated with patient survival: age at transplantation; hazard ratio (HR) 1.09 per year, 95% confidence interval (CI) (1.01-1.18), time on dialysis before transplantation; HR 1.29 per year 95% CI (1.06-1.59) and presence of diabetes at transplantation; HR 1.78 95% CI (1.00-3.16). Thirty-five patients (22%) experienced an acute rejection episode during the first 90 days post-transplant. Acute rejection episodes did not influence on patient or graft survival. Patients with post-transplant pathological oral glucose tolerance test (OGTT) at 10 weeks after transplantation had significantly inferior survival compared to patients with normal OGTT. CONCLUSIONS: In a population of kidney transplant recipients >70 years of age with relatively low incidence of acute rejection episodes, age, time on dialysis before transplantation, concomitant diabetes mellitus and development of a pathological OGTT 10 weeks after transplantation were associated with inferior patient survival. PMID- 21285132 TI - Very high quantitative tumor HER2 content and outcome in early breast cancer. AB - BACKGROUND: It is unknown how a very high tumor total HER2 (human epidermal growth factor receptor-2) content (H2T) influences outcome in early breast cancer treated with adjuvant trastuzumab plus chemotherapy. PATIENTS AND METHODS: H2T was measured using a novel quantitative assay (HERmark((r))) from formalin-fixed tumor tissue of 899 women who participated in the FinHer trial (ISRCTN76560285). In a chromogenic in situ hybridization (CISH) test, 197 (21.9%) patients had HER2 positive cancer and were randomly assigned to receive trastuzumab or control. RESULTS: Cancer H2T levels varied 1808-fold. High H2T levels were correlated with a positive HER2 status by CISH (P < 0.0001). A nonlinear association was present between H2T and the hazard of distant recurrence in a subpopulation treatment effect pattern plot analysis in CISH-positive disease. Patients with very high H2T (defined by >=22-fold the median of HER2-negative cancers; 13% of CISH positive cancers) did not benefit from adjuvant trastuzumab [hazard ratio (HR) 1.23; 95% confidence interval (CI) 0.33-4.62; P = 0.75], whereas the rest of the patients with HER2-positive disease by CISH (87%) did benefit (HR 0.52; 95% CI 0.28-1.00; P = 0.050). CONCLUSION: Patients with HER2-positive breast cancer with very high tumor HER2 content may benefit less from adjuvant trastuzumab compared with those whose cancer has more moderate HER2 content. PMID- 21285133 TI - The effect of exemestane, anastrozole, and tamoxifen on lipid profiles in Japanese postmenopausal early breast cancer patients: final results of National Surgical Adjuvant Study BC 04, the TEAM Japan sub-study. AB - BACKGROUND: In this Tamoxifen Exemestane Adjuvant Multinational Japan sub-study, we evaluated the time course of changes in serum lipids in postmenopausal women with hormone-sensitive early breast cancer treated with exemestane, anastrozole, or tamoxifen for postoperative adjuvant therapy. PATIENTS AND METHODS: A total of 154 breast cancer patients were assigned to receive exemestane, anastrozole, or tamoxifen in this randomized open-label study. Serum lipid parameters including triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were measured during 1 year of treatment. RESULTS: TC and LDL-C rapidly decreased in patients treated with tamoxifen at 3 months. Compared with anastrozole and exemestane patients, TC and LDL-C were significantly lower at all assessment time points in tamoxifen patients (P < 0.05). TG increased in tamoxifen patients; it was significantly higher compared with exemestane patients at all assessment time points (P < 0.05). HDL-C slightly decreased in exemestane patients; it was significantly lower compared with anastrozole patients at 3 months and 1 year (P = 0.0179 and 0.0013, respectively). CONCLUSION: Changes of lipid profiles in Japanese postmenopausal women treated with tamoxifen were relatively favorable, while exemestane and anastrozole had no clinically significant effect on the serum lipids. PMID- 21285134 TI - A multicentre study of capecitabine, oxaliplatin plus bevacizumab as perioperative treatment of patients with poor-risk colorectal liver-only metastases not selected for upfront resection. AB - BACKGROUND: Perioperative chemotherapy improves outcome in resectable colorectal liver-only metastasis (CLM). This study aimed to evaluate perioperative CAPOX (capecitabine-oxaliplatin) plus bevacizumab in patients with poor-risk CLM not selected for upfront resection. PATIENTS AND METHODS: Poor-risk CLM was defined as follows: more than four metastases, diameter >5 cm, R0 resection unlikely, inadequate viable liver function if undergoing upfront resection, inability to retain liver vascular supply, or synchronous colorectal primary presentation. Patients underwent baseline computed tomography, magnetic resonance imaging, and/or positron emission tomography (PET) for staging and received neoadjuvant CAPOX plus bevacizumab, with resectability assessed every four cycles. Primary end point was radiological objective response rate (ORR). RESULTS: Forty-six patients were recruited, of which 91% underwent PET to ensure metastases confined to liver. Following neoadjuvant CAPOX plus bevacizumab, the ORR was 78% (95% confidence interval 63% to 89%). This allowed 12 of 30 (40%) patients with initial nonsynchronous unresectable CLM to be converted to resectability. In addition, 10 of 15 (67%) patients with synchronous resectable CLM underwent liver resection, with four additional patients being observed alone due to excellent response to neoadjuvant therapy. No grade 3-4 perioperative complications were seen. CONCLUSION: Neoadjuvant CAPOX plus bevacizumab resulted in a high response rate for patients with CLMs with poor-risk features not selected for upfront resection and converted 40% of patients to resectability. PMID- 21285135 TI - Usefulness of a bidirectional e-learning material for explaining surgical anesthesia to cancer patients. AB - BACKGROUND: We developed an e-learning system, which is based on an interactive animation video that assists anesthesiologists in preanesthetic interviews. MATERIALS AND METHODS: First, the feasibility of the system was investigated in 18 anesthesiologists and 95 volunteers from the general public. Content/quantity, operability, and satisfaction were assessed with a five-point scale. Secondly, a randomized controlled trial was conducted on 211 cancer patients who were scheduled to undergo general anesthesia. They were divided into an e-learning group (n = 106) and a control group (n = 105). The patients in the e-learning group watched the interactive animation before a preanesthetic interview by an anesthesiologist. RESULTS: In 10 of the 11 items for content/quantity, operability, and satisfaction, the average score for both anesthesiologists and volunteers was >=3.0 in feasibility study. Then, the level of patient comprehension of preoperative rounds and postoperative complications in the e learning group was significantly higher than that in the control group (mean: 4.4 +/- 0.5 versus 4.1 +/- 0.7, P = 0.003, and 4.3 +/- 0.5 versus 4.2 +/- 0.5, P = 0.02); however, no significant difference in anxiety was seen between the two groups. Patient satisfaction in the e-learning group was significantly higher (mean: 4.3 +/- 0.5 versus 4.0 +/- 0.6, P = 0.002). CONCLUSION: The e-learning system is an effective supplementary tool for preanesthetic interviews in cancer patients. PMID- 21285136 TI - Dietary acrylamide and pancreatic cancer risk in an Italian case--control study. AB - BACKGROUND: Information on the relation between acrylamide exposure and risk of pancreatic cancer is scanty and inconsistent. PATIENTS AND METHODS: We investigated the issue in a case-control study conducted from 1991 to 2008 in Northern Italy. Cases were 326 patients with incident pancreatic cancer, admitted to major teaching and general hospitals. Controls were 652 subjects admitted to the same hospitals with acute non-neoplastic conditions. Acrylamide mean content of various food items was derived from international databases and Italian sources. Odds ratios (ORs) and 95% confidence intervals (CIs) of pancreatic cancer were derived using conditional logistic regression adjusted for several covariates, including energy intake. RESULTS: The ORs of pancreatic cancer for subsequent quintiles of acrylamide intake, as compared with the lowest one, were 1.48 (95% CI 0.88-2.50), 1.57 (95% CI 0.91-2.69), 1.70 (95% CI 0.98-2.96) and 1.49 (95% CI 0.83-2.70), with no trend in risk (P value 0.21). The OR for an increase in acrylamide intake of 10 MUg/day was 1.01 (95% CI 0.92-1.10). No meaningful difference between ORs was found in strata of smoking habit, alcohol drinking, body mass index and other selected covariates. CONCLUSION: This study found no association between dietary acrylamide and pancreatic cancer in an Italian population. PMID- 21285137 TI - Relationship between estrogen receptor, progesterone receptor, HER-2 and Ki67 expression and efficacy of aromatase inhibitors in advanced breast cancer. AB - BACKGROUND: Surprisingly few data are published on the relevance of even commonly used biomarkers of response to aromatase inhibitors (AIs) in advanced breast cancer. Here, we aim to determine the effectiveness of AIs in that setting according to quantitative levels of estrogen receptor (ER), progesterone receptor (PgR) and Ki67 or human epithelial growth factor receptor-2 (HER-2) status. PATIENTS AND METHODS: ER, PgR, HER-2 and Ki67 protein expressions were centrally assessed in 177 archival formalin-fixed paraffin-embedded primary or locally recurrent breast tumours from women who subsequently received AI treatment of advanced disease. RESULTS: Among ER-positive patients (n = 146), higher PgR, but not ER, levels were associated with increased time to AI treatment failure (TTF). Higher Ki67 staining was associated with decreased TTF. ER-positive/HER-2 positive patients showed a non-significant trend for decreased TTF compared with ER-positive/HER-2-negative patients. PgR level, but not Ki67, remained a significant predictor of TTF in multivariate analysis of ER-positive patients. CONCLUSIONS: Higher PgR and Ki67 levels are significantly associated with increased and decreased TTF, respectively, in ER-positive patients receiving AI treatment of advanced disease. The higher proliferation seen in PgR-negative tumours does not explain the poorer clinical responsiveness of this subgroup. PMID- 21285138 TI - The impact of national health care reform on adults with severe mental disorders. AB - OBJECTIVE: Little is known about the effect recent health care reform legislation will have on coverage of individuals with severe mental disorders. The authors examined current and predicted sources of insurance coverage and use of mental health services among adults with and without severe mental disorders and modeled postreform changes. METHOD: The authors obtained sociodemographic, health status, mental health care use, and insurance coverage data from the 2004-2006 Medical Expenditure Panel Surveys to estimate changes that will occur after reform is fully implemented in 2019. RESULTS: Adults with severe mental disorders, identified as self-reported severe depression or other psychological distress, were more likely than those without such disorders to be uninsured (21.0% compared with 16.5%). Only one-fifth of individuals with severe mental disorders who lacked full-year insurance coverage had any mental health service use in the 2004-2006 period, compared with approximately half of those who had coverage. The authors estimate that the expansion of insurance coverage under reform will lead to 1.15 million new users of mental health services, which represents a 4.5% increase. The authors estimate an increase of 2.3 million users of mental health services in Medicaid and nearly 2 million in private insurance. CONCLUSIONS: Public insurance programs that currently play a major role in financing mental health services will play an even greater role after reform is implemented. Significant increases can be expected both in the overall number of users of mental health services and in their resources to pay for care. PMID- 21285139 TI - Investigation of cortical thickness abnormalities in lithium-free adults with bipolar I disorder using cortical pattern matching. AB - OBJECTIVE: Although several lines of evidence implicate gray matter abnormalities in the prefrontal cortex and anterior cingulate cortex in patients with bipolar disorder, findings have been largely inconsistent across studies. Differences in patients' medication status or mood state or the application of traditional volumetric methods that are insensitive to subtle neuroanatomical differences may have contributed to variations in findings. The authors used MRI in conjunction with cortical pattern matching methods to assess cortical thickness abnormalities in euthymic bipolar patients who were not receiving lithium treatment. METHOD: Thirty-four lithium-free euthymic patients with bipolar I disorder and 31 healthy comparison subjects underwent MRI scanning. Data were processed to measure cortical gray matter thickness. Thickness maps were spatially normalized using cortical pattern matching and were analyzed to assess illness effects and associations with clinical variables. RESULTS: Relative to healthy comparison subjects, euthymic bipolar patients had significantly thinner gray matter in the left and right prefrontal cortex (Brodmann's areas 11, 10, 8, and 44) and the left anterior cingulate cortex (Brodmann's areas 24/32). Thinning in these regions was more pronounced in patients with a history of psychosis. No areas of thicker cortex were detected in bipolar patients relative to healthy comparison subjects. CONCLUSIONS: Using a technique that is highly sensitive to subtle neuroanatomical differences, significant regional cortical thinning was found in lithium-free euthymic patients with bipolar disorder. PMID- 21285140 TI - Copy number variants in schizophrenia: confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications. AB - OBJECTIVE: To evaluate previously reported associations of copy number variants (CNVs) with schizophrenia and to identify additional associations, the authors analyzed CNVs in the Molecular Genetics of Schizophrenia study (MGS) and additional available data. METHOD: After quality control, MGS data for 3,945 subjects with schizophrenia or schizoaffective disorder and 3,611 screened comparison subjects were available for analysis of rare CNVs (<1% frequency). CNV detection thresholds were chosen that maximized concordance in 151 duplicate assays. Pointwise and genewise analyses were carried out, as well as analyses of previously reported regions. Selected regions were visually inspected and confirmed with quantitative polymerase chain reaction. RESULTS: In analyses of MGS data combined with other available data sets, odds ratios of 7.5 or greater were observed for previously reported deletions in chromosomes 1q21.1, 15q13.3, and 22q11.21, duplications in 16p11.2, and exon-disrupting deletions in NRXN1. The most consistently supported candidate associations across data sets included a 1.6-Mb deletion in chromosome 3q29 (21 genes, TFRC to BDH1) that was previously described in a mild-moderate mental retardation syndrome, exonic duplications in the gene for vasoactive intestinal peptide receptor 2 (VIPR2), and exonic duplications in C16orf72. The case subjects had a modestly higher genome-wide number of gene-containing deletions (>100 kb and >1 Mb) but not duplications. CONCLUSIONS: The data strongly confirm the association of schizophrenia with 1q21.1, 15q13.3, and 22q11.21 deletions, 16p11.2 duplications, and exonic NRXN1 deletions. These CNVs, as well as 3q29 deletions, are also associated with mental retardation, autism spectrum disorders, and epilepsy. Additional candidate genes and regions, including VIPR2, were identified. Study of the mechanisms underlying these associations should shed light on the pathophysiology of schizophrenia. PMID- 21285141 TI - Clinical and psychosocial predictors of suicide attempts and nonsuicidal self injury in the Adolescent Depression Antidepressants and Psychotherapy Trial (ADAPT). AB - OBJECTIVE: The authors assessed whether clinical and psychosocial factors in depressed adolescents at baseline predict suicide attempts and nonsuicidal self injury over 28 weeks of follow-up. METHOD: Participants were 164 adolescents with major depressive disorder taking part in the Adolescent Depression Antidepressants and Psychotherapy Trial (ADAPT). Clinical symptoms, family function, quality of current personal friendships, and suicidal and nonsuicidal self-harm were assessed at baseline. Suicidal and nonsuicidal self-harm thoughts and behaviors were assessed during 28 weeks of follow-up. RESULTS: High suicidality, nonsuicidal self-injury, and poor family function at entry were significant independent predictors of suicide attempts over the 28 weeks of follow-up. Nonsuicidal self-injury over the follow-up period was independently predicted by nonsuicidal self-injury, hopelessness, anxiety disorder, and being younger and female at entry. CONCLUSIONS: Both suicidal and nonsuicidal self-harm persisted in depressed adolescents receiving treatment in the ADAPT study. A history of nonsuicidal self-injury prior to treatment is a clinical marker for subsequent suicide attempts and should be as carefully assessed in depressed youths as current suicidal intent and behavior. PMID- 21285142 TI - Evaluation of functionally meaningful measures for clinical trials of cognition enhancement in schizophrenia. AB - OBJECTIVE: Because reduction of psychotic symptoms in schizophrenia does not result in adequate community functioning, efforts have shifted to other areas, such as cognitive impairment. The U.S. Food and Drug Administration requires that drugs for cognition enhancement in schizophrenia show improvement on two distinct outcome measures in clinical trials: an accepted cognitive performance battery and a functionally meaningful coprimary measure. The authors examined the reliability, validity, and practicality of functionally meaningful measures. METHOD: In this four-site validation study, schizophrenia patients were assessed at baseline (N=166) and 4 weeks later (N=144) on performance-based (Independent Living Scales, Test of Adaptive Behavior in Schizophrenia [TABS], and UCSD Performance-based Skills Assessment [UPSA]) and interview-based (Cognitive Assessment Interview and Clinical Global Impression Scale for Cognition) candidate coprimary measures. In addition, cognitive performance, community functioning, and clinical symptoms were assessed. Both full and short forms of the performance-based measures were evaluated. RESULTS: All measures were well tolerated by patients, had adequate test-retest reliability, and showed good utility as a repeated measure. Measures differed in their correlation with cognitive performance, with performance-based measures having stronger correlations than interview-based measures. None of the measures had notable floor or ceiling effects or missing data. CONCLUSIONS: Among the full-form measures, the UPSA was judged to have the strongest overall properties. Among the short forms, the TABS and UPSA appeared to have the strongest features. Use of the short forms saves time, but at the cost of lower test-retest reliability and weaker correlations with cognitive performance. PMID- 21285143 TI - Deep brain stimulation for treatment-resistant depression: follow-up after 3 to 6 years. AB - OBJECTIVE: A prevalence of at least 30% for treatment-resistant depression has prompted the investigation of alternative treatment strategies. Deep brain stimulation (DBS) is a promising targeted approach involving the bilateral placement of electrodes at specific neuroanatomical sites. Given the invasive and experimental nature of DBS for treatment-resistant depression, it is important to obtain both short-term and long-term effectiveness and safety data. This report represents an extended follow-up of 20 patients with treatment-resistant depression who received DBS to the subcallosal cingulate gyrus (Brodmann's area 25). METHOD: After an initial 12-month study of DBS, patients were seen annually and at a last follow-up visit to assess depression severity, functional outcomes, and adverse events. RESULTS: The average response rates 1, 2, and 3 years after DBS implantation were 62.5%, 46.2%, and 75%, respectively. At the last follow-up visit (range=3-6 years), the average response rate was 64.3%. Functional impairment in the areas of physical health and social functioning progressively improved up to the last follow-up visit. No significant adverse events were reported during this follow-up, although two patients died by suicide during depressive relapses. CONCLUSIONS: These data suggest that in the long term, DBS remains a safe and effective treatment for treatment-resistant depression. Additional trials with larger samples are needed to confirm these findings. PMID- 21285144 TI - After GWAS: searching for genetic risk for schizophrenia and bipolar disorder. AB - Ten years ago it was widely expected that the genetic basis of common disease would be resolved by genome-wide association studies (GWAS), large-scale studies in which the entire genome is covered by genetic markers. However, the bulk of heritable variance remains unexplained. The authors consider several alternative research strategies. For instance, whereas it has been hypothesized that a common disease is associated primarily with common genetic variants, it is now plausible that multiple rare variants each have a potent effect on disease risk and that they could accumulate to become a substantial component of common disease risk. This idea has become more appealing since the discovery that copy number variants (CNVs) are a substantial source of human mutations and are associated with multiple common diseases. CNVs are structural genomic variants consisting of microinsertions, microdeletions, and transpositions in the human genome. It has been argued that numerous rare CNVs are plausible causes of a substantial proportion of common disease, and rare CNVs have been found to be potent risk factors in schizophrenia and autism. Another approach is to "parse the genome," i.e., reanalyze subsets of current GWAS data, since the noise inherent in genome wide approaches may be hiding valid associations. Lastly, technological advances and declining costs may allow large-scale genome-wide sequencing that would comprehensively identify all genetic variants. Study groups even larger than the 10,000 subjects in current meta-analyses would be required, but the outcomes may lead to resolution of our current dilemma in common diseases: Where is the missing heritability? PMID- 21285145 TI - Genetic modifiers of cancer risk for BRCA1 and BRCA2 mutation carriers. AB - Germline mutations in BRCA1 and BRCA2 confer high risks of female breast and ovarian cancer. However, there is strong evidence that these risks are modified by other factors, including familial or genetic factors. Genome-wide association studies have identified several breast cancer genetic susceptibility variants in the general population that are also associated with breast cancer risk for mutation carriers. The patterns of association for these variants vary between BRCA1 and BRCA2 mutation carriers and this variation appears to be driven by their differential associations with breast cancer subtypes defined by estrogen receptor status. We review the latest evidence regarding genetic modifiers of cancer risk for female BRCA1 and BRCA2 mutation carriers emerging from candidate gene studies, variants found in genome-wide association studies (GWAS) to be associated with cancer risk in the general population and GWAS specifically in mutation carriers. We also discuss the implications of these findings for cancer risk prediction in these women. BRCA1 and BRCA2 mutation carriers could potentially be among the first groups of individuals for whom clinically applicable risk profiling could be developed using the common breast cancer susceptibility variants identified through GWAS. PMID- 21285146 TI - Unclassified variants in BRCA genes: guidelines for interpretation. AB - In the last few years, several studies have focused on the interpretation of unclassified variants (UVs) of BRCA1 and BRCA2 genes. Analysis of UVs through a unique approach is not sufficient to understand their role in the development of tumors. Thus, it is clear that assembling results from different sources (genetic and epidemiological data, histopathological features, and in vitro and in silico analyses) represents a powerful way to classify such variants. Building reliable integrated models for UV classification requires the joining of many working groups to collaborative consortia, allowing data exchange and improvements of methods. This will lead to improvement in the predictivity of gene testing in BRCA1 and BRCA2 and, consequently, to an increase in the number of families that can be correctly classified as linked or unlinked to these genes, allowing more accurate genetic counseling and clinical management. PMID- 21285147 TI - Old and new concepts in histopathological characterization of familial breast cancer. AB - BRCA1- and BRCA2-deficient cells display genomic instability due to impaired DNA repair and may subsequently be predisposed to malignant transformation. Cancers arising in BRCA1 gene mutation carriers differ substantially from sporadic breast cancers of age-matched controls in their histopathological appearance. BRCA1 related breast cancers have been morphologically associated with poorly differentiated and medullary types, exhibiting triple negativity and 'basal phenotype'. There are different types of mutations listed in Breast Cancer Information Core professional databases and most of them are small insertions or deletions. Moreover, the search for more pathological alterations has led to identification of missense mutations, intronic variant sequences and unclassified variants, reporting an unclear role in breast cancer susceptibility. We review the latest evidence regarding analysis of various mutations in BRCA1/2 genes and low-risk breast cancer susceptibility genes. Preliminary data from our laboratories indicate that biomarkers for invasiveness may lead to better characterization of familial breast cancers. Multivariate regression analysis has allowed us to select the best combination of markers to predict familial or hereditary breast cancers. We found that a marker signature comprising human epidermal growth factor receptor 2 (HER2) negativity, Na(+)/H(+) exchanger regulatory factor 1 (NHERF1) negativity and BRCA1 positivity (designated 'triple biomarker' signature) is frequently associated with familial breast cancer and promises to be a reliable test in its molecular characterization. PMID- 21285148 TI - Hereditary breast cancer: clinical features and risk reduction strategies. AB - Risk-reduction interventions for BRCA-related breast cancer are relevant not only for clinical decisions in breast cancer patients but also for healthy subjects who are potential candidates to undergo similar interventions. The literature on the impact of different surgical options and adjuvant systemic approaches aimed towards risk reduction for ipsilateral and contralateral breast cancer recurrences is briefly reviewed. Breast-conserving surgery is associated with a higher probability of local recurrence, but is counterbalanced by effectiveness of chemotherapy in reducing this risk. Consistent support for the hypothesis that antiestrogens are effective in reducing contralateral breast cancer risks is available from the literature. On the other hand, data on chemoprevention approaches for healthy subjects are too preliminary to draw any conclusions. Studies including conventional and newer hormonal drugs are needed to demonstrate the benefit of chemoprevention approaches. These may also deepen our knowledge on possible differences in the likelihood of clinical benefit to be expected among BRCA1- and BRCA2-altered tumours. PMID- 21285149 TI - Innovative technology for cancer risk analysis. AB - After completion of the Human Genome Project, analysis of genetic and genomic variations in different pathological states became possible. The capillary system based on Sanger methods is still very expensive in terms of time, cost and professionalism required. For this reason, the National Human Genome Institute proposed an 'advanced sequencing technology development' project with the aim of sequencing a genome in 1 day for $1000. Three validated platforms are commercially available and single molecule sequencing methods have been recently introduced, which are not only competitive in time and costs, but display greater accuracy than 'past generation' sequencing. Next generation technology allows, in a single experiment, the identification of copy number variation and large rearrangements, or detection of fusion transcripts analysis thus permitting the evaluation of cancer risk at multiple levels (genomic, transcriptomic, proteomic, epigenetic). PMID- 21285150 TI - Impact of MRI surveillance and breast cancer detection in young women with BRCA mutations. AB - Based on several observational studies that have yielded consistent results, the combination of annual magnetic resonance imaging (MRI) plus mammography is now the standard of care for screening women with BRCA mutations who decline risk reducing mastectomy. However, many of these women will develop breast cancer at a young age and, while most of these cancers will be very early stage, oncologists need to be aware of the unique issues faced by women in this age group due to the diagnosis and treatment. Fear of death, loss of fertility, premature menopause, relationship stress, career disruption and financial losses are only some of the problems that are either unique to young women or much more pronounced in this age group. Urgent referral to a fertility specialist of any woman who has not yet completed her family should be made as soon as the possible need for systemic treatment is recognized. The oncologist should also have a low threshold for referring young women to professionals experienced in navigating young women and their families through the psychosocial trauma of a breast cancer diagnosis. PMID- 21285151 TI - Hereditary breast and ovarian cancer: risks and challenges. 10-12 September 2009: Bari, Italy. Introduction. PMID- 21285152 TI - Prevention of breast cancer: the case for studying inhibition of IGF-1 actions. AB - Measures to prevent breast cancer are receiving particular attention by women at high risk from either clinico-pathologic findings or genetic susceptibility. Life style and nutritional interventions have been difficult to quantify, but merit further study. Chemoprevention with tamoxifen and subsequently with the related raloxifene demonstrates some efficacy, but may be not be applicable to premenopausal women (with regard to raloxifene), or have low acceptance (with regard to tamoxifen). Based on the importance of the insulin-like growth factor-1 pathway in mammary gland development, and the availability of a potent inhibitor, pilot studies are ongoing to evaluate such an inhibitor in women with demonstrable high risk to develop breast cancer. Short-term interventions with the inhibitor have been completed, and subsequent interventions are planned. PMID- 21285153 TI - The clinical development of inhibitors of poly(ADP-ribose) polymerase. AB - A number of inhibitors of DNA repair have been evaluated or are undergoing development as potential cancer treatments. Inhibitors of poly(ADP-ribose) polymerase (PARP) are of particular interest in treating hereditary breast cancers occurring in patients who are carriers of BRCA1 or BRCA2 mutations. In vitro PARP inhibitors are highly cytotoxic to cell lines carrying BRCA mutations while only minimally toxic to cell lines without these mutations. This is thought to be due to a phenomenon known as synthetic lethality where the accumulation of single-strand breaks consequent on PARP inhibition are converted to double-strand breaks on cell division. Cancer cells in BRCA carriers are uniquely unable to repair the consequent double-strand breaks that result during cell division. PARP inhibitors were initially developed as possible chemo-potentiating agents but have now been evaluated clinically in BRCA-related tumors, showing remarkable single-agent activity. The potential future development and use is reviewed. PMID- 21285154 TI - Social and ethical implications of BRCA testing. AB - Oncologists are asked with increasing frequency to counsel their patients with respect to the medical, psychological and social repercussions of genetic testing for cancer susceptibility that may have been prescribed by physicians or carried out through direct-to-consumer tests. This article critically reviews the main ethical and social implications of BRCA testing, focusing on genetic responsibility and genetic discrimination. Genetic responsibility toward oneself and others is a highly debated implication of genetic testing for cancer predisposition that requires broad considerations of the boundaries between individual and community rights and a reappraisal of the notion of autonomy as relational. Physicians' duty to warn 'at risk' relatives can be an ethical quandary, yet confidentiality is key to the patient-doctor relationship. Mutation carriers may be subject to different forms and degrees of genetic discrimination and many individuals at risk have forgone BRCA testing to avoid potential discrimination. The scientific and medical community, together with patients and the public, has actively engaged against genetic discrimination. The legislation in many countries now protects against genetic discrimination by insurance companies and employers. Legal and regulatory issues are not the final answer to discrimination and profound cultural changes are required to create understanding and acceptance of all differences. PMID- 21285155 TI - Conclusions: fruits of the convergence of laboratory, clinic and public. AB - Genes implicated in the devastating occurrences of cancers mostly arising in the breast and ovaries within certain 'high-risk' families were mapped and then cloned not even two decades ago. Some clairvoyant students of the subject anticipated that this 'assignation of risk' would herald a new era in the prevention, treatment and insights into pathogenesis of neoplasia. However, few would have predicted the accelerated pace of knowledge that ensued. The successive symposia that we held on this subject have given us a unique perspective on the extent of this progress. This supplement and the selected papers that have been assembled document accomplishments in genetics, epidemiology, early detection, treatment, preventive measures, as well as in the ethical and psychosocial consequences enveloping families at risk. It also reveals how the convergence of the laboratory, the clinic and the public across two continents is able to ignite discovery and its applications. PMID- 21285156 TI - BRCA genes: lessons learned from experimental and clinical cancer. AB - Advances in the study of BRCA1 and BRCA2 gene functions have relied on the development of animal models for seeking to explore further what we have learned from the human disease. Specifically, mouse models of a 'triple-negative' breast cancer (utilizing conditional knockout of BRCA1 and p53 in the breast), of an endometrioid ovarian cancer (based on oncogenic kras and loss of function of pten), and of anatomic and functional consequences of BRCA1 mutations in granulosa cells, have led to further inquiry into the pathogenesis and therapeutic consequences of genetic alterations. A striking susceptibility of these murine malignancies to platinum drugs has emerged, providing further confidence in their relevance to the human disease. In addition to these models, the pathogenesis of high-grade serous disease derived from risk-reducing surgeries in mutation carriers has pointed to a role of mutations in p53 commonly encountered in tubal intraepithelial carcinomas. PMID- 21285157 TI - A new strategy with proton pump inhibitors for the prevention of acute exacerbations in COPD. AB - Acute exacerbations of chronic obstructive pulmonary disease (COPD), an acute worsening of respiratory symptoms, generally result in a poor prognosis. Successful prevention and management of such exacerbations is thus important for patient care. Viral infection, primarily with rhinovirus (RV), is the foremost cause of exacerbations in COPD patients. Proton pump inhibitors (PPIs) have been reported to inhibit RV infection in human airway epithelial cells in vitro. Furthermore, clinical trials of PPIs in patients with COPD resulted in a reduction in rates of both common cold and COPD exacerbations. In this review, we discuss the significance of COPD exacerbations, summarize a published trial of the effect of low-dose PPIs on COPD exacerbations, and postulate a mechanism for this effect. PMID- 21285158 TI - An international consensus survey of diagnostic criteria for macrophage activation syndrome in systemic juvenile idiopathic arthritis. AB - OBJECTIVE: To identify candidate diagnostic criteria for macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (sJIA) using international consensus formation through a Delphi questionnaire survey. METHODS: A questionnaire listing 28 clinical, laboratory, and histopathologic features of MAS elicited by literature review was sent to 505 pediatric rheumatologists worldwide. Respondents were asked to select the 10 features that they felt were most important and useful in the diagnosis of MAS, and to order the 10 selected features by assigning the number 10 to the most important, and ending with 1 as the least important. RESULTS: The response rate was 46% (232 physicians from 47 countries). The items selected by more than 50% of respondents were, in order of frequency, falling platelet count, hyperferritinemia, evidence of macrophage hemophagocytosis in the bone marrow, increased liver enzymes, falling leukocyte count, persistent continuous fever >= 38 degrees C, falling erythrocyte sedimentation rate, hypofibrinogenemia, and hypertriglyceridemia. CONCLUSION: Our process led to identification of features that were felt to be most important as candidate diagnostic criteria for MAS by a large sample of international pediatric rheumatologists. PMID- 21285159 TI - Work disability in patients with ankylosing spondylitis in Norway. AB - OBJECTIVE: To report the prevalence of work disability (WD) in a cross-sectional study of a large population of patients with ankylosing spondylitis (AS) and the associated demographic and clinical characteristics, including extraspinal features, that contribute to WD. METHODS: Patients with AS registered in a hospital database were invited to participate. A total of 360 patients took part. The survey period was 1998 to 2002. During an extended outpatient visit, data were collected according to a predefined data form. Demographic data were collected and a physical examination performed. RESULTS: After 22.6 years of disease duration, the cumulative prevalence of WD reached 43.6%, and an additional 8.9% of patients were nonparticipants in the labor force. Significant odds ratios indicating an independent association with WD were found for history of polyarthritis (9.6), coronary heart disease (CHD; 7.8), female sex (3.4), having children with spondyloarthritis (2.9), changing profession (2.8), lower level of education (1.4), mean score of the Bath AS Functional Index (1.2), increasing age (1.05), and increasing finger-to-floor distance (1.02). CONCLUSION: The longterm prevalence of WD among Norwegian patients with AS is considerably higher than in reports from other countries. Earlier polyarthritis and CHD were the strongest independent risk factors for WD. PMID- 21285160 TI - A 24-week, randomized, double-blind, placebo-controlled, parallel group study of the efficacy of oral SCIO-469, a p38 mitogen-activated protein kinase inhibitor, in patients with active rheumatoid arthritis. AB - OBJECTIVE: To evaluate the efficacy, safety, and tolerability of oral SCIO-469, a p38 MAPK inhibitor that blocks tumor necrosis factor-alpha, interleukin-1beta, and cyclooxygenase-2 synthesis in patients with active rheumatoid arthritis (RA). METHODS: Patients were randomized to receive SCIO-469 at either 30 or 60 mg three times daily in an immediate-release (IR) formulation or at 100 mg once daily in an extended-release (ER) formulation, or placebo for 24 weeks. The primary endpoint was American College of Rheumatology (ACR)20 response at Week 12. Safety was monitored through Week 26. RESULTS: Overall, 302 patients were randomized: 76 to placebo, 75 to 30 mg IR, 73 to 60 mg IR, and 78 to 100 mg ER. There were no significant differences in ACR20 responses at Week 12 between SCIO-469 and placebo. Declines in C-reactive protein and erythrocyte sedimentation rate during early treatment did not persist to Week 12 and were not a consequence of decreased SCIO-469 plasma levels. The 60 mg IR regimen showed a dose-limiting toxicity manifested by elevations in alanine aminotransferase. Adverse events were common in all groups (79.7% and 86.7% through 13 and 26 weeks, respectively). Twenty-one patients reported 28 serious adverse events (SAE). SAE were more common with IR SCIO-469 than with placebo (7% vs 4%) but were not reported with ER SCIO-469. CONCLUSION: In all regimens tested, SCIO-469 showed no greater efficacy compared to placebo in patients with RA. The transient effect of SCIO-469 on acute-phase reactants suggests a complex role of p38 MAPK in inflammation. PMID- 21285161 TI - Fibromyalgia criteria and severity scales for clinical and epidemiological studies: a modification of the ACR Preliminary Diagnostic Criteria for Fibromyalgia. AB - OBJECTIVE: To develop a fibromyalgia (FM) survey questionnaire for epidemiologic and clinical studies using a modification of the 2010 American College of Rheumatology Preliminary Diagnostic Criteria for Fibromyalgia (ACR 2010). We also created a new FM symptom scale to further characterize FM severity. METHODS: The ACR 2010 consists of 2 scales, the Widespread Pain Index (WPI) and the Symptom Severity (SS) scale. We modified these ACR 2010 criteria by eliminating the physician's estimate of the extent of somatic symptoms and substituting the sum of 3 specific self-reported symptoms. We also created a 0-31 FM Symptom scale (FS) by adding the WPI to the modified SS scale. We administered the questionnaire to 729 patients previously diagnosed with FM, 845 with osteoarthritis (OA) or with other noninflammatory rheumatic conditions, 439 with systemic lupus erythematosus (SLE), and 5210 with rheumatoid arthritis (RA). RESULTS: The modified ACR 2010 criteria were satisfied by 60% with a prior diagnosis of FM, 21.1% with RA, 16.8% with OA, and 36.7% with SLE. The criteria properly identified diagnostic groups based on FM severity variables. An FS score >= 13 best separated criteria+ and criteria- patients, classifying 93.0% correctly, with a sensitivity of 96.6% and a specificity of 91.8% in the study population. CONCLUSION: A modification to the ACR 2010 criteria will allow their use in epidemiologic and clinical studies without the requirement for an examiner. The criteria are simple to use and administer, but they are not to be used for self-diagnosis. The FS may have wide utility beyond the bounds of FM, including substitution for widespread pain in epidemiological studies. PMID- 21285162 TI - An analysis of connective tissue disease-associated interstitial lung disease at a US Tertiary Care Center: better survival in patients with systemic sclerosis. AB - OBJECTIVE: To compare survival of patients with connective tissue disease associated interstitial lung disease (CTD-ILD) versus idiopathic pulmonary fibrosis (IPF) and patients with systemic sclerosis-associated ILD (SSc-ILD) versus other CTD-ILD followed at our center. METHODS: We used the Stanford ILD database, which contains prospectively collected information on patients with ILD evaluated at our tertiary care center from 2002 to 2009. Survival at last followup from time of ILD diagnosis was calculated using the Kaplan-Meier estimator. Prognostic factors for survival in the overall cohort (IPF and CTD ILD) and in the CTD-ILD group were identified with univariate and multivariate Cox regression models. RESULTS: Of 427 patients with ILD, 148 (35%) had IPF and 76 (18%) had CTD-ILD at the baseline visit. The cumulative incidence of CTD was 4%. After a median followup of 4 years, 67 patients (36.4%) had died and 4 (2.2%) were lost to followup. Patients with IPF (n = 122) and CTD-ILD (n = 62) experienced similar survival rates (5-year survival about 50%). Patients with SSc ILD (n = 24) experienced better survival than those with other CTD-ILD (n = 38), with 1-year, 3-year, and 5-year survival rates of 100%, 90%, and 77%, respectively, versus 78%, 42%, and 38% (p = 0.01). The presence of SSc in patients with CTD-ILD decreased the risk of death by > 80% even after correcting for age at ILD diagnosis, sex, and ethnicity (HR = 0.17, 95% CI 0.04-0.83). CONCLUSION: Survival in patients with SSc-ILD was better than in patients with other CTD-ILD, potentially related to routine screening for and early detection of ILD in patients with SSc at our center. PMID- 21285163 TI - Evaluation of clinical measures and different criteria for diagnosis of adult onset Still's disease in a Chinese population. AB - OBJECTIVE: To determine the value of clinical measures in diagnosis of adult onset Still's disease (AOSD), and to identify the optimal set of proposed classification criteria, in a Chinese population. METHODS: A total of 70 patients with AOSD and 140 non-AOSD inpatients with fever were retrospectively identified at Zhongshan Hospital, Shanghai, from January 2003 to December 2009. Clinical measures and 4 sets of diagnostic criteria (Yamaguchi, Calabro, Cush, and Reginato) were evaluated by sensitivity, specificity, positive/negative predictive value (PPV, NPV), and positive/negative likelihood ratio (PLR, NLR) for diagnosis of AOSD. RESULTS: In our series, higher sensitivity included hyperpyrexia (temperature >= 39 degrees C, 94.29%), arthralgia (80.0%), polymorphonuclear neutrophils (PMN) >= 75% (84.29%), serum ferritin >= 2-fold the upper normal value (90.0%), negative antinuclear antibodies (85.29%), and rheumatoid factor (84.38%); while higher specificity included transient erythema (98.57%), sore throat (85.0%), leukocytes >= 15,000/mm(3) (87.86%), and PMN >= 85% (85.0%). Rash, arthralgia, and sore throat were found to have better sensitivity and specificity (PLR 3.29-4.86). Leukocytes >= 10,000/mm(3), PMN >= 80%, and serum ferritin >= 5-fold the upper normal limit were set as critical points. The Reginato criteria set had the highest specificity, 99.29%. The Yamaguchi set had the highest sensitivity, 78.57%, with a better accuracy of 87.14%. CONCLUSION: The Yamaguchi diagnostic criteria had better accuracy in Chinese patients. Indicators such as rash, arthralgia, sore throat, leukocytes >= 10,000/mm(3), PMN >= 80%, and serum ferritin >= 5-fold the upper normal limit were helpful for diagnosis of AOSD. We recommend using these indicators in combination instead of alone. PMID- 21285164 TI - Proteinase-activated receptor-2 gene disruption limits the effect of osteoarthritis on cartilage in mice: a novel target in joint degradation. AB - OBJECTIVE: Evidence indicates that proteinase-activated receptor (PAR)-2 participates in the degradative processes of human osteoarthritis (OA). We evaluated the in vivo effect of PAR-2 on articular lesions in a PAR-2-knockout (KO) mouse model of OA. METHODS: OA was surgically induced by destabilization of the medial meniscus of the right knee in C57Bl/6 wild-type (WT) and PAR-2 KO mice. Knee swelling was measured throughout the duration of the study (8 weeks postsurgery) and histologic evaluation of cartilage was done to assess structure, cellularity, matrix staining, and remodeling in the deep zone. Morphometric analysis of subchondral bone was also performed. RESULTS: Data showed significant knee swelling in the operated WT mice immediately following surgery, which increased with time (8 weeks post-surgery). Knee swelling was significantly lower (p <= 0.0001) in PAR-2 KO mice than in WT mice at both 4 and 8 weeks postsurgery. Cartilage damage was found in both operated WT and PAR-2 KO mice; however, lesions were significantly less severe (global score; p <= 0.05) in the PAR-2 KO mice at 4 weeks postsurgery. Operated WT mice showed reduced subchondral bone surface and trabecular thickness with significance reached at 4 weeks (p <= 0.03 and p <= 0.05, respectively), while PAR-2 KO mice demonstrated a gradual increase in subchondral bone surface with significance reached at 8 weeks (p <= 0.007). CONCLUSION: We demonstrated the in vivo implication of PAR-2 in the development of experimental OA, thus confirming its involvement in OA joint structural changes and reinforcing the therapeutic potential of a PAR-2 antagonist for treatment of OA. PMID- 21285165 TI - Evaluation of an inter-professional educational intervention to improve the use of arthritis best practices in primary care. AB - OBJECTIVE: To describe the evaluation of a community-based continuing health education program designed to improve the management of rheumatoid arthritis (RA) and osteoarthritis (OA), and to examine the results by discipline. METHODS: The Getting a Grip on Arthritis((c)) program was based on clinical practice guidelines adapted for the primary care environment (best practices). The program consisted of an accredited inter-professional workshop and 6 months of activities to reinforce the learning. Analyses compared best practice scores derived from responses to 3 standardized case scenarios (early and late RA; moderate knee OA) at baseline and 6 months post-workshop using the ACREU Primary Care Survey. RESULTS: In total, 553 primary care providers (nurses/licensed practical nurses 30.9%, rehabilitation professionals 22.5%, physicians 22.5%, nurse practitioners 10.9%, other healthcare providers/non-clinical staff/students 13.1%) attended one of 27 workshops across Canada; 275 (49.7%) completed followup surveys. Best practice scores varied by discipline at baseline (p < 0.05) and improved for all 3 case scenarios, with nurse practitioners and rehabilitation therapists improving the most (p <= 0.05). CONCLUSION: Results suggest that inter professional education may be an effective method for dissemination of guidelines and has potential to improve the delivery of arthritis care, particularly when nurse practitioners and rehabilitation therapists are involved in the care of patients. PMID- 21285166 TI - Role of rs1343151 IL23R and rs3790567 IL12RB2 polymorphisms in biopsy-proven giant cell arteritis. AB - OBJECTIVE: To assess the potential association between the rs1343151 IL23R and the rs3790567 IL12RB2 polymorphisms and giant cell arteritis (GCA). We also studied whether these polymorphisms might influence the phenotypic expression of GCA. METHODS: In total, 357 Spanish patients with biopsy-proven GCA and 574 matched controls were assessed. DNA from patients and controls was obtained from peripheral blood. Samples were genotyped for the rs1343151 IL23R and the rs3790567 IL12RB2 polymorphisms using a predesigned TaqMan allele discrimination assay and by polymerase chain reaction amplification. RESULTS: Regarding the rs1343151 IL23R polymorphism, no significant differences in the genotype or allele frequencies between GCA patients and healthy controls were observed. The frequency of the minor allele A of the rs3790567 IL12RB2 variant was increased in GCA patients compared with controls (30.1% vs 25.7%, respectively; p = 0.039, OR 1.25, 95% CI 1.01-1.54). An increased frequency of subjects carrying the minor allele A (GA+AA genotypes) of the rs3790567 IL12RB2 polymorphism was found among GCA patients compared with controls (52.8% vs 44.4%; p = 0.013, OR 1.40, 95% CI 1.06-1.85). Although a higher frequency of the combination of minor alleles (A-A) in the subgroup of patients with visual ischemic complications compared with the combination of both major alleles (G-G; p = 0.029) or with the other allelic combinations (p = 0.035) was found, logistic regression analysis showed that this association was no longer significant after adjustment for potential confounding factors (A-A vs G-G: OR 2.10, 95% CI 0.88-5.04, p = 0.096). CONCLUSION: Our results support a potential influence of the rs3790567 IL12RB2 polymorphism in the pathogenesis of GCA. PMID- 21285167 TI - Musculoskeletal ultrasonography in healthy subjects and ultrasound criteria for early arthritis (the ESPOIR cohort). AB - OBJECTIVE: To confirm the occurrence of bone erosions and synovitis in healthy subjects detectable by ultrasound (US) and to establish US criteria for early arthritis. METHODS: Our study involved 127 healthy subjects matched with a cohort of patients with early arthritis (the ESPOIR cohort). The second and fifth metacarpophalangeal (MCP) joints and the fifth metatarsophalangeal (MTP) joint of both hands and feet were assessed with US to detect bone erosion; and the second, third, fourth, and fifth MCP and the fifth MTP were evaluated for synovial thickening in B-mode US and synovial vascularity in power Doppler. Bone erosion and synovitis were defined according to the Outcome Measures in Rheumatology Clinical Trials consensus. RESULTS: Bone erosion and grade 2-3 synovial thickening in B-mode were detected in 11% and 9% of healthy subjects. To consider the diagnosis of early arthritis, a cutoff at 1 case of synovial thickening in B mode enabled discrimination between patients with early arthritis and healthy subjects, with a good sensitivity of 74.8% (95% CI 67.2%-82.3%) and a high specificity of 90.5% (95% CI 85.4%-95.6%). If higher specificity is required to confirm the diagnosis of early arthritis, cutoff at 2 cases of synovial thickening in B-mode or at 2 cases of bone erosion gave optimal results, with specificity of 98.4% (95% CI 96.2%-100%) and 100%, respectively, and lower sensitivity of 59.8% (95% CI 51.2%-68.3%) and 17% (95% CI 10.5%-23.5%) (area under the curve = 0.85 for synovitis and 0.63 for bone erosion). Neither the combination of power Doppler signal plus bone erosion, nor bone erosions plus synovial thickening on the same joint, were seen in healthy subjects. CONCLUSION: A single case of bone erosion or synovial thickening in B-mode is common in healthy subjects. However, more than 1 case of synovial thickening in B-mode or bone erosion is a strong argument for the diagnosis of early inflammatory arthritis. PMID- 21285168 TI - Do we need core sets of fibromyalgia domains? The assessment of fibromyalgia (and other rheumatic disorders) in clinical practice. AB - OBJECTIVE: An OMERACT consensus process recommended domains for investigation in fibromyalgia (FM) clinical trials. We used patient data to investigate variable importance in the determination of patient global and health-related quality of life (HRQOL) in FM and non-FM patients to determine whether variables were valued differently in FM compared with non-FM states. METHODS: We used ACR 2010 diagnostic FM criteria modified for epidemiological and clinical research to identify patients with rheumatoid arthritis (RA; N = 5884) with and without FM, and also characterized previously diagnosed patients with FM (N = 808) as to current criteria status. We measured variable importance by multivariable regression, decomposing regression variance by averaging over model orderings. We examined the distributions of key variables in the various disorders, and the distributions as a function of a FM severity index (fibromyalgianess). RESULTS: Out of 9 measures, pain, Health Assessment Questionnaire disability index, and fatigue explained more than 50% of explainable variance (50.49%-56.59%). Explained variance was similar across all disorders and diagnostic groups. In addition, the SF-36 physical component summary score varied across disorders as a function of fibromyalgianess. CONCLUSION: The main determinants of global severity and HRQOL in FM are pain, function, and fatigue. But these variables are also the main determinants in RA and other rheumatic diseases. The content and impact of FM, whether measured by discrete variables or a fibromyalgianess scale, seems to be independent of diagnosis. These data argue for a common set of variables rather than disease-specific variables. Clinical use is supported and enhanced by simple measures. PMID- 21285169 TI - Botulinum toxin for shoulder pain: a cochrane systematic review. AB - OBJECTIVE: To perform a Cochrane Systematic Review of benefits and harms of botulinum toxin for shoulder pain. METHODS: We included clinical trials of adults with shoulder pain (population), comparing botulinum toxin (intervention) to placebo or other therapies (comparison), and reporting benefits or harms (outcomes). We calculated relative risk (RR) for categorical outcomes and mean differences (MD) for continuous outcomes. RESULTS: Six randomized controlled trials (RCT) with 164 patients all comparing single botulinum toxin type A injections to placebo were included. Five RCT in patients with post-stroke shoulder pain found that an intramuscular injection of botulinum toxin type A significantly reduced pain at 3-6 months (MD -1.2 points on 0-10 scale, 95% CI 2.4 to -0.07) and improved shoulder external rotation at 1 month (MD 9.8 degrees , 95% CI 0.2 degrees to 19.4 degrees ). Number of adverse events did not differ between groups (RR 1.46, 95% CI 0.6 to 24.3). One RCT in arthritis-related shoulder pain showed that single intraarticular botulinum toxin type A injection reduced pain (MD -2.0 on 0-10 scale, 95% CI -3.7 to -0.3) and shoulder disability (MD -13.4 on 0-100 scale, 95% CI -24.9 to -1.9) and improved shoulder abduction (MD 13.8 degrees , 95% CI 3.2 degrees to 44.0 degrees ) at 1 month, compared with placebo. Serious adverse events did not differ between groups (RR 0.35, 95% CI 0.11, 1.12). CONCLUSION: With evidence from few studies with small sample sizes and medium to high risk of bias, botulinum toxin type A injections decreased pain and improved shoulder function in patients with chronic shoulder pain due to spastic hemiplegia or arthritis. PMID- 21285170 TI - Predictors of hip disease in the systemic arthritis subtype of juvenile idiopathic arthritis. AB - OBJECTIVE: Hip involvement occurs in 20%-40% of all cases of juvenile idiopathic arthritis (JIA). Patients with systemic JIA (sJIA) are affected most frequently. The aim of our study was to investigate the predictors of clinical hip disease and radiographic hip damage in sJIA. METHODS: The medical records (1997-2007) of all children (n = 98) with sJIA were reviewed. Potential clinical and laboratory predictors were examined at presentation and at 3 and 6 months. To account for censored observations, we used survival analysis. RESULTS: During the study period, 59 children met our inclusion criteria. The mean age at diagnosis was 7.8 years. Thirty patients (51%) developed clinical hip disease, with 12 (20%) developing radiographic evidence of hip damage. The median time to develop clinical hip disease was 24 months. Using Kaplan-Meier estimates, 25% of patients develop radiographically evident hip damage within 43 months. At presentation, patients in whom clinical hip disease later developed had polyarthritis (hazard ratio 2.51, p = 0.01), elevated IgG (HR 1.12, p = 0.01) and IgM (HR 2.71, p = 0.02), and higher CHAQ scores (HR 1.65, p = 0.02). At 3 months after disease onset, patients in whom radiographic hip damage later developed had fever (HR 4.78, p = 0.02), polyarthritis (HR 4.63, p = 0.02), and higher CHAQ scores (HR 3.20, p = 0.005). At 6 months, polyarthritis was the strongest predictor of both clinical hip disease and radiographic hip damage. CONCLUSION: Half of patients with sJIA develop clinical hip disease a median time of 24 months from diagnosis. Early identification of predictors of hip disease and damage in patients with sJIA may suggest earlier, more aggressive interventions to prevent joint destruction. PMID- 21285171 TI - Clinical consequences of delayed addition of adalimumab to methotrexate therapy over 5 years in patients with rheumatoid arthritis. AB - OBJECTIVE: This Year 5 analysis of an open-label extension (OLE) study assessed radiographic progression, clinical efficacy, and safety of adalimumab with concomitant methotrexate (MTX) for patients with active rheumatoid arthritis. METHODS: In a double-blind study (DE019, NCT00195702), inadequate responders to MTX were randomized to MTX plus either adalimumab 40 mg eow, adalimumab 20 mg weekly, or placebo for 52 weeks. Eligible patients entered an ongoing OLE and received adalimumab 40 mg eow plus MTX. Longterm efficacy and safety were evaluated. RESULTS: Of 457 patients who had enrolled in the OLE, 304 remained in the study at Year 5, including 112, 107, and 85 from the original adalimumab 40 mg, adalimumab 20 mg, and placebo groups, respectively. Year 5 radiographs demonstrated mean changes in modified total Sharp score for the original adalimumab 40 mg eow and 20 mg weekly groups of 0.8 and 2.6, respectively, versus 3.9 for placebo; 58% from the adalimumab 40 mg eow group had no radiographic progression versus 40% of those who initially received placebo. Of patients who received adalimumab 40 mg eow for 5 years, 26.1% achieved clinical remission (Disease Activity Score 28-joint count < 2.6), had no radio graphic progression (change in modified total Sharp score <= 0.5), and had normal function (Health Assessment Questionnaire <= 0.5), versus 11.9% of those who initially received placebo. Serious infection rate for 553 patients who received at least one dose of adalimumab was 4.4/100 patient-years. CONCLUSION: A 52-week delay in adding adalimumab to MTX led to worse radiographic, functional, and clinical outcomes at Year 5 for most patients who initially received placebo instead of adalimumab. PMID- 21285172 TI - Positive correlation between Beta-3-Adrenergic Receptor (ADRB3) gene and gout in a Chinese male population. AB - OBJECTIVE: The common polymorphism rs4994 [c. T387C, p. Trp64Arg (W64R)] of the lipolysis regulator beta-3-adrenergic receptor (ADRB3) was identified as a marker in the pathogenesis of hyperuricemia. As gout is characterized by elevated serum concentrations of uric acid, we investigated ADRB3 as a potential candidate for gout. METHODS: This was a prospective case-control study in a group of 421 male patients with gout and 312 gout-free male controls to genotype the single nucleotide polymorphism rs4994 of ADRB3 gene. RESULTS: Our results showed that the C allele carrier confers a significantly higher risk for development of gout [chi-square = 4.91, df = 1, p = 0.027, OR 1.95 (adjusted by age, total cholesterol level, and body mass index), 95% CI 1.22-3.13 by dominant mode]. There was significantly higher uric acid level in carriers of the Arg64/Arg64 genotype in controls compared to non-carriers (480.5 mmol/l vs 315.0 mmol/l, respectively). CONCLUSION: ADRB3 rs4994 polymorphism is a potential candidate for the pathogenesis of gout in a male Chinese population. PMID- 21285173 TI - Pharmacokinetic and pharmacodynamic interaction between allopurinol and probenecid in patients with gout. AB - OBJECTIVE: To investigate the pharmacokinetic and pharmacodynamic interaction between probenecid and oxypurinol (the active metabolite of allopurinol) in patients with gout. METHODS: This was an open-label observational clinical study. Blood and urine samples were collected to measure oxypurinol and urate concentrations. We examined the effects of adding probenecid to allopurinol therapy upon plasma concentrations and renal clearances of urate and oxypurinol. RESULTS: Twenty patients taking allopurinol 100-400 mg daily completed the study. Maximum coadministered doses of probenecid were 250 mg/day (n = 1), 500 mg/day (n = 19), 1000 mg/day (n = 7), 1500 mg/day (n = 3), and 2000 mg/day (n = 1). All doses except the 250 mg daily dose were divided and dosing was twice daily. Estimated creatinine clearances ranged from 28 to 113 ml/min. Addition of probenecid 500 mg/day to allopurinol therapy decreased plasma urate concentrations by 25%, from mean 0.37 mmol/l (95% CI 0.33-0.41) to mean 0.28 mmol/l (95% CI 0.24-0.32) (p < 0.001); and increased renal urate clearance by 62%, from mean 6.0 ml/min (95% CI 4.5-7.5) to mean 9.6 ml/min (95% CI 6.9-12.3) (p < 0.001). Average steady-state plasma oxypurinol concentrations decreased by 26%, from mean 11.1 mg/l (95% CI 5.0-17.3) to mean 8.2 mg/l (95% CI 4.0-12.4) (p < 0.001); and renal oxypurinol clearance increased by 24%, from mean 12.7 ml/min (95% CI 9.6-15.8) to mean 16.1 ml/min (95% CI 12.0-20.2) (p < 0.05). The additional hypouricemic effect of probenecid 500 mg/day appeared to be lower in patients with renal impairment. CONCLUSION: Coadministration of allopurinol with probenecid had a significantly greater hypouricemic effect than allopurinol alone despite an associated reduction of plasma oxypurinol concentrations. Australian Clinical Trials Registry ACTRN012606000276550. PMID- 21285174 TI - The effect of medication-related support on the quality of life of patients with vasculitis in relapse and remission. AB - OBJECTIVE: Few studies have investigated whether the utility of social support for patients with a relapsing, remitting illness varies by activity level of the disease. Our goal was to determine whether disease status (relapse vs remission) moderates the effect of medication-related support from physicians and partners on the health-related quality of life (HRQOL) of patients with vasculitis. METHODS: Patients with vasculitis (n = 228) completed baseline measures of disease status and medication-related support and a 3-month followup measure of HRQOL (RAND 36-item health survey 1.0). We calculated 8 HRQOL dimensions: physical functioning, physical role limitations, bodily pain, general health, vitality, social functioning, emotional role limitations, and mental health. Bonferroni-corrected t tests compared the HRQOL of patients in relapse to patients in remission, and multivariate analysis of covariance determined whether disease status moderated the effect of medication-related support from physicians and partners on patient HRQOL. Wilks' lambda assessed whether the support-by disease status interaction terms were significant. RESULTS: Relapsing patients reported significantly worse quality of life compared with nonrelapsing patients for every HRQOL dimension except physical role limitations. Disease status did not moderate the effect of physician (lambda = 0.48; p = 0.86) or partner (lambda = 1.51; p = 0.16) medication-related support on HRQOL, although greater physician and partner support predicted better HRQOL for all dimensions except bodily pain and vitality. CONCLUSION: Vasculitis patients experience compromised HRQOL but the magnitude of the compromise is greater for patients experiencing a relapse. Medication-related support from physicians and partners is beneficial for patients' HRQOL regardless of disease status. PMID- 21285175 TI - Relationship between cardiac valvular and arterial calcification in patients with rheumatoid arthritis and systemic lupus erythematosus. AB - OBJECTIVE: Cardiac valvular calcification has been linked with systemic atherosclerosis in the general population. The prevalence and relationship with arterial calcification in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) is unknown. We investigated the prevalence of valvular calcification in patients with RA and SLE and its relationship with arterial atherosclerotic calcification. METHODS: We compared aortic valve calcification (AVC), mitral valve calcification (MVC), and systemic vascular bed calcification using multidetector computed tomography in 110 patients (mean age 46.5 +/- 9.4 yrs, 97 women) with RA (n = 58) or SLE (n = 52) and 60 age and sex-matched healthy controls. RESULTS: Patients with RA and SLE, combined, had significantly higher prevalence of AVC (21.8% vs 3.3% in controls; p < 0.01), MVC (19.1% vs 0% in controls; p < 0.01), and arterial calcification in different vascular beds (all p < 0.05). AVC was not associated with any specific clinical characteristics, but MVC was associated with older age, hypertension, C-reactive protein level, and duration of disease. The presence of MVC was independently associated with coronary calcification and calcification in any vascular bed upon adjustment with clinical measures. CONCLUSION: Our study demonstrated that cardiac valvular calcification is more prevalent in patients with RA and SLE compared with healthy controls. The presence of MVC, but not AVC, independently predicted the occurrence of premature atherosclerosis with arterial calcification in patients with RA and SLE. PMID- 21285176 TI - Aspirin: antiinflammatory drug of choice in 2011? PMID- 21285177 TI - Breaking into a sweat... and risk of osteoarthritis! PMID- 21285178 TI - The impact triad (severity, importance, self-management) as a method of enhancing measurement of personal life impact of rheumatic diseases. PMID- 21285179 TI - Ultrasound-guided diagnostic and therapeutic approach to Retrocalcaneal Bursitis. PMID- 21285180 TI - Lupus, "rhupus" and "sjrupus". PMID- 21285181 TI - Autoantibody to PL-12 (Anti-Alanyl-tRNA synthetase) in an African American girl with juvenile dermatomyositis and resolution of interstitial lung disease. PMID- 21285182 TI - Hypocomplementemia associated with macrophage activation syndrome in systemic juvenile idiopathic arthritis and adult onset still's disease: 3 cases. PMID- 21285183 TI - Rapidly fatal pulmonary fibrosis in a patient with psoriatic arthritis treated with adalimumab. PMID- 21285184 TI - Ophthalmic herpes zoster infection in patients with rheumatoid arthritis who were treated with tocilizumab. PMID- 21285185 TI - The assessment and management of rectal prolapse, rectal intussusception, rectocoele, and enterocoele in adults. PMID- 21285186 TI - Definitely not acceptable: drug company sues journal over review. PMID- 21285187 TI - MEPs criticise WHO over H1N1 pandemic advice. PMID- 21285188 TI - Germany pushes for more organ donation. PMID- 21285189 TI - Bad medicine: cardiology. PMID- 21285190 TI - One billion people are affected by global shortage of healthcare workers. PMID- 21285191 TI - The ethics of impact factors. PMID- 21285192 TI - Is there an Indian nursing ethics? PMID- 21285193 TI - Clinical ethical conflicts of nurses and physicians. AB - Much of the literature on clinical ethical conflict has been specific to a specialty area or a particular patient group, as well as to a single profession. This study identifies themes of hospital nurses' and physicians' clinical ethical conflicts that cut across the spectrum of clinical specialty areas, and compares the themes identified by nurses with those identified by physicians. We interviewed 34 clinical nurses, 10 nurse managers and 31 physicians working at four different Canadian hospitals as part of a larger study on clinical ethics committees and nurses' and physicians' use of these committees. We describe nine themes of clinical ethical conflict that were common to both hospital nurses and physicians, and three themes that were specific to physicians. Following this, we suggest reasons for differences in nurses' and physicians' ethical conflicts and discuss implications for practice and research. PMID- 21285194 TI - Relational and embodied knowing: nursing ethics within the interprofessional team. AB - In this article we attempt to situate nursing within the interprofessional care team with respect to processes of ethical practice and ethical decision making. After briefly reviewing the concept of interprofessionalism, the idea of a nursing ethic as 'unique' within the context of an interprofessional team will be explored. We suggest that nursing's distinct perspective on the moral matters of health care stem not from any privileged vantage point but rather from knowledge developed through the daily activities of nursing practice. Because of their position vis-a-vis patients and families in everyday clinical care, nurses cultivate ethical knowledge of at least two forms: (1) relational knowledge; and (2) embodied knowledge. Through the integration of these forms of knowledge, nurses develop a unique moral perspective and can make a meaningful contribution to the realm of ethics in interprofessional care. PMID- 21285195 TI - The meaning of vulnerability to nurses caring for older people. AB - Research concerning work on caring for older people shows that care providers experience a variety of consuming emotions and stress. They can be said to be in a vulnerable position. It is not known, however, how the care providers themselves understand vulnerability. The aim of this study was to illuminate the meaning of vulnerability to care providers caring for older people. A qualitative interpretive approach was adopted. Data were collected through tape-recorded interviews with 16 female registered and practical nurses who were experienced in caring for older people. Qualitative analysis resulted in one core theme and six themes with subthemes. The core theme showed that, for the participating nurses, vulnerability essentially meant being human. The meanings of being human were illustrated by the six themes: having feelings; experiencing moral indignation; being harmed; having courage; protecting oneself; and maturing and developing. Analysis showed that vulnerability was a resource as well as a burden. PMID- 21285196 TI - Staff and family relationships in end-of-life nursing home care. AB - This article examines the involvement of residents and their relatives in end-of life decisions and care in Norwegian nursing homes. It also explores challenges in these staff-family relationships. The article is based on a nationwide survey examining Norwegian nursing homes' end-of-life care at ward level. Only a minority of the participant Norwegian nursing home wards 'usually' explore residents' preferences for care and treatment at the end of their life, and few have written procedures on the involvement of family caregivers when their relative is in the terminal phase. According to the respondents, most staff seem to comfort relatives well. However, several challenges were described. The study revealed a need for better procedures in the involvement of residents and relatives in nursing home end-of-life care. The findings emphasize a need to strengthen both the involvement of nursing home physicians and staff communication skills. PMID- 21285197 TI - Being a good nurse and doing the right thing: a replication study. AB - This qualitative research study, a replication of a study published in 2002, investigated the qualities of a good nurse and the role ethics plays in decision making. After reviewing the limitations of the published work, the current study implemented modifications related to the research questions, sample selection, data collection, and use of software for data analysis. The original study identified seven categories that related to being a good nurse and doing the right thing. In the present study, the use of relational analysis led to the recognition of four categories: (1) personal traits and attributes; (2) technical skills and management of care; (3) work environment and co-workers; and (4) caring and caring behaviors. To understand what it means to be a good nurse and do the right thing is a complex task; however, this research adds to the small amount of empirical data that exists to describe those characteristics. PMID- 21285198 TI - Violation of ethical principles in institutional care for older people. AB - This study focuses on issues of elder abuse in residential settings. Violation of ethical principles is shown in the results of this quantitative study aimed at defining the extent, nature and causes of such abuse by employees' unethical conduct towards clients in senior homes (i.e. residential nursing homes) in the Moravian-Silesian region of the Czech Republic. The research sample comprised 454 employees and 488 clients from 12 residential homes for older people. The data were collected from interviews with clients, who also received a questionnaire concerning their satisfaction with the institution. Two questionnaires were administered to the employees, one based on a pilot qualitative study and a second to investigate burnout. Outcomes were assessed according to the extent and form of elder abuse, the causes of elder abuse and the violation of basic ethical principles. The responses, in particular those of employees, revealed both psychological and physical abuse of older clients, and thus violation of two basic principles: respect for the person and non-maleficence. The group at risk of elder abuse comprised aggressive and dissatisfied clients, as well as those with mental problems and dementia. The employees most at risk of being abusers were those who had been employed in institutional care for more than five years, had inadequate knowledge about social services and suffered from burnout. The prevention of elder abuse is recommended to be through education focused on ethical principles, increasing employees' satisfaction by promoting a friendly and safe organizational culture, and providing adequate working conditions. PMID- 21285199 TI - Can supervising self-harm be part of ethical nursing practice? AB - It was reported in 2006 that a regime of 'supervised self harm' had been implemented at St George's Hospital, Stafford. This involves patients with a history of self-harming behaviour being offered both emotional and practical support to enable them to do so. This support can extend to the provision of knives or razors to enable them to self-harm while they are being supervised by a nurse. This article discusses, and evaluates from an ethical perspective, three competing responses to self-harming behaviours: to prevent it; to allow it; and to make provision for supervised self-harm. It is argued that of these three options the prevention strategy is the least plausible. A tentative conclusion is offered in support of supervised self-harm. PMID- 21285200 TI - Theory of protective empowering for balancing patient safety and choices. AB - Registered nurses in psychiatric-mental health nursing continuously balance the ethical principles of duty to do good (beneficence) and no harm (non-maleficence) with the duty to respect patient choices (autonomy). However, the problem of nurses' level of control versus patients' choices remains a challenge. The aim of this article is to discuss how nurses accomplish their simultaneous responsibility for balancing patient safety (beneficence and non-maleficence) with patient choices (autonomy) through the theory of protective empowering. This is done by reflecting on interview excerpts about caring from 17 registered nurses taking part in a grounded theory study conducted in three acute urban psychiatric hospital settings in Canada. The interplay between the protective and empowering dimensions of the theory of protective empowering was found to correspond with international, national, and local nursing codes of ethics and standards. The overall core process of protective empowering, and its associated reflective questions, is offered as a new lens for balancing patient safety with choices. PMID- 21285201 TI - Moral imagination in simulation-based communication skills training. AB - Clinical simulation is used in nursing education and in other health professional programs to prepare students for future clinical practice. Simulation can be used to teach students communication skills and how to deliver bad news to patients and families. However, skilled communication in clinical practice requires students to move beyond simply learning superficial communication techniques and behaviors. This article presents an unexplored concept in the simulation literature: the exercise of moral imagination by the health professional student. Drawing from the works of Hume, Aristotle and Gadamer, a conceptualization of moral imagination is first provided. Next, this article argues that students must exercise moral imagination on two levels: towards the direct communication exchange before them; and to the representative nature of simulation encounters. Last, the limits of moral imagination in simulation-based education are discussed. PMID- 21285202 TI - An embodied response: ethics and the nurse researcher. AB - The aim of this study is to reflect on situational ethics in qualitative research and on a researcher's embodied response to ethical dilemmas. Four narratives are presented. They are excerpts from field notes taken during an observational study on Norwegian public health nursing practice. The stories capture situational ethical challenges the author experienced during her research. The author's reflections on feelings of uncertainty, discomfort and responsibility, and Levinas' philosophy help to illuminate the ethical challenges faced. The study shows that the researcher always participates, to some degree, and is never merely a spectator making solely rational choices. Ethical challenges in field research cannot always be solved, yet must be acknowledged. Feelings of vulnerability are embodied responses that remind us of the primacy of ethics. More so, it is the primacy of ethics that gives rise to feelings of vulnerability and embodied responses. PMID- 21285203 TI - Is it appropriate for research ethics committees to make judgements about the scientific quality of research proposals?. PMID- 21285204 TI - Is managed care an oxymoron? PMID- 21285206 TI - Report: 11th International ICNE conference: Clinical ethics across the lifespan, 13-14 September 2010. PMID- 21285208 TI - Editorial Board member, Ebin Arries, interviewed by Ann Gallagher. PMID- 21285209 TI - NHS drug budget. Flawed assumption in analysis. PMID- 21285210 TI - Out of hospital cardiac arrest. Time for a national register. PMID- 21285217 TI - Infective endocarditis. NICE calls for a register. PMID- 21285218 TI - Access to clinical trial data. Data monitoring committees and selective outcome reporting. PMID- 21285219 TI - Reduced access to database. A publicly available database accelerates academic production. PMID- 21285220 TI - Flu questions and answers. Flu's impact on intensive care. PMID- 21285221 TI - Research approval. The regulation killing health research in the UK. PMID- 21285224 TI - Florida judge says entire health reform act is unconstitutional. PMID- 21285225 TI - Gates and Cameron pledge new money to eradicate polio. PMID- 21285226 TI - MPs support NHS reform as health bill passes first parliament debate. PMID- 21285227 TI - Monitoring head size and growth using the new UK-WHO growth standard. AB - In order to assess the extent to which children in the UK will follow the UK-WHO head circumference standard, the authors used head circumference data from the Southampton Women's Survey (n=3159) and the Avon Longitudinal Study of Parents and Children (n=15 208) in children aged 0-36 months, converted into z-scores using both the UK-WHO and UK1990 references. Rapid head growth was defined as crossing upwards through two major centile bands (1.33 SD). The UK-WHO standard identified many more infants with heads above the 98th centile than to the UK1990 reference (UK-WHO: 6-16% of infants at various ages; UK1990: 1-4%). Rapid head growth in the first 6-9 months was also much more common using the UK-WHO standard (UK-WHO: 14.6-15.3%; UK1990: 4.8-5.1%). Practitioners should be aware of these findings to avoid unnecessary referrals. PMID- 21285228 TI - 'Lest we forget...'. PMID- 21285229 TI - Weekly iron supplementation for the prevention of anemia in pre-school children: a randomized, double-blind, placebo-controlled trial. AB - OBJECTIVE: This study analyses the impact of weekly iron supplementation with ferrous sulphate heptahydrate (FeSO4) in 5-year-olds compared with placebo, on hemoglobin (Hb) and hematocrit (Ht) values and anemia. DESIGN: The study concerns a cluster-randomized, placebo-controlled double-blind trial. Intervention participants received 50 mg elemental iron for 14 weeks. SETTING: The study population comprised pre-school children (n = 135) from one randomly chosen public school in the northeast of Brazil. SUBJECTS: Participants were 5-year-old students from a public school. RESULTS: Mean Hb and Ht values increased after iron supplementation, with p < 0.0001. There was no statistically significant increase in the placebo group. After intervention, anemia prevalence reduced only in the intervention group, from 48.0% to 26.0%. CONCLUSIONS: Weekly iron supplementation was effective in reducing anemia in 5-year-olds. PMID- 21285230 TI - Biological mechanisms of chronic fatigue. AB - Chronic fatigue is a common, poorly understood and disabling phenomenon in many diseases. We aim to provide an overview of fatigue in chronic autoimmune and inflammatory disease. Fatigue measurement, prevalence and confounding factors such as depression, sleep disorders and pain are reviewed in the first half of the article. In the second half of the article, we describe explanatory models of fatigue and fatigue signalling, with an emphasis on cytokines and sickness behaviour, oxidative stress, mitochondrial dysfunction and the impact of certain genes on fatigue. PMID- 21285231 TI - The outcome of brittle type 1 diabetes--a 20 year study. AB - AIMS: To determine the long-term (20 years from presentation) outcome of brittle type 1 diabetes characterized by recurrent episodes of ketoacidosis (DKA). METHODS: The cohort studied was a group of brittle diabetic patients from various parts of UK originally identified between 1979 and 1985. Patients were traced, where possible, via their diabetic clinics and/or general practitioners. Data on survival or otherwise were obtained from hospital case notes and information from diabetes care team members. For survivors, clinical and demographic information obtained included complication status and whether they still had brittle characteristics. They were also compared with a matched case-control group of type 1 patients with no history of brittle behaviour. RESULTS: The original cohort comprised 33 patients- all female and mean +/- SD, aged 18 +/- 5 years and diabetes duration 8 +/- 4 years. Thirteen were not traceable and 10 of the remaining 20 (50%) had died during the mean 22 years of follow-up. Deaths occurred evenly throughout the period, and causes were chronic renal failure (3), DKA (3), hypoglycaemia (2), subarachnoid haemorrhage (1) and uncertain (1). Age at death ranged from 27 to 45 years. Of the 10 survivors, none remained brittle, but they had a substantial burden of complications. Compared with the non-brittle control group, there was a significant excess of nephropathy and autonomic neuropathy. CONCLUSION: We conclude that brittle diabetes characterized by recurrent DKA has high long-term outcome mortality. These deaths were premature and almost all diabetes related. Those who survived had resolution of brittleness, but suffered a significant complication burden. PMID- 21285232 TI - Lipidomic analyses of Mycobacterium tuberculosis based on accurate mass measurements and the novel "Mtb LipidDB". AB - The cellular envelope of Mycobacterium tuberculosis is highly distinctive and harbors a wealth of unique lipids possessing diverse structural and biological properties. However, the ability to conduct global analyses on the full complement of M. tuberculosis lipids has been missing from the repertoire of tools applied to the study of this important pathogen. We have established methods to detect and identify lipids from all major M. tuberculosis lipid classes through LC/MS lipid profiling. This methodology is based on efficient chromatographic separation and automated ion identification through accurate mass determination and searching of a newly created database (Mtb LipidDB) that contains 2,512 lipid entities. We demonstrate the sensitive detection of molecules representing all known classes of M. tuberculosis lipids from a single crude extract. We also demonstrate the ability of this methodology to identify changes in lipid content in response to cellular growth phases. This work provides a customizable framework and resource to facilitate future studies on mycobacterial lipid biosynthesis and metabolism. PMID- 21285234 TI - Intrinsic tendon healing requires the recycling of tendon collagen fibril segments. PMID- 21285235 TI - Periungual pilonidal sinus. PMID- 21285236 TI - Fracture of the proximal phalanx pyrocarbon implant after metacarpophalangeal arthroplasty. PMID- 21285237 TI - Revision of failed Sauve-Kapandji procedure for Madelung's deformity with an unusual anatomical variant. PMID- 21285238 TI - A congenital dislocation of the trapeziometacarpal joint. PMID- 21285239 TI - Long term follow-up of open realignment procedure for congenital dislocation of the radial head. PMID- 21285240 TI - Anomaly of the flexor digitorum superficialis in the ring finger causing difficulty in tendon grafting. PMID- 21285242 TI - The use of formalin fixed wax embedded tissue for proteomic analysis. AB - The potential of proteomic approaches to elucidate disease pathogenesis and biomarker discovery is increasingly being recognised. These studies are usually based on the use of fresh tissue samples. Problems in obtaining and storing fresh frozen samples, especially either for the investigation of rare diseases or for the study of microscopic disease foci, have led to the investigation of the possible use of formalin fixed wax embedded tissue for proteomic biomarker detection Overcoming problems with protein cross-linking associated with formalin fixation of tissues, especially by using heat-mediated retrieval techniques combined with highly sensitive methods for protein separation and identification are now emerging, giving promise to the use of formalin fixed wax embedded tissues for proteomic analysis. Formalin fixed wax embedded tissues, together with their associated clinical and pathological information outcome may provide significant potential opportunities for proteomics research. Such studies of formalin fixed wax embedded tissue will allow access to already acquired clinical tissue samples which can be readily correlated with clinical, pathological and outcome data. It also provides access to rare types of tissue/diseases that would be either difficult to collect prospectively in a timely manner or are unlikely to be available as fresh samples. The purpose of this review is to provide an overview of the issues associated with the use of formalin fixed wax embedded tissues for proteomics. PMID- 21285243 TI - Stability of measured and modelled spatial contrasts in NO(2) over time. AB - OBJECTIVES: Land use regression (LUR) modelling is a popular method to estimate outdoor air pollution concentrations at the home and/or work addresses of individual subjects in epidemiological studies. Typically, such models are constructed using measurements from dedicated monitoring campaigns lasting up to 1 year. It is unknown to what extent such models can adequately predict concentrations in earlier or later time periods. We tested the stability of measured and modelled spatial contrasts in outdoor nitrogen dioxide (NO(2)) pollution across the Netherlands over 8 years. METHODS: NO(2) measurements were conducted at 40 locations in the Netherlands in 1999-2000. In 2007, NO(2) was again measured at 144 locations, of which 35 were the same as in 1999-2000. This enabled us to compare measurements as well as model predictions between the two time periods. RESULTS: NO(2) measurements conducted in 2007 agreed well with NO(2) measurements taken in 1999-2000 at the same locations (R(2)=0.86). LUR models from 1999-2000 and 2007 explained 85% and 86% of observed spatial variance, respectively. The 2007 LUR model explained 77% of spatial variability in the 1999-2000 measurements and the 1999-2000 model explained 81% of variability in the 2007 measurements. CONCLUSION: We found good agreement between measured spatial contrasts in outdoor NO(2) in 1999-2000 and 2007. LUR models predicted spatial contrast 8 years in the past (2007 model) and 8 years in the future (1999-2000 model) well. This supports the use of LUR models in epidemiological studies with health data available for a later or earlier timepoint. PMID- 21285244 TI - Neural respiratory drive, pulmonary mechanics and breathlessness in patients with cystic fibrosis. AB - BACKGROUND: Neural respiratory drive (NRD) measured from the diaphragm electromyogram (EMGdi) reflects the load/capacity balance of the respiratory muscle pump and is a marker of lung disease severity. EMGdi measurement is invasive, but recording the EMG from the parasternal intercostal muscles using surface electrodes (sEMGpara) could provide a non-invasive method of assessing NRD and disease severity. Objectives To test the hypothesis that NRD measured by sEMGpara correlates with EMGdi, to provide an index of disease severity in cystic fibrosis (CF) and to relate to exercise-induced breathlessness. METHODS: 15 patients with CF (mean forced expiratory volume in 1 s (FEV(1)) 53.5% predicted) and 15 age-matched healthy controls were studied. sEMGpara and EMGdi were recorded at rest and during exercise. sEMGpara was recorded using surface electrodes and EMGdi using a multipair oesophageal electrode catheter. Signals were normalised using the peak EMG recorded during maximum respiratory manoeuvres and expressed as EMG%max. The respiratory pattern, metabolic data, oesophageal and gastric pressures and Borg scores were also recorded. RESULTS: Mean (SD) resting sEMGpara%max and EMGdi%max were higher in patients with CF than in controls (13.1 (7)% and 18.5 (7.5)% vs 5.8 (3)% and 7.5 (2)%, respectively, p<0.001). In the patients with CF, resting sEMGpara%max and EMGdi%max were related to the degree of airways obstruction (FEV(1)) (r = -0.91 and r = -0.82, both p<0.001), hyperinflation (r = 0.63 and r = 0.56, both p<0.001) and dynamic lung compliance (r = -0.53 and r = -0.59, both p<0.001). During exercise, sEMGpara%max and EMGdi%max were strongly correlated with breathlessness in the patients with CF before (r = 0.906, p<0.001) and after (r = 0.975, p<0.001) the onset of neuromechanical dissociation. CONCLUSION: sEMGpara%max provides a non invasive marker of neural drive, which reflects disease severity and exercise induced breathlessness in CF. PMID- 21285245 TI - Localization of retinitis pigmentosa 2 to cilia is regulated by Importin beta2. AB - Ciliopathies represent a newly emerging group of human diseases that share a common etiology resulting from dysfunction of the cilium or centrosome. The gene encoding the retinitis pigmentosa 2 protein (RP2) is mutated in X-linked retinitis pigmentosa. RP2 localizes to the ciliary base and this requires the dual acylation of the N-terminus, but the precise mechanism by which RP2 is trafficked to the cilia is unknown. Here we have characterized an interaction between RP2 and Importin beta2 (transportin-1), a member of the Importin-beta family that regulates nuclear-cytoplasmic shuttling. We demonstrate that Importin beta2 is necessary for localization of RP2 to the primary cilium because ablation of Importin beta2 by shRNA blocks entry both of endogenous and exogenous RP2 to the cilium. Furthermore, we identify two distinct binding sites of RP2, which interact independently with Importin beta2. One binding site is a nuclear localization signal (NLS)-like sequence that is located at the N-terminus of RP2 and the other is an M9-like sequence within the tubulin folding cofactor C (TBCC) domain. Mutation of the NLS-like consensus sequence did not abolish localization of RP2 to cilia, suggesting that the sequence is not essential for RP2 ciliary targeting. Interestingly, we found that several missense mutations that cause human disease fall within the M9-like sequence of RP2 and these mutations block entry of RP2 into the cilium, as well as its interaction with Importin beta2. Together, this work further highlights a role of Importin beta2 in regulation of the entry of RP2 and other proteins into the ciliary compartment. PMID- 21285246 TI - Drosophila UNC-45 accumulates in embryonic blastoderm and in muscles, and is essential for muscle myosin stability. AB - UNC-45 is a chaperone that facilitates folding of myosin motor domains. We have used Drosophila melanogaster to investigate the role of UNC-45 in muscle development and function. Drosophila UNC-45 (dUNC-45) is expressed at all developmental stages. It colocalizes with non-muscle myosin in embryonic blastoderm of 2-hour-old embryos. At 14 hours, it accumulates most strongly in embryonic striated muscles, similarly to muscle myosin. dUNC-45 localizes to the Z-discs of sarcomeres in third instar larval body-wall muscles. We produced a dunc-45 mutant in which zygotic expression is disrupted. This results in nearly undetectable dUNC-45 levels in maturing embryos as well as late embryonic lethality. Muscle myosin accumulation is robust in dunc-45 mutant embryos at 14 hours. However, myosin is dramatically decreased in the body-wall muscles of 22 hour-old mutant embryos. Furthermore, electron microscopy showed only a few thick filaments and irregular thick-thin filament lattice spacing. The lethality, defective protein accumulation, and ultrastructural abnormalities are rescued with a wild-type dunc-45 transgene, indicating that the mutant phenotypes arise from the dUNC-45 deficiency. Overall, our data indicate that dUNC-45 is important for myosin accumulation and muscle function. Furthermore, our results suggest that dUNC-45 acts post-translationally for proper myosin folding and maturation. PMID- 21285247 TI - PERP regulates enamel formation via effects on cell-cell adhesion and gene expression. AB - Little is known about the role of cell-cell adhesion in the development of mineralized tissues. Here we report that PERP, a tetraspan membrane protein essential for epithelial integrity, regulates enamel formation. PERP is necessary for proper cell attachment and gene expression during tooth development, and its expression is controlled by P63, a master regulator of stratified epithelial development. During enamel formation, PERP is localized to the interface between the enamel-producing ameloblasts and the stratum intermedium (SI), a layer of cells subjacent to the ameloblasts. Perp-null mice display dramatic enamel defects, which are caused, in part, by the detachment of ameloblasts from the SI. Microarray analysis comparing gene expression in teeth of wild-type and Perp-null mice identified several differentially expressed genes during enamel formation. Analysis of these genes in ameloblast-derived LS8 cells upon knockdown of PERP confirmed the role for PERP in the regulation of gene expression. Together, our data show that PERP is necessary for the integrity of the ameloblast-SI interface and that a lack of Perp causes downregulation of genes that are required for proper enamel formation. PMID- 21285248 TI - Phenotypic analysis of misato function reveals roles of noncentrosomal microtubules in Drosophila spindle formation. AB - Mitotic spindle assembly in centrosome-containing cells relies on two main microtubule (MT) nucleation pathways, one based on centrosomes and the other on chromosomes. However, the relative role of these pathways is not well defined. In Drosophila, mutants without centrosomes can form functional anastral spindles and survive to adulthood. Here we show that mutations in the Drosophila misato (mst) gene inhibit kinetochore-driven MT growth, lead to the formation of monopolar spindles and cause larval lethality. In most prophase cells of mst mutant brains, asters are well separated, but collapse with progression of mitosis, suggesting that k-fibers are essential for maintenance of aster separation and spindle bipolarity. Analysis of mst; Sas-4 double mutants showed that mitotic cells lacking both the centrosomes and the mst function form polarized MT arrays that resemble monopolar spindles. MT regrowth experiments after cold exposure revealed that in mst; Sas-4 metaphase cells MTs regrow from several sites, which eventually coalesce to form a single polarized MT array. By contrast, in Sas-4 single mutants, chromosome-driven MT regrowth mostly produced robust bipolar spindles. Collectively, these results indicate that kinetochore-driven MT formation is an essential process for proper spindle assembly in Drosophila somatic cells. PMID- 21285249 TI - Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer. AB - Inherited mutations in the BRCA2-interacting protein PALB2 are known to be associated with increased risks of developing breast cancer. To evaluate the contribution of PALB2 to familial breast cancer in the United States, we sequenced the coding sequences and flanking regulatory regions of the gene from constitutional genomic DNA of 1,144 familial breast cancer patients with wild type sequences at BRCA1 and BRCA2. Overall, 3.4% (33/972) of patients not selected by ancestry and 0% (0/172) of patients specifically of Ashkenazi Jewish ancestry were heterozygous for a nonsense, frameshift, or frameshift-associated splice mutation in PALB2. Mutations were detected in both male and female breast cancer patients. All mutations were individually rare: the 33 heterozygotes harbored 13 different mutations, 5 previously reported and 8 novel mutations. PALB2 heterozygotes were 4-fold more likely to have a male relative with breast cancer (P = 0.0003), 6-fold more likely to have a relative with pancreatic cancer (P = 0.002), and 1.3-fold more likely to have a relative with ovarian cancer (P = 0.18). Compared with their female relatives without mutations, increased risk of developing breast cancer for female PALB2 heterozygotes was 2.3-fold (95% CI: 1.5 4.2) by age 55 and 3.4-fold (95% CI: 2.4-5.9) by age 85. Loss of the wild-type PALB2 allele was observed in laser-dissected tumor specimens from heterozygous patients. Given this mutation prevalence and risk, consideration might be given to clinical testing of PALB2 by complete genomic sequencing for familial breast cancer patients with wild-type sequences at BRCA1 and BRCA2. PMID- 21285250 TI - The adaptor protein AMOT promotes the proliferation of mammary epithelial cells via the prolonged activation of the extracellular signal-regulated kinases. AB - The asymmetric organization of epithelial cells is a basic counter to cellular proliferation. However, the mechanisms whereby pro-growth pathways are modulated by intracellular factors that control cell shape are not well understood. This study demonstrates that the adaptor protein Amot, in addition to its established role in regulating cellular asymmetry, also promotes extracellular signal regulated kinase 1 and 2 (ERK1/2)-dependent proliferation of mammary cells. Specifically, expression of Amot80, but not a mutant lacking its polarity protein interaction domain, enhances ERK1/2-dependent proliferation of MCF7 cells. Further, expression of Amot80 induces nontransformed MCF10A cells to overgrow as disorganized cellular aggregates in Matrigel. Conversely, Amot expression is required for proliferation of breast cancer cells in specific microenvironmental contexts that require ERK1/2 signaling. Thus, Amot is proposed to coordinate the dysregulation of cell polarity with the induction of neoplastic growth in mammary cells. PMID- 21285252 TI - Small molecule inhibitors targeting the "achilles' heel" of androgen receptor activity. AB - Androgen ablation therapy remains the gold standard for the treatment of advanced prostate cancer, but unfortunately, it is not curative, and eventually the disease will return as lethal castration-resistant prostate cancer (CRPC). Mounting evidence supports the concept that development of CRPC is causally related to continued transactivation of androgen receptor (AR). All current therapies that target the AR are dependent on the presence of its C-terminal ligand-binding domain (LBD). However, it is the N-terminal domain (NTD) of the AR that is the "Achilles' heel" of AR activity, with AF-1 being essential for AR activity regardless of androgen. Recent efforts to develop drugs to the AR NTD have yielded EPI-001, a small molecule, sintokamide peptides, and decoys to the AR NTD with EPI-001, the best characterized and most promising for clinical development based upon specificity, low toxicity, and cytoreductive antitumor activity. PMID- 21285251 TI - DCAMKL-1 regulates epithelial-mesenchymal transition in human pancreatic cells through a miR-200a-dependent mechanism. AB - Pancreatic cancer is an exceptionally aggressive disease in great need of more effective therapeutic options. Epithelial-mesenchymal transition (EMT) plays a key role in cancer invasion and metastasis, and there is a gain of stem cell properties during EMT. Here we report increased expression of the putative pancreatic stem cell marker DCAMKL-1 in an established KRAS transgenic mouse model of pancreatic cancer and in human pancreatic adenocarcinoma. Colocalization of DCAMKL-1 with vimentin, a marker of mesenchymal lineage, along with 14-3-3 sigma was observed within premalignant PanIN lesions that arise in the mouse model. siRNA-mediated knockdown of DCAMKL-1 in human pancreatic cancer cells induced microRNA miR-200a, an EMT inhibitor, along with downregulation of EMT associated transcription factors ZEB1, ZEB2, Snail, Slug, and Twist. Furthermore, DCAMKL-1 knockdown resulted in downregulation of c-Myc and KRAS through a let-7a microRNA-dependent mechanism, and downregulation of Notch-1 through a miR-144 microRNA-dependent mechanism. These findings illustrate direct regulatory links between DCAMKL-1, microRNAs, and EMT in pancreatic cancer. Moreover, they demonstrate a functional role for DCAMKL-1 in pancreatic cancer. Together, our results rationalize DCAMKL-1 as a therapeutic target for eradicating pancreatic cancers. PMID- 21285253 TI - Forkhead transcription factor foxq1 promotes epithelial-mesenchymal transition and breast cancer metastasis. AB - Epithelial-mesenchymal transition (EMT) promotes cancer invasion and metastasis, but the integrative mechanisms that coordinate these processes are incompletely understood. In this study, we used a cross-species expression profiling strategy in metastatic cell lines of human and mouse origin to identify 22 up-regulated and 12 down-regulated genes that are part of an essential genetic program in metastasis. In particular, we identified a novel function in metastasis that was not previously known for the transcription factor Forkhead Box Q1 (Foxq1). Ectopic expression of Foxq1 increased cell migration and invasion in vitro, enhanced the lung metastatic capabilities of mammary epithelial cells in vivo, and triggered a marked EMT. In contrast, Foxq1 knockdown elicited converse effects on these phenotypes in vitro and in vivo. Neither ectopic expression nor knockdown of Foxq1 significantly affected cell proliferation or colony formation in vitro. Notably, Foxq1 repressed expression of the core EMT regulator E cadherin by binding to the E-box in its promoter region. Further mechanistic investigation revealed that Foxq1 expression is regulated by TGF-beta1, and that Foxq1 knockdown blocked TGF-beta1-induced EMT at both morphological and molecular levels. Our findings highlight the feasibility of cross-species expression profiling as a strategy to identify metastasis-related genes, and they reveal that EMT induction is a likely mechanism underlying a novel metastasis-promoting function of Foxq1 defined here in breast cancer. PMID- 21285255 TI - Influence of sample storage conditions on sweat chloride results. PMID- 21285256 TI - Consensus statement on the standardization and evaluation of growth hormone and insulin-like growth factor assays. AB - Growth hormone (GH) and insulin-like growth factor I (IGF-I) measurements are widely used in the diagnosis of disorders of GH secretion, evaluation of children with short stature from multiple causes, management of disorders that lead to nutritional insufficiency or catabolism, and monitoring both GH and IGF-I replacement therapy. Therefore, there is an ongoing need for accurate and precise measurements of these 2 peptide hormones. Representatives of the Growth Hormone Research Society, the IGF Society, and the IFCC convened an international workshop to review assay standardization, requirements for improving assay comparability, variables that affect assay interpretation, technical factors affecting assay performance, assay validation criteria, and the development and use of normative data. Special attention was given to preanalytical conditions, the use of international commutable reference standards, antibody specificity, matrix requirements, QC analysis, and interference by binding proteins. Recommendations for each of these variables were made for measurements of each peptide. Additionally, specific criteria for IGF-I were recommended for age ranges of normative data, consideration of Tanner staging, and consideration of the effect of body mass index. The consensus statement concludes that major improvements are necessary in the areas of assay performance and comparability. This group recommends that a commutable standard for each assay be implemented for worldwide use and that its recommendations be applied to accomplish the task of providing reliable and clinically useful results. PMID- 21285257 TI - Therapeutic drug monitoring of busulfan. PMID- 21285258 TI - Reverse concreteness effects are not a typical feature of semantic dementia: evidence for the hub-and-spoke model of conceptual representation. AB - The role of anterior temporal lobes (ATLs) in semantic processing is controversial. One theory, influenced by semantic dementia (SD) patients, is that this region is a pan-modal hub for all concepts. An alternative view is that atrophy in SD specifically affects knowledge for visual features. This is supported by reports of reverse concreteness effects in a few SD patients, suggesting that abstract word knowledge is spared relative to concrete words. However, it is not clear whether such effects are typical in SD, hence reliably associated with ATL damage, because most reports are of single cases and group studies have produced conflicting results. To address these contradictions, we investigated concreteness effects in 7 SD patients, using multiple tests from earlier studies in addition to new assessments. Comprehension was impaired for both word types but was better for concrete words. However, this pattern was not found uniformly across all tests and was most likely to be observed when: 1) concrete and abstract words were well matched for word frequency and 2) concrete and abstract words were selected with sufficient variation along the imageability scale. These factors account for the variability in previous studies and indicate that reverse concreteness effects are not common in SD. PMID- 21285259 TI - Vision of the body modulates somatosensory intracortical inhibition. AB - The magnitude of somatosensory evoked potentials (SEPs) elicited by simultaneous electrical stimulation of adjacent digits is generally less than the sum of potentials evoked by stimulation of each digit individually. This under additivity suggests suppression between representations of adjacent skin regions and may reflect a process of lateral inhibition by interneurons in somatosensory cortex. Given that simply viewing the body enhances tactile acuity and that tactile acuity depends on cortical lateral inhibition, we investigated how viewing the body modulates suppressive interactions between simultaneous afferent volleys from adjacent fingers. We recorded SEPs evoked by electrical stimulation of the right index and middle fingers, either individually or simultaneously, while participants viewed either their own hand or an object. In between trains of electrical stimuli, participants discriminated the orientation of tactile gratings applied to either finger. Consistent with previous findings, viewing the hand enhanced tactile acuity. Furthermore, viewing the hand increased the suppression of the P50 potential due to simultaneous electrical stimulation of both fingers. Moreover, the visual enhancement of tactile performance correlated across participants with the visual modulation of suppression. These results demonstrate that vision enhances somatosensation by modulating activity of inhibitory interneuronal circuits in the somatosensory cortex. PMID- 21285260 TI - Estimation of DNA concentration in forensic samples prior to multiplex PCR amplification. PMID- 21285261 TI - Construction and expression of oligonucleotide-based antisense cassettes. PMID- 21285262 TI - Preparation of mice for long-term intravital imaging of the mammary gland. PMID- 21285263 TI - Monitoring of vital signs for long-term survival of mice under anesthesia. PMID- 21285264 TI - Optical coherence tomography imaging of early quail embryos. PMID- 21285265 TI - General approach to adoptive transfer and cell labeling for immunoimaging. PMID- 21285266 TI - Induction of an immune response for imaging antigen-presenting cell/T-cell interactions. PMID- 21285267 TI - In situ lymph node imaging. PMID- 21285268 TI - In vivo lymph node imaging. PMID- 21285269 TI - Solution protein digest. PMID- 21285270 TI - Labeling lysosomes in live cells with neutral red. PMID- 21285271 TI - Labeling lysosomes in live cells with LysoTracker. PMID- 21285272 TI - Labeling pinocytotic vesicles and cytoplasm with fluorescently labeled ficoll or dextran. PMID- 21285273 TI - Microproteomics: quantitative proteomic profiling of small numbers of laser captured cells. PMID- 21285274 TI - SL trans-splicing in a Caenorhabditis elegans in vitro extract. PMID- 21285275 TI - Assay for courtship suppression in Drosophila. PMID- 21285276 TI - Family-based genetic association tests. PMID- 21285277 TI - Dynamic, long-term in vivo imaging of tumor-stroma interactions in mouse models of breast cancer using spinning-disk confocal microscopy. PMID- 21285278 TI - High-speed optical coherence tomography imaging of the beating avian embryonic heart. PMID- 21285279 TI - Immunoimaging: studying immune system dynamics using two-photon microscopy. PMID- 21285280 TI - Eyebrow sign in facial trauma. PMID- 21285281 TI - Growth arrest-specific protein 6 receptor antagonism impairs adipocyte differentiation and adipose tissue development in mice. AB - A low-molecular-weight receptor tyrosine kinase inhibitor, 1-(6,7-dihydro-5H benzo(6,7)cyclohepta(1,2-c)pyridazin-3-yl)-N3-((7-pyrrolidin-1-yl)-6,7,8,9 tetrahydro-5H-benzo(7)annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine (R428) with high affinity and selectivity for the growth arrest-specific protein 6 (GAS6) receptor Axl was used to study a potential role of GAS6 signaling in adiposity. In vitro, R428 caused a concentration-dependent inhibition of preadipocyte differentiation into mature adipocytes, as evidenced by reduced lipid uptake. Inhibition of Axl-mediated signaling was confirmed by reduced levels of phospho Akt activity. In vivo, oral administration of R428 for 5 weeks to mice kept on a high-fat diet resulted in significantly reduced weight gain and subcutaneous and gonadal fat mass. This was associated with marked adipocyte hypotrophy, enhanced macrophage infiltration, and apoptosis. Thus, affecting GAS6 signaling through receptor antagonism using a low-molecular-weight Axl antagonist impairs adipocyte differentiation and reduces adipose tissue development in a murine model of nutritionally induced obesity. PMID- 21285282 TI - Electrophysiological perspectives on the therapeutic use of nicotinic acetylcholine receptor partial agonists. AB - Partial agonist therapies rely variously on two hypotheses: the partial agonists have their effects through chronic low-level receptor activation or the partial agonists work by decreasing the effects of endogenous or exogenous full agonists. The relative significance of these activities probably depends on whether acute or chronic effects are considered. We studied nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus laevis oocytes to test a model for the acute interactions between acetylcholine (ACh) and weak partial agonists. Data were best-fit to a basic competition model that included an additional factor for noncompetitive inhibition. Partial agonist effects were compared with the nAChR antagonist bupropion in prolonged bath application experiments that were designed to mimic prolonged drug exposure typical of therapeutic drug delivery. A primary effect of prolonged application of nicotine was to decrease the response of all nAChR subtypes to acute applications of ACh. In addition, nicotine, cytisine, and varenicline produced detectable steady-state activation of alpha4beta2* [(alpha4)(2)(beta2)(3), (alpha4)(3)(beta2)(2), and (alpha4)(2)(beta2)(2)alpha5)] receptor subtypes that was not seen with other test compounds. Partial agonists produced no detectable steady-state activation of alpha7 nAChR, but seemed to show small potentiation of ACh-evoked responses; however, "run-up" of alpha7 ACh responses was also sometimes observed under control conditions. Potential off target effects of the partial agonists therefore included the modulation of alpha7 responses by alpha4beta2 partial agonists and decreases in alpha4beta2* responses by alpha7-selective agonists. These data indicate the dual effects expected for alpha4beta2* partial agonists and provide models and insights for utility of partial agonists in therapeutic development. PMID- 21285283 TI - Age-related autocrine diabetogenic effects of transgenic resistin in spontaneously hypertensive rats: gene expression profile analysis. AB - Increased circulating levels of resistin have been proposed as a possible link between obesity and insulin resistance; however, many of the potential metabolic effects of resistin remain to be investigated, including systemic versus local resistin action. We investigated potential autocrine effects of resistin on lipid and glucose metabolism in 2- and 16-mo-old transgenic spontaneously hypertensive rats (SHR) expressing a nonsecreted form of mouse resistin under control of the aP2 promoter. To search for possible molecular mechanisms, we compared gene expression profiles in adipose tissue in 6-wk-old transgenic SHR versus control rats, before development of insulin resistance, by digital transcriptional profiling using high-throughput sequencing. Both young and old transgenic rats showed moderate expression of the resistin transgene in adipose tissue but had serum resistin levels similar to control SHR and undetectable levels of transgenic resistin in the circulation. Young transgenic rats exhibited mild glucose intolerance. In contrast, older transgenic rats displayed marked glucose intolerance in association with near total resistance of adipose tissue to insulin-stimulated glucose incorporation into lipids (6 +/- 2 vs. 77 +/- 19 nmol glucose.g(-1).2 h(-1), P < 0.00001). Ingenuity Pathway Analysis of differentially expressed genes revealed calcium signaling, Nuclear factor-erythroid 2-related factor-2 (NRF2)-mediated oxidative stress response, and actin cytoskeletal signaling canonical pathways as those most significantly affected. Analysis using DAVID software revealed oxidative phosphorylation, glutathione metabolism, pyruvate metabolism, and peroxisome proliferator-activated receptor (PPAR) signaling as top Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. These results suggest that with increasing age autocrine effects of resistin in fat tissue may predispose to diabetes in part by impairing insulin action in adipose tissue. PMID- 21285284 TI - Can vascular function be assessed by the interpretation of retinal vascular diameter changes? PMID- 21285286 TI - On the presence of (O-acyl)-omega-hydroxy fatty acids and of their esters in human meibomian gland secretions. PMID- 21285287 TI - Inspiratory muscle training in bronchiectasis patients: a prospective randomized controlled study. AB - OBJECTIVE: To investigate the efficacy and feasibility of home-based inspiratory muscle training in patients with bronchiectasis. DESIGN: A prospective, single blind, randomized, controlled study. SETTING: Outpatient clinic of a tertiary care medical centre. METHODS: Twenty-six patients with bronchiectasis were randomly divided into inspiratory muscle training and control groups. In the inspiratory muscle training group (n = 13), the training programme started with an intensity of 30% maximal inspiratory pressure (MIP), which was increased by 2 cmH(2)O each week, for 30 minutes daily, 5 days a week for eight weeks. The control group (n = 13) did not receive inspiratory muscle training. Main outcome measures included spirometry, resting oxyhaemoglobin saturation by pulse oximetry (SpO(2)), lowest SpO(2) and Borg Scale during 6-minute walking tests, 6-minute walking distance (6MWD), 6-minute walking work (6M(work)), MIP, maximal expiratory pressure (MEP) and St George's Respiratory Questionnaire. RESULTS: There were significant differences in change from baseline in 6MWD (411.9 (133.5) vs. 473.2 (117.2) m, P = 0.021), 6M(work) (21 051.0 (8286.7) vs. 23 915.5 (8343.0) kg-m, P = 0.022), MIP (60.8 (21.8) vs. 84.6 (29.0) cmH(2)O, P = 0.004), and MEP (72.3 (31.1) vs. 104.2 (35.7) cmH(2)O, P = 0.004) in the inspiratory muscle training group. Significant improvements in both MIP (23.8 (25.3) vs. 2.3 (16.4) cmH(2)O, adjusted P-value = 0.005) and MEP (31.9 (30.8) vs. 11.5 (20.8) cmH(2)O, adjusted P-value = 0.038) levels after adjusting for age by linear regression analysis were observed between groups. CONCLUSIONS: An eight-week home based inspiratory muscle training is feasible and effective in improving both inspiratory and expiratory muscle strength, but has no effect on respiratory function and quality of life in patients with bronchiectasis. PMID- 21285288 TI - The effects of dynamic ankle-foot orthoses in chronic stroke patients at three month follow-up: a randomized controlled trial. AB - OBJECTIVE: To investigate the short- and long-term effects of dynamic ankle foot orthoses on functional ambulation activities in chronic hemiparetic patients. DESIGN: Randomized controlled trial. SETTING: University's neurological rehabilitation outpatient clinic and orthotics department. SUBJECTS: Twenty-eight chronic hemiparetic patients of level 3-5 according to Functional Ambulation Classification and with a maximum spasticity level of 3 according to Modified Ashworth Scale, were randomly assigned to the study and control groups. INTERVENTIONS: The control group (n = 14) was assessed with tennis shoes whereas the study group (n = 14) was assessed initially with tennis shoes and after three months with dynamic ankle foot orthosis. MEASURES: Functional Reach, Timed Up and Go, Timed Up Stairs, Timed Down Stairs, gait velocity and Physiological Cost Index. RESULTS: In the initial assessment no difference was found between the groups for any of the measured parameters (P > 0.05). After three months, intergroup comparisons while the patients in the study group were wearing dynamic ankle-foot orthosis showed a significant difference in favour of the study group for Timed Up Stairs 12.00 (10.21) seconds study versus 15.00 (7.29) seconds control group; for gait velocity 0.99 (0.45) m/s study versus 0.72 (0.20) m/s control group and for Physiological Cost Index 0.12 (0.06) beats/min study versus 0.28 (0.13) beats/min control group (P < 0.05). No difference was found between the groups for Functional Reach, Timed Up and Go, Timed Down Stairs (P > 0.05). CONCLUSION: Chronic hemiparetic patients may benefit from using dynamic ankle foot orthosis. PMID- 21285289 TI - A phospholipase Cgamma1-activated pathway regulates transcription in human vascular smooth muscle cells. AB - AIMS: Growth factor-induced repression of smooth muscle (SM) cell marker genes is an integral part of vascular SM (VSM) cell proliferation. This is partly regulated via translocation of extracellular signal-regulated kinase 1/2 (ERK1/2) to the nucleus which activates the transcription factor Elk-1. The mediators involved in ERK1/2 nuclear translocation in VSM cells are unknown. The aim of this study is to examine the mechanisms which regulate growth factor-induced nuclear translocation of ERK1/2 and gene expression in VSM cells. METHODS AND RESULTS: In cultured human VSM cells, phospholipase C (PLC)gamma1 expression was required for platelet-derived growth factor (PDGF)-induced ERK1/2 nuclear translocation, Elk-1 phosphorylation, and subsequent repression of SM alpha-actin gene expression. The mechanisms of a role for PLCgamma1 in ERK1/2 nuclear localization were further examined by investigating interacting proteins. The ERK1/2-binding phosphoprotein, protein enriched in astrocytes-15 (PEA-15), was phosphorylated by PDGF and this phosphorylation required activation of PLCgamma1. In cells pre-treated with PEA-15 siRNA, ERK1/2 distribution significantly increased in the nucleus and resulted in decreased SM alpha-actin expression and increased VSM cell proliferation. Overexpression of PEA-15 increased ERK1/2 localization in the cytoplasm. The regulatory role of PEA-15 phosphorylation was assessed. In VSM cells overexpressing a non-phosphorylatable form of PEA-15, PDGF induced ERK1/2 nuclear localization was inhibited. CONCLUSION: These results suggest that PEA-15 phosphorylation by PLCgamma1 is required for PDGF-induced ERK1/2 nuclear translocation. This represents an important level of phenotypic control by directly affecting Elk-1-dependent transcription and ultimately SM cell marker protein expression in VSM cells. PMID- 21285290 TI - Ablation of Nkx2-5 at mid-embryonic stage results in premature lethality and cardiac malformation. AB - AIMS: Human congenital heart disease linked to mutations in the homeobox transcription factor, NKX2-5, is characterized by cardiac anomalies, including atrial and ventricular septal defects as well as conduction and occasional defects in contractility. In the mouse, homozygous germline deletion of Nkx2-5 gene results in death around E10.5. It is, however, not established whether Nkx2 5 is necessary for cardiac development beyond this embryonic stage. Because human NKX2-5 mutations are related to septum secundum type atrial septal defects (ASD), we hypothesized that Nkx2-5 deficiency during the processes of septum secundum formation may cause cardiac anomalies; thus, we analysed mice with tamoxifen inducible Nkx2-5 ablation beginning at E12.5 when the septum secundum starts to develop. METHODS AND RESULTS: Using tamoxifen-inducible Nkx2-5 gene-targeted mice, this study demonstrates that Nkx2-5 ablation beginning at E12.5 results in embryonic death by E17.5. Analysis of mutant embryos at E16.5 shows arrhythmias, contraction defects, and cardiac malformations, including ASD. Quantitative measurements using serial section histology and three-dimensional reconstruction demonstrate growth retardation of the septum secundum and enlarged foramen ovale in Nkx2-5-ablated embryos. Functional cardiac defects may be attributed to abnormal expression of transcripts critical for conduction and contraction, including cardiac voltage-gated Na(+) channel pore-forming alpha-subunit (Na(v)1.5-alpha), gap junction protein connexin40, cardiac myosin light chain kinase, and sarcolipin within 4 days after tamoxifen injection. CONCLUSION: Nkx2 5 is necessary for survival after the mid-embryonic stage for cardiac function and formation by regulating the expression of its downstream target genes. PMID- 21285291 TI - Enhanced susceptibility to biomechanical stress in ACE2 null mice is prevented by loss of the p47(phox) NADPH oxidase subunit. AB - AIMS: Angiotensin-converting enzyme 2 (ACE2) is an important negative regulator of the renin-angiotensin system. Loss of ACE2 enhances the susceptibility to heart disease but the mechanism remains elusive. We hypothesized that ACE2 deficiency activates the NADPH oxidase system in pressure overload-induced heart failure. METHODS AND RESULTS: Using the aortic constriction model, we subjected wild-type (Ace2(+/y)), ACE2 knockout (ACE2KO, Ace2(-/y)), p47(phox) knockout (p47(phox)KO, p47(phox-)(/-)), and ACE2/p47(phox) double KO mice to pressure overload. We examined changes in peptide levels, NADPH oxidase activity, gene expression, matrix metalloproteinases (MMP) activity, pathological signalling, and heart function. Loss of ACE2 resulted in enhanced susceptibility to biomechanical stress leading to eccentric remodelling, increased pathological hypertrophy, and worsening of systolic performance. Myocardial angiotensin II (Ang II) levels were increased, whereas Ang 1-7 levels were lowered. Activation of Ang II-stimulated signalling pathways in the ACE2-deficient myocardium was associated with increased expression and phosphorylation of p47(phox), NADPH oxidase activity, and superoxide generation, leading to enhanced MMP-mediated degradation of the extracellular matrix. Additional loss of p47(phox) in the ACE2KO mice normalized the increased NADPH oxidase activity, superoxide production, and systolic dysfunction following pressure overload. Ang 1-7 supplementation suppressed the increased NADPH oxidase and rescued the early dilated cardiomyopathy in pressure-overloaded ACE2KO mice. CONCLUSION: In the absence of ACE2, biomechanical stress triggers activation of the myocardial NAPDH oxidase system with a critical role of the p47(phox) subunit. Increased production of superoxide, activation of MMP, and pathological signalling leads to severe adverse myocardial remodelling and dysfunction in ACE2KO mice. PMID- 21285292 TI - AMPK activation, a preventive therapeutic target in the transition from cardiac injury to heart failure. AB - Heart failure is a progressive muscular disorder leading to a deterioration of the heart characterized by a contractile dysfunction and a chronic energy deficit. As a consequence, the failing heart is unable to meet the normal metabolic and energy needs of the body. The transition between compensated left ventricular hypertrophy and the de-compensated heart is multifactorial, although metabolic disturbances are considered to play a significant role. In this respect, the AMP-activated protein kinase (AMPK) could be a potential target in heart failure development. AMPK senses the energy state of the cell and orchestrates a global metabolic response to energy deprivation. We briefly review here the current knowledge about the chronic energy deficit of the failing heart, as well as the role of AMPK in energy homeostasis and in the control of non metabolic targets in relation to cardiac hypertrophy and heart failure. The relative importance of energetic and non-metabolic effects in the potential cardioprotective action of AMPK is discussed. PMID- 21285293 TI - Cytokines present in smokers' serum interact with smoke components to enhance endothelial dysfunction. AB - AIMS: Cigarette smoking engenders inflammation and endothelial dysfunction, processes implicated in atherothrombotic disease. We hypothesized that an interaction between inflammatory cytokines in smokers' blood and circulating components of cigarette smoke is necessary to induce reactive oxygen species (ROS) and cyclooxygenase-2 (COX-2) in endothelium. We then explored the molecular mechanisms involved in these effects. METHODS AND RESULTS: Serum from nine healthy active smokers (AS) compared with serum from nine non-smokers (NS) showed higher levels of interleukin-1beta (IL-1beta) and tumour necrosis factor-alpha (TNF-alpha) and a greater ability to induce ROS production, p47phox translocation to the plasma membrane, and COX-2 mRNA and protein expression in endothelial cells (ECs). Similar results were obtained in vivo and in vitro after treatment with aqueous extracts of cigarette smoke plus IL-1beta and TNF-alpha(TS/IL 1beta/TNF-alpha). In ECs increased ROS production and COX-2 mRNA induced by serum from AS correlated positively with their serum levels of IL-1beta and TNF-alpha. Moreover, a positive correlation was observed between ROS generation and COX-2 mRNA. Simultaneous immuno-neutralization of IL-1beta and TNF-alpha prevented endothelial dysfunction induced by serum from AS. Inhibitors of NADPH oxidase and/or p47phox siRNA diminished ROS production and COX-2 expression as well as phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) and Akt mediated either by AS serum or by TS/IL-1beta/TNF-alpha. Finally, direct inhibition of p38MAPK and Akt activity also abolished COX-2 expression mediated by both types of stimuli. Our results suggest a crucial role played by interactions between inflammatory cytokines and tobacco smoke in the induction of endothelial dysfunction. PMID- 21285294 TI - Endothelial cell-borne platelet bridges selectively recruit monocytes in human and mouse models of vascular inflammation. AB - AIMS: Cells of the monocyte lineage are the most abundant inflammatory cells found in atherosclerotic lesions. Dominance of the inflammatory infiltrate by monocytes indicates that there is a disease-driven mechanism supporting their selective recruitment. Previous studies have demonstrated that interactions between endothelial cells (ECs) and platelets may promote monocyte recruitment. In this study, we sought to expand on this knowledge using a complex coculture model of the diseased vessel wall. METHODS AND RESULTS: Using primary human cells in an in vitro flow-based adhesion assay, we found that secretory arterial smooth muscle cells (SMCs), cocultured with ECs, promote preferential recruitment of monocytes from blood in a TGF-beta1-dependent manner. Approximately 85% of leucocytes recruited to the endothelium were CD14(+). Formation of adhesive platelet bridges on ECs was essential for monocyte recruitment as platelet removal or inhibition of adhesion to the ECs abolished monocyte recruitment. Monocytes were recruited from flow by platelet P-selectin and activated by EC derived CC chemokine ligand 2 (CCL2), although the presentation of CCL2 to adherent monocytes was dependent upon platelet activation and release of CXC chemokine ligand 4 (CXCL4). In an intravital model of TGF-beta1-driven vascular inflammation in mice, platelets were also necessary for efficient leucocyte recruitment to vessels of the microcirculation in the cremaster muscle. CONCLUSIONS: In this study, we have demonstrated that stromal cells found within the diseased artery wall may promote the preferential recruitment of monocytes and this is achieved by establishing a cascade of interactions between SMCs, ECs, platelets, and monocytes. PMID- 21285295 TI - MG53 participates in ischaemic postconditioning through the RISK signalling pathway. AB - AIMS: Recent studies show that ischaemic postconditioning (PostC), similar to the well-established ischaemic preconditioning (IPC), confers cardioprotection against ischaemia/reperfusion (IR) injury, and both IPC and PostC can activate the reperfusion injury salvage kinase (RISK) pathway and the survivor activating factor enhancement (SAFE) pathway. PostC is clinically more attractive because of its therapeutic application at the predictable onset of reperfusion. Our previous studies have demonstrated that MG53 is a primary component of the IPC machinery. Here, we investigated the potential role of MG53 in PostC-mediated myocardial protection and explored the underlying mechanism. METHODS AND RESULTS: Using Langendorff perfusion, we investigated IR injury in wild-type (wt) and MG53 deficient (mg53(-/-)) mouse hearts with or without PostC. IR-induced myocardial damage was markedly exacerbated in mg53(-/-) hearts compared with wt controls. PostC protected wt hearts against IR-induced myocardial infarction, myocyte necrosis, and apoptosis, but failed to protect mg53(-/-) hearts. The loss of PostC protection in mg53(-/-) hearts was attributed to selectively impaired PostC activated RISK signalling. Mechanistically, MG53 is required for the interaction between caveolin 3 (CaV3) and the p85 subunit of phosphoinositide 3-kinase (p85 PI3K) and PostC-mediated activation of the RISK pathway. Importantly, a structure function study revealed that the MG53 tripartite motif (TRIM) domain (aa1-284) physically interacted with CaV3 but not p85-PI3K, whereas the MG53 SPRY domain (aa285-477) interacted with p85-PI3K but not CaV3, indicating that MG53 binds to CaV3 and p85 at its N- and C-terminus, respectively. CONCLUSIONS: We conclude that MG53 participates in PostC-mediated cardioprotection largely through tethering CaV3 and PI3K and subsequent activation of the RISK pathway. PMID- 21285297 TI - Feature-based interference from unattended visual field during attentional tracking in younger and older adults. AB - The ability to attend to multiple objects that move in the visual field is important for many aspects of daily functioning. The attentional capacity for such dynamic tracking, however, is highly limited and undergoes age-related decline. Several aspects of the tracking process can influence performance. Here, we investigated effects of feature-based interference from distractor objects that appear in unattended regions of the visual field with a hemifield-tracking task. Younger and older participants performed an attentional tracking task in one hemifield while distractor objects were concurrently presented in the unattended hemifield. Feature similarity between objects in the attended and unattended hemifields as well as motion speed and the number of to-be-tracked objects were parametrically manipulated. The results show that increasing feature overlap leads to greater interference from the unattended visual field. This effect of feature-based interference was only present in the slow speed condition, indicating that the interference is mainly modulated by perceptual demands. High-performing older adults showed a similar interference effect as younger adults, whereas low-performing adults showed poor tracking performance overall. PMID- 21285296 TI - Two distinct phases of calcium signalling under flow. AB - AIMS: High shear stress (HSS) can have significant impact on angiogenesis and atherosclerosis in collateral arteries near the bifurcation and curvature regions. Here, we investigate the spatiotemporal pattern of HSS-induced intracellular calcium alteration. METHODS AND RESULTS: Genetically encoded biosensors based on fluorescence resonance energy transfer were targeted in the cytoplasm and the endoplasmic reticulum (ER) to visualize the subcellular calcium dynamics in bovine aortic endothelial cells under HSS (65 dyn/cm(2)). Upon HSS application, the intracellular Ca(2+) concentration ([Ca(2+)](i)) increased immediately and maintained a sustained high level, while the ER-stored calcium had a significant decrease only after 300 s. The perturbation of calcium influx across the plasma membrane (PM) by the removal of extracellular calcium or the blockage of membrane channels inhibited the early phase of [Ca(2+)](i) increase upon HSS application, which was further shown to be sensitive to the magnitudes of shear stress and the integrity of cytoskeletal support. In contrast, Src, phospholipase C(PLC), and the inositol 1,4,5-trisphosphate receptor (IP(3)R) can regulate the late phase of HSS-induced [Ca(2+)](i) increase via the promotion of the ER calcium efflux. CONCLUSION: The HSS-induced [Ca(2+)](i) increase consists of two well-co-ordinated phases with different sources and mechanisms: (i) an early phase due to the calcium influx across the PM which is dependent on the mechanical impact and cytoskeletal support and (ii) a late phase originated from the ER-calcium efflux which is regulated by the Src, PLC, and IP(3)R signalling pathway. Therefore, our work presented new molecular-level insights into systematic understanding of mechanotransduction in cardiovascular systems. PMID- 21285298 TI - Complementary, holistic, and integrative medicine: therapies for learning disabilities. PMID- 21285299 TI - Global child health. PMID- 21285300 TI - The common cold and decongestant therapy. PMID- 21285301 TI - Somatization disorders: diagnosis, treatment, and prognosis. PMID- 21285302 TI - Urine electrolytes. PMID- 21285303 TI - Ethical issues in organ donation. PMID- 21285304 TI - Distinguishing statistical significance from clinical importance: the value of the P value. PMID- 21285305 TI - Index of suspicion. Case 1: Nonbilious projectile vomiting in a neonate. Case 2: Fever, rash, headache, myalgia, and arthralgia in an 11-year-old boy. Case 3: Ecchymotic lesions on the backs of Asian boys. PMID- 21285306 TI - Cataracts. PMID- 21285307 TI - Balance and vertigo in children. PMID- 21285308 TI - Issues in chemotherapy. PMID- 21285309 TI - Plasma distribution and signaling activities of IGF-II precursors. AB - IGF-II is thought to function through activation of the IGF-I receptor (IGF-IR) and the A isoform of the IR, with the IGF-IR being relevant to tumorigenesis and the IR to both tumorigenesis and metabolic control. In the paraneoplastic syndrome of nonislet cell tumor hypoglycemia, tumor-derived IGF-II has been proposed to exert both proliferative and metabolic effects, exemplifying this dual mode of action. Increased levels of IGF-II precursors ("big" and pro-IGF-II) have been reported in the circulation of nonislet cell tumor patients and have been proposed to exert greater or different effects than mature IGF-II. However, most studies have not defined which version is being investigated, and the relative activation of the IR and IGF-IR by IGF-II precursors has not been delineated. In this study, we determined the distribution of IGF-II isoforms in normal human plasma and their ability to activate the alternative versions of the IR. The majority (71%) of total IGF-II in human plasma was the mature form, while "big" and pro-IGF-II comprised 16% and 13%, respectively, with more variation seen in the levels of mature IGF-II. In IGF-IR-deficient cells expressing similar levels of human IR-A or IR-B, mature and "big" IGF-II exhibited similar activation of IR signaling, while pro-IGF-II exhibited significantly less activation. Downstream activation of Akt by mature and "big" IGF-II was greater in IR-A cells, consistent with previous reports of the greater affinity of IR-A for IGF-II. Thus, both IGF-II precursor forms are present in human plasma but do not preferentially activate the IR. PMID- 21285310 TI - Distinct roles of deiodinases on the phenotype of Mct8 defect: a comparison of eight different mouse genotypes. AB - Mice deficient in the thyroid hormone (TH) transporter Mct8 (Mct8KO) have increased 5'-deiodination and impaired TH secretion and excretion. These and other unknown mechanisms result in the low-serum T(4), high T(3), and low rT(3) levels characteristic of Mct8 defects. We investigated to what extent each of the 5'-deiodinases (D1, D2) contributes to the serum TH abnormalities of the Mct8KO by generating mice with all combinations of Mct8 and D1 and/or D2 deficiencies and comparing the resulting eight genotypes. Adding D1 deficiency to that of Mct8 corrected the serum TH abnormalities of Mct8KO mice, normalized brain T(3) content, and reduced the impaired expression of TH-responsive genes. In contrast, Mct8D2KO mice maintained the serum TH abnormalities of Mct8KO mice. However, the serum TSH level increased 27-fold, suggesting a severely impaired hypothalamo pituitary-thyroid axis. The brain of Mct8D2KO manifested a pattern of more severe impairment of TH action than Mct8KO alone. In triple Mct8D1D2KO mice, the markedly increased serum TH levels produced milder brain defect than that of Mct8D2KO at the expense of more severe liver thyrotoxicosis. Additionally, we observed that mice deficient in D2 had an unexplained marked reduction in the thyroid growth response to TSH. Our studies on these eight genotypes provide a unique insight into the complex interplay of the deiodinases in the Mct8 defect and suggest that D1 contributes to the increased serum T(3) in Mct8 deficiency, whereas D2 mainly functions locally, converting T(4) to T(3) to compensate for distinct cellular TH depletion in Mct8KO mice. PMID- 21285311 TI - Estradiol alters Fos-immunoreactivity in the hippocampus and dorsal striatum during place and response learning in middle-aged but not young adult female rats. AB - Evidence from lesion and inactivation studies suggests that the hippocampus (HPC) and dorsal striatum compete for control over navigation behavior, and there is some evidence in males that the structure with greater relative activation controls behavior. Estradiol has been shown to enhance HPC-dependent place learning and impair dorsal striatum-dependent response learning in female rats, possibly by increasing hippocampal activation and/or decreasing striatal activation. We used Fos-immunoreactivity (Fos-IR) to examine the activation of several subregions of the HPC and striatum in ovariectomized female rats with or without estradiol replacement 30 min after place or response learning. In 4-month old rats, neither task nor estradiol increased Fos-IR above explore control levels in any subregion analyzed, even though estradiol impaired response learning. In 12-month-old rats, estradiol increased Fos-IR in the dentate gyrus, dorsal medial striatum, and dorsal lateral striatum in place task learners, while the absence of estradiol increased Fos-IR in these regions in response task learners. However, learning rate was not affected by estradiol in either task. We also included a group of long-term ovariectomized 12-month-old rats that displayed impaired place learning and altered Fos-IR in CA1 of the HPC. These results suggest that task-specific effects of estradiol on hippocampal and striatal activation emerge across age but that relative hippocampal and striatal activation are not related to learning rate during spatial navigation learning. PMID- 21285312 TI - Perinatal lack of maternal IL-6 promotes increased adiposity during adulthood in mice. AB - The perinatal environment appears important in establishing metabolic phenotypes in adulthood. Mice deficient in IL-6 (IL-6(-/-)) tend to develop mature-onset obesity, but it is unknown whether perinatal exposure to IL-6 produced by the dam influences the metabolism of adult offspring. To address this issue, we monitored IL-6(-/-) offspring of IL-6(-/-) or IL-6(+/-) dams, as well as wild-type (WT) mice. At adult age, IL-6(-/-) mice weighed significantly more and had more body fat than WT mice, regardless of maternal genotype, and had lower insulin sensitivity. This phenotype was more pronounced in IL-6(-/-) offspring of IL-6(-/ ) dams, because they gained weight significantly faster than IL-6(-/-) offspring of IL-6(+/-) dams and had more body fat and higher serum leptin levels at an earlier age. The leptin content was 2-fold higher in milk from IL-6(-/-) than WT dams. However, cross-fostering IL-6(-/-) mice with WT dams did not alter body weight, body composition, or adipocyte size at adult age compared with IL-6(-/-) mice fostered by IL-6(-/-) dams. Conversely, WT mice fostered by IL-6(-/-) dams weighed significantly more than those fostered by WT dams and had more body fat, larger adipocytes, and altered hypothalamic gene expression. We conclude that body fat of adult mice can be increased by perinatal exposure to factors affected by lack of maternal IL-6. PMID- 21285313 TI - Induction of murine neonatal tolerance against Graves' disease using recombinant adenovirus expressing the TSH receptor A-subunit. AB - Graves' disease is a common organ-specific autoimmune disease. The identity of its autoantigen, the TSH receptor (TSHR), was established and used to induce a typical animal model. A-subunit, the shed portion of TSHR, either initiates or amplifies the autoimmune response of the thyroid gland, thereby causing Graves' disease in humans. In the present study, we investigate the effect of the TSHR A subunit on the induction of murine neonatal tolerance for the development of Graves' disease. Female BALB/c mice were pretreated with different doses of adenovirus expressing the A-subunit of TSHR (Ad-TSHR289) by either ip or im injection within the first 24 h after their birth. Graves' disease was induced after the animals reached adulthood. Nearly all mice pretreated with the high dose of Ad-TSHR289 failed to develop TSHR antibodies, detected by the TSH-binding inhibition assay, hyperthyroidism, and thyroid follicular hyperplasia. The mice preimmunized im with the lower doses of Ad-TSHR289 developed a relatively low level of TSH-binding inhibition and the low incidence of hyperthyroidism. Accordingly, the percentages of splenic CD4+CD25+/CD4+ and CD25+Foxp3+/CD4+ Treg cells were increased in mice pretreated with the high dose of Ad-TSHR289. Taken together, our data strongly indicate that the immunotolerance against Graves' disease could be induced in neonatal mice using a specific TSHR antigen in a high dose either by ip or im injection, preventing the development of Graves' disease. PMID- 21285314 TI - KISS1R intracellular trafficking and degradation: effect of the Arg386Pro disease associated mutation. AB - The goal of this study was to investigate how the Arg386Pro mutation prolongs KiSS-1 receptor (KISS1R) responsiveness to kisspeptin, contributing to human central precocious puberty. Confocal imaging showed colocalization of wild-type (WT) KISS1R with a membrane marker, which persisted for up to 5 h of stimulation. Conversely, no colocalization with a lysosome marker was detected. Also, overnight treatment with a lysosome inhibitor did not affect WT KISS1R protein, whereas overnight treatment with a proteasome inhibitor increased protein levels by 24-fold. WT and Arg386Pro KISS1R showed time-dependent internalization upon stimulation. However, both receptors were recycled back to the membrane. The Arg386Pro mutation did not affect the relative distribution of KISS1R in membrane and internalized fractions when compared to WT KISS1R for up to 120 min of stimulation, demonstrating that this mutation does not affect KISS1R trafficking rate. Nonetheless, total Arg386Pro KISS1R was substantially increased compared with WT after 120 min of kisspeptin stimulation. This net increase was eliminated by blockade of detection of recycled receptors, demonstrating that recycled receptors account for the increased responsiveness of this mutant to kisspeptin. We therefore conclude the following: 1) WT KISS1R is degraded by proteasomes rather than lysosomes; 2) WT and Arg386Pro KISS1R are internalized upon stimulation, but most of the internalized receptors are recycled back to the membrane rather than degraded; 3) the Arg386Pro mutation does not affect the rate of KISS1R trafficking--instead, it prolongs responsiveness to kisspeptin by decreasing KISS1R degradation, resulting in the net increase on mutant receptor recycled back to the plasma membrane. PMID- 21285315 TI - Glucose-dependent changes in SNARE protein levels in pancreatic beta-cells. AB - Prolonged exposure to high glucose concentration alters the expression of a set of proteins in pancreatic beta-cells and impairs their capacity to secrete insulin. The cellular and molecular mechanisms that lie behind this effect are poorly understood. In this study, three either in vitro or in vivo models (cultured rat pancreatic islets incubated in high glucose media, partially pancreatectomized rats, and islets transplanted to streptozotozin-induced diabetic mice) were used to evaluate the dependence of the biological model and the treatment, together with the cell location (insulin granule or plasma membrane) of the affected proteins and the possible effect of sustained insulin secretion, on the glucose-induced changes in protein expression. In all three models, islets exposed to high glucose concentrations showed a reduced expression of secretory granule-associated vesicle-soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins synaptobrevin/vesicle-associated membrane protein 2 and cellubrevin but minor or no significant changes in the expression of the membrane-associated target-SNARE proteins syntaxin1 and synaptosomal-associated protein-25 and a marked increase in the expression of synaptosomal-associated protein-23 protein. The inhibition of insulin secretion by the L-type voltage-dependent calcium channel nifedipine or the potassium channel activator diazoxide prevented the glucose-induced reduction in islet insulin content but not in vesicle-SNARE proteins, indicating that the granule depletion due to sustained exocytosis was not involved in the changes of protein expression induced by high glucose concentration. Altogether, the results suggest that high glucose has a direct toxic effect on the secretory pathway by decreasing the expression of insulin granule SNARE-associated proteins. PMID- 21285316 TI - Impairment of peripheral circadian clocks precedes metabolic abnormalities in ob/ob mice. AB - Recent studies have demonstrated relationships between the dysfunction of circadian clocks and the development of metabolic abnormalities, but the chicken and-egg question remains unresolved. To address this issue, we investigated the cause-effect relationship in obese, diabetic ob/ob mice. Compared with control C57BL/6J mice, the daily mRNA expression profiles of the clock and clock controlled genes Clock, Bmal1, Cry1, Per1, Per2, and Dbp were substantially dampened in the liver and adipose tissue, but not the hypothalamic suprachiasmatic nucleus, of 10-wk-old ob/ob mice. Four-week feeding of a low calorie diet and administration of leptin over a 7-d period attenuated, to a significant and comparable extent, the observed metabolic abnormalities (obesity, hyperglycemia, hyperinsulinemia, and hypercholesterolemia) in the ob/ob mice. However, only leptin treatment improved the impaired peripheral clocks. In addition, clock function, assessed by measuring levels of Per1, Per2, and Dbp mRNA at around peak times, was also reduced in the peripheral tissues of 3-wk-old ob/ob mice without any overt metabolic abnormalities. Collectively these results indicate that the impairment of peripheral clocks in ob/ob mice does not result from metabolic abnormalities but may instead be at least partially caused by leptin deficiency itself. Further studies are needed to clarify how leptin deficiency affects peripheral clocks. PMID- 21285317 TI - Sexually dimorphic diet-induced insulin resistance in obese tissue inhibitor of metalloproteinase-2 (TIMP-2)-deficient mice. AB - Circulating levels of matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue inhibitor of metalloproteinases (TIMPs), are altered in human obesity and may contribute to its pathology. TIMP-2 exerts MMP-dependent (MMP inhibition and pro-MMP-2 activation) and MMP-independent functions. To assess the role of TIMP-2 in a murine model of nutritionally induced obesity, weight gain in wild-type and TIMP-2 deficient [knockout (KO)] mice fed a chow or high-fat diet (HFD) was determined. The effects of diet on glucose tolerance and insulin sensitivity, as well as pancreatic beta-cell and adipocyte physiology, were assessed. Chow-fed TIMP-2 KO mice of both sexes became obese but maintained relatively normal glucose tolerance and insulin sensitivity. Obesity was exacerbated on the HFD. However, HFD-fed male, but not female, TIMP-2 KO mice developed insulin resistance with reduced glucose transporter 2 and pancreatic and duodenal homeobox 1 levels, despite increased beta-cell mass and hyperplasia. Thus, although beta-cell mass was increased, HFD-fed male TIMP-2 KO mice develop diabetes likely due to beta-cell exhaustion and failure. TIMP-2 mRNA, whose expression was greatest in sc adipose tissue, was down-regulated in HFD-fed wild type males, but not females. Furthermore, HFD increased membrane type 1-MMP (MMP 14) expression and activity in male, but not female, sc adipose tissue. Strikingly, MMP-14 expression increased to a greater extent in TIMP-2 KO males and was associated with decreased adipocyte collagen. Taken together, these findings demonstrate a role for TIMP-2 in maintaining extracellular matrix integrity necessary for normal beta-cell and adipocyte physiology and that loss of extracellular matrix integrity may underlie diabetic and obesogenic phenotypes. PMID- 21285319 TI - The gsp oncogene disrupts Ras/ERK-dependent prolactin gene regulation in gsp inducible somatotroph cell line. AB - The MAPK ERK1/2 cascade regulates all the critical cellular functions, and in many pathological situations, these regulatory processes are perturbed. It has been clearly established that this cascade is an integrative point in the control of the pituitary functions exerted by various extracellular signals. In particular, ERK1/2 cross talk with the cAMP pathway is determinant in the control of somatolactotroph hormonal secretion exerted via neuropeptide receptors. GH secreting adenomas are characterized by frequent cAMP pathway alterations, such as constitutive activation of the alpha-subunit of the heterotrimeric Gs protein (the gsp oncogene), overexpression of Gsalpha, and changes in the protein kinase A regulatory subunits. However, it has not yet been established exactly how these alterations result in GH-secreting adenomas or how the ERK1/2 cascade contributes to the process of GH-secreting adenoma tumorigenesis. In this study on the conditional gsp-oncogene-expressing GH4C1 cell line, expression of the gsp oncogene, which was observed in up to 40% of GH-secreting adenomas, was found to induce sustained ERK1/2 activation, which required activation of the protein kinase A and the GTPases Ras and Rap1. All these signaling components contribute to the chronic activation of the human prolactin promoter. The data obtained here show that Ras plays a crucial role in these processes: in a physiopathological context, i.e. in the presence of the gsp oncogene, it switched from being a repressor of the cAMP/ protein kinase A ERK-sensitive prolactin gene control exerted by neuropeptides to an activator of the prolactin promoter. PMID- 21285318 TI - The adapter protein APPL1 links FSH receptor to inositol 1,4,5-trisphosphate production and is implicated in intracellular Ca(2+) mobilization. AB - FSH binds to its receptor (FSHR) on target cells in the ovary and testis, to regulate oogenesis and spermatogenesis, respectively. The signaling cascades activated after ligand binding are extremely complex and have been shown to include protein kinase A, mitogen-activated protein kinase, phosphatidylinositol 3-kinase/protein kinase B, and inositol 1,4,5-trisphosphate-mediated calcium signaling pathways. The adapter protein APPL1 (Adapter protein containing Pleckstrin homology domain, Phosphotyrosine binding domain and Leucine zipper motif), which has been linked to an assortment of other signaling proteins, was previously identified as an interacting protein with FSHR. Thus, alanine substitution mutations in the first intracellular loop of FSHR were generated to determine which residues are essential for FSHR-APPL1 interaction. Three amino acids were essential; when any one of them was altered, APPL1 association with FSHR mutants was abrogated. Two of the mutants (L377A and F382A) that displayed poor cell-surface expression were not studied further. Substitution of FSHR-K376A did not affect FSH binding or agonist-stimulated cAMP production in either transiently transfected human embryonic kidney cells or virally transduced human granulosa cells (KGN). In the KGN line, as well as primary cultures of rat granulosa cells transduced with wild type or mutant receptor, FSH-mediated progesterone or estradiol production was not affected by the mutation. However, in human embryonic kidney cells inositol 1,4,5-trisphosphate production was curtailed and KGN cells transduced with FSHR-K376A evidenced reduced Ca(2+) mobilization from intracellular stores after FSH treatment. PMID- 21285320 TI - Regulation of insulin-stimulated glucose uptake in rat white adipose tissue upon chronic central leptin infusion: effects on adiposity. AB - Leptin enhances the glucose utilization in most insulin target tissues and paradoxically decreases it in white adipose tissue (WAT), but knowledge of the mechanisms underlying the inhibitory effect of central leptin on the insulin dependent glucose uptake in WAT is limited. After 7 d intracerebroventricular leptin treatment (0.2 MUg/d) of rats, the overall insulin sensitivity and the responsiveness of WAT after acute in vivo insulin administration were analyzed. We also performed unilateral WAT denervation to clarify the role of the autonomic nervous system in leptin effects on the insulin-stimulated [(3)H]-2-deoxyglucose transport in WAT. Central leptin improved the overall insulin sensitivity but decreased the in vivo insulin action in WAT, including insulin receptor autophosphorylation, insulin receptor substrate-1 tyrosine-phosphorylation, and Akt activation. In this tissue, insulin receptor substrate-1 and glucose transporter 4 mRNA and protein levels were down-regulated after central leptin treatment. Additionally, a remarkable up-regulation of resistin, together with an augmented expression of suppressor of cytokine signaling 3 in WAT, was also observed in leptin-treated rats. As a result, the insulin-stimulated glucose transporter 4 insertion at the plasma membrane and the glucose uptake in WAT were impaired in leptin-treated rats. Finally, denervation of WAT abolished the inhibitory effect of central leptin on glucose transport and decreased suppressor of cytokine signaling 3 and resistin levels in this tissue, suggesting that resistin, in an autocrine/paracrine manner, might be a mediator of central leptin antagonism of insulin action in WAT. We conclude that central leptin, inhibiting the insulin-stimulated glucose uptake in WAT, may regulate glucose availability for triacylglyceride formation and accumulation in this tissue, thereby contributing to the control of adiposity. PMID- 21285321 TI - Rapid effects of estrogen receptor alpha and beta selective agonists on learning and dendritic spines in female mice. AB - Estrogen receptor (ER) agonists rapidly affect neural plasticity within 1 h, suggesting they play a functional role in learning and memory. However, behavioral learning experiments on such a rapid time scale are lacking. Therefore we investigated whether the ERalpha agonist propyl pyrazole triol (PPT) and ERbeta agonist diarylpropionitrile (DPN) could affect social recognition, object recognition, or object placement learning within 40 min of drug administration. At the same time, we examined their effects on CA1 hippocampal dendritic spines. Ovariectomized female CD1 mice were administered a range of PPT or DPN doses (0, 30, 50, 75, or 150 MUg/mouse). PPT at the middle doses improved social recognition, facilitated object recognition and placement at a dose of 75 MUg, and increased dendritic spine density in the stratum radiatum and lacunosum moleculare. In contrast, DPN impaired social recognition at higher doses, did not affect object recognition, but slightly facilitated object placement learning at the 75-MUg dose. DPN did not affect spines in the stratum radiatum but decreased spine density and increased spine length in the lacunosum-moleculare. This suggests that rapid estrogen-mediated learning enhancements may predominantly be mediated through ERalpha, while the effects of DPN are weaker and may depend on the learning paradigm. The role of ERalpha and ERbeta in learning and memory may vary depending on the timing of drug administration, as genomic studies often implicate ERbeta in enhancing effects on learning and memory. To our knowledge, this is the first report of estrogens' effects on learning within such a short time frame. PMID- 21285322 TI - Guinea pig kisspeptin neurons are depolarized by leptin via activation of TRPC channels. AB - Hypothalamic kisspeptin neurons are critical for driving reproductive function, but virtually nothing is known about their endogenous electrophysiological properties and the effects of leptin on their excitability. Therefore, we used the slice preparation from female guinea pigs to study the endogenous conductances and the effects of leptin on kisspeptin neurons. We targeted the arcuate kisspeptin neurons using visualized-patch whole-cell recording and identified kisspeptin neurons using immuocytochemical staining for kisspeptin or single cell RT-PCR. We also harvested dispersed arcuate neurons for analysis of expression of channel transcripts. Kisspeptin neurons exhibited a relatively negative resting membrane potential, and eighty percent of the neurons expressed a pacemaker current (h-current) and a T-type Ca(2+) current. Furthermore, the glutamate receptor agonist N-methyl D-aspartic acid depolarized and induced burst firing in kisspeptin neurons. Leptin activated an inward current that depolarized kisspeptin neurons and increased (burst) firing, but leptin hyperpolarized NPY neurons. Lanthanum, a TRPC-4,-5 channel activator, potentiated the leptin-induced inward current by 170%. The leptin-activated current reversed near -15 mV and was abrogated by the relatively selective TRPC channel blocker 2-APB. The leptin effects were also blocked by a Janus kinase inhibitor, a phosphatidylinositol 3 kinase inhibitor, and a phospholipase Cgamma inhibitor. In addition, the majority of these neurons expressed TRPC1 and -5 and phospholipase Cgamma1 based on single cell RT-PCR. Therefore, guinea pig kisspeptin neurons express endogenous pacemaker currents, and leptin excites these neurons via activation of TRPC channels. The leptin excitatory effects on kisspeptin neurons may be critical for governing the excitatory drive to GnRH neurons during different nutritional states. PMID- 21285323 TI - Neonatal exposure to bisphenol A alters rat uterine implantation-associated gene expression and reduces the number of implantation sites. AB - Endocrine disrupters have been associated with reproductive pathologies such as infertility and gynecological tumors. Using a rat model of early postnatal exposure to bisphenol A (BPA), we evaluated the long-term effects on 1) female reproductive performance, 2) uterine homeobox A10 (Hoxa10) and Hoxa10-target gene expression, and 3) ovarian steroid levels and uterine estrogen receptor alpha and progesterone (P) receptor expression. Newborn female rats received vehicle, BPA.05 (0.05 mg/kg . d), BPA20 (20 mg/kg . d), diethylstilbestrol.2 (0.2 MUg/kg . d), or diethylstilbestrol 20 (20 MUg/kg . d) on postnatal d 1, 3, 5, and 7. A significant decrease in the number of implantation sites was assessed in the xenoestrogen-exposed females. To address the molecular effects of postnatal xenoestrogen exposure on the pregnant uterus, we evaluated the expression of implantation-associated genes on d 5 of pregnancy (preimplantation uterus). All xenoestrogen-treated rats showed a lower expression of Hoxa10. In the same animals, two Hoxa10-downstream genes were misregulated in the uterus. beta(3) Integrin, which is up-regulated by Hoxa10 in controls, was decreased, whereas empty spiracles homolog 2, which is down-regulated by Hoxa10, was increased. Furthermore a clear down-regulation of estrogen receptor alpha and P receptor expression was detected without changes in estradiol and P serum levels. The early exposure to BPA produced a lower number of implantation sites in association with a defective uterine environment during the preimplantation period. Alterations in the endocrine-regulated Hoxa10 gene pathways (steroid receptors--Hoxa10--beta(3) integrin/empty spiracles homolog 2) could explain, at least in part, the BPA effects on the implantation process. PMID- 21285324 TI - Neuropeptide Y and agouti-related peptide mediate complementary functions of hyperphagia and reduced energy expenditure in leptin receptor deficiency. AB - Neuropeptide Y (NPY) and agouti-related peptide (AGRP) can produce hyperphagia, reduce energy expenditure, and promote triglyceride deposition in adipose depots. As these two neuropeptides are coexpressed within the hypothalamic arcuate nucleus and mediate a major portion of the obesity caused by leptin signaling deficiency, we sought to determine whether the two neuropeptides mediated identical or complementary actions. Because of separate neuropeptide receptors and signal transduction mechanisms, there is a possibility of distinct encoding systems for the feeding and energy expenditure aspects of leptin-regulated metabolism. We have genetically added NPY deficiency and/or AGRP deficiency to LEPR deficiency isolated to AGRP cells. Our results indicate that the obesity of LEPR deficiency in AGRP/NPY neurons can produce obesity with either AGRP or NPY alone with AGRP producing hyperphagia while NPY promotes reduced energy expenditure. The absence of both NPY and AGRP prevents the development of obesity attributable to isolated LEPR deficiency in AGRP/NPY neurons. Operant behavioral testing indicated that there were no alterations in the reward for a food pellet from the AGRP-specific LEPR deficiency. PMID- 21285325 TI - Maternal protein restriction in the rat inhibits placental insulin, mTOR, and STAT3 signaling and down-regulates placental amino acid transporters. AB - The mechanisms underlying reduced fetal growth in response to maternal protein restriction are not well established. Maternal levels of insulin, IGF-I, and leptin are decreased in rats fed a low protein (LP) diet. Because these hormones stimulate placental amino acid transporters in vitro, we hypothesized that maternal protein restriction inhibits placental leptin, insulin/IGF-I, and mammalian target of rapamycin signaling and down-regulates the expression and activity of placental amino acid transporters. Pregnant rats were fed either an isocaloric low protein (LP, 4% protein) or control diet (18% protein) and studied at gestational day (GD)15, GD19, or GD21 (term 23). At GD19 and GD21, placental expression of phosphorylated eukaryotic initiation factor 4E binding protein 1 (Thr-36/46 or Thr-70) and phosphorylated S6 ribosomal protein (Ser-235/236) was decreased in the LP group. In addition, placental expression of phosphorylated S6 kinase 1 (Thr-389), phosphorylated Akt (Thr-308), and phosphorylated signal transducer and activator of transcription 3 (Tyr-705) was reduced at GD21. In microvillous plasma membranes (MVM) isolated from placentas of LP animals, protein expression of the sodium-coupled neutral amino acid transporter (SNAT)2 and the large neutral amino acid transporters 1 and 2 was reduced at GD19 and GD21. MVM SNAT1 protein expression was reduced at GD21 in LP rats. SNAT4 and 4F2 heavy chain expression in MVM was unaltered. System A and L amino acid transporter activity was decreased in MVM from LP animals at GD19 and GD21. In conclusion, maternal protein restriction inhibits placental insulin, mammalian target of rapamycin signaling, and signal transducer and activator of transcription 3 signaling, which is associated with a down-regulation of placental amino acid transporters. We speculate that maternal endocrine and metabolic control of placental nutrient transport reduces fetal growth in response to protein restriction. PMID- 21285326 TI - Tonic extrasynaptic GABA(A) receptor currents control gonadotropin-releasing hormone neuron excitability in the mouse. AB - It is well established that the GABA(A) receptor plays an important role in regulating the electrical excitability of GnRH neurons. Two different modes of GABA(A) receptor signaling exist: one mediated by synaptic receptors generating fast (phasic) postsynaptic currents and the other mediated by extrasynaptic receptors generating a persistent (tonic) current. Using GABA(A) receptor antagonists picrotoxin, bicuculline methiodide, and gabazine, which differentiate between phasic and tonic signaling, we found that ~50% of GnRH neurons exhibit an approximately 15-pA tonic GABA(A) receptor current in the acute brain slice preparation. The blockade of either neuronal (NO711) or glial (SNAP-5114) GABA transporter activity within the brain slice revealed the presence of tonic GABA signaling in ~90% of GnRH neurons. The GABA(A) receptor delta subunit is only found in extrasynaptic GABA(A) receptors. Using single-cell RT-PCR, GABA(A) receptor delta subunit mRNA was identified in GnRH neurons and the delta subunit specific agonist 4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridin-3-ol was found to activate inward currents in GnRH neurons. Perforated-patch clamp studies showed that 4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridin-3-ol exerted the same depolarizing or hyperpolarizing effects as GABA on juvenile and adult GnRH neurons and that tonic GABA(A) receptor signaling regulates resting membrane potential. Together, these studies reveal the presence of a tonic GABA(A) receptor current in GnRH neurons that controls their excitability. The level of tonic current is dependent, in part, on neuronal and glial GABA transporter activity and mediated by extrasynaptic delta subunit-containing GABA(A) receptors. PMID- 21285327 TI - Cell wall hemicellulose contributes significantly to aluminum adsorption and root growth in Arabidopsis. AB - The cell wall (CW) has been recognized as the major target of aluminum (Al) toxicity. However, the components responsible for Al accumulation and the mechanisms of Al-induced CW function disruption are still elusive. The contribution of different CW components (pectin, hemicellulose 1 [HC1], and HC2) to adsorb Al and the effect of Al on xyloglucan endotransglucosylase/hydrolyase activity were investigated in Arabidopsis (Arabidopsis thaliana) in this study. A fractionation procedure was optimized to effectively extract different CW components, especially to prevent the HC fraction from pectin contamination. When CW materials extracted from Al-treated roots (50 MUm Al for 24 h) were fractionated, about 75% of CW Al accumulated in the HC1 fraction. A time dependent kinetic study showed that only when the HC1 fraction was removed was the amount of Al adsorbed decreased sharply. In vivo localization of xyloglucan endotransglucosylase (XET) activity showed that Al greatly inhibited this enzyme activity within 30 min of exposure, which was concomitant with Al-induced callose deposition in roots. Results from real-time reverse transcription-polymerase chain reaction indicated that three genes may constitute the major contributors to XET activity and that the inhibition of XET activity by Al is caused by transcriptional regulation. These results, to our knowledge for the first time, demonstrate that HC is the major pool for Al accumulation. Furthermore, Al induced reduction in XET activity could play an important role in Al-induced root growth inhibition. PMID- 21285328 TI - The R2R3 MYB transcription factor DUO1 activates a male germline-specific regulon essential for sperm cell differentiation in Arabidopsis. AB - The male germline in flowering plants arises through asymmetric division of a haploid microspore. The resulting germ cell undergoes mitotic division and specialization to produce the two sperm cells required for double fertilization. The male germline-specific R2R3 MYB transcription factor DUO1 POLLEN1 (DUO1) plays an essential role in sperm cell specification by activating a germline specific differentiation program. Here, we show that ectopic expression of DUO1 upregulates a significant number (~63) of germline-specific or enriched genes, including those required for fertilization. We validated 14 previously unknown DUO1 target genes by demonstrating DUO1-dependent promoter activity in the male germline. DUO1 is shown to directly regulate its target promoters through binding to canonical MYB sites, suggesting that the DUO1 target genes validated thus far are likely to be direct targets. This work advances knowledge of the DUO1 regulon that encompasses genes with a range of cellular functions, including transcription, protein fate, signaling, and transport. Thus, the DUO1 regulon has a major role in shaping the germline transcriptome and functions to commit progenitor germ cells to sperm cell differentiation. PMID- 21285330 TI - A cost analysis is premature. PMID- 21285331 TI - Six-day dexamethasone use may be hazardous in infants with bronchiolitis [correction of brochiolitis]. PMID- 21285332 TI - Economic impacts of bronchiolitis. PMID- 21285334 TI - Policy statement--recommended childhood and adolescent immunization schedules- United States, 2011. PMID- 21285335 TI - Neurodiagnostic evaluation of the child with a simple febrile seizure. AB - OBJECTIVE: To formulate evidence-based recommendations for health care professionals about the diagnosis and evaluation of a simple febrile seizure in infants and young children 6 through 60 months of age and to revise the practice guideline published by the American Academy of Pediatrics (AAP) in 1996. METHODS: This review included search and analysis of the medical literature published since the last version of the guideline. Physicians with expertise and experience in the fields of neurology and epilepsy, pediatrics, epidemiology, and research methodologies constituted a subcommittee of the AAP Steering Committee on Quality Improvement and Management. The steering committee and other groups within the AAP and organizations outside the AAP reviewed the guideline. The subcommittee member who reviewed the literature for the 1996 AAP practice guidelines searched for articles published since the last guideline through 2009, supplemented by articles submitted by other committee members. Results from the literature search were provided to the subcommittee members for review. Interventions of direct interest included lumbar puncture, electroencephalography, blood studies, and neuroimaging. Multiple issues were raised and discussed iteratively until consensus was reached about recommendations. The strength of evidence supporting each recommendation and the strength of the recommendation were assessed by the committee member most experienced in informatics and epidemiology and graded according to AAP policy. CONCLUSIONS: Clinicians evaluating infants or young children after a simple febrile seizure should direct their attention toward identifying the cause of the child's fever. Meningitis should be considered in the differential diagnosis for any febrile child, and lumbar puncture should be performed if there are clinical signs or symptoms of concern. For any infant between 6 and 12 months of age who presents with a seizure and fever, a lumbar puncture is an option when the child is considered deficient in Haemophilus influenzae type b (Hib) or Streptococcus pneumoniae immunizations (ie, has not received scheduled immunizations as recommended), or when immunization status cannot be determined, because of an increased risk of bacterial meningitis. A lumbar puncture is an option for children who are pretreated with antibiotics. In general, a simple febrile seizure does not usually require further evaluation, specifically electroencephalography, blood studies, or neuroimaging. PMID- 21285336 TI - A mechanistic and structural analysis of the inhibition of the 90-kDa heat shock protein by the benzoquinone and hydroquinone ansamycins. AB - The benzoquinone ansamycins inhibit the ATPase activity of the 90-kDa heat shock protein (Hsp90), disrupting the function of numerous client proteins involved in oncogenesis. In this study, we examine the role of NAD(P)H:quinone oxidoreductase 1 (NQO1) in the metabolism of trans- and cis-amide isomers of the benzoquinone ansamycins and their mechanism of Hsp90 inhibition. Inhibition of purified human Hsp90 by a series of benzoquinone ansamycins was examined in the presence and absence of NQO1, and their relative rate of NQO1-mediated reduction was determined. Computational-based molecular docking simulations indicated that the trans- but not the cis-amide isomers of the benzoquinone ansamycins could be accommodated by the NQO1 active site, and the ranking order of binding energies correlated with the relative reduction rate using purified human NQO1. The trans cis isomerization of the benzoquinone ansamycins in Hsp90 inhibition has been disputed in recent reports. Previous computational studies have used the closed or cocrystallized Hsp90 structures in an attempt to explore this isomerization step; however, we have successfully docked both the trans- and cis-amide isomers of the benzoquinone ansamycins into the open Hsp90 structure. The results of these studies indicate that both trans- and cis-amide isomers of the hydroquinone ansamycins exhibited increased binding affinity for Hsp90 relative to their parent quinones. Our data support a mechanism in which trans- rather than cis amide forms of benzoquinone ansamycins are metabolized by NQO1 to hydroquinone ansamycins and that Hsp90-mediated trans-cis isomerization via tautomerization plays an important role in subsequent Hsp90 inhibition. PMID- 21285337 TI - Screening breast MR imaging: comparison of interpretation of baseline and annual follow-up studies. AB - PURPOSE: To determine whether baseline screening breast magnetic resonance (MR) imaging studies have a higher rate of follow-up or biopsy recommendation than do studies with prior MR images available for comparison. MATERIALS AND METHODS: This was an institutional review board-approved, HIPAA-compliant, retrospective study. Informed consent was waived. Reports from 650 consecutive screening breast MR imaging examinations performed in women between September 2007 and December 2008 were reviewed. All examinations were performed by using the same protocol, and images were interpreted by the same radiologists. Presence of comparison studies, Breast Imaging Reporting and Data System (BI-RADS) category, and biopsy results were recorded. Data were analyzed by using the chi(2) test, the two sample test of proportions, and the Fisher exact test. RESULTS: Mean patient age was 51 years (range, 25-81 years). Of the baseline studies, findings in 31 of 307 (10.1%) were interpreted as BI-RADS category 3 and findings in 18 of 307 (5.9%) were interpreted as BI-RADS category 4 or 5. Of the examinations with findings classified as BI-RADS category 4 or 5, the results in two of 18 (11.1%) were positive for malignancy at biopsy. Of the examinations with prior MR images for comparison, findings in nine of 343 (2.6%) were interpreted as BI-RADS category 3 and findings in 16 of 343 (4.7%) were interpreted as BI-RADS category 4 or 5. Of the examinations with findings classified as BI-RADS category 4 or 5, the results in three of 16 (18.8%) were positive for malignancy at biopsy. The difference in the number of BI-RADS category 3 interpretations between the two groups was significant (P < .001), but there was no significant difference in BI-RADS category 4 or 5 interpretations or positive predictive values. CONCLUSION: Baseline screening MR imaging was associated with a higher likelihood of recommendation for short-interval follow-up than was MR imaging with prior images for comparison. PMID- 21285338 TI - Hypertension: Don't worry about the J curve--treat the patient. PMID- 21285339 TI - Q: How should one investigate a chronic cough? PMID- 21285340 TI - Caring for VIPs: nine principles. AB - Caring for very important persons (VIPs), including celebrities and royalty, presents medical, organizational, and administrative challenges, often referred to collectively as the "VIP syndrome." The situation often pressures the health care team to bend the rules by which they usually practice medicine. Caring for VIP patients requires innovative solutions so that their VIP status does not adversely affect the care they receive. We offer nine guiding principles in caring for VIP patients. PMID- 21285341 TI - Seek and treat: HIV update 2011. AB - Although mortality rates from human immunodeficiency virus (HIV) infection have declined dramatically in the United States, the incidence of new infections has not improved for more than a decade. The case is now strong for routine screening and early treatment of HIV infection to reduce transmission of the infection and to give patients an opportunity to live a reasonably healthy life. Clinicians in all health care settings should routinely and matter-of-factly test their patients for HIV infection, just as they screen for other diseases. PMID- 21285342 TI - Airway pressure release ventilation: an alternative mode of mechanical ventilation in acute respiratory distress syndrome. AB - Acute respiratory distress syndrome (ARDS) results in collapse of alveoli and therefore poor oxygenation. In this article, we review airway pressure release ventilation (APRV), a mode of mechanical ventilation that may be useful when, owing to ARDS, areas of the lungs are collapsed and need to be reinflated ("recruited"), avoiding cyclic alveolar collapse and reopening. PMID- 21285343 TI - Air travel and venous thromboembolism: minimizing the risk. AB - For those traveling on long flights, the risk of deep vein thrombosis or pulmonary embolism, generally referred to as venous thromboembolism (VTE), is real and dangerous if left unrecognized or untreated. The goal of this publication is to provide an overview of how best to prevent VTE during travel, and how to diagnose and treat it. PMID- 21285344 TI - Patient information. Exercises for air travel. PMID- 21285345 TI - Goal-directed antihypertensive therapy: lower may not always be better. AB - At least 16 treatment trials have been done in which patients were randomly assigned different blood pressure goals in an attempt to better define specific target pressures. We critically review the data. PMID- 21285346 TI - Research integrity in communication sciences and disorders: preface. AB - PURPOSE: A joint program on Research on Research Integrity sponsored by the National Institute of Neurological Disorders and Stroke and the Office of Research Integrity encouraged the examination of practices and policies promoting the responsible conduct of research (RCR). The authors' grant--Research Integrity in ASHA: Education and Publication--enabled American Speech-Language-Hearing Association's (ASHA) Research Integrity Grant Group to (a) identify patterns of teaching and learning in Communication Sciences and Disorders graduate programs about specific topics of research integrity on the conduct of science, (b) examine perceptions about concepts of research integrity as they apply to scientific journals within the discipline, and (c) evaluate policies and practices established by ASHA to protect the integrity of published scientific work. METHOD: The authors reviewed historical and contemporary literature, conducted surveys, and analyzed ASHA policies. CONCLUSION: This supplement of the Journal of Speech, Language, and Hearing Research has been written with the aim of informing and inspiring scientists, students, research institutions, and professional societies to practice responsible research in the 21st century and beyond. PMID- 21285347 TI - MSH3 mediates sensitization of colorectal cancer cells to cisplatin, oxaliplatin, and a poly(ADP-ribose) polymerase inhibitor. AB - The MSH3 gene is one of the DNA mismatch repair (MMR) genes that has undergone somatic mutation frequently in MMR-deficient cancers. MSH3, together with MSH2, forms the MutSbeta heteroduplex, which interacts with interstrand cross-links (ICLs) induced by drugs such as cisplatin and psoralen. However, the precise role of MSH3 in mediating the cytotoxic effects of ICL-inducing agents remains poorly understood. In this study, we first examined the effects of MSH3 deficiency on cytotoxicity caused by cisplatin and oxaliplatin, another ICL-inducing platinum drug. Using isogenic HCT116-derived clones in which MSH3 expression is controlled by shRNA expression in a Tet-off system, we discovered that MSH3 deficiency sensitized cells to both cisplatin and oxaliplatin at clinically relevant doses. Interestingly, siRNA-induced down-regulation of the MLH1 protein did not affect MSH3-dependent toxicity of these drugs, indicating that this process does not require participation of the canonical MMR pathway. Furthermore, MSH3-deficient cells maintained higher levels of phosphorylated histone H2AX and 53BP1 after oxaliplatin treatment in comparison with MSH3-proficient cells, suggesting that MSH3 plays an important role in repairing DNA double strand breaks (DSBs). This role of MSH3 was further supported by our findings that MSH3-deficient cells were sensitive to olaparib, a poly(ADP-ribose) polymerase inhibitor. Moreover, the combination of oxaliplatin and olaparib exhibited a synergistic effect compared with either treatment individually. Collectively, our results provide novel evidence that MSH3 deficiency contributes to the cytotoxicity of platinum drugs through deficient DSB repair. These data lay the foundation for the development of effective prediction and treatments for cancers with MSH3 deficiency. PMID- 21285348 TI - Sequential activation and inactivation of Dishevelled in the Wnt/beta-catenin pathway by casein kinases. AB - Dishevelled (Dvl) is a key component in the Wnt/beta-catenin signaling pathway. Dvl can multimerize to form dynamic protein aggregates, which are required for the activation of downstream signaling. Upon pathway activation by Wnts, Dvl becomes phosphorylated to yield phosphorylated and shifted (PS) Dvl. Both activation of Dvl in Wnt/beta-catenin signaling and Wnt-induced PS-Dvl formation are dependent on casein kinase 1 (CK1) delta/epsilon activity. However, the overexpression of CK1 was shown to dissolve Dvl aggregates, and endogenous PS-Dvl forms irrespective of whether or not the activating Wnt triggers the Wnt/beta catenin pathway. Using a combination of gain-of-function, loss-of-function, and domain mapping approaches, we attempted to solve this discrepancy regarding the role of CK1epsilon in Dvl biology. We analyzed mutual interaction of CK1delta/epsilon and two other Dvl kinases, CK2 and PAR1, in the Wnt/beta-catenin pathway. We show that CK2 acts as a constitutive kinase whose activity is required for the further action of CK1epsilon. Furthermore, we demonstrate that the two consequences of CK1epsilon phosphorylation are separated both spatially and functionally; first, CK1epsilon-mediated induction of TCF/LEF-driven transcription (associated with dynamic recruitment of Axin1) is mediated via a PDZ-proline-rich region of Dvl. Second, CK1epsilon-mediated formation of PS-Dvl is mediated by the Dvl3 C terminus. Furthermore, we demonstrate with several methods that PS-Dvl has decreased ability to polymerize with other Dvls and could, thus, act as the inactive signaling intermediate. We propose a multistep and multikinase model for Dvl activation in the Wnt/beta-catenin pathway that uncovers a built-in de-activation mechanism that is triggered by activating phosphorylation of Dvl by CK1delta/epsilon. PMID- 21285349 TI - Mapping the interactions between Escherichia coli TolQ transmembrane segments. AB - The tolQRAB-pal operon is conserved in Gram-negative genomes. The TolQRA proteins of Escherichia coli form an inner membrane complex in which TolQR uses the proton motive force to regulate TolA conformation and the in vivo interaction of TolA C terminal region with the outer membrane Pal lipoprotein. The stoichiometry of the TolQ, TolR, and TolA has been estimated and suggests that 4-6 TolQ molecules are associated in the complex, thus involving interactions between the transmembrane helices (TMHs) of TolQ, TolR, and TolA. It has been proposed that an ion channel forms at the interface between two TolQ and one TolR TMHs involving the TolR Asp(23), TolQ-Thr(145), and TolQ-Thr(178) residues. To define the organization of the three TMHs of TolQ, we constructed epitope-tagged versions of TolQ. Immunodetection of in vivo and in vitro chemically cross-linked TolQ proteins showed that TolQ exists as multimers in the complex. To understand how TolQ multimerizes, we initiated a cysteine-scanning study. Results of single and tandem cysteine substitution suggest a dynamic model of helix interactions in which the hairpin formed by the two last TMHs of TolQ change conformation, whereas the first TMH of TolQ forms intramolecular interactions. PMID- 21285350 TI - Phosphoinositide 3-kinase regulates plasma membrane targeting of the Ras-specific exchange factor RasGRP1. AB - Receptor-induced targeting of exchange factors to specific cellular membranes is the predominant mechanism for initiating and compartmentalizing signal transduction by Ras GTPases. The exchange factor RasGRP1 has a C1 domain that binds the lipid diacylglycerol and thus can potentially mediate membrane localization in response to receptors that are coupled to diacylglycerol generating phospholipase Cs. However, the C1 domain is insufficient for targeting RasGRP1 to the plasma membrane. We found that a basic/hydrophobic cluster of amino acids within the plasma membrane-targeting domain of RasGRP1 is instead responsible for plasma membrane targeting. This basic/hydrophobic cluster binds directly to phospholipid vesicles containing phosphoinositides via electrostatic interactions with polyanionic phosphoinositide headgroups and insertion of a tryptophan into the lipid bilayer. B cell antigen receptor ligation and other stimuli induce plasma membrane targeting of RasGRP1 by activating the phosphoinositide 3-kinase signaling pathway, which generates phosphoinositides within the plasma membrane. Direct detection of phosphoinositides by the basic/hydrophobic cluster of RasGRP1 provides a novel mechanism for coupling and co-compartmentalizing phosphoinositide 3-kinase and Ras signaling and, in coordination with diacylglycerol detection by the C1 domain, gives RasGRP1 the potential to serve as an integrator of converging signals from the phosphoinositide 3-kinase and phospholipase C pathways. PMID- 21285351 TI - Structure and function of PilQ, a secretin of the DNA transporter from the thermophilic bacterium Thermus thermophilus HB27. AB - Secretins are a family of large bacterial outer membrane protein complexes mediating the transport of complex structures, such as type IV pili, DNA and filamentous phage, or various proteins, such as extracellular enzymes and pathogenicity determinants. PilQ of the thermophilic bacterium Thermus thermophilus HB27 is a member of the secretin family required for natural transformation. Here we report the isolation, structural, and functional analyses of a unique PilQ from T. thermophilus. Native PAGE, gel filtration chromatography, and electrophoretic mobility shift analyses indicated that PilQ forms a macromolecular homopolymeric complex that binds dsDNA. Electron microscopy showed that the PilQ complex is 15 nm wide and 34 nm long and consists of an extraordinary stable "cone" and "cup" structure and five ring structures with a large central channel. Moreover, the electron microscopic images together with secondary structure analyses combined with structural data of type II protein secretion system and type III protein secretion system secretins suggest that the individual rings are formed by conserved domains of alternating alpha helices and beta-sheets. The unprecedented length of the PilQ complex correlated well with the distance between the inner and outer membrane of T. thermophilus. Indeed, PilQ was found immunologically in both membranes, indicating that the PilQ complex spans the entire cell periphery of T. thermophilus. This is consistent with the hypothesis that PilQ accommodates a PilA4 comprising pseudopilus mediating DNA transport across the outer membrane and periplasmic space in a single-step process. PMID- 21285352 TI - Phosphorylation of TCF proteins by homeodomain-interacting protein kinase 2. AB - Wnt pathways play essential roles in cell proliferation, morphogenesis, and cell fate specification during embryonic development. According to the consensus view, the Wnt pathway prevents the degradation of the key signaling component beta catenin by the protein complex containing the negative regulators Axin and glycogen synthase kinase 3 (GSK3). Stabilized beta-catenin associates with TCF proteins and enters the nucleus to promote target gene expression. This study examines the involvement of HIPK2 (homeodomain-interacting protein kinase 2) in the regulation of different TCF proteins in Xenopus embryos in vivo. We show that the TCF family members LEF1, TCF4, and TCF3 are phosphorylated in embryonic ectoderm after Wnt8 stimulation and HIPK2 overexpression. We also find that TCF3 phosphorylation is triggered by canonical Wnt ligands, LRP6, and dominant negative mutants for Axin and GSK3, indicating that this process shares the same upstream regulators with beta-catenin stabilization. HIPK2-dependent phosphorylation caused the dissociation of LEF1, TCF4, and TCF3 from a target promoter in vivo. This result provides a mechanistic explanation for the context dependent function of HIPK2 in Wnt signaling; HIPK2 up-regulates transcription by phosphorylating TCF3, a transcriptional repressor, but inhibits transcription by phosphorylating LEF1, a transcriptional activator. Finally, we show that upon HIPK2-mediated phosphorylation, TCF3 is replaced with positively acting TCF1 at a target promoter. These observations emphasize a critical role for Wnt/HIPK2 dependent TCF phosphorylation and suggest that TCF switching is an important mechanism of Wnt target gene activation in vertebrate embryos. PMID- 21285353 TI - hMSH2 recruits ATR to DNA damage sites for activation during DNA damage-induced apoptosis. AB - DNA damage response (DDR) activates a complex signaling network that triggers DNA repair, cell cycle arrest, and/or cell death. Depending on the type and severity of DNA lesion, DDR is controlled by "master" regulators including ATM and ATR protein kinases. Cisplatin, a major chemotherapy drug that cross-links DNA, induces ATR-dependent DDR, resulting in apoptosis. However, it is unclear how ATR is activated. To identify the key regulators of ATR, we analyzed the proteins that associate with ATR after cisplatin treatment by blue native-PAGE and co immunoprecipitation. The mismatch repair protein hMSH2 was found to be a major ATR-binding protein. Functionally, ATR activation and its recruitment to nuclear foci during cisplatin treatment were attenuated, and DNA damage signaling, involving Chk2, p53, and PUMA-alpha, was suppressed in hMSH2-deficient cells. ATR activation induced by the DNA methylating agent N-methyl-N-nitrosourea was also shown to be hMSH2-dependent. Intriguingly, hMSH2-mediated ATR recruitment and activation appeared independent of replication protein A, Rad17, and the Rad9 Hus1-Rad1 protein complex. Together the results support a hMSH2-dependent pathway of ATR activation and downstream Chk2/p53 signaling. PMID- 21285354 TI - Simple generation of human induced pluripotent stem cells using poly-beta-amino esters as the non-viral gene delivery system. AB - Reprogramming of somatic cells to induced pluripotent stem (iPS) cells can be achieved by the delivery of a combination of transcription factors, including Oct4, Sox2, Klf4, and c-Myc. Retroviral and lentiviral vectors are commonly used to express these four reprogramming factors separately and obtain reprogrammed iPS cells. Although efficient and reproducible, these approaches involve the time consuming and labor-intensive production of retroviral or lentiviral particles together with a high risk of working with potentially harmful viruses overexpressing potent oncogenes, such as c-Myc. Here, we describe a simple method to produce bona fide iPS cells from human fibroblasts using poly-beta-amino esters as the transfection reagent for the delivery of a single CAG-driven polycistronic plasmid expressing Oct4, Sox2, Klf4, c-Myc, and a GFP reporter gene (OSKMG). We demonstrate for the first time that poly-beta-amino esters can be used to deliver a single polycistronic reprogramming vector into human fibroblasts, achieving significantly higher transfection efficiency than with conventional transfection reagents. After a protocol of serial transfections using poly-beta-amino esters, we report a simple methodology to generate human iPS cells from human fibroblasts avoiding the use of viral vectors. PMID- 21285355 TI - A dominant-negative Galpha mutant that traps a stable rhodopsin-Galpha-GTP betagamma complex. AB - Residues comprising the guanine nucleotide-binding sites of the alpha subunits of heterotrimeric (large) G-proteins (Galpha subunits), as well as the Ras-related (small) G-proteins, are highly conserved. This is especially the case for the phosphate-binding loop (P-loop) where both Galpha subunits and Ras-related G proteins have a conserved serine or threonine residue. Substitutions for this residue in Ras and related (small) G-proteins yield nucleotide-depleted, dominant negative mutants. Here we have examined the consequences of changing the conserved serine residue in the P-loop to asparagine, within a chimeric Galpha subunit (designated alphaT*) that is mainly comprised of the alpha subunit of the retinal G-protein transducin and a limited region from the alpha subunit of Gi1. The alphaT*(S43N) mutant exhibits a significantly higher rate of intrinsic GDP GTP exchange compared with wild-type alphaT*, with light-activated rhodopsin (R*) causing only a moderate increase in the kinetics of nucleotide exchange on alphaT*(S43N). The alphaT*(S43N) mutant, when bound to either GDP or GTP, was able to significantly slow the rate of R*-catalyzed GDP-GTP exchange on wild-type alphaT*. Thus, GTP-bound alphaT*(S43N), as well as the GDP-bound mutant, is capable of forming a stable complex with R*. alphaT*(S43N) activated the cGMP phosphodiesterase (PDE) with a dose-response similar to wild-type alphaT*. Activation of the PDE by alphaT*(S43N) was unaffected if either R* or beta1gamma1 alone was present, whereas it was inhibited when R* and the beta1gamma1 subunit were added together. Overall, our studies suggest that the S43N substitution on alphaT* stabilizes an intermediate on the G-protein activation pathway consisting of an activated G-protein-coupled receptor, a GTP-bound Galpha subunit, and the beta1gamma1 complex. PMID- 21285356 TI - Non-B DNA-forming sequences and WRN deficiency independently increase the frequency of base substitution in human cells. AB - Although alternative DNA secondary structures (non-B DNA) can induce genomic rearrangements, their associated mutational spectra remain largely unknown. The helicase activity of WRN, which is absent in the human progeroid Werner syndrome, is thought to counteract this genomic instability. We determined non-B DNA induced mutation frequencies and spectra in human U2OS osteosarcoma cells and assessed the role of WRN in isogenic knockdown (WRN-KD) cells using a supF gene mutation reporter system flanked by triplex- or Z-DNA-forming sequences. Although both non-B DNA and WRN-KD served to increase the mutation frequency, the increase afforded by WRN-KD was independent of DNA structure despite the fact that purified WRN helicase was found to resolve these structures in vitro. In U2OS cells, ~70% of mutations comprised single-base substitutions, mostly at G.C base pairs, with the remaining ~30% being microdeletions. The number of mutations at G.C base-pairs in the context of NGNN/NNCN sequences correlated well with predicted free energies of base stacking and ionization potentials, suggesting a possible origin via oxidation reactions involving electron loss and subsequent electron transfer (hole migration) between neighboring bases. A set of ~40,000 somatic mutations at G.C base pairs identified in a lung cancer genome exhibited similar correlations, implying that hole migration may also be involved. We conclude that alternative DNA conformations, WRN deficiency and lung tumorigenesis may all serve to increase the mutation rate by promoting, through diverse pathways, oxidation reactions that perturb the electron orbitals of neighboring bases. It follows that such "hole migration" is likely to play a much more widespread role in mutagenesis than previously anticipated. PMID- 21285357 TI - Protein-arginine methyltransferase 1 (PRMT1) methylates Ash2L, a shared component of mammalian histone H3K4 methyltransferase complexes. AB - Multiple enzymes and enzymatic complexes coordinately regulate the addition and removal of post-translational modifications on histone proteins. The oncoprotein Ash2L is a component of the mixed lineage leukemia (MLL) family members 1-4, Setd1A, and Setd1B mammalian histone H3K4 methyltransferase complexes and is essential to maintain global trimethylation of histone H3K4. However, regulation of these complexes at the level of expression and activity remains poorly understood. In this report, we demonstrate that Ash2L is methylated on arginine residues both in vitro and in cells. We found that both protein-arginine methyltransferases 1 and 5 methylate Arg-296 within Ash2L. These findings are the first to demonstrate that post-translational modifications occur on the Ash2L protein and provide a novel example of cross-talk between chromatin-modifying enzyme complexes. PMID- 21285358 TI - Protein kinase D negatively regulates hepatitis C virus secretion through phosphorylation of oxysterol-binding protein and ceramide transfer protein. AB - Hepatitis C virus (HCV) RNA replicates its genome on specialized endoplasmic reticulum modified membranes termed membranous web and utilizes lipid droplets for initiating the viral nucleocapsid assembly. HCV maturation and/or the egress pathway requires host sphingolipid synthesis, which occur in the Golgi. Ceramide transfer protein (CERT) and oxysterol-binding protein (OSBP) play a crucial role in sphingolipid biosynthesis. Protein kinase D (PKD), a serine/threonine kinase, is recruited to the trans-Golgi network where it influences vesicular trafficking to the plasma membrane by regulation of several important mediators via phosphorylation. PKD attenuates the function of both CERT and OSBP by phosphorylation at their respective Ser(132) and Ser(240) residues (phosphorylation inhibition). Here, we investigated the functional role of PKD in HCV secretion. Our studies show that HCV gene expression down-regulated PKD activation. PKD depletion by shRNA or inhibition by pharmacological inhibitor Go6976 enhanced HCV secretion. Overexpression of a constitutively active form of PKD suppressed HCV secretion. The suppression by PKD was subverted by the ectopic expression of nonphosphorylatable serine mutant CERT S132A or OSBP S240A. These observations imply that PKD negatively regulates HCV secretion/release by attenuating OSBP and CERT functions by phosphorylation inhibition. This study identifies the key role of the Golgi components in the HCV maturation process. PMID- 21285360 TI - Assessing the effects of drug price reduction policies on older people in Taiwan. AB - This study investigates the initial effects of the government's prescription drug price reduction policies on outpatient hypertension treatment for the elderly in Taiwan. The National Health Insurance scheme has taken a number of steps in recent years to reduce drug prices. The data used in the study comprises the medical records of approximately 137,000 hypertension patients aged 65 and above. Regression analysis is used to determine whether the average cost of prescription drugs has declined as a result of the policy. In addition, the probit model is used to examine changes in physicians' prescribing behaviour for reduced-price and full-price drugs and the effect of drug substitution on health outcomes. We find that the average cost per prescription increased slightly despite the implementation of the price reduction policies. In addition, we found that physicians do substitute full-price drugs for reduced-price drugs. However, they appear to be reluctant to reduce the use of essential drugs, even when facing rate reductions. The evidence suggests that physicians consider the profit they can derive by prescribing certain drugs; hence, health policy officials should monitor the effects of possible drug substitutions when they design policies for their own countries. PMID- 21285359 TI - Phosphorylation of eIF2 facilitates ribosomal bypass of an inhibitory upstream ORF to enhance CHOP translation. AB - In response to different environmental stresses, phosphorylation of eukaryotic initiation factor-2 (eIF2) rapidly reduces protein synthesis, which lowers energy expenditure and facilitates reprogramming of gene expression to remediate stress damage. Central to the changes in gene expression, eIF2 phosphorylation also enhances translation of ATF4, a transcriptional activator of genes subject to the integrated stress response (ISR). The ISR increases the expression of genes important for alleviating stress or alternatively triggering apoptosis. One ISR target gene encodes the transcriptional regulator CHOP whose accumulation is critical for stress-induced apoptosis. In this study, we show that eIF2 phosphorylation induces preferential translation of CHOP by a mechanism involving a single upstream ORF (uORF) located in the 5'-leader of the CHOP mRNA. In the absence of stress and low eIF2 phosphorylation, translation of the uORF serves as a barrier that prevents translation of the downstream CHOP coding region. Enhanced eIF2 phosphorylation during stress facilitates ribosome bypass of the uORF due to its poor start site context, and instead it allows scanning ribosomes to translate CHOP. This new mechanism of translational control explains how expression of CHOP and the fate of cells are tightly linked to the levels of phosphorylated eIF2 and stress damage. PMID- 21285361 TI - Sociodemographic and socioeconomic determinants of health services utilization in Greece: the Hellas Health I study. AB - The purpose of the study was to estimate the demographic and socioeconomic determinants of utilization of the Greek primary and hospital health care services. Data were obtained from the cross-sectional nationwide household survey Hellas Health I (2006). The sample (N = 1005) was representative of the Greek adult population in terms of age and residency, and was selected by means of a three-stage, proportional-to-size sampling design. The presence of a family doctor was reported in a higher degree by participants of higher social classes and private insurance. After adjusting for self-perceived general health and chronic illness, contacts with health care professionals during the past four weeks were found less for residents of rural areas, while contacts with health care professionals during the past 12 months were found less for men than women, for individuals without private insurance and for individuals of lower education. More out-of-pocket payments were reported by the 34-44 age group, rural area residents and individuals with private insurance. Higher use of private health care services was reported by participants of higher social classes and residents of rural areas and private insurance. Only hospital admissions were not directly influenced by demographic and socioeconomic factors. The findings imply the existence of inequities in access and use of primary health services with clear implications to related policies. PMID- 21285362 TI - A management control approach to monitor large-scale change: an illustration in the context of reconfiguration. AB - The paper describes how Hospital Episode Statistics (HES) data can be retrospectively analysed over a number of years to evaluate and monitor organizational change in National Health Service (NHS) trusts. A methodology based on joinpoint regression analysis and management control theory has been developed which is able to represent in a framework (called an 'activity map') the complexity of HES data in a more user-friendly way than the unwieldy and often overwhelming tables or spreadsheets that are typically utilized. The 'activity map' has been designed to provide a common frame of reference for health professionals from different backgrounds to visualize and interpret the actual patterns of hospital activity changes that have occurred over the years. The aim is to facilitate a more effective, faster and more intuitive exploration of very large and unwieldy HES data-sets to assist health-care staff in monitoring planned and unplanned activity changes. It is hoped that making HES data more easily assimilated will encourage a greater sense of meaningful engagement in creatively contributing to service innovation. PMID- 21285363 TI - The effect on patient loyalty of service quality, patient visit experience and perceived switching costs: lessons from one Taiwan university hospital. AB - The reimbursement system changed from fee-for-service to fixed prospective payments in Taiwan, the effect on the physician-patient's relationship is worth being studied. We examined the relationship between patient visit experience, cost perceptions and the two important aspects of quality of care, curing and interpersonal performance, and patients' loyalty to the hospital physicians. A total of 404 patients from an acute care hospital in Taiwan, Kaohsiung Medical University Hospital (KMUH), were investigated using a self-administered mailing survey. All measures including patient loyalty (PL), curing service quality (CSQ), interpersonal service quality (ISQ), visit experience (VE) and perceived switching costs (PSC), were adapted and modified from existing scales. Our results showed that the physician's CSQ and ISQ positively affected patients' loyalty to KMUH. The interaction between the main effects of service quality, patients' VE and three types of switching visit costs, yielded additional insights into the importance of service quality for patient retention. The CSQ of physicians becomes a more important determinant of loyalty than ISQ as patients' VE increases. The importance of CSQ and ISQ increases in relation to PL as the perceived procedural and relational costs of changing care providers increases. Neither CSQ nor ISQ has a reduced relationship with PL as the perceived financial costs of switching hospitals increase. Our study indicates that the impact of CSQ and ISQ on loyalty varies according to the perceived visit costs of changing hospitals and the patients' VE. PMID- 21285364 TI - A planning model for the short-term management of cash. AB - This paper develops a model that enables the health administrator to identify the balance that minimizes the projected cost of holding cash. Adopting the principles of mathematical expectation, the model estimates the expected total costs of adopting each of the several strategies concerning the cash balance that the organization might maintain. Expected total costs consist of anticipated short costs, resulting from a potential shortage of funds. Long costs are associated with a potential surplus of funds and an opportunity cost represented by foregone investment income. Of importance to the model is the potential for the health service organization to realize a surplus of funds during periods characterized by a net cash disbursement. The paper also develops an interactive spreadsheet that enables the administrator to perform sensitivity analysis and examine the response of the desired or target cash balance to changes in the parameters that define the expected long and short cost functions. PMID- 21285365 TI - The interplay between policy guidelines and local dynamics in shaping the scope of networks: the experience of the Italian Departments of Mental Health. AB - In the mental health field, the creation of networks that can guarantee the smooth coordination of services and organizations across sectors is a priority in the policy agenda of several countries. In Italy, Departments of Mental Health (DMHs) have been designated responsible for the system of specialist mental health services, and also mandated as the conveners and leaders of interorganizational and cross-sectoral networks, by a system-wide reform. This study aims to understand how mental health networks have been assembled in this context and the factors and motivations that have shaped their scope. By combining an analysis of policies with a survey of DMH directors, we have determined that DMHs have preferentially formed collaborative relationships with social service providers (local governments) and the voluntary sector. In contrast, relationships with substance abuse and addiction services and primary care providers were weak and stifled by a lack of trust and by conflict about respective contributions to mental care. We explore the reasons for this selectivity in interorganizational relationships and propose that a lack of targeted incentives in policy guidelines, on the one hand, and the existence of a mandated network leadership, on the other, have led to a rather narrow range of collaborations. PMID- 21285366 TI - Characterizing perceptions of energy consumption. PMID- 21285367 TI - DNA phosphorothioation is widespread and quantized in bacterial genomes. AB - Phosphorothioate (PT) modification of DNA, with sulfur replacing a nonbridging phosphate oxygen, was recently discovered as a product of the dnd genes found in bacteria and archaea. Given our limited understanding of the biological function of PT modifications, including sequence context, genomic frequencies, and relationships to the diversity of dnd gene clusters, we undertook a quantitative study of PT modifications in prokaryotic genomes using a liquid chromatography coupled tandem quadrupole mass spectrometry approach. The results revealed a diversity of unique PT sequence contexts and three discrete genomic frequencies in a wide range of bacteria. Metagenomic analyses of PT modifications revealed unique ecological distributions, and a phylogenetic comparison of dnd genes and PT sequence contexts strongly supports the horizontal transfer of dnd genes. These results are consistent with the involvement of PT modifications in a type of restriction-modification system with wide distribution in prokaryotes. PMID- 21285368 TI - Dual interaction of factor H with C3d and glycosaminoglycans in host-nonhost discrimination by complement. AB - The alternative pathway of complement is important in innate immunity, attacking not only microbes but all unprotected biological surfaces through powerful amplification. It is unresolved how host and nonhost surfaces are distinguished at the molecular level, but key components are domains 19-20 of the complement regulator factor H (FH), which interact with host (i.e., nonactivator surface glycosaminoglycans or sialic acids) and the C3d part of C3b. Our structure of the FH19-20:C3d complex at 2.3-A resolution shows that FH19-20 has two distinct binding sites, FH19 and FH20, for C3b. We show simultaneous binding of FH19 to C3b and FH20 to nonactivator surface glycosaminoglycans, and we show that both of these interactions are necessary for full binding of FH to C3b on nonactivator surfaces (i.e., for target discrimination). We also show that C3d could replace glycosaminoglycan binding to FH20, thus providing a feedback control for preventing excess C3b deposition and complement amplification. This explains the molecular basis of atypical hemolytic uremic syndrome, where mutations on the binding interfaces between FH19-20 and C3d or between FH20 and glycosaminoglycans lead to complement attack against host surfaces. PMID- 21285369 TI - Presenilin 2 modulates endoplasmic reticulum (ER)-mitochondria interactions and Ca2+ cross-talk. AB - Presenilin mutations are the main cause of familial Alzheimer's disease (FAD). Presenilins also play a key role in Ca(2+) homeostasis, and their FAD-linked mutants affect cellular Ca(2+) handling in several ways. We previously have demonstrated that FAD-linked presenilin 2 (PS2) mutants decrease the Ca(2+) content of the endoplasmic reticulum (ER) by inhibiting sarcoendoplasmic reticulum Ca(2+)-ATPase (SERCA) activity and increasing ER Ca(2+) leak. Here we focus on the effect of presenilins on mitochondrial Ca(2+) dynamics. By using genetically encoded Ca(2+) indicators specifically targeted to mitochondria (aequorin- and GFP-based probes) in SH-SY5Y cells and primary neuronal cultures, we show that overexpression or down-regulation of PS2, but not of presenilin 1 (PS1), modulates the Ca(2+) shuttling between ER and mitochondria, with its FAD mutants strongly favoring Ca(2+) transfer between the two organelles. This effect is not caused by a direct PS2 action on mitochondrial Ca(2+)-uptake machinery but rather by an increased physical interaction between ER and mitochondria that augments the frequency of Ca(2+) hot spots generated at the cytoplasmic surface of the outer mitochondrial membrane upon stimulation. This PS2 function adds further complexity to the multifaceted nature of presenilins and to their physiological role within the cell. We also discuss the importance of this additional effect of FAD-linked PS2 mutants for the understanding of FAD pathogenesis. PMID- 21285371 TI - TBR1 directly represses Fezf2 to control the laminar origin and development of the corticospinal tract. AB - The corticospinal (CS) tract is involved in controlling discrete voluntary skilled movements in mammals. The CS tract arises exclusively from layer (L) 5 projection neurons of the cerebral cortex, and its formation requires L5 activity of Fezf2 (Fezl, Zfp312). How this L5-specific pattern of Fezf2 expression and CS axonal connectivity is established with such remarkable fidelity had remained elusive. Here we show that the transcription factor TBR1 directly binds the Fezf2 locus and represses its activity in L6 corticothalamic projection neurons to restrict the origin of the CS tract to L5. In Tbr1 null mutants, CS axons ectopically originate from L6 neurons in a Fezf2-dependent manner. Consistently, misexpression of Tbr1 in L5 CS neurons suppresses Fezf2 expression and effectively abolishes the CS tract. Taken together, our findings show that TBR1 is a direct transcriptional repressor of Fezf2 and a negative regulator of CS tract formation that restricts the laminar origin of CS axons specifically to L5. PMID- 21285372 TI - Cystic fibrosis transmembrane conductance regulator with a shortened R domain rescues the intestinal phenotype of CFTR-/- mice. AB - Gene transfer could provide a novel therapeutic approach for cystic fibrosis (CF), and adeno-associated virus (AAV) is a promising vector. However, the packaging capacity of AAV limits inclusion of the full-length cystic fibrosis transmembrane conductance regulator (CFTR) cDNA together with other regulatory and structural elements. To overcome AAV size constraints, we recently developed a shortened CFTR missing the N-terminal portion of the R domain (residues 708 759, CFTRDeltaR) and found that it retained regulated anion channel activity in vitro. To test the hypothesis that CFTRDeltaR could correct in vivo defects, we generated CFTR(-/-) mice bearing a transgene with a fatty acid binding protein promoter driving expression of human CFTRDeltaR in the intestine (CFTR(-/ );TgDeltaR). We found that intestinal crypts of CFTR(-/-);TgDeltaR mice expressed CFTRDeltaR and the intestine appeared histologically similar to that of WT mice. Moreover, like full-length CFTR transgene, the CFTRDeltaR transgene produced CFTR Cl(-) currents and rescued the CFTR(-/-) intestinal phenotype. These results indicate that the N-terminal part of the CFTR R domain is dispensable for in vivo intestinal physiology. Thus, CFTRDeltaR may have utility for AAV-mediated gene transfer in CF. PMID- 21285373 TI - Primary cilia dynamics instruct tissue patterning and repair of corneal endothelium. AB - Primary cilia are required for several signaling pathways, but their function in cellular morphogenesis is poorly understood. Here we show that emergence of an hexagonal cellular pattern during development of the corneal endothelium (CE), a monolayer of neural crest-derived cells that maintains corneal transparency, depends on a precise temporal control of assembly of primary cilia that subsequently disassemble in adult corneal endothelial cells (CECs). However, cilia reassembly occurs rapidly in response to an in vivo mechanical injury and precedes basal body polarization and cellular elongation in mature CECs neighboring the wound. In contrast, CE from hypomorphic IFT88 mutants (Tg737(orpk)) or following in vivo lentiviral-mediated IFT88 knockdown display dysfunctional cilia and show disorganized patterning, mislocalization of junctional markers, and accumulation of cytoplasmic acetylated tubulin. Our results indicate an active role of cilia in orchestrating coordinated morphogenesis of CECs during development and repair and define the murine CE as a powerful in vivo system to study ciliary-based cellular dynamics. PMID- 21285374 TI - Crosstalk between O-GlcNAcylation and proteolytic cleavage regulates the host cell factor-1 maturation pathway. AB - Host Cell Factor 1 (HCF-1) plays critical roles in regulating gene expression in a plethora of physiological processes. HCF-1 is first synthesized as a precursor, and subsequently specifically proteolytically cleaved within a large middle region termed the proteolytic processing domain (PPD). Although the underlying mechanism remains enigmatic, proteolysis of HCF-1 regulates its transcriptional activity and is important for cell cycle progression. Here we report that HCF-1 proteolysis is a regulated process. We demonstrate that a large proportion of the signaling enzyme O-linked-N-acetylglucosaminyl transferase (OGT) is complexed with HCF-1 and this interaction is essential for HCF-1 cleavage. Moreover, HCF-1 is, in turn, required for stabilizing OGT in the nucleus. We provide evidence indicating that OGT regulates HCF-1 cleavage via interaction with and O GlcNAcylation of the HCF-1 PPD. In contrast, although OGT also interacts with the basic domain in the HCF-1 amino-terminal subunit, neither the interaction nor the O-GlcNAcylation of this region are required for proteolysis. Moreover, we show that OGT-mediated modulation of HCF-1 impacts the expression of the herpes simplex virus immediate-early genes, targets of HCF-1 during the initiation of viral infection. Together the data indicate that O-GlcNAcylation of HCF-1 is a signal for its proteolytic processing and reveal a unique crosstalk between these posttranslational modifications. Additionally, interactions of OGT with multiple HCF-1 domains may indicate that OGT has several functions in association with HCF 1. PMID- 21285375 TI - p23H implicated as cis/trans regulator of AlaXp-directed editing for mammalian cell homeostasis. AB - The toxicity of mistranslation of serine for alanine appears to be universal, and is prevented in part by the editing activities of alanyl-tRNA synthetases (AlaRSs), which remove serine from mischarged tRNA(Ala). The problem of serine mistranslation is so acute that free-standing, genome-encoded fragments of the editing domain of AlaRSs are found throughout evolution. These AlaXps are thought to provide functional redundancy of editing. Indeed, archaeal versions rescue the conditional lethality of bacterial cells harboring an editing-inactive AlaRS. In mammals, AlaXps are encoded by a gene that fuses coding sequences of a homolog of the HSP90 cochaperone p23 (p23(H)) to those of AlaXp, to create p23(H)AlaXp. Not known is whether this fusion protein, or various potential splice variants, are expressed as editing-proficient proteins in mammalian cells. Here we show that both p23(H)AlaXp and AlaXp alternative splice variants can be detected as proteins in mammalian cells. The variant that ablated p23(H) and encoded just AlaXp was active in vitro. In contrast, neither the p23(H)AlaXp fusion protein, nor the mixture of free p23(H) with AlaXp, was active. Further experiments in a mammalian cell-based system showed that RNAi-directed suppression of sequences encoding AlaXp led to a serine-sensitive increase in the accumulation of misfolded proteins. The results demonstrate the dependence of mammalian cell homeostasis on AlaXp, and implicate p23(H) as a cis- and trans-acting regulator of its activity. PMID- 21285376 TI - The relationship between low-income and minority children's physical activity and academic-related outcomes: a review of the literature. AB - This article explores an innovative strategy for battling the obesity epidemic. The strategy involves demonstrating to policy makers and education leaders the value of promoting physical activity in school as a way of enhancing academic related outcomes to narrow the current achievement gap. A literature review was conducted to ascertain the feasibility of this strategy. Seven studies that examined the relationship between physical activity or fitness and academic related outcomes were reviewed. Although more research is needed in this area, the majority of the articles reviewed found that regardless of socioeconomic status or ethnicity, a positive relationship exists between physical activity and academic-related outcomes. These findings suggest that integrating more physical activity into the school day may be an effective strategy to reduce both health disparities and the achievement gap. PMID- 21285377 TI - Redesign and renewal. PMID- 21285378 TI - Adolescent sexual abstinence: a test of an integrative theoretical framework. AB - The purpose of this study was to test an integrative theoretical framework in explaining adolescents' sexual abstinence and intentions to remain abstinent and refine the framework to reflect which elements contribute more powerfully to the explanation of abstinence and intentions. We administered an anonymous, theory based questionnaire to two nonrandom samples of seventh- and eighth-graders (n = 451 and 447, respectively). Measurement modeling provided sufficient evidence for establishing construct validity. A refined structural equation model demonstrated good fit. Pro-abstinence standards predicted stronger beliefs toward staying abstinent, stronger perceptions that others endorse pro-abstinence norms, and a greater self-efficacy to remain sexually abstinent until marriage. In turn, beliefs, norms, and self-efficacy were predictive of intentions, which predicted sexual abstinence at a later time point. Similar findings emerged in a replication using a second set of sample data. Results suggest that this integrative theoretical framework is useful in explaining adolescents' intention and their subsequent sexual abstinence. PMID- 21285381 TI - Histopathologic and ultrastructural studies on experimental caprine besnoitiosis. AB - The distribution pattern and associated tissue reactions with progressive changes in Besnoitia caprae cysts were investigated in 6 experimentally infected 16- to 20-month-old male goats. Each goat was subcutaneously inoculated with approximately 13 * 10(8) B caprae bradyzoites. The animals were examined daily for development of clinical besnoitiosis, and skin biopsies from distal parts of the limbs were taken at weekly intervals. At 15, 30, 60, 120, 180, and 365 days postinfection (DPI), 1 goat was euthanized. Samples were collected at autopsy from various organs for histologic and ultrastructural studies. No cysts were seen in tissue sections on 15, 30, and 365 DPI, but large numbers were present at 60, 120, and 180 DPI in the skin of the distal limbs, scrotum, and ears, with fewer in the tongue, palate, sclera, testicles, and spermatic cord. No cysts were seen in the lungs, liver, kidneys, spleen, central nervous system, or lymph nodes. Cyst numbers peaked at 60 DPI, then declined from 120 to 180 DPI. Degenerated cysts were relatively rare at 60 DPI but more numerous at 180 compared with 120. A granulomatous reaction--predominantly characterized by macrophages, lymphocytes, and plasma cells--surrounded each degenerated cyst. All goats showed testicular tubular degeneration with little or no spermatogenic activity. The sizes of cysts and their wall thickness, with the size of bradyzoites and some of their organelles, exhibited progressive chronologic changes. PMID- 21285382 TI - Lyme neuroborreliosis in 2 horses. AB - Lyme neuroborreliosis--characterized as chronic, necrosuppurative to nonsuppurative, perivascular to diffuse meningoradiculoneuritis--was diagnosed in 2 horses with progressive neurologic disease. In 1 horse, Borrelia burgdorferi sensu stricto was identified by polymerase chain reaction amplification of B burgdorferi sensu stricto-specific gene targets (ospA, ospC, flaB, dbpA, arp). Highest spirochetal burdens were in tissues with inflammation, including spinal cord, muscle, and joint capsule. Sequence analysis of ospA, ospC, and flaB revealed 99.9% sequence identity to the respective genes in B burgdorferi strain 297, an isolate from a human case of neuroborreliosis. In both horses, spirochetes were visualized in affected tissues with Steiner silver impregnation and by immunohistochemistry, predominantly within the dense collagenous tissue of the dura mater and leptomeninges. PMID- 21285383 TI - Immunohistochemical expression of E-cadherin does not distinguish canine cutaneous histiocytoma from other canine round cell tumors. AB - Immunohistochemistry for E-cadherin (ECAD) has been used to distinguish canine cutaneous histiocytoma from other leukocytic neoplasms ("round cell tumors"). To determine the specificity of this test, 5 types of canine cutaneous round cell tumors were evaluated for immunohistochemical expression of ECAD. Tumors of all 5 types had variable cytoplasmic, plasma membrane, and/or paranuclear ECAD expression: All 13 cutaneous histiocytomas were ECAD+; all but 1 of 14 mast cell tumors expressed ECAD; 10 of 12 epitheliotropic lymphomas reacted with E-cadherin antibody; of 72 plasmacytomas, 54 were ECAD+; and 5 of 5 histiocytic sarcomas were positive. Conclusions based on these results include the following: First, immunoreactivity for ECAD is not limited to leukocytes of cutaneous histiocytoma; second, antibody to ECAD also labels neoplastic cells in most mast cell tumors, plasmacytomas, cutaneous histiocytic sarcomas, and epitheliotropic lymphomas; third, although most histiocytomas have membranous ECAD expression, the immunoreactivity varies among round cell tumors and is frequently concurrent in different cellular compartments; fourth, the distinctively paranuclear ECAD expression pattern in epitheliotropic lymphomas might distinguish them from other round cell tumors; and, fifth, ECAD should be used with other markers (eg, MUM1 for plasmacytomas, KIT for mast cell tumors, CD3 and CD79a for lymphomas) to distinguish among canine round cell tumors. PMID- 21285384 TI - Oral masses in two cats. AB - Incisional biopsies from the oral cavity of 2 adult cats were submitted for histological investigation. Cat No. 1 showed a solitary well-circumscribed neoplasm in the left mandible. Cat No. 2 demonstrated a diffusely infiltrating neoplasm in the left maxilla. Both tumors consisted of medium-size epithelial cells embedded in a fibrovascular stroma. The mitotic index was 0 to 1 mitosis per high-power field. The epithelial cells showed an irregular arrangement forming nests or streams in cat No. 1, whereas a palisading growth was noted in cat No. 2. Both tumors, especially that of cat No. 1, showed multifocal accumulations of amyloid as confirmed by Congo red staining and a distinct green birefringence under polarized light, which lacked cytokeratin immunoreactivity as well as and AL and AA amyloid immunoreactivity. In addition, the amyloid in cat No. 2 was positive for the odontogenic ameloblast-associated protein, formerly termed APin. In sum, both cats suffered from an amyloid-producing odontogenic tumor, but their tumors varied with respect to morphology and type of amyloid produced. PMID- 21285385 TI - Perceived impact of diabetes genetic risk testing among patients at high phenotypic risk for type 2 diabetes. AB - OBJECTIVE: Rapid advances in diabetes genetic epidemiology may lead to a new era of "personalized medicine" based on individual genetic risk assessment. There is minimal experience to guide how best to clinically implement such testing so that results (e.g., "higher" or "lower" relative genetic risk) improve rather than reduce patient motivation for behavior change. RESEARCH DESIGN AND METHODS: Between November 2009 and May 2010, we conducted in-depth interviews with 22 overweight participants at high phenotypic risk for type 2 diabetes to explore perceptions of diabetes genetic risk testing compared with currently available prediction using nongenetic risk factors (e.g., family history, abnormal fasting glucose, obesity). We used hypothetical scenarios to specifically investigate the impact of both "higher" and "lower" relative genetic risk results on participants' views about diabetes prevention. RESULTS: Many participants conferred a unique value on personal genetic risk information relative to nongenetic risk based on the perceived scientific certainty and durability of genetic results. In contrast, other participants considered their genetic risk within the overall context of their other measured risk factors. Reactions to diabetes genetic test results differed by current motivation levels. Whereas most subjects reported that "higher" risk results would motivate behavior change, subjects with lower current motivation often reported that "lower" genetic risk results would further reduce their motivation to engage in diabetes prevention behaviors. CONCLUSIONS: To be effective, future clinical implementation of type 2 diabetes genetic risk testing should be individualized based on each patient's risk perception and current level of motivation to prevent diabetes. PMID- 21285386 TI - Urine C-peptide creatinine ratio is a noninvasive alternative to the mixed-meal tolerance test in children and adults with type 1 diabetes. AB - OBJECTIVE: Stimulated serum C-peptide (sCP) during a mixed-meal tolerance test (MMTT) is the gold standard measure of endogenous insulin secretion, but practical issues limit its use. We assessed urine C-peptide creatinine ratio (UCPCR) as an alternative. RESEARCH DESIGN AND METHODS: Seventy-two type 1 diabetic patients (age of diagnosis median 14 years [interquartile range 10-22]; diabetes duration 6.5 [2.3-32.7]) had an MMTT. sCP was collected at 90 min. Urine for UCPCR was collected at 120 min and following a home evening meal. RESULTS: MMTT 120-min UCPCR was highly correlated to 90-min sCP (r = 0.97; P < 0.0001). UCPCR >= 0.53 nmol/mmol had 94% sensitivity/100% specificity for significant endogenous insulin secretion (90-min sCP >= 0.2 nmol/L). The 120-min postprandial evening meal UCPCR was highly correlated to 90-min sCP (r = 0.91; P < 0.0001). UCPCR >= 0.37 nmol/mmol had 84% sensitivity/97% specificity for sCP >= 0.2 nmol/L. CONCLUSIONS: UCPCR testing is a sensitive and specific method for detecting insulin secretion. UCPCR may be a practical alternative to serum C peptide testing, avoiding the need for inpatient investigation. PMID- 21285387 TI - Diagnosis of the metabolic syndrome is associated with disproportionately high levels of high-sensitivity C-reactive protein in non-Hispanic black adolescents: an analysis of NHANES 1999-2008. AB - OBJECTIVE: Whereas it is known that the metabolic syndrome (MetS) has a paradoxically lower prevalence in non-Hispanic black adolescents than in non Hispanic whites or Hispanics, the relative severity of MetS by race/ethnicity is unknown. Inflammation, indicated by high-sensitivity C-reactive protein (hsCRP), is a key factor linking MetS to cardiovascular disease and type 2 diabetes. Our goal was to determine whether elevations of hsCRP vary by race/ethnicity among adolescents with MetS. RESEARCH DESIGN AND METHODS: We used the National Health and Nutrition Examination Survey (1999-2008) and evaluated adolescents (age 12-19 years) using a pediatric/adolescent adaptation of the ATP III definition of MetS. We used linear regression to evaluate the interaction between MetS status and ethnicity with respect to hsCRP concentration. RESULTS: For male and female adolescents, MetS was associated with elevated hsCRP levels compared with adolescents without MetS. However, the elevation in hsCRP between adolescents with and without MetS was greater in non-Hispanic blacks compared with that in non-Hispanic whites (P = 0.04) but not that in Hispanics (P = 0.18). hsCRP concentrations correlated with individual MetS components similarly among all ethnicities. In an evaluation of adolescents diagnosed with MetS, non-Hispanic blacks had higher BMI and more hypertension than other ethnicities but there were no other racial/ethnic differences in the features of MetS. CONCLUSIONS: Non Hispanic black adolescents have a greater differential in hsCRP between those with and those without MetS than the differential in non-Hispanic whites but not that in Hispanics. Therefore, even though MetS has a low prevalence in non Hispanic blacks, MetS is a particularly good indicator of inflammation in non Hispanic black adolescents. PMID- 21285388 TI - Exenatide twice daily versus premixed insulin aspart 70/30 in metformin-treated patients with type 2 diabetes: a randomized 26-week study on glycemic control and hypoglycemia. AB - OBJECTIVE: Hypoglycemia causes recurrent morbidity in patients with type 2 diabetes. This study evaluated if exenatide twice daily (BID) was noninferior to premixed insulin aspart 70/30 BID (PIA) for glycemic control and associated with less hypoglycemia. RESEARCH DESIGN AND METHODS: In this open-label study, metformin-treated adults with type 2 diabetes were randomized to 26-week treatment with exenatide BID (4 weeks 5 MUg, then 10 MUg) or PIA. RESULTS: Exenatide BID (n = 181) was noninferior to PIA (n = 173) for A1C control (least squares [LS] mean change -1.0 vs. -1.14%; difference [95% CI] 0.14 [-0.003 to 0.291]) and associated with a lower risk for hypoglycemia (8.0 vs. 20.5%, P < 0.05). LS mean weight decreased by 4.1 kg and increased by 1.0 kg with PIA (P < 0.001). A total of 39.2 vs. 20.8% of patients reached the composite end point of A1C <7.0%, no weight gain, and no hypoglycemia (P < 0.001; post hoc analysis). CONCLUSIONS: In metformin-treated patients, exenatide BID was noninferior to PIA for glycemic control but superior for hypoglycemia and weight control. PMID- 21285389 TI - A new-generation ultra-long-acting basal insulin with a bolus boost compared with insulin glargine in insulin-naive people with type 2 diabetes: a randomized, controlled trial. AB - OBJECTIVE: Insulin degludec/insulin aspart (IDegAsp) is a soluble coformulation of the novel basal analog insulin degludec (IDeg: 70%) and insulin aspart (IAsp: 30%). We compared the safety and efficacy of IDegAsp, an alternative formulation (AF) (55% IDeg and 45% IAsp), and insulin glargine (IGlar) in insulin-naive subjects with type 2 diabetes inadequately controlled with oral antidiabetic drugs. RESEARCH DESIGN AND METHODS: In this 16-week, open-label trial, subjects (mean age 59.1 years, A1C 8.5%, BMI 30.3 kg/m(2)) were randomized to once-daily IDegAsp (n = 59), AF (n = 59), or IGlar (n = 60), all in combination with metformin. Insulin was administered before the evening meal and dose-titrated to a fasting plasma glucose (FPG) target of 4.0-6.0 mmol/L. RESULTS: After 16 weeks, mean A1C decreased in all groups to comparable levels (IDegAsp: 7.0%; AF: 7.2%; IGlar: 7.1%). A similar proportion of subjects achieved A1C <7.0% without confirmed hypoglycemia in the last 4 weeks of treatment (IDegAsp: 51%; AF: 47%; IGlar: 50%). Mean 2-h postdinner plasma glucose increase was lower for IDegAsp (0.13 mmol/L) and AF (0.24 mmol/L) than IGlar (1.63 mmol/L), whereas mean FPG was similar (IDegAsp: 6.8 mmol/L; AF: 7.4 mmol/L; IGlar: 7.0 mmol/L). Hypoglycemia rates were lower for IDegAsp and IGlar than AF (1.2, 0.7, and 2.4 events/patient year). Nocturnal hypoglycemic events occurred rarely for IDegAsp (1 event) and IGlar (3 events) compared with AF (27 events). CONCLUSIONS: In this proof-of concept trial, once-daily IDegAsp was safe, well tolerated, and provided comparable overall glycemic control to IGlar at similar low rates of hypoglycemia, but better postdinner plasma glucose control. PMID- 21285390 TI - Triglycerides and amputation risk in patients with diabetes: ten-year follow-up in the DISTANCE study. AB - OBJECTIVE: To determine the association between triglyceride levels and lower extremity amputation (LEA) risk in a large diabetic cohort. RESEARCH DESIGN AND METHODS: This is a 10-year survey follow-up study (from 1995-2006) of 28,701 diabetic patients with a baseline triglyceride measure. All patients were fully insured members of the Kaiser Permanente Medical Care Program and responded to a survey at baseline that included information on ethnicity, socioeconomic status, education, behavioral factors, and information required to determine type of diabetes. The relationship between triglycerides and time to incident nontraumatic LEA, defined by primary hospitalization discharge or procedures, was evaluated using Cox proportional hazards models. RESULTS: Triglyceride level was an independent, stepwise risk factor for nontraumatic LEAs within this large diabetic cohort: triglycerides 150-199 mg/dL, hazard ratio (HR) 1.10 (95% CI 0.92 1.32); 200-499 mg/dL, 1.27 (1.10-1.47); >500 mg/dL, 1.65 (1.30-2.10) (reference <150 mg/dL). CONCLUSIONS: Hypertriglyceridemia is a significant risk factor for LEA in diabetic patients even after controlling for known socioeconomic, health behavioral, and clinical factors. This previously unrecognized clinical risk needs to be further investigated to determine if treatment of triglycerides can reduce amputation risk. PMID- 21285391 TI - Empirical derivation to improve the definition of the metabolic syndrome in the evaluation of cardiovascular disease risk. AB - OBJECTIVE: To examine whether a quantitatively derived metabolic syndrome definition predicts incident cardiovascular disease (CVD) events better than do existing definitions. RESEARCH DESIGN AND METHODS: Data were pooled from the Atherosclerosis Risk in Communities, Cardiovascular Health, and Framingham Offspring studies (n = 20,581). Incident coronary heart disease and stroke events were ascertained over 9 years. RESULTS: The sensitivity for incident CVD events was higher and the specificity lower for the empirically derived versus the Adult Treatment Panel (ATP) III, International Diabetes Federation (IDF), or Harmonized metabolic syndrome definitions (sensitivity/specificity 0.65/0.53 vs. 0.53/0.63, 0.51/0.66, and 0.64/0.56, respectively), resulting in no overall improvement in discrimination. Multivariable-adjusted hazard ratios for incident CVD events were similar across definitions and were 1.7 (95% CI 1.6-1.9) for ATP III, 1.8 (1.6 2.0) for IDF, 1.9 (1.7-2.0) for Harmonized, and 1.7 (1.6-1.9) for the empirically derived definition. CONCLUSIONS: Empirical derivation of the metabolic syndrome definition did not improve CVD discrimination or risk prediction. PMID- 21285392 TI - The role of RANK-ligand inhibition in cancer: the story of denosumab. AB - The diagnosis of bone metastases is an event with certain consequences for the patient. They often mean pain and can also mean pathological fractures, hypercalcemia, and spinal cord compression, all synonymous with a diminished quality of life and often also hospitalization. Since the advent of the intravenous bisphosphonates, things began to look a bit brighter for patients with bone metastases-bone destruction was kept at bay a little longer. The next generation of bone metastasis treatments is well on its way in clinical development, and among them, the most advanced drug is denosumab. Denosumab is a fully human monoclonal antibody that inhibits osteoclast maturation, activation, and function by binding to receptor activator of nuclear factor kappa B ligand, with the final result being a reduced rate of bone resorption. In this review, we give an overview of relevant preclinical and clinical data regarding the use of denosumab in patients with solid tumors in general and prostate cancer in particular. PMID- 21285393 TI - Measuring the symptom burden of lung cancer: the validity and utility of the lung cancer module of the M. D. Anderson Symptom Inventory. AB - We conducted a study to establish the psychometric properties of a module of the M. D. Anderson Symptom Inventory (MDASI) developed specifically for patients with lung cancer (MDASI-LC). The MDASI measures 13 common "core" symptoms of cancer and its treatment. The MDASI-LC includes the 13 core MDASI symptom items and three lung cancer-specific items: coughing, constipation, and sore throat. MDASI LC items were administered to three cohorts of patients with lung cancer undergoing either chemotherapy or chemoradiotherapy. Known-group validity and criterion (concurrent) validity of the MDASI-LC were evaluated using the Eastern Cooperative Oncology Group performance status and the 12-item Short-Form Health Survey. The internal consistency and test-retest reliability of the module were adequate, with Cronbach coefficient alpha-values of 0.83 or higher for all module items and subscales. The sensitivity of the MDASI-LC to changes in patient performance status (disease progression) and to continuing cancer treatment (effects of treatment) was established. Cognitive debriefing of a subset of participants provided evidence for content validity and indicated that the MDASI core items and three additional lung cancer-specific items were clear, relevant to patients, and easy to understand; only two patients suggested additional symptom items. As expected, the item "sore throat" was sensitive only for patients receiving chemoradiotherapy. The MDASI-LC is a valid, reliable, and sensitive symptom-assessment instrument whose use can enhance clinical studies of symptom status in patients with lung cancer and epidemiological and prevalence studies of symptom severity across various cancer types. PMID- 21285394 TI - Early reperfusion therapy affects inducibility, cycle length, and occurrence of ventricular tachycardia late after myocardial infarction. AB - BACKGROUND: This study aimed to evaluate the impact of early reperfusion during acute myocardial infarction (MI) on ventricular tachycardia (Vt) inducibility, inducible Vt cycle length (CL), and occurrence of spontaneous Vt late after MI. METHODS AND RESULTS: Five hundred six patients (440 men; age, 63+/-11 years) with prior MI who underwent electrophysiology study before implantation of an implantable cardioverter-defibrillator for primary or secondary prevention were assessed. Patients were classified according to the reperfusion strategy (reperfusion: thrombolysis, n=44, or percutaneous coronary intervention, n=65, versus no reperfusion, n=397) during acute MI. Monomorphic sustained Vt was inducible in 351 (69%) patients. Inducibility in reperfused and nonreperfused patients was similar in primary prevention patients (56% versus 58%) but significantly higher for nonreperfused patients in secondary prevention patients (56% versus 79%, P=0.001). Induced VTCL was shorter (247+/-40 versus 287+/-63, P<0.001) and very fast Vt (CL <=250 ms) was more often induced in reperfused patients (71% versus 47%, P=0.001). In primary prevention patients, nonreperfusion was associated with a doubled risk for first spontaneous Vt during follow-up. CONCLUSIONS: There are important differences in Vt inducibility, induced VTCL, and occurrence of spontaneous Vt in the chronic infarct healing phase between patients with and those without successful reperfusion during acute MI. These findings suggest differences in the chronic arrhythmogenic substrate. PMID- 21285395 TI - Alternatively spliced variants of interleukin-4 promote inflammation differentially. AB - IL-4delta2 is a natural splice variant of IL-4 that lacks the region encoded by the second exon. Numerous reports have suggested that the expression levels of IL 4delta2 change in various diseases, especially those with pulmonary involvement, but the in vivo effects of this splice variant have never been studied. Replication-deficient, AdV-mediated gene delivery of mIL-4delta2 to mouse lungs in vivo was used, and the effects compared with similar adenoviral delivery of mIL-4 or with infection with a noncoding NULL viral construct. Overexpression of IL-4delta2 or IL-4 caused pulmonary infiltration by T and B lymphocytes, whereas in contrast to IL-4, IL-4delta2 did not induce eosinophilia or goblet cell hyperplasia. Microarray analysis of global gene expression revealed that IL 4delta2 and IL-4 had differential effects on gene expression. These splice variants also differentially regulated pulmonary levels of the cytokines TNF alpha, eotaxin, IL-1alpha, IFN-gamma, and MCP-1, whereas both tended to increase total lung collagen modestly. Pulmonary infiltration by lymphocytes in response to overexpression of IL-4delta2 was attenuated but not abrogated completely by germline deficiency of IL-4Ralpha or STAT6, whereas deficiency of endogenous IL-4 had no effect. Thus, IL-4delta2 promotes lymphocytic inflammation in vivo (although differentially from IL-4, in part), and the effects of IL-4delta2 are not mediated by endogenous IL-4. Differential targeting of IL-4delta2 and IL-4 may therefore be considered in developing future therapeutic agents. PMID- 21285396 TI - Cholesterol regulation of receptor-interacting protein 140 via microRNA-33 in inflammatory cytokine production. AB - Receptor interacting protein 140 (RIP140) is a nuclear receptor coregulator that affects a wide spectrum of biological processes. It is unclear whether and how the expression level of RIP140 can be modulated and whether RIP140 is involved in inflammatory diseases. Here, we examine how intracellular cholesterol regulates RIP140 expression, and we evaluate the effect of RIP140 expression on macrophage proinflammatory potential. Macrophages treated with modified low-density lipoprotein express higher RIP140 mRNA and protein levels. Consistently, simvastatin reduces RIP140 levels, which can be reversed by mevalonate. Moreover, a high-fat diet elevates RIP140 but lowers miR-33 levels in peritoneal macrophages, and increases the production of IL-1beta and TNF-alpha in macrophages. Mechanistically, miR-33 targets RIP140 mRNA by recognizing its target located in a highly conserved sequence of the 3'-untranslated region (3' UTR) of RIP140 mRNA. Consequentially, miR-33 reduces RIP140 coactivator activity for NF-kappaB, which is supported by the reduction in NF-kappaB reporter activity and the inflammatory potential in macrophages. This study uncovers a cholesterol miR-33-RIP140 regulatory pathway that modulates the proinflammatory potential in macrophages in response to an alteration in the intracellular cholesterol status, and identifies RIP140 as a direct target of miR-33 that mediates simvastatin triggered anti-inflammation. PMID- 21285397 TI - beta-Carotene and its cleavage enzyme beta-carotene-15,15'-oxygenase (CMOI) affect retinoid metabolism in developing tissues. AB - The mammalian embryo relies on maternal circulating retinoids (vitamin A derivatives) for development. beta-Carotene is the major human dietary provitamin A. beta-Carotene-15,15'-oxygenase (CMOI) has been proposed as the main enzyme generating retinoid from beta-carotene in vivo. CMOI is expressed in embryonic tissues, suggesting that beta-carotene provides retinoids locally during development. We performed loss of CMOI function studies in mice lacking retinol binding protein (RBP), an established model of embryonic vitamin A deficiency (VAD). We show that, unexpectedly, lack of CMOI in the developing tissues further exacerbates the severity of VAD and thus the embryonic malformations of RBP(-/-) mice. Since beta-carotene was not present in any of the mouse diets, we unveiled a novel action of CMOI independent from its beta-carotene cleavage activity. We also show for the first time that CMOI exerts an additional function on retinoid metabolism by influencing retinyl ester formation via modulation of lecithin:retinol acyltransferase (LRAT) activity, at least in developing tissues. Finally, we demonstrate unequivocally that beta-carotene can serve as an alternative vitamin A source for the in situ synthesis of retinoids in developing tissues by the action of CMOI. PMID- 21285398 TI - Bioenergetic defect associated with mKATP channel opening in a mouse model carrying a mitofusin 2 mutation. AB - Charcot-Marie-Tooth disease type 2A (CMT2A) is an autosomal dominant axonal form of peripheral neuropathy caused by mutations in the mitofusin 2 gene (MFN2), which encodes a mitochondrial outer membrane protein that promotes mitochondrial fusion. Emerging evidence also points to a role of MFN2 in the regulation of mitochondrial metabolism. To examine whether mitochondrial dysfunction is a feature of CMT2A, we used a transgenic mouse model expressing in neurons a mutated R94Q form of human MFN2 shown to induce a CMT2A phenotype. Oxygraphic and enzymatic measurements both revealed a combined defect of mitochondrial complexes II and V (40 and 30% decrease, respectively) in the brain of Tg-R94 mice, leading to a drastic decrease of ATP synthesis. These deficiencies were reversed by the mitochondrial ATP-sensitive potassium channel (mK(ATP)) inhibitor 5 hydroxydecanoate. Conversely, in controls and wild-type human MFN2 mice, the mK(ATP) activator diazoxide mimicked the deficiency observed with the R94Q mutation. The physical links between complexes II and V, previously proposed as part of mK(ATP), were reinforced in Tg-R94Q mice. Our results show that the R94Q MFN2 mutation induces a combined defect of complexes II and V linked to the opening of mK(ATP), which could participate in the pathophysiology of the disease. PMID- 21285399 TI - Prevention of recurrent atrial fibrillation with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers: a systematic review and meta analysis of randomized trials. AB - BACKGROUND: Controversy persists regarding the efficacy of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in the prevention of recurrent atrial fibrillation (AF). We performed a meta-analysis of randomized controlled trials (RCTs), not designed a priori to test this hypothesis, to explore whether ACEs and ARBs reduce recurrent AF. METHODS: We performed a systematic literature search for RCTs using ACEIs or ARBs and providing data on the outcome of recurrent AF. Statistical heterogeneity across the trials was tested using the Cochran Q statistic and I(2) was computed to quantify heterogeneity. A 2-sided alpha error of less than .05 was considered statistically significant (P < .05). RESULTS: The analysis was based on 8 RCTs including 2323 patients. The Mantel-Haenszel random-effect model was used to calculate relative risk (RR) for studies using ACEIs or ARBs, and for studies using ARBs. The fixed-effect model was used to calculate RR for studies using ACEIs. Meta-analysis of the studies revealed that ACEIs or ARBs significantly reduced the incidence of recurrent AF (RR, 0.611; 95% CI, 0.441-0.847; P = .003). The RR for recurrent AF was 0.643 (95% CI, 0.439-0.941; P = .023) for studies using ARBs and 0.54 (95% CI, 0.377-0.80; P = .002) for studies using ACEIs. CONCLUSION: In this meta-analysis of RCTs not designed a priori to test the hypothesis, ACEs and ARBs were associated with a significant reduction in recurrent AF. Large-scale randomized trials designed a priori to test the hypothesis are necessary to complete the totality of evidence. PMID- 21285400 TI - The effects of physiological adaptations to calorie restriction on global cell proliferation rates. AB - Calorie restriction (CR) reduces the rate of cell proliferation in mitotic tissues. It has been suggested that this reduction in cell proliferation may mediate CR-induced increases in longevity. However, the mechanisms that lead to CR-induced reductions in cell proliferation rates remain unclear. To evaluate the CR-induced physiological adaptations that may mediate reductions in cell proliferation rates, we altered housing temperature and access to voluntary running wheels to determine the effects of food intake, energy expenditure, percent body fat, and body weight on proliferation rates of keratinocytes, liver cells, mammary epithelial cells, and splenic T-cells in C57BL/6 mice. We found that ~20% CR led to a reduction in cell proliferation rates in all cell types. However, lower cell proliferation rates were not observed with reductions in 1) food intake and energy expenditure in female mice housed at 27 degrees C, 2) percent body fat in female mice provided running wheels, or 3) body weight in male mice provided running wheels compared with ad libitum-fed controls. In contrast, reductions in insulin-like growth factor I were associated with decreased cell proliferation rates. Taken together, these data suggest that CR induced reductions in food intake, energy expenditure, percent body fat, and body weight do not account for the reductions in global cell proliferation rates observed in CR. In addition, these data are consistent with the hypothesis that reduced cell proliferation rates could be useful as a biomarker of interventions that increase longevity. PMID- 21285401 TI - Increased muscular dehydroepiandrosterone levels are associated with improved hyperglycemia in obese rats. AB - This study was undertaken to assess the effects of dehydroepiandrosterone (DHEA) administration and exercise training on muscular DHEA and 5alpha dihydrotestosterone (DHT) levels and hyperglycemia in diet-induced obese and hyperglycemic rats. After 14 wk of a high-sucrose diet, obese male Wistar rats were assigned randomly to one of three 6-wk regimens: control, DHEA treatment, or exercise training (running at 25 m/min for 1 h, 5 days/wk; n = 10 each group). Results indicate that either 6 wk of DHEA treatment or exercise training significantly attenuated serum insulin and fasting glucose levels compared with the control group. Plasma and muscle concentrations of DHEA and DHT and expression levels of 5alpha-reductase were significantly higher in the DHEA treated and exercise-training groups. Moreover, both DHEA administration and exercise training upregulated GLUT4 translocation with concomitant increases in protein kinase B and protein kinase Czeta/lambda phosphorylation. Muscle DHEA and DHT concentrations closely correlated with blood glucose levels (DHEA treatment: r = -0.68, P < 0.001; exercise training: r = -0.65, P < 0.001), serum insulin levels, and activation of the GLUT4-regulated signaling pathway. Thus, increased levels of muscle sex steroids may contribute to improved fasting glucose levels via upregulation of GLUT4-regulated signaling in diet-induced obesity and hyperglycemia. PMID- 21285402 TI - Variable penetrance of metabolic phenotypes and development of high-fat diet induced adiposity in NEIL1-deficient mice. AB - Exposure to chronic and acute oxidative stress is correlated with many human diseases, including, but not limited to, cancer, heart disease, diabetes, and obesity. In addition to cellular lipids and proteins, cellular oxidative stress can result in damage to DNA bases, especially in mitochondrial DNA. We previously described the development of spontaneous late-onset obesity, hepatic steatosis, hyperinsulinemia, and hyperleptinemia in mice that are deficient in the DNA glycosylase nei-like 1 (NEIL1), which initiates base excision repair of several oxidatively damaged bases. In the current study, we report that exposure to a chronic oxidative stress in the form of a high-fat diet greatly accelerates the development of obesity in neil1(-/-) mice. Following a 5-wk high-fat diet challenge, neil1(-/-) mice gained significantly more body weight than neil1(+/+) littermates and had increased body fat accumulation and moderate to severe hepatic steatosis. Analysis of oxygen consumption by indirect calorimetry indicated a modest reduction in total oxygen consumption in neil1(-/-) mice that was abolished upon correction for lean body mass. Additionally, hepatic expression of several inflammatory genes was significantly upregulated in neil1( /-) mice following high-fat diet challenge compared with chow-fed or neil1(+/+) counterparts. A long-term high-fat diet also induced glucose intolerance as well as a significant reduction in mitochondrial DNA and protein content in neil1(-/-) mice. Collectively, these data indicate that NEIL1 deficiency results in an increased susceptibility to obesity and related complications potentially by lowering the threshold for tolerance of cellular oxidative stress in neil1(-/-) mice. PMID- 21285403 TI - Role of 12-lipoxygenase in decreasing P-cadherin and increasing angiotensin II type 1 receptor expression according to glomerular size in type 2 diabetic rats. AB - 12-lipoxygenase (12-LO) was implicated in the development of diabetic nephropathy (DN), in which the proteinuria was thought to be associated with a decreased expression of glomerular P-cadherin. Therefore, we investigated the role of 12-LO in the glomerular P-cadherin expression in type 2 diabetic rats according to the glomerular sizes. Rats fed with high-fat diet for 6 wk were treated with low-dose streptozotocin. Once diabetes onset, diabetic rats were treated with 12-LO inhibitor cinnamyl-3,4-dihydroxy-cyanocinnamate (CDC) for 8 wk. Then glomeruli were isolated from diabetic and control rats with a sieving method. RT-PCR, Western blotting, and immunofluorescent staining were used for mRNA and protein expressions of P-cadherin and angiotensin II (Ang II) type 1 receptor (AT1). We found that CDC did not affect the glucose levels but completely attenuated diabetic increases in glomerular volume and proteinuria. Diabetes significantly decreased the P-cadherin mRNA and protein expressions and increased the AT1 mRNA and protein expressions in the glomeruli. These changes were significantly prevented by CDC and recaptured by direct infusion of 12-LO product [12(S)-HETE] to normal rats for 7 days. The decreased P-cadherin expression was similar between large and small glomeruli, but the increased AT1 expression was significantly higher in the large than in the small glomeruli from diabetic and 12(S)-HETE-treated rats. Direct infusion of normal rats with Ang II for 14 days also significantly decreased the glomerular P-cadherin expression. These results suggest that diabetic proteinuria is mediated by the activation of 12-LO pathway that is partially attributed to the decreased glomerular P-cadherin expression. PMID- 21285404 TI - Diminished glucagon suppression after beta-cell reduction is due to impaired alpha-cell function rather than an expansion of alpha-cell mass. AB - Impaired suppression of glucagon levels after oral glucose or meal ingestion is a hallmark of type 2 diabetes. Whether hyperglucagonemia after a beta-cell loss results from a functional upregulation of glucagon secretion or an increase in alpha-cell mass is yet unclear. CD-1 mice were treated with streptozotocin (STZ) or saline. Pancreatic tissue was collected after 14, 21, and 28 days and examined for alpha- and beta-cell mass and turnover. Intraperitoneal (ip) glucose tolerance tests were performed at day 28 as well as after 12 days of subcutaneous insulin treatment, and glucose, insulin, and glucagon levels were determined. STZ treatment led to fasting and post-challenge hyperglycemia (P < 0.001 vs. controls). Insulin levels increased after glucose injection in controls (P < 0.001) but were unchanged in STZ mice (P = 0.36). Intraperitoneal glucose elicited a 63.1 +/- 4.1% glucagon suppression in control mice (P < 0.001), whereas the glucagon suppression was absent in STZ mice (P = 0.47). Insulin treatment failed to normalize glucagon levels. There was a significant inverse association between insulin and glucagon levels after ip glucose ingestion (r(2) = 0.99). beta-Cell mass was reduced by ~75% in STZ mice compared with controls (P < 0.001), whereas alpha-cell mass remained unchanged (P > 0.05). alpha-Cell apoptosis (TUNEL) and replication (Ki67) were rather infrequently noticed, with no significant differences between the groups. These studies underline the importance of endogenous insulin for the glucose-induced suppression of glucagon secretion and suggest that the insufficient decline in glucagon levels after glucose administration in diabetes is primarily due to a functional loss of intraislet inhibition of alpha-cell function rather than an expansion of alpha cell mass. PMID- 21285405 TI - High muscle lipid content in obesity is not due to enhanced activation of key triglyceride esterification enzymes or the suppression of lipolytic proteins. AB - The mechanisms underlying alterations in muscle lipid metabolism in obesity are poorly understood. The primary aim of this study was to compare the abundance and/or activities of key proteins that regulate intramyocellular triglyceride (IMTG) concentration in the skeletal muscle obtained from obese (OB; n = 8, BMI 38 +/- 1 kg/m(2)) and nonobese (NOB; n = 9, BMI 23 +/- 1 kg/m(2)) women. IMTG concentration was nearly twofold greater in OB vs. NOB subjects (75 +/- 15 vs. 40 +/- 8 MUmol/g dry wt, P < 0.05). In contrast, the activity and protein abundance of key enzymes that regulate the esterification of IMTG (i.e., glycerol-3 phosphate acyltransferase and diacylglycerol acyltransferase) were not elevated. We also found no differences between groups in muscle adipose triglyceride lipase and hormone-sensitive lipase (HSL) protein abundance and no differences in phosphorylation of specific sites known to affect HSL activity. However, we did find the elevated IMTG in obesity to be accompanied by a greater abundance of the fatty acid transporter FAT/CD36 in the membrane fraction of muscle from OB vs. NOB subjects (P < 0.05), suggestive of an elevated fatty acid transport capacity. Additionally, protein abundance of the lipid-trafficking protein perilipin 3 was lower (P < 0.05) in muscle from OB vs. NOB when expressed relative to IMTG content. Our findings indicate that the elevated IMTG content found in obese women was not due to an upregulation of key lipogenic proteins or to the suppression of lipolytic proteins. The impact of a low perilipin protein abundance relative to the amount of IMTG in obesity remains to be clarified. PMID- 21285406 TI - Low-density lipoprotein cholesterol and the risk of cancer: a mendelian randomization study. AB - BACKGROUND: Low plasma levels of low-density lipoprotein (LDL) cholesterol are associated with an increased risk of cancer, but whether this association is causal is unclear. METHODS: We studied 10 613 participants in the Copenhagen City Heart Study (CCHS) and 59 566 participants in the Copenhagen General Population Study, 6816 of whom had developed cancer by May 2009. Individuals were genotyped for PCSK9 R46L (rs11591147), ABCG8 D19H (rs11887534), and APOE R112C (rs429358) and R158C (rs7412) polymorphisms, all of which are associated with lifelong reduced plasma LDL cholesterol levels. Plasma LDL cholesterol was calculated using the Friedewald equation in samples in which the triglyceride level was less than 354 mg/dL and measured directly by colorimetry for samples with higher triglyceride levels. Risk of cancer was estimated prospectively using Cox proportional hazards regression analyses and cross-sectionally by logistic regression analyses. Causality was studied using instrumental variable analysis. All statistical tests were two-sided. RESULTS: In the CCHS, compared with plasma LDL cholesterol levels greater than the 66th percentile (>158 mg/dL), those lower than the 10th percentile (< 87 mg/dL) were associated with a 43% increase (95% confidence interval [CI] = 15% to 79% increase) in the risk of cancer. The polymorphisms were associated with up to a 38% reduction (95% CI = 36% to 41% reduction) in LDL cholesterol levels but not with increased risk of cancer. The causal odds ratio for cancer for a 50% reduction in plasma LDL cholesterol level due to all the genotypes in both studies combined was 0.96 (95% CI = 0.87 to 1.05), whereas the hazard ratio of cancer for a 50% reduction in plasma LDL cholesterol level in the CCHS was 1.10 (95% CI = 1.01 to 1.21) (P for causal odds ratio vs observed hazard ratio = .03). CONCLUSION: Low plasma LDL cholesterol levels were robustly associated with an increased risk of cancer, but genetically decreased LDL cholesterol was not. This finding suggests that low LDL cholesterol levels per se do not cause cancer. PMID- 21285407 TI - Use of Plerixafor with Granulocyte Colony-Stimulating Factor for Stem Cell Mobilization in a Pediatric Patient. AB - OBJECTIVE: To present a case where plerixafor was successfully used in combination with granulocyte colony-stimulating factor (G-CSF) for mobilization of hematopoietic stem cells in a pediatric patient. CASE SUMMARY: An 11-year-old boy with recurrent anaplastic large-cell lymphoma failed to yield an adequate number of CD34+ cells with G-CSF for mobilization. After a single subcutaneous dose of plerixafor 240 MUg/kg was administered in addition to filgrastim, sufficient CD34+ cells were harvested for transplantation. A local injection site reaction was the only adverse reaction reported. DISCUSSION: Several studies in adults have shown plerixafor to be effective for the mobilization of hematopoietic stem cells when used in combination with G-CSF in adults with non Hodgkin's lymphoma and multiple myeloma who failed to mobilize sufficient CD34+ cells with G-CSF alone. There is limited information regarding the safety and efficacy of plerixafor in pediatric patients. CONCLUSIONS: Plerixafor was effective in increasing the number of hematopoietic stem cells in the peripheral blood of an 11-year-old patient; studies are needed to evaluate the safety and effectiveness of plerixafor in pediatric patients. PMID- 21285408 TI - Safety of the HPV Bivalent and Quadrivalent Vaccines During Pregnancy. AB - OBJECTIVE: To evaluate the safety of the human papillomavirus (HPV) bivalent and quadrivalent vaccines in pregnancy. DATA SOURCE: PubMed (1966-August 2010) was searched using the terms human papillomavirus, human papillomavirus vaccine, and pregnancy. References were reviewed for relevant information. STUDY SELECTION AND DATA EXTRACTION: All studies including humans that were published in English with data describing HPV vaccine administration in pregnancy were evaluated. DATA SYNTHESIS: Two combined analyses of 7 Phase 3 efficacy trials have retrospectively evaluated the safety of unintentional administration of either the bivalent (n = 1786) or quadrivalent (n = 2085) HPV vaccine during pregnancy. In addition, postmarketing pregnancy registry surveillance data (prospective, n = 787; retrospective, n = 76) for the quadrivalent HPV vaccine have been published. However, only 279 pregnancies from the studies and 90 pregnancies from the registry occurred within 30 days of receiving the vaccination. Overall, the vaccine does not appear to be associated with an increased risk of spontaneous abortion, fetal malformations, or adverse pregnancy outcomes beyond that found in the general population. Although the data are limited, neither HPV vaccine appears to be associated with an increased risk of adverse pregnancy outcomes. However, limitations of the data include small patient populations, minimal to no adjustments for factors known to influence pregnancy outcomes or malformations, and the majority of the available pregnancy data are from retrospective analysis of Phase 3 efficacy trials. CONCLUSIONS: Neither HPV vaccine should be routinely administered during pregnancy. If a pregnancy occurs midseries, the remaining vaccines should be given after pregnancy completion. Further studies are required to determine actual risk. PMID- 21285409 TI - Bar Code Medication Administration Technology: Characterization of High-Alert Medication Triggers and Clinician Workarounds. AB - BACKGROUND: Bar code medication administration (BCMA) technology is gaining acceptance for its ability to prevent medication administration errors. However, studies suggest that improper use of BCMA technology can yield unsatisfactory error prevention and introduction of new potential medication errors. OBJECTIVE: To evaluate the incidence of high-alert medication BCMA triggers and alert types and discuss the type of nursing and pharmacy workarounds occurring with the use of BCMA technology and the electronic medication administration record (eMAR). METHODS: Medication scanning and override reports from January 1, 2008, through November 30, 2008, for all adult medical/surgical units were retrospectively evaluated for high-alert medication system triggers, alert types, and override reason documentation. An observational study of nursing workarounds on an adult medicine step-down unit was performed and an analysis of potential pharmacy workarounds affecting BCMA and the eMAR was also conducted. RESULTS: Seventeen percent of scanned medications triggered an error alert of which 55% were for high-alert medications. Insulin aspart, NPH insulin, hydromorphone, potassium chloride, and morphine were the top 5 high-alert medications that generated alert messages. Clinician override reasons for alerts were documented in only 23% of administrations. Observational studies assessing for nursing workarounds revealed a median of 3 clinician workarounds per administration. Specific nursing workarounds included a failure to scan medications/patient armband and scanning the bar code once the dosage has been removed from the unit-dose packaging. Analysis of pharmacy order entry process workarounds revealed the potential for missed doses, duplicate doses, and doses being scheduled at the wrong time. CONCLUSIONS: BCMA has the potential to prevent high-alert medication errors by alerting clinicians through alert messages. Nursing and pharmacy workarounds can limit the recognition of optimal safety outcomes and therefore workflow processes must be continually analyzed and restructured to yield the intended full benefits of BCMA technology. PMID- 21285410 TI - To be or not to be a Treg cell: lineage decisions controlled by epigenetic mechanisms. AB - Regulatory T (T(reg)) cells are a unique CD4(+) T cell lineage that plays a crucial role in the maintenance of immunological tolerance. The Forkhead box transcription factor Foxp3 is critically involved in T(reg) cell development and responsible for determining the suppressive function of these cells. The majority of Foxp3(+) T(reg) cells are generated during T cell development within the thymus and show features of a stable T cell lineage. New work indicates that both induction and stabilization of Foxp3 expression are under epigenetic control, which suggests that selective interference with the underlying chromatin remodeling mechanisms might enable the development of future therapeutic strategies targeting T(reg) cells. PMID- 21285411 TI - Wnt signaling regulates hepatic metabolism. AB - The contribution of the Wnt pathway has been extensively characterized in embryogenesis, differentiation, and stem cell biology but not in mammalian metabolism. Here, using in vivo gain- and loss-of-function models, we demonstrate an important role for Wnt signaling in hepatic metabolism. In particular, beta catenin, the downstream mediator of canonical Wnt signaling, altered serum glucose concentrations and regulated hepatic glucose production. beta-Catenin also modulated hepatic insulin signaling. Furthermore, beta-catenin interacted with the transcription factor FoxO1 in livers from mice under starved conditions. The interaction of FoxO1 with beta-catenin regulated the transcriptional activation of the genes encoding glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), the two rate-limiting enzymes in hepatic gluconeogenesis. Moreover, starvation induced the hepatic expression of mRNAs encoding different Wnt isoforms. In addition, nutrient deprivation appeared to favor the association of beta-catenin with FoxO family members, rather than with members of the T cell factor of transcriptional activators. Notably, in a model of diet-induced obesity, hepatic deletion of beta-catenin improved overall metabolic homeostasis. These observations implicate Wnt signaling in the modulation of hepatic metabolism and raise the possibility that Wnt signaling may play a similar role in the metabolic regulation of other tissues. PMID- 21285412 TI - Mitochondrial membrane potential is required for MAVS-mediated antiviral signaling. AB - Mitochondria, dynamic organelles that undergo cycles of fusion and fission, are the powerhouses of eukaryotic cells and are also involved in cellular innate antiviral immunity in mammals. Mitochondrial antiviral immunity depends on activation of the cytoplasmic retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling pathway and the participation of a mitochondrial outer membrane adaptor protein called MAVS (mitochondrial antiviral signaling). We found that cells that lack the ability to undergo mitochondrial fusion as a result of targeted deletion of both mitofusin 1 (Mfn1) and mitofusin 2 (Mfn2) exhibited impaired induction of interferons and proinflammatory cytokines in response to viral infection, resulting in increased viral replication. In contrast, cells with null mutations in either Mfn1 or Mfn2 retained their RLR induced antiviral responses. We also found that a reduced mitochondrial membrane potential (DeltaPsi(m)) correlated with the reduced antiviral response. The dissipation in DeltaPsi(m) did not affect the activation of the transcription factor interferon regulatory factor 3 downstream of MAVS, which suggests that DeltaPsi(m) and MAVS are coupled at the same stage in the RLR signaling pathway. Our results provide evidence that the physiological function of mitochondria plays a key role in innate antiviral immunity. PMID- 21285413 TI - Quantitative profiling of in vivo-assembled RNA-protein complexes using a novel integrated proteomic approach. AB - Identification of proteins in RNA-protein complexes is an important step toward understanding regulation of RNA-based processes. Because of the lack of appropriate methodologies, many studies have relied on the creation of in vitro assembled RNA-protein complexes using synthetic RNA and cell extracts. Such complexes may not represent authentic RNPs as they exist in living cells as synthetic RNA may not fold properly and nonspecific RNA-protein interactions can form during cell lysis and purification processes. To circumvent limitations in current approaches, we have developed a novel integrated strategy namely MS2 in vivo biotin tagged RNA affinity purification (MS2-BioTRAP) to capture bona fide in vivo-assembled RNA-protein complexes. In this method, HB-tagged bacteriophage protein MS2 and stem-loop tagged target or control RNAs are co-expressed in cells. The tight association between MS2 and the RNA stem-loop tags allows efficient HB-tag based affinity purification of authentic RNA-protein complexes. Proteins associated with target RNAs are subsequently identified and quantified using SILAC-based quantitative mass spectrometry. Here the 1.2 kb internal ribosome entry site (IRES) from lymphoid enhancer factor-1 mRNA has been used as a proof-of-principle target RNA. An IRES target was chosen because of its importance in protein translation and our limited knowledge of proteins associated with IRES function. With a conventionally translated target RNA as control, 36 IRES binding proteins have been quantitatively identified including known IRES binding factors, novel interacting proteins, translation initiation factors (eIF4A-1, eIF-2A, and eIF3g), and ribosomal subunits with known noncanonical actions (RPS19, RPS7, and RPL26). Validation studies with the small molecule eIF4A-1 inhibitor Hippuristanol shows that translation of endogenous lymphoid enhancer factor-1 mRNA is especially sensitive to eIF4A-1 activity. Our work demonstrates that MS2 in vivo biotin tagged RNA affinity purification is an effective and versatile approach that is generally applicable for other RNA protein complexes. PMID- 21285415 TI - The cover. Sor Juana Ines de la Cruz. PMID- 21285414 TI - Quantitative tracking of isotope flows in proteomes of microbial communities. AB - Stable isotope probing (SIP) has been used to track nutrient flows in microbial communities, but existing protein-based SIP methods capable of quantifying the degree of label incorporation into peptides and proteins have been demonstrated only by targeting usually less than 100 proteins per sample. Our method automatically (i) identifies the sequence of and (ii) quantifies the degree of heavy atom enrichment for thousands of proteins from microbial community proteome samples. These features make our method suitable for comparing isotopic differences between closely related protein sequences, and for detecting labeling patterns in low-abundance proteins or proteins derived from rare community members. The proteomic SIP method was validated using proteome samples of known stable isotope incorporation levels at 0.4%, ~50%, and ~98%. The method was then used to monitor incorporation of (15)N into established and regrowing microbial biofilms. The results indicate organism-specific migration patterns from established communities into regrowing communities and provide insights into metabolism during biofilm formation. The proteomic SIP method can be extended to many systems to track fluxes of (13)C or (15)N in microbial communities. PMID- 21285416 TI - A piece of my mind. Haiti. PMID- 21285417 TI - IOM endorses vitamin D, calcium only for bone health, dispels deficiency claims. PMID- 21285418 TI - Picture this: the average US child has nearly 8 imaging tests by age 18. PMID- 21285419 TI - Experts hope to clear confusion with first guidelines to tackle food allergy. PMID- 21285420 TI - Breast cancer in postmenopausal women after hormone therapy. PMID- 21285421 TI - Breast cancer in postmenopausal women after hormone therapy. PMID- 21285422 TI - Carriage of reduced-function CYP2C19 allele among patients treated with clopidogrel. PMID- 21285423 TI - Pregnancy incidence and outcomes in vertically and behaviorally HIV-infected youth. PMID- 21285424 TI - Association of hospice agency profit status with patient diagnosis, location of care, and length of stay. AB - CONTEXT: Medicare's per diem payment structure may create financial incentives to select patients who require less resource-intensive care and have longer hospice stays. For-profit and nonprofit hospices may respond differently to financial incentives. OBJECTIVE: To compare patient diagnosis and location of care between for-profit and nonprofit hospices and examine whether number of visits per day and length of stay vary by diagnosis and profit status. DESIGN, SETTING, AND PATIENTS: Cross-sectional study using data from the 2007 National Home and Hospice Care Survey. Nationally representative sample of 4705 patients discharged from hospice. MAIN OUTCOME MEASURES: Diagnosis and location of care (home, nursing home, hospital, residential hospice, or other) by hospice profit status. Hospice length of stay and number of visits per day by various hospice personnel. RESULTS: For-profit hospices (1087 discharges from 145 agencies), compared with nonprofit hospices (3618 discharges from 524 agencies), had a lower proportion of patients with cancer (34.1%; 95% CI, 29.9%-38.6%, vs 48.4%; 95% CI, 45.0%-51.8%) and a higher proportion of patients with dementia (17.2%; 95% CI, 14.1%-20.8%, vs 8.4%; 95% CI, 6.6%-10.6%) and other noncancer diagnoses (48.7%; 95% CI, 43.2% 54.1%, vs 43.2%; 95% CI, 40.0%-46.5%; adjusted P < .001). After adjustment for demographic, clinical, and agency characteristics, there was no significant difference in location of care by profit status. For-profit hospices compared with nonprofit hospices had a significantly longer length of stay (median, 20 days; interquartile range [IQR], 6-88, vs 16 days; IQR, 5-52 days; adjusted P = .01) and were more likely to have patients with stays longer than 365 days (6.9%; 95% CI, 5.0%-9.4%, vs 2.8%; 95% CI, 2.0%-4.0%) and less likely to have patients with stays of less than 7 days (28.1%; 95% CI, 23.9%-32.7%, vs 34.3%; 95% CI, 31.3%-37.3%; P = .005). Compared with cancer patients, those with dementia or other diagnoses had fewer visits per day from nurses (0.50 visits; IQR, 0.32 0.87, vs 0.37 visits; IQR, 0.20-0.78, and 0.41 visits; IQR, 0.26-0.79, respectively; adjusted P = .002) and social workers (0.15 visits; IQR, 0.07-0.31, vs 0.11 visits; IQR, 0.04-0.27, and 0.14 visits; IQR, 0.07-0.31, respectively; adjusted P < .001). CONCLUSION: Compared with nonprofit hospice agencies, for profit hospice agencies had a higher percentage of patients with diagnoses associated with lower-skilled needs and longer lengths of stay. PMID- 21285425 TI - Receipt of disease-modifying antirheumatic drugs among patients with rheumatoid arthritis in Medicare managed care plans. AB - CONTEXT: In 2005, the Healthcare Effectiveness Data and Information Set (HEDIS) introduced a quality measure to assess the receipt of disease-modifying antirheumatic drugs (DMARDs) among patients with rheumatoid arthritis (RA). OBJECTIVE: To identify sociodemographic, community, and health plan factors associated with DMARD receipt among Medicare managed care enrollees. DESIGN, SETTING, AND PARTICIPANTS: We analyzed individual-level HEDIS data for 93,143 patients who were at least 65 years old with at least 2 diagnoses of RA within a measurement year (during 2005-2008). Logistic regression models with generalized estimating equations were used to determine factors associated with DMARD receipt and logistic regression was used to adjust health plan performance for case mix. MAIN OUTCOME MEASURES: Receipt or nonreceipt of DMARD. RESULTS: The mean age of patients was 74 years; 75% were women and 82% were white. Overall performance on the HEDIS measure for RA was 59% in 2005, increasing to 67% in 2008 (P for trend <.001). The largest difference in performance was based on age: patients aged 85 years and older had a 30 percentage point lower rate of DMARD receipt (95% confidence interval [CI], -29 to -32 points; P < .001), compared with patients 65 to 69 years of age, even after adjusting for other factors. Lower percentage point rates were also found for patients who were men (-3 points; 95% CI, -5 to 2 points; P < .001), of black race (-4 points; 95% CI, -6 to -2 points; P < .001), with low personal income (-6 points; 95% CI, -8 to -5 points; P < .001), with the lowest zip code-based socioeconomic status (-4 points; 95% CI, -6 to 2 points; P < .001), or enrolled in for-profit health plans (-4 points; 95% CI, -7 to 0 points; P < .001); and in the Middle Atlantic region (-7 points; 95% CI, -13 to -2 points; P < .001) and South Atlantic regions (-11 points; 95% CI, -20 to -3 points; P < .001) as compared with the Pacific region. Performance varied widely by health plan, ranging from 16% to 87%. CONCLUSIONS: Among Medicare managed care enrollees carrying a diagnosis of RA between 2005 and 2008, 63% received a DMARD. Receipt of DMARDs varied based on demographic factors, socioeconomic status, geographic location, and health plan. PMID- 21285426 TI - Treatment-related mortality with bevacizumab in cancer patients: a meta-analysis. AB - CONTEXT: Fatal adverse events (FAEs) have been reported in cancer patients treated with the widely used angiogenesis inhibitor bevacizumab in combination with chemotherapy. Currently, the role of bevacizumab in treatment-related mortality is not clear. OBJECTIVE: To perform a systematic review and meta analysis of published randomized controlled trials (RCTs) to determine the overall risk of FAEs associated with bevacizumab. DATA SOURCES: PubMed, EMBASE, and Web of Science databases as well as abstracts presented at American Society of Clinical Oncology conferences from January 1966 to October 2010 were searched to identify relevant studies. STUDY SELECTION AND DATA EXTRACTION: Eligible studies included prospective RCTs in which bevacizumab in combination with chemotherapy or biological therapy was compared with chemotherapy or biological therapy alone. Summary incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated using fixed- or random-effects models. DATA SYNTHESIS: A total of 10,217 patients with a variety of advanced solid tumors from 16 RCTs were included in the analysis. The overall incidence of FAEs with bevacizumab was 2.5% (95% CI, 1.7%-3.9%). Compared with chemotherapy alone, the addition of bevacizumab was associated with an increased risk of FAEs, with an RR of 1.46 (95% CI, 1.09-1.94; P = .01; incidence, 2.5% vs 1.7%). This association varied significantly with chemotherapeutic agents (P = .045) but not with tumor types (P = .13) or bevacizumab doses (P = .16). Bevacizumab was associated with an increased risk of FAEs in patients receiving taxanes or platinum agents (RR, 3.49; 95% CI, 1.82-6.66; incidence, 3.3% vs 1.0%) but was not associated with increased risk of FAEs when used in conjunction with other agents (RR, 0.85; 95% CI, 0.25-2.88; incidence, 0.8% vs 0.9%). The most common causes of FAEs were hemorrhage (23.5%), neutropenia (12.2%), and gastrointestinal tract perforation (7.1%). CONCLUSION: In a meta-analysis of RCTs, bevacizumab in combination with chemotherapy or biological therapy, compared with chemotherapy alone, was associated with increased treatment-related mortality. PMID- 21285427 TI - Clinician integrity and limits to patient autonomy. AB - A 28-year-old man with chronic granulomatous disease developed worsening respiratory status in the setting of chronic bacterial and fungal infections. The attending physician recommended transfer to the intensive care unit (ICU), but the patient declined. The patient understood that the nurses in the ICU have expertise in caring for patients with poor respiratory function. He also understood that he faced an increased risk of dying if he remained on the medical ward. At the same time, the patient was familiar with the nurses on the medical ward and felt comfortable there. Unsure of whether it was appropriate for clinicians to agree to provide less than optimal care for a critically ill patient, the clinicians on the medical ward requested a bioethics consultation. This article reviews the ethical issues that arise when patients ask clinicians to provide less than optimal care. Although it is well established that clinicians ought to respect patient autonomy, that obligation conflicted, in the present case, with the clinicians' sense of professional integrity. Future research on this vital but underexplored topic is needed to determine the extent to which clinicians' professional integrity places limits on the types of patient requests to which they should agree. PMID- 21285428 TI - A physician management infrastructure. PMID- 21285429 TI - Mind matters in cancer survival. PMID- 21285430 TI - Hospital readmission as an accountability measure. PMID- 21285431 TI - Bevacizumab treatment for solid tumors: boon or bust? PMID- 21285432 TI - JAMA patient page. Generalized anxiety disorder. PMID- 21285433 TI - A systems biology approach to infectious disease research: innovating the pathogen-host research paradigm. AB - The twentieth century was marked by extraordinary advances in our understanding of microbes and infectious disease, but pandemics remain, food and waterborne illnesses are frequent, multidrug-resistant microbes are on the rise, and the needed drugs and vaccines have not been developed. The scientific approaches of the past-including the intense focus on individual genes and proteins typical of molecular biology-have not been sufficient to address these challenges. The first decade of the twenty-first century has seen remarkable innovations in technology and computational methods. These new tools provide nearly comprehensive views of complex biological systems and can provide a correspondingly deeper understanding of pathogen-host interactions. To take full advantage of these innovations, the National Institute of Allergy and Infectious Diseases recently initiated the Systems Biology Program for Infectious Disease Research. As participants of the Systems Biology Program, we think that the time is at hand to redefine the pathogen-host research paradigm. PMID- 21285434 TI - Essential metabolites of Mycobacterium tuberculosis and their mimics. AB - An organism requires a range of biomolecules for its growth. By definition, these are essential molecules which constitute the basic metabolic requirements of an organism. A small organic molecule with chemical similarity to that of an essential metabolite may bind to the enzyme that catalyzes its production and inhibit it, likely resulting in the stasis or death of the organism. Here, we report a high-throughput approach for identifying essential metabolites of an organism using genetic and biochemical approaches and then implement computational approaches to identify metabolite mimics. We generated and genotyped 5,126 Mycobacterium tuberculosis mutants and performed a statistical analysis to determine putative essential genes. The essential molecules of M. tuberculosis were classified as products of enzymes that are encoded by genes in this list. Although incomplete, as many enzymes of M. tuberculosis have yet to be identified and characterized, this is the first report of a large number of essential molecules of the organism. We identified essential metabolites of three distinct metabolic pathways in M. tuberculosis and selected molecules with chemical similarity using cheminformatics strategies that illustrate a variety of different pharmacophores. Our approach is aimed at systematic identification of essential molecules and their mimics as a blueprint for development of effective chemical probes of M. tuberculosis metabolism, with the ultimate goal of seeking drugs that can kill this pathogen. As an illustration of this approach, we report that compounds JFD01307SC and l-methionine-S-sulfoximine, which share chemical similarity with an essential molecule of M. tuberculosis, inhibited the growth of this organism at micromolar concentrations. PMID- 21285435 TI - Microbial communities of the upper respiratory tract and otitis media in children. AB - Streptococcus pneumoniae asymptomatically colonizes the upper respiratory tract of children and is a frequent cause of otitis media. Patterns of microbial colonization likely influence S. pneumoniae colonization and otitis media susceptibility. This study compared microbial communities in children with and without otitis media. Nasal swabs and clinical and demographic data were collected in a cross-sectional study of Philadelphia, PA, children (6 to 78 months) (n=108) during the 2008-2009 winter respiratory virus season. Swabs were cultured for S. pneumoniae. DNA was extracted from the swabs; 16S rRNA gene hypervariable regions (V1 and V2) were PCR amplified and sequenced by Roche/454 Life Sciences pyrosequencing. Microbial communities were described using the Shannon diversity and evenness indices. Principal component analysis (PCA) was used to group microbial community taxa into four factors representing correlated taxa. Of 108 children, 47 (44%) were colonized by S. pneumoniae, and 25 (23%) were diagnosed with otitis media. Microbial communities with S. pneumoniae were significantly less diverse and less even. Two PCA factors were associated with a decreased risk of pneumococcal colonization and otitis media, as follows: one factor included potentially protective flora (Corynebacterium and Dolosigranulum), and the other factor included Propionibacterium, Lactococcus, and Staphylococcus. The remaining two PCA factors were associated with an increased risk of otitis media. One factor included Haemophilus, and the final factor included Actinomyces, Rothia, Neisseria, and Veillonella. Generally, these taxa are not considered otitis media pathogens but may be important in the causal pathway. Increased understanding of upper respiratory tract microbial communities will contribute to the development of otitis media treatment and prevention strategies. PMID- 21285436 TI - Blood consult: acute myeloid leukemia and the t(8;21)(q22;22). PMID- 21285437 TI - In vitro requirement for periostin in B lymphopoiesis. AB - B lymphopoiesis arrests in rabbits by 4 months of age. To identify molecules that contribute to this arrest, cDNA-representational difference analysis on BM stromal cells from young and adult rabbits showed that expression of Postn that encodes for the extracellular matrix protein periostin dramatically reduced with age. Postn-small interfering RNA OP9 cells lost their capacity to support B-cell development from rabbit or murine BM cells, and reexpression of periostin restored this potential, indicating an in vitro requirement for periostin in B lymphopoiesis. In our system, we determined that periostin deficiency leads to increased cell death and decreased proliferation of B-lineage progenitors. Further, RGD peptide inhibition of periostin/alpha(v)beta(3) interaction resulted in a marked decrease in B lymphopoiesis in vitro. Microarray analysis of the Postn-small interfering RNA OP9 cells showed decreased expression of key B lymphopoietic factors, including IL-7 and CXCL12. In vivo, unidentified molecule(s) probably compensate periostin loss because Postn(-/-) mice had normal numbers of B-cell progenitors in BM. We conclude that the decline in periostin expression in adult rabbit BM does not solely explain the arrest of B lymphopoiesis. However, the interaction of periostin with alpha(v)beta(3) on lymphoid progenitors probably provides both proliferative and survival signals for cells in the B-cell development pathway. PMID- 21285438 TI - Activation of the unfolded protein response is associated with impaired granulopoiesis in transgenic mice expressing mutant Elane. AB - Severe congenital neutropenia (SCN) is an inborn disorder of granulopoiesis that in many cases is caused by mutations of the ELANE gene, which encodes neutrophil elastase (NE). Recent data suggest a model in which ELANE mutations result in NE protein misfolding, induction of endoplasmic reticulum (ER) stress, activation of the unfolded protein response (UPR), and ultimately a block in granulocytic differentiation. To test this model, we generated transgenic mice carrying a targeted mutation of Elane (G193X) reproducing a mutation found in SCN. The G193X Elane allele produces a truncated NE protein that is rapidly degraded. Granulocytic precursors from G193X Elane mice, though without significant basal UPR activation, are sensitive to chemical induction of ER stress. Basal and stress granulopoiesis after myeloablative therapy are normal in these mice. Moreover, inaction of protein kinase RNA-like ER kinase (Perk), one of the major sensors of ER stress, either alone or in combination with G193X Elane, had no effect on basal granulopoiesis. However, inhibition of the ER-associated degradation (ERAD) pathway using a proteosome inhibitor resulted in marked neutropenia in G193X Elane. The selective sensitivity of G913X Elane granulocytic cells to ER stress provides new and strong support for the UPR model of disease patho-genesis in SCN. PMID- 21285440 TI - On the strength of connections between localist mental modules as a source of frequency-of-occurrence effects. AB - Frequency-of-occurrence effects (e.g., effects of word frequency or familiarity) are widely thought to arise through differences in resting levels of activation in localist input-output modules. A different account posits that these effects at least partially reflect the strength of connections between various localist modules. Given that Arabic numerals appear more frequently than their alphabetic counterparts, we contrasted reaction times to stimuli in both formats in a naming/reading-aloud task and a parity-judgment task. The script effect (the difference between reaction times to Arabic and to alphabetic formats) was large in the parity-judgment task but absent in the naming/reading-aloud task. This script-by-task interaction follows naturally from the idea that at least part of the effect of frequency of occurrence of a printed word or digit (and other instances of familiarity) resides in the strength of connections between specialized localist input-output modules and a localist semantic module. This conclusion is likely applicable across a variety of domains. PMID- 21285439 TI - Prognostic impact of SNP array karyotyping in myelodysplastic syndromes and related myeloid malignancies. AB - Single nucleotide polymorphism arrays (SNP-As) have emerged as an important tool in the identification of chromosomal defects undetected by metaphase cytogenetics (MC) in hematologic cancers, offering superior resolution of unbalanced chromosomal defects and acquired copy-neutral loss of heterozygosity. Myelodysplastic syndromes (MDSs) and related cancers share recurrent chromosomal defects and molecular lesions that predict outcomes. We hypothesized that combining SNP-A and MC could improve diagnosis/prognosis and further the molecular characterization of myeloid malignancies. We analyzed MC/SNP-A results from 430 patients (MDS = 250, MDS/myeloproliferative overlap neoplasm = 95, acute myeloid leukemia from MDS = 85). The frequency and clinical significance of genomic aberrations was compared between MC and MC plus SNP-A. Combined MC/SNP-A karyotyping lead to higher diagnostic yield of chromosomal defects (74% vs 44%, P < .0001), compared with MC alone, often through detection of novel lesions in patients with normal/noninformative (54%) and abnormal (62%) MC results. Newly detected SNP-A defects contributed to poorer prognosis for patients stratified by current morphologic and clinical risk schemes. The presence and number of new SNP A detected lesions are independent predictors of overall and event-free survival. The significant diagnostic and prognostic contributions of SNP-A-detected defects in MDS and related diseases underscore the utility of SNP-A when combined with MC in hematologic malignancies. PMID- 21285441 TI - Stereopsis and artistic talent: poor stereopsis among art students and established artists. PMID- 21285442 TI - Articular cartilage changes in patients with osteoarthritis after osteotomy. AB - BACKGROUND: High tibial osteotomy (HTO) is a method used to treat medial compartmental osteoarthritis in the knee. The realignment of the knee changes the loading patterns within the joint and may allow for regeneration of articular cartilage. Magnetic resonance imaging methods can be used to assess the quality of the regenerated cartilage. HYPOTHESIS: Altering mechanical alignment through HTO will have predictable effects on articular cartilage, allowing cartilage preservation and possible regeneration. Quality of regenerated cartilage will be inferior to normal articular cartilage. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Ten patients undergoing medial opening wedge HTO were evaluated using dGEMRIC methods (ie, delayed gadolinium-enhanced magnetic resonance imaging of cartilage) preoperatively and at 6 months, 1 year, and 2 years after HTO. Magnetic resonance images were evaluated by hand segmentation, and T1(Gd) relaxation times reflective of glycosaminoglycan content were determined for these regions of interest using magnetic resonance imaging analysis software. RESULTS: The lateral compartment displayed higher T1(Gd) values than the medial compartment at baseline. Initially, a decrease in T1(Gd) values on the medial side were observed for all patients at 6 months and remained reduced for all but 2 participants at 1 year and 2 years after HTO. However, on the medial side after 6 months, the rate of change for T1(Gd) values shifted from being negative (-9.6 milliseconds per month) to being positive (1.7 milliseconds per month). A positive change in the T1(Gd) of the medial tibial plateau was responsible for the positive overall change in the medial compartment. There was no significant difference in the rate of change on the lateral side (P = .141), with the average over the 2-year period being a decrease of 2.28 milliseconds per month. CONCLUSION: Medial opening wedge HTO provides subjective improvements in pain and quality of life, but the potential benefit of allowing articular cartilage preservation and possible regeneration is not well established. Results showed that after a nonweightbearing period, the rate of change in the medial compartment changes from negative to positive, indicating the potential for articular cartilage recovery secondary to an improved mechanical environment. PMID- 21285443 TI - Sagittal alignment of the knee and its relationship to noncontact anterior cruciate ligament injuries. AB - BACKGROUND: Knee hyperextension and tibial posterior slope are related to sagittal alignment of the knee. The relationship of sagittal alignment to noncontact anterior cruciate ligament (ACL) injuries has been reported with conflicting results. PURPOSE: To determine whether there is a difference in sagittal alignment of the knee between an ACL-deficient group and a negative control group and to find risk factors contributing to noncontact ACL injuries. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Magnetic resonance images of the knee in full extension were acquired in the patient group, which consisted of 33 male and 40 female patients with noncontact ACL injuries, and in the negative control group, which consisted of 28 male and 30 female participants. Three angles were measured: the angle between the femoral axis and the tibial axis, designated as the extension angle; the femoral plateau angle, between the femoral axis and a line tangent to the concave profile of the medial tibial plateau (P line); and the tibial posterior slope angle, 90 degrees minus the angle made by the intersection of the tibial axis and the P line. RESULTS: In the female group, the femoral plateau angle and the tibial posterior slope angle were significantly larger in the ACL-deficient patients than in the negative control group, although these differences were not seen in the male group. In the female subjects, a negative correlation between the extension angle and the tibial posterior slope angle was seen in the ACL-deficient group, suggesting that knees with hyperextension had a small tibial posterior slope, whereas knees without hyperextension had a large tibial posterior slope. CONCLUSION: There were 2 types of large femoral plateau angles: one had its origin in an increasing tibial posterior slope; the other resulted from hyperextension of the knee. Large posterior tibial slope and hyperextension are both correlated with noncontact ACL injury in women. PMID- 21285444 TI - Sensitivity and specificity of subacute computerized neurocognitive testing and symptom evaluation in predicting outcomes after sports-related concussion. AB - BACKGROUND: Concussions affect an estimated 136 000 high school athletes yearly. Computerized neurocognitive testing has been shown to be appropriately sensitive and specific in diagnosing concussions, but no studies have assessed its utility to predict length of recovery. Determining prognosis during subacute recovery after sports concussion will help clinicians more confidently address return-to play and academic decisions. PURPOSE: To quantify the prognostic ability of computerized neurocognitive testing in combination with symptoms during the subacute recovery phase from sports-related concussion. STUDY DESIGN: Cohort study (prognosis); Level of evidence, 2. METHODS: In sum, 108 male high school football athletes completed a computer-based neurocognitive test battery within 2.23 days of injury and were followed until returned to play as set by international guidelines. Athletes were grouped into protracted recovery (>14 days; n = 50) or short-recovery (<=14 days; n = 58). Separate discriminant function analyses were performed using total symptom score on Post-Concussion Symptom Scale, symptom clusters (migraine, cognitive, sleep, neuropsychiatric), and Immediate Postconcussion Assessment and Cognitive Testing neurocognitive scores (verbal memory, visual memory, reaction time, processing speed). RESULTS: Multiple discriminant function analyses revealed that the combination of 4 symptom clusters and 4 neurocognitive composite scores had the highest sensitivity (65.22%), specificity (80.36%), positive predictive value (73.17%), and negative predictive value (73.80%) in predicting protracted recovery. Discriminant function analyses of total symptoms on the Post-Concussion Symptom Scale alone had a sensitivity of 40.81%; specificity, 79.31%; positive predictive value, 62.50%; and negative predictive value, 61.33%. The 4 symptom clusters alone discriminant function analyses had a sensitivity of 46.94%; specificity, 77.20%; positive predictive value, 63.90%; and negative predictive value, 62.86%. Discriminant function analyses of the 4 computerized neurocognitive scores alone had a sensitivity of 53.20%; specificity, 75.44%; positive predictive value, 64.10%; and negative predictive value, 66.15%. CONCLUSION: The use of computerized neurocognitive testing in conjunction with symptom clusters results improves sensitivity, specificity, positive predictive value, and negative predictive value of predicting protracted recovery compared with each used alone. There is also a net increase in sensitivity of 24.41% when using neurocognitive testing and symptom clusters together compared with using total symptoms on Post Concussion Symptom Scale alone. PMID- 21285445 TI - Effects of an age-specific anterior cruciate ligament injury prevention program on lower extremity biomechanics in children. AB - BACKGROUND: Implementing an anterior cruciate ligament injury prevention program to athletes before the age at which the greatest injury risk occurs (15-17 years) is important from a prevention standpoint. However, it is unknown whether standard programs can modify lower extremity biomechanics in pediatric populations or if specialized training is required. HYPOTHESIS/PURPOSE: To compare the effects of traditional and age-specific pediatric anterior cruciate ligament injury prevention programs on lower extremity biomechanics during a cutting task in youth athletes. The authors hypothesized that the age-specific pediatric program would result in greater sagittal plane motion (ie, hip and knee flexion) and less motion in the transverse and frontal plane (ie, knee valgus, knee and hip rotation) as compared with the traditional program. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Sixty-five youth soccer athletes (38 boys, 27 girls) volunteered to participate. The mean age of participants was 10 +/- 1 years. Teams (n, 7) were cluster randomized to a pediatric injury prevention program, a traditional injury prevention program, or a control group. The pediatric program was modified from the traditional program to include more feedback, progressions, and variety. Teams performed their programs as part of their normal warm-up routine. Three-dimensional lower extremity biomechanics were assessed during a sidestep cutting task before and after completion of the 9-week intervention period. RESULTS: The pediatric program reduced the amount of knee external rotation at initial ground contact during the cutting task, F ((2,62)) = 3.79, P = .03 (change: pediatric, 7.73 degrees +/- 10.71 degrees ; control, -0.35 degrees +/- 7.76 degrees ), as compared with the control group after the intervention period. No other changes were observed. CONCLUSION: The injury prevention program designed for a pediatric population modified only knee rotation during the cutting task, whereas the traditional program did not result in any changes in cutting biomechanics. These findings suggest limited effectiveness of both programs for athletes younger than 12 years of age in terms of biomechanics during a cutting task. PMID- 21285446 TI - Reproducibility and reliability of the Snyder classification of superior labral anterior posterior lesions among shoulder surgeons. AB - BACKGROUND: Previous studies of the reliability of classifications for superior labral anterior and posterior (SLAP) lesions suggest that intraobserver/interobserver reliability is poor. PURPOSE: The goals were to (1) evaluate intraobserver/interobserver reliability of the Snyder classification of labrum tears among experienced surgeons, (2) determine the effect of simplifying that classification into normal versus abnormal labrums, (3) determine the reliability of subdividing type II SLAP lesions, and (4) evaluate the effect of videotape quality on diagnostic confidence. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 3. METHODS: At 2 separate times, 5 experienced shoulder surgeons (all >10 years of practice) evaluated 90 videotapes of shoulder arthroscopy performed for SLAP lesions to identify lesion type, to grade video quality, and to determine degree of confidence in diagnosis. The results were compared for intraobserver reliability (kappa analysis) and interobserver reliability (intraclass correlation coefficients) and effect of video quality on diagnostic confidence. Significance was set at P < .05. RESULTS: When the choices were normal labrum or the 4 types of SLAP lesions, the intraobserver agreements (mean kappa, 0.670) and interobserver agreements (mean correlation, 0.804) were substantial. When the labrums were divided into normal (normal and type I) and abnormal (types II-IV), the intraobserver agreements (mean kappa, 0.792) and interobserver agreements (mean correlation, 0.648) were substantial. When the 3 type II SLAP lesion subvariants were evaluated, the intraobserver agreement (mean kappa, 0.598) was moderate, and the interobserver agreement (mean correlation, 0.804) was substantial. The confidence of the diagnosis was highly correlated with the perceived video quality (average Pearson correlation, 0.718; P < .01). Repeated measures analysis showed a significant relationship between confidence and quality (parameter estimate, 0.732; standard error, 0.021; P < .01) adjusting for rater and review. CONCLUSION: For experienced shoulder surgeons, the Snyder classification is a reliable system for identifying SLAP lesions. PMID- 21285447 TI - No effect of extracorporeal shockwave therapy on patellar tendinopathy in jumping athletes during the competitive season: a randomized clinical trial. AB - BACKGROUND: Patellar tendinopathy is a common overuse injury among jumping athletes. No evidence-based treatment guidelines exist. Extracorporeal shockwave therapy (ESWT) appears to be a promising treatment but its effectiveness has not been studied in athletes with patellar tendinopathy who have symptoms for 3 to 12 months and are still playing. PURPOSE: The TOPGAME study was created to determine the effectiveness of ESWT on pain, symptoms, and function in athletes with early symptomatic patellar tendinopathy who are still in training and competition. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Athletes playing volleyball, basketball, or handball with patellar tendinopathy for 3 to 12 months were randomized into the ESWT or placebo group during the first half of the season. The ESWT group received 3 ESWT treatments while the placebo group received sham ESWT. In-season follow-up measurements were 1, 12, and 22 weeks after treatment. The primary outcome was severity of patellar tendinopathy determined with the Victorian Institute of Sport Assessment-Patella (VISA-P) questionnaire. Secondary outcome measures were pain during activities of daily living and sports and after functional knee-loading tests rated on a visual analog scale and subjective improvement. Multilevel analyses were performed to determine differences between groups over time. RESULTS: Of the 127 symptomatic athletes invited to participate, 62 were eligible, gave consent, and were randomized into the ESWT (n = 31) or placebo group (n = 31). Mean VISA-P scores before and 1, 12, and 22 weeks after treatment were 59.4 (+/-11.7), 66.8 (+/ 16.2), 66.7 (+/-17.5), and 70.5 (+/-18.9) for the ESWT group and 62.4 (+/-13.4), 66.3 (+/-19.0), 68.9 (+/-20.3), and 72.7 (+/-18.0) for the placebo group. For the VISA-P, there was a significant effect for time (P < .01) but no treatment * time interaction effect (P = .82). The same pattern was seen in visual analog scale pain scores. One week after final treatment, significantly more athletes in the ESWT group reported subjective improvement (65% vs 32%; chi(2) = 6.46, P = .01). This was the only difference noted between the 2 groups. CONCLUSION: Extracorporeal shockwave therapy as a solitary treatment during the competitive season has no benefit over placebo treatment in the management of actively competing jumping athletes with patellar tendinopathy who have symptoms for less than 12 months. PMID- 21285448 TI - Local versus systemic influences on uterine vascular reactivity during pregnancy in the single-horn gravid rat. AB - This study was conducted to determine whether gestational changes in maternal uterine artery reactivity are primarily driven by local vs. systemic factors. Rats underwent surgical ligation of one oviduct, thereby restricting implantation and pregnancy to one uterine horn while maintaining a gestational endocrine milieu. Uterine arcuate arteries were isolated and cannulated to evaluate reactivity. Vessels from the implanted horn were significantly more sensitive to phenylephrine and less sensitive to sodium nitroprusside than those from the non implanted horn; endothelial basal calcium levels were only increased in the implanted horn. Conversely, there were no differences in sensitivity to acetylcholine, or its effects on endothelial cell calcium, although efficacy was greater in vessels from the implanted vs. non-implanted horn. These findings demonstrate that local factors are predominant in inducing changes in vascular smooth muscle function, while endothelial adaptations result from an interplay between local and systemic factors, with distinct effects attributable to each. PMID- 21285449 TI - First trimester serum 25-hydroxyvitamin D status and factors related to lower levels in gravids living in the Spanish Mediterranean coast. AB - OBJECTIVE: To assess first trimester serum 25-hydroxyvitamin D [25(OH)D] status and factors related to deficient levels in pregnant Spanish women. METHODS: This cross-sectional study was carried out among 502 gravids (11 to 14 weeks) living in the Spanish Mediterranean sea coast (near Almeria at latitude 36 degrees N, longitude 2 degrees W) to whom serum 25(OH)D levels were measured by electrochemiluminescence immunoassay. Logistic and multiple linear regression analysis were performed to assess the influence of ethnicity, immigration status, season of the year at blood sampling, body mass index (BMI), parity and smoking habit over 25(OH)D levels. RESULTS: The median (interquartile range, IQR) serum 25(OH)D levels for the entire sample was 27.4 ng/mL (IQR = 20.9-32.8). Only 35.9% of participants had adequate serum 25(OH)D levels (>=30 ng/mL) whereas in 41.4% and 22.7% these levels were found to be insufficient (20-29.9 ng/mL) and deficient (<20 ng/mL), respectively. Vitamin D status was found to be significantly lower in Arab women as compared to Caucasian women. 25(OH)D levels were positively correlated with gestational age at sampling and inversely with BMI values (univariate analysis). Logistic regression analysis determined that non-Caucasian ethnicity, season at sampling (autumn/winter), and nulliparity were factors related to deficient 25(OH)D levels. Multiple linear regression found a similar model yet also including maternal weight inversely correlating with 25(OH)D levels. CONCLUSION: Despite living in one of the sunniest, warmest, and driest climates of Europe, gravids displayed a high prevalence of first trimester insufficient/deficient serum 25(OH)D levels related to season at sampling, nulliparity, maternal weight, and non-Caucasian ethnicity. PMID- 21285450 TI - Pregnancy outcome in women with chronic kidney disease: a prospective cohort study. AB - OBJECTIVE: To evaluate pregnancy outcome in women with chronic kidney disease (CKD) or proteinuria in early pregnancy with concomitant risk for preeclampsia (PE). METHODS: Thirty-six women with CKD (Cr > 100 MUmol/L at booking or Cr > 125 MUmol/L prepregnancy or proteinuria >= 500 mg/24 hours at booking) and 30 women with proteinuria (>=2+) and known clinical risk for PE were enrolled at 14(+0) to 21(+6) weeks. Pregnancy outcomes were assessed. RESULTS: Women with mild CKD (prepregnancy Cr < 125 umol/Cr > 100 umol at booking; n = 22) had high rates of preeclampsia (40%), preterm delivery (<37 weeks' gestation; 54%), SGA infants (<10th adjusted centile; 64%)and perinatal death (5%). Women with moderate/severe CKD (prepregnancy creatinine > 125 umol; n = 14) had poor perinatal outcomes: preterm delivery (86%) and perinatal death (14%). Women with proteinuria (>=2+) and concomitant risk of PE also had high rates of pre-eclampsia (60%), preterm delivery (40%), and SGA infants (27%). CONCLUSIONS: Pregnancy complications for women with CKD remain high. Women with risk factors for PE with proteinuria (>=2+) at booking are also high-risk. PMID- 21285451 TI - Evaluation of 18FDG PET-CT in the diagnosis of endometriosis: a prospective study. AB - BACKGROUND: Noninvasive techniques have poor sensitivity and specificity in diagnosing endometriosis, which is often associated with an inflammatory process. In several benign diseases, measurement of hypermetabolism using fluorodeoxyglucose (18F 18FDG) reflects the degree of inflammation and aggressiveness of the disease. This prospective study evaluated the value of (18)FDG positron emission tomography (PET)-computed tomography (CT) in assessing the presence of endometriosis. METHODS: Ten consecutive patients suspected with endometriosis were prospectively included in this study. A preoperative 18FDG PET CT was performed in all the patients during the follicular phase of their cycle, which preceded laparoscopic surgery. Surgical endometriosis staging and histopathological analysis of removed tissue were confronted with the results from 18FDG PET-CT. RESULTS: Of the 10 patients, 9 had endometriosis confirmed by laparoscopy; 6 had advanced stage of the disease and 5 had histologically proven lesions. Nevertheless, none of the patients had 18FDG-demonstrated hypermetabolism at PET-CT. CONCLUSIONS: In this preliminary series, we did not observe hypermetabolic activity in relation to endometriosis using 18FDG PET-CT. This study's most important limitation is the use of 18FDG as an isotopic tracer, which is not specific to endometrial tissue. PMID- 21285452 TI - Effect of aminoguanidine in sperm DNA fragmentation in varicocelized rats: role of nitric oxide. AB - BACKGROUND AND PURPOSE: The sperm of infertile men with varicocele exhibit markedly high DNA damage that appears to be related to high oxidative stress (OS). Aminoguanidine (AG) is a specific inhibitor of the nitric oxide synthase (NOS) isoforms iNOS and an antioxidant, the effects of which decrease NO and peroxynitrite production. The aim of this study was to determine the effects of AG on sperm chromatin in varicocelized rats. METHODS: Thirty male Wistar rats were divided into 5 groups: control, sham, varicocele, and AG and placebo-treated groups. At 10 weeks after varicocele induction, sperm chromatin was evaluated in all groups, except in the treated groups. The treated groups received intraperitoneal injections of 50 mg/kg AG or placebo daily for 10 weeks and then were killed for chromatin assessment. Sperm chromatin was evaluated by aniline blue, acridine orange, toluidine blue, and chromomycin A(3) staining. RESULTS: The results of the 4 above tests were significantly increased between varicocele and control (and sham) groups (P < .05). CONCLUSION: The findings of this study suggest that AG improves sperm DNA fragmentation that is associated with infertility in varicocelized rats, and treatment with AG can reduce the damage to sperm DNA. PMID- 21285453 TI - Inhibin B and anti-Mullerian hormone in spermatic vein of subfertile men with varicocele. AB - INTRODUCTION: The pathophysiology of subfertility in men with varicocele remains unclear as well as the role of inhibin B (Inh-B) and anti-Mullerian hormone (AMH). The aim of this study was to evaluate Inh-B and AMH concentrations in the spermatic vein of subfertile men with varicocele. PATIENTS AND METHODS: A total of 61 subfertile men with varicocele and 31 fertile controls underwent standard andrological evaluation. All subfertile men underwent varicocelectomy, during which blood samples were obtained from the spermatic vein to evaluate Inh-B and AMH concentrations. RESULTS: Peripheral vein Inh-B concentrations in men with varicocele were lower as compared to controls (52.9 [8.3-136.0) vs 116+/-9.7 ng/dL, P = .001). There was no difference in AMH concentrations (10.2 [4.4-45.4]) vs 10.4+/-0.8 pg/dL, P = 0.9). Spermatic vein Inh-B concentrations in men with varicocele were higher compared to those of peripheral vein (87.6+/-4.4 vs 52.9 [8.3-136.0] ng/dL, P = .001). On the contrary, spermatic vein AMH concentrations were lower compared to those from peripheral vein (8.84 [3.9-47.7] vs 10.2 [4.4 45.4] pg/dL, P = .013). CONCLUSIONS: Inh-B constitutes a reliable marker of Sertoli cell function as well as spermatogenesis. On the contrary, the clinical significance of AMH in men with varicocele remains to be elucidated. PMID- 21285454 TI - Bilateral caudal zona incerta nucleus stimulation for essential tremor: outcome and quality of life. AB - BACKGROUND: Over the past few years, bilateral stimulation of the caudal or motor part of the zona incerta nucleus (cZI) has been performed by the authors in patients with essential tremor (ET). Outcomes including quality of life data in 15 patients with a follow-up period of up to 84 months (mean 31.7 +/- 28.6 months) are presented. METHODS: 15 consecutive ET patients underwent MRI guided bilateral cZI deep brain stimulation implantation. Patients were assessed by applying the Fahn-Tolosa-Marin Tremor Rating Scale and the Short Form Health Survey-36 (SF-36) to assess quality of life. RESULTS: The total tremor score improved by 73.8% (p<0.0001). The part A score (items 1-9) improved by 86.6% (p<0.0001). Postural tremor improved by 88.2% (p<0.0001) and action tremor by 82.2% (p<0.0001). The part B score, which evaluates the functional activities of the upper limbs, improved by 60.1% (p<0.0001). Part C score, which evaluates the activities of daily living, improved by 80.0% (p<0.0001). The SF-36 physical component score improved by 23.7% (p<0.0001) and the mental component score by 22.4% (p<0.0001). There was one wound infection and three patients developed stimulation related transient dysarthria. None developed any disequilibrium or tolerance to stimulation. CONCLUSION: Bilateral cZI stimulation is safe and effective in suppressing the postural and action component of ET. It is associated with a low incidence of stimulation related complications and patients do not develop tolerance to stimulation with maintained clinical benefit over a follow-up period of up to 7 years. PMID- 21285455 TI - A longitudinal functional MRI study of non-arteritic anterior ischaemic optic neuropathy patients. AB - BACKGROUND: Non-arteritic anterior ischaemic optic neuropathy (NA-AION) can cause disabling visual loss and traditionally, visual prognosis has been considered poor, although recent studies have demonstrated improvements in visual acuity in about 30% of patients over time. The aim of the study was to determine whether there was significant cortical reorganisation with functional MRI (fMRI) after acute NA-AION by comparing affected individuals with healthy controls. METHODS: 9 patients with NA-AION were studied acutely and then after 1, 2, 3 and 6 months. 23 healthy volunteers underwent scanning at least twice. At each time point, patients were assessed clinically and with fMRI. For the fMRI experiments, subjects underwent monocular visual stimulation (wearing goggles with flashing LED displays). RESULTS: When stimulating the affected eye, occipital activation was reduced in patients compared with controls. Also, within the NA-AION group, activation in the right Brodmann areas (BA) 44 and 45 was seen during the early phase of the condition. The same areas were activated within the NA-AION group several months later for fellow eye stimulation. When the NA-AION and healthy control groups were formally compared however, these areas (BA 44/45) were not significantly different. NA-AION subjects did show greater activation in visual related areas compared with controls when stimulating the fellow eye. Visual acuity was correlated with more occipital cortex activation when stimulating the affected eye. CONCLUSIONS: There is cortical re-organisation of the fMRI response in extra-visual areas, seen when both affected and fellow eyes are stimulated after NA-AION. PMID- 21285456 TI - Predictors for the emergence of the 2 multi-nucleoside/nucleotide resistance mutations 69 insertion and Q151M and their impact on clinical outcome in the Swiss HIV cohort study. AB - The 69 insertion and Q151M mutations are multi-nucleoside/nucleotide resistance mutations (MNR). The prevalence among 4078 antiretroviral therapy (ART) experienced individuals was <1.3%. Combined ART fully prevented MNR in subtype B infections. Case-control studies were performed to identify risk factors. Control subjects were patients with >= 3 thymidine-analogue mutations. The 69 insertion study (27 control subjects, 14 case patients) identified didanosine exposure as a risk (odds ratio, 5.0 per year; P = .019), whereas the Q151M study (which included 44 control subjects and 25 case patients) detected no associations. Following detection, individuals with Q151M tended to have lower suppression rates and higher mortality rates, relative to control subjects. Additional studies are needed to verify these findings in non-subtype B infections. PMID- 21285457 TI - Crystallographic and mutational analysis of the CD40-CD154 complex and its implications for receptor activation. AB - CD40 is a tumor necrosis factor receptor (TNFR) family protein that plays an important role in B cell development. CD154/CD40L is the physiological ligand of CD40. We have determined the crystal structure of the CD40-CD154 complex at 3.5 A resolution. The binding site of CD40 is located in a crevice formed between two CD154 subunits. Charge complementarity plays a critical role in the CD40-CD154 interaction. Some of the missense mutations found in hereditary hyper-IgM syndrome can be mapped to the CD40-CD154 interface. The CD40 interaction area of one of the CD154 subunits is twice as large as that of the other subunit forming the binding crevice. This is because cysteine-rich domain 3 (CRD3) of CD40 has a disulfide bridge in an unusual position that alters the direction of the ladder like structure of CD40. The Ser(132) loop of CD154 is not involved in CD40 binding but its substitution significantly reduces p38- and ERK-dependent signaling by CD40, whereas JNK-dependent signaling is not affected. These findings suggest that ligand-induced di- or trimerization is necessary but not sufficient for complete activation of CD40. PMID- 21285458 TI - Selective mutations in estrogen receptor alpha D-domain alters nuclear translocation and non-estrogen response element gene regulatory mechanisms. AB - The three main mechanisms of ERalpha action are: 1) nuclear, genomic, direct DNA binding, 2) nuclear, genomic, "tethered"-mediated, protein-protein interactions, and 3) non-nuclear, non-genomic, rapid action responses. Reports suggest the D domain or hinge region of ERalpha plays an important role in mechanisms 1 and 2 above. Studies demonstrating the functionality of the ERalpha hinge region have resected the full D-domain; therefore, site directed mutations were made to attribute precise sequence functionality to this domain. This study focuses on the characterization and properties of three novel site directed ERalpha- D domain mutants. The Hinge 1 (H1) ERalpha mutant has disrupted nuclear localization, can no longer perform tethered mediated responses and has lost interaction with c-Jun, but retains estrogen response element (ERE)-mediated functions as demonstrated by confocal microscopy, reporter assays, endogenous gene expression and co-immunoprecipitation. The H2 ERalpha mutant is non-nuclear, but translocates to the nucleus with estradiol (E2) treatment and maintains ERE mediated functionality. The H2+NES ERalpha mutant does not maintain nuclear translocation with hormone binding, no longer activates ERE-target genes, functions in ERE- or tethered-mediated luciferase assays, but does retain the non genomic, non-nuclear, rapid action response. These studies reveal the sequence(s) in the ERalpha hinge region that are involved in tethered-mediated actions as well as nuclear localization and attribute important functionality to this region of the receptor. In addition, the properties of these ERalpha mutants will allow future studies to further dissect and characterize the three main ERalpha mechanisms of action and determine the mechanistic role each action has in estrogen hormone regulation. PMID- 21285459 TI - Use of the Impella 2.5 in high-risk percutaneous coronary intervention. AB - The Impella 2.5 is a percutaneously placed partial circulatory assist device that is increasingly being used in high-risk coronary interventional procedures to provide hemodynamic support. The Impella 2.5 is able to unload the left ventricle rapidly and effectively and increase cardiac output more than an intra-aortic balloon catheter can. Potential complications include bleeding, limb ischemia, hemolysis, and infection. One community hospital's approach to establishing a multidisciplinary program for use of the Impella 2.5 is described. PMID- 21285460 TI - Using the Mehran risk scoring tool to predict risk for contrast medium-induced nephropathy in patients undergoing percutaneous angiography. AB - BACKGROUND: Patients who have radiological imaging with contrast material are at risk for contrast medium-induced nephropathy, reduced renal function, longer hospitalizations, and renal failure requiring dialysis. OBJECTIVE: To determine whether the Mehran risk scoring tool can be used to predict changes in hospitalized patients who had percutaneous angiography. METHODS: Data on 196 patients admitted for cardiac angiography who had Mehran risk scores higher than 6 were analyzed retrospectively. Creatinine levels, used as predictors of contrast medium-induced nephropathy, were evaluated at day 2, day 3, and day 4 through day 7. RESULTS: Creatinine levels were significantly higher in patients with a Mehran risk score of 11 or higher than in patients with a risk score of 6 to 10 at all times. CONCLUSIONS: The Mehran risk scoring tool provides reliable data before patients have percutaneous angiography. PMID- 21285462 TI - The importance of family health history: your patients' and your own. PMID- 21285463 TI - Packed red blood cell transfusions in critically ill patients. AB - Anemia, which is prevalent in critically ill patients, often requires frequent blood transfusions. These blood transfusions are not without risks. A critical review of 6 studies shows an association between red blood cell transfusion and increased mortality. However, when disease state was adjusted for in 2 studies, researchers found that red blood cell transfusion correlated with decreased mortality. Thus further research, particularly on leukoreduction and age of stored blood, must be done before a change in practice can be implemented. It is vital that nurses stay current on this research in order to improve patients' outcomes. PMID- 21285464 TI - Acute kidney injury: not just acute renal failure anymore? AB - Until recently, no uniform standard existed for diagnosing and classifying acute renal failure. To clarify diagnosis, the Acute Dialysis Quality Initiative group stated its consensus on the need for a clear definition and classification system of renal dysfunction with measurable criteria. Today the term acute kidney injury has replaced the term acute renal failure, with an understanding that such injury is a common clinical problem in critically ill patients and typically is predictive of an increase in morbidity and mortality. A classification system, known as RIFLE (risk of injury, injury, failure, loss of function, and end-stage renal failure), includes specific goals for preventing acute kidney injury: adequate hydration, maintenance of renal perfusion, limiting exposure to nephrotoxins, drug protective strategies, and the use of renal replacement therapies that reduce renal injury. PMID- 21285465 TI - Innovative techniques to decrease blood exposure and minimize interruptions in pediatric continuous renal replacement therapy. AB - Continuous renal replacement therapy (CRRT) allows gradual, precise removal of excess fluid and solutes. Special considerations are necessary for children who require CRRT because of their smaller circulating blood volumes and the potential for hemodynamic instability associated with the initiation of CRRT. In critically ill children, the CRRT circuit is often primed with blood rather than saline to prevent excessive hemodilution. Two innovative techniques have been designed to limit repeated exposure to donated blood, reduce hemodynamic instability associated with priming of the circuit with blood, and limit interruptions in CRRT. A circuit-to-circuit exchange technique offers a safe, effective alternative method for CRRT circuit changes in small children and infants. A concurrent technique that combines CRRT with plasmapheresis is effective in preventing interruptions of therapy when patients require multiple modes of supportive treatment. PMID- 21285466 TI - A review of acute cyanide poisoning with a treatment update. AB - Cyanide causes intracellular hypoxia by reversibly binding to mitochondrial cytochrome oxidase a(3). Signs and symptoms of cyanide poisoning usually occur less than 1 minute after inhalation and within a few minutes after ingestion. Early manifestations include anxiety, headache, giddiness, inability to focus the eyes, and mydriasis. As hypoxia progresses, progressively lower levels of consciousness, seizures, and coma can occur. Skin may look normal or slightly ashen, and arterial oxygen saturation may be normal. Early respiratory signs include transient rapid and deep respirations. As poisoning progresses, hemodynamic status may become unstable. The key treatment is early administration of 1 of the 2 antidotes currently available in the United States: the well-known cyanide antidote kit and hydroxocobalamin. Hydroxocobalamin detoxifies cyanide by binding with it to form the renally excreted, non-toxic cyanocobalamin. Because it binds with cyanide without forming methemoglobin, hydroxocobalamin can be used to treat patients without compromising the oxygen-carrying capacity of hemoglobin. PMID- 21285468 TI - Working with new or unfamiliar technology. PMID- 21285469 TI - Infection stops here. PMID- 21285471 TI - I am a critical care nurse. PMID- 21285472 TI - Association of physical activity and prognostic parameters in elderly patients with heart failure. AB - OBJECTIVE: Assessment of habitual physical activity (PA) in patients with heart failure. METHODS: This study included 50 patients with heart failure (61.9 +/- 4.0 yr). Seven days of PA were assessed by questionnaire (AQ), pedometer, and accelerometer and correlated with prognostic markers including VO(2peak), percent left-ventricular ejection fraction, N-terminal pro-B-type natriuretic peptide, and New York Heart Association (NYHA) functional class. RESULTS: Accelerometry showed a stronger correlation with VO(2peak) and NYHA class (R = .73 and R = .68; p < .001) than AQ (R = .58 and R = -.65; p < .001) or pedometer (R = .52 and R = -.50; p < .001). In the multivariable regression model accelerometry was the only consistent independent predictor of VO(2peak) (p = .002). Moreover, when its accuracy of prediction was tested, 59% of NYHA I and 95% of NYHA III patients were correctly classified into their assigned NYHA classes based on their accelerometer activity. CONCLUSION: PA assessed by accelerometer is significantly associated with exercise capacity in patients with heart failure and is predictive of disease severity. The data suggests that PA monitoring can aid in evaluating clinical status. PMID- 21285473 TI - Development of a fall-risk self-assessment for community-dwelling seniors. AB - OBJECTIVE: To determine seniors' beliefs about falls and design a fall-risk self assessment and educational materials to promote early identification of evidence based fall risks and encourage prevention behaviors. METHODS: Focus groups with community-dwelling seniors, conducted in two phases to identify perceptions about fall risks and risk reduction and to assess face validity of the fall-risk self assessment and acceptability of educational materials. RESULTS: Lay perception of fall risks was in general concordance with evidence-based research. Maintaining independence and positive tone were perceived as key motivators for fall prevention. Seniors intended to use information in the educational tool to stimulate discussions about falls with health care providers. IMPLICATIONS: An evidence-based, educational fall-risk self-assessment acceptable to older adults can build on existing lay knowledge about fall risks and perception that falls are a relevant problem and can educate seniors about their specific risks and how to minimize them. PMID- 21285474 TI - Adherence to physical activity recommendations in older adults: an Israeli national survey. AB - The trend of extended life expectancy along with a sedentary lifestyle is typical in Western cultures. OBJECTIVE: To explore adherence to physical activity recommendations in older adults in Israel. METHODS: A random sample of 1,536 Jews and 316 Arabs age 65+ were interviewed and divided into sufficiently active, insufficiently active, and inactive groups based on official guidelines. RESULTS: Only 36.4% of the Jewish sector and 19.6% of the Arab sector are sufficiently active. Men are more active than women, the secular are more active than the religious among both Jews and Arabs, and more years of education, a higher income, and fewer diseases and medications are related to higher levels of physical activity. DISCUSSION: To slow down biological age decline with physical activity, intervention programs specifically tailored for culturally diverse groups are suggested-for example, recruiting prominent religious leaders to promote physical activity in religious populations. PMID- 21285475 TI - Exercise can improve speed of behavior in older drivers. AB - The main aim of this research was to study the effects of a specific exercise program on the speed of behavior of older adults during on-the-road driving. Twenty-six drivers (55-78 yr old) were randomly assigned to either an exercise group or a control group. The exercise program (3 sessions of 60 min/wk for 8 wk) incorporated tasks that induced the participants to respond quickly to challenging situations. On-the-road driving tasks (under single- and dual-task conditions) included measures of simple and choice reaction time, movement time, and response time. Significant positive effects were found at follow-up resulting from participation in the exercise program: Improvements were found for several measures in all driving tasks, and a composite score reflected a better general drivers' speed of behavior. These results show that exercise can enhance speed of behavior in older drivers and should therefore be promoted. PMID- 21285476 TI - Does yoga engender fitness in older adults? A critical review. AB - Interest in yoga is growing, especially among older adults. This review critically summarizes the current literature to investigate whether physical fitness and function benefits are engendered through the practice of yoga in older adults. A comprehensive search yielded 507 studies; 10 studies with 544 participants (69.6 +/- 6.3 yr, 71% female) were included. Large variability in yoga styles and measurement outcomes make it challenging to interpret results across studies. Studies reported moderate improvements for gait (ES = 0.54, 0.80), balance (ES = 0.25-1.61), upper/lower body flexibility (ES = 0.25, 0.70), lower body strength (ES = 0.51), and weight loss (ES = 0.73, 0.99).Yoga may engender improvements in some components of fitness in older adults. However, more evidence is needed to determine its effectiveness as an alternative exercise to promote fitness in older adults. Further investigation into yoga as an exercise activity for older adults is warranted. PMID- 21285477 TI - Dynamic dual-energy chest radiography: a potential tool for lung tissue motion monitoring and kinetic study. AB - Dual-energy chest radiography has the potential to provide better diagnosis of lung disease by removing the bone signal from the image. Dynamic dual-energy radiography is now possible with the introduction of digital flat-panel detectors. The purpose of this study is to evaluate the feasibility of using dynamic dual-energy chest radiography for functional lung imaging and tumor motion assessment. The dual-energy system used in this study can acquire up to 15 frames of dual-energy images per second. A swine animal model was mechanically ventilated and imaged using the dual-energy system. Sequences of soft-tissue images were obtained using dual-energy subtraction. Time subtracted soft-tissue images were shown to be able to provide information on regional ventilation. Motion tracking of a lung anatomic feature (a branch of pulmonary artery) was performed based on an image cross-correlation algorithm. The tracking precision was found to be better than 1 mm. An adaptive correlation model was established between the above tracked motion and an external surrogate signal (temperature within the tracheal tube). This model is used to predict lung feature motion using the continuous surrogate signal and low frame rate dual-energy images (0.1 3.0 frames per second). The average RMS error of the prediction was (1.1 +/- 0.3) mm. The dynamic dual energy was shown to be potentially useful for lung functional imaging such as regional ventilation and kinetic studies. It can also be used for lung tumor motion assessment and prediction during radiation therapy. PMID- 21285478 TI - L0 constrained sparse reconstruction for multi-slice helical CT reconstruction. AB - In this paper, we present a Bayesian maximum a posteriori method for multi-slice helical CT reconstruction based on an L0-norm prior. It makes use of a very low number of projections. A set of surrogate potential functions is used to successively approximate the L0-norm function while generating the prior and to accelerate the convergence speed. Simulation results show that the proposed method provides high quality reconstructions with highly sparse sampled noise free projections. In the presence of noise, the reconstruction quality is still significantly better than the reconstructions obtained with L1-norm or L2-norm priors. PMID- 21285479 TI - In vivo study of myocardial elastography under graded ischemia conditions. AB - The capability of currently available echocardiography-based strain estimation techniques to fully map myocardial abnormality at early stages of myocardial ischemia is yet to be investigated. In this study, myocardial elastography (ME), a radio-frequency (RF)-based strain imaging technique that maps the full 2D transmural angle-independent strain tensor in standard echocardiographic views at both high spatial and temporal resolution is presented. The objectives were to (1) evaluate the performance of ME on mapping the onset, extent and progression of myocardial ischemia at graded coronary constriction levels (from partial to complete coronary flow reduction), and (2) validate the accuracy of the strain estimates against sonomicrometry (SM) measurements. A non-survival canine ischemic model (n = 5) was performed by gradually constricting the left anterior descending (LAD) coronary blood flow from 0% (baseline blood flow) to 100% (zero blood flow) at 20% increments. An open-architecture ultrasound system was used to acquire RF echocardiograms in a standard full short-axis view at the frame rate of 211 fps, at least twice higher than what is typically used in conventional echocardiographic systems, using a previously developed, fully automated composite technique. Myocardial deformation was estimated by ME and validated against sonomicrometry. ME estimates and maps transmural (1) 2D displacements using RF cross-correlation and recorrelation; and (2) 2D polar (radial and circumferential) strains, derived from 2D (i.e. both lateral and axial) displacement components, at high accuracy. Full-view strain images were shown and found to reliably depict decreased myocardial function in the region at risk at increased levels of coronary flow reduction. The ME radial strain was deemed to be a more sensitive, quantitative, regional measure of myocardial ischemia as a result of coronary flow reduction when compared to the conventional wall motion score index and ejection fraction. Good agreement (0.22% strain bias, 95% limits of agreement) using Bland-Altman analysis and good correlation (r = 0.84) were found between the ME and SM measurements. These findings demonstrate for the first time that ME could map angle-independent strains to non-invasively detect, localize and characterize the early onset of myocardial ischemia, i.e. at 40%, and possibly as low as 20%, LAD flow reduction, which could be further associated with the severity of coronary stenosis. PMID- 21285480 TI - A Monte Carlo investigation of contaminant electrons due to a novel in vivo transmission detector. AB - A novel transmission detector (IBA Dosimetry, Germany) developed as an IMRT quality assurance tool, intended for in vivo patient dose measurements, is studied here. The goal of this investigation is to use Monte Carlo techniques to characterize treatment beam parameters in the presence of the detector and to compare to those of a plastic block tray (a frequently used clinical device). Particular attention is paid to the impact of the detector on electron contamination model parameters of two commercial dose calculation algorithms. The linac head together with the COMPASS transmission detector (TRD) was modeled using BEAMnrc code. To understand the effect of the TRD on treatment beams, the contaminant electron fluence, energy spectra, and angular distributions at different SSDs were analyzed for open and non-open (i.e. TRD and block tray) fields. Contaminant electrons in the BEAMnrc simulations were separated according to where they were created. Calculation of surface dose and the evaluation of contributions from contaminant electrons were performed using the DOSXYZnrc user code. The effect of the TRD on contaminant electrons model parameters in Eclipse AAA and Pinnacle(3) dose calculation algorithms was investigated. Comparisons of the fluence of contaminant electrons produced in the non-open fields versus open field show that electrons created in the non-open fields increase at shorter SSD, but most of the electrons at shorter SSD are of low energy with large angular spread. These electrons are out-scattered or absorbed in air and contribute less to surface dose at larger SSD. Calculated surface doses with the block tray are higher than those with the TRD. Contribution of contaminant electrons to dose in the buildup region increases with increasing field size. The additional contribution of electrons to surface dose increases with field size for TRD and block tray. The introduction of the TRD results in a 12% and 15% increase in the Gaussian widths used in the contaminant electron source model of the Eclipse AAA dose algorithm. The off-axis coefficient in the Pinnacle(3) dose calculation algorithm decreases in the presence of TRD compared to without the device. The electron model parameters were modified to reflect the increase in electron contamination with the TRD, a necessary step for accurate beam modeling when using the device. PMID- 21285481 TI - Development and preliminary testing of a standardized method for quantifying excess water in over-hydrated skin using evaporimetry. AB - Although evaporimetry (the measurement of water vapour flux density from the skin) has often been used to study the impact on skin hydration of using products such as baby diapers and incontinence pads, it is difficult to interpret results and to compare data from different studies because of the diversity of unvalidated methodologies used. The aim of this work was to develop a robust methodology for measuring the excess water in over-hydrated skin and test it on volar forearm and hip skin which had been occluded with saline soaked patches. Three repeat measurements were made on the volar forearm and the hip of five young (31-44 years) and six older (67-85 years) women and moderately good within subject repeatability was found for both skin sites for both subject groups. Measurements taken from the hip were significantly higher (P = 0.001) than those from the arm and had larger coefficients of variation (3.5-22.1%) compared to arms (3.0-14.0%). There were no significant differences between young and older skin, implying that women for future studies could be recruited without regard to age. This is the first time that a robust evaporimetric methodology for quantifying excess water in over-hydrated skin has been described and validated, and it will form a solid basis for future work. PMID- 21285482 TI - Automated detection of sleep apnea from electrocardiogram signals using nonlinear parameters. AB - Sleep apnoea is a very common sleep disorder which can cause symptoms such as daytime sleepiness, irritability and poor concentration. To monitor patients with this sleeping disorder we measured the electrical activity of the heart. The resulting electrocardiography (ECG) signals are both non-stationary and nonlinear. Therefore, we used nonlinear parameters such as approximate entropy, fractal dimension, correlation dimension, largest Lyapunov exponent and Hurst exponent to extract physiological information. This information was used to train an artificial neural network (ANN) classifier to categorize ECG signal segments into one of the following groups: apnoea, hypopnoea and normal breathing. ANN classification tests produced an average classification accuracy of 90%; specificity and sensitivity were 100% and 95%, respectively. We have also proposed unique recurrence plots for the normal, hypopnea and apnea classes. Detecting sleep apnea with this level of accuracy can potentially reduce the need of polysomnography (PSG). This brings advantages to patients, because the proposed system is less cumbersome when compared to PSG. PMID- 21285483 TI - A systematic study of linear dynamic modeling of intracranial pressure dynamics. AB - Our group has proposed a generic time series data mining framework and demonstrated its potential as a noninvasive intracranial pressure (ICP) assessment approach. The linear dynamic model (LDM) was used in our previous work without rigorous justification. In the current study, we performed a systematic study of the practical performance of the LDM for ICP dynamics by investigating three important aspects to consider in using the LDM to model ICP dynamics. Those three aspects include the fitness of the LDM to data, the generalizability of the models, and the choice of input signals to the models. Our study results show that the fitness of the LDM to data is excellent and the LDM for ICP dynamics is well generalizable, which is of particular interest to adopting our time series data mining framework for noninvasive ICP assessment. PMID- 21285484 TI - Cone-beam optical computed tomography for gel dosimetry II: imaging protocols. AB - This work develops imaging protocols for improved dose readout of a Fricke xylenol orange-gelatin (FXG) gel-filled 1 L polyethylene terephthalate (PETE) jar dosimeter using a commercial Vista(TM) cone-beam optical computed tomography (CT) scanner from Modus Medical Devices Inc. (London, ON, Canada). To ensure good management of light source-detector stability, it was determined that (a) a minimum of 2 h warm-up time is necessary prior to dosimeter scanning, (b) the light source should be kept on until the completion of the last data scan except for the minimum amount of time required to acquire dark field images, and (c) the optional Vista software projection image normalization routine should be used in image reconstruction. The institution of dosimeter scan time and temperature control was strongly indicated from the experiments. A standard post-irradiation wait time of 30 min measured to within +/-30 s was established to minimize the measurement uncertainties due to dosimeter development and diffusion. To alleviate thermochromic behavior leading to inaccurate dose readout, holding bath warm up and pre-scan temperature adjustment procedures were developed to control dosimeter temperature to within +/-0.2 degrees C. The possibility of stray light minimizing protocols was also investigated and deemed to be unnecessary. The largest significant sources of stray light in the system were identified as being due to angled scatter from the dosimeter gelatin matrix and refraction from the jar wall interfaces. It was concluded that these phenomena would be better addressed through dosimeter modification and an inter-jar dose-to-attenuation calibration methodology, rather than by setting additional imaging protocols. PMID- 21285485 TI - Adaptive prostate IGRT combining online re-optimization and re-positioning: a feasibility study. AB - In prostate radiation therapy, inter-fractional organ motion/deformation has posed significant challenges on reliable daily dose delivery. To correct for this issue, off-line re-optimization and online re-positioning have been used clinically. In this paper, we propose an adaptive images guided radiation therapy (AIGRT) scheme that combines these two correction methods in an anatomy-driven fashion. The AIGRT process first tries to find a best plan for the daily target from a plan pool, which consists of the original CT plan and all previous re optimized plans. If successful, the selected plan is used for daily treatment with translational shifts. Otherwise, the AIGRT invokes the re-optimization process of the CT plan for the anatomy of the day, which is afterward added to the plan pool as a candidate for future fractions. The AIGRT scheme is evaluated by comparisons with daily re-optimization and online re-positioning techniques based on daily target coverage, organs at risk (OAR) sparing and implementation efficiency. Simulated treatment courses for 18 patients with re-optimization alone, re-positioning alone and AIGRT shows that AIGRT offers reliable daily target coverage that is highly comparable to daily re-optimization and significantly improves from re-positioning. AIGRT is also seen to provide improved OAR sparing compared to re-positioning. Apart from dosimetric benefits, AIGRT in addition offers an efficient scheme to integrate re-optimization to current re-positioning-based IGRT workflow. PMID- 21285486 TI - The effect of 13C enrichment in the glassing matrix on dynamic nuclear polarization of [1-13C]pyruvate. AB - Dimethyl sulfoxide (DMSO) can effectively form a glassy matrix necessary for dynamic nuclear polarization (DNP) experiments. We tested the effects of (13)C enrichment in DMSO on DNP of [1-(13)C]pyruvate doped with trityl radical OX063Me. We found that the polarization build-up time tau of pyruvate in (13)C-labeled DMSO glassing solution is twice as fast as the unenriched DMSO while the nuclear magnetic resonance enhancement was unchanged. This indicates that (13)C-(13)C spin diffusion is a limiting factor in the kinetics of DNP in this system, but it has a minimal effect on the absolute value of polarization achievable for the target. PMID- 21285487 TI - Implementation and workflow for PET monitoring of therapeutic ion irradiation: a comparison of in-beam, in-room, and off-line techniques. AB - An independent assessment of the dose delivery in ion therapy can be performed using positron emission tomography (PET). For that a distribution of positron emitters which appear as the result of interaction between ions of the therapeutic beam and the irradiated tissue is measured during or after the irradiation. Three concepts for PET monitoring implemented in various therapy facilities are considered in this paper. The in-beam PET concept relies on the PET measurement performed simultaneously to the irradiation by means of a PET scanner which is completely integrated into the irradiation site. The in-room PET concept allows measurement immediately after irradiation by a standalone PET scanner which is installed very close to the irradiation site. In the off-line PET scenario the measurement is performed by means of a standalone PET/CT scanner 10-30 min after the irradiation. These three concepts were evaluated according to image quality criteria, integration costs, and their influence onto the workflow of radiotherapy. In-beam PET showed the best performance. However, the integration costs were estimated as very high for this modality. Moreover, the performance of in-beam PET depends heavily on type and duty cycle of the accelerator. The in-room PET is proposed for planned therapy facilities as a good compromise between the quality of measured data and integration efforts. For facilities which are close to the nuclear medicine departments off-line PET can be suggested under several circumstances. PMID- 21285488 TI - A robotic approach to 4D real-time tumor tracking for radiotherapy. AB - Respiratory and cardiac motions induce displacement and deformation of the tumor volumes in various internal organs. To accommodate this undesired movement and other errors, physicians incorporate a large margin around the tumor to delineate the planning target volume, so that the clinical target volume receives the prescribed radiation dose under any scenario. Consequently, a large volume of healthy tissue is irradiated and sometimes it is difficult to spare critical organs adjacent to the tumor. In this study we have proposed a novel approach to the 4D active tracking and dynamic delivery incorporating the tumor motion prediction technique. This method has been applied to the two commercially available robotic treatment couches. The proposed algorithm can predict the tumor position and the robotic systems are able to continuously track the tumor during radiation dose delivery. Therefore a precise dose is given to a moving target while the dose to the nearby critical organs is reduced to improve the patient treatment outcome. The efficacy of the proposed method has been investigated by extensive computer simulation. The tumor tracking method is simulated for two couches: HexaPOD robotic couch and ELEKTA Precise Table. The comparison results have been presented in this paper. In order to assess the clinical significance, dosimetric effects of the proposed method have been analyzed. PMID- 21285489 TI - Quantitative MRI assessment of VX2 tumour oxygenation changes in response to hyperoxia and hypercapnia. AB - Magnetic resonance imaging (MRI) relaxation times provide indirect estimates of tissue O(2) for monitoring tumour oxygenation. This study provides insight into mechanisms underlying longitudinal (R(1) = 1/T(1)) and transverse effective (R(2)* = 1/T(2)*) relaxation rate changes during inhalation of 100% O(2) and 3%, 6% and 9% CO(2) (balanced O(2)) in a rabbit tumour model. Quantitative R(1), R(2)*, and dynamic contrast-enhanced (DCE) imaging was performed in six rabbits 12-23 days following implantation of VX2 carcinoma cells in the quadricep muscle. Invasive measurements of tissue partial pressure of O(2) (pO(2)) and perfusion were also performed, which revealed elevated pO(2) levels in all tumour regions for all hyperoxic gases compared to baseline (air) and reduced perfusion for carbogen. During 100% O(2) breathing, an R(1) increase and R(2)* decrease consistent with elevated pO(2) were observed within tumours. DCE-derived blood flow was weakly correlated with R(1) changes from air to 100% O(2). Further addition of CO(2) (carbogen) did not introduce considerable changes in MR relaxation rates, but a trend towards higher R(1) relative to breathing 100% O(2) was observed, while R(2)* changes were inconsistent. This observation supports the predominance of dissolved O(2) on R(1) sensitivity and demonstrates the value of R(1) over R(2)* for tissue oxygenation measures. PMID- 21285490 TI - The tunnel manganese oxide Na4.32Mn9O18: a new Na+ site discovered by single crystal X-ray diffraction. AB - The title compound, tetrasodium nonamanganese octadecaoxide, Na(4.32)Mn(9)O(18), was synthesized by reacting Mn(2)O(3) with NaCl. One Mn atom occupies a site of 2/m symmetry, while all other atoms sit on mirror planes. The compound is isostructural with Na(4)Ti(4)Mn(5)O(18) and suggestive of Mn(3+)/Mn(4+) charge ordering. It has a double-tunnel structure built up from double and triple chains of MnO(6) octahedra and single chains of MnO(5) square pyramids by corner sharing. Disordered Na(+) cations occupy four crystallographic sites within the tunnels, including an unexpected new Na(+) site discovered inside the large S shaped tunnel. A local-ordering model is used to show the possible Na(+) distribution, and the unit-cell evolution during charging/discharging is explained on the basis of this local-ordering model. PMID- 21285491 TI - Gadolinium ytterbium trifluoride, Gd0.81Yb0.19F3. AB - A new gadolinium ytterbium trifluoride has been grown for the first time by the Czochralski technique. Although GdF(3) and YbF(3) both present a high-temperature phase transition, the mixed compound Gd(0.81)Yb(0.19)F(3) maintains its crystallographic structure upon cooling to room temperature. Taking into account that both Gd(3+) and Yb(3+) ions are distributed randomly on a single site (Wyckoff position 4c), this is attributed to a mean cationic radius coincident with that of the Tb(3+) ion, so that the stability of the crystal structure resembles that of TbF(3). The grown crystal melts noncongruently at ~1413 K, it is transparent and colourless, and it has a high density. PMID- 21285492 TI - 1,1'-[(Ethane-1,2-diyldioxy)di-o-phenylene]bis(indoline-2,3-dione) (L) and a novel [Ag2L2]2+ metallocycle based on coordination-driven Ag-O and Ag-pi bonds. AB - 1,1'-[(Ethane-1,2-diyldioxy)di-o-phenylene]bis(indoline-2,3-dione), C(32)H(24)N(2)O(6), L or (I), adopts a trans conformation with the two terminal indoline-2,3-dione groups located on opposite sides of the central ether bridge, as required by a centre of inversion located at the mid-point of the ethane C-C bond. However, in the discrete binuclear Ag(I) metallocycle complex salt bis{MU 1,1'-[(ethane-1,2-diyldioxy)di-o-phenylene]bis(indoline-2,3-dione)}disilver(I) bis(hexafluoridoantimonate), [Ag(2)(C(32)H(24)N(2)O(6))(2)][SbF(6)](2), (II), synthesized by combination of L with AgSbF(6), L adopts a gauche conformation to bind Ag(I) via the two indolinedione O atoms and two C atoms from the phenoxy ring. One dione O atom from the opposite side of the ether bridge completes the irregular coordination environment of each Ag(I) atom. The complex is on a centre of inversion located between the Ag(I) atoms. In the solid state, these binuclear [Ag(2)L(2)](2+) metallocycles stack together via intermolecular pi-pi interactions to generate a one-dimensional chain motif, with the [SbF(6)](-) counter-ions, which are disordered, located between the chains. PMID- 21285493 TI - (5-tert-Butylporphyrinato)copper(II), a nonplanar porphyrin with only one sterically demanding meso residue. AB - The title compound, [Cu(C(24)H(20)N(4))], is a rare example of a porphyrin carrying only one substituent. Its crystal structure exhibits two molecules in the asymmetric unit. The bulky meso tert-butyl residue gives rise to a nonplanar macrocycle with significant ruf and sad distortions. As a result of the position of the substituent, the conformational effects are unsymmetric and to a significant extent localized in the affected quadrant of the macrocycle. In line with results for highly substituted nonplanar porphyrins, comparison with a free base and a nickel(II) complex shows that the conformation of the macrocycle is modulated via additional metal effects. PMID- 21285494 TI - Tricarbonyl(eta5-cyclopentadienyl)(trifluorohydroxyborato)tungsten. AB - The title compound, [W(C(5)H(5))(HOBF(3))(CO)(3)], has a four-legged piano-stool geometry which is typically found for C(5)H(5)W(CO)(3)X complexes. The HOBF(3)(-) anion is the hydrolysis product of BF(4)(-) and is coordinated via oxygen. PMID- 21285495 TI - catena-Poly[[bis(MU-2-sulfonatobenzoato)bis[triaquagadolinium(III)]]-MU-oxalato]. AB - The asymmetric unit of the title coordination polymer, [Gd(2)(C(7)H(4)O(5)S)(2)(C(2)O(4))(H(2)O)(6)](n) or [Gd(2 SB)(ox)(0.5)(H(2)O)(3)](2n) (2-SB is 2-sulfonatobenzoate and ox is oxalate), (I), consists of one Gd(III) ion, one 2-SB anion, three coordinated water molecules and one half of an ox ligand. The ox ligand is located on a crystallographic inversion centre. The Gd(III) centre shows a distorted tricapped trigonal prismatic coordination formed by nine O atoms from two 2-SB anions, one ox ligand and three coordinated water molecules. The carboxylate and sulfonate groups of the 2-SB anions adopt MU(2)-eta(1):eta(2) and MU(1)-eta(0):eta(0):eta(1) coordination modes to link two Gd(III) ions, generating a centrosymmetric binuclear [Gd(2)(2-SB)(2)(H(2)O)(6)](2-) subunit. The ox ligand acts as a bridge, linking the binuclear [Gd(2)(2-SB)(2)(H(2)O)(6)](2-) subunits into a one dimensional chain structure parallel to the b axis. Furthermore, extensive O H...O hydrogen bonds connect the chains into a three-dimensional supramolecular architecture. PMID- 21285496 TI - Hexakis(urea-kappaO)zinc(II) dinitrate at 110 and 250 K: uniaxial negative thermal expansion. AB - The crystal structure of the title compound, [Zn{CO(NH(2))(2)}(6)](NO(3))(2), has been determined at 110 and 250 K. The structure is stabilized by 12 individual hydrogen bonds, both intra- and intermolecular. Analysis of the thermal expansion tensor, based on unit cells determined over a temperature range of 180 K, shows uniaxial compression in the direction of the b axis during warming. The hydrogen bonds form layers perpendicular to this axis and these layers are connected by coordinative bonds parallel to the axis. As expected, the intermolecular hydrogen bonds expand during warming. Surprisingly, the coordinative bonds contract, accompanied by changes in the O-Zn-O angles. Overall, this behaviour can be described as an accordion-like effect. PMID- 21285497 TI - Poly[MU3-hydroxido-MU6-sulfato-MU3-(1,2,4-triazolato-kappa3N1:N2:N4) dicadmium(II)]: a cadmium-triazolate coordination polymer with a pseudo-cubane like tetranuclear cluster. AB - The title complex, [Cd(2)(C(2)H(2)N(3))(OH)(SO(4))](n), is a three-dimensional metal-organic framework consisting of pseudo-cubane-like tetranuclear cadmium clusters, which are formed by four Cd(II) atoms, two sulfate groups and two hydroxide groups. The tetranuclear cadmium clusters are connected into a layered substructure by Cd-O bonds and adjacent layers are linked by triazolate ligands into a three-dimensional network. A photoluminescent study revealed that the complex exhibits a strong emission in the visible region which probably originates from a pi-pi* transition. PMID- 21285498 TI - (6-Oxido-2-oxo-1,2-dihydropyrimidine-5-carboxylato-kappa2O5,O6)bis[2-(2-pyridyl) 1H-benzimidazole-kappa2N2,N3]manganese(II) monohydrate. AB - In the title compound, [Mn(C(5)H(2)N(2)O(4))(C(12)H(9)N(3))(2)].H(2)O, the Mn(II) centre is surrounded by three bidentate chelating ligands, namely, one 6-oxido-2 oxo-1,2-dihydropyrimidine-5-carboxylate (or uracil-5-carboxylate, Huca(2-)) ligand [Mn-O = 2.136 (2) and 2.156 (3) A] and two 2-(2-pyridyl)-1H-benzimidazole (Hpybim) ligands [Mn-N = 2.213 (3)-2.331 (3) A], and it displays a severely distorted octahedral geometry, with cis angles ranging from 73.05 (10) to 105.77 (10) degrees . Intermolecular N-H...O hydrogen bonds both between the Hpybim and the Huca(2-) ligands and between the Huca(2-) ligands link the molecules into infinite chains. The lattice water molecule acts as a hydrogen-bond donor to form double O...H-O-H...O hydrogen bonds with the Huca(2-) O atoms, crosslinking the chains to afford an infinite two-dimensional sheet; a third hydrogen bond (N H...O) formed by the water molecule as a hydrogen-bond acceptor and a Hpybim N atom further links these sheets to yield a three-dimensional supramolecular framework. Possible partial pi-pi stacking interactions involving the Hpybim rings are also observed in the crystal structure. PMID- 21285499 TI - Poly[diaquabis(MU-4,4'-bipyridine-kappa2N:N')bis(ethane-1,2-diol)di-MU-sulfato dicopper(II)]. AB - The title compound, [Cu(2)(SO(4))(2)(C(10)H(8)N(2))(2)(C(2)H(6)O(2))(2)(H(2)O)(2)](n), contains two crystallographically unique Cu(II) centres, each lying on a twofold axis and having a slightly distorted octahedral environment. One Cu(II) centre is coordinated by two bridging 4,4'-bipyridine (4,4'-bipy) ligands, two sulfate anions and two aqua ligands. The second is surrounded by two 4,4'-bipy N atoms and four O atoms, two from bridging sulfate anions and two from ethane-1,2-diol ligands. The sulfate anion bridges adjacent Cu(II) centres, leading to the formation of linear ...Cu1-Cu2-Cu1-Cu2... chains. Adjacent chains are further bridged by 4,4'-bipy ligands, which are also located on the twofold axis, resulting in a two-dimensional layered polymer. In the crystal structure, extensive O-H...O hydrogen-bonding interactions between water molecules, ethane 1,2-diol molecules and sulfate anions lead to the formation of a three dimensional supramolecular network structure. PMID- 21285500 TI - DL-alaninium semi-oxalate monohydrate. AB - The structure of the title compound, C(3)H(8)NO(2)(+).C(2)HO(4)(-).H(2)O, is formed by two chiral counterparts (L- and D-alaninium cations), semi-oxalate anions and water molecules, with a 1:1:1 cation-anion-water ratio. The structure is compared with that of the previously known anhydrous DL-alaninium semi-oxalate [Subha Nandhini, Krishnakumar & Natarajan (2001). Acta Cryst. E57, o666-o668] in order to investigate the role of water molecules in the crystal packing. The structure of the hydrate resembles that of anhydrous alaninium semi-oxalate, with the water molecule incorporated into the general three-dimensional network of hydrogen bonds where it forms four hydrogen bonds with neighbours disposed tetrahedrally about it. Although the main structural motifs in the hydrate and in the anhydrous form are topologically similar, the incorporation of water molecules in the network results in significant geometric distortion. There are several types of hydrogen bond in the crystal structure of the hydrate, two of which (O-H...O bonds between the semi-oxalate anions and O-H...O hydrogen bonds between water and alaninium cations) are very short. Such hydrogen bonds between semi-oxalate anions are also present in the anhydrous form of this compound. Short distances between semi-oxalate anions in neighbouring chains in the hydrate alternate with longer ones, whereas in the anhydrous structure they are equidistant. Despite the similarity of these compounds, dehydration of the hydrate on storage is not of a single-crystal to single-crystal type, but gives a polycrystalline pseudomorph, preserving the crystal habit. This transformation proceeds through the formation of an intermediate compound, presumably a hemihydrate. PMID- 21285501 TI - A structural and theoretical study of intermolecular interactions in nicotinohydrazide dihydrochloride. AB - In the title compound [systematic name: 3-(azaniumylcarbamoyl)pyridinium dichloride], C(6)H(9)N(3)O(2+).2Cl(-), the ions are connected by N-H...Cl hydrogen bonds to form layers and C-H...Cl interactions expand the layers into a three-dimensional net. The energies of the N-H...Cl interactions range from typical for very weak interactions (0.17 kcal mol(-1)) to those observed for relatively strong interactions (29.1 kcal mol(-1)). C-H...Cl interactions can be classified as weak and mildly strong (energies ranging from 2.2 to 8.2 kcal mol( 1)). Despite the short contacts existing between the parallel aromatic rings of the cations, pi-pi interactions do not occur. PMID- 21285502 TI - Arcyriaflavin A monohydrate. AB - The asymmetric unit of the title compound comprises the monohydrated form of the natural product arcyriaflavin A [systematic name: 12,13-dihydro-5H-indolo[2,3 a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione monohydrate], C(20)H(11)N(3)O(2).H(2)O. Individual molecular units are engaged in hydrogen-bonding interactions, forming two-dimensional zigzag supramolecular layers parallel to the (102) plane. The close packing of the layers is mediated by strong co-operative pi-pi stacking interactions, in tandem with interlayer hydrogen bonds involving the solvent water molecule. PMID- 21285503 TI - 2-Propynyl 2,3,4,6-tetra-O-acetyl-alpha-D-mannopyranoside. AB - The 2-propynyl group in the title compound, C(17)H(22)O(10), adopts an exoanomeric conformation, with the acetylenic group gauche with respect to position C1. Comparison of (13)C NMR chemical shifts from solution and the solid state suggest that the acetylenic group also adopts a conformation anti to C1 in solution. The pyranose ring adopts a (4)C(1) conformation. Of the three secondary O-acetyl groups, that on position O4, flanked by two equatorial groups, adopts a syn conformation, in agreement with recent generalizations [Gonzalez-Outeirino, Nasser & Anderson (2005). J. Org. Chem. 70, 2486-2493]. The acetyl group on position O3 adopts a gauche conformation, also in agreement with the recent generalizations, but that on position O2 adopts a syn conformation, not in agreement with the recent generalizations. PMID- 21285504 TI - Methyl 2-(4-bromophenyl)-1-(5-tert-butyl-1H-pyrazol-3-yl)-1H-benzimidazole-5 carboxylate: a hydrogen-bonded chain of edge-fused centrosymmetric rings. AB - In the title compound, C(22)H(21)BrN(4)O(2), the imidazole and pyrazole rings are almost orthogonal to each other, but the ester unit is effectively coplanar with the adjacent aryl rings. The molecules are linked into a chain of edge-fused centrosymmetric rings by a combination of N-H...O and C-H...pi(arene) hydrogen bonds. PMID- 21285505 TI - 4-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzoic acid: X-ray and DFT-calculated structure. AB - In the title compound, C(11)H(7)NO(4), there is a dihedral angle of 45.80 (7) degrees between the planes of the benzene and maleimide rings. The presence of O H...O hydrogen bonding and weak C-H...O interactions allows the formation of R(3)(3)(19) edge-connected rings parallel to the (010) plane. Structural, spectroscopic and theoretical studies were carried out. Density functional theory (DFT) optimized structures at the B3LYP/6-311 G(d,p) and 6-31++G(d,p) levels are compared with the experimentally determined molecular structure in the solid state. Additional IR and UV theoretical studies allowed the presence of functional groups and the transition bands of the system to be identified. PMID- 21285506 TI - Four stereoisomers of the novel MU-opioid receptor agonist tapentadol hydrochloride. AB - The crystal and molecular structures of four stereoisomers of tapentadol hydrochloride [systematic name: 3-(3-hydroxyphenyl)-N,N,2-trimethylpentan-1 aminium chloride], C(14)H(24)NO(+).Cl(-), a novel analgesic agent, have been determined by X-ray crystal structure analysis. Resolution of the isomers was carried out by reverse-phase and chiral high-performance liquid chromatographic (HPLC) methods. Stereoisomers (I) and (II) crystallize in the monoclinic space group P2(1), each with two tapentadol cations and two chloride anions in the asymmetric unit, while stereoisomers (III) and (IV) crystallize in the orthorhombic space group P2(1)2(1)2(1), with one tapentadol cation and one chloride anion in the asymmetric unit. The absolute configurations of the four enantiomers were determined unambiguously by X-ray crystallography. The crystal structures reveal the stereochemistries at the 3-ethyl and 2-methyl groups to be R,R, S,S, S,R and R,S in stereoisomers (I)-(IV), respectively. The ethyl and aminopropyl groups adopt different orientations with respect to the phenol ring for (I) and (IV). In all four structures, the chloride ions take part in N-H...Cl and O-H...Cl hydrogen bonds with the tapentadol molecules, resulting in one dimensional helical chains in the crystal packing in each case. PMID- 21285507 TI - 1,4-Phenylenebis(methylene) bis(9H-carbazole-9-carbodithioate). AB - The molecules of the title compound, C(34)H(24)N(2)S(4), lie across centres of inversion in the space group P2(1)/n. The spacer unit linking the benzene rings and carbazole units is effectively planar, while the carbazole unit itself is slightly folded. Molecules are linked into sheets by a single C-H...pi(arene) hydrogen bond and the hydrogen-bonded sheets are themselves linked into a three dimensional framework structure by a single pi-pi stacking interaction. PMID- 21285508 TI - Two 1,4-dihydropyridine derivatives with potential calcium-channel antagonist activity. AB - The title compounds, benzyl 4-(3-chloro-2-fluorophenyl)-2-methyl-5-oxo-4,5,6,7 tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate, C(23)H(19)ClFNO(3), (I), and 3 pyridylmethyl 4-[2-fluoro-3-(trifluoromethyl)phenyl]-2,6,6-trimethyl-5-oxo 1,4,5,6,7,8-hexahydroquinoline-3-carboxylate, C(26)H(24)F(4)N(2)O(3), (II), belong to a class of 1,4-dihydropyridines whose members sometimes display calcium modulatory properties. The 1,4-dihydropyridine ring in each structure has a shallower than usual shallow-boat conformation and is nearly planar in (I). In each structure, the halogen-substituted benzene ring is oriented such that the halogen substituents are in a synperiplanar orientation with respect to the 1,4 dihydropyridine ring plane. The oxocyclopentene ring in (I) is planar, while the oxocyclohexene ring in (II) has a half-chair conformation, which is less commonly observed than the envelope conformation usually found in related compounds. In (I), the frequently observed intermolecular N-H...O hydrogen bond between the amine group and the carbonyl O atom of the oxocyclopentene ring of a neighbouring molecule links the molecules into extended chains; there are no other significant intermolecular interactions. By contrast, the amine group in (II) forms an N H...N hydrogen bond with the pyridine ring N atom of a neighbouring molecule. Additional C-H...O interactions complete a two-dimensional hydrogen-bonded network. The halogen-substituted benzene ring has a weak intramolecular pi-pi interaction with the pyridine ring. A stronger pi-pi interaction occurs between the 1,4-dihydropyridine rings of centrosymmetrically related molecules. PMID- 21285509 TI - Mitigation of muscular dystrophy in mice by SERCA overexpression in skeletal muscle. AB - Muscular dystrophies (MDs) comprise a group of degenerative muscle disorders characterized by progressive muscle wasting and often premature death. The primary defect common to most MDs involves disruption of the dystrophin glycoprotein complex (DGC). This leads to sarcolemmal instability and Ca(2+) influx, inducing cellular necrosis. Here we have shown that the dystrophic phenotype observed in delta-sarcoglycan-null (Sgcd(-/-)) mice and dystrophin mutant mdx mice is dramatically improved by skeletal muscle-specific overexpression of sarcoplasmic reticulum Ca(2+) ATPase 1 (SERCA1). Rates of myofiber central nucleation, tissue fibrosis, and serum creatine kinase levels were dramatically reduced in Sgcd(-/-) and mdx mice with the SERCA1 transgene, which also rescued the loss of exercise capacity in Sgcd(-/-) mice. Adeno associated virus-SERCA2a (AAV-SERCA2a) gene therapy in the gastrocnemius muscle of Sgcd(-/-) mice mitigated dystrophic disease. SERCA1 overexpression reversed a defect in sarcoplasmic reticulum Ca(2+) reuptake that characterizes dystrophic myofibers and reduced total cytosolic Ca(2+). Further, SERCA1 overexpression almost completely rescued the dystrophic phenotype in a mouse model of MD driven solely by Ca(2+) influx. Mitochondria isolated from the muscle of SERCA1-Sgcd(-/ ) mice were no longer swollen and calpain activation was reduced, suggesting protection from Ca(2+)-driven necrosis. Our results suggest a novel therapeutic approach using SERCA1 to abrogate the altered intracellular Ca(2+) levels that underlie most forms of MD. PMID- 21285510 TI - Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay. AB - Defects in cholesterol synthesis result in a wide variety of symptoms, from neonatal lethality to the relatively mild dysmorphic features and developmental delay found in individuals with Smith-Lemli-Opitz syndrome. We report here the identification of mutations in sterol-C4-methyl oxidase-like gene (SC4MOL) as the cause of an autosomal recessive syndrome in a human patient with psoriasiform dermatitis, arthralgias, congenital cataracts, microcephaly, and developmental delay. This gene encodes a sterol-C4-methyl oxidase (SMO), which catalyzes demethylation of C4-methylsterols in the cholesterol synthesis pathway. C4 Methylsterols are meiosis-activating sterols (MASs). They exist at high concentrations in the testis and ovary and play roles in meiosis activation. In this study, we found that an accumulation of MASs in the patient led to cell overproliferation in both skin and blood. SMO deficiency also substantially altered immunocyte phenotype and in vitro function. MASs serve as ligands for liver X receptors alpha and beta(LXRalpha and LXRbeta), which are important in regulating not only lipid transport in the epidermis, but also innate and adaptive immunity. Deficiency of SMO represents a biochemical defect in the cholesterol synthesis pathway, the clinical spectrum of which remains to be defined. PMID- 21285511 TI - An N-terminal truncated carboxypeptidase E splice isoform induces tumor growth and is a biomarker for predicting future metastasis in human cancers. AB - Metastasis is a major cause of mortality in cancer patients. However, the mechanisms governing the metastatic process remain elusive, and few accurate biomarkers exist for predicting whether metastasis will occur, something that would be invaluable for guiding therapy. We report here that the carboxypeptidase E gene (CPE) is alternatively spliced in human tumors to yield an N-terminal truncated protein (CPE-DeltaN) that drives metastasis. mRNA encoding CPE-DeltaN was found to be elevated in human metastatic colon, breast, and hepatocellular carcinoma (HCC) cell lines. In HCC cells, cytosolic CPE-DeltaN was translocated to the nucleus and interacted with histone deacetylase 1/2 to upregulate expression of the gene encoding neural precursor cell expressed, developmentally downregulated gene 9 (Nedd9)--which has been shown to promote melanoma metastasis. Nedd9 upregulation resulted in enhanced in vitro proliferation and invasion. Quantification of mRNA encoding CPE-DeltaN in HCC patient samples predicted intrahepatic metastasis with high sensitivity and specificity, independent of cancer stage. Similarly, high CPE-DeltaN mRNA copy numbers in resected pheochromocytomas/paragangliomas (PHEOs/PGLs), rare neuroendocrine tumors, accurately predicted future metastasis or recurrence. Thus, CPE-DeltaN induces tumor metastasis and should be investigated as a potentially powerful biomarker for predicting future metastasis and recurrence in HCC and PHEO/PGL patients. PMID- 21285512 TI - Restoring expression of wild-type p53 suppresses tumor growth but does not cause tumor regression in mice with a p53 missense mutation. AB - The transcription factor p53 is a tumor suppressor. As such, the P53 gene is frequently altered in human cancers. However, over 80% of the P53 mutations found in human cancers are missense mutations that lead to expression of mutant proteins that not only lack p53 transcriptional activity but exhibit new functions as well. Recent studies show that restoration of p53 expression leads to tumor regression in mice carrying p53 deletions. However, the therapeutic efficacy of restoring p53 expression in tumors containing p53 missense mutations has not been evaluated. Here we demonstrate that restoring wild-type p53 expression halted tumor growth in mice inheriting a p53(R172H) missense mutation that is equivalent to a P53 missense mutation detected in approximately 6% of human cancers. However, it did not lead to tumor regression, as was observed in mice lacking p53. We further showed that the dominant-negative effect of the mutant p53 encoded by p53(R172H) dampened the activity of the restored wild-type p53. We therefore conclude that in a mutant p53 background, p53 restoration has the therapeutic potential to suppress tumor progression. Our findings support using p53 restoration as a strategy to treat human cancers with P53 missense mutations and provide direction for optimizing p53 restoration in cancer therapy. PMID- 21285513 TI - The biological activity of FasL in human and mouse lungs is determined by the structure of its stalk region. AB - Acute lung injury (ALI) is a life-threatening condition in critically ill patients. Injury to the alveolar epithelium is a critical event in ALI, and accumulating evidence suggests that it is linked to proapoptotic Fas/FasL signals. Active soluble FasL (sFasL) is detectable in the bronchoalveolar lavage (BAL) fluid of patients with ALI, but the mechanisms controlling its bioactivity are unclear. We therefore investigated how the structure of sFasL influences cellular activation in human and mouse lungs and the role of oxidants and proteases in modifying sFasL activity. The sFasL in BAL fluid from patients with ALI was bioactive and present in high molecular weight multimers and aggregates. Oxidants generated from neutrophil myeloperoxidase in BAL fluid promoted aggregation of sFasL in vitro and in vivo. Oxidation increased the biological activity of sFasL at low concentrations but degraded sFasL at high concentrations. The amino-terminal extracellular stalk region of human sFasL was required to induce lung injury in mice, and proteolytic cleavage of the stalk region by MMP-7 reduced the bioactivity of sFasL in human cells in vitro. The sFasL recovered from the lungs of patients with ALI contained both oxidized methionine residues and the stalk region. These data provide what we believe to be new insights into the structural determinants of sFasL bioactivity in the lungs of patients with ALI. PMID- 21285514 TI - Notch2 governs the rate of generation of mouse long- and short-term repopulating stem cells. AB - HSCs either self-renew or differentiate to give rise to multipotent cells whose progeny provide blood cell precursors. However, surprisingly little is known about the factors that regulate this choice of self-renewal versus differentiation. One candidate is the Notch signaling pathway, with ex vivo studies suggesting that Notch regulates HSC differentiation, although a functional role for Notch in HSC self-renewal in vivo remains controversial. Here, we have shown that Notch2, and not Notch1, inhibits myeloid differentiation and enhances generation of primitive Sca-1(+)c-kit(+) progenitors following in vitro culture of enriched HSCs with purified Notch ligands. In mice, Notch2 enhanced the rate of formation of short-term repopulating multipotential progenitor cells (MPPs) as well as long-term repopulating HSCs, while delaying myeloid differentiation in BM following injury. However, consistent with previous reports, once homeostasis was achieved, neither Notch1 nor Notch2 affected repopulating cell self-renewal. These data indicate a Notch2-dependent role in assuring orderly repopulation by HSCs, MPPs, myeloid cells, and lymphoid cells during BM regeneration. PMID- 21285516 TI - Comparison of different miR-21 inhibitor chemistries in a cardiac disease model. PMID- 21285515 TI - Particulate allergens potentiate allergic asthma in mice through sustained IgE mediated mast cell activation. AB - Allergic asthma is characterized by airway hyperresponsiveness, inflammation, and a cellular infiltrate dominated by eosinophils. Numerous epidemiological studies have related the exacerbation of allergic asthma with an increase in ambient inhalable particulate matter from air pollutants. This is because inhalable particles efficiently deliver airborne allergens deep into the airways, where they can aggravate allergic asthma symptoms. However, the cellular mechanisms by which inhalable particulate allergens (pAgs) potentiate asthmatic symptoms remain unknown, in part because most in vivo and in vitro studies exploring the pathogenesis of allergic asthma use soluble allergens (sAgs). Using a mouse model of allergic asthma, we found that, compared with their sAg counterparts, pAgs triggered markedly heightened airway hyperresponsiveness and pulmonary eosinophilia in allergen-sensitized mice. Mast cells (MCs) were implicated in this divergent response, as the differences in airway inflammatory responses provoked by the physical nature of the allergens were attenuated in MC-deficient mice. The pAgs were found to mediate MC-dependent responses by enhancing retention of pAg/IgE/FcepsilonRI complexes within lipid raft-enriched, CD63(+) endocytic compartments, which prolonged IgE/FcepsilonRI-initiated signaling and resulted in heightened cytokine responses. These results reveal how the physical attributes of allergens can co-opt MC endocytic circuitry and signaling responses to aggravate pathological responses of allergic asthma in mice. PMID- 21285518 TI - Expression of TNFRSF25 on conventional T cells and Tregs. PMID- 21285520 TI - The importance of integrating basic and clinical research toward the development of new therapies for Huntington disease. AB - Huntington disease (HD) is a dominantly inherited neurodegenerative disorder that results from expansion of the polyglutamine repeat in the huntingtin (HTT) gene. There are currently no effective treatments for this devastating disease. Given its monogenic nature, disease modification therapies for HD should be theoretically feasible. Currently, pharmacological therapies aimed at disease modification by altering levels of HTT protein are in late-stage preclinical development. Here, we review current efforts to develop new treatments for HD based on our current understanding of HTT function and the main pathological mechanisms. We emphasize the need to enhance translational efforts and highlight the importance of aligning the clinical and basic research communities to validate existing hypotheses in clinical studies. Human and animal therapeutic trials are presented with an emphasis on cellular and molecular mechanisms relevant to disease progression. PMID- 21285521 TI - Brain networks in Huntington disease. AB - Recent studies have focused on understanding the neural mechanisms underlying the emergence of clinical signs and symptoms in early stage Huntington disease (HD). Although cell-based assays have focused on cell autonomous effects of mutant huntingtin, animal HD models have revealed alterations in the function of neuronal networks, particularly those linking the cerebral cortex and striatum. These findings are complemented by metabolic imaging studies of disease progression in premanifest subjects. Quantifying metabolic progression at the systems level may identify network biomarkers to aid in the objective assessment of new disease-modifying therapies and identify new regions that merit mechanistic study in HD models. PMID- 21285522 TI - Energy deficit in Huntington disease: why it matters. AB - Huntington disease (HD) is an autosomal dominant neurodegenerative disease with complete penetrance. Although the understanding of the cellular mechanisms that drive neurodegeneration in HD and account for the characteristic pattern of neuronal vulnerability is incomplete, defects in energy metabolism, particularly mitochondrial function, represent a common thread in studies of HD pathogenesis in humans and animal models. Here we review the clinical, biochemical, and molecular evidence of an energy deficit in HD and discuss the mechanisms underlying mitochondrial and related alterations. PMID- 21285525 TI - Effectiveness of myofascial trigger point manual therapy combined with a self stretching protocol for the management of plantar heel pain: a randomized controlled trial. AB - STUDY DESIGN: A randomized controlled clinical trial. OBJECTIVE: To investigate the effects of trigger point (TrP) manual therapy combined with a self-stretching program for the management of patients with plantar heel pain. BACKGROUND: Previous studies have reported that stretching of the calf musculature and the plantar fascia are effective management strategies for plantar heel pain. However, it is not known if the inclusion of soft tissue therapy can further improve the outcomes in this population. METHODS: Sixty patients, 15 men and 45 women (mean +/- SD age, 44 +/- 10 years) with a clinical diagnosis of plantar heel pain were randomly divided into 2 groups: a self-stretching (Str) group who received a stretching protocol, and a self-stretching and soft tissue TrP manual therapy (Str-ST) group who received TrP manual interventions (TrP pressure release and neuromuscular approach) in addition to the same self-stretching protocol. The primary outcomes were physical function and bodily pain domains of the quality of life SF-36 questionnaire. Additionally, pressure pain thresholds (PPT) were assessed over the affected gastrocnemii and soleus muscles, and over the calcaneus, by an assessor blinded to the treatment allocation. Outcomes of interest were captured at baseline and at a 1-month follow-up (end of treatment period). Mixed-model ANOVAs were used to examine the effects of the interventions on each outcome, with group as the between-subjects variable and time as the within-subjects variable. The primary analysis was the group-by-time interaction. RESULTS: The 2 * 2 mixed-model analysis of variance (ANOVA) revealed a significant group-by-time interaction for the main outcomes of the study: physical function (P = .001) and bodily pain (P = .005); patients receiving a combination of self-stretching and TrP tissue intervention experienced a greater improvement in physical function and a greater reduction in pain, as compared to those receiving the self-stretching protocol. The mixed ANOVA also revealed significant group-by-time interactions for changes in PPT over the gastrocnemii and soleus muscles, and the calcaneus (all P<.001). Patients receiving a combination of self-stretching and TrP tissue intervention showed a greater improvement in PPT, as compared to those who received only the self-stretching protocol. CONCLUSIONS: This study provides evidence that the addition of TrP manual therapies to a self-stretching protocol resulted in superior short-term outcomes as compared to a self-stretching program alone in the treatment of patients with plantar heel pain. LEVEL OF EVIDENCE: Therapy, level 1b. PMID- 21285523 TI - Oligonucleotide therapeutic approaches for Huntington disease. AB - Huntington disease is an autosomal dominant neurodegenerative disorder caused by a toxic expansion in the CAG repeat region of the huntingtin gene. Oligonucleotide approaches based on RNAi and antisense oligonucleotides provide promising new therapeutic strategies for direct intervention through reduced production of the causative mutant protein. Allele-specific and simultaneous mutant and wild-type allele-lowering strategies are being pursued with local delivery to the brain, each with relative merits. Delivery remains a key challenge for translational success, especially with chronic therapy. The potential of disease-modifying oligonucleotide approaches for Huntington disease will be revealed as they progress into clinical trials. PMID- 21285526 TI - Acromioclavicular joint synovial chondromatosis. PMID- 21285527 TI - Eosinophilic granuloma in a patient with hip pain. PMID- 21285529 TI - Autophagy and apoptosis are redundantly required for C. elegans embryogenesis. AB - Apoptosis, the main form of regulated (or programmed) cell death, allows the organism to tightly control cell numbers and tissue size, and to protect itself from potentially damaging cells. This type of cellular self-killing has long been assumed to be essential for early development. In the nematode Caenorhabditis elegans, however, the core apoptotic cell death pathway appears to be dispensable for embryogenesis when most developmental cell deaths take place: mutant nematodes defective for apoptosis develop into adulthood, with superficially normal morphology and behavior. Accumulating evidence indicates a similar situation in mammalian systems as well. For example, apoptosis-deficient mice can grow as healthy, fertile adults. These observations raise the possibility that alternative cell death mechanisms may compensate for the lack of apoptotic machinery in developing embryos. Interestingly, C. elegans embryogenesis can also occur without autophagy, an alternative form of cellular self-destruction (also called autophagic cell death). In an upcoming paper we report that simultaneous inactivation of the autophagic and apoptotic gene cascades in C. elegans arrests development at early stages, and the affected embryos exhibit severe morphological defects. Double-mutant nematode embryos deficient in both autophagy and apoptosis are unable to undergo body elongation or to arrange several tissues correctly. This novel function of autophagy genes in morphogenesis indicates a more fundamental role for cellular self-digestion in tissue patterning than previously thought. PMID- 21285530 TI - Haemophilus influenzae vaccine candidate outer membrane protein P6 is not conserved in all strains. AB - An outer membrane protein of nontypeable Haemophilus influenzae (NTHi), P6, is a vaccine candidate because it has been characterized as conserved among all H. influenzae strains. Among 151 isolates from children, age 6 to 30 months, evaluating NTHi nasopharyngeal (NP) and oropharyngeal (OP) colonization and tympanocentesis confirmed acute otitis media we identified 14 strains (9.3%) that had variant protein sequences of P6. One atypical omp P6 isolate had sequence mutations in the binding site of a proposed major antigenic epitope of omp P6 identified by monoclonal antibody 7F3. Eight strains (5.3%) had non-homologous variations in amino acids that could result in significant changes to the protein structure of P6, and 5 other strains had amino acid substitutions at four previously described key residue sites. These results show that NTHi omp P6 is not invariant in its structure among respiratory isolates from children. PMID- 21285531 TI - Assessment of the safety, tolerability and kinetics of the immune response to A/H1N1v vaccine formulations with and without adjuvant in healthy pediatric subjects from 3 through 17 years of age. AB - BACKGROUND: The recent global A/H1N1v pandemic led to major efforts to develop effective vaccines against the novel virus, while global demand and limited production capacity focused attention on dose sparing and schedules. METHODS: An open-label phase III study of immunogenicity and safety of novel A/H1N1v vaccines included 392 Costa Rican children in two pediatric cohorts (3-8 and 9-17 years). They received two doses, of either an MF59(r)-adjuvanted formulation containing 7.5 MUg antigen or non-adjuvanted formulations containing 15 or 30 MUg antigen, three weeks apart. Immunogenicity was assessed as hemagglutination inhibition (HI) titers using the CBER licensure criteria. RESULTS: All three vaccines elicited immune responses in 9-17 year-olds meeting CBER criteria three weeks after one dose; responses were not enhanced by second dose. In 3-8 year-olds only the adjuvanted vaccine met the CBER criteria after one dose, but all three vaccines met criteria after second dose. All vaccines were well tolerated; no related Serious Adverse Events (SAE) and few severe solicited reactions were reported. MF59-adjuvanted vaccine was associated with more reports of injection site pain and tenderness and overall systemic solicited reactions, most notably in older subjects, all of which decreased after the second dose. CONCLUSION: One dose of non-adjuvanted A/H1N1v vaccine is adequate in 9-17 year-olds, but younger children require either one dose of MF59-adjuvanted vaccine or two doses of non adjuvanted vaccine to achieve protective titers. Enhanced immunogenicity with MF59 is associated with a small increase in reactogenicity, but no safety issues. PMID- 21285532 TI - Immunologic non-inferiority of a newly licensed inactivated trivalent influenza vaccine versus an established vaccine: a randomized study in US adults. AB - A trivalent inactivated influenza vaccine (Fluarix (TM) , GlaxoSmithKline Biologicals) was licensed under US accelerated approval regulations. We performed a randomized, observer-blind, post-approval study to demonstrate its immunological non-inferiority versus an established US-licensed vaccine (primary endpoint). Adult (including elderly) subjects received a single injection of newly-licensed vaccine (n = 923) or established vaccine (n = 922). Serum hemagglutination-inhibition titers were determined pre-vaccination and 21-28 days after vaccination. Non-inferiority was assessed by post-vaccination geometric mean titer (GMT) ratio (upper 95% confidence interval [CI] <= 1.5) and difference in seroconversion rate (upper 95% CI <= 0.1) for all three vaccine strains. Safety was monitored for 6 months. The newly-licensed vaccine was non-inferior to the established vaccine in all subjects (>= 18 years) and in elderly subjects (>= 65 years). Adjusted GMT ratios (established/newly-licensed) against the H1N1, H3N2 and B strains were 0.65 (95% CI: 0.58, 0.73), 0.93 (0.83, 1.04) and 1.13 (1.03, 1.25) for all subjects and 0.75 (0.67, 0.85), 0.95 (0.82, 1.09) and 1.13 (1.00, 1.27) for elderly subjects. Corresponding values for the differences in seroconversion rate (established minus newly-licensed) were -0.12 (-0.16, -0.07), -0.02 (-0.06, 0.03) and 0.01 (-0.04, 0.06) for all subjects and -0.11 (-0.16, 0.05), -0.02 (-0.07, 0.04) and 0.02 (-0.04, 0.08) for elderly subjects. The most common adverse events with both vaccines were injection site pain, fatigue and headache, and no serious adverse events or deaths were considered related; there were no clinically relevant differences between the vaccines. In conclusion, the newly-licensed vaccine was well tolerated and immunologically non-inferior to the established vaccine for all three vaccine strains in the whole population and the elderly. PMID- 21285533 TI - A universal influenza vaccine: where are we in the pursuit of this "Holy Grail"? PMID- 21285534 TI - Hepatitis A outbreaks in the vaccination era in Catalonia, Spain. AB - Hepatitis A outbreaks have a major impact on public health services and involve case investigation and intervention measures to susceptible contacts. At the end of 1998 a universal vaccination program with a combined hepatitis A+B vaccine was started in Catalonia (Spain) in 12-years-old preadolescents. The objective of this study was to compare the characteristics of hepatitis A outbreaks in the periods before and after the introduction of the preadolescent vaccination program and to estimate the preventable fraction of cases associated to outbreaks. The incidence rates of outbreaks, cases and hospitalization associated with each outbreak were calculated. Two periods were considered: before (1991 1998) and after (2000-2007) the introduction of mass vaccination. The preventable fraction and 95% confidence intervals (CI) of cases associated with outbreaks was calculated. The rate of associated cases with outbreaks was higher in the period before the vaccination program than in the post vaccination period (1.53 per 100,000 person-year vs 1.12 ; p< 0.001), but the rate of hospitalization was greater in the period after the introduction of vaccination program than in the period previous to vaccination (0.70 per million persons-year vs 0.08; p< 0.001). The preventable fraction of cases associated to outbreaks was 19.6%(95%CI 6.7 32.5) in the 0-4 years group and 16.7% (95% CI 6.0-27.5) in the 5-14 years group, but the highest figure (38.6%; 95%CI 21.3-55.9) was observed in the 15-24 years age group. The estimated proportion of cases associated with outbreaks that would theoretically have been prevented with the vaccination program suggests that substantial benefits have been obtained in Catalonia in people aged less than 25 years. PMID- 21285535 TI - Differences in sentinel influenza confirmed incidence rates and clinical presentation of influenza virus: 2008-09 seasonal vs 2009-10 pandemic influenza. AB - The Influenza sentinel surveillance network of Catalonia (PIDIRAC) allows for the study of circulating influenza virus (IV). The aim of this work was to assess differences between two influenza seasons, the 2008-2009 A(H3N2) season and the 2009-2010 season with predominance of pandemic influenza virus circulation. Incidence rate (IR) of confirmed influenza illness were calculated for both periods and age group. Clinical presentation features by age group (0-4,5-14,15 64 and > 64 y.o.) were studied and compared for both seasons. Statistical significance of proportion differences assessed by statistic z and Mantel Hanzel's Woolf test. The level of statistical significance was established at alpha=0.05. In both seasons studied, the 5-14 y.o. age group presented the highest confirmed influenza IR and highest presentation of cephalalgia as a symptom in the pandemic A(H1N1)2009 season. In conclusion, the significant burden of influenza, both seasonal and pandemic , on children should encourage upgrading vaccination coverage in these age groups and especially for those included in risk groups for whom yearly vaccination is recommended. PMID- 21285536 TI - Biosimilar, biobetter and next generation therapeutic antibodies. PMID- 21285537 TI - A novel platform to produce human monoclonal antibodies: The next generation of therapeutic human monoclonal antibodies discovery. AB - A new technology has been developed that allows human antibodies to be quickly generated against virtually any antigen. Using a novel process, naive human B cells are isolated from tonsil tissue and transformed with efficiency up to 85%, thus utilizing a large portion of the human VDJ/VJ repertoire. Through ex vivo stimulation, the B cells class switch and may undergo somatic hypermutation, thus producing a human "library" of different IgG antibodies that can then be screened against any antigen. Since diversity is generated ex vivo, sampling immunized or previously exposed individuals is not necessary. Cells producing the antibody of interest can be isolated through limiting dilution cloning and the human antibody from the cells can be tested for biological activity. No humanization is necessary because the antibodies are produced from human B cells. By eliminating immunization and humanization steps, and screening a broadly diverse library, this platform should reduce both the cost and time involved in producing therapeutic monoclonal antibody candidates. PMID- 21285646 TI - The value of volunteers. PMID- 21285649 TI - Oxygen use for preterm infants: factors that may influence clinical decisions surrounding oxygen titration. AB - Preterm infants in neonatal intensive care units frequently require oxygen therapy. Clinicians are responsible for titrating oxygen to maximize the benefits and minimize the risks of this therapy. Studies have identified various toxic effects of oxygen on the developing tissues of the preterm infant; however, optimal target SpO(2) ranges have not been identified. Current trends in neonatology are focusing on defining optimal oxygen saturation ranges to improve infant outcomes and to decrease complications associated with the oxygen use. Consequently, research-based guidelines are being developed in neonatal intensive care units to guide oxygen administration. As target oxygen saturation ranges are developed, issues regarding health care professional compliance with these ranges have been identified. The specific reasons for this noncompliance have not been widely explored. However, factors such as nursing shortages, staffing issues, and a de-emphasis on staff education surrounding oxygen use have been offered as possible reasons. Understanding factors shaping clinical decision-making about oxygen titration is critical when designing policies and educational programs to change oxygen titration practice and ultimately improve patient outcomes. In this article, the literature outlining the importance of oxygen titration for preterm infants is reviewed. Discussion then focuses on factors that influence clinical decision-making and how these factors may influence decisions surrounding the use of oxygen for preterm infants. PMID- 21285651 TI - Why is end-of-life care delivery sporadic?: A quantitative look at the barriers to and facilitators of providing end-of-life care in the neonatal intensive care unit. AB - PURPOSE: According to the Centers for Disease Control and Prevention Infant Mortality Statistics, 28 384 infants died in the United States in 2005. On examining the state of the science in providing end-of-life care for newborns, it is important to examine the practice of providing compassionate and dignified palliative care at the end of life. The purpose of this research study was to examine the barriers to and facilitators of providing a quality end-of-life care in one large Midwestern tertiary NICU. SUBJECTS: A convenience sample of 50 NICU registered nurses from a Level III Midwestern Facility participated. METHODS: A quantitative, prospective, cross-sectional design was used. Data were collected with the Neonatal Palliative Care Attitude Scale questionnaire. RESULTS: Five barriers and 8 facilitators to end-of-life care practice in the NICU were identified. The 5 barriers were the nurses' inability to express opinions values and beliefs regarding palliative care (M = 2.98, SD = 1.30), less than ideal physical environment (M = 2.70, SD = 1.31), technological imperatives (M = 3.22, SD = 1.11), parental demands (M = 3.46, SD = 1.07), and, finally, lack of education (M = 2.86, SD = 1.44). The 8 facilitators were supportive medical staff (M = 3.60, SD = 1.29), parental involvement of decisions (M = 3.76, SD = 1.17), parents informed of options (M = 3.32, SD = 1.22), support from medical team when palliative care is implemented (M = 3.20, SD = 1.28), staffing (M = 3.60, SD = 1.29), time spent with dying baby (M = 3.52, SD = 1.31), policies/guidelines supporting palliative care (M = 3.76, SD = 1.19), and available counseling (M = 3.566, SD = 1.26). CONCLUSIONS: Barriers and facilitators continue to exist within neonatal end-of-life care. There is significant importance for NICU nurses to recognize and understand the barriers to and facilitators of providing end-of life care within their specific unit. Further research is warranted regarding implementation of end-of-life care education in the NICU to improve patient care. PMID- 21285652 TI - Making the literature palatable at the bedside: Reference poster promotes oral feeding best practice. AB - Neonatal nurses often draw upon prior experiences and intuition to feed neonates. Such experience and skill vary from nurse to nurse and may not be based on recent research, nor tailored to each neonate's feeding skill. An evidence-based neonatal oral feeding guideline was produced to improve oral feeding practices among nurses and parents. The implementation was initially less than ideal, resulting in poor compliance. A bedside reference poster was designed to serve as a visual succinct reminder of the oral feeding guideline. PMID- 21285653 TI - Successful treatment of liver rupture in a premature infant. AB - Subcapsular rupture of the liver is a rare and usually lethal complication in preterm infants. A multidisciplinary approach is warranted to achieve the best possible outcome for these children. PMID- 21285654 TI - A parent's guide to a safe sleep environment. PMID- 21285655 TI - Regionalized systems of perinatal care: health policy considerations. AB - Over the past 2 decades, perinatal and neonatal health care has become less coordinated and more competitive in the United States. The impact at the state level has been the evolution of a fragmented, perinatal system with limited access and poorer outcomes. The evidence demonstrates lower mortality risk for very low-birth-weight infants born in designated tertiary centers. Regionalized systems of perinatal care are recommended to ensure that each mother and newborn achieve optimal outcomes. This article discusses the factors impacting implementation of this model at either the state or federal level as well as the incorporation of perinatal regionalization as part of the national agenda of health care reform. PMID- 21285656 TI - Neonatal Resuscitation Program (NRP) 2011: new science, new strategies. AB - In spring 2011, the American Academy of Pediatrics (AAP) will release sixth edition materials for the Neonatal Resuscitation Program (NRP). This edition brings changes in resuscitation practice and a new education methodology that shifts the instructor from "teacher" to "learning facilitator" and requires the NRP course participant to assume more responsibility for learning. The change from a lecture format to simulation-based learning requires instructors to learn new skills and meet new requirements to maintain instructor status.The sixth edition of the Textbook of Neonatal Resuscitation and the fifth edition of the Instructor's Manual for Neonatal Resuscitation are currently in press. The AAP granted permission to use material from these forthcoming publications in this article. PMID- 21285657 TI - The use of bedside ultrasonography for PICC placement and insertion. PMID- 21285658 TI - The experience of mothers whose very low-birth-weight infant requires the delivery of supplemental oxygen in the neonatal intensive care unit. AB - PURPOSE: This study examines the experience of mothers whose very low-birth weight infants require the delivery of supplemental oxygen during their hospitalization in the neonatal intensive care unit (NICU). SUBJECTS: Eleven mothers of very low-birth-weight infants who have received various supplemental oxygen delivery methods in the NICU for a minimum of 7 days were selected for interview. DESIGN: Qualitative descriptive. METHODS: One semistructured interview exploring mothers' experiences surrounding oxygen delivery methods was conducted. Qualitative content analysis was undertaken to describe mothers' experience. PRINCIPLE RESULTS: Four themes emerged related to the oxygen therapy and the various methods of delivery: Oxygen therapy is a positive, worries about the adverse effects for my baby now and in the future, a learning experience, and the delivery of supplemental oxygen is a barrier to mothering. CONCLUSION: Mothers balanced the positive aspects of oxygen therapy with their fears of the negative consequences. They were able to adapt to the equipment and trajectory of having their infant on supplemental oxygen delivery methods. Mothers were particularly distressed by the physical barriers created by oxygen delivery methods (ie, unable to hold, hear, or see their baby). Nurses in the NICU should support mothers' positive reframing as a way of coping, provide education about the consequences of this therapy, encourage mothers to touch and hold their infants, and provide opportunities for them to see their infants' faces. PMID- 21285659 TI - Accuracy of temporal artery thermometry in neonatal intensive care infants. AB - PURPOSE: To determine the accuracy of temporal artery and axillary temperatures and the discomfort level of stable neonates during temperature measurement. SUBJECTS: Convenience sample of neonates between the ages of 32 and 40 weeks' gestation cared for in an isolette or crib. DESIGN: A method-comparison design was used to compare different methods for noninvasive temperature monitoring (infra-red temporal artery; axillary electronic) to core body temperatures (indwelling rectal probe). MAIN OUTCOME MEASURE: Bias and precision of test temperature devices (temporal artery; axillary). RESULTS: Bias and precision for the temporal artery and axillary devices were 0.30 +/- 0.44 and 0.28 +/- 0.33, respectively. Analysis of variance found significant differences between both temporal and axillary temperatures compared to rectal temperatures (P < .01). Statistical differences were small and did not represent a clinically important difference. No statistical difference was found between temporal artery and axillary temperatures (P = .81). Increases in neonate discomfort after temperature measurement were significantly greater with axillary than increases after temporal artery temperature measurement (P = .03). CONCLUSIONS: This study found that body temperature measured with the temporal artery thermometer was similar to temperatures obtained with an axillary thermometer in stable, afebrile neonates. The use of temporal artery thermometry appears to be an acceptable approach for noninvasive temperature measurement in neonates, which causes less discomfort in neonates. PMID- 21285660 TI - Device-guided breathing and hypertension: a yet to be determined positioning. PMID- 21285661 TI - RESPeRATE: nonpharmacological treatment of hypertension. AB - Systemic hypertension has been well documented as a major risk factor for premature cardiovascular morbidity and mortality. Reduction of high blood pressure (BP) by nonpharmacological means is widely recommended, either as a primary prevention therapy or as an adjunctive treatment with antihypertensive drugs. RESPeRATE is a commercially available electronic device that presents a novel nonpharmacological approach to the treatment of hypertension. RESPeRATE guided slow-paced breathing aimed at achieving a respiratory frequency of <10 breaths per minute has been shown, in multiple studies, to reduce BP in hypertensive individuals by improving the autonomic balance through respiratory control. This article discusses RESPeRATE and the scientific evidence that supports the use of device-guided slow breathing to reduce BP. PMID- 21285662 TI - Rheos: an implantable carotid sinus stimulation device for the nonpharmacologic treatment of resistant hypertension. AB - Hypertension is a highly prevalent disorder in the United States. Of particular concern is resistant hypertension, which by definition is hypertension that cannot be adequately treated by conventional 3-drug regimens. The Rheos Baroreflex Hypertension Therapy System is a new implantable device that can treat patients with hypertension resistant to multidrug therapy, by activating the carotid baroreflex through electrical stimulation of the carotid sinus wall. Recent studies in both normotensive and hypertensive canine models have demonstrated sustained and clinically relevant reductions in arterial pressure and sympathetic activity with prolonged baroreflex activation. Clinical trials designed to evaluate the efficacy and safety of this therapy in patients with treatment resistant hypertension, are now ongoing in both Europe and the United States. PMID- 21285663 TI - Women's heart health: a worldwide challenge. PMID- 21285664 TI - Cardiovascular disease in young women: a population at risk. AB - Ischemic heart disease (IHD) is a leading cause of morbidity in the United States and worldwide. In women, it is the leading cause of death in all age groups except young women who rarely have clinically evident disease. However, when young women less than age 50 develop IHD, they are at high risk for mortality. This may be due in part to delay in diagnosis or less aggressive treatment. Young women may be less aggressively treated with medical therapies and percutaneous or surgical interventions despite studies that have shown benefit in women as well as men. Young women are an especially important population to target for treatment and study since prevention of IHD during this stage of life can have great personal and societal health consequences. Epidemiological studies, including the INTERHEART study, have identified risk factors including hypertension, diabetes, metabolic syndrome, smoking, and sedentary lifestyle that explain much of IHD in women. Several factors, including diabetes, metabolic syndrome, and tobacco use, are stronger predictors of IHD in young women as compared with older women. Healthcare practitioners who encounter young women should aggressively treat risk factors, maintain an appropriate index of suspicion for IHD, and treat acute coronary syndromes promptly and intensively to reduce the burden of IHD in young women. PMID- 21285665 TI - Childrearing women and their families: setting the stage for heart health. AB - The presence of cardiovascular disease risk factors (CVDRF) predicts the development of cardiac and other vascular diseases across all ages. Children and families with elevated CVRF have a much higher risk for CVD compared with families with normal CVRF and heart healthy lifestyles. Women and mothers play an important role in the CV health of their children, family, and community. A woman's understanding of her personal CVDRF, her active involvement in managing these RFs, and how this involvement translates into improved family heart health is not well understood. The purpose of this article is to discuss awareness in women regarding personal CVDRF, whether this awareness leads to improve personal heart health, and does awareness then translate into improved family heart health. PMID- 21285666 TI - Cardiovascular disease in women: challenge of the middle years. AB - Although heart disease remains the primary cause of death among women of all races and ethnic groups in the United States, many women are still unaware of these facts. Health care providers may also not be aware. Lack of awareness among providers may limit or delay the education and intervention to prevent future cardiovascular disease for women in their middle years. In addition, the metabolic syndrome may develop in these years of a woman's life because of today's lifestyle issues and the reported increases in obesity. The appearance of the metabolic syndrome already places a woman in a precarious position for the development of risk factors such as frank hypertension and diabetes. The metabolic syndrome presents an opportunity for providers to enhance surveillance and to educate their patients in the prevention of future events. Complications of pregnancy may also foreshadow the development of hypertension as well as type 2 diabetes mellitus later in life. Some investigators consider pregnancy as an excursion into the metabolic syndrome and as a failed "stress test," if complications such as gestational diabetes or preeclampsia develop. The emergence of those complications may give a more recognized prediction of future cardiovascular events. All primary care providers, including obstetricians and gynecologists, need to be alert as to the follow-up of these women, and incorporate continued vigilance within the standard office visit including waist measurement, annual lipid measurement, glucose monitoring, blood pressure assessment, and intense education and referrals when needed. PMID- 21285667 TI - Is cardiovascular disease in women inevitable?: preparing for menopause and beyond. AB - Cardiovascular disease (CVD) is the leading cause of death for American women. Women share many of the same risk factors (RFs) for CVD as men, and in both, women and men, these RFs are associated with age. Additionally, the prevalence of multiple RFs increases with age. Though menopause has been thought to increase CVD risk in women, the association between menopause and age obfuscates a causal relationship. While men's CVD mortality has decreased since the 1980s, women's CVD mortality has climbed until 2000. This has resulted in a sex-related CVD mortality gap, with women having higher mortality than men since 1984. Contributing to this female-majority CVD mortality gap is a lack of awareness of CVD risk among women and their physicians. Awareness campaigns, such as the Heart Truth and the Red Dress symbol, appear to have improved recognition of CVD risk in women. Further, female-specific guidelines have been developed to prevent and reduce CVD in women. Though the current understanding of the role of menopause in CVD is controversial, studies suggest that menopause does not exacerbate CVD independent of aging, and hormone replacement therapy is not effective for secondary prevention of CVD. PMID- 21285668 TI - Genetic analysis in cardiovascular disease: a clinical perspective. AB - Many forms of cardiovascular disease (CVD) demonstrate heritability and thus a genetic contribution is likely. This is most evident when considering the "simple" Mendelian traits such as hypertrophic cardiomyopathy. However, family history also influences our assessment of patients with complex traits such as coronary artery disease, hypertension, and common forms of hypercholesterolemia, as observed in clinical practice. Recent research has led to advances in our understanding of the genetic basis of both the simple and complex forms of CVD. This review presents the current state of knowledge regarding major gene disorders, as well as more common, complex forms of CVD such as coronary artery disease. It discusses the fundamental approaches being used to identify the genetic basis of the various disease states, as well as the practical implications of the discoveries to clinicians. It also focuses on our need to assess the extent by which genetic analysis can alter our calculation of an individual's risk of disease, and our ability to successfully target treatment that will modify this process. PMID- 21285669 TI - Potential benefits of aliskiren beyond blood pressure reduction. AB - There is now clear evidence that reducing blood pressure (BP) with a broad range of agents, including angiotensin converting enzyme inhibitors and angiotensin receptor blockers, improves cardiovascular and renal outcomes. There is also evidence suggesting that these drugs have beneficial effects that are independent of BP lowering. Aliskiren is a direct renin inhibitor that interrupts the renin angiotensin-aldosterone system (RAAS) at its rate-limiting step. Unlike angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, aliskiren produces a sustained reduction in plasma renin activity and reduces plasma levels of angiotensin II and aldosterone. Preclinical data and clinical trials in high-risk patients using surrogate markers increasingly suggest that aliskiren can reduce the progression of end-organ damage beyond that afforded by BP control. With its unique mechanism of action, combining aliskiren with another RAAS-blocking agent that has a different mechanism of action may provide more comprehensive blockade of the RAAS, potentially conferring additional clinical benefits. Evaluation of these end-organ effects in humans is underway in clinical trials designed to assess the effects of aliskiren alone and in combination with other antihypertensive agents on cardiovascular and renal outcomes. PMID- 21285670 TI - Ticagrelor: a novel reversible oral antiplatelet agent. AB - The complex mechanism of platelet activation creates an optimal target for pharmacological treatment in patients with acute coronary syndromes. Current antiplatelet medications that are used in addition to aspirin include the thienopyridines, clopidogrel and prasugrel, but there are several limitations to the use of these medications. Clopidogrel and prasugrel irreversibly bind to the P2Y12 receptor, creating a prolonged antiplatelet effect which can be undesirable when surgery is needed. Clopidogrel requires hepatic activation and produces variable platelet inhibition based on genetic polymorphisms. Prasugrel has more consistent platelet inhibition than clopidogrel but carries with it an increased risk of serious bleeds. Ticagrelor is a drug in a new chemical class that reversibly binds the P2Y12 receptor and noncompetitively blocks adenosine diphosphate-induced platelet activation. It was specifically designed to address the limitations of the available antiplatelet agents while maintaining comparable or better antiplatelet effects. It does not require metabolic activation and demonstrates greater platelet inhibition, a faster offset of action and comparable bleeding risk compared to clopidogrel. The pivotal PLATO (The Study of Platelet Inhibition and Patient Outcomes) trial in patients with an acute coronary syndrome demonstrated improved cardiovascular outcomes, including a reduction in myocardial infarctions and vascular events using ticagrelor as compared to clopidogrel with comparable rates of major bleeds. A puzzling finding from that trial was the lack of benefit with ticagrelor in patients enrolled from the United States, which has led to ticagrelor not being approved at this time in this country. The main adverse events with ticagrelor are bleeding and dyspnea, the latter of which is of unclear etiology and of unknown long-term clinical concern. In summary, ticagrelor is an exciting new oral antiplatelet drug that seems to be more efficacious than clopidogrel, with comparable safety. Whether issues of geographic disparities in response and the unusual side effect of dyspnea ultimately prove problematic has yet to be determined. Nonetheless, ticagrelor is a drug that has the potential to change the standard of care of patients with acute coronary syndromes. PMID- 21285671 TI - Unusual features of gastrointestinal stromal tumor on PET/CT and CT imaging. AB - Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. It can be benign or malignant in behavior. Stomach, being the most common site (70%) for GISTs, is followed by the small intestine (20%). Anorectal, colonic, and esophageal GISTs are uncommon, whereas extraintestinal GISTs are extremely rare. The presenting symptoms are highly dependent on tumor size and location, although a large number of GISTs are asymptomatic. The purpose of this article is to highlight the unusual characteristics of GISTs illustrated by PET/CT and CT imaging. These characteristics are organized into (1) unusual tumor location, (2) unusual clinical presentation, and (3) unusual sites of metastasis. Knowing the uncommon features of GISTs is important, as they are more often seen nowadays with the increasingly important role of PET/CT and CT in GIST management; and these tumors are associated with a poorer prognosis and unwanted delay in diagnosis is avoidable. With the availability of effective treatment by imatinib mesylate, a prompt and early diagnosis is essential for disease control. All GISTs illustrated in this article are pathologically proven. PMID- 21285672 TI - Value of lateral blood pool imaging in patients with suspected stress fractures of the tibia. AB - AIM: To critically evaluate the use of lateral blood pool imaging in athletes with lower limb pain and with a clinical suspicion of stress fracture. METHODS: Two experienced nuclear medicine physicians evaluated 3-phase bone scans using 99mTc-methylene diphosphonate performed in 50 consecutive patients referred from a specialist sports injury clinic for suspected tibial stress fracture. The vascularity to the tibia as seen on the blood pool (second phase) images in the anterior/posterior views was compared with the lateral/medial view assessments. Stress fractures were presumed to be present when on the delayed images (third phase) there was a focal or fusiform area of increased tracer uptake involving the tibial cortex. Shin splints which are a recognized cause of lower limb pain in athletes mimicking stress fracture were diagnosed if increased tracer uptake was seen extending along the posterior tibial surface with no significant focal or fusiform area of uptake within this. Inter-reviewer agreement for the assessment of vascularity was also assessed using Cohen's Kappa scores. RESULTS: Twenty-four stress fractures in 24 patients and 66 shin splints in 40 patients were diagnosed. In 18 patients stress fracture and shin splints coexisted. In 10 patients no tibial pathology was identified. Of the 24 patients diagnosed with stress fractures, lateral/medial blood pool imaging was superior in the assessment of blood pool activity (P < 0.001) identifying increased vascularity in 21 cases compared with the anterior/posterior views positive in only 11 cases. The inter-reviewer agreement was near perfect for lateral/medial views, kappa = 0.86 while very good for anterior/posterior views, kappa = 0.68. CONCLUSION: In patients with suspected tibial stress fractures, lateral views of the tibia provide the optimal method for evaluation of vascularity. Prospective studies with quantitative or semi-quantitative assessment of skeletal vascularity could provide supplementary information relating to the pathophysiology of stress fractures, for example, the time scale of vascular changes after a tibial stress fracture, and potentially could have clinical relevance as to the assessment of the severity of stress fractures and their prognosis. PMID- 21285673 TI - Diffuse hepatic and splenic uptake of Tc-99m methylene diphosphonate on bone scintigraphy after intravenous administration of gadolinium-containing MRI contrast. AB - Three patients with known lung cancer came on different days to our department to have a bone scan to evaluate possible osseous metastatic disease. The bone scan images showed increased Tc-99m methylene diphosphonate (Tc-99m MDP) activity in the liver and to a lesser degree in the spleen, whereas bone scan images from other patients on the same days showed no abnormal activity in the liver or spleen. On the same day, shortly before the bone scan, all 3 patients had a magnetic resonance imaging scan with an intravenous injection of Magnevist (Gadolinium-DTPA), which was not previously known to cause an altered Tc-99m MDP distribution. In the follow-up bone scans performed within 1 week of the initial bone scintigraphy, images from none of these 3 patients showed abnormal liver or spleen activity. The findings indicated that the increased Tc-99m MDP activity in the liver and spleen in the early studies was indeed an effect of Gadolinium containing magnetic resonance imaging contrast. This effect was further confirmed by an animal experiment. PMID- 21285674 TI - Increased liver and spleen accumulation of Tc-99m methylene diphosphonate associated with intravenous injection of MRI contrast gadolinium diethylenetriaminepentaacetic acid. AB - Several conditions that can cause diffuse hepatic or splenic uptake of Tc-99m methylene diphosphonate (Tc-99m MDP) have been previously reported. Nevertheless, diffuse abnormal liver and spleen uptake of Tc-99m MDP associated with intravenous injection of magnetic resonance imaging contrast gadolinium diethylenetriaminepentaacetic acid is not previously known. In our series, we reported diffuse increased Tc-99m MDP activity in the liver and spleen in bone scans in patients who received Tc-99m MDP injection shortly after contrast enhanced magnetic resonance imaging. PMID- 21285675 TI - Blinded-read of bone scintigraphy: the impact on diagnosis and healing time for stress injuries with emphasis on the foot. AB - AIM: This study evaluated the use of bone scintigraphy (BS) for the diagnosis of stress fractures in athletes and its validity for the prediction of healing time, with a focus on foot injuries. METHODS: In our retrospective study, 84 athletes with a total of 93 suspected stress fractures (foot, n = 66; others, n = 27) were included. A blinded-read of BS was performed by 3 observers. The standard of reference was established by an interdisciplinary truth-panel using all imaging data (scintigraphic, radiographic, and magnetic resonance imaging) and follow-up data (>12 month). Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for diagnosing stress fractures were calculated. Stress injuries were rated according to a 5-point grading score (0-4) and associated to the healing time. RESULTS: For the diagnosis of stress injuries (n = 50/93), mean sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 97.3%, 67.4%, 77.7%, 95.6%, and 83.5%, respectively. Interobserver analysis showed a high agreement between all 3 readers (mean kappa = 0.83). In univariate analysis healing time of grade 3 to 4 stress injuries was significantly higher (median, 87 days; interquartile range, 69-132 days) compared with grade 1 to 2 lesions (median, 63 days; interquartile range, 43-95 days; P = 0.0067). Moreover, healing time of scintigraphic high grade stress injuries was significantly longer in a general linear model with adjustment for cofactors (grade, 3-4 vs. 1-2; P = 0.033). CONCLUSIONS: BS is a sensitive and reliable method for the diagnosis of stress injuries. In addition, the simplified classification for mild and severe stress injuries allows an estimation of healing time. PMID- 21285677 TI - Tc99m-sestamibi thigh SPECT/CT images for noninvasive assessment of skeletal muscle injury in carbon monoxide intoxication with clinical and pathological correlation. AB - PURPOSE: Muscle weakness has been repeatedly reported in patients with carbon monoxide (CO) intoxication. In animal models, CO intoxication has been linked with mitochondrial electron transport dysfunction. The objectives of the present study were to use Tc-99m sestamibi thigh single-photon emission computed tomography/computed tomography (SPECT/CT) to evaluate the mitochondrial status in patients with CO intoxication, correlate this with clinical parameters, and compare with age-matched controls. MATERIAL AND METHODS: A total of 25 patients with delayed sequelae after CO intoxication (range: 1-60 months) and 17 sex- and age-matched healthy volunteers underwent Tc-99m sestamibi thigh SPECT/CT. Cognitive evaluation and muscle power according to medical research council (MRC) grading were collected. Both visual scoring from planar images and automatic volumetric analysis were used to rate the Tc-99m sestamibi uptake level. RESULTS: The visual scores showed that 14 patients (56.0%) were scored as moderate-to severe decrement. Volumetric analysis showed that a significant Tc99m-sestamibi uptake decrement was found in the CO intoxication group as compared with the controls, and 16 patients (64.0%) had uptakes below 1 standard deviation of the control group. In the CO group, the muscle power but not the cognitive evaluation correlated with Tc-99m sestamibi uptake in muscles. The decrement of muscle Tc99m sestamibi uptake was related to mitochondria swelling, increased mitochondrial numbers, and type II muscle atrophy in 1 patient. CONCLUSIONS: In this study, we demonstrated that patients with CO intoxication sustained defective mitochondrial metabolism in skeletal muscles as revealed by a decrement in Tc-99m sestamibi uptake either by visual or semiquantification of thigh SPECT/CT. Tc-99m sestamibi scanning provided noninvasive measurement of mitochondrial injury in muscles after CO intoxication and the correlation with clinical parameters was good. PMID- 21285676 TI - C11-acetate and F-18 FDG PET for men with prostate cancer bone metastases: relative findings and response to therapy. AB - PURPOSE OF THE REPORT: This study tested the feasibility of C11-acetate (acetate) positron emission tomography (PET) imaging to assess response to therapy in men with bone metastatic prostate cancer and compared results for disease detection and response evaluation with F-18 fluorodeoxyglucose (FDG) PET. MATERIALS AND METHODS: Men with >=3 prostate cancer bone metastases identified by Tc-99m methylene diphosphonate (MDP) bone scintigraphy and/or computed tomography were enrolled in a prospective study of serial acetate and FDG PET imaging. Patients were imaged before and 6 to 12 weeks after initial androgen deprivation therapy for new metastatic prostate cancer or first-line chemotherapy with docetaxel for castration-resistant prostate cancer. Qualitative assessment and changes in the tumor:normal uptake ratio were used to assess response by both acetate and FDG PET. In addition, the detection of bone metastases pretherapy was compared for acetate and FDG PET. RESULTS: A total of 8 patients with documented bone metastases were imaged, of which 6 were imaged both pre- and post-therapy. Acetate PET detected bone metastases in all 8 patients, whereas FDG PET detected lesions in 6 of the 7 imaged patients. Acetate PET generally detected more metastases with a higher tumor:normal uptake ratio. Qualitative and quantitative assessments of post-treatment response correlated with composite clinical designations of response, stable disease, or progression in 6 of 6 and 5 of 6 by acetate and 4 of 5 and 3 of 5 by FDG PET, respectively. CONCLUSIONS: In this pilot study, results indicate that acetate PET holds promise for response assessment of prostate cancer bone metastases and is complementary to FDG PET in bone metastasis detection. PMID- 21285678 TI - New scrutiny of outpatient therapy with I-131. AB - Recently, there has been a Congressional examination of the safety to the public when outpatients are treated with I-131. The regulations regarding this procedure are being scrutinized to make sure that public safety is being protected. An evaluation of the data indicates that when Nuclear Regulatory Commission regulations are properly followed, the use of I-131 therapy is safe for the community. Furthermore, doing these procedures as an outpatient saves money and is more convenient for the patient. However, physicians also recognize that a small minority of patients who need I-131 treatment should be treated in the hospital. PMID- 21285679 TI - Bone scintigraphy in painful os peroneum syndrome. AB - Lateral foot pain may be caused by various entities including the painful os peroneum syndrome. A case of a 68-year-old man is presented, who experienced a trauma with distortion of the right foot. Nine months later, he still had pain in the lateral part of the right foot. Bone scintigraphy showed uptake in the area where an os peroneum was located and thus confirmed the clinical assumption of painful os peroneum syndrome. Familiarity with the clinical and imaging findings can prevent undiagnosed lateral foot pain. PMID- 21285680 TI - F-18 FDG PET/CT imaging of bulky myxofibrosarcoma in chest wall. AB - Myxofibrosarcoma (MFS) has a spectrum of malignant fibroblastic lesions with variably myxoid stroma and pleomorphism. A 67-year-old man with a bulky mass on his chest wall was diagnosed with MFS. He underwent F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography for detection of metastasis. FDG positron emission tomography /computed tomography showed inhomogeneous high FDG uptake (max standardized uptake value, 10.1) in the bulky tumor with no evidence of metastasis, and the tumor was successfully resected. FDG uptake seemed to be reflected by the broad spectrum of pathologic heterogeneity. And MFS should be considered when making a diagnosis of inhomogeneous FDG-avid lesions in the bulky masses of soft tissue. PMID- 21285681 TI - Osteoblastoma in the nasal cavity: F-18 FDG PET/CT and Tc-99m MDP 3-phase bone scan findings with pathologic correlation. AB - A benign osteoblastoma of the nasal cavity is very rare. A 57-year-old woman, who had a radical hysterectomy for carcinoma of the uterine cervix 5 years ago, underwent F-18 FDG PET/CT. An expansile bone tumor with high glucose metabolism in the middle turbinate of the left nasal cavity was incidentally demonstrated. A subsequent Tc-99m methylene diphosphonate 3-phase bone scan revealed focal increased uptake of radionuclide in all 3 phases at the corresponding tumor. Histology confirmed a benign osteoblastoma that was composed of proliferating osteoblasts with woven bone spicules and rich vascular stroma. Scintigraphic findings, including F-18 FDG PET/CT and 3-phase bone scan, reflected the pathologic features well. PMID- 21285682 TI - Bone infarct-associated sarcoma detected on FDG PET/CT. AB - Secondary sarcomas arising on the background of a bone infarct are extremely uncommon. Based on the knowledge of classic imaging patterns, however, lesions like bone infarcts can be recognized during positron emission tomography/computed tomography studies, which are now being performed increasingly in cancer patients. We demonstrate the detection of this rare entity on positron emission tomography/computed tomography and its correlation on magnetic resonance imaging in a 56-year-old man with asymptomatic multifocal osteonecrosis secondary to steroid treatment for polymyositis. PMID- 21285683 TI - Incidental multiple focal uptakes of Tc-99m MDP in both lungs without lung parenchymal abnormality. AB - We report a case of incidental multiple focal uptakes of Tc-99m MDP in both the lungs without lung parenchymal abnormality. A 15-year-old girl who had no symptoms or history of pulmonary disorder was referred for Tc-99m MDP bone scintigraphy to evaluate temporomandibular joint disorders. Bone scintigraphy showed multiple focal uptakes in the chest. Single photon emission computed tomography/computed tomography scan performed on the same day showed that abnormal uptakes were located in both the lungs and no abnormalities in the corresponding pulmonary parenchymal sites. Abnormal uptakes resolved on bone scintigraphy after 7 days. PMID- 21285684 TI - A case of paranasal sinuses osteoma detected on bone SPECT/CT. AB - We present a 51-year-old woman with a history of colectomy for colon cancer who was referred to our department for bone assessment. Planar image revealed a focus of increased uptake of Tc-99m methylene diphosphonate in the nose root. According to the images of SPECT combined with low-dose CT, the abnormal radiotracer uptake at the site of left frontal sinus was considered to be osteoma. We conclude that SPECT/CT provides an accurate evaluation of the localization of the lesions and supplies anatomic information that can be valuable for diagnosis of nonmalignant bone diseases. PMID- 21285685 TI - Super-superscan on a bone scintigraphy. AB - Superscans on bone scintigraphy have been described mostly in metastatic and metabolic bone diseases, with different patterns and appearances of radiotracer uptake. This is a report of bone scintigraphy demonstrating superimposed metastatic and metabolic superscan in a patient with prostate cancer, who subsequently developed renal osteodystrophy. Two years after the first bone scintigraphy showing multiple metastases, the patient developed renal insufficiency, hyperphosphoremia, and hypocalcemia. Repeat bone scintigraphy demonstrates significantly different appearance from that of the first study. Caution should be exercised when interpreting a bone scintigraphy in patients with known malignancy and coexisting renal failure or metabolic bone disease. Superimposed appearances of metastatic and metabolic superscan may obscure recognition of osseous metastases. PMID- 21285686 TI - Extensive peritoneal uptake of technetium-99m-labelled hydroxy diphosphonate in a patient undergoing hemodialysis. AB - A 48-year-old African lady started peritoneal dialysis in 1994 after transplant failure. After several episodes of peritonitis and hemorrhagic ascites, hemodialysis was resumed in 2003 because of small bowel subocclusion. In 2006, an abdominal CT showed calcifications and dilatation of intestinal loops. Sclerosing peritonitis was diagnosed and she underwent enterolysis and resection of the peritoneal capsule. She remained asymptomatic until 2009 when she presented again with subocclusion. Because of generalized skeletal pain, a bone scan was performed, which showed Tc-99m hydroxy diphosphonate uptake on the peritoneum. The patient is currently on hemodialysis with parenteral nutrition. PMID- 21285687 TI - Usefulness of F-18 FDG PET/CT in a case of Kaposi sarcoma with an unexpected bone lesion. AB - Bone lesions of Kaposi sarcoma are rare. A 56-year-old man who was HIV positive and was diagnosed with Kaposi sarcoma on the basis of the results of a biopsy of skin lesions, underwent F-18 FDG PET/CT scan for detecting Kaposi sarcoma lesions and other AIDS-related diseases. An abnormal uptake was observed in the lumbar spine. MRI showed a diffuse enhanced spine lesion, and Ga-67 and 201Tl scanning were negative. As a result, the lesion was considered to be a Kaposi sarcoma, and the shrinkage of the lesion was noted after the therapy for Kaposi sarcoma. PMID- 21285688 TI - MDP uptake in peritoneal carcinomatosis and Krukenberg tumors from mucinous adenocarcinoma. AB - Altered biodistribution of Tc-99m methylene diphosphonate is a common occurrence on bone scintigraphy and mucin-producing neoplasms of the gastrointestinal tract are associated with dystrophic uptake. In addition to the uptake in the primary tumor, activity has been reported in metastasis within lymph nodes and liver. We present a case of Tc-99m methylene diphosphonate uptake in peritoneal carcinomatosis and metastatic Krukenberg tumors from a primary mucinous adenocarcinoma of the descending colon. Each of these findings is uncommon and their combination in this case is particularly unique. PMID- 21285689 TI - Solitary phalangeal metastasis of renal cell carcinoma on bone scintigram. AB - Renal cell carcinoma is known to cause lytic metastasis at various sites including axial and appendicular skeleton. However, it is unusual to find an isolated metastasis of renal cell carcinoma in the distal extremity on bone scintigraphy. A 70-year-old woman with renal cell carcinoma was referred to the Nuclear Medicine Department for a bone scintigram to exclude metastasis. The whole-body planar images were unremarkable, but the local views of the hands demonstrated a solitary metastasis in the middle phalanx of the finger. This rare experience illustrates the need for including local views of extremities in a standard whole-body study. PMID- 21285690 TI - Detection of extensive melorheostosis on bone scintigram performed for suspected metastases. AB - Melorheostosis is a rare but benign disorder characterized by asymmetric osteosclerotic dysplasia. Radiographic appearances are characteristic and described as "melting wax flowing down a candle." This disorder may involve more than one bone contiguously across the joints following a sclerotomal distribution. It is often asymptomatic but occasionally presents with pain and contractures. The authors report accidental detection of bilateral upper and lower limb melorheostosis in an elderly woman with the history of breast cancer and recent onset of low back pain, which was referred for a bone scintigram for suspected metastases. The images showed bilateral femoral and tibial melorheostosis, which was subsequently confirmed on plain radiograph and by clinical follow-up. PMID- 21285691 TI - A case of periostitis secondary to voriconazole therapy in a heart transplant recipient. AB - A 66-year-old man with a history of heart transplant for idiopathic dilated cardiomyopathy presented with progressive bone pain and myalgias. He has been on voriconazole for a pulmonary Aspergillus infection for 9 months. He had an elevated alkaline phosphatase of 280. There is no history of rheumatologic disease. Drug-induced periostitis has recently been reported in patients on long term voriconazole therapy after lung transplantation for prophylaxis and treatment of Aspergillus infection. This case demonstrates the same phenomenon in a heart transplant patient. This patient's symptoms improved after discontinuation of voriconazole. PMID- 21285692 TI - Multiple muscle metastases from lung cancer detected by FDG PET/CT. AB - A 71-year-old man with right lung mass, who was recently diagnosed histopathologically with pulmonary adenocarcinoma, was referred for staging of the primary tumor. Whole-body F-18 fluorodeoxyglucose positron emission tomography and computed tomography (FDG PET/CT) demonstrated multiple hypermetabolic foci in various skeletal muscle localizations, suggesting extensive metastatic muscle involvements in addition to increased FDG uptake in the primary tumor. Subsequent biopsy and histopathological study confirmed muscle metastasis from lung adenocarcinoma. Skeletal muscle metastasis from lung cancer is rare, but multiple muscle metastases are even more unusual. FDG PET/CT is able to detect unexpected metastatic involvements such as multiple muscle metastases in lung cancer patients. PMID- 21285693 TI - A rare case of pemphigus vegetans mimicking malignancy on F-18 FDG PET/CT. AB - A 42-year-old man with a history of chronic smoking and alcoholism was suspected to harbor a malignancy involving the perioral region and the scalp. He underwent an F-18 FDG PET/CT scan which revealed abnormal F-18 FDG accumulation in the oral mucosa and lips, extending to the nose, scalp, and bilateral cervical lymph nodes. Further work-up ultimately revealed the lesions to be secondary to pemphigus vegetans. Pemphigus vegetans is a rare variant of pemphigus vulgaris, an autoimmune bullous cutaneous disorder and involves mainly the flexural regions of the body. Unlike pemphigus vulgaris, lesions of pemphigus vegetans present as heaped up, eroded, and ulcerative plaques in the intertriginous regions of the body. Occasional lesions may be present on scalp and elsewhere in the Hallopeau variant of the disease. The use of F-18 FDG PET in the field of oncology is rapidly evolving; however, it is not tumor specific. The integration of CT into PET has increased the specificity of this modality. Nevertheless, there are many physiologic and benign conditions that may result in high accumulation of FDG, and may mimic malignancy. Familiarity with F-18 FDG-avid nonmalignant lesions may extend the use of F-18 FDG PET imaging beyond the field of oncology. To the best of our knowledge, this is the first description of PET/CT findings in pemphigus vegetans. PMID- 21285694 TI - Sagittal sinus tumor thrombosis in a case of NHL demonstrated on F-18 FDG PET/CT. AB - We report a case of a 60-year-old woman, diagnosed as a case of non Hodgkins lymphoma (NHL), referred for F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) following 6 cycles of chemotherapy to evaluate response to therapy. The scan revealed a curvilinear pattern of FDG accumulation in the midline extending anteroposteriorly, just adjacent to the inner table of the skull on the fused PET/CT images with no corresponding abnormality on the low-dose CT. Because this site anatomically corresponded to that of the sagittal sinus, an MRI and magnetic resonance venography was advised which confirmed the presence of sagittal sinus tumor deposits. This case highlights the pattern of sagittal sinus tumor thrombosis on FDG PET/CT and the possibility of its occurrence in NHL. PMID- 21285695 TI - FDG PET/CT imaging suggests lymphoma involving prostate may be more resistant to treatment. AB - FDG PET imaging is generally not useful for prostate cancer. Nevertheless, incidental intense FDG uptake in the prostate warrants further evaluation to assess for prostatic malignancy. We report a case where intense FDG uptake was incidentally noted in an enlarged prostate on FDG PET/CT scan performed for a large left hilar/mediastinal mass (that was also intensely FDG avid along with several additional FDG-avid lesions elsewhere). Biopsy of the prostate and mediastinal lesions revealed large B-cell non-Hodgkin lymphoma at both sites. Serial FDG PET/CT imaging in this patient revealed that the prostatic lymphomatous lesions showed a slower and incomplete response to chemotherapy compared with other sites of lymphomatous involvement (that showed a rapid and complete response to chemotherapy) in the same patient. PMID- 21285696 TI - Gallium-67 SPECT/CT for abdominal abscess. AB - An 80-year-old woman, who had suffered from end-stage renal disease under peritoneal dialysis, was presented with intermittent fever, leukocytosis, and elevated C-reactive protein for 4 months. She did not have symptom of abdominal pain. Culture of ascites showed Klebsiella pneumoniae. Abdominal utrasonography was negative. Whole-body gallium-67 imaging showed a segmental uptake mimicking bowels in right abdomen. SPECT/CT revealed the uptake in a soft tissue density beneath the abdominal wall instead of bowels. Contrast-enhanced CT demonstrated a low-density mass with peripheral enhancement at the aforementioned area. Her clinical condition stabilized gradually after CT-guided percutaneous drainage of pus from the abscess. PMID- 21285697 TI - Palpation thyroiditis seen on F-18 FDG PET/CT. AB - A 29-year-old woman presented with a new right supraclavicular mass on a background of resection of a malignant melanoma from her right shoulder before 4 years. F-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) imaging revealed uptake in a right supraclavicular node and the inferior pole of the left lobe of the thyroid gland. Subsequent resection and histology of the right supraclavicular node and the left lobe of the thyroid gland demonstrated metastatic melanoma and palpation thyroiditis, respectively. A number of malignant and benign pathologies of the thyroid demonstrate FDG uptake, with 75% being benign. To our knowledge, the findings of palpation thyroiditis on FDG PET/CT have never been previously described. PMID- 21285698 TI - Current readings in nuclear medicine. PMID- 21285700 TI - Technology-driven science: will it advance treatment of schizophrenia going into the second decade of the 21st century? PMID- 21285701 TI - Measuring psychosocial outcomes in schizophrenia patients. AB - PURPOSE OF REVIEW: Improvement in psychosocial functioning is nowadays considered an important and achievable goal of schizophrenia treatment. Therefore, treatment interventions are expected to have a positive influence both on symptoms and on social integration.In this nonsystematic literature review, we describe some of the available measures to assess social outcomes in schizophrenia treatment and their inherent limitations, and discuss future directions for research and clinical practice. RECENT FINDINGS: The lack of consensus on the appropriate terminology and standards applied to index patients' level of functioning remains an obstacle in assessing psychosocial outcomes in schizophrenia. Although some scales appear advantageous in terms of ease of administration and reliability, they lack enough solid evidence that they are related to real-world outcomes or sensitive to change. Performance-based measures are being more widely used to assess functional capacity because they appear effective in predicting independent living and work, as compared with both self-report and clinical measures. SUMMARY: We argue that assessment of psychosocial functioning should be an integral part of schizophrenia patients' assessment, in both the research and clinical setting. Ultimately, there exists no gold standard measure, but, of those available, the Personal and Social Performance (PSP) Scale and the UCSD Performance-based Skills Assessment (UPSA) have literature supporting their usefulness for assessing psychosocial outcomes in schizophrenia patients. PMID- 21285702 TI - Placebo response in clinical trials with schizophrenia patients. AB - PURPOSE OF REVIEW: The magnitude of placebo response is an important factor in the outcome of clinical trials, in that excessive placebo response can obscure true drug-placebo differences. There is ample evidence of the impact of elevated placebo response in trials of major depression, but less intensive research has been done in the area of schizophrenia. We present a current review of placebo response in clinical trials of schizophrenia. RECENT FINDINGS: The existing evidence suggests that placebo response in schizophrenia trials may be similar in magnitude, quality, and impact to that observed in depression trials, and has similarly increased over the past several years. We discuss factors influencing excessive placebo response during the conduct of clinical trials and how they may be managed to help minimize placebo response. SUMMARY: There does not appear to be any single major factor contributing to the high levels of placebo response in schizophrenia clinical trials; therefore, a multipronged approach to minimizing excessive placebo response or its impact is recommended. PMID- 21285703 TI - The concepts of remission and recovery in schizophrenia. AB - PURPOSE OF REVIEW: Until recently outcome studies in schizophrenia lacked standardized measures, and outcome expectations were generally pessimistic. The Remission in Schizophrenia Working Group (RSWG) published operationalized criteria for symptomatic remission in 2005. These criteria have been extensively applied in research settings and have stimulated research into other components of outcome, particularly functional outcome and quality of life. Attention has also shifted beyond remission to the more difficult to attain and complex concept of recovery. The purpose of this review is to examine recent studies on these topics and to assess whether progress has been made towards a broader definition of remission and recovery. RECENT FINDINGS: Reported remission rates vary widely across studies (17-88%). Patients in remission do better than their nonremitted counterparts in several other outcome domains. Predictors of remission include early treatment response, and baseline symptom severity and subjective well being. Patients move in and out of remission over time. At present, there is no consensus on methods of measuring other outcome domains, particularly functional status and quality of life. SUMMARY: The RSWG remission criteria are easy to apply and define an achievable and desirable treatment goal. Measures of social and occupational functional outcome, quality of life and cognitive status need to be further developed and standardized before remission and recovery criteria can be more broadly defined. PMID- 21285704 TI - Lessons from social network analyses for behavioral medicine. AB - PURPOSE OF REVIEW: This study presents an overview of the rapidly expanding field of social network analysis, with an emphasis placed on work relevant to behavioral health clinicians and researchers. I outline how social network analysis is a distinct empirical methodology within the social sciences that has the potential to deepen our understanding of how mental health and addiction are influenced by social environmental factors. RECENT FINDINGS: Whereas there have been a number of recent studies in the mental health literature that discuss social influences on mental illness and addiction, and a number of studies looking at how social networks influence health and behaviors, there are still relatively few studies that combine the two. Those that have suggest that mood symptoms as well as alcohol consumption are clustered within, and may travel along, social networks. SUMMARY: Social networks appear to have an important influence on a variety of mental health conditions. This avenue of research has the potential to influence both clinical practice and public policy. PMID- 21285705 TI - Use of 'chronic disease self-management strategies' in mental healthcare. AB - PURPOSE OF REVIEW: Medical care for chronic conditions imposes a substantial burden on healthcare systems designed originally for acute illness or injury. The notion of chronic disease self-management (CDSM) has been developed as a means of encouraging individuals with chronic conditions to self-manage their own health. It is known that successful chronic disease management reduces hospital admission rates and improves patients' quality of life. Although recognized widely by other medical disciplines, it is beginning to have an impact on psychiatric practice; therefore, a review of how the CDSM approach is implemented in psychiatry is timely. RECENT FINDINGS: The move toward self-management in general medicine can be seen by and large as a holistic approach that encourages the person to work in partnership with health professionals to improve outcomes and assist patients to better manage their healthcare needs. One of the defining features of CDSM approaches is the active collaboration between the patient and the healthcare professional. Five mechanisms that demonstrate such active collaboration are self directed care, illness management and recovery, shared decision-making, joint crisis planning and wellness planning. Their use in psychiatry is discussed. SUMMARY: The key feature of CDSM approaches is an active collaboration between healthcare professionals and healthcare consumers. It is a fundamental shift away from traditional active expert/passive patient treatment modes. Each of the five approaches discussed exemplifies the active participation in treatment planning by both consumers and mental health professionals. PMID- 21285706 TI - Internet-delivered treatment to promote health. AB - PURPOSE OF REVIEW: The aim of this paper is to provide an updated review of recent controlled trials of Internet interventions for health conditions and how the Internet is used to promote health. RECENT FINDINGS: We identified 18 published trials including studies on diabetes, cancer, pain conditions, obesity, irritable bowel syndrome, stress management, hypertension, metabolic syndrome, cerebral palsy, infertility, HIV infection, and fruit/vegetable consumption. Of the 18 trials, one-third targeted children and adolescents. Two cancer studies investigated the role of peer support in an online environment that failed to result in any major improvements. Overall, several trials did not result in any substantial significant improvements, but there are exceptions, such as treatment of irritable bowel syndrome, headache, and chronic pain. Although a few of the reviewed studies had sufficient sample sizes, the majority were small and underpowered. In particular, this was the case for the studies on children and adolescents. SUMMARY: This review suggests that Internet interventions hold some promise as a complement to other treatments such as cognitive behavior therapy. The benefits from participating in online peer support groups are not clear. Although studies on children and adolescents have emerged, there is a lack of studies on older adults with health problems. PMID- 21285707 TI - Current world literature. PMID- 21285709 TI - Current world literature. PMID- 21285711 TI - Synovial fluid analysis for crystals. AB - PURPOSE OF REVIEW: Describe why this review is timely and relevant. Identifying monosodium urate (MSU) and calcium pyrophosphate dehydrate (CPPD) crystals allows a quick and definitive diagnosis of both gout and CPPD arthritis, and remains the accepted gold standard. These diseases are still often diagnosed on inaccurate clinical grounds. Crystal identification has received little critical attention since its introduction, and it appears necessary to review the technique paying special attention to the possible reasons which deter clinicians. RECENT FINDINGS: Describe the main themes in the literature covered by the article. Synovial fluid analysis for crystals is a simple procedure allowing immediate and definite diagnosis of gout and CPPD arthritis when clinics are fitted with a proper microscope and the rheumatologists appropriately trained. This review also illustrates how crystal analysis in synovial fluid can be initially approached with both the widely available ordinary light microscope and a simple polarized one and with good results. SUMMARY: This study describes the implications of the findings for clinical practice or research. We hope that those not performing synovial fluid analysis will be stimulated to acquire or perfect the technique and obtain a compensated polarized microscope to comply with current standards. PMID- 21285712 TI - Entering a new era of prevention in rheumatic disease. PMID- 21285713 TI - Strategies to prevent rheumatoid arthritis in high-risk patients. AB - PURPOSE OF REVIEW: To examine potential interventions, including modification of environmental risk factors and use of pharmacologic agents, in at-risk populations to prevent progression to (or development of) rheumatoid arthritis (RA). This review is timely given the increasing interest in early intervention strategies and new opportunities to identify patients early in the pathogenesis of RA. RECENT FINDINGS: Despite the growing literature demonstrating a link between anticitrullinated protein antibodies, synovitis, genetic and environmental risk factors such as smoking and RA, there are no studies that have evaluated the effect of modifying environmental risk factors in late preclinical RA. This article describes several studies that have evaluated the ability of pharmacologic interventions to modify outcomes in patients at risk for RA. SUMMARY: The prevention of RA in at-risk populations is feasible; however, this will necessitate novel efforts to identify patients very early in disease development to examine the effectiveness and cost of preventive interventions. PMID- 21285715 TI - Current world literature. PMID- 21285714 TI - Risk factors for gout and prevention: a systematic review of the literature. AB - PURPOSE OF REVIEW: Our objective was to perform a systematic review of risk factors and prevention of gout. We searched Medline for fully published reports in English using keywords including but not limited to 'gout', 'epidemiology', 'primary prevention', 'secondary prevention', 'risk factors'. Data from relevant articles meeting inclusion criteria were extracted using standardized forms. RECENT FINDINGS: Of the 751 titles and abstracts, 53 studies met the criteria and were included in the review. Several risk factors were studied. Alcohol consumption increased the risk of incident gout, especially beer and hard liquor. Several dietary factors increased the risk of incident gout, including meat intake, seafood intake, sugar sweetened soft drinks, and consumption of foods high in fructose. Diary intake, folate intake, and coffee consumption were each associated with a lower risk of incident gout and in some cases a lower rate of gout flares. Thiazide and loop diuretics were associated with higher risk of incident gout and higher rate of gout flares. Hypertension, renal insufficiency, hypertriglyceridemia, hypercholesterolemia, hyperuricemia, diabetes, obesity, and early menopause were each associated with a higher risk of incident gout and/or gout flares. SUMMARY: Several dietary risk factors for incident gout and gout flares are modifiable. Prevention and optimal management of comorbidities are likely to decreased risk of gout. Research in preventive strategies for the treatment of gout is needed. PMID- 21285717 TI - Robotic microsurgery 2011: male infertility, chronic testicular pain, postvasectomy pain, sports hernia pain and phantom pain. AB - PURPOSE OF REVIEW: The use of robotic assistance during microsurgical procedures has evolved from its early beginnings in the early 2000s. Currently, its use is expanding in the treatment of male infertility and patients with chronic testicular or groin pain. The addition of this technology may allow an improvement in outcomes as when the operating microscope was introduced in microsurgery. However, this is yet to be proven. RECENT FINDINGS: This review covers new robotic microsurgical tools and applications of the robotic platform in microsurgical procedures such as vasectomy reversal, varicocelectomy, microsurgical denervation of the spermatic cord for chronic testicular or groin pain, post-vasectomy pain, sports hernia pain, postnephrectomy, donor nephrectomy and phantom groin pain. Preliminary animal studies show an advantage in terms of improved operative efficiency and improved surgical outcomes. Preliminary human clinical studies appear to support these findings. The use of robotic assistance during robotic microsurgical vasovasostomy appears to decrease operative duration and improve early postoperative sperm counts compared to the pure microsurgical technique. SUMMARY: Long-term prospective controlled trials are necessary to assess the true cost-benefit ratio for robotic assisted microsurgery. The preliminary findings are promising and evidence is mounting, but further evaluation is warranted. PMID- 21285718 TI - Urolithiasis. PMID- 21285719 TI - Update on technological and selection factors influencing shockwave lithotripsy of renal stones in adults and children. AB - PURPOSE OF REVIEW: The aim of this review is to evaluate recently published peer reviewed literature on the subject of shockwave lithotripsy. RECENT FINDINGS: Based on in-vitro animal studies, escalating voltage results in better stone comminution and ultimately applies less total voltage to the surrounding tissue, theoretically causing less harm. Several studies have also shown that a slower shockwave rate improves stone fragmentation for intrarenal stones. Stones measuring greater than 1000 HU require a significantly greater number of shocks to destroy. The current literature continues to support shockwave lithotripsy as both a safe and effective means for managing stone disease in pediatric patients. Medical expulsive therapy with alpha-blockers appears to be efficacious, shortening the time to stone and fragment expulsion as well as minimizing pain. Skin-to-stone distance, Hounsfield units, stone size, and location are the best studied and most validated parameters that correlate with shockwave lithotripsy success. SUMMARY: Shockwave lithotripsy continues to evolve with the advent of better technology, improved imaging, and the development of several parameters that can be used to predict success, to counsel our patients, and improve stone free rates. PMID- 21285720 TI - Urolithiasis in kidneys with abnormal lie, rotation or form. AB - PURPOSE OF REVIEW: The treatment options in urolithiasis in kidneys with abnormalities of form and location can be challenging due to abnormal anatomy (calyceal and renal orientation), relative immobility interfering with movement of equipment, and abnormal relation with other visceral organs. RECENT FINDINGS: In this review, we focus on the different techniques and results of various treatment modalities. The approach to managing these stones should be individualized. We also allude to the results of a few recent series and emphasize various treatment options. SUMMARY: Ultrasound helps in gaining access in ectopic kidneys, in addition to being a diagnostic tool. Computerized tomography is pivotal in helping to decide the management and choosing the method of treatment in anomalous kidneys. Flexible ureteroscopy can be a useful tool in stones less than 2 cm in size with the availability of smaller flexible ureteroscopes and access sheaths. However the surgeon should consider complete 'on table' clearance in these patients as the drainage is likely to be impaired. Ultrasound guided percutaneous approaches for ectopic kidneys should be performed by surgeons well versed with it. Laparoscopic assisted percutaneous nephrolithotomy has shown good clearance rates with minimal morbidity and less likelihood of ancillary procedures. Although adequate fragmentation can be achieved with extracorporeal shock wave lithotripsy, the drainage of fragments might be impaired due to the anatomical abnormalities. The choice of shock wave lithotripsy as a treatment option should be made prudently. PMID- 21285721 TI - Current world literature. PMID- 21285723 TI - Radiation-induced acute illness. Introduction. PMID- 21285724 TI - Biological consequences and health risks of low-level exposure to ionizing radiation: commentary on the workshop. AB - This paper provides an integration and discussion of the information presented at the workshop held from 2-5 May 2010 in Richland, WA, adjacent to the Pacific Northwest National Laboratory (PNNL). Consequently, this is commentary and not necessarily a consensus document. This workshop was in honor of Dr. Victor P. Bond in celebration of his numerous contributions to the radiation sciences. PMID- 21285725 TI - Biological system components. PMID- 21285726 TI - Responses in the system to primary effects. PMID- 21285727 TI - Secondary responses in the system--non-targeted effects. PMID- 21285728 TI - Spontaneous and radiogenic perturbations and cancer. PMID- 21285729 TI - Propagation of effects and low dose impact. PMID- 21285730 TI - Epidemiology of radiation-induced cancer. PMID- 21285731 TI - Implications on perception, medicine, and protection. PMID- 21285732 TI - Modeling of dose-risk functions. PMID- 21285733 TI - Final discussions, summary and recommendations. PMID- 21285737 TI - Real time three-dimensional echocardiographic evaluation of a congenitally corrected transposition of the great arteries in a 64-year-old asymptomatic man. PMID- 21285738 TI - Predictors of exercise capacity in patients with chronic heart failure. AB - BACKGROUND: Heart failure is a major and growing societal problem characterized by high mortality, frequent hospitalization, reduced quality of life and a complex therapeutic regimen. The six-minute walking test (6-MWT) may serve as a useful and reproducible test for assessing exercise capacity in heart failure patients and has been suggested as a simple, well-tolerated and inexpensive alternative to cardiopulmonary exercise testing (CPET). The CPET and 6-MWT are the most broadly used for assessing functional limitation in patients with heart failure. Echocardiography is well qualified to meet the growing need for noninvasive imaging in the expanding heart failure population. METHODS: This study included 132 consecutive patients (61 +/- 10 years, 45% women) with stable heart failure. All patients underwent 6-MWT and Doppler echocardiographic examination on the same day. Clinical, biochemical and echocardiographic predictors were analyzed to assess predictors of exercise capacity. Patients were divided into two groups based on the 6-MWT distance. The first group comprised patients with limited exercise performance (<= 300 m), and the second group, patients with good exercise performance (>300 m). RESULTS: In univariate analysis, patients' age [0.931 (0.895-0.968), P < 0.001], arterial hypertension [0.481 (0.239-0.967), P = 0.040], blood urea level [0.860 (0.759-0.975), P = 0.019], New York Heart Association (NYHA) class [0.441 (0.245-0.795), P = 0.006], early diastolic E wave [1.014 (1.000-1.029), P = 0.047], total isovolumic time (t IVT) [0.868 (0.796-0.947), P = 0.001], Tei index [0.112 (0.028-0.450), P = 0.002], and E' of left-ventricular (LV) lateral wall [1.188 (1.099-1.400), P = 0.039] independently predicted poor 6-MWT performance (<300 m). In multivariate analysis, only patients' age [0.948 (0.902-0.996), P = 0.034], arterial hypertension [0.351 (0.133-0.922), P = 0.034], and t-IVT [0.828 (0.725-0.946), P = 0.005] independently predicted poor 6-MWT performance (<300 m). CONCLUSION: In chronic stable heart failure patients, in addition to age, systemic hypertension as well as LV asynchrony, as reflected by prolonged t-IVT, are independent predictors of poor exercise capacity. PMID- 21285739 TI - European Society of Cardiology guidelines: preoperative cardiac risk assessment and perioperative cardiac management in noncardiac surgery. PMID- 21285740 TI - Thumbs up for using change theories to improve handoff communication. PMID- 21285742 TI - How do you support your staff? Promote EBP. PMID- 21285743 TI - Will they stay or will they go? Insight into nursing turnover. PMID- 21285744 TI - Understanding the Triple Aim. PMID- 21285745 TI - Accountable care organizations: are they the right answer? PMID- 21285746 TI - Too fast, too slow, too ugly: dangerous dysrhythmias. PMID- 21285747 TI - Matching nurse staffing to demand. PMID- 21285749 TI - Utilizing decision acceleration for Magnet(r) gap analysis. PMID- 21285750 TI - Nurse managers as knowledge workers. PMID- 21285751 TI - Developing an automated RRT trigger. PMID- 21285752 TI - Prioritizing staff issues; planning nursing's educational future. PMID- 21285753 TI - Facial fractures. AB - Fractures of the facial skeleton can result in the loss of an aesthetically pleasing appearance and basic function, and many cases subsequently require an operative intervention. The surgeon managing these facial fractures must, at the same time, be cognizant of concomitant injuries, including neurologic, ophthalmologic, and cervical spine issues. For most situations, early stabilization in anatomical position using rigid fixation will give the most accurate reduction for the optimal return of preoperative appearance and function, while reducing long-term soft-tissue contracture. PMID- 21285754 TI - Introducing the septocutaneous gluteal artery perforator flap: a simplified approach to microsurgical breast reconstruction. AB - BACKGROUND: Consistent septocutaneous perforators exist between the gluteus maximus and medius muscles. The existence of these septocutaneous perforators obviates the need for any intramuscular dissection when elevating a gluteal artery perforator flap. In this study, the authors present their experience with the septocutaneous gluteal artery perforator (sc-GAP) flap for microsurgical breast reconstruction. METHODS: The authors retrospectively reviewed 11 consecutive sc-GAP flaps performed for postmastectomy breast reconstruction in nine patients between February and July of 2008. Patient demographics, risk factors, perforator characteristics, operative technique, operative time, and outcome were analyzed. Preoperative imaging was used for all patients. RESULTS: Mean patient age was 52 years (range, 44 to 60 years). Mean body mass index was 22.2 (range, 17.2 to 29.1). Of the 11 flaps, five sc-GAP flaps were immediate (45 percent) and six were delayed reconstruction (55 percent); seven were unilateral (64 percent) and four were bilateral (36 percent). Mean operative time was 8.2 hours (range, 6.5 to 11 hours). All patients stayed in the hospital for 5 days. Mean pedicle length was 7.9 cm (range, 5 to 10 cm) and mean flap weight was 499 g (range, 360 to 640 g). Vessel size ranged from 1.8 to 3 mm. Complications included one take-back, one axillary seroma, one donor-site seroma, and one donor site hematoma. There were no flap losses. CONCLUSIONS: The sc-GAP flap is a viable technique for microsurgical breast reconstruction that may be easier to master than traditional musculocutaneous gluteal artery perforator flap procedures. The authors recommend the sc-GAP flap as a simplified approach to gluteal artery perforator flaps for microsurgical breast reconstruction. PMID- 21285755 TI - A combined anatomical and clinical study for quantitative analysis of the microcirculation in the classic perfusion zones of the deep inferior epigastric artery perforator flap. AB - BACKGROUND: The establishment of the perfusion zones for the deep inferior epigastric artery perforator (DIEP) flap is still under debate. Specifically, differences between clinical and anatomical studies have often been described. The purpose of this combined study was to evaluate the characteristics of a DIEP zoning in both clinical and anatomical settings by quantitatively assessing the perfusion dynamics and vascular anatomy. METHODS: In the first part of the study, the perfusion dynamics of 16 patients undergoing DIEP flap breast reconstruction were assessed, determining cutaneous oxygen supply and blood flow using an Oxygen to See device. In the second part of the study, 11 flaps were harvested from fresh female cadavers. All specimens were subjected to dynamic computed tomographic scanning to simulate single-perforator DIEP flaps. RESULTS: The perfusion dynamics of DIEP flaps show no significant difference (p <= 0.05) between the two immediately adjacent zones, regardless of the use of lateral or medial perforator rows. However, use of the cadaver medial row perforator more often illustrated a vascular pattern across the midline (zone II, 86.4 percent) as compared with the lateral row-perfused DIEP flap. CONCLUSIONS: The authors' combined study showed varying perfusion characteristics between anatomical and clinical settings, which could be caused by a number of complex systemic and local processes. Thus, the selection of the DIEP zones should be assessed individually depending on the anatomy in question and the characteristics of the perforators until the mentioned issues are clarified in detail. PMID- 21285756 TI - An 8-year experience of direct-to-implant immediate breast reconstruction using human acellular dermal matrix (AlloDerm). AB - BACKGROUND: The advent of skin- and nipple-sparing mastectomy in conjunction with the use of human acellular dermal matrix to provide lower pole coverage has made direct-to-implant immediate breast reconstruction following mastectomy feasible. The purpose of this study was to evaluate long-term complications associated with this technique. METHODS: All human acellular dermal matrix-assisted direct-to implant immediate reconstructions performed over an 8-year period were included in this analysis. Patient charts were reviewed for type of mastectomy (oncologic or prophylactic), incision type, complications during follow-up, length of follow up, rate and type of revision surgery in breasts without postoperative complications, contralateral procedures, and adjuvant radiotherapy. RESULTS: A total of 466 breasts (260 patients) were reconstructed; 68 percent were prophylactic and 32 percent were oncologic cases. Twenty-one breasts (4.5 percent) received radiotherapy. Mean implant size placed was 412.8 +/- 24.7 cc (range, 150 to 600 cc). Mean follow-up was 28.9 +/- 21.3 months (range, 0.3 to 97.7 months). The overall complication rate was 3.9 percent (implant loss, 1.3 percent; skin breakdown/necrosis, 1.1 percent; hematoma, 1.1 percent; human acellular dermal matrix exposure, 0.6 percent; capsular contracture, 0.4 percent; and infection, 0.2 percent). Type, incidence, and overall rate of complications did not differ significantly between prophylactic and oncologic breasts. Irradiated breasts had a fourfold higher rate of complications. In 354 breasts with more than 1 year of follow-up (mean, 36.7 +/- 18.6 months; range, 12.1 to 97.7 months), there were no long-term complications. CONCLUSIONS: Human acellular dermal matrix-assisted direct-to-implant breast reconstruction following mastectomy is safe and reliable, with a low overall long-term complication rate. The low incidence of capsular contracture supports the growing body of evidence that human acellular dermal matrix mitigates capsular contracture. PMID- 21285757 TI - Occult carcinoma in 866 reduction mammaplasties: preserving the choice of lumpectomy. AB - BACKGROUND: Occult breast carcinoma is occasionally found in reduction mammaplasty specimens. Historically, these patients were treated with mastectomy because the exact location of the tumor was unknown. Currently, breast conservation is the treatment of choice in 50 to 85 percent of breast cancers. The authors present a technique of routine specimen marking that allows localization of the tumor and preservation of the choice of lumpectomy. METHODS: This is a retrospective review of 866 patients who underwent reduction mammaplasty performed by a single surgeon between 1990 and 2009. Data were collected for patients who had occult cancer found in their specimens, including age, cancer risk factors, abnormality, nodal status, selected treatment, and survival status. Specimens were marked and oriented and then sent in separate bags to the pathologist. RESULTS: There were 10 cases of occult carcinoma among the 866 women (1.15 percent) who underwent reduction mammaplasty. Six cancers were found in patients undergoing reduction for symptomatic macromastia [n = 629 (0.95 percent)]. Four new cancers were found in the group of patients with a personal history of cancer [n = 237 (1.69 percent)]. All 10 patients had normal preoperative mammograms. Location, size, and margin status were easily identified and patients were offered the choice of lumpectomy or mastectomy. CONCLUSIONS: This article demonstrates that careful marking of reduction specimens in high risk patients or in women older than 40 years allows the pathologist to orient, localize, and further section tissue for margin status. Communication among plastic surgeon, pathologist, oncologist, and radiation therapist preserves the choice of breast conserving therapy for early cancers. PMID- 21285758 TI - Temporary banking of the nipple-areola complex in 97 skin-sparing mastectomies. AB - BACKGROUND: Despite the improved appearance associated with skin-sparing mastectomy, removal of the nipple-areola complex has a negative impact on the patient. Still, nipple-areola complex-sparing mastectomy results in preservation of a substantial amount of mammary tissue at risk. This may be prevented by preservation of the nipple-areola complex as a graft that is temporarily banked (e.g., in the groin region). METHODS: Ninety-seven nipple-areola complexes were banked as part of preventive (n = 62) or therapeutic (n = 35) skin-sparing mastectomies in 61 women with a median age of 41 years (range, 27 to 59 years) and a minimum follow-up of 2 years. The areola was harvested as a full-thickness skin graft with the nipple attached as a composite graft. In oncologic cases, the nipple-areola complexes were banked only after frozen section clearance. RESULTS: Seventy-five nipple-areola complexes were replanted onto the reconstructed mammary mound after 10 months (range, 3 to 26 months). Repeated graft take was moderate to good in 73 of these 75 nipple-areola complexes. The projection of the nipple and pigmentation of the areola were moderate to good in 45 and 74 of the 75 repeatedly transplanted grafts, respectively. CONCLUSIONS: In skin-sparing mastectomy, maximum oncologically safe conservation of autologous mammary structures can be realized by means of temporary banking of the nipple-areola complex. Even though such banking may not be successful in all women, it proved to be satisfactory in most. PMID- 21285759 TI - Matrix therapy with RGTA OTR4120 improves healing time and quality in hairless rats with deep second-degree burns. AB - BACKGROUND: ReGeneraTing Agents (RGTAs) are biodegradable polymers engineered to mimic heparan-sulfate in the extracellular matrix of damaged tissue. RGTAs improve tissue healing in several animal models by stabilizing and protecting heparin-binding growth factors and matrix proteins. RGTA restores the normal matrix architecture and supports tissue regeneration. In this study, the authors evaluated the effects of RGTA on epidermal repair and dermal remodeling in a rat burn model. METHODS: Deep second-degree burns were induced in 156 hairless rats, of which half (n = 78) received topical and intramuscular RGTA immediately after the burn followed by intramuscular RGTA weekly for 1 month. The controls (n = 78) received saline according to the same protocol. Rats were killed starting on each day of the first week and on days 14, 28, 60, 120, 240, and 365. The burns were evaluated by photography, histology, and immunohistochemistry. RESULTS: Coagulation necrosis involved the entire epidermis and superficial adnexa. Compared with the controls, speed of epidermal repair, as assessed between days 3 and 7 based on cell-layer number and anticytokeratin-14 staining, was faster in the RGTA group; and the zone of stasis, as assessed based on secondary vascular lesions in the dermis, was smaller. On day 7, reepithelialization was complete in both groups. On days 14 and 28, the remodeled dermal zone was smaller in the RGTA group. CONCLUSION: RGTA accelerated epidermal repair and protected the dermis from secondary effects of heat as quantified by zone-of-stasis size and extent of dermal remodeling. PMID- 21285760 TI - A novel mouse model of cutaneous radiation injury. AB - BACKGROUND: Radiation therapy is a cornerstone of oncologic treatment. Skin tolerance is often the limiting factor in radiotherapy. To study these issues and create modalities for intervention, the authors developed a novel murine model of cutaneous radiation injury. METHODS: The dorsal skin was isolated using a low pressure clamp and irradiated. Mice were followed for 8 weeks with serial photography and laser Doppler analysis. Sequential skin biopsy specimens were taken and examined histologically. Tensiometry was performed and Young's modulus calculated. RESULTS: High-dose radiation isolated to dorsal skin causes progressive changes in skin perfusion, resulting in dermal thickening, fibrosis, persistent alopecia, and sometimes ulceration. There is increased dermal Smad3 expression, and decreased elasticity and bursting strength. CONCLUSIONS: This model of cutaneous radiation injury delivers reproducible localized effects, mimicking the injury pattern seen in human subjects. This technique can be used to study radiation-induced injury to evaluate preventative and therapeutic strategies for these clinical issues. PMID- 21285761 TI - Prolongation of composite tissue allotransplant survival by treatment with bone marrow mesenchymal stem cells is correlated with T-cell regulation in a swine hind-limb model. AB - BACKGROUND: Recently published reports indicate that treatment with mesenchymal stem cells combined with bone marrow transplantation could prolong survival after composite tissue allotransplantation. This study investigated whether bone marrow mesenchymal stem cells combined with irradiation and short-term immunosuppressant therapy, but without bone marrow transplantation, could prolong composite tissue allotransplantation survival. Correlation with regulatory T-cell populations was also evaluated in a swine hind-limb model. METHODS: Heterotopic hind-limb transplantation was performed in outbred miniature swine. Group I (n = 4) was the untreated control. Group II (n = 3) received mesenchymal stem cells alone (on days -1, 3, 7, 14, and 21). Group III (n = 5) received cyclosporine A (on days 0 through 28). Group IV (n = 3) received irradiation (on day -1), mesenchymal stem cells (on days 1, 7, 14, and 21), and cyclosporine A (on days 0 to 28). Swine viability and signs of allograft rejection were monitored postoperatively. Histopathologic changes in allografts were examined. The expression and localization of CD4+/CD25+ and CD4+/FoxP3+ T cells were assessed using flow cytometry and immunohistochemistry. RESULTS: Treatment with mesenchymal stem cells along with irradiation and cyclosporine A resulted in significant increases in allograft survival as compared with other groups (>120 days; p = 0.018). Histologic examination revealed the lowest degree of rejection in grafted skin and interstitial muscle layers in the mesenchymal stem cell/irradiation/cyclosporine A group. Flow cytometric analysis revealed a significant increase in the percentage of CD4+/CD25+ and CD4+/FoxP3+ T cells in both the blood and graft in the mesenchymal stem cell/irradiation/cyclosporine A group. CONCLUSION: These results suggest that prolonged survival after composite tissue allotransplantation induced by treatment with mesenchymal stem cells combined with irradiation/cyclosporine A is correlated with regulatory T cells. PMID- 21285762 TI - Nell-1 enhances bone regeneration in a rat critical-sized femoral segmental defect model. AB - BACKGROUND: Effective regeneration of bone is critical for fracture repair and incorporation and healing of bone grafts used during orthopedic, dental, and craniofacial reconstructions. Nel-like molecule-1 (Nell-1) is a secreted protein identified from prematurely fused cranial sutures of craniosynostosis patients that has been found to specifically stimulate osteogenic cell differentiation and bone formation. To test the in vivo osteoinductive capacity of Nell-1, a critical sized femoral segmental defect model in athymic rats was used. METHODS: A 6-mm defect, which predictably leads to nonunion if left untreated, was created in the left femur of each rat. Three treatment groups (n = 8 each) were created consisting of rats treated with (1) 1.5 mg/ml Nell-1, (2) 0.6 mg/ml Nell-1, and (3) phosphate-buffered saline only as a Nell-free control. Phosphate-buffered saline or Nell-1 was mixed with demineralized bone matrix as a carrier before implantation. All animals were euthanized 12 weeks after surgery, and bone regeneration was evaluated using radiographic, three-dimensional micro-computed tomographic, and histologic analysis. RESULTS: Both Nell-1-treated groups had significantly greater bone formation compared with the Nell-free group, with bone volume increasing with increasing Nell-1 concentration. CONCLUSIONS: Nell-1 in a demineralized bone matrix carrier can significantly improve bone regeneration in a critical-sized femoral segmental defect in a dose-dependent manner. The results of this study demonstrate that Nell-1 is a potent osteospecific growth factor that warrants further investigation. Results also support the potential application of Nell-1 as a bone graft substitute in multiple clinical scenarios involving repair of critical bone loss when autograft bone is limited or unavailable. PMID- 21285763 TI - Novel animal model of calvarial defect in an infected unfavorable wound: reconstruction with rhBMP-2. AB - BACKGROUND: Recombinant human bone morphogenetic protein-2 (rhBMP-2) delivered on an absorbable collagen sponge has been shown to induce the healing of acute, primary, large-scale calvarial defects in rabbits. However, clinical circumstances often require the reconstruction of a previously infected and chronically scarred wound. This study was designed to evaluate the efficacy of rhBMP-2/absorbable collagen sponge to improve healing in the previously infected, unfavorable calvarial defect model. METHODS: Subtotal defects were made in the calvariae of 15 adult New Zealand White rabbits. The bone flap was inoculated with Staphylococcus aureus and replaced in situ. After a 2-week infection period, animals underwent bone flap removal and a 10-day course of antibiotic therapy. On postoperative day 42, the defect was exposed and treated with (1) no intervention/control (group 1; n = 5), or (2) absorbable collagen sponge with 0.43 mg/ml of rhBMP-2 (group 2; n = 10). Bone growth was analyzed with serial computed tomographic imaging and postmortem histology. Percentage bone healing was compared between groups using the t test. RESULTS: The treatment group (group 2) demonstrated statistically more healing (55.6 percent) compared with the control group (group 1) (29 percent; p < 0.01). However, rhBMP-2-induced bone was not histologically or radiographically similar to native bone, lacking both continuity and a well-defined diploic space. CONCLUSIONS: These data suggest that rhBMP-2-treated collagen sponges may be useful for the repair of calvarial defects following infection. However, the osseous healing observed in this study was significantly less than previous reports in acute, noninfected models and was dissimilar to native bone. Further work is needed to optimize treatment of the previously infected calvarial wound with rhBMP-2. PMID- 21285764 TI - Differential expression of sclerostin in adult and juvenile mouse calvariae. AB - BACKGROUND: An understanding of the molecular mechanisms controlling bone formation is central to skeletal tissue engineering efforts. The observation that immature animals are able to heal calvarial defects while adult animals are not has proven to be a useful tool for examining these mechanisms. Thus, the authors compared expression of sclerostin, a bone inhibitor, between the calvariae of juvenile and adult mice. METHODS: Parietal bone was harvested from juvenile (6 day-old; n = 20) and adult (60-day-old; n = 20) mice. Sclerostin transcript and protein levels were compared between the parietal bone of juvenile and adult mice using polymerase chain reaction, Western blotting, and immunohistochemistry. Finally, osteoblasts from the parietal bone of juvenile and adult mice were harvested and cultured under osteogenic differentiation conditions with and without recombinant sclerostin (200 ng/ml). Terminal osteogenic differentiation was assessed at 21 days with alizarin red staining. RESULTS: Polymerase chain reaction, Western blot analysis, and immunohistochemistry all confirmed greater expression of sclerostin in the parietal bone of adult mice when compared with that of juvenile mice. Osteoblasts, whether from juvenile or adult parietal bones, demonstrated reduced capacity for osteogenic differentiation when exposed to recombinant sclerostin. CONCLUSIONS: Given the role of sclerostin in inhibiting bone formation, the authors' findings suggest that differences in expression levels of sclerostin may play a role in the differential regenerative capacity of calvariae from juvenile and adult animals. These findings suggest it as a potential target to abrogate in future tissue engineering studies. PMID- 21285765 TI - Discussion. Five-year outcome of surgical treatment of migraine headaches. PMID- 21285766 TI - Variations in the lymphatic drainage pattern of the head and neck: further anatomic studies and clinical implications. AB - BACKGROUND: There is an increasing clinical need for accurate evaluation of the lymphatic anatomy of the head and neck. METHODS: Fourteen halves of the superficial tissues of the head and neck and six specimens of the anterior superficial neck tissue from 13 unembalmed human cadavers were studied. Six percent hydrogen peroxide was used to detect the lymphatic vessels by using a surgical microscope. These vessels were then injected with a radio-opaque lead oxide mixture. Each specimen was dissected, photographed, and radiographed to demonstrate lymphatic vessels in the tissue. The final results were then transferred to the computer for analysis. RESULTS: Lymph-collecting vessels were found in three regions of the superficial tissue of the head and neck: the scalp, face, and cervical region. They were dense in the scalp and lateral neck area but sparse in the facial, anterior, and posterior neck. Most vessels in the lateral neck were internodal lymphatics. Two layers of lymphatic vessels were found in the anterior superficial neck tissue coursing in different directions. CONCLUSIONS: An actual and accurate lymphatic map of the head and neck lymphatic drainage patterns is presented to upgrade our anatomical knowledge. This map will be of benefit for the clinical management of trauma and malignancies in this region. PMID- 21285767 TI - Reconstruction following traumatic partial amputation of the ear. AB - BACKGROUND: Reconstruction following traumatic amputation of the external ear remains a unique challenge to the plastic surgeon. The authors report a series of ear reconstructions with autologous costal cartilage in patients following traumatic partial amputation of the ear. Technical points regarding the carving of the cartilage framework and methods of skin coverage are discussed. METHODS: Fifty partial ear reconstructions with autologous costal cartilage were performed over a 4-year period. All patients had suffered previous traumatic amputation of part of the external auricle due to bite injuries (n = 36), road traffic accidents (n = 6), burns (n = 5), or torture (n = 3). A two-stage technique of reconstruction with autologous cartilage graft was used based on Nagata's adaptations of Brent's original technique. In nine cases, skin shortage or extensive scarring required preoperative tissue expansion (n = 4) or a temporoparietal fascial flap (n = 5) to provide adequate coverage of the cartilage framework. RESULTS: Forty-seven patients had a successful surgical outcome without complication. Two patients developed small areas of skin necrosis resulting in exposure of the cartilage framework. These healed with conservative management with minor loss of definition. One case of wound infection resulted in significant loss of definition of the construct, which required a further surgical procedure with additional costal cartilage graft. CONCLUSION: Reconstruction of the external ear with autologous costal cartilage following traumatic amputation can produce high-quality auricles consistently and is becoming the treatment of choice for such injuries, given access to a specialist center with exposure to a high volume of cases. PMID- 21285768 TI - Long-term follow-up of osseointegrated auricular reconstruction. AB - BACKGROUND: Auricular deformity presents a formidable challenge for the reconstructive surgeon, and osseointegrated auricular reconstruction provides a safe and reliable option. The authors sought to review long-term results of osseointegrated auricular reconstruction at the Institute for Reconstructive Sciences in Medicine. METHODS: A chart review examining demographics, skin reactions (defined by a modified Holgers classification), and complications at the Institute for Reconstructive Sciences in Medicine was completed. A multivariate binary linear logistic regression analysis was performed to determine whether there was a correlation between the likelihood of a skin reaction and certain patient demographics. A survey was then developed to assess patient satisfaction. RESULTS: Seventy-five osseointegrated auricular reconstructions were performed on 69 patients at the Institute for Reconstructive Sciences in Medicine from 1989 to 2007; mean patient age was 39 years (range, 9 to 76 years). The most common indication for reconstruction was posttraumatic, then congenital and oncologic. The frequency of Holgers reactions was as follows: no reaction, 69 percent; red tissue, 15 percent; excessive tissue, 10 percent; red and moist tissue, 3 percent; granulation tissue, 2 percent; and soft-tissue necrosis, 1 percent. Multivariate binary linear logistic regression analysis found that smoking, younger age, and female gender were associated with the occurrence of a reaction. The overall failure rate of osseointegration in the mastoid region was 2 percent. Survey results found generally satisfied patients willing to undergo the same procedure again, although 55 percent felt that they had had a skin reaction. CONCLUSION: The authors present long-term results showing both success and complications of the osseointegrated prosthetic ear reconstruction for a variety of different etiologies and age groups. PMID- 21285769 TI - Microvascular repair of heminasal, subtotal, and total nasal defects with a folded radial forearm flap and a full-thickness forehead flap. AB - BACKGROUND: The site, size, and depth of tissue loss, irradiation, or composite injury to adjacent cheek and lip may make local tissues inadequate or unavailable for the repair of major nasal defects. METHODS: In 13 patients, a single, folded, horizontal radial forearm flap was used to line the vault and columella, with an incontinuity fasciocutaneous extension to resurface the nasal floor, with or without primary dorsal support. Later, excess external forearm skin was turned over to adjust the nostril margin and alar base positions. Delayed primary cartilage grafts completed subunit support. A three-stage full-thickness forehead flap provided covering skin. Three-dimensional contouring of the midlayer framework was performed over the entire nasal surface, during an intermediate operation, before pedicle division. RESULTS: Good to excellent aesthetic and functional results were obtained in total and subtotal defects in five operations over 8 months, including a late revision. Partial necrosis of the folded columellar lining (n = 2) and dehiscence of unilateral alar lining (n = 1) were salvaged at forehead flap transfer by hinging over excess external forearm skin (n = 2) or by folding the extension of the forehead flap for columellar lining (n = 1). Indolent cartilage infection necessitated debridement (n = 4) and partial support replacement (n = 3). No free flaps were lost or required to salvage a complication. CONCLUSIONS: The approach is reliable, efficient, and applicable to varied defects and has the ability to correct design errors and complications before pedicle division. An unscarred lining sleeve, defined three-dimensional contour, and thin conforming skin cover are restored. PMID- 21285770 TI - The face as a sensory organ. AB - BACKGROUND: The human face is a highly specialized organ for receiving the sensory information from the environment and for its transmission to the cortex. The advent of facial transplantation has shown that excellent reconstruction of disfiguring defects can be achieved; thus, the expectations are now focused on functional recovery of the transplant. So far, restoration of facial sensation has not received the same attention as the recovery of motor function. METHODS: A thorough review of the literature was performed to investigate the current knowledge on the sensory pathways of the human face and their functions to evaluate current methods of sensory assessment and the available data on normal sensation. RESULTS: The presence of Meissner and Ruffini corpuscles, Merkel disks, hair-associated fibers, and intraepidermal free nerve endings was confirmed. Occurrence of extensive cross-communications between trigeminal and facial nerve was substantiated. Two-point discrimination and pressure thresholds represented the most objective measures of facial sensation. Age, sex, and smoker status of the patients were shown to influence normal sensibility values. The most suitable areas for sensory testing based on the tested modality and innervation were inferred. The anatomical course of the nerves and their variations had implications for the harvest of face allografts and repair of the sensory nerves. CONCLUSIONS: This review has illustrated the complexity of sensory pathways of the face and their influence on somatic and visceral responses. In view of the discussed data, during facial transplantation, it is important to consider different mechanisms of restoration of facial sensation. PMID- 21285771 TI - Is there a simple, definitive, and cost-effective way to diagnose osteomyelitis in the pressure ulcer patient? AB - BACKGROUND: Despite advances in managing pressure ulcers, there is still no definitive way to diagnose bone infection (osteomyelitis) short of open biopsy. An effective, less invasive diagnostic method might result in cost savings and improved care; however, needle aspiration, computed tomography scan, magnetic resonance imaging, ultrasound, and bone scans have proven unsatisfactory in predicting osteomyelitis. The authors reviewed preoperative radiologic studies of stage IV pressure ulcer patients and their bone biopsy results to determine which radiologic studies are most diagnostic for osteomyelitis. METHODS: Patients (n = 44) having surgical debridement of stage IV ulcers with open bone biopsy after prior radiographic imaging (plain films, ultrasound, computed tomography, magnetic resonance imaging, and/or nuclear bone scans) were included. Studies were interpreted by a single musculoskeletal radiologist blinded to information from the medical record and following standard radiologic criteria for the diagnosis of osteomyelitis. RESULTS: The percentage of patients with biopsy proven osteomyelitis identified with imaging was 50 percent using a computed tomography scan and 88 percent using a plain film of the bony area of involvement. The overall sensitivity of either radiologic study was 61 percent. The percentage of patients without osteomyelitis identified as not having the condition by imaging was 85 percent for the computed tomography scan and 32 percent for the plain film. Overall specificity of both studies was 69 percent. CONCLUSION: Preoperative radiologic studies for osteomyelitis in a pressure ulcer are far from definitive; however, if a radiologic study is used to make that diagnosis in a stage IV pressure ulcer, it would appear that a plain film would suffice. PMID- 21285772 TI - Versatility of the proximally pedicled anterolateral thigh flap and its use in complex abdominal and pelvic reconstruction. AB - BACKGROUND: The anterolateral thigh flap was described by Song et al. in 1984. Although more usually used as a free flap, it also has remarkable versatility as a pedicled flap. There are, however, no well-established guidelines that exist to define the extent of defects that can be reconstructed using this flap. In this article, the authors evaluate their experience with consecutive cases of the pedicled anterolateral thigh flap in complex abdominal and pelvic reconstruction. METHODS: A retrospective review of medical records and photographic archives was performed looking at 28 proximally pedicled anterolateral thigh flaps in 27 patients. RESULTS: The authors identified the arcs of rotation achieved, the types of defects reconstructed, points of surgical technique that enhanced their results, and some pitfalls of this flap. Useful points of surgical technique identified included suprafascial flap harvesting, extended harvesting of fascia, utilization of fascia to protect the pedicle, harvesting as a composite flap with the vastus lateralis, prudent preservation of large perforators that transgress the lateral aspect of the rectus femoris, synergistic use with a sartorius "switch," complete flap deepithelialization to fill dead space, and simple conversion to a free flap when pedicle length is inadequate. Pitfalls identified included the increased risk of pedicle avulsion in the morbidly obese, the risk of atherosclerotic plaque embolization in an atheromatous pedicle, and the potential inadequacy of thigh fascia for reconstituting abdominal wall integrity. CONCLUSIONS: This versatile flap has a wide arc of rotation. Multiple surgical modifications can be employed to tailor the flap to individual patient needs. PMID- 21285773 TI - A clinical characterization of familial keloid disease in unique African tribes reveals distinct keloid phenotypes. AB - BACKGROUND: This study is a clinical characterization of keloid scars in an African population comprising three rural tribes with familial keloids. Site distribution, morphologic features, and other characteristics of the scars were studied to assess whether each tribe had a specific scar phenotype. METHODS: Keloid scar clinics were set up at Soba Hospital in Khartoum, Sudan, for patient recruitment and management. In addition, familial keloid cases were recruited from rural tribal populations during field trips. A database including clinical and demographic data and digital photographs of all keloid cases was established. Statistical analysis was conducted using SPSS and SAS software. RESULTS: One hundred eleven individuals with keloid scarring (67 male subjects and 44 female subjects) were recruited. Patients were predominantly from three multigenerational pedigrees (total of 38 nuclear families) afflicted with keloid scars residing in different rural regions of Sudan. Two distinct morphologic phenotypes of keloid scarring were observed. The first phenotype has been designated "superficial spreading" (horizontal) keloid and the second has been designated "raised" (vertical) keloid. Clinically significant features and statistically measurable morphologic parameters were compared among these phenotypes (p = 0.001). Furthermore, linear claw-like extensions of keloid (transgression) were noted to be significantly higher in the superficial spreading keloid phenotype (p = 0.03). CONCLUSIONS: There is strong evidence of different phenotypes of keloid scarring. Two distinct phenotypes have been observed, described, and statistically verified. Each tribe demonstrated one particular phenotype, with two being superficial spreading and one being raised. Other significant clinical characteristics have been described. This is of significance in understanding both the clinical basis and the genetic basis of keloid scarring. PMID- 21285774 TI - Application of multidetector-row computed tomography in propeller flap planning. AB - BACKGROUND: The propeller flap is defined as (1) being island-shaped, (2) having an axis that includes the perforators, and (3) having the ability to be rotated around an axis. The advantage of the propeller flap is that it is a pedicle flap that can be applied to cover defects located at the distal ends of the extremities. The specific aims of the authors' study were (1) to evaluate the usefulness of multidetector-row computed tomography in the planning of propeller flaps and (2) to present a clinical case series of propeller flap reconstructions that were planned preoperatively using multidetector-row computed tomography. METHODS: The authors retrospectively analyzed all cases between April of 2007 and April of 2010 at Nippon Medical School Hospital in Tokyo, where multidetector-row computed tomography was used preoperatively to plan surgical reconstructions using propeller flaps. RESULTS: Thirteen patients underwent 16 flaps using the propeller flap technique. The perforators were identified accurately by multidetector-row computed tomography preoperatively in all cases. CONCLUSIONS: This is the first report describing the application of multidetector-row computed tomography in the planning of propeller flaps. Multidetector-row computed tomography is superior to other imaging methods because it demonstrates more precisely the perforator's position and subcutaneous course using high-resolution three-dimensional images. By using multidetector-row computed tomography to preoperatively identify a flap's perforators, the surgeon can better plan the flap design to efficiently conduct the flap surgery. PMID- 21285775 TI - Discussion. Application of multidetector-row computed tomography in propeller flap planning. PMID- 21285776 TI - The "Tokyo" consensus on propeller flaps. AB - BACKGROUND: Over the past few years, the use of propeller flaps, which base their blood supply on subcutaneous tissue or isolated perforators, has become increasingly popular. Because no consensus has yet been reached on terminology and nomenclature of the propeller flap, different and confusing uses of the term can be found in the literature. METHODS: In this article, the authors report the consensus on the definition and classification of propeller flaps reached by the authors that gathered at the First Tokyo Meeting on Perforator and Propeller Flaps in June of 2009. Some peculiar aspects of the surgical technique are discussed. RESULTS: A propeller flap can be defined as an "island flap that reaches the recipient site through an axial rotation." The classification is based on the nourishing pedicle (subcutaneous pedicled propeller flap, perforator pedicled propeller flap, supercharged propeller flap), the degrees of skin island rotation (90 to 180 degrees) and, when possible, the artery of origin of the perforator. CONCLUSIONS: The propeller flap is a useful reconstructive tool that can achieve good cosmetic and functional results. A flap should be called a propeller flap only if it fulfils the definition above. The type of nourishing pedicle, the source vessel (when known), and the degree of skin island rotation should be specified for each flap. PMID- 21285777 TI - Use of the upper medial thigh perforator flap (gracilis perforator flap) for lower extremity reconstruction. AB - BACKGROUND: The upper medial thigh perforator flap is a free-style skin flap elevated suprafascially from the upper medial thigh in a transverse manner based on any reliable perforator. METHODS: A total of 40 cases were performed in 40 patients with lower extremity soft-tissue defects from various causes. The anatomy of the flap, the elevation technique, and the results after reconstruction were evaluated. RESULTS: All flaps were raised suprafascially in a free-style flap approach. The average size of the flaps was 71.6 cm2 (vertical width, 6.4 cm; transverse length, 10.9 cm). An average number of 1.3 reliable pulsating pedicles was noted entering the flap, and 90 percent originated from the medial circumflex femoral artery. The perforators were one-third musculocutaneous and two-thirds septocutaneous type. The average length of the pedicle was 6 cm, and the average diameter of the artery was 0.8 mm. The flaps were thinned according to the needs of the patient. The donor sites were closed primarily. Thirty-nine flaps survived, and no recurrence of the original abnormality was seen during the follow-up period. CONCLUSIONS: Despite the short pedicle length, small diameter of the vessel, and inconsistent perforator position, the surgeon can use the upper medial thigh perforator flap to overcome the disadvantages by understanding the free-style free flap approach. The flap can obtain reasonable size, well-hidden scar, preservation of muscle function, good pliability, and superficial nerves and vein included for additional quality. This flap, in the hands of experienced surgeons, can be reliable for reconstructing the lower extremity. PMID- 21285778 TI - Reconstruction of the burned hand. AB - This article summarizes the initial management of acute burn injuries to the hand, in addition to treatment and reconstructive options. The goal of treatment for a burn injury to the hand is primarily a functional hand. This is best achieved by appropriate early treatment, the right selection from a wide range of possible reconstructive procedures, and focused occupational hand therapy. PMID- 21285779 TI - Is nasal mucoperiosteal closure necessary in cleft palate repair? AB - BACKGROUND: The goals of successful palate repair include optimizing speech and feeding, mitigating adverse maxillary growth effect, and avoiding fistulae. The necessity of vomerine and/or nasal-side mucosa repair has not been tested. The purpose of this study was to compare the outcome of palate repairs with and without nasal mucoperiosteal closure. The authors used the null hypothesis. METHODS: This was a retrospective analysis of consecutive cleft palate repairs performed between 2001 and 2004. Group 1 underwent two-layer repair (oral and nasal/vomerine mucoperiosteal flaps), and group 2 underwent one-layer closure (oral mucoperiosteal flaps) only. Both groups underwent double-opposing Z-plasty posteriorly. Demographic and perioperative outcome variables were recorded and compared statistically. RESULTS: Group 1 consisted of 51 children (23 boys and 28 girls), and 80 percent were nonsyndromic. Group 2 included 29 patients (15 boys and 14 girls), and 72 percent were without an associated diagnosis. Age at repair was similar (20.80 and 15.17 months, respectively). Operative time was less for one-layer repair (84 versus 135 minutes) (p = 0.0001). Complications, length of stay, and follow-up length were similar between the two cohorts. Velopharyngeal dysfunction was rare in both groups. A single fistula occurred in each group. Anthropometric data revealed larger maxillary arc and tragus-subnasale lengths in group 2. Growth velocities were similar in both groups. CONCLUSIONS: The goals of cleft palate repair can be efficiently achieved using a one-sided oral mucoperiosteal repair only. Omitting the nasal-side and vomer repair does not increase fistula formation or prove detrimental to velopharyngeal function, and may facilitate maxillary growth. PMID- 21285780 TI - Presurgical unilateral cleft lip anthropometrics: implications for the choice of repair technique. AB - BACKGROUND: It has been stated that height of the lateral lip is difficult to obtain with the rotation advancement repair only when the lateral lip is short in both its vertical and horizontal dimensions. The authors studied preoperative cleft lip anthropometry to determine the frequency of the "geometrically unfavorable lateral lip"--short in both vertical and transverse dimensions. METHODS: Direct caliper measurements were taken by a single observer of the heights and of the transverse lengths in 100 consecutive patients (age >=3 months and <6 months) with unilateral cleft lip (51 complete and 49 incomplete) who were under general anesthesia just before cleft lip repair. RESULTS: In 75 patients, the height of the lateral lip was less than that of the noncleft side; on average, 2.1 mm less than (or 82 percent of) the noncleft side (range, 50 to 133 percent). In 86 patients, the lateral lip transverse length was less than on the noncleft side; on average, 2.7 mm less than (or 86 percent of) the noncleft side (range, 66 to 114 percent). Of the 75 patients with height deficiency, 63 patients also had transverse length deficiency. There were 19 patients who exhibited vertical height deficiency of 4 mm or more (>1 SD from the mean), and 79 percent of these patients with extreme height deficiency also exhibited transverse length deficiency. CONCLUSIONS: The lateral lip is frequently short in both vertical and transverse dimensions. These findings warrant consideration for the use of repairs other than rotation advancement (and its variations) in the setting of lateral lip deficiency. PMID- 21285781 TI - Refined new technique for correction of the minor-form, microform cleft lip and minor-form bilateral cleft lip through the intraoral incision and long-term results. PMID- 21285782 TI - The fate of long-standing port-wine stain and its surgical management. AB - BACKGROUND: A port-wine stain begins with thin macular lesions and eventually becomes hypertrophic and forms nodules. Although laser therapy for port-wine stain is a safe treatment modality that has been well-established, the long standing port-wine stain has a tendency to respond less well to laser treatment. The authors performed total surgical resections of long-standing port-wine stain in the facial region, and attempted to clarify the histomorphologic changes. METHODS: The records of 15 patients with long-standing port-wine stain were reviewed for nodules and associated characteristics. After removal of the vascular lesions, the affected area was reconstructed with a radial forearm free flap or a skin graft depending on cosmetic considerations. All specimens obtained from resection were stained with hematoxylin and eosin and Victoria blue for elastic fibers for histomorphologic analysis. After a mean follow-up period of 12 years, the outcomes of surgical management were assessed. RESULTS: The nodules developed in 13 patients, and the mean age for nodule onset was 30 years. Victoria blue staining of the nodular lesions showed an intermingling of thick walled vessels with abundant elastic fibers and thin-walled vessels without elastic fibers, which are findings typical of arteriovenous malformations. After surgical management, most of the outcomes were satisfactory, without complications or recurrence at long-term follow-up. CONCLUSIONS: A long-standing nodular port-wine stain can convert to a high-flow malformation with an arterial component, and these lesions are different from early-stage port-wine stains. For the treatment of long-standing port-wine stain that is resistant to laser therapy, surgical methods will bring more satisfactory outcomes than traditional laser therapy. PMID- 21285783 TI - Expansion of the posterior cranial vault using distraction osteogenesis. AB - BACKGROUND: Expansion of the posterior cranial vault more profoundly enlarges intracranial volume compared with the anterior region. Conventional vault remodeling techniques are limited by scalp forces and may relapse with supine positioning. The purpose of this study was to demonstrate the efficacy of posterior vault distraction and evaluate perioperative variables compared with conventional methods in syndromic children. METHODS: This was a retrospective analysis of consecutive children who underwent posterior vault expansion using distraction osteogenesis. Information was compiled regarding demographics, perioperative details, distraction protocol, and complications. RESULTS: Eight children were identified, two boys and six girls. Diagnoses of Apert, Crouzon, Saethre-Chotzen, and Pfeiffer syndromes were present. Chiari malformation was present in two children. The posterior distraction procedure was undertaken at a mean of 21 months (range, 5 to 36 months). Mean operative time was 3.8 hours (range, 2.6 to 5 hours), blood loss averaged 487 ml (range, 300 to 2000 ml), and hospital stay was 3.25 days (range, 2 to 4 days). A latency period of 72 hours and rate of 2/3 mm/day was used in three patients, and 1 mm/day was used in five children. The mean advancement was 23 mm (range, 19 to 32 mm) and consolidation was 77 days (range, 42 to 100 days). One child experienced fracture of distraction arms during the activation period. Mean follow-up was 278 days (range, 90 to 548 days). CONCLUSIONS: These preliminary findings indicate that posterior vault distraction is a viable technique with a favorable perioperative profile compared with conventional treatment. Posterior distraction can be the initial strategy with which to address intracranial pressure, allowing delay of definitive frontoorbital advancement until later in childhood. PMID- 21285784 TI - Craniofacial microsomia soft-tissue reconstruction comparison: inframammary extended circumflex scapular flap versus serial fat grafting. AB - BACKGROUND: The authors investigated the use of serial autologous fat grafting to restore soft-tissue contour in craniofacial microsomia patients. METHODS: Patients with moderate to severe craniofacial microsomia were divided into two groups. Microvascular free flap patients had reconstruction with inframammary extended circumflex scapular flaps at skeletal maturity (n = 10). Alternatively, patients had fat grafting during multiple staged operations for mandible and ear reconstruction (n = 21). Sex, age, severity of deformity [determined by OMENS (orbital deformity, mandibular hypoplasia, ear deformity, nerve involvement, and soft-tissue deficiency) classification], number of procedures, operative times, and augmentation volumes were recorded. A digital three-dimensional photogrammetry system was used to determine "final fat take" and symmetry (affected side versus unaffected side). Physician and patient satisfaction were elicited. RESULTS: Microvascular free flap and fat grafting groups had similar OMENS scores, 2.4 and 2.3, and similar mean prereconstruction symmetry scores, 74 percent and 75 percent, respectively. Although the mean number of procedures was less for the microvascular free flap group versus the fat grafting group (2.2 versus 4.3), the combined surgical time was greater for the microvascular free flap group. The complication rate for the microvascular free flap group was 12 percent and that for the fat grafting group was 5 percent. The mean microvascular free flap volume implanted was 131 cc, with a final measured volume of 106 cc. Mean fat grafting volume injected per case was 33 cc, with total fat injections of 146 cc and a final measured volume of 121 cc. There was a mean fat loss of 25 cc and 83 percent fat take. Symmetry score was 121 percent for the microvascular free flap group and 99 percent for the fat grafting group. No statistically significant difference in patient or physician satisfaction was noted. CONCLUSION: Serial fat grafting provided a useful alternative to microvascular free tissue transfer after skeletal reconstruction. PMID- 21285785 TI - The spectrum of median craniofacial dysplasia. AB - Given the multiple permutations in craniofacial malformations, classification of median craniofacial dysplasia or midline Tessier no. 0 to 14 clefts has been difficult and disjointed. In this review, the authors present a summary of normal embryology, prior terminology, and their proposed new classification system. Median craniofacial dysplasia has tissue agenesis and holoprosencephaly at one end (the hypoplasias), frontonasal hyperplasia and excessive tissue (the hyperplasias) at the other end, and abnormal splitting or clefting and normal tissue volume (dysraphia) occupying the middle portion of the spectrum. These three distinct subclassifications have different forms of anomalies within their groups. PMID- 21285786 TI - Great auricular nerve injury, the "subauricular band" phenomenon, and the periauricular adipose compartments. AB - BACKGROUND: Experience with anatomical dissection has suggested that two potential complications of rhytidectomy are related to the anatomy of the periauricular adipose compartments: great auricular nerve injury and the "subauricular band" phenomenon. This study describes this anatomy and its relationship to these potential complications. METHODS: The results of 24 fresh hemifacial cadaver dissections were included in this study. Injections included the use of methylene blue and fixable dye injected into specific regions around the ear. The study incorporated digital macro photography, time-lapse photography, and three-dimensional cross-sections in multiple planes (coronal, sagittal, and axial planes) to identify structural relationships. RESULTS: This study defined five periauricular adipose compartments. The main branch of the great auricular nerve always ran within the subauricular membrane. The subauricular membrane was located between the subauricular and inferior adipose compartments. Inadequate dissection of the lateral neck and postauricular area along with failure to release this membrane completely results in banding of the lateral neck, a stigma of face lift surgery. McKinney's point was consistently found to lie where the great auricular nerve travels deep to the inferior border of Lore's fascia and the tail of the parotid. Below this point, the great auricular nerve is closer to the skin surface and more susceptible to potential injury. CONCLUSION: Two possible complications of rhytidectomy, great auricular nerve injury and the "subauricular band" phenomenon, are avoidable by understanding the anatomy of the periauricular adipose compartments. PMID- 21285787 TI - Modifying the upper eyelid crease in Asian patients with hyaluronic acid fillers. AB - BACKGROUND: Preliminary experience with the use of hyaluronic acid fillers as a nonsurgical alternative in the management of upper eyelid crease asymmetry and superior sulcus hollowing in Asian patients has proven promising. METHODS: This retrospective, interventional case series included seven patients (11 eyes) of various Asian ancestries. All patients had eyelid crease asymmetry or undesirably elevated eyelid creases along with hollowing of the upper eyelids. Upper eyelid crease asymmetry and hollowing of the superior sulcus were assessed before and after treatment. For all patients, hyaluronic acid fillers (Restylane, Medicis, Scottsdale, Ariz., or Juvederm, Allergan, Irvine, Calif.) were injected into the retro-septal superior sulcus for eyelid hollowing and into the preseptal eyelid fold for crease asymmetry. Pretreatment and posttreatment photographs were taken. Outcomes were assessed by the total volume injected; masked, independent assessment using preoperative and postoperative photographs; and the subjective assessment of results by the patient. RESULTS: The average age was 43.1 years. The average volume of hyaluronic acid filler injected was 0.61 cc per eye. All seven patients were satisfied with the cosmetic improvement after hyaluronic acid filler injections. No adverse effects were noted. To date, the treatment has remained effective for as long as 18 months. CONCLUSIONS: Hyaluronic acid filler injections into the upper eyelid and superior sulcus are effective in providing volume to recreate the fullness natively present in the Asian upper eyelid. Furthermore, this fullness lowers the surgically created eyelid crease in those patients with eyelid asymmetry following cosmetic blepharoplasty. It should be considered in Asian patients presenting with upper eyelid hollowing or asymmetric eyelid creases. PMID- 21285788 TI - Discussion. Macrolane for breast enhancement: 12-month follow-up. PMID- 21285789 TI - Analysis of postoperative complications for superficial liposuction: a review of 2398 cases. AB - BACKGROUND: Superficial liposuction has found its application in maximizing and creating a lifting effect to achieve a better aesthetic result. Due to initial high complication rates, these procedures were generally accepted as risky. In a response to the increasing concerns over the safety and efficacy of superficial liposuction, the authors describe their 14-year experience of performing superficial liposuction and analysis of postoperative complications associated with these procedures. METHODS: From March of 1995 to December of 2008, the authors performed superficial liposuction on 2398 patients. Three subgroups were incorporated according to liposuction methods as follows: power-assisted liposuction alone (subgroup 1), power-assisted liposuction combined with ultrasound energy (subgroup 2), and power-assisted liposuction combined with external ultrasound and postoperative Endermologie (subgroup 3). Statistical analyses for complications were performed among subgroups. RESULTS: The mean age was 42.8 years, mean body mass index was 27.9 kg/m2, and mean volume of total aspiration was 5045 cc. Overall complication rate was 8.6 percent (206 patients). Four cases of skin necroses and two cases of infections were included. The most common complication was postoperative contour irregularity. Power-assisted liposuction combined with external ultrasound with or without postoperative Endermologie was seen to decrease the overall complication rate, contour irregularity, and skin necrosis. There were no statistical differences regarding other complications. CONCLUSION: Superficial liposuction has potential risks for higher complications compared with conventional suction techniques, especially postoperative contour irregularity, which can be minimized with proper selection of candidates for the procedure, avoiding overzealous suctioning of superficial layer, and using a combination of ultrasound energy techniques. PMID- 21285790 TI - Discussion. Analysis of postoperative complications for superficial liposuction: a review of 2398 cases. PMID- 21285791 TI - A systematic review of interethnic variability in facial dimensions. AB - BACKGROUND: The earliest recorded facial proportional analysis is in the Greek neoclassical canons (c. 450 b.c.). In contemporary times, there has not yet been a study that describes the relative differences in facial proportions among the world's different ethnic groups. The specific aim of this project was to perform a systematic review of data from the existing literature to evaluate the degree of variability in the facial dimensions among various ethnic groups. METHODS: A PubMed database review identified primary articles containing measurements of facial proportions from various ethnic groups. These facial measurements included the heights and widths of the upper, middle, and lower face, which are the features originally described by the neoclassical canons. Coefficients of variation were calculated to derive a unit-free comparison of the degree of variability among different ethnic groups in each of the neoclassically measured facial dimensions. RESULTS: The authors' literature search identified 239 potential articles. After screening for the inclusion and exclusion criteria, seven relevant articles were selected. These articles contained data on 11 linear facial measurements from 2359 male and female individuals from 27 different ethnic groups; features that demonstrated the largest differences among the different ethnic populations were forehead height, interocular distance, and nasal width. CONCLUSIONS: The greatest interethnic variability in facial proportions exists in the height of the forehead. More pronounced differences among the ethnic groups are also present in the measurements of the eyes, nose, and mouth. There is no significant difference between sexes in the neoclassical facial proportions. PMID- 21285792 TI - An evidence-based approach to flexor tendon laceration repair. AB - The Maintenance of Certification module series is designed to help the clinician structure his or her study in specific areas appropriate to his or her clinical practice. This article is prepared to accompany practice-based assessment of preoperative assessment, anesthesia, surgical treatment plan, perioperative management, and outcomes. In this format, the clinician is invited to compare his or her methods of patient assessment and treatment, outcomes, and complications, with authoritative, information-based references. This information base is then used for self-assessment and benchmarking in parts II and IV of the Maintenance of Certification process of the American Board of Plastic Surgery. This article is not intended to be an exhaustive treatise on the subject. Rather, it is designed to serve as a reference point for further in-depth study by review of the reference articles presented. PMID- 21285793 TI - An evidence-based approach to zygomatic fractures. AB - The Maintenance of Certification module series is designed to help the clinician structure his or her study in specific areas appropriate to his or her clinical practice. This article is prepared to accompany practice-based assessment of preoperative assessment, anesthesia, surgical treatment plan, perioperative management, and outcomes. In this format, the clinician is invited to compare his or her methods of patient assessment and treatment, outcomes, and complications, with authoritative, information-based references. This information base is then used for self-assessment and benchmarking in parts II and IV of the Maintenance of Certification process of the American Board of Plastic Surgery. This article is not intended to be an exhaustive treatise on the subject. Rather, it is designed to serve as a reference point for further in-depth study by review of the reference articles presented. PMID- 21285794 TI - An evidence-based approach to genioplasty. AB - The Maintenance of Certification module series is designed to help the clinician structure his or her study in specific areas appropriate to his or her clinical practice. This article is prepared to accompany practice-based assessment of preoperative assessment, anesthesia, surgical treatment plan, perioperative management, and outcomes. In this format, the clinician is invited to compare his or her methods of patient assessment and treatment, outcomes, and complications, with authoritative, information-based references. This information base is then used for self-assessment and benchmarking in parts II and IV of the Maintenance of Certification process of the American Board of Plastic Surgery. This article is not intended to be an exhaustive treatise on the subject. Rather, it is designed to serve as a reference point for further in-depth study by review of the reference articles presented. PMID- 21285795 TI - An evidence-based approach to secondary cleft lip nasal deformity. AB - The Maintenance of Certification module series is designed to help the clinician structure his or her study in specific areas appropriate to his or her clinical practice. This article is prepared to accompany practice-based assessment of preoperative assessment, anesthesia, surgical treatment plan, perioperative management, and outcomes. In this format, the clinician is invited to compare his or her methods of patient assessment and treatment, outcomes, and complications, with authoritative, information-based references. This information base is then used for self-assessment and benchmarking in parts II and IV of the Maintenance of Certification process of the American Board of Plastic Surgery. This article is not intended to be an exhaustive treatise on the subject. Rather, it is designed to serve as a reference point for further in-depth study by review of the reference articles presented. PMID- 21285796 TI - An evidence-based approach to craniosynostosis. AB - The Maintenance of Certification module series is designed to help the clinician structure his or her study in specific areas appropriate to his or her clinical practice. This article is prepared to accompany practice-based assessment of preoperative assessment, anesthesia, surgical treatment plan, perioperative management, and outcomes. In this format, the clinician is invited to compare his or her methods of patient assessment and treatment, outcomes, and complications, with authoritative, information-based references. This information base is then used for self-assessment and benchmarking in parts II and IV of the Maintenance of Certification process of the American Board of Plastic Surgery. This article is not intended to be an exhaustive treatise on the subject. Rather, it is designed to serve as a reference point for further in-depth study by review of the reference articles presented. PMID- 21285797 TI - An evidence-based approach to treating thumb carpometacarpal joint arthritis. AB - The Maintenance of Certification module series is designed to help the clinician structure his or her study in specific areas appropriate to his or her clinical practice. This article is prepared to accompany practice-based assessment of preoperative assessment, anesthesia, surgical treatment plan, perioperative management, and outcomes. In this format, the clinician is invited to compare his or her methods of patient assessment and treatment, outcomes, and complications, with authoritative, information-based references. This information base is then used for self-assessment and benchmarking in parts II and IV of the Maintenance of Certification process of the American Board of Plastic Surgery. This article is not intended to be an exhaustive treatise on the subject. Rather, it is designed to serve as a reference point for further in-depth study by review of the reference articles presented. PMID- 21285798 TI - An evidence-based approach to lower extremity acute trauma. AB - The Maintenance of Certification module series is designed to help the clinician structure his or her study in specific areas appropriate to his or her clinical practice. This article is prepared to accompany practice-based assessment of preoperative assessment, anesthesia, surgical treatment plan, perioperative management, and outcomes. In this format, the clinician is invited to compare his or her methods of patient assessment and treatment, outcomes, and complications, with authoritative, information-based references. This information base is then used for self-assessment and benchmarking in parts II and IV of the Maintenance of Certification process of the American Board of Plastic Surgery. This article is not intended to be an exhaustive treatise on the subject. Rather, it is designed to serve as a reference point for further in-depth study by review of the reference articles presented. PMID- 21285799 TI - An evidence-based approach to pressure sores. AB - The Maintenance of Certification module series is designed to help the clinician structure his or her study in specific areas appropriate to his or her clinical practice. This article is prepared to accompany practice-based assessment of preoperative assessment, anesthesia, surgical treatment plan, perioperative management, and outcomes. In this format, the clinician is invited to compare his or her methods of patient assessment and treatment, outcomes, and complications, with authoritative, information-based references. This information base is then used for self-assessment and benchmarking in parts II and IV of the Maintenance of Certification process of the American Board of Plastic Surgery. This article is not intended to be an exhaustive treatise on the subject. Rather, it is designed to serve as a reference point for further in-depth study by review of the reference articles presented. PMID- 21285800 TI - An evidence-based approach to the treatment of nonmelanoma facial skin malignancies. AB - The Maintenance of Certification module series is designed to help the clinician structure his or her study in specific areas appropriate to his or her clinical practice. This article is prepared to accompany practice-based assessment of preoperative assessment, anesthesia, surgical treatment plan, perioperative management, and outcomes. In this format, the clinician is invited to compare his or her methods of patient assessment and treatment, outcomes, and complications, with authoritative, information-based references. This information base is then used for self-assessment and benchmarking in parts II and IV of the Maintenance of Certification process of the American Board of Plastic Surgery. This article is not intended to be an exhaustive treatise on the subject. Rather, it is designed to serve as a reference point for further in-depth study by review of the reference articles presented. PMID- 21285801 TI - An evidence-based approach to liposuction. AB - The Maintenance of Certification module series is designed to help the clinician structure his or her study in specific areas appropriate to his or her clinical practice. This article is prepared to accompany practice-based assessment of preoperative assessment, anesthesia, surgical treatment plan, perioperative management, and outcomes. In this format, the clinician is invited to compare his or her methods of patient assessment and treatment, outcomes, and complications, with authoritative, information-based references. This information base is then used for self-assessment and benchmarking in parts II and IV of the Maintenance of Certification process of the American Board of Plastic Surgery. This article is not intended to be an exhaustive treatise on the subject. Rather, it is designed to serve as a reference point for further in-depth study by review of the reference articles presented. PMID- 21285802 TI - Systematic reviews and meta-analysis. AB - BACKGROUND: Systematic reviews and meta-analyses are important research tools in modern medicine. They serve to condense and clarify large amounts of data into resources that can educate clinicians, enhance patient care, help formulate clinical guidelines, and guide future research endeavors. METHODS: The existing literature, including recently updated guidelines, on systematic reviews and meta analysis was reviewed and summarized. RESULTS: A brief background on the origins of systematic reviews is presented, and the advantages and disadvantages of this type of study are discussed. A step-by-step guide to conducting a proper systematic review is outlined, with many illustrative examples. The recently updated reporting guidelines for this type of study are included. CONCLUSIONS: Using clinical examples and published guidelines, a framework is presented to help the reader properly conduct a systematic review. These guidelines also help the reader conduct a critical appraisal of systematic reviews published in the scientific literature. Even more importantly, principles regarding application of systematic review results to individual patients are addressed. PMID- 21285803 TI - Maintenance of Certification, maintenance of public trust. AB - The Maintenance of Certification program has been well received by many physicians but has faced significant opposition from others who complain that it is overly tedious, costly, and irrelevant to their practice. This article offers a consolidated and concise history of the program and a summary of what plastic surgeons need to know to successfully complete the American Board of Plastic Surgery's own Maintenance of Certification requirements. The authors have justified each step of the board's Maintenance of Certification process in terms of how it improves the quality of care delivered to plastic surgery patients. Finally, a summary of research is presented that demonstrates both that the public supports the maintenance of certification process for all physicians and that continuing education and formal assessment and improvement initiatives have been linked in multiple studies to a better and more evidence-based medical practice. PMID- 21285804 TI - Level of evidence in plastic surgery research. AB - BACKGROUND: There has been a recent shift toward evidence-based medicine in the medical and surgical literature. The objective of this study was to determine the level of evidence of published plastic surgery articles. METHODS: A review of the following four major plastic surgery journal publications was performed to determine the level of evidence utilized in the published studies: Plastic and Reconstructive Surgery (PRS), Annals of Plastic Surgery (Annals), Journal of Plastic, Reconstructive, and Aesthetic Surgery (JPRAS), and American Journal of Aesthetic Surgery (Aesthetic) from January 1 to December 31, 2007. RESULTS: Of the 1759 articles reviewed, 726 (41 percent) were included (animal studies, cadaver studies, basic science studies, review articles, instructional course lectures, and correspondence were excluded). The articles were ranked according to their level [level I (highest evidence, e.g., randomized-controlled trials) to level IV (lowest evidence, e.g., case reports)]. The average level of evidence in each journal was as follows: PRS, 3.05; Aesthetic, 3.11; JPRAS, 3.35; and Annals, 3.31. The evidence differed significantly between journals (p < 0.05), except when JPRAS was compared with the Aesthetic journal. Only 2.2 percent of articles were level I evidence. CONCLUSIONS: The average level of evidence in four major plastic surgery journals was 3.2 (level III). In order for the plastic surgery profession to become a participant in higher-level evidence-based medicine, greater emphasis must be placed on prospective randomized blinded trials. PMID- 21285805 TI - So you want to be an international plastic surgeon? Plastic and Reconstructive Surgery visits China. PMID- 21285808 TI - Venous drainage disorders as a cause of severe chemosis following fronto-orbital advancement. PMID- 21285809 TI - Longevity of SMAS facial rejuvenation and support. PMID- 21285811 TI - The fascial planes of the temporal region related to the frontal branch of the facial nerve. PMID- 21285812 TI - Surgical procedure for direct excision of glabellar furrows may be problematic. PMID- 21285814 TI - Use of the reverse Yu flap for difficult reconstruction of the upper lip. PMID- 21285817 TI - Second human facial allotransplantation to restore a severe defect following radical resection of bilateral massive plexiform neurofibromas. PMID- 21285818 TI - An improved system for large volume lipomodeling. PMID- 21285819 TI - Voice restoration after laryngectomy. PMID- 21285820 TI - High- and low-evolutive-potential premalignant skin lesions: what about the role of photodynamic therapy? PMID- 21285821 TI - The buccal fat: a convenient and effective autologous option to prevent Frey syndrome and for facial contouring following parotidectomy. PMID- 21285823 TI - Bra stuffing for implant sizing? Satisfaction? Who, when, and compared to what? PMID- 21285825 TI - Where are the data? PMID- 21285827 TI - Preoperative sizing and breast asymmetry. PMID- 21285828 TI - Preoperative sizing in breast augmentation. PMID- 21285829 TI - Preoperative sizing for breast augmentation. PMID- 21285830 TI - Study suggests trend toward greater donor-site morbidity in TRAM flap patients. PMID- 21285833 TI - Marcaine for augmentation mammaplasty. PMID- 21285834 TI - Use of the subpectoral fascia flap for expander coverage in postmastectomy breast reconstruction. PMID- 21285836 TI - Oncoplastic breast surgery in Britain. PMID- 21285838 TI - Dominant radial artery perforator in the proximal forearm. PMID- 21285839 TI - Islanded posterior tibial artery perforator flap for lower limb reconstruction: review of lower leg anatomy. PMID- 21285840 TI - Perforasomes. PMID- 21285843 TI - The reconstructive ladder in light of evidence-based medicine. PMID- 21285845 TI - The role of academic plastic surgery institutions in addressing the global burden of surgical disease. PMID- 21285846 TI - Introduction of the implantable Doppler system did not lead to an increased salvage rate on compromised flaps: a multivariate analysis. PMID- 21285847 TI - Sequential heart and composite tissue allotransplantation in rats. PMID- 21285848 TI - Regulation of human adipose-derived stromal cell osteogenic differentiation by insulin-like growth factor-1 and platelet-derived growth factor-alpha. PMID- 21285854 TI - Association study of the GAB2 gene with the risk of Alzheimer disease in the chinese population. AB - PURPOSE: To assess genetic variations of GAB2 as a risk factor for developing Alzheimer disease (AD). DESIGN AND METHODS: A case-control study (n=310; age>50 y) was conducted to determine the prevalence of 5 single nucleotide polymorphisms (SNPs) of GAB2 (rs2373115, rs1385600, rs4945261, rs7101429, and rs7115850) in patients with AD in Chinese population of mainland China, and was investigated whether these polymorphisms are risk factors for AD. RESULTS: Our results supported a possible implication of 3 tested SNPs of GAB2 (rs4945261, rs7101429, and rs7115850) in AD in the ethnic Chinese Han, of which the maximal significance of association was at SNP rs7101429 C allele (P=4.0*10; odds ratio=2.0; 95% confidence interval, 1.4-2.8), and this observed association was not affected by APOEepsilon4 genotype. In the haplotypes analysis, the minor alleles of the 3 tested SNPs were composed of a TCG haplotype, which had a significant difference in haplotype distribution between the 2 groups (P=3.4*10; odds ratio=8.32; 95% confidence interval, 4.57-15.14). CONCLUSIONS: Our findings implicate an association between genetic variations of GAB2 and AD in Han Chinese, and the minor alleles of the 3 tested SNPs (rs4945261, rs7101429, and rs7115850) might increase the risk of AD. PMID- 21285855 TI - Emotional memory deficit and its psychophysiological correlate in family caregivers of patients with dementia. AB - This study examined the cortisol secretion pattern and declarative memory performance of dementia caregivers. An illustrated story paradigm memory task was used to evaluate the effects of emotional arousal on memory and assess the caregivers' cognitive compensation capacity. Younger (n=19) and elderly (n=24) noncaregivers and elderly caregivers (n=14) took part in 2 experiments to elucidate the effects of aging (experiment 1) and chronic stress (experiment 2) on memory performance and cortisol levels. Each group was divided in 2 subgroups: one that was exposed to an emotionally neutral story, and one that was exposed to a similar, but emotionally arousing story. Participants completed a multiple choice questionnaire in the test session. Salivary cortisol samples were collected at 8:00 AM, 4:00 PM, and 10:00 PM, 1 day after memory testing. Experiment 1 showed that, despite an age-related memory deficit, arousal manipulation produced a similar effect in both age groups. Experiment 2 showed that, in addition to the characteristic memory decline of aging, elderly caregivers did not benefit from emotionally arousing material as their noncaregiver counterparts did. This impairment correlated with elevated nighttime cortisol levels, indicating a potential worsening impact of caregiver burden on age-related cognitive decline. PMID- 21285856 TI - Functional impairment in the diagnosis of mild cognitive impairment. AB - The criterion on functional activity in the revised diagnostic criteria for mild cognitive impairment (MCI) seems to be conceptually and operationally problematic.We investigated the predictive validity for dementia of this criterion in 140 patients with MCI who participated in the baseline study of the Korean Longitudinal Study on Health and Aging and completed 18-month follow-up evaluation (mean duration of follow-up, 1.57+/-0.24 y). Annual conversion rates to dementia were compared between the patients who fulfilled the criterion on functional activity and those who did not. Annual conversion rates to dementia of the patients who fulfilled the criterion on functional activity was 4.76%, whereas that of the patients with MCI who did not was 33.07%, indicating that the criterion on functional activity was a significant negative predictor of dementia (odds ratio=0.12). Re-revision of the criterion on functional activity may be warranted to solve its conceptual and operational ambiguities. PMID- 21285857 TI - Prognostic factors for weight loss over 1-year period in patients recently diagnosed with mild Alzheimer Disease. AB - The aim of the study was to identify prognostic factors for weight loss in patients recently diagnosed with mild Alzheimer disease (AD), with special emphasis on the patients' social participation and living arrangements. The data used in this study was part of the Danish Alzheimer Intervention StudY. The patients were home-living patients with a clinical diagnosis, within the past 12 months, of probable AD or mixed AD; age >=50 years; mini-mental state examination score >=20; informed consent; and data available at 1-year follow-up. In total, 268 patients were included. We used a cut off of 4% in 1 year for defining weight loss. The mean age at inclusion was 76.1 years. Sixty-six patients (24.6%) lost more than 4% of their body weight during the study period. A logistic regression showed that an increase of 1 baseline body mass index point significantly increased the odds of weight loss by 9%. Furthermore, the results suggested a trend that for men, living alone was a risk factor for losing weight, whereas for women living with somebody was associated with a higher risk. However, further studies are pertinent within this area. As weight loss is a predictor of mortality in patients with AD, clinicians should be aware of prognostic social indicators to prevent or halt a potential negative development. PMID- 21285858 TI - Vulvar pseudoverrucous papules and nodules secondary to a urethral--vaginal fistula. AB - Irritant contact dermatitis is a common cause of genital eruptions representing at least one-fifth of presenting anogenital symptoms. A spectrum of inflammatory reactions have been identified, some of them with features severely mimicking more serious dermatoses, which may lead unnecessary workup and treatments. We report a case of a 10-year-old girl who presented at birth with cloacal atresia involving the rectum and the urethra. A diverting colostomy and a urethral vaginal fistula were created to correct the deformity. Physical examination reveals numerous shiny, white-gray, pseudoverrucous papules and nodules coalescing into plaques over the vulva and its surrounding skin. Histological examination showed psoriasiform epidermal hyperplasia with a marked reactive acanthosis and altered cornification with parakeratosis, hypogranulosis, and pale keratinocytes in the upper reaches of the epidermis. The lesions regress when the irritating factor was removed. This case represents a peculiar form of presentation of perianal pseudoverrucous papules and nodules, usually secondary to urinary incontinence or encopresis (inability to control the elimination of stool) after surgery for Hirschsprung disease. Because similar findings have not been previously observed in patients with urethral-vaginal fistula, we attempt to extend the spectrum of presentations for a better knowledge of this condition. PMID- 21285859 TI - A red cheek as first clinical sign of a sebaceous lymphadenocarcinoma of the parotid gland with lymphangiosis carcinomatosa and lymph node metastases. AB - Sebaceous lymphadenoma is a rare benign neoplasm presenting predominantly in the parotid gland or in periparotid lymph nodes. It rarely transforms into a malignant tumor. We present a sebaceous lymphadenoma with an unusual clinical presentation with a malignant component, infiltration of lymph nodes, and lymphangiosis carcinomatosa. Sebaceous lymphadenoma usually presents as a well circumscribed, painless, infraauricular mass. In our 87-years-old male patient, the clinical presentation was confluent reddish livid plaques at the left cheek and the left neck. In addition, cervical lymph node metastases were suspected. After skin biopsy, the tumor was excised by parotidectomy, skin excision, and neck dissection followed by a postoperative radiotherapy. To our knowledge, this is the sixth reported case of sebaceous lymphadenocarcinoma and the first case presenting with cervical lymph node metastases and dermatological symptoms revealing lymphangiosis carcinomatosa. PMID- 21285860 TI - Epstein-Barr virus--associated smooth muscle tumor mimicking cutaneous angioleiomyoma. AB - We present a case of a subcutaneous, unifocal, Epstein-Barr virus--associated smooth muscle tumor mimicking a cutaneous angioleiomyoma. The patient was immunocompromised due to a renal transplant. The tumor displayed diffuse and strong immunoreactivity for smooth muscle actin, H-caldesmon; focal positivity for desmin; and strong and diffuse positivity for Epstein--Barr virus RNA on in situ hybridization. This unique presentation emphasizes the importance of considering this pathologic entity when solitary smooth muscle tumors with the histological features of an angioleiomyoma are encountered in immunocompromised patients. PMID- 21285861 TI - Multiorgan histiocytosis after B-cell acute lymphoblastic leukemia. AB - The association of multiorgan histiocytosis after acute lymphoblastic leukemias is very rare as most cases are localized forms of Langerhans cell histiocytosis (LCH). We report on an 18-year-old man diagnosed with B-cell acute lymphoblastic leukemia (B-ALL) with p16 deletion (9p21). He was treated with induction chemotherapy using the Spanish PETHEMA group protocol and achieved complete remission. Three months after the diagnosis of B-ALL, he developed a severe multiorgan histiocytosis that is clinically suggestive of LCH but lacked typical immunohistochemical features of LCH and indeterminate cell histiocytosis: CD1a was strongly positive, CD68 and S-100 protein were moderately positive, and langerin was negative. The drugs of the first-line treatment recommended for LCH had been part of the chemotherapy of B-ALL that the patient had received. Therefore, we prescribed the second-line treatment for LCH (cytarabine and 2' chlorodeoxyadenosine), and he achieved partial remission. The patient died during the aplasia induced by the third cycle of chemotherapy from pneumonia. We could not demonstrate the transdifferentiation of tumoral lymphocytes into histiocytes, using p16 deletion (9p21) as a marker, because these cells did not share the mutation. Neither could we study immunoglobulin-H rearrangement as we had exhausted all the tissue samples. In the medical literature, there are a few reported cases of T-cell acute lymphoblastic leukemia followed by disseminated LCH and just 1 case of B-ALL followed by localized LCH affecting the bones. Therefore, our patient may be the first published case of B-ALL followed by histiocytosis, which had 2 singularities: it was multiorgan and the immunohistochemistry was not typical of LCH. PMID- 21285862 TI - Bacillary angiomatosis in an immunocompetent child: a case report and review of the literature. AB - Bacillary angiomatosis is an infectious disease caused by 2 gram-negative bacilli, Bartonella henselae and Bartonella quintana. This disease is characterized by vascular proliferations in the skin and/or visceral organs, and typically manifests in immunocompromised patients. However, we report a case of a 10-year-old immunocompetent female child with a questionable history of being scratched by a cat. Although initially diagnosed as a pyogenic granuloma, a diagnosis of bacillary angiomatosis was made based on histologic examination of the excised lesion demonstrating interstitial bacillary deposition on Warthin Starry silver stain. The patient was successfully treated with 2 weeks of azithromycin after which all symptoms resolved. PMID- 21285864 TI - Radiation exposure of the anesthesiologist in the neurointerventional suite. AB - BACKGROUND: Scatter radiation during interventional radiology procedures can produce cataracts in participating medical personnel. Standard safety equipment for the radiologist includes eye protection. The typical configuration of fluoroscopy equipment directs radiation scatter away from the radiologist and toward the anesthesiologist. This study analyzed facial radiation exposure of the anesthesiologist during interventional neuroradiology procedures. METHODS: Radiation exposure to the forehead of the anesthesiologist and radiologist was measured during 31 adult neuroradiologic procedures involving the head or neck. Variables hypothesized to affect anesthesiologist exposure were recorded for each procedure. These included total radiation emitted by fluoroscopic equipment, radiologist exposure, number of pharmacologic interventions performed by the anesthesiologist, and other variables. RESULTS: Radiation exposure to the anesthesiologist's face averaged 6.5 +/- 5.4 MUSv per interventional procedure. This exposure was more than 6-fold greater (P < 0.0005) than for noninterventional angiographic procedures (1.0 +/- 1.0) and averaged more than 3 fold the exposure of the radiologist (ratio, 3.2; 95% CI, 1.8-4.5). Multiple linear regression analysis showed that the exposure of the anesthesiologist was correlated with the number of pharmacologic interventions performed by the anesthesiologist and the total exposure of the radiologist. CONCLUSIONS: Current guidelines for occupational radiation exposure to the eye are undergoing review and are likely to be lowered below the current 100-150 mSv/yr limit. Anesthesiologists who spend significant time in neurointerventional radiology suites may have ocular radiation exposure approaching that of a radiologist. To ensure parity with safety standards adopted by radiologists, these anesthesiologists should wear protective eyewear. PMID- 21285865 TI - Anesthesiologists in the neurointerventional suite: what is appropriate radiation protection? PMID- 21285866 TI - Oxaliplatin as a radiosensitizing agent in rectal cancer. AB - The efficacy of oxaliplatin monotherapy against several solid tumors and its relative lack of nephrotoxicity and myelosupression, coupled with results of the Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer trial, led to a great deal of interest for the implementation of this chemotherapeutic agent in the preoperative setting for the management of adenocarcinoma of the rectum. Despite limited in-vitro and in-vivo data with regard to the radiosensitizing properties of oxaliplatin in rectal cancer, it rapidly entered phase I-III clinical trials. This study reviews the results of these trials and the current status of oxaliplatin as a radiosensitizing agent in the neoadjuvant management of rectal cancer. PMID- 21285867 TI - Novel modalities in the treatment of patients with KRAS-mutated colorectal cancer. AB - Mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) gene are a well-described mechanism of resistance to monoclonal antibodies that target the epidermal growth factor receptor in patients with metastatic and nonoperable colorectal cancer. Treatment options in this population are limited to conventional chemotherapy regimens and antiangiogenesis compounds. Numerous strategies have been proposed in preclinical models as being effective in the presence of KRAS mutations. As basic and translational research further unravels the complex interactions and regulation points in the pathways downstream of epidermal growth factor receptor, more drugs become available for clinical testing. Indeed, there are many ongoing clinical trials that focus on the safety and efficacy of novel compounds in patients with KRAS-mutated colorectal cancer. This is a review of the literature with regard to the rationale of various approaches on this topic and also a summary of the current active clinical trials limited to patients with KRAS-mutated colorectal cancer. PMID- 21285868 TI - Immunolocalization of VEGF A and its receptors, VEGFR1 and VEGFR2, in the liver from patients with biliary atresia. AB - In biliary atresia (BA), a cholangiopathy of elusive etiology invariably leads to cirrhosis, and a disturbed angiogenesis may be involved. We evaluated the hepatobiliary immunolocalization of vascular endothelial growth factor (VEGF) A, VEGF receptor 1 (R1), and R2 in BA. We analyzed biopsies obtained at portoenterostomy from infants with BA (n=52), including embryonic (n=14) and perinatal (n=38) types. Controls were infants with intrahepatic cholestasis (IC; n=7). In BA, VEGF A immunolocalization was also evaluated in explants (n=33) and at the porta hepatis (n=16). We morphometrically assessed the percentage of CK7 (PCK7) positivity in BA and the ratio medial layer thickness/luminal diameter in hepatic artery branches in BA and IC. We found that arteries were more frequently positive for VEGF A in BA at portoenterostomy (P=0.006) than in other groups. In explants, VEGF A immunolocalization was mainly lobular (P<0.001). VEGFR2 was less frequently positive in BA than IC in bile ducts (P=0.023) and hepatocytes (P=0.011). A higher PCK7 positivity was associated with arterial (P<0.001) and biliary (P=0.040) VEGF A positivity. PCK7 was correlated with biliary (P=0.031), arterial (P=0.031), and hepatocytic (P=0.032) VEGF A positivity in BA at portoenterostomy. VEGF A was positive in arteries and bile ducts at the porta hepatis mainly in the perinatal BA type (P=0.013). Biliary (P=0.016) and arterial (P=0.044) VEGF A positivity were associated with higher ratio medial layer thickness/luminal diameter values. Our findings suggest that hypoxia/ischemia affects the portal structures in BA at portoenterostomy, beginning at the porta hepatis, and it is associated both with the extent of biliary proliferation and medial layer thickening. PMID- 21285869 TI - The epithelial mesenchymal transition process in wilms tumor: a study based on a xenograft model. AB - BACKGROUND: Until now, only a few mouse-transplanted human tumors or experimental Wilms tumor (WT) cell lines have been described. The aim of this study was to show the biological behavior, including histology, immunohistochemistry (IHC), and molecular biology, of a WT including the original tumor and metastasis transferred into nude mice and followed for successive generations in xenografts. METHODS: A WT metastasis was xenotransplanted into nude mice and the mice was monitored for 7 passages over a period of 29 months; the original neoplasm was comparatively studied. The morphology was evaluated by optical and electron microscopy. The protein expression was analyzed by immunohistochemistry in whole sections and in tissue microarray. The molecular studies were carried out by multiplex ligation-dependent probe amplification and polymerase chain reaction analysis. RESULTS: The histology changed markedly between the fourth and fifth transfer. The tumor exhibited an increased epithelial component (>40%) together with a slowing in the growth rate (8 mo). An epithelial-mesenchymal transition seemed to take place in the fourth passage and increased thereafter. The genetic studies also showed a WT5 deletion and a MYCN gain in all the tumor samples in passage 4 and beyond, but did not show E-cadherin, beta-catenin, and APC mutations. CONCLUSIONS: An epithelial pattern was associated with slow tumor growth, whereas the predominance of mesenchymal spindle cells with striated muscle cell differentiation was related with a high growth rate. The in vivo reorganization of the tumor components (blastemal, epithelial, and mesenchymal) does not seem to be related with the Wnt and EMT pathways. PMID- 21285870 TI - Expression of PAX8 in normal and neoplastic tissues: a comprehensive immunohistochemical study. AB - PAX8 is a nephric-lineage transcription factor and is a crucial transcription factor for organogenesis of the thyroid gland, kidney, and Mullerian system. PAX8 is shown to be expressed in a high percentage of kidney and ovarian carcinomas. Limited information is known about the specificity of PAX8 in various neoplastic tumors. This comprehensive study examines the immuno-histochemical expression of PAX8 in multiple normal and neoplastic tissues including renal cell carcinoma and ovarian cancers. Renal cell carcinomas stained positive for PAX8 in 90% (110 of 122) of the cases and 100% of normal kidney stained PAX8 positive. In all cases of ovarian cancers 79% (181 of 229) expressed PAX8, and in thyroid cancer, PAX8 was expressed in 90% (9 of 10) cases. In endometrial cancers, 84% (113 of 134) of the cases were positive and in cervical cancer, 98% (1 of 60) squamous cell carcinomas cases were negative and 83% (5 of 6) cervical adenocarcinomas were positive. In bladder cancers, 93% of all the cases were negative including all bladder adenocarcinomas. PAX8 expression was observed in only one case of lung cancer (99% negative) and was 100% negative in cancers of the colon, breast, prostate, liver, testicular, stomach, esophagus, melanoma, gastrointestinal stromal tumors, leiomyosarcoma, and pheochromocytoma. The PAX8 specificity has been demonstrated in over 1100 cases of normal and neoplastic tissues. PAX8 is a specific and sensitive marker for renal cell and ovarian carcinomas and should be a valuable addition to the histopathology laboratory. PMID- 21285871 TI - Utilization of unlabeled probes for the detection of fibroblast growth factor receptor 2 exons 7 and 12 mutations in endometrial carcinoma. AB - BACKGROUND: Endometrial adenocarcinomas are associated with a variety of molecular abnormalities including microsatellite instability, Kirsten rat sarcoma viral oncogene homolog mutations, and phosphatase and tensin homolog inactivation. Recently, mutations in fibroblast growth factor receptor 2 (FGFR2) have been described but their frequency and clinicopathologic characteristics are incompletely known. METHODS: To determine the frequency of mutations in FGFR2 exons 7 and 12, 43 adenocarcinomas of the endometrium were studied by high resolution melting analysis utilizing unlabeled probes and sequencing. RESULTS: Three of 43 (7%) endometrial carcinomas harbored FGFR2 exon 7 mutations. All 3 mutations were S252W and occurred in endometrioid (type I) adenocarcinomas. Direct sequencing indicated that 2 of the S252W mutations were heterozygous, whereas 1 was presumably homozygous. No FGFR2 mutations were detected in exon 12. CONCLUSIONS: FGFR2 mutations occur in approximately 7% of adenocarcinomas of the endometrium. Only carcinomas of an endometrioid morphology contain FGFR2 mutations, and in our series all were S252W. FGFR2 exons 7 and 12 unlabeled DNA probes allow for easy screening of endometrial carcinoma for the 2 most common FGFR2 mutations (S252W and N550K). Identification of these mutations may have important implications in directed molecular therapy. PMID- 21285872 TI - Patterns of bone morphogenetic protein-2 expression in smooth muscle tumors of the uterine corpus and other uterine tissues. AB - Bone morphogenetic proteins (BMPs) are extracellular, multifunctional growth factors that constitute the largest subset of the transforming growth factor beta superfamily. BMP2 is involved in cardiovascular embryogenesis, in addition to a variety of other postnatal functions, such as neovascularization, osteoinduction, tumor signaling, and in the uterus, stromal decidualization at the implantation site. Estrogen receptor signaling is common in smooth muscle tumors of the uterus, and preclinical models suggest significant interactions between BMP2 and estrogen receptor-mediated signaling. The purpose of this study is to define the patterns of BMP2 expression, as assessed by immunohistochemistry, in smooth muscle tumors and other tissues of the uterine corpus, and to establish whether BMP2 expression has any prognostic significance in uterine leiomyosarcomas. BMP2 was positive (cytoplasmic pattern, typically focal) in 24% of leiomyosarcomas and 20.7% of leiomyomata, but was either infrequently expressed or not expressed in all other tissues evaluated, including normal myometrium and endometrium, endometrial stromal tumors, typical adenomyoma, adenomyosis, and serosal endometriosis. The endothelial cells of small, thin-walled vessels were frequently, but not invariably immunoreactive for BMP2. There was no significant difference between BMP2+ and BMP- leiomyosarcomas regarding average tumor size, average patient age, microvessel density, and proportions with high tumor grade, advanced stage and frequency of death from disease on follow-up. Two (29%) of 7 BMP2+ leiomyosarcomas were estrogen receptor+, compared with 5 (50%) of 10 BMP2- leiomyosarcomas, a statistically insignificant difference (P=0.62). It is concluded that BMP2 is only expressed in a minority of smooth muscle tumors of the uterine corpus, and lacks prognostic significance in leiomyosarcomas. BMP2 is rarely expressed in the other nonendothelial tissues of the human uterine corpus that were evaluated. The significance of frequent BMP2 expression in small vessels of the uterus requires further investigation. PMID- 21285873 TI - NR2B subunit-specific NMDA antagonist Ro25-6981 inhibits the expression of conditioned fear: a comparison with the NMDA antagonist MK-801 and fluoxetine. AB - N-methyl-D-asparate (NMDA)-mediated glutamatergic neurotransmission is strongly involved in the development of trauma-induced behavioral dysfunctions, and indirect evidence suggests that NR2B subunit-expressing NMDA receptors are primarily involved in this process. Earlier studies showed that NR2B blockers inhibit the acquisition of conditioned fear, a frequently used model of post traumatic stress disorder, but their effects on the expression of conditioned fear was poorly studied. We investigated here the effects of the selective serotonin reuptake blocker, fluoxetine, the NMDA blocker, MK-801, and the NR2B subunit blocker, Ro25-6981 on the expression of conditioned fear. Rats received 10 foot shocks administered over 5 min and were tested 24 h later in the shocking context. Treatments were administered 1 h before testing. Shocks dramatically increased freezing and reduced exploration. MK-801 and Ro25-6981 significantly ameliorated both changes. The effects of fluoxetine were less pronounced. In the open field, MK-801 increased locomotion, ataxia, and stereotypy (effects typical of NMDA blockade). Neither fluoxetine nor Ro25-6981 affected locomotion in the open field. Thus, the NR2B-specific NMDA blockade preserved the beneficial effects of general NMDA antagonists on the expression of conditioned fear but did not produce the locomotor side-effects typical of the latter. These findings warrant further studies on the effects of NR2B antagonists in models of post traumatic stress disorder. PMID- 21285874 TI - Modulation of src-kinase attenuates naloxone-precipitated opioid withdrawal syndrome in mice. AB - This study was designed to investigate the effect of 2,3-dihydro-N, N-dimethyl-2 oxo-3-[(4,5,6,7-tetrahydro-1H-indol-2-yl)methylene]-1H-indole-5-sulfonamide (SU 6656), a selective inhibitor of src family kinase, on the development of naloxone induced opioid withdrawal syndrome in mice. Subacute morphine administration followed by a single injection of naloxone (8 mg/kg, intraperitoneally) was used to precipitate the opioid withdrawal syndrome in mice. Behavioral observations were made immediately after naloxone treatment. The withdrawal syndrome was quantitatively assessed in terms of withdrawal severity score and frequency of jumping, rearing, forepaw licking, and circling. Daily single administration of SU-6656 was continued during the morphine treatment procedure. Injection of naloxone precipitated severe withdrawal in morphine-dependent mice. However, once daily administration of SU-6656 (1.5, 3, and 6 mg/kg, intraperitoneally) markedly and dose-dependently attenuated the naloxone-induced morphine withdrawal syndrome. Therefore, it seems that an src family-kinase-linked mechanism is involved in the development of physiological opioid dependence; thus, src family kinase may serve as a potential target to address the pathological condition of physiological dependence and abstinence associated with continuous opioid usage. PMID- 21285875 TI - Orexin-1 receptor antagonist SB-334867 reduces the acquisition and expression of cocaine-conditioned reinforcement and the expression of amphetamine-conditioned reward. AB - Preclinical evidence suggests an important role of the brain orexin system in behaviours related to drug addiction. This study aimed at assessing the effect of the orexin-1 receptor antagonist SB-334867 on aspects of psychostimulant conditioned behaviours that are thought to contribute to the maintenance of and relapse to psychostimulant drug use. Rats were first allowed to nose poke for cocaine infusions associated with a cue light presentation (conditioned stimulus; CS) over five daily sessions. Subsequently, drug-free rats were tested for the acquisition of a new response in which presses on a novel active lever led to the presentation of the previously paired CS. We tested SB-334867 in two conditions, SB-334867 was given either before each cocaine self-administration or before the initial four sessions of acquisition for a novel instrumental responding paired with the CS (conditioned reinforcement). The effect of SB-334867 was also tested on the expression of conditioned place preference to d-amphetamine. The rats treated with SB-334867 before each cocaine self-administration session subsequently showed reduced active lever pressing compared with controls in the initial days of the conditioned reinforcement. In the second study, untreated rats showed normal acquisition of discriminated responding preferential for the lever providing the cocaine cue. In contrast, SB-334867 decreased the number of active lever pressing (compared with the control) with significant effects in all sessions. Finally, SB-334867 blocked the expression of d-amphetamine-induced conditioned place preference. These results suggest that orexin-1 receptor antagonism could offer therapeutic potential in reducing the impact of psychostimulant-predictive stimuli that contribute to compulsive drug seeking in human drug users. PMID- 21285876 TI - Cutis laxa and fatal pulmonary hypertension: a newly recognized syndrome? PMID- 21285877 TI - Predictors of edge stenosis after paclitaxel-eluting stent implantation. AB - BACKGROUND: Although edge stenosis (ES) is a main limitation of drug-eluting stents, the predictors for ES are not well known. We evaluated the predictors for ES after paclitaxel-eluting stent implantation. METHODS: One hundred and eleven angina patients (64 men; 62.2+/-8.4 years of age) were divided into ES (n=9) and non-ES groups (n=102). The clinical findings, procedural factors, and intravascular ultrasound (IVUS) parameters were analyzed. RESULTS: Although clinical characteristics were not different between groups, diabetes mellitus (DM) was more common in the ES group (P=0.002). The vessel, plaque, and lumen areas of the lesions were not different between groups; however, the vessel area of the proximal and distal reference artery was smaller in the ES group. Lesions with positive remodeling were more common in the ES group (P=0.015). On the basis of univariate analysis, predictors of ES included DM, lesions with positive remodeling, IVUS parameters, and procedural factors. After adjusting for clinical findings, angiographic factors, and IVUS parameters, the presence of DM [odds ratio (OR): 9.20; 95% confidence interval (CI): 1.40-60.62, P=0.021] and lesions with positive remodeling (OR: 5.93; 95% CI: 1.13-31.02, P=0.035) were independent predictors of ES. The lumen area in the distal 1 mm reference segment was a protective factor for ES (OR: 0.05; 95% CI: 0.00-0.74, P=0.029). CONCLUSION: The risk of ES after paclitaxel-eluting stent implantation was higher in patients who had DM and lesions with positive remodeling. Of the IVUS parameters, the lumen area in the distal 1 mm reference segment was a protective factor against ES. PMID- 21285878 TI - Determination of preferred parameters for multichannel compression using individually fitted simulated hearing AIDS and paired comparisons. AB - OBJECTIVE: To determine preferred parameters of multichannel compression using individually fitted simulated hearing aids and a method of paired comparisons. DESIGN: Fourteen participants with mild to moderate hearing loss listened via a simulated five-channel compression hearing aid fitted using the CAMEQ2-HF method to pairs of speech sounds (a male talker and a female talker) and musical sounds (a percussion instrument, orchestral classical music, and a jazz trio) presented sequentially and indicated which sound of the pair was preferred and by how much. The sounds in each pair were derived from the same token and differed along a single dimension in the type of processing applied. For the speech sounds, participants judged either pleasantness or clarity; in the latter case, the speech was presented in noise at a 2-dB signal-to-noise ratio. For musical sounds, they judged pleasantness. The parameters explored were time delay of the audio signal relative to the gain control signal (the alignment delay), compression speed (attack and release times), bandwidth (5, 7.5, or 10 kHz), and gain at high frequencies relative to that prescribed by CAMEQ2-HF. RESULTS: Pleasantness increased with increasing alignment delay only for the percussive musical sound. Clarity was not affected by alignment delay. There was a trend for pleasantness to decrease slightly with increasing bandwidth, but this was significant only for female speech with fast compression. Judged clarity was significantly higher for the 7.5- and 10-kHz bandwidths than for the 5-kHz bandwidth for both slow and fast compression and for both talker genders. Compression speed had little effect on pleasantness for 50- or 65-dB SPL input levels, but slow compression was generally judged as slightly more pleasant than fast compression for an 80-dB SPL input level. Clarity was higher for slow than for fast compression for input levels of 80 and 65 dB SPL but not for a level of 50 dB SPL. Preferences for pleasantness were approximately equal with CAMEQ2-HF gains and with gains slightly reduced at high frequencies and were lower when gains were slightly increased at high frequencies. Speech clarity was not affected by changing the gain at high frequencies. CONCLUSIONS: Effects of alignment delay were small except for the percussive sound. A wider bandwidth was slightly preferred for speech clarity. Speech clarity was slightly greater with slow compression, especially at high levels. Preferred high-frequency gains were close to or a little below those prescribed by CAMEQ2-HF. PMID- 21285879 TI - Using the auditory steady state response to record response amplitude curves. A possible fast objective method for diagnosing dead regions. AB - OBJECTIVES: To assess a novel objective method of measuring response amplitude curves (RACs) using auditory steady state responses in adults. DESIGN: RACs were recorded in 20 normal-hearing adults. The RACs were measured by recording the changes in the amplitude of the auditory steady state response in the presence of (1) swept frequency narrowband masking noise and (2) fixed narrowband masking noise. RESULTS: The mean recorded RAC tip frequency for a 2-kHz signal was 2250 Hz for the swept masker method and 2239 Hz for the fixed masker method. The estimated repeatability coefficients, calculated using an assumed mean difference of zero, were 389 Hz for the swept method and 342 Hz for the fixed method. CONCLUSIONS: These initial results indicate that the swept- and fixed-masking methods appear to be viable and fast ways to record RACs in normal-hearing adults. Further work is needed to further optimize the accuracy of the tip frequency estimation and to establish the normative range of tip frequencies over a wide range of test frequencies in normal-hearing and hearing-impaired subjects. PMID- 21285880 TI - Cocaine-related medical and trauma problems: a consecutive series of 743 patients from a multicentre study in Italy. AB - OBJECTIVE: The purpose of this retrospective study was to describe the spectrum of medical and trauma complications associated with self-reported cocaine use. METHODS: Patient databases of 23 emergency departments were searched for consultations related to cocaine use between January 2007 and December 2008. RESULTS: The population included 569 men (84.4%) and 105 women (15.6%): 505 (74.9%) patients were nondependent cocaine users and 169 (25.1%) were dependent cocaine users. The majority of patients (63.8%) used other drugs in combination with cocaine. Psychiatric symptoms were most frequently reported (60.9%), followed by cardiopulmonary (38.2%), gastrointestinal (22.5%), neurological (20.8%) and constitutional (17.2%) symptoms. Of psychiatric complaints, anxiety was the most common (31.5%). Sex-adjusted and age-adjusted odds ratio (OR) showed that palpitations were associated within 12 h of cocaine use [OR 2.05; 95% confidence interval (CI): 1.12-3.76], and psychotic symptoms (OR 3.05; 95% CI: 1.02-9.18) and hallucinations (OR 7.50; 95% CI: 1.12-50.31) were associated within more than 12 h of the use of cocaine. In a comparison of dependent and nondependent cocaine users, after adjusting for age and sex, cardiopulmonary symptoms (OR 1.56; 95% CI: 1.08-2.24) and paranoia (OR 2.14; 95% CI: 1.08-4.24) were associated with nondependent use of cocaine, and lethargy (OR 7.14; 95% CI: 1.55-35.56) was associated with dependent use of cocaine. The primary cause of trauma was unintentional injuries (32.4%). Sex-adjusted and age-adjusted OR showed a major risk for unintentional injuries with nondependent use of cocaine (OR 6.17; 95% CI: 1.38-42.29). CONCLUSIONS: The study shows that cocaine users experience diverse symptoms and may present with a wide range of physical findings. PMID- 21285881 TI - Dipstick urinalysis for the emergency department evaluation of urinary tract infections in infants aged less than 2 years. AB - BACKGROUND: The clinical diagnosis of urinary tract infection (UTI) in infants under the age of 2 years is challenging because of the nonspecific symptoms and signs in this age group. Prompt diagnosis and treatment is critical, and although dipstick testing allows rapid testing, there is some doubt about its use in infants. We sought to show the use of the dipstick test in identifying or excluding UTI in infants under the age of 2 years presenting to the emergency department with a febrile illness. METHODS: We conducted a retrospective diagnostic cohort study for over a 12-month period in a UK Paediatric Emergency Department, including all febrile children who had a urine dipstick and a quantitative culture as part of their diagnostic workup. The gold standard was the quantitative culture. RESULTS: Three hundred and twenty-one samples were eligible for inclusion. The mean age of the children included was 9.3 months. Sixty-three percent were female children. A test positive for nitrite, leucocyte esterase and blood gave a specificity of 97.12% [95% confidence interval (CI): 94.17-98.60] and a positive likelihood ratio of 15.13 (95% CI: 6.99-32.76). A test negative for nitrite, LE, blood and protein had a sensitivity of 97.44% (95% CI: 91.12-99.29) and a negative likelihood ratio of 0.10 (95% CI: 0.02-0.39). CONCLUSION: In febrile infants who were below 2 years of age, dipstick urinalysis shows promising results in identifying or ruling out a UTI. PMID- 21285882 TI - How do emergency departments in England process the results of laboratory investigations? AB - AIMS: To determine how emergency departments in England process laboratory investigation results, to identify risk, and to note examples of good practice. METHODS: A telephone survey was conducted, and data were entered anonymously into Excel spreadsheets. Fisher's exact test was used to test the independence of pairs of variables. RESULTS: Data were collected from 167 out of 193 (87%) emergency departments in England. The majority had nurse-requested blood tests. There was a statistical association between nurse-requesting and failure by the clinician seeing the patient to check results. Fourteen (8%) departments did not allow patients to leave until all their results were available. A senior doctor did a second 'safety' check of results in 83 (50%) departments. Many respondents were able to give examples of patients who had been recalled to hospital after a second check. Only a minority of departments had information systems that could identify high-risk patients. CONCLUSION: A second 'safety' check by an experienced consultant, associate specialist or middle grade doctor identifies error. This is time-consuming, but could be supported and simplified by using intelligently designed information systems. PMID- 21285883 TI - Tylosis A with squamous cell carcinoma of the oesophagus in a Spanish family. AB - Palmoplantar tylosis is a focal nonepidermolytic palmoplantar hyperkeratosis, which is inherited as an autosomal dominant condition. Two types have been described: an early onset type B tylosis, which occurs in the first year of life and is usually benign, and type A tylosis, which occurs between the ages of 5 and 15 years. Type A tylosis has been associated with a high incidence of oesophageal carcinoma in three families in England, Germany and the USA. This study describes an additional family from Spain with tylosis A, without any known relation to those described before. PMID- 21285884 TI - Serum hepcidin and prohepcidin concentrations in inflammatory bowel disease. AB - BACKGROUND: Anemia is an important complication of inflammatory bowel disease (IBD). Recent data suggest that hepcidin is a major mediator of anemia with a central role in iron homeostasis and metabolism. The aim of this study was to evaluate the serum levels of hepcidin and its prohormone, prohepcidin, in patients with IBD in comparison with healthy controls. METHODS: One hundred patients with IBD [49 ulcerative colitis (UC), 51 Crohn's disease (CD)] and 102 healthy controls were enrolled. Serum hepcidin and prohepcidin levels were measured by commercially available enzyme-linked immunosorbent assays kits. Their relationship with clinical and laboratory parameters of UC and CD was assessed. RESULTS: Median hepcidin levels were significantly higher in both patients with UC and patients with CD compared with healthy controls (P<0.0001). Median prohepcidin levels were significantly lower in patients with IBD compared with healthy controls (P = 0.03). In the univariate analysis, serum hepcidin was significantly negatively correlated (r = -0.36, P = 0.0003), whereas serum prohepcidin was positively correlated (r = 0.65, P<0.0001) with the hemoglobin levels. Significant correlations of both hepcidin (r = 0.34, P = 0.0007) and prohepcidin (r = -0.21, P = 0.04) with ferritin levels were found in patients with IBD. Serum hepcidin was also correlated with disease activity (for UC, r = 0.36, P = 0.009) and C-reactive protein (r = 0.29, P = 0.004). After multivariate analysis serum hepcidin levels remained significantly correlated with ferritin (P = 0.0008) and disease activity (for UC, P = 0.004). CONCLUSION: Serum hepcidin and prohepcidin levels are significantly altered in patients with IBD compared with healthy controls. This finding suggests a substantial role of these two hormones in the development of anemia in IBD. PMID- 21285885 TI - Prevention of hepatorenal syndrome in patients with cirrhosis and ascites: a pilot randomized control trial between pentoxifylline and placebo. AB - BACKGROUND AND AIM: Pentoxifylline is effective in prevention of hepatorenal syndrome (HRS) in alcoholic hepatitis. The aim of this study was to assess the efficacy of pentoxifylline for prophylaxis of HRS in patients with cirrhosis and ascites. MATERIALS AND METHODS: One hundred and seventy-six consecutive patients with cirrhosis and ascites were screened. Patients with creatinine clearance (Ccl) between 41 and 80 ml/min and serum creatinine of less than 1.5 mg/dl in absence of renal disease were randomized to receive either pentoxifylline (group A, 1200 mg/day) or placebo (group B) for 6 months. Patients were followed monthly for 6 months, and kidney function tests were carried out at baseline, 1, 3, and 6 months. Primary endpoint was the development of HRS within 6-month follow-up. RESULTS: Thirty-five patients each were randomized to group A and group B. Of the 70 patients, 61 completed follow-up (group A, n = 30 and group B, n = 31). In group A, serum creatinine remained stable at 1 month (0.94+/-0.2 vs. 0.90+/-0.4 mg/dl, P = 0.43), at 3 months (0.94+/-0.2 vs. 0.80+/-0.3 mg/dl, P = 0.10), and at 6 months (0.94+/-0.2 vs. 0.8+/-0.2 mg/dl, P = 0.06). Improvement occurred in Ccl at 1 month (61.7+/-16.0 vs. 82.0+/-30.0 ml/min, P = 0.001) and at 3 months (61.7+/-16.0 vs. 86.2+/-30.7 ml/min, P = 0.001). Serum sodium in group A showed progressive improvement at 1 month (134.7+/-4.4 vs. 137.0+/-5.3 mmol/l, P = 0.006), at 3 months (134.7+/-4.4 vs. 138.4+/-5.4 mmol/l, P = 0.004), and at 6 months (134.7+/-4.4 vs. 137.6+/-4.9 mmol/l, P = 0.009). Similarly, mean arterial pressure (MAP) also showed progressive improvement at 1 month (76.7+/-6.7 vs. 81.8+/-6.9 mmHg, P = 0.001), at 3 months (76.7+/-6.7 vs.82.3+/-6.2 mmHg, P = 0.001), and at 6 months (76.7+/-6.7 vs. 82.6+/-6.1 mmHg, P = 0.01). Tumor necrosis factor (TNF) level measured at baseline and at 3 months (14.4+/-4.8 vs. 13.1+/-3.7 pg/ml, P = 0.28) showed no difference in group A patients. In group B, serum creatinine increased gradually at 1 month (0.80+/-0.2 vs. 1.0+/-0.2 mg/dl, P = 0.007), at 3 months (0.80+/-0.2 vs. 1.1+/-0.3 mg/dl, P = 0.001), and at 6 months (0.80+/-0.2 vs.1.1+/-0.2 mg/dl, P = 0.001). Ccl at 1 month (63.1+/-14.5 vs. 66.8+/-28.2 ml/min, P = 0.37) decreased at 3 months (63.1+/-14.5 vs. 54.4+/ 18.3 ml/min, P = 0.008). Serum sodium, in group B, showed progressive decline at 1 month (136.2+/-5.0 vs. 132.7+/-3.2 mmol/l, P = 0.02) and at 6 months (136.2+/ 5.0 vs. 132.7+/-3.4 mmol/l, P = 0.002). MAP remained stable at 1 month (75.1+/ 7.5 vs. 75.3.8+/-5.1 mmHg, P = 0.86), at 3 months (75.1+/-7.5 vs. 73.2+/-4.6 mmHg, P = 0.19), and at 6 months (75.1+/-7.5 vs. 74.1+/-6.1 mmHg, P = 0.06). TNF level also did not show any change at baseline and at 3 months (14.5+/-6.8 vs. 13.4+/-5.1 pg/ml, P = 0.31). Of the 12 patients who developed HRS, 10 patients were in group B (type 1 HRS, n = 9 and type 2 HRS, n = 1) and two patients (type 1 HRS, n = 2) were in group A (P = 0.01). Patients with HRS had higher baseline TNF-alpha (15.3+/-5.8 vs. 10.9+/-4.8 pg/ml, P = 0.01), lower MAP (68.0+/-3.8 vs. 77.8+/-6.5 mmHg, P = 0.01), and sodium level (131.2+/-3.0 vs. 135.6+/-4.7 mmol/l, P = 0.003) than those who did not develop HRS. CONCLUSION: Pentoxifylline is effective in preventing HRS in patients with cirrhosis and ascites at risk of HRS. PMID- 21285886 TI - Array comparative genomic hybridization analysis in patients with anophthalmia, microphthalmia, and coloboma. AB - PURPOSE: The goal of our study was to determine whether genomic copy number abnormalities (deletions and duplications) affecting genes involved in eye development contributed to the etiology of anophthalmia, microphthalmia, and coloboma. METHODS: The affected individuals were evaluated for the presence of deletions and duplications in genomic DNA by a very high-resolution array comparative genomic hybridization. RESULTS: Array analysis of 32 patients detected one case with a deletion encompassing the renal-coloboma syndrome associated gene PAX2. Nonpolymorphic copy number changes were also observed at several candidate chromosomal regions, including 6p12.3, 8q23.1q23.2, 13q31.3, 15q11.2q13.1, 16p13.13, and 20q13.13. CONCLUSIONS: This study identified the first patient with the typical phenotype of the renal-coloboma syndrome caused by a submicroscopic deletion of the coding region of the PAX2 gene. The finding suggests that PAX2 deletion testing should be performed in addition to gene sequencing as a part of molecular evaluation for the renal-coloboma syndrome. Array comparative genomic hybridization testing of 32 affected individuals showed that genomic deletions and duplications are not a common cause of nonsyndromic anophthalmia, microphthalmia, or coloboma but undoubtedly contribute to the etiology of these eye anomalies. Therefore, array comparative genomic hybridization testing represents an important and valuable addition to candidate gene sequencing in research and diagnostics of ocular birth defects. PMID- 21285887 TI - Impact of presymptomatic genetic testing for familial amyotrophic lateral sclerosis. AB - PURPOSE: The Pre-familial Amyotrophic Lateral Sclerosis (Pre-fALS) study is a longitudinal study of individuals potentially at risk for developing familial amyotrophic lateral sclerosis. Our goals were to (1) explore participants' decisions of whether to learn results of presymptomatic testing or not; (2) understand the psychosocial impact of these decisions; and (3) assess preferences for receiving results by telephone or in person. METHODS: The sample for this substudy comprised 20 participants drawn randomly from autosomal dominant mutant superoxide dismutase 1 families in the Pre-fALS study. Twenty participants completed a semistructured phone interview; prominent themes were identified and rated. RESULTS: Fourteen participants chose to learn results; six had mutant superoxide dismutase 1 and eight had wild-type superoxide dismutase 1. Of the six who initially elected nondisclosure, three were reconsidering their decision. Regardless of the results and method of counseling, participants had adapted well, at least in the short term. CONCLUSION: We recommend that (1) those considering presymptomatic genetic testing should undergo professional counseling to help decide whether to learn results; (2) discussion should include the option of telephone genetic counseling for those without easy access to in-person counseling; and (3) those who initially decline to learn results should be offered the opportunity to learn their mutation status as their decision evolves. PMID- 21285888 TI - Treatment monitoring in gliomas: comparison of dynamic susceptibility-weighted contrast-enhanced and spectroscopic MRI techniques for identifying treatment failure. AB - OBJECTIVE: To evaluate whether dynamic susceptibility-weighted contrast-enhanced (DSC), dynamic contrast-enhanced (DCE), and proton spectroscopic imaging ((1)H MRSI) can identify progression and predict treatment failure during follow-up before tumor size changes, contrast agent uptake, or when new lesions become obvious. The aim was also to find out which of the aforementioned techniques had the best diagnostic performance compared with each other and standard magnetic resonance imaging (MRI). MATERIALS AND METHODS: Thirty-seven patients with gliomas (21 women, 16 men; mean age at inclusion, 48 +/- 14 years [standard deviation]) were assessed prospectively by (1)H-MRSI (point-resolved spectroscopy), DCE, and DSC perfusion MRI, each after a single dose of gadobenate dimeglumine during follow-up. Histology was available in all cases (resection, N = 18; biopsy, N = 19). All patients with low-grade gliomas (n = 20) did not receive any radio- or chemotherapy after partial resection (n = 7) or biopsy (n = 13), whereas 17 patients with high-grade gliomas had received adjuvant radiotherapy immediately after surgery. Tumor progression (progressive disease, PD) was defined as increase in longest glioma diameter by at least 20% (Response Evaluation Criteria in Solid Tumors), appearance of new lesions, or new contrast enhancement. DSC, DCE, and MRSI image analyses comprised a detailed semiquantitative region of interest (ROI) analysis of the different parameters. Wilcoxon signed-rank test, Wilcoxon rank sum test, and Cox regression were used for statistical analysis. RESULTS: The median follow-up time was 607 days. Twenty patients showed PD (54%), 8 of 20 with low-grade (40%) and 12 of 17 with high grade gliomas (71%). In PD, significant positive differences between log2 transformed ROI ratios at the last measurement in comparison to the first measurement (baseline) could be detected for tumor blood flow (P < 0.006) and volume (P < 0.001) derived from DSC and for maximum choline within tumor tissue (P = 0.0029) and Cho/Cr (P = 0.032) but not choline/N-acetyl-aspartate (P = 0.37) derived from MRSI. In contrast, these parameters were not significantly higher at last measurement in stable disease. Also, the differences between last value and baseline were significantly different between PD and stable disease for tumor blood flow (P < 0.004) and volume (P < 0.002) as well as for maximum choline within tumor tissue (P = 0.0011). The best prognostic parameter for PD at Cox analysis was time-dependent difference to baseline of log2 of relative regional cerebral blood flow normalized on gray matter (hazard ratio, 2.67; 95% confidence interval, 1.25-6.08; P = 0.01), while a prognostic value of MRS parameters could not be demonstrated. CONCLUSION: DSC perfusion imaging can identify progression and can predict treatment failure during follow-up of gliomas with the best diagnostic performance. PMID- 21285889 TI - Evaluation of the effect of two gadolinium-containing contrast-enhancing agents, gadobutrol and gadoxetate disodium, on colorimetric calcium determinations in serum and plasma. AB - OBJECTIVE: To determine the extent to which the gadolinium-containing contrast agents, gadobutrol (Gadovist) and gadoxetate disodium (Primovist/Eovist), interfere with the colorimetric measurement of calcium concentrations in serum and plasma. MATERIALS AND METHODS: Gadobutrol and gadoxetate disodium were added in various concentrations to serum and plasma from healthy volunteers; the calcium concentration in these samples was then measured by standard colorimetry methods and atomic absorption. RESULTS: At clinically relevant concentrations, neither gadobutrol nor gadoxetate disodium influenced the results of the calcium measurement in serum or plasma. Only at the highest concentrations tested (50 mM gadobutrol; 25 mM gadoxetate disodium), an effect was seen in some cases. Results were confirmed by atomic absorption spectroscopy as the reference method. CONCLUSIONS: At clinically relevant concentrations, gadobutrol and gadoxetate disodium did not interfere with standard colorimetric methods for calcium determination. PMID- 21285890 TI - Dose response to Paclitaxel-coated balloon catheters in the porcine coronary overstretch and stent implantation model. AB - OBJECTIVE: There is little published information regarding the efficacy of paclitaxel-coated balloon catheters except for the iopromide-containing formulation, and less is known about the kind of toxicity at overdose. The aim of our study was to assess 2 different paclitaxel matrix formulations on angioplasty balloon catheters in vitro, with respect to pharmacokinetics, and efficacy and tolerance to determine the minimum effective dose and local toxicity at extremely high dose which is only achieved in experimental studies. METHODS AND MATERIALS: Adherence of coatings was tested in vitro in dry state and during passage through hemostatic valves, guiding catheters, and blood. Drug release, transfer to the vessel wall during coronary angioplasty, inhibition of neointimal proliferation, and tolerance were investigated in swine. Efficacy and tolerance of balloons were examined for doses ranging from 1 to 9 MUg/mm2 and 3 overlapping applications of balloons coated with 3 times the regular dose of 3 MUg/mm2. Paclitaxel concentrations were determined by high performance liquid chromatography, efficacy and tolerance by vital signs, clinical observation, quantitative coronary angiography, and histomorphometry 4 weeks after implanting premounted bare stents in coronary arteries applying 1:1.2 overstretch. RESULTS: Under worst case conditions, drug loss on the way through the guiding catheter and blood was in the range of 30%. After inflation of balloons coated with the clinically tested dose of 3 MUg/mm2 in a coronary artery about 10% of drug remained on balloons, 20% to 30% was taken up into the vessel wall (~200 MUg). Neointimal area on cross sections was 6.8 +/- 2.2 mm2 (uncoated control); 3.1 +/- 1.1 mm2 (iopromide-matrix) and 3.0 +/- 0.5 mm2 (urea-matrix) at 1 MUg/mm2; 2.0 +/- 0.4 mm2 versus 1.7 +/- 1.1 mm2 at 3 MUg/mm2 with no further decrease at higher doses. Thrombotic occlusions were observed in 3 of 15 vessel segments treated with overlapping inflations of 3 high-dose balloons but without any signs of aneurysms. CONCLUSION: In the animal model, 2 paclitaxel matrix formulations were similar in respect of uptake in the vessel wall, and effective already at a dose of 1 MUg/mm2. Except thrombotic events for the intentionally excessive dose, paclitaxel-coated balloons were well tolerated in the animal model. PMID- 21285891 TI - 3D fusion of functional cardiac magnetic resonance imaging and computed tomography coronary angiography: accuracy and added clinical value. AB - PURPOSE: To evaluate the accuracy and added diagnostic value of 3-dimensional (3D) image fusion of computed tomography coronary angiography (CTCA) and functional cardiac magnetic resonance (CMR) for assessing hemodynamically relevant coronary artery disease (CAD). METHODS: Twenty-seven patients with significant coronary stenoses on prospectively electrocardiography-gated dual source CTCA, confirmed by catheter angiography and perfusion defects on CMR at 1.5 T were included. Surface representations and volume-rendered images from 3D fused CTCA/CMR data were generated using a software prototype. Fusion accuracy was evaluated by calculating surface distances of blood pools and Dice similarity coefficients. Two independent, blinded readers assigned myocardial defects to culprit coronary arteries with side-by side analysis of CTCA and CMR and using fused CTCA/CMR. Added value of fused CTCA/CMR was defined as change in assignment of culprit coronary artery to myocardial defect compared with side-by-side analysis. RESULTS: 3D fusion of CTCA/CMR was feasible and accurate (surface distance of blood pools: 4.1 +/- 1.3 mm, range: 2.4-7.1 mm; Dice similarity coefficients: 0.78 +/- 0.08, range: 0.51-0.86) in all patients. Side-by-side analysis of CTCA and CMR allowed no assignment of a single culprit artery to a myocardial defect in 6 of 27 (22%) patients. Fused CTCA/CMR allowed further confinement of culprit coronary arteries in 3 of these 6 patients (11%). Myocardial defects were reassigned in 2 of 27 (7%) patients using fused CTCA/CMR, whereas the results remained unchanged in 22 of 27 (81%) patients. Interobserver agreement for assignment of culprit arteries to myocardial defects increased with fused CTCA/CMR (k = 0.66-0.89). CONCLUSION: 3D fusion of low-dose CTCA and functional CMR is feasible and accurate, and adds, at a low radiation dose, diagnostic value for the assessment of hemodynamically relevant CAD as compared with side-by-side analysis alone. This technique can be clinically useful for the following: planning of surgical or interventional procedures in patients having a high prevalence of CAD and for improved topographic assignment of coronary stenoses to corresponding myocardial perfusion defects. PMID- 21285892 TI - Aortic hemodynamics in patients with and without repair of aortic coarctation: in vivo analysis by 4D flow-sensitive magnetic resonance imaging. AB - OBJECTIVES: The purpose of this study was to characterize hemodynamic alterations and flow-derived vessel wall parameters in aortic coarctation (CoA) patients with and without operative repair by time-resolved, 3-dimensional, and 3-directional velocity sensitive, phase-contrast magnetic resonance imaging (4D PC MRI) in comparison with healthy subjects. METHODS AND MATERIAL: Twenty-four patients, 12.5 +/- 6.4 years after CoA repair, 4 patients without treatment for CoA, and 19 healthy subjects were examined. The study was approved by the institutional review board and signature of written informed consent was obtained from the participants. Echocardiography was performed in patients before participation. MRI studies were conducted by applying flow-sensitive 4D phase-contrast MRI at either 1.5 T (n = 5 patients) or 3 T (all 19 healthy subjects, n = 23 patients). Blood flow visualization was used to evaluate overall aortic helicity, presence of pronounced or additional localized helix flow, and vortex development. Quantitative evaluation comprised the calculation of regional time-averaged absolute wall shear stress (WSS(mag)), peak velocities, and oscillatory shear index at 8 locations distributed along the thoracic aorta and additionally at the site of CoA. Inter- and intraobserver variabilities of calculations were determined. RESULTS: Volunteers and patients demonstrated the same amount of overall aortic helicity. In contrast, the number of additional localized helix flow or vortex formation was significantly increased in patients (25/28 patients vs. 5/19 normal controls, Fisher exact test: P < 0.001). Vortices in the orifices of the supra-aortic branches were detected in 64.3% (18/28) of patients but in only 11.8% (2/19) of controls (P < 0.001). Quantitative analyses revealed a significant increase in overall aortic WSS(mag) (0.44 +/- 0.17 N/m(2) in patients vs. 0.27 +/- 0.08 N/m(2) in volunteers, P < 0.005) and a decrease in overall oscillatory shear index. Repeated quantitative analysis showed moderate interobserver and low intraobserver variability. Correlation with echocardiography showed good agreement with MRI which tended to underestimate peak velocities (r = 0.76; Bland-Altman analysis, limits of agreement = -0.57 2.16 m/s, mean = 0.79 m/s). CONCLUSION: Alterations in aortic hemodynamics after CoA repair are not limited to the specific region of repair, but can be found in the entire aorta. The presented findings highlight the systemic nature of the disease and the need for a systemic diagnostic approach which can be provided by flow-sensitive 4D PC MRI. Furthermore, valuable additional insights on the hemodynamic consequences of coarctation have been shown that may help understanding secondary complications such as restenosis, aneurysm formation, and arterial hypertension. PMID- 21285893 TI - Cognitive impairment as a mediator in the developmental pathway from infant malnutrition to adolescent depressive symptoms in Barbadian youth. AB - OBJECTIVE: Depressive symptoms are elevated in adolescents who experienced significant malnutrition early in life. Early malnutrition can also have a significant impact on cognitive functioning, presumably because of the adverse impact of the malnutrition on the very young brain. In the context of a developmental cascade model, we tested the hypothesis that the association between early malnutrition and adolescent depressive symptoms is mediated by the cognitive impairment that ensues from the malnutrition. METHODS: We evaluated Barbadian youth (N = 57) hospitalized for moderate to severe protein-energy malnutrition in the first year of life and healthy controls (N = 60) longitudinally. The primary hypothesis was tested by multiple regression models. RESULTS: After adjusting for covariates, early malnutrition predicted both cognitive functioning in childhood (IQ, p < .001; attention problems, p < .01; Common Entrance Examination, p < .01; and adolescent depressive symptoms, p < .05). Childhood cognitive functioning mediated the association between early malnutrition and depressive symptoms in adolescence (p < .001). Maternal depressive symptoms were a significant but independent predictor of adolescent depressive symptoms (p < .05). CONCLUSIONS: Cognitive compromise in childhood accounts indirectly for elevated depressive symptoms in previously malnourished adolescents, consistent with a developmental cascade model. The direct link between malnutrition and depressive symptoms in adolescence is small. PMID- 21285894 TI - Social participation in a nationally representative sample of older youth and young adults with autism. AB - OBJECTIVE: To describe social participation and identify factors that affect it in a nationally representative sample of adolescents and young adults with autism. METHODS: Longitudinal cohort study using data from the National Longitudinal Transition Study-2. The World Health Organization International Classification of Functioning, Disability, and Health model was used with participation as the dependent category. RESULTS: A nationally representative sample of 725 youth with autism representing a weighted sample of 21,010 individuals was followed up for 4 years. The mean age at first interview was 15.4 years and 19.2 years at follow-up. More than half the youth at follow-up had not gotten together with friends in the previous year and 64% had not talked on the phone with a friend. Being employed or in secondary education was associated with the following factors (odds ratios): problems conversing (0.67), being teased (0.17), mental retardation (0.06), being above the poverty level (4.17), not using prescription medicine (4.11), general health status (2.30), and parental involvement with school (1.69) (all p < .001). CONCLUSIONS: Many adolescents and young adults with autism become increasingly isolated. Although each aspect of social participation had its own distinct pattern of factors related to it, the ability to communicate effectively, less severe autism, coming from an environment that was not impoverished and having parents who advocated were associated with more positive outcomes. These data provide insights into the factors that affect the participation of youth with autism during their transition years and should ultimately lead to interventions that could improve those transitions. PMID- 21285895 TI - Consequences, characteristics, and causes of mathematical learning disabilities and persistent low achievement in mathematics. AB - The goals of the review are threefold: (a) to highlight the educational and employment consequences of poorly developed mathematical competencies; (b) overview the characteristics of children with mathematical learning disability (MLD) and with persistently low achievement (LA) in mathematics; and (c) provide a primer on cognitive science research that is aimed at identifying the cognitive mechanisms underlying these learning disabilities and associated cognitive interventions. Literatures on the educational and economic consequences of poor mathematics achievement were reviewed and integrated with reviews of epidemiological, behavioral genetic, and cognitive science studies of poor mathematics achievement. Poor mathematical competencies are common among adults and result in employment difficulties and difficulties in many common day-to-day activities. Among students, ~ 7% of children and adolescents have MLD and another 10% show persistent LA in mathematics, despite average abilities in most other areas. Children with MLD and their LA peers have deficits in understanding and representing numerical magnitude, difficulties retrieving basic arithmetic facts from long-term memory, and delays in learning mathematical procedures. These deficits and delays cannot be attributed to intelligence but are related to working memory deficits for children with MLD, but not LA children. These individuals have identifiable number and memory delays and deficits that seem to be specific to mathematics learning. Interventions that target these cognitive deficits are in development and preliminary results are promising. PMID- 21285896 TI - Novel use of zolpidem in cerebellar mutism syndrome. AB - Cerebellar mutism syndrome (CMS) is a complication of posterior fossa surgery seen primarily in pediatric patients after resection of medulloblastoma. CMS is characterized by mutism, ataxia, hypotonia, and irritability. Currently, there is no therapy of proven efficacy. Zolpidem, although primarily used as a sedative, has been shown to alleviate mutism and promote arousal in similar neurologic and psychiatric disorders. Here, we describe a child with severe CMS in whom zolpidem seemed to increase arousal, accelerate the resolution of mutism, and decrease emotional lability. Our report suggests that clinicians should consider using zolpidem for patients with CMS. PMID- 21285897 TI - The investigation of gingival iron accumulation in thalassemia major patients. AB - BACKGROUND: Thalassemia major (TM) is an autosomal-recessive genetic blood disorder. Regular blood transfusions to improve chronic anemia caused by ineffective erythropoiesis and hemolysis lead to iron overload in many organs in TM patients. The aim of this study was to investigate the periodontal status and the iron accumulation in gingival tissues of TM patients and assess whether iron deposition in gingival biopsies could be an alternative method for the diagnosis of body iron overload in TM patients. MATERIALS AND METHODS: This study was conducted on 22 TM patients and 20 healthy matched controls. Plaque index, gingival index, and probing pocket depth were measured and gingival biopsies were obtained in all subjects. Venous blood samplings and liver biopsies were carried out only in patients with thalassemia. Gingiva and liver tissue samples were evaluated histopathologically for inflammation, iron accumulation, and fibrosis. RESULTS: There was no difference between the groups regarding periodontal health, and all patients had mild gingivitis. Gingival iron accumulation was observed only in the TM group. The iron accumulation was detected in the liver of all the patients with thalassemia. The gingival iron accumulation was correlated with neither serum ferritin levels nor hepatic iron accumulations. CONCLUSIONS: The periodontal tissues are affected by iron accumulation as well as hepatic, cardiac, and endocrine tissues in TM patients. Further studies investigating the usage of the gingival biopsy for prediagnosis of body iron overload in TM patients are needed. PMID- 21285898 TI - Hydrochloric acid treatment of tunneled central venous catheter infections in children with cancer. AB - BACKGROUND: Long-term tunneled central venous catheters (CVCs) are often the source of catheter-associated bloodstream infections (CABSIs), which may be difficult to eradicate and may lead to premature catheter removal. PROCEDURE: This prospective controlled study used instillation of 2 M hydrochloric acid (HCl) as an adjuvant to the intravenous antibiotic treatment of children with bacteremia and compared the results with those from the immediate preceding period. The primary outcome variable was infection-related CVC removal within 100 days of bacteremia. Only patients with double lumen Hickman CVC with external tubings were included. RESULTS: During a period of 36 months, 109 episodes of bacteremia were treated, 51 during the period where HCl was not used and 58 during the period where HCl was used. Forty-two out of 58 bacteremias were treated with HCl during the "HCl period." An intention-to-treat analysis showed that the median time to infection-related CVC removal was significantly longer during the HCl period compared with the non-HCl period (94 d vs. 12.5 d). At day 100 significantly more CVCs remained in place compared with the non-HCl period. Of the 42 CVCs treated with HCl, 2 had to be removed because of infection before day 30 and further 7 CVCs were removed before day 100. There was no difference in the occurrence of new bacteremias within the first 30 days of bacteremia in the 2 groups. CONCLUSION: HCl may successfully supplement intravenous antibiotics in the treatment of CABSI and contribute to CVC salvage. PMID- 21285899 TI - Diagnostic and follow-up eosinophilia is not predictive of outcome in childhood acute myeloid leukemia. AB - BACKGROUND: Peripheral blood eosinophilia (PBE) and bone marrow eosinophilia (BME) are associated with various tumors. Eosinophilia is frequently paraclonal (because of cytokines and not part of the malignant clone), but in some cases of acute myeloid leukemia (AML), it may also be clonal. METHODS: We retrospectively evaluated 80 pediatric AML patients treated from June 2004 to December 2008 at our cancer center for PBE and BME at diagnosis and postinduction. RESULTS: At diagnosis, PBE was present in 18.8% patients whereas at postinduction it was observed in 7.7% patients. No patient had abnormal eosinophils. At diagnosis, PBE correlated with the absence of gum hypertrophy whereas BME correlated with the French-American-British-M2 subtype and absence of gum hypertrophy. PBE/BME did not have a significant correlation with event-free survival. After completion of therapy, on follow-up up to 2 years every 3 months, one-third of the patients had eosinophilia; however, it did not correlate with disease-free survival. CONCLUSIONS: This is the first study to evaluate the impact of eosinophilia at presentation, postinduction, and on follow-up with outcome in pediatric AML. Although eosinophilia was observed in one-fifth of the patients at diagnosis and in one-third of the patients on follow-up, it seems to be reactive in nature with no impact on outcome and thus it should not be a cause of alarm. PMID- 21285900 TI - Adolescent hodgkin lymphoma: are treatment results more favorable with pediatric than with adult regimens? AB - BACKGROUND: The aim of our work was to compare the treatment modalities and the survival rates in adolescents (14 to 21 y) with Hodgkin lymphoma (HL) treated with adult (A) or with pediatric (P) regimens. PROCEDURE: From January 1990 to December 2004, 134 (A) and 111 (P) adolescents with HL were treated. Male:female ratio was 1:1.48 (A) and 1:1.36 (P), the mean-age 18.6 (A) and 15.8 years (P), respectively. RESULTS: The patients were treated either with doxorubicin, bleomycin, vinblastine and dacarbazine (A) or with OPPA/OEPA +/- COPP regimens (P). About 82% (A) and 89% (P) of the patients received radiotherapy. Relapse rates were 13% (A) and 14% (P). Fourteen patients died in group (A) and 9 in group (P). There were no significant differences in the overall survival and event-free survival rates at 5 and 10 years between the 2 patient's groups. For children under age of 18 years old overall survival was 92.8 +/- 3% at 5 and 89.6 +/- 3% at 10 years in group (P) and 89.4 +/- 4% at 5 years and 83.1 +/- 6% at 10 years (P=0.2822) in group (A). For children under the age of 18 years event-free survival was 82.4 +/- 4% at 5 and 10 years in group (P) and 69.6 +/- 7% at 5 years and 59.1 +/- 8% at 10 years (P=0.0192) in group (A). CONCLUSION: In case of the patients younger than 18 years, the survival rates are more favorable by using pediatric regimens, so these patients might have a benefit if they are treated in pediatric institutes. PMID- 21285901 TI - Thiamine-responsive megaloblastic anemia syndrome with atrial standstill: a case report. AB - Thiamine-responsive megaloblastic anemia (TRMA) syndrome is an uncommon autosomal recessive disorder. The disease is caused by mutations in the gene, SLC19A2, encoding a high-affinity thiamine transporter, which disturbs the active thiamine uptake into cells. Major features include megaloblastic anemia, diabetes mellitus, and sensorineural deafness. Cardiac malformations with conduction defects and/or dysrhythmias, have also been described in some patients. To our knowledge, only 13 TRMA patients with cardiac defects have been reported. Here, we describe the first case of TRMA syndrome with atrial standstill, probably caused by a 2 base-pair deletion in exon 4 (1147delGT) of the gene SLC19A2. PMID- 21285902 TI - Antithymocyte globulin-induced acute lung injury during transplantation for aplastic anemia. AB - A 10-year-old boy with acquired, very severe aplastic anemia developed acute lung injury after the administration of equine antithymocyte globulin, during conditioning for allogenic bone marrow transplantation. Limited cases of antithymocyte globulin-induced acute lung injury have been described in adults. The respiratory worsening was sudden and required mechanical ventilation. The clinical course was complicated by sepsis with Escherichia coli, vancomycin resistant enterococci, and Stenotrophomonas maltophilia. Implications for treatment are discussed and earlier literature is reviewed. PMID- 21285903 TI - Mesenteric venous thrombosis in a child with type 2 protein S deficiency. AB - A 5-year-old girl presented with abdominal pain and bloody stools 2 weeks after suffering from influenza A infection. Enhanced computed tomographic scan showed widespread splanchnic venous thrombosis and small intestine necrosis. She recovered after the necrotic bowel was resected. The patient continues to receive anticoagulant therapy. Thrombophilia screening after the complete resolution consistently showed mildly decreased protein S (PS) activity with normal PS antigen levels. Sequence analysis detected a heterozygous K196E mutation in the PROS1 gene. Type 2 PS deficiency was diagnosed. This is the first report of mesenteric vein thrombosis in a child with a type 2 PS deficiency. PMID- 21285904 TI - Nephrotoxicity--what do we know and what don't we know? AB - Nephrotoxicity is the development of functional or structural kidney damage after exposure to one or more of a wide variety of drugs, other treatments or exogenous toxins, and may lead to a variety of functional consequences and structural lesions. Nephrotoxicity is important as it may occur in a substantial proportion of children treated with certain drugs and occasionally lead to severe renal impairment that may prevent the delivery of optimal anticancer treatment and/or reduce the quality of life of long-term survivors. This article describes what is currently known about nephrotoxicity occurring in children treated for malignancy by summarizing published information about the clinical characteristics and long term outcome of, and the risk factors for the development of, ifosfamide and platinum-induced renal toxicity. Published guidelines for the evaluation and surveillance of nephrotoxicity, and the still incomplete understanding of its pathogenesis, are also outlined. Many gaps in our knowledge of nephrotoxicity are highlighted, including the lack of detailed knowledge about its overall incidence and very long-term impact, the nephrotoxic potential of new drugs, the efficacy of surveillance protocols, the relevance of proteinuria as a component of nephrotoxicity, and our current inability to reliably predict or prevent many episodes of nephrotoxicity. PMID- 21285905 TI - A case of syndromic neutropenia and mutation in G6PC3. AB - BACKGROUND: A previously unrecognized syndrome with congenital neutropenia and various organ abnormalities has been described recently, caused by mutations in the gene encoding glucose-6-phosphatase, catalytic subunit 3 (G6PC3). OBSERVATION: A 10-year-old boy from Ecuador suffering from severe neutropenia and multiple nonhematopoietic abnormalities was admitted to our department. We identified a novel mutation in the G6PC3 gene (c. 765_delAG; p.S255fs). CONCLUSIONS: This is the first case of G6PC3 deficiency in a patient from South America, caused by a novel mutation in the G6PC3 gene. Our results give insights into the molecular and clinical variability of this disease. PMID- 21285906 TI - Hemophagocytic lymphohistiocytosis associated with 2009 pandemic influenza A (H1N1) virus infection. AB - Hemophagocytic lymphohistiocytosis (HLH) has not been described earlier in the context of 2009 pandemic influenza A (H1N1) virus infection, although certain populations are thought to be at risk for complicated pandemic influenza A disease. Here, we report the second case of HLH after infection with the influenza A H1N1 virus treated with peroral oseltamivir successfully. PMID- 21285907 TI - Managing painful procedures in children with cancer. AB - Children with cancer experience repeated invasive and painful medical procedures. Pain and distress does not decrease with repeated procedures and may worsen if pain is not adequately managed. In 1990, the first recommendations on the management of pain and anxiety associated with procedures for children with cancer were published. Guiding principles described in the recommendations continue to hold true today: maximize comfort and minimize pain, use nonpharmacologic and pharmacologic interventions, prepare the child and family, consider the developmental age of the child, support family and child involvement, assure provider competency in performing procedures and sedation, and use appropriate monitoring to assure safety. This article reviews these key components for managing painful procedures in children and reviews the latest pharmacological and nonpharmacological interventions most effective in minimizing pain and discomfort. PMID- 21285908 TI - Extracardiac abnormalities on rubidium-82 cardiac positron emission tomography/computed tomography. AB - BACKGROUND: The role of rubidium-82 (Rb) in recognizing extracardiac diseases is minimally investigated. The aim of this study was to evaluate the frequency and incremental added value of extracardiac findings on Rb cardiac positron emission tomography/computed tomography (PET/CT) studies. METHOD: The study included all consecutive patients who were referred from July 2008 to June 2010 for Rb cardiac PET/CT to our institution. A blinded reader reviewed the images retrospectively to assess abnormal extracardiac PET findings. RESULTS: Images of 406 patients (142 men; 264 women) with a mean age+/-standard deviation of 59.72+/-12.93 years (range: 18-91 years) were reviewed. Incidental extracardiac abnormalities were found in 67 of 406 patients (16.5%). Among them, eight patients had malignant etiologies (1.9%). CONCLUSION: Incidental extracardiac findings were present in a significant portion of patients undergoing Rb cardiac PET/CT studies. Although most of the extracardiac findings on Rb cardiac PET/CT studies represented clinically known pathologies, these incidental findings on routine Rb cardiac PET/CT scans may have a significant clinical impact on a small number of patients, and offer the referring physician the chance to obtain additional clinically relevant information. PMID- 21285909 TI - Radiolabeling of fab and f(ab')2 antibody fragments with 99mTc(I) tricarbonyl core using a new bifunctional tridentate ligand. AB - The objective of this study was to design and evaluate a new histidine-modified tridentate chelator for labeling antimesothelin fab and f(ab')2 antibody fragments with the Tc(I) tricarbonyl ([Tc(CO)3]) core. N-(ortho-phenol)-histidine chelator was synthesized by modifying the single amino acid L-histidine, a natural amino acid, with an additional phenol group to obtain the bifunctional tridentate ligand after reductive amination. Bioconjugation was based on the carbodiimide activation of the carboxylate of chelator and on further reaction with the amine groups present on the antibody fragments. Radiolabeling was accomplished by replacing the three aqua ligands of the complex precursor [Tc(CO)3(H2O)3] with the tridentate chelator. The antibody fragments radiolabeled with [Tc(CO)3] core were tested for stability by the cysteine challenge test. The immunoreactivity and binding affinity of the radiolabeled fragments were studied using in-vitro cell-binding assays. Radiochemical yields achieved for [Tc(CO)3] core labeling of fab and f(ab')2 were 91.6+/-9.1% and 80.7+/-8.5%, respectively. Stability studies of radiolabeled antibody fragments showed that the Tc label was stable to transchelation by cysteine. Both Tc-fab and Tc-f(ab')2 retained their reactivity and affinity to the mesothelin antigen. From our studies, it can be concluded that the newly synthesized N-(ortho-phenol)-histidine chelator is a promising candidate for [Tc(CO)3] labeling of biomolecules and for developing other novel Tc radiopharmaceuticals. PMID- 21285910 TI - Limiting the damage from acute kidney injury. PMID- 21285911 TI - Take the road less traveled. PMID- 21285912 TI - First global summit of national plastic surgery societies: joint statement. AB - This article constitutes the joint statement from the plastic surgery societies of Australia, Belgium, Brazil, France, Great Britain, New Zealand, South Africa, South Korea, Switzerland, and the United States. It reviews the background, history, and participants of the First Global Summit of National Plastic Surgery Societies, held on October 1, 2010, in Toronto, Canada. In addition, it documents the highlights of the meeting, focuses on areas of agreement among the representative societies, and looks forward to future actions of the participating societies. PMID- 21285913 TI - The etiology of acute nongonococcal urethritis--the enigma of idiopathic urethritis? PMID- 21285914 TI - Demographic, behavioral, and clinical characteristics of men with nongonococcal urethritis differ by etiology: a case-comparison study. AB - BACKGROUND: Nongonococcal urethritis (NGU) is common, yet up to 50% of cases have no defined etiology. The extent to which risk profiles and clinical presentations of pathogen-associated and idiopathic cases differ is largely unknown. METHODS: Urethral swabs and urine specimens were collected from 370 NGU treatment trial participants who sought care at a sexually transmitted disease clinic in Seattle, WA from 2007 to 2009 and had a visible urethral discharge and/or microscopic evidence of urethral inflammation assessed by Gram-stain (>=5 polymorphonuclear leukocytes per high-powered field [PMNs/HPF]). Neisseria gonorrhoeae, Chlamydia trachomatis (CT), Mycoplasma genitalium (MG), Trichomonas vaginalis (TV), and Ureaplasma urealyticum (UU) were detected in urine, using nucleic acid amplification tests. Cases negative for all assessed pathogens were considered idiopathic. Bivariate and multivariate analyses identified clinical, sociodemographic, and behavioral factors associated with detection of specific pathogens. RESULTS: After excluding 3 participants with gonococcal infection, pathogens were detected in only 50.7% of the 367 eligible cases: CT in 22.3%, MG in 12.5%, TV in 2.5%, and UU in 24.0%, with multiple pathogens detected in 9.5%. In all, 3.5% of cases were negative for CT, MG, and TV but lacked speciated ureaplasma results. The remaining cases (45.8%) were considered idiopathic. Pathogen detection was associated with young age, black race, risky sexual behaviors, cloudy or purulent discharge, and visible discharge plus>=5 PMNs/HPF. In contrast, idiopathic cases were more likely to report prior NGU, were older and less likely to be black, or have an abnormal urethral discharge on examination, compared to all other cases. These cases were not associated with any high risk behaviors. CONCLUSIONS: NGU is a heterogeneous condition. Pathogen detection was associated with a variety of traditional risk factors and clinical features; whereas, idiopathic cases tended to be diagnosed among lower-risk men. PMID- 21285915 TI - Memory T cells migrate to and reject vascularized cardiac allografts independent of the chemokine receptor CXCR3. AB - BACKGROUND: Memory T cells migrate to and reject transplanted organs without the need for priming in secondary lymphoid tissues, but the mechanisms by which they do so are not known. Here, we tested whether CXCR3, implicated in the homing of effector T cells to sites of infection, is critical for memory T-cell migration to vascularized allografts. METHODS: CD4 and CD8 memory T cells were sorted from alloimmunized CXCR3 and wildtype B6 mice and cotransferred to congenic B6 recipients of BALB/c heart allografts. Graft-infiltrating T cells were quantitated 20 and 72 hr later by flow cytometry. Migration and allograft survival were also studied in splenectomized alymphoplastic (aly/aly) recipients, which lack secondary lymphoid tissues. RESULTS: We found that polyclonal and antigen-specific memory T cells express high levels of CXCR3. No difference in migration of wildtype versus CXCR3 CD4 and CD8 memory T cells to allografts could be detected in wildtype or aly/aly hosts. In the latter, wildtype and CXCR3 memory T cells precipitated acute rejection at similar rates. Blocking CCR5, a chemokine receptor also upregulated on memory T cells, did not delay graft rejection mediated by CXCR3 memory T cells. CONCLUSIONS: CXCR3 is not critical for the migration of memory T cells to vascularized organ allografts. Blocking CXCR3 or CXCR3 and CCR5 does not delay acute rejection mediated by memory T cells. These findings suggest that the mechanisms of memory T cell-homing to transplanted organs may be distinct from those required for their migration to sites of infection. PMID- 21285916 TI - Altruistic kidney donation to a stranger: psychosocial and functional outcomes at two US transplant centers. AB - BACKGROUND: The number of living kidney donors with no preexisting relationship to the recipient has increased sharply. This study compared the psychosocial and functional outcomes of these altruistic donors to a stranger (ADs) with donors with a longstanding relationship with the recipient (traditional donors [TDs]). METHODS: ADs (n=39) and TDs (n=52), who were similar on age, sex, and year of donation, were recruited from two transplant programs in the United States. Participants completed validated measures of psychosocial and functional outcomes a median of 5 years after donation (range, 1-12 years). RESULTS: ADs and TDs did not differ significantly in the total number of donation motives. Both were motivated by a desire to help, the benefits to the recipient outweighing the risks to the donor, a sense of moral duty, and imagining oneself in the position of the recipient. Psychological benefits were endorsed equally by both types of donors, although TDs reported higher Quid Pro Quo scores relative to ADs (P=0.04). ADs and TDs did not differ significantly on any of the Short Form-36, Version 2 scales (P values ranged from 0.19 to 0.85). Few donors (3 ADs and 1 TD) regretted their donation decision. CONCLUSION: Overall, findings indicate that carefully screened ADs experience psychosocial and functional outcomes comparable with those of TDs and should not be systematically excluded from the opportunity to donate. PMID- 21285917 TI - Outcomes and discard of kidneys from pediatric donors after cardiac death. AB - BACKGROUND: Kidney transplants from pediatric donors after cardiac death (PDCD) have quadrupled in the past 9 years, but little data exist on outcomes using these donors. We hypothesized that pediatric organs might be more sensitive to the pathophysiology of cardiac death. METHODS: We evaluated outcomes and rates of discard of more than 12,000 pediatric kidneys recovered between 2000 and 2009. We compared short- and long-term graft function among adult and pediatric recipients of PDCD kidneys compared with recipients of pediatric kidneys from donors after brain death (PDBD). RESULTS: Overall, 6.3% of pediatric kidneys recovered were PDCD and 93.7% were PDBD. Discard rates were higher for PDCD kidneys (adjusted odds ratio=1.69, 95% confidence interval [CI]=1.31-2.18, P<0.001). Delayed graft function (DGF) was twice as common in recipients of PDCD grafts compared with PDBD (26.2% vs. 13.0%, P<0.001); however, among pediatric recipients, DGF rates were half of those observed in adults, and a statistically significant difference in DGF could not be detected between PDBD and PDCD grafts (6.9% vs. 4.9%, P=0.6). Among all recipients, PDCD kidneys had a greater risk of graft loss compared with PDBD kidneys (adjusted hazard ratio=1.32, 95% CI=1.06-1.65, P=0.01), although among pediatric recipients this increased risk was not statistically significant (adjusted hazard ratio=2.01, 95% CI=0.89-4.54, P=0.1). CONCLUSIONS: The differences in outcomes between adult recipients of PDCD and PDBD kidneys, and the attenuation of these differences among pediatric recipients, should be weighed against risks of prolonged waitlist time in recipients being considered for these grafts. PMID- 21285918 TI - Quantification of baboon thymopoiesis in porcine thymokidney xenografts by the signal-joining T-cell receptor excision circle assay. AB - BACKGROUND: Transplantation of vascularized donor thymic tissue along with a kidney transplant has markedly improved graft survival across the discordant pig to-baboon xenogeneic barrier. To quantify the production of baboon T cells by the porcine thymic tissue, we recently developed an assay to measure the excised DNA products of baboon T-cell receptor (TCR) gene rearrangement (signal-joining TCR excision circles, sjTREC). METHODS: Initial polymerase chain reaction (PCR) analysis documented that TCR deltaREC-psiJalpha rearrangement occurs in baboons. Primers, specific to baboon sjTREC sequence were designed and used to quantify sjTREC molecules in peripheral blood mononuclear cells and thymic tissue using a quantitative PCR assay. RESULTS: sjTREC levels were higher in phenotypically naive (CD3CD45RA) T cells (650 copies/100,000 cells) than in phenotypically memory (CD3CD45RA) T cells, with sjTREC below the limit of detection (40 copies/100,000 cells). Surgical removal of the native thymus in two baboons led to a significant decrease of sjTREC in peripheral blood (from 1104 and 920 copies to 184 and 190 copies/100,000 cells, respectively), confirming the role of the thymus in maintaining the peripheral T-cell pool. In two thymectomized baboons that received porcine thymokidney xenografts, sjTREC levels remained low in the peripheral blood (<40 copies/100,000 cells), but increased to 52 and 192 copies/100,000 cells in thymic biopsies, implying that baboon thymopoiesis had begun to occur in the porcine thymic xenografts. CONCLUSIONS: Baboon sjTREC can be quantified by quantitative PCR using primers specific to baboon sequence. Initial results suggest that baboon thymopoiesis occurs in vascularized porcine thymus xenografts. PMID- 21285919 TI - Role of intestinal hydrolase in the absorption of prenylated flavonoids present in Yinyanghuo. AB - PURPOSE: Yinyanghuo (Herba Epimdii) is a traditional Chinese herb containing prenylated flavonoids as its active constituents. The aim of this study was to examine the significance of the intestinal hydrolysis of prenylated flavonoids by lactase phlorizin hydrolase (LPH), an enzyme at the brush border membrane of intestinal cells. METHODS: A four-site perfused rat intestinal model was used. The concentration of the flavonoids of interest and their metabolites in different intestinal segements were analyzed by HPLC, and the apparent permeabilities were calculated. A lactase phlorizin hydrolase inhibitor (gluconolactone) was employed to investigate the mechanism of the intestinal absorption, and the metabolites of the four flavonoids were identified using LC/MS/MS. RESULTS: Diglycosides (icariin) or triglycosides (epimedin A, epimedin B, and epimedin C) were hydrolyzed rapidly in duodenum and jejunum producing one or two metabolites, while a monoglycoside (baohuoside I) was absorbed directly. When co-perfused with glucono-lactone, both the hydrolysis of diglycosides and triglycosides were significantly inhibited, with inhibition rates for icariin (62%, 50%, 40%, 46%), epimedin A, (55%, 26%, 21%, 14%); epimedin B (42%, 40%, 74%, 22%), and epimedin C (42%, 40%, 52%, 35%) in duodenum, jejunum, ileum, and colon, respectively. Also the metabolites of icariin, epimedin A, epimedin B, and epimedin C were identified as baohuoside I (one of two), sagittatoside A, sagittatoside B, and 2"-O-rhamnosylicariside II, respectively. CONCLUSIONS: The results showed that lactase phlorizin hydrolase was a major determinant of the intestinal absorption of prenylated flavonoids present in Yinyanghuo. PMID- 21285920 TI - Determination of ascorbic acid content of some fruit juices and wine by voltammetry performed at pt and carbon paste electrodes. AB - A method was developed for assessing ascorbic acid concentration in fruit juices and wine by differential pulse voltammetry. The oxidation peak for ascorbic acid occurs at about 530 mV (versus SCE) on a Pt strip working electrode and at about 470 mV on a carbon paste working electrode. The influence of the operational parameters like the pulse amplitude and the pulse period on the analytical signal was investigated. The obtained calibration graph shows a linear dependence between the peak height and ascorbic acid concentration within the range 0.31-20 mM with a Pt working electrode, and within the range 0.07-20 mM with a carbon paste working electrode. The equation of the calibration graph was y = 21.839x + 35.726, r2 = 0.9940, when a Pt strip electrode was used (where y represents the value of the current intensity measured for the peak height, expressed as uA and x the analyte concentration, as mM). R.S.D. = 2.09%, n = 10, C(ascorbic acid) = 2.5 mM. The equation of the calibration graph was y = 3.4429x + 5.7334, r2 = 0.9971, when a carbon paste electrode was used (where y represents the value of intensity measured for the peak height, expressed as uA and x the analyte concentration, as mM). R.S.D. = 2.35%, n = 10, C(ascorbic acid) = 2.5 mM. The developed method was applied to ascorbic acid assessment in fruit juices and wine. The ascorbic acid content determined ranged between 6.83 mg/100 mL juice for soft drinks (Fanta Madness) and 54.74 mg/100 mL for citrus (lemon) juices obtained by squeezing fruit. Different ascorbic acid concentrations (from standard solutions) were added to the analysed samples, the degree of recovery being comprised between 94.74 and 104.97%. The results of ascorbic acid assessment by differential pulse voltammetry were compared with those obtained by cyclic voltammetry. The results obtained by the two methods were in good agreement. PMID- 21285922 TI - Activity of endothelial factors on myocardial inotropy. AB - Both nitric oxide (NO) and endothelins can either increase or decrease myocardial contractility. A positive inotropic effect occurs in response to low NO concentrations, whereas a negative effect is brought about by high concentrations. Activation of protein kinase A and protein kinase G accounts for the increase and decrease in contractility respectively. Basal NO concentration is virtually unknown so that when NO-donors and NOS stimulators add newly released NO, the most frequent effect is a decrease in contractility. This negative inotropic effect represents a protection against the maladaptative activity of the increased production of angiotensin II and cathecholamines in heart failure. Unlike NO, the main effect of endothelins is an increase in contractility. While the increase in contractility is attributed to an activation of Na+/H+ and Na+/Ca2+ exchangers a decrease seems to depend on the triggering of NO-cGMP pathway by endothelin receptors B. Since endothelin concentration increases in several cardiovascular diseases, the blockade of endothelin receptors has been suggested as a therapeutic tool. The study of the endothelial dependent repolarizing factors revealed the inotropic activity of 14,15 isoform of epoxi-eicosatrienoic acids. PMID- 21285921 TI - Chemical composition, antimicrobial and antioxidant activities of essential oils from organically cultivated fennel cultivars. AB - Essential oils of the fruits of three organically grown cultivars of Egyptian fennel (Foeniculum vulgare var. azoricum, Foeniculum vulgare var. dulce and Foeniculum vulgare var. vulgare) were examined for their chemical constituents, antimicrobial and antioxidant activities. Gas chromatography/mass spectrometry analysis of the essential oils revealed the presence of 18 major monoterpenoids in all three cultivars but their percentage in each oil were greatly different. trans-Anethole, estragole, fenchone and limonene were highly abundant in all of the examined oils. Antioxidant activities of the essential oils were evaluated using the DPPH radical scavenging, lipid peroxidation and metal chelating assays. Essential oils from the azoricum and dulce cultivars were more effective antioxidants than that from the vulgare cultivar. Antimicrobial activities of each oil were measured against two species of fungi, two species of Gram negative and two species of Gram positive bacteria. All three cultivars showed similar antimicrobial activity. PMID- 21285923 TI - Could [18]F-fluorodeoxyglucose PET/CT change the therapeutic management of stage IV thyroid cancer with positive (131)I whole body scan? AB - AIM: Stage-IV differentiated thyroid cancer (DTC) patients may present elevated serum thyroglobulin (Tg) levels associated with positive [(131)I] whole-body-scan (WBS). Nevertheless some patients in whom WBS does not reveal new sites of disease show increased Tg levels. This finding prompts thorough restaging in order to exclude the presence of metastases unable to concentrate iodine. The aim of our study was to evaluate the impact of [(18)F]FDG-PET/CT in both the assessment of overall extent of the disease and the therapeutic management in a group of stage-IV DTC patients. METHODS: On suspicious of non-iodine concentrating additional metastases, 20 stage-IV DTC patients with increasing Tg levels and stable positive post-therapy WBS were enrolled. Conventional imaging (CI) procedures, including neck ultrasonography, bone-scintigraphy and computed tomography (CT) were performed before [(18)F]FDG-PET/CT. RESULTS: [(18)F]FDG PET/CT was positive in 16 out of 20 patients (80%). In 9 patients (45%) [(18)F]FDG PET/CT detected a larger number of tumour recurrences/metastatic sites than WBS+CI. [(18)F]FDG PET/CT findings prompted modification of the management of 11 patients (55%), in whom surgery or external radiotherapy were eventually considered more appropriate than radioactive iodine therapy. These further therapies improved the quality of life in several patients but did not change their survival rate. CONCLUSION: Our results showed that [18F]FDG-PET/CT can detect new radioiodine-negative metastases in advanced DTC patients with unchanged positive WBS and increasing Tg levels. [(18)F]FDG-PET/CT may constitute a useful tool in the choice of the best therapeutic strategy in such difficult cases. PMID- 21285924 TI - Performance of a SPECT collimator-detector response reconstruction algorithm: phantom studies and validation in inflammation clinical studies. AB - AIM: To evaluate evolution for bone (EfB), one of the recent corrective collimator detector response (CDR) image reconstruction packages, resolution recovery and iterative reconstruction protocols were compared to the standard Filtered Back Projection (FBP) protocol and the possibility of time reduced acquisition (15 instead of 30 seconds/projection) was evaluated. METHODS: Tomographic spatial resolution, contrast, noise and signal-to-noise ratio (SNR) were analyzed in phantom studies. Patient studies were conducted on sixteen [99mTc]HMPAO labeled leukocyte patients with suspected local inflammation, submitted to SPECT/CT and conventional leukocyte scintigraphy. Target background ratio (TBR) and boundary of each lesion were calculated. Images were also analyzed by visual inspection by two blinded expert physicians. RESULTS: a) Phantom: resolution in phantom improves with the use of EfB mainly due to iterative reconstruction methods vs FBP. EfB shows a reduction in noise. No differences were found in contrast data, while SNR changes were mainly due to changes in noise. Time reduction, while increasing image noise, does not modify resolution; nevertheless, half-time EfB noise is the same as full-time FBP noise. b) PATIENTS: lesion boundary is better defined in patient studies using iterative reconstruction vs FBP; no changes were observed for CDR vs iterative OSEM, or for full-time vs half-time acquisition. TBR is comparable in iterative and FBP protocols, while it is improved by EfB. At visual inspection, a higher score is always associated with EfB. CONCLUSION: Resolution, noise, SNR and TBR improve when applying the resolution recovery. EfB permits reduction of acquisition time without compromising image quality. PMID- 21285926 TI - Percutaneous drug-eluting stent implantation in diabetic patients: short and long term outcomes from an observational study. AB - AIM: The introduction of drug-eluting stents (DES) has markedly improved mid-term results of percutaneous coronary intervention (PCI) in diabetics. However, it is unclear whether the risk-benefit balance of DES in diabetics is maintained also at long-term and in insulin-requiring patients. We thus aimed to appraise long term outcomes of diabetic patients treated with PCI with DES, stratifying according to insulin therapy. METHODS: We retrospectively collected baseline, procedural and outcome data from all patients undergoing PCI with DES from July 2002 to June 2004 at our center. We distinguished three groups: insulin-requiring diabetics, non-insulin-requiring diabetics and patients without diabetes. The primary end-point was the long-term rate of major adverse cardiac events (MACE, i.e. the composite of death, myocardial infarction, or target vessel revascularization). We also considered stent thrombosis according to the Academic Research Consortium Definition. RESULTS: We included a total of 1266 patients, with 3% of insulin-requiring diabetes, 22% with non-insulin-requiring diabetes, and 75% without diabetes. There were significant differences across groups in prevalence of male gender (respectively, 32.4%, 74.6% and 81%, P<0.001), and DES usage (54.1%, 34%, and 30.4%, P=0.007). Thirty-day MACE occurred with similar frequency in the three groups (8.1%, 7.3% and 6.3%, P=0.78), with death in 3%, 2%, and 1.4% (P=0.71) and myocardial infarction in 5.4%, 1.8% and 0.8% (P=0.02). After a median follow-up period of 58 months, MACE occurred in 59.5% of patients with insulin-requiring diabetes, in 50.6% of non-insulin-requiring diabetics and in 38.9% of non-diabetics (P<0.001). Death occurred in 24.3%, 17.5% and 8.5%, (P<0.001), myocardial infarction in 10.8%, 6.6%, and 5.1% (P=0.25), repeat revascularization in 46%, 31.6%, and 30% (P=0.11), and definite stent thrombosis in 0%, 1.1%, and 1.3% (P=0.78). CONCLUSION: Our study confirms the high risk profile of diabetic patients, especially when ischemic disease it is known. In this setting, diabetic and comorbidities fix the price not only in term of need of further revascularization, but mainly in survival decrease. It can be concluded that not only revascularization but also - and especially - comorbidities treatment plays a determinant role reducing follow-up events. Further research on additional pharmacologic treatments or hybrid revascularization strategies may mitigate the burden of morbidity and mortality. PMID- 21285927 TI - A new echo-Doppler method to measure interatrial conduction time. Validation and clinical usefulness. AB - AIM: The aim of this study was to assess if knowing the interatrial conduction time is useful to better program atrioventricular delay in sequential pacing. The study proposes a new echo-Doppler method to measure interatrial conduction time, correlating it with electrophysiological measures. METHODS: The new method was tested in 30 subjects who underwent electrophysiological study. Interatrial conduction time by new method was taken during atrial pacing as the interval between the artefact of electrocardiogram pacing, shown on screen echo, and the onset of the A wave of the echo-Doppler mitral inflow. The electrophysiological measures were obtained, in the same subjects and at the same time, by a decapolar catheter in coronary sinus as intervals between the artefact of atrial pacing and the first positive left atrial deflection at proximal (C7C8) and distal (C1C2) electrodes. RESULTS: Echo-Doppler mean time was 114+/-12 ms, electrophysiological time was 107+/-14 ms at C7C8 and 124+/-11 ms at C1C2. Statistical analysis showed a good correlation (r=0.92, P<0.001) and accord (mean difference=6.6 ms) between the two methods. CONCLUSION: The new method to measure interatrial conduction time is consistent with the electrophysiological method; it could be particularly useful in programming the best AV delay in sequential and biventricular pacing, to avoid atrial contraction against a closed mitral valve. PMID- 21285928 TI - Atrial fibrillation ablation induces reverse remodelling and impacts cardiac function. AB - AIM: Atrio-ventricular anatomo-functional response to successful surgical atrial fibrillation (AF) ablation has been poorly investigated. Determinants of AF recurrence following surgical ablation are still debated. METHODS: Sixty-nine patients underwent AF ablation during major cardiac surgery. Main outcomes were clinical and echocardiographic results after monopolar and/or bipolar ablation were recorded. Secondary outcomes were freedom from AF, rehospitalization and congestive heart failure (CHF) at follow-up. Predictors of AF-recurrence were evaluated. RESULTS: Fifty-three patients (76.8%) were in sinus rhythm (SR) at 31.4+/-10.6 months of mean follow-up. Overall freedom from AF-recurrence was 61.4+/-6.6%, from hospital readmission 89.9+/-3.6%, from CHF 91.9+/-5.05%. Compared to AF-patients, SR-patients demonstrated better freedom from re hospitalization (98.1+/-1.9% vs. 62.5+/-12.1%; P=0.0001) and CHF (94.7+/-5.1% vs. 77.8+/-13.9%; P=0.006). At follow-up SR-patients demonstrated atrial (preoperative 5.9+/-1.2 cm vs. follow-up 5.2+/-1.0; P=0.01) and ventricular reverse remodelling (preoperative LVDd 5.8+/-1.6cm vs. follow-up 5.0+/-1.3 cm; P=0.002 - preoperative LVDs 4.2+/-1.8 cm vs. follow-up 3.8+/-1.2 cm; P=0.045). E/A ratio was normal in 90.6% of SR-patients (69.6% of the total population of the study). TDI at the level of the left lateral annulus showed an improved left ventricular systole (Sm), and diastole (Em, E/Em) for SR-patients compared to AF patients (Sm 9.30+/-1.66 vs. 7.81+/-1.41, P=0.001; Em: 10.55+/-1.87 vs. 7.44+/ 0.40, P=0.001; E/Em: 0.06+/-0.02 vs. 0.11+/-0.05, P=0.0001). Preoperative atrial diameter (OR=23.9; P=0.002) and tricuspid insufficiency at follow-up (OR=3.5; P=0.008) were independent predictors of AF-recurrence. Neither etiology, nor duration of AF, nor even ablation technique influenced SR recovery (P=NS for all measurement). CONCLUSION: Radiofrequency AF ablation achieves 76.8% of SR recovery at follow-up. Maintenance of SR improves clinical, haemodynamic and echocardiographic results. PMID- 21285929 TI - New drug-eluting stents with biodegradable polymers. AB - Current drug-eluting stents (DES) perform well compared to bare metal stents. However, long-term rates of major adverse events and in particular repeat revascularization by PCI are still an issue. In this concise review we will discuss the possibilities of biodegradable coatings to improve biocompatibility of DES. Among the various members of the synthetic biodegradable polymer family, polyesters are widely used and attractive for their ease of degradation, with degradation products often being resorbed through general metabolic pathways. A new development is surface functionalization of polyesters to improve endothelialization. PMID- 21285930 TI - The role of fractional flow reserve to guide stent implantation. AB - In routine clinical practice, a sizeable proportion of patients with suspected coronary artery disease (CAD) undergo coronary angiography without prior non invasive functional evaluation. In this situation, the decision wheter to perform revascularization is taken solely on the basis of angiographic parameters, which are often limited in assessing the lesions that are functionally significant and ultimately responsible for patients' symptoms. Fractional flow reserve (FFR) is a validated method for assessing hemodynamic significance of coronary stenoses based on the use of pressure wires and assessment of hyperemic pressure gradients across coronary lesions. FFR can guide clinical decision making in several anatomical settings: e.g. intermediate stenosis, left main stenoses, multivessel disease, bifurcation lesions. Treatment strategies guided by FFR have been shown to be equally safe and more efficacious than angiography-guided PCI. FFR is readily available in the catheterization laboratory, and can be easily measured during coronary angiography. FFR represents a unique tool for interventional cardiologists to combine anatomical and functional information, allowing the selection of optimal revascularization strategy in patients with CAD. PMID- 21285931 TI - Benefits of drug eluting stents versus bare metal stents in ST-elevation myocardial infarction: a contemporary review. AB - The efficacy of drug-eluting stents (DES) in reducing the rates of in-stent restenosis after percutaneous coronary intervention (PCI) compared to bare metal stents (BMS) in stable coronary artery disease has been well demonstrated. Thus, the Food and Drug Administration has approved the utilization of DES for stable coronary disease. However, there is still much debate surrounding the implantation of DES for patients with ST-segment elevation myocardial infarction (STEMI) given safety concerns about the possibility of increased rates of stent thrombosis with DES. The review of the current body of evidence comparing DES with BMS is consistent with results from previous trials in stable coronary disease and reveals lower rates of revascularization with DES in STEMI patients. The ultimate decision regarding the appropriate stent during PCI needs to be individualized as patients' compliance with dual antiplatelet therapy is critical. The data suggest that PCI with DES in STEMI patients who adhere to long term dual antiplatelet therapy is safe and effective. Randomized trials with longer-term follow-up are necessary to better elucidate the safety and efficacy of DES versus BMS in patients with STEMI. PMID- 21285932 TI - Secondary revascularization after coronary surgery. AB - World population is aging day after day and coronary atherosclerosis disease is becoming a worldwide pandemic disease. Whereas the number of patients with surgical or percutaneous coronary revascularization is increasing, a new revascularization procedure in a previously revascularized patient is a situation that is already being common in cath labs all over the world. Such patients present some special considerations, with a higher risk and worse prognosis than the usual patients and they require to take specific attitudes regarding prognosis, treatment and revascularization technique. At present, much has been achieved in this field, with new devices developed and many randomized clinical trials, but there is still sparse knowledge about this subject and some confusing points. The following article will discuss about the present-day knowledge of secondary coronary revascularization in patients previously operated, focusing in its indications and which are the technical considerations to keep in mind. Special attention will be paid to the percutaneous revascularization of saphenous vein grafts, the most complex and specific situation that we can find in such patients due to its special histopathology and behavior. Moreover, a mention will be made of the new advances that have been made in recent years, about all kind of devices, coronary stents, pharmacological treatment and new emerging revascularization strategies. PMID- 21285933 TI - Cardiogenic shock: role of revascularization. AB - The most common cause of cardiogenic shock is myocardial ischemia developing early or late in the course of acute myocardial infarction. The incidence of cardiogenic shock (CS) is around 7% in ST-segment elevation myocardial infarction (STEMI) patients and has remained constant over the last 20 years. Therapy should be chain based by increased patient's awareness. Early and prehospital diagnosis and treatment, with prompt transfer to a catheterization laboratory. Early revascularization is the cornerstone treatment of acute myocardial infarction complicated by cardiogenic shock. According to the guidelines, revascularization is effective up to 36 hours after the onset of CS and performed within 18 hours after the diagnosis of CS. Primary percutaneous coronary intervention (PCI) is the most efficient and easily available therapy to restore coronary flow in the infarct related artery. Although recommended, there is little evidence that immediate multivessel PCI is beneficial for CS. The growing numbers of reports suggest staged PCI procedures or CABG is preferred in CS patients with significant LM disease or 3-vessel disease. The use of hemodynamic support with newly available percutaneous left ventricular unloading devices may herald a new era enabling preservation of adequate perfusion to other vital organs such as the brain, kidney and bowel. Despite all current efforts, in-hospital mortality for CS remains around 50%. However, long-term outcome and quality of life in hospital survivors is similar to patients with ST-segment elevation myocardial infarction patients presenting without CS. PMID- 21285934 TI - Cardiac resynchronization therapy: an updateimpaired left ventricular systolic function. AB - Cardiac resynchronization therapy has been shown to reduce hospitalization and mortality, and to improve heart failure symptoms, in patients with systolic dysfunction and ventricular dyssynchrony. We review the current guidelines for cardiac resynchronization therapy, the underlying evidence, the latest developments in the field and directions of future research. PMID- 21285935 TI - Iloprost in the management of peripheral arterial disease in patients with diabetes mellitus. AB - Diabetic complications in the lower extremities, especially those secondary to diabetic macroangiopathy, have increasingly become a clinical emergency, given the high prevalence and progression of the disease. Until recently, the only approach to treating advanced stage disease was medical therapy and major amputation; however, the advent of revascularization procedures has radically improved the prognosis of patients with critical lower limb ischemia. In this setting, iloprost holds a dual position: as first-choice therapy in patients ineligible for revascularization and as complementary therapy in candidates for surgical or endovascular revascularization. PMID- 21285936 TI - Evaluation of re-endothelization extent at mid-term follow-up after drug eluting balloon plus bare metal stent implantation during primary coronary angioplasty: insight from OCT imaging. AB - One quarter of patients with STEMI submitted to primary percutaneous coronary intervention (PCI) need repeated target vessel revascularization (TVR) because of stent restenosis or thrombosis. Introduction of DES has effectively reduced the incidence of these complications but the safety of this type of stent in the setting of AMI is limited due to the unpredictable risk of stent malapposition and vessel remodelling in the long term follow-up. Recently, treatment with drug eluting balloon (DEB) in association with bare metal stenting (BMS) has been reported to have an excellent efficacy and safety profile. However, little is known regarding the extent of stent coverage in BMS after DEB utilization. PMID- 21285937 TI - Very late thrombosis of sirolimus-eluting stent despite dual antiplatelet therapy for 4 years in a patient with lung cancer. PMID- 21285938 TI - Cor triatriatum sinistrum: a real-time three-dimensional transthoracic echocardiography evaluation. PMID- 21285939 TI - Ectopic atrial rhythm associated with cannabis use. PMID- 21285940 TI - Body composition and body fat distribution in relation to later risk of acute myocardial infarction: a Danish follow-up study. AB - INTRODUCTION: Obesity is a modifiable risk factor for acute myocardial infarction (MI), but lean body mass (LBM) may also be an important factor. Low LBM may increase the risk of MI and LBM may modify the effect of obesity on MI. Thus, the inability of the classical anthropometric measures to evaluate LBM may lead to misclassification of MI risk in both lean and obese persons. We investigated the associations between incident MI and bioelectrical impedance analyses (BIA) derived measures of body composition in combination with body mass index (BMI) and anthropometric measures of body fat distribution. METHODS AND RESULTS: From 1993 to 1997, 27 148 men and 29 863 women, aged 50 to 64 year, were recruited into the Danish prospective study Diet, Cancer and Health. During 11.9 years of follow-up we identified 2028 cases of incident MI (1487 men and 541 women). BMI, waist circumference (WC), hip circumference and BIA of body composition including body fat mass (BFM), body fat percentage and LBM were measured at baseline. We used Cox proportional hazard models with age as time axis and performed extensive control for confounding. Weight, BMI, classical estimates of abdominal obesity and BIA estimates of obesity showed significant positive associations with incident MI. However, BFM adjusted for WC showed no association. Low LBM was associated with a higher risk of incident MI in both genders, and high LBM was associated with a higher risk in men. CONCLUSION: Obesity was positively associated with MI. Estimates of obesity achieved by BIA seemed not to add additional information to classical anthropometric measures regarding MI risk. Both high and low LBM may be positively associated with MI. PMID- 21285941 TI - Contributors to the obesity and hyperglycemia epidemics. A prospective study in a population-based cohort. AB - OBJECTIVE: Relatively unexplored contributors to the obesity and diabetes epidemics may include sleep restriction, increased house temperature (HT), television watching (TW), consumption of restaurant meals (RMs), use of air conditioning (AC) and use of antidepressant/antipsychotic drugs (ADs). DESIGN AND SUBJECTS: In a population-based cohort (n=1597), we investigated the possible association among these conditions, and obesity or hyperglycemia incidence at 6 year follow-up. Subjects with obesity (n=315) or hyperglycemia (n=618) at baseline were excluded, respectively, 1282 and 979 individuals were therefore analyzed. RESULTS: At follow-up, 103/1282 became obese; these subjects showed significantly higher body mass index, waist circumference, saturated fat intake, RM frequency, TW hours, HT, AC and AD use, and lower fiber intake, metabolic equivalent of activity in h per week (METS) and sleep hours at baseline. In a multiple logistic regression model, METS (odds ratio=0.94; 95% confidence interval (CI) 0.91-0.98), RMs (odds ratio=1.47 per meal per week; 1.21-1.79), being in the third tertile of HT (odds ratio=2.06; 1.02-4.16) and hours of sleep (odds ratio=0.70 per h; 0.57-0.86) were associated with incident obesity. Subjects who developed hyperglycemia (n=174/979; 17.8%) had higher saturated fat intake, RM frequency, TW hours, HT, AC and AD use at baseline and lower METS and fiber intake. In a multiple logistic regression model, fiber intake (odds ratio=0.97 for each g per day; 0.95-0.99), RM (1.49 per meal per week; 1.26-1.75) and being in the third tertile of HT (odds ratio=1.95; 1.17-3.26) were independently associated with incident hyperglycemia. CONCLUSIONS: Lifestyle contributors to the obesity and hyperglycemia epidemics may be regular consumption of RM, sleep restriction and higher HT, suggesting potential adjunctive non-pharmacological preventive strategies for the obesity and hyperglycemia epidemics. PMID- 21285942 TI - Adipose tissue macrophages inhibit adipogenesis of mesenchymal precursor cells via wnt-5a in humans. AB - In patients with obesity and type 2 diabetes, adipose tissue is infiltrated by macrophages known to alter adipogenesis of mesenchymal precursor cells via secretion of proinflammatory cytokines. Recently, it has been shown that under certain conditions, immune cells can also express wnt-5a, a factor known to inhibit adipogenesis in humans. Therefore, in this study we aimed to investigate whether macrophages affect adipogenesis of mesenchymal precursor cells via wnt 5a. Wnt-5a was found to be expressed in adipose tissue macrophages in obese and type 2 diabetic human subjects in vivo by immunohistochemistry of adipose tissue biopsies. Furthermore, wnt-5a was detectable in circulating CD14(+) blood monocytes of human subjects with obesity and type 2 diabetes on RNA level by real time PCR. Besides expression analysis in vivo, we also performed functional studies to explore the role of wnt-5a in low-grade inflammation of adipose tissue. In a cell culture experiment, macrophage-conditioned differentiation medium inhibited adipogenesis of 3T3-L1 cells. This inhibitory effect was restored by adding neutralising anti-wnt-5a antibodies. In conclusion, our data indicate that macrophages alter adipogenesis of 3T3-L1 cells not only via classical proinflammatory cytokines, but also via wnt signalling molecules. PMID- 21285943 TI - Long-term efficacy of group-based treatment for childhood obesity compared with routinely given individual counselling. AB - OBJECTIVE: We investigated the long-term efficacy of two childhood obesity treatment programs, routine counselling (two appointments for children) and group treatment (15 sessions separately for children and parents) in a randomised controlled trial. As published earlier, group treatment was more effective than routine counselling in the treatment of 7-9 year-old obese children in the short term. DESIGN: The children's heights and weights were measured 2 and 3 years after the beginning of the intervention and changes in weight for height, body mass index (BMI) and BMI standard deviation scores were used as outcome measures. RESULTS: There were no significant differences between the treatment arms in the changes of outcome measures from baseline to 2- or 3-years follow-up visits. CONCLUSION: In conclusion, novel efforts are needed for the improvement of the long-term results of childhood obesity treatment programs. PMID- 21285944 TI - Small RNA-mediated regulation of iPS cell generation. AB - Somatic cells can be reprogrammed to an ES-like state to create induced pluripotent stem cells (iPSCs) by ectopic expression of four transcription factors, Oct4, Sox2, Klf4 and cMyc. Here, we show that cellular microRNAs (miRNAs) regulate iPSC generation. Knock-down of key microRNA pathway proteins resulted in significant decreases in reprogramming efficiency. Three miRNA clusters, miR-17~92, miR-106b~25 and miR-106a~363, were shown to be highly induced during early reprogramming stages. Several miRNAs, including miR-93 and miR-106b, which have very similar seed regions, greatly enhanced iPSC induction and modulated mesenchymal-to-epithelial transition step in the initiation stage of reprogramming, and inhibiting these miRNAs significantly decreased reprogramming efficiency. Moreover, miR-iPSC clones reached the fully reprogrammed state. Further analysis revealed that Tgfbr2 and p21 are directly targeted by these miRNAs and that siRNA knock-down of both genes indeed enhanced iPSC induction. Here, for the first time, we demonstrate that miR-93 and its family members directly target TGF-beta receptor II to enhance iPSC generation. Overall, we demonstrate that miRNAs function in the reprogramming process and that iPSC induction efficiency can be greatly enhanced by modulating miRNA levels in cells. PMID- 21285945 TI - JTV1 co-activates FBP to induce USP29 transcription and stabilize p53 in response to oxidative stress. AB - c-myc and p53 networks control proliferation, differentiation, and apoptosis and are responsive to, and cross-regulate a variety of stresses and metabolic and biosynthetic processes. At c-myc, the far upstream element binding protein (FBP) and FBP-interacting repressor (FIR) program transcription by looping to RNA polymerase II complexes engaged at the promoter. Another FBP partner, JTV1/AIMP2, a structural subunit of a multi-aminoacyl-tRNA synthetase (ARS) complex, has also been reported to stabilize p53 via an apparently independent mechanism. Here, we show that in response to oxidative stress, JTV1 dissociates from the ARS complex, translocates to the nucleus, associates with FBP and co-activates the transcription of a new FBP target, ubiquitin-specific peptidase 29 (USP29). A previously uncharacterized deubiquitinating enzyme, USP29 binds to, cleaves poly ubiquitin chains from, and stabilizes p53. The accumulated p53 quickly induces apoptosis. Thus, FBP and JTV1 help to coordinate the molecular and cellular response to oxidative stress. PMID- 21285946 TI - The biophysical and molecular basis of TRPV1 proton gating. AB - The capsaicin receptor TRPV1, a member of the transient receptor potential family of non-selective cation channels is a polymodal nociceptor. Noxious thermal stimuli, protons, and the alkaloid irritant capsaicin open the channel. The mechanisms of heat and capsaicin activation have been linked to voltage-dependent gating in TRPV1. However, until now it was unclear whether proton activation or potentiation or both are linked to a similar voltage-dependent mechanism and which molecular determinants underlie the proton gating. Using the whole-cell patch-clamp technique, we show that protons activate and potentiate TRPV1 by shifting the voltage dependence of the activation curves towards more physiological membrane potentials. We further identified a key residue within the pore region of TRPV1, F660, to be critical for voltage-dependent proton activation and potentiation. We conclude that proton activation and potentiation of TRPV1 are both voltage dependent and that amino acid 660 is essential for proton-mediated gating of TRPV1. PMID- 21285947 TI - miRNAs control insulin content in pancreatic beta-cells via downregulation of transcriptional repressors. AB - MicroRNAs (miRNAs) were shown to be important for pancreas development, yet their roles in differentiated beta-cells remain unclear. Here, we show that miRNA inactivation in beta-cells of adult mice results in a striking diabetic phenotype. While islet architecture is intact and differentiation markers are maintained, Dicer1-deficient beta-cells show a dramatic decrease in insulin content and insulin mRNA. As a consequence of the change in insulin content, the animals become diabetic. We provide evidence for involvement of a set of miRNAs in regulating insulin synthesis. The specific knockdown of miR-24, miR-26, miR 182 or miR-148 in cultured beta-cells or in isolated primary islets downregulates insulin promoter activity and insulin mRNA levels. Further, miRNA-dependent regulation of insulin expression is associated with upregulation of transcriptional repressors, including Bhlhe22 and Sox6. Thus, miRNAs in the adult pancreas act in a new network that reinforces insulin expression by reducing the expression of insulin transcriptional repressors. PMID- 21285948 TI - A role for the universal Kae1/Qri7/YgjD (COG0533) family in tRNA modification. AB - The YgjD/Kae1 family (COG0533) has been on the top-10 list of universally conserved proteins of unknown function for over 5 years. It has been linked to DNA maintenance in bacteria and mitochondria and transcription regulation and telomere homeostasis in eukaryotes, but its actual function has never been found. Based on a comparative genomic and structural analysis, we predicted this family was involved in the biosynthesis of N(6)-threonylcarbamoyl adenosine, a universal modification found at position 37 of tRNAs decoding ANN codons. This was confirmed as a yeast mutant lacking Kae1 is devoid of t(6)A. t(6)A(-) strains were also used to reveal that t(6)A has a critical role in initiation codon restriction to AUG and in restricting frameshifting at tandem ANN codons. We also showed that YaeZ, a YgjD paralog, is required for YgjD function in vivo in bacteria. This work lays the foundation for understanding the pleiotropic role of this universal protein family. PMID- 21285949 TI - Helicobacter pylori cagA and vacA genotypes as predictors of progression of gastric preneoplastic lesions: a long-term follow-up in a high-risk area in Spain. AB - OBJECTIVES: There are no established predictive markers of progression of gastric preneoplastic lesions. The aim of this study was to analyze the relationship between Helicobacter pylori cagA and vacA genotypes and progression of gastric preneoplastic lesions. METHODS: This was a follow-up study that carried out in a province of Spain with a high risk of gastric cancer. A total of 312 patients who underwent upper endoscopy with gastric biopsy in 1988-1994 with diagnoses of normal mucosa, non-atrophic gastritis (NAG), non-metaplastic multifocal atrophic gastritis (MAG), and complete or incomplete intestinal metaplasia (IM), and who accepted to undergo a new biopsy during 2005-2007 or had an end point during follow-up, were included in this study. Detection and characterization of H. pylori cagA and vacA genotypes was performed directly in baseline paraffin embedded gastric biopsy specimens by PCR followed by reverse hybridization onto a line probe assay. Inter- and intra-observer variability of histological diagnosis was assessed. Analysis was done using unconditional logistic regression. RESULTS: The mean age of patients was 48.5 years (45% males) and the mean of follow-up was 12.8 years. H. pylori strains harboring cagA, vacA s1, and vacA m1 genotypes were more frequently found in patients with more advanced gastric preneoplastic lesions. Infection with cagA-positive, vacA s1, and vacA m1 strains was associated with progression of gastric preneoplastic lesions (multivariate odds ratio (OR)=2.28, 95% confidence interval (CI) 1.13-4.58; OR=2.90, 95% CI 1.38 6.13; and OR=3.38, 95% CI 1.34-8.53, respectively). Infection with strains that are simultaneously cagA positive and vacA s1/m1 was associated with progression of gastric precancerous lesions with an OR of 4.80 (95% CI 1.71-13.5) in relation to those infected with cagA-negative/vacA s2/m2 strains. CONCLUSIONS: H. pylori genotyping may be useful for the identification of patients at high risk of progression of gastric preneoplastic lesions and who need more intensive surveillance. PMID- 21285950 TI - ALKBH8-mediated formation of a novel diastereomeric pair of wobble nucleosides in mammalian tRNA. AB - Mammals have nine different homologues (ALKBH1-9) of the Escherichia coli DNA repair demethylase AlkB. ALKBH2 is a genuine DNA repair enzyme, but the in vivo function of the other ALKBH proteins has remained elusive. It was recently shown that ALKBH8 contains an additional transfer RNA (tRNA) methyltransferase domain, which generates the wobble nucleoside 5-methoxycarbonylmethyluridine (mcm(5)U) from its precursor 5-carboxymethyluridine (cm(5)U). In this study, we report that (R)- and 5-methoxycarbonylhydroxymethyluridine (mchm(5)U), hydroxylated forms of mcm(5)U, are present in mammalian tRNA-Arg(UCG), and tRNA-Gly(UCC), respectively, representing the first example of a diastereomeric pair of modified RNA nucleosides. Through in vitro and in vivo studies, we show that both diastereomers of mchm(5)U are generated from mcm(5)U, and that the AlkB domain of ALKBH8 specifically hydroxylates mcm(5)U into (S)-mchm(5)U in tRNA-Gly(UCC). These findings expand the function of the ALKBH oxygenases beyond nucleic acid repair and increase the current knowledge on mammalian wobble uridine modifications and their biogenesis. PMID- 21285951 TI - Tablet-level origin of toughening in abalone shells and translation to synthetic composite materials. AB - Nacre, the iridescent material in seashells, is one of many natural materials employing hierarchical structures to achieve high strength and toughness from relatively weak constituents. Incorporating these structures into composites is appealing as conventional engineering materials often sacrifice strength to improve toughness. Researchers hypothesize that nacre's toughness originates within its brick-and-mortar-like microstructure. Under loading, bricks slide relative to each other, propagating inelastic deformation over millimeter length scales. This leads to orders-of-magnitude increase in toughness. Here, we use in situ atomic force microscopy fracture experiments and digital image correlation to quantitatively prove that brick morphology (waviness) leads to transverse dilation and subsequent interfacial hardening during sliding, a previously hypothesized dominant toughening mechanism in nacre. By replicating this mechanism in a scaled-up model synthetic material, we find that it indeed leads to major improvements in energy dissipation. Ultimately, lessons from this investigation may be key to realizing the immense potential of widely pursued nanocomposites. PMID- 21285952 TI - High efficiency coherent optical memory with warm rubidium vapour. AB - By harnessing aspects of quantum mechanics, communication and information processing could be radically transformed. Promising forms of quantum information technology include optical quantum cryptographic systems and computing using photons for quantum logic operations. As with current information processing systems, some form of memory will be required. Quantum repeaters, which are required for long distance quantum key distribution, require quantum optical memory as do deterministic logic gates for optical quantum computing. Here, we present results from a coherent optical memory based on warm rubidium vapour and show 87% efficient recall of light pulses, the highest efficiency measured to date for any coherent optical memory suitable for quantum information applications. We also show storage and recall of up to 20 pulses from our system. These results show that simple warm atomic vapour systems have clear potential as a platform for quantum memory. PMID- 21285953 TI - Ultra-high-energy cosmic ray acceleration in engine-driven relativistic supernovae. AB - The origin of ultra-high-energy cosmic rays (UHECRs) remains an enigma. They offer a window to new physics, including tests of physical laws at energies unattainable by terrestrial accelerators. They must be accelerated locally, otherwise, background radiations would severely suppress the flux of protons and nuclei, at energies above the Greisen-Zatsepin-Kuzmin (GZK) limit. Nearby, gamma ray bursts (GRBs), hypernovae, active galactic nuclei and their flares have all been suggested and debated as possible sources. A local sub-population of type Ibc supernovae (SNe) with mildly relativistic outflows have been detected as sub energetic GRBs, X-ray flashes and recently as radio afterglows without detected GRB counterparts. Here, we measure the size-magnetic field evolution, baryon loading and energetics, using the observed radio spectra of SN 2009bb. We place such engine-driven SNe above the Hillas line and establish that they can readily explain the post-GZK UHECRs. PMID- 21285954 TI - Macroscopic invisibility cloaking of visible light. AB - Invisibility cloaks, which used to be confined to the realm of fiction, have now been turned into a scientific reality thanks to the enabling theoretical tools of transformation optics and conformal mapping. Inspired by those theoretical works, the experimental realization of electromagnetic invisibility cloaks has been reported at various electromagnetic frequencies. All the invisibility cloaks demonstrated thus far, however, have relied on nano- or micro-fabricated artificial composite materials with spatially varying electromagnetic properties, which limit the size of the cloaked region to a few wavelengths. Here, we report the first realization of a macroscopic volumetric invisibility cloak constructed from natural birefringent crystals. The cloak operates at visible frequencies and is capable of hiding, for a specific light polarization, three-dimensional objects of the scale of centimetres and millimetres. Our work opens avenues for future applications with macroscopic cloaking devices. PMID- 21285955 TI - Regulation of the co-evolved HrpR and HrpS AAA+ proteins required for Pseudomonas syringae pathogenicity. AB - The bacterial AAA+ enhancer-binding proteins (EBPs) HrpR and HrpS (HrpRS) of Pseudomonas syringae (Ps) activate sigma(54)-dependent transcription at the hrpL promoter; triggering type-three secretion system-mediated pathogenicity. In contrast with singly acting EBPs, the evolution of the strictly co-operative HrpRS pair raises questions of potential benefits and mechanistic differences this transcription control system offers. Here, we show distinct properties of HrpR and HrpS variants, indicating functional specialization of these non redundant, tandemly arranged paralogues. Activities of HrpR, HrpS and their control proteins HrpV and HrpG from Ps pv. tomato DC3000 in vitro establish that HrpRS forms a transcriptionally active hetero-hexamer, that there is a direct negative regulatory role for HrpV through specific binding to HrpS and that HrpG suppresses HrpV. The distinct HrpR and HrpS functionalities suggest how partial paralogue degeneration has potentially led to a novel control mechanism for EBPs and indicate subunit-specific roles for EBPs in sigma(54)-RNA polymerase activation. PMID- 21285956 TI - Tracking the Atlantic Multidecadal Oscillation through the last 8,000 years. AB - Understanding the internal ocean variability and its influence on climate is imperative for society. A key aspect concerns the enigmatic Atlantic Multidecadal Oscillation (AMO), a feature defined by a 60- to 90-year variability in North Atlantic sea-surface temperatures. The nature and origin of the AMO is uncertain, and it remains unknown whether it represents a persistent periodic driver in the climate system, or merely a transient feature. Here, we show that distinct, ~55- to 70-year oscillations characterized the North Atlantic ocean-atmosphere variability over the past 8,000 years. We test and reject the hypothesis that this climate oscillation was directly forced by periodic changes in solar activity. We therefore conjecture that a quasi-persistent ~55- to 70-year AMO, linked to internal ocean-atmosphere variability, existed during large parts of the Holocene. Our analyses further suggest that the coupling from the AMO to regional climate conditions was modulated by orbitally induced shifts in large scale ocean-atmosphere circulation. PMID- 21285957 TI - Oceanic spawning ecology of freshwater eels in the western North Pacific. AB - The natural reproductive ecology of freshwater eels remained a mystery even after some of their offshore spawning areas were discovered approximately 100 years ago. In this study, we investigate the spawning ecology of freshwater eels for the first time using collections of eggs, larvae and spawning-condition adults of two species in their shared spawning area in the Pacific. Ovaries of female Japanese eel and giant mottled eel adults were polycyclic, suggesting that freshwater eels can spawn more than once during a spawning season. The first collection of Japanese eel eggs near the West Mariana Ridge where adults and newly hatched larvae were also caught shows that spawning occurs during new moon periods throughout the spawning season. The depths where adults and newly hatched larvae were captured indicate that spawning occurs in shallower layers of 150-200 m and not at great depths. This type of spawning may reduce predation and facilitate reproductive success. PMID- 21285959 TI - A microRNA-regulated and GP64-pseudotyped lentiviral vector mediates stable expression of FVIII in a murine model of Hemophilia A. AB - The objective to use gene therapy to provide sustained, therapeutic levels of factor VIII (FVIII) for hemophilia A is compromised by the emergence of inhibitory antibodies that prevent FVIII from performing its essential function as a cofactor for factor IX (FIX). FVIII appears to be more immunogenic than FIX and an immune response is associated more frequently with FVIII than FIX gene therapy strategies. We have evaluated a modified lentiviral delivery strategy that facilitates liver-restricted transgene expression and prevents off-target expression in hematopoietic cells by incorporating microRNA (miRNA) target sequences. In contrast to outcomes using this strategy to deliver FIX, this modified delivery strategy was in and of itself insufficient to prevent an anti FVIII immune response in treated hemophilia A mice. However, pseudotyping the lentivirus with the GP64 envelope glycoprotein, in conjunction with a liver restricted promoter and a miRNA-regulated FVIII transgene resulted in sustained, therapeutic levels of FVIII. These modifications to the lentiviral delivery system effectively restricted FVIII transgene expression to the liver. Plasma levels of FVIII could be increased to around 9% that of normal levels when macrophages were depleted prior to treating the hemophilia A mice with the modified lentiviral FVIII delivery system. PMID- 21285958 TI - Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences. AB - Tumour cells release an abundance of microvesicles containing a selected set of proteins and RNAs. Here, we show that tumour microvesicles also carry DNA, which reflects the genetic status of the tumour, including amplification of the oncogene c-Myc. We also find amplified c-Myc in serum microvesicles from tumour bearing mice. Further, we find remarkably high levels of retrotransposon RNA transcripts, especially for some human endogenous retroviruses, such as LINE-1 and Alu retrotransposon elements, in tumour microvesicles and these transposable elements could be transferred to normal cells. These findings expand the nucleic acid content of tumour microvesicles to include: elevated levels of specific coding and non-coding RNA and DNA, mutated and amplified oncogene sequences and transposable elements. Thus, tumour microvesicles contain a repertoire of genetic information available for horizontal gene transfer and potential use as blood biomarkers for cancer. PMID- 21285960 TI - Improving adoptive T cell therapy by targeting and controlling IL-12 expression to the tumor environment. AB - Interleukin-12 (IL-12) is an important immunostimulatory cytokine, yet its clinical application has been limited by the systemic toxicity associated with its administration. In this work, we developed a strategy to selectively deliver IL-12 to the tumor environment using genetically engineered lymphocytes. However, peripheral blood lymphocytes (PBLs) transduced with a gamma-retroviral vector, which constitutively expressed IL-12, failed to expand in culture due to apoptosis. To circumvent this problem, a vector was designed where IL-12 expression was directed by a composite promoter-containing binding motifs for nuclear factor of activated T-cells (NFAT.hIL12.PA2). The NFAT-responsive promoter was activated to drive IL-12 expression upon the recognition of tumor specific antigen mediated by a T cell receptor (TCR) that was engineered into the same lymphocytes. We tested the efficacy of the inducible IL-12 vector in vivo in a murine melanoma model. Adoptive transfer of pmel-1 T cells genetically engineered with NFAT-murineIL12 (NFAT.mIL12.PA2) significantly enhanced regression of large established B16 melanoma. Notably, this targeted and controlled IL-12 treatment was without toxicity. Taken together, our results suggest that using the NFAT.hIL12.PA2 vector might be a promising approach to enhance adoptive cancer immunotherapy. PMID- 21285962 TI - Phenelfamycins G and H, new elfamycin-type antibiotics produced by Streptomyces albospinus Acta 3619. AB - Phenelfamycins G and H are new members of the family of elfamycin antibiotics with the basic structure of phenelfamycins E and F, respectively, which are also well known as ganefromycins alpha and beta. Phenelfamycins G and H differ from phenelfamycins E and F by an additional hydroxy group at position C-30, which is not described so far for any of the elfamycin-type antibiotics. The actinomycete strain that produced phenelfamycins G and H was identified to be Streptomyces albospinus based on its 16S rRNA gene sequence. Phenelfamycins G and H exhibit a narrow antibacterial spectrum with a pronounced inhibitory activity against Propionibacterium acnes. PMID- 21285961 TI - Lentiviral vector design and imaging approaches to visualize the early stages of cellular reprogramming. AB - Induced pluripotent stem cells (iPSCs) can be derived from somatic cells by gene transfer of reprogramming transcription factors. Expression levels of these factors strongly influence the overall efficacy to form iPSC colonies, but additional contribution of stochastic cell-intrinsic factors has been proposed. Here, we present engineered color-coded lentiviral vectors in which codon optimized reprogramming factors are co-expressed by a strong retroviral promoter that is rapidly silenced in iPSC, and imaged the conversion of fibroblasts to iPSC. We combined fluorescence microscopy with long-term single cell tracking, and used live-cell imaging to analyze the emergence and composition of early iPSC clusters. Applying our engineered lentiviral vectors, we demonstrate that vector silencing typically occurs prior to or simultaneously with the induction of an Oct4-EGFP pluripotency marker. Around 7 days post-transduction (pt), a subfraction of cells in clonal colonies expressed Oct4-EGFP and rapidly expanded. Cell tracking of single cell-derived iPSC colonies supported the concept that stochastic epigenetic changes are necessary for reprogramming. We also found that iPSC colonies may emerge as a genetic mosaic originating from different clusters. Improved vector design with continuous cell tracking thus creates a powerful system to explore the subtle dynamics of biological processes such as early reprogramming events. PMID- 21285963 TI - Three novel members of angucycline group from Streptomyces sp. N05WA963. AB - Three novel members of angucycline family named N05WA963A (1), B (2) and D (4), together with a new anthracycline named N05WA963C (3) were isolated from the culture broth of Streptomyces sp. N05WA963. The structures were elucidated on the basis of comprehensive spectral data analysis. All four compounds have shown antiproliferative effects on a panel of cancer cell lines such as SW620, K-562, MDA-MB-231, YES-4, T-98 and U251SP. PMID- 21285966 TI - Effect of pharmaceutical treatment on vasospasm, delayed cerebral ischemia, and clinical outcome in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. AB - As it is often assumed that delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) is caused by vasospasm, clinical trials often focus on prevention of vasospasm with the aim to improve clinical outcome. However, the role of vasospasm in the pathogenesis of DCI and clinical outcome is possibly smaller than previously assumed. We performed a systematic review and meta analysis on all randomized, double-blind, placebo-controlled trials that studied the effect of pharmaceutical preventive strategies on vasospasm, DCI, and clinical outcome in SAH patients to further investigate the relationship between vasospasm and clinical outcome. Effect sizes were expressed in pooled risk ratio (RR) estimates with corresponding 95% confidence intervals (CI). A total of 14 studies randomizing 4,235 patients were included. Despite a reduction of vasospasm (RR 0.80 (95% CI 0.70 to 0.92)), no statistically significant effect on poor outcome was observed (RR 0.93 (95% CI 0.85 to 1.03)). The variety of DCI definitions did not justify pooling the DCI data. We conclude that pharmaceutical treatments have significantly decreased the incidence of vasospasm, but not of poor clinical outcome. This dissociation between vasospasm and clinical outcome could result from methodological problems, sample size, insensitivity of clinical outcome measures, or from mechanisms other than vasospasm that also contribute to poor outcome. PMID- 21285967 TI - Proof of concept: pharmacological preconditioning with a Toll-like receptor agonist protects against cerebrovascular injury in a primate model of stroke. AB - Cerebral ischemic injury is a significant portion of the burden of disease in developed countries; rates of mortality are high and the costs associated with morbidity are enormous. Recent therapeutic approaches have aimed at mitigating the extent of damage and/or promoting repair once injury has occurred. Often, patients at high risk of ischemic injury can be identified in advance and targeted for antecedent neuroprotective therapy. Agents that stimulate the innate pattern recognition receptor, Toll-like receptor 9, have been shown to induce tolerance (precondition) to ischemic brain injury in a mouse model of stroke. Here, we demonstrate for the first time that pharmacological preconditioning against cerebrovascular ischemic injury is also possible in a nonhuman primate model of stroke in the rhesus macaque. The model of stroke used is a minimally invasive transient vascular occlusion, resulting in brain damage that is primarily localized to the cortex and as such, represents a model with substantial clinical relevance. Finally, K-type (also referred to as B-type) cytosine-guanine-rich DNA oligonucleotides, the class of agents employed in this study, are currently in use in human clinical trials, underscoring the feasibility of this treatment in patients at risk of cerebral ischemia. PMID- 21285969 TI - That lung cancer incidence falls in ex-smokers: misconceptions 2. AB - Misconceptions and ill-founded theories can arise in all areas of science. However, the apparent accessibility of many epidemiology findings and popular interest in the subject can lead to additional misunderstandings. The article below continues an occasional series of short editorials highlighting some current misinterpretations of epidemiological findings. Invited authors will be given wide scope in judging the prevalence of the misconception under discussion. We hope that this series will prove instructive to cancer researchers in other disciplines as well as to students of epidemiology. Adrian L Harris and Leo Kinlen. PMID- 21285970 TI - The need for a re-evaluation of best supportive care studies reported to date. PMID- 21285968 TI - Lactobacillus GG as an immune adjuvant for live-attenuated influenza vaccine in healthy adults: a randomized double-blind placebo-controlled trial. AB - BACKGROUND/OBJECTIVES: Live-attenuated influenza vaccine (LAIV) protects against influenza by mucosal activation of the immune system. Studies in animals and adults have demonstrated that probiotics improve the immune response to mucosally delivered vaccines. We hypothesized that Lactobacillus GG (LGG) would function as an immune adjuvant to increase rates of seroconversion after LAIV administration. SUBJECTS/METHODS: We conducted a randomized double-blind placebo-controlled pilot study to determine whether LGG improved rates of seroconversion after administration of LAIV. We studied 42 healthy adults during the 2007-2008 influenza season. All subjects received LAIV and then were randomized to LGG or placebo, twice daily for 28 days. Hemagglutinin inhibition titers were assessed at baseline, at day 28 and at day 56 to determine the rates of seroconversion. Subjects were assessed for adverse events throughout the study period. RESULTS: A total of 39 subjects completed the per-protocol analysis. Both LGG and LAIV were well tolerated. Protection rates against the vaccine H1N1 and B strains were suboptimal in subjects receiving LGG and placebo. For the H3N2 strain, 84% receiving LGG vs 55% receiving placebo had a protective titer 28 days after vaccination (odds of having a protective titer was 1.84 95% confidence interval 1.04-3.22, P=0.048). CONCLUSION: Lactobacillus GG is potential as an important adjuvant to improve influenza vaccine immunogenicity. Future studies of probiotics as immune adjuvants might need to specifically consider examining vaccine-naive or sero-negative subjects, target mucosal immune responses or focus on groups known to have poor response to influenza vaccines. PMID- 21285971 TI - Challenges and opportunities for converting renal cell carcinoma into a chronic disease with targeted therapies. AB - Optimum efficacy is the primary goal for any cancer therapy, and entails controlling tumour growth and prolonging survival as far as possible. The prognosis for patients with metastatic renal cell carcinoma (mRCC) has greatly improved with the introduction of targeted therapies. This review examines the development and efficacy of targeted agents for the management of mRCC, the challenges offered by their rapid emergence, and discusses how mRCC treatment may evolve in the future. Improvements in progression-free survival and overall survival rates, observed with targeted agents, indicate that it may now be possible to change mRCC from a rapidly fatal and largely untreatable condition into a chronic disease. The major challenges to further advances in targeted therapy for mRCC include overcoming drug resistance, identifying the most effective sequence or combination of targeted agents, optimising clinical trial design and managing the cost of treatment. PMID- 21285972 TI - The expression and prognostic impact of CXC-chemokines in stage II and III colorectal cancer epithelial and stromal tissue. AB - BACKGROUND: The CXC-chemokine expression is linked with colorectal cancer (CRC) progression but their significance in resected CRC is unclear. We explored the prognostic impact of such expression in stage II and III CRC. METHODS: Tissue microarrays were constructed from stage II and III CRC biopsies (n=254), and the expression of CXCL1 and CXCL8, and their receptors CXCR1 and CXCR2, in malignant and adjacent normal tissue was graded by immunohistochemistry and was correlated with prognostic factors. RESULTS: Expression of CXCL1, CXCR1 and CXCR2 was elevated in tumour epithelium relative to normal adjacent tissue (P<0.001). CXCL8 expression was detectable in the peritumoural inflammatory infiltrate. There was no overall association between CXCL1, CXCR1 or CXCR2 expression and prognostic endpoints; however, univariate subgroup survival analysis demonstrated an inverse association between CXCL1 and recurrence-free survival (RFS) in stage III patients (P=0.041). The CXCL8 positivity in the tumour infiltrate, however, correlated with earlier disease stage (P<0.001) and improved relapse-free survival across the cohort (P<0.001). Disease stage (P<0.001) and tumour infiltrate CXCL8 positivity (P=0.007) were associated with enhanced RFS in multivariate Cox regression analysis. CONCLUSION: Autocrine CXC-chemokine signalling may have adverse prognostic effects in early CRC. Conversely, CXCL8 positivity within the immune infiltrate may have good prognostic significance. PMID- 21285973 TI - Does the association of education with breast cancer replicate within twin pairs? A register-based study on Danish female twins. AB - BACKGROUND: A positive association between socio-economic position and breast cancer has been widely observed, but not hitherto within twin pairs, where shared familial factors were adjusted for. METHODS: We used data on education and other factors from the Danish Twin Registry, The Danish Cancer Registry, and official registers on a total of 16 310 twins. Unpaired and intrapair Cox regression analyses were compared. RESULTS: In the unpaired analysis, an educational gradient in breast cancer risk was found. Similar results were seen in the intrapair analyses of all twins, although no longer statistically significant. When intrapair analyses were stratified on zygosity, the effect of education was attenuated in the monozygotic twins. CONCLUSION: The main findings support an effect of education beyond shared familial factors. PMID- 21285974 TI - Fis1, Bap31 and the kiss of death between mitochondria and endoplasmic reticulum. PMID- 21285975 TI - A spicy family tree: TRPV1 and its thermoceptive and nociceptive lineage. PMID- 21285977 TI - Retraction. A promiscuous liaison between IL-15 receptor and Axl receptor tyrosine kinase in cell death control. PMID- 21285979 TI - The RNP bridge between two worlds. PMID- 21285981 TI - Head and neck cancer in Australia between 1982 and 2005 show increasing incidence of potentially HPV-associated oropharyngeal cancers. AB - BACKGROUND: Although tobacco- and alcohol-associated head and neck cancers are declining in the developed world, potentially human papillomavirus (HPV) associated oropharnygeal cancers are increasing. METHODS: We analysed oropharyngeal and oral cavity cancer rates in Australia in 1982-2005. Cancers from the oropharynx (base of tongue, tonsil and other specific oropharyngeal sites) were classified as potentially HPV associated (n=8844); cancers in other oral cavity and oropharyngeal sites not previously associated with HPV were classified as comparison (n=28,379). RESULTS: In 2000-2005, an average of 219, 159 and 110 cancers of the tonsil, base of tongue and other oropharyngeal sites were diagnosed annually, with incidences of 1.09 (95% CI: 1.03, 1.15), 0.79 (95% CI: 0.74, 0.84) and 0.55 (95% CI: 0.50, 0.59) per 100,000, respectively. An average of 1242 comparison cancers were diagnosed annually (6.17 (95% CI: 6.03, 6.31) per 100,000). In 1982-2005, there were significant annual increases in tonsil (1.39% (95% CI: 0.88, 1.92%)) and base of tongue cancers in males (3.02% (95% CI: 2.27, 3.78%)) and base of tongue cancer in females (3.45% (95% CI: 2.21, 4.70%)). There was a significant decrease in comparison cancers in men (-1.69% (95% CI: -1.96, -1.42%)), but not in females. CONCLUSION: Potentially HPV associated oropharyngeal cancer in Australia is increasing; the impact of HPV vaccination on these cancers should be monitored. PMID- 21285980 TI - HuR keeps an angiogenic switch on by stabilising mRNA of VEGF and COX-2 in tumour endothelium. AB - BACKGROUND: Tumour stromal cells differ from its normal counterpart. We have shown that tumour endothelial cells (TECs) isolated from tumour tissues are also abnormal. Furthermore, we found that mRNAs of vascular endothelial growth factor A (VEGF-A) and cyclooxygenase-2 (COX-2) were upregulated in TECs. Vascular endothelial growth factor-A and COX-2 are angiogenic factors and their mRNAs contain an AU-rich element (ARE). AU-rich element-containing mRNAs are reportedly stabilised by Hu antigen R (HuR), which is exported to the cytoplasm. METHODS: Normal endothelial cell (NEC) and two types of TECs were isolated. We evaluated the correlation of HuR and accumulation of VEGF-A and COX-2 mRNAs in TECs and effects of HuR on biological phenotypes of TECs. RESULTS: The HuR protein was accumulated in the cytoplasm of TECs, but not in NECs. Vascular endothelial growth factor-A and COX-2 mRNA levels decreased due to HuR knockdown and it was shown that these ARE-mRNA were bound to HuR in TECs. Furthermore, HuR knockdown inhibited cell survival, random motility, tube formation, and Akt phosphorylation in TECs. CONCLUSION: Hu antigen R is associated with the upregulation of VEGF-A and COX-2 mRNA in TECs, and has an important role in keeping an angiogenic switch on, through activating angiogenic phenotype in tumour endothelium. PMID- 21285982 TI - ALKBH3, a human AlkB homologue, contributes to cell survival in human non-small cell lung cancer. AB - BACKGROUND: We have demonstrated for the first time that a novel human AlkB homologue, ALKBH3, contributes to prostate cancer development, but its clinical and biological roles in lung cancer remain unclear. METHODS: Expression of both mRNA and protein of PCA-1 was examined by RT-PCR and western blotting. We also assessed association with senescence and in vivo ALKBH3 treatment on orthotopic tumour cell inoculation, and analysed it clinicopathologically. RESULTS: We have since found novel biological roles for ALKBH3 in human lung cancers, particularly in adenocarcinoma. Our immunohistochemical analysis of human adenocarcinomas and squamous cell carcinomas of the lung not only showed overexpression of ALKBH3 in these tumours but the percentage of cells positive for ALKBH3 also correlated statistically to recurrence-free survival in adenocarcinoma. Knockdown of ALKBH3 by siRNA transfection induced expression of p21(WAF1/Cip1) and p27(Kip1) in the human lung adenocarcinoma cell line A549, resulting in cell cycle arrest, senescence and strong suppression of cell growth in vitro. In vivo, peritoneal tumour growth and dissemination was inhibited in nude mice, previously inoculated with the A549 cell line, by intraperitoneal injection of ALKBH3 siRNA + atelocollagen, as demonstrated by the reduction in both number and diameter of tumours developing in the peritoneum. CONCLUSION: We suggest that ALKBH3 contributes significantly to cancer cell survival and may be a therapeutic target for human adenocarcinoma of the lung. PMID- 21285983 TI - PG545, a dual heparanase and angiogenesis inhibitor, induces potent anti-tumour and anti-metastatic efficacy in preclinical models. AB - BACKGROUND: PG545 is a heparan sulfate (HS) mimetic that inhibits tumour angiogenesis by sequestering angiogenic growth factors in the extracellular matrix (ECM), thus limiting subsequent binding to receptors. Importantly, PG545 also inhibits heparanase, the only endoglycosidase which cleaves HS chains in the ECM. The aim of the study was to assess PG545 in various solid tumour and metastasis models. METHODS: The anti-angiogenic, anti-tumour and anti-metastatic properties of PG545 were assessed using in vivo angiogenesis, solid tumour and metastasis models. Pharmacokinetic (PK) data were also generated in tumour bearing mice to gain an understanding of optimal dosing schedules and regimens. RESULTS: PG545 was shown to inhibit angiogenesis in vivo and induce anti-tumour or anti-metastatic effects in murine models of breast, prostate, liver, lung, colon, head and neck cancers and melanoma. Enhanced anti-tumour activity was also noted when used in combination with sorafenib in a liver cancer model. PK data revealed that the half-life of PG545 was relatively long, with pharmacologically relevant concentrations of radiolabeled PG545 observed in liver tumours. CONCLUSION: PG545 is a new anti-angiogenic clinical candidate for cancer therapy. The anti-metastatic property of PG545, likely due to the inhibition of heparanase, may prove to be a critical attribute as the compound enters phase I clinical trials. PMID- 21285984 TI - Targeted inhibition of mitochondrial Hsp90 suppresses localised and metastatic prostate cancer growth in a genetic mouse model of disease. AB - BACKGROUND: The molecular chaperone heat shock protein-90 (Hsp90) is a promising cancer drug target, but current Hsp90-based therapy has so far shown limited activity in the clinic. METHODS: We tested the efficacy of a novel mitochondrial targeted, small-molecule Hsp90 inhibitor, Gamitrinib (GA mitochondrial matrix inhibitor), in the Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model. The TRAMP mice receiving 3-week or 5-week systemic treatment with Gamitrinib were evaluated for localised or metastatic prostate cancer, prostatic intraepithelial neoplasia (PIN) or localised inflammation using magnetic resonance imaging, histology and immunohistochemistry. Treatment safety was assessed histologically in organs collected at the end of treatment. The effect of Gamitrinib on mitochondrial dysfunction was studied in RM1 cells isolated from TRAMP tumours. RESULTS: Systemic administration of Gamitrinib to TRAMP mice inhibited the formation of localised prostate tumours of neuroendocrine or adenocarcinoma origin, as well as metastatic prostate cancer to abdominal lymph nodes and liver. The Gamitrinib treatment had no effect on PIN or prostatic inflammation, and caused no significant animal weight loss or organ toxicity. Mechanistically, Gamitrinib triggered acute mitochondrial dysfunction in RM1 cells, with loss of organelle inner membrane potential and release of cytochrome-c in the cytosol. CONCLUSIONS: The Gamitrinib has pre-clinical activity and favourable tolerability in a genetic model of localised and metastatic prostate cancer in immunocompetent mice. Selective targeting of mitochondrial Hsp90 could provide novel molecular therapy for patients with advanced prostate cancer. PMID- 21285985 TI - Phase I clinical, pharmacokinetic and pharmacodynamic study of SB939, an oral histone deacetylase (HDAC) inhibitor, in patients with advanced solid tumours. AB - BACKGROUND: SB939 is an orally available, competitive histone deacetylase (HDAC) inhibitor selective for class I, II and IV histone deacetylases. Preclinical evaluation of SB939 revealed a profile suggesting improved efficacy compared to other HDAC inhibitors. This phase I study was carried out to determine the safety, dose-limiting toxicity, recommended phase II dose (RPTD), as well as pharmacokinetic (PK) and pharmacodynamic (PD) profiles of SB939 in a daily * 5 schedule in advanced solid tumours. METHODS: Sequential dose-escalating cohorts of patients were enrolled into 8 dose levels. At dose level 1, SB939 was taken on days 1-3 and 15-17 every 4 weeks, then on days 1-5 and 15-19 for other dose levels. Detailed PK sampling was performed in cycle 1, days 1 and 5. Peripheral blood mononuclear cells (PBMCs) were collected on cycle 1 at various time points for determination of acetylated histone H3 (AcH3) levels. RESULTS: In total, 38 patients received a total of 96 cycles of treatment. The maximal administered dose was 90 mg and the RPTD was 60 mg given 5 consecutive days every 2 weeks. The most frequent non-hematologic adverse events (AEs) of at least possible attribution to SB939 were fatigue, nausea, vomiting, anorexia and diarrhoea. Pharmacokinetic analysis showed dose-proportional increases in AUC across the doses evaluated. Elimination half-life was 5.6-8.9 h. There was no clear relationship between AcH3 changes and dose level or anti-tumour response. CONCLUSIONS: SB939 is well tolerated in patients with advanced solid tumours. The RPTD of this drug is 60 mg on a schedule of 5 consecutive days every 2 weeks. The toxicities of SB939 are consistent with other HDAC inhibitors. PMID- 21285986 TI - Docetaxel and epirubicin compared with docetaxel and prednisone in advanced castrate-resistant prostate cancer: a randomised phase II study. AB - BACKGROUND: This randomised phase II study compared the activity and safety of the combination docetaxel (D)/epirubicin (EPI) with the conventional treatment D/prednisone (P) in advanced castrate-resistant prostate cancer (CRPC) patients. MATERIALS AND METHODS: Patients were randomly assigned to D 30 mg m(-2) as intravenous infusion (i.v.) and EPI 30 mg m(-2) i.v. every week (D/EPI arm), or D 70 mg m(-2) i.v. every 3 weeks and oral P 5 mg twice daily (D/P arm). Chemotherapy was administered until disease progression or unacceptable toxicity. RESULTS: A total of 72 patients were enrolled in the study and randomly assigned to treatment: 37 to D/EPI and 35 to D/P. The median progression-free survival (PFS) was 11.1 months (95% CI 9.2-12.6 months) in the D/EPI arm and 7.7 months (95% CI 5.7-9.4 months) in the D/P arm (P=0.0002). The median survival was 27.3 months (95% CI 22.1-30.8 months) in the D/EPI arm and 19.8 months (95% CI 14.4 24.8 months) in the D/P arm (P=0.003). Both regimens were generally well tolerated. CONCLUSION: The treatment of advanced CRPC with weekly D combined with weekly EPI was feasible and tolerable, and led to superior PFS than the treatment with 3-weekly D and oral P. PMID- 21285987 TI - A Phase I clinical study of cisplatin-incorporated polymeric micelles (NC-6004) in patients with solid tumours. AB - BACKGROUND: On the basis of preclinical studies of NC-6004, a cisplatin incorporated micellar formulation, we hypothesised that NC-6004 could show lower toxicity than cisplatin and show greater anti-tumour activity in phase I study. METHODS: A total of 17 patients were recruited in a range of advanced solid tumour types. NC-6004 was administered intravenously (i.v.) every 3 weeks. The dose escalation started at 10 mg m(-2) and was increased up to 120 mg m(-2) according to the accelerated titration method and modified Fibonacci method. RESULTS: One dose-limiting toxicity (DLT) occurred in a patient who was given 90 mg m(-2) of NC-6004, otherwise any significant cisplatin-related toxicity was not observed or generally mild toxicity was observed. Despite the implementation of post-hydration and pre-medication regimen, renal impairment and hypersensitivity reactions still developed at 120 mg m(-2), which led to the conclusion that the maximum tolerated dose was 120 mg m(-2), and the recommended dose was 90 mg m( 2), although DLT was not defined as per protocol. Stable disease was observed in seven patients. The maximum concentration and area under the concentration-time curve of ultrafilterable platinum at 120 mg m(-2) NC-6004 were 34-fold smaller and 8.5-fold larger, respectively, than those for cisplatin. CONCLUSION: The delayed and sustained release of cisplatin after i.v. administration contributes to the low toxicity of NC-6004. PMID- 21285988 TI - Temsirolimus, an mTOR inhibitor, enhances anti-tumour effects of heat shock protein cancer vaccines. AB - BACKGROUND: Temsirolimus is a mammalian target of rapamycin (mTOR) inhibitor and rapamycin analogue that is approved for treating advanced renal cell carcinoma (RCC). It is being actively evaluated in clinical trials for melanoma. The mTOR inhibitors are also immunosuppressants and are used clinically to prevent rejection following solid-organ transplant. Novel immunotherapies are being actively developed for immunoresponsive tumours, such as RCC and melanoma. METHODS: Immune-modulating effects of temsirolimus were characterised when used in combination with cancer vaccines targeting RCC (RENCA) and melanoma (B16). Cancer vaccines were recombinant tumour-specific proteins (CA9 or gp100), and recombinant heat shock protein (HSP; hsp110) served as the immune adjuvant. RESULTS: In murine models, temsirolimus enhanced the anti-tumour activity of cancer vaccines used to treat established RENCA and B16 tumours. A tumour prevention model established that the enhanced anti-tumour activity associated with temsirolimus was immune mediated. In mice treated with an HSP-based anti tumour vaccine, temsirolimus-treated CD8 T cells had greater interferon-gamma and cytotoxic T-cell responses when compared with mice treated with vaccine alone. Temsirolimus also enhanced the formation of CD8 memory cells following administration of HSP-based cancer vaccine. CONCLUSION: These results provide a rationale for combining mTOR inhibitor with immunotherapy when treating immunoresponsive tumours. PMID- 21285989 TI - Interval cancers in the NHS breast cancer screening programme in England, Wales and Northern Ireland. AB - BACKGROUND: The United Kingdom NHS Breast Screening Programme was established in 1988, and women aged between 50 and 70 are routinely invited at three yearly intervals. Expected United Kingdom interval cancer rates have been calculated previously, but this is the first publication from an exercise to collate individual-based interval cancer data at a national level. METHODS: Interval cancer case ascertainment is achieved by the regular exchange of data between Regional Breast Screening Quality Assurance Reference Centres and Cancer Registries. The present analysis includes interval cancers identified in women screened between 1st April 1997 and 31st March 2003, who were aged between 50 and 64 at the time of their last routine screen. RESULTS: In the periods >0-<12 months, 12-<24 months and 24-<36 months after a negative screen, we found overall interval cancer rates and regional ranges of 0.55 (0.43-0.76), 1.13 (0.92-1.47) and 1.22 (0.93-1.57) per 1000 women screened, respectively. Rates in the period 33-<36 months showed a decline, possibly associated with early re-screening or delayed presentation. CONCLUSIONS: Interval cancer rates were higher than the expected rates in the 24-month period after a negative screen, but were similar to published results from other countries. Increases in background incidence may mean that the expected rates are underestimated. It is also possible that, as a result of incomplete case ascertainment, interval cancers rates were underestimated in some regions in which rates were less than the expected. PMID- 21285990 TI - A multi-centre randomised phase III trial of Dexamethasone vs Dexamethasone and diethylstilbestrol in castration-resistant prostate cancer: immediate vs deferred Diethylstilbestrol. AB - BACKGROUND: The role of further hormone therapy in castration-resistant prostate cancer (CRPC) remains unclear. We performed a multi-centre randomised phase III study comparing the use of Dexamethasone, Aspirin, and immediate addition of Diethylstilbestrol (DAiS) vs Dexamethasone, Aspirin, and deferred (until disease progression) addition of Diethylstilbestrol (DAdS). METHODS: From 2001 to 2008, 270 men with chemotherapy-naive CRPC were randomly assigned, in a 1 : 1 ratio, to receive either DAiS or DAdS. They were stratified for performance status, presence of bone metastases, and previous normalisation of prostate-specific antigen (PSA) to androgen deprivation. The study end points were the proportion of patients achieving a 50% PSA response, progression-free survival (PFS), overall survival, and quality of life. Intention-to-treat analysis was carried out. The effect of treatment was studied first by Kaplan-Meier curves and log rank test, and finally through multivariable stratified Cox's proportional hazards model adjusting for the effects of possible baseline prognostic factors. Quality of life was analysed using multivariate analysis of variance. RESULTS: At study entry, the median age was 76 years (inter-quartile range: 70-80 years), the median PSA was 79 ng ml(-1), and 76% of the cohort had metastatic disease. The response rates for DAiS (68%) and DAdS (64%) were not significantly different (P=0.49). Similar to the response rate, neither the PFS (median=8.1 months for both arms) nor the overall survival (19.4 vs 18.8 months) differed significantly between the DAiS and DAdS groups (P>0.20). However, the response rate for the DAiS (68%) was significantly higher than the response rate of DA (before adding Diethylstilbestrol) (50%) (P=0.002). Similarly, the median time to progression for DAiS (8.6 months) was significantly longer than that of DA (4.5 months) (P<0.001). Multivariable analysis showed that patients with previous haemoglobin >=11 g dl(-1) decreased the risk of death significantly (hazard ratio: 0.44, 95% CI: 0.25-0.77). Patients treated with previous anti-androgens alone had more than 5 times more risk of death compared with patients treated with gonadorelin analogues throughout their castration-sensitive phase. Treatment sequencing did not affect the quality of life but pre-treatment performance status did. The incidence of veno-thromboembolic events was 22% (n=28) in DAiS and 11% (n=14) in the DA arm (P=0.02). Painful gynaecomastia occurred in only 1% on DA, whereas in 40% on DAiS (P=0.001). CONCLUSION: Dexamethasone and immediate Diethylstilbestrol resulted in neither higher PSA response rate nor higher PFS compared with Dexamethasone with deferred Diethylstilbestrol. There was no suggestion of significantly improved overall survival or quality of life. Given the significantly higher toxicity of Diethylstilbestrol, deferring Diethylstilbestrol until failure of Dexamethasone is the preferred strategy when using these agents in CRPC. PMID- 21285991 TI - BRAF mutation is a powerful prognostic factor in advanced and recurrent colorectal cancer. AB - BACKGROUND: Activating mutation of KRAS and BRAF are focused on as potential prognostic and predictive biomarkers in patients with colorectal cancer (CRC) treated with anti-EGFR therapies. This study investigated the clinicopathological features and prognostic impact of KRAS/BRAF mutation in advanced and recurrent CRC patients. METHOD: Patients with advanced and recurrent CRC treated with systemic chemotherapy (n=229) were analysed for KRAS/BRAF genotypes by cycleave PCR. Prognostic factors associated with survival were identified by univariate and multivariate analyses using the Cox proportional hazards model. RESULTS: KRAS and BRAF mutations were present in 34.5% and 6.5% of patients, respectively. BRAF mutated tumours were more likely to develop on the right of the colon, and to be of the poorly differentiated adenocarcinoma or mucinous carcinoma, and peritoneal metastasis. The median overall survival (OS) for BRAF mutation-positive and KRAS 13 mutation-positive patients was 11.0 and 27.7 months, respectively, which was significantly worse than that for patients with wild-type (wt) KRAS and BRAF (40.6 months) (BRAF; HR=4.25, P<0.001, KRAS13; HR=2.03, P=0.024). After adjustment for significant features by multivariate Cox regression analysis, BRAF mutation was associated with poor OS (HR=4.23, P=0.019). CONCLUSION: Presence of mutated BRAF is one of the most powerful prognostic factors for advanced and recurrent CRC. The KRAS13 mutation showed a trend towards poor OS in patients with advanced and recurrent CRC. PMID- 21285992 TI - Prophylactic use of lamivudine for hepatitis B exacerbation in post-operative breast cancer patients receiving anthracycline-based adjuvant chemotherapy. AB - BACKGROUND: With the increasing incidence of breast cancer worldwide, in particular in southeast Asia (including Korea), and the common use of anthracyclines in the adjuvant and metastatic settings, the occurrence of Hepatitis B virus (HBV) reactivation may develop in this patient population. The use of prophylactic antiviral agents in cancer patients may result in a reduced HBV exacerbation. The purpose of the current study was to assess the efficacy of prophylactic lamivudine in reducing the incidence and severity of HBV reactivation in post-operative breast cancer patients undergoing adjuvant doxorubicin-containing chemotherapy. METHODS: The medical records of patients undergoing anthracycline-based adjuvant chemotherapy at Samsung Medical Center between January 2001 and September 2008 were reviewed. RESULTS: From the database, 1912 breast cancer patients who had received anthracycline-based adjuvant chemotherapy were identified. Of 131 patients who were HBV surface antigen positive, 55 and 76 did and did not receive prophylactic lamivudine, respectively. In all, 30 patients (23%) developed hepatitis during doxorubicin containing adjuvant chemotherapy. Of the 30 patients, 5 (9%) were in the prophylactic lamivudine group and 25 (33%) in the control group (P=0.001). In the prophylactic lamivudine group, there was significantly less HBV reactivation (1 patient (2%) vs 20 patients (16%); P=0.002), less disruption of chemotherapy (7 vs 14%; P=0.04), and less severe hepatitis (0 vs 17%; P=0.002). CONCLUSION: Prophylactic lamivudine significantly reduced the incidence and severity of HBV reactivation in breast cancer patients undergoing anthracycline-based adjuvant chemotherapy. PMID- 21285993 TI - Awareness under general anesthesia. AB - BACKGROUND: Awareness while under general anesthesia, and the later recall of what happened during surgery, can be experienced by patients as horrific events that leave lasting mental trauma behind. Patients may have both auditory and tactile perception, potentially accompanied by feelings of helplessness, inability to move, pain, and panic ranging to an acute fear of death. For some patients, the experience of awareness under anesthesia has no sequelae; for others, however, it can lead to the development of post-traumatic stress disorder, consisting of complex psychopathological phenomena such as anxiety, insomnia, nightmares, irritability, and depression possibly leading to suicidality. METHODS: The literature on the subject was selectively reviewed. RESULTS: In the absence of risk factors awareness phenomena occur in one to two per 1000 operations under general anesthesia (0.1% to 0.2%) and are thus classed as an occasionally occurring critical event. In children, the risk of such phenomena occurring is 8 to 10 times higher. These phenomena are due to an inadequate depth of anesthesia with incomplete unconsciousness. They can be promoted by a number of risk factors that are either patient-related (ASA class III or above, medication abuse), surgery-related (Caesarean section, emergency procedures, surgery at night), or anesthesia-related (anesthesia without benzodiazepines, use of muscle relaxants). CONCLUSION: Strategies for avoiding awareness phenomena under anesthesia include the training of staff to know about the problem and, specifically, the use of benzodiazepines, the avoidance of muscle relaxants if possible, and shielding the patient from excessive noise. EEG monitoring is effective but provides no guarantee against awareness. If awareness under anesthesia occurs despite these measures, the patient must be given expert, interdisciplinary treatment as soon after the event as possible in order to minimize its potential sequelae. PMID- 21285994 TI - Further potentially carcinogenic effects of chronodisruption. PMID- 21285996 TI - Electrocardiogram in athletes. PMID- 21285998 TI - Neonatal screening for metabolic and endocrine disorders. AB - BACKGROUND: Neonatal screening for treatable endocrinopathies and inborn errors of metabolism is an important preventive measure. Advances in the diagnosis and treatment of these diseases have made it necessary to expand the screening program. METHODS: This article is based on a selective literature review and our clinical experience. RESULTS: In 2005, neonatal screening in Germany was expanded from 3 to 14 diseases, as mandated by the responsible governmental authority (the Gemeinsamer Bundesausschuss, i.e., Joint Federal Committee). From 2005 to 2008, screening revealed diseases requiring treatment in 1932 out of a total of 2,758,633 newborns (prevalence, 1 in 1428). The expansion of the screening program resulted in a 57% increase in the overall number of cases detected and a 92% increase for metabolic diseases alone. CONCLUSION: The German neonatal screening program for treatable endocrinopathies and inborn errors of metabolism is a complex and integrated preventive measure that has become markedly more effective as a result of its expansion in 2005. PMID- 21285999 TI - Oocyte donation: a risk factor for pregnancy-induced hypertension: a meta analysis and case series. AB - BACKGROUND: In 2008 and 2009, the authors saw in their institution three women who had undergone oocyte donation and went on to develop severe de novo hypertension before the 26(th) week of gestation, with values above 180/110 mm Hg. Pregnancy was prematurely terminated in these cases because of the acute threat to the mother's life, and none of the three neonates survived. Five further cases with better outcomes were found to have occurred from 2006 to 2010. On the basis of this experience, the authors performed a meta-analysis to determine whether oocyte donation elevates the risk of pregnancy-induced hypertension (PIH). The cases are discussed in detail. METHODS: Systematic review of the literature on PIH after oocyte donation, with meta-analysis and calculation of an odds ratio. We also provide a retrospective chart review of our own case series. RESULTS: 28 publications were evaluated. The overall rate of PIH in a total of 2308 deliveries after oocyte donation was 22.6%. With the aid of data from 11 studies, the course of pregnancy in a total of 644 oocyte recipients was compared to that in a control group of 2320 women who were not oocyte recipients. The calculated odds ratio for PIH after oocyte donation, compared to conventional reproductive therapy, was 2.57 (95% CI, 1.91-3.47), while the calculated odds ratio for PIH after oocyte donation, compared to other women in the control group, was 6.60 (95% CI, 4.55-9.57). CONCLUSION: The data reveal that oocyte donation confers a considerable risk that the recipient will develop PIH. The very early and severe cases of preeclampsia that we report here are rather atypical; similar cases may have occurred elsewhere without finding their way into the relevant literature. The authors recommend close surveillance of pregnancies following allogenic oocyte transplantation by physicians with special expertise in prenatal medicine. PMID- 21286000 TI - The diagnosis and treatment of soft tissue sarcomas of the limbs. AB - BACKGROUND: The diagnosis of soft-tissue sarcomas of the limbs is often delayed, sometimes markedly so, even though prompt and appropriate treatment improves survival and lowers the amputation rate. METHODS: On the basis of a selective literature review and consideration of the relevant guidelines, we developed an algorithm that can serve as a guide to the diagnosis of soft-tissue tumors in general and to the treatment of soft-tissue sarcomas of the limbs. RESULTS: Surgical resection accompanied by multimodal therapy is the only treatment strategy for soft-tissue sarcoma that provides a chance of cure. Particularly when the tumor is located in the distal part of a limb, plastic-reconstructive surgical techniques often enable adequate local control, along with limb salvage and preservation of function. The role of adjuvant or neo-adjuvant radiotherapy and/or chemotherapy is currently debated. The overall survival rate at 5 years is 87% for low-grade sarcomas and 62% for high-grade sarcomas. CONCLUSION: Any solid mass of the limbs that has been present for more than four weeks requires diagnostic evaluation. Excisional biopsy is suitable only for epifascial lesions measuring less than 5 cm in diameter. All other lesions should be imaged with MRI and then diagnosed with an incisional biopsy. Patients with soft tissue sarcomas must be treated in an interdisciplinary collaboration so that they can undergo multimodal treatment. The proposed algorithm should help avoid delays in diagnosis and optimize treatment strategies. PMID- 21286001 TI - Children with problems at school. PMID- 21286002 TI - Early start of screening. PMID- 21286004 TI - Predictive accuracy of a health risk appraisal program using mortality risk age in 116,927 Korean men. AB - Health risk appraisal (HRA) is a tool for determining health risk factors and motivating individuals to maintain a healthy lifestyle. We performed this study to describe the HRA algorithm and evaluate the accuracy of an HRA program for 10 yr mortality prediction in Korean men. We used data derived from periodic health examinations of 116,927 male public officials and school personnel aged 20 or older. Risk age and the difference between risk age and calendar age were calculated. We obtained the hazard ratio (HR) of 10-yr mortality according to the calculated age difference. Of the 116,927 subjects, 1,900 (1.6%) died during the 10 yr after the 1992 medical examinations. The HR of 10-yr mortality increased significantly with age difference. Compared with the HR in the reference group (age difference below 2 yr), the HR in the group with a 2- to 6-yr age difference was 1.20 (95% confidence interval [CI]: 1.05 to 1.38) and HR in the group with more than 7-yr age difference was 1.35 (95% CI: 1.14 to 1.75). Risk age is a relatively good predictor of 10-yr mortality in Korean men and may be useful in identifying high-risk middle-aged men for health interventions. PMID- 21286005 TI - Respiratory health among Korean pupils in relation to home, school and outdoor environment. AB - There are few studies about school-environment in relation to pupils' respiratory health, and Korean school-environment has not been characterized. All pupils in 4th grade in 12 selected schools in three urban cities in Korea received a questionnaire (n = 2,453), 96% participated. Gaseous pollutants and ultrafine particles (UFPs) were measured indoors (n = 34) and outdoors (n = 12) during winter, 2004. Indoor dampness at home was investigated by the questionnaire. To evaluate associations between respiratory health and environment, multiple logistic- and multi-level regression models were applied adjusting for potential confounders. The mean age of pupils was 10 yr and 49% were boys. No school had mechanical ventilation and CO(2)-levels exceeded 1,000 ppm in all except one of the classrooms. The indoor mean concentrations of SO(2), NO(2), O(3) and formaldehyde were 0.6 ug/m(3), 19 ug/m(3), 8 ug/m(3) and 28 ug/m(3), respectively. The average level of UFPs was 18,230 pt/cm(3) in the classrooms and 16,480 pt/cm(3) outdoors. There were positive associations between wheeze and outdoor NO(2), and between current asthma and outdoor UFPs. With dampness at home, pupils had more wheeze. In conclusion, outdoor UFPs and even low levels of NO(2) may adversely contribute to respiratory health in children. High CO(2) levels in classrooms and indoor dampness/mold at home should be reduced. PMID- 21286006 TI - Etiology of invasive bacterial infections in immunocompetent children in Korea (1996-2005): a retrospective multicenter study. AB - The purpose of this study was to identify the major etiological agents responsible for invasive bacterial infections in immunocompetent Korean children. We retrospectively surveyed invasive bacterial infections in immunocompetent children caused by eight major pediatric bacteria, namely Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, Staphylococcus aureus, Streptococcus agalactiae, Streptococcus pyogenes, Listeria monocytogenes, and Salmonella species that were diagnosed at 18 university hospitals from 1996 to 2005. A total of 768 cases were identified. S. agalactiae (48.1%) and S. aureus (37.2%) were the most common pathogens in infants younger than 3 months. S. agalactiae was a common cause of meningitis (73.0%), bacteremia without localization (34.0%), and arthritis (50%) in this age group. S. pneumoniae (45.3%) and H. influenzae (20.4%) were common in children aged 3 months to 5 yr. S. pneumoniae was a common cause of meningitis (41.6%), bacteremia without localization (40.0%), and bacteremic pneumonia (74.1%) in this age group. S. aureus (50.6%), Salmonella species (16.9%), and S. pneumoniae (16.3%) were common in older children. A significant decline in H. influenzae infections over the last 10 yr was noted. S. agalactiae, S. pneumoniae, and S. aureus are important pathogens responsible for invasive bacterial infections in Korean children. PMID- 21286007 TI - Nasopharyngeal pneumococcal carriage of children attending day care centers in Korea: comparison between children immunized with 7-valent pneumococcal conjugate vaccine and non-immunized. AB - To confirm the effect of 7-valent pneumococcal conjugate vaccine (PCV7), pneumococcal nasopharyngeal (NP) carriage was compared between vaccinated (3 + 1 doses PCV7) and non-vaccinated children. Vaccinated subjects were recruited from highly vaccinated regions (>= 60%), Seoul and Incheon whereas control subjects were recruited from Jeju Island where vaccination rates are low (< 15%). NP swabs were obtained from 400 children aged 18-59 months. Serotype and antibiotic susceptibility was analyzed. Pneumococcal carriage rate was 18.0% (36/200) and 31.5% (63/200) for the vaccinated and control group, respectively. Among those vaccinated, 41.7% (15/36) of the serotypes were vaccine-related type (VRT: 6A, 6C, 19A) with the most common serotype 6C. The next common type was non typable/non-capsule 30.6% (11/36) followed by non-vaccine type 16.7% (6/36) and vaccine type (VT) serotypes were found in only 11.1% (4/36). In contrast, 52.4% (33/63) of the isolates in the control group were VT. Resistance rates for penicillin and erythromycin were lower in the vaccine group (vaccine vs control; penicillin 45.2% vs 71.4%, erythromycin 74.2% vs 90.5%, P < 0.05). Multi-drug resistance was also lower in vaccinated subjects (vaccine vs control; 45.2% vs 69.8%, P < 0.05). PCV7 reduces carriage in VT which leads to replacement of pneumococci by antibiotic susceptible VRT or non-vaccine type strains. PMID- 21286008 TI - Immunogenicity and safety of trivalent inactivated influenza vaccine: a randomized, double-blind, multi-center, phase 3 clinical trial in a vaccine limited country. AB - Influenza vaccines are the primary method for controlling influenza and its complications. This study was conducted as a phase 3, randomized, double-blind, controlled, multi-center trial at seven university hospitals to evaluate the immunogenicity and safety of an inactivated, split, trivalent influenza vaccine (GC501, Green Cross Corporation, Yongin, Korea), which was newly manufactured in Korea in 2008. Between September 21 and 26, a total of 329 healthy subjects were recruited for the immunogenicity analysis, while 976 subjects were enrolled for the safety analysis. The GC501 vaccine met both FDA and EMEA criteria with >= 80% of subjects achieving post-vaccination titers >= 40 for all three subtypes, even in the elderly. The vaccine was well tolerated with only mild systemic and local adverse events. In summary, GC501 showed excellent immunogenicity and a good safety profile in both young adults and the elderly. The licensure of GC501 might be an important basis in preparation for the future influenza pandemic. PMID- 21286009 TI - Clinical characteristics and etiology of travelers' diarrhea among Korean travelers visiting South-East Asia. AB - The morbidity of travelers' diarrhea (TD) is still high. This study examined the incidence of common pathogens and characteristics of TD among Korean travelers who visited South-East Asian countries. We performed a prospective study involving 479 Korean travelers with diarrheal disease from February 2009 to April 2009 and stool samples were examined and questionnaire surveys were done after arrival. Enterotoxigenic Escherichia coli (ETEC) was found in 36.0% of TD cases, as were the following: Enteroaggregative Escherichia coli (EAEC) in 27.0%, Vibrio parahaemolyticus in 13.1%, and Norovirus in 11.5%. The detected rate of classic TD was higher in men (P = 0.007), in patients who had a shorter duration trip (P = 0.023) and in patients who drank more than 1 liter of water per day (P = 0.037). Positive stool culture rates were higher in men (P = 0.005), in hospitalized patients (P = 0.013). and in those who consumed impure water or raw foods (P = 0.033). A higher severity of disease corresponded to a significantly higher culture positivity rate (P = 0.029). We should consider the possibility of other pathogens in addition to ETEC in patients with TD who visit South-East Asia. Travelers need to educate about risk factors associated with TD. PMID- 21286010 TI - Prevalence of allergic diseases and risk factors of wheezing in Korean military personnel. AB - The objective of this study was to evaluate the prevalence of asthma, allergic rhinitis, and atopic dermatitis, as well as the risk factors of wheezing among young adults in the Korean military. Young military conscripts in five areas completed a modified International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. For subjects with current wheeze in one sample area, baseline spirometry and bronchodilator response were measured. For subjects without a significant response to bronchodilator (improvement in FEV1 of more than 200 mL and 12%), methacholine challenge tests (MCT) were also performed. Of 3,359 subjects that completed the questionnaire, 354 (10.5%) had current wheeze, 471 (14.0%) had current allergic rhinitis, and 326 (9.7%) had current eczema. Current wheeze was associated with family history of allergic disease, overweight, current smoking, allergic rhinitis, and atopic dermatitis. Of 36 subjects with current wheeze who underwent PFT with or without MCT in the Anyang area, 24 (66.7%) were confirmed to have current asthma. In conclusion, the prevalence of allergic disease in young adults of Korean military is not low, and the risk factors of wheezing include family history of allergic disease, overweight, current smoking, allergic rhinitis, and atopic dermatitis. PMID- 21286011 TI - DNA methylation changes following 5-azacitidine treatment in patients with myelodysplastic syndrome. AB - DNA methyltransferase inhibitor, 5-azacitidine (AC) is effective in myelodysplastic syndromes (MDS) and can induce re-expression in cancer. We analyzed the methylation of 25 tumor suppressor genes in AC-treated MDS. Hypermethylation of CDKN2B, FHIT, ESR1, and IGSF4 gene was detected in 9/44 patients. In concordance with the clinical response, a lack of or decreased methylation in 4 patients with hematologic improvements and persistent methylation in 4 others with no response was observed. The mRNA expression of CDKN2B, IGSF4, and ESR1 was significantly reduced in MDS. Our results suggest that methylation changes contribute to disease pathogenesis and may serve as marker to monitor the efficacy of treatments. PMID- 21286012 TI - Could HBx protein expression affect signal pathway inhibition by gefitinib or selumetinib, a MEK inhibitor, in hepatocellular carcinoma cell lines? AB - Hepatitis B virus X (HBx) protein has been known to play an important role in development of hepatocellular carcinoma (HCC). The aim of this study is to find out whether HBx protein expression affects antiproliferative effect of an epidermal growth factor receptor-tyrosine kinase (EGFR-TK) inhibitor and a MEK inhibitor in HepG2 and Huh-7 cell lines. We established HepG2 and Huh-7 cells transfected stably with HBx gene. HBx protein expression increased pERK and pAkt expression as well as beta-catenin activity in both cells. Gefitinib (EGFR-TK inhibitor) inhibited pERK and pAkt expression and beta-catenin activity in both cells. Selumetinib (MEK inhibitor) reduced pERK level and beta-catenin activity but pAkt expression was rather elevated by selumetinib in these cells. Reduction of pERK levels was much stronger with selumetinib than gefitinib in both cells. The antiproliferative efficacy of selumetinib was more potent than that of gefitinib. However, the antiproliferative effect of gefitinib, as well as selumetinib, was not different between cell lines with or without HBx expression. Signal pathway activation by HBx might not be strong enough to attenuate the antiproliferative effect of EGFR-TK inhibitor. Future experiments are needed to understand the role of HBx protein expression in HCC treatment using molecular targeting agent. PMID- 21286013 TI - Effects of benzo(a)pyrene on the expression of heat shock proteins, pro inflammatory cytokines and antioxidant enzymes in hepatic tumors induced by rat hepatoma N1-S1 cells. AB - Benzo(a)pyrene (BaP) is a polycyclic aromatic hydrocarbon (PAH) that is easily introduced to humans via consumption of grilled or smoked meat. BaP causes harmful oxidative effects on cell development, growth and survival through an increase in membrane lipid peroxidation, oxidative DNA damage and mutagenesis. Therefore, the present study was conducted to evaluate the synergistic effects of BaP on oxidative stress in hepatic tumors. In this study, we established a hepatic tumor model by injecting rat hepatoma N1-S1 cells into healthy rats. Changes in the abundance of heat shock proteins (HSPs), antioxidant enzymes and pro-inflammatory cytokines were then investigated by western blot analysis. In addition, we examined changes in oxidative stress levels. Injection of N1-S1 cells or concomitant injection of BaP and N1-S1 cells resulted in the formation of hepatic tumors at the injection site. Evaluation of rat plasma reveals that hepatic tumors induced by BaP and N1-S1 cells expresses higher levels of Hsp27, superoxide dismutase (SOD), and tumor necrosis factor-alpha (TNF-alpha) when compared to those induced by N1-S1 cells only. The collective results of this study suggest that BaP exerts synergistic effects on the expression of HSP, cytokines and antioxidant enzymes in hepatic tumors induced by rat hepatoma N1-S1 cells. PMID- 21286014 TI - GSTM1 tissue genotype as a recurrence predictor in non-muscle invasive bladder cancer. AB - Tissue genotyping is more useful approach than using blood genomic DNA, which can reflect the effects of the somatic mutations in cancer. Although polymorphisms in glutathione S-transferase (GST) have been associated with the risk of bladder cancer (BC) development, few reports provide information about the prognosis of BC. We investigated glutathione S-transferase mu (GSTM1) and glutathione S transferase theta (GSTT1) genotypes using genomic DNA from primary 165 BC tissue samples to assess the association with disease prognosis. DNA samples from tumor were analyzed by multiplex polymerase chain reaction (PCR). The results were compared with clinicopathological parameters. The prognostic significance of the GSTs was evaluated by Kaplan-Meier and multivariate Cox regression model. Kaplan Meier estimates revealed significant differences in time to tumor recurrence according to the GSTM1 tissue genotype (P = 0.038) in non-muscle invasive bladder cancer (NMIBC). Multivariate Cox regression analysis also revealed that the tissue GSTM1 genotype (hazards ratio [HR]: 0.377, P = 0.031) was an independent predictor of bladder tumor recurrence in NMIBC. This identification of GSTM1 tissue genotype as a prognosticator for determining recurrence in NMIBC should prove highly useful in a clinical setting. PMID- 21286015 TI - Malignancy rate in sonographically suspicious thyroid nodules of less than a centimeter in size does not decrease with decreasing size. AB - We evaluated the malignancy and nondiagnostic rates using fine needle aspiration cytology (FNAC) results in thyroid nodules smaller than 1 cm according to the subdivided size. We retrospectively reviewed the medical records of all subjects underwent FNAC from 2003 to 2009 in our hospital, and 2,756 patients of subcentimeter thyroid nodules with one or more suspicious sonographic features and 7,105 with nodule sized 1 cm or more were included. The malignancy rate was higher in those subcentimeter nodules with suspicious sonographic findings than the nodule sized 1cm or more (19.7% vs 7.8%, P < 0.001). We grouped the nodules based on size with mm interval and observed that the malignancy rate did not decrease but the nondiagnostic results increased its size decrement. When we divided the subjects arbitrarily into a 5 mm or smaller and a 6-9 mm sized group, nondiagnostic cytology findings were reported more frequently in the smaller group (24.3% vs 18.1%, P = 0.001), while the rate of "malignant" was similar (18.3% vs 15.5%, P = 0.123) and the rate of "suspicious for malignancy" was higher (6.8% vs 2.9%, P < 0.001). Therefore when we decide to perform FNAC or not in subcentimeter-sized nodules, we should consider sonographic findings and other clinical risk factors but not the nodular size itself. PMID- 21286016 TI - The correlation between thyrotropin and dyslipidemia in a population-based study. AB - This study investigated the relationship between serum thyrotrophin levels and dyslipidemia in subclinical hypothyroid and euthyroid subjects. A total of 110 subjects with subclinical hypothyroidism and 1,240 euthyroid subjects enrolled in this study. Patients with subclinical hypothyroidism had significantly lower high density lipoprotein cholesterol (HDL-C) levels than those who were euthyroid. The lipid profiles were each categorized and mean thyrotrophin levels were higher in subjects in the dyslipidemia subclasses than subjects in the normal subclasses. Thyrotrophin was positively associated with serum triglyceride and negatively associated with serum HDL-C in women. Thyrotrophin was also positively associated with total cholesterol (TC) in the overweight population along with TC and LDL-C in overweight women. In the euthyroid population, thyrotrophin was positively associated with TC in the overweight population. In conclusion, serum thyrotrophin was correlated with dyslipidemia in subclinical hypothyroid and euthyroid subjects; the correlation was independent of insulin sensitivity. PMID- 21286017 TI - Gender differences in the effect of obesity on chronic diseases among the elderly Koreans. AB - The objective of this study is to investigate gender differences of obesity on major chronic diseases in elderly Korean males and females. This study applied a cross sectional design using the 2005 Korean National Health and Nutrition Examination Survey (KNHNES). We selected 508 elderly males and 830 elderly females who were 60 or more years old. Obesity was defined using Body Mass Index (BMI) (>= 25) or Waist Circumference (WC) (>= 90 for men and >= 85 for women). We applied a surveylogistic regression to determine gender differences in relation to the effect of obesity on eleven major chronic diseases. Using WC, 46.2% of females were obese compared to 34.3% for males. Similarly, using BMI, 42.2% of females were obese compared to 31.7% for males. While obese males and females had similar profiles for developing metabolic syndrome components including hypertension, dyslipidemia, and diabetes (odds ratios [ORs] were 1.8-2.6 for males and 1.7-2.5 for females), obese elderly females had additional risks for arthritis and urinary incontinence (ORs 1.5-1.8 for females) as well as higher prevalence for these diseases. A clearer understanding of gender differences in relation to the association between obesity and chronic diseases would be helpful for reducing the social burden of chronic diseases in the elderly. PMID- 21286018 TI - Cystatin C as an early biomarker of nephropathy in patients with type 2 diabetes. AB - This study was done to evaluate clinical usefulness of cystatin C levels of serum and urine in predicting renal impairment in normoalbuminuric patients with type 2 diabetes and to evaluate the association between albuminuria and serum/urine cystatin C. Type 2 diabetic patients (n = 332) with normoalbuminuria (n = 210), microalbuminuria (n = 83) and macroalbuminuria (n = 42) were enrolled. Creatinine, urinary albumin levels, serum/urine cystatin C and estimated glomerular filtration rate (eGFR by MDRD [Modification of Diet in Renal Disease] and CKD-EPI [Chronic Kidney Disease Epidemiology Collaboration] equations) were determined. The cystatin C levels of serum and urine increased with increasing degree of albuminuria, reaching higher levels in macroalbuminuric patients (P < 0.001). In multiple regression analysis, serum cystatin C was affected by C reactive protein (CRP), sex, albumin-creatinine ratio (ACR) and eGFR. Urine cystatin C was affected by triglyceride, age, eGFR and ACR. In multivariate logistic analysis, cystatin C levels of serum and urine were identified as independent factors associated with eGFR < 60 mL/min/1.73 m(2) estimated by MDRD equation in patients with normoalbuminuria. On the other hand, eGFR < 60 mL/min/1.73 m(2) estimated by CKD-EPI equation was independently associated with low level of high-density lipoprotein in normoalbuminuric patients. The cystatin C levels of serum and urine could be useful markers for renal dysfunction in type 2 diabetic patients with normoalbuminuria. PMID- 21286019 TI - Incidence and risk factors of steroid-induced diabetes in patients with respiratory disease. AB - Glucocorticoids are effective for treating several respiratory diseases. However, they can cause hyperglycemia. This study determined the incidence and risk factors of steroid-induced diabetes mellitus (S-DM) in patients treated with glucocorticoid for respiratory diseases. A retrospective study examined patients with respiratory diseases treated with a prednisolone-equivalent glucocorticoid dose exceeding 20 mg/day for at least 4 weeks between January 2003 and December 2008. Patients whose initial random glucose level exceeded 200 mg/dL or who had pre-existing diabetes were excluded. S-DM was defined as a fasting glucose concentration exceeding 126 mg/dL or a random glucose concentration exceeding 200 mg/dL at least twice after beginning steroid treatment. A total of 231 patients with respiratory diseases met the inclusion criteria. Their median age was 55 yr, and 139 were female. The median cumulative prednisolone-equivalent glucocorticoid dose was 4,965 mg, and the median duration of steroid treatment was 193 days. S DM was diagnosed in 34 (14.7%) of 231 patients. Multivariate logistic regression identified older age (odds ratio 1.05, 95% confidence interval 1.02-1.09) as a risk factor for S-DM. S-DM is frequent among patients with respiratory diseases treated with glucocorticoid. Clinicians should be aware of the possibility of S DM, especially among elderly patients. PMID- 21286020 TI - The risk of obstructive lung disease by previous pulmonary tuberculosis in a country with intermediate burden of tuberculosis. AB - We evaluated the effects of previous pulmonary tuberculosis (TB) on the risk of obstructive lung disease. We analyzed population-based, the Second Korea National Health and Nutrition Examination Survey 2001. Participants underwent chest X-rays (CXR) and spirometry, and qualified radiologists interpreted the presence of TB lesion independently. A total of 3,687 underwent acceptable spirometry and CXR. Two hundreds and ninety four subjects had evidence of previous TB on CXR with no subjects having evidence of active disease. Evidence of previous TB on CXR were independently associated with airflow obstruction (adjusted odds ratios [OR] = 2.56 [95% CI 1.84-3.56]) after adjustment for sex, age and smoking history. Previous TB was still a risk factor (adjusted OR = 3.13 [95% CI 1.86-5.29]) with exclusion of ever smokers or subjects with advanced lesion on CXR. Among never smokers, the proportion of subjects with previous TB on CXR increased as obstructive lung disease became more severe. Previous TB is an independent risk factor for obstructive lung disease, even if the lesion is minimal and TB can be an important cause of obstructive lung disease in never-smokers. Effort on prevention and control of TB is crucial in reduction of obstructive lung disease, especially in countries with more than intermediate burden of TB. PMID- 21286021 TI - Endobronchial ultrasound-guided transbronchial needle biopsy for diagnosis of mediastinal lymphadenopathy in patients with extrathoracic malignancy. AB - Mediastinal lymphadenopathy associated with extrathoracic malignancy or a metastasis of unknown origin (MUO) requires pathological verification. Surgical exploration or endoscopic ultrasound-guided fine needle aspiration is limited to application. We investigated the effectiveness of endobronchial ultrasound-guided transbronchial needle biopsy (EBUS-TBNA) for evaluating mediastinal lymphadenopathy in patients with an extrathoracic malignancy. We retrospectively analyzed data from 59 patients who underwent EBUS-TBNA with a core biopsy because of a suspected mediastinal metastasis between September 2008 and August 2010. All patients had previously been diagnosed with an extrathoracic malignancy (n = 39, 66.1%) or a suspected MUO without a thoracic lesion (n = 20, 33.9%). A total of 88 lymph nodes was analyzed. EBUS-TBNA findings indicated malignancies in 34 patients (57.6%). The EBUS-TBNA sensitivity and specificity for the detection of mediastinal malignancy in patients with a previous extrathoracic malignancy were 96.3% and 100%, respectively. For MUO patients without a thoracic lesion, the sensitivity and specificity were 61.5% and 100%, respectively. The overall sensitivity and specificity were 81.0% and 100%, respectively (P = 0.053). EBUS TBNA is a safe and effective modality for evaluating mediastinal lymphadenopathy in patients with a previous extrathoracic malignancy or a MUO without a thoracic lesion. The application of this diagnostic tool is likely to have significant clinical implications. PMID- 21286022 TI - Role of corticotrophin-releasing factor in the stress-induced dilation of esophageal intercellular spaces. AB - Corticotrophin-releasing factor (CRF) plays a major role in coordinating stress responses. We aimed to test whether blocking endogenous CRF activity can prevent the stress-induced dilation of intercellular spaces in esophageal mucosa. Eighteen adult male rats were divided into 3 groups: 1) a non-stressed group (the non-stressed group), 2) a saline-pretreated stressed group (the stressed group), 3) and an astressin-pretreated stressed group (the astressin group). Immediately after completing the experiments according to the protocol, distal esophageal segments were obtained. Intercellular space diameters of esophageal mucosa were measured by transmission electron microscopy. Blood was sampled for the measurement of plasma cortisol levels. Mucosal intercellular spaces were significantly greater in the stressed group than in the non-stressed group. Mucosal intercellular spaces of the astressin group were significantly smaller than those of the stressed group. Plasma cortisol levels in the stressed group were significantly higher than in the non-stressed group. Pretreatment with astressin tended to decrease plasma cortisol levels. Acute stress in rats enlarges esophageal intercellular spaces, and this stress-induced alteration appears to be mediated by CRF. Our results suggest that CRF may play a role in the pathophysiology of reflux-induced symptoms or mucosal damage. PMID- 21286023 TI - Trends in epidemiology of neonatal sepsis in a tertiary center in Korea: a 26 year longitudinal analysis, 1980-2005. AB - There were many reports of longitudinal changes in the causative organisms of neonatal sepsis in Western countries but few in Asia. We aimed to study longitudinal trends in the epidemiology of neonatal sepsis at Seoul National University Children's Hospital (SNUCH), a tertiary center in Korea, and compared the results to previous studies of Western countries. The medical records of all of the neonates who were hospitalized at SNUCH from 1996 to 2005 with positive blood cultures were reviewed. We also compared the findings to previous 16-yr (1980-1995). One hundred and forty-nine organisms were identified in 147 episodes from 134 infants. In comparison with the previous 16-yr studies, there was a decrease in the number of Escherichia coli infections (16.2% vs 8.7%: odds ratio [OR] 0.495; 95% confidence interval [CI], 0.255-0.962; P = 0.035), but an increase in Staphylococcus aureus (16.6% vs 25.5%: OR 1.720; 95% CI, 1.043-2.839; P = 0.033) and fungal infections (3.3% vs 18.7%: OR 6.740; 95% CI, 2.981-15.239; P < 0.001), predominantly caused by Candida species. In conclusion, the incidence of sepsis caused by E. coli decreases, but S. aureus and fungal sepsis increases significantly. Compared with Western studies, the incidence of sepsis caused by S. aureus and fungus has remarkably increased. PMID- 21286024 TI - Morphine postconditioning attenuates ICAM-1 expression on endothelial cells. AB - The purpose of this study is to determine 1) whether morphine post condition (MPostC) can attenuate the intercellular adhesion molecules-1 (ICAM-1) expression after reoxygenation injury and 2) the subtype(s) of the opioid receptors (ORs) that are involved with MPostC. Human umbilical vein endothelial cells (HUVECs) were subjected to 6 hr anoxia followed by 12 hr reoxygenation. Three morphine concentrations (0.3, 3, 30 uM) were used to evaluate the protective effect of MPostC. We also investigated blockading the OR subtypes' effects on MPostC by using three antagonists (a u-OR antagonist naloxone, a kappa-OR antagonist nor binaltorphimine, and a delta-OR antagonist naltrindole) and the inhibitor of protein kinase C (PKC) chelerythrine. As results, the ICAM-1 expression was significantly reduced in the MPostC (3, 30 uM) groups compared to the control group at 1, 6, 9, and 12 hours reoxygenation time. As a consequence, neutrophil adhesion was also decreased after MPostC. These effects were abolished by co administering chelerythrine, nor-binaltorphimine or naltrindole, but not with naloxone. In conclusion, it is assumed that MPostC could attenuate the expression of ICAM-1 on endothelial cells during reoxygenation via the kappa and delta-OR (opioid receptor)-specific pathway, and this also involves a PKC-dependent pathway. PMID- 21286025 TI - Catheter-related candidemia caused by Candida haemulonii in a patient in long term hospital care. AB - Candida haemulonii, one of the non-albicans Candida species, is an emerging yeast pathogen that is known to be resistant to amphotericin B and other antifungal agents such as azoles. These anti-fungal agents have often been associated with clinical treatment failure, so no treatment regimen has been clearly established for invasive C. haemulonii infections. We investigated a catheter-related infection of C. haemulonii candidemia in an adult patient in long-term hospital care. In the early stages, the candidemia remained persistent despite treatment with fluconazole. However, after changing the antifungal agent to caspofungin, the candidemia was resolved. Fluconazole and amphotericin B are not reliable empirical antifungal agents for invasive C. haemulonii infections, as shown in previous case reports. An echinocandin such as caspofungin may be an appropriate empirical choice of antifungal agent for an invasive C. haemulonii infection. PMID- 21286026 TI - Drug fever due to piperacillin/tazobactam loaded into bone cement. AB - Although drug fever may develop after administration of the drug by various routes, it has not been reported with antibiotic-loaded bone cement. Here, a case of drug fever induced by piperacillin/tazobactam loaded into bone cement is reported. A 72-yr-old woman presented with fever that developed two weeks after insertion of bone cement loaded with antibiotics including piperacillin/tazobactam into the knee joint for infectious arthritis. The fever was associated with a skin rash and blood eosinophilia. The work-up of the fever excluded several causes. Drug provocation test demonstrated that the piperacillin/tazobactam, which had been loaded in the bone cement, was the cause of the fever. The findings of this case suggest that drug fever can be induced by any drug placed and released continuously within the body. Therefore, the evaluation for possible drug fever should include all drugs the patient has been exposed to regardless of the route of administration. PMID- 21286027 TI - Extranodal interdigitating dendritic cell sarcoma presenting in the pleura: a case report. AB - Interdigitating dendritic cell sarcoma (IDCS) is an extremely rare neoplasm arising from the antigen-presenting cells of the immune system. This disease usually involves the lymph nodes, and rarely, extranodal sites may be affected. The authors report a case of extranodal IDCS presenting in the pleura. A 32-yr old man presented with progressive chest pain. Imaging studies showed diffuse pleural thickening with pleural effusion. Morphological and immunohistochemical analysis of an incisional biopsy of the pleura were consistent with a diagnosis of IDCS; tumor cells were positive for S100 and CD45, but negative for CD1a, CD21, CD35, B cell and T cell markers. The patient was administered chemotherapy, but died of progressive disease. Although its incidence is extremely rare, this case suggests that extranodal IDCS should be considered in the differential diagnosis of undifferentiated neoplasms and that immunohistochemical staining be performed using appropriate markers. PMID- 21286028 TI - Incontinentia pigmenti in a newborn with NEMO mutation. AB - Incontinentia pigmenti (IP) (OMIM #308300) is a rare X-linked dominant neuroectodermal multisystemic syndrome due to mutations in the gene for NF-kappaB essential modulator (NEMO). A term newborn girl who was born with erythematous vesicular eruptions developed recurrent seizures during the first and second weeks of her life. The serial MRIs demonstrated diffuse, progressive brain infarctions and subsequent encephalomalacia as well as brain atrophy. Skin biopsy found it was consistent with the vesicular stage of IP. Genetic analysis revealed a deletion exon 4-10 in NEMO gene associated with IP. We hereby report a Korean female baby with IP confirmed by mutation analysis of NEMO gene. PMID- 21286030 TI - Superfluous Redundancy: There's a Lot of It Going Around. PMID- 21286031 TI - Just a GP-Or a Family Doctor?: Two more views in the debate. PMID- 21286029 TI - Haddad syndrome with PHOX2B gene mutation in a Korean infant. AB - Congenital central hypoventilation syndrome with Hirschsprung's disease, also known as Haddad syndrome, is an extremely rare disorder with variable symptoms. Recent studies described that congenital central hypoventilation syndrome had deep relation to the mutation of the PHOX2B gene in its diagnosis and phenotype. We report a newborn male infant with clinical manifestations of recurrent hypoventilation with hypercapnea and bowel obstruction. These clinical manifestations were compatible with congenital central hypoventilation syndrome and Hirschsprung's disease, and polyalanine 26 repeats in the PHOX2B gene supported the diagnosis of congenital central hypoventilation. We described a first case of Haddad syndrome in Korean and its clinical and genetic characteristics were discussed. PMID- 21286032 TI - [Not Available]. PMID- 21286033 TI - [Not Available]. PMID- 21286034 TI - Reader dislikes 'liberal feminist' view. PMID- 21286035 TI - Rapid relief from croup. PMID- 21286036 TI - Breath of fresh air. PMID- 21286037 TI - Gee, thanks! PMID- 21286038 TI - A spot of praise for acne protocol. PMID- 21286039 TI - CFPC Fails Rural Members. PMID- 21286040 TI - Important issues misread? PMID- 21286041 TI - Infants and Cow's Milk. PMID- 21286043 TI - "A superb article". PMID- 21286042 TI - Academics taking over. PMID- 21286044 TI - More nose-blowing for foreign body removal. PMID- 21286047 TI - Who needs an investment counsellor? Maybe you do. PMID- 21286046 TI - Infant feeding: feds seek readers' help. PMID- 21286048 TI - Developmental screening in family medicine. AB - The Denver Developmental Screening Test (DDST) has been performed in a family medicine teaching unit for eight years as part of a package of health screening and maintenance. Between August 1979 and June 1980, 261 children were screened. The results identified five abnormal, 14 questionable and four untestable children. A review of the 238 normal results separated them into 39 low performers, nine who performed well in the DDST but were seen to have problems and the remainder who functioned satisfactorily. In total 21 referrals were made to specialists outside the department who verified the positive findings identified. Ten of these resulted directly from the DDST. The nurse associate performed the developmental screening as part of routine child care. The test has been helpful in detecting physical and emotional problems, and also in promoting positive parenting and coping abilities through discussions, counselling and health teaching. PMID- 21286049 TI - Effectiveness of the family physician in hypertension screening and management. AB - As the initial step of a large randomized trial to test a new strategy of caring for hypertensive patients, the state of blood pressure screening was studied in 34 community-based family practices in southwestern Ontario. The charts of all active adult patients, 20-65 years of age, were reviewed.At least one blood pressure reading was recorded in the last five years for 71% of the 40,453 patients. The proportion of patients screened increased with age; in each age group, a greater proportion of females than males had been screened. Overall, 8.9% of males and 9.6% of females were labelled hypertensive. The rate of patients so labelled increased with age to a maximum of 30% of the 55-65 age group. More than 50% of patients with diastolic pressures over 105 mm Hg were not taking hypotensive drugs. PMID- 21286050 TI - Tourette syndrome. AB - Tourette syndrome (Gilles de la Tourette disease) is a disorder of involuntary muscular tics, vocalizations and compulsive behavior. The tics and muscle movements vary in form and course; the complex repetitive patterns are eventually replaced by other patterns. The vocalization may be in the form of sounds, words or profanities and sometimes echolalia, echopraxia and palilalia. The onset may be from age two to 15 but is usually between ages eight and 12. Recent studies suggest that there is a hypersensitivity of dopamine receptors. Most patients respond well to haloperidol, but other drugs that may be of value include clonidine, pimozide, fluphenazine and trifluoroperazine. PMID- 21286051 TI - [Not Available]. AB - A book on infectious diseases based directly on clinical practice has been produced for family physicians. It identifies clear objectives oriented towards resolution of clinical problems. The book is organized on four fundamental principles: 1. to respond to pertinent problems in the practice of general medicine; 2. to respect the process of the family doctor's clinical practice, taking into account the means at his disposal; 3. to integrate the necessary basic science with the understanding of clinical and therapeutic decisions; 4. to limit the extent of basic and clinical knowledge, taking into account the nature and degree of complexity of the family doctor's decisions. Examples of these principles are given. PMID- 21286052 TI - Percutaneous transluminal angioplasty in peripheral vascular disease: a review. AB - Percutaneous transluminal angioplasty is a relatively new technique employed in the treatment of stenoses or occlusions of peripheral arteries. While the longterm success rates have yet to be determined, short-term results have been excellent. The procedure has greatest value in the dilatation of localized lesions, avoiding surgery and its attendant risks. However, PTA and surgery are complementary, not competing, modes of therapy. PTA complements the traditional therapy of peripheral vascular disease, which remains reconstructive surgery. PMID- 21286053 TI - Some hazards of passive smoking. AB - Non-smokers are exposed to three types of cigaret smoke: mainstream, sidestream and diffusional smoke, of which sidestream (produced while the cigaret smolders in an ashtray) is the most toxic. Studies of passive smoking show that while smoke is an unpleasant irritant, it appears to have no lasting effects on healthy passive smokers. It may, however, be a particular irritant to already sensitive individuals such as asthmatics, and to young children chronically exposed. Such children show an increase of respiratory disorders, and adults show an increase of small airway disease with a possible risk of lung cancer. More stringent legislation on smoking is desirable. PMID- 21286054 TI - Pinworms (enterobius vermicularis). AB - Pinworm infestation (enterobiasis, syn. oxyuriasis), though not usually dangerous, remains one of the commonest parasitic infections seen by the family physician. Particularly prevalent in the pediatric age group, pinworms also infect adults; in both groups the commonest symptom is pruritus ani. Detailed descriptions of history, life cycle, and epidemiology are given. In addition to hygienic measures useful in treatment, the particulars of drug therapy are also outlined. PMID- 21286055 TI - Anterior cruciate: methods of physical examination. AB - Tear of the anterior cruciate ligament is a common, serious injury. Since the long-range consequences of uncorrected anterior cruciate incompetence are better understood, and surgical and rehabilitative measures improved, early accurate diagnosis is increasingly important. Besides a careful history, diagnosis requires the use of specific physical examination methods to reproduce the symptomatic subluxation (anterior shift or internal rotation) and to assess functional performance of the knee. PMID- 21286056 TI - Well child care in family medicine part 2: immunization and nutrition. AB - Part 1 of this article, published last month, outlined the work of a University of Western Ontario committee in establishing criteria for the well child examination. This final section describes the committee's schedule for immunization, emphasizing that the schedule itself is far less important than the need to ensure completion of an immunization program. It also outlines the committee's findings on infant nutrition, with strategies for promotion of breast feeding. PMID- 21286057 TI - Occupational health and the family physician part 1: definition and resources. AB - The field of occupational health is of growing importance to family physicians, yet for many represents a nebulous field. This paper describes the main concepts and shows how a family physician can quickly obtain mastery of the field sufficient for any demands that may be made on his skill in this area. Part 1 names resources in occupational health most useful to family doctors and Part 2, to be published next month, outlines a method of taking an occupational history, and of determining the essential work structure of one's community. PMID- 21286059 TI - Training for family medicine: the Quebec position. PMID- 21286058 TI - As it happened: appendicitis or endometriosis? AB - Abdominal pain of a few hours' duration may indicate an innocent dysfunction or could be the beginning of some serious intra-abdominal organic disease. The physician's problem is to make the right decision at the right time. Acting too soon could result in an unnecessary operation; waiting too long could lead to unpleasant and risky complications. PMID- 21286060 TI - The national breast screening study: an opportunity for family physicians. PMID- 21286061 TI - [Not Available]. PMID- 21286062 TI - [Not Available]. PMID- 21286063 TI - Education for sexuality: which organs are which? PMID- 21286064 TI - Sexual silence: repression or modesty? PMID- 21286065 TI - More on blowing noses. PMID- 21286066 TI - The OMA and the Press: CFP Under Fire. PMID- 21286067 TI - The jenner appeal. PMID- 21286068 TI - Statistical significance: heads or tails? PMID- 21286069 TI - Christmas blues. PMID- 21286071 TI - Drug co. Accused of unethical advertising. PMID- 21286070 TI - Diagnosing UTI: Another Flip of the Coin? PMID- 21286072 TI - A directory of cancer support services in ontario. PMID- 21286073 TI - Office cure for hydrocele? PMID- 21286074 TI - Exploring general practice. AB - This paper describes the development of research in general practice in the United Kingdom and postulates that the stimulus for this was the need to solve the problems faced by general practitioners as the British National Health Service evolved. With rapid advances in medical knowledge, the need for research in this field will be even greater in the future. A course designed to train young principals in general practice to look critically at their work and carry out simple research is currently underway. PMID- 21286075 TI - Sore throats in adults: who sees a doctor? AB - In a study looking at the relationship of life stress events to health status, 500 individuals randomly selected from family practices in Hamilton, Ontario were asked to keep a health diary for three days every two weeks over a two year period. The compliance with diary keeping was remarkably high (85%), partly due to a novel method of reinforcing compliance. The present study involved reviewing these health diaries for symptoms of sore throat during the three month period January to March 1979. Over 2,700 diaries representing 8,148 person/days were reviewed; 48% recorded at least one symptom and 5.2% of all diaries recorded sore throat on at least one day. Eight to 16% of those individuals recording sore throat as a symptom contacted a health professional and/or took prescribed drugs.Although the group under study included only adults, the low medical contact rate of patients with sore throats raises questions about the effectiveness of any approach to sore throat/pharyngitis adopted in office practice. PMID- 21286076 TI - The canadian national breast screening study: why it deserves support. AB - The National Breast Screening Study was designed to show whether screening with mammography and physical examination of the breasts reduces mortality from breast cancer in volunteers aged 40-49 and to determine the incremental effect of mammography over and above any effect of physical examination in women aged 50 59.In spite of the high incidence of breast cancer in these two age groups, both physicians and the public have shown reluctance to support the trial. This reluctance appears to be based on lack of understanding of the nature of screening tests and on concern about the hazards of radiation. The design and justification for the study is discussed and placed in the context of the principles of screening. The risks of radiation are minimal; in the study the cumulative exposure will be less than one RAD after five annual mammograms, and new evidence shows that women in their forties are not as susceptible to risks from radiation to the breasts. PMID- 21286077 TI - Hodgkin's Disease: Treatment and Prognosis. AB - The prognosis of Hodgkin's disease (HD) has improved impressively in the past decade. Presently, no stage of disease is beyond cure or expectancy of a long disease-free survival. The extent of disease involvement governs the choice of therapy. The treatment of choice for localized disease is irradiation, although the techniques used vary considerably among different centres. Combination chemotherapy is recommended for stages 3B and 4. The management of stage 3A and some high-risk subsets of HD remains controversial. In specific situations, combined treatments are indicated. Therapy associated complications, immediate or delayed, deserve greater attention. Ironically, their impact upon the improved survivors might be morbid and devastating. PMID- 21286078 TI - Carcinogens in the workplace: a scientific, political and social problem. AB - Investigation, assessment, and management of carcinogenic risks are not only scientific but also political responsibilities. In Canada, this becomes cumbersome, since local, provincial and federal policies are involved. The process also involves workers and management. This article outlines Canadian legislative experience, the principles involved, the methods of risk assessment, and the classification of carcinogens in the workplace. PMID- 21286079 TI - Cancer of the cervix and the smoking husband. AB - Information was gathered on 22 patients with in situ and 11 patients with invasive carcinoma of the cervix as part of a 20-year follow up study. Patients were compared with 29 controls who had had hysterectomies for non-cancer reasons. A significant relationship was found between the amount of cigarets smoked by the husband and the occurrence of cancer of the cervix in the wife. When compared with other risk factors, data showed a smoking husband to be the most significant indicator of whether or not a woman developed cancer of the cervix. PMID- 21286080 TI - Mammography in screening for breast cancer: a viewpoint. AB - Controversy exists over the usefulness of mammographic screening for breast cancer. A discussion of the risk-benefit analysis and high risk women profile help the family physician in making a decision about who should be screened with mammography. Although earlier clinical trials show no benefit, and possible risks, of screening women under age 50, current techniques of mammography subject women to far less radiation and presumably far less risk. Based on this evidence, there is merit in screening women aged 40-49 with mammography every two to three years. PMID- 21286082 TI - Why do doctors hate hospital administrators? PMID- 21286081 TI - Smoking Cessation Strategies: The Family Physician's Role. AB - Family physicians are in an ideal position to help patients who smoke. Our most effective strategy is ourselves, offering clear information and advice to stop smoking, combined with a follow up plan. Although controlled research is lacking for most intervention strategies, a number of them do work at least for the short term. Combined with the physician's ongoing support and reinforcement, patients may choose from 'cold turkey', hypnotherapy, nicotine-containing gum, acupuncture, group programs or behavioral methods such as rapid smoking. The author's experience with some of these interventions is included. PMID- 21286083 TI - Homophobia: how physicians treat homosexual patients. AB - Doctors tend to be uncomfortable with homosexual patients, who make up a large part of an average practice. Homosexuality lies along the continuum of sexual expression and should not be considered a perversion. To a greater or lesser extent, it is present in all people, and is acted upon in a variety of ways. Physicians should be aware of the homosexual patient's lifestyle in order to give the best medical care. The epidemiology of disease differs in the homosexual and heterosexual population. PMID- 21286084 TI - Occupational Health and the Family Physician Part 2: History-taking-How Not to Miss an Occupationally-Related Disease. AB - In the first part of this article, occupational health was defined as part of the family physician's total care for his or her patient. This part deals with the components of the occupationally related history, the role of stress in the workplace, and knowledge of the work structure in the community. PMID- 21286085 TI - Letter to a friend. PMID- 21286086 TI - Pioneer physician and scientific translator: dr. Iser steiman. PMID- 21286087 TI - Tularemia. AB - A 37-year-old woman experienced local symptoms on returning from a camping trip. Within three weeks she developed generalized symptoms and was hospitalized. Tularemia, and often overlooked cause of bubo formation, is endemic in Nevada. The diagnosis should be considered when patients who have visited such an area present with enlarged, painful lymph nodes, skin pustules, ulcers, headache, myalgia, malaise and nausea. Cultures tend to be negative, because the causative organism, Francisella tularensis, needs cysteine. While there are five clinical forms of tularemia, man tends to get the ulceroglandular form, mostly from insect bites. Treatment consists of intramuscular streptomycin 0.5 g every 12 hours until the temperature is normal. PMID- 21286088 TI - Family medicine in hamilton 1965-1981: change over time. PMID- 21286089 TI - Sports medicine as part of family practice. PMID- 21286090 TI - [Not Available]. PMID- 21286092 TI - Internship or residency? PMID- 21286091 TI - [Not Available]. PMID- 21286093 TI - Kerosene 'remedy' causes grave concern. PMID- 21286094 TI - 'Word fuzz'-to the barricades! PMID- 21286095 TI - Kerosene 'remedy' causes grave concern. PMID- 21286096 TI - Words that should be banned. PMID- 21286097 TI - Aspartame and PKU. PMID- 21286098 TI - Religious-or Crazy? PMID- 21286099 TI - A missed diagnosis: error in judgment or negligence? PMID- 21286100 TI - The practical application of exercise training principles in family medicine. AB - As millions of Canadians take the message of Participaction to heart, family physicians are asked a multitude of questions about exercise. It can be viewed as a pharmacological agent: dosage, frequency, host response, side effects and sensitivities should be considered in the design of an exercise program. Complications of exercise result in overuse injury to muscle, tendon and bone. Important etiological areas involve training, biomechanical features and footwear. Adequate recovery from a training stimulus is necessary for physiological adaptation. Warm up, flexibility, and dosage of exercise need special consideration. Compensatory activity caused by genu varum and pes planus may be reduced by the use of orthotic devices. Study of the wear pattern of the running shoe may reveal clues about biomechanical alignment. The physician's direct practical guidance will minimize complications, as will proper design of the exercise program and selection of appropriate equipment. PMID- 21286101 TI - What do studies of exercise and cardiovascular mortality tell us? AB - Studies of exercise and cardiovascular mortality were reviewed to determine whether leisure-time or work activity affects mortality. Twenty-one prospective cohort and 12 rehabilitation case-control studies were reviewed based on epidemiological criteria. Most studies suffered from design deficits.Based on available information, physicians' recommendations about exercise should not include the possibility of increased life expectancy. PMID- 21286102 TI - The middle-aged marathon runner. AB - Middle-aged runners form an appreciable number of those engaged in marathon running. They tend to have above average intelligence, high socioeconomic status, and better levels of aerobic fitness than sedentary members of the same age group. "Too much too soon" is the commonest cause of injury. Training before a marathon should last 18 months to two years. Middle-aged runners tend to experience fewer injuries than other marathoners. However, relatively minor complaints will be disastrous to them if they have to stop running. Injuries can occur from lack of warm up exercises, environmental factors such as weather, poor street lighting, carbon monoxide from car exhausts, etc. Some contraindications to marathon running are: poorly controlled diabetes, recent acute pulmonary disease, active rheumatoid arthritis, and recent cardiac conditions. Finishing a marathon involves both agony and ecstasy. PMID- 21286103 TI - Sports related injuries: incidence, management and prevention. AB - The incidence of injury related to various sports is reviewed according to sport, area of injury, number of participants and hours per week spent at the sport. Organized sports accounted for fewer injuries than unsupervised recreational activities like tree climbing, skateboarding and running. The knee is the most commonly injured site. Sensitivity to patients' commitment to their sport is necessary: sometimes instead of rest, they can substitute a less hazardous form of exercise. Principles of prevention involve proper familiarity with the sport, proper equipment and proper conditioning. PMID- 21286104 TI - Tennis elbow. AB - Certain types of activity, particularly the wielding of a tennis racquet, put undue stress on the muscles of the forearm. The result can be extremely incapacitating as well as resistant to treatment. The earlier specific measures are introduced, the greater the success of conservative treatment. To provide this approach the physician must be aware of the multiple factors involved in the game. The backhand stroke appears to cause more problems than the forehand. Inexperienced players use the power of their elbows far more than the power of their whole bodies. Changes of technique or equipment may therefore be necessary. PMID- 21286105 TI - Eye injuries in canadian racquet sports. AB - Racquet sports eye injuries have increased steadily in recent years. To determine the magnitude of the problem, the Canadian Ophthalmological Society (COS) Athletic Eye Injury Committee has sent questionnaires to COS members since 1976 to be completed for all racquet sports eye injuries treated. In the first year of the questionnaire 48 injuries were reported, including three legally blind eyes. From July 1978 to May 1981, 154 squash and 91 racquetball eye injuries were reported. Half the injured players required hospitalization and surgery was frequent; some players had permanent vision loss. These findings led to assessment of available eye protectors. Open-type protectors can be penetrated by balls and some closed-type protectors are not sufficiently sturdy. Steps are underway to write a Canadian standard for racquet sports eye protectors. Meanwhile the public must be informed of the danger of racquet sports eye injuries and the importance of wearing closed-type protectors. PMID- 21286106 TI - Exercise and the asymptomatic individual: assessment and advice. AB - With the current popularity of physical fitness, the family physician is often asked to advise asymptomatic individuals who wish to undertake an exercise program. In the majority of cases, adequate assessment consists of a thorough history and physical examination, along with a few simple investigations, including a resting electrocardiogram. Exercise stress testing of asymptomatic individuals produces an unacceptably high frequency of false-positive results, and its use should be restricted to those patients with cardiac symptoms or major cardiac risk factors. The potential benefits of a longterm commitment to regular exercise should be discussed with the patient and guidance provided on the optimal form of exercise program for that individual. Exercise must not be considered in isolation. Other major cardiovascular risk factors should be sought and dealt with appropriately. PMID- 21286107 TI - Communication disorders in children: the role of the family physician. AB - Speech and language disorders are a common source of distress to children and their families. Examination and investigation should be geared to general health and development considerations, plus emotional state and family environment. Criteria for referral to a speech pathologist are given. PMID- 21286108 TI - The brief alcoholism rating scale: a new test for diagnosing. AB - A new scale, comprising 100 criteria based on medical history, physical examination and routine laboratory data, independent of a drinking history, can help physicians in the detection, diagnosis and early treatment of alcoholism. The scale also permits objective classification of alcoholism into mild, moderate and severe categories and overcomes the patient's denial-a major obstacle to early diagnosis. Results suggest that the instrument is accurate: 94% of patients were classified correctly by the scale. Further validation studies in clinical practice are necessary. PMID- 21286109 TI - Sex with Comfort-and Hite. PMID- 21286110 TI - Iron deficiency anemia in a distance runner. AB - This paper discusses a case study of a 19-year-old male student who engaged in daily long distance running and presented with complaints of fatigue and dizziness. Laboratory test revealed a hemoglobin of 7.7 g/dl and a bone marrow negative for iron. After a complete evaluation no source of blood loss was identified. His iron deficient state may be caused by his exposure to long distance running for some years. Recent work from Sweden reports iron deficiency in eight runners, demonstrated by bone marrow examination. Further work in West Germany shows low ferritin values in runners. Source of iron loss may be from hemoglobinuria and/or excessive sweating. Hemoglobin and ferritin values should be monitored in runners every six to 12 months. PMID- 21286112 TI - How Do You Feel About MDs' 'Study Sessions'? PMID- 21286111 TI - The need for a clearly stated curriculum. AB - Many of the problems which are presented to family physicians are not covered by their medical training. In a residency program, these aspects of family medicine must be stressed-preferably by the same teacher, preferably over a period of time not less than two three-month blocks. The political implications of this emphasis are many and varied, but all of them lead to the same endpoint: the need for a clearly stated curriculum. The only way critics of family medicine training programs can be answered is by clear statements of content intended to produce a particular type of physician. PMID- 21286113 TI - The Ontario CME Survey: A Provider's Perspective. PMID- 21286115 TI - Whatever happened to study credits? PMID- 21286114 TI - [Not Available]. PMID- 21286116 TI - Pre-employment physicals: worth it-or wasteful? PMID- 21286117 TI - Allergy: a double edged sword? PMID- 21286119 TI - Why read nurses' notes? PMID- 21286118 TI - Incidence of positive tuberculin tests by age and place of birth: a study. AB - In central Toronto tuberculin positive rates of 35% and 48% were found in young adult immigrants from the Caribbean and Asia. Foreign born residents, representing 22.2% of the population, contributed 68.3% of all the active cases of tuberculosis in Ontario in 1980.The incidence of active tuberculosis in Ontario in 1980 in males aged 70 years and over was 43.4 per 100,000 compared to 11.1 per 100,000 for males and females of all ages.The need for surveillance of immigrants and refugees as well as the elderly is emphasized. PMID- 21286120 TI - Consultation practice: competition or collaboration? AB - Concordance with recommendations, and two-way communication, are two prime factors in consultation. They tend to determine whether the consultation will be competitive or collaborative. The literature shows that privately consulted physicians tend to respond with written reports four times as frequently as residents on hospital services, or any teaching physician. The consultation process has three parts: preconsultation, consultation, and postconsultation. Different needs and problems arise at different stages. One large factor is respect, which needs to be taught and encouraged. PMID- 21286121 TI - Career change: nurse or doctor? AB - Society's emphasis on self-fulfillment has encouraged many professionals to change careers. This article examines the motives which might prompt a nurse to move into medicine, concluding that the health care system should be well aware of these reasons, as they may highlight some obstacles to full professional development within our present system. PMID- 21286122 TI - Social work services in family practice. AB - The physician-social worker team in family practice offers potential benefits to both physician and patient. A demonstration of such attachments in Kingston, Ontario involved the equivalent of 3.5 fulltime social workers and 41 physicians. Social work services were provided to each participating physician for approximately half a day per week. Physicians used the service extensively, referring 630 patients over 24 months for a wide range of problems. Physicians evaluated the services favorably and the study shows social worker attachments to be feasible in the primary care setting. PMID- 21286123 TI - Intrahepatic cholestasis as a side-effect of drug therapy. AB - Drug-induced hepatotoxicity causes 2-5% of hospitalization for jaundice; in the elderly this figure is close to 20%. The liver is particularly susceptible to drug damage because its blood supply delivers drugs in higher concentrations, and because of its role in metabolizing drugs. This article reviews the morphological, biochemical and clinical features of intrahepatic cholestasis, outlining the hypotheses for this frequent side-effect of drug therapy. PMID- 21286124 TI - Basic library list for family medical centres and small hospitals, 1982. PMID- 21286126 TI - Self-evoluotion program. PMID- 21286125 TI - Recruiting and retaining physicians in northern Canada. AB - Attracting and retaining physicians in isolated Canadian communities has long been a concern. A survey of physicians who lived in the north and a comprehensive literature review show that being needed, good hospital equipment, active involvement of family doctors in a nearby hospital, and professional freedom were all considered important positive features of northern practice. The disadvantages are cost of continuing medical education, isolation, lack of opportunities for spouse and lack of specialist backup. Continuing medical education programs could be facilitated by a close liaison between northern districts and southern medical schools to ease the sense of isolation. Similarly, innovative funding approaches could encourage participation in out-of-district continuing medical education. Northern referral centres could be developed to increase specialist availability. Workload, another common problem, could be eased if rotating on-call schedules were encouraged where possible. Recruiting could incorporate a more personal touch than in the past. PMID- 21286127 TI - Observation-or urgent action? AB - Certain cases do not reveal themselves as urgent initially, and may appear to justify conservative management. In retrospect, the outcome of the case may reveal all too vividly the importance of early diagnosis and management. In this instance, the patient's own reluctance to submit to examination contributed to the decision for conservative management. PMID- 21286128 TI - Continuing medical education in ontario: a primary care perspective. AB - A major study of continuing medical education practices, needs and problems in Ontario showed that the primary care physician is very active in maintaining his clinical skills and knowledge. Compared to his other specialty colleagues he utilizes more resources in his own community, depending less on formal programs. Members of the College of Family Physicians of Canada tend to be more like their other specialty colleagues than other primary care physicians. PMID- 21286129 TI - Hospital privileges out of date? PMID- 21286130 TI - Douse that spouse! PMID- 21286132 TI - [Awards and Grants CFPC 1982]. PMID- 21286131 TI - [Survey of continuing medical education in Ontario: the perspective of the provider]. PMID- 21286133 TI - CMA Task Force Seeks CFP Readers' Opinions. PMID- 21286134 TI - Podiatrists are up in arms over foot care. PMID- 21286135 TI - Podiatrists are up in arms over foot care. PMID- 21286137 TI - FPs and Hospitals. PMID- 21286136 TI - Marathon article 'mythological claptrap'. PMID- 21286138 TI - FPs and Hospitals. PMID- 21286139 TI - FPs and Hospitals. PMID- 21286140 TI - FPs and Hospitals. PMID- 21286141 TI - FPs and Hospitals. PMID- 21286142 TI - FPs and Hospitals. PMID- 21286143 TI - FPs and Hospitals. PMID- 21286144 TI - FPs and Hospitals. PMID- 21286145 TI - Cellulitis of the skin: clinical observations of 50 cases. AB - Fifty patients with cellulitis were seen consecutively during a six month period at the Jewish General Hospital. Two groups could be identified. Group 1 patients had no evidence of wound suppuration, no portal of entry was identified, there was no underlying disease state other than a history of having had cellulitis in the past, and a bacterial pathogen was isolated in 43.5% of the aspirates. In contrast, group 2 patients had small abscesses at a readily identifiable portal of entry, and the diagnosis was established on gram stain and culture of the aspirate in 89%. Streptococcus pyogenes and Staphylococcus pyogenes were isolated with equal frequency in both groups of patients. Implications for therapy are discussed. PMID- 21286146 TI - Practical topical therapy in dermatology. AB - Topical therapy in dermatology is often perplexing to nondermatologists. They have been taught by several clinicians how to treat a dermatologic case and in addition have been besieged by drug company personnel and by colorful journal advertisements on the virtues of preparations which should readily clear any rash. All these approaches usually lead to a hit or miss result. This presentation discusses a simple approach to skin eruptions, basing the treatment on the stage of the disorder rather than on the cause. PMID- 21286147 TI - Cutaneous markers of internal disease. AB - Cutaneous markers of internal disease are legion. This article discusses the pigmentary disorders, acanthosis nigricans, pruritus, the xanthomas and problems of photosensitivity, outlining the appropriate procedures to establish a definite diagnosis, and in some cases the management of such patients. PMID- 21286148 TI - Pseudomonas folliculitis. AB - Pseudomonas folliculitis has been reported by several authors in recent literature. So far, most of the outbreaks involved whirlpools in motels, health spas and private homes. This communication may be the first report of whirlpool folliculitis occurring in an apartment complex. This new clinical entity, which may be misdiagnosed as other pruritic dermatoses, can spread to involve many individuals with significant epidemiologic implications. PMID- 21286149 TI - New developments in acne treatment. AB - Acne is a metabolic disorder of the pilosebaceous appendage in which microorganisms, hormones, inflammatory cells and fatty acids seem to contribute to the pathologic process. Through education and judicious use of therapeutic agents including benzoyl peroxide, vitamin A acid, topical and systemic antibiotics and 13 cis retinoic acid, most patients with acne can enjoy good control of their disease. PMID- 21286150 TI - Prisoner and Doctor: Practice in a POW Camp. PMID- 21286151 TI - [The anxiety of the family physician]. AB - The family physician can become anxious when confronted by the limits of his abilities, especially with certain kinds of patients-the one who is "too intelligent", the one who lacks motivation, or the dying patient. "Counter transference" is another factor. The physician may use defense mechanisms such as denial or aggression. He must recognize the existence of this anxiety, establish a relationship of equality with the patient, and develop his affective potential. To do this requires knowledge of oneself. PMID- 21286153 TI - [Not Available]. PMID- 21286152 TI - Human in vitro fertilization and embryo transfer. PMID- 21286154 TI - [Not Available]. PMID- 21286155 TI - And to 'freudian hostility'. PMID- 21286156 TI - Readers object to 'anti-natalist' article.. PMID- 21286157 TI - Ah, shucks! PMID- 21286159 TI - Child Neglect Advocated in CFP? PMID- 21286158 TI - Family docs must 'do' as well as counsel. PMID- 21286160 TI - Cover commendation. PMID- 21286161 TI - One last look at study sessions. PMID- 21286162 TI - Sri lankan college. PMID- 21286163 TI - One last look at study sessions. PMID- 21286164 TI - Occupational health: first cdn. Program. PMID- 21286165 TI - Developmental screening in the community. PMID- 21286166 TI - One last look at study sessions. PMID- 21286167 TI - One last look at study sessions. PMID- 21286168 TI - One last look at study sessions. PMID- 21286169 TI - One last look at study sessions. PMID- 21286170 TI - Complication after infant circumcision: was the doctor at fault? PMID- 21286171 TI - Problems and prevention in proctology. AB - Pathology in the lower rectum, anal canal and perineum is common and causes much distress. It tends to be self-diagnosed and treated. Eventually a physician is consulted and the usual diagnosis proposed by the patient is "It's my hemorrhoids". However, this may conceal a considerable spectrum of pathology. Diagnosis is usually not difficult but the treatment may not always be so straightforward. This paper discusses hemorrhoids, fissure-in-ano, abscesses, anal fistulae, condylomata and pruritus ani. High risk groups for carcinoma of the colon and rectum are identified. Hemoccult(r) testing should be instituted at the annual physical examination for both of these conditions. PMID- 21286172 TI - Split thickness skin grafting. AB - Primary care physicians often see wounds in which skin loss is a major factor. Although most of these wounds will heal with local care and with a reasonable functional result, split thickness skin grafting as a simple outpatient or bedside procedure can speed healing more comfortably for the patient and with greatly improved functional results. This article outlines the techniques of skin grafting as part of a minor surgical armamentarium. PMID- 21286173 TI - A technique of newborn circumcision. AB - Although circumcision is a controversial procedure, there will always be some parents who want their infants circumcised. This article demonstrates the technique pictorially, and recommends that in groups, one physician perform all the circumcisions, in order to maintain the skill. PMID- 21286174 TI - Extensor tendon injuries and repairs in the hand. AB - Due to their superficial course, the extensor tendons are frequently lacerated over the dorsum of the hand and fingers. Excellent functional results are obtained in repairs of simple tendon lacerations. 'Open' mallet lacerations over the distal IP joint or involving the central extensor slip over the proximal IP joint require more precise suturing methods. More proximal extensor tendon divisions near the wrist involve dissection of the retracted finger extensors or long thumb extensor in the distal forearm and more formal tendon repairs, including a possible tendon transfer to the thumb. 'Closed injuries', with varying degrees of extensor tendon disruption, occur at three main sites. The mallet injury at the DIP joint and the boutonniere deformity over the PIP joint are sometimes recognized late, but respond to conservative splinting for a minimum of four weeks with guarded motion avoiding secondary stiffening of the remaining small joints of the hand. Surgery of closed injuries most frequently involves the intra-articular traction fracture type of mallet deformities in which the DIP joint has taken the brunt of the injury. PMID- 21286175 TI - Metacarpal and finger fractures. AB - If loss of hand function is to be avoided, metacarpal and finger fractures must be treated early, correctly, and for sufficient time. Maintaining the hand in a correct position of function during the healing process is vital. Immobilization should be for as short a period as possible, but as complete as possible. Patients tend to remove splints, making casts more advisable. Methods of anesthesia, reduction and fixation are described for metacarpal, thumb metacarpal, proximal, middle and distal phalangeal fractures. PMID- 21286176 TI - Wrist injuries. AB - Fractures of the carpal scaphoid account for 60-70% of all carpal injuries. This injury must be recognized early: scaphoid fracture should be suspected and treated until disproven on X-ray at two and four weeks. All displaced fractures must be reduced. Fractures of the distal radius are most commonly of two types: those with posterior displacement, and those with anterior displacement. Treatment is by closed reduction and splint or cast. Colles' fractures in young people take a great amount of force, therefore the complication rate is high. Hospital admission and months of rehabilitation are usually necessary. Colles' must be distinguished from Smith's fractures, which may be reduced by traction and must be observed for slipping. PMID- 21286177 TI - Sexual abuse of children. AB - Increasing emphasis is being placed on the identification and management of sexual abuse in children. Family physicians have a role to play in identifying and treating these children. Some common myths about sexual abuse are that assaults are made mostly by strangers, that sexual abuse is rare, and that there's nothing wrong with sex between adults and children. Indicators in the child may be physical or behavioral. In the family, indicators include fathers with low self-esteem, poor relationships with wives, tendency to be domineering and restrictive, and mothers who are passive. Immediate and longterm intervention includes legal, protective and treatment components. The essential factors in successful intervention are belief in the child's disclosure; communication of that belief to the child; and immediate protection of the child and siblings. PMID- 21286178 TI - The development of a rural team to deal with child abuse. AB - In the last ten years teams for dealing with child abuse have become established in many urban centres. More recently rural communities have started similar programs; such a team was established in rural Manitoba in 1976. A series of events since then has improved the operation of the team. Cooperation with an urban team has enhanced the functioning of the rural team. A broad base of community support for this work has been essential. A review of cases seen in the last 18 months indicates 12 cases are physical abuse, nine are sexual, six neglect, and one emotional abuse. PMID- 21286179 TI - Chronic Pain of Obscure Etiology: Lessening the Physician's Frustration. AB - Chronic pain of obscure etiology produces suffering in patient, family and physician. They share a helplessness which often leads to desperate and occasionally harmful attempts to resolve the suffering. Recent biological and psychosocial research on the etiology of chronic pain suggests an increased role for behavioral medicine in chronic pain management. A treatment approach based on patient education, and working with the patient to at least reduce the pain, may lead to more effective and rational management of these patients by reducing the physician's helplessness and frustration. PMID- 21286180 TI - Facial sinuses from dental pathosis. AB - Sinus tracts presenting on the face may be the result of dental pathosis. This etiologic possibility should be ruled out before such lesions are treated by prolonged antibiotic therapy or surgical excision. The diagnosis can often be confirmed by a good clinical intraoral examination supplemented by appropriate radiographs. Four cases are presented in which treatment of the underlying pathology resulted in resolution of the sinus tract. PMID- 21286181 TI - What is Unwarranted Use of a Doctor's Services? PMID- 21286182 TI - Doctors and the press: are readers irresponsible too? PMID- 21286183 TI - [Not Available]. PMID- 21286184 TI - [Not Available]. PMID- 21286185 TI - Our mistake. PMID- 21286186 TI - Reader provides more superfluous redundancies. PMID- 21286187 TI - And also too... PMID- 21286188 TI - FPs Don't Need to Justify Their Existence. PMID- 21286190 TI - Administration angst. PMID- 21286192 TI - Administration angst. PMID- 21286191 TI - Administration angst. PMID- 21286193 TI - Administration angst. PMID- 21286194 TI - Administration angst. PMID- 21286195 TI - Administration angst. PMID- 21286196 TI - Which family practice patients visit the emergency department? AB - The patients of a community health centre who visited a hospital emergency department were compared with a random sample of the patients who visited the health centre during the same four months. Visiting rate to the emergency department was higher for teenagers and patients over 60. Emergency department visitors were more frequent users of health care, both at the health centre and in the emergency department. No differences were found between the two groups concerning sex, length of time as a patient, continuity of care, and distance of home from hospital or health centre. PMID- 21286197 TI - Judging the appropriateness of patients' visits to the emergency department. AB - Physicians and nurses working in a community health centre developed criteria to allow them to judge the appropriateness of their patients' visits to the hospital emergency department. All patient visits to the hospital emergency department were judged by these criteria; 37% of visits were appropriate and 8% were inappropriate. In the remaining 55% agreement was not achieved. The source of disagreement may be related to the problems of giving 24 hour continuing care in family practice. The time of visits to the emergency department and hospitalization rate are different for health centre patients compared to other emergency department users. This may reflect a more appropriate use by health centre patients. PMID- 21286198 TI - The sting. AB - Anaphylactic reactions to insect stings occur in about 0.4% of the population and in up to 20% who are family members of beekeepers. Systemic reactions tend to worsen with subsequent stings. Probably four or five people die annually in Canada as a consequence of stings. Efficacy of venom immunotherapy is about 95%. Skin tests with in vitro assessments of venom-specific IgE (allergy antibody) and IgG (blocking antibody), along with leukocyte histamine release, are useful tests of hymenoptera allergy and monitors of treatment effectiveness. PMID- 21286199 TI - Allergy and occupation. AB - The skin and the respiratory tract are susceptible to sensitization by a wide range of substances encountered in the occupational environment. The responses of these two anatomical sites are discussed with particular attention to late and dual asthmatic reactions, which may cause diagnostic problems for the unwary. There are few data on the incidence and prevalence of occupational allergic reactions, but some estimated frequencies are given. Tables list the major industrial skin and respiratory sensitizing agents. The importance of a detailed history is stressed, as is the role of the family physician in identifying and documenting agents capable of sensitizing exposed workers. PMID- 21286200 TI - Allergic rash: does it exist? AB - IgE-mediated urticaria and angioedema, serum sickness and idiosyncratic mechanisms all cause rashes. However, only mechanisms involving IgE should be labelled allergic, and they are the only ones with potentially fatal results. The most common type of rash seen by an allergy specialist is urticaria, acute and chronic. Acute urticaria lasts less than six to eight weeks and is most often caused by infection, medication and some foods. Chronic urticaria is caused by animal dander, ASA, certain food additives and some systemic diseases. Treatment is removal of the allergen, plus H1 and H2 antagonists and beta agonists. Both forms of urticaria eventually resolve spontaneously. PMID- 21286201 TI - House-dust allergy. AB - House-dust allergy is a common cause of perennial allergic rhinitis and extrinsic asthma. Symptoms tend to be worse when the patient is in bed. A positive skin test properly performed and interpreted confirms the diagnosis. The house-dust mite is the most important antigenic component of house-dust. Treatment consists of environmental control directed at reducing the mite content of bedroom dust, plus control of symptoms with drugs. Immunotherapy is controversial. PMID- 21286202 TI - [Not Available]. AB - Almost 60% of food additives are colorings, flavorings and other appearance enhancers. Growth of the world's population and growth in demand for food represent the greatest technological challenge of our era. Consequently, usage of substances which preserve the quality and diminish spoilage of food is of prime importance. Nevertheless, the consumer fears that the cumulative effect of additives can lead to cancer, hyperkinesis or other disorders. Given the widespread use of additives, their impact on the health of populations is difficult to study even if certain observed differences between countries are attributed to their diet. Additives introduced during the last few years have satisfied rigorous testing-to which the majority of natural products are not submitted. In contrast, overeating, inactivity, excess saturated fat, alcohol and cigarets are still prevalent, even though the health risks they represent are clearly established. Seeing that the doctor is an authority on health matters, his or her contribution in dispensing information on nutrition and health is important in the battle against fear without scientific proof. PMID- 21286203 TI - [Not Available]. AB - Care of the aged necessitates a functional diagnosis, with which physicians have little familiarity. The author reviews the principles of autonomy and dependence, applying them to the health care context. He proposes a method of sifting the necessary factors in measuring functional autonomy in elderly people. PMID- 21286204 TI - The cost of providing office services in family medicine: a survey of Saskatchewan family physicians 1980-1981. AB - While office visits generate the bulk of a family doctor's income, they also generate costs. This survey of 58 Saskatchewan family physicians shows that the costs per patient visit range from $6.45 to $7.25, while the average income per office visit is $7.49. In Saskatchewan, the fee for the partial assessment is the one most frequently claimed, but also the one which generates the most cost to the physician (income $10, cost $7.49). PMID- 21286205 TI - Hypnosis: an alternate approach to insomnia. AB - Insomnia, the feeling of inability to go to sleep or to stay asleep, is a pervasive clinical problem. This paper examines the relationship and similarities between sleep and hypnosis. Research on the study of EEG patterns during hypnosis shows that many authors feel hypnosis is a waking phenomenon. Why hypnosis allows for the induction of sleep is not clear.Primary and secondary sleep disorders are classified. Primary disorders have an autonomous function in the central nervous system while secondary disorders can result from depression, pain, anxiety, lifestyle change, etc. Secondary disorders are most likely to be improved by hypnotherapeutic techniques, which include progressive relaxation and ego strengthening. PMID- 21286206 TI - Suicide attempts in the adolescent. AB - Suicide is a leading cause of death among North American adolescents. Drugs are the commonest method used, and are most frequently those found in the home. Common factors such as frequent moves, marital difficulties of the parents, and a family history of depression occur in these patients. In 47 cases seen at a Toronto hospital, 22 patients were admitted. Of these, 20 had made suicidal gestures; two had made serious attempts. Most were of lower or middle class background. There is often a long-standing problem in the history, plus a triggering event. Knowledge of risk factors can help family physicians identify high risk patients. Hospitalization of teenagers with suicidal intent is obviously preferable, especially since it convinces patient and family that the attempt or intent has been taken seriously. PMID- 21286207 TI - When Infections Co-exist: Infectious Mono and Diphtheria. AB - Infectious mononucleosis was tentatively diagnosed in a patient who presented with a temperature of 39.5 degrees C, red throat and enlarged nodes in the neck. He was given amoxycillin 250 mg tid and was admitted to hospital, where his clinical symptoms of diphtheria were investigated. Medication was switched to penicillin V 300 mg tid. On the fifth hospital day the laboratory reported a culture of a toxigenic strain of C. diphtheriae from an initial throat swab.On the same day, he developed an erythematous, highly pruritic maculopapular rash which was probably caused by the initial use of amoxycillin. The rash initially became generalized and slowly resolved in 7-9 days. He apparently had infectious mononucleosis and a coincidental pharyngeal infection with toxigenic C. diphtheriae.No indication exists for the use of antibiotics in infectious mononucleosis, unless throat cultures reveal bacterial pathogens. In that case, an appropriate antibiotic other than ampicillin-amoxycillin can be chosen. PMID- 21286208 TI - Breach of confidentiality: did the patient have a case? PMID- 21286209 TI - Setting goals for family practice departments. PMID- 21286210 TI - Priest, teacher-or trickster? Doctors through the ages. PMID- 21286211 TI - How do you feel? PMID- 21286212 TI - Cardiorenal syndromes. AB - Cardiorenal syndromes (CRS) have been subclassified as five defined entities which represent clinical circumstances in which both the heart and the kidney are involved in a bidirectional injury and dysfunction via a final common pathway of cell-to-cell death and accelerated apoptosis mediated by oxidative stress. Types 1 and 2 involve acute and chronic cardiovascular disease (CVD) scenarios leading to acute kidney injury or accelerated chronic kidney disease. Types 2 and 3 describe acute and chronic kidney disease leading primarily to heart failure, although it is possible that acute coronary syndromes, stroke, and arrhythmias could be CVD outcomes in these forms of CRS. Finally, CRS type 5 describes a simultaneous insult to both heart and kidneys, such as sepsis, where both organs are injured simultaneously. Both blood and urine biomarkers are reviewed in this paper and offer a considerable opportunity to enhance the understanding of the pathophysiology and known epidemiology of these recently defined syndromes. PMID- 21286213 TI - Hemodynamic assessment of pulmonary hypertension. AB - There has been significant progress in our understanding of the pathobiology, epidemiology and prognosis of pulmonary vascular disease and, over the past few years, there has been an explosion of clinical therapeutic trials for pulmonary arterial hypertension (PAH). The increasing number of different conditions now associated with PAH and the appearance of new diagnostic techniques have led to a need for a systematic diagnostic approaches and a new disease classification, which has resulted in notable improvements in the quality and efficacy of clinical care. We appreciate traditional resting right heart catheterization techniques (which still remain the gold standard for diagnosing PAH and managing patients on therapy) and look forward to novel invasive techniques (e.g. intravascular ultrasound) that add greatly to our understanding of right ventricle and pulmonary circulation, and for the interpretation of data from clinical trials as well. PMID- 21286214 TI - Effects of interventions on oxidative stress and inflammation of cardiovascular diseases. AB - Excessive oxidative stress and low-grade chronic inflammation are major pathophysiological factors contributing to the development of cardiovascular diseases (CVD) such as hypertension, diabetes and atherosclerosis. Accumulating evidence suggests that a compromised anti-oxidant system can lead to excessive oxidative stress in cardiovascular related organs, resulting in cell damage and death. In addition, increased circulating levels of pro-inflammatory cytokines, such as tumor necrosis factor alpha, interleukin-6 and C-reactive protein, are closely related to morbidity and mortality of cardiovascular complications. Emerging evidence suggests that interventions including nutrition, pharmacology and exercise may activate expression of cellular anti-oxidant systems via the nuclear factor erythroid 2-related factor 2-Kelch-like ECH-associated protein 1 signaling pathway and play a role in preventing inflammatory processes in CVD. The focus of the present review is to summarize recent evidence showing the role of these anti-oxidant and anti-inflammatory interventions in cardiovascular disease. We believe that these findings may prompt new effective pathogenesis oriented interventions, based on the exercise-induced protection from disease in the cardiovascular system, aimed at targeting oxidant stress and inflammation. PMID- 21286215 TI - Endothelium-derived hyperpolarizing factor and diabetes. AB - In addition to its role as a barrier between blood and tissues, the vascular endothelium is responsible for the synthesis and released of a number of vasodilators including prostaglandins, nitric oxide and endothelium-derived hyperpolarizing factor (EDHF). As one of these vasodilators, the specific nature of EDHF has not been fully elucidated, although a number of roles have been proposed. Importantly, many conditions, such as hypertension, hyperlipidemia, heart failure, ischemia-reperfusion and diabetes mellitus comprise vascular endothelial dysfunction with EDHF dysregulation. This article reviews reports on the role of EDHF in diabetes-related endothelial dysfunction. PMID- 21286216 TI - Future easy and physiological cardiac pacing. AB - The right atrial appendage (RAA) and right ventricular apex (RVA) have been widely considered as conventional sites for typical dual-chamber atrio ventricular cardiac (DDD) pacing. Unfortunately conventional RAA pacing seems not to be able to prevent atrial fibrillation in DDD pacing for tachycardia bradycardia syndrome, and the presence of a left bundle branch type of activation induced by RVA pacing can have negative effects. A new technology with active screw-in leads permits a more physiological atrial and right ventricular pacing. In this review, we highlight the positive effects of pacing of these new and easily selected sites. The septal atrial lead permits a shorter and more homogeneous atrial activation, allowing better prevention of paroxysmal atrial fibrillation. The para-Hisian pacing can be achieved in a simpler and more reliable way with respect to biventricular pacing and direct Hisian pacing. We await larger trials to consider this "easy and physiological pacing" as a first approach in patients who need a high frequency of pacing. PMID- 21286217 TI - Central obesity, hypertension and coronary artery disease: The seed and soil hypothesis. AB - Coronary artery disease (CAD) is a multifactorial disease wherein hereditary and environmental factors play a major role. Our hypothesis is that an individual's genetic profile functions as soil while various environmental factors such as physical inactivity, smoking, stress, etc. act as seeds in the etiopathogenesis of CAD. Much of the information regarding genetic and environmental factors can be determined in a pedigree chart by taking a history of the index patient, including details of major risk factors such as age, sex, smoking, hypertension, diabetes, coronary artery disease and stroke in the family. Preparing such a chart is a cost-effective way of initiating primary preventive measures in patients in a developing economy. The advantage of a detailed pedigree chart is to provide a snapshot view of the evident and underlying risk factors in the family as a whole, and not to merely study conventional risk factors. It elucidates the hidden stressors and hereditary factors responsible for cardiovascular disease in the family. We report herein an illustrative pedigree chart which exemplifies our above hypothesis. PMID- 21286218 TI - Enhanced recovery after surgery programs hasten recovery after colorectal resections. AB - Colorectal resection was traditionally associated with significant morbidity and prolonged stay in hospital. Laparoscopic colorectal resection was first described in 1991 as a minimally invasive form of colorectal surgery. It was later on assessed by multiple randomized controlled trials and meta-analysis and was found to be associated with a faster recovery, lower complication rates and a shorter stay in hospital compared with open resection. To assess the effect of enhanced recovery after surgery (ERAS) program on postoperative length of stay after elective colorectal resections, a literature review was conducted, supplemented by the results of 111 ERAS colorectal resections at regional NWS Hospital using a protocol based on the Fast Track approach described by Kehlet in 1999. ERAS has been shown to improve postoperative recovery, reduce length of stay and enhance early return to normal function when compared with traditional colorectal surgical protocols. The role of laparoscopic surgery in colorectal resections within a fast-track (ERAS) program is controversial. The current evidence suggests that within such a program, there is no difference between laparoscopic and open colorectal surgery in terms of postoperative recovery rates or length of hospital stay. PMID- 21286219 TI - Clinicopathological features and the outcome of surgical management for adenocarcinoma of the appendix. AB - AIM: To present a comprehensive analysis of incidence, clinicopathological features, appropriateness of surgical procedures, and survival for adenocarcinoma of the appendix. METHODS: A retrospective case analysis was conducted for the 10 year period 1998-2008. All patients diagnosed with adenocarcinoma of the appendix were analyzed for their demographics details, clinical features, tumor incidence and characteristics, tumor stage, surgical procedures performed, and their survival. RESULTS: Nine thousand three hundred and twenty-three patients underwent appendectomies during the study period, and of these, 10 (0.1%: 8 men and 2 women with a mean age of 53.1 years, age range 21-83 years) were found to have primary adenocarcinoma of the appendix. Appendicular neoplasia was not suspected pre-operatively in any of the patients. Six (60%) patients underwent secondary right hemicolectomy. Four (40%) cases had appendectomy alone, and two of them died, whereas all those who underwent right hemicolectomy are alive and disease free. Five (50%) were reported to have grade 1 disease, three (30%) grade 2, and two (20%) grade 3 with mean survival of 34, 48, and 22 mo, respectively. Six (60%) patients presented with advanced disease (Duke's C and D). At the end of follow up (mean period: 37.9 mo), eight patients are alive and disease free at the end of follow up. Overall mean survival was 36.3 mo (confidence interval; 16% 56%) with 41.3 and 16 mo for men and women, respectively. Mean survival for those with and without lymph node involvement was 33.6 and 40.2 mo, respectively. Right hemicolectomy gave better results than appendectomy alone, although the difference was not statistically significant due to the small number of cases. CONCLUSION: Adenocarcinoma of the appendix is extremely rare neoplasm with varied presentations, and is usually advanced when diagnosed. Right hemicolectomy is the treatment of choice for such tumors. PMID- 21286220 TI - Ileal lipoma - a rare cause of ileocolic intussusception in adults: Case report and literature review. AB - The occurrence of intussusception in adults is rare, accounting for less than 5% of all cases of intussusceptions and almost 1%-5% of bowel obstruction. The condition is found in less than 1 in 1300 abdominal operations and 1 in 100 patients operated for intestinal obstruction. The child to adult ratio is more than 20:1. We report a rare case of ileocolic intussusception in an adult secondary to an ileal lipoma. PMID- 21286221 TI - Peritoneovenous shunt for intractable ascites due to hepatic lymphorrhea after hepatectomy. AB - A peritoneovenous shunt has become one of the most efficient procedures for intractable ascites due to liver cirrhosis. A case of intractable ascites due to hepatic lymphorrhea after hepatectomy for hepatocellular carcinoma that was successfully treated by the placement of a peritoneovenous shunt is presented. A 72-year-old Japanese man underwent partial resection of the liver for hepatocellular carcinoma associated with hepatitis C viral infection. After hepatectomy, a considerable amount of ascites ranging from 800-4600 mL per day persisted despite conservative therapy, including numerous infusions of albumin and plasma protein fraction and administration of diuretics. Since the patient's general condition deteriorated, based on the diagnosis of intractable hepatic lymphorrhea, a subcutaneous peritoneovenous shunt was inserted. The patient's postoperative course was uneventful and the ascites decreased rapidly, with serum total protein and albumin levels and hepatic function improving accordingly. For intractable ascites due to hepatic lymphorrhea after hepatectomy, we recommend the placement of a peritoneovenous shunt as a procedure that can provide immediate effectiveness without increased surgical risk. PMID- 21286222 TI - Spiking patterns of neocortical L5 pyramidal neurons in vitro change with temperature. AB - A subset of pyramidal neurons in layer 5 of the mammalian neocortex can fire action potentials in brief, high-frequency bursts while others fire spikes at regularly spaced intervals. Here we show that individual layer 5 pyramidal neurons in acute slices from mouse primary motor cortex can adopt both regular and burst spiking patterns. During constant current injection at the soma, neurons displayed a regular firing pattern at 36-37 degrees C, but switched to burst spiking patterns upon cooling the slice to 24-26 degrees C. This change in firing pattern was reversible and repeatable and was independent of the somatic resting membrane potential. Hence these spiking patterns are not inherent to discrete populations of pyramidal neurons and are more interchangeable than previously thought. Burst spiking in these neurons is the result of electrical interactions between the soma and distal apical dendritic tree. Presumably the interactions between soma and distal dendrite are temperature-sensitive, suggesting that the manner in which layer 5 pyramidal neurons translate synaptic input into an output spiking pattern is fundamentally altered at sub physiological temperatures. PMID- 21286224 TI - Rheumatoid corneal melt: autoimmunity or infection? PMID- 21286223 TI - Executive functions and prefrontal cortex: a matter of persistence? AB - Executive function is thought to originates from the dynamics of frontal cortical networks. We examined the dynamic properties of the blood oxygen level dependent time-series measured with functional MRI (fMRI) within the prefrontal cortex (PFC) to test the hypothesis that temporally persistent neural activity underlies performance in three tasks of executive function. A numerical estimate of signal persistence, the Hurst exponent, postulated to represent the coherent firing of cortical networks, was determined and correlated with task performance. Increasing persistence in the lateral PFC was shown to correlate with improved performance during an n-back task. Conversely, we observed a correlation between persistence and increasing commission error - indicating a failure to inhibit a prepotent response - during a Go/No-Go task. We propose that persistence within the PFC reflects dynamic network formation and these findings underline the importance of frequency analysis of fMRI time-series in the study of executive functions. PMID- 21286225 TI - Frontal sinus cancer resection and reconstruction. PMID- 21286226 TI - Fibroelastomas of the left ventricular outflow tract. PMID- 21286227 TI - An unexpected cause of deranged liver function: pyogenic liver abscess. PMID- 21286228 TI - Frequency of abdominal wall hernias: is classical teaching out of date? AB - OBJECTIVES: Abdominal wall hernias are common. Various authors all quote the following order (in decreasing frequency): inguinal, femoral, umbilical followed by rarer forms. But are these figures outdated? We investigated the epidemiology of hernia repair (retrospective review) over 30 years to determine whether the relative frequencies of hernias are evolving. DESIGN: All hernia repairs undertaken in consecutive adult patients were assessed. Data included: patient demographics; hernia type; and operation details. Data were analysed using Microsoft Excel 2007 and SPSS. SETTING: A SINGLE UNITED KINGDOM HOSPITAL TRUST DURING THREE PERIODS: 1985-1988; 1995-1998; and 2005-2008. MAIN OUTCOME MEASURES: Frequency data of different hernia types during three time periods, patient demographic data. RESULTS: Over the three time periods, 2389 patients underwent 2510 hernia repairs (i.e. including bilateral and multiple hernias in a single patient). Inguinal hernia repair was universally the commonest hernia repair, followed by umbilical, epigastric, para-umbilical, incisional and femoral, respectively. Whereas femoral hernia repair was the second commonest in the 1980s, it had become the fifth most common by 2005-2008. While the proportion of groin hernia repairs has decreased over time, the proportion of midline abdominal wall hernias has increased. CONCLUSION: THE CURRENT RELATIVE FREQUENCY OF DIFFERENT HERNIA REPAIR TYPE IS: inguinal; umbilical; epigastric; incisional; para-umbilical; femoral; and finally other types e.g. spigelian. This contrasts with hernia incidence figures quoted in common reference books. PMID- 21286229 TI - The search on an ideal disease marker for childhood obstructive sleep apnea syndrome. PMID- 21286230 TI - Sleep duration and circulating adipokine levels. AB - INTRODUCTION: Short sleep duration is associated with systemic inflammation and diabetes; however the mechanisms by which reduced sleep leads to these complications are unclear. One possibility is sleep may impact secretion of adipocyte derived hormones that regulate inflammation and insulin resistance. In this study we assessed the association between sleep duration and 3 adipokine levels. METHODS: A total of 561 adults from the Cleveland Family Study underwent standardized laboratory polysomnography followed by a morning fasting blood draw assayed for leptin, visfatin, and retinol binding protein-4 (RBP4) levels. RESULTS: The cohort had an age of 44.5 (16.1) years and total sleep time (TST) of 6.2 (1.3) hours (mean [SD]). Each hour reduction in TST was associated with a 10% increase in leptin (P = 0.01) and a 14% increase in visfatin levels (P = 0.03) in analyses adjusted for age, gender, and race. After additional adjustment for obesity, sleep apnea severity, hypertension, and diabetes, each hour reduction in TST was associated with a 6% increase in leptin (P = 0.01) and a 14% increase in visfatin levels (P = 0.02). Leptin increased by 15% (P = 0.01) and visfatin increased by 31% (P = 0.05) for every 1-h decrease in REM sleep. In contrast, no association between sleep duration and RBP4 was found. CONCLUSIONS: Reduced sleep and reduced REM sleep are associated with elevations in leptin and visfatin, 2 adipokines associated with inflammation and insulin resistance. Further investigation of the effect of sleep on adipose tissue function should be pursued. PMID- 21286231 TI - Pd-catalyzed amination as an alternative to nucleophilic aromatic substitution for the synthesis of N-alkyltacrines and analogues. AB - A reliable Pd-catalyzed amination protocol is described for the synthesis of N alkyltacrines and analogues. The Josiphos ligand CyPFtBu was found to provide optimum yields: 16 examples are given. Compared to the typical high-temperature nucleophilic aromatic substitution (NAS) routes, Pd-catalyzed aminations proceed at significantly lower reaction temperatures, and enable the synthesis of otherwise inaccessible products. PMID- 21286232 TI - Gibbs Ensembles for Nearly Compatible and Incompatible Conditional Models. AB - Gibbs sampler has been used exclusively for compatible conditionals that converge to a unique invariant joint distribution. However, conditional models are not always compatible. In this paper, a Gibbs sampling-based approach - Gibbs ensemble -is proposed to search for a joint distribution that deviates least from a prescribed set of conditional distributions. The algorithm can be easily scalable such that it can handle large data sets of high dimensionality. Using simulated data, we show that the proposed approach provides joint distributions that are less discrepant from the incompatible conditionals than those obtained by other methods discussed in the literature. The ensemble approach is also applied to a data set regarding geno-polymorphism and response to chemotherapy in patients with metastatic colorectal. PMID- 21286233 TI - Continuous Localized Orbital Corrections to Density Functional Theory: B3LYP CLOC. AB - Our previous works have demonstrated the ability of our localized orbital correction (LOC) methodology to greatly improve the accuracy of various thermochemical properties at the stationary points of the Density Functional Theory (DFT) reaction coordinate (RC). Herein we extend this methodology from stationary points to the entire RC connecting any stationary points by developing continuous localized orbital corrections (CLOCs). We show that the resultant method, DFT-CLOC, is capable of producing RCs with far greater accuracy than uncorrected DFT and yet requires negligible computational cost beyond the uncorrected DFT calculations. Various post-Hartree-Fock (post-HF) reaction coordinate profiles were used, including a sigmatropic shift, Diels-Alder reaction, electrocyclization, carbon radical and three hydrogen radical reactions to show that this method is robust across multiple reaction types of general interest. PMID- 21286234 TI - Models of chronic kidney disease. AB - Chronic kidney diseases result from recurrent or progressive injuries in glomeruli, tubules, interstitium and/or vasculature. In order to study pathogenesis, mechanisms and effects of interventions, many animal models have been developed, including spontaneous, genetic and induced models. However, these models do not exactly simulate human diseases, and most of them are strain, gender or age dependent. We review key information on various rodent models of chronic kidney diseases. PMID- 21286235 TI - Differential scanning calorimetry investigations on Eu-doped fluorozirconate based glass ceramics. AB - The properties of Eu-doped fluorochlorozirconate (FCZ) glass ceramics upon thermal processing and the influence of Eu-doping on the formation of BaCl(2) nanocrystals therein have been investigated. Differential scanning calorimetry indicates that higher Eu-doping shifts the crystallization peak of the nanocrystals in the glass to lower temperatures, while the glass transition temperature remains constant. The activation energy and the thermal stability parameters for the BaCl(2) crystallization are determined. PMID- 21286236 TI - Age-Group Differences in Interference from Young and Older Emotional Faces. AB - Human attention is selective, focusing on some aspects of events at the expense of others. In particular, angry faces engage attention. Most studies have used pictures of young faces, even when comparing young and older age groups. Two experiments asked (1) whether task-irrelevant faces of young and older individuals with happy, angry, and neutral expressions disrupt performance on a face-unrelated task, (2) whether interference varies for faces of different ages and different facial expressions, and (3) whether young and older adults differ in this regard. Participants gave speeded responses on a number task while irrelevant faces appeared in the background. Both age groups were more distracted by own than other-age faces. In addition, young participants' responses were slower for angry than happy faces, whereas older participants' responses were slower for happy than angry faces. Factors underlying age-group differences in interference from emotional faces of different ages are discussed. PMID- 21286237 TI - Synthetic Studies on Palau'amine. Construction of the Cyclopentane Core via an Asymmetric 1,3-Dipolar Cycloaddition. AB - The cyclopentane core of palau'amine has been constructed in optically pure form through the use of an asymmetric azomethine ylid [1,3]-dipolar cycloaddition reaction. PMID- 21286238 TI - Discovery of New Human A(2A) Adenosine Receptor Agonists: Design, Synthesis, and Binding Mode of Truncated 2-Hexynyl-4'-thioadenosine. AB - The truncated C2- and C8-substituted-4'-thioadenosine derivatives 4a-d were synthesized from D-mannose, using palladium-catalyzed cross coupling reactions as key steps. In this study, an A(3) adenosine receptor (AR) antagonist, truncated 4'-thioadenosine derivative 3 was successfully converted into a potent A(2A)AR agonist 4a (K(i) = 7.19 +/- 0.6 nM) by appending a 2-hexynyl group at the C2 position of a derivative of 3 that was N(6)-substituted. However, C8-substitution greatly reduced binding affinity at the human A(2A)AR. All synthesized compounds 4a-d maintained their affinity at the human A(3)AR, but 4a was found to be a competitive A(3)AR antagonist/A(2A)AR agonist in cyclic AMP assays. This study indicates that the truncated C2-substituted-4'-thioadenosine derivatives 4a and 4b can serve as a novel template for the development of new A(2A)AR ligands. PMID- 21286239 TI - ZnS nanocrystals decorated single-walled carbon nanotube based chemiresistive label-free DNA sensor. AB - We fabricated ZnS nanocrystals decorated single-walled carbon nanotube (SWNT) based chemiresistive sensor for DNA. Since the charge transfer in the hybrid nanostructures is considered to be responsible for many of their unique properties, the role of ZnS nanocrystals toward its performance in DNA sensor was delineated. It was found that the free carboxyl groups surrounding the ZnS nanocrystals allowed large loading of single strand DNA (ssDNA) probe that provided an ease of hybridization with target complementary c-ssDNA resulting in large electron transfer to SWNT. Thus it provided a significant improvement in sensitivity toward c-ssDNA as compared to bare SWNT based DNA sensor. PMID- 21286240 TI - Electromechanical properties of Pb(In(1/2)Nb(1/2))O(3)-Pb(Mg(1/3)Nb(2/3))O(3) PbTiO(3) single crystals. AB - The Pb(In(1/2)Nb(1/2))O(3)-Pb(Mg(1/3)Nb(2/3))O(3)-PbTiO(3) (PIN-PMN-PT) crystals were studied as function of phase and orientation. The properties, including the Curie temperature T(C), ferroelectric-ferroelectric phase transition temperature T(R/O-T), coercive field, and piezoelectric/dielectric responses, were systematically investigated with respect to the composition of PIN-PMN-PT crystals. The Curie temperature T(C) was found to increase from 160 to 220 degrees C with ferroelectric-ferroelectric phase transition temperature T(R-T) and T(O-T) being in the range of 120-105 degrees C and105-50 degrees C, respectively. The piezoelectric activity of PIN-PMN-PT crystals was analyzed by Rayleigh approach. The ultrahigh piezoelectric response for domain engineered [001] (1600-2200 pC/N) and [011] (830-1550 pC/N) crystals was believed to be mainly from the intrinsic contribution, whereas the enhanced level of piezoelectric and dielectric losses at the compositions around morphotropic phase boundaries (MPBs) was attributed to the phase boundaries motion. PMID- 21286241 TI - Twelve months of nightly zolpidem does not lead to dose escalation: a prospective placebo-controlled study. AB - STUDY OBJECTIVES: To assess hypnotic self-administration and likelihood of dose escalation over 12 months of nightly use of zolpidem versus placebo in primary insomniacs. DESIGN: Randomized, double-blind, placebo-controlled, clinical trial. SETTING: Outpatient with tri-monthly one-week, sleep laboratory assessments. PARTICIPANTS: Thirty-three primary insomniacs, without psychiatric disorders or drug and alcohol abuse, 32-64 yrs old, 14 men and 19 women. INTERVENTIONS: Participants were randomized to take zolpidem 10 mg (n = 17) or placebo (n = 16) nightly for 12 months. In probes during month 1, 4, and 12, after sampling color coded placebo or zolpidem capsules on 2 nights, color-coded zolpidem or placebo was chosen on 5 consecutive nights and 1, 2, or 3 of the chosen capsules (5 mg each) could be self-administered on a given choice night. RESULTS: Zolpidem was chosen more nights than placebo (80% of nights) and number of nights zolpidem was chosen did not differ over the 12 months. More zolpidem than placebo capsules were self-administered, and the total number of placebo or zolpidem capsules self administered did not differ as a function of duration of use. In contrast, the total number of placebo capsules self-administered by the placebo group increased across time. The nightly capsule self-administration on zolpidem nights did not differ from that on placebo nights and neither nightly self-administration rates increased over the 12 months. An average 9.3 mg nightly dose was self administered. CONCLUSIONS: Zolpidem was preferred to placebo, but its self administration did not increase with 12 months of use. Chronic hypnotic use by primary insomniacs does not lead to dose escalation. PMID- 21286242 TI - Sleep related changes in blood pressure in hypocretin-deficient narcoleptic mice. AB - STUDY OBJECTIVES: Although blood pressure during sleep and the difference in blood pressure between sleep and wakefulness carry prognostic information, little is known on their central neural mechanisms. Hypothalamic neurons releasing hypocretin (orexin) peptides control wake-sleep behavior and autonomic functions and are lost in narcolepsy-cataplexy. We investigated whether chronic lack of hypocretin signaling alters blood pressure during sleep. DESIGN: Comparison of blood pressure as a function of the wake-sleep behavior between 2 different hypocretin-deficient mouse models and control mice with the same genetic background. SETTING: N/A. SUBJECTS: Hypocretin-ataxin3 transgenic mice with genetic ablation of hypocretin neurons (TG, n = 12); hypocretin gene knock-out mice (KO, n = 8); congenic wild-type controls (WT, n = 10). INTERVENTIONS: Instrumentation with electrodes for sleep recordings and a telemetric blood pressure transducer. MEASUREMENTS AND RESULTS: Blood pressure was significantly higher in either TG or KO than in WT during non-rapid eye movement sleep (NREMS; 4 +/- 2 and 7 +/- 2 mm Hg, respectively) and rapid eye movement sleep (REMS; 11 +/- 2 and 12 +/- 3 mm Hg, respectively), whereas it did not differ significantly between groups during wakefulness. Accordingly, the decrease in blood pressure between either NREMS or REMS and wakefulness was significantly blunted in TG and KO with respect to WT. CONCLUSIONS: Chronic lack of hypocretin signaling may entail consequences on blood pressure that are potentially adverse and that vary widely among wake-sleep states. PMID- 21286243 TI - Autonomic response to periodic leg movements during sleep in narcolepsy cataplexy. AB - STUDY OBJECTIVES: To test the hypothesis of autonomic nervous system dysfunction in patients with narcolepsy-cataplexy (NC) by assessing the physiologic activations associated with periodic limb movements during sleep (PLMS). DESIGN: Sleep and heart rate (HR) were recorded during 1 night of polysomnography. SETTING: Data were collected at the Sleep Disorders Center, Sacre-Coeur Hospital, Montreal, Canada. PARTICIPANTS: Data from 14 patients with NC (6 men, 8 women, mean age: 52.5 +/- 11.9 years) were compared with data from 14 healthy control subjects matched for age and sex. INTERVENTIONS: NA. MEASUREMENTS AND RESULTS: Analyses included sleep stages, PLMS, microarousals, RR intervals converted into beats per minute on segments lasting 25 heartbeats (10 RR intervals before PLMS and 15 after), and cardiac-activation amplitudes. A Group-by-Heartbeat interaction was noted for PLMS without microarousals; the patients had a tachycardia of lower amplitude and a delayed and lower-amplitude bradycardia, compared with normal control subjects. Similar significant HR modifications were observed for PLMS with microarousals between patients with NC and control subjects. Patients with NC had a reduced magnitude of cardiac activation associated with PLMS with and without microarousals, as compared with control subjects. A negative correlation was noted between cardiac-activation amplitude and age in patients with NC, but no correlation with PLMS index was found in either patients with NC or control subjects. CONCLUSION: A significant reduction in the amplitude of PLMS-related HR responses in both tachycardia and bradycardia was found in patients with NC. These findings favor the physiologic relevance of the action of hypocretin on autonomic function that may be of clinical significance, i.e., increasing the risk of cardiovascular diseases. PMID- 21286245 TI - Circadian type and bed-timing regularity in 654 retired seniors: correlations with subjective sleep measures. AB - STUDY OBJECTIVES: Using telephone interview data from retired seniors to explore how inter-individual differences in circadian type (morningness) and bed-timing regularity might be related to subjective sleep quality and quantity. DESIGN: MANCOVA with binary measures of morningness, stability of bedtimes, and stability of rise-times as independent variables; sleep measures as dependent variables; age, former shift work, and gender as covariates. SETTING: Telephone interviews using a pseudo-random age-targeted sampling process. PARTICIPANTS: 654 retired seniors (65 y+, 363M, 291F). INTERVENTION: none. MEASUREMENTS AND RESULTS: INDEPENDENT VARIABLES: (1) circadian type (from Composite Scale of Morningness [CSM]), and stability of (2) bedtime and (3) rise-time from the Sleep Timing Questionnaire (STQ). DEPENDENT VARIABLES: Pittsburgh Sleep Quality Index (PSQI) score, time in bed, time spent asleep, and sleep efficiency, from Sleep Timing Questionnaire (STQ). Morning-type orientation, stability in bedtimes, and stability in rise-times were all associated with better sleep quality (P < 0.001, for all; effect sizes: 0.43, 0.33, and 0.27). Morningness was associated with shorter time in bed (P < 0.0001, effect size 0.45) and time spent asleep (P < 0.005, effect size 0.26). For bedtime and rise-time stability the direction of effect was similar but mostly weaker. CONCLUSIONS: In retired seniors, a morning type orientation and regularity in bedtimes and rise-times appear to be correlated with improved subjective sleep quality and with less time spent in bed. PMID- 21286244 TI - Relationship of sleep quantity and quality with 24-hour urinary catecholamines and salivary awakening cortisol in healthy middle-aged adults. AB - OBJECTIVES: a. Explore the stability in sleep/wake patterns of middle-aged adults over a 3-year follow-up period. b. Explore the relationship between objectively measured sleep indices, urinary catecholamines, and salivary cortisol. DESIGN: Naturalistic follow-up for sleep/wake patterns (n = 114) by 2-week sleep log and cross-sectional design for objective sleep assessments and hormonal measures (n = 96) at follow-up period nearly 3 years after baseline measurements. SETTING: Community PARTICIPANTS: Healthy middle-aged adults INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: There were high correlations between baseline and follow-up period (2.6 +/- 0.5 years) on sleep/wake patterns (r = 0.6-0.79) as measured by 2-week sleep log. For wave 2 cross-sectional study, objective poor sleepers (3-day actigraphy sleep efficiency < 85%) had a higher 24-h urinary norepinephrine (NE) level (205.7 +/- 105 nmol/d vs 162.1 +/- 55.6 nmol/d, P = 0.03) and a nearly significantly higher 24-h urinary epinephrine (E) level (P = 0.12) than good sleepers. There were no differences in 3-day mean salivary awakening cortisol and 24-h urinary catecholamines (NE and E) between short and normal/long sleepers. Linear regression results, however, showed that shorter time in bed and actual sleep time, longer sleep onset latency, and lower sleep efficiency were correlated with higher 24-h urinary E and NE (all P < 0.05) but not salivary cortisol. The effect of poor sleep quality on 24-h urinary catecholamines was stronger in males than females. CONCLUSIONS: Increased sympathetic activity as measured by 24-h urinary catecholamines might play a critical role in the pathogenesis mediating the relationship of insufficient sleep (quantity and quality) with subsequent cardiovascular and metabolic complications. Salivary awakening cortisol was not associated with sleep quantity and quality in healthy middle-aged adults. PMID- 21286246 TI - Concurrent esterification and N-acetylation of amino acids with orthoesters: A useful reaction with interesting mechanistic implications. AB - The concurrent esterification and N-acetylation of amino acids has been studied with triethyl orthoacetate (TEOA) and triethyl orthoformate (TEOF). In a surprising finding, only one equivalent of TEOA in refluxing toluene was necessary to convert L-proline and L-phenylalanine to the corresponding N-acetyl ethyl esters in good yield. The same transformation using TEOF was not effective. Stereochemical outcome and stoichiometric studies as well as structural variation of the amino acids in this reaction provided unexpected mechanistic insight. PMID- 21286247 TI - Anti-Inflammatory Action of Insulin via Induction of Gadd45-beta Transcription by the mTOR Signaling Pathway. AB - Insulin regulates a large number of genes in a tissue-specific manner. We have identified genes modulated by insulin in the liver and in liver-derived cells that had not yet been characterized as insulin regulated, and these previous studies indicate that numerous genes are induced by insulin via the MEK-ERK pathway. We now describe new studies indicating that Gadd45-beta can be induced by acute insulin treatment. Although other regulators of Gadd45-beta expression may utilize the MEK-ERK pathway, the data indicate that insulin utilizes signaling pathways separate from either MEK-ERK, PI3-K or p38 signaling pathways in the regulation of Gadd45-beta transcription. Our findings show that activation of a downstream effector of multiple signaling pathways, mTOR, was required for insulin-induction of Gadd45-beta gene transcription. Increased expression of Gadd45-beta can inhibit c-Jun N-terminal kinase (JNK) activity. Since TNFalpha is increased during inflammation, and acts, at least in part, via the JNK signaling pathway, insulin induction of Gadd45-beta suggests a mechanism for the anti inflammatory actions of insulin. PMID- 21286248 TI - Short sleep and circulating adipokine concentrations: does the fat hit the fire? PMID- 21286249 TI - Sleep deprivation during early-adult development results in long-lasting learning deficits in adult Drosophila. AB - STUDY OBJECTIVES: Multiple lines of evidence indicate that sleep is important for the developing brain, although little is known about which cellular and molecular pathways are affected. Thus, the aim of this study was to determine whether the early adult life of Drosophila, which is associated with high amounts of sleep and critical periods of brain plasticity, could be used as a model to identify developmental processes that require sleep. SUBJECTS: Wild type Canton-S Drosophila melanogaster. DESIGN; INTERVENTION: Flies were sleep deprived on their first full day of adult life and allowed to recover undisturbed for at least 3 days. The animals were then tested for short-term memory and response-inhibition using aversive phototaxis suppression (APS). Components of dopamine signaling were further evaluated using mRNA profiling, immunohistochemistry, and pharmacological treatments. MEASUREMENTS AND RESULTS: Flies exposed to acute sleep deprivation on their first day of life showed impairments in short-term memory and response inhibition that persisted for at least 6 days. These impairments in adult performance were reversed by dopamine agonists, suggesting that the deficits were a consequence of reduced dopamine signaling. However, sleep deprivation did not impact dopaminergic neurons as measured by their number or by the levels of dopamine, pale (tyrosine hydroxylase), dopadecarboxylase, and the Dopamine transporter. However, dopamine pathways were impacted as measured by increased transcript levels of the dopamine receptors D2R and dDA1. Importantly, blocking signaling through the dDA1 receptor in animals that were sleep deprived during their critical developmental window prevented subsequent adult learning impairments. CONCLUSIONS: These data indicate that sleep plays an important and phylogenetically conserved role in the developing brain. PMID- 21286250 TI - Daytime sleepiness and REM sleep characteristics in myotonic dystrophy: a case control study. AB - STUDY OBJECTIVES: Excessive daytime sleepiness (EDS) and high daytime REM sleep pressure are important sleep features of myotonic dystrophy (DM1). Small and uncontrolled studies have focused on EDS phenotype; none have focused on nocturnal REM sleep characteristics in DM1. Our objectives were to compare polysomnographic and multiple sleep latency test (MSLT) parameters, and both tonic and phasic components of REM sleep between DM1 and controls. DESIGN AND PATIENTS: Forty consecutive DM1 patients and 40 sex- and age-matched controls were included. All subjects underwent overnight polysomnography followed by a MSLT. RESULTS: About 80% of DM1 patients complained of EDS through clinical interview: 31.4% had Epworth scores > 10, and 12.5% had objective sleepiness (latency < 8 min). Higher apnea and central apnea indexes, and a greater proportion of subjects with severe apnea/hypopnea syndrome were found in DM1. The number of SOREMP differed between DM1 and controls, one and two SOREMPs being present in 47.5% and 32.5%, and one control had one SOREMP. Higher percentages of slow wave sleep and REM sleep were found in DM1. DM1 patients had significantly more PLMW, PLMS in both NREM and REM sleep, and PLMS-associated microarousals. Higher REM density was found in DM1 with similar tendencies for either REM sleep without atonia or phasic EMG activity. CONCLUSIONS: This is the first case control sleep study in DM1 to demonstrate higher frequency of daytime sleepiness and abnormalities in REM sleep regulation, with an increased daytime and nighttime REM sleep propensity, REM density, and PLMS. These data suggest a primary central sleep regulation dysfunction in DM1. PMID- 21286251 TI - The sleep EEG as a marker of intellectual ability in school age children. AB - STUDY OBJECTIVES: To investigate the within-subject stability in the sleep EEG and the association between the sleep EEG and intellectual abilities in 9- to 12 year-old children. DESIGN: Intellectual ability (WISC-IV, full scale, fluid, and verbal IQ, working memory, speed of processing) were examined and all-night polysomnography was performed (2 nights per subject). SETTING: Sleep laboratory. PARTICIPANTS: Fourteen healthy children (mean age 10.5 +/- 1.0 years; 6 girls). MEASUREMENTS AND RESULTS: Spectral analysis was performed on artifact-free NREM sleep epochs (C3/A2). To determine intra-individual stability and inter individual variability of the sleep EEG, power spectra were used as feature vectors for the estimation of Euclidean distances, and intraclass correlation coefficients (ICC) were calculated for the 2 nights. Sleep spindle peaks were identified for each individual and individual sigma band power was determined. Trait-like aspects of the sleep EEG were observed for sleep stage variables and spectral power. Within-subject distances were smaller than between-subject distances and ICC values ranged from 0.72 to 0.96. Correlations between spectral power in individual frequency bins and intelligence scores revealed clusters of positive associations in the alpha, sigma, and beta range for full scale IQ, fluid IQ, and working memory. Similar to adults, sigma power correlated with full scale (r = 0.67) and fluid IQ (r = 0.65), but not with verbal IQ. Spindle peak frequency was negatively related to full scale IQ (r = -0.56). CONCLUSIONS: The sleep EEG during childhood shows high within-subject stability and may be a marker for intellectual ability. PMID- 21286252 TI - Sleep and sleepiness in children with nocturnal enuresis. AB - STUDY OBJECTIVES: To assess if sleep patterns and sleepiness are compromised in children with nocturnal enuresis (NE), in comparison with normal control subjects, and to evaluate the role of enuresis-related events during sleep. DESIGN: Assessment of natural sleep patterns at home in a sample of children referred to enuresis clinics and controls. SETTING: Children's homes. PARTICIPANTS: Thirty-two children (19 boys and 13 girls aged 5.1 to 9.1 years) who suffer from primary NE and 94 healthy control subjects (49 boys and 45 girls aged 5 to 8.58 years). INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Sleep measures were derived from 3 to 5 nights of actigraphy and daily logs. Additional information on events related to enuresis and daytime sleepiness was collected using daily reports. Children with NE slept significantly worse than did the control subjects. Their compromised sleep patterns were reflected in a higher number of actigraphic nighttime awakenings, the reduced percentages of motionless sleep, the higher number of reported nighttime awakening, and the increased sleep latency. Children with NE also reported higher levels of sleepiness in the morning and in the evening. CONCLUSIONS: Compared with the sleep of control subjects, the natural sleep of children with NE is significantly more fragmented, and the children with NE experience higher levels of daytime sleepiness. This phenomenology is associated with bedwetting episodes and attempts to keep the child dry during the night. These findings may suggest that children with NE suffer from sleep fragmentation, which may explain their higher arousal threshold. These findings have clinical implications for enuresis management. PMID- 21286253 TI - Non-invasive brain stimulation applied to Heschl's gyrus modulates pitch discrimination. AB - The neural basis of the human brain's ability to discriminate pitch has been investigated by functional neuroimaging and the study of lesioned brains, indicating the critical importance of right and left Heschl's gyrus (HG) in pitch perception. Nonetheless, there remains some uncertainty with regard to localization and lateralization of pitch discrimination, partly because neuroimaging results do not allow us to draw inferences about the causality. To address the problem of causality in pitch discrimination functions, we used transcranial direct current stimulation to downregulate (via cathodal stimulation) and upregulate (via anodal stimulation) excitability in either left or right auditory cortex and measured the effect on performance in a pitch discrimination task in comparison with sham stimulation. Cathodal stimulation of HG on the left and on the right hemispheres adversely affected pitch discrimination in comparison to sham stimulation, with the effect on the right being significantly stronger than on the left. Anodal stimulation on either side had no effect on performance in comparison to sham. Our results indicate that both left and right HG are causally involved in pitch discrimination, although the right auditory cortex might be a stronger contributor. PMID- 21286254 TI - T-wave alternans and arrhythmogenesis in cardiac diseases. AB - T-wave alternans, a manifestation of repolarization alternans at the cellular level, is associated with lethal cardiac arrhythmias and sudden cardiac death. At the cellular level, several mechanisms can produce repolarization alternans, including: 1) electrical restitution resulting from collective ion channel recovery, which usually occurs at fast heart rates but can also occur at normal heart rates when action potential is prolonged resulting in a short diastolic interval; 2) the transient outward current, which tends to occur at normal or slow heart rates; 3) the dynamics of early afterdepolarizations, which tends to occur during bradycardia; and 4) intracellular calcium cycling alternans through its interaction with membrane voltage. In this review, we summarize the cellular mechanisms of alternans arising from these different mechanisms, and discuss their roles in arrhythmogenesis in the setting of cardiac disease. PMID- 21286255 TI - Gait in children with arthrogryposis multiplex congenita. AB - PURPOSE: Lower limb contractures and muscle weakness are common in children with arthrogryposis multiplex congenita (AMC). To enhance or facilitate ambulation, orthoses may be used. The aim of this study was to describe gait pattern among individuals wearing their habitual orthotic devices. METHODS: Fifteen children with AMC, mean age 12.4 (4.3) years, with some lower limb involvement underwent 3 D gait analysis. Three groups were defined based on orthosis use; Group 1 used knee-ankle-foot orthoses with locked knee joints, Group 2 used ankle-foot orthoses or knee-ankle-foot orthoses with open knee joints and Group 3 used no orthoses. RESULTS: The greatest trunk and pelvis movements in all planes and the greatest hip abduction were observed in Group 1, compared to Groups 2 and 3, as well as to the gait laboratory control group. Maximum hip extension was similar in Groups 1 and 2, but in Group 3, there was less hip extension and large deviations from the control data. Lower cadence and walking speed were observed in Group 1 than in Groups 2 and 3. The step length was similar in all groups and also with respect to the gait laboratory reference values. CONCLUSIONS: Children with AMC were subdivided according to orthoses use. Kinematic data as recorded with 3-D gait analysis showed differences among the groups in trunk, pelvis and knee kinematics, and in cadence and walking speed. The step length was similar in all groups and to the gait laboratory reference values, which may be attributable to good hip extension strength in all participants. PMID- 21286256 TI - Surgical synovectomy of the knee in young haemophiliacs: long-term results of a monocentric series of 23 patients. AB - BACKGROUND: In haemophiliacs, synovectomy is indicated for recurrent joint bleedings, despite medical treatment. METHOD: We report a series of 23 surgical synovectomies of the knee with a median follow-up of 8.8 years. The median age of patients at surgery was 13.5 years. Clinical and radiological evaluations were made according to the Petrini and the Pettersson scores, at 1 and 5 years after surgery, and at the last follow-up. Wilcoxon and Spearman's tests were used for the statistical analysis. RESULT: The Petrini score improved at 1 and 5 years (P < 0.001). Nine patients have 20 years of follow-up and a stable result. In more than half of the knees, no episode of recurrent bleeding occurred. The effect of surgery on the range of motion (ROM) was moderate and mobilisation under anaesthesia did not improve it significantly. There was a progressive worsening of the radiological score, but no correlation between clinical and radiological score was noticed (rho = 0.08, P = 0.77). CONCLUSION: Complete synovectomy gives good long-term results in term of bleeding recurrence and overall function. PMID- 21286257 TI - Short hospitalization period with elastic stable intramedullary nails in the treatment of femoral shaft fractures in school children. AB - PURPOSE: To evaluate the safety and period of hospitalization of the treatment of femoral shaft fractures with titanium elastic nails (TEN) in the age range 5 to 14 years. The hypothesis was that TEN might be a low-cost treatment, with good clinical results and short length of hospitalization. METHODS: Thirty children with femur fractures were surgically treated with TEN. RESULTS: The patients spent an average of 9.4 days in hospital. The average period for the healing process was 7.7 weeks. Partial weight bearing was permitted 3.3 weeks after surgery. The incidence of overgrowth was 60%, with an average of 0.40 cm. CONCLUSIONS: The surgical method brings few complications and results in good limb alignment, with a short period of hospitalization and early return to daily activities and school. PMID- 21286258 TI - Bone and joint tuberculosis in children in the Blackburn area since 2006: a case series. AB - This report describes a series of four cases of children between the ages 5 and 14 years with bone or joint infection with Mycobacterium tuberculosis diagnosed between June 2006 and March 2008 in the Blackburn area of England. All of the cases were of South Asian descent. The diagnosis was confirmed by the presence of M. tuberculosis on the culture of bone, synovium or joint fluid, or by the presence of the typical histology of tuberculosis (TB). The sites of tuberculous disease were the hip joint, the sacro-iliac joint and the talus. A recent paper by Sandher et al. (J Bone Joint Surg Br 89:1379-1381, 2007) illustrated only two cases of childhood bone and joint TB in the same geographical area in the preceding 17 years. PMID- 21286259 TI - The creation of a Pavlik "hemi-harness" for a singly irreducible hip in bilateral dysplastic hips. AB - PURPOSE: The treatment of bilaterally dislocated hips with a Pavlik harness can have deleterious effects if one hip remains dislocated. We assess the success of potentially leaving the persistently dislocated hip free and the relocated hip in a "hemi-Pavlik" harness. METHODS: In this report, we retrospectively review three cases of bilaterally dislocated hips in children who were treated with a Pavlik harness. Only one hip was effectively reduced by the harness and, in each case, half of the harness was cut away to create a "hemi-Pavlik" harness and the free side was operated on at a later date. RESULTS: Initial follow-up has shown that the "hemi-Pavlik" harness is effective in maintaining reduction of one hip whilst leaving the other hip untreated, thus, avoiding the complications of prolonged use of the harness in an unreduced hip or having both hips dealt with operatively. CONCLUSIONS: We suggest, in the early stages, that if only one side of the bilaterally displaced hips can be reduced, the non-reduced side should be left free and an elective procedure carried out at a later stage. In the early stages, a "hemi-Pavlik" harness is effective in treating the reducible hip and causes no treatment obstacles for the irreducible side. PMID- 21286260 TI - Factors Associated with End-of-Life Health Service Use in Patients Dying of Cancer. AB - This study describes acute care hospital death, physician house calls and home care near the end of life among patients who died of cancer and the factors that are associated with these events and services. It is a population-based retrospective study that uses linked administrative healthcare data. The cohort includes all patients who died of cancer between 2000 and 2004 in Ontario, Canada.Fifty-five per cent of patients died in acute care hospital, 68% received home care in the last 6 months of life and 24% received at least one physician house call in the last 2 weeks of life. Increased age was associated with a decreased likelihood of each event or service. Women were less likely to die in acute care and more likely to receive home care. Residents in low-income neighbourhoods were less likely to receive house calls or home care. Patients who received home care or house calls were less likely to die in acute care.Our observations add to those in the literature, suggesting a need to increase the use of supportive care services at the end of life in hopes of decreasing the need for acute care. They also serve as a baseline for future comparison, which is of particular interest since new government policies directed at end-of-life care were recently introduced. PMID- 21286261 TI - Child and youth mental health service referrals: physicians' knowledge of mental health services and perceptions of a centralized intake model. AB - OBJECTIVE: We conducted a survey to assess physicians' attitudes and knowledge of mental health services and centralized intake services for mental health. METHOD: A survey consisting of 51 questions was sent to 735 physicians in active practice within the catchment area of a regional centralized intake for child and youth mental health services. The survey was conducted during the summer of 2006. RESULTS: Of 735 eligible physicians, 388 completed and returned the survey (52.8% response rate). The majority of physicians were aware of mental health services offered by their hospital. Physicians reported lower confidence levels for delivering counselling and psychopharmacological treatments for mental health. Furthermore, over 72% indicated that they did not feel they had time in practice to provide mental health counselling. Over 65% of physicians reported that mental health referrals should have appropriate/defined criteria. The majority (92%) of physicians had referred to specialized mental health services provided by their hospital. With respect to centralized intake services, 57.2% of physicians indicated they were aware of the service and 73.9% said it should be continued. However, only 34% reported satisfaction with the centralized intake referral service. Predictors of satisfaction with the service were satisfaction with mental health feedback and satisfaction with response time of the centralized intake service. CONCLUSIONS: Physician confidence levels in providing mental health services vary greatly. While doctors favour a centralized intake for mental health services, their satisfaction with such a service somewhat depends on variables beyond the control of the centralized intake, such as wait times and feedback from mental health providers. PMID- 21286262 TI - Public perspectives on health human resources in primary healthcare: context, choices and change. AB - The purpose of this study was to examine factors identified by patients as relevant to health human resources (HHR) planning for primary healthcare (PHC). Eleven focus groups were conducted in British Columbia and a thematic analysis was undertaken, informed by a needs-based HHR planning framework. Three themes emerged: (a) the importance of geographic context, (b) change management at the practice level and (c) the need for choices and changes in delivery of PHC. Findings suggest that more attention could be focused on overcoming geographic barriers to providing services, change management within office-based practices, and providing support structures that allow primary care providers to work closer to their full scope of practice. That these factors align with many strategic directions set out by government and planners signals the readiness for change in how PHC is delivered and HHR planned. PMID- 21286264 TI - Revels, reviews and renewal: looking back, looking ahead. PMID- 21286263 TI - Increasing Access to Cognitive-Behavioural Therapy (CBT) for the Treatment of Mental Illness in Canada: A Research Framework and Call for Action. AB - International studies suggest that cognitive-behavioural therapy (CBT) for the treatment of mental disorders results in improved clinical and economic outcomes. In Canada, however, publicly funded CBT is scarce, representing an inequity in service delivery. A research framework to evaluate the Canadian health economic impact of increasing access to CBT is proposed. Canadian data related to the epidemiology of mental disorders, patterns of usual care, CBT effectiveness, resource allocation and costs of care will be required and methodologies should be transparent and outcomes meaningful to Canadian decision-makers. Findings should be delivered by multidisciplinary teams of researchers and health professionals. Barriers to funding reform must be identified and knowledge translation strategies delineated and implemented. Canadian clinical and economic outcomes data are essential for those seeking to provide decision-makers with the evidence they need to evaluate whether CBT represents value for mental health dollars spent. PMID- 21286265 TI - Pharaoh and the Prospects for Productivity in HHR. AB - When Pharaoh refused to supply straw, productivity plummeted in the Egyptian brick industry. But Pharaoh had other concerns. Anyway, the costs fell on Israelites, not Egyptians. Productivity improvement in the health sector is similarly constrained by competing objectives, and by the distribution of resulting gains and losses. Furthermore, health services have value only insofar as they improve health outcomes. Increased output of ineffective services is not productivity in any meaningful sense. Yet most of the literature on health human resources productivity focuses on outputs, not outcomes, ignoring serious questions about effectiveness. Proposals to refine the treatment of the health sector within the national accounts are similarly flawed. Proliferation of beneficial, harmful or simply unnecessary services would all be recorded as "productivity growth." PMID- 21286266 TI - The continuing saga of emergency room overcrowding: are we aiming at the right target? AB - Emergency room utilization in Canada is considerably higher than in other industrialized countries. Despite significant investments, recurrent emergency room crises persist. Focusing particularly on the situation in Quebec, this paper examines the evolution of Canada's and Quebec's healthcare systems over the past 40 years and identifies the key developments that resulted in today's problems and the challenges that must be addressed. In this historical overview, we argue that emergency room problems arise from past decisions that gave hospitals a predominant role in the healthcare system and partly modified their original mission, as well as from counterproductive funding modalities. Other decisions have also weakened primary care services, which are strongly focused on acute health problems and are poorly coordinated with the rest of the system. Symptomatic remedies have only eased the pressure on emergency rooms, but the real solution is more complex and must address the historical residues that are paralyzing our healthcare system. PMID- 21286267 TI - Canada's Access to Medicines Regime: Promise or Failure of Humanitarian Effort? AB - There is often a gap between promises made politically and the will to implement these promises meaningfully. One example is Canada's Access to Medicines Regime (CAMR). CAMR was enacted following a WTO decision that changed global intellectual property rules, allowing countries to issue compulsory licences for the production and export of domestically patented medicines to countries without pharmaceutical manufacturing capacity. Ideally, CAMR would be a vital part of Canada's international assistance. However, in the three years since CAMR was implemented, this attempt to improve medicines access by the world's neediest appears instead to be largely a failure of Canadian humanitarian efforts. PMID- 21286268 TI - Making health system performance measurement useful to policy makers: aligning strategies, measurement and local health system accountability in ontario. AB - This study examined the experience of the Ontario Ministry of Health and Long Term Care in enhancing its stewardship and performance management role by developing a health system strategy map and a strategy-based scorecard through a process of policy reviews and expert consultations, and linking them to accountability agreements. An evaluation of the implementation and of the effects of the policy intervention has been carried out through direct policy observation over three years, document analysis, interviews with decision-makers and systematic discussion of findings with other authors and external reviewers. Cascading strategies at health and local health system levels were identified, and a core set of health system and local health system performance indicators was selected and incorporated into accountability agreements with the Local Health Integration Networks. despite the persistence of such challenges as measurement limitations and lack of systematic linkage to decision-making processes, these activities helped to strengthen substantially the ministry's performance management function. PMID- 21286269 TI - Wait time management strategies for scheduled care: what makes them succeed? AB - OBJECTIVES: To assess experts' perceptions of the contextual and local factors that promote or inhibit the implementation of waiting time management strategies (WTMS) in Canadian healthcare organizations. METHODS: We conducted 16 semi structured interviews and one focus group with individuals involved in WTMS at the federal, provincial or organizational level. RESULTS: The most frequently cited local factor was physicians' participation. Physicians' leadership made the greatest difference in bringing resistant physicians on board. To be effective, however, local leadership had to be supported by senior management. Alignment of financial incentives between the contextual and local levels was also frequently cited, and interviewees stressed the importance of tools used to design, monitor, evaluate and prioritize WTMS. CONCLUSIONS: Finding the right balance between supportive resources and tools and an effective management system is a tough challenge. But achieving this balance will help reconcile contradictions between top-down and bottom-up WTMS. PMID- 21286271 TI - Commentary on development of a support tool for complex decision-making. PMID- 21286270 TI - Development of a support tool for complex decision-making in the provision of rural maternity care. AB - CONTEXT: Decisions in the organization of safe and effective rural maternity care are complex, difficult, value laden and fraught with uncertainty, and must often be based on imperfect information. Decision analysis offers tools for addressing these complexities in order to help decision-makers determine the best use of resources and to appreciate the downstream effects of their decisions. OBJECTIVE: To develop a maternity care decision-making tool for the British Columbia Northern Health Authority (NH) for use in low birth volume settings. DESIGN: Based on interviews with community members, providers, recipients and decision makers, and employing a formal decision analysis approach, we sought to clarify the influences affecting rural maternity care and develop a process to generate a set of value-focused objectives for use in designing and evaluating rural maternity care alternatives. SETTING: Four low-volume communities with variable resources (with and without on-site births, with or without caesarean section capability) were chosen. PARTICIPANTS: Physicians (20), nurses (18), midwives and maternity support service providers (4), local business leaders, economic development officials and elected officials (12), First Nations (women [pregnant and non-pregnant], chiefs and band members) (40), social workers (3), pregnant women (2) and NH decision-makers/administrators (17). RESULTS: We developed a Decision Support Manual to assist with assessing community needs and values, context for decision-making, capacity of the health authority or healthcare providers, identification of key objectives for decision-making, developing alternatives for care, and a process for making trade-offs and balancing multiple objectives. The manual was deemed an effective tool for the purpose by the client, NH. CONCLUSIONS: Beyond assisting the decision-making process itself, the methodology provides a transparent communication tool to assist in making difficult decisions. While the manual was specifically intended to deal with rural maternity issues, the NH decision-makers feel the method can be easily adapted to assist decision-making in other contexts in medicine where there are conflicting objectives, values and opinions. Decisions on the location of new facilities or infrastructure, or enhancing or altering services such as surgical or palliative care, would be examples of complex decisions that might benefit from this methodology. PMID- 21286272 TI - Cost shifting and timeliness of drug formulary decisions in atlantic Canada. AB - CONTEXT: Our objectives were to investigate the timeliness of formulary decision making in Atlantic Canada, including the Common Drug Review (CDR) process and the adoption of positive CDR recommendations by Atlantic Canadian provincial public drug plans, and to determine the degree of cost shifting to private payers. METHODS: Dates of formulary listing decisions from Atlantic Canadian provincial drug plan formularies and utilization analyses from Medavie Blue Cross were used to calculate the timeliness of decisions and cost shifting from public payers to a private payer. RESULTS: The median time period between the issuance of a positive CDR recommendation and the addition of a drug to an Atlantic Canadian provincial drug plan was 26.7 weeks (sigma=19.1). Cost shifting to employer sponsored health plans provided by Medavie Blue Cross was minimal. DISCUSSION: There is significant variation in the timing of provincial drug formulary listings among the four Atlantic Canadian provinces and the uptake of CDR recommendations. CONCLUSION: Atlantic Canadian provincial governments should support the mandate of the CDR by aiming for a more timely consideration of recommendations. PMID- 21286273 TI - Pulmonary hypertension in cardiac surgery. AB - Pulmonary hypertension is an important prognostic factor in cardiac surgery associated with increased morbidity and mortality. With the aging population and the associated increase severity of illness, the prevalence of pulmonary hypertension in cardiac surgical patients will increase. In this review, the definition of pulmonary hypertension, the mechanisms and its relationship to right ventricular dysfunction will be presented. Finally, pharmacological and non pharmacological therapeutic and preventive approaches will be presented. PMID- 21286274 TI - Surgical ventricular restoration to reverse left ventricular remodeling. AB - Heart failure is one of the major health care issues in the Western world. An increasing number of patients are affected, leading to a high rate of hospitalization and high costs. Even with administration of the best available medical treatment, mortality remains high. The increase in left ventricular volume after a myocardial infarction is a component of the remodeling process. Surgical Ventricular Restoration (SVR) has been introduced as an optional therapeutic strategy to reduce left ventricular volume and restore heart geometry. So far, it has been established that SVR improves cardiac function, clinical status, and survival in patients with ischemic, dilated cardiomyopathy and heart failure. Since its first description , SVR has been refined in an effort to standardize the procedure and to optimize the results. This review will discuss the rationale behind surgical reversal of LV remodeling, the SVR technique, its impact on cardiac function and survival, and future expectations. PMID- 21286275 TI - Limitations and potential clinical application on contrast echocardiography. AB - Myocardial contrast echocardiography (MCE) is a relatively simple myocardial perfusion imaging technique which should be used in different clinical settings. The ability of MCE to provide a comprehensive assessment of cardiac structure, function, and perfusion is likely to make it the technique of choice for non invasive cardiac imaging.Contrast agents are encapsulated microbubbles (MB) filled with either air or high-molecular-weight gas. They are innocuous, biologically inert and when administered intravasculary, the sound backscatter from the blood poll is enhanced because MB have the enormous reflective ability due to a large acoustic impedance mismatch between the bubble gas and surrounding blood.MCE is an ideal imaging tool for the assessment of left heart contrast and the myocardial microcirculation. MCE detects contrast MB at the capillary level within the myocardium and, thus, has the potential to assess tissue viability and the duration of the contrast effect. MCE was equivalent to SPECT for the detection of CAD with a tendency toward higher sensitivity of MCE compared with SPECT in microvascular disease and CAD. MCE is also a bedside technique that can be used early in patients presenting with acute heart failure to rapidly assess LV function (regional and global) and perfusion (rest and stress). PMID- 21286276 TI - Leptin and the Regulation of Renal Sodium Handling and Renal Na-Transporting ATPases: Role in the Pathogenesis of Arterial Hypertension. AB - Leptin, an adipose tissue hormone which regulates food intake, is also involved in the pathogenesis of arterial hypertension. Plasma leptin concentration is increased in obese individuals. Chronic leptin administration or transgenic overexpression increases blood pressure in experimental animals, and some studies indicate that plasma leptin is elevated in hypertensive subjects independently of body weight. Leptin has a dose- and time-dependent effect on urinary sodium excretion. High doses of leptin increase Na(+) excretion in the short run; partially by decreasing renal Na(+),K(+)-ATPase (sodium pump) activity. This effect is mediated by phosphatidylinositol 3-kinase (PI3K) and is impaired in animals with dietary-induced obesity. In contrast to acute, chronic elevation of plasma leptin to the level observed in patients with the metabolic syndrome impairs renal Na(+) excretion, which is associated with the increase in renal Na(+),K(+)-ATPase activity. This effect results from oxidative stress-induced deficiency of nitric oxide and/or transactivation of epidermal growth factor receptor and subsequent stimulation of extracellular signal-regulated kinases. Ameliorating "renal leptin resistance" or reducing leptin level and/or leptin signaling in states of chronic hyperleptinemia may be a novel strategy for the treatment of arterial hypertension associated with the metabolic syndrome. PMID- 21286277 TI - Palliative combined percutaneous balloon aortic valvuloplasty and unprotected left main stenting in end stage renal disease. AB - With the aging population and high prevalence of atherosclerosis, an increasing number of patients presenting with heart failure and angina are found to have severe coronary artery disease and severe valvular disease. These patients tend to have multiple co-morbidities such as end stage renal disease and are considered high-risk for surgery. In patients with severe coronary artery disease, severe aortic stenosis, and heart failure with depressed left ventricular systolic function, the options are limited as they are not usually offered surgery, but palliative percutaneous high-risk procedures might be a viable alternative.Though long term results after balloon aortic valvuolpasty are not promising, there is a role for these procedures in high-risk inoperable patients for either palliation or as a bridge to surgery. Unprotected left main percutaneous interventions are also feasible with low complication rates. This review provides mounting evidence that it is reasonable to perform combined palliative balloon aortic valvuolpasty and high-risk coronary artery stenting in certain inoperable patients. An illustrative case is presented that extends the findings of the current literature and demonstrates that combined balloon aortic valvuolpasty and left main stenting could be a safe and effective alternative in the setting of heart failure, left ventricular dysfunction, and end stage renal disease. PMID- 21286278 TI - Mechanical circulatory support of the critically ill child awaiting heart transplantation. AB - The majority of children awaiting heart transplantation require inotropic support, mechanical ventilation, and/or extracorporeal membrane oxygenation (ECMO) support. Unfortunately, due to the limited pool of organs, many of these children do not survive to transplant. Mechanical circulatory support of the failing heart in pediatrics is a new and rapidly developing field world-wide. It is utilized in children with acute congestive heart failure associated with congenital heart disease, cardiomyopathy, and myocarditis, both as a bridge to transplantation and as a bridge to myocardial recovery. The current arsenal of mechanical assist devices available for children is limited to ECMO, intra-aortic balloon counterpulsation, centrifugal pump ventricular assist devices, the DeBakey ventricular assist device Child; the Thoratec ventricular assist device; and the Berlin Heart. In the spring of 2004, five contracts were awarded by the National Heart, Lung and Blood Institute to support preclinical development for a range of pediatric ventricular assist devices and similar circulatory support systems. The support of early development efforts provided by this program is expected to yield several devices that will be ready for clinical trials within the next few years. Our work reviews the current international experience with mechanical circulatory support in children and summarizes our own experience since 2005 with the Berlin Heart, comparing the indications for use, length of support, and outcome between these modalities. PMID- 21286279 TI - Sleep duration as a risk factor for cardiovascular disease- a review of the recent literature. AB - Sleep loss is a common condition in developed countries, with evidence showing that people in Western countries are sleeping on average only 6.8 hour (hr) per night, 1.5 hr less than a century ago. Although the effects of sleep deprivation on our organs have been obscure, recent epidemiological studies have revealed relationships between sleep deprivation and hypertension (HT), coronary heart disease (CHD), and diabetes mellitus (DM). This review article summarizes the literature on these relationships. Because sleep deprivation increases sympathetic nervous system activity, this increased activity serves as a common pathophysiology for HT and DM. Adequate sleep duration may be important for preventing cardiovascular diseases in modern society. PMID- 21286280 TI - Ghrelin and cardiovascular diseases. AB - Ghrelin, a newly discovered bioactive peptide, is a natural endogenous ligand of the growth hormone (GH) secretagogue receptor and initially identified as a strong stimulant for the release of GH. Subsequent research has shown that ghrelin and its various receptors are ubiquitous in many other organs and tissues. Moreover, they participate in the regulation of appetite, energy, bodyweight, metabolism of glucose and fat, as well as modulation of gastrointestinal, cardiovascular, pulmonary, immune functions and cell proliferation/apoptosis. Increasing evidence has demonstrated that ghrelin has a close relationship with cardiovascular system. Ghrelin and its receptors are widely distributed in cardiovascular tissues, and there is no doubt that the effects of ghrelin in the cardiovascular system are mediated not only via its growth-hormone-releasing effect but also by its direct effects on the heart. Exogenous administration of ghrelin can dilate peripheral blood vessels, constrict coronary artery, improve endothelial function, as well as inhibit myocardial cell apoptosis. So, ghrelin may have cardiovascular protective effect, including lowering of blood pressure, regulation of atherosclerosis, and protection from ischemia/reperfusion injury as well as improving the prognosis of myocardial infarction and heart failure. Some of these new functions of ghrelin may provide new potential therapeutic opportunities for ghrelin in cardiovascular medicine. In this paper, we will review the existing evidence for cardiovascular effects of ghrelin, including the cardiovascular function, the variations in ghrelin plasma levels in pathophysiologicalogical conditions, the possible protective mechanisms of ghrelin, as well as its future potential therapeutic roles. PMID- 21286281 TI - Angina in Women without Obstructive Coronary Artery Disease. AB - Angina in the absence of obstructive coronary artery disease, sometimes referred to as cardiac syndrome X (CSX), is a debilitating condition that disproportionately affects women. More than 50% of women evaluated for angina have non-obstructive disease by cardiac catheterization, although the total numbers of women affected by CSX are unknown. Varying clinical definitions and the lack of large scale epidemiologic studies focusing on this illness have resulted in limited knowledge about its risk factors, although there appears to be an association with black race, estrogen deficiency, and insulin resistance. Contrary to prior beliefs about the benign nature of this entity, these women suffer considerable morbidity with costly economic implications that approach the lifetime costs of healthcare utilization for those with obstructive coronary disease. Two prevailing hypotheses have emerged to explain CSX: the ischemic hypothesis detailing abnormal coronary microvascular function and the non ischemic hypothesis describing altered pain perception and myocardial hypersensitivity. Treatment strategies have focused on both of these pathways with the main goal of improving symptoms. Beta blockers provide the most convincing evidence for benefit, with other antianginals having secondary roles. Other promising pharmacologic therapies include xanthine derivatives, estrogen replacement therapy, ACE inhibitors, and statin medications, among other emerging treatment options. Neurostimulation and lifestyle factors including exercise can also be beneficial in reducing symptoms. However, managing patients with CSX can be frustrating for both patients and physicians, as there is a lack of data regarding an optimal treatment algorithm including few large-scale randomized controlled trials to clarify effective therapies. PMID- 21286282 TI - David e. Beck, m.d. PMID- 21286283 TI - Laparoscopy and endoscopy. PMID- 21286284 TI - A primer on endoscopic electronic medical records. AB - Endoscopic electronic medical record systems (EEMRs) are now increasingly utilized in many endoscopy centers. Modern EEMRs not only support endoscopy report generation, but often include features such as practice management tools, image and video clip management, inventory management, e-faxes to referring physicians, and database support to measure quality and patient outcomes. There are many existing software vendors offering EEMRs, and choosing a software vendor can be time consuming and confusing. The goal of this article is inform the readers about current functionalities available in modern EEMR and provide them with a framework necessary to find an EEMR that is best fit for their practice. PMID- 21286285 TI - Bowel preparation for colonoscopy. AB - Colonoscopy is the premier method for colonic evaluation and its diagnostic accuracy and therapeutic safety depends on the quality of the colonic cleansing. Bowel cleansing with polyethylene glycol and sodium phosphate provides cleansing with high-quality preparations with an acceptably low morbidity rate and a high degree of patient satisfaction in a cost-effective manner. Modifications have reduced the volume of the polyethylene glycol preparations. Sodium phosphate has been associated with electrolyte and osmolarity imbalances and nephrocalcinosis; therefore, its clinical use has been questioned. Polyethylene glycol may be safer in patients with a history of significant renal, heart, or liver disease. PMID- 21286286 TI - Sedation, analgesia, and monitoring. AB - Endoscopic procedures are common and sedation is frequently used to minimize anxiety and discomfort, reduce the potential for physical injury during the procedure, and improve overall patient tolerability and satisfaction. In this article, the authors review the variety of options for sedation and analgesia available to the gastroenterologist or surgical endoscopist. PMID- 21286287 TI - Current status of chromoendoscopy and narrow band imaging in colonoscopy. AB - Colonoscopy, the preferred procedure for colon cancer screening, has well documented limitations. To improve colonoscopy's effectiveness, augmented endoscopy techniques, such as chromoendoscopy and narrow band imaging (NBI) have been evaluated. Both techniques are inexpensive, safe, and relatively easy to perform. Chromoendoscopy has an increasingly important role in surveillance of IBD, but significant work is needed to determine the optimal staining techniques and mucosal surface pattern analysis before this technique can be incorporated into routine clinical practice. NBI is a much newer technology with far less data. Well-designed prospective randomized controlled trials have failed to identify a benefit of NBI in screening colonoscopy, in surveillance for high-risk populations or as an adjunct for therapeutic procedures. PMID- 21286288 TI - Endoscopic treatment for lower gastrointestinal bleeding. AB - Lower gastrointestinal bleeding is common and can result from several colonic causes including diverticulosis, arteriovenous malformations, ischemia, inflammatory bowel disease, infectious colitis, neoplasm, postpolypectomy, and anastomotic and radiation proctitis. Following resuscitation and evaluation, colonoscopy can be used for diagnosis and treatment. Most physicians prescribe a bowel preparation for their patients. Therapeutic options include injection, coagulation (monopolar or bipolar cautery, argon plasma coagulator), and mechanical (clips, bands, detachable loops) devices. PMID- 21286289 TI - Endoscopic colonic stents and dilatation. AB - Colonic obstruction is common with malignancy as the most common cause. Endoscopic placement of intraluminal self-expanding stents is a newer option to manage this challenging problem. In benign disease, endoscopic dilatation may play a role whereas stenting can serve as a bridge to surgery. Indications and placement techniques are discussed along with a summary of published results and complications. PMID- 21286290 TI - Laparoscopy for benign colorectal diseases. AB - The applicability of laparoscopy to many complex intraabdominal colorectal procedures continues to expand, and has been shown to be feasible and safe in experienced hands. Data are available on the elderly, rectal prolapse, diverticulitis, Hartman's takedown, small bowel obstruction, Crohn's disease, and ulcerative colitis. Clinically relevant advantages have been clearly demonstrated in selected patient populations. Laparoscopic surgery for benign colorectal disease should be considered in patients suitable for this approach to an abdominal operation. PMID- 21286291 TI - Laparoscopy for colon and rectal cancer. AB - Laparoscopy has emerged as a useful tool in the surgical treatment of diseases of the colon and rectum. Specifically, in the application of colon cancer, a laparoscopic-assisted approach offers short-term benefits to patients while maintaining a long-term oncologic outcome. Hand-assisted laparoscopic surgery may help decrease operative times while preserving the benefits of laparoscopy. The literature on the use of laparoscopy for rectal cancer is still in its early stages. Limited data suggest short-term benefits without compromising oncologic outcome; however, data from large multicenter trials will clarify the role of laparoscopy in the treatment of rectal cancer. Robotic proctectomy is a novel technique that may offer considerable advantage and overcome some limitations laparoscopy creates while working in the confines of the pelvis. The improved magnification and visualization offered with the robot may also assist in preserving bladder and sexual function. Transanal endoscopic microsurgery (TEM) for the treatment of T1 rectal cancers with low-risk features appears to be safe. However, TEM has a significantly higher recurrence rate when used to treat invasive cancer. Endoluminal techniques and equipment are under development and could offer more minimally invasive approaches to the treatment of colon and rectal cancer. Credentialing and training of surgeons and teams involved in the use of laparoscopy is important prior to making these techniques ubiquitous. PMID- 21286292 TI - What I say to medical students and paediatric residents. PMID- 21286293 TI - Langerhans cell histiocytosis: A complex recurrent disease. PMID- 21286294 TI - The health of Canada's children. Part II: Health mechanisms and pathways. AB - The present article provides models that explain how exposures to differing quality living circumstances result in health inequalities among children. Living circumstances - the social determinants of health - operate through a variety of mechanisms to shape children's health and cognitive, emotional and social development. Specific processes set children off on trajectories such that these exposures - in interaction with their environments - not only shape their health as children but also provide the foundations for their health status as adults. In addition to specifying the mechanisms that mediate the relationship between living circumstances and health outcomes, the article also identifies some of the economic and political factors that shape the quality of the living circumstances to which Canadian children are exposed. PMID- 21286295 TI - Promoting optimal monitoring of child growth in Canada: Using the new World Health Organization growth charts - Executive Summary. PMID- 21286297 TI - "Is my child growing well?" Questions and answers for parents. PMID- 21286296 TI - A health professional's guide for using the new WHO growth charts. PMID- 21286298 TI - Chih-hung lin, m.d. And fu-chan wei, m.d. PMID- 21286299 TI - Extremity-saving surgery and reconstruction: from microsurgery reconstruction to transplantation. PMID- 21286300 TI - High-energy trauma and damage control in the lower limb. AB - Management of traumatic lower-limb vascular injury can offer special challenges even to experienced surgeons. Recent U.S. conflicts have advanced the practice of vascular trauma surgery on the battlefield and offer important lessons learned for management of similar injury in urban trauma centers. Damage control techniques for complex injuries when associated with hemodynamic instability may provide an opportunity to save both life and limb. This article provides an overview of damage control principles in the management of high-energy traumatic vascular injuries of the lower limb during recent U.S. military combat operations. PMID- 21286301 TI - Hand allotransplantation. AB - In the past decade, more than 100 different composite tissue allotransplantation (CTA) procedures have been performed around the world including more than 50 hand and 8 facial transplants with encouraging graft survival and excellent functional outcomes. Broader clinical application of CTA, however, continues to be hampered by requirement for long-term, high-dose, multidrug maintenance immunosuppression to prevent graft rejection mediated particularly by composite tissue allograft's highly immunogenic skin component. Medication toxicity could result in severe adverse events including metabolic and infectious complications or malignancy. Notably, unlike in solid organs, clinical success is dictated not only by graft acceptance and survival but also by nerve regeneration, which determines ultimate functional outcomes. Novel strategies such as cellular and biologic therapies that integrate the concepts of immune regulation with those of nerve regeneration have shown promising results in small and large animal models. Clinical translation of these insights to reconstructive transplantation and CTA could further minimize the need of immunosuppression and optimize functional outcomes. This will enable wider application of such treatment options for patients in need of complex reconstructive surgery for congenital deformities or devastating injuries that are not amenable to standard methods of repair. PMID- 21286302 TI - Limb salvage in malignant tumors. AB - Limb-sparing resection and reconstruction has become the treatment of choice in extremity malignancies, as amputation does not provide better long-term survival rates or functional advantages. R0 resection, the removal of the tumor in sano, remains the prerequisite and most important oncologic parameter to avoid local recurrence. Successful treatment requires the combination of surgical eradication and the patient's specific functional and aesthetic rehabilitation. Our clinical rationale resulting from more than 2000 cases will be demonstrated. The problematic aspects of different tumor entities and the locoregional clearance of lymphatic pathways will be discussed. Differential diagnosis and multimodality treatment in high-volume tumor centers is likely to achieve superior oncologic statistics. Long-term survivors after microsurgical reconstructions and possible secondary malignancies will be addressed. PMID- 21286303 TI - Microsurgical coverage reconstruction in upper and lower extremities. AB - Trauma is one of the main causes of upper- and lower-limb defects. Limb injuries frequently result in complex defects, hence reconstruction can be demanding. The basic principles of trauma management and methods of reconstruction are analyzed. Then, the evolution of free tissue transfer is reviewed with particular attention to the use of anterolateral thigh flap in reconstruction of upper- and lower-limb trauma cases. The anterolateral thigh flap is the workhorse flap in our department due to its versatility in the reconstruction of complex defects. Finally, the concept of free-style perforator flaps is presented. Microsurgery has supplied the armamentarium of the plastic surgeon with a very powerful tool. Essentially, microsurgery may almost always provide a solution in cases of complex defects that cannot be covered with the simpler options of the reconstructive ladder. The recently acquired perforator flap concept will gradually become the most popular method of microsurgical reconstruction, as it minimizes donor-site morbidity and replaces "like tissue with like tissue." PMID- 21286304 TI - Functional reconstruction of the diabetic foot. AB - The diabetic triad of neuropathy, vasculopathy, and foot deformity can be surgically challenging to the reconstructive surgeon. Soft tissue deficits must be closed to protect underlying structures from infection and to provide a stable environment for healing. It is critical to have adequate blood flow and to debride the wound to clean healthy tissue before considering reconstruction. Surgical options commonly used include healing by secondary intention, local flap closure, skin grafts, pedicled flaps, and free tissue transfer. Despite a surgeon's best operative efforts, these strategies may fail perioperatively due to postoperative shear forces created by premature joint motion and/or pressure (either weight bearing or decubitus). In the properly selected patient population, external fixators serve as an indispensable adjunct to wound healing in the Charcot foot by providing temporary but reliable offloading and/or immobilization of joints. Using a team approach is critical to the success of diabetic limb reconstruction. PMID- 21286305 TI - Brachial plexus injury: nerve reconstruction and functioning muscle transplantation. AB - Adult brachial plexus injury remains a dilemma to a reconstructive microsurgeon, especially when attempting to reconstruct cases of total root avulsion. Different degrees and different levels of injury require different strategies of reconstruction. The purpose of this article is to illustrate the author's reconstructive strategy in correlation with the injury level of classification. Nerve transfer, functioning free muscle transplantation, and other palliative surgery are reconstructive options for level 1 injuries. Neurolysis, nerve repair, nerve grafts (free nerve graft or vascularized ulnar nerve graft), nerve transfer if associated with level 1 lesion in other spinal nerves, and palliative reconstruction are chosen options for level 2, 3, and 4 lesions. A clavicle osteotomy is often required in level 3 lesions. Nerve grafts are frequently applied in level 4 lesions, which result in less aberrant reinnervation and a better prognosis. PMID- 21286306 TI - Avoiding unfavorable results in microsurgical reconstruction in upper-extremity trauma. AB - The treatment of hand and upper-extremity injuries is complex. The treatment goals are to restore maximal hand function and, if possible, preinjury form. Several complications are frequently encountered while treating hand and upper extremity injuries. Complications such as edema, direct structural destruction, and nerve palsies are the result of the inflicting injury. Skin graft contraction, fascial adhesions causing restricted tendon motion, and diminution of muscle function with time during staged reconstructions are treatment-related complications. The nature of these complications as well as means for their prevention and treatment are reviewed. PMID- 21286307 TI - The reconstruction of the mutilated hand. AB - The challenging reconstructive treatment of defects in the upper extremity requires a sound working knowledge of a variety of flaps. As the hand surgeon weighs the pros and cons of each possible flap to obtain definitive closure, he or she must also integrate the priorities of function, contour, and stability as well as the anticipation of further reconstructive surgery in choosing the flap of choice. This review describes the various flaps available for closure of soft tissue defects of the upper extremity. The principles of management of wounds of the upper extremity is described to guide hand surgeons in the early treatment of massive wounds that will eventually need free tissue coverage. Currently used flaps include fasciocutaneous, fascial, musculocutaneous, muscle, and osteocutaneous flaps. Flap selection is based on the characteristics of the defect including size, shape, and location, the availability of donor sites, and the goals of reconstruction. Improved techniques of microsurgery and an ever increasing repertoire of flaps provide the framework for hand surgeons to offer the most appropriate flap based on donor site, thickness, amount of tissue needed, and composition. A discussion of the selection of ideal flaps for any given defect should enable the reconstructive hand surgeon to provide the most appropriate coverage of wounds to the hand and upper extremity. PMID- 21286308 TI - Discovering tumor suppressor genes through genome-wide copy number analysis. AB - Classical tumor suppressor gene discovery has largely involved linkage analysis and loss-of-heterozygosity (LOH) screens, followed by detailed mapping of relatively large chromosomal regions. Subsequent efforts made use of genome-wide PCR-based methods to detect rare homozygous deletions. More recently, high resolution genomic arrays have been applied to cancer gene discovery. However, accurate characterization of regions of genomic loss is particularly challenging due to sample heterogeneity, the small size of deleted regions and the high frequency of germline copy number polymorphisms. Here, we review the application of genome-wide copy number analysis to the specific problem of identifying tumor suppressor genes. PMID- 21286309 TI - Therapeutics Based on microRNA: A New Approach for Liver Cancer. AB - Hepatocellular carcinoma (HCC) is a serious public health hazard. Polygenes involvement, accumulation of genetic and epigenetic changes and immune response of viral vector during gene therapy have resulted in the high mortality rate without marked change. To provide a safeguard for gene therapy and the feasibility for a clinical application, efforts have been focused predominantly upon constructing liver-targeted vector recently. MicroRNAs (miRNAs), a class of short endogenous RNAs, regulate the gene expression at the post-transcriptional level through imperfect base pairing with the 3'-untranslated region of target mRNAs. miRNAs, especially the liver-specific miRNA: miR-122, have multiple functions in liver development and abnormal expression of miRNAs could lead to liver diseases. Altered miRNA expressions have been observed in HCCs, viral hepatitis and hepatic fibrosis. The different expression profiles of miRNAs in HCC suggest that miRNAs may serve as either novel potential targets acting directly as oncogenes or therapeutic molecules working as tumor suppressor genes. Moreover, the abundance in general and liver specificity in particular, all together make them attractive to be considered as elements for hepatic specific targeting viral vector. This review describes recent progress in miRNA investigation on liver associated for better understanding the relationship between miRNA and liver cancer in order to raise prospects for therapy. PMID- 21286310 TI - DNA instability at chromosomal fragile sites in cancer. AB - Human chromosomal fragile sites are specific genomic regions which exhibit gaps or breaks on metaphase chromosomes following conditions of partial replication stress. Fragile sites often coincide with genes that are frequently rearranged or deleted in human cancers, with over half of cancer-specific translocations containing breakpoints within fragile sites. But until recently, little direct evidence existed linking fragile site breakage to the formation of cancer-causing chromosomal aberrations. Studies have revealed that DNA breakage at fragile sites can induce formation of RET/PTC rearrangements, and deletions within the FHIT gene, resembling those observed in human tumors. These findings demonstrate the important role of fragile sites in cancer development, suggesting that a better understanding of the molecular basis of fragile site instability is crucial to insights in carcinogenesis. It is hypothesized that under conditions of replication stress, stable secondary structures form at fragile sites and stall replication fork progress, ultimately resulting in DNA breaks. A recent study examining an FRA16B fragment confirmed the formation of secondary structure and DNA polymerase stalling within this sequence in vitro, as well as reduced replication efficiency and increased instability in human cells. Polymerase stalling during synthesis of FRA16D has also been demonstrated. The ATR DNA damage checkpoint pathway plays a critical role in maintaining stability at fragile sites. Recent findings have confirmed binding of the ATR protein to three regions of FRA3B under conditions of mild replication stress. This review will discuss recent advances made in understanding the role and mechanism of fragile sites in cancer development. PMID- 21286312 TI - The Fuzzy Logic of MicroRNA Regulation: A Key to Control Cell Complexity. AB - Genomic and clinical evidence suggest a major role of microRNAs (miRNAs) in the regulatory mechanisms of gene expression, with a clear impact on development and physiology; miRNAs are a class of endogenous 22-25 nt single-stranded RNA molecules, that negatively regulate gene expression post-transcriptionally, by imperfect base pairing with the 3' UTR of the corresponding mRNA target. Because of this imperfection, each miRNA can bind multiple targets, and multiple miRNAs can bind the same mRNA target; although digital, the miRNAs control mechanism is characterized by an imprecise action, naturally understandable in the theoretical framework of fuzzy logic.A major practical application of fuzzy logic is represented by the design and the realization of efficient and robust control systems, even when the processes to be controlled show chaotic, deterministic as well unpredictable, behaviours. The vagueness of miRNA action, when considered together with the controlled and chaotic gene expression, is a hint of a cellular fuzzy control system. As a demonstration of the possibility and the effectiveness of miRNA based fuzzy mechanism, a fuzzy cognitive map -a mathematical formalism combining neural network and fuzzy logic- has been developed to study the apoptosis/proliferation control performed by the miRNA-17-92 cluster/E2F1/cMYC circuitry.When experimentally demonstrated, the concept of fuzzy control could modify the way we analyse and model gene expression, with a possible impact on the way we imagine and design therapeutic intervention based on miRNA silencing. PMID- 21286311 TI - Indispensable Roles of Plastids in Arabidopsis thaliana Embryogenesis. AB - The plastid is an organelle vital to all photosynthetic and some non photosynthetic eukaryotes. In the model plant Arabidopsis thaliana, a number of nuclear genes encoding plastid proteins have been found to be necessary for embryo development. However, the exact roles of plastids in this process remain largely unknown. Here we use publicly available datasets to obtain insights into the relevance of plastid activities to A. thaliana embryogenesis. By searching the SeedGenes database (http://www.seedgenes.org) and recent literature, we found that, of the 339 non-redundant genes required for proper embryo formation, 108 genes likely encode plastid-targeted proteins. Nineteen of these genes are necessary for development of preglobular embryos and/or their conversion to globular embryos, of which 13 genes encode proteins involved in non photosynthetic metabolism. By contrast, among 38 genes which are dispensable for globular embryo formation but necessary for further development, only one codes for a protein involved in metabolism. Products of 21 of the 38 genes play roles in plastid gene expression and maintenance. Examination of RNA profiles of embryos at distinct growth stages obtained in laser-capture microdissection coupled with DNA microarray experiments revealed that most of the identified genes are expressed throughout embryo morphogenesis and maturation. These findings suggest that metabolic activities are required at preglobular and throughout all stages of embryo development, whereas plastid gene expression becomes necessary during and/or after the globular stage to sustain various activities of the organelle including photosynthetic electron transport. PMID- 21286313 TI - Functional genomics: new insights into the 'function' of low levels of gene expression in stem cells. AB - Understanding the global gene expression profile of stem cells and their multilineage differentiation will be essential for their ultimate therapeutic application. Efforts to characterize stem cells have relied on analyzing the genome-wide expression profiles that are biased towards the identification of genes that display the most pronounced differential expression. Rather than being viewed as a "blank" state, recent studies suggest that stem cells express low levels of multiple lineage specific genes prior to differentiation, a phenomenon known as "lineage priming." It is not likely that low levels of lineage-specific genes produce sufficient amounts of differentiation factors, but rather to provide rapid transcription to a wide range of lineage programs prior to differentiation. Thus, stem cell differentiation may involve the elimination of other potential pathways and the activation of a specific lineage program. PMID- 21286314 TI - Genetics talks to epigenetics? The interplay between sequence variants and chromatin structure. AB - Transcription is regulated by two major mechanisms. On the one hand, changes in DNA sequence are responsible for genetic gene regulation. On the other hand, chromatin structure regulates gene activity at the epigenetic level. Given the fundamental participation of these mechanisms in transcriptional regulation of virtually any gene, they are likely to co-regulate a significant proportion of the genome. The simple concept behind this idea is that a mutation may have a significant impact on local chromatin structure by modifying DNA methylation patterns or histone type recruitment. Yet, the relevance of these interactions is poorly understood. Elucidating how genetic and epigenetic mechanisms co participate in regulating transcription may assist in some of the unresolved cases of genetic variant-phenotype association. One example is loci that have biologically predictable functions but genotypes that fail to correlate with phenotype, particularly disease outcome. Conversely, a crosstalk between genetics and epigenetics may provide a mechanistic explanation for cases in which a convincing association between phenotype and a genetic variant has been established, but the latter does not lie in a promoter or protein coding sequence. Here, we review recently published data in the field and discuss their implications for genetic variant-phenotype association studies. PMID- 21286316 TI - Reviews on spinal cord injury - a comment. PMID- 21286317 TI - Ear cropping and tail docking - a comment. PMID- 21286315 TI - The nature of protein domain evolution: shaping the interaction network. AB - The proteomes that make up the collection of proteins in contemporary organisms evolved through recombination and duplication of a limited set of domains. These protein domains are essentially the main components of globular proteins and are the most principal level at which protein function and protein interactions can be understood. An important aspect of domain evolution is their atomic structure and biochemical function, which are both specified by the information in the amino acid sequence. Changes in this information may bring about new folds, functions and protein architectures. With the present and still increasing wealth of sequences and annotation data brought about by genomics, new evolutionary relationships are constantly being revealed, unknown structures modeled and phylogenies inferred. Such investigations not only help predict the function of newly discovered proteins, but also assist in mapping unforeseen pathways of evolution and reveal crucial, co-evolving inter- and intra-molecular interactions. In turn this will help us describe how protein domains shaped cellular interaction networks and the dynamics with which they are regulated in the cell. Additionally, these studies can be used for the design of new and optimized protein domains for therapy. In this review, we aim to describe the basic concepts of protein domain evolution and illustrate recent developments in molecular evolution that have provided valuable new insights in the field of comparative genomics and protein interaction networks. PMID- 21286320 TI - Veterinary medical ethics. An ethicist's commentary on castration of cats on farm. PMID- 21286321 TI - Actinobacillus equuli as a primary pathogen in breeding sows and piglets. AB - The death of over 300 sows in 2 months on a 3000 sow farrow-to-isowean operation in Manitoba was attributed to infection with Actinobacillus equuli. This pathogen commonly infects foals, and is rarely reported in swine. Our report is the second recently published case of this pathogen in North American swine. PMID- 21286322 TI - Gross postmortem and histologic examination findings from abortion losses and calf mortalities in western Canadian beef herds. AB - Production losses from abortions, stillbirths, and early calf mortality were described for the 2002 calf crop in 203 beef herds in western Canada. A total of 1689 calves were examined. A summary diagnosis was reported for 64% of aborted calves, 78% of stillborn calves, 88% of neonatal calves, and 94% of the calves > 3 d of age. Diagnoses for aborted calves included: thyroid gland lesions, pneumonia, developmental anomalies, placentitis, and myocardial necrosis or myopathy. For stillborn calves, diagnostic findings included: dystocia, thyroid gland lesions, myocardial necrosis or myopathy, developmental anomalies, and skeletal myopathy or necrosis. The most common diagnoses for neonatal calves (<= 3 d) were: pneumonia, skeletal myopathy or necrosis, myocardial necrosis or myopathy, accident or trauma, and septicemia. For older calves (3 d to 3 mo), the most common diagnoses included: starvation, abomasal ulcer or perforation, enteritis or colitis, pneumonia, and intestinal volvulus, obstruction, or perforation. PMID- 21286323 TI - A study of heart diseases without clinical signs of heart failure in 47 cattle. AB - In this retrospective study, features of 47 cattle suffering from heart disease (HD) without clinical signs of heart failure (HF) were reviewed. The most common reasons for referral were respiratory problems (n =14), anorexia (n = 13), fever (n = 10), and lameness (n = 9). Thirty-nine animals were tachypneic. In 31 cases, cardiac auscultation revealed abnormalities. The final diagnoses were bacterial endocarditis (BE; n = 19), congenital heart disease (CHD; n = 18), pericarditis (n = 8), cardiomyopathy (n = 1), and lymphoma (n = 1). Echocardiography was performed in 39 cases. Gross pathology examination confirmed the echocardiographic diagnosis in 4 of 5 cases of pericarditis, 6 of 6 cases of BE, and 4 of 6 cases of CHD. Short-term prognosis was guarded with 19 cases (40.4%) being discharged. Premature death within 2 mo after discharge (n = 5), early culling because of poor breeding performance (n = 5), and normal productive life in the herd (n = 5) were observed in the cases that were followed. Echocardiography may be the most sensitive tool for the antemortem diagnosis of heart disease in cattle. PMID- 21286324 TI - Diaphragmatic herniation in the horse: 31 cases from 2001-2006. AB - Diaphragmatic rent and visceral herniation in the horse is seldom diagnosed, but historically carries a poor prognosis. The objective of this study was to document the presentation and surgical management of all diaphragmatic rents as presented to 2 referral institutions over a 5-year period. A review of 31 cases demonstrated that even with advances in surgical management of abdominal and thoracic conditions, little has been done to change the prognosis for this condition. Success rate was 23% for all horses presented for colic and were ultimately diagnosed with a diaphragmatic hernia, and 46% for those cases for which surgical management was elected. PMID- 21286325 TI - Thiamine status of feedlot cattle fed a high-concentrate diet. AB - As thiamine status of ruminants is adversely affected by rumen acidity, this study investigated whether or not thiamine deficiency occurs in feedlot cattle fed a high concentrate diet. Fifty 1- to 2-year-old feedlot cattle fed a high concentrate diet (75% barley) for at least 3 mo (high concentrate diet group) and 15 healthy feedlot cattle of similar ages (control group) that were fed a low concentrate diet (30% barley) were used. Rumen fluid samples were obtained by rumenocentesis and their pH was determined with a portable pH meter. Blood samples taken from all animals from a jugular vein were used to determine erythrocyte transketolase enzyme activity, and hence thiamine pyrophosphate (TPP) effect. Odor and mean pH values of ruminal fluid samples from the high concentrate diet and control group were acidic (pH 5.3) and aromatic (pH 6.1), respectively. The mean TPP effect % in the high concentrate diet group (47.2 +/- 3.2) was significantly higher than in the control group (19.53 +/- 2.5) (P < 0.001). The study provides evidence of a TPP effect in feedlot cattle fed a high concentrate diet. PMID- 21286326 TI - An analysis of the movement of dairy cattle through 2 large livestock markets in the province of Ontario, Canada. AB - Data pertaining to the movement of dairy cattle through 2 large livestock markets in the province of Ontario were collected for 1 week per month throughout 2004. Counts and postal codes of sellers and buyers of adult dairy cattle, veal calves, and dairy calves were obtained. Three assumptions were made to represent the level of mixing among animals that could take place at the markets. We estimated the number of livestock holdings that could be exposed to a highly contagious disease agent, should infected animals have been sold through the market in the same week. The estimates ranged from 8 to 20 holdings, when assuming no mixing at the market, to 51 to 171 holdings when assuming complete mixing. These markets are important hubs in the dairy cattle movement network in Ontario and pose the risk of infecting a large number of livestock holdings should animals infected with a highly contagious disease agent pass through them. PMID- 21286327 TI - Clinical and pathologic features of an adenomatous polyp of the colon in a domestic ferret (Mustela putorius furo). AB - A 6-year-old castrated male domestic ferret (Mustela putorius furo) with a 4-week history of intermittent diarrhea and straining during defecation had an intraluminal mass in the descending colon identified by abdominal ultrasound. The histopathological diagnosis of the resected mass was an adenomatous polyp of the colon. No post-operative complications were identified over a 32-month follow-up period. PMID- 21286328 TI - Combination of cyclosporin A and prednisolone for juvenile cellulitis concurrent with hindlimb paresis in 3 English cocker spaniel puppies. AB - Three 7-week-old, English cocker spaniel littermates were diagnosed as having juvenile cellulitis with concurrent neurologic signs based on history, histopathology, and therapeutic response. The puppies were treated with cyclosporin A and prednisolone. Skin lesions and hindlimb paresis improved following treatment. PMID- 21286329 TI - Utilization of the scrotum as a full thickness skin graft in a dog. AB - A 1.5-year-old, intact, male dog was presented for degloving wounds to the distal pelvic limbs due to vehicular trauma. Treatment involved serial debridement of the wounds and use of the scrotal skin as a full thickness, meshed skin graft applied to the dorsal aspect of the left pes with a successful outcome. PMID- 21286330 TI - The use of an angularis oris axial pattern flap in a dog after resection of a multilobular osteochondroma of the hard palate. AB - An 11-year-old neutered male boxer was presented for treatment of a multilobular osteochondroma of the hard palate. The mass was surgically resected and the hard palate defect was reconstructed using an angularis oris axial pattern buccal mucosal flap. No local recurrence was reported 6 mo after surgery. PMID- 21286331 TI - Cyclosporine treatment of perianal gland adenoma concurrent with benign prostatic hyperplasia in a dog. AB - A 13-year-old, intact male, mixed-breed dog was evaluated for multiple intradermal nodules around the anus. The nodules were diagnosed as perianal gland adenoma based on histopathologic examination. After therapy with cyclosporin A for 5 wk, the perianal masses were moderately shrunken. The dog's condition has remained stable over 6 mo. PMID- 21286332 TI - A retrospective diagnostic laboratory survey of antimicrobial resistance in fecal Escherichia coli isolated from spring calves in western Canada. AB - Diagnostic laboratory data on antimicrobial susceptibility of Escherichia coli isolated from feces of spring calves were evaluated retrospectively for the 5 year period from 1999 to 2003. The antimicrobials to which resistance was most prevalent were tetracycline, ampicillin, and trimethoprim/sulphamethoxazole. Resistance to 3 or more antimicrobials was found in 52.5% [95% confidence interval (CI): 47.9 to 56.6] of the E. coli isolates. Incomplete records reduced the usefulness of the diagnostic laboratory data for surveillance. Standardized patient information submitted by veterinary clinics would increase the value of this data for surveillance. PMID- 21286333 TI - 2010 report of veterinarians employed in Government, Industry, and Academe. PMID- 21286334 TI - The enigma of Pictou cattle disease. PMID- 21286335 TI - Diagnostic ophthalmology. PMID- 21286336 TI - The role of lipopolysaccharide/toll-like receptor 4 signaling in chronic liver diseases. AB - Toll-like receptor 4 (TLR4) is a pattern recognition receptor that functions as lipopolysaccharide (LPS) sensor and whose activation results in the production of several pro-inflammatory, antiviral, and anti-bacterial cytokines. TLR4 is expressed in several cells of healthy liver. Despite the constant confrontation of hepatic TLR4 with gut-derived LPS, the normal liver does not show signs of inflammation due to its low expression of TLR4 and ability to modulate TLR4 signaling. Nevertheless, there is accumulating evidence that altered LPS/TLR4 signaling is a key player in the pathogenesis of many chronic liver diseases (CLD). In this review, we first describe TLR4 structure, ligands, and signaling. Later, we review liver expression of TLR4 and discuss the role of LPS/TLR4 signaling in the pathogenesis of CLD such as alcoholic liver disease, nonalcoholic fatty liver disease, chronic hepatitis C, chronic hepatitis B, primary sclerosing cholangitis, primary biliary cirrhosis, hepatic fibrosis, and hepatocarcinoma. PMID- 21286337 TI - Non-invasive assessment of changes in liver fibrosis via liver stiffness measurement in patients with chronic hepatitis B: impact of antiviral treatment on fibrosis regression. AB - BACKGROUND: Liver stiffness measurement (LSM) can assess liver fibrosis in patients with chronic hepatitis B (CHB). We evaluated whether LSM can be used to assess changes in liver fibrosis during antiviral treatment using nucleos(t)ide analogs in patients with CHB. METHODS: We recruited 41 patients with CHB who had significant liver fibrosis, normal or slightly elevated serum alanine aminotransferase (ALT) levels (<=2 * upper limit of normal), and detectable serum hepatitis B virus DNA before antiviral treatment. Patients in Group 1 (n = 23) and Group 2 (n = 18) underwent follow-up LSM after antiviral treatment for 1 and 2 years, respectively. RESULTS: The mean age, ALT and LSM value of all patients (34 men and 7 women) before antiviral treatment were 46.6 +/- 9.5 years, 40.6 +/- 17.2 IU/L and 12.9 +/- 8.6 kPa, respectively. Hepatitis B e antigen (HBeAg) was detected in 31 patients (75.6%). Fibrosis stage was F2 in 12 (29.3%), F3 in 6 (14.6%) and F4 in 23 (56.1%) patients. After antiviral treatment, LSM values and DNA positivity decreased significantly as compared to baseline (P = 0.018 and P < 0.001 in Group 1; P = 0.017 and P < 0.001 in Group 2, respectively), whereas ALT levels were unchanged (P = 0.063 in Group 1; P = 0.082 in Group 2). CONCLUSIONS: Our preliminary data suggest that LSM can be used to assess liver fibrosis regression after antiviral treatment using nucleos(t)ide analogs in patients with CHB. PMID- 21286338 TI - Epidemiologic risk factors of hepatocellular carcinoma in a rural region of Egypt. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is a major health problem worldwide, including Egypt. In the recent past, HCC has become the second most prevalent cancer among men in Egypt. Since HCC has not been well studied in the rural population of Egypt, this case-control study was conducted to investigate the epidemiologic risk factors of HCC in the predominantly rural region of Gharbiah, Egypt. METHODS: A total of 150 cases and 150 controls matched to cases on age (+/ 5 years) and sex were recruited from the Gharbiah Cancer Society and Tanta Cancer Center. Exposure data were collected by an interviewer-administered standardized questionnaire about epidemiologic, occupational, medical and family history of HCC. Conditional logistic regression was utilized to calculate unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (CI). The effect modification of HCC risk between viral infection and environmental risk factors was also assessed. RESULTS: Being an industrial worker was an independent risk for developing HCC (OR 3.54, 95% CI 1.18, 10.63) after adjusting for viral infection, schistosomiasis and tobacco smoking. High relative risk of HCC was observed among HCV-infected individuals who were farmers (OR 9.60, 95% CI 3.72, 24.76), industrial workers (OR 12.90, 95% CI 4.33, 38.43) or active smokers (OR 5.95, 95% CI 2.20, 16.08). CONCLUSION: Occupational exposure may play an important role in the development of HCC. Farming, industrial exposures and cigarette smoking may increase the risk of HCC among HCV-seropositive individuals. Future research focusing on mechanisms of occupational exposures among HCV patients in this population is needed. PMID- 21286339 TI - Fibrosis and AST to platelet ratio index predict post-operative prognosis for solitary small hepatitis B-related hepatocellular carcinoma. AB - PURPOSE: Although advanced liver fibrosis is crucial in the development of hepatocellular carcinoma (HCC) for patients with chronic hepatitis B, whether it is associated with the recurrence of HCC after resection remains obscure. This study was aimed to compare the outcomes for patients with minimal or advanced fibrosis in solitary small hepatitis B virus (HBV)-related HCC. METHODS: This study enrolled 76 patients with small (<5 cm) solitary HBV-related HCC who underwent resection. The outcomes of patients with minimal and advanced fibrosis in non-tumor areas were compared. Serum markers were tested to assess the stage of hepatic fibrosis and to predict prognosis. RESULTS: Fourteen patients with an Ishak fibrosis score of 0 or 1 were defined as having minimal fibrosis; the remaining 62 patients were defined as having advanced fibrosis. During a follow up period of 77.0 +/- 50.7 months, 41 patients died. The overall survival rate was significantly higher (P = 0.018) and recurrence rate was lower (P = 0.018) for patients in the minimal fibrosis group. Aspartate aminotransferase-platelet ratio index (APRI) exhibited the most reliable discriminative ability for predicting advanced fibrosis. The overall survival rate was significantly higher (P = 0.003) and recurrence rate was lower (P = 0.005) for patients with an APRI of 0.47 or less. CONCLUSIONS: For patients with solitary small HBV-related HCC who underwent resection, minimal fibrosis is associated with a lower incidence of recurrence and with better survival. APRI could serve as a reliable marker for assessing hepatic fibrosis and predicting survival. PMID- 21286340 TI - Liver stiffness measurement in the risk assessment of hepatocellular carcinoma for patients with chronic hepatitis. AB - BACKGROUND/AIMS: [corrected] The risk of hepatocellular carcinoma (HCC) increased with progression of hepatic fibrosis as assessed by liver stiffness measurement (LSM). This study used LSM to assess the risk of HCC presence in patients with chronic hepatitis. METHODS: The patients with liver tumor or chronic hepatitis indicated for biopsy were prospectively enrolled. LSM was performed on the same day as biopsy. The diagnostic performances of clinical parameters and LSM in predicting HCC presence were compared with the areas under receiver operating characteristics curves (AUROC). The risk of HCC presence was assessed with stratum-specific likelihood ratios (SSLR). The cut-off values and its diagnostic validity were calculated for LSM. RESULTS: A total of 435 patients, including 106 HCC and 329 chronic hepatitis, were enrolled. The AUROC in predicting HCC presence was 0.736, 0.733, 0.594, 0.579 and 0.532 for LSM, alpha-fetoprotein, platelet count, total bilirubin, and aspartate aminotransferase-platelet ratio index, respectively. Multivariate analysis showed liver stiffness was an independent factor for HCC presence (odds ratio 1.07, 95% confidence interval (CI) 1.05-1.09). SSLR for HCC presence by liver stiffness was 0.43 (95% CI 0.32 0.57) in <12 kPa, 1.28 (0.89-1.84) in 12-24 kPa, and 5.94 (3.77-9.35) in >24 kPa. With 12 and 24 kPa as the cut-offs in predicting HCC presence, the sensitivity was 69.8 and 41.5%, respectively. The specificity was 69.6 and 92.7%, respectively. CONCLUSIONS: LSM identified the risk group for HCC presence in chronic hepatitis patients and had high specificity in the prediction of HCC with the cut-off of 24 kPa. PMID- 21286341 TI - Long-term efficacy of nucleoside monotherapy in preventing HBV infection in HBsAg negative recipients of anti-HBc-positive donor livers. AB - BACKGROUND AND AIM: Transmission of hepatitis B virus (HBV) infection occurs in up to 87.5% of HBsAg-negative recipients of anti-HBc-positive donor livers in the absence of HBV prophylaxis. There is no standardized prophylactic regimen to prevent HBV infection in this setting. The aim of this study was to determine the long-term efficacy of nucleoside analogue to prevent HBV infection in this setting. METHODS: A retrospective study of HBsAg-negative patients receiving liver transplantation (LT) from anti-HBc-positive donors during a 10-year period. RESULTS: Twenty patients were studied, mean age was 50.2 +/- 8.3 years, 40% were men, and 90% were Caucasian. The median MELD score at the time of LT was 18 (12 40). None of the patients received hepatitis B immune globulin. Eighteen patients received nucleoside analogue monotherapy: 10 received lamivudine and 8 received entecavir. None of these 18 patients developed HBV infection after a median follow up of 32 (1-75) months. One patient received a second course of hepatitis B vaccine 50 months after LT with anti-HBs titer above 1,000 mIU/mL. Lamivudine was discontinued and the patient remained HBsAg negative 18 months after withdrawal of lamivudine. Two patients who were anti-HBs positive before LT were not started on HBV prophylaxis after LT; both developed HBV infection after LT. CONCLUSIONS: Nucleoside monotherapy is sufficient in preventing HBV infection in HBsAg-negative recipients of anti-HBc-positive donor livers. HBV prophylaxis is necessary in anti-HBs-positive recipients of anti-HBc-positive donor livers. PMID- 21286342 TI - Reduction of liver stiffness following resolution of acute flares of chronic hepatitis B. AB - BACKGROUND: Measuring liver stiffness is becoming more popular as a non-invasive tool for assessing liver fibrosis. AIM: To assess the effect of severe hepatitis B flare on liver stiffness and determine factors that correlate with liver stiffness measurements. METHODS: Twenty-nine patients with severe hepatitis B flare (ALT > 10 * upper limit of normal) were followed up for 1 year. Serial transient elastography was performed at the time of flare, 3-6, and 12 months after flare. RESULTS: At the time of flare, the median liver stiffness was 16.8 kPa, with no patients having normal liver stiffness (<6 kPa). There was a significant decrease in liver stiffness from baseline to 3-6 months (16.8 vs. 7.9 kPa, respectively, P < 0.001), and a further smaller decline from 3-6 to 12 months (7.9 vs. 6.9 kPa, respectively, P = 0.039). By 12 months, 10 (34%) had normalized their liver stiffness. Baseline parameters which correlated with liver stiffness include bilirubin, ALT, albumin, prothrombin time and platelet levels (all P < 0.05). CONCLUSION: Liver stiffness was increased in patients with severe hepatitis B flares, with return to near normal levels by 6 months. Transient elastography for proper assessment of liver fibrosis should be performed at least 6 months after flare. PMID- 21286343 TI - Superior response to pegylated interferon and ribavirin in Asians with chronic hepatitis C. AB - PURPOSE: Reported sustained virological response (SVR) rates in Asians with chronic hepatitis C (CHC) exceed those of other ethnic groups, but differences in body weight across races potentially confound this observed superior response. Our aim was to determine whether Asian race independently predicts SVR within a multicultural clinic setting. METHODS: Patients with genotype 1, 2 and 3 CHC prescribed peginterferon and weight-based ribavirin were included in this retrospective study. Logistic regression was performed to identify factors associated with SVR. RESULTS: Three-hundred ninety-two patients (BMI 26.9 +/- 5.0 kg/m(2), genotype 1 66%, viral load 5.9 +/- 0.66 log(10) IU/ml, advanced fibrosis 53%) were included in this study. Caucasians comprised 81%, South Asians 9% and Asians (Non-South) 10%. SVR was achieved by 54% overall, but was highest amongst Asians (Non-South) (79%) compared with South Asians (56%, P = 0.04) and Caucasians (50%, P < 0.001) despite a predominance of genotype 3 infection amongst the South Asians. Asians (Non-South) had the highest SVR rate even amongst those infected with genotype 1 (75%) and those with advanced fibrosis (77%). Independent of viral genotype, Asian (Non-South) race was a strong predictor of SVR (OR 5.10 vs. Caucasians, 95% CI 1.72-17.71, OR 7.84 vs. South Asians, 95% CI 1.62-37.84), as were treatment naive status (OR 3.85, 95% CI 1.76 8.89), non-diabetic status (OR 3.70, 95% CI 1.30-11.11), non-obesity (OR 2.13, 95% CI 1.06-4.35), peginterferon alpha2a (2.08 vs. alpha2b, 95% CI 1.16-3.85), steatosis <10% (OR 2.0, 95% CI 1.05-3.85) and ribavirin exposure (mg/kg/day) (OR 1.13, 95% CI 1.01-1.28). CONCLUSION: Asian (Non-South) race is a strong independent predictor of SVR. PMID- 21286344 TI - Comparison of adverse effects related to pegylated interferon-based therapy for patients with chronic hepatitis B and chronic hepatitis C in Taiwan. AB - PURPOSE: Pegylated interferon (Peg-IFN)-based therapy is effective in treating chronic hepatitis B (CHB) and C (CHC) but frequently induces adverse events (AEs). This study was conducted to compare the incidence of Peg-IFN-based therapy associated AEs in Taiwanese patients with CHB and CHC. METHODS: Fifty-six patients with CHB and 103 age-, sex- and treatment duration-matched patients with CHC were enrolled. Patients with CHB were treated with Peg-IFN-alpha-2a 180 MUg/week for 24 weeks (HBeAg(+), n = 31) or 48 weeks (HBeAg(-), n = 25); patients with CHC were treated with Peg-IFN-alpha-2a 180 MUg/week plus ribavirin 1,000 1,200 mg/day for 24 weeks (genotype 2/3, n = 57) or 48 weeks (genotype 1, n = 46). RESULTS: Significantly higher incidences of Peg-IFN-related AEs, especially neuropsychiatric symptoms, and ribavirin-associated skin manifestations were observed in patients with CHC compared with those with CHB, with either the 24- or 48-week regimen. Frequencies of laboratory abnormalities, except for anemia, were comparable in both groups. Neither group showed overt hepatic decompensation. Frequency of dose reduction was similar between the groups. Substantially higher rates of early termination and severe AEs were observed in patients with CHC. CONCLUSIONS: Patients with CHB treated with Peg-IFN had fewer AEs than patients with CHC treated with Peg-IFN/ribavirin. All patients were treated safely. PMID- 21286345 TI - Effects of nuclear receptor FXR on the regulation of liver lipid metabolism in patients with non-alcoholic fatty liver disease. AB - OBJECTIVE: The aim of this study was to explore the role of farnesoid X receptor (FXR) in liver lipid metabolism of non-alcoholic fatty liver disease (NAFLD) patients. METHODS: In this study, pathology and clinical criteria confirmed NAFLD in patients. Fatty acid synthetase (FAS)-positive liver cells were visualized by laser scanning confocal microscopy. Levels of FXR, liver X receptor (LXR), sterol regulatory element binding protein 1C (SREBP-1C), and small heterodimer partner (SHP) proteins were detected by Western blot. FXR, LXR, and SHP mRNA levels were measured by real-time PCR. RESULTS: In patients with NAFLD, a significant positive relationship between the degree of hepatic steatosis and serum triglycerides and cholesterol (correlation coefficient > 0.5, P < 0.05) was seen. The NAFLD patients had more FAS protein in liver, which suggests that there could have been more of fatty acid synthesis in hepatic cells (P < 0.05). The levels of FXR protein and mRNA were decreased in patients with NAFLD (P < 0.05), while those of LXR and SREBP-1C were increased (P < 0.05). The levels of SREBP-1C positively correlated with the degree of hepatic steatosis. There were no differences between the levels of SHP protein and mRNA both in NAFLD patients and normal controls (P > 0.05). CONCLUSION: Our data showed that the decreased expression of hepatic FXR is associated with an increased expression of LXR, SREBP-1C, and hepatic triglyceride synthesis; furthermore, increased SREBP-1C is associated with the degree of hepatic steatosis in the NAFLD patients. PMID- 21286346 TI - Rebleeding rates following TIPS for variceal hemorrhage in the Viatorr era: TIPS alone versus TIPS with variceal embolization. AB - PURPOSE: To compare rebleeding rates following treatment of variceal hemorrhage with TIPS alone versus TIPS with variceal embolization in the covered stent-graft era. METHODS: In this retrospective study, 52 patients (M:F 29:23, median age 52 years) with hepatic cirrhosis and variceal hemorrhage underwent TIPS insertion between 2003 and 2008. Median Child-Pugh and MELD scores were 8.5 and 13.5. Generally, 10-mm diameter TIPS were created using covered stent-grafts (Viatorr; W.L. Gore and Associates, Flagstaff, AZ). A total of 37 patients underwent TIPS alone, while 15 patients underwent TIPS with variceal embolization. The rates of rebleeding and survival were compared. RESULTS: All TIPS were technically successful. Median portosystemic pressure gradient reductions were 13 versus 11 mmHg in the embolization and non-embolization groups. There were no statistically significant differences in Child-Pugh and MELD score, or portosystemic pressure gradients between each group. A trend toward increased rebleeding was present in the non-embolization group, where 8/37 (21.6%) patients rebled while 1/15 (6.7%) patients in the TIPS with embolization group rebled (P = 0.159) during median follow-up periods of 199 and 252 days (P = 0.374). Rebleeding approached statistical significance among patients with acute hemorrhage, where 8/32 (25%) versus 0/14 (0%) rebled in the non-embolization and embolization groups (P = 0.055). A trend toward increased bleeding-related mortality was seen in the non embolization group (P = 0.120). CONCLUSIONS: TIPS alone showed a high incidence of rebleeding in this series, whereas TIPS with variceal embolization resulted in reduced recurrent hemorrhage. The efficacy of embolization during TIPS performed for variceal hemorrhage versus TIPS alone should be further compared with larger prospective randomized trials. PMID- 21286347 TI - Fluidized-bed bioartificial liver assist devices (BLADs) based on microencapsulated primary porcine hepatocytes have risk of porcine endogenous retroviruses transmission. AB - PURPOSE: Bioartificial liver assist devices (BLADs) are expected to bridge liver failure patients to liver transplantation, but porcine endogenous retroviruses (PERVs) still pose a potential risk in pig-to-human xenotransplantation and thereby limit the use of bioartificial liver therapy. In our lab, fluidized-bed BLADs based on microencapsulated primary porcine hepatocytes have been successfully used to treat liver failure pigs. We detected the risk of PERVs transmission of microencapsulated primary porcine hepatocytes-the key component of fluidized-bed BLADs, to evaluate the biosafety of this device for further clinical applications. METHODS: Microencapsulated primary porcine hepatocytes (cell diameter = 300 MUm) were cultured in Dulbecco's modified Eagles medium (DMEM). Microencapsulated cell culture supernatants were collected at 6, 12, 24 and 72 h. HEK-293 were cocultured with these supernatants, and the cocultured cells were harvested every 7 days. RT-PCR was used to detect PERVs transmission. RT-qPCR was used to get the number of virus copies. PK-15 was used as the positive control whereas HepG2 was used as the negative control. RESULTS: PERV was detected in all supernatants, and the viral load of the supernatants increased with time. Moreover, cocultured 293 cells were positive for PERV specific sequences. CONCLUSION: The kind of fluidized-bed BLADs based on microencapsulated primary porcine hepatocytes have risk of PERVs transmission. Further extensive pre-clinical study focused on biosafety is warranted. PMID- 21286348 TI - Brush border enzymes and absorptive capacity in extrahepatic portal venous obstruction in children. AB - BACKGROUND AND OBJECTIVE: Portal hypertension may affect intestinal functions, brush border enzymes and absorption parameters. Information about these in extrahepatic portal venous obstruction (EHPVO) in children is limited and poorly reported. We therefore studied the brush border enzymes and absorptive capacity in EHPVO in children. METHODS: The study was conducted on 52 children of EHPVO. The diagnosis of EHPVO was made on the basis of clinical presentation and ultrasound examination. All patients underwent upper gastrointestinal endoscopy. Endoscopic tissue biopsies from duodenum were taken on aluminum foils and kept immediately at -20 degrees C for estimation of brush border enzymes. Tissue biopsies were homogenized in sodium maleate buffer, 0.1 M pH 6.0, by a homogenizer and processed for the enzymes: lactase, maltase, and sucrase. Enzyme levels were compared to normal healthy controls (n = 20). d-Xylose test, stool acid steatocrit for fat excretion in stools and stool alpha-1 antitrypsin were done to know about the absorptive parameters. RESULTS: Enzyme levels of lactase (6.21 +/- 5.67 IU/mg) and sucrase (37.07 +/- 21.06 IU/mg) in EHPVO group were significantly lower as compared to lactase (23.32 +/- 10.48 IU/mg) and sucrase (95.96 +/- 46.55 IU/mg) in normal healthy controls. Maltase levels were lower, but difference was not statistically significant in EHPVO group (56.90 +/- 28.65 IU/mg) as compared to normal controls (63.28 +/- 22.88 IU/mg). There was no significant difference of urinary d-xylose and stool fat in patients with normal or short stature EHPVO patients. CONCLUSION: EHPVO leads to decrease in levels of brush border enzymes in small bowel but their absorption capacity remains normal. PMID- 21286349 TI - Study of adiponectin in chronic liver disease and cholestasis. AB - PURPOSE: Adiponectin is an adipocytokine suggested to have a hepatoprotective effect. To date, little information is available in the literature regarding changes in serum adiponectin levels in cirrhosis and cholestasis and the associated metabolic disturbances. In order to elucidate the role of adiponectin in chronic liver disease our aim was to determine serum adiponectin in patients with different grades of cirrhosis and cholestasis and to correlate it with markers of liver injury, inflammation and cholestasis. We also aimed to correlate adiponectin with markers of metabolic syndrome such as body mass index and insulin resistance. METHODS: Forty patients with cirrhosis; 30 patients with cirrhosis and cholestasis; and 20 matched controls were studied. They were subjected to clinical assessment, laboratory investigations: serum bilirubin, ALT, AST, alkaline phosphatase, GGT, albumin, C-reactive protein, prothrombin activity, fasting blood sugar, insulin. HOMA index was calculated. Abdominal ultrasonography and upper GI endoscopy were performed. RESULTS: Adiponectin was elevated in patients with cirrhosis and cirrhosis/cholestasis and was significantly higher in Child A and B. Adiponectin showed correlation with liver cell injury, marker of inflammation, synthetic liver function and markers of cholestasis. Adiponectin did not correlate with complications of cirrhosis as ascites and esophageal varices nor did it correlate with BMI or HOMA. CONCLUSIONS: Adiponectin is elevated in cirrhosis and shows correlation with degree of hepatocellular injury and cholestasis. Finally, adiponectin levels in cirrhosis do not correlate with parameters of body composition or metabolism but exclusively with reduced liver function. PMID- 21286350 TI - Usefulness of multi-detector helical CT with multiplanar reconstruction for depicting the duodenal varices with multiple collateral shunt vessels. AB - Duodenal varices are a rare complication in patients with portal hypertension. Bleeding from duodenal varices often results in a severe prognosis. Diagnosis of the disease is usually based on findings obtained by endoscopy or angiography. However, it occasionally fails to detect the lesion and demonstrate its porto systemic shunt vessels which are necessary information to decide an appropriate treatment. Recent advances in CT may make it possible for us to reveal duodenal varices with complicated porto-systemic shunt vessels. We report the case of a 58 year-old man with liver cirrhosis with repeated bleeding from duodenal varices. Esophagogastroduodenoscopy (EGD) revealed multinodular varices in the third portion of the duodenum. Then we conducted a capsule endoscopy (CE) and found fresh blood in the duodenum, suggesting duodenal variceal hemorrhage. Angiography depicted the varices with one afferent and two efferent vessels. Abdominal CT examination was conducted using a four-channel multi-detector row CT scanner. The multiplanar reconstructed images revealed not only the varices, but also three afferent and two efferent vessels. The patient was treated by surgical ligation and sclerotherapy, because of its complicated porto-systemic shunt and reserved liver function. No gastrointestinal bleeding has been seen after the surgery. Our case suggests the usefulness of multi-detector CT with multiplanar reconstruction (MPR) for the diagnosis and therapeutic decision of duodenal varices. PMID- 21286351 TI - Sclerosing cholangitis associated with retroperitoneal fibrosis: a case of multisystem fibroinflammatory disorder. AB - INTRODUCTION: Retroperitoneal fibrosis is a fibroinflammatory disease of unknown etiology that can be associated with other fibroinflammatory disorders. Lately, there have been several reports showing that retroperitoneal fibrosis is a manifestation of IgG4-related sclerosing disease, which often presents as autoimmune pancreatitis. CASE REPORT: This report shows the case of IgG4-related sclerosing cholangitis associated with retroperitoneal fibrosis independent of autoimmune pancreatitis. The patient presented with cholestatic jaundice and picture of sclerosing cholangitis in endoscopic retrograde cholangiography. The combination of endoscopic biliary drainage and steroid therapy was an effective treatment in this case. CONCLUSION: The diagnosis of IgG4-related sclerosing disease should always be taken into consideration in patients with sclerosing cholangitis, especially when it is associated with any fibroinflammatory disorder. PMID- 21286352 TI - Giant cystic lymphangioma of the liver. AB - BACKGROUND: Giant cystic lymphangiomas of the liver are rare malformations of the lymphatic system usually found in children. CASE PRESENTATION: A 35-year-old man presenting with right upper quadrant abdominal pain for 7 months visited our clinic. Ultrasound, CT, and MRI examination demonstrated a giant cystic mass in the right trisegment of the liver. The patient underwent surgical resection and histological results of the resected specimen confirmed the diagnosis of giant cystic lymphangioma. The right upper quadrant abdominal pain subsided after the surgical resection and the patient recovered well. CONCLUSION: Surgical resection is an effective therapy in treating giant cystic lymphangioma. PMID- 21286355 TI - Upper extremity resurfacing via an expanded latissimus dorsi musculocutaneus flap for large circumferential defects: the "spiral" reconstruction technique. AB - We present an expanded latissimus dorsi musculocutaneus (LDMC) flap to treat circumferential upper extremity defects via resurfacing and "spiral reconstruction" in 5 patients during a 17-year period. Five patients with different indications for tissue expansion from burns to congenital hairy nevi were operated. The expansion was done in a longitudinal direction, and a rectangular tissue expander (TE) was inserted under the LD muscle to expand the flap in a longitudinal direction thereby forming a "long" flap rather than a "wide" one. After excising the circumferential lesion, the expanded "elongated" flap was wrapped spirally around the extremity to cover the defect; the donor site was closed as usual. The 5 patients we treated via LDMC flaps in a spiral fashion were free of complications, and all were satisfied with the outcome. All the flaps survived and the spiral reconstruction allowed for a tension-free donor site closure and near complete recipient coverage. This technique is indicated for large circumferential extremity skin defects and deformities. Application of expanded LDMC flaps in a spiral fashion can be used by the reconstructive surgeon to resurface large circumferential upper extremity lesions when indicated. The idea of a long and thinned expansion flap must be in a longitudinal direction and we need this long expanded and thin flap to "spiral" it around the extremity to cover a large defect. The "spiral" flap coverage introduced here for large circumferential extremity defects enables the surgeon to cover the defect with simultaneous donor site closure and good results. PMID- 21286356 TI - Open interlocked nailing without a targeting device or X-ray guidance for non union of the femur: a case series. AB - From October 2005 to August 2007, we operated on six patients who had femoral non unions and performed interlocked intramedullary nailing without X-ray guidance or a targeting device. There were three fractures of the distal femur, two fractures of the mid-shaft and one of the proximal femur. Fatigue failure of a non interlocked Kuntscher nail and one nail migration were the presenting features in two patients. The presence of sclerosis of the bone ends in four cases and a need for cancellous bone grafts at the site of non-union in all patients made wide dissection and open reduction unavoidable. There was a limb length discrepancy in all patients before surgical intervention. Partial weight bearing was commenced at 6 weeks post-operation. There was no case of wound infection. There was no misplaced screw. Minimum range of knee flexion was 105 degrees at 2 months post operation. These early results call for a closer look at this cheap, safe and effective means of handling femoral non-union in third world societies where there is paucity of instrumentation and implants for interlocked nailing. PMID- 21286357 TI - The correction of the relapsed club foot by closed distraction. AB - Correction of a relapsed clubfoot deformity by distraction with an external fixator is a recognized alternative to open surgery. Most published series report a good outcome but none are prospective observational studies using the scoring system of the International Clubfoot Study Group (ICFSG). We present a series of 9 relapsed club feet treated with closed gradual distraction using this scoring method. PMID- 21286358 TI - Femoral lengthening with a rail external fixator: tips and tricks. AB - Lengthening the femur with an external fixator is commonly practised for a wide variety of pathologies. This technical report includes tips derived from observation and experience in a busy limb reconstruction unit. It focuses on the use of a rail fixator, although some of the descriptions are applicable to lengthening by circular fixators. PMID- 21286359 TI - Hypertrophic nonunion of the ulna in a child: treatment with an elastic stable intramedullary nail without bone graft. AB - Nonunion following diaphyseal forearm fracture is an uncommon complication in children. Compression plate fixation with bone grafting has been the standard method to treat this complication. We report a case of hypertrophic nonunion of the ulna in a child who was treated surgically using an elastic stable intramedullary nail (ESIN) without bone grafting. The nonunion healed 4 months after surgery. PMID- 21286360 TI - Non-vascularized fibular graft reconstruction after resection of giant aneurysmal bone cyst (ABC). AB - The aim of this study was to present the results of non-vascularized fibular graft for reconstruction of bone defects after en block resection of giant aneurysmal bone cyst (ABC) of the extremities. Between 1998 and 2006, three patients, aged 6, 8 and 23 years, with giant aneurysmal bone cysts were treated. The cysts were located in the humerus, proximal femur and metatarsal. All patients were given en bloc resection of the cyst followed by non-vascularized fibular bone graft, with the graft length ranging from 6 to 18 cm. All patients needed supplementary fixation with a single Kirschner wire or plate and screws. At the final follow-up, bony union was achieved in each case, and there was no recurrence, limitation of range of motion or disability. In addition, complete regeneration of the fibula at the donor site was seen in the two children. We propose a criterion for giant ABC, when the transverse diameter of the cyst is up to three times or more of the transverse diameter of the nearby bone, it is then called a giant ABC. Non-vascularized fibular graft is an optimal and valuable method for the reconstruction of bone defects after resection of giant ABC in the extremities. PMID- 21286361 TI - Repair of a wide lower extremity defect with cross-leg free transfer of latissimus dorsi and serratus anterior combined flap: a case report. AB - Composite tissue loss in extremities involving neurovascular structures has been a major challenge for reconstructive surgeons. Reconstruction of large defects can only be achieved with microsurgical procedures. The success of free flap operations depends on the presence of healthy recipient vessels. In cases with no suitable donor artery and vein or in which even the use of vein grafts would not be feasible, the lower limb can be salvaged with a cross-leg free flap procedure. We present a case with a large composite tissue loss that was reconstructed with cross-leg free transfer of a combined latissimus dorsi and serratus anterior muscle flap. This case indicates that this large muscle flap can survive with the cross-leg free flap method and this technique may be a viable alternative for large lower extremity defects that have no reliable recipient artery. PMID- 21286362 TI - A new device to treat intra-capsular fracture neck of femur non-union. AB - In adolescents and young adults, femoral neck fractures often result from high velocity trauma. These fractures are usually of vertical shear pattern. There is an increased incidence of avascular necrosis and non-union, which is difficult to treat. Non-union of fractured neck of femur in young adults is a serious problem. There is growing evidence that these fractures should be treated with an angle stable device to improve biomechanics at the fracture site. An ideal implant should prevent varus deformation and retroversion of the fracture in order to prevent failure of the osteosynthesis and thus preventing cut-out of implant and non-union at the fracture site. We report the first use of an Orthofix Gottfried Percutaneous Compression Plate (PC.C.P.) (Orthofix, Guilford, UK) to treat a non union of an intra-capsular fractured neck of femur. We recommend this, in combination with autologous bone grafting, via a mini hip modification of the Smith-Petersen approach. PMID- 21286363 TI - The role of behavioral genetics in child and adolescent psychiatry. PMID- 21286364 TI - Genetic Overlap between ADHD Symptoms and Reading is largely Driven by Inattentiveness rather than Hyperactivity-Impulsivity. AB - OBJECTIVE: To assess the genetic and environmental etiology of the co-occurence of ADHD symptoms and reading difficulties using the largest sample to date, distinguishing two dimensions of ADHD and two of reading. METHOD: Data were obtained from 6428 12-year old twin pairs drawn from the population-based Twins Early Development Study. ADHD symptoms (combined ADHD, inattentiveness and hyperactivity-impulsivity) were assessed using parent ratings. Reading was assessed using a battery of reading comprehension and word decoding tests. RESULTS: Heritabilities were high, around 70% for ADHD symptoms and 45-65% for the reading measures. Some of the same genes affected combined ADHD and reading with a genetic correlation of -.31. The most notable finding was that the genetic correlation with reading was significantly greater for inattentiveness (-.31) than for hyperactivity-impulsivity (-.16), suggesting that genetic overlap between combined ADHD and reading is largely driven by inattentiveness. Moreover results showed that it is word decoding rather than reading comprehension that is differentially related to the ADHD dimensions (lower genetic correlation to hyperactivity-impulsivity than to inattentiveness). CONCLUSIONS: Genetic overlap between ADHD and reading is largely driven by inattentiveness rather than hyperactivity-impulsivity. PMID- 21286365 TI - Association between DRD4 genotype and Autistic Symptoms in DSM-IV ADHD. AB - OBJECTIVE: To explore the association of the DRD4 exon 3 7-repeat allele with clinically significant levels of autistic symptoms among children and adolescents with DSM-IV Attention-Deficit/Hyperactivity Disorder (ADHD). METHODS: Subjects included in the main analysis were 954 Missouri-born twins from a study of the genetic epidemiology of ADHD with complete data on DSM-IV ADHD diagnosis, DRD4 genotype and the parent-rated Social Responsiveness Scale (SRS). Logistic regression was used to investigate the association of the DRD4 7-repeat allele with clinically elevated SRS score. RESULTS: Among individuals with DSM-IV ADHD (any subtype), the DRD4 7-repeat allele was associated with high SRS score. The distribution of raw SRS scores appeared bimodal among subjects with at least one copy of the DRD4 7-repeat allele, suggesting a possible interaction between this DRD4 genotype and other, unmeasured variables. CONCLUSIONS: The DRD4 7-repeat allele may increase the risk for clinically elevated autistic symptoms in children and adolescents with ADHD. Further studies are needed to confirm this finding and explore the role of specific gene-gene and gene-environment interactions in the development of autistic symptoms and other co-occurring psychopathology among individuals with ADHD. PMID- 21286366 TI - A genetic study on attention problems and academic skills: results of a longitudinal study in twins. AB - OBJECTIVE: Several studies reported a negative association between ADHD symptoms and academic achievement. We investigated the etiology of the association between Attention Problems (AP, one of the core symptoms in ADHD) in early childhood and four academic skills across childhood in a genetically informative design. METHOD: Academic skills (mathematics, spelling, reading and comprehension) were measured with standardized tests performed at school in grade 2, 4, and 6. AP were measured with mother ratings of the Devereux Child Behavior Rating Scale at age 5 and the Child Behavior Checklist at age 7. Subjects were 767 Dutch twins from 445 families. RESULTS: AP were negatively associated with most academic skills in each grade, and this association was stable over time. Correlations of AP with mathematics and comprehension were around -0.20, and with spelling around -0.15. Correlations with reading were not significant. A significant genetic correlation (-0.40) between AP and mathematics across time indicated that shared genes play a role for these measures. The genetic correlations of AP with spelling and comprehension (both -0.28, p= 0.09) were non-significant. CONCLUSIONS: More complex academic skills, requiring higher cognitive processes, like mathematics and comprehension, are especially negatively associated with attention problems. The association between AP and mathematics is partly due to shared genes, while the association with comprehension, and spelling was driven by unique environmental factors. PMID- 21286367 TI - Adolescent self-report of emotional and behavioral problems: interactions of genetic factors with sex and age. AB - OBJECTIVE: The aim of the current study was to investigate the sex and age effects on the mean levels and the genetic architecture of adolescent self reported emotional and behavioral problems. METHOD: Survey data on psychopathology as assessed by the Youth Self Report (YSR; Achenbach & Rescorla, 2001) were collected in a large sample of Dutch adolescent twins and their non twin siblings (6381 twins and 1195 siblings from 3511 families) aged 12 to 20 years. Sex and age effects on the levels of emotional and behavioral problems and on the genetic architecture were investigated using genetic structural equation modeling. RESULTS: For all syndrome scales of the YSR (except for Aggressive Behavior) and for the broadband scales Internalizing and Externalizing sex differences in mean levels were found. Females score higher than males on Internalizing problems and its subscales (Anxious/Depressed and Withdrawn/Depressed), while males score higher than females on Externalizing behavior and its subscale Rule-Breaking. Age-effects on mean levels vary in strength and direction by syndrome and sex. An increase in problems with increasing age was seen for Anxiety/Depressed, while a decrease was observed for Somatic Complaints, Aggressive Behavior, and Social and Thought Problems. Significant genotype interactions with age and with sex were found for most scales of the YSR. These effects vary in strength and direction, resulting in differences in genetic architecture between males and females and developmental changes in genetic architecture throughout adolescence. For example the heritability for Anxious/Depressed and Withdrawn/Depressed behavior increases and the heritability of Externalizing behavior decreases throughout adolescence. CONCLUSIONS: Age and sex are found to be important moderators of both mean levels and the heritability of self-reported adolescent emotional and behavioral problems. Differences between adolescents in YSR syndrome and broadband scales are accounted for by genetic and non-shared environmental influences. We observed no influence of shared environment in this large sample. Clinical implications of the age and sex effects on the genetic architecture are discussed. PMID- 21286368 TI - Clinical case rounds in child and adolescent psychiatry: enuresis and ADHD in older children and an adolescent treated with stimulant medication: a case series. AB - Uncommonly, older children and adolescents can present with a history of enuresis. Resolution of enuresis followed the diagnosis and treatment of Attention Deficit Hyperactivity Disorder (ADHD) in each child in this case series. Subjects were three children with DSM-IV-TR ADHD, who presented with a history of primary nocturnal enuresis (PNE). Our results reveal that a subgroup of children with ADHD plus enuresis, when treated with stimulant medication, demonstrated resolution of enuresis as well as ADHD. These results suggest clinical implications for providers treating children and adolescents with enuresis and ADHD. PMID- 21286369 TI - Commentary: enuresis and ADHD in older children and an adolescent treated with stimulant medication: a case series. PMID- 21286370 TI - Systematic reviews and meta-analyses. PMID- 21286371 TI - SSRIs and SNRIs: A review of the Discontinuation Syndrome in Children and Adolescents. AB - OBJECTIVE: To review the occurrence, clinical relevance and characteristics of the discontinuation syndrome in children and adolescents who have been on a selective serotonin reuptake inhibitor (SSRI) or a serotonin/norepinephrine re uptake inhibitor (SNRI) for various conditions as an update for physicians prescribing these medications in this population. METHOD: An on-line literature search was done using MEDLINE, PubMed, CINAHL, PsychARTICLES, and PsychINFO with the following key words: selective serotonin reuptake inhibitors or SSRIs, serotonin/norepinephrine re-uptake inhibitors or SNRIs, discontinuation syndrome, pediatric or children or adolescents, occurrences and characteristics. RESULTS: Not a single randomized placebo-controlled trial was found that addresses this condition solely in the child and adolescent population. A couple of papers written by the same authors indicate that children and adolescents taking an SSRI definitely experience discontinuation reactions that can be mild, moderate or severe when the medication is stopped suddenly or high doses are reduced substantially. Among the SSRIs paroxetine seems to be the worst offender and fluoxetine the least while sertraline and fluvoxamine tend to be intermediate. However, the most serious discontinuation reactions came from the SNRI venlafaxine. There was no study or reports found on citalopram, another SSRI that is commonly prescribed in children and youth. While the adult literature abounds with papers describing the different aspects of this condition including clinical features, diagnostic criteria, management and prevention, the limited information available to-date in children and adolescents indicate that the essential features of the discontinuation syndrome may not be significantly different than in adults. There were no specific characteristics identified relating to the child population. CONCLUSION: In considering the use of an SSRI in children, physicians must seriously weigh the not so clear benefits against the risks of adverse reactions including the discontinuation syndrome. The frequency and severity of this reaction seem dependent on the SSRI half-life and although children metabolize drugs much faster than adults the reactions to-date have been reported as similar. The use of fluoxetine with its long half-life appears safer in this respect with paroxetine and venlafaxine causing the most concerns. Patients and their families should be well informed of the risks of stopping the medication abruptly and instructed not to do so without consulting their physician. Physicians in Canada who are using these medications off-label in children need to be knowledgeable and vigilant about such adverse reactions. These could be avoided through adequate follow ups which will also ensure better adherence. They may benefit from this review even though the information comes mostly form the adult literature. More prospective studies are needed to clarify this issue and identify any specific features relating to the pediatric population. PMID- 21286372 TI - Induction of antitumor immunity by dendritic cells loaded with membrane translocating mucin 1 Peptide antigen. AB - To investigate the role of enhanced antigen presentation in dendritic cell (DC) based immunotherapy. Here, we describe the development of a cell-penetrating mucin 1 (MUC1) antigen and its immunotherapeutic potential against tumors. After animal groups received two immunizations of MUC1-MPA(11)P-pulsed DCs, we observed a marked tumor regression compared with the mice treated with DCs alone or DCs pulsed with MUC1 peptide. We confirmed the migration and homing of DCs in the popliteal lymph node using magnetic resonance imaging during the study. In summary, enhanced antigen uptake using an MPA(11)P delivery molecule improves cell therapy. PMID- 21286373 TI - Interleukin 22 signaling promotes cell growth in mantle cell lymphoma. AB - Mantle cell lymphoma (MCL) is a specific type of aggressive B-cell non-Hodgkin lymphoma. We recently found that IL-22RA1, one of the two subunits of the interleukin 22 (IL-22) receptor, is expressed in MCL cell lines but not benign lymphocytes. In view of normal functions of IL-22 signaling, we hypothesized that the aberrant expression of IL-22RA1 may contribute to the deregulation of various cell signaling pathways, thereby promoting cell growth in MCL. In this study, we first demonstrated the expression of IL-22RA1 in all three MCL cell lines and eight frozen tumors examined using reverse transcription-polymerase chain reaction and Western blot analysis. In support of the concept that IL-22 signaling is biologically important in MCL, we found that MCL cells treated with recombinant IL-22 had a significant increase in cell growth that was associated with STAT3 activation. To investigate the mechanism underlying the aberrant expression of IL-22RA1, we analyzed the gene promoter of IL-22RA1, and we found multiple binding sites for NF-kappaB, a transcriptional factor strongly implicated in the pathogenesis of MCL. Pharmacologic inhibition of NF-kappaB resulted in a substantial reduction in the level of IL-22RA1 protein expression in MCL cells. To conclude, IL-22RA is aberrantly expressed in MCL, and we have provided evidence that IL-22 signaling contributes to the pathogenesis of MCL. PMID- 21286374 TI - CXCR2-Dependent Endothelial Progenitor Cell Mobilization in Pancreatic Cancer Growth. AB - Neovascularization is essential for tumor growth. We have previously reported that the chemokine receptor CXCR2 is an important regulator in tumor angiogenesis. Here we report that the mobilization of bone marrow (BM)-derived endothelial progenitor cells (EPCs) is impaired in CXCR2 knockout mice harboring pancreatic cancers. The circulating levels of EPCs (positive for CD34, CD117, CD133, or CD146) are decreased in the bone marrow and/or blood of tumor-bearing CXCR2 knockout mice. CXCR2 gene knockout reduced BM-derived EPC proliferation, differentiation, and vasculogenesis in vitro. EPCs double positive for CD34 and CD133 increased tumor angiogenesis and pancreatic cancer growth in vivo. In addition, CD133(+) and CD146(+) EPCs in human pancreatic cancer are increased compared with normal pancreas tissue. These findings indicate a role of BM derived EPC in pancreatic cancer growth and provide a cellular mechanism for CXCR2 mediated tumor neovascularization. PMID- 21286375 TI - Potential role of coregistered photoacoustic and ultrasound imaging in ovarian cancer detection and characterization. AB - Currently, there is no adequate technology to detect early stage ovarian cancers. Most of the cancers in the ovary are detected when the cancer has already metastasized to other parts of the body. As a result, ovarian cancer has the highest mortality of all gynecologic cancers with a 5-year survival rate of 30% or less. Thus, there is an urgent need to improve the current diagnostic techniques. Photoacoustic imaging (PAI) is an emerging modality with a great potential to assist ultrasound for detecting ovarian cancer noninvasively. In this article, we report the first study of coregistered ultrasound and PAI of 33 ex vivo human ovaries. An assessment of the photoacoustic images has revealed light absorption distribution in the ovary, which is directly related to the vasculature distribution and amount. Quantification of the light absorption levels in the ovary has indicated that, in the postmenopausal group, malignant ovaries showed significantly higher light absorption than normal ones (P = .0237). For these two groups, we have obtained a sensitivity of 83% and a specificity of 83%. This result suggests that PAI is a promising modality for improving ultrasound diagnosis of ovarian cancer. PMID- 21286376 TI - Isolation of Fully Human Antagonistic RON Antibodies Showing Efficient Block of Downstream Signaling and Cell Migration. AB - RON belongs to the c-MET family of receptor tyrosine kinases. As its well-known family member MET, RON and its ligand macrophage-stimulating protein have been implicated in the progression and metastasis of tumors and have been shown to be overexpressed in cancer. We generated and tested a large number of human monoclonal antibodies (mAbs) against human RON. Our screening yielded three high affinity antibodies that efficiently block ligand-dependent intracellular AKT and MAPK signaling. This effect correlates with the strong reduction of ligand activated migration of T47D breast cancer cell line. By cross-competition experiments, we showed that the antagonistic antibodies fall into three distinct epitope regions of the RON extracellular Sema domain. Notably, no inhibition of tumor growth was observed in different epithelial tumor xenografts in nude mice with any of the antibodies. These results suggest that distinct properties beside ligand antagonism are required for anti-RON mAbs to exert antitumor effects in vivo. PMID- 21286377 TI - STAT-Related Profiles Are Associated with Patient Response to Targeted Treatments in Locally Advanced SCCHN. AB - The anti-epidermal growth factor receptor antibody cetuximab (Erbitux, CTX) is currently used for the treatment of locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN), as yet with modest effectiveness, prompting for the identification of response predictors to this treatment and for the targeting of additional pathways implicated in this disease. Within this scope, we investigated the effect of SRC/STAT pathway components on LA-SCCHN patient outcome. SRC, STAT1, STAT3, STAT5A, STAT5B, ANXA1, CAV1, IGFBP2, EPHA2, EPHB2, and MSN relative gene expression, as well as Stat protein activation, were assessed on LA-SCCHN tumor tissues from 35 patients treated with combined radiotherapy (RT) and CTX-based regimens. Stat1, Stat3, and Stat5 proteins were usually found activated in neoplastic nuclei (70.4%, 85.7%, and 70.8%, respectively). Activated Stat3 and Stat5 were associated with each other (P = .017) and with a CAV1(high)/MSN(high)/IGFBP2(low) profile. All patients with tumors expressing high STAT5A/EPHA2 experienced a complete response on RT-CTX based treatments (12/15 complete responders, P < .0001) and a longer progression free survival (P = .024). Few tumors expressed high ANXA1/CAV1/EPHA2 and low IGFBP2, a putative dasatinib response-related profile, whereas high ANXA1 was associated with shorter overall survival (P = .003). In conclusion, Stat activation is common in LA-SCCHN, where overexpression of STAT5A and EPHA2 may predict for response to RT-CTX treatments. The STAT5A/EPHA2 profile seems of particular interest for validation in larger cohorts and in multiple tumor types because markers for the positive selection of patients to benefit from CTX containing treatments are currently lacking. PMID- 21286378 TI - Involvement of hepatic innate immunity in alcoholic liver disease. AB - Excessive alcohol consumption is one of the critical causative factors leading to alcoholic liver disease (ALD). ALD is characterized by a wide spectrum of liver damage, ranging from simple uncomplicated liver steatosis (fatty liver) to steatohepatitis and liver fibrosis/cirrhosis. It has been believed that the obvious underlying cause for ALD is due to hepatocyte death induced by alcohol itself. However, recent sparkling studies have shown that diverse immune responses contribute to ALD because liver is enriched with numerous immune cells. Especially, a line of evidence has suggested that innate immune cells such as Kupffer cells and natural killer (NK)/NKT cells are significantly involved in the pathogenesis of ALD via production of pro-inflammatory cytokines and other mediators. Indeed, more interestingly, hepatic stellate cells (HSCs), known as a major cell inducing liver steatosis and fibrosis, can be killed by liver NK cells, which could be suppressed by chronic alcohol consumption. In this review, with the view of liver as predominant innate immune organ, we describe the pathogenesis of ALD in which what roles of innate immune cells are and how they are interacting with HSCs. PMID- 21286379 TI - Dendritic cell activation by glucan isolated from umbilicaria esculenta. AB - BACKGROUND: Lichen-derived glucans have been known to stimulate the functions of immune cells. However, immunostimulatory activity of glucan obtained from edible lichen, Umbilicaria esculenta, has not been reported. Thus we evaluated the phenotype and functional maturation of dendritic cells (DCs) following treatment of extracted glucan (PUE). METHODS: The phenotypic and functional maturation of PUE-treated DCs was assessed by flow cytometric analysis and cytokine production, respectively. PUE-treated DCs was also used for mixed leukocyte reaction to evaluate T cell-priming capacity. Finally we detected the activation of MAPK and NF-kappaB by immunoblot. RESULTS: Phenotypic maturation of DCs was shown by the elevated expressions of CD40, CD80, CD86, and MHC class I/II molecules. Functional activation of DCs was proved by increased cytokine production of IL 12, IL-1beta, TNF-alpha, and IFN-alpha/beta, decreased endocytosis, and enhanced proliferation of allogenic T cells. Polymyxin B, specific inhibitor of lipopolysaccharide (LPS), did not affect PUE activity, which suggested that PUE was free of LPS contamination. As a mechanism of action, PUE increased phosphorylation of ERK, JNK, and p38 MAPKs, and enhanced nuclear translocation of NF-kappaB p50/p65 in DCs. CONCLUSION: These results indicate that PUE induced DC maturation via MAPK and NF-kappaB signaling pathways. PMID- 21286380 TI - Codelivery of IL-7 Augments Multigenic HCV DNA Vaccine-induced Antibody as well as Broad T Cell Responses in Cynomolgus Monkeys. AB - BACKGROUND: A crucial limitation of DNA vaccines is its weak immunogenicity, especially in terms of eliciting antibody responses in non-human primates or humans; therefore, it is essential to enhance immune responses to vaccination for the development of successful DNA vaccines for humans. METHODS: Here, we approached this issue by evaluating interleukin-7 (IL-7) as a genetic adjuvant in cynomolgus monkeys immunized with multigenic HCV DNA vaccine. RESULTS: Codelivery of human IL-7 (hIL-7)-encoding DNA appeared to increase DNA vaccine-induced antibody responses specific for HCV E2 protein, which plays a critical role in protecting from HCV infection. HCV-specific T cell responses were also significantly enhanced by codelivery of hIL-7 DNA. Interestingly, the augmentation of T cell responses by codelivery of hIL-7 DNA was shown to be due to the enhancement of both the breadth and magnitude of immune responses against dominant and subdominant epitopes. CONCLUSION: Taken together, these findings suggest that the hIL-7-expressing plasmid serves as a promising vaccine adjuvant capable of eliciting enhanced vaccine-induced antibody and broad T cell responses. PMID- 21286381 TI - Induction of 90K-specific Cytotoxic T Lymphocytes for Colon Cancer Immunotherapy. AB - BACKGROUND: Dendritic cell (DC)-based tumor vaccine is an attractive modality for the treatment of colon cancer because it has been recurred and produced few side effects in patients. Secretory glycoprotein 90K has been found at elevated level in various cancer tissues and sera. We investigated to establish a more effective DC vaccine for the treatment of colon cancer in which the levels of 90K are elevated. METHODS: We obtained the concentrated 90K from 293T cells stably expressing 90K. DCs were cultured from peripheral blood monocytes, and a DC vaccine pulsed with tumor lysate was compared with a DC vaccine pulsed with 90K. We measured the functional activity for CTLs by using IFN-gamma-enzyme linked immunoabsorbent spot (ELISPOT) assay. RESULTS: DCs pulsed with tumor lysate+90K exhibited the enhanced T cell stimulation, polarization of naive T cell toward Th1. The CTLs generated by DCs pulsed with 90K efficiently lysed HCT116 cells. The results indicate that 90K-speicifc-CTLs can recognize 90K proteins naturally presented by colon cancer cells. CONCLUSION: Our study suggests that 90K-specific CTLs generated by 90K-pulsed DCs could be useful effector cells for immunotherapy in colon cancer. PMID- 21286382 TI - The Stem Bark of Kalopanax pictus Exhibits Anti-inflammatory Effect through Heme Oxygenase-1 Induction and NF-kappaB Suppression. AB - BACKGROUND: The stem bark of Kalopanax pictus (KP) has been used in traditional medicine to treat rheumatoidal arthritis, neurotic pain and diabetes mellitus in China and Korea. In this study, the mechanism responsible for anti-inflammatory effects of KP was investigated. METHODS: We examined the effects of KP on NO production, nitric oxide synthase (iNOS) and HO-1 expression, NF-kappaB, Nrf2 and MAPK activation in mouse peritoneal macrophages. RESULTS: The aqueous extract of KP inhibited LPS-induced NO secretion as well as inducible iNOS expression, without affecting cell viability. KP suppressed LPS-induced NF-kappaB activation, phosphorylation and degradation of IkappaB-alpha, phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK). Furthermore, KP induced HO-1 expression and Nrf2 nuclear translocation. CONCLUSION: These results suggest that KP has the inhibitory effects on LPS induced NO production in macrophages through NF-kappaB suppression and HO-1 induction. PMID- 21286383 TI - NDRG2-mediated Modulation of SOCS3 and STAT3 Activity Inhibits IL-10 Production. AB - BACKGROUND: N-myc downstream regulated gene 2 (NDRG2) is a member of the NDRG gene family. Our previous report indicated a possible role for NDRG2 in regulating the cytokine, interleukin-10 (IL-10), which is an important immunosuppressive cytokine. Several pathways, including p38-MAPK, NF-kappaB, and JAK/STAT, are used for IL-10 production, and the JAK/STAT pathway can be inhibited in a negative feedback loop by the inducible protein, SOCS3. In the present study, we investigated the effect of NDRG2 gene expression on IL-10 signaling pathway that is modulated via SOCS3 and STAT3. METHODS: We generated NDRG2-overexpressing U937 cell line (U937-NDRG2) and treated the cells with PMA to investigate the role of NDRG2 in IL-10 production. U937 cells were also transfected with SOCS3- or NDRG2-specific siRNAs to examine whether the knockdown of SOCS3 or NDRG2 influenced IL-10 expression. Lastly, STAT3 and SOCS3 induction was measured to identify the signaling pathway that was associated with IL-10 production. RESULTS: RT-PCR and ELISA assays showed that IL-10 was increased in U937-mock cells upon stimulation with PMA, but IL-10 was inhibited by overexpression NDRG2. After PMA treatment, STAT3 phosphorylation was decreased in a time-dependent manner in U937-mock cells, whereas it was maintained in U937 NDRG2 cells. SOCS3 was markedly reduced in U937-NDRG2 cells compared with U937 mock cells. IL-10 production after PMA stimulation was reduced in U937 cells when SOCS3 was inhibited, but this effect was less severe when NDRG2 was inhibited. CONCLUSION: NDRG2 expression modulates SOCS3 and STAT3 activity, eventually leading to the inhibition of IL-10 production. PMID- 21286384 TI - Activation of Macrophages by Exopolysaccharide Produced by MK1 Bacterial Strain Isolated from Neungee Mushroom, Sarcodon aspratus. AB - BACKGROUND: The MK1 strain, a novel bacterial isolate from soft-rotten tissue of the Neungee mushroom, produces copious amounts of exopolysaccharide (EPS) in a dextrose minimal medium. This study examined the molecular characteristics and immunomodulatory activity of MK1 EPS. METHODS: The EPS in the culture supernatant was purified by cold ethanol precipitation, and characterized by SDS-PAGE/silver staining and Bio-HPLC. The immunomodulatory activities of the EPS were examined using the mouse monocytic cell line, RAW 264.7 cells. RESULTS: The molecular weights of the purified EPS were rather heterogeneous, ranging from 10.6 to 55 kDa. The EPS was composed of glucose, rhamnose, mannose, galactose, and glucosamine at an approximate molar ratio of 1.00:0.8:0.71:0.29:0.21. EPS activated the RAW cells to produce cytokines, such as TNF-alpha and IL-1beta, and nitric oxide (NO). EPS also induced the expression of co-stimulatory molecules, such as B7-1, B7-2 and ICAM-1, and increased the phagocytic activity. The macrophage-activating activity of EPS was not due to endotoxin contamination because the treatment of EPS with polymyin B did not reduce the macrophage activating activity. CONCLUSION: The EPS produced from the MK1 strain exerts macrophage-activating activity. PMID- 21286385 TI - Characterization of a Novel Monoclonal Antibody (27H2) Recognizing Human CD34 Class III Epitope. AB - BACKGROUND: Monoclonal antibodies (mAbs) recognizing Class III epitope of CD34 are essential for flow cytometric diagnosis of leukemia. METHODS: 27H2 mAb was developed from a mouse alternatively immunized with human acute leukemia cell lines, KG1 and Molm-1. Using flow cytometric analysis of various leukemic cell lines and peripheral blood, immunohistochemical study of frozen tonsil, we characterized 27H2 mAb. Antigen immunoprecipitated with 27H2 mAb immunobloted with anti-CD34 mAb. A case of bone marrow sample of acute lymphoblastic leukemia (ALL) patient was obtained at CBNU Hospital. For epitope identification enzyme treatment with neuraminidase and O-sialoglycoprotein endopeptidase (OSGE) and blocking assay with known classIII mAb (HPCA-2) were done. RESULTS: Only KG1 and Molm-1 revealed positive immunoreactivity. Immunohistochemical staining disclosed strong membranous immunoreactivity on high endothelial venules. Antigen immunoprecipitated by 27H2 mAb showed approximately 100 kDa sized band immunoblotted with anti-CD34 under non-reducing conditions. Epitope recognized by 27H2 mAb disclosed resistancy to both neuraminidase and OSGE treatment and completely blocked with known class III mAb preincubation. CD34 positive leukemic cells in BM of pre B cell ALL patient detected by FITC-conjugated 27H2 and HPCA-2 were identified with similar sensitivity. CONCLUSION: A novel murine mAb recognizing class III epitope of human CD34 with high affinity, which is useful for flow cytometric diagnosis of leukemia, was developed. PMID- 21286386 TI - Presence of Foxp3-expressing CD19(+)CD5(+) B Cells in Human Peripheral Blood Mononuclear Cells: Human CD19(+)CD5(+)Foxp3(+) Regulatory B Cell (Breg). AB - Foxp3 is a transcript factor for regulatory T cell development. Interestingly, Foxp3-expressing cells were identified in B cells, especially in CD19(+)CD5(+) B cells, while those were not examined in CD19(+)CD5(-) B cells. Foxp3-expressing CD5(+) B cells in this study were identified in human PBMCs and were found to consist of 8.5+/-3.5% of CD19(+)CD5(+) B cells. CD19(+)CD5(+)Foxp3(+) B cells showed spontaneous apoptosis. Rare CD19(+)CD5(+) Foxp3(+) regulatory B cell (Breg) population was unveiled in human peripheral blood mononuclear cells and suggested as possible regulatory B cells (Breg) as regulatory T cells (Treg). The immunologic and the clinical relevant of Breg needs to be further investigated. PMID- 21286387 TI - The cross-metathesis of methyl oleate with cis-2-butene-1,4-diyl diacetate and the influence of protecting groups. AB - BACKGROUND: alpha,omega-Difunctional substrates are useful intermediates for polymer synthesis. An attractive, sustainable and selective (but as yet unused) method in the chemical industry is the oleochemical cross-metathesis with preferably symmetric functionalised substrates. The current study explores the cross-metathesis of methyl oleate (1) with cis-2-butene-1,4-diyl diacetate (2) starting from renewable resources and quite inexpensive base chemicals. RESULTS: This cross-metathesis reaction was carried out with several phosphine and N heterocyclic carbene ruthenium catalysts. The reaction conditions were optimised for high conversions in combination with high cross-metathesis selectivity. The influence of protecting groups present in the substrates on the necessary catalyst loading was also investigated. CONCLUSIONS: The value-added methyl 11 acetoxyundec-9-enoate (3) and undec-2-enyl acetate (4) are accessed with nearly quantitative oleochemical conversions and high cross-metathesis selectivity under mild reaction conditions. These two cross-metathesis products can be potentially used as functional monomers for diverse sustainable polymers. PMID- 21286388 TI - Thermal rearrangement of tert-butylsulfinamide. AB - tert-Butylsulfinamides are unstable above room temperature, and in chlorinated solvents they undergo rearrangement to form the more stable N-(tert-butylthio) tert-butylsulfonamide. PMID- 21286389 TI - Stereoselectivity of supported alkene metathesis catalysts: a goal and a tool to characterize active sites. AB - Stereoselectivity in alkene metathesis is a challenge and can be used as a tool to study active sites under working conditions. This review describes the stereochemical relevance and problems in alkene metathesis (kinetic vs. thermodynamic issues), the use of (E/Z) ratio at low conversions as a tool to characterize active sites of heterogeneous catalysts and finally to propose strategies to improve catalysts based on the current state of the art. PMID- 21286390 TI - Hoveyda-Grubbs type metathesis catalyst immobilized on mesoporous molecular sieves MCM-41 and SBA-15. AB - A commercially available Hoveyda-Grubbs type catalyst (RC303 Zhannan Pharma) was immobilized on mesoporous molecular sieves MCM-41 and on SBA-15 by direct interaction with the sieve wall surface. The immobilized catalysts exhibited high activity and nearly 100% selectivity in several types of alkene metathesis reactions. Ru leaching was found to depend on the substrate and solvent used (the lowest leaching was found for ring-closing metathesis of 1,7-octadiene in cyclohexane - 0.04% of catalyst Ru content). Results of XPS, UV-vis and NMR spectroscopy showed that at least 76% of the Ru content was bound to the support surface non-covalently and could be removed from the catalyst by washing with THF. PMID- 21286391 TI - Identification and synthesis of impurities formed during sertindole preparation. AB - Sertindole (1), an atypical anti-psychotic drug is used for the treatment of schizophrenia. During the laboratory optimization and later during its bulk synthesis the formation of various impurities was observed. The impurities formed were monitored and their structures were tentatively assigned on the basis of their fragmentation patterns in LC-MS. Most of the impurities were synthesized and their assigned constitutions confirmed by co-injection in HPLC. We describe herein the formation, synthesis and characterization of these impurities. Our study will be of immense help to others to obtain chemically pure sertindole. PMID- 21286392 TI - Stereoselective synthesis of four possible isomers of streptopyrrolidine. AB - The synthesis of (4R,5R)-streptopyrrolidine (1), (4S,5R)-streptopyrrolidine (2) (4R,5S)-streptopyrrolidine (3) and (4S,5S)-streptopyrrolidine (4) have been achieved in a concise and highly efficient manner via a highly stereoselective aldol type reaction with the trimethylsilyl enolate of ethyl acetate and Lewis acid mediated lactamization as the key reactions in ~42% yield over six steps starting from D-phenylalanine and L-phenylalanine, respectively. The absolute configuration of the natural product was shown to be (4S,5S) by comparing its spectral and analytical data with the reported values. PMID- 21286393 TI - The intriguing modeling of cis-trans selectivity in ruthenium-catalyzed olefin metathesis. AB - In this study we have investigated computationally the origin of the cis-trans selectivity in the Ru-catalyzed cross metathesis (CM) of a prototype monosubstituted olefin, i.e., propene. Our calculations suggest that the origin of the preferential formation of trans-olefins is in the product release step, which prevents the initially formed cis-olefin from escaping the metal, and returns it to the reaction pool until the trans-olefin is formed. PMID- 21286394 TI - A new fluorescent chemosensor for fluoride anion based on a pyrrole-isoxazole derivative. AB - Molecules containing polarized NH fragments that behave as anion-binding motifs are widely used as receptors for recognition and sensing purposes in aprotic solvents. We present here a new example of a receptor, 3-amino-5-(4,5,6,7 tetrahydro-1H-indol-2-yl)isoxazole-4-carboxamide (receptor 1), which contains pyrrole, amide and amino subunits. This receptor shows both changes in its UV-vis absorption and fluorescence emission spectra upon the addition of F(-), resulting in highly selectivity for fluoride detection over other anions, such as Cl(-), Br(-), I(-), HSO(4) (-), H(2)PO(4) (-) and AcO(-) in CH(3)CN. (1)H NMR titration, time-dependent density functional theory (TDDFT) calculations and other experiments confirm that the sensing process is brought about by deprotonation of the pyrrole-NH in receptor 1. PMID- 21286395 TI - Surfactant catalyzed convenient and greener synthesis of tetrahydrobenzo[a]xanthene-11-ones at ambient temperature. AB - An efficient and greener protocol for the synthesis of 12-aryl-8,9,10,12 tetrahydrobenzo[a]xanthen-11-one using tetradecyltrimethylammonium bromide (TTAB) at room temperature in water is described. PMID- 21286396 TI - Palladium- and copper-mediated N-aryl bond formation reactions for the synthesis of biological active compounds. AB - N-Arylated aliphatic and aromatic amines are important substituents in many biologically active compounds. In the last few years, transition-metal-mediated N aryl bond formation has become a standard procedure for the introduction of amines into aromatic systems. While N-arylation of simple aromatic halides by simple amines works with many of the described methods in high yield, the reactions may require detailed optimization if applied to the synthesis of complex molecules with additional functional groups, such as natural products or drugs. We discuss and compare in this review the three main N-arylation methods in their application to the synthesis of biologically active compounds: Palladium catalysed Buchwald-Hartwig-type reactions, copper-mediated Ullmann-type and Chan Lam-type N-arylation reactions. The discussed examples show that palladium catalysed reactions are favoured for large-scale applications and tolerate sterically demanding substituents on the coupling partners better than Chan-Lam reactions. Chan-Lam N-arylations are particularly mild and do not require additional ligands, which facilitates the work-up. However, reaction times can be very long. Ullmann- and Buchwald-Hartwig-type methods have been used in intramolecular reactions, giving access to complex ring structures. All three N arylation methods have specific advantages and disadvantages that should be considered when selecting the reaction conditions for a desired C-N bond formation in the course of a total synthesis or drug synthesis. PMID- 21286397 TI - An easy assembled fluorescent sensor for dicarboxylates and acidic amino acids. AB - Two mesitylene based neutral receptors 1 and 2 bearing two thiourea binding sites were constructed as fluorescent probes for sensing dicarboxylates. Their binding affinities toward dicarboxylates, aspartate and glutamate have been investigated in acetonitrile solution by fluorescence titration experiments. Both fluorescent sensors exhibited some ability to discriminate the antipodal forms of aspartate and glutamate. PMID- 21286398 TI - Recent advances in the development of alkyne metathesis catalysts. AB - The number of well-defined molybdenum and tungsten alkylidyne complexes that are able to catalyze alkyne metathesis reactions efficiently has been significantly expanded in recent years.The latest developments in this field featuring highly active imidazolin-2-iminato- and silanolate-alkylidyne complexes are outlined in this review. PMID- 21286399 TI - Olefin metathesis in nano-sized systems. AB - The interplay between olefin metathesis and dendrimers and other nano systems is addressed in this mini review mostly based on the authors' own contributions over the last decade. Two subjects are presented and discussed: (i) The catalysis of olefin metathesis by dendritic nano-catalysts via either covalent attachment (ROMP) or, more usefully, dendrimer encapsulation - ring closing metathesis (RCM), cross metathesis (CM), enyne metathesis reactions (EYM) - for reactions in water without a co-solvent and (ii) construction and functionalization of dendrimers by CM reactions. PMID- 21286400 TI - Synthesis of Ru alkylidene complexes. AB - The present work describes the robust synthesis of Ru alkylidene complexes (PCy(3))(2)Cl(2)Ru=CHR - precursors for metathesis catalysts. Moreover, the dynamic behavior of complexes where R = 2-naphthyl and 2-thienyl was studied. (1)H NMR techniques were employed to establish the preferred conformations in solution for both complexes and the energy barrier for rotation around single (Ru=)CH-C(thienyl) bond was estimated (DeltaG(?) (303K) = 12.6 kcal/mol). PMID- 21286401 TI - Early nutrition and adult health: Perspectives for international and community nutrition programs and policies. AB - Recent economic changes throughout the world, either development or crises and recessions, have prompted a host of nutrition related problems, including a decreased prevalence of undernutrition, an increase in the prevalence of diet related diseases, widespread food insecurity as crop prices increase, and so on. In addition, evidence is mounting that suggests that exposure to poor nutrition early in life is a predisposing factor for chronic diseases in adulthood. Thus, the role of international or community nutrition professionals is vital to not only studying and understanding the interplay between economics, food policy, and health, but also to improving the ability to intervene and prevent many problems related to food insecurity in developed and developing countries. The purpose of this review is to outline and describe these issues as a means to open discussion on how to best alleviate major nutrition problems in the world. PMID- 21286402 TI - The effects of nutrient depleted microenvironments and delta-like 1 homologue (DLK1) on apoptosis in neuroblastoma. AB - The tumor microenvironment, particularly sufficient nutrition and oxygen supply, is important for tumor cell survival. Nutrition deprivation causes cancer cell death. Since apoptosis is a major mechanism of neuronal loss, we explored neuronal apoptosis in various microenvironment conditions employing neuroblastoma (NB) cells. To investigate the effects of tumor malignancy and differentiation on apoptosis, the cells were exposed to poor microenvironments characterized as serum-free, low-glucose, and hypoxia. Incubation of the cells in serum-free and low-glucose environments significantly increased apoptosis in less malignant and more differentiated N-type IMR32 cells, whereas more malignant and less differentiated I-type BE(2)C cells were not affected by those treatments. In contrast, hypoxia (1% O(2)) did not affect apoptosis despite cell malignancy. It is suggested that DLK1 constitutes an important stem cell pathway for regulating self-renewal, clonogenicity, and tumorigenicity. This raises questions about the role of DLK1 in the cellular resistance of cancer cells under poor microenvironments, which cancer cells normally encounter. In the present study, DLK1 overexpression resulted in marked protection from apoptosis induced by nutrient deprivation. This in vitro model demonstrated that increasing severity of nutrition deprivation and knock-down of DLK1 caused greater apoptotic death, which could be a useful strategy for targeted therapies in fighting NB as well as for evaluating how nutrient deprived cells respond to therapeutic manipulation. PMID- 21286403 TI - Effect of dietary protamine on lipid metabolism in rats. AB - Protamine has been widely used as a pharmaceutical product and natural food preservative. However, few studies have been conducted to assess the beneficial function of dietary protamine. This study examined the effects of dietary salmon protamine on serum and liver lipid levels and the expression levels of genes encoding proteins involved in lipid homeostasis in the liver of rats. Groups of male Wistar rats were fed AIN93G diet containing 2% or 5% protamine. After 4 weeks of feeding these diets, markedly decreased serum and liver cholesterol (CHOL) and triacylglycerol levels were noted. Increased activity of liver carnitine palmitoyltransferase-2 and acyl-CoA oxidase, which are key enzymes of fatty acid beta-oxidation in the mitochondria and peroxisomes, was found in rats fed on protamine. Furthermore, rats fed protamine showed enhanced fecal excretion of CHOL and bile acid and increased liver mRNA expression levels of ATP-binding cassette (ABC) G5 and ABCG8, which form heterodimers and play a major role in the secretion of CHOL into bile. The decrease in triacylglycerol levels in protamine fed rats was due to the enhancement of liver beta-oxidation. Furthermore, rats fed protamine exhibited decreased CHOL levels through the suppression of CHOL and bile acid absorption and the enhancement of CHOL secretion into bile. These results suggest that dietary protamine has beneficial effects that may aid in the prevention of lifestyle-related diseases such as hyperlipidemia and atherosclerosis. PMID- 21286404 TI - Effects of a soluble dietary fibre NUTRIOSE(r) on colonic fermentation and excretion rates in rats. AB - The resistant dextrin NUTRIOSE(r), developed from starch, is expected to act as a prebiotic. The aim of this study was to determine the effects of NUTRIOSE(r) on cecal parameters, short-chain fatty acid (SCFA) concentrations, and fecal excretion in rats. In an initial experiment, twenty-four male Fischer F344 rats were randomly assigned to one of the following four treatments for 14 days: G0 (control diet), G2.5 (control diet + 2.5% of dextrin), G5 (control diet + 5% of dextrin), and G10 (control diet + 10% of dextrin). After 14 days, total cecal weight, cecal content, and cecal wall weight were significantly increased in G5 and G10 compared to G0. At the same time, cecal pH was significantly lower in G10 compared to G0. Total SCFA concentration was significantly higher in G10 than in G5, G2.5, and G0, and significantly higher in G5 than in G0. Acetate, butyrate, and propionate concentrations were significantly increased in G5 and G10 compared to the controls. In a second trial based on a similar design, eighteen male Fischer F344 rats were treated with a control diet supplemented with 5% of dextrin or 5% of fructo-oligosaccharide. The results obtained with NUTRIOSE(r) were similar to those obtained with the fructo-oligosaccharide. In a third experiment, two groups of 5 Fischer F344 rats were orally treated with 100 and 1,000 mg/kg NUTRIOSE(r), respectively, and from 18% to 25% of the dextrin was excreted in the feces. The results of these three studies show that the consumption of NUTRIOSE(r), by its effects on total cecal weight, cecal content, cecal wall weight, pH, and SCFA production, could induce healthy benefits since these effects are reported to be prebiotic effects. PMID- 21286405 TI - Changes in lipid and carnitine concentrations following repeated fasting refeeding in mice. AB - The purpose of this study was to evaluate the effects of repeated fasting and refeeding on lipid metabolism. Thirty male ICR mice, aged 6 weeks, were fed an AIN-93 control diet during the experimental period. The mice were divided into 5 groups: Non fasting group (ad libitum-fed, NF), fasting for 3 days (F), fasting for 3 days and then refeeding for 4 days repeated once (FRF1), fasting for 3 days and then refeeding for 4 days repeated twice (FRF2), and fasting for 3 days and then refeeding for 4 days repeated three times (FRF3). Rates of body weight gain, epididymal fat weight, and serum TG were significantly decreased in the F, FRF1, FRF2, and FRF3 groups, compared to the NF group. LDL-cholesterol was significantly higher in the FRF3 group than the NF and F groups, but HDL cholesterol and HDL/TC were significantly lower in the FRF3 group than in the NF and F groups. Serum total carnitine was significantly lower in the FRF1, FRF2, FRF3 groups than the NF and F groups. However, rates of serum and hepatic acyl carnitine concentration were significantly lower in FRF1, FRF2, and FRF3 than in NF and F. Repeated fasting-refeeding resulted in visible reductions of body weight and fat mass, but it caused ill-effects with lipid and carnitine metabolism in the body. PMID- 21286406 TI - Hypoglycemic effects of Welsh onion in an animal model of diabetes mellitus. AB - Tight control of blood glucose is the most important strategy for the treatment of diabetes mellitus. Here, we investigated the beneficial effects of Welsh onion on fasting and postprandial hyperglycemia. Inhibitory activities of hot water extracts from the green stalk and white bulb, which are the edible portions of the Welsh onion, and the fibrous root extract against yeast alpha-glucosidase were measured in vitro. To study the effects of Welsh onion on postprandial hyperglycemia, a starch solution (1 g/kg) with and without Welsh onion fibrous root extract (500 mg/kg) or acarbose (50 mg/kg) was administered to streptozotocin-induced diabetic rats after an overnight fast. Postprandial plasma glucose levels were measured and incremental areas under the response curve were calculated. To study the hypoglycemic effects of chronic feeding of Welsh onion, five-week-old db/db mice were fed an AIN-93G diet or a diet containing either Welsh onion fibrous root extract at 0.5% or acarbose at 0.05% for 7 weeks after 1 week of adaptation. Fasting plasma glucose and blood glycated hemoglobin were measured. Compared to the extract from the edible portions of Welsh onion, the fibrous root extract showed stronger inhibition against yeast alpha-glucosidase, with an IC(50) of 239 ug/mL. Oral administration of Welsh onion fibrous root extract (500 mg/kg) and acarbose (50 mg/kg) significantly decreased incremental plasma glucose levels 30-120 min after oral ingestion of starch as well as the area under the postprandial glucose response curve, compared to the control group (P < 0.01). The plasma glucose and blood glycated hemoglobin levels of the Welsh onion group were significantly lower than those of the control group (P < 0.01), and were not significantly different from those fed acarbose. Thus, we conclude that the fibrous root of Welsh onion is effective in controlling hyperglycemia in animal models of diabetes mellitus. PMID- 21286407 TI - Low HDL cholesterol is associated with increased atherogenic lipoproteins and insulin resistance in women classified with metabolic syndrome. AB - Both metabolic syndrome (MetS) and elevated LDL cholesterol (LDL-C) increase the risk for cardiovascular disease (CVD). We hypothesized that low HDL cholesterol (HDL-C) would further increase CVD risk in women having both conditions. To assess this, we recruited 89 women with MetS (25-72 y) and LDL-C >= 2.6 mmol/L. To determine whether plasma HDL-C concentrations were associated with dietary components, circulating atherogenic particles, and other risk factors for CVD, we divided the subjects into two groups: high HDL-C (H-HDL) (>= 1.3 mmol/L, n = 32) and low HDL-C (L-HDL) (< 1.3 mmol/L, n = 57). Plasma lipids, insulin, adiponectin, apolipoproteins, oxidized LDL, Lipoprotein(a), and lipoprotein size and subfractions were measured, and 3-d dietary records were used to assess macronutrient intake. Women with L-HDL had higher sugar intake and glycemic load (P < 0.05), higher plasma insulin (P < 0.01), lower adiponectin (P < 0.05), and higher numbers of atherogenic lipoproteins such as large VLDL (P < 0.01) and small LDL (P < 0.001) than the H-HDL group. Women with L-HDL also had larger VLDL and both smaller LDL and HDL particle diameters (P < 0.001). HDL-C was positively correlated with LDL size (r = 0.691, P < 0.0001) and HDL size (r = 0.606, P < 0.001), and inversely correlated with VLDL size (r = -0.327, P < 0.01). We concluded that L-HDL could be used as a marker for increased numbers of circulating atherogenic lipoproteins as well as increased insulin resistance in women who are already at risk for CVD. PMID- 21286408 TI - Overestimation of own body weights in female university students: associations with lifestyles, weight control behaviors and depression. AB - The study aimed to analyze the lifestyles, weight control behavior, dietary habits, and depression of female university students. The subjects were 532 students from 8 universities located in 4 provinces in Korea. According to percent ideal body weight, 33 (6.4%), 181 (34.0%), 283 (53.2%), 22 (4.1%) and 13 (2.5%) were severely underweight, underweight, normal, overweight and obese, respectively, based on self-reported height and weight. As much as 64.1% and only 2.4%, respectively, overestimated and underestimated their body weight status. Six overweight subjects were excluded from overestimation group for the purpose of this study, resulting in overestimation group consisting of only underweight and normal weight subjects. Compared to those from the normal perception group, significantly more subjects from the overestimation group were currently smoking (P = 0.017) and drank more often than once a week (P = 0.015), without any significant differences in dietary habits. Despite similar BMIs, subjects who overestimated their own weight statuses had significantly higher weight dissatisfaction (P = 0.000), obesity stress (P = 0.000), obsession to lose weight (P = 0.007) and depression (P = 0.018). Also, more of them wanted to lose weight (P = 0.000), checked their body weights more often than once a week (P = 0.025) and had dieting experiences using 'reducing meal size' (P = 0.012), 'reducing snacks' (P = 0.042) and 'taking prescribed pills' (P = 0.032), and presented 'for a wider range of clothes selection' as the reason for weight loss (P = 0.039), although none was actually overweight or obese. Unlike the case with overestimating one's own weight, being overweight was associated with less drinking (P = 0.035) and exercising more often (P = 0.001) and for longer (P = 0.001) and healthier reasons for weight control (P = 0.002), despite no differences in frequency of weighing and depression. The results showed that weight overestimation, independent of weight status, is associated with risky lifestyles, weight control behaviors, and mental conditions. Preventive interventions should focus not only on obesity, but also on body weight overestimation. PMID- 21286409 TI - Relationship between vitamin K status, bone mineral density, and hs-CRP in young Korean women. AB - Vitamin K intake has been reported as an essential factor for bone formation. The current study was conducted under the hypothesis that insufficient vitamin K intake would affect inflammatory markers and bone mineral density in young adult women. The study was a cross-sectional design that included 75 women in their 20s. Physical assessments, bone mineral density measurements, 24-hr dietary recalls, and biochemical assessments for high sensitivity C-reactive protein (hs CRP) and percentages of undercarboxylated osteocalcin (%ucOC) were performed. An analysis of vitamin K nutritional status was performed comparing first, second, and third tertiles of intake based on %ucOC in plasma. Vitamin K intake levels in the first, second, and third tertiles were 94.88 +/- 51.48 ug, 73.85 +/- 45.15 ug, and 62.58 +/- 39.92 ug, respectively (P < 0.05). The T-scores of the first and third tertiles were 1.06 and -0.03, respectively, indicating that bone mineral density was significantly lower in the group with lower vitamin K intake (P < 0.05). There was a tendency for different serum hs-CRP concentrations between the first (0.04 +/- 0.02) and third tertiles (0.11 +/- 0.18), however this was not statistically significant. Regression analysis was performed to identify the correlations between vitamin K nutritional status, inflammatory markers, and bone mineral density after adjusting for age and BMI. Serum hs-CRP concentrations were positively correlated with vitamin K deficiency status (P < 0.05). And bone mineral density, which was represented by speed, was negatively correlated with vitamin K deficiency status (P < 0.05). In conclusion, status of vitamin K affects inflammatory status and bone formation. Therefore, sufficient intake of vitamin K is required to secure peak bone mass in young adult women. PMID- 21286410 TI - Diet of children under the government-funded meal support program in Korea. AB - The purpose of this study was to investigate the diet of children under the government-funded meal support program. The 143 children (67 boys and 76 girls) participated in this study among 4(th)-6(th) elementary school students receiving free lunches during the summer vacation of 2007 and living in Gwanak-gu, Seoul, Korea. The subjects consisted of four groups supported by Meal Box Delivery (n = 26), Institutional Foodservice (n = 53), Restaurant Foodservice (n = 27), or Food Delivery (n = 37). A three-day 24-hour dietary recall and a self-administered survey were conducted. In addition, the children's heights and weights were measured. The average energy intake of the children was 1,400 kcal per day, much lower than the Estimated Energy Requirements of the pertinent age groups. The results also showed inadequate intake of all examined nutrients; of particular concern was the extremely low intake of calcium. On average, the children consumed eight dishes and 25 food items per day. The children supported by Meal Box Delivery consumed more various dishes and food items than the other groups. The percentage of children preferring their current meal support method was the highest in those supported by Meal Box Delivery and the lowest in those supported by Food Delivery. We requested 15 children among the 143 children participating in the survey to draw the scene of their lunch time. The drawings of the children supported by Institutional Foodservice showed more positive scenes than the other groups, especially in terms of human aspects. In conclusion, the overall diet of children under the government-funded meal support program was nutritionally inadequate, although the magnitude of the problems tended to differ by the meal support method. The results could be utilized as basic data for policy and programs regarding the government-funded meal support program for children from low-income families. PMID- 21286411 TI - Diet intervention to improve cardiovascular risk factors among Iranian postmenopausal women. AB - Cardiovascular disease is a leading cause of death and disability and remains so in the future. The aim of this study was to detect the impact of a 6-month diet intervention on cardiovascular risk factors in postmenopausal Iranian women. It was a randomized controlled trial that carried out in the East Health Clinic in Ahvaz-Iran. This study started on June 2007 and was completed on May 2008. A total 64 healthy postmenopausal women recruited and randomly assigned to the intervention group (35) and control (29). Over the six months follow-up, the intervention group received five educational sessions (two face to face and three lecture discussion classes with slide demonstration) at the first month. These sessions were about menopause, cardiovascular disease and healthy diet. Every participant in the intervention group received one face to face education session at the 3(rd) month, and also received a telephone call at the end of each month starting with the second month to remain on the diet. Pre-intervention and post intervention anthropometric measurements, blood pressure, blood lipids and dietary intake were assessed. Data analyzed using the SPSS version 15. Descriptive (means and SD), univariate (Paired-t test, Chi-Square and Independent T-test) and multivariate (GLM Repeated Measure) statistics were used. Participants in the diet group had significantly lower weight (-0.9 kg), body mass index (-0.4 kg/m(2)), and fasting blood sugar (-4.5 mg/dl). The diet group significantly increased their daily intake of fiber (+2.3 g, P = 0.05), decreased their intake of sodium (-28 mg, P = 0.04), and consumption of fruit and vegetable >= 5 serving a day (80%, P = 0.03) compared to the control group. Post menopausal women are at a greater risk for cardiovascular disease. Healthy diet using educational intervention can be an effective means of reducing cardiovascular risk in postmenopausal women. PMID- 21286412 TI - Adolescents' health behaviors and obesity: Does race affect this epidemic? AB - This study explores the influence of health behaviors and individual attributes on adolescent overweight and obesity using data from Wave II (Add Health). Structural equation model/path analysis using maximum likelihood estimation was utilized to analyze the relationships of health behaviors and attributes with obesity. Results of the model reveal that the causal paths (adolescents' attributes and health behaviors) for overweight and obesity were different for African American and Caucasian adolescents. Generally, African Americans were more susceptible to overweight and obesity than Caucasians. Although increasing levels of vigorous physical activities lowers the risk for obesity among African American and Caucasian adolescents alike, low family SES and being sedentary were associated with overweight and obesity among Caucasians. No significant associations were found among African Americans. Increased hours of sleep at night relate positively with obesity among African Americans. These findings suggest important elements in the consideration of race in developing effective intervention and prevention approaches for curbing the obesity epidemic among U.S. adolescents. PMID- 21286413 TI - Food safety knowledge and practice by the stages of change model in school children. AB - In this study, 342 grade 4-6 elementary school students in Gyeonggi-do were recruited to determine their readiness to change food safety behavior and to compare their food safety knowledge and practices by the stages of change. The subjects were divided into three stages of change; the percentage of stage 1 (precontemplation) was 10.1%, the percentage of stage 2 (contemplation and preparation) was 62.4%, and that of stage 3 (action and maintenance) was 27.5%. Food safety knowledge scores in stage 3 (4.55) or stage 2 (4.50) children were significantly higher than those in stage 1 children (4.17) (P < 0.05). The two food safety behavior items "hand washing practice" and "avoidance of harmful food" were significantly different among the three groups (P < 0.05). Stages of change were significantly and positively correlated with food safety knowledge and practice. Age was significantly and negatively correlated with the total food safety behavior score (r = -0.142, P < 0.05). The most influential factor on the stage of change was a mother's instruction about food safety (P < 0.01). PMID- 21286414 TI - Midazolam hypersensitivity during the transportation to theater -A case report-. AB - This report describes a rare case of perioperative midazolam hypersensitivity in a patient without any history of allergy. A 39-year-old man was admitted for endoscopic pansinus surgery. During transportation to the operating room after injecting antibiotic and midazolam intravenously, the patient complained of shortness of breath. At 3 months after the event, an intradermal sensitivity test for midazolam proved positive indicating the incident was caused by midazolam hypersensitivity. PMID- 21286415 TI - Transesophageal echocardiography (TEE)-induced Mallory-Weiss laceration in a patient who underwent aortic and mitral valve replacement -A case report-. AB - Transesophageal echocardiography (TEE) is a relatively noninvasive and highly valuable diagnostic modality to monitor cardiac surgery. TEE is utilized to estimate the results of the surgical correction or the cardiac function on a real time basis. Accordingly, the frequency of TEE usage is increasing. Previous studies have shown low risk of TEE-associated complications; nonetheless, major gastrointestinal trauma can occur on a rare occasion. We herein present a case of Mallory-Weiss laceration after an intraoperative TEE examination. PMID- 21286416 TI - Bloody cerebrospinal fluid during replacement of descending thoracic aorta -A case report-. AB - Cerebrospinal fluid (CSF) drainage is a routinely used adjunct to thoracoabdominal aortic surgery which may reduce the incidence of preoperative paraplegia by improving spinal cord perfusion. However, this procedure infrequently causes complications. Bloody or bloody-tinged CSF may be associated with intracranial or spinal hematoma. We present herein a case of bloody CSF during the replacement of the descending thoracic aorta. PMID- 21286417 TI - Acute, fatal postoperative myocardial infarction after laparoscopic cholecystectomy in a cardiac patient -A case report-. AB - This report presents the case of a 63-year-old man who had a myocardial infarction leading to coronary artery bypass graft 2 years earlier who subsequently underwent elective laparoscopic cholecystectomy. After an uneventful operation, the patient developed an acute postoperative myocardial infarction in the recovery room and died 19 days postoperatively. Anesthesiologists should be aware of the rare possibility of acute, fatal postoperative myocardial infarction and consider this complication when they perform the preoperative risk evaluation, anesthesia, and postoperative care for cardiac patients undergoing noncardiac surgery. PMID- 21286418 TI - Long QT syndrome provoked by induction of general anesthesia -A case report-. AB - Long QT syndrome (LQTS) is an arrhythmogenic cardiovascular disorder resulting from mutations in cardiac ion channels. LQTS is characterized by prolonged ventricular repolarization and frequently manifests itself as QT interval prolongation on the electrocardiogram (ECG). A variety of commonly prescribed anesthetic drugs possess the adverse property of prolonging cardiac repolarization and may provoke serious ventricular tachyarrhythmia called 'torsades de pointes', ventricular fibrillation, and sudden death. We experienced a case of ventricular tachycardia and ventricular fibrillation after anesthetic induction and it came out into the open that anesthetic induction provoked long QT syndrome. PMID- 21286419 TI - Anesthesia for liver transplantation from a maastricht category 4 non-heart beating donor -A case report-. AB - Great improvements in patient selection, surgical techniques, perioperative care, and immunosuppression have been made for the optimization of liver transplantation. To increase the number of organs available for liver transplantation, transplant centers have used marginal donors, split livers, living donors, or non-heart-beating donors (NHBDs). Despite recent enthusiasm for NHBDs in liver transplantation, warm ischemic injury to recovered organs has been an obstacle for the wide acceptance of NHBD. In the present case, we have conducted a liver transplantation from a Maastricht Category 4 NHBD. Warm ischemic time was 20 minutes and cold ischemic time was 5 hour 43 minutes. Consequently, the liver was successfully transplanted into the recipient. PMID- 21286420 TI - Cardiac arrest from acute hyperkalemia during liver surgery -A case report-. AB - We experienced a case of sudden onset of hyperkalemia during liver lobectomy and this was followed by ventricular tachycardia and cardiac arrest. The main cause of this fatality is assumed to be the wide range of surgical manipulation that induced reduced hepatic blood flow and ischemic necrosis of the hepatic cells. We report here on this case and we review the relevant medical literature. PMID- 21286421 TI - Dynamic left ventricular outflow tract obstruction in living donor liver transplantation recipients -A report of two cases-. AB - We present two cases of dynamic left ventricular outflow tract obstruction in 2 patients who were undergoing living donor liver transplantation. On the preoperative transthoracic echocardiography, the first patient showed normal ventricular function and a normal wall thickness, but severe hemodynamic deterioration developed during the anhepatic period and this was further aggravated after reperfusion in spite of volume resuscitation and catecholamine therapy. Intraoperative transesophageal echocardiography revealed the systolic anterior motion of the mitral valve leaflet together with left ventricular outflow tract obstruction. The second patient showed left ventricular hypertrophy with left ventricular outflow tract obstruction on the preoperative echocardiography. Intraoperative transesophageal echocardiography was used to guide fluid administration and the hemodynamic management throughout the procedure and a temporary portocaval shunt was established to mitigate the venous pooling during the anhepatic period. The purpose of this report is to emphasize the clinical significance of dynamic left ventricular outflow tract obstruction in patients who are undergoing living donor liver transplantation and the role of intraoperative echocardiography to detect and manage it. PMID- 21286422 TI - Anesthetic experience of an adult patient with an unrecognized tracheal bronchus A case report-. AB - We present a case of problematic tracheal intubation in an adult patient with an unrecognized tracheal bronchus. Immediately after tracheal intubation and position change to prone, bilateral breath sounds were almost absent, and there was a diminished tidal volume. In order to resolve the ventilatory difficulty, the wire-reinforced tube was replaced with a conventional tube, and proper positioning of the tube was completed under fiberoptic guidance. A tracheal bronchus (originating about 1.2 cm above the carina, and supplying the right upper lobe) was found on the postoperative chest CT. In the presence of tracheal bronchus, tracheal intubation may cause pulmonary complications. Anesthesiologists should keep in mind the anesthetic implications of tracheal bronchus, and must be familiar with the use of fiberoptic bronchoscopy for proper positioning of endotracheal tube. PMID- 21286423 TI - Multiple cerebral infarction and paradoxical air embolism during hepatectomy using the Cavitron Ultrasonic Surgical Aspirator -A case report-. AB - A venous air embolism and paradoxical air embolism (PAE) are serious complications in patients undergoing a hepatectomy. We report a case of PAE and cerebral infarctions in a patient undergoing a hepatic resection using a Cavitron Ultrasonic Surgical Aspirator (CUSA(r)). A 65-year-old woman underwent a left lobe hepatectomy. During the middle phase of the liver resection with CUSA(r), there was a sudden decrease in arterial blood pressure, end-tidal carbon dioxide and SpO(2). With resuscitation, intraoperative ultrasonography revealed massive air emboli in both her left and right heart, which lasted for 40 min. The hepatectomy was completed after the disappearance of the air emboli from her heart. After surgery, her mental status was stuporous. The brain CT and MRI revealed multiple acute cerebral infarctions. Finally, she died from septic shock. This case highlights the need for anesthetists and surgeons to be aware of the potential for CUSA(r)-related massive PAE. PMID- 21286424 TI - Temporary cardiac arrest in patient under robotically assisted total thyroidectomy causing carotid sinus hypersensitivity -A case report-. AB - Carotid sinus hypersensitivity (CSH) is an exaggerated response to carotid sinus baroreceptor stimulation. Bradycardia, hypotension, and syncope are common manifestations of CSH. A 31-year-old female patient was scheduled for a robotically assisted endoscopic total thyroidectomy. No problems occurred during anesthetic induction. Sudden cardiac arrest occurred near dissection of the diseased thyroid. However, while atropine was administered, the patient soon recovered to normal sinus rhythm. Subsequent bradycardia or hypotension was not followed until the end of surgery. PMID- 21286425 TI - Transfusion-free anesthetic management for open heart surgery in a neonate -A case report-. AB - In small infants or neonates, open heart surgery without transfusion can have many risks regarding inadequate oxygen delivery and coagulopathy. However, if parents refuse blood transfusion, cardiac surgery without transfusion should be considered. We report a case of bloodless cardiac surgery in a 2.89 kg neonate with Jehovah's Witness parents. Blood conserving strategies were used. Preoperatively, erythropoietin and iron were supplemented to increase the hemoglobin level. Intraoperatively, techniques for minimizing blood loss were used, such as reducing priming volume for cardiopulmonary bypass, a blood salvage system, and modified ultrafiltration. Postoperatively, pharmacologic agents were administered and blood sampling was minimized. PMID- 21286426 TI - Acute hypertensive pulmonary edema after Cesarean section in a patient with an antepartum myocardial infarction -A case report-. AB - We report a case of 29-year-old, morbidly obese, diabetic primigravida who had undergone previously primary percutaneous coronary intervention with stent placement for an inferior wall myocardial infarction at 10 weeks of gestation. She remained asymptomatic with medication during the remainder of her pregnancy, but preoperative echocardiography revealed left ventricular dilation and a restrictive diastolic dysfunction with a preserved ejection fraction (46%). She developed acute pulmonary edema associated with hypertension after an elective Cesarean delivery under continuous epidural anesthesia despite the meticulous restriction of fluid. PMID- 21286427 TI - Combined spinal-epidural anesthesia for cesarean section in a patient with Moyamoya disease -A case report-. AB - Moyamoya disease is a rare progressive occlusive disease of the internal carotid arteries. We report a case of combined spinal-epidural anesthesia in a patient with Moyamoya disease presenting for Cesarean section. Hypotension associated with spinal anesthesia for Cesarean section is the most common and serious adverse effect despite the use of uterine displacement and volume preload. We continuously infused phenylephrine and ephedrine to prevent hypotension. The intraoperative hemodynamic state was stable. The patient had no significant postoperative complications. PMID- 21286428 TI - Anesthetic management of the ex utero intrapartum treatment (EXIT) procedure -A case report-. AB - The ex utero intrapartum treatment (EXIT) procedure is a very rare technique performed in cases of fetal congenital malformations. The EXIT procedure increases the rate of survival at delivery by maintaining the uteroplacental circulation until the airway of the fetus is secured. To maintain the uteroplacental circulation, a higher dose of inhalational anesthetics and/or intravenous nitroglycerin can be used as compared to conventional Cesarean section. The aim of this report is to share our anesthetic experience during the EXIT procedure with members of the Korean society of anesthesiology for the first time, and to highlight the maternal implications of the use of inhalational anesthetics and nitroglycerin during Cesarean section for the EXIT procedure. PMID- 21286429 TI - Amniotic fluid embolism that took place during an emergent Cesarean section -A case report-. AB - Amniotic fluid embolism (AFE) is a rare but fatal obstetric emergency, characterized by sudden cardiovascular collapse, dyspnea or respiratory arrest and altered mentality, disseminated intravascular coagulation (DIC). It can lead to severe maternal morbidity and mortality, but the prediction of its occurrence and treatment are very difficult. We experienced a case of AFE during emergent Cesarean section in a 40(+6) weeks healthy pregnant woman, age 33. Sudden dyspnea, hypotension, signs of pulmonary edema and DIC were developed during Cesarean section, and cardiac arrest followed after these events. The course of these events was so rapid and catastrophic, which was consistent with AFE. Thus, we report this case precisely and review pathophysiology, diagnosis, treatment of AFE by referring to up-to-date literatures. PMID- 21286430 TI - Bilateral upper lobe pulmonary edema during gynecologic laparoscopic surgery in the Trendelenberg position -A case report-. AB - A 25-year-old woman was diagnosed with a ruptured ectopic pregnancy. During laparoscopic surgery, the patient was in the Trendelenberg position (20 degrees degrees). Massive froth in the endotracheal tube was observed at the end of surgery. A portable chest x-ray, checked at the end of the operation, showed diffuse haziness in both upper lung fields. After one hour of aggressive treatment with drugs and positive mechanical ventilation, the amount of froth in the endotracheal tube was reduced considerably. Considering the symptom and radiologic findings, we concluded that diffuse bilateral upper lung field haziness was due to atypical pulmonary edema. We speculated that the rapid improvement of pulmonary edema was due to redistribution of fluid to the lowest part of lung by immediate reversing the patient's Trendelenberg position, along with aggressive treatment. PMID- 21286431 TI - Anesthetic management for emergent Cesarean section in a patient with toxic epidermal necrolysis -A case report-. AB - Toxic epidermal necrolysis (TEN) is rare but serious cutaneous reaction with significant mortality and long-term morbidity. Various etiologies, particularly numerous medications and infectious agents have been implicated. It is characterized as inflammatory bullous lesions of the skin and mucous membrane and can develop serious complications such as pneumonia, pneumothorax, sepsis and renal failure. In general, patients with TEN are managed as severe second-degree burn patients with preventing excessive fluid deficit and infections. In this case, we aimed to present anesthetic management of a 26-year-old pregnant woman with TEN who received general anesthesia during emergent cesarean section. PMID- 21286432 TI - Damage to the cuff of EMG tube at endotracheal intubation by using a lightwand -A case report-. AB - Electromyogpraphic endotracheal tube (EMG tube) is a new device used to monitor recurrent laryngeal nerve integrity during thyroid surgery. The EMG tube has 2 pairs of electrodes on the surface of silicon-based tube reached to inner space of tube cuff. We experienced an unusual endotracheal tube-related problem from the distinct structural feature of the EMG tube. In this case, we intubated a patient who had difficult airway with the EMG tube using a lightwand. After successful endotracheal intubation, we could not expand the pilot balloon and ventilate the patient effectively. We removed the EMG tube and found that one of electrodes of the EMG tube is bended and made a right angle with the long axis of the tube, and perforated the tube cuff. So we report this case to make anesthesia providers aware that much more attention is needed to use EMG tube during endotracheal intubation. PMID- 21286433 TI - Fatal pulmonary embolism caused by thrombosis of contralateral axillary vein after arthroscopic right rotator cuff repair -A case report-. AB - A clinically apparent thromboembolism associated with arthroscopic shoulder surgery is extremely rare. We report a case of a fatal pulmonary embolism developed after an arthroscopic rotator cuff repair in a 45-year-old woman. On the first day after surgery, she experienced syncope that was complicated by cardiac arrest. No hemostasis impairment was noted. A computed tomography scan revealed a pulmonary embolism, and Doppler ultrasound revealed thrombosis of the axillary vein on the contralateral shoulder. She died from multiple organ failure 13 days after surgery. This case shows that clinicians must be aware of the potential occurrence of a pulmonary thromboembolism in patients undergoing prolonged arthroscopic shoulder surgery. PMID- 21286434 TI - Rupture of external iliac artery during microscopic lumbar disc surgery -A case report-. AB - Iatrogenic vascular injury during lumbar disc surgery is a rare but serious complication. This paper reports a patient who sustained an injury to the iliac artery while undergoing intervertebral disc surgery at the lumbar region. He suffered from massive bleeding and shock. An urgent laparatomy was performed under cardiopulmonary bypass, and the vascular injuries were repaired successfully. This case shows that a rapid diagnosis and immediate intervention can result in a favorable outcome. PMID- 21286435 TI - Anesthetic management with scalp nerve block and propofol/remifentanil infusion during awake craniotomy in an adolescent patient -A case report-. AB - Despite of various neurophysiologic monitoring methods under general anesthesia, functional mapping at awake state during brain surgery is helpful for conservation of speech and motor function. But, awake craniotomy in children or adolescents is worrisome considering their emotional friabilities. We present our experience on anesthetic management for awake craniotomy in an adolescent patient. The patient was 16 years old male who would undergo awake craniotomy for removal of brain tumor. Scalp nerve block was done with local anesthetics and we infused propofol and remifentanil with target controlled infusion. The patient endured well and was cooperative before scalp suture, but when surgeon sutured scalp, he complained of pain and was suddenly agitated. We decided change to general anesthesia. Neurosurgeon did full neurologic examinations and there was no neurologic deficit except facial palsy of right side. Facial palsy had improved with time. PMID- 21286436 TI - Recurred pneumocephalus in a head trauma patient following positive pressure mask ventilation during induction of anesthesia -A case report-. AB - Pneumocephalus is a condition which usually results from head trauma. It has been known that iatrogenic pneumocephalus can occur as a complication of positive pressure mask ventilation during induction of anesthesia or ventilatory care for head trauma patients. We report a case of mask ventilation during anesthesia induction in a 50-year-old male patient with head trauma. Initial pneumocephalus associated with cerebrospinal fluid leakage was diagnosed immediate following head injury involving facial sinuses. He was managed with emergent lumbar drainage and supportive care. Pneumocephalus recurred following positive pressure mask ventilation (PPMV) during anesthesia induction for surgery on the right arm. Recurred pneumocephalus was managed with high flow oxygen and supportive care. Anesthesiologists should be aware of pneumocephalus as a potential complication of PPMV in head trauma patients, even after resolution of previous pneumocephalus. PMID- 21286437 TI - Retroperitoneal hematoma after coil embolization of cerebral aneurysm -A case report-. AB - We present the case of a 57-year-old man who developed retroperitoneal hemorrhage due to unintentional arterial puncture during femoral artery cannulation for Guglielmi detachable coil embolization. On emergence from anesthesia, he developed severe hypotension. Computed tomographic angiogram of the abdomen showed retroperitoneal hematomas around the urinary bladder, liver, and spleen. Because femoral artery cannulation is a common procedure for intravascular embolization in neuroradiologic procedures, Clinicians should be aware of the development of severe hematomas as a consequence of femoral artery puncture. PMID- 21286438 TI - Intraoperative acute brain swelling when performing indirect anastomosis in a patient with moyamoya disease -A case report-. AB - A 6-year-old male patient who was suffering from a cold and a transient ischemic attack was scheduled to undergo encephalo-duro-arterio-synangiosis for treating his moyamoya disease. Acute brain edema occurred just after opening the dura mater. Head elevation, reduction of the head rotation and hyperventilation were done. The inhalational agents were discontinued and total intravenous anesthesia was started. The swelling was reduced after intravenously infusing mannitol. An abrupt return from hypocapnia to normocapnea during the induction of general anesthesia was thought to be the cause of the acute brain swelling. In conclusion, correction of hypocapnea needs to be performed gradually during the induction of anesthesia and when performing an operation for treating a patient with moyamoya disease. PMID- 21286439 TI - Acute respiratory alkalosis occurring after endoscopic third ventriculostomy -A case report-. AB - An endoscopic third ventriculostomy was performed in a 55-year-old man with an obstructive hydrocephalus due to aqueductal stenosis. The vital signs and laboratory studies upon admission were within the normal limits. Anesthesia was maintained with nitrous oxide in oxygen and 6% desflurane. The patient received irrigation with approximately 3,000 ml normal saline during the procedure. Anesthesia and operation were uneventful. However, he developed postoperative hyperventilation in the recovery room, and arterial blood gas analysis revealed acute respiratory alkalosis. We report a rare respiratory alkalosis that occurred after an endoscopic third ventriculostomy. PMID- 21286440 TI - Extensive demyelinating change in cerebrum after a total knee replacement -A case report-. AB - Demyelination is characterized by the loss of myelin with the preservation of axons. Demyelinating diseases can be classified into several categories: demyelination due to inflammation, viral infection, osmotic derangements and hypoxic ischemia. In particular, osmotic myelinolysis is representative, and is associated with hyperosmolality, hypokalemia or rapid correction of hyponatremia. Osmotic myelinolysis was reported to be associated with underlying conditions, such as alcoholism, diuretics and malnutrition. A 67-year-old woman with hypertension was scheduled to undergo both total knee replacements (TKR). She was observed to be lethargic with dysphagia and quadriplegia after the second TKR. She had been taking diuretics for a long time, and did not have an adequate amount of food intake due to patient controlled analgesia and a gastric ulcer after the first TKR. A laboratory examination revealed hypokalemia but normonatremia. T2 weighted-MRI revealed abnormal high signal intensity in the basal ganglia and periventricular area. This case was diagnosed with osmotic myelinolysis associated with hypokalemia without an apparent sodium imbalance. PMID- 21286441 TI - Re-insufflation after deflation of a pneumoperitoneum is a risk factor for CO(2) embolism during laparoscopic prostatectomy -A case report-. AB - Although symptomatic carbon dioxide (CO(2)) embolism is rare, it recognized as a potentially fatal complication of laparoscopic surgery. Sudden hemodynamic instability could be a CO(2) embolism especially during insufflation. A 65-year old man received laparoscopic prostatectomy for 5 hours under CO(2) pneumoperitoneum without any problem. After resection of prostate, it was stopped following deflation. Thirty minutes later, peumoperitoneum was re-induced to continue the operation. Shortly after re-insufflation, the patient revealed hemodynamic instability suggested a CO(2) embolism; severe hypotension, tachyarrythmia, hypoxemia, increased CVP, and changed end-tidal CO(2). Gas insufflation was stopped. He was managed with Durant's position, fluid and cardiotonics for 20 minutes. The residual was completed by open laparotomy. Re insufflation, inducing gas entry through the injured vessels, might be a risk factor for CO(2) embolism in this case. The risk to the patient may be minimized by the surgical team's awareness of CO(2) embolism and continuous intra-operative monitoring of end-tidal CO(2). PMID- 21286442 TI - Cerebral fat embolism after bilateral total knee replacement arthroplasty -A case report-. AB - Fat embolism syndrome is a rare and potentially lethal complication most commonly seen in long bone fractures and intramedullary manipulation. The clinical triad of fat embolism syndrome consists of mental confusion, respiratory distress, and petechiae. This study reports a case of cerebral fat embolism syndrome following elective bilateral total knee replacement. After an uneventful anesthesia and initial recovery, the patient developed neurologic symptoms nine hours postoperatively. PMID- 21286443 TI - Left mainstem bronchial rupture during one-lung ventilation with Robertshaw double lumen endobronchial tube -A case report-. AB - Lung separation using a double-lumen endobronchial tube is necessary for video assisted thoracoscopy (VATs). Bronchial rupture after intubation with a double lumen endobronchial tube has been rarely reported. We report a case of a 70-year old man who had solitary pulmonary nodule in his right upper lobe. He was intubated with a left-sided Robertshaw double-lumen endobronchial tube. He underwent a VATs right upper lobectomy with the one-lung ventilation of left lung. During the operation, the rupture of the left mainstem bronchus was detected. Immediately, the thoracotomy was performed and the ruptured left mainstem bronchus was repaired with absorbable sutures (vicryl). Seven days later he had a bronchoscopy to examine the left mainstem bronchus. There was no evidence of the bleeding, leakage and inflammation. Subsequent course was uneventful. Tracheobronchial injuries related to the double-lumen endobronchial tube are discussed. PMID- 21286444 TI - Bilateral hydrothorax and cardiac tamponade after right subclavian vein catheterization -A case report-. AB - Central venous catheterization is typically used for the anesthetic management of patients undergoing a major surgery or care of patients in Intensive Care Unit (ICU). The occurrence of complications associated with central venous catheterization such as pneumothorax or vascular injury have decreased, while delayed complications such as hydrothorax, hydromediastinum, or cardiac tamponade have risen recently. We report a case of complications of bilateral hydrothorax with cardiac tamponade by superior vena cava perforation due to continuous mechanical force of the looped central venous catheter tip against SVC wall after subclavian vein cannulation. PMID- 21286445 TI - Barotrauma developed during intra-hospital transfer -A case report-. AB - A 74-year-old male patient receiving ventilatory support due to aspiration pneumonia developed bilateral pneumothorax, pneumopericardium, pneumomediastinum, pneumo-retroperitoneum, and subcutaneous emphysema, after manual ventilation while being transferred from the intensive care unit (ICU) to the operating room (OR). These complications were assumed to be secondary to inappropriate manual ventilation of the intubated patient. In addition, it is likely that the possible migration of an already marginally acceptable endotracheal tube (ETT) position during transport was the cause of these complications. Finally, aggravation of a latent pneumothorax might have contributed to these complications. PMID- 21286446 TI - Transient cauda equina syndrome related to a sacral schwannoma with cauda equine compression after a lumbar epidural block -A case report-. AB - A 53-year-old man had chronic low back and leg pain for four years without any history of trauma or neurological manifestations. There was a reduction in symptoms after a lumbar epidural block. Two hours later after the procedure, the patient complained of perineal numbness and lower extremity weakness. The neurological evaluation revealed loss of sensation in the saddle area and the posterior aspect of the leg. The deep-tendon reflexes were decreased in the leg. The patient was unable to urinate. The MRI revealed a schwannoma at the S3 level of the sacral spine with cauda equina compression. The patient's symptoms improved slightly over the next few hours. The patient had a gradual return of motor function and could feel the Foley catheter. All of the symptoms completely resolved over the next nine hours and the patient was discharged to home once completely recovered. This case illustrates the importance of clinical examination and continued vigilance for evaluation of neurological deterioration after epidural injections. PMID- 21286447 TI - Spinal cord stimulator malfunction caused by radiofrequency neuroablation -A case report-. AB - The implantation of spinal cord stimulators (SCSs) to treat chronic intractable pain is steadily increasing. And there is an increased likelihood of instances where other therapies or procedures are found to interfere with SCS function, which in turn may result in pain. Since SCS utilize electric impulses as well as magnets, special considerations need for patients with a SCS in situ who require these procedures. The present report describes a case where radiofrequency (RF) ablation of the third occipital nerve resulted in spontaneous activation of a cervical SCS device. PMID- 21286448 TI - Posterior auricular pain caused by the trigger points in the sternocleidomastoid muscle aggravated by psychological factors -A case report-. AB - Psychological factors play a significant role in the pain mechanism, and psychological approaches may be useful complements to traditional medical and surgical treatments in pain management. The authors report a case of recurrent severe posterior auricular pain caused by trigger points in the right sternocleidomastoid muscle and influenced by stressful psychological situations (e.g., family affairs, job loss) in a 50-year-old man. PMID- 21286449 TI - A case of back pain caused by Salmonella spondylitis -A case report-. AB - Salmonella spondylitis is a rare illness, and it generally occurs in patients who have already had sickle cell anemia, and it is even rarer in patients who are without sickle cell anemia. A 61-year-old male patient was hospitalized for the evaluation of his renal function and then treatment was started for his back pain. His back pain had developed about 2 months previously without any specific trauma. Only a bulging disc was detected on the initial lumbar MRI. Regarding his fever, it was diagnosed as possible atypical pneumonia, scrub typhus, etc., and multiple antibiotic therapy was administered. At the time of transfer, the leucocytes and hs-CRP were normal and the ESR was elevated. A diagnostic epidural block was performed for his back pain, but his symptoms were not improved. Lumbar MRI was performed again and it showed findings of infective spondylitis. Salmonella D was identified on the abscess culture and so he was diagnosed as suffering from Salmonella spondylitis. After antibiotic treatment, his back pain was improved and the patient was able to walk. PMID- 21286450 TI - Pulsed radiofrequency lesioning for treatment of chronic breast neuropathic pain after breast reduction -A case report-. AB - Breast surgery is a common procedure performed in women. Many women who undergo breast surgery suffer from ill-defined pain syndromes. A nerve block is used in the treatment of the acute and chronic pain, but the effectiveness of the treatment has been limited because of its short duration. Recently, the advent of pulsed radiofrequency lesioning (PRF) has proved a successful treatment for chronic refractory pain involving the peripheral nerves. We experienced a case of a 52-year-old female patient complaining of chronic breast neuropathic pain after breast reduction, which was relieved after PRF lesioning of the 4th thoracic spinal nerve and its root. PMID- 21286451 TI - Pneumomediastinum and pneumothorax after orthognathic surgery -A case report-. AB - The occurrences of pneumomediastinum and pneumothorax after oral and/or maxillofacial surgery are rare, but both are potentially life-threatening complications. Most of the cases that present pneumomediastinum and pneumothorax in the oral and/or maxillofacial surgery result from air dissecting down the fascial planes of the neck. We report a case of a 23-year-old male patient who underwent bilateral sagittal split ramus osteotomy under general anesthesia and developed pneumomediastinum and pneumothorax without any traumatic introduction of air through the cervical fascia three days postoperatively. The possible causes and its prevention are discussed with a review of the relevant literature. PMID- 21286452 TI - Awake Glidescope(r) intubation in a patient with a huge and fixed supraglottic mass -A case report-. AB - Intubating patients with a huge, fixed supraglottic mass causing an obstruction of the glottis is difficult to most anesthesiologists. We attempted awake fiberoptic orotracheal intubation assisted by Glidescope(r) Videolaryngoscope (GVL) following topical anesthesia with 4% lidocaine spray and remifentanil infusion. The glottis could not be identified by the GVL view. However, by entering toward the right side of the mass with bronchoscope, the glottis was found. Due to stiffness of the mass, we were unable to further enter the area using the bronchoscope. Alternatively, we attempted to expose the glottis by GVL blade and then successfully intubated the patient by manually pressing the cricoids cartilage. GVL is nonetheless an excellent instrument in airway management compared to fiberoptic bronchoscope for patients with a huge and fixed supraglottic mass. PMID- 21286453 TI - Pseudoaneurysm in the inferior epigastric artery and scrotal hematoma following removal of a femoral vein catheter -A case report-. AB - We report a rare case of pseudoaneurysm of the inferior epigastric artery and inguinal hematoma extending to the scrotum following the removal of a femoral venous catheter in a 24-year-old male patient undergoing two consecutive neurosurgical procedures. PMID- 21286454 TI - Reversible airway obstruction caused by changing the size and length of an endotracheal tube in a premature neonate with suspected tracheomalacia -A case report-. AB - Tracheomalacia is a malformation of the tracheal membranosa. It is maintained during spontaneous breathing but can be altered by bronchoscopy or positive airway pressure. Tracheomalacia is associated with a high mortality and may cause prolonged intubation and ventilation. Here, the case of a 13-day-old infant with jejunoileal stenosis that had surgery is reported. During induction of general anesthesia, endotracheal intubation was attempted several times with different sized endotracheal tubes. Airway obstruction occurred after the endotracheal intubation. After the airway was maintained, the operation was completed. Tracheomalacia was diagnosed after otolaryngology evaluation postoperatively. PMID- 21286455 TI - Airway management using laryngeal mask airway in insertion of the Montgomery tracheal tube for subglottic stenosis -A case report-. AB - The Montgomery tracheal tube (T-tube) is a device used as a combined tracheal stent and airway after laryngotracheoplasty for patients with tracheal stenosis. This device can present various challenges to anesthesiologists during its placement, including the potential for acute loss of the airway, inadequate administration of inhalation agents, and inadequacy of controlled mechanical ventilation. The present case of successful airway management used a laryngeal mask airway under total intravenous anesthesia with propofol and remifentanil in the insertion of a Montgomery T-tube in a tracheal resection and thyrotracheal anastomosis because of severe subglottic stenosis. PMID- 21286456 TI - Hyperkalemia in a patient with rhabdomyolysis and compartment syndrome -A case report-. AB - Rhabdomyolysis is a life-threatening syndrome caused by skeletal muscle injury, which results in the leakage of myoglobin, other intracellular proteins and electrolytes into the circulatory system and urine. Acute kidney injury occurs in 13-50% of patients with rhabdomyolysis, which is the principal cause of their mortality. This is to report an emergency operation performed on a patient with traumatic rhabdomyolysis and compartment syndrome who developed life-threatening hyperkalemia caused by reperfusion injury after vascular anastomosis. The patient was treated with intravascular volume expansion, sodium bicarbonate, diuretics, insulin and Continuous Renal Replacement Therapy, but the patient expired 5 days after the operation. PMID- 21286457 TI - Rhabdomyolysis after laparoscopic radical nephrectomy -A case report-. AB - Rhabdomyolysis is a rare but potentially lethal clinical syndrome that results from acute muscle fiber necrosis with leakage of muscle constituents into blood. This devastating disease could be due to muscle compression caused by urologic positioning for a lengthy nephrectomy. In this regard, laparoscopic renal surgery may be a risk for the development of rhabdomyolysis. This phenomenon of massive muscle necrosis can produce secondary acute renal failure. The risk factors have to be managed carefully during anesthetic management. Here, we report a case of a patient with rhabdomyolysis that developed in the flexed lateral decubitus position during laparoscopic nephrectomy. PMID- 21286458 TI - Airway obstruction by extrinsic tracheal compression during spinal surgery under prone position -A case report-. AB - Tracheal compression by vascular anomalies in adults is uncommon and most related reports are of children. A 79-year-old woman without any respiratory history underwent a lumbar spine surgery under general anesthesia. She suddenly developed airway obstruction after a position change from supine to prone. A fiberoptic bronchoscopy showed the obstruction of endotracheal tube. The obstruction was relieved after we changed the depth of endotracheal tube and supported the patient's neck with a cotton roll. The surgery ended without any other event and the patient recovered safely. A computed tomography revealed the rightward tracheal deviation and tortuous innominate artery contact with trachea. The patient didn't manifest any respiratory related symptoms during postoperative period, and she was discharged without any treatment. PMID- 21286459 TI - Lower leg compartment syndrome following prolonged orthopedic surgery in the lithotomy position -A case report-. AB - Surgical procedures necessitating the prolonged use of the lithotomy position can be associated with neuromuscular dysfunction. Compartment syndrome of the lower leg is a grave complication which, if unrecognized, can lead to either permanent neuromuscular dysfunction or limb loss. We report a case of compartment syndrome of lower leg that occurred in male patient aged 20 years after 380 minutes arthroscopic surgery in the lithotomy position. PMID- 21286460 TI - Cardiovascular crisis after small dose local infiltration of epinephrine in patient with asymptomatic subarachnoid hemorrhage -A case report-. AB - The infiltration of dilute epinephrine solution has been used for many years to provide hemostasis. However, epinephrine has adverse cardiovascular effects, such as arrhythmia, pulmonary edema, and even cardiac arrest. We have experienced epinephrine-induced cardiovascular crisis, with severe hypertension, tachycardia, and cardiac arrest after subcutaneous infiltration of a 2% lidocaine and 1 : 200,000 epinephrine solution in a patient with an asymptomatic subarachnoid hemorrhage. We provided successfully advanced cardiac life support in the operating room and cardioverted the patient back into a sinus rhythm with no untoward effects. The patient recovered without any apparent sequelae after intensive care. PMID- 21286461 TI - Paroxysmal atrial fibrillation developed during incomplete epidural anesthesia -A case report-. AB - Atrial fibrillation (AF) is the most common sustained tachyarrhythmia, and occurs in organic heart disease such as rheumatic, atherosclerotic and hypertensive heart disease. In recent studies, the sympathetic and parasympathetic nervous systems have been shown to have important roles in initiating paroxysmal AF. We report here a patient who developed paroxysmal AF that might be a result of an imbalance of the sympathetic-parasympathetic systems due to epidural anesthesia, and that was potentiated by pain with inadequate analgesia. A 69-year-old woman was scheduled for operation of a right-sided ankle fracture. Twenty minutes after epidural drug injection, paroxysmal AF occurred. Even after intravenous administration of esmolol and digoxin, AF continued. After transfer to the intensive care unit, her heart rate gradually decreased and AF disappeared. During perioperative anesthetic management, the proper preoperative prevention and intraoperative treatment are needed in AF high-risk patients. PMID- 21286462 TI - A case of malignant hyperthermia during anesthesia induction with sevoflurane -A case report-. AB - We experienced a case of malignant hyperthermia (MH) in 6-year-old boy during anesthesia induction for strabismus surgery. It has been generally reported that sevoflurane can induce the delayed onset of MH in the absence of succinylcholine. Our case of MH was elicited after about 2-3 min of sevoflurane administration with N(2)O, O(2) and rocuronium. However, we successfully treated the patient by early recognition of his condition and administering symptomatic treatment and dantrolene. PMID- 21286463 TI - Recurrent spinal myoclonus after two episodes of spinal anesthesia at a 1-year interval -A case report-. AB - Spinal myoclonus is an unusual, self-limiting, adverse event that may occur during spinal anesthesia. The exact cause and underlying biochemical mechanism of spinal myoclonus remain unclear. A few cases of spinal myoclonus have been reported after administration of intrathecal bupivacaine. We report a case in which spinal myoclonus recurred after two episodes of spinal anesthesia with bupivacaine at a 1-year interval in a 35-year-old woman. The myoclonus was acute and transient. The patient recovered completely, with no neurologic sequelae. PMID- 21286464 TI - Epidural anesthesia for the patient with type IV spinal muscular atrophy -A case report-. AB - Spinal muscular atrophy (SMA) is a rare lower motor neurone disease in which anesthetic management is often difficult as a result of muscle weakness, hypersensitivity to non-depolarizing neuromuscular blocking agent, and succinylcholine induced hyperkalemia. We describe a 50-year-old patient with type IV SMA for synovectomy. We decided to use an epidural technique to avoid muscle relaxants and tracheal intubation. After operation, there was no exacerbation of neurologic signs and symptoms. PMID- 21286465 TI - Foraminal stenosis complicating retained broken epidural needle tip -A case report-. AB - Lumbar epidural anesthesia is useful in a variety of chronic benign pain syndromes, including lumbar radiculopathy, low back pain syndrome, spinal stenosis, and vertebral compression fractures. Given the increased number of epidural nerve blocks being performed, some have reported unexplained complications of a transient or permanent nature and with varying degrees of severity. However, no case has been reported of a broken epidural needle tip retained in the lumbar facet joint area. This represents the first reported case presentation of foraminal stenosis developing in a patient after a retained epidural needle tip. PMID- 21286466 TI - Thoracic paravertebral block for breast surgery in a pregnant woman -A case report-. AB - Non-obstetrical surgery during the first trimester is stressful to both the mother and the fetus. Anesthesiologists are also stressed, not only because of the effects of surgery itself, but also because of the uncertain influences of anesthesia thrown upon on the fetus. The authors present a case of breast surgery successfully performed on a woman 8 weeks pregnant requiring removal of breast abscess by the application of thoracic paravertebral block without any complications. Thoracic paravertebral block may be a safe anesthetic method for non-obstetric surgery during early pregnancy. PMID- 21286467 TI - Development of multifocal atrial tachycardia in a patient using aminophylline -A case report-. AB - An 82-year-old female, with left femoral neck fracture was scheduled for left hip hemiarthroplasty, under spinal anaesthesia. She had been suffering from diabetes, hypertension, lung cancer and was previously treated with IV aminophylline for respiratory insufficiency. She was given spinal anaesthesia with 10 mg of 0.5% hyperbaric bupivacaine, and T6 sensory block level was established. After 10 minutes, her blood pressure dropped to 80/60 mmHg, so intravenous ephedrine was given. At that moment, multifocal atrial tachycardia (MAT) appeared on electrocardiogram (ECG). Intravenous infusion of phenylephrine and procainamide was given and conversion of MAT to sinus rhythm was successfully achieved. We report a case of MAT after spinal anaesthesia, in a patient with respiratory insufficiency previously treated with IV aminophylline, which was successfully treated by intravenous infusion of phenylephrine and procainamide. PMID- 21286468 TI - Pulmonary thromboembolism after tourniquet inflation under spinal anesthesia -A case report-. AB - Pulmonary thromboembolism is one of the most important causes of morbidity and mortality in patients undergoing lower extremity orthopedic surgery. Early diagnosis and appropriate management are important clinical challenges. In this case, massive pulmonary embolism causing sudden cardiac arrest was attributed to use of tourniquet inflation during lower extremity orthopedic surgery. Resuscitation procedures were initiated and transesophageal echocardiography revealed pulmonary thromboembolism. Patients with high suspicion for the presence of deep vein thrombus must be monitored thoroughly during limb exsanguinations. PMID- 21286469 TI - Meralgia paresthetica affecting parturient women who underwent cesarean section A case report-. AB - Meralgia paresthetica is commonly caused by a focal entrapment of lateral femoral cuteneous nerve while it passes the inguinal ligament. Common symptoms are paresthesias and numbness of the upper lateral thigh area. Pregnancy, tight cloths, obesity, position of surgery and the tumor in the retroperitoneal space could be causes of meralgia paresthetica. A 29-year-old female patient underwent an emergency cesarean section under spinal anesthesia without any problems. But two days after surgery, the patient complained numbness and paresthesia in anterolateral thigh area. Various neurological examinations and L-spine MRI images were all normal, but the symptoms persisted for a few days. Then, electromyogram and nerve conduction velocity test of the trunk and both legs were performed. Test results showed left lateral cutaneous nerve injury and meralgia paresthetica was diagnosed. Conservative treatment was implemented and the patient was free of symptoms after 1 month follow-up. PMID- 21286470 TI - Transient bilateral vocal cord paralysis after endotracheal intubation with double-lumen tube -A case report-. AB - Vocal cord paralysis is one of the most serious anesthetic complications related to endotracheal intubation. The practitioner should take extreme care, as bilateral vocal cord paralysis can obstruct the airway and lead to disastrous respiratory problems. There have been many papers on bilateral vocal cord paralysis after neck surgery, but reports on such a condition after lung surgery are very rare. We report a case of bilateral vocal cord paralysis detected after removal of a double-lumen endotracheal tube in a 67-year-old patient who underwent wedge resection by video-assisted thoracoscopic surgery. We also note that he recovered spontaneously without complications within a day. PMID- 21286471 TI - Ultrasound-guided supraclavicular brachial plexus block in pediatric patients -A report of four cases-. AB - Supraclavicular brachial plexus blocks are not common in pediatric patients due to the risk of pneumothorax. Ultrasonography is an important tool for identifying nerves during regional anesthesia. Directly visualizing the target nerves and monitoring the distribution of the local anesthetic are potentially significant. In addition, ultrasound monitoring helps avoid complications, such as inadvertent intravascular injection or pneumothorax. This paper reports four cases of pediatric patients who received ultrasound-guided supraclavicular brachial plexus block for upper limb surgery. PMID- 21286472 TI - Transient quadriplegia after fluoroscopic-guided selective cervical nerve root block in a patient who received cervical interbody fusion -A case report-. AB - Selective cervical nerve root block is executed for patients who have symptoms of cervical radiculopathy for diagnostic and therapeutic purposes. However several catastrophic complications caused by this procedure have been reported including neurological complications. A 43-year-old male received a C5 selective cervical nerve root block procedure due to continuous radiating pain even after cervical discectomy and interbody fusion was performed. At the time of the procedure, the contrast outline revealed reflux of the nerve root and epidural space. But after the procedure was performed, the patient experienced decreased sensation in the upper and low extremities as well as motor paralysis of both extremities. Our sspecting diagnosis was anterior spinal artery syndrome but both sensory and motor functions were subsequently recovered within a few hours after the procedure was completed. Due to the difficult nature of this case, we reported these complications and reviewed current literature related to this study. PMID- 21286473 TI - Anaphylaxis caused by latex surgical gloves immediately after starting surgery -A case report-. AB - Anaphylaxis is an acute and fatal systemic allergic reaction to an allergen, and it can be an unpredictable and life-threatening cause during anesthesia. Latex is the second most common cause of anaphylaxis following the use of neuromuscular blocking agents during general anesthesia or surgery. We report on a 67-year-old male who had undergone surgery under general anesthesia without any problem but who presented with severe intraoperative anaphylaxis to latex surgical gloves. This case emphasizes the need for anesthesiologists to quickly diagnose and properly manage an allergic reaction in patients under general anesthesia. PMID- 21286474 TI - In vivo Tracking of Transplanted Bone Marrow-Derived Mesenchymal Stem Cells in a Murine Model of Stroke by Bioluminescence Imaging. AB - OBJECTIVE: This study was designed to validate the cell trafficking efficiency of the in vivo bioluminescence image (BLI) study in the setting of transplantation of the luciferase expressing bone marrow-derived mesenchymal stem cells (BMSC), which were delivered at each different time after transient middle cerebral artery occlusion (MCAO) in a mouse model. METHODS: Transplanting donor BMSC were prepared by primary cell culture from transgenic mouse expressing luciferase (LUC). Transient focal infarcts were induced in 4-6-week-old male nude mice. The experiment mice were divided into five groups by the time of MSC transplantation : 1) sham-operation group, 2) 2-h group, 3) 1-day group, 4) 3-day group, and 5) 1 week group. BLI for detection of spatial distribution of transplanted MSC was performed by detecting emitted photons. Migration of the transplanted cells to the infarcted area was confirmed by histological examinations. Differences between groups were evaluated by paired t-test. RESULTS: A focal spot of bioluminescence was observed at the injection site on the next day after transplantation by signal intensity of bioluminescence. After 4 weeks, the mean signal intensities of 2-h, 1-day, 3-day, and 1-week group were 2.6*10(7) +/- 7.4*10(6), 6.1*10(6) +/- 1.2*10(6), 1.7*10(6) +/- 4.4*10(5), and 8.9*10(6) +/- 9.5*10(5), respectively. The 2-h group showed significantly higher signal intensity (p < 0.01). The engrafted BMSC showed around the infarct border zones on immunohistochemical examination. The counts of LUC-positive cells revealed the highest number in the 2-h group, in agreement with the results of BLI experiments (p < 0.01). CONCLUSION: In this study, the results suggested that the transplanted BMSC migrated to the infarct border zone in BLI study and the higher signal intensity of LUC-positive cells seen in 2 hrs after MSC transplantation in MCAO mouse model. In addition, noninvasive imaging in real time is an ideal method for tracking stem cell transplantation. This method can be widely applied to various research fields of cell transplantation therapy. PMID- 21286475 TI - Role of 'Spot Sign' on CT Angiography to Predict Hematoma Expansion in Spontaneous Intracerebral Hemorrhage. AB - OBJECTIVE: Patients with spontaneous intracerebral hemorrhage (ICH) presenting within 24 hours of symptom onset are known to be increased risk of hematoma expansion which is closely correlated with morbidity and mortality. We investigated whether tiny enhancing foci ('Spot sign') on axial view of 3 dimensional computed tomography angiography (3D-CTA) source images can predict subsequent hematoma expansion in spontaneous ICH. METHODS: During a 2-year period (March 2007-March 2009), we prospectively evaluated 3D-CTA of 110 patients with spontaneous ICH. Based on source images of 3D-CTA, patients were classified according to presence or absence of 'Spot sign'; 'Spot sign' (+) group, 'Spot sign' (-) group. Radiological factors and clinical outcomes were compared between two groups. RESULTS: Hematoma expansion occurred in 16 patients (15%). Mean Glasgow Coma Scale (GCS) score of patients with hematoma expansion was significantly different compared to score of patients without hematoma expansion (5 vs. 9, p < 0.001). Nineteen patients (16%) of 110 ICH patients demonstrated 'spot sign' on 3D-CTA. Among the 'spot sign' (+) group, 53% of patients developed hematoma expansion. Conversely 7% of patients without 'spot sign' demonstrated the hematoma expansion (p < 0.001). Initial volume and location of hematoma were significantly not associated with hematoma expansion except shape of hematoma. CONCLUSION: Our study showed that patients with hematoma expansion of spontaneous ICH had significant clinical deterioration. And the fact that 'spot sign' (+) group have higher risk of hematoma expansion suggests the presence of 'spot sign' on source images of 3D-CTA can give a clue to predict hematoma expansion in spontaneous ICH. PMID- 21286476 TI - Hypopharyngeal Wall Exposure within the Surgical Field : The Role of Axial Rotation of the Thyroid Cartilage during Anterior Cervical Surgery. AB - OBJECTIVE: Esophageal/hypopharyngeal injury can be a disastrous complication of anterior cervical surgery. The amount of hypopharyngeal wall exposure within the surgical field has not been studied. The objective of this study is to evaluate the chance of hypopharyngeal wall exposure by measuring the amount of axial rotation of the thyroid cartilage (ARTC) and posterior projection of the hypopharynx (PPH). METHODS: The study was prospectively designed using intraoperative ultrasonography. We measured the amount of ARTC in 27 cases. The amount of posterior projection of the hypopharynx (PPH) also was measured on pre operative CT and compared at three different levels; the superior border of the thyroid cartilage (SBTC), cricoarytenoid joint and tip of inferior horn of the thyroid cartilage (TIHTC). The presence of air density was also checked on the same levels. RESULTS: The angle of ARTC ranged from -6.9 degrees to 29.7 degrees , with no statistical difference between the upper and lower cervical group. The amount of PPH was increased caudally. Air densities were observed in 26 cases at the SBTC, but none at the TIHTC. CONCLUSION: Within the confines of the thyroid cartilage, surgeons are required to pay more attention to the status of hypopharynx/esophagus near the inferior horn of the thyroid cartilage. The hypopharynx/esophagus at the TIHTC is more likely to be exposed than at the upper and middle part of the thyroid cartilage, which may increase the risk of injury by pressure. Surgeons should be aware of the fact that the visceral component at C6-T1 surgeries also rotates as much as when the thyroid cartilage is engaged with a retractor. The esophagus at lower cervical levels warrants more careful retraction because it is not protected by the thyroid cartilage. PMID- 21286477 TI - Lumbar Interbody Fusion Outcomes in Degenerative Lumbar Disease : Comparison of Results between Patients Over and Under 65 Years of Age. AB - OBJECTIVE: To evaluate the clinical and radiological outcomes of lumbar interbody fusion and its correlation with various factors (e.g., age, comorbidities, fusion level, bone quality) in patients over and under 65 years of age who underwent lumbar fusion surgery for degenerative lumbar disease. METHODS: One-hundred thirty-three patients with lumbar degenerative disease underwent lumbar fusion surgery between June 2006 and June 2007 and were followed for more than one year. Forty-eight (36.1%) were older than 65 years of age (group A) and 85 (63.9%) were under 65 years of age (group B). Diagnosis, comorbidities, length of hospital stay, and perioperative complications were recorded. The analysis of clinical outcomes was based on the visual analogue scale (VAS). Radiological results were evaluated using plain radiographs. Clinical outcomes, radiological outcomes, length of hospital stay, and complication rates were analyzed in relation to lumbar fusion level, the number of comorbidities, bone mineral density (BMD), and age. RESULTS: The mean age of the patients was 61.2 years (range, 33-86 years) and the mean BMD was -2.2 (range, -4.8 to -2.8). The mean length of hospital stay was 15.0 days (range, 5-60 days) and the mean follow-up was 23.0 months (range, 18-30 months). Eighty-five (64.0%) patients had more than one preoperative comorbidities. Perioperative complications occurred in 27 of 133 patients (20.3%). The incidence of overall complication was 22.9% in group A, and 18.8% in group B but there was no statistical difference between the two groups. The mean VAS scores for the back and leg were significantly decreased in both groups (p < 0.05), and bony fusion was achieved in 125 of 133 patients (94.0%). There was no significant difference in bony union rates between groups A and B (91.7% in group A vs. 95.3% in group B, p = 0.398). In group A, perioperative complications were more common with the increase in fusion level (p = 0.027). Perioperative complications in both groups A (p = 0.035) and B (p = 0.044) increased with an increasing number of comorbidities. CONCLUSION: Elderly patients with comorbidities are at a high risk for complications and adverse outcomes after lumbar spine surgery. In our study, clinical outcomes, fusion rates, and perioperative complication rates in older patients were comparable with those in younger populations. The number of comorbidities and the extent of fusion level were significant factors in predicting the occurrence of postoperative complications. However, proper perioperative general supportive care with a thorough fusion strategy during the operation could improve the overall postoperative outcomes in lumbar fusion surgery for elderly patients. PMID- 21286478 TI - Computed tomography fluoroscopy-guided selective nerve root block for acute cervical disc herniation. AB - OBJECTIVE: To analyze the clinical outcomes of computed tomography (CT) fluoroscopy-guided selective nerve root block (SNRB) for severe arm pain caused by acute cervical disc herniation. METHODS: The authors analyzed the data obtained from 25 consecutive patients who underwent CT fluoroscopy-guided SNRB for severe arm pain, i.e., a visual analogue scale (VAS) score of 8 points or more, caused by acute soft cervical disc herniation. Patients with chronic arm pain, motor weakness, and/or hard disc herniation were excluded. RESULTS: The series comprised 19 men and 6 women whose mean age was 48.1 years (range 35-72 years). The mean symptom duration was 17.5 days (range 4-56 days) and the treated level was at C5-6 in 13 patients, C6-7 in 9, and both C5-6 and C6-7 in 3. Twenty three patients underwent SNRB in 1 session and 2 underwent the procedure in 2 sessions. No complications related to the procedures occurred. At a mean follow up duration of 11.5 months (range 6-22 months), the mean VAS score and NDI significantly improved from 9 and 58.2 to 3.4 and 28.1, respectively. Eighteen out of 25 patients (72%) showed successful clinical results. Seven patients (28%) did not improve after the procedure, and 5 of these 7 underwent subsequent anterior cervical discectomy and fusion. CONCLUSION: CT fluoroscopy-guided SNRB may play a role as a primary conservative treatment for severe arm pain caused by acute cervical disc herniation. PMID- 21286479 TI - Neuroradiologic and neurophysiologic findings of neuralgic amyotrophy. AB - OBJECTIVE: Neuralgic amyotrophy (NA) is a distinct clinical syndrome that is characterized by the acute onset of shoulder and arm pain, weakness, and sensory loss. The purpose of this study was to assess the clinical characteristics of NA and to determine appropriate diagnostic modalities. METHODS: We reviewed the medical and radiologic records of 10 patients diagnosed with NA retrospectively. Neurophysiologic studies were performed in all patients and magnetic resonance neurography was performed in the last three patients. RESULTS: A total of 10 patients were enrolled in our study. All patients had clinical findings compatible with NA. The most common clinical presentation was severe shoulder pain and weakness in seven patients (70%). Neurophysiologic study results were abnormal in all patients. Brachial plexus magnetic resonance neurography showed that the affected brachial plexus showed a thickened and hyper-intense trunk. All patients were managed conservatively with analgesics and physical therapy. The pain and paralysis of all patients improved clinically within 6 months of the initiation of treatment. CONCLUSION: NA is a rare disease but the symptoms of NA can mimic those of other diseases. Neurophysiologic studies and magnetic resonance neurography are extremely useful tools for the diagnosis of NA. PMID- 21286480 TI - Remifentanil-propofol sedation as an ambulatory anesthesia for carpal tunnel release. AB - OBJECTIVE: This prospective study evaluated the use of continuous sedation using propofol and remifentanil when carpal tunnel release (CTR) was performed under local anesthesia. METHODS: We sedated 60 patients undergoing CTR using local anesthesia with remifentanil at loading and continuous doses of 0.5 ug kg(-1) and 0.05 ug kg(-1)min(-1), respectively, and propofol, using a target controlled infusion (TCI) pump set to a target of 2 ug mL(-1) (group A), or with the same drug doses except that the continuous remifentanil dose was 0.07 ug kg(-1)min(-1) (group B) or 0.1 ug kg(-1)min(-1) (group C). RESULTS: In group B, the levels of pain when local anesthetics were administered (p = 0.001), intraoperative pain (p < 0.001) and anxiety (p = 0.001) were significantly lower than those of group A. Furthermore, the incidence of adverse events, including desaturation (p < 0.001) and vomiting (p = 0.043), was significantly lower in group B than in group C. CONCLUSION: Continuous sedation using an appropriate dose of remifentanil and propofol can be used as safe, efficacious ambulatory anesthesia in cases of CTR under local anesthesia, performed using only 2 mL of local anesthetic, with a high degree of patient satisfaction. PMID- 21286481 TI - Cerebral aneurysm in the long fenestration at the middle portion of m1 segment. AB - We report a unique case of bilateral mirror image M1 aneurysms, one of which was an unruptured aneurysm arising from the proximal end of right middle cerebral artery fenestration with long loop and the other ruptured aneurysm from the contralateral side. We clipped ruptured aneurysm first and unruptured one in three months after the first operation. The difficulties of identifying this unusual vascular anomaly and possible problems during the surgery of an aneurysm at the site of fenestration are discussed with a review of the literature. PMID- 21286482 TI - A case of temporal intracerebral hemorrhage that presented with sudden bilateral hearing loss as the initial symptom. AB - A 57-year-old man presented to the outpatient department with sudden bilateral hearing loss. The otological examination suggested bilateral severe sensorineural hearing loss. After several hours, the patient complained of a headache and became drowsy. The brain computed tomography showed a 3 * 4 cm intracerebral hemorrhage (ICH) of the left temporal lobe. Surgery was performed and 34 days after the procedure the patient was discharged from the hospital with severe bilateral sensorineural hearing loss (SNHL). Temporal lobe ICH should be considered in the differential diagnosis of patients with sudden bilateral hearing loss, regardless of the other neurological symptoms. PMID- 21286483 TI - Fibrous dysplasia of the clivus. AB - Fibrous dysplasia (FD) of craniofacial structures is well documented, however, its involvement of the clivus is seldom described. We report a case of clival FD in a young man who presented with headache localized to the occipital area. The radiological studies revealed a monostotic disease confined to the clivus, with typical findings of hypointensity on magnetic resonance images and ground-glass density on computed tomography. The diagnosis of FD was confirmed on pathological examination of specimens taken through transsphenoidal surgery. The patient showed reduction of symptoms and no change of residual lesion on follow-up imaging taken 2.5 years later after surgery. This study includes clinical aspect, radiographic appearance, differential diagnosis and treatment strategy of this rare skull base lesion. PMID- 21286484 TI - Juvenile pilomyxoid astrocytoma in the opticohypothalamus. AB - Pilomyxoid astrocytoma (PMA) is a newly recognized variant of a pilocytic astrocytoma. This report describes a case of a pilomyxoid astrocytoma that occurred in the opticohypothalamus. The patient was a 18-year-old girl who complained decreased visual acuity and visual field over a period of two years. Magnetic resonance imaging (MRI) showed an irregular lobulated tumor with heterogeneous enhancement at the suprasellar region involving the hypothalamus. The mass was partially removed via the subfrontal approach. Its pathology was confirmed to be PMA. Adjuvant chemotherapy with cisplatin and vincristine was started following tumor resection. After four cycles, the mass showed a partial response to the chemotherapy. Although long-term outcome is yet to be determined, the administration of combined cisplatin and vincristine treatment seems to be an effective regimen for a pilomyxoid astrocytoma. PMID- 21286485 TI - Primary intramedullary spinal sarcoma : a case report and review of the current literatures. AB - Primary central nervous system (CNS) sarcomas are exceedingly rare, and, to the best of our knowledge, there has not yet been a report of intramedullary sarcoma. Here, we report a primary intradural intramedullary sarcoma of the spinal cord in a four-year-old boy who presented with low back pain and a radiculopathy involving both lower extremities. The tumor showed significant enhancement on magnetic resonance (MR) images due to its extreme vascularity. Gross total tumor removal was performed with microelectrical pulse recording, and the patient also received adjuvant radiotherapy and chemotherapy. After the operation, the patient's sensory deficits were improved. Because CNS dissemination is common, entire neuraxis evaluation is essential, although there was no evidence of dissemination in this case. The prognosis of primary CNS sarcoma is poor due to infiltrative nature and early CNS dissemination is common, and the treatment of choice is radical surgical resection. Adjuvant therapy is also beneficial with radiotherapy and chemotherapy. PMID- 21286486 TI - Traumatic atlantoaxial rotatory fixation with accompanying odontoid and c2 articular facet fracture. AB - Traumatic atlantoaxial rotatory fixation (AARF) with accompanying odontoid and C2 articular facet fracture is a very rare injury, and only one such case has been reported in the medical literature. We present here a case of a traumatic AARF associated with an odontoid and comminuted C2 articular facet fracture, and this was treated with skull traction and halo-vest immobilization for 3 months. After removal of the halo-vest immobilization, his neck pain was improved and his neck motion was preserved without any neurologic deficits although mild torticolis was still observed in closer inspection. PMID- 21286487 TI - Pyogenic spondylodiscitis after percutaneous endoscopic lumbar discectomy. AB - We reviewed 9 cases of pyogenic spondylodiscitis following percutaneous endoscopic lumbar discectomy (PELD). Microbiologic cultures revealed 6 causative organisms. Five patients were managed conservatively and four were treated surgically. The mean follow-up period was 20.6 months and the average length of hospitalization was 24 days. Radiological evidence of spinal fusion was noted and infection was resolved in all patients. Although PELD is a safe and effective procedure, the possibility of pyogenic spondylodiscitis should always be considered. PMID- 21286488 TI - Primary paravertebral low-grade fibromyxoid sarcoma. AB - The authors report a 58-year-old woman with low-grade fibromyxoid sarcoma primarily located in the right paravertebral area with extension to L4 neural foramen. The patient complained lower back pain with radiating pain along the posterolateral aspect of the right lower leg. She underwent subtotal surgical removal and Cyber Knife therapy. Diagnosis was made by strikingly characteristic microscopic appearance of a bland spindle cell sarcoma which contained numerous giant collagen rosettes and was also supported by immunohistological findings. The diagnostic image findings and literatures are reviewed and discussed. PMID- 21286489 TI - Cervical radiculopathy caused by vertebral artery loop formation : a case report and review of the literature. AB - Vertebral artery loop formation causing encroachment on cervical neural foramen and canal is a rare cause of cervical radiculopathy. We report a case of 61-year old woman with vertebral artery loop formation who presented with right shoulder pain radiating to her arm for 2 years. Plain radiograph and computed tomography scan revealed widening of the right intervertebral foramen at the C5-6 level. Magnetic resonance imaging and angiogram confirmed the vertebral artery loop formation compressing the right C6 nerve root. We had considered microdecompressive surgery, but the patient's symptoms resolved after conservative management. Clinician should keep in mind that vertebral artery loop formation is one of important causes of cervical radiculopathy. Vertebral artery should be visualized using magnetic resonance angiography in suspected case. PMID- 21286490 TI - Multiparametric MRI biomarkers for measuring vascular disrupting effect on cancer. AB - Solid malignancies have to develop their own blood supply for their aggressive growth and metastasis; a process known as tumor angiogenesis. Angiogenesis is largely involved in tumor survival, progression and spread, which are known to be significantly attributed to treatment failures. Over the past decades, efforts have been made to understand the difference between normal and tumor vessels. It has been demonstrated that tumor vasculature is structurally immature with chaotic and leaky phenotypes, which provides opportunities for developing novel anticancer strategies. Targeting tumor vasculature is not only a unique therapeutic intervention to starve neoplastic cells, but also enhances the efficacy of conventional cancer treatments. Vascular disrupting agents (VDAs) have been developed to disrupt the already existing neovasculature in actively growing tumors, cause catastrophic vascular shutdown within short time, and induce secondary tumor necrosis. VDAs are cytostatic; they can only inhibit tumor growth, but not eradicate the tumor. This novel drug mechanism has urged us to develop multiparametric imaging biomarkers to monitor early hemodynamic alterations, cellular dysfunctions and metabolic impairments before tumor dimensional changes can be detected. In this article, we review the characteristics of tumor vessels, tubulin-destabilizing mechanisms of VDAs, and in vivo effects of the VDAs that have been mostly studied in preclinical studies and clinical trials. We also compare the different tumor models adopted in the preclinical studies on VDAs. Multiparametric imaging biomarkers, mainly diffusion weighted imaging and dynamic contrast-enhanced imaging from magnetic resonance imaging, are evaluated for their potential as morphological and functional imaging biomarkers for monitoring therapeutic effects of VDAs. PMID- 21286491 TI - CT patterns of nodal disease in pediatric chest tuberculosis. AB - AIM: To highlight various patterns of nodal involvement and post treatment changes in pediatric chest tuberculosis based on contrast enhanced computed tomography (CECT) scans of chest. METHODS: This was a retrospective study consisting of 91 patients aged less than 17 years, who attended Paediatrics OPD of All India Institute of Medical Sciences with clinically diagnosed tuberculosis or with chest radiographs suggestive of chest tuberculosis. These patients had an initial chest radiograph as well as CECT of the chest and follow up imaging after 6 mo, and in some cases 9 mo, of completion of anti-tubercular treatment (ATT). CECT of these patients was reviewed for the location and extent of nodal involvement along with determination of site, size, enhancement pattern and calcification. RESULTS: Enlargement of mediastinal or hilar lymph nodes was found in 88/91 patients (96.7%), with the most common locations being paratracheal (84.1%), and subcarinal (76.1%). The most common pattern of enhancement was found to be inhomogenous. The nodes were conglomerate in 56.8% and discrete in 43.2%. In addition, perinodal fat was obscured in 84.1% of patients. In the post treatment scan, there was 87.4% reduction in the size of the nodes. All nodes post-treatment were discrete and homogenous with perinodal fat present. Calcification was found both pre- and post-treatment, but there was an increase in incidence after treatment (41.7%). There was hence a reduction in size, change in enhancement pattern, and appearance of perinodal fat with treatment. CONCLUSION: Tubercular nodes have varied appearance and enhancement pattern. Conglomeration and obscuration of perinodal fat suggest activity. In residual nodes decision to continue ATT requires clinical correlation. PMID- 21286492 TI - Content-based image retrieval applied to BI-RADS tissue classification in screening mammography. AB - AIM: To present a content-based image retrieval (CBIR) system that supports the classification of breast tissue density and can be used in the processing chain to adapt parameters for lesion segmentation and classification. METHODS: Breast density is characterized by image texture using singular value decomposition (SVD) and histograms. Pattern similarity is computed by a support vector machine (SVM) to separate the four BI-RADS tissue categories. The crucial number of remaining singular values is varied (SVD), and linear, radial, and polynomial kernels are investigated (SVM). The system is supported by a large reference database for training and evaluation. Experiments are based on 5-fold cross validation. RESULTS: Adopted from DDSM, MIAS, LLNL, and RWTH datasets, the reference database is composed of over 10 000 various mammograms with unified and reliable ground truth. An average precision of 82.14% is obtained using 25 singular values (SVD), polynomial kernel and the one-against-one (SVM). CONCLUSION: Breast density characterization using SVD allied with SVM for image retrieval enable the development of a CBIR system that can effectively aid radiologists in their diagnosis. PMID- 21286493 TI - Breast and lung metastasis from pancreatic neuroendocrine carcinoma. AB - Pancreatic neuroendocrine tumors (PNETs) are an uncommon malignancy, accounting for a small percentage of all pancreatic malignancies. Due to their insidious course, most PNETs present with metastatic disease. Although reports in the literature describe PNET metastasis to the liver, lung and brain, to date there are no reports of stage IV disease involving the breast. Moreover, the lack of consensus regarding classification and treatment of this entity leaves practitioners without standards of practice or a firm base from which to formulate prognosis. In this report, the case of a previously healthy 51-year-old woman with stage IV PNET is examined. After combined neoadjuvant therapy with 5 fluorouracil, carboplatin, etoposide and radiation, surgical resection revealed metastatic PNET to the breast and lung, with no microscopic evidence of residual disease within the pancreas. An extensive analysis of the presentation, diagnosis, imaging modalities, treatment options, and prognosis is included in the discussion. As demonstrated by our review, there is a need for further studies to delineate inconclusive evidence with respect to subtype classification, treatment and prognosis of PNETs. PMID- 21286494 TI - Gallstone in jejunal limb with jejunocolonic fistula 10 years after Roux-en-Y choledochojejunostomy. AB - Roux-en-Y choledochojejunostomy is a common biliary reconstruction procedure. The collection of gallstones in the jejunal limb is a rare complication. Here we present a case of a 61-year-old Chinese female who received Roux-en-Y choledochojejunostomy 10 years ago. Diagnosis of recurrent bile duct stones accompanying infection was made before operation. She also had an abdominal mass which was possibly an intussuscepted colon or a huge fecolith. At laparotomy, an oval stone (5 cm in diameter) and 3 smaller multifaceted stones (2 cm in diameter) were found in the jejunal limb. A fistula between this jejunum and colon was also found. Although the typical manifestations of diarrhea were present, the diagnosis of a biliary colonic fistula was missed before operation. Partial colectomy was performed with the fistulous opening repaired. A T-tube was left in the jejunal limb and the mesocolon aperture was enlarged and revised. Her postoperative convalescence was uneventful. We report this case hoping to sharpen our diagnostic acumen. PMID- 21286495 TI - Does timing of alcohol administration affect sleep? AB - STUDY OBJECTIVES: To explore the time of day effects of alcohol on sleep, we examined sleep following alcohol administered at four times of day and three homeostatic loads during a 20-hr forced desynchrony (FD) protocol. PARTICIPANTS: Twenty-six healthy young adults (21-25 yrs) were studied. DESIGN: Participants were dosed at 4 clock times: 0400 (n = 6; 2 females), 1600 (n = 7; 4 females), 1000 (n = 6; 1 female) or 2200 (n = 7; 2 females). Participants slept 2300 to 0800 for at least 12 nights before the in-lab FD study. Double blind placebo and alcohol (vodka tonic targeting 0.05g% concentration) beverages were each administered three times during FD at different homeostatic loads: low (4.25 or 2.24 hrs awake), medium (8.25 or 6.25 hrs awake), high (12.25 or 10.25 hrs awake) in the 0400 and 1600 or 1000 and 2200 groups, respectively. Sleep was staged and subjected to spectral analysis. MEASUREMENTS AND RESULTS: Breath Alcohol Concentration (BrAC) confirmed targeted maximal levels. At bedtime, BrAC was 0 in the low and medium homeostatic load conditions; however, at high homeostatic load, BrAC was still measurable. Spectral characteristics of sleep were unaffected with alcohol at any time of day. Few alcohol related changes were seen for sleep stages; however, with alcohol given at 0400 at a high homeostatic load there was an increase in wake. CONCLUSIONS: These data lend support to the idea that alcohol may be disruptive to sleep; however, our findings are inconsistent with the idea that a low dose of alcohol is a useful sleep aid when attempting to sleep at an adverse circadian phase. PMID- 21286496 TI - The prospects for enhancing sleep across the lifespan. PMID- 21286497 TI - Macrophage migratory inhibitory factor (MIF) may be a key factor in inflammation in obstructive sleep apnea. AB - STUDY OBJECTIVES: This study investigated the 24-hour variation of macrophage migratory inhibitory factor (MIF), a cytokine which induces insensitivity to the anti-inflammatory effects of glucocorticoids, in patients with untreated obstructive sleep apnea (OSA) as compared to healthy adults with no OSA. PARTICIPANTS: Fifty-three men and women with OSA (mean apnea/hypopnea index [AHI] = 39.5) and 24 healthy adults (Non-OSA, AHI = 5.1). MEASUREMENTS: Over a 24-h period, blood was collected every 2 h for MIF and cortisol determination. The following night, sleep was monitored with polysomnography. RESULTS: MIF showed a strong 24-h variation, with a peak at 04:00 and a nadir at 22:00. Patients with OSA showed 25% higher MIF levels (area under the curve) over 24 h than healthy controls. Furthermore, MIF levels were significantly associated with AHI and total arousal index (ArI), even after adjusting for BMI. Cortisol showed the expected 24-h variation (peaking at 06:00), but no cortisol differences were observed between OSA and Non-OSA groups. CONCLUSION: MIF is elevated in patients with OSA and is related to OSA severity, while there was no difference in cortisol levels. MIF is a pro-inflammatory cytokine which additionally inhibits the anti-inflammatory effects of glucocorticoids. Thus, elevated MIF levels in OSA may contribute to elevated inflammation. PMID- 21286498 TI - Predictors of the trajectories of self-reported sleep disturbance in men with prostate cancer during and following radiation therapy. AB - STUDY OBJECTIVES: To examine how self-reported ratings of sleep disturbance changed from the time of the simulation visit to four months after the completion of radiation therapy (RT) and to investigate whether specific patient, disease, and symptom characteristics predicted the initial levels of sleep disturbance and/or characteristics of the trajectories of sleep disturbance. DESIGN: Prospective longitudinal study. SETTING: Two radiation therapy centers. PATIENTS: Patients (n = 82) who underwent primary or adjuvant RT for prostate cancer. MEASUREMENTS AND RESULTS: Changes in self-reported sleep disturbance were measured using the General Sleep Disturbance Scale (GSDS). Depressive symptoms were assessed using the Center for Epidemiologic Studies-Depression Scale. Trait and state anxiety were measured using the Spielberger State-Trait Anxiety Inventory. Hierarchical linear modeling was used to answer the study aims. Self reported sleep disturbance increased during the course of RT and then decreased following the completion of RT. Predictors of higher levels of sleep disturbance included younger age, higher levels of trait anxiety, higher levels of depressive symptoms, and higher levels of sleep disturbance at the initiation of RT. CONCLUSIONS: Sleep disturbance is a significant problem in patients with prostate cancer who undergo RT. Younger men with co-occurring depression and anxiety may be at greatest risk for sleep disturbance during RT. PMID- 21286500 TI - Prevention of Smoking: It's Our Business. PMID- 21286501 TI - [Not Available]. PMID- 21286499 TI - Peripheral blood leukocyte gene expression patterns and metabolic parameters in habitually snoring and non-snoring children with normal polysomnographic findings. AB - BACKGROUND: Children who snore but do not have gas exchange abnormalities or alterations of sleep architecture have primary snoring (PS). Since increasing evidence suggest that PS may be associated with morbidity, we hypothesized that assessing genome-wide gene expression in peripheral blood leukocytes (PBL) will identify a distinct signature in PS children. METHODS: Children (aged 4-9 years) with and without habitual snoring and a normal PSG were designated as either PS or controls. Whole genome expression profiles of PBL and metabolic parameters in 30 children with PS and 30 age-, gender-, ethnicity-, and BMI-matched controls were compared. Pathway-focused gene network analysis of the PBL transcriptome was performed. Metabolic parameters were measured in an independent follow-up cohort of 98 children (64 PS and 34 controls) to evaluate the computationally derived findings. RESULTS: PS was not associated with a distinct transcriptional signature in PBL. Exploratory functional network analysis of enriched gene sets identified a number of putative pathways-including those mapping to insulin signaling, adipocyte differentiation, and obesity-with significant alterations in glucose metabolism and insulin sensitivity emerging in the follow-up cohort of children with PS, but no differences in lipid profiles. CONCLUSIONS: PS children do not exhibit global perturbations in their PBL transcriptional response, suggesting that current normative PSG criteria are overall valid. However, subtle differences in functionally coherent pathways involved in glycemic homeostasis were detected and confirmed in a larger independent pediatric cohort indicating that PS may carry increased risk for end-organ morbidity in susceptible children. PMID- 21286502 TI - Employment Physicals 'Should be Forbidden'. PMID- 21286503 TI - Revised DDST Too Time Consuming for FPs? PMID- 21286504 TI - A better test for ectopic pregnancy? PMID- 21286505 TI - New 'dark age' of cervical cancer. PMID- 21286506 TI - Why vitamin e? PMID- 21286507 TI - 'Dangerous' treatment for infant hydrocele. PMID- 21286508 TI - Practical CME, Please! PMID- 21286509 TI - Otitis media: an unresolved problem. PMID- 21286510 TI - Training for CPR: A Community Service. PMID- 21286511 TI - What about nurses? PMID- 21286512 TI - Factors affecting patients' compliance with doctors' advice. AB - To what extent, and with what success, are family physicians advising patients to diet, exercise and reduce smoking? A study of 24 family physicians in Nova Scotia and New Brunswick and 66 patients with cardiovascular problems showed that two thirds of the patients received some such advice during the audiotaped visit. Of those who did receive such advice, 29% reported at a home interview ten days later that they remembered the advice. The doctor's behavior in the interaction was found to influence the patient's memory of the advice. However, the patient's attitudes and problems were the only variables shown to affect whether or not he followed the advice. PMID- 21286513 TI - Chronic home care in ontario: five year follow up. AB - The first 218 patients admitted to the Kingston Chronic Home Care program (CHC) after its inception in October, 1975 were followed to March 31, 1981. Their average number of admissions to CHC was 2.3, and they averaged 16 months in CHC. Twenty-eight percent died before any admission to a longterm care institution; 44% were admitted to such an institution at or after last separation from CHC. The study suggests that CHC results in a significant degree of prevention or delay of admission to institutions. PMID- 21286514 TI - High risk pregnancy: detection and management. AB - Risk in pregnancy relates to events which lead to perinatal morbidity and mortality. Numerous risk scoring systems have been devised to bring attention to risk factors so that problems can be prevented, identified and treated. However, by carrying out very few fundamental assessments at regular antenatal office visits: checking blood pressure, testing urine for protein, measuring the symphysis to fundus height and carefully establishing the expected date of confinement during the first trimester, the principal causes of perinatal morbidity and mortality-intrauterine growth retardation, prematurity, congenital anomalies, infection, abruptio placentae and meconium aspiration-can be identified and treated. Appropriate perinatal management of the very premature fetus/neonate (less than 34 weeks gestation) is a critical factor which will influence outcome. Whenever possible the mother should be transferred to a centre equipped and staffed for all necessary intrapartum and neonatal care, to minimize the risk of adverse outcome: postnatal transfer of the deteriorating, sick, small neonate is at best hazardous. PMID- 21286515 TI - Optimal prenatal care. AB - Optimal prenatal care begins before conception, when health habits can be reviewed. The most important task of the initial prenatal assessment is establishing dates. Ongoing assessments should emphasize measurement of symphisis to fundus height, maternal nutrition and screening, especially for urinary tract infection and gestational diabetes. Prenatal care is an excellent opportunity for patient education and involvement of the family. Good prenatal care is today's best health investment. PMID- 21286516 TI - Pregnancy and psychological preparation for parenthood. AB - Recent evidence suggests that pregnancy is a normal developmental period requiring psychological adaptation by the new parents. This period involves upheavals in emotions, relationships, values and roles which demand considerable attention. Studies have shown that unsuccessful resolution of these upheavals has been associated with difficulties of pregnancy and delivery, postpartum depression and child abuse and neglect. The family physician is in a key position to observe adaptations to pregnancy, to facilitate such adaptations and to intervene when necessary. PMID- 21286517 TI - Are your patients burning out? AB - The term burnout came into the literature in the 1970s. Since then it has become a popularized and misunderstood concept. In this article burnout is seen to be an interaction between idealistically high personal expectations and a willingness to sacrifice personal needs to the workplace, with unrealistic expectations within the work environment. Physical, psychological and occupational symptoms accompany this syndrome, which must be differentiated from clinical depression. Suggestions for treatment include changes at both the personal and organizational level. PMID- 21286518 TI - Falls in children. AB - One-third of all injuries seen at The Hospital for Sick Children's emergency department in 1977 resulted from falls; 10% of the children who had fallen were admitted. Falls from heights and those from the same level were of equal proportion (49%). Superficial injuries were most common. Family physicians may help prevent injuries due to falls by giving parents anticipatory guidance about their child's developmental stages and the risk situations that may be encountered at each level of development. PMID- 21286519 TI - Noise injury: etiology and prevention. AB - Exposure to noise might be responsible for a wide and varied spectrum of physical and mental morbidity, although many of the claims of cause and effect relationship are controversial and unproven. The etiological relationship between noise and high frequency hearing loss is, however, well documented. While noise induced hearing loss is considered to be primarily an occupational problem, current leisure time activities have created the potential for it to become more common in the community at large. Once developed, this hearing loss is permanent and cannot be influenced by therapy. Noise-induced hearing loss is almost completely preventable and the family physician has an important responsibility for primary and secondary prevention, whether the noise source is in the workplace or in some other location. PMID- 21286520 TI - Electrical contact injuries. AB - Electrical contact injuries result in death and irreparable damage in electrical system workers. The pattern of injury is different from other burns, and younger employees are the most at risk. Two factors cause most injuries: unsafe work practice or defective equipment. Primary prevention lies beyond the scope of the medical practitioner, but secondary and tertiary prevention provide some opportunity to modify the devastation of these injuries. Secondary prevention involves education of the work force to act promptly in aiding an injured fellow worker; tertiary prevention usually involves rehabilitation of an amputee. PMID- 21286521 TI - Screening for carcinoma of the colon: a family practice perspective. AB - Carcinoma of the colon is the second commonest malignancy in both sexes in North America. With little hope for a suitable method of primary prevention, physicians are forced to look for an effective secondary preventive technique. Through a collaborative effort between the physician and family practice nurse, an effective protocol for screening was developed and implemented on 355 patients aged over 40. Of these, 17 were positive. Ten of those were true positive and seven false positive. One false negative was found, but no carcinoma has been found to date-the positive patients have polyps, diverticular disease or hemorrhoids. In view of increasing evidence for the polyp-cancer sequence, this finding may be significant. Widespread use of Hemoccult II in this fashion will clarify the usefulness of this test. PMID- 21286522 TI - The family doctor and the prevention of suicide. AB - Suicide rates are rising almost everywhere in the west; 3,500 Canadians currently take their lives each year. The causes are complex: conditions in society interact with individual life situations as well as with emotional disturbance, particularly depression. The family doctor has a role to play at primary, secondary and tertiary levels of prevention. As a group, doctors can press for social action aimed at influencing conditions rooted in society, but doctors act most effectively in their own offices when they routinely consider depression and suicide potential in their patients. The article suggests how this may be done and how suicidal thinking and behavior may be managed. PMID- 21286523 TI - The family physician and health promotion: do-gooding or really doing well? AB - Conventional health promotion efforts, whether attempted by the individual physician or by community-wide health charities, suffer from a lack of creativity, timeliness, and an awareness of the principles of effective advertising. The difference between do-gooding and really doing well lies in carefully identifying the promoters of adverse health behavior (such as cigaret advertisers), studying their success, and-on an individual and community-wide basis-counteracting their influence by investing time and money in individualized, positive health strategies. PMID- 21286524 TI - Benzodiazepines: uses and abuses. AB - Anxiety is ubiquitous in our society. Although non-drug treatments should always be used, benzodiazepines are the drugs of choice when drugs are indicated. In double blind studies the benzodiazepines are superior to placebo in controlling acute anxiety and autonomic over-activity in psychosomatic disorders. They are also useful in a variety of other conditions such as the treatment or prevention of muscle spasms and pain, status epilepticus, drug withdrawal, stage 4 sleep disorders and akathisia. However, benzodiazepines have many side effects, produce tolerance, dependence and withdrawal syndromes and should be used cautiously. There is no evidence that benzodiazepines are useful in chronic anxiety. The short-acting drugs are safer with elderly patients and those with hepatic disease or hypoalbuminemia. Small amounts of prescription benzodiazepines should be used for the shortest possible period. Educational programs concerning the proper use of benzodiazepines should be increased. PMID- 21286525 TI - Residency training in family practice: how many residents, faculty and rotations? PMID- 21286527 TI - Smoking in Hospitals: Should it be Allowed? PMID- 21286526 TI - Residency programs in family practice: a response. PMID- 21286528 TI - A New Chapter in CFPC History: Certification in Emergency Medicine. PMID- 21286529 TI - The CMA and Family Doctors: Shout Louder. PMID- 21286530 TI - [Not Available]. PMID- 21286531 TI - [Not Available]. PMID- 21286532 TI - MDs Should Promote A 'Healthy Lifestyle'. PMID- 21286533 TI - Nurses 'leaders in geriatric care'. PMID- 21286535 TI - Imferon warning. PMID- 21286534 TI - Treating cellulitis. PMID- 21286536 TI - Incorrect statement. PMID- 21286537 TI - An Acne Therapy That's 'Old as Man'. PMID- 21286538 TI - Leave the R in mrs. PMID- 21286539 TI - Acute chest pain: emergency evaluation and management. AB - Since cardiovascular and pulmonary disorders have significant morbidity and mortality, triage of patients who complain of chest pain is paramount. The less sophisticated the triage system, the more important the protocol should be to have these patients evaluated immediately. History and physical are still the most important diagnostic tools; information should be gathered from all available sources. Advanced cardiac life support training is most useful. Eight diagnostic classifications are described, together with the distinctions of onset, duration, location, radiation, precipitating and relieving factors, character and associated symptoms. The protocol for initial management is outlined, emphasizing coincident management wherever possible. PMID- 21286540 TI - Hemodynamic monitoring in the critically ill. AB - Hemodynamic monitoring gives early warning of changes in a critically ill patient's condition. Accuracy is essential; for example, a blood pressure cuff is inaccurate at low pressures. Hospitalized adults will usually have a higher central venous pressure, so a CVP less than 4 cm H(2)O may indicate hypovolemia. Correlation between CVP level and blood volume is very poor in critically ill patients, so measurement of pulmonary capillary wedge pressure becomes essential. Measurement of cardiac output eliminates the need for arterial and mixed venous blood samples, and can be valuable in decision-making. Calculation of vascular resistance can also be very important in management of the critically ill. With today's facilities, routine clinical assessment is no longer adequate care for these patients. PMID- 21286541 TI - Trauma: a preventable disease. AB - While driver restraints have reduced fatalities in those provinces which have enacted seatbelt legislation, motor vehicle accidents still account for 80% of all deaths in those aged 15-24. Prevention is paramount, but better prehospital care could prevent much morbidity and mortality. This article describes seven years' experience in British Columbia with emergency health services, including the organization of an ambulance service, construction of emergency vehicles, training of emergency medical assistants, operation of air ambulance services, and education of the public. PMID- 21286542 TI - Nutrition for the critically ill. AB - Standard IV therapy for a critically ill patient is a form of semi-starvation. The rate of complications and mortality can be as much as 50% higher in malnourished patients. Assessing patients' nutritional state as it was before the surgery or illness by asking about eating patterns indicates how severely a patient may react to further malnourishment. Even more important is assessment of the patient's immune defense system. Rate of hypermetabolism in the critically ill will indicate the amounts of nutrients needed and when. Enteral feeding is best, where possible. The physician must know the exact contents of whatever liquid diet is being used. If parenteral nutrition is used, stringent aseptic technique must be employed. PMID- 21286543 TI - Dental emergencies. AB - Emergency dental problems can result from trauma, dental pathology, or from dental treatment itself. While the physician can treat many instances of dental trauma, the patient should see a dentist as soon as possible so that teeth can be saved. Emergency treatment of dental pathology usually involves relief of pain and/or swelling. Bleeding is the most frequent post-treatment emergency. The physician should be able to make the patient comfortable until definitive dental treatment can be available. In many areas dentists have set up 'on-call' systems; doctors in small communities may find these facilities particularly useful. PMID- 21286544 TI - Poisoning: effective clinical intervention. AB - Poisoning accounts for 40-60% of suicides, is the commonest medical emergency in small children, and an important source of occupational injury. Prevention of unintentional poisoning involves primarily education of parents. In intervention, the patient-not the poison-must be treated. Self-poisoners require supportive but firm handling. Treatment is directed towards prevention of further absorption, removal of absorbed poison, symptomatic or supportive therapy, and administration of systemic antidotes. Careful attention should be paid to the physician's legal responsibilities in cases of poisoning. PMID- 21286545 TI - Non-narcotic relief of acute migraine. AB - While many drugs have recently been found useful in migraine prophylaxis, the abortive treatment of severe acute migraine continues to rest heavily on ergotamines and narcotic analgesics. A small dose of intravenous chlorpromazine may provide an alternative. It is relatively safe, gives exceedingly prompt relief, and has minimal addictive potential. PMID- 21286546 TI - Lactose intolerance and the irritable colon. AB - Symptoms of lactase deficiency include nausea, abdominal pain, distension, bloating and diarrhea after ingesting foods which contain lactose. Lactose intolerance and bowel motility disorders have similar symptoms, and people with irritable bowel syndrome and unexplained abdominal pain may have lactose intolerance. A definite diagnosis can be made by detecting hydrogen in the breath after a lactose load, by lactase assay from a small bowel biopsy specimen or by lactose intolerance testing. Lactose intolerance is more likely in blacks, Asians and South Americans. If lactose intolerance is present without concomitant bowel motility disorder, the response to a lactose free diet is excellent. PMID- 21286547 TI - The stages of schizophrenia and their management. AB - Schizophrenia is a common and chronic disease with acute exacerbations. The chronic form of the disease results in a long-standing thought disorder and psychosocial impairment. The fluctuating nature of the disease results in a variety of presentations, for which the physician must choose the appropriate biological, psychological and social therapies. The stages of schizophrenia are described in terms of the patient's reaction to his symptoms and disabilities: anxiety, denial, ambivalence, depression and acceptance. The treatment plan must be modified according to these stages and the patient's circumstances. PMID- 21286548 TI - Ventricular defibrillation: problems of electrical management. AB - Correction of anoxia, acidosis and intracellular potassium derangement coupled with ECG monitoring is critical to the successful treatment of ventricular fibrillation. Many reports of problems with cardiac defibrillators necessitate review of the energy levels required to achieve an optimum therapeutic effect with electrical countershock. Factors influencing therapeutic threshold, particularly the dose per body weight and adverse side effects of electro-shock, are discussed. Many experts now believe that the maximal delivered energy for each single delivery should not be higher than 250-300 joules. PMID- 21286549 TI - A clinical note. PMID- 21286550 TI - What would you have done? AB - So many situations in family medicine will not fit the nice, neat formulae of history, physical, findings and treatment that are presented in traditional 'grand rounds'. Frequently, the most logical, or the most medically sensible course of action is not possible. The family physician is left negotiating a situation in which there is not necessarily a 'right' way to act. The College's Self-Evaluation Program Committee has prepared a series of such cases to invite response from family physicians on how they would handle such situations. Responses, with comments from the presenter of the case, will be published in upcoming issues. Readers are invited to submit similar cases from their own experience. PMID- 21286551 TI - Comment: Should FPs or Emergency Medicine Specialists Staff Hospital Emergency Departments? PMID- 21286552 TI - Problems playing god. PMID- 21286553 TI - [Not Available]. PMID- 21286554 TI - CME's Hidden Benefits. PMID- 21286557 TI - Unrecognized injury: is negligence involved? PMID- 21286558 TI - An asthma rehabilitation program for families. AB - The Family Asthma Rehabilitation Program of the Ontario Crippled Children's Centre is for children with severe asthma whose symptoms have not previously been well controlled. The severity of asthma symptoms on admission to the program was assessed for 75 children and the effects of the treatment were determined by means of severity ratings at time of discharge. Follow up interviews with families of children who graduated from the program between 1973 and 1978 suggest that the children remained well controlled, and parents were able to manage their children with minimized anxiety and stress. The issue of lack of continuity in the longterm care of the children was raised by many families: implications for the centre and for family physicians are considered. PMID- 21286559 TI - Industrial lung cancer. AB - There are many known chemical and physical causes of industrial lung cancer. Their common feature is a long latent period-usually ten to 40 years-between initial exposure to the carcinogen and clinical recognition of the lesion. Occupationally induced lung cancer is indistinguishable from lung cancer of unknown etiology or that caused by cigaret smoking. Smoking alone is responsible for a very large proportion of all lung cancer and it potentiates the effect of most other carcinogens. Most cases of lung cancer in the next 20-30 years will be the result of exposures which have already occurred. In these cases, early diagnosis of pre-invasive resectable lesions offers the only hope for prolonging life. PMID- 21286560 TI - Diagnosis and management of tuberculosis. AB - The incidence of pulmonary tuberculosis in technically advanced and economically well-developed countries is decreasing, and the disease has become more subtle in presentation. In a recent study from British Columbia, about half the deaths from tuberculosis were diagnosed at autopsy. Most of these patients had died in hospital and their mean duration of stay was 14.5 days. The chemotherapeutic agents available today can cure most cases and prevent further spread of infection. The appropriate use of chemoprophylaxis can substantially reduce the size of the infected pool at risk of developing tuberculosis. PMID- 21286561 TI - Xanthines in respiratory diseases. AB - Xanthines have been widely used for almost 50 years to treat bronchospastic conditions. They have a number of pharmacological properties, but the clinical applications are limited as bronchodilators. Current applications include intravenous preparations for acute asthma and prophylactically for other respiratory conditions that have bronchospasm as a common denominator. Sustained release preparations provide longterm, smooth plasma concentration levels. With easily performed and reliable blood levels, the risk of toxic, occasionally fatal side effects can be minimized. Not following patients with serial blood determinations of theophylline is almost inexcusable. A better knowledge of pharmacokinetics has established comprehensive guidelines, in particular, to its use in different clinical situations like pulmonary edema or liver failure, as well as its interaction with other drugs. PMID- 21286562 TI - Allergic rhinitis. AB - Allergic rhinitis is the result of an immediate hypersensitivity immune response of the nasal mucosa to one or more allergens. Clinical features may be indistinguishable from non-allergic rhinitis. Accurate diagnosis demands specialized laboratory investigations, meticulous history and careful physical examination. Management includes control of allergen and irritant exposures, pharmacotherapy and immunotherapy. Recent development of intranasal corticosteroid aerosols has significantly reduced morbidity. Modified allergens for immunotherapy show promise but require further study. PMID- 21286563 TI - Topical treatment of allergic rhinitis. AB - Topical medications have dramatically changed the treatment of rhinitis. While systemic treatment is often more potent, topical treatment has fewer side effects. However, topical preparations also have side effects which should be considered when treating rhinitis. Topical steroids are potent anti inflammatories but may cause nasal bleeding; sodium cromoglycate improves allergic and general inflammation but is less potent than steroids. Topical decongestants are beneficial for short-term use when there is nasal obstruction or copious discharge, but can cause damage to nasal epithelium or atrophy and dryness of the nasal mucous membrane after years of use. Anticholinergic spray is effective when watery discharge predominates, and saline is helpful when there is nasal dryness. Treatment of associated conjunctivitis is also discussed. PMID- 21286564 TI - Farmer's Lung Disease. AB - Farmer's lung disease (FLD) is a hypersensitivity pneumonitis secondary to the inhalation of moldy hay spores. Its prevalence is likely underestimated despite the fact it may result in significant acute and chronic respiratory disability. The immunologic mechanisms are best explained as Gell and Coombs Type III & IV reactions. FLD is usually recognized by history and appropriate laboratory confirmation. Therapy requires removal of the patient from the offending antigens, although corticosteroids may be useful for constitutional symptoms. PMID- 21286565 TI - Chronic cough in childhood. AB - Persistent cough in children is a symptom, and the cause should be ascertained. Reactive airways disease is the most common reason for chronic cough in children over three to six months of age, especially at night. Under three months, the cause is likely to be more serious. Cough often disturbs parents more than the child, and physicians should consider parents' need for sleep and relief when deciding whether or not to prescribe cough suppressants. Investigations depend on the child's age, the history, duration and severity of the cough. A cause for the cough should always be sought. PMID- 21286566 TI - Toxic Shock Syndrome: A Family Physician's Perspective. AB - Although similar cases have been reported as far back as 1927, the term toxic shock syndrome was coined in 1978 to describe an acute fever involving Staph. aureus. The reported mortality rate in Canada is 3.8%, but may be much higher. Association with tampon use was made in 1980, but is still unclear. Treatment remains supportive and is aimed at reducing risk of recurrence, until the role of the exotoxin can be explained. This article reviews reported cases to date, listing diagnostic criteria, signs and symptoms. A high index of suspicion for this new syndrome is recommended. PMID- 21286567 TI - Genital herpetic infection: a family practice perspective. AB - Several major breakthroughs have occurred in our understanding of the epidemiology, immunology and biological behavior of the human herpes virus I and II. The family physician, however, is still confronted with four basic clinical situations: patients who present with a genital erosion or ulcer, affected patients in the reproductive age group, patients who ask if herpes causes cervical cancer, and patients who are very troubled by endless recurrences. As syphilitic chancre is becoming rare, the family physician has to recognize the increasing importance of herpes viruses in the etiology of the genital erosion ulcer syndrome to acquire the clinical and laboratory skills to make that distinction. The prevention of neonatal disease is now possible in the majority of cases provided that pregnancies at risk are identified. Adequate virological surveillance should make it possible to virtually eliminate the disease. The evidence for the oncogenecity is circumstantial. Potential intra- and interpersonal effects of the disease are outlined. PMID- 21286568 TI - Medical screening of sports divers. AB - Sports divers encounter heavy physical exertion in a cold, stressful environment. They must also pass rapidly through large, ambient pressure changes. These stresses demand that the diver be emotionally and physically fit, and able to perform maneuvers to equalize internal and external pressures. Medical screening of sports diving candidates requires that the examiner has a knowledge of diving and the stresses encountered by the sports diver. PMID- 21286569 TI - 'The flu'-or an allergen? AB - This patient was initially diagnosed as having the flu. He was given two courses of antibiotics but became progressively more ill. He was extensively investigated in hospital, but the diagnosis could have been made from his history. This was confirmed later with further exposure. PMID- 21286570 TI - The seemingly trivial complaint. AB - A patient presented to his family physician with a sore shoulder. At first his complaint seemed insignificant, and little appeared wrong. However, his family physician had known him for 20 years, and recalled that he was a 'non complainer'. A more thorough examination revealed dullness on percussion over the right lower lung, and further investigation showed that the patient had malignant non-Hodgkin's lymphoma. He was given chemotherapy, after which he went into complete remission. The family physician noted that the seriousness of the disease could easily have been missed if he had been unfamiliar with his patient's uncomplaining personality. PMID- 21286571 TI - 'For the public good': early birth control clinics in Canada. PMID- 21286572 TI - Training physicians to practice in remote canadian communities. AB - Of 31 hospital administrators from small northern Ontario hospitals, 20 indicated in a survey that their areas need more doctors. Of the 183 doctors practicing in these areas, 47% do not have local bacteriology services, 34% do not have blood gas analysis available, and 23% do not have a local physiotherapist. Of the 24 hospitals where surgery is done, only 16 have specialist surgeons on staff. Twenty-nine of the hospitals treat obstetrical cases, but only two have obstetricians; similarly, 29 of the hospitals treat myocardial infarction but only two have internists on staff. More younger general physicians are tending to have extra training in anesthesia. Only one hospital has a pediatrician. If general physicians are to care for patients in the absence of consultant back-up, they will need extra training. The University of Western Ontario is beginning a third year family medicine fellowship in an attempt to meet this need. PMID- 21286573 TI - Family Medicine: Whose Discipline is it Anyway? PMID- 21286574 TI - [Not Available]. PMID- 21286575 TI - [Not Available]. PMID- 21286576 TI - Difficulty of Assessing TB Patients' Infectivity. PMID- 21286577 TI - Diet and otitis media. PMID- 21286578 TI - OB/GYN training. PMID- 21286579 TI - Black stump to ivory tower: a personal view of research in general practice. AB - This article describes the author's own voyage of discovery in research, from the curiosity of his medical school days, through the isolation of general practice in the Australian outback, through development of a major survey, to participation in the formulation of the International Classification of Health Problems in Primary Care. PMID- 21286580 TI - Chronic facial pain: a clinical approach. AB - Facial pain is a common presenting complaint requiring patience and diagnostic acumen. The proliferation of eponyms attached to various syndromes complicates the subject. The most frequent cause of pain is likely to be muscle spasm in masticatory or temporalis muscles. This article presents a rank order for the common causes of facial pain that present diagnostic difficulty, such as temporomandibular joint pain, trigeminal neuralgia, giant cell arteritis, and post-herpetic neuralgia. PMID- 21286581 TI - Recognition and management of threatened stroke. AB - Completed stroke may often be prevented by early recognition and appropriate management of the stroke-threatened patient. About 80% of strokes are ischemic, the remainder hemorrhagic. Roughly half of ischemic strokes are heralded by transient ischemic attacks (TIA). The clinical picture of TIA depends upon which part of the brain is involved. The investigation of such patients is outlined, together with current approaches to medical and surgical therapy. Intracerebral hemorrhage rarely provides any advanced warning, but occasionally subarachnoid hemorrhage may be preceded by a warning leak, the clinical picture of which is described. PMID- 21286582 TI - Complications of therapy in Parkinson's disease. AB - Despite several more effective combinations, the incidence of disability and intractable complications from levodopa therapy for Parkinson's disease is unchanged. Many of these appear to be related to the development of denervation hypersensitivity as well as to drug tolerance and loss of effect. They include dyskinesia, 'wearing off' phenomenon, 'on-off' phenomenon, and various psychic changes. More current forms of therapy with bromocriptine and drug holidays are described, emphasizing methods of preventing and controlling the incapacitating complications associated with long term drug therapy. Some future therapeutic considerations are also described. PMID- 21286583 TI - Febrile seizures: controversy and consensus. AB - Although febrile convulsions are a relatively common complaint, the approach to their management is far from uniform and highly controversial. This article reviews the consensus statement on febrile convulsions arrived at by the Consensus Development Conference held in 1980 by the National Institutes of Health, together with other literature of interest to family physicians. Guidelines are given for the assessment, diagnosis and emergency treatment of febrile seizures. Epilepsy and atypical febrile convulsions are distinguished from simple febrile seizures. Prognosis, prevention, and the importance of counselling parents are discussed, as well as the controversial issue of prophylactic treatment. PMID- 21286584 TI - Multiple sclerosis: new techniques in earlier diagnosis. AB - Improved laboratory methods provide an objective means of evaluating the central nervous system, and give supporting evidence in the diagnosis of multiple sclerosis. Measurement of gamma globulins and identification of oligoclonal bands in the cerebrospinal fluid are reliable indicators. Visual, auditory, and sensory evoked responses reveal a high instance of abnormalities in MS, and may establish the existence of asymptomatic lesions, providing additional evidence in early cases. The enhanced CT scan detects cerebral lesions consistent with the diagnosis. The laboratory methods are incorporated in the new classification and diagnostic criteria of multiple sclerosis. PMID- 21286585 TI - Counselling the epileptic patient. AB - Today, most epileptics can participate freely in a wide range of activities. However, their epilepsy does create some special problems. The degree to which they participate in sports is governed by their degree of seizure control, as are their employment opportunities and driving privileges. Epilepsy does not appear to be a major stress factor in marriage as long as the spouse is knowledgeable about the condition. Epileptic women usually have normal pregnancies though their relative risks are perhaps double those for the non-epileptic population. Children of epileptic women have about four times the general population's risk of seizure but the absolute level of risk is not high. PMID- 21286586 TI - Vascular headaches and oral contraceptives. AB - Two groups of patients with increasing vascular headache unrelieved by antimigrainous medication were selected; 1800 were taking the birth control pill and a further 200 were taking estrogens for 'hot flashes'. Each group showed reduction, relief or control of the headache with antimigrainous medication when the pill or estrogen was stopped. A history of vascular headache is therefore a contraindication to the use of these medications. PMID- 21286587 TI - New drugs for epilepsy: a review. AB - Four relatively new drugs used as symptomatic treatment against epileptic seizures-carbamazepine (Tegretol), valproic acid (Depakene), clonazepam (Rivotril) and nitrazepam (Mogadon)-are reviewed from the standpoint of pharmacokinetic parameters, clinical indication, toxicity and practical use. PMID- 21286588 TI - A practical approach to migraine management. AB - Migraine is a benign constitutional disorder of neurovascular function characterized by recurrent headaches and autonomic and/or CNS symptoms. The diagnosis is made entirely on clinical grounds, and should not be difficult. The sequence of treatment is removal of migraine trigger factors, analgesic compounds, ergotamine, and migraine prophylactic agents. Providing that their specific contraindications are observed, and their side-effects mitigated by commonsense measures, these agents are safe and effective. A correct combination should result in improvement for most patients with migraine. PMID- 21286589 TI - Aphasia in clinical practice. AB - Aphasia is a central language impairment with word finding and comprehension deficit and paraphasias. The highlights of the essential language tests and the classification based on a scorable assessment are presented. The clinical syndromes of Broca's, global, Wernicke, conduction, anomic and transcortical aphasias are detailed with definition, localization, and prognosis. Modality specific disorders associated with aphasic syndromes are discussed. The management of the aphasic patient, consisting of informed support and coordination of available services, is often the responsibility of the family physician. PMID- 21286590 TI - The amenorrheic athlete. AB - With the growing number of women who undertake strenuous physical exercise, an effect of such activity on reproductive function has become apparent. This may be due to many factors including low body fat and altered peripheral steroid metabolism. Impaired prolactin release may also be a factor, but all factors must be considered together. Management includes decrease of workload and return to ideal body weight, plus medication if necessary. PMID- 21286592 TI - Is our health care system underfunded? PMID- 21286591 TI - A seminar on working with families. AB - Teaching family practice residents how to work with families is an important part of their training. An eight week seminar given to family practice residents during their rotation in a pediatric hospital is presented. The learning objectives and the teaching strategies are described. Informal assessment indicates the experience was a stimulus for attitudinal change and some degree of skill development among the residents despite its relatively short duration. PMID- 21286593 TI - Design of biocompatible dendrimers for cancer diagnosis and therapy: current status and future perspectives. AB - In the past decade, nanomedicine with its promise of improved therapy and diagnostics has revolutionized conventional health care and medical technology. Dendrimers and dendrimer-based therapeutics are outstanding candidates in this exciting field as more and more biological systems have benefited from these starburst molecules. Anticancer agents can be either encapsulated in or conjugated to dendrimer and be delivered to the tumour via enhanced permeability and retention (EPR) effect of the nanoparticle and/or with the help of a targeting moiety such as antibody, peptides, vitamins, and hormones. Imaging agents including MRI contrast agents, radionuclide probes, computed tomography contrast agents, and fluorescent dyes are combined with the multifunctional nanomedicine for targeted therapy with simultaneous cancer diagnosis. However, an important question reported with dendrimer-based therapeutics as well as other nanomedicines to date is the long-term viability and biocompatibility of the nanotherapeutics. This critical review focuses on the design of biocompatible dendrimers for cancer diagnosis and therapy. The biocompatibility aspects of dendrimers such as nanotoxicity, long-term circulation, and degradation are discussed. The construction of novel dendrimers with biocompatible components, and the surface modification of commercially available dendrimers by PEGylation, acetylation, glycosylation, and amino acid functionalization have been proposed as available strategies to solve the safety problem of dendrimer-based nanotherapeutics. Also, exciting opportunities and challenges on the development of dendrimer-based nanoplatforms for targeted cancer diagnosis and therapy are reviewed (404 references). PMID- 21286594 TI - Infrared multiple photon dissociation spectroscopy of trapped ions. AB - This tutorial review presents the technique of infrared multiple-photon dissociation (IRMPD) spectroscopy of mass-selected trapped ions. This requires coupling of a tunable infrared laser with mass spectrometry instrumentation. IRMPD spectroscopy has recently blossomed due to the emergence of widely tunable free electron lasers, as well as on-going developments of benchtop lasers. The merits of different trapping approaches in mass spectrometry are discussed in the light of photodissociation experiments. This tutorial discusses current capabilities, as well as limitations of the technique. PMID- 21286595 TI - Probing the catalytic potential of chloro nitrosyl rhenium(I) complexes. AB - The reduction of the mononitrosyl Re(II) salt [NMe(4)](2)[ReCl(5)(NO)] (1) with zinc in acetonitrile afforded the Re(i) dichloride complex [ReCl(2)(NO)(CH(3)CN)(3)] (2). Subsequent ligand substitution reactions with PCy(3), PiPr(3) and P(p-tolyl)(3) afforded the bisphosphine Re(i) complexes [ReCl(2)(NO)(PR(3))(2)(CH(3)CN)] (3, R = Cy a, iPr b, p-tolyl c) in good yields. The acetonitrile ligand in 3 is labile, permitting its replacement with H(2) (1 bar) to afford the dihydrogen Re(I) complexes [ReCl(2)(NO)(PR(3))(2)(eta(2) H(2))] (4, R = Cy a, iPr b). The catalytic activity of 2, 3 and 4 in hydrogen related catalyses including dehydrocoupling of Me(2)NH.BH(3), dehydrogenative silylation of styrenes, and hydrosilylation of ketones and aryl aldehydes were investigated, with the main focus on phosphine and halide effects. In the dehydrocoupling of Me(2)NH.BH(3), the phosphine-free complex 2 exhibits the same activity as the bisphosphine-substituted systems. In the dehydrogenative silylation of styrenes, 3a and 4a bearing PCy(3) ligands exhibit high catalytic activities. Monochloro Re(I) hydrides [Re(Cl)(H)(NO)(PR(3))(2)(CH(3)CN)] (5, R = Cy a, iPr b) were proven to be formed in the initiation pathway. The phosphine free complex 2 showed in dehydrogenative silylations even higher activity than the bisphosphine derivatives, which further emphasizes the importance of a facile phosphine dissociation in the catalytic process. In the hydrosilylation of ketones and aryl aldehydes, at least one rhenium-bound phosphine is required to ensure high catalytic activity. PMID- 21286596 TI - An uranyl citrate coordination polymer with a 3D open-framework involving uranyl cation-cation interactions. AB - A novel uranyl-organic compound incorporating citrate linker exhibits a 3D open framework. It is built up from the connection of infinite chains of uranyl centered polyhedra with citrate ligands, generating layers, which are further linked perpendicularly by isolated uranium tetranuclear motifs, involving uranyl cation-cation interactions. PMID- 21286597 TI - Transformation of peptide nanotubes into a vesicle via fusion driven by stereo complex formation. AB - Two types of peptide nanotubes, one is prepared from an amphiphilic peptide having a right-handed helix segment and the other from that having a left-handed helix segment, are shown to transform the morphology into a vesicle by membrane fusion due to stereo-complex formation between these helical segments. PMID- 21286598 TI - Perturbation of solute transport at a liquid-liquid interface by polyethylene glycol (PEG): implications for PEG-induced biomembrane fusion. AB - The effect of polyethylene glycol 400 (PEG) dissolved at various concentrations (0-40% v/v) in water, on the interfacial transport of methyl nicotinate across an aqueous-isopropyl myristate interface was investigated with a rotating diffusion cell. At four temperatures studied (20-37 degrees C), the presence of PEG decreased the rate of solute transfer both into and out of the organic phase in a concentration-dependent fashion. The bulk partition coefficient of the solute (organic/aqueous) increased with increasing PEG in the aqueous phase. Analysis of the temperature dependence of the interfacial transfer kinetics allowed thermodynamic activation energy parameters for the phase transport process to be determined. Although the free energy of activation (DeltaG(?)) for transfer was not affected by PEG, the relative enthalpic and entropic contributions were dramatically altered. At PEG concentrations of 10-40% v/v the enthalpic portion of DeltaG(?) was decreased by about a factor of two, while the entropic contribution (which is large and positively favorable in the absence of PEG) was reduced considerable such that it was totally eliminated at higher PEG levels. These observations suggest novel and direct experimental evidence for the concept that high PEG concentrations substantially alter water structure at an aqueous solution-organic liquid biomembrane model interface. The results support the hypothesis that the critically important function of PEG in inducing cell-cell and liposome-liposome fusion is to remove the hydration layer that impedes the close apposition of converging phospholipid bilayers. PMID- 21286599 TI - Synthesis of reduced graphene oxide-anatase TiO2 nanocomposite and its improved photo-induced charge transfer properties. AB - The construction of reduced graphene oxide or graphene oxide with semiconductor has gained more and more attention due to its unexpected optoelectronic and electronic properties. The synthesis of reduced graphene oxide (RGO) or graphene oxide-semiconductor nanocomposite with well-dispersed decorated particles is still a challenge now. Herein, we demonstrate a facile method for the synthesis of graphene oxide-amorphous TiO(2) and reduced graphene oxide-anatase TiO(2) nanocomposites with well-dispersed particles. The as-synthesized samples were characterized by transmission electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy, UV-Vis absorption spectroscopy, Fourier transform infrared spectrometry, and thermogravimetric analysis. The photovoltaic properties of RGO-anatase TiO(2) were also compared with that of similar sized anatase TiO(2) by transient photovoltage technique, and it was interesting to find that the combination of reduced graphene oxide with anatase TiO(2) will significantly increase the photovoltaic response and retard the recombination of electron-hole pairs in the excited anatase TiO(2). PMID- 21286604 TI - Negishi cross-coupling of secondary alkylzinc halides with aryl/heteroaryl halides using Pd-PEPPSI-IPent. AB - Pd-PEPPSI-IPent has proven to be an excellent catalyst for the Negishi cross coupling reaction of secondary alkylzinc reagents with a wide variety of aryl/heteroaryl halides. Importantly, beta-hydride elimination/migratory insertion of the organometallic leading to the production of isomeric coupling products has been significantly reduced using the highly-hindered Ipent ligand. PMID- 21286605 TI - Light-emitting electrochemical cells based on a supramolecularly-caged phenanthroline-based iridium complex. AB - The complex [Ir(ppy)(2)(pphen)][PF(6)] (Hppy = 2-phenylpyridine, pphen = 2-phenyl 1,10-phenanthroline) has been prepared and evaluated as an electroluminescent component for light-emitting electrochemical cells (LECs). Like in analogous LECs using bpy-based iridium(III) complexes a significant enhancement of the device stability is observed. PMID- 21286606 TI - Structures, electronic properties and solid state luminescence of Cu(I) iodide complexes with 2,9-dimethyl-1,10-phenanthroline and aliphatic aminomethylphosphines or triphenylphosphine. AB - The luminescent complexes of triphenylphosphine and two interesting aminomethylphosphines: P(CH(2)N(CH(2)CH(2))(2)NCH(3))(3) and P(CH(2)N(CH(2)CH(2))(2)O)(3) with copper(I) iodide and 2,9-dimethyl-1,10 phenanthroline (dmp): [CuI(dmp)PPh(3)], [CuI(dmp)P(CH(2)N(CH(2)CH(2))(2)NCH(3))(3)] and [CuI(phen)P(CH(2)N(CH(2)CH(2))(2)O)(3)] are presented in this work. These complexes were characterized in solution by means of NMR spectroscopy and their structures were crystallographically determined in the solid state. All complexes crystallize as the discrete dimers bound by pi-stacking interactions between dmp rings. The coordination geometry about the Cu(I) centre is pseudo-tetrahedral showing small flattening and large rocking distortions. The investigated compounds exhibit intense orange photoluminescence in the solid state (emission peaks at r.t.: lambda(max) = 588-592 nm; tau = 1.7-2.2 and 6.4-10.0 MUs; at 77 K: lambda(max) = 605-612 nm; tau = 4.8-6.5 and 32-47 MUs), which is several orders higher than the luminescence of the analogous complexes with 1,10-phenanthroline (phen). Electronic and structural properties of the [CuI(dmp/phen)PR(3)] complexes were characterized using DFT methods to interpret their photophysics. On the basis of TDDFT calculations the broad CT bands observed in UV-Vis spectra are interpreted as the two mixed transitions from sigma(CuI) bond with a small admixture of sigma(CuP) bond to pi* phen or dmp ligand: (MX,MPR(3))LCT, while the emissions most probably occur from two triplet states which are in thermal equilibrium. PMID- 21286607 TI - Site-selective localization of analytes on gold nanorod surface for investigating field enhancement distribution in surface-enhanced Raman scattering. AB - Understanding detailed electric near-field distributions around noble metal nanostructures is crucial to the rational design of metallic substrates for maximizing surface-enhanced Raman scattering (SERS) efficiency. We obtain SERS signals from specific regions such as the ends, the sides and the entire surfaces of gold nanorod by chemisorbing analytes on the respective areas. Different SERS intensities from designated surfaces reflect their electric near-field intensities and thus the distributions. Our experimental results show that approximately 65% of the SERS enhancement emanated from the ends of gold nanorods which occupies only 28% of the total surface area, quantitatively exhibiting the strongly localized electric field around the ends. The reliability and generality of the investigation is confirmed by employing analytes with different chemical characteristics: positively and negatively charged, neutral, hydrophobic and hydrophilic ligands, which are selectively adsorbed on the different sites. Numerical simulations of the electric near-field distributions around the nanorod are in well agreement with our experimental results. In addition, we observed that the SERS intensities of colloidal gold nanospheres are independent of surface areas being functionalized by analytes, indicating a homogenous electric near-field distribution around gold nanospheres. PMID- 21286608 TI - Functionalisation of aldehydes via aerobic hydroacylation of azodicarboxylates 'on' water. AB - Herein we report the functionalisation of aldehydes via hydroacylation of azodicarboxylates. A range of functionalised aldehydes are employed as the limiting reagent including chiral non-racemic aldehydes bearing alpha stereocentres which are functionalised giving access to enantiomerically pure products. The resultant hydrazides can be employed as acyl donors in the synthesis of amides. PMID- 21286609 TI - Concurrent oxidations with tandem biocatalysts in one pot: green, selective and clean oxidations of methylene groups to ketones. AB - A novel tandem-biocatalysts system consisting of a monooxygenase-containing microorganism and an alcohol dehydrogenase is developed for the concurrent oxidations of methylene groups to ketones in one pot, providing green, clean and simple access to valuable ketones with high yield, excellent selectivity and efficient cofactor recycling. PMID- 21286610 TI - Copper-cascade catalysis: synthesis of 3-functionalized indoles. AB - A three-component reaction of indoles, sulfonyl azides and terminal alkynes afforded 3-functionalized indoles in a single step via copper-cascade catalysis. PMID- 21286611 TI - Coulombic inter-ligand repulsion effects on the Pt(II) coordination chemistry of oligocationic, ammonium-functionalized triarylphosphines. AB - The Pt(II) coordination chemistry of oligocationic ammoniomethyl- and neutral aminomethyl-substituted triarylphosphines (L) is described. Complexes of the type PtX(2)(L)(2) (X = Cl, I) have been isolated and characterized. For the hexa-meta ammoniomethyl-substituted ligands [1](6+) and [2](6+), two ligands always occupy a trans-configuration with respect to each other in complexes of the type PtX(2)(L)(2), while for the tri-para-ammoniomethyl-substituted ligand [7](3+), the trans/cis ratio is dependent on the ionic strength of the solution. This behaviour was not observed for the neutral aminomethyl-substituted ligands. In the crystal structure of trans-[PtI(2)(1)(2)]I(12), the geometrical parameters of the phosphine ligand [1](6+) are very similar to those found in the analogous complex of the benchmark ligand PPh(3), i.e. trans-PtI(2)(PPh(3))(2), indicating that no significant increase in the steric congestion is present in the complex. Instead, the coordination chemistry of this class of phosphine ligands is dominated by repulsive Coulombic inter-ligand interactions. PMID- 21286615 TI - Highly ordered mesoporous Nafion membranes for fuel cells. AB - A highly ordered mesoporous Nafion membrane with a remarkable water retention ability was synthesized via a micelle templating method with self-assembled Pluronic F108 surfactants and its capability to operate under completely dry gas streams is demonstrated. PMID- 21286616 TI - Septonex-tetraphenylborate screen-printed ion selective electrode for the potentiometric determination of Septonex in pharmaceutical preparations. AB - A screen-printed electrode (SPE) was fabricated for the determination of 1 (ethoxycarbonyl)pentadecyltrimethylammonium bromide (Septonex) based on the use of Septonex-tetraphenylborate as the electroactive substance, and o nitrophenyloctylether (o-NPOE) as the plasticizing agent. The electrode passes a near-Nernstian cationic slope of 59.33 +/- 0.85 mV from activity between pH values of 2 to 9 with a lower detection limit of 9*10(-7) M and response time of about 5 s and exhibits an adequate shelf-life of 6 months. The method was applied for the determination of Septonex in pharmaceutical preparations. A percentage recovery of 99.88% was obtained with RSD=1.24%. The electrode was successfully applied in the determination of Septonex in laboratory-prepared samples by direct potentiometric, calibration curve and standard addition methods. Potentiometric titration of Septonex with sodium tetraphenylborate and phosphotungstic acid as a titrant was monitored with the modified screen-printed electrode as an end-point indicator electrode. Selectivity coefficients for Septonex relative to a number of potential interfering substances were determined. The sensor was highly selective for Septonex over a large number of compounds. Selectivity coefficient data for some common ions show negligible interference; however, cetyltrimethylammonium bromide and iodide ions interfere significantly. The analytical usefulness of the proposed electrode was evaluated by its application in the determination of Septonex in laboratory-prepared pharmaceutical samples with satisfactory results. The results obtained with the fabricated sensor are comparable with those obtained by the British Pharmacopeia method. PMID- 21286617 TI - Substrate-free, large-scale, free-standing and two-side oriented single crystal TiO2 nanorod array films with photocatalytic properties. AB - A substrate-free, large-scale, free-standing and two-side oriented single crystal rutile TiO(2) nanorod array film with a thickness of over ten micrometers, self assembled via a facile hydrothermal reaction of titanium powder in a mixture solution of H(2)O(2) and HCl, exhibits high activity for the photocatalytic degradation of methyl orange. PMID- 21286618 TI - Ionic liquids: structuration agents in a fluorinated matrix. AB - The use of ionic liquids as functional building blocks based on pyridinium, imidazolium and phosphonium cations to achieve materials combining a structuration at nanoscale with the dramatic mechanical properties of the resulting ionomers has been successfully demonstrated for the first time in a fluorinated matrix. PMID- 21286619 TI - A new and general one-pot synthesis of propargyl alcohols from esters. AB - Intermediates easily prepared by partial reduction of various esters with LDBBA as a reducing agent smoothly react with lithium acetylides to give propargyl alcohols, without isolation of partial reduction intermediates, in good yields (73-83%). PMID- 21286620 TI - Synthesis of isoxazoles by hypervalent iodine-induced cycloaddition of nitrile oxides to alkynes. AB - Treatment of oximes with hypervalent iodine leads to substituted isoxazoles via rapid formation of nitrile oxides. Reaction with terminal alkynes led to a series of 3,5-disubstituted isoxazoles with complete regioselectivity and high yield, in a procedure mild enough to prepare a range of nucleoside and peptide conjugates. Exceptionally high reaction rates were found for the formation of 3,4,5 trisubstituted isoxazoles from a cyclic alkyne. PMID- 21286621 TI - A facile and efficient method for the incorporation of multiple unnatural amino acids into a single protein. AB - One stone, two birds: Here, we have developed a simple and efficient method for the incorporation of multiple unnatural amino acids in a single protein. This single protein exhibited two different novel functionalities acquired from the genetically incorporated unnatural amino acids, which is an interesting and not an inherent property of the protein. PMID- 21286622 TI - Single-crystal-to-single-crystal transformations and selective adsorption of porous copper(II) frameworks. AB - A unique 4-fold interpenetrated (10,3)-b copper(II) framework exhibits reversible dehydration and rehydration in a single-crystal-to-single-crystal (SC-SC) process, and the dehydrated material can encapsulate CH(3)OH molecules, again in a SC-SC fashion, and shows selective adsorption of H(2) and CO(2) over N(2). PMID- 21286623 TI - Single-walled carbon nanotubes chemiresistor aptasensors for small molecules: picomolar level detection of adenosine triphosphate. AB - Here we report single walled-carbon nanotubes (SWNTs)-based chemiresistor aptasensors for highly sensitive and selective detection of weakly or uncharged molecules using the displacement format. As a proof-of-concept we demonstrate the detection of ATP, a small weakly charged molecule, by displacement of the ssDNA anti-ATP aptamer hybridized to a small capture oligonucleotide covalently attached on SWNTs, with picomolar sensitivity and selectivity over GTP. PMID- 21286624 TI - Copper(II) carboxylate tetramers formed from an enantiopure ligand containing a pi-stacking supramolecular synthon: single-crystal to single-crystal enantioselective ligand exchange. AB - An enantiopure ligand built from connecting the pi...pi stacking 1,8 naphthalimide supramolecular synthon with L-asparagine, L(asn)(-), forms tetrameric [Cu(4)(L(asn))(8)(py)(MeOH)]. The methanol ligand, located in a chiral pocket, is replaced enantioselectively when exposed to racemic ethyl lactate vapor to yield [Cu(4)(L(asn))(8)(py)((S)-ethyl lactate)], in a single-crystal to single-crystal gas/solid transformation. PMID- 21286625 TI - A highly specific rhodamine-based colorimetric probe for hypochlorites: a new sensing strategy and real application in tap water. AB - By fully utilizing the oxidation property of hypochlorites and different coordinating properties of Cu(+) and Cu(2+), the Cu(2+) sensor could act as a new good probe toward hypochlorites with high sensitivity as low as 8.1 * 10(-7) M, providing a novel approach to develop new probes for oxidants. PMID- 21286626 TI - DNA-capped nanoparticles designed for doxorubicin drug delivery. AB - The anticancer drug, doxorubicin (DOX), was loaded onto DNA-capped gold nanoparticles (AuNP) designed for specific DOX intercalation. Drug binding was confirmed by monitoring DNA melting temperature, AuNP plasmon resonance maximum, and hydrodynamic radius increase, as a function of [DOX]/[DNA] ratio. The capacity for drug release to target DNA was confirmed. PMID- 21286627 TI - Plasmonic nanoparticle interactions for high-performance imaging fluorosensors. AB - We demonstrate a nanoparticle based ratiometric fluorosensor suitable for non invasive high-resolution imaging of complex samples. Coextraction generates a movement of a solvatochromic dye, with a consequent shift from plasmophore coupled emission towards longer wavelength scattering enhanced emission. The nanoparticle doped sensors confirmed superior sensitivity, reversibility, durability and overall image quality. PMID- 21286628 TI - Biocompatible reduced graphene oxide prepared by using dextran as a multifunctional reducing agent. AB - A large-scale, cost-effective, and environmentally friendly synthetic strategy for biocompatible reduced graphene oxide (RGO) by using dextran as a reducing and stabilization agent has been developed. Dextran-coated RGO (D-RGO) was readily soluble in water with high biocompatibility. PMID- 21286629 TI - A bright tetranuclear iridium(III) complex. AB - A cyclic tetranuclear cyclometallated iridium(III) complex using cyanide anions as bridging ligands and displaying a tetrahedrally distorted square geometry has been obtained with high yield; photo- and electrochemical characterizations show that most interesting properties of mononuclear cyclometallated iridium complexes are retained in the tetranuclear assembly. PMID- 21286630 TI - Molecular mechanisms of antibiotic resistance. AB - Over the past decade, resistance to antibiotics has emerged as a crisis of global proportion. Microbes resistant to many and even all clinically approved antibiotics are increasingly common and easily spread across continents. At the same time there are fewer new antibiotic drugs coming to market. We are reaching a point where we are no longer able to confidently treat a growing number of bacterial infections. The molecular mechanisms of drug resistance provide the essential knowledge on new drug development and clinical use. These mechanisms include enzyme catalyzed antibiotic modifications, bypass of antibiotic targets and active efflux of drugs from the cell. Understanding the chemical rationale and underpinnings of resistance is an essential component of our response to this clinical challenge. PMID- 21286631 TI - Intrinsic pKa values of 3'-N-alpha-l-aminoacyl-3'-aminodeoxyadenosines determined by pH dependent 1H NMR in H2O. AB - 3'-(alpha-L-Aminoacylamido)deoxyadenosines are ribosomal A-site binders and mimic the nascent peptide accepting 3'-terminus of aminoacyl transfer RNA. Their alpha amino groups exhibit intrinsic basicities in bulk water that differ by up to 1.8 pK(a) units. Only the neutral form of these nucleophiles can be active during ribosomal peptidyl transfer catalysis. PMID- 21286632 TI - Recent developments in the total synthesis of fungicidal natural products--a crop protection perspective. AB - Natural products play an important role as lead structures for the identification of novel active ingredients in crop protection. As it is the case in the pharmaceutical industry, however, many crop protection companies have substantially decreased their in-house efforts in natural product exploration. Therefore, joint projects with academic research groups become more and more important in the field. This review describes several examples for successful collaborations in the field of fungicidal natural products. PMID- 21286633 TI - Unexpected preparation of (Z)-chloromethyleneketals and their sulfur analogues by a novel three-component condensation. AB - A novel multicomponent condensation, leading to the rare (Z) chloromethyleneketals and their sulfur analogues, has been discovered. The mechanism of this reaction has been studied in some detail and subsequent modifications were performed on the adducts, leading to unusual Umpolung transforms. PMID- 21286634 TI - A photolabile linker for the solid-phase synthesis of 4-substituted NH-1,2,3 triazoles. AB - This communication presents the synthesis of a novel photolabile azidolinker based on the o-nitroveratryl group. The application of this linker for the synthesis and photolytic release of NH-1,2,3-triazoles is described. PMID- 21286635 TI - Two-dimensional DNA origami assemblies using a four-way connector. AB - Two-dimensional self-assembly of DNA origami structures was carried out using a connector that has connection sites at all four edges. By utilizing this four-way connector, five and eight origami monomers were assembled to form a cruciate and a hollow square structure, respectively. PMID- 21286636 TI - Direct experimental evidence for an enamine radical cation in SOMO catalysis. AB - SOMO catalysis has lately obtained large interest as a new and powerful version of enantioselective organocatalysis which includes radical steps initiated by a one-electron oxidation. The intermediate enamine radical cation has been postulated, but has not been observed directly so far. This communication now reports the direct detection of this key intermediate. PMID- 21286637 TI - A blue digermene (t-Bu2MeSi)2Ge=Ge(SiMet-Bu2)2. AB - A novel tetrakis(trialkylsilyl)digermene, featuring rather unusual structural and chemical properties, was synthesized by a straightforward synthetic protocol: reduction of the corresponding dichlorobis(trialkylsilyl)germane precursor with potassium graphite. PMID- 21286638 TI - Steric control of conformation in self-assembly metallacalix[4]arenes derived from AlMe3 or GaMe3 with benzimidazolyl ligands. AB - Metallacalix[4]arenes [bzimAlMe(2)](4) (1), [bzimGaMe(2)](4) (2), [mbzimAlMe(2)](4) (3) and [mbzimGaMe(2)](4) (4) were obtained by self-assembly. The larger cavity of 3 and 4 allows them to function as hosts of benzene molecules. PMID- 21286639 TI - Paper spray ionization of polar analytes using non-polar solvents. AB - Non-polar solvents like hexane allow ionization of insoluble drugs, peptides, nucleotides and phospholipids as solids from paper. Ambient ionization is achieved simply by application of a high voltage to the wet paper. Transport and ionization mechanisms are discussed, including the possibility of field desorption from dendritic structures formed on the paper. PMID- 21286640 TI - Concerted halogen and hydrogen bonding in [RuI2(H2dcbpy)(CO)2]...I2...(CH3OH)...I2...[RuI2(H2dcbpy)(CO)2]. AB - A new type of concerted halogen bond-hydrogen bond interaction was found in the solid state structure of [RuI(2)(H(2)dcbpy)(CO)(2)]...I(2)...(MeOH)...I(2)...[RuI(2)(H(2)dcbpy)(CO)(2)]. The iodine atoms of the two I(2) molecules interact simultaneously with each other and with the OH group of methanol of crystallization. The interaction was characterized by single crystal X-ray measurements and by computational charge density analysis based on DFT calculations. PMID- 21286641 TI - Catalytic asymmetric syntheses of isoxazoline-N-oxides under phase-transfer conditions. AB - Catalytic asymmetric syntheses of various isoxazoline-N-oxides have been accomplished by asymmetric phase-transfer conjugate addition of bromomalonate to nitroolefins and subsequent ring-closing O-alkylation. PMID- 21286642 TI - Direct Sp3alpha-C-H activation and functionalization of alcohol and ether. AB - Seven kinds of sp(3)alpha-C-H activation/C-C formation reactions of alcohols and ethers have been reviewed in this tutorial review, from the viewpoint of both methodology and synthetic application, towards the efficiency, chemo-, regio- and stereoselectivity, catalytic system, substrate scope and mechanistic study. Section 2 describes radical-mediated alpha-C-H activation and addition/elimination of ethers with unsaturated (C=C and C[triple bond]C) species. Sections 3-8 discuss the alpha-C-H activation and additions of alcohols and/or ethers with unsaturated (C=C, C[triple bond]C, C=O and C=N) compounds, which involve the key processes of radical mediation, carbenoid insertion, 1,5-H migration, oxidative dehydrogenation coupling, transfer hydrogenative coupling, and metal-mediated C=C insertion into the C-H bond. PMID- 21286643 TI - Dansyl-anthracene dyads for ratiometric fluorescence recognition of Cu2+. AB - Dansyl-anthracene dyads 1 and 2 in CH(3)CN-H(2)O (7:3) selectively recognize Cu(2+) ions amongst alkali, alkaline earth and other heavy metal ions using both absorbance and fluorescence spectroscopy. In absorbance, the addition of Cu(2+) to the solution of dyads 1 or 2 results in appearance of broad absorption band from 200 nm to 725 nm for dyad 1 and from 200 nm to 520 nm for dyad 2. This is associated with color change from colorless to blue (for 1) and fluorescent green (for 2). This bathochromic shift of the spectrum could be assigned to internal charge transfer from sulfonamide nitrogen to anthracene moiety. In fluorescence, under similar conditions dyads 1 and 2 on addition of Cu(2+) selectively quench fluorescence due to dansyl moiety between 520-570 nm (for 1)/555-650 nm (for 2) with simultaneous fluorescence enhancement at 470 nm and 505 nm for dyads 1 and 2, respectively. Hence these dyads provide opportunity for ratiometric analysis of 1-50 MUM Cu(2+). The other metal ions viz. Fe(3+), Co(2+), Ni(2+), Cd(2+), Zn(2+), Hg(2+), Ag(+), Pb(2+), Li(+), Na(+), K(+), Mg(2+), Ca(2+), Ba(2+) do not interfere in the estimation of Cu(2+) except Cr(3+) in case of dyad 1. The coordination of dimethylamino group of dansyl unit with Cu(2+) causes quenching of fluorescence due to dansyl moiety between 520-600 nm and also restricts the photoinduced electron transfer from dimethylamino to anthracene moiety to release fluorescence between 450-510 nm. This simultaneous quenching and release of fluorescence respectively due to dansyl and anthracene moieties emulates into Cu(2+) induced ratiometric change. PMID- 21286644 TI - Stable pi-pi dependent electron conduction band of TPP[M(Pc)L2]2 molecular conductors (TPP = tetraphenylphosphonium; M = Co, Fe; Pc = phthalocyaninato; L = CN, Cl, Br). AB - The partially-oxidized TPP[M(Pc)L(2)](2) molecular conductors exhibit variable electronic and magnetic transport bulk materials properties due to central metal and axial ligand molecular modifications. The controllable electrical conductivity and giant negative magnetoresistance can be mainly attributable to the varying ligand field energy and physical bulkiness of the axial ligands which cause modulation in the intra-molecular pi-d (Pc-M) and inter-molecular pi-pi (Pc Pc) interactions in the TPP[M(Pc)L(2)](2) system, respectively. Characterization of the electronic conduction band utilizing one-dimensional (1-D) tight-binding approximation from infrared reflectance and thermoelectric power profile reveal consistent band widths of 0.43 eV-0.62 eV for the Co series (L = Br < Cl < CN) and 0.44-0.56 eV for the Fe series (L = Br < Cl < CN). The fixed band width suggests that stable electron conduction bands (transport pathway) can be constructed which can withstand the molecular pi-d interaction modifications that severely alter the bulk electronic and magnetic materials properties of the TPP[M(Pc)L(2)](2) molecular conductors. PMID- 21286645 TI - Synthesis and self-assembly of spin-labile and redox-active manganese(III) complexes. AB - New amphiphilic and spin-labile Mn(III) complexes based on dianionic N(4)O(2) hexadentate sal(2)trien or sal(2)bapen ligands, which contain OC(6)H(13), OC(12)H(25), or OC(18)H(37) alkoxy substituents at different positions of the salicylidene unit were prepared (H(2)sal(2)trien = N,N'''-bis(salicylidene) 1,4,7,10-tetraazadecane, H(2)sal(2)bapen = N,N'''-bis(salicylidene)-1,5,8,12 tetraazadodecane). According to electrochemical measurements, these complexes undergo two (quasi)reversible redox processes. Temperature-dependent magnetic measurements revealed a high-spin configuration for all sal(2)trien complexes (S = 2) and gradual spin crossover for sal(2)bapen complexes from high to low spin (S = 1). The chain length strongly influences the spin crossover, as C(18) functionalization stabilizes the low spin state at much higher temperatures than shorter alkyl chains. Moreover, long alkyl chains allow for spontaneous self assembly of the molecules, which was investigated in single crystals and in Langmuir-films at the air-water interface. Long alkyl chains (C(12) or C(18)) as well as a mutual syn-orientation of these molecular recognition sites were required for the Langmuir monolayers to be stable. PMID- 21286646 TI - An innovative statistical approach for analysing non-continuous variables in environmental monitoring: assessing temporal trends of TBT pollution. AB - The current work presents an innovative statistical approach to model ordinal variables in environmental monitoring studies. An ordinal variable has values that can only be compared as "less", "equal" or "greater" and it is not possible to have information about the size of the difference between two particular values. The example of ordinal variable under this study is the vas deferens sequence (VDS) used in imposex (superimposition of male sexual characters onto prosobranch females) field assessment programmes for monitoring tributyltin (TBT) pollution. The statistical methodology presented here is the ordered logit regression model. It assumes that the VDS is an ordinal variable whose values match up a process of imposex development that can be considered continuous in both biological and statistical senses and can be described by a latent non observable continuous variable. This model was applied to the case study of Nucella lapillus imposex monitoring surveys conducted in the Portuguese coast between 2003 and 2008 to evaluate the temporal evolution of TBT pollution in this country. In order to produce more reliable conclusions, the proposed model includes covariates that may influence the imposex response besides TBT (e.g. the shell size). The model also provides an analysis of the environmental risk associated to TBT pollution by estimating the probability of the occurrence of females with VDS >= 2 in each year, according to OSPAR criteria. We consider that the proposed application of this statistical methodology has a great potential in environmental monitoring whenever there is the need to model variables that can only be assessed through an ordinal scale of values. PMID- 21286647 TI - Biomonitoring 21 degrees Po and 21 degrees Pb in marine brachyuran crabs collected along the coast of Kudankulam, Gulf of Mannar (GOM), India. AB - Activities of 210Po and 210Pb in whole-body and in various tissues of brachyuran crabs collected along the Kudankulam coast were studied. A non-uniform distribution of these radionuclides was observed between the various tissues. Of all the tissues, 210Po and 210Pb were found to accumulate more in the hepatopancreas and intestine. Among the crabs studied, Charybdis lucifera registered higher 210Po and 210Pb activity. Muscle tissue in all the species registered lower activity. The 210Po/210Pb activity ratio was found to be greater than unity. The biological concentration factor for organs varied between ~ 104 and 106 for 210Po and ~102 and 104 for 210Pb. A significant variation in the accumulation of 210Po and 210Pb was noted between species and between seasons (p < 0.05). The mean whole-body internal dose ranged from 1.42 to 6.86 MUGy h-1 for 210Po and from 3.0 * 10-3 to 8.0 * 10-3 MUGy h-1 for 210Pb. The external dose for 210Po and 210Pb was 2.41 * 10-6 to 5.76 * 10-6 MUGy h-1 and 4.14 * 10-5 to 8.26 * 10-5 MUGy h-1, respectively. The activity levels recorded are in agreement with values recorded in related organisms in other parts of the world. The total committed effective dose due to the intake of both radionuclides ranged from 80.3 to 871.7 MUSv y-1. The median dose calculated due to 210Po and 210Pb in certain crabs in Kudankulam is less and would not pose any significant radiological impact on health or a cancer risk to the public, and the seafood is considered safe for human consumption. PMID- 21286648 TI - Nanocavity electrode array for recording from electrogenic cells. AB - We present a new nanocavity device for highly localized on-chip recordings of action potentials from individual cells in a network. Microelectrode recordings have become the method of choice for recording extracellular action potentials from high density cultures or slices. Nevertheless, interfacing individual cells of a network with high resolution still remains challenging due to an insufficient coupling of the signal to small electrodes, exhibiting diameters below 10 um. We show that this problem can be overcome by a new type of sensor that features an electrode, which is accessed via a small aperture and a nanosized cavity. Thus, the properties of large electrodes are combined with a high local resolution and a good seal resistance at the interface. Fabrication of the device can be performed with state-of-the-art clean room technology and sacrificial layer etching allowing integration of the devices into sensor arrays. We demonstrate the capability of such an array by recording the propagation of action potentials in a network of cardiomyocyte-like cells. PMID- 21286649 TI - Development of a classification and ranking method for the identification of possible biomarkers in two-dimensional gel-electrophoresis based on principal component analysis and variable selection procedures. AB - The identification of biomarkers is one of the leading research areas in proteomics. When biomarkers have to be searched for in spot volume datasets produced by 2D gel-electrophoresis, problems may arise related to the large number of spots present in each map and the small number of samples available in each class (control/pathological). In such cases multivariate methods are usually exploited together with variable selection procedures, to provide a set of possible biomarkers: they are however usually aimed to the selection of the smallest set of variables (spots) providing the best performances in prediction. This approach seems not to be suitable for the identification of potential biomarkers since in this case all the possible candidate biomarkers have to be identified to provide a general picture of the "pathological state": in this case exhaustivity has to be preferred to provide a complete understanding of the mechanisms underlying the pathology. We propose here a ranking and classification method, "Ranking-PCA", based on Principal Component Analysis and variable selection in forward search: the method selects one variable at a time as the one providing the best separation of the two classes investigated in the space given by the relevant PCs. The method was applied to an artificial dataset and a real case-study: Ranking-PCA exhaustively identified the potential biomarkers and provided reliable and robust results. PMID- 21286650 TI - Biodegradable cross-linked poly(amino alcohol esters) based on LMW PEI for gene delivery. AB - Polyethylenimine (PEI, especially with M(w) of 25,000) has been known as an efficient gene carrier and a gold standard of gene transfection due to its high transfection efficiency (TE). However, high concomitant cytotoxicity limited the application of PEI. In this report, several cationic polymers derived from low molecular weight (LMW) PEI (M(w) 600) linked with diglycidyl adipate (DA-PEI) or its analogs (diglycidyl succinate, DS-PEI and diglycidyl oxalate, DO-PEI; D-PEIs for all 3 polymers) were prepared and characterized. GPC gave M(w)s of DA-PEI, DS PEI and DO-PEI as 6861, 16,015 and 35,281, respectively. Moreover, degradation of the ester-containing DS-PEI was also confirmed by GPC. In addition, hydroxyls in these polymers could improve their water solubility. These polymers exhibited good ability to condense plasmid DNA into nanoparticles with the size of 120-250 nm. zeta-potentials of the polyplexes were found to be around +10-20 mV under weight ratios (polymer/DNA) from 0.5 to 32. Agarose gel retardation showed that DNA could be released from the polyplexes after being pre-incubated for 30 h. In vitro experiments were carried out and it was found that DS-PEI showed about 5 times of TE compared to that of the PEI/DNA polyplex under a weight ratio of 1 in A549 cells. Meanwhile, the cytotoxicity of D-PEIs assayed by MTT is lower than that of 25 kDa PEI in HEK293 cells. These results suggested that this series of PEI derivatives would be promising non-viral biodegradable vectors for gene delivery. PMID- 21286651 TI - Preventing metal-mediated oxidative DNA damage with selenium compounds. AB - Copper and iron are two widely studied transition metals associated with hydroxyl radical (OH) generation, oxidative damage, and disease development. Because antioxidants ameliorate metal-mediated DNA damage, DNA gel electrophoresis assays were used to quantify the ability of ten selenium-containing compounds to inhibit metal-mediated DNA damage by hydroxyl radical. In the Cu(I)/H(2)O(2) system, selenocystine, selenomethionine, and methyl-selenocysteine inhibit DNA damage with IC(50) values ranging from 3.34 to 25.1 MUM. Four selenium compounds also prevent DNA damage from Fe(II) and H(2)O(2). Additional gel electrophoresis experiments indicate that Cu(I) or Fe(II) coordination is responsible for the selenium antioxidant activity. Mass spectrometry studies show that a 1 : 1 stoichiometry is the most common for iron and copper complexes of the tested compounds, even if no antioxidant activity is observed, suggesting that metal coordination is necessary but not sufficient for selenium antioxidant activity. A majority of the selenium compounds are electroactive, regardless of antioxidant activity, and the glutathione peroxidase activities of the selenium compounds show no correlation to DNA damage inhibition. Thus, metal binding is a primary mechanism of selenium antioxidant activity, and both the chemical functionality of the selenium compound and the metal ion generating damaging hydroxyl radical significantly affect selenium antioxidant behavior. PMID- 21286653 TI - CuO nanostructures supported on Cu substrate as integrated electrodes for highly reversible lithium storage. AB - Arrays of CuO nanostructures, including nanorods and nanosheets, supported on a Cu substrate have been rationally fabricated from their morphology-controlled Cu(2)(OH)(3)NO(3) precursors by thermal annealing. The as-prepared CuO samples can be directly used as integrated electrodes for lithium-ion batteries without the addition of other ancillary materials such as carbon black or a binder to enhance electrode conductivity and cycling stability. The unique nanostructural features endower them excellent electrochemical performance as demonstrated by high capacities of 450-650 mAh g(-1) at 0.5-2 C and almost 100% capacity retention over 100 cycles after the second cycle. PMID- 21286652 TI - Circular dichroism spectra of cytochrome c oxidase. AB - Circular dichroism spectra of bovine heart aa(3)-type cytochrome c oxidase have been studied with a major focus on the Soret band pi -> pi* transitions, B(0(x,y)), in the two iron porphyrin groups of the enzyme. The spectra of the fully reduced and fully oxidized enzyme as well as of its carbon monoxide and cyanide complexes have been explored. In addition, CD spectra of the reduced and oxidized ba(3)-type cytochrome c oxidase from Thermus thermophilus were recorded for comparison. An attempt is made to interpret the CD spectra of cytochrome c oxidase with the aid of a classical model of dipole-dipole coupled oscillators taking advantage of the known 3D crystal structure of the enzyme. Simultaneous modeling of the CD and absorption spectra shows that in the bovine oxidase, the dipole-dipole interactions between the hemes a and a(3), although contributing significantly, cannot account either for the lineshape or the magnitude of the experimental spectra. However, adding the interactions of the hemes with 22 aromatic amino acid residues located within 12 A from either of the two heme groups can be used to model the CD curves for the fully reduced and fully oxidized oxidase with reasonable accuracy. Interaction of the hemes with the peptide bond transition dipoles is found to be insignificant. The modeling indicates that the CD spectra of cytochrome oxidase in both the reduced and oxidized states are influenced significantly by interaction with Tyr244 in the oxygen-reducing center of the enzyme. Hence, CD spectroscopy may provide a useful tool for monitoring the redox/ionization state of this residue. The modeling confirms wide energy splitting of the orthogonal B(x) and B(y) transitions in the porphyrin ring of heme a. PMID- 21286654 TI - A facile approach to highly functional trisubstituted furans via intramolecular Wittig reactions. AB - An efficient and mild synthesis of trisubstituted furans, starting from alpha,beta-unsaturated ketones, tributylphosphine, and acyl chlorides, is described. The strategy employs the intramolecular Wittig protocol as a key step to install the crucial furan ring, leading to a wide variety of highly functional furans in one step. PMID- 21286655 TI - A sensitive and selective resonance light scattering bioassay for homocysteine in biological fluids based on target-involved assembly of polyethyleneimine-capped Ag-nanoclusters. AB - A specific resonance light scattering bioassay for homocysteine is developed on the basis of target-involved assembly of polyethyleneimine-capped Ag nanoclusters. The bioassay permits discriminating homocysteine from cysteine, glutathione and other amino acids, and allows sensitive and selective detection of homocysteine with a detection limit of 42 nM. PMID- 21286656 TI - Synthesis and incorporation of a furan-modified adenosine building block for DNA interstrand crosslinking. AB - 2'-O-(3-(Furan-2-yl)propyl)adenosine was synthesized and evaluated for interstrand crosslink (ICL) formation in DNA duplexes. In situ oxidation of the furan moiety with NIS showed rapid crosslink formation to dA and dC, while dT and dG were inactive. PMID- 21286657 TI - Ultrathin nickel hydroxidenitrate nanoflakes branched on nanowire arrays for high rate pseudocapacitive energy storage. AB - An ultrathin nickel hydroxidenitrate nanoflake-ZnO nanowire hybrid array has been synthesized by a facile low-cost solution route and has demonstrated high-rate energy storage in pseudocapacitor application with remarkable specific capacitance and excellent cycling stability. PMID- 21286658 TI - Mechanism and electronic effects in nitrogen ylide-promoted asymmetric aziridination reaction. AB - The mechanism and stereoselectivity of the aziridination reaction between guanidinium ylide and a series of para-substituted benzaldehydes have been studied by using density functional theory methods. The mechanistic details and analyses of the key elementary steps involved in (a) the addition of nitrogen ylide to benzaldehydes and (b) subsequent fragmentation of the resulting oxaspirocyclic intermediate are presented. The relative energies of important transition states and intermediates are found to be useful toward rationalizing reported diastereoselective product formation. The relative energies of the key transition states could be rationalized on the basis of the differences in steric, electrostatic, and other stabilizing weak interactions. The deformation analysis of the transition state geometries exhibited good correlation with the predicted activation barriers. The changes in cis/trans diastereoselectivity preferences upon changes in the electron donating/withdrawing abilities of the para substituents on benzaldehyde are identified as arising due to vital differences in the preferred pathways. The large value of reaction constant (rho > 4.8) estimated from the slope of good linear Hammett plots indicated high sensitivity to the electronic nature of substituents on benzaldehyde. The formation of trans-aziridine in the case of strong electron donating groups and cis-aziridines with weakly electron donating/withdrawing group has been explained by the likely changes in the mechanistic course of the reaction. In general, the predicted trends are found to be in good agreement with the earlier experimental reports. PMID- 21286659 TI - Affinity reagents for lab on chips. PMID- 21286660 TI - High resolution BrainPET combined with simultaneous MRI. AB - After the successful clinical introduction of PET/CT, a novel hybrid imaging technology combining PET with the versatile attributes of MRI is emerging. At the Forschungszentrum Julich, one of four prototypes available worldwide combining a commercial 3T MRI with a newly developed BrainPET insert has been installed, allowing simultaneous data acquisition with PET and MRI. The BrainPET is equipped with LSO crystals of 2.5 mm width and Avalanche photodiodes (APD) as readout electronics. Here we report on some performance characteristics obtained by phantom studies and also on the initial BrainPET studies on various patients as compared with a conventional HR+ PET-only scanner. MATERIAL, METHODS: The radiotracers [18F]-fluoro-ethyl-tyrosine (FET), [11C]-flumazenil and [18F]-FP-CIT were applied. RESULTS: Comparing the PET data obtained with the BrainPET to those of the HR+ scanner demonstrated the high image quality and the superior resolution capability of the BrainPET. Furthermore, it is shown that various MR images of excellent quality could be acquired simultaneously with BrainPET scans without any relevant artefacts. DISCUSSION, CONCLUSION: Initial experiences with the hybrid MRI/BrainPET indicate a promising basis for further developments of this unique technique allowing simultaneous PET imaging combined with both anatomical and functional MRI. PMID- 21286661 TI - RAP-PCR fingerprinting reveals time-dependent expression of matrix-related molecules following stem-cell based TGFbeta1-induced chondrocyte development. AB - Different approaches of engineering cartilage to treat defects in the articulating surfaces of the joints have been designed, which mainly use mesenchymal stem cells or autologous chondrocytes for in situ transplantation. However, these cells are poorly characterized with respect to viability, degree of differentiation and morphology or production of extracellular matrix. At present, one of the key approaches to generate chondrocytes is the stimulation of stem cells with transforming growth factor (TGF) beta1. To characterize the molecular alterations occurring during the cellular transformation induced by TGF beta1 exposure, the differentiation process of bone marrow-derived stem cells into chondrocytes was investigated using an in vitro chondrogenesis model and the RNA arbitrarily primed PCR (RAP-PCR) fingerprinting technique. Distinct genes were found to be differentially regulated during chondrocyte development beginning on day 1: collagen type I, non-muscle myosin MYH9, followed by manganese superoxide dismutase and sodium-potassium ATPase on day 7. The results suggest that using RAP-PCR for differential display fingerprinting is a useful tool to investigate the differentiation process of bone marrow-derived stem cells following TGF-beta1-stimulation. PMID- 21286662 TI - Polymer fraction of Aloe vera exhibits a protective activity on ethanol-induced gastric lesions. AB - For centuries, Aloe has been used as a herbal plant remedy against skin disorders, diabetes, and for its cardiac stimulatory activity. Here, we examined the gastroprotective effects of an Aloe vera polymer fraction (Avpf; molecular weight cut-off >=50 kDa; 150 mg/kg body weight, p.o.) on an ethanol-induced gastric lesion mouse model. Mice pre-treated with Avpf had significantly fewer gastric lesions than their respective controls. To further examine the potential mechanism underlying this effect, we used reverse transcription-polymerase chain reaction to examine nitric oxide synthase and matrix metalloproteinase (MMP)mRNA expression on tissues from gastric lesions. Our results revealed that the mRNA expressions of inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS) were each reduced by ~50% in Avpf-treated mice vs. the controls, whereas, the mRNA expression levels of endothelial nitric oxide synthase remained unchanged. MMP-9, an index for gastric lesions, also alleviated the ethanol treated gastric ulceration during Avpf treatment. These findings collectively suggest that Avpf significantly protects the gastric mucosa against ethanol induced gastric damage, at least in part, by decreasing mRNA expression levels of not only iNOS and nNOS, but also MMP-9. PMID- 21286663 TI - Ethanolic extract of Brazilian green propolis sensitizes prostate cancer cells to TRAIL-induced apoptosis. AB - Prostate cancer represents an ideal disease for chemopreventive intervention. Propolis possesses immuno-modulatory, anti-tumour and chemopreventive properties. The tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is an important endogenous anti-cancer agent that induces apoptosis selectively in tumour cells. However, some cancer cells are resistant to TRAIL-mediated apoptosis. Naturally occurring phenolic and polyphenolic compounds sensitize TRAIL-resistant cancer cells and augment the apoptotic activity of TRAIL. The ethanolic extract of Brazilian green propolis (EEP) is rich in phenolic components. Our in vitro results indicate the potential targets in the TRAIL induced apoptotic pathway for the cancer chemopreventive activity of Brazilian propolis. We examined the cytotoxic and apoptotic effects of Brazilian EEP and its bioactive components in combination with TRAIL on LNCaP prostate cancer cells. The chemical composition of Brazilian green propolis was determined by high performance liquid chromatography-diode array detection. The cytotoxicity was measured by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl-tetrazolium and lactate dehydrogenase assays. Apoptosis was detected using annexin V-FITC by flow cytometry and fluorescence microscopy. The mitochondrial membrane potential (?Psim) was evaluated using DePsipher staining by fluorescence microscopy. Flow cytometry was used to analyse death receptor (TRAIL-R1 and TRAIL-R2) expression in LNCaP cells. The inhibition of nuclear factor-kappaB (NF-kappaB) (p65) activation in cancer cells was confirmed by the ELISA-based TransAM NF-kappaB kit. The LNCaP cells were shown to be resistant to TRAIL-induced apoptosis. Our study demonstrates that EEP sensitizes TRAIL-resistant prostate cancer cells. The main phenolic components detected in Brazilian green propolis are artepillin C, quercetin, kaempferol and p-coumaric acid. Brazilian propolis and its bioactive components markedly augmented TRAIL-mediated apoptosis and cytotoxicity in prostate cancer cells. Brazilian EEP enhanced the expression of TRAIL-R2 and the activity of NF-kappaB in LNCaP cells. The co-treatment of prostate cancer cells with 100 ng/ml TRAIL and 50 ug/ml EEP increased the percentage of apoptotic cells to 65.8 +/- 1.2% and caused a significant disruption of ?Psim in LNCaP cells. We show that Brazilian EEP helped cells overcome TRAIL resistance by engaging both intrinsic and extrinsic apoptotic pathways and regulating NF-kappaB activity. The data demonstrate the important role of Brazilian green propolis and its bioactive compounds in prostate cancer chemoprevention through the enhancement of TRAIL mediated apoptosis. PMID- 21286664 TI - Possible involvement of loss of imprinting in immortalization of human fibroblasts. AB - Disruption of the normal pattern of parental origin-specific gene expression is referred to as loss of imprinting (LOI), which is common in various cancers. To investigate a possible role of LOI in the early stage of human cell transformation, we studied LOI in 18 human fibroblast cell lines immortalized spontaneously, by viral oncogenes, by chemical or physical carcinogens, or by infection with a retrovirus vector encoding the human telomerase catalytic subunit, hTERT cDNA. LOI was observed in all the 18 immortal cell lines. The gene most commonly exhibiting LOI was NDN which displayed LOI in 15 of the 18 cell lines (83%). The other genes exhibiting LOI at high frequencies were PEG3 (50%), MAGE-L2 (61%) and ZNF 127 (50%). Expression of NDN that was lost in the immortal cell lines was restored by treatment with 5-aza-2'-deoxycytidine. The ratio of histone H3 lysine 9 methylation to histone H3 lysine 4 methylation of the chromatin containing the NDN promoter in the immortal WI-38VA13 cells was greater than that in the parental cells, suggesting chromatin structure-mediated regulation of NDN expression. We previously demonstrated that inactivation of the p16INK4a/pRb pathway is necessary for immortalization of human cells. Human fibroblasts in the pre-crisis phase and cells with an extended lifespan that eventually senesce, both of which have the normal p16INK4a/pRb pathway, did not show LOI at any imprinted gene examined. Although it is not clear if LOI plays a causal role in immortalization of human cells or is merely coincidental, these findings indicate a possible involvement of LOI in immortalization of human cells or a common mechanism involved in both processes. PMID- 21286665 TI - Down-regulation of XIAP by AEG35156 in paediatric tumour cells induces apoptosis and sensitises cells to cytotoxic agents. AB - Resistance to conventional chemotherapy is a major problem in several paediatric tumours. One explanation for this is that tumour cells are unable to engage apoptosis after cytotoxic drug-induced damage. Inhibitor of apoptosis proteins (IAPs) function by inhibiting both effector (9) and initiator (3 and 7) caspases. Repression of the widely expressed X-linked IAP (XIAP) by RNAi sensitises adult tumour cells to cytotoxics in vitro. Antisense oligonucleotide (ASO)-induced down regulation of XIAP is effective at inducing cell death and delaying the growth of adult tumour cells as xenografts and these agents are currently in phase II clinical trials. The importance of XIAP in paediatric tumours has not been characterised but high expression correlates with poor survival in childhood AML. We have used the novel XIAP ASO (AEG35156) to evaluate the effects of down regulation of XIAP in paediatric tumour cells. Here, we show that AEG35156 can down-regulate XIAP in a number of paediatric cell lines including models of osteosarcoma, rhabdomyosarcoma and Ewing's sarcoma. Cell death assays demonstrated a higher proportion of dead cells after XIAP down-regulation by ASO and these cells displayed increased levels of cleaved caspase-3 and cleaved PARP, showing cell death was due to apoptosis. In long-term clonogenic assays, XIAP ASO sensitised 791T osteosarcoma cells to doxorubicin, etoposide and vincristine. The work presented here suggests that AEG35156, as a monotherapy or in combination with cytotoxic agents, may be of benefit in the treatment of paediatric tumours. PMID- 21286666 TI - Lentiviral-mediated siRNA targeted against osteopontin suppresses the growth and metastasis of gastric cancer cells. AB - The expression of osteopontin (OPN) has been correlated with tumor growth and metastasis. However, the mechanisms by which OPN promotes tumor metastasis remain unclear. In this study, we aimed to investigate the anti-tumor effects of OPN by silencing OPN expression in the gastric cancer cell line SGC7901, using lentiviral-OPN small interfering RNA (siRNA) technology. Plasmid vectors containing OPN siRNAs were generated, encoded with lentiviral vector and transfected into SGC7901 cells (SGC-OPN- cells). OPN mRNA and protein expression were examined using real-time reverse transcription polymerase chain reaction (RT PCR) and Western blotting techniques. The tumorigenicity and metastatic potential of SGC7901 cells were studied in nude mice. Expression of OPN and vascular endothelial growth factor (VEGF) in lung metastatic tumor specimens were also examined using immunohistochemistry (IHC). Among the three siRNA sequences tested, siRNA2 most remarkably inhibited mRNA levels of OPN; lentiviral-siRNA2 was stably transfected into SGC7901 cells to generate SGC-OPN- cells. SGC-OPN- cells had significantly decreased OPN expression compared to control cells (relative intensities were 0.14 +/- 0.06 vs. 0.95 +/- 0.16 in controls, P<0.01). A substantial reduction in detectable tumors was found in mice implanted with SGC OPN- cells compared to controls (4.62 +/- 1.24 vs. 8.35 +/- 2.27 cm3 in controls, P<0.01). In addition, mice implanted with SGC-OPN- cells survived longer (101.2 +/- 22.5 vs. 89.2 +/- 24.6 d, P<0.01) and were demonstrated to have less metastases compared to mice implanted with SGC7901 control cells. Interestingly, lentiviral-siRNA2 also suppressed the expression of OPN and VEGF in metastatic lung specimens. Lentiviral-mediated OPN siRNA significantly reduced OPN gene expression, suppressing the growth and metastasis of gastric cancers, which might be related to reduced expression of VEGF. Therefore, OPN could serve as a promising therapeutic target for gastric cancer. PMID- 21286667 TI - Molecular analysis of Fanconi anemia and mismatch repair genes in patients with colorectal carcinoma. AB - A cohort of 206 consecutively-collected patients with colorectal carcinoma (CRC) were screened for germline mutations in the principal DNA mismatch repair (MMR) genes, MLH1 and MSH2, and in the Fanconi anemia (FA) genes involved in homologous recombination DNA repair. Mutation analysis was performed by denaturing high performance liquid chromatography (DHPLC) and automated sequencing. Available paraffin-embedded tumor tissues were evaluated for gene expression by immunohistochemistry. Genes of the FA pathway were found to participate in CRC pathogenesis, being silenced during disease progression and metastasis formation. Conversely, MLH1 and MSH2 genes seem to be inactivated at earlier stages of the disease. Finally, very few (about 5%) cases presented a simultaneous inactivation of the MMR and FA genes. Overall, our findings indicated that: i) mismatch DNA repair remains the main mechanism to be altered at both germline and somatic levels among CRC patients; ii) functional impairments of mismatch DNA repair and FA-related repair may represent two different pathogenetic alterations which are concurring in colorectal cancer progression. PMID- 21286668 TI - Genetic polymorphisms of ERCC1 and their effects on the efficacy of cisplatin based chemotherapy in advanced esophageal carcinoma. AB - The aim of this study was to investigate the relationship between the ERCC1 C8092A, ERCC1-C19007T and GSTP1-A105G genetic polymorphisms and the curative effect of cisplatin-based chemotherapy in advanced esophageal carcinoma. A total of 256 pathologically confirmed advanced esophageal carcinoma patients were given regimens of cisplatin and 5-fluorouracil. Clinical evaluations were obtained from 241 patients who completed the therapy. The remission rate of patients with ERCC1 C8092A, A/C or A/A was higher compared to that of patients with C/C (51.75 vs. 29.59%, P<0.01). Progression-free survival of patients with ERCC1-C8092A, A/C or A/A was longer compared to that of patients with C/C (7.5 months vs. 4.5 months, P<0.0001). The C19007T and GSTP1-A105G genetic polymorphisms were not positively correlated with remission rates and progression-free survival of patients. In conclusion, the ERCC1-C8092A genetic polymorphism may be correlated with the efficacy of cisplatin-based chemotherapy in cases of advanced esophageal carcinoma. Further studies with a larger sample size are needed for tailored chemotherapy treatment of advanced esophageal carcinoma. PMID- 21286669 TI - NAIF1 is down-regulated in gastric cancer and promotes apoptosis through the caspase-9 pathway in human MKN45 cells. AB - Many key proteins are down-regulated or lose their function during cancer genesis and accelerate the progress of cancer. We found that nuclear apoptosis-inducing factor 1 (NAIF1) was highly expressed in normal gastric tissues but was down regulated or lost in gastric cancer tissues (P<0.001). NAIF1 expression was higher in well-differentiated (P=0.004) than in moderately- or poorly differentiated gastric cancer. NAIF1 expression was associated with different T stages (P=0.024). In vitro, NAIF1 can inhibit tumor cell proliferation and induce G0/G1 phase cell cycle arrest in the MKN45 cell line. NAIF1 can induce apoptosis through activation of procaspase-9 rather than procaspase-8 followed by activation of the caspase-3 pathway. We designed and constructed two truncation mutants, pEGFP-N1-NLS and pEGFP-N1-GRR, and identified the N-terminal 1-90 amino acid domain of NAIF1, which is a helix-turn-helix motif and which was sufficient for inducing apoptosis. Therefore, these findings suggest that NAIF1 plays an inhibitory role in the initial steps of gastric cancer genesis and may provide new strategies for developing anti-cancer drugs using small molecular polypeptides. PMID- 21286670 TI - Genetic alterations of tumor suppressor ING1 in human non-small cell lung cancer. AB - The aim of this study was to investigate the function of the ING1 gene in lung carcinoma. To detect the inhibitory effect of ING1 in human lung cancer, recombinant ING1b plasmids were transfected into two lung cancer cell lines with different p53 status, A549 with wild-type p53 (wtp53) and SK-MES-1 with mutant p53. Apoptosis, cell cycle, growth rate and the expression of downstream gene p21waf1 were analyzed. In addition, the complex of p33ING1b and p53 was analyzed with coimmunoprecipitation. To detect the gene alteration and the expression of ING1, 70 cases of fresh-frozen lung carcinomas and 217 cases of formalin-fixed, paraffin-embedded specimens were examined for loss of heterozygosity (LOH) and p33ING1b protein expression by polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) and immunohistochemistry using tissue microarrays, respectively. Overexpression of ING1b inhibited the cell growth of A549 and SK-MES-1, induced cell cycle arrest and apoptosis. p21waf1 was up regulated and a complex of p33ING1b and wtp53 was found after transfection of ING1b in the wtp53-positive lung cancer cell. High LOH frequency was found in lung carcinomas (55.7%) and p33ING1b expression was lost in 115 of 217 carcinomas (53.0%). Furthermore, there was a highly significant inverse correlation between expression and LOH frequency (P<0.05). ING1 can inhibit the growth of lung cancer cell lines through the induction of cell cycle arrest and apoptosis by forming a complex with wtp53 and up-regulating p21waf1. In human lung cancer, expression of the ING1 gene was reduced or lost and high LOH frequency of ING1 microsatellites was found. The LOH of microsatellites may down-regulate p33ING1b and/or affect its function, thereby, contributing to lung cell carcinogenesis. PMID- 21286671 TI - [Heart failure. Excitation-contraction coupling and novel therapeutic options]. AB - Heart failure (HF) is a disease with an increasing prevalence and results in both reduced quality of life and decreased lifespan for patients. Despite improved therapy mortality remains very high. HF is induced by events that lead to reduced function of the heart, e.g. myocardial infarction and increased chronic afterload through arterial hypertension. For compensation to occur, neurohumoral mechanisms temporarily maintain cardiac function. Over time this results in left ventricular remodelling and, by means of a vicious circle, compensated HF becomes symptomatic HF. The myocardium of patients with HF is characterised by a dysfunction in excitation-contraction coupling (ECC), which causes reduced cell contractility due to reduced Ca(2+) transients and SR Ca(2+) load. The Ca(2+)/calmodulin dependent protein kinase IIdelta (CaMKIIdelta) plays an important role in the onset of HF. CaMKIIdelta phosphorylates several functional key proteins, leads to reduced SR Ca(2+) load and Ca(2+)-transients in HF, acts as an arrhythmogenic protein by increasing late I(Na), and contributes to diastolic dysfunction by accumulation of intracellular Ca(2+). CaMKIIdelta also plays an important role in atrial fibrillation. Interestingly, with regard to increased cardiac load, CaMKIIdelta is activated in increased afterload but not in preload. The important role of CaMKIIdelta in HF implies new therapeutic options to improve HF therapy in the future. PMID- 21286672 TI - [Fixator with motion capacity and distraction arthrodiatasis in post-traumatic elbow stiffness]. AB - Elbow stiffness may result from trauma, burns and head injuries. It is defined as a total range of motion of <100 degrees with no relevant loss of forearm rotation. Of particular relevance is the flexion deficit. A detailed analysis regarding the development of the elbow stiffness is required together with an exact diagnosis in order to plan the surgical intervention. Closed distraction of the elbow joint as arthrodiatasis with an external fixator is described and evaluated. Adequate long-term results can be achieved with this technique, which reflects proper selection of patients as well as coordination between surgeon, aftercare and physiotherapist. Contraindications are poor compliance, poorly controlled diabetes mellitus, active hepatitis B and C infection, HIV infection and acute articular infection. PMID- 21286673 TI - [External fixation with motion capacity in acute dislocations and fracture dislocations of the elbow. Fixation with motion capacity]. AB - Dislocations and fracture dislocations with their typical fracture patterns may substantially affect the complex anatomy and integrity of the elbow joint. The more components of the joint are injured, the more technically demanding is the therapy. Standardized diagnostic and therapeutic algorithms help to avoid misinterpretations regarding the severity of the injury and the subsequent complications. In elbow dislocations and fracture dislocations with persistent instability the hinged external fixator is an excellent device to improve joint stability and allows physiotherapeutic assistance at an early stage. PMID- 21286674 TI - [External fixation with motion capacity and radius fractures. Methods and results]. AB - Both the radiocarpal and distal radioulnar joints are often affected in"distal radius fractures". The incidence of this injury increases markedly among women over the age of 40. Bearing in mind the wide variety of distal radius fractures, a fixation system should be used which permits trans- and extra-articular application and subsequent reduction by means of distraction, as well as wrist mobilization. It is important that both reduction and position of the carpal bones can be checked. The possibility of extra-articular (radioradial) fixation should always be considered. AO group A2 and A3 fractures with sufficiently large fragments are suitable for this procedure. In other cases, transarticular application is advised. Complementary measures are justified in the case where two or more cortices in AP and lateral X-rays are destroyed. Adequate implants are also used to stabilize the articular surface. Large bone defects should be filled with corticocancellous material. PMID- 21286675 TI - [External fixator with motion capacity]. PMID- 21286676 TI - [New oral anticoagulants in atrial fibrillation]. AB - Atrial fibrillation (AF) causes at least 20% of all ischemic strokes. In large randomized trials of primary and secondary stroke prevention, anticoagulation with vitamin K antagonists (VKA) protected much more efficiently than antiplatelet agents against stroke. Because of the problematic pharmacological properties of VKA only part of the AF patients are currently being treated with oral anticoagulants (OAK). The targeted development of specific oral inhibitors of the central coagulation factors thrombin and factor Xa allows reliable anticoagulation without regular coagulation monitoring. In the present review, pharmacological properties of the different agents are compared. Of the four large randomized phase 3 studies in AF (RELY, ROCKET-AF, ARISTOTLE, ENGAGE-AF) with the primary efficacy endpoint stroke and systemic embolism, the published data from the RELY trial indicate a superior efficacy of dabigatran etexilate (2 * 150 mg/day) and a lower risk of intracranial hemorrhage compared to warfarin. Favorable preliminary results have been demonstrated for the factor Xa inhibitor rivaroxaban. Apixaban was more efficacious than ASA and had a similar risk of hemorrhage in the AVERROES study. Thus, the available data suggest a favorable benefit-risk ratio for the new substances in addition to improved patient comfort. Currently unresolved issues relate to the verification of patient adherence by suitable coagulation tests and to the emergency coagulation diagnostics and therapy in acute ischemic or hemorrhagic strokes under the new OAC. PMID- 21286677 TI - [Development of mortality and morbidity of vascular diseases: variations between coronary heart disease and stroke]. AB - INTRODUCTION: Cardiovascular diseases represent a central challenge for our health care system because of their individual and societal consequences. The manuscript compares the current development of mortality and morbidity of coronary heart disease and stroke in Germany. RESULTS: Coronary heart diseases are one of the leading causes of death and one of the major causes for adult disability. In Germany the average life expectancy has increased by more then 2 years per decade within recent years. The greatest contribution to the increase in life expectancy between 1980 and 2002 in Germany was attributed in previous studies to the decline in mortality rates of cardiovascular diseases; for example in Germany 134,648 persons died in 2008 from coronary heart disease (ICD-10 I20 I25) and 63,060 persons from stroke (ICD-10 I60-I64) compared to 178,759 persons and 90,241 persons in 1998, respectively. Statistical models from other countries estimated that the decrease in coronary heart disease mortality is attributed by about 40% to better treatment and by about 60% to changes in risk factors in the population. Comparable data for stroke are lacking. CONCLUSION: Despite the substantial knowledge on cardiovascular diseases in Germany a continuous and timely documentation of their determinants, time trends of risk factors and impact regarding mortality and morbidity is compulsory to assess the effectiveness of initiated population health measures and to identify future options for improving prevention and treatment of cardiovascular diseases in Germany. PMID- 21286678 TI - [Interface between heart and brain: challenges and opportunities]. PMID- 21286679 TI - [Value of CT and MR angiography for diagnostics of intracranial aneurysms]. AB - Digital subtraction angiography (DSA) is still considered the gold standard in neurovascular imaging. However, due to permanent progress in the field of cross sectional imaging modalities many questions can be answered with these less invasive methods. The following article gives an overview of the principles of computed tomography angiography (CTA) and magnetic resonance angiography (MRA) and demonstrates the growing importance in the diagnosis and follow-up of intracranial aneurysms. PMID- 21286680 TI - QTL analysis for yield components and kernel-related traits in maize across multi environments. AB - Huangzaosi, Qi319, and Ye478 are foundation inbred lines widely used in maize breeding in China. To elucidate genetic base of yield components and kernel related traits in these elite lines, two F(2:3) populations derived from crosses Qi319 * Huangzaosi (Q/H, 230 families) and Ye478 * Huangzaosi (Y/H, 235 families), as well as their parents were evaluated in six environments including Henan, Beijing, and Xinjiang in 2007 and 2008. Correlation and hypergeometric probability function analyses showed the dependence of yield components on kernel related traits. Three mapping procedures were used to identify quantitative trait loci (QTL) for each population: (1) analysis for each of the six environments, (2) joint analysis for each of the three locations across 2 years, and (3) joint analysis across all environments. For the eight traits measured, 90, 89, and 58 QTL for Q/H, and 72, 76, and 51 QTL for Y/H were detected by the three QTL mapping procedures, respectively. About 70% of the QTL from Q/H and 90% of the QTL from Y/H did not show significant QTL * environment interactions in the joint analysis across all environments. Most of the QTL for kernel traits exhibited high stability across 2 years at the same location, even across different locations. Seven major QTL detected under at least four environments were identified on chromosomes 1, 4, 6, 7, 9, and 10 in the populations. Moreover, QTL on chr. 1, chr. 4, and chr. 9 were detected in both populations. These chromosomal regions could be targets for marker-assisted selection, fine mapping, and map-based cloning in maize. PMID- 21286681 TI - Influence of diabetes on endothelial cell response during sepsis. AB - AIMS/HYPOTHESIS: Several endothelial pathways of cell adhesion, coagulation and vascular endothelial growth factor (VEGF) signalling are activated during sepsis. The objective of this analysis was to investigate the influence of diabetes on biomarkers of endothelial cell activation in sepsis. METHODS: This was a prospective observational cohort study of a convenience sample of adult patients (age >= 18 years) for whom infection was clinically suspected and who presented to an urban tertiary care emergency department between February 2005 and November 2008. We investigated the association of diabetes and sepsis with various endothelial activation biomarkers of cell adhesion (E-selectin, vascular cell adhesion molecule 1 [VCAM-1] and intercellular adhesion molecule 1 [ICAM-1]), coagulation (plasminogen activator inhibitor 1 [PAI-1]) and VEGF signalling (soluble fms-like tyrosine kinase-1 [sFLT-1]). RESULTS: A total of 207 patients (34% with sepsis, 32% with severe sepsis and 34% with septic shock) were studied, including 63 (30%) with diabetes. Compared with patients without diabetes, patients with diabetes had significantly increased E-selectin and sFLT-1 levels overall; this was most pronounced during septic shock in the stratified analysis. Multivariate models including age, sex, sepsis severity and other variables as potential covariates confirmed the association of diabetes with elevated circulating plasma levels of E-selectin (standardised beta 0.24, p < 0.001) and sFLT-1 (standardised beta 0.19, p < 0.01), but there was no significant association with VCAM-1, ICAM-1 or PAI-1. CONCLUSIONS/INTERPRETATION: During septic shock, patients with diabetes had higher levels of circulating biomarkers of endothelial cell adhesion (E-selectin) and VEGF signalling (sFLT-1). Future studies should address whether enhanced activation of the endothelium places patients with diabetes at increased risk for the development of sepsis and worsening morbidity and mortality. PMID- 21286682 TI - Low transition rate from normo- and low microalbuminuria to proteinuria in Japanese type 2 diabetic individuals: the Japan Diabetes Complications Study (JDCS). AB - AIMS/HYPOTHESIS: The aim of the study was to determine the transition rate and factors associated with the progression of normo- and low microalbuminuria to diabetic nephropathy (overt proteinuria). METHODS: For 8 years we prospectively observed 1,558 Japanese patients with type 2 diabetes mellitus whose basal urinary albumin:creatinine ratio (UACR) had been measured as <17.0 mg/mmol at entry. The incidence of nephropathy (UACR >33.9 mg/mmol) was determined by measuring UACR twice a year. RESULTS: Progression to nephropathy occurred in 74 patients. The annual transition rate was 0.67%, and was substantially higher for the low-microalbuminuric group than for the normoalbuminuric group (1.85% and 0.23%, respectively; hazard ratio for the low-microalbuminuric group 8.45, p < 0.01). The hazard ratio for an HbA(1c) of 7-9% or >=9% was 2.72 (p < 0.01) or 5.81 (p < 0.01) relative to HbA(1c) <7.0%, respectively. In comparison with individuals with a systolic blood pressure (SBP) of <120 mmHg, the hazard ratios for patients with an SBP of 120-140 mmHg or >=140 mmHg were 2.31 (p = 0.06) and 3.54 (p < 0.01), respectively. Smoking also affected progression to proteinuria (hazard ratio 1.99, p < 0.01). In contrast, 30.3% of the low-microalbuminuric group returned to normoalbuminuria (i.e. were in remission). CONCLUSIONS/INTERPRETATION: These results suggest that if patients with type 2 diabetes mellitus are receiving treatment from diabetologists for hyperglycaemia and hypertension when they are in the early stages of nephropathy (i.e. normo- or low microalbuminuria), their rate of transition to proteinuria is considerably lowered, and that differentiating patients with low microalbuminuria from those with high microalbuminuria might be clinically useful. TRIAL REGISTRATION: UMIN Clinical Trials Registry C000000222. PMID- 21286683 TI - Elaboration on the association between immigration and schizophrenia: a population-based national study disaggregating annual trends, country of origin and sex over 15 years. AB - PURPOSE: Generally, immigrant status and male sex are separately documented to increase the risk of schizophrenia; although population-based risk trends by sex and immigration over time have not been examined. This study aims to examine the extent to which immigration acts as a risk factor for schizophrenia, delineated by origin, sex and year, using national population-based data over 15 years. METHOD: Data on all first psychiatric admissions from 1978 to 1992 (n = 10,892) from the National Psychiatric Hospitalization Case Registry of the State of Israel were merged with aggregate national data from the Israeli Central Bureau of Statistics. RESULTS: Compared to native-born Israelis, people who migrated prior to the age of 15 (n = 2,335) were at a greater risk of schizophrenia (n = 8,557; RR = 1.6, 95% CI = 1.53; 1.68), particularly those from Far Eastern (RR = 2.43, 95% CI = 1.91; 3.1) and Caribbean and South American (RR = 1.94, 95% CI = 1.51; 2.51) countries. Aggregate risk was higher among female than male immigrants and over the 15-year study immigration-related risk declined across the sexes. CONCLUSION: The current findings replicate past research showing that immigrants, particularly from a social minority, as suggested by the social defeat-hypothesis, are at an increased risk of schizophrenia, and extend past findings to show that risk at least in Israel has decreased with time irrespective of sex. PMID- 21286684 TI - Predicting outcome of assertive outreach across England. AB - BACKGROUND: Assertive community treatment for the severely mentally ill is being implemented increasingly internationally. It is unclear whether recommended characteristics of assertive outreach (AO) teams influence care and outcomes. We hypothesised that recommended characteristics of AO teams such as joint health and social care management would predict reduced hospitalisation in the first year of an AO client programme and related outcomes throughout England. METHODS: A two-stage design was used: a stratified sample of 100 of the 186 'stand-alone' AO teams in England and a systematic sample of clients from each team with stratification for black and ethnic minority patients. Team characteristics, treatment and outcomes were collected from teams. Analyses took account of patients' histories, clustering and ethnic minority over-sampling. RESULTS: Under AO the proportion of time spent in hospital following admission decreased. Only 3/1,096 patients went missing in 9 months. Although patient' histories significantly predicted outcomes almost no team characteristics predicted re admission or other patient outcomes after 1 and 3 years. Ethnic minority clients were more likely to be on compulsory orders only on jointly managed teams (P = 0.030). Multidisciplinary teams and teams not working out of hours significantly predicted that patients received psychological interventions, but only 17% of sampled patients received such treatments. CONCLUSIONS: Characteristics of AO teams do not explain long-term patient outcomes. Since recommended team characteristics are not effective new models of care should be developed and the process of care tested. Managing teams to implement evidence-based psychological interventions might improve outcomes. PMID- 21286685 TI - Transoesophageal echocardiography during prone positioning for ARDS: watching the heart to care for the lung. PMID- 21286686 TI - Adherence to treatment of primary osteoporosis and its association to fractures- the Swedish Adherence Register Analysis (SARA). AB - SUMMARY: Osteoporosis treatments reduce the risk of fractures. The objective of this study was to investigate adherence to treatment of osteoporosis and its association to fractures in Sweden. Adherence to treatment of osteoporosis in Sweden is poor, and time on treatment was found to be significantly associated with fracture incidence. INTRODUCTION: The objective of this study was to estimate persistence and compliance to treatment of primary osteoporosis in Sweden. A second aim was to investigate the determinants of non-persistence and the association between adherence and fracture incidence. METHODS: Patients were identified through filled prescriptions for alendronate, risedronate, strontium ranelate, and raloxifene between 2005 and 2009 from the Swedish Prescribed Drug Register. Persistence was investigated using survival analysis. Medication possession ratio (MPR) was used to measure compliance in persistent patients. The outcome measure in the analysis of adherence and fracture incidence was hospitalized osteoporotic fractures. RESULTS: The final cohort consisted of 56,586 treatment-naive patients (mean age 71, 86% women). A total of 51%, 35%, 25%, and 14% were still on treatment (switching allowed) after 1, 2, 3, and 4 years, respectively. Average MPR in persistent patients was 94.2% (CI(95) 94.2 94.3%). Compared with <1 month of therapy, treatment for 1 month to 1 year, 1 to 2 years, and 2 to 3 years was associated with a lower 3-year fracture incidence (HR 0.86, p = 0.091; HR 0.67, p < 0.001; and HR 0.59, p < 0.001, respectively). No significant relationship was identified between MPR and fracture risk. CONCLUSIONS: Persistence to treatment of osteoporosis in Sweden is poor and approximately 50% of all treatment-naive patients discontinue therapy within 1 year. Average refill compliance, estimated only while the patients were persistent, was found to be close to perfect. A strong association was identified between treatment persistence and fracture incidence, which calls for action to improve the current situation. PMID- 21286687 TI - Protective properties of quercetin against DNA damage and oxidative stress induced by methylmercury in rats. AB - Aim of the study was to find out whether consumption of quercetin (QC), an abundant flavonoid in the human diet, protects against DNA damage caused by exposure to organic mercury. Therefore, rats were treated orally with methylmercury (MeHg) and the flavonoid with doses that reflect the human exposure. The animals received MeHg (30 MUg/kg/bw/day), QC (0.5-50 mg/kg/bw/day), or combinations of both over 45 days. Subsequently, the glutathione levels (GSH) and the activities of glutathione peroxidase (GPx) and catalase (CAT) were determined, and DNA damage was measured in hepatocytes and peripheral leukocytes in single cell gel electrophoresis assays. MeHg decreased the concentration of GSH and the activity of GPx by 17 and 12%, respectively and caused DNA damage to liver and blood cells, while with QC no such effects were seen. When the flavonoid was given in combination with MeHg, the intermediate and the highest concentrations (5.0 and 50.0 mg/kg/bw/day) were found to cause DNA protection; DNA migration was reduced by 54 and 65% in the hepatocytes and by 27 and 36% in the leukocytes; furthermore, the reduction in GSH and GPx levels caused by MeHg treatment was restored. In summary, our results indicate that consumption of QC rich foods may protect Hg-exposed humans against the adverse health effects of the metal. PMID- 21286689 TI - Inhibitor screening of pharmacological chaperones for lysosomal beta glucocerebrosidase by capillary electrophoresis. AB - Pharmacological chaperones (PCs) represent a promising therapeutic strategy for treatment of lysosomal storage disorders based on enhanced stabilization and trafficking of mutant protein upon orthosteric and/or allosteric binding. Herein, we introduce a simple yet reliable enzyme assay using capillary electrophoresis (CE) for inhibitor screening of PCs that target the lysosomal enzyme, beta glucocerebrosidase (GCase). The rate of GCase-catalyzed hydrolysis of the synthetic substrate, 4-methylumbelliferyl-beta-D: -glucopyranoside was performed using different classes of PCs by CE with UV detection under standardized conditions. The pH and surfactant dependence of inhibitor binding on recombinant GCase activity was also examined. Enzyme inhibition studies were investigated for five putative PCs including isofagomine (IFG), ambroxol, bromhexine, diltiazem, and fluphenazine. IFG was confirmed as a potent competitive inhibitor of recombinant GCase with half-maximal inhibitory concentration (IC(50)) of 47.5 +/- 0.1 and 4.6 +/- 1.4 nM at pH 5.2 and pH 7.2, respectively. In contrast, the four other non-carbohydrate amines were demonstrated to function as mixed-type inhibitors with high micromolar activity at neutral pH relative to acidic pH conditions reflective of the lysosome. CE offers a convenient platform for characterization of PCs as a way to accelerate the clinical translation of previously approved drugs for oral treatment of rare genetic disorders, such as Gaucher disease. PMID- 21286690 TI - Comparison of the efficiency of different extraction methods for the simultaneous determination of mycotoxins and pesticides in milk samples by ultra high performance liquid chromatography-tandem mass spectrometry. AB - A rapid multi-analyte method has been developed for the simultaneous determination of pesticides and mycotoxins in milk by ultra high-performance liquid chromatography coupled to triple quadrupole mass spectrometry (UHPLC-QqQ MS/MS). A variety of methodologies has been evaluated, including solid-phase extraction (SPE), "dilute-and-shoot" (liquid-liquid extraction-based procedures), and QuEChERS (quick, easy, cheap, effective, rugged, and safe)-based methods. The optimization and development process was carried out considering that the maximum residue level for aflatoxin M1 (AFM1) in milk in the European Union (EU) is set at 0.05 MUg kg(-1), which is the lowest tolerance in the target compounds. The selected method consisted of an extraction by SPE using C18 as sorbent and methanol as elution solvent. The final determination was performed by UHPLC-QqQ MS/MS. Matrix-matched standard calibration was used for quantification, obtaining recoveries in the range 60-120% with relative standard deviations <25%, at three spiking levels: 0.5, 10, and 50 MUg kg(-1) (ten times lower for AFM1). Limits of quantification ranged from 0.20 to 0.67 MUg kg(-1), which were always below or equal to the established tolerance levels by the EU. Finally, the selected method was applied to different types of milk. PMID- 21286691 TI - Complementary gain modifications of the cervico-ocular (COR) and angular vestibulo-ocular (aVOR) reflexes after canal plugging. AB - To determine whether the COR compensates for the loss of aVOR gain, independent of species, we studied cynomolgus and rhesus monkeys in which all six semicircular canals were plugged. Gains and phases of the aVOR and COR were determined at frequencies ranging from 0.02 to 6 Hz and fit with model-based transfer functions. Following canal plugging in a rhesus monkey, the acute stage aVOR gain was small and there were absent responses to thrusts of yaw rotation. In the chronic state, aVOR behavior was characterized by a cupula/endolymph time constant of ~ 0.07 s, responding only to high frequencies of head rotation. COR gains were ~ 0 before surgery but increased to ~ 0.15 at low frequencies just after surgery; the COR gains increased to ~ 0.4 over the next 12 weeks. Nine weeks after surgery, the summated aVOR + COR responses compensated for head velocity in space in the 0.5-3 Hz frequency range. The gains and phases continued to improve until the 35th week, where the combined aVOR + COR stabilized with gains of ~ 0.5-0.6 and the phases were compensatory over all frequencies. Two cynomolgus monkeys operated 3-12 years earlier had similar frequency characteristics of the aVOR and COR. The combined aVOR + COR gains were ~ 0.4-0.8 with compensatory phases. To achieve gains close to 1.0, other mechanisms may contribute to gaze compensation, especially with the head free. Thus, while there are individual variations in the time of adaptation of the gain and phase parameters, the essential functional organization of the adaption to vestibular lesions is uniform across these species. PMID- 21286692 TI - Neuromuscular electrical stimulation has a global effect on corticospinal excitability for leg muscles and a focused effect for hand muscles. AB - The afferent volley generated during neuromuscular electrical stimulation (NMES) can increase the excitability of human corticospinal (CS) pathways to muscles of the leg and hand. Over time, such increases can strengthen CS pathways damaged by injury or disease and result in enduring improvements in function. There is some evidence that NMES affects CS excitability differently for muscles of the leg and hand, although a direct comparison has not been conducted. Thus, the present experiments were designed to compare the strength and specificity of NMES-induced changes in CS excitability for muscles of the leg and hand. Two hypotheses were tested: (1) For muscles innervated by the stimulated nerve (target muscles), CS excitability will increase more for the hand than for the leg. (2) For muscles not innervated by the stimulated nerve (non-target muscles), CS excitability will increase for muscles of the leg but not muscles of the hand. NMES was delivered over the common peroneal (CP) nerve in the leg or the median nerve at the wrist using a 1-ms pulse width in a 20 s on, 20 s off cycle for 40 min. The intensity was set to evoke an M-wave that was ~15% of the maximal M-wave in the target muscle: tibialis anterior (TA) in the leg and abductor pollicis brevis (APB) in the hand. Ten motor-evoked potentials (MEPs) were recorded from the target muscles and from 2 non-target muscles of each limb using transcranial magnetic stimulation delivered over the "hotspot" for each muscle before and after the NMES. MEP amplitude increased significantly for TA (by 45 +/- 6%) and for APB (56 +/- 8%), but the amplitude of these increases was not different. In non-target muscles, MEPs increased significantly for muscles of the leg (42 +/- 4%), but not the hand. Although NMES increased CS excitability for target muscles to the same extent in the leg and hand, the differences in the effect on non-target muscles suggest that NMES has a "global" effect on CS excitability for the leg and a "focused" effect for the hand. These differences may reflect differences in the specificity of afferent projections to the cortex. Global increases in CS excitability for the leg could be advantageous for rehabilitation as NMES applied to one muscle could strengthen CS pathways and enhance function for multiple muscles. PMID- 21286693 TI - Internal models of self-motion: computations that suppress vestibular reafference in early vestibular processing. AB - In everyday life, vestibular sensors are activated by both self-generated and externally applied head movements. The ability to distinguish inputs that are a consequence of our own actions (i.e., active motion) from those that result from changes in the external world (i.e., passive or unexpected motion) is essential for perceptual stability and accurate motor control. Recent work has made progress toward understanding how the brain distinguishes between these two kinds of sensory inputs. We have performed a series of experiments in which single-unit recordings were made from vestibular afferents and central neurons in alert macaque monkeys during rotation and translation. Vestibular afferents showed no differences in firing variability or sensitivity during active movements when compared to passive movements. In contrast, the analyses of neuronal firing rates revealed that neurons at the first central stage of vestibular processing (i.e., in the vestibular nuclei) were effectively less sensitive to active motion. Notably, however, this ability to distinguish between active and passive motion was not a general feature of early central processing, but rather was a characteristic of a distinct group of neurons known to contribute to postural control and spatial orientation. Our most recent studies have addressed how vestibular and proprioceptive inputs are integrated in the vestibular cerebellum, a region likely to be involved in generating an internal model of self-motion. We propose that this multimodal integration within the vestibular cerebellum is required for eliminating self-generated vestibular information from the subsequent computation of orientation and posture control at the first central stage of processing. PMID- 21286694 TI - Characterization of butyrate uptake by nontransformed intestinal epithelial cell lines. AB - Butyrate (BT) is one of the main end products of anaerobic bacterial fermentation of dietary fiber within the human colon. Among its recognized effects, BT inhibits colon carcinogenesis. Our aim was to characterize uptake of BT by two nontransformed intestinal epithelial cell lines: rat small intestinal epithelial (IEC-6) and fetal human colonic epithelial (FHC) cells. Uptake of 14C-BT by IEC-6 cells was (1) time- and concentration-dependent; (2) pH-dependent; (3) Na+-, Cl-- and energy-dependent; (4) inhibited by BT structural analogues; (5) sensitive to monocarboxylate transporter 1 (MCT1) inhibitors; and (6) insensitive to DIDS and amiloride. IEC-6 cells express both MCT1 and Na+-coupled monocarboxylate transporter 1 (SMCT1) mRNA. We conclude that 14C-BT uptake by IEC-6 cells mainly involves MCT1, with a small contribution of SMCT1. Acute exposure to ethanol, acetaldehyde, indomethacin, resveratrol and quercetin reduced 14C-BT uptake. Chronic exposure to resveratrol and quercetin reduced 14C-BT uptake but had no effect on either MCT1 or SMCT1 mRNA levels. Uptake of 14C-BT by FHC cells was time- and concentration-dependent but pH-, Na+-, Cl-- and energy-independent and insensitive to BT structural analogues and MCT1 inhibitors. Although MCT1 (but not SMCT1) mRNA expression was found in FHC cells, the characteristics of 14C-BT uptake by FHC cells did not support either MCT1 or SMCT1 involvement. In conclusion, uptake characteristics of 14C-BT differ between IEC-6 and FHC cells. IEC-6 cells demonstrate MCT1- and SMCT1-mediated transport, while FHC cells do not. PMID- 21286695 TI - Differentiation between benign and malignant orbital tumors at 3-T diffusion MR imaging. AB - INTRODUCTION: To differentiate between malignant and benign orbital tumors at 3-T diffusion MR imaging. METHODS: A retrospective study was conducted on 47 patients (34 males and 13 females aged 4-74 years) with orbital masses. They underwent echo-planar diffusion-weighted MR imaging of the orbit with b-factor of 0, 500, and 1,000 s/mm(2) at 3-T MR unit. Apparent diffusion coefficient (ADC) maps were reconstructed, and the ADC value of the orbital mass was calculated. RESULTS: The mean ADC value of the malignant orbital tumors (0.84 +/- 0.34 * 10(-3) mm(2)/s) was significantly lower (P = 0.001) than that of the benign orbital tumors (1.57 +/- 0.33 * 10(-3) mm(2)/s). The selection of an ADC value of 1.15 * 10(-3) mm(2)/s as a threshold value for differentiating malignant orbital tumors from benign lesions has a sensitivity of 95%, a specificity of 91%, and an accuracy of 93%. There was a significant difference in the ADC value between well- and poorly differentiated malignancies (P = 0.005). CONCLUSION: Apparent diffusion coefficient value at 3 T is an additional noninvasive imaging parameter that can be used for the differentiation of malignant orbital tumors from benign lesions, the characterization of some orbital tumors, as well as the grading of orbital malignancy. PMID- 21286696 TI - Polymorphisms in the extracellular region of dopamine receptor D4 within and among avian orders. AB - Polymorphisms in the dopamine receptor D4 gene (DRD4) have been widely investigated to assess their correlation with variations in animal behavior. We precisely examined polymorphisms in the extracellular region of DRD4 in 75 avian species belonging to 16 orders and detected high degrees of polymorphism at inter and intraordinal levels. The existence of a variable number of proline repeats (2 to 12 times) in the extracellular region was a common feature in all Neognathae, and a strong codon bias at synonymous sites was found among Passeriformes, Galliformes, and other non-passerine Neoaves. Furthermore, significantly higher values of the pairwise disparity index were detected in Passeriformes, suggesting either a substantial difference in the evolutionary processes or a higher level of mutation rate in the passerine clade. The differences in both codon bias and other genetic parameters among avian taxa would be explained by different levels of selective pressure on the extracellular region of DRD4. Our study suggested that different conformations determined in a sequence-dependent manner at the extracellular region could be one of the key factors affecting the efficiency and accuracy of DRD4 expression. Our findings further imply a possibility that behavioral diversity, which would be important during the processes of adaptive radiation, may be enhanced by the selection acting on indels or single-nucleotide substitutions in the extracellular region of DRD4. PMID- 21286697 TI - Assessment of the exposure to elements from silver jewelry by hair mineral analysis. AB - The aim of the present article was to assess the effect of wearing silver jewelry on mineral composition of human scalp hair. To investigate the possible effect of gender, a group of females and males was distinguished. Subjects, who declared in the questionnaire wearing silver jewelry, constituted 55% of the whole population. It was found that individuals wearing jewelry had increased levels of Ag (~3 times), Ba (30%), Ca (33%), La (40%), Li (25%), and Zn (27%) in hair and lowered level of: Al (34%), K (79%), and Na (32.5%) in comparison with the group that did not wear jewelry. Those differences were statistically significant. Lower levels of K and Na in hair of subjects wearing jewelry was probably related with an antagonism between Ag-K and Ag-Na found in the present work. Analyzing the effect of two grouping variables-gender and wearing silver jewelry-on hair composition, it was observed that statistically significant differences were determined for the following elements: As, Ba, Ca, and Se. Female hair contained two times more Ca, four times Ba, 36% less As, and five times less Se. It was found that 34% of the population wearing silver jewelry had higher Ag content in hair than the upper value of the reference range (0.567 mg/kg) determined for subjects who did not wear jewelry. Ag and other metals (especially Cu and Zn) from jewelry could be absorbed through the skin and therefore hair mineral analysis is useful in the assessment of this exposure. The study was carried out on Poles, among which silver jewelry is particularly popular. The population can be thus considered as exposed. PMID- 21286698 TI - Relating injury to the forest ecosystem near Palmerton, PA, to zinc contamination from smelting. AB - The forest on Blue Mountain, near Lehigh Gap, has been injured by emissions from two historical zinc (Zn) smelters in Palmerton, PA, located at the northern base of the mountain. The uppermost mineral soil and lower litter from sites along a transect, just south of the ridgetop, contained from 64 to 4400 mg/kg Zn. We measured forest metrics at 15 sampling sites to ascertain how forest structure, species composition and regeneration are related to soil concentrations of Zn, the probable principal cause of the injury. Understanding how ecotoxicological injury is related to soil Zn concentrations helps us quantify the extent of injury to the ecosystem on Blue Mountain as well as to generalize to other sites. The sum of canopy closure and shrub cover, suggested as a broadly inclusive measure of forest structure, was decreased to half at approximately 2060 mg/kg Zn (102 mg/kg Sr(N0(3))(2)-extractable Zn). Tree-seedling density was decreased by 80% (from 10.5/m(2) to 2.1/m(2)) at a much lower concentration: 1080 mg/kg Zn (59 mg/kg Sr(N0(3))(2)-extractable Zn). Changes in species composition and richness were not as useful for quantifying injury to the forest. Phytotoxicity, desiccation from exposure, and a gypsy moth infestation combined to form a barren area on the ridgetop. Liming the strongly acid Hazleton soils at the sites would partially ameliorate the observed phytotoxicity and should be considered in planning restoration. PMID- 21286699 TI - Investigating arsenic bioavailability and bioaccumulation by the freshwater oligochaete Lumbriculus variegatus. AB - The complex and variable composition of natural sediments makes it difficult to predict the bioavailability and bioaccumulation of sediment-bound contaminants. Several approaches, including an experimental model using artificial particles as analogues for natural sediments, have been proposed to overcome this problem. For this work, we applied this experimental device to investigate the uptake and bioaccumulation of As(III) by the freshwater oligochaete Lumbriculus variegatus. Five different particle systems were selected, and particle-water partition coefficients for As(III) were calculated. The influence of different concentrations of commercial humic acids was also investigated, but this material had no effect on bioaccumulation. In the presence of particulate matter, the bioaccumulation of As(III) by the oligochaetes did not depend solely on the levels of chemical dissolved but also on the amount sorbed onto the particles and the strength of that binding. This study confirms that the use of artificial particles may be a suitable experimental model for understanding the possible interactions that may occur between contaminants and particulate matter. In addition, it was found that the most hydrophobic resin induced an increase in arsenic bioavailability, leading to the highest bioaccumulation to L. variegatus compared with animals that were exposed to water only. PMID- 21286700 TI - Peroxisome proliferator activated receptor-alpha (PPARalpha) and PPAR gamma coactivator-1alpha (PGC-1alpha) regulation of cardiac metabolism in diabetes. AB - Cardiovascular disease is a leading cause of mortality among patients with diabetes, and heart failure exists even in the absence of coronary disease. Myocardial metabolism is altered in the diabetic heart as a result of changes in substrate availability secondary to insulin resistance. The nuclear receptor peroxisome proliferator activated receptor-alpha (PPARalpha) and PPAR-gamma coactivator-1alpha (PGC-1alpha) play important roles in transcriptional regulation of myocardial metabolism and contribute significantly to the changes that occur in the diabetic heart. This review summarizes the role of PPARalpha and PGC-1alpha in myocardial metabolism in the normal heart and in the diabetic heart. PMID- 21286701 TI - Microbial deterioration of artistic tiles from the facade of the Grande Albergo Ausonia & Hungaria (Venice, Italy). AB - The Grande Albergo Ausonia & Hungaria (Venice Lido, Italy) has an Art Nouveau polychrome ceramic coating on its facade, which was restored in 2007. Soon after the conservation treatment, many tiles of the facade decoration showed coloured alterations putatively attributed to the presence of microbial communities. To confirm the presence of the biological deposit and the stratigraphy of the Hungaria tiles, stereomicroscope, optical and environmental scanning electron microscope observations were made. The characterisation of the microbial community was performed using a PCR-DGGE approach. This study reported the first use of a culture-independent approach to identify the total community present in biodeteriorated artistic tiles. The case study examined here reveals that the coloured alterations on the tiles were mainly due to the presence of cryptoendolithic cyanobacteria. In addition, we proved that the microflora present on the tiles was generally greatly influenced by the environment of the Hungaria hotel. We found several microorganisms related to the alkaline environment, which is in the range of the tile pH, and related to the aquatic environment, the presence of the acrylic resin Paraloid B72(r) used during the 2007 treatment and the pollutants of the Venice lagoon. PMID- 21286702 TI - Bacterioplankton community variation across river to ocean environmental gradients. AB - Coastal zones encompass a complex spectrum of environmental gradients that each impact the composition of bacterioplankton communities. Few studies have attempted to address these gradients comprehensively. We generated a synoptic, 16S rRNA gene-based bacterioplankton community profile of a coastal zone by applying the fingerprinting technique denaturing gradient gel electrophoresis to water samples collected from the Columbia River, estuary, and plume, and along coastal transects covering 360 km of the Oregon and Washington coasts and extending to the deep ocean (>2,000 m). Communities were found to cluster into five distinct groups based on location in the system (ANOSIM, p < 0.003): estuary, plume, epipelagic, shelf bottom (depth < 150 m), and slope bottom (depth > 650 m). Across all environments, abiotic factors (salinity, temperature, depth) explained most of the community variability (rho = 0.734). But within each coastal environment, biotic factors explained most of the variability. Thus, structuring physical factors in coastal zones, such as salinity and temperature, define the boundaries of many distinct microbial habitats, but within these habitats variability in microbial communities is explained by biological gradients in primary and secondary productivity. PMID- 21286703 TI - Intestinal microbiota was assessed in cirrhotic patients with hepatitis B virus infection. Intestinal microbiota of HBV cirrhotic patients. AB - To unravel the profile of intestinal microecological parameters in Chinese patients with asymptomatic carriage of hepatitis B virus (HBV), chronic hepatitis B, decompensated HBV cirrhosis, and health controls and to establish their correlation with liver disease progression, we performed quantitative PCR and immunological techniques to investigate fecal parameters, including population of fecal predominant bacteria and the abundance of some virulence genes derived from Escherichia coli, Bacteroides fragilis, Clostridium difficile, and Clostridium perfringens in fecal crude DNA and some immunological parameters in extracts of all fecal samples. Data analysis indicated that 16S rRNA gene copy numbers for Faecalibacterium prausnitzii, Enterococcus faecalis, Enterobacteriaceae, bifidobacteria, and lactic acid bacteria (Lactobacillus, Pediococcus, Leuconostoc, and Weissella) showed marked variation in the intestine of HBV cirrhotic patients. The Bifidobacteria/Enterobacteriaceae (B/E) ratio, which may indicate microbial colonization resistance of the bowel, was decreased significantly in turn from 1.15 +/- 0.11 in healthy controls, 0.99 +/- 0.09 in asymptomatic carriers, and 0.76 +/- 0.08 in patients with chronic hepatitis B to 0.64 +/- 0.09 in patients with decompensated HBV cirrhosis (for all, P < 0.01). This suggests that B/E ratio is useful for following the level of intestinal microecological disorder in the course of liver disease progression. The data for virulence gene abundance suggested increased diversity of virulence factors during liver disease progression. Fecal secretory IgA and tumor necrosis factor alpha in decompensated HBV cirrhotic patients were present at higher levels than in other groups, which indicates that a complicated autoregulatory system tries to achieve a new intestinal microecological balance. PMID- 21286704 TI - Cyclic antimicrobial R-, W-rich peptides: the role of peptide structure and E. coli outer and inner membranes in activity and the mode of action. AB - This study compares the effect of cyclic R-, W-rich peptides with variations in amino acid sequences and sizes from 5 to 12 residues upon Gram negative and Gram positive bacteria as well as outer membrane-deficient and LPS mutant Escherichia coli (E. coli) strains to analyze the structural determinants of peptide activity. Cyclo-RRRWFW (c-WFW) was the most active and E. coli-selective sequence and bactericidal at the minimal inhibitory concentration (MIC). Removal of the outer membrane distinctly reduced peptide activity and the complete smooth LPS was required for maximal activity. c-WFW efficiently permeabilised the outer membrane of E. coli and promoted outer membrane substrate transport. Isothermal titration calorimetric studies with lipid A-, rough-LPS (r-LPS)- and smooth-LPS (s-LPS)-doped POPC liposomes demonstrated the decisive role of O-antigen and outer core polysaccharides for peptide binding and partitioning. Peptide activity against the inner E. coli membrane (IM) was very low. Even at a peptide to lipid ratio of 8/1, c-WFW was not able to permeabilise a phosphatidylglycerol/phosphatidylethanolamine (POPG/POPE) bilayer. Low influx of propidium iodide (PI) into bacteria confirmed a low permeabilising ability of c WFW against PE-rich membranes at the MIC. Whilst the peptide effect upon eukaryotic cells correlated with the amphipathicity and permeabilisation of neutral phosphatidylcholine bilayers, suggesting a membrane disturbing mode of action, membrane permeabilisation does not seem to be the dominating antimicrobial mechanism of c-WFW. Peptide interactions with the LPS sugar moieties certainly modulate the transport across the outer membrane and are the basis of the E. coli selectivity of this type of peptides. PMID- 21286705 TI - Special issue on membrane-active peptides. PMID- 21286706 TI - Association of Mx1 Asn631 variant alleles with reductions in morbidity, early mortality, viral shedding, and cytokine responses in chickens infected with a highly pathogenic avian influenza virus. AB - Myxovirus-resistance (Mx) proteins are produced by host cells in response to type I interferons, and some members of the Mx gene family in mammals have been shown to limit replication of influenza and other viruses. According to an early report, chicken Mx1 variants encoding Asn at position 631 have antiviral activity, whereas variants with Ser at 631 lack activity in experiments evaluating Mx1 complementary DNA (cDNA) expressed ectopically in a cell line. We evaluated whether the Mx1 631 dimorphism influenced pathogenesis of highly pathogenic avian influenza virus (HPAIV) infection in chickens of two commercial broiler lines, each segregating for Asn631 and Ser631 variants. Following intranasal infection with HPAIV strain A/Chicken/Queretaro/14588-19/1995 H5N2, chickens homozygous for Asn631 allele were significantly more resistant to disease based on early mortality, morbidity, or virus shedding than Ser631 homozygotes. Higher amounts of splenic cytokine transcripts were observed in the Ser631 birds after infection, consistent with higher viral loads seen in this group and perhaps contributing to their higher morbidity. Nucleotide sequence determination of Mx1 cDNAs demonstrated that the Asn631 variants in the two chicken lines differed at several amino acid positions outside 631. In vitro experiments with a different influenza strain (low pathogenicity) failed to demonstrate an effect of Mx1 Asn631 on viral replication suggesting that in vivo responses may differ markedly from in vitro, or that choice of virus strain may be critical in demonstrating effects of chicken Mx1. Overall, these studies provide the first evidence that Mx1 has antiviral effects in chickens infected with influenza virus. PMID- 21286707 TI - Special content of this issue. "International Symposium on Biopolymers 2010" (ISBP2010). PMID- 21286708 TI - Native and artificial forisomes: functions and applications. AB - Forisomes are remarkable protein bodies found exclusively in the phloem of the Fabaceae. When the phloem is wounded, forisomes are converted from a condensed to a dispersed state in an ATP-independent reaction triggered by Ca(2+), thereby plugging the sieve tubes and preventing the loss of photoassimilates. Potentially, forisomes are ideal biomaterials for technical devices because the conformational changes can be replicated in vitro and are fully reversible over a large number of cycles. However, the development of technical devices based on forisomes has been hampered by the laborious and time-consuming process of purifying native forisomes from plants. More recently, the problem has been overcome by the production of recombinant artificial forisomes. This is a milestone in the development of forisome-based devices, not only because large quantities of homogeneous forisomes can be produced on demand, but also because their properties can be tailored for particular applications. In this review, we discuss the physical and molecular properties of native and artificial forisomes, focusing on their current applications in technical devices and potential developments in the future. PMID- 21286709 TI - Diversity and quantity of ammonia-oxidizing Archaea and Bacteria in sediment of the Pearl River Estuary, China. AB - The diversity and abundance of ammonia-oxidizing archaea (AOA) and ammonia oxidizing bacteria (AOB) in the sediment of the Pearl River Estuary were investigated by cloning and quantitative real-time polymerase chain reaction (qPCR). From one sediment sample S16, 36 AOA OTUs (3% cutoff) were obtained from three clone libraries constructed using three primer sets for amoA gene. Among the 36 OTUs, six were shared by all three clone libraries, two appeared in two clone libraries, and the other 28 were only recovered in one of the libraries. For AOB, only seven OTUs (based on 16S rRNA gene) and eight OTUs (based on amoA gene) were obtained, showing lower diversity than AOA. The qPCR results revealed that AOA amoA gene copy numbers ranged from 9.6 * 10(6) to 5.1 * 10(7) copies per gram of sediment and AOB amoA gene ranged from 9.5 * 10(4) to 6.2 * 10(5) copies per gram of sediment, indicating that the dominant ammonia-oxidizing microorganisms in the sediment of the Pearl River Estuary were AOA. The terminal restriction fragment length polymorphism results showed that the relative abundance of AOB species in the sediment samples of different salinity were significantly different, indicating that salinity might be a key factor shaping the AOB community composition. PMID- 21286710 TI - Proteomic understanding of intracellular responses of recombinant Chinese hamster ovary cells cultivated in serum-free medium supplemented with hydrolysates. AB - In order to understand the intracellular responses in recombinant CHO (rCHO) cells producing antibody in serum-free medium (SFM) supplemented with optimized hydrolysates mixtures, yielding the highest specific growth rate (MU, SFM#S1) or the highest specific antibody productivity (q(Ab,) SFM#S2), differentially expressed proteins in rCHO cells are measured by two-dimensional gel electrophoresis combined with nano-LC-ESI-Q-TOF tandem MS. The comparative proteomic analysis with basal SFM without hydrolysates revealed that the addition of hydrolysate mixtures significantly altered the profiles of CHO proteome. In SFM#S1, the expression of metabolism-related proteins, cytoskeleton-associated proteins, and proliferation-related proteins was up-regulated. On the other hand, the expression of anti-proliferative proteins and pro-apoptotic protein was down regulated. In SFM#S2, the expression of various chaperone proteins and proliferation-linked proteins was altered. 2D-Western blot analysis of differentially expressed proteins confirmed the proteomic results. Taken together, identification of differentially expressed proteins in CHO cells by a proteomic approach can provide insights into understanding the effect of hydrolysates on intracellular events and clues to find candidate genes for cell engineering to maximize the protein production in rCHO cells. PMID- 21286711 TI - Sustained release of PI3K inhibitor from PHA nanoparticles and in vitro growth inhibition of cancer cell lines. AB - The phosphoinositide-3-kinases (PI3Ks) are a conserved family of lipid kinases that phosphorylate the 3-hydroxyl group of phosphatidylinositols in response to extracellular stimuli. PI3K pathway is enrolled in different kinds of human cancer and plays a prominent role in cancer cell growth and survival. Several PI3K inhibitors have been recently identified but some PI3K inhibitors with high potency in vitro do not show satisfactory effects in animal cancer models because of the poor pharmaceutical properties in vivo such as poor solubility, instability, and fast plasma clearance rate. In this study, we developed a sustained release system of PI3K inhibitor (TGX221) based on polyhydroxyalkanoate nanoparticles (NP) and used it to block proliferation of cancer cell lines. TGX221 was gradually released from PHA-based NP and growth of cancer cell lines was significantly slower in NP-TGX221-treated cells than in either negative controls or in cells receiving free TGX221. Since poor bioavailability and limited in vivo half-life are common features of hydrophobic PI3K inhibitors, our results open the way to similar formulation of other PI3K blockers and to new strategies in cancer treatment. PMID- 21286712 TI - Reduction of produced elementary sulfur in denitrifying sulfide removal process. AB - Denitrifying sulfide removal (DSR) processes simultaneously convert sulfide, nitrate, and chemical oxygen demand from industrial wastewater into elemental sulfur, dinitrogen gas, and carbon dioxide, respectively. The failure of a DSR process is signaled by high concentrations of sulfide in reactor effluent. Conventionally, DSR reactor failure is blamed for overcompetition for heterotroph to autotroph communities. This study indicates that the elementary sulfur produced by oxidizing sulfide that is a recoverable resource from sulfide-laden wastewaters can be reduced back to sulfide by sulfur-reducing Methanobacterium sp. The Methanobacterium sp. was stimulated with excess organic carbon (acetate) when nitrite was completely consumed by heterotrophic denitrifiers. Adjusting hydraulic retention time of a DSR reactor when nitrite is completely consumed provides an additional control variable for maximizing DSR performance. PMID- 21286713 TI - Defining a reference range of acetabular inclination and center-edge angle of the hip in asymptomatic individuals. AB - PURPOSE: Acetabular morphology is an important predictor of the severity of osteoarthrosis and survival of hip prostheses but there is limited data on the normal range of acetabular measurements on plain radiographs. The aim of this project was to determine the statistically normal ranges of acetabular inclination (AI) and center-edge angle (CEA). METHOD: One hundred coronal CT localizers (50 men and 50 women aged 20-30 years) were included in this study. All the patients underwent CT examination for thoracic or intra-abdominal indications. Patients with pelvic disease, fractures, history of serious trauma, or previous pelvic surgery were excluded. One pair of independent observers measured the AI and pelvic tilt (PT), and a further pair measured the center-edge angle (CEA), using electronic calipers on a high-resolution PACS workstation. RESULTS: AI and CEA measurements were obtained for 200 hips. There was very good intra-class correlation between the observers (r = 0.7-0.8). The mean AI was 38.8 degrees (2SD 32.1-45.5 degrees ). That in men was 38.0 degrees (2 SD 31.8-44.1 degrees ) and 39.6 degrees (2 SD 32.7-46.8 degrees ) in women, which was statistically significantly different (p < 0.001). The mean CEA measurement for all patients was 36.3 degrees (SD 13.8 degrees ), for men 37.7 degrees (SD 10.8 degrees ) and for women 34.9 degrees (SD 11.4 degrees ) with a statistically significant gender difference (p < 0.001). The mean pelvic tilt measurement (sacro-coccygeal-pubic symphysis) was 38.3 mm (2 SD 18.3-58.3 mm) with a significant gender difference (p < 0.001). CONCLUSIONS: The results of this study define reference ranges of two common measures of acetabular morphology and confirm statistically significant differences between men and women. PMID- 21286714 TI - A new grading system of lumbar central canal stenosis on MRI: an easy and reliable method. AB - OBJECTIVE: To introduce a new grading system of lumbar central canal stenosis, evaluate its reliabilities, and compare it to the cross-sectional area and anterior-posterior diameter of the dural sac. MATERIALS AND METHODS: Lumbar central canal stenosis is defined as obliteration of the anterior CSF space in front of the cauda equina. Four musculoskeletal radiologists independently graded lumbar central canal stenosis by this new grading system based on separation degree of the cauda equina on T2-weighted axial images (grade 0 = no lumbar stenosis without obliteration of anterior CSF space; grade 1 = mild stenosis with separation of all cauda equina; grade 2 = moderate stenosis with some cauda equina aggregated; and grade 3 = severe stenosis with none of the cauda equina separated) in 81 patients to determine inter- and intra-reader reliability. One radiologist measured cross-sectional areas and anterior-posterior diameters and compared these to lumbar central canal stenosis grades. RESULTS: Inter-reader reliabilities were substantial to almost perfect (ICC reliability = 0.730-0.953). Intra-reader reliability was almost perfect (kappa value = 0.863-0.900). Cross sectional areas and anterior-posterior diameters were different according to grades at all levels (p = 0.000-0.049), except between grades 2 and 3 of L2-3. At L5-S1, only anterior-posterior diameter was different between grades 0 and 1 (p = 0.005) and between grades 0 and 2 (p = 0.022). CONCLUSIONS: This new grading system may be helpful to clinicians for simple and practical evaluation of lumbar central canal stenosis and for communicating with each other. PMID- 21286717 TI - Clinical spectrum and prognosis of follicular lymphoma with blastoid transformation: case series and a review of the literature. AB - Follicular lymphoma (FL) with blastoid transformation (FL-BT) is a rare entity. FL-BT has a dismal prognosis due to intrinsic biological characteristics, lack of evidence-based therapeutic guidelines, and exclusion from clinical trials. In order to understand the natural course of the disease and reconcile treatment strategies in patients with FL-BT, we reviewed available data. Thirty patients were identified, three from our institution (Roswell Park Cancer Institute) and 27 patients from peer-reviewed literature. Demographic, clinical, treatment, pathological, and cytogenetic characteristics were described. Most of the patients (90%) were treated with chemotherapy at transformation. Complete and partial responses to treatment were observed in 38.9% and 22.3% of the patients, respectively. The median overall survival for the entire group of patients was 11 months (range 0.8-30 months); half of the patients were found to have concurrent genetic alterations in the BCL-2 and C-MYC gene rearrangements (double hit). FL BT with a double hit had a shorter median overall survival when compared to nondouble hit FL-BT (7 months vs. 26 months, respectively, P = 0.005). In our experience, FL-BT is a rare and grave clonal evolution in FL characterized by an aggressive clinical course, inferior response to standard chemoimmunotherapy, and poor clinical outcome. C-MYC rearrangements are common in FL-BT and may play a role in the progression from FL to FL-BT or the poor clinical outcomes observed. Periodic updates from academic institutions treating FL-BT may improve patient care. PMID- 21286716 TI - Defining the cancer master switch. AB - BACKGROUND: Recent research has focused on signaling cascades and their interactions yielding considerable insight into which genetic pathways are targeted and how they tend to be altered in tumors. Therapeutic interventions now can be designed based on the knowledge of pathways vital to tumor growth and survival. These critical targets for intervention, master switches for cancer, are termed so because the tumor attempts to "flip the switch" in a way that promotes its survival, whereas molecular therapy aims to "switch off" signals important for tumor-related processes. METHODS: Literature review. CONCLUSIONS: Defining useful targets for therapy depends on identifying pathways that are crucial for tumor growth, survival, and metastasis. Because not all signaling cascades are created equal, selecting master switches or targets for intervention needs to be done in a systematic fashion. This discussion proposes a set of criteria to define what it means to be a cancer master switch and provides examples to illustrate their application. PMID- 21286718 TI - Cetuximab enhances the activities of irinotecan on gastric cancer cell lines through downregulating the EGFR pathway upregulated by irinotecan. AB - PURPOSE : Treatment effects of advanced gastric cancer (AGC) are unsatisfactory, and novel therapeutic approaches are much needed. The epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab inhibits the growth of several human cancer cells but has been tested rarely for the treatment of GC. The synergy between cetuximab and irinotecan has been reported in colorectal cancer, but the mechanisms are still not fully clarified. Consequently, we hypothesized cetuximab/irinotecan combination should enhance the antitumor activity of irinotecan in GC cells. METHODS : The in vitro antiproliferative, pro-apoptotic, cell cycle arrest effects and induction of senescence were examined in SGC-7901 and MKN-45 GC cell lines. The effects of cetuximab or irinotecan as single agents or the combination on the expression of p53, p16, and EGFR signaling pathways were also studied. RESULTS : The study revealed that cetuximab alone did not show any antiproliferative, pro-apoptotic, cell cycle arrest or cellular senescence effect on GC cells but when combined with irinotecan synergistically inhibits GC cell proliferation and induces apoptosis and G2/M phase arrest. Irinotecan increases phosphorylation of EGFR, MAPK, and AKT and decreases the expression of P27(Kip1), which could be all abrogated by its combination with cetuximab. The combination could also inhibit the expression of Cyclin D1 and phosphorylated mTOR while had no impact on p53, p16, PTEN, and HIF-1alpha. CONCLUSIONS : Cetuximab enhances the activities of irinotecan on GC cells via the downregulation of the EGFR pathway upregulated by irinotecan. Combination therapy with cetuximab and irinotecan, a novel therapeutic approach, warrants further study in GC. PMID- 21286719 TI - Genetic variation in radiation and platinum pathways predicts severe acute radiation toxicity in patients with esophageal adenocarcinoma treated with cisplatin-based preoperative radiochemotherapy: results from the Eastern Cooperative Oncology Group. AB - PURPOSE: Germline genetic variations may partly explain the clinical observation that normal tissue tolerance to radiochemotherapy varies by individual. Our objective was to evaluate the association between single-nucleotide polymorphisms (SNPs) in radiation/platinum pathways and serious treatment-related toxicity in subjects with esophageal adenocarcinoma who received cisplatin-based preoperative radiochemotherapy. METHODS: In a multicenter clinical trial (E1201), 81 eligible treatment-naive subjects with resectable esophageal adenocarcinoma received cisplatin-based chemotherapy concurrent with radiotherapy, with planned subsequent surgical resection. Toxicity endpoints were defined as grade >=3 radiation-related or myelosuppressive events probably or definitely related to therapy, occurring during or up to 6 weeks following the completion of radiochemotherapy. SNPs were analyzed in 60 subjects in pathways related to nucleotide/base excision- or double stranded break repair, or platinum influx, efflux, or detoxification. RESULTS: Grade >=3 radiation-related toxicity (mostly dysphagia) and myelosuppression occurred in 18 and 33% of subjects, respectively. The variant alleles of the XRCC2 5' flanking SNP (detected in 28% of subjects) and of GST-Pi Ile-105-Val (detected in 65% of subjects) were each associated with higher odds of serious radiation-related toxicity compared to the major allele homozygote (47% vs. 9%, and 31% vs. 0%, respectively; P = 0.005). No SNP was associated with myelosuppression. CONCLUSIONS: This novel finding in a well characterized cohort with robust endpoint data supports further investigation of XRCC2 and GST-Pi as potential predictors of radiation toxicity. PMID- 21286720 TI - Multidrug-resistant enterococci in animal meat and faeces and co-transfer of resistance from an Enterococcus durans to a human Enterococcus faecium. AB - Forty-eight isolates resistant to at least two antibiotics were selected from 53 antibiotic-resistant enterococci from chicken and pig meat and faeces and analysed for specific resistance determinants. Of the 48 multidrug-resistant (MDR) strains, 31 were resistant to two antibiotics (29 to erythromycin and tetracycline, 1 to erythromycin and vancomycin, 1 to vancomycin and tetracycline), 14 to three (erythromycin, tetracycline and vancomycin or ampicillin) and 3 to four (erythromycin, vancomycin, ampicillin and gentamicin). erm(B), tet(M), vanA and aac (6')-Ie aph (2'')-Ia were the antibiotic resistance genes most frequently detected. All 48 MDR enterococci were susceptible to linezolid and daptomycin. Enterococcus faecalis (16), Enterococcus faecium (8), Enterococcus mundtii (2) and Enterococcus gallinarum (1) were identified in meat, and E. faecium (13) and Enterococcus durans (13) in faeces. Clonal spread was not detected, suggesting a large role of gene transfer in the dissemination of antibiotic resistance. Conjugative transfer of resistance genes was more successful when donors were enterococcal strains isolated from faeces; co transfer of vanA and erm(B) to a human E. faecium occurred from both E. faecium and E. durans pig faecal strains. These data show that multidrug resistance can be found in food and animal species other than E. faecium and E. faecalis, and that these species can efficiently transfer antibiotic resistance to human strains in inter-specific matings. In particular, the occurrence of MDR E. durans in the animal reservoir could have a role in the emergence of human enterococcal infections difficult to eradicate with antibiotics. PMID- 21286721 TI - Germinant generation from delta-endotoxin of Bacillus thuringiensis strain 1.1. AB - The novel finding of this study is that the delta-endotoxin present in the spore coat of Bacillus thuringiensis strain 1.1 (Bt1.1), plays a central role in spore germination by generation of germinant via its beta-glucosidase activity and is based on the following: (i) the crystals of Bt1.1 consist of the 140 kDa delta endotoxin which exhibits beta-glucosidase enzymatic activity. Besides crystals, delta-endotoxin is also located in the spore coat and at this site displays beta glucosidase activity, resulting in glucose production; (ii) glucose is an efficient germinant of both Bt1.1 and acrystalliferous Bt4.1 strain; (iii) substrates of beta-glucosidase can activate the germination of Bt1.1 spores, but not those of the acrystalliferous Bt4.1 sister strain that do not contain the 140 kDa delta-endotoxin; (iv) Reduction or enhancement of enzymatic activity of delta endotoxin, results in retardation or acceleration of germination and outgrowth, respectively. Bt1.1 cells secrete a 60 kDa polypeptide which displays beta glucosidase activity as indicated by zymogram analysis and which is immunologically related to the 140 kDa delta-endotoxin. PMID- 21286722 TI - Ankylosing spondylitis in Ireland: patient access and response to TNF-alpha blockers. AB - To investigate a group of Irish ankylosing spondylitis patients: current prescription practice for TNF blockers and patient response. All patients presenting with ankylosing spondylitis (AS) and treated with TNF-alpha between January 2006 and 2008 in the midwestern region of Ireland were studied. Response was evaluated using Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), and CRP results at 6 months. A total of 47 AS patients (32 men: 15 women, mean age 37.7 years, median disease duration 20 years, 80% HLA B27 positive) were identified; 66% were on disease-modifying anti-rheumatic drugs (DMARDs) concomitantly. All patients satisfied BSR/ASAS disease severity criteria for TNF-alpha at baseline, and mean BASDAI was 6.2, BASFI 6.9, and CRP 27.5 mg/L. At 6 months, these had reduced to a mean BASDAI of 3.8, BASFI 4.6, and CRP of 8.9 mg/L. Patients with advanced AS (disease duration >10 years, mean BASFI 7.5) responded at least as well. No allergies or serious side effects were encountered, and one patient successfully switched TNF agent due to secondary failure. Initial good responses at 6 months were seen to be maintained in sub-group analysis at 12 months. Disease severity in patients gaining access to treatment for active AS with TNF blockers in Ireland is very high. Patients mainly satisfy international guidelines for the use of biologics (BSR, EULAR) with some minor exceptions. High disease activity and long disease duration may predict better treatment response. Response rates were good and treatment was well tolerated, and no differences in response were noted between the 3 agents employed. PMID- 21286723 TI - The CD226 gene in susceptibility of rheumatoid arthritis in the Chinese Han population. AB - Recent case-control studies have identified some loci that are associated with rheumatoid arthritis (RA). Among these, a single nucleotide polymorphism (SNP), Gly307Ser (rs763361), in the CD226 gene was first discovered to confer the risk of RA in populations with European and Colombian ancestry. Because the effect of genetic factors varies in different races, the association between RA and CD226 is yet to be evaluated in other non-European populations. Here, we report the significant association between CD226 and RA in a Chinese population of 423 randomly enrolled individuals. The statistical results show that the rs763361 SNP in the CD226 gene is significantly associated with RA in the Chinese population group (P (obs) = 0.005, odds ratio = 1.52). After adjusting for sex and age using multivariate logistics regression analysis, the association is still positive (P (adj) = 0.029, odds ratio = 1.45). Meta-analysis confirms the association between rs763361 and RA (overall P < 0.001, overall odds ratio = 1.12). The test of odds ratio heterogeneity also suggests that the rs763361 SNP confers the same risk of RA in both the Chinese and the Colombian populations, and indicates that rs763361 may play a more important role in non-European populations compared with the European population (P = 0.031). These results demonstrate a genetic association between the CD226 gene and RA in a Chinese Han population with a potentially greater genetic effect than in the European population. PMID- 21286724 TI - The role of randomized controlled trials in evidence-based urology. AB - PURPOSE: To review the current and future role of randomized controlled trials (RCTs) in urology. METHODS: A review of the urological literature was performed to assess the current role of RCTs in urology. These findings were put in context of current practice, and methodologic limitations of observational study design were discussed. RESULTS: Several RCTs have improved treatment of urology patients. However, overall, few studies in the urologic literature convey high level evidence. RCTs represent the only study design that can assess causality, thus are the only means to significantly advance knowledge about therapy and improve patient care. Increased incidence and improved quality of RCTs may be achieved through education, community outreach, and better access to research infrastructure. CONCLUSIONS: RCTs have significantly improved urologic practice. RCTs are superior to observational studies because of decreased risk of bias and confounding. To further advance clinical practice, clinical trials must play a predominant role and should be embraced by the urology community. PMID- 21286725 TI - The crossroads of evidence-based medicine and health policy: implications for urology. AB - As healthcare spending in the United States continues to rise at an unsustainable rate, recent policy decisions introduced at the national level will rely on precepts of evidence-based medicine to promote the determination, dissemination, and delivery of "best practices" or quality care while simultaneously reducing cost. We discuss the influence of evidence-based medicine on policy and, in turn, the impact of policy on the developing clinical evidence base with an eye to the potential effects of these relationships on the practice and provision of urologic care. PMID- 21286726 TI - Validation of the preoperative aspects and dimensions used for an anatomical (PADUA) score in a robot-assisted partial nephrectomy series. AB - OBJECTIVES: PADUA score is a standardized anatomical classification of renal tumors proposed with the aim to objectivize the decision-making process of any urologist evaluating kidney tumors potentially suitable for nephron-sparing surgery. The system was proposed in a series of patients treated with open partial nephrectomy (PN) and was recently validated in a series of patients treated with either open or laparoscopic PN. The purpose of the present study was to validate the PADUA score in a series of consecutive patients who underwent robot-assisted PN (RPN). METHODS: We evaluated retrospectively all the MRI or CT images of 62 consecutive patients who underwent RPN for renal tumors at a nonacademic teaching institution by a single surgeon between September 2006 and November 2009. RESULTS: PADUA score (6-7 vs. 8-11) was correlated with warm ischemia time (WIT) (P = 0.002), console time (P = 0.001), blood loss (P = 0.009), percentage of pelvicaliceal repair (P = 0.002), and overall complications (P = 0.02). PADUA score was the only variable able to predict the risk of the overall complications (P = 0.02). PADUA score turned out to be an independent predictor of WIT >20 min in multivariable analysis (OR 5.4; P = 0.002), once adjusted for surgeon's experience Finally, PADUA score was the only independent predictor of the need for pelvicaliceal repair (OR 3.7; P = 0.006). CONCLUSIONS: PADUA classification was an effective tool to predict WIT and risk of perioperative complications also in patients who underwent RPN. This classification must be considered useful to improve patients counseling and selection for RPN. PMID- 21286727 TI - Local interneuron diversity in the primary olfactory center of the moth Manduca sexta. AB - Local interneurons (LNs) play important roles in shaping and modulating the activity of output neurons in primary olfactory centers. Here, we studied the morphological characteristics, odor responses, and neurotransmitter content of LNs in the antennal lobe (AL, the insect primary olfactory center) of the moth Manduca sexta. We found that most LNs are broadly tuned, with all LNs responding to at least one odorant. 70% of the odorants evoked a response, and 22% of the neurons responded to all the odorants tested. Some LNs showed excitatory (35%) or inhibitory (33%) responses only, while 33% of the neurons showed both excitatory and inhibitory responses, depending on the odorant. LNs that only showed inhibitory responses were the most responsive, with 78% of the odorants evoking a response. Neurons were morphologically diverse, with most LNs innervating almost all glomeruli and others innervating restricted portions of the AL. 61 and 39% of LNs were identified as GABA-immunoreactive (GABA-ir) and non-GABA-ir, respectively. We found no correlations between odor responses and GABA-ir, neither between morphology and GABA-ir. These results show that, as observed in other insects, LNs are diverse, which likely determines the complexity of the inhibitory network that regulates AL output. PMID- 21286728 TI - Growing old with the immune system: a study of immunosenescence in the zebra finch (Taeniopygia guttata). AB - Immunosenescence has not received much attention in birds and the few existing studies indicate that the occurrence of immunosenescence and/or its extent may differ between species. In addition, not much information is available on the immunosenescence patterns of different immune parameters assessed simultaneously in both sexes within a single species. The present study reports the results on immunosenescence in innate immunity and both cellular and humoral acquired immunity of both sexes in a captive population of zebra finch (Taeniopygia guttata) using three age groups (approximately 0.2, 2.5 and 5.1 years). Both male and female finches showed an inverse U-shaped pattern in cellular immune function with age, quantified by a PHA response. Males showed stronger responses than females at all ages. In contrast, an increase with age in humoral immunity, quantified through total plasma immunoglobulin Y levels, was found in both sexes. However, our measurements of innate immunity measured through the bacteria killing ability against Escherichia coli gave inconclusive results. Still, we conclude that both cellular and humoral acquired immunity are susceptible to immunosenescence, and that the sexes differ in cellular immunity. PMID- 21286729 TI - Transumbilical approach for ventriculoperitoneal shunt placement in infants and small children: a 6-year experience. AB - INTRODUCTION: Improved cosmesis has been demonstrated using a transumbilical incision for placement of the peritoneal end of a ventriculoperitoneal shunt. We now present our experience with this technique. PATIENTS AND METHODS: From January 2005 until present, a prospective cohort of 25 children underwent placement of a ventriculoperitoneal shunt with the peritoneal shunt catheter being introduced into the peritoneum via an incision into the umbilicus. There were 17 boys and 8 girls. The age range at insertion was 6 days to 5 years (mean 1.2 years). RESULTS: The mean follow-up for this group was 3.2 years (range 2 months to 6 years). Of all patients, only one complication (4%) has occurred, although this did not lead to long-term issues. The infection rate for this small group was 0%. CONCLUSIONS: Placement of the peritoneal end of a ventriculoperitoneal shunt via an umbilical incision is effective, cosmetically appealing, and not more prone to complications than other standard incisions used on the anterior abdominal wall. Additionally, and based on our experience, this approach is quicker and almost bloodless with no long-term complications. PMID- 21286730 TI - Clinico-radiological outcomes following gamma knife radiosurgery for pediatric arteriovenous malformations. AB - PURPOSE: The aim of this study was to evaluate clinico-radiological outcomes following gamma knife radiosurgery (GKS) for pediatric arteriovenous malformations (AVMs). METHODS: The present series included 39 children (3-17 years of age) who underwent GKS for cerebral AVMs between January 2002 and February 2008. Twenty-five patients presented with hemorrhages. The median AVM volume was 1.5 cm3, and the median marginal dose was 20 Gy. All patients continued to have follow-up for more than 24 months with serial magnetic resonance images (MRIs)/angiograms. Current school performance has been evaluated using a telephone survey answered by the patients' parents. RESULTS: Follow-up angiograms, available in 34 patients, confirmed complete obliteration in 16 patients. Serial MRIs indicated obliteration of the nidus in one of five patients without angiography. The diffuse nidus structure and low marginal dose were significantly associated with incomplete obliteration. Twelve patients underwent a second GKS, and subsequent angiographies, available in six patients, demonstrated complete obliteration in two of them. Complications included new onset seizures (n = 1), apraxia (n = 1), and temporal horn entrapment requiring a shunt operation (n = 1). School performance declined in 14 out of 32 patients. Both the AVM volume and modified AVM score were found to be reliable predictors of school performance. CONCLUSIONS: The results of the present study substantiate the diffuse and other atypical features of pediatric AVMs as major determinants of treatment failure following GKS. Considering the apparent declination of school performance, future prospective studies would be required to investigate the possible late-effects of GKS on neuropsychological function. PMID- 21286731 TI - Development of an acute obstructive hydrocephalus model in rats using N-butyl cyanoacrylate. AB - PURPOSE: Previous animal models of obstructive hydrocephalus that was frequently combined with subarachnoid inflammation are not suitable for investigating cerebrospinal fluid (CSF) flow between ventricles and cisterns in obstructive hydrocephalus. In this study, we attempted to develop a new animal model for obstructive hydrocephalus in rats sparing subarachnoid space using N-butyl cyanoacrylate (NBCA). METHODS: Hydrocephalus was induced in adult male Sprague Dawley rats with NBCA (n=15) or with kaolin (n=10). For the NBCA model, a silicone tube was inserted through the foramen of Magendie into the fourth ventricle, into which 20 MUL of a mixture of NBCA and ethiodized oil was injected. For the kaolin model, 100 MUL of 20% kaolin solution was injected into the cistern magna. The rats in the NBCA and kaolin groups were sacrificed 3 and 21 days after surgery, respectively. RESULTS: Eleven rats in the NBCA group developed hydrocephalus (73.3%), with a 13.3% mortality rate. The kaolin group showed hydrocephalus in eight rats (80%), with a 20% mortality rate. The mean Evans' indices were 0.37 +/- 0.02, 0.45 +/- 0.04, and 0.53 +/- 0.09 in the control, NBCA, and kaolin groups, respectively (p < 0.05). There was no remarkable arachnoid adhesion or inflammatory change of the ventricular wall in the NBCA group. CONCLUSIONS: The NBCA model seems to be a useful animal model for acute obstructive hydrocephalus with preserved subarachnoid CSF pathway. This model can be useful for studying CSF flow between ventricles and cisterns. PMID- 21286732 TI - The outcome of laparoscopic portoenterostomy for biliary atresia in children. AB - AIM: There were only a few reports on laparoscopic portoenterostomy for biliary atresia in children. We report our experience on laparoscopic Kasai operation for biliary atresia. MATERIAL AND METHODS: A retrospective review of all children who had biliary atresia underwent laparoscopic portoenterostomy from January 2002 to September 2006 were included and analyzed. RESULTS: Sixteen children (five boys and eleven girls) with a mean age of 66 days (range 47-106 days) at operation were included in this study. All patients had type III biliary atresia. There was no conversion to open procedure. The operative time ranged from 193 to 435 min (mean 292 min). At a median follow-up of 72 months (range 33-89 months), eight patients were free of jaundice with bilirubin level <20 MUmol/L and did not require liver transplantation. Seven patients underwent liver transplantation. One patient who had persistent elevated bilirubin defaulted follow-up. One patient complicated with volvulus of intestine post-operatively. All patients survived except one patient who had combined liver and intestine transplantation. CONCLUSION: Laparoscopic portoenterostomy in children with biliary atresia is technically feasible. 50% of children who had type III biliary atresia were free of jaundice and did not require liver transplantation. A longer follow-up is required to assess the long-term outcome. PMID- 21286733 TI - Inflammatory myofibroblastic tumor of the trachea. AB - This report described a 2-year-old boy who was presented with severe respiratory distress and stridor. Bronchoscopy and CT revealed a mass in the left anterolateral tracheal wall and histopathology showed a tracheal inflammatory myofibroblastic tumor. Initial removal by rigid bronchoscopy resulted in prompt recurrence of the tumor. Therefore, he underwent tracheal surgical resection. A bronchoscopy at 12 months after surgery did not show any recurrence sign. PMID- 21286734 TI - Captopril modulates acetylcholinesterase in human keratinocytes. AB - Human keratinocytes synthesize and secrete non-neuronal acetylcholine, which acts as a local cell signaling molecule, regulating functions like proliferation, cell adhesion, motility, desmosomal cell contact, and glandular activity. The keratinocyte acetylcholine axis is composed of the enzymes mediating acetylcholine synthesis (acetyltransferase) and degradation (acetylcholinesterase), and two classes of acetylcholine receptors. In this study we investigated the effect of captopril, an ACE-inhibitor, on acetylcholinesterase and acetylcholine secretion in human keratinocytes. We analyzed the level of acetylcholinesterase in HaCat and NHEK cells by RT-PCR and Western blotting analysis. In addition, the effect of captopril on AChE activity was evaluated. We found that captopril induces a strong AChE up-regulation leading to ACh degradation and reduced secretion. Our results suggest that acantholysis induced by ACE-inhibitors might be linked to altered level of Ach. PMID- 21286735 TI - A preliminary study of differentially expressed genes in expanded skin and normal skin: implications for adult skin regeneration. AB - In adults, severely damaged skin heals by scar formation and cannot regenerate to the original skin structure. However, tissue expansion is an exception, as normal skin regenerates under the mechanical stretch resulting from tissue expansion. This technique has been used clinically for defect repair and organ reconstruction for decades. However, the phenomenon of adult skin regeneration during tissue expansion has caused little attention, and the mechanism of skin regeneration during tissue expansion has not been fully understood. In this study, microarray analysis was performed on expanded human skin and normal human skin. Significant difference was observed in 77 genes, which suggest a network of several integrated cascades, including cytokines, extracellular, cytoskeletal, transmembrane molecular systems, ion or ion channels, protein kinases and transcriptional systems, is involved in the skin regeneration during expansion. Among these, the significant expression of some regeneration related genes, such as HOXA5, HOXB2 and AP1, was the first report in tissue expansion. Data in this study suggest a list of candidate genes, which may help to elucidate the fundamental mechanism of skin regeneration during tissue expansion and which may have implications for postnatal skin regeneration and therapeutic interventions in wound healing. PMID- 21286736 TI - Photosensitizers and light sources for photodynamic therapy of the Bowen's disease. AB - Bowen's disease is a neoplastic skin disease, known as squamous cell carcinoma in situ. The treatment options for Bowen's disease are: cryotherapy, curettage, surgery, topical therapy and radiotherapy. In the past recent years, photodynamic therapy was used as a new treatment method. The purpose of this paper is to summarize the results of clinical and research studies with respect to the photodynamic therapy of Bowen's disease. A search of three databases was conducted using specific keywords and explicit inclusion and exclusion criteria for the study of photosensitizers, light sources and their efficacy in photodynamic therapy of Bowen's disease. Two photosensitizers have been used mainly for photodynamic therapy of Bowen's disease therapy: delta-aminolevulinic acid and methyl aminolevulinate. These photosensitizers have been activated with both coherent (lasers) and non-coherent (lamps and LEDs) light sources. Fluence has been set in a large domain (10-240 J/cm(2)) and irradiance was 0.23-100 mW/cm(2). All these light sources have the same efficacy. The high response rates were obtained using methyl aminolevulinate and light emitting diode as light source. These results have demonstrated that photodynamic therapy using methyl aminolevulinate as photosensitizer could be considered as one of the first therapeutic options for Bowen' disease. PMID- 21286737 TI - Verrucous carcinoma (carcinoma cuniculatum) of the head and neck: what do we know now that we did not know a decade ago? PMID- 21286738 TI - Internuclear chromosome distribution of dysplastic megakaryocytes in myelodysplastic syndromes is dependent on the level of ploidy. AB - Megakaryopoiesis is largely disturbed in myelodysplastic syndromes (MDS), and megakaryocytes (MKs) frequently show multinucleation. Here, we investigated dysplastic mono-, bi-, and multinuclear MKs (n = 169) of seven patients with MDS and one patient with myelodysplastic/myeloproliferative neoplasm by sequential multilocus FISH. Analysis of binuclear MKs with a combined DNA content of 4 N (n = 46) indicated a significantly even (symmetric) chromosome distribution between the two separate nuclei (p = 0.0223), which suggests bipolar spindle orientation and symmetric chromosome segregation during the first endomitotic cell cycle. In contrast, multinuclear MKs of higher ploidy (>4 N, n = 108) demonstrated a significantly uneven (asymmetric) chromosome distribution between the separate nuclei (p = 0.0248). Thus, the internuclear chromosomal distribution of dysplastic MKs depends on the level of ploidy. In addition, centrosomal aberrations were not found in dysplastic MKs. Our results indicate that megakaryocytic multinucleation in MDS originates from dysregulated endomitosis, including restoration of karyokinesis. PMID- 21286739 TI - Body mass and corrective factor: impact on temperature-based death time estimation. AB - Model-based methods play an important role in temperature-based death time determination. The most prominent method uses Marshall and Hoare's double exponential model with Henssge's parameter determination. The formulae contain body mass as the only non-temperature parameter. Henssge's method is well established since it can be adapted to non-standard cooling situations varying the parameter body mass by multiplying it with the corrective factor. The present study investigates the influence of measurement errors of body mass m as well as of variations of the corrective factor c on the error of the Marshall and Hoare Henssge death time estimator t (D). A formula for the relative error of t (D) as a function of the relative error of m is derived. Simple approximations of order 1 and 0 nevertheless yield acceptable results validated by Monte Carlo simulations. They also provide the rule of thumb according to which the quotient of the standard deviations D(t (D)) of the estimated death time and D(m) of the body mass is equal to the quotient of the estimated death time t (D) and the body mass m (D(t (D))/D(m) ~ t (D)/m). Additionally, formulae and their approximations are derived to quantify the influence of Henssge's body mass corrective factor c on death time estimation. In a range of body masses between 50 and 150 kg, the relative variation of the body mass corrective factor is approximately equal to the relative variation of the death time (Deltat (D) = (t (D)/c)Deltac). This formula is applied and compared to computations and to experimental cooling data with good results. PMID- 21286740 TI - Transcranial magnetic stimulation primes the effects of exercise therapy in multiple sclerosis. AB - Exercise therapy (ET) can be beneficial in disabled multiple sclerosis (MS) patients. Intermittent transcranial magnetic theta burst stimulation (iTBS) induces long-term excitability changes of the cerebral cortex and may ameliorate spasticity in MS. We investigated whether the combination of iTBS and a program of ET can improve motor disability in MS patients. In a double-blind, sham controlled trial, 30 participants were randomized to three different interventions: iTBS plus ET, sham stimulation plus ET, and iTBS alone. Before and after 2 weeks of treatment, measures of spasticity through the modified Ashworth scale (MAS) and the 88 items Multiple Sclerosis Spasticity Score questionnaire (MSSS-88), fatigue through the Fatigue Severity Scale (FSS), daily living activities (ADL) through the Barthel index and health-related quality of life (HRQoL) through the 54 items Multiple Sclerosis Quality of life inventory (MSQoL 54) were collected. iTBS plus ET reduced MAS, MSSS-88, FSS scores, while in the Barthel index and MSQoL-54, physical composite scores were increased. iTBS alone caused a reduction of the MAS score, while none of the measured scales showed significant changes after sham iTBS plus ET. iTBS associated with ET is a promising tool for motor rehabilitation of MS patients. PMID- 21286741 TI - Brainstem hemorrhage after neural therapy for decreased libido in a 31-year-old woman. PMID- 21286743 TI - Parkinson's disease: news on tremor, subthalamic stimulation and impulse control disorders. PMID- 21286742 TI - Lazar Solomonovich Minor (1855-1942). PMID- 21286744 TI - Acute pulmonary edema caused by a multiple sclerosis relapse. PMID- 21286745 TI - Clinical predictors of death in young and middle-aged patients with ischemic stroke or transient ischemic attack: long-term results of the Vienna Stroke Registry: clinical predictors of ischemic stroke mortality in patients <60 years. AB - Data on long-term survival of younger patients with ischemic stroke (IS) are limited. We assessed mortality rates and clinical predictors of survival in patients with IS or transient ischemic attack (TIA) <60 years. Consecutive patients with IS or TIA <60 years admitted to nine neurological departments in Vienna between 1998 and 2001 were included into the current study. The endpoint was overall mortality. Univariate Cox regression analyses were performed. Significant variables after Bonferroni adjustment were further considered in a multivariate Cox regression analysis. Kaplan-Meier curves and ROC curves were plotted. After excluding patients who died within the first 30 days, 661 patients (65% male, mean age 50.2) were followed for a mean of 8.8 years. The cumulative mortality rate was 2.4% after 1 year and 7.8% after 5 years. Diabetes, heavy drinking, heart failure, and age remained significantly associated with mortality in the multivariate Cox regression analysis. Separate analysis of the patient groups <50 and >= 50 years showed none of the included factors to be significantly associated with mortality in the younger patient group. In the patient group, >= 50 of the same risk factors as in the whole group analysis showed a statistically significant influence. The observed mortality rates were lower compared to earlier studies conducted in younger patient groups. Although we found subgroups at higher risk of death in the entire population, in patients <50 years of age, predictors of survival remained elusive. PMID- 21286746 TI - A brief history of trp: commentary and personal perspective. AB - The history of the discovery of the transient receptor potential (TRP) cation channel superfamily began in 1969 with Cosens and Manning's isolation of the Drosophila transient receptor potential mutant, in which the photoreceptor response decays during continuous illumination. Early studies from Minke found that the elementary light response was unaffected in trp mutants, and he attributed the defect to an intermediate stage of phototransduction. Montell and Rubin cloned the trp gene in 1989: they recognised it as a transmembrane protein, but also concluded that it did not encode the light-sensitive channels. In 1991, Minke and Selinger proposed that TRP represented a Ca2+ transporter required for refilling intracellular InsP3-sensitive Ca2+ stores, in turn required for activation of the light-sensitive channels. Also in 1991, after developing a photoreceptor patch clamp preparation, I showed that the light-sensitive channels themselves were highly permeable to Ca2+, questioning the need for such a dedicated Ca2+ transporter. In 1992, in collaboration with Minke, I resolved this paradox by showing there were two classes of light-sensitive channels, one highly Ca2+ permeable and eliminated in trp mutants. This represented the first and compelling evidence that TRP represented a light-sensitive channel and was supported by the cloning of the second light-sensitive channel, TRPL, by Kelly's lab. Three years later, in 1995, the labs of Montell and Birnbaumer independently cloned TRPC1, the first of 29 vertebrate TRP isoforms distributed amongst seven subfamilies. PMID- 21286747 TI - The involvement of a protein kinase in phototaxis and gravitaxis of Euglena gracilis. AB - The unicellular flagellate Euglena gracilis shows positive phototaxis at low light intensities (<10 W/m(2)) and a negative one at higher irradiances (>10 W/m(2)). Phototaxis is based on blue light-activated adenylyl cyclases, which produce cAMP upon irradiation. In the absence of light the cells swim upward in the water column (negative gravitaxis). The results of sounding rocket campaigns and of a large number of ground experiments led to the following model of signal perception and transduction in gravitaxis of E. gracilis: The body of the cell is heavier than the surrounding medium, sediments and thereby exerts a force onto the lower membrane. Upon deviation from a vertical swimming path mechano sensitive ion channels are activated. Calcium is gated inwards which leads to an increase in the intracellular calcium concentration and causes a change of the membrane potential. After influx, calcium activates one of several calmodulins found in Euglena, which in turn activates an adenylyl cyclase (different from the one involved in phototaxis) to produce cAMP from ATP. One further element in the sensory transduction chain of both phototaxis and gravitaxis is a specific protein kinase A. We found five different protein kinases A in E. gracilis. The blockage of only one of these (PK.4, accession No. EU935859) by means of RNAi inhibited both phototaxis and gravitaxis, while inhibition of the other four affected neither phototaxis nor gravitaxis. It is assumed that cAMP directly activates this protein kinase A which may in turn phosphorylate a protein involved in the flagellar beating mechanism. PMID- 21286748 TI - Flower development in garlic: the ups and downs of gaLFY expression. AB - The lack of sexual processes prohibits genetic studies and conventional breeding in commercial cultivars of garlic. Recent restoration of garlic flowering ability by environmental manipulations has opened new avenues for physiological and genetic studies. The LEAFY homologue gaLFY has been shown to be involved in the floral development, while two alternatively spliced gaLFY transcripts are expressed in flowering genotypes. In the present work, quantitative real-time PCR and two techniques of RNA in situ hybridization were employed to analyze spatiotemporal expression patterns of the gaLFY during consequent stages of the garlic reproductive process. Temporal accumulation of gaLFY is strongly associated with reproductive organs, significantly increased during florogenesis and gametogenesis, and is down-regulated in the vegetative meristems and topsets in the inflorescence. The two alternative transcripts of the gene show different expression patterns: a high level of the long gaLFY transcript coincided only with floral transition, while further up-regulation of this gene in the reproductive organs is associated mainly with the short gaLFY transcript. It is concluded that gaLFY is involved at different stages of the sexual reproduction of garlic. These new insights broaden our basic understanding of flower biology of garlic and help to establish conventional and molecular breeding systems for this important crop. PMID- 21286749 TI - Adolescent alcohol intoxication in Dutch hospital centers of pediatrics: characteristics and gender differences. AB - Gender differences in alcohol intoxication among adolescents are still largely unknown, whereas these differences have been studied in adults. To investigate possible differences, this study analyzed pediatric admissions for alcohol intoxication to the majority of Dutch hospitals between 2007 and 2009. Another aim was to explore key characteristics (e.g. blood alcohol concentration, duration of reduced consciousness, and age) and trends of alcohol intoxication among adolescents in the period 2007-2009. We analyzed data from the Dutch Pediatric Surveillance system, which monitors alcohol intoxication among children in pediatric departments of Dutch hospitals. Patients aged 11-17 years with reduced consciousness due to alcohol intoxication were included. The number of adolescents admitted with alcohol intoxication increased sharply from 2007 to 2009. The average age of the patients treated for alcohol intoxication increased from 15.3 years in 2007 and 15.4 years in 2008 to 15.7 years in 2009. The duration of reduced consciousness due to alcohol intoxication also increased over the 3-year period: from 2.2 to 3.1 h. Gender differences were observed regarding alcohol intoxication characteristics. Most strikingly, intoxicated girls were younger (15.3 vs. 15.7 years), had a lower blood alcohol concentration (1.79 vs. 1.94 g/l) and were hospitalized for shorter times than boys. No association was found between alcohol intoxication and other, possibly illicit drug use. The drinks most consumed prior to hospital admission were spirits and beer. Alcohol intoxication among adolescents is an emerging problem. Differences in intoxication characteristics between boys and girls were observed. These findings are important for future prevention and intervention strategies. In the Netherlands, special policlinics for children with alcohol intoxication have already been established. PMID- 21286750 TI - Different structure and mRNA expression of Entamoeba invadens chitinases in the encystation and excystation. AB - Entamoeba histolytica forms chitin-walled cysts during encystation process, where formation of the cyst wall needs not only chitin synthase but also chitinase. During excystation, quadruplet amoebae emerge from the chitin-walled cysts by dissolving the wall, so that chitinase may be necessary for excystation process as well. There is, however, no report on chitinase expression during excystation. In this study, we used Entamoeba invadens, a reptilian amoeba, as a model for encystation and excystation of E. histolytica, and studied chitinase mRNA expression in those processes. Although expression of three E. invadens chitinases designated EiChit1, EiChit2, and EiChit3 during encystation has been reported, we identified another enzyme named as EiChit4 in the E. invadens genome database. Therefore, we investigated the primary structure and mRNA expression of these four chitinases of Ei in the excystation as well as the encystation by real time reverse transcription polymerase chain reaction (RT-PCR). Like EiChit1, EiChit4 had an 8 * Cys chitin-binding domain (CBD) and a hydrophilic spacer between the CBD and catalytic domain, and was also closer to EiChit1 than EiChit2 and EiChit3 in the phylogenetic tree. During encystation, the expression of all four chitinases increased in the early phase; the increase in EiChit1 and EiChit4 was much higher than in EiChit2 and EiChit3. Then, the expression of all four chitinases sharply decreased in the later phase. In cysts, EiChit1 was most abundantly expressed and EiChit4 was at a lower level, while the expressions of EiChit2 and EiChit3 were virtually absent. Following the induction of excystation, mRNA levels of EiChit1 and EiChit4 in cysts 5 h after induction were significantly lower than those in cysts before induction, while those of EiChit2 and EiChit3 were remarkably higher than before induction. The mRNAs of only EiChit2 and EiChit3 remarkably increased when the excystation was induced in the presence of cytochalasin D. These data demonstrate different structures and expressions of four chitinases in the differentiation of E. invadens. PMID- 21286751 TI - A comprehensive molecular survey of Echinococcus granulosus in formalin-fixed paraffin-embedded tissues in human isolates in Turkey. AB - Cystic echinococcosis (CE) due to the formation of a hydatic cyst is a disease commonly seen in humans and animals that can be mortal sometimes. This disease, which is present in many countries around the world, constitutes a great problem for public health and the economy. The aim of this study was to identify Echinococcus granulosus genotypes in formalin-fixed, paraffin-embedded tissues. Tissue samples from 70 human patients with histologically confirmed echinococcosis were analysed by direct PCR of the 12S rRNA gene and by DNA sequence analysis of the CO1 gene of E. granulosus. Of the 70 samples, 29 (41.6%) could be genotypically characterized. Specifically, 26 of 70 were positive by direct G1-3 PCR of the 12S rRNA gene, two of which were identified as G1 by additional CO1 gene sequencing. All the 44 unidentified samples underwent CO1 sequencing, which yielded one G3 and two G6 records, while the remaining 41 samples gave no or inconclusive results. In conclusion, the results from the analysis of human isolates of E. granulosus confirmed the occurrence of G1, G3 and G6 genotypes in Turkey and indicated G1/G3 cluster (E. granulosus sensu stricto) as the predominant genotype. PMID- 21286752 TI - Histopathology of the reproductive system of male sheep experimentally infected with Toxoplasma gondii. AB - The aim of this study was to investigate the histopathological changes in reproductive system (testicles, epididymis, seminal vesicles, and prostate) of small male ruminants after Toxoplasma gondii infection. Eight sheep were inoculated with T. gondii: group I, four sheep (2.0 * 10(5) P-strain oocysts); group II, four sheep (1.0 * 10(6) RH-strain tachyzoites); and group III, two uninfected sheep maintained as control. Infection with T. gondii was confirmed by seroconversion (indirect fluorescent antibody test-IgG) in all the infected animals beginning on post-inoculation day (PID) 7. On PID 70, all the animals were euthanized and tissue samples (testicles, epididymis, seminal vesicles, and prostate) were collected and processed for histological analysis. The main changes detected were a focal mononuclear interstitial inflammatory infiltrate in the prostate and seminal vesicles; diffuse testicular degeneration associated with calcification foci and a multifocal mononuclear interstitial inflammatory infiltrate; and a mononuclear interstitial infiltrate and focal necrotic areas of the muscle fibers surrounding the seminal vesicles. The histopathological findings of this work, along with the detection of T. gondii in the examined parenchyma tissues (immunohistochemistry) and the results obtained by other authors examining different tissues, suggest that histological changes diagnosed in the reproductive system of rams infected with T. gondii are strongly suggestive of toxoplasmatic infection. PMID- 21286753 TI - Naturally acquired IgG antibodies against the C-terminal part of Plasmodium falciparum sporozoite threonine-asparagine-rich protein in a low endemic area. AB - Plasmodium falciparum sporozoite threonine-asparagine-rich protein (STARP), a 78 kDa surface protein, is considered a potential vaccine candidate. The C-terminal part of STARP has been evolved under positive selection, suggesting the presence of immunodominant epitopes. However, little is known about the immune responses against STARP among individuals upon natural malaria exposure. In this study, we have cloned and expressed in Escherichia coli the recombinant C-terminal part of STARP spanning 118 amino acids in order to examine the humoral immune response against this protein. Blood samples were randomly collected from 74 individuals living in a malaria endemic area of Thailand who were acutely infected with P. falciparum (n = 54) and with Plasmodium vivax (n = 20). Malaria-negative blood samples were also obtained from 27 individuals living in the same endemic area who had experienced prior infection with P. falciparum 6 months to 1 year before sample collection and 20 healthy subjects without history of malaria exposure. Western blot analysis revealed that IgG antibodies against this recombinant peptide were found in 23 of 54 serum samples (42.6%) from P. falciparum-infected individuals. All serum samples from P. vivax-infected cases, non-infected individuals, and those who experienced prior infection with P. falciparum gave negative results, indicating that naturally acquired IgG antibodies against the C terminal part of STARP are species-specific and short-lived. Provided that antibodies against STARP could confer protection, it is likely that malaria vaccine derived from the C-terminal part of STARP could probably be boosted upon natural exposure to P. falciparum. PMID- 21286754 TI - Diurnally subperiodic filariasis in India-prospects of elimination: precept to action? AB - The elimination of lymphatic filariasis in the Andaman and Nicobar Islands provides unique opportunities and challenges at the same time. Since these islands are remote, are sparsely populated, and have poor transport networks, mass drug administration programs are likely to be difficult to implement. Diurnally subperiodic Wuchereria bancrofti vectored by Downsiomyia nivea was considered for the scope of vector control options. Considering the bioecology of this mosquito, vector control including personal protection measures may not be feasible. However, since these islands are covered by separate administrative machinery which also plays an important role in regulating the food supply, the use of diethylcarbamazine (DEC)-fortified salt as a tool for the interruption of transmission is appealing. DEC-fortified salt has been successfully pilot tested in India and elsewhere, operationally used by China for eliminating lymphatic filariasis. Administration of DEC-fortified salt though simple, rapid, safe, and cost-effective, challenges are to be tackled for translating this precept into action by evolving operationally feasible strategy. Although the use of DEC fortified salt is conceptually simple, it requires commitment of all sections of the society, an elaborate distribution mechanism that ensures the use of DEC fortified salt only in the endemic communities, and a vigorous monitoring mechanism. Here, we examine the inbuilt administrative mechanisms to serve the tribal people, health infrastructure, and public distribution system and discuss the prospects of putting in place an operationally feasible strategy for its elimination. PMID- 21286755 TI - Expression of a mammalian aquaporin 3 homolog in the anterior pituitary gonadotrophs of the tree frog, Hyla japonica. AB - Aquaporins (AQPs) are a family of water channel proteins that play a major role in maintaining water homeostasis in various organisms. Several AQPs have been identified in the tree frog, Hyla japonica. Of these, AQP-h3BL, which is expressed in the basolateral membrane of the epithelial cells, is a homolog of mammalian AQP3. Using immunohistochemistry and in situ RT-PCR, we have demonstrated that AQP-h3BL is expressed in the anterior pituitary gonadotrophs of the tree frog but not in the other hormone-producing cells of the anterior pituitary. In gonadotrophs labeled for luteinizing hormone subunit-beta (LHbeta), AQP-h3BL protein was found to reside in the plasma membrane, the nuclear membrane and the cytoplasm. Double-labeling of AQP-h3BL mRNA and LHbeta protein revealed that AQP-h3BL mRNA is expressed in the gonadotrophs. Following stimulation by gonadotropin-releasing hormone (GnRH), the label for AQP-h3BL localized in the plasma membrane became more intense, concomitant with the transport of LHbeta positive materials to the plasma membrane. These developments coincided with a decrease in the labeling density in the cytoplasm and near the nuclear membrane, suggesting that the latter localizations may function as "storage area" for AQP h3BL. Immunoelectron microscopy also confirmed these localizations of AQP-h3BL protein. Based on these results, we suggest that AQP-h3BL protein in the frog gonadotrophs is involved in the formation of secretory granules, the swelling and increase in the volume of the granules and exocytosis. PMID- 21286756 TI - Implications of autophagy for glomerular aging and disease. AB - Glomerular diseases lead to a progressive decline in renal function and account for the vast majority of end-stage kidney diseases. Injury and loss of glomerular podocytes are common determining factors of glomerular disease progression and renal failure. Podocytes are a primary glomerular target of toxic, immune, metabolic, and oxidant stress, but little is known of the factors that counteract cellular stress signaling pathways. This review focuses on recent findings that identify autophagy as a critical homeostatic and quality control mechanism maintaining glomerular homeostasis. PMID- 21286757 TI - Immobilization and characterization of benzoylformate decarboxylase from Pseudomonas putida on spherical silica carrier. AB - If an adequate biocatalyst is identified for a specific reaction, immobilization is one possibility to further improve its properties. The immobilization allows easy recycling, improves the enzyme performance, and it often enhances the stability of the enzyme. In this work, the immobilization of the benzoylformate decarboxylase (BFD) variant, BFD A460I-F464I, from Pseudomonas putida was accomplished on spherical silica. Silicagel is characterized by its high mechanical stability, which allows its application in different reactor types without restrictions. The covalently bound enzyme was characterized in terms of its activity, stability, and kinetics for the formation of chiral 2 hydroxypropiophenone (2-HPP) from benzaldehyde and acetaldehyde. Moreover, temperature as well as pressure dependency of immobilized BFD A460I-F464I activity and enantioselectivity were analyzed. The used wide-pore silicagel shows a good accessibility of the immobilized enzyme. The activity of the immobilized BFD A460I-F464I variant was determined to be 70% related to the activity of the free enzyme. Thereby, the enantioselectivity of the enzyme was not influenced by the immobilization. In addition, a pressure-induced change in stereoselectivity was found both for the free and for the immobilized enzyme. With increasing pressure, the enantiomeric excess (ee) of (R)-2-HPP can be increased from 44% (0.1 MPa) to 76% (200 MPa) for the free enzyme and from 43% (0.1 MPa) to 66% (200 MPa) for the immobilized enzyme. PMID- 21286758 TI - Hypertension and hemodialysis: pathophysiology and outcomes in adult and pediatric populations. AB - Hypertension is prevalent in adult and pediatric end-stage renal disease patients on hemodialysis. Volume overload is a primary factor contributing to hypertension, and attaining true dry weight remains a priority for nephrologists. Other contributing factors to hypertension include activation of the sympathetic and renin-angiotensin-aldosterone systems, endothelial cell dysfunction, arterial stiffness, exposure to hypertensinogenic drugs, and electrolyte imbalances during hemodialysis. Epidemiologic studies in adults show that uncontrolled hypertension results in cardiovascular morbidity, but reveal increased mortality risk at low blood pressure, so that it remains unclear what the target blood pressure should be. Despite the lack of a definitive BP target, gradual dry weight reduction should be the first intervention for BP control. Renin-angiotensin-aldosterone system inhibitors have been shown to improve cardiovascular morbidity and mortality and are recommended as the initial pharmacologic therapy for hypertensive hemodialysis patients. Short-daily or nocturnal hemodialysis are also good therapeutic options for these patients. It is already established that hypertension in pediatric hemodialysis patients is associated with adverse cardiovascular outcomes, and there is emerging evidence that the mechanisms causing hypertension are similar to adults. Hypertension in adult and pediatric hemodialysis patients warrants aggressive management, although clinical trial evidence of a target BP that improves mortality does not currently exist. PMID- 21286759 TI - A quality control program for mutation detection in KIT and PDGFRA in gastrointestinal stromal tumours. AB - BACKGROUND: Although most gastrointestinal stromal tumours (GIST) carry oncogenic mutations in KIT exons 9, 11, 13 and 17, or in platelet-derived growth factor receptor alpha (PDGFRA) exons 12, 14 and 18, around 10% of GIST are free of these mutations. Genotyping and accurate detection of KIT/PDGFRA mutations in GIST are becoming increasingly useful for clinicians in the management of the disease. METHOD: To evaluate and improve laboratory practice in GIST mutation detection, we developed a mutational screening quality control program. Eleven laboratories were enrolled in this program and 50 DNA samples were analysed, each of them by four different laboratories, giving 200 mutational reports. RESULTS: In total, eight mutations were not detected by at least one laboratory. One false positive result was reported in one sample. Thus, the mean global rate of error with clinical implication based on 200 reports was 4.5%. Concerning specific polymorphisms detection, the rate varied from 0 to 100%, depending on the laboratory. The way mutations were reported was very heterogeneous, and some errors were detected. CONCLUSION: This study demonstrated that such a program was necessary for laboratories to improve the quality of the analysis, because an error rate of 4.5% may have clinical consequences for the patient. PMID- 21286760 TI - Perforation of the sigmoid colon due to intradiscal spacer dislocation. AB - A case of late dislocation of a disc spacer L5/S1 with perforation of the sigmoid colon and transanal passage 4 years after implantation is reported. The objective is to describe an uncommon complication of anterior endoscopic spondylodesis L5/S1. To our knowledge, this is the first report on this rare complication. A 39 year-old patient suffering from a spondylolisthesis L5/S1 (Meyerding grade 2) with bilateral lysis L5 was operated with posterior instrumentation L5/S1 and anterior endoscopic insertion of two disc spacers. 4 years after surgery the patient noticed one of the spacers in the toilet. Radiographic examination of the colon with contrast dye revealed a perforation at the distal sigmoid colon. At the lumbosacral junction there was a bony defect at the site of the absent spacer and an anterior dislocation of the second spacer. A partial resection of the colon at the perforation site with end-to-end anastomosis was performed. The second spacer was removed, and the defect was packed with autologous cancellous bone and local antibiotics. The further course was uneventful. 2 weeks postoperatively the patient was discharged without signs of infection. The radiographic examination after 6 months showed healing of the bone graft with bony fusion L5/S1. In case of incomplete or absent bony fusion the dislocation of intradiscal spacers may arise even years after the primary surgery. In consequence periodical radiographic examinations of spinal instrumentations are recommended until complete bony fusion occurred. Unclear abdominal symptoms following anterior spine surgery require immediate examination. PMID- 21286761 TI - Circadian rhythms of serum atrial natriuretic peptide. PMID- 21286762 TI - Bilateral open-door expansive laminoplasty using unilateral posterior midline approach with preservation of posterior supporting elements for management of cervical myelopathy and radiculomyelopathy--analysis of clinical and radiological outcome and surgical technique. AB - BACKGROUND: The purpose of this study was to evaluate bilateral open-door cervical laminoplasty for management of cervical canal stenosis secondary to multisegmental cervical spondylosis and ossified posterior longitudinal ligament. The importance of unilateral posterior approach with preservation of posterior supporting element is emphasized. METHODS: Thirty-four patients had expansive laminoplasty. Posterior tension band consisting of nuchal ligaments and supraspinous and interspinous ligaments was secured. Paraspinal deep extensor muscles attached to one side of spinous process were also preserved. Hydroxyapatite-collagen spacers were positioned between split laminae in midline and secured with Ethibond. All patients had features of myelopathy with weakness, hypertonia, clonus, and hyperreflexia in both upper and lower limbs. Bladder and bowel involvement was seen in 11.7% and sexual dysfunction in 5.8%. Preoperative dynamic study of cervical spine, MRI, and/or CT were done in all patients and compared with postoperative studies to see the efficacy of the surgical procedure. RESULTS: Preoperative and postoperative neurosurgical cervical spine scale was used to compare results in relation to age, sex, duration of symptoms, neurosurgical cervical spine score, bladder, bowel, and sexual abnormalities. Elderly patients, lower neurosurgical score, signs and symptoms of more than 2 years, and bladder, bowel, and sexual dysfunction had poorer outcome. Complications were few. All patients had adequate diameter of spinal canal postoperatively. Cervical alignment and range of motion of segment subjected to laminoplasty were preserved satisfactorily in follow-up. CONCLUSIONS: Bilateral open-door expansive laminoplasty using unilateral posterior midline approach provides preservation of posterior supporting tension band and excellent reconstruction of spinal canal. This technique also does not compromise contralateral paraspinal muscles attached to spinous process. PMID- 21286763 TI - Role of calcification in the outcomes of treated, unruptured, intracerebral aneurysms. AB - PURPOSE: This study examined clinical and aneurysm characteristics in patients with unruptured aneurysms, treated with either coiling or clipping at a single institution, with the primary outcome-Glasgow Outcome Score (GOS)-measured at 6 months after treatment. METHODS: Data was obtained by a retrospective review of a prospective registry of consecutive cases of unruptured intracranial aneurysms treated at a single institution from 2002 to mid 2007. Demographic data, number, location, and size of aneurysms, calcification, mode of treatment, ASA score, presence of a stroke on post-op imaging, and GOS were recorded. Medical 9.4 for PC was utilized for statistical analysis. RESULTS: There were 225 procedures performed in 208 patients to treat 252 aneurysms. The mean age was 54.6 years, 74.5% were female, the mean ASA score was 2.45, and 72.2% were smokers. Mean aneurysm size was 8.6 mm. A total of 157 (70%) craniotomies and 68 (30%) coiling procedures were performed. Coiling was utilized more frequently in the posterior circulation [18/32 (56%) posterior circulation, 50/193 (29.9%) anterior circulation, p < 0.001 Chi-square]. Length of hospital stay averaged 5.3 days [6.2 vs. 3.2 clip/coil, p < 0.001, Mann-Whitney]. Overall favorable outcome of GOS 4-5 measured at 6 months post-procedure was 93.3% [145/157 (92.3%) clip, 66/68 (97%) coil, p = 0.3 Chi-square], with a single mortality in the coil group. There was radiographic evidence of a post-procedure stroke on CT in 31 (13.8%) [28/157 (17.8%) clip, 3/68 (4.4%) coil, p < 0.001, Chi-square], but only 11(35%) were symptomatic. All long-term morbidity was attributable to stroke except for one case of late hydrocephalus. Utilizing a logistic regression multivariate analysis (forward), none of the examined factors (age, ASA score, sex, surgeon, posterior circulation, number of aneurysms treated at one sitting, size of aneurysm, smoking status, or type of therapy) related to outcome except calcified aneurysm [20/25 (80%) calcified, 191/200 (95.5%) non-calcified, p < 0.01 Chi square] with an OR = 7.8 (2.2-28.4, 95% C.I.). Although a univariate analysis of aneurysm size versus outcome achieves statistical significance [p = 0.05, logistic regression (forced)], when the calcified cases are removed from consideration, it does not [p = 0.55, OR = .95, (.82-1.1), 95% C.I.]. Excluding patients with calcified aneurysms resulted in the following calculation of favorable outcome: 94.2% (130/138) clip and 98.4% (61/62) coil [p = 0.33, Chi square]. CONCLUSIONS: In this study, the presence of calcification in an aneurysm was the sole marker of adverse outcome. Larger aneurysms tended to be more likely to be calcified. Size by itself did not have an adverse affect on outcome. Clipping or clip reconstruction of calcified aneurysms is a significant source of morbidity in the treatment of unruptured aneurysms (Odds ratio 7.8). PMID- 21286764 TI - Effects of baicalein on Sendai virus in vivo are linked to serum baicalin and its inhibition of hemagglutinin-neuraminidase. AB - Parainfluenza viruses are significant respiratory-tract pathogens that are notorious for infecting children. However, there are no clinical drugs to control the infection caused by these viruses. Sendai virus (SeV) belongs to the family Paramyxoviridae and causes fatal pneumonia in mice, its natural host. Baicalein is a flavonoid derived from the root of Scutellaria baicalensis, which is a traditional Chinese medicine that has been used for hundreds of years and has demonstrated a variety of biological activities. Our findings reveal that oral administration of baicalein to mice infected with Sendai virus results in a significant reduction in virus titers in the lungs and protection from death. The in vivo inhibitory effects of baicalein on Sendai virus are determined by baicalin in the serum. The mean IC(50) of baicalin was 0.71 MUg/ml in an HA inhibition assay and 3.22 MUg/ml in an NA inhibition assay. The mean IC(50) of baicalin in a CPE assay was measured to be 0.70 MUg/ml, and significant inhibition was observed in a plaque assay at a concentration of 1.6 MUg/ml baicalin in overlay medium, which suggests that baicalein is a potential anti parainfluenzaviral agent in vivo. PMID- 21286765 TI - An ultrastructural study of cytomixis in tobacco pollen mother cells. AB - Intercellular chromatin migration (cytomixis) in the pollen mother cells of two tobacco (Nicotiana tabacum L.) lines was analyzed by electron microscopy during the first meiotic prophase. The maximal manifestation of cytomixis was observed in the pachytene. As a rule, several cells connected with one another by cytomictic channels wherein the nuclei migrated were observable at this stage. In the majority of cases, nuclei passed from cell to cell concurrently through several closely located cytomictic channels. Chromatin migrated between cells within the nuclear envelope, and its disintegration was unobservable. The nucleus, after passing through cytomictic channels into another cell, can be divided into individual micronuclei or, in the case of a direct contact with another nucleus, can form a nuclear bridge. It has been demonstrated that the chromatin structure after intracellular migration visually matches the chromatin structure before it passed through the cytomictic channel. No signs of pyknosis were observable in the chromatin of the micronuclei formed after cytomixis, and the synaptonemal complex was distinctly seen. The dynamics of changes in the nucleoli during cytomixis was for the first time monitored on an ultrastructural level. Possible mechanisms determining cytomixis are discussed and the significance of this process in plant development is considered. PMID- 21286766 TI - Preventing mental disorders: the challenge ahead. PMID- 21286767 TI - "Deep-media culture condition" promoted lumen formation of endothelial cells within engineered three-dimensional tissues in vitro. AB - In the field of tissue engineering, the induction of microvessels into tissues is an important task because of the need to overcome diffusion limitations of oxygen and nutrients within tissues. Powerful methods to create vessels in engineered tissues are needed for creating real living tissues. In this study, we utilized three-dimensional (3D) highly cell dense tissues fabricated by cell sheet technology. The 3D tissue constructs are close to living-cell dense tissue in vivo. Additionally, creating an endothelial cell (EC) network within tissues promoted neovascularization promptly within the tissue after transplantation in vivo. Compared to the conditions in vivo, however, common in vitro cell culture conditions provide a poor environment for creating lumens within 3D tissue constructs. Therefore, for determining adequate conditions for vascularizing engineered tissue in vitro, our 3D tissue constructs were cultured under a "deep media culture conditions." Compared to the control conditions, the morphology of ECs showed a visibly strained cytoskeleton, and the density of lumen formation within tissues increased under hydrostatic pressure conditions. Moreover, the increasing expression of vascular endothelial cadherin in the lumens suggested that the vessels were stabilized in the stimulated tissues compared with the control. These findings suggested that deep-media culture conditions improved lumen formation in engineered tissues in vitro. PMID- 21286768 TI - Longer storage of dialyzers increases elution of poly(N-vinyl-2-pyrrolidone) from polysulfone-group dialysis membranes. AB - The objective of this study was to evaluate the effect of protracted storage of dialyzers on the amount of poly(N-vinyl-2-pyrrolidone) (PVP) eluted from polysulfone-group dialysis membranes. We tested five dialysis membranes: APS-15SA (Asahi Kasei Kuraray, wet), CX-1.6U (Toray, moist), FX140 (Fresenius, dry), PES 15Salpha (Nipro, dry), and FDX-150GW (Nikkiso, wet). Each dialyzer was stored for 1, 3, 14, and 18 months after sterilization. The dialysis-fluid side compartment was primed with reverse osmosis (RO) water at 500 mL/min for 5 min at 310 K. The blood side compartment was primed with RO water at 200 mL/min for 5 min at 310 K. Finally, 1 L RO water was circulated through the blood side compartment at 200 mL/min for 4 h at 310 K. Eluted PVP was determined by use of the iodine method, using 0.02 N: iodine solution. PVP was mainly eluted from wet-type dialyzers during priming. Thus, the standard 5 min priming of the wet-type dialyzer according to the maker manual inhibits PVP elution during circulation. PVP was eluted in the dialysis-fluid side of the moist-type dialyzer during priming but no PVP was eluted in the blood side. PVP was mainly eluted from dry-type dialyzers during circulation. We recommend more than the standard 5 min priming, particularly for dry-type dialyzers stored for protracted periods, because 5 min insufficient to inhibit PVP elution during circulation. PMID- 21286769 TI - Successful treatment of mediastinitis after ventricular assist device implantation with rerouting of the outflow vascular prosthesis. AB - We report successful treatment of mediastinitis with rerouting of the outflow vascular prosthesis after bi-ventricular assist device (Bi-VAD) implantation. A 23 years-old male with fulminant myocarditis underwent VAD implantation. He required sternotomy three times. Mediastinitis developed after the third surgery, and negative pressure wound therapy (NPWT) with irrigation was applied. The infection was well controlled, but after 3 months of NPWT hemorrhage developed because of injury of the outflow vascular prosthesis in the anterior mediastinum. We rerouted the outflow vascular prosthesis to the descending aorta via the left thoracic cavity. After rerouting, artificial material was removed from the anterior mediastinum. The sternal wound healed completely after NPWT. Intractable mediastinitis after extra-corporeal VAD implantation may be treated with irrigation and NPWT, but there is a possibility of outflow graft injury. A sternal wound could be closed as a secondary healing process by rerouting the outflow vascular prosthesis. PMID- 21286770 TI - A case of iatrogenic ilio-iliac arteriovenous fistula after percutaneous cardiopulmonary support in a patient with a tortuous iliac artery. AB - Percutaneous cardiopulmonary support (PCPS) has repeatedly been used with success as a tool for resuscitation in various life-threatening emergencies. PCPS-related vascular injuries are common, but ilio-iliac arteriovenous fistula (AVF) formation after PCPS has not been reported so far. We experienced a case of iatrogenic ilio-iliac AVF after PCPS, in which association between iliac artery tortuosity and AVF formation was strongly suspected. This case suggests that the risk of iatrogenic iliac AVF should be considered when PCPS is performed, especially in elderly patients whose arteries are frequently tortuous. PMID- 21286771 TI - Effective treatment of Kimura's disease with leflunomide in combination with glucocorticoids. AB - Kimura's disease (KD) is a rare, benign, chronic inflammatory disease which typically presents as persisting or recurring tumor-like lesions in the head and neck area that can be easily misdiagnosed. We report one patient with KD treated with leflunomide in combination with glucocorticoids and analyzed the literature on treatment of KD. The patient had a recurrent mass in the left upper arm with eosinophilia and elevated serum IgE but no renal involvement. The clinical manifestations improved markedly within 1 month, and blood eosinophil count and serum IgE normalized. Corticosteroids were then tapered gradually without recurrence or severe side effects in the 2-year follow-up period. Literature analysis identified four different non-drug interventions and 18 different drugs for treating KD, most of which were obtained from case reports. Our use of combination therapy of leflunomide and glucocorticoids suggests the need for a controlled trial for the treatment of this rare disorder. PMID- 21286772 TI - Transient gene expression system established in Porphyra yezoensis is widely applicable in Bangiophycean algae. AB - The establishment of transient gene expression systems in the marine red macroalga Porphyra yezoensis has been useful for the molecular analysis of cellular processes in this species. However, there has been no successful report about the expression of foreign genes in other red macroalgae, which has impeded the broader understanding of the molecular biology of these species. We therefore examined whether the P. yezoensis transient gene expression system was applicable to other red macroalgae. The results indicated that a codon-optimized GUS, designated PyGUS, and plant-adapted sGFP(S65T) were successfully expressed under the control of the P. yezoensis PyAct1 promoter in gametophytic cells of six Porphyra species and also in Bangia fuscopurpurea, all of which are classified as Bangiophyceae. In contrast, there were no reporter-expressing cells in the Florideophycean algae examined. These results indicate the availability of PyGUS and sGFP as reporters and the 5' upstream region of the PyAct1 gene as a heterologous promoter for transient gene expression in Bangiophycean algae, which could provide a clue to the efficient expression of foreign genes and transformation in marine red macroalgae. PMID- 21286773 TI - Low-dose MDCT findings of blunt hepatobiliary trauma. AB - This pictorial essay shows low-dose multi-detector computed tomography (MDCT) findings of blunt hepatobiliary trauma, and describes the indications and protocol for MDCT. Given the universal usage of MDCT in assessing the liver in blunt abdominal trauma, reduction of patient dose is essential. The new l0se MDCT protocol presented here can achieve up to 50% dose reduction while maintaining diagnostic image quality and thus facilitate dose sensitive patient management. Our institution's blunt hepatobiliary MDCT imaging algorithm can help determine which patients require operative therapy. Injury to the liver is graded on various schemes, one being the Organ Injury Scale devised by the American Association for the Surgery of Trauma classification based on the extension of the lesion and bleeding. PMID- 21286774 TI - Meningitis and septicemia caused by nontypeable Haemophilus influenzae in a previously healthy 2-year-old girl. AB - Nontypeable Haemophilus influenzae (NTHi) commonly colonizes the upper respiratory tract of children and causes otitis media, sinusitis, and bronchitis. Invasive NTHi diseases such as meningitis and septicemia have rarely been reported, especially in children with underlying predisposing conditions such as head trauma and immune compromise. However, we report a previously healthy 2-year old girl who developed meningitis and septicemia caused by NTHi biotype IotaIotaIota. She was treated with dexamethasone, meropenem, and ceftriaxone, and recovered uneventfully. We wish to emphasize that NTHi should be borne in mind as a potential pathogen that can cause meningitis and septicemia, even in previously healthy children. PMID- 21286775 TI - Primary floral allocation per flower in 12 Pedicularis (Orobanchaceae) species: significant effect of two distinct rewarding types for pollinators. AB - For animal-pollinated hermaphrodite plants, the factors that affect floral allocation were usually assigned to extrinsic (environment) and intrinsic ones (resources status). Few studies focused on the effect of rewarding type of plants (pollen vs. nectar and pollen). In this study, we investigated the variation in floral allocation per flower with respect to two distinct rewarding types for pollinators in 12 Pedicularis species in alpine regions, testing for the effects of species, plant size, and elevation simultaneously. The result showed that the rewarding type affected floral allocation significantly, and there was a female biased floral allocation pattern in nectarless rewarding species relative to nectar and pollen rewarding ones and provided a new insight into variation in floral allocation. It was discussed with respect to activities and foraging behavior of pollinators on the basis of sex allocation theory. Moreover, environmental conditions (elevation) may also play a relatively important role in determining patterns of variation in floral allocation per flower, whereas plant size may not. PMID- 21286776 TI - Experience with importation of electronic images into the medical record from physical media. AB - The purpose of this article is to describe a system we developed for importing images on compact discs (CDs) from external imaging departments into our clinical image viewing system, and to report on key metrics regarding veracity of information seen on the CDs. We recommend careful attention to the process of CD importation because of the error rate we have seen. We developed a system and process for importing images on CD into our EMR. The importation system scans the CD for digital imaging and communications in medicine (DICOM) images, and collects all patient information seen. That information is presented to the patient for verification. Once validated, the image data is copied into our clinical viewing system. The importation system includes facilities for collecting instances of incorrect data. About 90% of images are now exchanged between our healthcare enterprise and other entities via CD. Data for the wrong patient (e.g., the wrong CD) is seen in about 0.1% of cases, and a similar number of CDs have data for more than one patient on the CD(s) the patient bring to our facility. Most data are now exchanged via DICOM files. DICOM images burned onto CD media are now commonly used for image exchange. However, applications to import DICOM images are not enough. One must implement a process to assure high confidence that the data imported belongs to the patient you are importing. PMID- 21286777 TI - Genetic polymorphisms of TP53 and FAS promoter modulate the progression of coronary artery disease after coronary artery bypass grafting: a gender-specific view. AB - INTRODUCTION: Progression of coronary artery disease (CAD) after primary coronary artery bypass grafting (CABG) is frequent and may lead to recurrent symptoms. Various data indicate that apoptosis is the main event occurring during development and progression of atherosclerotic plaque. Plaque vascular smooth muscle cells (VSMCs) are more sensitive than regular VSMCs to TP53-mediated apoptosis. METHODS: We investigated EDTA blood of 192 patients (18% female, age 60.9 +/- 7.4 years) who had primary CABG more than 5 years ago. CAD progression was defined as clinical endpoints: re-operation (n = 88; 46%), catheter re intervention (n = 58; 30%), or angina at follow-up (n = 89; 46%). Apoptotic gene polymorphisms (Toll-like receptor 2 A753G, FAS ligand C-844T, FAS promoter G 670A, TP53 Arg72Pro, and CD14 C-260T) were investigated by PCR-RFLP and compared to healthy controls (n = 200, 24% female, age 63.4 +/- 5.4). Gender-specific analysis was carried out. RESULTS: Heterozygous, homozygous and wild-type expression of all five genetic polymorphisms showed almost identical distribution between patients with CAD and healthy controls. Looking at clinical endpoints, with GG expression of Toll-like receptor 2 polymorphism and GG expression of FAS promoter polymorphism, results showed a relative increased risk (p = 0.09) for recurrent symptoms and re-intervention. Patients with FAS promoter polymorphism with AA expression had an increased risk of suffering from recurrent symptoms (n = 28, p = 0.04). We found that patients with homozygous expression of TP53 polymorphisms (n = 3, all male) were prone to needing re-intervention after prior CABG (p = 0.03), but not re-operation. Over a period up to 15 years, the re intervention rate was significantly different in homozygous genotypes of FAS LG, FAS promoter and TP53. CONCLUSIONS: Patients presenting with polymorphisms of FAS LG, FAS promoter and TP53 have an increased risk of CAD progression, as they have a higher rate of re-interventions. PMID- 21286780 TI - The notorious "drug lag" for oncology drugs in Japan. AB - This study aimed to analyze the oncology "drug lag" (i.e., the delay in time required for the approval of oncology drugs) in Japan compared with that in the United States of America (US) or the European Union (EU) and to identify the factors associated with this lag. Using publicly available information, we collected data on 42 approvals of 30 oncology drugs in Japan, the US, and the EU that included dates of drug development initiation, submission, review, and approval. Lags in each step of the process were then examined and compared among the three regions. We found that median submission and approval lag times between Japan and the US were 20.0 and 29.9 months, respectively, while those between Japan and the EU were 14.9 and 21.3 months, respectively. The median review periods for Japan, the US, and the EU were 14.3, 6.0, and 13.2 months, respectively, and the median lag in initiation of oncology drug development between Japan and the US/EU was 38.9 months. The proportion of approvals for which Japanese Phase I registration trials started after corresponding approvals in the US were 39% compared with 47% for the EU. Multivariate analysis suggests that delays in the initiation of drug development and the extended length of the regulatory review period in Japan may contribute to the longer oncology drug lag observed in Japan compared with that of the US or EU. PMID- 21286781 TI - A cytotoxic ribonuclease reduces the expression level of P-glycoprotein in multidrug-resistant cell lines. AB - We have previously described a cytotoxic human pancreatic-ribonuclease variant, named PE5, which is able to cleave nuclear RNA, inducing the apoptosis of cancer cells. We have investigated whether PE5 could specifically inhibit the accumulation of P-glycoprotein in multidrug-resistant cells, since P-glycoprotein overexpression is one of the most important mechanisms contributing to the multiple drug resistance phenotype. We show that PE5 is able to reduce the amount of P-glycoprotein in two different multidrug-resistant cell lines, NCI/H460-R and NCI/ADR-RES, while glutathione S-transferase-l is not affected. We also show that onconase, an amphibian ribonuclease that is undergoing phase II/III clinical trials as an antitumor drug, does not affect the expression of these proteins. The reduction of P-glycoprotein accumulation, which has been functionally confirmed by flow cytometry analysis, may be caused by the previously reported underphosphorylation of JNK induced by PE5. We also show that PE5 has synergistic cytotoxicity with doxorubicin on the NCI/ADR-RES multidrug-resistant cell line. In conclusion, PE5 is a cytotoxic ribonuclease that cleaves nuclear RNA and decreases the expression of P-glycoprotein, showing anticancer activity in multidrug-resistant cell lines. PMID- 21286783 TI - Retained bee stinger in the tarsal plate. PMID- 21286784 TI - Transferable scoring function based on semiempirical quantum mechanical PM6-DH2 method: CDK2 with 15 structurally diverse inhibitors. AB - A semiempirical quantum mechanical PM6-DH2 method accurately covering the dispersion interaction and H-bonding was used to score fifteen structurally diverse CDK2 inhibitors. The geometries of all the complexes were taken from the X-ray structures and were reoptimised by the PM6-DH2 method in continuum water. The total scoring function was constructed as an estimate of the binding free energy, i.e., as a sum of the interaction enthalpy, interaction entropy and the corrections for the inhibitor desolvation and deformation energies. The applied scoring function contains a clear thermodynamical terms and does not involve any adjustable empirical parameter. The best correlations with the experimental inhibition constants (ln K (i)) were found for bare interaction enthalpy (r (2) = 0.87) and interaction enthalpy corrected for ligand desolvation and deformation energies (r (2) = 0.77); when the entropic term was considered, however, the correlation becomes worse but still acceptable (r (2) = 0.52). The resulting correlation based on the PM6-DH2 scoring function is better than previously published function based on various docking/scoring, SAR studies or advanced QM/MM approach, however, the robustness is limited by number of available experimental data used in the correlation. Since a very similar correlation between the experimental and theoretical results was found also for a different system of the HIV-1 protease, the suggested scoring function based on the PM6-DH2 method seems to be applicable in drug design, even if diverse protein-ligand complexes have to be ranked. PMID- 21286785 TI - A simple biosynthetic method for stereospecific resonance assignment of prochiral methyl groups in proteins. AB - A new method for stereospecific assignment of prochiral methyl groups in proteins is presented in which protein samples are produced using U-[(13)C]glucose and subsaturating amounts of 2-[(13)C]methyl-acetolactate. The resulting non-uniform labeling pattern allows proR and proS methyl groups to be easily distinguished by their different phases in a constant-time two-dimensional (1)H-(13)C correlation spectra. Protein samples are conveniently prepared using the same media composition as the main uniformly-labeled sample and contain higher levels of isotope-enrichment than fractional labeling approaches. This new strategy thus represents an economically-attractive, robust alternative for obtaining isotopically-encoded stereospecific NMR assignments of prochiral methyl groups. PMID- 21286786 TI - Genetic and biochemical analyses of chromosome and plasmid gene homologues encoding ICL and ArCP domains in Vibrio anguillarum strain 775. AB - Anguibactin, the siderophore produced by Vibrio anguillarum 775 is synthesized from 2,3-dihydroxybenzoic acid (DHBA), cysteine and hydroxyhistamine via a nonribosomal peptide synthetase (NRPS) mechanism. Most of the genes encoding anguibactin biosynthetic proteins are harbored by the pJM1 plasmid. In this work we report the identification of a homologue of the plasmid-encoded angB on the chromosome of strain 775. The product of both genes harbor an isochorismate lyase (ICL) domain that converts isochorismic acid to 2,3-dihydro-2,3-dihydroxybenzoic acid, one of the steps of DHBA synthesis. We show in this work that both ICL domains are functional in the production of DHBA in V. anguillarum as well as in E. coli. Substitution by alanine of the aspartic acid residue in the active site of both ICL domains completely abolishes their isochorismate lyase activity in vivo. The two proteins also carry an aryl carrier protein (ArCP) domain. In contrast with the ICL domains only the plasmid encoded ArCP can participate in anguibactin production as determined by complementation analyses and site directed mutagenesis in the active site of the plasmid encoded protein, S248A. The site-directed mutants, D37A in the ICL domain and S248A in the ArCP domain of the plasmid encoded AngB were also tested in vitro and clearly show the importance of each residue for the domain function and that each domain operates independently. PMID- 21286787 TI - Identification of tertiary butyl alcohol (TBA)-utilizing organisms in BioGAC reactors using 13C-DNA stable isotope probing. AB - Biodegradation of the gasoline oxygenates methyl tertiary-butyl ether (MTBE) and ethyl tertiary-butyl ether (ETBE) can cause tertiary butyl alcohol (TBA) to accumulate in gasoline-impacted environments. One remediation option for TBA contaminated groundwater involves oxygenated granulated activated carbon (GAC) reactors that have been self-inoculated by indigenous TBA-degrading microorganisms in ground water extracted from contaminated aquifers. Identification of these organisms is important for understanding the range of TBA metabolizing organisms in nature and for determining whether self-inoculation of similar reactors is likely to occur at other sites. In this study (13)C-DNA stable isotope probing (SIP) was used to identify TBA-utilizing organisms in samples of self-inoculated BioGAC reactors operated at sites in New York and California. Based on 16S rRNA nucleotide sequences, all TBA-utilizing organisms identified were members of the Burkholderiales order of the beta-proteobacteria. Organisms similar to Cupriavidus and Methylibium were observed in both reactor samples while organisms similar to Polaromonas and Rhodoferax were unique to the reactor sample from New York. Organisms similar to Hydrogenophaga and Paucibacter strains were only detected in the reactor sample from California. We also analyzed our samples for the presence of several genes previously implicated in TBA oxidation by pure cultures of bacteria. Genes Mpe_B0532, B0541, B0555, and B0561 were all detected in (13)C-metagenomic DNA from both reactors and deduced amino acid sequences suggested these genes all encode highly conserved enzymes. One gene (Mpe_B0555) encodes a putative phthalate dioxygenase-like enzyme that may be particularly appropriate for determining the potential for TBA oxidation in contaminated environmental samples. PMID- 21286788 TI - One and four layer acellular bladder matrix for fascial tissue reconstruction. AB - To determine whether the use of multiple layers of acellular bladder matrix (ABM) is more suitable for the treatment of abdominal wall hernia than a single layered ABM. The feasibility, biocompatibility and mechanical properties of both materials were assessed and compared. Biocompatibility testing was performed on 4 and 1 layered ABM. The matrices were used to repair an abdominal hernia model in 24 rabbits. The animals were followed for up to 3 months. Immediately after euthanasia, the implant site was inspected and samples were retrieved for histology, scanning electron microscopy and biomechanical studies. Both acellular biomaterials demonstrated excellent biocompatibility. At the time of retrieval, there was no evidence of infection. The matrices demonstrated biomechanical properties comparable to native tissue. Three hernias (25%) were found in the single layer ABM group and only 1 hernia (8%) was found in the 4 layer ABM group. Histologically, the matrix structure was intact and the cell density within the matrices decreased with time. The dominant cell type present within the matrices shifted from lymphocytes to fibroblasts over time. Both ABMs maintained adequate strength over time when used for hernia repair, and there was an extremely low incidence of adhesion formation. The single layer ABM showed enhanced cellular integration, while the 4 layer ABM reduced hernia formation. Either of these matrices may be useful as an off-the-shelf biomaterial for patients requiring fascial repair. PMID- 21286792 TI - A three-stage expert system based on support vector machines for thyroid disease diagnosis. AB - In this paper, we present a three-stage expert system based on a hybrid support vector machines (SVM) approach to diagnose thyroid disease. Focusing on feature selection, the first stage aims at constructing diverse feature subsets with different discriminative capability. Switching from feature selection to model construction, in the second stage, the obtained feature subsets are fed into the designed SVM classifier for training an optimal predictor model whose parameters are optimized by particle swarm optimization (PSO). Finally, the obtained optimal SVM model proceeds to perform the thyroid disease diagnosis tasks using the most discriminative feature subset and the optimal parameters. The effectiveness of the proposed expert system (FS-PSO-SVM) has been rigorously evaluated against the thyroid disease dataset, which is commonly used among researchers who use machine learning methods for thyroid disease diagnosis. The proposed system has been compared with two other related methods including the SVM based on the Grid search technique (Grid-SVM) and the SVM based on Grid search and principle component analysis (PCA-Grid-SVM) in terms of their classification accuracy. Experimental results demonstrate that FS-PSO-SVM significantly outperforms the other ones. In addition, Compared to the existing methods in previous studies, the proposed system has achieved the highest classification accuracy reported so far by 10-fold cross-validation (CV) method, with the mean accuracy of 97.49% and with the maximum accuracy of 98.59%. Promisingly, the proposed FS-PSO-SVM expert system might serve as a new candidate of powerful tools for diagnosing thyroid disease with excellent performance. PMID- 21286791 TI - A force-activated kinase in a catch smooth muscle. AB - Permeabilized anterior byssus retractor muscles (ABRM) from Mytilus edulis were used as a simple system to test whether there is a stretch dependent activation of a kinase as has been postulated for titin and the mini-titin twitchin. The ABRM is a smooth muscle that shows catch, a condition of high force maintenance and resistance to stretch following stimulation when the intracellular Ca(++) concentration has diminished to sub-maximum levels. In the catch state twitchin is unphosphorylated, and the muscle maintains force without myosin crossbridge cycling through what is likely a twitchin mediated tether between thick and thin filaments. In catch, a small change in length results in a large change in force. The phosphorylation state of an added peptide, a good substrate for molluscan twitchin kinase, with the sequence KKRAARATSNVFA was used as a measure of kinase activation. We find that there is about a two-fold increase in phosphorylation of the added peptide with a 10% stretch of the ABRM in catch. The increased phosphorylation is due to activation of a kinase rather than to an inhibition of a phosphatase. The extent of phosphorylation of the peptide is decreased when twitchin is phosphorylated and catch force is not present. However, there is also a large increase in peptide phosphorylation when the muscle is activated in pCa 5, and the catch state does not exist. The force-sensitive kinase activity is decreased by ML-9 and ML-7 which are inhibitors of twitchin kinase, but not by the Rho kinase inhibitor Y-27632. There is no detectable phosphorylation of myosin light chains, but the phosphorylation of twitchin increases by a small, but significant extent with stretch. It is possible that twitchin senses force output resulting in a force-sensitive twitchin kinase activity that results in autophosphorylation of twitchin on site(s) other than those responsible for relaxation of catch. PMID- 21286793 TI - Pyrophosphate selective recognition in aqueous solution based on fluorescence enhancement of a new aluminium complex. AB - A novel and simple fluorescence enhancement method for selective pyrophosphate(PPi) sensing was proposed based on a 1:1 metal complex formation between bis(8-hydroxy quinoline-5-solphonat) chloride aluminum(III) (Al(QS)(2)Cl), (L) and PPi in aqueous solution. The linear response range covers a concentration range of 1.6 * 10(-7) to 1.0 * 10(-5) mol/L of PPi and the detection limit of 2.3 * 10(-8) mol/L. The association constant of L-PPi complex was calculated 2.6 * 10(5) L/mol. L was found to show selectively and sensitively fluorescence enhancement toward PPi over than I(3)(-), NO(3)(-), CN(-), CO(3)(2 ), Br(-), Cl(-), F(-), H(2)PO4(-) and SO(4)(2-), which was attributed to higher stability of inorganic complex between pyrophosphate and L. PMID- 21286794 TI - Azonium-ammonium tautomerism and inclusion complexation of 1-(2,4-diamino phenylazo) naphthalene and 4-aminoazobenzene. AB - Spectral characteristics of 1-(2,4-diamino phenylazo) naphthalene (FBRR, fat brown RR) and 4-aminoazobenzene (AAB) have been studied in various solvents, varying hydrogen ion concentrations and in beta-cyclodextrin (beta-CD). The inclusion complex of FBRR and AAB with beta-CD were analysed by UV-visible, fluorometry and CAche-DFT methods. Solvent study reveals that only azo tautomer is present in both compounds and the large red shifted absorption and emission maxima of FBRR indicate naphthalene ring effectively increases the pi-pi* transition. Unusual red shift is observed in acid solutions suggests azonium ammonium tautomer is present in both molecules. In beta-CD solutions, the large hypsochromic shift is observed in S(0) and S(1) states indicates ortho amino group of FBRR molecule is entrapped in the beta-CD cavity and the large bathochromic shift for AAB in the S(1) state indicates 1:1 inclusion complex is formed. PMID- 21286795 TI - The role of mitochondrial DNA damage in the citotoxicity of reactive oxygen species. AB - Mitochondria contain their own genome, a small circular molecule of around 16.5 kbases. The mitochondrial DNA (mtDNA) encodes for only 13 polypeptides, but its integrity is essential for mitochondrial function, as all 13 proteins are regulatory subunits of the oxidative phosphorylation complexes. Nonetheless, the mtDNA is physically associated with the inner mitochondrial membrane, where the majority of the cellular reactive oxygen species are generated. In fact, the mitochondrial DNA accumulates high levels of oxidized lesions, which have been associated with several pathological and degenerative processes. The cellular responses to nuclear DNA damage have been extensively studied, but so far little is known about the functional outcome and cellular responses to mtDNA damage. In this review we will discuss the mechanisms that lead to damage accumulation and the in vitro models we are establishing to dissect the cellular responses to oxidative damage in the mtDNA and to sort out the differential cellular consequences of accumulation of damage in each cellular genome, the nuclear and the mitochondrial genome. PMID- 21286796 TI - Chemical mediators of inflammation and resolution in post-operative abdominal aortic aneurysm patients. AB - Temporal-metabolomic studies of local mediators during inflammation and its resolution uncovered novel pathways and mediators, e.g., lipoxins, resolvins, and protectins that stimulate key resolution responses. Since these studies were carried out with isolated human cells and in animal models, it is important to determine in humans whether temporal profiles between pro-inflammatory mediators and pro-resolving mediators are demonstrable in vivo. To this end, we examined patients undergoing abdominal aortic aneurysm (AAA) surgery. Profiles of mediators including eicosanoids were assessed in addition to pro-resolving mediators. The results demonstrate temporal relationships for local-acting peptides (e.g., VEGF, IL-10, TGF(beta)) and lipid mediators (leukotrienes and resolvins). In addition, profiles obtained for AAA patients divided into two groups based on their temporal profile: one group consistent with a pro inflammatory and another with a resolving profile. Together, these translational metabolomic profiles demonstrate for the first time the temporal relationships between local mediators in humans relevant in inflammation resolution. PMID- 21286797 TI - First complete genomic characterization of two tick-borne encephalitis virus isolates obtained from wild rodents in South Korea. AB - We determined for the first time the complete genome sequences of two Korean strains of the tick-borne encephalitis virus (TBEV), designated KrM 93 and KrM 213, isolated from the lung tissues of wild rodents in 2006. The genomes are 11,097 nucleotides (nt) in length and consist of a 132 nt 5'-noncoding region (NCR), a 10,245 nt open reading frame (ORF) containing 10 viral protein-coding regions (3,415 amino acids), and a 720 nt 3'-NCR. Compared with the 31 fully sequenced TBEV strains currently available, KrM 93 and KrM 213 show genomic nucleotide (and deduced amino acid) sequence divergences ranging from 1.8 (0.7) to 19.2 (26.6)% and 1.9 (0.8) to 19.3 (26.7)%, respectively. Phylogenetic and recombination analyses based on the complete genome sequence were performed to identify genetic variations and relationships between the TBEV strains. These showed that the Korean TBEV strains clustered with the Western subtype rather than with Far-Eastern or Siberian subtypes, and phylogenetic trees derived from capsid (C), envelope (E), nonstructural (NS) 4B and NS5 regions represented the same branching pattern shown by the complete genome-based tree. Although no recombination events were identified in these two Korean strains, 11 putative recombination events were identified within the NS5 regions or in the 3'-NCRs of TBEV strains in general. The results provide insight into the genetics of TBEV strains to understand the molecular epidemiology, genetic diversity, and evolution of TBEV. PMID- 21286798 TI - Development of reverse transcription loop-mediated isothermal amplification for rapid detection of porcine epidemic diarrhea virus. AB - In this study, a reverse transcription loop-mediated isothermal amplification (RT LAMP) was developed for detection of porcine epidemic diarrhea virus (PEDV). Six primers were designed to amplify the nucleocapsid (N) gene of PEDV. The optimization, sensitivity, and specificity of the RT-LAMP were investigated. The results showed that the optimal reaction condition for RT-LAMP amplifying PEDV N gene was achieved at 63 degrees C for 50 min. The RT-LAMP assay was more sensitive than gel-based RT-PCR and enzyme-linked immunosorbent assay. It was capable of detecting PEDV from clinical samples and differentiating PEDV from Porcine transmissible gastroenteritis virus, Porcine rotavirus, Porcine pseudorabies virus, Porcine reproductive and respiratory syndrome virus, and Avian infectious bronchitis virus. PMID- 21286799 TI - Psychosocial predictors of smoking among secondary school students in Al-Hassa, Saudi Arabia. AB - The objective of this study was to determine the prevalence and determinants of the current smoking status among secondary school students in Al-Hassa, Saudi Arabia. A total of 1,652 secondary school adolescents were selected by multistage proportionate sampling method. Data collection was carried out through self administered anonymous questionnaire including: Arabic version of the Global Youth Tobacco Survey, modified Fagerstrom Test for Nicotine Dependence and Patient Health Questionnaire to asses for anxiety and depressive disorders. This study revealed that the prevalence of current smokers was 21.7. Seventy-one percent of current cigarette smokers were minimally nicotine dependent. Major depressive and anxiety disorders were significantly higher among current smokers. Hierarchical regression analysis shows that, male, older age, smoking of close relatives and friends, anxiety disorders and socializing motives were statistically significant determinants of current smoking status among the included adolescents. Family members should be made aware of the detrimental influence their smoking behavior has on their youth. Counseling and preventive psychiatric services should be an integral part of the clinical facilities caring for secondary school students. PMID- 21286800 TI - Religion and preventive service use: do congregational support and religious beliefs explain the relationship between attendance and utilization? AB - Religious individuals are more likely to engage in healthy practices, including using preventive services; however, the underlying mechanisms have not been adequately explored. To begin addressing this, the current study examines the association between religious attendance, four aspects of congregational support, two health-related religious beliefs, and the use of preventive services (cholesterol screening, flu shot, and colonoscopy) among a national sample of Presbyterian adults (n = 1,076). The findings show that two aspects of congregational support are relevant to these types of behavioral health. First, church-based health activities are significantly related to the use of cholesterol screenings and flu shots (OR = 1.13, P < .05; OR = 1.10, P < .05, respectively). Second, discussing health-related issues with fellow church members is also significantly associated with reporting a cholesterol screening (OR = 1.15, P < .05), as well as moderately predictive of colonoscopy use (OR = 1.10, P < .10). Neither of the religious beliefs related to health, such as the God locus of health control scale or beliefs about the sanctity of the body, are related to preventive service use in this population. Although attendance is predictive of service use in unadjusted models, the association appears to be explained by age rather than by the congregational or belief variables. These findings contribute to a more nuanced understanding of the various ways in which religion might impact health behaviors and may also help to shape and refine interventions designed to improve individual well-being. PMID- 21286801 TI - Estrogens in the breast tissue: a systematic review. AB - The role of estrogens in breast carcinogenesis has been investigated at the level of whole body (plasma) and cell (molecular, receptors, etc.). Growing attention focused on the breast tissue being an intracrine organ, with potentially important local estrogen production in the breast. However, very little is known about the local breast tissue estrogen levels. Understanding the role of the tissue estrogens in breast carcinogenesis might open new avenues in breast cancer prevention. This systematic review summarizes published studies that measured local estrogen levels in the breast and offers suggestions for strategies to fill gaps in our existing scientific knowledge. PMID- 21286802 TI - Healthy eating index and ovarian cancer risk. AB - The evidence for a role of diet on ovarian cancer prevention remains inconclusive. While many studies have evaluated individual foods and food groups, the evaluation of a comprehensive dietary quality index for predicting cancer risk has received little attention. This study investigates the association between the Healthy Eating Index (HEI), which reflects adherence to the current USDA Dietary Guidelines for Americans and ovarian cancer risk in a population based case-control study in New Jersey. A total of 205 cases and 390 controls completed the Block 98.2 food frequency questionnaire (FFQ) in addition to reporting on potential risk factors for ovarian cancer. FFQ data were then utilized to calculate the HEI score, and cup, ounce, gram, or caloric equivalents for the 12 different food groups comprising the index. In multivariate models, the OR for the highest tertile of the HEI score compared with the lowest (reflecting a better diet compared with a worse diet) was 0.90 (95% CI: 0.55 1.47). There was limited evidence for a statistically significant association between any of the 12 individual food components and ovarian cancer risk. Based on this study's results, neither individual food groups nor dietary quality showed potential for preventing ovarian cancer. PMID- 21286803 TI - A meta-analytic review of the role of child anxiety sensitivity in child anxiety. AB - Conflicting findings exist regarding (1) whether anxiety sensitivity (AS) is a construct distinct from anxiety in children and (2) the specific nature of the role of AS in child anxiety. This study uses meta-analytic techniques to (1) determine whether youth (ages 6-18 years) have been reported to experience AS, (2) examine whether AS differentiates anxiety disordered youth from youth without diagnoses, and (3) ascertain whether AS distinguishes youth with panic disorder from those with other anxiety disorders. The weighted mean effect size analyses included 15 studies and 6,579 participants. Results suggested positive correlational relationships between AS and anxiety for children (r = 0.26) and adolescents (r = 0.36) and higher levels of AS for anxiety disordered youth than non-clinical youth (d = 0.64). Findings tentatively suggested higher levels of AS for youth with panic disorder than youth diagnosed with other anxiety disorders. Implications and future directions in the research of child AS are discussed. PMID- 21286804 TI - A non-BRCA1/2 hereditary breast cancer sub-group defined by aCGH profiling of genetically related patients. AB - Germline mutations in BRCA1 and BRCA2 explain approximately 25% of all familial breast cancers. Despite intense efforts to find additional high-risk breast cancer genes (BRCAx) using linkage analysis, none have been reported thus far. Here we explore the hypothesis that BRCAx breast tumors from genetically related patients share a somatic genetic etiology that might be revealed by array comparative genomic hybridization (aCGH) profiling. As BRCA1 and BRCA2 tumors can be identified on the basis of specific genomic profiles, the same may be true for a subset of BRCAx families. Analyses used aCGH to compare 58 non-BRCA1/2 familial breast tumors (designated BRCAx) to sporadic (non-familiar) controls, BRCA1 and BRCA2 tumors. The selection criteria for BRCAx families included at least three cases of breast cancer diagnosed before the age of 60 in the family, and the absence of ovarian or male breast cancer. Hierarchical cluster analysis was performed to determine sub-groups within the BRCAx tumor class and family heterogeneity. Analysis of aCGH profiles of BRCAx tumors indicated that they constitute a heterogeneous class, but are distinct from both sporadic and BRCA1/2 tumors. The BRCAx class could be divided into sub-groups. One subgroup was characterized by a gain of chromosome 22. Tumors from family members were classified within the same sub-group in agreement with the hypothesis that tumors from the same family would harbor a similar genetic background. This approach provides a method to target a sub-group of BRCAx families for further linkage analysis studies. PMID- 21286805 TI - Predicting biological impairment from habitat assessments. AB - The goal of biological monitoring programs is to determine impairment classification and identify local stressors. Biological monitoring performs well at detecting impairment but when used alone falls short of determining the cause of the impairment. Following detection a more thorough survey is often conducted using extensive biological, chemical, and physical analysis coupled with exhaustive statistical treatments. These methods can be prohibitive for small programs that are limited by time and budget. The objective of this study was to develop a simple and useful model to predict the probability of biological impairment based on routinely collected habitat assessments. Biological communities were assessed with the Index of Biotic Integrity (IBI), and habitat was assessed with the Qualitative Habitat Evaluation Index. Two models were constructed from a validation dataset. The first predicted a binary outcome of impaired (IBI < 35) or non-impaired (IBI >= 35) and the second predicted a categorical gradient of impairment. Categories include very poor, poor, fair, good, and excellent. The models were then validated with an independently collected dataset. Both models successfully predicted biological integrity of the validation dataset with an accuracy of 0.84 (binary) and 0.75 (categorical). Based on the binary outcome model, 22 sites were observed to be impaired while the model predicted them to not be impaired. The categorical model misclassified 47 samples while only seven of those were misclassified by two or more categories. The impairment source was subsequently identified by known stressors. The models developed here can be easily applied to other datasets from the Eastern Corn Belt Plain to aid in stressor identification by predicting the probability of observing an impaired fish community based on habitat. Predicted probabilities from the models can also be used to support conclusions that have already been determined. PMID- 21286806 TI - Glycomimicry: display of fucosylation on the lipo-oligosaccharide of recombinant Escherichia coli K12. AB - We recently described the design of Escherichia coli K12 and Salmonella enterica sv Typhimurium to display the gangliomannoside 3 (GM3) antigen on the cell surface. We report here the fucosylation of modified lipooligosaccharide in a recombinant E.coli strain with a truncated lipid A core due to deletion of the core glycosyltransferases genes waaO and waaB. This truncated structure was used as a scaffold to assemble the Lewis Y motif by consequent action of the heterologously expressed beta-1,4 galactosyltransferase LgtE (Neisseria gonorrheae), the beta-1,3 N-acetylglucosaminyltransferase LgtA and the beta-1,3 galactosyltransferase LgtB from Neisseria meningitidis, as well as the alpha-1,2 and alpha-1,3 fucosyltransferases FutC and FutA from Helicobacter pylori. We show the display of the Lewis Y structure by immunological and chemical analysis. PMID- 21286807 TI - Optimization of answer keys for script concordance testing: should we exclude deviant panelists, deviant responses, or neither? AB - The Script Concordance Test (SCT) uses a panel-based, aggregate scoring method that aims to capture the variability of responses of experienced practitioners to particular clinical situations. The use of this type of scoring method is a key determinant of the tool's discriminatory power, but deviant answers could potentially diminish the reliability of scores by introducing measurement error. (1) to investigate the effects on SCT psychometrics of excluding from the test's scoring key either deviant panelists or deviant answers; (2) to propose a method for excluding either deviant panelists or deviant answers. Using an SCT in radiation oncology, we examined three methods for reducing panel response variability. One method ('outliers') entailed removing from the panel members with very low total scores. Two other methods ('distance-from-mode' and 'judgment by-experts') excluded widely deviant responses to individual questions from the test's scoring key. We compared the effects of these methods on score reliability, correlations between original and adjusted scores, and between-group effect sizes (panel-residents; panel-students; and residents-students). With a large panel (n = 45), optimization methods have no effect on reliability of scores, correlation and effect size. With a smaller panel (n = 15) no significant effect of optimization methods were observed on reliability and correlation, but significant variation on effect size was observed across samples. Measurement error resulting from deviant panelist responses on SCTs is negligible, provided the panel size is sufficiently large (>15). However, if removal of deviant answers is judged necessary, the distance-from-mode strategy is recommended. PMID- 21286808 TI - Flower power: the armoured expert in the CanMEDS competency framework? AB - Competency frameworks based on roles definitions are currently being used extensively in health professions education internationally. One of the most successful and widely used models is the CanMEDS Roles Framework. The medical literature has raised questions about both the theoretical underpinnings and the practical application of outcomes-based frameworks, however little empirical research has yet been done examining specific roles frameworks. This study examines the historical development of an important early roles framework, the Educating Future Physicians of Ontario (EFPO) roles, which were instrumental in the development of the CanMEDS roles. Prominent discourses related to roles development are examined using critical discourse analysis methodology. Exploration of discourses that emerged in the development of this particular set of roles definitions highlights the contextual and negotiated nature of roles construction. The discourses of threat and protection prevalent in the EFPO roles development offer insight into the visual construction of a centre of medical expertise surrounded by supporting roles (such as collaborator and manager). Non medical expert roles may perhaps play the part of 'armour' for the authority of medical expertise under threat. This research suggests that it may not be accurate to consider roles as objective ideals. Effective training models may require explicit acknowledgement of the socially negotiated and contextual nature of roles definitions. PMID- 21286809 TI - Changes in hyphal morphology and activity of phenoloxidases during interactions between selected ectomycorrhizal fungi and two species of Trichoderma. AB - Patterns of phenoloxidase activity can be used to characterize fungi of different life styles, and changes in phenoloxidase synthesis were suspected to play a role in the interaction between ectomycorrhizal and two species of Trichoderma. Confrontation between the ectomycorrhizal fungi Amanita muscaria and Laccaria laccata with species of Trichoderma resulted in induction of laccase synthesis, and the laccase enzyme was bound to mycelia of ectomycorrhizal fungi. Tyrosinase release was noted only during interaction of L. laccata strains with Trichoderma harzianum and T. virens. Ectomycorrhizal fungi, especially strains of Suillus bovinus and S. luteus, inhibited growth of Trichoderma species and caused morphological changes in its colonies in the zone of interaction. In contrast, hyphal changes occurred less often in the ectomycorrhizal fungi tested. Species of Suillus are suggested to present a different mechanism in their interaction with other fungi than A. muscaria and L. laccata. PMID- 21286810 TI - Short-term efficacy of Click City(r): Tobacco: changing etiological mechanisms related to the onset of tobacco use. AB - This paper described the short-term results from an ongoing randomized controlled efficacy study of Click City(r): Tobacco, a tobacco prevention program designed for 5th graders, with a booster in sixth grade. Click City(r): Tobacco is an innovative school-based prevention program delivered via an intranet, a series of linked computers with a single server. The components of the program target theoretically based and empirically supported etiological mechanisms predictive of future willingness and intentions to use tobacco and initiation of tobacco use. Each component was designed to change one or more etiological mechanisms and was empirically evaluated in the laboratory prior to inclusion in the program. Short-term results from 47 elementary schools (24 schools who used Click City(r): Tobacco, and 23 who continued with their usual curriculum) showed change in intentions and willingness to use tobacco from baseline to 1-week following the completion of the 5th grade sessions. The results demonstrate the short-term efficacy of this program and suggest that experimentally evaluating components prior to including them in the program contributed to the efficacy of the program. The program was most efficacious for students who were most at risk. PMID- 21286811 TI - The expression of a carbon concentrating mechanism in Chlamydomonas acidophila under variable phosphorus, iron, and CO2 concentrations. AB - The CO(2) acquisition was analyzed in Chlamydomonas acidophila at pH 2.4 in a range of medium P and Fe concentrations and at high and low CO(2) condition. The inorganic carbon concentrating factor (CCF) was related to cellular P quota (Q(p)), maximum CO(2)-uptake rate by photosynthesis (V(max,O2)), half saturation constant for CO(2) uptake (K(0.5)), and medium Fe concentration. There was no effect of the medium Fe concentration on the CCF. The CCF increased with increasing Q(p) in both high and low CO(2) grown algae, but maximum Q(p) was 6 fold higher in the low CO(2) cells. In high CO(2) conditions, the CCF was low, ranging between 0.8 and 3.5. High CCF values up to 9.1 were only observed in CO(2)-limited cells, but P- and CO(2)-colimited cells had a low CCF. High CCF did not relate with a low K(0.5) as all CO(2)-limited cells had a low K(0.5) (<4 MUM CO(2)). High C(i)-pools in cells with high Q(p) suggested the presence of an active CO(2)-uptake mechanism. The CCF also increased with increasing V(max,O2) which reflect an adaptation to the nutrient in highest demand (CO(2)) under balanced growth conditions. It is proposed that the size of the CCF in C. acidophila is more strongly related to porter density for CO(2) uptake (reflected in V(max,O2)) and less- to high-affinity CO(2) uptake (low K(0.5)) at balanced growth. In addition, high CCF can only be realized with high Q(p). PMID- 21286812 TI - Barriers and facilitators to using 9-1-1 and emergency medical services in a limited English proficiency Chinese community. AB - Effective communication during a medical emergency is crucial for an appropriate emergency medical services (EMS) response. This exploratory qualitative study explored intentions to use 9-1-1 in a Chinese speaking community and the barriers and facilitators to accessing EMS. Focus groups with Chinese adults who self reported limited English proficiency were conducted. An inductive iterative approach was used to categorize and connect themes identified in the discussions. Language difficulties, negative perceptions of EMS, perceived costs of using emergency services, and no previous experience with 9-1-1 were commonly described as barriers to calling EMS during emergencies. Positive past experiences with EMS and encountering an emergency situation perceived as too great to manage alone are common facilitators for calling 9-1-1. Further exploration is necessary to assess barriers to calling 9-1-1 unique to specific communities, test findings, and tailor interventions to improve EMS communication. PMID- 21286813 TI - Estimating the effects of immigration status on mental health care utilizations in the United States. AB - Immigration status is a likely deterrent of mental health care utilization in the United States. Using the Medical Expenditure Panel Survey and National Health Interview survey from 2002 to 2006, multivariable logistic regressions were used to estimate the effects of immigration status on mental health care utilization among patients with depression or anxiety disorders. Multivariate regressions showed that immigrants were significantly less likely to take any prescription drugs, but not significantly less likely to have any physician visits compared to US-born citizens. Results also showed that improving immigrants' health care access and health insurance coverage could potentially reduce disparities between US-born citizens and immigrants by 14-29% and 9-28% respectively. Policy makers should focus on expanding the availability of regular sources of health care and immigrant health coverage to reduce disparities on mental health care utilization. Targeted interventions should also focus on addressing immigrants' language barriers, and providing culturally appropriate services. PMID- 21286814 TI - Minimum spanning tree reflects the alterations of the default mode network during Alzheimer's disease. AB - This study analyzes the connectivity pattern of the default mode network (DMN) in patients with Alzheimer's disease (AD) in comparison with young and elderly controls using the minimum spanning tree (MST). This tree is a tool from graph theory and connects all the nodes of a graph with the minimum cost. The findings revealed that the alterations of the basic structure represented by the MST might provide valuable insights about the physiopathology of the disease. Additionally, by making use of the MST for functionally clustering the DMN, it was shown that the functional subnetworks comprising the DMN differed among the three subject groups. Nonetheless, there were intact prefrontal and temporal networks in elderly controls and AD patients, as well. The analysis shows that although the topologies of the MST characterized by the degree distributions do not differ significantly among the groups, the DMN of the AD patients exhibits a higher segregation, insomuch that posterior cingulate/precuneus and hippocampus/parahippocampus are heavily isolated from rest of the network. We conclude that the MST can be used effectively for analyzing cortical networks. PMID- 21286815 TI - A preliminary study of bending stiffness alteration in shape changing nitinol plates for fracture fixation. AB - Nitinol is a promising biomaterial based on its remarkable shape changing capacity, biocompatibility, and resilient mechanical properties. Until now, very limited applications have been tested for the use of Nitinol plates for fracture fixation in orthopaedics. Newly designed fracture-fixation plates are tested by four-point bending to examine a change in equivalent bending stiffness before and after shape transformation. The goal of stiffness alterable bone plates is to optimize the healing process during osteosynthesis in situ that is customized in time of onset, percent change as well as being performed non-invasively for the patient. The equivalent bending stiffness in plates of varying thicknesses changed before and after shape transformation in the range of 24-73% (p values <0.05 for all tests). Tests on a Nitinol plate of 3.0 mm increased in stiffness from 0.81 to 0.98 Nm2 (corresponding standard deviation 0.08 and 0.05) and shared a good correlation to results from numerical calculation. The stiffness of the tested fracture-fixation plates can be altered in a consistent matter that would be predicted by determining the change of the cross-sectional area moment of inertia. PMID- 21286816 TI - Do christian denominations exhibit higher rates of alcohol consumption? A study of Korean American women in California. AB - Although Korean American women show high levels of involvement in religious practices and high prevalence of alcohol consumption, no studies have assessed the association between religious denomination and alcohol intake among this group of women. This cross-sectional study examined the associations of religious denomination and religious commitment to alcohol consumption among Korean American women in California. Polychotomous regression models were used to provide estimates of the associations between religious denomination and religious commitment to alcohol consumption. Catholic Korean American women (OR 5.61 P < 0.01) and Independent Christian women (OR 4.87 P < 0.01) showed stronger associations to heavy alcohol consumption when compared to Conservative Christian Korean American women. Path analysis suggested that specific denominations had both direct and indirect effects on the outcome of interest, and that religious commitment and drinking models served as moderators for this phenomenon. PMID- 21286817 TI - Influence of religiosity on the quality of life and on pain intensity in chronic pancreatitis patients after neurolytic celiac plexus block: case-controlled study. AB - The quality of life in patients with chronic pancreatitis (CP) is reduced due to their suffering of high levels of pain. It has been presented that quality of life can also be linked to religiosity and/or spirituality. The aim of this study is to assess the influence of religious practices on the quality of life and on the subjective level of pain in CP patients. Ninety-two patients (37 women and 55 men) with chronic pancreatitis were treated invasively for pain with neurolytic celiac plexus block (NCPB). The religiosity of the patients was recorded and served as a dichotomizer. Group 1 was for patients who claimed to have no contact with the church or to have very sporadic contact (N = 35 patients). Group 2 was for patients who claimed to have deep faith and were regular participants at church activities (N = 57 patients). Visual analogue scale was used to assess pain, while the quality of life was measured by using QLQ C-30 questionnaire adapted for chronic pancreatitis patients in Polish population. The patients were assessed prior to the pain-relieving intervention and subsequently 2 and 8 weeks after it. The intensity of pain was reduced in both groups significantly after performing the NCPB. Patients who declared a deep faith reported higher level of pain on the VAS scale prior to intervention than non-religious patients. Quality of life in both groups of patients significantly improved after NCPB. Following NCPB, global quality of life in patients who declared higher religiosity/church attendance was significantly higher (79.88) than for those patients who have no contact or sporadic contact with the church (44.21, P < 0.05). NCPB resulted in significant reduction of pain and increase in quality of life in both groups of patients with CP. Nevertheless, in the group declaring higher religiosity/church attendance, reported pain was higher, but, despite that, quality of life better. It may be concluded that religious practices might serve as an additional factor improving quality of life and coping in patients suffering from chronic pancreatitis. PMID- 21286818 TI - A blocking-free microfluidic fluorescence heterogeneous immunoassay for point-of care diagnostics. AB - In this article, a rapid, sensitive, and disposable microfluidic immunosensor is presented for point-of-care (POC) testing and clinical diagnosis. For the first time, the blocking process is eliminated from a microfluidic heterogeneous immunoassay by using protein A functionalized polydimethylsiloxane microchannels. The nonspecific binding of the assay is maintained around the chip background level by using a pair of antibodies with different affinity to protein A under optimized experimental conditions. C-reactive protein (CRP), a biomarker for inflammation and cardiovascular disease risk assessment, is selected as a model analyte to demonstrate the sensitivity of this blocking-free microfluidic heterogeneous immunoassay. A four parameter logistic function is used to model and assess the data. The limit of detection obtained is 0.54 MUg/mL, which is lower than the cut-off value for clinical diagnosis. The overall assay is completed in 5 min. The protein A modified PDMS chips wet-stored at 4 degrees C can maintain biofunctionality up to 14 months. The developed blocking-free microfluidic heterogeneous immunoassay will immediately provide benefits to most immunosensing microdevices targeted for POC diagnostics by shortening analysis time, simplifying fluid transportation, reducing sample consumption, and lowering waste generation. PMID- 21286819 TI - A probabilistic model for predicting the probability of no-show in hospital appointments. AB - The number of no-shows has a significant impact on the revenue, cost and resource utilization for almost all healthcare systems. In this study we develop a hybrid probabilistic model based on logistic regression and empirical Bayesian inference to predict the probability of no-shows in real time using both general patient social and demographic information and individual clinical appointments attendance records. The model also considers the effect of appointment date and clinic type. The effectiveness of the proposed approach is validated based on a patient dataset from a VA medical center. Such an accurate prediction model can be used to enable a precise selective overbooking strategy to reduce the negative effect of no-shows and to fill appointment slots while maintaining short wait times. PMID- 21286821 TI - Primary aldosteronism and a Texas two-step. AB - Primary aldosteronism is unquestionably the most common secondary cause of hypertension, and effective approaches to diagnosis and targeted treatments exist. Even the most conservative estimates of the prevalence of primary aldosteronism, however, indicate that the condition is grossly underdiagnosed. Part of the reason why diagnosis and treatment lag far behind is the lack of expertise, even among endocrinologists and hypertension specialists, in the approach to the patient with possible primary aldosteronism. We will never make an impression on this important problem unless general internists and primary care physicians actively participate in the screening and referral process. A healthcare delivery team need not fear an overwhelming and fruitless battle with an intractable conundrum if a practical and staged approach to workup and treatment is taken. This review discusses the approach we have taken in Dallas, a strategy of targeted screening, referral for positive screens, and individualized management. PMID- 21286822 TI - Lifestyle and quality of life in colorectal cancer survivors. AB - PURPOSE: As cancer survival rates improve, there is growing interest in the role of lifestyle in longer-term health and quality of life (QoL). This study examined the prevalence of health-related behaviours, and the associations between health behaviours and QoL, in colorectal cancer survivors. METHODS: Patients diagnosed with colorectal cancer within the last 5 years identified from five London (UK) hospitals (N = 495) completed a survey that included measures of fruit and vegetable (F&V) intake, physical activity, smoking status and alcohol consumption. The EORTC-QLQ-C30 questionnaire was used to index QoL. RESULTS: The majority of respondents were overweight/obese (58%), not physically active (<5 bouts of moderate activity per week; 82%) and ate fewer than five portions of F&V a day (57%). Few were smokers (6%) or heavy drinkers (weekly alcohol units >21 for men and >14 for women; 8%). Physical activity showed the strongest association with functional QoL and was also associated with lower fatigue, pain and insomnia (P < 0.05). F&V intake was associated with higher global QoL and physical, role and cognitive function (P < 0.05). Using a total health behaviour score (calculated by assigning one point for each of the following behaviours: not smoking, consuming >=5 portions of F&V a day, being physically active and having moderate alcohol consumption), there was a linear relationship with global QoL, physical function and fatigue (P < 0.05). CONCLUSION: A high proportion of colorectal cancer survivors in the UK have suboptimal health behaviours, and this is associated with poorer QoL. PMID- 21286823 TI - Identification and surveillance of 19 Lynch syndrome families in southern Italy: report of six novel germline mutations and a common founder mutation. AB - Lynch syndrome (LS), or hereditary non-polyposis colorectal cancer (HNPCC), is an autosomal dominant condition responsible for early onset cancer mostly in the colonrectum and endometrium as well as in other organ sites. Lynch syndrome is caused by germline mutations in mismatch repair genes, prevalently in hMSH2, hMLH1, and less frequently in hMSH6 and hPMS2. Twenty-nine non-related index cases with colorectal cancer (CRC) were collected from a region in southeast Italy (Apulia). Among this set of patients, fifteen fulfilled the Amsterdam criteria II. The presence of tumor microsatellite instability (MSI) was assessed in all index cases and 19 (15 AC+/4 AC-) were classified as MSI-H. Mutation analysis performed on all patients, identified 15 pathogenic mutations in hMLH1 and 4 in hMSH2. 4/15 mutations in hMLH1 and 2/4 hMSH2 mutations have not been previously reported. Three previously reported mutations were further investigated for the possibility of a common founder effect. Genetic counseling was offered to all probands and extended to 183 relatives after molecular testing and 85 (46%) mutation carriers were identified. Eighty mutation carriers underwent an accurate clinical and instrumental surveillance protocol. Our results confirm that the identification of LS patients based exclusively on family history may miss patients carrying germline mutations in the MMR genes. Moreover, our results demonstrated that molecular screening and subsequent instrumental surveillance are very effective in identifying CRCs at earlier stages and reducing the number of deaths from secondary cancers in HNPCC patients. PMID- 21286824 TI - Night-time atmospheric chemistry of methacrylates. AB - BACKGROUND, AIM, AND SCOPE: Methacrylates are alpha, beta-unsaturated esters that are widely used in the polymer plastics and resins production. Kinetic information of NO(3) radical reactions is especially scarce and a good understanding of all the atmospheric oxidation processes of these compounds is necessary in order to determine lifetimes in the atmosphere and to evaluate the impact of these reactions on the formation of ozone and other photooxidants. MATERIALS AND METHODS: The experiments have been carried out using the relative technique in a static Teflon reactor at room temperature and atmospheric pressure (N(2) as bath gas) using gas chromatography (GC)-flame ionization detection (FID) as detection system. Products were analyzed using solid phase microextraction (SPME)-GC-mass spectrometry (MS) technique and Fourier transform infrared spectroscopy (FTIR) using air as bath gas. RESULTS: The following rate coefficients were obtained (in cm(3) molecule(-1) s(-1)): methyl methacrylate + NO(3) = (3.55 +/- 0.62) * 10(-15), ethyl methacrylate + NO(3) = (5.42 +/- 1.90) * 10(-15), butyl methacrylate + NO(3) = (7.87 +/- 3.86) * 10(-15). Methylpyruvate, ethylpyruvate, and butylpyruvate/butanol were identified as main degradation products respectively in the GC-MS analysis. Nitrates compounds were also identified in the FTIR study. DISCUSSION: The reactivity increases with the substitution and with the chain of the alkyl group in -C(O)OR. An electrophilic addition mechanism is proposed as dominant degradation process. Estimations of the atmospheric lifetimes clearly indicate that the dominant atmospheric loss process for methacrylate esters is their daytime reaction with the hydroxyl radical. NO(3) and ozone are the main oxidants at night time. RECOMMENDATIONS AND PERSPECTIVES: A detailed products analysis including quantification could elucidate the mechanism for butanol generation for butyl methacrylate reaction. PMID- 21286825 TI - Dissolution of primary intimate relationships during incarceration and implications for post-release HIV transmission. AB - Incarceration is associated with sexually transmitted infections (STIs) including human immunodeficiency virus (HIV). Incarceration may contribute to STI/HIV by disrupting primary intimate relationships that protect against high-risk relationships. Research on sexual network disruption during incarceration and implications for post-release sexual risk behavior is limited. We interviewed a sample of HIV-positive men incarcerated in North Carolina to assess how commonly inmates leave partners behind in the community; characteristics of the relationships; and the prevalence of relationship dissolution during incarceration. Among prison inmates, 52% reported having a primary intimate partner at the time of incarceration. In the period prior to incarceration, 85% of men in relationships lived with and 52% shared finances with their partners. In adjusted analyses, men who did not have a primary cohabiting partner at the time of incarceration, versus those did, appeared to have higher levels of multiple partnerships (adjusted prevalence ratio (PR), 1.5; 95% confidence interval (CI) 0.9-2.6; p = 0.11) and sex trade, defined as giving or receiving sex for money, goods, or services (adjusted PR, 2.1; 95% CI 0.9-4.8; p = 0.08) in the 6 months prior to incarceration. Involvement in financially interdependent partnerships appeared to be associated with further reductions in risk behaviors. Of men in primary partnerships at the time of prison entry, 55% reported their relationship had ended during the incarceration. The findings suggest that involvement in primary partnerships may contribute to reductions in sexual risk taking among men involved in the criminal justice system but that many partnerships end during incarceration. These findings point to the need for longitudinal research into the effects of incarceration-related sexual network disruption on post-release HIV transmission risk. PMID- 21286826 TI - Housing circumstances are associated with household food access among low-income urban families. AB - Household food insecurity is a pervasive problem in North America with serious health consequences. While affordable housing has been cited as a potential policy approach to improve food insecurity, the relationship between conventional notions of housing affordability and household food security is not well understood. Furthermore, the influence of housing subsidies, a key policy intervention aimed at improving housing affordability in Western countries, on food insecurity is unclear. We undertook a cross-sectional survey of 473 families in market rental (n = 222) and subsidized (n = 251) housing in high-poverty urban neighborhoods to examine the influence of housing circumstances on household food security. Food insecurity, evident among two thirds of families, was inversely associated with income and after-shelter income. Food insecurity prevalence did not differ between families in market and subsidized housing, but families in subsidized housing had lower odds of food insecurity than those on a waiting list for such housing. Market families with housing costs that consumed more than 30% of their income had increased odds of food insecurity. Rent arrears were also positively associated with food insecurity. Compromises in housing quality were evident, perhaps reflecting the impact of financial constraints on multiple basic needs as well as conscious efforts to contain housing costs to free up resources for food and other needs. Our findings raise questions about current housing affordability norms and highlight the need for a review of housing interventions to ensure that they enable families to maintain adequate housing and obtain their other basic needs. PMID- 21286827 TI - Patterns of exchange sex and HIV infection in high-risk heterosexual men and women. AB - Heterosexual partnerships involving the trade of money or goods for sex are a well-described HIV risk factor in Africa and Southeast Asia, but less research has been conducted on exchange partnerships and their impact on HIV infection in the United States. In our study, men and women were recruited from high-risk risk neighborhoods in New York City through respondent-driven sampling in 2006-2007. We examined the factors associated with having an exchange partner in the past year, the relationship between exchange partnerships and HIV infection, and the risk characteristics of those with exchange partners by the directionality of payment. Overall, 28% of men and 41% of women had a past-year exchange partner. For men, factors independently associated with exchange partnerships were older age, more total sexual partners, male partners, and frequent non-injection drug use. For women, factors were homelessness, more total sexual partners, more unprotected sex partners, and frequent non-injection drug use. Exchange partnerships were associated with HIV infection for both men and women, although the relationships were substantially confounded by other behavioral risks. Those who both bought and sold sex exhibited the highest levels of risk with their exchange and non-exchange partners. Exchange partnerships may be an HIV risk both directly and indirectly, given the overlap of this phenomenon with other risk factors that occur with both exchange and non-exchange partners. PMID- 21286828 TI - Considerations and challenges for planning a public health approach to asthma. AB - Addressing asthma from a public health perspective is a relatively new concept for which the literature provides little guidance. A public health approach seeks to decrease the burden of asthma and improve health outcomes at the population level, such as communities, cities, or states, by reaching large numbers of individuals with effective interventions and at reasonable cost. Projects designed to achieve a measureable impact at the population level are fundamentally different from projects or interventions designed to improve outcomes among individuals. This paper uses the experience of the Controlling Asthma in American Cities Project and a review of the relevant literature to explore some of the unique questions and considerations that are implicit when planning large-scale asthma projects intended to improve population outcomes. The paper is intended to inform decision making by local and state government agencies, managed care organizations, health systems, community coalitions, and funders. Analysis of asthma and other chronic disease projects aiming to achieve population-level impact is an area for continued public health research. PMID- 21286829 TI - Biological surface modification of titanium surfaces using glow discharge plasma. AB - To improve the biological activity of titanium, by using of glow discharge plasma (GDP), albumin-grafted titanium disk have been implemented and carefully studied. Titanium disks were pre-treated with GDP in an environment filled with argon and allylamine gas. Glutaraldehyde was used as a cross-linking agent for albumin grafting. Then, the surface of the albumin-grafted titanium was examined using scanning electron microscopy and X-ray photoelectron spectroscopy. In addition, the static water contact angles of the albumin-grafted titanium disks were measured using goniometry. To observe the effects of albumin adsorption on cell behavior, MG-63 osteoblast-like cells were cultured on the surface-modified titanium disks. Blood coagulation resistance of the modified titanium was monitored and compared to the control titanium disks. The results demonstrated that MG-63 osteoblast-like cells cultured on the albumin-grafted titanium disks expressed better-differentiated morphology compare to cells grown on the control disks. Furthermore, albumin-grafting treatment significantly improved the surface wettability of the titanium disks and resulted in a significantly negative effect on thrombus formation. Based on these results, it was believed that the GDP can potentially improve the biofunctionality of titanium surfaces. PMID- 21286830 TI - Measurement of the local aortic stiffness by a non-invasive bioelectrical impedance technique. AB - Aortic stiffness measurement is well recognized as an independent predictor of cardiovascular mortality and morbidity. Recently, a simple method has been proposed for the evaluation of the local aortic stiffness (AoStiff) using a non invasive bioelectrical impedance (BI) technique. This approach relies on a novel interpretation of the arterial stiffness where AoStiff is computed from the measurement of two new BI variables: (1) the local aortic flow resistance (AoRes) exerted by the drag forces onto the flow; (2) the local aortic wall distensibility (AoDist). Herein, we propose to detail and compare these three indices with the reference pulse wave velocity (PWV) measurement and the direct assessment of the aortic drag forces (DF) and distensibility (DS) obtained by the magnetic resonance imaging technique. Our results show a significant correlation between AoStiff and PWV (r = 0.79; P < 0.0001; 120 patients at rest; mean age 44 +/- 16 years), and also between AoRes and DF (r = 0.95; P = 0.0011) and between AoDist and DS (r = 0.93; P = 0.0022) on eight patients at rest (mean age 52 +/- 19 years). These first results suggest that local aortic stiffness can be explored reliably by the BI technique. PMID- 21286831 TI - Characterization and prediction of mRNA polyadenylation sites in human genes. AB - The accurate identification of potential poly(A) sites has contributed to all many studies with regard to alternative polyadenylation. The aim of this study was the development of a machine-learning methodology that will help to discriminate real polyadenylation signals from randomly occurring signals in genomic sequence. Since previous studies have revealed that RNA secondary structure in certain genes has significant impact, the authors tried to computationally pinpoint common structural patterns around the poly(A) sites and to investigate how RNA secondary structure may influence polyadenylation. This involved an initial study on the impact of RNA structure and it was found using motif search tools that hairpin structures might be important. Thus, it was propose that, in addition to the sequence pattern around poly(A) sites, there exists a widespread structural pattern that is also employed during human mRNA polyadenylation. In this study, the authors present a computational model that uses support vector machines to predict human poly(A) sites. The results show that this predictive model has a comparable performance to the current prediction tool. In addition, it was identified common structural patterns associated with polyadenylation using several motif finding programs and this provides new insight into the role of RNA secondary structure plays in polyadenylation. PMID- 21286832 TI - A continuum mathematical model of the developing murine retinal vasculature. AB - Angiogenesis, the process of new vessel growth from pre-existing vasculature, is crucial in many biological situations such as wound healing and embryogenesis. Angiogenesis is also a key regulator of pathogenesis in many clinically important disease processes, for instance, solid tumour progression and ocular diseases. Over the past 10-20 years, tumour-induced angiogenesis has received a lot of attention in the mathematical modelling community and there have also been some attempts to model angiogenesis during wound healing. However, there has been little modelling work of vascular growth during normal development. In this paper, we describe an in silico representation of the developing retinal vasculature in the mouse, using continuum mathematical models consisting of systems of partial differential equations. The equations describe the migratory response of cells to growth factor gradients, the evolution of the capillary blood vessel density, and of the growth factor concentration. Our approach is closely coupled to an associated experimental programme to parameterise our model effectively and the simulations provide an excellent correlation with in vivo experimental data. Future work and development of this model will enable us to elucidate the impact of molecular cues upon vasculature development and the implications for eye diseases such as diabetic retinopathy and neonatal retinopathy of prematurity. PMID- 21286834 TI - HIV-1 gp120-induced axonal injury detected by accumulation of beta-amyloid precursor protein in adult rat corpus callosum. AB - HIV-1 brain infection induces neurodegeneration. While most studies focus on HIV 1-mediated neuronal injury, relatively few have investigated HIV-1-associated white matter damage. Corpus callosum (CC) is one of frequently involved white matter structures in HIV-1-associated white matter damage. Utilizing a model of ex vivo treatment of brain slice containing CC with HIV-1 glycoprotein 120 (gp120), we examined axonal injury by analyzing beta-amyloid precursor protein (beta-APP) accumulation in the axon. Incubation of CC slice with gp120 produced a significant higher density of beta-APP in the CC tissue compared with non-gp120 treated controls, suggesting the presence of axonal damage in the CC. The gp120 induced CC axonal damage was blocked by a chemokine CXCR4 receptor antagonist T140 but not by an NMDA receptor blocker MK801 as demonstrated by Western blot analysis of beta-APP, indicating that gp120 evokes the CC axonal injury through CXCR4 receptor. Immunocytochemical studies revealed a surprisingly high density of CXCR4-positive immunoreactivity in the CC. The CXCR4-positive labeling was distributed along the nerve fibers. Moreover, double labeling of anti-CXCR4 with either anti-neuronal nuclei or anti-myelin/oligodendrocyte-specific protein antibody revealed co-localization of CXCR4 and myelin/oligodendrocytes in some fiber-like structures, inferring that some neurons and oligodendrocytes in the CC express CXCR4. Taken together, these results indicate that gp120 induced axonal damage via CXCR4 in the CC. PMID- 21286833 TI - Mitogen-activated protein kinase p38 in HIV infection and associated brain injury. AB - Infection with human immunodeficiency virus-1 (HIV-1) often leads to HIV associated neurocognitive disorders (HAND) prior to the progression to acquired immunodeficiency syndrome (AIDS). At the cellular level, mitogen-activated protein kinases (MAPK) provide a family of signal transducers that regulate many processes in response to extracellular stimuli and environmental stress, such as viral infection. Recently, evidence has accumulated suggesting that p38 MAPK plays crucial roles in various pathological processes associated with HIV infection, ranging from macrophage activation to neurotoxicity and impairment of neurogenesis to lymphocyte apoptosis. Thus, p38 MAPK, which has generally been linked to stress-related signal transduction, may be an important mediator in the development of AIDS and HAND. PMID- 21286835 TI - Modulation of macrophage fatty acid content and composition by exposure to dyslipidemic serum in vitro. AB - Macrophages in arterial walls accumulate lipids leading to the development of atherosclerotic plaques. However, mechanisms underlying macrophage lipid accumulation and foam cell formation are often studied without accounting for risk factors such as dyslipidemia. We investigated the effect of varying concentrations of triglyceride (TG) within physiological range on macrophage fatty acid (FA) accumulation and expression of cholesterol efflux proteins. Human monocytes were cultured in media supplemented with 10% sera containing low (0.7 mmol/L) to high (1.4 mmol/L) TG. The resulting macrophages were harvested after 10 days for analysis of FA content and composition and expression of genes involved in lipid metabolism. Exposure to higher TG and lower HDL concentrations in media increased macrophage lipid content. Macrophages exposed to higher TG had increased total FA content compared with controls (876 MUg/mg protein vs. 652 MUg/mg protein) and greater proportions of C16:0, C18:1 and C18:2. Macrophage expression of both ABCA1 and ABCG1 cholesterol efflux proteins were reduced when higher TG concentrations were present in the media. Expression of scavenger receptor CD36, involved in lipoprotein uptake, was also downregulated in macrophages exposed to higher TG. Culturing macrophages in conditions of higher versus lower TG influenced macrophage FA content and composition, and levels of regulatory proteins. Replicating in vitro levels of dyslipidemia encountered in vivo may provide an informative model for investigation of atherogenesis. PMID- 21286836 TI - Extended evaluation of a longitudinal medical school evidence-based medicine curriculum. AB - BACKGROUND: Evidence-based medicine (EBM) is an important element of medical education. However, limited information is available on effective curricula. OBJECTIVE: To evaluate a longitudinal medical school EBM curriculum using validated instruments. DESIGN, PARTICIPANTS, MEASUREMENTS: We evaluated EBM attitudes and knowledge of medical students as they progressed through an EBM curriculum. The first component of the curriculum was an EBM "short course" with didactic and small-group sessions occurring at the end of the second year. The second component integrated EBM assignments with third-year clinical rotations. The 15-point Berlin Questionnaire was administered before the course in 2006 and 2007, after the short course, and at the end of the third year. The 212-point Fresno Test was administered before the course in 2007 and 2008, after the short course, and at the end of the third year. Self-reported knowledge and attitudes were also assessed in all three classes of medical students. RESULTS: EBM knowledge scores on the 15-point Berlin Questionnaire increased from baseline by 3.0 points (20.0%) at the end of the second year portion of the course (p < 001) and by 3.4 points (22.7%) at the end of the third year (p < 001). EBM knowledge scores on the 212-point Fresno Test increased from baseline by 39.7 points (18.7%) at the end of the second year portion of the course (p < 001) and by 54.6 points (25.8%) at the end of the third year (p < 001). On a 5-point scale, self rated EBM knowledge increased from baseline by 1.0 and 1.4 points, respectively (both p < 001). EBM was felt to be of high importance for medical education and clinical practice at all time points, with increases noted after both components of the curriculum. CONCLUSIONS: A longitudinal medical school EBM was associated with markedly increased EBM knowledge on two validated instruments. Both components of the curriculum were associated with gains in knowledge. The curriculum was also associated with increased perceptions of the importance of EBM for medical education and clinical practice. PMID- 21286837 TI - Projected survival gains from revising state laws requiring written opt-in consent for HIV testing. AB - BACKGROUND: Although the Centers for Disease Control and Prevention recommends HIV testing in all settings unless patients refuse (opt-out consent), many state laws require written opt-in consent. OBJECTIVE: To quantify potential survival gains from passing state laws streamlining HIV testing consent. DESIGN: We retrieved surveillance data to estimate the current annual HIV diagnosis rate in states with laws requiring written opt-in consent (19.3%). Published data informed the effect of removing that requirement on diagnosis rate (48.5% increase). These parameters then served as input for a model-driven projection of survival based on consent method. Other inputs included undiagnosed HIV prevalence (0.101%); and annual HIV incidence (0.023%). PATIENTS: Hypothetical cohort of adults (>13 years) living in written opt-in states. MEASUREMENTS: Life years gained (LYG). RESULTS: In the base-case, of the 53,036,383 adult persons living in written opt-in states, 0.66% (350,040) will be infected with HIV. Due to earlier diagnosis, revised consent laws yield 1.5 LYG per HIV-infected person, corresponding to 537,399 LYG among this population. Sensitivity analyses demonstrate that diagnosis rate increases of 24.8-72.3% result in 304,765-724,195 LYG. Net survival gains vanish if the proportion of HIV-infected persons refusing all testing in response to revised laws exceeds 18.2%. CONCLUSIONS: The potential survival gains of increased testing are substantial, suggesting that state laws requiring opt-in HIV testing should be revised. PMID- 21286838 TI - Different black box warning labeling for same-class drugs. AB - INTRODUCTION: Black box warnings (BBWs) are the strongest medication-related safety warnings in a drug's labeling information and highlight major risks. Absence of a BBW or asynchronous addition of a BBW among same-class drugs could have major implications. METHODS: We identified the 20 top-selling drugs in 2008 (10 with BBWs and 10 without BBWs on their label) that belonged to different drug classes. We collected labeling information on all drugs belonging in these 20 classes, and recorded differences in the presence and timing of acquisition of BBWs for same-class drugs. RESULTS: Across the 20 evaluated drug classes, we identified 176 different agents, of which 7 had been withdrawn for safety reasons. The reasons for the withdrawals became BBWs in other same-class agents only in two of the seven cases. Differences were identified in 9 of the 20 classes corresponding to 15 BBWs that were not present in all drugs of the same class. The information for 10 of the 15 different BBWs were included in the labels of same-class drugs as simple warnings or text, while it was absent entirely in 5 BBWs. The median interval from the time the BBW had appeared in another drug of the same class was 66 months. DISCUSSION: Differences in BBW labeling in same-class drugs are common and shape impressions about the safety of similar agents. BBW labeling needs to become more systematic. PMID- 21286839 TI - Hospital do-not-resuscitate orders: why they have failed and how to fix them. AB - Do-not-resuscitate (DNR) orders have been in use in hospitals nationwide for over 20 years. Nonetheless, as currently implemented, they fail to adequately fulfill their two intended purposes--to support patient autonomy and to prevent non beneficial interventions. These failures lead to serious consequences. Patients are deprived of the opportunity to make informed decisions regarding resuscitation, and CPR is performed on patients who would have wanted it withheld or are harmed by the procedure. This article highlights the persistent problems with today's use of inpatient DNR orders, i.e., DNR discussions do not occur frequently enough and occur too late in the course of patients' illnesses to allow their participation in resuscitation decisions. Furthermore, many physicians fail to provide adequate information to allow patients or surrogates to make informed decisions and inappropriately extrapolate DNR orders to limit other treatments. Because these failings are primarily due to systemic factors that result in deficient physician behaviors, we propose strategies to target these factors including changing the hospital culture, reforming hospital policies on DNR discussions, mandating provider communication skills training, and using financial incentives. These strategies could help overcome existing barriers to proper DNR discussions and align the use of DNR orders closer to their intended purposes of supporting patient self-determination and avoiding non beneficial interventions at the end of life. PMID- 21286840 TI - Examining the evidence: a systematic review of the inclusion and analysis of older adults in randomized controlled trials. AB - BACKGROUND: Due to a shortage of studies focusing on older adults, clinicians and policy makers frequently rely on clinical trials of the general population to provide supportive evidence for treating complex, older patients. OBJECTIVES: To examine the inclusion and analysis of complex, older adults in randomized controlled trials. REVIEW METHODS: A PubMed search identified phase III or IV randomized controlled trials published in 2007 in JAMA, NEJM, Lancet, Circulation, and BMJ. Therapeutic interventions that assessed major morbidity or mortality in adults were included. For each study, age eligibility, average age of study population, primary and secondary outcomes, exclusion criteria, and the frequency, characteristics, and methodology of age-specific subgroup analyses were reviewed. RESULTS: Of the 109 clinical trials reviewed in full, 22 (20.2%) excluded patients above a specified age. Almost half (45.6%) of the remaining trials excluded individuals using criteria that could disproportionately impact older adults. Only one in four trials (26.6%) examined outcomes that are considered highly relevant to older adults, such as health status or quality of life. Of the 42 (38.5%) trials that performed an age-specific subgroup analysis, fewer than half examined potential confounders of differential treatment effects by age, such as comorbidities or risk of primary outcome. Trials with age specific subgroup analyses were more likely than those without to be multicenter trials (97.6% vs. 79.1%, p < 0.01) and funded by industry (83.3% vs. 62.7%, p < 0.05). Differential benefit by age was found in seven trials (16.7%). CONCLUSION: Clinical trial evidence guiding treatment of complex, older adults could be improved by eliminating upper age limits for study inclusion, by reducing the use of eligibility criteria that disproportionately affect multimorbid older patients, by evaluating outcomes that are highly relevant to older individuals, and by encouraging adherence to recommended analytic methods for evaluating differential treatment effects by age. PMID- 21286841 TI - SSAT/AHPBA Joint Symposium: Today's approaches to colorectal cancer (CRC) liver metastases. PMID- 21286842 TI - Aspirin for lower limb arthroplasty thromboprophylaxis: review of international guidelines. AB - INTRODUCTION: Aspirin is one of the pharmacological agents used for thromboprophylaxis. MATERIALS AND METHODS: National thromboprophylaxis guidelines, peer-reviewed studies and data from national joint register of England and Wales were analysed for evidence regarding the efficacy of aspirin versus other agents in thromboprophylaxis and the recommendations of guidelines. RESULTS: Two of five guidelines reviewed recommend the use of aspirin for thromboprophylaxis. Aspirin is used as thromboprophylactic agent in approximately 25% of patients undergoing total hip and total knee arthroplasty in year 2006 in England and Wales. There is no difference in mortality in these patients compared to patients on other pharmacological agents. CONCLUSION: There is conflicting evidence and differences in interpretation of the data from the literature. If specific outcome measures and complications such as symptomatic DVT, PE and bleeding were logged in arthroplasty registers, the resulting data would be useful in individualised decision-making. PMID- 21286843 TI - A five-year review of publication productivity among Irish orthopaedic units. AB - BACKGROUND: The academic productivity of trainees, consultants and institutions is frequently judged by the quantity of articles published in peer-reviewed medical journals. AIM: To assess the publication history of Irish orthopaedic units over a 5-year period, and to identify patterns of publication. METHODS: A PubMed search was performed of each consultant affiliated with each orthopaedic unit in the country for between 2004 and 2008. Publications were classified by individual, institution, publication type and impact factor. RESULTS: Over the 5 years of the study, 239 papers were published from 19 orthopaedic units, in 69 different journals. Fifty-six consultants had at least one senior author publication, with seven consultants having more than ten. Impact factors of the journals targeted varied considerably and reveals an interesting duality among authors when opting for profile or prestige. CONCLUSION: We feel this study represents a comprehensive and novel review of the state of publishing in a surgical specialty. PMID- 21286844 TI - Intracoronary delivery of mesenchymal stem cells reduces proarrhythmogenic risks in swine with myocardial infarction. AB - INTRODUCTION: The electrophysiological consequences of mesenchymal stem cell (MSC) therapy in ischemic heart disease have not been fully understood. METHODS: Swine myocardial infarction (MI) model by intracoronary balloon occlusion received MSC solution or 0.9% NaCl. Six weeks later, heart rate turbulence (HRT), dispersion of action potential durations (APD) and repolarization time (RT) (APDd and RTd), slope of APD reconstitution curve and programmed electrical stimulation were used to evaluate the ventricular arrhythmic risks. RESULTS: MSC treatment could significantly ameliorate the abnormal HRT, APD(90), APDd, RT and RTd. The slope of APD reconstitution curve in MSC group was higher than control group but lower than MI group. MSC therapy markedly reduced inducible malignant ventricular arrhythmias (VAs), and improved impaired cardiac performances and cardiac fibrosis. CONCLUSIONS: This study provides strong evidence that MSC infusion via intracoronary route does not cause VAs but tends to reduce the risk of malignant VAs. PMID- 21286845 TI - Evaluation of essential trace and toxic elements in scalp hair samples of smokers and alcohol user hypertensive patients. AB - The incidence of hypertension has been associated to cigarette smoking and consumption of alcohol. In the present study, trace and toxic elements were determined in scalp hair of patients diagnosed with hypertension who are smokers and habitual alcohol drinkers living in Dublin, Ireland. These results were compared with age- and sex-matched healthy, nonsmokers, nondrinking controls. The concentrations of trace and toxic elements were measured by inductively coupled plasma atomic emission spectrophotometer after microwave-assisted acid digestion. The validity and accuracy of the methodology were checked using certified reference material (NCS ZC 81002b) and by the conventional wet acid digestion method on the same certified reference material and on real samples. The recovery of all the studied elements was found to be in the range of 97.5%-99.7% in certified reference material. The results of this study showed that the mean values of cadmium, copper, iron, nickel and lead were significantly higher in scalp hair samples of both smoker and nonsmoker hypertensive patients than referents (P < 0.001); whereas, the concentration of zinc was lower in the scalp hair samples of hypertensive patients of both genders. The deficiency of zinc and the high exposure of trace and toxic metals as a result of cigarette smoking and alcohol consumption may be synergistic with risk factors associated with hypertension. PMID- 21286846 TI - Dynamic pattern of gene expression of ZnT-4, caspase-3, LC3, and PRG-3 in rat cerebral cortex following flurothyl-induced recurrent neonatal seizures. AB - Zinc transporters, plasticity-related genes, and autophagic/apoptotic pathway both are associated with developmental seizure-induced brain excitotoxicity. Here, for the first time, we report the timing of expression pattern of zinc transporter 4 (ZnT-4), plasticity-related gene 3 (PRG-3), specific marker of autophagic vacuoles (LC3), and apoptotic marker caspase-3 in cerebral cortex following neonatal seizures. A seizure was induced by inhalant flurothyl daily in neonatal Sprague-Dawley rats from postnatal day 6 (P6). Rats were assigned into the recurrent-seizure group (RS, seizures induced in six consecutive days) and the control group. At 1.5 h, 3 h, 6 h, 12 h, 24 h, 48 h, 7 days, and 14 days after the last seizure, the mRNA level of the four genes in cerebral cortex was detected using RT-PCR method. At an early period 6 h or 12 h after the last seizures, both ZnT-4 and LC3 showed significantly up-regulated mRNA level while PRG-3 showed significantly down-regulated mRNA level at 12 h in cerebral cortex of RS group than those at the corresponding time point in control group. In the long-term time point of 7 days after the last seizure, the mRNA level of caspase 3 down-regulated; meanwhile, there was up-regulated mRNA level of LC-3 in RS group when compared to the control rats. This is the first report investigating the gene expression pattern of ZnT-4, PRG-3, LC-3, and caspase-3 in the developing brain. The results suggest that the disturbed expression pattern of the four genes might play a role in the pathophysiology of recurrent neonatal seizure-induced acute and long-term brain damage. PMID- 21286847 TI - Potential phytoextraction and phytostabilization of perennial peanut on copper contaminated vineyard soils and copper mining waste. AB - This study sought to evaluate the potential of perennial peanut (Arachis pintoi) for copper phytoremediation in vineyard soils (Inceptisol and Mollisol) contaminated with copper and copper mining waste. Our results showed high phytomass production of perennial peanut in both vineyard soils. Macronutrient uptakes were not negatively affected by perennial peanut cultivated in all contaminated soils. Plants cultivated in Mollisol showed high copper concentrations in the roots and shoots of 475 and 52 mg kg(-1), respectively. Perennial peanut plants showed low translocation factor values for Cu, although these plants showed high bioaccumulation factor (BCF) for both vineyard soils, Inceptisol and Mollisol, with BCF values of 3.83 and 3.24, respectively, being characterized as a copper hyperaccumulator plant in these soils. Copper phytoextraction from Inceptisol soil was the highest for both roots and entire plant biomass, with more than 800 mg kg(-1) of copper in whole plant. The highest potential copper phytoextraction by perennial peanut was in Inceptisol soil with copper removal of 2,500 g ha(-1). Also, perennial peanut showed high potential for copper phytoremoval in copper mining waste and Mollisol with 1,700 and 1,500 g of copper per hectare, respectively. In addition, perennial peanuts characterized high potential for phytoextraction and phytostabilization of copper in vineyard soils and copper mining waste. PMID- 21286848 TI - Influence of dietary selenomethionine supplementation on performance and selenium status of broiler breeders and their subsequent progeny. AB - The study was conducted to investigate the effects of dietary maternal selenomethionine or sodium selenite supplementation on performance and selenium status of broiler breeders and their next generation. Two hundred and forty 39 week-old Lingnan yellow broiler breeders were allocated randomly into two treatments, each of which included three replicates of 40 birds. Pretreatment period was 2 weeks, and the experiment lasted 8 weeks. The groups were fed the same basal diet supplemented with 0.30 mg selenium/kg of sodium selenite or selenomethionine. After incubation, 180 chicks from the same parental treatment group were randomly divided into three replicates, with 60 birds per replicate. All the offspring were fed the same diet containing 0.04 mg selenium/kg, and the experiment also lasted 8 weeks. Birth rate was greater (p < 0.05) in hens fed with selenomethionine than that in hens fed with sodium selenite. The selenium concentration in serum, liver, kidney, and breast muscle of broiler breeders, selenium deposition in the yolk, and albumen and tissues' (liver, kidney, breast muscle) selenium concentrations of 1-day-old chicks were significantly (p < 0.01) increased by maternal selenomethionine supplementation compared with maternal sodium selenite supplementation. The antioxidant status of 1-day-old chicks was greatly improved by maternal selenomethionine intake in comparison with maternal sodium selenite intake and was evidenced by the increased glutathione peroxidase activity in breast muscle (p < 0.05), superoxide dismutase activity in breast muscle and kidney (p < 0.05), glutathione concentration in kidney (p < 0.01), total antioxidant capability in breast muscle and liver (p < 0.05), and decreased malondialdehyde concentration in liver and pancreas (p < 0.05) of 1-day-old chicks. Feed utilization was better (p < 0.05), and mortality was lower (p < 0.05) in the progeny from hens fed with selenomethionine throughout the 8-week growing period compared with those from hens fed with sodium selenite. In summary, we concluded that maternal selenomethionine supplementation increased birth rate and Se deposition in serum and tissues of broiler breeders as well as in egg yolk and egg albumen more than maternal sodium selenite supplementation. Furthermore, maternal selenomethionine intake was also superior to maternal sodium selenite intake in improving the tissues Se deposition and antioxidant status of 1-day-old chicks and increasing the performance of the progeny during 8 weeks of post-hatch life. PMID- 21286849 TI - Trace elements analysis of urine and hair in tuberculous pleurisy. AB - In this study, copper, zinc, magnesium, manganese, selenium, and iron of urine and hair were measured in the patients with tuberculous (TB) pleurisy (n = 24) and in the control group (n = 20). Selenium, magnesium, and zinc of hair were found to be significantly lower in TB pleurisy cases than those in the control group (p < 0.05, p < 0.001, and p < 0.01, respectively). On the contrary, selenium and magnesium of urine were found to be significantly elevated in TB pleurisy cases than those in the control group (p < 0.05 and p < 0.001, respectively). There was no significant difference in the value of manganese and iron between TB pleurisy and the control group (p > 0.05). Copper level were significantly increased in hair and decreased in urine of the patients (p < 0.01). The occurrence of these abnormalities constitutes new information regarding trace elements in TB pleurisy patients. These results may provide an additional disease correlate for assessing TB pleurisy risk. PMID- 21286850 TI - Interferon-alpha-2a and zinc combination therapy in children with chronic hepatitis B infection. AB - Zinc has been reported to enhance the response to interferon (IFN) or PEG-IFN plus ribavirin therapy, improve liver function, and ameliorate hematologic side effects in patients with chronic hepatitis C. However, the role of zinc supplementation during IFN therapy in chronic hepatitis B infection (CHB) remains unclear. We therefore aimed to report the results of zinc and IFN-alpha-2a therapy in children with CHB. Twenty-two naive, HBeAg-positive children (mean age 10.4 +/- 4.4 years) received IFN-alpha2a (9 MU/m(2) sc) for 6 months plus peroral zinc (7.5 mg/day for <10 years and 10 mg/day for >10 years) for 12 months. Serum zinc, alanine aminotransferase (ALT), complete blood count, hepatitis B virus DNA (HBV DNA), and serological markers were measured. Histological (HR) and sustained response (SR) were evaluated at 6 months after completion of therapy. Normalization of ALT, HBeAg seroconversion, and HBV DNA < 10,000 copies/ml were considered as SR. HR was defined as decrease in Knodell histological activity index (HAI) score by at least 2 points compared to baseline. End of therapy ALT level and log HBV DNA were significantly lower than pretherapy levels (p = 0.001 and p = 0.001, respectively), while zinc level was not different. Portal inflammation score significantly decreased after therapy (p = 0.043), however, total HAI and other HAI components were not different. SR and HR were 25% and 52.9%. In conclusion as a first study investigating the effect of zinc and IFN combination therapy in children with CHB, SR and HR rates were not better than previously reported monotherapy or combination therapies. PMID- 21286851 TI - Continuous positive airway pressure therapy reduces oxidative stress markers and blood pressure in sleep apnea-hypopnea syndrome patients. AB - Sleep apnea-hypopnea syndrome (SAHS) is characterized by recurrent episodes of hypoxia/reoxygenation, which seems to promote oxidative stress. SAHS patients experience increases in hypertension, obesity and insulin resistance (IR). The purpose was to evaluate in SAHS patients the effects of 1 month of treatment with continuous positive airway pressure (CPAP) on oxidative stress and the association between oxidative stress and insulin resistance and blood pressure (BP). Twenty-six SAHS patients requiring CPAP were enrolled. Measurements were recorded before and 1 month after treatment. Cellular oxidative stress parameters were notably decreased after CPAP. Intracellular glutathione and mitochondrial membrane potential increased significantly. Also, total antioxidant capacity and most of the plasma antioxidant activities increased significantly. Significant decreases were seen in BP. Negative correlations were observed between SAHS severity and markers of protection against oxidative stress. BP correlated with oxidative stress markers. In conclusion, we observed an obvious improvement in oxidative stress and found that it was accompanied by an evident decrease in BP with no modification in IR. Consequently, we believe that the decrease in oxidative stress after 1 month of CPAP treatment in these patients is not contributing much to IR genesis, though it could be related to the hypertension etiology. PMID- 21286852 TI - A fever-like effect of central infusion of CNTF in freely moving mice with diet induced obesity. AB - Ciliary neurotrophic factor (CNTF), an inducer of neurogenesis in the hypothalamus, has been known to cause a permanent fall of body mass in mice made obese by a fat-rich diet. In the present study, energetics of obese mice was followed during and after a 7-days long intracerebroventricular infusion of CNTF (720 ng/day) using an ALZET minipump. The animals were previously implanted with MINIMITTER biotelemetry transmitter allowing monitoring of abdominal core temperature (Tc) and locomotor activity (Act). The fat-rich diet induced a rise in body mass by about 40% over a period of 2 months and led to a prompt decrease of circadian Tc excursions by about 50% and an increase of 24-h Tc averages without a change in Act. Infusion of CNTF resulted in an expected reduction of body mass of obese mice beyond the period of infusion. This response was accompanied by a rise in daily averages of Tc together with a decrease in daily Tc excursions and a fall in Act. The observed fall of body mass, rise of Tc and probably a decrease of food intake belong to the components of sickness behaviour. PMID- 21286853 TI - Unsecured intracranial aneurysms and induced hypertension in cerebral vasospasm: is induced hypertension safe? AB - BACKGROUND: Induced hypertension is an established therapy to treat cerebral vasospasm (CVS) following subarachnoid hemorrhage (SAH) to prevent delayed ischemic deficits. Currently, there is minimal evidence available assessing the risk of induced hypertension in the presence of unsecured aneurysms. The aim of this study was to investigate the impact of induced hypertension on the rupturing of unsecured aneurysms in treating CVS. METHODS: We conducted a retrospective analysis between 1999 and 2009. Patients with unsecured aneurysms treated with induced hypertension were identified and stratified as having (1) additional unruptured unsecured aneurysms or (2) ruptured unsecured aneurysms. Hemodynamic parameters were analyzed and any bleeding recorded. RESULTS: Forty-five patients were included. Of those, 41 had 71 additional unruptured unsecured aneurysms and four patients had four ruptured unsecured aneurysms. The mean size of unsecured aneurysms was: 4.0 +/- 1.9 mm (additional unruptured) and 5.3 +/- 2.2 mm (ruptured), respectively. No aneurysm ruptured during therapy. Combining our data with previously published studies, there appears to be no increase of risk for aneurysm rupture by induced hypertension when compared to the natural history (0.5% for group 1, 2.9% for group 2). CONCLUSION: These data corroborate that induced hypertension may be a safe treatment option to prevent cerebral infarction in CVS, even in the presence of unsecured aneurysms. Our findings suggest that induced hypertension does not increase rupture of unsecured aneurysms. Given the high risk for cerebral infarction in severe CVS, we conclude that induced hypertension should not be omitted due to the presence of unsecured aneurysms. PMID- 21286854 TI - Risk factors and outcome of seizures after chronic subdural hematoma. AB - BACKGROUND: Seizures are important neurologic complications of chronic subdural hematoma (CSDH). A better understanding of risk factors of seizures following CSDH is needed to identify the patient who will require treatment. METHODS: This one-year retrospective study enrolled 100 adult CSDH patients. Baseline prognostic variables were analyzed by Cox's proportional hazards model after a minimum of 18 months of follow-up. RESULTS: Seizures occurred in 11 CSDH patients, including acute symptomatic seizures in 6.0% (6/100) and unprovoked seizures in 5.0% (5/100). None progressed to status epilepticus during hospitalization. After a minimum of 18 months of follow-up, the mean Glasgow Outcome Scores (GOSs) were 4.1 +/- 1.4 and 4.7 +/- 0.7 for patients with and without seizures, respectively. Cox's proportional hazards model showed that only the mean GCS on admission (P = 0.004, OR = 0.78, 95% CI = 0.67-0.93) was independently associated with seizures, and a decrease of one mean GCS increased the seizure rate by 21.6%. CONCLUSION: Lower mean GCS on admission is independently predictive of seizures, most of which occur within the first three months after CSDH. PMID- 21286855 TI - Role of endothelin-1 in human aneurysmal subarachnoid hemorrhage: associations with vasospasm and delayed cerebral ischemia. AB - BACKGROUND: Endothelin-1 (ET-1) is a potent vasoconstrictor implicated in the pathogenesis of vasospasm and delayed cerebral ischemia (DCI) in aneurysmal subarachnoid hemorrhage (aSAH) patients. The aim of this study was to investigate the relationship between cerebrospinal fluid (CSF) ET-1 levels and angiographic vasospasm and DCI. METHODS: Patients with aSAH were consented (n = 106). Cerebral vasospasm was determined by angiography. DCI was determined by transcranial Doppler (TCD) results and/or angiogram results with corresponding clinical deterioration. CSF ET-1 levels over 14 days after the initial insult was quantified by ELISA. ET-1 analysis included a group-based trajectory analysis and ET-1 exposure rate during 24, 48, and 72 h prior to, as well as 72 h post angiography, or clinical deterioration. RESULTS: Trajectory analysis revealed two distinct groups of subjects with 56% of patients in the low ET-1 trajectory group (mean at day 1 = 0.31 pg/ml; SE = 0.04; mean at day 14 = 0.41 pg/ml; SE = 0.15) and 44% of patients in the high ET-1 trajectory group (mean at day 1 = 0.65 pg/ml; SE = 0.08; mean at day 14 = 0.61 pg/ml; SE = 0.06). Furthermore, we observed that ET-1 exposure rate 72 h before angiography and clinical spasm was a significant predictor of both angiographic vasospasm and DCI, whereas, ET-1 exposure after angiography and clinical spasm was not associated with either angiographic vasospasm or DCI. CONCLUSION: Based on these results we conclude that ET-1 concentrations are elevated in a sub-group of patients and that the acute (72 h prior to angiography and clinical neurological deterioration), but not chronic, elevations in CSF ET-1 concentrations are indicative of the pathogenic alterations of vasospasm and DCI in aSAH patients. PMID- 21286856 TI - Brain natriuretic peptide concentrations after aneurysmal subarachnoid hemorrhage: relationship with hypovolemia and hyponatremia. AB - BACKGROUND: Hyponatremia and hypovolemia occur often after aneurysmal subarachnoid hemorrhage (SAH) and are associated with poor outcome. The authors investigated whether brain natriuretic peptide (BNP) is related to hypovolemia and hyponatremia after SAH and whether it can differentiate between hypovolemic and non-hypovolemic hyponatremia. METHODS: In 58 SAH patients, the authors daily measured serum BNP and sodium concentrations, and circulating blood volume by means of pulse dye densitometry, during the initial 10 days. For each patient, mean BNP concentrations were calculated until occurrence of the following events: hyponatremia (Na <130 mmol/l), hypovolemia (blood volume <60 ml/kg), and severe hypovolemia (blood volume <50 ml/kg). The median day of onset of each event was calculated. In patients without an event, the authors calculated and used for comparison the mean BNP concentration until the median day of onset of the particular event. Odds Ratio's (OR) for high versus low mean BNP concentrations (dichotomized on median values per event) were calculated for the occurrence of each event and adjusted for relevant baseline characteristics. RESULTS: Patients with BNP above median more often had severe hypovolemia (adjusted OR 4.2, 95% confidence interval, CI 1.2-15.0) and showed a trend toward hyponatremia (adjusted OR 3.3, 95% CI 0.7-9.2). In the 12 hyponatremic patients, BNP could not differentiate between hypovolemic and non-hypovolemic hyponatremia. CONCLUSIONS: High BNP concentrations are related to the occurrence of severe hypovolemia and possibly hyponatremia. These data do not support a role for BNP measurements to differentiate between hypovolemic and non-hypovolemic hyponatremia in SAH patients. PMID- 21286857 TI - Parathyroid hemangioma: a case report in proof of its existence. AB - Hemangiomas are benign vascular tumors that are most commonly found superficially in the head and neck. Cavernous hemangiomas are located in deeper structures and have been reported in a variety of endocrine tumors. However, parathyroid hemangiomas are exceedingly rare, with only three previously reported cases in the literature, all of which were associated with hyperparathyroidism. Here, we present the first case of an intraparenchymal cavernous hemangioma of the parathyroid gland without accompanying hyperparathyroidism in an otherwise unremarkable gland, accompanied by a brief review of the relevant literature. PMID- 21286858 TI - Nuclear structure, organization, and oncogenesis. AB - The genetic code has received a great amount of attention from investigators, and the media since its discovery, and then again with the sequencing of the human genome in 2000. A decade later, investigators are beginning to look beyond the raw sequence to other mechanisms that affect gene expression. The main function of the nucleus is to maintain the genome and regulate gene expression. Changes in the expression of genes can drastically change the properties of the cell therefore giving the nucleus a role as the cell's "command post." In the past few years, one of the most notable discoveries in the study of the nucleus is that this organelle is not homogeneous. It is also not randomly organized; everything within the nucleus has a specific location with a specific function. Chromosome location within the nucleus relative to its center is directly related to transcription level. Additionally, there are specific regions of the nucleus where content and function differ. The various structures of the nucleus such as the membranes and matrix that supply support to the well protected chromatin offer ever increasing layers of complexity to the nucleus. Here, we focus on the nuclear matrix and its possible effects on signaling and cellular transformation leading to cancer. PMID- 21286859 TI - Hypovitaminosis D as predisposing factor for atrophic type A gastritis: a case control study and review of the literature on the interaction of Vitamin D with the immune system. AB - 1,25-Dihydroxyvitamin D displays immunoregulatory and anti-inflammatory properties, and the cells involved in innate and adaptive immune response express the vitamin D receptor and can both produce and respond to this hormone. This article aims at describing the complex immune regulatory role of vitamin D and depicting whether a correlation exists between atrophic type A gastritis and hypovitaminosis. We studied 62 autoimmune gastritis (AIG) patients and compared them to 54 lymphocytic gastritis patients, 21 Helicobacter pylori gastritis patients and 212 healthy subjects. We also statistically analyzed vitamin D concentration in 36,384 outpatients referred to our clinical laboratories. 25 Hydroxyvitamin D levels, the measurable metabolite used to determine vitamin D status in plasma, were measured by a chemiluminescent method. Average level of 25 OHD in AIG subjects was 9.8 +/- 5.6 ng/mL (95% confidence interval (CI) 8.4 11.2), 11.1 +/- 8.4 (CI 7.5-14.7) in H. pylori gastritis patients, 22.2 +/- 13.5 (CI 18.6-25.8) in nonspecific lymphocytic gastritis patients, 21.3 +/- 12.2 (CI 19.7-22.9) in healthy subjects, and 21.8 +/- 13.1 (CI 21.7-21.9) in the 36,384 outpatients. Vitamin D levels in AIG patients were significantly lower than in patients with nonspecific gastritis or in the general population, supporting the hypothesis that hypovitaminosis D might be a risk factor for the development of autoimmune diseases. The low vitamin D concentration in H. pylori gastritis patients might act as predisposing factor for a more severe Th1-type aggression to the stomach epithelium. PMID- 21286860 TI - Take the wind out your sails: [corrected] relationship among energy drink abuse, hypertension, and break-up of cerebral aneurysm. PMID- 21286861 TI - DW-MRI ADC values can predict treatment response in patients with locally advanced breast cancer undergoing neoadjuvant chemotherapy. AB - The purpose of this study was to evaluate the importance of diffusion-weighted magnetic resonance imaging (DW-MRI) apparent diffusion coefficient (ADC) values to predict treatment response to neoadjuvant chemotherapy (NCT) in patients with locally advanced breast cancer (LABC). Thirty-two patients with LABC underwent 2 4 cylces of NCT (docetaxel and epirubicin). The DW-MRI scans were performed within one week prior to chemotherapy and after the first course of treatment, respectively. Accordingly, tumor volumes, changes in tumor ADC values, and their degree of correlation were analyzed. The overall response (OR) was observed in 62.5% (95% CI, 45.7-79.3%) of patients after 2 cycles of NCT. The clinical complete response (CR) rate and pathological CR (pCR) rate were 15.6 and 9.4%, respectively. The stable disease (SD) rate was 34.4% (11 patients), and progressive disease (PD) was observed in only one patient (3.1%). After the first cycle of NCT, the ADC values in the CR + PR group significantly increased (P < 0.001). The initial ADC values before chemotherapy in the OR group were significantly lower than those in the SD + PD group (P < 0.001). The initial ADC values and the changes in tumor volume after chemotherapy were negatively correlated (r = -0.58, P = 0.02). The lower the initial tumor ADC value was the more obvious the decrease in tumor volume after chemotherapy. The changes in ADC values of tumors after chemotherapy and the changes in tumor volume were positively correlated (r = 0.96, P < 0.001). After chemotherapy, the greater the change in ADC value, the more the tumor volume was reduced. Using the initial ADC values of breast cancer tumors and the early changes in ADC values after NCT, we may be able to predict tumor response to chemotherapy. Tumors with low initial ADC values may be sensitive to chemotherapy; tumors with significantly increasing ADC values early after chemotherapy may be sensitive to chemotherapy. PMID- 21286862 TI - Accuracy of GFR estimation by the Cockroft and Gault, MDRD, and Wright equations in Oncology patients with renal impairment. AB - Estimation of renal function is crucial to guidance of systemic chemotherapy. With stable creatinine levels, the glomerular filtration rate (GFR) is often estimated from a single measurement of serum creatinine. We compared accuracy of the Cockroft and Gault (C&G), modifying diet in renal diseases (MDRD) and Wright estimates in Oncology patients with renal impairment. Analysis was carried out on the basis of monodentate platinum treatment as the nephrotoxic mechanism of these drugs may affect accuracy of these estimates. Sixty-two consecutive patients with stable creatinine levels who had isotopic GFR measurement of <= 60 ml min(-1) at a regional cancer center were reviewed. Twenty-nine were on monodentate platinum treatment. Isotopic GFR was compared with estimated GFR by the three equations. We defined three categories of estimate based on the fractional difference from isotopic GFR: 'perfect' (< 10%), 'reasonable' (>= 10% but < 30%) and 'poor' (>= 30%). There was a trend toward provision of more perfect estimates by the MDRD equation particularly in patients on monodentate platinum treatment. Similar numbers had poor estimates from either of these equations, particularly at extremes of body weight. The MDRD formula may be the most accurate of these equations in Oncology patients with renal impairment, particularly with monodentate platinum treatment. PMID- 21286863 TI - Transported neonates by a specialist team - how STABLE are they. AB - The study was designed to compare the biochemical characteristics of neonates transported by qualified transport team, before and after stabilization, interventions required and setbacks during these transports. Prospective cohort study of all neonatal transports during a period of 13 months from various maternity and pediatric centers was conducted; 151 babies who fulfilled the criteria were included in the study. 58% of babies < 32 wks were hypothermic, 21% of the total babies were hypotensive and a total of 25% of the babies were hypoxic at the referral hospital. Intubation was done by the transport team in 23% of babies and 25 % of the babies were transported on a ventilator. There was a significant improvement in the clinical condition of all these babies in relation to temperature control, sugar control, oxygenation and blood pressure after stabilization. PMID- 21286864 TI - Effectiveness of communication skills training on perceptions and practice of pediatric residents. AB - OBJECTIVE: To assess the effectiveness of a structured communication skills training workshop on the perceptions and practice of pediatric residents. METHODS: The perceptions and practice of pediatric residents with regard to doctor- patient (parent) communication were evaluated before and 6 weeks after a communication skills training workshop, using a structured questionnaire. RESULTS: Twenty pediatric residents participated in the study. They included nine residents who had completed 1 year of pediatric training and 11 residents who had completed 2 years or more of pediatric training. 9 were female residents and 11 were males. Before the intervention, majority of the residents rated themselves poorly on assessment of their perceptions and practice of communication skills. After the workshop there was overall improvement in the communication skills of the residents. CONCLUSIONS: Communication skills of pediatric residents are generally inadequate. Structured training programs will help to improve their communication skills. There is a need to incorporate communication skills training in the pediatric postgraduate curriculum. PMID- 21286865 TI - Hypertension due to loss of clock: novel insight from the molecular analysis of Cry1/Cry2-deleted mice. AB - In our consumer-oriented society, in which productivity requires around-the-clock activity and demanding shift work, the biologic system that regulates our internal rhythms is being compromised. Poor sleep patterns and hectic lifestyle are detrimental to harmonious physiological and metabolic body systems, with severe impact on public health. Over a trillion peripheral cellular clocks throughout the body, supervised by the master clock located in the hypothalamic suprachiasmatic nucleus, govern most aspects of physiology and behavior. To exemplify the importance of the biologic clock for health, we have recently demonstrated that mice that are arrhythmic because of the deletion of Cry1 and Cry2 clock genes suffer from salt-sensitive hypertension. In these mice, a novel 3beta-hydroxyl-steroid dehydrogenase (3beta-Hsd) gene under clock control is severely overexpressed specifically in aldosterone-producing cells in the adrenal cortex, leading to hyperaldosteronism and ultimately to salt-sensitive hypertension. The human homologue of this aldosterone-producing, cell-specific enzyme was also characterized and represents a new possibility in the pathogenesis of hypertension. PMID- 21286866 TI - Diagnosis and treatment of pain in small-fiber neuropathy. AB - Small-fiber neuropathy manifests in a variety of different diseases and often results in symptoms of burning pain, shooting pain, allodynia, and hyperesthesia. Diagnosis of small-fiber neuropathy is determined primarily by the history and physical exam, but functional neurophysiologic testing and skin biopsy evaluation of intraepidermal nerve-fiber density can provide diagnostic confirmation. Management of small-fiber neuropathy depends on the underlying etiology with concurrent treatment of associated neuropathic pain. A variety of recent guidelines proposes the use of antidepressants, anticonvulsants, opioids, topical therapies, and nonpharmacologic treatments as part of the overall management of neuropathic pain. Unfortunately, little data about the treatment of pain specifically in small-fiber neuropathy exist because most studies combine mixed neuropathic pain syndromes in the analysis. Additional studies targeting the treatment of pain in small-fiber neuropathy are needed to guide decision making. PMID- 21286867 TI - Diagnosis of acute headache. PMID- 21286868 TI - Aripiprazole to treat irritability associated with autism: a placebo-controlled, fixed-dose trial. PMID- 21286869 TI - Changing the perspective: current trends in the assessment of functional outcome in patients with head and neck cancer. AB - Functional outcome and quality of life have become frequent outcome measures in head and neck cancer (HNC) clinical trials. Many thoroughly validated outcome measures are available. Still, there is a low degree of standardization and comparability among measures. It seems difficult to fully translate the new insights into clinical routine. The aims of this paper are 1) to acknowledge the diversity of outcome measures and many of the past milestones that have been reached, but also 2) to capture a growing need to concentrate and reach consensus. The hypothesis is to gain more benefit from changing the perspective toward consensus rather than diversity in functional outcome assessment. The next steps are to adopt a unique "language" to describe functional outcome and implement clear end points that assist clinical decision making. The International Classification of Functioning, Disability, and Health was adopted by the WHO and offers an internationally accepted classification to describe disability in HNC. PMID- 21286870 TI - Compression therapy for treatment of venous disease and limb swelling. AB - OPINION STATEMENT: Although compression therapy was initially described over 2,000 years ago (Felty and Rooke Semin Vasc Surg Mar 18:36-40, 1), several patients with edema do not receive appropriate compression therapy. Instead, most patients with edema are treated primarily with diuretics. Compression therapy is the cornerstone of treatment of venous edema and lymphatic disorders. Compression therapy decreases the foot and leg volume and reduces venous reflux and venous hypertension. Compression can be achieved by multiple different modalities, such as inelastic bandages; multilayered wraps; short, medium, and long stretch bandages; graduated compression stockings; and pneumatic compression devices. The major criticism of compression therapy is poor patient compliance. Compliance can be improved by selecting appropriate compression therapy tailored to the needs of the individual patient and by providing adequate patient education. PMID- 21286872 TI - Recurrent and relapsing pancreatitis. AB - Recurrent acute pancreatitis is a common clinical problem. Most cases of pancreatitis are identified by a careful history and physical examination. Despite advanced evaluation, the cause is not apparent in about 10% of cases. The etiology of recurrent acute pancreatitis appears to be multifactorial, with genetic and environmental influences playing a significant role. The strength of evidence for certain etiologies is highly variable, and natural history data are limited. Controversy exists regarding the most appropriate diagnostic and therapeutic approach. Recurrent acute pancreatitis often represents a continuum with chronic pancreatitis. PMID- 21286873 TI - On 'doing' memory and self in different cultural contexts. AB - After a brief and pointed recapitulation of the main issues of Demuth, Chaudhary and Keller's article, Memories of me. Comparisons from Osnabruck (Germany) and Delhi (India) students and their mothers (doi: 10.1007/s12124-010-9136-5 ), alternative or complementary approaches to the investigation of 'doing' memory and self in different cultural contexts are outlined in a sketch of three interrelated proposals. These proposals turn around a) 'contemporaneousness of the non-contemporaneous' (Gleichzeitigkeit des Ungleichzeitigen) and the analysis of 'cultural hybrids', b) 'indigenous concepts of memory and self' and c) 'memory and self in actual cultural practice'. PMID- 21286874 TI - Sclerosing polycystic adenosis of the parotid gland: report of a bifocal, paucicystic variant with ductal carcinoma in situ and pronounced stromal distortion mimicking invasive carcinoma. AB - We present a case (female patient, age 45 years) with a bifocal, paucicystic variant of sclerosing polycystic adenosis of the parotid gland with cribriform ductal carcinoma in situ (DCIS) and pronounced stromal distortion affecting the in situ component to such an extent that it gave a distinct impression of intralesional invasive adenocarcinoma. P63-and calponin-positive myoepithelial cells were present in the periphery of the acini and ducts in the benign component, somewhat discontinuously in the DCIS-component, and even in the periphery of the small irregular atypical cell nests that appeared infiltrative on the haematoxylin and eosin stained sections. Strong cytoplasmic immunoreactivity for GCDFP-15 was detected in the benign component with a variable, patchy and mostly weak positivity in the DCIS. More than 90% of the cells in the DCIS component displayed strong nuclear immunoreactivity for androgen receptors and 10% of the benign ducts showed positivity. Weak to moderate nuclear immunoreactivity for estrogen receptors was seen in 30% of cells in the benign ductal component whereas the DCIS was negative. Occasional cells in the adenosis-component were weakly positive for PR. The proliferative activity (Mib-1/Ki-67) was low (1-2%) in the benign component whereas increased proliferation was seen in the DCIS and in the areas with pseudoinfiltration which also featured atypical mitoses. PMID- 21286875 TI - Angiomyxolipoma (vascular myxolipoma) of the oral cavity. Report of a case and review of the literature. AB - Angiomyxolipoma is a rare tumor characterized by a proliferation of adipose tissue associated with a myxoid stroma and multiple vascular channels. To date, ten cases of angiomyxolipoma located in subcutaneous tissue, spermatic cord and subungual area have been reported in the literature. We describe the clinical and histopathologic findings of the first case of intraoral angiomyxolipoma in a 12 year-old male, as well as the utility of immunohistochemistry as a useful tool in differential diagnosis of this particular lesion with respect to other benign and malignant lesions derived from adipose tissue. PMID- 21286876 TI - Synchronous histiocytic sarcoma and diffuse large B cell lymphoma involving the stomach: a case report and review of the literature. AB - We present a 62-year-old Chinese woman with histiocytic sarcoma (HS) and diffuse large B cell lymphoma (DLBL) located in the stomach. HS showed abundant eosinophilic cytoplasm with large, pleomorphic nuclei. Tumor giant and multinucleated cells were also prominent. Hemophagocytosis was common in the neoplastic cells. These cells were positive for CD68, CD45RO, and leukocyte common antigen (LCA), partly positive for S-100 and lysozyme, and negative for CD3, CD5, CD20, Pax-5, CD79a, CD1a, CD21, CD35, CD34, myeloperoxidase, HMB45 and cytokeratin (CK). These cells invaded the submucosa, muscularis mucosa, and serosa. DLBL was located in the mucosa and engulfed the covering epithelium and gland. The nuclei of tumor cells were medium-to-large in size, being >=twice the size of normal lymphocytes. They were diffusely positive for CD20, Pax-5, and LCA, partly positive for vimentin, CD79a, CD10, CD30, CD15, and epithelial membrane antigen, and negative for S-100, CD1a, CD21, CD5, cyclin D1, CD23, CD35, HMB45, and CD68. Both types of tumor cell were positive for Oct-2, Bcl-2, and Bcl 6. These results suggest that HS may have shared a common clonal origin with DLBL, or may have transdifferentiated from DLBL The patient refused further chemotherapy, and died 7 months after surgical resection. PMID- 21286877 TI - Establishment of a cell line panel for the detection of antibodies against human platelet antigen 4b. AB - Antibodies against human platelet antigens (HPAs) play important roles in thrombocytopenia. In Japan, HPA-4b antibody is frequently responsible for HPA related neonatal alloimmune thrombocytopenia. A highly sensitive assay using platelets has been developed for the detection of antibodies against HPAs. However, it is difficult to obtain the platelets expressing specific HPAs required for the assay. Therefore, an alternative method not requiring platelets would be helpful to detect antibodies against HPAs. Glycoprotein IIIa (GPIIIa) cDNA encoding HPA-4b was individually co-transduced with that of wild-type GPIIb in K562 cells, which is a non-adherent cell line, using a retroviral vector. The expression of transgene products in cultured cells were observed for over 6 months. Next, to evaluating the sensitivity and specificity of this cell line panel, we performed monoclonal antibody-specific immobilization of platelet antigens (MAIPA) assay with a serum previously identified by another method. All HPA-4b antibodies in serum samples were positive, and all serum samples, including normal serum and serum containing HLA antibodies were negative. No difference was observed in the specificity and sensitivity between our method and conventional MAIPA using platelets. The present results indicate that this established cell line panel permits highly sensitive detection of specific antibodies against HPA-4b. PMID- 21286878 TI - Acute lymphoblastic leukemia and Down syndrome: the collaborative study of the Tokyo Children's Cancer Study Group and the Kyushu Yamaguchi Children's Cancer Study Group. AB - The Tokyo Children's Cancer Study Group (TCCSG) and the Kyushu Yamaguchi Children's Cancer Study Group (KYCCSG) performed a collaborative analysis of data on children with Down syndrome and acute lymphoblastic leukemia (DS-ALL). Among the 1,139 patients who were enrolled in the TCCSG L99-15, L99-1502, or the KYCCSG ALL 96 study, 13 patients with newly diagnosed ALL had DS. In the DS patients, a significantly higher proportion of patients developed ALL at age 5 years or older compared with the non-DS ALL patients (P < 0.001). The 5-year relapse-free or overall survival of DS-ALL patients was 50.0 or 61.5%, respectively. Relapse accounted for all causes of death. In the TCCSG L99-15 cohort, the overall survival of DS-ALL patients was 42.9%, which was significantly worse compared with 87.9% in the non-DS population (P < 0.001). The survival of patients who received reduced-dose chemotherapy was significantly worse than those who received full-dose chemotherapy (P < 0.001). However, a higher dose of methotrexate was not associated with a better outcome. Results of our preliminary study suggest that the survival of DS-ALL patients could be improved by treatment without dose reduction if possible, although the appropriate dose of methotrexate for DS-ALL needs to be determined. PMID- 21286880 TI - Assessment of the influence factors on nasal spray droplet velocity using phase Doppler anemometry (PDA). AB - Droplet velocity is an important parameter that can be used to characterize nasal spray products. In this study, a phase-Doppler anemometry (PDA) system was used to measure the droplet velocities of nasal sprays. A survey of seven commercial nasal spray products showed a range of droplet velocities from 6.7 to 19.2 m/s, all significantly different from each other. A three-level, four-factor Box Behnken design of experiments (DOE) methodology were applied to investigate the influences of actuation parameters and formulation properties on nasal spray droplet velocity using a set of placebo formulations. The DOE study shows that all four input factors (stroke length, actuation velocity, concentration of the gelling agent, and concentration of the surfactant) have significant influence on droplet velocity. An optimized quadratic model generated from the DOE results describes the inherent relationships between the input factors and droplet velocity thus providing a better understanding of the input factor influences. Overall, PDA provides a new in vitro characterization method for the evaluation of inhalation drugs through assessment of spray velocity and may assist in product development to meet drug delivery equivalency requirements. PMID- 21286881 TI - Templated ultrathin polyelectrolyte microreservoir for delivery of bovine serum albumin: fabrication and performance evaluation. AB - The aim of the study was to develop ultrathin polyelectrolyte microreservoir (UPM) using two combinations of synthetic/synthetic (S/s; poly(allylamine hydrochloride) (PAH)/sodium poly(styrenesulfonate)) and synthetic/natural (S/n; PAH/sodium alginate) polyelectrolytes over spherical porous CaCO(3) core particles (CP) followed by core removal and to evaluate its biocompatibility and integrity of loaded model protein bovine serum albumin (BSA). A novel process for synthesis of CP was developed to obtain maximum yield of monodisperse vaterite (spherical) polymorph. The prepared UPM was characterized for surface morphology, layer-by-layer growth, pay load efficiency, integrity of BSA, as well as viability and cell adhesion using murine J 774 macrophages (Phi). In vitro release profile revealed that both S/s and S/n UPM were able to provide sufficient diffusion barrier to release protein at physiological pH. It has been observed that S/n UPM are fully biocompatible due to obvious reason of using natural polymer. In a separate experiment, the S/s UPM surface was modified with pluronic F-68 to tune biocompatibility which provides evidences for safety and tolerability of the S/s UPM as well. In nutshell, the proposed system could successfully be used for the delivery of proteins, and moreover, the system can be tailored to impart desired properties at any stage of layering especially in terms of drug release and to retain the integrity of proteins. PMID- 21286882 TI - Product lifecycle approach to cascade impaction measurements. AB - Over the lifecycle of an orally inhaled product (OIP), multi-stage cascade impactor (CI) measurements are used for different purposes and to address different questions. Full-resolution CIs can provide important information during product development and are widely used but are time- and resource-intensive, highly variable, and suboptimal for OIP quality control (QC) testing. By contrast, Efficient Data Analysis (EDA) combined with Abbreviated Impactor Measurement (AIM) systems pertinent either for QC and-possibly-for adult Human Respiratory Tract (pHRT) has been introduced for OIP performance assessment during and post-development. This article summarizes available evidence and discusses a strategy for using either abbreviated or full-resolution CI systems depending on the purpose of the measurement, such that adequate, accurate, and efficient testing of aerodynamic particle size distribution (APSD) of OIPs can be achieved throughout the lifecycle of a product. Under these proposals, a comprehensive testing program should initially be conducted by full-resolution CI in OIP development to ascertain the product's APSD. Subsequently, correlations should be established from the selected AIM CIs to the corresponding full resolution system, ideally developing specifications common to both techniques. In the commercial phase, it should be possible to release product using AIM/EDA, keeping the full-resolution CI for investigations, change control, and trouble shooting, thus optimizing resources for APSD characterization throughout the product lifecycle. If an in vitro-in vivo relationship is established and clinically relevant sizes are known, an AIM-pHRT could serve as a quick indicator that clinically relevant fractions have not changed and also, in the management of post-approval changes. PMID- 21286883 TI - Introduction of a theoretical splashing degree to assess the performance of low viscosity oils in filling of capsules. AB - These days an alternative to soft capsules is liquid-filled hard capsules. Their filling technology was investigated earlier with highly viscous formulations, while hardly any academic research focused on low-viscosity systems. Accordingly, this work addressed the filling of such oils that are splashing during the dosing process. It was aimed to first study capsule filling, using middle-chain triglycerides as reference oil, in order to then evaluate the concept of a new theoretical splashing degree for different oils. A laboratory-scale filling machine was used that included capsule sealing. Thus, the liquid encapsulation by microspray technology was employed to seal the dosage form. As a result of the study with reference oil, the filling volume and the temperature were found to be significant for the rate of leaking capsules. The filling volume was also important for weight variability of the capsules. However, most critical for this variability was the diameter of the filling nozzle. We proposed a power law for the coefficient of weight variability as a function of the nozzle diameter and the obtained exponent agreed with the proposed theory. Subsequently, a comparison of different oils revealed that the relative splashing degree shared a correlation with the coefficient of the capsule weight variability (Pearson product moment correlation of r=0.990). The novel theoretical concept was therefore found to be predictive for weight variability of the filled capsules. Finally, guidance was provided for the process development of liquid-filled capsules using low-viscosity oils. PMID- 21286884 TI - Practical considerations in the measurement of the internal relative humidity of pharmaceutical packages with data loggers. AB - The utility of temperature/humidity data loggers are evaluated as a low-cost approach to enrich practical understanding of the actual time dependent humidity that a pharmaceutical product is exposed to. While this approach is found to have significant utility in general, small systematic biases in the measurements due to the presence of the data logger are observed. Taking these biases into account enables more productive extrapolation of measured time/humidity profiles. PMID- 21286885 TI - A method to localize the radial nerve using the 'apex of triceps aponeurosis' as a landmark. AB - BACKGROUND: The relationship of the radial nerve is described with various osseous landmarks, but such relationships may be disturbed in the setting of humerus shaft fractures. Alternative landmarks would be helpful to more consistently and reliably allow the surgeon to locate the radial nerve during the posterior approach to the arm. QUESTIONS/PURPOSES: We investigated the relationship of the radial nerve with the apex of triceps aponeurosis, and describe a technique to locate the nerve. MATERIALS AND METHODS: We performed dissections of 10 cadavers and gathered surgical details of 60 patients (30 patients and 30 control patients) during the posterior approach of the humerus. We measured the distance of the radial nerve from the apex of the triceps aponeurosis along the long axis of the humerus in cadaveric dissections and patients. This distance was correlated with the height and arm length. For all patients, we recorded time until first observation of the radial nerve, blood loss, and postoperative radial nerve function. RESULTS: The mean distance of the radial nerve from the apex of the triceps aponeurosis was 2.5 cm, which correlated with the patients' height and arm length. The mean time until the first observation of the radial nerve from beginning the skin incision was 6 minutes, as compared with 16 minutes in the control group. Mean blood loss was 188 mL and 237 mL, respectively. With the numbers available, we observed no difference in the incidence of patients with postoperative nerve palsy: none in the study group and three in the control group. CONCLUSION: The apex of the triceps aponeurosis appears to be a useful anatomic landmark for localization of the radial nerve during the posterior approach to the humerus. PMID- 21286886 TI - Does tranexamic acid save blood in minimally invasive total knee arthroplasty? AB - BACKGROUND: Tranexamic acid (TEA) reportedly reduces perioperative blood loss in TKA. However, whether it does so in minimally invasive TKA is not clear. QUESTIONS/PURPOSES: We asked whether TEA would reduce blood loss and blood transfusion requirements after minimally invasive TKA. PATIENTS AND METHODS: We prospectively enrolled 100 patients who underwent minimally invasive TKAs: 50 received one intravenous injection of TEA before deflation of the tourniquet and a control group of 50 patients received an equivalent volume of placebo. We compared changes in hemoglobin, postoperative drainage, total blood loss, and transfusion rates between the two groups. RESULTS: The total blood loss was less for patients in the TEA group than for the control group: 833 mL (374-1014 mL) versus 1453 mL (733-2537 mL), respectively. The rate of blood transfusion also was less for patients in the TEA group than in the control group (4% versus 20%). The hemoglobin levels on the second and fourth postoperative days were greater for patients in the TEA group than in the control group. CONCLUSIONS: Our data suggest one intraoperative injection of TEA decreased the total blood loss and need for transfusion after minimally invasive TKA. LEVEL OF EVIDENCE: Level II, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence. PMID- 21286887 TI - Bony increased-offset reversed shoulder arthroplasty: minimizing scapular impingement while maximizing glenoid fixation. AB - BACKGROUND: Scapular notching, prosthetic instability, limited shoulder rotation and loss of shoulder contour are associated with conventional medialized design reverse shoulder arthroplasty. Prosthetic (ie, metallic) lateralization increases torque at the baseplate-glenoid interface potentially leading to failure. QUESTIONS/PURPOSES: We asked whether bony lateralization of reverse shoulder arthroplasty would avoid the problems caused by humeral medialization without increasing torque or shear force applied to the glenoid component. PATIENTS AND METHODS: We prospectively followed 42 patients with rotator cuff deficiency treated with bony increased-offset reverse shoulder arthroplasty. A cylinder of autologous cancellous bone graft, harvested from the humeral head, was placed between the reamed glenoid surface and baseplate. Graft and baseplate fixation was achieved using a lengthened central peg (25 mm) and four screws. Patients underwent clinical, radiographic, and CT assessment at a minimum of 2 years after surgery. RESULTS: The humeral graft incorporated completely in 98% of cases (41 of 42) and partially in one. At a mean of 28 months postoperatively, no graft resorption, glenoid loosening, or postoperative instability was observed. Inferior scapular notching occurred in 19% (eight of 42). The absolute Constant Murley score improved from 31 to 67. Thirty-six patients (86%) were able to internally rotate sufficiently to reach their back over the sacrum. CONCLUSIONS: Grafting of the glenoid surface during reverse shoulder arthroplasty effectively creates a long-necked scapula, providing the benefits of lateralization. Bony increased-offset reverse shoulder arthroplasty is associated with low rates of inferior scapular notching, improved shoulder rotation, no prosthetic instability and improved shoulder contour. In contrast to metallic lateralization, bony lateralization has the advantage of maintaining the prosthetic center of rotation at the prosthesis-bone interface, thus minimizing torque on the glenoid component. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 21286888 TI - Arteriovenous malformation of the pancreatic head--difficulties in diagnosis and treatment. AB - A patient with pancreatic arteriovenous malformation who presented diagnostic and therapeutic difficulties is presented. The initial tests appeared to suggest inflammatory bowel disease, but the diagnosis was clinched by the finding of blood issuing from the ampulla of Vater. Repeated angiographic embolization did not obliterate the vascular malformation, and the symptoms eventually resolved after Whipple's pancreaticoduodenectomy. PMID- 21286889 TI - A time course study on prothrombotic parameters and their modulation by anti platelet drugs in hyperlipidemic hamsters. AB - The present study was undertaken to assess the chronology of major pathological events associated with high cholesterol (HC) diet and their modulation by anti platelet drugs. Male Golden Syrian hamsters were fed HC diet up to 90 days. Plasma lipid, glucose and coagulation parameters (commercial kits), platelet activation (whole blood aggregation and static adhesion), endothelial dysfunction (aortic ring vasoreactivity), splenocyte TNF-alpha, IFN-gamma and iNOS mRNA transcripts (RT-PCR), and ferric chloride (time to occlusion) induced thrombosis were monitored at 15, 30, 60, and 90 days after HC feeding and compared with normolipidemic hamsters. A significant increase in plasma lipid levels was observed at 15 days of HC feeding, but other parameters remain unaltered. Enhanced ADP, collagen, and thrombin-induced platelet aggregation, splenocyte TNF alpha expression along with endothelial dysfunction were observed from 30 to 90 days of HC feeding. Platelet adhesion on collagen-/fibrinogen-coated surface and IFN-gamma expression were augmented only after 60 days, while enhanced iNOS expression, reduction in thrombin time, and potentiation of ferric chloride induced thrombosis was observed only at 90 days of HC feeding. Thus, pathological changes induced by HC diet depend on the duration and extent of hyperlipidemia. Moreover, hamsters treated with anti-platelet drugs aspirin (5 mg/kg) or clopidogrel (10 mg/kg) along with HC feeding exhibited reduction in platelet activation as well as subsequent changes observed in the abovementioned parameters following HC feeding. Since reduction in TNF-alpha was associated with reversion in endothelial dysfunction and prothrombotic state, the role of platelets is implicated in the pathological changes associated with HC feeding. PMID- 21286890 TI - An educator's credo: They don't learn what you expect, but what you inspect. PMID- 21286892 TI - Suggested baseline ranges for performance testing of the Fujifilm FCR Capsula XL computed radiography system. AB - Due to the difficulty in obtaining expected baseline values from the supplier for the performance testing of the Fujifilm FCR Capsula XL computed radiography system, performance test results from the acceptance testing of 42 Capsula systems were reviewed. Guidance ranges are provided for nine system performance tests which can be applied to future testing of calibrated systems. PMID- 21286893 TI - Acute pancreatitis associated with primary hyperparathyroidism. AB - Coexistence of primary hyperparathyroidism and acute pancreatitis has widely been reported in literature, but a causal relationship remains controversial. A case of acute pancreatitis as a first symptom of primary hyperparathyroidism with severe hypercalcemia is reported. In this patient a reduction of serum calcium level was obtained with medical therapy and resulted in the resolution of acute pancreatitis symptoms within 10 days. At the same time a parathyroid adenoma was clinically identified and elective parathyroidectomy was performed with complete normalization of intact parathyroid hormone and serum calcium level. At three year follow-up, no recurrence or complications of pancreatitis were documented. The presented case suggests a cause and effect relationship between acute pancreatitis and severe hypercalcemia which should be kept in mind in the differential diagnosis of non-biliary, non-alcoholic acute pancreatitis. Reduction of hypercalcemia with medical treatment can represent a good chance for elective surgical neck exploration. PMID- 21286894 TI - Rare abdominal metastases from occult lobular breast cancer: report of two cases. AB - Intra-abdominal metastases from breast carcinomas are rarely reported in the literature. Least are those originating from occult breast primary. We report, one case of pancreatic metastasis and one case of metastatic infiltration of the colonic wall, both by occult lobular breast carcinoma. The first patient underwent pancreaticoduodenectomy for obstructive jaundice, with unexpected histological finding of infiltration of distal bile duct, pancreatic gland, portal vein and retroperitoneal soft tissue by lobular carcinoma of the breast. The second patient complained of diffuse abdominal pain associated with constipation and rectal bleeding and underwent endoscopic biopsy of three intestinal strictures, revealing metastatic lobular carcinoma with signet-ring cell morphology. In both cases, a subsequent complete diagnostic work-up demonstrated asymptomatic multiple breast nodules, diagnosed as lobular carcinoma by fine needle aspiration cytology. PMID- 21286895 TI - Seizure attack and Morgagni diaphragmatic hernia: incidental diagnosis or direct correlation? AB - Asymptomatic Morgagni hernia can be discovered in adults as an incidental finding or because of acute gastrointestinal symptoms. We report a case of a 76-year-old man with an incidental diagnosis of seizure attack. Obesity and the increased abdominal pressure caused by abdominal muscles contraction during seizure could have contributed to the clinical presentation. The omentum, small bowel, and transverse colon were found in the right side of the chest using an open transabdominal approach. The hernia sac was excised and the diaphragmatic defect closed by direct suturing. The postoperative period was uneventful and the shortness of breath attributed to obesity disappeared. PMID- 21286896 TI - Laparoscopic versus open distal gastrectomy for locally advanced gastric cancer: a case-control study. AB - In a non-specialized setting, laparoscopic distal gastrectomy (LDG) for locally advanced diseases remains controversial, particularly given to the technical demands of the learning curve required to perform an adequate resection with D2 lymph node dissection. Inclusion criteria for this statistically generated matching controlled study were all patients who underwent subtotal laparoscopic gastrectomies from January 2006 until September 2009 for locally advanced gastric adenocarcinoma (stage II-IIIb), compared with matched patients who underwent the same procedure in an open fashion during the same period. Sixty case-matched patients were evaluated (30 laparoscopic vs. 30 open). Operative time was significantly longer (p < 0.05) for LDG. Benefits for LDG (p < 0.05) were observed among surgical short-term outcome (postoperative hospital stay, ambulation, first bowel movement, first flatus, first stool, first eating and use of analgesic drugs) and postoperative non-surgical site complications (cardiopulmonary, urinary, etc.). The 42 months' overall survival was similar (p = 0.646). Laparoscopic gastrectomy is a safe technique in a non-academic hospital setting for locally advanced gastric cancer; it seems to be adequate in terms of margin status and adequate lymph node retrieval and is associated with additional benefits as a decreased length of hospital stay, a decreased narcotic use and fewer complications. PMID- 21286897 TI - Secondary extinction in Pavlovian fear conditioning. AB - Pavlov (1927/1960) reported that following the conditioning of several stimuli, extinction of one conditioned stimulus (CS) attenuated responding to others that had not undergone direct extinction. However, this secondary extinction effect has not been widely replicated in the contemporary literature. In three conditioned suppression experiments with rats, we further explored the phenomenon. In Experiment 1, we asked whether secondary extinction is more likely to occur with target CSs that have themselves undergone some prior extinction. A robust secondary extinction effect was obtained with a nonextinguished target CS. Experiment 2 showed that extinction of one CS was sufficient to reduce renewal of a second CS when it was tested in a neutral (nonextinction) context. In Experiment 3, secondary extinction was observed in groups that initially received intermixed conditioning trials with the target and nontarget CSs, but not in groups that received conditioning of the two CSs in separate sessions. The results are consistent with the hypothesis that CSs must be associated with a common temporal context during conditioning for secondary extinction to occur. PMID- 21286898 TI - The reactivation of associated information affects source monitoring. AB - In this study, we examined a source-monitoring phenomenon that arises from reactivated related information from the study phase. Three experiments showed that source attributions for target events were influenced not only by the target item itself, but also by studied information about related items. In Experiment 1, source memory for target items that have a high forward association value to a single related study item (e.g., credit) were affected by the source of the associated information (e.g., card), so that memory performance was better when associated items were presented in the same source rather than a different source. A similar effect occurred with bidirectional associates (Exp. 2), as well as with synonymous pairs of words (Exp. 3). We argue that the source information of the reactivated material can be commingled with information about a candidate during a source judgment at retrieval and thereby can affect performance. PMID- 21286899 TI - Implicit memory for novel associations between pictures: effects of stimulus unitization and aging. AB - Studies of implicit memory for novel associations have focused primarily on verbal materials and have highlighted the contribution of conceptually unitized representations to such priming. Using pictorial stimuli in a perceptual identification task, we examined whether new association priming can occur at a purely perceptual level. By manipulating the spatial contiguity of stimuli, we also evaluated whether such priming requires the creation of perceptually unitized representations. Finally, we examined the status of such priming in aging. In Experiment 1, we found that spatial contiguity of stimuli is not necessary for novel pictorial association priming to emerge, although such contiguity does enhance the magnitude of associative priming. In Experiment 2, we found that new association priming is age invariant, regardless of spatial contiguity. In Experiment 3, we provide additional evidence that pictorial association priming is perceptually based. These findings expand the scope and delineate the conditions of novel association priming and inform theories about the nature of implicit memory for new associations. PMID- 21286900 TI - A doubled haploid rye linkage map with a QTL affecting alpha-amylase activity. AB - A rye doubled haploid (DH) mapping population (Amilo * Voima) segregating for pre harvest sprouting (PHS) was generated through anther culture of F(1) plants. A linkage map was constructed using DHs, to our knowledge, for the first time in rye. The map was composed of 289 loci: amplified fragment length polymorphism (AFLP), microsatellite, random amplified polymorphic DNA (RAPD), retrotransposon microsatellite amplified polymorphism (REMAP), inter-retrotransposon amplified polymorphism (IRAP), inter-simple sequence repeat (ISSR) and sequence-related amplified polymorphism (SRAP) markers, and extended altogether 732 cM (one locus in every 2.5 cM). All of the seven rye chromosomes and four unplaced groups were formed. Distorted segregation of markers (P <= 0.05) was detected on all chromosomes. One major quantitative trait locus (QTL) affecting alpha-amylase activity was found, which explained 16.1% of phenotypic variation. The QTL was localized on the long arm of chromosome 5R. Microsatellites SCM74, RMS1115, and SCM77, nearest to the QTL, can be used for marker-assisted selection as a part of a rye breeding program to decrease sprouting damage. PMID- 21286901 TI - Identification and characterization of seed-specific transcription factors regulating anthocyanin biosynthesis in black rice. AB - Black rice is rich in anthocyanin and is expected to have more healthful dietary potential than white rice. We assessed expression of anthocyanin in black rice cultivars using a newly designed 135 K Oryza sativa microarray. A total of 12,673 genes exhibited greater than 2.0-fold up- or down-regulation in comparisons between three rice cultivars and three seed developmental stages. The 137 transcription factor genes found to be associated with production of anthocyanin pigment were classified into 10 groups. In addition, 17 unknown and hypothetical genes were identified from comparisons between the rice cultivars. Finally, 15 out of the 17 candidate genes were verified by RT-PCR analysis. Among the genes, nine were up-regulated and six exhibited down-regulation. These genes likely play either a regulatory role in anthocyanin biosynthesis or are related to anthocyanin metabolism during flavonoid biosynthesis. While these genes require further validation, the results here underline the potential use of the new microarray and provide valuable insight into anthocyanin pigment production in rice. PMID- 21286905 TI - [Quality circle in a trauma network of the German Association for Trauma Surgery. Upgrading patient care]. AB - In industry, especially in the automobile industry, improvements in efficiency could be demonstrated by quality management and quality circles. There is no doubt that in medicine, major trauma is also a very complex challenge.The German Association for Trauma Surgery published the White Paper on the Management of the Seriously Injured in 2006. The White Paper specifies the demand for quality of care, sets the level of structural requirements for trauma care and postulates the cooperation of regional hospitals within a network of dedicated trauma centres. The Trauma Network Eastern Bavaria (TNO) was the first certified trauma network in Germany. One of the reasons for this success is the fact that cooperation between trauma surgeons has already had a long tradition in this geographic area. The key factor is communication which is supported by all technical and organisational means. The formal installation of quality circles on each level of trauma care, e.g. within and across institutions, was accepted by all partners within the network. The goal is the improvement of patient care in trauma above and beyond the guidelines of the White Paper. This paper shows the instruments used to enhance the quality of trauma care within a network. PMID- 21286906 TI - [External fixation with motion capacity in complex dislocation of the knee joint and associated injuries]. AB - Closed and open dislocations of the knee joint with vascular and nerve injuries are treated immediately and may present an indication for external fixation. In acute trauma definitive treatment and reconstruction of the complex capsule and ligamentous injuries are often impossible. The application of a medial transarticular external fixator with motion capacity combines the treatment of remaining joint instability with the benefit of early joint movement. Disadvantages of prolonged joint immobilisation until definitive stabilisation of the knee are reduced. PMID- 21286907 TI - [Osteosynthesis in distal intra-articular humeral fractures. External fixation with motion capacity]. AB - The rising incidence of distal intra-articular humeral fracture in elderly patients associated with osteoporosis frequently leads to difficulties in acute reconstruction and may result in early failure of internal fixation. The biomechanics of the elbow joint and especially the flexor group as well as the brachioradialis muscle as part of the extensor group is analyzed. The complex motion pattern of the transarticular muscle groups increases the load on internal fixation and may affect the interface between implant and osteoporotic bone. An external fixator with motion capacity serves to protect the internal osteosynthesis and secures the fixation in osteoporotic bone. PMID- 21286908 TI - [Use of upper limb external fixation with motion capacity. Anatomical considerations]. AB - The use of external fixation in the upper limb requires detailed anatomical knowledge. The centre of rotation in the elbow joint has to be understood and the bony landmarks have to be identified. The joint mechanics and the mechanics of the external fixation device have to be collinear in a wide range of the natural motion capacity. Insertion of humeral and ulnar pins considering the specific anatomy is described and post-operative diagnostic aspects are illustrated. PMID- 21286909 TI - [Trauma care - a global challenge. Experience gathered in a (trauma) center managing urban violence in Nigeria]. AB - Internal fixation of fractures is an integral part of health care. However this is a privilege of the developed world. For humanitarian aid internal fixation has always been considered as too prone to infection given the poor hygienic conditions, too specialized, too costly and the infrastructure of so-called developing countries too weak to perform internal fixation successfully. Due to the globally increasing density of road traffic an alarming increase in victims of road traffic accidents can be observed. The World Health Organization (WHO) estimates that in 2030 road traffic accidents will be responsible for twice as many deaths as caused by HIV/AIDS.Road traffic accidents are considered to be the new global epidemic. Since the victims are generally young, their rehabilitation has not only a humanitarian, but also an economic impact for low-income countries. The organization Doctors Without Borders (Medecins Sans Frontieres; MSF) is not only providing surgical care for victims of violence in war and conflict regions, but has expanded its portfolio to include victims of road traffic accidents and started to perform internal fixation under good hygienic circumstances in closed fractures. The following is a report about the work in a hospital for surgical trauma care in Port Harcourt, Nigeria where victims of road traffic accidents are treated besides victims of urban violence. PMID- 21286910 TI - [Operative treatment of rhizarthritis: comparison of ligament reconstruction according to Epping with trapezectomy and interposition of pyrocarbon spacers as replacement of the trapezium]. AB - BACKGROUND: Rhizarthritis is the most common form of arthritis of the hand with a frequency of 10% and conservative as well as surgical methods of treatment are available. The aim of this study was to compare the results of resection suspension arthroplasty according to Epping with trapezium replacement using pyrocarbon spacers. MATERIAL AND METHODS: Between January 2001 and December 2008 a total of 84 patients were surgically treated for rhizarthritis in our clinic. Of these patients 12 were treated with other surgical procedures, 40 with resection suspension arthroplasty according to Epping and 32 with pyrocarbon spacers as trapezium replacement. The patients were examined in a retrospective study and success of treatment was evaluated according to the Buck-Gramcko criteria. RESULTS: According to the evaluation criteria over 80% of patients in both collectives achieved very good or good operative results with the same degree of satisfaction. CONCLUSION: The results of this study confirm the value of resection suspension arthroplasty according to Epping for surgical treatment of rhizarthritis. Using trapezectomy with interposition of pyrocarbon spacers good or very good results can be achieved in the majority of cases. Essential points of criticism are the current material cost of 930 Euros and 4 dislocations in our collective but with good multiaxial movement and loading capacity. Comparable results using alternative procedures indicate that the results of further studies and long-term results will be decisive for establishment of this operational procedure. PMID- 21286911 TI - [Stiffening effect of a transsacral fusion system for the lumbosacral junction. A probabilistic finite element analysis and sensitivity study]. AB - The novel transsacral fusion system AxiALIF allows stabilization of the lumbosacral junction. The system consists of a screw with two different diameters. With additional facet screws or internal fixation devices 360 degrees fusion can be achieved. The effects of different parameters such as length, diameter combination and material of the transsacral screw, type of additional fixation and stiffness of the bone are unknown. In a probabilistic finite element analysis, the input parameters were randomly varied. The rotational angles and the axial forces in the various implants were calculated for four different load scenarios. In a subsequent sensitivity study the influences of single input parameters on the variance of the results were calculated. A transsacral screw significantly reduces the motion in the treated segment, except for axial rotation. An additional fixation has a strong effect on the variance of rotation angles. The other parameters usually explain less than 10% of the variance. The novel lumbosacral fusion system allows good stabilization of the segment, especially when additional fixation via facet screws or fixators is performed. PMID- 21286912 TI - Three years of paediatric regulation in the European Union. AB - PURPOSE: To investigate whether the Paediatric Regulation has already succeeded in addressing the needs of the paediatric population both quantitatively with respect to paediatric development plans and trials, and qualitatively with respect to the content of the plans. The Paediatric Regulation No 1901/2006 entered into force in Europe on 26 January 2007, with the aim to improve the development of medicinal products, to address the lack of age-appropriate formulations and to provide information on efficacy, safety and dosing for the paediatric population. The Regulation requires applications for marketing authorisations to be accompanied by either a product-specific waiver or a paediatric investigation plan, to be agreed by the Paediatric Committee (PDCO) of the European Medicines Agency (EMA). METHODS: A retrospective analysis of the applications for Paediatric Investigation Plans (PIPs) and Waivers submitted to the EMA, from 2007 until end of 2009, was performed. The content of scientific opinions adopted by the Paediatric Committee was compared to the proposals submitted by industry, and the paediatric clinical trials registered in the European Union Drug Regulating Authorities Clinical Trials (EudraCT) database were examined. RESULTS: An increasing paediatric medicine development can be expected following the adoption of this legal framework. The highest number of PIPs was in the fields of endocrinology (13.4%), oncology (11%) and infectious (10.8%) and cardiovascular diseases (7.1%), but most therapeutic areas now benefit from paediatric development. A large number of PIPs include measures for the development of age-appropriate formulations (23%), and most include studies on dosing, efficacy and safety to cover the respective paediatric subsets, including the mostly neglected neonates (26%). In many proposals (38%), however, the PDCO had to request major modifications to the proposed PIPs to ensure that the results will meet the needs, in particular by requesting better methodology. The proportion of paediatric trials as a percentage of all clinical trials has moderately increased (from 8.2 to 9.4% of all trials), and this may reflect the fact that paediatric trials are generally deferred (82%) until after adult development. CONCLUSIONS: This is the first analysis of the general impact of the Paediatric Regulation on the development of medicinal products in Europe. Three years after the implementation of the Paediatric Regulation, we were able to identify that the PIPs address the main gaps in knowledge on paediatric medicines. The key objective of the Paediatric Regulation, namely, the availability of medicines with age-appropriate information, is going to be achieved. It is clear also that modifications of the initial proposals as requested by the PDCO are necessary to ensure the quality of paediatric developments. The impact on the number of clinical trials performed remains modest at this point in time, and it will be of high interest to monitor this performance indicator, which will also inform us whether paediatric medicine research takes place in Europe or elsewhere. PMID- 21286914 TI - QuIRI (quality improvement and research in imaging) program: a means to promote and coordinate research and quality-improvement activities in radiology. PMID- 21286917 TI - Comments on Hsu et al.: surgical treatment of syndesmotic diastasis: emphasis on effect of syndesmotic screw on ankle function. PMID- 21286918 TI - Internal fixation of femoral neck fractures with posterior comminution: a biomechanical comparison of DHS(r) and Intertan nail(r). AB - BACKGROUND AND PURPOSE: Internal fixation is a therapeutic mainstay for treatment of undisplaced femoral neck fractures and fractures without posterior comminution. The best treatment for unstable and comminuted fractures, however, remains controversial, especially in older patients. The present study was designed to assess the utility of the Intertan Nail(r) (IT) for stabilization of comminuted Pauwels type III fractures compared to dynamic hips screw (DHS). METHODS: Randomized on the basis of bone mineral density, 32 human femurs were assigned to four groups. Pauwels type III fractures were osteomized with a custom made saw guide. In 16 specimens the posteromedial support was removed and all femurs were instrumented with an IT or a DHS. All constructs were tested with nondestructive axial loading to 700N, cyclical compression to 1,400N (10,000 cycles), and loading to failure. Outcome measures included number of survived cycles, mechanical stiffness, head displacement and load to failure. RESULTS: Postoperative mechanical stiffness and stiffness after cyclical loading were significantly reduced in all constructs regardless of the presence of a comminution defect (p = 0.02). Specimens stabilized with the IT had a lower construct displacement (IT, 8.5 +/- 0.5 mm vs. DHS, 14.5 +/- 2.2 mm; p = 0.007) and sustained higher failure loads (IT, 4929 +/- 419 N vs. DHS, 3505 +/- 453 N; p = 0.036) than the DHS constructs. INTERPRETATION: In comminuted Pauwels type III fractures, the fixation with the IT provided sufficient postoperative mechanical strength, comparable rate of femoral head displacement, and a similar tolerance of physiological loads compared to fractures without comminution. The absence of the posteromedial support in comminuted fractures tended to reduce the failure load regardless of the fixation method. PMID- 21286919 TI - Cetuximab and panitumumab in KRAS wild-type colorectal cancer: a meta-analysis. AB - BACKGROUND: Anti-epidermal growth factor receptor monoclonal antibodies (panitumumab [P] and cetuximab [C]) are approved and effective only in KRAS wild type patients with advanced colorectal cancer. The purpose of our meta-analysis is to evaluate the real effects of C and P in KRAS wild-type patients treated in randomized trials. PATIENTS AND METHODS: Eligible studies included prospective, randomized, and controlled trials in which either C or P had been added to standard antineoplastic therapy or best supportive care and data for KRAS wild type patients only had been calculated. Six thousand three hundred ninety-five patients' tumor samples have been analyzed (total wild-type n = 3,254; experimental arm n = 1,608; control arm n = 1,646). Relative risks (RRs) with 95% confidence intervals (CIs) for response rate were calculated, as well as hazard ratios (HRs)for progression-free survival (PFS) and overall survival. RESULTS: The overall RR of response rate is 1.69 (p = 0.003) in all trials. The overall HRs for PFS and survival are 0.65 (p = 0.0006) and 0.84 (p = 0.03), respectively, and both are significant. The HRs for PFS and survival in C trials are 0.64 and 0.79, respectively, and 0.65 and 0.87, respectively, in P trials, although only the results achieved in P trials are significant (p = 0.0007 and p = 0.03). Both response rate (RR = 10.94) and PFS (HR = 0.51) have increased more in pretreated patients than in first-line trials. CONCLUSION: The addition of anti-EGFR monoclonal antibodies to standard anticancer therapy in KRAS wild-type colorectal cancer showed an overall significantly increased risk of objective response rate and increased progression-free and overall survival. Only the results achieved in P randomized trials are significant, and the strongest results have been achieved in pretreated patients. PMID- 21286920 TI - Safety, feasibility, and tolerance of early oral feeding after colorectal resection outside an enhanced recovery after surgery (ERAS) program. AB - INTRODUCTION: It is generally believed that resumption of feeding after colorectal resection is indicated only after recovery of bowel function. This study was designed to verify safety, feasibility, and tolerance of early oral postoperative feeding (EOF) outside an enhanced recovery after surgery (ERAS) program. MATERIALS AND METHODS: One hundred patient candidates to elective colorectal resection were prospectively enrolled in an EOF program. Feeding was started on postoperative day (POD) 1 with oral nutritional supplement (ONS). On POD 2, patients had normal food plus ONS to reach 1,000-1,200 kcal/day with progressive increase until 1,800-2,000 kcal/day. Results were compared with historical controls (n = 100) in whom oral feeding was allowed only after full bowel function recovery. The ERAS program was not applied in both groups. RESULTS: The EOF group had a better recovery of short half-life protein synthesis compared with the control group (P < 0.001). Stool canalization occurred after a median of 3 days (range, 1-6 days) in the EOF group versus 5 days (range, 2-8 days) in the control group (P = 0.001). The feeding protocol was completed in 89 patients within POD 5. Tolerance to resumption of feeding was similar in the two groups. The overall rate of postoperative complication was 22% in the EOF group vs. 27% in the control group (P = 0.51). The median length of hospitalization was 9 days (range, 6-25 days) in the EOF group vs. 12 days (range, 6-31 days) in controls (P = 0.01). CONCLUSIONS: EOF after colorectal operations is feasible and safe outside an ERAS program. PMID- 21286921 TI - Influence of percutaneous abscess drainage on severe postoperative septic complications in patients with Crohn's disease. AB - PURPOSE: Severe postoperative intra-abdominal septic complications (IASC) such as an anastomotic leak, intra-abdominal abscess, and fistula are significantly associated with the presence of spontaneous intra-abdominal abscess at the time of laparotomy in patients with Crohn's disease (CD). The purpose of this study was to compare the incidence of severe postoperative IASC in patients undergoing intestinal resections with and without preoperative percutaneous abscess drainage (PAD) before definitive surgery. METHODS: Using a prospective surgical database, we searched for patients with CD and spontaneous intra-abdominal abscesses who underwent intestinal resection at our hospital from May 2005 to February 2009. Postoperative IASC were defined as anastomotic leaks, abscess, and fistula within 1 month after surgery. We compared the incidence of postoperative IASC in patients with (group I) and without (group II) preoperative PAD (Fisher's exact test). RESULTS: We identified 25 patients (15 men, 10 women; mean age, 31 years) with spontaneous intra-abdominal abscesses. PAD was performed in 12 of 25 patients (48%), with an average of 37 days before surgery (range, 6-83 days). The overall rate of postoperative IASC was 48% (12 of 25 patients). In group I, postoperative IASC occurred in 3 of 12 patients (25%). In group II, postoperative IASC were assessed in 9 of 13 patients (69%). The differences between these two groups were considered to be statistically significant (p = 0.04). CONCLUSION: PAD of intra-abdominal abscesses before surgery could significantly reduce the occurrence of severe postoperative IASC in patients with CD. PMID- 21286922 TI - Effect of a 2-h hyperglycemic-hyperinsulinemic glucose clamp to promote glucose storage on endurance exercise performance. AB - Carbohydrate stores within muscle are considered essential as a fuel for prolonged endurance exercise, and regimes for enhancing such stores have proved successful in aiding performance. This study explored the effects of a hyperglycaemic-hyperinsulinemic clamp performed 18 h previously on subsequent prolonged endurance performance in cycling. Seven male subjects, accustomed to prolonged endurance cycling, performed 90 min of cycling at ~65% VO(2max) followed by a 16-km time trial 18 h after a 2-h hyperglycemic-hyperinsulinemic clamp (HCC). Hyperglycemia (10 mM) with insulin infused at 300 mU/m(2)/min over a 2-h period resulted in a total glucose uptake of 275 g (assessed by the area under the curve) of which glucose storage accounted for about 73% (i.e. 198 g). Patterns of substrate oxidation during 90-min exercise at 65% VO(2max) were not altered by HCC. Blood glucose and plasma insulin concentrations were higher during exercise after HCC compared with control (p < 0.05) while plasma NEFA was similar. Exercise performance was improved by 49 s and power output was 10-11% higher during the time trial (p < 0.05) after HCC. These data suggest that carbohydrate loading 18 h previously by means of a 2-h HCC improves cycling performance by 3.3% without any change in pattern of substrate oxidation. PMID- 21286923 TI - Assay conditions in laboratory experiments: is the use of constant rather than fluctuating temperatures justified when investigating temperature-induced plasticity? AB - Temperature is an important selective agent in nature. Consequently, temperature induced plasticity which may help buffering detrimental effects of temperature variation has received considerable attention over recent decades. Laboratory studies have almost exclusively used constant temperatures, while in nature, temperature typically shows pronounced daily fluctuations. Using a factorial design with constant versus fluctuating temperatures and a higher versus a lower mean temperature, we here investigate in the butterfly Lycaena tityrus whether the use of constant temperatures is justified. Fluctuating compared to constant temperatures caused shorter development times, increased heat but decreased cold stress resistance, decreased heat-shock protein expression, and increased immunocompetence. Thus, overall, fluctuating temperatures were more beneficial to the butterflies compared to constant ones. However, despite substantial variation across temperature regimes, the ranking of trait values among treatments remained largely unaffected (e.g. lower constant as well as fluctuating temperatures caused increased pupal mass). Thus, we tentatively conclude that there is no general reason for concern about using constant temperatures in studies investigating phenotypic plasticity, which seem to comprise a fair proxy. However, substantial differences in mean values as well as interactive effects suggest that one needs to be cautious. We further demonstrate negative effects of high temperatures on butterfly immune function, which seem to result from a trade off between the latter and the heat shock response. PMID- 21286924 TI - Effects of recruiting age on senescence, lifespan and lifetime reproductive success in a long-lived seabird. AB - Theories of ageing predict that early reproduction should be associated with accelerated reproductive senescence and reduced longevity. Here, the influence of age of first reproduction on reproductive senescence and lifespan, and consequences for lifetime reproductive success (LRS), were examined using longitudinal reproductive records of male and female blue-footed boobies (Sula nebouxii) from two cohorts (1989 and 1991). The two sexes showed different relationships between age of first reproduction and rate of senescent decline: the earlier males recruited, the faster they experienced senescence in brood size and breeding success, whereas in females, recruiting age was unrelated to age specific patterns of reproductive performance. Effects of recruiting age on lifespan, number of reproductive events and LRS were cohort- and/or sex-specific. Late-recruiting males of the 1989 cohort lived longer but performed as well over the lifetime as early recruits, suggesting the existence of a trade-off between early recruitment and long lifespan. In males of the 1991 cohort and females of both cohorts, recruiting age was apparently unrelated to lifespan, but early recruits reproduced more frequently and fledged more chicks over their lifetime than late recruits. Male boobies may be more likely than females to incur long term costs of early reproduction, such as early reproductive senescence and diminished lifespan, because they probably invest more heavily than females. In the 1991 cohort, which faced the severe environmental challenge of an El Nino event in the first year of life, life-history trade-offs of males may have been masked by effects of individual quality. PMID- 21286925 TI - Polyneuropathy and dementia in old age: common inflammatory and vascular parameters. AB - Thirty-three inpatients (22 females, 11 males, aged 79.4 +/- 9.5 years) were investigated in this prospective cohort study to study the prevalence of polyneuropathy (PNP) and dementia in geriatric inpatients. Clinical and electrodiagnostic investigations, routine laboratory, including thyroid parameters, folic acid, vitamin B(12), homocysteine, neopterin, fibrinogen and glycosylated hemoglobin were measured in serum, the mini-mental state examination and computed tomographic scanning were performed in each patient. PNP was found clinically and electrodiagnostically in 96% of patients. Age was the most precipitating factor for PNP, and was significantly correlated to electrodiagnostic changes in the nerves investigated in both, upper and lower extremities, while clinical symptoms were confined only to the feet. Correlation was seen between homocysteine and the amplitude of the sural nerve (surAmpl) (rs = -0.406, p = 0.029) as well as the sural nerve conduction velocity (surNCV) (rs = -0.389, p = 0.037), and between neopterin and the grade of denervation (rs = 0.445, p = 0.014) in our patients. Neopterin and fibrinogen did not correlate significantly, but there was a trend to higher fibrinogen concentrations in patients with higher neopterin levels (rs = 0.344, p = 0.062). A trend of a correlation was seen between higher homocysteine concentrations and the number of changes in electrodiagnostic measurements (rs = 0.354, p = 0.055). Twenty-one of the 33 patients (64%) were demented, 9 (27%) presented clinically as mild cognitive impairment, 3 (9%) were not demented. Vascular risk factors were found in 83%: hypertension in 58%, hypercholesterinemia in 39%, cardiac disease in 36%, diabetes mellitus (DM) in 21%, peripheral arterial disease (PAD) in 9%. A significant correlation was found between homocysteine and folic acid concentrations (rs = -0.401, p = 0.028). Falls were reported in 48% of cases, indicating PNP as a risk factor in this group of patients. In conclusion, PNP was found very common with a high coincidence with dementia and a female preponderance, suggesting an influence on daily life (falls) in our subjects studied. PNP correlated significantly with markers for vascular disease as well as immune activation (homocysteine and neopterin) similar to earlier findings in patients with neurodegenerative disorders, suggesting common therapeutic options in patients with PNP and dementia. PMID- 21286928 TI - Antibiotic administration longer than eight hours after triage and mortality of community-acquired pneumonia in patients with diabetes mellitus. AB - Studies have established that diabetic patients with community-acquired pneumonia (CAP) may have increased mortality. The primary objective of this study was to investigate if time to first appropriate antibiotic in the emergency department (ED) was associated with in-hospital mortality of CAP in patients with diabetes mellitus (DM). This was a retrospective cohort study of adult diabetic patients who were admitted with CAP. Patients were stratified into two groups: those who received first dose of appropriate antibiotic within 8 hours of triage and those who received it later than 8 hours. A multiple logistic regression analysis was performed. Two hundred six patients were included in the study. Fifty-nine patients (28.6%) had complications of CAP on admission and 31 patients (16%) died. In-hospital mortality was higher in patients who received their initial appropriate antibiotic after 8 hours of triage than those who received it within 8 hours [18 (35.3%), 15 (9.7%), p < 0.0001]. Time to first appropriate antibiotic later than 8 hours of triage was associated with increased in-hospital mortality (OR 4, 95% CI 1.2-13.1, p = 0.02). Antibiotic administration later than 8 hours of triage in the ED was associated with increased in-hospital mortality of CAP among patients with DM. PMID- 21286929 TI - Detection of human bocavirus 3 in China. AB - Since its first identification in 2005, four species of human bocavirus (HBoV1-4) have been documented. HBoV1 and HBoV2 have been shown to be associated with respiratory tract illnesses, as well as with acute gastroenteritis (AGE), worldwide. However, reports on the prevalence, clinical significance, and molecular characteristics of the two most newly identified HBoV species, HBoV3 and HBoV4, are very limited. To detect and characterize HBoV3 and HBoV4 infections in children with AGE in China, stool specimens were collected from 366 children with AGE. HBoVs in these samples were amplified by nested polymerase chain reaction (PCR), sequenced, and phylogenetically analyzed. HBoVs were detected in 44 samples (12%), of which nine were HBoV1, 33 were HBoV2, and two were HBoV3. HBoV4 was not detected. Most HBoV-positive samples (35/44) were co detected with other viral pathogens. Both HBoV3 samples were co-detected with rotavirus. Analysis of the HBoV3 (46-BJ07) genome sequence indicates that HBoV3 may be a recombinant derived from HBoV1 and HBoV2 or from HBoV1 and HBoV4. To our knowledge, this is the first report of HBoV3 in China. However, it is unclear whether HBoV3 is associated with AGE because of its low detection rate in AGE patients and its co-infection with other AGE-causing viruses. PMID- 21286930 TI - Prevalence and role of efflux pump activity in ciprofloxacin resistance in clinical isolates of Klebsiella pneumoniae. AB - We investigated the prevalence and role of efflux pump activity and possible drug influx resistance in ciprofloxacin susceptibility amongst 26 distinct clinical isolates of Klebsiella pneumoniae of varying ciprofloxacin susceptibilities and known quinolone resistance-determining region (QRDR) genotypes. Cellular [(14)C]ciprofloxacin accumulation patterns and the amount of cell-associated [(14)C]ciprofloxacin of mid-logarithmic phase cells were determined before and after challenging with the efflux pump inhibitor carbonyl cyanide 3 chlorophenylhydrazone (CCCP). Most isolates (24/26), and all with ciprofloxacin minimum inhibitory concentrations (MICs) >1 ug/ml, had efflux activity that could extrude up to 90% of cell-associated [(14)C]ciprofloxacin; none had significant influx resistance. In isolates with no QRDR mutations, efflux alone reduced ciprofloxacin susceptibility. In isolates with QRDR mutations, the efflux activity varied: in one isolate with no efflux activity, the most common fluoroquinolone resistance-causing QRDR mutation did not bring about clinically significant ciprofloxacin resistance; isolates with multiple mutations had high MICs and, usually, high levels of efflux activity. Fluoroquinolone efflux activity is much more common in clinical isolates of K. pneumoniae than previously reported and it can contribute to decreased ciprofloxacin susceptibility. PMID- 21286932 TI - Partial nitrification using an electrolytic aerating bioreactor with ammonia oxidizing bacteria-dominant activated sludge. AB - An electrolytic aerating bioreactor was used to partially nitrify ammonia from wastewater. Activated sludge was cultured for 8 months to increase the population of ammonia-oxidizing bacteria (AOB) and then used in the bioreactor. The maximum ammonia removal rate was 0.64 mM NH(3)/l h in a 50 ml reactor using 5.4 g mixed liquor suspended solids per litre of AOB-dominant activated sludge. PMID- 21286933 TI - Cross-mating experiments with geographically different populations of Amblyomma cajennense (Acari: Ixodidae). AB - The present study evaluated the reproductive compatibility of the crosses between adult ticks of the following three geographically different populations of Amblyomma cajennense: State of Sao Paulo (SP), southeastern Brazil; State of Rondonia (RO), northern Brazil; and Colombia (CO). In addition, crosses between A. cajennense ticks from Argentina (AR) and SP ticks were also performed. The Argentinean population (AR) was compatible with SP because their crosses resulted in high % egg hatching (mean values ranging from 71.5 to 93.5%), similarly to all homologous (intrapopulational) crosses. In contrast, the tick populations SP, RO, and CO were shown to be incompatible with each other, since their heterologous (interpopulational) crosses always resulted in very low % egg hatching (range: 0 5%). The F(1) larval offspring derived from some of these females that yielded 5% egg hatching were reared until the F(1) adult stage. In all cases, only adult females molted from engorged nymphs. These F(1) females were likely to be a product of thelytokous parthenogenesis of the SP, RO, and CO females that were used in the heterologous crosses. Reproductive incompatibility is not expected to occur between different populations of a single species. Thus, our results suggest that the taxon A. cajennense might be represented by a complex of different species, whereas SP and AR ticks might represent a single species. Further populational genetic studies, coupled with extensive morphological analyses, are needed to clarify and determine a possible complex of valid species that might have been classified under the taxon A. cajennense. PMID- 21286934 TI - Longitudinal associations of alcohol involvement with subjective well-being in adolescence and prediction to alcohol problems in early adulthood. AB - Adolescent alcohol involvement is associated with numerous negative outcomes, but also appears to have positive correlates, including subjective well-being. Additional research is needed to understand these paradoxical findings. The current study examines alcohol use, adverse alcohol-related (and other substance related) consequences, and subjective well being in adolescence, and prediction to problem alcohol use in early adulthood. Participants in this longitudinal study, which extended from age 11 to age 21, were 208 rural teens (109 girls) and their families. Covariates included early substance use, early conduct problems, early depressed mood, gender, and parent educational attainment. Structural equation modeling showed that subjective well-being at age 16 positively predicted increased alcohol use at age 18. Alcohol use was not a significant predictor of subjective well-being; however, alcohol use at age 18 positively predicted alcohol problems at age 21, even while controlling for earlier adverse consequences and other predictors. Results help to further elucidate both the negative and positive correlates of underage drinking, and support the value of delaying alcohol initiation. PMID- 21286935 TI - Methane on breath testing is associated with constipation: a systematic review and meta-analysis. AB - BACKGROUND: A growing body of literature suggests an association between methane and constipation. Studies also link degree of methane production to severity of constipation and have shown constipation is improved following antibiotics. AIMS: We aim to conduct a systematic review and meta-analysis to examine the cumulative evidence regarding the association between methane and constipation. METHODS: A literature search was performed using MEDLINE and Embase to identify studies where the presence (or absence) of methane was assessed in constipated subjects. Search terms included "methane," "breath test," "constipation," "motility," "transit," "irritable bowel syndrome" and/or "IBS." Pooled odds ratios were generated using a random effects model. In a separate analysis, studies that measured intestinal transit in methane and non-methane subjects were systematically reviewed. RESULTS: Nine studies met inclusion criteria for the meta-analysis. Among these, 1,277 subjects were examined by breath testing (N = 319 methane producers and N = 958 methane non-producers). Pooling all studies, a significant association was found between methane on breath test and constipation (OR = 3.51, CI = 2.00-6.16). Among adults only, methane was significantly associated with constipation (OR = 3.47, CI = 1.84-6.54). Similar results were seen when only examining subjects with IBS (OR = 3.60, CI = 1.61-8.06). The systematic review identified eight additional papers which all demonstrated an association between methane and delayed transit. CONCLUSIONS: We demonstrate that methane present on breath testing is significantly associated with constipation in both IBS and functional constipation. These results suggest there may be merit in using breath testing in constipation. Moreover, methane may be used to identify candidates for antibiotic treatment of constipation. PMID- 21286937 TI - Detection of colorectal neoplasia by colonoscopy in average-risk patients age 40 49 versus 50-59 years. AB - BACKGROUND: The USPSTF recommends beginning colorectal cancer screening at age 50. A recent study showed prevalence of colorectal adenomas among individuals aged 40-49 was similar to that among those aged 50-59. AIM: To assess the prevalence of colorectal neoplasia, detected during colonoscopy, by age among average-risk patients. METHODS: Nine-hundred and ninety-four colonoscopies were analyzed (247 ages 40-49, 747 ages 50-59). We included consecutive patients of ages 40-59 undergoing their first colonoscopy. Colonoscopies that did not reach the cecum and patients at increased risk of colorectal cancer were excluded. The primary endpoint was the prevalence of colorectal neoplasia by age. Secondary endpoints included the prevalence of colorectal neoplasia by gender, ethnicity, and BMI. RESULTS: The prevalence of colorectal neoplasia was 12.1% in patients aged 40-49 and 22.6% in those aged 50-59. Compared with individuals aged 40-49 there was a significantly greater prevalence of adenomas (chi-squared = 12.72, P = 0.0004) and of advanced adenomas or cancer (chi-squared = 5.73, P = 0.01) in individuals aged 50-59. After adjusting for gender, race, and BMI the effect of age remained significant (OR 0.5, 95% CI 0.33-0.76). Higher BMI was associated with increased risk of colorectal neoplasia (OR 1.03, 95% CI 1.00-1.06). The number that had to be screened to detect one advanced lesion in the 40-49 age group was 49 compared with 20 in those aged 50-59. CONCLUSION: Individuals aged 40-49 have a lower but measurable risk of colorectal neoplasia compared with those aged 50-59. Although there may be population subgroups for which screening below the age of 50 may be indicated, our results do not support lowering the age threshold for colonoscopy in the general population. PMID- 21286938 TI - Sub-pleural bullous changes in two adults with Mucopolysaccharidosis type I (Hurler-Scheie). AB - Two unrelated adult patients with MPS I (Hurler-Scheie) demonstrated sub-pleural bullous emphysema. This complication of MPS I should be looked for due to the risk of spontaneous pneumothorax. PMID- 21286936 TI - Endoscopy in the diagnosis and management of motility disorders. AB - BACKGROUND: Gastrointestinal illness may result from either an underlying structural abnormality (e.g. neoplastic obstruction), or a functional disorder (e.g. motor diarrhea), or both (e.g. achalasia with squamous esophageal cancer). AIMS: The purpose of this study was to highlight the potential value and role of endoscopy in the recognition and management of patients with functional and motility disorders. METHODS: We performed a literature review in PubMed. RESULTS: Diagnostic and therapeutic endoscopy may be under-used by motility-oriented gastroenterologists; in contrast, motility and other functional studies may be under-used by endoscopists. Yet, many areas of cross-exchange exist. CONCLUSIONS: This review aims to guide the appropriate indications for the use of endoscopy in diagnosing and treating functional GI and motility disorders and serve as a bridge and a forum of exchange between endoscopists and motility specialists. PMID- 21286940 TI - Importin-alpha1 as a novel prognostic target for hepatocellular carcinoma. AB - BACKGROUND: Perturbations in the nuclear microenvironment, including transport systems, play a critical role in malignant progression, but the nuclear import abnormalities remain unclear in hepatocarcinogenesis. We analyzed the role of importin in hepatocellular carcinoma (HCC). METHODS: Gene expression profiling of the importin family was performed in HCC tissues. The significance of importin protein expression was analyzed in vitro as well as clinicopathologically. RESULTS: According to the microarray profiles, the importin-alpha1 was dominantly overexpressed in HCC tissues as compared to the adjacent noncancerous tissues. By means of human HCC cell lines, a knockdown of importin-alpha1 by its siRNA greatly reduced cellular proliferation by 15.2-26.6% (P < 0.005). Immunohistochemical analysis on tissue samples demonstrated cancer-specific overexpression in 36.3% of HCCs. The overexpression of importin-alpha1 was correlated statistically with high levels of alfa-fetoprotein ( P = 0.0017), the tumor number (P = 0.0116), histological dedifferentiation (P = 0.0054), tumor morphology (P = 0.0433), portal vein invasion (P = 0.0007), hepatic vein invasion (P = 0.0081), Fc (P = 0.0367), Fc-inf (P = 0.0122), and the tumor, node, metastasis stage (P = 0.0026); this resulted in a significantly poorer prognosis in both overall survival (P = 0.0164) and recurrence-free survival (P = 0.0101). Multivariate analysis of recurrence-free survival revealed importin-alpha1 expression to be a statistically significant factor (P = 0.0361). In addition, early recurrence after curative resection was observed more frequently in the importin-alpha1-positive group as compared to the negative group (P = 0.0023). The multivariate analysis identified importin-alpha1 as the only independent predictor of early recurrence after HCC resection (odds ratio = 5.291, P = 0.0191). CONCLUSIONS: Because importin-alpha1 might be closely associated with HCC progression, further analysis should be pursued to evaluate it as a novel prognostic target. PMID- 21286939 TI - Antiangiogenic therapy for primary liver cancer: correlation of changes in dynamic contrast-enhanced magnetic resonance imaging with tissue hypoxia markers and clinical response. AB - BACKGROUND: This study utilized the imaging data of primary liver cancer (PLC) treated with floxuridine (FUDR) and bevacizumab to test the hypothesis that dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters correlate with tissue hypoxia markers and treatment outcome. METHODS: Seventeen patients with PLC were treated with hepatic artery infusional (HAI) FUDR for 14 days followed by systemic bevacizumab therapy. DCE-MRI images were obtained at baseline and after HAI FUDR and bevacizumab therapy. The parameters (K(trans), AUC) pertaining to perfusion and vascular permeability of the tumor and adjacent liver parenchyma were measured with DCE-MRI. Tissue obtained at baseline was stained for hypoxia markers (anti-hypoxia inducible factor-1alpha, anti-carbonic anhydrase IX, and vascular endothelial growth factor). Changes in DCE-MRI parameters were correlated with tissue hypoxia and time to progression (TTP). RESULTS: The median TTP was 8.8 months. Significant decreases in AUC90 (P = 0.004), AUC180 (P = 0.004), and K(trans) (P = 0.05) were noted in tumors after bevacizumab but not in nontumor areas. TTP correlated inversely with changes in AUC90 and AUC180 after bevacizumab (P = 0.002 and P = 0.0001). Reductions in tumor perfusion (AUC90 and AUC180) were greater in tumors expressing anti-hypoxia inducible factor-1alpha (P = 0.02 and 0.03), vascular endothelial growth factor (P = 0.01 and P = 0.01), and anti-carbonic anhydrase IX (P = 0.009 and P = 0.009). CONCLUSIONS: In patients with PLC, bevacizumab induces a reduction in tumor perfusion measured by DCE-MRI. These changes correlate with TTP and tissue markers of tumor hypoxia. PMID- 21286941 TI - Tumor site and perigastric nodal status are the most important predictors of para aortic nodal involvement in advanced gastric cancer. AB - BACKGROUND: This study was designed to identify pathological predictors of para aortic nodal invasion in advanced gastric cancer. METHODS: Between 1990 and 2007, 294 patients with advanced gastric cancer underwent gastrectomy with D2 lymphadenectomy + para-aortic nodal dissection in Siena and Verona, Italy. RESULTS: Forty-seven (16%) patients had para-aortic node metastases. Of these, 91%, 88%, and 74%, respectively, also had metastases at stations No. 3, No. 1, and No. 7. Para-aortic node metastases were never observed when stations No. 1 and No. 3 were both negative. Patients were divided into three groups, according to the risk of para-aortic node invasion: (1) high-risk group (n = 24, 8.2%), presenting a 42% risk and comprising T3/T4 cancers with mixed/nonintestinal histology, arising from the upper third; (2) low-risk group (n = 138, 46.9%), presenting a 0-10% risk and including middle-lower third tumors-either T2 irrespective of histology, or T3/T4 with intestinal histology; (3) intermediate risk group, comprising all other patients (n = 132, 44.9%). Their risk ranged between 16% and 30%, but increased up to 21-37.5% after excluding 33 patients with negative No. 1 and No. 3 stations. CONCLUSIONS: The combination of tumor site, histology, and T stage with perigastric nodal status allowed identification of patients at higher risk of para-aortic nodal invasion who could benefit from para-aortic nodal dissection. PMID- 21286942 TI - Screening of pancreaticoduodenal endocrine tumours in patients with MEN 1: multidetector-row computed tomography vs. endoscopic ultrasound. AB - PURPOSE: The authors compared multidetector-row computed tomography (MDCT) and endoscopic ultrasound (EUS) in the identification of pancreaticoduodenal endocrine tumours (PETs) in patients with multiple endocrine neoplasia type 1 (MEN 1). MATERIALS AND METHODS: Fourteen consecutive patients (eight men and six women, aged 26-54 years) with MEN 1 underwent MDCT performed with a 4- (n=5) or 64- (n=9) detector-row system and EUS done with a radial transducer (7.5-20 MHz) within 7-28 days of each other. Prior to MDCT examination, patients were given 750 cc of water and asked to lie down in the right lateral decubitus for 15 min. Multiphase MDCT images were acquired both before and after the injection of nonionic iodinated contrast material (2 cc/kg) at an injection rate of 4 ml/s, with technical parameters and scan delay varying in relation to the system used. Images were all reconstructed at 3-mm intervals for the three phases (arterial, pancreatic and portal) and evaluated on a dedicated workstation. RESULTS: MDCT detected a total of 25 PETs (3-18 mm) in nine patients. Of these lesions, nine were situated within the duodenal wall and 16 in either the pancreatic head (n=3), body (n=7), or tail (n=6). Three additional lesions were detected retrospectively after EUS imaging. Most (18/22, 81%) were hypervascular nodules, and four appeared as either hypoattenuating or cystic lesions. EUS detected a total of 32 PETs (2-18 mm) in 11 patients. Most lesions (29/32, 90%) appeared hypoechoic and were situated in the duodenal wall (n=15) or in either the pancreatic head (n=10), body (n=6) or tail (n=1). CONCLUSIONS: Our preliminary data indicate that MDCT is complementary to EUS in the identification of PETs in MEN-1 patients. PMID- 21286943 TI - Determination of methyl parathion in water and its removal on zirconia using optical enzyme assay. AB - A simple, miniaturized microplate chemiluminescence assay for determination of methyl parathion (MP) was developed in 384-microwell plates. Zirconia (ZrO(2)) was added in microwell for adsorption of acetylcholinesterase (AChE). The developed assay is based on inhibition of AChE by MP. A good dynamic range 0.008 1,000 ng/mL was obtained for MP with limit of detection 0.008 ng/mL. Intrabatch and interbatch reproducibility for miniaturized assay was obtained with % RSD up to 3.07 and 5.66, respectively. In 384 well plate formats, 70 samples were simultaneously analyzed within 20 min with assay volume of 41.5 MUL. The application of developed assay was extended for MP remediation. Column containing ZrO(2) was utilized for remediation where MP was selectively adsorbed. Under optimized condition, adsorption of MP on ZrO(2) was found to be 98-99% with 2-h contact time in real water samples. Adsorption of MP on ZrO(2) column followed by quantification using developed bioassay provides a novel approach to monitor remediation. The applicability of assay was successfully extended for determination of MP in water samples after removal through ZrO(2). PMID- 21286944 TI - Converting carbohydrates extracted from marine algae into ethanol using various ethanolic Escherichia coli strains. AB - Marine algae, which make up about 80% of the world's living organisms, contain many energy sources, such as sugars and lipids. Therefore, the possibility of utilizing structural carbohydrates from marine algae for bioethanol production has been studied. In order to obtain monosaccharides, Undaria pinnatifida, Chlorella vulgaris, and Chlamydomonas reinhardtii were used for the saccharification experiments. The pretreatment was carried out by dilute acid hydrolysis and enzymatic treatment. To find the optimal conditions, experiments were performed at several temperatures, acid concentrations, pH conditions and durations. To test bioethanol production, several ethanolic E. coli W3110 strains, which were developed previously, were used. The maximum yield of bioethanol, 0.4 g ethanol/g biomass, was achieved with pretreated C. vulgaris and E. coli SJL2526, derived from wild-type E. coli W3110 and which includes the adhB, pdc, galP, and glk genes. PMID- 21286945 TI - Production of a monoclonal antibody by simultaneous immunization of staphylococcal enterotoxin A and B. AB - In this paper, a method of simultaneous immunizing BALB/c mice with staphylococcal enterotoxin (SE) A and B (SEA and SEB) to prepare a monoclonal antibody (3F2) for detecting both of SEA and SEB was developed. The results showed that antibody 3F2 had high titers against both SEA and SEB by enzyme linked immunosorbent assay (ELISA). The sensitivities of 3F2 to SEA and SEB detected by ELISA were 133.2 and 82.5 ng/mL, respectively, and the detection limits for the two enterotoxins were about 1 ng/mL. The antibody 3F2 had high specificities and affinities to both SEA and SEB, and had no cross-reaction with SEC(1), bovine serum albumin, and ovalbumin. SEs-free skimmed milk samples were spiked with different concentrations of SEA, SEB, or both of them, respectively. Average recoveries of SEA and SEB from the spiked samples were all nearly between 82% and 104%. The result suggested that one cell fusion with simultaneous immunization by multiple antigen to prepare monoclonal antibody against them was possible, simple, and economic. The monoclonal antibody could be used in simultaneous detecting multifarious SEs. PMID- 21286946 TI - Dataset of magnetic resonance images of nonepileptic subjects and temporal lobe epilepsy patients for validation of hippocampal segmentation techniques. AB - The hippocampus has become the focus of research in several neurodegenerative disorders. Automatic segmentation of this structure from magnetic resonance (MR) imaging scans of the brain facilitates this work. Segmentation techniques must be evaluated using a dataset of MR images with accurate hippocampal outlines generated manually. Manual segmentation is not a trivial task. Lack of a unique segmentation protocol and poor image quality are only two factors that have confounded the consistency required for comparative study. We have developed a publicly available dataset of T1-weighted (T1W) MR images of epileptic and nonepileptic subjects along with their hippocampal outlines to provide a means of evaluation of segmentation techniques. This dataset contains 50 T1W MR images, 40 epileptic and ten nonepileptic. All images were manually segmented by a widely used protocol. Twenty five images were selected for training and were provided with hippocampal labels. Twenty five other images were provided without labels for testing algorithms. The users are allowed to evaluate their generated labels for the test images using 11 segmentation similarity metrics. Using this dataset, we evaluated two segmentation algorithms, Brain Parser and Classifier Fusion and Labeling (CFL), trained by the training set. For Brain Parser, an average Dice coefficient of 0.64 was obtained with the testing set. For CFL, this value was 0.75. Such findings indicate a need for further improvement of segmentation algorithms in order to enhance reliability. PMID- 21286947 TI - Genetics of neurodegeneration with brain iron accumulation. AB - The condition originally called Hallervorden-Spatz syndrome is a collection of related disorders involving abnormal iron accumulation in the basal ganglia, usually manifesting with a movement disorder. To date, mutations in the following genes have been associated with neurodegeneration with brain iron accumulation (NBIA) phenotypes: PANK2, PLA2G6, FA2H, ATP13A2, C2orf37, CP, and FTL. This collection, now classified under the umbrella term NBIA, continues to evolve as new genes and associated phenotypes are recognized. As this body of information continues to grow, better approaches to diagnosis and treatment have become available. Continued investigations of the underlying pathogenesis of disease, with a focus on lipid, iron, and energy metabolism, will lead to the identification of new therapeutic targets. PMID- 21286949 TI - The use of the CTrachTM Laryngeal Mask Airway in pediatric patients: a retrospective review of 25 cases. PMID- 21286948 TI - Inherited neuropathies. AB - OPINION STATEMENT: Inherited peripheral neuropathies are among the most common hereditary diseases of the nervous system. Charcot-Marie-Tooth (CMT) disease, also known from previous classifications as hereditary motor and sensory neuropathy (HMSN), is certainly the most common inherited neuropathy. In the past several years, various treatments for CMT have been proposed, although specific therapies are not yet available. In clinical practice, rehabilitative strategies remain the most helpful therapeutic approach to these patients. There is still a lack of consensus on the best way to rehabilitate patients affected by CMT. Based on our personal experience and on a review of the literature, we first recommend the prescription of ankle-foot orthoses (AFO) for patients affected by CMT; the choice of which patient, which AFO, and when to apply it depends on the individual condition of each patient and on the experience of the physician/therapist. Second, adaptive equipment (eg, button hook, long-handled shoehorn, elastic shoe laces) is available to compensate for hand deformities, sensory loss, and weakness. Third, moderate to intense strength training and aerobic exercise are well tolerated by patients affected by CMT; further studies are needed to establish whether these approaches are effective in improving their motor function and strength. There is not enough evidence to recommend muscle stretching exercises or proprioceptive kinesiotherapy, although in our experience both approaches may be helpful in selected CMT patients to prevent tendon retractions, muscle tightening, and loss of strength, and to improve balance. There is growing knowledge of the underlying genetic defects and molecular pathophysiology in CMT. To date, only a few clinical trials in CMT patients have been performed. A neurotrophic factor, neurotrophin 3, was used in a small sample of CMT1A patients with promising results, but it has not been tested in a larger cohort and there is currently no reason to suggest this therapy for CMT1A neuropathy. Based on positive results in an animal model of CMT1A, three trials with ascorbic acid (AA) were completed in a large number of patients with this neuropathy, with results that were negative overall. Therefore, it is not possible to recommend the use of AA in CMT1A patients at this time, but the results of a larger Italian-UK study and an American trial with higher doses of AA are still awaited. It is important to remember that a superimposed inflammatory/disimmune process may complicate the course of the neuropathy; in this case, severe worsening (especially motor) in a matter of weeks or months is a "red flag" that should suggest immunosuppressive or immunomodulatory treatment such as steroids, intravenous immunoglobulin, or plasma exchange. In fact, steroid-sensitive cases of HMSN were described many years ago, well before the genetic diagnosis was available. Symptomatic treatment to reduce neuropathic and nociceptive pain, both of which have been reported in patients affected by CMT, should be prescribed according to recently published guidelines for the therapy of pain. No evidence suggests any specific surgical intervention or change in diet or lifestyle for patients affected by various types of CMT. PMID- 21286950 TI - Catalog of scaled verbal material. AB - Atotal of 172 studies presenting informationon scaledverbal material (letters, CVCs, words, ete.) were summarized and indexed. For each study, the following information was abstracted: kind of materials, type and number of subjects, task, and data presentation format. These studies were indexed accordingto the type of materials sealed and, within material type, by type of seale information (objective information, subjective rating, or subject production). All studies were from a readily accessible English language source. PMID- 21286951 TI - Integration of intention and outcome in moral judgment. AB - This experiment studied how the intention of an actor affected moral judgment. Subjects received information about the intention of an actor, and about the value of the outcome of his action to a used as stimuli, and both gave similar results. The main data followed the parallelism prediction, evidence for the operation of some simple integration model. Auxiliary data provided a critical test that eliminated the adding rule and supported the averaging rule. These results suggest that previous work on the cognitive algebra of human judgment may generalize to the moral realm. These results also illustrate how information integration theory can provide a significant advance upon phenomenonological approaches to moral judgment such as have been used by Heider and Piaget. PMID- 21286952 TI - The storage of physical and name properties in short-term visual memory. AB - Two experiments investigated the hypothesis that short-term visual memory is based primarily on physical features of the visual input. Subjects were required to recall visually presented figures or the names of those figures presented either visually or aurally at a number of different retention intervals. Subjects shadowed words during the retention interval presented aurally in Experiment I and visually in Experiment II. In both experiments, figures were recalled better than names and no differences in recall of names were found due to presentation modality. Recall of both names conditions showed a steady decline across retention intervals whereas recall of figures remained at a relatively high level. These findings were interpreted as providing further support for the existence of short-term visual memory not subject to auditory recoding and based primarily on physical features of the input. It was suggested that such visual memory is limited in capacity so that input exceeding this capacity is recoded into an auditory-verbal-linguistic form. PMID- 21286953 TI - Short-term retention of pictures and words as a function of type of distraction and length of delay interval. AB - Picture and word triads were tested in a Brown-Peterson short-term retention task at varying delay intervals (3, 10, or 30 sec) and under acoustic and simultaneous acoustic and visual distraction. Pictures were superior to words at all delay intervals under single acoustic distraction. Dual distraction consistently reduced picture retention while simultaneously facilitating word retention. The results were interpreted in terms of the dual coding hypothesis with modality specific interference effects in the visual and acoustic processing systems. The differential effects of dual distraction were related to the introduction of visual interference and differential levels of functional acoustic interference across dual and single distraction tasks. The latter was supported by a constant 2/1 ratio in the backward counting rates of the acoustic vs. dual distraction tasks. The results further suggest that retention may not depend on total processing load of the distraction task, per se, but rather that processing load operates within modalities. PMID- 21286954 TI - List length and the time course of recognition in immediate memory. AB - The response signal method of Reed (1973) was used to study the time-course of list membership recognition after 2 sec of uncontrolled rehearsal, with lists of one, two, and four consonants. Fourteen specific hypotheses about the time course of this process were derived from various theories (Anderson, 1973; Anderson & Bower, 1973; Baddeley & Ecob, 1973; Corballis, Kirby, & Miller, 1972; Kirsner, 1972; Murdock, 1971; Sternberg, 1966, 1969; Theios, Smith, Haviland, Traupmann, & Moy, 1973; etc.) and additional assumptions about the effect of the response signal. When members of the to-be-learned lists are drawn from a small population of highly confusable items, as in the current experiment, list membership recognition appears to follow the model of Theios et al. (1973). Latency functions of signal lag appear to be particularly useful in differentiating among hypotheses which predict similar speed-accuracy tradeoff functions. The lag by positive-negative interaction for latencies of correct responses is highly significant for lists of one consonant, a result predicted by the hypothesis derived from the model of Theios et al. and incompatible with hypotheses derived from exhaustive search and single-threshold strength models. PMID- 21286955 TI - Parallel scanning of physical and category information. AB - In Sternberg's memory scan paradigm, subjects were required to scan for category membership or physical identity. In Experiment I, the scan rate when checking for either type of relationship at the same time was less than the sum of the scan rates when checking for either relationship separately. In Experiment II, presenting memory sets consisting of items from a single category affected the category scan function but not the physical scan function. The results were interpreted as evidence for the capacity to conduct parallel scans of independent memory encodings when retrieving remembered information. PMID- 21286956 TI - Eye movements while reading and searching spatially transformed text: A developmental examination. AB - The effects of spatial manipulation on eye movement when subjects either read or searched through paragraphs were examined. Adults, third, and fifth graders were presented with paragraphs which were typed normally or in alternating case (upper and lower). The spacing between the words was either normal, filled, or absent. The results show that approximately twice as many character spaces are processed during search as during reading. Subjects made more fixations of shorter duration during search than reading. The data indicated that the ability to vary the size of the perceptual unit develops with experience. When spatial cues were unavailable, all subjects resorted to a letter-by-letter-like processing strategy in reading but not in search. Although reading and search were found to be sensitive to the same types of spatial manipulations, discrepancies of span and speed suggest qualitative differences; comprehension demands during reading can account for these differences. The data were interpreted to provide support for the two-stage model of Hochberg (1970). PMID- 21286957 TI - Invariance of the weight parameter in information integration. AB - The relative effect of each informational dimension in an information integration task is a joint function of its weight and the range of values over which it is varied. A method is developed for separating these two factors. Weights obtained by this method were compared across variations of stimulus range. Subjects rated the performance of students on the basis of midterm exam scores and final exam scores. For some subjects, the range of scores on the final exam was twice that on the midterm and the reverse was true for other subjects. An averaging model was shown to describe the results, and weights did not differ for different stimulus ranges. This was true for each of two instructional conditions: one in which a particular weighting strategy was prescribed and one in which there was no prescribed weighting. Students who were instructed to use a 2?1 weighting were found to assign more than twice as much weight to the final as to the midterm. PMID- 21286958 TI - Processing strategies in sentence comprehension. AB - Response latencies in sentence-picture verification tasks were compared as a function of whether a mismatch was located in the logical subject (LS), verb (V), or logical object (LO) of the sentence. Sentences were presented auditorily and varied in voice and reversibility. The comparison process for nonreversibles was clearly serial self-terminating: latencies for both actives and passives were ordered LS < V < LO, or, after practice with a small number of mismatch types, LS < LO < V. Latencies for reversibles were ordered V < LS = LO, suggesting either a verb-first comparison process or an LS-V-LO comparison process which did not terminate with a subject-mismatch because of the confusability of the subject and object. The results attest to the importance of considering the "naturalness" of stimuli in sentence processing tasks, and the flexibility of subjects' encoding and comparison strategies both within and across task contexts. PMID- 21286959 TI - Terminating and exhaustive search in lexical access. AB - Two experiments which test predictions derived from the assumption that lexical access involves a search process are reported. In the first experiment, test items must be classified as ambiguous or unambiguous, and in the second experiment, they are classified according to their syntactic properties. In both experiments, it is shown that when the target of the search is a nonexistent entry, an exhaustive search is involved, even though the test items are words. Further, in these conditions, frequency of occurrence is no longer related to decision time, as it is in lexical decision experiments. It is concluded that the search model adequately explains the procedure whereby the most common meaning of a homograph is accessed, but that the less common meaning is accessed in some completely different manner. PMID- 21286960 TI - Preselection and response biasing in short-term motor memory. AB - Two experiments were performed comparing preselected (subject defined) and constrained (experimenter defined) movements. In the first experiment, subjects made reproduction responses immediately or under unfilled and filled 15-sec retention intervals. Results indicated that recall of preselected movements was clearly superior until the interpolation of information processing activity. In addition, preselected movements demonstrated no forgetting over a 15-sec retention interval while constrained movements evidenced spontaneous memory lass, suggesting that preselected movements possess a stronger representation in memory. The second experiment examined this interpretation in a response biasing paradigm. Subjects made criterion responses under preselected or constrained conditions, while the interpolated movement was always in the constrained mode and +/- 40 deg from the criterion. The subjects' task was to attend to both movements and recall each when instructed. While preselected recall was clearly superior' to constrained recall, response biasing was clearly evident in both. The failure to find differential biasing effects was discussed in terms of the relative trace strength hypothesis (Stelmach & Welsh, 1972). PMID- 21286961 TI - Processing sets of letters for order: Evidence from reaction time experiments. AB - In two experiments, subjects were required to impose different levels of organization on randomly ordered letters. In a between-subject design, the subject was to identify the letter in the set coming first in the alphabet or to reorganize the set into an alphabetic sequence. In a within-subject design, presentation of the letters was followed by an instruction to carry out the identification or reorganization task or to recite the letters in left-to-right order. Reaction time varied systematically with level of required organization, size of the presented set, and position and spacing of the letter set in the alphabet. The results are discussed in terms of two simple models. PMID- 21286962 TI - Effects of fundamental frequency contrast on discrimination and identification of dichotic CV syllables at various temporal delays. AB - Dichotic CV syllables (identical and nonidentical pairs) were presented at nine temporal offsets between 0 and 500 msec. One task consisted in judging quickly whether the syllables in a pair were phonetically the same or different; the other task was to identify both syllables. The fundamental frequency (pitch) of the synthetic stimuli was either the same or different, and either predictable or unpredictable. The pitch variable had surprisingly little effect on the latencies of "same"-"different" judgments, and the expected "preparation" effect of pitch predictability was ba]rely present. Instead, there were strong effects on the frequencies of errors at short temporal delays, which suggests shifts or biases in the phonetic "same"-"different" criterion with context. A comparison with analogous errors in the identification task revealed identical patterns. Further analysis of identification errors showed no overall "feature sharing advantage": The direction of this effect depends on the kind of error committed. Also, a lag effect was found only in nonidentical pairs that received two identical responses. The results are discussed in the framework of a two-stage information processing model. Effects of pitch are tentatively explained as biases from implicit (pitch) decisions at the auditory level on phonetic decisions in the presence of uncertainty. Four sources of errors are identified: fusion at the auditory level; "integration," confusions, and transpositions at the phonetic level. PMID- 21286963 TI - Visual vs. verbal stimulus set in a letter-classification task. AB - In three experiments, subjects classified briefly presented letters as belonging to either the first or the second half of the alphabet. Prior to each target letter, the subjects were given either a verbally named letter (verbal set), a letter presented visually for 3 sec (visual set), or no prior alternative (control). The target was equally likely to be the same as the prior alternative (same trials) or from the opposite half of the alphabet (different trials). Classification accuracy was always greater for visual set than for the control condition. Verbal-set accuracy was no better than control accuracy when the verbal alternative immediately preceded the target but was equal to visual-set accuracy when the alternative preceded the target by 3 sec. In both set conditions, subjects tended to choose the same half of the alphabet as the prior alternative. It was concluded that type and timing of prior alternatives are important variables in accounting for enhanced classification accuracy. PMID- 21286964 TI - Generative processes in character classification: Evidence for a probe encoding set. AB - The role of rehearsal in a varied set memory scanning task was investigated by asking the subjects to rehearse subvocally the one to four target characters cyclically at a self-paced rate until the probe was presented. After making a manual positive or negative response to the probe, the subjects reported the last item rehearsed before the probe was presented. The results indicate that, when the last rehearsed item matched the probe, RTs were significantly faster than when it differed. Mean RTs over target set size were generally well fit by linearly increasing RT functions, with comparable slope values for negative responses and positive responses when the last rehearsal was the same as or different from the probe. The data suggest that rehearsal may reduce the duration of the probe encoding stage through some mechanism of pathway activation by providing the subject with a generated representation of what may appear next as a probe. PMID- 21286965 TI - The attentional demands of mnemonic control processes. AB - In order to assess the processing (i.e., attentional) demands of different control processes, subjects were required to perform a secondary choice reaction time task in addition to primary verbal tasks. The performance of the secondary task yielded a measure termedexpended processing capacity (EPC), which was used to infer the attentional demands of the primary tasks. Two factors, mediator type (experimenter-supplied vs. subject-generated) and intentionality (incidental vs. intentional), were varied in a paired-associate situation in an effort to affect the degree of elaboration processing. Only mediator type had an effect on recall accuracy and on EPC during both initial processing and recall. Subject-generated mediators resulted in higher recall and in higher EPC during initial processing, but in lower EPC during recall, than did experimenter-supplied mediators. Implications of these findings are discussed. PMID- 21286966 TI - Retroactive inhibition as a function of the conceptual structure of original and interpolated lists. AB - Subjects learned either a hierarchically structured serial list of concept instances or a list made up of the same words but without structure. These two original lists were followed by one of four interpolated lists varying in number of hierarchical levels and consisting of new instances of the concepts which occurred in the original lists. Recall of the original structured list showed heavy retroactive inhibition, with the magnitude being independent of the number of conceptual levels in the interpolated lists. For the unstructured original list, retroactive inhibition decreased as the number of conceptual levels in the interpolated list increased. Some mechanisms believed involved in producing these outcomes were discussed. PMID- 21286967 TI - Editorial announcement. PMID- 21286968 TI - Free recall and complexity of pictorial stimuli. AB - In order to explore variables underlying primacy and recency effects in free recall of pictorial material, norms were developed using 120 subjects who rated the vividness and complexity of slides. Two experiments were then run in which two levels of each of these variables (extreme high and low ratings) were factorially combined. In the first experiment 24 subjects were shown three mixed lists, two short and one long (consisting of materials of all four combinations of vividness and complexity), and in the second experiment 12 subjects were shown four pure lists (consisting of materials of a single type). Analysis of variance showed list length in the mixed list experiment and complexity in both experiments to be strong determinants of recall. Greatest recall was for items of low complexity in short lists. Weak, but statistically significant, serial position effects were evident, particularly for less complex items. The effects of primacy and recency seem to decrease with increasing complexity of visual materials, perhaps because of the greater difficulty in rehearsing more complex pictures either verbally or iconically. PMID- 21286969 TI - Facilitation of recall with intralist cues: Time-dependent characteristics of cued recall. AB - List items were given as retrieval cues in a free-recall experiment which factorially combined the presence or absence of cues with the amount of time allowed for use of each cue (10 sec or 30 sec). A categorizable list of 75 randomly presented words was learned, and 48 h later a free-recall test trial was given, followed by a final memory search task. During the final task, cued subjects received words from categories that had not been recalled during the free-recall test. With both time intervals, cued subjects recalled more words than noncued subjects, indicating that random presentation of categorized words does not necessarily preclude the observation of a cueing effect with list items, as has been reported previously. The composition of recall, whether from previously recalled or nonrecalled categories, varied as a function of time for both groups. The results were interpreteod in terms of retrieval strategies employed by cued and noncued subjects and the effect of time on these strategies. PMID- 21286970 TI - Spontaneous categorizers retain more than spontaneous alphabetizers. AB - Immediate and delayed free recall of unstructured verbal materials were assessed for alphabetizers and categorizers after varying study times. Alphabetizers and categorizers did not differ in immediate recall, but retention following a 6-day interval was consistently higher for categorizers than for alphabetizers. Both immediate and delayed recall increased with study time, which did not interact with learning strategy. In the next experiment alphabetizers and categorizers learned two lists, the second of which was categorically structured or unstructured. No retroactive interference on first-list recall was produced by the learning of the structured list, but the learning of the unstructured list produced retroactive interference for the alphabetizers only. It was suggested that, although both alphabetizers and categorizers probably use their respective strategies for other verbal tasks, the categoric strategy should create less interference because specific 'categories are rarely encountered in successive tasks. PMID- 21286971 TI - Long-term memory for speaker's voice and source location. AB - One hundred and twenty-eight subjects tried to recall 20 simple sentences that for some subjects were presented in two different voices or were presented from two loudspeakers on different sides of the room. In addition, some subjects were instructed to remember not only the sentences, but also their voice and location attributes. Intentional instructions for location resulted in poorer recall of the sentences, but intentional instructions for voice did not. The voice attribute seemed to be automatically coded under both intentional and incidental instructions for remembering the attribute, whereas the location attribute seemed to require cognitive processing in addition to that required for encoding the meaning of the sentence. A test for clustering by voice in recall was done to determine if the evidence for automatic ceding of voice was merely an artifact resulting from better recall because of organization. However, no clustering was found. The ideas that speaker's voice and sentence meaning were processed in parallel by different hemispheres of the brain and that the connotation of the voice influenced the meaning of each sentence were offered as two possible explanations of the results. PMID- 21286972 TI - Priming and property dominance effects in semantic memory. AB - Retrieval from semantic memory was examined by means of reaction times to property statements (e.g., sparrow has beak). The variables of interest were normatively defined property dominance (frequency), type of priming between related sentences (sparrow-sparrow vs. sparrow-robin), and separation or lag between related sentences. Statements asserting a high-dominant property (1) were verified more quickly than those containing low-dominant properties, (2) were primed by a preceding related sentence of either high or low dominance, and (3) revealed decay of priming from Lag 1 to 4. The differences between priming with and without stimulus repetition were nonsignificant when stimuli were treated as a random effect. In support of the Collins and Quillian (1972) model of semantic memory, the priming and property dominance factors interacted. PMID- 21286973 TI - Encoding processes in memory scanning tasks. AB - Three experiments are presented that deal with the effect of stimulus probability on the encoding of both alphanumeric characters and nonsense figures. Experiment I replicated a previous finding of an interaction between stimulus probability and stimulus quality in a memory scanning task with numbers as stimuli. Experiments II and III investigated the same paradigm with unfamiliar visual forms as stimuli, and no interaction was found. Results were interpreted as showing that probability affects the encoding mechanism only when the encoding process results in a representation of the name of the stimulus. When stimulus materials are visual forms without names, probability does not appear to affect encoding processes. PMID- 21286974 TI - Differences in encoding for free recall vs. recognition. AB - Three experiments examined effects of test expectancy on memory for relatively unrelated words. In Experiment I, where preliminary recall or recognition practice was given, both recall and recognition were superior when the subjects expected and had practiced for recall. Free study led to better recall and recognition than paced presentation, but did not interact with test expectancy. Experiment II demonstrated that recall was better for subjects expecting a recall vs. a recognition test in the absence of preliminary practice. In Experiment III all subjects practiced both recall and recognition prior to presentation of the critical list. Study time also was varied. With longer study, recall was better when a recall test was expected, with no test expectancy effect on recognition. There were no appreciable expectancy effects with the short study period. Self reports and other data suggested that the critical encoding differences produced by test expectancy manipulation were quantitative in nature. PMID- 21286975 TI - Retroactive inhibition as a function of the locus of categorized response sets. AB - The effects which list-level taxonomic attributes should have upon retroactive inhibition (RI) producing mechanisms in both response-set interference theory (Postman & Stark, 1969) and Petrich's (1975) retrieval model are discussed. A test of the theories was performed by manipulating the presence (1) or absence (0) of categorized response sets in both original learning (OL) and interpolated learning IIL), and comparing their predictions concerning the relative degree of RI expected in the four conditions (0-0, 0-1, 1-0, 1-1). In line with Petrich's predictions, OL categorization significantly reduced RI, IL categorization significantly increased RI, and 0-1 produced significantly greater RI than 1-0. Moreover, the obtained ranking of the means for the experimental groups in degree of RI (0-1>0-0>1-0 ? 1-1) was in close agreement with the ranking predicted by Petrich's (1975) model. The results provide support for Petrich's (1975) retrieval model and pose explanatory problems for response-set interference theory (Postman & Stark, 1969). PMID- 21286976 TI - When are nonwords easy to see? AB - The influences of presentation mode (mixed vs. blocked trials) and target variability on the detection of targets in words and in random letter strings were examined. The results indicated that there was a substantial word superiority effect in mixed lists of words and nonwords, but that this effect was eliminated when pure lists of words and nonwords were compared. Also, target variability affected the shape of the serial position curve. When subjects searched repeatedly for a single target, the serial position curve had only a significant linear component. However, when the identity of the target varied from trial to trial, the serial position curve had a significant quartic component (i.e.. it was M-shaped). These results were interpreted in terms of strategies and feature learning. PMID- 21286977 TI - Mental size scaling examined. AB - Observers made same-different shape judgments of stimuli that were identical in shape and size different in shape but not in size, or differed in relative size along a number of steps for both same- and different- shaped forms. "Same" judgment RTs increased monotonically with increases in the magnitude of the relative size difference. In contrast, "different" judgment RTs were unaffected by changes in relative size. A second experiment in which stimulus presentation was successive rather than simultaneous yielded essentially the same results. Consideration was given to a dual- process model in which a time-consuming analog process normalizes stimuli that are size discrepant prior to a comparison stage that is operative for those structures responsible for "same" decisions but not for "different" judgments. Some evidence that seems inconsistent with a normalization process which operates prior to contact with memory was discussed, and an alternative explanation in which the early detection of a size difference causes changes in decision criteria was suggested. PMID- 21286978 TI - Triadic decision making in lexical memory. AB - Word and category recognition was investigated in the context of other stimuli, where the semantic distance relationships among the stimuli were derived from multidimensional scaling. On each trial, three horizontal strings of letters were presented. In the word condition, a positive response was required when the three strings formed three words; in the category condition, a positive response was required when the three strings formed words belonging to the same category. The results indicated that: (a) category decisions take about 150-200 msec longer than do word decisions, (b) word decisions are facilitated by a common categorical membership but semantic distances within the category are relatively unimportant, and (c)within-category semantic distances systematically altered response time for the category condition. It was hypothesized that semantic distance relationships may be sensitized for categorical decisions, but that only large semantic distances function effectively for word decisions. PMID- 21286979 TI - Recall memory for visually presented chess positions. AB - A series of three experiments replicated and extended earlier research reported by Chase and Simon (1973), de Groot (1965), and Charness (Note 1). The first experiment demonstrated that the relationship between memory for chess positions and chess skill varies directly with the amount of chess-specific information in the stimulus display. The second experiment employed tachistoscopic displays to incrementally "build" tournament chess positions by meaningful or nonmeaningful chunks and demonstrated that meaningful piece groupings during presentation markedly enhance subsequent recall performance. The third experiment tested memory for one of two positions presented in immediate sequence and demonstrated that explanations based on a limited-capacity short-term memory (Chase & Simon, 1973) are not adequate for explaining performance on this memory task. PMID- 21286980 TI - Encoding variability theory and the spacing effect in associate learning. AB - Encoding variability theory accounts for the spacing effect by assuming that, as the lag between repetitions increases, the memorial representations approach independence. A method for testing this assumption in determining repetition effects in associative learning is suggested. In the independence hypothesis, we simply assume that each presentation of a word pair is represented independently, so that the expected proportion recalled is simple, P=P1+P2 - PIP2. Two studies are reported using a continuous paired-associate task representing a factorial combination of lag and retention interval as well as single-presentation control conditions. The results indicate that for moderately long retention intervals, as the lag between repetitions increases, the observed proportion recalled is first less, then eventually exceeds, and then returns to the level expected by an independence hypothesis. PMID- 21286981 TI - Knowing not. AB - Ontario Institute for Studies in Education, 252 Bloor Street, Toronto, Ontario, Canada M5S 1V6 People often know rapidly and reliably that they do not know something. A review of contemporary theory reveals that the issue has not received much attention; moreover, the accounts available assume that recognition that one does not know something is achieved only by failure to establish that one does know it. A reaction time experiment assessed two aspects of knowing not, by asking people whether they knew common nouns well enough to use them in sentences and whether they had visited certain cities. The findings were that affirmations of negation were often more rapid than positive reports; hence, the account of knowing not as the complement of knowing that something is the case is not necessarily correct. We suggest that knowing not may be attained as rapidly as positive knowledge on the basis of ability to carry out analytical procedures. PMID- 21286982 TI - Short-term memory limitations in children: Capacity or processing deficits? AB - This paper evaluates the assertion that short-term memory (STM) capacity increases with age. Initially an analysis is made of the STM system in terms of its parameters and control processes. No evidence was found that can suggest conclusively that either the capacity or the rate of information loss from STM varies with age. On the other hand, substantial evidence exists to show that the processing strategies used by adults are unavailable or deficient in children. Furthermore, considerable differences in the contents and complexity of the long term memory (LTM) knowledge base (semantic and recognition networks can produce grossly different STM performance between age groups. The second half of this paper reviews three STM-related paradigms-memory span, serial probed recall, and recognition under limited exposure-that have consistently shown performance deficits in children. These deficits are explained in terms of the lack of proper control processes (or processing strategies), as well as an impoverished LTM knowledge base rather than a limitation in STM capacity. PMID- 21286983 TI - Interactive visual imagery and memory search for words and pictures. AB - In a short-term recognition memory experiment with words, subjects: (1) subvocally rehearsed the words, (2) generated a separate visual image for each word, (3) generated an interactive scene with such images, or (4) composed a covert sentence using the words in the memory set. Contrary to Seamon's (1972) results in a similar study, a serial memory search was found in all conditions, instead of the simultaneous scan which was expected when items were combined in interactive images. In a second study with pictures as stimuli, subjects who generated imaginal interactions between separate pictures, viewed interacting pictures, or viewed separate pictures also showed a serial search, i.e., longer RTs were obtained when more stimuli were held m memory. Since interactive imagery facilitated performance in an unexpected paired-associate task with memory set stimuli, one can argue that subjects actually processed or generated such interactions. It was suggested that memory search might not be simultaneous in tasks where the test stimulus constitutes only part of a memory image. PMID- 21286984 TI - An analysis of double-function lists. AB - Double-function list acquisition was analyzed in three experiments which used mixed-list designs and forced-choice recognition tests. Findings showed that specific associative interference occurred both during learning and performance phases, that its source was limited to the immediate backward associate during the learning phase, but that it also involved items further removed in both the forward and backward directions during the performance phase, probably by way of mediated chaining. PMID- 21286985 TI - Dual semantic encoding of homographs and homophones embedded in context. AB - Dual encoding of homographs and homophones was inferred from the intrusion of their alternative meanings across trials in two experiments using a modified Brown-Peterson paradigm. In Experiment 1 subjects heard a word triad and then engaged in a 10.5-sec distractor task. Written recall was then demanded. On context trials a homophone with alternative meanings belonging to two distinct categories was embedded in a triad biasing one meaning, e.g., helpless,/wik/, fragile. On the next trial, words from the category of the other meaning were presented, e.g., year, month, decade. A significant number of intrusions of the alternative coding of the homophone, e.g., WEEK, across the category boundary were observed. Experiment 2 employed visual presentation of embedded homographs, e.g., plunged, jumped, DOVE, and oral recall but was logically similar to Experiment 1. Intrusions of the alternative codings of homographs across category boundaries, e.g., pigeon, sparrow,/d Lambda v/, were again noted. PMID- 21286986 TI - Levels of coding in picture-picture comparison tasks. AB - Two experiments are reported in which subjects had to match pairs of pictures of objects. "Same" pairs could be either identical (Ps), pictures of different views of the same object (Pv), or pictures of different objects having the same name (Pd). With line drawings as stimuli, RTs for Condition Ps were shorter than for Condition Pv, which in turn were shorter than for Condition Pd. Visual similarity had no effect on Pd RTs. However, in Experiment II, where photographs of objects with high-frequency (HF) and low-frequency (LF) names were used, no difference was found between Conditions Ps(HF), Ps(LF) and Condition Pv(HF); and no difference occurred between Conditions Pd(HF), Pd(LF) and Condition Pv(LF), the latter set of conditions being associated with longer RTs than the former. This pattern of results was found with both a .25-sec and a 2-sec ISI. The results are discussed in terms of the levels of coding involved in processing information from picture stimuli. It is concluded that at least two levels are involved in matching photographs of real objects (an object-code level and a nonvisual semantic code level), while a third level may be used in matching tasks involving stylized line drawings (a picture-code level). PMID- 21286987 TI - Integration of information during problem solving due to a meaningful context of learning. AB - Ninety-seven subjects memorized nine associations among six interlocking elements that were presented as links among nonsense letters, connections among spies with word code names (after Hayes, 1966), or airline flights among major US cities. On tests of problem solving and true-false judgments, the letters group and the words group performed nearly identically; however, relative to these two groups, the cities group performed worse or about the same on short recall problems and much better on longer problems requiring chunking of learned information. The conditions and effects of a meaningful learning context for problem solving were discussed. PMID- 21286988 TI - Dual vs. single encoding in recognition memory as a function of lag, delay, and availability of semantic information. AB - One objective of the study was to assess the view of Winograd and Raines (1972) that the absence of a difference between dual as opposed to single encodings of a word at long lags may be due to the fact that subjects can establish two independent temporal tags when a to-be-remembered (TBRI word is presented at long lags. Winograd and Raines' argument that the effectiveness of any such temporal tags should diminish over time was examined. A second objective was to determine whether providing information about the semantic senses used during encoding operations would facilitate recognition, as "sense tagging" theories require. Words were presented twice in either the same low-frequency context or the same high-frequency context, or once in both a high- and low-frequency context at Lags 0 and 15. A recognition test was given immediately, or after a 1-week delay. The test was either context free or each word was accompanied by phrases which, in the case of TBR words, cued subjects with respect to the semantic senses of the word used in initial encoding. All manipulations influenced performance, but not in accordance with theoretical expectations. PMID- 21286989 TI - Partially selective search of memory for letters and digits. AB - Three experiments failed to provide evidence that subjects could search just the digits, or just the letters, of a mixed list of digits and letters in deciding whether a probe item was a member of the list. Providing a precue as to the category of the probe shortly before the presentation of the probe decreased the time needed to encode it, but did not change the memory search process. Repeating the category of the probe from one trial to the next, however, did change the pattern of memory search. A "partially selective search" model was proposed which claimed that a mixed list was stored as two categorized sublists, and that a self terminating search of the sublists could occur in which the first sublist searched was the one which had been probed on the previous trial. PMID- 21286990 TI - The order of recall and the recall of order. AB - Adelphi University, Garden City, Long Island, New York 11530 Four experiments are described. The first three lend support to the assertion that retrieval from short-term storage (STS) is improved, possibly to a maximum, if items are recalled in their originally presented order. In the fourth experiment a modified recall condition was introduced in which written position of recall reflected order information. Although the subject was not constrained to recall the items in order under this modified recall condition, both item and order retention increased in comparison to both free and serial recall conditions. Within the theoretical framework adopted, the results indicate that retrieval from STS is improved by recalling in order; while long-term storage (LTS) is reduced by the constraint to recall in order. However, LTS is increased by the retention of order information when recalling in order is not required. PMID- 21286991 TI - An hypothesis approach to the solution of anagrams. AB - The attempts of subjects to reorganize the letters of an anagram were construed as a series of hypotheses about the correct letter order. It was predicted, consequently, that variables which reduce the number of tenable hypotheses or influence the order in which hypotheses are generated will affect problem difficulty. Five such variables, plus solution word frequency, were used to predict solution probabilities in two studies. The multiple Rs obtained were .92 and .82 and the two regression equations were effectively interchangeable. The process of anagram solution was described as entailing the retrieval of words from memory storage on the basis of letter order cues generated by the subject or, less usually, present in the anagram itself. PMID- 21286992 TI - Recognition memory for deducible information. AB - Recent research in language comprehension indicates a constructive encoding process in which the linguistic input is transformed into some more general semantic structure which is stored. In attempting to characterize the nature of such structures, some conflicting findings have been observed for paragraphs which describe similar set-theoretic relations, linear orderings and set inclusions. While the linear ordering research supports the constructivist theory, the set inclusion work does not. The set inclusion studies, however, employed true-false tests and not the usual recognition tests. The present study investigated the processing of set inclusion paragraphs in a self-paced study/recognition test paradigm. Results supported the constructivist theory and were contrary to predictions based upon the previous set inclusion research. Subjects were unable to differentiate between presented information and unpresented deducible information. These results were discussed in terms of accuracy constraints of different tasks on memorial performance and a possible interaction of Type of Test by Universal Quantification. PMID- 21286993 TI - Semantic priming and retrieval from lexical memory: Evidence for facilitatory and inhibitory processes. AB - Immediately prior to each visually presented target letter string to which the subject made a speeded word-nonword classification response, a visually presented prime to which no overt response was required was shown for 360, 600, or 2,000 msec. For word (W) target trials, the priming event was either a semantically neutral warning signal (Condition NX), a word semantically related to the target word (Condition R), or a word semantically unrelated to the target word (Condition U); for nonword (N) target trials, the priming event was either the neutral warning signal (Condition NX) or a word prime (Condition WP). For the W target trials, reaction times (RTs) were slower in Condition U than in Condition NX and equally so for all three prime durations; RTs were faster in Condition R than in Condition NX and to a greater degree for the 600- and 2,000-msec prime durations than for the 360-msec prime duration. For the N targets, RTs were faster in Condition WP than in Condition NX and equally so for all prime durations. These results were interpreted within the framework of a two-factor theory of attention proposed by Posner and Snyder (1975a). PMID- 21286994 TI - Further examinations of the category-recall function. AB - Subjects were assigned to use either three or six categories and were given either 5 or 10 trials in a word-sorting task. Subsequent to sorting, they recalled as many words as they could. A measure of sorting consistency showed that the six-category sort was a more difficult task than was the three-category sort. Number of categories did not have a significant effect on recall performance regardless of whether 5 or 10 sorting trials were used. A correlational analysis raised questions about the relationship of the sorting tasks to recall performance and clustering. PMID- 21286995 TI - Individual differences and interrelationships among a select set of cognitive skills. AB - An experiment was conducted to investigate individual differences and interrelationships in performance on three short-term memory processing and visual processing tasks. Parameters of models for these tasks were correlated. High correlations (.97 and .83) were obtained for some intertask parameters. indicating that elemental component processes for different tasks can be identified that are similar or highly related. Psychometric measures (SATM and SATV) were also correlated with the information processing model parameters. High multiple correlations of SATV and SATM were obtained using model parameters as predictors. when the data were analyzed separately for female and male subjects. The results are suggestive of sex differences in the interrelationships of the cognitive processes under investigation. PMID- 21286996 TI - Performance biases and recognition memory for semantic and formal changes in connected discourse. AB - In an experiment comparing memory for formal and semantic information, the confounding effects of attentional and response biases were controlled using an adaptation of Sachs' (1967, 1974) method. Subjects attempted to recognize semantic or formal changes in test sentences following short passages of connected discourse. Attentional biases were controlled by using a single type of change in an experimental session, and response biases were controlled with methods from signal detection theory. Semantic recognition scores were consistently above formal scores, both within subjects and within passages, indicating that superiority of semantic performance is attributable to differences in memorability rather than to biases favoring semantic performance. However, formal scores were above chance, suggesting that the poor memory for formal information, as reported previously, may have been due to performance factors. PMID- 21286997 TI - The relationship between repetition and depth of processing. AB - The relationship between depth of information processing and stimulus repetitions was investigated using a simultaneous category judgment task. Several levels of processing were defined involving (1) physically identical items, (2) physically different but same-name items, (3) different items from the same semantic category, and (4) items from different categories. Stimulus pairs were represented by words and pictures, and each pair was presented one, three, or five times. Response times for categorization judgments increased with the level of processing and decreased with repetitions. Repetitions produced greater facilitation for decisions at deeper levels of processing. In a final incidental recall task, more items were remembered from category-same trials than from same item trials, but level of processing did not interact with number of presentations. Repetitions produced an equivalent increase in final recall probability for items involved in all decision types, indicating that distributed repetitions can lead to the formation of stronger memory traces at several levels of processing. PMID- 21286998 TI - Reprocessing as a recognition cue. AB - The use of mental operations as recognition cues was investigated. Two experiments support the hypothesis that processing details are retained in memory and that a re-creation of those processing details can effectively cue recognition. Four subjects performed a mental arithmetic task that emphasized speed and accuracy while discouraging memorization of the numbers. Recognition was cued either by single numbers or by a pair of numbers that, when added, replicated an episode of the original task. Reprocessing an episode was the most effective recognition cue. Of the two single-number cues, the intermediate subtotals were recognized, whereas the numbers that had been physically displayed were not. The study suggests: (1) that the sequence of mental operations is retained in memory, (2) that reprocessing uses this trace to facilitate performance, and (3) that the detection of facilitated reprocessing aids recognition. PMID- 21286999 TI - Speed-accuracy tradeoff in double stimulation: II. Effects on the second response. AB - In the double-stimulation paradigm subjects respond to two successive stimuli. Previous research (Knight & Kantowitz, 1974) showed that a subject's speed accuracy tradeoff (SAT) strategy interacted with the interval between the two stimuli to determine response performance to the first stimulus. The present experiment examined the influence of SAT strategy on response performance to the second stimulus. Interest focused on effects of SAT strategy upon the psychological refractory period (PRP) effect. If a single mechanism underlies beth first-and second-response performance (e.g., the PRP effect) in double stimulation, effects of SAT upon the second response should be similar to effects upon the first response. Results showed that the PRP effect appeared only when second-response accuracy was stressed. Under speed emphasis double-stimulation second-response latency never exceeded a single-stimulation baseline. This was analogous to first-response latency effects found by Knight and Kantowitz (1974). Response grouping was strongly influenced by SAT strategy and two response grouping mechanisms were distinguished. Implications of these and interresponse time data for models of double-stimulation performance are discussed. PMID- 21287000 TI - Effects of simultaneous interference upon free recall learning and retention. AB - Learning and retention were examined under varying amounts of intratask interference during learning. All subjects were required to learn the same list of auditorily presented words while concurrently processing a visually presented interfering list. Differential amounts of interference were produced by varying the relatedness of the interfering list to the learning list. The common learning list consisted of four general categories that also contained members of more restricted subcategories. Some subjects were instructed about the existence and names of the subcategories. The results showed that interference lengthened learning but, in some cases, facilitated retention relative to control groups. Restricted category knowledge facilitated learning but had no effect on retention. There were no significant retention differences after I week, but after 5 weeks retention performance was significantly better for groups that learned under related interference conditions. The results were interpreted in terms of more elaborate encoding of the items in the high intratask interference conditions. PMID- 21287001 TI - Temporal characteristics of primary-secondary message interference in a dichotic listening task. AB - Previous experiments have shown that during performance of a shadowing task the unattended message is processed at a semantic level. Four experiments are reported that deal with the question of how processing of the unattended message influences the difficulty of shadowing the attended message. Experiment I demonstrated that pupil dilation measures the difficulty associated with a shadowing task. In Experiment II it was shown that during shadowing of 20-item lists pupil dilation decreases as shadowing continues when either words or white noise are in the unattended channel. These results support the idea that it takes time for the attentional mechanism to focus on the attended message. In Experiments III and IV it was found that this decrease in difficulty of shadowing is much less when the attended and unattended messages come from the same stimulus category (letter-letter, digit-digit). The results indicate that, when the unattended message is from the same stimulus category as the attended message, it can interfere with the ability of the attentional system to focus on the attended message. PMID- 21287002 TI - Labeling effects on memory for nonsense pictures. AB - It has been shown that labeling nonsense pictures improves memory for them, but how the label takes effect is uncertain. In this study subjects viewed nonsense pictures with or without labels; in the former case, the labels were either meaningful or nonmeaningful with respect to the pictures. Then the subjects took part in a free recall test, followed by recall in the presence of cues. Only the meaningful labels facilitated free recall of the pictures, but both types of labels facilitated cued recall. The results suggest that a meaningful label affects picture encoding by providing a conceptual interpretation for the picture; a nonmeaningful label, in contrast, appears to provide only an ad hoc associative cue. PMID- 21287003 TI - Short-term memory as a response preparation state. AB - This review considers recent findings on motor-response programming which indicate that there is a temporary mode of storage for response commands. This storage, which is distinct from long-term memory, is required for emission of a programmed response even when there are no explicit requirements for memory. Although this system is considered to be primarily a stage in response control rather than a memory system, it may mediate verbal short-term memory when encoded in articulatory form. The implications of this perspective on short-term memory are considered. PMID- 21287004 TI - Logical processing of set inclusion relations in meaningful text. AB - The present experiments attempted to resolve some recent conflicting findings in cognitive structure research between processing linear ordering and set inclusion relations described in meaningful paragraphs of text. In a self-paced study-test paradigm, college students studied such paragraphs. Definite processing differences were found for the two set-theoretic relations. Set inclusion test results were found to be due to faulty logical processing and not to memory retrieval problems. Subjects made invalid conversions of universally quantified statements and failed to make valid transitive inferences between such statements. This failure was found to be an increasing function of the distance separating the two terms in the set inclusion. No such problems were observed for linear orderings. The usual distance function was found: Accuracy on test questions about the ordering was an increasing function of the distance between the terms in the question. Results similar to those for linear orderings were observed for set inclusions when subjects were given special instructions about the validity and invalidity of symmetric and transitive inferences. PMID- 21287005 TI - The within-list distributed practice effect: Tests of the varied context and varied encoding hypotheses. AB - The present studies provided separate tests of the varied context and varied encoding hypotheses of the MP-DP effect. The investigation of varied encoding used an incidental learning procedure in which the nature of the orienting task was manipulated such that the subject attended to different attributes of words (varied encoding) or only one attribute (same encoding). While the prediction that the recall of MP-DP items should be comparable under comparable levels of encoding was not supported, differences were obtained in recall of items under same and variable orienting task conditions. An MP-DP effect was obtained under the incidental learning procedure. Tests of varied context involved the presentation of target items in list contexts which were the same or different from list contexts on previous occurrences of the item. The prediction that recall of items surrounded by different context should exceed that of items surrounded by the same context was not supported. PMID- 21287006 TI - An eye fixation analysis of choice and judgment with multiattribute stimuli. AB - The present paper examined the selection of processing heuristics for choice and judgment across a range of stimuli. Eye fixations were monitored while six subjects made choices or judgments of pairs of gambles, vacations, or gifts. Each stimulus was represented by three attributes that varied in the amount of dimensional interdependency. The two heuristics of interest were dimensional and holistic evaluation. Each manifested a characteristic pattern of eye fixations. Dimensional evaluation required alternating fixations from a single attribute of one stimulus to the same attribute of the other stimulus. Holistic evaluation was characterized by transitions from attribute to attribute within a single stimulus. The results demonstrated that when the stimulus attributes were either interdependent (gambles) or dissimilar (gifts), the processing heuristic was determined by stimulus characteristics. When the stimulus dimensions were neither interdependent nor dissimilar (vacations), the selection of a processing strategy was determined by the prescribed task. This study suggests that any global theory of choice or judgment must be validated over a wide range of stimuli. PMID- 21287007 TI - Direct visual access in reading for meaning. AB - Two experiments examined whether phonological receding is an obligatory stage in reading for meaning or whether direct access to a word's semantic representation is the general rule. The first study demonstrated that the time to make a semantic decision about a pair of words was much more delayed by misspelling than was the time to make a phonological one. The second study investigated the effect of varying the syllabic length of a word on reaction time in a category decision task. While reaction time varied with the semantic difficulty of the category decision, it generally proved invariant with respect to syllabic length. It is argued that reading for meaning generally uses a direct route from visual form to semantic representation. PMID- 21287008 TI - Effects of generative processes on probe identification time. AB - Studies of character classification have shown that reaction time is reduced when the probe is the same as the last-rehearsed target item. If rehearsal functions as a generative process to reduce response time by stimulus activation, comparable results should be obtained if the task is changed from probe classification to probe naming. A letter identification baseline was obtained in Session 1 where subjects named single probe letters as quickly as possible. In Sessions 2 and 3, each probe letter was preceded by a target of three to five letters, which were rehearsed individually prior to the probe, and subjects reported their last rehearsal after naming the probe. The results showed that (1) naming latencies were longer in Sessions 2 and 3 than in Session 1, suggesting that rehearsal requires conscious attention; (2) letter probes that matched the last-rehearsed target item were named faster than those that were different; (3) when performance was examined in terms of the rehearsal distance between the target items and probe, target set size had no effect on probe identification time. Generative processes were suggested to influence probe encoding time through stimulus preprocessing. PMID- 21287009 TI - Capacity limitations in human information processing. AB - The nature of processing demands during a letter-match task was investigated in an extension of the Posner and Boies (1971) paradigm. In Experiment I, a visual probe was employed in addition to an auditory probe in two different experimental conditions. The shape of the auditory probe reaction time (RT) function was similar to that found by Posner and Boies. However, in contrast to their findings, RT was greatly increased shortly after presentation of the first letter for the visual probe function. It was concluded that perceptual as well as postperceptual limitations on processing capacity exist. A second experiment provided further support for this hypothesis. PMID- 21287010 TI - Salience of initial attitude, magnitude of incentive, and attitude change in a forced compliance paradigm. AB - To examine the application of interpersonal simulation findings to cognitive dissonance and incentive theories of attitude change in the forced compliance paradigm, 60 Ss were paid 50 cents or $2.50 to write counterattitudinal essays with salient or nonsalient initial attitudes. Findings showed that the larger incentive yielded greater change for salient pretest attitudes but that the smaller incentive led to more change of nonsalient pretest attitudes. Measures of error in attitude recall and a correlational analysis between pretest, posttest, and recalled attitudes were also consistent with Bem's (1967) hypothesis of isomorphism between the attributions of Ss and observers. It is proposed that remaining simulation data reported in the cognitive dissonance/self-perception controversy may identify additional parameters of attitude changes in forced compliance experiments. PMID- 21287011 TI - Admission of suspicion as a function of information source: Tip-off vs. situational cues. AB - Two studies were run in which subjects received information about a fake opponent in a two-person game either from a confederate tip off or from situational cues designed to allow the subject to penetrate the deception unaided. In both experiments, subjects given the tip off reported less suspicion of the opponent than did those using situational cues. Probes were run to check tip-off information transmission in both experiments. In Experiment II a preinstruction manipulation was used to check for awareness of the actual purpose of the experiment and suspicion of the confederate tip off, but no evidence for these unwanted artifacts was found. The results suggest that subjects may be candid about their interpretations, at least if their suspicions do not derive from peers. PMID- 21287012 TI - Stimulus suffix effects with speech and nonspeech sounds. AB - The stimulus suffix effect (SSE) was examined with short sequences of words and meaningful nonspeech sounds. In agreement with previous findings, the SSE for word sequences was obtained with a speech, but not a nonspeech, suffix. The reverse was true for sounds. The results contribute further evidence for a functional distinction between speech and nonspeech processing mechanisms in auditory memory. PMID- 21287013 TI - Memory and frequency estimation processes in a decision task. AB - Two experiments examined the role of information storage and frequency estimation processes in a simple decision task. On each trial from one to five simultaneous sequences of information were presented, and subjects were required to monitor and respond to each sequence. In one study independent groups of subjects gave decisions, recognition responses. or frequency judgments. In a second study recall responses were obtained from subjects as part of the decision and frequency judgment tasks. Changes in performance as the number of simultaneous sequences increased suggested an independence of decisions from memory for specific information. Performance on the decision and frequency judgment tasks exceeded at times that which was possible on the basis of specific information available. Other data suggested that subjects in the frequency estimation tasks maintained an accurate frequency count when possible, but in the decision task kept little more than a record of their currently favored hypothesis. When direct counting was prevented in the second experiment. performance in the two tasks was not significantly different, suggesting that the two processes are very similar under such conditions. PMID- 21287014 TI - Differential encoding as a function of semantic polarity and form of visual stimulus presentation. AB - The present study investigated the saliency of form of visual stimulus presentation (printed word or picture) and of the semantic evaluative dimension (positive or negative) as encoding attributes for fifth-grade children. Three short-term memory trials within one visual form of presentation or one pole of the evaluative dimension were followed by a fourth short-term memory trial on which the stimulus material was shifted on one or both attributes (experimentals) or held constant (controls). The recall of the experimental groups consistently exceeded that of the control groups on the shift trial, providing evidence for a release from proaetive inhibition and implying the saliency of both the form of visual stimulus presentation and the evaluative polarity of the stimulus concepts as encoding dimensions. PMID- 21287015 TI - Two mechanisms in the stimulus suffix effect. AB - The stimulus suffix is a redundant item presented immediately after a stimulus list. Its effect is the selective impairment of recall of the final items in a serially recalled, auditorily presented list of unconnected items. Two experiments indicate that there was no difference between the effects of suffixes .5 and 1.0 sec after the end of a digit list presented at a rate of one digit/sec. This suggests that the effect of the suffix, in this case the vowel sound "ah," is not a simple function of its time of arrival after the final digit, as has been thought. The possibility of more complex factors was supported in a further experiment which showed a slight reduction in the size of the suffix effect by repeating the suffix three times. PMID- 21287016 TI - Self-attribution of attitude as a function of belief feedback. AB - Previous research has found that subjects listening to a communication can be persuaded more when they receive false physiological feedback concerning their emotional state than when such feedback is not presented. Such results, in conjunction with Bem's (1972) postulate that subjects infer their attitude from the external circumstances of their behavior, suggested that false feedback of belief or disbelief would affect persuasion. Subjects listened to a speech while observing their (false) reactions on a "belief meter." Half of the subjects received strong positive belief feedback, and the other half received strong disbelief feedback. Demand characteristics were varied by telling half of the subjects in each group that the meter was highly reliable and valid and the other half that is was of questionable validity. Results showed that the meter feedback affected self-attributions of attitude. Subjects receiving disbelief feedback rated their attitude the same as a control group who merely completed the attitude scale. Subjects receiving belief feedback were persuaded more than a control group receiving only the communication. The implications of the data for the construct of attitude were discussed. PMID- 21287017 TI - The word superiority effect: Dependence on short-term memory factors. AB - Two experiments were conducted to test whether the word superiority effect, that letters in words are perceived more accurately than letters in nonwords, could be attributed to short-term memory (STM) factors. One hypothesis attributed the word superiority effect to superior maintenance of words in STM. Another hypothesis was that letters in STM have considerable positional uncertainty which is overcome by the orthographic characteristics of the words. Both experiments utilized a simultaneous same-different task, where subjects compared two four letter strings, one on top of the other, which were presented tachistoscopically. In Experiment I, the two presented strings were either both words or both nonwords and a word superiority effect was obtained. This result was interpreted as disconfirming the STM maintenance hypothesis. In Experiment II, letters were removed from one of the two letter strings, making the serial position of the comparison unambiguous. The word superiority effect disappeared. This result was interpreted as supporting the positional uncertainty hypothesis. PMID- 21287018 TI - Picture-word differences and conceptual frequency judgments. AB - Recent evidence suggests that while pictures are more easily recognized, discriminated, associated, and recalled than their corresponding verbal labels, this is not the case in concept acquisition/utilization tasks. If such evidence is interpreted in terms of a "frequency theory" perspective, one would expect the typically obtained frequency judgment differences between pictures and words to be reduced if "conceptual" frequency judgments are required. This expectation was confirmed in three experiments. PMID- 21287019 TI - Sex and coding strategy effects on reaction time to hemispheric probes. AB - Two experiments were conducted to investigate the influence of coding instructions on cerebral laterality differences. Experiment I required 20 subjects (10 female) to use either rehearsal or imagery coding strategies in a recognition task with word probes to the right and left hemispheres. No hemispheric differences were found, but sex of subject was found to be related to coding strategy. Ten subjects (5 female) in Experiment II performed a similar task, except picture probes were used. Subjects using rehearsal coding responded faster to left-hemisphere probes, but faster to right-hemisphere probes when imagery coding was employed. The differing laterality effects in these experiments were attributed to naming responses implicitly required in Experiment II. PMID- 21287020 TI - Retention of phonemic and semantic features of words. AB - Subjects were asked to detect either repetitions, rhymes, or words from the same category during an auditory or visual list presentation. It was discovered in both cases that the number of intervening words had a differential effect on probability of detection, with phonemic feature detection deteriorating more rapidly than semantic. However, "rate" of presentation did not have a differential effect on the probability of feature detection, since phonemic and semantic feature detection improved equally with increased interword interval time. It was suggested that phonemic feature retention might be more vulnerable than semantic feature retention to interference. PMID- 21287021 TI - Perceptibility of schematic face stimuli: Evidence for a perceptual Gestalt. AB - The perceptibility of face, scrambled face, and single-feature stimuli was investigated in three experiments. Stimuli were presented tachistoscopically, followed by a visual noise mask and a forced-choice test of one of three features (eyes, nose, and mouth). In Experiment I, two processing strategies which have been proposed for word perception (involving expectancy and redundancy) were investigated for the stimuli employed here. In Experiments II and III, experimentally induced familiarity was studied for its effect on recognition and perception, and an immediate and delayed perceptual test was employed. Across all three experiments, perception of single-feature and face stimuli were consistently superior to scrambled faces; in Experiment III, differences between single features and faces were eliminated. The effects of perceptual expectancy, internal feature redundancy, familiarity, guessing biases, etc., were shown to be insufficient to account for the superiority of face to scrambled face stimuli. It was argued that the perceptibility of nonredundant features are enhanced when those features are aligned in a well-defined form class. The view that familiarity operates directly on recognitive processes but indirectly on perceptual ones was discussed. PMID- 21287022 TI - Holographic and trace strength models of rehearsal effects in the item recognition task. AB - Two models are described that are capable of generating latency predictions in the item recognition task based on the sequence and timing of rehearsals. It is shown that equal positive and negative slopes are possible when the average number of rehearsals per item increases with list length but that when no rehearsal occurs the positive slope is predicted to be substantially steeper than the negative. Serial position effects are also analyzed for the various rehearsal strategies seen when subjects are asked to rehearse out loud. PMID- 21287023 TI - Letter search through words and nonwords: The effect of fixed, absent, or mutilated targets. AB - The present study attempted to eliminate the word superiority effect found in letter search by holding the target letter fixed across trials. The expectation was that the target would thereby become so familiar and salient that the subject would "see" only that letter during search. Even with the target-letter held fixed (Experiment I), however, search was still faster through words than through nonwords, indicating that nontarget letters had been "seen" as well. Search also remained faster through words than through nonwords when the number of exposures to the target was further increased by having the subject search for the absence rather than the presence of the target letter (Experiment III). In line with the notion of "proofreader's errors," however, search became relatively more accurate on nonwords than on words when it required detection of the "mutilation" produced by substituting an F for an E, e.g., BASKFT, BAKFRY (Experiment IV). PMID- 21287024 TI - The role of letter recognition in word recognition. AB - In a paradigm that avoids methodological problems of earlier studies, evidence was gathered addressed to the question of whether we read letter by letter. If word recognition involves letter recognition, then the difficulty of recognizing a word should vary with the difficulty of recognizing its letters. This was tested by assessing letter difficulty in two letter discrimination tasks and in a letter naming task, and then comparing 15 adult subjects' visual recognition latency to 72 easy-letter words and to 72 difficult-letter words. Word frequency and word length were also manipulated. Results indicated no effect for letter difficulty, although recognition latency reliably decreased with word frequency and monotonically increased with word length (21 msec/letter), suggesting that we do not read letter by letter, but that whatever plays a role in word recognition is smaller than the word and correlated with word length in letters. PMID- 21287025 TI - Apparent duration of long meaningful events and meaningless intervals. AB - Time estimates of 1 1/2-, 51/4-, and 14 1/2-min intervals were obtained from 12 American graduate students and 12 Indian graduate students by the methods of verbal estimation and cross-modality matching. Material presented during stimulus intervals varied in degree of meaningfulness. Each subject was tested on 4 successive days with basically the same material in order to determine the effects of repetition. The relationship between perceived and physical time was found to follow Stevens' power law, and confidence limits of exponents obtained in this study include the exponents previously reported for short durations. Neither actual judgments nor exponents were affected by cultural background or by cognitive factors such as memory for material presented in the interval, familiarity, complexity, degree of meaningfulness, and repetition. It had previously been reported that time judgments were dependent on these cognitive factors. In light of the present research, it is necessary to review and replicate those studies which support a cognitive view of time perception. PMID- 21287026 TI - Relational information and the context effect in recognition memory. AB - A role for relational information was examined for the paradigm in which recognition-memory performance on items tested in the same context in which they were studied is compared with performance on items tested in different contexts. Over a series of five experiments, randomly formed pairs were used to manipulate the context of high-frequency English words. Comparisons were made between instructional manipulations designed to influence the use of relational information, and between yes/no, confidence rating (both between- and within subject), and forced-choice tasks. There was a context effect not due to the use of inappropriate response strategies. However, high-criterion subjects resembled those subjects who were specifically instructed to use relational information, while low-criterion subjects showed little or no context effect. A model specifying the relationship between item and relational information and how relational information influences decisions in recognition-memory paradigms was proposed. PMID- 21287027 TI - Reminiscence and item recovery in free recall. AB - The item recovery or reminiscence component of recall in RTT procedures was investigated in two free recall experiments. In the first, Erdelyi and Becker's (1974) "hypermnesia" effect was found with pictures as the to-be-remembered material: total amount recalled increased over two successive test trials, and included a large reminiscence effect, with some 27% of previously unrecalled items appearing in the second test. The second experiment, with word lists, showed that the frequency of occurrence of new items was greater following a 12 min separation of two test trials than in two relatively massed tests. This kind of item recovery is relevant to models of output interference and retrieval limitations in free recall, and may be also related to spontaneous recovery effects. PMID- 21287028 TI - Methodological problems with the use of the retroactive interference design to infer what is stored. AB - The retroactive interference paradigm has been used in a variety of settings to investigate the nature of the representation of memory. Much of the research using this paradigm is methodologically flawed because it involves treatment comparisons which are inappropriate. It is argued that comparisons must be made between presentation conditions having the same interpolated activity and that, in addition, evidence is required that the differences are not confounded by acquisition level differences if one is to infer mode-specific interference and representation. The methodological issues are discussed in detail and the utility of the retroactive interference design is questioned. Studies employing the design are reviewed, and several conclusions are drawn: (1) there has been no unambiguous demonstration of visual mode-specific interference, (2) there has been no clear demonstration that imagery instructions produce memories that are more susceptible to visual than to auditory interpolation, and (3)no clear demonstrations are yet available that memory for spatial location is more susceptible to visual interference than memory for letters. PMID- 21287029 TI - Another look at the relationship between phonetic symbolism and the feeling of knowing. AB - Koriat (1975), using a word-matching phonetic symbolism task, found a significant relationship between translation accuracy and the degree of subjective confidence associated with the response. This study examined the hypothesis that since responses on which subjects are in consensus are more likely correct than incorrect, confidence ratings may actually be related to the degree of consensus, regardless of the correctness of the response. The results strongly supported this hypothesis. For items with a consensually correct response, translation accuracy increased with degree of subjective confidence, while for items with a consensually incorrect response it decreased. Consensual responses were judged subjectively more compelling than nonconsensual responses regardless of their accuracy. Some implications of these findings are outlined. PMID- 21287030 TI - Comprehension as affected by structure of problem representation. AB - A problem-like branching system describing what prizes (A through F) were awarded for particular outcomes of a tournament of games among three teams was presented to 200 subjects as either a verbal list with "go to" structure (Jump), a shortened verbal list (Short-Jump), nested verbal paragraphs with "if ... then..., else" structure (Nest), a matrix table (Example), or as diagrammatic representations of each of these. In tests of comprehension, the overall performance increased from lowest to highest as follows: Jump < Short-Jump ? Nest < Example, and this order was particularly strong for performance on complex questions relative to less complex questions. Jump and Short-Jump performance was relatively higher with diagrams and Example was lower with diagrams. Implications for a theory of problem representation and for development of computer programming languages were discussed. PMID- 21287031 TI - Recognition memory for words and pictures at short and long retention intervals. AB - In two experiments, subjects studied a long series of words and pictures for recognition. Retention intervals varied from several minutes to a few months. The complicated testing procedures in Experiment I required the use of a traditional correction for guessing to obtain estimates of subjects' memory performance. A comparable, but simpler, design in Experiment II permitted the calculation of sensitivity and bias measures. In both studies, pictorial memory was superior to verbal memory at all retention intervals tested, and this advantage was essentially constant over time. In addition, the experiments identified an increasing tendency to call verbal test items "old" over time. Bias scores in Experiment H revealed that subjects adopted a more lenient criterion in responding to words than to pictures, and increased leniency was noted for both item types over time. Explanations of the results are offered in terms of differences in initial encoding and of a loss of discrimination between experimental and extraexperimental materials. PMID- 21287032 TI - Auditory and visual similarity effects in recognition and recall. AB - The role of auditory and visual factors in short-term recall and recognition performance was evaluated. Auditory similarity, but not visual similarity, was found to be predictive of the probability of a correct response and response confidence for both types of tests. The results were interpreted as support for a single-trace model of recall and recognition performance. PMID- 21287033 TI - Alternative processes in the identification of familiar pictures. AB - Individual differences in perceptual processing were investigated in a task requiring subjects to match words (either general or specific category names) with simultaneously presented pictures. Based on the results of previous research, individual differences in processing were inferred from the effect, on "same" reaction time, of rotating the pictures into an unfamiliar orientation. For subjects inferred to emphasize an analytic mode of processing, word-picture matches were faster for general than for specific category names, supporting the hypothesis that analytic subjects would attend to the minimal number of features necessary to infer the categorical identity of the pictures. For subjects inferred to emphasize a structural mode of processing, there was little difference in word-picture matching time between specific and general category names, supporting the hypothesis that structural subjects would attend to all the information in the pictures, regardless of the category level specified by the word. PMID- 21287034 TI - On the limits of Kagan's impulsive reflective distinction. AB - A logical analysis is made of the Matching Familiar Figures (MFF) Test on the basis of which children have been classified as "impulsive" or "reflective." The reflective strategy is implicitly preferred to the impulsive because the reflective child makes fewer errors though generally taking longer to make his first response. We show that the test allows the choice of a number of "game plans" and speed-accuracy tradeoffs which in practice may not be very different. Error rates may not indicate perceptual sensitivity, in any case, since sensitivity and response factors may be confounded in the error rate. Using a visual running-memory-span task to avoid the inherent difficulties of the MFF test, we found that children previously classified on the basis of that test as impulsive or reflective did not differ in recognition accuracy but did differ in response bias and response latency. Accuracy and bias are estimated by way of Luce's choice theory (Luce, 1963), and the results are discussed in those terms. PMID- 21287035 TI - Manipulation of response-contingent unconditioned-stimulus intensity in human eyelid conditioning: A two-phase model analysis. AB - Four groups of human subjects were given 360 classical eyeblink conditioning trials. All groups received the same UCS (unconditioned stimulus) intensity on[Formula: see text] (nonconditioned response) trials but differed in the intensity presented on CR trials. Response probability increased as a positive function of UCS intensity on CR trials. Phase 1 of the two-phase model was longer when no UCS was presented on CR trials, but did not differ in duration among the remaining three groups. Most subjects could be described with a single operator in Phase 2, the operator limit increasing as a positive function of CR-contingent UCS intensity. For subjects requiring different operator limits on CR and[Formula: see text] trials, the latter was lower with high CR-trial intensities but higher with low CR-trialintensities. The results were interpreted to be more consistent with drive theory than with "law-of-effect" or two-factor theories. PMID- 21287036 TI - Understanding sentences with relative clauses. AB - Sentences containing self-embedded relative clauses are generally believed to be difficult to understand because such clauses interrupt the clauses in which they are embedded. However, the experiments that purport to have demonstrated this have confounded the self-embedded or fight-branching location of the relative clauses with their internal structure, comparing self-embedded object relatives with right-branching subject relatives. In order to break this confounding, Experiment I compared the comprehension difficulty of self-embedded and right branching object relative clauses on two measures of comprehension difficulty. Experiment II made the same self-embedded vs. fight-branching comparison for subject relative clauses. The results of both experiments consistently failed to support the interruption hypothesis. PMID- 21287037 TI - Can imagery be distinguished from other forms of internal representation? Evidence from studies of information retrieval times. AB - This paper provides support for the notion that images, once formed, are a distinct form of internal representation, processed differently than other forms of internal representation. In two experiments, subjects decided as quickly as possible whether or not named animals had given properties. When imagery was not used, people verified properties more quickly in accordance with how strongly associated the property was with the animal in question. When images of the whole animal were consulted, in contrast, subjects were faster in accordance with increasing size of the property, and not with increasing association strength. However, if subjects imaged only the local region where a property ought to be found, and did not consult an image of the whole animal, the size of a property no longer influenced verification time. These results and their implications for the debate over imagery vs. propositional representation were discussed. PMID- 21287038 TI - Simultaneous paired associate and verbal discrimination learning as a simulation of the double-function list. AB - In the critical condition, the subject was required to learn associations between words in the pairs and to learn to identify simultaneously the word in each pair that had been underlined on study trials. Over trials, both types of responding were required for each pair. Control conditions were used to assess the influence of these procedures. Paired associate learning was only modestly impaired, but the verbal discrimination learning (identifying the underlined word) appeared comparable to that for a double-function verbal discrimination list. The correlational evidence indicated that insofar as the present procedures simulated a double-function list, the association between the words in a pair is not involved in a causal way for the small amount of learning that occurs across trials in a double-function list. PMID- 21287039 TI - Phenomenal background frequency and the concreteness/imagery effect in verbal discrimination learning. AB - College students gave frequency ratings for concrete and abstract words which were equated on normative frequency. The results replicated the finding of Galbraith and Underwood (1973) that abstract words are perceived to be higher in frequency than concrete words. Different subjects then learned verbal discrimination lists consisting of both abstract and concrete pairs. While the usual concreteness effect was obtained when abstract and concrete items differed widely on phenomenal frequency, it disappeared when these items were equated on perceived frequency. The finding that appropriate frequency manipulations can eliminate the concreteness/imagery effect, coupled with similar findings for other stimulus characteristics, lends strong support to the frequency theory of discrimination learning. PMID- 21287040 TI - Multiple encoding of word attributes in memory. AB - Two experiments employing the release from PI method were conducted to determine whether degree of release could be predicted by the amount of denotative attribute overlap between the control and experimental groups. This theory was very appropriate for predicting the results of the first experiment, but was less successful in the second unless a connotative attribute is also introduced. It is suggested that this class of attribute should be included in semantic memory conceptualization. PMID- 21287041 TI - Subject strategies in part-whole transfer in free recall. AB - The effect of instructing subjects as to the nature of the relationship between the two lists of a part-to-whole transfer situation has been studied in a number of cases with conflicting results. Some studies have shown that instructions to the subject produce positive transfer, while in others only slight effects from instructions may be noted. Detailed analysis of subject output protocols in a part-to-whole experiment demonstrated that subjects who maintained their List 1 organization showed positive transfer to the whole list. Reanaiysis of several studies in the literature supported the conclusion that subjects who maintain their organization will show positive transfer under these conditions. In a second experiment, it is demonstrated that subjects can be instructed to maintain their List 1 organization during List 2 and that such instruction enhances the amount of positive transfer obtained. The results are viewed as consistent with a hierarchical version of an organization theory for recall performance. PMID- 21287042 TI - The relation between comprehending and remembering some complex sentences. AB - This research concerns the distinction between processes in sentence comprehension and those in sentence memory. Comprehension was monitored by timing subjects while they decided whether a sentence was true or false of their knowledge of the world. The memory process was tapped by examining subjects' incidental memory for the sentences they had previously verified. The verification latencies indicated that at the time of comprehension, sentences likeIt is true that a fire isn't cold were often recoded into an equivalent affirmative form, namely,It is true that a fire is hot. However, negative sentences likeIt isn't true that a fire is cold were not recoded during comprehension. Recoding in recall occurred only for those types of sentences that were recoded at the time of comprehension. PMID- 21287043 TI - Memory for concrete and abstract words in bilingual speakers. AB - The dual-code hypothesis of Paivio was taken to imply that bilingual speakers should show poorer memory for the language in which concrete words appeared than the language in which abstract words appeared. The results of two experiments with German-English bilinguals, one using a recognition memory procedure and the other using the free recall task, found the opposite state of affairs. Semantic recognition, free recall, and memory for language of occurrence were all found to be superior for concrete words. Two hypotheses were advanced. One, called the "cultural imagery hypothesis," assumes that images may be culture specific, while the other hypothesis interprets the outcome in terms of the relations between stored attributes. An analysis of the experiment as an attribute-memory procedure is presented. PMID- 21287044 TI - Combining information from sources that vary in credibility. AB - Models describing the role of source credibility in information integration were tested in two experiments. In the first experiment, subjects estimated the value of used cars based on two cues: blue book value and an estimate provided by one of three friends who examined the car. The three sources were described as differing in mechanical expertise. In the second experiment, subjects rated the likeableness of persons described by either one or two adjectives, each adjective contributed by a different source. The sources differed with respect to the length of their acquaintance with the person to be rated. In both experiments, credibility of the source magnified the impact of the information he provided. Further, this multiplicative effect of a source was inversely related to the credibility of the other source, in violation of additive or constant-weight averaging models, but consistent with a relative-weight averaging model. PMID- 21287045 TI - Experimental differentiation of meaning change and averaging explanations for context effects. AB - The effects of contexts on correlations between evaluations of traits were examined to provide a differentiation of meaning change and averaging explanations for context effects in evaluative impression formation. Two different types of traits (ambiguous and nonambiguous) were evaluated under two different instructional conditions (P, or person description, and W, or random words). Both types of traits manifested shifts in mean levels of evaluation in Condition P, but not in W, with little evidence for differentml efiects across types of traits. Correlational analyses revealed differences between ambiguous and nonambiguous traits. Ambiguous traits manifested large shifts in the magnitude of intratrait correlations across contexts in Condition P, indicating that meaning change had occurred. There was little evidence for such effects among nonambiguous traits. It was concluded that meaning change is a highly restricted effect and does not represent a serious challenge to averaging explanations for context effects on component ratings in impression formation. PMID- 21287046 TI - Revisiting the "strong but wrong" effect. AB - In the 1930s, J. M. Stephens found that strong verbal associations called wrong are more likely to be changed than weak verbal associations called wrong, relative to items with no feedback. The present study produced a much larger "strong but wrong" effect, apparently as a result of defining "strong" in terms of meanings presumably stored in long-term memory. It was also found that such items are followed by high recall of feedback on the next trial, and that, indeed, when feedback recall is statistically controlled, the effect disappears. An explanation of why feedback is better recalled for "strong but wrong" items is offered, and several predictions are generated, some of which are tested (and confirmed) from the present data. PMID- 21287047 TI - Duaal processes in recognition and in recognition failure. AB - It is argued that adherence of the results of experiments in the recognition failure paradigm to the function observed by Tulving and Wiseman (1975) reflects the operation of two distinct processes in recognition similar to those described by Mandler (1979, 1980). Familiarity decisions based on the target word alone can occur when target and list cue have not been integrated and result in some measure of dependence between recall and recognition. Contextual retrieval can operate in recognition when integration has occurred, and is independent of success in recall. It is further contended that deviations from the Tulving Wiseman function arise because special instructions given to subjects produce more or less cue-target integration than is normal, and differentially affect the relative proportion of items recognized via contextual retrieval and via familiarity decisions. The first part of the paper argues that the contextual retrieval involved in recognition failure experiments takes the form of an attempted backward recall of the list cue from the target, consistent with the suggestions of Rabinowitz, Mandler, and Barsalou (1977) and claims that the results of a paper by Fisher (1979) strongly support this view. PMID- 21287048 TI - Erratum to: Semantic congruity in symbolic comparisons: Salience, expectancy, and associative priming. PMID- 21287049 TI - Contextual imagery in meaning and memory. AB - Three hundred homonyms were selected, and sentence fragments were written to emphasize two meanings of each. The words were rated on image-arousing capacity both in and out of context and on frequency of occurrence in context. Imagery values for the words out of context were predicted quite well by an average of the contextual imagery ratings, weighted by their relative frequencies. The finding is consistent with the hypothesis that words presented in isolation are interpreted in specific senses according to a frequency bias, with imagery ratings reflecting those senses. In a memory experiment. words were selected to vary orthogonally on both contextual and out-of-context imagery. Recall of words in isolation was a function of out-of-context imagery, while recall of words presented in context was a function of contextual imagery, further supporting the hypothesis. PMID- 21287050 TI - Three interrelated problems in reading: A review. AB - In this review, three interrelated problems are discussed with respect to reading. The skilled S may recognize words not so much by a serial letter-by letter analysis, but rather by some sort of interactive process permitting the extraction of higher order distinctive features. Some semantic information may be available from words beyond the one currently fixated, even though orthographic or phonological information is preconscious or rapidly lost. Finally, the accessing of meaning from the written representation may proceed directly, without any prior or intervening phonological stage. These conclusions are considered within the context of the possibly different aims of the reader at different times, the distinctions between easy and difficult material, and the experienced and tile novice reader. Implications for alternative coding systems, such as a syllabary, are discussed in terms of the roles of the phoneme and the syllable as fundamental units in speech perception. PMID- 21287051 TI - Single-item recognition following a verbal discrimination study trial. AB - A verbal discrimination (VD) study phase was followed by a single-item (i.e., one item at a time) test phase. Prior right (R) items from the VD list were found to have higher old-new hit rates on the test phase than prior wrong (W) items. However, prior W items had higher hit rates than prior R items in terms of recognition of their intrapair function. These results were interpreted in terms of a high criterion model whereby an old test item must prossess a large number of frequency units before it is identified as being R. In addition, false recognition effects were demonstrated for new test items that were homophones of prior R items, but not for new test items that were homophones of prior W items. These results were interpreted in terms of a feature analytic extension of frequency theory. PMID- 21287052 TI - The effect of orienting tasks on recognition memory. AB - The effect of orienting tasks on recognition memory for words and faces was investigated. It was found that relevant orienting tasks improved recognition memory for both classes of stimuli compared with a nonrelevant orienting task and the control condition of testing recognition memory without an orienting task. Attention is drawn to the possibility of qualitative differences between recall and recognition for the effect of orienting tasks. The findings are related to recognition theories. It is suggested that the findings lend support to those theories which hold that retrieval processes play a major role in recognition memory. PMID- 21287053 TI - Interference among memory traces. AB - Several sources of interference in memory are identified. These sources may be grossly classified as processing interference, i.e., that due to disruption of whatever activity occurs during the input or output of to-be-remembered material, or trace interaction, i.e., that due to interference among the stored memories themselves. The latter would appear to be due to simultaneous activation of correct and incorrect associations mediated by confusion among cue stimuli. A consideration of the means by which interference is reduced suggests that interfering associates are not weakened, unlearned, or suppressed except possibly when nominal stimuli are identical and sets of target and interfering items are temporally discriminable. Discriminative encoding of cue stimuli may eliminate these associations, if it operates at the perceptual level. Otherwise, potential interfering associates are activated, but may be rendered functionally impotent by discriminating them from correct associations on the basis of either backward association with discriminative stimulus attributes or differential contextual attributes such as frequency, time, order, and strength. PMID- 21287054 TI - The effect of first response complexity on the psychological refractory period: A reanalysis. AB - The effect of first signal complexity on the delay of the second response within the paradigm of PRP has been the subject of several recent papers. The results show that, for the same interstimulus interval, the more complex the first reaction, the more the second response is delayed. This paper reports a reanalysis of the data presented by these investigators in terms of comparable response-stimulus intervals. The implications for theories of limited attention are discussed. PMID- 21287055 TI - Effect of locus of warning tone on auditory choice reaction time. AB - Forty Ss pressed a left- or right-hand key depending on the ear in which they heard a 500-Hz stimulus tone. Half of the Ss were instructed to press the key on the same side as the ear stimulated (corresponding condition), while the other half pressed the key on the opposite side (noncorresponding condition). A 200-Hz warning tone preceded the stimulus tone by either 200 or 400 msec. The warning tone was presented to the left ear, the right ear, or to both ears in a predetermined random sequence. The locus of the warning tone affected RT on noncorresponding trials but not on corresponding trials. The effect consisted of a significant slowing of information processing on trials where the warning tone was contralateral to the response. Results were explained in terms of an initial tendency to respond toward the source of the warning tone. PMID- 21287056 TI - An experimental test of three choice shift hypotheses*. AB - The present experiment pitted three choice shift hypotheses against each other in an attempt to eliminate one or more of the hypotheses and find support for those remaining. Ss responded three times to the 12 CDQ items, once as a pretest and twice following presentation of homogeneous sets of three arguments which advocated either a risky or a cautious position. The risk-as-value, relevant arguments, and conformity/attitude change hypotheses generated three separate predictions for the Ss' responses. Results mirrored the prediction of the relevant arguments hypothesis: New information, whether contained in cautious or risky arguments, caused a shift toward the type of argument presented. The risk as-value and the conformity/attitude change hypotheses could not explain the present data. PMID- 21287057 TI - Detection and identification of words and letters in simulated visual search of word lists. AB - Ss were shown a rapid sequence of words and had to (a) make a speeded response to the presentation of a predefined target and (b) report a "response word" which they thought immediately followed the target in the sequence. In Experiment I presentation rate was varied orthogonally with the number of alternative targets. Detection errors and latency increased with target set size, as did the distance of the response word from the target in the list sequence. Increases in presentation rate produced greater target-response distance without affecting detection time. In Experiment II Ss were in some conditions given only the initial letter of the targets; the response could be either the whole word following the target or only its initial letter. The results indicated that Ss could, within limits, concurrently detect initial letters and identify words. Alternatives to hierarchical-type models of stimulus processing in visual search were discussed. PMID- 21287058 TI - Persistence of the effects of choice on paired-associate learning. AB - Four experiments are reported in which half of the subjects were permitted to choose either the stimulus or response members of S-R pairs from groupings of alternative stimuli or responses following the procedures of Perlmuter, Monty, and Kimble. The other subjects were exposed to the materials and were forced to learn the material chosen by their yoked partners. Approximately 24 h later, both groups learned PA lists comprised of either the chosen or forced material. Choosing either the stimulus or the response facilitated performance irrespective of whether the other member of the S-R pair was present at the time of choosing. This finding ruled out an associative hookup interpretation in favor of a purely motivational hypothesis and demonstrated the temporal durability of the effect of choosing. PMID- 21287059 TI - Reading and visual search. AB - Four experiments were conducted comparing the ways in which reading and search are affected by manipulations of word shape and word boundary. Word shape was manipulated by variations in type (normal, capitals, and alternating upper- and lowercase), while word boundary was manipulated by variations in spacing (normal, filled, and absent). The variations were combined factorially for nine space-type combinations. Experiments I and II were basic studies examining the effects of the manipulations on reading and on search, respectively. Search was found to be 2 to 2.5 times faster than reading. Reading and search both slowed to one-third of the normal speeds when spaces were removed and type altered. A significant interaction of Type by Space was found for reading but not for search. Experiments III and IV examined contextual and typographical effects on high speed visual search through paragraphs. Form-class expectancy and target word predictability, respectively, were manipulated. In both experiments, subjects found the expected predictable words faster than the unexpected unpredictable words. The data were interpreted as providing support for the peripheral and cognitive search guidance processes hypothesized to be active in reading. PMID- 21287060 TI - Interitem encoding and directed search in free recall. AB - The paper proposes a cognitive structure consistent with principles of encoding and a rule for its utilization in verbal recall. The encoding and utilization rules lead to phenomena similar to known serial position effects. A detailed analysis of overt rehearsal data and other experimental results are presented in support of the claim that encoding and search mechanisms characterized by these rules could be important factors in serial position effects of verbal recall. Similar rules might be helpful in dealing with other tasks which seem to mirror the utilization of a cognitive structure. PMID- 21287061 TI - Structural and transient components of memory. AB - The decomposition of free recall serial position curves into permanent and transient components (primary and secondary memory, Waugh & Norman, 1965) is widely accepted. In this paper, a hypothesis is proposed directly relating the permanent memory component to a vector quantity which reflects sequential allocation of attention during encoding. In conjunction with a previously published model for encoding and retrieval in free recall (Hogan, 1975), the hypothesis is shown to break down predicted serial position curves into permanent and transient components, in a manner analogous to but in various ways less restrictive than the decomposition proposed by Waugh and Norman. PMID- 21287062 TI - Comprehension and memory for pictures. AB - The thesis advanced is that people remember nonsensical pictures much better if they comprehend what they are about. Two experiments supported this thesis. In the first, nonsensical "droodles" were studied by subjects with or without an accompanying verbal interpretation of the pictures. Free recall was much better for subjects receiving the interpretation during study. Also, a later recognition test showed that subjects receiving the interpretation rated as more similar to the original picture a distractor which was close to the prototype of the interpreted category. In Experiment II, subjects studied pairs of nonsensical pictures, with or without a linking interpretation provided. Subjects who heard a phrase identifying and interrelating the pictures of a pair showed greater associative recall and matching than subjects who received no interpretation. The results suggest that memory is aided whenever contextual cues arouse appropriate schemata into which the material to be learned can be fitted. PMID- 21287063 TI - Simultaneous processing of verbal and spatial information. AB - Two experiments investigated the generality of the selective interference phenomenon by studying several different concurrent tasks, each involving either verbal or spatial information, and a range of retention intervals from 10 to 30 sec. The results supported the selective interference predictions, since the interference in performance was greater when the two simultaneous tasks both involved either verbal information or spatial information than when one of the tasks involved verbal and the other spatial information. It was concluded that not only was the selective interference phenomenon a rather general effect but that, since it was unaffected by changes in the nature of the component tasks, it was also probably caused by central processing capacity limitations rather than by competition for a specific structural mechanism. PMID- 21287064 TI - Coding strategies, perceptual grouping, and the "variability effect" in free recall. AB - Three experiments examined the effects of constant vs. varied input of letter strings on recall, and then examined the effects of such training in the learning of new lists of letter strings. Letter strings were constructed from pairs of trigrams spatially grouped, and were presented either consistently or with different spatial groupings on successive presentations. In Experiments I and II, varied input produced substantially greater recall than constant input. When transferred to a new list of letter strings, containing either the same general structure or a new scrambled structure, recall of the second list was determined primarily by conditions of first-list input, and unaffected by second-list structure. Although the "variability effect" did not appear in the training phase of Experiment III, Varied input led subjects to regroup or integrate the letter sequences more frequently and produced similar transfer effects as in Experiments I and II. PMID- 21287065 TI - Can subjects maintain a constant criterion in a memory task? AB - In two recognition memory experiments, subjects rated how certain they were that a given test item had been shown previously. Subjects either received standard instructions about their rating criteria or were explicitly instructed to maintain criteria defined in the manner of Healy and Jones (1973) or along the lines of signal detection theory. When a priori probability varied, subjects in all instruction groups held constant the criteria defined by signal detection theory at the expense of shifting the criteria proposed by Healy and Jones. The results were taken as evidence for the psychological validity of recognition memory analyses based on signal detection theory. PMID- 21287066 TI - Sensory features and the reduction of imaginal interference. AB - Interference generated among the sensory features of PA stimulus words is not eliminated by processing at the imaginal level. This experiment was planned to test the reverse possibility. Will interference generated by similar imaginal referents be eliminated by sensory overlap between the stimuli and their responses? Thus, stimulus words did or did not evoke similar images, pairs did or did not share initial letters, and lists were acquired either under an instructional set t o form interacting images or to repeat the items aloud. The results indicated that the imagery strategy was superior to the repetition strategy in all conditions, and that stimulus interference was statistically eliminated when pairs shared the same initial letters. The findings were interpreted as consistent with a levels of processing conceptualization. PMID- 21287067 TI - Spatial coding of auditory signals. AB - Sequences of nine binary auditory signals (dots and dashes) were presented to 20 subjects in Experiment I. The subjects were instructed to internally organize the signals into two-dimensional arrays. Visual patterns (letters) could be recognized in these imaginary arrays in both upright and rotated orientations. In Experiment II, a group of nine subjects, which was instructed to use spatial imagery of this kind, reproduced significantly longer sequences of signals than nine control subjects. By means of internal spatial organization, experimental subjects were able to reproduce sequences up to 45 signals in length, whereas control subjects recalled near the chance level for portions of sequences longer than nine signals. Three levels of information processing were postulated to account for the results, with spatial organization occupying a mediating level between acoustic and verbal levels. PMID- 21287068 TI - Physical features vs meaning: A difference in decay. AB - The encoding of either physical or semantic features of words was biased in an intentional learning situation. A modified recognition test was then employed to assess the effectiveness of this study manipulation and its consequences for retention. The Ss were required to select test items that were either physically similar, semantically similar, or identical to a study word. Results revealed that Ss biased toward physical encoding were more successful in selecting physically similar than semantically similar test items, while the opposite was true of Ss biased toward semantic encoding. The Ss in the two study conditions did not differ in their ability to select test items that were identical to a study word. This pattern of results was interpreted as evidence that semantic and physical information can be equally well retained over the long term. Limits on the generality of prior findings of rapid decay for physical information are discussed. PMID- 21287069 TI - Individual and sex differences in reminiscence. AB - Inverted alphabet printing, rotary pursuit, and mirror tracking tasks were administered to 84 subjects in order to ascertain (a) reproducibility of reminiscence scores within and between tasks and (b)sex differences in reminiscence. With prerest performance levels held constant by second-order partial correlation procedures, reproducibility of individual reminiscence differences within tasks was significant but quite low, while predictability of reminiscence from one task to another was negligible. The sexes reminisced essentially alike on inverted alphabet printing, but females reminisced more than males on the other tasks, presumably because they were relatively more depressed by massed practice on these tasks. Thus, individual and sex differences were essentially task specific. Implications of results for reminiscence theories and for the credibility of alleged relationships between reminiscence and other organismic variables were discussed. PMID- 21287070 TI - Individual differences in the verbal coding of familiar visual stimuli. AB - Two experiments were performed both of which involved the same-different comparison of pairs of alphabet letters. "Same" reaction times were obtained for both physical matches (e.g., AA) and name matches (e.g., aA). The results of both experiments supported the hypothesis that individual subjects would differ with respect to whether or not they based their physical matches on a comparison of verbal codes. In Experiment I, subjects differed in the size of their reaction time difference between physical and name matches, and in Experiment II, individuals differed with respect to whether or not the frequency of usage of the letters affected their reaction time for physical matches. In both experiments, the individual differences in verbally coding physical matches were related to Hock's (1973) individual differences distinction between subjects emphasizing analytic processes and subjects emphasizing structural processes. PMID- 21287071 TI - Facilitation by repetition in recognition memory for tonal pitch. AB - Subjects made delayed pitch comparisons when the standard and comparison tones were separated by a sequence of interpolated tones. In some conditions, a tone of the same pitch as the standard tone was included among the interpolated tones. Recognition performance was superior for sequences where the standard tone pitch was repeated, even compared with control sequences of reduced size. The improvement in performance produced by the repeated tone depended on its position in the intervening sequence. Improvement was substantial and highly significant when the standard tone pitch was repeated in the second serial position of a sequence of six interpolated tones, but small and insignificant when it was repeated in the fifth serial position. PMID- 21287072 TI - An eye fixation analysis of multialternative choice. AB - Eye fixations were recorded while subjects chose their most preferred of six used cars. Fixation sequences of the form X-Y-X-... were used to identify pair comparisons. This assumption was validated by verbal protocols and by a comparison between X-Y-X and X-Y-X-Y-... patterns. The results of three experiments showed: (1) that the multialternative choice process was composed primarily of pair comparisons; (2) that evaluative processing took placeonly during these comparisons; (3) that strategies for selecting the pairs were based primarily on information processing convenience; (4) that the sequence of pair comparisons was not used by the subjects as a sequential elimination process; and (5)that subjects changed their strategies to adapt to different task environments. These results have implications for current choice models and for the use of eye fixations in other complex tasks. PMID- 21287073 TI - Skin conductance response conditioning with CS intensities equal to and greater than UCS intensity. AB - With .2-sec bursts of white noise as both conditioned stimulus (CS) and unconditioned stimulus (UCS), conditioning of first-interval skin conductance responses was obtained when the intensity of the CS equaled and exceeded that of the UCS. There was no evidence that second-interval response conditioning occurred. Nonspecific response frequencies were also affected by the variations in stimulus intensity, this raising some question about typical controls employed in SCR conditioning. There was some evidence that second interval responses were suppressed by the intense CS values. It was concluded that the existence of simple conditioning with a CS/UCS intensity ratio equal to or greater than unity was contrary to the Pavlovian proposition that a CS must be biologically less salient than the UCS in order for conditioning to occur. It was noted, however, that the suppression of second-interval responses might indicate that anticipatory CRs which are not confounded with orienting reflexes are prevented from exhibiting a conditioning effect when a high CS/UCS intensity ratio is employed. PMID- 21287074 TI - Encoding variability and the concreteness effect in paired-associate learning. AB - In an attempt to explain the concreteness effect in PA learning, encoding variability (as measured by contextual variety) was manipulated factorially on the stimulus and response sides within abstract and within concrete noun pairs. The results showed a strong concreteness effect, with increasing encoding variability having no effect on the stimulus side, and a direct positive effect on the response side. The applicability of these results to the encoding variability hypothesis was discussed. PMID- 21287075 TI - What causes the spacing effect? Some effects of repetition, duration, and spacing on memory for pictures. AB - Three experiments examined effects of the spacing of repetitions on memory for pictures. In Experiment I, the duration of the first presentation (P(1)) was manipulated, as was P(1)-P(2) spacing. The effect of spacing on judged frequency was independent of P(1) duration. In Experiment II, pictures were given M massed presentations just prior to the P(M)-P(M+1) spacing interval. The form of the spacing curve was independent of M. Neither experiment confirmed the prediction of "overhabituation," derived from the habituation-recovery explanation of the spacing effect. In Experiment III, subjects made both duration and frequency judgments. The duration judgment results were not consistent with the notion that subjects remember multiple massed presentations as single occurrences of especially long duration. Some evidence from Experiments I and III suggests that an interrupted stimulus is recognized better than one that is not interrupted-a finding that, if replicable, would support the habituation-recovery account of the spacing effect. PMID- 21287076 TI - Some functional properties of iconic storage in retarded and nonretarded subjects. AB - Four experiments, which examine some functional properties of iconic storage in mildly retarded subjects, are reported. Experiments I and III demonstrated that retardates report about three items, or one item less than normal subjects, after a single brief tachistoscopic exposure and that this span of attention was independent of size of array. Both normal and retarded groups reported more items correctly when arrays were arranged on two lines. Experiment II determined that exposure durations up to 250 msec did not influence the number of items reported by either group. Experiment IV compared the form of decay for both groups by cuing report of each of seven positions at five poststimulus delays. The presence of the typical W-shaped curve for both groups at all delays permitted the inference that items in iconic storage decay together rather than individually. Although quantitative differences existed between groups, in no case did intelligence interact with the manipulated variables. The results were discussed in relation to control processes and structural features within an information processing model of memory. PMID- 21287077 TI - Locus of the effect of a distinguishing feature in a memory search task. AB - Subjects memorized one to four 8- or 16-sided random forms in a memory search task. The positive set forms ("yes" response) differed in number of sides from the negative set forms ("no" response) for the different set (DS) group, but this distinguishing feature was not available to the same set (SS) group. Mean reaction time increased as a linear function of log(2) of the positive set size for both groups, but the increase was greater for the SS than the DS group, suggesting that memory search rather than an encoding stage of information processing was influenced by the availability of a distinguishing feature. In a transfer task which followed, new forms were introduced in which the positive and negative set forms differed in number of sides for both groups. In this task, the two groups did not differ in memory search, but in encoding. It was proposed that (a) availability of a distinguishing feature influences search time because the information specifying the number of sides of the set of memorized forms can be used to influence the speed with which individual forms are examined in memory; (b) previous experience with a distinguishing feature influences encoding because the DS group had learned to extract the information specifying the set of memorized forms (not the information specifying individual forms) more efficiently than the SS group. PMID- 21287078 TI - Contingent associations and the double-function, verbal-discrimination task. AB - Three experiments examined the role of contingent associations in learning double function, verbal-discrimination lists. Some 15-pair lists of category instances were constructed in such a way that the learning of three contingent associations based on category names would mediate correct performance for all 15 pairs. The first experiment gave no evidence that the three contingencies aided learning. The second experiment showed that subjects could be taught the three contingent associations in isolation and that they could then apply them successfully to the double-function list. To make the contingencies more apparent to the subjects, the category names were used during feedback in the third experiment. The learning was not facilitated by such feedback. It was concluded that the learning observed for the usual double-function list does not involve contingent associations. PMID- 21287079 TI - Recall of logical and pragmatic implications in sentences with dichotomous and continuous antonyms. AB - Thirty-six subjects recalled sentences containing dichotomous or continuous antonyms in affirmative or negative form. The subjects made a considerable number of meaning-preserving recall errors for both dichotomous antonyms (not alive recalled asdead) and continuous antonyms (not hot recalled ascold). The negation of a dichotomous antonym logically implies its antonym, whereas the negation of a continuous antonym only pragmatically implies its antonym. Thus, the results suggest that subjects hearing sentences containing a logical or pragmatic implication tend to make the logical or pragmatic inference involved. Then, in recall, they do not remember that this was an inference and make the error of recalling the logical or pragmatic implication in place of the presented sentence. PMID- 21287080 TI - The attentional demands of negation in a memory-scanning task. AB - Subjects were run in a Sternberg recognition memory task modified to occasionally require a transformation prior to response. The transformation was similar to logical negation since onplus or nontransformed trials subjects responded "yes" if the probe was from the current memory set and "no" otherwise, while onminus or transformed trials subjects responded "no" to memory set probes and "yes" to nonmemory set probes. Two models proposed to account for the effects of logical negation were compared: The encoding and comparison model predicts that logical negation requires an additional processing stage, while the capacity sharing model argues that negation adds a processing stage and also retards the rate of memory search. The results indicated that minus probes had 50% larger mean reaction time by set size slopes than the corresponding plus probes. This finding offers clear support for the capacity sharing model. PMID- 21287081 TI - How do children form impressions of persons? They average. AB - The experiment reported was concerned with impression formation in children. Twelve subjects in each of Grades K, 2, 4, and 6 rated several sets of single trait words and trait pairs. The response scale consisted of a graded series of seven schematic faces which ranged from a deep frown to a happy smile. A basic question was whether children use an orderly integration rule in forming impressions of trait pairs. The answer was clear. At all grade levels a simple averaging model adequately accounted for pair ratings. A second question concerned how children resolve semantic inconsistencies. Responses to two highly inconsistent trait pairs suggested that subjects responded in the same fashion, essentially averaging the two traits in a pair. Overall, the data strongly supported an averaging model, and indicated that impression formation of children is similar to previous results obtained from adults. PMID- 21287082 TI - Spatial direction and grammatical form of instructions affect the solution of spatial problems. AB - One hundred and forty-eight undergraduate women were orally instructed to repeatedly and quickly draw circles in spatial relation to squares printed on sheets of paper. On each trial, the instructions required the circle to be drawn either above, below, to the right of, or to the left of the square. The instructions were expressed so that the circle was either the logical subject (e.g., "circle above square") or the logical object (e.g., "square below circle") of the statement. Each subject received all experimental conditions for a total of 24 separate drawings per subject. Analysis of variance of the total number of errors disclosed significant effects of all experimental variables. Performance was significantly more accurate when the circle was the logical subject, when the orientations were "above" and "right of" rather than "below" and "left of" and for the vertical dimension. The results are discussed in terms of current theories on "asymmetries" in information processing. PMID- 21287083 TI - The associative learning of the deaf: The effects of word imagery and signability. AB - In two experiments, deaf and hearing subjects learned paired associate lists in which rated visual imagery and signability (a measure of the ease with which a word can be represented as a gestural sign) were orthogonally varied. Visual presentation of three alternating study-recall trials resulted in significant positive effects of imagery for both deaf and hearing subjects, whereas signability facilitated recall only for deaf subjects. Examination of the relation between item attributes and reported learning strategy indicated that both deaf and hearing subjects used imaginal mediators more frequently for high imagery than low-imagery pairs. A gestural sign strategy was reported almost exclusively by deaf subjects, particularly for high-signability pairs. These results suggest that an examination of the effects of sign language variables will contribute to an understanding of the qualitative differences in the associative learning of the deaf and hearing. PMID- 21287084 TI - Retrieval in cued recall. AB - Three experiments examined retrieval in a cued recall paradigm by manipulating the pattern of output cues. In the first two experiments, subjects were paced through recall of a categorized list by recalling one word at a time in response to a category name as a retrieval cue. The pattern of these output cues exerted a strong influence on performance. Subjects recalled considerably more when the cues were blocked by category than when required to recall successive words from different categories. This output effect increased over trials, and was interpreted in terms of a model in which subjects develop a retrieval strategy that can be interfered with by the circumstances of output. The last experiment contrasted structural and strategy models in a hierarchical recall paradigm. Subjects were given a set of postinput recall cues that either made evident the hierarchical structure of the input list or contained the same cue words but with no hierarchical information. Information about the hierarchical structure improved performance even when provided only during recall. The data were discuss in terms of recent models of recall, and a compromise was suggested. PMID- 21287085 TI - Effect of meaningfulness on judgments of computability. AB - The University of Michigan, Ann Arbor, Michigan 48104 After memorizing a set. of four equations, subjects were given problem frames specifying an unknown variable and two, three, or four given variables. The task on each item was to judge whether the presented variables corresponded to a problem that could be computed. (No values were given and no computation was carried out.) The main finding was a strong interaction: With formulas consisting of uninterpreted letters, judgments of uncomputable items were much slower than judgments of computable items; however, the difference between positive and negative items was much smaller when formulas consisted of meaningful concepts. Attempts to remove the interaction by presenting the nonsense formulas as an integrated network or by using a format allowing easy chunking of the variables in each formula did not succeed. At this point it appears most promising to investigate effects of meaningfulness on basic component processes, such as decisions about whether pairs of items come from the same formula. PMID- 21287086 TI - Effects of meaningfulness and organization on problem solving and computability judgments. AB - When subjects were required to calculate answers for computable problems and answer questions, an interaction was found corresponding to that obtained by Kieras and Greeno (1975) from judgments of computability. With nonsense formulas, much longer times were required to identify noncomputable problems than to compute answers, with a much smaller difference when formulas consisted of meaningful concepts. The better performance on noncomputable problems and questions with meaningful formulas corroborates an interpretation that those items test the connection of algorithms with general conceptual knowledge. Finally, it was found that for relatively complex problems, solution times and time to judge computability were longer if nonsense formulas were learned in separate sets than if they were learned in a single set; however, no such effect was found with meaningful formulas. It was concluded that learning conditions influenced the integration of cognitive structure in the case of nonsense formulas, while subjects were able to adjust organization of the meaningful formulas. PMID- 21287087 TI - Effects of task success or failure on causal attributions and person perception. AB - An actor's outcome on a task (success-failure) was manipulated orthogonally to information that the actor either used or did not use drugs. Casual attributions for success-failure were obtained as well as trait ratings of the actor. Subjects read a case study of an artist who either succeeded or failed in his profession. For half of the subjects, the artist was described as using hard drugs, and no mention of drugs was made for. the other half. It was predicted and confirmed that success-failure interacted with drugs-no drugs in determining attributions of ability. It was also found, as expected, that success was attributed to ability and motivation more than was failure. Further, success tended to be internally attributed to the actor, while failure was externally attributed. The interaction obtained for ability attribution was not obtained for a measure of trying, nor for the trait ratings. The results confirmed Kepka and Brickman's (1971) suggestion that ability and motivation are qualitatively different concepts in naive psychology, but some of their specific conclusions are questioned. PMID- 21287088 TI - The effect of reference field organization on language processing. AB - Memorial University of Newfoundland, St. John's, Newfoundland, Canada Subjects were exposed to a miniature artificial language in which auditorily presented nonsense words were correlated to a visually presented reference field. Both the organization of the reference field and the order of words were manipulated to test whether subjects were encoding on the basis of an English-based semantic code or a code based on the nonverbal reference field. Results indicated that the code used was based on the organization of the nonverbal reference field. PMID- 21287089 TI - Evaluative judgments are based on evaluative information: Evidence against meaning change in evaluative context effects. AB - Trait adjectives commonly employed in person perception studies have both evaluative and denotative meanings. Evaluative ratings of single traits shift with variations in the context of other traits ascribed to the stimulus person; the extent to which denotative changes underlie these evaluative context effects has been a theoretical controversy. In the first experiment, it was shown that context effects on quantitative ratings of denotation can be largely accounted for by evaluative halo effects. In the second experiment, increasing the denotative relatedness of context traits to the test trait didnot increase the effect of the context. Only the evaluative meaning of the context affected evaluation of the rated test trait. These studies suggest that the denotative relationship between a test adjective and its context has little influence on context effects in person perception, and that denotative meaning changes do not mediate context effects. Instead, evaluative judgments appear to be based on evaluative meaning. PMID- 21287090 TI - Visual and semantic factors in recognition from long-term memory. AB - In recognition tests, physical and semantic relationships between targets and distractors have been shown, in separate manipulations, to affect the latency of subject's decision. Recognition was tested for distractors which were visually similar or dissimilar to targets and which belonged to the target categories or to nontarget categories in order to examine the interaction of these dimensions. Rejection latency was longer for target category than for nontarget category distractors. Latency was also longer for visually similar than visually dissimilar distractors, but only when combined with target category probes. This interaction can be explained by the hypothesis that word recognition depends on the analysis of several dimensions of the probe stimulus, and rejection can occur before all such analyses have been completed. PMID- 21287091 TI - Alcoholic intoxication and memory storage dynamics. AB - Strength retention functions were obtained for English words from 2 min to 50 min within a continuous recognition memory session and from I to 14 days subsequent to the session, with subjects being sober or moderately intoxicated. A small, but significant, decrement was obtained in memory performance under alcoholic intoxication. However, there was no difference in forgetting rate either within the continuous session or over the subsequent 1- to 14-day period. Single-trace fragility theory provided an excellent fit to the data. The entire effect of alcoholic intoxication was on degree of learning with no effect on the form of the retention function or rate of forgetting. No state-dependent retrieval effects were obtained. White noise during learning and/or retrieval had no effect on acquisition, storage, or retrrieval. PMID- 21287092 TI - The effect of constant vs. varied encoding and massed vs. distributed presentations on recall of paired associates. AB - The variables of coding (constant vs. varied) and spacing (massed vs. distributed) were factorially combined in an independent-groups design. Sixteen nominal pairs were presented twice, with the two presentations being either massed or distributed. A given nominal pair (e.g., AR-LE) was accompanied either by the same word-pair code on both presentations (e.g.,arm-leg) or by a different code on each presentation (e.g.,arm-leg; arrive-leave). On a subsequent recall test, the nominal stimulus only was shown. Better recall of the nominal response was found after constant coding and after distributed presentations, and there was no interaction between the spacing and coding variables. The results (a) support none of the current proposed explanations for the distributed practice effect, and (b) suggest that the critical factor in determining the probability of response recall is the strength of the strongest potential route to the response, not the number of different routes. This research was supported by a grant from the Graduate School of the University of Wisconsin. PMID- 21287093 TI - Queer sentences, ambiguity, and levels of processing. AB - Subjects judged linguistic strings "meaningful" or "meaningless." Meaningful sentences were identical for all subjects; however, for each of five groups, meaningless foils containing different kinds of linguistic violation were interspersed among the meaningful sentences. Type of foil influenced processing time for meaningful items, suggesting that laboratory language processing may be determined by the entire set of linguistic materials used. Effect of foil type on comprehension depth for meaningful items was assessed from the extent to which three kinds of ambiguity slowed judgments on those items as compared to unambiguous sentences. Foil type appears to affect depth of meaningful sentence processing in such a way as to support a "levels of analysis" view of sentence comprehension. Foil type and kind of ambiguity interacted to suggest that sentence comprehension requires computation of underlying logical relationships prior to computation of surface structural relationships and the unequivocal determination of word meanings. PMID- 21287094 TI - The effect of directed forgetting on the time to remember. AB - A recognition memory task was used to determine whether the search set is reduced by cueing subject to forget a part of the input. Correct recognition reaction time was used to infer the size of the search set. The principal results were that RT on forget trials was faster than RT on remember trials and that RT was fastest when the forget cue was presented at the outset of the trial rather than after the material had been presented. These findings are generally consistent with the hypothesis that selective search is responsible for the enhancement of recall produced by forget instructions in earlier studies. PMID- 21287095 TI - Implicit associational responses produced by words in pairs of unrelated words. AB - The purpose of this study was to determine if implicit associational responses (IARs) occur to individual words presented as pairs for associative learning. The occurrence of IARs was determined by a YES-NO recognition test, and IARs for words presented singly for study provided a base line. For all conditions, false recognitions to assumed IARs occurred; the magnitude was equivalent for words presented for study as pairs as for the same words presented singly. No evidence was found that IARs occurred during the testing phase. PMID- 21287096 TI - Semantic memory for metaphor: The conceptual base hypothesis. AB - The idea that people can encode and use an extremely abstract and general form of a complex linguistic (proverb) input-a conceptual base-was examined in two experiments. In Experiment I, each proverb was accompanied by either a conceptually related (good, mediocre, or poor) or an unrelated interpretation. The related interpretations were more effective recall prompts than were the unrelated interpretations, but only for high-imagery proverbs. In Experiment II, subjects wrote interpretations of the proverbs and then received either the proverb subject-noun or a brief story as a prompt. As was the case for the interpretations in Experiment I, the stories did not share any major vocabulary or propositional structure with their proverb source. Nonetheless, the stories were as effective as the nouns. Also, quality of proverb interpretation and of recall performance were positively related, with the correlations involving low imagery proverbs, and stories, tending to be higher. Both experiments provided support for the conceptual-base notion, and underlined the importance of interpretive context, but more definitive evidence is needed. PMID- 21287097 TI - Parallel scanning of auditory and visual information. AB - Two experiments involving memory retrieval of auditorilv and visually presented materials were performed. In Experiment I, subjects were presented with memory sets of 1, 2, or 4 stimuli and then with a test item to be classified as belonging or not belonging to the memory set. In Condition 1, each memory stimulus was a single, auditorily presented letter. In Condition 2, each memory stimulus was a visually presented letter. In Conditions 3 and 4, each memory stimulus was a pair of letters, one presented visually and the other auditorily. Mean reaction time (RT) for the classification task increased as a function of number of memory stimuli at equal rates for all four conditions. This was interpreted as evidence for a parallel scanning process in Conditions 3 and 4 where the auditory item and visual item of each memory stimulus pair can be scanned simultaneously. Experiment II compared memory retrieval for a simultaneous condition in which auditory and visual memory items were presented as pairs with a sequential condition in which mixed auditory-visual memory sets were presented one item at a time. RTs were shorter for the simultaneous condition. This was interpreted as evidence that parallel scanning may depend upon memory input parameters. PMID- 21287098 TI - The effects on induced passive rehearsal and the von Restorff phenomenon on the free recall of normals and retardates. AB - Noninstitutionalized retardates and normal children of equal mental age (approximately 8 years) listened to 11 orders of 20 nouns with no instructions to overtly or covertly rehearse. All subjects were in each of three list conditions: (a) when all words were at the same decibel (dB) level, (b) when the 11th item was at a higher dB level, and (c) when the items were repeated at the same dB level using the rehearsal protocol of Rundus (1971). The normals' overall recall was superior to that of the retardates' recall. Repetition of items had no effect on the performance of either group except in the recency portion of the learning curve and on the initial trial for both groups and the fifth trial for the retarded group. The normal group was more susceptible to the yon Restorff effect than was the retarded group. These results were discussed in terms of the changing and different recall strategies of the two groups. PMID- 21287099 TI - The effects of visual presentation method on single-trial free recall. AB - In two experiments four different conditions of visual presentation were studied with the purpose of furthering our understanding of the role of temporal and spatial factors underlying modality effects in single-trial free recall. Enriching spatial factors in the visual presentation did not produce a higher performance in the recency part of the serial-position curve, and it was therefore concluded that the modality effect could not be due to any visual handicap. A lag distribution measure was suggested and applied to the data to characterize output order (the order of recall) in single-trial free recall. The two experiments carried out used a within-subjects and a between-subjects design, respectively, and illustrate the importance of the methodological difference between these two designs. PMID- 21287100 TI - Simplicity, symmetry, and syntely: Stimulus measures of binary pattern structure. AB - A simple parameter free algorithm based solely on the sequential run and alternation structure of binary sequences is elaborated. The algorithm is designed to measure the sequence's syntely: the degree to which past consequences within a sequence converge on the continuation of that sequence's terminal run. This syntely algorithm is shown to predict subjects' expectancies in a sequential prediction task using short binary sequences. Other algorithms measuring the symmetry and simplicity of short binary patterns are demonstrated, and their measures shown to be correlated with each other, but not correlated with syntely. Goodness and strength of expectancy are unrelated. The syntely algorithm is shown to be successful in predicting the error profiles of subjects learning short recurrent patterns of binary sequences. The syntely algorithm is based on the straightforward principle of induction by enumeration: the composite of past events controls the expectancy of future events. The success of this algorithm, even though it may embody the principle of induction only imperfectly, provides good evidence that this principle is a useful normative grade for understanding the human processing of contingencies in binary sequences, making complicated schemes of rules and hypotheses unnecessary. PMID- 21287101 TI - Linguistic influences on visual memory. AB - The Whorf-Sapir hypothesis has raised considerable controversy in the literatures of psychology and anthropology. Several misconceptions of the hypothesis are reviewed, and the hypothesis was experimentally supported in a visual reproduction paradigm. Subjects were first given label training for a set of figures, and were then asked to recall by drawing the shapes. Training with categorized labels resulted in a 25% improvement in recall when compared to a condition with nonword (paralog) labels. Even stronger evidence of linguistic influence on visual memory was obtained by examining the order of recall. The conceptual relationships among labels strongly influenced the sequence of reproductions. PMID- 21287102 TI - Encoding processes and the spacing effect. AB - The differential encoding theory of the spacing effect was tested utilizing Martin's (1968) encoding variability notion, in which it is hypothesized that low meaningfulness items are more variable in their encodings than are high meaningfulness items. In a series of three experiments using a continuous paired associate learning task, it was predicted that the spacing vs. performance curves for CCC items would show a faster improvement in performance than would the curves for high-meaningfulness CVC items. None of the experiments supported this prediction. In addition, it was found that items recognized on their second presentation were more likely to be recalled than were those items not recognized. It was concluded that an item's repetitions are more effective if one code is formed and elaborated with each repetition rather than if more than one code is formed. PMID- 21287103 TI - Memory for ideas: Synonym substitution. AB - Subjects memorized sentences that contained a word with a synonym in English. There were large numbers of synonym substitution responses in recall (varying from 6.0% in Experiment I to 27.7% in Experiment III). Synonym substitution responses tended to be unidirectional and occurred with roughly equal frequency in abstract and concrete sentences. The results were interpreted as opposed to surface structure theories of sentence memory, since explanation in terms of word associations and sequential dependencies proved unsuccessful. The results were also taken to be opposed to image theories of sentence memory, since image theories predict few ff any synonym substitution responses for abstract sentences, while Experiment III found large numbers of synonym substitutions in both abstract and concrete sentences. The results support the position that memory for sentences is in terms of nonlinguistic, nonimage, abstract representations (ideas). PMID- 21287104 TI - FIRE: an SPSS program for variable selection in multiple linear regression analysis via the relative importance of predictors. AB - We provide an SPSS program that implements currently recommended techniques and recent developments for selecting variables in multiple linear regression analysis via the relative importance of predictors. The approach consists of: (1) optimally splitting the data for cross-validation, (2) selecting the final set of predictors to be retained in the equation regression, and (3) assessing the behavior of the chosen model using standard indices and procedures. The SPSS syntax, a short manual, and data files related to this article are available as supplemental materials from brm.psychonomic-journals.org/content/supplemental. PMID- 21287105 TI - Contextual self-organizing map: software for constructing semantic representations. AB - In this article, we introduce a software package that applies a corpus-based algorithm to derive semantic representations of words. The algorithm relies on analyses of contextual information extracted from a text corpus--specifically, analyses of word co-occurrences in a large-scale electronic database of text. Here, a target word is represented as the combination of the average of all words preceding the target and all words following it in a text corpus. The semantic representation of the target words can be further processed by a self-organizing map (SOM; Kohonen, Self-organizing maps, 2001), an unsupervised neural network model that provides efficient data extraction and representation. Due to its topography-preserving features, the SOM projects the statistical structure of the context onto a 2-D space, such that words with similar meanings cluster together, forming groups that correspond to lexically meaningful categories. Such a representation system has its applications in a variety of contexts, including computational modeling of language acquisition and processing. In this report, we present specific examples from two languages (English and Chinese) to demonstrate how the method is applied to extract the semantic representations of words. PMID- 21287106 TI - Analysing playing using the note-time playing path. AB - This article introduces a new method of data analysis that represents the playing of written music as a graph. The method, inspired by Miklaszewski, charts low level note timings from a sound recording of a single-line instrument using high precision audio-to-MIDI conversion software. Note onset times of pitch sequences are then plotted against the score-predicted timings to produce a Note-Time Playing Path (NTPP). The score-predicted onset time of each sequentially performed note (horizontal axis) unfolds in performed time down the page (vertical axis). NTPPs provide a visualisation that shows (1) tempo variations, (2) repetitive practice behaviours, (3) segmenting of material, (4) precise note time positions, and (5) time spent on playing or not playing. The NTPP can provide significant new insights into behaviour and cognition of music performance and may also be used to complement established traditional approaches such as think-alouds, interviews, and video coding. PMID- 21287107 TI - Selecting the best unbalanced repeated measures model. AB - This study examined the performance of selection criteria available in the major statistical packages for both mean model and covariance structure. Unbalanced designs due to missing data involving both a moderate and large number of repeated measurements and varying total sample sizes were investigated. The study also investigated the impact of using different estimation strategies for information criteria, the impact of different adjustments for calculating the criteria, and the impact of different distribution shapes. Overall, we found that the ability of consistent criteria in any of the their examined forms to select the correct model was superior under simple covariance patterns than under complex covariance patterns, and vice versa for the efficient criteria. The simulation studies covered in this paper also revealed that, regardless of method of estimation used, the consistent criteria based on number of subjects were more effective than the consistent criteria based on total number of observations, and vice versa for the efficient criteria. Furthermore, results indicated that, given a dataset with missing values, the efficient criteria were more affected than the consistent criteria by the lack of normality. PMID- 21287108 TI - A validation of Amazon Mechanical Turk for the collection of acceptability judgments in linguistic theory. AB - Amazon's Mechanical Turk (AMT) is a Web application that provides instant access to thousands of potential participants for survey-based psychology experiments, such as the acceptability judgment task used extensively in syntactic theory. Because AMT is a Web-based system, syntacticians may worry that the move out of the experimenter-controlled environment of the laboratory and onto the user controlled environment of AMT could adversely affect the quality of the judgment data collected. This article reports a quantitative comparison of two identical acceptability judgment experiments, each with 176 participants (352 total): one conducted in the laboratory, and one conducted on AMT. Crucial indicators of data quality--such as participant rejection rates, statistical power, and the shape of the distributions of the judgments for each sentence type--are compared between the two samples. The results suggest that aside from slightly higher participant rejection rates, AMT data are almost indistinguishable from laboratory data. PMID- 21287109 TI - A sharp image or a sharp knife: norms for the modality-exclusivity of 774 concept property items. AB - According to recent embodied cognition theories, mental concepts are represented by modality-specific sensory-motor systems. Much of the evidence for modality specificity in conceptual processing comes from the property-verification task. When applying this and other tasks, it is important to select items based on their modality-exclusivity. We collected modality ratings for a set of 387 properties, each of which was paired with two different concepts, yielding a total of 774 concept-property items. For each item, participants rated the degree to which the property could be experienced through five perceptual modalities (vision, audition, touch, smell, and taste). Based on these ratings, we computed a measure of modality exclusivity, the degree to which a property is perceived exclusively through one sensory modality. In this paper, we briefly sketch the theoretical background of conceptual knowledge, discuss the use of the property verification task in cognitive research, provide our norms and statistics, and validate the norms in a memory experiment. We conclude that our norms are important for researchers studying modality-specific effects in conceptual processing. PMID- 21287110 TI - Computerized assessment of syntactic complexity in Alzheimer's disease: a case study of Iris Murdoch's writing. AB - Currently, the majority of investigations of linguistic manifestations of neurodegenerative disorders such as Alzheimer's disease are conducted based on manual linguistic analysis. Grammatical complexity is one of the language use characteristics sensitive to the effects of Alzheimer's disease and is difficult to operationalize and measure using manual approaches. In the current study, we demonstrate the application of computational linguistic methods to automate the analysis of grammatical complexity. We implemented the Computerized Linguistic Analysis System (CLAS) based on the Stanford syntactic parser (Klein and Manning, Pattern Recognition, 38(9), 1407-1419, 2005) for longitudinal analysis of changes in syntactic complexity in language affected by neurodegenerative disorders. We manually validated CLAS scoring and used it to analyze writings of Iris Murdoch, a renowned Irish author diagnosed with Alzheimer's disease. We found clear patterns of decline in grammatical complexity consistent with previous analyses of Murdoch's writing conducted by Garrard, Maloney, Hodges, and Patterson (Brain, 128(250-260, 2005). CLAS is a fully automated system that may be used to derive objective and reproducible measures of syntactic complexity in language production and can be particularly useful in longitudinal studies with large volumes of language samples. PMID- 21287111 TI - Assessing learning processes with the gain-loss model. AB - Within the framework of knowledge space theory, a probabilistic skill multimap model for assessing learning processes is proposed. The learning process of a student is modeled as a function of the interaction between his competence state and the effect of a learning object on specific skills. Model parameters are initial probabilities of the skills, effects of learning objects on gaining and losing the skills, careless error, and lucky guess probabilities of the problems. A simulation study assessed model identifiability and goodness-of-recovery under several conditions. Practical implications of using the model are discussed, and the MATLAB code for simulating, estimating and testing it is available in the Psychonomic Society supplemental archive. PMID- 21287112 TI - Measuring the meter: on the constancy of lightness scales seen against different backgrounds. AB - The constancy of a 16-step achromatic Munsell scale was tested with regards to background variations in two experiments. In experiment 1 three groups of observers were asked to find lightness matches for targets in simultaneous lightness displays by using a 16-step achromatic Munsell scale placed on a white, black, or white-black checkered background. In experiment 2, a yellow-blue checkered background and a green-red checkered background replaced Munsell scales on the black and on the white backgrounds. Significant effects of scale background on matches were found only in experiment 1, suggesting that background luminance is a crucial factor in the overall appearance of the scale. The lack of significant differences in experiment 2, however, may stand for an overall robustness of the scale with respect to background luminance changes occurring within certain luminance ranges. PMID- 21287113 TI - The masked priming toolbox: an open-source MATLAB toolbox for masked priming researchers. AB - The Masked Priming Toolbox is an open-source collection of MATLAB functions that utilizes the free third-party PsychToolbox-3 (PTB3: Brainard, Spatial Vision, 10, 433-436, 1997; Kleiner, Brainard & Pelli, Perception, 36, 2007; Pelli, Spatial Vision, 10, 437-442, 1997). It is designed to allow a researcher to run masked (and unmasked) priming experiments using a variety of response devices (including keyboards, graphics tablets and force transducers). Very little knowledge of MATLAB is required; experiments are generated by creating a text file with the required parameters, and raw and analyzed data are output to Excel (as well as MATLAB) files for further analysis. The toolbox implements a variety of stimuli for use as primes and targets, as well as a variety of masks. Timing, size, location, and orientation of stimuli are all parameterizable. The code is open source and made available on the Web under a Creative Commons License. PMID- 21287114 TI - ADPROCLUS: a graphical user interface for fitting additive profile clustering models to object by variable data matrices. AB - In many areas of psychology, one is interested in disclosing the underlying structural mechanisms that generated an object by variable data set. Often, based on theoretical or empirical arguments, it may be expected that these underlying mechanisms imply that the objects are grouped into clusters that are allowed to overlap (i.e., an object may belong to more than one cluster). In such cases, analyzing the data with Mirkin's additive profile clustering model may be appropriate. In this model: (1) each object may belong to no, one or several clusters, (2) there is a specific variable profile associated with each cluster, and (3) the scores of the objects on the variables can be reconstructed by adding the cluster-specific variable profiles of the clusters the object in question belongs to. Until now, however, no software program has been publicly available to perform an additive profile clustering analysis. For this purpose, in this article, the ADPROCLUS program, steered by a graphical user interface, is presented. We further illustrate its use by means of the analysis of a patient by symptom data matrix. PMID- 21287115 TI - Recording online processes in task-oriented reading with Read&Answer. AB - We present an application to study task-oriented reading processes called Read&Answer. The application mimics paper-and-pencil situations in which a reader interacts with one or more documents to perform a specific task, such as answering questions, writing an essay, or similar activities. Read&Answer presents documents and questions with a mask. The reader unmasks documents and questions so that only a piece of information is available at a time. This way the entire interaction between the reader and the documents on the task is recorded and can be analyzed. We describe Read&Answer and present its applications for research and assessment. Finally, we explain two studies that compare readers' performance on Read&Answer with students' reading times and comprehension levels on a paper-and-pencil task, and on a computer task recorded with eye-tracking. The use of Read&Answer produced similar comprehension scores, although it changed the pattern of reading times. PMID- 21287116 TI - Defining eye-fixation sequences across individuals and tasks: the Binocular Individual Threshold (BIT) algorithm. AB - We propose a new fully automated velocity-based algorithm to identify fixations from eye-movement records of both eyes, with individual-specific thresholds. The algorithm is based on robust minimum determinant covariance estimators (MDC) and control chart procedures, and is conceptually simple and computationally attractive. To determine fixations, it uses velocity thresholds based on the natural within-fixation variability of both eyes. It improves over existing approaches by automatically identifying fixation thresholds that are specific to (a) both eyes, (b) x- and y- directions, (c) tasks, and (d) individuals. We applied the proposed Binocular-Individual Threshold (BIT) algorithm to two large datasets collected on eye-trackers with different sampling frequencies, and compute descriptive statistics of fixations for larger samples of individuals across a variety of tasks, including reading, scene viewing, and search on supermarket shelves. Our analysis shows that there are considerable differences in the characteristics of fixations not only between these tasks, but also between individuals. PMID- 21287117 TI - Can computer mice be used as low-cost devices for the acquisition of planar human movement velocity signals? AB - The main goal of this work is to determine whether a computer mouse can be used as a low-cost device for the acquisition of two-dimensional human movement velocity signals in the context of psychophysical studies and biomedical applications. A comprehensive overview of the related literature is presented, and the problem of characterizing mouse movement acquisition is analyzed and discussed. Then, the quality of velocity signals acquired with this kind of device is measured on horizontal oscillatory movements by comparing the mouse data to the signals acquired simultaneously by a video motion tracking system and a digitizing tablet. A synthesis of the information gathered in this work indicates that the computer mouse can be used for the reliable acquisition of biosignals in the context of human movement studies, particularly for many applications dealing with the velocity of the end effector of the upper limb. This paper concludes by discussing the possibilities and limitations of such use. PMID- 21287118 TI - A computer-generated face database with ratings on realism, masculinity, race, and stereotypy. AB - Ratings of realism, masculinity, race, and racial stereotypy were collected on a set of computer-generated faces representing European, South East Asian, and African American ethnicities. To determine if these faces are processed in the same way as photographs of real faces, we demonstrated with these faces superior memory performance for upright faces over inverted faces (the face inversion effect). Further, in observers of European decent, we found both superior memory for European faces and a larger inversion effect for European than African American faces. Based on these results, we believe that this set of faces may be of use in perceptual investigations in which race is a critical manipulation. PMID- 21287119 TI - A set of semantic norms for German and Italian. AB - The psychological community frequently investigates semantic norms of properties produced by native speakers after being presented concept words, and these norms are of great value for a wide variety of psychological experiments. This paper presents a new set of norms that includes a collection of properties from a production experiment for the German and the Italian languages. Stimuli consisted of 50 concrete objects taken from 10 different concept classes. The data comprise annotations of semantic relation types and several statistical measures, which facilitate the comparison of the two target languages. PMID- 21287120 TI - Age of acquisition estimates for 1,208 ambiguous and polysemous words. AB - Age of acquisition (AoA) estimates are provided for 3,460 senses of 1,208 words (i.e., words with multiple meanings e.g., duck). The AoA rating estimates appear to be relatively consistent across participants. The Spearman-Brown split-half reliability coefficient is .95, while the correlations between each participant's ratings and the overall mean ratings yielded correlation coefficients between .325 to .794 with a mean of .69 (SD = .10). These estimates will be of use to those interested in: (a) the influence of AoA on word processing, (b) the influence of AoA on meaning access, (c) the structure of semantic memory, and (d) developmental trends in lexical ambiguity resolution. These AoA estimates can be downloaded from the Psychonomic Society's Web archive of norms, stimuli, and data at www.psychonomic.org/archive. PMID- 21287121 TI - Exploring media bias with semantic analysis tools: validation of the Contrast Analysis of Semantic Similarity (CASS). AB - Text-analytic methods have become increasingly popular in cognitive science for understanding differences in semantic structure between documents. However, such methods have not been widely used in other disciplines. With the aim of disseminating these approaches, we introduce a text-analytic technique (Contrast Analysis of Semantic Similarity, CASS, www.casstools.org), based on the BEAGLE semantic space model (Jones & Mewhort, Psychological Review, 114, 1-37, 2007) and add new features to test between-corpora differences in semantic associations (e.g., the association between democrat and good, compared to democrat and bad). By analyzing television transcripts from cable news from a 12-month period, we reveal significant differences in political bias between television channels (liberal to conservative: MSNBC, CNN, FoxNews) and find expected differences between newscasters (Colmes, Hannity). Compared to existing measures of media bias, our measure has higher reliability. CASS can be used to investigate semantic structure when exploring any topic (e.g., self-esteem or stereotyping) that affords a large text-based database. PMID- 21287122 TI - A new method to evaluate order and accuracy of inaccurately and incompletely reproduced movement sequences. AB - Studying imitation learning of long sequences requires the evaluation of inaccurately and incompletely reproduced movement sequences. In order to evaluate the movement reproduction, it has to be assigned to the original stimulus. We developed an assignment algorithm that considers the Spatial Neighborhood and Order of reproduction (SNOA). To evaluate the features of this analysis it was applied to human performance during learning of long pointing sequences under two conditions: stimulus-guided reproduction with high spatial accuracy and imitation learning with low spatial accuracy. The results were compared with a simple assignment considering Spatial Neighborhood only (SNA) and with a Manual Assignment (MA). In the stimulus-guided reproduction the error measures did not differ between the algorithms. In contrast, with imitation learning, SNOA and MA generated higher estimates of order and omission errors than SNA. The results show that SNOA can be used to automatically quantify the similarity of both movement structure and metric information between long target sequences and inaccurate and incomplete movement reproductions. PMID- 21287123 TI - A free, easy-to-use, computer-based simple and four-choice reaction time programme: the Deary-Liewald reaction time task. AB - Reaction time tasks are used widely in basic and applied psychology. There is a need for an easy-to-use, freely available programme that can run simple and choice reaction time tasks with no special software. We report the development of, and make available, the Deary-Liewald reaction time task. It is initially tested here on 150 participants, aged from 18 to 80, alongside another widely used reaction time device and tests of fluid and crystallised intelligence and processing speed. The new task's parameters perform as expected with respect to age and intelligence differences. The new task's parameters are reliable, and have very high correlations with the existing task. We also provide instructions for downloading and using the new reaction time programme, and we encourage other researchers to use it. PMID- 21287124 TI - Implicit causality bias in English: a corpus of 300 verbs. AB - This study provides implicit verb causality norms for a corpus of 305 English verbs. A web-based sentence completion study was conducted, with 96 respondents completing fragments such as "John liked Mary because..." The resulting bias scores are provided as supplementary material in the Psychonomic Society Archive, where we also present lexical and semantic verb features, such as the frequency, semantic class and emotional valence. Our results replicate those of previous studies with much smaller numbers of verbs and respondents. Novel effects of gender and its interaction with verb valence illustrate the type of issues that can be investigated using stable norms for a large number of verbs. The corpus will facilitate future studies in a range of areas, including psycholinguistics and social psychology. PMID- 21287125 TI - A convenient and accurate parallel Input/Output USB device for E-Prime. AB - Psychological and neurophysiological experiments require the accurate control of timing and synchrony for Input/Output signals. For instance, a typical Event Related Potential (ERP) study requires an extremely accurate synchronization of stimulus delivery with recordings. This is typically done via computer software such as E-Prime, and fast communications are typically assured by the Parallel Port (PP). However, the PP is an old and disappearing technology that, for example, is no longer available on portable computers. Here we propose a convenient USB device enabling parallel I/O capabilities. We tested this device against the PP on both a desktop and a laptop machine in different stress tests. Our data demonstrate the accuracy of our system, which suggests that it may be a good substitute for the PP with E-Prime. PMID- 21287126 TI - The bit in the middle and why it's important: a computational analysis of the linguistic features of body paragraphs. AB - This study examines the relationship between the linguistic characteristics of body paragraphs of student essays and the total number of paragraphs in the essays. Results indicate a significant relationship between the total number of paragraphs and a variety of linguistic characteristics known to affect student essay scores. These linguistic characteristics (e.g., semantic overlap, syntactic complexity) contribute to two underlying factors (i.e., textual cohesion and difficulty) that are used as dependent variables in mixed-effect models. Results suggest that student essays with 5-8 paragraphs tend to be more linguistically consistent than student essays with 3, 4, and 9 paragraphs. Essays with totals of 5-8 paragraphs, considered by many educators to contain an optimal number of paragraphs, may include functionally and structurally similar paragraphs. These findings could aid writing researchers and educators in obtaining a clearer view of the relationship between the total number of paragraphs comprising an essay and the linguistic characteristics that affect essay evaluation. Consequently, writing interventions may become better equipped to pinpoint student difficulties and facilitate student writing skills by providing more detailed and informed feedback. PMID- 21287127 TI - Validated intraclass correlation statistics to test item performance models. AB - A new method, with an application program in Matlab code, is proposed for testing item performance models on empirical databases. This method uses data intraclass correlation statistics as expected correlations to which one compares simple functions of correlations between model predictions and observed item performance. The method rests on a data population model whose validity for the considered data is suitably tested and has been verified for three behavioural measure databases. Contrarily to usual model selection criteria, this method provides an effective way of testing under-fitting and over-fitting, answering the usually neglected question "does this model suitably account for these data?" PMID- 21287128 TI - Quantifying talk: developing reliable measures of verbal productivity. AB - Measuring talkativeness is of interest to several areas of research. However, there are few brief, validated measures available. We examined test-retest reliability, inter-relationships and convergent/divergent validity for five brief measures of verbal productivity. Nineteen men and 32 women participated in four sessions, completing five speech tasks that varied in demand, purpose of speech and sociability. Several potential metrics (word count, duration and rate) were examined. All tasks except a novel Unprompted Speech task demonstrated good word count test-retest reliability (interclass correlation coefficients from .71 to .85). Factor analysis revealed low-demand, non-functional tasks formed one factor ("Voluntary Talkativeness"), while higher demand tasks formed a second factor ("Speech Ability"). This finding and examination of relationships with IQ, personality and gender indicate "Voluntary Talkativeness" is not wholly accounted for by verbal ability, and is only weakly related to self-reported personality. Recommendations for the measurement of "Voluntary Talkativeness" are made. PMID- 21287129 TI - Descriptive norms for 245 Italian idiomatic expressions. AB - The present study reports descriptive normative measures for 245 Italian verbal idiomatic expressions. For each of the idiomatic expressions the following variables are reported: Length, Knowledge, Familiarity, Age of Acquisition, Predictability, Syntactic flexibility, Literality and Compositionality. Syntactic flexibility was assessed using five syntactic operations: adverb insertion, adjective insertion, left dislocation, passive and movement. The psycholinguistic relevance of each dimension, their measures and the correlations among them are provided and discussed. The databases are freely available for down-loading from the Psychonomic Society Web archive at www.psychonomic.org/archive/. PMID- 21287131 TI - Transcriptional and Posttranscriptional Programming by Long Noncoding RNAs. AB - Recently, several lines of evidence have suggested that noncoding RNAs, which include both small and long noncoding RNAs (ncRNAs), contribute to a significant portion of the transcriptome in eukaryotic organisms. However, the functional significance of this wide-spread occurrence of ncRNAs, and in particular, the long ncRNAs (lncRNAs), for organismal development and differentiation is unclear. The available evidence from a subset of lncRNAs suggests that certain lncRNAs, and/or the act of their transcription, are involved in important biological functions at the transcriptional and posttranscriptional level. This chapter discusses the epigenetic and nonepigenetic mechanisms by which lncRNAs and/or their transcription are involved in the programming of various biological functions in model systems, from yeast to mammals. PMID- 21287132 TI - Long noncoding RNA as a regulator for transcription. AB - Investigation of noncoding RNAs is in rapid progress, especially regarding translational repression by small (short) noncoding RNAs like microRNAs with 20 25 nucleotide-lengths, while long noncoding RNAs with nucleotide length of more than two hundred are also emerging. Indeed, our analysis has revealed that a long noncoding RNA transcribed from cyclin D1 promoter of 200 and 300 nucleotides exerts transcriptional repression through its binding protein TLS instead of translational repression. Translational repression is executed by short noncoding RNAs, while transcriptional repression is mainly done by long noncoding RNAs. These long noncoding RNAs are heterogeneous molecules and employ divergent molecular mechanisms to exert transcriptional repression. In this review, I overview recent publications regarding the transcription regulation by long noncoding RNAs and explore their biological significance. In addition, the relation between a random transcriptional activity of RNA polymerase II and the origin of long noncoding RNAs is discussed. PMID- 21287133 TI - Long Noncoding RNAs and X Chromosome Inactivation. AB - In female somatic cells, one of the two X chromosomes is inactivated to equalize the dose of sex-linked gene products between female and male cells. X chromosome inactivation X chromosome inactivation (XCI) is initiated very early during development and requires Xist Xist , which is a noncoding X-linked gene. Upon initiation of XCI, Xist-RNA spreads along the X chromosome in cis, and Xist spreading is required for the recruitment of different chromatin remodeling complexes involved in the establishment and maintenance of the inactive X chromosome. Because XCI acts chromosomewise, Xist-mediated silencing has served as an important paradigm to study the function of noncoding RNAs (ncRNA) in gene silencing. In this chapter, we describe the current knowledge about the structure and function of Xist. We also discuss the important cis- and trans-regulatory elements and proteins in the initiation, establishment, and maintenance of XCI. In addition, we highlight new findings with other ncRNAs involved in gene repression and discuss these findings in relation to Xist-mediated gene silencing. PMID- 21287134 TI - TERRA: Long Noncoding RNA at Eukaryotic Telomeres. AB - Telomeres protect the ends of linear eukaryotic chromosomes from being recognized as DNA double-stranded breaks, thereby maintaining the stability of our genome. The highly heterochromatic nature of telomeres had, for a long time, reinforced the idea that telomeres were transcriptionally silent. Since a few years, however, we know that DNA-dependent RNA polymerase II transcribes telomeric DNA into TElomeric Repeat-containing RNA (TERRA) molecules in a large variety of eukaryotes. In this chapter, we summarize the current knowledge of telomere structure and function and extensively review data accumulated on TERRA biogenesis and regulation. We also discuss putative functions of TERRA in preserving telomere stability and propose future directions for research encompassing this novel and exciting aspect of telomere biology. PMID- 21287135 TI - Transcription of Satellite DNAs in Mammals. AB - Centromeric and pericentric regions have long been regarded as transcriptionally inert portions of chromosomes. A number of studies in the past 10 years disproved this dogma and provided convincing evidence that centromeric and pericentric sequences are transcriptionally active in several biological contexts.In this chapter, we provide a comprehensive picture of the various contexts (cell growth and differentiation, stress, effect of chromatin organization) in which these sequences are expressed in mouse and human cells and discuss the possible functional implications of centromeric and pericentric sequences activation and/or of the resulting noncoding RNAs. Moreover, we provide an overview of the molecular mechanisms underlying the activation of centromeric and pericentromeric sequences as well as the structural features of encoded RNAs. PMID- 21287136 TI - Multiple Roles of Alu-Related Noncoding RNAs. AB - Repetitive Alu and Alu-related elements are present in primates, tree shrews (Scandentia), and rodents and have expanded to 1.3 million copies in the human genome by nonautonomous retrotransposition. Pol III transcription from these elements occurs at low levels under normal conditions but increases transiently after stress, indicating a function of Alu RNAs in cellular stress response. Alu RNAs assemble with cellular proteins into ribonucleoprotein complexes and can be processed into the smaller scAlu RNAs. Alu and Alu-related RNAs play a role in regulating transcription and translation. They provide a source for the biogenesis of miRNAs and, embedded into mRNAs, can be targeted by miRNAs. When present as inverted repeats in mRNAs, they become substrates of the editing enzymes, and their modification causes the nuclear retention of these mRNAs. Certain Alu elements evolved into unique transcription units with specific expression profiles producing RNAs with highly specific cellular functions. PMID- 21287137 TI - roX RNAs and Genome Regulation in Drosophila Melanogaster. AB - Organisms with dimorphic sex chromosomes suffer a potentially lethal imbalance in gene expression in one sex. Addressing this fundamental problem can be considered the first, and most essential, aspect of sexual differentiation. In the model organisms Drosophila, Caenorhabditis elegans, and mouse, expression from X-linked genes is modulated by selective recruitment of chromatin-modifying complexes to X chromatin. In both flies and mammals, large noncoding RNAs have a central role in recruitment and activity of these complexes. This review will summarize current knowledge of the function of the noncoding roX genes in this process in Drosophila. Identification of an autosomal function for the roX RNAs raises intriguing questions about the origin of the modern dosage compensation system in flies. PMID- 21287138 TI - Transcription of Satellite DNAs in Insects. AB - The very complex life cycle and extreme diversity of insect life forms require a carefully regulated network of biological processes to switch on and off the right genes at the right time. Chromatin condensation is an important regulatory mechanism of gene silencing as well as gene activation for the hundreds of functional protein genes harbored in heterochromatic regions of different insect species. Being the major heterochromatin constituents, satellite DNAs (satDNAs) serve important roles in heterochromatin regulation in insects in general. Their expression occurs in all developmental stages, being the highest during embryogenesis. satDNA transcripts range from small RNAs, corresponding in size to siRNAs, and piwiRNAs, to large, a few kb long RNAs. The long transcripts are preferentially nonpolyadenylated and remain in the nucleus. The actively regulated expression of satDNAs by cis or trans elements as well as by environmental stress, rather than constitutive transcription, speaks in favor of their involvement in differentiation, development, and environmental response. PMID- 21287139 TI - Long Nonprotein-Coding RNAs in Plants. AB - In recent years, nonprotein-coding RNAs (or npcRNAs) have emerged as a major part of the eukaryotic transcriptome. Many new regulatory npcRNAs or riboregulators riboregulators have been discovered and characterized due to the advent of new genomic approaches. This growing number suggests that npcRNAs could play a more important role than previously believed and significantly contribute to the generation of evolutionary complexity in multicellular organisms. Regulatory npcRNAs range from small RNAs (si/miRNAs) to very large transcripts (or long npcRNAs) and play diverse functions in development and/or environmental stress responses. Small RNAs include an expanding number of 20-40 nt RNAs that function in the regulation of gene expression by affecting mRNA decay and translational inhibition or lead to DNA methylation and gene silencing. They generally involve double-stranded RNA or stem loops and imply transcriptional or posttranscriptional gene silencing (PTGS). RNA silencing besides small interfering RNA and microRNA, gene silencing in plants is also mediated by tasiRNAs (trans-acting siRNAs) and nat-siRNAs (natural antisense mediated siRNAs). In contrast to small RNAs, much less is known about the large and diverse population of long npcRNAs, and only a few have been implicated in diverse functions such as abiotic stress responses, nodulation and flower development, and sex chromosome-specific expression. Moreover, many long npcRNAs act as antisense transcripts or are substrates of the small RNA pathways, thus interfering with a variety of RNA-related metabolisms. An emerging hypothesis is that long npcRNAs, as shown for small si/miRNAs, integrate into ribonucleoprotein particles (RNPs) to modulate their function, localization, or stability to act on target mRNAs. As plants show a remarkable developmental plasticity to adapt their growth to changing environmental conditions, understanding how npcRNAs work may reveal novel mechanisms involved in growth control and differentiation and help to design new tools for biotechnological applications. PMID- 21287141 TI - Glucose oscillations, more than constant high glucose, induce p53 activation and a metabolic memory in human endothelial cells. AB - AIMS/HYPOTHESIS: Damage persists in HUVECs exposed to a constant high glucose concentration long after glucose normalisation, a phenomenon termed 'metabolic memory'. Evaluation of the effects of exposure of HUVECs to oscillating high glucose on the induction of markers of oxidative stress and DNA damage (phospho gamma-histone H2AX and PKCdelta) and onset of metabolic memory, and the possible role of the tumour suppressor transcriptional factor p53 is of pivotal interest. METHODS: HUVECs were incubated for 3 weeks in 5 or 25 mmol/l glucose or oscillating glucose (24 h in 5 mmol/l glucose followed by 24 h in 25 mmol/l glucose) or for 1 week in constant 5 mmol/l glucose after being exposed for 2 weeks to continuous 25 mmol/l high glucose or oscillating glucose. Transcriptional activity of p53 was also evaluated in the first 24 h after high glucose exposure. RESULTS: High constant glucose upregulated phospho-gamma histone H2AX and protein kinase C (PKC)delta compared with control. Oscillating glucose was even more effective than both normal and constant high glucose. Both constant and oscillating glucose resulted in a memory effect, which was more pronounced in the oscillating condition. Transcriptional activity of p53 peaked 6 h after glucose exposure, showing a predicted oscillatory behaviour. CONCLUSIONS/INTERPRETATION: Exposure to oscillating glucose was more deleterious than constant high glucose and induced a metabolic memory after glucose normalisation. Hyperactivation of p53 during glucose oscillation might be due to the absence of consistent feedback inhibition during each glucose spike and might account for the worse outcome of this condition. PMID- 21287142 TI - Suicidality related to first-time admissions to psychiatric hospital. AB - BACKGROUND: The epidemiology of suicidality shows considerable variation across sites. However, one of the strongest predictors of suicide is a suicidal attempt. Knowledge of the epidemiology of suicidal ideas and attempts in the general population as well as in the health care system is of importance for designing preventive strategies. In this study, we will explore the role of the psychiatric hospital in suicide prevention by investigating treated incidence of suicidal ideation and attempt, and further, discern whether sociodemographic, clinical and service utilization factors differ between these two groups at admission. METHODS: The study was a prospective cohort study on treated incidence in a 1 year period and 12-month follow-up. The two psychiatric hospitals in northern Norway, serving a population of about 500,000 people, participated in the study. A total of 676 first-time admissions were retrospectively checked for suicidality at the time of admission. A study sample of 168 patients was found eligible for logistic regression analysis to elucidate the risk profiles of suicidal ideators versus suicidal attempters. GAF, HoNOS and SCL-90-R were used to assess symptomatology at baseline. RESULTS: 52.2% of all patients admitted had suicidal ideas at admission and 19.7% had attempted suicide. In the study sample, there were no differences in risk profile between the two groups with regard to sociodemographic and clinical factors. Males who had made a suicide attempt were less likely to have been in contact with an out-patient clinic before the attempt. The rating scales not measuring suicidality directly showed no differences in symptomatology. CONCLUSION: The findings provide evidence for the importance of the psychiatric hospital in suicide prevention. About half of the admissions were related to suicidality and the similar risk profiles found in suicidal ideators and suicidal attempters indicate that it is the ideators who mostly need treatment that get admitted to the hospital, and should be evaluated and treated with equal concern as those who have attempted suicide. PMID- 21287143 TI - Anxiety and depression in a post-September 11 sample of Arabs in the USA. AB - OBJECTIVE: Scant research has examined the mental health of Arab Americans. This study aimed to determine the levels of anxiety and depression in a sample of Arab Americans and compare the rates to normative community samples and samples of other minority ethnic/racial groups. METHODS: A non-probability sampling approach resulted in 601 adult Arab American respondents from 35 US states. Respondents completed anxiety and depression questionnaires at a form-based Internet site. RESULTS: One-fourth of participants reported moderate to severe anxiety levels as measured by the Beck Anxiety Inventory (BAI), and one-half reported depression scores that met clinical caseness as assessed by the Center for Epidemiologic Studies-Depression Scale (CES-D). The present sample of Arab Americans reported significantly higher levels of anxiety and depression compared to standardization samples and community samples of four other minority groups. CONCLUSIONS: Arab Americans may be at risk for anxiety and depression. Further studies should be conducted to replicate and validate these results, identify stressors that affect this population, and develop recommendations for clinical interventions. PMID- 21287144 TI - Obsessive-compulsive disorder in the community: 12-month prevalence, comorbidity and impairment. AB - BACKGROUND: Although subthreshold conditions are associated with impairment in numerous disorders, research on obsessive-compulsive disorder (OCD) below the diagnostic threshold of DSM-IV in the general population is limited. PURPOSE: To estimate the DSM-IV 12-month prevalence, comorbidity and impairment of OCD, subthreshold OCD (i.e., fulfilling some but not all core DSM-IV criteria), and obsessive-compulsive symptoms (OCS) (i.e., endorsement of OCS without fulfilling any core DSM-IV criteria) in a general population sample. METHODS: Data from the German National Health Interview and Examination Survey-Mental Health Supplement (N = 4181, age 18-65 years), based on the standardized diagnostic Munich Composite International Diagnostic Interview. RESULTS: The 12-month prevalence of OCD was 0.7%, subthreshold OCD was 4.5%, and OCS was 8.3%. Subjects in all three groups showed higher comorbidity (odds ratios [ORs] >= 3.3), compared to those without OCS. The OCD, subthreshold OCD and OCS were all associated with increased odds of substance abuse/dependence-, mood-, anxiety- and somatoform disorders, with especially strong associations with possible psychotic disorder (ORs >= 4.1) and bipolar disorders (ORs >= 4.7). Participants in all three groups showed higher impairment (ORs >= 3.1) and health-care utilization (ORs >= 2.4), compared to those without OCS, even after controlling for covariates. CONCLUSIONS: Individuals with subthreshold OCD and OCS, not currently captured by DSM-IV OCD criteria, nevertheless show substantial comorbidity, impairment and health-care utilization. This should be taken into account in future conceptualization and classification of OCD and clinical care. PMID- 21287145 TI - A national survey of Italian physicians' attitudes towards end-of-life decisions following the death of Eluana Englaro. AB - BACKGROUND: Ethical issues regarding patient care have recently been raised in Italy by the case of Eluana Englaro, a 36-year-old woman who remained in a persistent vegetative state (PVS) for 17 years. There are no specific laws on the books in Italy regarding euthanasia and physician-assisted suicide. In November 2008, a controversial decision by the Italian Supreme Court granted the woman's father his wish to discontinue nutrition and hydration provided to her. Because of this historic decision, the authors carried out a survey of Italian physicians' beliefs regarding end-of-life practices. METHODS: A questionnaire was e-mailed to 70,000 physicians working for the Italian Public Health System and University Medical Hospitals. RESULTS: A total of 22,219 doctors responded to the questionnaire (32.3%), of whom 17,252 (77.6%) had some experience in treating PVS patients. Nearly 70% of responding doctors were aware of PVS diagnostic criteria; most of them (61%) considered tube feeding to be a medical therapy, and 66% of respondents believed that withdrawal of assisted nutrition and hydration (ANH) might be appropriate depending on the patient's wishes. Moreover, even though 50% of doctors surveyed were not in favor of euthanasia, a significant percentage (42%) did approve of it, while 8% of this sample was uncertain. CONCLUSIONS: Italian doctors probably have the least experience in end-of-life decisions in Europe, therefore this national survey is a great chance to understand their authentic opinions regarding such remarkable issues. There is broad consensus that a clear legislative position regarding euthanasia and ANH is needed. PMID- 21287146 TI - A clinical information system reduces medication errors in paediatric intensive care. AB - PURPOSE: To determine the effect of electronic prescribing (EP) with a clinical information system (Intellivue Clinical Information Portfolio, Philips, UK) on prescribing errors and omitted doses in a paediatric intensive care unit (PICU). METHODS: Prospective audit of prescribing errors and omitted doses for 96 h periods in three epochs: (1) before implementation of EP, (2) 1 week and (3) 6 months later. RESULTS: There was a non-significant reduction in prescribing errors: 8.8% (95% CI 4.4-13.2) pre-implementation of EP versus 8.1% (4.4-11.8) 1 week after implementation and 4.6% (2.0-7.2) 6 months later. The prevalence of omitted doses decreased significantly 6 months following implementation, changing from 8.1% (5.8-10.4) pre-implementation to 10.6% (6.5-14.7) 1 week after implementation and 1.4% (CI 0-2.8%) 6 months after implementation (P < 0.05). CONCLUSION: EP within a clinical information system increases medication safety in a PICU. PMID- 21287147 TI - Utility of ultrasonography for detection of gastric fluid during urgent endotracheal intubation. AB - PURPOSE: Aspiration of gastric contents is a dangerous complication of urgent endotracheal intubation (UEI). Left upper quadrant (LUQ) ultrasonography may have the potential to decrease this complication by identifying patients with gastric fluid content, thereby allowing the UEI team to evacuate gastric contents prior to intubation. METHODS: This was an observational study of 80 UEIs where LUQ ultrasonography was performed in a medical intensive care unit of a tertiary care hospital. The subjects were 80 patients requiring UEI. Gastric fluid content was identified as an anechoic or hypoechoic space in the appropriate anatomic position. If potentially consequential fluid was identified, it was evacuated using a gastric tube. Repeat LUQ ultrasonography confirmed removal of gastric contents prior to induction. RESULTS: A total of 80 patients had LUQ ultrasonography performed; 19 (24%) had gastric fluid content identified and 13 (16%) had sufficient gastric fluid content such that the UEI team proceeded with gastric tube insertion. Following gastric fluid removal, repeat ultrasonography showed absence of gastric fluid. Gastric fluid volume removed was 553 +/- 290 ml (mean +/- standard deviation, SD). None of the 80 patients had a clinically consequential aspiration event. Performance of ultrasonography took fewer than 2 min. No patient had complication related to the ultrasonography or removal of gastric contents. CONCLUSIONS: Ultrasonography is useful for the detection of gastric fluid. This technique may have utility in reducing risk of a clinically consequential aspiration event during UEI. PMID- 21287148 TI - A meta-analysis of the effect of strontium ranelate on the risk of vertebral and non-vertebral fracture in postmenopausal osteoporosis and the interaction with FRAX((r)). AB - The aim of the present study was to determine the efficacy of strontium ranelate as a function of baseline fracture risk. Treatment with strontium ranelate was associated with a significant 31% decrease in all clinical osteoporotic fractures (vertebral fractures included). Hazard ratios for the effect of strontium ranelate on the fracture outcome did not change significantly with increasing fracture probability. INTRODUCTION: Two previous studies have suggested that the efficacy of intervention may be greater in the segment of the population at highest fracture risk as assessed by the FRAX((r)) algorithms. The aim of the present study was to determine whether the anti-fracture efficacy of strontium ranelate was dependent of the level of fracture risk. METHODS: The primary data of the two phase III studies (SOTI and TROPOS) of the effects of strontium ranelate in postmenopausal osteoporosis were combined. Country-specific probabilities were computed using the FRAX((r)) tool (version 2.0). The primary outcome variable comprised all clinical osteoporotic fractures (including clinical vertebral fractures). Interactions between fracture probability and efficacy were explored by Poisson regression. RESULTS: The 10-year probability of major osteoporotic fractures (with BMD) ranged from 2.5% to 90.8%. FRAX((r)) based hip fracture probabilities ranged from 0.1% to 90.3%. The incidence of clinical osteoporotic fractures (vertebral fractures excluded) and morphometric vertebral fractures increased with increasing baseline fracture probabilities. Treatment with strontium ranelate was associated with a 31% (95% CI = 20-39%) decrease in osteoporotic clinical fractures and a 40% decrease in vertebral fractures assessed by semiquantitative morphometry (95% CI = 31-48%) Hazard ratios for the effect of strontium ranelate on the fracture outcomes did not change significantly with increasing fracture probability. CONCLUSION: Strontium ranelate significantly decreased the risk of osteoporotic clinical fractures, non vertebral fractures and morphometric vertebral fractures in women. Overall, the efficacy of strontium ranelate was not dependent of the level of fracture risk assessed by FRAX. PMID- 21287149 TI - In vivo and ex vivo percutaneous absorption of [14C]-bisphenol A in rats: a possible extrapolation to human absorption? AB - Bisphenol A (BPA) is a monomer used mainly in the synthesis of polycarbonates and epoxy resins. Percutaneous absorption is the second source of exposure, after inhalation, in the work environment. However, studies on this route of absorption are lacking or incomplete. In this study, percutaneous BPA absorption was measured in vivo and ex vivo in the rat, and ex vivo in humans. An approximately 12-fold difference in permeability between rat skin and human skin was found, with permeability being higher in the rat. In addition, inter- and intra individual variability of up to tenfold was observed in humans. No accumulation of BPA in the skin was found during exposure. The skin clearance rate following exposure was estimated at 0.4 MUg/cm2/h. Ex vivo and in vivo percutaneous absorption fluxes of BPA in the rat were in the same range (about 2.0 MUg/cm2/h), suggesting that extrapolation to the in vivo situation in humans may be possible. The European tolerable daily intake (TDI) of BPA is 50 MUg/kg body weight. However, many research projects have highlighted the significant effects of BPA in rodents at doses lower than 10 MUg/kg/day. A 1-h occupational exposure over 2,000 cm2 (forearms and hands) may lead to a BPA absorption of 4 MUg/kg/day. This is 8% of the European TDI and is very close to the value at which effects have been observed in animals. This absorption must therefore be taken into account when evaluating risks of BPA exposure, at least until more relevant results on the toxicity of BPA in humans are available. PMID- 21287150 TI - Weight loss and hypophagia after high-dose AT1-blockade is only observed after high dosing and depends on regular leptin signalling but not blood pressure. AB - AT(1)-blockade has been shown to induce weight loss in animals or patients. The aim of this study was to investigate whether weight reduction after AT(1) blockade is dependent on dose, blood pressure reduction and leptin signalling. Spontaneously hypertensive rats (SHR) and lean and obese Zucker rats were treated for 4 weeks with candesartan (0, 2, 6 or 16 mg/kg/day). Body weight, food intake and hypothalamic mRNA levels of (an)orexigenic peptides were determined. Obese Zucker rats served as a model of primary leptin resistance. In SHR, body mass index and food intake were decreased selectively by 16 mg/kg/day candesartan but not after using normal (2 mg/kg/day) or supranormal (6 mg/kg/day) doses. Correlation analysis between blood pressure and body weight indicated no relationship of hypotensive potency on weight loss. The hypothalamic mRNA levels of the orexigenic peptide MCH (melanin-concentrating hormone) were diminished in parallel. Consistent to the results in SHRs, 16 mg/kg/day candesartan revealed a decrease of body weight, food intake and hypothalamic MCH mRNA levels in lean Zucker rats. In obese Zucker rats, none of these parameters were reduced by candesartan. Loss of body weight and hypophagia are not general features of AT(1) blockers, since neither was seen after normal or moderately supranormal doses, but they were, after the highest doses. These actions of AT(1)-blockers occur independently of their ability to lower blood pressure. They do depend on an intact leptin signalling, since they were absent in obese Zucker rats that feature a genetic mutation of the leptin receptor. PMID- 21287152 TI - The human semicircular canal model of galvanic vestibular stimulation. AB - A vector summation model of the action of galvanic stimuli on the semicircular canals has been shown to explain empirical balance and perceptual responses to binaural-bipolar stimuli. However, published data suggest binaural-monopolar stimuli evoke responses that are in the reverse direction of the model prediction. Here, we confirm this by measuring balance responses to binaural monopolar stimulation as movements of the upper trunk. One explanation for the discrepancy is that the galvanic stimulus might evoke an oppositely directed balance response from the otolith organs that sums with and overrides the semicircular canal response. We tested this hypothesis by measuring sway responses across the full range of head pitch. The results showed some modulation of sway with pitch such that the maximal response occurred with the head in the primary position. However, the effect fell a long way short of that required to reverse the canal sway response. This indicates that the model is incomplete. Here, we examine alterations to the model that could explain both the bipolar and monopolar-evoked behavioural responses. An explanation was sought by remodelling the canal response with more recent data on the orientation of the individual canals. This improved matters but did not reverse the model prediction. However, the model response could be reversed by either rotating the entire labyrinth in the skull or by altering the gains of the individual canals. The most parsimonious solution was to use the more recent canal orientation data coupled with a small increase in posterior canal gain. PMID- 21287153 TI - Reliable- and unreliable-warning cues in the Sustained Attention to Response Task. AB - The Sustained Attention to Response Task (SART) is a Go-No-Go signal detection task developed to measure lapses of attention. In this study, we examined the impact that warning signals, reliable and unreliable, have on SART performance. Eighteen participants performed a no-warning, reliable-warning, or unreliable warning SART. Response times were faster, errors of commission lower, but errors of omission higher in the reliable-warning SART in comparison with the no-warning or unreliable-warning SART. There was a significant negative correlation between participants' errors of commission rate and their response times in the unreliable-warning and no-warning SART. This correlation was reduced in the reliable-warning SART. Making the task perceptually easier reduces the errors of commission, in contradiction to the mindlessness perspective, and reduces the speed-accuracy trade-off. These results, overall, support the view that the SART is primarily a measure of response strategy, not sustained attention per se. PMID- 21287154 TI - Temporal binding of auditory and rotational stimuli. AB - Integration of cues from multiple sensory channels improves our ability to sense and respond to stimuli. Cues arising from a single event may arrive at the brain asynchronously, requiring them to be "bound" in time. The perceptual asynchrony between vestibular and auditory stimuli has been reported to be several times greater than other stimulus pairs. However, these data were collected using electrically evoked vestibular stimuli, which may not provide similar results to those obtained using actual head rotations. Here, we tested whether auditory stimuli and vestibular stimuli consisting of physiologically relevant mechanical rotations are perceived with asynchronies consistent with other sensory systems. We rotated 14 normal subjects about the earth-vertical axis over a raised-cosine trajectory (0.5 Hz, peak velocity 10 deg/s) while isolated from external noise and light. This trajectory minimized any input from extravestibular sources such as proprioception. An 800-Hz, 10-ms auditory tone was presented at stimulus onset asynchronies ranging from 200 ms before to 700 ms after the onset of motion. After each trial, subjects reported whether the stimuli were "simultaneous" or "not simultaneous." The experiment was repeated, with subjects reporting whether the tone or rotation came first. After correction for the time the rotational stimulus took to reach vestibular perceptual threshold, asynchronies spanned from -41 ms (auditory stimulus leading vestibular) to 91 ms (vestibular stimulus leading auditory). These values are significantly lower than those previously reported for stimulus pairs involving electrically evoked vestibular stimuli and are more consistent with timing relationships between pairs of non-vestibular stimuli. PMID- 21287155 TI - Prolonged reduction of motion sickness sensitivity by visual-vestibular interaction. AB - The angular vestibulo-ocular reflex (aVOR) and optokinetic nystagmus (OKN) were elicited simultaneously at low frequencies to study effects of habituation of the velocity storage time constant in the vestibular system on motion sickness. Twenty-nine subjects, eleven of whom were susceptible to motion sickness from common transportation, were habituated by sinusoidal rotation at 0.017 Hz at peak velocities from 5 to 20 degrees /s, while they watched a full-field OKN stimulus. The OKN stripes rotated in the same direction and at the same frequency as the subjects, but at a higher velocity. This produced an OKN opposite in direction to the aVOR response. Motion sickness sensitivity was evaluated with off-vertical axis rotation (OVAR) and by the response to transportation before and after 5 days of visual-vestibular habituation. Habituation did not induce motion sickness or change the aVOR gains, but it shortened the vestibular time constants in all subjects. This greatly reduced motion sickness produced by OVAR and sensitivity to common transport in the motion susceptible subjects, which persisted for up to 18 weeks. Two motion susceptible subjects who only had aVOR/OKN habituation without being tested with OVAR also became asymptomatic. Normal subjects who were not habituated had no reduction in either their aVOR time constants or motion sickness sensitivity. The opposing aVOR/OKN stimulation, which has not been studied before, was well tolerated, and for the first time was an effective technique for rapid and prolonged habituation of motion sickness without exposure to drugs or other nauseating habituation stimuli. PMID- 21287156 TI - Neural adaptation is related to face repetition irrespective of identity: a reappraisal of the N170 effect. AB - Event-related potentials offer evidence for face distinctive neural activity that peaks at about 170 ms following the onset of face stimuli (the N170 effect). We investigated the role of the perceptual mechanism reflected by the N170 effect by comparing the adaptation of the N170 amplitude when target faces were preceded either by identical face images or by different faces relative to when they were preceded by objects. In two experiments, we demonstrate that the N170 is equally adapted by repetition of the same or different faces. Thus, our findings show that the N170 is sensitive to the category rather than the identity of a face. This outcome supports the hypothesis that the N170 effect reflects the activity of a perceptual mechanism which discriminates faces from objects and streams face stimuli to dedicated circuits, specialized in encoding and decoding information about the face. PMID- 21287157 TI - Motor equivalence and self-motion induced by different movement speeds. AB - This study investigated pointing movements in 3D asking two questions: (1) Is goal-directed reaching accompanied by self-motion, a component of the joint velocity vector that leaves the hand's movement unaffected? (2) Are differences in the terminal joint configurations among different speeds of reaching motor equivalent (i.e., terminal joint configurations differ more in directions of joint space that do not produce different pointer-tip positions than in directions that do) or non-motor equivalent (i.e., terminal joint configurations differ equally or more in directions of joint space that lead to different pointer-tip positions than in directions that do not affect the pointer-tip position). Subjects reached from an identical starting joint configuration and pointer-tip location to targets at slow, moderate, and fast speeds. Ten degrees of freedom of joint motion of the arm were recorded. The relationship between changes in the joint configuration and the three-dimensional pointer-tip position was expressed by a standard kinematic model, and the range- and null subspaces were computed from the associated Jacobian matrix. (1) The joint velocity vector and (2) the difference vector between terminal joint configurations from pairs of speed conditions were projected into the two subspaces. The relative length of the two components was used to quantify the amount of self-motion and the presence of motor equivalence, respectively. Results revealed that reaches were accompanied by a significant amount of self-motion at all reaching speeds. Self motion scaled with movement speed. In addition, the difference in the terminal joint configuration between pairs of different reaching speeds revealed motor equivalence. The results are consistent with a control system that takes advantage of motor redundancy, allowing for flexibility in the face of perturbations, here induced by different movement speeds. PMID- 21287158 TI - Mental transformation abilities in patients with unilateral and bilateral vestibular loss. AB - Vestibular information helps to establish a reliable gravitational frame of reference and contributes to the adequate perception of the location of one's own body in space. This information is likely to be required in spatial cognitive tasks. Indeed, previous studies suggest that the processing of vestibular information is involved in mental transformation tasks in healthy participants. In this study, we investigate whether patients with bilateral or unilateral vestibular loss show impaired ability to mentally transform images of bodies and body parts compared to a healthy, age-matched control group. An egocentric and an object-based mental transformation task were used. Moreover, spatial perception was assessed using a computerized version of the subjective visual vertical and the rod and frame test. Participants with bilateral vestibular loss showed impaired performance in mental transformation, especially in egocentric mental transformation, compared to participants with unilateral vestibular lesions and the control group. Performance of participants with unilateral vestibular lesions and the control group are comparable, and no differences were found between right and left-sided labyrinthectomized patients. A control task showed no differences between the three groups. The findings from this study substantiate that central vestibular processes are involved in imagined spatial body transformations; but interestingly, only participants with bilateral vestibular loss are affected, whereas unilateral vestibular loss does not lead to a decline in spatial imagery. PMID- 21287159 TI - Role of parathyroid hormone in bone fragility of postmenopausal women with vitamin D insufficiency. AB - Vitamin D insufficiency is related to an increase in PTH, which might be critical for an increase in bone fragility. However, the role of endogenous PTH in vitamin D insufficiency-induced fracture risk remains unclear. The present study was performed to examine the relationships among vitamin D insufficiency, bone fragility, and PTH in 202 Japanese postmenopausal women. Serum 25-hydroxyvitamin D (25[OH]D) levels were measured. The percentages of subjects with 25(OH)D levels below 10, 15, and 20 ng/ml were 5.0, 41.0, and 80.7%, respectively. Serum 25(OH)D levels were negatively related to age and serum levels of Cr and PTH; they were positively related to bone mineral density (BMD). In multiple regression analysis, BMD was significantly related to 25(OH)D levels when adjusted for age, body mass index (BMI), and serum levels of Cr and PTH. Multiple logistic regression analysis showed that lower 25(OH)D levels were significantly related to prevalent fracture risk when adjusted for age, BMI, serum levels of Cr and PTH, as well as femoral neck BMD. The proportion of subjects with prevalent fractures was significantly higher in the group with lower PTH and lower 25(OH)D than in the group with lower PTH and higher 25(OH)D or higher PTH and higher 25(OH)D. In conclusion, vitamin D insufficiency was found to be related to prevalent fracture risk independently of PTH. Functional hypoparathyroidism, rather than functional hyperparathyroidism, might be a risk factor for bone fragility in vitamin D insufficiency. PMID- 21287161 TI - Simultaneous effects of lead and cadmium on primary cultures of rat proximal tubular cells: interaction of apoptosis and oxidative stress. AB - The combined effects of lead (Pb) and cadmium (Cd) on primary cultures of rat proximal tubular (rPT) cells were studied. These cells were either treated with Pb acetate (0.5 and 1 MUM) alone, Cd acetate (2.5 and 5 MUM) alone, or a combination of Pb and Cd acetate, and then joint cytotoxicity was evaluated. The results showed that the combination of these two metals decreased cell viability and increased the number of apoptotic and necrotic cells and lactate dehydrogenase release synergistically. Simultaneously, increased intracellular reactive oxygen species, malondialdehyde, and calcium levels and decreased mitochondrial membrane potential, intracellular acidification, and inhibition of Na(+), K(+)-, and Ca(2+)-ATPase activities were shown during the exposure. In addition, apoptotic morphological changes induced by these treatments in rPT cells were demonstrated by Hoechst 33258 staining. The apoptosis was markedly prevented by N-acetyl-L-cysteine, whereas necrosis was not affected. In summary, there was a synergistic cytototic effect of Pb combined with Cd on rPT cells. Cell death induced by Pb-Cd mixture was mediated by an apoptotic and a necrotic mechanism. Apoptotic death was the chief mechanism. Changes of intracellular events were intimately correlated with both oxidative stress and mitochondrial dysfunction, which promoted the development of apoptosis. PMID- 21287160 TI - Do pharmacokinetic polymorphisms explain treatment failure in high-risk patients with neuroblastoma? AB - PURPOSE: Neuroblastoma is the most common extracranial solid tumour in childhood. It accounts for 15% of all paediatric oncology deaths. In the last few decades, improvement in treatment outcome for high-risk patients has not occurred, with an overall survival rate <30-40%. Many reasons may account for such a low survival rate. The aim of this review is to evaluate whether pharmacogenetic factors can explain treatment failure in neuroblastoma. METHODS: A literature search based on PubMed's database Medical Subject Headings (MeSH) was performed to retrieve all pertinent publications on current treatment options and new classes of drugs under investigation. One hundred and fifty-eight articles wer reviewed, and relevant data were extracted and summarised. RESULTS AND CONCLUSIONS: Few of the large number of polymorphisms identified thus far showed an effect on pharmacokinetics that could be considered clinically relevant. Despite their clinical relevance, none of the single nucleotide polymorphisms (SNPs) investigated can explain treatment failure. These findings seem to reflect the clinical context in which anti-tumour drugs are used, i.e. in combination with multimodal therapy. In addition, many pharmacogenetic studies did not assess (differences in) drug exposure, which could contribute to explaining pharmacogenetic associations. Furthermore, it remains unclear whether the significant activity of new drugs on different neuroblastoma cell lines translates into clinical efficacy, irrespective of resistance or myelocytomatosis viral related oncogene, neuroblastoma derived (MYCN) amplification. Elucidation of the clinical role of pharmacogenetic factors in the treatment of neuroblastoma demands an integrated pharmacokinetic-pharmacodynamic approach to the analysis of treatment response data. PMID- 21287162 TI - Rapid, low-cost MR imaging protocol to document central nervous system and sinus abnormalities prior to pediatric hematopoietic stem cell transplantation. AB - Patients undergoing bone marrow transplant (BMT) are at risk for infectious complications, including those of the sinus. Central nervous system (CNS) abnormalities related to the chemotherapy or radiation that the patient received for the treatment of underlying malignancy or to transplant-related effects are also commonly seen. The only effective way to differentiate pre- and post transplant causes is to have a baseline evaluation prior to the admission for transplant. The current method used to evaluate these patients is head CT. However, CT is not accurate to demonstrate CNS abnormalities and exposes the patient to radiation. MRI, despite better sensitivity for white matter abnormalities, has not been routinely used because of the higher cost and longer duration of the exam. Therefore, we designed a fast, low-cost and radiation-free MRI-based protocol to simultaneously evaluate sinus and brain abnormalities. PMID- 21287163 TI - Menthol diminishes Staphylococcus aureus virulence-associated extracellular proteins expression. AB - Staphylococcus aureus is a significant human pathogen that is the major cause of a broad spectrum of illnesses, ranging from minor skin infections to life threatening deep tissue infections and toxinosis. The ability of the organism to cause such a broad range of infections is, to a great extent, attributed to the secretion of a myriad of virulence-related extracellular proteins. Therefore, virulence as a target for antimicrobial chemotherapy has gained great interest. Menthol is a monocyclic terpene alcohol that occurs naturally in plants of the Mentha species lacking anti-S. aureus activity. In this paper, we demonstrate via hemolytic activity assays, tumor necrosis factor release assays, Western blot assays, and real-time reverse transcription-PCR assays that low concentrations of menthol can markedly inhibit the expression of alpha-hemolysin, enterotoxins A and B, and toxic shock syndrome toxin 1 in S. aureus. Our results indicate that menthol may be useful in managing S. aureus infections when used in combination with beta-lactam antibiotics, which can often increase S. aureus toxin secretion when used at subinhibitory concentrations. In addition, the menthol basic structure has potential applications in the development of new anti-virulence drugs. PMID- 21287164 TI - Intracellular salicylic acid is involved in signal cascade regulating low ammonium-induced taxoid biosynthesis in suspension cultures of Taxus chinensis. AB - It was previously reported that low initial ammonium (2 mM) in medium had significant stimulating effects on the biosynthesis of taxuyunnanine C (Tc) by Taxus chinensis cells. However, the secondary metabolism induction mechanism of the low initial ammonium is yet unknown in plant cells. To provide an insight into the defense signals response to the low initial ammonium, oxidative burst and intracellular salicylic acid (SA) were detected, and their influences on the expression of important genes in taxoid biosynthetic pathway were examined in the cell cultures of T. chinensis. Induced H(2)O(2) production, elevated phenylalanine ammonia-lyase (PAL) activity, and enhanced SA biosynthesis were observed. Interestingly, inhibition of SA biosynthesis by paclobutrazol and (BOC aminooxy) acetic acid significantly depressed the Tc stimulation and up regulation of Tc biosynthetic genes of geranylgeranyl diphosphate synthase and taxadiene synthase. The role of intracellular SA in regulating Tc biosynthesis was further confirmed by applying exogenous SA in normal ammonium (20 mM) medium. The results indicated that SA acted as a signal in low initial ammonium-induced Tc biosynthesis. A signal transduction cascade from defense signal response to activated transcription of taxoid biosynthetic genes and enhanced Tc production is proposed. PMID- 21287165 TI - Effect of operational conditions on the degradation of organic matter and development of microalgae-bacteria consortia when treating swine slurry. AB - There is great controversy regarding the best substrate (fresh or anaerobically digested swine slurry) for the development of microalgae-bacteria consortia. This study aims to elucidate the best substrate by assessing biomass productivity, microorganism predominance, and their ability for organic matter removal. In addition to the different substrates, different operational conditions and influent strengths were evaluated. Increasing organic matter content when favourable temperature and illumination conditions were present improved biomass production. However, these conditions were not favourable for microalgal growth, but they were favourable for bacteria. Regardless of the operational conditions, reactors fed with fresh slurry not only resulted in the highest biomass productivity, but also the greatest removal of total and soluble chemical oxygen demand (COD). On the other hand, reactors fed with digested slurry showed biomass productivity and COD removal values lower than those obtained for reactors fed with fresh slurry, most probably due to the recalcitrant nature of the former. Nevertheless, digested slurry was the substrate more appropriate for microalgae growth under harsh operational conditions (16 degrees C and 9-h illumination) at low influent strength and optimum operational conditions (30 degrees C and 24-h illumination) at higher influent strength. PMID- 21287166 TI - Improved p-hydroxybenzoate production by engineered Pseudomonas putida S12 by using a mixed-substrate feeding strategy. AB - The key precursors for p-hydroxybenzoate production by engineered Pseudomonas putida S12 are phosphoenolpyruvate (PEP) and erythrose-4-phosphate (E4P), for which the pentose phosphate (PP) pathway is an important source. Since PP pathway fluxes are typically low in pseudomonads, E4P and PEP availability is a likely bottleneck for aromatics production which may be alleviated by stimulating PP pathway fluxes via co-feeding of pentoses in addition to glucose or glycerol. As P. putida S12 lacks the natural ability to utilize xylose, the xylose isomerase pathway from E. coli was introduced into the p-hydroxybenzoate producing strain P. putida S12palB2. The initially inefficient xylose utilization was improved by evolutionary selection after which the p-hydroxybenzoate production was evaluated. Even without xylose-co-feeding, p-hydroxybenzoate production was improved in the evolved xylose-utilizing strain, which may indicate an intrinsically elevated PP pathway activity. Xylose co-feeding further improved the p-hydroxybenzoate yield when co-fed with either glucose or glycerol, up to 16.3 Cmol% (0.1 g p-hydroxybenzoate/g substrate). The yield improvements were most pronounced with glycerol, which probably related to the availability of the PEP precursor glyceraldehyde-3-phosphate (GAP). Thus, it was demonstrated that the production of aromatics such as p-hydroxybenzoate can be improved by co feeding different carbon sources via different and partially artificial pathways. Moreover, this approach opens new perspectives for the efficient production of (fine) chemicals from renewable feedstocks such as lignocellulose that typically has a high content of both glucose and xylose and (crude) glycerol. PMID- 21287167 TI - Value of 18F-fluorodeoxyglucose uptake in positron emission tomography/computed tomography in predicting survival in multiple myeloma. AB - PURPOSE: We assessed the role of the maximum standardized uptake value (SUV(max)) of bone marrow and the extramedullary lesion with the highest SUV(max) in positron emission tomography/computed tomography (PET/CT) of newly diagnosed multiple myeloma (MM) patients in predicting overall survival (OS). METHODS: A total of 61 newly diagnosed patients (55 MM and 6 plasmacytoma) were enrolled in the study [37 men and 24 women with a median age of 57 years (range 28-80 years)]. The SUV(max) of bone marrow and the extramedullary lesion in PET/CT was correlated with the levels of beta(2)-microglobulin, C-reactive protein (CRP), albumin, creatinine, per cent of bone marrow plasma cells, serum free light chain (FLC) ratio, International Staging System (ISS) score and Durie-Salmon stage. RESULTS: The extramedullary lesion with the highest SUV(max) showed significant correlation with bone marrow fluorodeoxyglucose (FDG) uptake (p = 0.027) and near significant correlation with ISS (p = 0.048). Bone marrow SUV(max) correlated significantly with the per cent of bone marrow plasma cell count (p = 0.024), CRP (p = 0.012) and ISS (p = 0.013). In stage III MM the mean values of SUV(max) in extramedullary lesions were significantly higher than stages I and II (6.23 +/- 6.32 vs 2.85 +/- 3.44, p = 0.023). The serum FLC ratio did not show any correlation with SUV(max) of lesions and bone marrow (p > 0.05). Forty-four MM patients with FDG-positive lesions in PET/CT showed inferior 5-year estimated survival (61.73%) when compared to 11 patients without FDG-positive lesions, all of whom were alive (p = 0.01). In multivariate analysis an extramedullary lesion with the highest SUV(max) was the only independent predictor of OS (p = 0.03). CONCLUSION: PET/CT allows identification of high-risk myeloma patients, and extramedullary lesions with the highest SUV(max) independently predict inferior OS. PMID- 21287168 TI - Iterative reconstruction or filtered backprojection for semi-quantitative assessment of dopamine D2 receptor SPECT studies? AB - PURPOSE: In routine clinical practice striatal dopamine D(2) receptor binding is generally assessed using data reconstructed by filtered backprojection (FBP). The aim of this study was to investigate the use of an iterative reconstruction algorithm (ordered subset expectation maximization, OSEM) and to assess whether it may provide comparable or even better results than those obtained by standard FBP. METHODS: In 56 patients with parkinsonian syndromes, single photon emission computed tomography (SPECT) scans were acquired 2 h after i.v. application of 185 MBq [(123)I]iodobenzamide (IBZM) using a triple-head gamma camera (Siemens MS 3). The scans were reconstructed both by FBP and OSEM (3 iterations, 8 subsets) and filtered using a Butterworth filter. After attenuation correction the studies were automatically fitted to a mean template with a corresponding 3-D volume of interest (VOI) map covering striatum (S), caudate (C), putamen (P) and several reference VOIs using BRASS software. RESULTS: Visual assessment of the fitted studies suggests a better separation between C and P in studies reconstructed by OSEM than FBP. Unspecific background activity appears more homogeneous after iterative reconstruction. The correlation shows a good accordance of dopamine receptor binding using FBP and OSEM (intra-class correlation coefficients S: 0.87; C: 0.88; P: 0.84). Receiver-operating characteristic (ROC) analyses show comparable diagnostic power of OSEM and FBP in the differentiation between idiopathic parkinsonian syndrome (IPS) and non-IPS. CONCLUSION: Iterative reconstruction of IBZM SPECT studies for assessment of the D(2) receptors is feasible in routine clinical practice. Close correlations between FBP and OSEM data suggest that iteratively reconstructed IBZM studies allow reliable quantification of dopamine receptor binding even though a gain in diagnostic power could not be demonstrated. PMID- 21287169 TI - Feasibility of 62Cu-ATSM PET for evaluation of brain ischaemia and misery perfusion in patients with cerebrovascular disease. AB - PURPOSE: [(62)Cu]Diacetyl-bis(N (4)-methylthiosemicarbazone) ((62)Cu-ATSM) was used to evaluate brain haemodynamic impairment in patients with cerebrovascular disease (CVD) as a simplified evaluation method. The tracer distribution was compared with haemodynamic parameters obtained by (15)O positron emission tomography (PET). METHODS: Ten patients with major cerebral arterial occlusive disease (aged 66 +/- 7 years) underwent PET with (62)Cu-ATSM and (15)O tracers ((15)O-water, (15)O(2) and C(15)O). Seven healthy volunteers also underwent (62)Cu-ATSM PET as normal controls. After the injection of (62)Cu-ATSM, 20-min dynamic PET data acquisition was started. Early- and delayed-phase images of (62)Cu-ATSM were obtained by averaging the initial 3-min and the last 10-min frame data, which were used for perfusion and retention images. Cerebral blood flow (CBF), blood volume, metabolic rate of oxygen (CMRO(2)) and oxygen extraction fraction (OEF) were measured by (15)O-gas and water studies and compared with early- and delayed-phase (62)Cu-ATSM images and delayed to early (D/E) ratio. Regional values were compared after all parametric images were coregistered to individual MRI. The asymmetry index (AI) was also calculated for OEF and Cu-ATSM D/E ratio, and diagnostic ability for detecting misery perfusion was compared. RESULTS: In the affected hemisphere of the patients, the mean values of haemodynamic parameters were CBF = 33.8 +/- 5.9 ml/100 g per min, CMRO(2) = 2.6 +/- 0.3 ml/100 g per min and OEF = 48 +/- 7%. Standardized uptake values (SUVs) for (62)Cu-ATSM in early and delayed phases were 2.00 +/- 0.13 and 1.04 +/- 0.09 in the ipsilateral hemisphere and 2.13 +/- 0.14 and 1.04 +/- 0.08 in the contralateral hemisphere, respectively. The early-phase (62)Cu-ATSM images corresponded well to CBF images, and the D/E ratio images were similar to OEF images. Regional values obtained from D/E ratio images were significantly correlated with regional OEF. AIs of OEF and D/E ratio showed a significant correlation and diagnostic ability of misery perfusion was slightly better in AI of D/E ratio than that of OEF. CONCLUSION: Dynamic PET acquisition with (62)Cu ATSM provided information on CBF distribution and local elevation of OEF in patients with chronic CVD. The findings of the present study showed the feasibility of the noninvasive molecular imaging method for diagnosing misery perfusion with a single venous tracer injection. PMID- 21287170 TI - Effect of the positron range of 18F, 68Ga and 124I on PET/CT in lung-equivalent materials. AB - PURPOSE: The aim of this study was to investigate the effect of positron range on visualization and quantification in (18)F, (68)Ga and (124)I positron emission tomography (PET)/CT of lung-like tissue. METHODS: Different sources were measured in air, in lung-equivalent foams and in water, using a clinical PET/CT and a microPET system. Intensity profiles and curves with the cumulative number of annihilations were derived and numerically characterized. RESULTS: (68)Ga and (124)I gave similar results. Their intensity profiles in lung-like foam had a peak similar to that for (18)F, and tails of very low intensity, but extending over distances of centimetres and containing a large fraction of all annihilations. For 90% recovery, volumes of interest with diameters up to 50 mm were required, and recovery within the 10% intensity isocontour was as low as 30%. In contrast, tailing was minor for (18)F. CONCLUSION: Lung lesions containing (18)F, (68)Ga or (124)I will be visualized similarly, and at least as sharp as in soft tissue. Nevertheless, for quantification of (68)Ga and (124)I large volumes of interest are needed for complete activity recovery. For clinical studies containing noise and background, new quantification approaches may have to be developed. PMID- 21287171 TI - Primary malignant fibrous histiocytoma of the liver: CT findings in five histopathological proven patients. AB - BACKGROUND: To describe imaging features of primary hepatic malignant fibrous histiocytoma (MFH), especially its dynamic enhancement pattern. MATERIALS: The CT manifestations of five patients with histopathological proven primary hepatic MFH retrospectively reviewed. RESULTS: Six hepatic masses were detected in the five patients at CT examinations. All tumors were hypodense on plain CT scanning related to adjacent hepatic parenchyma. Five lesions were heterogeneous with predominantly cystic or necrosis areas and one lesion was homogeneous solid. After administration of contrast material, solid components of the four tumors with cystic or necrotic areas and the solid lesion showed a "fast rushing in and washing out" enhancement pattern with marked enhancement at the arterial dominated phase and fast decreasing at the portal vein dominated phase and the delay phase. The remaining one tumor showed slight enhancement of its solid components. Portal lymph node enlargement was observed in one patient and the inferior vena cava was invaded in one patient, respectively. CONCLUSION: The CT manifestations of primary hepatic MFH are various and nonspecific. A "fast rushing in and washing out" enhancement pattern of MFH in our series has not been reported before. These manifestations could help radiologists to include primary hepatic MFH in the differential diagnosis list. PMID- 21287172 TI - Long-term results of anterior cruciate ligament reconstruction: a comparison with non-operative treatment with a follow-up of 17-20 years. AB - PURPOSE: The aim of our study was to review the clinical and radiological outcome of patients who had undergone anterior cruciate ligament (ACL) reconstruction in comparison to a group of non-operatively treated patients. METHODS: In a retrospective study we compared ACL reconstruction using a bone-patellar tendon bone graft with a non-operatively treated group of patients 17-20 years later. Fifty-four patients that met the inclusion criteria, with arthroscopically proven ACL rupture, were treated between 1989 and 1991. Thirty-three patients underwent ACL reconstruction, forming group one. Eighteen non-reconstructed patients continued with rehabilitation and modification of activities (group two). The International Knee Documentation Committee (IKDC) subjective and objective evaluation forms and the Lysholm and Tegner scale were used to assess the knees at follow-up. Radiographic assessment was performed using the IKDC grading scale. RESULTS: Follow-up results showed that 83% of reconstructed patients had stable knees and normal or nearly normal IKDC grade. Patients in the non-reconstructed group had unstable knees with 84% having abnormal or severe laxity. The subjective IKDC score was significantly in favour of group one: 83.15 compared to 64.6 in group two. The Lysholm and Tegner score was also significantly better in group one. Conservatively treated patients all had unstable knees and worse scores. The rate of osteoarthritis showed more severe changes in non reconstructed patients with additional meniscus injury. CONCLUSIONS: We can conclude that 94% of patients who underwent ACL reconstruction had stable knees after 15-20 years and there was a significantly lower percentage of osteoarthritis in comparison to conservatively treated patients. PMID- 21287173 TI - Scalloped thoracic stent-graft for treatment of aortic arch aneurysms with unfavourable landing zones. AB - Endovascular treatments are limited in cases of thoracic aortic aneurysms extending up or proximal to the origin of the left subclavian artery (LSCA). In such cases, the LSCA is usually either occluded or revascularised. We report our first experience of four patients who underwent thoracic aneursym treatment with new custom-made grafts with a scallop in situ for the LSCA. The graft is tailor made per case, and a re-enforced scallop is positioned proximally allowing for the stent to be deployed beyond the origin of the LSCA; the origin of the LSCA remains patent, thus negating the need for revascularisation of the head and neck vessels on the left. The stent contains markers for identifying the scallop and are located along the midline to ensure correct alignment. All of the patients who underwent this procedure had technical success with flow through the LSCA both immediately after stent deployment and on follow-up imaging. This new stent has further expanded endovascular treatment options for patients with thoracic aneurysms extending up to and beyond the LSCA, which can play a part in improving outcome and decreasing mortality rates because surgery for revascularization will not be needed. PMID- 21287174 TI - Overexpression in tobacco of a tomato GMPase gene improves tolerance to both low and high temperature stress by enhancing antioxidation capacity. AB - GDP-mannose pyrophosphorylase (GMPase: EC 2.7.7.22) plays a crucial role in the synthesis of L-ascorbate (AsA) and the consequent detoxification of reactive oxygen species (ROS). Herein, a GMPase (accession ID DQ449030) was identified and cloned from tomato. The full-length cDNA sequence of this gene contains 1,498 bp nucleotides encoding a putative protein with 361 amino acid residues of approximate molecular weight 43 kDa. Northern blot analysis revealed that the GMPase was expressed in all examined tomato tissues, but its expression level was up-regulated in tomato plants subjected to abnormal temperatures. We then overexpressed this tomato GMPase in tobacco plants and observed that the activity of GMPase and the content of AsA were significantly increased by two- to fourfold in the leaves of transgenic tobacco plants. The effect of this gene overexpression was superimposed by the treatments of high or low temperature in tobacco, since the activities of both chloroplastic SOD (superoxide dismutase EC 1.15.1.1), APX (ascorbate peroxidase EC 1.11.1.7) and the content of AsA in leaves were significantly higher in transgenic plants than those of WT, while the contents of H(2)O(2) and O(2)(-.) were reduced. Meanwhile, relative electric conductivity increased less in transgenic plants than that in WT, and the net photosynthetic rate (P(n)) and the maximal photochemical efficiency of PSII (F(v)/F(m)) of transgenic plants were notably higher than those of WT under temperature stresses. In conclusion, the overexpression of GMPase increased the content of AsA, thereby leading to the increase in tolerance to temperature stress in transgenic plants. PMID- 21287175 TI - Induced ectopic expression of At-CBF1 in marker-free transgenic tomatoes confers enhanced chilling tolerance. AB - In an attempt to improve chilling stress tolerance, an Arabidopsis C-repeat binding factor 1 (At-CBF1) gene driven by the inducible promoter RD29A was co transferred into tomato var. Shalimar. Marker (NPTII)-free transgenic were obtained in T(1) generation because of unlinked integration of CBF1 and NPTII genes. Reverse transcription-polymerase chain reaction confirmed the expression of CBF1 in T(1) transgenic lines. Study of expression pattern in T(1) transgenic line showed a gradual increase with increasing chilling stress period and also confirmed the reversibility of expression on removal of stress. The transgenic plants exhibited no morphological and agronomical differences as compared to non transformed plants. When young transgenic plants were exposed to chilling stress (4 degrees C) for 3 days, increased survival (50%) was observed in transgenic lines than non-transformed plants (10%). Transgenic plants subjected to the chilling stress showed a significant decrease in membrane injury index and lipid peroxidation and also increased significantly free proline content in the leaf tissues as compared to non-transformed plants. Thus, these findings indicate that marker-free transgenic tomato plants expressing Arabidopsis CBF1 gene provided protection and conferred cold tolerance to transgenic tomato without any phenotypic variation. PMID- 21287177 TI - Feasibility of dynamic MRI for evaluating velopharyngeal insufficiency in children. AB - OBJECTIVE: To demonstrate the feasibility of dynamic MRI with near-real-time temporal resolution for analysing velopharyngeal closure. METHODS: Eleven children and young adults (seven girls, four boys, mean age: 8.4 years) with suspected velopharyngeal insufficiency (VPI), and one healthy volunteer underwent MRI (1.5 Tesla) using T2 fast imaging sequences. Imaging was done without any sedation at rest and during various phonations in the axial and sagittal planes. Images were analysed by two radiologists, a plastic surgeon and a speech therapist. RESULTS: The MRI examinations were well tolerated by even the youngest patient. A qualitative analysis found that the sagittal dynamic sequences during phonation were in relation to the clinical data in all patients. A quantitative analysis enabled calculation of the elevation angle of the soft palate in relation to the hard palate, the velar eminence angle and the percentage of reduction of the antero-posterior diameter of the pharyngeal lumen. CONCLUSION: Dynamic MRI is a non-invasive, rapid and repeatable method. It can be considered a complementary tool to endoscopy and fluoroscopy, particularly in children, for assessing VPI without any sedation or radiation exposure. PMID- 21287176 TI - Application of proteomics to investigate stress-induced proteins for improvement in crop protection. AB - Proteomics has contributed to defining the specific functions of genes and proteins involved in plant-pathogen interactions. Proteomic studies have led to the identification of many pathogenicity and defense-related genes and proteins expressed during phytopathogen infections, resulting in the collection of an enormous amount of data. However, the molecular basis of plant-pathogen interactions remains an intensely active area of investigation. In this review, the role of differential analysis of proteins expressed during fungal, bacterial, and viral infection is discussed, as well as the role of JA and SA in the production of stress related proteins. Resistance acquired upon induction of stress related proteins in intact plant leaves is mediated by potentiation of pathogens via signal elicitors. Stress related genes extensively used in biotechnology had been cited. Stress related proteins identified must be followed through for studying the molecular mechanism for plant defense against pathogens. PMID- 21287178 TI - [Thrombophilic and systemic risk factors in patients with retinal vein occlusion]. AB - Over the past years there has been a dramatic increase in the number of identifiable causes of thrombophilia. However, as retinal vein occlusions (RVO) have a strong pathogenic correlation with the presence of hypertension or arteriosclerosis and the average age of affected patients is usually within the sixth or seventh decade of life, thrombophilia screening of RVO patients poses a particularly difficult diagnostic challenge. It is clear that to use medical resources appropriately and improve the level of interdisciplinary patient care in RVO, subgroup analysis is required. Just recently, some studies have demonstrated the significant role of coagulation disorders in specific subgroups of RVO patients and have provided recommendations for clinical practice. These results indicate that thrombophilic risk factors are significantly more prevalent among patients equal or less than 45 years of age at the time of RVO or a previous thromboembolic event, among patients with a remarkable family history of thromboembolism prior to the age of 45 years, or among patients without cardiovascular risk factors. According to these data, thrombophilia screening should be considered in these selected subgroups. PMID- 21287179 TI - Alice-in-Wonderland syndrome--a case-based update and long-term outcome in nine children. AB - PURPOSE: There are some reports of so-called Alice-in-Wonderland syndrome mostly concerning differential diagnosis, association with a variety of infectious diseases and even some case reports on functional imaging. Long-term data are rare. METHODS: Nine boys aged 6 to 11 years that had been diagnosed with Alice-in Wonderland syndrome between 2003 and 2008 were contacted for a long-term follow up study in summer, 2009, with a mean follow-up of 4.6 years. RESULTS: At the time of the follow-up study, all children were in good general and mental health. Symptoms of Alice-in-Wonderland syndrome had ceased within weeks or months. In two patients, episodes of metamorphopsia returned after a symptom-free latency of 3 years and 1 year, respectively. Five children had a family history of migraine or epilepsy. In one case, the father was reported to have experienced similar symptoms when he was a child. CONCLUSION: Our follow-up study shows that Alice-in Wonderland is most likely a benign, self-terminating childhood condition, although occasional recurrences of symptoms are possible. PMID- 21287180 TI - Harvey Cushing's early experience with pediatric gliomas. AB - PURPOSE: Diagnosing and operating pediatric patients with intracranial lesions posed a greater diagnostic challenge for physicians during the early twentieth century. At the time, an intracranial neoplasm was indistinctively diagnosed as a glioma, encompassing a broad category of brain tumor pathologies. The treatment and surgical interventions followed for children diagnosed with gliomas is not well-described in the literature from this time. METHODS: Following IRB approval, and through the courtesy of the Alan Mason Chesney Archives, we reviewed the Johns Hopkins Hospital surgical files from 1896-1912. Patients 18 years or younger, who underwent surgical intervention by Cushing for suspected intracranial tumors, were selected. RESULTS: Of the eight pediatric cases diagnosed with gliomas by Cushing, four cases were later diagnosed as medulloblastomas by Dr. Cushing in 1925. Of the remaining four pediatric cases, one was diagnosed as a brainstem glioma and another as a ventricular glioma. We describe the remaining two cases. CONCLUSION: These examples illustrate Cushing's approach to treating brain tumors diagnosed as gliomas in pediatric patients, focusing on an initial decompression and followed by a thorough surgical exploration for tumor. Furthermore, these cases demonstrate Cushing's early attempts to manage such lesions in children and highlight the challenges faced in diagnosing and localizing intracranial lesions within this group of patients. PMID- 21287181 TI - Gender differences in reduced substance P (SP) in children with slow-transit constipation. AB - PURPOSE: Adult slow-transit constipation (STC) occurs predominantly in females and is associated with low numbers of substance P (SP)-containing nerves in colonic circular muscle. AIM: To determine if reduced SP nerves is female predominant in paediatric STC. METHODS: Children with STC were identified from records of more than 600 nuclear transit studies (NTS) and intestinal biopsies done for intractable chronic constipation between November 1998 and March 2009. Colonic seromuscular biopsies collected from hepatic and splenic flexures, and sigmoid colon were processed for immunohistochemistry. Nerve fibre density in circular muscle containing SP was measured qualitatively by a pathologist. RESULTS: Eighty-eight children with chronic constipation had both NTS and intestinal biopsies. Seventy-eight children (52 M; age 2-15.5 years; mean 7.7 years) had STC diagnosed by NTS. SP was reduced in 10/26 girls, but only 11/52 boys. CONCLUSION: In this sample, STC was more common in boys than girls. However, in girls with STC, SP deficiency occurred in 40%, when compared with 20% of boys. During puberty, the percentage of girls with reduced SP decreased, whilst the percentage of boys increased. These results suggest that STC is heterogeneous and that there are some gender differences, the implication of which requires further investigation. PMID- 21287182 TI - Fibrotic response of tissue remodeling in COPD. AB - Lung tissue remodeling in chronic obstructive pulmonary disease (COPD) involves diverse processes characterized by epithelial disruption, smooth muscle hypertrophy/hyperplasia, airway wall fibrosis, and alveolar destruction. According to the accepted current theory of COPD pathogenesis, tissue remodeling in COPD is predominantly a consequence of an imbalance between proteolytic and antiproteolytic activities. However, most of the studies carried out during the last few years have focused on mechanisms related to degradation of extracellular matrix (ECM) structural proteins, neglecting those involved in ECM protein deposition. This review revisits some of the latest findings related to fibrotic changes that occur in the airway wall of COPD patients, as well as the main cellular phenotypes relevant to these processes. PMID- 21287183 TI - Mononeuropathy multiplex associated with acute parvovirus B19 infection: characteristics, treatment and outcome. AB - To describe the characteristics of peripheral neuropathy related to acute parvovirus B19 (B19V) infection. We reviewed clinical, electrophysiological and histological data of three patients with peripheral neuropathy and positive B19V detection (IgG, IgM and PCR) compatible with acute infection. The neuropathy fulfilled criteria for mononeuropathy multiplex (MM). It could be preceded by or concurrent with a limited purpuric eruption, but systemic manifestations were absent. The first neurological symptoms were always sensory and localized in a hand. Neuropathy was initially limited to a restricted sensory part of a nerve trunk territory. The course was subacute with successive and asymmetric injury of the limb and cranial nerves. Electromyographic study confirmed the diagnosis of MM with multifocal asymmetric sensory and motor axonal loss in two patients, whereas the neuropathy was purely sensory and limited to two nerves in the other patient. Nerve biopsies showed no evidence of necrotizing vasculitis but, in one patient, revealed a lymphocytic perivascular infiltrate evocative of hypersensitivity vasculitis secondary to an infectious agent. Intravenous immunoglobulin (IVIg) was systematically administered. Long-term outcome was good but with incomplete sensory recovery and, for one patient, persistence of a functional disability. B19 V infection should be considered in the etiological assessment of MM, especially in the event of a progressive sensory disorder in the hands and a concomitant history of rash. IVIg may be an effective treatment for this inflammatory disorder. PMID- 21287184 TI - Do supine position and deprivation of visual environment influence spatial neglect? AB - It has been suggested that in spatial neglect, placing the patient in a supine position and performing tasks in the dark would reduce the rightward bias in line bisection and cancellation tasks. However, these findings remain debated and have not been extended to other tasks such as reading or visual exploration. Here, in the same study, we examined the effect of body position (BP) and visual environment (VE) on relatively ecological tests of spatial neglect. Among 17 patients with right-hemisphere stroke, 12 were neglect and five were non-neglect in clinical tests. They were compared with 12 healthy control participants in four tasks: line bisection, text reading, number reading, and visual exploration. Tasks were performed on a computer screen in two BP (sitting and supine) and two VE (light and dark) conditions. We found that placing patients in darkness reduced contralesional omissions in the visual exploratory task and, to a smaller extent, in number reading. Conversely, the supine position did not influence performance, and even resulted in cognitive slowing, especially in reading. In conclusion, we confirmed that reducing visual information can improve performance, but only to a limited extent. This justifies strict control of peripheral visual information when exploring neglect patients. Conversely, positioning neglect patients in the supine position can have a discrete negative effect on cognitive functioning, and this effect must be taken into account during therapy. PMID- 21287185 TI - Diffusion tensor imaging and olfactory identification testing in early-stage Parkinson's disease. AB - Evidence from imaging, clinical studies, and pathology suggests that Parkinson's disease is preceded by a prodromal stage that predates clinical diagnosis by several years but there is no established method for detecting this stage. Olfactory impairment, which is common in Parkinson's disease and often predates clinical diagnosis, may be a useful biomarker for early Parkinson's. Evidence is emerging that diffusion imaging parameters might be altered in olfactory tract and substantia nigra in the early stages of clinical Parkinson's disease, possibly reflecting pathological changes. However, no study has examined olfaction and diffusion imaging in olfactory tract and substantia nigra in the same group of patients. The present study compared newly diagnosed Parkinson's disease patients with a matched control group using both olfactory testing and diffusion tensor imaging of the substantia nigra and anterior olfactory structures. Fourteen patients with stage 1-2 Hoehn & Yahr Parkinson's disease were matched to a control group by age and sex. All subjects then completed the University of Pennsylvania Smell Identification Test, as well as a series of MRI scans designed to examine diffusion characteristics of the olfactory tract and the substantia nigra. Olfactory testing revealed significant impairment in the patient group. Diffusion tensor imaging revealed significant group differences in both the substantia nigra and anterior olfactory region, with fractional anisotropy of the olfactory region clearly distinguishing the Parkinson's subjects from controls. This study suggests that there may be value in combining behavioral (olfaction) and MRI testing to identify early Parkinson's disease. Since loss of olfaction often precedes the motor symptoms in Parkinson's disease, the important question raised is "will the combination of olfactory testing and MRI (DTI) testing identify pre-motor Parkinson's disease?" PMID- 21287186 TI - Psychosocial aspects in myasthenic patients treated by plasmapheresis. AB - Knowledge about the postintervention psychosocial status of myasthenia gravis (MG) is limited and based on questionnaire studies. In this study, the effects of improvement in muscle strength with plasmapheresis treatment on both quality of life (QoL) and psychological status of MG patients were studied. Between January 2008 and December 2009, 29 MG patients were enrolled to receive one course of plasmapheresis treatment. Differences in baseline and posttherapy clinical, laboratory, and psychosocial measures were determined. The mean MG score decreased from 7.8 points at baseline to 4.2 after plasmapheresis, accompanied by the mean antibody clearance of 56%. Psychosocial tests showed significant pre- and posttherapy differences in illness identity (mean scores 23.62 and 20.79 points, respectively) and disability (mean scores 11.28 and 7.63 points, respectively) (p < 0.01). No significant differences were found for the other indices. Although both anxiety and depression scores did not differ significantly, there was a clear change in patients, as evidenced by their decreases in severity after treatment. The mean mental components scores of QoL were still less than 40 after treatment, indicating that myasthenic patients need assistance in adapting to their disease. Thus, although plasmapheresis treatment achieved immediate improvement of myasthenic symptoms, reduced disability, and better illness identity, both emotional status and QoL did not differ significantly after intervention. Systematical evaluation for patients' illness perceptions and emotional problems are warranted and related strategies should be taken for long-term stabilization of psychosocial function. PMID- 21287187 TI - Combined stimulation of the substantia nigra pars reticulata and the subthalamic nucleus is effective in hypokinetic gait disturbance in Parkinson's disease. PMID- 21287188 TI - Central neuropathic pain after cerebral venous thrombosis is not so uncommon: an observational study. AB - Central neuropathic pain (CNP) after stroke has not been studied in sufficient detail and published studies have only included patients with cerebral artery infarct or hemorrhage. This study evaluates the prevalence and factors associated with CNP after cerebral venous (and sinus) thrombosis (CVT). This observational study included all patients admitted to our stroke unit for CVT between January 2002 and December 2007. Clinical data for each patient were collected prospectively and were combined with retrospective review of neuroradiological imaging. CVT patients were systematically examined at the outpatient clinic at 6 months, 12 months, and annually thereafter, and information on long-term functional outcome, including the presence of CNP, were obtained by open-ended questions. A standardized CNP assessment was performed during the last outpatient visit and was based on the patient's interview and clinical examination. Pain characteristics were assessed by the DN4-questionnaire. CNP was considered when the patient met the following criteria: painful area within the area of sensory abnormalities and follow-up MRI showing brain parenchymal lesion. Among the 43 patients admitted for CVT, seven (16%) developed CNP during the first year of follow-up. Standardized CNP assessment was performed 24.9 +/- 11.6 months after CVT: eight patients (19%) suffered from CNP. Initial motor deficit (87 vs. 17%, p < 0.001), initial sensory deficit (62 vs. 20%, p = 0.03), cerebral infarction (75 vs. 23%, p = 0.009), right-sided lesion on initial MRI (62 vs. 17%, p = 0.017), thalamic (37 vs. 0%, p = 0.005) and basal ganglia involvement (25 vs. 0%, p = 0.03) and vein of Galen occlusion (25 vs. 0%) were significantly associated with CNP. Despite several methodological limitations, CNP after CVT seems to be frequent, accounting for one-fifth of all cases of CVT. Some clinical and radiological factors might contribute to the development of CNP. PMID- 21287189 TI - The effect of bleach duration and age on the ERG photostress test. AB - BACKGROUND: The ERG photostress test assesses the recovery of the focal 41 Hz ERG following exposure to a bright light that bleaches a significant proportion of photopigment. The aims of this study were: 1) to compare the repeatability of the ERG photostress test recovery time constant following long and short duration light exposure, and 2) to determine the effect of age on the ERG photostress test recovery time constant. METHODS: Focal 41 Hz ERGs were recorded from 23 participants (age range 20-71 years) at 20-second intervals for 5 minutes following either a short-duration (photoflash) or long-duration (equilibrium) light exposure. After a 5-minute wash-out period, the procedure was repeated using the second bleach modality. The time constant of cone recovery was determined by fitting an exponential model to the amplitude recovery data. The whole procedure was repeated on a second occasion. The co-efficient of repeatability (CoR) was calculated for each bleaching technique. The relationship between the time constant of recovery and age was investigated (Pearson's correlation coefficient). RESULTS: The time constant of recovery following an equilibrium bleach was more repeatable than recovery following a photoflash (CoR = 85s and 184s respectively). Eight trials (from seven participants) failed to show a reduction in amplitude following the photoflash, suggesting that a blink or fixation loss had occurred. All participants were reliably light-adapted by the equilibrium bleach. For the equilibrium bleach data, the time constant of recovery increased with age at a rate of 27 seconds per decade. CONCLUSIONS: The equilibrium bleach was more reliable and repeatable than the photoflash. Increasing participant age was shown to result in a lengthening of the recovery time constant, of a magnitude comparable to previously published psychophysical data. PMID- 21287190 TI - Evaluation of perifoveal capillary blood flow velocity before and after vitreous surgery for epiretinal membrane. PMID- 21287191 TI - The parameters of the porcine eyeball. AB - BACKGROUND: The eye of the domestic pig (Sus scrofa domestica) is an ex vivo animal model often used in vision sciences research (retina studies, glaucoma, cataracts, etc.). However, only a few papers have compiled pig eye anatomical descriptions. The purpose of this paper is to describe pig and human eye anatomical parameters to help investigators in their choice of animal model depending on their study objective. METHODS: A wide search of current medical literature was performed (English language) using PubMed. Anteroposterior axial length and corneal radius, astigmatism, vertical and horizontal diameter, and pachymetry (slit-scan and ultrasound) were measured in five enucleated pig eyes of animals 6 to 8 months old. RESULTS: Horizontal corneal diameter was 14.31 +/- 0.25 mm (CI 95% 14.03 mm-14.59 mm), vertical diameter was 12.00 +/- 0 mm, anteroposterior length was 23.9 +/- 0.08 mm (CI 95% 23.01 mm-29.99 mm), central corneal ultrasound pachymetry was 877.6 +/- 13.58 MUm (CI 95% 865.70 MUm-889.50 MUm) and slit-scan pachymetry was 906.2 +/- 15.30 MUm (CI 95% 892.78 MUm-919.61 MUm). Automatic keratometry (main meridians) was 41.19 +/- 1.76D and 38.83 +/- 2.89D (CI 95% 40.53D-41.81D and 37.76D-39.89D respectively) with an astigmatism of 2.36 +/- 1.70D (CI 95% 1.72D-3.00D), and manual keratometry was 41.05 +/- 0.54D and 39.30 +/- 1.15D (CI 95% 40.57D-41.52D and 38.29D-40.31D respectively) with an astigmatism of 1.75 +/- 1.31D (CI 95% 0.60D-2.90D). CONCLUSION: This paper describes the anatomy of the pig eyeball for easy use and interpretation by researchers who are considering their choice of animal model in vision sciences research. PMID- 21287192 TI - Visualization of Reinke's crystals in normal and cryptorchid testis. AB - Within the human testis, Reinke's crystals are found in Leydig cells but their nature and function are poorly understood. The aim of our study was to investigate the properties of Reinke's crystals in man with the normal morphology of the testis (control group) and infertile patients diagnosed with cryptorchidism. 20 biopsies from infertile patients and six biopsies from men with regular spermatogenesis (20-30 years.) were used. Sections of the testis tissue were stained with haematoxylin and eosin and a modified Masson's method. Specimens were observed by bright field, confocal and transmission electron microscopy (TEM). The number of Reinke's crystals in investigated groups was determined applying stereological methods. In both groups, Reinke's crystals were noted within the cytoplasm and nuclei of Leydig cells. Some "free" crystals were found within the interstitial space, outside Leydig cells. Confocal microscopy proved to be very useful in the assessment of the shape and 3D reconstruction of the crystal. TEM analysis confirmed a hexagonal form of the crystal, while crystallographic data on sections of 70-300 nm thickness provided a better insight into the organization of the crystal lattice. Stereological analysis revealed a significant increase in the number of crystals in cryptorchid testes when compared with controls. Increased number of crystals in cryptorchid specimens leads to the assumption that the prolonged exposure to higher (abdominal) temperature might stimulate enzymes involved in the synthesis of the proteins of the crystal. However, the exact molecular nature of the crystal lattice remains in both normal and cryptorchid testis obscure. PMID- 21287193 TI - Impact of simulated microgravity on microvascular endothelial cell apoptosis. AB - Cardiovascular deconditioning is known to occur in astronauts exposed to microgravity. Endothelial dysfunction at microcirculatory sites might contribute to cardiovascular deconditioning induced by weightlessness. Recent studies have reported changes in the morphology and gene expression of endothelial cells exposed to conditions of simulated microgravity. The present study was aimed at examining the effects of microgravity on the apoptosis of microvascular endothelial cells and the mechanism underlying these effects. We simulated a microgravity environment and found that microgravity induced microvascular endothelial cell apoptosis and that this effect was correlated with the downregulation of the PI3K/Akt pathway, increased expression of NF-kappaB, and depolymerization of F-actin. These findings may provide important insights into the origin of the adverse physiological changes occurring due to exposure to microgravity conditions. PMID- 21287194 TI - Exercise training enhances rat pancreatic islets anaplerotic enzymes content despite reduced insulin secretion. AB - Endurance exercise has been shown to reduce pancreatic islets glucose-stimulated insulin secretion (GSIS). Anaplerotic/cataplerotic pathways are directly related to GSIS signaling. However, the effect of endurance training upon pancreatic islets anaplerotic enzymes is still unknown. In this sense, we tested the hypothesis that endurance exercise decreases GSIS by reducing anaplerotic/cataplerotic enzymes content. Male Wistar rats were randomly assigned to one of the four experimental groups as follows: control sedentary group (CTL), trained 1 day per week (TRE1*), trained 3 days per week (TRE3*) and trained 5 days per week (TRE5x) and submitted to an 8 weeks endurance-training protocol. After the training protocol, pancreatic islets were isolated and incubated with basal (2.8 mM) and stimulating (16.7 mM) glucose concentrations for GSIS measurement by radioimmunoassay. In addition, pyruvate carboxylase (PYC), pyruvate dehydrogenase (PDH), pyruvate dehydrogenase kinase 4 (PDK4), ATP-citrate lyase (ACL) and glutamate dehydrogenase (GDH) content were quantified by western blotting. Our data showed that 8 weeks of chronic endurance exercise reduced GSIS by 50% in a dose-response manner according to weekly exercise frequency. PYC showed significant twofold increase in TRE3*. PYC enhancement was even higher in TRE5* (p < 0.0001). PDH and PDK4 reached significant 25 and 50% enhancement, respectively compared with CTL. ACL and GDH also reported significant 50 and 75% increase, respectively. The absence of exercise-induced correlations among GSIS and anaplerotic/cataplerotic enzymes suggests that exercise may control insulin release by activating other signaling pathways. The observed anaplerotic and cataplerotic enzymes enhancement might be related to beta-cell surviving rather than insulin secretion. PMID- 21287195 TI - Acute effects of static stretching on leg-spring behavior during hopping. AB - Despite the fact that a stiffer leg spring is prerequisite for achieving a better performance during sports activities, effects of various types of warm-up on the leg stiffness is not well-known. The purpose of this study was to determine if static stretching influences the leg stiffness during two-legged hopping. Fourteen male subjects performed two-legged hopping at 2.2 Hz before and after a 3-min passive stretching of the triceps surae (dorsiflexion of 30 degrees ). Based on a spring-mass model, we calculated leg stiffness, which is defined as the ratio of maximal ground reaction force to maximum center of mass displacement at the middle of the stance phase. It was found that there was no significant difference in leg stiffness after passive static stretching. These results suggest that 3-min passive static stretching does not affect the leg-spring behavior and stiffness regulation during two-legged hopping. Finally, possible explanations for the invariant leg stiffness after the passive stretching are discussed. PMID- 21287196 TI - Optimum loading for maximizing muscle power output: the effect of training history. AB - Although the effect of external load on the mechanical output of individual muscle has been well documented, the literature still provides conflicting evidence regarding whether the optimum loading (L(opt)) for exerting the maximum muscle power output (MPO) could be different for individuals with different levels of strength and power. The aim of this study was to explore the effect of training history on L(opt) that maximizes MPO during the 6-s maximal cycling sprint test. Forty healthy young males (strength-and speed-trained athletes, and physically active and sedentary non-athletes) were tested on maximum strength, and on peak MPO when loaded 5-12% of body weight (BW). As expected, the strength trained and sedentary participants, respectively, revealed the highest and lowest strengths and MPO (p < 0.001). However, the main finding was a significant across group difference in L(opt) (p < 0.001) revealing the values 9.7% (for strength trained), 9.2% (speed trained), 8.7% (active), and 8.0% of BW (sedentary individuals). This suggests that the effects of external loading on maximum MPO in complex functional movements could be training history dependent. In addition to revealing a sensitivity of the 6-s maximal cycling sprint tests (and, perhaps, other maximum cycling tests), the results suggest that the external loading in routine MPO tests should not be solely adjusted to a fixed percentage of subject's BW (as routinely done in standard tests), but also to their training history. The same phenomenon remains to be evaluated in a number of other routine tests of MPO and other maximum performance tasks. PMID- 21287197 TI - Robot-assisted prostatectomy: the new standard of care. AB - INTRODUCTION: Robot-assisted radical prostatectomy (RARP) has first been performed in 2000 and has since then become a widespread and often performed therapy option for surgical treatment of prostate cancer. The purpose of this review was to highlight the current clinical concepts for radical prostatectomy. DISCUSSION AND CONCLUSIONS: Actual literature search was performed in PubMed database and reviewed. Different surgical techniques for RARP are presented. Oncologic and functional outcomes of RARP are discussed and compared to radical retropubic prostatectomy. In conclusion, RARP has equal oncologic and functional outcome in localized prostate cancer. RARP as a less invasive treatment option for patients with localized prostate cancer should be considered as a new standard of care by now. PMID- 21287198 TI - The history of TRP channels, a commentary and reflection. AB - The transient receptor potential (TRP) family of cation channels has redefined our understanding of sensory physiology. In one animal or another, all senses depend on TRP channels. These include vision, taste, smell, hearing, and various forms of touch, including the ability to sense changes in temperature. The first trp gene was identified because it was disrupted in a Drosophila mutant with defective vision. However, there was no clue as to its biochemical function until the cloning, and analysis of the deduced amino acid sequence suggested that trp encoded a cation channel. This concept was further supported by subsequent electrophysiological studies, including alteration of its ion selectivity by an amino acid substitution within the pore loop. The study of TRP channels emerged as a field with the identification of mammalian homologs, some of which are direct sensors of environmental temperature. At least one TRP channel is activated downstream of a thermosensory signaling cascade, demonstrating that there exist two modes of activation, direct and indirect, through which TRP channels respond to changes in temperature. Mutations in many TRP channels result in disease, including a variety of sensory impairments. PMID- 21287199 TI - Motor skill learning in the middle-aged: limited development of motor chunks and explicit sequence knowledge. AB - The present study examined whether middle-aged participants, like young adults, learn movement patterns by preparing and executing integrated sequence representations (i.e., motor chunks) that eliminate the need for external guidance of individual movements. Twenty-four middle-aged participants (aged 55 62) practiced two fixed key press sequences, one including three and one including six key presses in the discrete sequence production task. Their performance was compared with that of 24 young adults (aged 18-28). In the middle aged participants motor chunks as well as explicit sequence knowledge appeared to be less developed than in the young adults. This held especially with respect to the unstructured 6-key sequences in which most middle-aged did not develop independence of the key-specific stimuli and learning seems to have been based on associative learning. These results are in line with the notion that sequence learning involves several mechanisms and that aging affects the relative contribution of these mechanisms. PMID- 21287200 TI - Ductal plates in hepatic ductular reactions. Hypothesis and implications. I. Types of ductular reaction reconsidered. AB - This article focuses on the observation that most hepatic ductular reactions (DRs) have ductal plate (DP)-like patterns. Considering old and recent data, it hypothesizes that in DR, dedifferentiation of hepatocytes in ductular metaplasia may lead to the de novo development of liver stem/progenitor cells (LPCs). The three recognized types of DR are reconsidered, and an additional fourth type, DR type 2B, is added. In DR type 1 whose pattern differs from DP, the pre-existing cholangiocytes multiply and adjust the ductal structure in response to micro environmental changes induced by oedema and inflammation. This DR fails to establish new canaliculo-ductular connections. DRs types 2A, 2B and 3 represent progenitor cell-based reactions in DP configuration which establish canaliculo ductular connections similar to DPs in embryonic and foetal liver development. DR type 2A occurs in periportal areas in chronic cholestatic and inflammatory diseases and is interpreted as a reaction of LPCs, which either pre-exist or derive from dedifferentiated hepatocytes. DR type 2B occurs in centrolobular areas and zones of parenchymal hypoxia, is induced by hypoxia and corresponds to "ductular metaplasia" like type 2A with a presumably similar cellular origin. DR type 3 relates to the well-recognized activation of LPCs that reside in the canals of Hering. All DRs in DP configuration play a role in progression of fibrosis in chronic liver diseases. PMID- 21287201 TI - Ascorbic acid and alpha-tocopherol supplement starting prenatally enhances the resistance of nucleus tractus solitarius neurons to hypobaric hypoxic challenge. AB - Hypobaric hypoxia, encountered at high altitude, could result in severe consequences. Ascorbic acid (AA) and alpha-tocopherol (alphaTC), the two readily available over-the-counter antioxidants, are known to protect nervous tissue against oxidative stress. Here we study whether AA or alphaTC supplement starting prenatally protects animals against hypobaric hypoxic challenge at adulthood. Expressions of c-fos and the NR1 subunit of the N-methyl-D-aspartate receptors in the nucleus tractus solitarius (NTS) subserving cardiorespiratory functions were investigated. AA and alphaTC supplement reduced the number of c-fos immunoreactive neurons and intensity of NR1 expression in young and adult animals under normoxia. The treatment, in addition, attenuated the activation of NTS neurons, in terms of c-fos and NR1 expressions, and reduced the anxiety behaviors of adult rats subjected to hypobaric hypoxic challenge. Reduction of c-fos immunoreactive neurons was found concentrated in the chemoreceptor, baroreceptor, and tracheobronchial tree NTS subnuclei that receive corresponding afferents. The protective effect was not found in normal adult animals supplemented with AA or alphaTC a week before hypobaric hypoxic challenge. In short, prenatal and sustained AA or alphaTC supplement altered NTS substrate and ameliorated animals' reactions to hypobaric hypoxic insult, suggesting that this may be considered to protect animals from hypoxic insults from young to adult. PMID- 21287202 TI - The typing of Trypanosoma evansi isolates using mobile genetic element (MGE) PCR. AB - The mobile genetic element PCR (MGE-PCR) is a simple and sensitive technique that can be used to detect genetic variability in Trypanosoma brucei ssp. To investigate the reliability of MGE-PCR in genotyping Trypanosoma evansi, stocks that were isolated directly from camels and after their respective passage in mice were analyzed. Construction of a dendrogram using the MGE-PCR banding profiles revealed a clear distinction between T. evansi and T. brucei, as well as discriminating the T. evansi strains (T. evansi with minicircle types B and A). A minor host-dependent clustering shows a genetic difference of <15%. Changes in the banding profiles were observed after serial passage of T. evansi type B in mice, while those of T. evansi type A were identical. It is apparent that significant random insertion mobile element positional variation occurs when T. evansi isolates are introduced into a new host, a factor that needs to be considered when MGE-PCR is used to determine genetic variation in T. evansi isolates that have different host origins. PMID- 21287203 TI - Lingo2 variants associated with essential tremor and Parkinson's disease. AB - LINGO2, a member of LRR gene family, has been linked with both Essential tremor (ET) and Parkinson's disease (PD). However, there is a lack of conclusive evidence regarding the etiologic role of LINGO2 genetic variants. We investigated the association of LINGO2 variants with ET and PD in two independent Asian countries. A total of 1,262 subjects comprising 499 controls, 436 PD patients, and 327 ET patients were included. Eight LINGO2 variants, including four single nucleotide polymorphisms (SNPs) and four coding variants, were initially analyzed in one Asian population. SNPs that showed positive association were then replicated in the second independent Asian population, and a pooled analysis was carried out. Out of the eight variants, two SNPs (rs7033345 and rs10812774) revealed significant or strong positive trend in the first Asian population, and these were analyzed in the second Asian population. In the pooled analysis, the CC genotype at rs7033345 had a higher risk of developing PD (OR = 1.67, 95% CI = 1.18, 2.35, p = 0.003) and ET (OR = 1.50, 95% CI = 1.02, 2.20, p = 0.04) under a recessive model. The C allele at rs10812774 increased the risk of ET (OR = 1.56 95% CI = 1.10, 2.22, p = 0.01) via a recessive model. The effect size and direction of trend were in the same direction in each of the two populations. Our study demonstrated for the first time that rs7033345 is associated with PD and ET and rs10812774 with ET among Asians, suggesting that LINGO2 might act as a susceptibility gene for both conditions. PMID- 21287204 TI - Differential distribution of synaptotagmin-1, -4, -7, and -9 in rat adrenal chromaffin cells. AB - Neurons and certain kinds of endocrine cells, such as adrenal chromaffin cells, have large dense-core vesicles (LDCVs) and synaptic vesicles or synaptic-like microvesicles (SLMVs). These secretory vesicles exhibit differences in Ca(2+) sensitivity and contain diverse signaling substances. The present work was undertaken to identify the synaptotagmin (Syt) isoforms present in secretory vesicles. Fractionation analysis of lysates of the bovine adrenal medulla and immunocytochemistry in rat chromaffin cells indicated that Syt 1 was localized in LDCVs and SLMVs, whereas Syt 7 was the predominant isoform present in LDCVs. In contrast to PC12 cells and the pancreatic beta cell line INS-1, Syt 9 was not immunodetected in LDCVs in rat chromaffin cells. Double-staining revealed that Syt 9-like immunoreactivity was nearly identical with fluorescent thapsigargin binding, suggesting the presence of Syt 9 in the endoplasmic reticulum (ER).The exogenous expression of Syt 1-GFP in INS-1 cells, which had a negligible level of endogenous Syt 1, resulted in an increase in the amount of Syt 9 in the ER, suggesting that Syt 9 competes with Syt 1 for trafficking from the ER to the Golgi complex. We conclude that LDCVs mainly contain Syt 7, whereas SLMVs contain Syt 1, but not Syt 7, in rat and bovine chromaffin cells. PMID- 21287205 TI - Epiglottic prolapse induced by lighted stylet tracheal intubation. AB - We report a case of epiglottic prolapse induced by lighted stylet tracheal intubation perceived by following upper gastrointestinal endoscopy. A 68-year-old male was to undergo endoscopic mucosal resection (EMR) under general anesthesia for a superficial orolarynx cancer spreading over the root of the tongue. Because the mucosal change was so minimal, intubation was performed with a lighted stylet instead of a direct laryngoscope, to prevent its metal blade spoiling the delicate endoscopic findings. After intubation, endoscopy revealed that the epiglottis folded down completely into the laryngeal vestibule. Immediate extubation with a ventilating tube exchanger failed to turn the entrapped epiglottis back to normal, and the inlet of the larynx remained obstructed. After reintubation, the epiglottis was restored to its normal position with endoscopic forceps. The postoperative course was uneventful and he was discharged on the sixth postoperative day. Retrospective evaluation of preoperative gastrointestinal endoscopy showed the epiglottis was flat and thin enough to have a tendency to become attached to the posterior pharynx wall, even though the procedure was performed in the decubitus position. Epiglottic prolapse induced by lighted stylet tracheal intubation is a quite rare complication but we should be aware of it as a potential injury which could cause upper airway obstruction if not recognized before extubation. PMID- 21287206 TI - Ultrasound-guided peripheral nerve blocks for a patient receiving four kinds of anticoagulant and antiplatelet drugs: a case report. PMID- 21287207 TI - Quercus rubra-associated ectomycorrhizal fungal communities of disturbed urban sites and mature forests. AB - The presence and quality of the belowground mycorrhizal fungal community could greatly influence plant community structure and host species response. This study tests whether mycorrhizal fungal communities in areas highly impacted by anthropogenic disturbance and urbanization are less species rich or exhibit lower host root colonization rates when compared to those of less disturbed systems. Using a soil bioassay, we sampled the ectomycorrhizal fungal (EMF) communities associating with Quercus rubra (northern red oak) seedlings in soil collected from seven sites: two mature forest reference sites and five urban sites of varying levels of disturbance. Morphological and polymerase chain reaction restriction fragment length polymorphism analyses of fungi colonizing root tips revealed that colonization rates and fungal species richness were significantly lower on root systems of seedlings grown in disturbed site soils. Analysis of similarity showed that EMF community composition was not significantly different among several urban site soils but did differ significantly between mature forest sites and all but one urban site. We identified a suite of fungal species that occurred across several urban sites. Lack of a diverse community of belowground mutualists could be a constraint on urban plant community development, especially of late-successional woodlands. Analysis of urban EMF communities can add to our understanding of urban plant community structure and should be addressed during ecological assessment before pragmatic decisions to restore habitats are framed. PMID- 21287208 TI - Effect of ozone on periodontopathogenic species--an in vitro study. AB - The in vitro study was aimed to determine the effect of ozone on periodontopathogenic microorganisms. Ozone was generated for 6 s-2 * 24 s (corresponding to 0.56 mg-2 * 2.24 mg of ozone) against 23 mainly anaerobic periodontopathogenic species. Agar diffusion test was used as a screening method. Then, the killing activity was tested in a serum-free environment and with 25% v/v inactivated serum. Further, the effect of ozone on bactericidal activity of native serum was analyzed against Fusobacterium nucleatum, Porphyromonas gingivalis, and Aggregatibacter actinomycetemcomitans. Agar diffusion test showed a high efficacy of ozone against microorganisms, especially against Porphyromonas gingivalis. This result was confirmed by the killing tests; most of the strains in a concentration of 10(5) were completely eliminated after twofold 18-s application of ozone. Only four of the six potentially "superinfecting" species (Staphylococcus aureus, Enterococcus faecalis, Enterobacter cloacae, Candida albicans) survived in part. Addition of heat-inactivated serum reduced the killing rate of ozone by 78% after 6-s and by 47% after twofold 18-s exposures; no strain was completely eradicated after any application of ozone. The bactericidal effect of native serum was enhanced after application of ozone; no effect was visible on the included A. actinomycetemcomitans strain which was found to be completely resistant to the bactericidal action of serum. In conclusion, (a) ozone has a strong antibacterial activity against putative periodontopathogenic microorganisms, and (b) the bactericidal effect is reduced in the presence of serum. Ozone may have potential as an adjunctive application to mechanical treatment in periodontitis patients. PMID- 21287209 TI - Surface thermodynamic homeostasis of salivary conditioning films through polar apolar layering. AB - Salivary conditioning films (SCFs) form on all surfaces exposed to the oral cavity and control diverse oral surface phenomena. Oral chemotherapeutics and dietary components present perturbations to SCFs. Here we determine the surface energetics of SCFs through contact angle measurements with various liquids on SCFs following perturbations with a variety of chemotherapeutics as well as after renewed SCF formation. Sixteen-hour SCFs on polished enamel surfaces were treated with a variety of chemotherapeutics, including toothpastes and mouthrinses. After treatment with chemotherapeutics, a SCF was applied again for 3 h. Contact angles with four different liquids on untreated and treated SCF-coated enamel surfaces were measured and surface free energies were calculated. Perturbations either caused the SCF to become more polar or more apolar, but in all cases, renewed SCF formation compensated these changes. Thus, a polar SCF attracts different salivary proteins or adsorbs proteins in a different conformation to create a more apolar SCF surface after renewed SCF formation and vice versa for apolar SCFs. This polar-apolar layering in SCF formation presents a powerful mechanism in the oral cavity to maintain surface thermodynamic homeostasis--defining oral surface properties within a narrow, biological range and influencing chemotherapeutic strategies. Surface chemical changes brought about by dietary or chemotherapeutic perturbations to SCFs make it more polar or apolar, but new SCFs are rapidly formed compensating for changes in surface energetics. PMID- 21287210 TI - Risk of chipping or facings failure of metal ceramic fixed partial prostheses--a retrospective data record analysis. AB - This retrospective study investigated the frequency and time history of chipping or facings failure of three-unit and four-unit tooth-supported metal ceramic (MC) fixed partial prostheses (FPDs). Six hundred fifty-four MC FPDs were inserted according to a standardized treatment protocol at the Department of Prosthodontics of the Regensburg University Medical Center between 1984 and 2009. Frequency and time history of chipping or facings failure as well as possible risk factors were evaluated on the basis of historical clinical data. We estimated the survival times of FPDs by means of the Kaplan-Meier analysis. The 5 year survival rate (time to renewal of a FPD) of all MC FPDs was 94%; the 10-year survival rate was 87%. Twenty-eight (4.3%) MC FPDs showed chipping; the 5-year free-of-event rate of chipping was 95%, the 10-year rate was 94%. Possible risk factors had no statistically significant influence on chipping or facings failure. The annual hazard rate of MC chipping in the first year was 0.03, i.e., 3 out of 100 person-years of exposure showed chipping. The annual hazard rates for the next 6 years dropped to 0.009, 0.003, 0.007, 0.004, 0.005, and 0.007. Thus, about 3-9 out of 1,000 person-years of exposure showed chipping. Patients with MC FPD may expect a long survival rate of their restoration. During the first year, the risk of chipping may be higher than during the following years. Despite the long period of experience with MC FPDs, chipping of the facing will still occur. PMID- 21287211 TI - Salinivibrio sharmensis sp. nov., a novel haloalkaliphilic bacterium from a saline lake in Ras Mohammed Park (Egypt). AB - A novel haloalkaliphilic, facultative anaerobic and Gram-negative Salinivibrio like microorganism (designated strain BAG(T)) was recovered from a saline lake in Ras Mohammed Park (Egypt). Cells were motile, curved rods, not spore-forming and occurred singly. Strain BAG(T) grew optimally at 35 degrees C (temperature growth range 25-40 degrees C) with 10.0% (w/v) NaCl [NaCl growth range 6.0-16.0% (w/v)] and at pH 9.0 (pH growth range 6.0-10.0). Strain BAG(T) had phosphatidylethanolamine (PEA) and phosphatidylglycerol (PG) as the main polar lipids, C16:0 (54.0%) and C16:1 (26.0%) as the predominant cellular fatty acids and Q-8 as the major respiratory quinone. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain BAG(T) was a member of Salinivibrio genus, with the highest sequence similarities of 99.1, 98.4 and 98.1% to Salinivibrio siamensis JCM 14472(T), Salinivibrio proteolyticus DSM 19052(T) and Salinivibrio costicola subsp. alcaliphilus DSM 16359(T), respectively. DNA-DNA hybridization values of strain BAG(T) with members of Salinivibrio genus were lower than 55.0%. DNA G + C content was 51.0 mol%. On the basis of the polyphasic taxonomic results revealed in this study, strain BAG(T) should be classified as a novel species of Salinivibrio genus, for which the name Salinivibrio sharmensis sp. nov. is proposed, with the type strain BAG(T) (=ATCC BAA-1319(T) = DSM 18182(T)). PMID- 21287212 TI - The cooperativity between hydrogen and halogen bond in the XY...HNC...XY (X, Y = F, Cl, Br) complexes. AB - The cooperativity between hydrogen and halogen bonds in XY...HNC...XY (X, Y = F, Cl, Br) complexes was studied at the MP2/aug-cc-pVTZ level. Two hydrogen-bonded dimers, five hydrogen-bonded dimers, and ten trimers were obtained. The hydrogen- and halogen-bonded interaction energies in the trimers were larger than those in the dimers, indicating that both the hydrogen bonding interaction and the halogen bonding interaction are enhanced. The binary halogen bonding interaction plays the most important role in the ternary system. The hydrogen donor molecule influences the magnitude of the halogen bonding interaction much more than the hydrogen bonding interaction in the trimers with respect to the dimers. Our calculations are consistent with the conclusion that the stronger noncovalent interaction has a bigger effect on the weaker one. The variation in the vibrational frequency in the HNC molecule was considered. The NH antisymmetry vibration frequency has a blue shift, whereas the symmetry vibration frequency has a red shift. A dipole moment enhancement is observed upon formation of the trimers. The variation in topological properties at bond critical points was obtained using the atoms in molecules method, and was consistent with the results of the interaction energy analysis. PMID- 21287213 TI - Microsolvation of aminoethanol: a study using DFT combined with QTAIM. AB - The microsolvation of aminoethanol (AE) with one, two, three or four water molecules was investigated using a density functional theory (DFT) approach. Quantum theory of atoms in molecules (QTAIM) analyses were employed to elucidate the hydrogen-bonding characteristics of AE-(H(2)O)( n ) (n = 1-4) complexes. The results showed that AE tends to break its intramolecular OH(AE)...N(AE) hydrogen bond (H-bond) upon microsolvation and form intermolecular H-bonds with water molecules, while complexes that retain the intramolecular OH(AE)...N(AE) H-bond show reduced stabilities. The intermolecular H-bond that forms between the nitrogen atom of AE and the hydroxyl of a water molecule is the strongest one for the most stable AE-(H(2)O)( n ) (n = 1-4) complexes, and as n increases from 1 to 4 they grow stronger. The partial covalent character of this H-bond was confirmed by QTAIM analyses. Many-body interaction analysis showed that the relaxation energies and two- and three-body energies make significant contributions to the binding energies of the complexes. PMID- 21287214 TI - Graphene-based pressure nano-sensors. AB - We perform atomistic simulations to study the failure behavior of graphene-based pressure sensor, which is made of a graphene nanoflake suspended over a well in a silicon-carbide substrate and clamped on its surrounding edge by the covalent bonds between the graphene flake and the substrate. Two distinct types of mechanical failure are identified: the first one is characterized by complete detachment of the graphene nanoflake from the silicon-carbide substrate via breaking the covalent bonds between the carbon atoms of the graphene flake and the silicon atoms of the substrate; the second type is characterized by the rupture of the graphene nanoflake via breaking the carbon-carbon bonds within the graphene. The type of mechanical failure is determined by the clamped area between the graphene flake and the substrate. The failure pressure can be tuned by changing the clamped area and the well radius. A model is proposed to explain the transition between the two types of failure mode. The present work provides a quantitative framework for the design of graphene-based pressure sensors. PMID- 21287215 TI - Theoretical study of isotope effects on the stereodynamics of H++HD and its isotopic variant D++HD. AB - The stereodynamics for H(+)+HD and its isotopic variant D(+)+HD were studied with a quasi-classical trajectory (QCT) method at a collision energy of 0.7 eV on the ground 1(1)A' potential energy surface (PES). The polarization-dependent differential cross-sections (PDDCSs) in the center-of-mass frame are presented here. Furthermore, the distribution of the angle between k and j', p(theta ( r )) and the distribution of the dihedral angle p(phi ( r )) were calculated and are discussed. The results indicate that isotopic substitution exerts substantial effects on the differential cross-section and the product's rotational polarization. PMID- 21287216 TI - Molecular dynamics simulations and binding free energy analysis of DNA minor groove complexes of curcumin. AB - Curcumin is a natural phytochemical that exhibits a wide range of pharmacological properties, including antitumor and anticancer activities. The similarity in the shape of curcumin to DNA minor groove binding drugs is the motivation for exploring its binding affinity in the minor grooves of DNA sequences. Interactions of curcumin with DNA have not been extensively examined, while its pharmacological activities have been studied and documented in depth. Curcumin was docked with two DNA duplexes, d(GTATATAC)(2) and d(CGCGATATCGCG)(2), and molecular dynamics simulations of the complexes were performed in explicit solvent to determine the stability of the binding. In all systems, the curcumin is positioned in the minor groove in the A.T region, and was stably bound throughout the simulation, causing only minor modifications to the structural parameters of DNA. Water molecules were found to contribute to the stability of the binding of the ligand. Free energy analyses of the complexes were performed with MM-PBSA, and the binding affinities that were calculated are comparable to the values reported for other similar nucleic acid-ligand systems, indicating that curcumin is a suitable natural molecule for the development of minor groove binding drugs. PMID- 21287217 TI - Ossifying fibroma with non-specific cystic degeneration: a case report. AB - BACKGROUND: Fibro-osseous lesion are a group histologically similar lesions but with characteristic clinical and radiographic features. The definitive diagnosis of these lesions requires integration of clinical, radiological, histological, and gross surgical features. Ossifying fibroma is an encapsulated lesion that is often found in the mandible of middle-aged females. CASE REPORT: We report a case of ossifying fibroma in a 25-year-old female with associated non-specific cystic changes and mimicking simple bone cyst. CONCLUSION: The case reported here is diagnostically challenging and requires proper integration of clinical, radiological, histological, and gross surgical features to reach definitive diagnosis. PMID- 21287218 TI - C4ORF48, a gene from the Wolf-Hirschhorn syndrome critical region, encodes a putative neuropeptide and is expressed during neocortex and cerebellar development. AB - In order to identify novel genes involved in mental retardation/intellectual disability, we focused on a microdeletion reported in a patient with a mild form of Wolf-Hirschhorn syndrome. This patient presented with attention-deficit hyperactivity disorder, some learning and fine motor deficits as well as facial abnormalities. The deleted region included three genes. Here, we report the first characterization of one of these genes, C4ORF48. C4ORF48 encodes a short (139 aa) evolutionarily conserved protein with a predicted signal peptide and two potential dibasic convertase cleavage sites. In mice, we demonstrated expression of the corresponding protein exclusively in brain tissue using an anti-mouse C4Orf48 polyclonal antibody. Detailed RNA in situ hybridization experiments revealed expression of C4Orf48 in different zones during cortical and cerebellar development, as well as in almost all cortical and subcortical regions of the adult mouse brain. Based on the present data, we propose that C4Orf48 probably encodes a novel neuropeptide, which, if hemizygously deleted, may be involved in the observed intellectual and fine motor disabilities and thus in the overall neurological aspects of Wolf-Hirschhorn syndrome. PMID- 21287219 TI - Comparison of two diode lasers on bactericidity in root canals--an in vitro study. AB - This in vitro study compares two 810-nm and 940-nm diode lasers on bacterial kill in root canals of extracted human teeth and shows the clinical relevance of different treatment modalities. Ninety root canals of single-rooted human teeth were prepared up to ISO 70, steam sterilized, and assigned to two test groups (810 nm, 940 nm) and one control group. Following an initiatory experiment in which access opening of root canals and surrounding cavity were excluded from irradiation in the main experiment, 60 teeth were inoculated with 2 MUl of either Escherichia coli or Enterococcus faecalis suspension. Laser irradiation was performed, additionally including access opening of root canals and surrounding cavity in the laser treatment. Excluding access opening of root canals and surrounding cavity from the laser treatment, the diode laser achieved an average bacterial reduction of Escherichia coli of 76.06% (810 nm) and 68.15% (940 nm), while including access cavities showed an average bacterial reduction of Escherichia coli of 97.84% (810 nm) and 98.83% (940 nm) and an average bacterial reduction of Enterococcus faecalis of 98.8% (810 nm) and 98.66% (940 nm). Diode laser wavelengths are effective in endodontic therapy. It seems to be clinically relevant that additional irradiation of the access cavity produces significantly better bactericidal results. PMID- 21287220 TI - Malone appendicostomy: an unexpected complication. AB - The Malone appendicostomy is a novel option for surgical management of faecal incontinence and chronic constipation, by permitting the administration of antegrade colonic enemas for colonic evacuation. We report the case of a 54-year old female who had undergone abdomino perineal resection for low rectal cancer followed by total perineal reconstruction with perineal colostomy, dynamic double graciloplasty and Malone appendicostomy. After 7-year follow-up, functional results and quality of life scores were satisfactory. Suddenly the patient described increasing difficulty with intubation of her appendicostomy and complete reflux of the enema liquid, which radiology referred to a calcified body of 35 mm within the Malone appendicostomy causing nearly complete obstruction of the conduit. A surgical exploration was necessary to extract the fecolith allowing full recovery with return to satisfactory Malone appendicostomy function. To our knowledge, this is the first report of a fecolith causing obstruction within a Malone appendicostomy. PMID- 21287221 TI - Young atmosphere in the eternal city: the Third Educational Colorectal Meeting. PMID- 21287222 TI - Prophylactic surgery in Lynch syndrome. AB - Lynch syndrome (LS) is caused by a germline mutations in DNA mismatch repair genes and is a dominantly inherited syndrome, responsible for 2-5% of all colorectal cancer (CRC) cases. Mutation carriers have a 60-85% risk of developing CRC. With the increasing use of genetic predisposition testing, patients and health care providers must decide on cancer risk-reduction strategies. The cancers observed in families with LS are diagnosed at an unusually early age and may be multiple. The decision about which surgery is suitable should be made on the basis of patient factors and preferences, with special emphasis on age, comorbidity, sphincteric function, and the ability of the patient to cope with intensive surveillance. Colectomy decreases the risk of second CRC significantly. The estimated lifetime risk for endometrial adenocarcinoma is 40-60% in women with LS, and the mean age at diagnosis is around 50 years. This risk equals or exceeds the risk of CRC. The optimal management of the elevated risk for cancer in carriers of mutations for hereditary nonpolyposis colorectal cancer is unclear. Patients who are gene mutation carriers should receive counseling about colectomy, and if women, prophylactic hysterectomy and bilateral oophorectomy. PMID- 21287224 TI - Single-incision laparoscopic colectomy: a novel approach through a Pfannenstiel incision. AB - BACKGROUND: Single-incision laparoscopic colectomy is evolving as a safe and feasible approach for the management of various diseases of the colon and rectum. The modality affords completion of "scarless" surgery through a transumbilical incision; however, this approach is associated with several limitations when performing colorectal procedures involving the pelvis. Collinear alignment of the camera and instruments through a single umbilical incision results in restricted visualization, inadequate dissection and mobilization, and the potential for inadvertent injury. We have developed an innovative approach utilizing a Pfannenstiel incision for single-incision access to the pelvis. METHODS: Single incision laparoscopic colon resection was performed using a single-access device placed through a mini-Pfannenstiel incision. RESULTS: Three consecutive patients underwent single-incision laparoscopic anterior rectosigmoid resection for recurrent diverticulitis through a 4-cm Pfannenstiel incision. The procedures were performed at 150, 180, and 195 min with an estimated blood loss of 50, 150, and 75 mL, respectively. The resected specimen lengths were 10.5, 20.2, and 15.0 cm, respectively. There were no conversions to multi-port laparoscopic or open surgery. The length of hospital stay was 4 days for patients 1 and 2, and 3 days for patient 3. There were no major complications or readmissions during postoperative follow-up. CONCLUSION: Single-incision laparoscopic anterior rectosigmoid resection for diverticulitis can be performed successfully through a Pfannenstiel incision. This approach facilitates direct visualization and access for rectal and pelvic dissection while maintaining adequate exposure to the left colon and splenic flexure during the procedure. PMID- 21287223 TI - Pouch-related dysplasia and adenocarcinoma following restorative proctocolectomy for ulcerative colitis. AB - BACKGROUND: Restorative proctocolectomy (RPC) is the criterion standard surgical treatment for ulcerative colitis (UC). Restorative proctocolectomy is indicated for UC that is refractory to medical treatment, for emergency conditions, and in case of neoplastic transformation. The procedure substantially reduces the risk of UC-associated dysplasia/neoplasia. However, after RPC surgery, even with mucosectomy, cancers of the pouch and/or the anal-transitional zone (ATZ) have been reported with increasing frequency since the first report in 1984. This review highlights pouch-related dysplastic and neoplastic transformation, prevalence and adverse events, risk factors and surveillance following surgery for UC. METHODS: Reports in the literature about patients undergoing pouch surgery from different institutions reported through May 2010 were reviewed to identify patients who developed these complications, and an attempt was made to develop a rational follow-up policy based on the data available. RESULTS: To date, there are 43 reported cancers of the pouch or inlet after RPC for UC: 16 from retrospective series, 1 from a prospective study, and 26 in case reports. Thirty patients underwent mucosectomy and 13 had stapled anastomoses. To date, the number of 28 patients has been diagnosed with dysplasia after RPC for UC. Mucosectomy was performed in 27 of them and in 1 a stapled anastomosis was constructed without mucosectomy. In all cases reviewed, the time interval from the onset of UC to dysplasia/neoplasia was over 10 years. CONCLUSION: Neoplastic lesions occurring in UC patients after RPC have been shown to be absolutely inevitable. Even mucosectomy does not completely eliminate the risk. There is little evidence to support routine biopsy of the ileal mucosa or the anal transition zone except in patients with histological type C changes, sclerosing cholangitis, and unremitting pouchitis in the ileal mucosa. Such patients should be selected for endoscopic surveillance to detect dysplasia preceding pouch adenocarcinoma. PMID- 21287225 TI - The National Bowel Cancer Audit Project: what do trusts think of the National Bowel Cancer Audit and how can it be improved? AB - PURPOSE: The National Bowel Cancer Audit Project (NBOCAP) collects data from hospitals in the UK and aims to improve surgical outcomes and quality of care for patients. The aims of this study were to understand why trusts were/were not participating in the NBOCAP and how to improve the quality of data collected and feedback. METHODS: This was a prospective e-survey on colorectal surgeons' attitudes towards and opinions of the NBOCAP, within trusts in the UK. A questionnaire was emailed to members of the Association of Coloproctology of Great Britain and Ireland (ACPGBI). RESULTS: Of the 171 trusts contacted by email, 66% of trusts (n = 117) had at least 1 consultant respond. Of the 117 trusts that responded, 60 (51.2%) had submitted data to the NBOCAP. A total of 549 consultants received the questionnaire, and 159 (29.0%) consultants responded. Fifty-one per cent (n = 60) of the trusts had submitted data to the NBOCAP. Reasons for data submission included the following: comparison of a units' data with national data (56.8%), a national audit improves outcomes (45.9%) and generation of information for use at a local level (42.6%). The main reasons for non-submission were as follows: lack of technical support (23.6%), lack of funding (19.6%) and lack of dedicated audit time (18.9%). Ninety-six (60.4%) consultants felt that the audit report should identify individual trust results. Fifty-three per cent of consultants (n = 87) rated their trusts' resources for audit as being very poor or poor. CONCLUSION: Consultant members of the Association of Coloproctology of Great Britain and Ireland (ACPGBI) within hospital trusts in the UK feel participation in the National Bowel Cancer Audit improves patients' quality of care and surgical outcomes. Increased awareness of the benefits of the NBOCAP and improved allocation of resources from hospital trusts could improve participation. PMID- 21287226 TI - In vitro susceptibility of enterococci strains isolated from urine samples to fosfomycin and other antibiotics. AB - Enterococci are mostly isolated from urinary tract infections (UTIs). Increasing antibiotic resistance affects the success rate in empirical treatment, thus makes antibiotic susceptibility tests important. The aim of this study was to determine the species distribution and resistance patterns of Enterococcus strains isolated from urine samples to antibacterial agents including fosfomycin in a teaching hospital, Istanbul. The identification of 100 Enterococcus strains were determined by using conventional methods and API 20 Strep (bioMerieux France). The susceptibility testing was performed by disk diffusion and Etest. The majority of isolates were E. faecalis (67%), followed by E. faecium (33%). The ratio of E. faecalis to E. faecium was 2.03/1. E. faecalis and E. faecium strains were resistant to penicillin (38.8, 93.9%), ampicillin (4.8, 84.8%), vancomycin (1.5, 18.2%), teicoplanin (1.5, 18.2%), gentamicin (13.4, 58%), ciprofloxacin (34.3, 84.8%), levofloxacin (34.3, 87.9%), norfloxacin (38.8, 84.8%), tetracycline (89.6, 48.5%), nitrofurantoin (1.5, 39.4%), and fosfomycin (2.3, 0%) (p < 0.0001), respectively. Resistance to fosfomycin was observed in neither E. faecium strains, nor vancomycine-resistant enterococci strains. It was concluded that, enterococci are important pathogens for UTI; species identification and periodic evaluation of antibiotic susceptibility pattern would be guide for early empirical treatment and in uncomplicated UTI, fosfomycin could be an alternative option for therapy. PMID- 21287228 TI - Increased resistance to cucumber mosaic virus (CMV) in Lilium transformed with a defective CMV replicase gene. AB - Lilium cv Acapulco was transformed with a defective cucumber mosaic virus (CMV) replicase gene (CMV2-GDD) construct using Agrobacterium tumefaciens. Four lines were analyzed for gene expression and resistance to CMV-O strain. Expression of the CMV2-GDD gene in the transgenic plants was confirmed by reverse transcription PCR (RT-PCR). When these four lines were mechanically inoculated with CMV-O, no signal of coat protein (CP) messages using RT-PCR was detected in newly produced leaves of two transgenic lines. Dot-immunobinding assay (DIBA) of CP was performed to examine the presence of the CMV in the newly produced leaves of challenged plants. Results, similar to those obtained with RT-PCR of the CP messages, were observed in DIBA. Therefore, our results imply that the two lines show increased levels of resistance to CMV, and CMV-GDD replicase gene is an effective construct that has protection against CMV in Lilium. PMID- 21287227 TI - Adalimumab (HumiraTM): a promising monoclonal anti-tumor necrosis factor alpha in ophthalmology. AB - Tumor necrosis factor alpha (TNF-alpha) is a key soluble mediator involved in the inflammatory cascade of many disorders including uveitis. Among the anti-TNF alpha agents, one of the most used in immune-mediated diseases, such as inflammatory arthropathies, is adalimumab (HumiraTM, Abbott Pharmaceutical Inc.), a fully humanized antibody. The purpose of this review is to analyze the main pharmacological and clinical aspects of adalimumab and its efficacy both in systemic and ocular inflammatory disorders. Adalimumab was effective in treating several autoimmune diseases, such as rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. In recent years, adalimumab has been used successfully in refractory cases of intraocular inflammation. Moreover, this biological agent showed good safety and efficacy profiles in ocular use including childhood uveitis. Switching from other anti-TNF-alpha agents to adalimumab may offer several advantages, such as easier administration, better patient compliance, and lower rate of adverse events. Adalimumab is a promising drug for the therapy of uveitis, although further studies are needed on its application in uveitis. PMID- 21287229 TI - Constitutive over-expression of pectinases in Penicillium occitanis CT1 mutant is transcriptionally regulated. AB - The CT1 mutant of Penicillium occitanis hyperproduces extracellular pectinases constitutively since it secretes pectinases even on glucose-containing medium. We show here that all other hydrolytic enzymes remain at low activities in CT1, confirming the specificity of the regulatory mutation towards pectinases. We isolated, by RT-PCR and through the construction of a cDNA library, three fragments coding for: a pectin lyase (pnl1), a polygalacturonase (pga1) and a pectate lyase (pal1). These fragments were used as probes in Northern blots analysis of the wild type strain CL100 and the CT1 mutant of P. occitanis grown in three culture conditions. The CT1 mutant showed a very high amount of pnl1, pga1 and pal1 mRNA either in pectin, glucose or glycerol grown cells while in the wild type CL100 strain, all transcripts were undetectable even on pectin. These results suggest that the CT1 mutation affects a trans-regulatory transcriptional factor regulating pectinase expression. PMID- 21287230 TI - ATP photosynthetic vesicles for light-driven bioprocesses. AB - We prepared ATP photosynthetic vesicles from inside-out membranes of Escherichia coli cells that express delta-rhodopsin (a novel light-driven H(+) transporter) and TF(0)F(1)-ATP synthase (a thermo-stable ATP synthase). These vesicles showed light-dependent ATP synthesis. Furthermore, coupling the ATP photosynthetic vesicles with an ATP-hydrolyzing hexokinase enabled light-dependent glucose consumption. The ATP photosynthetic vesicles indicate their potential to applied to light-driven ATP-regenerating bioprocess for various ATP-hydrolyzing bioproductions. PMID- 21287231 TI - Expression of a novel thermostable Cu, Zn-superoxide dismutase from Chaetomium thermophilum in Pichia pastoris and its antioxidant properties. AB - A new superoxide dismutase (SOD) gene from the thermophilic fungus Chaetomium thermophilum (Ctsod) was cloned and expressed in Pichia pastoris and its gene product was characterized. The specific activity of the purified CtSOD was 2,170 U/mg protein. The enzyme was inactivated by KCN and H(2)O(2) but not by NaN(3), confirming that it belonged to the type of Cu, ZnSOD. The amino acid residues involved in coordinating copper and zinc were conserved. The recombinant CtSOD exhibited optimum activity at pH 6.5 and 60 degrees C. The enzyme retained 65% of the maximum activity at 70 degrees C for 60 min and the half-life was 22 and 7 min at 80 and 90 degrees C, respectively. The recombinant yeast exhibited higher stress resistance than the control yeast cells to salt and superoxide-generating agents, such as paraquat and menadione. PMID- 21287232 TI - Co-loading of bisphosphonates and antibiotics to a biomimetic hydroxyapatite coating. AB - We have incorporated bisphosphonates and antibiotics simultaneously into a biomimetic hydroxyapatite implant coating aiming to use the interaction between drug-molecules and hydroxyapatite to enable local release of the two different substances to obtain a dual biological effect. A sustained release over for 43 h of antibiotics (cephalothin) was achieved without negative interference from the presence of the bisphosphonate (clodronate) which, in turn, successfully bonded to the coating surface. To our knowledge, this is the first study that indicates the possibility to simultaneously incorporate both antibiotics and bisphosphonates to an implant coating, a strategy that is believed to improve implant stability and reduce implant-related infections. PMID- 21287233 TI - A comparison between osteogenic differentiation of human unrestricted somatic stem cells and mesenchymal stem cells from bone marrow and adipose tissue. AB - To evaluate the potential of three stem cells for cell therapy and tissue engineering applications, the biological behavior and osteogenic capacity of the newly introduced cord-blood-derived, unrestricted somatic stem cells (USSC) were compared with those of mesenchymal stem cells isolated from bone marrow (BM-MSC) and adipose tissue (AT-MSC). There was no significant difference between the rates of proliferation of the three stem cells. During osteogenic differentiation, alkaline phosphatase (ALP) activity peaked on day 7 in USSC compared to BM-MSC which showed the maximum value of ALP activity on day 14. However, BM-MSC had the highest ALP activity and mineralization during osteogenic induction. In addition, AT-MSC showed the lowest capacity for mineralization during differentiation and had the lowest ALP activity on days 7 and 14. Although AT-MSC expressed higher levels of collagen type I, osteonectin and BMP-2 in undifferentiated state, but these genes were expressed higher in BM-MSC during differentiation. BM-MSC also expressed higher levels of ALP, osteocalcin and Runx2 during induction. Taking together, BM-MSC showed the highest capacity for osteogenic differentiation and hold promising potential for bone tissue engineering and cell therapy applications. PMID- 21287234 TI - Rachiplusia nu larva as a biofactory to achieve high level expression of horseradish peroxidase. AB - A process based on orally-infected Rachiplusia nu larvae as biological factories for expression and one-step purification of horseradish peroxidase isozyme C (HRP C) is described. The process allows obtaining high levels of pure HRP-C by membrane chromatography purification. The introduction of the partial polyhedrin homology sequence element in the target gene increased HRP-C expression level by 2.8-fold whereas it increased 1.8-fold when the larvae were reared at 27 degrees C instead of at 24 degrees C, summing up a 4.6-fold overall increase in the expression level. Additionally, HRP-C purification by membrane chromatography at a high flow rate greatly increase D the productivity without affecting the resolution. The V(max) and K(m) values of the recombinant HRP-C were similar to those of the HRP from Armoracia rusticana roots. PMID- 21287235 TI - High throughput determination of glucan and xylan fractions in lignocelluloses. AB - The analysis of structural glucan and xylan in lignocellulose was scaled down from original two-stage sulfuric acid hydrolysis methods (Moore WE and Johnson DB 1967 Procedures for the chemical analysis of wood and wood products. U.S. Forest Products Laboratory, U.S. Department of Agriculture., Madison, WI) and integrated into a recently-developed, high throughput pretreatment and enzymatic saccharification system. Novel 96*1.8 ml-well Hastelloy reactor plates (128*86*51 mm) based on previously described 96-well pretreatment reactor plates were paired with custom aluminum filler plates (128*86*18 mm) for use in Symyx Powdernium solids dispensing systems. The incorporation of glucose oxidase and xylose dehydrogenase linked assays to speed post-hydrolysis sugar analysis dramatically reduced the time for analysis of large lignocellulosic sample sets. The current system permits the determination of the glucan and xylan content of 96 replicates (per reactor plate) in under 6 h and parallel plate processing increases the analysis throughput substantially. PMID- 21287236 TI - shRNA targeting SFRP2 promotes the apoptosis of hypertrophic scar fibroblast. AB - Hypertrophic scars result from a dysregulated process in wound healing. Although the basic mechanism is unclear, increased proliferation and decreased cell apoptosis are noticed in the development of hypertrophic scar. In previous study, we found that secreted frizzled-related protein 2 (SFRP2), which was associated with cell proliferation, apoptosis, and differentiation, was dramatically upregulated in hypertrophic scar (HS) tissue. In this study short hairpin RNA (shRNA) targeting SFRP2 was employed to characterize SFRP2 function in hypertrophic scar-derived fibroblasts (HSFb). Cell proliferation was assessed by MTT, dynamic growth curves, and BRDU assays. Meanwhile, Cell apoptosis was detected using fluorescence-activated cell sorting (FACS). Caspase-3 activity was assayed by spectrophotometry. Fibroblast populated collagen lattice (FPCL) model was employed to evaluate the contractility of HSFb. Further, real-time PCR and western blot were used to measure the mRNA and protein expressions of alpha-SMA in HSFb. In addition, mRNA levels of type I and III procollagen were assayed by quantitative real-time PCR. The results revealed that shRNA targeting SFRP2 significantly promoted the apoptosis of HSFb, while it had no effect on the cell proliferation. Decreased synthesis of a-smooth muscle actin (alpha-SMA) in HSFb and reduced contraction of fibroblasts in the FPCL model were observed. Quantitative RT-PCR suggested that the mRNAs of type I and III procollagen were significantly downregulated. In conclusion, as a novel anti-apoptosis gene, SPRP2 was present in hypertrophic scars. Importantly, shRNA targeting SFRP2 may provide a new approach to preventing the formation of HS. PMID- 21287237 TI - Study of release speeds and bacteria inhibiting capabilities of drug delivery membranes fabricated via electrospinning by observing bacteria growth curves. AB - The study found that biodegradable drug delivery membranes that were fabricated from Poly(a-L-alanine) (PLLA) and chlorhexidine (CHX)-gluconate via electrospinning could steadily and continuously inhibit the growth of bacteria. Bacterial growth curves were used to evaluate on a real-time basis the relationship between drug delivery speeds of the membranes and growth rates of bacteria in different phases. The results showed that PLLA/CHX (50:50 in terms of volume) drug delivery membranes could do what drug delivery systems can normally do. SEM morphology observations, FTIR, and Raman spectra analyses were conducted on the drug delivery membranes. This is the first study that confirms that biodegradable CHX delivery membranes fabricated via electrospinning are a rate preprogrammed drug delivery system by comparing the growth curves of competent cell and plasmid inserted competent cell, bacteria that are of the same strain but grow at different speeds due to the insertion. PMID- 21287238 TI - Fabrication and cell affinity of biomimetic structured PLGA/articular cartilage ECM composite scaffold. AB - An ideal scaffold for cartilage tissue engineering should be biomimetic in not only mechanical property and biochemical composition, but also the morphological structure. In this research, we fabricated a composite scaffold with oriented structure to mimic cartilage physiological morphology, where natural nanofibrous articular cartilage extracellular matrix (ACECM) was used to mimic the biochemical composition, and synthetic PLGA was used to enhance the mechanical strength of ACECM. The composite scaffold has well oriented structure and more than 89% of porosity as well as about 107 MUm of average pore diameter. The composite scaffold was compared with ACECM and PLGA scaffolds. Cell proliferation test showed that the number of MSCs in ACECM and composite scaffolds was noticeably bigger than that in PLGA scaffold, which was coincident with results of SEM observation and cell viability staining. The water absorption of ACECM and composite scaffolds were 22.1 and 10.2 times respectively, which was much higher than that of PLGA scaffolds (3.8 times). The compressive modulus of composite scaffold in hydrous status was 1.03 MPa, which was near 10 times higher than that of hydrous ACECM scaffold. The aforementioned results suggested that the composite scaffold has the potential for application in cartilage tissue engineering. PMID- 21287239 TI - In vitro study in stimulating the secretion of angiogenic growth factors of strontium-doped calcium polyphosphate for bone tissue engineering. AB - Angiogenesis of tissue-engineered bone remains a limited factor for the engineering of larger bone tissue constructs. Attempts to stimulate angiogenesis, using recombinant protein or gene transfer of angiogenic growth factors, have been proposed; however, these approaches have been associated with some problems regarding such as complex technique, expensive prices as well as safety problems and short half-life of angiogenic growth factors. This study was performed to determine the ability of strontium-doped calcium polyphosphate (SCPP) to induce angiogenesis via researching its effect on the mRNA expressions and protein secretion of VEGF and bFGF in/from cultured osteoblasts (ROS17/2.8 cells). We cultured osteoblasts with SCPP scaffolds containing various doses of strontium as well as calcium polyphosphate (CPP) scaffold. Through the detection of MTT and SEM, we have found that SCPP could promote cell proliferation and maintain their morphology. The results of RT-PCR and ELISA indicated that, compared with those in CPP group, the mRNA expression as well as protein levels of VEGF and bFGF in/from cultured osteoblasts were dose-dependent increasing in response to increasing strontium before reaching the peak in SCPP groups, and 8% SCPP showed the optimal promoting role. Therefore, SCPP containing proper dose of strontium could be served as a potential biomaterial with stimulating angiogenesis in bone tissue engineering and bone repair. PMID- 21287240 TI - Surface modification of Ti-6Al-4V alloy for biomineralization and specific biological response: Part I, inorganic modification. AB - Titanium and its alloys represent the gold standard for orthopaedic and dental prosthetic devices, because of their good mechanical properties and biocompatibility. Recent research has been focused on surface treatments designed to promote their rapid osteointegration also in case of poor bone quality. A new surface treatment has been investigated in this research work, in order to improve tissue integration of titanium based implants. The surface treatment is able to induce a bioactive behaviour, without the introduction of a coating, and preserving mechanical properties of Ti6Al4V substrates (fatigue resistance). The application of the proposed technique results in a complex surface topography, characterized by the combination of a micro-roughness and a nanotexture, which can be coupled with the conventional macro-roughness induced by blasting. Modified metallic surfaces are rich in hydroxyls groups: this feature is extremely important for inorganic bioactivity (in vitro and in vivo apatite precipitation) and also for further functionalization procedures (grafting of biomolecules). Modified Ti6Al4V induced hydroxyapatite precipitation after 15 days soaking in simulated body fluid (SBF). The process was optimised in order to not induce cracks or damages on the surface. The surface oxide layer presents high scratch resistance. PMID- 21287241 TI - Surface properties and cell adhesion onto allylamine-plasma and amine-plasma coated glass coverslips. AB - Surface properties of nanoparticles to be used for radioimmunotherapy need to be optimized to allow antibody conjugation while ensuring biocompatibility. We aimed to investigate cell adhesion and proliferation onto different coatings to be used for nanoparticles. C, CH(x) or SiO(x) coatings deposited onto glass coverslips by magnetron deposition as well as nitrogen functionalized materials synthetized using different reactive sputtering conditions and PPAA (plasma polymerized allylamine) coating, were compared. Amine functionalization did increase hydrophilicity in all the materials tested. Biocompatibility was assessed by measuring cell viability, morphology, attachment, spreading, and pro-inflammatory cytokine secretion. The results show that C and CN(x) were the most biocompatible substrates while SiO(x) and SiO(x)N(y) were the most toxic materials. PPAA coatings displayed unexpectedly an intermediate biocompatibility. A correlation could be observed between wettability and cell proliferation except for C coated surface, indicating that more complex processes than hydrophilicity alone are taking place that affect cell functions. PMID- 21287242 TI - Corneal epithelialisation on surface-modified hydrogel implants: artificial cornea. AB - The objective was to investigate corneal re-epithelialisation of surface-modified polymethacrylate hydrogel implants in order to evaluate them as potential materials for an artificial cornea. Polymethacrylate hydrogels were modified with amines and then coated with different extracellular matrix proteins (collagen I, IV, laminin and fibronectin). The modified hydrogels were surgically implanted into bovine corneas maintained in a 3-D culture system for 5 days. The epithelial growth across the implant surface was evaluated using fluorescent, light and electron microscopy. Full epithelialisation was achieved on 1,4-diaminobutane modified hydrogels after coating with collagen IV. Hydrogels modified with 1,4 diaminobutane but without further coating only showed partial re epithelialisation. Hydrogels modified with other amines (1,2-diaminoethane or 1,3 diaminopropane) showed only partial re-epithelialisation; further coating with extracellular matrix proteins improved epithelialisation of these surfaces but did not result in complete re-epithelialisation. Evaluation of the corneas implanted with the 1,4-diaminobutane-modified hydrogels coated with collagen IV showed that the artificial corneas remain clear, integrate well and become covered by a healthy stratified epithelium. In conclusion the 1,4-diaminobutane surface-modified hydrogel coated with collagen IV supported the growth of a stable stratified epithelium. With further refinement this hydrogel has the potential to be used clinically for an artificial cornea. PMID- 21287243 TI - Synthesis and characterization of ionic charged water soluble arginine-based poly(ester amide). AB - A family of water soluble and positively charged L-arginine based poly(ester amide)s (Arg-PEAs) was synthesized and characterized. These biodegradable polymers consist of three nontoxic building blocks: L-arginine, diols, and dicarboxylic acids. The Arg-PEAs were prepared by solution polycondensation reaction of tetra-p-toluenesulfonic acids salts of bis-(L-arginine) alpha, omega alkylene diesters and di-p-nitrophenyl esters of dicarboxylic acids. Optimal conditions of the monomers and polymers synthesis were investigated, and the monomers and Arg-PEAs were chemically characterized. Arg-PEAs were found to have good solubility in water and many other polar solvents. Structure-function relationship of the Arg-PEAs revealed that changing the number of methylene groups in the diol or/and diacid segment could finely tune the hydrophobic and cationic properties of the Arg-PEAs. MTT assay showed that all the prepared Arg PEAs were non-toxic to the cell lines even at very large doses. Arg-PEAs with double bond functionality could be photo-crosslinked with polyethylene glycol diacrylate to form cationic hybrid hydrogels. PMID- 21287244 TI - In vivo performance of bilayer hydroxyapatite scaffolds for bone tissue regeneration in the rabbit radius. AB - The objective of this study was to investigate the in vivo biomechanical performance of bone defects implanted with novel bilayer hydroxyapatite (HAp) scaffolds that mimic the cortical and cancellous organization of bone. The scaffolds maintained architectural continuity in a rabbit radius segmental defect model and were compared to an untreated defect group (negative control) and autologous bone grafts (positive control). Micro-CT evaluations indicated total bone and scaffold volume in the experimental group was significantly greater than the defect group but lesser than the autologous bone graft treatment. The flexural toughness of the scaffold and the autograft groups was significantly greater than the flexural toughness of the defect group. Interestingly, the absolute density of the bone mineral as well as calcium to phosphorus (Ca/P) ratio in that mineral for the scaffold and autograft contralateral bones was significantly higher than those for the defect contralaterals suggesting that the scaffolds contributed to calcium homeostasis. It was concluded from this study that new bone regenerated in the bilayer HAp scaffolds was comparable to the empty defects and while the HAp scaffolds provided significant increase in modulus when compared to empty defect and their flexural toughness was comparable to autografts after 8 weeks of implantation. PMID- 21287245 TI - Stimulated osteoblastic proliferation by mesoporous silica xerogel with high specific surface area. AB - Specific surface area is a critical parameter of mesoporous silica-based biomaterials, however, little is known about its effects on osteoblast responses in vitro. In the present study, mesoporous silica xerogels (MSXs) with different surface area (401, 647 and 810 m(2)/g, respectively) were synthesized by a sol gel process. Surface silanol contents decreased with the increase of surface area with which protein adsorption capability positively correlated. And the apatite like surface seemed to form faster on MSXs with higher surface area determined by XRD analysis. Using MG63 osteoblast-like cells as models, it was found that cell proliferations were promoted on MSXs with higher surface area, based on the premise that the effects of Si released from materials on osteoblast viability were excluded by real-time Transwell((r)) assay. RT-PCR results indicated cell adhesion-related integrin subunits alpha5 were up-regulated by higher surface area at day 1, which was further confirmed by flow cytometry analysis. The data suggest that increasing SSA of MSXs could promote surface cellular affinity by adsorbing serum proteins and accelerating apatite-like layer formation, which results in promoted osteoblastic proliferation via integrin subunit alpha5 at initial adhesion stage. Regulating SSA, an effective approach in designing mesoporous silica-based materials, provides an alternative method to obtain desirable tissue-response in bone regeneration and drug-delivery system. PMID- 21287246 TI - Low-temperature 1H-NMR spectroscopic study of doxorubicin influence on the hydrated properties of nanosilica modified by DNA. AB - The effect of the anticancer drug--doxorubicin (Dox) on hydration properties of a nanocomposite material deposited on silica and modified by small amount of DNA (0.6 wt%) was studied by means of (1)H NMR spectroscopy at low temperatures (in the range of 200-280 K). Signals of either weakly (WAW) or strongly (SAW) associated water, as well as water associated with electrondonor groups of the composite surface (ASW), were observed. The findings reveal that, depending on the temperature and the composition of the dispersion medium, fast molecular exchange takes place between different forms of interphase water. The presence of Dox (0.1-0.2 wt%) in the dispersion medium leads to change of the relative concentrations of different forms of water. PMID- 21287247 TI - Characterization of self-organized TiO2 nanotubes on Ti-4Zr-22Nb-2Sn alloys and the application in drug delivery system. AB - In this study, the self-organized TiO(2) nanotubes grown by anodization of Ti-4Zr 22Nb-2Sn at different potentials, concentration of NH(4)F and anodization time was investigated. The morphology of nanotubes was observed by FE-SEM. The drug loaded nanotubes were also fabricated in aqueous media containing minocycline hydrochloride. They were characterized by SEM, XPS and FT-IR. The results showed that the drug of minocycline hydrochloride (MH) was loaded in the nanotubes. The release effects were studied in phosphate buffer solution (PBS). The release rate of MH from TiO(2) nanotubes with shorter tube length in PBS was lower than the one of MH from longer nanotubes. The sustaining release time could last at least 150 h. Hence, it is a promising method to eliminate the harmful reactions by carrying drug in the tubes when the titanium alloys were used as biomedical implants. PMID- 21287248 TI - Reproduction, survival, and life table parameters of the predatory mite Cheyletus malaccensis (Acari: Cheyletidae) at various constant temperatures. AB - Reproduction, survival, and life table parameters of the predatory mite Cheyletus malaccensis Oudemans were evaluated at six constant temperatures: 17.5, 20, 25, 30, 32.5 and 35 degrees C, feeding on Tyrophagus putrescentiae (Schrank). Preoviposition period of fertilized and virgin females varied with temperature from ca. 9 days at 17.5 degrees C to ca. 1.5 day at 32.5 degrees C and then increased to ca. 3 days at 35 degrees C. Virgin female oviposition period was significantly shorter than for fertilized females at the temperatures examined with the exception of 17.5 degrees C. The mean total number of eggs per fertilized (169.7 +/- 6.6) and virgin female (60.7 +/- 4.3) was highest at the temperature of 30 degrees C. The data indicated a significant positive and nearly doubling effect of fertilization on female fecundity at the temperatures examined with the exception of 17.5 degrees C. Age-specific fecundity was described by a temperature dependent model from which the maximum daily fecundity rate was estimated for fertilized and virgin females at 10.3 (at 30 degrees C) and 6.8 (at 32.5 degrees C) eggs/female, respectively. Virgin female longevity was significantly shorter than for fertilized females at 20, 30 and 32.5 degrees C, and decreased from ca. 57 days at 17.5 degrees C to ca. 17 days at 35 degrees C. The Weibull function that was used to describe the age specific survival of fertilized and virgin females produced excellent fits to the survival data. Estimates of intrinsic rate of increase, net reproductive rate, mean generation time, doubling time and finite rate of increase, were obtained. The r(m) value increased with temperature from 0.03 (day(-1)) at 17.5 degrees C to 0.21 (day( 1)) at 32.5 degrees C, after which it decreased to 0.15 (day(-1)) at 35 degrees C. These data indicate that C. malaccensis can reproduce at temperatures between 17.5 and 35 degrees C and can be used for biological control of astigmatid mites within the temperature range where the pest occurs. PMID- 21287249 TI - Inhalable sustained-release formulation of glucagon: in vitro amyloidogenic and inhalation properties, and in vivo absorption and bioactivity. AB - PURPOSE: The present study aimed to develop novel glucagon-loaded PLGA nanospheres without cytotoxic fibril formation for chronic glucagon replacement therapy. METHODS: Glucagon-loaded nanospheres (GLG/NS) were prepared by an emulsion solvent diffusion method in oil, and a respirable powder formulation (GLG/NS-RP) was prepared with a jet mill. Physicochemical and inhalation properties of GLG/NS-RP were characterized, and pharmacokinetic behavior and hyperglycemic effect of intratracheally instilled GLG/NS-RP were evaluated in rats. RESULTS: Although preparation of GLG/NS using glucagon solution at concentrations over 10 mg/mL led to significant formation of cytotoxic glucagon aggregates, glucagon solution at less than 5 mg/mL did not cause structural changes. Drug release behavior of GLG/NS showed a biphasic pattern with an initial burst and slow diffusion. Laser diffraction and cascade impactor analyses of GLG/NS-RP suggested high dispersion and deposition in the respiratory organs with a fine particle fraction of 20.5%. After the intratracheal administration of the GLG/NS-RP (200 MUg glucagon/kg) in rats, glucagon was released in a sustained manner, leading to sustained hyperglycemic effects compared with those of normal glucagon powder. CONCLUSION: These data would suggest a therapeutic benefit of the newly developed GLG/NS-RP as an alternative to the injection form of glucagon currently used. PMID- 21287250 TI - In vivo bioequivalence and in vitro similarity factor (f2) for dissolution profile comparisons of extended release formulations: how and when do they match? AB - PURPOSE: To investigate how likely two extended release formulations are to be bioequivalent when they demonstrate f2 similarity. METHOD: Dissolution profiles were simulated using the Weibull model and varying model parameters around those of a reference profile. The f2 values were calculated for the comparisons of each simulation with the reference profile. The in vivo inputs obtained from an in vitro-in vivo correlation model were convolved with a unit impulse response function. The AUC, Cmax, and Tmax from each simulated in vivo concentration profile were compared to the reference profile. The AUCR (AUC ratio) and CmaxR (Cmax ratio) were determined. The consistency between f2 and bioequivalence was investigated. RESULTS: The relationships between AUCR, CmaxR, f2 and the Weibull model parameters demonstrate that the bioequivalence regions enclosed by the contour lines of 80% and 125% of AUCR and CmaxR were generally close to the regions enclosed by the f2 = 50 contour line, but did not exactly match, especially when Dmax and B deviated from the reference values. CONCLUSIONS: When f2 is used for in vitro dissolution profile comparison, the completeness of the dissolution profiles should not differ more than 10%, and the shapes of the dissolution profiles should not be significantly different. PMID- 21287252 TI - Photoluminescence studies of Pr3+ doped lead germanate glass. AB - The Pr(3+)doped PbO-GeO(2) glass samples have been synthesized by melting and quenching process. The nephelauxetic ratio, covalency and bonding parameter which provides the information about the type of bonding between the rare earth ion and neighbor oxygen atoms calculated. The optical parameters such as radiative transition probabilities, radiative lifetime, branching ratios etc. of Pr(3+) ions have been determined by Judd-Ofelt analysis. An upconversion emission using the excitation at ~594 nm supported by energy transfer process due to dipole dipole interaction in the (1)D(2) metastable state has been found. PMID- 21287251 TI - Denaturation mechanism of BSA by urea derivatives: evidence for hydrogen-bonding mode from fluorescence tools. AB - Urea and alkyl urea derivatives, which posses a free N-H moiety in the urea molecular framework is responsible for the fluorescence quenching of BSA. Fluorescence quenching accompanied with a blue initially and subsequently a red shift in the emission maximum of BSA is observed on the addition of urea derivatives containing N-H moieties. On the contrary, a fluorescence enhancement accompanied with a shift in the emission maximum towards the blue region is observed on the addition of tetramethylurea (TMU). Urea derivatives, which posses a free N-H moiety acts as a perfect denaturant by direct hydrogen-bonding interaction with BSA resulting in the unfolding process. The unfolding of the buried tryptophan moieties to the aqueous phase does not occur, when all the N-H moieties in the urea are methyl substituted (TMU). Fluorescence spectral techniques reveal that the direct hydrogen-bonding interaction of the N-H moiety of urea molecular framework with the carbonyl oxygen moieties of BSA results in the unfolding of the tryptophan moieties to the aqueous phase, while that of the carbonyl oxygen of urea with the N-H moieties of BSA is definitely not involved in the denaturation process. Steady state and time-resolved fluorescence studies illustrate that the extent of protein folding occurs at a relatively lower concentration of unsymmetrical alkyl urea derivatives (butyl urea (BU) and ethyl urea (EU)), compared to that of urea. PMID- 21287253 TI - Development of the Contextual Assessment of Social Skills (CASS): a role play measure of social skill for individuals with high-functioning autism. AB - This study piloted a role play assessment of conversational skills for adolescents and young adults with high-functioning autism/Asperger syndrome (HFA/AS). Participants completed two semi-structured role plays, in which social context was manipulated by changing the confederate's level of interest in the conversation. Participants' social behavior was rated via a behavioral coding system, and performance was compared across contexts and groups. An interaction effect was found for several items, whereby control participants showed significant change across context, while participants with HFA/AS showed little or no change. Total change across contexts was significantly correlated with related social constructs and significantly predicted ASD. The findings are discussed in terms of the potential utility of the CASS in the evaluation of social skill. PMID- 21287254 TI - Judgments of cause and blame: sensitivity to intentionality in Asperger's syndrome. AB - Sensitivity to intentionality in people with Asperger's syndrome (AS) and matched controls was investigated using two scenario-based tasks. The first compared intentional and unintentional human actions and physical events leading to the same negative outcomes. The second compared intentional actions that varied in their subjective and objective likelihood of bringing about a negative outcome. Whilst adults with AS did not differ from controls in their judgments of causality, or in their blame judgments in relation to non-mentalistic factors, they showed heightened sensitivity to mentalistic considerations in their attributions of blame. They made greater differentiation than controls between intentional and unintentional actions, and also between actions that the protagonists believed to be likely versus unlikely to lead to negative consequences. PMID- 21287255 TI - Avatar assistant: improving social skills in students with an ASD through a computer-based intervention. AB - This study assessed the efficacy of FaceSay, a computer-based social skills training program for children with Autism Spectrum Disorders (ASD). This randomized controlled study (N = 49) indicates that providing children with low functioning autism (LFA) and high functioning autism (HFA) opportunities to practice attending to eye gaze, discriminating facial expressions and recognizing faces and emotions in FaceSay's structured environment with interactive, realistic avatar assistants improved their social skills abilities. The children with LFA demonstrated improvements in two areas of the intervention: emotion recognition and social interactions. The children with HFA demonstrated improvements in all three areas: facial recognition, emotion recognition, and social interactions. These findings, particularly the measured improvements to social interactions in a natural environment, are encouraging. PMID- 21287256 TI - Phylogenetic analysis of the E2 gene of classical swine fever virus from the Guangxi Province of southern China. AB - In this study, suspected classical swine fever (CSF) samples from the Guangxi Province of China were obtained from pigs with acute CSF, aborted fetuses, newborn pigs that died at 1-2 days of age, tonsils of healthy pigs, and leukocytes of immunized sows during 2001-2009. About 92 of 775 samples were found to be positive by RT-PCR, and 41 isolates were obtained. Phylogenetic analysis was performed on the 31 isolates by sequencing the E2 gene, and the isolates were found to cluster into two groups: (1) isolates from aborted fetuses (except GXGZ02), deceased newborn baby pigs, tonsils of healthy pigs, and leukocytes of immunized sows belonged to group 1.1, along with vaccine strain, HCLV, and standard virulent strain, Shimen, of China, and (2) 20 isolates from pigs with acute CSF belonged to group 2.1, 13 of which were clustered into subgroup 2.1b with isolates from other provinces of China, and 7 of which were clustered into subgroup 2.1a with isolates from Italy and Germany. PMID- 21287257 TI - Deletion of the M2-2 gene from avian metapneumovirus subgroup C impairs virus replication and immunogenicity in Turkeys. AB - The second matrix (M2) gene of avian metapneumovirus subgroup C (aMPV-C) contains two overlapping open reading frames (ORFs), encoding two putative proteins, M2-1 and M2-2. Both proteins are believed to be involved in viral RNA transcription or replication. To further characterize the function of the M2-2 protein in virus replication, the non-overlapping region of the M2-2 ORF was deleted from an infectious cDNA clone of the aMPV-C strain, and a viable virus was rescued by using reverse genetics technology. The recombinant virus, raMPV-C DeltaM2-2, was characterized in vitro and in vivo. In Vero cells, raMPV-C DeltaM2-2 replicated slightly less efficiently than the parental virus, 10-fold reduction at 48-h post infection. The raMPV-C DeltaM2-2 virus induced typical cytopathic effects (CPE) that were indistinguishable from those seen with the parental virus infection. In specific-pathogen-free (SPF) turkeys, raMPV-C DeltaM2-2 was attenuated and caused no clinical signs of disease. Less than 20% of the inoculated birds shed detectable virus in tracheal tissue during the first 5 days post-infection, and no virus shedding was detected afterward. Forty percent of infected birds produced a weak antibody response at 14 days post-infection. Upon challenge with a virulent aMPV-C strain, more than 80% of the raMPV-C DeltaM2-2-inoculated birds showed typical disease signs and virus shedding in tracheal tissue. These results suggest that the M2-2 protein of aMPV-C virus is not essential for virus replication in vitro, but is required for sufficient virus replication to maintain pathogenicity and immunogenicity in the natural host. PMID- 21287258 TI - Cigarette smoking shortens the survival of patients with low-risk myelodysplastic syndromes. AB - Myelodysplastic syndromes (MDS) are a group of hematological malignancies with poor survival. Although previous studies have identified the prognostic role of multiple demographic and clinical characteristics, the potential role of lifestyle factors has not been evaluated. In this study, we conducted an extensive assessment of the predictors of MDS survival, with a special focus on lifestyle factors. A total of 616 patients (median survival = 4.1 years) were included in the analysis, and multivariate Cox proportional hazard models were utilized to estimate hazard ratios. Compared with non-smokers, MDS patients who smoked at the initial clinical encounter had a significantly increased risk of death [hazard ratio (HR) = 1.46, 95% confidence intervals (CI): 1.07-2.00]. The elevated risk was restricted to men (HR = 1.76, 95% CI: 1.21-2.56) and not observed among women (HR = 0.98, 95% CI: 0.51-1.85). When patients were stratified by the IPSS categorization, a near three fold increased risk of death was associated with smoking among patients with low-risk MDS (HR = 2.83, 95% CI: 1.48-5.39), whereas smoking did not appear to influence the survival of patients with intermediate- or high-risk MDS. This study was the first to identify smoking as a significant and independent predictor of MDS survival, particularly among low-risk patients. PMID- 21287259 TI - Associations of body size and reproductive factors with circulating levels of sex hormones and prolactin in premenopausal Japanese women. AB - OBJECTIVE: Body size and reproductive factors are important risk factors of breast cancer. The aim of the present study was to examine the associations of these factors with blood concentrations of sex hormones and prolactin in premenopausal Japanese women. METHODS: We measured the plasma concentrations of estradiol, estrone, testosterone, dehydroepiandrosterone sulfate (DHEAS), sex hormone-binding globulin (SHBG), follicle-stimulating hormone, luteinizing hormone, and prolactin among 436 women who had regular menstrual cycles less than 40 days long. Information on menstrual and reproductive factors including history of breastfeeding was obtained using a self-administered questionnaire. Height and weight were measured. RESULTS: After controlling for age and the phase of the menstrual cycle, the body mass index (BMI) was significantly inversely associated with total estradiol, estrone and SHBG and significantly positively associated with total and free testosterone and DHEAS. Nulliparous women had significantly higher levels of total and free testosterone, DHEAS, and prolactin than parous women. Duration of breastfeeding for the first child was significantly inversely associated with free testosterone and prolactin levels. CONCLUSIONS: The data suggest that an increased risk of premenopausal breast cancer associated with low BMI is partially mediated by an increased total estradiol. Androgens and prolactin may explain the breast cancer protection provided by giving birth and breastfeeding. PMID- 21287260 TI - The centrosome and spindle as a ribonucleoprotein complex. AB - The notion of nucleic acids in the spindle, and particularly, the centrosome has a long history of inquiry, doubt, and debate. However, the association of specific RNAs with these structures is now confirmed by several investigators. What their presence means for the assembly, function, and evolution of the cell division apparatus is not known; but with newly available information and probes, these are questions that can finally be addressed. The present article summarizes the history of this field, what we know about the molecules in question, and in light of these findings, emphasizes the need to view the cell division apparatus for what it is by definition, a ribonucleoprotein complex. PMID- 21287261 TI - Like a fish out of water: reconsidering disaster recovery and the role of place and social capital in community disaster resilience. AB - In this paper we draw on the findings of a critical, multi-sited ethnographic study of two rural communities affected by a wildfire in British Columbia, Canada to examine the salience of place, identity, and social capital to the disaster recovery process and community disaster resilience. We argue that a reconfiguration of disaster recovery is required that more meaningfully considers the role of place in the disaster recovery process and opens up the space for a more reflective and intentional consideration of the disorientation and disruption associated with disasters and our organized response to that disorientation. We describe a social-psychological process, reorientation, in which affected individuals and communities navigate the psychological, social and emotional responses to the symbolic and material changes to social and geographic place that result from the fire's destruction. The reorientation process emphasizes the critical importance of place not only as an orienting framework in recovery but also as the ground upon which social capital and community disaster resilience are built. This approach to understanding and responding to the disorientation of disasters has implications for community psychologists and other service providers engaged in supporting disaster survivors. This includes the need to consider the complex dynamic of contextual and cultural factors that influence the disaster recovery process. PMID- 21287262 TI - A structural model of racial discrimination, acculturative stress, and cultural resources among Arab American adolescents. AB - Despite evidence towards the risk for discrimination and acculturative stress that Arab American adolescents may face, the link between socio-cultural adversities and psychological well-being in this population has not been established. This study examined the role of socio-cultural adversities (discrimination and acculturative stress) and cultural resources (ethnic identity, religious support and religious coping) in terms of their direct impact on psychological distress. Using structural equation modeling, the proposed model was tested with 240 Arab American adolescents. The results indicated a strong positive relationship between socio-cultural adversities and psychological distress. Furthermore, this study supported a promotive model of cultural resources, where a negative association between cultural resources and psychological distress was found. Understanding the manner in which socio cultural adversities and resources are linked to psychological distress can inform the development of culturally appropriate interventions that can effectively mitigate mental health concerns for understudied and vulnerable populations. PMID- 21287265 TI - The effect of surgeon empathy and emotional intelligence on patient satisfaction. AB - We investigated the associations of surgeons' emotional intelligence and surgeons' empathy with patient-surgeon relationships, patient perceptions of their health, and patient satisfaction before and after surgical procedures. We used multi-source approaches to survey 50 surgeons and their 549 outpatients during initial and follow-up visits. Surgeons' emotional intelligence had a positive effect (r = .45; p < .001) on patient-rated patient-surgeon relationships. Patient-surgeon relationships had a positive impact on patient satisfaction before surgery (r = .95; p < .001). Surgeon empathy did not have an effect on patient-surgeon relationships or patient satisfaction prior to surgery. But after surgery, surgeon empathy appeared to have a significantly positive and indirect effect on patient satisfaction through the mediating effect of patients' self-reported health status (r = .21; p < .001). Our study showed that long-term patient satisfaction with their surgeons is affected less by emotional intelligence than by empathy. Furthermore, empathy indirectly affects patient satisfaction through its positive effect on health outcomes, which have a direct effect on patients' satisfaction with their surgeons. PMID- 21287264 TI - Heavy metal contents in whitefish (Coregonus lavaretus) along a pollution gradient in a subarctic watercourse. AB - Metallurgic industry is a source of serious environmental pollution related to the emission of heavy metals. Freshwater systems are focal points for pollution, acting as sinks for contaminants that may end up in fish and humans. The Pasvik watercourse in the border area between Finland, Norway and Russia is located in the vicinity of the Pechenganickel metallurgic enterprises, and the lower part of the watershed drains the Nikel smelters directly through Lake Kuetsjarvi. Heavy metal (Ni, Cu, Cd, Zn, Pb and Hg) concentrations in environment (water and sediments) and whitefish Coregonus lavaretus tissue (gills, liver, kidney and muscle) were contrasted between five lake localities situated along a spatial gradient of increasing distance (5-100 km) to the smelters. The heavy metal concentrations, in particular Ni, Cu and Cd, were highly elevated in Kuetsjarvi, but steeply declined with increasing distance to the smelters and were moderate or low in the other four localities. The study demonstrates that the majority of metal emissions and runoffs are deposited near the pollution source, and only moderate amounts of the heavy metal contaminants seem to be transported at further distances. Bioaccumulation of Hg occurred in all investigated tissues, and higher Hg concentrations in planktivorous versus benthivorous whitefish furthermore indicated that pelagic foraging is associated with higher levels of Hg biomagnification. Potential population ecology impacts of high heavy metal contaminations where mainly observed in whitefish in Kuetsjarvi, which showed depletions in growth rate, condition factor and size and age at maturation. PMID- 21287266 TI - Adaptability of Typha domingensis to high pH and salinity. AB - The aim of this work was to compare the adaptability of two different populations of Typha domingensis exposed to high pH and salinity. The plants were sampled from an uncontaminated natural wetland (NW) and a constructed wetland (CW) for the treatment of an industrial effluent with high pH and salinity. The plants from each population were exposed to the following combined treatments of salinity (mg l(-1)) and pH: 8,000/10 (values found in the CW); 8,000/7; 200/10 and 200/7 (typical values found in the NW). Chlorophyll concentration, relative growth rates (RGR) and root structure parameters (cross-sectional areas of root, stele and metaxylem vessels) were measured. Images of roots and leaves by scanning electronic microscopy (SEM) were obtained, and X-ray microanalysis in different tissues was carried out. In all treatments, the RGR and chlorophyll increase were significantly lower in the plants from the NW than in the plants from the CW. However, stress was observed when the plants from the CW were exposed to treatment 200/7. In treatment 8,000/10 the tissues of the plants from the NW showed severe damages. The root structure of plants from the CW was modified by salinity, while pH did not produce changes. In plants from the CW there were no differences between Na concentration in leaves of the treatments 8,000/10 and 200/7, indicating that Na was not transported to leaves. The CW population already possesses physiological and morphological adaptations due to the extreme conditions of pH and salinity. Because of its adaptive capacity, T. domingensis is an efficient species to treat wastewater of high pH and salinity. PMID- 21287267 TI - Expression and function of Sox21 during mouse cochlea development. AB - The development of the inner ear is an orchestrated process of morphogenesis with spatiotemporally controlled generations of individual cell types. Recent studies have revealed that the Sox gene family, a family of evolutionarily conserved HMG type transcriptional factors, is differentially expressed in each cell type of the mammalian inner ear and plays critical roles in cell-fate determination during development. In this study, we examined the expression pattern of Sox21 in the developing and adult murine cochlea. Sox21 was expressed throughout the sensory epithelium in the early otocyst stage but became restricted to supporting cells during adulthood. Interestingly, the expression in adults was restricted to the inner phalangeal, inner border, and Deiters' cells: all of these cells are in direct contact with hair cells. Evaluations of the auditory brainstem-response revealed that Sox21(-/-) mice suffered mild hearing impairments, with an increase in hair cells that miss their appropriate planar cell polarity. Taken together with the previously reported critical roles of SoxB1 families in the morphogenesis of inner ear sensory and neuronal cells, our results suggest that Sox21, a counteracting partner of the SoxB1 family, controls fine-tuned cell fate decisions. Also, the characteristic expression pattern may be useful for labelling a particular subset of supporting cells. PMID- 21287268 TI - Abeta peptide toxicity is reduced after treatments decreasing phosphatidylethanolamine content in differentiated neuroblastoma cells. AB - We investigated whether the toxicity of oligomeric amyloid-beta peptide (Abeta1 42) upon differentiated human neuroblastoma SH-SY5Y cells, can be affected by changes of membrane lipid composition. An immunostaining technique, using lipids extracted from the cells and separated by thin layer chromatography, suggested that Abeta preferentially binds to phosphatidylethanolamine (PE), one of the major lipids in the cell extract. For this reason, we utilized treatments with putative inhibitors of phosphatidylethanolamine biosynthesis (choline, phosphocholine, R59949) to decrease its proportion in the cell membrane; choline treatment (2.5 mM, 24 h) showed the best performance, reducing phosphatidylethanolamine content from 5.7 to 3.3 MUg phosphorous/mg protein. Either the extent of Abeta binding or its toxicity decreased onto choline-treated cells. These data may open the possibility to develop future strategies aiming to reduce Abeta toxicity in Alzheimer disease. PMID- 21287269 TI - Upregulation of inflammatory mediators in a model of chronic pain after spinal cord injury. AB - Chronic neuropathic pain is a disabling condition observed in large number of individuals following spinal cord injury (SCI). Recent progress points to an important role of neuroinflammation in the pathogenesis of central neuropathic pain. The focus of the present study is to investigate the role of proinflammatory molecules IL-1beta, TNF-alpha, MCP-1, MMP-9 and TIMP-1 in chronic neuropathic pain in a rodent model of SCI. Rats were subjected to spinal cord contusion using a controlled linear motor device with an injury epicenter at T10. The SCI rats had severe impairment in locomotor function at 7 days post-injury as assessed by the BBB score. The locomotor scores showed significant improvement starting at day 14 and thereafter showed no further improvement. The Hargreaves' test was used to assess thermal hyperalgesia for hindpaw, forepaw and tail. A significant reduction in withdrawal latency was observed for forepaw and tail of SCI rats at days 21 and 28, indicating the appearance of thermal hyperalgesia. Changes in expression of mRNAs for IL-1beta, TNF-alpha, MCP-1, MMP-9 and TIMP-1 were assessed using real-time polymerase chain reaction in spinal cord including the injury epicenter along with regions above and below the level of lesion at day 28 post-injury. A significant increase was observed in the expression of MCP 1, TNF-alpha, TIMP-1 and IL-1beta in the injury epicenter, whereas only TIMP-1 was upregulated in the area below the injury epicenter. The results of the study suggest that prolonged upregulation of inflammatory mediators might be involved in chronic neuropathic pain in SCI, and that TIMP-1 may play a role in maintenance of chronic below level pain. PMID- 21287270 TI - Lipoxygenases and poly(ADP-ribose) polymerase in amyloid beta cytotoxicity. AB - The 12/15-lipoxygenase(s) (LOX), poly(ADP-ribose) polymerase (PARP-1) activity and mitochondrial apoptosis inducing factor (AIF) protein in the amyloid beta (Abeta) toxicity were investigated in PC12 cells that express either wild-type (APPwt) or double Swedish mutation (APPsw) forms of human Abeta precursor protein. Different levels of Abeta secretion and free radicals formation characterize these cells. The results demonstrated a relationship between the Abeta levels and LOX protein expression and activity. High Abeta concentration in APPsw cells correlated with a significant increase in free radicals and LOX activation, which leads to translocation of p65/NF-kappaB into the nucleus. An increase in AIF expression in mitochondria was observed concurrently with inhibition of PARP-1 activity in the nuclear fraction of APPsw cells. We suggested that AIF accumulation in mitochondria may be involved in adaptive/protective processes. However, inhibition of PARP-1 may be responsible for the disturbances in transcription and DNA repair as well as the degeneration of APP cells. Under conditions of increased nitrosative stress, evoked by the nitric oxide donor, sodium nitroprusside (SNP, 0.5 mM), 70-80% of all cells types died after 24 h, significantly more in APPsw cells. There was no further significant change in mitochondrial AIF level and PARP-1 activity compared to corresponding non-treated cells. Only one exception was observed in PC12 control, where SNP significantly inhibits PARP-1 activity. Moreover, SNP significantly activated gene expression for 12/15-LOX in all types of investigated cells. Inhibitors of all LOX isoforms and specific inhibitor of 12-LOX enhanced the survival of cells that were subjected to SNP. We conclude that the LOX pathways may play a role in Abeta toxicity and in nitrosative-stress-induced cell death and that inhibition of these pathways offers novel protective strategies. PMID- 21287271 TI - Viral distribution and lesions in Kunming mice experimentally infected with porcine circovirus type 2b. AB - The viral distribution and lesions in Kunming mice experimentally infected with porcine circovirus type 2b (PCV-2b) were investigated. Seventy special pathogen free mice were divided into 2 groups with 35 mice in each group. The test group (TG) was infected with PCV-2b, the control group (CG) was inoculated with sterile cell cultures. Five mice in each group were sacrificed at 3, 7, 14, 21, 28, 35 and 42 dpi (day post infection), respectively. Necropsies were performed on all mice and tissues were collected for testing by histopathology, immunohistochemistry, transmission electron microscope (TEM) and polymerase chain reaction (PCR). Apoptosis and necrosis in lymphoid organs were observed in virus infected mice, and became severe from 14 to 28 dpi. The proportion of PCV-2b antigen-positive cells was moderate in lung, heart, thymus, liver or kidney, and low in brain from TG. In spleen and cervical lymph node, the proportions of PCV 2b antigen-positive cells were low to high from 7 to 28 dpi, and moderate from 35 to 42 dpi. PCV-2b DNA was detected in all tissues examined in TG from 7 to 42 dpi. Viral inclusion bodies presented in the cytoplasm of lymphocytes, macrophages, hepatocytes, podocytes, neurocytes, spermatids and uterine epithelial cells in TG. In CG, no viruses and viral lesions were detected. PCV-2b could replicate in mice, and PCV-2b associated lesions in mice were similar to those observed in pigs. The present results indicate that it is possible to use Kunming mouse as an animal model for PMWS research. PMID- 21287272 TI - Excitation energy transfer in the LHC-II trimer: from carotenoids to chlorophylls in space and time. AB - Exciton model for description of experimentally determined excitation energy transfer from carotenoids to chlorophylls in the LHC-II trimer of spinach is presented. Such an approach allows connecting the excitonic states to the spatial structure of the complex and hence descriptions of advancements of the initially created excitations in space and time. Carotenoids were excited at 490 nm and at 500 nm and induced absorbance changes probed in the Chl Q(y) region to provide kinetic data that were interpreted by using the results from exciton calculations. Calculations included the 42 chlorophylls and the 12 carotenoids of the complex, Soret, Q(x) and Q(y) states of the chlorophylls, and the main absorbing S(2) state of the carotenoids. According to the calculations excitation at 500 nm populates mostly a mixed Lut S(2) Chl a Soret state, from where excitation is transferred to the Q(x) and Q(y) states of the Chl a's on the stromal side. Internal conversion of the mixed state to a mixed Lut S(1) and Chl a Q(y) state provides a channel for Lut S(1) to Chl a Q(y) energy transfer. The results from the calculations support a picture where excitation at 490 nm populates primarily a mixed neoxanthin S(2) Chl b Soret state. From this state excitation from neoxanthin is transferred to iso-energetic Chl b Soret states or via internal conversion to S(1) Chl b Q(y) states. From the Soret states excitation proceeds via internal conversion to Q(y) states of Chl b's mostly on the lumenal side. A rapid Chl b to Chl a transfer and subsequent transfer to the stromal side Chl a's and to the final state completes the process after 490 nm excitation. The interpretation is further supported by the fact that excitation energy transfer kinetics after excitation of neoxanthin at 490 nm and the Chl b Q(y) band at 647 nm (Linnanto et al., Photosynth Res 87:267-279, 2006) are very similar. PMID- 21287273 TI - Recent progresses on the genetic basis of the regulation of CO2 acquisition systems in response to CO2 concentration. AB - Marine diatoms, the major primary producer in ocean environment, are known to take up both CO(2) and HCO(3)(-) in seawater and efficiently concentrate them intracellularly, which enable diatom cells to perform high-affinity photosynthesis under limiting CO(2). However, mechanisms so far proposed for the inorganic carbon acquisition in marine diatoms are significantly diverse despite that physiological studies on this aspect have been done with only limited number of species. There are two major hypotheses about this; that is, they take up and concentrate both CO(2) and HCO(3)(-) as inorganic forms, and efficiently supply CO(2) to Rubisco by an aid of carbonic anhydrases (biophysical CO(2) concentrating mechanism: CCM); and as the other hypothesis, biochemical conversion of HCO(3)(-) into C(4) compounds may play a major role to supply concentrated CO(2) to Rubisco. At moment however, physiological evidence for these hypotheses were not related well to molecular level evidence. In this study, recent progresses in molecular studies on diatom-carbon-metabolism genes were related to the physiological aspects of carbon acquisition. Furthermore, we discussed the mechanisms regulating CO(2) acquisition systems in response to changes in pCO(2). Recent findings about the participation of cAMP in the signaling pathway of CO(2) concentration strongly suggested the occurrences of mammalian-type-signaling pathways in diatoms to respond to changes in pCO(2). In fact, there were considerable numbers of putative adenylyl cyclases, which may take part in the processes of CO(2) signal capturing. PMID- 21287274 TI - Vulnerability to stress in migratory contexts: a study with Eastern European immigrants residing in Portugal. AB - The assessment of individual vulnerability to stress emerges as a predictive factor of a higher risk of developing stress-related disorders. In the last decade, the geography of immigration in Portugal experienced intense transformations in terms of recruitment and patterns of geographic settlement, with an increasing and exponential inflow of new and diversified migratory groups. The immigrant populations coming from Eastern European countries are a recent migratory flow, with linguistic, cultural and socio-demographic specificities which are very different from the general Portuguese population. This makes them a paradigmatic group in potential transcultural studies on mental health issues. The primary aim of the study was to describe the characteristics of vulnerability to stress and determine their impact on the mental health status of Russian-speaking immigrants residing in Portugal. The relationship between vulnerability to stress, sociodemographic variables, mental health status and social support were analyzed, using the SSQ6, GHQ28, 23QVS and a socio demographic questionnaire. A comparative analysis was carried out, using a control group of 110 Portuguese subjects without previous migratory experiences, matched by sex, age group and academic qualifications. The eastern European immigrants reported high levels of vulnerability to stress assessed by the cut off point of the 23QVS. Immigrants also reported higher percentage of vulnerability to stress and lower social support levels of social support versus the control group. Several factors inherent to the dynamics of the migratory process were related to the presence of vulnerability to stress. The findings suggest that vulnerability to stress is positively correlated with worse mental health outcomes and negatively correlated with the social support perceived as available--number of supporters and satisfaction with social support. PMID- 21287275 TI - Hemocompatibility of silicon-based substrates for biomedical implant applications. AB - Silicon membranes with highly uniform nanopore sizes fabricated using microelectromechanical systems (MEMS) technology allow for the development of miniaturized implants such as those needed for renal replacement therapies. However, the blood compatibility of silicon has thus far been an unresolved issue in the use of these substrates in implantable biomedical devices. We report the results of hemocompatibility studies using bare silicon, polysilicon, and modified silicon substrates. The surface modifications tested have been shown to reduce protein and/or platelet adhesion, thus potentially improving biocompatibility of silicon. Hemocompatibility was evaluated under four categories-coagulation (thrombin-antithrombin complex, TAT generation), complement activation (complement protein, C3a production), platelet activation (P-selectin, CD62P expression), and platelet adhesion. Our tests revealed that all silicon substrates display low coagulation and complement activation, comparable to that of Teflon and stainless steel, two materials commonly used in medical implants, and significantly lower than that of diethylaminoethyl (DEAE) cellulose, a polymer used in dialysis membranes. Unmodified silicon and polysilicon showed significant platelet attachment; however, the surface modifications on silicon reduced platelet adhesion and activation to levels comparable to that on Teflon. These results suggest that surface-modified silicon substrates are viable for the development of miniaturized renal replacement systems. PMID- 21287276 TI - Low stress tendon fatigue is a relatively rapid process in the context of overuse injuries. AB - To stimulate healing and prevent tendinosis through optimized physical exercise, it is important to elucidate the tendon response to repetitive mechanical loading. However, the study of this response is challenging due to complex cell matrix interactions. In an initial approximation, the authors examined tendon mechanical response only, and did not consider cellular activity. The authors investigated the hypothesis that mechanical degradation occurs relatively rapidly (< 24 h) even at very low stress levels. The authors subjected rat tail tendons to mechanical loadings oscillating between 0 and 1.5 MPa up to one of three fatigue levels: 4% strain, 8% strain, or rupture. Using non-destructive mechanical tests, changes in tendon strain and compliance over the entire fatigue testing period were evaluated. Using microscopy techniques, the structural evidence of mechanical degradation was examined. The changes in tendon strain and compliance progressed nonlinearly and accelerated before rupture which took place around the 15-h mark. Histological analyses revealed a higher degree of alteration in the collagen network at increased fatigue levels. At rupture, local zones of damage with low fibril density were evident. These results imply that a repair process must act rapidly at critical sites; otherwise, enzymatic degradation could cause further damage in the manner of a vicious cycle. PMID- 21287278 TI - Utility of nonspecific resting electrocardiographic features for detection of coronary artery stenosis by computed tomography in acute chest pain patients: from the ROMICAT trial. AB - Twelve-lead surface electrocardiography (ECG) and computed tomography (CT) are used to evaluate for myocardial ischemia and coronary artery disease (CAD), respectively. We aimed to determine features on resting ECG that predict coronary artery stenosis by cardiac CT. In 309 acute chest pain patients, we compared the initial triage resting ECG to contrast-enhanced 64-slice cardiac CT angiography. We assessed for 6 quantitative (QT interval, QTc interval, QTc > 440 ms, gender specific QTc, QT dispersion and QRS duration) and 4 qualitative ECG parameters (ST depression >0.05 to <=0.1 mV, T wave inversion >=0.1 mV, T wave flattening, and any T wave abnormalities) and for the presence of coronary stenosis by CT (>50% luminal narrowing). Specificities of these ECG parameters were excellent (83.6-97.0%) while sensitivities were poor (12.2-29.3%). For coronary stenosis detection, the ECG features with the greatest performance were the presence of ST depression (positive likelihood ratio [LR+] 4.09) and T wave inversion (LR+ 4.58). In multivariable analyses, the risk for coronary stenosis increased by 33 41% for every 20 ms prolongation of the QTc interval after adjusting for age, gender, and cardiac risk factors or adjustment for Framingham risk score. Similarly, there was an increase of fourfold with the presence of ST depression >0.05 to <=0.1 mV or T wave inversion >=0.1 mV. In acute chest pain patients, resting ECG features of QTc interval prolongation, mild ST depression, and T wave inversion are independently associated with the presence of CT coronary stenosis and their presence suggests an increase risk of CAD. PMID- 21287279 TI - Illness as unhomelike being-in-the-world? Phenomenology and medical practice. AB - Scientific medicine has been successful by ways of an ever more detailed understanding and mastering of bodily functions and dysfunctions. Biomedical research promises new triumphs, but discontent with medical practice is all around. Since several decades this has been acknowledged and discussed. The philosophical traditions of phenomenology and hermeneutics have been proposed as promising ways to approach medical practice, by ways of a richer understanding of the meaning structures of health and illness. In 2000, Swedish philosopher Fredrik Svenaeus published a book where he proposes that the phenomenological hermeneutics of Martin Heidegger and also the reflections on health and illness of Hans-Georg Gadamer offer important ways to approach the nature of medicine. In particular, Svenaeus argues that the goal of medicine is to promote and restore health, and that health ought to be seen as "homelike being-in-the-world". Unhealth, illness, consequently should be understood as a situation where a person's "being-in-the-world" in characterized by that lack of the rhythm, balance and "tune" of everyday living that characterizes not "being at home". In this article, Svenaeus' position is briefly outlined. Questions are raised whether "unhomelikeness" is to be seen as a metaphor, and, if so, if it is a fruitful such. Furthermore, I discuss whether or not a discourse on health and illness in these terms may be misleading in a situation where the ontological presuppositions of Heidegger are lost out of sight and the popular understanding of health psychology predominates. I also approach the question whether Svenaeus' assumptions may inadvertently lead us to an unjustifiably broad understanding of the tasks of medicine. It is finally concluded that Svenaeus phenomenological and hermeneutical approach is both interesting and promising. There are, however, several questions that ought to be pursued further, and the step from philosophical analysis to everyday clinical discourse may be unexpectedly long and risky. PMID- 21287280 TI - Quality of life among parents of children with cancer or brain tumors: the impact of child characteristics and parental psychosocial factors. AB - PURPOSE: Understanding the impact of childhood cancer on the family is increasingly important. This study aimed to (1) examine the relationship between child clinical characteristics and health-related quality of life (QOL) among parents of children with cancer or brain tumors, and (2) determine how parental psychosocial factors impact this relationship. METHODS: Using a within-group approach, this study examined 75 children with cancer or brain tumors and their parent. In-person interviewer-assisted surveys assessed sociodemographics, psychosocial factors, and QOL. Child clinical characteristics were obtained through medical record abstraction. Regressions were performed to determine factors related to parental QOL. RESULTS: Children's activity limitation and active treatment status were associated with worse parental mental QOL (5.4 and 4.4 points lower, respectively; P < 0.05). Adding parental psychosocial characteristics to the model eliminated the relationship between child clinical characteristics and parental mental QOL (P > 0.05 for all child characteristics). CONCLUSIONS: While child clinical characteristics appear to be related to poor parental QOL, this relationship was mediated by caregiver burden and stress. Interventions to reduce burden and stress may mitigate the deleterious effects of caregiving. Systematic screening of parents' mental and physical health may facilitate interventions and improve the health and well-being of parents and children. PMID- 21287281 TI - The florid subtype of lobular carcinoma in situ: marker or precursor for invasive lobular carcinoma? AB - BACKGROUND: Lobular carcinoma in situ (LCIS) is considered a risk factor-not a precursor-for both invasive lobular and ductal carcinoma. Florid LCIS (F-LCIS) is an architectural subtype of LCIS that does not express E-cadherin, yet has the histologic and often radiographic appearance of solid-type ductal carcinoma in situ (DCIS). Since DCIS is considered a precursor to invasive ductal carcinoma, should F-LCIS be considered a precursor to invasive lobular carcinoma (ILC)? METHODS: Review of an institutional database identified cases of LCIS and solid type DCIS diagnosed by excisional biopsy, segmentectomy, or mastectomy between 1991 and 2000 to determine the prevalence of associated invasive breast cancer. Archival specimens were evaluated for florid and nonflorid LCIS, nuclear grade of LCIS, and the presence and subtype of invasive breast cancer. Solid-type DCIS that lacked E-cadherin expression was classified as F-LCIS. RESULTS: Of 210 consecutive specimens of LCIS examined, 171 had nonflorid LCIS (81%) and 39 had F LCIS (19%). Nonflorid LCIS had a diffuse pattern, whereas F-LCIS appeared as discrete foci adjacent to ILC. An invasive component was identified with 87% of F LCIS lesions versus 73% of nonflorid LCIS lesions (P = 0.064); this component was lobular in 100% of F-LCIS lesions versus 82% of nonflorid LCIS lesions, a significant difference (P = 0.0044) that persisted when the analysis was adjusted for nuclear grade (P = 0.0082). CONCLUSION: Its close spatial relationship to an invasive component and increased association with ILC suggest that F-LCIS may be a precursor for ILC. PMID- 21287282 TI - The advantages of humeral anteromedial plate osteosynthesis in the middle third shaft fractures. AB - BACKGROUND: Humeral shaft fractures account for 1.2% of all fractures and occur in a slightly younger population. Their causes include a fall from standing or from height, motor vehicle accident, but can be also pathological. In order to clarify which of both surgeries we performed in our Department for treating humeral shaft fractures had more advantages (anterolateral or anteromedial plating through anterolateral approach) we analyzed incidence of postoperative iatrogenic radial palsies and mean operation time required to complete each surgery. METHODS: During January 1992 to December 2009 on Department of Surgery, Division for Traumatology of Clinical Hospital Center Rijeka, 420 patients (340 males and 80 females with mean age of 38.11 +/- 9.29 years) were treated for middle third humeral shaft fracture by anterolateral approach and internal fixation using AO/DCP or LCP plates that was positioned on anteromedial humeral surface in 141 patients (33.57%) and on anterolateral humeral surface in 279 patients (66.43%). RESULTS: None of the patients who had osteosynthesis by using plate on anteromedial humeral sufrace had lesions of the radial nerve. Therefore, chi(2) test revealed significantly higher frequency of postsurgical radial nerve injuries in patients who were treated by anterolateral plating than in patients where anteromedial plating was performed (chi(2) = 17.51; p< 0.05). Anterolateral plating required longer mean operation time than anteromedial plating and the difference in its duration determined by t-test for independent samples showed statistically significant difference (t= 14.57; p< 0.05). CONCLUSION: An anteromedial plating of humeral shaft fractures through anterolateral approach was determinated to be a simple, safe, effective and also fast surgical treatment and we highly recommend it as operative technique for treating humeral shaft fractures. PMID- 21287283 TI - Uptake and distribution of metals by water lettuce (Pistia stratiotes L.). AB - BACKGROUND, AIM AND SCOPE: Water quality impairment by heavy metal contamination is on the rise worldwide. Phytoremediation technology has been increasingly applied to remediate wastewater and stormwater polluted by heavy metals. MATERIALS AND METHODS: Laboratory analysis and field trials were conducted to evaluate the uptake of metals (Al, Ca, Cd, Co, Cr, Cu, Fe, K, Mg, Mn, Na, Ni, Pb, and Zn) by an aquatic plant, water lettuce (Pistia stratiotes L.), and metal distribution in the plant. RESULTS: The growth of water lettuce reduced Al, Fe, and Mn concentrations in water by >20%, K and Cu by >10%, and Ca, Mg, Zn, and Na to a lesser extent. A larger proportion of Ca, Cd, Co, Fe, Mg, Mn, and Zn was adsorbed or deposited on the external root surfaces while more Al, Cr, Cu, Ni, and Pb were absorbed and accumulated within the roots. DISCUSSION: Water lettuce has a great ability in concentrating metals from its surrounding water with a concentration factor (CF) >=10(2). The bio-concentration factor (BCF), which excludes the part on the root surfaces, is a more appropriate index than the CF for the differentiation of hyperaccumulation, accumulation, or non-accumulation plants for metals. CONCLUSIONS: Water lettuce is a hyperaccumulator for Cr, Cu, Fe, Mn, Ni, Pb, and Zn and can be applied for the remediation of surface waters. RECOMMENDATIONS AND PERSPECTIVES: Further study on the bioavailability of metals in the water lettuce is needed for the beneficial use of metal-enriched plant biomass. PMID- 21287284 TI - Investigation of photodegradation and hydrolysis of selected substituted urea and organophosphate pesticides in water. AB - INTRODUCTION: Photodegradation and hydrolysis of two substituted urea herbicides, monolinuron [3-(4-chlorophenyl)-1-methoxy-1-methylurea] and linuron [3-(3,4 dichlorophenyl)-1-methoxy-1-methylurea], and one organophosphorous insecticide, phoxim [2-(diethoxyphosphinothioyloxyimino)-2-phenylacetonitrile], were studied using buffered sterilized distilled water (pH 4, 7 and 9). METHODS: Experiments were performed in the absence and presence of light (320-740 nm), while the effect of nitrates and humic acids on photodegradation was investigated for all pH values. An analytical method was developed and validated for the determination of target compounds in water samples using liquid chromatography positive ion electrospray-mass spectrometry. RESULTS: According to the results, substituted ureas neither hydrolyzed, at all tested pH values, nor photodegraded at pH 7 and 9. Slow photodegradation of the compounds was observed at pH 4. During 70 days of light exposure, initial concentrations of linuron and monolinuron were decreased by 54% and 31%, respectively, while the presence of nitrates slightly enhanced photodegradation of these compounds. On the other hand, phoxim was found to be very unstable for all the tested conditions and an increase of pH resulted to higher degradation. During hydrolysis experiments, the degradation of the compound ranged from 41% (pH 4) to 85% (pH 9) and the half-lives varied from 10 h (pH 9) to 204 h (pH 4). The presence of light enhanced phoxim degradation and as a result half-lives of 37, 22 and 9h were calculated for pH 4, 7 and 9, respectively. The addition of nitrates and humic acids did not significantly affect the photodegradation of phoxim. CONCLUSIONS: The results indicated that among the three tested pesticides, phoxim found to be the most sensitive in both photodegradation and hydrolysis. PMID- 21287285 TI - Microbial biomass carbon and enzyme activities of urban soils in Beijing. AB - INTRODUCTION: To promote rational and sustainable use of soil resources and to maintain the urban soil quality, it is essential to assess urban ecosystem health. In this study, the microbiological properties of urban soils in Beijing and their spatial distribution patterns across the city were evaluated based on measurements of microbial biomass carbon and urease and invertase activities of the soils for the purpose of assessing the urban ecosystem health of Beijing. MATERIALS AND METHODS: Grid sampling design, normal Kriging technique, and the multiple comparisons among different land use types were used in soil sampling and data treatment. The inherent chemical characteristics of urban soils in Beijing, e.g., soil pH, electronic conductivity, heavy metal contents, total N, P and K contents, and soil organic matter contents were detected. The size and diversity of microbial community and the extent of microbial activity in Beijing urban soils were measured as the microbial biomass carbon content and the ratio of microbial biomass carbon content to total soil organic carbon. RESULTS AND DISCUSSION: The microbial community health measured in terms of microbial biomass carbon, urease, and invertase activities varied with the organic substrate and nutrient contents of the soils and were not adversely affected by the presence of heavy metals at p < 0.01. It was shown that the older and the biologically more stable part of city exhibited higher microbial activity levels than the more recently developed part of the city and the road areas of heavy traffic. It was concluded that the land use patterns in Beijing urban soils influenced the nature and activities of the microbial communities. PMID- 21287286 TI - A preliminary investigation of the environmental impact of a thermal power plant in relation to PCB contamination. AB - PURPOSE: The most significant application of polychlorinated biphenyls (PCBs) is in transformers and capacitors. Therefore, power plants are important suspected sources for entry of PCBs into the environment. In this context, the levels and distribution of PCBs in sediment, soil, ash, and sludge samples were investigated around Seyitomer thermal power plant, Kutahya, Turkey. Moreover, identity and contribution of PCB mixtures were predicted using the chemical mass balance (CMB) receptor model. METHODS: United States Environmental Protection Agency methods were applied during sample preparation, extraction (3540C), cleanup (3660B, 3665A, 3630C), and analysis (8082A). RESULTS: SigmaPCB concentrations in the region ranged from not detected to 385 ng/g dry weight, with relatively higher contamination in sediments in comparison to soil, sludge, and ash samples collected from around the power plant. Congener profiles of the sediment and soil samples show penta-, hexa-, and hepta-chlorobiphenyls as the major homolog groups. The results from the CMB model indicate that PCB contamination is largely due to Clophen A60/A40 and Aroclor 1254/1254(late)/1260 release into the sediment and sludge samples around the thermal power plant. CONCLUSIONS: Since there are no other sources of PCBs in the region and the identity of PCB sources estimated by the CMB model mirrors PCB mixtures contained in transformers formerly used in the plant, the environmental contamination observed especially in sediments is attributed to the power plant. Release of PCBs over time, as indicated by the significant concentrations observed even in surface samples, emphasizes the importance of the need for better environmental management. PMID- 21287287 TI - Biomechanical modeling of brace treatment of scoliosis: effects of gravitational loads. AB - The biomechanics of bracing in adolescent idiopathic scoliosis is still not fully understood. Finite element models (FEM) have been used but the gravity forces were not included and the production of spinal stresses not evaluated. An improved FEM to simulate brace treatment was thus developed. The 3D geometry of the spine, rib cage, pelvis, and of the trunk external surface of five scoliotic patients was acquired using a multi-view X-ray technique and surface topography. A FEM of the patient's trunk including gravity forces was created. Custom-fit braces were modeled and their installation simulated. Immediate geometrical corrections and pressures were computed and validated. The resulting compressive loads on the vertebral endplates were quantified. The influence of the strap tension, spine stiffness, and of the gravity forces was evaluated. Results showed that the brace biomechanical action was importantly to prevent the scoliotic spine from bending under the gravity forces. The immediate correction depended on the strap tension and spine stiffness. The distribution and amplitude of computed pressures were similar to those measured with the real braces. After the brace installation, the coronal asymmetrical compressive loading on the vertebral endplates was significantly reduced. In conclusion, the model developed presents improvements over previous models and could be used to better understand and optimize brace treatment. PMID- 21287288 TI - Dietary cocoa butter or refined olive oil does not alter postprandial hsCRP and IL-6 concentrations in healthy women. AB - Contrary to other long chain saturated fatty acids (SFA), fats high in stearic acid do not raise plasma cholesterol concentrations, however, a slight elevation in inflammatory markers, plasma fibrinogen and interleukin-6 (IL-6), has been observed in the fasting state. The effect of stearic acid on inflammation in the postprandial state has not yet been reported. We conducted a single blind crossover, randomized, postprandial study to compare the effects of a fat load of cocoa butter high in stearic acid and olive oil in ten healthy women. The test meals contained 1 g of fat per kg body weight (mean 62 g). Blood samples were collected at 0 (fasting), 4 and 6 h. Both diets resulted in a significant increase in serum triacylglycerol (TAG) concentration over time (P = 0.003) and a decrease in serum IL-6 concentration after 4 h followed by an increase to post absorptive values after 6 h (P < 0.001); whereas serum high sensitivity C reactive protein (hsCRP) concentration was not affected. There was no difference between diets in effects on serum TAG, hsCRP and IL-6 concentrations and no association between postprandial lipemia and inflammatory markers. High intake of dietary fats increase postprandial serum TAG, however, may not affect inflammatory markers postprandially. Thus, fat rich in stearic acid does not seem to increase postprandial inflammation. PMID- 21287289 TI - Regeneration and functional recovery of intrapelvic nerves removed during extensive surgery by a new artificial nerve conduit: a breakthrough to radical operation for locally advanced and recurrent rectal cancers. AB - PURPOSE: In the current strategy against locally advanced and recurrent rectal cancers possibly involving intrapelvic nerves, there has been a serious dilemma between extensive surgery and limited surgery. The former can attain high tumor curability by sacrificing the nerve functions while the latter prioritizes the patient quality of life by preserving the nerve functions but with a compromised curability. Here we present a new surgical strategy for locally advanced and recurrent rectal cancers, which realize both high tumor curability and good quality of life. METHODS: A new artificial nerve conduit (polyglycolic acid collagen tube) developed by in site tissue engineering technology was applied to recovery the disturbed functions after removing the nerves from 11 patients undergoing extensive surgery for intrapelvic advanced or recurrent colorectal cancers. The reconstructed nerves included eight autonomic nerves which are essential for the genitourinary function and three somatic nerves which control the sensation and mobility of the legs. RESULTS: Out of ten cases followed up more than 2 years and evaluated fully, eight including two report cases showed a functional recovery of the disturbed autonomic and somatic nerves clinically. The nerve function started to recover from 3 to 6 months after the operation and continued to improve with times. No specific complications associated with the nerve repair have been noted. CONCLUSIONS: The new strategy utilizing the nerve conduit can be a breakthrough in radical operations for locally advanced and recurrent rectal cancers to resolve the problems between tumor curability and the patient quality of life. PMID- 21287290 TI - Regional variations in testicular cancer rates in Ireland: clusters and communities. PMID- 21287291 TI - Initial experiences with isolated limb perfusion for unresectable melanoma of the limb. AB - AIMS: Our initial results with isolated limb perfusion (ILP) using melphalan +/- TNF alpha in patients with unresectable melanoma of the limb were analyzed. METHODS: 15 ILPs were performed between 2001 and 2006. Indications for ILP were stage III or IV metastatic melanoma. Complete and partial response rates, time to local and systemic tumour progression rates, disease free and overall survival rates were retrospectively analyzed. RESULTS: Overall response rate was 93%, with a 67% complete response and a 26% partial response rate. In eight cases grade II, while in six cases grade III local toxicity was detected. However, one mortality was detected in the early postoperative phase due to a grade V complication. With a mean follow-up period of 2.7 years, eight patients had local progression and in four of those, systemic progression was detected. CONCLUSIONS: ILP was generally well tolerated and limb salvage was achieved in all cases. PMID- 21287292 TI - Gastric emptying of orally administered glucose solutions and incretin hormone responses are unaffected by laparoscopic adjustable gastric banding. AB - BACKGROUND: Laparoscopic adjustable gastric banding (LAGB) provides weight loss in obese individuals and is associated with improved glucose homeostasis and resolution of type 2 diabetes. However, in most available reports, potentially inappropriate methodology has been applied when measuring the impact of LAGB on glucose intolerance. In order to clarify the applicability of the diagnostic 75 g oral glucose tolerance test (OGTT) to measure the effect of LAGB on glucose metabolism, we investigated the effect of LAGB on gastric emptying for liquids as well as pancreatic and incretin hormone responses. METHODS: Eight obese patients (three with normal glucose tolerance, three with impaired glucose tolerance, and two with type 2 diabetes; age 47.5 +/- 1.1 years (mean+/-SEM); body mass index 44 +/- 1 kg/m2; HbA(1)c 6.2 +/- 0.4%) underwent a 75 g-oral glucose tolerance test with 1 g acetaminophen before and ~6 weeks after LAGB. RESULTS: A small weight reduction was seen after LAGB (125 +/- 8 vs. 121 +/- 8 kg, P = 0.014). No differences in determinants of gastric emptying were observed before and after LAGB (area under the serum acetaminophen curve 10.1 +/- 0.6 vs. 9.8 +/- 0.5 mM x 4 h, P = 0.8; peak acetaminophen concentration 62 +/- 3 vs. 61 +/- 3 MUM, P = 0.8; acetaminophen peak time 98 +/- 6 vs. 100 +/- 6 min, P = 0.9). No differences in plasma glucose, insulin, C-peptide, glucagon, glucose-dependent insulinotropic polypeptide, or glucagon-like peptide-1 responses to the OGTT were observed before as compared to after LAGB. CONCLUSIONS: OGTT can be used to evaluate glucose tolerance in obese patients before and after LAGB without bias from changes in gastric emptying. LAGB has no direct impact on incretin hormone secretion. PMID- 21287293 TI - Complexity: against systems. AB - This article assumes a specific intuitive notion of complexity as a difficulty to generate and/or assess the plausibility of models. Based on this intuitive understanding of complexity, it identifies two main causes of complexity, namely, radical openness and contextuality. The former is the idea that there are no natural systems. The modeler always needs to draw artificial boundaries around phenomena to generate feasible models. Contextuality is intimately connected to the requirement to simplify models and to leave out most aspects. Complexity occurs when contextuality and radical openness cannot be contained that is when it is not clear where the boundaries of the system are and which abstractions are the correct ones. This concept of complexity is illustrated using a number of example from evolution. PMID- 21287294 TI - Somatostatin and dopamine receptor profile of gastroenteropancreatic neuroendocrine tumors: an immunohistochemical study. AB - Somatostatin and its synthetic analogs act through five specific somatostatin receptors (sstr1-5), found on the cell membrane of various tumors, including endocrine ones. Dopamine--a known neurotransmitter--acts through five membranous dopamine receptors (D1R-D5R) which have recently been found to be expressed in endocrine tumors. We evaluated the immunohistochemical expression of the sstrs and D2R in a large series of gastroenteropancreatic neuroendocrine tumors (GEP NETs). A total of 22 (28.94%) well-differentiated NETs (WDNETs), 6 (7.89%) WDNETs of uncertain biology, 26 (34.21%) well-differentiated neuroendocrine carcinomas, and 22 (28.94%) poorly differentiated neuroendocrine carcinomas were studied. Overall, 76.31% of the tumors were positive for different types of sstrs with variable intensity of the membranous staining whereas 36.95% were positive for D2R alone. The sstr2A was the most frequently expressed, followed by sstr2B, sstr1, and sstr5. Co-expression of sstrs and D2R was seen in 88.23% of positive tumors. The high rates of sstr2A and sstr2B and in a lower extent of sstr5 expression are of great importance for more accurate imaging, staging and targeted therapy of the disease. The co-expression of sstrs and D2R in a significant number of the studied cases offers a potential therapeutic alternative for GEP-NETs. PMID- 21287295 TI - Prolactin and autoimmunity: hyperprolactinemia correlates with serositis and anemia in SLE patients. AB - Evidence points to an association of prolactin to autoimmune diseases. We examined the correlation between hyperprolactinemia and disease manifestations and activity in a large patient cohort. Age- and sex-adjusted prolactin concentration was assessed in 256 serum samples from lupus patients utilizing the LIASON prolactin automated immunoassay method (DiaSorin S.p.A, Saluggia, Italy). Disease activity was defined as present if European Consensus Lupus Activity Measurement (ECLAM) > 2 or Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) > 4. Lupus manifestations were grouped by organ involvement, laboratory data, and prescribed medications. Hyperprolactinemia was presented in 46/256 (18%) of the cohort. Hyperprolactinemic patients had significantly more serositis (40% vs. 32.4%, p = 0.03) specifically, pleuritis (33% vs. 17%, p = 0.02), pericarditis (30% vs. 12%, p = 0.002), and peritonitis (15% vs. 0.8%, p = 0.003). Hyperprolactinemic subjects exhibited significantly more anemia (42% vs. 26%, p = 0.02) and marginally more proteinuria (65.5% vs. 46%, p = 0.06). Elevated levels of prolactin were not significantly associated with other clinical manifestations, serology, or therapy. Disease activity scores were not associated with hyperprolactinemia. Hyperprolactinemia in lupus patients is associated with all types of serositis and anemia but not with other clinical, serological therapeutic measures or with disease activity. These results suggest that dopamine agonists may be an optional therapy for lupus patients with hyperprolactinemia. PMID- 21287296 TI - Lupus nephritis in Colombians: contrasts and comparisons with other populations. AB - Lupus nephritis (LN) is one of the most serious complications of systemic lupus erythematosus (SLE) since it is the major predictor of poor prognosis. The purpose of this study was to examine the clinical and immunological characteristics associated with LN development during the course of SLE in Colombians. Therefore, patients with SLE followed at five different referral centers in Medellin, Bogota, and Cali were included in this cross-sectional and multicenter study. Factors influencing LN were assessed by conditional logistic regression analysis, adjusting by gender, age at onset, duration of disease, and city of origin. The entire sample population included 467 patients, of whom 51% presented with LN. The presence of anti-dsDNA antibodies (adjusted odds ratio (AOR), 2.06; 95% confidence interval (CI), 1.16-3.65), pleuritis (AOR, 3.82; 95% CI, 1.38-10.54), and hypertension (AOR, 2.63; 95% CI, 1.23-5.62) were positively associated with LN, whereas the presence of anti-La antibodies was a protective factor against LN development (AOR, 0.4; 95% CI, 0.19-0.85). A review of literature on LN in different populations is made. The identified clinical- and laboratory-associated factors would assist earlier diagnosis and guide decisions on therapeutic interventions on this critical and frequent complication of SLE. PMID- 21287297 TI - Bright field neuronal preparation optimized for automatic computerized reconstruction, a case with cerebellar climbing fibers. PMID- 21287298 TI - RNAi-mediated downregulation of NOB1 suppresses the growth and colony-formation ability of human ovarian cancer cells. AB - Nin one binding protein (NOB1p), encoded by the NOB1 gene, is a crucial molecule in the maturation of the 20S proteasome and protein degradation. The present study evaluates whether NOB1 is an appropriate molecular target for cancer gene therapy. In two ovarian cancer cell lines, SKOV3 and HEY, NOB1 expression was knocked down by a lentiviral short hairpin RNA (shRNA) delivery system. The RNA interference (RNAi)-mediated the downregulation of NOB1 expression markedly reduced the proliferative and colony-formation ability of ovarian cancer cells. Additionally, NOB1 shRNA-expressing lentivirus-treated ovarian cancer cells tended to arrest in the G0/G1 phase. These results suggested that NOB1 may act as an oncogenic factor in ovarian cancer and could be a potential molecular target for ovarian cancer gene therapy. PMID- 21287299 TI - Use of echocardiographic variables in addition to E/e' to improve prediction of elevated left ventricular filling pressures. PMID- 21287300 TI - Genome-wide association studies complemented with mechanistic biological studies identify sortilin 1 as a novel regulator of cholesterol trafficking. PMID- 21287301 TI - Vasculotoxic effects of insulin and its role in atherosclerosis: what is the evidence? AB - As a result of ambiguous results from several recent trials in diabetes, scrutiny has focused on the potential effects of insulin and its role in atherosclerosis. This article reviews the premise that anti-diabetes therapy (type 2 diabetes) with insulin causes vascular impairment that leads to atherothrombosis and compromises vascular integrity, which may further potentiates cardiovascular morbidity and mortality. Underlying mechanisms are discussed, including metabolic derangements (blood pressure, lipids, body weight, and glucose) and how these factors trigger insulin-like growth factor (IGF) receptors, leading to cancer. Cellular and molecular mechanisms are discussed, as well as whether the negative results seen in recent glucose trials support this premise. As with most drug therapy, aggressive therapies designed to reach glucose control targets trigger multiple and inter-related mechanisms that, in many cases, go far beyond the pre determined physiologic targets. From a clinical perspective, physicians should always stress lifestyle modifications, including physical exercise and diet, to their patients who show the first signs of metabolic impairment. Yet even within this context, diet and exercise should be the cornerstone of good therapy when pharmacotherapy is necessary. Given the amount of evidence seen to date with existing agents and the amount of information we do not yet know, patient centered approaches to modifying behavior before intensive drug therapy are needed should be stressed. PMID- 21287302 TI - 1H, 13C and 15N chemical shift assignments of the thioredoxin from the obligate anaerobe Desulfovibrio vulgaris Hildenborough. AB - Thioredoxins are ubiquitous key antioxidant enzymes which play an essential role in cell defense against oxidative stress. They maintain the redox homeostasis owing to the regulation of thiol-disulfide exchange. In the present paper, we report the full resonance assignments of (1)H, (13)C and (15)N atoms for the reduced and oxidized forms of Desulfovibrio vulgaris Hildenborough thioredoxin 1 (Trx1). 2D and 3D heteronuclear NMR experiments were performed using uniformly (15)N-, (13)C-labelled Trx1. Chemical shifts of 97% of the backbone and 90% of the side chain atoms were obtained for the oxidized and reduced form (BMRB deposits with accession number 17299 and 17300, respectively). PMID- 21287303 TI - Livedo reticularis and related disorders. AB - OPINION STATEMENT: Livedo reticularis is a violaceous mottling of the skin with a "fishnet" reticular appearance. Primary and secondary etiologies exist, including a pathologic variant termed livedo racemosa. No evidence-based medicine exists to guide therapy for this disorder, but most patients with primary and secondary livedo reticularis are asymptomatic and do not require treatment. In the rare instance that a patient with primary livedo reticularis experiences mild symptoms such as episodic numbness and tingling, avoidance of cold and vasoconstricting substances should be encouraged. Lastly, judicious dosing of a vasodilator such as a calcium channel blocker can be prescribed. Patients with secondary livedo reticularis or livedo racemosa may benefit from these same therapeutic suggestions; however, treating the proximate cause of livedo with a systemic association is encouraged and is most likely to yield cutaneous improvement. Although antiplatelet and/or anticoagulant therapy is often required when treating a patient with the antiphospholipid antibody syndrome or Sneddon's syndrome, the attendant livedo racemosa typically remains unchanged or progresses despite this treatment. PMID- 21287304 TI - Sleep disorders in machado-joseph disease: frequency, discriminative thresholds, predictive values, and correlation with ataxia-related motor and non-motor features. AB - Sleep disorders are common complaints in patients with neurodegenerative diseases such as spinocerebellar ataxia type 3 (SCA3) or Machado-Joseph disease (MJD)- SCA3/MJD. We evaluated the frequency of sleep disorders in SCA3/MJD patients against controls matched by age and gender, and correlated data with demographic and clinical variables. The main sleep disorders evaluated were rapid eye movement (REM) sleep behavior disorder (RBD), restless leg syndrome (RLS), and excessive daytime sleepiness (EDS). We recruited 40 patients with clinical and molecular-proven SCA3/MJD and 38 controls. We used the following clinical scales to evaluate our primary outcome measures: RBD Screening Questionnaire, International RLS Rating Scale, and Epworth Sleepiness Scale. To evaluate ataxia related motor and non-motor features, we applied the International Cooperative Ataxia Rating Scale, the Scale for the Assessment and Rating of Ataxia, and the Unified Parkinson's Disease Rating Scale part III. Psychiatric manifestations were tested with the Hamilton Anxiety Scale, and Beck Depression Inventory. The frequency of RBD and RLS were significantly higher in the SCA3/MJD group than in the control group (p < 0.001). There was no difference between both groups with regard to EDS. The accuracy of RDBSQ to discriminate between cases and controls was considered the best area under the ROC curve (0.86). Within-SCA3/MJD group analysis showed that anxiety and depression were significantly correlated with RDB, but not with RLS. Additionally, depression was considered the best predictive clinical feature for RDB and EDS. PMID- 21287305 TI - DNA microarray profiling identified a new role of growth hormone in vascular remodeling of rat ductus arteriosus. AB - The ductus arteriosus (DA), a fetal arterial connection between the pulmonary artery and the aorta, has a character distinct from the adjacent arteries. We compared the transcriptional profiles of the DA and the aorta of Wistar rat fetuses on embryonic day 19 (preterm) and day 21 (near-term) using DNA microarray analyses. We found that 39 genes were expressed 2.5-fold greater in the DA than in the aorta. Growth hormone (GH) receptor (GHR) exhibited the most significant difference in expression. Then, we found that GH significantly promoted migration of DA smooth muscle cells (SMCs), thus enhancing the intimal cushion formation of the DA explants. GH also regulated the expression of cytoskeletal genes in DA SMCs, which may retain a synthetic phenotype in the smooth muscle-specific cytoskeletal genes. Thus, the present study revealed that GH-GHR signal played a role in the vascular remodeling of the DA. PMID- 21287306 TI - The relationship between Candida species cultured from the respiratory tract and systemic inflammation in critically ill patients with ventilator-associated pneumonia. AB - PURPOSE: In patients with ventilator-associated pneumonia (VAP), the isolation of Candida species (spp.) in respiratory secretions has been associated with worse outcomes. It is unclear whether Candida colonization is causally related or is a marker of disease severity. The objective of this study was to compare systemic inflammatory markers in patients with a clinical suspicion of VAP with Candida in respiratory tract (RT) cultures vs patients who have bacteria and those with no pathogens. METHODS: This was a prospective observational study in adults with a clinical suspicion of VAP who were enrolled within 24 hr of intensive care unit (ICU) admission. Patients were divided into four groups according to RT cultures, i.e., bacterial pathogens only, Candida spp. only, culture negative, and a control group with no clinical suspicion of VAP. Clinical outcomes were collected and compared as were systemic inflammatory and coagulation markers, including procalcitonin (PCT), C-reactive protein (CRP) and interleukin (IL)-6. RESULTS: The PCT, CRP, and IL-6 levels were similar in the Candida, bacterial pathogen, and culture negative groups but were significantly increased between the Candida group and the control group (P < 0.05). In the first 28 days, the number of ICU free days was significantly lower in the Candida group compared with the other groups, and mortality at 28 days was greater (Candida 42.9%, bacterial pathogen 25.0%, culture negative 19.8%, control 0.0%; P < 0.05). CONCLUSIONS: In patients with a clinical suspicion of VAP, the presence of Candida spp. only in the RT is associated with similar levels of inflammation and worse clinical outcomes compared with patients without Candida in RT secretions. PMID- 21287307 TI - Recurrent endotracheal tube leak: ask and take a look. PMID- 21287309 TI - Follow-up assessment of health consequences after a chlorine release from a train derailment--Graniteville, SC, 2005. AB - INTRODUCTION: After a train derailment released chlorine gas in Graniteville, South Carolina, in 2005, a multiagency team performed an epidemiologic assessment of chlorine exposure and resulting health effects. Five months later, participants were resurveyed to determine their health status and needs and to assist in planning additional interventions in the community. METHODS: Questionnaires were mailed to 279 patients interviewed in the initial assessment; follow-up telephone calls were made to nonresponders. The questionnaire included questions regarding duration of symptoms experienced after exposure and a posttraumatic stress disorder (PTSD) assessment tool. RESULTS: Ninety-four questionnaires were returned. Seventy-six persons reported chronic symptoms related to the chlorine exposure, 47 were still under a doctor's care, and 49 were still taking medication for chlorine-related problems. Agreement was poor between the first and second questionnaires regarding symptoms experienced after exposure to the chlorine (kappa=0.30). Forty-four respondents screened positive for PTSD. PTSD was associated with post-exposure hospitalization for three or more nights [relative risk (RR) = 1.7; 95% confidence interval (CI)=1.1-2.6] and chronic symptoms (RR=9.1; 95% CI=1.3-61.2), but not with a moderate-to-extreme level of chlorine exposure (RR=1.2; 95% CI=0.8-1.8). CONCLUSIONS: Some victims of this chlorine exposure event continued to experience physical symptoms and continued to require medical care 5 months later. Chronic mental health symptoms were prevalent, especially among persons experiencing the most severe or persistent physical health effects. Patients should be interviewed as soon as possible after an incident because recall of acute symptoms experienced can diminish within months. PMID- 21287311 TI - Training experiences of lay and professional patient navigators for colorectal cancer screening. AB - Patient navigation (PN) is increasingly used in cancer care, but little is known about the identification and training of patient navigators. PN may be implemented by professional health care providers, paraprofessionals, or lay health workers and, therefore, presents an opportunity to compare professional and lay interventionist experiences. The goal of the current report is to compare the training experiences of four professional (Pro) and five lay (LHW) patient navigators enlisted to increase colonoscopy adherence among African American primary care patients. The results of early assessments showed that LHWs' intervention-related knowledge was significantly lower than that of Pros. However, there were no significant differences in knowledge scores between LHWs and Pros for most subsets of knowledge items in later assessments. Furthermore, there were no significant differences in LHWs' and Pros' reported self-efficacy and satisfaction with training. Findings support the use of diverse strategies to train and prepare LHWs as patient navigators. PMID- 21287310 TI - Age-related regulation of excitation-contraction coupling in rat heart. AB - Hearts from subjects with different ages have different Ca(2+) signaling. Release of Ca(2+) from intracellular stores in response to an action potential initiates cardiac contraction. Both depolarization-stimulated and spontaneous Ca(2+) releases, Ca(2+) transients and Ca(2+) sparks, demonstrate the main events of excitation-contraction coupling (ECC). Global increase in free Ca(2+) concentration ([Ca(2+)]( i )) consists of summation of Ca(2+) release events in cardiomyocytes. Since the Ca(2+) flux induced by Ca(2+) sparks reports a summation of ryanodine-sensitive Ca(2+) release channels (RyR2s)'s behavior in a spark cluster, evaluation of the properties of Ca(2+) sparks and Ca(2+) transients may provide insight into the role of RyR2s on altered heart function between 3-month-old (young adult) and 6-month-old (mature adult) rats. Basal [Ca(2+)]( i ) and Ca(2+) sparks frequency were significantly higher in mature adult rats compared to those of young adults. Moreover, amplitudes of Ca(2+) sparks and Ca(2+) transients were significantly smaller in mature adults than those of young adults with longer time courses. A smaller L-type Ca(2+) current density and decreased SR Ca(2+) load was observed in mature adult rats. In addition, RyR2s were markedly hyperphosphorylated, and phosphorylation levels of PKA and CaMKII were higher in heart from mature adults compared to those of young adults, whereas their SERCA protein levels were similar. Our data demonstrate that hearts from rats with different ages have different Ca(2+) signaling including hyperphosphorylation of RyR2s and higher basal [Ca(2+)]( i ) together with increased oxidized protein-thiols in mature adult rats compared to those of young adults, which play important roles in ECC. Finally, we report that ECC efficiency changes with age during maturation, partially related with an increased cellular oxidation level leading to reduced free protein-thiols in cardiomyocytes. PMID- 21287312 TI - Concurrent extinction does not render appetitive conditioning context specific. AB - In an experiment with rats, an appetitive conditioning method was used to investigate the generality of the hypothesis that extinction should arouse attention to contextual cues, resulting in all learning in that context becoming context specific. Rats received appetitive conditioning with a tone either while extinction of a flasher occurred (Group With Extinction) or while it did not (Group No Extinction). Half of each group was subsequently tested in extinction in the context in which training had taken place or in a different context. The results revealed a three-way interaction of extinction and context with trials, in a direction opposite to the one the hypothesis would suggest. When rats were tested in a different context, there was generally better responding in Group With Extinction than in Group No Extinction. In the same context, there was generally lower responding in Group With Extinction than in Group No Extinction. Subsequent testing showed an ABA recovery effect. Results are discussed in terms of the challenges they pose for the revised retrieval theory presented by Callejas-Aguilera and Rosas (2011). PMID- 21287313 TI - Preserved nodal number effects under equal reinforcement. AB - The present set of experiments tested the hypothesis that the nodal number effects observed in previous studies of stimulus equivalence were due to the confounding factor of training structure that resulted in unequal reinforcement across trial types. In Experiment 1, two 5-member equivalence classes were trained across equal and unequal reinforcement conditions, both with and without a limited hold. A significant nodal effect, as measured by response speed, was found in the equal reinforcement, no-limited-hold condition. In Experiment 2, two 6-member equivalence classes were trained in equal and unequal reinforcement conditions without limited hold. In a transfer-of-function test, clear nodal effects were observed in the equal reinforcement condition. Experiment 3 replicated and extended the findings of Experiments 1 and 2 with an increased number of baseline training trials. The results of the present study suggest that the effects of nodal number are independent of differential reinforcement. Furthermore, a transfer-of-function test was most sensitive to nodal effects, response speed was the next most sensitive measure, and response accuracy was the least sensitive measure of nodal effects. PMID- 21287314 TI - Blind individuals show pseudoneglect in bisecting numerical intervals. AB - Neurologically normal individuals typically show a leftward bias--known as pseudoneglect--in bisecting physical lines as well as numerical intervals. The latter bias may reflect the spatial nature in which numbers are represented (i.e., the mental number line). In previous studies, we found that congenitally blind individuals show such leftward bias in haptic bisection. Here, we demonstrate that blind individuals also show a consistent leftward bias in numerical bisection. The leftward bias was greater when numbers were presented in descending rather than ascending order, and the magnitude of the leftward bias was comparable to that shown by a control group of blindfolded sighted participants. Our findings thus support the view that pseudoneglect operates at a mental representational level rather than being perceptually based. Moreover, the consistent leftward bias shown by blind individuals in both line and numerical bisection suggests that the right hemisphere dominance in spatial processing, resulting in an overestimation of the left side of space, develops even in the absence of any visual input. PMID- 21287315 TI - The contents of visual working memory reduce uncertainty during visual search. AB - Information held in visual working memory (VWM) influences the allocation of attention during visual search, with targets matching the contents of VWM receiving processing benefits over those that do not. Such an effect could arise from multiple mechanisms: First, it is possible that the contents of working memory enhance the perceptual representation of the target. Alternatively, it is possible that when a target is presented among distractor items, the contents of working memory operate postperceptually to reduce uncertainty about the location of the target. In both cases, a match between the contents of VWM and the target should lead to facilitated processing. However, each effect makes distinct predictions regarding set-size manipulations; whereas perceptual enhancement accounts predict processing benefits regardless of set size, uncertainty reduction accounts predict benefits only with set sizes larger than 1, when there is uncertainty regarding the target location. In the present study, in which briefly presented, masked targets were presented in isolation, there was a negligible effect of the information held in VWM on target discrimination. However, in displays containing multiple masked items, information held in VWM strongly affected target discrimination. These results argue that working memory representations act at a postperceptual level to reduce uncertainty during visual search. PMID- 21287316 TI - Aging affects attunement in perceiving length by dynamic touch. AB - Earlier studies have revealed age-dependent differences in perception by dynamic touch. In the present study, we examined whether the capacity to learn deteriorates with aging. Adopting an ecological approach to learning, the authors examined the process of attunement--that is, the changes in what informational variable is exploited. Young and elderly adults were trained to perceive the lengths of unseen, handheld rods. It was found that the capacity to attune declines with aging: Contrary to the young adults, the elderly proved unsuccessful in learning to detect the specifying informational variables. The fact that aging affects the capacity to attune sets a new line of research in the study of perception and perceptual-motor skills of elderly. The authors discuss the implications of their findings for the ongoing discussions on the ecological approach to learning. PMID- 21287317 TI - Ganciclovir-resistant human herpesvirus-6 encephalitis in a liver transplant patient: a case report. AB - Human herpesvirus-6 (HHV-6) was initially isolated in 1986 from patients with lymphoproliferative disorders (Ablashi et al. 1987). Since that time, two genetically distinct variants were sequenced, HHV-6A and HHV-6B (Ablashi and Balachandran 1991). Both variants have been linked with neurologic disease (Crawford et al. 2007). HHV-6 encephalitis has been well described in literature, typically presenting with confusion, coma, seizure, and headache. The majority of HHV-6 encephalitis has been limited to post-transplant recipients (Singh and Paterson 2000). Encephalitis due to HHV-6 infection has been reported in two liver transplant recipients (Massih and Razonable 2009 and Montejo et al. 2002). Although there has been in vitro studies regarding the potential resistance patterns for HHV-6 virus, there has been only one clinic case report supporting these findings (Isegawa et al. 2009). We describe the first case of ganciclovir resistant HHV-6 encephalitis in a post-liver transplant patient. PMID- 21287318 TI - [Sarcoma gene signatures]. AB - This review reports the main gene signature specific for the diagnosis, prognosis or prediction of drug response in sarcomas. Almost half of sarcomas show a simple genetic lesion which is specific for the diagnosis: recurrent translocations in 10 to 15% of sarcomas, specific activating and inactivating mutations in GIST and rhabdoid tumor respectively, and MDM2 amplification in well-differentiated and dedifferentiated liposarcomas as well as in intimal sarcoma. A recent study reported a gene expression signature which is much better than histological grading for predicting metastasis outcome. This signature is composed of 67 genes all belonging to pathways involved in chromosome integrity suggesting an important role of these mechanisms in the development of metastases. On the other hand, and except for GIST with KIT and PDGFRA mutations, there is no validated predictive gene signature so far. PMID- 21287319 TI - [Surgical margins in soft tissue sarcoma of the extremities]. AB - Negative surgical margins (R0 resection) play a key role in the prevention of local recurrences of soft tissue sarcoma of the extremities in the multimodal therapy concept. The prognostic relevance for long-term survival is still under dispute. Despite the fact that numerous recommendations and guidelines have existed for over 100 years, strong evidence-based data from prospective randomized studies are still not available today. These studies should include parameters like tumor localization, subtype and biological aggressiveness. Recommendations as to surgical therapy diverge considerably. They range from amputation and compartment resection to centimetre and millimetre surgical margins. The present article analyses currently available data and definitions and discusses the impact on functional restriction, lymph drainage, local recurrence and the perioperative irradiation field. In the absence of surgical standards, it is doubtful whether existing studies and multicenter trials currently underway are valid. Close co-operation between surgeon and pathologist is imperative to further substantiate the significance of histological examinations and resection margins. PMID- 21287323 TI - The pig as a model animal for studying cognition and neurobehavioral disorders. AB - In experimental animal research, a short phylogenetic distance, i.e., high resemblance between the model species and the species to be modeled is expected to increase the relevance and generalizability of results obtained in the model species. The (mini)pig shows multiple advantageous characteristics that have led to an increase in the use of this species in studies modeling human medical issues, including neurobehavioral (dys)functions. For example, the cerebral cortex of pigs, unlike that of mice or rats, has cerebral convolutions (gyri and sulci) similar to the human neocortex. We expect that appropriately chosen pig models will yield results of high translational value. However, this claim still needs to be substantiated by research, and the area of pig research is still in its infancy. This chapter provides an overview of the pig as a model species for studying cognitive dysfunctions and neurobehavioral disorders and their treatment, along with a discussion of the pros and cons of various tests, as an aid to researchers considering the use of pigs as model animal species in biomedical research. PMID- 21287324 TI - Animal models of ADHD. AB - Studies employing animal models of attention-deficit/hyperactivity disorder (ADHD) present clear inherent advantages over human studies. Animal models are invaluable tools for the study of underlying neurochemical, neuropathological and genetic alterations that cause ADHD, because they allow relatively fast, rigorous hypothesis testing and invasive manipulations as well as selective breeding. Moreover, especially for ADHD, animal models with good predictive validity would allow the assessment of potential new therapeutics. In this chapter, we describe and comment on the most frequently used animal models of ADHD that have been created by genetic, neurochemical and physical alterations in rodents. We then discuss that an emerging and promising direction of the field is the analysis of individual behavioural differences among a normal population of animals. Subjects presenting extreme characteristics related to ADHD can be studied, thereby avoiding some of the problems that are found in other models, such as functional recovery and unnecessary assumptions about aetiology. This approach is justified by the theoretical need to consider human ADHD as the extreme part of a spectrum of characteristics that are distributed normally in the general population, as opposed to the predominant view of ADHD as a separate pathological category. PMID- 21287325 TI - Regulatory T cells: history and perspective. AB - Despite the skepticism that once prevailed among immunologists, it is now widely accepted that the normal immune system harbors a T-cell population, called regulatory T cells (Treg cells), specialized for immune suppression. It was first shown that depletion of a T-cell subpopulation from normal rodents produced autoimmune disease. Search for a molecular marker specific for such autoimmune preventive Treg cells has revealed that the majority, if not all, of them constitutively express the CD25 molecule as depletion of CD25(+)CD4(+) T cells spontaneously evokes autoimmune disease in otherwise normal rodents. The expression of CD25 by Treg cells has made it possible to delineate their developmental pathways, in particular their thymic development, and establish simple in vitro assay for assessing their suppressive activity. The marker and the in vitro assay have helped to identify human Treg cells with similar functional and phenotypic characteristics. Recent efforts have shown that natural Treg cells specifically express the transcription factor Foxp3 and that mutations of the Foxp3 gene produce a variety of immunological diseases in humans and rodents. Specific expression of Foxp3 in natural Treg cells has enabled their functional and developmental characterization by genetic approach. These studies altogether have provided firm evidence for Foxp3(+)CD25(+)CD4(+) Treg cells as an indispensable cellular constituent of the normal immune system for establishing and maintaining immunologic self-tolerance and immune homeostasis. Treg cells are now within the scope of clinical use to treat immunological diseases and control physiological and pathological immune responses. PMID- 21287326 TI - In vitro Treg suppression assays. AB - Determining the activity of a regulatory T-cell population in vitro is often the first step in analyzing its function. To obtain reliable and reproducible results, it is critical to follow the protocol that is most applicable to your experimental question. We have outlined below a basic in vitro suppression assay as well as a variety of alternative/additional protocols that can be utilized alone or in combination as desired. PMID- 21287327 TI - Generation of T cell hybridomas from naturally occurring FoxP3+ regulatory T cells. AB - Generation of regulatory T cells (or Treg) derived hybridomas offers a tool to study their antigen specificity. T cells hybridomas are produced by fusing TCR alpha-beta-thymoma BW5147 with highly dividing T cell population. In vitro anergy of Tregs is an obstacle in generation of highly dividing Treg population for their fusion. In this chapter, we describe a simple and efficient method to generate large number of blasting Treg and their successful fusion with thymoma BW5147. The resultant hybridomas lose Treg-specific transcription factor FoxP3, respond to antigenic stimulation by producing IL-2, and thus allow the evaluation of antigen specific, Tregs-derived TCRs. PMID- 21287328 TI - In vitro and in vivo analyses of regulatory T cell suppression of CD8+ T cells. AB - The study of regulatory T cells (Treg) requires methods for both in vivo and in vitro analyses, both of which have different limitations, but which complement each other to give a more complete picture of physiological function than either method alone. Our analyses have focused on Treg-mediated suppression of CD8(+) T cells, and in particular Tregs induced by viral infection. One of the unique characteristics of virus-induced Tregs is that they can suppress CD8(+) T cell function in vitro without the requirement for additional stimulation. This ability correlates with their suppressive capacity and activated status in vivo. Interestingly, while virus-induced Tregs suppress CD8(+) T cell function in vitro and in vivo, they do not suppress proliferation unless they are further activated in vitro. PMID- 21287329 TI - Flow cytometric profiling of mature and developing regulatory T cells in the thymus. AB - Natural Regulatory T (Treg) cells are a subset of CD4(+) T cells characterized by expression of the transcription factor Foxp3 and the ability to suppress immune responses. Treg cells develop in the thymus in response to highly specific interactions between the T cell receptor (TCR) and self-antigens. These processes can be recapitulated in antigen-specific systems using transgenic mice that coexpress a TCR with its cognate peptide as a neoself-antigen. Here, we describe a method for using such a system to establish a flow cytometric profile of phenotype markers expressed by developing and mature Treg cells in the thymus. Our approach is to compare antigen-specific thymocytes developing in the presence or absence of Treg cell-selecting ligands to identify phenotypic changes that characterize thymocytes undergoing selection into the Treg cell lineage. PMID- 21287330 TI - ChIP-on-chip for FoxP3. AB - Regulatory T (Treg) cells play a key role in dominant suppression of immune response and maintenance of immune homeostasis. Foxp3, a member of the forkhead transcription factor family, is indispensable for Treg cell development and function. Mice and human with Foxp3 mutations are severely impaired in Treg cell generation and develop lethal autoimmune diseases. We combined chromatin immuno precipitation and mouse whole genome tiling array profiling (ChIP-on-Chip) to identify the direct downstream targets of Foxp3 in regulatory T cells. Our result showed that Foxp3 not only directly determines expression of a number of Treg signature molecules, but also regulates a group of transcription factors, which potentially control the expression of other Treg-specific genes. PMID- 21287331 TI - Live imaging of dendritic cell-Treg cell interactions. AB - The decision to launch an immune response is made during the interaction of helper T cells and regulatory T cells with dendritic cells. Recognition of antigen leads to formation of immunological synapses at the interface between the cells and to activation of the T cells. The length of interaction between the T cells and dendritic cells influences the functional outcome. We have shown that in the absence of proinflammatory stimuli, regulatory T cells and naive helper T cells interact differently with dendritic cells. Neuropilin-1, which is expressed by most regulatory T cells but not naive helper T cells, promotes prolonged interactions with immature dendritic cells, resulting in higher sensitivity to limiting amounts of antigen. We tracked T cell-dendritic cell interactions in real-time using time-lapse microscopy, assessed synapse formation by immunofluorescence, and measured regulatory T cell activation by dendritic cells using suppression assays. PMID- 21287332 TI - Genetic tools for analysis of FoxP3+ regulatory T cells in vivo. AB - The discovery of Foxp3 as a reliable marker for murine regulatory T cells has led to an explosion in the development of genetic tools for investigating the biology of regulatory T cells. More than 25 Foxp3-based mouse strains have been published with a variety of characteristics. The effects of Foxp3 expression can be analyzed using null, hypomorphic, conditional, altered control, and over expression strains. Reporter strains are available to efficiently isolate Foxp3+ cells, with various reporter designs in terms of construct (fusion, replacement, and bicistronic positioning), and reporter system (GFP, YFP, RFP, Luciferase, Thy1.1). Multifunction strain fusion, replacement, and bicistronic positionings add functional proteins under the control of the Foxp3 promoter allowing induced apoptosis or lineage-specific Cre recombinase activity. In this chapter, we discuss the uses of the cornucopia of genetic tools, in isolation and in combination, for research on Foxp3(+) regulatory T cells. PMID- 21287333 TI - In vivo Treg suppression assays. AB - To fully examine the functionality of a regulatory T cell (T(reg)) population, one needs to assess their ability to suppress in a variety of in vivo models. We describe five in vivo models that examine the suppressive capacity of T(regs) upon different target cell types. The advantages and disadvantages of each model including resources, time, and technical expertise required to execute each model are also described. PMID- 21287334 TI - In vivo depletion of FoxP3+ Tregs using the DEREG mouse model. AB - In recent years, researchers have increasingly focused on the modulation of regulatory T cell (Treg) function to interfere with the outcome of virtually every type of immune response. For a long time, specific in vivo targeting of Tregs was precluded due to the lack of appropriate markers. Only after the discovery of Foxp3 as a Treg-specific transcription factor, was the development of Treg-specific mouse models feasible. We generated DEREG mice (DEpletion of REGulatory T cells), a BAC (bacterial artificial chromosome) transgenic mouse line, which allows direct in vivo analysis and depletion of this exceedingly important cell type. Our DEREG mice carry a DTR-eGFP transgene under the control of an additional Foxp3 promoter, thereby allowing specific depletion of Treg by application of diphtheria toxin at any desired point of time during an ongoing immune response. This chapter will elaborate the advantages and disadvantages of employing different genetic approaches and discuss further parameters used in the studies focusing on employment of diphtheria toxin and its degree of general toxicity in mice. Additionally, we will address the question: to which extent DEREG mice are suitable for studying the effect of long-term Treg depletion during specific immune responses. PMID- 21287335 TI - Antigen-specific induction of regulatory T cells in vivo and in vitro. AB - The peripheral induction of Foxp3-expressing regulatory T cells outside the thymus is required in order to maintain local homeostasis in distinct microenvironments such as the gut. Extrathymic induction of Treg may also be exploited to prevent unwanted immune responses. Here, we discuss the methodology allowing for the stable de novo generation of Tregs specific for foreign antigens in peripheral lymphoid tissue via subimmunogenic peptide delivery using either peptide contained in fusion antibodies directed against the DEC205 endocytotic receptor on steady-state dendritic cells or the implantation of peptide delivering osmotic mini-pumps. Furthermore, we also address methods in order to achieve TGFbeta-dependent Treg conversion in vitro, thereby mainly focusing on the role of retinoic acid (RA) to enhance TGFbeta-dependent conversion into Tregs. PMID- 21287336 TI - In vitro expansion of alloantigen-specific regulatory T cells and their use in prevention of allograft rejection. AB - Regulatory T lymphocytes expressing CD4, high levels of CD25, and the transcription factor Foxp3 play a crucial role in the control of immune responses to self and nonself antigens. In contrast to immunosuppressive drugs currently used to treat immunopathology, these cells act in a very specific manner. Consequently, their clinical potential in the treatment of autoimmune disorders, inflammatory diseases, graft-versus-host disease, and allograft rejection is currently extensively studied in experimental animal models as well as in clinical trials. We have previously shown that appropriately in vitro stimulated CD4(+)CD25(high) regulatory T cells can be used to prevent rejection of bone marrow, skin, and heart allografts in the Mouse. We here describe the protocols used in our laboratory to isolate mouse regulatory T cells, to stimulate them in vitro in order to enrich in cells specific for donor-antigens, and to transplant bone marrow under cover of regulatory T cells. Thus, generated hematopoietic chimeras may subsequently be transplanted with solid tissues and organs from the same donor. PMID- 21287337 TI - Analysis of human FOXP3+ Treg cells phenotype and function. AB - Naturally occurring regulatory T (nT( Reg )) cells play a critical role in the establishment of immunological self-tolerance in humans. Currently, the analysis of nT( Reg ) cell function from bulk PBMC has led to discrepancies, largely due to the failure to discriminate T( Reg ) cells from other antigen-experienced CD4(+) T cells in states of inflammation. We developed a novel, multiparametric, single-cell strategy approach, which consists of isolating and expanding individual CD4(+)CD25(+) T cells into clones, in turn allowing us to discriminate bona fide T( Reg ) cells from activated, FOXP3(+) T( Eff ) cells, which frequently confound bulk CD25(High) T( Reg ) functional assays. This approach enabled us to compare their phenotype and function at the single-cell level and to uncover the functional heterogeneity that exists among the CD4(+)FOXP3(+) T( Reg ) cell population in human PBMC. PMID- 21287338 TI - Depletion of human regulatory T cells. AB - Regulatory T cells (Treg) have become increasingly relevant in the study of human disease including cancer. Treg cells have been shown to inhibit anti-tumor immune responses, and elevated Treg levels have been associated with certain types of cancer. Similarly, depletion of Tregs by various methods can also enhance anti tumor immune responses. We have found a prevalence of Treg in cancer patients when compared to normal volunteers. In addition, we have shown that the depletion of Treg using the IL-2 fusion protein denileukin diftitox decreased Treg function and increased antigen-specific T cell response to a cancer vaccine. These results indicate the potential for combining Treg depletion with anti-cancer vaccines to enhance tumor antigen-specific immune responses and the need to explore the dose and schedule of Treg depletion strategies in optimizing vaccine efforts. PMID- 21287339 TI - Assessment of suppressive capacity by human regulatory T cells using a reproducible, bi-directional CFSE-based in vitro assay. AB - Regulatory T cells are involved in the maintenance of tolerance. Alterations in their functional capacity are implicated in the development of autoimmunity. In the case of common autoimmune disorders the defects in suppression may be partial, and may be due to a loss of Treg function, or a resistance to suppression by responder T cells. Thus in order to assess Treg function, an in vitro assay that is sensitive enough to demonstrate modest alterations in suppression, and which can differentiate between impaired suppression due to Treg dysfunction, and responder cell resistance is ideal. In this chapter we describe a CFSE based proliferation assay that utilizes a bead based activation system, which is reproducible, consistent and able to distinguish between defects in Treg function and the resistance of responder T cells. PMID- 21287340 TI - Measurement of proliferation and disappearance of regulatory T cells in human studies using deuterium-labeled glucose. AB - The in vivo proliferation and disappearance kinetics of lymphocytes may be estimated in humans from rates of deuterium-labeled glucose ((2)H(2)-glucose) incorporation into DNA. This protocol describes its application to regulatory T cells (Treg). Because Treg divide frequently, (2)H(2)-glucose is a suitable precursor, achieving high levels of enrichment over a short period. Being nonradioactive and readily administered, it is appropriate for human studies.There are four phases to the method: labeling, sampling, analysis and modeling. Labeling consists of administration of (2)H(2)-glucose, either intravenously or orally; during this phase, small blood samples are taken to monitor plasma glucose enrichment. Sampling occurs over the ensuing ~3 weeks; PBMC are collected and sorted according to surface marker expression. Cell separation can be achieved by fluorescence-activated cell sorting (FACS) using CD4, CD45RA and CD25 to define memory Treg (CD4(+)CD25(hi)), or by a combination of magnetic bead separation and FACS. Analysis consists of DNA extraction, hydrolysis, derivatization to the pentafluoro tri-acetate (PFTA) derivative, and quantitation of deuterium content by gas-chromatography mass-spectrometry (GC/MS). The ratio of deuterium enrichment in cellular DNA relative to plasma glucose is used to derive the fraction of new cells in the sorted population, and this is modeled as a function of time to derive proliferation and disappearance kinetics. PMID- 21287341 TI - Flow cytometric detection of human regulatory T cells. AB - Tregs are absolutely required for the maintenance of self tolerance in mouse and man. Major abnormalities in Treg number or function cause rare but fatal syndromes with autoimmune, allergic and inflammatory features. Whether subtle Treg abnormalities contribute to the pathogenesis of sporadic autoimmune, allergic and immunoinflammatory diseases in man remains controversial. Robust methods for identifying and isolating human Tregs in patients and healthy controls are essential if we are to understand their role in these increasingly common diseases. We have outlined below a flow cytometric technique to detect and isolate the entire human Treg population based on expression of CD4, CD25, and CD127. Use of a number of additional antibodies for defining subsets within the Treg compartment is described. For analysis, anti-Foxp3 can be added to the cocktail, but the necessity for fixation and permeabilisation may reduce the signal from other antibodies. PMID- 21287342 TI - Behavioral economics of food reinforcement and the effects of prefeeding, extinction, and eticlopride in dopamine D2 receptor mutant mice. AB - RATIONALE: Several studies have investigated the reinforcing effects of food in genetically engineered mice lacking dopamine D(2) receptors (DA D(2)Rs); however, behavioral economic analyses quantifying reinforcement have not been conducted. OBJECTIVE: The role of DA D(2)Rs in food reinforcement was examined by comparing responding under various fixed-ratio (FR) schedules of reinforcement, and effects of extinction, satiation, and the DA D(2)R antagonist eticlopride, in mice with and without genetic deletions of the receptor. RESULTS: Response rates of DA D(2)R knockout (KO) mice were generally lower than those of littermate wild-type (WT) and heterozygous (HET) mice. The demand curve (consumption vs. FR value) for KO mice decreased more steeply than that of HET or WT mice, suggesting that reinforcing effectiveness is decreased with DA D(2)R deletion. Prefeeding decreased, whereas extinction increased overall response rates as a proportion of baseline, with no significant genotype differences. Both (+)- and (-)-eticlopride dose-dependently decreased responding in all genotypes with (-)-eticlopride more potent than (+)-eticlopride in all but KO mice. The enantiomers were equipotent in KO mice, and similar in potency to (+)-eticlopride in WT and HET mice. CONCLUSIONS: That prefeeding and extinction did not vary across genotypes indicates a lack of involvement of DA D(2)Rs in these processes. Differences between (-)-eticlopride effects and extinction indicate that DA D(2)R blockade does not mimic extinction. The maintenance of responding in KO mice indicates that the DA D(2)R is not necessary for reinforcement. However, the economic analysis indicates that the DA D(2)R contributes substantially to the effectiveness of food reinforcement. PMID- 21287345 TI - Diversity of cervicovaginal microbiota associated with female lower genital tract infections. AB - The female genital tract (FGT) harbors very large numbers of bacterial species that are known to play an important role on vaginal health. Previous studies have focused on bacterial diversity in the vagina, but little is known about the ectocervical microbiota associated with FGT infections. In our study, vaginal swabs and ectocervical swabs were collected from 100 participants in China, including 30 women with bacterial vaginosis (BV; BV group), 22 women with cervicitis (Cer group), 18 women with BV in combination with cervicitis (BC group) and 30 healthy control women (CN group). The diversity and richness of cervicovaginal microbiota were investigated with culture-independent polymerase chain reaction (PCR)-denaturing gradient gel electrophoresis (DGGE) and quantitative PCR (qPCR) targeting 11 microorganisms that have been associated with FGT infections. Despite significant interpersonal variations, the PCR-DGGE profiles revealed that vaginal microbiota and ectocervical microbiota were clearly much more complex in the BV group, while the ectocervical microbiota showed no significant difference between healthy and diseased participants. Using species-specific qPCR, BV and cervicitis were significantly associated with a dramatic decrease in Lactobacillus species (p < 0.05), and potential pathogenic species such as Gardnerella, Atopobium, Eggerthella, Leptotrichia/Sneathia, and Prevotella were more common and in higher copy numbers in BV than in CN samples (p values ranged from 0.000 to 0.021). No significant differences were observed between healthy and cervicitis samples (p > 0.05) in ectocervical microbiota. The total numbers of bacteria were significantly lower in the ectocervix as compared in the vagina (p < 0.05). Intriguingly, vaginal microbiota from participants with BV in combination with cervicitis was quite different from that of participants with BV or cervicitis alone. Our study demonstrated that the cervicovaginal microbiota was actively involved in the process of FGT infections. The predominant bacteria of the cervicovaginal communities were clearly associated with BV; however, there was not sufficient evidence that the ectocervical microbiota is directly involved in the development of cervicitis. PMID- 21287346 TI - Unraveling cyanobacteria ecology in wastewater treatment plants (WWTP). AB - Cyanobacteria may be important components of wastewater treatment plants' (WWTP) biological treatment, reaching levels of 100% of the total phytoplankton density in some systems. The occurrence of cyanobacteria and their associated toxins in these systems present a risk to the aquatic environments and to public health, changing drastically the ecology of microbial communities and associated organisms. Many studies reveal that cyanotoxins, namely microcystins may not act as antibacterial compounds but they might have negative impacts on protozoans, inhibiting their growing and respiration rates and leading to changes in cellular morphology, decreasing consequently the treatment efficacy in WWTP. On the other side, flagellates and ciliates may ingest some cyanobacteria species while the formation of colonies by these prokaryotes may be seen as a defense mechanism against predation. Problems regarding the occurrence of cyanobacteria in WWTP are not limited to toxin production. Other cyanobacterial secondary metabolites may act as antibacterial compounds leading to the disruption of bacterial communities that biologically convert organic materials in WWTP being fundamental to the efficacy of the process. Studies reveal that the potential antibacterial capacity differs according to cyanobacteria specie and it seems to be more effective in Gram (+) bacteria. Thus, to understand the effects of cyanobacterial communities in the efficiency of the waste water treatment it will be necessary to unravel the complex interactions between cyanobacterial populations, bacteria, and protozoa in WWTP in situ studies. PMID- 21287347 TI - Incidence of adult acquired severe aplastic anemia was not increased in Shanghai, China. PMID- 21287348 TI - Pain and anxiety associated with bone marrow aspiration and biopsy: a prospective study on 152 Italian patients with hematological malignancies. PMID- 21287349 TI - Long-term survival of patients with a history of venous thromboembolism. AB - Limited data are available regarding long-term survival following venous thromboembolism (VTE). The objectives of this study are to evaluate long-term survival by retrospective survival analysis in patients with a history of VTE and to compare their survival with that of the general population. Patients with a history of VTE (min. 3 months after VTE) without cancer, who were referred to our department between 1994 and 2007, were included in the analysis. Information concerning mortality was available through the Austrian Central Death Register. The survival of patients was compared with that of the age- and gender-matched general Austrian population. Three thousand two hundred-nine patients (mean age, 46.2; range, 14-89 years) were included. Median time interval between the first VTE and inclusion was 14 months; median observation period was 6.6 years. During the considered time period, 169 patients (5.3%) died. The cumulative survival in patients was 0.97 and 0.87 after 5 and 10 years; men had a higher death rate than women; patients with idiopathic VTE had a less favourable survival than those with a triggering event. When patients were compared to the general population, the cumulative relative survival was 1.02 (95% CI 1.00-1.03). In none of the analysed subgroups (different sites of VTE; idiopathic vs. secondary VTE) was a reduced cumulative relative survival found. The relative survival of male patients was even slightly better, whereas that of women equalled that of the normal population. Our results indicate that after the initial phase, VTE does not seem to impair long-term survival of patients with a history of VTE without cancer. PMID- 21287350 TI - Impact of leukocytosis on thrombotic risk and survival in 532 patients with essential thrombocythemia: a retrospective study. AB - Established risk factors for thrombosis in essential thrombocythemia (ET) include age (>= 60 years) and previous vascular events. Recently, also leukocytosis has been proposed in risk stratification of ET patients. We report a retrospective study on 532 ET patients followed for a median of 7.6 years. Sixty-four patients (12%) developed 95 thrombotic events during follow-up. Together with the high risk condition, a white blood cell (WBC) value above 11 * 109/L, corresponding to the fourth percentile value, significantly correlated with a higher thrombotic risk (p = 0.033) by Cox proportional hazards. Moreover, the cumulative risk of thrombosis was significantly higher in high-risk patients with WBC >11 * 109/L. JAK2 V617F mutation did not correlate with thrombosis. Overall, 123 (23%) patients died. Three independent parameters were noted as prognostic factors for survival in multivariate analysis: age > 60 years, leukocytosis >11 * 109/L, and hemoglobin level below normal values. Based on these parameters, three groups of risk were defined, with significantly different survivals. Baseline leukocytosis correlated with a higher thrombotic risk in high-risk patients and identified a cohort of patients with worse survival. PMID- 21287351 TI - An unusual case of pancreatic and gastric neoplasms (2010: 12b). Malignant GISTs originating from the pancreas and stomach. AB - Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract and are believed to originate from the neoplastic transformation of the interstitial cells of Cajal from their precursors. GIST can occur anywhere but mainly affects the stomach (60%), jejunum and ileum (30%), duodenum (4-5%), rectum (4%), colon, appendix and esophagus. Primary GISTs of the pancreas are very rare, with only five previous cases reported. This is an unusual case of multiple GISTs in the pancreas and stomach. PMID- 21287352 TI - Paraventricular nucleus corticotrophin releasing hormone contributes to sympathoexcitation via interaction with neurotransmitters in heart failure. AB - Recent studies indicate that systemic administration of tumor necrosis factor (TNF)-alpha induces increases in corticotrophin releasing hormone (CRH) and CRH type 1 receptors in the hypothalamic paraventricular nucleus (PVN). In this study, we explored the hypothesis that CRH in the PVN contributes to sympathoexcitation via interaction with neurotransmitters in heart failure (HF). Sprague-Dawley rats with HF or sham-operated controls (SHAM) were treated for 4 weeks with a continuous bilateral PVN infusion of the selective CRH-R1 antagonist NBI-27914 or vehicle. Rats with HF had higher levels of glutamate, norepinephrine (NE) and tyrosine hydroxylase (TH), and lower levels of gamma-aminobutyric acid (GABA) and the 67-kDa isoform of glutamate decarboxylase (GAD67) in the PVN when compared to SHAM rats. Plasma levels of cytokines, NE, ACTH and renal sympathetic nerve activity (RSNA) were increased in HF rats. Bilateral PVN infusions of NBI 27914 attenuated the decreases in PVN GABA and GAD67, and the increases in RSNA, ACTH and PVN glutamate, NE and TH observed in HF rats. These findings suggest that CRH in the PVN modulates neurotransmitters and contributes to sympathoexcitation in rats with ischemia-induced HF. PMID- 21287353 TI - Clopidogrel improves endothelial function and NO bioavailability by sensitizing adenylyl cyclase in rats with congestive heart failure. AB - Clopidogrel treatment in patients with coronary artery disease not only inhibits platelet activation but also improves endothelial function and nitric oxide (NO) bioavailability. Congestive heart failure (CHF) is associated with endothelial dysfunction and increased platelet activation. In rats with CHF following myocardial infarction (MI), we investigated whether treatment with clopidogrel modifies endothelial function. Eight weeks after coronary artery ligation, rats with CHF were randomized to placebo or the P2Y(12) receptor antagonist clopidogrel (5 mg/kg twice daily, given by gavage) for another 2 weeks. Afterwards, endothelial function was assessed in isolated aortic rings in organ bath experiments. Acetylcholine-induced, endothelium-dependent, nitric oxide mediated vasorelaxation was significantly attenuated in CHF rats compared to sham operated animals, and was significantly improved by treatment with clopidogrel. Adenosine-induced vasorelaxation via adenylyl cyclase stimulation was attenuated in CHF and significantly improved by clopidogrel. Increased vasoconstriction to phenylephrine was observed in CHF, particularly evident under cyclooxygenase inhibition, but prevented by clopidogrel treatment. Vasoconstriction by the P2Y(12) activator 2MeS-ADP was increased in CHF. Clopidogrel-treated CHF animals displayed enhanced phosphorylation of AKT and eNOS. In conclusion, clopidogrel improved endothelial function and NO bioavailability in heart failure. During CHF, sensitivity to P2Y(12) signaling was increased leading to impaired adenylyl cyclase-mediated signaling. Chronic P2Y(12)-blockade with clopidogrel improved adenylyl cyclase-mediated signaling including increased AKT- and eNOS phosphorylation contributing to improved NO-mediated vasorelaxation. PMID- 21287354 TI - What is the biological basis of sensorimotor integration? AB - This Prospects presents the problems that must be solved by the vertebrate nervous system in the process of sensorimotor integration and motor control. The concepts of efference copy and inverse model are defined, and multiple biological mechanisms are described, including those that form the basis of integration, extrapolation, and comparison/cancellation operations. Open questions for future research include the biological basis of continuous and distributed versus modular control, and somatosensory-motor coordination. PMID- 21287355 TI - Fast estimation of motion from selected populations of retinal ganglion cells. AB - We explore how the reconstruction efficiency of fast spike population codes varies with population size, population composition and code complexity. Our study is based on experiments with moving light patterns which are projected onto the isolated retina of a turtle Pseudemys scripta elegans. The stimulus features to reconstruct are sequences of velocities kept constant throughout segments of 500 ms. The reconstruction is based on the spikes of a retinal ganglion cell (RGC) population recorded extracellularly via a multielectrode array. Subsequent spike sorting yields the parallel spike trains of 107 RGCs as input to the reconstruction method, here a discriminant analysis trained and tested in jack knife fashion. Motivated by behavioral response times, we concentrate on fast reconstruction, i.e., within 150 ms following a trigger event defined via significant changes of the population spike rate. Therefore, valid codes involve only few (<=3) spikes per cell. Using only the latency t(1) of each cell (with reference to the trigger event) corresponds to the most parsimonious population code considered. We evaluate the gain in reconstruction efficiency when supplementing t(1) by spike times t(2) and t(3). Furthermore, we investigate whether sub-populations of smaller size benefit significantly from a selection process or whether random compilations are equally efficient. As selection criteria we try different concepts (directionality, reliability, and discriminability). Finally, we discuss the implications of a selection process and its inter-relation with code complexity for optimized reconstruction. PMID- 21287356 TI - Are great toes always abnormal in patients with fibrodysplasia ossificans progressiva? PMID- 21287357 TI - Application of the new pediatric criteria and Tel Hashomer criteria in heterozygous patients with clinical features of FMF. AB - Recently, a new set of criteria was established for the diagnosis of familial Mediterranean fever (FMF) in childhood. The aim of this study is to validate the new criteria set among heterozygous patients with clinical features of FMF. The study group consisted of FMF patients, who had a mutation at a single allele, who were followed in four pediatric nephrology-rheumatology centers in Turkey. Patients were evaluated by the new criteria set and also by the Tel Hashomer criteria. According to the new criteria, the diagnosis of FMF was established by the presence of two or more of five criteria (fever, abdominal pain, chest pain, arthritis, family history of FMF). The study group consisted of 110 FMF (54 male, 56 female) patients. Majority of the patients had heterozygous pM694V mutation (65%). The sensitivity of the new criteria set and that of the Tel Hashomer criteria in our study group were found to be 93% and 100%, respectively. In conclusion, this study designates that sensitivity of the new criteria set is also high in patients who had a mutation at a single allele. PMID- 21287358 TI - The SH3 domain of HS1 protein recognizes lysine-rich polyproline motifs. AB - HS1 is a protein involved in erythroid proliferation and apoptotic cell death, containing several structurally significant motifs including a C-terminal SH3 domain. HPK1 is a member of the Ste20-related kinase family, which contains four proline-rich sequences and is constitutively associated with HS1 in hematopoietic cells. Recombinant fusion protein GST-SH3(HS1) was expressed to assess the binding properties of 16 peptides derived from the HPK1 proline-rich regions. The binding affinities were determined by non-immobilized ligand interaction assay by circular dichroism. Our results revealed that the classical PxxPxK class II binding motif is not sufficient to induce the interaction with the GST-SH3(HS1) domain, an event dependent on the presence of additional basic residue(s) located at the C-terminus of the PxxPxK motif: Lys(-5) in P2 peptide and Lys(-8) in P4c peptide. Lys replacement by Arg residues decreases the ligand binding affinity. The finding that both SH3(HS1) domain and full-length HS1 protein bind to P2 peptide with similar affinity demonstrates that the whole protein sequence does not affect the interaction properties of the domain. In silico models of SH3(HS1) as a complex with P2 or P4c highlight the domain residues that interact with the recognition determinants of the peptide ligand and that cooperate in the complex stabilization. PMID- 21287359 TI - Prevalence of patient-reported comorbidities in early and established psoriatic arthritis cohorts. AB - The aim of this study is to describe the comorbidity profile in patients with early and established psoriatic arthritis (PsA). Patients with PsA were selected from a registry of patients with psoriasis in Newfoundland. Patients with a diagnosis of psoriasis according to the CASPAR classification criteria are entered in the registry at the time of diagnosis, questioned on their medical history, and are followed indefinitely. Patients who were diagnosed with PsA within the last 2 years were included in the early PsA cohort, whereas the established cohort was comprised of patients with a diagnosis for >=2 years. The general population of Newfoundland without psoriasis or PsA was used as external standard to conduct age- and gender-adjusted comparison of the comorbidity profile of the PsA cohorts to the general population. A total of 108 (65.5%) and 57 (34.5%) patients were included in the established and early PsA cohort, respectively. Patients with early and established PsA had significantly higher age- and gender-adjusted prevalence of hypertension, diabetes, depression, Crohn's disease, and chronic obstructive pulmonary disease. In addition, in the early PsA cohort, the age-adjusted prevalence of coronary heart disease and angina was significantly higher when compared to the general population. Distinct comorbidities are associated with PsA even at early stages of disease progression, the early detection and management of which could improve the patients' disability, morbidity, and quality of life. PMID- 21287360 TI - The significant role of mast cells in cancer. AB - Mast cells (MC) are a bone marrow-derived, long-lived, heterogeneous cellular population that function both as positive and negative regulators of immune responses. They are arguably the most productive chemical factory in the body and influence other cells through both soluble mediators and cell-to-cell interaction. MC are commonly seen in various tumors and have been attributed alternatively with tumor rejection or tumor promotion. Tumor-infiltrating MC are derived both from sentinel and recruited progenitor cells. MC can directly influence tumor cell proliferation and invasion but also help tumors indirectly by organizing its microenvironment and modulating immune responses to tumor cells. Best known for orchestrating inflammation and angiogenesis, the role of MC in shaping adaptive immune responses has become a focus of recent investigations. MC mobilize T cells and antigen-presenting dendritic cells. They function as intermediaries in regulatory T cells (Treg)-induced tolerance but can also modify or reverse Treg-suppressive properties. The central role of MC in the control of innate and adaptive immunity endows them with the ability to tune the nature of host responses to cancer and ultimately influence the outcome of disease and fate of the cancer patient. PMID- 21287361 TI - Hesperidin suppresses ovalbumin-induced airway inflammation in a mouse allergic asthma model. AB - Hesperidin, a flavanone glycoside comprised of the flavanone hesperetin and the disaccharide rutinose, is a plentiful and inexpensive by-product of citrus cultivation. It has been reported to exert a wide range of pharmacological effects that include antioxidant, anti-inflammatory, and anticarcinogenic properties. In this study, we attempt to determine whether hesperidin inhibits inflammatory mediators in the mouse allergic asthma model. Mice were sensitized and challenged by ovalbumin (OVA) to induce chronic airway inflammation and airway remodeling. The administration of hesperidin significantly decreased the number of infiltrating inflammatory cells and Th2 cytokines in bronchoalveolar lavage (BAL) fluid compared with the OVA-induced group of mice. In addition, hesperidin reduced OVA-specific IgE levels in serum. Hesperidin markedly alleviated the OVA-induced airway hyperresponsiveness (AHR) to inhaled methacholine. Based on lung histopathological studies using hematoxylin and eosin and alcian blue-periodic acid-Schiff staining, hesperidin inhibited inflammatory cell infiltration and mucus hypersecretion compared with the OVA-induced group of mice. These findings provide new insight into the immunopharmacological role of hesperidin in terms of its effects in a murine model of asthma. PMID- 21287362 TI - The prognoses of metaplastic breast cancer patients compared to those of triple negative breast cancer patients. AB - Metaplastic breast carcinoma (MBC) is a rare, heterogeneous breast cancer characterized by admixture of adenocarcinoma with metaplastic elements, low hormone receptor expression, and poor outcomes. The authors retrospectively reviewed the medical records of 47 MBC patients and 1,346 invasive ductal carcinoma (IDC) patients. Two hundred eighteen of the IDC patients were triple negative (TN-IDC) for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 (ER-/PR-/HER2-). Patients were surgically treated at the Samsung Medical Center between 2005 and 2009. The MBC patients presented with a larger tumor size, lower lymph node involvement, higher histological and nuclear grades, higher triple negativity (ER-/PR-/HER2-) and higher p53, CK5/6, and EGFR expressions compared with those of the IDC group. However, there were no significant differences in clinicopathological characteristics between MBC and TN-IDC. During the follow-up period (median duration of 30.3 months, range 2.6-56.3 months), seven (14.9%) MBC patients, and 98 (7.1%) IDC patients had disease recurrence. The three-year disease-free survival (DFS) rate was 78.1% in the MBC group and 91.1% in IDC group (P < 0.001). The three-year DFS rate was not significantly different between the MBC and TN-IDC groups (78.1 vs. 84.9%, P = 0.114). However, in patients with lymph node metastasis who underwent adjuvant chemotherapy, the three-year DFS rate was 44.4% in the MBC group and 72.5% in the TN-IDC group (P = 0.025). The authors found that MBC had a poorer clinical outcome than did IDC. In breast cancer patients with nodal metastasis, MBC had a poorer prognosis than did TN-IDC, despite adjuvant chemotherapy. PMID- 21287364 TI - Effect of concentrate supplementation on performance, ovarian response, and some biochemical profile of Malpura ewes. AB - Effect of feed flushing on ovulation rate was investigated during the autumn seasons on 24 adult Malpura ewes (BW 34.8 +/- 0.58 kg and age 4-7 years) equally divided into two groups. Ewes in G1 (group 1) were grazed 8-10 h daily on Cenchrus ciliaris pasture interspersed with seasonal shrub. In addition to grazing, concentrate was provided at 1.5% of BW to the animals in G2 (group 2) for a period of 35 days. Estrus was synchronized by a double injection schedule of PGF(2alpha) at 0 and 10 days of the experiment and detected by parading aproned rams at 6 h intervals. Blood samples were collected at weekly interval during the estrous cycle. A rumen fermentation study was conducted on day 23 of the experiment at 0 and 4 h post-concentrate feeding. Ovarian responses in terms of number of corpora lutea and large follicles was examined on all the ewes by laparoscopy after 3 to 6 days of each estrus and were found to be similar in both the groups. Hemoglobin and packed cell volume, total protein, albumin, and globulin were similar among the groups. Concentration of plasma glucose (12 and 22 days) was higher (P < 0.05) in G2 vis-a-vis control. Plasma urea was higher (P < 0.01) in the control than G2. Rumen liquor pH, concentration of total N, TCA ppt N, NH(3)-N, and TVFA were significantly higher (P < 0.01) in G2 than the control. Thus, it can be concluded that concentrate supplementation in ewes prior to mating (flushing) did not enhance ovulation response during the autumn season. PMID- 21287365 TI - Cloning and characterization of ribulose-1,5-bisphosphate carboxylase/oxygenase small subunit (RbcS) cDNA from green microalga Ankistrodesmus convolutus. AB - An initial study on gene cloning and characterization of unicellular green microalga Ankistrodesmus convolutus was carried out to isolate and characterize the full-length cDNA of ribulose-1,5-bisphosphate carboxylase/oxygenase small subunit (RbcS) as a first step towards elucidating the structure of A. convolutus RbcS gene. The full-length of A. convolutus RbcS cDNA (AcRbcS) contained 28 bp of 5' untranslated region (UTR), 225 bp of 3' non-coding region, and an open reading frame of 165 amino acids consisting of a chloroplast transit peptide with 24 amino acids and a mature protein of 141 amino acids. The amino acid sequence has high identity to those of other green algae RbcS genes. The AcRbcS contained a few conserved domains including protein kinase C phosphorylation site, tyrosine kinase phosphorylation site and N-myristoylation sites. The AcRbcS was successfully expressed in Escherichia coli and a ~21 kDa of anticipated protein band was observed on SDS-PAGE. From the phylogenetic analysis of RbcS protein sequences, it was found that the RbcS of A. convolutus has closer genetic relationship with green microalgae species compared to those of green seaweed and green macroalgae species. Southern hybridization analysis revealed that the AcRbcS is a member of a small multigene family comprising of two to six members in A. convolutus genome. Under different illumination conditions, RT-PCR analysis showed that AcRbcS transcription was reduced in the dark, and drastically recovered in the light condition. Results presented in this paper established a good foundation for further study on the photosynthetic process of A. convolutus and other green algae species where little information is known on Rubisco small subunit. PMID- 21287366 TI - Pineal mixed germ cell tumor with a synchronous sellar lesion in the sixth decade. AB - Intracranial germ cell tumors (GCTs) typically affect children and adolescents. We here report on a 59-year-old male patient presenting with diplopia, polydipsia and polyuria. On clinical examination, slight restriction of the upward gaze was seen on the left side. Computed tomography demonstrated calcifications in the pineal region and enhanced neurohypophysis. Magnetic resonance imaging displayed a heterogeneous pineal mass of 3-cm diameter, which was multicystic with an enhanced cyst wall, and also swelling of the pituitary stalk. The pineal lesion of the tumor, which included calcifications and keratinaceous components, was totally excised using an occipital transtentorial approach. Histopathological examination showed it to be a mixed GCT with germinoma and mature teratoma components. Postoperative chemoradiotherapy provided complete disappearance of the suprasellar lesion. To our knowledge, this is the first case of mixed bifocal GCT in an older adult reported in the literature, although a few cases of tumors with a single histological component have been reported. Hence, our case further underlines the possibility of the occurrence of GCTs in older adults and advocates the consideration of GCTs in the differential diagnosis of such cases for appropriate management. PMID- 21287367 TI - Effects of dietary iodine and selenium on nutrient digestibility, serum thyroid hormones, and antioxidant status of Liaoning cashmere goats. AB - Forty-eight 2-year-old Liaoning Cashmere goats (body weight = 38.0 +/- 2.94 kg) were used to investigate the effects of dietary iodine (I) and selenium (Se) supplementation on nutrient digestibility, serum thyroid hormones, and antioxidant status during the cashmere telogen period to learn more about the effects of dietary I and Se on nutrition or health status of Cashmere goats. The goats were equally divided into six groups of eight animals each that were treated with 0, 2, or 4 mg of supplemental I/kg dry matter (DM) and 0 or 1 mg of supplemental Se/kg DM in a 2 * 3 factorial arrangement of treatments. The six treatments were I(0)Se(0), I(2)Se(0), I(4)Se(0), I(0)Se(1), I(2)Se(1), and I(4)Se(1). The concentrations of I and Se in the basal diet were 0.67 and 0.09 mg/kg DM, respectively. The study started in March and proceeded for 45 days. Supplemental I or Se alone had no effect on nutrient digestibility and nitrogen metabolism. However, the interaction between I and Se was significant regarding the digestibility of acid detergent fiber (ADF; P < 0.05), and compared with group I(4)Se(1), the digestibility of ADF was significantly increased in group I(4)Se(0) (P < 0.05). Selenium supplementation did not affect serum triiodothyronine (T(3)) or thyroxine (T(4)) concentrations. However, the concentration of serum T(4) but not that of T(3) was significantly increased with I supplementation (P < 0.05). In addition, serum superoxide dismutase (SOD) activity was not affected (P > 0.05), but serum glutathione peroxidase (GSH-Px) activity was significantly decreased by I supplementation (P < 0.05). The antioxidant status was improved by Se supplementation, and the activities of SOD and GSH-Px were significantly increased (P < 0.05). PMID- 21287368 TI - Unsynchronized Nasal Intermittent Positive Pressure Ventilation to prevent extubation failure in neonates: a randomized controlled trial. AB - OBJECTIVE: To evaluate the role of Unsynchronized Nasal Intermittent Positive Pressure Ventilation (NIPPV) in prevention of extubation failure in mechanically ventilated preterm neonates weighing less than 2,000 g. METHODS: This randomized controlled trial was conducted in the neonatal intensive care unit of a tertiary care teaching hospital. Preterm neonates weighing less than 2,000 g, mechanically ventilated for more than 24 h were included after extubation. Neonates were randomized into two groups. Group 1 was given unsynchronized nasal intermittent positive pressure ventilation with shortened endotracheal tube by ventilator and Group 2 was given head box oxygen, fraction of oxygen in inspired air was 50%. Primary outcome variable was rate of extubation failure within 72 h of extubation. RESULTS: Birth weight, gestational age, age at intubation, indication for mechanical ventilation and antenatal details were comparable in the two groups. Extubation failure rate was 16% in Group 1 vs 63% in Group 2 (RR = 0.25; 95% CI: 0.12, 0.51, p value = 0.00), that is a reduction of 47%. Unsynchronized nasal intermittent positive pressure ventilation did not have any serious side effects, however it did not reduce total hospital stay. CONCLUSIONS: Unsynchronized Nasal Intermittent Positive Pressure Ventilation is a simple technique of noninvasive ventilation which significantly reduces the rate of extubation failure in preterm neonates and is not associated with serious side effects. PMID- 21287369 TI - Transient myeloproliferative disorder and GATA1 mutation in neonates with and without Down syndrome. AB - OBJECTIVE: To report clinical experiences and cytogenetic findings of transient myeloproliferative disorder (TMD) in neonates with and without Down syndrome (DS). METHODS: GATA1 gene was screened in DNA samples from neonates presenting with TMD during their leukemic and remission status. RESULTS: Six neonates (2 phenotypically normal and 4 DS) born in the past 6 years had presented with TMD; all had trisomy 21 during leukemic status. Two DS infants died during early infancy, one of hepatic failure and one of cardiac complication. One non-DS infant evolved into myelodysplastic syndrome (MDS) and acute leukemia since 14 months old. Three other patients have not developed true leukemia after follow-up of 8, 9, and 70 months, respectively. The authors detected mutations within exon 2 of GATA1 gene in 3 DS and 2 non-DS infants. All these mutations disappeared after remission of TMD, but an identical mutation was detected in one non-DS patient when evolving into MDS. Trisomy 21 was confined to leukemic clone in non DS patients. CONCLUSIONS: TMD should be considered in case of congenital leukemia with megakaryoblastic features and accompanied by trisomy 21 and GATA1 mutation. Both DS and non-DS patients will possibly develop true leukemia within few years. PMID- 21287370 TI - A comparison of the image quality of full-time myocardial perfusion SPECT vs wide beam reconstruction half-time and half-dose SPECT. AB - OBJECTIVES: Wide Beam Reconstruction (WBR) (UltraSPECT, Ltd) uses resolution recovery and noise modeling to cope with decreased SPECT count statistics. Because WBR processing reconstructs half the usual SPECT count statistics, we postulate that image quality equivalent to a full-time acquisition can be achieved in either half the time or with half the radiopharmaceutical activity. METHODS: In 156 consecutive patients (pts) rest and 8-frame gated post-stress myocardial perfusion SPECT was performed following 333-444 and 1184-1480 MBq (9 12 and 32-40 mCi) Tc-99m sestamibi injections, respectively, with full-time (rest = 14 min; stress = 12.3 min) acquisitions processed with OSEM and also separate "half-time" acquisitions processed with WBR. A subsequent group of 160 consecutive pts matched in gender, weight, and chest circumference received "half dose" rest and stress injections 214.6 +/- 22.2 and 647.5 +/- 92.5 MBq (5.8 +/- 0.6 and 17.5 +/- 2.5 mCi) with full-time SPECT acquisitions. Image quality (1 = poor to 5 = excellent) was judged by myocardial count density and uniformity, endocardial edge definition, perfusion defect delineation, right ventricular visualization, and background noise. RESULTS: Mean image quality for rest, stress, and post-stress gated images were 3.6 +/- 0.7, 3.8 +/- 0.7, and 3.9 +/- 1.0, respectively, for "full-time OSEM; 3.7 +/- 0.8, 4.0 +/- 0.7, and 4.8 +/- 0.4 for "half-time" WBR; and 4.3 +/- 0.8, 4.6 +/- 0.6, and 4.7 +/- 0.6 for "half dose" WBR. "Half-time" and "half-dose" WBR image quality were both superior to standard full-time OSEM (P's < .001). There was no significant difference between the summed stress and rest scores for "full-time" OSEM vs "half-time" WBR in 82 patients with perfusion defects. CONCLUSIONS: Both "half-time" and "half-dose" WBR provide myocardial perfusion SPECT quality superior to full-time OSEM, with an associated decrease in scan acquisition time and patient radiation exposure, respectively. PMID- 21287371 TI - Pattern and clinical aspects of congenital heart diseases and their management in Cameroon. AB - The aim of the study was to investigate the occurrence, pattern and clinical aspects of congenital heart diseases and their management in Cameroon. In this multicentred retrospective study from January 2006 till November 2009, out of 51,636 consulting in three referral centres, 505 were recruited. All the patients presented with the following symptoms: cyanosis, clubbing, frequent respiratory tract infections, failure to thrive, growth retardation, precordial murmur and dyspnoea. Patients were sent for the screening of congenital heart disease. After the comprehensive Doppler echocardiography, the recruited patients were diagnosed with congenital (67.2%) and in few, acquired heart disease. Heart murmur, dyspnoea and growth retardation was the triad mostly encountered. The occurrence of congenital heart diseases in Cameroon is 9.87%. In Douala, isolated ventricular septal defect, interatrial septal defect and isolated pulmonary valve stenosis were more diagnosed than in Shisong (P <0.05) and Yaounde (P <0.05). In Yaounde, there were more cases of common arterial trunk, transposition of great arteries with ventricular septal defect and Ebstein disease than in Shisong (P <0.05) and Douala (P < 0.05). At Shisong, tetralogy of Fallot, arterial duct, coarctation of the aorta, congenital mitral valve regurgitation, atresia of the tricuspid valve, double outlet right ventricle, anomalous pulmonary venous return and left isomerism were more diagnosed than in Yaounde (P <0.05) and in Douala (P <0.05). Thirty percent of the patients were operated abroad; 9% in the cardiac centre. CONCLUSION: Our data show that congenital heart diseases are represented in Cameroon as in the literature; isolated ventricular septal defect is the predominant pathology. PMID- 21287372 TI - [Case management and diagnosis of severe malaria in adults and the application of national guidelines in Burkina Faso]. AB - The purpose of this study was to assess the application of national guidelines on the diagnosis and treatment of severe malaria in adults in Burkina Faso. We conducted a retrospective study of medical records of the patients admitted for severe malaria in the emergency service of the regional hospital of Fada N'Gourma in the east of Burkina Faso in the year 2008; 165 records were chosen by simple random sampling. We reported all the severe clinical and biological signs of malaria and its treatment. We compared them with the criteria of severe malaria diagnosis and its treatment according to the national guidelines. The mean age of patients was 38 +/- 16.2 and male to female ratio was 0.96. The most frequent period of admissions was between July and October. Fever or recent past of fever was reported in 142 cases (86.1%). According to the two criteria for severe malaria (means existing of at least one of the severe signs associated and positive parasitemia with Falciparum plasmodium), we noted that only 74 cases had at least one of the severe signs (44.8%) which were: anemia (51.3%), cardiovascular collapse (7.9%), jaundice (7.3%), dyspnea (6.7%), impairment of consciousness (5.5%), prostration (5.5%), renal failure (4.8%), hypoglycemia (2.4%), hemorrhage (1.8%) and seizures (1.2%). The biological signs were not systematically searched. Parasitological exam was conducted in 91 cases (55.1%). Only 18 were positive (19.8%). In total, only 18 cases (10.9%) met the guidelines' criteria of severe malaria. The other cases were over-diagnosed; note that the investigation was not complete for 74 of these cases (50.3%). Among the 165 cases, the treatment was appropriate in 146 (88.5%) and 19 cases (11.5%) didn't receive treatment for malaria. CONCLUSION: So much we observed an over diagnosis of severe malaria in adults that we can suggest an under diagnosis of the disease due to the lack of biological investigations. PMID- 21287373 TI - Process training derived from a computer simulation theory. AB - Kotovsky and Simon (1973) identified four basic subprocesses in their computer simulation of adult and adolescent performance on Thurstone letter series completion problems. In Experiment I, children from Grades 1 to 6 were pretested on those problems, and then experimental subjects were trained on two of the four processes as an attempt to experimentally support a correspondence between the computer subroutines and human cognitive processes. A posttest administered in the experimental and control conditions revealed a significantly greater improvement for experimental subjects, although both groups made significant gains. The children's distributions of errors were consistent with Kotovsky and Simon's predictions. In Experiment II, children from Grades 3 and 5 took four series completion tests without intervening training. The additional practice was sufficient for Grade 5 subjects to make improvements similar in magnitude to those produced by training. Grade 3 subjects, however, made no gains. These results are related to Tulving and Pearlstone's (1966) distinction between the availability and the accessibility of memory traces. PMID- 21287374 TI - Stimulus redundancy and immediate recall. AB - This study examined immediate recall in two stimulus prefix and two stimulus suffix conditions and in a condition that combined a prefix and suffix. Suffixes and the combination of a prefix with a suffix interfered more with recall overall than did prefixes. Performance in each of the conditions that included a prefix was significantly better overall than in appropriate control conditions, in which interference was augmented by a redundant element in recall. It was suggested that prefixes and suffixes lie operationally on a continuum and that their effects result from the subject's inability to dissociate the redundant element from the memory series. However, the location of redundancy imposes different processing requirements that differentially influence recall. PMID- 21287375 TI - The role of semantic knowledge in retrieval from episodic long-term memories: Implications for a model of retrieval. AB - Two experiments were conducted, using a paired-associate recall reaction time paradigm, to assess the role semantic knowledge plays in retrieval of long-term episodic memories. In Experiment I, word frequency and meaningfulness were manipulated; high-frequency stimuli led to significantly longer reaction times, while meaningfulness had no significant effect. In Experiment II, the role of the distribution of preexperimental associates of the stimulus was further investigated by comparing retrieval time when the stimulus had either a high- or low-strength primary associate; the former resulted in longer reaction times. The implications of these results for a model of retrieval were discussed. Exhaustive search models were found inadequate, but viable parallel and serial self terminating models were developed. In both of these models, retrieval time is a function of strength of the correct associate, relative to total strength of a restricted set of semantic associates of the stimulus. PMID- 21287376 TI - Erratum to: The attention demands of mnemonic control processes. PMID- 21287377 TI - Persistence of the spacing effect in free recall under varying incidental learning conditions. AB - In three incidental learning experiments, an attempt was made to eliminate the processing deficit under massed presentation that is assumed to be responsible for the spacing effect in free recall, according to the attenuation of attention hypothesis. This was to be accomplished in Experiment I by requiring subjects to attend specifically to the total exposure duration of each item and in Experiments II and III by requiring subjects to rate the successive occurrences of repeated items on different semantic rating scales. The results of the three experiments consistently showed that these manipulations were ineffective in eliminating the spacing effect. Subsidiary analyses indicated that the activities involved in doing the semantic rating tasks do not provide direct access to retrieval cues useful for subsequent recall. Instead, it appears that, in order to perform the semantic rating tasks reliably, subjects must compare the to-be rated item with previously rated items, and this comparison process may serve as the source of retrieval cues for subsequent recall. PMID- 21287378 TI - A context-sensitive representation of word meanings. AB - This study provides a numerical representation of contextual effects on the meanings of words, constructed from the order judgments of 19 subjects concerning the word "red" in 19 sentences. Subjects judged whether or not the red object mentioned in a sentence was redder than, less red than, or could be equally as red as the red object mentioned in each of the other sentences. These judgments were well described as an interval order. This means that the red ascribed in a sentence can be represented by a real interval with judgments of equally red corresponding to overlapping intervals. Semiorder axioms were not met, indicating that the width of the interval varied from sentence to sentence. Possible ways of incorporating the result into theories of semantic memory were discussed, as well as ways of accounting for the pronounced individual differences which were observed. The research described herein was supported by the National Institute of Education under Contract HEW NIE-G-74-0007. PMID- 21287379 TI - The use of visual and name codes in scanning and classifying colors. AB - The effect of incongruent color words on speed of classifying ink colors was measured in visual scanning tasks and in card sorting tasks. In both cases, little or no interference effects were noted when the classification allowed focusing on a single ink color or a set of highly similar colors (adjacent hues). Substantial interference occurred when the task required grouping of three dissimilar colors (nonadjacent hues). These findings suggest that the relative efficiency of name and visual codes in making perceptual classifications is largely dependent upon the memory requirements imposed by the task. PMID- 21287380 TI - The spacing effect: Additions to the theoretical and empirical puzzles. AB - Four studies examined the MP-DP effect (spacing effect) in four quite different situations: recognition of letters, verbal discrimination, short free recall lists, and recall of MP items presented twice, with an intervening interval inserted to produce forgetting. MP-DP differences were found in all studies. Of particular interest were three interactions. Subjects with a low criterion of responding in the letter study lost the MP-DP effect over a 30-sec delay, and subjects with a high criterion did not. A clear MP-DP effect, but no lag effect, was found only with unmixed verbal discrimination lists. In free recall, a sharp lag effect was shown for words presented three times but not for words presented twice. A forgetting interval inserted between the two occurrences of an MP item did not appreciably aid its recall. The results were found to pose severe problems for current theoretical ideas about the spacing effect. PMID- 21287381 TI - Sequential search processes in long-term memory. AB - In an experiment employing the symbol-element recognition task (Mohs, Wescourt, & Atkinson, 1975), subjects first learned six lists consisting of four words (elements) each. Each list was associated with a unique consonant (symbol). Subsequently, on each of a series of test trials, subjects were presented with one, two, or four symbol-element pairs. A positive response was required if all test words were correctly paired with their associated consonants and a negative response if any one test word was incorrectly paired with a consonant. Of primary concern was the way reaction time (RT) varied with number of pairs presented, the type of response required, and, on negative trials, the position of the mismatched pair in the test display. RT increased with the number of pairs presented on a trial and the increase was greater for positive than for negative trials. For negative pair trials, RT increased with the distance of the mismatched pair from the top of the test display. On negative trials in which the top pair in the test display was the mismatched pair, RT increased with the total number of pairs presented on the trial. A serial, probabilistic order of processing model is proposed to account for these results, and applications of the model to other paradigms are discussed. PMID- 21287382 TI - Evaluation of informational control and preparatory response factors in classical aversive conditioning. AB - Subjects performed in a differential eyelid conditioning paradigm with either airpuff or infraorbital shock as the UCS. The trial series included interpolated UCS-alone presentations, and subjects rated UCS aversiveness on all trials. Ratings of the airpuff, but not the shock UCS, were negatively correlated with the magnitude of anticipatory eyelid CRs, as predicted by preparatory response or law-of-effect models of classical conditioning. However, subjects showed no tendency to rate signaled (CS-UCS) trials as less aversive than unsignaled (UCS alone) trials, and showed no significant preference for the signaled ucs. These results suggest that the operation of informational control and preparatory response factors is more complex than is assumed by available theories. Also, instrumental shaping and preparatory response mechanisms may not be involved in the acquisition of CRs. PMID- 21287383 TI - Semantic processing and organization in free recall. AB - It was hypothesized that both semantic processing and organizational activity are necessary for optimal free recall performance. In a series of three experiments, subjects were presented with a list of randomly selected nouns and were asked to make up a meaningful sentence for each noun. The subjects also rated the difficulty of using each noun. The subjects were instructed to try to remember words that were labeled "remember" words. For words that were labeled "story" words, the subjects were instructed only to make each sentence, using the word, part of an ongoing story which each subject was to make up. A test of retention for all presented words, using retention intervals of both 1 min and 24 h, showed that the story words were always recalled better than were the remember words. However, the amount of sequential organization was the same for both the story and the remember words. Recognition performance was found to be the same for both types of words. In addition, the story words were rated as being more difficult than the remember words. It was concluded that extensive semantic processing without organization is not sufficient for optimal recall. PMID- 21287384 TI - Recognition memory for elements of sentences. AB - Although several theoretical positions and a variety of empirical tasks indicate the importance of verbs to sentences, nouns are generally recalled and recognized better in memorial tasks. Three main models can be identified to explain this discrepancy ("Fillenbaum's paradox"). To try to resolve this paradox, several experiments explored the efficiency of various sentence elements as cues in recognition memory. In Experiment I, concreteness of the stimuli did not interact with the type of distractor; however, verb phrase changes were harder to recognize than noun phrase changes when synonym distractors were used. This result was replicated in a forced-choice recognition paradigm (Experiment II) and with whole sentences where the derivational similarity of verbs and nouns was controlled (Experiment IV). The effect could not be attributed to characteristics of the English language (Experiment III) or to superior memory for form information in nouns (Experiment V). The total results are interpreted as suggesting that subjects process different parts of a sentence to different semantic levels, with verbs receiving more semantic representation and nouns more orthographic or phonological representation. The results are taken as support for a "semantic encoding model" of Fillenbaum's paradox. PMID- 21287385 TI - Associative processes and strategies in disjunctive reaction time. AB - Scaling analysis based on variable criterion theory has been applied to the c reaction form of disjunctive RT. In addition to previously identified sensory growth functions, two associative processes have been identified and functions of time describing their growth have been obtained. Associative strength to the positive stimulus begins at about 200 msec, or after, and grows with initial positive and later negative acceleration. Associative inhibition to the negative stimulus begins earlier, shortly after the sensory detection functions, and grows rapidly with negative acceleration. Subjects may adopt strategies which emphasize the use of either of these associative processes. With the pure inhibitory strategy, they respond to the positive stimulus entirely on the basis of sensory detection, but associatively inhibit response to the negative stimulus. With either strategy, the speed-accuracy tradeoff was determined by the level of criterion adjustment. PMID- 21287386 TI - The effects of labeling dimensional values on setting differences in shift performance of kindergarten children. AB - A reversal-shift paradigm was used to study the effects of dimensional labeling on the performance of 270 kindergarten children. Task 1 was a simultaneous discrimination problem in which form, size, and color were redundant relevant dimensions, In the shift task, one of the dimensions remained relevant with reward contingencies reversed, and the other two dimensions were made irrelevant. In both tasks, the children named the stimulus object to be chosen, prior to choosing, in terms of one of the three sets of dimensionnal values. Shift performance was predicted to be superior in groups required to name relevant dimensional values in comparison with groups required to name irrelevant dimensional values. Moreover shift performance was predicted to differ, within groups, for four different types of stimulus settings. Fmally, differences in performance on the settings were predicted to be larger for the irrelevant labeling groups than for the relevant-labelmg groups. The results were found to be in good agreement with these predictions. The findings were discussed in relation to the subproblem analysis proposed by Tighe and Tighe (1972). PMID- 21287387 TI - Recognition memory: One-component strength functions In the "short-term to long term transition region". AB - Experimental manipulationofthe upper bound on the retention interval (30 sec, with average duration of 11 sec, vs. 2 min, with average duration of 18 sec) failed to produce evidence for independent adjustment of initial long-term and short-term storage strengths. Very accurate strength functions of retention time were obtained; these were fitted equally well by a two-component equation and a one-componentequation derived from a theory postulating sequential employment of an active attentional buffer and a one-trace passive storage system. The latter theory appears to be capable of accounting for both post-attentional and two phase experimental strength data, using fewer free parameters than strength theories which postulate the simultaneous existence of short-term and long-term traces. Other arguments for two traces are also discussed In relation to the postulate of a single post-attentional trace. PMID- 21287388 TI - Efficiency of arithmetic operations in bilinguals as a function of language. AB - English-Spanish bilinguals solved simple arithmetic problems and were required to respond In their preferred (P) language. the language In which they originally learned arithmetic, or In their nonpreferred (NP) language. Each arithmetic problem required one. two, or three addition operations. Reaction time was a linear function of number of operations. The intercept for the P language was lower than that for the NP language. but there were no differences In slope. The intercept difference was interpreted In terms of translation time. either as translation of the sum from the P to the NP language or as translation from an abstract representation to the NP as opposed to the P language. PMID- 21287389 TI - The water quality of Izmir bay: a case study. AB - About 30 studies from the published literature were reviewed to determine the status of several categories of pollutants (i.e., nutrients, heavy metals, and organic compounds) in the Izmir Bay. The Izmir Bay of western Turkey is one of the great natural bays of the Mediterranean Sea. The city of Izmir is an important industrial and commercial center and is a cultural focal point for this area. In this review, I review the results of studies performed by researchers over a period of two decades to glean what probable impact has resulted from human activities in the bay. I also summarize available data on the contamination levels found in the bay and the effects generated by these levels on the ecosystem of the bay. In addition, I provide a monitoring analysis that provides the distribution of inorganic nutrients and chlorophyll-a that have been investigated and the N/P ratios that were determined in Izmir Bay during 1996 2008. To identify the temporary trends in the monitoring data, linear regression analyses were performed. Significant negative trends were observed in TNOx concentrations in Izmir Bay. No significant trend was found in metal concentrations except Pb in the sediment. A significant negative existed for Hg in fish. Unfortunately, there are only limited data available for the organic contaminations from Izmir Bay. Therefore, any attempt to create a regional scale assessment from organic contaminant data available in the literature is limited by the scarcity of available information. PMID- 21287390 TI - Teratogenicity and embryotoxicity in aquatic organisms after pesticide exposure and the role of oxidative stress. AB - Many pesticides have been documented to induce embryotoxicity and teratogenicity in non-target aquatic biota such a fish, amphibians and invertebrates. Our review of the existing literature shows that a broad range of pesticides, representing several different chemical classes, induce variable toxic effects in aquatic species. The effects observed include diverse morphological malformations as well as physiological and behavioral effects. When development malformations occur, the myoskeletal system is among the most highly sensitive of targets. Myoskeletal effects that have been documented to result from pesticides were also known to interfere with the development of organ systems including the eyes or the heart and are also known to often cause lethal or sublethal edema in exposed organisms. The Physiological, behavioral, and population endpoints affected by pesticides include low or delayed hatching, growth suppression, as well as embryonal or larval mortality. The risks associated with pesticide exposure increase particularly during the spring. This is the period of time in which major pepticide applications take place, and this period unfortunately also coincides with many sensitive reproductive events such as spawning, egg laying, and early development of many aquatic organisms. Only few experimental studies with pesticides have directly linked developmental toxicity with key oxidative stress endpoints, such as lipid peroxidation, oxidative DNA damage, or modulation of antioxidant mechanisms. On the other hand, it has been documented in many reports that pesticide-related oxidative damage occurs in exposed adult fish, amphibians, and invertebrates. Moreover, the contribution of oxidative stress to the toxicity of pesticides has been emphasized in several recent review papers that have treated this topic. In conclusion, the available experimental data, augmented by several indirect lines of evidence, provide support to the concept that oxidative stress is a highly important mechanism in pesticide-induce reproductive or developmental toxicity. Other stressors may also act by oxidative mechanisms. This notwithstanding, there is much yet to learn about the details of this phenomenon and further research is needed to more fully elucidate the effects that pesticides have and the environmental risks they pose in the early development of aquatic organisms. PMID- 21287391 TI - Mixtures of environmental pollutants: effects on microorganisms and their activities in soils. AB - Soil is the ultimate sink for most contaminants and rarely has only a single contaminant. More than is generally acknowledge, environmental pollutants exist as mixtures (organic-organic, inorganic-inorganic, and organic-inorganic). It is much more difficult to study chemical mixtures than individual chemicals, especially in the complex soil environment. Similarly, understanding the toxicity of a chemical mixture on different microbial species is much more complex, time consuming and expensive, because multiple testing designs are needed for an increased array of variables. Therefore, until now, scientific enquiries worldwide have extensively addressed the effects of only individual pollutants toward nontarget microorganisms. In this review, we emphasize the present status of research on (i) the environmental occurrence of pollutant mixtures; (ii) the interactions between pollutant mixtures and ecologically beneficial microorganisms; and (iii) the impact of such interactions on environmental quality. We also address the limitations of traditional cultivation based methods for monitoring the effects of pollutant mixtures on microorganisms. Long-term monitoring of the effects of pollutant mixtures on microorganisms, particularly in soil and aquatic ecosystems, has received little attention. Microbial communities that can degrade or can degrade or can develop tolerance to, or are inhibited by chemical mixtures greatly contribute to resilience and resistance in soil environments. We also stress in this review the important emerging trend associated with the employment of molecular methods for establishing the effects of pollutant mixtures on microbial communities. There is currently a lack of sufficient cogent toxicological data on chemical mixtures for making informed decision making in risk assessment by regulators. Therefore, not only more toxicology information on mixtures is needed but also there is an urgent need to generate sufficient, suitable, and long-term modeling data that have higher predictability when assessing pollutant mixture effects on microorganisms. Such data would improve risk assessment at contaminated sites and would help devise more effective bioremediation strategies. PMID- 21287392 TI - Fluoride in the environment and its metabolism in humans. AB - The presence of environmental fluoride and its impact on human health is well documented. When consumed in adequate quantity, fluoride prevents dental caries, assists in the formation of dental enamels, and prevents deficiencies in bone mineralization. At excessive exposure levels, ingestion of fluoride causes dental fluorosis skeletal fluorosis, and manifestations such as gastrointestinal, neurological, and urinary problems. The distribution of fluoride in the environment is uneven and largely is believed to derive from geogenic causes. The natural sources of fluoride are fluorite, fluorapatite, and cryolite, whereas anthropogenic sources include coal burning, oil refining, steel production, brick making industries, and phosphatic fertilizer plants, among others. Among the various sources of fluoride in the environment, those of anthropogenic origin have occasionally been considered to be major ones. The gourndwater is more susceptible to fluoride accumulation and contamination than are other environmental media, primarily because of its contact with geological substrates underneath. The high fluoride concentration in water usually reflects the solubility of fluoride (CaF2). High concentrations are also often associated with soft, alkaline, and calcium-deficient waters. The fluoride compounds that occur naturally in drinking water are almost totally bioavailable (90%) and are completely absorbed from the gastrointestinal tract. As a result, drinking water is considered to be the potential source of fluoride that causes fluorosis. Because the bioavailability of fluoride is generally reduced in humans when consumed with milk or a calcium-rich diet, it is highly recommended that the inhabitants of fluoride-contaminated areas should incorporate calcium-rich foods in their routine diet. Guidelines for limiting the fluoride intake from drinking water have been postulated by various authorities. Such limits are designed to protect public health and should reflect all fluoride intake sources, including dietary fluoride. The toxicological risks posed by fluoride could be better understood if epidemiological surveillance for dental and skeletal fluorosis would be systematically conducted in fluoride-affected areas. Such input would greatly improve understanding of the human dose-response relationship. Such surveillance of potentially high fluoride areas is also important because it would help to delineate, much earlier, the remedial measures that are appropriate for those areas. PMID- 21287393 TI - Glial nuclear aggregates of superoxide dismutase-1 are regularly present in patients with amyotrophic lateral sclerosis. AB - The most common cause of amyotrophic lateral sclerosis (ALS) is mutations in superoxide dismutase-1 (SOD1). Since there is evidence for the involvement of non neuronal cells in ALS, we searched for signs of SOD1 abnormalities focusing on glia. Spinal cords from nine ALS patients carrying SOD1 mutations, 51 patients with sporadic or familial ALS who lacked such mutations, and 46 controls were examined by immunohistochemistry. A set of anti-peptide antibodies with specificity for misfolded SOD1 species was used. Misfolded SOD1 in the form of granular aggregates was regularly detected in the nuclei of ventral horn astrocytes, microglia, and oligodendrocytes in ALS patients carrying or lacking SOD1 mutations. There was negligible staining in neurodegenerative and non neurological controls. Misfolded SOD1 appeared occasionally also in nuclei of motoneurons of ALS patients. The results suggest that misfolded SOD1 present in glial and motoneuron nuclei may generally be involved in ALS pathogenesis. PMID- 21287394 TI - A distinct region of the MGMT CpG island critical for transcriptional regulation is preferentially methylated in glioblastoma cells and xenografts. AB - O(6)-Methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein that removes alkyl DNA adducts such as those induced by alkylating agents. Loss of MGMT expression through transcriptional silencing by hypermethylation of its CpG island (CGI) is found in diverse human cancers including glioblastomas. Glioblastomas that have MGMT methylation respond to temozolomide, an alkylating agent, resulting in improved survival. Consequently, assessment of MGMT methylation has become a therapy response and prognostic indicator. However, it is not clear whether the region of the MGMT CGI commonly analysed is the critical region involved in transcriptional control. We measured methylation levels at each CpG site for the entire MGMT CGI using bisulfite modification and pyrosequencing, and compared them with MGMT mRNA expression in glioblastoma cell lines, xenografts and normal brain tissues (41 samples). Two critical regions were identified (DMR1 and DMR2). DMR2 encompasses the commonly analysed region and was always methylated when DMR1 was methylated. A luciferase reporter assay showed that substitutions of several specific CpG sites within DMR2 significantly attenuated the promoter activity of the MGMT CGI. Our results indicate that several CpG sites within DMR2 play a critical role in the transcriptional control of MGMT, making DMR2 the optimal target for methylation testing. However, given the highly variable patterns of MGMT methylation associated with transcriptional silencing observed in this region among the tumours in this study, methylation levels need to be measured at a number of individual CpGs within DMR2 to confidently predict transcriptional silencing and thus sensitivity to alkylating agents. PMID- 21287395 TI - Modeling interlamellar interactions in angle-ply biologic laminates for annulus fibrosus tissue engineering. AB - Mechanical function of the annulus fibrosus of the intervertebral disc is dictated by the composition and microstructure of its highly ordered extracellular matrix. Recent work on engineered angle-ply laminates formed from mesenchymal stem cell (MSC)-seeded nanofibrous scaffolds indicates that the organization of collagen fibers into planes of alternating alignment may play an important role in annulus fibrosus tissue function. Specifically, these engineered tissues can resist tensile deformation through shearing of the interlamellar matrix as layers of collagen differentially reorient under load. In the present work, a hyperelastic constitutive model was developed to describe the role of interlamellar shearing in reinforcing the tensile response of biologic laminates, and was applied to experimental results from engineered annulus constructs formed from MSC-seeded nanofibrous scaffolds. By applying the constitutive model to uniaxial tensile stress-strain data for bilayers with three different fiber orientations, material parameters were generated that characterize the contributions of extrafibrillar matrix, fibers, and interlamellar shearing interactions. By 10 weeks of in vitro culture, interlamellar shearing accounted for nearly 50% of the total stress associated with uniaxial extension in the anatomic range of ply angle. The model successfully captured changes in function with extracellular matrix deposition through variations in the magnitude of model parameters with culture duration. This work illustrates the value of engineered tissues as tools to further our understanding of structure-function relations in native tissues and as a test-bed for the development of constitutive models to describe them. PMID- 21287396 TI - Gene expression profiles of T cells from hepatitis E virus infected patients in acute and resolving phase. AB - BACKGROUND AND AIMS: Approximately 50% of acute viral hepatitis in young adults and in pregnant women is due to hepatitis E virus (HEV) infection in developing countries. T cell-mediated immune injury probably plays a key role in the pathogenesis of acute hepatitis illness. However, there is a paucity of data on the global gene expression programs activated on T cells, which are subsequently responsible for T cell recruitment to the liver and triggering of immune injury. PATIENTS AND METHODS: We performed a flow cytometric analysis of T cells in individuals with acute hepatitis E (AVH-E; n=10), resolving phase of HEV (n=9), and ten healthy controls (HC). Further transcriptional profiling analysis was performed using Affymetrix GeneChip DNA microarrays to identify the genes that were differentially expressed in AVH-E and HC. RESULTS: Patients with AVH-E showed higher frequencies of CD8+ (27 +/- 4%; P=0.02) and activated CD38+ CD69+ T cells (25% +/- 3%; P=0.04) than in resolving phase patients (20 +/- 2% and 9.1 +/ 4%, respectively), who in turn exhibited higher CCR9 expression than cells from patients in active phase. The naive T cell population (CD3+ CD45RA+) was decreased upon HEV infection (29 +/- 4% in AVH-E vs. 53.1 +/- 3.2% in HC; P=0.05); however, the CD11a high subpopulation within CD4+ CD45RA+ cells was increased in both AVH-E (6.1%) and resolving phase (7.7%) patients. Gene ontology analysis suggested that during AVH-E infection, there is in CD4+ T cells an activation of genes involved in pro-inflammatory responses. Additional RT-PCR analysis confirmed that in cells from AVH-E patients, there is an increased expression of CCR5, CCR9, CXCR3, CXCR4, STAT1, IRF-9, IFN-alpha, and TNF-alpha, together with a down-regulation of IL-2, SOCS3, and IL-10, with respect to cells from resolving phase patients. CONCLUSIONS: Our findings suggest the involvement of a circulating CD45RA+ CD11a high population with CCR5 expression in the pathogenesis processes of AVH-E. The obtained results help to understand the underlying inflammatory process occurring in HEV infection, which can lead to either resolution or immunopathology. PMID- 21287398 TI - Spermidine delays eye lens opacification in vitro by suppressing transglutaminase catalyzed crystallin cross-linking. AB - A Ca(2+)-dependent TG activity, identified in the eye lens of several mammalian species, has long been implicated in cataract formation. The precise mechanism of the involvement of this enzyme in this process remains unclear. The purpose of this work was to investigate the modulatory effect of polyamines on TG activity during rabbit eye lens in vitro opacification. We observed, in an in vitro Ca(2+) induced cataract model, a rapid decrease of the endogenous levels of SPD with the progression of opacification, paralleled by an increase of crystallin cross linking by bis(gamma-glutamyl)SPD. This pattern was reversed adding exogenous SPD to the incubation medium. Indeed, endogenous SPD levels were restored and cross linking by bis(gamma-glutamyl)SPD were drastically reduced. Surprisingly, under this experimental condition, the loss of transparency of lens was delayed. We found that exogenous SPD incubation led to a remarkable increase of mono(gamma glutamyl)SPD, likely responsible of the inhibition of cross-linking of lens crystallins and of the transparency persistence. PMID- 21287397 TI - The histone peptide H4 71-94 alone is more effective than a cocktail of peptide epitopes in controlling lupus: immunoregulatory mechanisms. AB - Tolerance therapy with nucleosomal histone peptides H4(71-94), H4(16-39), or H1'(22-42) controls disease in lupus-prone SNF1 mice. It would be clinically important to determine whether a cocktail of the above epitopes would be superior. Herein, we found that compared with cocktail peptides, H4(71-94) monotherapy more effectively delayed nephritis onset, prolonged lifespan, diminished immunoglobulin G autoantibody levels, reduced autoantigen-specific Th1 and Th17 responses and frequency of T(FH) cells in spleen and the helper ability of autoimmune T cells to B cells, by inducing potent CD8 Treg cells. H4(71-94) therapy was superior in "tolerance spreading," suppressing responses to other autoepitopes, nucleosomes, and ribonucleoprotein. We also developed an in vitro assay for therapeutic peptides (potentially in humans), which showed that H4(71 94), without exogenous transforming growth factor (TGF)-beta, was efficient in inducing stable CD4(+)CD25(+)Foxp3(+) T cells by decreasing interleukin 6 and increasing TGF-beta production by dendritic cells that induced ALK5-dependent Smad-3 phosphorylation (TGF-beta signal) in target autoimmune CD4(+) T cells. PMID- 21287399 TI - Homocysteine alters glutamate uptake and Na+,K+-ATPase activity and oxidative status in rats hippocampus: protection by vitamin C. AB - In the present study we investigate the effect of homocysteine on glutamate uptake, Na+,K+-ATPase, enzymatic antioxidant defenses, as well as reactive species levels in hippocampus of rats. The influence of vitamin C, a classic antioxidant, on the effects elicited by homocysteine was also tested. Results showed that chronic hyperhomocysteinemia decreased glutamate uptake and the activities of Na+,K+-ATPase, catalase and superoxide dismutase in hippocampus of rats. Reactive species levels were increased by chronic homocysteine administration. Concomitant administration of vitamin C significantly prevented these alterations caused by homocysteine. According to our results, it seems possible to suggest that the reduction in glutamate uptake and Na+,K+-ATPase activity may be mediated by oxidative stress, since vitamin C prevented these effects. We suggest that the administration of antioxidants should be considered as an adjuvant therapy to specific diet in homocystinuria. PMID- 21287400 TI - Aboriginal experiences of aging and dementia in a context of sociocultural change: qualitative analysis of key informant group interviews with Aboriginal seniors. AB - Examining the role of culture and cultural perceptions of aging and dementia in the recognition, diagnosis, and treatment of age-related cognitive impairment remains an understudied area of clinical neuropsychology. This paper describes a qualitative study based on a series of key informant group interviews with an Aboriginal Grandmothers Group in the province of Saskatchewan. Thematic analysis was employed in an exploration of Aboriginal perceptions of normal aging and dementia and an investigation of issues related to the development of culturally appropriate assessment techniques. Three related themes were identified that highlighted Aboriginal experiences of aging, caregiving, and dementia within the healthcare system: (1) cognitive and behavioural changes were perceived as a normal expectation of the aging process and a circular conception of the lifespan was identified, with aging seen as going back "back to the baby stage", (2) a "big change in culture" was linked by Grandmothers to Aboriginal health, illness (including dementia), and changes in the normal aging process, and (3) the importance of culturally grounded healthcare both related to review of assessment tools, but also within the context of a more general discussion of experiences with the healthcare system. Themes of sociocultural changes leading to lifestyle changes and disruption of the family unit and community caregiving practices, and viewing memory loss and behavioural changes as a normal part of the aging process were consistent with previous work with ethnic minorities. This research points to the need to understand Aboriginal perceptions of aging and dementia in informing appropriate assessment and treatment of age-related cognitive impairment and dementia in Aboriginal seniors. PMID- 21287401 TI - Cryopreservation of whole ovaries with vascular pedicles: vitrification or conventional freezing? AB - PURPOSE: To compare the efficacy of vitrification and conventional freezing of whole ovaries. METHODS: Ovaries obtained from 5-year-old female bovines were cryopreserved by conventional freezing, rapid freezing and vitrification. The ovarian cortical strips were cryopreserved by conventional freezing. Follicular viability was assessed using the trypan blue test; the percentage of morphologically normal primordial follicles, hormones concentrations in the culture supernatants, and lactate dehyrogenase levels were measured. RESULTS: The efficacy of cryopreservation of whole ovaries by vitrification was higher than those by conventional freezing and rapid freezing. Conventional freezing of ovarian cortical strips was more effective than cryopreservation of whole ovaries by conventional freezing, rapid freezing, and vitrification. CONCLUSIONS: Vitrification seems to be more suitable than conventional freezing for cryopreservation of whole ovaries. However, further studies are required to improve the efficacy of vitrifying whole ovaries. PMID- 21287402 TI - Description of the parasite Wucheria bancrofti microfilariae identified in follicular fluid following transvaginal oocyte retrieval. AB - INTRODUCTION: This case study presents an unusual finding of filarial infection within follicular fluid obtained during an in vitro fertilization (IVF) oocyte retrieval procedure. CASE: A 41 year-old G4P1030 immigrant from western Africa underwent in vitro fertilization (IVF). At the time of inspection of the follicular fluid obtained at oocyte retrieval, mobile worm-like organisms were observed and identified as Wuchereria bancrofti microfilariae (filariasis). The patient successfully underwent treatment for filariasis and Onchocerciasis co infection. Following treatment, the patient underwent embryo transfer that failed to result in a pregnancy. DISCUSSION: Recent years have seen an increase in international travel and immigration. Therefore, practitioners must become familiar not only with illnesses that are endemic to their geographic region but also diseases that are more common in remote regions of the world. The infertility evaluation and treatment offers physicians a unique opportunity to identify and initiate treatment for diseases that might otherwise go undiagnosed. PMID- 21287403 TI - The effects of male aging on semen quality, sperm DNA fragmentation and chromosomal abnormalities in an infertile population. AB - PURPOSE: To investigate the effects of male aging on semen quality, DNA fragmentation and chromosomal abnormalities in the spermatozoa of infertile patients and fertile men. METHODS: Semen samples of 140 infertile patients (24-76 years) and 50 men with proven fertility (25-65 years) were analyzed according to WHO guidelines. DNA fragmentation was detected by TUNEL assay, while aneuploidy was assessed by FISH. RESULTS: In the patient group, semen volume and vitality of spermatozoa decreased significantly with age, while sperm concentration showed a statistically significant increase with age. DNA fragmentation as well as disomy of sex chromosomes and disomy 8 did not show a statistically significant change with age. However, the diploidy rate was significantly increased with patient's age. In the control group, conventional semen parameters as well as DNA fragmentation and chromosomal abnormalities did not show a statistically significant with age. CONCLUSION: Increased age in infertile men is associated with an increase in sperm concentration and diploidy, as well as a decline in semen volume and sperm vitality. However motility, morphology and DNA fragmentation are not affected by male age. PMID- 21287404 TI - A method to type the potential angucycline producers in actinomycetes isolated from marine sponges. AB - Angucyclines are aromatic polyketides with antimicrobial, antitumor, antiviral and enzyme inhibition activities. In this study, a new pair of degenerate primers targeting the cyclase genes that are involved in the aromatization of the first and/or second ring of angucycline, were designed and evaluated in a PCR protocol targeting the jadomycin cyclase gene of Streptomyces venezuelae ISP5230. The identity of the target amplicon was confirmed by sequencing. After validation, the primers were used to screen 49 actinomycete isolates from three different marine sponges to identify putative angucycline producers. Seven isolates were positively identified using this method. Sequence analysis of the positive amplicons confirmed their identity as putative angucycline cyclases with sequence highly similar to known angucycline cyclases. Phylogenetic analysis clustered these positives into the angucycline group of cyclases. Furthermore, amplifications of the seven isolates using ketosynthase-specific primers were positive, backing the results using the cyclase primers. Together these results provided strong support for the presence of angucycline biosynthetic genes in these isolates. The specific primer set targeting the cyclase can be used to identify putative angucycline producers among marine actinobacteria, and aid in the discovery of novel angucyclines. PMID- 21287405 TI - Compounds isolated from Curcuma aromatica Salisb. inhibit human P450 enzymes. AB - Curcuma species (Zingiberaceae) are used as both food and medicine in Asia. Ten sesquiterpenes (1-10) and two curcuminoids (11 and 12) were isolated from the rhizomes of Curcuma aromatica Salisb. and identified. The compounds were evaluated for their ability to inhibit cytochrome P450 (CYP). Among them, the sesquiterpene (4S,5S)-(+)-germacrone-4,5-epoxide (7) inhibited certain subtypes of CYP more potently than or at levels comparable to the curcuminoids curcumin (11) and demethoxycurcumin (12); 7 (IC(50) = 1.0 +/- 0.2 MUM) > 12 (IC(50) = 7.0 +/- 1.7 MUM) > 11 (IC(50) = 14.9 +/- 1.4 MUM) for CYP3A4 inhibition; 12 (IC(50) = 1.4 +/- 0.2 MUM) > 11 (IC(50) = 6.0 +/- 1.4 MUM) > 7 (IC(50) = 7.6 +/- 2.5 MUM) for CYP2C9 inhibition; and 7 (IC(50) = 33.2 +/- 3.6 MUM) = 12 (IC(50) = 34.0 +/- 14.2 MUM) > 11 (IC(50) > 100 MUM) for CYP1A2 inhibition. These results suggest the possibility that Curcuma aromatica Salisb. may cause food-drug interactions via cytochrome P450 inhibition by sesquiterpene 7 and curcuminoids 11 and 12. PMID- 21287406 TI - Sedative effects of vapor inhalation of the essential oil of Microtoena patchoulii and its related compounds. AB - Microtoena patchoulii (Labiatae) is a perennial herb that grows in southern China. In the present study, the sedative activity of the essential oil of the leaves was evaluated using mice when the volatile oil was administered by inhalation. The inhalation of the oil by mice significantly reduced the spontaneous motor activity. Fractionation of the oil revealed that the main constituents in the oil were 1-octen-3-ol, terpinolene, patchouli alcohol, and methyl salicylate. Each 1-octen-3-ol, terpinolene, or patchouli alcohol significantly reduce the locomotor activity when it was administered singly. However, the essential oil fraction containing both patchouli alcohol and methyl salicylate did not exhibit any effects. It is suggested that methyl salicylate might negate the sedative effect of patchouli alcohol, and that the concentration ratios of the compounds in vapor would play important roles as sedatives. In order to clarify the mechanism of action, the effects of these compounds on caffeine-induced excitation and pentobarbital-induced elongation of sleeping time in mice were tested. Each 1-octen-3-ol or terpinolene reduced the locomotor activity excited by caffeine to those of normal levels. Elongation of sleeping time induced by pentobarbital was further elongated by the inhalation of terpinolene, but not by that of 1-octen-3-ol. It is indicated that terpinolene is a potent suppressor of the central nervous system. PMID- 21287407 TI - Selected topics on lymphoid lesions in the head and neck regions. AB - Lymphoid tissue located in the head and neck region include multiple regional lymph node chains as well as mucosa associated lymphoid tissue of the conjunctiva, buccal and nasopharyngeal cavities (Waldeyer's ring), and thyroid and salivary glands. This region is a rich source of antigenic stimuli including infectious agents coming from the outside environment. Many reactive conditions that affect lymphoid tissue in this region may mimic neoplasia. In fact, distinguishing between benign and malignant lymphoid proliferations in the head and neck region is a relatively frequent diagnostic challenge and in many instances, this distinction is not straightforward. It therefore behooves the practicing pathologist to be able to recognize the benign lymphoproliferative disorders that affect this region so as to effectively guide the appropriate clinical management of such patients. Kimura disease, Epstein Barr lymphadenitis, HIV associated salivary gland disease and chronic sialadenitis are benign conditions that not infrequently affect lymphoid tissue in the head and neck region and that share certain overlapping features with malignant lymphoma. In this brief review, we discuss these conditions and highlight clinicopathological features that may help distinguish them from neoplastic lymphoproliferations that may share similar features. PMID- 21287408 TI - Clinical features of severe acquired ADAMTS13 deficiency in thrombotic thrombocytopenic purpura: the Korean TTP registry experience. AB - The clinical significance of ADAMTS13 activity for response to treatment, mortality rate, recurrence, and prognosis is unclear. Therefore, we investigated the characteristics of severe ADAMTS13 deficiency and evaluated its prognostic features in Thrombotic thrombocytopenic purpura (TTP). The Korean TTP Registry includes 66 patients from 13 teaching hospitals in Korea who received the diagnosis of TTP from January 2005 to December 2008. Blood samples obtained upon admission were sent for ADAMTS13 analysis (multimer analysis by sodium dodecyl sulfate electrophoresis) to a central laboratory along with patient clinical information. Patients with severe ADAMTS13 deficiency had lower serum creatinine levels (P = 0.001) than patients with non-severe ADAMTS13 deficiency. Although severe ADAMTS13 deficiency was associated with better response rate (75 vs. 53%, P = 0.145), remission rate (81 vs. 61%, P = 0.209), and mortality rate (19 vs. 31%, P = 0.508) than non-severe ADAMTS13 deficiency, treatment outcomes did not differ significantly between groups. After adjusting for clinical and laboratory features, multivariate analysis did not reveal any independent risk factors for TTP-associated mortality. Patients with severe ADAMTS13 deficiency had lower serum creatinine levels at presentation, but severe ADAMTS13 activity deficiency at TTP diagnosis does not appear to have prognostic significance. PMID- 21287409 TI - Effect of arsenic trioxide on the treatment of children with newly diagnosed acute promyelocytic leukemia in China. AB - To explore the efficacy of treatment for childhood acute promyelocytic leukemia (APL) with a combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (As(2)O(3)) for remission induction, we reviewed the clinical course and outcome of 37 children with APL from January 1999 to December 2003. Among the 37 children (<=14 years) with newly diagnosed APL, we applied treatments that consisted of ATRA alone or in combination with As(2)O(3) in induction followed by consolidation and maintenance treatment. Overall, 35 (94.6%) of 37 children achieved complete remission (CR). Two patients died of intracerebral hemorrhage on days 1 and 2. The 5-year estimates of event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) rates for the 37 patients were 79.2, 83.7, and 91.5%, respectively. There were 27 patients with white blood cell (WBC) count lower than 10 * 10(9)/L. In 27 patients with a WBC count <10 * 10(9)/L, 17 patients (group-I) were treated with ATRA alone and 10 patients (group-II) were treated with ATRA which was switched to As(2)O(3) due to the side effects of ATRA. Although the 5-year estimate of DFS between group-I and group-II showed no significant difference (P = 0.108), the DFS rate improved by 25% in group-II. Our results suggest that the combination of As(2)O(3) and ATRA might decrease the relapse rate compared with ATRA alone in induction therapy for childhood APL, at least in those with a WBC count less than 10 * 10(9)/L. PMID- 21287410 TI - Evaluation of the functional status questionnaire in heart failure: a sub-study of the second cardiac insufficiency bisoprolol survival study (CIBIS-II). AB - AIMS: We evaluated a generic quality of life (QoL) Functional Status Questionnaire (FSQ), in patients with chronic heart failure (CHF). The FSQ assesses the 3 main dimensions of QoL: physical functioning, mental health and social role. It also includes 6 single item questions about: work status, frequency of social interactions, satisfaction with sexual relationships, days in bed, days with restricted activity and overall satisfaction with health status. The FSQ was compared to the Minnesota Living with Heart Failure questionnaire (MLwHF). METHODS AND RESULTS: The FSQ was evaluated in a substudy (n = 340) of the second Cardiac Insufficiency Bisoprolol Survival study (CIBIS-II), a placebo controlled mortality trial. 265 patients (75%) patients completed both questionnaires at 6 months of follow-up. Both questionnaires indicated substantially impaired QoL. The FSQ demonstrated high internal consistency (Cronbach's alpha > 0.7 for all items except "social activity" = 0.66) and construct and concurrent validity. After 6 months, the only item on either questionnaire to show a difference between the placebo- and bisoprolol-treatment groups was the single item FSQ question about "days in bed" (p = 0.018 in favour of bisoprolol). CONCLUSIONS: The FSQ performed well in this study, provided additional information to the MLwHF questionnaire and allowed interesting comparisons with other chronic medical conditions. The FSQ may be a useful general QoL instrument for studies in CHF. PMID- 21287411 TI - Chronic istaroxime improves cardiac function and heart rate variability in cardiomyopathic hamsters. AB - PURPOSE: Istaroxime is a new luso-inotropic compound. It exerts inotropic action by reducing Na+/K+-ATPase activity, and simultaneously it stimulates sarcoplasmic reticulum Ca(2+)-ATPase function, thus also inducing lusitropic action. The aim of present study is to assess the effect of chronic istaroxime treatment on cardiac function and heart rate variability in Bio TO.2 Syrian hamster model of progressive heart failure. METHODS: Bio TO.2 hamsters were daily treated, from 12 to 28 weeks of age, with 30 mg/kg/day oral istaroxime. Age-matched Bio TO.2 and Bio F1B hamsters were treated with vehicle and used as diseased and healthy controls. At the end of treatment, hearts function and autonomic cardiac control were evaluated. RESULTS: Hearts from vehicle-treated Bio TO.2 when compared with hearts from Bio F1B showed higher heart/body weight ratio, and lower left ventricular systolic pressure (LVSP), positive and negative derivative of LV pressure (dP/dT), coronary flow rate (CFR). Hearts from istaroxime-treated when compared with those of vehicle-treated hamsters, showed the reduction of heart/body weight ratio, and the increase of LVSP, of both positive and negative dP/dT, and of CFR. Autonomic cardiac control, evaluated by HRV analysis, indicated in vehicle-treated Bio TO.2 hamsters, when compared to healthy, a shift towards increased sympathetic and decreased parasympathetic activities. Istaroxime-treatment preserved parasympathetic activity. CONCLUSIONS: Chronic istaroxime improves cardiac function and heart rate variability in Bio TO.2 Syrian hamster model of progressive heart failure. PMID- 21287412 TI - An opinion and practice survey on the structure and management of data and safety monitoring boards. AB - There is little to no empirical data available on how data and safety monitoring boards (DSMBs) are structured and how they operate. The purpose of this study was to provide data on this. To accomplish this goal, we administered a random survey on current structure and management practices and opinions as reported by principal investigators (PIs) and biostatisticians. We also surveyed Institutional Review Board (IRB) community members, as proxies for the public, as to their opinions on how DSMBs should be structured and managed. A final purpose was to compare opinions about what should be taking place to what is actually happening. PMID- 21287413 TI - Bad news about bad news: the disclosure of risks to insurability in research consent processes. AB - One of the phenomena associated with research is "incidental findings," that is, unexpected findings made during the research, and outside the scope of the research, which have potential health importance. One underappreciated risk of incidental findings is the potential loss of the research subject's insurability; or if a research subject fails to disclose incidental findings when applying for insurance, the insurance contract may be voidable by the insurer. In this article, we seek to explain the insurability risks associated with incidental findings and to make recommendations for how researchers and research ethics committees should address the issue of disclosure of these risks. PMID- 21287414 TI - Conflicted medical journals and the failure of trust. AB - Journals are failing in their obligation to ensure that research is fairly represented to their readers, and must act decisively to retract fraudulent publications. Recent case reports have exposed how marketing objectives usurped scientific testing and compromised the credibility of academic medicine. But scant attention has been given to the role that journals play in this process, especially when evidence of research fraud fails to elicit corrective measures. Our experience with The Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP) illustrates the nature of the problem. The now-infamous Study 329 of paroxetine in adolescent depression was negative for efficacy on all eight protocol-specified outcomes and positive for harm, but JAACAP published a report of this study that concluded that "paroxetine is generally well tolerated and effective for major depression in adolescents." The journal's editors not only failed to exercise critical judgment in accepting the article, but when shown evidence that the article misrepresented the science, refused either to convey this information to the medical community or to retract the article. PMID- 21287415 TI - Undergraduate women's reactions to body image and eating disorder research. AB - The purpose of the study was to determine college women's (N = 405) reactions to body image and eating disorder research as well as predictors of negative reactions. Results suggested that the majority of women (94%) did not experience negative reactions and reported benefits to participating. Regression analyses revealed that disordered eating and poorer body esteem were predictive of negative reactions to research participation. Additional analyses were conducted to better understand those participants (N = 26; 6%) who reported negative reactions. Overall, results indicated that body image and eating disorder research is not distressing for the vast majority of participants. PMID- 21287416 TI - Text messaging for HIV prevention with young Black men: formative research and campaign development. AB - This article describes the formative research and campaign development for a pilot study to test the feasibility of using cell phone text messaging to promote HIV prevention for young African-American men. We conducted six focus groups with Black men aged 16-20 (N=43) in order to obtain feedback on the campaign content and how best to convey sexual health information via text message using cell phones. We present three main findings: (1) the participants' ideas for conducting this research and how to structure our campaign design; (2) how we broadened our theoretical perspective from an individual focus to an empowerment and social capital focus in order to best communicate a culturally relevant program; and (3) the young adult's specific suggestions for how best to operationalize theoretical constructs related to empowerment and social capital. We found that young Black men were receptive to the idea of receiving text messages for an HIV prevention campaign. As technology proliferates, this work offers specific ideas for how to capitalize on new technological modalities to deliver important communications on prevention. PMID- 21287417 TI - Impact of a nutritional counseling program on prevention of HAART-related metabolic and morphologic abnormalities. AB - The advent of highly active antiretroviral therapy (HAART) improved HIV infection prognosis. However, adverse metabolic and morphologic effects emerged, highlighting a lack of investigation into the role of nutritional interventions among this population. The present study evaluated the impact of a nutritional counseling program on prevention of morphologic and metabolic changes in patients living with HIV/AIDS receiving HAART. A 12-month randomized clinical trial was conducted with 53 adults of both genders in use of HAART. Subjects were allocated to either an intervention group (IG) or a control group (CG). Nutritional counseling was based on the promotion of a healthy diet pattern. Anthropometrical, biochemical, blood pressure, and food intake variables were assessed on four separate occasions. Sub scapular skin-fold results showed a significant tendency for increase between time 1 (Mean IG = 14.9 mm; CG = 13.6 mm), time 3 (Mean IG = 16.7 mm; CG = 18.2 mm), and time 4 (Mean IG = 16.4 mm; CG = 17.7 mm). Lipid percentage intake presented a greater increase among controls (time 1 mean = 26.3%, time 4 mean = 29.6%) than among IG subjects (time 1 mean = 29.1%, time 4 mean = 28.9%). Moreover, participants allocated to the IG presented an increase in dietetic fiber intake of almost 10 grams. The proposed nutritional counseling program proved to be effective in improving diet by reducing fat consumption and increasing fiber intake. PMID- 21287418 TI - Rural HIV-infected women's access to medical care: ongoing needs in California. AB - HIV-infected women living in rural areas often have considerably less access to care than their urban and suburban counterparts. In much of the USA, little is known about HIV care among rural populations. This study elucidated barriers to care for rural women in California. Methods included retrospective structured interviews conducted with 64 women living in rural areas and receiving HIV care at 11 California healthcare facilities. Facilities were randomly sampled and all HIV-infected female patients seeking care at those facilities during a specified time period were eligible. The most commonly cited barriers to accessing care included physical health problems that prevented travel to care (32.8%), lack of transportation (31.2%), and lack of ability to navigate the healthcare system (25.0%). Being divorced/separated/widowed (compared to being either married or single) was associated with reporting physical health as a barrier to care (p=0.03); being unemployed (p=0.003) or having to travel 31-90 minutes (p=0.007, compared to less than 31 or greater than 90) were both associated with transportation as a barrier; and speaking English rather than Spanish was associated with reporting "difficulty navigating the system" (p=0.04). Twenty nine women (45.3%) reported difficulty in traveling to appointments. Overall, 24 (37.5%) women missed an HIV medical appointment in the previous 12-month period, primarily due to their physical health and transportation limitations. Physical health and transportation problems were both the major barriers to accessing health services and the primary reasons for missing HIV care appointments among this population of HIV-infected women living in rural areas. Providing transportation programs and/or mobile clinics, as well as providing support for patients with physical limitations, may be essential to improving access to HIV care in rural areas. PMID- 21287419 TI - Access to HIV community services by vulnerable populations: evidence from an enhanced HIV/AIDS surveillance system. AB - HIV disproportionately affects vulnerable populations such as black and minority ethnic groups, men who have sex with men (MSM) and migrants, in many countries including those in the UK. Community organisations in the UK are charitable non governmental organisations with a proportion of the workforce who volunteer, and provide invaluable additional support for people living with HIV (PLWHIV). Information on their contribution to HIV care in vulnerable groups is relatively sparse. Data generated from an enhanced HIV surveillance system in North West England, UK, was utilised for this study. We aimed to determine the characteristics of individuals who chose to access community services in addition to clinical services (1375 out of 4195 records of PLWHIV in clinical services). Demographic information, risk factors including residency status, uniquely gathered in this region, and deprivation scores were examined. Multivariate logistic regression modelling was conducted to predict the relative effect of patient characteristics on attendance at community services. Attendance at community services was highest in those living in the most, compared with least, deprived areas (p<0.001), and was most evident in MSM and heterosexuals. Compared to white UK nationals attendance was significantly higher in non-UK nationals of uncertain residency status (Adjusted odds ratio [AOR] = 21.91, 95% confidence interval [CI] 10.48-45.83; p<0.001), refugees (AOR = 5.75, 95% CI 3.3-10.03; p<0.001), migrant workers (AOR = 5.48, 95% CI 2.22-13.51; p<0.001) and temporary visitors (AOR = 3.44, 95% CI 1.68-7.05; p<0.001). Community services, initially established predominantly to support MSM, have responded to the changing demography of HIV and reach the most vulnerable members of society. Consequent to their support of migrant populations, community services are vital for the management of HIV in black and minority groups. Paradoxically, this coincides with increasing funding pressures on these services. PMID- 21287420 TI - Computer technology-based interventions in HIV prevention: state of the evidence and future directions for research. AB - Computer technology-based interventions (CBIs) represent a promising area for HIV prevention behavioral intervention research. Such programs are a compelling prevention option given their potential for broad reach, customized content, and low cost delivery. The purpose of the current article is to provide a review of the state of the literature on CBIs. First, we define CBIs in HIV prevention and highlight the many advantages of such interventions. Next, we provide an overview of what is currently known regarding the efficacy of CBIs in HIV prevention, focusing on two recent meta-analyses of this literature. Finally, we propose an agenda for future directions for research in the area of CBIs, using the RE-AIM model as an organizing guide. We conclude that with the continued growth of computer technologies, opportunities to apply such technologies in HIV prevention will continue to blossom. Further research is greatly needed to advance an understanding of not only how and under what circumstances CBIs can be efficacious, but also how the reach, adoption, implementation, and maintenance of such programs in clinical and community settings can be achieved. PMID- 21287421 TI - Functions and sources of perceived social support among children affected by HIV/AIDS in China. AB - While the relationship between perceived social support (PSS) and psychosocial well-being has been well documented in the global literature, existing studies also suggest the existence of multiple domains in definition and measurement of PSS. The current study, utilizing data from 1299 rural children affected by HIV/AIDS in central China, examines the relative importance of PSS functional measures (informational/emotional, material/tangible, affectionate, and social interaction) and PSS structural measures (family/relatives, teachers, friends, and significant others) in predicting psychosocial outcomes including internalizing problems, externalizing problems, and educational resilience. Both functional and structural measures of PSS provided reliable measures of related but unique aspects of PSS. The findings of the current study confirmed the previous results that PSS is highly correlated with children's psychosocial well being and such correlations vary by functions and sources of the PSS as well as different psychosocial outcomes. The findings in the current study suggested the roles of specific social support functions or resources may need to be assessed in relation to specific psychosocial outcome and the context of children's lives. The strong association between PSS and psychosocial outcomes underscores the importance of adequate social support to alleviate stressful life events and improve psychosocial well-being of children affected by HIV/AIDS. Meanwhile, the study findings call for gender and developmentally appropriate and situation specific social support for children and families affected by HIV/AIDS. PMID- 21287422 TI - Working memory influences processing speed and reading fluency in ADHD. AB - Processing-speed deficits affect reading efficiency, even among individuals who recognize and decode words accurately. Children with ADHD who decode words accurately can still have inefficient reading fluency, leading to a bottleneck in other cognitive processes. This "slowing" in ADHD is associated with deficits in fundamental components of executive function underlying processing speed, including response selection. The purpose of the present study was to deconstruct processing speed in order to determine which components of executive control best explain the "processing" speed deficits related to reading fluency in ADHD. Participants (41 ADHD, 21 controls), ages 9-14 years, screened for language disorders, word reading deficits, and psychiatric disorders, were administered measures of copying speed, processing speed, reading fluency, working memory, reaction time, inhibition, and auditory attention span. Compared to controls, children with ADHD showed reduced oral and silent reading fluency and reduced processing speed-driven primarily by deficits on WISC-IV Coding. In contrast, groups did not differ on copying speed. After controlling for copying speed, sex, severity of ADHD-related symptomatology, and GAI, slowed "processing" speed (i.e., Coding) was significantly associated with verbal span and measures of working memory but not with measures of response control/inhibition, lexical retrieval speed, reaction time, or intrasubject variability. Further, "processing" speed (i.e., Coding, residualized for copying speed) and working memory were significant predictors of oral reading fluency. Abnormalities in working memory and response selection (which are frontally mediated and enter into the output side of processing speed) may play an important role in deficits in reading fluency in ADHD, potentially more than posteriorally mediated problems with orienting of attention or perceiving the stimulus. PMID- 21287423 TI - Interference of acute cigarette smoking with [13C]methacetin breath test. AB - It is essential to establish whether and how environmental factors affect the reliability of [(13)C]methacetin breath test ((13)C-MBT). In 12 healthy volunteers (smokers), a standard (13)C-MBT with 75 mg [(13)C]methacetin was performed twice in random order: on a control day without smoking and on another day with smoking two cigarettes antecedently. A considerable flattening of the curve of the momentary (13)C recovery within the expiratory air was observed when the (13)C-MBT was performed after smoking. The maximum of the momentary (13)C recovery, D(max), decreased from 37.20+/-2.58 to 25.39+/-2.29% dose/h (p=0.00052). Moreover, the time to reach D(max) was prolonged after cigarette smoking (26.5+/-3.1 vs. 16.5+/-1.9 min, p=0.0199). The curve of the cumulative (13)C recovery on the cigarette smoking day appeared to be shifted downwards, and statistically significant differences relative to the control situation were found between the 24th and 75th minute following [(13)C]methacetin administration. Smoking cigarettes immediately prior to the (13)C-MBT diminishes the ability of the liver to handle methacetin, and hence a possibility of such an interaction should be excluded in order to interpret the results of the test correctly. PMID- 21287424 TI - Season of birth, Geschwind and Galaburda hypothesis, and handedness. AB - Geschwind and Galaburda (1985a, 1985b) suggested that the season of conception is a non-genetic random variable that may affect laterality and handedness, probably due to seasonal variations in the hormonal influences on the foetal brain. According to this suggestion it is logical to expect seasonal anisotropy in the incidence of birth of right- and non-right-handers. The present study analysed data obtained from a sample of 3182 young Bulgarians: 2825 right-handers and 357 non-right-handers. Significant difference in the seasonal distribution of births of right- and non-right-handers was found in males only. The incidence of non right-handedness was highest among participants born in winter. In right-handers increased birth rate was observed in spring and summer. The results in males seem to support the Geschwind and Galaburda suggestion. One can speculate that the high levels of mother's androgens during spring and early summer play the role of a "left shift" factor for the male foetuses with genetic potential for non-right handedness. PMID- 21287425 TI - The focus of attention in working memory: evidence from a word updating task. AB - Three experiments examined the cognitive costs of item switching within working memory with a novel word updating task, thereby extending previous research to the field of linguistic stimuli and linguistic-graphemic updating operations. In Experiments 1 and 2 costs for switching between working memory items were evident on the word level, and they increased with an increasing word set size (Experiment 2). In contrast, a surprisingly similar switch effect on the level of letters was not affected by word set size (Experiment 2). Experiment 3 showed that this effect is not simply based on the need for re-orienting visual spatial attention. To account for the overall picture of results, a recursive model of attentional foci is proposed. Moreover, individual working memory span appears to be associated with the accuracy of item switching, but not with its speed. PMID- 21287426 TI - The contribution of phonological short-term memory to artificial grammar learning. AB - Three experiments investigated the contribution of phonological short-term memory (STM) to grammar learning by manipulating rehearsal during study of an auditory artificial grammar made up from a vocabulary of spoken Mandarin syllables. Experiment 1 showed that concurrent, irrelevant articulation impaired grammar learning compared with a nonverbal control task. Experiment 2 replicated and extended this finding, showing that repeating the grammatical strings at study improved grammar learning compared with suppressing rehearsal or remaining silent during learning. Experiment 3 found no effects of rehearsal on grammar learning once participants had learned the component syllables. The findings suggest that phonological STM aids artificial grammar learning via effects on vocabulary learning. PMID- 21287427 TI - Observed reach trajectory influences executed reach kinematics in prehension. AB - Previous studies have demonstrated that the observation of action can modulate motor performance. This literature has focused on manipulating the observed goal of the action, rather than examining whether action observation effects could be elicited by changing observed kinematics alone. In the study presented here, observed reach trajectory kinematics unrelated to the goal of the action were manipulated in order to examine whether observed movement kinematics alone could influence the action of the observer. Participants observed an experimenter grasp a target object using either a normal or an exaggeratedly high reaching action (as though reaching over an invisible obstacle). When participants observed the experimenter perform actions with a high reach trajectory, their own movements took on aspects of the observed action, showing greater wrist height throughout their reaching trajectory than under conditions in which they observed normal reaching actions. The data are discussed in relation to previous findings which suggest that kinematic aspects of observed movements can prime action through kinematic or intention based matching processes. PMID- 21287428 TI - [Aspirations of medical students: "planning for a secure career" - results of an online-survey among students at five medical schools in Germany]. AB - BACKGROUND: In times of shortage of doctors, expectations and interests of the future generation of doctors towards their career aspiration is of major importance. The aim of this study was to analyze expectations of medical students at the five medical schools in the State of Baden-Wuerttemberg (Germany) concerning their career choice and factors influencing it. METHODS: Between January and February 2010, 1299 medical students (out of 12 062 medical students at the five medical schools) participated in an online-survey. In addition to sociodemographic items, career choice and aspects of planning reliability were raised. RESULTS: Three quarters of the students assign a medical profession for their future occupation. There is a dominance of internal medicine (n = 152), gynaecology (n = 127), paediatrics (n = 125), surgery (n = 115), anaesthesiology (n = 101), and family medicine (n = 88). The time point of decision varies between the different undergraduate years of medical school and specialty. Students at the beginning of their studies seem to be interested mostly in surgery. During medical school the interests towards internal medicine grows. Regarding planning dependability important aspects for medical students were to work in a job that has a future (61.2 % fully agree), to have a safe job (57.7 %), and to have a safe income (57.1 %). Less important seems to be to have good opportunity to earn money (29.6 %). CONCLUSIONS: Interest in a certain specialty changes markedly at during medical school. Factors such as economical guarantee, good future prospects and also the studies itself have an essential impact for students on choosing a specific career. Strategies to face physicians' shortage in different specialties need to be close to the needs and expectations of future physicians. This is not only valid for the undergraduate time period but also for the work circumstances of their future. PMID- 21287429 TI - [Dyspnea in a 45-year-old man with liver cirrhosis]. AB - HISTORY AND ADMISSION FINDINGS: During evaluation for a liver transplantation in a 45-year-old man with alcoholic liver he complained of exertional dyspnea. He had grade 3 chronic obstructive pulmonary disease (COPD) after nicotine abuse of 50 pack-years. One and a half years earlier the patient had been treated for tuberculosis. INVESTIGATIONS: The diagnostic procedures showed a respiratory insufficiency with a PO(2) of 52 mm Hg. Notable was a missing improvement of oxygenation after the supply of 100 % oxygen. Lung perfusion scintigraphy showed a shunt of about 14 %, a contrast-medium echocardiography demonstrating a right to-left shunt. These findings indicated that the patient had a hepatopulmonary syndrome. TREATMENT AND COURSE: The only causal therapy of a hepatopulmonary syndrome was a liver transplantation. However, the tuberculosis diagnosed one and a half years earlier had not been treated adequately, so that an antituberculotic therapy was essential before starting an immunosuppression. Therefore the only option of treatment was to continue the long-term oxygen therapy. As a matter of differential diagnosis and because of the intrapulmonary shunt, a pulmonary venous disconnection for a shunt caused by tuberculous cavities or by the COPD had to be taken into account. CONCLUSION: Treating patients with advanced liver cirrhosis and dyspnea a hepatopulmonary syndrome must be taken into consideration. Typically there will be found a right-left-shunt. In addition, coexistent comorbidities as a reason for dyspnea have to be excluded. PMID- 21287430 TI - [The ergometry stress test and its interpretation]. AB - Despite the rising challenge of new, specialized diagnostic methods such as stress-echocardiography and stress-MRI, ergometry is still one of the most commonly used basic examinations of patients with or suspected of heart disease. A careful selection of these patients and an accurate test protocol can improve the validity of outcomes in those patients with coronary heart disease and set the right directions for subsequent examinations of those with cardiac arrhythmia. In the past few years some global parameters different from classical changes of the ST-segment, including the course of blood pressure and rate during ergometry, have been gaining attention and have shown some value in determining prognosis. PMID- 21287431 TI - [Prospective observational studies of the development of type 1 diabetes during childhood and puberty]. AB - The incidence of type 1 diabetes is increasing rapidly. Detecting the mechanisms underlying the autoimmune disease is a main goal of research. Studies investigating the pathogenesis of type 1 diabetes are working on the identification and characterization of exogenous, endogenous and genetic factors which induce or modify autoimmunity. Islet cell autoimmunity can be detected through screening for islet cell autoantibodies. This quantitative analysis allows the stratification of the individual risk for the development of type 1 diabetes. Prospective observational studies are most suitable to assess persons at risk, either because of the occurrence of type 1 diabetes in the family or because of a genotype associated with increased risk. Age-related factors which are analysed in observational studies include nutrition, increase in height and weight, childhood diseases and vaccinations as well as psychosocial aspects. Identification and characterization of these risk factors will serve as a basis for working on new approaches to prevent or to cure type 1 diabetes. Aim of this article is to provide an overview of the most relevant observational studies. PMID- 21287432 TI - [Elastic compression stockings for prevention of deep vein thrombosis - is there any evidence?]. AB - Elastic compression stockings (ECS) as a physical tool for prevention of deep vein thrombosis were introduced in the 70 s and 80 s of the last century and they are still used today. Two recent studies have arisen a discussion regarding the benefit of the combined used of ECS and pharmaceutical prophylaxis over pharmaceutical prophylaxis alone. One study on patients receiving total hip replacement and one study on patients suffering from stroke did not show an advantage of the combination. In addition the German, the American and the British Guidelines do not give precise and mandatory indication for the use of ECS in addition to pharmaceutical prophylaxis. They describe the lack of adequate data and the problems in patient care using ECS. Thus, due to the lack of evidence and the possibility of adverse events a routine use of ECS is not justified. The only generally accepted indication for ECS is in patients with moderate and high risk for venous thromboembolism when pharmaceutical prophylaxis is not possible. PMID- 21287434 TI - [Reversal of oral anticoagulation in intracranial hemorrhage]. PMID- 21287435 TI - Phosphoproteomic identification of a PDX-1/14-3-3epsilon interaction in pancreatic beta cells. AB - Glucose-dependent activation of the homeodomain transcription factor PDX-1 leads to its phosphorylation, to an increase in DNA binding capacity, and to NLS dependent translocation into the nucleus. To uncover unknown mediators of PDX-1 activation, PDX-1 interacting proteins were analysed by pull-down from (32)P labelled, glucose-stimulated MIN6 cells. Recovered proteins were analysed by 2D gel electrophoresis and mass spectrometry. We identified 14-3-3epsilon as a novel PDX-1 binding protein and confirmed the interaction in vivo by Fluorescence Resonance Energy Transfer (FRET) analysis. We propose that 14-3-3epsilon interacts directly with PDX-1 to regulate its cellular distribution in pancreatic beta cells. PMID- 21287436 TI - Increased familial clustering of autoimmune thyroid diseases. AB - Data regarding familial prevalence and recurrence risk ratio of autoimmune thyroid diseases (AITD) in Germany are lacking. The data from 179 German families of AITD patients encompassing 1 229 relatives were collected using standardized clinical and laboratory diagnostic criteria. Of this large collective, 86 AITD index cases with their 139 children and 106 AITD index cases with their 157 siblings were included. The familial prevalence was estimated by the recurrence risk ratio. This quotient indicates whether first degree relatives display an increased risk for developing AITD, compared with the general population. AITD were present in 14% of children and 15% of siblings of patients with AITD. Female gender was frequently affected in both offspring (female:male ratio=3:1) and siblings (11:1). Daughters (19%) and sisters (24%) were more frequently affected than sons (7%) and brothers (3%). The risk for developing AITD was 16-fold and 15 fold increased in children and siblings, respectively, of patients with AITD. In particular, children and siblings of index cases with Hashimoto's thyroiditis had a 32-fold and 21-fold increased risk, respectively, for developing immunthyroiditis. In comparison, the risk for developing Graves' disease was enhanced 7-fold in both children and siblings. The high prevalence of AITD in first degree, foremost female, relatives of patients with AITD demonstrates the importance of family history for developing AITD. Hence, regular screening of children and siblings of patients with AITD for presence of immunethyroiditis is recommended. PMID- 21287437 TI - Periplogenin, isolated from Lagenaria siceraria, ameliorates L-T4-induced hyperthyroidism and associated cardiovascular problems. AB - The importance of glycoside in the regulation of thyroid dysfunction is not well understood. In the present investigation, effects of periplogenin-3- O-D glucopyranosyl (1->6)(1->4)-D-cymaropyranoside, isolated from the vegetable, LAGENARIA SICERARIA, in L-thyroxine (L-T4)-induced hyperthyroidism and in related cardiovascular abnormalities have been revealed in Wistar albino rats. L-T4 (500 MUg/kg, s. c./d) administration for 12 days significantly increased serum concentrations of thyroxine (T4), triidothyronine (T3), and hepatic 5'-deiodinase I (5'-DI) activity with a parallel increase in lipid peroxidation (LPO) in different organs such as heart, liver and kidney; serum glucose and insulin concentrations and a decrease in cardiac Na (+)-K (+)-ATPase activity as well as serum total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol and triglycerides. Most of these adverse effects were reversed following the administration of isolated periplogenin. However, out of its 3 different concentrations (5.0, 10, and 25 mg/kg), 5 mg/kg appeared to be the most effective one as it could nearly normalize the level of T3, glucose, insulin, Na (+)-K (+) ATPase activity, tissue LPO and different serum lipids suggesting the protective role of periplogenin against thyrotoxicosis and associated cardiovascular problems. It appears that the periplogenin actions are mediated through its direct antithyroidal and/or LPO inhibiting properties. PMID- 21287438 TI - [Irritable bowel syndrome: German consensus guidelines on definition, pathophysiology and management]. PMID- 21287439 TI - [Is there a need for intrapectoral injection in autologous fat transplantation to the breast? - An MRI volumetric study]. AB - INTRODUCTION: Autologous fat transplantation to the female breast is becoming generally accepted as a standard procedure in plastic surgery. Periglandular planes and also intrapectoral planes are used, based on the idea of having a highly vascularised matrix. To assess this surgical technique a reproducible and exact tool for volume analysis is necessary. METHODS: The volume of pectoral muscles and breast tissue including periglandular fat was analysed by MRI volumetry before and 6 months after autologous fat transplantation in 10 patients. The volume of the glandular tissue itself was also analysed to evaluate the effect of volume up-, and down-turns between the 6 months. RESULTS: A comparison of the volumes calculated with MRI volumetry preoperatively and postoperatively revealed a mean volume persistence of 64% (+/- 13%) within the pectoral muscle and of 81% (+/- 8%) within the periglandular fat. Glandular volume had a mean alternation of 7% (+/- 4%). In relation to the region of interest for breast volumetry the glandular tissue represented 15% (+/- 5%) preoperatively und 13% (+/- 4%) postoperatively. CONCLUSION: In autologous fat transplantation to the breast the periglandular plane is superior to the intramuscular plane in terms of volume persistence. As bolus injections of fat tissue must be strictly avoided, the pectoral muscles offer an additional receptor tissue for fat transplantation, and might be especially needed in smaller breasts to achieve the desired volume augmentation. The alternation of glandular tissue within the 2 points of time was low and in relation to the whole region of interest for breast volumetry rather inconsequential. Nevertheless consideration and subtraction of the glandular volume in mamma volumetry optimises the exactness of the volumetry. PMID- 21287440 TI - [Commentary to "update on tumour biology and treatment of merkel cell carcinoma"]. PMID- 21287441 TI - Ultraslim endoscope-assisted therapeutic ERCP for inaccessible papilla by a double-balloon enteroscope in patients with Roux-en-Y anastomosis. PMID- 21287442 TI - Recurrence after polypectomy for a pedunculated polyp with subtle invasion but no unfavorable histology. PMID- 21287443 TI - Asymptomatic duodenal perforation from obstructed and migrated biliary stent. PMID- 21287444 TI - ERCP for the treatment of traumatic biliobronchial and biliocutaneous fistulas. PMID- 21287445 TI - Endoscopic resection of an anal gland cyst. PMID- 21287446 TI - Endoscopic drainage of pancreatic fluid collections into fourth portion of duodenum: a new approach to disconnected pancreatic duct syndrome. PMID- 21287447 TI - Endoscopic sphincterotomy using a pull-type sphincterotome with an attached stabilizer in patients with Billroth II gastrectomy. PMID- 21287448 TI - Pneumomediastinum, pneumoperitoneum, pneumoretroperitoneum, and subcutaneous emphysema after ultrathin endoscopy. PMID- 21287449 TI - Successful treatment of cervical esophageal obstruction using combined antegrade and retrograde dilation with an endoscopic ultrasound needle and fully covered stent. PMID- 21287450 TI - Closure of a gastrotracheal fistula using a cardiac septal occluder device. PMID- 21287451 TI - Atypical clinical presentation of typical endoscopic finding of Bouveret's syndrome. PMID- 21287452 TI - Gastric rupture before puncture of the stomach in percutaneous gastrostomy. PMID- 21287453 TI - Colonic schistosomiasis mimicking submucosal tumor. PMID- 21287454 TI - Endoscopic stent treatment of a duodenal ulcer perforation. PMID- 21287455 TI - Pancreatic cystic lymphangioma in a 6-year-old girl, diagnosed by endoscopic ultrasound (EUS) fine needle aspiration. PMID- 21287456 TI - Endoscopic reduction of a jejunogastric intussusception. PMID- 21287457 TI - Result variation and efficiency kinetics in real-time PCR. AB - Fluorescent monitoring of DNA amplification is the basis of real-time PCR. Absolute quantification can be achieved using a standard curve method. The standard curve is constructed by amplifying known amounts of standards under identical conditions to that of the samples.The objective of the current study is to propose a mathematical model to assess the acceptability of PCR results. Four commercial standards for HCV-RNA (hepatitis C virus RNA) along with 6 patient samples were measured by real-time PCR, using two different RT-PCR reagents. The standard deviation of regression (Sy,x) was calculated for each group of standard and compared by F-Test. The efficiency kinetics was computed by logistic regression, c2 goodness of fit test was preformed to assess the appropriateness of the efficiency curves.Calculated efficiencies were not significantly different from the value predicted by logistic regression model. Reactions with more variation showed less stable efficiency curves, with wider range of amplification efficiencies.Amplification efficiency kinetics can be computed by fitting a logistic regression curve to the gathered fluorescent data of each reaction. This model can be employed to assess the acceptability of PCR results calculated by standard curve method. PMID- 21287458 TI - Anti-mutagenic and pro-apoptotic effects of apigenin on human chronic lymphocytic leukemia cells. AB - Diet can play a vital role in cancer prevention. Nowadays the scientists are looking for food materials which can potentially prevent the cancer occurrence. The purpose of this research is to examine anti-mutagenic and apoptotic effects of apigenin in human lymphoma cells. In present study human chronic lymphocytic leukemia (Eheb cell line) were cultured in RPMI 1640 (Sigma), supplemented with 10% fetal calf serum, penicillin-streptomycin, L-glutamine and incubated at 37 oC for 2 days. In addition cancer cell line was treated by and apigenin and cellular vital capacity was determined by MTT assay. Then effect of apigenin in human lymphoma B cells was examined by flow cytometry techniques. The apigenin was subsequently evaluated in terms of anti-mutagenic properties by a standard reverse mutation assay (Ames test). This was performed with histidine auxotroph strain of Salmonella typhimurium (TA100). Thus, it requires histidine from a foreign supply to ensure its growth. The aforementioned strain gives rise to reverted colonies when exposed to sodium azide as a carcinogen substance. During MTT assay, human chronic lymphocytic leukemia revealed to have a meaningful cell death when compared with controls (P<0.01) Apoptosis was induced suitably after 48 hours by flow cytometry assay. In Ames test apigenin prevented the reverted mutations and the hindrance percent of apigenin was 98.17%.These results have revealed apigenin induced apoptosis in human lymphoma B cells in vitro. PMID- 21287459 TI - Effects of alpha- tocopherol on the velocity of low density lipoprotein oxidation by cupric ions. AB - We studied the effect of different concentrations of alpha-tocopherol on in vitro cupric ions induced oxidation of low density lipoproteins (LDL). Human native LDL (50 ug protein/ml) oxidation was induced by 10 umol/L of CuSO4. Conjugated dienes were measured spectrophotometrically for up to 440 minutes. The length of the lag phase (Tlag), maximum velocity of the reaction (Vmax) and the maximum amount of generated dienes were obtained from kinetic data. Alpha-tocopherol increased Tlag and decreased Vmax with a dependence upon concentration (0-100 umol/L). There was no difference between the Dmax obtained with cupric ions alone or in the presence of the various concentrations of alpha-tocopherol. The results suggest that alpha tocopherol may decrease free radicals presence in LDL and thus decrease velocity of LDL oxidation by cupric ions. This mechanism may be a reason for alpha tocopherol effect in ameliorating atherosclerosis. PMID- 21287460 TI - The effect of topical nifedipine in treatment of chronic anal fissure. AB - Chronic anal fissure is the most common cause of anal pain associated with internal anal sphincter hypertonia. Reduction of hypertonocity is a special treatment for fissure healing. For this purpose chronic anal fissures were conventionally treated by anal dilatation or by lateral sphincterotomy. However, both of these methods may cause a degree of incontinence in some patients. The uptake of medical therapies that create a reversible chemical sphincterotomy has recently become widespread. The aim of this prospective clinical trial study was to assess the effectiveness of nifedipine in healing anal fissure, a calcium channel blocker that reduces sphincter pressure. A single-blind randomized comparative trial was setup to compare traditional treatment with stool softeners and 2% lidocaine cream against 0.5% nifedipine cream for 4 weeks. 110 patients were included in this study, 60 patients in the nifedipine group and 50 patients in the control group and the therapeutic outcome and side effects were recorded. Healing had occurred in 70% of patients in the nifedipine group and in 12% of patients in the control group after 4 weeks treatment (P < 0.005). Recurrence of symptoms occurred in four of healed patients in the nifedipine group and three patients in the control group in two months. The final result of nifedipine application after 12 months follow up was recurrence in 11 patients (26.19%). Mild headache occurred in four patients (6.6%) of the nifedipine group. Patients in the nifedipine group showed significant healing and relief from pain compared with patients in the control group. Recurrence rate with nifedipine use in spite of control of predisposing factors such as constipation was significant. Another finding was low complication rate with this treatment. PMID- 21287461 TI - Serum leptin concentrations during the menstrual cycle in Iranian healthy women. AB - Leptin, a circulating 16-kd polypeptide consisting of 167 amino acids, appears to be involved in the body weight homeostasis. Moreover leptin plays an important role for the reproductive system, early embryogenesis, and fat metabolism during pregnancy and puberty. Significant correlations have been found between leptin and sexual hormones, which is a cytokine and has hormonal properties. The aim of this study was to determine serum leptin levels during the menstrual cycle, and the association between serum leptin and reproductive hormones in young, healthy Iranian women. 42 healthy women volunteered for the study. They all had regular menstrual cycles, with cycle length varying between 26 and 32 days. None of them used oral contraceptives. All were of normal weight, with body mass index ( BMI) < 25 Kg/m2. Fasting blood samples were collected during the follicular phase, mid cycle and luteal phase of the menstrual cycle. FSH and LH were measured with coated tube immunoradiometric assay. Estrogen and progesterone were measured using antibody -coated tubes. Serum Leptin concentration were measured by Leptin (sandwich) ELISA. In menstruating women, serum leptin increased from 13.15+/-1.60 ng/ml in the early follicular phase to 16.57+/-1.68 ng/ml (P<0.01) at the luteal phase. Serum leptin concentration negatively correlated with LH and progesterone (P<0.05). Mean serum leptin levels correlated with body mass index (BMI) (r =0.78, P<0.001). PMID- 21287462 TI - Comparison of the frequency of old septal deviation in patients with and without traumatic nasal bone fracture. AB - Investigating the frequency of traumatic nasal bone fracture in patients with and without old septal deviation and possible deviation. Prospective study of 105 patients with nose trauma conducted and cases were divided into two groups: a study group 35 patients with nasal fracture and a control group of 70 patients without nasal fracture. Diagnosis of septal condition was made by anterior rhinos copy and endoscopy using manipulation of septum. 31 (89%) of the patients with nasal fracture after trauma were diagnosed with old septal deviation. In comparison, only 39 (34%) of patients in the control group were diagnosed with old septal deviation. In comparison, only 39 (54%) of patients in the control group were diagnosed with old septal deviation. Existing old septal deviation significantly increases the risk of traumatic nasal bone fracture. PMID- 21287463 TI - Epidemiology of traumatic spinal injury: a descriptive study. AB - Acute injuries of the spine and spinal cord are among the most causes of severe disability and death after trauma. Data about spine fracture with or without cord damage are different. The aim of this study was to determine epidemiology and demographics of spinal injury in main trauma center, Guilan, an Iranian province. The present study was a descriptive study of all cases of traumatic spine injury. Who were admitted to Poursina Hospital, main trauma center of Gilan. The scoring Systems used to evaluate severity of injury were American Spinal Injury association (ASIA) and The Injury Severity Score. Among a total of 245 cases, 71.8%were male and 28.2% were female. Male/Female ratio was 2.55:1. The most common age group at which spinal injury occurred in males was 25-44year-olds and in females was 45-64 year olds. The most common causes were motorcycle vehicle accidents and falls. The most common fracture in spine was thoracolumbar (T10 L2). Among forty four of patient with abnormal findings on neurological examination, fifteen of them had complete spinal cord injury (class A of ASIA) and twenty nine of them had incomplete spinal cord injury (class B, C, D, of ASIA). Our focus on the spinal injury and its major etiology revealed that efforts should be made to prevention. More detailed information about the causes of spinal injury should be sought as it might lead to more targeted intervention. PMID- 21287464 TI - Changing trend of empirical antibiotic regimen: experience of two studies at different periods in a neonatal intensive care unit in Tehran, Iran. AB - Bacterial sepsis is one of the most common causes of mortality and morbidity in neonates. It has been recognized a gradual change in spectrum of organisms responsible for neonatal sepsis. In this study we have evaluated changing trend of incidence and antibiotic susceptibility in neonatal late - onset sepsis (LOS) in 2-periods. This study is based on results of blood culture in neonatal late onset sepsis, in 2--periods study throughout 12 - years. Neonatal LOS was defined as clinical signs suggestive of infection with a positive blood culture (B/C) after 72 hrs of birth. During first study (period: 1990-1992), the most common bacteremia in LOS was staphylococcus aureus (staph aureus) (34%). Overall gram- negative bacteria (GNB) were the predominant organism (66%). It was shown that 60% of GNB were resisted to gentamicin and 3% to amikacin, while in case of gram positive bacteria (GPB); about 95% were resisted to ampicillin and 28% to cephalothin. In the second study (period: 2004-2007), the vast majority (56.6%) of septic cases were caused by GNB. The most common cause of late- onset sepsis was klebsiela p. (31%). The GPB were resistant to cephalothin (90%). There has been a dramatic increase resistance to cephalothin and aminoglycosides and 3rd generation cephalosporins. The combination of cephalothin plus amikacin in suspected LOS was no longer the effective therapeutic regimen in our neonatal intensive care unit (NICU). Now, it seems the best choice for empiric antibiotic regimen in suspected LOS is the combination vancomycin plus amikacin. Constant surveillance is important to guide empirical antibiotic therapy and changes in trends. PMID- 21287465 TI - Changes in growth pattern after adenotonsillectomy in children under 12 years old. AB - The aim of the present study was to determine the effects of adenotonsillectomy on height, weight and body mass index (BMI) in children under 12 years old, with or without airway obstruction and evaluation of the risk of overweight in them. In this case-control study, 120 children with the age of 2-12 years old were studied; 60 children as case group who underwent adenotonsillectomy and 60 healthy children as control group. After collecting the data related to appetite status and sleep breathing disorder of the case group, height, weight and BMI have been measured for all children in two stages; preoperatively and 6 months later. Also in the case group, BMI percentiles, pre and postoperatively have been calculated. Patients with Low appetite in the initiation and at the end of the study in the case group were 80% and 8.3% respectively (P=0.01). Mean of height, weight and BMI variation after 6 months were significantly different between case and control groups (P<0.05). BMI percentiles in the case group preoperatively were: 20% underweight, 67% healthy weight, 10% at risk of over weight, 3% over weight. Postoperatively, after 6 months BMI percentiles in order of above frequency were: 10%, 57%, 22% and 11% (P=0.02). Analysis of the results showed that adenotonsillectomy can lead to increase of height, weight, BMI and appetite not only in the children with low weight due to airway obstruction but also in the normal weight and over weight children. Therefore risk of overweight should be mentioned as a probable undesirable outcome of adenotonsillectomy. PMID- 21287466 TI - The incidence of nosocomial toxigenic clostridium difficile associated diarrhea in Tehran tertiary medical centers. AB - Clostridium difficile is the most common cause of nosocomial diarrhea. It is usually a consequence of antibiotic treatment, But sporadic cases can occur. This study was aimed to determine the frequency of the nosocomial Clostridium difficile (C. difficile) associated diarrhea in Tehran University of Medical Sciences hospitals and study of antibacterial susceptibility of isolates. In this study a total of 942 stool samples from patients with nosocomial diarrhea that were hospitalized in Imam Khomeini hospital, Shariati hospital and Children clinical center were collected. The samples were cultured on a selective cycloserine cefoxitin fructose agar (CCFA) and incubated in anaerobic conditions, at 37 degrees C for 5 days. Isolates were characterized to species level by conventional biochemical tests. Bacterial cytotoxicity was assayed on tissue culture (vero). Antimicrobial sensitivity of isolated toxigenic C. difficile were investigated by kirby Beuer method (disk diffusion). Our findings show that, of the total patients, 57 toxigenic C. difficile (6.1%) were isolated. Results of statistical analysis show significant differences between the rate of isolated toxigenic C. difficile and age group of patients (P<0.05). Among the wards of selected hospitals, in gastroenterology of Children clinical center, Toxigenic C. difficile was isolated from patients most frequently. The sensitivity of isolates to vancomycin, Chloramphenicol and ceftriaxone were higher than other antibiotics. Toxigenic C. difficile is a common hospital-acquired infection. The organism was found in 6.1% hospitalized patients. Further studies to evaluate the rate and role of toxigenic C. difficile in nosocomial diarrheal processes, ecological and pathogenic terms are suggested. PMID- 21287467 TI - The relationship of centralization, organizational culture and performance indexes in teaching hospitals affiliated to Tehran University of Medical Sciences. AB - One of the main problems in the efficiency and efficacy of an organization is its structural issue. Organizational culture is also considered as an effective factor in the performance of many organizations. The main goal of the present study was to determine the relationship of Centralization and organizational culture and performance indexes in Teaching Hospitals affiliated to Tehran University of Medical Sciences. This correlation study was performed in the year 2007. The population studied consisted of 4408 personnel from 13 hospitals among whom 441 subjects were selected and studied via a class sampling method. Data was compiled using a check list concerning the evaluation status of Centralization and another form concerning performance indexes as well as Robbin's organizational culture questionnaire. Data were obtained from the subjects by self answering and analyzed by using descriptive statistical indexes, T- test and Fisher's exact tests. Among the organizational culture indexes of the hospitals studied, control and organizational identity was better as compared to others (mean=3.32 and 3.30). Concerning the extent of Centralization in the hospitals studied, 53.85 % and 46.15 % were reported to have upper and lower organizational Centralization, respectively. Mean ratio of surgical operations to inpatients was 40%, the mean rate of admissions per active bed was 60.83, mean bed occupancy coefficient was 70.79%, average length of stay was 6.96 days, and mean net death rate was 1.41%. No significant correlation was seen between Centralization degree, organizational culture and performance indexes in teaching hospitals Tehran university of medical sciences. (with 95% confidence interval). Due to the fact that first grade Teaching hospitals use board certified members, expert personnel, and advanced equipments and because of the limitation of patients choice and, the extent of Centralization and many organizational culture components have no significant correlation with performance indexes of these hospitals. Further research regarding structure is suggested in the future. PMID- 21287468 TI - Teaching evidence-based medicine more effectively. AB - Evidence-based Medicine (EBM) is becoming an integral component of graduate medical education competency and a requirement for grad medical education practice-based learning core competency. This study tries to compare the efficacy of conferences utilizing small-group discussions with the traditional conference method in enhancing EBM competency. The participants in this randomized controlled trial (RCT) were 170 members of the medical faculty who were divided into two groups of 86 (intervention) and 84 (control). Following the intervention, EBM competency was assessed by a written examination. statistical analysis made use of chi-square test, independent sample t-test and relative risks for univariate analysis. Mantel-Hanszel was used for bivariate analysis. Cox proportional hazard models were used to evaluate multivariate-adjusted associations between EBM educational intervention and EBM knowledge, attitude and skills. A new indicator of number needed to intervention (NNI) was defined and computed. RESULTS: The results proved conference along with small-group discussion to be a more effective teaching method with P=0.001 on knowledge, P<0.001 for attitude and skills P<0.001 in an EBM exam when compared with medical faculty members who did not participate in EBM educational intervention (n=84). Moreover, they had also increased confidence with critical appraisal skills, and searching EBM resources. CONCLUSIONS: Conferences followed by small-group discussions significantly enhance EBM knowledge, attitude, critical appraisal skills and literature review skills. PMID- 21287469 TI - New procedure for treatment of atrial fibrillation in patients with valvular heart disease. AB - Patients with valvular heart disease suffer from atrial fibrillation for more than 12 months after valve surgery and have a low probability of remaining in sinus rhythm. We performed an intra-operative procedure similar to surgical maze III procedure for conversion of this arrhythmia to sinus rhythm. We did this study to evaluate the efficacy of this procedure to restore the sinus rhythm in patients with valvular heart disease. 28 patients with valvular heart disease and chronic persistent atrial fibrillation underwent different combinations of valve surgery and concomitant reduction of left and right atrial size and resection of both atrial auricles in Shahid Madani cardiothoracic center from September 2004 to October 2008. The procedure for atrial fibrillation treatment was performed with cardiopulmonary bypass and after mitral valve replacement. There was one in hospital death postoperatively because of respiratory failure, but no other complication till 6 months after the operation. Out of 28 patients, 23 were in sinus rhythm one week after the operation, one patient had junctional rhythm after the operation that restored to sinus rhythm and 4 patients had persistent atrial fibrillation. During the 12-month follow up, atrial fibrillation was corrected in 82.14%. Doppler echocardiography in these patients with sinus rhythm demonstrated good atrial contractility. This procedure on both atria is effective and less invasive than the original maze procedure to eliminate the atrial fibrillation, and can be performed in patients with valvular heart disease without increasing the risk of operation. PMID- 21287470 TI - The C60-fullerene porphyrin adducts for prevention of the doxorubicin-induced acute cardiotoxicity in rat myocardial cells. AB - This is a fullerene-based low toxic nanocationite designed for targeted delivery of the paramagnetic stable isotope of magnesium to the doxorubicin (DXR)-induced damaged heart muscle providing a prominent effect close to about 80% recovery of the tissue hypoxia symptoms in less than 24 hrs after a single injection (0.03 - 0.1 LD50). Magnesium magnetic isotope effect selectively stimulates the ATP formation in the oxygen-depleted cells due to a creatine kinase (CK) and mitochondrial respiratory chain-focusing "attack" of 25Mg2+ released by nanoparticles. These "smart nanoparticles" with membranotropic properties release the overactivating cations only in response to the intracellular acidosis. The resulting positive changes in the energy metabolism of heart cell may help to prevent local myocardial hypoxic (ischemic) disorders and, hence, to protect the heart muscle from a serious damage in a vast variety of the hypoxia-induced clinical situations including DXR side effects. PMID- 21287471 TI - Handlebar hernia: a rare type of abdominal wall hernia. AB - Traumatic abdominal wall hernias are a type of acquired hernia secondary to blunt trauma Caused, by direct trauma from handlebar like objects. This rare hernia is named 'Handlebar hernia'. We report a case of such hernia without any significant intra-abdominal injury. The abdominal wall defect was repaired in layers by Jones technique. Postoperative course was uneventful. The authors recommend clinical suspicion for traumatic hernia in all patients with traumatic abdominal wall injury. Definitive treatment includes surgical exploration with primary repair of all tissue layers of the abdominal wall. PMID- 21287472 TI - Large lipoma of the larynx: a case report. AB - Fewer than 15% of lipomas occur in the head and neck. Lipomas of the larynx are very rare benign laryngeal tumors (0.6%). To date less than 100 case of laryngeal lipoma have been reported in the literature.Clinical manifestation include progressive horseness, dyspnea, and even dysphagia. In the direct exam smooth or pedunculated mass is seen in the larynx and sometimes if tumor is large enough a mass palpated in the neck. In the computed tomography (CT) low attenuation mass is seen. Treatment of laryngeal lipoma consists of endoscopic removal or external surgical approach depending on tumor size. The authors present a case of laryngeal lipoma that involved the true vocal cord. The following is a report of a single case of laryngeal lipoma, Including esteroboscopy, radiologic and intraoperative finding as well as review of the literature. PMID- 21287473 TI - Appropriate iodine nutrition in Iran: 20 years of success. AB - Iodine is a trace element in the human body, its only known function is the synthesis of thyroid hormones. Effects of iodine deficiency, termed iodine deficiency disorders (IDD), include endemic goiter, hypothyroidism, cretinism, decreased fertility rate, increased infant mortality and mental retardation. 2.2 billion people worldwide are at risk for IDD. Of these, 30-70% have goiter and 1 10% have cretinism. Two decades ago the I.R. Iran was among the countries most severely affected by iodine deficiency, but during the last two decades has made much progress in the development of universal salt iodization strategies and IDD prevention, and since 1996 meets all WHO/UNICEF/ICCIDD criteria for the sustainable elimination of iodine deficiency. PMID- 21287474 TI - Comparative assay of glutathione S-transferase (GSTs) activity of excretory secretory materials and somatic extract of Fasciola spp parasites. AB - Fascioliasis is a worldwide parasitic disease in human and domestic animals. The causative agents of fascioliasis are Fasciola hepatica and Fasciola gigantica. In the recent years, fasciola resistance to drugs has been reported in the many of publications. Fasciola spp has detoxification system including GST enzyme which may be responsible for its resistance. Therefore , the aim of the study was to assay of GST enzyme activity in fasciola parasites. Fasciola gigantica and Fasciola hepatica helminths were collected from abattoir as a live and cultured in buffer media for 4 h at 37 degrees C. Excretory-Secretory products were collected and stored in -80?C. F. gigantica and Fasciola hepatica were homogenized with homogenizing buffer in a glass homogenizer to prepare of somatic extract. Suspension was then centrifuged and supernatant was stored at -80 degrees C. In order to assay the enzyme activity, excretory-secretory and somatic extracts in the form of cocktails (potassium phosphate buffer, reduced glutathione and 1-chloro-2,4-dinitrobenzene substrates) were prepared and their absorbance recorded for 5 minutes at 340 nm. The total and specific GST activity of F. gigantica somatic and ES products were obtained as 2916.00, 272.01 micromole/minute and 1.33, 1.70 micromole/minute/mg protein, respectively. Fasciola hepatica also showed 2705.00, 276.86 micromole/minute and 1.33, 1.52 micromole/minute/mg protein, respectively. These results are important for analysis of parasite survival / resistance to drugs which use for treatment of fascioliasis. PMID- 21287475 TI - A survey of relationship between rheumatoid arthritis and hearing disorders. AB - RA (rheumatoid arthritis) is a chronic multisystem disease with a variety of systemic manifestations. One of these manifestations, is hearing disorder, so study of the relation between RA and hearing disorders is seem important. This was a case-control study which has done from December 2004 to August 2006. This study compared 50 patients with RA, with age, sex and job-matched as control. Audiometric tests in different frequencies show that hearing threshold in high frequencies specially in 8000 Hz had a significant difference between two groups, also acoustic reflexes were absent in case groups and had significant difference between two groups too. The evaluation of sensory neural hearing loss showed that this hearing loss is sensory not neural. Based on this study, frequent evaluation of audiometric tests is recommended for controlling hearing disorders by therapeutic and rehabilitation procedures in RA patients. PMID- 21287476 TI - Energy and protein intake and its relationship with pulmonary function in chronic obstructive pulmonary disease (COPD) patients. AB - Chronic Obstructive Pulmonary Disease (COPD) is a public health problem worldwide. Increased energy and protein needs, decreased energy and protein intake are common in COPD patients. Adequate intake is essential to improve pulmonary function and immune system, prevention of weight loss and maintaining muscle mass and strength. Assessment of energy and protein intake and its relationship with pulmonary function in COPD patients was performed in this study. The study group included 63 COPD patients. For all subjects, evaluation of energy and protein intake by Food Frequency Questionnaire (FFQ) and 24-hour recall, spirometry for measuring pulmonary function and determining disease severity were performed. The subjects were divided into three groups based on disease severity according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages. Relationship between energy and protein intake with pulmonary function was assessed. Energy and protein intake were lower than the calculated energy and protein demand for all groups. Significant relationship was found between the amount of protein intake extrapolated from food frequency questionnaire with Forced Vital Capacity (FVC) (r=0.2, P=0.02) and Vital Capacity (VC) (r=0.3, P=0.008). The results of the study suggest that accurate evaluation of protein and energy intake and requirements should be included in the goals of medical treatment of COPD patients. PMID- 21287477 TI - Analgesic effects of intrathecal sufentanil added to lidocaine 5% in elective cesarean section. AB - The quality of subarachnoid block can be improved by adding opioids to the local anesthetics. We compared the analgesic effects of different doses of intrathecal sufentanil added to lidocaine %5 for elective cesarean section. This study was a prospective, randomized, double-blind, controlled trial. 90 pregnant women with ASA class I-II, scheduled for elective cesarean section under spinal anesthesia were enrolled in this study. Three groups were made of them by random; Group 1 (control group) was given lidocaine 5% (75 mg) and 2 ml of normal saline. Patients in Group 2 received lidocaine 5% (75 mg) and 5 micrograms sufentanil plus 1ml normal saline. Group 3 patients received lidocaine 5% (75 mg) and 10 micrograms sufentanil. Duration of sensory block and effective analgesia (need to analgesic) were measured. Opioid related side effects were recorded. Duration of sensory block and effective analgesia were prolonged in sufentanil groups in comparison of control group(50.3+/-4) that was significantly more in group 3 (128 +/- 4) versus group 2 (58.3 +/- 10)(P < 0.001) . There was mild to moderate respiratory depression in sufentanil groups which was more noted in group 3 (p < 0.001). No differences were detected in other side effects such as hypotension, nausea & vomiting. The addition of sufentanil 10 versus 5 micrograms to lidocaine 5% provided more duration of analgesia for cesarean delivery. So, the adding of 10 micrograms sufentanil to lidocaine 5% for cesarean section has more effective analgesia with minimum side effects. PMID- 21287478 TI - Incidence of fever and bacteriemia following flexible fiberoptic bronchoscopy: a prospective study. AB - The latest American Heart Association (AHA) statement for preventing infectious endocarditis, has not recommended prophylactic antibiotic therapy prior to fiberoptic bronchoscopy (FB) except for patients with preexisting predisposing cardiac conditions. Our aim was to determine the incidence of bacteriemia and fever following FB in our experience and compare with those which have been mentioned in AHA guideline as well as other studies. Venous blood of 85 consecutive patients was evaluated for both aerobic and anaerobic cultures before (for detecting possible previous bacteriemia) and after FB. None of the patients were treated with antibiotics prior to the procedure. All the patients were examined during the first 24 hours after FB for detecting fever defined as temperature more than 38 degrees C. Positive hemocultures were noted in 7 (8.2 %) patients after FB examination. Coagulase negative Staphylococcus, coagulase positive Staphylococcus, beta haemolytic Streptococcus, Citrobacter freundii and Streptococcus viridans were found in 4, 1, 1 and 1 cultures of patients, respectively. By excluding 6 contaminated samples, the rate of bacteriemia reduced to 1 (1.1%) patient in whom the identical pathogen (Streptococcus viridans) was found both in bronchial lavage and venous blood culture. We also found fever in 9 (10.5 %) cases in the first 24 hours following the bronchoscopy. Our results were in consistent with AHA recommendations regarding prevention of infectious endocarditis as a practical gridline in patients who schedule for FB. Besides, transient fever following bronchoscopy is a common self-limited event which does not need medical intervention. PMID- 21287479 TI - Comparison between Ultroid and rubber band ligation in treatment of internal hemorrhoids. AB - Hemorrhoid is one of the most common surgical diseases and different methods are available for its treatment. This study is a comparison between two methods of treatment of internal hemorrhoid, Monopolar low voltage instrument (Ultroid) and Rubber Band Ligation. This method has been carried out prospectively in which 50 patients who were treated with rubber band ligation and 50 patients with Ultroid were compared according to the incidence of complications, post-operative pain and treatment response. According to this study complete success rate with Ultroid was 82% and partial success rate was 10% and no response to treatment was seen in 8%. In Rubber Band method the complete response rate was 94% (P=0.2). With Ultroid, 74% of patient reported no postoperative pain, 24% reported mild and moderate pain and 2% of patients complained of severe pain. With Rubber band ligation, 72% of patients reported no post-operative pain, 26% reported mild and moderate pain and 1% complained of severe pain (P=0.00). Rubber Band ligation and Ultroid are both considered as outpatient procedures for treatment of hemorrhoids. Both methods are mostly used for grade 1, 2 and sometime grade 3 hemorrhoids. In Ultroid method the operator is required to hold the probe for a period of time, and in most cases, the surgeon should spend between 20-25 minutes for the coagulation of three piles. Some surgeons do not have patience for this modality of internal hemorrhoid treatment. In this study we achieved acceptable results comparable with those of other techniques. PMID- 21287480 TI - Prevalence and factors associated with HCV (hepatitis C virus) seropositivity in Islamabad, Pakistan. AB - An estimated 150-200 million people worldwide are infected with hepatitis C. Prevalence is higher in some countries in Asia and Africa. Only limited information about the epidemiology of Hepatitis C Virus (HCV) infection especially in females is available. The aim of this study is to determine the prevalence of anti-HCV antibodies and the possible factors for transmission in the female population of a largely urban city Islamabad. A cross sectional study was conducted from May 2006 to August 2006 in Islamabad. We select 252 female households (n=252) following the selection criteria. The primary outcome variables were HCV seropositivity and factors like history of major surgical procedure, blood transfusion, Intravenous drug use etc. The results showed mean age of the sample was 33.21 (+/-9.95) years and HCV seropositivity was present in 62 (24.6%) females. Final Forward Stepwise multiple logistic regression showed blood transfusion [OR, 10.094 95% CI 1.950-52.257], dental procedure [OR, 5.381 95% CI 2.315-12.507] and dilation and curettage [OR, 3.869 95% 1.867-8.015] were significantly associated with HCV seropositivity in females. The study highlights poor quality of care provided and a massive need to educate general population including patients as well as health professionals and allied health workers. PMID- 21287481 TI - Severe neonatal hyperbilirubinemia; causes and contributing factors leading to exchange transfusion at Ghaem Hospital in Mashhad. AB - Hyperbilirubinemia is common in neonates; it can have a serious rising course. Due to its critical morbidity called "kernicterus", severe neonatal hyperbilirubinemia causes which lead to exchange transfusion, should be clarified. This descriptive cross sectional study performed with reviewing of files of 118 neonates weighting 2kg and more who had exchange transfusion in pediatrics ward at Ghaem training hospital in Mashhad from April 2004 to March 2007. Among 118 patients, 75 (63.6%) were male, and 43 patients (36.4%) were female. The most common cause of exchange transfusion was ABO incompatibility (38.1%). In order of frequency, unknown etiology (25.4%), Rh incompatibility (16.1%) with no immune hydrops, Sepsis(8.5%), urinary tract infection (5.1%) and others (3.4%) (Including Crigler-Najjar and cephalohematoma) were next ones. Vaginal delivery and exclusive breast feeding were detected as associated factors. Mean serum bilirubin levels was 28.7 mg/dl (SD. 9.2) ABO incompatibility. ABO incompatibility was the main cause of exchange transfusion. Male gender, vaginal delivery and exclusive breast feeding were seen more among patients who need to be exchanged. So in case of ABO incompatibility especially when delivery route is vaginal, newborns should be visited soon again after early discharge from hospital. PMID- 21287482 TI - Seroprevalence of cytomegalovirus in patients with and without coronary artery diseases at Madani Heart Center, Iran. AB - Inflammation plays a major role in coronary artery disease (CAD). Currently, it is unclear, whether Cytomegalovirus (CMV) infection is associated with the risk of the atherosclerosis. The aim of this study was to determine the prevalence of anti- CMV antibodies in CAD and non CAD patients undergoing artery bypass surgery. Sera from 157 patients who underwent coronary angiography were tested for CMV by enzyme linked immunosorbent assay (ELISA) at Madani Heart Hospital, Tabriz University of Medical Sciences, Iran. Our study population was 58.6% male and 41.4% female, with an age range of 38 to 86 years. The prevalence of CMV positivity tended to be higher in coronary artery diseases patients than in those without non coronary artery diseases (83.2% versus 63.6%) (P= 0.01). This analysis demonstrated that CMV seropositivity may be a risk factor for CAD in the present study population. PMID- 21287483 TI - Misunderstanding prescription physician's oral instructions in patients with low back pain. AB - Medication errors and adverse drug events can bring about hospitalization, permanent injury, or death. Patients due to lack of adequate understanding of instruction may unintentionally misuse a prescribed medicine. The aims of the study were to examine whether patients with low back pain were correctly able to understand physician's instructions regarding drug use and also to identify influencing factors in patient's misunderstanding. The sample of the study included patients with low back pain who had been referred to five clinics in order to follow their treatment procedure. The patients completed a questionnaire to assess understanding of physician's instructions by the patients. Afterwards, physician provided them oral instructions on how they must use medications. Once the physician finished the oral instruction, he was asked patients to repeat whatever he said about the instructions. This procedure repeated frequently until the patients described correctly Instructions of the medications use. One hundred and five patients participated in the study. The mean age of the participants was 57.5 (+/- 13.9) years. Thirty three patients were female (31.4%) and 75.2 percent were married. Almost 80% of the patients misunderstood the oral prescription instructions at first time of presentation instruction. Gender, educational level, back pain history and drug use history were risk factors for misunderstanding prescription medication oral instructions for patients. The study affirmed that patients with low back pain suffered from a poor understanding of oral instruction. PMID- 21287484 TI - A well-known lesion in an unusual location: infantile myofibroma of the eyelid: a case report and review of literature. AB - Myofibroma is a neoplasia of myofibroblasts that can be solitary or multiple and it is found most commonly in the head & neck region including scalp, forehead, parotid region and oral cavity. In the eyelid it is rarely reported. It has a benign course in the solitary form and fatal in its multiple form. A 4 month male infant referred to Farabi hospital -the referral center for eye diseases- with a 2 month history of a mass in his eyelid with gradual enlargement with no other complaints. The only abnormal physical finding was a 2.5 cm mass in the eyelid. This mass was excised and sent to the hospital pathology laboratory. When confronting a spindle cell lesion with a nodular or multinodular growth pattern which appears biphasic due to alteration of light and dark staining areas, the surgical pathologist should think to the possibility of myofibroma. Its pattern of growth and architecture rules out the other differential diagnoses like nodular fasciitis, fibrous histiocytoma, infantile fibromatosis, and peripheral primitive neuroectodermal tumor, mesenchymal chondrosarcoma, malignant hemangiopericytoma, juvenile fibrosarcoma and poorly differentiated synovial sarcoma. In difficult cases immunohistochemical staining is helpful that is Vimentin & Actin positivity & Desmin, CK, EMA & S100 negativity. PMID- 21287485 TI - Cervical transverse myelitis after chickenpox in an immunocompetent patient. AB - Varicella-zoster viruses complications involving the CNS are estimated to occur rarely, transverse myelitis after Varicella-zoster virus in most patients is characterized by an abrupt onset of progressive weakness and sensory disturbance in the lower extremities , like other viruses. We describe the case of 17 year old boy who experienced cervical transverse myelitis after chickenpox with inability to walk and with urinary retention. He was not treated with any medication but complete recovery has been occurred. PMID- 21287486 TI - Ruptured giant hepatic hemangioma: report of a case. AB - Hemangiomas are the most common benign liver masses with a frequency of 0.4-7.3% at autopsy. They are usually discovered incidentally and a few require surgery. Spontaneous or traumatic ruptures are among indications of surgery for hemangiomas. We report a case of giant hepatic hemangioma presenting as hemoperitoneum following use of the slimming belt that underwent an emergent laparotomy. Abdominal exploration revealed that both right and left lobes of the liver were involved with giant hemangiomas. The liver was compressed by tightly packing laparotomy pads. After the operation, the patient was admitted to the surgical intensive care unit. Two days later, a second surgery was performed to remove the laparotomy pads. On the 6th day, the patient was discharged. One month later, to shrink the tumor, percutaneous transarterial embolization of the hepatic artery was performed. PMID- 21287487 TI - [Neurovascular discrimination: now the problem might be us]. PMID- 21287488 TI - [Personality factors, degree of disability and therapeutic management of patients with migraine visiting a neurology unit for the first time (Psicomig study)]. AB - INTRODUCTION: Migraine has recently been associated to certain personality profiles and styles of coping. AIM: To explore the association between personality factors, disability and the therapeutic management of migraine. PATIENTS AND METHODS: We conducted an epidemiological, cross-sectional, multi centre study with patients with migraine visiting a neurology unit for the first time. Socio-demographic and clinical data were collected about the patients. The NEO-FFI (Neuroticism-Extraversion-Openness Five-Factor Inventory) was used to evaluate personality factors; the degree of disability was evaluated using the Headache Impact Test (HIT-6) and the number of lost workday equivalents (LWDE) was measured. Bivariate logistic regression analyses were also performed. RESULTS: A total of 736 patients were recruited, of whom 700 were suitable for inclusion in the analysis (75.6% females; mean age: 35.5 +/- 11.5 years). In all, 68.9% presented migraine without aura, 1-4 seizures/month (66.7%) and of moderate intensity (58.1%). A total of 76.1% of patients had severe disability according to the HIT-6. Of the 554 active patients, the mean number of lost workday equivalents in the previous three months was 6.8 +/- 8.2. Patients showed greater emotional instability than the general population and they scored lower on extraversion, openness, agreeableness and conscientiousness. All the patients were being treated for their migraine: 47.3% by means of stepped treatment between seizures; 39.9% intra-seizures, and stratified in only 12.9%. CONCLUSIONS: This study confirms the impact of migraine in terms of disability and in terms of loss of labour output, together with its association with personality factors. PMID- 21287489 TI - [Overall quality of life in persons with dementia]. AB - AIM: To assess overall quality of life (QoL) among persons with dementia and to investigate variables associated with subjective perception of QoL. PATIENTS AND METHODS: This was a cross-sectional study in six health and social care centres in Barcelona and Tarragona. Ninety nine persons with mild-moderate dementia, living at home with a known caregiver completed a face-to-face interview including sociodemographic information; health perception, a list of chronic medical conditions, depressive symptoms and activities of daily living. Overall QoL was measured with the single item of the World Health Organization Quality of Life-BREF. RESULTS: 40.6% assessed their overall QoL as very good/good. Univariate logistic regression analyses showed a lack of association between QoL with sociodemographic information, severity of dementia and functioning, but significant association between QoL with depressive symptoms, satisfaction with relationships, enjoying life and meaning in life. Ordinal and binary multivariate regression analysis showed that better perception of health and greater satisfaction with personal relationships was associated with better QoL. In addition, fewer depressive symptoms in the ordinal multivariate regression analysis and dementia severity and enjoy life in the binary regression analysis appeared significant. CONCLUSIONS: Persons with mild-moderate dementia can inform about their overall QoL and subjective states. In addition to health status, other dimensions, as personal relationships and positive aspects should be systematically assessed in this population. PMID- 21287490 TI - [Ageing and working memory: the role of complexity and the type of information]. AB - INTRODUCTION: Although there is agreement that working memory in older adults diminished with age, there is still controversy whether this reduction occurs equally for all kind of information or it is more pronounced for a particular type of information. AIM: To compare verbal working memory with visual and spatial working memory in young and older adults. These comparisons were examined at two levels of complexity. SUBJECTS AND METHODS: Two experiments were conducted, in one of them subjects performed the verbal and visual tasks, and in the other the verbal and spatial tasks. Forty-two subjects participated in each experiment: 21 young adults and 21 older adults. The n-back task (1-back and 2 back) was used with letters, abstract figures and circles at different positions to evaluate verbal, visual and spatial working memory, respectively. RESULTS: Older adults performed lower than young adults in the visual and spatial high difficult tasks. Working memory efficiency in the verbal task was equivalent in both groups, independently of the level of complexity; however, older adults' accuracy was lower in high complexity verbal task relative to the low complexity task. CONCLUSIONS: The findings suggest that working memory deficits during aging do not depend on the type of information but on the amount of resources from the memory system that each type of information requires to be processed. PMID- 21287491 TI - [Clinical variability in neuromyelitis optica: three case reports]. AB - INTRODUCTION: Three cases of neuromyelitis optica (NMO) admitted in our hospital with a heterogeneous clinical characteristics are presented. CASE REPORTS: Case 1: a middle-aged woman with five acute transverse myelitis episodes and a high latency of the P100 in the visual evoked potentials. The MRI and the NMO antibodies were both negatives. Case 2: a young lady with a two months duration episode of optic neuritis in one eye first, and both myelitis and optic neuritis on the other eye burst secondly, with a very good evolution and positive NMO antibodies. Case 3: a 72 years-old woman with three episodes of acute transverse myelitis. After three years she had two more acute myelitis bursts and finally one optic neuritis, with no lesions in the brain MRI and negative NMO antibodies. CONCLUSIONS: The concept of the NMO has changed from its original description. Today it is conceived as a clinical spectrum by a well definite diagnostic criteria, but very heterogeneous as for the clinical characteristics, the outbreak age, or the response to the treatment, since it remains reflected in this three cases. PMID- 21287492 TI - [Lacosamide: a new generation in the treatment of epilepsy]. AB - Despite the large number of antiepileptic drugs (AED) available today, more than 30% of patients with epilepsy do not manage to achieve adequate control over their seizures. For patients, the administration of the latest AED can be a good alternative, prior to surgery or when there are contraindications against it. Third generation AED offer different mechanisms of action and tolerability profiles that are more favourable than those of the first and second generations. Lacosamide has recently been approved by the European Medicines Agency (EMEA) and its United States counterpart (FDA) as an adjuctive AED in partial onset seizures in adults over the age of 16, thus making it a novel option in the treatment of epilepsy. PMID- 21287493 TI - [Cognitive remediation in addictions treatment]. AB - More recent theories of addiction suggest that neurocognitive mechanisms, such as attentional processing, cognitive control, and reward processing play a key role in the development or maintenance of addiction. Ultimately, the addiction (with or without substances) is based on the alteration of brain decision-making processes. The neurosciences, particularly those responsible for behavior modification, must take into account the neurobiological processes underlying the observable behavior. Treatments of addiction usually do not take into account these findings, which may be at the base of the low retention rates and high dropout rates of addicted patients. Considered as an alteration of brain functioning, addiction could be addressed successfully through cognitive rehabilitation treatments used in other clinical pathologies such as brain damage or schizophrenia. Although there are few studies, it is suggest that intervention to improve patients' cognitive functioning can improve the efficiency of well established cognitive-behavioral therapies, such as relapse prevention. This paper reviews the available evidence on cognitive rehabilitation in treating addiction as well as in other pathologies, in order to formulate interventions that may be included in comprehensive rehabilitation programs for people with addictive disorders. PMID- 21287494 TI - [Cys-loop ligand-gated ion channels modulation by protein kinases A and C]. AB - INTRODUCTION: In the nervous system, rapid chemical neurotransmission is mediated by ionotropic receptors that are activated by ligand binding. Ligand binding to its receptor promotes the selective flow of ions into the cell which changes the electrical potential of the cell membrane. Cys-loop type receptors belong to the ligand-gated ion channel superfamily including the nicotinic acetylcholine receptor, the gamma-aminobutyric acid, glycine, serotonin and zinc. Several studies showed that the activity of these receptors was modified in response to protein kinases A and C activation; the different results, apparently contradictory, could be explained by the involvement of several factors such as the type of subunits that make up these receptors, components of the cytoskeleton and sub-types of kinases and phosphatases present in nerve tissue studied. AIM: To review the effect of protein kinases A and C on the activity of cys-loop receptors. DEVELOPMENT: In this review we describe experiments conducted in different regions where it was determined the effect of these kinases on the function of neurotransmitter receptors mostly distributed in the nervous system. CONCLUSIONS: The cys-loop receptors regulation by protein kinases occurs through the activation of other receptors (cross-talk) that are expressed at different stages of development and nervous system areas. PMID- 21287496 TI - [Focal hyperperfusion associated to ictal periodic lateralised epileptiform discharges]. PMID- 21287497 TI - [Deletion of the LIS1, ASPA, TRPV1 and CAMTA2 genes in region 17p13.3 in a patient with Miller-Dieker syndrome]. PMID- 21287499 TI - [Prenatal diagnosis of oculocutaneous albinism type IV and discovery of a novel mutation]. AB - OBJECTIVE: To provide guidance for clinical genetic counseling and prenatal diagnosis of oculocutaneous albinism (OCA) in China. METHODS: PCR and automatic DNA sequencing were applied to obtain the genotypes of the patients and their parents in three Chinese albinism families. Prenatal gene diagnoses were performed at early pregnancy by chorionic villus sampling (CVS) or by amniocentesis at mid-pregnancy. RESULTS: The three patients were all OCA4, whose genotypes were G349R/c.870delC, G349R/P419L and G349R/D160H, respectively. The three couples had been diagnosed as carriers. In family 1, the first fetus was diagnosed as affected. Termination of pregnancy was opted following genetic counseling. The second fetus (monozygotic twin) was heterozygous only with the paternal G349R mutation. The fetus in family 2 did not get either one of the two mutations. The fetus in family 3 was heterozygous only with the paternal G349R mutation. CONCLUSION: This study detected three reported pathogenic mutations of the membrane associated transporter protein gene (MATP), including G349R, D160H and P419L, and identified a novel pathogenic mutation c.870delC. The prenatal gene diagnosis of OCA4 will be important to prevent the birth of affected child. PMID- 21287500 TI - [Keratin 17 mutation in pachyonychia congenita type 2 in a Chinese Han family]. AB - OBJECTIVE: To investigate the keratin 17 gene (KRT17) mutation in a pedigree with pachyonychia congenita type 2 (PC-II). METHODS: DNA was extracted from the blood samples of the patients, unaffected members of the pedigree, and 100 unrelated healthy controls. PCR was performed to amplify the hot spots in KRT17 gene. PCR products were directly sequenced to detect mutation. RESULTS: A heterozygous 296T ->C mutation was found in all the affected members of this family, which resulted in the substitution of leucine by proline in codon 99 (L99P) in the 1A domain of the KRT17, but not in the healthy individuals from the family and the 100 unrelated controls. CONCLUSION: The mutation of KRT17 may play a major role in the pathogenesis of this pedigree with pachyonychia congenita type 2. PMID- 21287501 TI - [An inherited coagulation factor VII deficiency pedigree caused by homozygous mutation of His348Gln]. AB - OBJECTIVE: To investigate the gene mutation and the molecular pathogenesis of an inherited coagulation factor VII (F VII) deficiency pedigree with consanguineous marriage. METHODS: The diagnosis was validated by coagulant parameter assay on the prothrombin time (PT), activated partial thromboplastin time, fibrinogen and coagulation factor activity. F VII gene mutations were analyzed in the proband and other family members by direct DNA sequencing of the PCR products of all exons, exon-intron boundaries and 5'and 3' untranslated sequences. The mutations were confirmed by reverse sequencing. RESULTS: The values of PT and F VII activity in the proband were significantly abnormal, they were 30.9 s and 3% respectively. The PT of her daughter, father and mother was slightly extended to 21.2 s, 16.3 s and 16.1 s respectively, and the F VII activity was reduced to 22%, 25% and 35% respectively. The coagulant parameters of her younger brother were within normal range. Homozygous T-->G transition at position 11482 in exon 8 was identified in the proband resulting in His348Gln, and heterozygosity for His348Gln was confirmed in her daughter and her parents, and the normal wild-type was observed in her younger brother. CONCLUSION: Homozygous missense mutation of His348Gln was found in a pedigree of hereditary F VII deficiency. The mutation was inherited from her heterozygote parents. PMID- 21287502 TI - [Mutational analysis of CHRNB2 and CHRNA2 genes in southern Chinese population with autosomal dominant nocturnal frontal lobe epilepsy]. AB - OBJECTIVE: To investigate the gene mutations of CHRNB2 and CHRNA2 in Chinese population with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). METHODS: One hundred and six Han nationality patients (74 sporadic and 32 familial) were recruited and studied. Mutational screening was performed by sequencing all the 6 coding exons of the CHRNB2 gene and exons 6 and 7 of the CHRNA2 gene including the donor and acceptor splice sites. RESULTS: The results excluded the involvement of all known published mutations of the CHRNB2 and CHRNA2 genes. However, a novel synonymous mutation c.483C>T (H161H) and a single nucleotide polymorphism (c.1407C>G) of CHRNB2 gene were detected in two ADNFLE sporadic patients respectively. The nucleotide variation H161H was heterozygous and absent in 200 healthy control samples. The mutation was also found in the proband's unaffected mother. CONCLUSION: Our study suggests that the mutations of CHRNB2 and CHRNA2 genes may be rare in Chinese ADNFLE population. The novel synonymous mutation of H161H has not been reported previously and its impact on the pathogenesis of ADNFLE needs to be further studied. PMID- 21287503 TI - [Improvement and application of DXS52(St14) in gene diagnosis of hemophilia A]. AB - OBJECTIVE: To improve the experimental method of DXS52 (St14) and apply it to genetic testing for hemophilia A (HA). METHODS: PCR of DXS52 and agarose gel electrophoresis were performed for genetic testing in 61 non-inversion HA families. Linkage analysis of 7 loci within the FVIII gene including Bcl I, Hind III, Xba I, STR1, STR13, STR22 and STR24 were also carried out for the 61 families. RESULTS: DXS52 can provide information in 43 out of 61 families and the diagnostic rate was 70.5%. Eight families can be diagnosed only by DXS52 locus, accounting for 13.1%. Two families were found to have recombination between DXS52 and FVIII. CONCLUSION: The new experimental conditions can reach accurate and clear results in DXS52 genetic testing. This gene maker has high diagnostic rate, so it is an indispensable linkage analysis method in HA gene diagnosis. More caution should be paid when using the extragenic locus DXS52 to perform gene diagnosis because of its high recombinant rate with FVIII. PMID- 21287504 TI - [Relationship between promoter methylation of p16, DAPK and RAR beta genes and the clinical data of non-small cell lung cancer]. AB - OBJECTIVE: To investigate the effects of promoter methylation of p16, death associated protein kinase (DAPK) and retinoic acid receptor-beta (RAR beta) genes on clinical data in non-small cell lung cancers, and to study the effect of smoking on the risk of gene methylation. METHODS: The promoter methylation of p16, DAPK and RAR beta genes in 200 primary non-small cell lung cancers and the corresponding nonmalignant lung tissues were determined by methylation-specific PCR. RESULTS: Methylation in the tumor tissues was detected in 51.0% for p16, 60.0% for DAPK, and 58.0% for RAR beta gene, with significant differences (P < 0.05) when compared with those in the corresponding nonmalignant tissues(12.5%, 11.5% and 15.0%) respectively. p16 gene methylation in tumor tissue was associated with age significantly in unconditional logistic regression analysis (P < 0.01) and histologic type (P < 0.05). DAPK gene methylation in tumor tissue was associated significantly with age (P < 0.05), gender (P < 0.05) and clinical type (P < 0.05). RAR beta gene methylation in tumor tissue was associated with clinical type (P < 0.05) and tumor stage (P < 0.05) significantly. The interaction odds ratio (OR) for the gene-gene interaction in tumor tissue between p16 and DAPK was 1.987 (95%CI:1.055-3.743). The results of the gene-smoking analyses revealed that a relationship existed between cigarette smoking and p16 gene methylation (OR = 3.139, 95%CI: 1.046-9.419), the OR for the relationship of DAPK gene methylation and cigarette smoking was 3.585(95%CI: 1.270-10.123) in tumor tissue. The RAR beta gene methylation did not differ based on the smoking status of patients in tumor tissue. CONCLUSION: The p16, DAPK and RAR beta genes methylation are strongly associated with clinical data of non-small cell lung cancer, and methylation of p16 and DAPK genes are associated with tobacco smoking. PMID- 21287505 TI - [An analysis of RHD zygosity of Rh(D)-positive Chinese Han population]. AB - OBJECTIVE: To investigate the RHD zygosity of Rh(D)-positive Chinese Hans in order to study the mother-fetus Rh isoimmunization prophylaxis. METHODS: Rh(D) blood group of 31 115 donors were serotyped, and the RHD zygosities were analyzed, or determined through a PCR method for 3628 donors of Rh(D)-positive individuals. RESULTS: Among the 31 115 donors, 99 were tested Rh(D)-negative by indirect antiglobulin test (IAT) (0.318%). The d frequency was 0.056 41, D was 0.943 59, and Dd heterozygosity was 0.106 45 (10.6%). However the rate was 0.090 32 (about 9.0%) after excluding DEL (IAT-negative). For the 3628 PCR tested donors, 3383 were DD (93.2%), 245 were Dd (6.8%). After excluding nonfunctional RHD alleles, 7.4% of the donors were carrying one functional RHD. It showed that an Rh(D)-negative Chinese Han woman gives an Rh(D)-negative child at a rate of 3.7%-4.5% when her husband is Rh(D)-positive. CONCLUSION: Fetus Rh(D) genotyping may be unnecessary for Chinese Hans if invasive operation was needed for prenatal diagnosis. The Rh prophylaxis could be chosen assuming an Rh(D)-positive fetus. PMID- 21287506 TI - [Establishment of B lymphoblastoid cell lines of Miao pedigree with Bardet-Biedl syndrome]. AB - OBJECTIVE: To establish immortalized lymphoblastoid cell lines of a Miao core pedigree with Bardet-Biedl syndrome (BBS), in order to provide a long-term source of material for research. METHODS: With Epstein-Barr virus transformation of B cells and addition of cyclosporine A to inhibit the activity of T cells, fresh anticoagulated blood samples with heparin were collected from 12 members of the core pedigree, and were used to establish the immortalized lymphoblastoid cell lines of B lymphocytes. RESULTS: Twelve immortalized lymphoblastoid cell lines of the core BBS pedigree were obtained successfully. CONCLUSION: The immortalized B lymphoblastoid cell lines of the Miao pedigree with BBS can preserve the whole genome information and provide long-term research materials for BBS study. PMID- 21287507 TI - [Study on polymorphism of membrane glycoprotein genes related to human platelet alloantigens]. AB - OBJECTIVE: To investigate the polymorphisms of platelet membrane glycoprotein genes related to human platelet alloantigen (HPA)-1 to 17w. METHODS: The DNA segments of platelet membrane glycoprotein genes related to HPA-1 to 17w were amplified using author's designed primers. The amplification products were purified and directly sequenced to identify the HPA genotype and glycoprotein gene polymorphisms. RESULTS: Thirteen new single nucleotide polymorphisms (SNPs) and a micro-satellite sequence were found in the glycoprotein genes from the 112 random samples, in which two SNPs (1333G/A and 1960G/A) in ITGB3 gene result in two amino acid change (V419M and E628K) on glycoprotein GPIIIa. CONCLUSION: New variants in platelet membrane glycoprotein genes were identified, which may lead to structure change of platelet membrane glycoprotein and affect the accuracy of partial HPA genotyping method. PMID- 21287508 TI - [Relationship of interleukin-10 gene polymorphism with restenosis after percutaneous coronary intervention in Chinese]. AB - OBJECTIVE: To investigate the relationship of interleukin-10 gene (IL-10) polymorphism and the serum IL-10 level with restenosis after percutaneous coronary intervention (PCI) in Tianjin Chinese Han population and study the effect of IL-10 gene polymorphism on serum IL-10 level. METHODS: Four hundred and thirty-seven patients who successfully underwent PCI with a follow-up angiography were divided into a restenosis group (n = 166) and non-restenosis group (n = 271). The IL-10 gene promoter polymorphism at position -592 was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Meanwhile their serum IL-10 level before and 24 h after PCI was determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: (1) There was no significant difference in frequencies of -592 genotypes and alleles between the two groups (P > 0.05); (2) The 24 h post-PCI IL-10 serum level of restenosis group was significantly lower than that of the non-restenosis group [(82.67 +/- 35.02) ng/L vs. (95.08 +/- 32.26) ng/L, P < 0.05]; (3) The serum level of the A allele carriers (AA+AC) was significantly lower than that of the CC carriers [(86.13 +/- 34.77) ng/L vs. (102.50 +/- 27.52) ng/L, P < 0.05]; (4) In the restenosis group, the 24 h post-PCI serum level of IL-10 in the A allele carriers was also significantly lower than that in those without the A allele [(78.51 +/- 34.09) ng/L vs. (102.19 +/- 33.66) ng/L, P < 0.05]; (5) Logistic regression analysis revealed positive correlations between acute coronary syndrome patients, pre-PCI degree of stenosis, length of target stenosis lesion and restenosis (OR = 5.90, 1.86, 2.83 respectively); and there were negative correlations between 24 h post-PCI serum level of IL-10, the stent diameter, the diameter of reference vessel before stent implantation and restenosis(OR = 0.99, 0.70, 0.46 respectively). CONCLUSION: (1) The IL-10 gene -592 C/A polymorphism was not associated with restenosis in the Tianjin Chinese Han population; (2) IL-10 is an early post-PCI inflammatory cytokine, 24 h post-PCI serum IL-10 level was an independent predictive factor for restenosis, the IL-10 A allele carriers may have increased incidence of in-stent restenosis (ISR) by reducing the serum IL-10 levels. PMID- 21287509 TI - [Current limitations and difficulties in application of microarray comparative genomic hybridization in prenatal diagnosis]. AB - Subchromosomal abnormalities can be positioned by the detection of copy number variation (CNV) using microarray comparative genomic hybridization (aCGH). aCGH has become a powerful tool in understanding the association between gene and genetic etiology in both research and clinical laboratories. Meanwhile as a new technique, controversies inevitably arose in its clinical application. As for the phenotype of CNV, little has been disclosed. For the clinicians, the difficulty in explanation of the CNV to the patients is obvious, which makes many doctors refuse to use aCGH for clinical diagnosis. Customized arrays have been exploited to decrease the uncertainty and efforts to search for a balance between overloaded information and insufficient information have been made. The purpose of this review is to discuss the current limitations and difficulties in application of aCGH in prenatal diagnosis and its application prospect from the point of a clinician. PMID- 21287510 TI - [Fragile X-associated tremor/ataxia syndrome]. AB - Fragile X-associated tremor/ataxia syndrome(FXTAS) is a neurodegenerative disease caused by FMR1 gene permutation(PM). The main clinical manifestations are intention tremor and/or ataxia, and the pathogenesis was related to RNA toxicity. In this paper, the research progress of clinical manifestatios, pathological characteristics, epidemiology and molecular mechanisms will be reviewed. PMID- 21287511 TI - [Genetic counseling and clinical outcome of fetus with de novo chromosomal aberrations]. AB - OBJECTIVE: To analyze the chromosome rearrangements and clinical outcome in fetus detected at prenatal diagnosis, and provide information for genetic counseling about de novo chromosomal aberrations. METHODS: From January 2006 to December 2009, we found 12 cases of de novo chromosomal aberrations in 2 583 cases of prenatal cytogenetic analyses and reviewed the karyotypes, other experimental analyses data, fetal ultrasound findings and clinical outcomes. RESULTS: Out of the 12 de novo chromosomal aberrations, 10 had unbalanced translocations and 2 had balanced reciprocal translocations. Eight of the 10 unbalanced translocation cases were terminated therapeutically, and 2 were delivered with full term. Neonates were phenotypically normal in the 2 cases with unbalanced translocations, but 1 had language retardation when followed up. The two balanced translocation cases were delivered with full term, and the neonates were phenotypically normal and clinical examinations were normal too. CONCLUSION: Detailed cytogenetic and molecular study will be adjunctive tools for predicting the phenotype of fetus with de novo chromosomal aberrations. Fetal ultrasound examination will provide convincible demonstration to determine the outcome of pregnancy. PMID- 21287512 TI - [Association of haptoglobin 1/2 polymorphism with coronary heart disease in Chinese]. AB - OBJECTIVE: To assess the association of haptoglobin (HP)1/2 polymorphism with coronary heart disease (CHD) in Chinese Hans. METHODS: One hundred and eighty nine CHD patients and 242 healthy controls confirmed with angiography were recruited. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was utilized to genotype the HP1 and HP2 alleles and genotype frequencies in cases and controls were compared. RESULTS: The frequency of HP2-2 genotype was significantly higher in CHDs than in controls (0.54 vs.0.35, P = 0.000). The HP2-2 genotype significantly increased the risk for CHD in univariable analysis (OR = 2.166, 95%CI: 1.467-3.196). Multifactor Logistic regression analysis indicated that HP2-2 genotype is an independent risk factor to CHD (P = 0.002; OR = 2.101, 95%CI: 1.311-3.367). Similarly, the HP2 allele frequency in the CHD group was significantly higher than that in the control subjects (0.74 vs.0.61, P = 0.000). CONCLUSION: The HP2-2 genotype is associated with CHD in Chinese. HP2-2 genotype may be an independent risk factor to CHD, and HP2 allele may be a genetic susceptibility factor to CHD in Chinese. PMID- 21287513 TI - [Negative association of STAMP2 gene polymorphisms with essential hypertension in Xinjiang Uygur population]. AB - OBJECTIVE: To investigate the relationship between the genetic polymorphisms of the six transmembrane protein of prostate 2 gene (STAMP2) and essential hypertension in Xinjiang Uygur population. METHODS: The sequences of STAMP2 gene functional region were sequenced in Xinjiang Uygur population with hypertension. The representative variations selected were genotyped by TaqMan-PCR method in 2047 Uygur individuals, including 810 patients with hypertension and 1237 healthy subjects. The association of the genetic variations of the STAMP2 gene with hypertension in Uygur was analyzed. RESULTS: In the three representative variations (rs8122, rs1981529 and rs34741656) genotyped, there were no significant differences in genotype distribution and allele frequencies between the essential hypertension and control groups (P > 0.05). In ANCOVA analysis, none of the polymorphisms was significantly associated with systolic blood pressure and diastolic blood pressure (P > 0.05). There were no significant differences in haplotype frequencies between the two groups either(P > 0.05). CONCLUSION: There was no association of the three polymorphisms (rs8122, rs1981529 and rs34741656) in the STAMP2 gene with essential hypertension in Xinjiang Uygur population. PMID- 21287514 TI - [No association of K469E polymorphism of intercellular adhesion molecule-1 with rheumatoid arthritis]. AB - OBJECTIVE: To investigate the association of the intercellular adhesion molecule 1 gene (ICAM-1) K469E polymorphism and rheumatoid arthritis (RA). METHODS: Two hundred and seventy-five patients with RA and 254 healthy individuals were collected and enrolled in the study. The K469E polymorphism of ICAM-1 gene was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: The genotype frequencies of KK, KE and EE of K469E polymorphism were 0.535,0.411 and 0.054 respectively in the RA patients, and 0.512,0.437 and 0.051 respectively in the healthy individuals, and there was no significant difference between the two groups (chi2 = 0.371, P = 0.831). The frequencies of the K469 allele were 0.74 and 0.73 in the RA patients and the controls respectively (chi2 = 0.127, P = 0.721, OR = 1.051, 95%CI:0.800-1.381). No significant difference was observed in KK + KE genotype frequencies between the two groups (P = 0.863), with an odds ratio of 0.935 (95%CI:0.436-2.005). CONCLUSION: The K469E polymorphism of the ICAM-1 gene was not associated with the susceptibility of rheumatoid arthritis. PMID- 21287515 TI - [Association of apolipoprotein A5 gene polymorphism with coronary heart disease in Uygur population of Xinjiang]. AB - OBJECTIVE: To investigate the association of the -12238T/C polymorphism of apolipoprotein A5 (APOA5) gene with coronary heart disease (CHD) and the influence of serum lipid levels in Chinese Uygur population of Xinjiang. METHODS: The -12238T/C polymorphism of APOA5 gene in 344 patients with CHD and 408 controls was analyzed by polymerase chain reaction-restriction fragment length polymorphism; the serum lipid levels were detected as well. RESULTS: The frequencies of CC, TC and TT genotype were 6.69%, 43.31% and 50.00% in the CHD group, while they were 14.95%, 45.10% and 39.95% in the control group. There was significant difference in the distribution of genotypes between the two groups (P < 0.01). Logistic regression analyses adjusted for age, gender, smoking, serum total cholesterol, presence of hypertension and diabetes revealed that individuals carrying CC genotype had an increased risk of CHD compared with TT genotype (OR = 0.328, 95%CI: 0.154-0.700). There was also significant difference in serum triglyceride level in genotypes between these two groups (P < 0.01). Patients in CHD group who carried CC and TC genotypes had lower serum triglyceride level than the TT genotype carriers. CONCLUSION: The -12238T/C polymorphism of APOA5 gene has influence on the serum triglyceride level in Uygur population of Xinjianxg. This polymorphism might be associated with development of CHD, and the CC genotype might be a protective factor in the development of CHD. PMID- 21287516 TI - [Genetic variation and association of STEAP4 gene with metabolic syndrome in Chinese Uygur patients]. AB - OBJECTIVE: To investigate the genetic variations of the six transmembrane epithelial antigen of prostate 4 gene (STEAP4) in Chinese Uygur patients with metabolic syndrome (MetS) and to analyze the association of the representative genetic variations of STEAP4 gene with MetS in the population. METHODS: The sequences of STEAP4 gene functional region (all exons, exon-intron boundaries and the putative promoter region, including the -1 kb 5'and 3'untranslated regions) were amplified and sequenced for patients with MetS. The representative variations were selected based on the function (missense mutation) and linkage disequilibrxium (gamma2 > 0.8) and genotyped with TaqMan-PCR method in 1910 general populations (682 MetS and 1228 non-MetS controls). The subjects were selected from the cross-sectional study of obesity, hypertension, diabetes, dyslipidemia from January to February 2007 among Uygur people, a relatively isolated population with a relatively homogeneous environment, in Hextian area in Xinjiang Uygur Autonomous Region. RESULTS: (1) Fourteen novel and six known single nucleotide polymorphisms (SNPs) or mutations, including 2 missense mutations, were identified at the functional region of STEAP4 gene in 96 Uygur patients with MetS. The minor allele frequencies of the SNPs of STEAP4 gene in Uygur population were different from that in European and Chinese Han in Beijing area. (2) The SNP 364G/A (rs34741656, Ala122Thr) was significantly associated with MetS [dominant model P = 0.034, OR = 0.757(95%CI: 0.584-0.982) adjusted for age and gender], and was associated with fasting blood glucose (FBG) (P = 0.049) and 2-hour postprandial glucose (2HPG) (P = 0.027) levels in controls. In this SNP, the AA carriers had lower blood glucose levels compared with subjects carrying GG and GT genotypes. (3) The common haplotype H4 (rs8122/rs1981529/ rs34741656, G-A-A), may be associated with MetS (permutation P = 0.089). CONCLUSION: STEAP 4 genetic polymorphisms may be associated with MetS risk in Chinese Uygur population. PMID- 21287517 TI - [Cloning and sequence analysis of 5'untranslated region of human ABO gene]. AB - OBJECTIVE: To clone and investigate the polymorphism of the 5'-untranslated region (5'-UTR) of the human ABO gene, in order to provide the basis for exploring the transcriptional regulation of the human ABO histo-blood group genes. METHODS: ABO phenotypes of 30 unrelated healthy blood donors were determined by serological technique, their genotypes were analyzed by sequencing the exons 6 and 7 of the ABO gene. Nearly 5 kb of the 5'-UTR of ABO gene was obtained by PCR amplification and sequencing was performed bidirectionally. Haplotypes of samples with heterozygous sites in the 5'-UTR of ABO gene were separated and analyzed after cloning. RESULTS: Twenty polymorphic sites were identified in these samples where ABO genotypes were consistent with serological phenotypes. It included sixteen nucleotide sequence variations, one 8 bp deletion, one 6 bp deletion/insertion, one 36 bp insertion and one 43 bp repeats. Among them, 11 were novel polymorphic sites. Seven different haplotypes of 5'-UTR of ABO gene were defined to the cis/trans linkage of those mutations. CONCLUSION: There were polymorphisms in the 5'-UTR of ABO gene and the nucleotide sequences near the proximal promoter were conservative. PMID- 21287518 TI - [Sequence analysis of a novel human leukocyte antigen allele B*5827]. AB - OBJECTIVE: To investigate the molecular basis for a novel human leukocyte antigen (HLA) allele B*5827. METHODS: DNA from the proband was analyzed by polymerase chain reaction-sequence specific oligonucleotide (PCR-SSO) typing. The amplified product was sequenced bidirectionally. RESULTS: Abnormal HLA-B locus was observed and its nucleotide sequence was different from the known HLA-B allele sequences, with highest homology to HLA-B*5820 allele. It differs from HLA-B*5820 by 8 nucleotide substitutions in exon 3, i.e., nt 290 (G > C), nt 346 (T > A), nt 390 (A > C), nt 404 (G > C), nt 413 (C > G), nt 471 (A > G), nt 486 (A > G) and nt 487 (C > A), resulting in an amino acid change from ser > arg at nt 97, phe >tyr at nt 115, ser > arg at nt 130, thr > ala at nt 157 and thr > glu at nt 162. Nucleotide differences of nt 404 (G > C) and nt 413( C > G) did not change amino acid. CONCLUSION: The sequences of the novel allele have been submitted to GenBank (access No.GU071234). A novel HLA class I allele B*5827 has been officially assigned by the WHO HLA Nomenclature Committee in Jan. 2010. PMID- 21287519 TI - [A study on allele frequencies and mismatching proportion of HLA-A, B, Cw, DRB1 and DQB1 on high-resolution donor-recipient typing in Chinese Han population]. AB - OBJECTIVE: To analyze the allele frequencies and polymorphism of human leukocyte antigens (HLA) -A, B, Cw, DRB1 and DQB1 between donors-recipients on high resolution typing; and to analyze the matching and mismatching proportion between donors and recipients. METHODS: HLA high-resolution types were determined by sequence based typing (SBT), sequence specific oligonucleotide probe (SSOP) and sequence specific primer (SSP) on 2540 unrelated Chinese Han individuals including 1168 recipients and 1372 donors, then statistical analyses were carried out. RESULTS: Forty-four HLA-A alleles were detected, and among them the frequencies of A*1101, A*2402, A*0201, A*0207, A*3303, A*0206 and A*3001 exceeded 0.05, and accounted for 80.4%. Eighty-one HLA-B alleles were detected, and the frequencies of B*4001, B*4601, B*5801, B*1302 and B*5101 exceeded 0.05, and accounted for 43.0% of total. There were 44 HLA-Cw alleles, among them the frequencies of Cw*0702, Cw*0102, Cw*0304, Cw*0801, Cw*0602, Cw*0303, Cw*0302 and Cw*0401 exceeded 0.05, and were 80.3% of total. There were 61 HLA-DRB1 alleles, the frequencies of DRB1*0901, DRB1*1501, DRB1*1202, DRB1*0803, DRB1*0701, DRB1*0405, DRB1*0301 and DRB1*1101 exceeded 0.05, and were 70.1% of total. Finally, 22 HLA-DQB1 alleles were detected, the frequencies of DQB1*0301, DQB1*0303, DQB1*0601, DQB1*0602, DQB1*0202, DQB1*0302, DQB1*0401, DQB1*0502 and DQB1*0201 exceeded 0.05, and they were 87.4% of total. All the five loci were of heterozygote deficiency. The HLA-A, B and DRB1 loci conformed to Hardy-Weinberg equilibrium (HWE) (P > 0.05); but HLA-Cw and HLA-DQB1 loci did not (P < 0.05). Except several particular genotypes, all the five loci conformed to HWE. After comparing data between donors and recipients, only 22.4% of recipients found HLA matched donors (10/10); 24.6% of recipients found single HLA allele mismatched donors (9/10); 26.3% of recipients had two HLA alleles mismatched donors (8/10). CONCLUSION: The characteristics of allele frequencies and polymorphism of HLA-A, B, Cw, DRB1 and DQB1 on high-resolution typing in Chinese Han population is valuable for donor searching in unrelated hematopoietic stem cell transplantation, and it provides genetic basis for donor registry and usage of donor resource for Chinese Marrow Donor Program. PMID- 21287520 TI - [Identification of a novel allele HLA-DRB1*1219]. AB - OBJECTIVE: To identify a novel HLA DRB1 allele in a Chinese leukemia family. METHODS: A new HLA-DRB1 allele was initially detected by polymerase chain reaction-sequence specific primer and unusual reaction pattern by Luminex RSSO, then DNA sequencing was performed to identify the sequence of the novel allele. RESULTS: The DNA sequencing revealed the presence of the new allele which differs from the closest matching HLA-DRB1*120201 by a single nucleotide substitution at position (341 C > T in exon 2), resulting in an amino acid change from Ala to Val at coden 85. CONCLUSION: A novel allele was confirmed by DNA sequencing and has been designated HLA-DRB1*1219 by the WHO Nomenclature Committee. PMID- 21287521 TI - [Genetic polymorphisms of nine non-DNA combined index system short tandem repeat loci in Hebei Han population and application in paternity testing]. AB - OBJECTIVE: To investigate the polymorphisms of 9 non-DNA combined index system (CODIS) short tandem repeats (STRs), i.e., D7S3048, D8S1132, D11S2368, D2S1772, D6S1043, D13S325, D12S391, GATA198B05, D18S1364 in Hebei Han population, and evaluate the usage of them in paternity testing. METHODS: One hundred and forty seven unrelated healthy individuals from the Han population of Hebei province were genotyped using STRtyper10G kit including 9 STR loci on ABI 3130 Genetic Analyzer. Hardy-Weinberg equilibrium and population genetic parameters were calculated. Fourteen cases of motherless paternity testing and 2 cases of standard trios with mutation in 1 locus were detected using STRtyper10G. RESULTS: (1) Ninety-nine alleles and 336 genotypes were observed in the 9 STR loci in the population. The cumulative discrimination power(DP) was higher than 0.999,999,999. The cumulative probability of exclusion (PE) for trios and duos were 0.999,974 and 0.998,759 respectively. Departure from Hardy-Weinberg equilibrium was not observed in any of the 9 loci. (2) The combined paternity index (PI) of the 14 cases of motherless paternity testing ranged from 103-106 for 15 STR loci in ID, whereas it reached 105-109 for 22 independent STR loci included in ID and STRtyper 10G. Possible mutation in FGA and vWA was observed in 2 cases of trios, and the combined PI was 5945 and 1840 respectively for 15 STR loci in ID. Adding STRtyper 10G to detect these 2 cases, the combined PI reached 2.76 * 107 and 4.88 * 107 respectively. CONCLUSION: The genetic polymorphism of the 9 non-CODIS STR loci included in STRtyper 10G was quite high in Chinese Hebei Han population, indicating the 9 STR loci are valuable as complement markers for ID and PP16 kit in motherless paternity testing, paternity testing with mutation and other kinds of complicated paternity testing. PMID- 21287523 TI - Parametric sensitivity analysis and reduction of a detailed nutritional model of plant cell cultures. AB - A kinetic model of plant nutrition described by Cloutier et al. (Cloutier et al., 2008. Biotechnol Bioeng 99:189-200) is progressively simplified so as to obtain a predictive model that describes the evolution of the biomass and the extracellular and intracellular concentrations of three determining nutrients, that is, free intracellular nitrogen, phosphate, and carbohydrate compounds. Three techniques of global sensitivity analysis are successively applied to assess the model parameter influence and potential correlation. The resulting dynamic model is able to predict plant growth for the two most encountered plant bioprocesses, namely suspension cells and hairy roots. PMID- 21287524 TI - Clinical implications of UGT1A1*28 genotype testing in colorectal cancer patients. AB - BACKGROUND: Metastatic colorectal cancer is frequently treated with irinotecan, a topoisomerase-I inhibitor. The UGT1A1 gene encodes for an enzyme that metabolizes irinotecan, and its genetic variants were shown to be associated with increased drug toxicity. We evaluated clinical outcomes associated with the UGT1A1*28 variant. METHODS: The study included 329 colorectal cancer patients from the Israeli population-based Molecular Epidemiology of Colorectal Cancer study who were treated with a chemotherapy regimen that included irinotecan. Patients with metastases or disease recurrence were followed up for a median period of 2 years after occurrence of the event. Study end points were appearance of grade 3-4 hematological and gastroenterological toxicity, hospitalization due to toxic events (mostly neutropenia, fever, diarrhea, or vomiting), length of hospitalization, and overall survival. UGT1A1*28 was genotyped from peripheral blood DNA by fragment analysis and reported as number of TATA sequence repeats in the promoter of the gene. RESULTS: The 7/7 variant of UGT1A1*28 was detected in 11.9% of the 329 participants. Grade 3-4 hematological toxicity was significantly higher in 7/7 carriers compared with 6/7 and 6/6 carriers (48.0%,10.2%, and 7.7% respectively; P < .001), as was the risk of toxicity-related hospitalization (45.8%, 25.3%, and 14.4% respectively; P = .001). Both short-term death within 2 months of treatment start (12.8%, 5.2%, and 2.9%, respectively) and median overall survival (1.6, 2.0, and 2.4 years, respectively; P = .01) were significantly worse in the 7/7 carriers. The age/stage-adjusted hazard ratio for patients with the 7/7 genotype compared with 6/6 was 1.7 (95% confidence interval, 1.1-2.3). CONCLUSIONS: The UGT1A1*28 7/7 genotype is strongly associated with severe hematological toxicity and higher hospitalization rate and predicts lower survival of colorectal cancer in users of irinotecan. PMID- 21287525 TI - RECK in osteosarcoma: a novel role in tumour vasculature and inhibition of tumorigenesis in an orthotopic model. AB - BACKGROUND: Targeted therapy in osteosarcoma (OS) is needed to improve patient outcomes. Human RECK may have a role because it inhibits cancer invasion and regulates angiogenesis. This study aimed to characterize RECK expression in human OS, to examine in vitro effects of RECK on vascular endothelium and OS cell behavior, and to analyze the effect of RECK on OS grown orthotopically in nude mice. METHODS: RECK was examined in human OS samples. Interactions between RECK and VEGF were studied in tissue and cells. RECK transfection was used to study its effects on vascular endothelial (HMEC-1) and OS (SaOS-2) cell behavior in vitro and in vivo. SaOS-2 co-culture with RAW 246.7-derived osteoclasts on osteoslides was used to assess effects on osteoclast activity. RESULTS: RECK was absent from OS cells but was expressed in tumor vessel endothelium. Via microarray analysis, RECK mRNA was elevated in samples with low proliferative activity, a trend most evident in poorly differentiated samples. VEGF induced RECK expression in HMEC-1. RECK transfection inhibited HMEC-1 invasion and induced thicker, although more numerous, tube formation. RECK inhibited SaOS-2 invasion, proliferation, colony formation, and osteoclast activity but supported SaOS-2 adhesion to collagen I. In vivo, RECK inhibited SaOS-2 tumor growth, bone destruction, and consequent metastasis. CONCLUSIONS: RECK expression is downregulated in highly proliferative OS but is present in tumor vessels and upregulated in endothelium by VEGF. RECK inhibits invasion and tumorigenic properties in SaOS-2, as confirmed in vivo. Further testing of RECK delivery in OS is warranted. PMID- 21287526 TI - Oncologic outcomes of open conservation laryngectomy for radiorecurrent laryngeal carcinoma: a systematic review and meta-analysis of English-language literature. AB - BACKGROUND: The role of open conservation (partial) laryngeal surgery in radiorecurrent laryngeal cancers is unclear, and the procedure is not widely accepted or practiced. The objective of this review was to assess the oncologic and functional outcomes of partial laryngectomy in radiorecurrent tumors of the larynx reported in the literature. METHODS: The systematic review was performed using independently developed search strategies and included Medline, Embase, Zetoc, conference proceedings, and, when appropriate, a manual search. Inclusion criteria for the articles were set a priori. All included articles were subjected to quality assessment. Pooled estimates of local control at 24 months and of disease-free and overall survival rates were calculated using both a fixed effects model (inverse square) and a random-effects model (DerSimonian-Laird). RESULTS: The search identified 401 publications, of which 26 studies satisfied all inclusion criteria. Ten studies had a quality score >=6 (good), and 16 had a score of 4 or 5 (fair). The pooled estimates of oncologic outcomes using the random-effects model were as follows: The local control rate at 24 months for 560 patients was 86.9% (95% CI, 84%-89.5%), the disease-free survival rate for 352 patients was 91.2% (95% CI, 88.2%-93.9%), and the overall survival rate for 360 patients was 83.1% (95% CI, 79.1%-86.7%). Decannulation of tracheostomy occurred in 95.1% (95% CI, 92.6%-97.2%) of the patients who were analyzed (n = 315), whereas the pooled mean larynx preservation rate was 83.9% (95% CI, 80.7%-87%; n = 502) CONCLUSIONS: The current results indicated that open partial laryngectomies are oncologically sound procedures in the salvage setting and have a high larynx preservation rate. PMID- 21287527 TI - Adjuvant radiotherapy for completely resected stage 2 thymoma. AB - BACKGROUND: The clinical benefit of postoperative mediastinal radiation for completely resected Masaoka stage 2 thymoma remains controversial. Due to its indolent nature and infrequent recurrences, no study has definitively determined the optimal approach. METHODS: We retrospectively reviewed 175 consecutive patients who underwent thymic resection from January 1990 to July 2008 at the University of Pennsylvania. The primary endpoint was local recurrence, defined as recurrence within the surgical bed, treated by resection alone versus resection plus radiation. Patients with high recurrence risk were referred for adjuvant radiotherapy. RESULTS: Seventy-four Masaoka stage 2 patients were resected; 62 underwent complete resections with adequate postsurgical follow-up. Thirty-seven patients received adjuvant radiotherapy and 25 patients were observed. The median radiation dose was 5040 cGy. The median follow-up for all patients was 52 months. The local recurrence rate was 3.2%. The proportion of recurrences in patients observed after surgery was 8% versus 0% in those who received adjuvant radiotherapy (P = .15). Size was not an independent predictor of recurrence (P = .81). The tumor-related death rate was 0%, and overall death rate was 3.2%. One death occurred in each group, observation, and radiation. There were no grade 3 or 4 complications with radiation. CONCLUSIONS: Recurrence rates were low following resection of stage 2 thymoma either with or without adjuvant radiotherapy. Adjuvant radiotherapy, although well-tolerated, did not significantly decrease the local relapse rate. Differences may be observed in future studies of patients who are at higher risk for local recurrence, based on completeness of resection, World Health Organization histology, and tumor size. PMID- 21287528 TI - Hyperbaric oxygen treatment improved neurophysiologic performance in brain tumor patients after neurosurgery and radiotherapy: a preliminary report. AB - BACKGROUND: Cognitive performance often is impaired permanently in long-term brain tumor survivors after neurosurgery and radiotherapy. Hyperbaric oxygen treatment (HBOT) stimulates neovascularization of hypoperfused tissue and may result in improved functionality of damaged tissue. In this pilot study, clinical neurophysiologic tests were used to assess the effect of HBOT on brain performance. METHODS: Ten long-term brain tumor survivors received HBOT for severe cognitive deficits after neurosurgery and radiosurgery. Patients were tested before HBOT and at 6 weeks and 4 months after HBOT. The tests comprised a quantitative electroencephalographic (EEG) examination, the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) for memory performance, and 2 cognitive tests, the number connection test (NCT) and the continuous reaction time test (CRTT). Late event-related components (LERCs) of averaged evoked EEG responses to a visual odd-ball stimulus were analyzed from whole-head activity maps. For comparison, a control group of healthy individuals (no HBOT) also were investigated. RESULTS: After HBOT, the amplitude of the LERC with the longest latency, P3b (involved in object interpretation) was improved significantly (P = .02). The amplitudes of the N200 (occipital, negative) and the intermediate P3a (centroparietal, positive), LERCs with shorter latencies, and of a small, positive, occipital visual component did not change. Neither latencies nor reaction times changed after HBOT. However, P3a and P3b (parietal, positive) latencies were longer in survivors than in healthy individuals. The NCT produced inconclusive results, but the IQCODE revealed an improvement. When outcomes of the NCT, CRTT, IQCODE, and P3b amplitudes were evaluated in common tests, HBOT appeared to provide substantial improvement (P<.006). CONCLUSIONS: On the basis of the current results, the authors concluded tentatively that HBOT improves neurophysiologic performance in long-term brain tumor survivors. PMID- 21287529 TI - Effect of the histone deacetylase inhibitor SNDX-275 on Fas signaling in osteosarcoma cells and the feasibility of its topical application for the treatment of osteosarcoma lung metastases. AB - BACKGROUND: Patients with lung metastases from osteosarcoma (OS) have poor response to salvage therapy. Understanding the mechanisms involved in the metastatic process of OS may lead to new effective therapeutic approaches. The authors reported previously that up-regulation of the Fas receptor by transfecting OS cells with Fas plasmid inhibited the in vivo growth of metastases in the lungs. METHODS: In the current study, the authors treated OS cells with the histone deacetylase inhibitor SNDX-275 and studied its cytotoxicity and its effect on Fas signaling in vitro and in vivo. RESULTS: Subtoxic doses of SNDX-275 were able to activate the Fas pathway in OS cells by increasing the expression of Fas messenger RNA; however, the increased expression was not always followed by increased levels of Fas receptor expression on the cell surface. The treatment of cells with a combination of SNDX-275 and Fas ligand (FasL) had a stronger cytotoxic effect on tested OS cells than either agent alone. Inhibition of the Fas pathway in cells by inhibition of the Fas-associated death domain (FADD) molecule eliminated this combination effect, indicating that activity of FADD is important for the efficacy of this agent in the FasL-expressing environment of the lungs. Intranasal administration of SNDX-275 in mice with OS lung metastases revealed that SNDX-275 may inhibit metastatic growth at a dose of 0.13 mg/kg, which is approximately 200-fold lower than the therapeutically effective oral dose reported previously. CONCLUSIONS: The current findings indicated that SNDX 275 can activate Fas signaling in OS cells in vitro and in vivo and that the administration of SDNX-275 by inhalation is feasible as a treatment for OS metastases and warrants its further investigation. PMID- 21287530 TI - Intensity-modulated radiation therapy versus conventional radiation therapy for squamous cell carcinoma of the anal canal. AB - BACKGROUND: The purpose of this study was to compare outcomes in patients with anal canal squamous cell carcinoma (SCCA) who were treated with definitive chemoradiotherapy by either intensity-modulated radiation therapy (IMRT) or conventional radiotherapy (CRT). METHODS: Forty-six patients who received definitive chemoradiotherapy from January 1993 to August 2009 were included. Forty-five patients received 5-fluorouracil with mitomycin C (n = 39) or cisplatin (n = 6). Seventeen (37%) were treated with CRT and 29 (63%) with IMRT. The median dose was 54 Gy in both groups. Median follow-up was 26 months (CRT) and 32 months (IMRT). T3-T4 stage (P = .18) and lymph node-positive disease (P = .6) were similar between groups. RESULTS: The CRT group required longer treatment duration (57 days vs 40 days, P < .0001), more treatment breaks (88% vs 34.5%, P = .001), and longer breaks (12 days vs 1.5 days, P < .0001) than patients treated with IMRT. Eleven (65%) patients in the CRT group experienced grade >2 nonhematologic toxicity compared with 6 (21%) patients in the IMRT group (P = .003). The 3-year overall survival (OS), locoregional control (LRC), and progression-free survival were 87.8%, 91.9%, and 84.2%, respectively, for the IMRT groups and 51.8%, 56.7%, and 56.7%, respectively, for the CRT group (all P < .01). On multivariate analysis, T stage, use of IMRT, and treatment duration were associated with OS, and T stage and use of IMRT were associated with LRC. CONCLUSIONS: The use of IMRT was associated with less toxicity, reduced need for treatment breaks, and excellent LRC and OS compared with CRT in patients with SCCA of the anal canal. PMID- 21287531 TI - A novel serum carbohydrate marker on mucin 5AC: values for diagnostic and prognostic indicators for cholangiocarcinoma. AB - BACKGROUND: The incidence of cholangiocarcinoma (CCA) is increasing globally. Currently, there is no powerful marker for the diagnosis of CCA, which has led to late diagnosis and poor patient outcome. This study was designed to establish a new monoclonal antibody (MoAb) for detecting a serum marker associated with CCA. METHODS: Pooled CCA tissue extracts were immunized to germinal center associated nuclear protein (GANP)-transgenic mice. The antibody-producing hybridomas were prepared and initially screened by using an indirect enzyme-linked immunosorbent assay (ELISA). A positive clone that reacted strongly with CCA serum or tumor tissue extract and failed to react with normal human serum and liver extract was selected. RESULTS: An S121 immunoglobulin M MoAb that recognized a novel glycan epitope was obtained. Immunohistochemistry of CCA tissues revealed that the MoAb reacted strongly with hyperplastic/dysplastic and neoplastic bile ducts but not with normal bile ducts. In addition, experiments demonstrated that mucin 5AC (MUC5AC) is a core glycoprotein for the S121 epitope. A sandwich ELISA using soybean agglutinin and an S121 MoAb was developed for detecting S121 reactive antigen in patient sera. The level of serum S121 from patients with CCA was reduced significantly after tumor removal, indicating the tumor origin of this antigen. The test was able to distinguish patients with CCA from healthy individuals, active Opisthorchis viverrini-infected individuals and patients with various gastrointestinal cancers, hepatoma, and benign hepatobiliary diseases with 87.63% sensitivity, 89.58% specificity, an 80.95% positive predictive value, and a 93.47% negative predictive value. Moreover, high serum S121 levels were related to a poor patient outcome. CONCLUSIONS: The sugar antigen recognized by S121 MoAb is a new serum marker for the diagnosis and prognosis of CCA. PMID- 21287533 TI - Combination of gemcitabine and cisplatin is highly active in women with endometrial carcinoma: results of a prospective phase 2 trial. PMID- 21287534 TI - ERCC5/XPG, ERCC1, and BRCA1 gene status and clinical benefit of trabectedin in patients with soft tissue sarcoma. AB - BACKGROUND: The objective of this study was to determine whether specific single nucleotide polymorphisms (SNPs) from nucleotide excision repair (NER) and homologous recombination (HR) DNA repair pathways are associated with sensitivity to trabectedin in patients with soft tissue sarcoma (STS). METHODS: The authors analyzed excision repair cross-complementation group 5/xeroderma pigmentosum group G (ERCC5/XPG) (NER), excision repair cross-complementation group 1 (ERCC1) (NER), and breast cancer 1 (BRCA1) (HR) SNPs and messenger RNA expression levels in tumor specimens from 113 patients with advanced STS who were enrolled in previously published phase 2 trials or in a compassionate-use program. The 6 month progression-free rate (PFR), progression-free survival (PFS), and overall survival (OS) were analyzed according to ERCC5, ERCC1, and BRCA1 status using log rank tests. RESULTS: High expression of the common allele (aspartic acid at codon 1104) of ERCC5, high expression of ERCC1, and BRCA1 haplotype were associated significantly with improved PFR, PFS, and OS. The ERCC1 thymine-to-cytosine (T >C) SNP at codon 19007 and BRCA1 expression were not associated with outcome. On univariate analysis, tumor histology, favorable NER status (high expression of common ERCC5 and/or high ERCC1 expression status), and favorable BRCA1 haplotype (at least 1 triple-adenine plus guanine [AAAG] allele) were the sole variables associated significantly with PFS and OS. CONCLUSIONS: In the current study, ERCC5, ERCC1, and BRCA1 status represented a potential DNA repair signature that could be used for the prediction of clinical response to trabectedin in patients with STS. PMID- 21287535 TI - Trends in the use of implantable accelerated partial breast irradiation therapy for early stage breast cancer in the United States. AB - BACKGROUND: In 2002, the US Food and Drug Administration approved an implantable balloon catheter that delivers accelerated partial breast irradiation (APBI) after breast-conserving surgery (BCS). The objective of the current study was to determine the use of implantable APBI (IAPBI) in the United States and factors associated with IAPBI use. METHODS: By using the Surveillance, Epidemiology, and End Results database, the authors conducted a retrospective analysis of patients who received whole-breast radiotherapy (WBRT) or IAPBI after BCS for ductal carcinoma in situ, AJCC stage I, or stage II breast cancer from 2000 to 2007. WBRT and IAPBI rates were determined across time and demographic and tumor factors using chi-square tests and Cochran-Armitage tests for trend for the unadjusted analyses. RESULTS: A total of 127,257 patients who met inclusion criteria were identified. Over the study period, the proportion of patients receiving IAPBI increased by 1600% (from 0.4% in 2000 to 6.8% in 2007; P <.001). This trend remained significant when using logistic regression (odds ratio, 20.3; 95% confidence interval, 15.5-26.6). The increase in IAPBI use was statistically significant across all stage and age categories >40 years (P <.001). The use of IAPBI was most notable in older women (ages 70-79 years), with a >2100% increase in use noted during the study period (0.4% in 2000 vs 9.0% in 2007; P <.001). The authors also found significant variation in IAPBI use by region. CONCLUSIONS: IAPBI use has markedly increased since 2000, particularly in the elderly population. The rapid and widespread adoption of IAPBI is concerning, because large multicenter randomized controlled trials have not yet demonstrated the long term effectiveness of IAPBI compared with WBRT. PMID- 21287536 TI - A phase 2 study of temsirolimus (CCI-779) in patients with soft tissue sarcomas: a study of the Mayo phase 2 consortium (P2C). AB - BACKGROUND: The primary goal of this trial was to evaluate the confirmed response rate of temsirolimus (CCI-779), a mammalian target of rapamycin in patients with advanced soft tissue sarcomas (STS). METHODS: Patients >=18 years with measurable advanced STS, no prior chemotherapy for metastatic disease (adjuvant and neoadjuvant chemotherapy allowed), adequate organ function, and performance status of <=2 were eligible. After premedication with an antihistamine, CCI-779 was given intravenously at 25 mg over 30 minutes on Days 1, 8, 15, and 22, repeated every 4 weeks. The primary endpoint was confirmed response rate per Response Evaluation Criteria in Solid Tumors. RESULTS: Between June 2004 and November 2005, a total of 41 patients were enrolled and began treatment; 40 patients are evaluable for response and adverse events. The median age was 62 years (range, 28-72 years) with 56% women. Eighty percent had high-grade STS, and 22% had prior adjuvant chemotherapy. There were 2 patients (5%; 95% confidence interval [CI], 1-17) (undifferentiated fibrosarcoma and uterine leiomyosarcoma) who achieved a confirmed partial response lasting 3 and 17 months, respectively. Thirty-nine (95%) patients have progressed, with a median time to progression of 2.0 months (95% CI, 1.8-3.5). The median overall survival was 7.6 months (95% CI, 6.1-15.9). Forty-three percent experienced grade 3+ adverse events that were possibly related to therapy. CONCLUSIONS: Temsirolimus in this patient population of STS had limited clinical activity and had moderate toxicities. PMID- 21287537 TI - Hypomethylating agents for the treatment of acute myeloid leukemia in the elderly: for all, none, or which patients? PMID- 21287538 TI - Boswellia serrata acts on cerebral edema in patients irradiated for brain tumors: a prospective, randomized, placebo-controlled, double-blind pilot trial. AB - BACKGROUND: Patients irradiated for brain tumors often suffer from cerebral edema and are usually treated with dexamethasone, which has various side effects. To investigate the activity of Boswellia serrata (BS) in radiotherapy-related edema, we conducted a prospective, randomized, placebo-controlled, double-blind, pilot trial. METHODS: Forty-four patients with primary or secondary malignant cerebral tumors were randomly assigned to radiotherapy plus either BS 4200 mg/day or placebo. The volume of cerebral edema in the T2-weighted magnetic resonance imaging (MRI) sequence was analyzed as a primary endpoint. Secondary endpoints were toxicity, cognitive function, quality of life, and the need for antiedematous (dexamethasone) medication. Blood samples were taken to analyze the serum concentration of boswellic acids (AKBA and KBA). RESULTS: Compared with baseline and if measured immediately after the end of radiotherapy and BS/placebo treatment, a reduction of cerebral edema of >75% was found in 60% of patients receiving BS and in 26% of patients receiving placebo (P = .023). These findings may be based on an additional antitumor effect. There were no severe adverse events in either group. In the BS group, 6 patients reported minor gastrointestinal discomfort. BS did not have a significant impact on quality of life or cognitive function. The dexamethasone dose during radiotherapy in both groups was not statistically different. Boswellic acids could be detected in patients' serum. CONCLUSIONS: BS significantly reduced cerebral edema measured by MRI in the study population. BS could potentially be steroid-sparing for patients receiving brain irradiation. Our findings will need to be further validated in larger studies. PMID- 21287539 TI - Measuring success in ovarian cancer risk reducing strategies. PMID- 21287541 TI - Activity and safety of dose-adjusted infusional cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy with rituximab in very elderly patients with poor-prognostic untreated diffuse large B-cell non-Hodgkin lymphoma. PMID- 21287542 TI - Comparative risk-adjusted mortality outcomes after primary surgery, radiotherapy, or androgen-deprivation therapy for localized prostate cancer. PMID- 21287543 TI - Progression-free survival as a surrogate marker of overall survival: Is it the good question? PMID- 21287545 TI - PI3Kgamma deficiency delays the onset of experimental autoimmune encephalomyelitis and ameliorates its clinical outcome. AB - PI3Ks control signal transduction triggered by growth factors and G-protein coupled receptors and regulate an array of biological processes, including cellular proliferation, differentiation, survival and migration. Herein, we investigated the role of PI3Kgamma in the pathogenesis of EAE. We show that, in the absence of PI3Kgamma expression, clinical signs of EAE were delayed and mitigated. PI3Kgamma-deficient myelin oligodendrocyte glycoprotein (MOG)(35-55) specific CD4(+) T cells appeared later in the secondary lymphoid organs and in the CNS than their WT counterparts. Transfer of WT CD4(+) cells into PI3Kgamma(-/ ) mice prior to MOG(35-55) immunisation restored EAE severity to WT levels, supporting the relevance of PI3Kgamma expression in Th cells for the pathogenesis of EAE; however, PI3Kgamma was dispensable for Th1 and Th17 differentiation, thus excluding an altered expression of these pathogenetically relevant cytokines as the cause for ameliorated EAE in PI3Kgamma(-/-) mice. These findings demonstrate that PI3Kgamma contributes to the development of autoimmune CNS inflammation. PMID- 21287546 TI - Mutation of the BAFF furin cleavage site impairs B-cell homeostasis and antibody responses. AB - B-cell-activating factor of the TNF family (BAFF)/BLyS contributes to B-cell homeostasis and function in the periphery. BAFF is expressed as a membrane-bound protein or released by proteolytic cleavage, but the functional importance of this processing event is poorly understood. Mice expressing BAFF with a mutated furin consensus cleavage site, i.e. furin-mutant BAFF (fmBAFF), were not different from BAFF-deficient mice with regard to their B-cell populations and responses to immunization. It is however noteworthy that an alternative processing event releases some soluble BAFF in fmBAFF mice. Mild overexpression (~ 5-fold) of fmBAFF alone generated intermediate levels of B cells without improving humoral responses to immunization. Processed BAFF was however important for B-cell homeostasis, as peripheral B-cell populations and antibody responses were readily restored by administration of soluble BAFF trimers in BAFF-deficient mice. However, the rescue of CD23 expression in B cells of BAFF-deficient mice required both soluble BAFF trimers and fmBAFF, or a polymeric form of soluble BAFF (BAFF 60-mer). These results point to a predominant role of processed BAFF for B-cell homeostasis and function, and indicate possible accessory roles for membrane-bound BAFF. PMID- 21287547 TI - Nucleosome-induced neutrophil activation occurs independently of TLR9 and endosomal acidification: implications for systemic lupus erythematosus. AB - The nucleosome is a major autoantigen known to activate PMN in systemic lupus erythematosus (SLE). TLR9 recognizes bacterial and even mammalian DNA under certain circumstances. Nevertheless, the role of TLR9 in SLE development is still unclear. Since nucleosomes are composed of DNA, we investigated whether TLR9 is required for nucleosome-induced PMN activation. Isolated neutrophils were cultured with nucleosomes, plasma from lupus patients and other stimuli in the presence/absence of various inhibitors. Cells were analyzed by flow cytometry, ELISA and confocal microscopy. We found that nucleosomes circulating in lupus plasma induce the secretion of pro-inflammatory cytokines by PMN. Nucleosomes activate human PMN independently of unmethylated CpG sequences in nucleosomal DNA, leading to IL-8/IL-6/TNF secretion and CD11b up-regulation. Nucleosomes accumulate in the cytoplasm of PMN upon endocytosis, induce TLR9 up-regulation and act synergistically with TLR9 ligands. Nucleosome-induced activation was not inhibited by polymyxin B (PB), chloroquine (CQ), ammonium chloride (AC) or a TLR9 antagonist. Moreover, both PMN isolated from WT and TLR9-KO mice were activated by nucleosomes, as detected by MIP-2 secretion and CD11b up-regulation. Activation occurred therefore independently of endotoxins, endosomal acidification, TLR9 and CpG motifs. TLR9 may thus be differently required in the triggering of nucleosome-induced innate immunity and anti-nucleosome B-cell autoimmunity. PMID- 21287548 TI - 1,25-Dihydroxyvitamin D3 acts directly on the T lymphocyte vitamin D receptor to inhibit experimental autoimmune encephalomyelitis. AB - Multiple sclerosis (MS) is an incurable autoimmune neurodegenerative disease. Environmental factors may be key to MS prevention and treatment. MS prevalence and severity decrease with increasing sunlight exposure and vitamin D(3) supplies, supporting our hypothesis that the sunlight-dependent hormone, 1,25 dihydroxyvitamin D(3) (1,25-(OH)(2) D(3) ), inhibits autoimmune T-cell responses in MS. Moreover, 1,25-(OH)(2) D(3) inhibits and reverses experimental autoimmune encephalomyelitis (EAE), an MS model. Here, we investigated whether 1,25-(OH)(2) D(3) inhibits EAE via the vitamin D receptor (VDR) in T lymphocytes. Using bone marrow chimeric mice with a disrupted VDR only in radio-sensitive hematopoietic cells or radio-resistant non-hematopoietic cells, we found that hematopoietic cell VDR function was necessary for 1,25-(OH)(2) D(3) to inhibit EAE. Furthermore, conditional targeting experiments showed that VDR function in T cells was necessary. Neither 1,25-(OH)(2) D(3) nor T-cell-specific VDR targeting influenced CD4(+) Foxp3(+) T-cell proportions in the periphery or the CNS in these studies. These data support a model wherein 1,25-(OH)(2) D(3) acts directly on pathogenic CD4(+) T cells to inhibit EAE. PMID- 21287549 TI - A poxviral homolog of the Pellino protein inhibits Toll and Toll-like receptor signalling. PMID- 21287550 TI - IFN-alpha-producing PDCA-1+ Siglec-H- B cells mediate innate immune defense by activating NK cells. AB - B cells have multiple functions in adaptive immunity, including antibody production, antigen presentation and regulation of T-cell responses. Recent evidences indicate that B cells have more subsets than previously thought and may have non-classical functions, such as involvement in innate immunity and immune regulation; however, how B cells respond to microbial infection and elicit innate defense remain unclear. In this study, we identified a new subset of PDCA-1(+) Siglec-H(-) CD19(+) B cells in mice during the early period of bacterial infection with Listeria monocytogenes. PDCA-1(+) Siglec-H(-) CD19(+) B cells secreted large amounts of IFN-alpha and thus facilitated IFN-gamma production and cytotoxicity function of natural killer (NK) cells via IFN-alpha. B-cell deficient Btk(-/-) mice were incapable of producing PDCA-1(+) CD19(+) B cells, and were more sensitive to L. monocytogenes infection. Adoptive transfer of PDCA 1(+) CD19(+) B cells to Btk(-/-) mice normalized their resistance to L. monocytogenes infection. Furthermore, we found that macrophages were essential for the inducible generation of PDCA-1(+) Siglec-H(-) CD19(+) B cells via CD40 CD40L ligation. Therefore, we have identified a new subset of PDCA-1(+) Siglec-H( ) CD19(+) B cells, which enhances innate immune responses against bacterial infection by activating NK cells via secretion of IFN-alpha. PMID- 21287551 TI - Telomere-dependent replicative senescence of B and T cells from patients with type 1a common variable immunodeficiency. AB - A subset of patients with common variable immunodeficiency (CVID), group 1a of the Freiburg classification, is characterized by increased B cells expressing low levels of CD21 (CD21(low) ), lymphoproliferation and autoimmunity. The CD21(low) B cells have been shown to be profoundly anergic, and defects of BCR-mediated calcium signaling and of T cells have been described in CVID 1a. We found that also the classical naive B cells from CVID 1a patients, but not from CVID non-1a patients, proliferated poorly. The B cells of CVID 1a patients had a reduced capacity to divide reminiscent of the proliferative arrest associated with replicative senescence. Thus, we investigated whether lymphocyte dysfunction in CVID 1a was related to telomere-dependent replicative senescence, and found that both the B and the T cells from CVID 1a patients had significantly shorter telomeres compared with B and T cells from CVID non-1a patients. Telomere lengths in B and T cells were significantly correlated, indicating that the rate of telomere attrition in lymphocytes is an individual characteristic of CVID patients. Our findings suggest that telomere-dependent replicative senescence contributes to the immune dysfunction of CVID 1a patients, and may provide an important clue for a better understanding of the pathogenesis of CVID. PMID- 21287552 TI - Characterization of the immunoregulatory function of human TCR-alphabeta+ CD4- CD8- double-negative T cells. AB - Regulatory T cells (Tregs) play an important role in the maintenance of immune tolerance to self-antigens and are involved in modulating immune responses in autoimmunity, transplant rejection, and tumor immunity. Recently, a novel subset of TCR-alphabeta(+) CD4(-) CD8(-) (double negative, DN) T cells has been described to specifically suppress T-cell responses in mice. Here, we demonstrate that human DN T cells are highly potent suppressors of both CD4(+) and CD8(+) T cell responses. In contrast to naturally occurring CD4(+) CD25(+) Tregs, DN T cells have to be activated by antigen-presenting cells (APCs) to induce their regulatory potential. The suppressive activity of DN T cells is neither mediated indirectly by modulation of APCs nor by competition for T-cell growth factors. Furthermore, DN T-cell-mediated suppression toward responder T cells is TCR dependent and requires novel protein synthesis. In contrast to murine DN T cells, which eliminate effector T cells via Fas/FasL or perforin/granzyme, human DN T cells suppress proliferation of responder T cells by cell contact-dependent mechanisms. Taken together, our data indicate that human DN T cells exert strong immunosuppressive effects on both CD4(+) and CD8(+) T cells and may serve as a new therapeutic approach to treat autoimmunity and transplant rejection. PMID- 21287553 TI - PKCdelta regulates IL-12p40/p70 production by macrophages and dendritic cells, driving a type 1 healer phenotype in cutaneous leishmaniasis. AB - The protein kinase C (PKC) family is involved in the regulation of many intracellular signalling pathways. Here, we report that the PKCdelta isoform regulates IL-12p40/p70 production in macrophages and DC and that PKCdelta deficiency in mice transforms the 129/Sv healer to a non-healer strain during cutaneous leishmaniasis. Leishmania major-infected PKCdelta(-/-) 129/Sv mice developed a rapid increase in footpad swelling and parasite burden with disease progression, leading to necrosis and ulceration similar to non-healer BALB/c mice. Moreover, PKCdelta(-/-) mice failed to develop delayed-type hypersensitivity responses against Leishmania antigen. PKCdelta(-/-) macrophages were fully functional with normal MHC class II surface expression and GM-CSF production, recruitment to the draining lymph node and killing effector functions by NO production. In contrast, macrophages and DC produced significantly reduced IL-12p40 and IL-12p70 compared to the WT cells. Decreased IL-12 production resulted in diminished Th1 differentiation, as determined by a striking reduction in IFN-gamma by antigen-specific stimulated CD4(+) T cells isolated from popliteal lymph nodes of L. major-infected PKCdelta(-/-) mice, explaining the "non-healer" phenotype. We conclude from these data that PKCdelta is a regulator of IL-12p40/p70 production by DC and macrophages, driving the healer phenotype during cutaneous leishmaniasis. PMID- 21287554 TI - In vivo suppressive function of myeloid-derived suppressor cells is limited to the inflammatory site. AB - Current paradigms suggest that, despite the heterogeneity of myeloid-derived suppressor cells (MDSC), all Gr-1(+) CD11b(+) cells can exert suppressive function when exposed to inflammatory stimuli. In vitro evaluation shows that MDSC from multiple tissue sites have suppressive activity, and in vivo inhibition of MDSC enhances T-cell function; however, the relative capacity of MDSC present at localized inflammatory sites or in peripheral tissues to suppress T-cell responses in vivo has not been directly evaluated. In the current study, we observed that during a tissue-specific inflammatory response, MDSC inhibition of CD8(+) T-cell proliferation and IFN-gamma production was restricted to the inflammatory site. Using a prostate-specific inflammatory model and a heterotopic prostate tumor model, we showed that MDSC from inflammatory sites or from tumor tissue possess immediate capacity to inhibit T-cell function, whereas those isolated from peripheral tissues (spleens and liver) were not suppressive without activation of iNOS by exposure to IFN-gamma. These data suggest that MDSC are important regulators of immune responses in the prostate during acute inflammation and the chronic inflammatory setting of tumor growth, and that regulation of T-cell function by MDSC during a localized inflammatory response is restricted in vivo to the site of an ongoing immune response. PMID- 21287555 TI - The interleukin-7 receptor alpha chain contributes to altered homeostasis of regulatory T cells in multiple sclerosis. AB - Treg homeostasis is disturbed in multiple sclerosis (MS). Frequencies of recent thymic emigrant (RTE)-Treg are reduced and the disparity between RTE-Treg and long-lived memory Treg coincides with the MS-associated Treg defect, as shown previously. Recent studies demonstrate that IL-7 and thymic stromal lymphopoietin (TSLP) are critical for Treg maturation. Therefore, altered signaling through their receptors (IL-7R, TSLP receptor (TSLPR)), sharing the IL-7Ralpha-chain (IL 7Ralpha), might contribute to impaired Treg development. Using blood samples from 56 patients with MS and 33 healthy controls, we assessed IL-7Ralpha-expression on conventional T cells; frequencies, phenotypes and suppressive activities of Treg, plasma levels of IL-7 and soluble IL-7Ralpha; and screened for MS-associated IL 7RA gene polymorphism rs6897932. Moreover, we determined Treg expressing two different TCR Valpha-chains designating thymus-originated cells. As TSLP/TSLPR signaling in thymic myeloid dendritic cells (MDCs) promotes Treg differentiation, we measured TSLPR expression on peripheral MDCs to indirectly test whether altered TSLPR expression might add to compromised Treg neogenesis. We found reduced IL-7Ralpha expression on conventional T cells and upregulated IL-7 plasma levels together with reduction of RTE-Treg frequencies and Treg function in MS, without clear genetic influence. Decreased IL-7Ralpha expression in MS correlated with declined dual-receptor-Treg and reduced MDC TSLPR expression, indicating contracted thymic Treg output. We suggest that altered IL-7R/TSLPR signaling contributes to impaired Treg neogenesis in MS, which is compensated by expanded memory-Treg and finally results in dysfunctional Treg. PMID- 21287556 TI - Improved pharmacokinetics of AMG 517 through co-crystallization part 2: analysis of 12 carboxylic acid co-crystals. AB - Intrinsic dissolution, powder dissolution, and the pharmacokinetics (PK) of 12 carboxylic acid co-crystals of AMG 517 were determined and compared. Dissolution studies were performed in fasted simulated intestinal fluid (FaSIF). A control dissolution experiment was conducted with the free base in FaSIF plus sorbic acid to compare with the AMG 517 sorbic acid co-crystal (SRA). Suspension formulations in 1% polyvinylpyrrolidone K25 in water were administered orally at 100 mg/kg to rats. All co-crystals were found to have faster intrinsic and powder dissolution rates in FaSIF as well as higher area under the concentration-time curves (AUC) in rat PK investigations compared with the free base. The control dissolution experiment indicates that the increase in dissolution rate of SRA over the free base is not due to the presence of sorbic acid in the dissolution medium. Linear correlation of dissolution rate and AUC among the 12 co-crystals was moderate, indicating that in vitro dissolution is a valuable method to predict whether a co crystal will improve the exposure of a poorly soluble pharmaceutical ingredient; however, in vivo testing may be required to determine the extent. PMID- 21287557 TI - Characterization of site-specific glycation during process development of a human therapeutic monoclonal antibody. AB - A therapeutic recombinant monoclonal antibody (mAb1) was found to be highly susceptible to glycation during production. Up to 42% glycation was observed in mAb1, which was significantly greater than the glycation observed in 17 other monoclonal antibodies (mAbs). The majority of the glycation was localized to lysine 98 of a unique sequence in the heavy chain complementarity determining region 3. Upon incubation with 5% glucose at 37 degrees C for 5 days, the level of glycation rose to 80% of the total protein where the majority of the additional glycation was on the lysine 98 residue. These data suggested that the lysine 98 residue was highly susceptible to glycation. However, three other mAbs with a lysine residue in the same position did not show high rates of glycation in the forced glycation assay, suggesting that primary and perhaps secondary structural constraints could contribute to the rate of glycation at that lysine. Interestingly, a portion of the glycation in mAb1 was found to be reversible and upon incubation in phosphate buffer (pH 7) at 37 degrees C for 5 days, the glycation dropped from starting levels of 42% to 20%. Variation was observed in the total glycation levels between different lots of mAb1. The variability in glycation introduced charge heterogeneity in the form of an acidic peak on cation exchange chromatography and lead to product inconsistency. Mutation of lysine 98 to arginine reduced the starting level of glycation without any impact on potency. PMID- 21287558 TI - Study of the antioxidant properties of extracts obtained from nopal cactus (Opuntia ficus-indica) cladodes after convective drying. AB - BACKGROUND: The process of convective drying was evaluated in terms of the bioactive compounds contained in nopal samples before and after dehydration. Total polyphenol, flavonoid, flavonol, carotene and ascorbic acid contents were determined in undehydrated and dehydrated samples. Two drying temperatures (45 and 65 degrees C) and two air flow rates (3 and 5 m s(-1) ) were evaluated. The rheology of samples under the best drying conditions was also studied, since it provides important information regarding processing (mixing, flow processing) as well as the sensory attributes (texture) of rehydrated samples. RESULTS: Non Newtonian shear-thinning behaviour was observed for samples dried at 45 degrees C, while samples dried at 65 degrees C showed shear-thickening behaviour, possibly caused by thermal chain scission of high-molecular-weight components. CONCLUSION: The best conditions for bioactive compound preservation were a drying temperature of 45 degrees C and an air flow rate of 3 m s(-1) , resulting in 40.97 g phenols, 23.41 g flavonoids, 0.543 g beta-carotene and 0.2815 g ascorbic acid kg(-1) sample as shown in table 3. PMID- 21287559 TI - Cortical representation sites of mimic movements after facial nerve reconstruction: a functional magnetic resonance imaging study. AB - OBJECTIVES/HYPOTHESIS: To describe cortical reorganization after classic hypoglossal-facial nerve anastomosis (HFA) (four patients), hypoglossal-facial nerve jump anastomosis (HFJA) (three patients), and facial nerve interpositional graft (FNIG) (three patients). STUDY DESIGN: Prospective case series. METHODS: Functional magnetic resonance imaging (fMRI) was performed during lip and tongue movement using a block or an event-related design. RESULTS: Despite the presence of some intersubject variability, the following general brain activation patterns were revealed: As expected, lip movements after FNIG led to selective brain activation in the original facial motor cortex, and lip movements after HFA were associated with activation in the hypoglossal motor cortex. Following HFJA, lip movements resulted in overlapping activation encompassing both the original facial and the hypoglossal motor cortex, but tongue movements led solely to strong activation within the original hypoglossal motor cortex. In contrast, tongue movements after HFA were associated with strong activation in the original hypoglossal motor cortex and weaker activation in the facial motor cortex. CONCLUSIONS: Direct facial nerve repair (FNIG) leads to restoration of the original cortical activation. A cross nerve suture (HFA or HFJA) changes cortical activation and leads to different patterns of cortical activation during lip and tongue movements. PMID- 21287560 TI - Treatment of postinfectious olfactory disorders with minocycline: a double-blind, placebo-controlled study. AB - OBJECTIVES/HYPOTHESIS: Infection of the upper respiratory tract is one of the most common causes of olfactory loss. One of the possible underlying pathologic pathways is an increase of apoptosis of olfactory receptor neurons. Therefore, treatment with the antibiotic minocycline, which has been shown to act as an antiapoptotic agent, is thought to accelerate improvement of olfactory function. To investigate this idea, 55 patients with postinfectious olfactory dysfunction were tested for their olfactory ability. STUDY DESIGN: Randomized, prospective, double-blind, placebo-controlled. METHODS: Olfactory function was examined by means of a standardized psychophysical method (Sniffin' Sticks) before and 7 months after a 3-week treatment with either minocycline (2 * 50 mg/d) or a placebo. RESULTS: Statistical analyses did not reveal any influence of the treatment on the progress of olfactory function, possibly indicating that pathologic changes other than apoptosis contribute to postinfectious olfactory loss, either on a peripheral level (e.g., scarring/reorganization of the olfactory epithelium) or on a central nervous level. CONCLUSIONS: In conclusion, the present results indicate that minocycline in the given dosage has little or no effect on the recovery of human olfactory function following postinfectious olfactory loss. However, spontaneous recovery is found in approximately 20% of the patients over an observation period of 7 months. PMID- 21287561 TI - Pedicled nasoseptal flap is not the standard of care for skull base defects. PMID- 21287562 TI - Injection of cultured autologous fibroblasts for human vocal fold scars. AB - OBJECTIVES: This study evaluated the safety and effectiveness of injection of autologous fibroblasts into the lamina propria layer to treat vocal fold scarring. STUDY DESIGN: A prospective, open-label, single arm, pilot study at a single tertiary care center. METHODS: Autologous fibroblasts were expanded in cell culture from punch biopsies of the buccal mucosa of five human subjects with vocal fold scarring. Three doses of 1-2 * 10(7) cells/mL were injected into the superficial lamina propria layer of each scarred vocal fold at four-week intervals. The primary efficacy measure was an objective evaluation of the mucosal wave grade; secondary measures included acoustic analyses, a patient completed voice handicap index (VHI) survey, and voice quality questionnaire. Safety assessments included clinical laboratory blood tests, vital signs, and monitoring for adverse events. Patients were followed for 12 months following the first treatment. RESULTS: Mucosal wave grade improved and the improvement was sustained through month 12. Sustained improvements through month 12 were also noted for the VHI and voice quality questionnaire. Multiple injections of autologous fibroblasts into the lamina propria were well tolerated. Temporary otalgia was noted following treatment in two subjects. CONCLUSIONS: This study demonstrates that injection of autologous fibroblasts into the scarred vocal fold lamina propria layer is safe. Sustained trends for improved outcome were supported by 12-month data for mucosal wave grade, VHI, and voice quality questionnaire. PMID- 21287563 TI - Clinical comparison of hearing-impaired patients with DFNB1 against heterozygote carriers of connexin 26 mutations. AB - OBJECTIVES: The aim of the study is to assess clinical characteristics of individuals with nonsyndromic sensorineural hearing loss (NSSNHL) with genetic mutations in GJB2 and/or GJB6. We describe and compare one group with biallelic mutations against a group of heterozygote mutation carriers. METHODS: A total of 350 patients between the ages of 3 months and 80 years referred to a tertiary care outpatient otology practice for NSSNHL were screened for genetic mutations. Direct sequencing of GJB2 and polymerase chain reaction analysis of GJB6 was performed and clinical data from history and physical, audiologic testing and radiographic studies were reviewed. RESULTS: Thirty-two patients were found to have biallelic mutations (incidence of 9.1%). Twenty-five patients were found to have only one GJB2 mutation (incidence of 7.1%). Severe to profound hearing loss occurred in 85% of the homozygote group and 38% of the heterozygote group. Both groups similarly had a propensity toward bilateral, symmetric, nonprogressive hearing loss with rare inner ear malformations on radiologic imaging. CONCLUSIONS: These two patient populations have similar incidences in a cohort of patients evaluated for NSSNHL, which is higher than general population heterozygote carrier rates. Heterozygote mutation carriers had less hearing impairment, but most other factors demonstrated no differences. These results support the theory of an unidentified genetic factor contributing to hearing loss in some heterozygote carriers. Therefore, genetic counseling should consider the complexity of their genetic factors and the limitations of current screening. PMID- 21287564 TI - Variable changes in PET activity before and after rTMS treatment for tinnitus. AB - OBJECTIVES/HYPOTHESIS: The objective was to determine whether low-frequency repetitive transcranial magnetic stimulation (rTMS) improves tinnitus by decreasing neural activity in auditory processing regions of the temporal cortex and the utility of positron emission tomography (PET) for targeting treatment. STUDY DESIGN: Randomized, sham-controlled crossover. METHODS: Patients received a five-day course of active and sham 1-Hz rTMS (1800 pulses at 110% of motor threshold) to the temporal cortex, with a week separating active and sham treatment. Visual analogue ratings of tinnitus loudness (VARL) were assessed at baseline and the end of each treatment week; regional brain blood flow (rBBF) and glucose metabolism (via PET) were measured before and after treatment in regions of interest (ROI) beneath the stimulating coil and control sites. RESULTS: The VARL for both ears significantly decreased after active but not sham treatment. Responders comprised 43% of patients, experiencing at least a 33% drop in tinnitus loudness. The site most consistently associated with a positive response was the secondary auditory cortex (Brodmann Area 22) in either hemisphere. PET asymmetries were variable across patients and not always accessible to rTMS. Whereas PET activity decreased significantly beneath the stimulating coil following active treatment, similar changes occurred at control sites and after sham stimulation. Change in tinnitus perception did not correlate significantly with change in PET activity at the treatment site ROI. CONCLUSIONS: Active TMS led to a significant reduction in tinnitus loudness, but PET scans failed to support the hypothesis that low-frequency rTMS improves tinnitus by reducing cortical activation at the stimulation site, questioning the utility of PET for targeting rTMS. PMID- 21287565 TI - Is hyperoxic ventilation important to treat acute coronary syndromes such as myocardial infarction? AB - After reviewing the literature, I was unable to find hard evidence that the use of supplemental oxygen (hyperbaric or normobaric) in an uncomplicated acute myocardial infarction (AMI) is beneficial, and there is some evidence that it may be harmful. PMID- 21287566 TI - Nuchal translucency measurement in fetuses with spinal muscular atrophy. AB - OBJECTIVE: Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder with a high carrier frequency in the general population. The severity of this disorder indicates the importance of early prenatal detection. In medical literature, there are a few published case reports of enlarged nuchal translucency (NT) measurement in association with a diagnosis of SMA in the fetus. Our goal is to determine whether SMA in infants is associated with a history of an increased NT measurement during pregnancy. METHODS: Using contact information obtained through SMA family support groups, women who had recently given birth to infants affected with SMA were identified and queried about NT ultrasound results during the pregnancy. NT values were confirmed via ultrasound report to determine whether SMA was associated with a history of an enlarged NT measurement. RESULTS: Twelve SMA affected infants with confirmed NT results during the pregnancy were identified. All fetuses had normal NT values ranging from 0.7 to 2.4 mm. CONCLUSION: In this series, SMA did not appear to be associated with an enlarged NT. PMID- 21287567 TI - Fetal myocardial injury progressing to ventricular septal rupture and aneurysm formation. PMID- 21287568 TI - The role of fatty acids in anti-inflammatory effects of low-intensity extremely high-frequency electromagnetic radiation. AB - The effects of low-intensity extremely high-frequency electromagnetic radiation (EHF EMR; 42.2 GHz, 0.1 mW/cm(2) , exposure duration 20 min) on the fatty acid (FA) composition of thymic cells and blood plasma in normal mice and in mice with peritoneal inflammation were studied. It was found that the exposure of normal mice to EHF EMR increased the content of polyunsaturated FAs (PUFAs) (eicosapentaenoic and docosapentaenoic) in thymic cells. Using a model of zymosan induced peritoneal inflammation, it was shown that the exposure of mice to EHF EMR significantly increased the content of PUFAs (dihomo-gamma-linolenic, arachidonic, eicosapentaenoic, docosapentaenoic, and docosahexaenoic) and reduced the content of monounsaturated FAs (MUFAs) (palmitoleic and oleic) in thymic cells. Changes in the FA composition in the blood plasma were less pronounced and manifested themselves as an increase in the level of saturated FAs during the inflammation. The data obtained support the notion that MUFAs are replaced by PUFAs that can enter into the thymic cells from the external media. Taking into account the fact that the metabolites of PUFAs are lipid messengers actively involved in inflammatory and immune reactions, we assume that the increase in the content of n-3 and n-6 PUFAs in phospholipids of cellular membranes facilitates the realization of anti-inflammatory effects of EHF EMR. PMID- 21287569 TI - Recent advances in search of oral heparin therapeutics. AB - Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) are first choices of clinicians among available anticoagulants. Currently, these agents are administered either parenterally or subcutaneously, which reduces patient compliance and acceptability. Oral heparin may serve as an alternative to both parenteral heparin as well as presently available oral anticoagulants such as warfarin. This review focuses mainly upon recent perspectives in the development of heparin as an oral anticoagulant. The possibility of its success with special emphasis to nanotechnological approaches has been elaborated. Important strategies such as the use of penetration enhancers, the development of lipid conjugates of heparin, and the incorporation of heparin in polymeric matrix systems have been discussed. Additionally, introductory information on biological activities, physiochemical aspects, and pharmacokinetic and pharmacodynamic parameters of heparin is summarized. A brief comparison of UFH and LMWH is also included for reader's benefit. Informative discussion on clinical trials with the successes and limitations of oral heparin formulations is also presented. Overall, the present review provides complete insight to the research that has been carried out for the development of heparin as oral anticoagulant. PMID- 21287570 TI - Transporters that translocate nucleosides and structural similar drugs: structural requirements for substrate recognition. AB - Nucleoside transporters (NT) are integral membrane proteins implicated in the salvage of natural nucleobases and nucleosides for nucleic acid synthesis. These proteins also play a crucial role as carriers of nucleoside analogs used in anticancer and antiviral therapies. In fact, differential expression patterns of NT subtypes among tissues and individuals as well as the existence of genetic variants affect nucleoside-derived drug permeation, and consequently, their pharmacokinetic and cytotoxic properties. Thus, NT expression patterns may be effective predictive markers of therapeutic response. While the structures of NT proteins are yet to be solved, specific residues responsible for interaction with substrates and inhibitors have been identified, providing further insights into their structure-function relationship. In addition to transporter structural features, several experimental approaches have been used to identify the structural requirements of nucleosides for interaction with Concentrative Nucleoside Transporters and Equilibrative Nucleoside Transporters (SLC28 and SLC29 gene families, respectively). Pharmacophore models proposed for both protein families may prove suitable for optimizing drug design. Additional transporter proteins, including Organic Anion Transporters, Organic Cation Transporters (members of the SLC22 gene family), and Peptide Transporters (SLC15 gene family), have been implicated in the uptake of nucleoside-derived drugs, particularly those currently used in antiviral therapies. In this review, we focus on the pharmacological profiles of these transporter proteins, summarizing the documented studies covering structure-function and substrate structural requirement properties that determine drug-carrier interaction and efficient substrate translocation across the plasma membrane of target cells. PMID- 21287571 TI - Endomorphins: potential roles and therapeutic indications in the development of opioid peptide analgesic drugs. AB - The application of endomorphins as clinical available analgesic drugs has been impeded by their relatively poor receptor selectivity compared with alkaloid analgesics, rapid degradation in vivo, inefficient to penetrate the blood-brain barrier (BBB), and undesirable or toxic effects, such as acute tolerance and physical dependence, respiratory depression, and inhibition of gastrointestinal motility. Extensive studies have been performed so far striving to conquer these problems. In this article we review and discuss conformational and topographical modifications of the peptide amide bond and amino acid side groups to attain the most appropriate receptor binding affinity and high receptor selectivity; diverse strategies such as insertion of unnatural amino acids, covalent or noncovalent constraints as well as cyclization of linear peptides to enhance the enzymatic stability; designing of peptidomimetic ligands, glycopeptides, and N-terminal amidinationed analogues (such as incorporating guanidine into endomorphins) to penetrate the BBB. Also, several pertinent examples of bivalent and/or multivalent (such as mixed u-agonist/delta-antagonist profile) compounds are discussed based on the existing literature and current data intending to give an insight into the development of opioid peptides expressing low tendency to produce acute tolerance and physical dependence. PMID- 21287572 TI - Targeted drug delivery and penetration into solid tumors. AB - Delivery and penetration of chemotherapeutic drugs into tumors are limited by a number of factors related to abnormal vasculature and altered stroma composition in neoplastic tissues. Coupling of chemotherapeutic drugs with tumor vasculature homing peptides or administration of drugs in combination with biological agents that affect the integrity of the endothelial lining of tumor vasculature is an appealing strategy to improve drug delivery to tumor cells. Promising approaches to achieve this goal are based on the use of Asn-Gly-Arg (NGR)-containing peptides as ligands for drug delivery and of NGR-TNF, a peptide-tumor necrosis factor-alpha fusion protein that selectively alters drug penetration barriers and that is currently tested in a randomized Phase III trial in patients with malignant pleural mesothelioma. PMID- 21287573 TI - Oleoyl-estrone. AB - Oleoyl-estrone (OE) is a powerful slimming agent that is also present in plasma and adipose tissue, where it is synthesized. It acts through the formation of a derivative W. OE effects (and W levels) are proportional to the dose. OE reduces food intake but maintains energy expenditure (thermogenesis). The energy gap is fulfilled with adipose tissue fat, sparing body protein and maintaining glycemia (and glycogen) with lower insulin and leptin levels. OE (in fact W) acts through specific receptors, different from those of estrogen. OE increases cholesterol catabolism, reducing hypercholesterolemia in obese rats. The main metabolic effect on adipose tissue is lowering of lipid synthesis, maintaining unchanged the intracellular lipolytic processes; the imbalance favors the progressive loss of fat, which is largely used by the muscle. OE administration induces additive effects with other antiobesity agents, such as beta(3)-adrenergic agonists, forcing a massive loss of lipid. Corticosteroids markedly limit OE action by altering the liver control of lipogenesis. OE also inhibits the action of 17beta hydroxysteroid dehydrogenase, decreasing the synthesis of beta-estradiol and testosterone. Discontinuous treatment allows for maximal efficacy both in rats and humans. OE has the advantage that the loss of fat is maintained and does not require additional dietary limitations. PMID- 21287574 TI - First survey of the three gene polymorphisms (PON1 Q192R, eNOS E298D and eNOS C 786T) potentially associated with coronary artery spasm in African populations and comparison with worldwide data. AB - Three polymorphisms, Paraoxonase 1 (PON1) Q192R (C/G), endothelial nitric oxide synthase (eNOS) E298D (G/T) and eNOS T-786C have been suggested to be potentially associated with coronary artery spasm in Japanese patients. Data on worldwide populations are needed to clarify whether these associations could hold true for other populations. However, few data are available especially in Africans, spasm of which has been suggested to be an aetiology of myocardial infarction. Therefore, these polymorphisms were investigated in three Africans, Ovambos (n = 123), Ghanians (n = 118) and Xhosas (n = 96), together with Japanese (n = 96), by using polymerase chain reaction-restriction fragment length polymorphism analysis. Genotype-distributions of all these SNPs in African populations were significantly different from those in Caucasians, whereas were similar to those in Japanese population. African populations exhibit relatively higher frequency of spasm-associated G192 allele in PON1 Q192R being similar to Japanese population, however frequencies of spasm-associated T298 allele and -C786 allele in SNP eNOS E298D and T-786C, respectively, were conversely lower in Africans than Caucasians. Although healthy subjects have been recruited in this study, these findings may provide genetic background for elucidation of aetiology of spasm. PMID- 21287575 TI - Participation of the liver gluconeogenesis in the glibenclamide-induced hypoglycaemia in rats. AB - We previously demonstrated an increased liver gluconeogenesis (LG) during insulin induced hypoglycaemia. Thus, an expected effect of sulphonylureas induced hypoglycaemia (SIH) could be the activation of LG. However, sulphonylureas infused directly in to the liver inhibits LG. Considering these opposite effects we investigated herein LG in rats submitted to SIH. For this purpose, 24 h fasted rats that received glibenclamide (10 mg kg(-1) ) were used (SIH group). Control group received oral saline. Glycaemia at 30, 60, 90, 120 and 150 min after oral administration of glibenclamide were evaluated. Since the lowest glycaemia was obtained 120 min after glibenclamide administration, this time was chosen to investigate LG in situ perfused livers. The gluconeogenesis from precursors that enters in this metabolic pathway before the mitochondrial step, i.e. L-alanine (5 mM), L-lactate (2 mM), pyruvate (5 mM) and L-glutamine were decreased (p < 0.05). However, the gluconeogenic activity using glycerol (2 mM), which enters in the gluconeogenesis after the mitochondrial step was maintained. Taken together, the results suggest that the inhibition of LG promoted by SIH overcome the activation of this metabolic pathway promoted by IIH and could be attributed, at least in part, to its effect on mitochondrial function. PMID- 21287576 TI - Ceftriaxone ameliorates cyclosporine A-induced oxidative nephrotoxicity in rat. AB - A growing body of evidence now suggested that cyclosporine A (CycA)-induced nephrotoxicity is a crucial clinical problem and oxidative stress is importantly responsible for its toxicity. Ceftriaxone induced antioxidant effect in brain and neuronal tissues against oxidative damage although its antioxidant potential effect on kidney has not been clarified. The aim of this study was to evaluate whether ceftriaxone protects CycA-induced oxidative stress kidney injury in rats. Twenty-four rats were equally divided into four groups. First group was used as control. Ceftriaxone (200 mg/kg) and CycA (15 mg/kg) were administrated to second and third groups for 10 days, respectively. The ceftriaxone and CycA combination was given to rats constituting the fourth group for 10 days. Lipid peroxidation (LP), urea nitrogen and lactate dehydrogenase (LDH) levels were higher in CycA group than in control and ceftriaxone groups although LP, urea nitrogen and LDH levels were lower in ceftriaxone + CycA group than in control and ceftriaxone groups. Glutathione peroxidase and catalase activities were lower in CycA group than in control whereas their activities were increased in control and ceftriaxone groups. Superoxide dismutase activity did not change by the treatments. Ceftriaxone administration recovered also CycA-induced atrophy, vacuolization and exfoliations of tubular epithelium and glomerular collapse in histopathological evaluation of kidney. In conclusion, we observed that ceftriaxone is beneficial on CycA-induced oxidative stress in kidney of rats by modulating oxidative and antioxidant system. PMID- 21287577 TI - Estrogen receptor alpha is essential for the proliferation of prostatic smooth muscle cells stimulated by 17beta-estradiol and insulin-like growth factor 1. AB - Estradiol (E2) and its receptor estrogen receptor alpha (ERalpha) are implicated in the pathology of stromal-predominant benign prostatic hyperplasia (BPH). Insulin-like growth factor 1(IGF1) is produced primarily by stromal cells in the prostate. Recent study showed that E2-mediated regulation of IGF1 in mouse uterus requires the DNA binding ability of ERalpha. However, the crosstalk between ERalpha and IGF1 in the prostate has not been addressed yet. Therefore, in this study we employed mouse prostatic smooth muscle cells (PSMCs) as a model to demonstrate that E2 stimulated the proliferation of PSMCs and up-regulated the expression of IGF1 and its receptor IGF1R as well as cyclin D1 in PSMCs, all of which could be inhibited by shRNA-mediated knockdown of ERalpha. Furthermore, we found that exogenous IGF1 could not promote cell proliferation and cyclin D1 expression in PSMCs subjected to shRNA-mediated knockdown of ERalpha. Interestingly, blockage of IGF1R by antibody could inhibit E2-stimulated PSMCs proliferation. Altogether our present study provides the first line of evidence that there is crosstalk between ERalpha and IGF1 signaling in PSMCs proliferation in which ERalpha up-regulates the expression of IGF1 and IGF1R, and IGF1 signaling is indispensable to mediate downstream effects of E2 and ERalpha. PMID- 21287578 TI - An activator of PHD2, KRH102140, decreases angiogenesis via inhibition of HIF 1alpha. AB - Hypoxia-inducible transcription factors (HIFs) play a pivotal role in the response of cells to hypoxia. HIFs are dimers of an oxygen-sensitive alpha subunit (HIF-1alpha or HIF-2alpha), and a constitutively expressed beta-subunit. In normoxia, HIF-1alpha is destabilized by post-translational hydroxylation of Pro-564 and Pro-402 by a family of oxygen-sensitive dioxygenases. Prolyl hydroxylation leads to von Hippel-Lindau protein-dependent ubiquitination and rapid degradation of HIF-1alpha. We previously reported that KRH102053, an activator of PHD2, rapidly decreased HIF-1alpha and eventually inhibited angiogenesis. Here, we report a potent activator of PHD2, KRH102140, which has a structure similar to KRH102053. KRH102140 more efficiently suppressed HIF-1alpha than KRH102053 in human osteosarcoma cells under hypoxia. Furthermore, KRH102140 decreased the mRNA levels of HIF-regulated downstream target genes associated with angiogenesis and energy metabolism such as vascular endothelial growth factor, adrenomedullin, Glut1, aldolase A, enolase 1 and monocarboxylate transporter 4. KRH102140 also inhibited tube formation in human umbilical vein endothelium cells. The results suggest that KRH102140 has potential therapeutic effects in alleviating various diseases associated with HIFs. PMID- 21287579 TI - Effects of structural analogues of nociceptin(1-13)NH2 on brain antioxidant status in kainic acid-treated rats. AB - The in vivo effects of nociceptin (N/OFQ(1-13)NH(2) ) and its structural analogues ([Dab(9) ]N/OFQ(1-13)NH(2) , [Dap(9) ]N/OFQ(1-13)NH(2) and [Cav(9) ]N/OFQ(1-13)NH(2) ) on the levels of lipid peroxidation and cell antioxidants (enzyme and non-enzyme) in brain of control and kainic acid (KA)-treated rats were studied. In control animals, [Dab(9) ]N/OFQ(1-13)NH(2) and [Dap(9) ]N/OFQ(1 13)NH(2) , unlike N/OFQ(1-13)NH(2) and [Cav(9) ]N/OFQ(1-13)NH(2) , slightly increased the brain lipid peroxidation; the rest of the parameters were unchanged by all neuropeptides tested. KA (0.25 ug in 0.5 ul, i.c.v) increased the lipid peroxidation (4 and 24 h after KA-injection) and decreased the glutathione level (1 h after KA-administration). One hour after KA-administration, the neuropeptides (2 ug in 0.5 ul, injected 30 min before KA) showed the following effects: a slight decrease in the KA-induced lipid peroxidation by all nociceptin analogues and an enhancement of the KA-decreased GSH level, but by [Cav(9) ]N/OFQ(1-13)NH(2) only. The brain antioxidant enzyme activities were unchanged in all used experimental groups. In addition, the nociceptin analogues, especially [Can(9) ]N/OFQ(1-13)NH(2) , showed a good antioxidant capacity in chemical systems, generating reactive oxygen species. In conclusion, the substitution of lysin (Lys) in N/OFQ(1-13)NH(2) molecule with other amino acids might contribute to changes in its antioxidant properties. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 21287580 TI - Effect of ubiquitin carboxy-terminal hydrolase 37 on apoptotic in A549 cells. AB - Proteins destined for degradation by the ubiquitin-proteasome system are labelled with a 76-amino acid peptide, ubiquitin, through a series of conjugation steps by the E1, E2 and E3 enzymes respectively. Ubiquitin carboxy-terminal hydrolase 37 (UCH37) belongs to the UCH proteases family that deubiquitinates ubiquitin protein conjugates in the ubiquitin-proteasome system. However, it is few reports about the relationship between UCH37 and apoptosis. In order to clarify the role of UCH37 on apoptosis, the A549 cells were chosen for this study. We transfected UCH37 siRNA and pcDNA3.1-UCH37 plasmid into A549 cells, respectively. Using MTT assay, Western blot, Hoechst 33342 staining assay and flow cytometry, we found that silencing of UCH37 in A549 cells induced apoptosis. The ratio of Bax/Bcl-2 was higher in silencing of UCH37 than that in control group after silencing of UCH37 in A549 cells. Meanwhile, experiments with the A549 cell line disclose that silencing of UCH37 could induce efficiently A549 cell apoptosis through activation of caspase-9 and caspase-3. On the other hand, over-expression of UCH37 led to the opposite effect. Hence, UCH37 might play an important role in apoptotic through altering Bax/Bcl-2 ratio and enzymatic activities of caspase-9 and caspase-3. PMID- 21287581 TI - Quantification of 1-(13) C-L-methionine in rat serum with hydrophilic interaction liquid chromatography coupled with tandem mass spectrometry and its application in pharmacokinetic study. AB - A rapid, selective and sensitive hydrophilic interaction liquid chromatography (HILIC) coupled with tandem mass spectrometry (MS/MS) method was developed to determine 1-(13) C-l-methionine in rat serum. Proteins in serum were precipitated using acetonitrile and the supernatant was separated after centrifugation. 1-(13) C-l-phenylalnine was used as the internal standard. HILIC-tandem mass spectrometry analysis was performed on a hydrophilic interaction silica column (TSK-GEL AMIDE-80) using a linear gradient elution system, acetonitrile-5 mm ammonium acetate containing 0.1% formic acid and multiple reaction monitoring mode for 1-(13) C-l-methionine and 1-(13) C-l-phenylalnine. The assay was validated with a linear range between 10 and 150 ng mL(-1) (r >= 0.99) and a lower limit of quantification of 10 ng mL(-1) , calculated with weighted (1/x(2) ) least squares linear regression. The RSD of intra-day precision was smaller than 3.6% and the inter-day RSD less than 6.5%, while the average recovery was 100.48% with an RSD of accuracy within 2.9%, determined from quality control samples. The HILIC-MS/MS method was fully validated and successfully applied to the in vivo pharmacokinetic study of stable-isotope 1-(13) C-l-methionine in rats. PMID- 21287582 TI - Determination of spinetoram in leafy vegetable crops using liquid chromatography and confirmation via tandem mass spectrometry. AB - Spinetoram is a second-generation member of the spinosyn class, all members of which have been shown to be effective in insect control via a novel mode of action. Spinetoram is a mixture of 3'-O-ethyl-5, 6-dihydro spinosyn J (XDE-175-J) and 3'-O-ethyl spinosyn L (XDE-175-L). In order to establish a determination method for the analysis of spinetoram residues in crops, commercial product (5% suspension concentrate spinetoram) was applied to two leafy vegetables (Garland chrysanthemum and Aster scaber) on different spraying schedules. The analytical method used herein was based on a reversed-phase separation on a C(18) column, isocratic elution and UV detection. The analytes were confirmed via tandem mass spectrometry. The method was linear over a concentration range of 0.05-10 ppm with a correlation coefficient in excess of 0.9998. The recoveries of XDE-175-J and XDE-175-L from the two vegetables ranged between 86.04 and 98.87% at spiking levels of 1 and 5 ppm. The relative standard deviations were no more than 7% for all recovery tests conducted herein. The calculated limits of detection and quantification were 0.01 and 0.03 ppm for both XDE-175-J and XDE-175-L. The levels of residues in two vegetables treated under a fixed schedule in the greenhouse were 6.21-0.55 ppm (maximum residue limit (MRL) = 7 ppm). In sum, this method constitutes an easy and reliable technique for the determination of spinetoram in leafy vegetables. PMID- 21287583 TI - Application of dried blood spot sampling combined with LC-MS/MS for genotyping and phenotyping of CYP450 enzymes in healthy volunteers. AB - An early clinical development study (phase I) was conducted to determine the usefulness of dried blood spot (DBS) sampling as an alternative to venous sampling for phenotyping and genotyping of CYP450 enzymes in healthy volunteers. Midazolam (MDZ) was used as a substrate for phenotyping CYP3A4 activity; the concentrations of MDZ and its main metabolite 1'-hydroxymidazolam (1-OH MDZ) were compared between the DBS method from finger punctures, plasma and whole blood (WB), drawn by venipuncture, whereby several methodological parameters were studied (i.e. punch width, amount of dots analyzed and storage time stability). Genotyping between DBS and venous WB samples was compared for CYP2D6 (*3, *4, *6), CYP2C19 (*2, *3), CYP3A4 (*1B) and CYP3A5 (*3C). In addition, the subject's and phlebotomist's satisfaction with venous blood sampling compared with the DBS method was evaluated using a standardized questionnaire. An LC-MS/MS method for the quantification of the MDZ and 1-OH MDZ concentrations in DBS samples was developed and validated in the range of 0.100-100 ng/mL. No compromises were made for the limits of quantification of the DBS-LC-MS/MS method vs the authentic plasma and WB methods. PMID- 21287584 TI - Rapid determination of rifaximin on dried blood spots by LC-ESI-MS. AB - The use of blood spot collection cards is a simple way to obtain specimens for therapeutic drug monitoring, assessing adherence to medications and preventing toxicity in a clinical setting. A high-throughput liquid chromatography electrospray ionization mass spectrometric (LC-ESI-MS) method for determination of rifaximin on dried blood spots (DBS) was developed and validated. It involves solvent extraction of a punch of DBS followed by reversed-phase LC on a monolithic column consisting of a silica rod with bimodal pore structure and detection by ESI-MS. Rifampicin was used as an internal standard (IS). The run time was within 5.0 min with a very low back-pressure at a flow rate of 0.5 mL/min. The assay was linear from 0.1 to 10 ng/mL. The mean recovery was 98.42%. The developed method is very simple, rapid and useful for clinical applications. PMID- 21287585 TI - A comparative study on testicular microstructure and relative sperm production in gorillas, chimpanzees, and orangutans. AB - We performed histological analyses for comparing testicular microstructure between the gorilla, chimpanzee, and orangutan. Testicular samples were obtained by autopsy or biopsy from 10 gorillas, 11 chimpanzees, and 7 orangutans from several zoos and institutes. The seminiferous epithelia were thick in the chimpanzee and orangutan but thin in the gorilla. Leydig cells in the interstitial tissue were abundant in the gorilla. The acrosomic system was extremely well developed in the orangutans. Our study reveals that the cycle of seminiferous epithelium in orangutan testis can be divided into ten stages, whereas that in human, chimpanzee, and gorilla testes can be divided into only six stages. Phylogenetic analyses of the number of divisions may indicate that the seminiferous epithelium of our common ancestor has changed since the orangutan diverged from it. Furthermore, we performed comparative analyses of testicular microstructure to estimate relative sperm production among these three animals, and proposed a new indicator (namely the spermatogenic index, SI) closely related to sperm production. The SI indicated that a chimpanzee usually produces about 223 times more sperm than a gorilla and about 14 times more than an orangutan. Our data demonstrate the significance of the SI for estimating sperm production, thus aiding our understanding of the reproductive strategy as well as testis weight and relative testis size in investigated primates. PMID- 21287586 TI - Measuring disease burden in the older population using the slope-intercept method for population log-linear estimation (SIMPLE). AB - Estimating disease burden in the older population can be problematic, due to a dearth of measurements that take into account population dynamics, small population sizes, and age-related disease distribution issues. Age itself explains a substantial amount of the variability in population disease rates. However, in many common techniques to account for age, such as age standardization and age categorization, age is treated as a nuisance parameter. In this paper, we present a method, the slope-intercept method for population log linear estimation (SIMPLE), to assess disease burden in the Medicare population of the US. We demonstrate the utility and potential limitations of this straightforward and crude method in assessing age-related morbidity, mortality, and case-fatality on multiple geographic levels. We highlight several examples of when this measure is most applicable using examples abstracted from a comprehensive administrative database of hospitalizations in older adults. Traditional measurements of disease burden are compared with the measurements extracted from this modeling method for comparison purposes. We also present spatial and temporal associations between the two measurements the SIMPLE method produces. PMID- 21287587 TI - Power of tests for comparing trend curves with application to national immunization survey (NIS). AB - To develop statistical tests for comparing trend curves of study outcomes between two socio-demographic strata across consecutive time points, and compare statistical power of the proposed tests under different trend curves data, three statistical tests were proposed. For large sample size with independent normal assumption among strata and across consecutive time points, the Z and Chi-square test statistics were developed, which are functions of outcome estimates and the standard errors at each of the study time points for the two strata. For small sample size with independent normal assumption, the F-test statistic was generated, which is a function of sample size of the two strata and estimated parameters across study period. If two trend curves are approximately parallel, the power of Z-test is consistently higher than that of both Chi-square and F test. If two trend curves cross at low interaction, the power of Z-test is higher than or equal to the power of both Chi-square and F-test; however, at high interaction, the powers of Chi-square and F-test are higher than that of Z-test. The measurement of interaction of two trend curves was defined. These tests were applied to the comparison of trend curves of vaccination coverage estimates of standard vaccine series with National Immunization Survey (NIS) 2000-2007 data. PMID- 21287588 TI - Adjusting for confounding by neighborhood using complex survey data. AB - Recently, we examined methods of adjusting for confounding by neighborhood of an individual exposure effect on a binary outcome, using complex survey data; the methods were found to fail when the neighborhood sample sizes are small and the selection bias is strongly informative. More recently, other authors have adapted an older method from the genetics literature for application to complex survey data; their adaptation achieves a consistent estimator under a broad range of circumstances. The method is based on weighted pseudolikelihoods, in which the contribution from each neighborhood involves all pairs of cases and controls in the neighborhood. The pairs are treated as if they were independent, a pairwise pseudo-conditional likelihood is thus derived, and then the corresponding score equation is weighted with inverse-probabilities of sampling each case-control pair. We have greatly simplified the implementation by translating the pairwise pseudo-conditional likelihood into an equivalent ordinary weighted log-likelihood formulation. We show how to program the method using standard software for ordinary logistic regression with complex survey data (e.g. SAS PROC SURVEYLOGISTIC). We also show that the methodology applies to a broader set of sampling scenarios than the ones considered by the previous authors. We demonstrate the validity of our simplified implementation by applying it to a simulation for which previous methods failed; the new method performs beautifully. We also apply the new method to an analysis of 2009 National Health Interview Survey (NHIS) public-use data, to estimate the effect of education on health insurance coverage, adjusting for confounding by neighborhood. PMID- 21287589 TI - Longitudinal analysis of large social networks: estimating the effect of health traits on changes in friendship ties. AB - We develop novel mixed effects models to examine the role of health traits on the status of peoples' close friendship nominations in the Framingham Heart Study. The health traits considered are both mutable (body mass index (BMI), smoking, blood pressure, body proportion, muscularity, and depression) and, for comparison, basically immutable (height, birth order, personality type, only child, and handedness); and the traits have varying degrees of observability. We test the hypotheses that existing ties (i.e. close friendship nominations) are more likely to dissolve between people with dissimilar (mutable and observable) health traits whereas new ties are more likely to form between those with similar (mutable and observable) traits while controlling for persons' age, gender, geographic separation, and education. The mixed effects models contain random effects for both the nominator (ego) and nominated (alter) persons in a tie to account for the fact that people were involved in multiple relationships and contributed observations at multiple exams. Results for BMI support the hypotheses that people of similar BMI are less likely to dissolve existing ties and more likely to form ties, while smoker to non-smoker ties were the least likely to dissolve and smoker to smoker ties were the most likely to form. We also validated previously known findings regarding homophily on age and gender, and found evidence that homophily also depends upon geographic separation. PMID- 21287590 TI - Monitoring bone marrow-originated mesenchymal stem cell traffic to myocardial infarction sites using magnetic resonance imaging. AB - How stem cells promote myocardial repair in myocardial infarction (MI) is not well understood. The purpose of this study was to noninvasively monitor and quantify mesenchymal stem cells (MSC) from bone marrow to MI sites using magnetic resonance imaging (MRI). MSC were dual-labeled with an enhanced green fluorescent protein and micrometer-sized iron oxide particles prior to intra-bone marrow transplantation into the tibial medullary space of C57Bl/6 mice. Micrometer-sized iron oxide particles labeling caused signal attenuation in T(2)*-weighted MRI and thus allowed noninvasive cell tracking. Longitudinal MRI demonstrated MSC infiltration into MI sites over time. Fluorescence from both micrometer-sized iron oxide particles and enhanced green fluorescent protein in histology validated the presence of dual-labeled cells at MI sites. This study demonstrated that MSC traffic to MI sites can be noninvasively monitored in MRI by labeling cells with micrometer-sized iron oxide particles. The dual-labeled MSC at MI sites maintained their capability of proliferation and differentiation. The dual labeling, intra-bone marrow transplantation, and MRI cell tracking provided a unique approach for investigating stem cells' roles in the post-MI healing process. This technique can potentially be applied to monitor possible effects on stem cell mobilization caused by given treatment strategies. PMID- 21287591 TI - Intravoxel incoherent motion imaging of tumor microenvironment in locally advanced breast cancer. AB - Diffusion-weighted imaging plays important roles in cancer diagnosis, monitoring, and treatment. Although most applications measure restricted diffusion by tumor cellularity, diffusion-weighted imaging is also sensitive to vascularity through the intravoxel incoherent motion effect. Hypervascularity can confound apparent diffusion coefficient measurements in breast cancer. We acquired multiple b-value diffusion-weighted imaging at 3 T in a cohort of breast cancer patients and performed biexponential intravoxel incoherent motion analysis to extract tissue diffusivity (D(t)), perfusion fraction (f(p)), and pseudodiffusivity (D(p)). Results indicated significant differences between normal fibroglandular tissue and malignant lesions in apparent diffusion coefficient mean (+/-standard deviation) values (2.44 +/- 0.30 vs. 1.34 +/- 0.39 MUm(2)/msec, P < 0.01) and D(t) (2.36 +/- 0.38 vs. 1.15 +/- 0.35 MUm(2)/msec, P < 0.01). Lesion diffusion weighted imaging signals demonstrated biexponential character in comparison to monoexponential normal tissue. There is some differentiation of lesion subtypes (invasive ductal carcinoma vs. other malignant lesions) with f(p) (10.5 +/- 5.0% vs. 6.9 +/- 2.9%, P = 0.06), but less so with D(t) (1.14 +/- 0.32 MUm(2)/msec vs. 1.18 +/- 0.52 MUm(2)/msec, P = 0.88) and D(p) (14.9 +/- 11.4 MUm(2)/msec vs. 16.1 +/- 5.7 MUm(2)/msec, P = 0.75). Comparison of intravoxel incoherent motion biomarkers with contrast enhancement suggests moderate correlations. These results suggest the potential of intravoxel incoherent motion vascular and cellular biomarkers for initial grading, progression monitoring, or treatment assessment of breast tumors. PMID- 21287592 TI - Improvements in multislice parallel imaging using radial CAIPIRINHA. AB - Multislice parallel imaging involves the simultaneous sampling of multiple parallel slices which are subsequently separated using parallel imaging reconstruction. The CAIPIRINHA technique improves this reconstruction by manipulating the phase of the RF excitation pulses to shift the aliasing pattern such that there is less aliasing energy to be reconstructed. In this work, it is shown that combining the phase manipulation used in CAIPIRINHA with a non Cartesian (radial) sampling scheme further decreases the aliasing energy for the parallel imaging algorithm to reconstruct, thereby further increasing the degree to which a multi-channel receiver array can be utilized for parallel imaging acceleration. In radial CAIPIRINHA, individual bands (slices) in a multislice excitation are modulated with view-dependent phase, causing a destructive interference of entire slices. This destructive interference leads to a reduction in aliasing compared to the coherent shifts one observes when using this same technique with a Cartesian trajectory. Recovery of each individual slice is possible because the applied phase pattern is known, and a conjugate-gradient reconstruction algorithm minimizes the contributions from other slices. Results are presented with a standard 12-channel head coil with acceleration factors up to 14, where radial CAIPIRINHA produces an improved reconstruction when compared with Cartesian CAIPIRINHA. PMID- 21287593 TI - Custom-fitted 16-channel bilateral breast coil for bidirectional parallel imaging. AB - A 16-channel receive-only, closely fitted array coil is described and tested in vivo for bilateral breast imaging at 3 T. The primary purpose of this coil is to provide high signal-to-noise ratio and parallel imaging acceleration in two directions for breast MRI. Circular coil elements (7.5-cm diameter) were placed on a closed "cup-shaped" platform, and nearest neighbor coils were decoupled through geometric overlap. Comparisons were made between the 16-channel custom coil and a commercially available 8-channel coil. SENSitivity Encoding (SENSE) parallel imaging noise amplification (g-factor) was evaluated in phantom scans. In healthy volunteers, we compared signal-to-noise ratio, parallel imaging in one and two directions, Autocalibrating Reconstruction for Cartesian sampling (ARC) g factor, and high spatial resolution imaging. When compared with a commercially available 8-channel coil, the 16-channel custom coil shows 3.6* higher mean signal-to-noise ratio in the breast and higher quality accelerated images. In patients, the 16-channel custom coil has facilitated high-quality, high resolution images with bidirectional acceleration of R = 6.3. PMID- 21287594 TI - Quantitative cerebral blood flow in dynamic susceptibility contrast MRI using total cerebral flow from phase contrast magnetic resonance angiography. AB - Dynamic susceptibility contrast magnetic resonance imaging during bolus injection of gadolinium contrast agent is commonly used to investigate cerebral hemodynamics. The large majority of clinical applications of dynamic susceptibility contrast magnetic resonance imaging to date have reported relative cerebral blood flow values because of dependence of the result on the accuracy of determining the arterial input function, the robustness of the singular value decomposition algorithm, and others. We propose a calibration approach that directly measures the total (i.e., whole brain) cerebral blood flow in individual subjects using phase contrast magnetic resonance angiography. The method was applied to data from 11 patients with intracranial pathology. The sum of squares variance about the mean (uncorrected: white matter = 105.6, gray matter = 472.2; corrected: white matter = 34.1, gray matter = 99.8) after correction was significantly lower for white matter (P = 0.045) and for gray matter (P = 0.011). However, the mean gray and white matter cerebral blood flow in the contralateral hemisphere were not significantly altered by the correction. The proposed phase contrast magnetic resonance angiography calibration technique appears to be one of the most direct correction schemes available for dynamic susceptibility contrast magnetic resonance imaging cerebral blood flow values and can be performed rapidly, requiring only a few minutes of additional scan time. PMID- 21287595 TI - Spectral localization by imaging using multielement receiver coils. AB - A new spectral localization technique for in vivo magnetic resonance spectroscopy is introduced. Structural information extracted from anatomical imaging is used for defining compartments which provide the basis for spectral localization. The inherent spatial heterogeneity of multiple receiver coil elements is used along with optional phase encoding to resolve signals from different compartments. This technique allows a few compartmental spectra to be reconstructed from multichannel data acquired with no or very few phase encoding steps, resulting in short scan time and high efficiency. Alternatively, this technique also allows a significant number of compartmental spectra to be reconstructed if sufficient phase encoding steps are used. A procedure is developed to semiautomatically generate a significant number of compartments of comparable sizes, which allows one to obtain spectra from small regions of interest with curvilinear shapes. This may be useful for obtaining spectra from relatively small stroke lesions or tumors. Phantom experiments and in vivo magnetic resonance spectroscopy of stroke patients have been performed to demonstrate this technique. PMID- 21287597 TI - Does levodopa affect metaiodobenzylguanidine myocardial accumulation in Parkinson's disease? PMID- 21287596 TI - Slice encoding for metal artifact correction with noise reduction. AB - Magnetic resonance imaging (MRI) near metallic implants is often hampered by severe metal artifacts. To obtain distortion-free MR images near metallic implants, SEMAC (Slice Encoding for Metal Artifact Correction) corrects metal artifacts via robust encoding of excited slices against metal-induced field inhomogeneities, followed by combining the data resolved from multiple SEMAC encoded slices. However, as many of the resolved data elements only contain noise, SEMAC-corrected images can suffer from relatively low signal-to-noise ratio. Improving the signal-to-noise ratio of SEMAC-corrected images is essential to enable SEMAC in routine clinical studies. In this work, a new reconstruction procedure is proposed to reduce noise in SEMAC-corrected images. A singular value decomposition denoising step is first applied to suppress quadrature noise in multi-coil SEMAC-encoded slices. Subsequently, the singular value decomposition denoised data are selectively included in the correction of through-plane distortions. The experimental results demonstrate that the proposed reconstruction procedure significantly improves the SNR without compromising the correction of metal artifacts. PMID- 21287598 TI - Modulation of subthalamic alpha activity to emotional stimuli correlates with depressive symptoms in Parkinson's disease. AB - BACKGROUND: Deep brain stimulation of the subthalamic nucleus is an effective treatment for patients with advanced Parkinson's disease. However, affective side effects following subthalamic deep brain stimulation have been reported. Here, we aim to elucidate the influence of affective state on emotional processing as indexed by local field potential activity and to identify neurophysiological markers in patients at risk of developing depressive symptoms during subthalamic deep brain stimulation. METHODS: Subthalamic local field potentials were directly recorded via electrodes implanted for deep brain stimulation in 12 Parkinson's disease patients while viewing emotionally salient and neutral pictures. Parkinson's disease patients were assessed for depressive symptoms using the Beck depression inventory at the time of operation and 3 months after continuous subthalamic nucleus deep brain stimulation. RESULTS: We found a significant event related desynchronization in the local alpha frequency band (8-12 Hz) for emotionally arousing but not neutral pictures. The the event-related desynchronization (ERD) in the alpha frequency band was reduced for pleasant stimuli in patients with mild to moderate depressive symptoms compared with patients without depression. The alpha-ERD to unpleasant stimuli showed the opposite pattern. Consistently, the index of event-related alpha desynchronization (alpha ERD for pleasant stimuli minus alpha ERD for unpleasant stimuli) correlated with the Beck depression inventory at the time of the recordings and at 3 months after continuous deep brain stimulation. The alpha ERD to unpleasant pictures correlated significantly with the Beck depression inventory score at 3 months after chronic deep brain stimulation. DISCUSSION: In conclusion, we found mood-congruent stimulus processing in the subthalamic nucleus of Parkinson's disease patients. Electrophysiological markers such as event-related desynchronization of subthalamic alpha activity reflect state dependent emotional processing and may potentially be used to predict depressive mood disturbances in Parkinson's disease patients with chronic subthalamic deep brain stimulation at an early stage. PMID- 21287599 TI - Accuracy of magnetic resonance parkinsonism index for differentiation of progressive supranuclear palsy from probable or possible Parkinson disease. AB - BACKGROUND: Combined measurements on conventional magnetic resonance imaging (MRI), such as midbrain area/pons area or magnetic resonance parkinsonism index (MRPI) (pons area/midbrain area * middle cerebellar peduncle width/superior cerebellar peduncle width), have been proposed as powerful tools in the differential diagnosis between progressive supranuclear palsy (PSP) and Parkinson disease (PD). In this study, we evaluated the accuracy of MRPI, compared with midbrain/pons ratio, in distinguishing PSP from probable and possible PD. METHODS: Forty-two PSP patients, 170 probable PD patients, 132 possible PD patients, and 38 control subjects underwent MRI and, for each patient, midbrain/pons ratio and MRPI were calculated. RESULTS: Midbrain/pons ratio showed low accuracy in distinguishing PSP patients from those with probable PD (92.9% sensitivity; 85.3% specificity; 86.8% diagnostic accuracy) or those with possible PD (88.1% sensitivity, 88.3% specificity, and 88.2% diagnostic accuracy) and control subjects (97.6% sensitivity, 92.1% specificity, and 95% diagnostic accuracy). By contrast, MRPI showed higher accuracy to distinguish PSP from probable PD (100% sensitivity, 99.4% specificity, and 99.5% diagnostic accuracy), from possible PD (100% sensitivity, 99.2% specificity, and 99.4% diagnostic accuracy), and from control subjects (sensitivity, specificity, and diagnostic accuracy of 100%). CONCLUSIONS: Our study confirms that MRPI is a more accurate measure than midbrain/pons ratio for differentiation of patients with PSP from those with probable and possible PD. PMID- 21287600 TI - Quantitative assessment of the evolution of cerebellar signs in spinocerebellar ataxias. AB - BACKGROUND: Responsive ataxia rating scales are essential for determining outcome measures in clinical trials. METHODS: We evaluated the responsiveness over time of the composite cerebellar functional severity score, a quantitative score measuring cerebellar ataxia in 133 patients with autosomal dominant cerebellar ataxias (ADCA), which were prospectively evaluated at inclusion and after one year of follow-up. A more responsive tool was developed, the Cerebellar Functional Severity score writing, incorporating the writing test at dominant hand to the Cerebellar Functional Severity score. RESULTS: Within the one-year follow-up period, the Cerebellar Functional Severity score and its writing version increased significantly and the Scale for the Assessment and Rating of Ataxia decreased significantly reflecting increased severity of the cerebellar symptoms. The Cerebellar Functional Severity score writing responsiveness was best in genotypes SCA1, 2, and 3 compared with the other genotypes (effect size = 0.196, standardized response mean (SRM) = 0.624 versus effect size = -0.051, SRM = -0.150). The Cerebellar Functional Severity score writing used as an outcome measure would require only 163 SCA1, 2, or 3 patients per group in a two-arm interventional trial for a 50% reduction in progression and 80% of power. DISCUSSION: Our study demonstrates that the Cerebellar Functional Severity score and Cerebellar Functional Severity score writing are responsive quantitative scores for evaluating sensitivity to change in ADCA patients and can be used as outcome measures in clinical trials, especially when targeting genotypes SCA1, 2 and 3. PMID- 21287601 TI - Survival of Korean patients with multiple system atrophy. AB - METHODS: We conducted a retrospective medical record review to determine the survival of 455 Korean multiple system atrophy (MSA) patients and examined the effect of clinical factors that could possibly influence survival. The patients comprised 222 men and 233 women. RESULTS: Age at onset was 60.1 +/- 8.8 years (mean +/- SD) and did not differ between the sexes. Parkinsonism was the most prevalent initial symptom, followed by cerebellar dysfunction and dysautonomia. Age at onset was significantly older in patients with predominant parkinsonism at the last visit (MSA-P) than in the other patients. At the time of data collection, 107 patients had died. Median survival time was 10 years. The survival rate of women was slightly better than that of men, especially in MSA-P patients. CONCLUSIONS: Survival was not affected by age at onset, initial symptom, or predominant symptom at the last visit or by the presence of autonomic symptoms or multiple symptoms at disease onset. PMID- 21287603 TI - Characterizing mild cognitive impairment in Parkinson's disease. AB - There is growing interest in identifying Parkinson's disease (PD) patients with mild cognitive impairment (PD-MCI), but widely disparate criteria have been used. We assessed 143 PD patients and 50 matched controls on 20 measures across 4 cognitive domains (executive function, attention and working memory, learning and memory, visuoperception). Twenty-four patients met criteria for dementia (PD-D); nondementia patients were classified as either with normal cognition or MCI for 12 neuropsychological criteria. We compared the influence of these criteria on the distribution of global cognitive performance in the resulting PD-MCI groups relative to the control and PD-D groups. Different criteria produced substantial variation in the proportion of PD-MCI cases identified. Fourteen percent PD-MCI was found when using 2 scores in 1 domain at 2 standard deviations (SD) below normative scores, with no controls identified as MCI, through to 89% PD-MCI with 1 score in 1 domain at 1 SD below normative scores, when 70% of controls were identified as MCI. The balance of cases with impaired cognition but not those with generally intact cognition was better served by using criteria that required 2 specific deficit scores or deficits across 2 domains. As comparisons with external normative data may have greater applicability across centers, we suggest that 2 scores at -1.5 SD within any single domain (30% PD-MCI) or 1 score at -1.5 SD in each of 2 domains (37% PD-MCI) provide suitable criteria to minimize the inclusion of cognitively well patients. Clinical dementia rating did not improve the relative identification of cognitively impaired and unimpaired nondementia PD patients. PMID- 21287604 TI - An intragenic duplication in guanosine triphosphate cyclohydrolase-1 gene in a dopa-responsive dystonia family. AB - BACKGROUND: Autosomal dominant dopa-responsive dystonia is commonly caused by mutations in the guanosine triphosphate cyclohydrolase-1 gene. METHODS: We report a British family that has been followed for more than 20 years in which no mutations were previously identified. RESULTS: Reanalysis of this pedigree detected a duplication of guanosine triphosphate cyclohydrolase-1 exon 2 in affected family members. mRNA analysis showed a mutant transcript with a tandem exon 2 duplication. Four family members developed dopa-responsive dystonia, with onset in their late teens, and subsequently developed restless leg syndrome and migraine. CONCLUSIONS: This is the first report of an intragenic guanosine triphosphate cyclohydrolase-1 duplication in a dopa-responsive dystonia family. PMID- 21287605 TI - Structural insights into a low-spin myoglobin variant with bis-histidine coordination from molecular modeling. AB - Rational design of functional enzymes is a powerful strategy to gain deep insights into more complex native enzymes, such as nitric oxide reductase (NOR). Recently, we engineered a functional model of NOR by creating a two His and one Glu (2-His-1-Glu) non-heme iron center in sperm whale myoglobin (swMb L29E, F43H, H64, called Fe(B)Mb(-His)). It was found that Fe(B) Mb(-His) adopts a low-spin state with bis-His coordination in the absence of metal ions binding to the designed metal center. However, no structural information was available for the variant in this special spin state. We herein performed molecular modeling of Fe(B)Mb(-His) and compared with the X-ray structure of its copper bound derivative, Cu(II)-CN(-)-Fe(B) Mb(-His), resolved recently at a high resolution (1.65 A) (PDB entry 3MN0). The simulated structure shows that mutation of Leu to Glu at position 29 in the hydrophobic heme pocket alters the folding behavior of Mb. The hydrogen bond between Glu29 and His64 further plays a role in stabilizing the bis-His (His64/His93) coordination structure. This study offers an excellent example of using molecular modeling to gain insights in rational design of both structural and functional proteins. PMID- 21287606 TI - Remeasuring HEWL pK(a) values by NMR spectroscopy: methods, analysis, accuracy, and implications for theoretical pK(a) calculations. AB - Site-specific pK(a) values measured by NMR spectroscopy provide essential information on protein electrostatics, the pH-dependence of protein structure, dynamics and function, and constitute an important benchmark for protein pK(a) calculation algorithms. Titration curves can be measured by tracking the NMR chemical shifts of several reporter nuclei versus sample pH. However, careful analysis of these curves is needed to extract residue-specific pK(a) values since pH-dependent chemical shift changes can arise from many sources, including through-bond inductive effects, through-space electric field effects, and conformational changes. We have re-measured titration curves for all carboxylates and His 15 in Hen Egg White Lysozyme (HEWL) by recording the pH-dependent chemical shifts of all backbone amide nitrogens and protons, Asp/Glu side chain protons and carboxyl carbons, and imidazole protonated carbons and protons in this protein. We extracted pK(a) values from the resulting titration curves using standard fitting methods, and compared these values to each other, and with those measured previously by 1H NMR (Bartik et al., Biophys J 1994;66:1180-1184). This analysis gives insights into the true accuracy associated with experimentally measured pK(a) values. We find that apparent pK(a) values frequently differ by 0.5-1.0 units depending upon the nuclei monitored, and that larger differences occasionally can be observed. The variation in measured pK(a) values, which reflects the difficulty in fitting and assigning pH-dependent chemical shifts to specific ionization equilibria, has significant implications for the experimental procedures used for measuring protein pK(a) values, for the benchmarking of protein pK(a) calculation algorithms, and for the understanding of protein electrostatics in general. PMID- 21287602 TI - Predictors of time to requiring dopaminergic treatment in 2 Parkinson's disease cohorts. AB - The rate of progression of Parkinson's disease (PD) is highly variable. Knowledge of factors associated with disease milestones and commonly used research outcome measures helps with patient counseling and guides the design and interpretation of clinical studies. The objective of the study was to identify prognostic factors for time to acquiring disability requiring dopaminergic therapy that are reproducible within 2 large prospectively followed cohorts. Potential prognostic factors were identified using data from the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) trial, and their reproducibility was examined using data from the Parkinson Research Examination of CEP-1347 trial (PRECEPT). In multivariable analyses of the DATATOP cohort, higher baseline Unified Parkinson's Disease Rating Scale (UPDRS) scores, full-time employment, a lesser smoking history, and onset on the left side were associated with a shorter time to disability requiring dopaminergic therapy. PRECEPT data confirmed the associations of higher baseline UPDRS scores and full-time employment with shorter time to requiring treatment. Any clinical trial using the end point of time to disability requiring dopaminergic therapy should ensure that groups are well balanced with respect to baseline UPDRS scores and the proportion of subjects employed full time and should consider including these variables as covariates in the statistical model for primary analysis of treatment effects. We suspect that individuals employed full time may have a lower threshold for requiring dopaminergic therapy because of occupational demands. PMID- 21287607 TI - Kinetics, in silico docking, molecular dynamics, and MM-GBSA binding studies on prototype indirubins, KT5720, and staurosporine as phosphorylase kinase ATP binding site inhibitors: the role of water molecules examined. AB - With an aim toward glycogenolysis control in Type 2 diabetes, we have investigated via kinetic experiments and computation the potential of indirubin (IC50 > 50 MUM), indirubin-3'-oxime (IC50 = 144 nM), KT5720 (K(i) = 18.4 nM) and staurosporine (K(i) = 0.37 nM) as phosphorylase kinase (PhKgammatrnc) ATP-binding site inhibitors, with the latter two revealed as potent inhibitors in the low nM range. Because of lack of structural information, we have exploited information from homologous kinase complexes to direct in silico calculations (docking, molecular dynamics, and MMGBSA) to predict the binding characteristics of the four ligands. All inhibitors are predicted to bind in the same active site area as the ATP adenine ring, with binding dominated by hinge region hydrogen bonds to Asp104:O and Met106:O (all four ligands) and also Met106:NH (for the indirubins). The PhKgammatrnc-staurosporine complex has the greatest number of receptor-ligand hydrogen bonds, while for the indirubin-3'-oxime and KT5720 complexes there is an important network of interchanging water molecules bridging inhibitor-enzyme contacts. The MM-GBSA results revealed the source of staurosporine's low nM potency to be favorable electrostatic interactions, while KT5720 has strong van der Waals contributions. KT5720 interacts with the greatest number of protein residues either by direct or 1-water bridged hydrogen bond interactions, and the potential for more selective PhK inhibition based on a KT5720 analogue has been established. Including receptor flexibility in Schrodinger induced-fit docking calculations in most cases correctly predicted the binding modes as compared with the molecular dynamics structures; the algorithm was less effective when there were key structural waters bridging receptor-ligand contacts. PMID- 21287608 TI - Predicting kinetic constants of protein-protein interactions based on structural properties. AB - Elucidating kinetic processes of protein-protein interactions (PPI) helps to understand how basic building blocks affect overall behavior of living systems. In this study, we used structure-based properties to build predictive models for kinetic constants of PPI. A highly diverse PPI dataset, protein-protein kinetic interaction data and structures (PPKIDS), was built. PPKIDS contains 62 PPI with complex structures and kinetic constants measured experimentally. The influence of structural properties on kinetics of PPI was studied using 35 structure-based features, describing different aspects of complex structures. Linear models for the prediction of kinetic constants were built by fitting with selected subsets of structure-based features. The models gave correlation coefficients of 0.801, 0.732, and 0.770 for k(off), k(on), and K(d), respectively, in leave-one-out cross validations. The predictive models reported here use only protein complex structures as input and can be generally applied in PPI studies as well as systems biology modeling. Our study confirmed that different properties play different roles in the kinetic process of PPI. For example, k(on) was affected by overall structural features of complexes, such as the composition of secondary structures, the change of translational and rotational entropy, and the electrostatic interaction; while k(off) was determined by interfacial properties, such as number of contacted atom pairs per 100 A2. This information provides useful hints for PPI design. PMID- 21287609 TI - FINDSITE-metal: integrating evolutionary information and machine learning for structure-based metal-binding site prediction at the proteome level. AB - The rapid accumulation of gene sequences, many of which are hypothetical proteins with unknown function, has stimulated the development of accurate computational tools for protein function prediction with evolution/structure-based approaches showing considerable promise. In this article, we present FINDSITE-metal, a new threading-based method designed specifically to detect metal-binding sites in modeled protein structures. Comprehensive benchmarks using different quality protein structures show that weakly homologous protein models provide sufficient structural information for quite accurate annotation by FINDSITE-metal. Combining structure/evolutionary information with machine learning results in highly accurate metal-binding annotations; for protein models constructed by TASSER, whose average Calpha RMSD from the native structure is 8.9 A, 59.5% (71.9%) of the best of top five predicted metal locations are within 4 A (8 A) from a bound metal in the crystal structure. For most of the targets, multiple metal-binding sites are detected with the best predicted binding site at rank 1 and within the top two ranks in 65.6% and 83.1% of the cases, respectively. Furthermore, for iron, copper, zinc, calcium, and magnesium ions, the binding metal can be predicted with high, typically 70% to 90%, accuracy. FINDSITE-metal also provides a set of confidence indexes that help assess the reliability of predictions. Finally, we describe the proteome-wide application of FINDSITE-metal that quantifies the metal-binding complement of the human proteome. FINDSITE-metal is freely available to the academic community at http://cssb.biology.gatech.edu/findsite-metal/. PMID- 21287610 TI - Solution structures of chicken parvalbumin 3 in the Ca(2+)-free and Ca(2+)-bound states. AB - Birds express two beta-parvalbumin isoforms, parvalbumin 3 and avian thymic hormone (ATH). Parvalbumin 3 from chicken (CPV3) is identical to rat beta parvalbumin (beta-PV) at 75 of 108 residues. CPV3 displays intermediate Ca(2+) affinity--higher than that of rat beta-parvalbumin, but lower than that of ATH. As in rat beta-PV, the attenuation of affinity is associated primarily with the CD site (residues 41-70), rather than the EF site (residues 80-108). Structural data for rat alpha- and beta-parvalbumins suggest that divalent ion affinity is correlated with the similarity of the unliganded and Ca(2+)-bound conformations. We herein present a comparison of the solution structures of Ca(2+)-free and Ca(2+)-bound CPV3. Although the structures are generally similar, the conformations of residues 47 to 50 differ markedly in the two protein forms. These residues are located in the C helix, proximal to the CD binding loop. In response to Ca(2+) removal, F47 experiences much greater solvent accessibility. The side-chain of R48 assumes a position between the C and D helices, adjacent to R69. Significantly, I49 adopts an interior position in the unliganded protein that allows association with the side-chain of L50. Concomitantly, the realignment of F66 and F70 facilitates their interaction with I49 and reduces their contact with residues in the N-terminal AB domain. This reorganization of the hydrophobic core, although less profound, is nevertheless reminiscent of that observed in rat beta-PV. The results lend further support to the idea that Ca(2+) affinity correlates with the structural similarity of the apo- and bound parvalbumin conformations. PMID- 21287611 TI - Recognition of beta-calcineurin by the domains of calmodulin: thermodynamic and structural evidence for distinct roles. AB - Calcineurin (CaN, PP2B, PPP3), a heterodimeric Ca(2+)-calmodulin-dependent Ser/Thr phosphatase, regulates swimming in Paramecia, stress responses in yeast, and T-cell activation and cardiac hypertrophy in humans. Calcium binding to CaN(B) (the regulatory subunit) triggers conformational change in CaN(A) (the catalytic subunit). Two isoforms of CaN(A) (alpha, beta) are both abundant in brain and heart and activated by calcium-saturated calmodulin (CaM). The individual contribution of each domain of CaM to regulation of calcineurin is not known. Hydrodynamic analyses of (Ca(2+))4-CaM(1-148) bound to betaCaNp, a peptide representing its CaM-binding domain, indicated a 1:1 stoichiometry. betaCaNp binding to CaM increased the affinity of calcium for the N- and C-domains equally, thus preserving intrinsic domain differences, and the preference of calcium for sites III and IV. The equilibrium constants for individual calcium saturated CaM domains dissociating from betaCaNp were ~1 MUM. A limiting K(d) <= 1 nM was measured directly for full-length CaM, while thermodynamic linkage analysis indicated that it was approximately 1 pM. betaCaNp binding to 15N (Ca(2+))4-CaM(1-148) monitored by 15N/1HN HSQC NMR showed that association perturbed the N-domain of CaM more than its C-domain. NMR resonance assignments of CaM and betaCaNp, and interpretation of intermolecular NOEs observed in the 13C-edited and 12C-14N-filtered 3D NOESY spectrum indicated anti-parallel binding. The sole aromatic residue (Phe) located near the betaCaNp C-terminus was in close contact with several residues of the N-domain of CaM outside the hydrophobic cleft. These structural and thermodynamic properties would permit the domains of CaM to have distinct physiological roles in regulating activation of betaCaN. PMID- 21287612 TI - Simplified modeling approach suggests structural mechanisms for constitutive activation of the C5a receptor. AB - Molecular modeling of conformational changes occurring in the transmembrane region of the complement factor 5a receptor (C5aR) during receptor activation was performed by comparing two constitutively active mutants (CAMs) of C5aR, NQ (I124N/L127Q), and F251A, to those of the wild-type C5aR and NQ-N296A (I124N/L127Q/N296A), which have the wild-type phenotype. Modeling involved comprehensive sampling of various rotations of TM helices aligned to the crystal template of the dark-adapted rhodopsin along their long axes. By assuming that the relative energies of the spontaneously activated states of CAMs should be lower or at least comparable to energies characteristic for the ground states, we selected the plausible models for the conformational states associated with constitutive activation in C5aR. The modeling revealed that the hydrogen bonds between the side chains of D82-N119, S85-N119, and S131-C221 characteristic for the ground state were replaced by the hydrogen bonds D82-N296, N296-Y300, and S131-R134, respectively, in the activated states. Also, conformational transitions that occurred upon activation were hindered by contacts between the side chains of L127 and F251. The results rationalize the available data of mutagenesis in C5aR and offer the first specific molecular mechanism for the loss of constitutive activity in NQ-N296A. Our results also contributed to understanding the general structural mechanisms of activation in G-protein coupled receptors lacking the "ionic lock", R(3.50) and E/D(6.30). Importantly, these results were obtained by modeling approaches that deliberately simplify many elements in order to explore potential conformations of GPCRs involving large-scale molecular movements. PMID- 21287613 TI - Structures of parasitic CDPK domains point to a common mechanism of activation. AB - We recently determined the first structures of inactivated and calcium-activated calcium-dependent protein kinases (CDPKs) from Apicomplexa. Calcium binding triggered a large conformational change that constituted a new mechanism in calcium signaling and a novel EF-hand fold (CAD, for CDPK activation domain). Thus we set out to determine if this mechanism was universal to all CDPKs. We solved additional CDPK structures, including one from the species Plasmodium. We highlight the similarities in sequence and structure across apicomplexan and plant CDPKs, and strengthen our observations that this novel mechanism could be universal to canonical CDPKs. Our new structures demonstrate more detailed steps in the mechanism of calcium activation and possible key players in regulation. Residues involved in making the largest conformational change are the most conserved across Apicomplexa, leading us to propose that the mechanism is indeed conserved. CpCDPK3_CAD and PfCDPK_CAD were captured at a possible intermediate conformation, lending insight into the order of activation steps. PfCDPK3_CAD adopts an activated fold, despite having an inactive EF-hand sequence in the N terminal lobe. We propose that for most apicomplexan CDPKs, the mode of activation will be similar to that seen in our structures, while specific regulation of the inactive and active forms will require further investigation. PMID- 21287614 TI - Effects of somatic mutations on CDR loop flexibility during affinity maturation. AB - Prior studies suggest that antibody affinity maturation is achieved, in part, via prearranging the CDRs for binding. The implication is that the entropy cost of binding is reduced and that this rigidification occurs as a consequence of somatic mutations during maturation. However, how these mutations modulate CDR flexibility is unclear. Here, molecular dynamics simulations captured CDR flexibility differences between four mature antibodies (7G12, AZ28, 28B4, and 48G7) and their germline predecessors. Analysis of their trajectories: (1) rationalized how mutations during affinity maturation restrict CDR motility, (2) captured the equilibrium between bound and unbound conformations for the H3 loop of unliganded 7G12, and (3) predicted a set of new mutations that, according to our simulations, should diminish binding by increasing flexibility. PMID- 21287615 TI - Role of conformational sampling in computing mutation-induced changes in protein structure and stability. AB - The prediction of changes in protein stability and structure resulting from single amino acid substitutions is both a fundamental test of macromolecular modeling methodology and an important current problem as high throughput sequencing reveals sequence polymorphisms at an increasing rate. In principle, given the structure of a wild-type protein and a point mutation whose effects are to be predicted, an accurate method should recapitulate both the structural changes and the change in the folding-free energy. Here, we explore the performance of protocols which sample an increasing diversity of conformations. We find that surprisingly similar performances in predicting changes in stability are achieved using protocols that involve very different amounts of conformational sampling, provided that the resolution of the force field is matched to the resolution of the sampling method. Methods involving backbone sampling can in some cases closely recapitulate the structural changes accompanying mutations but not surprisingly tend to do more harm than good in cases where structural changes are negligible. Analysis of the outliers in the stability change calculations suggests areas needing particular improvement; these include the balance between desolvation and the formation of favorable buried polar interactions, and unfolded state modeling. PMID- 21287616 TI - Predicting protein flexibility through the prediction of local structures. AB - Protein structures are valuable tools for understanding protein function. However, protein dynamics is also considered a key element in protein function. Therefore, in addition to structural analysis, fully understanding protein function at the molecular level now requires accounting for flexibility. However, experimental techniques that produce both types of information simultaneously are still limited. Prediction approaches are useful alternative tools for obtaining otherwise unavailable data. It has been shown that protein structure can be described by a limited set of recurring local structures. In this context, we previously established a library composed of 120 overlapping long structural prototypes (LSPs) representing fragments of 11 residues in length and covering all known local protein structures. On the basis of the close sequence-structure relationship observed in LSPs, we developed a novel prediction method that proposes structural candidates in terms of LSPs along a given sequence. The prediction accuracy rate was high given the number of structural classes. In this study, we use this methodology to predict protein flexibility. We first examine flexibility according to two different descriptors, the B-factor and root mean square fluctuations from molecular dynamics simulations. We then show the relevance of using both descriptors together. We define three flexibility classes and propose a method based on the LSP prediction method for predicting flexibility along the sequence. The prediction rate reaches 49.6%. This method competes rather efficiently with the most recent, cutting-edge methods based on true flexibility data learning with sophisticated algorithms. Accordingly, flexibility information should be taken into account in structural prediction assessments. PMID- 21287617 TI - Protein domain assignment from the recurrence of locally similar structures. AB - Domains are basic units of protein structure and essential for exploring protein fold space and structure evolution. With the structural genomics initiative, the number of protein structures in the Protein Databank (PDB) is increasing dramatically and domain assignments need to be done automatically. Most existing structural domain assignment programs define domains using the compactness of the domains and/or the number and strength of intra-domain versus inter-domain contacts. Here we present a different approach based on the recurrence of locally similar structural pieces (LSSPs) found by one-against-all structure comparisons with a dataset of 6373 protein chains from the PDB. Residues of the query protein are clustered using LSSPs via three different procedures to define domains. This approach gives results that are comparable to several existing programs that use geometrical and other structural information explicitly. Remarkably, most of the proteins that contribute the LSSPs defining a domain do not themselves contain the domain of interest. This study shows that domains can be defined by a collection of relatively small locally similar structural pieces containing, on average, four secondary structure elements. In addition, it indicates that domains are indeed made of recurrent small structural pieces that are used to build protein structures of many different folds as suggested by recent studies. PMID- 21287618 TI - The effects of the L29F mutation on the ligand migration kinetics in crystallized myoglobin as revealed by molecular dynamics simulations. AB - By using multiple molecular dynamics (MD) trajectories, a quantitative description of carbon monoxide (CO) migration within crystal of L29F myoglobin mutant (L29F-Mb) was obtained. The aim was to provide a detailed model for ligand diffusion in the protein to be compared to the available L29F-Mb experimental computational data and to the corresponding model kinetics we previously obtained for photolyzed CO within crystallized wild-type myoglobin (wt-Mb). Results suggest a clear migration pathway from distal pocket to the proximal site, similar to the one observed in wt-Mb, with a relaxation kinetics differing from the wt-Mb one essentially for the escape rate which is much higher in the mutant. Moreover MD data indicated a clear correlation between CO location within the protein and the conformation adopted by Phe29, well matching the available experimental data as obtained by time-resolved X-ray density maps. Such data, further validating the model used in the simulations, point out the subtle mutual effect between ligand diffusion and protein functional motions possibly explaining the observed dramatic variation of CO exit rate in L29F-Mb. PMID- 21287619 TI - Application of long-range order to predict unfolding rates of two-state proteins. AB - Predicting the experimental unfolding rates of two-state proteins and models describing the unfolding rates of these proteins is quite limited because of the complexity present in the unfolding mechanism and the lack of experimental unfolding data compared with folding data. In this work, 25 two-state proteins characterized by Maxwell et al. (Protein Sci 2005;14:602-616) using a consensus set of experimental conditions were taken, and the parameter long-range order (LRO) derived from their three-dimensional structures were related with their experimental unfolding rates ln(k(u)). From the total data set of 30 proteins used by Maxwell et al. (Protein Sci 2005;14:602-616), five slow-unfolding proteins with very low unfolding rates were considered to be outliers and were not included in our data set. Except all beta structural class, LRO of both the all-alpha and mixed-class proteins showed a strong inverse correlation of r = 0.99 and -0.88, respectively, with experimental ln(k(u)). LRO shows a correlation of -0.62 with experimental ln(k(u)) for all-beta proteins. For predicting the unfolding rates, a simple statistical method has been used and linear regression equations were developed for individual structural classes of proteins using LRO, and the results obtained showed a better agreement with experimental results. PMID- 21287620 TI - Prediction of protein binding regions. AB - Identifying protein binding sites provides important clues to the function of a protein. Experimental methods to identify the binding sites such as determining the crystal structures of protein complexes are extremely laborious and expensive. Here, we present a computational technique called spatial aggregation propensity (SAP) based on molecular simulations to predict protein binding sites. We apply this technique to two model proteins, an IgG1 antibody and epidermal growth factor receptor (EGFR) and demonstrate that SAP predicts protein binding regions with very good accuracy. In the case of the IgG1 antibody, SAP accurately predicts binding regions with the Fc-receptor, protein-A, and protein-G. For EGFR, SAP accurately predicts binding regions with EGF, TGFalpha, and with another EGFR. The resolution of SAP is varied to obtain a detailed picture of these binding sites. We also show that some of these binding sites overlap with protein self-aggregation prone regions. We demonstrate how SAP analysis can be used to engineer the protein to remove unfavorable aggregation prone regions without disturbing protein binding regions. The SAP technique could be also used to predict the yet unknown binding sites of numerous proteins, thereby providing clues to their function. PMID- 21287621 TI - Salt bridges: geometrically specific, designable interactions. AB - Salt bridges occur frequently in proteins, providing conformational specificity and contributing to molecular recognition and catalysis. We present a comprehensive analysis of these interactions in protein structures by surveying a large database of protein structures. Salt bridges between Asp or Glu and His, Arg, or Lys display extremely well-defined geometric preferences. Several previously observed preferences are confirmed, and others that were previously unrecognized are discovered. Salt bridges are explored for their preferences for different separations in sequence and in space, geometric preferences within proteins and at protein-protein interfaces, co-operativity in networked salt bridges, inclusion within metal-binding sites, preference for acidic electrons, apparent conformational side chain entropy reduction on formation, and degree of burial. Salt bridges occur far more frequently between residues at close than distant sequence separations, but, at close distances, there remain strong preferences for salt bridges at specific separations. Specific types of complex salt bridges, involving three or more members, are also discovered. As we observe a strong relationship between the propensity to form a salt bridge and the placement of salt-bridging residues in protein sequences, we discuss the role that salt bridges might play in kinetically influencing protein folding and thermodynamically stabilizing the native conformation. We also develop a quantitative method to select appropriate crystal structure resolution and B factor cutoffs. Detailed knowledge of these geometric and sequence dependences should aid de novo design and prediction algorithms. PMID- 21287622 TI - Exploring the role of structure and dynamics in the function of chymotrypsin inhibitor 2. AB - Increasing awareness of the possible role of internal dynamics in protein function has led to the development of new methods for experimentally characterizing protein dynamics across multiple time scales, especially using NMR spectroscopy. A few analyses of the conformational dynamics of proteins ranging from nonallosteric single domains to multidomain allosteric enzymes are now available; however, demonstrating a connection between dynamics and function remains difficult on account of the comparative lack of studies examining both changes in dynamics and changes in function in response to the same perturbations. In previous work, we characterized changes in structure and dynamics on the ps-ns time scale resulting from hydrophobic core mutations in chymotrypsin inhibitor 2 and found that there are moderate, persistent global changes in dynamics in the absence of gross structural changes (Whitley et al., Biochemistry 2008;47:8566-8576). Here, we assay those and additional mutants for inhibitory ability toward the serine proteases elastase and chymotrypsin to determine the effects of mutation on function. Results indicate that core mutation has only a subtle effect on CI2 function. Using chemical shifts, we also studied the effect of complex formation on CI2 structure and found that perturbations are greatest at the complex interface but also propagate toward CI2's hydrophobic core. The structure-dynamics-function data set completed here suggests that dynamics plays a limited role in the function of this small model system, although we do observe a correlation between nanosecond-scale reactive loop motions and inhibitory ability for mutations at one key position in the hydrophobic core. PMID- 21287624 TI - The alpha-sheet: a missing-in-action secondary structure? AB - The alpha-sheet has been speculated to play a role as a toxic conformer in amyloid diseases. However, except for relatively short fragments, its detection has remained elusive. Here, we present molecular dynamics simulations that support the existence of the alpha-sheet as a stable, metastable, or long-lived secondary structure in polyglutamine and, to a lesser extent, in polyasparagine aggregates. PMID- 21287623 TI - In silico modeling of pH-optimum of protein-protein binding. AB - Protein-protein association is a pH-dependent process and thus the binding affinity depends on the local pH. In vivo the association occurs in a particular cellular compartment, where the individual monomers are supposed to meet and form a complex. Since the monomers and the complex exist in the same micro environment, it is plausible that they coevolved toward its properties, in particular, toward the characteristic subcellular pH. Here we show that the pH at which the monomers are most stable (pH-optimum) or the pH at which stability is almost pH-independent (pH-flat) of monomers are correlated with the pH-optimum of maximal affinity (pH-optimum of binding) or pH interval at which affinity is almost pH-independent (pH-flat of binding) of the complexes made of the corresponding monomers. The analysis of interfacial properties of protein complexes demonstrates that pH-dependent properties can be roughly estimated using the interface charge alone. In addition, we introduce a parameter beta, proportional to the square root of the absolute product of the net charges of monomers, and show that protein complexes characterized with small or very large beta tend to have neutral pH-optimum. Further more, protein complexes made of monomers carrying the same polarity net charge at neutral pH have either very low or very high pH-optimum of binding. These findings are used to propose empirical rule for predicting pH-optimum of binding provided that the amino acid compositions of the corresponding monomers are available. PMID- 21287626 TI - Crystal structures of a family 8 polysaccharide lyase reveal open and highly occluded substrate-binding cleft conformations. AB - Bacterial enzymatic degradation of glycosaminoglycans such as hyaluronan and chondroitin is facilitated by polysaccharide lyases. Family 8 polysaccharide lyase (PL8) enzymes contain at least two domains: one predominantly composed of alpha-helices, the alpha-domain, and another predominantly composed of beta sheets, the beta-domain. Simulation flexibility analyses indicate that processive exolytic cleavage of hyaluronan, by PL8 hyaluronate lyases, is likely to involve an interdomain shift, resulting in the opening/closing of the substrate-binding cleft between the alpha- and beta-domains, facilitating substrate translocation. Here, the Streptomyces coelicolor A3(2) PL8 enzyme was recombinantly expressed in and purified from Escherichia coli and biochemically characterized as a hyaluronate lyase. By using X-ray crystallography its structure was solved in complex with hyaluronan and chondroitin disaccharides. These findings show key catalytic interactions made by the different substrates, and on comparison with all other PL8 structures reveals that the substrate-binding cleft of the S. coelicolor enzyme is highly occluded. A third structure of the enzyme, harboring a mutation of the catalytic tyrosine, created via site-directed mutagenesis, interestingly revealed an interdomain shift that resulted in the opening of the substrate-binding cleft. These results add further support to the proposed processive mechanism of action of PL8 hyaluronate lyases and may indicate that the mechanism of action is likely to be universally used by PL8 hyaluronate lyases. PMID- 21287625 TI - Analysis of the peroxiredoxin family: using active-site structure and sequence information for global classification and residue analysis. AB - Peroxiredoxins (Prxs) are a widespread and highly expressed family of cysteine based peroxidases that react very rapidly with H2O2, organic peroxides, and peroxynitrite. Correct subfamily classification has been problematic because Prx subfamilies are frequently not correlated with phylogenetic distribution and diverge in their preferred reductant, oligomerization state, and tendency toward overoxidation. We have developed a method that uses the Deacon Active Site Profiler (DASP) tool to extract functional-site profiles from structurally characterized proteins to computationally define subfamilies and to identify new Prx subfamily members from GenBank(nr). For the 58 literature-defined Prx test proteins, 57 were correctly assigned, and none were assigned to the incorrect subfamily. The >3500 putative Prx sequences identified were then used to analyze residue conservation in the active site of each Prx subfamily. Our results indicate that the existence and location of the resolving cysteine vary in some subfamilies (e.g., Prx5) to a greater degree than previously appreciated and that interactions at the A interface (common to Prx5, Tpx, and higher order AhpC/Prx1 structures) are important for stabilization of the correct active-site geometry. Interestingly, this method also allows us to further divide the AhpC/Prx1 into four groups that are correlated with functional characteristics. The DASP method provides more accurate subfamily classification than PSI-BLAST for members of the Prx family and can now readily be applied to other large protein families. PMID- 21287627 TI - Molecular dynamics simulation of beta2-microglobulin in denaturing and stabilizing conditions. AB - beta2-Microglobulin has been a model system for the study of fibril formation for 20 years. The experimental study of beta2-microglobulin structure, dynamics, and thermodynamics in solution, at atomic detail, along the pathway leading to fibril formation is difficult because the onset of disorder and aggregation prevents signal resolution in Nuclear Magnetic Resonance experiments. Moreover, it is difficult to characterize conformers in exchange equilibrium. To gain insight (at atomic level) on processes for which experimental information is available at molecular or supramolecular level, molecular dynamics simulations have been widely used in the last decade. Here, we use molecular dynamics to address three key aspects of beta2-microglobulin, which are known to be relevant to amyloid formation: (1) 60 ns molecular dynamics simulations of beta2-microglobulin in trifluoroethanol and in conditions mimicking low pH are used to study the behavior of the protein in environmental conditions that are able to trigger amyloid formation; (2) adaptive biasing force molecular dynamics simulation is used to force cis-trans isomerization at Proline 32 and to calculate the relative free energy in the folded and unfolded state. The native-like trans-conformer (known as intermediate 2 and determining the slow phase of refolding), is simulated for 10 ns, detailing the possible link between cis-trans isomerization and conformational disorder; (3) molecular dynamics simulation of highly concentrated doxycycline (a molecule able to suppress fibril formation) in the presence of beta2-microglobulin provides details of the binding modes of the drug and a rationale for its effect. PMID- 21287628 TI - Fingerprint-based structure retrieval using electron density. AB - We present a computational approach that can quickly search a large protein structural database to identify structures that fit a given electron density, such as determined by cryo-electron microscopy. We use geometric invariants (fingerprints) constructed using 3D Zernike moments to describe the electron density, and reduce the problem of fitting of the structure to the electron density to simple fingerprint comparison. Using this approach, we are able to screen the entire Protein Data Bank and identify structures that fit two experimental electron densities determined by cryo-electron microscopy. PMID- 21287629 TI - The structure of the ends of alpha-helices in globular proteins: effect of additional hydrogen bonds and implications for helix formation. AB - We prepared a set of about 2000 alpha-helices from a relational database of high resolution three-dimensional structures of globular proteins, and identified additional main chain i <- i+3 hydrogen bonds at the ends of the helices (i.e., where the hydrogen bonding potential is not fulfilled by canonical i <- i+4 hydrogen bonds). About one-third of alpha-helices have such additional hydrogen bonds at the N-terminus, and more than half do so at the C-terminus. Although many of these additional hydrogen bonds at the C-terminus are associated with Schellman loops, the majority are not. We compared the dihedral angles at the termini of alpha-helices having or lacking the additional hydrogen bonds. Significant differences were found, especially at the C-terminus, where the dihedral angles at positions C2 and C1 in the absence of additional hydrogen bonds deviate substantially from those occurring within the alpha-helix. Using a novel approach we show how the structure of the C-terminus of the alpha-helix can emerge from that of constituent overlapping alpha-turns and beta-turns, which individually show a variation in dihedral angles at different positions. We have also considered the direction of propagation of the alpha-helix using this approach. If one assumes that helices start as a single alpha-turn and grow by successive addition of further alpha-turns, the paths for growth in the N -> C and C -> N directions differ in a way that suggests that extension in the C -> N direction is favored. PMID- 21287630 TI - Crystal structure of Toll-like receptor 2-activating lipoprotein IIpA from Vibrio vulnificus. PMID- 21287632 TI - Applications of bio-inspired special wettable surfaces. AB - In this review we focus on recent developments in applications of bio-inspired special wettable surfaces. We highlight surface materials that in recent years have shown to be the most promising in their respective fields for use in future applications. The selected topics are divided into three groups, applications of superhydrophobic surfaces, surfaces of patterned wettability and integrated multifunctional surfaces and devices. We will present how the bio-inspired wettability has been integrated into traditional materials or devices to improve their performances and to extend their practical applications by developing new functionalities. PMID- 21287633 TI - Orthogonal processing and patterning enabled by highly fluorinated light-emitting polymers. PMID- 21287634 TI - Tailored highly transparent composite hole-injection layer consisting of PEDOT:PSS and SiO2 nanoparticles for efficient polymer light-emitting diodes. PMID- 21287635 TI - V2O5 loaded on SnO2 nanowires for high-rate li ion batteries. PMID- 21287636 TI - p- and n-Type bipolar redox-active radical polymer: Toward totally organic polymer-based rechargeable devices with variable configuration. PMID- 21287637 TI - A new approach for molecular electronic junctions with a multilayer graphene electrode. PMID- 21287638 TI - Transparent nanometric organic luminescent films as UV-active components in photonic structures. PMID- 21287639 TI - Morphology of all-solution-processed "bilayer" organic solar cells. PMID- 21287640 TI - Growth of directly transferable In2O3 nanowire mats for transparent thin-film transistor applications. PMID- 21287641 TI - An electrochemical avenue to green-luminescent graphene quantum dots as potential electron-acceptors for photovoltaics. PMID- 21287642 TI - Block copolymer nanotubes by melt-infiltration of nanoporous aluminum oxide. PMID- 21287643 TI - Doxorubicin release triggered by alginate embedded magnetic nanoheaters: a combined therapy. PMID- 21287644 TI - High-performance supercapacitors based on intertwined CNT/V2O5 nanowire nanocomposites. PMID- 21287645 TI - Nature of N 2p, Ti 3d, O 2p hybridization of N-doped TiO2 nanotubes and superior photovoltaic performance through selective atomic N doping. PMID- 21287646 TI - Naphthalene and related systems peri-substituted by Group 15 and 16 elements. AB - Synthetic and bonding aspects of heavier Group 15 (P, As, Sb, Bi) and 16 (S, Se, Te) peri-substituted naphthalenes, are discussed in this review. An important and unifying feature of the chemistry of these systems is the lively discussion about the nature of the interaction between peri-atoms. Are atoms bonded when they are closer than the sum of their van der Waals radii? Is there any (weak) bonding, or just a strained repulsive interaction? Positioning atoms of Group 15 and 16 at the naphthalene 1,8-positions provides leading systems with which to study these bonding issues. PMID- 21287647 TI - Kinetic and theoretical studies on alkaline ethanolysis of 4-nitrophenyl salicylate: effect of alkali metal ions on reactivity and mechanism. AB - Pseudo-first-order rate constants (k(obsd)) for reactions of 4-nitrophenyl salicylate (7) with alkali metal ethoxides (EtOM, M = K, Na, and Li) in anhydrous ethanol have been measured spectrophotometrically. Interestingly, the k(obsd) value decreases significantly as the concentration of EtOM increases. Because the phenolic moiety of substrate 7 would be deprotonated and exist as an anionic form (i.e., 7(-)) under kinetic conditions, the ground-state stabilization of 7(-) through formation of a six-membered cyclic complex with M(+) (i.e., 8) is proposed to be responsible for the decreasing k(obsd) trend. The k(obsd) value at a given concentration of EtOK increases steeply upon addition of [18]crown-6 ether (18C6) up to [18C6]/[EtOK] = 1 in the reaction mixture and then remains relatively constant thereafter. In contrast, k(obsd) decreases upon addition of salts (e.g., LiClO(4) or KSCN) to the reaction mixture, which indicates that M(+) ions inhibit the reaction. However, in the presence of 18C6, the k(obsd) value is independent of the concentration of EtOK but remains constant, which indicates that the reaction proceeds through a unimolecular mechanism in the presence of the complexing agent. Although two conceivable unimolecular pathways (formation of ketene 9 and lactone 10) can account for the kinetic results, the reaction has been concluded to proceed via formation of ketene 9 as the reactive intermediate on the basis of theoretical calculations. PMID- 21287648 TI - Colorimetric detection of DNA by modulation of thrombin activity on gold nanoparticles. AB - A colorimetric, non-cross-linking aggregation-based gold-nanoparticle (AuNP) probe has been developed for the detection of DNA and the analysis of single nucleotide polymorphism (SNP). The probe acts by modulating the enzyme activity of thrombin relative to fibrinogen. A thrombin-binding aptamer with a 29-base long oligonucleotide (TBA(29)) assembled on the nanoparticles (TBA(29)-AuNPs) through sandwich DNA hybridization was found to possess ultra-high anticoagulant potency. The enzyme inhibition of thrombin was determined by thrombin-induced aggregation of fibrinogen-functionalized 56 nm AuNPs (Fib-AuNPs). The potency of the inhibition of TBA(29)-AuNPs relative to thrombin--and thus the degree of aggregation of the Fib-AuNPs--is highly dependent on the concentration of perfectly matched DNA (DNA(pm)). Under optimal conditions [Tris-HCl (20 mM, pH 7.4), KCl (5 mM), MgCl(2) (1 mM), CaCl(2) (1 mM), NaCl (150 mM), thrombin (10 pM), and TBA(29)-AuNPs (20 pM)], the new TBA(29)-AuNP/Fib-AuNP probe shows linear sensitivity to DNA(pm) in the concentration range 20-500 pM with a correlation coefficient of 0.96. The limit of detection for DNA(pm) was experimentally determined to be 12 pM, based on a signal-to-noise ratio (S/N) of 3. The new probe was successfully applied to the analysis of an SNP that is responsible for sickle cell anemia. Relative to conventional molecular-beacon-based probes, the new probe offers the advantages of higher sensitivity and selectivity towards DNA and lower cost, showing its great potential for practical studies of SNPs. PMID- 21287649 TI - Crystalline-state cis-to-trans transformation of a two-dimensional spin-crossover system. PMID- 21287650 TI - A review of traditional remedies of ciguatera fish poisoning in the Pacific. AB - Ciguatera fish poisoning (CFP) is an illness caused by eating tropical coral fish contaminated with ciguatoxins (CTXs). The clinical management of patients with CFP is generally supportive and symptomatic in nature as no antidote exists. Of the many drugs prescribed, several have been claimed to be efficient in small, uncontrolled studies, but the outcomes of treatments with these medicines are often contradictory. In New Caledonia, traditional remedies are commonly employed in the treatment of CFP and of the 90 plant species catalogued as useful in CFP, the most popular herbal remedy by far is a decoction prepared from the leaves of Heliotropium foertherianum Diane & Hilger (Boraginaceae). Other important plants used in the treatment of CFP include Euphorbia hirta L. (Euphorbiaceae) and Vitex L. sp. (Lamiaceae). This review focuses on the evidence for efficacy of these species and pharmacological studies which support their use. Other plants used in CFP and the conventional treatment of CFP are also discussed briefly. PMID- 21287651 TI - Different transport activity of human triallelic MDR1 893Ala/Ser/Thr variant and its association with herb extracts. AB - Individual pharmacokinetic differences for herb-drug interaction have been associated with genetic variations of the multidrug resistance (MDR) gene. A high level expression of MDR protein increases cellular efflux and might decrease drug sensitivity. This study investigated the drug efflux activity difference of human MDR1 triallelic variant 2677G/T/A (rs2032582), as a nonsynonymous 893Ala/Ser/Thr, using Xenopus laevis oocytes and MDR1 overexpressing LLC-PK1 cells. Two MDR1 variants (2667T/893Ser and 2667A/893Thr) were generated using human MDR1 cDNA (2677G/893Ala). No significant difference in the expression of MDR1 893Ala/Ser/Thr was found in X. laevis oocytes. However, the MDR1 2667A/893Thr variant interestingly showed a significant decrease of efflux activity for both digoxin and daunorubicin compared with those of 893Ala and 893Ser variants. In further investigation assessing the inhibitory effects of three herbal extracts on MDR1, 893Ala and 893Ser showed significant decreases of efflux activities in treatments with P. cocos (p = 0.005 for 893Ser) and D. dasycarpus (p = 0.0009 for 893Ala; p = 0.002 for 893Ser) in X. laevis oocytes. The results in this study suggest that herbal medicines could interact with other drugs and change the therapeutic effects depending on the genetic polymorphisms of individuals. PMID- 21287652 TI - Screening of medicinal plants from Iranian traditional medicine for acetylcholinesterase inhibition. AB - To find new herbal compounds with an acetylcholinesterase (AChE) inhibitory effect, this study focused on herbal drugs and resins which have been used in Iranian traditional medicine for the treatment of cognitive disorders. Forty drugs were selected from authoritative written documents of Iranian traditional medicine. Each drug was extracted by accelerated solvent extraction using dichloromethane followed by methanol. The 80 extracts were screened for AChE inhibitory activity by a TLC bioautography method. The inhibiting effect of the 32 most active extracts was measured by a microplate colorimetric assay. Due to the best activity, the seeds of Peganum harmala L. were investigated in detail. From the TLC bioautography assay the alkaloids harmaline and harmine were identified as active compounds. This result was confirmed by means of HPLC-DAD. The IC(50) values were 41.2 MUg/mL for the methanol extract, 95.5 MUg/mL for the dichloromethane extract, 8.4 MUg/mL for harmaline and 10.9 MUg/mL for harmine. The concentrations of active compounds in the extracts were determined by a fast and precise HPLC method. As the amounts of harmaline and harmine in the extracts were correlated with the IC(50) values of the extracts, it can be concluded that these two alkaloids are responsible for the AChE inhibitory activity of P. harmala. PMID- 21287653 TI - Ovarian serous surface papillary borderline tumors form sea anemone-like masses. AB - PURPOSE: To clarify the imaging characteristics of ovarian serous surface papillary borderline tumor (SSPBT), whose prognosis is far better than that of serous surface papillary adenocarcinoma (SSPC). MATERIALS AND METHODS: We retrospectively reviewed the clinical and imaging findings of six cases (age range, 26-58 years; mean, 43 years) with SSPBT encountered at our institute from 1996 to 2008. RESULTS: Serum levels of CA125 were elevated, and they were clinically suspected to have ovarian cancer. All masses were almost entirely solid and showed hyperintense papillary architecture with hypointense internal branching on T2-weighted MRI. Five patients had peritoneal implants, and two had lymph node enlargement, and all tumors were accompanied by ascites. In all cases, contralateral ovaries had cystic masses with mural nodules or mixed solid and cystic masses, of which the solid part was similar to the contralateral mass. No evidence of recurrence was noted at a follow-up of >12 months postoperatively. CONCLUSION: SSPBT, which has more favorable prognosis than those of flank ovarian carcinoma, is characterized by a solid mass with papillary architecture and internal branching resembling a sea anemone on MR. PMID- 21287654 TI - In vivo assessment of peripheral nerve regeneration by diffusion tensor imaging. AB - PURPOSE: To evaluate the sensitivity of diffusion tensor imaging (DTI) in assessing peripheral nerve regeneration in vivo. We assessed the changes in the DTI parameters and histological analyses after nerve injury to examine degeneration and regeneration in the rat sciatic nerves. MATERIALS AND METHODS: For magnetic resonance imaging (MRI), 16 rats were randomly divided into two groups: group P (permanently crushed; n = 7) and group T (temporally crushed; n = 9). Serial MRI of the right leg was performed before the operation, and then performed at the timepoints of 1, 2, 3, and 4 weeks after the crush injury. The changes in fractional anisotropy (FA), axial diffusivity (lambda(?)), and radial diffusivity (lambda(?)) were quantified. For histological analyses, the number of axons and the myelinated axon areas were quantified. RESULTS: Decreased FA and increased lambda(?) were observed in the degenerative phase, and increased FA and decreased lambda(?) were observed in the regenerative phase. The changes in FA and lambda(?) were strongly correlated with histological changes, including axonal and myelin regeneration. CONCLUSION: DTI parameters, especially lambda(?) , can be good indicators for peripheral nerve regeneration and can be applied as noninvasive diagnostic tools for a variety of neurological diseases. PMID- 21287655 TI - HYPR TOF: time-resolved contrast-enhanced intracranial MR angiography using time of-flight as the spatial constraint. AB - PURPOSE: To investigate the feasibility of using time-of-flight (TOF) images as a constraint in the reconstruction of a series of highly undersampled time-resolved contrast-enhanced MR images (HYPR TOF), to allow simultaneously high temporal and spatial resolution and increased SNR. MATERIALS AND METHODS: Ten healthy volunteers and three patients with aneurysms underwent a HYPR TOF study, which includes a clinical routine TOF scan followed by a first pass time-resolved contrast-enhanced exam using an undersampled three-dimensional (3D) projection trajectory (VIPR). Image quality, waveform fidelity and signal to background variation ratio measurements were compared between HYPR TOF images and VIPR images without HYPR reconstruction. RESULTS: Volunteer results demonstrated the feasibility of using the clinical routine TOF as the spatial constraint to reconstruct the first pass time-resolved contrast-enhanced MRA acquired using highly undersampled 3D projection trajectory (VIPR). All the HYPR TOF images are superior to the corresponding VIPR images with the same temporal reconstruction window on both spatial resolution and SNR. CONCLUSION: HYPR TOF improves the spatial resolution and SNR of the rapidly acquired dynamic images without losing the temporal information. PMID- 21287656 TI - Neurogenin3 initiates stepwise delamination of differentiating endocrine cells during pancreas development. AB - During development, pancreatic endocrine cells are specified within the pancreatic epithelium. They subsequently delaminate out of the epithelium and cluster in the mesenchyme to form the islets of Langerhans. Neurogenin3 (Ngn3) is a transcription factor required for the differentiation of all endocrine cells and we investigated its role in their delamination. We observed in the mouse pancreas that most Ngn3-positive cells have lost contact with the lumen of the epithelium, showing that the delamination from the progenitor layer is initiated in endocrine progenitors. Subsequently, in both mouse and chick newly born endocrine cells at the periphery of the epithelium strongly decrease E-cadherin, break-down the basal lamina and cluster into islets of Langerhans. Repression of E-cadherin is sufficient to promote delamination from the epithelium. We further demonstrate that Ngn3 indirectly controls Snail2 protein expression post transcriptionally to repress E-cadherin. In the chick embryo, Ngn3 independently controls epithelium delamination and differentiation programs. PMID- 21287657 TI - Local burn versus local cold induced acute effects on in vivo microcirculation and histomorphology of the human skin. AB - BACKGROUND: The impact of burns and colds on human skin microcirculation and histomorphology has not been compared as yet. Reflectance confocal microscopy (RCM) enables in vivo insight in human skin on cellular and subcellular levels. We evaluated analogies and differences of thermal injuries on microcirculation and histomorphology in vivo using RCM. METHODS: Local superficial burn (6 female, 4 male; aged 28.4 +/- 2.9 years, burn group) versus superficial cold (4 female, 6 male; aged 30.4 +/- 5.2 years, cold group) was induced on the dorsum of the hand in an experimental immersion hand model. In vivo RCM was performed prior (control), immediately (t1) and 15 minutes (t2) following thermal injury to evaluate: Individual blood cell flow (IBCF), functional capillary density (FCD), epidermal thickness (ET), and granular cell size (GCS). RESULTS: In the burn group, IBCF was increased at t1 (78.02 +/- 2.60/min) and remained elevated at t2 (84.16 +/- 3.04/min). In the cold group, IBCF decreased at t1 (12.62 +/- 2.12 min) and increased at t2 (74.24 +/- 3.14/min, P < 0.05) compared to the controls (58.23 +/- 3.21/min). FCD was 6.74 +/- 0.52/mm(2) in controls and increased at both t1 (7.82 +/- 0.72/mm(2)) and t2 (8.02 +/- 0.81/mm(2)) in the burn group. In the cold group, FCD decreased at t1 (2.60 +/- 0.42/mm(2)) and increased at t2 (7.92 +/- 0.44/mm(2), P < 0.05). ET increased at both t1 (43.12 +/- 4.08 MUm, P > 0.05) and t2 (47.26 +/- 4.72 MUm, P < 0.05) in the burn group. In the cold group, ET decreased at t1 (39.92 +/- 3.14 MUm, P > 0.05) and increased at t2 (44.72 +/- 4.06 MUm, P < 0.05) compared to the controls (41.26 +/- 3.82 MUm). Control GCS was 726.9 +/- 59.4 MUm(2) and increased at both t1 (739.8 +/- 69.8 MUm(2), P > 0.05) and t2 (762.6 +/- 71.4 MUm(2), P < 0.05) in the burn group. In the cold group, GCS decreased at t1 (712.4 +/- 53.8 MUm(2), P > 0.05) and increased at t2 (742.6 +/- 64.8 MUm(2), P < 0.05). CONCLUSIONS: Superficial burn induces more cellular destruction and cold leads to huge fluctuation in tissue perfusion, however, with moderate impact on histomorphology. The effect on dermal capillaries suggests a selective neural control and cold injuries might down regulate this system, much more than burns can activate it. PMID- 21287658 TI - Early changes induced by short-term low-dose cadmium exposure in rat ventral and dorsolateral prostates. AB - Prostate cancer (PCa) is the most commonly diagnosed cancer in men. The etiology of PCa in humans is multifactorial and includes age, ethnicity, environmental factors, and other unknown causes. Epidemiological and experimental evidence has shown that cadmium is associated with PCa both in humans and rodents. This metal can act as an endocrine disruptor during prostate development, and it induces prostate lesions late in life. In this study, we investigated the effects of low dose cadmium on rat prostate morphology during puberty. Two-month-old male Wistar rats were randomized into two experimental groups: cadmium-treated and control. The ventral and dorsolateral prostates were dissected, weighed, and immunohistochemically stained with specific antibodies against Ki-67 and the androgen receptor (AR). The concentration of cadmium was measured in the blood and prostate, and testosterone concentration was measured from the plasma. Our results show that cadmium concentration was increased in both the blood and the prostate of cadmium-treated rats, but there were no changes in the prostatic weight, epithelial cell height, or testosterone levels. However, AR immunostaining and epithelial cell proliferation (Ki-67 index) were increased in both prostates with an increase in apoptosis only in the dorsal lobe. Furthermore, atypical hyperplasic proliferative lesions were found in the dorsolateral lobe after cadmium exposure. Cadmium treatment reduced collagen fiber absolute volume in both prostates. Thus, low-doses of cadmium, even for a short period of time, can interfere with prostate epithelium-stroma homeostasis, and this disruption might be an important factor in the onset of prostate lesions late in life. PMID- 21287659 TI - N-cadherin is overexpressed in Crohn's stricture fibroblasts and promotes intestinal fibroblast migration. AB - BACKGROUND: Intestinal fibroblasts mediate stricture formation in Crohn's disease (CD). Transforming growth factor-beta1 (TGF-beta1) is important in fibroblast activation, while cell attachment and migration is regulated by the adhesion molecule N-cadherin. The aim of this study was to investigate the expression and function of N-cadherin in intestinal fibroblasts in patients with fibrostenosing CD. METHODS: Intestinal fibroblasts were cultured from seromuscular biopsies from patients undergoing resection for terminal ileal fibrostenosing CD (n = 14) or controls patients (n = 8). N-cadherin expression was assessed using Western blot and quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Fibroblasts were stimulated with TGF-beta1 and selective pathway inhibitors Y27632, PD98050, and LY294002 were used to examine the Rho/ROCK, ERK-1/2, and Akt signaling pathways, respectively. Cell migration was assessed using a scratch wound assay. N-cadherin was selectively overexpressed using a plasmid. RESULTS: Fibroblasts from fibrostenosing CD express increased constitutive N-cadherin mRNA and protein and exhibit enhanced basal cell migration relative to those from directly adjacent normal bowel. Control fibroblasts treated with TGF-beta1 induced N-cadherin in a dose-dependent manner which was inhibited by Rho/ROCK and Akt pathway modulation. Control fibroblasts exhibited enhanced cell migration in response to treatment with TGF-beta1 or transfection with an N-cadherin plasmid. CONCLUSIONS: Fibroblasts from strictures in CD express increased constitutive N cadherin and exhibit enhanced basal cell migration. TGF-beta1 is a potent inducer of N-cadherin in intestinal fibroblasts resulting in enhanced cell migration. The TGF-beta1-mediated induction of N-cadherin may potentiate Crohn's stricture formation. PMID- 21287660 TI - INSPIRE study: does stress management improve the course of inflammatory bowel disease and disease-specific quality of life in distressed patients with ulcerative colitis or Crohn's disease? A randomized controlled trial. AB - BACKGROUND: The use of stress management psychotherapy is hypothesized to produce greater improvement in disease course and disease-specific quality of life (IBDQ) compared to usual medical care alone in patients with ulcerative colitis (UC) or Crohn's disease (CD) showing high levels of stress (based on the Perceived Stress Questionnaire [PSQ]). METHODS: Fifty-eight patients with UC and 56 patients with CD who had experienced continuous disease activity or had relapsed over the previous 18 months, with an activity index for UC or CD >= 4, a PSQ >= 60, and without serious psychiatric disorders or other serious medical conditions were randomized to receive either treatment as usual (TAU) or TAU plus stress management psychotherapy. Psychotherapy consisted of three group sessions (psychoeducation, problem-solving, relaxation) and 6-9 individual sessions based on cognitive behavior therapy-related methods with 1-3 booster sessions at 6 and 12 months follow-up. Gastroenterologists blinded to intervention group assessed disease activity and course at baseline and at 3, 6, 12, and 18 months. Patients completed the IBDQ at baseline, 6, 12, and 18 months. RESULTS: The intervention did not improve disease or reduce relapse; however, it increased the IBDQ score (P = 0.009, mean differences 16.3 [SD 6.1]). On analysis of UC and CD separately, improvement of IBDQ was only found in the UC group. CONCLUSIONS: Stress management psychotherapy does not appear to improve disease course or reduce relapse in patients with IBD. It might improve quality of life, particularly in patients with UC. PMID- 21287661 TI - Noninvasive imaging of the small bowel in Crohn's disease: the final frontier. AB - The substantial morbidity and mortality associated with Crohn's disease underlines the importance of accurate assessment at presentation, during follow up, when investigating complications, and when evaluating the response to therapeutic interventions. Accurate methods are required to quantify the severity and extent of disease. PMID- 21287662 TI - Development and validation of the Crohn's disease perceived work disability questionnaire. AB - BACKGROUND: No validated instruments have been developed to measure work disability in Crohn's disease (CD). The aim of our study was to develop and validate a CD perceived work disability questionnaire (CPWDQ). METHODS: Development phase: an initial questionnaire containing 52 items was obtained from patients' interviews plus additional sources; it was completed by 106 patients and the 16 most significant items were selected using a psychometric method in order to create the CPWDQ. Validation phase: The validation assessed the questionnaire's convergent validity, discriminant validity, test-retest reproducibility, and internal consistency in 108 patients. Spearman rank correlation, t-test, intraclass correlation, and Cronbach's alpha were used for the analysis. RESULTS: Convergent validity was confirmed by good correlations between the CPWDQ and: clinical activity (r = 0.59, P < 0.01), the Short Inflammatory Bowel Disease Questionnaire, IBDQ-9, (r = 0.76, P < 0.001), Euroqol 5D (r = 0.53, P < 0.01), and overall work impairment (WPAI_CD) r = 0.66 (P < 0.01). Discriminant validity: CPWQ scores were higher in patients expected to have more severe disability, that is, in patients with active disease (n = 38) 32.3 +/- 7.3 versus inactive (n = 70) 22.6 +/- 5.9 (P < 0.001), in those requiring previous sick leave 30.7 +/- 7.5 (n = 45) versus no sick leave 22.6 +/- 6.6 (n = 63) (P < 0.01), and in those requiring hospitalization 32.2 +/- 8.6 (n = 18) versus no hospitalization 24.7 +/- 7.1 (n = 90) (P < 0.01). Internal consistency was also good (Cronbach's alpha = 0.89). Reproducibility: CPWDQ measures obtained 2 weeks apart showed an excellent intraclass correlation coefficient: 0.89 (95% CI: 0.83-0.93). CONCLUSIONS: The CPWDQ seems to be a valid, reliable tool for measuring subjective work disability in CD. PMID- 21287663 TI - IL23R, ATG16L1, IRGM, OCTN1, and OCTN2 mRNA expression in inflamed and noninflamed mucosa of IBD patients. PMID- 21287664 TI - Dissecting the mucosal expression of human leucine-rich repeat family genes in inflammatory bowel disease patients. PMID- 21287665 TI - Long-term outcome of treatment with infliximab in pediatric-onset Crohn's disease: a population-based study. AB - BACKGROUND: We examined short- and long-term benefits and safety of infliximab (IFX) in a population-based cohort of Crohn's disease (CD) patients <17 years old at diagnosis. METHODS: The following parameters were assessed: short- and long term efficacy of IFX, impact of drug efficacy, and mode of administration on rate of resection surgery, growth and nutritional catch-up, and adverse events (AEs). RESULTS: In all, 120 patients (69 female) required IFX with a median duration of 32 months (Q1 = 8-Q3 = 60). Median age at diagnosis was 14.5 years (12-16) and median interval between diagnosis and IFX initiation was 41 months (22-78). Median follow-up since CD diagnosis was 111 months (75-161). Fifty patients (42%) received episodic and 70 (58%) maintenance therapy. Sixty-five (54%) patients were in the "IFX efficacy" group: 38 (32%) still receiving IFX at the last visit and 27 (22%) stopping IFX while in remission. The "IFX failure" group included 55 (46%) patients: 17 (14%) who stopped IFX due to AEs and 38 (32%) nonresponders. The risk of surgery was reduced (P = 0.009) in the "IFX efficacy" group and lower (P = 0.03) in patients with scheduled versus episodic therapy. Patients in the "IFX efficacy" group had significant catch-up growth (P = 0.04), while those in the "IFX failure" group did not. Twenty-four patients presented AEs leading to cessation of IFX in 17 of them. CONCLUSIONS: In this population-based cohort of pediatric-onset CD, IFX treatment was effective in more than half of patients during a median follow-up of 32 months. Long-term IFX responders had a lower rate of surgery and improved catch-up in growth, especially when receiving scheduled IFX therapy. PMID- 21287666 TI - GCMS-based metabolomic study in mice with colitis induced by dextran sulfate sodium. AB - BACKGROUND: Metabolomics provides data about all the metabolic processes of a cell or organism. So far, the changes that occur in the levels of metabolites during the development of colitis have not been fully elucidated. Here we examined the changes of metabolite levels in the serum and colon tissue of colitis mice using gas chromatography mass spectrometry (GC/MS) with the aim of achieving a detailed understanding of the pathogenesis of inflammatory bowel disease (IBD). METHODS: To induce colitis, C57BL/6J mice were administered 3.0% dextran sulfate sodium (DSS) in their drinking water for 5 days and were subsequently given drinking water alone. RESULTS: A total of 77 and 92 metabolites were detected in serum and colon tissue, respectively, and among the metabolites the compositions of TCA cycle intermediates and amino acids changed depending on the degree of colitis. Then, partial least square discriminant analysis (PLS-DA), a multiple classification analysis, showed distinct clustering and clear separation of the groups according to the degree of colitis. Furthermore, PLS-DA loadings plots revealed that succinic acid, indole-3-acetic acid, glutamic acid, and glutamine were the main contributors to the separation of each stage of colitis. In addition, it was revealed that supplementation with glutamine, the level of which was significantly decreased in the acute phase of colonic inflammation, attenuated colitis induced by DSS. CONCLUSIONS: Our results suggest that metabolomics is capable of representing the various degrees of colitis, and our findings will aid in the discovery of therapeutic agents for IBD and other inflammatory disorders by metabolomic approaches. PMID- 21287668 TI - Eruptive benign melanocytic naevi during immunosuppressive therapy in a Crohn's disease patient. PMID- 21287667 TI - Sex differences in statural growth impairment in Crohn's disease: role of IGF-1. AB - BACKGROUND: Growth impairment in Crohn's disease (CD) is more common in males than females for unknown reasons. Since insulin-like growth factor-1 (IGF-1) is important for statural growth, we hypothesized that IGF-1 levels are lower in males with CD. METHODS: Sex differences in hormone Z-scores based on chronological age (CA-Z) and bone age (BA-Z) were examined in a cross-sectional study of 82 CD patients <21 years of age (43% female). RESULTS: IGF-1 CA-Z and BA Z-scores were 0.50 units (P = 0.04) and 1.24 units (P = 0.003) lower in males. Mean bone age (12.2 years) was lower than chronological age (13.1 years) (P < 0.0001). Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and albumin did not differ by sex (P >= 0.08), but were associated with IGF-1 CA-Z and BA-Z-scores (P <= 0.02). Insulin-like growth factor binding protein-3 (IGFBP 3) CA-Z and BA-Z-scores were 0.71 units (P = 0.004) and 1.26 units (P < 0.001) lower in males. Inflammatory markers were correlated with sex hormone CA-Z and BA Z and pituitary hormone BA-Z-scores in males (P <= 0.03), but not females (P >= 0.25). IGF-1 BA-Z-scores were positively associated with height BA-Z-scores (P = 0.03). Mean height BA-Z-scores were lower in males (P = 0.03). CONCLUSIONS: Lower IGF-1 levels in males may explain sex differences in growth impairment in CD. Inflammation appears to more adversely affect hormone levels and statural growth in males. Prospective longitudinal studies are needed to further clarify the role of IGF-1 in sex differences in statural growth impairment in pediatric CD. PMID- 21287669 TI - Cryptococcus neoformans infection in ulcerative colitis with immunosuppressants. PMID- 21287670 TI - Crohn's disease and liver abscess due to Pediococcus sp. PMID- 21287671 TI - Mood and nonmood components of perceived stress and exacerbation of Crohn's disease. AB - BACKGROUND: Diverse psychological factors are involved in the pathophysiology of stress. In order to devise effective intervention strategies, it is important to elucidate which factors play the most important role in the association between psychological stress and exacerbation of Crohn's disease (CD). We hypothesized that the association between perceived stress and exacerbation of CD would remain after removal of mood and anxiety components, which are largely involved in stress perception. METHODS: In all, 468 adults with CD were recruited and followed in different hospitals and private practices of Switzerland for 18 months. At inclusion, patients completed the Perceived Stress Questionnaire and anxiety and depression were assessed using the Hospital Anxiety and Depression Scale. During the follow-up, gastroenterologists assessed whether patients presented with a CD exacerbation. By means of binary logistic regression analysis, we estimated the factor by which one standard deviation of perceived stress would increase the odds of exacerbation of CD with and without controlling for anxiety and depression. RESULTS: The odds of exacerbation of CD increased by 1.85 times (95% confidence interval 1.43-2.40, P < 0.001) for 1 standard deviation of perceived stress. After removing the anxiety and depression components, the residuals of perceived stress were no longer associated with exacerbation of CD. CONCLUSIONS: The association between perceived stress and exacerbation of CD was fully attributable to the mood components, specifically anxiety and depression. Future interventional studies should evaluate the treatment of anxiety and depression as a strategy for potential prevention of CD exacerbations. PMID- 21287672 TI - Differential association of two PTPN22 coding variants with Crohn's disease and ulcerative colitis. AB - BACKGROUND: The PTPN22 gene is an important risk factor for human autoimmunity. The aim of this study was to evaluate for the first time the role of the R263Q PTPN22 polymorphism in ulcerative colitis (UC) and Crohn's disease (CD), and to reevaluate the association of the R620W PTPN22 polymorphism with both diseases. METHODS: A total of 1677 UC patients, 1903 CD patients, and 3111 healthy controls from an initial case-control set of Spanish Caucasian ancestry and two independent sample sets of European ancestry (Dutch and New Zealand) were included in the study. Genotyping was performed using TaqMan SNP assays for the R263Q (rs33996649) and R620W (rs2476601) PTPN22 polymorphisms. Meta-analysis was performed on 6977 CD patients, 5695 UC patients, and 9254 controls to test the overall effect of the minor allele of R620W and R263Q polymorphisms. RESULTS: The PTPN22 263Q loss-of-function variant showed initial evidence of association with UC in the Spanish cohort (P = 0.026, odds ratio [OR] = 0.61, 95% confidence interval [CI]: 0.39-0.95), which was confirmed in the meta-analysis (P = 0.013 pooled, OR = 0.69, 95% CI: 0.51-0.93). In contrast, the 263Q allele showed no association with CD (P = 0.22 pooled, OR = 1.16, 95% CI: 0.91-1.47). We found in the pooled analysis that the PTPN22 620W gain-of-function variant was associated with reduced risk of CD (P = 7.4E-06 pooled OR = 0.81, 95% CI: 0.75-0.89) but not of UC (P = 0.88 pooled, OR = 0.98, 95% CI: 0.85-1.15). CONCLUSIONS: Our data suggest that two autoimmunity-associated polymorphisms of the PTPN22 gene are differentially associated with CD and UC. The R263Q polymorphism only associated with UC, whereas the R620W was significantly associated with only CD. PMID- 21287673 TI - Thrombin generation in pediatric patients with Crohn's disease. AB - BACKGROUND: Patients with inflammatory bowel disease (IBD) have an increased risk of thromboembolic complications. The pathogenesis of IBD is not really clear and a high thrombin activity might contribute to the pathogenesis. We measured thrombin generation by means of calibrated automated thrombography (CAT), a new tool better reflecting overall hemostasis, in children with Crohn's disease (CD) during active and inactive disease and compared it to conventional markers of activity. We wanted to see whether children with CD have a higher potential for thrombin generation and if there is a correlation between hypercoagulability and disease activity. METHODS: Plasma samples were collected from 22 patients with CD and from 61 healthy children. Thrombin generation was measured by means of CAT. The disease activity was estimated using the Pediatric Crohn's Disease Activity Index (PCDAI). In addition, F1+2, TAT, tissue factor pathway inhibitor (TFPI), fibrinogen, prothrombin (FII), antithrombin (AT), erythrocyte sedimentation rate (ESR), platelet count, alpha2-globulin, and orosomucoide were measured. RESULTS: In all patients we found a significantly higher endogenous thrombin potential (ETP) and higher peak values during active disease. In accordance with this we also found significantly higher mean ETP values during active disease compared with the control group. We observed a significantly positive correlation between PCDAI and thrombin generation parameters. CONCLUSIONS: Our study clearly shows that the active state of CD in children is associated with the potential for high thrombin generation, but this seems to be caused mainly by the inflammatory process and not by a preexisting propensity for high thrombin generation. PMID- 21287674 TI - Oral versus intravenous steroids to define refractory ulcerative colitis. PMID- 21287675 TI - Role of the interleukin 24 in patients with ulcerative colitis. PMID- 21287676 TI - No large ulcer: a predictor of latent cytomegalovirus infection in ulcerative colitis. PMID- 21287677 TI - Diagnostic pitfalls: cancerization in IBD versus mantle cell lymphoma presenting with multiple lymphomatous polyposis. PMID- 21287678 TI - Time-dependent FRET with single enzymes: domain motions and catalysis in H(+)-ATP synthases. AB - H(+)-ATP synthases are molecular machines which couple transmembrane proton transport with ATP synthesis from ADP and inorganic phosphate by a rotational mechanism. Single-pair fluorescence resonance energy transfer (spFRET) in single molecules is a powerful tool to analyse conformational changes. It is used to investigate subunit movements in H(+)-ATP synthases from E. coli (EF(0)F(1)) and from spinach chloroplasts (CF(0)F(1)) during catalysis. The enzymes are incorporated into liposome membranes, and this allows the generation of a transmembrane pH difference, which is necessary for ATP synthesis. After labelling of appropriate sites on different subunits with fluorescence donor and acceptor, the kinetics of spFRET are measured. Analysis of the E(FRET) traces reveals rotational movement of the epsilon and gamma subunits in 120 degrees steps with opposite directions during ATP synthesis and ATP hydrolysis. The stepped movement is characterized by a 120 degrees step faster than 1 ms followed by a rest period with an average dwell time of 15 ms, which is in accordance with the turnover time of the enzyme. In addition to the three conformational states during catalysis, also an inactive conformation is found, which is observed after catalysis. PMID- 21287679 TI - Surface functionalization of superparamagnetic nanoparticles for the development of highly efficient magnetic resonance probe for macrophages. AB - In vivo magnetic resonance imaging (MRI) tracking of macrophages plays an important role in monitoring and understanding numerous human diseases with high macrophage activity. In this work, superparamagnetic iron oxide nanoparticles (SPIONs) of ~12 nm were surface-functionalized with poly(DL-lactic acid-co-malic acid) copolymer (PLMA) via a nanoprecipitation method. The r(1), r(2) and r(2) /r(1) values of the PLMA-SPIONs obtained at a magnetic field of 3 T were 0.38, 196 and 516 mM(-1) s(-1) , respectively. The high r(2)/r(1) ratio can be expected to provide enhanced MR contrast. The PLMA-SPIONs were readily taken in by macrophages and the high iron uptake was confirmed via Prussian Blue staining and quantified by inductively coupled plasma mass spectrometry (ICP-MS). No significant cytotoxicity was found even at a high nanoparticle loading of 67.7 pg Fe per cell. A linear relationship between R(2) and R2* values and the number of PLMA-SPIONs labeled cells was observed in vitro. As a result of the significantly higher R2* than R(2) effects, an in vitro detection threshold of about 2820 labeled cells was achieved with short labeling time and low nanoparticle concentration using a clinical 3 T MRI scanner. Thus, the PLMA-SPIONs can be potentially useful as magnetic resonance probes for targeting and tracking macrophages. PMID- 21287680 TI - Real-time 3D MRI of contrast agents in whole living mice. AB - A specific mouse whole body coil and a dedicated gradient system at 4.7 T were coupled with an ultra-fast 3D gradient echo MRI and keyhole reconstruction technique to obtain 3D whole-body dynamic T(1)-weighted or T(2)*-weighted imaging. The technique was used to visualize the real-time distribution of non targeting T(1) and T(2)* contrast agent (CA) in a glioma-bearing mouse model. T(1) dynamic contrast-enhancement imaging was performed with a fast imaging with steady-state precession sequence [echo time/repetition time (TE/TR), 1.32/3.7 ms] before and after CA injection (Gd-DOTA and BSA-Gd-DOTA) for 21 min. The temporal resolution was 1 image/6.5 s. T(2)* imaging (TE/TR, 4/8 ms) was performed before and after iron-based (small and ultra-small particles of iron oxide) CA injection for 45 min. The temporal resolution was 1 image/14 s. Signal-to-noise ratio curves were determined in various mouse organs. The whole-body coil and gradient systems made it possible to acquire data with sufficient and homogeneous signal to-noise ratio on the whole animal. The spatial resolution allowed adequate depiction of the major organs, blood vessels and brain glioma. The distribution and the time-course of T(1) and T(2)* contrasts upon contrast agent injection were also assessed. 3D whole-body mouse MRI is feasible at high spatial resolution in movie mode and can be applied successfully to visualize real-time contrast agent distribution. This method should be effective in future preclinical molecular imaging studies. PMID- 21287681 TI - Involvement of MAPK and PI3K signaling pathway in sterigmatocystin-induced G2 phase arrest in human gastric epithelium cells. AB - SCOPE: Sterigmatocystin (ST), a mycotoxin commonly found in foodstuff and feedstuff, has been shown to be a carcinogenic mycotoxin in animal models. Many studies showed that the high level of ST contamination in grains might be related to the high incidence of gastric carcinoma in rural areas of China. However, up to now, the potential effects of ST on human gastric epithelium cells remain largely unknown. In this study, we explored the effects of ST on cell-cycle distribution and the regulatory mechanism in immortalized human gastric epithelium cells (GES-1). METHODS AND RESULTS: The effects of ST on the cell cycle distribution of GES-1 cells were determined with flow cytometric (FCM) analysis, Giemsa staining and immunofluorescence staining, while that on the expression of related gene-Cdc25C, Cdc2, CyclinB1 and the complex of CyclinB1 Cdc2 were studied with Western blot, reverse transcription polymerase chain reaction (RT-PCR) and immunoprecipitation assay respectively. We found that ST induced GES-1 cells arrested at G2 phase by regulating the expression of Cdc25C, Cdc2, CyclinB1 and the formation of CyclinB1-Cdc2 complex. Further study suggested JNK, ERK and PI3K/AKT/mTOR pathways to be involved in the process of G2 arrest induced by ST. The specific inhibitors of JNK and ERK reversed the role of ST, whereas that of PI3K/AKT/mTOR reinforced the effect of ST on cell-cycle distribution. CONCLUSION: This study demonstrates that JNK, ERK and PI3K/AKT/mTOR pathways participated in the G2 arrest induced by ST through the deregulation of CyclinB1, Cdc2 and Cdc25C. It may play some roles in the gastric carcinogenesis in ST exposure populations. PMID- 21287685 TI - Laser applications in life sciences. PMID- 21287686 TI - Multi-dimensional fluorescence microscopy of living cells. AB - An overview on fluorescence microscopy with high spatial, spectral and temporal resolution is given. In addition to 3D microscopy based on confocal, structured or single plane illumination, spectral imaging and fluorescence lifetime imaging microscopy (FLIM) are used to probe the interaction of a fluorescent molecule with its micro-environment. Variable-angle total internal reflection fluorescence microscopy (TIRFM) permits selective measurements of cell membranes or cell substrate topology in the nanometre scale and is also combined with spectral or time-resolved detection. In addition to single cells or cell monolayers, 3 dimensional cell cultures are of increasing importance, since they are more similar to tissue morphology and function. All methods reported are adapted to low dose of illumination, which is regarded as a key parameter to maintain cell viability. Applications include cancer diagnosis and cell tomography under different physiological conditions. PMID- 21287687 TI - Long-living nanobubbles of dissolved gas in aqueous solutions of salts and erythrocyte suspensions. AB - Results of experiments combining laser modulation interference microscopy and Mueller matrix scatterometry show that macroscopic scatterers of light are present in liquids free of external solid impurities. Experimental data on distilled water and aqueous NaCl solutions of various concentrations as well as physiological saline solution are reported. The experimental data can be interpreted by using a model of micron-scale clusters composed of polydisperse air nanobubbles having effective radii of 70-100 nm. Their concentration increases with the growth of ionic content. We hypothesize that under certain conditions those clusters of nanobubbles can affect the erythrocyte structure. PMID- 21287688 TI - Photons bring light into DNA repair: the comet assay and laser microbeams for studying photogenotoxicity of drugs and ageing. AB - This contribution reviews recent applications of micromanipulation, by UV photons, in DNA repair and ageing research as well as in the evaluation of the phototoxicity of drugs. In some cases, micromanipulation is combined with the comet assay, a technique, which allows a direct view on DNA damages. It is shown that, in humans, the sensitivity of DNA to UV induced damage and its subsequent repair is surprisingly stable up to high age and that drugs which are usually non toxic induce DNA damage when irradiated in parallel by UV irradiation. Using the immune fluorescent comet assay, IFCA, a variant of the comet assay, direct comparison of the effects of ionizing (137) Cs radiation with those of localized UV radiation is possible. When a laser microbeam is used to damage DNA in a cell nucleus with high temporal and spatial resolution, it can be observed directly how repair molecules accumulate (are recruited) at the site of damage. Comparison of the recruitment speed allows establishing an order of DNA repair events. PMID- 21287689 TI - Light-induced effects on Brownian displacements. AB - Earlier work on particles in aqueous solution indicated that particle hydration could be expanded by incident light. To assess the effects of expanded hydration we measured Brownian displacements of microspheres exposed to light of varying intensities and wavelengths. Displacements were consistently diminished in an intensity-dependent and wavelength-dependent fashion, and center-to-center distances between microspheres were shifted to higher values. We conclude that suspended microspheres are surrounded by hydration zones substantial enough to impact Brownian displacements. PMID- 21287690 TI - Ultrafast electron transfer processes studied by pump-repump-probe spectroscopy. AB - The photodetachment of Br(-), I(-) and OH(-) in aqueous solution is studied by 2- and 3-pulse femtosecond spectroscopy. The UV excitation leads to fast electron separation followed by formation of a donor-electron pairs. An additional repump pulse is used for secondary excitation of the intermediates. The 3-pulse technique allows distinguishing the pair-intermediate from the fully separated electron. Using this method we observe a novel geminate recombination channel of .OH with adjacent hydrated electrons. The process leads to an ultrafast quenching (0.7 ps) of almost half the initial number of radicals. The phenomenon is not observed in Br(-) and I(-). Our results demonstrate the potential of the 3-pulse spectroscopy to elucidate the mechanism of ultrafast ET reactions. Photodetachment of aqueous anions studied by two- and three pulse spectroscopy. PMID- 21287691 TI - Preservation of fine-needle aspiration specimens for future use in RNA-based molecular testing. AB - BACKGROUND: The application of ancillary molecular testing is becoming more important for the diagnosis and classification of disease. The use of fine-needle aspiration (FNA) biopsy as the means of sampling tumors in conjunction with molecular testing could be a powerful combination. FNA is minimally invasive, cost effective, and usually demonstrates accuracy comparable to diagnoses based on excisional biopsies. Quality control (QC) and test validation requirements for development of molecular tests impose a need for access to pre-existing clinical samples. Tissue banking of excisional biopsy specimens is frequently performed at large research institutions, but few have developed protocols for preservation of cytologic specimens. This study aimed to evaluate cryopreservation of FNA specimens as a method of maintaining cellular morphology and ribonucleic acid (RNA) integrity in banked tissues. METHODS: FNA specimens were obtained from fresh tumor resections, processed by using a cryopreservation protocol, and stored for up to 27 weeks. Upon retrieval, samples were made into slides for morphological evaluation, and RNA was extracted and assessed for integrity by using the Agilent Bioanalyzer (Agilent Technologies, Santa Clara, Calif). RESULTS: Cryopreserved specimens showed good cell morphology and, in many cases, yielded intact RNA. Cases showing moderate or severe RNA degradation could generally be associated with prolonged specimen handling or sampling of necrotic areas. CONCLUSIONS: FNA specimens can be stored in a manner that maintains cellular morphology and RNA integrity necessary for studies of gene expression. In addition to addressing quality control (QC) and test validation needs, cytology banks will be an invaluable resource for future molecular morphologic and diagnostic research studies. PMID- 21287692 TI - TTF-1 and Napsin A double stain: a useful marker for diagnosing lung adenocarcinoma on fine-needle aspiration cell blocks. AB - BACKGROUND: Immunohistochemistry (IHC) for thyroid transcription factor-1 (TTF-1) is used to confirm the diagnosis of lung adenocarcinoma. Napsin A also has shown positivity in lung adenocarcinoma. A combined double stain for TTF-1 and napsin A has been proposed to achieve higher sensitivity and specificity. In this study, the authors evaluated the utility of this double stain in the diagnosis of lung adenocarcinoma in cell blocks of fine-needle aspirates (FNA). METHODS: The authors used a cohort comprising 35 FNA cell blocks of lung adenocarcinoma and 24 FNA cell blocks of lung squamous cell carcinoma (SqCCA). IHC was performed; expressions of TTF-1 as brown nuclear stain and of napsin A as red cytoplasmic stain were identified. RESULTS: Twenty-six of 35 (74%) lung adenocarcinomas were positive for double staining with TTF-1/napsin A. Of 35 lung adenocarcinomas, only 2 (5%) were positive for TTF-1 alone and 3 (8%) were positive for napsin A alone. For the double stain TTF-1/napsin A, 3 of 24 (12%) lung SqCCAs were positive for both. Six of 24 (25%) cases were positive for TTF-1 alone, and none were positive for napsin A alone. For lung adenocarcinoma, TTF-1/napsin A has a sensitivity of 74%, specificity of 87%, accuracy of 79%, and a positive predictive value of 89%. CONCLUSIONS: The double IHC stain, TTF-1/napsin A, for the identification of pulmonary adenocarcinoma in FNA cell block materials was diagnostically useful. The use of napsin A alone demonstrated a greater degree of accuracy and appeared diagnostically useful as a single IHC stain. PMID- 21287693 TI - Analysis of methyloxime derivatives of intact esters of testosterone and boldenone in equine plasma using ultra high performance liquid chromatography tandem mass spectrometry. AB - Analysis of equine plasma samples to detect the abuse of anabolic steroids can be complicated when the parent steroid is endogenous to the animal. Anabolic steroids are usually administered intramuscularly as synthetic esters and therefore detection of the exogenous esters provides unequivocal proof of illegal administration. An ultra high performance liquid chromatography tandem mass spectrometric (UPLC-MSMS) method for the analysis of esters of testosterone (propionate, phenylpropionate, isocaproate, and decanoate) and boldenone (undecylenate) in equine plasma has been developed. Esters were extracted from equine plasma using a mixture of hexane and ethyl acetate and treated with methoxyamine hydrochloride to form methyloxime derivatives. Metenolone enanthate was used as an internal standard. After chromatographic separation, the derivatized steroid esters were quantified using selected reaction monitoring (SRM). The limit of detection for all of the steroid esters, based on a signal to noise ratio (S/N) of 3:1, was 1-3 pg/mL. The lower limit of quantification (LLOQ) for the all of the steroid esters was 5 pg/mL when 2 mL of plasma was extracted. Recovery of the steroid esters was 85-97% for all esters except for testosterone decanoate which was recovered at 62%. The intra-day coefficient of variation (CV) for the analysis of plasma quality control (QC) samples was less than 9.2% at 40 pg/mL and less than 6.0% at 400 pg/mL. The developed assay was used to successfully confirm the presence of intact testosterone esters in equine plasma samples following intramuscular injection of Durateston(r) (mixed testosterone esters). PMID- 21287694 TI - Precision improvement for omeprazole determination through stability evaluation. AB - A new spectrofluorimetric method for the determination of omeprazole (OMP) based on its degradation reaction catalyzed by ultraviolet (UV) light is proposed. OMP in aqueous solution is very unstable, which renders a serious difficulty for controlling its quality. It does not show native fluorescence, but when exposed to UV radiation, it generates a highly fluorescent degradation product with adequate stability for indirect OMP quantification. Under the studied optimal experimental conditions (pH, temperature, exposure time to UV radiation), a specific rate constant of 2.851 min-1--described by zero-order kinetic--was obtained for the degradation reaction. Using lambda(exc) 293 nm and lambda(em) 317 nm, a linear relationship was obtained (r2 0.9998) in the concentration range of 0.1 to 1.3 ug mL-1, with a detection limit of 1.07 10-3 ug mL-1 (S/N = 3). The methodology developed was successfully applied to OMP quality control in pure drugs and tablet dosage forms without previous treatment, with good tolerance to common excipient, and a high level of concordance between the nominal and experimental values. This work constitutes an important contribution to knowledge of the degradation mechanism of OMP. It has been shown to be appropriate for OMP quality control, to have an adequate sampling rate, low cost instrument, and to be a less polluting procedure. PMID- 21287695 TI - A novel chemiluminescence quenching method for determination of sulfonamides in pharmaceutical and biological fluid based on luminol-Ag(III) complex reaction in alkaline solution. AB - A novel chemiluminescence (CL) quenching method for the determination of sulfonamides is proposed. The CL reaction between Ag(III) complex [Ag(HIO6)2]5- and luminol in alkaline solution was investigated. The quenching effect of sulfonamides on CL emission of [Ag(HIO6)2]5--luminol system was found. Quenching degree of CL emission was proportional to sulfonamide concentration. The effects of the reaction conditions on CL emission and quenching were examined. Under optimal conditions, the detection limits (s/n = 3) were 7.2, 17 and 8.3 ng/mL for sulfadiazine, sulfameter, and sulfadimethoxine, respectively. The recoveries of the three drugs were in the range of 91.3-110% with RSDs of 1.9-2.7% for urine samples, and 106-112% with RSDs of 1.6-2.8% for serum samples. The proposed method was used for the determination of sulfadiazine at clinically relevant concentrations in real urine and serum samples with satisfactory results. PMID- 21287696 TI - Prostate cancer: A rocky road to overcoming castration resistance. PMID- 21287697 TI - Prostate cancer: Colorectal cancer increased by ADT? PMID- 21287698 TI - Prostate cancer: Dutasteride improves accuracy of diagnosis but may not prevent cancer development. PMID- 21287699 TI - Prostate cancer: Cadherin 2: an important new player in castration resistance. PMID- 21287700 TI - Pediatrics: Optimizing caudal analgesia for minor urologic procedures. PMID- 21287701 TI - Pediatrics: alpha-Blocker resolves VUR caused by bladder neck dysfunction. PMID- 21287702 TI - Pediatrics: Challenging the disorders of sex development dogma. PMID- 21287703 TI - Stones: New pathway to prevention of L-cystine stones. PMID- 21287704 TI - Stones: Morning spot urine samples are better than 24 h urine for assessment of lithogenic risk in children. PMID- 21287705 TI - Stones: Low-dose dual-energy CT. PMID- 21287706 TI - BHP: Silodosin an effective new drug for BPH-associated LUTS. PMID- 21287707 TI - Bladder cancer: Reperitonealization after extended PLND and cystectomy improves postoperative pain and recovery of bowel function. PMID- 21287708 TI - Microbial genetics: social amoebae get ready for sex. PMID- 21287709 TI - Bacterial pathogenesis: legionella effector under friendly fire. PMID- 21287710 TI - Environmental microbiology: boring bacteria? PMID- 21287711 TI - Virology: host RNA editor restricts measles. PMID- 21287712 TI - Environmental microbiology: biohydrogen production gets airbone. PMID- 21287713 TI - Bacterial genetics: can you hear me now? PMID- 21287715 TI - Abstracts of the American Society for Clinical Pharmacology and Therapeutics 2011 Annual Meeting. March 2-5, 2011. Dallas, Texas, USA. PMID- 21287714 TI - Short-term and long-term outcomes of autoimmune pancreatitis. AB - OBJECTIVE: To examine the short-term and long-term clinical courses of patients with autoimmune pancreatitis (AIP) who underwent different treatments and identify predictive factors for relapse of AIP after steroid therapy. METHODS: Clinical courses of 50 AIP patients followed up for more than 1 year (median 40 months, range: 12-173 months) were examined. Patients were subdivided according to initial treatments as follows: surgical procedures in 10 patients, supportive therapy in 11 patients, and steroid therapy in 29 patients. RESULTS: Of the surgically treated patients, two underwent steroid therapy later because of progressive extensive lymphadenopathy and retroperitoneal fibrosis, respectively. Five conservatively followed-up patients were later given steroid therapy because of exacerbation of AIP involving the bile duct. Steroid therapy was effective in all patients. Pancreatic endocrine and exocrine dysfunctions and salivary gland dysfunction improved after steroid therapy in 100, 85, and 75% of patients, respectively. AIP relapsed in five patients initially treated with steroid, and presence of hilar bile duct stenosis and elevated serum IgG4 levels were significantly associated with relapse. Two relapsed AIP patients developed a pancreatic stone 2 and 3 years later. Although seven patients died, no patient died of AIP-related diseases or developed pancreatic carcinoma. CONCLUSION: Most AIP patients treated with steroid had good short-term and long-term outcomes clinically, morphologically, and functionally. Hilar bile duct stenosis and elevated serum IgG4 levels were predictors of AIP relapse after steroid therapy. As some patients developed pancreatic stone formation or a malignancy during or after steroid therapy, AIP patients should be rigorously followed up. PMID- 21287716 TI - Orlistat without a prescription. The SPC now contains more situations where patients are advised to consult a doctor. AB - Despite the broad media attention given to this self-medication product, patients are still not getting their money's worth. PMID- 21287718 TI - Abstracts of the British Society for Paediatric and Adolescent Rheumatology (BSPAR) Annual Conference. October 14-15, 2010. Newcastle Upon Tyne, United Kingdom. PMID- 21287717 TI - Truffle volatiles: from chemical ecology to aroma biosynthesis. AB - Truffles (Tuber spp.) are symbiotic fungi that develop underground in association with plant roots. Food connoisseurs describe their scent as sensual, seductive and unique. These mysterious fungi, however, do not produce their aroma for the mere pleasure of humans. Truffle volatiles act as odorant cues for mammals and insects which are thus able to locate the precious fungi underground and spread their spores. They also freely diffuse in the soil and mediate interactions with microorganisms and plant roots, potentially regulating a complex molecular dialogue among soil fauna and flora. The aim of this review is to synthesize 30 yr of research on truffle volatiles, spanning fields of study from chemical ecology to aroma biosynthesis. Specific aspects of truffle volatile ecology and biology will be discussed, including which species have been studied so far and for what purpose, what ecological role has been demonstrated or speculated to exist for specific truffle volatiles, which volatiles are common or unique to certain species and what their biosynthetic route might be. Future challenges in truffle aroma research will also be addressed, focusing on how high-throughput post-genomic technologies may advance our understanding of truffle aroma biosynthesis and chemical ecology. PMID- 21287719 TI - The diagnostic significance of serum IgG4 levels in patients with autoimmune pancreatitis: a UK study. AB - BACKGROUND: Autoimmune pancreatitis (AIP) is recognised as an end organ manifestation of the systemic condition known as IgG4-sclerosing disease. One major characteristic of this disease, regardless of its location in the body, is the presence of high levels of circulating serum IgG, in particular IgG4 antibody. In the case of AIP, differential diagnosis from other conditions of the pancreas and biliary system, particularly cancers, can be difficult, but could result in avoiding invasive procedures and surgery. Earlier studies have evaluated the use of checking IgG4 levels in AIP diagnosis; these have produced variable results. OBJECTIVE: To further assess the diagnostic significance of serum IgG4 levels in AIP and investigate its value in differentiating from cancer of the gastroenterological system. METHODS: A retrospective study of 196 IgG4 requested samples from a 24-month period was examined. Samples were sorted into confirmed AIP, cancer or other pancreatic conditions including primary sclerosing cholangitis. RESULTS: Patients with AIP possessed a mean serum IgG level that was significantly higher compared with all other groups (mean serum IgG level=19.0 g/l+/-2.5, P<0.001). The mean serum IgG4 level of AIP patients was also significantly higher compared with all other conditions including cancer patients (mean IgG4 level=3.7 g/l+/-0.5, P<0.001). CONCLUSION: This data lends support to circulating IgG4 levels only being used as an accompanying diagnostic marker to imaging, histology and clinical presentation. In particular, this may help in differentiating between AIP and pancreatic carcinoma. PMID- 21287720 TI - A study comparing an endoscopy nurse and an endoscopy physician in capsule endoscopy interpretation. AB - OBJECTIVE: Complete review of wireless capsule endoscopy (WCE) recordings by a physician is time-consuming and laborious and may be perceived as a limitation to perform WCE. The aim of this study was to evaluate the efficacy of a nurse in interpreting WCE. METHODS: A total of 102 WCE videos were evaluated by a single gastroenterologist and a nurse experienced as an assistant in diagnostic and interventional endoscopy and trained in WCE. After independently reviewing WCE videos, the two readers discussed their findings and came to a consensus. RESULTS: The mean capsule reading time was significantly longer for the nurse compared with the gastroenterologist (117.3+/-24.8 vs. 63.8+/-8.5 min, P<0.001). No statistical differences were observed regarding the correct recognition of first gastric, duodenal and caecal images between the two readers. For the gastroenterologist, both sensitivity and specificity in detecting abnormal findings were 100% except for angiodysplasia [sensitivity 88.5%, 95% confidence interval (CI): 70-97.4]. For the nurse, the lowest sensitivity rates were in detecting polyps (70%, 95% CI: 34.9-92.3) and angiodysplasias (92.3%, 95% CI: 74.8-98.9). The interobserver agreement as determined by Cohen's kappa coefficient was excellent except for polyps (k=0.71, 95% CI: 0.46-0.96). CONCLUSION: A trained nurse is highly accurate in detecting abnormal findings and interpreting WCE recordings. Physician's role could be limited to consider and confirm thumbnails created by a nurse. PMID- 21287721 TI - [Turbulent times]. PMID- 21287722 TI - [Hypopituitarism associated dwarfism in German Shepherds, saarloos wolf dogs and Czechoslovakian wolf dogs. Access to genetic testing]. PMID- 21287723 TI - [Lap work]. PMID- 21287724 TI - [Joke van der Giessen: 'Fighting together against zoonotic threats'. Interview by Berrie Klein Swormink]. PMID- 21287726 TI - [Intensive cooperation KNMVD and WVAA. First result: combined liability and legal protection insurance]. PMID- 21287725 TI - [Pregnant and working healthy in a veterinary clinic. Ionizing radiation, zoonoses and physical burden]. PMID- 21287727 TI - [Symposium Zoonoses: antibiotic resistance]. PMID- 21287728 TI - [The Danish system]. PMID- 21287729 TI - [Emerging infectious diseases and antibiotic resistance]. PMID- 21287730 TI - [A new journal for veterinary medicine]. PMID- 21287731 TI - [The suppression of c-fos in neuron apoptosis induced by heroin]. AB - OBJECTIVE: To explore the changes of c-fos in apoptosis of cerebellar granular neuron of neonatal SD rats induced by heroin and the mechanisms of neuronal injury caused by heroin. METHODS: Primary cerebellar granular neuron were cultured in vitro, the model of apoptosis induced by heroin was established. Reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting were adopted to investigate the changes of c-fos in cell models. RESULTS: Ten microg/mL of heroin was the optimal dose to induce the apoptosis of cerebellar granular neuron at 48 h. Both Western blotting and RT-PCR showed down regulation of c-fos expression. CONCLUSION: Heroin could induce apoptosis of cerebellar granular neuron and down regulation of c-fos, which may be one of the apoptosis mechanisms. PMID- 21287732 TI - [Immunohistochemical expression of HO-1 in traumatic human brain tissue]. AB - OBJECTIVE: To investigate the expression of heme oxygenase-1 (HO-1) at different intervals and to provide evidence for estimation on injury intervals after brain contusion in human. METHODS: Twenty-four patients died of serious brain injury were assigned as injury group and 4 patients died of non-brain injury were served as control group. HO-1 expression was analyzed in brain tissue at different time intervals (3 h, 6-9 h, 12-24 h, 36 h-3d, 5-8d, 17-20d) by immunohistochemistry and auto-image analysis system. RESULTS: The level of HO-1 expression started to increase in 3 h after brain contusion compared to the control group (P < 0.05). The level of HO-1 expression highest level in 12-24 h group, and maintained high level in 36 h-3 d, then decreased gradually. CONCLUSION: The expression of HO-1 might be a strong evidence for human brain contusion time estimation. PMID- 21287733 TI - [Expression of CAR in myocardial of viral myocarditis and dilated cardiomyopathy]. AB - OBJECTIVE: In order to improve accuracy and reliability of forensic diagnosis of sudden cardiac death, pathogenesis and relationship between the viral myocarditis (VMC) and dilated cardiomyopathy (DCM) were investigated. METHODS: Improved immunohistochemical technique was used to detect the expression of the CAR in myocardium samples, including 22 deceased with VMC, 20 deceased with DCM and 16 control deceased. RESULTS: The brown staining on the cell membrane of myocardium showed positive result. There was a prominent CAR expression in VMC group and DCM group, which were statistically significant difference compared with control group (P < 0.05). CONCLUSION: The CAR expression showed significantly higher in VMC and DCM groups. The viral infection can result in myocardial necrosis and impaired cardiac functions. These abnormalities can trigger a cascade of events that contributed to the progress of VMC to DCM. PMID- 21287734 TI - [Estimation time of death by necrophagous flies life cycle]. AB - OBJECTIVE: To study the nature of necrophagous flies, their developmental cycle and seasonal variation. METHODS: Animal corpse was used to be baiting. Eight kinds of necrophagous flies on their developmental cycle and the pattern of seasonal variation were analyzed. RESULTS: The community of necrophagous flies at high temperature in summer were more abundant than at low temperature in winter. Eight necrophagous flies through longer time at high temperature during every state than at low temperature. CONCLUSION: The life cycle and seasonal variation pattern of necrophagous flies could be used to estimate the time of death in practical cases. PMID- 21287735 TI - [Comparison of mtDNA extraction from different parts of sarcosaphagous insects]. AB - OBJECTIVE: To explore mitochondrial DNA (mtDNA) extraction effects of different parts from sarcosaphagous insects using improved cetyltriethylammnonium bromide (CTAB) method. METHODS: Thirteen Lucilia sericata (Meigen) and 13 Nicrophorus fossor (Erichson) were collected from the corpses of rabbits placed on the outdoor lawn in Huhehot district. Four parts (head, chest muscle, legs and wings) of insect were collected, and the mtDNA of all samples were extracted using CTAB method. The purity and concentration were tested using protein and nucleic acid spectrophotometry. The integrity of the extracted mtDNA and PCR products were checked by agarose gel electrophoresis. The PCR products were sequenced and the obtained sequences were imputed into GenBank for comparison. RESULTS: mtDNA were successfully extracted from 10 head samples, 6 legs samples, 4 wing samples and 13 chest muscle samples of the Lucilia sericata (Meigen). Also, mtDNA were successfully extracted from 5 head samples, 8 legs samples, 3 wing samples and 13 chest muscle samples of the Nicrophorus fossor (Erichson). CONCLUSION: mtDNA can be obtained from chest muscle and other parts of sarcosaphagous insects using the improved CTAB method. PMID- 21287736 TI - [Determination of bloodstain formation time by RNA analysis]. AB - OBJECTIVE: To investigate the expression of 18S rRNA and beta-actin mRNA in bloodstain between 8 and 15 days after death and extrapolate the time of bloodstain formation. METHODS: RNA in dried bloodstain at different times was extracted, then quantified for 18S rRNA and beta-actin mRNA by real-time RT-PCR. The bloodstain formation time was deduced based on the changes of the ratio of 18S rRNA to beta-actin mRNA at different time points. RESULTS: The ratio of 18S rRNA to beta-actin mRNA increased gradually with time, indicating that rRNA and mRNA degraded in different rate with time. CONCLUSION; The ratio of 18S rRNA to beta-actin mRNA could be used for estimating the time of bloodstain formation in some period. PMID- 21287737 TI - [InDel_typer30: a multiplex PCR system for DNA identification among five Chinese populations]. AB - OBJECTIVE: To develop a multiplex PCR system, using insertion/deletion (InDel) polymorphism markers, for forensic DNA identification among Han, Hui, Uighur, Mongolian and Tibetan populations in China. METHODS: Highly polymorphic InDel markers from human autosomes were selected using the Human Genome Browser in Galaxy system and dbSNP database. Multiplex PCR primer pairs of selected InDel markers were designed using Primer 3 software. The multiplex PCR system was developed using a five fluorescence dye labeling system. Genetic polymorphisms of selected InDel markers were investigated using the multiplex PCR system among five populations in China. RESULTS: A new multiplex genotyping system, named InDel_typer30, was successfully developed and validated in this study. The InDel_typer30 system consisted of 30 highly polymorphic InDel markers and 1 Amelogenin gender marker. The average expected heterozygosity of the 30 InDel markers was 0.464, 0.460, 0.453, 0.466 and 0.469 for the Han, Hui, Uighur, Mongolian and Tibetan populations, respectively. The average discrimination power was 0.595, 0.585, 0.586, 0.589 and 0.595 for the Han, Hui, Uighur, Mongolian and Tibetan populations, respectively. The cumulative discrimination power (CDP) were all above 0.999 999 999 996 for the 5 populations. CONCLUSION: InDel_typer30 was a useful forensic DNA identification tool for human identification among Han, Hui, Uighur, Mongolian and Tibetan populations in China. PMID- 21287738 TI - [STR profiling of genomic DNA from HE stained tissue sections]. AB - OBJECTIVE: To develop a STR analysis method for analyzing DNA from stained tissue sections and to evaluate the capability of this protocol in forensic application. METHODS: Eight kinds of HE stained human tissue, for example heart, liver, lung and intestine, were collected from two autopsy cases. The genomic DNA from those tissues was extracted using a QIAgen kit. DNA quantitation was performed using the TaqMan PCR method. The concentration of DNA isolated was determined based on Ct values. Internal positive controls (IPC) were used to monitor inhibitors. DNA amplifications were performed using Identifiler PCR Amplification kit. PCR products were analyzed on 3100-Avant Genetic Analyzer. RESULTS: The concentrations of DNA obtained from all samples were greater than 1 ng/microL. PCR inhibition was not observed. However, DNA degradation, potentially due to the effect of residual formalin fixative, was observed among tissue samples stored for long periods of time. CONCLUSION: Sufficient amounts of DNA were extracted from HE stained tissue sections. STR profiles were successfully generated. The number of genotype alleles detected decreased as sample storage time increased. PMID- 21287739 TI - [Preliminary study on civil capacity rating scale for mental disabled patients]. AB - OBJECTIVE: To create civil capacity rating scale for mentally disabled patients, and explore its feasibility during the forensic psychiatric expertise. METHODS: The civil capacity-related items were determined after discussion and consultation. The civil capacity rating scale for mentally disabled patients was established and the manual was created according to the logistic sequence of the assessment. The rating scale was used during the civil assessment in four institutes. RESULTS: There were 14 items in civil capacity rating scale for mentally disabled patients. Two hundred and two subjects were recruited and divided into three groups according to the experts' opinion on their civil capacities: full civil capacity, partial civil capacity and no civil capacity. The mean score of the three groups were 2.32 +/- 2.45, 11.62 +/- 4.01 and 25.02 +/- 3.90, respectively, and there was statistical differences among the groups. The Cronbach alpha of the rating scale was 0.9724, and during the split reliability test, the two-splited part of the rating scale were highly correlated (r = 0.9729, P = 0.000). The Spearman correlative coefficient between each item and the score of the rating scale was from 0.643 to 0.882 (P = 0.000). There was good correlation between the conclusion according to the rating scale and the experts' opinion (kappa = 0.841, P = 0.000). When the discriminate analysis was used, 7 items were included into the discrimination equation, and 92.6% subjects were identified as the correct groups using the equation. CONCLUSION: There is satisfied reliability and validity on civil capacity rating scale for mentally disabled patients. The rating scale can be used as effective tools to grade their civil capacity during the forensic expertise. PMID- 21287740 TI - [Toxicokinetics of ketamine in rabbits]. AB - OBJECTIVE: To investigate the toxicokinetics profiles of ketamine and its main metabolite norketamine in rabbits. METHODS: The rabbits were administered orally the hydrochloride of ketamine with a dose of 0.15 g/kg. The serum and urine samples were collected before administration and at different time points after drug administration. The concentrations of ketamine and norketamine were determined by GC-NPD and GC-MS. Compartment model and toxicokinetics parameters were simulated and calculated by WinNorLin program. Changes of important vital signs of rabbits were recorded during the experiment. RESULTS: The mean serum concentration-time profile of ketamine and norketamine were fitted to a two compartment open model with first order kinetics. The kinetic equation of ketamine and norketamine were p(t) = 121.760 e(-0.0025t) +0.980 e(-0.002t) +4.579 e(-0.021 t) and p(t) = 640.919 e(-0.03 t) +1.023 e(-0.001 t) +9.784 e (-0.031 t), respectively. The peak time and the peak concentration of ketamine in serum were (40.950 +/- 12.098) min and (9.015 +/- 1.344) microg/mL, respectively. The elimination half-time of ketamine in rabbits was (430.370 +/- 28.436) min. The serum and urine showed a middle relation in concentrations of ketamine during 30 240 min after drug administration. After oral administration ketamine to rabbits, the toxic symptom on the rabbits occurred at 30 min and disappeared after 120 min. CONCLUSION: The toxicokinetics parameters and kinetic equation of ketamine and norketamine in rabbits may provide the theoretical basis for forensic identification of reasonable specimen collection and inferring the time of oral administration ketamine from the ketamine concentration in serum. PMID- 21287741 TI - [Forensic analysis of LCN DNA using sample concentration methods followed by miniSTR genotyping]. AB - OBJECTIVE: To optimize low copy number (LCN) DNA analysis methods for forensic STR genotyping. METHODS: Two groups of DNA sample, extracted using either Magnetic bead method or Chelex-100 methods, were previously amplified with a Identifiler PCR Amplification kit, but no genotype was detected. The DNA samples were concentrated using either a drying method or the Microcon-100 method, then amplified using an miniFiler PCR Amplification kit and genotyped. RESULTS: Among the 127 DNA samples, 47 samples, previously extracted using the Magnetic bead method, were genotyped with 36% success rate. Eighty samples, previously extracted using the Chelex-100 method, were genotyped with 30% success rate. CONCLUSION: The application of sample concentration methods and miniFiler kit can improve the success rate of LCN STR analysis. PMID- 21287742 TI - [The investigation of event-related brain potentials in malingered neurocognitive deficit]. AB - In the fields of judicial psychiatric identification, about 40%-60% of the people maybe exaggerate their injury for personal profit. Though some psychological tests are effective in identification, they are limited in cunning liars. This article summarizes previous experimental mode, results and effects of event related potential (ERP) in detecting cognitive malingering. ERP technology can be highly sensitive and specific. It is a kind of objective physiological index and is a promising technology in detecting cognitive malingering. PMID- 21287743 TI - [The present study situation and application prospect of nail analysis for abused drugs]. AB - In forensic toxicology analysis, various types of biological samples have their own special characteristics and scope of applications. In this article, the physiological structure of nails, methods for collecting and pre-processing samples, and for analyzing some poisons and drugs in the nails are reviewed with details. This paper introduces the influence factors of drug abuse of the nails. The prospects of its further applications are concluded based on the research results. Nails, as an unconventional bio-sample without general application, show great potential and advantages in forensic toxicology. PMID- 21287744 TI - [Metabonomics and its perspective on forensic medicine]. AB - Metabolomics is a new study, which use chromatography, mass spectrometry, nuclear magnetic resonance (NMR), capillary electrophoresis (CE) techniques on the cells, organs and other body fluids and metabolites in samples were isolated, purified and testing, re-use bioinformatics tools on the obtained data are analyzed to obtain one or a set of biomarker information. Based on analysis of the literatures in recent years, metabolomics was summarized from history, concept, advantage, methods, application, difficulties and challenges, journals and books, websites, and its application in forensic medicine was forecasted. As a new branch of global system biology, metabonomics developed rapidly, and its perspective on forensic medicine was feasible and very optimistic. PMID- 21287745 TI - [Occupational environment in primary health care. Well filled days that are not long enough]. PMID- 21287746 TI - [Swedish aortic surgery is evidence-based. Both open and endovascular techniques defend their place]. PMID- 21287747 TI - [Weight reduction with non-alcohol regime in obese persons]. PMID- 21287748 TI - [More severe bacterial infections could be prevented with vaccine. Rotavirus, influenza and varicella cause thousands of hospital admissions]. PMID- 21287749 TI - [Aortic aneurysm routinely treated endovascularly in spite of deficient evidence. Weak basis that endovascular method is better than open surgery]. PMID- 21287750 TI - [The aging population. Continuing increase of average longevity is a controversial and exciting question]. PMID- 21287751 TI - [Telomeres, aging and life style--research with contradictory finding]. PMID- 21287752 TI - [Hand infections]. PMID- 21287753 TI - [Good effect of valproate against aggression in Huntington disease. Only two cases reported earlier]. PMID- 21287754 TI - [French medical licence]. PMID- 21287755 TI - [Yes, it's difficult to assess late problems after cervical distorsion! But...]. PMID- 21287756 TI - [Sure, Glenn Gould must have had an autism spectrum disorder]. PMID- 21287757 TI - [Ivar Lo-Johansson's freedom was constantly threatened by disease]. PMID- 21287758 TI - [Image of the month. Nevus lipomatosis cutaneous superficialis of Hoffmann Zurhelle]. PMID- 21287759 TI - [Clinical case of the month. An uncommon cause of sciatica: lumbar synovial cyst]. AB - We describe the case of a 46-year-old woman suffering from an hyperalgic sciatica caused by a lumbar synovial cyst. These are uncommon lesions associated with degenerative spine disease. They may be asymptomatic or may produce symptoms resulting from nervous structures compression. They are commonly found at the L4 L5 level, the site of maximum mobility. Their etiopathogeny is still unclear but degenerative spinal instability is the strongest factor for their growth. MRI is the most effective for the diagnosis. Conservative management is usually unsuccessful. Resection with or without fusion remains the more appropriate therapeutic option. PMID- 21287760 TI - [Primary and secondary prevention of skin cancers]. AB - The occurrence of the vast majority of skin cancers depends on the environment, in particular on exposure to ultraviolet light radiations. Several modalities of primary and secondary prevention are possible. The first modality relies on proper covering or remaining hidden under shadow. Textiles exhibit some photoprotective function the efficacy of which depends on their nature and diverse modulating factors. Sun protection cream, some food habits, the intake of non steroidal anti-inflammatory drugs, and that of specific food complements are supposed to be beneficial at various levels. PMID- 21287761 TI - [Tachycardia-related cardiomyopathy: a case report]. AB - Tachycardia-mediated cardiomyopathy is a form of dilated cardiomyopathy and heart failure induced by a persistent/chronic supraventricular or ventricular tachyarythmia. The incidence and the patho-physiology remain unspecified. Sometimes related to a previous cardiomyopathy, the diagnosis is always retrospective, but important because of the clinical and the significant haemodynamic improvement following the control of heart rate. PMID- 21287762 TI - [Hemolytic uremic syndrome with an atypical presentation]. AB - The hemolytic uremic syndrome (HUS) is rare and of guarded prognosis in adults. It expresses a renal thrombotic microangiopathy. We report the case of a young patient whose clinical presentation and exploration make a diagnosis of HUS likely. The atypical presentation provides an opportunity not only to discuss all diagnostic elements based on recent pathophysiological hypotheses, but also to highlight recommendations for the management of this severe disease. PMID- 21287763 TI - [Efficacy diacetylmorphine (pharmaceutical heroin) for heroin treatment ]. AB - Before implementing the TADAM project in Belgium (a heroin-assisted treatment trial), our research team studied the trials in other countries. Since 1994, six randomised controlled trials have been developed using the same treatment model of heroin-assisted treatment (HAT). Each trial concluded that HAT had more efficacy than methadone treatment. We analysed those trials in order to find on which levels patients in a HAT treatment are expected to improve. Improvements appeared after at least six months on the level of street heroin use, (physical and mental) health and criminal behaviour. In the longer term, the continuation of treatment had positive but limited effects on the social level. Due to his higher cost, this treatment should remain a second-line treatment for this special target group: severe heroin addicts, using continuously street heroin in spite of a methadone treatment. PMID- 21287764 TI - [Chilblains, differential diagnosis and risk factors]. AB - Chilblain results from environmental nonfreezing cold exposure. It is a localized inflammatory lesion most frequently localized on the toes and fingers. Chilblains are often idiopathic, but they may be part of lupus erythematosus. PMID- 21287765 TI - [The "Orf" virus: focus and review of the literature]. AB - Orf is an infection often unknown to practicians throughout the world. The first known cases were registered at the end of the 19th century. The virus affects ovines and caprins and is characterized by cutaneous and/or mucosae lesions. It is strongly resistant and the survival time is important in the outside environment. The morbidity of Orf is far higher than its mortality. The virus is transmitted by direct and indirect contact among humans, who became vectors themselves. Those subjects that are in contact with the animals in question due to professional reasons are at risk in particular. The same goes for attendants and participants of religious feasts. The preferred localization of lesions in humans is the hands. The diagnostic is easily set by the anamnesis and the clinical characteristics of the lesions except when it happens to be a particular form. The complications are nearly exclusively related to the unawareness of the virus in form of inappropriate medical acts. The evolution is spontaneous and the unique treatment is the prophylaxis of bacterial infection as well as a constant surveillance. PMID- 21287766 TI - [How I explore...a skin tumor in a transplant patient]. AB - Immunosuppressive therapy associated with organ transplant leads to an increased risk to develop skin cancers. In such circumstances, squamous cell carcinomas and basal cell carcinomas represent the most frequent tumors. Other neoplasms include malignant melanoma, Merkel cell carcinoma and Kaposi disease. Histopathology is primordial in the establishment of the diagnosis. In addition, bioengineering devices and skin imaging methods are useful in establishing the risk of cancers and for detecting incipient tumoral lesions. PMID- 21287767 TI - [Ulipristal acetate: an emergency contraception extended to 5 days using a progesterone receptor modulator (Ellaone)]. AB - Emergency contraception is a second chance for prevention of pregnancy after unprotected intercourse. Hormonal emergency contraception with levonorgestrel 1.5 mg, only provides an effective contraception from 0 to 72 hours after intercourse with decreasing effectiveness as time elapses. It was accordingly mandatory to develop an alternative approach with a stable contraceptive efficacy and good tolerance for 5 days, knowing additionally that the estimated lifespan of sperm in the female genital tract is about 5 days. In comparative studies bearing on more than 3000 young women, the progesterone receptor modulator (PRM) ulipristal acetate, a progesterone antagonist (taken in a single dose of 30 mg), or levonorgestrel (1.5 mg) were administered. Results indicated that the PRM was as effective as levonorgestrel, or even more, kept a stable efficacy for 120 hours after an unprotected intercourse, and was well tolerated. This establishes ulipristal acetate as the new standard for hormonal emergency contraception. PMID- 21287768 TI - [Medication of the month. A new combined oral contraceptive containing estradiol valerate and dienogest (Qlaira)]. AB - In combined oral contraception (OC), a drastic reduction of both ethinylestradiol and androgenic progestins mostly derived from 19 NOR testosterone, allowed to moderately reduce the adverse impact of classical combined pills on metabolism and circulation (both arterial and venous). However, the marked hepatic action of ethinylestradiol, even in small dosages, lessens the expected risk reduction. For the first time, an OC has been developed, which contains estradiol valerate (with reduced hepatic action because of lack of a 17alpha ethinyl group) with dienogest, a 19 NOR testosterone-derived nonandrogenic progestin, which powerfully inhibits endometrial proliferation. Thanks to a dynamic modulation of estrogen and progestin doses (26 active days + 2 placebo days), an adequate contraceptive effectiveness, a good cycle control and drug tolerance are achieved, similar to those obtained with a classical low-dose OC. Recent data indicate that this new combination reduces the usually observed metabolic impact. An adequate cycle control (with 20% amenorrhea) is achieved for the first time with estradiol valerate + progestin,, in opposition with prior catastrophic results with other formulations containing 17beta-estradiol. A second combination containing estradiol + nomegestrol acetate (monophasic, 24 active days + 4 placebo days) is under study and seems also to yield promising results. Of course, in-depth study of metabolic and vascular effects of these new combinations is mandatory - and ongoing. PMID- 21287769 TI - Reflections on 50+ years in practice. PMID- 21287770 TI - Assessment and management of fungating wounds. PMID- 21287771 TI - Itch: association with chronic venous disease, pain, and quality of life. AB - PURPOSE: The purpose of the study was to examine the symptom of itch and its relationship with chronic venous disease, pain, and quality of life. DESIGN: The study used an exploratory, cross-sectional design. METHODS: One hundred and sixty one participants completed demographic, health, substance abuse, itch, and pain questionnaires and the SF-12v2 Health Survey to measure health related quality of life. RESULTS: Participants were mostly men (n=95, 59%), African American (113, 70.2%), and had a mean age of 44.19 years. A history of injection drug use was reported by 91.4%. Using the clinical score of the Clinical-Etiology-Anatomy Pathophysiology (CEAP) Classification of the worst leg, the most common classification was Class 3, edema without skin changes (45.9%); 18.6% had severe venous disease (Classes 5 and 6). Eighty-eight participants (54.7%) reported itch somewhere on their body with 74 of them (45.9%) reporting itch on the legs or feet. Fourteen participants who reported itch of their legs or feet had wounds on the legs or feet. A positive correlation between magnitude of reported itch and CEAP clinical classification was noted (0.26, P =.025). This relationship was not strictly linear with itch increasing at a faster rate at higher levels of the CEAP classification. Persons with leg or feet itch had poorer health related quality of life, more comorbidities, and higher leg pain than those without itch. Because the SF-12v2 Health Survey is norm based, persons with itch were more than 1 standard deviation below the mean for the United States for their mental and physical health scores. CONCLUSIONS: Itch on the legs or feet is a clinically relevant problem that is related to the level of venous disease. Persons with lower extremity itch have higher pain ratings and lower quality of life. PMID- 21287772 TI - Social connectivity in those 24 months or less postsurgery. AB - PURPOSE: This purpose of this study is to characterize the prevalence of social isolation and determine the impact of influencing factors in a sample of adults with ostomies. SUBJECTS AND SETTINGS: Five hundred sixty adults with an ostomy, residing in North America and the United Kingdom, less than 24 months postsurgery, participated in the study. METHODS: Data were extracted from the Ostomy Comprehensive Health and Life Assessment (Hollister Incorporated, Libertyville, Illinois) electronic database. Data collection began in 2004; the database included approximately 3000 persons with an ostomy. This was a cross sectional survey and not a clinical investigation. All survey respondents were provided complete anonymity. No identifying data were incorporated into the database, or held as a matter of record. We defined 2 groups characterized as polar opposites. They are (1) adults whose responses indicate they are very socially isolated or experience low levels of social support and display dissatisfaction or low levels of life satisfaction; and (2) adults whose responses indicate they are socially connected and displaying moderate or high levels of life satisfaction. I hypothesized that life-influencing differences exist within the gradient from high satisfaction and social connectivity to dissatisfaction and social isolation, and that these differences would be most evident in these 2 groups. RESULTS: Study findings support the hypothesis that social isolation and social connectivity are associated with different levels of life satisfaction. Statistically significant correlations between social isolation, emotional support, and life satisfaction are demonstrated. Furthermore, assessment of body image perception between the groups indicates statistically significant differences in perception. In addition, analysis reveals that pre- and postoperative nursing intervention significantly influences these outcomes. CONCLUSION: The study provides evidence that social isolation exists in some adults with ostomies, which is associated with low levels of life satisfaction and emotional support. A lack of social connectivity is identifiable and WOC nurses and other clinicians may incorporate counseling into their treatment regimens to facilitate its negative impact on life satisfaction following ostomy surgery. PMID- 21287773 TI - Predicting improvement in urinary and bowel incontinence for home health patients using electronic health record data. AB - PURPOSE: The purpose of the study was to discover which patient and support system characteristics and interventions documented by home health clinicians were associated with improvement in urinary and bowel incontinence contrasting logistic regression and data mining approaches. SUBJECTS AND SETTING: Seventeen hundred ninety-three patients in this study experienced 2072 episodes of care. The study sample comprised all nonmaternity patients aged 18 years or older receiving skilled home health services in 2004. Subjects were drawn from a convenience sample of 15 home health agencies . DESIGN: We completed a secondary analysis of data from 15 home health agencies' electronic health records. Data for this study were documented by home care clinicians using the Outcome and Assessment Information Set (OASIS) structured assessment form and the Omaha System interventions, which is a standardized terminology. RESULTS: There were 684 patients with urinary incontinence and 187 with bowel incontinence. By discharge 38% improved in urinary incontinence and 45% improved their bowel incontinence. Using logistic regression, no patient or support system characteristics were identified that associated with improvement in either urinary or bowel incontinence, only a limited number of interventions were significant. A data mining decision tree was producible only for bowel incontinence, demonstrating a combination of patient and support system factors as well as selected interventions were important in determining whether patients would improve in bowel incontinence. CONCLUSIONS: Home health patients have complex comorbid conditions requiring home care nurses to have broad, generalized knowledge. Future research is needed to determine if the inclusion of a certified WOC nurse would improve outcomes. PMID- 21287774 TI - Medicare, Medicaid, and Children's Health Insurance Programs; additional screening requirements, application fees, temporary enrollment moratoria, payment suspensions and compliance plans for providers and suppliers. Final rule with comment period. AB - This final rule with comment period will implement provisions of the ACA that establish: Procedures under which screening is conducted for providers of medical or other services and suppliers in the Medicare program, providers in the Medicaid program, and providers in the Children's Health Insurance Program (CHIP); an application fee imposed on institutional providers and suppliers; temporary moratoria that may be imposed if necessary to prevent or combat fraud, waste, and abuse under the Medicare and Medicaid programs, and CHIP; guidance for States regarding termination of providers from Medicaid and CHIP if terminated by Medicare or another Medicaid State plan or CHIP; guidance regarding the termination of providers and suppliers from Medicare if terminated by a Medicaid State agency; and requirements for suspension of payments pending credible allegations of fraud in the Medicare and Medicaid programs. This final rule with comment period also discusses our earlier solicitation of comments regarding provisions of the ACA that require providers of medical or other items or services or suppliers within a particular industry sector or category to establish compliance programs. We have identified specific provisions surrounding our implementation of fingerprinting for certain providers and suppliers for which we may make changes if warranted by the public comments received. We expect to publish our response to those comments, including any possible changes to the rule made as a result of them, as soon as possible following the end of the comment period. Furthermore, we clarify that we are finalizing the adoption of fingerprinting pursuant to the terms and conditions set forth herein. PMID- 21287775 TI - Varenicline-induced grand mal seizure. PMID- 21287776 TI - ISHIB2010. Abstracts from the 25th Annual International Interdisciplinary Conference on Hypertension and Related Risk Factors in Ethnic Populations. Washington, DC, USA, July 9-11, 2010. PMID- 21287777 TI - [Abstracts of the 73rd National SIMLII Congress, 1-4 December 2010, Rome, Italy]. PMID- 21287778 TI - Retraction notice. PMID- 21287779 TI - Correlation of the cerebral microvascular blood flow with brain temperature and electro-acupuncture stimulation. AB - OBJECTIVE: To investigate the relationship between the temperature and the microvascular blood flow of the cerebral cortex, and the influence of electro acupuncture (EA) on the cortical microcirculation. METHODS: High temperature spots on the anterior ectosylvian and low temperature spots on the posterior suprasylvian on the cortical surface of 20 cats were identified using cortical infrared thermography (CIT); the blood flow in the microcirculation on these spots was measured with laser-Doppler flowmetry. EA was given at Zusanli (ST 36) and changes in the blood flow in the cerebral cortex microcirculation were detected. RESULTS: 1) The mean temperatures on the high (34.83 +/- 0.24 degrees C) and low (32.28 +/- 0.27 degrees C) temperature spots were significantly different (P < 0.001); this was indicative of a temperature difference on the cortical surface; 2) The average blood flow in the microcirculation of the high (266.8 +/-19.2 PU) and low (140.8 +/- 9.9 PU) temperature spots was significantly different (P < 0.001). 3) On the cortical high temperature spots, the mean blood flow in the microcirculation significantly increased from 266.8 +/- 86.8 PU before EA, to 422.5 +/- 47.4 PU following 5 minutes of EA (58.35%; P < 0.01), and 431.8 +/- 52.8 PU 5 minutes after ceasing EA (61.84%; P < 0.01). 4) On the low temperature spots, there were no significant differences in blood flow following 5 minutes of EA (146.3 +/- 11.5 PU), and 5 minutes after ceasing EA (140.5 +/- 11.6 PU), when compared with that before acupuncture (140.8 +/- 9.9 PU; P > 0.9). CONCLUSION: The high temperature spots of the cortex are active functional regions of neurons with higher blood flow and a stronger response to EA. EA induces a significant increase in blood flow in the high temperature spots of the cortex. PMID- 21287780 TI - Study on the mechanism of xiaotan sanjie recipe for inhibiting proliferation of gastric cancer cells. AB - OBJECTIVE: To explore the mechanism of Xiaotan Sanjie Recipe (XtSjR, Recipe for dissolving phlegm to eliminate stagnation) in inhibiting proliferation of gastric cancer cells. METHODS: The nude mouse human gastric cancer MKN-45 in situ transplantation tumor model was established by use of OB glue, and 40 model mice were randomized into 5 groups, model group, low-dose XtSjR group, middle-dose XtSjR group, high-dose XtSjR group, and 5-Fu group, 8 rats in each group. Human gastric cancer MKN-45 telomerase reverse transcriptase (hTERT) protein and mRNA expressions were assayed by immunohistochemical method and real-time fluorescence quantitative RT-PCR, and influences of XtSjR on the expressions of hTERT protein and mRNA were investigated in the nude mouse human gastric cancer MKN-45 in situ tumor transplantation model. RESULTS: 1) There were significant differences in the mean tumor weight between the low-, middle-, high-dose XtSjR groups and the model group (all P < 0.01); 2) There were significant differences in the hTERT positive expression rate between the middle- and high-dose XtSjR groups and the model group (P < 0.05 or P < 0.01); 3) There were significant differences in the hTERT mRNA content between the middle- and high-dose XtSjR groups and the model group (P < 0.05 or P < 0.01). CONCLUSION: 1) XtSjR has a marked inhibitory effect on the growth of gastric cancer cells; 2) XtSjR inhibits telomerase activity by down-regulating the expressions of hTERT protein and mRNA, shortening the length of cancer cell telomeres gradually, losing the ability to infinitely proliferate, and finally inhibiting the growth and proliferation of tumor cells. PMID- 21287781 TI - Effects of preventive administration of juanbi capsules on TNF-alpha, IL-1 and IL 6 contents of joint fluid in the rabbit with knee osteoarthritis. AB - OBJECTIVE: To probe into the mechanism of the Chinese herbs with functions of reinforcing kidney and supplementing qi for preventing knee osteoarthritis of the rabbit. METHODS: Totally 72 healthy Japan long-ear white rabbits, aged 4 months, were randomly divided into 6 groups, blank group (A), model group (B), high dose Chinese herb group (C), middle dose Chinese herb group (D), small dose Chinese herb group (E), aminoglucose hydrochloride capsule control group (F), 12 rabbits in each group. All the rabbits in the groups, except the group A, were fixed with plaster cast for six weeks to establish rabbit knee osteoarthritis. At the same time of modeling, the different doses of Juanbi Capsules and aminoglucose hydrochloride capsule were administrated intragastrically in the group C, D, E, F, respectively, for 4 weeks, for preventive treatment. In the group B, the rabbit was administrated intragastrically with equal volume of normal saline to the medication groups, twice each day, in the morning and the evening, and in the group A, nothing was administrated. After modeling for 6 weeks, the joint fluid was taken and TNF-alpha, IL-1 and IL-6 contents were detected with ELISA method, and the articular cartilage was taken for macroscopic and microscopic examinations. RESULTS: In all the preventive treatment groups, the articular cartilage color changed to varying degrees with formation of osteophyte and bone cyst, superficial erosion on the chondral articular surface, and the cartilage defect reached to the mid layer in a part of specimens with cartilage exfoliation, but which in the extent were significantly lower than those in the model group. There were significant differences between the group A and B in TNF alpha, IL-1 and IL-6 contents in the joint fluid (P < 0.05), indicating that the modeling is successful; and there were significant differences as group B compared with the group C,D, E, F, showing that TNF-alpha , IL-1 and IL-6 contents are decreased in all the medication groups; and significant differences between group C, D, E suggests that the increase of Chinese herb doses strengthened the effect of reducing TNF-alpha, IL-1 and IL-6 contents in joint fluid. CONCLUSION: The Juanbi Capsule prevents osteoarthritis possibly through decreasing serum TNF-alpha, IL-1 and IL-6 contents. PMID- 21287782 TI - Study of anti-myocardial cell oxidative stress action and effect of tanshinone IIA on prohibitin expression. AB - OBJECTIVE: To investigate the protective action of tanshinone IIA (TSN) on myocardial apoptosis induced by hydrogen peroxide (H2O2) and its effect on prohibitin (PHB) expression to probe the role of PHB in the oxidation stress of myocardial cells. METHODS: Primary cultured neonate rat myocardial cells were cultured with TSN (1 x 10(-4) mol/L) for 24 hours, and then the medium was supplemented with 200 micromol/L hydrogen peroxide for 2 h to initiate myocardial cell oxidative stress injury. PHB in myocardial cells was knocked down by small interfering RNA (siRNA), and the expression level of PHB was determined by western blot analysis. Flow cytometry was used to detect the apoptosis rate, intracellular calcium ion concentration ([Ca2+]i) and mitochondrial membrane potential (MMP). RESULTS: The PHB expression, [Ca2+]i and the apoptotic rate significantly increased, and the MMP significantly decreased in the oxidative stress group compared with the control. The PHB expression, apoptosis rate and [Ca2+]i decreased, and MMP increased significantly in the TSN group compared with the oxidative stress group. Compared with the siRNA negative control group, the PHB expression level in myocardial cells was down-regulated, and the apoptosis rate and [Ca2+]i increased, and MMP decreased significantly in the siRNA group. CONCLUSION: TSN can reduce PHB expression in oxidative stress-injured myocardial cells hence protecting the myocardial cells. PMID- 21287783 TI - Changes of color and blood flow of the tongue in the mini-swine of immune hepatic injury. AB - OBJECTIVE: To investigate color and microvascular blood flow of the tongue in the mini-swine with immune hepatic injury. METHODS: Six Chinese mini-swine for experimental use, 3 males and 3 females, were randomly divided into two groups, normal group and model group, 3 swine in each group. The swine in the model group was administrated by injection of 5 mg/kg ConA into the vein of auricular back, once every other day, 3 times each week, for 2 weeks in total. The animal in the control group was administrated with equal volume of saline. At 9 o'clock in the morning of the 15th day of the experiment, each swine was anesthetized with intramuscular injection of 9 ml 2.5% pentobarbital sodium and 3 ml Maleate, and then picture of the tongue was taken, microvascular blood flow on the tongue and the liver was detected with a laser Doppler blood flowmeter; Blood was taken from the precaval vein. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (Tbil) and total protein (TP) were determined; Pathological changes of the liver and tongue tissues were investigated by means of HE staining; Serum TNF-alpha content was detected with ELISA assay. RESULTS: In the mini-swine with immune hepatic injury induced by ConA, the tongue color showed cyanotic color, microvascular perfusion in the liver and the tongue, and partial pressure of oxygen in the tongue tissue significantly decreased; and the microcirculatory perfusion of the tongue was significantly correlated with that of the liver and the HIS color spatial value of the tongue; Serum TNF-alpha content significantly increased. CONCLUSION: The mini-swine with immune hepatic injury induced by ConA conforms to pathological characteristics of immune hepatic injury. Formation of the cyanotic tongue is related with microcirculatory disturbance of the tongue, which can indirectly reflect hepatic microcirculatory state in the immune hepatic injury. PMID- 21287784 TI - Study on modified shengmai yin injection for prevention and treatment of brain impairment in endotoxin shock rats. AB - OBJECTIVE: To examine the effects of modified Shenmai Yin on invigorating vital energy, promoting blood flow, and protection against neural impairment in an endotoxin-induced shock rat model. METHODS: Ninety-six SD rats were randomly divided into four groups: sham operation (saline 20 ml/kg), shock model (lipopolysaccharide, LPS, 8 mg/kg), Reformed Shengmai Yin (Pulse-activating Decoction) (LPS 8 mg/kg + reformed Shengmai Yin Injection 10 ml/kg), and dexamethasone (LPS 8 mg/kg + dexamethasone 5 mg/kg) groups. Each group was subdivided into 1 h, 2 h, 3 h, and 6 h time points for observation. The carotid artery was separated and connected with a biological functional system to monitor mean arterial pressure (MAP). Brain water levels, malonaldehyde (MDA) content, and superoxide dismutase (SOD) activity were also determined. RESULTS: In the shock model group, MAP was progressively decreased after injection of LPS, brain water and MDA contents were increased, brain SOD activity was decreased, and capillary vessel edema in brain tissue was also observed. All these parameters were improved significantly in both treatment groups, although the effects were more marked with Shengmai Yin than with dexamethasone. CONCLUSION: Modified Shengmai Yin exhibits strong anti-shock and neuroprotective effects against Endotoxin-induced shock. PMID- 21287785 TI - Effects of buyang huanwu tang combined with bone marrow mesenchymal stem cell transplantation on the expression of VEGF and Ki-67 in the brain tissue of the cerebral ischemia-reperfusion model rat. AB - OBJECTIVE: To explore the mechanism of Buyang Huanwu Tang (Decoction Invigorating Yang for Recuperation) combined with bone marrow mesenchymal stem cells (MSCs) transplantation in protecting nerves of cerebral ischemic injury. METHODS: Local cerebral ischemia-reperfusion rat model was established with modified Zea-Longa thread-occlusion method, and MSCs were injected into the caudal vein, and Buyang Huanwu Tang was administrated. Vascular endothelial growth factor (VEGF) and Ki 67 expression in the ischemic side of the brain in the cerebral ischemic reperfusion rat were detected with immuno-histochemical staining method. RESULTS: VEGF and Ki-67 expressions were significantly up-regulated in the MSCs group and the combination group, with significant differences as compared with the model group and the sham operation group (P < 0.05), and with the most strongest effect in the combination group. CONCLUSION: Buyang Huanwu Tang combined with MSCs transplantation repairs the injured blood vessels and lesion tissues possibly by up-regulation of VEGF and Ki-67 expression. PMID- 21287786 TI - Study on perfume stimulating olfaction with volatile oil of Acorus gramineus for treatment of the Alzheimer's disease rat. AB - OBJECTIVE: To probe into the therapeutic effect of perfume stimulating olfaction with volatile oil of Acorus Gramineus on the Alzheimer's disease (AD) rat. METHODS: Totally 50 adult SD rats, male,weighing 300 +/- 10 g, were randomly divided into 5 groups, normal group (group A), olfactory nerve severing model group (group B), AD model group (group C), AD model plus perfume stimulation group (group D), AD model olfactory nerve severing plus perfume stimulation group (group E), 10 rats in each group. After perfume stimulation, Morris maze test was conducted for valuating the learning and memory ability; Malondaldehyde (MDA) content, and superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in the brain, and the brain weight were detected. RESULTS: Compared with the AD model group, the average escape latency and swimming distance in 6 days were significantly shorter than those in the group A, B, D (P < 0.01), with no significant differences between the group C and the group E (P > 0.05); Compared with the group A, B and D, MDA content in the group C significantly increased (P < 0.01), and SOD and GSH-Px activities significantly decreased (P < 0.01), and brain weight/body weight decreased significantly in the group C (P < 0.01), with no significant differences between the group C and the group E (P > 0.05). CONCLUSION: Perfume stimultating olfaction with volatile oil of Acorus Gramineus can significantly increase the learning-memory ability, decrease MDA content and increase SOD and GSH-Px activities and weight of brain in AD rats. PMID- 21287787 TI - Research on component law of Chinese patent medicine for anti-influenza and development of new recipes for anti-influenza by unsupervised data mining methods. AB - OBJECTIVE: To analyze the component law of Chinese patent medicines for anti influenza and develop new prescriptions for anti-influenza by unsupervised data mining methods. METHODS: Chinese patent medicine recipes for anti-influenza were collected and recorded in the database, and then the correlation coefficient between herbs, core combinations of herbs and new prescriptions were analyzed by using modified mutual information, complex system entropy cluster and unsupervised hierarchical clustering, respectively. RESULTS: Based on analysis of 126 Chinese patent medicine recipes, the frequency of each herb occurrence in these recipes, 54 frequently-used herb pairs, 34 core combinations were determined, and 4 new recipes for influenza were developed. CONCLUSION: Unsupervised data mining methods are able to mine the component law quickly and develop new prescriptions. PMID- 21287788 TI - Study on the drug selection law for treatment of chronic gastritis with spleen deficiency and stomach dryness by complex system entropy cluster. AB - OBJECTIVE: To study on Prof. GAO Zhong-ying's drug selection law for treatment of chronic gastritis with data mining technique. METHODS: The 407 medical records of chronic gastritis treated by Prof. GAO Zhong-ying were collected and the study on these drugs in the recipes was carried out with data mining method. Among them, the recipe composed of one drug was studied with frequency statistical method, correlativity between drug pairs with improved mutual information, correlativity among multi-drugs with complex system entropy cluster technique. RESULTS: In treatment of chronic gastritis by Prof. GAO Zhong-ying there were 30 drugs with a higher use frequency of over 38 times, 94 commonly-used drug pairs with correlation coefficient of over 0.05, 11 commonly-used drug core combinations. CONCLUSION: The results attained with data mining technique for studying experience of famous and old TCM physicians conform to the clinical practice and the method is of an important significance for summarization of famous and old TCM physicians' experiences. PMID- 21287789 TI - Clinical observations on curative effect of TCM massage on dyssomnia of infants. AB - OBJECTIVE: To observe the curative effect of TCM massage on difficulty in falling asleep, waking during night and other sleep disorder of infants. METHODS: The 51 outpatients were treated by basic recipe for massage treatment and modified recipe according to syndromes. RESULTS: The total Athens Insomnia Scale (AIS) score 3.2800 +/- 1.5784 after treatment is lower than 9.2400 +/- 1.4286 before treatment (P < 0.01), there is statistical difference in AIS scores before and after treatment. CONCLUSION: TCM massage can remarkably improve sleep condition of infants with dyssomnia. PMID- 21287790 TI - Nineteen clinical features of fever in Chinese medicine. AB - Based on the 4,067 descriptions about fever in the medical records of the well known Chinese medicine physicians throughout the ages, 19 different clinical features of fever are summarized as follows: chilly fever, high fever, low fever, dull fever, bones fever, alternating chills and fever, tidal fever, head fever, face fever, chest fever, back fever, abdomen fever, waist fever, palms and soles fever, lower extremity fever, afternoon fever, evening fever, postpartum fever, and menstrual fever. Although, some of these fever features have not be paid close attention to in Western medicine, stage-division and classification about fever in Western medicine deserve to be used by Chinese medicine for reference. PMID- 21287791 TI - Recent advances of HIV/AIDS treatment with traditional Chinese medicine in China. PMID- 21287792 TI - Comments on selection of non-acupoints beyond meridians in studies of acupuncture and moxibustion. PMID- 21287793 TI - Effect of a tailor-made continuous medical education program for primary care physicians on self-perception of physicians' roles and quality of care. AB - BACKGROUND: A survey conducted among Israel Defense Force primary care physicians in 2001 revealed that they consider patients' needs more than they do organizational needs and that the education PCPs currently receive is inadequate. In 2003 the medical corps initiated a multi-format continuous medical education program aimed at improving skills in primary care medicine. OBJECTIVES: To measure and analyze the effect of the tailor-made CME program on PCPs' self perception 3 years after its implementation and correlate it to clinical performance. METHODS: In 2006 a questionnaire was delivered to a representative sample of PCPs in the IDF. The questionnaire included items on demographic and professional background, statements on self-perception issues, and ranking of roles. We compared the follow-up survey (2006) to the results of the original study (2001) and correlated the survey results with clinical performance as measured through objective indicators. RESULTS: In the 2006 follow-up survey PCPs scored higher on questions dealing with their perception of themselves as case managers (3.8 compared to 4.0 on the 2001 survey on a 5 point scale, P = 0.046), perceived quality of care and education (3.5 vs. 3.8, P = 0.06), and on questions dealing with organizational commitment (3.5 vs. 3.8, P = 0.01). PCPs received higher scores on clinical indicators in the later study (odds ratio 2.05, P < 0.001). CONCLUSIONS: PCPs in the IDF perceived themselves more as case managers as compared to the 2001 survey. A tailor-made CME program may have contributed to the improvement in skills and quality of care. PMID- 21287794 TI - Factors influencing the willingness of volunteer paramedics to re-volunteer in a time of war. AB - BACKGROUND: Professional volunteers play a crucial role in reinforcing emergency medical services in Israel. In order to encourage volunteers to return for additional shifts, the organization should provide conditions that will assure the return, particularly at a time of self-risk such as war. In 2009 Israeli emergency medical services (Magen David Adom) were required to increase preparedness in the southern part of the country due to missile attacks on civilian populations, while continuing their routine activities, i.e., responding promptly to emergency events. In order to perform these multiple functions, MDA stations in the towns under attack were strengthened with volunteers from other regions of the country. These volunteers, trained as paramedics, served in 24-48 hour shifts. OBJECTIVES: To identify the factors influencing the willingness of volunteers to return. METHODS: A questionnaire was used to assess the satisfaction of volunteers participating in the reinforcement with regard to their physical environment, job assignment and the actual activity they were involved in. Data were analyzed using SPSS statistical software. RESULTS: During the 10 days of the study, 121 volunteers reinforced southern MDA stations and 99 (81%) of them responded to the questionnaire. We found that volunteers' willingness to return to do more shifts was affected by their welcome and reception at the station, their job assignment, and their training and preparation for performing the necessary tasks. The sleeping conditions and the number of events they participated in were also contributing factors. CONCLUSIONS: Factors that contribute to the willingness of volunteers to re volunteer should be taken into account by organizations that rely on them. PMID- 21287795 TI - Objective measures of attention-deficit/hyperactivity disorder: a pilot study. AB - BACKGROUND: Most aspects of attention-deficit/hyperactivity disorder diagnosis rely on subjective judgment. Computerized continuous performance tests are designed to improve the validity of the process but are controversial due to low odds ratios. There is a need to find more definitive measures of assessment. OBJECTIVES: To test the validity and reliability of a new tool, a computerized continuous performance functions test, which includes a multi-task approach designed to achieve a higher odds ratio of assessment. METHODS: We applied this test to 58 children aged 6-12 years: 45 were diagnosed as ADHD and 13 non-ADHD children served as a control group. RESULTS: The CPF test was able to differentiate between non-ADHD and ADHD children. CPF test results were more accurate than other continuous performance tests. The results were statistically significant in all test parameters, confirming the test's validity and reliability. CONCLUSIONS: The CPF test includes a combination of tasks based on an algorithm designed to test several domains of attention. In this pilot study the CPF test was found to be a valid and reliable tool for the diagnosis of ADHD in children. This test might increase the diagnostic utility of computerized tests. The research points to the need for developing a more definitive process for ADHD diagnosis. PMID- 21287796 TI - Effect of antiviral amantadine treatment on elderly chronic schizophrenia patients. AB - BACKGROUND: In compliance with public health measures initiated by the Israel Ministry of Health following an outbreak of influenza, amantadine was administered to all patients in the psychogeriatric department of Lev Hasharon Mental Health Center to reduce transmission and illness severity in this susceptible population. OBJECTIVES: To evaluate the potential beneficial effects of amantadine on elderly hospitalized patients with persistent schizophrenia. METHODS: We conducted a retrospective case review of the treatment effects of amantadine on the mental, cognitive and clinical states of elderly chronic schizophrenic patients who received concomitant amantadine treatment and were routinely evaluated with the Positive and Negative Syndrome Scale, the Mini Mental State Examination, and Sandoz Clinical Assessment Geriatric Scale. RESULTS: No significant differences before and after amantadine treatment were noted. CONCLUSION: Amantadine did not influence the mental, cognitive and clinical states of elderly schizophrenia patients and thus can be considered as an anti-influenza preventive measure for this population, when indicated. PMID- 21287797 TI - The impact of prenatal diagnosis and termination of pregnancy on the relative incidence of malformations at birth among Jews and Muslim Arabs in Israel. AB - BACKGROUND: Ultrasound examination of the fetus enables diagnosis of many major malformations during pregnancy, providing the possibility to consider termination of the pregnancy. As a result, in many cases the incidence of malformations at birth does not represent their true incidence. OBJECTIVES: To determine the impact of prenatal diagnosis and pregnancy termination on the relative incidence of malformations at birth among Jews and Muslim Arabs in Israel. METHODS: Data on selected major malformations in 2000-2003 were collected from the two large central databases of the Ministry of Health and the Central Bureau of Statistics which contain information regarding births, stillbirths and terminations of pregnancies. RESULTS: For many malformations the total incidence was much higher than the incidence at birth. For almost all of the malformations studied, the total incidence was higher in Muslims than in Jews and the differences were further accentuated among the liveborn because of the differences in the rate of pregnancy terminations. CONCLUSIONS: In order to detect possible influences of environmental or genetic factors on major malformations in Israel, it is critical to look at data including pregnancy terminations, stillbirths and live births. PMID- 21287798 TI - A simplified approach to the management of gastric residual volumes in critically ill mechanically ventilated patients: a pilot prospective cohort study. AB - BACKGROUND: Enteral nutrition in the critically ill patient is often complicated by gastrointestinal intolerance, manifested by a large gastric residual volume. The frequency of GRV assessment and the intolerant level above which feeding is stopped is controversial. OBJECTIVES: To evaluate a novel approach to EN by allowing high GRV and once-daily assessment that was correlated with the paracetamol absorption test. METHODS: We conducted a pilot prospective study in an 18 bed general intensive care unit. The study group comprised 52 consecutive critically ill mechanically ventilated patients. Enteral nutrition was started at full delivery rate. Once-daily assessment of GRV with three consecutively repeated threshold volumes of 500 ml was performed before stopping EN. The paracetamol absorption test was performed and correlated to GRV. Patients were divided into two groups: low GRV (< 500 ml) and high GRV (at least one measurement of GRV > 500 ml). Clinical outcome included maximal calories delivered, incidence of pneumonia, ICU length of stay, and ICU and hospital mortality. RESULTS: There were 4 patients (9.5%) with ventilator-associated pneumonia in the low GRV group and 3 (30%) in the high GRV group (P = 0.12). GRV was inversely correlated to paracetamol absorption; however, neither GRV nor paracetamol absorption was associated with the development of pneumonia. Both groups had similar ICU length of stay (11.0 +/- 8.2 vs. 13.8 +/- 14.4 days, P = 0.41), and similar ICU (21% vs. 40%, P = 0.24) and hospital mortality (35% vs. 40%, P = 1.0). CONCLUSIONS: In critically ill mechanically ventilated patients, allowing larger gastric residual volumes, measured once daily, enables enteral feeding with fewer interruptions which results in high calorie intake without significant complications or side effects. PMID- 21287799 TI - A protocol for genetic evaluation of patients with multiple colorectal adenomas and without evidence of APC gene mutation. AB - BACKGROUND: Patients with multiple (< 100) colorectal adenomatous polyps are at increased risk for colorectal cancer. Genetic evaluation of those patients who test negative forAPCgene mutation is both a clinical and economic burden but is critical for counseling and surveillance. In Israel, this is confounded by the fact that national health insurance does not fully cover genetic evaluation of APC gene exon 16. OBJECTIVES: To perform a comprehensive genetic evaluation of APC gene mutation-negative polyposis patients with the aim of developing a future evaluation protocol. METHODS: Genetic analyses were performed in 29 APC gene mutation-negative Jewish individuals with 5 to > or = 40 colonic adenomas who did not fulfill Amsterdam (clinical) criteria for Lynch syndrome. Analyses included completion of APC gene exon 16 sequencing, analysis for APC gene copy number variations (deletions or duplications), MUTYH gene sequencing, and microsatellite instability in CRC patients fulfilling "Bethesda" (laboratory investigation) criteria for Lynch syndrome. RESULTS: Completion of APC gene exon 16 sequencing revealed one patient with the E1317Q polymorphism. All were normal by APC multiplex ligation-dependent probe amplification analysis. Pathogenic MUTYH mutations were found in three patients, all of North African origin; two additional patients had variants of unknown significance. One of six patients with Bethesda-positive criteria was MSI-High with immunohistology consistent with MLH1 mutation. CONCLUSIONS: Based on this small but well-characterized cohort with multiple colorectal adenomas, Lynch syndrome needs to be excluded if there are compatible criteria; otherwise MUTYH sequencing is probably the first step in evaluating APC-negative patients, especially for Jews of North African descent. Completing APC exon 16 sequencing and copy number variations analysis should probably be the last evaluations. PMID- 21287800 TI - Pediatric poisonings in Israel: National Poison Center data. AB - BACKGROUND: Poisonings are a significant cause of pediatric morbidity and mortality. The Israel Poison Information Center provides clinical consultations on poisonings and drug information 24 hours a day. OBJECTIVE: To evaluate the epidemiologic characteristics of pediatric poison exposures in Israel. METHODS: We reviewed computerized queries and performed a descriptive analysis of the Poison Center database pertaining to patients under 18 years old during 2007. RESULTS: A total of 15,005 pediatric poison exposures were recorded, 80.3% of them occurring in children under 6 years old. Of the calls to the Poison Center, 78.6% were made by the public, 20.7% by physicians, and in 74.4% the call was within 2 hours of exposure. Most exposures occurred at home (89.3%) and were unintentional (89.5%). Among adolescents, most exposures were intentional (49.3%, 38.2% suicides), the time lapse until consultation was longer (37% > 2 hours), and more physicians (54.8%) consulted the Poison Center. Most cases were asymptomatic or mildly affected (92.3%), 54.4% in adolescents. The commonest substances involved in single poison exposure were detergents, antimicrobials, topical preparations, acetaminophen and scale removers; in adolescents the most common substances were acetaminophen, methylphenidate, non-steroidal anti inflammatory drugs, atropine and ethanol. Moderate to severe toxicity was commonly associated with organophosphates, alkali, ethanol, Vipera palaestinae and neuroleptics. Most patients could be observed at home (66.6%), while more adolescents were referred to emergency departments (42.2% vs. 9.9%) or hospitalized (14.5% vs. 1.9%). CONCLUSIONS: Pediatric poisonings are a significant health problem. The magnitude of the problem is greater in the young age group but more severe in adolescence, probably due to deliberate self poisoning. Greater national efforts should be directed towards improved poison prevention, rational management of pediatric poisoning, and creating a national poisoning registry. PMID- 21287801 TI - The role of upper gastrointestinal swallow study in patients undergoing proximal or total gastrectomy. AB - BACKGROUND: One of the ominous complications following proximal gastrectomy or total gastrectomy is a leak from the esophagogastric or esophagojejunal anastomosis. An upper gastrointestinal swallow study is traditionally performed to confirm the anastomotic patency and lack of any leak before oral feeding can be initiated. OBJECTIVES: To challenge the routine use of UGISs following proximal or total gastrectomy in order to check the integrity of the gastroesophageal or jejunoesophageal anastomosis. METHODS: The charts of 99 patients who underwent PG or TG for malignant pathology were retrospectively reviewed. UGISs were performed on day 6 following surgery using a water-soluble material. RESULTS: The UGISs were normal in 95 patients, with none displaying any complication related to the gastroesophageal or jejunoesophageal anastomosis. All four patients who experienced a leak from the anastomosis had an early stormy postoperative course. CONCLUSIONS: Routine use of an UGIS to detect a leak following PG orTG is not justified. UGIS should be performed whenever signs of abdominal sepsis develop following this type or surgery. PMID- 21287802 TI - Frequency, characteristics, and outcome of patients with aortic stenosis, left ventricular dysfunction, and high (versus low) trans-aortic pressure gradient. AB - BACKGROUND: Trans-aortic pressure gradient in patients with aortic stenosis and left ventricular systolic dysfunction is typically low but occasionally high. OBJECTIVES: To examine the distribution of trans-aortic PG in patients with severe AS and severe LV dysfunction and compare the clinical and echocardiographic characteristics and outcome of patients with high versus low PG. METHODS: Using the echocardiographic laboratory database at our institution, 72 patients with severe AS (aortic valve area < or = 1.0 cm2) and severe LV dysfunction (LV ejection fraction < or = 30%) were identified. The characteristics and outcome of these patients were compared. RESULTS: PG was high (mean PG > or = 35 mmHg) in 32 patients (44.4%) and low (< 35 mmHg) in 40 (55.6%). Aortic valve area was slightly smaller in patients with high PG (0.63 + 0.15 vs. 0.75 +/- 0.16 cm2 in patients with low PG, P = 0.003), and LV ejection fraction was slightly higher in patients with high PG (26 +/- 5 vs. 22 +/- 5% in patients with low PG, P = 0.005). During a median follow-up period of 9 months 14 patients (19%) underwent aortic valve replacement and 46 patients (64%) died. Aortic valve replacement was associated with lower mortality (age and gender adjusted hazard ratio 0.19, 95% confidence interval 0.05-0.82), whereas trans aortic PG was not (P = 0.41). CONCLUSIONS: A large proportion of patients with severe AS have relatively high trans-aortic PG despite severe LV dysfunction, a finding partially related to more severe AS and better LV function. Trans-aortic PG is not related to outcome in these patients. PMID- 21287803 TI - Intraocular pressure changes in the contralateral eye after topical treatment: does an "ophthalmotonic consensual reaction" exist? AB - BACKGROUND: The existence of "ophthalmotonic consensual reaction," a contralateral change in intraocular pressure in the fellow eye induced by treatment of the first eye only, was suggested in 1924. Since then, the validity of this mechanism has been controversial. OBJECTIVES: To assess intraocular pressure changes in the contralateral fellow eyes of patients treated with IOP lowering medication in one eye, and investigate the existence of an ophthalmotonic consensual reaction. METHODS: The study population included 38 patients with newly diagnosed bilateral ocular hypertension or early open angle glaucoma. One eye of each patient was randomly treated with one of five compounds: prostaglandin analogues, beta-blockers, alpha-2 agonists, carbonic anhidrase inhibitors and a combination therapy: dorzolamide hydrochloride-timolol maleate (Cosopt, Merck Sharpe & Dohme). The eye with the higher baseline IOP was selected to be the treated eye. After 3 weeks a masked examiner measured the IOP in both the treated and untreated eye. RESULTS: Mean IOP of the treated eyes at baseline was 26.1 +/- 4.2 mmHg and at follow-up 20.2 +/-2.9 mmHg, a reduction of IOP from baseline of -6 +/- 3.8 mmHg, a mean percent reduction of -22 +/- 10.1%. In the contralateral eyes, the mean IOP at baseline was 24.2 +/- 3 mmHg and 23.1 +/- 3.1 mmHg at follow-up; IOP reduction from baseline was -1.2 +/- 1.8 mmHg, or mean percent reduction -4.7 +/- 7.1%. A major contralateral IOP decrease was seen only in the beta-blockers and the combination (Cosopt) treatment groups (-6.1 +/- 8.3% and -12.3 +/- 8.3% mean percent reduction, respectively, P < 0.05). The contralateral eyes in the prostaglandin analogues, CAI or alpha2-agonist groups showed only a small change in IOP (-2.6 +/- 4.6%, -3.2 +/- 2.6%, +0.7 +/- 3.3%, mean percent reduction, respectively, P < 0.05). CONCLUSIONS: The existence of an ophthalmotonic consensual reaction was not supported. PMID- 21287804 TI - Laparoscopic colectomy for colorectal cancer. AB - The laparoscopic approach to the treatment of colon and rectal cancer remains controversial long after it was accepted for benign conditions. Laparoscopic cancer resection should meet appropriate oncologic standards and achieve a long term oncologic outcome at least equivalent to that of open resection. Several international randomized controlled trials have provided adequate data to ascertain the oncologic quality of laparoscopic colon resection, showing a benefit in short-term outcome over open resection. The use of laparoscopic resection for rectal cancer is awaiting further investigation. PMID- 21287805 TI - Attention to testing and testing of attention. PMID- 21287807 TI - Out of Africa: ascariasis initially diagnosed by computed tomography. PMID- 21287806 TI - Active tuberculosis in a patient with rheumatoid arthritis treated with tumor necrosis factor-alpha inhibitor. PMID- 21287808 TI - [Haplotypes of mtDNA-HV1/HV2 in non-related individuals of Caucasian population living in the Slovak Republic]. AB - Evaluation of the frequency index for mtDNA particular sequences in the Caucasian population is crucial for forensic practice. There are two hypervariable regions in the mtDNA D-loop, HV1 and HV2. Both of them, 610 bp altogether, were sequenced, 342 bp from the hypervariable region HV1 (16024-16365) and 268 bp from the hypervariable region HV2 (73-340). We have analyzed 374 randomly selected non related individuals of th e Caucasian population and 192 individuals of the Roma subpopulation living in Slovakia. The main goals of the work were to introduce and standardize methods of analysis of variability of the HV1 and HV2 regions of mtDNA for forensic use; to characterize the variability of mtDNA in the Slovakian population taking into account the subpopulations; classification of mtDNA profiles into haplotype groups, and comparison with other haplotype groups in Europe in the frame of phylogenetic studies. PMID- 21287809 TI - Novel gene P28GANK confers multidrug resistance by modulating the expression of MDR-1, Bcl-2 and Bax in osteosarcoma cells. AB - As previously reported, a novel gene P28GANK conferred a multidrug resistant phenotype in gastric cancer cells. The aim of this study was to explore the role of P28GANK in the development of multidrug resistance (MDR) in osteosarcoma cells. P28GANK gene was found to be overexpressed at the mRNA level and the protein level in a cisplatin induced MDR osteosarcoma cell line Saos-2/CDDP compared to its parent cell line Saos-2. Here, we transfected the osteosarcoma cell line Saos-2 with eukaryotic expression vector of P28GANK. In vitro drug sensitivity assay suggested that Saos-2-P28GANK cells conferred resistance to both P-glycoprotein (P-gp)-related and P-gp-nonrelated drugs. Blocking P28GANK expression in MDR osteosarcoma cells Saos-2/CDDP by P28GANK-specific small interfering RNA (siRNA) increased the cell sensitivity to various chemotherapeutic drugs. Flow cytometry examination suggested that P28GANK gene expression could suppress Adriamycin-induced apoptosis accompanied by decreased accumulation and increased release of Adriamycin. Semiquantitative RT-PCR, Western blot and Luciferase reporter assay suggested that P28GANK gene could significantly up-regulate the expression of MDR-1 and Bcl-2, transcription of the MDR-1 gene and down-regulate the expression of Bax. In addition, inhibition of P28GANK expression by RNA interference or P-gp inhibition could partially reverse P28GANK-mediated MDR. Taken together, our findings suggest that down-regulation of P28GANK gene expression could sensitize osteosarcoma cells to chemotherapeutic drugs by down-regulation of the MDR-1 and Bcl-2 and up-regulation of Bax gene expression, without altering the glutathione S-transferase activity, or intracellular glutathione content in osteosarcoma cells. Further study on biological function of P28GANK may be helpful for understanding MDR mechanism of osteosarcoma and developing a strategy for osteosarcoma treatment. PMID- 21287810 TI - History belongs to those who show up. PMID- 21287811 TI - We are done with "Access to care". PMID- 21287812 TI - Planning with purpose: strengthening the Star of the North meeting. PMID- 21287813 TI - Dental whitening--revisiting the myths. AB - The popularity of dental bleaching has increased with the introduction of at-home whitening. Currently available whitening methods include those prescribed by a dental professional for use at home, those applied by the professional in the dental office, a combination of the two, or systems available over the counter. This article reviews the effect, efficacy, and safety of bleaching techniques and materials. Most whitening techniques are considered effective and safe when carried out under the supervision of a dental professional. This article also compares the efficacy and safety of some of the most popular bleaching techniques, including at-home whitening with carbamide peroxide, over-the-counter (OTC) systems, and in-office whitening. Some of these whitening techniques are illustrated in this article. PMID- 21287814 TI - Wake up call from the Northeastern District Dental Society: initiative concerning drug-seeking activity. PMID- 21287815 TI - Social media: the word of mouth revolution. AB - Many dental practices today find themselves uncertain about the new social media universe, and in particular with how to relate to younger patients. The power of social networking is its immediate access to the word of mouth exchange of information, and the word of mouth avenue itself is recognized as the single most effective form of advertising. To tap into that phenomenon, begin by investing a small amount of time and effort to understand the basics of social networking. Sign up for Facebook and Twitter. First-hand experience interacting in a social network is the vital first step. The bottom line is simply this: To begin to understand this new arena of communication, you first have to join the conversation. PMID- 21287816 TI - Happy hours open. PMID- 21287817 TI - Devolution. Border patrol. PMID- 21287818 TI - Public engagement. Power to the people. PMID- 21287819 TI - GP commissioning. GPs get a check-up of their own as a new era dawns. PMID- 21287821 TI - Technology. Working smart on workforce. PMID- 21287820 TI - Productivity. Part two of three. The big four enablers that bring about big change. PMID- 21287822 TI - Special issue on bone tissue engineering. PMID- 21287823 TI - Bone grafting, orthopaedic biomaterials, and the clinical need for bone engineering. AB - As the population ages, the number of operations performed on bone is expected to increase. Diseases such as arthritis, tumours, and trauma can lead to defects in the skeleton requiring an operation to replace or restore the lost bone. Surgeons can use autografts, allografts, and/or bone graft substitutes to restore areas of bone loss. Surgical implants are also used in addition or in isolation to replace the diseased bone. This review considers the application of available bone grafts in different clinical settings. It also discusses recently introduced bioactive biomaterials and highlights the clinical difficulties and technological deficiencies that exist in our current surgical practice. PMID- 21287824 TI - Periodontal regeneration: a challenge for the tissue engineer? AB - Periodontitis affects around 15 per cent of human adult populations. While periodontal treatment aimed at removing the bacterial cause of the disease is generally very successful, the ability predictably to regenerate the damaged tissues remains a major unmet objective for new treatment strategies. Existing treatments include the use of space-maintaining barrier membranes (guided tissue regeneration), use of graft materials, and application of bioactive molecules to induce regeneration, but their overall effects are relatively modest and restricted in application. The periodontal ligament is rich in mesenchymal stem cells, and the understanding of the signalling molecules that may regulate their differentation has increased enormously in recent years. Applying these principles for the development of new tissue engineering strategies for periodontal regeneration will require further work to determine the efficacy of current experimental preclinical treatments, including pharmacological application of growth factors such as bone morphogenetic proteins (BMPs) or Wnts, use of autologous stem cell reimplantation strategies, and development of improved biomaterial scaffolds. This article describes the background to this problem, addresses the current status of periodontal regeneration, including the background biology, and discusses the potential for some of these experimental therapies to achieve the goal of clinically predictable periodontal regeneration. PMID- 21287825 TI - Bioactive composites for bone tissue engineering. AB - One of the major challenges for bone tissue engineering is the production of a suitable scaffold material. In this review the currently available composite material options are considered and the methods of production and assessing the scaffolds are also discussed. The production routes range from the use of porogens to produce the porosity through to controlled deposition methods. The testing regimes include mechanical testing of the produced materials through to in vivo testing of the scaffolds. While the ideal scaffold material has not yet been produced, progress is being made. PMID- 21287826 TI - Bioactive glass scaffolds for bone regeneration and their hierarchical characterisation. AB - Scaffolds are needed that can act as temporary templates for bone regeneration and actively stimulate vascularized bone growth so that bone grafting is no longer necessary. To achieve this, the scaffold must have a suitable interconnected pore network and be made of an osteogenic material. Bioactive glass is an ideal material because it rapidly bonds to bone and degrades over time, releasing soluble silica and calcium ions that are thought to stimulate osteoprogenitor cells. Melt-derived bioactive glasses, such as the original Bioglass composition, are available commercially, but porous scaffolds have been difficult to produce because Bioglass and similar compositions crystallize on sintering. Sol-gel foam scaffolds have been developed that avoid this problem. They have a hierarchical pore structure comprising interconnected macropores, with interconnect diameters in excess of the 100 microm that is thought to be needed for vascularized bone ingrowth, and an inherent nanoporosity of interconnected mesopores (2-50 nm) which is beneficial for the attachment of osteoprogenitor cells. They also have a compressive strength in the range of cancellous bone. This paper describes the optimized sol-gel foaming process and illustrates the importance of optimizing the hierarchical structure from the atomic through nano, to the macro scale with respect to biological response. PMID- 21287827 TI - Temperature-driven processing techniques for manufacturing fully interconnected porous scaffolds in bone tissue engineering. AB - The development of structures with a predefined multiscale pore network is a major challenge in designing tissue engineering (TE) scaffolds. To address this, several strategies have been investigated to provide biocompatible, biodegradable porous materials that would be suitable for use as scaffolds, and able to guide and facilitate the cell activity involved in the generation of new tissue regeneration. This study seeks to provide an overview of different temperature driven process technologies for developing scaffolds with tailored porosity, in which pore size distribution is strictly defined and pores are fully interconnected. Here, three-dimensional (3D) porous composite scaffolds based on poly(epsilon-caprolactone) (PCL) were fabricated by thermally induced phase separation (TIPS) and by melt co-continuous polymer blending (MCPB). The combination of these processes with a salt leaching technique enables the establishment of bimodal porosity within the polymer network. This feature may be exploited in the development of substrates with fully interconnected pores, which can be used effectively for tissue regeneration. Various combinations of the proposed techniques provide a range of procedures for the preparation of porous scaffolds with an appropriate combination of morphological and mechanical properties to reproduce the requisite features of the extracellular matrix (ECM) of hard tissues such as bone. PMID- 21287828 TI - Physico-chemical characterization of functional electrospun scaffolds for bone and cartilage tissue engineering. AB - Mimicking the zonal organization of the bone-cartilage interface will aid the production of functional osteochondral grafts for regeneration of skeletal joint defects. This study investigates the potential of the electrospinning technique to build a three-dimensional construct recapitulating the zonal matrix of this interface. Poly(lactic-co-glycolic acid) (PLGA) and PLGA-collagen solutions containing different concentrations of hydroxyapatite nanoparticles (nHAp) were electrospun on a thin layer of phosphate buffer saline solution spread on the collector in order to facilitate membrane detachment and recovery. Incorporation of increasing amounts of nHAp in PLGA solutions did not affect significantly the average diameter of the fibres, which was about 700 nm. However, in the presence of collagen, fibres with diameters below 100 nm were generally observed and the number of these fibres was inversely proportional to the ratio PLGA:collagen and proportional to the content of nHAp. PLGA membranes were rather hydrophobic, although the aqueous drop contact angles progressively fell from 125 degrees to 110 degrees when the content of nHAp was increased from 0 per cent to 50 per cent (w/v). PLGA-collagen membranes were more hydrophilic with contact angles between 60 degrees and 110 degrees; the values being proportional to the ratio PLGA:collagen and the content of nHAp. Also, the addition of nHAp from 0 per cent to 50 per cent (w/v) in the absence of collagen resulted in decreasing dramatically both the Young's modulus (Ym), from 34.3 +/- 1.8 MPa to 0.10 +/- 0.06 MPa, and the ultimate tensile strain (epsilon max), from a value higher than 40 per cent to 5 per cent. However, the presence of collagen together with nHAp allowed the creation of membranes much stiffer, although more brittle, as shown for membranes made with a ratio 8:2 and 10 per cent of nHAp, for which Ym = 70.0 +/- 6.6 MPa and epsilon max = 7 per cent. PMID- 21287829 TI - Osteoblasts in bone tissue engineering. AB - Osteoblasts are integral to the development, growth, function, repair and maintenance of bone. The osteoblast forms organic, non-mineralized bone matrix and is involved in complex interactions with a variety of factors, mediators and cell types. Degeneration, pathology, and trauma cause disruption and destruction of the normal skeletal environment and may lead to bone loss. There is a rise in active populations involved in trauma, elderly patients with fragility fractures and an overall increase in primary, revision and reconstructive bone and joint surgery. Despite the rapid evolution of implant technologies and bone grafting techniques, there is still a great demand for novel bone replacement strategies. Bone tissue engineering is the state of the art science with the potential to regenerate bone with natural form and function. This review presents the biology of osteoblasts and their current applications in bone tissue engineering biotechnologies and role in stem cell, bioactive factor, recombinant signalling molecule and gene therapy research. PMID- 21287830 TI - Focal adhesions in osteoneogenesis. AB - As materials technology and the field of tissue engineering advance, the role of cellular adhesive mechanisms, in particular, interactions with implantable devices, becomes more relevant in both research and clinical practice. A key tenet of medical device technology is to use the exquisite ability of biological systems to respond to the material surface or chemical stimuli in order to help to develop next-generation biomaterials. The focus of this review is on recent studies and developments concerning focal adhesion formation in osteoneogenesis, with an emphasis on the influence of synthetic constructs on integrin-mediated cellular adhesion and function. PMID- 21287831 TI - Skeletal stem cells and bone regeneration: translational strategies from bench to clinic. AB - Clinical imperatives for new bone to replace or restore the function of traumatized or bone lost as a consequence of age or disease has led to the need for therapies or procedures to generate bone for skeletal applications. Tissue regeneration promises to deliver specifiable replacement tissues and the prospect of efficacious alternative therapies for orthopaedic applications such as non union fractures, healing of critical sized segmental defects and regeneration of articular cartilage in degenerative joint diseases. In this paper we review the current understanding of the continuum of cell development from skeletal stem cells, osteoprogenitors through to mature osteoblasts and the role of the matrix microenvironment, vasculature and factors that control their fate and plasticity in skeletal regeneration. Critically, this review addresses in vitro and in vivo models to investigate laboratory and clinical based strategies for the development of new technologies for skeletal repair and the key translational points to clinical success. The application of developmental paradigms of musculoskeletal tissue formation specifically, understanding developmental biology of bone formation particularly in the adult context of injury and disease will, we propose, offer new insights into skeletal cell biology and tissue regeneration allowing for the critical integration of stem cell science, tissue engineering and clinical applications. Such interdisciplinary, iterative approaches will be critical in taking patient aspirations to clinical reality. PMID- 21287832 TI - Relative influence of surface topography and surface chemistry on cell response to bone implant materials. Part 1: physico-chemical effects. AB - Knowledge of the complexity of cell-material interactions is essential for the future of biomaterials and tissue engineering, but we are still far from achieving a clear understanding, as illustrated in this review. Many factors of the cellular or the material aspect influence these interactions and must be controlled systematically during experiments. On the material side, it is essential to illustrate surface topography by parameters describing the roughness amplitude as well as the roughness organization, and at the scales pertinent for the cell response, i.e., from the nano-scale to the micro-scale. Authors interested in this field must be careful to develop surfaces or methods systematically, allowing perfect control of the relative influences of surface topography and surface chemistry. PMID- 21287833 TI - Relative influence of surface topography and surface chemistry on cell response to bone implant materials. Part 2: biological aspects. AB - A current medical challenge is the replacement of tissue which can be thought of in terms of bone tissue engineering approaches. The key problem in bone tissue engineering lies in associating bone stem cells with material supports or scaffolds that can be implanted in a patient. Beside bone tissue engineering approaches, these types of materials are used daily in orthopaedics and dental practice as permanent or transitory implants such as ceramic bone filling materials or metallic prostheses. Consequently, it is essential to better understand how bone cells interact with materials. For several years, the current authors and others have developed in vitro studies in order to elucidate the mechanisms underlying the response of human bone cells to implant surfaces. This paper reviews the current state of knowledge and proposes future directions for research in this domain. PMID- 21287834 TI - Mechanisms of fluid-flow-induced matrix production in bone tissue engineering. AB - Matrix production by tissue-engineered bone is enhanced when the growing tissue is subjected to mechanical forces and/or fluid flow in bioreactor culture. Cells deposit collagen and mineral, depending upon the mechanical loading that they receive. However, the molecular mechanisms of flow-induced signal transduction in bone are poorly understood. The hyaluronan (HA) glycocalyx has been proposed as a potential mediator of mechanical forces in bone. Using a parallel-plate flow chamber the effects of removal of HA on flow-induced collagen production and NF kappaB activation in MLO-A5 osteoid osteocytes were investigated. Short periods of fluid flow significantly increased collagen production and induced translocation of the NF-kappaB subunit p65 to the cell's nuclei in 65 per cent of the cell population. Enzymatic removal of the HA coat and antibody blocking of CD44 (a transmembrane protein that binds to HA) eliminated the fluid-flow-induced increase in collagen production but had no effect on the translocation of p65. HA and CD44 appear to play roles in transducing the flow signals that modulate collagen production over long-term culture but not in the short-term flow-induced activation of NF-kappaB, implying that multiple signalling events are initiated from the commencement of flow. Understanding the mechanotransduction events that enable fluid flow to stimulate bone matrix production will allow the optimization of bioreactor design and flow profiles for bone tissue engineering. PMID- 21287835 TI - Bioreactors for bone tissue engineering. AB - Engineering bone tissue for use in orthopaedics poses multiple challenges. Providing the appropriate growth environment that will allow complex tissues such as bone to grow is one of these challenges. There are multiple design factors that must be considered in order to generate a functional tissue in vitro for replacement surgery in the clinic. Complex bioreactors have been designed that allow different stress regimes such as compressive, shear, and rotational forces to be applied to three-dimensional (3D) engineered constructs. This review addresses these considerations and outlines the types of bioreactor that have been developed and are currently in use. PMID- 21287836 TI - In vitro models for bone mechanobiology: applications in bone regeneration and tissue engineering. AB - Healthy bone healing is a remarkable, mechanically sensitive, scar-free process that leads rapidly to repair tissue of high mechanical quality and functionality, and knowledge of this process is essential for driving advances in bone tissue engineering and regeneration. Gaining this knowledge requires the use of models to probe and understand the detailed mechanisms of healing, and the tight coupling of biology and mechanics make it essential that both of these aspects are controlled and analysed together, using a mechanobiological approach. This article reviews the literature on in vitro models used for this purpose, beginning with two-dimensional (2D) cell culture models used for applying controlled mechanical stimuli to relevant cells, and detailing the analysis techniques required for understanding both substrate strain and fluid flow stimuli in sufficient detail to relate them to biological response. The additional complexity of three-dimensional (3D) models, enabling more faithful representation of the healing situation, can require correspondingly more sophisticated tools for mechanical and biological analysis, but has recently uncovered exciting evidence for the mechanical sensitivity of angiogenesis, essential for successful healing. Studies using explanted tissue continue to be vital in informing these approaches, providing additional evidence for the relevance of effects in biological and mechanical environments close to those in the living organism. Mechanobiology is essential for the proper analysis of models for bone regeneration, and has an exciting integrative role to play not only in advancing knowledge in this area, but also in ensuring successful translation of new tissue engineering and regenerative therapies to the clinic. PMID- 21287837 TI - Mechanobiology of bone healing and regeneration: in vivo models. AB - Mechanical boundary conditions are well known to influence the regeneration of bone and mechanobiology is the study of how mechanical or physical stimuli regulate biological processes. In vivo models have been applied over many years to investigate the effects of mechanics on bone healing. Early models have focused on the influence of mechanical stability on healing outcome, with an interest in parameters such as the magnitude of interfragmentary movement, the rate and timing of application of micromotion and the number of loading cycles. As measurement techniques have been refined, there has been a shift in orders of magnitude from investigations targeted at the organ level to those targeted at the tissue level and beyond. An understanding of how mechanics influences tissue differentiation during repair and regeneration crucially requires spatial and temporal knowledge of both the local mechanical environment in the healing tissue and a characterization of the tissues formed over the course of regeneration. Owing to limitations in the techniques available to measure the local mechanical conditions during repair directly, simulation approaches, such as the finite element method, are an integral part of the mechanobiologist's toolkit, while histology remains the gold standard in the characterization of the tissue formed. However, with rapid advances occurring in imaging modalities and methods to characterize tissue properties, new opportunities exist to better understand the role of mechanics in the biology of bone regeneration. Combined with developments in molecular biology, mechanobiology has the potential to offer exciting, new regenerative treatments for bone healing. PMID- 21287838 TI - Telestroke. When location, location, location doesn't matter. PMID- 21287839 TI - Human resources. The art of persuasion. PMID- 21287840 TI - Legal. Sometimes less really is more. PMID- 21287842 TI - Teach students compassion by being an excellent role model. PMID- 21287843 TI - Safety when giving insulin in hospital. PMID- 21287844 TI - Designing a training programme to improve staff attitudes towards people with dementia. AB - Nurses in acute settings often lack the knowledge and experience to provide appropriate care for patients with dementia. Two specialist nurses at the Biggart Hospital in South Ayrshire, Scotland, used a questionnaire to determine staff attitudes to patients with dementia and designed a multidisciplinary training programme to improve practice in dementia care. This article describes the development, implementation and evaluation of the first stage of the programme. PMID- 21287845 TI - Using dolls to enhance the wellbeing of people with dementia in residential care. AB - An increasing body ofevidence suggeststhe use of dolls can have a positive impact on people with dementia in residential care. This literature review explores the benefits and potential problems of using dolls as a therapeutic intervention in dementia. PMID- 21287846 TI - Does protein and energy supplementation benefit older people at risk of malnutrition? PMID- 21287847 TI - Fitness to practise for student nurses: principles, standards and procedures. AB - Since 2009, all schools of nursing have been required to establish a fitness to practise committee to consider any pre-registration student health or character issues (Nursing and Midwifery Council, 2008). In 2009, fitness to practice standards were published (NMC, 2009a). This article outlines how fitness to practise procedures apply to nursing and midwifery students in the U.K. and explains the key differences between how they are applied to trainees and to registered nurses. PMID- 21287848 TI - Are you--and your trust--ready for older patients? PMID- 21287849 TI - You may be born to nurse or take the scenic route. PMID- 21287850 TI - Tension expected as merger plans set out. PMID- 21287851 TI - Advance care planning ensures patient choice on place of death. PMID- 21287852 TI - Evaluating the strengths and weaknesses of NHS workforce planning methods. AB - This article examines the different methods used in NHS workforce planning and development and their strengths and weaknesses. It is a summary and update of the nurse staffing study commissioned by the Department of Health (Hurst, 2003). The article is designed to help nurse managers select and apply methods for reviewing or estimating their staffing needs, and looks at the future for workforce planning and development. PMID- 21287853 TI - Delivering a support group for siblings of children with learning disabilities. AB - This article describes the development of a group for siblings of children with learning disabilities. It looks at issues relating to setting up and running the group and gives examples of the problems that maybe encountered by the children. PMID- 21287854 TI - Medical management in the community as an option for first trimester miscarriage. AB - Outpatient medical management of first trimester miscarriage was introduced at the Royal Infirmary of Edinburgh in 2009 after a number of trials found it to be a safe and effective approach. An audit showed positive results, in terms of both treatment success and patient satisfaction. This approach appears to be more successful than inpatient management. PMID- 21287855 TI - Dignity in care: meanings, myths and the reality of making it work in practice. AB - In recent years, dignity in care has become a catch all phrase in nursing and healthcare. This article looks at different definitions of the concept and at the origins of dignity in care campaigns and champions. It questions whether dignity in care campaigns are a genuine attempt to improve the patient experience or a political and professional ploy to delude the public that something is being done, which detracts from serious debate about the nature and structure of nursing and healthcare. PMID- 21287856 TI - Reasons for intermittent catheterisation. PMID- 21287857 TI - Comparing indwelling and intermittent catheterisation. PMID- 21287858 TI - Female intermittent self catheterisation. PMID- 21287859 TI - Patient information and education. PMID- 21287860 TI - Cuts must not threaten time for dignified care. PMID- 21287862 TI - Leadership changes and budget woes set the stage for the 2011 legislative session. PMID- 21287861 TI - What saving is next? Papier mache hats for the police? PMID- 21287863 TI - Safe medication administration in the operating room. AB - In perioperative settings, medications are removed from their original identifying containers; therefore, scrub personnel (RN's and OR Technicians) need to label all medications placed on the sterile field. In this study, medication labeling practices will be evaluated in the operating room of a 187-bed, Charlotte, North Carolina hospital. Subsequently, blank and preprinted labels will be used to test compliance of safe medication practices. The results of the Performance Improvement study indicate that scrub persons are likely to label medications and syringes more often and more accurately when preprinted labels are provided. The data obtained from this project led to supplying preprinted labels for all procedures in order to improve patient safety in the operating room. PMID- 21287864 TI - Record slowdown, bigger share. While 2009 saw a historic slowing of growth in healthcare spending, its share of GDP saw an unprecedented increase. AB - The Great Recession brought a historic slowdown in healthcare spending, but hospitals adjusted to keep their books in order. ThedaCare curbed its spending through efficiency efforts under way since 2003 and concerted efforts to limit hiring during 2009 to essential positions, says John Ross, left, vice president of finance at the Wisconsin system. PMID- 21287865 TI - On the up and up. Construction spending down, but still high. PMID- 21287866 TI - GOP brings repeal fever. Republicans take over the House, but chances of overturning ACA small. PMID- 21287867 TI - Settlement necessity. Questions over kyphoplasty narrow legal options. PMID- 21287868 TI - Changes for NCHL. Organization's new identity in transition. PMID- 21287869 TI - Acquisition hindsight. FTC: sale gives ProMedica too much clout. PMID- 21287871 TI - Playing the repeal game. When focus should be on economy, maneuvering seems counterproductive. PMID- 21287870 TI - Clinic tackles tax challenge. Supreme Court to rule on exemption eligibility. PMID- 21287872 TI - Nurses take the lead. RNs share techniques on quality improvement, staff involvement. PMID- 21287873 TI - No mere dispenser. Community pharmacists offer low-cost, quality care for chronic illnesses. PMID- 21287874 TI - Change is in the air for reform in 2011. Priorities shift to revising parts of Affordable Care Act, implementation. PMID- 21287876 TI - Largest professional liability carriers. Ranked by direct premiums written for medical professional liability in the U.S. in 2009. PMID- 21287875 TI - Time to modernize. CMS plans IT upgrade to handle growing demands. PMID- 21287877 TI - Hospital CMO pay up. But their peers didn't fare as well. PMID- 21287878 TI - Obamacare goes under the knife. PMID- 21287879 TI - Long-range survey of BCG vaccine administered to medical students. PMID- 21287880 TI - How the humanities inform medicine. PMID- 21287881 TI - The Memory Art Project: medical students and older adults. AB - BACKGROUND: The humanities are increasingly recognized as an important component of medical student education. This study addresses whether early exposure to healthy older adults through the humanities may prepare medical students for positive relationships with aging patients. Few studies have presented a detailed example of a humanistic endeavor organized by medical students to facilitate student interactions with healthy older adults. OBJECTIVE: To report the results of a unique art project organized to promote rapport between medical students and healthy older adults. METHODS: Twelve first- and second-year students at the Medical College of Wisconsin were paired with 12 older adult residents at a local independent living facility. Participation was voluntary, and all participants were asked to complete 3 sessions over the course of 2 months. During the first session, partners met each other and formed a relationship. A professional art instructor provided a lesson and supervised practice in acrylic painting. In the second session, all student and older adult participants created a painting to represent their partner. The third session featured a reception to celebrate the artwork and new friendships. RESULTS: Ten medical student/older adult pairs completed the project. Reactions were positive, and the project was perceived as beneficial to both students and older adults. CONCLUSION: The Memory Art Project effectively promoted positive communication between medical students and an aging population that will need to interact meaningfully with medical professionals in the future. PMID- 21287882 TI - A description of 200 consecutive admissions to an adolescent male treatment unit. AB - OBJECTIVES: The objective of this study is to characterize patients admitted to a mental health Adolescent Male Treatment Unit (AMTU) over an 18-month interval. METHODS: The study is a cross-sectional retrospective chart review. Data concerning medication management was abstracted along with age, psychiatric diagnoses, degree of impairment, length-of-stay (LOS), and episodes of locked seclusion/restraint. RESULTS: Two hundred consecutive admissions were analyzed. It was common for a patient to be receiving multiple psychiatric medications. Multiple psychiatric diagnoses were the rule, and externalizing disorders were very frequent. Based on LOS, 4 distinct categories emerged. Patients in Categories I and II accounted for two-thirds of admissions to AMTU and had an LOS of 2 weeks or less. Patients in Category III and IV were one-third of admissions, were more ill, needed locked seclusion/restraint, and required a longer LOS to stabilize and treat them. Treatment tended to include a reduction in the number of psychiatric medications previously prescribed. CONCLUSIONS: The majority of patients could be stabilized and discharged in 2 weeks or less. A minority required more intensive intervention including a long LOS. Receiving multiple psychiatric medications may not be of benefit for some patients. Psychiatric medications may induce behavioral adverse effects in at least a subset of patients. PMID- 21287883 TI - Perceptions of underage drinkers by bartenders in a midwestern university town. AB - BACKGROUND: Alcohol consumption by Wisconsin college students is associated with both morbidity and mortality; underage bar access is a significant contributor to this problem. This two-part study will review strategies used by the city of Madison to reduce underage drinking in bars and will introduce pilot data exploring bartenders as potential partners in prevention. METHODS: First, data and strategies from the City of Madison Office of the Mayor regarding underage drinking were reviewed. Second, a convenience sample of 15 employed bartenders completed a one-on-one interview. Questions explored bartenders' views regarding identifying and serving underage patrons. Data were collected via written notes and analyzed by all authors to obtain thematic consensus. RESULTS: Current Madison underage drinking prevention efforts focus on enforcement, alcohol establishment licensing and bartender training. Citation data suggests prevention efforts have decreased individual and increased bar citations. Bartender interview data revealed 3 major themes: (1) Bartenders felt they could identify underage patrons; (2) Bartenders were not concerned with legal or employment ramifications regarding serving an underage patron; (3) Bartenders described barriers to participation in prevention. CONCLUSION: Additional opportunities for prevention efforts exist. Further research should consider strategies to change local policies, modify bartenders' work environments, and establish motivators for bartender prevention participation. PMID- 21287884 TI - Contraception in Wisconsin: a review. AB - The Contraceptive Equality Mandate took effect in Wisconsin on January 1, 2010. This mandate from the Wisconsin Office of the Commissioner of Insurance requires all insurance companies in the state of Wisconsin to cover all types of contraception, making Wisconsin the 28th state to do so. This article reviews the literature related to several types of contraception including Implanon (a newly available implantable contraception), drospirenone-containing oral contraceptive pills, and intrauterine devices. We also review evidence regarding depot medroxyprogesterone acetate and bone mineral density, and new cycling regimens for oral contraceptive pills. PMID- 21287885 TI - Gallstone ileus 30 years status postcholecystectomy. AB - Gallstone ileus is an uncommon cause of small bowel obstruction which occurs in patients with chronic cholecystitis and gallstones who develop a cholecystoenteric fistula. Although gallstone ileus is relatively rare, it has a substantial mortality rate due in part to patient comorbidities and delays in treatment. We describe the case of a 94-year-old woman who presented with nausea, vomiting, mild abdominal tenderness, leukocytosis, and a 2.5-cm obstruction in her small bowel. Even though this patient underwent a total cholecystectomy 30 years prior, a 2.5-cm gallstone was surgically removed from her ileum. This case illustrates the importance of including gallstone ileus in the differential diagnosis for patients who present with small bowel obstruction even decades postcholecystectomy. PMID- 21287886 TI - A demonstration project for using the electronic health record to identify and treat tobacco users. AB - BACKGROUND: While the majority of smokers visit a primary care physician each year, only a small proportion of them receive evidence-based tobacco dependence treatment. The electronic health record (EHR) provides an opportunity to prompt clinicians to deliver tobacco dependence treatment in primary care. METHODS: Over 1 year, Dean Health Systems worked with the University of Wisconsin School of Medicine and Public Health to modify the existing Dean EHR system (Epic Systems Corp, Verona, Wisconsin) to improve identification and treatment of adult smokers visiting primary care clinics. Modifications included evidence-based prompts that helped guide medical assistants to identify smokers and clinicians to deliver a brief tobacco cessation intervention (medication and Wisconsin Tobacco Quit Line referral). Eighteen primary care clinics provided data 1 year before and 1 year after implementing the EHR modifications. RESULTS: A higher percentage of adult patients had their tobacco use status identified after EHR modification compared to pre-implementation (71.6% versus 78.4%, P < .001). During the post implementation year, 6.3% of adult smokers were prescribed tobacco cessation medication, 2.5% of adult smokers had documentation of counseling, and 1.5% of adult smokers had counseling billed (pre-implementation data not available). CONCLUSIONS: This demonstration project showed that a large health care system can increase the delivery of tobacco dependence treatment interventions (increased identification of smokers and relatively high rates of delivering specific tobacco dependence clinical interventions) building on an existing EHR platform. The project demonstrated that brief, evidence-based tobacco dependence interventions can be incorporated into primary care, especially when the EHR is used to improve clinic workflow. PMID- 21287887 TI - Improving the quality of care for patients with HIV through information sharing. PMID- 21287888 TI - The haircut. PMID- 21287889 TI - In support of embryonic stem cell research. PMID- 21287890 TI - An overview of MetaStar's activities. PMID- 21287891 TI - The use of emerging informatics techniques to evaluate the delivery of NMAETC programs to address HIV and AIDS disparities. AB - BACKGROUND: Information technologies are employed to evaluate health program and better target recruitment of health care workforce for underserved communities, where needs for providers are greatest. With increased resources in reducing human immunodeficiency virus (HIV)/AIDS disparities and provider training, it may be important to know whether training is delivered in geographic areas where HIV/AIDS demonstrates high prevalence. The present study employs an informatics approach to identifying effectiveness of AIDS educational intervention in minority populations adversely affected by the disease. We seek to assess the National Minority AIDS Education and Training Center (NMAETC) on whether training activities are delivered appropriately in areas with high AIDS prevalence. METHODS: A geographic information systems application was developed to relate NMAETC provider training activities to its spatial relationship of AIDS prevalence of 4 major US racial/ethnic groups (fiscal years 2005-2006). Trainees' locations were geocoded by zip code. We overlaid AIDS prevalence of major demographic communities by state with the US Census region and division boundaries to visually inspect the patterns of distribution and potential spatial association. RESULTS: NMAETC training better targeted providers in 3 US Census regions and census divisions. The regions with higher provider training level generally corresponded to geographic areas with high AIDS prevalence for some minority populations. Additional efforts could be extended to recruit providers in the areas where the incidences were high for some communities. CONCLUSIONS: Most NMAETC provider training activities occurred in the states with a high AIDS prevalence. Additional efforts could be extended to recruit the providers in those regions where HIV/AIDS are more prevalent for some minority populations. PMID- 21287892 TI - Pilot assessment of HIV gene therapy-hematopoietic stem cell clinical trial acceptability among minority patients and their advisors. AB - Clinical trials involving technologically involved novel treatments such as gene therapy delivered through hematopoietic stem cells as human immunodeficiency virus (HIV) treatment will need to recruit ethnically diverse patients to ensure the acceptance among broad groups of individuals and generalizability of research findings. Five focus groups of 47 HIV-positive men and women, religious and community leaders and health providers, mostly from African American and low income communities, were conducted to examine knowledge about gene therapy and stem cell research and to assess the moral and ethical beliefs that might influence participation in clinical trials. Three themes emerged from these groups: (1) the need for clarification of terminology and the ethics of understanding gene therapy-stem cell research, (2) strategies to avoid mistrust of medical procedures and provider mistrust, and (3) the conflict between science and religious beliefs as it pertains to gene therapy-stem cell research. PMID- 21287893 TI - Recent trends in hospital utilization and mortality for HIV infection: 2000-2005. AB - OBJECTIVE: Ethnic minority populations have been disproportionately affected by the HIV disease. The objective of this report was to assess the prevalence and trend of HIV-related hospitalization and mortality in Florida in 2000 through 2005 by 6 sex- race/ethnic groups. METHODS: Using data from the Florida Agency for Health Care Administration from 2000 through 2005, discharge records with primary or secondary diagnosis of HIV infection were included, and chi2 and Cochran-Armitage tests and multiple regression models were used in analyses. RESULTS: Of all HIV-related hospitalizations (N = 159695), about 56%, 28%, and 12% of records belonged to blacks, whites, and Hispanics, respectively. The average proportions of HIV hospitalization during the period of 2000-2005 were approximately 29% (black male), 27% (black female), 22% (white male), 9% (Hispanic male), 6% (white female), and 3% (Hispanic female) (all p < .01). The frequencies of death were the highest among black males followed by black females, white males, Hispanic males, white females, and Hispanic females. CONCLUSION: Sex-racial/ethnic disparities are evident in the HIV-related hospital utilizations and deaths. Further research is needed to understand the reasons for the disparities among hospitalized patients to reduce both health and economic consequences associated with HIV disease in Florida. PMID- 21287894 TI - HIV/AIDS and African American men: urban-rural differentials in sexual behavior, HIV knowledge, and attitude towards condoms use. AB - OBJECTIVES: We assessed the differences and similarities in knowledge, attitude, beliefs, myths, and misconceptions; and the various high-risk behavioral factors that influence the rate of infectivity of human immunodeficiency virus (HIV)/AIDS among African American men in urban and rural communities of Mississippi. METHODS: A cross-sectional sample survey was conducted on 466 African American men in 2 sites between 2005 and 2007. With the main outcome variables of knowledge, attitude/feelings, behavior/practices, and potentials for behavior change, we administered a 64-item, ethnically sensitive, gender-specific instrument to the subjects via a person-to-person interview. RESULTS: Of the 466 respondents (urban, 33%; rural, 67%), 70%, 14.4%, and 16.6%, respectively, were heterosexual, bisexual, and men who have sex with men (MSM). The number of the respondents' sexual partners in the previous 12 months were: 1 to 2 (54%), 3 to 4 (25.7%), and 5 or more (20.2%). Statistically significant differences were observed between the 2 populations on HIV knowledge (p < .001), HIV/sexually transmitted infection testing history (p < .001), sexual partners (p = .038), unprotected sexual intercourse with drug users (p < .001), unprotected casual sex (p < .001), intercourse in an open relationship or marriage (p < .001), and communication with potential sex partners regarding sexual limits prior to intercourse (p = .027). CONCLUSIONS: Although the level of HIV/AIDS knowledge and education were lower among urban than rural respondents, subjects' negative overall beliefs, attitude/feelings, behavior and potentials for behavioral change did not differ significantly among the African American men in the 2 communities. PMID- 21287895 TI - HIV testing among Deep South residents 50 to 64 years old with cardiovascular disease and/or diabetes. AB - PURPOSE: To describe HIV testing among Deep South residents aged 50 to 64 years old with cardiovascular disease (CVD) and/or diabetes. METHODS: Deep South residents from Alabama, Georgia, Louisiana, Mississippi, North Carolina, and South Carolina who completed the 2008 Behavioral Risk Factor Surveillance System (BRFSS) survey were sampled. Associations between chronic health conditions (CVD, diabetes) and human immunodeficiency virus (HIV) testing were examined. RESULTS: Fewer than one-third (30.8%) of the sample (n = 1017) reported that they had been tested for HIV. Of the weighted sample of adults tested for HIV, the mean age- 56.63 +/- 0.20 SE (95% confidence interval [CI], 56.24-57.03)--was significantly lower than that of those who had never been tested for HIV--57.60 +/- 0.12 SE (95% CI, 57.37-57.84; p < .0001). Although not statistically significant, HIV testing was slightly higher among men (53.3%) (p = .9432). Persons with CVD or diabetes were 22% less likely to report that they had been tested for HIV, compared to those with both CVD and diabetes (adjusted odds ratio [AOR], 0.776; 95% CI, 0.611-0.985). CONCLUSIONS: Chronic conditions (CVD, diabetes) among HIV infected persons can be adversely affected by antiretroviral regimens. All adults 50 to 64 years old should be routinely offered an HIV test if their HIV serostatus is unknown, regardless of perceived risk for HIV/AIDS. Our findings suggest that linking HIV testing with routine checkups for persons with CVD and/or diabetes is a potentially missed opportunity for earlier diagnosis of HIV infection, especially among older adults who are at a greater risk of being diagnosed with AIDS within 1 year of an initial HIV-positive diagnosis. PMID- 21287896 TI - Rapid HIV testing and obstetrical characteristics of women with unknown HIV serostatus at time of labor and delivery. AB - OBJECTIVE: To describe the obstetrical characteristics of women without prenatal care and/or undocumented human immunodeficiency virus (HIV) serostatus who presented for delivery and to assess the usefulness of rapid HIV screening in these women. MATERIALS AND METHODS: The study design was a retrospective analysis. Demographics, labor, delivery characteristics, and pregnancy outcomes of women without prenatal care and/or unknown HIV serostatus were reviewed. RESULTS: Three hundred fifty parturients met the inclusion criteria: 15.2% presented at complete cervical dilation, 48.6% with cervical dilation of at least 5 cm, and 43.1% with ruptured membranes. Twenty-two percent of parturients delivered within 1 hour of admission, 47.6% delivered within 4 hours of admission, and 5.5% delivered prior to arrival to the hospital. With the lengthy admission process and procurement of zidovudine from the pharmacy requiring at least 1 hour at best, 27.5% would not have the benefit of intrapartum zidovudine treatment. Single Use Diagnostic System HIV-1 rapid test was reactive and confirmed in 7 women (2.5%). CONCLUSION: Rapid HIV screening is a useful tool for guiding immediate obstetrical management and coordinated care for the neonate. In some circumstances, the full benefit of rapid HIV detection will not be realized due to advanced labor, ruptured members, or delivery prior to arrival. PMID- 21287897 TI - A model for routine hospital-wide HIV screening: lessons learned and public health implications. AB - BACKGROUND: Approximately 232700 (21%) of Americans are unaware of their HIV seropositive status; this represents a potential for virus transmission. Revised recommendations from the Centers for Disease Control for HIV screening promote routine screening in the health care setting. We describe the implementation of a hospital-wide routine HIV screening program in the District of Columbia. METHODS: Rapid HIV testing was conducted at Howard University Hospital on consenting patients at least 18 years of age using the OraSure OraQuick Advance Rapid HIV 1/2 Antibody Test. The study population includes Howard University Hospital patients who were offered HIV screening over a 12-month period at no cost. Screened patients received immediate test results and, for those patients found to be preliminarily reactive, confirmatory testing and linkage to care were offered. RESULTS: Of the 12836 patients who were offered testing, 7528 (58.6%) consented. Preliminary reactive test results were identified in 176 patients (2.3%). Overall, 45.5% were confirmed, of which 82.5% were confirmed positive. Screening protocol changes have led to 100% confirmation since implementation. CONCLUSIONS: Hospital-wide routine HIV screening is feasible and can be implemented effectively and efficiently. The HIV screening campaign instituted at Howard University Hospital identified a substantial number of HIV-positive individuals and provided critical connection to follow-up testing, counseling, and disease management services. PMID- 21287898 TI - HIV knowledge and its contribution to sexual health behaviors of low-income African American adolescents. AB - OBJECTIVES: Although many factors contribute to racial disparities in human immunodeficiency virus (HIV)/AIDS among young African Americans, knowledge is a particularly modifiable factor. However, little information has been published about the current HIV knowledge of African American teens or to what extent knowledge independently contributes to their sexual behavior and health. This study aimed to describe the level of knowledge among this at-risk population and determine whether knowledge contributes to variance in sexual behavior and health beyond that of sociodemographic and psychological factors. METHODS: African American adolescents (n = 1658) were recruited in 2 northeastern and 2 southeastern US cities (74% eligible for free or reduced-price school lunch). Analyses utilized data gathered from adolescents using an audio computer-assisted self-interview program. RESULTS: On average, participants answered only 50% of HIV knowledge items correctly and were least accurate concerning effective condom use and HIV testing. Controlling tor associated sociodemographic and psychological factors, greater knowledge was associated with sexual experience and, among experienced adolescents, with sexually transmitted infection/HIV testing and--unexpectedly--less condom use. CONCLUSIONS: HIV knowledge, which is modifiable, is limited among at-risk African American adolescents and is an important contributor to sexual behavior and health. Findings indicate a need for more comprehensive HIV/AIDS education, particularly with regard to condom use and the benefits of routine sexually transmitted infection/HIV testing. Although knowledge might not be sufficiently protective in and of itself, having accurate information about HIV may benefit sexual health by impacting health-promoting attitudes necessary for successful engagement in health care-seeking behavior. PMID- 21287899 TI - Substance abuse treatment as HIV prevention: more questions than answers. AB - This report examines associations between the availability of human immunodeficiency virus (HIV)-related health services in substance abuse treatment programs and characteristics of the programs and the patients they serve. In a cross-sectional, descriptive design and via a validated survey, program administrators within the National Drug Abuse Treatment Clinical Trials Network provided information on program characteristics, patient characteristics (rates of risky sexual and drug behaviors and HIV infection), and the availability of 31 different HIV-related health services. Of 319 programs, 84% submitted surveys. Service availability rates ranged from: 10% (pneumococcal vaccination) to 86% (drug testing) for the 6 HIV-related services offered to all patients, 13% (Pap smear for women) to 54% (tuberculin skin testing) for the 6 services offered to new patients, 2% (sterile injection equipment) to 64% (male condoms) for the 4 risk-reduction services, 37% (Pap smear for women) to 61% (tuberculin skin testing) for the 11 biological assessments offered to HIV-positive patients, and 33% (medical treatments) to 52% (counseling) for the 4 other services offered to HIV-positive patients. The availability of these HIV-related services was associated with clinical settings, the types of addiction treatment services, the rates of risky drug and sexual behaviors, and HIV infection rates among patients. Availability of such services was below published guidelines. While the results provide another basis for the infection-related prevention benefits of substance abuse treatment, the variability in the availability of HIV-related health care deserves further study and has health policy implications in determining how to utilize substance abuse treatment in reducing drug-related HIV transmission. PMID- 21287900 TI - Nephrotic syndrome in adult black South Africans: HIV-associated nephropathy as the main culprit. AB - BACKGROUND: Glomerular diseases, accompanied by nephrotic syndrome, contribute significantly to end-stage renal disease (ESRD) worldwide. We sought to show the distribution and frequency of biopsy-proven causes of nephrotic syndrome in native black Africans attending the Groote Schuur Hospital in Cape Town, South Africa. METHODS: We retrospectively reviewed the biopsy data of 294 black South Africans with biopsy-proven cause of nephrotic syndrome in Cape Town over a 10 year period. Nephrotic proteinuria was accepted as urine protein excretion of at least 3.5 g in 24 hours. Glomerular diseases were classified into primary and secondary types. Serum creatinine concentrations were stratified into 3 levels to reflect the degree of renal dysfunction at the time of presentation. The frequency and distribution of disease were recorded according to age and gender. RESULTS: Young adults (< or = 40 years of age) constituted 74.1% of the study population. Secondary glomerular diseases were more frequent (58.8%) and human immunodeficiency virus-associated nephropathy (HIVAN) was observed as the leading cause of nephrotic syndrome in both males and females (42.8%). Most patients with HIVAN (73.6%) presented for the first time with severe renal impairment and more than half of patients with non-HIVAN glomerular diseases presented with an abnormal serum creatinine. Of the primary glomerular diseases, mesangiocapillary glomerulonephritis was the commonest cause of the nephrotic syndrome (19.0%), while IgA nephropathy was the least common cause (1.7%). CONCLUSIONS: HIVAN is a major cause of nephrotic syndrome in black South Africans and may be responsible for the rising incidence of ESRD in Africa. PMID- 21287901 TI - Sex with bisexual men among black female students at historically black colleges and universities. AB - BACKGROUND: Human immunodeficiency virus (HIV) disproportionately affects black women. Nearly two-thirds of all female HIV cases reported to the CDC are black, and HIV is the leading cause of death among black women aged 25 to 34 years. The greatest HIV transmission risk among black women is sexual intercourse with a man, although the role of bisexual men is not clear. METHODS: The CDC and collaborating partners conducted behavioral surveys at 7 historically black colleges and universities from January 2005 to April 2007. RESULTS: Of the 2705 black female students aged 18 to 29 years who were surveyed, 2040 (75%) reported being sexually active in the previous 12 months and, among sexually active women, 291 (14%) reported having sex with a bisexual man in the previous 12 months. Women who reported sex with a bisexual man were more likely than women who did not to report having at least 2 sex partners in the previous 12 months, having male and female sex partners, not using a condom at last intercourse, being in a committed relationship, never or infrequently attending church, and believing they were at increased risk for HIV infection. CONCLUSION: Heterosexually active black women who have engaged in sexual intercourse with bisexual men have a different HIV risk profile than other heterosexually active black women. PMID- 21287902 TI - A critical literature review to identify possible causes of higher rates of HIV infection among young black and Latino men who have sex with men. AB - Black and Latino young men who have sex with men (YMSM) are disproportionately impacted by HIV infection; however, the reason for this disparity is unclear. To identify possible causes of the higher rates of HIV infection in this population, data from studies of HIV infection and risk-related behaviors among black and Latino YMSM were used to evaluate a series of hypotheses adapted from Millett et al's literature review that might explain the disparity. High rates of HIV infection might be attributable to unrecognized HIV infection, social/sexual networks, and a history of childhood sexual abuse; however, they were not attributable to risk-related behaviors. More research is needed to understand the risk factors for HIV infection and how to address them in HIV prevention interventions. PMID- 21287903 TI - College students' perceptions and experiences with health insurance. AB - OBJECTIVES: Most research on perceptions of health insurance has examined gender- and race-based differences across sections of the adult population. This is the first study to examine differences based on demographic characteristics of undergraduate college students' coverage and perceptions of health insurance. METHODS: The participants were undergraduates at 12 of the 13 public universities in Ohio. Valid and reliable 40-item questionnaires (n = 1800) were equally distributed to faculty at 12 public universities. RESULTS: A total of 1367 (70%) surveys were completed. Most students (59.9%) believed that the federal government should have the primary responsibility to ensure that Americans have health insurance and 53.3% felt that the best way was through universal health insurance from the federal government. Perceptions varied by race, political affiliation, and health insurance status. CONCLUSIONS: Undergraduate students appear to have formed opinions about health insurance similar to general adult populations. These perceptions may have been obtained by transfer of perceptions from family and friends. A more formalized undergraduate education approach to educating future leaders of society regarding health insurance should be considered. Policy changes to reduce disparities in health status among groups of college students must be explored. PMID- 21287904 TI - A novel approach to quality improvement in a safety-net practice: concurrent peer review visits. AB - OBJECTIVE: Concurrent peer review visits are structured office visits conducted by clinician peers of the primary care clinician that are specifically designed to reduce competing demands, clinical inertia, and bias. We assessed whether a single concurrent peer review visit reduced clinical inertia and improved control of hypertension, hyperlipidemia, and diabetes control among underserved patients. METHODS: We conducted a randomized encouragement trial to evaluate concurrent peer review visits with a community health center. Seven hundred twenty-seven patients with hypertension, hyperlipidemia, and/or diabetes who were not at goal for systolic blood pressure (SBP), low-density lipoprotein cholesterol (LDL-C), and/or glycated hemoglobin (A1c) were randomly assigned to an invitation to participate in a concurrent peer review visit or to usual care. We compared change in these measures using mixed models and rates of therapeutic intensification during concurrent peer review visits with control visits. RESULTS: One hundred seventy-one patients completed a concurrent peer review visit. SBP improved significantly (p < .01) more among those completing concurrent peer review visits than among those who failed to respond to a concurrent peer review invitation or those randomized to usual care. There were no differences seen for changes in LDL-C or A1c. Concurrent peer review visits were associated with statistically significant greater clinician intensification of blood pressure (p < .001), lipid (p < .001), and diabetes (p < .005) treatment than either for control visits for patients in either the nonresponse group or usual care group. CONCLUSIONS: Concurrent peer review visits represent a promising strategy for improving blood pressure control and improving therapeutic intensification in community health centers. PMID- 21287905 TI - Perceptions of health care communication: examining the role of patients' psychological distress. AB - OBJECTIVE: We sought to gain a better understanding of the relationship between patients' serious psychological distress (SPD) and their perception of interactions with health care providers and their ratings of the health care quality. METHODS: We analyzed data from 6286 adult respondents to the 2007 Health Information National Trends Survey. We conducted cross-tabulations to compare sociodemographic characteristics between those with SPD and those without SPD. Using odds ratios and 95% confidence intervals from logistic regression models, we assessed the association between psychological status and indicators of perceived health care communication and the overall health care quality after controlling for sociodemographic variables. RESULTS: Patients with SPD were less likely to report that their provider "always" paid attention to their feelings and emotions, "always" ensured their understanding of the needed care, and "always" assisted them dealing with uncertain feelings. These distressed patients were also less satisfied with the overall health care quality. CONCLUSIONS: Patients' psychological distress is negatively associated with their perceived quality of communication with health providers. Further knowledge on the health care need of patients with SPD would be important in improving health service delivery and optimizing the psychological care of medical patients. PMID- 21287906 TI - Lassa virus infection in Nigeria: clinical perspective overview. AB - Lassa fever is a severe, often fatal, hemorrhagic fever caused by Lassa virus, an Arenavirus that can be transmitted to humans from asymptomatically infected multimammate rats. The speculation is that Lassa viral infection may affect between 2 to 3 million people each year in certain portions of the West African region, causing a mortality of about 10000 during the same period. Lassa fever is one of the endemic zoonosis in Nigeria with a high probability for nosocomial transmission due to several health care sector challenges. Although treatment is available for Lassa fever, early diagnosis is still difficult in almost all Nigerian health care institutions. The intention of this clinical overview is to: (1) summarize the pertinent literature for clinicians in primary, secondary, and tertiary health care centers; and (2) suggest a need to use the information from basic research and laboratory diagnosis to incorporate international best practices into public health and clinical practice guidelines. PMID- 21287907 TI - A woman with complications from radiation therapy. PMID- 21287908 TI - Pulmonary sarcoidosis in an HIV/human T-cell lymphotrophic viruses I/II coinfected patient. AB - Coexistence of HIV, pulmonary sarcoidosis, and human T-cell lymphotrophic viruses (HTLV) I/II has not been well reported and studied. Although the exact etiology of sarcoidosis is unknown, immunologic abnormalities have been the focus of human immunodeficiency virus (HIV)-related sarcoidosis and it is thought to be a manifestation of immune reconstitution inflammatory syndrome. We report the case of an African American woman with HIV and HTLV I/II coinfection who developed pulmonary sarcoidosis several months after the initiation of antiretroviral therapy. Despite the fact that most common etiologies of pulmonary nodules in HIV patients include mycobacterial and fungal infections, sarcoidosis should be considered in differential diagnosis. This disease may continuously rise due to the increasing number of people who are receiving antiretroviral therapy, leading to an improved immune system. PMID- 21287909 TI - Acute agitated delirious state associated with Taser exposure. AB - BACKGROUND: The use of the Taser (Taser International, Scottsdale, Arizona) as a form of nonlethal force is increasingly common because of its safety profile. Tasers have been associated with in-custody mortality particularly in agitated individuals, though potential explanatory mechanisms are poorly understood. While Tasers are often used to subdue acutely agitated individuals, no study has reported Taser exposure precipitating agitation or delirium, even though high voltage electrical exposure is well documented independently to precipitate acute delirium. OBJECTIVES: We present a case of an acute agitated or delirious state occurring post-Taser exposure in a resting, otherwise nonagitated individual. CASE REPORT: The patient was a 37-year-old African American male with no prior psychiatric history, tasered multiple times during an arrest episode. He became delirious and agitated while in the emergency department, requiring sedation and intubation, followed by 3 days of continued refractory delirium. Toxicology screening demonstrated therapeutic doses of methadone and trace amounts of marijuana, not thought to be associated with the acute onset of the patient's agitated or delirious state. Imaging, neurological, and psychiatric assessments were similarly not contributory. CONCLUSION: The occurrence of acute agitation and delirium in this patient without any prior psychiatric history or significant substance use suggests an association with Taser exposure. This case report is thought to be the first report demonstrating a temporal association between Taser exposure and an acute or delirious state. Further studies to explore the association between Taser exposure and acute agitation are needed. PMID- 21287910 TI - Endomyocardial fibrosis presenting outside the tropical rain forest. AB - Endomyocardial fibrosis (EMF), an idiopathic cardiac disorder, occurs predominantly in the tropical and subtropical regions of the world. We present herein a report of EMF in a young man from the savannah belt of Nigeria. He was a 19-year-old young man who presented with recent onset of palpitation and dyspnea and was followed up elsewhere for 3 years as a case of chronic liver disease due to progressive abdominal distension. Clinical examination revealed an undernourished young man with atrial fibrillation and features of heart failure. His electrocardiogram showed features of atrial fibrillation, while echocardiogram showed enlarged right atrium, tricuspid incompetence, and signs of fibrosis in the ventricles. Although EMF occurs primarily in the subtropical regions of Africa in its typical manifestation, in this report it was in the savannah belt. PMID- 21287911 TI - Stiff-person syndrome: a case report and review of the literature. AB - We report a case of stiff-person syndrome associated with several autoimmune diseases. A 49-year-old male with type 1 diabetes presented with a 6-month history of muscle rigidity and spasms of his upper and lower extremities. Anti glutamic acid decarboxylase 65 antibody was elevated at 609 nmol/L. Electromyography revealed continuous motor unit activity in agonist and antagonist muscles. He responded favorably to diazepam, baclofen, and intravenous immunoglobulin infusions. This case report describes stiff-person syndrome in association with pernicious anemia and diabetes mellitus. A review of the literature discusses the diagnosis and treatment of this rare entity. PMID- 21287912 TI - A key strategy for reducing HIV in African American communities: promoting HIV testing. PMID- 21287913 TI - Marcella Nunez Smith, MD, MHS. PMID- 21287919 TI - Workforce planning shake-up prompts fears of staff shortfall. PMID- 21287920 TI - 'Job cuts are unavoidable if trusts have to keep paying increments'. PMID- 21287921 TI - Care in the air. Interview by Jo Carlowe. AB - Two experienced emergency care nurses are looking after patients in some of the UK's most remote areas. PMID- 21287922 TI - Give peace a chance. Interview by Jenny Knight. AB - Following a tough childhood in south London, Mustafa Shiyanbola has made a successful career in nursing. He is now using his personal experience to mentor others. PMID- 21287923 TI - The time of your life. AB - The Healthtalkonline website has a section to help women going through the menopause. PMID- 21287924 TI - Bump bonding. AB - Antenatal care based on partnership encourages women to take an active role in the decisions that affect them and their babies. PMID- 21287925 TI - Pain management in patients following limb amputation. AB - Phantom limb pain is common in patients who have amputations. This article outlines the different theories that explain the pathophysiology of phantom limb pain, including peripheral, spinal and central mechanisms. Treatment options are targeted at addressing these mechanisms, combining analgesic techniques with physical and psychological rehabilitation. PMID- 21287926 TI - Promoting healthy ageing: the importance of lifestyle. AB - The UK has a rapidly ageing population with increased healthcare needs. While the population can, on the whole, look forward to longer years of good health, many people will be living with one or more chronic conditions. However, modifiable lifestyle, such as a healthy diet and physical activity, can encourage healthy ageing and improve the quality of life of older people. Nurses are ideally placed to provide advice on nutrition and physical activity to older people in an effort to reduce the burden of age-related disease. This is likely to require new ways of working, with nurses being trained to recognise opportunities for health promotion with older patients, as well as how to plan for and conduct health promotion so that it becomes integral to practice. PMID- 21287927 TI - Best practice in audit. PMID- 21287928 TI - A practical approach to the treatment of acne vulgaris. AB - This article aims to provide healthcare professionals with the necessary knowledge and skills to assess, diagnose and treat acne vulgaris. The article discusses the epidemiology and pathogenesis of the condition and uses a case study to highlight common issues. It emphasises the importance of the four pathogenic factors in formulating a management plan for the patient with acne. Treatments are explored in a holistic approach to the nursing care of a patient with acne. PMID- 21287929 TI - Interactions between drugs and four common medicinal herbs. AB - Herbal remedies are popular in the UK, but there is evidence that some of the most commonly used herbs can interact with conventional drugs, sometimes with potentially serious consequences. This article looks at four common herbal remedies and examines the scientific evidence for their interactions with drugs. PMID- 21287930 TI - Made to measure. PMID- 21287931 TI - 'Our mentors gave us confidence'. Interview by Frances Pickersgill. PMID- 21287932 TI - Patient care on the agenda. Interview by Jenny Knight. PMID- 21287933 TI - Getting patients to 'like' your practice. PMID- 21287935 TI - Making a difference. PMID- 21287934 TI - Easing the transition to electronic health records. PMID- 21287936 TI - The good, the bad, and the ugly. PMID- 21287937 TI - Lessons from my father. PMID- 21287938 TI - All things yin and yang. PMID- 21287939 TI - EHRs, insurance, and government: when did we lose sight of the patient? PMID- 21287940 TI - It's time to optimize primary care for a healthier population. PMID- 21287941 TI - EHR-related risk lowered if records safe, accessible. PMID- 21287942 TI - Imaging criteria for diagnosis of chronic rhinosinusitis in children. AB - Symptoms of chronic rhinosinusitis (CRS) are nasal blockage, nasal discharge, postnasal drip, facial pain, headache, and reduction or loss of smell, but they are often subtle and make it difficult to obtain a firm diagnosis based only on clinical data, and especially to distinguish CRS from persistent rhinitis. A diagnosis of certainty of CRS relies upon either direct observation by nasal fibroendoscopy of nasal turbinates, middle meatus, and rhinopharynx, detecting mucopurulent discharge from the middle meatus, and/or oedema or mucosal obstruction, or by imaging of the rhinosinusal cavities. Imaging techniques such as computed tomography (CT) scanning and magnetic resonance (MR) are currently recommended in consensus documents, while plain radiography is considered of poor diagnostic value. However, recent studies indicated that radiography by the Waters'projection had a sensitivity of 84.2% and a specificity of 76.6%, which suggests to use it routinely in suspected CRS, limiting the number of more expensive imaging investigations. This seems important in the current economic landscape that requires a cost-effectiveness evaluation in each diagnostic procedure. PMID- 21287943 TI - Co-recognition of lipid trasfer protein in pollen and foods in northern Italy: clinician's view. AB - BACKGROUND: Lipid transfer proteins (LTP) are pan-allergens in plant derived foods that have been also detected in several pollens. The observed cross reactivity between pollen and plant-food LTPs has led to hypothesize that primary sensitisation to this allergen may occur through the airways. OBJECTIVE: The present study looked at the prevalence of hypersensitivity to different L TP containing pollen sources among peach-allergic subjects sensitized to LTP. METHODS: Sixty-six adults (M/F 25/41; mean age 33.7 yrs) with allergy to peach LTP living in the area of Milan underwent SPT with mugwort, plane and olive pollen extracts. IgE to the same allergen sources as well as to peach were measured in 16 cases. RESULTS: Skin tests with Artemisia, Platanus, and Olea pollen extracts scored positive in 16 (24%), 10 (15%), and 10 (15%) patients, respectively. Peach-specific IgE were detected in 16/16 patients, whereas IgE to Artemisia, Platanus, and Olea pollen were found in 7 (44%), 10 (62%), and 8 (50%) cases. In all cases peach-specific IgE levels were higher than levels of IgE to the three pollens, and a strong correlation between peach-specific IgE levels and the levels of IgE specific for mugwort (r = 0.84; p < 0.001) and plane (r = 0.96; p < 0.001) pollen was recorded. CONCLUSIONS: In northern Italy olive, plane, and mugwort pollen seem an unlikely source of LTP sensitisation and the most likely primary sensitizer to this protein remains the peach. PMID- 21287944 TI - Ragweed pollen in France: origin, diffusion, exposure. AB - PURPOSE OF THE STUDY: To detect the origin of ragweed pollen and to measure the impact of this pollen exposure on allergic patients, so their sensitivity can be noted (using specific IgE production: sIgEw1) in order to inform the population about an "allergy" against those ragweed pollen grains. MATERIAL AND METHODS: To measure population exposure to ragweed pollen, the R.N.S.A (National Aerobiological Monitoring Network, a French association) has a pollen trap network located in urban areas. These traps allow continuous recording of airborne pollen, the light microscope analysis (with a bi-hourly time step) allows one to know the daily concentrations of ragweed grains and the circadian rhythm of grains impaction. It is thus possible to follow the evolution of pollination during each day ofeach season and to compare seasons and years at each station. Biomnis is a biological laboratory which performs more than 85% of ragweed specific IgE assay in France. It seems to be clear that when allergists ask ragweed IgE for a patient, it is because they think that this patient seems to be allergic to this specific pollen. The statistical analysis of results about specific IgE (for ragweed) from the Allergology laboratories Biomnis (located in Lyon and Paris) can determine the number ofpatients sensitized to ragweed in French departments. RESULTS: The distribution ofsensitized patients to ragweed is compared to ragweed pollen distribution studied by the R.N.S.A from the year 2005 to 2008 in France, whatever the ragweed plant' origin: local (closed topollen trap) or imported (by wind). CONCLUSION: The biological database (Health impact) allows a correlation between the geographical distribution ofragweed pollen and the number ofpatients with specific IgE against ragweed (sIgEw1), i.e., whose sensitization is due to local plants. That also permits one to estimate the expected number of allergy cases in the next years, because the sensitivity precedes the allergy. PMID- 21287945 TI - Long-term tolerability of etoricoxib in different types of NSAID-intolerant subjects. AB - BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are a frequent cause of hypersensitivity reactions, therefore, in clinical practice, it's important to find safe and effective substances. OBJECTIVE: To evaluate the tolerability of etoricoxib and its subsequent actual use and safety at home. METHODS: Etoricoxib tolerance was assessed by single-blind-placebo-controlled oral challenges and its subsequent use was checked by a standardized telephone call. The test was performed in 139 subjects (83 single NSAID reactors and 56 multiple NSAID reactors). RESULTS: The drug was not tolerated in 4 cases (2.8%) causing wheals on the face area in 3 single reactors and a severe generalised reaction occurring three hours after the intake of a therapeutic dose in a multiple reactor. The phone calls showed that 64 (52.8%) patients did not take etoricoxib, mostly due to the fear of adverse effects; in 5 cases (4.2%), the practitioner prescribed a different NSAIDs. Only 52 (43%) subjects took etoricoxib after oral challenges; all tolerated the drug but 2 single reactors, who reported a very mild labial oedema. CONCLUSION: Our study confirmed the good long-term tolerability of etoricoxib in patients with a history of hypersensitivity to other NSAIDs without differences between single and multiple reactors. Nonetheless, in NSAID intolerant subjects this drug should be first challenged in specialised centres due to the risk ofsevere reactions. PMID- 21287946 TI - Human insulin allergy: four case reports. AB - Insulin allergy was not uncommon in the past, but has lowered with the introduction of human recombinant insulin. Human recombinant insulin allergy is a rare condition, now reported in less than 1% of treated patients. However, it is a serious condition that requires an immediate allergological work-up. In this study, we describe 4 cases of IgE-mediated reaction to human recombinant insulin, emphasizing some practical aspects in diagnosis and treatment. PMID- 21287947 TI - Pre-existing condition exclusions: the government's bumpy road to enhance access to insurance coverage. PMID- 21287948 TI - Trends in cardiovascular diseases in Bosnia and Herzegovina and perspectives with heartscore programme. AB - Cardiovascular diseases are still the major cause of death, morbidity, mortality and loss of quality of life in European countries and worldwide. In Bosnia and Herzegovina we have burden of cardiovascular diseases with higher rate of morbidity and mortality than in the countries of EU zone or broader Europe. The cause of mortality is in close relation to multiple risk factors but also with specific conditions in our country; post war situation, transition and overall economic position. The main mission of European Society of Cardiology is to improve quality of life in the European population by reducing the impact of cardiovascular diseases. HeartScore web based program and PS Standalone program are introduce to assesses the overall risk of cardiovascular death for a period of 10 years, based on variables such as age, sex, smoking, systolic blood pressure and cholesterol levels in the blood, or total cholesterol/HDL ratio. Standalone PS HeartScore is practical to use, requires no permanent internet connection, the system offers its own database for each patient and the print version of the guidelines to reduce risk factors, based on evidence based medicine Program is tailored to patients, the system provides a graphical representation of the absolute risk of CVD, a version for our country is developed on the principle of high-risk populations and is available in the languages of the peoples of Bosnia and Herzegovina. Program is available for all types of medical practice which is equipped with computers, the laptop, and suitable for community nursing service as well. PMID- 21287949 TI - Correlation of arterial hypertension and type 2 diabetes mellitus with type of polyvascular atherosclerotic disease. AB - Atherosclerosis is a systemic disease of blood vessels which in most of the cases affects two or three vascular beds. The occurrence and development of atherosclerotic disease is accelerated by multiple risk factors among which the significant role has arterial hypertension and diabetes mellitus. AIM of this article is to evaluate presence of hypertension and diabetes mellitus type 2 in patients with polyvascular atherosclerotic disease and compare them to those who have isolated disease of one vascular bed. MATERIAL AND METHODS: we enrolled total of 160 consecutive patients. Patients were divided into 4 groups, in relation to the type of their atherosclerotic disease. COR-group included patients with coronary atherosclerotic disease, CAR-IF group included patients with carotid and iliac-femoral atherosclerotic disease, COR-IF group consists of patients with coronary and iliac-femoral atherosclerotic disease, and COR-CAR-IF group consists of patients with atherosclerotic disease in three vascular beds: coronary, carotid and iliac-femoral. We followed clinical variables: age, gender, arterial hypertension, tobacco smoking, total cholesterol and diabetes mellitus with focus on arterial hypertension and diabetes mellitus. RESULTS: we had significant percentage of patients with arterial hypertension in all four groups in relation to those with normal blood pressure. Hypertension in male subjects was significantly higher in those with polyvascular disease i.e. COR-CAR-IF, and COR-IF groups, compared to monovascular disease i.e. COR group, (p < 0.05). In females the prevalence of hypertension was significantly higher in COR-CAR-IF and COR-IF groups, (< 0.05). Males had higher systolic values in the COR-CAR-IF group compared to other groups, but only signif. differ. was between COR-CAR-IF group vs. CAR-IF group, (p < 0.05). In females we found signif. differ. in systolic values in COR-CAR-IF group compared to COR group, p < 0,05. In diastolic values we found no signif. differ. between groups. The significant percentage of diabetics was in COR-CAR-IF group (77.5%), and the difference to other groups was statistically significant, p < 0.05. We found significant percentage of diabetics in COR-CAR-IF group (77.5%), and the difference between the diabetics versus non diabetics was statistically significant. The largest percentage of diabetics both men (76.1%) and women (84.2%) belonged to the patients with polyvascular disease i.e. COR-CAR-IF group respondents. CONCLUSIONS: prevalence of arterial hypertension and type 2 diabetes mellitus was statistically higher in individuals with polyvascular atherosclerotic disease. PMID- 21287950 TI - The role of exercise test in stratifying the risk of asymptomatic patients with moderate/severe aortic stenosis. AB - OBJECTIVES: The role of exercise test in risk stratifying of asymptomatic patients with moderate and severe aortic stenosis (AS) in recent literature is still controversial. The aim of this study was to evaluate the role of exercise test in stratifying the risk of patients with moderate to severe aortic stenosis. METHODS: At the Internal Medicine Clinic, Department of Cardiology in Tuzla, in the period from January 2008 until January 2010 was followed 33 patients with clinical and echocardiographic parameters of moderate to severe asymptomatic aortic stenosis (mean effective orifice area EOA 0.9 +/- 0.34 cm2). In statistical analysis we used descriptive statistics, t-test, chi-square test and Kaplan-Meier life table for predictive values, sensitivity and specificity. A significance level of 0.05 was used. RESULTS: Two patients were excluded due to exclusion criteria, so 31 patient was followed up during 12 months period. Eighteen patients (58%) with EOA pounds sterling 0.8 cm2 had limiting symptoms during the test. During follow-up period, 11 patients developed serious spontaneous symptoms, and out of them 8 patients underwent surgical valve replacement, one patient died (sudden cardiac death), and 2 patients had serious complications (ischemic cerebral stroke). Twenty patients remained asymptomatic. The highest positive predictive accuracy had EOA pounds sterling 0.8 cm2 with limiting symptoms and it was 85%. The highest negative predictive accuracy had ST depression. CONCLUSION: only limiting symptoms along with EOA pounds sterling 0.8 cm2 had positive predictive accuracy. PMID- 21287951 TI - Intrahospital sudden cardiac death (SCD) at internal medicine clinic of University Clinical Hospital Mostar. AB - AIM: Evaluation of general and specific sudden cardiac death (SCD) mortality and comorbidity which advances to SCD in patients of Internal Clinic of UCH Mostar in period from 2000 to 2009. METHODS: AND RESULTS: We analysed 2547 death of patients, part of general population of 26.471 hospitalised over this time period. Registered general mortality was 9.6%, specific SCD mortality was 5.85%, and hospitalised sudden death occurred in 1548 or 60.78% patients. Factors causing death of SCD patients in observed period were as follows: CHF was present in 368 or 23.8%, death after AIM was 344 or 22.2%, ICV was 212 or 13.7%, Shock cardiogenes was 200 or 12.9%, AHF with oedema pulmonum (145 or 9.4%), cardiac arrest was 121 or 7.8%, 89 patients experienced sudden death on the street and were transported to Clinic, electrical instability with malignant arrhythmias VF/ VT was found in 22 or 1.4%, dissection of aortae 16 or 1.03%, thrombosi a. mesentericae in 12 or 0.78%, and circumstances and end-presentation of death. Age structure was changing, with increase in numbers of younger patients. The results reflects general trend in SCD in grater Mostar region and whose inhabitants gravitate toward our Clinic. CONCLUSION: There is continuous increase in SCD in our patients and in the numbers and comorbidities, which explain existing burden. Although incidence of SCD increases with age, existed continuous trend of increase in SCD in the young people accelerates over time. PMID- 21287952 TI - Mortality at the Clinic of Internal Medicine of University Clinical Center in Tuzla during 2008. AB - INTRODUCTION: Accurate information about the cause of death is given by expert teams based on pathological or forensic expertise. Reliable information can be obtained from doctors from clinical-hospital institutions if the deceased person was treated in such an institution and with previously diagnosed disease (hospital mortality). Analysis of hospital mortality provides a lot of data that can be used in planning the hospital beds capacities, the amount of drug procurement, purchasing equipment, organization and creation of highly specialized medical teams (medical team for resuscitation), the number of reanimation techniques, the number of pathologists who are required for autopsy procedures, etc. GOAL was to determine the total number of deaths, the most common causes of death and the 10 leading diagnoses of deceased patients at the Clinic for Internal Medicine of Clinical Center in Tuzla during 2008. MATERIAL AND METHODS: We used the material from the archive (medical records and reports on deceased patients, delivered by physicians working at the Clinic for Internal Medicine of Clinical Center in Tuzla). RESULTS: During 2008 at the Clinic for Internal Medicine 368 patients died. According to the analyzed data leading cause of death and leading diagnosis as cause of death at the Clinic for Internal Medicine in 2008 were as follows: cardiogenic shock in 73 (19.84%), cerebrovascular stroke in 46 (12.50%), coma due to stroke in 32 (8.70%), coma not classified as cerebral in 25 (6.79%) (metabolic 13 (3.53%) and hepatic 12 (3.26%), cardiomyopathy in 22 (5.98%), malignant neoplasm of the abdomen in 17 (4.62%), respiratory insufficiency in 17 (4.62%), acute myocardial infarction and myocardial infarction with rupture in 17 (4.62%), pulmonary edema in 16 (4.35%), and cardiorespiratory arrest in 13 (3.53%) deaths. CONCLUSION: During 2008 at the Clinic for Internal Medicine of Clinical Center in Tuzla died a total of 368 patients. The most common cause of death of patients at the Clinic for Internal Medicine of Clinical Center in Tuzla are cardiovascular disease (n = 175; 47.55% of deaths), in second place was cerebrovascular disease (n = 76; 20.65% of deaths) for a total of 251 (68.20%) of deaths from cardiovascular and cerebrovascular disease. PMID- 21287953 TI - Analyzing recent trends in coronary heart disease (CHD) deaths among the elderly in the United States using data from official statistical sources. AB - Total mortality rates and coronary heart disease (CHD) mortality rates are declining in the USA. Accordingly, the oldest individuals (85+ years) comprise the fastest growing segment of the population. How do these declines in mortality apply to and re-apportion other age groups? We examined trends in CHD mortality for the USA population over 25 years of age, focusing on changes occurring among individuals 65-74 and 75-84 years of age. PMID- 21287954 TI - Primary percutaneous coronary interventions network in Bosnia and Herzegovina- Sarajevo's proposal. AB - Reperfusion therapy is the most useful part of the treatment for patients suffering from an acute coronary syndrome. Start time of reperfusion therapy is an important factor which influenced positively on the number of days of hospitalization, and readmission, the risk of reinfarction, as well as both, short and long-term mortality. Today, several models of reperfusion therapy are available: thrombolytic treatment (pre-hospital or in-hospital setting), primary percutaneous coronary intervention (primary PCI or pPCI) or a combination of both. pPCI is preferred, as soon as possible, in centers with experienced teams, especially for patients in shock, or those with contraindicated fibrinolytic therapies. We will compared, very shortly, the daily practices in 4 countries (Czech Republic, Austria, Croatia, Serbia ), where (well) developed primary PCI hospital networks works efficiently for a years, with the current situation in Bosnia and Herzegovina. Our goal is to describe the easiest and quickest way of establishing the primary PCI network in Bosnia and Herzegovina. By combining the efforts of both Entities of Bosnia and Herzegovina will be possible in the forthcoming period, that B&H becomes a participant in the Stent for life initiative. PMID- 21287955 TI - Stem cells in cardiovascular disease. AB - Advances in stem cell biology over the past decade have fueled interest in new therapies for acute and chronic cardiovascular diseases. Pre-clinical work with a variety of cell types has suggested efficacy in improving ischemia and ventricular function, although mechanisms of effect remain to be fully explained. Human studies using certain cell types have shown modest clinical efficacy, while the safety of these experimental therapies supports continuing patient-oriented research. PMID- 21287956 TI - Advantages of renin-angiotensin system blockade in the treatment of cardiovascular diseases. AB - The renin angiotensin system (RAS) plays a key role in the regulation of cardiovascular function, with angiotensin II being involved in hemodynamic and non-hemodynamic mechanism in the pathophysiology of cardiovascular disease. A number of studies demonstrated that pharamacological modulation of the RAS, either with angiotensin converting (ACE) inhibitor or an angiotensin II receptor blocker (ARB), provides cardiovascular and renal protection. Blockade of the RAS, either with ACE inhibitors or ARBs, decreases cardiovascular morbidity and mortality in high risk patients. ACE inhibitors as well as ARBs are drugs of choice in congestive heart failure, as well as in diabetic nephropathy. Especially, the combined RAS blockade with ACE inhibitors and ARBs was more effective than monotherapy in diabetic or non-diabetic nephropathy with proteinuria. However, this combined RAS blockade was not equally dominant in treatment of hypertension and was not recommended for widespread antihypertensive use. PMID- 21287957 TI - Stress echocardiography in differentiation of fixed vs. low flow-low gradient and pseudo severe aortic stenosis. AB - PURPOSE: To present the importance of stress echocardiography in diagnosis of low flow-low gradient aortic stenosis (AS). MATERIAL AND METHOD: Two patients were tested, one male patient, aged 62, weight 72 kg, height 172 cm, and BSA 1.86 cm2, and the other one was female, aged 59, weight 83 kg, height 168 cm and BSA, were found to have at least moderate ASs with low flow and low gradients at rest. Dobutamine stress test was performed using standard protocol starting at 2.5 mcg/kg/min at rest as continuous infusion and increasing every five minutes intervals with stepwise increase up to 20 mcg/kg/min. Monitoring with 12-lead ECG and blood pressure measurements at each step was performed. After completing the test, transthoracic echocardiography (TTE) showed in male patient increasing in transvalvular flow and gradients across aortic valve and ejection fraction (EF) measured by Simpson method increased from 33% at rest up to 40% following Dobutamine administration. EOA (effective aortic valve area) from 0.8 cm2 at rest increased insignificantly to 0.85 cm, (0.425 m2) afterwards. CONCLUSION: Final diagnosis therefore was severe aortic stenosis with preserved contractile reserve. The patient was scheduled for surgical valve replacement. In female patient after DST, the area of aortic valve increased significantly from 0.75 cm2 up to 1.05 cm2, while all transvalvular gradients remained almost unchanged. Pseudo-Aortic Stenosis and surgical valve replacement had not been indicated at this time. PMID- 21287958 TI - Echocardiographic diagnosis of divided right atrium-cor triatriatum dextrum. AB - First reported in 1868, cor triatriatum, that is, a heart with 3 atria (triatrial heart), is a congenital anomaly in which the left atrium (cor triatriatum sinistrum) or right atrium (cor triatriatum dextrum) is divided into two parts by a fold of tissue, a membrane, or a fibromuscular band. As far as division of the morphologically left atrium (cor triatriatum) is a recognized clinical and surgical entity. Division of the right atrium (prominence of the eustachian and thebesian valves) is recognized pathologically, but is rare. A partition division the right atrium was attached to the orifice of the inferior caval vei. The dividing partition is placed between the systemic venous sinus and the distal part of the right atrium, made up of the vestibule and appendage. This report describes a case of a divided right atrium, associated with a large atrial septal defect and valvular pulmonary stenosis. PMID- 21287959 TI - Supraventricular tachycardia in pregnancy. AB - Treatment of paroxysmal supraventricular tachycardia during pregnancy is necessary to protect both mother and the fetus. In case of hemodynamic deterioration, pharmacological treatment is the treatment of choice. There are limited reports for the safety and efficacy of verapamil use in pregnancy for treatment of paroxysmal supraventricular tachycardia. Numerous case reports and a retrospective study suggest that adenosine is safe and effective for these kinds of arrhythmias. PMID- 21287960 TI - Ruptured aneurysm of the noncoronary sinus of valsalva into the right atrium. AB - Sinus of Valsalva (SV) aneurysm is rare cardiac lesion with variable clinical presentation. We presented a case of a 41-year-old female who was admitted to our Center because of severe heart failure and a signs of ruptured aneurysm of the SV into the right atrium. Transthoracic echocardiography confirmed communication between noncoronary SV and right atrium measuring 12 mm in diameter, tricuspid insufficiency, biatrial dilatation and preserved left ventricular function. Urgent heart catheterization showed normal coronary arteries. Surgical repair with patch repair of the ruptured aneurysm was performed. Control echocardiography showed no communication with regression in tricuspid insufficiency. Eight days after surgery the patient was discharged home in good condition with no symptoms. Rupture of SV aneurysm may produce serious hemodynamic instability with heart failure or sudden death. Our experience supports the concept that early diagnosis and surgical treatment can save lives for most of the patients. PMID- 21287961 TI - On occasion of 800th anniversary of birth of Ibn al-Nafis--discoverer of cardiac and pulmonary circulation. AB - With Ibn Sina great Canon came the "golden age of Arabic medicine", almost to its peak. Since the beginning of XI century, when Ibn Sina died, until the middle of XIII century, when creative was Ibn al-Nafis, medical science continues to develop and progress, and had its brilliant minds. For that time characteristic is the fact that neither the strong authority as Avicenna was could paralyze the progress of medical science. Three hundred years before Paracelsus, in Cairo appears a medical scientist who dares to touch the authority of Ibn Sina-Avicenna in the infallibility of Canon-"Medical Bible". The scholar was called Alauddin Ibn al-Nafis (1210-1288). He, 250 years ago Servet, (Michael Servetus, XVI century) reveals the truly describes the small or pulmonary circulation, but also gives a description of the great forerunner of the bloodstream. In his separate work on the anatomy, Ibn al-Nafis in five places contested arguments of Galen's teachings, which also Ibn Sina was accepted. He very persuasively argues that the blood does not oxidize ("does not mix with air "), passing through some hypothetical pores in the partition between the right half of the heart, in which blood is collected and left half, in which, supposedly is the air, but that this happen when the blood is going from the right ventricle through the pulmonary artery into the lungs, where it is mixed with air and thus "converted" murmurs through the pulmonary vein into the left half of the heart. On occasion of the 800th anniversary of Ibn al-Nafis birth, one of the largest Arab and world doctors of all times we publish this article so that readers get something closer image his creative work, especially the one which relates to his contribution to the discovery of cardiac and pulmonary circulation, revolutionary discoveries in the world of medicine. In the year 1924 a heated debate started regarding the discovery of the pulmonary circulation. This discovery was attributed only to European scholars. It stemmed back to the sixteenth century. When Michael Servetus (1511-1553), Anderea Vesalius (?1514-1654), Nicolai Massa (1485-1569), Realdo Colombo (1520-1654), Valverde De Hamusco (1508-1565), Andera Cesalpino (1519-1603), Fabrici d'Aquapendent (1533-1619) and William Harvey (1578-1657) developed the concept. However, Muhyi-d-din At-Tatawi (1896-1945) presented his thesis "Der Lungenkreislauf nach El-Korachi. Dissert, z.eil. d. Doktorwrde, Freiburg im Brisgau 1924" of the blood circulation according to al Qurashi relaying on his discovery of his description of pulmonary circulation in one of ancient manuscripts, He proposed that the real credit for the discovery of the pulmonary circulation belongs this eminent physician of the thirteenth century: Ibn al-Nafis. Later another doctor Abdul Kareem Chihade (1922- ) presented another dissertation in Paris 1951 entitled" decouverte de la circulatio pulmonaire chez Ibn an-Nafis". Published by Institut Francais De Damas 1955. Other prominent professors like: Paul Galiounji and Salman Qatayyah researched extensively in his manuscripts and produced very important monographs. The general consensus is that Ibn al-Nafis' work exerted great influence on the development of medical science, both in the Islamic world and Europe. A closer look on Ibn al-Nafis contribution would indicate that he also described the coronary circulation, the cranial nerves the gall bladder anatomy and many new aspect of ophthalmology. He advocated as well therapy through nutrition. His work integrated the medical knowledge with great clarity and emphasized precision. PMID- 21287962 TI - Turning points in the progression of obsessive relational intrusion and stalking. AB - This study examined the critical events defining the temporal progression of unwanted relationship pursuit. Retrospective interviews elicited the experiences of 42 victims of obsessive relational intrusion (ORI) and its extreme manifestation, stalking. Participants described turning points within their ORI experiences, and constructed graphs representing the progression of turning points over time in terms of changes in perceived severity. Inductive data analysis revealed 17 distinct turning point types. Some turning point types were associated with increases in ORI severity and others were associated with decreases. Five temporal trajectories of ORI progression also were identified. Results indicate that ORI does not necessarily progress along linear and continuous paths. Some findings support coping advice commonly given to victims of ORI and stalking. PMID- 21287963 TI - Parent-child aggression: association with child abuse potential and parenting styles. AB - The present investigation predicted that greater use of corporal punishment as well as physical maltreatment would be associated with child abuse potential and selected parenting styles. Three independent studies were examined, two with community samples and a third with a clinical at-risk sample of parents. Parents across all studies anonymously completed the Child Abuse Potential Inventory, the Parent-Child Conflict Tactics Scale to assess physical discipline and maltreatment, as well as the Parenting Scale to measure dysfunctional parenting styles. Findings support that overall parent-child aggression, as well as physical maltreatment behaviors specifically, were associated with child abuse potential. Parent-child aggression was also related to dysfunctional parenting styles, particularly an overreactive, authoritarian parenting style. Permissive parenting was also identified as potentially associated with physical maltreatment, although the findings regarding such lax parenting styles are less clear. Intriguing findings emerged regarding the connection of psychological aggression to both child abuse potential and dysfunctional parenting style. Child abuse potential was also associated with dysfunctional parenting style, particularly harsh, overreactive approaches. Recommendations for future study with at-risk samples and additional research on permissive parenting and psychological aggression are discussed. PMID- 21287964 TI - Narrative coherence and the trauma experience: an exploratory mixed-method analysis. AB - The current study examines trauma narratives from 28 survivors of interpersonal violence. A mixed-method approach assessed coherence and explored narrative characteristics among differentially exposed groups. The quantitative analysis revealed: (1) exposure to repetitive interpersonal violence was described with greater perception of severity and emotional tone than single interpersonal violence episodes, and (2) exposure to interpersonal violence in childhood was described with greater emotional tone than exposure to interpersonal violence in adulthood. The qualitative analysis revealed: (1) traumatic events were connected to proceeding adverse experiences, (2) attempted avoidance of memories of the violence, (3) an altered view of the self, and (4) lacked recognition that the violence was abnormal. The study supports the "dose-response relationship" of trauma exposure, and the life-altering, transformative nature of trauma exposure. PMID- 21287965 TI - Does community violence exposure predict trauma symptoms in a sample of maltreated youth in foster care? AB - Previous studies find that childhood exposure to family and community violence is associated with trauma symptoms. Few studies, however, have explored whether community violence exposure (CVE) predicts trauma symptoms after controlling for the effects associated with family violence exposure (FVE). In the current study, CVE and FVE were examined in a sample of 179 youth with a recent history of maltreatment. CVE was associated with trauma symptoms after controlling for FVE, but FVE was not associated with trauma symptoms after controlling for CVE. In addition, negative coping strategies (e.g., self-harm, interpersonal aggression) partially mediated the association between CVE and trauma symptoms. These findings are discussed in terms of their implications for interventions aimed at addressing the needs of children exposed to violence. PMID- 21287966 TI - Attachment and personality predicts engagement in sexual harassment by male and female college students. AB - The purpose of this study was to examine a trait model of personality (Five Factor Model) as a mediator of the relationship between attachment styles and sexually harassing behavior in a sample of male (N = 148) and female (N = 278) college students. We found that gender (male) and low Agreeableness predicted engaging in sexual harassment and all three of its subtypes; gender harassment, unwanted sexual attention, and sexual coercion. Further, low Conscientiousness predicted overall sexual harassment, gender harassment, and unwanted sexual attention. Personality traits mediated the relationship between insecure attachment styles (Preoccupation with Relationships and Relationships as Secondary) and sexually harassing behaviors. Thus, factors beyond gender can help predict students' propensity to sexually harass others. PMID- 21287967 TI - The impact of childhood sexual abuse and intimate partner violence on sexually transmitted infections. AB - Childhood sexual abuse (CSA) and adult intimate partner violence (IPV) have both been found to be associated with sexually transmitted infections (STIs) independently, but studies of STIs have rarely looked at victimization during both childhood and adulthood. This paper examines the relationship between CSA, IPV and STIs using data from a nested case-control study of 309 women recruited from multiple health care settings. Overall, 37.3% of women experienced no violence, 10.3% experienced CSA only, 27.3% experienced IPV only, and 25.0% experienced both CSA and IPV. Having ever been diagnosed with an STI was associated with violence (CSA only, odds ratios [OR] = 2.8, 95% confidence intervals [CI] = 1.0-7.5; IPV only, OR = 2.2, 95% CI = 1.0-4.9; CSA and IPV: OR = 4.0, 95% CI = 1.7-9.4), controlling for demographic characteristics. Women who experienced CSA were younger when they were first diagnosed. Understanding how both childhood and adult victimization are associated with diagnosis of STIs is important to reducing the incidence and prevalence of STIs, as well as the associated consequences of STIs. PMID- 21287968 TI - Culturally specific treatment for partner-abusive Latino men: a qualitative study to identify and implement program components. AB - Research based on a demographic survey and qualitative interviews of Latino intimate partner violence perpetrators in Southern California forms the basis of a Spanish-language treatment program designed to be culturally appropriate for Latino immigrant men, and piloted for 4 years with their input. Culturally specific topics emphasized by participants and integrated into the program are: effective parenting skills for men; gender roles; discussion of discrimination towards immigrants and women; immigration and changing gender roles; marital sexual abuse; and spirituality as related to violence prevention. Attention is given to alcohol abuse and childhood trauma. Results suggest the desirability of an empathic and culturally-sensitive approach, without diminishing responsibility. This program was designed to help clinicians refine their skills and effectiveness in working with this rapidly expanding population. PMID- 21287969 TI - Domestic violence and South Korean women: the cultural context and alternative experiences. AB - The present research contributes to the growing body of cross-cultural research on domestic violence. This is accomplished by answering the question of how severity of intimate partner abuse varies for (1) women incarcerated for the homicides of their male partners (2) abused women who sought domestic violence shelter, short of killing their intimate assailants, and (3) a group of South Korean females outside of domestic violence shelters or prison. The article concludes with a discussion of potential policy implications of the findings as well as promising directions for future research. PMID- 21287970 TI - Anatomy and anatomists in Tuscany in the 17th century. AB - The 17th century was characterized by a real revolution in the field of scientific research due to the introduction of the experimental method, promoted by Galileo Galilei who was the most representative scientist of this period. Therefore, medical disciplines, particularly Anatomy, underwent innovative and deep changes shattering traditional culture and representing the background for the modern science. In this fermenting period, Tuscany played a significant role since numerous distinguished scientists were gathered by Medici Grand Dukes (especially Ferdinando the 2nd and Cosimo the 3rd) at Pisa University and at their court in Florence. Among them, it must be mentioned Giovanni Alfonso Borelli, creator of iathromechanics, Marcello Malpighi, founder of microscopic Anatomy, Francesco Redi, who denied the insect spontaneous generation, Nils Steensen who continued in Florence his anatomical studies on lymph nodes and salivary glands while setting also the bases of modern geology. Moreover, at the end of the 17th century, the anatomical wax modelling techniques arose and developed in Florence thanks to the work of Gaetano Zumbo (or Zummo), capable of creating some real masterpieces, still very well preserved and collected in the Museum of Natural Sciences "La Specola". PMID- 21287971 TI - Completing the puzzle of blood circulation: the discovery of capillaries. AB - Marcello Malpighi is considered to be the founder of microscopic anatomy. For almost 40 years he used the newly invented microscope to study and discover many structures of human body, animals and plants. One of his greatest contributions to science was the establishment by direct observation of an anatomical linkage between arteries and veins, the capillary network, a monumental work that completed Harvey's theory of blood circulation. PMID- 21287972 TI - Assessment of internal diameters of abdominal and femoral blood vessels in 250 living subjects using color Doppler ultrasonography. AB - Acquiring data about venous or arterial vessel size is important for several reasons, given the increasing incidence of thomboembolic phenomena and arterial aneurysms and the emerging new vascular techniques. We studied 250 healthy subjects (125 men and 125 women; age range: 50 to 91 years) with no known vascular pathology, nor hypertension, nor diabetes. We assessed the caliber of abdominal aorta, inferior vena cava, iliac and femoral arteries and viens by color doppler ultrasonography, and analyzed the results with regard to sex, height, weight and body surface of each subject. The mean caliber measure of the large abdominal vessels appeared lower than the value obtained from cadavers. There was a direct proportion between the left and right vessels of the same subject. The difference in vessel caliber between male and female subjects was statistically significant. There was no correlation between vessel caliber and age, height or body surface area. PMID- 21287973 TI - Internal jugular vein valves: an assessment of prevalence, morphology and competence by color Doppler echography in 240 healthy subjects. AB - The presence of valves in the head and neck veins is known since classical anatomical dissections. Previous studies have investigated whether jugular veins show constant valves at their ostium and whether these valves are physiologically competent, but, unluckily, these studies have reported conflicting results. Further, recent observations have raised the question whether the incompetence of jugular vein valves might play a pivotal role in neurological disorders related to venous engorgement of the brain. In this study we examined 462 internal jugular veins by using an echocolorodoppler apparatus. In particular, we assessed the presence, morphology and competence of valves at their ostium. Unilateral jugular vein valves were present in 406 cases (88%), mainly on the right side. The most frequently observed morphology (75%, 305 cases) was the two-leaflet valve, and jugular vein valves were incompetent in the huge majority of cases (365 cases, 90%). Our findings confirm the anatomical variability predicted from classical anatomical studies but, unluckily, do not provide additional evidence on the possible role of jugular vein valves in physiology and pathology. Further studies are strongly needed to determine whether these valves actually play an important role in counteracting chest venous pressure and in preventing reflux towards the brain. PMID- 21287974 TI - Use of chitosan scaffolds for repairing rat sciatic nerve defects. AB - Neurotmesis must be surgically treated by direct end-to-end suture of the two nerve stumps or by a nerve graft harvested from elsewhere in the body in case of tissue loss. To avoid secondary damage due to harvesting of the nerve graft, a tube-guide can be used to bridge the nerve gap. Previously, our group developed and tested hybrid chitosan membranes for peripheral nerve tubulization and showed that freeze-dried chitosan type III membranes were particularly effective for improving peripheral nerve functional recovery after axonotmesis. Chitosan type III membranes have about 110 microm pores and about 90% of porosity, due to the employment of freeze-drying technique. The present study aimed to verify if chitosan type III membranes can be successfully used also for improving peripheral nerve functional recovery after neurotmesis of the rat sciatic nerve. Sasco Sprague-Dawley adult rats were divided into 6 groups: Group 1: end-to-end neurorrhaphy enwrapped by chitosan membrane type III (End-to-EndChitll); Group 2: 10mm-nerve gap bridged by an autologous nerve graft enwrapped by chitosan membrane type III (Graf180degreeChitIII); Group 3: 10 mm-nerve gap bridged by chitosan type III tube-guides (GapChitIII); These 3 experimental groups were compared with 3 control groups, respectively: Group 4: 10 mm-nerve gap bridged by an autologous nerve graft (Graft180degree); Group 5: 10 mm-nerve gap bridged by PLGA 90:10 tube-guides (PLGA); Group 6: end-to-end neurorrhaphy alone (End-to End). Motor and sensory functional recovery were evaluated throughout a healing period of 20 weeks using extensor postural thrust (EPT), withdrawal reflex latency (WRL) and ankle kinematics. Regenerated nerves withdrawn at the end of the experiment were analysed histologically. Results showed that nerve regeneration was successful in all experimental and control groups and that chitosan type III tubulization induced a significantly better nerve regeneration and functional recovery in comparison to PLGA tubulization control. Further investigation is needed to explore the mechanisms at the basis of the positive effects of chitosan type III on axonal regeneration. PMID- 21287975 TI - Modifications of atrial natriuretic peptide and vasopressin peptides in the rat hypothalamic supraoptic nucleus during resistance training. AB - Many studies have demonstrated the involvement of atrial natriuretic peptide (ANP) and vasopressin (VP) in the homeostasis of body fluids, but few studies have regarded the hypothalamic magnocellular neurosecretory system during physical exercises. The aim of the present immunohistochemical work is to study the activity of ANP and VP secreting neurons of the hypothalamic supraoptic nucleus during and after resistance training. The study was carried out in Wistar rats trained by a physical resistance-type exercise, using a rung ladder and a varying load fastened to the tail of each rat; the exercise lasted 20 min everyday for periods of 15, 30 and 45 days. Animal groups were sacrificed at the end of each training period and one group was sacrificed after 60 days from the beginning of training, i.e.15 days after completing a 45 day training. The results show that ANP and VP-immunopositivity is at first lesser in the trained rats than in the corresponding controls and then increases from the 15th to the 45th day of training; the increase of the immunopositivity in the trained rats indicates a decreased degranulation of the neurons. The comparison between VP and ANP-immunopositivity suggests that in the early phase of training VP-release in the bloodstream is higher than ANP-release, therefore the antidiuretic action of VP is expected to prevail on ANP action and an electrolyte unbalance may occur. PMID- 21287976 TI - Relationship between body mass index and the development of cranium in Arak newborns (central Iran). AB - Adaptive responses which occur under changing environment enable a species existence during long periods of time. This study aimed at investigating the relationship between body mass index (BMI and characteristic of brain in newborns. This study was undertaken on 1800 healthy live born singletons (822 males and 978 females) routinely delivered at the Gynecology Hospital of Arak Medical Sciences University between 2002 and 2003. Anthropometric data were analyzed by linear regression and regression analysis using SPSS software for Windows (version 15). The results showed that BMI (body mass index) was significantly associated with cerebral index upon adjusting for sex. The strict correlation between BMI and cerebral index suggests that newborn fat deposition may have increased to allow for high myelination in the human brain. The extraordinary fat storage in newborns would be a consequence of the selection for larger brain size in hominid evolution. PMID- 21287977 TI - Anatomic variations of superficial peroneal nerve: clinical implications of a cadaver study. AB - Superficial peroneal nerve and its branches are frequently at risk for iatrogenic damage. Although different studies on anatomical variations of superficial peroneal nerve are available in the medical literature, such reports are rare from India. Hence the present study was undertaken on Indian population. A total of 60 specimens of inferior extremities from 30 properly embalmed and formalin fixed cadavers were dissected and examined for the location and course of the superficial peroneal nerve including number, level, course and distributions of branches. The superficial peroneal nerve in 28.3% specimens was located in the anterior compartment of the leg. In 8.3% specimens the superficial peroneal nerve branched before piercing between the peroneus longus and extensor digitorum longus muscle whereas in 11.7% specimens it branched after piercing the aforementioned muscles and before piercing the deep fascia. In 41 out of 60 specimens the sensory division of superficial peroneal nerve branched into the medial dorsal cutaneous nerve and intermediate dorsal cutaneous nerve distal to its emergence from the deep fascia and proximal to its relation to the extensor retinaculum. In 20 out of 60 specimens the accessory deep peroneal nerve, an additional branch from the sensory division of superficial peroneal nerve, through its course in the anterior compartment of the leg passed deep to the extensor retinaculum and supplied the ankle and the dorsum of foot. Hopefully the present study will help in minimizing iatrogenic damage to the superficial peroneal nerve and its branches while performing arthroscopy, local anesthetic block, surgical approach to the fibula, open reduction and internal fixation of lateral malleolar fractures, application of external fixators, elevation of a fasciocutaneous or fibular flaps for grafting, surgical decompression of neurovascular structures, or miscellaneous surgery on leg, foot and ankle. PMID- 21287978 TI - Anatomy of the septomarginal trabecula in goat hearts. AB - Our aim in this study was to examine the right septomarginal trabecula of goats regarding the frequency, origin course of the septal and free component, attachment to the papillaris magnus muscle and size . The material used consisted in 32 hearts from non-pedigree goats of both sexes, preserved in 10% formalin. The right septomarginal trabecula was present in all hearts. It could also present a prominence in the form of a cord in the septum before detaching and going towards the wall or the papillary muscle. We called this a septal component and found it in 69% of all hearts studied. In the remaining specimens, the exit of the septomarginal trabecula was abrupt, without presenting a septal component. It could be attached solely to the papillaris magnus muscle or to the papillary muscle and the ventricle wall, originated in the cranial third of the septum, and was attached to the middle third of the papillary muscle or its caudal third. Its free part, from the septum to the papillaris magnus muscle, ranged in length from 1.3 cm to 2.6 cm. The mean value was 1.7 cm, and the most frequent values were 1.9 and 1.5 cm. In conclusion, in goats, the septomarginal trabecula is a constant and invariable structure. PMID- 21287979 TI - Lung morphology: a cadaver study in Indian population. AB - Knowledge of anatomical variations of lung is required by clinicians for accurate interpretation on different imaging techniques. During routine dissection in the anatomy department, a single lung extending uniformly throughout the thoracic cavity was detected in a 35 year old male cadaver. Thereafter a cadaver study was undertaken to report the prevalence of variations involving number, lobes and fissures of lung in Indian population. The thoracic cavities of 29 properly embalmed cadavers containing lungs were dissected and morphological features like number, fissures and lobes were observed for the presence of anatomical variations. The aforementioned single lung cadaver had associated dextrocardia. One accessory lobe on the inferior aspect was observed in 27.2% of lungs studied, whereas supernumerary fissures which were most common in right lower lobe were detected in 35% of lung specimens. The transverse fissure on the right lung was absent in 7.1% and incomplete in 50% of lung specimens. In the right lung, the oblique fissure was absent in 7.1% and incomplete in 39.3% of specimens. The oblique fissure was absent in 10.7% and incomplete in 35.7% of left lungs. Comparative analysis of our work with previous data in the literature suggest that different studies performed on radiological images reported greater prevalence of incomplete or absent pulmonary fissures as compared to various cadaver studies. Our aforementioned findings regarding the variations seen in fissures and lobes of both lungs were different from previous studies. Variations of lung anatomy are important for both the diagnosis and treatment of various diseases involving all the domains of medicine. PMID- 21287980 TI - A rare case of left additional renal artery in a Nigerian goat. AB - The report of the occurrence of additional renal arteries in domestic animals is rare in the literature. We report a case of an additional renal artery in the left kidney found in a Red Sokoto goat cadaver. The additional renal artery originated from the abdominal aorta 3.80 cm cranial to the origin of the main renal artery. The additional renal artery was relatively long, being 6.30 cm from its origin to the cranial pole region of the kidney where it supplied the kidney. This to the best of our knowledge is the first report in the literature indexed in the Medline of an additional renal artery in a goat. PMID- 21287981 TI - Public health. The root of the problem. PMID- 21287982 TI - alpha-Tocopherol-loaded Polycaprolactone (PCL) nanoparticles as a heat-activated oxygen scavenger. AB - A nanoencapsulation technique was applied to an oxygen-scavenging system, and thermal processing was investigated as an activator to trigger the oxygen scavenging reaction. alpha-Tocopherol-loaded polycaprolactone (PCL) nanoparticles (NPs) were prepared using an oil-in-water emulsion solvent evaporation method. The influences of iron(II) chloride, water, and thermal processing on the oxygen scavenging capability were investigated. NPs without iron(II) chloride, moisture, and thermal processing had no oxygen-scavenging effect. However, the oxygen content (%) in the cup headspace of 20.9% decreased to 20.4% when the oxygen scavenging system contained NPs, water, and iron(II) chloride. The oxygen content (%) decreased further to 19.5% when water was eliminated from the mixture. In this research, NPs and iron(II) chloride with thermal processing had an oxygen scavenging capacity of 6.44 cm3 of O2/g and an oxygen-scavenging rate of 0.21 cm3 of O2 g(-1) day(-1). Results indicated that NPs and iron(II) chloride in an oxygen-scavenging system can be used as a heat-activated oxygen scavenger. PMID- 21287983 TI - Measuring single small molecule binding via rupture forces of a split aptamer. AB - The rupture force of a split (bipartite) aptamer that forms binding pockets for adenosine monophosphate (AMP) was measured by atomic force spectroscopy. Changes in the rupture force were observed in the presence of AMP, while this effect was absent when mutant aptamers or inosine were used. Thus, changes in the rupture force were a direct consequence of specific binding of AMP to the split aptamer. The split aptamer concept allowed the detection of nonlabeled AMP and enabled us to determine the dissociation constant on a single-molecule level. PMID- 21287985 TI - Synthesis of docosasaccharide arabinan motif of mycobacterial cell wall. AB - Mycobacterial arabinan is a common constituent of both arabinogalactan (AG) and lipoarabinomannan (LAM). In this study, synthesis of beta-Araf containing common arabinan docosasaccharide motif (22 Araf monomer units) of mycobacterial cell wall was achieved. Our synthetic strategy toward arabinan involves (1) the stereoselective beta-arabinofuranosylation using both 3,5-O-TIPDS-protected and NAP-protected arabinofuranosyl donors for straightforward intermolecular glycosylation and intramolecular aglycon delivery (IAD), respectively, and (2) the convergent fragment coupling with branched fragments at the linear sequence using thioglycoside donor obtained from the corresponding acetonide at the reducing terminal of each fragment through a three-step procedure. Because the acetonide at the reducing terminal of all fragments would be converted to thioglycoside as the glycosyl donor, and mainly Bn ether protections were used, our strategy will be readily applicable to the synthesis of more complex arabinan, arabinogalactan, and arabinomycolate derived from mycobacterial CWS. PMID- 21287984 TI - Paramagnetic-based NMR restraints lift residual dipolar coupling degeneracy in multidomain detergent-solubilized membrane proteins. AB - Residual dipolar couplings (RDCs) are widely used as orientation-dependent NMR restraints to improve the resolution of the NMR conformational ensemble of biomacromolecules and define the relative orientation of multidomain proteins and protein complexes. However, the interpretation of RDCs is complicated by the intrinsic degeneracy of analytical solutions and protein dynamics that lead to ill-defined orientations of the structural domains (ghost orientations). Here, we illustrate how restraints from paramagnetic relaxation enhancement (PRE) experiments lift the orientational ambiguity of multidomain membrane proteins solubilized in detergent micelles. We tested this approach on monomeric phospholamban (PLN), a 52-residue membrane protein, which is composed of two helical domains connected by a flexible loop. We show that the combination of classical solution NMR restraints (NOEs and dihedral angles) with RDC and PRE constraints resolves topological ambiguities, improving the convergence of the PLN structural ensemble and giving the depth of insertion of the protein within the micelle. The combination of RDCs with PREs will be necessary for improving the accuracy and precision of membrane protein conformational ensembles, where three-dimensional structures are dictated by interactions with the membrane mimicking environment rather than compact tertiary folds common in globular proteins. PMID- 21287986 TI - A structurally characterized nitrous oxide complex of vanadium. AB - Nitrous oxide (N(2)O), a widespread greenhouse gas, is a thermodynamically potent and environmentally green oxidant that is an attractive target for activation by metal centers. However, N(2)O remains underutilized owing to its high kinetic stability, and the poor ligand properties of this molecule have made well characterized metal-N(2)O complexes a rarity. We now report a vanadium-pyrrolide system that reversibly binds N(2)O at room temperature and provide the first single-crystal X-ray structure of such a complex. Further characterization by vibrational spectroscopy and DFT calculations strongly favor assignment as a linear, N-bound metal-N(2)O complex. PMID- 21287987 TI - Interaction between casein micelles and whey protein/kappa-casein complexes during renneting of heat-treated reconstituted skim milk powder and casein micelle/serum mixtures. AB - Casein micelles were separated from unheated reconstituted skim milk powder (RSMP) and were resuspended in the serum of RSMP that had been heated, with and without dialysis of this serum against unheated RSMP. Using size-exclusion chromatography, it was found that the soluble complexes of whey protein (WP) with kappa-casein in the serum of the heated milk bind progressively to unheated casein micelles during renneting, even prior to the onset of clotting. Similar trends were noted when casein micelles from RSMP heated at pH values of 6.7, 7.1, or 6.3, each with different amounts of WP coating the micelles, were renneted in the presence of soluble WP/kappa-casein complexes. No matter what was the initial load of micelle-bound WP complexes, all micelle types were capable of binding additional serum protein complexes during renneting. However, it is not clear that this binding of WP/kappa-casein complexes to the micellar surface is a direct cause of the impaired rennet clotting of the RSMP. PMID- 21287988 TI - Glutathione S-transferases of italian ryegrass (Lolium multiflorum): activity toward some chemicals, safener modulation and persistence of atrazine and fluorodifen in the shoots. AB - Many varieties of Italian ryegrass (Lolium multiflorum) show resistance to herbicides; while this ability was frequently attributed to alterations in the target sites of the herbicide's action of the plant or to an efficient oxidative metabolism, little attention has been paid to glutathione S-transferases (GSTs), which are a family of detoxifying enzymes involved in the inactivation of many toxic compounds. To investigate the role of GSTs, seedlings of Italian ryegrass were treated with four herbicides (atrazine, fenoxaprop-ethyl, fluorodifen, metolachlor) and a safener (fenchlorazol-ethyl). All the treatments were well tolerated by the plant, with very low decreases in terms of fresh weight and length of shoots. Regarding GST activity, the chemicals generally determined significant increases in the above enzyme activity toward the model-substrate CDNB. Therefore, the herbicides most GST inducing and the safener were tested themselves as enzyme substrates: constitutive GST activities toward atrazine, fluorodifen and fenchlorazol-ethyl were found, and, in addition, these activities were significantly induced by the safener. Following these results, a HPLC procedure was standardized in order to investigate the persistence of atrazine and fluorodifen in the seedlings of Italian ryegrass and the effect on this of the safener. It was found that the residual amounts of the two herbicides in the shoots were significantly reduced following the safener treatments. PMID- 21287989 TI - Flavonoid Glycosides from the Seeds of Litchi chinensis. AB - Seven flavonoid glycosides, including one new (1) and five previously uncharacterized (3-7), were obtained from the seeds of lychee ( Litchi chinensis Sonn. cv. Heiye) by means of repetitive column chromatography and high performance liquid chromatography (HPLC) preparation. They were identified as litchioside D (1), (-)-pinocembrin 7-O-neohesperidoside (2), (-)-pinocembrin 7-O rutinoside (3), taxifolin 4'-O-beta-d-glucopyranoside (4), kaempferol 7-O neohesperidoside (5), tamarixetin 3-O-rutinoside (6), and phlorizin (7) on the basis of spectroscopic analysis and comparison of their data to the values reported in the literatures. Among them, compounds 1, 4, and 5 showed in vitro antitumor activity against A549, LAC, Hep-G2, and HeLa cell lines in the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay. PMID- 21287990 TI - Effect of exogenous gamma-aminobutyric acid treatment on proline accumulation and chilling injury in peach fruit after long-term cold storage. AB - The effect of exogenous gamma-aminobutyric acid (GABA) on chilling injury of peach fruit was investigated. Freshly harvested peaches were treated with 1, 5, or 10 mM GABA at 20 degrees C for 10 min and then stored at 1 degrees C for up to 5 weeks. The results showed that all of the GABA treatments could reduce chilling injury of peach fruit with 5 mM being the most effective concentration. GABA treatment significantly enhanced the accumulation of endogenous GABA and proline, which resulted from the increased activities of glutamate decarboxylase, Delta(1)-pyrroline-5-carboxylate synthetase, and ornithine delta-aminotransferase and decreased proline dehydrogenase activity. Our results revealed that GABA treatment may be a useful technique to alleviate chilling injury in cold-stored peach fruit, and the reduction in chilling by GABA may be due to the induction of endogenous GABA and proline accumulation. These data are the first evidence that exogenous GABA induced chilling tolerance in postharvest horticultural products. PMID- 21287991 TI - Design, synthesis, pharmacological evaluation, and structure-activity study of novel endomorphin analogues with multiple structural modifications. AB - This study reports on new proteolytically stable, pharmacologically active endomorphin analogues, incorporating Dmt(1), Achc(2), pFPhe(4), or betaMePhe(4) unnatural amino acids. Consistent with earlier results, it was found that the analogues carrying Dmt(1) and Achc(2) residues displayed the highest MU-opioid receptor affinities, depending upon the configuration of the incorporated Achc(2). Combination of such derivatives with pFPhe(4) or betaMePhe(4) yielded further compounds with variable binding potencies. Combined application of Dmt(1), cis-(1S,2R)Achc(2), and pFPhe(4) (compound 16) resulted in the most potent analogue. Ligand stimulated [(35)S]GTPgammaS binding assays indicated that the analogues retained their agonist activities and opioid receptor specificities. NMR and molecular modeling studies of the analogues containing betaMePhe(4) or pFPhe(4) confirmed the predominance of bent structures, however, it is apparent that bent structures are energetically more favored than random/extended structures for all studied compounds. PMID- 21287992 TI - Ambient carbon dioxide capture by boron-rich boron nitride nanotube. AB - Carbon dioxides (CO(2)) emitted from large-scale coal-fired power stations or industrial manufacturing plants have to be properly captured to minimize environmental side effects. From results of ab initio calculations using plane waves [PAW-PBE] and localized atomic orbitals [ONIOM(wB97X-D/6-31G*:AM1)], we report strong CO(2) adsorption on boron antisite (B(N)) in boron-rich boron nitride nanotube (BNNT). We have identified two adsorption states: (1) A linear CO(2) molecule is physically adsorbed on the B(N), showing electron donation from the CO(2) lone-pair states to the B(N) double-acceptor state, and (2) the physisorbed CO(2) undergoes a carboxylate-like structural distortion and C?O pi bond breaking due to electron back-donation from B(N) to CO(2). The CO(2) chemisorption energy on B(N) is almost independent of tube diameter and, more importantly, higher than the standard free energy of gaseous CO(2) at room temperature. This implies that boron-rich BNNT could capture CO(2) effectively at ambient conditions. PMID- 21287993 TI - Surface and charge transport characterization of polyaniline-cellulose acetate composite membranes. AB - This study elucidates the charge transport processes of polyaniline (PANI) composite membranes and correlates them to the PANI deposition site and the extent of PANI surface layering on the base microporous membranes. PANI was deposited either as a surface layer or inside the pores of cellulose acetate microporous membranes using various in situ chemical polymerization techniques. The extent of PANI layering at the surface of the base membrane and its oxidation and doping states were characterized using Fourier transform infrared (FTIR) spectroscopy and X-ray photoelectron spectroscopy (XPS). PANI deposition on the membranes showed a strong dependence on the polymerization technique and polymerization time within a single technique. In XPS, the deconvolution of C 1s and N 1s core-level spectra of the composite membranes was used to quantify the extent of PANI layering at the surface along with its oxidation and doping states. PANI incompletely covered the surface of the base microporous membranes for all the employed techniques. However, the extent of the layering increased with the polymerization time in a particular technique. The charge transport through the bulk membrane and charge transfer at the membrane/electrode interface were studied by electrochemical impedance spectroscopy (EIS). The data were analyzed using the equivalent circuit modeling technique. The modeling parameters revealed that PANI deposition at the surface enhanced the interfacial charge transfer but the process depended on the extent of the surface coverage of the membrane. In addition, the charge transport in the bulk membrane depended on the PANI intercalation level, which varied depending on the polymerization technique employed. In addition, the EIS of electrolyte-soaked membranes was also conducted to evaluate the effects of PANI deposition site on charge transport in the presence of an electrolyte. PANI layering at the pore walls of the base membrane from diaphragmatic polymerization in a two-compartment cell showed that charge transport processes were strongly affected by the interaction of the electrolyte with the PANI layer at the pore surface. This study successfully showed the dependence of charge transport mechanisms of PANI composite membranes on the PANI deposition site and extent of surface layering at the membrane surface. PMID- 21287994 TI - From high-temperature orientationally disordered mixed crystals to low temperature complex formation in the two-component system (CH3)3CBr + Cl3CBr. AB - The phase diagram of the two-component systems (CH(3))(3)CBr + Cl(3)CBr has been experimentally determined by means of differential scanning calorimetry and X-ray powder diffraction techniques from the low-temperature ordered phases to the liquid state. Before melting, both components have the same orientationally disordered (OD) face-centered cubic (FCC) and rhombohedral (R) phases, and the two-phase equilibria [FCC + L] and [R + FCC] are accounted for by means of the existence of an isomorphic relationship between the OD phases of pure compounds. The thermodynamic assessment of such equilibria enables us to get the excess properties of the involved OD phases and to rationalize the existence of a maximum and a minimum in the [R + FCC] equilibrium on the basis of the contribution of the entropic term in the excess Gibbs energy function. At low temperature, two complexes, (CH(3))(3)CBr:Cl(3)CBr (1:1) and (CH(3))(3)CBr:2Cl(3)CBr (1:2), appear. The structures of 1:1 and 1:2 complexes have been determined to be monoclinic (P2(1)/n, c, Z = 4) and hexagonal (P6(3), Z = 6). Within both "ordered" structures, the Cl(3)CBr entities of the asymmetric unit were found to be disordered so that sites have fractional occupancies of 0.75 and 0.25 for Cl and Br atoms, in the same way that it occurs for the low temperature monoclinic (C2/c, Z = 32) phase of Cl(3)CBr. Finally, the existence of complexes is connected with the special intermolecular interactions appearing between a methyl group and a halogen, as previously inferred by Calvet et al. [T. Calvet et al. J. Chem. Phys. 1999, 110, 4841]. PMID- 21287995 TI - Atomic scale determination of enzyme flexibility and active site stability through static modes: case of dihydrofolate reductase. AB - A Static Mode approach is used to screen the biomechanical properties of DHFR. In this approach, a specific external stimulus may be designed at the atomic scale granularity to arrive at a proper molecular mechanism. In this frame, we address the issues related to the overall molecular flexibility versus loop motions and versus enzymatic activity. We show that backbone motions are particularly important to ensure DHFR domain communication and notably highlight the role of a alpha-helix in Met20 loop motion. We also investigate the active site flexibility in different bound states. Whereas in the occluded conformation the Met20 loop is highly flexible, in the closed conformation backbone motions are no longer significant, the Met20 loop is rigidified by new intra- and intermolecular weak bonds, which stabilizes the complex and promotes the hydride transfer. Finally, while various simulations, including I14 V and I14A mutations, confirm that Ile14 is a key residue in catalytic activity, we isolate and characterize at the atomic scale how a specific intraresidue chemical group makes it possible to assist ligand positioning, to direct the nicotinamide ring toward the folate ring. PMID- 21287996 TI - Two glass transitions and secondary relaxations of methyltetrahydrofuran in a binary mixture. AB - We investigate the molecular dynamics in the binary glass forming system methyltetrahydrofuran (M-THF) and tristyrene. Although the components are miscible in the full concentration and temperature range, two glass transitions can clearly be distinguished in differential scanning calorimetry. We selectively probe the reorientational dynamics of M-THF and tristyrene by means of dielectric spectroscopy and depolarized dynamic light scattering, respectively. While, apart from the observed plasticizer effect, the motion of the larger molecules remains almost unchanged, it is shown that the smaller M-THF molecules take part in both glass transitions. Moreover, below the upper T(g) of the mixture, the remaining mobile M-THF molecules clearly show confinement effects in their relaxation behavior. In order to elucidate the nature of the observed secondary relaxation processes, we first characterize the influence of the methyl group of M-THF on the dynamics in the mixtures by comparing the results obtained so far with the relaxation behavior observed in blends of THF and tristyrene. Finally, we employ (2)H NMR spectroscopy to clarify the nature of the secondary relaxations of THF d(8) in the latter mixtures and conclude on the basis of the NMR and dielectric results that the high-frequency wing observed in neat M-THF appears as a genuine Johari-Goldstein beta-relaxation in the mixtures, whereas the faster secondary process is due to internal degrees of freedom of the nonrigid THF ring. PMID- 21287997 TI - Entropy-enthalpy compensation in chemical reactions and adsorption: an exactly solvable model. AB - The free energies of reaction or activation for many systems respond in a common fashion to a perturbing parameter, such as the concentration of an "inert" additive. Arrhenius plots as a function of the perturbing parameter display a "'compensation temperature" at which the free energy appears to be independent of the perturber, an entropy-enthalpy compensation process. Thus, as the perturber's concentration varies, Arrhenius plots of the rate constant or equilibrium constant exhibit a rotation about the fixed compensation temperature. While this (isokinetic/isoequilibrium) component of the phenomenon of entropy-enthalpy compensation appears in a huge number of situations of relevance to chemistry, biology, and materials science, statistical mechanical descriptions have been almost completely lacking. We provide the general statistical mechanical basis for solvent induced isokinetic/isoequilibrium entropy-enthalpy compensation in chemical reactions and adsorption, understanding that can be used to control of rate processes and binding constants in diverse applications. The general behavior is illustrated with an analytical solution for the dilute gas limit. PMID- 21287998 TI - Correlation between cellular localization and binding preference to RNA, DNA, and phospholipid membrane for luminescent ruthenium(II) complexes. AB - Because of their unique photophysical properties, sensitively depending on environment, ruthenium dipyridophenazine (dppz) complexes are interesting as probes for cellular imaging with fluorescence microscopy. Here three complexes derivatized with alkyl ether chains of varied length, which exhibit distinctly different cellular staining patterns by confocal laser scanning microscopy, are studied regarding their binding preference for rRNA compared with calf thymus DNA (ct-DNA) and phospholipid membranes. Co-staining with commercial RNA and membrane specific dyes shows that whereas the least lipophilic complex exclusively stains DNA inside the nucleus, the most lipophilic complex preferentially stains membrane-rich parts of the cell. Interestingly, only the intermediate lipophilic complex shows intense staining of the RNA-rich nucleoli. The intracellular localizations of the probes correlate with their binding preferences concluded from spectroscopy measurements. PMID- 21287999 TI - Multiplexed optical operation of distributed nanoelectromechanical systems arrays. AB - We report a versatile all optical technique to excite and read-out a distributed nanoelectromechanical systems (NEMS) array. The NEMS array is driven by a distributed, intensity modulated optical pump through the photothermal effect. The ensuing vibrational response of the array is multiplexed onto a single probe beam in the form of a high frequency phase modulation. The phase modulation is optically down converted to a low frequency intensity modulation using an adaptive full-field interferometer, and subsequently detected using a CCD array. Rapid and single step mechanical characterization of ~44 nominally identical high frequency resonators is demonstrated. The technique may enable sensitivity improvements over single NEMS resonators by averaging signals coming from a multitude of devices in the array. In addition, the diffraction limited spatial resolution may allow for position-dependent read-out of NEMS sensor chips for sensing multiple analytes or spatially inhomogeneous forces. PMID- 21288000 TI - Light-driven wettability changes on a photoresponsive electrospun mat. AB - Novel nanofibers of biodegradable polycaprolactone (PCL) modified with light responsive azobenzene were prepared by electrospinning upon a facile one-pot reaction. The surface chemistry of the nanofibers was probed by X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS). Both XPS and ToF-SIMS spectra proved the successful conjugation of azobenzene with PCL. ToF-SIMS not only enabled chemical mapping but also provided morphology information, supplementary to scanning electron microscopy (SEM). The large, reversible, and light-responsive wettability changes of the functional fibrous surfaces were further demonstrated using UV-vis spectroscopy and contact angle (CA) measurements. PMID- 21288001 TI - Optically transparent recombinant silk-elastinlike protein polymer films. AB - Recombinant protein polymers, evaluated extensively as biomaterials for applications in drug delivery and tissue engineering, are rarely reported as being optically transparent. Here we report the notable optical transparency of films composed of a genetically engineered silk-elastinlike protein polymer SELP 47K. SELP-47K films of 100 MUm in thickness display a transmittance of 93% in the wavelength range of 350-800 nm. While covalent cross-linking of SELP-47K via glutaraldehyde decreases its transmittance to 77% at the wavelength of 800 nm, noncovalent cross-linking using methanol slightly increases it to 95%. Non- and covalent cross-linking of SELP-47K films also influences their secondary structures and water contents. Cell viability and proliferation analyses further reveal the excellent cytocompatibility of both non- and covalently cross-linked SELP-47K films. The combination of high optical transparency and cytocompatibility of SELP-47K films, together with their previously reported outstanding mechanical properties, suggests that this protein polymer may be useful in unique, new biomedical applications. PMID- 21288003 TI - Hydrophobic, aromatic, and electrostatic interactions play a central role in amyloid fibril formation and stability. AB - Amyloid-like fibrous crystals formed by the peptide KFFEAAAKKFFE have been previously characterized and provide an ideal model system to examine the importance of specific interactions by introducing specific substitutions. We find that the removal of any phenylalanine residue completely abrogates assembly ability, while charged residues modulate interactions within the structure resulting in alternative fibrillar morphologies. X-ray fiber diffraction analysis reveals that the essential backbone packing of the peptide molecules is maintained, while small changes accommodate differences in side chain size in the variants. We conclude that even very short peptides are adaptable and add to the growing knowledge regarding amyloid polymorphisms. Additionally, this work impacts on our understanding of the importance of residue composition for amyloidogenic peptides, in particular the roles of electrostatic, aromatic, and hydrophobic interactions in amyloid assembly. PMID- 21288002 TI - Structure and mechanisms of lysine methylation recognition by the chromodomain in gene transcription. AB - Histone methylation recognition is accomplished by a number of evolutionarily conserved protein domains, including those belonging to the methylated lysine binding Royal family of structural folds. One well-known member of the Royal family, the chromodomain, is found in the HP1/chromobox and CHD subfamilies of proteins, in addition to a small number of other proteins that are involved in chromatin remodeling and gene transcriptional silencing. Here we discuss the structure and function of the chromodomain within these proteins as methylated histone lysine binders and how the functions of these chromodomains can be modulated by additional post-translational modifications or binding to nucleic acids. PMID- 21288004 TI - Interactions of nonprotic organic solvents with [val5]angiotensin in water. AB - Intermolecular solvent-solute nuclear Overhauser effects have been used to explore interactions of the organic component of acetonitrile-water, acetone water, and dimethyl sulfoxide-water mixtures with the peptide hormone [val(5)]angiotensin. As reported by the NOEs, many cross relaxation terms for interactions of these organic cosolvents are adequately accounted for using a hard spheres interaction model in which encounters of peptide and cosolvent molecules take place by mutual diffusion. However, there are indications of localized solvent-peptide interactions that are not well described by this model. In dimethyl sulfoxide-water at 0 degrees C, organic solvent near the C-terminal Phe8 residue and the Val3 residue produce strongly enhanced cross-relaxation terms. NOEs for all peptide N-H protons and the protons of the Tyr4 aromatic ring were significantly more positive than expected in 33% acetone-water (v/v) at 0 degrees C, while those for most side-chain protons were close to predictions of the hard sphere model. All peptide-organic solvent NOEs in 35% acetonitrile water (v/v) at 0 degrees C are consistent with the hard spheres interaction model. PMID- 21288005 TI - Diphenylanthracene macrocylces from reductive zirconocene coupling: on the edge of steric overload. AB - Trimeric diphenylanthracene macrocycles were synthesized via the zirconocene mediated coupling of 9,10-bis-[4-trimethylsilyl(ethynyl)phenyl]anthracene. The macrocycles feature a strained architecture due to orientation of the anthracene units into the plane of the macrocycle. The demetalated cyclophane exhibits a considerably higher flexibility in solution, while the zirconocene-containing macrocycle is quite rigid. PMID- 21288006 TI - Planar-chiral macrocyclic host pillar[5]arene: no rotation of units and isolation of enantiomers by introducing bulky substituents. AB - Enantiomers of bulky percyclohexylmethyl-substituted pillar[5]arene (Cy-C1 Pillar) were able to be separated by chiral column chromatography, and the separated enantiomers did not racemize. Even though modified with the bulky cyclohexylmethyl-substituents at both rims, Cy-C1-Pillar was able to capture a guest molecule. PMID- 21288007 TI - Highly enantioselective synthesis of polysubstituted tetrahydroquinolines via organocatalytic Michael/Aza-Henry tandem reactions. AB - Highly enantioselective chiral bifunctional thiourea catalyzed asymmetric tandem reactions for synthesis of substituted tetrahydroquinolines are described. Substituted tetrahydroquinolines were given in good yields (up to 98%), high enantioselectivities (up to >99% ee), and diastereoselectivities (up to 20:1 dr). PMID- 21288008 TI - Copper catalyzed C-H functionalization for direct Mannich reactions. AB - A protocol for a practical and direct addition of alpha- and gamma-alkyl azaarenes to N-sulfonyl aldimines has been developed. Copper salts act as efficient Lewis acid catalysts for direct Mannich-type reactions providing a mild and fast access to various functionalized heterocycles. PMID- 21288009 TI - Catalytic enantioselective conjugate allylation of unsaturated methylidene ketones. AB - The use of unsaturated methylidene ketones in catalytic conjugate allylations allows a significant expansion in substrate scope and, with appropriate chiral ligands, occurs in a highly enantioselective fashion. PMID- 21288010 TI - Ruthenium-catalyzed regioselective [2 + 2 + 2] cyclotrimerization of trifluoromethyl group substituted internal alkynes. AB - It found that the Ru(3)(CO)(12) coordinated with 2 (diphenylphosphino)benzonitrile (2-DPPBN) to effectively catalyze the [2 + 2 + 2] cyclotrimerization of the trifluoromethyl group substituted internal alkynes in high yields with up to >98% regioselectivity. Isolation of a ruthenacyclopentadiene was successful and confirmed that the complex is a reaction intermediate. PMID- 21288011 TI - Transfer of chirality by the use of an all carbon tether. AB - Methylketone side chains can be used to direct the creation of one or more chiral centers, including quaternary centers, by exploiting the ability of the radical xanthate transfer process to mediate six-membered ring formation. PMID- 21288012 TI - Enhanced binding of apolipoprotein A-I variants associated with hypertriglyceridemia to triglyceride-rich particles. AB - Hypertriglyceridemia (HTG) is a common lipid abnormality in humans. However, its etiology remains largely unknown. It was shown that severe HTG can be induced in mice by overexpression of wild-type (WT) apolipoprotein E (apoE) or specific apoA I mutants. Certain mutations in apoE4 were found to affect plasma triglyceride (TG) levels in mice overexpressing the protein. HTG appeared to positively correlate with the ability of the apoE4 variants to bind to TG-rich particles, protein destabilization, and the exposure of protein hydrophobic surface in solution. Here, we propose that the apoA-I mutations that cause HTG may also lead to changes in the conformation and stability that promote binding of apoA-I to TG rich lipoproteins. To test this hypothesis, we studied binding to TG-rich emulsion and biophysical properties of the apoA-I mutants that induce HTG, apoA I[E110A/E111A] and apoA-I[Delta(61-78)], and compared them to those of WT apoA-I and another apoA-I mutant, apoA-I[Delta(89-99)], that does not induce HTG but causes hypercholesterolemia in mice. We found that the apoA-I[E110A/E111A] and apoA-I[Delta(61-78)] mutations lead to enhanced binding of apoA-I to TG-rich particles, destabilization, and greater exposure of the hydrophobic surface of the protein. The apoA-I[Delta(89-99)] mutant did not show enhanced binding to the emulsion or a more exposed hydrophobic surface. Thus, like apoE4, the apoA-I variants that cause HTG in mice have the altered conformation and stability that facilitate their binding to TG-rich lipoproteins and thereby may lead to the reduced level of lipolysis of these lipoproteins. While many factors may be involved in induction of HTG, we suggest that an increased level of association of destabilized loosely folded apolipoproteins with TG-rich lipoproteins may contribute to some cases of HTG in humans. PMID- 21288014 TI - Utility of mass spectrometry in the diagnosis of prion diseases. AB - We developed a sensitive mass spectrometry-based method of quantitating the prions present in a variety of mammalian species. Calibration curves relating the area ratios of the integrated MRM signals from selected analyte peptides and their oxidized analogues to their homologous stable isotope labeled internal standards were prepared. The limit of detection (LOD) and limit of quantitation (LOQ) for the synthetic peptides from human, sheep, deer, cow, and mouse PrP were determined to be below 100 amol. Nonanalyte peptides that were characteristic of prions were included in the multiple reaction monitoring method, thereby allowing for both the quantitation and confirmation of the presence of prions in the attomole range. This method was used to quantitate the prions present in brains of hamsters or mice 5 weeks after inoculation (ic) with either four hamster adapted prion strains (139H, drowsy, 22AH, and 22CH) or four mouse-adapted prion strains (Me7, Me7-298, RML, and 79A). The prions from different brain regions of a sheep naturally infected with scrapie were quantitated. All of the rodent adapted prion strains were detectable in the asymptomatic animals. In sheep, prions were detectable in the obex, anterior portion of the cerebrum, and the nonobex/nonanterior portion of the cerebrum. This mass spectrometry-based approach can be used to quantitate and confirm the presence of prions before detectable pathology. PMID- 21288015 TI - Nanochromatography driven by the coffee ring effect. AB - The coffee ring phenomenon has long been known for its ability to concentrate particles at the rim of a dried liquid droplet, yet little is known about its particle separation capability. Here, we elucidate the physics of particle separation during coffee ring formation, which is based on a particle-size selection mechanism near the contact line of an evaporating droplet. On the basis of this mechanism, we demonstrate nanochromatography of three relevant biological entities (proteins, micro-organisms, and mammalian cells) in a liquid droplet, with a separation resolution on the order of ~100 nm and a dynamic range from ~10 nm to a few tens of micrometers. These findings have direct implications for developing low-cost technologies for disease diagnostics in resource-poor environments. PMID- 21288016 TI - Hydrochloric acid: an overlooked driver of environmental change. AB - Research on the ecosystem impacts of acidifying pollutants, and measures to control them, has focused almost exclusively on sulfur (S) and nitrogen (N) compounds. Hydrochloric acid (HCl), although emitted by coal burning, has been overlooked as a driver of ecosystem change because most of it was considered to redeposit close to emission sources rather than in remote natural ecosystems. Despite receiving little regulatory attention, measures to reduce S emissions, and changes in energy supply, have led to a 95% reduction in United Kingdom HCl emissions within 20 years. Long-term precipitation, surface water, and soil solution data suggest that the near-disappearance of HCl from deposition could account for 30-40% of chemical recovery from acidification during this time, affecting both near-source and remote areas. Because HCl is highly mobile in reducing environments, it is a more potent acidifier of wetlands than S or N, and HCl may have been the major driver of past peatland acidification. Reduced HCl loadings could therefore have affected the peatland carbon cycle, contributing to increases in dissolved organic carbon leaching to surface waters. With many regions increasingly reliant on coal for power generation, HCl should be recognized as a potentially significant constituent of resulting emissions, with distinctive ecosystem impacts. PMID- 21288017 TI - Universal method for determining electrolyte temperatures in capillary electrophoresis. AB - Temperature increase in capillary electrophoresis (CE) due to Joule heating is an inherent limitation of this powerful separation technique. Active cooling systems can decrease the temperature of a large part of the capillary but they leave "hot spots" at the capillary ends which can completely ruin some CE analyses despite their short lengths. Here, we introduce a "universal method for determining electrolyte temperatures" (UMET) that can determine temperatures in both efficiently- and inefficiently-cooled parts of the capillary. UMET can be applied to all electrolytes, as it does not involve any probe; it requires only measuring current versus voltage for different voltages and processing the data using an iterative algorithm. To demonstrate the universality of UMET, we measured temperatures for electrolytes of different ionic strengths as well as for different capillary diameters. We further propose a "simplified universal method for predicting electrolyte temperatures" (SUMET) which only requires one measurement of current and voltage (that can be completed in 1 min) and uses two empirical equations to predict temperatures in the efficiently- and inefficiently cooled parts of the capillary. The equations include several instrument-specific empirical parameters that are determined using a large set of current-voltage data obtained with UMET for a range of electrolytes and different capillaries. To demonstrate the utility of SUMET, we obtained the required data set for a Beckman MDQ CE instrument and produced all required empirical parameters that enable a user of this instrument to predict the temperature for every new experimental set in a matter of minutes. We confirmed the accuracy of SUMET by measuring the temperature-sensitive dissociation rate constant of a protein-DNA complex. We foresee that UMET will be used to produce instrument-specific empirical parameters for all CE instruments and then SUMET will be routinely used for temperature prediction in CE. PMID- 21288018 TI - Thermostable esterase 2 from Alicyclobacillus acidocaldarius as biosensor for the detection of organophosphate pesticides. AB - Pesticides are the plague of modern times, although much needed in agriculture, causing damage to the entire ecosystem, including humans. The high operative costs and the requirement of specialized personnel for pesticide detection, incentive to develop alternative solutions such as the set up of cheap, rapid, and simple to use biosensors. In this work, we evaluate the possibility to use the esterase 2 from Alicyclobacillus acidocaldarius as a biosensor for the detection of specific organophosphate pesticides. With the recent demonstration of the very high affinity of esterase 2 toward paraoxon, a more complete analysis on the detection methods in water as well as in purposely contaminated fruit juices was carried out. The inhibitory effects of a wide range of other pesticides on esterase 2 were investigated, showing a better selectivity with respect to nonspecific reaction of acethylcholinesterases, the main target of organophosphate pesticides. The applied methodology allowed one to detect 2.75 * 10(-3) ppm of neurotoxic agent, comparable to the efficiency of other acethylcholinesterase-based biosensors. Finally, a raw biosensor, based on EST2 immobilization on a nitrocellulose membrane, was devised and tested for paraoxon detection, showing longtime stability, reproducibility, and sensibility. PMID- 21288019 TI - Electrical readout of protein microarrays on regular glass slides. AB - A new approach for the electrical readout of microarrays prepared on regular glass slides, using an array of impedimetric transducers (interdigitated electrodes, IDEs) is presented in this work. Impedance detection relies on the use of a urease-labeled immunoassay scheme. Urease is able to produce an increase in conductivity by hydrolysis of the urea substrate, which is measured with the IDEs and directly related to the amount of target analyte. Unlike previous electrical microarrays, the assay does not take place on top of the transducers but on a regular glass slide, which may enable the development of compact multiplexed analytical systems with lower cost per assay. A droplet of solution with the enzymatic substrate is deposited on each transducer of the array, and the microarray is positioned at a short distance (300 MUm) so that each droplet wets one transducer and one spot of the microarray. This procedure allows reusing the transducer array for readout of a virtually unlimited number of microarrays. A microarray based on an immunoassay for the detection of a mouse generic protein in a concentration range from 0.03 to 30 MUg mL(-1) was carried out to assess the performance of the electrical readout approach. A sigmoid response with a limit of detection of 0.1 MUg mL(-1) and a dynamic range of 1 order of magnitude was obtained. A comparative study was also carried out with two well established analytical procedures. First, the urease-based immunoassay was tested in a 96 well microtiter plate using phenol red pH indicator and absorbance detection. Second, the microarray was carried out using the same target protein concentration range but applying a Cy3 label and fluorescence detection. Both assays allowed for the validation of the performance of the presented electrical readout system. PMID- 21288020 TI - Studies on the atmospheric degradation of chlorpyrifos-methyl. AB - The gas-phase atmospheric degradation of chlorpyrifos-methyl (a widely used organophosphate insecticide in Southern European regions) has been investigated at the large outdoor European Photoreactor (EUPHORE) in Valencia, Spain. Photolysis under sunlight conditions and reaction with ozone were shown to be unimportant. The rate constant for reaction of chlorpyrifos-methyl with OH radicals was measured using a conventional relative rate method with cyclohexane and n-octane employed as reference compounds with k = (4.1 +/- 0.4) * 10(-11) cm(3) molecule(-1) s(-1) at 300 +/- 5 K and atmospheric pressure. The available evidence indicates that tropospheric degradation of chlorpyrifos-methyl is mainly controlled by reaction with OH radicals and that the tropospheric lifetime is estimated to be around 3.5 h. Significant aerosol formation was observed following the reaction of chlorpyrifos-methyl with OH radicals, and the main carbon-containing products detected in the gas phase were chlorpyrifos-methyl oxone and 3,5,6-trichloro-2-pyridinol. PMID- 21288021 TI - Mercury distribution and transport across the ocean-sea-ice-atmosphere interface in the Arctic Ocean. AB - The Arctic sea-ice environment has been undergoing dramatic changes in the past decades; to which extent this will affect the deposition, fate, and effects of chemical contaminants remains virtually unknown. Here, we report the first study on the distribution and transport of mercury (Hg) across the ocean-sea-ice atmosphere interface in the Southern Beaufort Sea of the Arctic Ocean. Despite being sampled at different sites under various atmospheric and snow cover conditions, Hg concentrations in first-year ice cores were generally low and varied within a remarkably narrow range (0.5-4 ng L(-1)), with the highest concentration always in the surface granular ice layer which is characterized by enriched particle and brine pocket concentration. Atmospheric Hg depletion events appeared not to be an important factor in determining Hg concentrations in sea ice except for frost flowers and in the melt season when snowpack Hg leaches into the sea ice. The multiyear ice core showed a unique cyclic feature in the Hg profile with multiple peaks potentially corresponding to each ice growing/melting season. The highest Hg concentrations (up to 70 ng L(-1)) were found in sea-ice brine and decrease as the melt season progresses. As brine is the primary habitat for microbial communities responsible for sustaining the food web in the Arctic Ocean, the high and seasonally changing Hg concentrations in brine and its potential transformation may have a major impact on Hg uptake in Arctic marine ecosystems under a changing climate. PMID- 21288023 TI - Preparation and characterization of nanoparticles based on hydrophobic alginate derivative as carriers for sustained release of vitamin D3. AB - Hydrophobic alginate derivative was prepared by modification of alginate by acid chloride reaction using oleoyl chloride without organic solvents. The conjugate of oleoyl alginate ester (OAE) was confirmed by FT-IR and (1)H NMR. The degree of substitution (DS) of OAE was determined by (1)H NMR, and it ranged from 0.84 to 3.85. In distilled water, OAE formed self-assembled nanoparticles at low concentrations in aqueous medium, and nanoparticles retained their structural integrity both in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). The loading and release characteristics of nanoparticles based on OAE were investigated using vitamin D(3) as a model nutraceutical. As the concentration of vitamin D(3) increased, the loading capacity (LC) increased, whereas the loading efficiency (LE) decreased. Nanoparticles could release vitamin D(3) at a sustained rate in gastrointestinal fluid. These results revealed the potential of OAE nanoparticles as oral carriers for sustained release of vitamin D(3). PMID- 21288024 TI - Synthesis and characterization of highly flexible thermoplastic films from cyanoethylated corn distillers dried grains with solubles. AB - Corn distillers dried grains with solubles (DDGS) can be made into highly flexible thermoplastic films without the need for plasticizers. DDGS is an abundantly available coproduct of ethanol production that is inexpensive ($80 130/ton) compared to most of the polymers used for thermoplastic applications. In this research, oil-and-zein-free DDGS was cyanoethylated using acrylonitrile, and cyanoethylation conditions were optimized to obtain high percent weight gain of up to 42%. Cyanoethylated DDGS was characterized using (1)H NMR, FTIR, DSC, and TGA. Cyanoethylated DDGS was compression molded into thermoplastic films, and the tensile properties of the films were studied. It was found that DDGS films with elongation as high as 38% and strength of 14 MPa could be obtained without the use of any plasticizers. Alternatively, films with strength as high as 651 MPa but with relatively low elongation (2.5%) were obtained by varying the extent of cyanoethylation. This research showed that cyanoethylation could be a viable approach to develop biothermoplastics from biopolymers for applications such as packing films, extrudates, and resins for composites. PMID- 21288025 TI - Physical-chemical aspects of protein corona: relevance to in vitro and in vivo biological impacts of nanoparticles. AB - It is now clearly emerging that besides size and shape, the other primary defining element of nanoscale objects in biological media is their long-lived protein ("hard") corona. This corona may be expressed as a durable, stabilizing coating of the bare surface of nanoparticle (NP) monomers, or it may be reflected in different subpopulations of particle assemblies, each presenting a durable protein coating. Using the approach and concepts of physical chemistry, we relate studies on the composition of the protein corona at different plasma concentrations with structural data on the complexes both in situ and free from excess plasma. This enables a high degree of confidence in the meaning of the hard protein corona in a biological context. Here, we present the protein adsorption for two compositionally different NPs, namely sulfonated polystyrene and silica NPs. NP-protein complexes are characterized by differential centrifugal sedimentation, dynamic light scattering, and zeta-potential both in situ and once isolated from plasma as a function of the protein/NP surface area ratio. We then introduce a semiquantitative determination of their hard corona composition using one-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis and electrospray liquid chromatography mass spectrometry, which allows us to follow the total binding isotherms for the particles, identifying simultaneously the nature and amount of the most relevant proteins as a function of the plasma concentration. We find that the hard corona can evolve quite significantly as one passes from protein concentrations appropriate to in vitro cell studies to those present in in vivo studies, which has deep implications for in vitro-in vivo extrapolations and will require some consideration in the future. PMID- 21288026 TI - Galactoglucomannan Oligosaccharides (GGMO) from a molasses byproduct of pine ( Pinus taeda ) fiberboard production. AB - "Temulose" is the trade name for a water-soluble molasses produced on a large scale (300-400 tonnes per year) as a byproduct of the fiberboard industry. The feedstock for Temulose is predominantly a single species of pine ( Pinus taeda ) grown and harvested in stands in southeastern Texas. Because of the method of production, the molasses was predicted to consist of water-soluble hemicelluloses, mainly arabinoxylan-type and galactoglucomannan-type oligosaccharides, plus minor components of lignin, but no detailed structural study had been reported. The structure and composition of the molasses has now been deduced by a combination of MALDI-TOF mass spectrometry, size exclusion chromatography, proton and (13)C NMR techniques, and classic carbohydrate analysis. Limited acid hydrolysis released a series of galactoglucomannan oligosaccharides (GGMO) that were selectively recovered from the acid-labile arabinogalactan by precipitation with ethanol. The precipitate was named "Temulose brown sugar" because of its appearance, and is shown to consist of GGMO with a degree of polymerization (DP) from 4 to 13, with the major component being DP 5-8. The structure of these oligosaccharides is a beta-1,4-linked backbone of Man and Glc residues, with occasional alpha-1,6 branching by single galactosyl units. PMID- 21288027 TI - In vitro digestion and fermentation characteristics of temulose molasses, a coproduct of fiberboard production, and select temulose fractions using canine fecal inoculum. AB - It is of interest to discover new fermentable carbohydrate sources that function as prebiotics. This study evaluated the hydrolytic digestibility, fermentative capacity, and microbiota modulating properties of Temulose molasses, four hydrolyzed fractions of Temulose molasses, short-chain fructooligosaccharides (scFOS), and a yeast cell wall preparation (Safmannan). These substrates resisted in vitro hydrolytic digestion. Each substrate was fermented in vitro using dog fecal inoculum, and fermentation characteristics were quantified at 0 and 12 h. All Temulose molasses substrates decreased pH by at least 0.64 unit and resulted in greater (P < 0.05) butyrate and total short-chain fatty acid (SCFA) production compared to scFOS and Safmannan. Temulose molasses substrates resulted in higher (P < 0.01) or equal Bifidobacterium spp. concentrations compared to scFOS. Temulose molasses substrate and its fractions demonstrated prebiotic characteristics as indicated by low hydrolytic digestibility, high fermentability, and enhanced growth of microbiota considered to be beneficial to health. PMID- 21288028 TI - Use of Saccharomyces cerevisiae and Caenorhabditis elegans as model organisms to study the effect of cocoa polyphenols in the resistance to oxidative stress. AB - Developing functional foods to improve the quality of life for elderly people has great economic and social impact. Searching for and validating ingredients with in vivo antioxidant effects is one of the key steps in developing this kind of food. Here we describe the combined use of simple biological models and transcriptomics to define the functional intracellular molecular targets of a polyphenol-enriched cocoa powder. Cocoa powder supplemented culture medium led to increased resistance to oxidative stress, in both the budding yeast Saccharomyces cerevisiae and the nematode Caenorhabditis elegans, and, in the latter, lifespan was also increased. These effects are fully dependent on the polyphenols present in the cocoa powder and on the sirtuins Hst3 (yeast) and SIR-2.1 (worm). The transcription factor DAF-16 also plays an important role in the case of the nematode, indicating that the insulin/IGF-1 (insulin-like growth factor) signaling pathway is related with the antioxidative effect of cocoa polyphenols. All in all, these results confirm that this polyphenol-enriched cocoa powder, with antioxidant activity, has great potential use as a functional food ingredient for elderly people. Furthermore, this work reveals the value of using simple biological models to screen for compounds that are of interest for the food and pharmacological industry. PMID- 21288029 TI - Mineralization of metoprolol by electro-Fenton and photoelectro-Fenton processes. AB - Solutions of about 0.25 mM of the beta-blocker metoprolol tartrate (100 mg L(-1) total organic carbon) with 0.5 mM Fe(2+) in the presence and absence of 0.1 mM Cu(2+) of pH 3.0 have been comparatively degraded under electro-Fenton (EF) and photoelectro-Fenton (PEF) conditions. The electrolyses were carried out with two systems: (i) a single cell with a boron-doped diamond (BDD) anode and an air diffusion cathode (ADE) for H(2)O(2) electrogeneration and (ii) a combined cell with a BDD/ADE pair coupled with a Pt/carbon felt (CF) cell. Overall mineralization was reached in all PEF treatments using both systems due to the efficient production of hydroxyl radical ((*)OH) from Fenton's reaction induced by UVA light and the quick photolysis of Fe(III) carboxylate complexes formed. In EF, the combined cell was much more potent than the single one by the larger (*)OH generation from the continuous Fe(2+) regeneration at the CF cathode, accelerating the oxidation of organics. However, almost total mineralization in EF was feasible using the combined cell in the presence of 0.1 mM Cu(2+), because of the parallel quick oxidation of Cu(II) carboxylate complexes by (*)OH. Metoprolol decay always followed a pseudo-first-order reaction. Aromatic products related to consecutive hydroxylation/oxidation reactions of metoprolol were detected by gas chromatography-mass spectrometry. The evolution of the aromatic 4 (2-methoxyethyl)phenol and generated carboxylic acids was followed by HPLC. The degradation rate and mineralization degree of metoprolol tartrate were limited by the removal of Fe(III) and Cu(II) complexes of ultimate carboxylic acids such as formic, oxalic, and oxamic. NH(4)(+) ion and to a lesser extent NO(3)(-) ion were released in all treatments, being quantified by ionic chromatography. PMID- 21288030 TI - Redox-switchable chromophores based on metal (Ni, Pd, Pt) mixed-ligand dithiolene complexes showing molecular second-order nonlinear-optical activity. AB - The synthesis and full characterization of the redox-active nickel triad mixed ligand dithiolene complexes based on Bz(2)pipdt = 1,4-dibenzylpiperazine-3,2 dithione and dmit = 2-thioxo-1,3-dithiole-4,5-dithiolate ligands are reported. These complexes show a reversibly bleacheable solvatochromic peak and a remarkably high negative molecular first hyperpolarizability, whose values depend on the metal being highest for the platinum(II) compound. PMID- 21288031 TI - Bacterial retention on superhydrophobic titanium surfaces fabricated by femtosecond laser ablation. AB - Two-tier micro- and nanoscale quasi-periodic self-organized structures, mimicking the surface of a lotus Nelumbo nucifera leaf, were fabricated on titanium surfaces using femtosecond laser ablation. The first tier consisted of large grainlike convex features between 10 and 20 MUm in size. The second tier existed on the surface of these grains, where 200 nm (or less) wide irregular undulations were present. The introduction of the biomimetic surface patterns significantly transformed the surface wettabilty of the titanium surface. The original surface possessed a water contact angle of theta(W) 73 +/- 3 degrees , whereas the laser treated titanium surface became superhydrophobic, with a water contact angle of theta(W) 166 +/- 4 degrees . Investigations of the interaction of S. aureus and P. aeruginosa with these superhydrophobic surfaces at the surface-liquid interface revealed a highly selective retention pattern for two pathogenic bacteria. While S. aureus cells were able to successfully colonize the superhydrophobic titanium surfaces, no P. aeruginosa cells were able to attach to the surface (i.e., any attached bacterial cells were below the estimated lower detection limit). PMID- 21288032 TI - A biochemical framework for SLC4A11, the plasma membrane protein defective in corneal dystrophies. AB - Mutations in the SLC4A11 protein, reported as a sodium-coup-led borate transporter of the human plasma membrane, are responsible for three corneal dystrophies (CD): congenital hereditary endothelial dystrophy type 2, Harboyan syndrome, and late-onset Fuch's CD. To develop a rational basis to understand these diseases, whose point mutations are found throughout the SLC4A11 sequence, we analyzed the protein biochemically. Hydropathy analysis and an existing topology model for SLC4A1 (AE1), a bicarbonate transporter with the lowest evolutionary sequence divergence from SLC4A11, formed the basis to propose an SLC4A11 topology model. Immunofluorescence studies revealed the cytosolic orientation of N- and C-termini of SLC4A11. Limited trypsinolysis of SLC4A11 partially mapped the folding of the membrane and cytoplasmic domains of the protein. The binding of SLC4A11 to a stilbenedisulfonate inhibitor resin (SITS Affi-Gel) was prevented by preincubation with H(2)DIDS, with a significantly higher half-maximal effective concentration than AE1. We conclude that stilbenedisulfonates interact with SLC4A11 but with a lower affinity than other SLC4 proteins. Disease-causing mutants divided into two classes on the basis of the half-maximal [H(2)DIDS] required for resin displacement and the fraction of protein binding H(2)DIDS, likely representing mildly misfolded and grossly misfolded proteins. Disease-causing SLC4A11 mutants are retained in the endoplasmic reticulum of HEK 293 cells. This phenotype could be partially rescued in some cases by growing the cells at 30 degrees C. PMID- 21288034 TI - Stability and tunability of O/W nanoemulsions prepared by phase inversion composition. AB - We report on an analysis of the parameters that control both the stability and tunability of O/W nanoemulsions prepared by the phase inversion composition (PIC). These nanoemulsions are prepared with Tween 80 and Span 80, two nonionic surfactants, that can be mixed to adjust the hydrophilic lipophilic balance (HLB). We used a process mixture design method, which combines mixture and process design with phase diagrams, to describe the cross-link between parameters like composition, temperature of preparation, and HLB. Nanoemulsions, stable for several days, are obtained by this method, and they remain unchanged even at high concentration. We have identified the different critical distances of interactions that control the degree of freedom in the motion of the oil droplets. The diameter of these oil droplets could be adjusted between 50 and 300 nm. Different parameters, among them the temperature of preparation, the surfactant over oil ratio (S/O), and the HLB, allow control the final size of the nanoemulsions. As these parameters can exhibit opposite effects on the oil droplet size, the process mixture design method allowed us to illustrate these cross-interactions. PMID- 21288033 TI - Robust self-association is a common feature of mammalian visual arrestin-1. AB - Arrestin-1 binds light-activated phosphorhodopsin and ensures rapid signal termination. Its deficiency in humans and mice results in prolonged signaling and rod degeneration. However, most of the biochemical studies were performed on bovine arrestin-1, which was shown to self-associate forming dimers and tetramers, although only the monomer binds rhodopsin. It is unclear whether self association is a property of arrestin-1 in all mammals or a specific feature of bovine protein. To address this issue, we compared self-association parameters of purified human and mouse arrestin-1 with those of its bovine counterpart using multiangle light scattering. We found that mouse and human arrestin-1 also robustly self-associate, existing in a monomer-dimer-tetramer equilibrium. Interestingly, the combination of dimerization and tetramerization constants in these three species is strikingly different. While tetramerization of bovine arrestin-1 is highly cooperative (K(D,dim)(4) > K(D,tet)), K(D,dim) ~ K(D,tet) in the mouse form and K(D,dim) ? K(D,tet) in the human form. Importantly, in all three species at very high physiological concentrations of arrestin-1 in rod photoreceptors, most of it is predicted to exist in oligomeric form, with a relatively low concentration of the free monomer. Thus, it appears that maintenance of low levels of the active monomer is the biological role of arrestin-1 self-association. PMID- 21288035 TI - Tuning nanoscale friction on Pt nanoparticles with engineering of organic capping layer. AB - Nanoscale friction and adhesion on Pt colloid nanoparticles coated with different organic capping layers were probed with atomic/friction force microscopy. Platinum colloid nanoparticles with four types of capping layers have been synthesized and used as model lubricant systems: TTAB (tetradecyltrimethylammonium bromide), HDA (hexadecylamine), HDT (hexadecylthiol), and PVP (poly(vinylpyrrolidone)). Two-dimensional arrays of colloid nanoparticles were prepared using the Langmuir-Blodgett method. We found that the friction and adhesion properties on colloid nanoparticles are lower than those on a silicon surface. The variation of friction when changing the capping layers is ~30%, and it appears that the friction depends on the packing and ordering of the capping layers. Partial removal of the capping layers using ultraviolet light (UV)-ozone surface treatment resulted in increased friction. These results suggest a new method of tuning nanometer scale friction and adhesion by engineering organic capping layers on nanoparticles. PMID- 21288036 TI - Phase behavior and rheological analysis of reverse liquid crystals and W/I2 and W/H2 gel emulsions using an amphiphilic block copolymer. AB - This article reports the phase behavior determi-nation of a system forming reverse liquid crystals and the formation of novel disperse systems in the two phase region. The studied system is formed by water, cyclohexane, and Pluronic L 121, an amphiphilic block copolymer considered of special interest due to its aggregation and structural properties. This system forms reverse cubic (I2) and reverse hexagonal (H2) phases at high polymer concentrations. These reverse phases are of particular interest since in the two-phase region, stable high internal phase reverse emulsions can be formed. The characterization of the I2 and H2 phases and of the derived gel emulsions was performed with small-angle X ray scattering (SAXS) and rheometry, and the influence of temperature and water content was studied. The H2 phase experimented a thermal transition to an I2 phase when temperature was increased, which presented an Fd3m structure. All samples showed a strong shear thinning behavior from low shear rates. The elastic modulus (G') in the I2 phase was around 1 order of magnitude higher than in the H2 phase. G' was predominantly higher than the viscous modulus (G''). In the gel emulsions, G' was nearly frequency-independent, indicating their gel type nature. Contrarily to water-in-oil (W/O) normal emulsions, in W/I2 and W/H2 gel emulsions, G', the complex viscosity (|eta*|), and the yield stress (tau0) decreased with increasing water content, since the highly viscous microstructure of the continuous phase was responsible for the high viscosity and elastic behavior of the emulsions, instead of the volume fraction of dispersed phase and droplet size. A rheological analysis, in which the cooperative flow theory, the soft glass rheology model, and the slip plane model were analyzed and compared, was performed to obtain one single model that could describe the non-Maxwellian behavior of both reverse phases and highly concentrated emulsions and to characterize their microstructure with the rheological properties. PMID- 21288037 TI - Characteristics of wasteform composing of phosphate and silicate to immobilize radioactive waste salts. AB - In the radioactive waste management, metal chloride wastes from a pyrochemical process is one of problematic wastes not directly applicable to a conventional solidification process. Different from a use of minerals or a specific phosphate glass for immobilizing radioactive waste salts, our research group applied an inorganic composite, SAP (SiO(2)-Al(2)O(3)-P(2)O(5)), to stabilize them by dechlorination. From this method, a unique wasteform composing of phosphate and silicate could be fabricated. This study described the characteristic of the wasteform on the morphology, chemical durability, and some physical properties. The wasteform has a unique "domain-matrix" structure which would be attributed to the incompatibility between silicate and phosphate glass. At higher amounts of chemical binder, "P-rich phase encapsulated by Si-rich phase" was a dominant morphology, but it was changed to be Si-rich phase encapsulated by P-rich phase at a lower amount of binder. The domain and subdomain size in the wasteform was about 0.5-2 MUm and hundreds of nm, respectively. The chemical durability of wasteform was confirmed by various leaching test methods (PCT-A, ISO dynamic leaching test, and MCC-1). From the leaching tests, it was found that the P-rich phase had ten times lower leach-resistance than the Si-rich phase. The leach rates of Cs and Sr in the wasteform were about 10(-3)g/m(2). day, and the leached fractions of them were about 0.04% and 0.06% at 357 days, respectively. Using this method, we could stabilize and solidify the waste salt to form a monolithic wasteform with good leach-resistance. Also, the decrease of waste volume by the dechlorination approach would be beneficial in the final disposal cost, compared with the present immobilization methods for waste salt. PMID- 21288038 TI - Modulating surface density of proteins via caged surfaces and controlled light exposure. AB - We demonstrate the possibility of tuning the degree of functionalization of a surface using photoactivatable chemistries and controlled light exposure. A photosensitive organosilane with a protected amine terminal group and a tetraethyleneglycol spacer was synthesized. A o-nitrobenzyl cage was used as the photoremovable group to cage the amine functionality. Surfaces with phototunable amine densities were generated by controlled irradiation of silica substrates modified with the photosensitive anchor. Protein layers with different densities could be obtained by successive coupling and assembly steps. Protein surface concentrations were quantified by reflectance interference. Our results demonstrate that the protein density correlates with the photogenerated ligand density. The density control was proved over four coupling steps (biotin, SAv, (BT)tris-NTA, MBP, or GFP), indicating that the interactions between underlying layer and soluble targets are highly specific and the immobilized targets at the four levels maintain their full functionality. Protein micropatterns with a gradient of protein density were also obtained. PMID- 21288039 TI - Oriented catalytic platinum nanoparticles on high surface area strontium titanate nanocuboids. AB - Platinum nanoparticles grown on SrTiO(3) nanocuboids via atomic layer deposition exhibit cube-on-cube epitaxy with the predicted Winterbottom shape, consistent with literature values of the interfacial and surface free energies. This thermodyamically stable configuration should survive the rigors of catalytic conditions to create stable, high surface area, face-selective catalysts. PMID- 21288040 TI - Carbon nanotube/polyaniline composite nanofibers: facile synthesis and chemosensors. AB - An initiator is applied to synthesize single-walled carbon nanotube/polyaniline composite nanofibers for use as high-performance chemosensors. The composite nanofibers possess widely tunable conductivities (10(-4) to 10(2) S/cm) with up to 5.0 wt % single-walled carbon nanotube (SWCNT) loadings. Chemosensors fabricated from the composite nanofibers synthesized with a 1.0 wt % SWCNT loading respond much more rapidly to low concentrations (100 ppb) of HCl and NH(3) vapors compared to polyaniline nanofibers alone (120 s vs 1000 s). These nanofibrillar SWCNT/polyaniline composite nanostructures are promising materials for use as low-cost disposable sensors and as electrodes due to their widely tunable conductivities. PMID- 21288041 TI - Triterpenoid saponins from Symplocos lancifolia. AB - Three new bidesmosidic saponins (1-3) and a new ursane triterpenoid, 2alpha,3beta,11alpha,23-tetrahydroxyurs-12-en-28-oic acid (4), along with seven known compounds, were isolated from a methanolic extract of the leaves of Symplocos lancifolia. The bidesmosidic saponins were found to possess the same sugar unit part, composed of two beta-d-glucose moieties and one alpha-l-rhamnose moiety, linked to maslinic acid, arjunolic acid, and asiatic acid, respectively. Their structures were elucidated by interpretation of their 1D and 2D NMR spectra and completed by analysis of the HRESIMS data. The antibacterial activity of the isolated triterpenoids was evaluated against Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, and Pseudomonas aeruginosa, and several showed activity against Gram-positive bacteria. PMID- 21288042 TI - Biexciton quantum yield of single semiconductor nanocrystals from photon statistics. AB - Biexciton properties strongly affect the usability of a light emitter in quantum photon sources and lasers but are difficult to measure for single fluorophores at room temperature due to luminescence intermittency and bleaching at the high excitation fluences usually required. Here, we observe the biexciton (BX) to exciton (X) to ground photoluminescence cascade of single colloidal semiconductor nanocrystals (NCs) under weak excitation in a g((2)) photon correlation measurement and show that the normalized amplitude of the cascade feature is equal to the ratio of the BX to X fluorescence quantum yields. This imposes a limit on the attainable depth of photon antibunching and provides a robust means to study single emitter biexciton physics. In NC samples, we show that the BX quantum yield is considerably inhomogeneous, consistent with the defect sensitivity expected of the Auger nonradiative recombination mechanism. The method can be extended to study X,BX spectral and polarization correlations. PMID- 21288043 TI - Observable temperature-dependent compaction-decompaction of cationic polythiophene in the presence of iodide. AB - Investigation on compaction and decompaction of polymers is very important since it is a fundamental problem in polymer physics. With the aids of atomic force microscope (AFM) and dynamic light scattering (DLS) measurements in this contribution, the temperature-dependent compaction/decompaction transition process of water-soluble cationic polythiophene (PT) was investigated in the presence of KI. The above process is characterized by the red-to-yellow color change and fluorescence recovery and is reversible during the heating-cooling cycles in the range from 25 to 55 degrees C, indicating that the compaction and decompaction of polymer can be employed as a temperature indicator. PMID- 21288044 TI - Asymmetric total synthesis of (+)-danicalipin A. AB - A convergent asymmetric total synthesis of (+)-danicalipin A is accomplished, in which two chlorinated fragments are stereoselectively joined by 1,3-dipolar coupling, leading to the confirmation of the absolute configuration of the natural product. PMID- 21288045 TI - Modular approach for synthesis of vicinal diamines containing axial chiral 1,1' binaphthyl from 1,2-diaminoethane by Pd-catalyzed N-arylation reactions. AB - A very convenient and efficient modular approach for the synthesis of vicinal diamines containing axial chiral 1,1'-binaphthyl from 1,2-diaminoethane by Pd catalyzed N-arylation reactions has been developed. The resulting chiral diamines could be easily converted into NHC precursors, imidazole salts, in good yields. PMID- 21288046 TI - Strain-release assembly of nanowires on stretchable substrates. AB - A simple yet effective method for assembly of highly aligned nanowires (NWs) on stretchable substrates is reported. In this method, NWs were first transferred to a strained stretchable substrate. After the strain was released, the NWs aligned in the transverse direction and the area coverage of the NWs on the substrate increased. This method can be applied to any NWs deposited on a stretchable film and can be repeated multiple times to increase the alignment and density of the NWs. For silver (Ag) and silicon (Si) NWs on poly(dimethylsiloxane) (PDMS) substrates, the probability of NW alignment increased from 29% to 90% for Ag NWs, and from 25% to 88% for Si NWs after two assembly steps; the density increased by 60% and 75% for the Ag and Si NWs, respectively. The large-strain elasticity of the substrate and the static friction between the NWs and the substrate play key roles in this assembly method. We find that a model that takes into account the volume incompressibility of PDMS reliably predicts the degree of NW alignment and NW density. The utility of this assembly method was demonstrated by fabricating a strain sensor array composed of aligned Si NWs on a PDMS substrate, with a device yield of 95%. PMID- 21288047 TI - Doxorubicin-loaded (PEG)3-PLA nanopolymersomes: effect of solvents and process parameters on formulation development and in vitro study. AB - This study is focused on the preparation of doxorubicin-loaded nanopolymersomes (PolyDoxSome) and assessment of the effects of various solvents and process variables on the size and drug loading during preparation of formulation. PolyDoxSome was prepared by nanoprecipitation method using amphiphilic (PEG)3-PLA copolymer, and the formation of polymersomes was assessed by dynamic light scattering and optical and transmission electron microscopy and evaluated for in vitro release profile and in vitro cytotoxicity. A systematic investigation indicated that solvent composition, order of addition, aqueous phase, copolymer concentration, and external energy input have significant influence on size and dispersity of PolyDoxSome. Under optimized conditions, PolyDoxSome had a size range of 130-180 nm with PDI < 0.2, a zeta potential ~-8 mV, and a drug loading at ~11% w/w with an encapsulation efficiency at ~53% w/w. In vitro release profile of PolyDoxSome at 37 degrees C demonstrated that doxorubicin release was pH dependent and gave higher release at pH 5.5 in comparison to the release at pH 7.4 (similarity factor, f2 < 50). PolyDoxSome exhibited enhanced cellular uptake of doxorubicin compared to free doxorubicin solution in MCF-7 cell line and showed a better cytotoxicity of doxorubicin at equivalent dose in nanopolymersomes. In conclusion, size and dispersity were strongly influenced by duration of magnetic stirring and overall composition of organic/aqueous media; however, size and dispersity were retained against different degrees of dilution. PolyDoxSome was able to control the release of doxorubicin in pH dependent manner and effectively deliver the drug in active form to MCF-7 breast cancer cells. PMID- 21288048 TI - Comment on "Unbiased statistical analysis for multi-stage proteomic search strategies". AB - Everett et al. recently reported on a statistical bias that arises in the target decoy approach to false discovery rate estimation in two-pass proteomics search strategies as exemplified by X!Tandem. This bias can cause serious underestimation of the false discovery rate. We argue here that the "unbiased" solution proposed by Everett et al., however, is also biased and under certain circumstances can also result in a serious underestimate of the FDR, especially at the protein level. PMID- 21288049 TI - Synthesis and spectroscopic characterization of CN-substituted bipyridyl complexes of Ru(II). AB - A series of ruthenium complexes having the general form [Ru(bpy)(3-n)(CN-Me bpy)(n)](PF(6))(2) (where bpy = 2,2'-bipyridine, CN-Me-bpy = 4,4'-dicyano-5,5' dimethyl-2,2'-bipyridine, and n = 1-3 for complexes 1-3, respectively) have been synthesized and characterized using a variety of steady-state and nanosecond time resolved spectroscopies. Electrochemical measurements indicate that the CN-Me-bpy ligand is significantly easier to reduce than the unsubstituted bipyridine (on the order of ~500 mV), implying that the lowest energy (3)MLCT (metal-to-ligand charge transfer) state will be associated with the CN-Me-bpy ligand(s) in all three compounds. Comparison of the Huang-Rhys factors derived from spectral fitting analyses of the steady state emission spectra of complexes 1-3 suggests all three compounds are characterized by excited-state geometries that are less distorted relative to their ground states as compared to [Ru(bpy)(3)](PF(6))(2); the effect of the more nested ground- and excited-state potentials is reflected in the unusually high radiative quantum yields (13% (1), 27% (2), and 40% (3)) and long (3)MLCT-state room-temperature lifetimes (1.6 MUs, 2.6 MUs, and 3.5 MUs, respectively) for these compounds. Coupling of the pi* system into the CN groups is confirmed by nanosecond step-scan IR spectra which reveal a ~40 cm(-1) bathochromic shift of the CN stretching frequency, indicative of a weaker CN bond in the (3)MLCT excited state relative to the ground state. The fact that the shift is the same for complexes 1-3 is evidence that, in all three complexes, the long-lived excited state is localized on a single CN-Me-bpy ligand rather than being delocalized over multiple ligands. PMID- 21288050 TI - Polymer-binding peptides for the noncovalent modification of polymer surfaces: effects of peptide density on the subsequent immobilization of functional proteins. AB - Peptides that specifically bind to polyetherimide (PEI) were selected, characterized, and used for the noncovalent modification of the PEI surface. The peptides were successfully identified from a phage-displayed peptide library. A chemically-synthesized peptide composed of the Thr-Gly-Ala-Asp-Leu-Asn-Thr sequence showed an extremely high binding constant for the PEI films (5.6 * 10(8) M(-1)), which was more than three orders of magnitude greater than that for the reference polystyrene films. The peptide was biotinylated and immobilized onto the PEI films to further immobilize streptavidin (SAv). The amount of SAv bound depended on the density of immobilized peptide. It gradually increased with an increasing density of immobilized peptide and achieved a maximum (2.1 pmol cm( 2)) at a peptide density of 19.8 pmol cm(-2). The ratio of peptide used for immobilizing SAv at the maximum value was only 11%, and was partially due to the low accessibility of SAv to the biotin moieties on the PEI films. Moreover, the amount of SAv bound gradually decreased at higher peptide densities, suggesting that the clustering of the peptides also inhibited the binding of SAv. Furthermore, peptides on the PEI films promoted the uniform immobilization of SAv with less structural denaturing. The immobilized SAv was able to further immobilize probe DNA to hybridize with its complementary DNA. These present results suggest that the density of immobilized peptide has a great impact on the surface modifications using polymer-binding peptides. PMID- 21288051 TI - Intrinsic electrophilicity of a 4-substituted-5-cyano-6-(2-methylpyridin-3 yloxy)pyrimidine derivative: structural characterization of glutathione conjugates in vitro. AB - Isopropyl 9-anti-[5-cyano-6-(2-methyl-pyridin-3-yloxy)-pyrimidin-4-yloxy]-3-oxa-7 aza-bicyclo[3.3.1]nonane-7-carboxylate (1) represents a prototypic compound from a lead chemical series of G protein-coupled receptor 119 agonists, intended for treatment of type 2 diabetes. When compound 1 was incubated with NADPH supplemented human liver microsomes in the presence of glutathione, two thioether conjugates M4-1 and M5-1 were observed. Omission of NADPH from the microsomal incubations prevented the formation of M5-1 but not M4-1. The formation of M4-1 was also discerned in incubations of 1 and glutathione with human liver cytosol, partially purified glutathione transferase, and in phosphate buffer at pH 7.4. M4 1 was isolated, and its structure ascertained from LC-MS/MS and NMR analysis. The mass spectral and NMR data suggested that M4-1 was obtained from a nucleophilic displacement of the 6-(2-methylpyridin-3-yloxy) group in 1 by glutathione. In addition, mass spectral studies revealed that M5-1 was derived from an analogous displacement reaction on a monohydroxylated metabolite of 1; the regiochemistry of hydroxylation was established to be on the isopropyl group. Of great interest were the findings that replacement of the 5-cyano group in 1 with a 5-methyl group resulted in 2, which was practically inert toward reaction with glutathione. This observation suggests that the electron-withdrawing potential of the C5 cyano group serves to increase the electrophilicity of the C6 carbon (via stabilization of the transition state) and favors reaction with the nucleophilic thiol. The mechanistic insights gained from these studies should assist medicinal chemistry efforts toward the design of analogs that retain primary pharmacology but are latent toward reaction with biological nucleophiles, thus mitigating the potential for toxicological outcome due to adduction with glutathione or proteins. PMID- 21288052 TI - Pharmacokinetics of venlafaxine extended release 75 mg and desvenlafaxine 50 mg in healthy CYP2D6 extensive and poor metabolizers: a randomized, open-label, two period, parallel-group, crossover study. AB - BACKGROUND: Genetically driven variations in the level of cytochrome P450 (CYP) 2D6 metabolic activity have been shown to significantly affect the pharmacokinetic behaviour of medications that are substrates of this enzyme. OBJECTIVE: To evaluate the impact of CYP2D6 extensive metabolizer (EM) and poor metabolizer (PM) phenotypes on the pharmacokinetics of single doses of venlafaxine extended release (ER) and desvenlafaxine (administered as desvenlafaxine succinate). METHODS: This study used a randomized, open-label, two period, parallel-group, crossover design. The enrolled healthy subjects participated in the study for approximately 8 weeks, which included <= 6 weeks of screening procedures and two separate 1-week partial inpatient confinement periods (separated by a 4-day washout period), during which venlafaxine ER or desvenlafaxine was administered and blood samples were collected. Subjects were admitted to partial inpatient confinement in a laboratory setting for the two separate study periods where each study drug was individually administered. Blood samples for pharmacokinetic analyses were collected during the 120 hours following administration of each study drug. Plasma concentrations of the study drugs were measured by a third-party analyst using liquid chromatography-tandem mass spectrometry. Healthy subjects were recruited through newspaper advertisements and genotyped to determine their CYP2D6 metabolic phenotype (i.e. EM or PM) using internally developed and commercially available assays. Subjects were reimbursed for their participation in this study. Single, sequentially administered oral doses of the dual-acting, serotonin and norepinephrine reuptake inhibiting antidepressants venlafaxine ER (75 mg) and desvenlafaxine (50 mg) were administered. The main outcome measures were differences in the geometric means for area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) and peak plasma concentration (C(max)) between EMs and PMs. Comparisons were made using a 2-tailed Wilcoxon exact test. RESULTS: No carryover effect was observed between treatment sequence groups. There was no statistically significant difference in either C(max) or AUC(infinity) of O desmethylvenlafaxine between PMs (n = 7) and EMs (n = 7) following administration of desvenlafaxine 50 mg. However, when subjects received venlafaxine ER 75 mg, the AUC(infinity) and C(max) of O-desmethylvenlafaxine (the primary active metabolite) were 445% and 434% higher, respectively, in EMs compared with PMs (p <= 0.001), and the AUC(infinity) and C(max) of venlafaxine were 445% and 180% higher, respectively, in PMs compared with EMs (p < 0.01). In addition, the ratios of O-desmethylvenlafaxine : venlafaxine AUC(infinity) and C(max) for subjects receiving venlafaxine ER 75 mg were higher for EMs (6.2 and 3.3) than PMs (0.21 and 0.22; p <= 0.001 for both comparisons). CONCLUSION: In contrast to venlafaxine ER 75 mg, the pharmacokinetics of desvenlafaxine 50 mg is not significantly impacted by CYP2D6 genetic polymorphisms. PMs receiving venlafaxine ER 75 mg had significantly lower O-desmethylvenlafaxine and higher venlafaxine plasma concentrations. PMID- 21288053 TI - Effects of structured follow-up and of more effective acid inhibitory treatment in the management of GORD patients in a Swedish primary-care setting: a randomized, open-label study. AB - BACKGROUND: Despite the high prevalence of gastro-oesophageal reflux disease (GORD) and the documented impact of GORD symptoms on individual health-related quality of life (HR-QOL) and on socioeconomic factors, structured management of GORD has had a low priority in Swedish routine primary health care. OBJECTIVE: The primary objective of this study (IMPROVE) was to evaluate the effects of a structured follow-up and management regimen for primary-care GORD patients with symptomatic breakthrough despite standard proton pump inhibitor (PPI) treatment. Patients received either an increased dose of current PPI treatment or were switched to the more effective acid inhibitor esomeprazole. METHODS: GORD patients with symptomatic breakthrough despite standard PPI treatment were identified through medical records and by a postal survey using the GERD Impact Scale (GIS) questionnaire. Patients rated the severity and frequency of GORD symptoms, general health status (EuroQol Group 5-Dimension Self-Report Questionnaire) and the impact of GORD symptoms on work productivity (Work Productivity and Activity Impairment) before and 4 weeks following randomization to open-label treatment with either increased acid suppressive therapy or an adjusted, higher dosage of the PPI previously used. The patients' valuation, in monetary terms, of the treatment they received pre-study versus the treatment given during the study was documented through willingness-to-pay (WTP) questions. RESULTS: Following more effective acid suppression, 66.3% of the study population experienced complete relief of heartburn, with no difference between the groups; HR-QOL was restored to a level comparable to that of a normal Swedish population and ability to work efficiently was significantly improved. Access to a better acid suppressive treatment was highly valuable to the patients in terms of WTP. CONCLUSION: An improved GORD management strategy including structured follow-up of treatment given and initiation of more effective acid inhibitor therapy when symptoms persist will be of great benefit to GORD patients. [ClinicalTrials.gov Identifier: NCT00272701]. PMID- 21288054 TI - Trends in the kidney cancer incidence and mortality in the Slovak and Czech Republics in 1980-2005 - in the context of an international comparison. AB - Incidence rates of kidney cancer vary in global standards more than tenfold, the highest worldwide rates are repeatedly registered in the Czech Republic (hereafter CR) and in other geographically neighbouring countries in Central Europe, including the Slovak Republic (hereafter SR). The aim of the study was to analyse the changes in time trends of incidence and mortality from kidney cancer in two geographically close countries (CR and SR) and to compare detected differences with the worldwide data. In spite of high rates of incidence and its global growth in analyses in 1980 - 2005, the character of its progress in time was changed in both countries. While in 1980 - 1994 the incidence of kidney cancer in males and females in both analysed countries increased significantly, after 1994 (to 2005) stagnation in males in SR and significant slowdown of its growth in males in CR were reported. In females in SR after 1994 significant slowdown of the incidence growth was reported and in CR there was even its non significant fall. Mortality trend in both sexes in both countries in 1980-2005 was slower than the incidence. After 1994 (to 2005) in males in SR statistically non-significant slowdown of mortality growth was reported, in CR it was statistically significant fall of mortality rates. In women after 1994 (to 2005) statistically non-significant decrease was reported, in CR the decrease was significant. The increase of total incidence of the disease is not explained only by the growth of asymptomatic localized tumors due to high quality diagnostic methods, but it likely reflects actual growth of new cases of the disease. Assumed partial cause of the mortality stabilization and slowdown of the incidence growth after its previous culmination in 1994 is the decline of smoking and obesity prevalence in the last decades in men, although this fact does not reflect situation in women. More striking mortality decrease in CR in comparison with SR might be influenced by potentially more radical surgical therapy (rate of the amount of surgery within primary therapy according to the data in National Cancer Registry CR raises, in SR the data are not available) and by more significant increase of the disease rate in the clinical stages I and II in CR (in SR only short-time data are available). PMID- 21288055 TI - Long-term dosing, safety, and tolerability of fentanyl buccal tablet in the management of noncancer-related breakthrough pain in opioid-tolerant patients. AB - OBJECTIVE: To evaluate the long-term dosing, safety, and tolerability of fentanyl buccal tablet (FBT) in a large cohort of opioid-tolerant patients with chronic noncancer pain and breakthrough pain (BTP). DESIGN: Combined analysis of three double-blind, placebo-controlled, and two open-label studies. RESULTS: Of 1160 patients who received >=1 dose of FBT, 83% achieved a successful dose, ranging from 100 to 800 MUg, mostly at 600 or 800 MUg. Not all of the patients included in this analysis were enrolled in long-term studies and 156 (13%) patients were still receiving ongoing treatment when their study site closed. Median treatment duration was 106.0 days. The mean FBT dose in the post-titration population (n = 946) increased from 2108 to 3132 MUg/day, with >=1 FBT dose increase in 27% of patients; most dose increases occurred during the first 6 months. The FBT daily dose as a proportion of the daily opioid dose remained fairly stable (59-65%) throughout the treatment period. Overall, 925 (80%) enrolled patients had >=1 adverse event (AE). The most frequent AEs were nausea (21% of patients), vomiting (11%), dizziness (10%), and headache (10%). Common AEs generally occurred within 7 days of starting treatment and lasted for <=2 days. Serious AEs occurred in 136 (12%) patients and included six deaths (none related to FBT) and 11 instances of opioid overdose (all with satisfactory resolution). AE-related discontinuations occurred in 163 (14%) patients and were similar to the common AEs. CONCLUSIONS: Despite the limitations, including the controlled clinical setting, this pooled analysis of several clinical studies provides valuable information for the long term management of BTP with FBT. Patients require regular evaluation and, when necessary, adjustment of opioid medications to maintain adequate pain control. FBT was generally safe and well tolerated in this setting. PMID- 21288056 TI - Influence of microenvironment on engraftment of transplanted beta-cells. AB - Pancreatic islet transplantation into the liver provides a possibility to treat selected patients with brittle type 1 diabetes mellitus. However, massive early beta-cell death increases the number of islets needed to restore glucose homeostasis. Moreover, late dysfunction and death contribute to the poor long term results of islet transplantation on insulin independence. Studies in recent years have identified early and late challenges for transplanted pancreatic islets, including an instant blood-mediated inflammatory reaction when exposing human islets to the blood microenvironment in the portal vein and the low oxygenated milieu of islets transplanted into the liver. Poor revascularization of remaining intact islets combined with severe changes in the gene expression of islets transplanted into the liver contributes to late dysfunction. Strategies to overcome these hurdles have been developed, and some of these interventions are now even tested in clinical trials providing a hope to improve results in clinical islet transplantation. In parallel, experimental and clinical studies have, based on the identified problems with the liver site, evaluated the possibility of change of implantation organ in order to improve the results. Site specific differences clearly exist in the engraftment of transplanted islets, and a more thorough characterization of alternative locations is needed. New strategies with modifications of islet microenvironment with cells and growth factors adhered to the islet surface or in a surrounding matrix could be designed to intervene with site-specific hurdles and provide possibilities to improve future results of islet transplantation. PMID- 21288057 TI - Respiratory-related medical expenditure and inpatient utilisation among COPD patients receiving long-acting bronchodilator therapy. AB - OBJECTIVE: To evaluate chronic obstructive pulmonary disease (COPD)-related expenditure and hospitalisation in COPD patients treated with tiotropium versus alternative long-acting bronchodilators (LABDs). METHODS: Data were from the Thomson Reuters MarketScan Research Databases. COPD patients >= 35 years with at least one LABD claim between July 1, 2004 and June 30, 2006 were classified into five cohorts based on index LABD: monotherapy with tiotropium, salmeterol/fluticasone propionate, formoterol fumarate, or salmeterol or combination therapy. Demographic and clinical characteristics were evaluated for a 6-month pre-period and COPD-related utilisation and total costs were evaluated for a 12-month follow-up period. LABD relationship to COPD-related costs and hospitalisations were estimated by multivariate generalised linear modelling (GLM) and multivariate logistic regression, respectively. RESULTS: Of 52,274 patients, 53% (n = 27,457) were male, 71% (n = 37,271) were >= 65 years, and three LABD cohorts accounted for over 90% of the sample [53% (n = 27,654) salmeterol/fluticasone propionate, 23% (n = 11,762) tiotropium, and 15% (n = 7755) combination therapy]. Patients treated with salmeterol/fluticasone propionate (p < 0.001), formoterol fumarate (p = 0.032), salmeterol (p = 0.004), or with combination therapy (p < 0.001) had higher COPD-related costs and a greater risk of inpatient admission (p < 0.01 for all) versus tiotropium. LIMITATIONS: These data are based on administrative claims and as such do not include clinical information or information on risk factors, like smoking status, that are relevant to this population. CONCLUSIONS: Patients treated with tiotropim had lower COPD-related expenditures and risk of hospitalisation than patients treated with other LABDs. PMID- 21288058 TI - Cost effectiveness of atazanavir-ritonavir versus lopinavir-ritonavir in treatment-naive human immunodeficiency virus-infected patients in the United States. AB - OBJECTIVE: To evaluate lifetime cost effectiveness of atazanavir-ritonavir (ATV + r) versus lopinavir-ritonavir (LPV/r), both with tenofovir-emtricitabine, in US HIV-infected patients initiating first-line antiretroviral therapy. METHODS: A Markov microsimulation model was developed to calculate quality-adjusted life years (QALYs) based on CD4 and HIV RNA levels, coronary heart disease (CHD), AIDS, opportunistic infections (OIs), diarrhea, and hyperbilirubinemia. A million member cohort of HIV-1-infected, treatment-naive adults progressed at 3-month intervals through eight health states. Baseline characteristics, virologic suppression, cholesterol changes, and diarrhea and hyperbilirubinemia rates were based on 96-week CASTLE trial results. HIV mortality, OI rates, adherence, costs, utilities, and CHD risk were from literature and experts. LIMITATIONS: The incremental cost-effectiveness ratio (ICER) may be overestimated because the ATV + r treatment effect was based on an intention-to-treat analysis. The QALY weights used for diarrhea, hyperbilirubinemia, and CHD events are uncertain; however, the ICER remained < $50,000/QALY when these values were varied in sensitivity analyses. RESULTS: ATV + r patients received first-line therapy longer than LPV/r patients (97.3 vs. 70.7 months), had longer quality-adjusted survival (11.02 vs. 10.76 years), similar overall survival (18.52 vs. 18.51 years), and higher costs ($275,986 vs. 269,160). ATV+r [corrected] patients had lower rates of AIDS (19.08 vs. 20.05 cases/1000 patient-years), OIs (0.44 vs.0.52), diarrhea (1.27 vs. 6.26), and CHD events(5.44 vs. 5.51), but higher hyperbilirubinemia rates (6.99 vs. 0.25. ATV + r added 0.26 QALYs at a cost of $6826, for $26,421/QALY. CONCLUSIONS: By more effectively reducing viral load with less gastrointestinal toxicity and a better lipid profile, ATV + r lowered rates of AIDS and CHD, increased quality-adjusted survival, and was cost effective (< $50,000/QALY) compared with LPV/r. PMID- 21288059 TI - Budget impact of erlotinib for maintenance therapy in advanced non-small cell lung cancer. AB - OBJECTIVE: Assess the budgetary impact of adding erlotinib for maintenance therapy (MTx) in advanced non-small cell lung cancer (NSCLC) from a US health plan perspective. METHODS: A budget impact model was developed to analyze the costs (drug, administration, adverse events) associated with adding erlotinib MTx to a hypothetical 500,000 member US health plan. Treatment durations and dosing were derived from randomized controlled trials, FDA labeling, and National Comprehensive Cancer Network guidelines. Treatment patterns and assumptions were based on market research data, the SEER registry, and published literature. Cost data were obtained from Centers for Medicare and Medicaid Services payment rates and a drug pricing database. Sensitivity analyses were conducted to assess uncertainty. RESULTS: Overall health plan expenditures increased by $0.010 per member per month (PMPM). The main driver of additional cost was the erlotinib drug cost (~$66,000) with the administration ($464) and side-effect ($47) costs being relatively modest. One-way sensitivity analyses showed that the results were most sensitive to the proportion of members receiving MTx; however, the PMPM did not exceed $0.013. CONCLUSIONS: The overall budget impact to a health plan of expanding the use of erlotinib from the 2nd/3rd-line advanced NSCLC setting to include the maintenance setting was relatively small. This was primarily due to the proportion of patients who would receive erlotinib MTx, the low cost of side effects and minimal cost of drug administration. Additional research may be warranted to estimate the relative clinical and economic impacts of erlotinib MTx versus alternative MTx treatments. PMID- 21288060 TI - Speech perception abilities for spectrally modified signals in individuals with auditory dys-synchrony. AB - OBJECTIVE: The objective of the study was to determine the speech perception abilities for spectrally modified speech signals in individuals with auditory dys synchrony. STUDY SAMPLE: The speech identification scores of 30 normal hearing and 12 individuals diagnosed as having auditory dys-synchrony were studied. DESIGN: Phonemically balanced words in Kannada developed by Yathiraj and Vijayalakshmi (2005) were presented unfiltered and filtered at 1700 Hz low-pass and 1700 Hz high-pass cut-off frequencies, and speech identification performance was assessed. RESULTS: Results revealed that there is a highly significant difference in speech identification scores for unfiltered and low-pass filtered words. This difference could be attributed to the physiological coding deficits of low frequency information which are usually coded by phase locked responses in auditory nerve fibers ( Sek & Moore, 1995 ). CONCLUSIONS: Thus, low-pass filtered words can be used as an effective tool to identify individuals with auditory dys synchrony, especially those who have good speech identification scores in quiet. PMID- 21288061 TI - Music activities and responses of young cochlear implant recipients. AB - OBJECTIVE: The development of auditory receptive skills and spoken language is often delayed in children who use cochlear implants, which may affect their appreciation of and responses to music. This in turn may be interpreted as disinterest in music. A questionnaire was developed to determine whether differences in exposure and responses to music exist between young cochlear implant recipients and their normally hearing peers. DESIGN: The questionnaire was developed by a multidisciplinary team and distributed to parents of preschool children with normal hearing and to parents of preschool children who had been implanted at least one year prior. STUDY SAMPLE: The cochlear implant group comprised 23 children and was gender and age matched (within +/-2 months) to a group of children with normal hearing. RESULTS & CONCLUSIONS: Young cochlear implant recipients receive similar exposure to audiovisual music media, parental singing and musical instruments at home. However, the data suggest that they receive less exposure to children's music presented without visual stimuli. Parents also reported less sophisticated responses to music for this group. The findings of this study have important implications concerning the provision of age-appropriate music habilitation materials and activities for young cochlear implant recipients. PMID- 21288062 TI - Explore the world of hearing loss prevention. Foreword. PMID- 21288063 TI - Distributions of pure-tone hearing threshold levels among adolescents and adults in the United States by gender, ethnicity, and age: Results from the US National Health and Nutrition Examination Survey. AB - Cumulative distributions of audiometric pure-tone thresholds for a non occupationally noise-exposed population vary with demographic characteristics (e.g. gender, ethnicity, age), tested ear, and stimulus frequency. However, commonly-used audiometric databases either do not take these differences into account, or account for them using data not easily generalized to the US population. The objective of this study was to obtain distributions that are generalizable to the US population without significant history of exposure to occupational noise. Cumulative pure tone threshold distributions from the National Health and Nutrition Examination Survey (NHANES) III and the 1999-2004 data from the continuous NHANES were fitted with an asymmetric sigmoid function with reverse asymmetry, by gender, ethnicity, age, ear, and the stimulus frequency. Results indicated that conditional distributions based on these factors are warranted. Percentiles on the cumulative distribution functions can be transformed into standard normal variates (i.e. z-scores) to facilitate combination of results over time or across individuals with different demographic characteristics. However, combinations across frequency could obscure meaningful differences between the reference group and the hearing test results under analysis. PMID- 21288064 TI - Evidence of hearing loss in a 'normally-hearing' college-student population. AB - We report pure-tone hearing threshold findings in 56 college students. All subjects reported normal hearing during telephone interviews, yet not all subjects had normal sensitivity as defined by well-accepted criteria. At one or more test frequencies (0.25-8 kHz), 7% of ears had thresholds >=25 dB HL and 12% had thresholds >=20 dB HL. The proportion of ears with abnormal findings decreased when three-frequency pure-tone-averages were used. Low-frequency PTA hearing loss was detected in 2.7% of ears and high-frequency PTA hearing loss was detected in 7.1% of ears; however, there was little evidence for 'notched' audiograms. There was a statistically reliable relationship in which personal music player use was correlated with decreased hearing status in male subjects. Routine screening and education regarding hearing loss risk factors are critical as college students do not always self-identify early changes in hearing. Large scale systematic investigations of college students' hearing status appear to be warranted; the current sample size was not adequate to precisely measure potential contributions of different sound sources to the elevated thresholds measured in some subjects. PMID- 21288065 TI - Noise-induced hearing loss in Asia. AB - The aim of this manuscript is to summarize the current scenarios encompassing noise exposure in the workplace and the risk of noise-induced hearing loss (NIHL) in Asia. NIHL is the most prevalent and preventable occupational disease in most Asian countries. Sources of noise in these countries include manufacturing and agriculture industries, exploitation of natural resources, and urban traffic. The highest attributable fraction of adult-onset hearing loss resulting from noise exposure in the world comes from Asian countries. NIHL is a serious health problem in Asia, not only because of the number of affected labourers, but also because the majority of Asian countries are still developing economies where access to health services and preventive programmes are limited. Lack of awareness about NIHL among employers, employees, and health care professionals is one of the main barriers for the prevention of NIHL in Asia. In this paper, the sources of noise, NIHL prevalence in different industries, local legislation, and research publications on NIHL from Asia are discussed. PMID- 21288066 TI - Schools of music and conservatories and hearing loss prevention. AB - Music students are not being taught that music is a sound source capable of harming hearing. Ensemble directors of public school and college bands, orchestras, and choirs, are unaware and unprepared to recognize and manage risk from excessive sound exposures. Schools of music and conservatories around the world, and the organizations that accredit them, need to embrace the idea that schools of music are best suited to facilitate change, conduct research, create and impart knowledge, institute competency, and most importantly, cultivate a culture of responsibility and accountability throughout the music discipline. By drawing attention to actions pursued at and through the College of Music at the University of North Texas, the purpose of this paper is to encourage change and to assist others in efforts to reach the best conditions for preventing irreversible hearing disorders associated with music. PMID- 21288067 TI - Better protection from blasts without sacrificing situational awareness. AB - A large number of soldiers returning from war report hearing loss and/or tinnitus. Many deployed soldiers decline to wear their hearing protection devices (HPDs) because they feel that earplugs interfere with their ability to detect and localize the enemy and their friends. The detection problem is easily handled in electronic devices with low-noise microphones. The localization problem is not as easy. In this paper, the factors that reduce situational awareness--hearing loss and restricted bandwidth in HPD devices--are discussed in light of available data, followed by a review of the cues to localization. Two electronic blast plug earplugs with 16-kHz bandwidth are described. Both provide subjectively transparent sound with regard to sound quality and localization, i.e., they sound almost as if nothing is in the ears, while protecting the ears from blasts. Finally, two formal experiments are described which investigated localization performance compared to popular existing military HPDs and the open ear. The tested earplugs performed well regarding maintaining situational awareness. Detection-distance and acceptance studies are underway. PMID- 21288068 TI - The World Journal of Biological Psychiatry vol. 12, issue 1. PMID- 21288069 TI - World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of Alzheimer's disease and other dementias. AB - OBJECTIVES: To define a practice guideline for biological treatment of dementia and to make transparent the development of the guideline connecting the original data with the resulting recommendations. METHODS: This guideline includes pharmacologic treatment considerations for patients with Alzheimer's disease, vascular dementia, DLB, and fronto-temporal dementia. Studies were selected that represent double-blind placebo-controlled trials of at least 3 months duration in patients with a diagnosis of dementia according to accepted international diagnostic criteria (for example the NINCDS/ADRDA or NINDS/AIREN criteria). Moreover, to be included studies had to fulfill a restrictive set of methodological criteria. Original studies and not meta-analyses determined the evaluation and the development of recommendations. RESULTS: Antidementia pharmaceuticals neither cure nor arrest the disease. A modest effect of improvement of symptoms compared with placebo can be observed. Antidementia pharmaceuticals show different efficacy and side effect profiles. The type of dementia, the individual symptom constellation and the tolerability should determine what medication should be used. There are hints that combination therapy of drugs with different therapeutic mechanisms might improve the efficacy. In treating neuropsychiatric symptoms (NPS), psychosocial intervention should be the treatment of first choice. Pharmaceuticals can only be recommended when psychosocial interventions is not adequate. However, even then the side effects of pharmaceuticals limit their use. CONCLUSIONS: Depending on the diagnostic entity and the pathology treated different anti-dementia drugs can be recommended to improve symptoms. In the management of NPS, side effects limit the use of medications even when psychosocial interventions have failed. Thus, there is an urgent need to develop more efficacious medications for the treatment of dementia. PMID- 21288070 TI - Inflexible information acquisition strategies mediate visuo-spatial reasoning in stabilized schizophrenia patients. AB - OBJECTIVES: Cognitive deficits are of fundamental importance to the clinical picture of schizophrenia and are on the verge to be included as diagnostic criteria in the DSM-V. While focusing on information processing deficits, no emphasis has been put on whether patients' deficits can be accounted for by maladaptive information acquisition strategy deployment. METHODS: We tested 24 stabilized patients with schizophrenia and 25 matched controls in a visuo-spatial analogy task with graded difficulty. Eye movement recordings served to identify information acquisition strategies. RESULTS: Patients compared to healthy controls showed slower reaction times in the easiest condition and higher error rates in the more difficult conditions. Eye movement recordings illustrated that overall mean fixation duration increased with increasing task difficulty in healthy controls only. Further, patients deployed a more efficient strategy ("constructive matching") less often than healthy controls in the easier conditions. CONCLUSIONS: These results suggest that information acquisition strategies mediate visuo-spatial cognitive performance in schizophrenia. Patients adopt a less efficient strategy independently of task difficulty indicated by a characteristic behavioural pattern. Our results point to a powerful tool of improving patients' performance in cognitively demanding tasks by training them in more flexible cognitive (e.g., information acquisition) strategy deployment. PMID- 21288071 TI - Analyses of donor-derived keratinocytes in hairy and nonhairy skin biopsies of female patients following allogeneic male bone marrow transplantation. AB - Skin samples taken from 6 female patients receiving allogeneic bone marrow transplants (BMT) from male siblings (n=5) or from unrelated human leukocyte antigen (HLA)-matched male donor (n=1) due to hematological malignancies were studied for the presence of donor cells. One nontransplanted male and 1 female control that received female BM were used as further controls of the technique. Skin biopsies were taken from the scalp and the back from each patient 12-16 years after the successful BMT. We have found donor chimerism in all of the 6 patients in both of their biopsies. Using single and double immunostainings in combination with Y chromosome hybridization, we observed that there are cytokeratin-expressing donor-derived cells in the epidermis of all the 6 patients, the numbers being slightly higher in the scalp (0.37%-1.78%) than in the back (0.32%-1.08%) biopsies. The indication for BMT, and the age of the patient did not seem to have any effect on the numbers found. A few of the double labeled cells also stained for Ki67, a marker of cellular proliferation, suggesting that the engrafted cells were able to further divide in the epidermis. In 2 patients we observed patches of donor keratinocytes within the epidermis, suggesting a clonal origin. We conclude that in agreement with some and in contrast to other published studies, BM-derived circulating cells are able to engraft in the human skin and to further proliferate there and thus contribute to tissue renewal. These data raise the possibility to use BM cells in regenerative medicine to help in extended injuries, large surface burns, or lack of skin due to other reasons. PMID- 21288072 TI - Is an interest in computers or individual/team sports associated with adolescent psychiatric disorders? AB - The Internet plays a major role in adolescents' free time activities and communication nowadays. The aim here was to investigate the possibility of an association of computers and video games or sports (team, individual) with psychiatric disorders among underage psychiatric inpatients. The series of adolescents (n = 508) had been diagnosed using semistructured interviews (K-SADS PL). The results showed that an interest in computers and video games did not increase the risk of any specific psychiatric disorder among these adolescent inpatients, but the likelihood of a substance-related disorder was statistically significantly lower among the boys with computers as a hobby. Team sports were related to increased likelihood of conduct disorder among the boys, whereas the likelihood of an affective disorder was reduced. No such association was found in individual sports or among the girls. We conclude that social contacts and peers play an important role in preventing adolescent depression. PMID- 21288073 TI - Employee safety as a goal creates communication, cooperation, and using the best data available. PMID- 21288074 TI - Fluorine--a current literature review. An NRC and ATSDR based review of safety standards for exposure to fluorine and fluorides. AB - BACKGROUND: A review of the literature of the element fluorine and its bonded form, fluoride, was undertaken. Generally regarded as safe, an expanding body of literature reveals that fluoride's toxicity has been unappreciated, un scrutinized, and hidden for over 70 years. The context for the literature search and review was an environmental climate-change study, which demonstrated widespread fluoride contamination by smokestack emissions from coal-fired electricity-generating plants. The objective of this review is to educate and inform regarding the ubiquitous presence and harmful nature of this now ever present corrosive and reactive toxin. METHODS: Methods include examination of national health agency reviews, primarily the National Research Council (NRC), Agency for Toxic Substances & Disease Registry (ATSDR), standard medical toxicology references, text books, as well as reports and documents from both private and public research as well as consumer-based NGOs. Study criteria were chosen for relevancy to the subject of the toxicity of fluoride. RESULTS: Fluoride is the extreme electron scavenger, the most corrosive of all elements, as well as the most-reactive. Fluoride appears to attack living tissues, via several mechanisms. Fluoride renders strong evidence that it is a non-biological chemical, demonstrating no observed beneficial function or role in organic chemistry, beyond use as a pesticide or insecticide. Fluorine has a strong role to play in industry, having been utilized extensively in metals, plastics, paints, aluminium, steel, and uranium production. CONCLUSION: Due to its insatiable appetite for calcium, fluorine and fluorides likely represent a form of chemistry that is incompatible with biological tissues and organ system functions. Based on an analysis of the affects of fluoride demonstrated consistently in the literature, safe levels have not been determined nor standardized. Mounting evidence presents conflicting value to its presence in biological settings and applications. Evidence examined in this review of the literature, and specifically the recent report by the National Research Council (NRC), offer strong support for an immediate reconsideration concerning risk vs benefit. Consensus recommendations from several sources are presented. PMID- 21288075 TI - The closer the relationship, the more the interaction on facebook? Investigating the case of Taiwan users. AB - This study argues for the necessity of applying offline contexts to social networking site research and the importance of distinguishing the relationship types of users' counterparts when studying Facebook users' behaviors. In an attempt to examine the relationship among users' behaviors, their counterparts' relationship types, and the users' perceived acquaintanceships after using Facebook, this study first investigated users' frequently used tools when interacting with different types of friends. Users tended to use less time- and effort-consuming and less privacy-concerned tools with newly acquired friends. This study further examined users' behaviors in terms of their closeness and intimacy and their perceived acquaintanceships toward four different types of friends. The study found that users gained more perceived acquaintanceships from less close friends with whom users have more frequent interaction but less intimate behaviors. As for closer friends, users tended to use more intimate activities to interact with them. However, these activities did not necessarily occur more frequently than the activities they employed with their less close friends. It was found that perceived acquaintanceships with closer friends were significantly lower than those with less close friends. This implies that Facebook is a mechanism for new friends, rather than close friends, to become more acquainted. PMID- 21288076 TI - Achieving effective learning effects in the blended course: a combined approach of online self-regulated learning and collaborative learning with initiation. AB - In many countries, undergraduates are required to take at least one introductory computer course to enhance their computer literacy and computing skills. However, the application software education in Taiwan can hardly be deemed as effective in developing students' practical computing skills. The author applied online self regulated learning (SRL) and collaborative learning (CL) with initiation in a blended computing course and examined the effects of different combinations on enhancing students' computing skills. Four classes, comprising 221 students, participated in this study. The online SRL and CL with initiation (G1, n = 53), online CL with initiation (G2, n = 68), and online CL without initiation (G3, n = 68) were experimental groups, and the last class, receiving traditional lecture (G4, n = 32), was the control group. The results of this study show that students who received the intervention of online SRL and CL with initiation attained significantly best grades for practical computing skills, whereas those that received the traditional lectures had statistically poorest grades among the four classes. The implications for schools and educators who plan to provide online or blended learning for their students, particularly in computing courses, are also provided in this study. PMID- 21288077 TI - Neuroblastomas with discordant genotype-phenotype relationships: report of four cases with MYCN amplification and favorable histology. AB - MYCN amplification prevents cellular differentiation and promotes mitotic and karyorrhectic activities in neuroblastomas. Hence, MYCN-amplified tumors typically show an appearance of neuroblastoma of either an undifferentiated or a poorly differentiated subtype with a high mitosis-karyorrhexis index. In addition, they are classified as part of the unfavorable histology group, according to the International Neuroblastoma Pathology Classification. Large cell type and/or presence of prominent nucleoli is also reported to be an additional hallmark of MYCN amplification. However, there are few neuroblastomas having MYCN amplification and favorable histology. Four cases of MYCN amplification and favorable histology were identified in our file of 63 cases of neuroblastoma. The patients (M?F = 3?1) were diagnosed between 6 and 13 months of age, and all had adrenal primary tumors and were treated with high-dose therapy and autologous stem cell rescue. Three patients (stages 1, 3, and 4) are alive and well 7 years, 26 months, and 19 months after diagnosis, respectively. One patient with stage 4 disease died 8 months after diagnosis. Their tumors showed the same histologic feature of neuroblastoma: poorly differentiated subtype with a low mitosis karyorrhexis index; they were not qualified as large cell type and had no prominent nucleoli. MYCN amplification of those tumors was confirmed by fluorescence in situ hybridization in all 4 cases, but MYCN protein expression was not demonstrated by immunohistochemistry (4 cases) and MYCN mRNA was not detected by reverse transcriptase polymerase chain reaction (1 case). Those cases showed a discrepant genotype-phenotype that was not simply a laboratory observation but could indicate the concept that that MYCN amplification did not automatically equate to a poor prognosis in this group of patients. PMID- 21288078 TI - Fidaxomicin versus vancomycin for Clostridium difficile infection. AB - BACKGROUND: Clostridium difficile infection is a serious diarrheal illness associated with substantial morbidity and mortality. Patients generally have a response to oral vancomycin or metronidazole; however, the rate of recurrence is high. This phase 3 clinical trial compared the efficacy and safety of fidaxomicin with those of vancomycin in treating C. difficile infection. METHODS: Adults with acute symptoms of C. difficile infection and a positive result on a stool toxin test were eligible for study entry. We randomly assigned patients to receive fidaxomicin (200 mg twice daily) or vancomycin (125 mg four times daily) orally for 10 days. The primary end point was clinical cure (resolution of symptoms and no need for further therapy for C. difficile infection as of the second day after the end of the course of therapy). The secondary end points were recurrence of C. difficile infection (diarrhea and a positive result on a stool toxin test within 4 weeks after treatment) and global cure (i.e., cure with no recurrence). RESULTS: A total of 629 patients were enrolled, of whom 548 (87.1%) could be evaluated for the per-protocol analysis. The rates of clinical cure with fidaxomicin were noninferior to those with vancomycin in both the modified intention-to-treat analysis (88.2% with fidaxomicin and 85.8% with vancomycin) and the per-protocol analysis (92.1% and 89.8%, respectively). Significantly fewer patients in the fidaxomicin group than in the vancomycin group had a recurrence of the infection, in both the modified intention-to-treat analysis (15.4% vs. 25.3%, P=0.005) and the per-protocol analysis (13.3% vs. 24.0%, P=0.004). The lower rate of recurrence was seen in patients with non-North American Pulsed Field type 1 strains. The adverse-event profile was similar for the two therapies. CONCLUSIONS: The rates of clinical cure after treatment with fidaxomicin were noninferior to those after treatment with vancomycin. Fidaxomicin was associated with a significantly lower rate of recurrence of C. difficile infection associated with non-North American Pulsed Field type 1 strains. (Funded by Optimer Pharmaceuticals; ClinicalTrials.gov number, NCT00314951.) PMID- 21288079 TI - The search for effective treatment of Clostridium difficile infection. PMID- 21288080 TI - The more things change .... PMID- 21288081 TI - An evaluation of the occluding effects of Er;Cr:YSGG, Nd:YAG, CO2 and diode lasers on dentinal tubules: a scanning electron microscope in vitro study. AB - OBJECTIVE AND BACKGROUND: Dentin hypersensitivity (DH) is one of the most frequent problems causing patients' complaints following stimulation of cervically exposed dentin. Studies have shown that different lasers have various occluding effects on dentinal tubules. This study is aimed at evaluating the occluding effects of Er;Cr:YSGG (P:0.25W,F:20Hz,Pd:140MUS), Nd:YAG (P:1W,F:20Hz), CO(2) (P:1W, Pd:50MUs), and 810-nm diode (P:2 W, Pd:30ms) lasers on dentinal tubules. METHODS: Fifteen human third molars were collected and ground-sectioned vertically on the buccal and lingual surfaces to yield two dentin disks of 2-mm thickness. Then, four sites for laser irradiation and one control site were marked in the cervical areas of the dentin disks. Before laser application, specimens were exposed to a 14% EDTA solution to expose dentinal tubules and were then evaluated by scanning electron microscopy (SEM). The tubules' entrance diameters were determined by "scale-bar" software (Phillips Scale-Bar, Phillips, Amsterdam, The Netherlands), which is specifically designed for SEM. The mean diameters for the tubules were then estimated for each site and analyzed statistically. RESULTS: The mean dentinal tubule entrance diameters for Er;Cr:YSGG, 810-nm diode, CO(2), and Nd:YAG, were 1.73, 3.27, 2.10, and 1.64 microns, respectively, compared with 3.52 microns before laser irradiation. Overall, the furthest reduction in mean tubule diameter resulted from the Nd: YAG laser (53%). However, tubular diameter reduction in all laser groups (p<0.05) was found to be statistically significant. In all laser groups, melting of the peritubular dentin was the dominant observed phenomenon. CONCLUSION: Our results indicate that Nd: YAG, Er; Cr: YSGG, and CO(2) lasers, through their ability to melt peritubular dentin, can occlude dentinal tubules partially or totally, and therefore reduce patients' hypersensitivity symptoms. The 810-nm diode laser sealed tubules to a far lesser degree, with negligible effects on desensitization. PMID- 21288083 TI - Photomedicine and LLLT literature watch. PMID- 21288085 TI - Trans-splicing, more than meets the eye: multifaceted therapeutics for spinal muscular atrophy. PMID- 21288086 TI - Mesenchymal stromal cells for graft-versus-host disease. AB - Mesenchymal stromal cells (MSCs) have been shown to mediate immune responses in vitro and in vivo. These observations have led to clinical trials of MSC administration to ameliorate acute graft-versus-host disease (GVHD), the most serious complication arising after allogeneic hematopoietic cell transplantation. Clinical data suggest a benefit in approximately two-thirds of patients with steroid-resistant acute GVHD. Preliminary studies have been reported on the use of MSCs to treat de novo acute GVHD, for prophylaxis of the condition, and more recently, in the management of chronic GVHD. Although preclinical data inferred a possible role of MSCs in affecting GVHD mechanisms, more robust animal models became available only after numerous clinical trials with these cells had been undertaken. Further clinical trials, the development of more appropriate animal models and an effective means of tracking and imaging the introduced cells in real time in patients, are required to better define their role in this important area of medicine. PMID- 21288087 TI - Accountable care organizations at academic medical centers. PMID- 21288088 TI - Clearing out the underbrush in constitutional challenges to health insurance reform. PMID- 21288089 TI - Accountable care at academic medical centers--lessons from Johns Hopkins. PMID- 21288090 TI - Safety of influenza A (H1N1) vaccine in postmarketing surveillance in China. AB - BACKGROUND: On September 21, 2009, China began administering vaccines, obtained from 10 different manufacturers, against 2009 pandemic influenza A (H1N1) virus infection in priority populations. We aimed to assess the safety of this vaccination program. METHODS: We designed a plan for passive surveillance for adverse events after immunization with the influenza A (H1N1) vaccine. Physicians or vaccination providers were required to report the numbers of vaccinees and all adverse events to their local Center for Disease Control and Prevention (CDC), which then reported the data to the Chinese CDC through the online National Immunization Information System's National Adverse Event Following Immunization Surveillance System. Data were collected through March 21, 2010, and were verified and analyzed by the Chinese CDC. RESULTS: A total of 89.6 million doses of vaccine were administered from September 21, 2009, through March 21, 2010, and 8067 vaccinees reported having an adverse event, for a rate of 90.0 per 1 million doses. The age-specific rates of adverse events ranged from 31.4 per 1 million doses among persons 60 years of age or older to 130.6 per 1 million doses among persons 9 years of age or younger, and the manufacturer-specific rates ranged from 4.6 to 185.4 per 1 million doses. A total of 6552 of the 8067 adverse events (81.2%; rate, 73.1 per 1 million doses) were verified as vaccine reactions; 1083 of the 8067 (13.4%; rate, 12.1 per 1 million doses) were rare and more serious (vs. common, minor events), most of which (1050) were allergic reactions. Eleven cases of the Guillain-Barre syndrome were reported, for a rate of 0.1 per 1 million doses, which is lower than the background rate in China. CONCLUSIONS: No pattern of adverse events that would be of concern was observed after the administration of influenza A (H1N1) vaccine, nor was there evidence of an increased risk of the Guillain-Barre syndrome. PMID- 21288091 TI - Videos in clinical medicine. Arterial puncture for blood gas analysis. PMID- 21288092 TI - Images in clinical medicine. Pseudomembranous colitis. PMID- 21288093 TI - Focus on research: weighing the benefits and costs of HPV vaccination of young men. PMID- 21288094 TI - Efficacy of quadrivalent HPV vaccine against HPV Infection and disease in males. AB - BACKGROUND: Infection with human papillomavirus (HPV) and diseases caused by HPV are common in boys and men. We report on the safety of a quadrivalent vaccine (active against HPV types 6, 11, 16, and 18) and on its efficacy in preventing the development of external genital lesions and anogenital HPV infection in boys and men. METHODS: We enrolled 4065 healthy boys and men 16 to 26 years of age, from 18 countries in a randomized, placebo-controlled, double-blind trial. The primary efficacy objective was to show that the quadrivalent HPV vaccine reduced the incidence of external genital lesions related to HPV-6, 11, 16, or 18. Efficacy analyses were conducted in a per-protocol population, in which subjects received all three vaccinations and were negative for relevant HPV types at enrollment, and in an intention-to-treat population, in which subjects received vaccine or placebo, regardless of baseline HPV status. RESULTS: In the intention to-treat population, 36 external genital lesions were seen in the vaccine group as compared with 89 in the placebo group, for an observed efficacy of 60.2% (95% confidence interval [CI], 40.8 to 73.8); the efficacy was 65.5% (95% CI, 45.8 to 78.6) for lesions related to HPV-6, 11, 16, or 18. In the per-protocol population, efficacy against lesions related to HPV-6, 11, 16, or 18 was 90.4% (95% CI, 69.2 to 98.1). Efficacy with respect to persistent infection with HPV-6, 11, 16, or 18 and detection of related DNA at any time was 47.8% (95% CI, 36.0 to 57.6) and 27.1% (95% CI, 16.6 to 36.3), respectively, in the intention-to-treat population and 85.6% (97.5% CI, 73.4 to 92.9) and 44.7% (95% CI, 31.5 to 55.6) in the per-protocol population. Injection-site pain was significantly more frequent among subjects receiving quadrivalent HPV vaccine than among those receiving placebo (57% vs. 51%, P<0.001). CONCLUSIONS: Quadrivalent HPV vaccine prevents infection with HPV-6, 11, 16, and 18 and the development of related external genital lesions in males 16 to 26 years of age. (Funded by Merck and others; ClinicalTrials.gov number, NCT00090285.). PMID- 21288095 TI - NT5E mutations and arterial calcifications. AB - BACKGROUND: Arterial calcifications are associated with increased cardiovascular risk, but the genetic basis of this association is unclear. METHODS: We performed clinical, radiographic, and genetic studies in three families with symptomatic arterial calcifications. Single-nucleotide-polymorphism analysis, targeted gene sequencing, quantitative polymerase-chain-reaction assays, Western blotting, enzyme measurements, transduction rescue experiments, and in vitro calcification assays were performed. RESULTS: We identified nine persons with calcifications of the lower-extremity arteries and hand and foot joint capsules: all five siblings in one family, three siblings in another, and one patient in a third family. Serum calcium, phosphate, and vitamin D levels were normal. Affected members of Family 1 shared a single 22.4-Mb region of homozygosity on chromosome 6 and had a homozygous nonsense mutation (c.662C->A, p.S221X) in NT5E, encoding CD73, which converts AMP to adenosine. Affected members of Family 2 had a homozygous missense mutation (c.1073G->A, p.C358Y) in NT5E. The proband of Family 3 was a compound heterozygote for c.662C->A and c.1609dupA (p.V537fsX7). All mutations found in the three families result in nonfunctional CD73. Cultured fibroblasts from affected members of Family 1 showed markedly reduced expression of NT5E messenger RNA, CD73 protein, and enzyme activity, as well as increased alkaline phosphatase levels and accumulated calcium phosphate crystals. Genetic rescue experiments normalized the CD73 and alkaline phosphatase activity in patients' cells, and adenosine treatment reduced the levels of alkaline phosphatase and calcification. CONCLUSIONS: We identified mutations in NT5E in members of three families with symptomatic arterial and joint calcifications. This gene encodes CD73, which converts AMP to adenosine, supporting a role for this metabolic pathway in inhibiting ectopic tissue calcification. (Funded by the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute of the National Institutes of Health.). PMID- 21288096 TI - Clinical practice. Gout. PMID- 21288097 TI - Myocardial infarction due to percutaneous coronary intervention. PMID- 21288098 TI - Images in clinical medicine. Madelung's disease. PMID- 21288099 TI - Clinical problem-solving. Avoiding a rash diagnosis. PMID- 21288100 TI - Equipoise and the dilemma of randomized clinical trials. PMID- 21288101 TI - CYP2C19 genotype and outcomes of clopidogrel treatment. PMID- 21288102 TI - CYP2C19 genotype and outcomes of clopidogrel treatment. PMID- 21288104 TI - Endometriosis-associated ovarian carcinomas. PMID- 21288105 TI - Endometriosis-associated ovarian carcinomas. PMID- 21288107 TI - Profound deafness in childhood. PMID- 21288109 TI - Rejection of the kidney allograft. PMID- 21288111 TI - More on aprepitant for erlotinib-induced pruritus. PMID- 21288112 TI - More on aprepitant for erlotinib-induced pruritus. PMID- 21288114 TI - p53 lesions in leukemic transformation. PMID- 21288118 TI - The use of Pro Re Nata or Statim medications for behavioral control: a summary of experience at a tertiary care children's mental health center. AB - The present study aims to identify patterns for use of medication given pro re nata (PRN or "on an as needed [preordered] basis") or statim (STAT [a new order] or "at once, immediately") and their efficacy in controlling aggressive behavior in the mental health (MH) services environment. PRN and STAT medication data were combined and referred to as PRN throughout this article, as the data were not collected in a manner required to differentiate between PRN and STAT medication administration. Analyzed data were extracted from the clinical records of a sample of children and youth admitted for the first time to a tertiary MH center. MH Program patients (characterized by at least one Axis I psychiatric diagnosis [Axis I group]) were compared to Dual Diagnosis Program patients (characterized by an Axis I diagnosis in addition to an Axis II diagnosis of mental retardation [Axis II group]). Age, gender, Program (Axis I or II group), and the length of stay for treatment produced significant differences in the use of PRNs between the two groups. Further, the study investigated the precipitating factors leading to use of PRNs, in conjunction with the level of supervision and the de escalation techniques used to avoid the use of PRNs. Axis I patients were more likely to endanger others, whereas Axis II patients were more likely to endanger themselves. Both groups of patients demonstrated a need for an increased level of supervision prior to the crisis. Olanzapine, chlorpromazine, and lorazepam were effective in calming patients and preventing further aggressive outbursts. PMID- 21288119 TI - Medication refusal in children with oppositional defiant disorder or conduct disorder and comorbid attention-deficit/hyperactivity disorder: medication history and clinical correlates. AB - Abstract Objective: This study examines the characteristics of 96 children with attention-deficit/hyperactivity disorder (ADHD) and their families who refused a recommendation for medication as part of their treatment for disruptive disorders. METHODS: The ADHD cases were taken from a sample of 139 youth (age 6 11) who were recruited for a clinical trial that compared the administration of a modular psychosocial treatment in an outpatient clinic or community settings. Medication management was an optional treatment module for children with ADHD in both conditions. Children who were (vs. were not) taking medication at intake, and children who accepted (vs. refused) medication recommendations during the study were compared on diagnostic and clinical measures related to child, school, parent, and family domains of functioning. RESULTS: Parents of 30% of the children refused study medication for ADHD. Parental medication acceptability and intake correlated highly with both medication history and study refusal of medication. Increased parental self-efficacy and emotional support for their youth correlated with medication refusal. No demographics and few child or school factors were associated with medication refusal. Medication use was associated with reductions in some key ADHD symptoms, but did not affect disruptive behaviors as did the psychosocial interventions. CONCLUSION: Medication refusers remain poorly understood but certain correlates, such as parental self-efficacy, parental emotional support for their youth, and medication acceptability, warrant further evaluation. PMID- 21288120 TI - Assessment of core competencies in childhood attention-deficit/hyperactivity disorder practice. AB - The study assessed competencies and practices of a large group of healthcare providers in childhood attention-deficit/hyperactivity disorder (ADHD), and identified barriers to improving care. Methods were self-assessment using an Internet questionnaire with a standardized patient case; analysis compared with professional association recommendations; and measurement of provider self efficacy levels. Of 2,103 participants who completed the assessment, 44% were only "somewhat confident" and 20% "not at all confident" in being up-to-date in diagnosis and management of ADHD. Based on American Board of Psychiatry and Neurology's Child and Adolescent Core Competencies and American Academy of Child and Adolescent Psychiatry Practice Parameters, participants selected appropriate responses 60% of the time, 57% for items on diagnosis, and 62% for treatment. Providers under-used the family interview, and relied on ADHD rating scales for diagnosis. Lack of effective communication between provider, child, family, and teachers was the top barrier cited, yet participants rated involving the child and family as very important. In conclusion, education should include training on effective communication with the family to improve care for children with ADHD and dedication of further health education resources in the area of ADHD is needed. PMID- 21288121 TI - A comparison of atomoxetine administered as once versus twice daily dosing on the school and home functioning of children with attention-deficit/hyperactivity disorder. AB - OBJECTIVE: This secondary analysis examined the efficacy and tolerability of atomoxetine (ATX) dosed once (QD) versus twice (BID) daily in 55 children aged 6 12 with attention-deficit/hyperactivity disorder (ADHD). METHODS: The original 8 week trial was designed to assess the benefits of adding behavioral therapy to ATX. In it, all subjects were treated openly with ATX, with 50% randomly assigned to additional behavioral treatments. Every subject was started on QD dosing with a target dose of 1.2 mg/kg per day. A switch to BID dosing was allowed at study midpoint to improve tolerability and efficacy. Subjects not responding to ATX at midpoint were also given the option of 0.6 mg/kg dose increase. ADHD and oppositional defiant disorder (ODD) symptoms, global functioning, side effects, and classroom performance were measured weekly. RESULTS: There were 22 subjects (40%) who switched to BID dosing at midpoint (mean dose = 1.56 mg/kg per day) with the other 33 remaining on QD dosing (mean dose = 1.33 mg/kg per day). The BID group did not display any improvement in parent-rated ODD symptoms during the first 4 weeks of the study on QD dosing, but there was a significant improvement seen after the addition of the second ATX dose (p < 0.05). However, BID dosing was not associated with differential rates of change for parent-rated ADHD symptoms or impairment, teacher ratings, or other measures of classroom functioning. BID dosing was associated with decreased rates of stomachaches (p < 0.05) but more persistent appetite loss than QD dosing. The degree of improvement observed during the first half of the study in ratings of global impairment and ODD but not ADHD symptoms predicted a switch to BID dosing at midpoint (p < 0.05). CONCLUSIONS: The addition of an afternoon dose of ATX was associated with improved control of ODD symptoms at home, with no change in school functioning. PMID- 21288122 TI - Early diagnoses and psychotherapeutic medication treatment experiences of a cohort of children under 6 years old who received antipsychotic treatment in Florida's Medicaid program. AB - OBJECTIVE: To describe the diagnostic characteristics and psychotherapeutic medication experiences of a cohort of children who received antipsychotic treatment before their sixth birthday. METHODS: Children enrolled in Florida's Medicaid program were identified as having initiated an index episode of antipsychotic treatment before their sixth birthday. The characteristics of these children were compared to nonrecipients who were less than 6 years old on January 1, 2004. An index episode is described as the filling of at least two consecutive antipsychotic prescriptions with a gap no greater than 15 days between the last day supplied of the first prescription and the fill date of the second prescription. We describe the diagnoses and psychotherapeutic medication experiences of these children during the 365 days before the start of their index episodes (preindex periods) and during the 365 days immediately after the start of their index episodes (index periods). RESULTS: Five hundred twenty-eight recipients were identified. Recipients were more likely than nonrecipients to be male, to be older, and to have a supplemental security income enrollment status. Recipients were exposed to psychotherapeutic medications at very early ages. Four hundred thirty-nine (83%) had already been treated with some psychotherapeutic medication during their preindex periods. Of these children, 303 (69%) filled at least one prescription for an antipsychotic medication. Index antipsychotic episodes were often lengthy. Mean +/- standard deviation and median episode lengths were 266.9 +/- 286.8 and 174 days, respectively. During the index periods half of the children were found to have attention-deficit/hyperactivity disorder and 18% had disruptive behavior disorders. Treatment during these periods included other classes of psychotherapeutic medications for 73% of children. Nearly 30% (29.6%) received two or more classes of medications in addition to antipsychotics. CONCLUSIONS: We found a large group of very young children who were persistently treated with antipsychotic medications. This early and extensive exposure is a cause for concern. PMID- 21288123 TI - Relatively mild symptoms after an olanzapine intoxication in a 2-year-old girl with excessively high serum levels. PMID- 21288124 TI - "I want to be taking my own last breath": patients' reflections on illness when presenting to the emergency department at the end of life. AB - OBJECTIVE: To understand perceptions regarding their illness of patients who present to the Emergency Department at the end of life. METHODS: Semistructured one-on-one interviews were performed with a convenience sample of seriously ill, Emergency Department (ED) patients with advanced illness presenting to an urban, public hospital. A bilingual Latina health promoter used a predetermined discussion guide to conduct all interviews. Non-English- or Non-Spanish-speaking patients and those with uncontrolled symptoms or cognitive deficits were excluded. All interviews were recorded and transcribed, and grounded theory methodology was used to analyze the results. RESULTS: Thirteen patients with advanced illness participated, 8 of whom were Spanish-speaking only. Because of difficulty accessing care and financial concerns, patients with advanced illness present to EDs when their pain or other symptoms are out of control. The majority derive great comfort and strength from their faith in God, who they believe determines their fate. Most listed spending time with family, and not being a burden, as most important at the end of life, and many expressed a preference to die at home surrounded by loved ones. Almost none had spoken to physicians about their care preferences. CONCLUSIONS: Patients with advanced illness present to the ED of a safety net hospital when symptoms are out of control. They have many financial concerns, want to spend their remaining days with family, and do not want to be a burden. Most derive immense comfort from faith in God, but do not feel they have control over their own fate. PMID- 21288125 TI - Can we make reports of end-of-life care quality more consumer-focused? results of a nationwide quality measurement program. AB - OBJECTIVES: The goal of this study was to define families' priorities for various aspects of end-of-life care, and to determine whether scores that reflect these priorities alter facilities' quality rankings. DESIGN: Nationwide telephone survey. SETTING: 62 VA medical centers, including acute and long term care. PARTICIPANTS: For each patient who died in a participating facility, one family member was invited to participate. MEASUREMENTS: A survey included 14 items describing key aspects of the patient's care in his or her last month of life, and one global rating. A weighted score was calculated based on the association between each item and the global rating. RESULTS: Interviews were completed with family members for 3,897 of 7,110 patients (55%). Items showed an approximately 5 fold range of weights, indicating a wide variation in the importance that families placed on aspects of palliative care (low: pain management, weight = 0.54, 95% CI 0.38-0.70;/P/<0.001; high: providers were "kind, caring, and respectful: weight = 2.46, 95% CI 2.24-2.68;/P/<0.001). Weights were homogeneous across patient subgroups, and there were no significant changes in facilities' quality rankings when weights were used. Both weighted and unweighted scores showed similar evidence of the impact of process measures. CONCLUSION: There appears to be wide variation in the importance that families place on several aspects of end-of-life care. However, the impact of weighting was generally even across patient subgroups and facilities. Therefore, the use of weights to account for families' priorities is not likely to alter a facility's quality score. PMID- 21288126 TI - The role of laparoscopic techniques in children with suspected post transplantation lymphoproliferative disorders. AB - AIM: To assess the role of minimally invasive surgery (MIS) to diagnose post transplantation lymphoproliferative disorder (PTLD) in pediatric patients. METHODS: Thirty-four patients (20 male, 14 female) underwent organ transplantation (14 liver, 14 kidney, 3 heart, 2 lung, 1 heart-lung) from May 1992 to November 2008 (mean age at transplantation, 66 months; range, 5-277), in whom a biopsy was performed for suspected PTLD from May 1993 to September 2009. The time point of onset, type of PTLD, rate of intraabdominal manifestations with need of MIS, and its accuracy were assessed. RESULTS: Twenty-four of 34 patients (70%) had biopsies of superficial lymph nodes (9), oropharyngeal biopsy (5), gastrointestinal endoscopy or bronchoscopy (5), ultrasound-guided biopsies (3), biopsy of the bone marrow (1), or of the orbita (1). Data of the technique used were unavailable in 3 (9%). Due to lack of superficially located lesions, 6 of 34 patients (18%) had laparoscopic biopsy, of which 4 had abdominal organ graft. Laparoscopic biopsy was successful in 5 of 6 cases (83%). Abscess formation at area of transplanted kidney led to conversion in 1. Tumor extension to the abdominal wall led to a primary biopsy via a mini-laparotomy in another case. One patient with abdominal Burkitt's lymphoma developed a trocar metastasis, successfully treated by systemic chemotherapy. No other complications were observed after MIS. Accuracy of MIS biopsies was 100%. The onset of PTLD was significantly later diagnosed in cases of explicit intraabdominal PTLD (81 +/- 6.3 versus 28 +/- 5.3 months; P < .001). Morbidity and mortality were not influenced by biopsy technique or time point of PTLD onset. CONCLUSIONS: In 20% of pediatric PTLD cases an intraabdominal biopsy is required due to explicit intraabdominal manifestation. As laparoscopic surgery was even feasible in patients after prior abdominal organ transplantation, we suggest laparoscopic biopsy as a safe tool for diagnosing PTLD. PMID- 21288127 TI - Technical skill set training in natural orifice transluminal endoscopic surgery: how should we approach it? AB - BACKGROUND: The boundaries in minimally invasive techniques are continually being pushed further. Recent years have brought new and exciting changes with the advent of natural orifice transluminal endoscopic surgery. With the evolution of this field of surgery come challenges in the development of new instruments and the actual steps of the procedure. Included in these challenges is the idea of developing a proficiency-based curriculum for training. METHODS: A review of the currently available literature was performed to support the points discussed. RESULTS: In this article we address and discuss the issues of who, when, where, and how to teach suitable trainees in the technique of natural orifice transluminal endoscopic surgery. CONCLUSION: What comes to the fore is the importance of providing safe and structured training in these techniques. PMID- 21288128 TI - Observation of miRNA gene expression in zebrafish embryos by in situ hybridization to microRNA primary transcripts. AB - MicroRNAs (miRNAs) add a previously unexpected layer to the post-transcriptional regulation of protein production. Although locked nucleic acids (LNAs) reveal the distribution of mature miRNAs by in situ hybridization (ISH) experiments in zebrafish and other organisms, high cost has restricted their use. Further, LNA probes designed to recognize mature miRNAs do not distinguish expression patterns of two miRNA genes that produce the same mature miRNA sequence. Riboprobes are substantially less expensive than LNAs, but have not been used to detect miRNA gene expression because they do not bind with high affinity to the short, 22 nucleotide-long mature miRNAs. To solve these problems, we capitalized on the fact that miRNAs are initially transcribed into long primary transcripts (pri mRNAs). We show here that conventional digoxigenin-labeled riboprobes can bind to primary miRNA transcripts in zebrafish embryos. We tested intergenic and intronic miRNAs (miR-10d, miR-21, miR-27a, miR-126a, miR-126b, miR-138, miR-140, miR-144, miR-196a1, miR-196a2, miR-196a2b [miR-196c], miR-196b, miR-196b1b [miR-196d], miR 199, miR-214, miR-200, and miR-222) in whole mounts and some of these in histological sections. Results showed that pri-miRNA ISH provides an attractive and cost-effective tool to study miRNA expression by ISH. We use this method to show that miR-126a and miR-126b are transcribed in the caudal vasculature in the pattern of their neighboring gene ci116 or host gene egfl7, respectively, and that the chondrocyte miRNA mir-140 lies downstream of Sox9 in development of the craniofacial skeleton. PMID- 21288129 TI - Determination of O6-methylguanine DNA methyltransferase promoter methylation in non-small cell lung cancer. AB - Aberrant methylation of promoter CpG islands is known to be a major inactivation mechanism of the tumor-related genes including DNA repair genes. The objective of this study was to determine the frequency of promoter methylation of the O6 methylguanine DNA methyltransferase (MGMT) gene as a DNA repair gene in nonsmall cell lung cancer (NSCLC) and to analyze the correlation with clinicopathological parameters including age, gender, smoking status, histological subtype, and clinical stage. Eighty patients with NSCLC were included in this study. The analysis of DNA methylation was performed on formalin-fixed, paraffin-embedded lung cancer tissues. Following DNA isolation and bisulfite treatment, DNA methylation was analyzed by methylation-specific real-time polymerase chain reaction. MGMT promoter methylation was detected in 51 of 80 (64%) NSCLC patients. There was a significant correlation between MGMT methylation and tumor stage (p = 0.01). The frequencies of the promoter methylation of MGMT gene in smokers and older patients were higher than in their counterparts. In conclusion, the present study provides strong evidence for a higher frequency of promoter methylation of the MGMT gene in NSCLC, indicating that it is a common event during the carcinogenesis of NSCLC. PMID- 21288130 TI - Identification of Escherichia coli O157 by using a novel colorimetric detection method with DNA microarrays. AB - Shiga toxin-producing Escherichia coli O157 is a leading cause of foodborne illness worldwide. To evaluate better methods to rapidly detect and genotype E. coli O157 strains, the present study evaluated the use of ampliPHOX, a novel colorimetric detection method based on photopolymerization, for pathogen identification with DNA microarrays. A low-density DNA oligonucleotide microarray was designed to target stx1 and stx2 genes encoding Shiga toxin production, the eae gene coding for adherence membrane protein, and the per gene encoding the O157-antigen perosamine synthetase. Results from the validation experiments demonstrated that the use of ampliPHOX allowed the accurate genotyping of the tested E. coli strains, and positive hybridization signals were observed for only probes targeting virulence genes present in the reference strains. Quantification showed that the average signal-to-noise ratio values ranged from 47.73 +/- 7.12 to 76.71 +/- 8.33, whereas average signal-to-noise ratio values below 2.5 were determined for probes where no polymer was formed due to lack of specific hybridization. Sensitivity tests demonstrated that the sensitivity threshold for E. coli O157 detection was 100-1000 CFU/mL. Thus, the use of DNA microarrays in combination with photopolymerization allowed the rapid and accurate genotyping of E. coli O157 strains. PMID- 21288131 TI - In vitro studies on the effect of pH and volatile fatty acid concentration, as influenced by diet, on the survival of inoculated nonacid- and acid-adapted Salmonella in bovine rumen fluid and feces. AB - The aim of this study was to examine the effect of pH and volatile fatty acids concentrations, as influenced by bovine diet, on the survival of Salmonella in inoculated rumen fluid and feces, thus providing preliminary data on the potential application of dietary manipulation as a preharvest control strategy to reduce Salmonella contamination at slaughter. The in vitro survival of nonacid- and acid-adapted (AA) Salmonella cocktails (Salmonella serovars: Dublin, Enteritidis, Newport, Typhimurium, and Typhimurium DT104) in rumen fluid and feces, collected from fistulated cattle fed five different diets ([1] grass, [2] grass + concentrate, [3] grass silage, [4] hay, and [5] a high grain diet), was examined at 6 degrees C and 15 degrees C (feces) and at 37 degrees C (rumen fluid). The pH of the rumen fluid ranged from 5.77 to 6.61 and the feces from 6.86 to 7.06. Salmonella D-values in rumen fluid were statistically similar, regardless of dietary source. Although prolonged survival (up to 84 days) was observed in feces, diet did affect survival with significantly (p < 0.05) higher D-values obtained in feces from diets 3 and 4 (AA cells at 6 degrees C) and significantly (p < 0.05) lower D-values for diet 5 (AA cells at 15 degrees C). It was concluded that changes in rumen pH and volatile fatty acids profile and concentrations, based on dietary manipulation, may not reduce the persistence and dissemination of Salmonella in cattle. PMID- 21288132 TI - Different enteropathogenic Yersinia strains found in wild boars and domestic pigs. AB - Yersinia enterocolitica and Yersinia pseudotuberculosis strains isolated from wild boars and fattening pigs were characterized and compared with each other. In wild boars, ail-positive Y. enterocolitica strains belonged to bioserotypes 4/O:3 (36%, 5/14), 2/O:9 (29%, 4/14), and 2/O:5,27 (21%, 3/14). Additionally, two ail positive strains were untypable. Among fattening pigs, the bioserotype 4/O:3 was dominating (91%, 71/78), and bioserotypes 2/O:5,27 (8%, 6/78) and 2/O:9 (1%, 1/78) were rare. inv-positive Y. pseudotuberculosis strains of serotypes O:1 and O:2 were isolated only from wild boars. Antimicrobial resistance patterns between wild boar and fattening pig strains differed. Most of the ail-positive Y. enterocolitica strains carried yst, hreP, and virF genes. Several genotypes of Y. enterocolitica strains were obtained by PFGE using NotI, ApaI, XhoI, and SpeI enzymes. All genotypes of wild boar strains differed from fattening pig strains. Especially strains of bioserotype 4/O:3 were clearly different with all four enzymes. These results show that wild boar strains differed from domestic pig strains. More wild boar strains should be isolated to show that wild boars and domestic pigs are reservoirs for different Y. enterocolitica and Y. pseudotuberculosis strains. PMID- 21288133 TI - Classifying and profiling Social Networking Site users: a latent segmentation approach. AB - Social Networking Sites (SNSs) have showed an exponential growth in the last years. The first step for an efficient use of SNSs stems from an understanding of the individuals' behaviors within these sites. In this research, we have obtained a typology of SNS users through a latent segmentation approach, based on the frequency by which users perform different activities within the SNSs, sociodemographic variables, experience in SNSs, and dimensions related to their interaction patterns. Four different segments have been obtained. The "introvert" and "novel" users are the more occasional. They utilize SNSs mainly to communicate with friends, although "introverts" are more passive users. The "versatile" user performs different activities, although occasionally. Finally, the "expert-communicator" performs a greater variety of activities with a higher frequency. They tend to perform some marketing-related activities such as commenting on ads or gathering information about products and brands as well as commenting ads. The companies can take advantage of these segmentation schemes in different ways: first, by tracking and monitoring information interchange between users regarding their products and brands. Second, they should match the SNS users' profiles with their market targets to use SNSs as marketing tools. Finally, for most business, the expert users could be interesting opinion leaders and potential brand influencers. PMID- 21288134 TI - An empirical analysis of online gamers' perceptions of game items: modified theory of consumption values approach. AB - The aims of this article are (1) to propose a modified theory of consumption values (MTCV) for investigation of online gamer perceptions of the value of purchasable game items and (2) to apply the developed MTCV to multiple game genres and player age groups. To address these aims, 327 valid questionnaires were obtained and analyzed. The original theory of consumption values (TCV) was modified to apply to the specific characteristics of online games. The original TCV specifies five types of consumption values: functional value, social value, emotional value, conditional value, and epistemic value. After revising the TCV to apply to the examination of online games, we proposed that the MTCV be composed of character competency value, enjoyment value, visual authority value, and monetary value. The validity of the MTCV was proven by statistically analyzing the responses provided by the 327 valid questionnaires. To examine the second aim, experiments were conducted to examine the MTCV in three online game genres-massive multiplayer online role-playing games, first-person shooters games, and casual games. The second aim was also studied via questionnaires that examined the ages of online gamers. It was determined that massive multiplayer online role-playing games players regard visual authority value and monetary value as more important than do casual gamers. It was also determined that younger gamers tend to be more interested in visual authority, whereas older gamers tend to be more interested in character competency. This research provides a foundation for future studies to extend the MTCV to consider other user factors, such as cultural effects. PMID- 21288135 TI - Problematic video game play in a college sample and its relationship to time management skills and attention-deficit/hyperactivity disorder symptomology. AB - Although numerous benefits have been uncovered related to moderate video game play, research suggests that problematic video game playing behaviors can cause problems in the lives of some video game players. To further our understanding of this phenomenon, we investigated how problematic video game playing symptoms are related to an assortment of variables, including time management skills and attention-deficit/hyperactivity disorder (ADHD) symptoms. Additionally, we tested several simple mediation/moderation models to better explain previous theories that posit simple correlations between these variables. As expected, the results from the present study indicated that time management skills appeared to mediate the relationship between ADHD symptoms and problematic play endorsement (though only for men). Unexpectedly, we found that ADHD symptoms appeared to mediate the relation between time management skills and problematic play behaviors; however, this was only found for women in our sample. Finally, future implications are discussed. PMID- 21288136 TI - Virtual/real transfer of spatial knowledge: benefit from visual fidelity provided in a virtual environment and impact of active navigation. AB - The purpose of this study was to evaluate the effect the visual fidelity of a virtual environment (VE) (undetailed vs. detailed) has on the transfer of spatial knowledge based on the navigation mode (passive vs. active) for three different spatial recall tasks (wayfinding, sketch mapping, and picture sorting). Sixty four subjects (32 men and 32 women) participated in the experiment. Spatial learning was evaluated by these three tasks in the context of the Bordeaux district. In the wayfinding task, the results indicated that the detailed VE helped subjects to transfer their spatial knowledge from the VE to the real world, irrespective of the navigation mode. In the sketch-mapping task, the detailed VE increased performances compared to the undetailed VE condition, and allowed subjects to benefit from the active navigation. In the sorting task, performances were better in the detailed VE; however, in the undetailed version of the VE, active learning either did not help the subjects or it even deteriorated their performances. These results are discussed in terms of appropriate perceptive-motor and/or spatial representations for each spatial recall task. PMID- 21288137 TI - Emergence and dominance of CTX-M-15 extended spectrum beta-lactamase among Escherichia coli isolates from children. AB - Of forty-seven extended-spectrum cephalosporin-resistant Escherichia coli isolates, collected from children at the Children's Hospital in 2006 (Tunis, Tunisia), we analyzed 32 isolates that were genotypically different by enterobacterial repetitive intergenic consensus -polymerase chain reaction. For all isolates, the double-disk diffusion test revealed synergy between clavulanate and cefotaxime and/or ceftazidime, suggesting the production of extended-spectrum beta-lactamases. Polymerase chain reaction experiments, performed on plasmid DNA, and sequencing revealed the presence of bla(TEM-1B) (26 isolates, 81%), bla(TEM 34(IRT-6)) (3 isolates, 9%), bla(SHV-12) (2 isolates, 6%), and bla(CTX-M-15) (31 isolates, 97%). Further, the insertion sequence ISEcp1 was found upstream from the bla(CTX-M-15) gene in 11 isolates. The bla genes were found alone or in various combinations in a single isolate. bla(TEM-1B) and bla(CTX-M-15) genes were detected in 26 out of the 32 isolates. Three isolates harbored both bla(TEM 34(IRT-6)) and bla(CTX-M-15). bla(SHV-12) was identified either alone or with bla(CTX-M-15) in a single isolate. Our investigation showed the dominance of CTX M-type extended-spectrum beta-lactamases, with CTX-M-15 particularly common, and to our best knowledge, this is the first report of the coexistence of CTX-M-15 and IRT-6 in E. coli isolates from children in Tunisia. PMID- 21288138 TI - Angiotensin II Type-2 receptors modulate inflammation through signal transducer and activator of transcription proteins 3 phosphorylation and TNFalpha production. AB - Angiotensin subtype-1 receptor (AT(1)R) influences inflammatory processes through enhancing signal transducer and activator of transcription proteins 3 (STAT3) signal transduction, resulting in increased tumor necrosis factor-alpha (TNF alpha) production. Although angiotensin subtype-2 receptor (AT(2)R), in general, antagonizes AT(1)R-stimulated activity, it is not known if AT(2)R has any anti inflammatory effects. In this study, we tested the hypothesis that AT(2)R activation plays an anti-inflammatory role by reducing STAT3 phosphorylation and TNF-alpha production. Changes in AT(2)R expression, TNF-alpha production, and STAT3 phosphorylation were quantified by Western blotting, Bio-Plex cytokine, and phosphoprotein cellular signaling assays in PC12W cells that express AT(2)R but not AT(1)R, in response to the AT(2)R agonist, CGP-42112 (CGP, 100 nm), or AT(2)R antagonist PD-123319 (PD, 1 MUm). A 100% increase in AT(2)R expression in response to stimulation with its agonist CGP was observed. Further, AT(2)R activation reduced TNF-alpha production by 39% and STAT3 phosphorylation by 83%. In contrast, PD decreased AT(2)R expression by 76%, increased TNF-alpha production by 84%, and increased STAT3 phosphorylation by 67%. These findings suggest that increased AT(2)R expression may play a role in the observed decrease in inflammatory pathway activation through decreased TNF-alpha production and STAT3 signaling. Restoration of AT(2)R expression and/or its activation constitute a potentially novel therapeutic target for the management of inflammatory processes. PMID- 21288139 TI - Short communication: CD8(+) T cell polyfunctionality profiles in progressive and nonprogressive pediatric HIV type 1 infection. AB - Pediatric HIV-1 infection is characterized by rapid disease progression and without antiretroviral therapy (ART), more than 50% of infected children die by the age of 2 years. However, a small subset of infected children progresses slowly to disease in the absence of ART. This study aimed to identify functional characteristics of HIV-1-specific T cell responses that distinguish children with rapid and slow disease progression. Fifteen perinatally HIV-infected children (eight rapid and seven slow progressors) were longitudinally studied to monitor T cell polyfunctionality. HIV-1-specific interferon (IFN)-gamma(+) CD8(+) T cell responses gradually increased over time but did not differ between slow and rapid progressors. However, polyfunctional HIV-1-specific CD8(+) T cell responses, as assessed by the expression of four functions (IFN-gamma, CD107a, TNF-alpha, MIP 1beta), were higher in slow compared to rapid progressors (p=0.05) early in infection, and was associated with slower subsequent disease progression. These data suggest that the quality of the HIV-specific CD8(+) T cell response is associated with the control of disease in children as has been shown in adult infection. PMID- 21288140 TI - The effect of gluten-free diet on Th1-Th2-Th3-associated intestinal immune responses in celiac disease. AB - OBJECTIVE: To study T-helper (Th)1-Th2-Th3 gene activation profile in the small intestine and peripheral blood of children with celiac disease (CD) with special interest in the response to the gluten-free diet (GFD) treatment in order to elucidate an immune dysregulation not triggered by gluten. MATERIAL AND METHODS: Small intestinal biopsies and venous blood were taken from seven children with CD (mean age: 8 years, four girls) at presentation and after 1 year of strict GFD. The Th1-Th2-Th3 gene expression profile was examined by real-time PCR arrays. The findings were compared with the corresponding expressions in peripheral blood and small intestinal biopsies from six reference children without CD (mean age: 6 years, four girls). RESULTS: The Th1 gene expression profile including interferon (IFN)-gamma, signal transducer and activator of transcription (STAT) 1 and interferon regulatory factor (IRF) 1 together with reduced interleukin (IL)-2 expression was pronounced in small intestinal biopsies from children with untreated CD. A downregulation of IFN-gamma transcripts was seen after 1 year of GFD, but there was still increased expression of STAT1 and IRF1 in association with low IL-2 expression in spite of eliminated exposure to wheat gluten. By contrast, the decreased intestinal expression of Th2 gene markers observed at presentation was normalized with GFD. The alterations in the mucosal gene expression profile were not reflected in peripheral blood. CONCLUSION: The GFD did not correct the increased activation of the IFN-gamma signaling pathway related markers and reduced IL-2 expression, suggesting that they represent an immune dysregulation not dependent on gluten exposure. PMID- 21288141 TI - Cystic pancreatic lesions: current evidence for diagnosis and treatment. AB - Pancreatic cystic neoplasms are detected at an increasing frequency due to an increased use and quality of abdominal imaging. There are well known differential diagnostic difficulties concerning these lesions. The aim is to review current literature on the diagnostic options and the following treatment for cystic lesions in the pancreas focusing on serous cystadenomas, primary mucinous neoplasm of the pancreas and mucinous cystadenocarcinomas, as well as intraductal papillary mucinous neoplasms, starting with excluding pseudocysts. A conservative approach is feasible in patients with a clinical presentation suggestive of an asymptomatic serous cystadenoma. Surgical management, as well as follow-up, is discussed for each of the types of neoplastic lesions, including an uncharacterized cyst, based on patient data, symptoms, serum analysis, cyst fluid analysis and morphological features. Aspects for future diagnostics and management of these neoplasia are commented upon. PMID- 21288142 TI - Changes in fat mass and fat-free mass during the adiposity rebound: FLAME study. AB - OBJECTIVE: To determine the changes in body composition from 3 to 7 years of age in children undergoing adiposity rebound (AR) at different ages. METHODS: Body composition was measured bi-annually by bioelectrical impedance in 229 children from a birth cohort. Age at AR was calculated from changes in weight and height velocity over time. Early AR was defined as < 6.1 years (boys) and < 5.6 years (girls). Differences in fat mass (FM) and fat-free mass (FFM) and the velocity of change in these measures were calculated between early and late rebounders. Physical activity (accelerometry), time in sedentary activity, birth factors, and parental weight were compared. RESULTS: Children with early and late AR did not differ in body composition at 3 years of age, except for greater FFM in boys (by 0.8 kg, P = 0.022). In both sexes, change in body mass index (BMI) was significantly higher in early compared with late AR, and was entirely due to differences in the rate of weight gain, rather than any discrepancy in height velocity. This weight differential is predominantly due to increased deposition of FM in girls and FFM in boys. However, in both sexes, children with early rebound have significantly greater increases in FM velocity from 5 years of age. Few differences in any environmental influences were observed. CONCLUSIONS: Variation in BMI associated with the timing of AR is due to differences in weight rather than height, and sex differences in the relative contribution of FM and FFM to this additional weight gain are apparent. PMID- 21288143 TI - Effects of Cox inhibitors on bone and tendon healing. PMID- 21288144 TI - Comparison of alprazolam versus captopril in high blood pressure: a randomized controlled trial. AB - OBJECTIVE. Anxiety is an important cause of acute blood pressure (BP) elevation. However, the role of anxiolysis in this situation is still controversial. In this study, the relationship of anxiety with BP and the effect of anxiolytic treatment on BP were investigated. METHODS. Emergency department (ED) patients with an initial systolic BP (SBP) >= 160 mmHg or diastolic BP (DBP) >= 100 mmHg but no end organ damage were approached for inclusion in the study. In those consenting to participate, anxiety levels were measured using the State-Trait Anxiety Index (STAI) and Visual Analog Scale for Anxiety (VAS-A). Patients were randomly assigned to receive oral alprazolam 0.5 mg or captopril 25 mg. BP and anxiety levels were measured at baseline and at 1 and 2 h after administration of the study medication. RESULTS. Of 133 patients meeting inclusion criteria, 53 patients agreed to participate. Of these, 27 patients (50.9%) received captopril and 26 patients (49.1%) received alprazolam. The majority of the patients had a high-level trait (96.2%, n = 51) and state anxiety (81.1%, n = 43). The mean SBP and VAS-A values of both patient groups dropped significantly over the 2 h, with no significant difference between the two groups. A significant association between SBP and VAS-A scores was found (F((2,50)) = 6.27, p = 0.004). CONCLUSION: A significant association exists between the level of BP and anxiety in hypertensive ED patients. Alprazolam is as effective as captopril in lowering BP in ED patients with an initial SBP > 160 mmHg. PMID- 21288146 TI - Enhanced elimination in acute barbiturate poisoning - a systematic review. AB - CONTEXT: Despite a worldwide decline in barbiturate use, cases of acute poisoning with severe toxicity are still noted, particularly in developing countries. Severe poisonings often require prolonged admission to an intensive care unit, so enhanced elimination might be useful to hasten recovery. Information regarding the efficacy of these techniques for individual barbiturates is not available in standard textbooks. OBJECTIVE: To determine the evidence supporting the effect of enhanced elimination and its role in the management of acute barbiturate poisoning. METHODS: A systematic review was conducted using broad search criteria in three databases. All potentially relevant articles were obtained, and reference lists were manually reviewed. Ninety-four publications fulfilling inclusion criteria were located. Studies were classified as controlled or uncontrolled, and clinical and pharmacokinetic end points were manually extracted. If not directly stated, standard pharmacokinetic methods were used to calculate the clearance and efficiency of enhanced elimination techniques for each barbiturate and tabulated for direct comparison. PROSPECTIVE CONTROLLED CLINICAL TRIALS: Two of the 94 publications were prospective controlled studies (only one stated that allocation was via blinded randomisation), and both assessed the effect of multiple-dose activated charcoal for acute phenobarbital poisoning. These studies demonstrated enhanced elimination with a decrease in elimination of half-life from approximately 80 to 40?h, but only one study reported clinical benefits. UNCONTROLLED SERIES AND SINGLE CASE REPORTS: Sufficient data to determine the clearance due to enhanced elimination were available in only 52 of these papers. Barbiturate clearances by enhanced elimination varied markedly among studies. While extracorporeal modalities appeared to increase the direct clearance of many barbiturates, there was insufficient information to confirm a clinical benefit. CONCLUSIONS: There is limited evidence to support the use of enhanced elimination in the treatment of poisoning with most barbiturates. There is no role for urine alkalinisation, while multiple-dose activated charcoal may be useful for most phenobarbital and possibly primidone poisonings. Extracorporeal techniques appear to enhance elimination, but the clinical benefits, relative to the potential complications and cost, are poorly defined. Extracorporeal techniques such as haemodialysis and haemoperfusion can be considered for patients with life-threatening barbiturate toxicity such as refractory hypotension. PMID- 21288147 TI - Clinical picture of envenoming with the Meadow Viper (Vipera (Acridophaga) ursinii). AB - OBJECTIVE: The vipers in the Vipera (Acridophaga) ursinii complex are small-sized insectivorous snakes found in parts of central and southern Europe. Subspecies include Vipera ursinii ursinii, Vipera ursinii moldavica, Vipera ursinii macrops, Vipera ursinii rakosiensis, and Vipera ursinii graeca and are commonly known as the meadow vipers. These are the least known European Vipera from a clinical point of view. METHODS: We identified cases of V. ursinii envenomations through three methods, including literature search in PubMed, ISI web of Knowldge, JSTOR, Biological Abstracts, Zoological Record, using the various combination of the following terms: snakebite, envenoming, bite, venom, ursinii, meadow viper, steppe viper (in English, French, Italian, Hungarian, Croatian, Serbian, Romanian), review of paper-based medical case records of hospitals in Hungary (four) and Romania (one) covering the 1970-July 2010 period, and personal communications of professional and amateur herpetologists studying V. ursinii and snake-handlers bitten by these snakes. RESULTS: We identified 64 cases from subspecies: V. u. ursinii (14), V. u. moldavica (8), V. u. macrops (5), and V. u. rakosiensis (37). Forty-five bites were collected from the literature, 5 from hospitals, 10 cases were communicated by seven herpetologists and four cases by two snake keepers. Bites were mostly asymptomatic. Forty-five envenomings (70%) resulted in mild and moderate local symptoms, involving pain with low-intensity, pruritus, numbness, swelling with or without erythema and/or local hematoma. Bullae (n = 3, 5%), mild superficial necrosis (n = 4, 6%), cellulitis (n = 1, 2%), and moderately extended edema (n = 8, 13%) of the bitten extremity rarely develop. Massive limb edema was recorded in eight (13%) cases. The most common systemic symptoms were dizziness caused by transient hypotension and tachycardia. Gastrointestinal disorders (i.e. nausea, vomiting) were rare (n = 2, 3%) compared to other Vipera, and probably triggered only by anxiety. Symptomatic and supportive therapy was applied in the relatively severe envenomings and antivenom therapy in six cases. Complete recovery ranged from 12 h to 2 weeks. Moderate and severe envenomings required significantly longer recovery. Application of first aid was associated with significantly longer recovery times. Neither the age (i.e. juvenile or adult) of the culprit specimen, nor the anatomical location of the bite determined the severity of symptoms. CONCLUSION: Professional and amateur herpetologists, and snake keepers are mainly at risk. Most V. ursinii bites do not require first aid or medical intervention, since only local symptoms develop and resolve spontaneously. The rare hospitalized cases require symptomatic and supportive treatment only. Antivenom therapy is not indicated. PMID- 21288148 TI - Formulation changes and time trends in outcome following paraquat ingestion in Sri Lanka. AB - INTRODUCTION: Deliberate self-harm with pesticides is a significant public health problem in rural Asia. We have previously shown an improved survival of patients with paraquat self-poisoning following the introduction of a new formulation with an increased emetic concentration, an alginate and a purgative in Sri Lanka. Further, formulation changes were introduced in October 2006; this study was designed to assess the impact of these changes on 6-week mortality following paraquat ingestion. METHODS: Prospective, cohort study of patients admitted with paraquat poisoning to 10 hospitals across Sri Lanka between September 2006 and September 2008. RESULTS: Overall, there was a significant (p < 0.001) increase in survival in the 533 patients included in this study compared to previous data (44.5 vs. 35.2% before September 2006 and 27.1% before October 2004). Patients ingesting the new INTEON formulation had a higher survival rate than those ingesting standard formulation (40.2 vs. 31.0%), but this effect was not statistically significant in Cox's proportional hazards model (hazard ratio 0.81, 95% CI 0.61?1.08 (unadjusted) and 1.17, 95% CI 0.82?1.68 (fully adjusted), respectively). CONCLUSIONS: This study has confirmed a continued improvement in survival of patients following self-harm with paraquat in Sri Lanka in recent years; however, in contrast to previous investigations, a beneficial effect associated with the INTEON formulation could not be substantiated. This may be partly due to the large number of patients in whom paraquat concentrations were too low for analytical confirmation of the formulation (n = 105) and who had a very high survival rate (86.7%). PMID- 21288149 TI - White phosphorus poisoning by oral ingestion of firecrackers or little devils: current experience in Ecuador. AB - BACKGROUND: White phosphorus (WP) is widely used illicitly in fireworks in South America. We report our experience in seven Ecuadorian hospitals. METHODS: A cross sectional study of patients presented during 2009. Inclusion criteria included: reported oral ingestion of firecrackers (little devils) in any age. Data were gathered using inpatient records and a written survey of the victims. RESULTS: The mean age of the patients was 21.6+/-7.1 years (women 63.5%); 64.7% of cases occurred in November, December and January. In 46% of cases, the number of units ingested was between 1 and 5 (~0.3 to 1.5 g WP), maximum 40 (~12 g). Forty-seven cases attended within 12 hours (55.3%); 5.9% died and 2.4% were readmitted. The remainder were eventually discharged well. Clinical features included: abdominal pain, cramps, diarrhoea, jaundice, nausea and vomiting, abnormal liver enzymes, and coagulation times and hypoglycaemia. CONCLUSIONS: The typical case was an adolescent woman between 16 and 19 years with self-harm around Christmas. There was no specific treatment, but early attendance was associated with improved prognosis. Further studies are necessary to establish an adequate protocol of treatment. PMID- 21288150 TI - Amitraz poisoning in South Africa: a two year survey (2008-2009). AB - INTRODUCTION: Analysis of the annual pesticide poisoning statistics of the Tygerberg Poison Information Centre (TPIC) for the period 2005-2007 showed an increase in the number of amitraz poisonings. This prompted a 2-year survey (2008 2009) to establish the extent of amitraz poisoning in South Africa. Amitraz is a pesticide used as a tick dip. It acts as an alpha(2)-adrenoceptor agonist and the principal clinical effects of amitraz poisoning are related to its stimulation of these receptors; METHODS: Data from amitraz poisoning cases in humans were evaluated for 2 years and analyzed for: demographic data, type of exposure, type of formulation, and clinical details. Serious cases were followed up; RESULTS: 4.6% of the pesticide poisoning cases were amitraz-related which comprised 0.8% of all TPIC poisoning consultations. Ingestion of amitraz formulations accounted for the majority of the cases (94%). Forty-one percent of cases were children (n = 28) and all were accidental exposures. Of the adult cases (59%), 88% were intentional ingestions. The majority of the cases were from the predominantly rural province of KwaZulu Natal (44.9%). CNS depression was the most common clinical sign (76.8%) followed by bradycardia 34.8%, respiratory depression 27.5%, miosis 27.5%, and hypotension 23.1%. Mechanical ventilation was required in 15.9% of cases. Other commonly reported clinical signs were hypothermia 15.9%, mydriasis 10.1%, and hyperglycaemia 7.2%. Supportive and symptomatic care was shown to be adequate treatment. Amitraz poisoning was misdiagnosed as cholinesterase inhibitor poisoning in 17.4% of cases; CONCLUSION: This is the first report of amitraz poisoning in humans in Africa. The data suggest a different demographic pattern in South Africa to that currently reported in the literature. The study identified a very high incidence of intentional poisoning in adults. The misuse of amitraz for deliberate self-harm emphasizes the necessity for continued toxicovigilance. PMID- 21288151 TI - Is elevated creatinine a reliable marker for methanol toxicity in nitromethane containing model fuel ingestions in children? AB - CONTEXT: In the absence of a rapid serum methanol level estimation, it is difficult to assess the risk from unintentional childhood ingestion of model fuels containing methanol and nitromethane (MFNM). Previous reports have documented false elevations of serum creatinine from the nitromethane in these fuels, suggesting its utility as a readily available marker of significant methanol ingestion. METHOD: We performed a 2-year retrospective chart review of cases of ingestion of MFNM in children, with both a methanol level and measured creatinine level. RESULTS: Seven children, ages 19 months to 3 years, ingested MFNM. All seven children were seen in a hospital and had measured methanol and creatinine levels. All blood samples for methanol and creatinine were drawn within 3 hours of ingestion with methanol estimation delayed up to 24 hours. Creatinine ranged from 0.39 (0.034 mmol/l) to 10.7 mg/dl (0.95 mmol/l). All methanol levels were <10 mg/dl (0.31 mmol/l) or reported as negative. Fomepizole was initiated empirically in two patients due to delay in obtaining methanol analysis results. DISCUSSION: Transient elevations of creatinine occurred in five of the seven children. Blood urea nitrogen was within normal limits, and there was no history of renal impairment in these children, suggesting the elevated creatinine was mostly related to nitromethane ingestion. No child had a significantly elevated methanol level. CONCLUSION: Elevated creatinine level, as measured by Jaffe colorimetric method, is not a reliable marker for elevated methanol levels after unintentional ingestion of MFNM. PMID- 21288152 TI - Hyperammonemia following glufosinate-containing herbicide poisoning: a potential marker of severe neurotoxicity. AB - Glufosinate-ammonium (GLA) is the active ingredient of certain widely used non selective contact herbicides ("e.g.," Basta). Although it is thought to be much less toxic to humans than to plants, deliberate ingestion of GLA could still lead to serious effects ("e.g.," neurotoxicity) or even death. Three cases presented with delayed-onset neurotoxicity including stupor, delirium, seizures, coma, and amnesia after ingesting large amount of Basta. Considering that GLA could irreversibly inhibit glutamine synthetase (GS) in plants, we performed serial measurements of serum ammonia in those patients and revealed marked hyperammonemia in all of them. All patients recovered with the sequelae of persistent amnesia after receiving intensive care and hemodialysis. We speculated that the occurrence of hyperammonemia might at least be partially related to GS inhibition in humans. Moreover, hyperammonemia could serve as a potential marker of severe neurotoxicity, especially prolonged amnesia, following massive ingestion of GLA-containing herbicides. The possible dose-response relation between GLA exposure and serum ammonia level, however, needs more investigations. PMID- 21288153 TI - Richard Mead: one for the ages. AB - Richard Mead (1673-1754) was an important figure in the development of medical science and toxicology. He wrote the first book in the English Language solely devoted to poisons, was an advocate for evidence-based medicine, advanced the social role of physicians in serving the poor and disadvantaged, supported the wider medical and scientific communities, and serves as a life role model for any age. PMID- 21288154 TI - Cybersuicide with "homemade Valium". PMID- 21288155 TI - Diphenhydramine dose response. PMID- 21288158 TI - Production of an optimized tissue-engineered pig connective tissue for the reconstruction of the urinary tract. AB - Nonurological autologous tissues are used for urethral reconstruction to correct urinary tract disorders but are still leading to complications. Other substitutes have been studied on small animal models without great success. For preclinical tests, we selected the porcine model for its similarity to the human urinary tract. Up to now, porcine skin fibroblasts were not able to synthesize enough extracellular matrix under standard conditions to sustain the formation of an adequate tissue for transplantation purposes. Therefore, our goal was to optimize the harvesting site and culture conditions to obtain a thick and easy to handle porcine fibroblast tissue. The oral mucosa was found to be the ideal harvesting site, and a culture temperature of 39 degrees C enabled the formation of a good porcine fibroblast sheet. We successfully superimpose three fibroblast sheets that merged into a thick and resistant tissue where physiological extracellular matrix was produced. Mechanical resistance evaluation by uniaxial traction on the three-layer fibroblast constructs also demonstrated its suitable properties. The production of this porcine connective tissue offers an interesting option in the field of urological tissue engineering. Autologous experiments on a larger animal model are now possible and accessible, allowing the performance of long-term in vivo studies. PMID- 21288160 TI - Evaluation of multiplex immunoassays, used for determination of adiponectin, resistin, leptin, and ghrelin from human blood samples, in comparison to ELISA assays. AB - BACKGROUND: Many different multiplex biomarker immunoassays based on Luminex(r) technology have been developed during recent years. We have evaluated the performance of two multiplex immunoassays for determination of adiponectin, resistin, ghrelin and leptin in comparison to corresponding, conventional ELISA assays. METHODS: Human serum or plasma samples were analysed by commercially available multiplex and ELISA immunoassays manufactured by Millipore Corp. RESULTS: The correlation between tested multiplex and ELISA immunoassays was good, r > 0.9 for all analytes. The agreement between the methods was acceptable but there were differences in analytical levels. Intra- and inter-assay variation was comparable between both assays. The coefficient of variation for all analytes, independent of method, was <=15% and for most of them <10%. CONCLUSION: The performance of the tested multiplex assays was reasonable and they can be considered as valid options to the conventional ELISA assays. However, results obtained with the two different techniques are not necessarily interchangeable due to differences in the concentration levels. PMID- 21288159 TI - Heme oxygenase-1 induction enhances cell survival and restores contractility to unvascularized three-dimensional adult cardiomyocyte grafts implanted in vivo. AB - Autologous adult cardiomyocytes are not utilized for heart repair strategies because of their rapid apoptosis after implantation. We examined whether induction of heme oxygenase-1 (HO-1), a mediator of preconditioning, could enhance early postimplant myocyte survival. Three-dimensional 5*5 mm patches of full-thickness adult murine atrial wall, including cardiomyocytes, capillary networks, and extracellular matrix, were cultured with or without HO-1 inducer cobalt protoporphyrin (CoPP), or the HO-1 inhibitor, tin protoporphyrin (SnPP), or both. Patches were then implanted subcutaneously. Freshly procured atrial wall patches implanted without preculturing served as additional controls. By 14 days postimplant, graft cardiomyocyte content was significantly greater in CoPP treated patches than in either control group (p<0.02). Adult cardiomyocytes did not contract in culture or immediately after implantation. However, by 14 days postimplant, spontaneous contraction had recovered in 47% of CoPP-treated patches, but in only 6% of precultured patches without CoPP, 0% of SnPP-treated patches, and 0% of uncultured patches (p<0.03). CoPP-treated adult cardiomyocyte patches were also observed to remodel spontaneously into endothelial-lined chambers that pumped nonclotting blood. These findings demonstrate that adult cardiomyocytes have more plasticity and capacity for functional recovery than previously recognized and could have application as an autologous cardiomyocyte source for tissue engineering. PMID- 21288161 TI - A contemporary review of stereotactic radiotherapy: inherent dosimetric complexities and the potential for detriment. AB - OBJECTIVE: The advantages of highly localised, conformal treatments achievable with stereotactic radiotherapy (SRT) are increasingly being extended to extracranial sites as stereotactic body radiotherapy with advancements in imaging and beam collimation. One of the challenges in stereotactic treatment lies in the significant complexities associated with small field dosimetry and dose calculation. This review provides a comprehensive overview of the complexities associated with stereotactic radiotherapy and the potential for detriment. METHODS: This study is based on a comprehensive review of literature accessible via PubMed and other sources, covering stereotactic radiotherapy, small-field dosimetry and dose calculation. FINDINGS: Several key issues were identified in the literature. They pertain to dose prescription, dose measurement and dose calculation within and beyond the treatment field. Field-edge regions and penumbrae occupy a significant portion of the total field size. Spectral and dosimetric characteristics are difficult to determine and are compounded by effects of tissue inhomogeneity. Measurement of small-fields is made difficult by detector volume averaging and energy response. Available dosimeters are compared, and emphasis is given to gel dosimetry which offers the greatest potential for three-dimensional small-field dosimetry. The limitations of treatment planning system algorithms as applied to small-fields (particularly in the presence of heterogeneities) is explained, and a review of Monte Carlo dose calculation is provided, including simplified treatment planning implementations. Not incorporated into treatment planning, there is evidence that far from the primary field, doses to patients (and corresponding risks of radiocarcinogenesis) from leakage/scatter in SRT are similar to large fields. CONCLUSIONS: Improved knowledge of dosimetric issues is essential to the accurate measurement and calculation of dose as well as the interpretation and assessment of planned and delivered treatments. This review highlights such issues and the potential benefit that may be gained from Monte Carlo dose calculation and verification via three-dimensional dosimetric methods (such as gel dosimetry) being introduced into routine clinical practice. PMID- 21288162 TI - The phosphoprotein phosphatase family of Ser/Thr phosphatases as principal targets of naturally occurring toxins. AB - Phosphoprotein phosphatases (PPPs) constitute one of three otherwise unrelated families of enzymes that specialize in removing the phosphate group from phosphorylated serine and threonine residues. The involvement of PPP enzymes in the regulation of processes such as gene expression, DNA replication, morphogenesis, synaptic transmission, glycogen metabolism, and apoptosis has underscored their potential as targets for the treatment of a variety of conditions such as cancer, diabetes, or Alzheimer's disease. Interestingly, PPP enzymes also constitute the physiological target of multiple naturally occurring toxins, including microcystins from cyanobacteria and cantharidin from beetles. This review is devoted to the PPP family of enzymes--with a focus on the human PPPs--and the naturally occurring toxins that are known to potently impair their activity. The interaction of the toxins with the enzymes is evaluated in atomic detail to obtain insight on two complementary aspects: (1) which specific structural differences within the similarly folded catalytic core of the PPP enzymes explain their diverse sensitivities to toxin inhibition and (2) which structural features presented by the various toxins account for the differential inhibitory potency towards each PPP. These analyses take advantage of numerous site-directed mutagenesis studies, structure-activity evaluations, and recent crystallographic structures of PPPs bound to different toxins. PMID- 21288163 TI - Dermal absorption of benzene in occupational settings: estimating flux and applications for risk assessment. AB - There is growing emphasis in the United States and Europe regarding the quantification of dermal exposures to chemical mixtures and other substances. In this paper, we determine the dermal flux of benzene in neat form, in organic solvents, and in aqueous solutions based on a critical review and analysis of the published literature, and discuss appropriate applications for using benzene dermal absorption data in occupational risk assessment. As part of this effort, we synthesize and analyze data for 77 experimental results taken from 16 studies of benzene skin absorption. We also assess the chemical activity of benzene in simple hydrocarbon solvent mixtures using a thermodynamic modeling software tool. Based on the collective human in vivo, human in vitro, and animal in vitro data sets, we find that the steady-state dermal flux for neat benzene (and benzene saturated aqueous solutions) ranges from 0.2 to 0.4 mg/(cm2.h). Observed outlier values for some of the animal in vivo data sets are possibly due to the use of test species that have more permeable skin than humans or study conditions that resulted in damage to the skin barrier. Because relatively few dermal absorption studies have been conducted on benzene-containing organic solvents, and available test results may be influenced by study design or vehicle effects, it is not possible to use these data to quantify the dermal flux of benzene for other types of solvent mixtures. However, depending on the application, we describe several potential approaches that can be used to derive a rough approximation of the steady-state benzene dermal flux for these mixtures. Important limitations with respect to quantifying and evaluating the significance of dermal exposures to benzene in occupational settings include a lack of data on (1) factors that affect the dermal uptake of benzene, (2) the dermal flux of benzene for different organic solvent mixtures, (3) meaningful metrics for evaluating the dermal uptake of benzene, (4) steady-state versus non-steady-state dermal flux values for benzene, (5) the effect of skin damage on the dermal flux of benzene, (6) standardized test methods for estimating the dermal flux of benzene, and (7) robust estimates of the evaporation rate of benzene from different liquid vehicles. PMID- 21288164 TI - A comparison of creatinine vs. specific gravity to correct for urinary dilution of cotinine. AB - CONTEXT: The validity of urinary correction standards has not been established for most analytes. METHODS: We compared urinary creatinine and specific gravity as dilution correction standards for cotinine in a community-based study of smokers. RESULTS: Models of blood cotinine regressed against CR or SG (measured by total soluble solids) significantly improved the fit compared to a model without a dilution measure (P < 0.01). There were no differences in model fit between CR- and SG-corrected values. Both CR and SG were significant predictors of urinary cotinine regressed against cigarettes smoked per day (P < 0.01). CONCLUSION: CR and SG are valid and interchangeable correction standards. PMID- 21288165 TI - An increase in mouse tumor growth by an in vivo immunomodulating effect of titanium dioxide nanoparticles. AB - Here, we investigated whether titanium dioxide (TiO2) nanoparticles affect in vivo tumor growth through the modulation of mononuclear leukocytes. In vitro lymphocyte proliferation by lipopolysaccharide (LPS) or concanavalin A (ConA) was reduced by < 25 nm TiO2 with a dose-dependent manner. Similarly, TiO2 nanoparticles inhibited nitric oxide (NO) production from bone marrow-derived macrophages obtained from naive mice. When mice were intraperitoneally (IP) injected with < 25 or < 100 nm TiO2 once a day for 7 days, total cell number of splenocytes was reduced in the spleen of TiO2 nanoparticle-exposed mice. Both CD4+ and CD8+ T-lymphocyte numbers were significantly decreased and B-lymphocyte development was retarded by host exposure to the TiO2 nanoparticles. LPS stimulated spleen cell proliferation was significantly reduced by host exposure to < 25 or < 100 nm TiO2, but no changes were detected in ConA-stimulated spleen cell proliferation. Further, LPS-stimulated cytokine production by peritoneal macrophages and the percentage of NK1.1+ natural killer cells among splenocytes was reduced by the host exposures to the TiO2 nanoparticles. When mice were IP injected with TiO2 nanoparticles once a day for 28 days prior to the subcutaneous implantation of B16F10 melanoma cells, tumor growth was subsequently significantly increased. Collectively, these results show that TiO2 nanoparticles may damage the development and proliferation of B- and T-lymphocytes, reduce the activity of macrophages, and decrease natural killer (NK) cell population levels, outcomes that appear to lead to an increase in tumor growth in situ. These studies allow us to suggest that TiO2 nanoparticles might have the potential to enhance tumor growth through immunomodulation of B- and T-lymphocytes, macrophages, and NK cells. PMID- 21288166 TI - Coagulation assays based on the Luminescent Oxygen Channeling Immunoassay technology 1). AB - BACKGROUND: The Luminescent Oxygen Channeling Immunoassay (LOCI) technology is a well-established homogeneous assay format that allows for fast, accurate, and highly sensitive quantitation of analytes. We set out to develop and prove a novel concept to establish a LOCI format that should principally allow for the determination of the activity of coagulation factors and anticoagulants of clinical relevance. METHODS: The concept is based on the linkage of LOCI nano beads by a peptide that can be cleaved by a coagulation factor. To prove the principle, we used a peptide that can be cleaved by thrombin. RESULTS: We were able to show that coagulation activation of plasma or whole blood samples that were combined with the LOCI components degraded the thrombin-sensitive peptide and consequently, led to a reduction of the LOCI signal. Signal reduction was proportional to the amount of active thrombin generated. The research prototype assay allowed for the detection of factor deficiencies in both the extrinsic and intrinsic coagulation pathways, and for the quantification of hirudin, a direct thrombin inhibitor. CONCLUSIONS: Taken together, we conclude that the LOCI technology has the potential for extension to functional blood coagulation assays. PMID- 21288167 TI - Genetic variability of the fructosamine 3-kinase gene in diabetic patients. AB - BACKGROUND: Nonenzymatic glycation appears to be an important factor in the pathogenesis of diabetic complications. Fructosamine 3-kinase (FN3K), initially identified in erythrocytes, appears to be responsible for the removal of fructosamine from proteins, suggesting a protective role in nonenzymatic glycation. Recently, genetic variants in the FN3K gene have been studied in diabetic patients. The aim of our study was the molecular characterization of the FN3K gene in a representative group of Italian patients with type 1 (T1DM) and 2 (T2DM) diabetes mellitus and in a cohort of healthy controls. METHODS: Seventy diabetic subjects (35 type 1 and 35 type 2) with stable glycemic control and 33 healthy control subjects were evaluated using PCR and direct sequencing of the FN3K gene. Denaturing high performance liquid chromatography (DHPLC) was used in controls for screening for the presence of the genetic variants previously found in diabetic patients. RESULTS: Seven different genetic variants were identified, five of them already reported and two new: the p.R187X and p.Y239C mutations identified in two females affected by T2DM. No significant association was found between certain polymorphisms and diabetes conditions. Preliminary haplotype studies are also reported. With respect to genotypes, we noted that some were not present in all the investigated cohort, and some were found related to higher glycated hemoglobin compared to others, although not at a significant level, probably because of the small number of subjects investigated. CONCLUSIONS: In conclusion, this study identified two new mutations and additional variants within the FN3K gene. This is the first study on FN3K in Italy. Future work is needed to achieve a better understanding of the FN3K enzyme and its possible clinical utility in the management of diabetic patients. PMID- 21288168 TI - Evaluation of the iChem(r) VelocityTM urine chemistry analyzer in a hospital routine laboratory. AB - BACKGROUND: The novel urine chemistry analyzer iChem Velocity (IRIS Diagnostics) offers improved urinalysis automation options through integration with the well established iQ200 urine microscopy analyzer. In the course of optimizing the workflow in our hospital routine laboratory, we evaluated the performance of the iChem Velocity. METHODS: A total of 257 random urine samples were analyzed with the iChem Velocity, iQ200, Clinitek Atlas (Siemens Healthcare Diagnostics) and by manual microscopy. RESULTS: Depending on the parameter, 93% (hemoglobin) to 100% (urobilinogen), the iChem Velocity and Clinitek Atlas results agreed within the same rank or within one level of difference. The Clinitek Atlas featured a higher sensitivity for hemoglobin (area under the curve 0.86) and leukocyte esterase (area under the curve 0.85) compared with the iChem Velocity (area under the curve for hemoglobin 0.73, leukocytes 0.78). Imprecision was highest for hemoglobin and leukocytes in a pathological sample pool. While the precision of the Clinitek Atlas for hemoglobin measurements was superior, the iChem Velocity was more precise in analyzing protein and pH. CONCLUSIONS: Through urinalysis automation with the iChem Velocity and iQ200, we achieved a reduction of hands-on time by 89%. The sensitivity of this new system should be further improved through ongoing development. PMID- 21288169 TI - Laboratory assessment of new anticoagulants. AB - With the introduction of new anticoagulant agents, there is a need for information on which coagulation tests are most suitable. These agents react differently to assays used to monitor older anticoagulant agents because they have alternative modes of action. Therefore, other tests, or modifications of existing tests which are more appropriate for newer agents, are needed. The prothrombin time test (with conversion to the international normalized ratio) is usually used to monitor warfarin. However, conversion to the international normalized ratio is not appropriate for measuring the effects of fondaparinux, dabigatran, rivaroxaban or apixaban. Instead, chromogenic assays, one-step prothrombinase-induced clotting time test and the HepTest with reduced incubation time, are among the different or modified tests that appear to give the most reproducible and accurate results. The tests show variations in response to anticoagulants - some of which have clinical relevance. Thus, it is important to be aware of the observed variations in order to prevent the misinterpretation of test results. PMID- 21288170 TI - Parkinson's disease--the continuing search for biomarkers. AB - There is currently no well-established biomarker for Parkinson's disease. The need to better diagnose the condition, define the subtypes of disease, and follow its course independent of any symptomatic drug effects is well-established. In this review, we will begin by reviewing the evidence for biological fluid biomarkers in Parkinson's disease. We will then touch upon the role of brain imaging in diagnosis and defining prognosis, as well as the value of studying motor phenotype and its potential applications for characterising Parkinson's disease subtypes with differing natural histories. PMID- 21288171 TI - The effect of a one-year weight reduction program on serum uric acid in overweight/obese children and adolescents. AB - BACKGROUND: Hyperuricemia may underlie obesity and related disorders, but the impact of weight reduction and metformin on serum uric acid (sUA) in Caucasian children/adolescents is unknown. METHODS: One hundred and thirteen children/adolescents were enrolled (83 completed) into 1-year weight reduction program (diet+exercise) without or with metformin. Anthropometric and biochemical measurements were conducted at baseline and at the end of follow-up (13 +/- 3 months). RESULTS: sUA decreased in 86% females and 67% males. Significantly more patients substantially (>= 10%) reduced their sUA than body mass index (BMI)%. In females, sUA decreased regardless of type of intervention, but more markedly in the metformin group, and DeltasUA correlated positively with DeltaBMI%, DeltaWHtR (waist-to-height ratio), Deltainsulin, DeltaHOMA (homeostasis model of assessment), and Deltatriglycerides/high density lipoprotein (HDL), but correlated negatively with baseline sUA, HOMA, insulin, and triglycerides/HDL. Of these, metformin treatment, baseline sUA, and DeltaBMI% were independent predictors of sUA reduction, explaining 77% of data variability. In males, sUA reduction was significant in the metformin group only, and negatively correlated with DeltaWHR (waist-to-hip ratio), DeltaWHtR, Deltaleptin, baseline sUA, and waist circumference. Of these, baseline sUA and DeltaBMI% were independent predictors of sUA reduction, explaining 69% of data variability. Except for sUA, females reduced their BMI%, waist circumference, triglycerides, triglycerides/HDL and increased HDL, while males reduced total cholesterol. CONCLUSIONS: A longitudinal weight reduction program encompassing diet/exercise with or without metformin was more efficient in reducing sUA than weight and its effect on sUA and other metabolic parameters differed between genders. Weight loss did not condition sUA reduction, which was strongly dependent on baseline levels. The sUA reducing effects of metformin may contribute to its effects on blood pressure lowering and endothelial function-improving properties in females. PMID- 21288172 TI - Carotid restenosis is associated with plasma ADMA concentrations in carotid endarterectomy patients. AB - BACKGROUND: The aim of this work has been to study the association between plasma asymmetric dimethylarginine (ADMA) concentrations and carotid stenosis in a group of 64 patients undergoing carotid endarterectomy (CEA). METHODS: Arginine, ADMA and symmetric dimethylarginine (SDMA) were measured using capillary electrophoresis with UV detection. An evaluation of plasma concentrations of total cysteine (tCys) and total homocysteine (tHcy) was also performed. RESULTS: Pearson's analysis show a positive correlation between ADMA and carotid stenosis (r=0.37, p=0.003), which is also confirmed after stepwise multiple linear regression analysis. ADMA plasma concentrations were significantly associated with tHcy (r=0.40, p=0.001) and to a lesser extent, even if not significantly, with tCys (r=0.23, p=0.07). CONCLUSIONS: Our data suggest that plasma ADMA is involved in carotid narrowing after CEA intervention. This suggests that this molecule may have an important role in the events that lead to stenosis. PMID- 21288173 TI - Clauss assay and fibrinogen protein estimated by capillary zone electrophoresis. AB - BACKGROUND: The clottability and the amount of total protein in fibrinogen provide information about qualitative or quantitative alterations. We aimed to evaluate whether capillary zone electrophoresis (CZE) Capillarys II analyzer with the protein 6 buffer is able to estimate the amount of fibrinogen antigen. METHODS: Citrated plasmas were assayed for clottable fibrinogen, and any relationship with the beta(2)-globulin fraction (percentage of the area under the curve) was evaluated. The integration method used was "tangent skimming" in order to reduce the overestimation due to high protein background. Linearity was optimized according to the ICH Q2R1 recommendations and evaluated using polynomial regression. The precision was computed in accordance with the Clinical and Laboratory Standards Institute EP5-A2 protocol. In patients, clottable fibrinogen (Clauss method) was compared to its protein CZE amount by Passing and Bablok regression and the Bland-Altman plot. RESULTS: The correlation was linear y=0.0744+0.8991x (R(2)=0.9707) within the range of 2.26-17.26 MUmol/L. The repeatability and the within-device precision were <15% for three levels of percentage of the beta(2)-globulin fraction (1.61%, 3.51%, and 9.24%). In patients, clottable fibrinogen and its protein amount were similar ( 0.1779+0.9654x). The ratio activity/protein was 1.08 +/- 0.32 (mean +/- 2 SD). CONCLUSIONS: CZE with the Capillarys II and the buffer protein 6 is an easy method. It is a good candidate for estimation of the concentration of fibrinogen antigen, which may have diagnostic utility for the screening of quantitative or qualitative fibrinogen abnormalities. PMID- 21288174 TI - An increase in serum uric acid concentrations is associated with an increase in the Framingham risk score in Korean adults. AB - BACKGROUND: Uric acid is a novel cardiovascular disease (CVD) factor, but its use as an independent risk factor for CVD remains controversial. Here, we examined the correlation between Framingham risk score (FRS) and serum uric acid concentrations in asymptomatic Korean adults. METHODS: This cross-sectional study was performed on 8035 Korean adults. Besides FRS, we measured body mass index, fasting blood glucose, homeostasis model assessment of insulin resistance, creatinine, gamma-glutamyltransferase, the lipid profile, uric acid, high sensitive C-reactive protein, and the white blood cell count. All subjects were placed into one of three risk groups according to their FRS. RESULTS: All CVD related factors were significantly different in the three FRS groups. The increments of uric acid increased significantly FRS from the 10-year risk 0%-9% group to the >10% group after adjusting for other CVD-related factors using ordinal logistic regression analysis. Analyses of the three age groups showed similar effects. CONCLUSIONS: An increased uric acid concentration is associated with an increase in coronary heart disease risk calculated from the FRS, and doctors need to pay attention to this CVD risk in apparently healthy adults with hyperuricemia. PMID- 21288175 TI - Analytical variability in sport hematology: its importance in an antidoping setting. AB - Hematologic parameters are commonly utilized in sports medicine and antidoping testing. However, there are no universally accepted methodologies for comparing the performance of automated blood analyzer systems. To address this problem, we selected and examined 19 studies from a review of literature published from 2000 to 2010. Meaningful discrepancies were found between measurements obtained with different analytical systems. Because harmonization and clear standardization of methods are lacking, the analytical variability often largely exceeds intra- and inter-individual biological differences, producing equivocal test results unreliable for clinical and antidoping testing. A central criticality to applying the Bayesian approach is analytical variability, but the use of different analytical technologies precludes the comparison of inter-methods for determining the robustness of blood variables and their clinical significance. Therefore, future multicenter studies are needed to compare analytical methodologies and blood analyzer systems, and to establish worldwide-accepted standards and quality control protocols. PMID- 21288176 TI - Glycosylation of proteins in healthy and neoplastic human salivary glands - a preliminary study. AB - BACKGROUND: In cancer tissue, altered glycosylation of proteins is observed. There are some typical changes; for example, sialyl-Lewis(a/x) glycoforms are more abundant in many types of cancers. The current study investigated the differences in glycosylation of proteins between neoplastic and healthy human salivary glands. METHODS: Sugar structures on proteins with a molecular mass above 30 kDa were determined by enzyme-linked immunosorbent assay (ELISA) with biotinylated lectins. RESULTS: The expression of sialic acid in cancer tissues was higher in comparison with healthy ones. The same observations were revealed for Fuc alpha1-6, alpha1-2, T, Tn antigens and alpha1-6 mannose. CONCLUSIONS: Glycosylation of proteins in cancer salivary gland tissues is altered in comparison with healthy tissue. PMID- 21288177 TI - Patient safety: patient identification wristband errors. PMID- 21288178 TI - The ROMA (Risk of Ovarian Malignancy Algorithm) for estimating the risk of epithelial ovarian cancer in women presenting with pelvic mass: is it really useful? AB - BACKGROUND: The study is aimed at evaluating the performance of the predictive model ROMA (Risk of Ovarian Malignancy Algorithm), which utilizes the combination of human epididymis protein 4 (HE4) and CA125 values to assess the risk of epithelial ovarian cancer (EOC) in women with a pelvic mass. METHODS: One hundred and four women diagnosed with a pelvic mass (55 EOC and 49 benign cases) and scheduled to have surgery were enrolled, along with 49 healthy females. Preoperative serum concentrations of HE4 and CA125 were measured. Separate logistic regression algorithms ROMA for pre-menopausal and post-menopausal women were used to categorize patients into low- and high-risk groups for EOC. The area under the curve (AUC), sensitivity and specificity were calculated for HE4, CA125 and ROMA for the diagnosis of ovarian cancer using receiver operating characteristic (ROC) analysis. RESULTS: The median CA125 and HE4 serum concentrations were significantly higher among EOC patients than in healthy females (both p<0.05) and those with a benign mass (both p<0.05). The pre menopausal group included 36 benign cases (29 of which were classified by ROMA as low-risk with a specificity of 80.6%; 95% CI: 64.0%-91.8%), and 15 EOC (eight of which were classified by ROMA as high-risk, with a sensitivity of 53.3%; 95% CI: 26.6%-78.7%). The post-menopausal group enclosed 13 benign cases (11 of which were classified by ROMA as low-risk with a specificity of 84.6%; 95% CI: 54.6% 98.0%), and 40 EOC (33 of which were classified by ROMA as high-risk with a sensitivity of 82.5%; 95% CI: 67.2%-92.7%). In the pre-menopausal group, the AUC was 0.64 (p=0.12, 95% CI: 0.44-0.83) for CA125, 0.77 (p=0.003, 95% CI: 0.62-0.92) for HE4 and 0.77 (p=0.002, 95% CI: 0.63-0.92) for ROMA. In the post-menopausal group, the AUC was 0.84 (p=0.0003, 95% CI: 0.73-0.94) for CA125, 0.94 (p<0.0001, 95% CI: 0.88-0.99) for HE4 and 0.92 (p<0.0001, 95% CI: 0.85-0.99) for ROMA. CONCLUSIONS: The ROMA is a simple scoring system which shows excellent diagnostic performance for the detection of EOC in post-menopausal women, but not in pre menopausal women. Moreover, the dual marker combination of HE4 and CA125 (ROMA) does not show better performance than HE4 alone. PMID- 21288179 TI - Cross-reactivity of 25-hydroxy vitamin D2 from different commercial immunoassays for 25-hydroxy vitamin D: an evaluation without spiked samples. PMID- 21288180 TI - ROMA or death: advances in epithelial ovarian cancer diagnosis. PMID- 21288181 TI - Diagnostic, prognostic and therapeutic relevance of B-type natriuretic hormone and related peptides in children with congenital heart diseases. AB - The aim of this article is to review the diagnostic and prognostic relevance of measurement of brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) in pediatric patients with congenital cardiac diseases (CHD). A computerized literature search in the National Library of Medicine using the keywords "BNP assay" and "NT-proBNP assay"+neonate/s and newborn/s was performed. Next, we refined the analysis to include only the studies specifically designed to evaluate the clinical usefulness of BNP and NT proBNP measurements in children with CHD. Several authors suggested that BNP/NT proBNP is clinically helpful as a diagnostic and prognostic marker for children with suspected CHD. BNP values are age dependent, even in paediatric populations. Unfortunately, accurate reference values for BNP and NT-proBNP for neonatal ages have only recently become available. As a result, the lack of homogenous and accurate decisional levels in the neonatal period greatly limits the clinical impact of the BNP assay, and also contributed to the production of conflicting results. Regardless of age, there is great variability in BNP/NT-proBNP values among CHD characterized by different hemodynamic and clinical conditions. In particular, cardiac defects characterized by left ventricular volume and pressure overload usually show a higher BNP response than CHD which is characterized by right ventricular volume or pressure overload. BNP and NT-proBNP may be considered helpful markers in the integral clinical approach for patients with CHD. Measurement of BNP cannot replace cardiac imaging (including echocardiography, angiography and magnetic resonance), but provide independent, low cost and complementary information for the evaluation of cardiac function and clinical status. PMID- 21288182 TI - Confirmation of congenital adrenal hyperplasia by adrenal steroid profiling of filter paper dried blood samples using ultra-performance liquid chromatography tandem mass spectrometry. AB - BACKGROUND: The specificity of screening for congenital adrenal hyperplasia by direct measurement of 17-hydroxyprogesterone in filter paper dried blood spot samples by immunoassay is low and has a high false-positive rate. In order to reduce the false-positive rate of this test, we developed a rapid, robust, specific confirmatory procedure in which cortisol, 4-androstene-3,17-dione and 17 hydroxyprogesterone were measured simultaneously by ultra-performance liquid chromatography-tandem mass spectrometry. METHODS: After extraction, samples were analysed by ultra-performance liquid chromatography-tandem mass spectrometry and 17-hydroxyprogesterone was quantified accurately. Other steroids were determined using stable deuterated internal standards. In total, 25 patient blood spot samples and 92 control samples were analysed. RESULTS: The assay was linear for 17-hydroxyprogesterone, with a coefficient of determination >0.997 and imprecision <= 6.5%. An upper limit of normal for 17-hydroxyprogester-one of 4.45 nmol/L was established by analysing a cohort of samples from unaffected newborns. In addition, a cut-off of 3.5 for the peak areas ratio (17-hydroxyprogesterone+4 androstene-3,17-dione)/cortisol, allows confirmation of the affected steroidogenic enzyme. CONCLUSIONS: A high throughput method for the detection of steroids related to congenital adrenal hyperplasia has been developed, allowing the false-positive rate associated with screening for 17-hydroxyprogesterone by immunoassay to be determined. PMID- 21288183 TI - Snake charmer NOTES: a two-luminal access for hybrid NOS operations. AB - Despite recent advances in NOTES, NOS, SILS and related techniques, the feasibility of performing extensive surgery is still limited. Colon surgery usually requires additional access sites or complex technical means for triangulation and retraction. A method is presented that enables single-port colon surgery, supported by flexible colonoscopy. Single-port sigmoidectomy was performed in five cases on the porcine model. Flexible colonoscopy was used to manoeuvre the colon and expose its mesentery for dissection. The specimen was retrieved transrectally by invagination. Single-port sigmoidectomy supported by colonoscopy was feasible in all cases. The method provided a fixed framework, excellent organ guidance and exposition of the mesentery and enabled bowel-close mesocolic preparation. The access angle for preparation and visualisation could be altered during the procedure using the colonoscope. During autopsy on day 21, competent anastomotic healing with only rare interenteric adhesions was observed. One animal had a small preperitoneal abscess in the umbilical region while demonstrating completed skin healing. Flexible colonoscopy provided a fixed reference frame that enabled single-port preparation and dissection of the sigmoid colon. Under colonoscopic guidance, the access angle for dissection could be adapted according to the surgeon's needs. The procedures could be performed safely and effectively. PMID- 21288184 TI - Pharmacotherapy for overactive bladder: minimally invasive treatment -- botulinum toxins. AB - INTRODUCTION: Considered by many a 'revolution' in the treatment of intractable overactive bladder (OAB) and with an increasing number of centers including it in their practice worldwide, botulinum neurotoxin A (BoNT/A) injected into the bladder wall is a treatment of significant potential. In anticipation of the results of multicenter, placebo-controlled, dose-ranging studies, this is a critical review of the available literature on the use of botulinum toxins in the treatment of either neurogenic or idiopathic OAB. AREAS COVERED: The review is based on the English-language literature published by Medline on the use of botulinum toxins in neurogenic or idiopathic detrusor overactivity/OAB since the seminal publication in 2000. The reader is exposed to the cumulative data as well as to a more critical insight on the clinical efficacy of single and repeat injections of the most widely used formulations, the injection techniques, including different doses, dilutions and injection sites, the mechanism of action, the side effects and the cost-effectiveness of the treatment. EXPERT OPINION: Despite the markedly heterogeneous methodologies, published studies suggest that BoNT/A is effective when a number of outcomes are considered, and is considered safe. As results of large registration studies are awaited, additional research on the optimization of clinical practice parameters such as benefit-risk ratio, injection technique, predictors of response and long-term safety, as well as on the mechanism of action and the cost-effectiveness of the treatment, would be welcome. PMID- 21288185 TI - Platelet-derived growth factor applications in periodontal and peri-implant bone regeneration. AB - INTRODUCTION: Achieving successful tissue regeneration following traditional therapeutic protocols, combining bone grafts and barrier membranes, may be challenging in certain clinical scenarios. A deeper understanding of periodontal and peri-implant wound healing and recent advances in the field of tissue engineering have provided clinicians with novel means to obtain predictable clinical outcomes. The use of growth factors such as recombinant human platelet derived growth factor-BB (rhPDGF) with biocompatible matrices to promote tissue regeneration represents a promising approach in the disciplines of periodontology and implantology. AREAS COVERED: This review covers the basic principles of bone and periodontal regeneration, and provides an overview of the biology of PDGF and its potential to predictably and reproducibly promote bone regeneration in regular clinical practice. The results of preclinical and clinical human studies evaluating the effectiveness of growth-factor-enhanced matrices are analyzed and discussed. EXPERT OPINION: Current available evidence supports the use of rhPDGF enhanced matrices to promote periodontal and peri-implant bone regeneration. PMID- 21288186 TI - Telomeres as targets for anticancer therapies. AB - INTRODUCTION: The limitless replicative potential of cancer cells relies on telomere integrity (which is guaranteed by a complex interaction between several specialized proteins and telomeric DNA) and the activation of specific mechanisms for telomere length maintenance. Two mechanisms are currently known in human cancer, namely telomerase activity and the alternative lengthening of telomere pathway. EXPERT OPINION: In this review, we summarize the available data concerning the therapeutic strategies proposed thus far and the current challenges posed for the development of innovative telomere-based therapeutic approaches with broad-spectrum anticancer activity and for their translation into the clinical setting. AREAS COVERED: Due to their essential role in tumor cell proliferation, telomere maintenance mechanisms have become extremely attractive targets for the development of new anticancer interventions. Although numerous efforts have been made to identify specific approaches to interfere with telomere maintenance mechanisms in human cancers, the only molecule currently tested in clinical trials is the oligonucleotide GRN163L. However, a growing body of evidence suggests that interfering with telomeres, through the direct targeting of telomeric G-quadruplex structures, may be a valuable antitumor therapeutic strategy, independent of the specific telomere maintenance mechanism operating in the tumor. PMID- 21288187 TI - Serum apolipoproteins, apoB/apoA-I ratio and objectively measured physical activity in elderly. AB - OBJECTIVES: Several studies have suggested that subjectively reported physical activity is associated with favorable apolipoproteins and apoB/apoA-I ratio but this association has not been studied much in elderly, and seldom with objective methods. The specific aim of the current study was to increase our understanding of the association between objectively measured physical activity, and apolipoproteins and apoB/apoA-I ratio in elderly subjects. DESIGN: In a long-term follow-up of coronary artery bypass graft surgery patients, a total of 89 subjects (55-88 years old) were recruited. Peak oxygen uptake was measured by ergospirometry and physical activity by accelerometry. Subjects were divided into two groups based on their activity levels (i.e. more or less than 30 minutes of moderate activity per day). RESULTS: Only 26% (23/89) of participants achieved the recommended 30 min/day of moderate intensity activity. Objectively measured physical activity was associated with higher apolipoprotein A-I levels and smaller apoB/apoAI ratio and lower body mass index, whereas no significant association with apolipoprotein B was observed. CONCLUSION: The significant association of objectively measured physical activity with favorable apolipoprotein A-I levels and a apoB/apoA-I ratio stresses the importance of being physically active. PMID- 21288188 TI - A hypothesis-generating review of the water method for difficult colonoscopy. AB - OBJECTIVE: Several factors such as significant procedure-related discomfort, excessive intubation time or failed cecal intubation have been associated with difficult colonoscopy. An update of these factors and colonoscopy techniques reported to be efficacious in enhancing completion of cecal intubation in difficult colonoscopy patients is provided in this review. MATERIAL AND METHODS: A Medline search (January 2006 to July 2010) was conducted using the following search terms: colonoscopy, difficult, abdominal pain, and discomfort. RESULTS: Reviewed data are tabulated for presentation. Several water-related techniques have been described separately as adjuncts to usual air insufflation to minimize discomfort, reduce intubation time and improve success rate of cecal intubation. A combination of these techniques was subjected to trial-and-error modifications followed by randomized controlled comparisons. Progressive improvement in colonoscopy outcomes that paralleled stepwise incorporation of exclusion of air insufflation, removal of residual colonic air by suction and removal of residual feces by water exchange during the insertion phase has been described. CONCLUSIONS: The water method is potentially important for improving results of colonoscopy (cecal intubation) especially in unsedated patients. The unsedated option may lower costs. The success of the water method in difficult cases should be evaluated in randomized controlled trials. The call should be considered and explored by endoscopists interested in improving the quality of colonoscopy. A multicenter study to optimize the number of cases will be most desirable. In pragmatic terms, the use of the water method in difficult (unsedated) colonoscopy in the United States did receive recent editorial endorsement. PMID- 21288190 TI - Hemichannels in the neurovascular unit and white matter under normal and inflamed conditions. AB - In the normal brain, cellular types that compose the neurovascular unit, including neurons, astrocytes and endothelial cells express pannexins and connexins, which are protein subunits of two families that form plasma membrane channels. Most available evidence in mammals indicated that endogenously expressed pannexins only form hemichannels, and connexins form both gap junction channels and hemichannels. While gap junction channels connect the cytoplasm of contacting cells and coordinate electrical and metabolic activities, hemichannels communicate intra- and extracellular compartments and serve as diffusional pathways for ions and small molecules. Here, evidence supporting the functional role of hemichannels in the neurovascular unit and white matter under physiological and pathological conditions are reviewed. A sub-threshold acute pathological threatening condition (e.g., stroke and brain infection) leads to glial cell activation, which maintains an active defense and restores the normal function of the neurovascular unit. However, if the stimulus is deleterious, microglia and the endothelium become overactivated, both releasing bioactive molecules (e.g., glutamate, cytokines, prostaglandins and ATP) that increase the activity of astroglial hemichannels, reducing the astrocyte neuroprotective functions, and further reducing neuronal cell viability. Moreover, ATP is known to contribute to myelin degeneration of axons. Consequently, hemichannels might play a relevant role in the excitotoxic response of oligodendrocytes observed in ischemia and encephalomyelitis. Regulated changes in hemichannel permeability in healthy brain cells can have positive consequences in terms of paracrine/autocrine signaling, whereas persistent changes in cells affected by neurological disorders can be detrimental. Therefore, blocking hemichannels expressed by glial cells and/or neurons of the inflamed central nervous system might prevent neurovascular unit dysfunction and neurodegeneration. PMID- 21288191 TI - Recent patents in cationic lipid carriers for delivery of nucleic acids. AB - Gene therapy is a medical technique intended for treatment of disorders caused by defective, missing, or overexpressing genes. Efficient delivery vectors are necessary in order to transport genetic material to the target cells. Such vectors include viral and non-viral carriers. Viral vectors transfect cells efficiently, however risks associated with their use have limited their clinical applications. Nonviral delivery systems are safer, easier to prepare, more versatile and cost effective. However, their transfection efficiency still falls behind that of the viral vectors. Considerable research into nonviral gene delivery has been conducted in the last two decades on synthetic soft materials such as cationic lipids, polymers, surfactants, and dendrimers as prospective nucleotide carriers for gene delivery. So far, cationic lipids are the most widely used constituents of nonviral gene carriers, with multiple strategies employed to improve their in vitro and in vivo transfection. Efforts in synthesizing new cationic lipids were not fully successful in closing the gap between the efficiency of the viral vectors and that of binary cationic lipid/DNA complexes. Current efforts for improving lipofection efficiency are focused on the development of multicomponent carriers including cationic lipids as key constituents. This review summarizes the recent patents on new cationic lipids as well as on multicomponent formulations enhancing their efficiency as nucleotide carriers. PMID- 21288189 TI - Targeting TNF-alpha to elucidate and ameliorate neuroinflammation in neurodegenerative diseases. AB - Inflammatory signals generated within the brain and peripheral nervous system direct diverse biological processes. Key amongst the inflammatory molecules is tumor necrosis factor-alpha (TNF-alpha), a potent pro-inflammatory cytokine that, via binding to its associated receptors, is considered to be a master regulator of cellular cascades that control a number of diverse processes coupled to cell viability, gene expression, synaptic integrity and ion homeostasis. Whereas a self-limiting neuroinflammatory response generally results in the resolution of an intrinsically or extrinsically triggered insult by the elimination of toxic material or injured tissue to restore brain homeostasis and function, in the event of an unregulated reaction, where the immune response persists, inappropriate chronic neuroinflammation can ensue. Uncontrolled neuroinflammatory activity can induce cellular dysfunction and demise, and lead to a self propagating cascade of harmful pathogenic events. Such chronic neuroinflammation is a typical feature across a range of debilitating common neurodegenerative diseases, epitomized by Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, in which TNF-alpha expression appears to be upregulated and may represent a valuable target for intervention. Elaboration of the protective homeostasis signaling cascades from the harmful pathogenic ones that likely drive disease onset and progression could aid in the clinical translation of approaches to lower brain and peripheral nervous system TNF-alpha levels, and amelioration of inappropriate neuroinflammation. PMID- 21288192 TI - MicroRNAs in human diseases. AB - The discovery of microRNAs (miRNAs), a new class of negative regulator that represses gene expression by pairing with their target messenger RNAs (mRNAs), has revealed a natural pathway for controlling gene expression. There are hundreds of miRNAs encoded in the human genome and thousands of target mRNAs, which illustrates the important regulatory roles of miRNAs in cell developmental, differentiation, proliferation and apoptosis pathways. In this scenario, it is not surprising that deregulated miRNAs have been involved in the pathogenesis of many human diseases. The recent development of technologies and compounds to identify and modulate miRNAs has opened new avenues for diagnosis, prognosis and therapeutic applications. Here, we summarize most of the recent patents related to the detection and profiling of miRNAs from pathological samples and to miRNA modulators used as new therapies for disease, including cancer and viral infections, as well as methods for their delivery. PMID- 21288193 TI - Revealing biological information using data structuring and automated learning. AB - The intermediary steps between a biological hypothesis, concretized in the input data, and meaningful results, validated using biological experiments, commonly employ bioinformatics tools. Starting with storage of the data and ending with a statistical analysis of the significance of the results, every step in a bioinformatics analysis has been intensively studied and the resulting methods and models patented. This review summarizes the bioinformatics patents that have been developed mainly for the study of genes, and points out the universal applicability of bioinformatics methods to other related studies such as RNA interference. More specifically, we overview the steps undertaken in the majority of bioinformatics analyses, highlighting, for each, various approaches that have been developed to reveal details from different perspectives. First we consider data warehousing, the first task that has to be performed efficiently, optimizing the structure of the database, in order to facilitate both the subsequent steps and the retrieval of information. Next, we review data mining, which occupies the central part of most bioinformatics analyses, presenting patents concerning differential expression, unsupervised and supervised learning. Last, we discuss how networks of interactions of genes or other players in the cell may be created, which help draw biological conclusions and have been described in several patents. PMID- 21288194 TI - Patented applications of gene silencing in plants: manipulation of traits and phytopathogen resistance. AB - RNA silencing is the name of a broad family of phenomena including RNA interference (RNAi) in animals and basal eukaryotes, quelling in fungi and posttranscriptional gene silencing (PTGS) in plants. PTGS is a fertile research field and since its discovery many applications have been developed related to plant breeding. This minireview summarizes those patents which apply engineered gene silencing to specific problems. The range of inventions is divided in two main sections: manipulation of traits and resistance to phytopathogens and pests. Subtopics like manipulation of tolerances to abiotic stress, alteration of lignin, biofactories, alkaloids biosynthesis and flowering time fall within the first section, and introduction of resistances to insects, nematodes, bacteria, virus and fungi can be found within the second one. PMID- 21288195 TI - Recent patents in RNA silencing in plants: constructs, methods and applications in plant biotechnology. AB - RNA silencing is a recently discovered mechanism to regulate gene expression at transcriptional and posttranscriptional levels. It is based on the recognition and methylation of target genes or cleavage of target mRNAs by small RNA molecules, with length varying from 21 to 24 nucleotides. RNA silencing plays an important role modulating most of the important cell processes, such as growth, development or stress response. During the past few years, diverse strategies have been applied to exploit RNA silencing as a tool to create plants with enhanced economical properties or able to cope with pathogens or abiotic stress. This review describes the most important patents related to RNA silencing in plants, which disclose vectors designed to induce RNA silencing by hairpin RNAs, amplicons or virus-based plasmids, methods for detection and quantification of silencing as well as general uses in plant biotechnology. PMID- 21288196 TI - High-throughput methods in identification of protein tyrosine phosphatase inhibitors and activators. AB - Reversible protein tyrosine phosphorylation, catalysed by the counter-actors protein tyrosine phosphatases (PTPs) and protein tyrosine kinases (PTKs), is a fundamentally important regulatory mechanism of proteins in living cells, controlling cell communication, proliferation, differentiation, motility, and molecular trafficking. The activities of PTPs and PTKs are derailed in several diseases such as cancer and type II diabetes, making them attractive drug targets. Developing drugs against PTKs has started a decade earlier than that on PTPs, and at present there are several molecules targeting PTKs on the market. PTPs in turn are of raising interest, with PTP1B on the lead for its effects on type II diabetes and obesity. In the search for modulators of PTP activity, high throughput methods are important as the initial step to find suitable lead compounds for drug development. Also, high-throughput methods are very useful in elucidating the specific function of different PTPs. In this review, the different high-throughput studies performed to find inhibitors and activators of classical PTPs are discussed. PMID- 21288197 TI - Dual-specificity MAP kinase phosphatases as targets of cancer treatment. AB - The protein tyrosine phosphatase family (PTP) contains a group of dual specificity phosphatases (DUSPs) that regulate the activivity of MAP kinases (MAPKs), which are key effectors in the control of cell growth and survival in physiological and pathological processes, including cancer. These phosphatases, named as MKP-DUSPs, include the MAPK phosphatases (MKPs) as well as a group of small-size atypical DUSPs structurally and functionally related to the MKPs. MKP DUSPs, in most of the cases, are direct inactivators of MAPKs by dephosphorylation of both the Thr and the Tyr regulatory residues at the MAPKs catalytic loop. In some other cases, MKP-DUSPs regulate the activity of MAPKs indirectly, acting through upstream MAPK pathways components. The active involvement of MKP-DUSPs in oncogenesis or resistance to cancer therapies is now well documented, making the search and validation of MKP-DUSPs inhibitors a prominent area in clinical cancer research. Here, we review the current knowledge on the role of MKP-DUSPs in human cancer, the status of the preclinical development and validation of specific MKP-DUSP inhibitors, and the potential of MKP-DUSPs as targets for anti-cancer drugs. PMID- 21288198 TI - Protein phosphatase 2A as a potential target for anticancer therapy. AB - The kinase oncogenes are well-characterized drivers of cancer development, and several targeted therapies focused on both specific and selectively nonselective kinase inhibitors have now been approved for clinical use. In contrast, much less is known about the role of protein phosphatases, although modulation of their activities might form the foundation for an effective anti-cancer approach. The serine-threonine protein phosphatase 2A (PP2A) is implicated in the regulation of numerous signaling pathways and may function as a tumor suppressor. Recently pharmacological modulation of PP2A activity has been showed to have a potent anti tumor activity in both in vitro and in vivo cancer models. These studies implicate PP2A as a promising therapeutic target for the treatment of cancer. PMID- 21288199 TI - RAS - a central feature in cancer targeted therapy. PMID- 21288200 TI - New therapeutic advances and perspectives in tumour angiogenesis. PMID- 21288201 TI - Special edition myeloproliferative neoplasia - disease pathogenesis and treatment options. PMID- 21288202 TI - SUMO E3 ligases are expressed in the retina and regulate SUMOylation of the metabotropic glutamate receptor 8b. AB - The central nervous system regulates neuronal excitability by macromolecular signalling complexes that consist of functionally related proteins, including neurotransmitter receptors, enzymes and scaffolds. The composition of these signal complexes is regulated by post-translational modifications, such as phosphorylation and SUMOylation (SUMO is small ubiquitin-related modifier). In the present study, we searched for proteins interacting with the intracellular C termini of the metabotropic glutamate receptors mGluR8a and mGluR8b and identified proteins of the SUMOylation and NEDDylation machinery. The SUMO E3 ligases Pias1 [Pias is protein inhibitor of activated STAT (signal transducer and activator of transcription)] and Pias3L interacted strongly with mGluR8b, and were co-localized with the E2-conjugating Ubc9, SUMO1 and mGluR8b in cell bodies present in the ganglion cell layer of the mammalian retina. SUMO1 conjugation of Lys882, present in a bona fide consensus sequence for SUMOylation (VKSE) in the mGluR8b C-terminus, was enhanced by addition of Pias1, consistent with an interaction between both proteins. Mutation of Lys882 to arginine reduced, but did not abolish, mGluR8b SUMOylation. Co-mutating a second lysine residue (Lys903) located in the mGluR8b isoform-specific C-terminus largely prevented SUMO1 conjugation by Ubc9. Modelling studies suggested that Lys903 contacts Ubc9 and thus is part of the non-canonical SUMOylation site VKSG. In summary, the results of the present study show in vivo SUMOylation of the complete mGluR8b and co-localize proteins of the SUMOylation machinery in the retina. PMID- 21288203 TI - Altered adipose tissue metabolism in offspring of dietary obese rat dams. AB - To investigate further the mechanisms of developmental programming, we analysed the effects of maternal overnutrition and of postnatal high-fat feeding on adipose tissue metabolism in the offspring. Postnatal changes in serum adiponectin, leptin and TAG [triacylglycerol (triglyceride)] levels, adipose tissue TAGs, fatty acids and enzyme activities were determined in offspring of cafeteria-diet-fed dams during gestation and lactation, weaned on to standard chow or on to cafeteria diet. Obese rats showed higher adiposity (+35% to 85%) as well as a significant increase in serum glucose, insulin, leptin, adiponectin and TAG levels (P<0.01) and adipose tissue LPL (lipoprotein lipase) and GPDH (glycerol-3-phosphate dehydrogenase) activities (P<0.01), compared with control pups at weaning (day 21) and at adulthood (day 90). Adipose HSL (hormone sensitive lipase) activity was increased only at day 90 (P<0.05), and FAS (fatty acid synthase) activity remained unchanged. The proportions of SFAs (saturated fatty acids) and MUFAs (mono-unsaturated fatty acids) and the Delta(9) desaturation index were significantly increased (P<0.05), whereas PUFAs (polyunsaturated fatty acids) were decreased (P<0.01) in serum and adipose TAGs of obese pups compared with controls. The cafeteria diet at weaning induced more severe abnormalities in obese rats. In conclusion, maternal overnutrition induced permanent changes in adipose tissue metabolism of the offspring. These pre existing alterations in offspring were worsened under a high-fat diet from weaning to adulthood. Consequently, adipose adipokines and enzymes could provide a potential therapeutic target, and new investigations in this field could constitute strategies to improve the impact of early-life overnutrition. PMID- 21288205 TI - Why do we have to predict mortality rates? PMID- 21288204 TI - The curious case of NG2 cells: transient trend or game changer? AB - It has been 10 years since the seminal work of Dwight Bergles and collaborators demonstrated that NG2 (nerve/glial antigen 2)-expressing oligodendrocyte progenitor cells (NG2 cells) receive functional glutamatergic synapses from neurons (Bergles et al., 2000), contradicting the old dogma that only neurons possess the complex and specialized molecular machinery necessary to receive synapses. While this surprising discovery may have been initially shunned as a novelty item of undefined functional significance, the study of neuron-to-NG2 cell neurotransmission has since become a very active and exciting field of research. Many laboratories have now confirmed and extended the initial discovery, showing for example that NG2 cells can also receive inhibitory GABAergic synapses (Lin and Bergles, 2004) or that neuron-to-NG2 cell synaptic transmission is a rather ubiquitous phenomenon that has been observed in all brain areas explored so far, including white matter tracts (Kukley et al., 2007; Ziskin et al., 2007; Etxeberria et al., 2010). Thus, while still being in its infancy, this field of research has already brought many surprising and interesting discoveries, and has become part of a continuously growing effort in neuroscience to re-evaluate the long underestimated role of glial cells in brain function (Barres, 2008). However, this area of research is now reaching an important milestone and its long-term significance will be defined by its ability to uncover the still elusive function of NG2 cells and their synapses in the brain, rather than by its sensational but transient successes at upsetting the old order established by neuronal physiology. To participate in the effort to facilitate such a transition, here we propose a critical review of the latest findings in the field of NG2 cell physiology--discussing how they inform us on the possible function(s) of NG2 cells in the brain--and we present some personal views on new directions the field could benefit from in order to achieve lasting significance. PMID- 21288206 TI - New perspectives for day-case spinals! Old drugs for an ancient technique? PMID- 21288207 TI - Mortality reduction in cardiac anesthesia and intensive care: results of the first International Consensus Conference. AB - There is no consensus on which drugs/techniques/strategies can affect mortality in the perioperative period of cardiac surgery. With the aim of identifying these measures, and suggesting measures for prioritized future investigation we performed the first International Consensus Conference on this topic. The consensus was a continuous international internet-based process with a final meeting on 28 June 2010 in Milan at the Vita-Salute University. Participants included 340 cardiac anesthesiologists, cardiac surgeons, and cardiologists from 65 countries all over the world. A comprehensive literature review was performed to identify topics that subsequently generated position statements for discussion, voting, and ranking. Of the 17 major topics with a documented mortality effect, seven were subsequently excluded after further evaluation due to concerns about clinical applicability and/or study methodology. The following topics are documented as reducing mortality: administration of insulin, levosimendan, volatile anesthetics, statins, chronic beta-blockade, early aspirin therapy, the use of pre-operative intra-aortic balloon counterpulsation, and referral to high-volume centers. The following are documented as increasing mortality: administration of aprotinin and aged red blood cell transfusion. These interventions were classified according to the level of evidence and effect on mortality and a position statement was generated. This International Consensus Conference has identified the non-surgical interventions that merit urgent study to achieve further reductions in mortality after cardiac surgery: insulin, intra aortic balloon counterpulsation, levosimendan, volatile anesthetics, statins, chronic beta-blockade, early aspirin therapy, and referral to high-volume centers. The use of aprotinin and aged red blood cells may result in increased mortality. PMID- 21288208 TI - Chloroprocaine for spinal anesthesia: a retrospective analysis. AB - BACKGROUND: Recent volunteer and clinical studies of chloroprocaine (CP) have evaluated its use for outpatient spinal anesthesia. This retrospective review describes the discharge characteristics and reported side effects of spinal CP in a large number of patients undergoing outpatient procedures. METHODS: All patients who received spinal anesthesia for ambulatory procedures over a 20-month period were accessed using computer-generated reports. Charts from 601 anesthetics were analyzed for spinal drug used, block characteristics, side effects and discharge data. RESULTS: CP was the most frequently used spinal anesthetic (84% of cases, n=503) for outpatient procedures. CP (median dose 40 mg, range 20-60 mg) times from injection to ambulation and discharge were 107+/ 24 and 171+/-45 min, respectively. Lidocaine (median dose 60 mg, range 30-100 mg, n=84) times from injection to ambulation and discharge were 155+/-40 and 224+/-57 min, respectively (P<0.05). The incidence of urinary retention, the most common side effect, was similar in both groups. There were no reports of transient neurologic symptoms. CONCLUSIONS: For ambulatory patients at our institution, the time to achievement of discharge criteria was significantly reduced with CP 40 vs. lidocaine 60 mg. There have been no reports of perioperative neurologic injury with the introduction of CP as a spinal anesthetic at our institution. PMID- 21288209 TI - Pregabalin reduces post-operative pain after mastectomy: a double-blind, randomized, placebo-controlled study. AB - BACKGROUND: Pregabalin is used for the treatment of neuropathic pain and has shown analgesic efficacy in post-operative pain. The aim of this randomized, double-blinded, placebo-controlled trial (Clinical Trials.gov ID NCT00938548) was to investigate the efficacy and safety of pregabalin for reducing post-operative pain in patients after mastectomy. METHODS: Eighty-four women scheduled for elective mastectomy were randomly assigned to groups that received either pregabalin (75 mg) or placebo, 1 h before surgery and 12 h after the initial dose. Assessments of pain [verbal numerical rating scale (VNRS), at rest and with arm abduction] and side effects were performed at 1, 6, 24 and 48 h post operatively. After discharge from the hospital, pain was assessed by telephone interview at post-operative 1 week and 1 month. RESULTS: VNRS scores for pain at rest were lower in the pregabalin group (n=42) than the placebo group (n=42) at 1, 24 and 48 h post-operatively (P<0.05). VNRS scores for pain with arm abduction were lower in the pregabalin group (n=42) than the placebo group (n=42) at 1 and 24 h, and 1 week post-operatively (P<0.05). Incidences of side effects such as nausea and vomiting, headache, dizziness and blurred vision were similar in both groups. CONCLUSION: Perioperative administration of pregabalin for a single day (75 mg twice daily) was easy, safe and effective in reducing post-operative pain in patients undergoing mastectomy. PMID- 21288210 TI - Pregabalin and dexamethasone improves post-operative pain treatment after tonsillectomy. AB - BACKGROUND: Post-tonsillectomy pain can be severe. We investigated the analgesic effect from combinations of paracetamol, pregabalin and dexamethasone in adults undergoing tonsillectomy. METHODS: In this randomized double-blind study, 131 patients were assigned to either group A (paracetamol+placebo), group B (paracetamol+pregabalin+placebo) or group C (paracetamol+pregabalin+dexamethasone). Pre-operatively, patients received either paracetamol 1000 mg, pregabalin 300 mg, dexamethasone 8 mg or placebo according to their allocation. Post-operative pain treatment included paracetamol 1000 mg 4* and ketobemidone 2.5 mg p.n. Ketobemidone consumption, pain scores [visual analogue scale (VAS)], nausea, sedation, dizziness, number of vomits and consumption of ondansetron were recorded 2, 4 and 24 h after the operation. P<0.05 was considered statistically significant. RESULTS: The mean 24-h VAS-pain score at rest was reduced in group C (P<0.003) vs. group A. The mean 24-h VAS pain scores during swallowing were reduced in group B (P=0.009) and group C (P<0.003) vs. group A. Consumption of ketobemidone (1-4 h post-operatively) was lower in group B (P=0.003) and group C (P=0.003) vs. group A. The mean 24-h dizziness score was higher in group B (P<0.003) and C (P=0.003) vs. group A. Other parameters including re-operation for post-tonsillectomy bleeding were not different between groups. CONCLUSION: Pregabalin and pregabalin+dexamethasone reduced post-operative pain scores and consumption of ketobemidone following tonsillectomy. Dizziness was increased with pregabalin. PMID- 21288211 TI - Optimal dose of pre-incision/post-incision gabapentin for pain relief following lumbar laminectomy: a randomized study. AB - BACKGROUND: Gabapentin has been introduced as an effective agent for post operative pain control. This study aimed to test the effects of pre- and post incision administration of different doses of gabapentin on post-operative morphine requirement and pain following lumbar laminectomy. METHODS: In this randomized clinical trial, 175 patients were allocated into seven groups of 25 patients each to receive placebo or gabapentin 600, 900 or 1200 mg pre- or post incision. Total patient-controlled intravenous morphine consumption during the first 24 post-operative hours, and the time to the first demand for morphine were recorded. Pain score at rest (visual analogue scale) was recorded every 30 min in the first 4 h and then every 2 h until 24 h post-operatively. Side-effects were observed. RESULTS: In the first 12 h, morphine consumption was less, pain scores were lower and the time to the first demand for analgesia was longer in groups receiving gabapentin 900 or 1200 mg either pre- or post-incision, compared with placebo and gabapentin 600 mg (P<0.001). There was no difference between gabapentin 900 and 1200 mg. Pain score, morphine consumption and time to the first demand for analgesia in equal pre- or post-incision doses of gabapentin were not significantly different. No differences in the side-effects were observed between groups. CONCLUSION: Gabapentin 900 or 1200 mg, administered either pre- or post-incision, was found to be effective in pain management following lumbar laminectomy. Similar doses of gabapentin provide the same post operative analgesia whether administered pre- or post-incision. PMID- 21288212 TI - Mortality risk prediction in cardiac surgery: comparing a novel model with the EuroSCORE. AB - BACKGROUND: Several models for prediction of early mortality after open-heart surgery have been developed. Our objectives were to develop a local mortality risk prediction model, compare it with the European System for Cardiac Operative Risk Evaluation (EuroSCORE), and investigate whether the addition of intra operative variables could enhance the accuracy of risk prediction. METHODS: All 5029 patients undergoing open-heart surgery in 2000-2007 were included in the study. Logistic regression with bootstrap methods was used to develop a pre operative risk prediction model for in-hospital mortality. Next, several intra operative variables were added to the pre-operative model. Calibration and discrimination were assessed, and the model was internally validated for prediction in future datasets. We thereafter compared the pre-operative model with the additive and logistic EuroSCOREs. RESULTS: Our pre-operative model included eight risk factors that are routinely registered in our department: age, gender, degree of urgency, operation type, previous cardiac surgery, and renal, cardiac, and pulmonary dysfunction. The model estimated mortality accurately throughout the dataset except in the 1% of patients at extremely high risk, in which mortality was somewhat overestimated. The estimated shrinkage factor was 0.930. The areas under the receiver operating characteristic curve for our pre operative model and the logistic EuroSCORE were 0.857(0.823-0.891) and 0.821(0.785-0.857) (P=0.02). There was no significant difference in performance between the pre-operative and the intra-operative model (P>0.10). CONCLUSION: Our pre-operative model was simple and easy to use, and showed good predictive ability in our population. Internal validation indicated that it would accurately predict mortality in a future dataset. PMID- 21288213 TI - Pulse oximetry during intraaortic balloon pump application. AB - BACKGROUND: Pulse oximeters are multiple used devices in anaesthesiology and intensive care medicine and must provide reliable data during various conditions of signal interference, including light, motion and reduced perfusion. The aim of this study was to evaluate the reliability of different new-generation pulse oximeters during intraaortic balloon pump (IABP) therapy. METHODS: In the experimental setting, the validity of three pulse oximetry technologies (Masimo Radical 7, Nellcor N-600 and Datex Ohmeda TruSat) was evaluated in patients with IABP treatment. Arterial blood gas analysis (BGA-SaO2) data were compared with the pulse oximetric values (SpO2) during 1:1, 1:2 and 1:3 support ratio. RESULTS: The mean differences (bias) during 1:1, 1:2 and 1:3 IABP support between BGA-SaO2 and Datex-SpO2 were 3.38% [95% confidence intervals (CI):+/-1.39%], 1.41% (95% CI 1.14%) and 2.10% (95% CI:+/-0.94%), respectively. Between BGA-SaO2 and Nellcor SpO2, a bias of 0.77% (95% CI:+/-0.46%), 0.85% (95% CI:+/-0.40%) and 0.59% (95% CI:+/-0.38%) was found. In the comparison of BGA-SaO2 and Masimo-SpO2, a bias of 0.58% (95% CI:+/-0.56%), 0.19% (95% CI:+/-0.40%) and -0.01% (95% CI:+/-0.43%) was found, respectively. CONCLUSIONS: In patients with IABP support, the pulse oximetric values of the Masimo Radical 7 are accurate in 1:2 and 1:3 support ratio compared with blood gas analysis. In these support ratios, the Masimo Radical 7 is superior to the Nellcor N-600. The Datex Ohmeda TruSat showed a significant difference between the measured pulse oximetric values and blood gas analysis in all support ratios. PMID- 21288214 TI - Acceleromyography to assess neuromuscular recovery: is calibration before measurement mandatory? AB - BACKGROUND: Acceleromyography has been shown to be an appropriate method in the detection of residual paralysis. However, the clinical importance of an individual calibration of the device in the single patient to improve reliability in detecting residual paralysis remains unclear. METHODS: Observational study in 100 patients undergoing general anaesthesia with endotracheal intubation and a neuromuscular block with atracurium. In all patients, an individually calibrated acceleromyograph was used to estimate a possible residual block at the end of surgery. Immediately after finishing the calibrated measurements at the end of surgery, a non-calibrated measurement was performed. Agreements between the two measurements were tested using Cohen's kappa and a Bland-Altman analysis. RESULTS: Data from 96 patients were analysed. At the end of surgery, a discordance in the calibrated and the non-calibrated train-of-four ratio was found in 88 patients. Bland-Altman analysis showed a mean (bias) of 0.01, with limits of agreement of 0.15/-0.15. kappa was calculated with kappa=0.84 for the absence or presence of a potential residual block if defined as a train-of-four ratio of 1.0 as a threshold. CONCLUSIONS: The results imply a good agreement in the detection of the presence or absence of a residual neuromuscular block between calibrated and non-calibrated acceleromyography if a train-of-four ratio of 1.0 has been chosen as the threshold. However, the estimated train-of-four values are not transferable between calibrated and non-calibrated measurements. PMID- 21288215 TI - Optimal dose of propofol for intubation after sevoflurane inhalation without neuromuscular blocking agent in children. AB - BACKGROUND: This study was designed to determine the optimal dose of propofol for excellent intubating conditions in children without neuromuscular blockade at various alveolar concentrations of sevoflurane. METHODS: Sixty-three children, aged 0.5-5 years, were randomized to three groups of end-tidal sevoflurane concentration (ETsevo) 3%, 3.5%, and 4%. Inhalation anesthesia was started with sevoflurane 7% in 100% oxygen. When the patients became unconscious, inspired concentration was adjusted to obtain the target ETsevo for each group. When ETsevo reached the target concentration, a predetermined dose of propofol was given and tracheal intubation was performed. The proper dose of propofol was determined using the 'up-and-down' method. RESULTS: The median dose (95% confidence intervals) of propofol for excellent tracheal intubating conditions in 50% of children were 1.25 mg/kg (0.84-1.75) at ETsevo of 3%, 0.76 mg/kg (0.35 1.21) at 3.5%, and 0.47 mg/kg (0.26-1.09) at 4%. The frequency of adverse effects was not different between groups during induction and recovery. CONCLUSION: Propofol 1.5-2 mg/kg provides excellent intubating conditions at 3-4% ETsevo in children without using any neuromuscular blocking agent. PMID- 21288216 TI - Up-down sequential allocation and regional anaesthesia. PMID- 21288217 TI - Allow elective ventilation to recruit more organ donors. AB - Transplantation surgery started >50 years ago and has developed into an established medical practice in many countries. We consider it positive if our dead body could be used as an organ or tissue donor. If transplanted, our organs confer other human beings with a longer and better life. There is, however, a relative lack of organs compared with the needs, and many potential recipients die while on the waiting list for transplantation. PMID- 21288218 TI - Withholding or withdrawing therapy in Danish regional ICUs: frequency, patient characteristics and decision process. AB - BACKGROUND: New options for intensive therapy have increased the necessity of considering withholding or withdrawing therapy at intensive care units (ICUs), but the practice varies according to regional and cultural differences. The aim of this study was to investigate the frequency of withholding or withdrawing therapy in two secondary Danish ICUs, to describe the characteristics of patients in whom such decisions were made and to examine the existing documentation of the decision process. METHODS: A retrospective review of hospital records for all patients admitted to two regional Danish ICUs in 2008. The records were searched for all information regarding deliberations or decisions on withholding or withdrawing therapy. RESULTS: Of 1665 patients admitted to the ICUs, 176 patients (10.6%) died; of these, 34 (19.3%) died while still receiving full active therapy, 25 (14.2%) died after therapy was withheld and 117 (66.5%) died after therapy was withdrawn. An additional 88 patients (5.3%) were discharged alive with therapy either withheld or withdrawn. The patients who died had higher severity scores, were older and were more likely to be men than those who were discharged with full therapy. The main reasons for withholding or withdrawing therapy were prognosis for acute illness and the deemed futility of therapy. The median time from admission to a decision on withholding or withdrawing therapy was 1.4 days. CONCLUSION: Withholding or withdrawing therapy is common in Danish ICUs but more research is needed to explore the different aspects of withholding or withdrawing therapy in Danish ICUs. PMID- 21288219 TI - Variation in use of peroperative inotropic support therapy in cardiac surgery: time for reflection? AB - BACKGROUND: There is no well-established evidence-based clinical guidelines on the most appropriate use of peroperative inotropic support in cardiac surgery. We aimed to identify patient- and procedure-related factors associated with the use of peroperative inotropic support and to estimate physician-level variation. METHODS: A population-based study using data from the Western Denmark Heart Registry on 3585 consecutive cardiac surgery cases from three university hospitals. Inotropic support was defined as infusion of inotropic drugs or nor epinephrine at the separation from cardiopulmonary bypass. Poisson's regression modelling was used to determine predictors of inotropic support and to compare use of high-dose inotropic support among experienced cardiac anaesthesiologists. RESULTS: We identified a range of factors that were independently associated with an increased use of inotropic support therapy including pre-operative left ventricular dysfunction, pre-operative renal dysfunction, complex procedures, prior cardiac surgery, emergency surgery, pre-operative pulmonary hypertension, critical pre-operative state, extended extra corporal circulation-time and female gender. Further, we found substantial variation in use of inotropic support both at hospital- and at physician-level. The adjusted odds ratio of high-intensity inotropic support varied significantly at physician level from 2.3 [95% confidence interval (CI) 1.83-2.71] to 0.3 (95% CI 0.15-0.61) when the individual physicians were compared with the rest. CONCLUSION: The use of inotropic support during cardiac surgery is associated with the pre-operative state of the patient, as well as type of surgery. However, the present study indicates that use of peroperative inotropic support is also highly dependent on physician's preferences, indicating the need for an evidence-based approach when initiating inotropic therapy in cardiac surgery. PMID- 21288220 TI - Pharmacokinetics of dexmedetomidine in Chinese post-surgical intensive care unit patients. AB - BACKGROUND: Dexmedetomidine is a rather new drug in China. We sought to describe the pharmacokinetics of dexmedetomidine in patients requiring post-operative sedation and ventilation in our surgical intensive care unit. METHODS: Twenty-two patients received post-operative infusions of dexmedetomidine at 6 MUg/kg/h for 10 min, followed by 0.4 MUg/kg/h for 350 min. Venous blood samples were drawn and assayed for plasma concentration. The pharmacokinetics were analysed using a nonlinear mixed-effect model with an interindividual and intraindividual error model. An initial estimation was performed to determine which of the one-, two- or three-compartment models is best to describe the concentration-time data. The covariates age, gender, weight, height, lean body mass (LBM), body surface area (BSA) and body mass index (BMI) were tested for significant effects on parameters using a stepwise forward addition and backward elimination approach. Covariate effects were judged based on changes in the objective function value (OFV). RESULTS: The pharmacokinetics of dexmedetomidine were best described by a three compartment model. The model was further improved when height was a covariate of systemic clearance (Cl1), with a decrease in OFV by -13.56 (P<0.01). From the heights of 155-178 cm, Cl1 increased by approximately 143%. The final pharmacokinetic parameter values were as follows: V1 =63.4 l, V2=41.3 l, V3 =284.3 l, Cl1=0.47*(height/160 cm)(6.42) l/min, Cl2=2.43 l/min and Cl3=0.086 l/min. CONCLUSIONS: This study identified (i) the effect of height on the pharmacokinetics of dexmedetomidine; (ii) that there is no influence of age, gender, weight, LBM, BSA and BMI on pharmacokinetic parameters; and (iii) it established a preliminary population pharmacokinetic model for Chinese patients. PMID- 21288221 TI - A train-of-four ratio of 0.9 may not certify adequate recovery after sugammadex. PMID- 21288222 TI - Severe arterial air embolism following electromyography of the trapezius muscle. PMID- 21288224 TI - Pre-hospital transcranial Doppler in severe traumatic brain injury: a pilot study. AB - BACKGROUND: Investigation of the feasibility and usefulness of pre-hospital transcranial Doppler (TCD) to guide early goal-directed therapy following severe traumatic brain injury (TBI). METHODS: Prospective, observational study of 18 severe TBI patients during pre-hospital medical care. TCD was performed to estimate cerebral perfusion in the field and upon arrival at the Level 1 trauma centre. Specific therapy (mannitol, noradrenaline) aimed at improving cerebral perfusion was initiated if the initial TCD was abnormal (defined by a pulsatility index >1.4 and low diastolic velocity). RESULTS: Nine patients had a normal initial TCD and nine an abnormal one, without a significant difference between groups in terms of the Glasgow Coma Scale or the mean arterial pressure. Among patients with an abnormal TCD, four presented with an initial areactive bilateral mydriasis. Therapy normalized TCD in five patients, with reversal of the initial mydriasis in two cases. Among these five patients for whom TCD was corrected, only two died within the first 48 h. All four patients for whom the TCD could not be corrected during transport died within 48 h. Only patients with an initial abnormal TCD required emergent neurosurgery (3/9). Mortality at 48 h was significantly higher for patients with an initial abnormal TCD. CONCLUSIONS: Our preliminary study suggests that TCD could be used in pre-hospital care to detect patients whose cerebral perfusion may be impaired. PMID- 21288225 TI - Comparison of four pain scales in patients with hip fracture or other lower limb trauma. AB - BACKGROUND: The applicability of the Visual Analogue Scale (VAS) has been questioned in the assessment of pain in the elderly. We compared VAS with three other pain scales, Verbal Rating Scale (VRS), Red Wedge Scale (RWS) and Box Scale (BS), in hip fracture patients. METHODS: VAS, VRS, RWS and BS were compared in 140 analysable patients undergoing surgery, 70 with hip fracture and 70 with other lower limb trauma. Pain scores were recorded once a day, repeated after 10 min, for 4 subsequent days starting pre-operatively. The primary endpoint was the rate of successful pain measurements in hip fracture patients and 90% was chosen as a sufficient level for an applicable pain scale. RESULTS: Age was different between the groups (hip fracture 78 +/- 11, other trauma 49 +/- 11 years, P<0.0001). In hip fracture patients, 67-83% of pain measurements were successful with VAS, 82-100% with VRS, 83-96% with RWS and 79-91% with BS. The success rate with VAS was significantly <90% on 2 days (P<0.0001) and with BS on 1 day (P=0.04). All the other success rates with the four scales in both groups were above or not different from 90%. CONCLUSION: VRS and RWS were the most applicable scales, unlike VAS, which appeared to be an unreliable pain scale in perioperative hip fracture patients. In patients with other lower limb trauma, all four scales provided excellent applicability. Our results are in accordance with the accumulating evidence suggesting that VAS is not an ideal tool for pain measurement in the elderly. PMID- 21288226 TI - A preliminary validation of the Swedish version of the Critical-Care Pain Observation Tool in adults. AB - BACKGROUND: Assessing pain in critically ill patients can be complicated, especially for those unable to communicate. A recently developed pain assessment tool, the Critical-Care Pain Observation Tool (CPOT), has been shown to be a reliable tool for pain assessment in the Intensive Care Unit (ICU). The aim of the study was to validate the Swedish version of the CPOT. METHODS: Conscious and unconscious adults were observed during two procedures: one non-nociceptive procedure (NNP) (arm- and face wash) and one nociceptive procedure (NP) (turning). In total, there were 240 patient assessments pre-, per- and post procedure performed by two independent staff members at rest, during and 15 min after the different procedures. Measures of interrater reliability, internal consistency and discriminant validity of the CPOT were obtained to examine the properties of the Swedish version of CPOT. RESULTS: The results provide indications of good agreement between the independent raters (ICC=0.84). There was an adequate discriminant validity of the Swedish version of CPOT established by a significant peak for CPOT scores during the NP (per-procedure). There was also a consistent pattern of significant correlations between CPOT and the mean artery pressure (rho=0.32-0.45). CONCLUSION: The Swedish version of the CPOT is a suitable instrument for assessing pain in critically ill adults. The overall reliability and validity measures converge with findings from previous studies of the CPOT, but in order to achieve enhanced generalizability of the CPOT, we encourage further evaluation of CPOT in broader groups of critically ill patients. PMID- 21288227 TI - Repeated but not single isoflurane exposure improved the spatial memory of young adult mice. AB - BACKGROUND: Exposure to general anesthesia damages the spatial memory of aged rodents, but its role in the young adult has not been well investigated. This study was conducted to determine the effects of single and repeated isoflurane exposure on spatial memory in young adult mice. METHODS: The experimental design comprised three series of experiments. In the first series, animals (2 months old) were randomly exposed to 1.4% isoflurane for 2 or 6 h or vehicle gas for 6 h (n=15 in each group). The Morris water maze (MWM) test was performed at 48 h after anesthetic exposure to evaluate spatial memory. In the second part, animals were randomly exposed to 1.4% isoflurane (isoflurane group, n=15) or vehicle gas only (control group, n=15) for 2 h/day on 5 consecutive days. Forty-eight hours later, the MWM was performed. In the third part, animals were randomized into an isoflurane group (n=15) and a control group (n=15) as in the second part of the experiment. Two weeks later, the MWM was performed. RESULTS: The mean escape latency time and the mean pathway length measured at 48 h after repeated isoflurane exposure decreased significantly compared with the control. However, there was no difference between the two groups when tested at 2 weeks after repeated isoflurane exposure. A single exposure to isoflurane lasting 2 or 6 h had no effect on the performance of mice in the MWM as compared with the control. CONCLUSION: Repeated but not single isoflurane exposure temporarily improved the spatial memory of young adult mice. PMID- 21288228 TI - Timing of intravenous patient-controlled remifentanil bolus during early labour. AB - BACKGROUND: Remifentanil labour analgesia is superior to nitrous oxide but less potent than epidural analgesia. The short onset and offset times of effect suggest that the timing of the bolus in the contraction cycle could have importance. We hypothesised that administering a remifentanil bolus during contraction pause would improve analgesia in early labour. METHODS: With permission from the ethical committee and the National Authority of Medicines, 50 parturients with uncomplicated singleton pregnancies and informed consent participated in a double blind cross-over study. Intravenous doses of 0.4 MUg/kg remifentanil with 1-min infusion times were used during two study periods lasting six to eight contractions. Remifentanil and saline syringes were attached to two patient-controlled devices, one of which administered the bolus immediately after a trigger and the other targeted to start 140 s before the next contraction. The parturients assessed contraction pain, pain relief, sedation and nausea. Oxygen saturation (SaO(2)) pulse and blood pressure were recorded. SaO(2)<95% was the indication for oxygen supplement. RESULTS: Forty-one parturients were included in the analyses. Because of the period effect, pain and pain relief scores were analysed separately for each of the study periods. The mean pain and pain relief scores were similar during the two different dosing regimens. Side effects, the need for supplemental oxygen, SaO(2) and haemodynamics were similar. In a subgroup with long and regular contractions, however, delayed boluses were associated with lower pain scores. CONCLUSIONS: Administering a remifentanil bolus during the uterine contraction pause does not improve pain relief. PMID- 21288229 TI - Patterns and predictors of recovery from exhaustion in older adults: the cardiovascular health study. AB - OBJECTIVES: To estimate the likelihood of, and factors associated with, recovery from exhaustion in older adults. DESIGN: Secondary analysis of a cohort study. SETTING: Six annual examinations in four U.S. communities. PARTICIPANTS: Four thousand five hundred eighty-four men and women aged 69 and older. MEASUREMENTS: Exhaustion was considered present when a participant responded "a moderate amount" or "most of the time" to either of two questions: "How often have you had a hard time getting going?" and "How often does everything seem an effort?" RESULTS: Of the 964 participants who originally reported exhaustion, 634 (65.8%) were exhaustion free at least once during follow-up. When data from all time points were considered, 48% of those who reported exhaustion were exhaustion free the following year. After adjustment for age, sex, race, education, and marital status, 1-year recovery was less likely in individuals with worse self-rated health and in those who were taking six or more medications or were obese, depressed, or had musculoskeletal pain or history of stroke. In proportional hazards models, the following risk factors were associated with more persistent exhaustion over 5 years: poor self-rated health, six or more medications, obesity, and depression. Recovery was not less likely in participants with a history of cancer or heart disease. CONCLUSION: Exhaustion is common in old age but is dynamic, even in those with a history of cancer and congestive heart failure. Recovery is especially likely in seniors who have a positive perception of their overall health, take few medications, and are not obese or depressed. These findings support the notion that resiliency is associated with physical and psychological well-being. PMID- 21288230 TI - Functional recovery of elderly patients hospitalized in geriatric and general medicine units. The PROgetto DImissioni in GEriatria Study. AB - OBJECTIVES: To investigate the characteristics of patients who regain function during hospitalization and the differences in terms of functional outcomes between patients admitted to geriatric and general medicine units. DESIGN: Multicenter, prospective cohort study. SETTING: Acute care geriatric and medical wards of five Italian hospitals. PARTICIPANTS: One thousand forty-eight elderly patients hospitalized for acute medical diseases. MEASUREMENTS: Functional status 2 weeks before hospital admission (baseline), at admission, and at discharge, as measured using the Barthel Index (BI). RESULTS: Geriatric patients were older (P<.001) and had lower preadmission functional levels (P<.001) than medical patients. Between baseline and discharge, 43.2% of geriatric and 18.9% of medical patients declined in physical function. In the subpopulation of 464 patients who had declined before hospitalization (between baseline and admission), 59% improved during hospitalization (45% of geriatric and 75% of medical patients), whereas only approximately 1% declined further. High baseline function (odds ratio (OR)=1.03, 95% confidence interval (CI)=1.02-1.04, per point of BI) and greater functional decline before hospitalization (OR 0.95, 95% CI 0.94-0.97, per % point of BI decline) were significant predictors of in-hospital functional improvement; type of hospital ward and age were not. CONCLUSION: Although geriatric patients have overall worse functional outcomes, in-hospital functional recovery may be frequent even in geriatric units, particularly in patients with greater preadmission functional loss and high baseline level of function. PMID- 21288231 TI - An educational intervention for providers to promote bone health in high-risk older patients. AB - OBJECTIVES: To design, implement, and assess an educational intervention for providers focused on osteoporosis screening and management in older patients with chronic obstructive pulmonary disease or asthma who have been prescribed prolonged courses of oral or high-dose inhaled corticosteroids or both and are therefore at high risk for bone loss and fractures. DESIGN: One-group pretest posttest. SETTING: Academic outpatient pulmonary practice. PARTICIPANTS: Nineteen pulmonary specialists at an academic medical center. INTERVENTION: Educational theory and a needs assessment and attitude survey guided the development of a multicomponent educational intervention. MEASUREMENTS: Change in provider behavior was assessed by auditing the electronic medical records for adherence to osteoporosis management guidelines in high-risk patients seen by participants at baseline and for 6 months after the educational intervention. Knowledge transfer and changes in attitude were assessed using pre- and posttests and surveys. RESULTS: A 19% increase in overall rate of adherence to osteoporosis management guidelines in high-risk patients was observed: 45% before intervention to 64% after intervention (n=249 patients, P=.003). Postintervention surveys and test scores also showed statistically significant gains from baseline. CONCLUSION: An educational intervention improved adherence to osteoporosis management guidelines of academic pulmonary specialists. The results of this study provide evidence for the positive effect of a multimodal educational program in altering practice behaviors. PMID- 21288232 TI - Age-based testing for driver's license renewal: potential implications for older Australians. AB - OBJECTIVES: To investigate the effect of age-based testing (ABT) for driver's license renewal policies on older Australians. DESIGN: Secondary data analysis of a pooled dataset. SETTING: Community-based samples drawn from three Australian states. PARTICIPANTS: Five thousand two hundred six adults aged 65 to 103 from the Dynamic Analyses to Optimise Ageing (DYNOPTA) project. MEASUREMENTS: Self reported driving status, age-based testing (ABT) for driver's license renewal status, demographics, medical conditions, Mini-Mental State Examination (MMSE), and visual acuity. RESULTS: After accounting for significant demographic and health covariates, logistic regression analyses revealed that older adults required to undergo ABT were between 2.2 (95% confidence interval (CI)=1.35-3.57, P=.001) and 1.5 (95% CI=1.18-1.92, P=.001) times as likely to report not driving. Similar proportions of drivers with cognitive or visual impairments were found regardless of ABT status. CONCLUSION: Required ABT for license renewal was associated with lower rates of driving. The proportion of drivers with probable cognitive or visual impairments was similar in those who had ABT and those who did not. Future investigation of the effect of current ABT policies on crash rates and the potential to use other scientifically designed ABT strategies is therefore needed. PMID- 21288233 TI - The response of elderly veterans to daily vitamin D3 supplementation of 2,000 IU: a pilot efficacy study. AB - OBJECTIVES: To determine the prevalence of hypovitaminosis D (serum 25 hydroxyvitamin D<32 ng/mL; HVD) in a population of elderly veterans and conduct a preliminary assessment of the efficacy of supplementation with cholecalciferol in correcting HVD. DESIGN: Randomized, double-blind, placebo-controlled clinical trial. SETTING: Geriatric clinic at the Bruce W. Carter Veterans Affairs Medical Center, Miami, Florida. PARTICIPANTS: Veterans aged 70 and older. INTERVENTION: Oral cholecalciferol 2,000 IU daily or placebo for 6 months. MEASUREMENTS: Serum calcium, 25-hydroxyvitamin D, parathyroid hormone, and 24-hour urinary calcium. RESULTS: Of the 34 participants who completed the study, 62% had HVD at baseline. In the treatment group, mean serum 25-hydroxyvitamin D level rose from 28.4+/-7.9 ng/mL at baseline to 42.7+/-10.5 ng/mL at the end of the trial, but levels remained less than 32 ng/mL in three of 17 (18%) of the participants. In the placebo group, the baseline level of 27.7+/-8.3 ng/mL remained unchanged (28.8+/ 8.7 ng/mL). Supplementation did not alter serum or urinary calcium levels and did not result in any adverse events. CONCLUSION: These initial observations suggest that, in older veterans, cholecalciferol 2,000 IU daily for 6 months is generally safe and corrects HVD in most but not all individuals. PMID- 21288234 TI - Mortality risk in older men associated with changes in weight, lean mass, and fat mass. AB - OBJECTIVES: To evaluate risk of all-cause mortality associated with changes in body weight, total lean mass, and total fat mass in older men. DESIGN: Longitudinal cohort study. SETTING: Six U.S. clinical centers. PARTICIPANTS: Four thousand three hundred thirty-one ambulatory men aged 65 to 93 at baseline. MEASUREMENTS: Repeated measurements of body weight and total lean and fat mass were taken using dual-energy X-ray absorptiometry 4.6 +/- 0.4 years apart. Percentage changes in these measures were categorized as gain (+5%), loss (-5%), or stable (-5% to +5%). Deaths were verified centrally according to death certificate reviews, and proportional hazard models were used to estimate the risk of mortality. RESULTS: After accounting for baseline lifestyle factors and medical conditions, a higher risk of mortality was found for men with weight loss (hazard rat (HR)=1.84, 95% confidence interval (CI)=1.50-2.26), total lean mass loss (HR=1.78, 95% CI=1.45-2.19), and total fat mass loss (HR=1.72, 95% CI=1.34 2.20) than for men who were stable for each body composition measure. Men with total fat mass gain had a slightly greater mortality risk (HR=1.29, 95% CI=0.99 1.67) than those who remained stable. These associations did not differ according to baseline age, obesity, or self-reported health status (P for interactions >.10), although self-reported weight loss intent altered mortality risks with total fat mass (P for interaction=.04) and total lean mass (P for interaction=.09) change. CONCLUSION: Older men who lost weight, total lean mass, or total fat mass had a higher risk of mortality than men who remained stable. PMID- 21288235 TI - Cellular telephones measure activity and lifespace in community-dwelling adults: proof of principle. AB - OBJECTIVES: To describe a system that uses off-the-shelf sensor and telecommunication technologies to continuously measure individual lifespace and activity levels in a novel way. DESIGN: Proof of concept involving three field trials of 30, 30, and 21 days. SETTING: Omaha, Nebraska, metropolitan and surrounding rural region. PARTICIPANTS: Three participants (48-year-old man, 33 year-old woman, and 27-year-old male), none with any functional limitations. MEASUREMENTS: Cellular telephones were used to detect in-home position and in community location and to measure physical activity. Within the home, cellular telephones and Bluetooth transmitters (beacons) were used to locate participants at room-level resolution. Outside the home, the same cellular telephones and global positioning system (GPS) technology were used to locate participants at a community-level resolution. Physical activity was simultaneously measured using the cellular telephone accelerometer. RESULTS: This approach had face validity to measure activity and lifespace. More importantly, this system could measure the spatial and temporal organization of these metrics. For example, an individual's lifespace was automatically calculated across multiple time intervals. Behavioral time budgets showing how people allocate time to specific regions within the home were also automatically generated. CONCLUSION: Mobile monitoring shows much promise as an easily deployed system to quantify activity and lifespace, important indicators of function, in community-dwelling adults. PMID- 21288236 TI - An automatic segmentation algorithm for 3D cell cluster splitting using volumetric confocal images. AB - With the rapid advance of three-dimensional (3D) confocal imaging technology, more and more 3D cellular images will be available. Segmentation of intact cells is a critical task in automated image analysis and quantification of cellular microscopic images. One of the major complications in the automatic segmentation of cellular images arises due to the fact that cells are often closely clustered. Several algorithms are proposed for segmenting cell clusters but most of them are 2D based. In other words, these algorithms are designed to segment 2D cell clusters from a single image. Given 2D segmentation methods developed, they can certainly be applied to each image slice with the 3D cellular volume to obtain the segmented cell clusters. Apparently, in such case, the 3D depth information with the volumetric images is not really used. Often, 3D reconstruction is conducted after the individualized segmentation to build the 3D cellular models from segmented 2D cellular contours. Such 2D native process is not appropriate as stacking of individually segmented 2D cells or nuclei do not necessarily form the correct and complete 3D cells or nuclei in 3D. This paper proposes a novel and efficient 3D cluster splitting algorithm based on concavity analysis and interslice spatial coherence. We have taken the advantage of using the 3D boundary points detected using higher order statistics as an input contour for performing the 3D cluster splitting algorithm. The idea is to separate the touching or overlapping cells or nuclei in a 3D native way. Experimental results show the efficiency of our algorithm for 3D microscopic cellular images. PMID- 21288237 TI - Revealing the 3D internal structure of natural polymer microcomposites using X ray ultra microtomography. AB - Properties of composite materials are directly affected by the spatial arrangement of reinforcement and matrix. In this research, partially hydrolysed cellulose microcrystals were used to fabricate polycaprolactone microcomposites. The spatial distribution of cellulose microcrystals was characterized by a newly developed technique of X-ray ultra microscopy and microtomography. The phase and absorption contrast imaging of X-ray ultra microscopy revealed two-dimensional and three-dimensional information on CMC distribution in polymer matrices. The highest contrast and flux (signal-to-noise ratio) were obtained using vanadium foil targets with the accelerating voltage of 30 keV and beam current of >200 nA. The spatial distribution of cellulose microcrystals was correlated to the mechanical properties of the microcomposites. It was observed that heterogeneous distribution and clustering of cellulose microcrystals resulted in degradation of tensile strength and elastic modulus of composites. The utilization of X-ray ultra microscopy can open up new opportunities for composite researchers to explore the internal structure of microcomposites. X-ray ultra microscopy sample preparation is relatively simple in comparison to transmission electron microscopy and the spatial information is gathered at much larger scale. PMID- 21288238 TI - Multiscale toggle contrast operator-based mineral image enhancement. AB - Mineral image is one type of crucial data for mineral research and analysis. However, some mineral images are not clear in some cases. To efficiently enhance mineral images and therefore benefit the applications of these images, a multiscale toggle contrast operator based algorithm is proposed in this paper. First, the toggle contrast operator is discussed. Secondly, the multiscale toggle contrast operator using structuring elements with different sizes is given. Thirdly, the multiscale toggle contrast operator is used to enhance the original image at different scales. Finally, the final enhanced image is constructed from the multiscale enhanced results. Because multiscale structuring elements are used, the algorithm performs efficiently and produces few noises. Experimental results show that the proposed algorithm is efficient for mineral image enhancement. More importantly, the proposed algorithm could be also used in other types of images, such as visual image, medical image and so on, for image enhancement. PMID- 21288239 TI - The influence of diabetes on glutamate metabolism in retinas. AB - Excised retinas from euglycemic and diabetic Sprague-Dawley rats were studied to evaluate differences in glutamate metabolism related to diabetes. Reports suggest, neuronal cell death possibly caused by glutamate excitotoxicity, is an early consequence of diabetes. To monitor the influence of diabetes on glutamate metabolism, we measured glutamatergic neurotransmission, anaplerotic glutamate synthesis from (14) CO(2) and pyruvate as well as rates of glutamate cataplerosis ([U-(14) C]glutamate to (14) CO(2) and (14) C-pyruvate). The data suggest the presence of a glutamate buffering anaplerotic/cataplerotic metabolic cycle in controls which is uncoupled by diabetes. For cycle operation, anaplerosis is initiated by a small pyruvate pool which is also the product of cataplerosis. In the cataplerotic pathway, glutamate conversion to alpha-ketoglutarate and then to CO(2) and pyruvate is reduced by 90% in diabetic retinal Muller cells because glutamate transamination by branched chain aminotransferase is competitively inhibited by branched chain amino acids (BCAAs). BCAAs, but not the ketoacids, were almost twice as high in diabetic compared to euglycemic rat retinas. The data suggest the hypothesis that glutamate levels in retinal Muller cells from diabetic rats are elevated because of the presence of excess BCAAs, and that elevated glutamate in Muller cells causes glutamate excitotoxicity. PMID- 21288240 TI - Carbon cycling in tropical ecosystems. PMID- 21288241 TI - Seeing the forest for the trees: statistical phylogeography in a changing world. PMID- 21288242 TI - Sensing microtubule states through the mitogen-activated protein kinase pathway during mitosis and morphogenesis. PMID- 21288243 TI - Heterosis: one boat at a time, or a rising tide? PMID- 21288244 TI - Global vegetation and terrestrial carbon cycle changes after the last ice age. AB - * In current models, the ecophysiological effects of CO2 create both woody thickening and terrestrial carbon uptake, as observed now, and forest cover and terrestrial carbon storage increases that took place after the last glacial maximum (LGM). Here, we aimed to assess the realism of modelled vegetation and carbon storage changes between LGM and the pre-industrial Holocene (PIH). * We applied Land Processes and eXchanges (LPX), a dynamic global vegetation model (DGVM), with lowered CO2 and LGM climate anomalies from the Palaeoclimate Modelling Intercomparison Project (PMIP II), and compared the model results with palaeodata. * Modelled global gross primary production was reduced by 27-36% and carbon storage by 550-694 Pg C compared with PIH. Comparable reductions have been estimated from stable isotopes. The modelled areal reduction of forests is broadly consistent with pollen records. Despite reduced productivity and biomass, tropical forests accounted for a greater proportion of modelled land carbon storage at LGM (28-32%) than at PIH (25%). * The agreement between palaeodata and model results for LGM is consistent with the hypothesis that the ecophysiological effects of CO2 influence tree-grass competition and vegetation productivity, and suggests that these effects are also at work today. PMID- 21288245 TI - Little change in the fir tree-line position on the southeastern Tibetan Plateau after 200 years of warming. AB - * As one of the world's highest natural tree lines, the Smith fir (Abies georgei var. smithii) tree line on the southeastern Tibetan Plateau is expected to vary as a function of climate warming. However, the spatial patterns and dynamics of the Smith fir tree line are not yet well understood. * Three rectangular plots (30 m * 150 m) were established in the natural alpine tree-line ecotone on two north-facing (Plot N1, 4390 m asl; Plot N2, 4380 m asl) and one east-facing (Plot E1, 4360 m asl) slope. Dendroecological methods were used to monitor the tree line patterns and dynamics over a 50-yr interval. * The three study plots showed a similar pattern of regeneration dynamics, characterized by increased recruitment after the 1950s and an abrupt increase in the 1970s. Smith fir recruitment was significantly positively correlated with both summer and winter temperatures. However, Smith fir tree lines do not show a significant upward movement, despite warming on the Tibetan Plateau. * The warming in the past 200 yr is already having a significant impact on the population density of the trees, but not on the position of the Smith fir tree line. PMID- 21288246 TI - Early effects of salt stress on the physiological and oxidative status of Cakile maritima (halophyte) and Arabidopsis thaliana (glycophyte). AB - Early changes in physiological and oxidative status induced by salt stress were monitored in two Brassicaceae plants differing in their tolerance to salinity, Cakile maritima (halophyte) and Arabidopsis thaliana (glycophyte). Growth response and antioxidant defense of C. maritima under 400 mM NaCl were compared with those of A. thaliana exposed to 100 mM NaCl. Salinity induced early growth reduction that is less pronounced in C. maritima than in A. thaliana. Maximum hydrogen peroxide (H2O2) level occurred in the leaves of both species 4 h after the onset of salt treatment. A rapid decline in H2O2 concentration was observed thereafter in C. maritima, whereas it remained high in A. thaliana. Correlatively, superoxide dismutase, catalase and peroxidase activities increased at 4 h of treatment in C. maritima and decreased thereafter. However, the activity of these enzymes remained higher in treated plants than that in controls, regardless of the duration of treatment, in A. thaliana. The concentrations of malondialdehyde (MDA) reached maximum values at 24 h of salt stress in both species. Again, MDA levels decreased later in C. maritima, but remained high in A. thaliana. The contents of alpha-tocopherol remained constant during salt stress in C. maritima and decreased during the first 24 h of salt stress and then remained low in A. thaliana. The results clearly showed that C. maritima, in contrast to A. thaliana, can rapidly evolve physiological and antioxidant mechanisms to adapt to salt and manage the oxidative stress. This may explain, at least partially, the difference in salt tolerance between halophytes and glycophytes. PMID- 21288247 TI - Genetic engineering of woody plants: current and future targets in a stressful environment. AB - Abiotic stress is a major factor in limiting plant growth and productivity. Environmental degradation, such as drought and salinity stresses, will become more severe and widespread in the world. To overcome severe environmental stress, plant biotechnologies, such as genetic engineering in woody plants, need to be implemented. The adaptation of plants to environmental stress is controlled by cascades of molecular networks including cross-talk with other stress signaling mechanisms. The present review focuses on recent studies concerning genetic engineering in woody plants for the improvement of the abiotic stress responses. Furthermore, it highlights the recent advances in the understanding of molecular responses to stress. The review also summarizes the basis of a molecular mechanism for cell wall biosynthesis and the plant hormone responses to regulate tree growth and biomass in woody plants. This would facilitate better understanding of the control programs of biomass production under stressful conditions. PMID- 21288248 TI - Operation of dual mechanisms that both lead to photoinactivation of Photosystem II in leaves by visible light. AB - Photosystem II (PS II) is photoinactivated during photosynthesis, requiring repair to maintain full function during the day. What is the mechanism(s) of the initial events that lead to photoinactivation of PS II? Two hypotheses have been put forward. The 'excess-energy hypothesis' states that excess energy absorbed by chlorophyll (Chl), neither utilized in photosynthesis nor dissipated harmlessly in non-photochemical quenching, leads to PS II photoinactivation; the 'Mn hypothesis' (also termed the two-step hypothesis) states that light absorption by the Mn cluster in PS II is the primary effect that leads to dissociation of Mn, followed by damage to the reaction centre by light absorption by Chl. Observations from various studies support one or the other hypothesis, but each hypothesis alone cannot explain all the observations. We propose that both mechanisms operate in the leaf, with the relative contribution from each mechanism depending on growth conditions or plant species. Indeed, in a single system, namely, the interior of a leaf, we could observe one or the other mechanism at work, depending on the location within the tissue. There is no reason to expect the two mechanisms to be mutually exclusive. PMID- 21288249 TI - Magnetic field protects plants against high light by slowing down production of singlet oxygen. AB - Recombination of the primary radical pair of photosystem II (PSII) of photosynthesis may produce the triplet state of the primary donor of PSII. Triplet formation is potentially harmful because chlorophyll triplets can react with molecular oxygen to produce the reactive singlet oxygen (1O2). The yield of 1O2 is expected to be directly proportional to the triplet yield and the triplet yield of charge recombination can be lowered with a magnetic field of 100-300 mT. In this study, we illuminated intact pumpkin leaves with strong light in the presence and absence of a magnetic field and found that the magnetic field protects against photoinhibition of PSII. The result suggests that radical pair recombination is responsible for significant part of 1O2 production in the chloroplast. The magnetic field effect vanished if leaves were illuminated in the presence of lincomycin, an inhibitor of chloroplast protein synthesis, or if isolated thylakoid membranes were exposed to light. These data, in turn, indicate that 1O2 produced by the recombination of the primary charge pair is not directly involved in photoinactivation of PSII but instead damages PSII by inhibiting the repair of photoinhibited PSII. We also found that an Arabidopsis thaliana mutant lacking alpha-tocopherol, a scavenger of 1O2, is more sensitive to photoinhibition than the wild-type in the absence but not in the presence of lincomycin, confirming that the target of 1O2 is the repair mechanism. PMID- 21288250 TI - Role of charge recombination processes in photodamage and photoprotection of the photosystem II complex. AB - Light-induced damage of the photosynthetic apparatus is an important and complex phenomenon, which affects primarily the photosystem II (PSII) complex. Here, the author summarizes the current state of understanding, which concerns the role of charge recombination reactions in photodamage and photoprotection. The main mechanism of photodamage induced by visible light appears to be mediated by acceptor side modifications, which develop under light intensity conditions when the capacity of light-independent photosynthetic processes limits the utilization of electrons produced in the initial photoreactions. This situation facilitates triplet chlorophyll formation and singlet oxygen production in the reaction center of PSII, which initiates the damage of electron transport components and protein structure. This mechanism is an important, but not exclusive, pathway of photodamage, and light-induced inactivation of the Mn cluster of water oxidation may occur in parallel with the singlet oxygen-dependent pathway. PMID- 21288251 TI - Regulatory environment for allergen-specific immunotherapy. AB - Products for specific immunotherapy (SIT) are medicinal products according to the European Regulations. To obtain a marketing authorization (MA) within the European Community, the quality, safety and efficacy have to be proven. During the development phase of a medicinal product, applicants have the opportunity to apply for scientific advice by national competent authorities or the European Medicines Agency (EMA) to compile a suitable development plan for the examination of quality and performance of nonclinical and clinical trials. Moreover, a paediatric investigation plan has to be submitted to the Paediatric Committee of the EMA and has to be approved before submission of an application for MA. Several regulatory procedures exist for obtaining a MA in the European Community. The national procedure leads only to marketability in one country whereas the Mutual Recognition, the Decentralized and Centralized Procedures (CP) are intended for MA in several or all member states of the European Union. The CP is mandatory for certain medicinal products, for example for drug substances derived by biotechnological processes such as recombinant allergens. Named Patient Products for SIT are a specialty because they are manufactured on the basis of an individual prescription and marketed without a MA. PMID- 21288252 TI - Collectible toys and decisions to share: I will gift you one to expand my set. AB - Two studies were used to examine the collecting behaviour of preschool children. Prior studies of collecting have defined the behaviour as exhibited by older children and adults. To understand childhood collecting, existing theoretical perspectives were discussed in terms of how they might apply to children's behaviour as collectors. Results showed that some preschool children are motivated to engage in collecting and possess the developmental capacities required for successful collecting. Individual differences in executive functioning (Study 1, N= 57) and theory of mind (Study 2, N= 46) explained why some preschoolers were more oriented towards collecting than others. Study 2 showed that the motivational pull of collectible toys can be very strong, with some children agreeing to pay the 'cost' of sharing with a confederate child in order to obtain a collectible toy. This research highlights similarities and differences between adult and child collecting. Suggestions are provided for parents and for policy considerations regarding the appropriateness of marketing collectible toys to preschoolers. PMID- 21288253 TI - Effects of early child-care on cognition, language, and task-related behaviours at 18 months: an English study. AB - This study investigated the effects of different characteristics of early child care in England on the development of cognition, language, and task-related attention and behaviour (orientation/engagement and emotion regulation during the Bayley assessment) at 18 months. Data were drawn from a prospective longitudinal study of 1,201 infants. As found in previous studies, socio-demographic characteristics and maternal caregiving (especially 'opportunities for stimulation') were significant predictors of all child outcomes. There were also effects of quantity of individual and group care, and quality of non-maternal care. Controlling for demographics and maternal caregiving, more hours of group care (nurseries) were related to higher cognitive scores, while more hours of individual care (e.g., grandparents, nannies etc.) were related to lower orientation/engagement scores. Non-maternal caregiving was observed in a subsample of 345 children, and after controlling for all covariates as well as quantity and stability of care, quality of care was found to be predictive of higher cognitive ability and better orientation/engagement. Although the effect sizes were small in magnitude, in line with other similar studies, such modest effects from a large English sample are important when viewed in light of the widespread use of non-maternal care during infancy and early childhood. PMID- 21288254 TI - The effects of adults' affective expression and direction of visual gaze on 12 month-olds' visual preferences for an object following a 5-minute, 1-day, or 1 month delay. AB - Between 12- and 14 months of age infants begin to use another's direction of gaze and affective expression in learning about various objects and events. What is not well understood is how long infants' behaviour towards a previously unfamiliar object continues to be influenced following their participation in circumstances of social referencing. In this experiment, we examined infants' sensitivity to an adult's direction of gaze and their visual preference for one of two objects following a 5-min, 1-day, or 1-month delay. Ninety-six 12-month olds participated. For half of the infants during habituation (i.e., familiarization), the adults' direction of gaze was directed towards an unfamiliar object (look condition). For the remaining half of the infants during habituation, the adults' direction of gaze was directed away from the unfamiliar object (look-away condition). All infants were habituated to two events. One event consisted of an adult looking towards (look condition) or away from (look away condition) an object while facially and vocally conveying a positive affective expression. The second event consisted of the same adult looking towards or away from a different object while conveying a disgusted affective expression. Following the habituation phase and a 5-min, 1-day, or 1-month delay, infants' visual preference was assessed. During the visual preference phase, infants saw the two objects side by side where the adult conveying the affective expression was not visible. Results of the visual preference phase indicate that infants in the look condition showed a significant preference for object previously paired with the positive affect following a 5-min and 1-day delay. No significant visual preference was found in the look condition following a 1-month delay. No significant preferences were found at any retention interval in the look-away condition. Results are discussed in terms of early learning, social referencing, and early memory. PMID- 21288255 TI - Perspective taking in children's narratives about jealousy. AB - This study explored relationships between perspective-taking, emotion understanding, and children's narrative abilities. Younger (23 5-/6-year-olds) and older (24 7-/8-year-olds) children generated fictional narratives, using a wordless picture book, about a frog experiencing jealousy. Children's emotion understanding was assessed through a standardized test of emotion comprehension and their ability to convey the jealousy theme of the story. Perspective-taking ability was assessed with respect to children's use of narrative evaluation (i.e., narrative coherence, mental state language, supplementary evaluative speech, use of subjective language, and placement of emotion expression). Older children scored higher than younger children on emotion comprehension and on understanding the story's complex emotional theme, including the ability to identify a rival. They were more advanced in perspective-taking abilities, and selectively used emotion expressions to highlight story episodes. Subjective perspective taking and narrative coherence were predictive of children's elaboration of the jealousy theme. Use of supplementary evaluative speech, in turn, was predictive of both subjective perspective taking and narrative coherence. PMID- 21288256 TI - On-line ostracism affects children differently from adolescents and adults. AB - This research examines adults', and for the first time, children's and adolescents' reaction to being ostracized and included, using an on-line game, 'Cyberball' with same and opposite sex players. Ostracism strongly threatened four primary needs (esteem, belonging, meaning, and control) and lowered mood among 8- to 9-year-olds, 13- to 14-year-olds, and adults. However, it did so in different ways. Ostracism threatened self-esteem needs more among 8- to 9-year olds than older participants. Among 13- to 14-year-olds, ostracism threatened belonging more than other needs. Belonging was threatened most when ostracism was participants' first experience in the game. Moreover, when participants had been included beforehand, ostracism threatened meaning needs most strongly. Gender of other players had no effect. Practical and developmental implications for social inclusion and on-line experiences among children and young people are discussed. PMID- 21288257 TI - Three-year-old children intervene in third-party moral transgressions. AB - We investigated children's moral behaviour in situations in which a third party was harmed (the test case for possession of agent-neutral moral norms). A 3-year old and two puppets each created a picture or clay sculpture, after which one puppet left the room. In the Harm condition, the remaining (actor) puppet then destroyed the absent (recipient) puppet's picture or sculpture. In a Control condition, the actor acted similarly but in a way that did not harm the recipient. Children protested during the actor's actions, and, upon the recipient's return, tattled on the actor and behaved prosocially towards the recipient more in the Harm than in the Control condition. This is the first study to show that children as young as 3 years of age actively intervene in third party moral transgressions. PMID- 21288258 TI - The influence of gender and ethnicity on children's peer collaborations. AB - Gender and ethnicity are important aspects of children's everyday social relationships, yet little is known about how these social categories influence children's collaborative interactions. In the present study, 322 White (Caucasian) and South Asian boys and girls (mean age, 7.5 years) collaborated in pairs on easy and difficult versions of a model completion task. As expected, girls were less assertive than boys in conversation, yet this relation held only for all-Asian pairs (i.e., an Asian boy and girl in conversation). Also consistent with expectations, levels of conversational affiliation were lowest in cross-ethnic interaction. The influence of gender and ethnicity on conversations did not vary in light of contrasting cognitive demands of the tasks. Results are discussed in relation to work on effective peer collaboration and the potential role of contact in promoting positive ethnic and gender group attitudes. PMID- 21288259 TI - Developmental differences in the use of task goals in a cued version of the stroop task. AB - The ability of children (M= 8.8 years) and adults (M= 25.6 years) to maintain task goals was examined by comparing their performance on a cued version of the Stroop colour-word task. The experimental task presented a cue on each trial that instructed the participant to either read aloud the forthcoming word or name the colour of the word's lettering. Participants were tested with each of two cue stimulus delays (1,000 and 5,000 ms). Analysis of error rates in the colour naming condition revealed that children experienced greater interference than adults at each of the cue-stimulus delays. In an effort to separate the relative contributions of colour-naming and word-reading processes, additional analyses were performed based on the process dissociation procedure of Lindsay and Jacoby (1994). While colour-naming process estimates did not vary with age group or cue stimulus delay, word-reading process estimates were found to vary with age group and cue-stimulus delay. Specifically, adults were superior to children in the inhibition of irrelevant word information only during a long cue-stimulus delay. Collectively, these findings indicate that children have difficulty maintaining task goals in order to suppress stronger, goal-irrelevant responses. PMID- 21288261 TI - P2 porin and loop L7 from Haemophilus influenzae modulate expression of IL-6 and adhesion molecules in astrocytes. AB - During neuropathological conditions such as infections and degenerative diseases, astrocytes can be activated by infiltrating immune cells. Activated astrocytes can produce chemokines, cytokines and adhesion molecules. In this study, the production of IL-6 and adhesion molecules intercellular adhesion molecule-1 (ICAM 1), vascular cellular adhesion molecule-1 (VCAM-1) and E-selectin by human astroglioma cells stimulated with Gram-negative surface components was investigated. Haemophilus influenzae type b porin P2 and its selected active peptide, loop L7, were found to induce MEK1-MEK2/ mitogen-activated protein kinase phosphorylation in U87-MG cells as demonstrated by ELISA, and up-regulate cellular adhesion molecule and interleukin-6 (IL-6) production as shown by RT-PCR and ELISA. Using two potent and selective inhibitors of MEK activation by Raf-1 (PD-098059) and p38 (SB-203580), it was also demonstrated that both ERK1/2 and p38 pathways play key roles in the production of IL-6 as well as in ICAM-1, VCAM 1 and E-selectin expression by Hib porin. PMID- 21288262 TI - Survival in a large cohort of Greek patients with transfusion-dependent beta thalassaemia and mortality ratios compared to the general population. AB - BACKGROUND: With transfusions and chelation therapy, the prognosis for transfusion-dependent beta thalassaemia has changed from being fatal in early childhood to a chronic disorder with prolonged survival. DESIGN AND METHODS: In this historical prospective study, we present survival, causes of death and mortality ratios compared to the general population in 1044 Greek patients with transfusion-dependent beta thalassaemia. RESULTS: At the age of 50years, the overall survival was 65.0%, while the cardiac death-free survival was 77%. Birth cohort had a significant effect on survival (P<0.001) with a negative trend towards past decades. The standardised mortality ratio (standardised for sex and ages 20-40years) compared to the general population improved significantly from 28.9 in 1990-1999 to 13.5 in 2000-2008, while the standardised cardiac mortality ratio reduced from 322.9 to 106.6, respectively. CONCLUSIONS: Survival in thalassaemia has dramatically improved over the last twenty years but mortality remains significantly increased, compared to the general population. PMID- 21288263 TI - Preparation of different types of miso with mixture of starters and their effects on endogenous antioxidant of liver and kidney of mice. AB - The present study was undertaken to evaluate the effects of feeding the male mice with miso that was prepared with a mixture of microbial starters on the level of lipid peroxidation as a marker of oxidative stress, antioxidant power of hepatocytes, the enzymatic and non-enzymatic antioxidant. The starters that were used in the preparation of miso were Aspergillus oryzae and Pleurotus ostreaus or A. oryzae and Bacillus subtilis. The miso that was prepared with A. oryzae and Bacillus subtilis has more effect on suppressing the oxidative stress and enhancement of endogenous antioxidant of hepatocytes and renal tissue of mice. PMID- 21288264 TI - OTP70 is a pentatricopeptide repeat protein of the E subgroup involved in splicing of the plastid transcript rpoC1. AB - Over 20 proteins of the pentatricopeptide repeat (PPR) family have been demonstrated to be involved in RNA editing in plant mitochondria and chloroplasts. All of these editing factors contain a so-called 'E' domain that has been shown to be essential for editing to occur. The presumption has been that this domain recruits the (unknown) editing enzyme to the RNA. In this report, we show that not all putative E-class PPR proteins are directly involved in RNA editing. Disruption of the OTP70 gene leads to a strong defect in splicing of the plastid transcript rpoC1, leading to a virescent phenotype. The mutant has a chloroplast transcript pattern characteristic of a reduction in plastid-encoded RNA polymerase activity. The E domain of OTP70 is not required for splicing, and can be deleted or replaced by the E domain from the known editing factor CRR4 without loss of rpoC1 splicing. Furthermore, the E domain of OTP70 is incapable of inducing RNA editing when fused to the RNA binding domain of CRR4. We conclude that the truncated E domain of OTP70 is no longer functional in RNA editing, and that the protein has acquired a new function in promoting RNA splicing. PMID- 21288265 TI - The specific overexpression of a cyclin-dependent kinase inhibitor in tomato fruit mesocarp cells uncouples endoreduplication and cell growth. AB - The size of tomato fruit results from the combination of cell number and cell size, which are respectively determined by the cell division and cell expansion processes. As fruit growth is mainly sustained by cell expansion, the development of fleshy pericarp tissue is characterized by numerous rounds of endoreduplication inducing a spectacular increase in DNA ploidy and mean cell size. Although a clear relationship exists between endoreduplication and cell growth in plants, the exact role of endoreduplication has not been clearly elucidated. To decipher the molecular basis of endoreduplication-associated cell growth in fruit, we investigated the putative involvement of the tomato cyclin dependent kinase inhibitor SlKRP1. We studied the kinetics of pericarp development in tomato fruit at the morphological and cytological levels, and demonstrated that endoreduplication is directly proportional to cell and fruit diameter. We established a mathematical model for tissue growth according to the number of divisions and endocycles. This model was tested in fruits where we managed to decrease the extent of endoreduplication by over-expressing SlKRP1 under the control of a fruit-specific promoter expressed during early development. Despite the fact that endoreduplication was affected, we could not observe any morphological, cytological or metabolic phenotypes, indicating that determination of cell and fruit size can be, at least conditionally, uncoupled from endoreduplication. PMID- 21288266 TI - Uncoupling phosphate deficiency from its major effects on growth and transcriptome via PHO1 expression in Arabidopsis. AB - Inorganic phosphate (Pi) is one of the most limiting nutrients for plant growth in both natural and agricultural contexts. Pi-deficiency leads to a strong decrease in shoot growth, and triggers extensive changes at the developmental, biochemical and gene expression levels that are presumably aimed at improving the acquisition of this nutrient and sustaining growth. The Arabidopsis thaliana PHO1 gene has previously been shown to participate in the transport of Pi from roots to shoots, and the null pho1 mutant has all the hallmarks associated with shoot Pi deficiency. We show here that A. thaliana plants with a reduced expression of PHO1 in roots have shoot growth similar to Pi-sufficient plants, despite leaves being strongly Pi deficient. Furthermore, the gene expression profile normally triggered by Pi deficiency is suppressed in plants with low PHO1 expression. At comparable levels of shoot Pi supply, the wild type reduces shoot growth but maintains adequate shoot vacuolar Pi content, whereas the PHO1 underexpressor maintains maximal growth with strongly depleted Pi reserves. Expression of the Oryza sativa (rice) PHO1 ortholog in the pho1 null mutant also leads to plants that maintain normal growth and suppression of the Pi-deficiency response, despite the low shoot Pi. These data show that it is possible to unlink low shoot Pi content with the responses normally associated with Pi deficiency through the modulation of PHO1 expression or activity. These data also show that reduced shoot growth is not a direct consequence of Pi deficiency, but is more likely to be a result of extensive gene expression reprogramming triggered by Pi deficiency. PMID- 21288267 TI - Male gametophyte defective 4 encodes a rhamnogalacturonan II xylosyltransferase and is important for growth of pollen tubes and roots in Arabidopsis. AB - In flowering plants, the growth of pollen tubes is essential for the delivery of sperm to the egg cells. Although many factors (including cell-wall properties) are involved in this process, little is known about the underlying molecular mechanisms that regulate the growth of pollen tubes. We report here the characterization of an Arabidopsis mutant male gametophyte defective 4 (mgp4) that is severely defective in pollen tube growth. The mgp4 mutation also impairs root growth of pollen-rescued mgp4 mutant plants generated by expressing MGP4 cDNA under the control of a pollen grain/tube-specific promoter. The MGP4 gene encodes a putative xylosyltransferase and is expressed in many organs/tissues, including pollen tubes and roots. MGP4 protein expressed in Pichia pastoris exhibited xylosyltransferase activity and transferred d-xylose onto l-fucose. The pectic polysaccharide rhamnogalacturonan II (RG-II), isolated from 7-day-old pollen-rescued mutant seedlings, exhibited a 30% reduction in 2-O-methyl d-xylose residues. Furthermore, an exogenous supply of boric acid enhanced RG-II dimer formation and partially restored the root growth of the pollen-rescued mutant seedlings. Taken together, these results suggest that MGP4 plays important roles in pollen tube and root growth by acting as a xylosyltransferase involved in the biosynthesis of pectic RG-II. PMID- 21288268 TI - The DUF579 domain containing proteins IRX15 and IRX15-L affect xylan synthesis in Arabidopsis. AB - Xylan is the principal hemicellulose in the secondary cell walls of eudicots and in the primary and secondary cell walls of grasses and cereals. The biosynthesis of this important cell wall component has yet to be fully determined although a number of proteins have been shown to be required for xylan synthesis. To discover new genes involved in xylan biosynthesis we explored the psyllium (Plantago ovata Forsk) seed mucilaginous layer through EST profiling. This tissue synthesizes large amounts of a complex heteroxylan over a short period of time. By comparing abundant transcripts in this tissue with abundant transcripts specifically present during secondary cell wall formation in Arabidopsis thaliana, where glucuronoxylan biosynthesis is pronounced, we identified two Arabidopsis genes likely involved in xylan biosynthesis. These genes encode proteins containing a Domain of Unknown Function (DUF) 579 and were designated IRREGULAR XYLEM (IRX) 15 and IRX15-LIKE (IRX15-L). We obtained Arabidopsis T-DNA knockout lines for the two genes and analyzed their lower stems for changes in neutral monosaccharide composition. No changes were observed in each of these mutants, although the irx15 irx15-L double mutant displayed a moderate reduction in stem xylose. Further characterization of the irx15 irx15-L mutant revealed irregular secondary cell wall margins in fiber cells and a lower xylan degree of polymerization. Through these studies we conclude that IRX15 and IRX15-L function in a redundant manner and are involved in xylan biosynthesis. PMID- 21288269 TI - Automated analysis of hypocotyl growth dynamics during shade avoidance in Arabidopsis. AB - Plants that are adapted to environments where light is abundant are especially sensitive to competition for light from neighboring vegetation. As a result, these plants initiate a series of changes known as the shade avoidance syndrome, during which plants elongate their stems and petioles at the expense of leaf development. Although the developmental outcomes of exposure to prolonged shade are known, the signaling dynamics during the initial exposure of seedlings to shade is less well studied. Here, we report the development of a new software based tool, called HyDE (Hypocotyl Determining Engine) to measure hypocotyl lengths of time-resolved image stacks of Arabidopsis wild-type and mutant seedlings. We show that Arabidopsis grows rapidly in response to the shade stimulus, with measurable growth after just 45 min shade exposure. Similar to other mustard species, this growth response occurs in multiple distinct phases, including two phases of rapid growth and one phase of slower growth. Using mutants affected in shade avoidance phenotypes, we demonstrate that most of this early growth requires new auxin biosynthesis via the indole-3-pyruvate pathway. When activity of this pathway is reduced, the first phase of elongation growth is absent, and this is correlated with reduced activity of auxin-regulated genes. Finally, we show that varying shade intensity and duration can affect the shape and magnitude of the growth response, indicating a broad range of the elongation response to shade. PMID- 21288270 TI - Young people's views on sharing health-related stories on the Internet. AB - There is an increasing interest in the use of stories in healthcare practice and education. However, there are few stories from young people concerning health and little is known about their views on sharing such stories on the Internet. The aim of this study was to explore young people's perspectives in this area. A qualitative method was used and a project website was purposely built to facilitate data collection. An online focus group with 13 young people was carried out in an asynchronous format. Participants valued highly the therapeutic effect of storytelling and the use of digital stories to share feelings and experiences with a wide range of audiences, suggesting that well-produced stories could be a useful learning resource. A number of concerns were also raised, including embarrassment, reaction of other people and online safety. Having stories available on the Internet can be beneficial; however, concerns especially about safety associated with Internet use and support for storytellers should be taken into consideration. A better understanding of young people's perceptions can provide valuable insights for future work with this age group on storytelling. PMID- 21288271 TI - Environmental gradients structure Daphnia pulex * pulicaria clonal distribution. AB - The rarity of eukaryotic asexual reproduction is frequently attributed to the disadvantage of reduced genetic variation relative to sexual reproduction. However, parthenogenetic lineages that evolved repeatedly from sexual ancestors can generate regional pools of phenotypically diverse clones. Various theories to explain the maintenance of this genetic diversity as a result of environmental and spatial heterogeneity [frozen niche variation (FNV), general-purpose genotype] are conceptually similar to community ecological explanations for the maintenance of regional species diversity. We employed multivariate statistics common in community ecological research to study population genetic structure in the freshwater crustacean, Daphnia pulex * pulicaria. This parthenogenetic hybrid arose repeatedly from sexual ancestors. Daphnia pulex * pulicaria populations harboured substantial genetic variation among populations and the clonal composition at each pond corresponded to nutrient levels and invertebrate predator densities. The interclonal selection process described by the FNV hypothesis likely structured our D. pulex * pulicaria populations. PMID- 21288272 TI - Indirect genetics effects and evolutionary constraint: an analysis of social dominance in red deer, Cervus elaphus. AB - By determining access to limited resources, social dominance is often an important determinant of fitness. Thus, if heritable, standard theory predicts mean dominance should evolve. However, dominance is usually inferred from the tendency to win contests, and given one winner and one loser in any dyadic contest, the mean proportion won will always equal 0.5. Here, we argue that the apparent conflict between quantitative genetic theory and common sense is resolved by recognition of indirect genetic effects (IGEs). We estimate selection on, and genetic (co)variance structures for, social dominance, in a wild population of red deer Cervus elaphus, on the Scottish island of Rum. While dominance is heritable and positively correlated with lifetime fitness, contest outcomes depend as much on the genes carried by an opponent as on the genotype of a focal individual. We show how this dependency imposes an absolute evolutionary constraint on the phenotypic mean, thus reconciling theoretical predictions with common sense. More generally, we argue that IGEs likely provide a widespread but poorly recognized source of evolutionary constraint for traits influenced by competition. PMID- 21288273 TI - Land planarians (Platyhelminthes) as a model organism for fine-scale phylogeographic studies: understanding patterns of biodiversity in the Brazilian Atlantic Forest hotspot. AB - The Brazilian Atlantic Forest is one of the richest biodiversity hotspots of the world. Paleoclimatic models have predicted two large stability regions in its northern and central parts, whereas southern regions might have suffered strong instability during Pleistocene glaciations. Molecular phylogeographic and endemism studies show, nevertheless, contradictory results: although some results validate these predictions, other data suggest that paleoclimatic models fail to predict stable rainforest areas in the south. Most studies, however, have surveyed species with relatively high dispersal rates whereas taxa with lower dispersion capabilities should be better predictors of habitat stability. Here, we have used two land planarian species as model organisms to analyse the patterns and levels of nucleotide diversity on a locality within the Southern Atlantic Forest. We find that both species harbour high levels of genetic variability without exhibiting the molecular footprint of recent colonization or population expansions, suggesting a long-term stability scenario. The results reflect, therefore, that paleoclimatic models may fail to detect refugia in the Southern Atlantic Forest, and that model organisms with low dispersal capability can improve the resolution of these models. PMID- 21288274 TI - Our approach to management of patients with pulmonary vein stenosis following AF ablation. AB - Despite advances in the approach to pulmonary vein isolation, pulmonary vein stenosis remains an important morbid complication affecting approximately 1.3% of procedures. Patients with symptomatic pulmonary vein stenosis are typically referred for intervention with either balloon angioplasty or stenting. A significant portion of patients with severe pulmonary vein stenosis are asymptomatic and are identified only if routine screening is preformed following ablation. Based on available evidence, CT scanning 3 months postablation appears to be an effective and reliable screening tool that can be used to identify asymptomatic patients with significant stenosis. The best clinical management for asymptomatic patients with severe stenosis is poorly defined. We typically refer these patients for pulmonary vein intervention; however, the patient's age, comorbidities, functional capacity, as well as the size of the pulmonary vein affected, all need to be carefully considered with the patient before proceeding. PMID- 21288275 TI - Cavotricuspid isthmus ablation guided by electroanatomic mapping in a patient with a mechanical tricuspid valve replacement after a total correction of tetralogy of Fallot. AB - Atrial arrhythmias are a common sequel after surgery for congenital heart disease, and often eventually cause late morbidity and mortality. Nowadays, percutaneous catheter ablation of atrial flutter (AFL) is widely practised, and is highly successful and safe. Patients with a tricuspid valve replacement (TVR) represent a distinct group for whom the appropriate nonpharmacologic therapy for AFL has not yet been established. We report a case of a 55-year-old woman with a history of a total correction of tetralogy of Fallot (ToF) who developed AFL before and after receiving a tricuspid valve prosthesis. Based on the results of the activation mapping, counterclockwise and clockwise AFL were identified. Completion of a cavotricuspid isthmus (CTI) line on the atrial side successfully terminated the AFL, with resumption of sinus rhythm. Guided by a 3D mapping system, CTI ablation is feasible and safe in patients with a prosthetic tricuspid valve. PMID- 21288276 TI - Brugada syndrome caused by a large deletion in SCN5A only detected by multiplex ligation-dependent probe amplification. AB - A 14-year-old boy presented with atrial flutter. His ECG showed Brugada changes, first-degree AV block and major sinus pauses. Polymorphic VT was inducible at electrophysiology study. A pacemaker defibrillator was placed. Classic sequencing for SCN5A was normal. Multiplex ligation-dependent probe amplification, however, detected a major deletion in SCN5A. It is predicted that this deletion would result in haploinsufficiency. The report is the first description of a large scale rearrangement of the SCN5A gene and supports the association between the molecular pathology and the phenotypic expression. PMID- 21288277 TI - Direct visualization of epicardial structures and ablation utilizing a visually guided laser balloon catheter: preliminary findings. AB - BACKGROUND: Intrapericardial mapping and ablation can be utilized to target epicardial arrhythmic circuits. Current epicardial ablation strategies are associated with risk of damage to adjacent structures, including the coronary vasculature and phrenic nerves. OBJECTIVES: The purpose of this study was to evaluate the feasibility of an investigational, visually guided laser balloon catheter for manipulation within the pericardial space, visualization of epicardial structures, and delivery of laser ablation lesions to the ventricular myocardium. METHODS: Pericardial access was obtained in 4 anesthetized swine by subxyphoid puncture. The laser balloon catheter was introduced into the pericardial space via a deflectable sheath, and was manipulated to predefined regions in all animals. Visually guided laser ablation was performed on the ventricular myocardium, with post mortem examination of lesion size and depth. RESULTS: The laser ablation catheter could be manipulated to all targeted regions in all animals. Associated structures, including epicardial coronary arteries and veins as well as an endocardial catheter in the left atrial appendage, were easily visualized. A total of 9 laser energy applications at varying power/time settings were performed. Ablation utilizing moderate (7-8.5 W) power produced relatively uniform lesions (diameter 5-12 mm, depth 6-9 mm), while high (14 W) power produced a visible "steam pop" with a large, hemorrhagic lesion (22 * 11 * 11 mm). CONCLUSIONS: The investigational laser balloon catheter can be manipulated within the epicardial space, allowing for direct visualization of surrounding structures during ablation. Titration of laser power can be utilized to create moderate-sized ablation lesions while avoiding steam pops. PMID- 21288278 TI - Effects of dronedarone on clinical outcomes in patients with lone atrial fibrillation: pooled post hoc analysis from the ATHENA/EURIDIS/ADONIS studies. AB - INTRODUCTION: Dronedarone has been shown to reduce cardiovascular hospitalizations or death in patients with atrial fibrillation (AF) and additional risk factors. This post hoc exploratory analysis examines its effects in the subgroup of lone AF patients. METHODS AND RESULTS: Individual data from patients with lone AF enrolled in the EURIDIS, ADONIS, and ATHENA trials were entered in a central database. The effects of dronedarone compared to placebo on the composite endpoint of cardiovascular hospitalizations or death, and their individual components, were evaluated. A total of 432 (192 placebo and 240 dronedarone) patients (7% of the total population) were classified as having lone AF (69.4% male patients, mean age 64 +/- 13 years). The patients were followed for 13.8 +/- 7.2 months. The risk for first cardiovascular hospitalizations or death from any cause in the placebo group after 1 year was 25% in the lone AF group compared to 29% the rest of the population. For patients with lone AF, dronedarone led to a 44% reduction of cardiovascular hospitalizations or death (hazard ratio (HR) 0.56; 95%CI 0.36-0.88, P = 0.004) and to a 46% reduction in cardiovascular hospitalizations alone (HR 0.54; 95%CI 0.34-0.87, P = 0.004) compared to placebo. HR for all-cause mortality was 1.02 (95%CI 0.31-3.34, P = 0.885). All findings were homogeneous across the 3 studies and similar to those observed in the overall population. CONCLUSION: According to this post hoc analysis, patients with lone AF have a high risk for cardiovascular hospitalization within 1 year. Dronedarone when added to standard of care reduces the risk of cardiovascular hospitalizations in this population. PMID- 21288279 TI - Impact of patent foramen ovale on left atrial linear lesions in the context of atrial fibrillation ablation. AB - INTRODUCTION: We investigated the impact of the mode of left atrial (LA) access via patent foramen ovale (PFO) versus transseptal (TS) puncture on LA linear lesions during atrial fibrillation (AF) ablation. METHODS AND RESULTS: We investigated 139 (PFO: 25) consecutive patients who underwent mitral isthmus (MI) and/or LA roof linear ablation. Technical endpoint was completeness of linear lesions and duration of radiofrequency (RF) application. During the initial procedure, complete MI and LA roof blocks were created in 13 of 19 (68%) and 14 of 17 (82%) patients in the PFO group, and in 57 of 94 (61%) and 54 of 70 (74%) patients in the TS group, respectively (P = NS). There was no significant difference in RF durations at MI (11.1 +/- 8.9 and 15.1 +/- 7.6 minutes, P = 0.11), and LA roof (10.1 +/- 3.5 and 8.3 +/- 5.0 minutes, P = 0.21) between the 2 groups. Among 28 patients who underwent repeat linear ablation, complete MI and LA roof blocks were created in 3 of 4 (75%) and 0 of 1 (0%) patients in the PFO group, and in 16 of 21 (76%) and 7 of 10 (70%) patients in the TS group, respectively (P = NS). There was no significant difference in RF durations at MI (15.3 +/- 8.3 and 19.5 +/- 18.3 minutes, P = 0.71), and LA roof (19.0 and 10.3 +/ 5.4 minutes, P = 0.19) between the 2 groups. Clinical outcomes at 12 months were also similar. CONCLUSION: There were no significant differences in the procedural success rates, durations of RF application, 12-month clinical outcomes, and complication rates of LA linear ablation between the PFO and TS groups. Accessing the LA via a PFO is not an unfavorable approach toward LA linear ablation. PMID- 21288280 TI - Routine transthoracic echocardiography to assess pericardial collections in patients after extensive left atrial catheter ablation: a prospective study. AB - INTRODUCTION: Little is known about the incidence and timing of reactive pericardial collections developing after left atrial catheter ablation (LACA), and when and if transthoracic echocardiography (TTE) should be performed routinely in these patients postprocedure. METHODS AND RESULTS: Two hundred consecutive LACA patients for persistent atrial fibrillation (AF) (107), paroxysmal AF (75) or atrial tachycardia (AT) (18) underwent on-table TTE at the end of the procedure, and the next day prior to discharge. One patient developed tamponade at the time of transseptal puncture. Thirty-three percent of the remaining 199 who underwent on-table TTE, had a pericardial collection. On next day TTE, there were significantly more pericardial collections (53%, P < 0.0001). Persistent rather than paroxysmal arrhythmia at the time of the procedure was the only predictor of a pericardial collection, either on-table (chi(2)= 9.64; P = 0.002) or next day (chi(2)= 5.95; P = 0.02). Eight patients had collections on next day TTE >= 1.5 cm. One needed drainage because of clinical tamponade. Repeated TTEs in the other 7 patients demonstrated resolution of collections over 1-2 weeks. CONCLUSION: Pericardial collections are common in LACA patients. Almost all are not associated with clinical compromise. The only predictor of collection size is arrhythmia type at ablation, which may correspond to ablation at sites specific to persistent rather than paroxysmal arrhythmias. Performing on table TTE routinely may help guide immediate anticoagulation protocols, but even larger on-table collections are not associated with tamponade and resolve spontaneously. TTE does not need to be performed routinely unless there are clinical signs of tamponade. PMID- 21288281 TI - Histogram analysis: a novel method to detect and differentiate fractionated electrograms during atrial fibrillation. AB - INTRODUCTION: Complex fractionated atrial electrograms (CFAEs) might identify the critical substrate maintaining AF. We developed a method based upon histogram analysis of interpeak intervals (IPIs) to automatically quantify fractionation and differentiate between subtypes of CFAEs. METHODS: Two experts classified 1,681 fibrillatory electrograms recorded in 13 patients with persistent AF into 3 categories (gold standard): normal electrograms, discontinuous CFAEs, or continuous CFAEs. Histogram analysis of IPI was performed to calculate the P5, P50, P95, and the mean of IPIs, in addition to the total number of IPI (N(Total)), and the number of IPI within predetermined ranges: 10-60 (N(Short)), 60-120 (N(Intermediate)), and >120 ms (N(Long)). RESULTS: P50 and N(Long) were higher in the normal electrograms compared to the other 2 categories (P < 0.001). N(Intermediate) was higher in the discontinuous CFAE category compared to the other 2 categories. P95, mean IPI, N(Total), and N(Short) were all significantly different among the 3 categories (P < 0.001) and correlated with the degree of fractionation (r =-0.52, -0.55, 0.68, and 0.67, respectively). Receiver operating characteristic (ROC) curves showed good diagnostic accuracy (area under curve, AUC > 0.8) of P50 and N(Long) to detect normal electrograms. An algorithm using N(Intermediate) showed good diagnostic accuracy (AUC > 0.7) to detect discontinuous CFAEs, whereas P95, mean, N(Total), and N(Short) all revealed high diagnostic accuracy (AUC > 0.85) to detect continuous CFAEs. This was confirmed in a prospective data set. CONCLUSIONS: Histogram analysis of IPI can differentiate between normal electrograms, discontinuous and continuous fractionated electrograms. This method might be used to standardize and optimize ablation strategies in AF. PMID- 21288282 TI - Cryosurgery as adjuvant to Mohs micrographic surgery in the management of subungual squamous cell carcinoma. PMID- 21288283 TI - Bufalin and cinobufagin induce apoptosis of human hepatocellular carcinoma cells via Fas- and mitochondria-mediated pathways. AB - Bufadienolides bufalin and cinobufagin are cardiotonic steroids isolated from the skin and parotid venom glands of the toad Bufo bufo gargarizans Cantor. They have been shown to induce a wide spectrum of cancer cell apoptosis. However, the detailed molecular mechanisms of inducing apoptosis in hepatocellular carcinoma (HCC) are still unclear. In the present study, the apoptosis-inducing effect of bufalin and cinobufagin on HCC cell line HepG(2) was investigated. We found bufalin and cinobufagin induced marked changes in apoptotic morphology and significantly increased the proportion of apoptotic cells. This apoptotic induction was associated with an increase in Fas, Bax and Bid expression, a decrease in Bcl-2 expression, disruption of the mitochondrial membrane potential, release of cytochrome c, activation of caspase-3, -8, -9 and -10, and the cleavage of poly(ADP-ribose)polymerase (PARP), which indicated that bufalin and cinobufagin induced apoptosis through both Fas- and mitochondria-mediated pathways. In addition, caspase activation during bufalin- and cinobufagin-induced apoptosis was further confirmed by caspase-3 inhibitor Z-DEVD-FMK, caspase-8 inhibitor Z-IETD-FMK, caspase-9 inhibitor Z-LEHD-FMK and caspase-10 inhibitor Z AEVD-FMK. The results showed that bufalin- and cinobufagin-induced apoptosis was blocked by these inhibitors and particularly by caspase-10 inhibitor. Taken together, bufalin and cinobufagin induce apoptosis of HepG(2) cells via both Fas- and mitochondria-mediated pathways, and a Fas-mediated caspase-10-dependent pathway might play a crucial role. PMID- 21288284 TI - Inhibition of nuclear factor-kappaB suppresses peritoneal dissemination of gastric cancer by blocking cancer cell adhesion. AB - Currently, patients with peritoneal dissemination of gastric cancer must accept a poor prognosis because there is no standard effective therapy. To inhibit peritoneal dissemination it is important to inhibit interactions between extracellular matrices (ECM) and cell surface integrins, which are important for cancer cell adhesion. Although nuclear factor-kappa B (NF-kappaB) is involved in various processes in cancer progression, its involvement in the expression of integrins has not been elucidated. We used a novel NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), to study whether NF-kappaB blocks cancer cell adhesion via integrins in a gastric cancer dissemination model in mice and found that DHMEQ is a potent suppressor of cancer cell dissemination. Dehydroxymethylepoxyquinomicin suppressed the NF-kappaB activity of human gastric cancer cells NUGC-4 and 44As3Luc and blocked the adhesion of cancer cells to ECM when compared with the control. Dehydroxymethylepoxyquinomicin also inhibited expression of integrin (alpha2, alpha3, beta1) in in vitro studies. In the in vivo model, we injected 44As3Luc cells pretreated with DHMEQ into the peritoneal cavity of mice and performed peritoneal lavage after the injection of cancer cells. Viable cancer cells in the peritoneal cavities were evaluated sequentially by in vivo imaging. In mice injected with DHMEQ-pretreated cells and lavaged, live cancer cells in the peritoneum were significantly reduced compared with the control, and these mice survived longer. These results indicate that DHMEQ could inhibit cancer cell adhesion to the peritoneum possibly by suppressing integrin expression. Nuclear factor-kappa B inhibition may be a new therapeutic option for suppressing postoperative cancer dissemination. PMID- 21288287 TI - 'Immunomodulatory effects of opioids,' by Odunayo et al. PMID- 21288288 TI - The effect of noncardiac disease on plasma brain natriuretic peptide concentration in dogs. AB - OBJECTIVE: To evaluate the effects of noncardiac disease on c-terminal brain natriuretic peptide (cBNP) concentrations in dogs. DESIGN: Prospective observational study. SETTING: Urban university veterinary hospital. ANIMALS: Thirty-eight apparently healthy dogs, 28 dogs with cardiac disease (14 CHF, 14 non-CHF), and 81 dogs with primary noncardiac diseases. INTERVENTIONS: none. MATERIALS AND METHODS: Plasma was collected from each dog and analyzed for active (cBNP) B-type natriuretic peptide using an assay that is being investigated for commercial use (Biosite). MEASUREMENTS AND MAIN RESULTS: Dogs with CHF had significantly higher plasma cBNP concentrations than dogs with subclinical cardiac disease, apparently healthy dogs, or dogs with primary noncardiac disease. However, 21% (28/133) of dogs without CHF (including healthy dogs, dogs with primary noncardiac disease, and dogs with subclinical cardiac disease) had cBNP concentrations above previously identified diagnostic thresholds for CHF, reiterating the importance of reestablishing new diagnostic cutoffs when considering comorbidities affecting B-type natriuretic peptide levels. CONCLUSIONS: A clinically relevant proportion of nondyspneic dogs with primary noncardiac diseases have increased cBNP concentrations that exceed previously identified diagnostic thresholds, potentially limiting the ability of this test to identify CHF when noncardiac comorbidities exist. Interpretation of increased cBNP concentrations in such cases must be appropriately interpreted with further diagnostic investigation. PMID- 21288289 TI - Evaluation of respiratory parameters at presentation as clinical indicators of the respiratory localization in dogs and cats with respiratory distress. AB - OBJECTIVE: To describe clinical respiratory parameters in cats and dogs with respiratory distress and identify associations between respiratory signs at presentation and localization of the disease with particular evaluation between the synchrony of abdominal and chest wall movements as a clinical indicators for pleural space disease. Design - Prospective observational clinical study. SETTING: Emergency service in a university veterinary teaching hospital. ANIMALS: Cats and dogs with respiratory distress presented to the emergency service between April 2008 and July 2009. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The following parameters were systematically determined at time of admission: respiratory rate, heart rate, temperature, type of breathing, movement of the thoracic and abdominal wall during inspiration, presence of stridor, presence and type of dyspnea, and results of thoracic auscultation. Abdominal and chest wall movement was categorized as synchronous, asynchronous, or inverse. Diagnostic test results, diagnosis, and outcome were subsequently recorded. Based on the final diagnoses, animals were assigned to 1 or more of the following groups regarding the anatomical localization of the respiratory distress: upper airways, lower airways, lung parenchyma, pleural space, thoracic wall, nonrespiratory causes, and normal animals. One hundred and seventy-six animals (103 cats and 73 dogs) were evaluated. Inspiratory dyspnea was associated with upper airway disease in dogs and expiratory dyspnea with lower airway disease in cats. Respiratory noises were significantly associated and highly sensitive and specific for upper airway disease. An asynchronous or inverse breathing pattern and decreased lung auscultation results were significantly associated with pleural space disease in both dogs and cats (P<0.001). The combination is highly sensitive (99%) but not very specific (45%). Fast and shallow breathing was not associated with pleural space disease. Increased or moist pulmonary auscultation findings were associated with parenchymal lung disease. CONCLUSIONS: Cats and dogs with pleural space disease can be identified by an asynchronous or inverse breathing pattern in combination with decreased lung sounds on auscultation. PMID- 21288290 TI - Blood gas analysis and cooximetry in retired racing Greyhounds. AB - OBJECTIVE: The purposes of this study were to evaluate the oxygen affinity of hemoglobin (Hb) in healthy retired racing Greyhounds via cooximetry, and to establish reference intervals for blood gases and cooximetry in this breed. DESIGN: Prospective clinical study. SETTING: University Teaching Hospital. ANIMALS: Fifty-seven Greyhounds and 30 non-Greyhound dogs. INTERVENTIONS: Venous blood samples were collected from the jugular vein and placed into heparinized tubes. The samples were analyzed within 30 minutes of collection using a blood gas analyzer equipped with a cooximeter. MEASUREMENTS AND MAIN RESULTS: Greyhounds had significantly higher pH, PO(2) , oxygen saturation, oxyhemoglobin, total Hb, oxygen content, and oxygen capacity and significantly lower deoxyhemoglobin and P(50) when compared with non-Greyhound dogs. CONCLUSION: These findings support the fact that this breed is able to carry a higher concentration of total oxygen in the blood. As reported previously, this breed also has lower P(50) and, therefore, high oxygen affinity. In light of recent findings suggesting that in certain tissues a high affinity for oxygen is beneficial, this adaptation may be of benefit during strenuous exercise. PMID- 21288291 TI - Evaluation of gastric pressures as an indirect method for measurement of intraabdominal pressures in the horse. AB - OBJECTIVE: To develop an indirect method for measurement of intraabdominal pressures in the standing horse using measurement of gastric pressures as a less invasive technique, and to compare this method with direct intraabdominal pressures obtained from the peritoneal cavity. DESIGN: Prospective, experimental study. SETTING: University-based equine research facility. ANIMALS: Ten healthy adult horses, 7 geldings and 3 mares. INTERVENTIONS: Gastric pressures were measured using a nasogastric tube with a U-tube manometry technique, while intraperitoneal pressures were measured with a peritoneal cannula. Measurements of intraabdominal pressure were obtained by both methods, simultaneously, and were evaluated using 5 increasing volumes of fluid infused into the stomach (0, 400, 1,000, 2,000, and 3,000 mL). Bias and agreement between the 2 methods were determined using Bland-Altman analysis and Lin's concordance correlation coefficients. MEASUREMENTS AND MAIN RESULTS: Mean gastric pressure was 14.44 +/- 4.69 cm H(2)O and ranged from 0 to 25.8 cm H(2)O. Intraperitoneal pressure measurements were generally subatmospheric, and ranged from -6.6 to 3.1 cm H(2) O (mean +/- SD, -1.59 +/- 2.09 cm H(2)O). Measurements of intraperitoneal pressures were repeatable; however, intra- and interindividual variance was significantly larger for measurements of gastric pressures. The mean and relative bias for comparison between the 2 techniques was 15.9 +/- 5.3 cm H(2)O and 244.3 +/- 199.2%, respectively. The Lin's concordance correlation coefficient between gastric and intraperitoneal pressures was -0.003 but this was not statistically significant (P=0.75). CONCLUSIONS: There was no statistical concordance between measurements of intraabdominal pressure using gastric and intraperitoneal pressure measurement, indicating that gastric pressures cannot be substituted for intraperitoneal pressure measurement. Direct measurement of intraperitoneal pressures may be a more consistent method for comparison of intraabdominal pressures between horses, due to less variability within and between individuals. PMID- 21288292 TI - Evaluation of initial plasma lactate values as a predictor of gastric necrosis and initial and subsequent plasma lactate values as a predictor of survival in dogs with gastric dilatation-volvulus: 84 dogs (2003-2007). AB - OBJECTIVE: To test whether an initial plasma lactate >= 6.0 mmol/L is associated with the presence of macroscopic gastric wall necrosis and overall survival in dogs presenting with gastric dilatation-volvulus (GDV). Additionally, if no association was identified we sought to identify a different predictive initial plasma lactate concentration and to examine whether serial plasma lactate concentrations provide better prediction of survival. DESIGN: Retrospective study over a 5-year period (2003-2007). SETTING: Urban private referral small animal teaching hospital. ANIMALS: Eighty-four client-owned dogs with a diagnosis of GDV and plasma lactate measurements. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There was no statistically significant relationship found between survival and the presence of macroscopic gastric wall necrosis with the initial plasma lactate >= 6 mmol/L. There was a significant relationship between the initial plasma lactate >2.9 mmol/L for predicting necrosis and <4.1 mmol/L for predicting survival to discharge. Forty dogs that had an increased initial plasma lactate (>2.5 mmol/L) also had a subsequent plasma lactate measured within 12 hours of presentation, with 37/40 dogs surviving and 70% of these surviving dogs having the subsequent lactate decrease by >= 50% within 12 hours. The 3/40 that died failed to decrease their plasma lactate by >= 50% from the initial blood lactate. CONCLUSION: The results of this study indicate that an initial presenting plasma lactate concentration >= 6.0 mmol/L is not predictive of macroscopic gastric wall necrosis or survival in dogs presenting with GDV. A decrease in plasma lactate concentrations >= 50% within 12 hours may be a good indicator for survival. Limitations to the study include its retrospective nature, the small number of patients, and the number of dogs that were euthanized rather than allowed to progress to a natural outcome. PMID- 21288293 TI - Treatment of primary immune-mediated hemolytic anemia with mycophenolate mofetil in two cats. AB - OBJECTIVE: To describe the use of oral mycophenolate mofetil (MMF) as an adjunctive therapy in 2 cats with primary immune-mediated hemolytic anemia. CASE SERIES SUMMARY: Two cats suffering from presumptive primary immune mediated hemolytic were treated with MMF as part of their treatment regimens. Both cats had improved complete blood counts following therapy. NEW OR UNIQUE INFORMATION PROVIDED: This is the first reported use of oral MMF as adjunctive treatment for cats with immune-mediated hemolytic anemia. Outcome was favorable in both cats and no adverse effects were noted from the MMF. PMID- 21288294 TI - Coccygeal epidural with local anesthetic for catheterization and pain management in the treatment of feline urethral obstruction. AB - OBJECTIVE: To describe the technique for performing a coccygeal epidural injection of local anesthetic to facilitate catheterization in male cats with urethral obstructions using low-dose sedation. SIGNIFICANCE: Prompt diagnosis and relief of urethral obstructions is important as many cats may have developed marked metabolic abnormalities at the time of presentation. General anesthesia in these patients may be associated with significant risk for complications. Pain management is also an essential treatment goal, and this technique relieves urethral and penile pain during the unblocking process. CONCLUSION: Coccygeal epidurals can be used safely to provide analgesia to the penis and urethra and to the authors' knowledge, is a novel treatment modality to aid in the relief of urethral obstructions in male cats. PMID- 21288302 TI - A novel ErbB2 epitope targeted by human antitumor immunoagents. AB - Two novel human antitumor immunoconjugates, engineered by fusion of a single chain antibody fragment against human ErbB2 receptor, termed Erbicin, with either a human RNase or the Fc region of a human IgG(1) , are selectively cytotoxic for ErbB2-positive cancer cells in vitro and in vivo. These Erbicin-derived immunoagents (EDIAs) do not show the most negative properties of Herceptin, the only humanized mAb against ErbB2 used in the therapy of breast carcinoma: cardiotoxicity and the inability to act on resistant tumors. These differences are probably attributable to the different ErbB2 epitopes recognized by EDIAs and Herceptin, respectively, as we have previously reported that they induce different signaling mechanisms that control tumor and cardiac cell viability. Thus, to accurately identify the novel epitope recognized by EDIAs, three independent and complementary methodologies were used. They gave coherent results, which are reported here: EDIAs bind to a different ErbB2 epitope than Herceptin and the other human/humanized antibodies against ErbB2 reported so far. The epitope has been successfully located in region 122-195 of extracellular domain I. These findings could lead to the identification of novel epitopes on ErbB2 that could be used as potential therapeutic targets to mitigate anti-ErbB2 associated cardiotoxicity and eventually overcome resistance. PMID- 21288303 TI - Sirt1 and mir-9 expression is regulated during glucose-stimulated insulin secretion in pancreatic beta-islets. AB - MicroRNA mir-9 is speculated to be involved in insulin secretion because of its ability to regulate exocytosis. Sirt1 is an NAD-dependent protein deacetylase and a critical factor in the modulation of cellular responses to altered metabolic flux. It has also been shown recently to control insulin secretion from pancreatic beta-islets. However, little is known about the regulation of Sirt1 and mir-9 levels in pancreatic beta-cells, particularly during glucose-dependent insulin secretion. In this article, we report that mir-9 and Sirt1 protein levels are actively regulated in vivo in beta-islets during glucose-dependent insulin secretion. Our data also demonstrates that mir-9 targets and regulates Sirt1 expression in insulin-secreting cells. This targeting is relevant in pancreatic beta-islets, where we show a reduction in Sirt1 protein levels when mir-9 expression is high during glucose-dependent insulin secretion. This functional interplay between insulin secretion, mir-9 and Sirt1 expression could be relevant in diabetes. It also highlights the crosstalk between an NAD-dependent protein deacetylase and microRNA in pancreatic beta-cells. PMID- 21288304 TI - Nested graft in chronic wounds: a new solution for an old problem. AB - It is well shown that chronic wounds are populated by cells unable to respond to re-epithelising stimulus. Large ulcers that remain unhealed for several months are more difficult to treat probably because of the depletion of active factors. Yet in 1869 Reverdin realised that the partial coverage of an ulcer with small fragments of healthy skin was able to lead to wound healing; unfortunately, its employment was limited to granulating wounds. Recently, the importance of factors such as cytokines, chemokines and adhesion molecules in wound healing, and the involvement of all cellular types resident or transiting in the skin has been partially elucidated. In this study, we proposed to simultaneously provide a new cellular and molecular reservoir with the efficient stimulus to trigger it. We created receiving site inside the ulcer, able to contain a full-thickness graft taken from a donor site. Our aim was not to cover the entire defect, but to use the minigraft as 'fount' of functional cells and to give an acute stress through the chambers created inside the ulcer. A complete wound healing was obtained in all patients treated in a short period of time. This technique does not require special equipment and assistance in maintaining costs at very low levels. PMID- 21288305 TI - Some binding-related drug properties are dependent on thermodynamic signature. AB - The binding affinity is determined by the Gibbs energy of binding (DeltaG) which is the sum of enthalpic (DeltaH) and entropic (-TDeltaS) contributions. Because the enthalpy and entropy contribute in an additive way to the binding energy, the same binding affinity can be achieved by many different combinations of enthalpic and entropic contributions; however, do compounds with similar binding affinities but different thermodynamic signatures (i.e., different DeltaH, -TDeltaS combinations) exhibit the same functional effects? Are there characteristics of compounds that can be modulated by modifying their thermodynamic signatures? In this paper, we consider the minimization of unwanted conformational effects arising during the development of CD4/gp120 inhibitors, a new class of HIV-1 cell entry inhibitors. Competitive inhibitors of protein/protein interactions run the risk of triggering the very same signals that they are supposed to inhibit. Here, we show that for CD4/gp120 inhibitors, the magnitude of those unwanted effects is related to the proportion in which the enthalpy and entropy changes contribute to the binding affinity. The thermodynamic optimization plot (TOP) previously proposed to optimize binding affinity can also be used to obtain appropriate enthalpy/entropy combinations for drug candidates. PMID- 21288306 TI - Reconciling the Krogh and Ussing interpretations of epithelial chloride transport - presenting a novel hypothesis for the physiological significance of the passive cellular chloride uptake. AB - In 1937, August Krogh discovered a powerful active Cl(-) uptake mechanism in frog skin. After WWII, Hans Ussing continued the studies on the isolated skin and discovered the passive nature of the chloride uptake. The review concludes that the two modes of transport are associated with a minority cell type denoted as the gamma-type mitochondria-rich (MR) cell, which is highly specialized for epithelial Cl(-) uptake whether the frog is in the pond of low [NaCl] or the skin is isolated and studied by Ussing chamber technique. One type of apical Cl(-) channels of the gamma-MR cell is activated by binding of Cl(-) to an external binding site and by membrane depolarization. This results in a tight coupling of the uptake of Na(+) by principal cells and Cl(-) by MR cells. Another type of Cl( ) channels (probably CFTR) is involved in isotonic fluid uptake. It is suggested that the Cl(-) channels serve passive uptake of Cl(-) from the thin epidermal film of fluid produced by mucosal glands. The hypothesis is evaluated by discussing the turnover of water and ions of the epidermal surface fluid under terrestrial conditions. The apical Cl(-) channels close when the electrodiffusion force is outwardly directed as it is when the animal is in the pond. With the passive fluxes eliminated, the Cl(-) flux is governed by active transport and evidence is discussed that this is brought about by an exchange of cellular HCO(3) (-) with Cl(-) of the outside bath driven by an apical H(+) V-ATPase. PMID- 21288307 TI - Ameliorative effect of NAP on laser-induced retinal damage. AB - PURPOSE: NAP is the smallest active element of activity-dependent neuroprotective protein (ADNP) in the non-myelinated neural tissue. This study evaluated the neuroprotective effect of NAP in reducing the spread of laser-induced retinal damage in rat. METHODS: Laser lesions were created in 72 DA pigmented rats. Two groups were treated by one intravenous or intravitreal injection of NAP immediately after exposure to laser. Two control groups were similarly administered saline injection. Histological and morphometrical evaluations of the lesions were preformed 3, 20 and 60 days after photocoagulation. RESULTS: After intravitreal treatment with NAP, a significant reduction in the diameter of the laser-induced lesions was found 3 days after photocoagulation (p < 0.001) but not after 20 and 60 days while the systemic treatment significantly reduced lesion diameter 20 and 60 days after photocoagulation (p = 0.001). Significant difference in photoreceptor cell loss was found in eyes treated intravitreally only 3 days after photocoagulation (p = 0.002). In the systemically treated animals such effect was found only after 20 and 60 days (p < 0.001). CONCLUSIONS: Treatment with NAP ameliorates laser-induced retinal lesions. Intravitreal treatment had an early short-term effect while the effect of systemic administration was delayed and prolonged. This treatment may be of clinical significance in reducing laser-induced retinal injuries in humans. PMID- 21288308 TI - Corneal biomechanics measured with the ocular response analyser in patients with unilateral open-angle glaucoma. AB - PURPOSE: To evaluate the relationship between biomechanical properties of the cornea and intraocular pressure (IOP) and the role of biomechanical properties in eyes of patients with unilateral primary open-angle glaucoma (POAG). METHODS: The biomechanical properties of corneal hysteresis (CH) and the corneal resistance factor (CRF) were measured with the ocular response analyser (ORA). In an experimental setting, three human donor eyes with Schiotz-tonometry-controlled IOP were investigated. In addition, a series of patients with unilateral POAG were evaluated. Main outcome measures were CH, CRF, corneal-compensated IOP (IOPcc), standard automated perimetry parameters mean defect (MD) and pattern standard deviation, central corneal thickness, Goldmann applanation tonometry (GAT), and cup-to-disc ratio. RESULTS: A highly significant linear correlation between CH and the corneal-compensated IOP (IOPcc, r = -0.926; p < 0.001) was found. The correlation between IOP(CC) and CRF was not significant (r = 0.335; p = 0.08). In total, 36 eyes of 18 patients with unilateral POAG were examined. Regarding uncorrected CH (mean 7.73 +/- 1.46 mmHg glaucomatous eye and 9.28 +/- 1.42 mmHg fellow eye), there was a highly significant difference between both eyes. This difference disappears, when CH was corrected for IOP (9.44 +/- 3.78 mmHg and 9.97 +/- 3.22 mmHg, respectively). CONCLUSIONS: Corneal hysteresis but not corneal resistance factor is dependent on IOP. In patients with unilateral POAG, IOP is higher in the affected eye. When CH is corrected for IOP, corneal biomechanical properties do not differ in both eyes of patients with unilateral POAG. PMID- 21288309 TI - Automated alternation flicker for the detection of optic disc haemorrhages. AB - PURPOSE: Optic disc haemorrhages are associated with active glaucomatous neurodegeneration and ongoing visual field loss. We sought to determine whether automated alternation flicker enhances the detection of disc haemorrhages in serial images from patients with glaucoma when compared to side-by-side photographic evaluation and single-image display. METHODS: Serial sets of optic nerve photographs of 394 eyes from 234 patients followed for glaucoma at the authors' institutions were included in this study. Eyes with disc haemorrhages were graded for difficulty level and randomized along with nondisc haemorrhage control images into one of three presentation groups (automated alternation flicker, side-by-side or single image). Seven graders viewed all images and assessed for the presence or absence of disc haemorrhages. RESULTS: The sensitivity of automated alternation flicker for disc haemorrhage detection (0.878) was higher than side-by-side (0.705; p = 0.002) and single photographs (0.757; p = 0.01). There was no specificity difference between pairs of presentation groups (all p >= 0.7). CONCLUSION: Automated alternation flicker was a more sensitive method for disc haemorrhage detection than the current clinical standards and may have an important role in the management of glaucoma. PMID- 21288311 TI - Lack of awareness of kidney complications despite familiarity with diabetes: a multi-ethnic qualitative study. AB - BACKGROUND: Comparing South Asians with White Europeans and examining the cultural context of any observed differences is a necessary step in achieving culturally competent services and in helping to reduce inequalities which exist in outcomes for South Asian patients with End Stage Renal Disease. METHODS: Newly referred South Asian and White adult patients with diabetes were recruited from nephrology outpatient clinics in three UK centres--Luton, West London and Leicester. A semi-structured qualitative interview was conducted with 48 patients and a thematic analysis of the data produced is reported. RESULTS: Access to knowledge about renal complications of diabetes, was related to referral to renal services and recent monitoring and not to previous medical encounters. South Asian patients were aware of the high prevalence of diabetes within South Asian communities and a small number reported experience of kidney problems in other family members although any connection with diabetes was not made. CONCLUSION: Ongoing renal care information should be provided to people with diabetes and the cultural context of any information exchange needs to be addressed. PMID- 21288312 TI - Malnutrition-inflammation-atherosclerosis syndrome in patients with end-stage renal disease. AB - Malnutrition-inflammation-atherosclerosis (MIA) syndrome is where three dominant clinical entities which occur in patients with end-stage renal disease- malnutrition, inflammation and atherosclerosis--coexist and interact with each other. This literature review aims to present the factors which are responsible for the existence of MIA syndrome in patients with end-stage chronic kidney disease (CKD) on renal replacement therapy. Studies have shown that the main role in the pathogenesis of the MIA syndrome is played by inflammatory cytokines. The main inflammatory cytokines are tumour necrosis factor-a, interleukin-1 and interleukin-6. The following work examines these cytokines, indicating their main characteristics and the basic mode of action in patients with end-stage CKD as well as the further development of the syndrome. The existence of this syndrome is responsible for the high rates of morbidity and mortality in this group of patients who reach a level comparable with persons suffering from metastatic cancer. PMID- 21288313 TI - Dietary egg whites for phosphorus control in maintenance haemodialysis patients: a pilot study. AB - BACKGROUND: High dietary protein intake is associated with greater survival in maintenance haemodialysis (MHD) patients. High-protein foods may increase dietary phosphorus burden, which is associated with increased mortality in these patients. Hypothesis is: an egg white based diet with low phosphorus to protein ratio (<1.4 mg/g) will lower serum phosphorus without deteriorating the nutritional status in MHD patients. OBJECTIVE: We assessed serum phosphorus and albumin levels in MHD patients who agreed to ingest one meal per day with pasteurised liquid egg whites without phosphorus additives, as principal protein source. METHODS: Thirteen otherwise stable MHD patients with serum phosphorus >4.0 mg/dl agreed to consume eight ounces (225 g) of pasteurised liquid egg whites one meal per day for six weeks. Recipes were suggested to improve diet variety. RESULTS: Thirteen participating patients included seven women, three African Americans and five diabetics. Twelve patients exhibited drop in serum phosphorus. Mean population fall in serum phosphorus was 0.94 mg/dl, i.e. from 5.58 +/- 1.34 (mean +/- SD) to 4.63 +/- 1.18 (p = 0.003). Serum albumin showed an increase by 0.19 g/dl, i.e. from 4.02 +/- 0.29 to 4.21 +/- 0.36 g/dl (p = 0.014). Changes in phosphorus pill count were not statistically significant (p = 0.88). The egg white diet was well tolerated, and recipe variety appreciated. CONCLUSION: Pasteurised liquid egg whites may be an effective diet component lowering serum phosphorus without risking malnutrition. Controlled trials are indicated to examine egg white based dietary interventions in MHD patients at home or during haemodialysis treatment. PMID- 21288314 TI - Lactic acidosis after concomitant treatment with metformin and tenofovir in a patient with HIV infection. AB - We present an uncommon case of lactic acidosis after concomitant administration of Metformin and Tenofovir. This is a 74-year-old man with a history of diabetes mellitus receiving treatment with metformin. He had coronary artery disease and HIV infection treated with emtricitabine, tenofovir and recently started on efavirenz. He presented with zoster-like abdominal pain, tachypnoea, nausea and vomiting. On clinical examination, the patient was afebrile, hypotensive and tachycardic, he was markedly dehydrated and oliguric. The abdomen was soft, tender on palpation, not distended without rebound tenderness. The arterial blood gases revealed marked lactic acidosis and the laboratory tests on admission showed acute renal failure. The patient received nine treatments of slow continuous veno-venous hemofiltration (CVVHF). Despite the prolonged period of anuria, urine output progressively improved after 25 days and serum biochemical parameters of renal function returned to normal within 40 days. Health professionals must be aware of this uncommon effect in patients on antiretroviral treatment. Prompt initiation of CVVHF resulted in resolution of both lactic acidosis and renal failure. PMID- 21288315 TI - Depressive symptoms and dietary adherence in patients with end-stage renal disease. AB - Depressive symptoms may be associated with fluid and dietary non adherence which could lead to poorer outcomes. The purpose of this study was to examine the relationship between depressive symptoms and fluid and dietary adherence in 100 patients with end-stage renal disease (ESRD) receiving haemodialysis. A descriptive, cross-sectional design with a convenience sample of 100 patients with ESRD receiving maintenance haemodialysis completed instruments that measured self-reported depressive symptoms and perceived fluid and dietary adherence. Demographic and clinical data and objective indicators of fluid and diet adherence were extracted from medical records. As many as two-third of these subjects exhibited depressive symptoms and half were non adherent to fluid and diet prescriptions. After controlling for known covariates, patients determined to have moderate to severe depressive symptoms were more likely to report non adherence to fluid and diet restrictions. Depressive symptoms in patients with ESRD are common and may contribute to dietary and fluid non adherence. Early identification and appropriate interventions may potentially lead to improvement in adherence of these patients. PMID- 21288316 TI - The evolution of the Nephrology Educators' Network. AB - Nephrology nurse educators face many challenges related to professional development and resource sharing. In Australia and New Zealand, as well as other countries where the 'tyranny of distance' is a feature, access, equity and lack of educational support due to the geographical isolation of many nephrology units, present particular challenges. This paper reports the findings from a case study of 51 nephrology nurse educators in Australia. Using an exploratory descriptive approach, the study aimed to identify current issues facing nephrology nurse educators and determine the feasibility of developing an online community of practice to support them in their role. An outcome of the study was the establishment of The Nephrology Educators' Network. This network seeks to enhance peer support, collegiality, critical companionship, collaboration, knowledge sharing and the benchmarking of practices for those involved in nephrology nurse education. In this paper, we describe and reflect on some of the outcomes and challenges faced in developing this network. PMID- 21288317 TI - Total dose infusion of intravenous iron in patients with chronic kidney disease receiving haemodialysis. AB - A regimen of a single high dose iron administration was initially adopted for patients commencing haemodialysis (HD) treatment. Iron stores are established and iron metabolism and erythropoiesis stabilise allowing haematinic parameters to be more confidently assessed for use in anaemia management decisions. High doses of IV iron delay the need for subsequent iron supplementation. A high-dose, low frequency iron infusion regimen for all HD patients was adopted. The outcomes of administering this dosage regimen are reported as observational retrospective analysis using patient record data in 2009. Patients received three [median; semi interquartile range (SIQR) 0.5] high-dose iron infusions during the year. The median infusion dose was 1100 mg iron (SIQR 0.0) and the median amount of iron received during the year by each patient was 3200 mg (SIQR 750). The median haemoglobin (Hb) level prior to infusion was 108 g/l and post infusion 114 g/l; ZHb = 2.656, p = 0.008). Ferritin levels increased from a median of 376 MUg/l preinfusion to 690 MUg/l postinfusion; Zferritin =-4.796, p < 0.001. The median time between infusions was 125 days (approximately four months). The 51 patients (76%) who received three or less infusions within the study period received 2537 mg (mean) of iron. These findings indicate that both Hb and ferritin levels can be adequately managed using a high-dose, low-frequency regimen of IV iron in patients undergoing HD. PMID- 21288318 TI - Prevention of infection in patients with chronic kidney disease. Part II: healthcare-associated infections. AB - This second article, in a three-part CE series on the prevention of infection in patients with chronic kidney disease, focuses on healthcare-associated infections and blood borne viruses that are prevalent within the haemodialysis environment. It also informs the reader of the relevant infection and prevention precaution guidelines and their application within a haemodialysis setting. PMID- 21288321 TI - Fine-tuning the space, time, and host distribution of mycobacteria in wildlife. AB - BACKGROUND: We describe the diversity of two kinds of mycobacteria isolates, environmental mycobacteria and Mycobacterium bovis collected from wild boar, fallow deer, red deer and cattle in Donana National Park (DNP, Spain), analyzing their association with temporal, spatial and environmental factors. RESULTS: High diversity of environmental mycobacteria species and M. bovis typing patterns (TPs) were found. When assessing the factors underlying the presence of the most common types of both environmental mycobacteria and M. bovis TPs in DNP, we evidenced (i) host species differences in the occurrence, (ii) spatial structuration and (iii) differences in the degree of spatial association of specific types between host species. Co-infection of a single host by two M. bovis TPs occurred in all three wild ungulate species. In wild boar and red deer, isolation of one group of mycobacteria occurred more frequently in individuals not infected by the other group. While only three TPs were detected in wildlife between 1998 and 2003, up to 8 different ones were found during 2006-2007. The opposite was observed in cattle. Belonging to an M. bovis-infected social group was a significant risk factor for mycobacterial infection in red deer and wild boar, but not for fallow deer. M. bovis TPs were usually found closer to water marshland than MOTT. CONCLUSIONS: The diversity of mycobacteria described herein is indicative of multiple introduction events and a complex multi-host and multi pathogen epidemiology in DNP. Significant changes in the mycobacterial isolate community may have taken place, even in a short time period (1998 to 2007). Aspects of host social organization should be taken into account in wildlife epidemiology. Wildlife in DNP is frequently exposed to different species of non tuberculous, environmental mycobacteria, which could interact with the immune response to pathogenic mycobacteria, although the effects are unknown. This research highlights the suitability of molecular typing for surveys at small spatial and temporal scales. PMID- 21288322 TI - Malignant fibrous histiocytoma originating from the mesorectum: a case report. AB - BACKGROUND: Malignant fibrous histiocytoma (MFH) is a common sarcoma affecting soft tissues of the body, especially of the extremities or trunk. Prognosis of the abdominal MFH is usually poor. CASE PRESENTATION: A 52-year-old female presented to our surgical outpatient clinic with a lower abdominal tumor that had been gradually increasing in size. Clinical examination revealed a firm, irregularly surfaced, fixed, painless, child-head-sized tumor located in her lower abdomen. Computed tomography (CT) and magnetic resonance imaging (MRI) of the abdomen revealed a polycystic tumor at the lower abdomen which was 15 * 13 * 11 cm in diameter and encased the colorectum to the left back side. A barium enema and a colonoscopy showed direct invasion to the rectum. In 2001, the tumor had been excised along with a low anterior resection of the rectum because of direct invasion. The origin of this tumor was the mesorectum. The weight of the excised tumor was 1,500 g, including 800 ml of a brown fluid. A histopathological diagnosis revealed a common type of MFH, in which mitotic figures are frequently seen. CONCLUSION: This patient has survived without recurrence, for approximately 8 years since the completed tumor resection. It is important to obtain a complete resection during the MFH treatment. PMID- 21288323 TI - The terminal region of the E. coli chromosome localises at the periphery of the nucleoid. AB - BACKGROUND: Bacterial chromosomes are organised into a compact and dynamic structures termed nucleoids. Cytological studies in model rod-shaped bacteria show that the different regions of the chromosome display distinct and specific sub-cellular positioning and choreographies during the course of the cell cycle. The localisation of chromosome loci along the length of the cell has been described. However, positioning of loci across the width of the cell has not been determined. RESULTS: Here, we show that it is possible to assess the mean positioning of chromosomal loci across the width of the cell using two-dimension images from wide-field fluorescence microscopy. Observed apparent distributions of fluorescent-tagged loci of the E. coli chromosome along the cell diameter were compared with simulated distributions calculated using a range of cell width positioning models. Using this method, we detected the migration of chromosome loci towards the cell periphery induced by production of the bacteriophage T4 Ndd protein. In the absence of Ndd production, loci outside the replication terminus were located either randomly along the nucleoid width or towards the cell centre whereas loci inside the replication terminus were located at the periphery of the nucleoid in contrast to other loci. CONCLUSIONS: Our approach allows to reliably observing the positioning of chromosome loci along the width of E. coli cells. The terminal region of the chromosome is preferentially located at the periphery of the nucleoid consistent with its specific roles in chromosome organisation and dynamics. PMID- 21288324 TI - Geodemographics profiling of influenza A and B virus infections in community neighborhoods in Japan. AB - BACKGROUND: The spread of influenza viruses in a community are influenced by several factors, but no reports have focused on the relationship between the incidence of influenza and characteristics of small neighborhoods in a community. We aimed to clarify the relationship between the incidence of influenza and neighborhood characteristics using GIS and identified the type of small areas where influenza occurs frequently or infrequently. METHODS: Of the 19,077 registered influenza cases, we analyzed 11,437 influenza A and 5,193 influenza B cases that were diagnosed by the rapid antigen test in 66-86 medical facilities in Isahaya City, Japan, from 2004 to 2008. We used the commercial geodemographics dataset, Mosaic Japan to categorize and classify each neighborhood. Furthermore, we calculated the index value of influenza in crude and age adjusted rates to evaluate the incidence of influenza by Mosaic segmentation. Additional age structure analysis was performed to geodemographics segmentation to explore the relationship between influenza and family structure. RESULTS: The observed number of influenza A and B patients in the neighborhoods where young couples with small children lived was approximately 10-40% higher than the expected number (p < 0.01) during all seasons. On the contrary, the number of patients in the neighborhoods of the aging society in a rural area was 20-50% lower than the expected number (p < 0.01) during all seasons. This tendency was consistent after age adjustment except in the case of influenza B, which lost significance in higher incidence areas, but the overall results indicated high transmission of influenza in areas where young families with children lived. CONCLUSIONS: Our analysis indicated that the incidence of influenza A and B in neighborhood groups is related to the family structure, especially the presence of children in households. Simple statistical analysis of geodemographics data is an effective method to understand the differences in the incidence of influenza among neighborhood groups, and it provides a valuable basis for community strategies to control influenza. PMID- 21288325 TI - Intensified treatment with high dose rifampicin and levofloxacin compared to standard treatment for adult patients with tuberculous meningitis (TBM-IT): protocol for a randomized controlled trial. AB - BACKGROUND: Tuberculous meningitis is the most severe form of tuberculosis. Mortality for untreated tuberculous meningitis is 100%. Despite the introduction of antibiotic treatment for tuberculosis the mortality rate for tuberculous meningitis remains high; approximately 25% for HIV-negative and 67% for HIV positive patients with most deaths occurring within one month of starting therapy. The high mortality rate in tuberculous meningitis reflects the severity of the condition but also the poor antibacterial activity of current treatment regimes and relatively poor penetration of these drugs into the central nervous system. Improving the antitubercular activity in the central nervous system of current therapy may help improve outcomes. Increasing the dose of rifampicin, a key drug with known poor cerebrospinal fluid penetration may lead to higher drug levels at the site of infection and may improve survival. Of the second generation fluoroquinolones, levofloxacin may have the optimal pharmacological features including cerebrospinal fluid penetration, with a ratio of Area Under the Curve (AUC) in cerebrospinal fluid to AUC in plasma of >75% and strong bactericidal activity against Mycobacterium tuberculosis. We propose a randomized controlled trial to assess the efficacy of an intensified anti-tubercular treatment regimen in tuberculous meningitis patients, comparing current standard tuberculous meningitis treatment regimens with standard treatment intensified with high-dose rifampicin and additional levofloxacin. METHODS/DESIGN: A randomized, double blind, placebo-controlled trial with two parallel arms, comparing standard Vietnamese national guideline treatment for tuberculous meningitis with standard treatment plus an increased dose of rifampicin (to 15 mg/kg/day total) and additional levofloxacin. The study will include 750 patients (375 per treatment group) including a minimum of 350 HIV-positive patients. The calculation assumes an overall mortality of 40% vs. 30% in the two arms, respectively (corresponding to a target hazard ratio of 0.7), a power of 80% and a two-sided significance level of 5%. Randomization ratio is 1:1. The primary endpoint is overall survival, i.e. time from randomization to death during a follow-up period of 9 months. Secondary endpoints are: neurological disability at 9 months, time to new neurological event or death, time to new or recurrent AIDS defining illness or death (in HIV-positive patients only), severe adverse events, and rate of treatment interruption for adverse events. DISCUSSION: Currently very few options are available for the treatment of TBM and the mortality rate remains unacceptably high with severe disabilities seen in many of the survivors. This trial is based on the hypothesis that current anti-mycobacterial treatment schedules for TBM are not potent enough and that outcomes will be improved by increasing the CSF penetrating power of this regimen by optimising dosage and using additional drugs with better CSF penetration. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number ISRCTN61649292. PMID- 21288326 TI - Sample size requirements for separating out the effects of combination treatments: randomised controlled trials of combination therapy vs. standard treatment compared to factorial designs for patients with tuberculous meningitis. AB - BACKGROUND: In certain diseases clinical experts may judge that the intervention with the best prospects is the addition of two treatments to the standard of care. This can either be tested with a simple randomized trial of combination versus standard treatment or with a 2 x 2 factorial design. METHODS: We compared the two approaches using the design of a new trial in tuberculous meningitis as an example. In that trial the combination of 2 drugs added to standard treatment is assumed to reduce the hazard of death by 30% and the sample size of the combination trial to achieve 80% power is 750 patients. We calculated the power of corresponding factorial designs with one- to sixteen-fold the sample size of the combination trial depending on the contribution of each individual drug to the combination treatment effect and the strength of an interaction between the two. RESULTS: In the absence of an interaction, an eight-fold increase in sample size for the factorial design as compared to the combination trial is required to get 80% power to jointly detect effects of both drugs if the contribution of the less potent treatment to the total effect is at least 35%. An eight-fold sample size increase also provides a power of 76% to detect a qualitative interaction at the one-sided 10% significance level if the individual effects of both drugs are equal. Factorial designs with a lower sample size have a high chance to be underpowered, to show significance of only one drug even if both are equally effective, and to miss important interactions. CONCLUSIONS: Pragmatic combination trials of multiple interventions versus standard therapy are valuable in diseases with a limited patient pool if all interventions test the same treatment concept, it is considered likely that either both or none of the individual interventions are effective, and only moderate drug interactions are suspected. An adequately powered 2 x 2 factorial design to detect effects of individual drugs would require at least 8-fold the sample size of the combination trial. TRIAL REGISTRATION: Current Controlled Trials ISRCTN61649292. PMID- 21288327 TI - Cloning approach and functional analysis of anti-intimin single-chain variable fragment (scFv). AB - BACKGROUND: Intimin is an important virulence factor involved in the pathogenesis of enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic Escherichia coli (EHEC). Both pathogens are still important causes of diarrhea in children and adults in many developing and industrialized countries. Considering the fact that antibodies are important tools in the detection of various pathogens, an anti-intimin IgG2b monoclonal antibody was previously raised in immunized mice with the conserved sequence of the intimin molecule (int388-667). In immunoblotting assays, this monoclonal antibody showed excellent specificity. Despite good performance, the monoclonal antibody failed to detect some EPEC and EHEC isolates harboring variant amino acids within the 338-667 regions of intimin molecules. Consequently, motivated by its use for diagnosis purposes, in this study we aimed to the cloning and expression of the single-chain variable fragment from this monoclonal antibody (scFv). FINDINGS: Anti-intimin hybridoma mRNA was extracted and reversely transcripted to cDNA, and the light and heavy chains of the variable fragment of the antibody were amplified using commercial primers. The amplified chains were cloned into pGEM-T Easy vector. Specific primers were designed and used in an amplification and chain linkage strategy, obtaining the scFv, which in turn was cloned into pAE vector. E. coli BL21(DE3)pLys strain was transformed with pAE scFv-intimin plasmid and subjected to induction of protein expression. Anti-intimin scFv, expressed as inclusion bodies (insoluble fraction), was denatured, purified and submitted to refolding. The protein yield was 1 mg protein per 100 mL of bacterial culture. To test the functionality of the scFv, ELISA and immunofluorescence assays were performed, showing that 275 ng of scFv reacted with 2 mg of purified intimin, resulting in an absorbance of 0.75 at 492 nm. The immunofluorescence assay showed a strong reactivity with EPEC E2348/69. CONCLUSION: This study demonstrated that the recombinant anti-intimin antibody obtained is able to recognize the conserved region of intimin (Int388-667) in purified form and the EPEC isolate. PMID- 21288329 TI - Flow situations during everyday practice in a medical hospital ward. Results from a study based on experience sampling method. AB - BACKGROUND: Nursing is a constant balance between strain and stimulation and work and health research with a positive reference point has been recommended. A health-promoting circumstance for subjective experience is flow, which is a psychological state, when individuals concurrently experience happiness, motivation and cognitive efficiency. Flow situations can be identified through individuals' estimates of perceived challenge and skills. There is, to the best of our knowledge, no published study of flow among health care staff. The aim of this study was to identify flow-situations and study work-related activities and individual factors associated with flow situations, during everyday practice at a medical emergency ward in Sweden, in order to increase the knowledge on salutogenic health-promoting factors. METHODS: The respondents consisted of 17 assistant nurses and 14 registered nurses, who randomly and repeatedly answered a small questionnaire, through an experience sampling method, during everyday nursing practice. The study resulted in 497 observations. Flow situations were defined as an exact match between a high challenge and skill estimation and logistic regression models were used to study different variables association to flow situations. RESULTS: The health care staff spent most of its working time in individual nursing care and administrative and communicative duties. The assistant nurses were more often occupied in individual nursing care, while the registered nurses were more involved in medical care and administrative and communicative duties. The study resulted in 11.5% observations of flow situations but the relative number of flow situations varied between none to 55% among the participants. Flow situations were positively related to medical care activities and individual cognitive resources. Taking a break was also positively associated with flow situations among the assistant nurses. CONCLUSIONS: The result showed opportunities for work-related interventions, with an adherent increase in flow situations, opportunity for experience of flow and work-related health among the nursing staff in general and among the assistant nurses in particular. PMID- 21288330 TI - Advances in understanding ischemic acute kidney injury. AB - Acute kidney injury (AKI) is independently associated with increased morbidity and mortality. Ischemia is the leading cause of AKI, and short of supportive measures, no currently available therapy can effectively treat or prevent ischemic AKI. This paper discusses recent developments in the understanding of ischemic AKI pathophysiology, the emerging relationship between ischemic AKI and development of progressive chronic kidney disease, and promising novel therapies currently under investigation. On the basis of recent breakthroughs in understanding the pathophysiology of ischemic AKI, therapies that can treat or even prevent ischemic AKI may become a reality in the near future. PMID- 21288331 TI - Impaired dermal wound healing in discoidin domain receptor 2-deficient mice associated with defective extracellular matrix remodeling. AB - BACKGROUND: The wounding response relies on tightly regulated crosstalk between recruited fibroblasts and the collagenous extracellular matrix (ECM). Discoidin domain receptor 2 (DDR2) is a tyrosine kinase receptor for fibrillar collagen expressed during pathologic scarring, for example wound healing, arthritis and cancer. We have previously shown that DDR2 phosphorylation drives key wounding responses in skin fibroblasts including proliferation, chemotactic migration and secretion of both metalloproteinases and fibrillar collagen. In this study we compared healing of cutaneous wounds in DDR2+/+ and DDR2-/- mice and analyzed specific fibroblast responses. RESULTS: Cutaneous wound healing was significantly delayed in DDR2-/- mice compared with DDR2+/+ animals. Reduced alpha-smooth muscle actin (alphaSMA) expression and matrix metalloproteinase 2 (MMP2) activity in the DDR2-/- wound extracts indicated defective recruitment of skin fibroblasts. DDR2-/- wounds showed decreased tensile strength during healing, which correlated with a significant reduction in collagen content and defective collagen crosslinking. Non-wounded skin in DDR2-/- mice expressed less mRNA of the crosslinking enzymes lysyl oxidase (LOX), lysyl hydroxylase1 (LH1) and matricellular 'secreted protein, acidic and rich in cysteine' (SPARC; also known as osteonectin). Skin fibroblasts isolated from DDR2-/- mice displayed altered mRNA expression of a cluster of collagens, proteoglycans, integrins and MMPs that have been previously correlated with DDR2 expression, and reduced LOX, LH1 and SPARC mRNA levels and proteins. Stable reconstitution of wild-type DDR2 by retroviral infection restored LOX, LH1 and SPARC mRNA and protein levels in DDR2 /- fibroblasts. Contraction of collagen gels was reduced in DDR2-/- fibroblasts, accompanied by significantly reduced phosphorylated SrcY418. Inhibition of either LOX activity by beta-aminoproprionitrile or MMP activity by N-[(2R)-2 (hydroxamido carbonylmethyl)-4-methylpentanoyl]-l-tryptophan methylamide (GM6001) reduced collagen gel contraction by skin fibroblasts after DDR2 induction with soluble collagen type I. CONCLUSIONS: DDR2 contributes to skin fibroblast responses during tissue injury. Defective synthesis of collagen type I, crosslinking molecules and MMP2 predispose DDR2-/- mice to defective dermal wounding. PMID- 21288332 TI - Quantification and clinical relevance of gene amplification at chromosome 17q12 q21 in human epidermal growth factor receptor 2-amplified breast cancers. AB - INTRODUCTION: Human epidermal growth factor receptor 2 (HER2)-amplified breast cancers represent a tumor subtype with chromosome 17q rearrangements that lead to frequent gene amplifications. The aim of this study was to quantify the amplification of genes located on chromosome 17q and to analyze the relations between the pattern of gene amplifications and the patients' characteristics and survival. METHODS: Patients with HER2-positive breast tumors (HER2 score of 3+ by immunohistochemistry or positive for HER2 amplification by fluorescence in situ hybridization (FISH)) (n = 86) and with HER2-negative breast tumors (n = 40) (negative controls) were included in this study. Using a quantitative polymerase chain reaction method and DNA extracted from frozen tumor specimens, 11 genes (MED1, STARD3, HER2, GRB7, THRA, RARA, TOP2A, IGFBP4, CCR7, KRT20, KRT19 and GAS), which are localized within Chr17q12-q21 and have a putative role in breast cancer development, were quantified. Relapse-free and overall survival rates were estimated from the date of surgery to the date of the event of interest (recurrence or death) using the Kaplan-Meier method. RESULTS: Gene amplification was observed only in HER2-positive tumors, and the frequency of amplification decreased with the distance of the gene from HER2. HER2 presented the highest level of amplification. TOP2A was not included in the smallest region of amplification involving HER2. Amplification of RARA, KRT20 and KRT19 was significantly associated with node-positive breast cancer (P = 0.030, P = 0.002 and P = 0.033, respectively). During a median follow-up period of 55 months (range, 6 to 81 months), the subgroup of patients with hormone receptor-negative cancer and without TOP2A amplification showed the worst survival (relapse-free survival: hazard ratio (HR) = 0.29, 95% confidence interval (95% CI), 0.13 to 0.65, P = 0.001; and overall survival: HR = 0.28, 95% CI, 0.10 to 0.76, P = 0.008). CONCLUSIONS: HER2 amplification seems to drive genomic instability along chromosome 17q, leading to different patterns of gene amplification. This study confirms the clinical importance of identifying, among patients with HER2 positive breast tumors, the subgroup of patients with hormone receptor-negative and nonamplified TOP2A cancers as they have the worst prognosis. PMID- 21288333 TI - Microstructure and biomechanical characteristics of bone substitutes for trauma and orthopaedic surgery. AB - BACKGROUND: Many (artificial) bone substitute materials are currently available for use in orthopaedic trauma surgery. Objective data on their biological and biomechanical characteristics, which determine their clinical application, is mostly lacking. The aim of this study was to investigate structural and in vitro mechanical properties of nine bone substitute cements registered for use in orthopaedic trauma surgery in the Netherlands. METHODS: Seven calcium phosphate cements (BoneSource(r), Calcibon(r), ChronOS(r), Eurobone(r), HydroSetTM, Norian SRS(r), and Ostim(r)), one calcium sulphate cement (MIIG(r) X3), and one bioactive glass cement (Cortoss(r)) were tested. Structural characteristics were measured by micro-CT scanning. Compression strength and stiffness were determined following unconfined compression tests. RESULTS: Each bone substitute had unique characteristics. Mean total porosity ranged from 53% (Ostim(r)) to 0.5% (Norian SRS(r)). Mean pore size exceeded 100 MUm only in Eurobone(r) and Cortoss(r) (162.2 +/- 107.1 MUm and 148.4 +/- 70.6 MUm, respectively). However, 230 MUm pores were found in Calcibon(r), Norian SRS(r), HydroSetTM, and MIIG(r) X3. Connectivity density ranged from 27/cm3 for HydroSetTM to 0.03/cm3 for Calcibon(r). The ultimate compression strength was highest in Cortoss(r) (47.32 MPa) and lowest in Ostim(r) (0.24 MPa). Young's Modulus was highest in Calcibon(r) (790 MPa) and lowest in Ostim(r) (6 MPa). CONCLUSIONS: The bone substitutes tested display a wide range in structural properties and compression strength, indicating that they will be suitable for different clinical indications. The data outlined here will help surgeons to select the most suitable products currently available for specific clinical indications. PMID- 21288334 TI - Utility and safety of draining pleural effusions in mechanically ventilated patients: a systematic review and meta-analysis. AB - INTRODUCTION: Pleural effusions are frequently drained in mechanically ventilated patients but the benefits and risks of this procedure are not well established. METHODS: We performed a literature search of multiple databases (MEDLINE, EMBASE, HEALTHSTAR, CINAHL) up to April 2010 to identify studies reporting clinical or physiological outcomes of mechanically ventilated critically ill patients who underwent drainage of pleural effusions. Studies were adjudicated for inclusion independently and in duplicate. Data on duration of ventilation and other clinical outcomes, oxygenation and lung mechanics, and adverse events were abstracted in duplicate independently. RESULTS: Nineteen observational studies (N = 1,124) met selection criteria. The mean PaO2:FiO2 ratio improved by 18% (95% confidence interval (CI) 5% to 33%, I2 = 53.7%, five studies including 118 patients) after effusion drainage. Reported complication rates were low for pneumothorax (20 events in 14 studies including 965 patients; pooled mean 3.4%, 95% CI 1.7 to 6.5%, I2 = 52.5%) and hemothorax (4 events in 10 studies including 721 patients; pooled mean 1.6%, 95% CI 0.8 to 3.3%, I2 = 0%). The use of ultrasound guidance (either real-time or for site marking) was not associated with a statistically significant reduction in the risk of pneumothorax (OR = 0.32; 95% CI 0.08 to 1.19). Studies did not report duration of ventilation, length of stay in the intensive care unit or hospital, or mortality. CONCLUSIONS: Drainage of pleural effusions in mechanically ventilated patients appears to improve oxygenation and is safe. We found no data to either support or refute claims of beneficial effects on clinically important outcomes such as duration of ventilation or length of stay. PMID- 21288335 TI - Anti-malarial activity of Holarrhena antidysenterica and Viola canescens, plants traditionally used against malaria in the Garhwal region of north-west Himalaya. AB - BACKGROUND: The increasing number of multidrug-resistant Plasmodium strains warrants exploration of new anti-malarials. Medicinal plant research has become more important, particularly after the development of Chinese anti-malarial drug artemisnin from Artemisia annua. The present study shows evaluation of anti malarial effects of two plants commonly used against malaria in the Garhwal region of north-west Himalaya, in order to discover the herbal-based medicine. METHODS: In vitro anti-plasmodial sensitivity of plant extracts was assessed using schizont maturation and parasite lactate dehydrogenase (pLDH) assay. Cytotoxic activities of the examined extracts were determined on L-6 cells of rat skeletal muscle myoblast. The 4-day test for anti-malarial activity against a chloroquine sensitive Plasmodium berghei NK65 strain in Swiss albino mice was used for monitoring in vivo activity of plant extracts. RESULTS: Chloroform extract of H. antidysenterica (HA-2) and petroleum ether extract of V. canescens (VC-1) plants significantly reduced parasitaemia in P. berghei infected mice. The extract HA-2 showed in vitro anti-plasmodial activity with its IC50 value 5.5 MUg/ml using pLDH assay and ED50 value 18.29 mg/kg in P. berghei infected Swiss albino mice. Similarly petroleum ether extract of V. canescens (VC-1) showed in vitro anti-plasmodial activity with its IC50 value 2.76 MUg/ml using pLDH assay and ED50 15.8 mg/kg in P. berghei infected mice. The extracts coded as HA-2 at 30 mg/kg and VC-1 at 20 mg/kg exhibited parasite inhibition in mice: 73.2% and 63.0% respectively. Of these two plant extracts, petroleum ether extract of V. canescens was found slightly cytotoxic. CONCLUSION: The present investigation reflects the use of these traditional medicinal plants against malaria and these plants may work as potential source in the development of variety of herbal formulations for the treatment of malaria. PMID- 21288336 TI - Chiropractic wellness on the web: the content and quality of information related to wellness and primary prevention on the Internet. AB - BACKGROUND: The Internet has become a common source of information for patients wishing to learn about health information. Previous studies found information related to back pain poor and often contradictory to current guidelines. Wellness has become a common topic in the field of chiropractic and accrediting agencies have standards on delivery of wellness-based content in college curricula as well as directives for clinical applications. The purpose of this study was to evaluate the quality of the information on the Internet using the terms "chiropractic wellness," or "wellness chiropractic". METHODS: Five commonly used search engines were selected and the first 10 sites found using the strategy above were evaluated by two raters. Demographic assessments of the sites were made along with whether they were Health on the Net Foundation (HON) certified, contained standard wellness content, mentioned any Healthy People Focus Areas, and other chiropractic topics. Kappa statistics compared inter-rater agreement. RESULTS: Potential patients appeared to be the audience 87% of the time and a private doctor of chiropractic appeared to be the typical site owner. The sites usually promoted the provider. No sites displayed HON certification logo nor did any appear to meet the HON certification criteria. Twenty-six sites (55%) promoted regular physical activity in some manner and 18 (38%) had information on health risks of tobacco. Four (9%) had mental health or stress-reduction content but none had information supportive of vaccination. Some had information contradictory to common public health measures. CONCLUSIONS: Patients searching the Internet for chiropractic wellness information will often find useless information that will not help them maintain health or become well. Most simply market the chiropractic practice or allow for a patients to provide personal information in exchange for more 'wellness' information. More research should be done on how providers determine site content, pay any attention to the details on their sites, or agree with content as some appear to be prefabricated sites. Website content could be enhanced by sharing of information from reputable sources like US Centers for Disease Control, the National Institutes of Health and other authoritative sources. HON certification should also be sought. PMID- 21288337 TI - An assessment of orofacial clefts in Tanzania. AB - BACKGROUND: Clefts of the lip (CL), the palate (CP), or both (CLP) are the most common orofacial congenital malformations found among live births, accounting for 65% of all head and neck anomalies. The frequency and pattern of orofacial clefts in different parts of the world and among different human groups varies widely. Generally, populations of Asian or Native American origin have the highest prevalence, while Caucasian populations show intermediate prevalence and African populations the lowest. To date, little is known regarding the epidemiology and pattern of orofacial clefts in Tanzania. METHODS: A retrospective descriptive study was conducted at Bugando Medical Centre to identify all children with orofacial clefts that attended or were treated during a period of five years. Cleft lip and/or palate records were obtained from patient files in the Hospital's Departments of Surgery, Paediatrics and medical records. Age at presentation, sex, region of origin, type and laterality of the cleft were recorded. In addition, presence of associated congenital anomalies or syndromes was recorded. RESULTS: A total of 240 orofacial cleft cases were seen during this period. Isolated cleft lip was the most common cleft type followed closely by cleft lip and palate (CLP). This is a departure from the pattern of clefting reported for Caucasian and Asian populations, where CLP or isolated cleft palate is the most common type. The distribution of clefts by side showed a statistically significant preponderance of the left side (43.7%) (chi2 = 92.4, p < 0.001), followed by the right (28.8%) and bilateral sides (18.3%). Patients with isolated cleft palate presented at very early age (mean age 1.00 years, SE 0.56). Associated congenital anomalies were observed in 2.8% of all patients with orofacial clefts, and included neural tube defects, Talipes and persistent ductus arteriosus. CONCLUSIONS: Unilateral orofacial clefts were significantly more common than bilateral clefts; with the left side being the most common affected side. Most of the other findings did not show marked differences with orofacial cleft distributions in other African populations. PMID- 21288338 TI - Hierarchical graphs for rule-based modeling of biochemical systems. AB - BACKGROUND: In rule-based modeling, graphs are used to represent molecules: a colored vertex represents a component of a molecule, a vertex attribute represents the internal state of a component, and an edge represents a bond between components. Components of a molecule share the same color. Furthermore, graph-rewriting rules are used to represent molecular interactions. A rule that specifies addition (removal) of an edge represents a class of association (dissociation) reactions, and a rule that specifies a change of a vertex attribute represents a class of reactions that affect the internal state of a molecular component. A set of rules comprises an executable model that can be used to determine, through various means, the system-level dynamics of molecular interactions in a biochemical system. RESULTS: For purposes of model annotation, we propose the use of hierarchical graphs to represent structural relationships among components and subcomponents of molecules. We illustrate how hierarchical graphs can be used to naturally document the structural organization of the functional components and subcomponents of two proteins: the protein tyrosine kinase Lck and the T cell receptor (TCR) complex. We also show that computational methods developed for regular graphs can be applied to hierarchical graphs. In particular, we describe a generalization of Nauty, a graph isomorphism and canonical labeling algorithm. The generalized version of the Nauty procedure, which we call HNauty, can be used to assign canonical labels to hierarchical graphs or more generally to graphs with multiple edge types. The difference between the Nauty and HNauty procedures is minor, but for completeness, we provide an explanation of the entire HNauty algorithm. CONCLUSIONS: Hierarchical graphs provide more intuitive formal representations of proteins and other structured molecules with multiple functional components than do the regular graphs of current languages for specifying rule-based models, such as the BioNetGen language (BNGL). Thus, the proposed use of hierarchical graphs should promote clarity and better understanding of rule-based models. PMID- 21288339 TI - Multimodality imaging of anomalous pulmonary veins. AB - Partial anomalous pulmonary venous connection (PAPVC) is an extremely rare congenital condition where one or more of the pulmonary veins are connected to the venous circulation. Although initially suspected with unexplained right ventricular enlargement on transthoracic echocardiography (TTE), cardiac MRI is able to delineate the anatomical variant. We present a case of a 65-year-old male diagnosed with left sided PAPVC using multimodality cardiac imaging. PMID- 21288340 TI - The OPERA trial: protocol for a randomised trial of an exercise intervention for older people in residential and nursing accommodation. AB - BACKGROUND: Depression is common in residents of Residential and Nursing homes (RNHs). It is usually undetected and often undertreated. Depression is associated with poor outcomes including increased morbidity and mortality. Exercise has potential to improve depression, and has been shown in existing trials to improve outcomes among younger and older people. Existing evidence comes from trials that are short, underpowered and not from RNH settings. The aim of the OPERA trial is to establish whether exercise is effective in reducing the prevalence of depression among older RNH residents. METHOD: OPERA is a cluster randomised controlled trial. RNHs are randomised to one of two groups with interventions lasting 12 months. INTERVENTION GROUP: a depression awareness and physical activity training session for care home staff, plus a whole home physical activation programme including twice weekly physiotherapist-led exercise groups. The intervention lasts for one year from randomisation, or CONTROL GROUP: a depression awareness training session for care home staff.Participants are people aged 65 or over who are free of severe cognitive impairment and willing to participate in the study. Our primary outcome is the prevalence of depressive symptoms, a GDS-15 score of five or more, in all participants at the end of the one year intervention period. Our secondary depression outcomes include remission of depressive symptoms and change in GDS-15 scores in those with depressive symptoms prior to randomisation. Other secondary outcomes include, fear of falling, mobility, fractures, pain, cognition, costs and health related quality of life. We aimed to randomise 77 RNHs. DISCUSSION: Home recruitment was completed in May 2010; 78 homes have been randomised. Follow up will finish in May 2011 and results will be available late 2011. TRIAL REGISTRATION: [ISRCTN: ISRCTN43769277]. PMID- 21288341 TI - The OPERA trial: a protocol for the process evaluation of a randomised trial of an exercise intervention for older people in residential and nursing accommodation. AB - BACKGROUND: The OPERA trial is large cluster randomised trial testing a physical activity intervention to address depression amongst people living in nursing and residential homes for older people. A process evaluation was commissioned alongside the trial and we report the protocol for this process evaluation. Challenges included the cognitive and physical ability of the participants, the need to respect the privacy of all home residents, including study non participants, and the physical structure of the homes. Evaluation activity had to be organised around the structured timetable of homes, leaving limited opportunities for data collection. The aims of this process evaluation are to provide findings that will assist in the interpretation of the clinical trial results, and to inform potential implementation of the physical activity intervention on a wider scale. METHODS/DESIGN: Quantitative data on recruitment of homes and individuals is being collected. For homes in the intervention arm, data on dose and fidelity of the intervention delivered; including individual rates of participation in exercise classes are collected. In the control homes, uptake and delivery of depression awareness training is monitored. These data will be combined with qualitative data from an in-depth study of a purposive sample of eight homes (six intervention and two control). DISCUSSION: Although process evaluations are increasingly funded alongside trials, it is still rare to see the findings published, and even rarer to see the protocol for such an evaluation published. Process evaluations have the potential to assist in interpreting and understanding trial results as well as informing future roll outs of interventions. If such evaluations are funded they should also be reported and reviewed in a similar way to the trial outcome evaluation. TRIAL REGISTRATION: ISRCTN No: ISRCTN43769277. PMID- 21288342 TI - Presence of mechanical dyssynchrony in Duchenne muscular dystrophy. AB - BACKGROUND: Cardiac dysfunction in boys with Duchenne muscular dystrophy (DMD) is a leading cause of death. Cardiac resynchronization therapy (CRT) has been shown to dramatically decrease mortality in eligible adult population with congestive heart failure. We hypothesized that mechanical dyssynchrony is present in DMD patients and that cardiovascular magnetic resonance (CMR) may predict CRT efficacy. METHODS: DMD patients (n = 236) were stratified into 4 groups based on age, diagnosis of DMD, left ventricular (LV) ejection fraction (EF), and presence of myocardial fibrosis defined as positive late gadolinum enhancement (LGE) compared to normal controls (n = 77). Dyssynchrony indices were calculated based on timing of CMR derived circumferential strain (ecc). The calculated indices included cross-correlation delay (XCD), uniformity of strain (US), regional vector of variance (RVV), time to maximum strain (TTMS) and standard deviation (SD) of TTMS. Abnormal XCD value was defined as > normal + 2SD. US, RVV, TTMS and SD were calculated for patients with abnormal XCD. RESULTS: There was overall low prevalence of circumferential dyssynchrony in the entire DMD population; it increased to 17.1% for patients with abnormal EF and to 31.2% in the most advanced stage (abnormal EF with fibrosis). All but one DMD patient with mechanical dyssynchrony exhibited normal QRS duration suggesting absence of electrical dyssynchrony. The calculated US and RVV values (0.91 +/- 0.09, 1.34 +/ 0.48) indicate disperse rather than clustered dyssynchrony. CONCLUSION: Mechanical dyssynchrony is frequent in boys with end stage DMD-associated cardiac dysfunction. It is associated with normal QRS complex as well as extensive lateral fibrosis. Based on these findings, it is unlikely that this patient population will benefit from CRT. PMID- 21288343 TI - Cognitive function and quality of life in multiple sclerosis patients: a cross sectional study. AB - BACKGROUND: Nearly half of all patients diagnosed with multiple sclerosis (MS) will develop cognitive dysfunction. Studies highlighted from no/weak impact to a strong impact of cognitive impairment on quality of life (QoL). The aim of this study was to assess the impact of cognitive dysfunction on self-reported QoL in MS patients while considering key confounding factors. METHODS: DESIGN: cross sectional study. INCLUSION CRITERIA: MS patients of any disease subtype. DATA COLLECTION: sociodemographic (age, gender, marital status, education level, and occupational activity) and clinical data (MS subtype, disease duration); MS disability (Expanded Disability Status Scale, EDSS); depression (Beck Depression Inventory); fatigue (Modified Fatigue Impact Scale); QoL (SF36 and MusiQoL); and neuropsychological performance (Brief Repeatable Battery of Neuropsychological Tests, BRB-N). STATISTICAL ANALYSIS: multiple linear regressions (forward stepwise selection). RESULTS: One hundred and twenty-four patients were enrolled. Performance on BRB-N subtests varied widely (6% to 70% abnormal). The BRB-N classified 37-78% of the patients as cognitively impaired, depending on the definition of cognitive impairment. No links were found between the MusiQoL index and cognitive subtests, whereas marital status, EDSS, and depression were found to be independent predictive factors. CONCLUSIONS: The present study demonstrated the weak and scarce association between cognitive impairment and QoL, when the key confounding factors were considered. These results need to be confirmed with larger samples and more accurate tests of cognitive function. PMID- 21288344 TI - Identification of a fibrinogen-related protein (FBN9) gene in neotropical anopheline mosquitoes. AB - BACKGROUND: Malaria has a devastating impact on worldwide public health in many tropical areas. Studies on vector immunity are important for the overall understanding of the parasite-vector interaction and for the design of novel strategies to control malaria. A member of the fibrinogen-related protein family, fbn9, has been well studied in Anopheles gambiae and has been shown to be an important component of the mosquito immune system. However, little is known about this gene in neotropical anopheline species. METHODS: This article describes the identification and characterization of the fbn9 gene partial sequences from four species of neotropical anopheline primary and secondary vectors: Anopheles darlingi, Anopheles nuneztovari, Anopheles aquasalis, and Anopheles albitarsis (namely Anopheles marajoara). Degenerate primers were designed based on comparative analysis of publicly available Aedes aegypti and An. gambiae gene sequences and used to clone putative homologs in the neotropical species. Sequence comparisons and Bayesian phylogenetic analyses were then performed to better understand the molecular diversity of this gene in evolutionary distant anopheline species, belonging to different subgenera. RESULTS: Comparisons of the fbn9 gene sequences of the neotropical anophelines and their homologs in the An. gambiae complex (Gambiae complex) showed high conservation at the nucleotide and amino acid levels, although some sites show significant differentiation (non synonymous substitutions). Furthermore, phylogenetic analysis of fbn9 nucleotide sequences showed that neotropical anophelines and African mosquitoes form two well-supported clades, mirroring their separation into two different subgenera. CONCLUSIONS: The present work adds new insights into the conserved role of fbn9 in insect immunity in a broader range of anopheline species and reinforces the possibility of manipulating mosquito immunity to design novel pathogen control strategies. PMID- 21288345 TI - Evaluation of prevalence's of pfdhfr and pfdhps mutations in Angola. AB - BACKGROUND: Malaria is the major cause of morbidity and mortality in Angola. The most vulnerable groups to Plasmodium falciparum infection are pregnant women and children under five years of age. The use of an intermittent preventive treatment (IPT) with sulphadoxine/pyrimethamine (SP) in pregnant women was introduced in Angola in 2006 by the National Malaria Control Programme, and currently this strategy has been considered to be used for children malaria control. Considering the previous wide use of SP combination in Angola, together to the reported cases of SP treatment failure it is crucial the evaluation of the prevalence of five mutations in pfdhfr and pfdhps genes associated to P. falciparum resistance to SP before the introduction of S/P IPT in children. METHODS: The study was conducted in five provinces, with different transmission intensities: Huambo, Cabinda, Uige, Kwanza Norte, and Malanje. The detection of the mutations in pfdhfr and pfdhps genes was carried out in 452 P. falciparum blood samples by PCR RFLP. RESULTS: For pfdhfr gene, 90,3% of the samples carried the mutation 51I, with 7.5% of mixed infections; 51% carried wild type allele 59C, with 29.2% mixed infections and; 99.1% of isolates harboured the mutant allele 108N. Concerning, pfdhps gene, 83,1% were mutant type 437G with 11% mixed infections , while 87% of the studied isolates were wild type for codon 540. DISCUSSION: This is the first representative epidemiological study of the whole Angola country on the prevalence of the genotypes associated with SP chemoresistance. A high frequency of individual mutations in both genes (51I and 108N in pfdhfr, and 437G in pfdhps) was found, besides a low prevalence of the quintuple mutation. CONCLUSION: The data showed that the implementation IPT using SP in children needs to be reviewed. PMID- 21288346 TI - Empowerment of personal injury victims through the internet: design of a randomized controlled trial. AB - BACKGROUND: Research has shown that current claims settlement process can have a negative impact on psychological and physical recovery of personal injury (PI) victims. One of the explanations for the negative impact on health is that the claims settlement process is a stressful experience and victims suffer from renewed victimization caused by the claims settlement process. PI victims can experience a lack of information, lack of involvement, lack of 'voice', and poor communication. We present the first study that aims to empower PI victims with respect to the negative impact of the claims settlement process by means of an internet intervention. METHODS/DESIGN: The study is a two armed, randomized controlled trial (RCT), in which 170 PI victims are randomized to either the intervention or control group. The intervention group will get access to a website providing 1) an information module, so participants learn what is happening and what to expect during the claims settlement process, and 2) an e coach module, so participants learn to cope with problems they experience during the claims settlement process. The control group will get access to a website with hyperlinks to commonly available information only. Participants will be recruited via a PI claims settlement office. Participants are included if they have been involved in a traffic accident which happened less than two years ago, and are at least 18 years old.The main study parameter is the increase of empowerment within the intervention group compared to the control group. Empowerment will be measured by the mastery scale and a self-efficacy scale. The secondary outcomes are perceived justice, burden, well being, work ability, knowledge, amount of damages, and lawyer-client communication. Data are collected at baseline (T0 measurement before randomization), at three months, six months, and twelve months after baseline. Analyses will be conducted according to the intention-to-treat principle. DISCUSSION: This study evaluates the effectiveness of an internet intervention aimed at empowerment of PI victims. The results will give more insight into the impact of compensation proceedings on health over time, and they can have important consequences for legal claims settlement. Strengths and limitations of this study are discussed. TRIAL REGISTRATION: Netherlands Trial Register NTR2360. PMID- 21288347 TI - Gait kinematic analysis in patients with a mild form of central cord syndrome. AB - BACKGROUND: Central cord syndrome (CCS) is considered the most common incomplete spinal cord injury (SCI). Independent ambulation was achieved in 87-97% in young patients with CCS but no gait analysis studies have been reported before in such pathology. The aim of this study was to analyze the gait characteristics of subjects with CCS and to compare the findings with a healthy age, sex and anthropomorphically matched control group (CG), walking both at a self-selected speed and at the same speed. METHODS: Twelve CCS patients and a CG of twenty subjects were analyzed. Kinematic data were obtained using a three-dimensional motion analysis system with two scanner units. The CG were asked to walk at two different speeds, at a self-selected speed and at a slower one, similar to the mean gait speed previously registered in the CCS patient group. Temporal, spatial variables and kinematic variables (maximum and minimum lower limb joint angles throughout the gait cycle in each plane, along with the gait cycle instants of occurrence and the joint range of motion - ROM) were compared between the two groups walking at similar speeds. RESULTS: The kinematic parameters were compared when both groups walked at a similar speed, given that there was a significant difference in the self-selected speeds (p < 0.05). Hip abduction and knee flexion at initial contact, as well as minimal knee flexion at stance, were larger in the CCS group (p < 0.05). However, the range of knee and ankle motion in the sagittal plane was greater in the CG group (p < 0.05). The maximal ankle plantar-flexion values in stance phase and at toe off were larger in the CG (p < 0.05). CONCLUSIONS: The gait pattern of CCS patients showed a decrease of knee and ankle sagittal ROM during level walking and an increase in hip abduction to increase base of support. The findings of this study help to improve the understanding how CCS affects gait changes in the lower limbs. PMID- 21288348 TI - Twenty-four hour metabolic rate measurements utilized as a reference to evaluate several prediction equations for calculating energy requirements in healthy infants. AB - BACKGROUND: To date, only short-duration metabolic rate measurements of less than four hours have been used to evaluate prediction equations for calculating energy requirements in healthy infants. Therefore, the objective of this analysis was to utilize direct 24-hour metabolic rate measurements from a prior study to evaluate the accuracy of several currently used prediction equations for calculating energy expenditure (EE) in healthy infants. METHODS: Data from 24-hour EE, resting (RMR) and sleeping (SMR) metabolic rates obtained from 10 healthy infants, served as a reference to evaluate 11 length-weight (LWT) and weight (WT) based prediction equations. Six prediction equations have been previously derived from 50 short-term EE measurements in the Enhanced Metabolic Testing Activity Chamber (EMTAC) for assessing 24-hour EE, (EMTACEE-LWT and EMTACEE-WT), RMR (EMTACRMR-LWT and EMTACRMR-WT) and SMR (EMTACSMR-LWT and EMTACSMR-WT). The last five additional prediction equations for calculating RMR consisted of the World Health Organization (WHO), the Schofield (SCH-LWT and SCH-WT) and the Oxford (OXFORD-LWT and OXFORD-WT). Paired t-tests and the Bland & Altman limit analysis were both applied to evaluate the performance of each equation in comparison to the reference data. RESULTS: 24-hour EE, RMR and SMR calculated with the EMTACEE WT, EMTACRMR-WT and both the EMTACSMR-LWT and EMTACSMR-WT prediction equations were similar, p = NS, to that obtained from the reference measurements. However, RMR calculated using the WHO, SCH-LWT, SCH-WT, OXFORD-LWT and OXFORD-WT prediction equations were not comparable to the direct 24-hour metabolic measurements (p < 0.05) obtained in the 10 reference infants. Moreover, the EMTACEE-LWT and EMTACRMR-LWT were also not similar (p < 0.05) to direct 24-hour metabolic measurements. CONCLUSIONS: Weight based prediction equations, derived from short-duration EE measurements in the EMTAC, were accurate for calculating EE, RMR and SMR in healthy infants. PMID- 21288349 TI - Self-reported pain and disability outcomes from an endogenous model of muscular back pain. AB - BACKGROUND: Our purpose was to develop an induced musculoskeletal pain model of acute low back pain and examine the relationship among pain, disability and fear in this model. METHODS: Delayed onset muscle soreness was induced in 52 healthy volunteers (23 women, 17 men; average age 22.4 years; average BMI 24.3) using fatiguing trunk extension exercise. Measures of pain intensity, unpleasantness, and location, and disability, were tracked for one week after exercise. RESULTS: Pain intensity ranged from 0 to 68 with 57.5% of participants reporting peak pain at 24 hours and 32.5% reporting this at 48 hours. The majority of participants reported pain in the low back with 33% also reporting pain in the legs. The ratio of unpleasantness to intensity indicated that the sensation was considered more unpleasant than intense. Statistical differences were noted in levels of reported disability between participants with and without leg pain. Pain intensity at 24 hours was correlated with pain unpleasantness, pain area and disability. Also, fear of pain was associated with pain intensity and unpleasantness. Disability was predicted by sex, presence of leg pain, and pain intensity; however, the largest amount of variance was explained by pain intensity (27% of a total 40%). The second model, predicting pain intensity only included fear of pain and explained less than 10% of the variance in pain intensity. CONCLUSIONS: Our results demonstrate a significant association between pain and disability in this model in young adults. However, the model is most applicable to patients with lower levels of pain and disability. Future work should include older adults to improve the external validity of this model. PMID- 21288350 TI - Effects of grapefruit, grapefruit juice and water preloads on energy balance, weight loss, body composition, and cardiometabolic risk in free-living obese adults. AB - BACKGROUND: Reducing dietary energy density has proven to be an effective strategy to reduce energy intakes and promote weight control. This effect appears most robust when a low energy dense preload is consumed before meals. Yet, much discussion continues regarding the optimal form of a preload. The purpose of the present study was to compare effects of a solid (grapefruit), liquid (grapefruit juice) and water preload consumed prior to breakfast, lunch and dinner in the context of caloric restriction. METHODS: Eighty-five obese adults (BMI 30-39.9) were randomly assigned to (127 g) grapefruit (GF), grapefruit juice (GFJ) or water preload for 12 weeks after completing a 2-week caloric restriction phase. Preloads were matched for weight, calories, water content, and energy density. Weekly measures included blood pressure, weight, anthropometry and 24-hour dietary intakes. Resting energy expenditure, body composition, physical performance and cardiometabolic risk biomarkers were assessed. RESULTS: The total amount (grams) of food consumed did not change over time. Yet, after preloads were combined with caloric restriction, average dietary energy density and total energy intakes decreased by 20-29% from baseline values. Subjects experienced 7.1% weight loss overall, with significant decreases in percentage body, trunk, android and gynoid fat, as well as waist circumferences (-4.5 cm). However, differences were not statistically significant among groups. Nevertheless, the amount and direction of change in serum HDL-cholesterol levels in GF (+6.2%) and GFJ (+8.2%) preload groups was significantly greater than water preload group ( 3.7%). CONCLUSIONS: These data indicate that incorporating consumption of a low energy dense dietary preload in a caloric restricted diet is a highly effective weight loss strategy. But, the form of the preload did not have differential effects on energy balance, weight loss or body composition. It is notable that subjects in GF and GFJ preload groups experienced significantly greater benefits in lipid profiles. TRIAL REGISTRATION: ClinicalTrials.gov NCT00581074. PMID- 21288351 TI - Evaluating the effects of sevelamer carbonate on cardiovascular structure and function in chronic renal impairment in Birmingham: the CRIB-PHOS randomised controlled trial. AB - BACKGROUND: Serum phosphate is an independent predictor of cardiovascular morbidity and mortality in patients with chronic kidney disease and the general population. There is accumulating evidence that phosphate promotes arterial stiffening through structural vascular alterations such as medial calcification, which are already apparent in the early stages of chronic kidney disease. AIM: To determine the effects of phosphate binding with sevelamer carbonate on left ventricular mass and function together with arterial stiffness in patients with stage 3 chronic kidney disease. METHODS/DESIGN: A single-centre, prospective, randomised, double-blind, placebo-controlled trial of 120 subjects with stage 3 chronic kidney disease recruited from University Hospitals Birmingham NHS Foundation Trust. Baseline investigations include transthoracic echocardiography and cardiac magnetic resonance imaging to assess ventricular mass, volumes and function, applanation tonometry to determine pulse wave velocity and pulse wave analysis as surrogate measures of arterial stiffness and dual energy x-ray absorptiometry scanning to determine bone density. During an open-label run in phase, subjects will receive 1600 mg sevelamer carbonate with meals for four weeks. They will then be randomised to either continue sevelamer carbonate or receive an identical placebo (60 subjects per arm) for the remaining 36 weeks. Four-weekly monitoring of serum electrolytes and bone biochemistry will be performed. All baseline investigations will be repeated at the end of the treatment period. The primary endpoint of the study is a reduction in left ventricular mass after 40 weeks of treatment. Secondary endpoints are: i) change in aortic compliance; ii) change in arterial stiffness; iii) change in arterial elastance; iv) change in left ventricular systolic and diastolic elastance; v) change in left ventricular function; and vi) change in bone density. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov: NCT00806481 and Current Controlled Trials: ISRCTN35254279. PMID- 21288352 TI - The relevance of non-human primate and rodent malaria models for humans. AB - At the 2010 Keystone Symposium on "Malaria: new approaches to understanding Host Parasite interactions", an extra scientific session to discuss animal models in malaria research was convened at the request of participants. This was prompted by the concern of investigators that skepticism in the malaria community about the use and relevance of animal models, particularly rodent models of severe malaria, has impacted on funding decisions and publication of research using animal models. Several speakers took the opportunity to demonstrate the similarities between findings in rodent models and human severe disease, as well as points of difference. The variety of malaria presentations in the different experimental models parallels the wide diversity of human malaria disease and, therefore, might be viewed as a strength. Many of the key features of human malaria can be replicated in a variety of nonhuman primate models, which are very under-utilized. The importance of animal models in the discovery of new anti malarial drugs was emphasized. The major conclusions of the session were that experimental and human studies should be more closely linked so that they inform each other, and that there should be wider access to relevant clinical material. PMID- 21288353 TI - WINPEPI updated: computer programs for epidemiologists, and their teaching potential. AB - BACKGROUND: The WINPEPI computer programs for epidemiologists are designed for use in practice and research in the health field and as learning or teaching aids. The programs are free, and can be downloaded from the Internet. Numerous additions have been made in recent years. IMPLEMENTATION: There are now seven WINPEPI programs: DESCRIBE, for use in descriptive epidemiology; COMPARE2, for use in comparisons of two independent groups or samples; PAIRSetc, for use in comparisons of paired and other matched observations; LOGISTIC, for logistic regression analysis; POISSON, for Poisson regression analysis; WHATIS, a "ready reckoner" utility program; and ETCETERA, for miscellaneous other procedures. The programs now contain 122 modules, each of which provides a number, sometimes a large number, of statistical procedures. The programs are accompanied by a Finder that indicates which modules are appropriate for different purposes. The manuals explain the uses, limitations and applicability of the procedures, and furnish formulae and references. CONCLUSIONS: WINPEPI is a handy resource for a wide variety of statistical routines used by epidemiologists. Because of its ready availability, portability, ease of use, and versatility, WINPEPI has a considerable potential as a learning and teaching aid, both with respect to practical procedures in the planning and analysis of epidemiological studies, and with respect to important epidemiological concepts. It can also be used as an aid in the teaching of general basic statistics. PMID- 21288354 TI - Assessing community variation and randomness in public health indicators. AB - BACKGROUND: Evidence-based health indicators are vital to needs-based programming and epidemiological planning. Agencies frequently make programming funds available to local jurisdictions based on need. The use of objective indicators to determine need is attractive but assumes that selection of communities with the highest indicators reflects something other than random variability from sampling error. METHODS: The authors compare the statistical performance of two heterogeneity measures applied to community differences that provide tests for randomness and measures of the percentage of true community variation, as well as estimates of the true variation. One measure comes from the meta-analysis literature and the other from the simple Pearson chi-square statistic. Simulations of populations and an example using real data are provided. RESULTS: The measure based on the simple chi-square statistic seems superior, offering better protection against Type I errors and providing more accurate estimates of the true community variance. CONCLUSIONS: The heterogeneity measure based on Pearson's chi2 should be used to assess indices. Methods for improving poor indices are discussed. PMID- 21288355 TI - The GLEaMviz computational tool, a publicly available software to explore realistic epidemic spreading scenarios at the global scale. AB - BACKGROUND: Computational models play an increasingly important role in the assessment and control of public health crises, as demonstrated during the 2009 H1N1 influenza pandemic. Much research has been done in recent years in the development of sophisticated data-driven models for realistic computer-based simulations of infectious disease spreading. However, only a few computational tools are presently available for assessing scenarios, predicting epidemic evolutions, and managing health emergencies that can benefit a broad audience of users including policy makers and health institutions. RESULTS: We present "GLEaMviz", a publicly available software system that simulates the spread of emerging human-to-human infectious diseases across the world. The GLEaMviz tool comprises three components: the client application, the proxy middleware, and the simulation engine. The latter two components constitute the GLEaMviz server. The simulation engine leverages on the Global Epidemic and Mobility (GLEaM) framework, a stochastic computational scheme that integrates worldwide high resolution demographic and mobility data to simulate disease spread on the global scale. The GLEaMviz design aims at maximizing flexibility in defining the disease compartmental model and configuring the simulation scenario; it allows the user to set a variety of parameters including: compartment-specific features, transition values, and environmental effects. The output is a dynamic map and a corresponding set of charts that quantitatively describe the geo-temporal evolution of the disease. The software is designed as a client-server system. The multi-platform client, which can be installed on the user's local machine, is used to set up simulations that will be executed on the server, thus avoiding specific requirements for large computational capabilities on the user side. CONCLUSIONS: The user-friendly graphical interface of the GLEaMviz tool, along with its high level of detail and the realism of its embedded modeling approach, opens up the platform to simulate realistic epidemic scenarios. These features make the GLEaMviz computational tool a convenient teaching/training tool as well as a first step toward the development of a computational tool aimed at facilitating the use and exploitation of computational models for the policy making and scenario analysis of infectious disease outbreaks. PMID- 21288356 TI - Efficient Wnt mediated intestinal hyperproliferation requires the cyclin D2 CDK4/6 complex. AB - Inactivation of the gene encoding the adenomatous polyposis coli (APC) tumour suppressor protein is recognized as the key early event in the development of colorectal cancers (CRC). Apc loss leads to nuclear localization of beta-catenin and constitutive activity of the beta-catenin-Tcf4 transcription complex. This complex drives the expression of genes involved in cell cycle progression such as c-Myc and cyclin D2. Acute loss of Apc in the small intestine leads to hyperproliferation within the intestinal crypt, increased levels of apoptosis, and perturbed differentiation and migration. It has been demonstrated that c-Myc is a critical mediator of the phenotypic abnormalities that follow Apc loss in the intestine. As it may be difficult to pharmacologically inhibit transcription factors such as c-Myc, investigating more druggable targets of the Wnt-c-Myc pathway within the intestine may reveal potential therapeutic targets for CRC. Recent work in our laboratory has shown that the cyclin D2-cyclin-dependent kinase 4/6 (CDK4/6) complex promotes hyperproliferation in Apc deficient intestinal tissue and ApcMin/+ adenomas. We showed that the hyperproliferative phenotype associated with Apc loss in vivo was partially dependent on the expression of cyclin D2. Most importantly, tumour growth and development in ApcMin/+ mice was strongly perturbed in mice lacking cyclin D2. Furthermore, pharmacological inhibition of CDK4/6 suppressed the proliferation of adenomatous cells. This commentary discusses the significance of this work in providing evidence for the importance of the cyclin D2-CDK4/6 complex in colorectal adenoma formation. It also argues that inhibition of this complex may be an effective chemopreventative strategy in CRC. PMID- 21288357 TI - Prevalence of head lice and hygiene practices among women over twelve years of age in Sindh, Balochistan, and North West Frontier Province: National Health Survey of Pakistan, 1990-1994. AB - BACKGROUND: Head lice infestation is an infection of the scalp and skin which causes blood loss, discomfort, and social and psychological distress with the possibility of secondary bacterial infections occurring at scratch sites. In Pakistan, although some small scale studies have been conducted to investigate prevalence of head lice in school children and the general population, no population based estimates have been reported. The National Health Survey of Pakistan (NHSP 1990 - 94) was a nationally representative health examination survey of the Pakistani population. The NHSP is the first population based household survey to collect data on the prevalence of head lice in adult women in Pakistan. In this paper we use data from the NHSP to present an epidemiological profile of personal hygiene practices and head lice infestation among women aged 12 years or older in three provinces of Pakistan; Balochistan, Sindh and North West Frontier Province (NWFP). RESULTS: Overall about 7% women aged 12 years and older suffered from head lice infestation. Multivariable logistic regression analysis identified factors independently associated with presence of head lice. Age less than 16 years and crowding at home were associated with higher infestation-rates. The impact of household socio-economic status on infestation rates among women was different in urban and rural settings; urban women with low socio-economic status were more vulnerable than similar women in rural settings. Bathing infrequently in summer was associated with higher prevalence rates only in Sindh, possibly due to the fact that among the three provinces Sindh has a hotter and more humid summer. CONCLUSIONS: The results of our analysis of NHSP indicate high levels of head lice infestation among girls and women in the three Provinces. The epidemiological profile of hygienic practices of women indicated that NWFP and Balochistan as compared to Sindh, and rural as compared to urban areas were less developed with respect to access to water supply and soap for maintaining personal hygiene. Simple and cost-effective measures such as provision of water and soap, and improving awareness regarding maintaining personal hygiene can contribute significantly towards improving public health status of the women in Pakistan. PMID- 21288358 TI - Long-term effects of flooding on mortality in England and Wales, 1994-2005: controlled interrupted time-series analysis. AB - BACKGROUND: Limited evidence suggests that being flooded may increase mortality and morbidity among affected householders not just at the time of the flood but for months afterwards. The objective of this study is to explore the methods for quantifying such long-term health effects of flooding by analysis of routine mortality registrations in England and Wales. METHODS: Mortality data, geo referenced by postcode of residence, were linked to a national database of flood events for 1994 to 2005. The ratio of mortality in the post-flood year to that in the pre-flood year within flooded postcodes was compared with that in non-flooded boundary areas (within 5 km of a flood). Further analyses compared the observed number of flood-area deaths in the year after flooding with the number expected from analysis of mortality trends stratified by region, age-group, sex, deprivation group and urban-rural status. RESULTS: Among the 319 recorded floods, there were 771 deaths in the year before flooding and 693 deaths in the year after (post-/pre-flood ratio of 0.90, 95% CI 0.82, 1.00). This ratio did not vary substantially by age, sex, population density or deprivation. A similar post flood 'deficit' of deaths was suggested by the analyses based on observed/expected deaths. CONCLUSIONS: The observed post-flood 'deficit' of deaths is counter-intuitive and difficult to interpret because of the possible influence of population displacement caused by flooding. The bias that might arise from such displacement remains unquantified but has important implications for future studies that use place of residence as a marker of exposure. PMID- 21288359 TI - First report of the infection of insecticide-resistant malaria vector mosquitoes with an entomopathogenic fungus under field conditions. AB - BACKGROUND: Insecticide-resistant mosquitoes are compromising the ability of current mosquito control tools to control malaria vectors. A proposed new approach for mosquito control is to use entomopathogenic fungi. These fungi have been shown to be lethal to both insecticide-susceptible and insecticide-resistant mosquitoes under laboratory conditions. The goal of this study was to see whether entomopathogenic fungi could be used to infect insecticide-resistant malaria vectors under field conditions, and to see whether the virulence and viability of the fungal conidia decreased after exposure to ambient African field conditions. METHODS: This study used the fungus Beauveria bassiana to infect the insecticide resistant malaria vector Anopheles gambiae s.s (Diptera: Culicidae) VKPER laboratory colony strain. Fungal conidia were applied to polyester netting and kept under West African field conditions for varying periods of time. The virulence of the fungal-treated netting was tested 1, 3 and 5 days after net application by exposing An. gambiae s.s. VKPER mosquitoes in WHO cone bioassays carried out under field conditions. In addition, the viability of B. bassiana conidia was measured after up to 20 days exposure to field conditions. RESULTS: The results show that B. bassiana infection caused significantly increased mortality with the daily risk of dying being increased by 2.5 * for the fungus exposed mosquitoes compared to the control mosquitoes. However, the virulence of the B. bassiana conidia decreased with increasing time spent exposed to the field conditions, the older the treatment on the net, the lower the fungus-induced mortality rate. This is likely to be due to the climate because laboratory trials found no such decline within the same trial time period. Conidial viability also decreased with increasing exposure to the net and natural abiotic environmental conditions. After 20 days field exposure the conidial viability was 30%, but the viability of control conidia not exposed to the net or field conditions was 79%. CONCLUSIONS: This work shows promise for the use of B. bassiana fungal conidia against insecticide-resistant mosquitoes in the field, but further work is required to examine the role of environmental conditions on fungal virulence and viability with a view to eventually making the fungal conidia delivery system more able to withstand the ambient African climate. PMID- 21288360 TI - Familial Takayasu arteritis - a pediatric case and a review of the literature. AB - Takayasu arteritis (TA) is a rare chronic inflammatory disease of the aorta and its major branches. It is seen predominantly in females during the second and third decades of life, although it can occur in childhood. The aetiology of TA remains unknown. To date, familial cases of TA have been considered rare; however, a review of the literature suggests that cases are accumulating. We report a case of two sisters affected by severe TA, and review other reported familial cases. PMID- 21288361 TI - The use of cessation assistance among smokers from China: Findings from the ITC China Survey. AB - BACKGROUND: Stop smoking medications significantly increase the likelihood of smoking cessation. However, there are no population-based studies of stop-smoking medication use in China, the largest tobacco market in the world. This study examined stop-smoking medication use and its association with quitting behavior among a population-based sample of Chinese smokers. METHODS: Face-to-face interviews were conducted with 4,627 smokers from six cities in the ITC China cohort survey. Longitudinal analyses were conducted using Wave 1 (April to August, 2006) and Wave 2 (November 2007 to January 2008). RESULTS: Approximately 26% of smokers had attempted to quit between Waves 1 and 2, and 6% were abstinent at 18-month follow-up. Only 5.8% of those attempting to quit reported NRT use and NRT was associated with lower odds of abstinence at Wave 2 (OR = 0.11; 95%CI = 0.03-0.46). Visiting a doctor/health professional was associated with greater attempts to quit smoking (OR = 1.60 and 2.78; 95%CI = 1.22-2.10 and 2.21-3.49 respectively) and being abstinent (OR = 1.77 and 1.85; 95%CI = 1.18-2.66 and 1.13 3.04 respectively) at 18-month follow-up relative to the smokers who did not visit doctor/health professional. CONCLUSIONS: The use of formal help for smoking cessation is low in China. There is an urgent need to explore the use and effectiveness of stop-smoking medications in China and in other non-Western markets. PMID- 21288362 TI - Influenza C virus NS1 protein counteracts RIG-I-mediated IFN signalling. AB - The nonstructural proteins 1 (NS1) from influenza A and B viruses are known as the main viral factors antagonising the cellular interferon (IFN) response, inter alia by inhibiting the retinoic acid-inducible gene I (RIG-I) signalling. The cytosolic pattern-recognition receptor RIG-I senses double-stranded RNA and 5' triphosphate RNA produced during RNA virus infections. Binding to these ligands activates RIG-I and in turn the IFN signalling. We now report that the influenza C virus NS1 protein also inhibits the RIG-I-mediated IFN signalling. Employing luciferase-reporter assays, we show that expression of NS1-C proteins of virus strains C/JJ/50 and C/JHB/1/66 considerably reduced the IFN-beta promoter activity. Mapping of the regions from NS1-C of both strains involved in IFN-beta promoter inhibition showed that the N-terminal 49 amino acids are dispensable, while the C-terminus is required for proper modulation of the IFN response. When a mutant RIG-I, which is constitutively active without ligand binding, was employed, NS1-C still inhibited the downstream signalling, indicating that IFN inhibitory properties of NS1-C are not necessarily linked to an RNA binding mechanism. PMID- 21288363 TI - Slow oocyte freezing and thawing in couples with no sperm or an insufficient number of sperm on the day of in vitro fertilization. AB - BACKGROUND: The clinical results of in vitro fertilization of slowly frozen thawed oocytes are known to be significantly worse than those obtained by fresh oocytes. Little is known about the factors affecting the clinical outcome of frozen-thawed oocytes. The aim of this retrospective study was to explore the role of oocyte cryopreservation in the group of patients with no available sperm on the day of in vitro fertilization. Additionally, the effects of the female serum FSH level and sperm quality on the clinical outcome of frozen-thawed oocytes were evaluated. METHODS: Oocytes were slowly frozen and thawed in 22 infertile couples with no sperm or insufficient number of sperm on the day of in vitro fertilization (IVF). In 9 couples with severe azoospermia or oligoasthenoteratozoospermia frozen-thawed oocytes were fertilized by autologous sperm of bad quality when available (Group 1). In 13 couples with non-ejaculation due to psychological stress on the day of classical IVF or severe azoospermia frozen-thawed oocytes were fertilized by autologous or donated sperm of normal quality (Group 2). Oocytes were thawed in 23 cycles and microinjected by the autologous or donated sperm, when available. The clinical outcome of intracytoplasmic sperm injection--ICSI (fertilization, blastocyst, and pregnancy rates) was compared to the outcome of fresh oocytes of the same group of patients; additionally, the female serum FSH level and the sperm quality were compared. RESULTS: In all couples, 70.5% of oocytes survived the freeze-thaw procedure. After ICSI, 61.5% of thawed oocytes were fertilized. Twenty one% of embryos developed to the blastocyst stage. The pregnancy rates per embryo transfer and freeze-thaw cycle were 33.3% and 17.4%, respectively. All pregnancies ended in the birth of a baby without congenital anomalies. In patients with severe azoospermia or oligoasthenoteratozoospermia there was no statistically significant difference in pregnancy rates per cycle obtained by thawed oocytes vs. fresh oocytes in previous ICSI cycles (14.2% vs. 13.6%) but there was a higher proportion of abnormal, non-cleaved or triploid zygotes when frozen-thawed oocytes were microinjected (33.3% vs. 11.8%; P < 0.01). The female serum FSH levels did not affect the survival and fertilization of frozen-thawed oocytes, but in patients with increased serum FSH level no pregnancies were achieved. After the complete freeze-thaw cycle, there was a significantly higher fertilization rate and tendency to higher pregnancy rates per thawing cycle after the microinjection of autologous or donated sperm of normal quality than autologous sperm of poor quality. CONCLUSION: The slow oocyte freezing and thawing is a valuable method when no or insufficient number of sperm are available on the day of in vitro fertilization. The quality of sperm is an important factor affecting the clinical outcome achieved by frozen-thawed oocytes. PMID- 21288364 TI - Acute effects of coffee on QT interval in healthy subjects. AB - The coronary endothelial function is recognized to have an important role in the physiology of the diastolic ventricular relaxation, a phase of the heart cycle that influences the electrocardiographic QT interval. Endothelial function is investigated in vivo by flow mediated dilation (FMD) in the brachial artery and has proven to be a strong predictor of both coronary endothelial function and cardiovascular events. It has been reported that coffee acutely induces FMD changes. In particular, the brachial artery FMD seems to decrease after caffeinated coffee (CC) and to increase after decaffeinated coffee (DC) ingestion. Since the cardiovascular effects of coffee are still a debated matter, this study aimed at investigating with a randomized, double-blind crossover design, if the QT interval of adult healthy subjects (19 males and 21 females) changes in the hour following CC or DC ingestion. Both systolic and diastolic blood pressure were higher in the hour following the ingestion of CC; the heart rate significantly increased 30 minutes after CC ingestion. A significant increase of the QT duration was observed one hour after DC ingestion (398.9 +/- 3.8 vs 405.3 +/- 3.7 msec; P < 0.05), not after CC. The QT interval corrected for heart rate did not significantly change following CC or DC ingestion. In conclusion, despite CC and DC previously demonstrated to influence the FMD they do not seem to induce a significant unfavourable acute change of the left ventricular repolarization. Further investigations are required to elucidate the effects of coffee in subjects with cardiovascular diseases. PMID- 21288365 TI - Plasma carotenoids are associated with socioeconomic status in an urban Indigenous population: an observational study. AB - BACKGROUND: Indigenous Australians experience poorer health than other Australians. Poor diet may contribute to this, and be related to their generally lower socioeconomic status (SES). Even within Indigenous populations, SES may be important. Our aim was to identify factors associated with plasma carotenoids as a marker of fruit and vegetable intake among urban dwelling Indigenous Australians, with a particular focus on SES. METHODS: Cross sectional study in urban dwelling Indigenous Australians participating in the DRUID (Darwin Region Urban Indigenous Diabetes) Study. An SES score, based on education, employment, household size, home ownership and income was computed and plasma carotenoids measured by high performance liquid chromatography in 897 men and women aged 15 81 years (mean 36, standard deviation 15). Linear regression analysis was used to determine the relationship between SES and plasma carotenoids, adjusting for demographic, health and lifestyle variables, including frequency of intakes of food groups (fruit, vegetables, takeaway foods, snacks and fruit/vegetable juice). RESULTS: SES was positively associated with plasma concentrations of lutein/zeaxanthin (p trend <0.001), lycopene (p trend = 0.001), alpha- and beta carotene (p trend = 0.019 and 0.026 respectively), after adjusting for age, sex, glucose tolerance status, smoking, alcohol use, hypercholesterolemia, dyslipidemia, self-reported health, waist to hip ratio and body mass index. These associations remained after adjustment for self-reported frequency of intake of fruit, vegetables, takeaway foods and fruit juice, which all showed some association with plasma carotenoids. Even in the highest SES quintile, concentrations of all carotenoids (except lycopene) were lower than the mean concentrations in a non-Indigenous population. CONCLUSIONS: Even within urban Indigenous Australians, higher SES was associated with higher concentrations of plasma carotenoids. Low plasma carotenoids have been linked with poor health outcomes; increasing accessibility of fruit and vegetables, as well as reducing smoking rates could increase concentrations and otherwise improve health, but our results suggest there may be additional factors contributing to lower carotenoid concentrations in Indigenous Australians. PMID- 21288366 TI - Exploring the impact of a decision support intervention on vascular access decisions in chronic hemodialysis patients: study protocol. AB - BACKGROUND: In patients with Stage 5 Chronic Kidney Disease who require renal replacement therapy a major decision concerns modality choice. However, many patients defer the decision about modality choice or they have an urgent or emergent need of RRT, which results in them starting hemodialysis with a Central Venous Catheter. Thereafter, efforts to help patients make more timely decisions about access choices utilizing education and resource allocation strategies met with limited success resulting in a high prevalent CVC use in Canada. Providing decision support tailored to meet patients' decision making needs may improve this situation. The Registered Nurses Association of Ontario has developed a clinical practice guideline to guide decision support for adults living with Chronic Kidney Disease (Decision Support for Adults with Chronic Kidney Disease.) The purpose of this study is to determine the impact of implementing selected recommendations this guideline on priority provincial targets for hemodialysis access in patients with Stage 5 CKD who currently use Central Venous Catheters for vascular access. METHODS/DESIGN: A non-experimental intervention study with repeated measures will be conducted at St. Michaels Hospital in Toronto, Canada. Decisional conflict about dialysis access choice will be measured using the validated SURE tool, an instrument used to identify decisional conflict. Thereafter a tailored decision support intervention will be implemented. Decisional conflict will be re-measured and compared with baseline scores. Patients and staff will be interviewed to gain an understanding of how useful this intervention was for them and whether it would be feasible to implement more widely. Quantitative data will be analyzed using descriptive and inferential statistics. Statistical significance of difference between means over time for aggregated SURE scores (pre/post) will be assessed using a paired t-test. Qualitative analysis with content coding and identification of themes will be conducted for the focus group and patient interview data. DISCUSSION: Coupling the SURE tool with a decision support system structured so that a positive test result triggers providers to help patients through the decision-making process and/or refer patients to appropriate resources could benefit patients and ensure they have the opportunity to make informed HD access choices. PMID- 21288367 TI - A novel tumor suppressor gene ECRG4 interacts directly with TMPRSS11A (ECRG1) to inhibit cancer cell growth in esophageal carcinoma. AB - BACKGROUND: The esophageal carcinoma related gene 4 (ECRG4) was initially identified and cloned from human normal esophageal epithelium in our laboratory (GenBank accession no.AF325503). ECRG4 has been described as a novel tumor suppressor gene associated with prognosis in esophageal squamous cell carcinoma (ESCC). METHODS: In this study, binding affinity assay in vitro and co immunoprecipitation experiment in vivo were utilized to verify the physical interaction between ECRG4 and transmembrane protease, serine 11A (TMPRSS11A, also known as ECRG1, GenBank accession no. AF 071882). Then, p21 protein expression, cell cycle and cell proliferation regulations were examined after ECRG4 and ECRG1 co-transfection in ESCC cells. RESULTS: We revealed for the first time that ECRG4 interacted directly with ECRG1 to inhibit cancer cell proliferation and induce cell cycle G1 phase block in ESCC. Binding affinity and co-immunoprecipitation assays demonstrated that ECRG4 interacted directly with ECRG1 in ESCC cells. Furthermore, the ECRG4 and ECRG1 co-expression remarkably upregulatd p21 protein level by Western blot (P < 0.001), induced cell cycle G1 phase block by flow cytometric analysis (P < 0.001) and suppressed cell proliferation by MTT and BrdU assay (both P < 0.01) in ESCC cells. CONCLUSIONS: ECRG4 interacts directly with ECRG1 to upregulate p21 protein expression, induce cell cycle G1 phase block and inhibit cancer cells proliferation in ESCC. PMID- 21288368 TI - School-based surveys of malaria in Oromia Regional State, Ethiopia: a rapid survey method for malaria in low transmission settings. AB - BACKGROUND: In Ethiopia, malaria transmission is seasonal and unstable, with both Plasmodium falciparum and Plasmodium vivax endemic. Such spatial and temporal clustering of malaria only serves to underscore the importance of regularly collecting up-to-date malaria surveillance data to inform decision-making in malaria control. Cross-sectional school-based malaria surveys were conducted across Oromia Regional State to generate up-to-date data for planning malaria control interventions, as well as monitoring and evaluation of operational programme implementation. METHODS: Two hundred primary schools were randomly selected using a stratified and weighted sampling frame; 100 children aged five to 18 years were then randomly chosen within each school. Surveys were carried out in May 2009 and from October to December 2009, to coincide with the peak of malaria transmission in different parts of Oromia. Each child was tested for malaria by expert microscopy, their haemoglobin measured and a simple questionnaire completed. Satellite-derived environmental data were used to assess ecological correlates of Plasmodium infection; Bayesian geostatistical methods and Kulldorff's spatial scan statistic were employed to investigate spatial heterogeneity. RESULTS: A total 20,899 children from 197 schools provided blood samples, two selected schools were inaccessible and one school refused to participate. The overall prevalence of Plasmodium infection was found to be 0.56% (95% CI: 0.46-0.67%), with 53% of infections due to P. falciparum and 47% due to P. vivax. Of children surveyed, 17.6% (95% CI: 17.0-18.1%) were anaemic, while 46% reported sleeping under a mosquito net the previous night. Malaria was found at 30 (15%) schools to a maximum elevation of 2,187 metres, with school-level Plasmodium prevalence ranging between 0% and 14.5%. Although environmental variables were only weakly associated with P. falciparum and P. vivax infection, clusters of infection were identified within Oromia. CONCLUSION: These findings demonstrate the marked spatial heterogeneity of malaria in Oromia and, in general, Ethiopia, and provide a strong epidemiological basis for planning as well as monitoring and evaluating malaria control in a setting with seasonal and unstable malaria transmission. PMID- 21288369 TI - Behavioural and chemical evidence for multiple colonisation of the Argentine ant, Linepithema humile, in the Western Cape, South Africa. AB - BACKGROUND: The Argentine ant, Linepithema humile, is a widespread invasive ant species that has successfully established in nearly all continents across the globe. Argentine ants are characterised by a social structure known as unicoloniality, where territorial boundaries between nests are absent and intraspecific aggression is rare. This is particularly pronounced in introduced populations and results in the formation of large and spatially expansive supercolonies. Although it is amongst the most well studied of invasive ants, very little work has been done on this ant in South Africa. In this first study, we investigate the population structure of Argentine ants in South Africa. We use behavioural (aggression tests) and chemical (CHC) approaches to investigate the population structure of Argentine ants within the Western Cape, identify the number of supercolonies and infer number of introductions. RESULTS: Both the aggression assays and chemical data revealed that the Western Cape Argentine ant population can be divided into two behaviourally and chemically distinct supercolonies. Intraspecific aggression was evident between the two supercolonies of Argentine ants with ants able to discriminate among conspecific non-nestmates. This discrimination is linked to the divergence in cuticular hydrocarbon profiles of ants originating from the two supercolonies. CONCLUSIONS: The presence of these two distinct supercolonies is suggestive of at least two independent introductions of this ant within the Western Cape. Moreover, the pattern of colonisation observed in this study, with the two colonies interspersed, is in agreement with global patterns of Argentine ant invasions. Our findings are of interest because recent studies show that Argentine ants from South Africa are different from those identified in other introduced ranges and therefore provide an opportunity to further understand factors that determine the distributional and spread patterns of Argentine ant supercolonies. PMID- 21288370 TI - Criticism of Australian Society of Otolaryngology-Head and Neck Surgery guidelines incorrect. PMID- 21288371 TI - Research letter. Body composition in subtypes of depression--a population-based survey. PMID- 21288372 TI - A review of ultrastructural and ultracytochemical studies of infection processes in some plant wilt diseases: the opaque matter extensively involved, its links with pathogen elements, insights into its nature. AB - The present review is based on results of several years of investigation on the pathogenesis of plant wilt diseases using for one of the main aspects, several labeling techniques at the ultrastructural level: autoradiography with (3)H thymidine; gold-tagged lectins, enzymes, polyclonal, and monoclonal antibodies. Thus, opaque matter (OM), labeling for DNA with the appropriate markers, can be abundant in and associated with host tissue reactions and pronounced alterations (particularly in newly differentiated xylem). The presence of structures (called P-elements) in OM, paralleled by a similar occurrence in nuclei of both the host and pathogen cells, is considered as being also indicative of a cytoplasmic nature for this OM and most likely originating from fungal elements. PMID- 21288373 TI - Endoplasmic reticulum stress and lipid dysregulation. AB - Cellular cholesterol homeostasis is a fundamental and highly regulated process. Transcription factors known as sterol regulatory element binding proteins (SREBPs) coordinate the expression of many genes involved in the biosynthesis and uptake of cholesterol. Dysregulation of SREBP activation and cellular lipid accumulation has been associated with endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). This review will provide an overview of ER stress and the UPR as well as cholesterol homeostasis and SREBP regulation, with an emphasis on their interaction and biological relevance. PMID- 21288374 TI - Parotid mass: an unusual presentation of gastroesophageal malignancy. AB - OBJECTIVE: To report an extremely rare case of gastroesophageal carcinoma presenting initially with salivary gland metastasis. METHOD: Case report and English language literature review concerning metastasis of adenocarcinoma of the gastroesophageal junction, with emphasis on clinical presentation. RESULTS: A 66 year-old man presented to the ENT rapid-access clinic with a right-sided neck swelling located in the tail of the right parotid gland. Fine needle aspiration cytology suggested adenocarcinoma. An urgent Oesophago-Gastro-Duodenoscopy (OGD) and biopsy confirmed the presence of the primary tumour at the gastroesophageal junction. CONCLUSION: To our best knowledge, this is the first report in the English language literature of a parotid mass as the presenting feature of gastroesophageal carcinoma. PMID- 21288375 TI - Blood pressure and BMI in adolescents in Aracaju, Brazil. AB - OBJECTIVE: To assess the prevalence of high blood pressure (BP) and the association of overweight and obesity with high BP among adolescents in Aracaju, Brazil. DESIGN: Cross-sectional study. The main outcome measure was the proportion of adolescents with high BP (sex-, age- and height-specific >= 95th percentile). The main predictor variables were overweight and obesity defined according to the criteria of the International Obesity Task Force. Other covariates included age, socio-economic status and leisure-time physical activity. SETTING: Aracaju, Brazil, capital city of Sergipe State, north-eastern Brazil. SUBJECTS: A random sample of 1002 adolescents (442 boys and 560 girls) aged 12-17 years selected from twenty public schools and ten private schools were studied. RESULTS: The prevalence of high BP was 16.9 % (95 % CI 13.1, 21.7) in boys and 12.9 % (95 % CI 9.0, 18.0) in girls. After adjusting for age, socio economic status and leisure-time physical activity in both boys and girls, overweight (prevalence ratio (PR) = 1.93, 95 % CI 1.08, 3.48; PR = 4.34, 95 % CI 2.58, 7.30, respectively) and obesity (PR = 4.87, 95 % CI 2.35, 10.11; PR = 5.18, 95 % CI 2.67, 10.06, respectively) were found to be associated with high BP. CONCLUSIONS: These findings indicate a high prevalence of high BP in both boys and girls in Aracaju, Brazil. Overweight and obesity were strongly associated with high BP. These findings underscore the urgent need for public health measures to prevent increasing high BP in adolescents in Brazil. Targeting intervention in adolescence may be a critical method for preventing high BP in later life. PMID- 21288376 TI - A tool for assessing healthy food knowledge in 5-6-year-old Australian children. AB - OBJECTIVE: In the early years of life, influential attributes are formed and may be difficult to change later in life. Early childhood is now recognised as a key target in the prevention of overweight and obesity, and the knowledge that children gain at this time about food and its health benefits may have an important influence on their dietary choices and preferences in later life. Therefore, an activity was designed using age-appropriate methods to assess nutrition knowledge of young children. DESIGN: The Healthy Food Knowledge Activity was developed using a list of thirty healthy and unhealthy foods and drinks generated from the Australian Guide to Healthy Eating. SETTING: The activity was conducted with individual children from reception classes of South Australian schools. SUBJECTS: Children aged 5-6 years undertook the activity in a pilot study (n 13) and in the main study (n 192). RESULTS: Pilot data indicated good test-retest reliability of the activity (r = 0.84, P < 0.01). In the main study, there was a good distribution of scores with acceptable skewness and kurtosis statistics. A breakdown of responses indicated good face validity, with more obvious foods being more correctly classified. CONCLUSIONS: Children as young as 5-6 years of age can correctly identify healthy foods, and this can be measured objectively. This activity also provides interesting insights regarding misconceptions about foods that could be attributed to influences such as media advertising and that can be addressed by educators of this age group. PMID- 21288377 TI - Eating until feeling full and rapid eating both increase metabolic risk factors in Japanese men and women. AB - OBJECTIVE: To investigate the association between eating behaviour and metabolic risk in the broader population. DESIGN: The association between metabolic risk factors (overweight, hypertension, hyperglycaemia, hypertriacylglycerolaemia, low HDL cholesterol, hyperuricaemia and fatty liver) and various eating behaviours were compared for four groups defined by subjective reporting: not eating until feeling full and not eating rapidly (G1); eating until feeling full only (G2); eating rapidly only (G3); and eating both rapidly and until feeling full (G4). SETTING: A medical centre for health examinations in Tokyo, Japan. SUBJECTS: Men (n 8240) and women (n 2955) who underwent health examinations. RESULTS: The distribution of participants in G1 to G4 was 49.8 %, 11.5 %, 26.3 % and 12.4 % among men and 55.3 %, 15.0 %, 19.0 % and 10.7 % among women, respectively. Compared with G1, the age-adjusted OR (95 % CI) for overweight were significantly higher in G2 to G4, being respectively 1.85 (1.58, 2.17), 1.98 (1.76, 2.23) and 3.46 (2.99, 4.01) for men and 2.20 (1.62, 2.97), 2.59 (1.97, 3.39) and 3.12 (2.27, 4.26) for women. The age-adjusted OR were also significantly higher for hypertriacylglycerolaemia, hyperuricaemia and fatty liver in G2 and for all risks in G3 and G4 among men; and for hyperuricaemia in G2, for hyperglycaemia, hypertriacylglycerolaemia and fatty liver in G3 and for hypertriacylglycerolaemia and fatty liver in G4 among women. CONCLUSIONS: Both eating until feeling full and eating rapidly increase metabolic risk factors. Although the mechanism between rapid eating and metabolic risk requires further exploration, eating slowly and ending meals shortly before feeling full are important public health messages for reducing metabolic risk factors. PMID- 21288378 TI - Healthy eating in early years settings: a review of current national to local guidance for North West England. AB - OBJECTIVE: To determine the extent to which national and local UK guidelines for the early years sector address key recommendations for encouraging healthy eating based on best available evidence. DESIGN: Phase 1 comprised a literature review to identify new evidence to assess current relevance of the Caroline Walker Trust (CWT) 'Eating well for under-5 s in child care' guidelines. Phase 2 assessed the completeness of seven local to national-level government guidelines by comparison with the 'gold standard' CWT guidelines. SETTING: Desk-based review using secondary data. SUBJECTS: Research literature and statutory guidelines on healthy eating in early years settings. RESULTS: Phase 1 retrieved seventy-five papers, of which sixty were excluded as they addressed compliance with nutritional and food-based standards only. One report examined a social marketing tool and was deemed too narrow. The remaining fourteen documents assessed interventions to encourage healthy eating in early years settings. Following quality assessment, seven documents were included. Nine key recommendations were identified: (i) role of government; (ii) early years setting policy/guidelines; (iii) training; (iv) menu planning; (v) parents; (vi) atmosphere and encouragement; (vii) learning through food; (viii) sustainability; and (ix) equal opportunities. Phase 2 identified that all seven guidelines included the nine key recommendations but sporadic cover of sub-key recommendations. CONCLUSIONS: More detail is needed on how early years settings can encourage children to eat healthily. Research is required to develop second-layer guidance for interactive materials. Clear processes of communication and support for parents are required. Ways food relates to children's wider learning and social development need further thought, requiring collaboration between the Department of Health and the Department for Education. PMID- 21288379 TI - The evolution and psychology of self-deception. AB - In this article we argue that self-deception evolved to facilitate interpersonal deception by allowing people to avoid the cues to conscious deception that might reveal deceptive intent. Self-deception has two additional advantages: It eliminates the costly cognitive load that is typically associated with deceiving, and it can minimize retribution if the deception is discovered. Beyond its role in specific acts of deception, self-deceptive self-enhancement also allows people to display more confidence than is warranted, which has a host of social advantages. The question then arises of how the self can be both deceiver and deceived. We propose that this is achieved through dissociations of mental processes, including conscious versus unconscious memories, conscious versus unconscious attitudes, and automatic versus controlled processes. Given the variety of methods for deceiving others, it should come as no surprise that self deception manifests itself in a number of different psychological processes, and we discuss various types of self-deception. We then discuss the interpersonal versus intrapersonal nature of self-deception before considering the levels of consciousness at which the self can be deceived. Finally, we contrast our evolutionary approach to self-deception with current theories and debates in psychology and consider some of the costs associated with self-deception. PMID- 21288409 TI - Distinctive pain course during first year after total ankle arthroplasty: a prospective, observational study. AB - BACKGROUND: Patients and health care professionals alike are often surprised by the course of pain after total ankle arthroplasty (TAA). The current study aimed to determine the baseline patterns of postoperative symptoms during the first year following uncomplicated TAA. MATERIALS AND METHODS: In a prospective observational study 28 patients with unilateral posttraumatic osteoarthritis were tested for pain with a visual analogue scale, swelling (min grade, 0; max grade, 4), ankle range of motion, and AOFAS ankle score. Assessments were performed preoperatively and 6 weeks, 3, 6, 9, and 12 months after TAA. RESULTS: At 6 weeks all variables had improved significantly. However, at 3 months a relapse with deterioration of mean variables was found. These improved asymptotically during assessments at 6, 9, and 12 months. CONCLUSION: Our data suggest patients undergoing uncomplicated TAA have to overpass what we believe is an adaptive inflammatory phase with increased periarticular pain and swelling about 3 months after surgery. This distinctive course may influence patient education and increase confidence of healthcare professionals involved in the rehabilitation of TAA patients. PMID- 21288410 TI - Outcomes of ankle fractures in patients with uncomplicated versus complicated diabetes. AB - BACKGROUND: Patients with diabetes who sustain an ankle fracture are at increased risk for complications including higher rates of in hospital mortality, in hospital postoperative complications, length of stay and non-routine discharges. The purpose of this study was to retrospectively compare the complications associated with operatively treated ankle fractures in a group of patients with uncomplicated diabetes versus a group of patients with complicated diabetes. Complicated diabetes was defined as diabetes associated with end organ damage such as peripheral neuropathy, nephropathy and/or PAD. Uncomplicated diabetes was defined as diabetes without any of these associated conditions. Our hypothesis was that patients with uncomplicated diabetes would experience fewer complications than those patients with complicated diabetes. MATERIALS AND METHODS: We compared the complication rates of ankle fracture repair in 46 patients with complicated diabetes and 59 patients with uncomplicated diabetes and calculated odds ratios (OR) for significant findings. RESULTS: At a mean followup of 21.4 months we found that patients with complicated diabetes had 3.8 times increased risk of overall complications 3.4 times increased risk of a non infectious complication (malunion, nonunion or Charcot arthropathy) and 5 times higher likelihood of needing revision surgery/arthrodesis when compared to patients with uncomplicated diabetes. Open ankle fractures in this diabetic population were associated with a three times higher rate of complications and 3.7 times higher rate of infection. CONCLUSION: Patients with complicated diabetes have an increased risk of complications after ankle fracture surgery compared to patients with uncomplicated diabetes. Careful preoperative evaluation of the neurovascular status is mandatory, since many patients with diabetes do not recognize that they have neuropathy and/or peripheral artery disease. PMID- 21288411 TI - Preservation of lesser metatarsophalangeal joints in rheumatoid forefoot reconstruction. AB - BACKGROUND: A standard rheumatoid forefoot reconstruction consists of arthrodesis of the first metatarsophalangeal (MTP) joint and resection arthroplasty of the lesser metatarsal heads. However, preservation of the metatarsal heads has gained renewed interest since the medical treatment of rheumatoid arthritis has improved dramatically. MATERIAL AND METHODS: Nineteen consecutive patients with severe rheumatoid forefoot deformities underwent 24 forefoot reconstructions including first MTP arthrodesis with lesser MTP resection arthroplasty (resection arthroplasty group, ten feet), arthrolysis (arthrolysis group, six feet), or a combination of both (combined group, eight feet). Subjective, functional, and radiographic results were evaluated at 28 and 133 months (mean) followup. RESULTS: The overall AOFAS Forefoot Score at short- and long-term followup improved significantly (all p < 0.0001). There were no substantial differences between groups with regard to subjective rating, function, use of orthopaedic aids or shoewear, and walking capacity. Radiographic evaluation revealed a significant increase in axial malalignment of the lesser toes at long-term followup in all groups (all p < 0.018). Sagittal malalignment increased substantially in the resection arthroplasty group only. Reoperation rate was comparable among all groups, and a single third MTP arthrolysis (3%, 1/40) was converted to resection arthroplasty. CONCLUSION: In combination with first MTP arthrodesis, arthrolysis with preservation of all or only the lateral lesser MTP joints in rheumatoid forefoot reconstruction was a viable and durable alternative to resection arthroplasty when the joint destruction was mild to moderate. PMID- 21288412 TI - Stability criteria for nonoperative ankle fracture management. AB - BACKGROUND: This study was designed to see if stability based criteria are useful in choosing between nonoperative and operative treatment of ankle fractures. MATERIALS AND METHODS: One hundred sixty ankle fractures in skeletally mature patients were retrospectively analyzed to obtain an epidemiological profile in a population of about 130,000. One hundred thirty patients had followup of more than 2 years. A decision between operative and nonoperative treatment was made by the surgeon-on-duty, based on accepted stability criteria. Fractures were classified according to Weber and Lauge-Hansen systems. Clinical outcome was assessed using the scoring systems of Olerud-Molander, the RAND 36-Item Health Survey and the Visual Analogue Scale (VAS), measuring pain and function. RESULTS: The overall incidence of ankle fractures was 154/100,000. Nonoperatively treated patients had more displacement of the distal fibula after treatment, but less pain and better Olerud-Molander (good or excellent, 89% vs. 71%) and VAS functional scores. Independent factors for worse outcome were female gender, older age, unstable fracture and co-morbidity. No nonoperatively treated patients needed operative fixation during followup. CONCLUSION: Stability-based fracture classification was a simple and useful tool in decision-making for the treatment of ankle fractures. We found lateral malleolar fractures could be treated nonoperatively with success if the ankle mortise was stable. Displacement of the distal fibula after treatment did not affect functional scores or pain. PMID- 21288413 TI - Hemiarthroplasty and distal oblique first metatarsal osteotomy for hallux rigidus. AB - BACKGROUND: In a retrospective study, we evaluated the effect of the addition of a decompressive osteotomy to hemiarthroplasty of the great toe in terms of clinical and radiographic outcomes. MATERIAL AND METHODS: Twenty-one consecutive patients affected by Grade III hallux rigidus underwent distal oblique osteotomy of the first metatarsal and hemiarthroplasty of the hallux metatarsophalageal joint. Clinical evaluation included the American Orthopaedic Foot and Ankle Society scoring system (AOFAS) and the Short Form 36 questionnaire (SF-36), preoperatively and at followup visits. Standard weightbearing radiographs were performed to assess implant alignment, loosening, and bone loss. The mean followup was 26.4 (range, 16 to 29) months. RESULTS: The mean AOFAS score improved from 47.5 +/- 11.5 preoperatively to 76.0 +/- 15.5 postoperatively (p < 0.01). At the last followup the SF-36 subscales Physical functioning, Bodily pain and Emotional role scores were increased from baseline. At the last followup, six patients (28.5%) were very satisfied with the outcome, ten patients (47.6%) were satisfied and five patients (23.8%) were dissatisfied. In the dissatisfied group, two patients had persistent joint pain with stiffness and subluxation of the prosthesis. Dorsal subsidence of the implant was present in ten patients at the last radiographic followup. CONCLUSION: Hemiarthroplasty of the proximal phalanx and distal oblique metatarsal osteotomy for Grade III hallux rigidus at 2-years followup yielded mixed patient satisfaction and unsatisfactory radiographic outcome. PMID- 21288414 TI - Long-term results after modified Brostrom procedure without calcaneofibular ligament reconstruction. AB - BACKGROUND: The short-term results of modified Brostrom procedures (MBP) have been satisfactory. However, the long-term results of anatomical reconstruction have been less frequently reported. We report on our long-term results in our patient group. MATERIALS AND METHODS: Thirty patients with chronic ankle instability who were treated using the MBP without CFL reconstruction from March 1997 to June 1999 were evaluated retrospectively. This consecutive series of patients was comprised of 26 males and four females. The mean age of the patients at the time of operation was 23 years. The mean followup period was 10.6 years. Twenty-four of the 30 were high-level amateur or professional athletes. The operation procedure involved only ATFL imbrication with inferior extensor retinaculum (IER) reinforcement. Clinical outcomes were evaluated by reviewing clinical charts, retrospectively. Functional outcome scores were obtained using the Hamilton scale, a VAS, and AOFAS score at final followup visit, when each patient underwent a physical examination and stress radiography. RESULTS: Mean AOFAS score was 91 and the mean VAS at final followup was 87. According to the Hamilton classification, 12 achieved an excellent result, 16 a good result, and two a fair result. Mean anterior translation values at final followup were 6.9 and 6.1 mm on ipsilateral and contralateral sides. Furthermore, mean talar tilt angles were 3.0 and 2.5 degrees for ipsilateral and contralateral sides. Twenty eight of the 30 patients were restored to pre-injury activity levels. CONCLUSION: The long-term surgical results of the MBP without CFL reconstruction for chronic lateral ankle instability were good to excellent in terms of functional, clinical, and radiographic assessments. PMID- 21288415 TI - Fixation of first tarsometatarsal arthrodesis: a retrospective comparative cohort of two techniques. AB - BACKGROUND: Presently, indications for the Lapidus procedure include patients with many pathologies of the first metatarsocuneiform joint. Currently the standard in many areas is that of two or three crossed screws through the first tarsometatarsal region. This type of fixation requires an extended period of nonweightbearing and may be difficult for patient compliance. MATERIALS AND METHODS: The present study is a retrospective comparison of crossed screw fixation to locking plate fixation without a lag screw on union rates, time to weightbearing, and complications. RESULTS: One hundred forty-three first TMT fusions met the inclusion criteria. There were 96 fused by crossed screw construct (CS) and 47 by the locked plate with or without compression screw (LP). There was a significant difference in time to full weightbearing and union rate. Time to full weightbearing was 8.8 (range, 3 to 16) weeks and 7.8 (range, 1.5 to 34) weeks in the CS and LP groups, respectively (p < 0.001). Union rate was 89.4% (88 of 96 joints) and 98.5% (46 of 47 joints) in the CS and LP groups, respectively (p < 0.001). CONCLUSIONS: We found that when using a dorsal-medial locked plate with or without lag screw lead to a superior rate of union compared to standard crossed screw constructs even while allowing earlier return to full weightbearing. PMID- 21288416 TI - Peripheral nerve sheath tumors of the foot and ankle. AB - BACKGROUND: Peripheral nerve sheath tumors (PNSTs) are soft tissue neoplasms found in intimate association with a peripheral nerve. They are rarely seen in the foot and ankle where they have an innocuous appearance, but these tumors have the potential to become malignant. This study reports a large series of foot and ankle PNSTs surgically treated at a single institution. MATERIALS AND METHODS: Retrospectively, all cases of PNSTs confirmed by biopsy and surgically treated from 1992 to 2008 were included in the study. Preoperative, perioperative and postoperative variables were collected. Foot and ankle tumors were compared with the overall group of PNSTs. Fisher's test and Student's t-test were implemented to address the significance of the findings (p <= 0.05). RESULTS: From all PNSTs identified (n = 137), there were 14 (10.2%) foot and ankle. A painful mass was the most common presenting symptom. Schwannoma represented the most common histologic type. Two cases of malignant foot and ankle PNSTs were identified. Foot and ankle PNSTs were significantly smaller in size and showed fewer postoperative neurologic deficits than the overall group of PNSTs. No differences were found in terms of histologic type distribution, age at diagnosis, duration of symptoms and postoperative tumor recurrence, but there was a preponderance of females in this series of foot and ankle tumors. CONCLUSION: PNSTs of the foot and ankle usually present as innocuous, slow-growing masses leading to misdiagnosis and suboptimal surgical treatment of a potentially malignant lesion. A comprehensive diagnostic evaluation, preoperative planning and meticulous surgical excision are required to prevent tumor recurrence and minimize the incidence of postoperative sequelae, thus improving postoperative functional outcomes. PMID- 21288417 TI - High rate of osteolytic lesions in medium-term followup after the AES total ankle replacement. AB - BACKGROUND: Some previous studies have shown a high percentage of early-onset and rapidly progressing osteolysis associated with total ankle arthroplasty (TAA) by the Ankle Evolutive System (AES). The purpose of our study was to analyze medium term results at our institution. MATERIALS AND METHODS: Altogether 38 TAAs using AES prostheses were carried out between 2003 and 2007. Diagnoses were rheumatoid arthritis (71%), post-traumatic and idiopathic osteoarthritis (29%). The mean age was 54 years, followup 28 months. Tibial and talar components had hydroxyapatite coating on metal (Co-Cr) components (HA-coated). Since 2005 the design was changed and components were porous coated with titanium and hydroxyapatite (dual coated). RESULTS: Two-year survival was 79% (95% CI: 56 to 98). At followup 34 (89%) primary tibial and talar components were preserved. In 19 (50%) TAAs osteolysis (more than or equal to 2 mm) occurred in the periprosthetic bone area and in nine (24%) comprised large "cyst-like osteolysis''. In HA-coated prostheses radiolucent lines (less than or equal to 2 mm) or osteolysis (more than or equal to 2 mm) were detected in 11 (100%) cases and in dual-coated prostheses in 19 (74%) (p = 0.08). On the other hand there was more large "cyst like osteolysis'' around the dual-coated prosthesis and lesions were larger (p = 0.017). In rheumatoid arthritis osteolysis was detected in 14 (52%) and large "cyst-like osteolysis'' in seven (26%) prostheses and in the group of traumatic and idiopathic osteoarthritis in six (55%) and two (18%), respectively. CONCLUSION: This study showed a high frequency of osteolysis in medium-term followup after the AES ankle replacement. The outcome was not sufficiently beneficial and we have discontinued use of this prosthesis. PMID- 21288418 TI - Correction of severe foot deformities using the Taylor spatial frame. AB - BACKGROUND: This study was conducted to evaluate the treatment of severe foot deformities using the Taylor spatial frame. MATERIALS AND METHODS: The treatment of seven patients with nine severe foot deformities was reviewed. The mean age of the patients at surgery was 16 years with a mean followup of 21.5 months. The following parameters were assessed: etiology of deformity, date of surgery, surgical procedure, age at surgery, previous surgical or conservative treatments, preoperative symptoms, preoperative and postoperative deformity and affected side, complications during correction, duration of TSF, duration of hospital stay, occurrence of secondary osteoarthritis, recurrence of deformity, surgical revisions or subsequent surgeries. The pre- and postoperative deformity was assessed clinically. The final outcome was categorized as good, fair, or poor. RESULTS: The results were good in eight feet and poor in one foot. Early complications included pin tract infection, temporary hypoesthesia and temporary shortening of the tendon of the flexor digitorum longus. Recurrence of deformity occurred in no patient. One patient required a subtalar arthrodesis for symptomatic, secondary osteoarthritis in one foot. CONCLUSION: The present study showed that TSF is a viable solution to correct severe foot deformities but we believe a surgeon should be aware of the possible complications. PMID- 21288419 TI - Ankle and foot contributions to extreme plantar- and dorsiflexion in female ballet dancers. AB - BACKGROUND: Female ballet dancers require extreme ankle motion. The objective of this study was to quantify the relative contributions of the ankle and various foot joints to extreme plantarflexion (PF) and dorsiflexion (DF) in female ballet dancers using an X-ray superimposition technique and digital graphics software. MATERIALS AND METHODS: One asymptomatic ankle was studied in each of seven experienced female ballet dancers. Three lateral weightbearing X-rays were taken of each ballet dancer's ankle: en pointe (maximum PF), in neutral position, and in demi-plie (maximum DF). Using graphics software, a subject's three X-ray images were superimposed and the tali were aligned. On each image the tibia, navicular, intermediate cuneiform, and first metatarsal were marked. Positional differences of a bone's line among the three images demonstrated angular movement of the bone in degrees. The neutral position was the reference from which PF and DF of the bones were calculated. RESULTS: The talocrural joint contributed the most motion of any pair of bones evaluated for both PF and DF, with mean movements of 57.6 +/- 5.2 degrees en pointe and 24.6 +/- 9.6 degrees in demi plie. Approximately 70% of total PF and DF were attributable to the talocrural joint, with the remaining 30% coming from motion between adjacent pairs of the studied foot bones. CONCLUSION: Superimposed X-rays for assessing ankle and foot contributions to the extreme positions required of female ballet dancers offer insight into how these positions are attained that is not available via goniometry. CLINICAL RELEVANCE: Functional information gained from this study may assist clinicians in assessing ankle and foot pain in these individuals. PMID- 21288420 TI - Validity of the posterior tibial edema sign in posterior tibial tendon dysfunction. AB - BACKGROUND: Posterior tibial tendon dysfunction (PTTD) is a common malady leading to acquired flatfoot, which frequently causes foot and ankle pain and swelling. We hypothesized that patients with PTTD and pitting edema along the course of the posterior tibial tendon (PTT) would have evidence of fluid within the tendon sheath on MRI. We introduce and validate a novel, yet simple physical examination finding, the posterior tibial edema (PTE) sign, to help distinguish PTTD from other causes of foot and ankle pain and swelling. PATIENTS AND METHODS: To determine an association between the PTE sign and changes to the PTT evident on MRI, we reviewed the medical records of patients with PTTD who underwent magnetic resonance imaging (MRI). RESULTS: Of 186 patients identified with PTTD, 49 underwent MRI, and 42 (86%) demonstrated imaging characteristics consistent with tendonitis, tendinosis, or tenosynovitis. Presence or absence of increased posterior malleolar pitting edema agreed with presence or absence of these MRI findings in 43 patients (88%), making the clinical examination finding significantly predictive of MRI results (p= 0.01). The sensitivity of the test for PTE was 86%, with specificity of 100%. CONCLUSION: The PTE sign refers to pitting edema along the course of the PTT, not associated with acute trauma and not accompanied by other areas of edema. Physical examination signs that are highly sensitive and specific to the condition may help lower the cost of diagnosis by eliminating the need for expensive tests that are not always necessary. PMID- 21288421 TI - Definition of coordinate system for three-dimensional data analysis in the foot and ankle. AB - BACKGROUND: Three-dimensional data is required to have advanced knowledge of foot and ankle kinematics and morphology. However, studies have been difficult to compare due to a lack of a common coordinate system. Therefore, we present a means to define a coordinate frame in the foot and ankle and its clinical application. MATERIALS AND METHODS: We carried out ten CT scans in anatomically normal feet and segmented them in a general purpose segmentation program for grey value images. 3D binary formatted stereolithography files were then create and imported to a shape analysis program for biomechanics which was used to define a coordinate frame and carry out morphological analysis of the forefoot. RESULTS: The coordinate frame had axes standard deviations of 2.36 which are comparable to axes variability of other joint coordinate systems. We showed a strong correlation between the lengths of the metatarsals within and between the columns of the foot and also among the lesser metatarsal lengths. CONCLUSION: We present a reproducible method for construction of a coordinate system for the foot and ankle with low axes variability. CLINICAL RELEVANCE: To conduct meaningful comparison between multiple subjects the coordinate system must be constant. This system enables such comparison and therefore will aid morphological data collection and improve preoperative planning accuracy. PMID- 21288422 TI - Minimally invasive plate osteosynthesis (MIPO) for periprosthetic fracture after total ankle arthroplasty: a case report. PMID- 21288423 TI - Balloon reduction of displaced calcaneus fractures: surgical technique and case series. PMID- 21288424 TI - Technique tip: interposition of extensor digitorum longus after resection arthroplasty of lesser metatarsophalangeal joints for rheumatoid forefoot deformity. PMID- 21288425 TI - Casting technique tip: the cure for curled edges. PMID- 21288426 TI - Surgical strategies: the management of varus ankle deformity with joint replacement. PMID- 21288427 TI - Effect of knee position on gap size following acute Achilles rupture. AB - BACKGROUND: Acute traumatic rupture of the tendoachilles is a common problem. Following a recent Cochrane review, operative treatment has been shown to have a lower re-rupture rate compared with conservative treatment, but is associated with a slightly higher rate of other complications. Debate concerning the method and duration of conservative treatment remains. We aimed to assess the effect of knee position on the gap in acute tendoachilles ruptures. MATERIALS AND METHODS: Patients with a history and examination consistent with an acute rupture were collected prospectively. They were investigated by the same musculoskeletal consultant radiologist using ultrasonography. Tendon gap was measured with the foot in neutral and full tolerable equinus with the knee both flexed to 90 degrees and fully extended. A pilot study of 10 patients was used to provide data for a power calculation. Following this a total of 25 consecutive patients were recruited for inclusion. A paired Student t-test was used to compare mean differences between the knee flexed/ankle plantarflexed and knee extended/ankle plantarflexed positions on the gap at the rupture site. RESULTS: A diagnosis of acute tendoachilles rupture was confirmed in all patients and tendon gap was measured with the knee flexed and extended with the ankle either neutral or plantarflexed. This confirmed there was no significant difference in the tendon gap with the knee flexed or extended provided the foot was in full equinus (p>0.05). CONCLUSION: This study showed that knee position had no significant effect on the tendon gap at the rupture site. This study could have considerable implications on the rationale behind conservative treatment and splinting of acute tendoachilles ruptures with no apparent role for knee flexed immobilization. PMID- 21288428 TI - Association between plantar fasciitis and isolated contracture of the gastrocnemius. AB - BACKGROUND: Current evidence suggests that limited ankle dorsiflexion is an etiologic factor for plantar fasciitis. This limitation can arise from either an isolated contracture of the gastrocnemius or from a contracture of the gastrocnemius-soleus complex. This study's aim was to determine the proportion of patients with plantar fasciitis that have an associated isolated gastrocnemius contracture. MATERIALS AND METHODS: This investigation was a prospective evaluation of patients with either acute or chronic plantar fasciitis. Two hundred fifty-four patients with plantar fasciitis were included. Patients were assessed for the existence of limited ankle dorsiflexion which was further characterized by noting the presence of an isolated gastrocnemius contracture or contracture of the gastrocnemius-soleus complex. The patient's duration of symptoms, type of occupation, and body mass index were also documented. Patients with acute plantar fasciitis were defined as having symptom duration of 9 months or less while those with chronic plantar fasciitis were those with over 9 months of symptoms. The Wilcoxon rank sum and chi square tests were used to compare characteristics between the acute and chronic populations. RESULTS: Eighty-three percent (211 of 254 patients) had limited ankle dorsiflexion. Fifty-seven percent (145 of 254) had an isolated contracture of the gastrocnemius, 26% (66 of 254) had a contracture of the gastrocnemius-soleus complex, and 17% (43 of 254) did not have a dorsiflexion limitation. Patients were further stratified into acute versus chronic symptom duration at the time of presentation. Equinus contracture was noted in 83% (129 of 155) of acute cases, and 82% (82 of 99) of chronic cases. An isolated contracture of the gastrocnemius was found in 60% (93 of 155) of acute, and 52% (52 of 99) of chronic cases. A gastrocnemius-soleus complex contracture was noted in 23% (36 of 155) of acute cases, and 30% (30 of 99) of chronic cases. Patients with chronic plantar fasciitis had a significantly higher number (p<0.05) of medical comorbidities than those with acute plantar fasciitis. CONCLUSION: Limited ankle dorsiflexion is commonly associated with plantar fasciitis and more than half of these patients had evidence of an isolated gastrocnemius contracture. These findings can be utilized to develop and further refine non-operative and operative treatment strategies for those with recalcitrant plantar fasciitis. PMID- 21288429 TI - Achilles tendon ruptures in elite athletes. AB - BACKGROUND: The management of Achilles tendon (AT) ruptures in elite athletes can be challenging. We performed a retrospective review of prospectively collected data study to evaluate the results of percutaneous repair of an acute AT rupture in elite athletes. MATERIALS AND METHODS: Seventeen elite athletes with prodromal tendinous problems sustained an acute tear of the AT and underwent percutaneous surgical repair. We performed preoperative evaluations the day of surgery, and report the results of postoperative evaluation at a final followup at an average of 72 months from the procedure. Each patient was evaluated for limb dominance, trauma history, duration and type of preoperative symptoms, and postoperative AT Total Rupture Score (ATRS). RESULTS: All patients were able to fully weightbear on the operated limb by the end of the 8th postoperative week. The average time to return to full sport participation was 4.8+/-0.9 months. Two of the 15 elite athletes on whom we have full data suffered from a superficial infection of the surgical wound. CONCLUSION: Our study suggests that percutaneous repair of the AT is a good option for elite athletes, allowing a safe and prompt return to sport activities. PMID- 21288430 TI - Epidemiology of metatarsal stress fractures versus tibial and femoral stress fractures during elite training. AB - BACKGROUND: The training of elite infantry recruits takes a year or more. Stress fractures are known to be endemic in their basic training and the clinical presentation of tibial, femoral, and metatarsal stress fractures are different. Stress fracture incidence during the subsequent progressively more demanding training is not known. The study hypothesis was that after an adaptation period, the incidence of stress fractures during the course of 1 year of elite infantry training would fall in spite of the increasingly demanding training. MATERIALS AND METHODS: Seventy-six male elite infantry recruits were followed for the development of stress fractures during a progressively more difficult training program composed of basic training (1 to 14 weeks), advanced training (14 to 26 weeks), and unit training (26 to 52 weeks). Subjects were reviewed regularly and those with clinical suspicion of stress fracture were assessed using bone scan and X-rays. RESULTS: The incidence of stress fractures was 20% during basic training, 14% during advanced training and 23% during unit training. There was a statistically significant difference in the incidence of tibial and femoral stress fractures versus metatarsal stress fractures before and after the completion of phase II training at week 26 (p=0.0001). Seventy-eight percent of the stress fractures during phases I and II training were either tibial or femoral, while 91% of the stress fractures in phase III training were metatarsal. Prior participation in ball sports (p=0.02) and greater tibial length (p=0.05) were protective factors for stress fracture. CONCLUSION: The study hypothesis that after a period of soldier adaptation, the incidence of stress fractures would decrease in spite of the increasingly demanding elite infantry training was found to be true for tibial and femoral fractures after 6 months of training but not for metatarsal stress fractures. Further studies are required to understand the mechanism of this difference but physicians and others treating stress fractures should be aware of this pattern. PMID- 21288431 TI - Minimally invasive deltoid ligament reconstruction for stage IV flatfoot deformity. AB - BACKGROUND: Stage IV is the most advanced form of acquired adult flatfoot deformity (AAFD). It is present when valgus tibiotalar angulation occurs with foot deformities associated with AAFD. Tibiotalocalcaneal or pantalar fusion has been the gold standard for treatment of Stage IV AAFD. However, in some of these patients the tibiotalar deformity is correctable. We sought to determine whether minimally invasive deltoid ligament reconstruction in conjunction with triple arthrodesis (MIDLR/Triple) allows tibiotalar joint sparing surgical therapy in Stage IV-A AAFD patients. MATERIALS AND METHODS: Patients diagnosed with Stage IV A AAFD were given the option of undergoing ankle joint sparing surgery with the MIDLR/Triple technique. Those that chose this option were followed longitudinally. Eight patients underwent the ankle joint sparing procedure. Average followup was 36 months. Radiographic and functional outcome measures were obtained. Success was defined as maintenance of 3 degrees or less of valgus tibiotalar angulation and greater than 2 mm of lateral joint space remaining at final followup. RESULTS: At final followup, five were judged to have a successful outcome. In those, tibiotalar valgus angulation was reduced from 6.4+/-2.9 degrees to 2.0+/-2.0 degrees, lateral ankle joint space was maintained at preoperative levels and SF-12 functional scores were equal to age matched normative scores. The only parameter found to be predictive of successful outcome was the magnitude of preoperative tibiotalar tilt. CONCLUSIONS: MIDLR/triple is a new treatment option that requires significant care in patient selection and surgical execution. It is a choice that allows for preservation of ankle motion in patients diagnosed with Stage IV-A AAFD who have less than 10 degrees of valgus tibiotalar tilt on preoperative standing ankle radiographs. PMID- 21288432 TI - Limb salvage in severe diabetic foot infection. AB - BACKGROUND: The purpose of our study was to determine the efficacy of a management algorithm that includes negative pressure wound therapy (NPWT) in diabetic feet with limb-threatening infection. MATERIALS AND METHODS: Forty-five septic diabetic feet were treated with NPWT between 2006 and 2008. After emergent abscess evacuation, early vascular intervention was performed if necessary. Debridement, with or without partial foot amputation, was followed by NPWT. Wound progress was measured using a digital scanner. A limb was considered salvaged if complete healing was achieved without any or with minor amputation through or below the ankle. The mean followup after complete wound healing was 17 (range, 6 to 35) months. RESULTS: Thirty-two cases (71%) were infected with two or more organisms. Negative pressure wound therapy was applied for 26.2+/-14.3 days. The median time to achieve more than 75% wound area granulation was 23 (range, 4 to 55) days and 104 (range, 38 to 255) days to complete wound healing. Successful limb salvage was achieved in 44 cases (98%); 14 (31%) without any amputation and 30 (67%) with partial foot amputations. Total number of operations per limb was 2.4+/-1.3. One case of repeated infection and necrosis was managed with a transtibial amputation. There were no complications associated with NPWT. CONCLUSION: This study provides the outcome of a management algorithm which includes NPWT in salvaging severely infected diabetic feet. With emergent evacuation of abscess, early vascular intervention and appropriate debridement, NPWT can be a useful adjunct to the management of limb-threatening diabetic foot infections. PMID- 21288433 TI - Wound complications in thyroxine-supplemented patients following foot and ankle surgery. AB - BACKGROUND: Our hypothesis was that thyroxine supplementation in patients undergoing foot and ankle surgery would be associated with increased postoperative wound complications and wound dehiscence compared to patients without thyroxine supplementation. MATERIALS AND METHODS: A retrospective review of 48 patients supplemented with thyroxine that underwent foot and ankle surgery was conducted and analyzed for wound complications. All patients were non diabetic. A total of 94 historical controls were used to compare the incidence of wound complications to the thyroxine sample. Patient demographics, medical comorbidities, principal diagnosis and procedure performed were recorded. The presence or absence of wound dehiscence, infection or other wound complications was recorded for all patients based on the followup clinical notes in the electronic record. RESULTS: In the thyroxine group, the most common diagnosis was degenerative arthritis (31%, n=15), which also occurred in 28.7% of control patients (n=27). Wound dehiscence was reported in 36.2% (n=17) of thyroxine supplemented patients compared to 10.8% of control patients (n=10). After adjusting for age, gender, hypertension diagnosis, and vascular disease diagnosis, the odds for wound dehiscence remained significantly greater for the thyroxine group compared to control patients (adjusted OR=3.7; 95% CI: (1.3, 11.4); p=0.01). CONCLUSION: Overall, our results suggest increased wound dehiscence complications in the postoperative period for thyroxine-supplemented patients compared to control patients. This finding remained even after adjusting for the associated cardiovascular comorbidities seen in thyroxine-supplemented patients. PMID- 21288434 TI - Short-term outcome of retrograde tibiotalocalcaneal arthrodesis with a curved intramedullary nail. AB - BACKGROUND: The aim of this study was to investigate the potential clinical benefit of tibiotalocalcaneal arthrodesis (TTCA) with an intramedullary nail with a valgus curve, two compression options, and angle-stable locking. MATERIAL AND METHODS: Patients who had undergone TTCA at two tertiary hospitals were eligible. Patients who had undergone TTCA before the beginning of the study were evaluated retrospectively, then all following patients were examined prospectively. There were 59 TTCAs; 55 patients were available for analysis. Twenty-eight were evaluated retrospectively, 27 prospectively. Main Outcome Measures were an SF-36, Mazur-, and AOFAS ankle-hindfoot rating scores and radiographic examination. RESULTS: Bony union was obtained in 53 patients. Fifty-one patients were satisfied with the outcome. Fifty-one patients had marked subjective improvement in mobility. The mean AOFAS score of the 55 patients at the latest followup was 66.8 (range, 38 to 86). The mean Mazzur score was 68.0 (range, 30 to 83). In the prospective group, the scores were significantly improved: AOFAS score by an average of 39.6 points (p<0.001); Mazur score by an average of 43 points (p<0.001); SF-36 physical component summary score (p<0.001) and mental component summary score also improved (p<0.048). Radiology showed good hindfoot alignment. The complication rate was 25%. CONCLUSION: Compared with the literature, the data obtained in this study show a good outcome and a high rate of bony union, with comparable complication rates. Patient satisfaction was good. However, the patients still had limitations. The clinical benefit of the nail used was confirmed. PMID- 21288435 TI - Plantar pressure with and without custom insoles in patients with common foot complaints. AB - BACKGROUND: Although many patients with foot complaints receive customized insoles, the choice for an insole design can vary largely among foot experts. To investigate the variety of insole designs used in daily practice, the insole design and its effect on plantar pressure distribution were investigated in a large group of patients. MATERIALS AND METHODS: Mean, peak, and pressure-time integral per sensor for 204 subjects with common foot complaints for walking with and without insoles was measured with the footscan(r) insole system (RSscan International). Each insole was scanned twice (precision3D), after which the insole height along the longitudinal and transversal cross section was calculated. Subjects were assigned to subgroups based on complaint and medial arch height. Data were analyzed for the total group and for the separate subgroups (forefoot or heel pain group and flat, normal or high medial arch group). RESULTS: The mean pressure significantly decreased under the metatarsal heads II-V and the calcaneus and significantly increased under the metatarsal bones and the lateral foot (p<0.0045) due to the insoles. However, similar redistribution patterns were found for the different foot complaints and arch heights. There was a slight difference in insole design between the subgroups; the heel cup was significantly higher and the midfoot support lower for the heel pain group compared to the forefoot pain group. The midfoot support was lowest in the flat arch group compared to the high and normal arch group (p<0.05). CONCLUSION: Although the insole shape was specific for the kind of foot complaint and arch height, the differences in shape were very small and the plantar pressure redistribution was similar for all groups. CLINICAL RELEVANCE: This study indicates that it might be sufficient to create basic insoles for particular patient groups. PMID- 21288436 TI - Percutaneous lateral ankle stabilization: an anatomical investigation. AB - BACKGROUND: The current study investigated the topographic anatomy of the percutaneous anatomical lateral ankle stabilization in relation to the neurovascular hindfoot structures. The study should serve as an aid for performance of this new minimally invasive technique. MATERIALS AND METHODS: Eleven cadaver specimens were dissected exposing the nerves, vessels, ligaments and tendons. The portals and transosseous tunnels were performed with Kirschner wires. All distances of the Kirschner wires and the neurovascular structures were measured with reference to clearly identifiable bony landmarks. RESULTS: On the medial side the average distance of the Kirschner wire to the medial calcaneal branch of the tibial nerve was found to be 7 mm (SD+/-4). The medial calcaneal branch was hit twice by the transosseous Kirschner wire. On the lateral side the mean distance of the fibular exit point of the Kirschner wire to the sural nerve was 13 mm (SD+/-4). The closest distance of the superficial peroneal nerve to the footprint of the ATFL averaged 11.5 mm (SD+/-3) and its anterior location in relation to the tip of the fibula was 28 mm (SD+/-8). The posterior tibial artery was found at a mean distance of 41 mm from the perforating Kirschner wire (SD+/ 6). CONCLUSION: The current study introduced a novel percutaneous approach to treat chronic ankle instability that had minimal risk to neurovascular structures in a cadaver model. CLINICAL RELEVANCE: Further clinical studies must be undertaken to identify whether this technique would also be superior when compared with open surgery. PMID- 21288437 TI - Comparison of initial compression of the medial, lateral, and posterior screws in an ankle fusion construct. AB - BACKGROUND: One of the requirements for successful ankle arthrodesis is adequate compression by the fixation across the fusion surfaces. A common screw construct for ankle fusion is three crossed screws from proximal-to-distal. Because the screws are inserted nearly orthogonal to each other, it is possible minimal additional compression is obtainable once the first screw is inserted. The aim of this study was to determine which of the three screws gave the greatest initial compression and theoretically should be inserted first. MATERIALS AND METHODS: Seventeen cadaver limbs were dissected to expose the anterior and posterior aspects of the tibiotalar joint. Three Fuji film templates were created for each ankle joint with a hole to accommodate a 7.0-mm cannulated screw. Each film was tested with a single medial, lateral, or posterior screw. The Fuji films were then analyzed for contact area, percent contact area, and pressure. RESULTS: There was no difference in the total contact area, percent contact area, or pressure generated between the three screws. The mean contact area for all screws was 11% of the joint surface. All three screws had greater contact area and percent contact area over the anterior half of the ankle joint. CONCLUSION: The medial, lateral, and posterior screws were equivalent with respect to contact area, percent contact area, and pressure generated across the tibiotalar joint. All three screws had greater contact area over the anterior half of the joint. Only 11% of the tibiotalar joint surface came in contact following the insertion of a single partially threaded screw. CLINICAL RELEVANCE: In a neutrally aligned ankle arthrodesis the order of screw insertion does not affect the amount of compression ultimately achieved at the fusion site. PMID- 21288438 TI - Effect of impeded medial longitudinal arch drop on vertical ground reaction force and center of pressure during static loading. AB - BACKGROUND: Arch supports commonly used to alleviate foot pain can impede the normal drop of medial longitudinal arch (MLA) thereby altering its function. The purpose of the study was to examine the effect of using arch supports on vertical ground reaction force (GRF) and center of pressure (COP) during simulated midstance while the foot was statically loaded. MATERIALS AND METHOD: Ten healthy young subjects were recruited. Two dimensional (2D) analysis of the MLA was captured for both barefoot (BF) and arch support conditions before and after loading via a custom made weight loading apparatus. The foot was loaded and positioned to simulate the midstance phase of walking. Two-dimensional reflective markers demarcated the MLA and captured with the loaded foot on a force platform. The impeded MLA drop was compared between the unloaded BF, loaded BF and loaded arch support conditions. The vertical GRF, the anterior-posterior and the medial lateral COP displacements were also measured in response to the impeded MLA by the arch supports. RESULTS: The arch supports impeded the MLA drop (p<0.05) and shifted the COP toward the medial side (p<0.05), specifically for the rearfoot (calcaneal segment region), but no changes were determined for the vertical GRF (p>0.05). CONCLUSION: The impedance of MLA drop by the arch support altered the pattern of the ML COP shift in the rearfoot region. CLINICAL RELEVANCE: The use of arch supports may not relieve painful foot conditions that are associated with excessive calcaneal eversion indicated by altering COP shifts in localized foot regions. PMID- 21288439 TI - Stress fracture of the anterior process of the calcaneus associated with a calcaneonavicular coalition: a case report. PMID- 21288440 TI - Reverse distal chevron osteotomy to treat iatrogenic hallux varus after overcorrection of the intermetatarsal 1-2 angle: technique tip. PMID- 21288441 TI - Cincinnati incision approach for posterior ankle and calcaneal pathology: technique tip. PMID- 21288442 TI - Symposium: Adult acquired flatfoot deformity. PMID- 21288443 TI - FootForum: graded levels of responsibility and patient responsibility. PMID- 21288444 TI - A review on immunostimulatory plants. AB - The use of medicinal plants to cure human illness has been practiced from time immemorial. Nowadays, the vast majority of people still rely on their traditional materia medica for their daily health care needs. The use of plant species for treatment of various human ailments has been mentioned in Ayurveda and other Indian literature. Some of these drugs are believed to enhance the natural resistance of body to infection. So there are many plants having immunostimulatory activity. This paper reviews plants which have shown reported immunostimulatory activity. PMID- 21288445 TI - [Traditional Chinese medicine for cancer pain]. AB - Pain is one of the common symptoms of cancer which seriously affects the quality of life of the patients. Cancer pain is mainly treated with the three-step method, biological therapy or nerve block therapy based on antitumor therapy. However, up to 50 percent of patients with cancer-related pain do not receive adequate pain relief, affecting their physical and psychological well-being, and leading to a lower quality of life for the patient after conventional treatment. Clinical observation suggests that traditional Chinese medicine may alleviate cancer-related pain either by oral administration, topical administration, acupuncture or other means with continuing non-addictive and non-drug-resistant qualities. However, scientific evaluation of the efficacy of herbs in the treatment of pain is insufficient; the underlying mechanisms are unclear and, safety and toxicity remain a concern. PMID- 21288446 TI - [Treatment of non-alcoholic fatty liver disease based on traditional Chinese medicine therapies for warming yang to activate qi]. AB - Fatty liver disease is caused by abnormal accumulation of lipids within hepatocytes. According to traditional Chinese medicine (TCM) theory, lipids belong to the category of essence obtained from cereals and the normal distribution of essence relies on the function of spleen yang. When spleen yang is injured, the normal distribution of essence (lipids) will be affected, leading to formation of phlegm retention in the liver. That is the TCM pathogenesis of fatty liver disease. Hence the treatment of fatty liver disease should be concentrated on warming yang to activate qi. With such a treatment, the normal distribution of essence will be restored, essence will be distributed, and phlegm will be dissipated. PMID- 21288447 TI - General issues and precautions in the design for clinical trials of investigational new drugs. AB - The general problems existing in the clinical trials of investigational new drugs involve some key aspects such as the guiding principles, research designs, quality controls and statistical analyses. This paper explores the eight general issues in the clinical trials of investigational new drugs and presents precautionary measures with high operability. Research on the clinical trials of investigational new drugs is a complex project, which should be carried out strictly according to the policies, laws, criteria and operating rules set by related agencies. The neglect of research designs and data analyses will lead clinical trials to failure. PMID- 21288448 TI - [Correlation between T lymphocyte subsets and different syndrome types in patients with influenza A (H1N1): a retrospective study]. AB - OBJECTIVE: To investigate the changes in T lymphocyte subsets in patients with different syndrome types infected by influenza A (H1N1) virus after treatment. METHODS: In this retrospective study, 111 patients with H1N1 influenza were enrolled and divided into three groups according to their syndromes: exterior heat syndrome group (55 cases), exterior cold syndrome group (20 cases) and heat toxin invading lung (HTIL) syndrome group (36 cases). Patients were treated with Western medicine (acetaminophen or ibuprofen suspension), traditional Chinese medicine (herbal medicine according to their syndromes), or a combination of Western medicine and traditional Chinese medicine with patient's intentions. Another 20 healthy people were selected as normal control. Phenotypic features of T lymphocyte subsets in peripheral vein blood of patients before and after treatment were determined by flow cytometry. RESULTS: Before treatment, the numbers of CD3- and CD4-positive T lymphocytes were lower in H1N1 patients with the three types of syndromes than in the normal controls (P<0.01), and the numbers of CD8-positive T lymphocytes were lower in exterior heat syndrome and HTIL syndrome groups than in normal control group (P<0.01). The ratio of CD4 positive to CD8-positive T lymphocytes in exterior cold syndrome group showed no difference as compared with the normal control group, and the ratios of CD4 positive to CD8-positive T lymphocytes in exterior heat syndrome and HTIL syndrome groups were higher than that in the normal control group (P<0.01). After treatment, the numbers of CD4-positive T lymphocytes increased in all the three types of syndromes in patients with H1N1, and showed no difference compared with the normal control group. The numbers of CD3-positive T lymphocytes in patients with exterior heat syndrome and exterior cold syndrome increased, and showed no difference compared with the normal control group. The number of CD3-positive T lymphocytes in H1N1 patients with HTIL syndrome was lower than that in the normal control group (P<0.05), whereas the numbers of CD8-positive T lymphocytes in patients with exterior heat syndrome and HTIL syndrome were lower than that in the normal control group (P<0.05). The ratio of CD4-positive to CD8-positive T lymphocytes in patients with HTIL syndrome was decreased, and displayed no difference as compared with the normal control group. The ratio of CD4-positive to CD8-positive T lymphocytes in patients with exterior heat syndrome was higher than that in the normal control group (P<0.05). CONCLUSION: Analysis of T lymphocyte subsets may provide experimental data to support for syndrome differentiation in traditional Chinese medicine and a sound method to establish syndrome differentiation typing for H1N1. PMID- 21288449 TI - [An analysis of subhealth status based on partial least squares]. AB - OBJECTIVE: To explore the discrimination model of subhealth with statistical method of partial least squares (PLS). METHODS: This study was based on the Subhealth State Rating Scale (SHSRS). A total of 88 subhealth subjects (scoring less than 85 in SHSRS) and 64 healthy people (scoring over 85 in SHSRS) were enrolled randomly. Information regarding the clinical symptoms was screened by stepwise regression as independent variables. Mathematical models were established by leave-one-out in PLS program for subhealth recognition before and after stepwise regression respectively. Accuracy rates were observed and compared by using the Visual Basic 6.0. RESULTS: The practical accuracy rate of PLS models in subhealth recognition was 89.47%, and increased to 92.10% after stepwise regression for variables. CONCLUSION: PLS has certain reference value in establishing subhealth discrimination models. It can also play an important part in item selection of the scale. PMID- 21288450 TI - [A traditional Chinese medicine therapy warming meridians to nourish blood in treating chronic pain due to soft tissue injury of the neck and shoulder: a randomized controlled trial]. AB - BACKGROUND: Pain due to chronic soft tissue injury of the neck and shoulder is a commonly encountered and frequently occurring condition. Traditional Chinese medicine is a common course of treatment for soft tissue injury and may have better therapeutic effects than biomedical options. OBJECTIVE: To evaluate the clinical therapeutic effects of Chinese herbal medicine warming meridians to nourish blood on chronic pain due to soft tissue injury in the neck and shoulder. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: A random and control method was adopted. Sixty-three patients with pain of the neck and shoulder due to chronic soft tissue injury, presenting with blood deficiency and cold coagulation syndrome, were randomly divided into treatment group (n=32) and control group (n=31). There was a drop-out case in treatment group. All the patients were collected from the clinic service of the Department of Rehabilitation at the General Hospital of the People's Liberation Army. Patients received oral and written information about clinical procedures before signing their written informed consent. Patients in the treatment group were treated with Chinese herbal decoctions for warming meridians to nourish blood and cervical traction. Patients in the control group were treated with cervical traction. The course of treatment was 14 days. MAIN OUTCOME MEASURES: A visual analog scale (VAS) was used to record test data in the two groups before and after treatment, and therapeutic effect was compared after treatment between the two groups. RESULTS: After treatment, VAS scores of the treatment group and the control group were decreased as compared with before treatment (t=5.01, P<0.01; t=4.91, P<0.01). Difference of VAS scores between before and after treatment in the treatment group was higher than that in the control group (t=2.44, P0.05). CONCLUSION: The treatment method of warming meridians to nourish blood combined with cervical traction has better therapeutic effect than only applying traction for chronic pain due to soft tissue injury of the neck and shoulder. PMID- 21288451 TI - [Analysis of plasma metabonomics of mini-swines with qi deficiency and blood stasis syndrome due to chronic myocardial ischemia]. AB - OBJECTIVE: To study the changes of plasma metabolites of mini-swines with qi deficiency and blood stasis syndrome due to chronic myocardial ischemia and to explore the relationship between plasma metabonomics and qi deficiency and blood stasis syndrome. METHODS: Twenty-two mini-swines were used in this study and were divided into sham-operation group (n=10) and model group (n=12). Ameroid constrictors were placed around the left anterior descending coronary artery of mini-swines in model group to induce chronic myocardial ischemia. Twelve weeks after Ameroid placement, physical signs, coronary angiography and echocardiography were used to evaluate qi deficiency and blood stasis syndrome; gas chromatography-mass spectrometry (GC-MS) and data mining method were used to analyze plasma metabolites of the mini-swines. RESULTS: Twelve weeks after operation, mini-swines in model group were confirmed with qi deficiency and blood stasis syndrome. Principal component analysis (PCA) found that plasma GC-MS spectra of the two groups were significantly different. Compared with sham operation group, endogenous metabolites in plasma were changed in model group. The levels of lipid metabolites such as glycerol, acetic acid and tricosadiynoic acid, myo-inositol, as well as amino acid metabolite proline were raised, while concentrations of glucose (eg. d-glucose, and a-D-glucoside), amino acid (eg. alanine, phenylalanine, and urea) and lipid metabolites (eg. hexadecanoic acid, propionic acid, butanoic acid, and octadecanoic acid) were declined. CONCLUSION: Significant differences in metabolic spectrum exist in mini-swines with qi deficiency and blood stasis syndrome due to chronic myocardial ischemia and normal mini-swines. Disorders in glucose, amino acid and lipid metabolism result in a deterioration of coronary artery disease; citric acid, glucose, octadecanoic acid, hexadecanoic acid, glycerol and acetic acid are contributory to separation of the healthy from qi deficiency and blood stasis syndrome. These metabolites pattern may be used in clinical diagnosis and treatment of coronary artery disease, and also can provide a new approach to objective research in traditional Chinese medicine syndrome. PMID- 21288452 TI - [Dose-dependent effects of daidzein in regulating bone formation through estrogen receptors and peroxisome proliferator-activated receptor gamma]. AB - OBJECTIVE: To investigate different doses of daidzein (DAI) in regulating bone formation of osteoblasts, and the regulating mechanisms of estrogen receptors (ERs) and peroxisome proliferator-activated receptor gamma (PPARgamma) in bone formation. METHODS: Human fetal osteoblasts (hFOBs) incubated without any treatment were served as controls (control group). The hFOBs were exposed to DAI of 10(-9), 10(-7) and 10(-5) mol/L for 72 h, and to beta-estradiol-17-valerate (E(2)) of 10(-8) mol/L as positive control, respectively. Methyl thiazolyl tetrazolium assay was employed to determine the proliferation status of osteoblasts, and 4-nitrophenyl phosphate disodium salt (PNPP) method was employed to determine the activity of alkaline phosphatase (ALP). ER antagonist ICI 182780 (ICI), ERalpha-selective antagonist methyl-piperidino-pyrazole (MPP) and irreversible PPARgamma antagonist GW9662 (GW) were used to block the corresponding receptor, while hFOBs were exposed to E(2) or different concentrations of DAI for 48 h. MTT assay and PNPP method were used respectively to determine the proliferation status and ALP activity of osteoblasts cultured in vitro. RESULTS: The osteoblast proliferation rate decreased progressively as the dose of DAI increased. Compared with the controls, the osteoblast proliferation rate in the DAI 10(-9) mol/L group increased significantly, while DAI 10(-5) mol/L group decreased significantly (P<0.05). ALP level decreased progressively as the dose of DAI increased, but there was no significant difference between groups (P>0.05). When ERs were blocked by ICI, proliferation rates in the E(2) group and DAI 10(-9), 10(-7) and 10(-5) mol/L groups were 88.16%, 76.30%, 81.18% and 83.19% respectively, which were all significantly lower than before (P<0.05). After ERalpha was blocked by MPP alone, proliferation rates in E(2) group and DAI 10(-9), 10(-7) and 10(-5) mol/L groups were 69.78%, 63.31%, 70.71% and 78.43%, respectively, which were also significantly lower than before (P<0.05). ALP level in the DAI 10(-9) mol/L group decreased significantly when ERalpha was blocked alone. When PPARgamma inhibitor GW was added to the culture system, proliferation rates in E(2) group and DAI 10(-9), 10(-7) and 10(-5) mol/L groups were 103.14%, 96.99%, 112.88% and 122.22%, respectively. Compared with before, proliferation rates in DAI 10(-7) and 10(-5) mol/L groups increased significantly (P<0.05), and ALP level increased significantly (P<0.05) in the DAI 10(-5) mol/L group. CONCLUSION: DAI shows a biphasic effect on osteoporosis, whereby the effect is dose-dependent; a low-dose DAI stimulates proliferation of osteoblasts, while a high-dose DAI inhibits proliferation of osteoblasts. Low-dose DAI mainly acts on ERs, whereas high-dose DAI mainly acts on PPARgamma to inhibit proliferation of osteoblasts and to some extent, acts on ERs to promote the proliferation of osteoblasts. PMID- 21288453 TI - [Effects of Drynaria total flavonoids on apoptosis of osteoblasts mediated by tumor necrosis factor-alpha]. AB - OBJECTIVE: To investigate the influence of Drynaria total flavonoids on proliferation and apoptosis of osteoblasts in tumor necrosis factor-alpha (TNF alpha)- mediated medium, so as to explore the mechanism of Drynaria total flavonoids in preventing and treating osteoporosis of rheumatoid arthritis. METHODS: Twenty Wistar rats with average weight of (200+/-20) g were randomly divided into two groups: blank control group and Qianggu capsule (Drynaria total flavonoids) group. Rats in Qianggu capsule group were fed with 75 mg Qianggu capsule daily for continuous 3 d. One hour after the last feed, blood samples were collected. The in vitro experiment of four groups was designed: blank control serum group, Drynaria total flavonoids-containing serum group, blank control serum plus TNF-alpha group and Drynaria total flavonoids-containing serum plus TNF-alpha group. Methyl thiazolyl tetrazolium method was used to detect the proliferation of osteoblasts. Flow cytometry was used to detect the apoptosis of osteoblasts and real-time fluorescent quantitative polymerase chain reaction to detect the expressions of Bcl-2 and Bax mRNAs in osteoblasts. RESULTS: Compared with the control serum, Drynaria total flavonoids-containing serum promoted the proliferation and decreased the apoptosis of osteoblasts in TNF-alpha-mediated inflammatory environment (P<0.05), and increased the ratio of Bcl-2 mRNA to Bax mRNA. CONCLUSION: In TNF-alpha-mediated inflammatory environment, Drynaria total flavonoids can promote the proliferation and decrease the apoptosis of osteoblasts by improving the ratio of Bcl-2 mRNA to Bax mRNA, which may be one of the mechanisms of Drynaria total flavonoids in preventing and treating osteoporosis of rheumatoid arthritis. PMID- 21288454 TI - [Effects of active ingredients in three kidney-tonifying Chinese herbal drugs on gene expression profile of bone marrow stromal cells from a rat model of corticosterone-induced osteoporosis]. AB - OBJECTIVE: To observe the effects of icariin, psoralen and oleanolic acid, the three active ingredients of Yinyanghuo (Herba Epimedii Brevicornus), Buguzhi (Fructus Psoraleae) and Nuzhenzi (Fructus Ligustri Lucidi), respectively, on gene expression profile of bone marrow stromal cells (BMSCs) from rats with corticosterone-induced osteoporosis. METHODS: Fifty Sprague-Dawley rats were randomly divided into normal control group, untreated group, icariin group, psoralen group and oleanolic acid group (the last three groups are called treatment groups). Rats in untreated group and treatment groups were subcutaneously injected with corticosterone once a day for 14 d while rats in normal control group were injected isodose of olive oil. Rats in the treatment groups were intragastrically administered with icarrin, or psoralen, or oleanolic acid at 20 mg/(kg.d), respectively, 5 d prior to modeling for 19 d. The body weight of rats was recorded on the 1st, 4th, 7th, 11th, and 14th day after modeling, respectively. All rats were sacrificed and the fourth lumbar vertebrae were harvested for micro-CT scanning to evaluate bone mass. BMSCs were obtained ex vivo by the methods of bone marrow adherent culture. The mRNAs of BMSCs were detected by using gene chip technique on the 7th day of culture. RESULTS: There was no significant difference in body weight of rats between untreated group and treatment groups. Micro-CT showed no significant difference in lumbar vertebral morphometry between the untreated and the normal control, or the untreated and treatment groups. In microarray, icariin, psoralen and oleanolic acid changed expressions of 11, 12 and 15 genes compared to the normal level, respectively. These three active ingredients all acted on 5 genes involving osteoblast differentiation, cell cycle regulation, cell metabolism and Notch signal pathway. CONCLUSION: Traditional Chinese herbal drugs with the effect of tonifying the kidney may promote BMSCs to differentiate into osteoblasts by regulating BMSCs cycles and cell metabolism, and show therapeutic effect on osteoporosis. However, the exact mechanisms need to be further studied. PMID- 21288455 TI - [Anti-angiogenic effects of genistein on synovium in a rat model of type II collagen-induced arthritis]. AB - OBJECTIVE: To explore the anti-angiogenic effects of genistein on synovium in a rat model of type II collagen-induced arthritis (CIA). METHODS: Forty SD rats were randomly divided into normal group, model group, genistein group, methotrexate (MTX) group and Gen plus MTX group with 8 rats in each group. Arthritis in rats was induced by subcutaneous injection of type II collagen combined with complete Freund's adjuvant (CFA). On the second day after the injection, 1 mL of suspension liquid of genistein (30 mg/kg body weight, once daily) and MTX (0.2 mg/kg body weight, once a week) were administered by oral gavage respectively. The rats in normal group and model group were administered with normal saline in the same volume. Synovium of knee joints and peripheral serum were collected from the CIA rats. Microvessel density in synovium (MVD) was detected by immunohistochemical method and serum vascular endothelial growth factor (VEGF) and matrix metallopeptidase (MMP)-1, 2 and 9 levels were detected by using Western blotting. RESULTS: Arthritis index score, paw volume of rats in the model group were significantly higher than those in the normal group (P<0.05), which suggested that a model of CIA induced by injection of type II collagen and CFA was successfully constructed. The arthritis index scores of rats in the treatment groups were decreased compared with the model group. The results of Western blotting showed that genistein obviously attenuate the levels of VEGF and MMP-1, 2 and 9 in serum (P<0.05). Immunohistochemical method showed that MVDs in the treatment groups were reduced as compared with the model group. CONCLUSION: The expressions of VEGF and MMP-1, 2 and 9 are related to the synovial pannus formation in CIA rats. The anti-angiogenic activity of genistein may correlate to its inhibitory effect on the expressions of VEGF and MMP-1, 2 and 9 in serum of CIA rats; genistein plus MTX are superior to single agents in treating rheumatoid arthritis. PMID- 21288456 TI - Hepatoprotective activity of methanol extract of Amaranthus caudatus Linn. against paracetamol-induced hepatic injury in rats. AB - OBJECTIVE: Methanol extract of whole plant of Amaranthus caudatus (MEAC) was screened for hepatoprotective potency against paracetamol (PCM)-induced liver damage in Wistar rats. METHODS: Rats of five groups were given sodium carboxy methyl cellulose, PCM, MEAC (200 and 400 mg/kg, respectively) plus PCM, and silymarin plus PCM, respectively. Fourteen days after administration, blood samples were collected for biochemical estimation, then animals were sacrificed and liver samples were collected, weighed and subjected for histopathological studies. Liver marker enzymes such as serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and serum albumin (ALB), total protein (TP), total bilirubin (TB) and direct bilirubin (DB) levels and the markers for oxidative defense namely malondialdehyde (MDA), reduced glutathione (GSH), total thiols (TT) and catalase (CAT) were measured. RESULTS: MEAC at 200 and 400 mg/kg significantly normalized the PCM-induced biochemical changes compared with PCM treated group (P<0.01); increased ALT, AST, TB and DB levels and decreased serum ALB were significantly reversed by the MEAC treatment (200 and 400 mg/kg). Treatment with MEAC (200 and 400 mg/kg) significantly prevented the rise of MDA and TP levels (P<0.01), and prevented the reduction of GSH, CAT and TT levels significantly compared with PCM-treated group (P<0.01). Histopathological examination of the liver sections also proved the hepatoprotective activity of MEAC. CONCLUSION: MEAC shows significant hepatoprotective activity against PCM induced liver damage in rats. This finding supports the use of the plant in ethnomedicine for the treatment of liver diseases. PMID- 21288457 TI - Effects of vitamin E on mercuric chloride-induced renal interstitial fibrosis in rats and the antioxidative mechanism. AB - OBJECTIVE: To observe the effects of vitamin E (Vit E) on mercuric chloride (HgCl2)-induced renal interstitial fibrosis (RIF) in rats and discuss its antioxidative mechanism. METHODS: A total of 32 Sprague-Dawley rats were randomly assigned to three groups: normal group, model group and Vit E group. RIF was induced by oral administration of HgCl(2) at a dose of 8 mg/kg body weight once a day for 9 weeks. Rats in Vit E group were administered with Vit E capsule at 100 mg/kg body weight, and rats in normal and model groups were treated with normal saline. At the end of the 9th week, rats were sacrificed and renal hydroxyproline (Hyp)'s trichrome and periodic acid-silver methenamine (PASM) staining. The activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and contents of glutathione (GSH) and malondialdehyde (MDA) in kidney tissue were tested with commercial kits. The expressions of nuclear factor-kappaB (NF kappaB), inhibitor-kappaB (IkappaB), phospho-IkappaB (p-IkappaB) and tumor necrosis factor-alpha (TNF-alpha) were determined by Western blot. The expression of alpha-smooth muscle actin (alpha-SMA) was assayed by Western blot and immunofluorescent staining. RESULTS: Renal Hyp content, HE, Masson's trichrome and PASM staining results and alpha-SMA expression confirmed development of HgCl2 induced RIF in rats. Oxidative stress markers GSH, GSH-Px and MDA confirmed oxidative stress in RIF rats. Compared with model rats, rats in Vit E group had lower kidney Hyp content (P<0.01). GSH and MDA contents decreased significantly in Vit E group compared with model group (P<0.01). The expressions of NF-kappaB and IkappaB had no significant difference among all groups (P>0.05). In Vit E group, the expressions of p-IkappaB and TNF-alpha decreased significantly compared with model group (P<0.01). The expression of alpha-SMA in Vit E group was also decreased significantly compared with model group (P<0.01). CONCLUSION: Vit E has a protective effect on experimental RIF induced by HgCl(2) in rats and it is related to inhibition of lipid peroxidation, which involves blocking of NF kappaB signaling pathway and the activation of cells producing extracellular matrix. PMID- 21288458 TI - Effects of Chinese herbal medicine Yinsiwei compound on spatial learning and memory ability and the ultrastructure of hippocampal neurons in a rat model of sporadic Alzheimer disease. AB - OBJECTIVE: To study the effects of Chinese herbal medicine Yinsiwei compound (YSW) on spatial learning and memory ability in rats with sporadic Alzheimer disease (SAD) and the ultrastructural basis of the hippocampal neurons. METHODS: A rat model of SAD was established by intracerebroventricular injection of streptozotocin. The rats were divided into six groups: sham-operation group, model group, donepezil control group, and YSW low, medium and high dose groups. Drug interventions were started on the 21st day after modeling and each treatment group was given the corresponding drugs by gavage for two months. Meanwhile, the model group and the sham-operation group were given the same volume of distilled water by gavage once a day for two months. The Morris water maze was adopted to test spatial learning and memory ability of the rats. The place navigation test and the spatial probe test were conducted. The escape latency, total swimming distance and swimming time in the target quadrant of the rats were recorded. Also, the hippocampus tissues of rats were taken out and the ultrastructure of hippocampus neurons were observed by an electron microscope. RESULTS: In the place navigation test, compared with the model group, the mean escape latency and the total swimming distance of the donepezil group and the YSW low, medium and high dose groups were significantly shortened (P<0.05 or P<0.01). In the space probe test, the swimming time of each treatment group in the target quadrant was significantly longer than that of the model group (P<0.05 or P<0.01). For most of the test period, the donepezil group had no significant change compared with the YSW low, medium and high dose groups, respectively. The ultrastructure of the hippocampus neurons under the electron microscope also confirmed the efficacy of the drug treatment. CONCLUSION: Chinese herbal medicine YSW compound can improve spatial learning and memory impairment of rats with SAD. The ultrastructural basis may be that it can protect the microtubule structures of hippocampal neurons and prevent nerve axons from being damaged. PMID- 21288459 TI - Analgesic effects of methanolic extracts of the leaf or root of Moringa oleifera on complete Freund's adjuvant-induced arthritis in rats. AB - OBJECTIVE: Moringa oleifera (family Moringaceae) has been widely used in African folk medicine, and researchers have recently revealed its anti-inflammatory effects in human. This study aimed to evaluate the analgesic properties of methanolic extracts of M. oleifera in complete Freund's adjuvant (CFA)-induced arthritis in rats. METHODS: Adult male Wistar rats, weighing 200 to 220 g, were used in this study. Adjuvant arthritis was induced on day 0 by a single subcutaneous injection of CFA. The prepared extracts from both the root and leaf (200, 300 and 400 mg/kg) of M. oleifera were administered intraperitonealy to rats in the treatment groups 0, 3 and 6 d after CFA injection and indomethacin (5 mg/kg) was used as a positive control drug. Thermal hyperalgesia and mechanical allodynia were evaluated for the analgesic effect 0, 3 and 6 d after CFA injection. Combined methanolic root and leaf extracts of M. oleifera (200 mg/kg) were also tested for the analgesic effect. RESULTS: The potency of the root or leaf extracts of M. oleifera (300 and 400 mg/kg) was similar to that of indomethacin, resulted in significant reductions in both thermal hyperalgesia and mechanical allodynia in rats with CFA-induced arthritis compared with the control group after 3 and 6 d, respectively (P<0.01 or P<0.05). Combined root and leaf extracts (200 mg/kg) of M. oleifera resulted in a significant reduction in thermal hyperalgesia compared with the control group after 3 and 6 d, respectively (P<0.01). Prophylactic injections of combined root and leaf extracts of M. oleifera (200 mg/kg) resulted in a significant reduction in thermal hyperalgesia compared with the control group, the root extracts group, and the leaf extracts group after 3 and 6 d, respectively (P<0.01). CONCLUSION: The methanolic extracts of the root or leaf of M. oleifera are effective in the reduction of pain induced by CFA in rats. A comparison of single and combination therapies of root and leaf extracts also showed a synergistic effect on pain reduction. PMID- 21288460 TI - Comparative study on WHO Western Pacific Region and World Federation of Chinese Medicine Societies international standard terminologies on traditional medicine: Syndrome Differentiation of Heart Diseases. PMID- 21288461 TI - [Translation techniques for explanations of traditional Chinese medicine formula]. PMID- 21288462 TI - Evaluating biological containment strategies for pollen-mediated gene flow. AB - Several biological containment methods have been developed to reduce pollen dispersal; many of them only have a proof of concept in a model plant species. This review focuses on biological containment measures which were tested for their long-term efficiency at the greenhouse or field scale level, i.e. plastid transformation, transgene excission, cleistogamy and cytoplasmic male sterility (CMS). Pollen-mediated gene transfer in transplastomic tobacco could occur at very low frequencies if the predominant mode of inheritance is maternal. Transgene excision from tobacco pollen can be made highly efficient by coexpression of two recombinases. For cleistogamous oilseed rape it was shown that some flowers were partially open depending on genotypes, environment and recording dates. Reports on the stability of CMS in maize and sunflower indicated that there is a high variability for different genotypes under different environmental conditions and over successive years. But for both crop types some stable lines could be selected. These data demonstrate that the biological containment methods discussed are very promising for reducing gene flow but that no single containment strategy provides 100% reduction. However, the necessary efficiency of biological containment methods depends on the level of containment required. The containment level may need to be higher for safety purposes (e.g. production of special plant-made pharmaceuticals), while much lower containment levels may already be sufficient to reach coexistence goals. It is concluded that where pollen-mediated gene flow must be prevented altogether, combinations of complementary containment systems will be required. PMID- 21288463 TI - Gene flow in Prunus species in the context of novel trait risk assessment. AB - Prunus species are important commercial fruit (plums, apricot, peach and cherries), nut (almond) and ornamental trees cultivated broadly worldwide. This review compiles information from available literature on Prunus species in regard to gene flow and hybridization within this complex of species. The review serves as a resource for environmental risk assessment related to pollen mediated gene flow and the release of transgenic Prunus. It reveals that Prunus species, especially plums and cherries show high potential for transgene flow. A range of characteristics including; genetic diversity, genetic bridging capacity, inter- and intra-specific genetic compatibility, self sterility (in most species), high frequency of open pollination, insect assisted pollination, perennial nature, complex phenotypic architecture (canopy height, heterogeneous crown, number of flowers produced in an individual plant), tendency to escape from cultivation, and the existence of ornamental and road side Prunus species suggest that there is a tremendous and complicated ability for pollen mediated gene movement among Prunus species. Ploidy differences among Prunus species do not necessarily provide genetic segregation. The characteristics of Prunu s species highlight the complexity of maintaining coexistence between GM and non-GM Prunus if there were commercial production of GM Prunus species. The results of this review suggest that the commercialization of one GM Prunus species can create coexistence issues for commercial non-GM Prunus production. Despite advances in molecular markers and genetic analysis in agroecology, there remains limited information on the ecological diversity, metapopulation nature, population dynamics, and direct measures of gene flow among different subgenera represented in the Prunus genus. Robust environmental impact, biosafety and coexistence assessments for GM Prunus species will require better understanding of the mechanisms of gene flow and hybridization among species within the Prunus species complex. PMID- 21288464 TI - Diabrotica-resistant Bt-maize DKc5143 event MON88017 has no impact on the field densities of the leafhopper Zyginidia scutellaris. AB - Auchenorrhyncha (planthoppers and leafhoppers) are herbivorous organisms that can ingest Cry proteins from genetically engineered Bt-crops depending on their feeding behaviour. Consequently, they might be directly affected by non-target Bt protein action and more importantly serve as a source of Cry protein exposure to beneficial predatory arthropods. During a three year field study, we surveyed the community of Auchenorrhyncha in Diabrotica-resistant Bt-maize DKc5143-Bt (event MON88017), its near-isogenic line and two conventional hybrids using sweep netting and custom made sticky traps. Zyginidia scutellaris (Herrich-Schaffer) (Hemiptera: Cicadellidae) represented more than 60% of all captured individuals, indicating that it is the dominant leafhopper within the maize community. The statistical analysis of Z. scutellaris data using confidence intervals for the ratios of mean abundance showed no consistent differences between the Bt-maize and the near-isogenic cultivar, indicating no negative impact of event MON88017. The two conventional hybrids Benicia and DK315 exhibited differences in terms of Z. scutellaris densities, which were greater than those observed between MON88017 and the near-isogenic line, but also not consistent over the years. Six more species accounted for an additional 39% of all captured specimens, while ten more species were found only as single individuals and can be considered vagrants from neighbouring habitats. These results inform future field work on the non-target impact of Bt-maize on this group of arthropods and monitoring approaches to assess biological control function by surveying herbivore communities. PMID- 21288465 TI - Assessing the effects of cultivating genetically modified glyphosate-tolerant varieties of soybeans (Glycine max (L.) Merr.) on populations of field arthropods. AB - We assessed the effects of cultivating two genetically modified (GM) glyphosate tolerant soybean varieties (Glycine max (L.) Merr.) derived from Event 40-3-2 and a Japanese conventional variety on arthropods under field conditions, with weed control using glyphosate and conventional weed control for two years. Plant height and dry weight of the conventional variety were significantly larger than those of the GM varieties, but the GM varieties bore more pods than the conventional variety. We found arthropods of nine taxonomic orders (Araneae, Acari, Thysanoptera, Homoptera, Heteroptera, Coleoptera, Diptera, Lepidoptera, and Hymenoptera) on the plants. The arthropod incidence (number per plant unit weight pooled for each taxonomic order) on the soybean stems and leaves generally did not differ significantly between the GM and conventional varieties. However, the incidence of Thysanoptera and total incidence (all orders combined) were greater on the GM variety in the second year. The weed control regimes had no significant influence on the arthropod incidence on the soybean stems and leaves. The number of flower-inhabiting Thysanoptera (the dominant arthropod in the flowers) was not significantly different between the GM and conventional varieties. Asphondylia yushimai (Diptera, Cecidomyiidae) was more numerous on the pods of the GM variety in both years. Neither the soybean variety nor the weed control regime significantly affected the density of soil macro-organisms. However, the glyphosate weed control affected arthropods between the rows of plants by decreasing the abundances of Homoptera, Heteroptera, Coleoptera and Lepidoptera, and diversity of arthropods. PMID- 21288466 TI - Biomechanical aspects of pelvic ring reconstruction techniques: Evidence today. AB - Despite the remarkable advances achieved within the boundaries of the new discipline of Pelvic surgery, pelvic ring disruptions remain challenging and complex problems in orthopaedics. The long-term complications related to reconstruction techniques of these injuries have motivated researchers and surgeons to explore various alternative treatment modalities. Several biomechanical studies have addressed these issues. We performed a medline search including studies published during the last 30 years. Our search yielded 114 studies, 39 of which met the pre-specified inclusion criteria and were further critically analysed and discussed regarding the biomechanical aspects of pelvic ring reconstruction techniques. Based on observational approach and evaluation of the studies specific keypoints are highlighted comprising the clinical translation of the biomechanical supported findings. PMID- 21288467 TI - Treatment of periprosthetic femoral fractures with two different minimal invasive angle-stable plates: Biomechanical comparison studies on cadaveric bones. AB - INTRODUCTION: The introduction of fixed-angle plate osteosynthesis techniques has provided us a further means to treat periprosthetic femoral fractures. The goal of this experimental study is to evaluate the biomechanical properties and stability of treated periprosthetic fractures when using two different plate systems, which vary in the locking mechanism and the screw placement (monocortical or bicortical) with respect to the prosthesis stem. MATERIALS AND METHODS: Using five pairs of formalin-fixed femora, a Vancouver B1 periprosthetic fracture was treated either with a 13-hole LISS((r)) titanium plate using four monocortical periprosthetic screws or with a non-contact bridging plate (NCB) DF((r)) plate using bicortical angle-stable blocked screws positioned ventrally or dorsally to the prosthesis stem. Bones were loaded under axial and cyclic compression with a progressively increased load until failure. Displacement at the osteotomy gap was measured during loading using an ultra-sound measuring system. RESULTS: The mean displacement in the region of the fracture gap was not significantly different at any time during the experiments for the two models. The mean force resulting in subsequent model failure was similar in both models; the failure morphology varied slightly between the models, however. Four of the five LISS((r)) models exhibited either a tear-out of the monocortical screws or a decortication from the bony shaft of the cortical lamella surrounding the screws. On the other side, two of the NCB models showed macroscopically visible fissures along the osteosynthesis plates at the height of the osteotomy gap, and were hence considered implant failures. Only one NCB model showed tear-out of the bicortically placed screws. CONCLUSION: Bicortical screw placement provides more stable anchoring when compared to monocortical screw fixation. However, in relation to the amount of motion at the osteotomy gap and to failure loads, stabilisation of periprosthetic femoral fractures can be equally well achieved using either the LISS((r)) plate with periprosthetic monocortical screws or the NCB plate with poly-axially placed bicortical screws. PMID- 21288468 TI - Estimated prevalence of orthopaedic fractures in Taiwan--A cross-sectional study based on nationwide insurance data. AB - BACKGROUND: Injury is the most common diagnostic category in the emergency unit, but no survey of epidemiological data for trauma or orthopaedic fractures has been made to date in Taiwan. A nationwide study of orthopaedic injuries is therefore necessary and would be of benefit to the Taiwanese population. METHODS: A qualified dataset, provided by a governmental authority, containing the original claims data of 1,000,000 randomly-sampled claimants from the year 2005 in Taiwan was analyzed, and a survey was made of 12 categories of orthopaedic fracture based on the ICD9-CM codes using two sets of data: inpatient data and ambulatory care data. RESULTS: The prevalence of orthopaedic fractures in Taiwan was estimated to be 234.9 (95% CI: 226.8-235.0) per 10,000 for ambulatory visitors and 61.2 (95% CI: 59.7-62.7) per 10,000 for inpatients. After combining these two datasets, the overall prevalence of fractures of various bones were estimated to be as follows (per 10,000): clavicle or scapula, 16.8; humerus, 15.9; radius or ulna, 38.6; carpal, metacarpal or phalanges, 31.5; femoral neck, 17.4; femur, 13.5; patella, 6.1; tibia or fibula, 24.8; ankle, 13.1; tarsal, metatarsal or foot phalanges, 22.7; vertebrae, 42.4; and pelvis, 4.6. The estimated lifetime prevalence of any fracture was calculated at 23.4% for female and 15.8% for male Taiwanese aged 85 years. CONCLUSIONS: The prevalence of various orthopaedic fractures increases with age, and a higher prevalence of orthopaedic fractures but a lower admission rate were found in Taiwan in comparison with other countries. In addition, the estimated lifetime fracture rates for men and women were more equal and lower in Taiwan than in other countries. PMID- 21288469 TI - In memoriam:Ahuva Dovrat, Ph.D. 1947-2010. PMID- 21288470 TI - Schizophrenia and tobacco smoking comorbidity: nAChR agonists in the treatment of schizophrenia-associated cognitive deficits. AB - Tobacco smoking is a preventable cause of morbidity and mortality throughout the world. Very high rates of tobacco smoking are seen in patients with schizophrenia. Importantly, smokers with schizophrenia generally have higher nicotine dependence scores, experience more severe withdrawal symptoms upon smoking cessation, have lower cessation rates than healthy individuals, and suffer from significant smoking-related morbidity and premature mortality compared with the general population. Interestingly, significant disturbances in cholinergic function are reported in schizophrenia patients. The high smoking schizophrenia comorbidity observed in schizophrenia patients may be an attempt to compensate for this cholinergic dysfunction. Cholinergic neurotransmission plays an important role in cognition and is hypothesized to play an important role in schizophrenia-associated cognitive deficits. In this review, preclinical evidence highlighting the beneficial effects of nicotine and subtype-selective nicotinic receptor agonists in schizophrenia-associated cognitive deficits, such as working memory and attention, is discussed. Furthermore, some of the challenges involved in the development of procognitive medications, particularly subtype-selective nicotinic receptor agonists, are also discussed. Amelioration of schizophrenia associated cognitive deficits may help in the treatment of schizophrenia-smoking comorbidity by promoting smoking cessation and thus help in the better management of schizophrenia patients. PMID- 21288471 TI - Concurrent upregulation of postsynaptic L-type Ca(2+) channel function and protein kinase A signaling is required for the periadolescent facilitation of Ca(2+) plateau potentials and dopamine D1 receptor modulation in the prefrontal cortex. AB - Further understanding of how prefrontal cortex (PFC) circuit change during postnatal development is of great interest due to its role in working memory and decision-making, two cognitive abilities that are refined late in adolescence and become altered in schizophrenia. While it is evident that dopamine facilitation of glutamate responses occurs during adolescence in the PFC, little is known about the cellular mechanisms that support these changes. Among them, a developmental facilitation of postsynaptic Ca(2+) function is of particular interest given its role in coordinating neuronal ensembles, a process thought to contribute to maturation of PFC function. Here we conducted whole-cell patch clamp recordings of deep-layer pyramidal neurons in PFC brain slices and determined how somatic-evoked Ca(2+)-mediated plateau depolarizations change throughout postnatal day (PD) 25 (juvenile) to adulthood (PD 80). Postsynaptic Ca(2+) potentials in the PFC increase in duration throughout postnatal development. A remarkable shift from short to prolonged depolarizations was observed after PD 40. This change is reflected by an enhancement of L-type Ca(2+) channel function and postsynaptic PKA signaling. We speculate that such a protracted developmental facilitation of Ca(2+) response in the PFC may contribute to improvement of working memory performance through adolescence. PMID- 21288472 TI - Fluoxetine prevents MPTP-induced loss of dopaminergic neurons by inhibiting microglial activation. AB - Parkinson's disease (PD) is characterized by degeneration of nigrostriatal dopaminergic (DA) neurons. Mice treated with MPTP (1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine) exhibit microglial activation-induced oxidative stress and inflammation, and nigrostriatal DA neuronal damage, and thus serve as an experimental model of PD. Here, we report that fluoxetine, one of the most commonly prescribed antidepressants, prevents MPTP-induced degeneration of nigrostriatal DA neurons and increases striatal dopamine levels with the partial motor recovery. This was accompanied by inhibiting transient expression of proinflammatory cytokines and inducible nitric oxide synthase; and attenuating microglial NADPH oxidase activation, reactive oxygen species/reactive nitrogen species production, and consequent oxidative damage. Interestingly, fluoxetine was found to protect DA neuronal damage from 1-methyl-4-phenyl-pyridinium (MPP(+)) neurotoxicity in co-cultures of mesencephalic neurons and microglia but not in neuron-enriched mesencephalic cultures devoid of microglia. The present in vivo and in vitro findings show that fluoxetine may possess anti-inflammatory properties and inhibit glial activation-mediated oxidative stress. Therefore, we carefully propose that neuroprotection of fluoxetine might be associated with its anti-inflammatory properties and could be employed as novel therapeutic agents for PD and other disorders associated with neuroinflammation and microglia derived oxidative damage. PMID- 21288473 TI - Enduring sensorimotor gating abnormalities following predator exposure or corticotropin-releasing factor in rats: a model for PTSD-like information processing deficits? AB - A deficit in prepulse inhibition (PPI) can be one of the clinically observed features of post-traumatic stress disorder (PTSD) that is seen long after the acute traumatic episode has terminated. Thus, reduced PPI may represent an enduring psychophysiological marker of this illness in some patients. PPI is an operational measure of sensorimotor gating and refers to the phenomenon in which a weak stimulus presented immediately before an intense startling stimulus inhibits the magnitude of the subsequent startle response. The effects of stress on PPI have been relatively understudied, and in particular, there is very little information on PPI effects of ethologically relevant psychological stressors. We aimed to develop a paradigm for evaluating stress-induced sensorimotor gating abnormalities by comparing the effects of a purely psychological stressor (predator exposure) to those of a nociceptive physical stressor (footshock) on PPI and baseline startle responses in rats over an extended period of time following stressor presentation. Male Sprague-Dawley rats were exposed (within a protective cage) to ferrets for 5 min or left in their homecage and then tested for PPI immediately, 24 h, 48 h, and 9 days after the exposure. The effects of footshock were evaluated in a separate set of rats. The effects seen with stressor presentation were compared to those elicited by corticotropin-releasing factor (CRF; 0.5 and 3 MUg/6 MUl, intracerebroventricularly). Finally, the effects of these stressors and CRF administration on plasma corticosterone were measured. PPI was disrupted 24 h after ferret exposure; in contrast, footshock failed to affect PPI at any time. CRF mimicked the predator stress profile, with the lowdose producing a PPI deficit 24 h after infusion. Interestingly, the high dose also produced a PPI deficit 24 h after infusion, but with this dose, the PPI deficit was evident even 9d later. Plasma corticosterone levels were elevated acutely (before PPI deficits emerged) by both stressors and CRF, but returned to normal control levels 24 h later, when PPI deficits were present. Thus, predator exposure produces a delayed disruption of PPI, and stimulation of CRF receptors recapitulates these effects. Contemporaneous HPA axis activation is neither necessary nor sufficient for these PPI deficits. These results indicate that predator exposure, perhaps acting through CRF, may model the delayed-onset and persistent sensorimotor gating abnormalities that have been observed clinically in PTSD, and that further studies using this model may shed insight on the mechanisms of information-processing deficits in this disorder. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'. PMID- 21288474 TI - Irving Page Lecture: 5-HT(2A) serotonin receptor biology: interacting proteins, kinases and paradoxical regulation. AB - 5-Hydroxytryptamine(2A) (5-HT(2A)) serotonin receptors are important pharmacological targets for a large number of central nervous system and peripheral serotonergic medications. In this review article I summarize work mainly from my lab regarding serotonin receptor anatomy, pharmacology, signaling and regulation. I highlight the role of serotonin receptor interacting proteins and the emerging paradigm of G-protein coupled receptor functional selectivity. PMID- 21288476 TI - Microtubule association of a neuronal RNA-binding protein HuD through its binding to the light chain of MAP1B. AB - RNA-binding proteins (RBPs) play a vital role in the post-transcriptional regulation of gene expression during neuronal differentiation and synaptic plasticity. One such RBP family, the neuronal Hu protein family, serves as an early marker of neuronal differentiation and targets several mRNAs containing adenine/uridine-rich elements. Recently, we reported that one of the neuronal Hu proteins, HuD stimulates cap-dependent translation through interactions with eIF4A and poly (A) tail. Nevertheless, little is known with respect to how neuronal Hu proteins contribute to the local translation of target mRNAs in neuronal differentiation. Here, we found that neuronal Hu proteins, but not the ubiquitously expressed HuR protein, directly interact with the light chain of microtubule-associated proteins MAP1B (LC1). We also show that HuD simultaneously binds both RNA and LC1 in vitro and that it tightly associates with microtubules in cells in an LC1-dependent manner, raising the possibility that HuD recruits target mRNAs to microtubules. These results uncover the neuronal binding partners for neuron-specific Hu proteins and suggest the involvement of Hu proteins in microtubule-mediated regulation of mRNA expression within neuronal processes. PMID- 21288475 TI - Cannabinoid receptor activation modifies NMDA receptor mediated release of intracellular calcium: implications for endocannabinoid control of hippocampal neural plasticity. AB - Chronic activation or inhibition of cannabinoid receptors (CB1) leads to continuous suppression of neuronal plasticity in hippocampus and other brain regions, suggesting that endocannabinoids may have a functional role in synaptic processes that produce state-dependent transient modulation of hippocampal cell activity. In support of this, it has previously been shown in vitro that cannabinoid CB1 receptors modulate second messenger systems in hippocampal neurons that can regulate operation of intracellular processes including receptors which release calcium from intracellular stores. Here we demonstrate in hippocampal slices a similar endocannabinoid action on excitatory glutamatergic synapses via modulation of NMDA-receptor mediated intracellular calcium levels in confocal imaged neurons. Calcium entry through glutamatergic NMDA-mediated ion channels increases intracellular calcium concentrations by modifying release from ryanodine-sensitive channels in endoplasmic reticulum. The studies reported here show that NMDA-elicited increases in Calcium Green fluorescence are enhanced by CB1 receptor antagonists (i.e., Rimonabant), and inhibited by CB1 agonists (i.e., WIN 55,212-2). Suppression of endocannabinoid breakdown by either reuptake inhibition (AM404) or fatty-acid amide hydrolase inhibition (URB597) produced suppression of NMDA-elicited calcium increases comparable to WIN 55,212-2, while enhancement of calcium release provoked by endocannabinoid receptor antagonists (Rimonabant) was shown to depend on the blockade of CB1receptor mediated de phosphorylation of Ryanodine receptors. Such CB1 receptor modulation of NMDA elicited increases in intracellular calcium may account for the respective disruption and enhancement by CB1 agents of trial-specific hippocampal neuron ensemble firing patterns during performance of a short-term memory task, reported previously from this laboratory. PMID- 21288477 TI - Quiescence regulators for hematopoietic stem cell. AB - Hematopoietic stem cell (HSC) either stays in quiescence or proliferates toward differentiation for the production of mature blood cells, or toward self-renewal for giving rise to itself. In order to both maintain a supply of mature blood cells and not exhaust HSCs throughout the lifetime of an individual, under steady state, most HSCs remain quiescent and only a small number enter the cell cycle. Quiescence of HSCs is not only critical for protecting the stem cell compartment and sustaining stem cell pools over long periods, but it is also critical for protecting stem cells by minimizing their accumulation of replication-associated mutations. The balance between quiescence and proliferation is tightly controlled by both HSC-intrinsic and -extrinsic mechanisms. In recent years, through reductionistic strategies, a wide variety of molecules or pathways critical for HSC quiescence regulation have been identified. This regulation network involves both positive and negative regulators. Understanding quiescence regulation in HSC is of great importance not only for understanding the physiological foundation of HSCs, but also for understanding the pathophysiological origins of many related disorders. In this article, I will briefly review the current advance in the quiescence regulators for the HSCs. PMID- 21288478 TI - Flt3-ITD alters chemotherapy response in vitro and in vivo in a p53-dependent manner. AB - OBJECTIVE: The FLT3 internal tandem duplication (Flt3-ITD) confers a worse prognosis for patients with acute myeloid leukemia (AML); however, the mechanisms involved are unknown. As AML is treated with cytarabine (Ara-C) and an anthracycline, we sought to determine the effects of the Flt3-ITD on response to these agents. MATERIALS AND METHODS: A genetically defined mouse model of AML was used to examine the effects of the Flt3-ITD on response to cytarabine and doxorubicin in vitro and in vivo. RESULTS: In vitro, the Flt3-ITD conferred resistance to doxorubicin and doxorubicin plus Ara-C, but sensitivity to Ara-C alone. This resistance was reversible by the Flt3-ITD inhibitor sorafenib. The Flt3-ITD did not affect DNA damage levels after treatment, but was associated with increased levels of p53. The p53 response was critical to the observed changes as the Flt3-ITD had no effect on chemotherapy response in the setting of p53 null AML. In vivo, the Flt3-ITD accelerated engraftment that was partially reversible by Ara-C but not doxorubicin. Additionally, Ara-C provided a significant reduction in disease burden and a survival advantage that was not increased by the addition of doxorubicin. Doxorubicin alone led to only minimal disease reduction and no survival benefit. CONCLUSIONS: These data demonstrate that the Flt3-ITD confers sensitivity to Ara-C, but resistance to doxorubicin in a manner that depends on p53. Thus, patients with Flt3-ITD positive AML may not benefit from treatment with an anthracycline. PMID- 21288479 TI - The role of microRNAs in self-renewal and differentiation of mesenchymal stem cells. AB - MicroRNAs (miRNAs) are short non-coding RNAs involved in post-trascriptional regulation of gene expression and diverse biological activities. They are crucial for self-renewal and behavior of embryonic stem cells, but their role in mesenchymal stem cells has been poorly understood. Recently emerging evidence suggests that miRNAs are closely involved in controlling key steps of mesenchymal stem cell differentiation into certain cell lineages. This review focuses on miRNAs identified recently that regulate mesenchymal stem cell differentiation and other activities. PMID- 21288480 TI - Characterization of rickettsial adhesin Adr2 belonging to a new group of adhesins in alpha-proteobacteria. AB - BACKGROUND: Rickettsia prowazekii is the etiological agent of epidemic typhus and is an obligate intracellular bacterium that grows as a parasite freely within the cytoplasm of a eukaryotic host cell. Previous studies have shown that rOmpA and rOmpB which belong to the family of rickettsial cell surface antigens are involved in vitro in the adhesion of Rickettsiae to epithelial cells. Recently, two putative rickettsial adhesins have been identified using high resolution 2D PAGE coupled with mass spectrometry. In this study, we further characterize and describe the adhesin Adr2 from R. prowazekii. METHODOLOGY/PRINCIPAL FINDINGS: Using an overlay assay coupled with mass spectrometry two adhesins, Adr1 (RP827) and Adr2 (RP828), were identified from the R. prowazekii proteome Recombinant R. prowazekii Adr2 was expressed through fusion with Dsbc in Escherichia coli, purified and concentrated, thus allowing production of specific monoclonal antibodies, as confirmed by western blot assays. Finally, inhibition of rickettsiae-induced cytotoxicity with monoclonal anti-Adr2 antibody has showed a greatest impact on bacterial cell entry at 8 h post-infection (ca50%) and then decreased progressively to attempt 18% of inhibition at day 7. These, correlated to the inhibition of rickettsiae-induced cytotoxicity with monoclonal anti-rOmpB antibody. Thus, Adr2 is sufficient to mediate R. prowazekii entry into the cell at early stage of mammalian cell infection. CONCLUSIONS: Our results suggest that R. prowazekii Adr2 could be the main actor promoting the entry of rickettsiae into the host cells. The present study opens the framework for future investigations for better understanding of the Adr2 -mediated mechanisms involved in adhesion/invasion or intracellular survival of R. prowazekii. PMID- 21288481 TI - Acinetobacter baumannii-induced lung cell death: role of inflammation, oxidative stress and cytosolic calcium. AB - A growing body of evidence supports the notion that susceptible Acinetobacter baumannii strain ATCC 19606 induces human epithelial cells death. However, most of the cellular and molecular mechanisms associated with this cell death remain unknown, and also the degree of the cytotoxic effects of a clinical panresistant strain compared with a susceptible strain has never been studied. Due to the role of proinflammatory cytokine release, oxidative stress and cytosolic calcium increase in the cell death-induced by other Gram-negative bacteria, we investigated whether these intracellular targets were involved in the cell death induced by clinical panresistant 113-16 and susceptible ATCC 19606 strains. Data presented here show that 113-16 and ATCC 19606 induce time-dependent cell death of lung epithelial cells involving a perturbation of cytosolic calcium homeostasis with subsequent calpain and caspase-3 activation. Prevention of this cell death by TNF-alpha and interleukin-6 blockers and antioxidant highlights the involvement of proinflammatory cytokines and oxidative stress in this phenomenon. These results demonstrate the involvement of calpain calcium-dependent in cell death induced by A. baumannii and the impact of proinflammatory cytokines and oxidative stress in this cell death; it is noteworthy to stress that some mechanisms are less induced by the panresistant strain. PMID- 21288482 TI - Homologous gene clusters of nicotine catabolism, including a new omega-amidase for alpha-ketoglutaramate, in species of three genera of Gram-positive bacteria. AB - Gram-positive soil bacteria Arthrobacter nicotinovorans, Nocardioides sp. JS614 and Rhodococcus opacus were shown to contain similarly organized clusters of homologous genes for nicotine catabolism. An uncharacterized gene of a predicted nitrilase within these gene clusters was cloned from A. nicotinovorans and biochemical data unexpectedly showed that the protein exhibited omega-amidase activity toward alpha-ketoglutaramate. Structural modelling of the protein suggested the presence of the catalytic triad Cys-Glu-Lys, characteristic of this class of enzymes, and supported alpha-ketoglutaramate as substrate. A ketoglutaramate could be generated by hydrolytic cleavage of the C-N bond of the trihydroxypyridine ring produced by nicotine catabolism in these bacteria. This omega-amidase, together with glutamate dehydrogenase, may form a physiologically relevant enzyme couple, leading to transformation of metabolically inert alpha ketoglutaramate derived from trihydroxypyridine into glutamate, a central compound of nitrogen metabolism. PMID- 21288483 TI - Dichloromethane-degrading bacteria in the genomic age. AB - Dichloromethane (DCM) is a volatile toxic halogenated solvent mainly produced and used industrially. DCM-degrading bacteria have long been models of choice for studying bacterial dehalogenation metabolism at the physiological, biochemical and genetic levels, and have also been used in bioremediation processes. DCM degrading strains isolated in recent years will be discussed in the context of enzymes known to catalyze dehalogenation of DCM. Insights into the modes of adaptation of bacteria to DCM gained by comparative genomic analysis, highlight the importance of horizontal gene transfer in the dissemination of genes for DCM metabolism in the environment. PMID- 21288484 TI - Anaerobic ammonium oxidation mediated by Mn-oxides: from sediment to strain level. AB - Nitrite and (29)N(2) productions in slurry incubations of anaerobically sediment after (15)NO(3) or (15)NH(4) labelling in the presence of Mn-oxides suggested that anaerobic Mn-oxides mediated nitrification coupled with denitrification in muddy intertidal sediments of Arcachon Bay (SW Atlantic French coast). From this sediment, bacterial strains were isolated and physiologically characterized in terms of Mn-oxides and nitrate reduction as well as potential anaerobic nitrification. One of the isolated strain, identified as Marinobacter daepoensis strain M4AY14, was a denitrifier. Nitrous oxide production by this strain was demonstrated in the absence of nitrate and with Mn-oxides and NH(4) amendment, giving indirect proof of anaerobic nitrate or nitrite production. Anaerobic Mn oxide-mediated nitrification was confirmed by (29)N(2) production in the presence of (15)NO(3) and (14)NH(4) under denitrifying conditions. Anaerobic nitrification by M4AY14 seemed to occur only in the absence of nitrate, or at nitrate levels lower than that of Mn-oxides. Most of the other isolates were affiliated with the Shewanella genus and were able to use both nitrate and Mn-oxides as electron acceptors. When both electron acceptors were present, whatever their concentrations, nitrate and Mn-oxide reduction co-occurred. These data indicate that bacterial Mn-oxide reduction could be an important process in marine sediments with low oxygen concentrations, and demonstrate for the first time the role of bacteria in anaerobic Mn-mediated nitrification. PMID- 21288485 TI - Production of pristane and phytane in the marine environment: role of prokaryotes. AB - This paper reviews studies dealing with the formation of pristane and phytane in the marine environment and focuses on the role played by prokaryotes in these processes. Prokaryotes may notably: (i) contribute to the formation of pristane during invertebrate feeding; (ii) hydrogenate isomeric pristenes and phytenes arising from degradation of the chlorophyll phytyl side-chain and/or alpha tocopherol (vitamin E) to pristane and phytane, respectively; and (iii) convert trimeric oxidation products of alpha-tocopherol (produced abiotically in the water column and in the oxic zone of sediments) to pristane. Moreover, thermal maturation of isoprenoid components of archaea (isopranyl glyceryl ethers) also constitutes another potential source of pristane and phytane in thermally mature sediments. Prokaryotes thus appear to play a key role in formation of these isoprenoid alkanes in the marine environment. PMID- 21288486 TI - Impact of pH on bacterial growth and activity of recent fluoroquinolones in pooled urine. AB - Acidification of urine is widely recommended for prevention and treatment of urinary tract infections. We set out to describe the effect of modification of pH on bacterial growth of relevant bacteria as well as on activity of modern fluoroquinolones in urine in vitro. Bacterial growth of Escherichia coli ATCC 25922 and Klebsiella oxytoca ATCC 700324 was determined in pooled human urine adjusted to pH levels between 5.0 and 8.0. Minimal inhibitory concentrations (MICs) and time-kill curves were performed for ciprofloxacin, levofloxacin and moxifloxacin in pH-adjusted urine and Mueller-Hinton Broth (MHB). Uptake of radioactive labeled [C(14)]-ciprofloxacin into bacterial cells was investigated at different pHs. While no difference in bacterial growth of E. coli and K. oxytoca was observed at pH values between 5.0 and 8.0, acidification of urine led to major impairment of antimicrobial activity of all tested fluoroquinolones, indicated by an up to 40-fold increase in MIC compared to MHB and nearly total neutralization of activity in time-kill experiments. The most probable mechanism behind this observation may have been reduced uptake of fluoroquinolones into bacterial cells, as indicated by bacterial uptake of [C(14)]-ciprofloxacin and a reversibility of the effect. The observed reduction in activity of modern fluoroquinolones confirms previous observations from older compounds. PMID- 21288487 TI - Gamma-caprolactone stimulates growth of quorum-quenching Rhodococcus populations in a large-scale hydroponic system for culturing Solanum tuberosum. AB - Bacteria degrading quorum sensing (QS) signals have been proposed as biocontrol agents able to quench QS-dependent expression of virulence symptoms caused by Pectobacterium on potato plants. We report here that gamma-caprolactone (GCL) treatment stimulated growth of the native QS-degrading bacterial community in an industrial plant hydroponic system for culturing Solanum tuberosum. Post-GCL treatment, QS-degrading bacteria were mainly identified as Rhodococcus isolates, while Agrobacterium isolates dominated under similar untreated conditions. Most of the assayed Rhodococcus isolates exhibited efficient biocontrol activity for protecting potato tubers. Analytical chemistry approach revealed the rapid degradation of GCL introduced in the plant cultures. PMID- 21288488 TI - Evolutionary genomics of Entamoeba. AB - Entamoeba histolytica is a human pathogen that causes amoebic dysentery and leads to significant morbidity and mortality worldwide. Understanding the genome and evolution of the parasite will help explain how, when and why it causes disease. Here we review current knowledge about the evolutionary genomics of Entamoeba: how differences between the genomes of different species may help explain different phenotypes, and how variation among E. histolytica parasites reveals patterns of population structure. The imminent expansion of the amount genome data will greatly improve our knowledge of the genus and of pathogenic species within it. PMID- 21288489 TI - Molecular analysis of nutritional and hormonal regulation of female reproduction in the red flour beetle, Tribolium castaneum. AB - Female reproduction includes maturation of oocytes and the synthesis of yolk proteins (vitellogenin, Vg) in the fat body and their deposition into the oocytes. Our recent studies showed that juvenile hormone (JH) regulates Vg synthesis and 20-hydroxyecdysone (20E) regulates oocyte maturation in the red flour beetle (Tribolium castaneum). Here, we report on the role of nutritional signaling on vitellogenesis and oogenesis. Comparison of gene expression between fed and starved beetles by microarray analysis showed the up-regulation of genes involved in energy homeostasis and down-regulation of genes involved in egg production in the starved beetles. The RNA interference (RNAi) aided knock-down in the expression of genes involved in insulin and TOR signaling pathways showed that both these signaling pathways play key roles in Vg synthesis and oocyte maturation. Starvation of female beetles resulted in a block in Vg synthesis but not in the progression of primary oocyte development to the resting stage. Feeding after starvation induced Vg synthesis and the progression of primary oocytes from the resting stage to the mature stage. However, in the beetles where JH or 20E synthesis or action was blocked by RNAi, both Vg synthesis and oocyte maturation were affected suggesting that both these hormones (JH and 20E) and nutritional signaling and their cross-talk regulate vitellogenesis and oogenesis. PMID- 21288490 TI - PoCRIP1, Paralichthys olivaceus cysteine-rich intestinal protein 1: molecular characterization, expression analysis upon Edwardsiella tarda challenge and a possible role in the immune regulation. AB - Cysteine-rich intestinal protein (CRIP) is a LIM domain protein containing a zinc finger motif and plays a role in the regulation of the inflammatory immune response. In the present study, we isolated a CRIP1 cDNA, designated PoCRIP1, from an olive flounder Paralichthys olivaceus intestine cDNA library by EST analysis. The PoCRIP cDNA consists of 421 bp with a polyadenylation signal sequence, AATAAA, and a poly(A) tail; it encodes a polypeptide of 76 amino acids containing a double zinc-finger motif (Cys(2)HisCys and Cys(4) sequences). The deduced amino acid sequence of PoCRIP1 showed 75.3-94.7% homology with CRIP1s of other species, including mammals. The PoCRIP1 transcript was highly expressed in the intestine and pyloric ceca and moderately expressed in the gill, heart, kidney, liver, muscle, spleen, skin, and stomach of normal conditioned flounder. Inducible expression of the PoCRIP1 transcript was observed in flounder challenged with Edwardsiella tarda, an economically important pathogen for aquaculture of flounder. Over-expression of PoCRIP1 augmented p65-driven flounder IL-6 promoter activity in HINAE cells. These results suggest that PoCRIP1 may function in the immune response of the flounder through the regulation of cytokine expression. PMID- 21288491 TI - Molecular cloning and characterization of caspase-3 in large yellow croaker (Pseudosciaena crocea). AB - Caspases-3, a member of the cysteine-aspartic acid protease (caspase) family, plays critical roles in the execution of apoptotic pathway. In this study, a caspase-3 homologue was cloned and characterized from large yellow croaker (Pseudosciaena crocea). The full-length cDNA of large yellow croaker caspase-3 (Lyccasp3) is 2222bp with an open reading frame of 858 bp encoding a polypeptide of 285 amino acids (aa). Lyccasp3 exhibited a conserved caspase-3 architecture including a prodomain, a large subunit and a small subunit. Moreover, several residues known to be critical in the caspase-3 catalytic centre and binding pocket, as well as the active-site pentapeptide motif Q(172)ACRG(176) were present in the deduced Lyccasp3. Recombinant Lyccasp3 (rLyccasp3) produced in Escherichia coli exhibited obvious hydrolyzing activity against synthetic peptide substrate Ac-DEVD-pNA. The Lyccasp3 was constitutively expressed in all the tissues examined, although the expression levels varied from tissue to tissue. Real-time PCR analysis revealed that Lyccasp3 transcript in spleen and kidney was quickly increased after stimulation with either poly (I:C) or inactivated trivalent bacterial vaccine. Enzyme activities of Lyccasp3 were also up-regulated in these two tissues post-stimulation when analyzed by hydrolyzing activity assay. Since the activity of large yellow croaker caspase-9 (Lyccasp9) in the spleen and kidney also increased when the fish was stimulated with the poly(I:C) or bacterial vaccine [1], we therefore proposed that the intrinsic apoptotic pathway, which is initiated by caspase-9 and executed by caspase-3, was activated during the immune response induced by poly(I:C) or bacterial vaccine in large yellow croaker. PMID- 21288492 TI - Identification of a retinoic acid-inducible gene I from grass carp (Ctenopharyngodon idella) and expression analysis in vivo and in vitro. AB - RIG-I (retinoic acid inducible gene-I) is a key mediator of antiviral immunity, able to couple detection of infection by RNA and DNA viruses to the induction of interferons. In the present study, a RIG-I gene from grass carp Ctenopharyngodon idella (CiRIG-I) was isolated and characterized. The full-length cDNA of CiRIG-I was of 3198 bp and encoded a polypeptide of 947 amino acids with an estimated molecular mass of 108,730 Da and a predicted isoelectric point of 5.85, including six main overlapping structural domains: two CARDs (caspase activation and recruitment domain), one ResIII (conserved restriction domain of bacterial type III restriction enzyme), one DEXDc (DEAD/DEAH box helicase domain), one HELICc (helicase superfamily c-terminal domain) and one RD (regulatory domain). The CiRIG-I mRNA was widespread expression in the tested 15 tissues by semi quantitative RT-PCR (sqRT-PCR) assay. The CiRIG-I expressions in spleen and liver were significantly induced following grass carp reovirus (GCRV) infection. CiRIG I mRNA expression was rapidly and significantly up-regulated in vitro after GCRV infection, and the CiRIG-I transcripts were also significantly enhanced in vitro post the synthetic double stranded RNA polyinosinic-polycytidylic potassium salt (poly(I:C)) stimulation. These results collectively suggested that CiRIG-I was an inducible protein, involved in the antiviral innate immune defense to GCRV in grass carp, and laid the foundation for the further mechanism research of RIG-I in fishes. PMID- 21288493 TI - QseBC controls flagellar motility, fimbrial hemagglutination and intracellular virulence in fish pathogen Edwardsiella tarda. AB - The inter-kingdom communication with the mammalian hosts mediated by autoinducer 3 (AI-3)/epinephrine (Epi)/norepinephrine (NE), and transduced by two-component systems QseBC has recently been described. As a fish pathogen and opportunistic pathogen for human beings, Edwardsiella tarda develops surface structures such as flagellar and fimbriae to cause different hemagglutination phenotypes and serotypes and initiate pathogen-host recognition and invasion process. E. tarda survives within macrophages in fish using type III secretion system (TTSS). Here, the genes of E. tarda two-component system, qseB and qseC, were found to be co transcribed. Phylogenetic analysis indicated that evolution of QseC strongly correlated to different host niches. Compared with the wild type and their complemented strains, DeltaqseB and DeltaqseC mutants exhibited significant impaired flagellar motilities. Mammalian Epi was able to stimuli the flagellar motility in E. tarda via QseBC. Hemagglutination caused by fimbriae was induced in DeltaqseB but repressed in DeltaqseC. Disruption of qseB or qseC down regulated the intracellular expressions of TTSS elements EseB and EsaC, and impaired their intracellular survival capabilities as well as in vivo competitive abilities. Furthermore, in vitro tests indicated that expression of EseB was induced by Epi via QseBC. Our results revealed that the QseBC system modified the virulence-related surface structures (flagellum, fimbriae and secretion system) and that hormone might stimulate the virulence of the pathogen in fish. PMID- 21288494 TI - A lytic mechanism based on soluble phospholypases A2 (sPLA2) and beta-galactoside specific lectins is exerted by Ciona intestinalis (ascidian) unilocular refractile hemocytes against K562 cell line and mammalian erythrocytes. AB - Hemocytes from the ascidian Ciona intestinalis exert in vitro Ca2+-dependent cytotoxic activity toward mammalian erythrocytes and K562 cells. To examine the lytic mechanism, hemocyte populations were separated (B1-B6 bands) through a Percoll discontinuous density gradient, the hemocyte cytotoxic activity (HCA) and the lytic activity of the hemocyte lysate supernatant (HLS) were assayed. In addition the separated hemocytes were cultured and the cell-free culture medium (CFM) assayed after 3 h culture. Results support that unilocular refractile hemocytes (URGs), enriched in B5, are cytotoxic. The B5-HLS contains lysins and the activity of B5-CFM shows that lysins can be released into a culture medium. The B5 activity was blocked by D-galactose, alpha-lactose, lactulose, LacNAc, thiodigalactoside (TDG), L-fucose, D-mannose, D-glucose, sphingomyelin (SM), and soluble phospholipase A2 (sPLA2) inhibitors (dibucain, quinacrine). Accordingly, HLS chemico-physical properties (alkaline medium, high thermostability, Ca2+ dependence, trypsin treatment, protease inhibitors) and SEM observations of the affected targets suggested that sPLA2 could be responsible for changes and large alterations of the target cell membrane. An apoptotic activity, as recorded by a caspase 3, 7 assay, was found by treating K562 cells with very diluted HLS. A lytic mechanism involving sPLA2 and lectins promptly released by URGs and morula cells respectively is suggested, whereas target cell membrane SM could be a modulator of the enzyme activity. PMID- 21288495 TI - Busulfan dosing in children with BMIs >= 85% undergoing HSCT: a new optimal strategy. AB - Childhood obesity has more than tripled in the past 30 years. The prevalence of overweight and obese children has also increased in the pediatric cancer setting, causing substantial concern over proper chemotherapeutic dosing in this population. The purpose of this study was to determine if children with an increased body mass index (BMI) have an alteration in busulfan pharmacokinetics during hematopoietic stem cell transplant (HSCT) conditioning. We retrospectively reviewed data on busulfan pharmacokinetics (PK) on HSCT subjects (subjects were part of a prospective study previously reported by our group at Children's Memorial Hospital) to determine appropriateness of dosing. Subjects were divided into appropriate BMI categories (<25th percentile, 25th-85th percentile, >= 85th percentile) and busulfan PK dosing was analyzed (test dose, regimen dose, area under the curve [AUC], and clearance). The dosing based on PK test dose data of children with BMI >= 85% was compared against the package insert dosing recommendations of using adjusted ideal body weight (AIBW) in obese patients to determine which dosing schema was most accurate. Children with high BMIs had higher AUCs when dosing on actual weight then their normal or low BMI counterparts. This indicates that children with a high BMI require less drug (2.9 mg/kg using actual body weight) to achieve the same AUC as children with normal BMI (4.0 mg/kg) or low BMI (3.6 mg/kg). Using the recommended AIBW dosing schema, 53% of the patients with high BMIs would have had regimen dose AUCs >= 20% over/under the target; whereas with the PK test dose method, only 16% of the patients with high BMIs had regimen dose AUCs >= 20% over/under the target. PK testing continues to be the gold standard for busulfan dosing in children. Particular vigilance should be paid to PK monitoring in high BMI categories because of the potential risk of imprecise dosing when using the AIBW schema. PMID- 21288496 TI - Proliferative responses of Brugia malayi TPX-1 and its epitopic peptide(29-43) in an endemic population of human lymphatic filariasis. AB - Although the antioxidant thioredoxin peroxidase (TPX) is a putative target exploited in vaccine studies of lymphatic filariasis, the high sequence homology with host peroxiredoxins remains a great concern. The emergence of immunomics offers a powerful tool for novel vaccine design. Further, due to the cellular hypo-response in filariasis, analysis of T epitope repertoire becomes imperative in disease control. Here, we report the cellular responses of filarial TPX-1 and the identification of T epitope (29-43) in the host non-homologous region. The strong proliferative responses induced by the peptide mimetic in mice splenocytes and human PBMC's prove the existence of T epitope recognized in endemic population. PMID- 21288497 TI - Unilateral agenesis of the internal carotid artery. AB - Unilateral agenesis of the internal carotid artery (ICA) is an extremely rare anomaly. Diagnosis is often incidental in a radiological examination. Recognition of this anomaly has important clinical implications because other life threatening conditions can be associated and it must be taken into account when planning carotid surgery. We report a case of 64-year-old man with agenesis of the ICA. PMID- 21288498 TI - Using the visual world paradigm to study language processing: a review and critical evaluation. AB - We describe the key features of the visual world paradigm and review the main research areas where it has been used. In our discussion we highlight that the paradigm provides information about the way language users integrate linguistic information with information derived from the visual environment. Therefore the paradigm is well suited to study one of the key issues of current cognitive psychology, namely the interplay between linguistic and visual information processing. However, conclusions about linguistic processing (e.g., about activation, competition, and timing of access of linguistic representations) in the absence of relevant visual information must be drawn with caution. PMID- 21288499 TI - [Primary melanoma with multiple skin metastases]. PMID- 21288500 TI - [Linear Darier disease]. PMID- 21288501 TI - Physical activity in women with polycystic ovary syndrome: prevalence, predictors, and positive health associations. AB - OBJECTIVE: The purpose of this study was to describe the prevalence and predictors of physical activity in women with polycystic ovary syndrome (PCOS) and to explore the potential health benefits that are associated with physical activity in this population. STUDY DESIGN: This was a cross-sectional assessment of 150 women with PCOS. Active women (those who met Department of Health and Human Services [DHHS] guidelines for exercise) were compared with inactive women with regards to demographic and psychosocial variables and health characteristics. RESULTS: Fifty-nine percent (88/150 women) met the DHHS guidelines for physical activity. Active women were more likely than inactive women to be nulliparous (64.1% vs 40.0%; P = .04) and white (71.6% vs 42.6%; P = .0004). Inactive women were more likely to have mild depression (adjusted odds ratio, 2.2; 95% confidence interval, 1.01-4.79; P = .048). CONCLUSION: Women with PCOS who met the DHHS guidelines for physical activity were more likely to enjoy a variety of health benefits. Our findings identify several groups that are at risk for inadequate physical activity. PMID- 21288502 TI - Is it time to revisit the Pedersen hypothesis in the face of the obesity epidemic? AB - The Pedersen hypothesis was formulated more than 50 years ago. Jorgen Pedersen primarily cared for women with type 1 diabetes. He suggested that fetal overgrowth was related to increased transplacental transfer of glucose, stimulating the release of insulin by the fetal beta cell and subsequent macrosomia. Optimal maternal glucose control decreased perinatal mortality and morbidity. However, over the ensuing decades, there have been increases in maternal obesity and subsequently gestational diabetes mellitus (GDM) and type 2 diabetes. The underlying pathophysiology of type 1 and GDM/type 2 diabetes are fundamentally different, type 1 diabetes being primarily a disorder of beta cell failure and type 2 diabetes/GDM including both insulin resistance and beta cell dysfunction. As such the metabolic milieu in which the developing fetus is exposed may be quite different in type 1 diabetes and obesity. In this review we examine the metabolic environment of obese diabetic women and lipid metabolism affecting fetal adiposity. The importance of understanding these issues relates to the increasing trends of obesity worldwide with perinatal programming of metabolic dysfunction in the offspring. PMID- 21288503 TI - Advanced maternal age, short interpregnancy interval, and perinatal outcome. AB - OBJECTIVE: The purpose of this study was to evaluate whether the association between short interpregnancy intervals and perinatal outcome varies with maternal age. STUDY DESIGN: We performed a retrospective cohort study among 263,142 Dutch women with second deliveries that occurred between 2000 and 2007. Outcome variables were preterm delivery (<37 weeks of gestation), low birthweight in term deliveries (<2500 g) and small-for-gestational age (<10th percentile for gestational age on the basis of sex- and parity-specific Dutch standards). RESULTS: Short interpregnancy intervals (<6 months) was associated positively with preterm delivery and low birthweight, but not with being small for gestational age. The association of short interpregnancy interval with the risk of preterm delivery was weaker among older than younger women. There was no clear interaction between short interpregnancy interval and maternal age in relation to low birthweight or small for gestational age. CONCLUSION: The results of this study indicate that the association of short interpregnancy interval with preterm delivery attenuates with increasing maternal age. PMID- 21288504 TI - A comparison of in vitro erosion-like mineral loss between continuous and intermittent acidic exposure with and without human saliva. AB - AIM: This in vitro study aimed to compare erosion-like mineral loss following intermittent or continuous acidic exposures, and considered the role that human saliva may play. MATERIALS AND METHODS: 180 bovine enamel blocks were divided randomly into four equally-sized groups and exposed to one of the 4 protocols 6 times daily over 6 days (total acidic exposure time of 6h): Group 1, continuous 10 min in orange juice (OJ) followed by 10 min in deionised water; Group 2, continuous 10 min in OJ followed by 10 min in stimulated saliva; Group 3, ten 1 min OJ exposures alternating with ten 1-min deionised water exposures; Group 4, ten 1-min OJ exposures alternating with ten 1-min stimulated saliva exposures. Specimens were stored in a remineralising solution between acidic exposures. Sections were cut and transverse microradiography was used to measure lesion depth in each specimen. RESULTS: Mean (sd) lesion depths were 21.5 (8.1), 21.2 (6.2), 81.7 (12.2) and 72.8 (12.4) MUm for Groups 1-4, respectively. Significant differences existed between all protocols except Groups 1 and 2 (mean difference 0.3 MUm, 95% CI: -6.1 to 5.5). The mean difference between Groups 3 and 4 was 8.9 MUm (95% CI: 3.2-14.7). CONCLUSIONS: Repeated, intermittent exposure to an acidic drink in vitro resulted in greater lesion depth than a continuous exposure of the same duration. Saliva offered some protection against intermittent acidic exposure. PMID- 21288505 TI - Dysfunction of preattentive visual information processing among patients with major depressive disorder. AB - BACKGROUND: Major depressive disorder (MDD) is a mental disorder characterized by depressed mood and inability to experience pleasure. Mismatch negativity (MMN) has been established as a correlate of preattentive change detection. In this study, preattentive processing of visual information in MDD patients was investigated using visual MMN (vMMN), and an abnormal vMMN was predicted in depressed patients relative to healthy participants because of dysfunction at the preattentive level. The processes underlying vMMN in MDD patients were also explored, and memory-based comparison preattentive processing was hypothesized to be impaired in MDD patients. METHODS: Subjects included 14 medication-free patients (41.4 +/- 12.6 years) with a DSM-IV diagnosis of MDD and 14 age-matched healthy volunteers (41.7 +/- 17.5 years). vMMN was investigated using event related potentials. The protocol used both an equiprobable sequence and a traditional oddball sequence, and three kinds of difference waves (i.e., deviant minus-standard, deviant-minus-control, and control-minus-standard) were investigated. Mean amplitudes and peak latencies were subjected to repeated measures analysis of variance. RESULTS: Although MDD patients showed no reduction in the oddball-vMMN (deviant-minus-standard), they showed a significantly decreased deviant-minus-control difference waves and a trend for an increased control-minus-standard difference waves compared with healthy participants. CONCLUSIONS: These data provide evidence for anomalous preattentive information processing in MDD patients. In particular, the abnormality may be due to an attenuated memory-based comparison process and an enhanced refractory process. PMID- 21288506 TI - Imaging changes in glutamate transmission in vivo with the metabotropic glutamate receptor 5 tracer [11C] ABP688 and N-acetylcysteine challenge. AB - BACKGROUND: An imaging method to probe glutamate levels in vivo would allow the study of glutamate transmission in disease states and in response to therapeutic interventions. Here we demonstrate the feasibility of this approach for the first time using positron emission tomography and [(11)C] ABP688, a radiotracer for an allosteric site on the metabotropic glutamate receptor 5. METHODS: We conducted two sets of experiments in anesthetized baboons: test and retest without pharmacologic challenge and in combination with N-acetylcysteine (NAC), a promoter of the cystine-glutamate antiporter that increases extrasynaptic glutamate release. The goal was to assess whether NAC-induced changes in [(11)C] ABP688 binding potential, DeltaBP(ND), could be detected above the noise in the measurement. RESULTS: Linear mixed modeling comparing DeltaBP(ND) from test retest to DeltaBP(ND) from NAC challenge across all brain regions showed a highly significant effect of treatment [F(1,40) = 21.2, p < .001]. DeltaBP(ND) was significantly different from zero following NAC [F(1,20) = 76.6, p < .001] but not after test-retest studies. CONCLUSIONS: NAC induced decrease in [(11)C] ABP688 DeltaBP(ND) may be the result of allosteric modulation, although other mechanisms may be at play. We outline steps needed to replicate and validate this method as a new tool to measure in vivo glutamate transmission. PMID- 21288507 TI - Syntheses of chitin-based imprinting polymers and their binding properties for cholesterol. AB - A novel chitin derivative, cholesteryl chitin carbonate (Chitin-Chol), was synthesized from chitin and cholesteryl chloroformate. This product was characterized by Fourier transform infrared (FTIR) spectroscopy and solid-state 13C nuclear magnetic resonance (13C NMR), and was used as a covalently bound template precursor for imprinting cholesterol. After cross-linking with toluene 2,4-diisocyanate, it was efficiently cleaved hydrolytically to afford a guest binding site accompanying the easy and efficient removal of a sacrificial spacer. The selectivity and efficacy of a chitin-based imprinting polymer for steroid binding were assessed by a chromatographic screening process. The results of binding experiments showed that this molecular imprinting polymer (MIP) has a high binding capacity with cholesterol. The target discrimination towards cholesterol over its close structural analogue suggested that the polymer recognition site was possible on the basis of the inversion of configuration of a single hydroxyl group. In addition, non-covalent imprinting was done using chitin as a precursor and its binding properties for cholesterol were also evaluated. PMID- 21288508 TI - An association between understanding cardinality and analog magnitude representations in preschoolers. AB - The preschool years are a time of great advances in children's numerical thinking, most notably as they master verbal counting. The present research assessed the relation between analog magnitude representations and cardinal number knowledge in preschool-aged children to ask two questions: (1) Is there a relationship between acuity in the analog magnitude system and cardinality proficiency? (2) Can evidence of the analog magnitude system be found within mappings of number words children have not successfully mastered? To address the first question, Study 1 asked three- to five-year-old children to discriminate side-by-side dot arrays with varying differences in numerical ratio, as well as to complete an assessment of cardinality. Consistent with the analog magnitude system, children became less accurate at discriminating dot arrays as the ratio between the two numbers approached one. Further, contrary to prior work with preschoolers, a significant correlation was found between cardinal number knowledge and non-symbolic numerical discrimination. Study 2 aimed to look for evidence of the analog magnitude system in mappings to the words in preschoolers' verbal counting list. Based on a modified give-a-number task (Wynn, 1990, 1992), three- to five-year-old children were asked to give quantities between 1 and 10 as many times as possible in order to assess analog magnitude variability within their developing cardinality understanding. In this task, even children who have not yet induced the cardinality principle showed signs of analog representations in their understanding of the verbal count list. Implications for the contribution of analog magnitude representations towards mastery of the verbal count list are discussed in light of the present work. PMID- 21288509 TI - Bacterial diversity characterization of bioaerosols from cage-housed and floor housed poultry operations. AB - BACKGROUND: Although bioaerosols from both cage-housed (CH) and floor-housed (FH) poultry operations are highly concentrated, workers from CH operations have reported a greater prevalence of respiratory symptoms. OBJECTIVE: The objective of this study was to directly compare bacteria, both quantitatively and qualitatively, in bioaerosols from CH and FH poultry facilities. METHODS: Bioaerosols were collected from fifteen CH and fifteen FH poultry operations, using stationary area samplers as well as personal sampling devices. Dust, endotoxin and bacteria were quantified and bacterial diversity was investigated using PCR followed by denaturing gradient gel electrophoresis (DGGE). RESULTS: Dust (p<0.001), endotoxin (p<0.05) and bacteria (p<0.05) were significantly higher in personal bioaerosols of FH poultry operations than CH bioaerosols. Although dust and endotoxin did not differ significantly between area and personal samples within each barn type, clustering analysis of DGGE profiles of bacteria revealed that area and personal samples shared less than 10% similarity. These data suggest that area samples are not representative of personal bacteria exposures, which may be affected by worker movement, bacteria carried on the worker and worker location. Personal DGGE profiles from CH and FH operations shared less than 20% similarity and composite analysis showed that bacteria were more prevalent in personal samples from CH bioaerosols than FH bioaerosols. CONCLUSIONS: Bacteria concentration and diversity are significantly different between bioaerosols from CH and FH poultry operations. PMID- 21288510 TI - Adequacy of flexible sigmoidoscopy with biopsy for diarrhea in patients under age 50 without features of proximal disease. AB - BACKGROUND: The optimal endoscopic investigation of diarrhea in patients under age 50 without specific features of right-sided colonic/ileal disease is inadequately defined. OBJECTIVE: To assess the potential additional yield of colonoscopy over flexible sigmoidoscopy (FS) in this group. DESIGN: Retrospective cohort study. SETTING: Two teaching hospital endoscopy units. PATIENTS: This study involved all patients under age 50 who had a colonoscopy between 1997 and 2007 to investigate diarrhea, without high-risk features of right-sided colonic/ileal disease, inflammatory bowel disease (IBD), or rectal bleeding. INTERVENTION: Colonoscopy and biopsy. MAIN OUTCOME MEASUREMENTS: Diagnostic yield of colonoscopy over FS with biopsy. RESULTS: Colonoscopic appearances were abnormal in 126 of 625 eligible patients (20%); 72% of abnormalities were within reach of FS. The most common endoscopic abnormality was suspected inflammation in 60 patients (10% overall), reportedly confined to the proximal colon or ileum in 22 patients (37% of this group). Histology from areas of suspected inflammation revealed features of IBD in 68% of patients, but results were normal in the remainder. In the 22 patients with suspected isolated proximal disease, 8 patients (36%) had normal histology results, and a further 6 had left-side colon biopsies demonstrating IBD. In patients with macroscopically normal colons, histological evidence of IBD or microscopic colitis occurred in 14 and 12 patients, respectively, with changes in the left side of the colon in 93% of patients. In this patient group, 85% of IBD or microscopic colitis could have been detected by FS and biopsy. The negative predictive value of FS with biopsy was 98% for IBD and 99% for microscopic colitis. LIMITATIONS: Retrospective study. CONCLUSION: FS is adequate for the investigation of diarrhea in patients under age 50 who lack other features, but its yield depends on biopsy of the left side of the colon. PMID- 21288511 TI - A prospective, randomized trial of esophageal submucosal tunnel closure with a stent versus no closure to secure a transesophageal natural orifice transluminal endoscopic surgery access site. AB - BACKGROUND: Secure esophagotomy closure methods are a critical element in the advancement of transesophageal natural orifice transluminal endoscopic surgery (NOTES) procedures. OBJECTIVE: To compare the clinical outcomes in swine receiving an esophageal stent or no stent after a submucosal tunnel NOTES access procedure. DESIGN: Prospective, randomized, controlled trial in 10 Yorkshire swine. SETTING: Academic center. INTERVENTION: An endoscopic mucosectomy device was used to create an esophageal mucosal defect. An endoscope was advanced through a submucosal tunnel into the mediastinum and thorax, and diagnostic mediastinoscopy and thoracoscopy were performed. Ten animals were randomized to no stenting (n = 5) or stenting (n = 5) with a prototype small-intestine submucosa-covered stent. MAIN OUTCOME MEASUREMENTS: Gross and histologic appearance of the mucosectomy and esophagotomy sites as well as clinical outcomes. RESULTS: There was a significant difference in the overall procedure time between the animals that received a stent (35.0 min, range 27-46.0 min) and those with no closure (19.0 min, range 17-32 min) (P value = .018). The unstented group achieved endoscopic and histologic evidence of complete re epithelialization and healing (100%) at the mucosectomy site compared with the stented group (20%, P = .048). Stent migration into the stomach occurred in two swine. Both groups had complete closure of the submucosal tunnel and well-healed esophagotomy sites. LIMITATIONS: Animal study, small number of subjects. CONCLUSION: The placement of a covered esophageal stent significantly interferes with mucosectomy site healing. PMID- 21288512 TI - A comparison of angiographic embolization with surgery after failed endoscopic hemostasis to bleeding peptic ulcers. AB - BACKGROUND: In patients with bleeding peptic ulcers in whom endoscopic hemostasis fails, surgery usually follows. Transarterial embolization (TAE) has been proposed as an alternative. OBJECTIVE: To compare the outcomes of TAE and salvage surgery for patients with peptic ulcers in whom endoscopic hemostasis failed. DESIGN: Retrospective study. SETTING: A university hospital. PATIENTS: Patients with peptic ulcer bleeding in whom endoscopic hemostasis failed. INTERVENTIONS: TAE and surgery as salvage of peptic ulcer bleeding. MAIN OUTCOMES MEASUREMENTS: All-cause mortality, rebleeding, reintervention, and complication rate. RESULTS: Thirty-two patients underwent TAE and 56 underwent surgery. In those who underwent TAE, the bleeding vessels were gastroduodenal artery (25 patients), left gastric artery (4 patients), right gastric artery (2 patients), and splenic artery (1 patient). Active extravasation was seen in 15 patients (46.9%). Embolization was attempted in 26 patients, and angiographic coiling was successful in 23 patients (88.5%). Bleeding recurred in 11 patients (34.4%) in the TAE group and in 7 patients (12.5%) in the surgery group (P=.01). More complications were observed in patients who underwent surgery (40.6% vs 67.9%, P=.01). There was no difference in 30-day mortality (25% vs 30.4%, P=.77), mean length of hospital stay (17.3 vs 21.6 days, P=.09), and need for transfusion (15.6 vs 14.2 units, P=.60) between the TAE and surgery groups. LIMITATIONS: Retrospective study. CONCLUSIONS: In patients with ulcer bleeding after failed endoscopic hemostasis, TAE reduces the need for surgery without increasing the overall mortality and is associated with fewer complications. PMID- 21288513 TI - Endoscopic removal of two giant fibrovascular polyps of the esophagus using the "two channel, two devices technique". PMID- 21288514 TI - Paclitaxel-eluting covered metal stents versus covered metal stents for distal malignant biliary obstruction: a prospective comparative pilot study. AB - BACKGROUND: In unresectable malignant biliary obstruction, stent insertion can be the treatment of choice. However, metal stents are susceptible to occlusion by tumor ingrowth or overgrowth. The recently introduced paclitaxel-eluting covered metal stents (PECMSs) may prevent occlusion from tumor ingrowth by the antitumor effect of paclitaxel. OBJECTIVE: Our goal was to compare the efficacy and complication rates of PECMSs and the control covered metal stents (CCMSs) in patients with malignant biliary obstruction. DESIGN: Prospective, randomized pilot study. SETTING: Single tertiary referral center. PATIENTS: From November 2006 to June 2008, 52 patients with unresectable distal malignant biliary obstruction were enrolled. A PECMS was inserted in 26 patients and a CCMS in 26 patients. Of these patients, 2 patients in the PECMS group and 1 patient in the CCMS group were excluded. Finally 49 patients (24 patients in the PECMS group and 25 patients in the CCMS group) were included in the analysis. INTERVENTIONS: PECMSs and CCMSs were inserted by using the standard ERCP technique. RESULTS: The mean follow-up period was 194.0 +/- 144.2 days in the PECMS group and 238.8 +/- 147.4 days in the CCMS group (P = .287). The stent patency duration and survival time were not significantly different between the 2 groups (P = .307 and P = .596, respectively). Stent occlusion caused by tumor ingrowth occurred in 5 patients in the PECMS group. In the CCMS group, stent occlusion caused by tumor ingrowth (n = 4) or distal stent migration (n = 4) occurred in 8 patients. In the PECMS group, 3 cases of transient cholangitis-like symptoms without stent occlusion and 1 case of pancreatitis occurred after stent insertion. One patient in the CCMS group experienced pancreatitis. LIMITATIONS: This study was a pilot study in which no power calculation was done. It was performed at a single center and was performed in a nonblinded fashion. CONCLUSIONS: PECMSs may be safe with acceptable complication rates. There were no significant differences in the duration of stent patency and patient survival time between PECMSs and CCMSs in patients with distal malignant biliary obstruction. However, a larger study powered to detect differences must be done to conclude that there is any benefit of PECMSs. PMID- 21288515 TI - Obstructive jaundice caused by grenade splinter migration. PMID- 21288516 TI - Malakoplakia: an unusual cause of lower GI bleeding in a child. PMID- 21288517 TI - A case of portal vein thrombosis caused by ingestion of a foreign body. PMID- 21288518 TI - Capsule endoscopy versus positron emission tomography for detection of small bowel metastatic melanoma: a pilot study. AB - BACKGROUND: Melanoma is the most common tumor to metastasize to the GI tract, where it mainly involves the small bowel. OBJECTIVE: To compare capsule endoscopy (CE) and (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET)-CT scanning, the current standard and most sensitive investigation modality, in detecting small-bowel metastases in patients with metastatic melanoma. DESIGN: A prospective study of patients with metastatic melanoma who were undergoing FDG PET-CT scanning. CE was performed and the results read by two independent observers without knowledge of the other investigation results. SETTING: Tertiary care centers. PATIENTS: This study involved 21 patients with a median age of 52 years (range 22-88 years). INTERVENTION: CE. MAIN OUTCOME MEASUREMENTS: Detection of small-bowel melanoma. RESULTS: FDG PET-CT scanning showed increased abdominal uptake in 12 patients, but only 5 of these patients were found to have small bowel melanoma on CE. Importantly, in 1 patient with a bleeding small-bowel tumor on CE, the FDG PET-CT scan result was negative. One patient with positive FDG PET CT scan results and negative CE results subsequently developed symptomatic small bowel melanoma 10 months after CE. LIMITATIONS: Small-bowel melanoma could not be excluded entirely in 7 patients with positive FDG PET-CT scan results and negative CE results, and follow-up is ongoing. The number of patients in this study was small. CONCLUSION: CE was better than FDG PET-CT scanning in localizing small-bowel melanoma. This study suggests that CE is an ideal complementary investigation modality for patients with known metastatic melanoma undergoing preoperative work-ups and in those with unexplained anemia or GI symptoms. PMID- 21288519 TI - Absorbable ligation loops for flexible endoscopy: a necessary tool for natural orifice transluminal endoscopic surgery. AB - BACKGROUND: One of the main challenges of natural orifice transluminal endoscopic surgery (NOTES) remains the development of safe and reliable tools. In this study, we introduce the first absorbable ligatures specifically designed for NOTES. OBJECTIVE: To determine the feasibility of a new absorbable ligation loop (NOTES loop) and to compare this new type of suture with the nonabsorbable loop (Endoloop) most commonly used until now. DESIGN: Prospective, comparative animal trial/survival animal study (observation period 21 days) with subsequent histopathological assessment (blinded observer design). SETTING: Veterinarian center. SUBJECTS: This study used 12 female domestic piglets. INTERVENTION: Every pig underwent two transgastric uterine horn ligations, one with an absorbable loop and one with a nonabsorbable loop. Additional uterine horn resections on both sides were done on 6 pigs. MAIN OUTCOME MEASUREMENTS: Intervention success, loop reliability, foreign-body reaction, extent of inflammatory response (MUm). RESULTS: Transgastric flexible intra-abdominal ligation of the uterine horns was performed safely with both loops in all cases. During a 3-week observation period, 11 of 11 NOTES loops and 10 of 11 Endoloops were reliable. Microscopically, foreign-body reaction was minimal around both sutures (P = .303). The overall inflammatory response was larger around the Endoloops (P = .046). Uterine horn resection had an influence on the extent of inflammation. LIMITATIONS: Animal study. CONCLUSION: Ligation was feasible with both loops. The absorbable loops were reliable during a 3-week observation period and can be recommended for use during NOTES appendectomies. PMID- 21288520 TI - Do smokers with chronic obstructive pulmonary disease report their smoking status reliably? A comparison of self-report and bio-chemical validation. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is predominantly caused by cigarette smoking and is considered a worldwide preventable chronic illness. Smoking cessation is considered the primary intervention for disease management and nurses should play a major role in assisting patients to stop smoking. Currently there is a lack of professional consensus on how cessation interventions should be evaluated. The vast array of biochemical markers reported in the literature can be confusing and can make the comparisons of results difficult. OBJECTIVE: To validate self-report data on smoking with exhaled carbon monoxide in patients with chronic obstructive pulmonary disease over twelve months. DESIGN: We performed a secondary analysis of a previously published randomized controlled trial evaluating nursing interventions to assist respiratory patients to stop smoking. SETTING: Northern Ireland's Regional Respiratory Centre. PARTICIPANTS: A total of 91 cigarette smokers attending secondary care for the treatment for COPD participated in the study. METHOD: Self reported smoking status and cigarettes smoked per day were compared to exhaled carbon monoxide readings at baseline, 2, 3, 6, 9 and 12 months. The cut-off value of <=10 ppm was used to identify non-smokers. The p-values are based on Pearson's correlation coefficient and Kappa Coefficient as appropriate. RESULTS: Findings suggest self-reported smoking status and cigarette consumption amongst patients with chronic obstructive pulmonary disease was highly consistent with exhaled carbon monoxide results (p = 0.001-0.003). CONCLUSION: The majority of patients with chronic obstructive pulmonary disease reliably report their cigarette consumption. PMID- 21288521 TI - Biomechanical outcomes and neural correlates of cutaneous reflexes evoked during rhythmic arm cycling. AB - During walking cutaneous stimulation of the foot yields neural and mechanical reflexes that serve a functional purpose to correct or assist the ongoing movement. Concurrently, while cutaneous stimulation of the hand during rhythmic arm movement parallel the neural responses observed in the legs, studies of rhythmic arm movement have only limited mechanical measurements. Therefore it is difficult to determine whether reflex responses in the arms during rhythmic arm movement serve a functional purpose similar to those seen in the lower limbs. The purpose of this study was to explore the mechanical outcomes of stimulating a cutaneous nerve innervating the hand during arm cycling. We hypothesized that there would be measurable mechanical effects to cutaneous stimulation during arm cycling that function to correct or assist the task of arm cycling. Specifically, kinetic responses measured at the handle would be considered assistive if they were tangential to the arm cycling path in the direction of forward progression. Also, limb kinematic responses would be considered corrective if they allowed limb movement that would result in removal of the limb from stimulus while not altering the kinetic profile at the handle necessary for arm cycling progression. Participants performed seated arm cycling while EMG was recorded from the arm and trunk muscles, kinematic data was recorded from the right arm, and kinetic data was recorded from the handle. Cutaneous reflexes were evoked by stimulating the superficial radial nerve. The results show that there are observable mechanical responses to cutaneous stimulation of the hand during arm cycling. Subjects responded to cutaneous stimulation of the hand during arm cycling with significant changes in backward and lateral forces at the handle as well as wrist abduction/adduction and wrist flexion/extension kinematics. These responses, related to the task and phase of movement, are consistent with the anatomical location of the stimulus and are correlated to the neural responses. Therefore, these responses are comparable to functionally relevant responses in the legs during rhythmic movement. However, while there is a single observation of a kinematic corrective strategy, the kinetics measured at the handle are not tangential to the arm cycling path and therefore not considered an assistive response. Therefore, unlike the observations in the lower limbs, the mechanical responses during arm cycling are not clearly related to the functional context of the ongoing task. PMID- 21288522 TI - The effect of valgus braces on medial compartment load of the knee joint - in vivo load measurements in three subjects. AB - Knee osteoarthritis occurs predominately at the medial compartment. To unload the affected compartment, valgus braces are used which induce an additional valgus moment in order to shift the load more laterally. Until now the biomechanical effect of braces was mainly evaluated by measuring changes in external knee adduction moments. The aim of this study was to investigate if and to which extent the medial compartment load is reduced in vivo when wearing valgus braces. Six components of joint contact load were measured in vivo in three subjects, using instrumented, telemeterized knee implants. From the forces and moments the medio-lateral force distribution was calculated. Two braces, MOS Genu (Bauerfeind AG) and Genu Arthro (Otto Bock) were investigated in neutral, 4 degrees and 8 degrees valgus adjustment during walking, stair ascending and descending. During walking with the MOS brace in 4 degrees /8 degrees valgus adjustment, medial forces were reduced by 24%/30% on average at terminal stance. During walking with the GA in the 8 degrees valgus position, medial forces were reduced by only 7%. During stair ascending/descending significant reductions of 26%/24% were only observed with the MOS (8 degrees ). The load reducing ability of the two investigated valgus braces was confirmed in three subjects. However, the load reduction depends on the brace stiffness and its valgus adjustment and varies strongly inter-individually. Valgus adjustments of 8 degrees might, especially with the MOS brace, not be tolerated by patients for a long time. Medial load reductions of more than 25% can therefore probably not be expected in clinical practise. PMID- 21288523 TI - Computed-tomography-based finite-element models of long bones can accurately capture strain response to bending and torsion. AB - Finite element (FE) models of long bones constructed from computed-tomography (CT) data are emerging as an invaluable tool in the field of bone biomechanics. However, the performance of such FE models is highly dependent on the accurate capture of geometry and appropriate assignment of material properties. In this study, a combined numerical-experimental study is performed comparing FE predicted surface strains with strain-gauge measurements. Thirty-six major, cadaveric, long bones (humerus, radius, femur and tibia), which cover a wide range of bone sizes, were tested under three-point bending and torsion. The FE models were constructed from trans-axial volumetric CT scans, and the segmented bone images were corrected for partial-volume effects. The material properties (Young's modulus for cortex, density-modulus relationship for trabecular bone and Poisson's ratio) were calibrated by minimizing the error between experiments and simulations among all bones. The R(2) values of the measured strains versus load under three-point bending and torsion were 0.96-0.99 and 0.61-0.99, respectively, for all bones in our dataset. The errors of the calculated FE strains in comparison to those measured using strain gauges in the mechanical tests ranged from -6% to 7% under bending and from -37% to 19% under torsion. The observation of comparatively low errors and high correlations between the FE-predicted strains and the experimental strains, across the various types of bones and loading conditions (bending and torsion), validates our approach to bone segmentation and our choice of material properties. PMID- 21288524 TI - Indentation measurements of the subendothelial matrix in bovine carotid arteries. AB - Artery biomechanics are an important factor in cardiovascular function and atherosclerosis development; as such, the macro-mechanics of whole arteries are well-characterized. However, much less is known about the mechanical properties of individual layers in the blood vessel wall. Since there is significant evidence to show that cells can sense the mechanical properties of their matrix, it is critical to characterize the mechanical properties of these individual layers at the scale sensed by cells. Here, we measured subendothelium mechanics in bovine carotid arteries using atomic force microscopy (AFM) indentation. To specifically indent the subendothelium, we evaluated three potential de endothelialization methods: scraping, paper imprinting, and saponin incubation. Using scanning electron microscopy, histology stains, immunohistochemistry, and multiphoton microscopy, we found that scraping was the only effective de endothelialization method capable of removing endothelial cells and leaving the subendothelial matrix largely intact. To determine the indentation modulus of the subendothelial matrix, both untreated and scraped (de-endothelialized) bovine carotid arteries were indented with a spherical AFM probe and the data were fit using the Hertz model. Both the endothelium on the untreated artery and the en face subendothelium had similar indentation moduli: E=2.5 +/- 1.9 and 2.7 +/- 1.1 kPa, respectively. These measurements are the first to quantify the micro-scale mechanics of the subendothelial layer, and constitute a critical step in understanding the relationship between altered subendothelial micromechanics and disease progression. PMID- 21288525 TI - Design and validation of surface-marker clusters for the quantification of joint rotations in general movements in early infancy. AB - Lack of complexity in general movements in early infancy is an important marker of potential motor disorders of neurological origin, such as cerebral palsy. Quantitative approaches to characterising this complexity are hampered by experimental difficulties in recording from infants in their first few months of life. The aim of this study was to design and validate bespoke surface-marker clusters to facilitate data acquisition and enable full quantification of joint rotations. The clusters were validated by recording the controlled movements of a soft-body dummy doll simultaneously with an optical (Qualisys) and inertial (XSens) motion capture system. The angles estimated from the optical system were compared with those measured by the inertial system. We demonstrate that the surface-marker based approach compares well with the use of an inertial system to obtain "direct" readings of the rotations whilst alleviating the issues associated with the use of an optical motion capture system. We briefly report use of this technique in 1-5 month old infants. By enabling full quantification of joint rotation, use of the custom made markers could pave the way for early diagnosis of movement disorders. PMID- 21288526 TI - Rupture of plasma membrane under tension. AB - We present a study on the rupture behavior of single NIH 3T3 mouse fibroblasts under tension using micropipette aspiration. Membrane rupture was characterized by breaking and formation of an enclosed membrane linked to a tether at the cell apex. Three different rupture modes, namely: single break, initial multiple breaks, and continuous multiple breaks, were observed under similar loading condition. The measured mean tensile strengths of plasma membrane were 3.83 +/- 1.94 and 3.98 +/- 1.54mN/m for control cells and cells labeled with TubulinTracker, respectively. The tensile strength data was described by Weibull distribution. For the control cells, the Weibull modulus and characteristic strength were 1.86 and 4.40 mN/m, respectively; for cells labeled with TubulinTracker, the Weibull modulus and characteristic strength were 2.68 and 4.48 mN/m, respectively. Based on the experimental data, the estimated average transmembrane proteins-lipid cleavage strength was 2.64 +/- 0.64 mN/m. From the random sampling of volume ratio of transmembrane proteins in cell membrane, we concluded that the Weibull characteristic of plasma membrane strength was likely to be originated from the variation in transmembrane proteins-lipid interactions. PMID- 21288527 TI - RandomPOD--a new method and device for advanced wear simulation of orthopaedic biomaterials. AB - A 16-station wear simulator of the pin-on-disc type, called RandomPOD, was designed, built, and validated. The primary area of application of the RandomPOD is wear studies of orthopaedic biomaterials. The type of relative motion between the bearing surfaces, generally illustrated as shapes of slide tracks, has been found to have a strong effect on the type and amount of wear produced. The computer-controlled RandomPOD can be programmed to produce virtually any slide track shape and load profile. In the present study, the focus is on the biomechanically realistic random variation in the track shape and load. In the reference test, the established combination of circular translation and static load was used. In addition, the combinations of random motion/static load, and circular translation/random load were included. The pins were conventional ultra high molecular weight polyethylene (UHMWPE), the discs were polished CoCr, and the lubricant was diluted calf serum. The UHMWPE wear factor resulting from random motion was significantly higher than that resulting from circular translation. This was probably caused by the fact that in the random motion the direction of sliding changed more than in circular translation with the same sliding distance. The type of load, random vs. static, was unimportant with respect to the wear factor produced. The principal advantage of using the present random track is that possible unrealistic wear phenomena related to the use of fixed track shapes can be avoided. PMID- 21288528 TI - Separation and characterization of gold nanoparticle mixtures by flow-field-flow fractionation. AB - We show that using asymmetric flow-field-flow fractionation and UV-vis detector it is possible to separate, characterize, and quantify the correct number size distribution of gold nanoparticle (AuNP) mixtures of various sizes in the 5-60 nm range for which simple dynamic light scattering measurements give misleading information. The size of the collected nanoparticles fractions can be determined both in solution and in the solid state, and their surface chemistry characterized by NMR. This method will find widespread applications both in the process of "size purification" after the synthesis of AuNP and in the identification and characterization of gold-based nanomaterials in consumer products. PMID- 21288529 TI - Magnetic retrieval of graphene: extraction of sulfonamide antibiotics from environmental water samples. AB - A new technique of retrieving graphene from aqueous dispersion was proposed in the present study. Two-dimensional planar graphene sheets were immobilized onto silica-coated magnetic microspheres by simple adsorption. The graphene sheets were used as adsorbent material to extract six sulfonamide antibiotics (SAs) from water samples. After extraction, they were conveniently separated from the aqueous dispersion by an external magnetic field. Under the optimal conditions, a rapid and effective determination of SAs in environmental water samples was achieved. The limits of detection for six SAs ranged from 0.09 to 0.16 ng/mL. Good reproducibility was obtained. The relative standard deviations of intra- and inter-day analysis were less than 10.7% and 9.8%, respectively. PMID- 21288530 TI - Solvent properties governing protein partitioning in polymer/polymer aqueous two phase systems. AB - Distribution coefficients of various proteins were measured in aqueous Dextran Ficoll, Dextran-PES, and Ficoll-PES two-phase systems, containing 0.15M NaCl in 0.01 M phosphate buffer, pH 7.4. The acquired data were combined with data for the same proteins in different systems reported previously and known solvatochromic solvent properties of the systems to characterize the protein solvent interactions. The relative susceptibilities of proteins to solvent dipolarity/polarizability, solvent hydrogen bond acidity, solvent hydrogen bond basicity, and solvent ability to participate in ion-ion and ion-dipole interactions were characterized. These parameters, which are representative of solute-solvent interactions, adequately described the partitioning of the proteins in each system. It was found that the relative susceptibilities of proteins to solvent dipolarity/polarizability are interrelated with their relative susceptibilities to solvent hydrogen bond acidity and solvent hydrogen bond basicity similarly to those established previously for small nonionic organic compounds. PMID- 21288531 TI - Kinetics of adsorption of oxalic acid on different titanium dioxide samples. AB - FTIR-ATR kinetic studies on the adsorption of oxalic acid on different TiO(2) films were performed. The particulate films were obtained through the evaporation of TiO(2) suspensions. The evolution of the IR bands followed a pseudo-first order behavior, as previously observed. Systematic studies as a function of the oxalic acid concentration afforded the specific rate constant for adsorption (k(a)) and desorption (k(d)). The influence of physical parameters of the samples, i.e., specific BET area, crystalline domain size, TiO(2) load, film area, and pore size, on the kinetic parameters k(a) and k(d) was analyzed. A mechanism in which the adsorption and desorption processes are controlled by the diffusion through the pores of the films is proposed (intraparticle diffusion). It is concluded that all the samples behave in the same way. Thicker films or those with smaller particle size (higher specific surface area, smaller pores) show the slowest rates of adsorption and desorption. These results are relevant for the design of efficient heterogeneous catalysts and sensors, and for the interpretation of pollutant adsorption. PMID- 21288532 TI - Heterogeneous photocatalysis of methylene blue over titanate nanotubes: effect of adsorption. AB - Titanate nanotubes were synthesized with hydrothermal reaction using TiO(2) and NaOH as the precursors and subsequent calcination at 400 degrees C for 2h. The products were characterized with SEM and XRD. Adsorption and photocatalysis of methylene blue over titanate nanotubes and TiO(2) were investigated. The results indicated that titanate nanotubes exhibited a better photocatalytic degradation of methylene blue in a simultaneous adsorption and photodegradation system than that in equilibrium adsorption followed by a photodegradation system, whereas TiO(2) showed no significant differences in photocatalytic activity in the two systems. The methylene blue overall removal efficiency over TNTs in the first system even exceeded that over TiO(2). The different catalytic performances of titanate nanotubes in the two systems were tentatively attributed to different effects of adsorption of methylene blue, i.e., the promoting effect in the former and the inhibition effect in the latter. Decantation experiments showed that the titanate nanotube photocatalyst could be easily separated from the reaction medium by sedimentation. Thus titanate nanotubes with high sedimentation rates and concurrent adsorption represent a new catalyst system with a strong potential for commercial applications. PMID- 21288533 TI - Simple statistical thermodynamic model of the heteroaggregation and gelation of dispersions and emulsions. AB - The heteroaggregation behaviour of mixtures of equal-sized particles (type A+type B) exhibiting short-ranged attractive interactions is investigated using the sticky hard-sphere model. The average cluster size is calculated as a function of the total particle volume fraction, the binary mixture composition, and the A-B stickiness interaction parameter tau(AB)(-1). We show that a value of tau(AB)( 1)=10(2), equivalent to an attractive well depth of ~5kT in a realistic continuous pair potential, leads to a state of heteroaggregation just below the gelation threshold of the equimolar mixture of volume fraction 0.1. We discuss the conditions under which the assumptions of this statistical thermodynamic model are satisfied experimentally, with particular reference to recent data on the heteroaggregation behaviour of protein-stabilized emulsions and latex particle dispersions. PMID- 21288534 TI - Continuous synthesis of CdSe(x)Te(1-x) nanocrystals: chemical composition gradient and single-step capping. AB - A capillary microreactor was firstly utilized to continuously synthesize near infrared emitting CdSe(x)Te(1-)(x) nanocrystals (NCs). By using trioctylphosphine oxide and trioctylphosphine as the solvents for anion precursor as well as oleic acid and oleylamine as the solvents for cation precursor, high quantum yield zinc blend CdSe(x)Te(1-)(x) NCs with a chemical composition gradient internal structure and tunable emission from 634 to 783 nm were synthesized. Thus, the nonlinear relationship between the composition and the emission energies were verified. Moreover, a facile single-step capping approach was developed by using the dissolution of cadmium oxide and free element sulfur in oleic acid, and a very thin CdS shell was successfully epitaxial grown around the as-prepared CdSe(x)Te(1-)(x) NCs to enhance the photostability. After the capping process, the core/shell structured CdSe(x)Te(1-)(x)/CdS NCs remained 15-40% of their initial PL intensity after 3h of illumination. PMID- 21288535 TI - Separation profile of model water-in-oil emulsions followed by nuclear magnetic resonance (NMR) measurements: application range and comparison with a multiple light scattering based apparatus. AB - The application range and validity of two new NMR sequences (hereafter called sequence 1 and sequence 2) for the study of water-in-oil emulsions (w/o) has been assessed using model emulsions and comparison with results obtained by a commercial apparatus (Turbiscan). These new NMR sequences allow to determine the brine profile i.e. the vertical variations of the dispersed phase content (brine) in the NMR tube. Measuring these parameters as a function of time allows to monitor the separation (sedimentation and coalescence rate) between oil and water. The results obtained on model water-in-oil emulsions with both NMR sequences are consistent and meaningful for both stable and coalescing emulsions and are similar, even if not strictly identical, to the ones obtained with the Turbiscan. It also appears that the second NMR sequence is faster (30s to obtain a profile compared with 3 min for the 1st one in the conditions used in this article) and has a broader application range. Indeed, for these two methods, the oil phase must have a viscosity higher or equal than values which is around 5 mPas for the sequence 2 and 20-25 mPas for the method 1. PMID- 21288536 TI - Concomitant synthesis of polyaniline and highly branched gold nanoparticles in the presence of DNA. AB - The reduction of chloroauric acid using aniline adsorbed on DNA produces highly branched dendritic gold nanoparticles with concomitant formation of polyaniline (PANI) in contrast to the formation of spherical Au nanoparticles in the absence of DNA. The conformation of DNA remains intact in the process as evident from circular dichroism (CD) spectra. The UV-Vis spectrum exhibits a broad absorption peak at 520-900 nm, for a combined effect of the gold surface plasmon and pi band to localized polaron band transition of DNA-doped PANI. Both the dendritic Au PANI-DNA and the spherical Au-PANI systems emit two peaks for excitation with radiation of 300 nm and the intensity ratio of the emission and FRET peak is higher in the dendritic Au-PANI than that in the spherical Au-PANI system. The dc conductivity values of spherical Au-PANI and dendritic Au-PANI-DNA systems are 1.2*10(-10) and 1.7*10(-8) S/cm at 30 degrees C, respectively. PMID- 21288537 TI - Spreading of fluids on solids under pressure: slip and stick effects. AB - Spreading of different types of fluid on solids under an impressed force is an interesting problem. Here we study spreading of four fluids, having different hydrophilicity and viscosity on two substrates - glass and perspex, under an external force. The area of contact of fluid and solid is video-photographed and its increase with time is measured. The results for different external forces can be scaled onto a common curve. We try to explain the nature of this curve on the basis of existing theoretical treatment where either the no-slip condition is used or slip between fluid and substrate is introduced. We find that of the eight cases under study, in five cases quantitative agreement is obtained using a positive slip coefficient. The remaining three can be explained with a negative slip coefficient, equivalent to a sticking effect. PMID- 21288538 TI - Adsorption of atrazine from aqueous electrolyte solutions on humic acid and silica. AB - The adsorption of, the still widely used, herbicide atrazine on model soil components, such as humic acid and humic acid-silica gel mixtures, was investigated in a series of batch experiments, under different experimental conditions (ionic strength, temperature, and pH). The investigation aimed at obtaining an estimate of the contribution of each of the soil components on the adsorption of atrazine from aqueous solutions. The kinetics of atrazine adsorption on humic acid showed two steps: a fast step, of a few hours duration, and a second slow step, which continued for weeks. The kinetics of adsorption data gave a satisfactory fit to the Elovich equation. Tauhe adsorption of atrazine on the test substrates was found to be reversible in all cases. The atrazine uptake data on the test substrates were fitted best with the Freundlich adsorption isotherm. The ionic strength of the atrazine aqueous solutions did affect the amount of the atrazine adsorbed on the test substrates, suggesting that electrostatic forces between atrazine molecules and soil play a significant role in the adsorption process. An increase of temperature resulted in a decrease of atrazine adsorption on humic acid at low atrazine equilibrium concentrations. However, for higher levels of equilibrium concentrations (>=3 mg/L) the amount of atrazine adsorbed onto the test substrate increased as temperature increased. The calculated isosteric enthalpies of adsorption ranged between slightly exothermic at low atrazine uptake and slightly endothermic at high atrazine uptake, all values being in the range of physisorption. PMID- 21288539 TI - Exploring the outcomes of a novel computer-assisted treatment program targeting expressive-grammar deficits in preschoolers with SLI. AB - PURPOSE: The impact of a newly designed computer-assisted treatment (C-AT) program, My Sentence Builder, for the remediation of expressive-grammar deficits in children with specific language impairment (SLI) was explored. This program was specifically designed with features to directly address expressive-grammar difficulties, thought to be associated with hypothesized deficits in verbal working memory (VWM). METHOD: Thirty-four preschoolers with deficits in expressive-grammar morphology participated. Using the randomization procedure of consecutive sampling, participants were recruited. Twenty-two participants were consecutively assigned to one of two treatment groups, C-AT or non C-AT (nC-AT). The nC-AT utilized conventional language stimulation procedures containing features which have been traditionally used to address expressive-grammar deficits. A group of equivalent children awaiting treatment and chosen from the same sample of children as the treatment participants served as a control group. Blind assessments of outcomes were completed pre-, post-, and 3-months post treatment in a formal and informal context. RESULTS: C-AT and nC-AT participants significantly outperformed controls pre-to-post to 3-months post-treatment in both assessment contexts. No significant differences in treatment gains were found between C-AT and nC-AT. CONCLUSION: Results suggested that treatments designed to directly address expressive-grammar deficits were better than no treatment for preschool SLI. Further, use of a C-AT program may be another feasible treatment method for this disorder population. LEARNING OUTCOMES: As a result of this activity, the reader will recognize that: (1) expressive-grammar treatment is better than no treatment for immediate and continued language growth, (2) use of a C-AT program containing specific features designed to directly address expressive-grammar deficits is another viable, but not necessarily a better treatment option for the remediation of expressive-grammar deficits in preschool children with SLI, and (3) different outcome contexts yield distinct yet equally important findings about growth in children's expressive grammar skills with treatment. PMID- 21288540 TI - Age differences in understanding precedent-setting decisions and authorities' responses to violations of deontic rules. AB - To examine age trends in precedent-setting decisions and the effects of these decisions on perceptions of authorities, preadolescents and adolescents were presented with deontic rule infractions that occurred in the absence or presence of mitigating circumstances. In Study 1, in the absence of mitigating circumstances, adolescents recommended punishing rule violations more than preadolescents; when mitigating circumstances were present, adolescents recommended punishing infractions less than preadolescents. In Study 2, before and after receiving information that authorities had punished or permitted rule violations, participants indicated their beliefs in authority legitimacy, rule strength, and rule deterrence value. In the absence of mitigating circumstances, beliefs strengthened when infractions were punished and beliefs weakened when infractions were permitted. When mitigating circumstances were present and authorities punished violations, preadolescents' legitimacy and deterrence beliefs strengthened. Adolescents' deterrence beliefs strengthened, but their beliefs in authority legitimacy weakened. When justifiable infractions were permitted, preadolescents' legitimacy and deterrence beliefs weakened, whereas adolescents' beliefs strengthened. Discussion focuses on age differences in legitimacy beliefs and understanding the consequences of setting precedents and on the relevance of the findings to theories of deontic reasoning, moral judgments, and epistemological development. PMID- 21288541 TI - Evolutionary recruitment of a flavin-dependent monooxygenase for stabilization of sequestered pyrrolizidine alkaloids in arctiids. AB - Pyrrolizidine alkaloids are secondary metabolites that are produced by certain plants as a chemical defense against herbivores. They represent a promising system to study the evolution of pathways in plant secondary metabolism. Recently, a specific gene of this pathway has been shown to have originated by duplication of a gene involved in primary metabolism followed by diversification and optimization for its specific function in the defense machinery of these plants. Furthermore, pyrrolizidine alkaloids are one of the best-studied examples of a plant defense system that has been recruited by several insect lineages for their own chemical defense. In each case, this recruitment requires sophisticated mechanisms of adaptations, e.g., efficient excretion, transport, suppression of toxification, or detoxification. In this review, we briefly summarize detoxification mechanism known for pyrrolizidine alkaloids and focus on pyrrolizidine alkaloid N-oxidation as one of the mechanisms allowing insects to accumulate the sequestered toxins in an inactivated protoxic form. Recent research into the evolution of pyrrolizidine alkaloid N-oxygenases of adapted arctiid moths (Lepidoptera) has shown that this enzyme originated by the duplication of a gene encoding a flavin-dependent monooxygenase of unknown function early in the arctiid lineage. The available data suggest several similarities in the molecular evolution of this adaptation strategy of insects to the mechanisms described previously for the evolution of the respective pathway in plants. PMID- 21288542 TI - Community perceptions of tuberculosis: A qualitative exploration from a gender perspective. AB - OBJECTIVE: To explore community laypersons' perspective on tuberculosis (TB) related illness experiences, meanings, behaviours and impact with reference to gender. STUDY DESIGN: Qualitative, conducted in rural Bangladesh. METHODS: Eleven focus group discussions (FGDs) were conducted (six female and five male) in five subdistricts where the non-governmental organization BRAC operates. On average, seven purposively chosen poor, illiterate, non-TB patients participated in each FGD. Discussions were audiotaped, translated verbatim into English and analysed using MAXQDA software for qualitative data analysis, used it to assign codes to text segments to identify themes from participants' narratives. RESULTS: TB was recognized as a deadly disease that could affect anyone. The discussants were fairly aware of the psychological, financial and social impacts of TB. Women faced with adverse consequences more often than men, such as trouble in ongoing and prospective marital affairs. Coughing up sputum in public by women is culturally frowned upon, resulting in enormous suffering. Women tended to describe the clinical features more vaguely than men, and often specified fewer characteristic symptoms such as blood in sputum. CONCLUSIONS: The gender differences in the health and socio-economic impact of TB included perceived causality, curability, stigma, family and community support, fear of disclosure, and use of self-help or home remedies. Interactive health education covering various consequences of TB could be indispensable to changing negative beliefs. PMID- 21288543 TI - Effect of forest bathing on physiological and psychological responses in young Japanese male subjects. AB - OBJECTIVE: To provide scientific evidence supporting the efficacy of forest bathing as a natural therapy by investigating its physiological benefits using biological indicators in outdoor settings. STUDY DESIGN: Within-group comparisons were used to examine psychological and physiological responses to exposure to real forest and urban environments. METHODS: Young Japanese male adults participated in a 3-day, 2-night field experiment. Physiological responses as well as self-reported psychological responses to forest and urban environmental stimuli were measured in real settings. The results of each indicator were compared against each environmental stimulus. RESULTS: Heart rate variability analysis indicated that the forest environment significantly increased parasympathetic nervous activity and significantly suppressed sympathetic activity of participants compared with the urban environment. Salivary cortisol level and pulse rate decreased markedly in the forest setting compared with the urban setting. In psychological tests, forest bathing significantly increased scores of positive feelings and significantly decreased scores of negative feelings after stimuli compared with the urban stimuli. CONCLUSION: Physiological data from this field experiment provide important scientific evidence on the health benefits of forest bathing. The results support the concept that forest bathing has positive effects on physical and mental health, indicating that it can be effective for health promotion. Despite the small sample size in this study, a very clear tendency towards positive physiological and psychological outcomes in forests was observed. PMID- 21288544 TI - From containment to community: Trigger points from the London pandemic (H1N1) 2009 influenza incident response. AB - OBJECTIVE: In the UK, during the first wave of pandemic (H1N1) 2009 influenza, a national 'containment' strategy was employed from 25 April to 2 July 2009, with case finding, treatment of cases, contact tracing and prophylaxis of close contacts. The aim of the strategy was to delay the introduction and spread of pandemic flu in the UK, provide a better understanding of the course of the novel disease, and thereby allow more time for the development of treatment and vaccination options. STUDY DESIGN: Descriptive study of the management of the containment phase of pandemic (H1N1) 2009 influenza. METHODS: Analysis of data reported to the London Flu Response Centre (LFRC). RESULTS: The average number of telephone calls and faxes per day from health professionals before 15 June 2009 was 188, but this started to rise from 363 on 12 June, to 674 on 15 June, and peaked on 22 June at 2206 calls. The number of cases confirmed [by pandemic (H1N1) 2009 influenza specific H1 and N1 polymerase chain reaction] in London rose to a peak of 200 cases per day. There were widespread school outbreaks reporting large numbers of absences with influenza-like illnesses. Activity in the LFRC intensified to a point where London was declared a 'hot spot' for pandemic (H1N1) 2009 influenza on 19 June 2009 because of sustained community transmission. The local incident response was modified to the 'outbreak management phase' of the containment phase. CONCLUSIONS: The sharp rise in the number of telephone calls and the rise in school outbreaks appeared to be trigger points for community transmission. These indicators should inform decisions on modifying public health strategy in pandemic situations. PMID- 21288545 TI - Factors associated with occupational strain among Chinese teachers: a cross sectional study. AB - OBJECTIVES: With the reform of the education system in China, teachers are suffering from more occupational strain, which is believed to impair their working state indirectly and affect their health. This study assessed occupational strain and explored the related factors among Chinese teachers. STUDY DESIGN: Cross-sectional with cluster sampling. METHODS: The study population was composed of 3570 school teachers working in 64 primary and middle schools in Heping District in Shenyang, China. Data were collected using a self administered questionnaire (the Chinese version of the Occupational Stress Inventory scale). Multivariate linear regression analyses were performed to study the factors related to occupational strain. RESULTS: The average score on the Personal Strain Questionnaire (PSQ) for the whole study population was 106.5 (107.5 in men and 106.3 in women). Teachers with chronic disease, a greater number of days of sick leave, recent experience of a stressful life event and divorced/separated/widowed status tended to suffer greater strain than their peers. Regression analyses showed that the PSQ score was significantly associated with role overload, role boundary, responsibility and physical environment, and inversely associated with recreation and rational coping. The most crucial predictors of occupational strain were chronic disease, days of sick leave, recent experience of a stressful life event and marital status. Being a class teacher was the strongest indicator of interpersonal strain. Self-care was associated with vocational strain and psychological strain, and inversely associated with physical strain. CONCLUSIONS: Most teachers in this study experienced a high degree of occupational strain. Chronic disease, days of sick leave, recent experience of a stressful life event and divorced/separated/widowed status played prominent roles in occupational strain. In addition, role overload, role boundary, responsibility and physical environment induce occupational strain, while recreation and rational coping have a positive effect on occupational strain. Interventions such as proper management of chronic diseases and establishment of a balanced work-family life are crucial to reduce occupational strain. Recreation and training in coping abilities are needed to enhance positive working environments and attenuate the occupational strain imposed on teachers. PMID- 21288546 TI - Knowledge, attitudes and practices of caregivers regarding Japanese encephalitis in Shaanxi Province, China. AB - OBJECTIVES: To describe the level of knowledge, attitudes and practices (KAP) of caregivers regarding Japanese encephalitis (JE) before and after the launch of a demonstration project to transition JE vaccination into the routine Expanded Programme on Immunization and strengthen the JE immunization programme in Baoji Prefecture, Shaanxi Province; and to identify factors determining vaccination. STUDY DESIGN: Cross-sectional surveys on KAP on JE disease and vaccination at baseline and post intervention. METHODS: KAP surveys among caregivers were conducted in six counties of Baoji Prefecture using the World Health Organization probability proportional to size sampling method. RESULTS: The surveys at baseline (3781 respondents) and after a 2-year project (3780 respondents) demonstrated that the intervention resulted in a significant increase in the level of knowledge about, and changes in attitudes towards JE disease and vaccination, and an improvement in the proportion of children vaccinated. A probit regression of pooled pre- and post-intervention survey data suggested that knowledge, education level and age of caregivers were significantly associated with the likelihood of a child getting vaccinated. CONCLUSIONS: Routine availability of vaccine and information, education and communication strategies played important roles in improving knowledge and achieving high vaccination rates. PMID- 21288547 TI - Soil-transmitted helminth infections and risk factors in preschool children in southern rural Lao People's Democratic Republic. AB - The current widespread school-based control of soil-transmitted helminth (STH) infections is also advocated for preschool children. The objective of this study was to assess infection with STHs as well as their determinants in preschool children (<60 months) in southern rural Lao People's Democratic Republic (Lao PDR). A cluster survey was carried out from October to December 2006 in three districts of Savannakhet Province. The prevalence of Ascaris lumbricoides, hookworm and Trichuris trichiura was 27.4% (95% CI 27.0-27.6%), 10.9% (95% CI 10.7-11.0%) and 10.9% (95% CI 10.7-11.1%), respectively. Of the children studied, 28.4% had a monoparasitic infection and 9.3% had a polyparasitic infection. Older children had a higher risk for hookworm infection [odds ratio (OR) = 1.75, 95% CI 1.03-3.01; P = 0.041] and multiple infections (OR = 1.81, 95% CI 1.01-3.20; P = 0.044). Low socioeconomic status was associated with A. lumbricoides (OR = 0.61, 95% CI 0.38-0.98; P = 0.043) and monoparasitic infections (OR = 0.62, 95% CI 0.38 0.99; P = 0.049). In Lao PDR, deworming of preschool children is warranted. Preventive measures should address important risk factors. Health education regarding personal hygiene, appropriate water management and the construction and proper use of latrines are additional essential elements. PMID- 21288548 TI - Influence of ultrasonic vibration on micro-extrusion. AB - Micro-forming is a miniaturization technology with great potential for high productivity. Some technical challenges, however, need to be addressed before micro-forming becomes a commercially viable manufacturing process. These challenges include severe tribological conditions, difficulty in achieving desired tolerances, and short tool-life due to inability of available die materials to withstand the forces exerted on miniature dies and punches. Some of these problems can be mitigated using ultrasonic technology. The principal objectives of this work were to investigate the possibility of applying ultrasonic vibrations in the micro-forming process, to design a set of tooling for ultrasonic micro-extrusion and to observe experimentally how ultrasonic oscillations influences the forming load and the surface finish. The test results showed a significant drop on the forming load when ultrasonic vibrations were imposed, and also a significant improvement in the surface of the micro-formed parts. Based on the preliminary test results, the study demonstrated high potential for using ultrasonic oscillations as a way to overcome the difficulties brought by the miniaturization. PMID- 21288549 TI - Removal of arsenic(V) from spent ion exchange brine using a new class of starch bridged magnetite nanoparticles. AB - Ion exchange (IX) is considered by US EPA as one of the best available technologies for removing arsenic from drinking water. However, typical IX processes will generate large volumes of arsenic-laden regenerant brine that requires costly further handling and disposal. This study aimed to develop an engineered strategy to minimize the production and arsenic leachability of the process waste residual. We prepared and tested a new class of starch-bridged magnetite nanoparticles for removal of arsenate from spent IX brine. A low-cost, "green" starch at 0.049% (w/w) was used as a stabilizer to prevent the nanoparticles from agglomerating and as a bridging agent allowing the nanoparticles to flocculate and precipitate while maintaining their high arsenic sorption capacity. When applied to a simulated spent IX brine containing 300 mg/L As and 6% (w/w) NaCl, nearly 100% removal of arsenic was achieved within 1 h using the starch-bridged nanoparticles at an Fe-to-As molar ratio of 7.6, compared to only 20% removal when bare magnetite particles were used. Increasing NaCl in the brine from 0 to 10% (w/w) had little effect on the arsenic sorption capacity. Maximum uptake was observed within a pH range of 4-6. The Langmuir capacity coefficient was determined to be 248 mg/g at pH 5.0. The final treatment sludge was able to pass the TCLP (Toxicity Characteristic Leaching Procedure) based leachability of 5 mg/L as As. PMID- 21288550 TI - Pilot-scale evaluation of ozone and biological activated carbon for trace organic contaminant mitigation and disinfection. AB - In an effort to validate the use of ozone for contaminant oxidation and disinfection in water reclamation, extensive pilot testing was performed with ozone/H(2)O(2) and biological activated carbon (BAC) at the Reno-Stead Water Reclamation Facility in Reno, Nevada. Three sets of samples were collected over a five-month period of continuous operation, and these samples were analyzed for a suite of trace organic contaminants (TOrCs), total estrogenicity, and several microbial surrogates, including the bacteriophage MS2, total and fecal coliforms, and Bacillus spores. Based on the high degree of microbial inactivation and contaminant destruction, this treatment train appears to be a viable alternative to the standard indirect potable reuse (IPR) configuration (i.e., membrane filtration, reverse osmosis, UV/H(2)O(2), and aquifer injection), particularly for inland applications where brine disposal is an issue. Several issues, including regrowth of coliform bacteria in the BAC process, must be addressed prior to full-scale implementation. PMID- 21288551 TI - Seasonal variations of hydroxylated and methoxylated brominated diphenyl ethers in blue mussels from the Baltic Sea. AB - Hydroxylated polybrominated diphenyl ethers (OH-PBDEs) and methoxylated polybrominated diphenyl ethers (MeO-PBDEs) found at high levels in the Baltic biota are mainly natural products, but can also be formed through metabolism or abiotic oxidation of polybrominated diphenyl ethers (PBDEs). The formation of OH PBDEs is of concern since there is growing evidence of phenolic toxicity. This study investigates seasonal variations in levels of OH-PBDEs and MeO-PBDEs, focusing on an exposed species, the blue mussel (Mytilus edulis), sampled in the Baltic Sea in May, June, August and October of 2008. Both the OH-PBDE and MeO PBDE levels in the mussels showed seasonal variations from May to October, the highest concentration of each congener appearing in June. The seasonal variation was more marked for OH-PBDEs than in MeO-PBDEs, but all congeners showed the same trends, except 6-MeO-BDE47 and 2'-MeO-BDE68, which did not significantly decline in concentrations after June. Biotic or abiotic debromination is suggested as a possible reason for the rapid decrease in methoxylated penta- and hexa-BDE concentrations observed in blue mussels from June to August, while the tetraBDE concentrations were stable. In addition, 1,3,7/1,3,8-tribrominated dibenzo-p dioxins showed the same seasonal variation. The seasonal variations indicates natural formation and are unlikely to be due to transformation of anthropogenic precursors. The levels of PBDEs were fairly constant over time and considerably lower than those of the OH-PBDEs and MeO-PBDEs. The timing of the peaks in concentrations suggests that filamentous macro-algae may be important sources of these compounds found in the blue mussels from this Baltic Sea location. PMID- 21288552 TI - Ex situ bioremediation of a soil contaminated by mazut (heavy residual fuel oil)- a field experiment. AB - Mazut (heavy residual fuel oil)-polluted soil was exposed to bioremediation in an ex situ field-scale (600 m(3)) study. Re-inoculation was performed periodically with biomasses of microbial consortia isolated from the mazut-contaminated soil. Biostimulation was conducted by adding nutritional elements (N, P and K). The biopile (depth 0.4m) was comprised of mechanically mixed polluted soil with softwood sawdust and crude river sand. Aeration was improved by systematic mixing. The biopile was protected from direct external influences by a polyethylene cover. Part (10 m(3)) of the material prepared for bioremediation was set aside uninoculated, and maintained as an untreated control pile (CP). Biostimulation and re-inoculation with zymogenous microorganisms increased the number of hydrocarbon degraders after 50 d by more than 20 times in the treated soil. During the 5 months, the total petroleum hydrocarbon (TPH) content of the contaminated soil was reduced to 6% of the initial value, from 5.2 to 0.3 g kg( 1) dry matter, while TPH reduced to only 90% of the initial value in the CP. After 150 d there were 96%, 97% and 83% reductions for the aliphatic, aromatic, and nitrogen-sulphur-oxygen and asphaltene fractions, respectively. The isoprenoids, pristane and phytane, were more than 55% biodegraded, which indicated that they are not suitable biomarkers for following bioremediation. According to the available data, this is the first field-scale study of the bioremediation of mazut and mazut sediment-polluted soil, and the efficiency achieved was far above that described in the literature to date for heavy fuel oil. PMID- 21288553 TI - Characterization of binding site heterogeneity for copper within dissolved organic matter fractions using two-dimensional correlation fluorescence spectroscopy. AB - The heterogeneity of copper binding characteristics for dissolved organic matter (DOM) fractions was investigated based on the fluorescence quenching of the synchronous fluorescence spectra upon the addition of copper and two-dimensional correlation spectroscopy (2D-COS). Hydrophobic acid (HoA) and hydrophilic (Hi) fractions of two different DOM (algal and leaf litter DOM) were used for this study. For both DOM, fluorescence quenching occurred at a wider range of wavelengths for the HoA fractions compared to the Hi fractions. The combined information of the synchronous and asynchronous maps derived from 2D-COS provided a clear picture of the heterogeneous distribution of the copper binding sites within each DOM fraction, which was not readily recognized by a simple comparison of the changes in the synchronous fluorescence spectra upon the addition of copper. For the algal DOM, higher stability constants were exhibited for the HoA versus the Hi fractions. The logarithms of the stability constants ranged from 4.8 to 6.1 and from 4.5 to 5.0 for the HoA and the Hi fractions of the algal DOM, respectively, depending on the associated wavelength and the fitted models. In contrast, no distinctive difference in the binding characteristics was found between the two fractions of the leaf litter DOM. This suggests that influences of the structural and chemical properties of DOM on copper binding may differ for DOM from different sources. The relative difference of the calculated stability constants within the DOM fractions were consistent with the sequential orders interpreted from the asynchronous 2D-COS. It is expected that 2D-COS will be widely applied to other DOM studies requiring detailed information on the heterogeneous nature and subsequent effects under a range of environmental conditions. PMID- 21288554 TI - Comparative study of the accumulation and detoxification of Cu (essential metal) and Hg (nonessential metal) in the digestive gland and gills of mussels Mytilus galloprovincialis, using analytical and histochemical techniques. AB - The aim of the present study is the comparative examination of accumulation and detoxification of Cu and Hg in digestive gland and gills of mussels Mytilus galloprovincialis, using atomic absorption spectrophotometry and autometallography. Mussels were exposed to 0.08 mg L(-1) Cu, 0.08 mg L(-1) Hg, as well as to a mixture of 0.08 mg L(-1) Hg and 0.08 mg L(-1) Cu for 11 d. After the experimental exposure, animals were kept under laboratory conditions for a detoxification period of 7d. An antagonistic effect of Cu against to Hg accumulation was noted in the digestive gland of mussels after the experimental exposure, as well as after the detoxification period, supporting the protective role of Cu against to Hg toxicity in this tissue. Digestive gland was suggested as a main organ for Hg accumulation and gills as a target position for Cu accumulation. Additionally, lower time was evaluated for Hg detoxification in the digestive gland and gills of mussels, in relation to those addressed for Cu detoxification in the same tissues. The evaluation of black silver deposits (BSD) extent performed in digestive gland and gills was suggested as a less sensitive approach, in relation to atomic absorption spectrophotometry (AAS), to identify the concentration of heavy metals in tissues of mussels. The toxic effects of Hg, Cu and a mixture of them on lysosomal system of the digestive cells are also discussed. PMID- 21288555 TI - Perineurioma of the parotid gland: first case report. AB - SUMMARY: Neurogenic neoplasms account for approximately 1% of salivary gland tumors. A 45-year-old woman presented with a slowly growing unilateral parotid gland mass that was excised completely by lateral parotidectomy. No recurrence was detectable 6 months after surgery. The resection specimen contained a 1.7 * 1.2 * 1-cm whitish nodular lesion that was firm, well circumscribed, and completely surrounded by compressed normal glandular tissue. The tumor was composed of spindle cells with bipolar tapering, wavy nuclei, and palely stained cytoplasm. The tumor cells were arranged in storiform, lamellar, and whorled patterns. Nuclear atypia, necrosis, and significant mitotic activity were absent. Immunohistochemistry showed expression of epithelial membrane antigen, glucose transporter 1, claudin-1, and collagen IV. All other lineage-specific markers including protein S100 were negative in the tumor cells. To our knowledge, this case represents the first report of soft tissue perineurioma in the salivary gland. Lack of previous reports suggests underrecognition of this tumor entity at this unusual anatomical site. PMID- 21288556 TI - Desquamating apoptotic variant of high-grade prostatic intraepithelial neoplasia: a possible precursor of intraductal prostatic carcinoma. AB - Various patterns of high-grade prostatic intraepithelial neoplasia have been have been described, many of which show morphologic similarity to patterns of prostatic intraductal carcinoma, which is thought to develop either directly from high-grade prostatic intraepithelial neoplasia or by invasion of existing ducts by Gleason pattern 4 or 5 carcinoma. We document a rare and previously unreported "desquamating apoptotic variant" of high-grade prostatic intraepithelial neoplasia where desquamating cells containing apoptotic nuclear material coalesce in the gland lumens to form basophilic intraluminal masses in up to one third of involved acini. This lesion shares features of both high-grade prostatic intraepithelial neoplasia and prostatic intraductal carcinoma and supports the hypothesis that some forms of prostatic intraductal carcinoma evolve directly from high-grade prostatic intraepithelial neoplasia. PMID- 21288557 TI - Expression of secretagogin in clear-cell renal cell carcinomas is associated with a high metastasis rate. AB - Renal cell carcinomas are divided into several subgroups according to their histopathologic characteristics. The outcome, therapy responses, and the applicability of molecular-targeted therapies depend on the tumor classification and on the tumor stage. Recent advances within the biomarker research facilitated the exact classification of the molecular character of the renal tumor. For example, the calcium-binding proteins parvalbumin and S-100A1 are characteristically expressed in renal cell carcinoma subgroups. This led us to investigate the expression of the novel calcium-binding protein secretagogin in renal cell carcinomas. Tissue microarray cylinders including 94 clear-cell renal cell carcinomas, 61 non-clear-cell renal cell carcinomas (37 papillary renal cell and 24 chromophobe carcinomas), and 30 oncocytomas were analyzed by immunohistochemistry. This showed remarkable secretagogin expression in 37% of the clear-cell renal cell carcinomas. Non-clear-cell renal cell carcinomas and oncocytomas were completely negative. Consequently performed immunoblotting analyses confirmed this expression profile. Because publicly available data direct toward a formation of a hierarchical cluster of secretagogin overexpressing clear-cell renal cell carcinomas, we conducted a clinical follow up of the patients with clear-cell renal cell carcinoma. This revealed significantly more metastasis within the secretagogin-positive clear-cell renal cell carcinoma subgroup (49% versus 28%; P < .05). In conclusion, we report on detection of the novel calcium-binding protein secretagogin within a subgroup of clear-cell renal cell carcinomas. The increased metastasis rates within the secretagogin-positive subgroup of clear-cell renal cell carcinomas direct toward a clinical impact of our findings. PMID- 21288558 TI - RNA-binding protein LIN28 is a marker for testicular germ cell tumors. AB - LIN28 is an RNA-binding protein involved in maintaining the pluripotency of embryonic stem cells. Using formalin-fixed, paraffin-embedded tissue blocks, we performed immunohistochemical staining of LIN28 in 103 primary and 81 metastatic testicular germ cell tumors (54 intratubular germ cell neoplasias, unclassified type; 49 primary and 20 metastatic classic seminomas; 35 primary and 24 metastatic embryonal carcinomas; 35 primary and 15 metastatic yolk sac tumors; 23 primary and 12 metastatic teratomas; 6 primary and 10 metastatic choriocarcinomas; and 5 spermatocytic seminomas). The percentage of tumor cell stained was scored as 0 (0%), 1+ (<=30%), 2+ (31%-60%), 3+ (61%-90%), and 4+ (>90%). We stained LIN28 in 327 non-germ cell tumors to determine its specificity. We also compared LIN28 with SALL4 (Sal-like 4) and OCT4 (octamer binding transcription factor 4) in all germ cell tumors. The staining was cytoplasmic for LIN28 and nuclear for SALL4 and OCT4. Strong 4+ LIN28 staining was seen in all 54 intratubular germ cell neoplasias, 59 embryonal carcinomas, and 50 yolk sac tumors. Positive LIN28 staining was seen in all 69 classic seminomas (1+ in 3, 3+ in 3, and 4+ in 63) (63, strong). Variable staining of LIN28 was seen in 10 of 35 teratomas (1+ to 3+, weak to strong intensity), 12 of 16 choriocarcinomas (1+ to 4+, weak to strong intensity), and 1 of 5 spermatocytic seminomas (2+, weak). Only 10 of 327 non-germ cell tumors showed 1+ weak LIN28 staining. Therefore, LIN28 is a highly sensitive marker for testicular intratubular germ cell neoplasias, classic seminomas, embryonal carcinomas, and yolk sac tumors with relatively high specificity. LIN28 can be used as a diagnostic marker for these tumors and has demonstrated a similar level of diagnostic utility as SALL4 (except for a few classic seminomas), although it does not show an advantage over SALL4. The major advantage of LIN28 over OCT4 is in diagnosing yolk sac tumors (yolk sac tumors negative for OCT4). PMID- 21288559 TI - Patterns of glomerular injury in kidneys infiltrated by lymphoplasmacytic neoplasms. AB - Glomerular injury may occur as a result of immune dysfunction in patients with remote lymphoplasmacytic neoplasms. Glomerular injury concurrent with direct infiltration of the kidney by lymphoplasmacytic neoplasms has been reported but is not extensively characterized. We identified 18 patients, all presenting with elevated serum creatinine and many with proteinuria, whose renal biopsies showed direct involvement of kidney by a variety of neoplasms, including chronic leukocytic leukemia/small lymphocytic lymphoma (n = 7), diffuse large B-cell lymphoma (n = 6), multiple myeloma (n = 4), or B-cell lymphoblastic lymphoma (n = 1). In 10 cases (55%), there was coexistent glomerular pathology: 5 of these cases, including glomerulonephritis with membranoproliferative glomerulonephritis like pattern of injury (n = 4) and membranous nephropathy (n = 1), featured deposition of immune complexes; 2 demonstrated deposition of monoclonal immunoglobulin components: lambda light chain amyloidosis (n = 1) and light chain deposition disease (n = 1); 2 showed minimal change disease; and, in 1 case, there was focal crescentic pauci-immune-type glomerulonephritis. In addition, 1 biopsy revealed diabetic nephropathy and 3 showed nonspecific ischemic changes. In the remaining 4 cases, there were no significant glomerular abnormalities. In 11 cases (61%), the diagnosis of lymphoproliferative disease was established following the kidney biopsy. Our study indicates that lymphoplasmacytic neoplasms may be first diagnosed in renal biopsies performed for evaluation of renal dysfunction with or without proteinuria. Concurrent glomerular injury may be a direct result of the lymphoplasmacytic disorder through a paraprotein deposition process resulting in amyloid or monoclonal immunoglobulin deposition disease, or may be caused indirectly through immune-mediated mechanisms, as in the cases of glomerulonephritis with membranoproliferative glomerulonephritis-like pattern of injury, membranous nephropathy, and possibly minimal change disease. PMID- 21288560 TI - Global burden of disease as a result of indoor air pollution in Shaanxi, Hubei and Zhejiang, China. AB - Indoor air pollution in developing countries is a major global health problem, yet estimates of the global burden of disease vary widely and are associated with large uncertainty. The World Health Organization uses the fuel based approach to estimate 1.6 million premature deaths globally each year associated with exposure to indoor air pollution, of which 420000 are in China. The fuel based approach uses a ventilation factor to account for differences in indoor air concentrations and exposures in different parts of the world based on regional differences in stove technology. In China this approach assumes that flues eliminate the majority of indoor air pollution, with a ventilation factor of 0.25. To account for historic exposure leading to current disease patterns the ventilation factor was adjusted to 0.5 for adult health endpoints. Measurements in three Chinese provinces, Shaanxi, Hubei and Zhejiang, however, show that high PM(4) concentrations are present in kitchens and living rooms even with stoves with flues as a result of multiple stove and flue use. Comparison of Indian and Chinese indoor air concentrations suggests more appropriate ventilation factors in the range 0.76-1.0 for women and children, and 1.0 for men. Premature mortality in the three provinces using these estimates would be closer to 60600, rather than current estimates of 46000. With the addition of cardiovascular diseases these estimates would increase by 92000. Pollutant based estimates using measured indoor air concentrations and combined with dose-response estimates would imply a burden of disease of 157800 premature deaths including cardiovascular diseases, a tripling of current estimates. PMID- 21288561 TI - A model of greenhouse gas emissions from the management of turf on two golf courses. AB - An estimated 32,000 golf courses worldwide (approximately 25,600 km(2)), provide ecosystem goods and services and support an industry contributing over $ 124 billion globally. Golf courses can impact positively on local biodiversity however their role in the global carbon cycle is not clearly understood. To explore this relationship, the balance between plant-soil system sequestration and greenhouse gas emissions from turf management on golf courses was modelled. Input data were derived from published studies of emissions from agriculture and turfgrass management. Two UK case studies of golf course type were used, a Links course (coastal, medium intensity management, within coastal dune grasses) and a Parkland course (inland, high intensity management, within woodland). Playing surfaces of both golf courses were marginal net sources of greenhouse gas emissions due to maintenance (Links 0.4 +/- 0.1Mg CO(2)e ha(-1)y(-1); Parkland 0.7 +/- 0.2Mg CO(2)e ha(-1)y(-1)). A significant proportion of emissions were from the use of nitrogen fertiliser, especially on tees and greens such that 3% of the golf course area contributed 16% of total greenhouse gas emissions. The area of trees on a golf course was important in determining whole-course emission balance. On the Parkland course, emissions from maintenance were offset by sequestration from trees which comprised 48% of total area, resulting in a net balance of -4.3 +/- 0.9 Mg CO(2e) ha(-1)y(-1). On the Links course, the proportion of trees was much lower (2%) and sequestration from links grassland resulted in a net balance of 0.0 +/- 0.2Mg CO(2e) ha(-1)y(-1). Recommendations for golf course management and design include the reduction of nitrogen fertiliser, improved operational efficiency when mowing, the inclusion of appropriate tree-planting and the scaling of component areas to maximise golf course sequestration capacity. The findings are transferrable to the management and design of urban parks and gardens, which range between fairways and greens in intensity of management. PMID- 21288562 TI - Feasibility and safety of type C2 total extraperitoneal abdominal radical hysterectomy (TEARH) for locally advanced cervical cancer. AB - INTRODUCTION: Radical hysterectomy represents the gold standard treatment in patients with early-stage cervical cancer and a valid choice of treatment, after neoadjuvant chemotherapy (NACT), in locally advanced tumors. Laparotomy is still considered the standard approach for radical hysterectomy; however, the extraperitoneal route has been described as a valid alternative for pelvic lymphadenectomy, with shorter operative time, shorter ileus and reduced postoperative pain and hospitalization. We designed the first prospective study to evaluate the technique of total extraperitoneal radical hysterectomy for surgical treatment of locally advanced cervical cancer after platinum-based NACT, in terms of feasibility and safety. METHODS: Consecutive patients affected by locally advanced cervical carcinoma were considered for eligibility in this observational study. After a primary complete evaluation, all patients were submitted to platinum-based NACT. Inclusion criteria were: stage IB2-IIIB cervical carcinoma already submitted to neoadjuvant chemotherapy with a complete or partial response after three cycles of chemotherapy, WHO performance status<=1, adequate renal, hepatic and cardiac function, BMI<40, age<=75 years, no concurrent or previous malignant disease, no previous radiation therapy, and signed informed consent. Patients included in the study were submitted to type C2 extraperitoneal radical hysterectomy. RESULTS: From January 2006 to October 2008, 46 patients were enrolled and compared with a control group selected from the historical database. The mean operative time in the extraperitoneal radical hysterectomy group was 195 min (range: 120-240) versus 235 min (range: 215-310) in the intraperitoneal radical hysterectomy group (P<0.05). Median postoperative ileus was 32 h (range: 24-36) versus 67 h (range: 42-78) (P<0.05). VAS (Visual Analogue Scale) score at 24 and 48 h was 8 (range: 6-8) versus 8 (range: 6-9) (P=NS) and 3.5 (range: 2-7) versus six (range: 5-9) (P<0.05) respectively. No differences in terms of intraoperative and postoperative complications were recorded. CONCLUSIONS: Total extraperitoneal radical hysterectomy in locally advanced cervical cancer is feasible and safe. If compared with intraperitoneal abdominal radical hysterectomy, no significant differences in terms of surgical data or complications were found. Extraperitoneal radical hysterectomy seems to compare favorably to the intraperitoneal approach in terms of operative time, postoperative ileus, and VAS score at 48 h. PMID- 21288564 TI - Racial disparities in ovarian cancer surgical care: a population-based analysis. AB - OBJECTIVE: To investigate differences according to racial classification in the frequency of ovarian cancer-related surgical procedures and in access to high volume surgical providers among women undergoing initial surgery for ovarian cancer. METHODS: The Maryland Health Services Cost Review Commission database was accessed for women age >18years undergoing a surgical procedure that included oophorectomy for a malignant ovarian neoplasm between 7/1/01 and 6/30/09. Multivariate logistic regression analyses were used to evaluate for differences in the likelihood of selected surgical procedures and access to high-volume surgical providers (surgeons>=10 cases/year; hospitals>=20 case/year) according racial classification. RESULTS: A total of 2487 patients were identified who underwent a primary surgical procedure that included oophorectomy for a malignant ovarian neoplasm: White=1884 (75.4%), African-American=400 (16.1%), and other/unknown=203 (8.2%). Compared to White patients, African-American patients were significantly younger (mean age 55.4years vs 59.9years, P<0.0001) and less likely to have commercial insurance (28.5% vs 39.5%, p<0.0001). Compared to White patients, African-American racial classification was associated with a statistically significant and independent lower likelihood of hysterectomy (OR=0.53, 95%CI=0.42-0.66, p<0.0001), colon resection (OR=0.65, 95%CI=0.48-0.87, p=0.004), lymphadenectomy (OR=0.67, 95%CI=0.50-0.91, p=0.01), and surgery by a high-volume surgeon (OR=0.55, 95%CI=0.44-0.69, p<0.0001). CONCLUSIONS: Among women undergoing initial surgery for ovarian cancer, African-American patients are significantly less likely to be operated on by a high-volume surgeon and to undergo important ovarian cancer-specific surgical procedures compared to White patients. PMID- 21288565 TI - Challenges for the effective molecular imprinting of proteins. AB - Molecular imprinting is a technique that is used to create artificial receptors by the formation of a polymer network around a template molecule. This technique has proven to be particularly effective for molecules with low molecular weight (<1500 Da), and during the past five years the number of research articles on the imprinting of larger (bio)templates is increasing considerably. However, expanding the methodology toward imprinted materials for selective recognition of proteins, DNA, viruses and bacteria appears to be extremely challenging. This paper presents a critical analysis of data presented by several authors and our own experiments, showing that the molecular imprinting of proteins still faces some fundamental challenges. The main topics of concern are proper monomer selection, washing method/template removal, quantification of the rebinding and reproducibility. Use of charged monomers can lead to strong electrostatic interactions between monomers and template but also to undesired high aspecific binding. Up till now, it has not been convincingly shown that electrostatic interactions lead to better imprinting results. The combination of a detergent (SDS) and AcOH, commonly used for template removal, can lead to experimental artifacts, and should ideally be avoided. In many cases template rebinding is unreliably quantified, results are not evaluated critically and lack statistical analysis. Therefore, it can be argued that presently, in numerous publications the scientific evidence of molecular imprinting of proteins is not convincing. PMID- 21288566 TI - Enhancement of neurite outgrowth in PC12 cells by iron oxide nanoparticles. AB - Despite the many potential therapeutic applications of iron oxide nanoparticle such as its use as an imaging and targeting tool, its biological effects have not yet been extensively characterized. Herein, we report that iron oxide nanoparticles taken up by PC12 cells can enhance neurite outgrowth. PC12 cells exposed to both iron oxide nanoparticles and nerve growth factor (NGF) synergistically increased the efficiency of neurite outgrowth in a dose-dependent manner. This may have resulted from the activation of cell adhesion molecules that are associated with cell-matrix interactions through iron. Immunoblotting assays also revealed that both neural specific marker protein and cell adhesion protein expression were upregulated by iron oxide nanoparticles compared with non treated cells via activation of the mitogen-activated protein kinase (MAPK) signaling pathway. Our findings point to the possibility that iron oxide nanoparticles can affect cell-substrate interactions and regulate cell behaviors, which provides clinical insights into potential neurologic and therapeutic applications of iron oxide nanoparticles. PMID- 21288567 TI - The influence of the scaffold design on the distribution of adhering cells after perfusion cell seeding. AB - In natural tissues, the extracellular matrix composition, cell density and physiological properties are often non-homogeneous. Here we describe a model system, in which the distribution of cells throughout tissue engineering scaffolds after perfusion seeding can be influenced by the pore architecture of the scaffold. Two scaffold types, both with gyroid pore architectures, were designed and built by stereolithography: one with isotropic pore size (412 +/- 13 MUm) and porosity (62 +/- 1%), and another with a gradient in pore size (250-500 MUm) and porosity (35%-85%). Computational fluid flow modelling showed a uniform distribution of flow velocities and wall shear rates (15-24 s(-1)) for the isotropic architecture, and a gradient in the distribution of flow velocities and wall shear rates (12-38 s(-1)) for the other architecture. The distribution of cells throughout perfusion-seeded scaffolds was visualised by confocal microscopy. The highest densities of cells correlated with regions of the scaffolds where the pores were larger, and the fluid velocities and wall shear rates were the highest. Under the applied perfusion conditions, cell deposition is mainly determined by local wall shear stress, which, in turn, is strongly influenced by the architecture of the pore network of the scaffold. PMID- 21288568 TI - The mechanical coupling of adult marrow stromal stem cells during cardiac regeneration assessed in a 2-D co-culture model. AB - Postnatal cardiomyocytes undergo terminal differentiation and a restricted number of human cardiomyocytes retain the ability to divide and regenerate in response to ischemic injury. However, whether these neo-cardiomyocytes are derived from endogenous population of resident cardiac stem cells or from the exogenous double assurance population of resident bone marrow-derived stem cells that populate the damaged myocardium is unresolved and under intense investigation. The vital challenge is to ameliorate and/or regenerate the damaged myocardium. This can be achieved by stimulating proliferation of native quiescent cardiomyocytes and/or cardiac stem cell, or by recruiting exogenous autologous or allogeneic cells such as fetal or embryonic cardiomyocyte progenitors or bone marrow-derived stromal stem cells. The prerequisites are that these neo-cardiomyocytes must have the ability to integrate well within the native myocardium and must exhibit functional synchronization. Adult bone marrow stromal cells (BMSCs) have been shown to differentiate into cardiomyocyte-like cells both in vitro and in vivo. As a result, BMSCs may potentially play an essential role in cardiac repair and regeneration, but this concept requires further validation. In this report, we have provided compelling evidence that functioning cardiac tissue can be generated by the interaction of multipotent BMSCs with embryonic cardiac myocytes (ECMs) in two-dimensional (2-D) co-cultures. The differentiating BMSCs were induced to undergo cardiomyogenic differentiation pathway and were able to express unequivocal electromechanical coupling and functional synchronization with ECMs. Our 2-D co-culture system provides a useful in vitro model to elucidate various molecular mechanisms underpinning the integration and orderly maturation and differentiation of BMSCs into neo-cardiomyocytes during myocardial repair and regeneration. PMID- 21288569 TI - The suppression of prion propagation using poly-L-lysine by targeting plasminogen that stimulates prion protein conversion. AB - Poly-l-lysine (PLL), a homopolymer of amino acid l-lysine (LL), has been frequently used for drug delivery. Here, we report that PLL is an effective agent to inhibit propagation of prions that cause fatal and incurable neurologic disorders in humans and animals, termed prion diseases. In our recent investigation on prion propagation facilitated by conversion of the cellular prion protein (PrP) to the misfolded, disease-associated PrP (PrP(Sc)), we demonstrated that plasminogen stimulates PrP conversion as a cellular cofactor. In the current study, we targeted plasminogen using PLL and assessed its anti prion efficacy. The results showed that PLL strongly inhibited PrP(Sc) propagation in the cell-free, cell culture, and mouse models of prion disease. These results confirm the role of plasminogen in PrP(Sc) propagation, validates plasminogen as a therapeutic target to combat prion disease, and suggests PLL as a potential anti-prion agent. Therefore, our study represents a proof-of-concept that targeting plasminogen, a cofactor for PrP conversion, using PLL results in suppression of prion propagation, which represents a successful translation of our understanding on details of prion propagation into a potential therapeutic strategy for prion diseases. PMID- 21288570 TI - Mechanisms by which the inhibition of specific intracellular signaling pathways increase osteoblast proliferation on apatite surfaces. AB - Osteoblasts proliferate slowly on the surface of calcium phosphate apatite which is widely used as a substrate biomaterial in bone regeneration. Owing to poor adhesion signaling in the cells grown on the calcium phosphate surface, inadequate growth factor signaling is generated to trigger cell cycle progression. The present study investigated an intracellular signal transduction pathway involved in the slow cell proliferation in osteoblasts grown on the calcium phosphate surface. Small GTPase RhoA and phosphatase and tensin homolog (PTEN) were more activated in cells grown on the surface of calcium phosphate apatite than on tissue culture plate. Specific inhibition of RhoA and PTEN induced the cells on calcium phosphate apatite surface to proliferate at a similar rate as cells on tissue culture plate surface. Specific inhibition of ROCK, which is a downstream effector of RhoA and an upstream activator of PTEN also increased proliferation of these osteoblasts. Present results indicate that physical property of calcium phosphate crystals that impede cell proliferation may be surmounted by the inhibition of the RhoA/ROCK/PTEN pathway to rescue delayed proliferation of osteoblasts on the calcium phosphate apatite surface. In addition, specific inhibition of ROCK promoted cell migration and osteoblast differentiation. Inhibition of the RhoA/ROCK/PTEN intracellular signaling pathway is expected to enhance cell activity to promote and accelerate bone regeneration on the calcium phosphate apatite surface. PMID- 21288571 TI - Polycythemia vera evolving into a rapidly progressive Ph-negative del(5q) positive myeloproliferative neoplasm refractory to lenalidomide. PMID- 21288572 TI - WITHDRAWN: Focal adhesion kinase comes into focus for B-cell acute lymphoblastic leukemia treatment. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 21288573 TI - Structural and functional comparison of cytokine interleukin-1 beta from chicken and human. AB - Interleukin-1 beta (IL-1beta) is an important cytokine in the immune system. The properties of avian IL-1betas are less well understood than the mammalian IL 1betas, and there is no available structure of avian IL-1betas in the Protein Data Bank. Here, we report the crystal structures of wild-type and Y157F mutant IL-1betas from chicken. Both the wild-type and mutant IL-1betas share a beta trefoil conformation similar to that of human IL-1beta and also have an internal hydrophobic cavity. However, the cavity sizes clearly differ from that of human IL-1beta due to the packing of hydrophobic residues. Our studies also reveal that the relative thermal stability of IL-1betas does not correlate with cavity size but rather is dependent on the amino acid residues present around the cavity. This cavity serves as a scaffold for maintaining the structure of the IL-1beta core region but does not have a biological function per se. Moreover, we found that human IL-1beta cannot induce chemokine expression in chicken fibroblasts or elevate plasma cortisol levels in chickens, implying a lack of cross-species bioactivity. Close examination reveals that significant structural and sequence differences occur in the terminal and some loop regions between human and chicken IL-1betas. These variable regions have been shown to be critical for receptor binding, thus resulting in a lack of species cross-reactivity between human and chicken IL-1beta. PMID- 21288574 TI - p21 is dispensable for AID-mediated class switch recombination and mutagenesis of immunoglobulin genes during somatic hypermutation. AB - In B cells, activation-induced cytidine deaminase (AID) induces somatic hypermutation (SHM) at rearranged immunoglobulin (Ig) variable (V) regions. Previous studies have shown that both monoubiquitination of proliferating cell nuclear antigen (PCNA) and translesional DNA polymerase activity are important for inducing mutagenesis during SHM. Regulation of PCNA ubiquitination by p21, also known as Cdkn1a and p21(Cip1/Waf1), is an important mechanism that controls mutation loads in mammalian cells. In this study, we have assessed whether p21 has an in vivo function in regulating mutagenesis in B cells by analyzing SHM frequency in p21-deficient mice. Our results show that p21 is dispensable for SHM. This suggests that, during SHM of Ig genes, p21 does not act to regulate mutagenesis load. We also show that p21 transcript levels are the same in both wildtype and AID-deficient B cells during B cell activation, and that AID mediated class switch recombination (CSR) is not affected by p21 deficiency; thereby indicating that p21 regulation in B cells is not altered by AID-induced DNA damage and that p21 has no affect on AID-dependent Ig gene diversification. Our results suggest that regulation of p21 in activated B cells is probably more important for maintaining proper cell cycle progression as opposed to promoting SHM of Ig genes. PMID- 21288575 TI - Sequence analysis of Toll-like receptor genes 1-10 of goat (Capra hircus). AB - This study involved cloning and sequencing of the coding regions of all 10 Toll like receptor (TLR) genes of goat. Goat TLR 1-10 gene sequences revealed a high degree of nucleotide identity with sheep and cattle sequences (>90%) and 75-85% with pig, mouse and human sequences. At the amino acid level, 85-99% similarity was observed with sheep and cattle and 60-85% with pig, mouse and human. TLR9c DNA of goat showed the highest amino acid identity to that of sheep (99%) while TLR8 cDNA showed the lowest identity of 88.7% to that of sheep. Variations were seen in the number of leucine rich repeats (LRRs) of goat TLRs as compared to other ruminant species with maximum differences in the TLR3 gene. Phylogenetic analysis through molecular evolution and genetic analysis (MEGA) software and multi dimensional scaling revealed a high degree of conservation of goat TLRs with those from other species. However when the TIR domain of all the TLRs were compared, goat TLR7 TIR alone showed a high divergence of 19.3 as compared to sheep sequences. This is the first report of the full-length cDNA sequences of all the 10 TLR genes of goats which would be a useful tool for the study of evolutionary lineages and for phylogenetic analysis. PMID- 21288576 TI - Treatment of cattle with DNA-encoded Flt3L and GM-CSF prior to immunization with Theileria parva candidate vaccine antigens induces CD4 and CD8 T cell IFN-gamma responses but not CTL responses. AB - Theileria parva antigens recognized by cytotoxic T lymphocytes (CTLs) are prime vaccine candidates against East Coast fever in cattle. A strategy for enhancing induction of parasite-specific T cell responses by increasing recruitment and activation of dendritic cells (DCs) at the immunization site by administration of bovine Flt3L and GM-CSF prior to inoculation with DNA vaccine constructs and MVA boost was evaluated. Analysis of immune responses showed induction of significant T. parva-specific proliferation, and IFN-gamma-secreting CD4(+) and CD8(+) T cell responses in immunized cattle. However, antigen-specific CTLs were not detected. Following lethal challenge, 5/12 immunized cattle survived by day 21, whereas all the negative controls had to be euthanized due to severe disease, indicating a protective effect of the vaccine (p<0.05). The study demonstrated the potential of this technology to elicit significant MHC class II and class I restricted IFN gamma-secreting CD4(+) and CD8(+) T cells to defined vaccine candidate antigens in a natural host, but also underscores the need to improve strategies for eliciting protective CTL responses. PMID- 21288577 TI - Cranial conjoined twins: surgical and anesthetic challenges for a routine procedure: adenoidectomy and examination of ears. AB - Craniopagus conjoined twins have long been the subject of interest because of the rarity and peculiarity of their juxtaposition. We present the surgical, airway and anesthetic challenges in craniopagus conjoined twins, in which one of the twins underwent adenoidectomy for obstructive sleep breathing disorder. The surgical procedure required a special setting from an anesthetic perspective whereby both children needed anesthesia due to the complex physiology of their brains and cardiovascular systems. As well, we took the opportunity to do bilateral ear examinations of both twins. PMID- 21288578 TI - Correlation of physical aptitude; functional capacity, corporal balance and quality of life (QoL) among elderly women submitted to a post-menopausal physical activities program. AB - The objective of this study was to evaluate the effect of physical activity from the "Menopause in Form" program on physical aptitude, functional capacity, corporal balance and QoL among elderly women. In addition, correlations among these variables were examined. The present work was a longitudinal study that was quasi-experimental and correlational. A total of 323 elderly women (age: 69.0+/ 5.53 years) participated in this study. Subjects were non-institutionalized, post menopausal individuals residing at the Elderly Care Center in Belem Municipality (Para, Brazil) and practiced one activity (i.e., dancing or walking) over a 10 month period. The assessment protocols used were the following: the Fullerton functional fitness test battery (physical aptitude); the activities of daily living (ADL) indices (functional capacity); the Tinetti-scale (corporal balance); and the WHOQOL-OLD questionnaire (QoL). The adopted significance level was p<0.05. Results from the Wilcoxon test demonstrated significant differences for the post-test assessment of functional capacity (Delta%=5.63%; p=0.0001) and general QoL (Delta%=9.19%; p=0.001). These results suggest that the physical activities employed during the "Menopause in Form" program resulted in significant improvements in the functional capacity and QoL of post-menopausal elderly women. PMID- 21288579 TI - Incidence of early postoperative cognitive dysfunction and other adverse events in elderly patients undergoing elective total hip replacement (THR). AB - In elderly patients cognitive dysfunction and other adverse events (AEs) can impair the outcome of surgical procedures. As THR is performed with increasing frequency in aging populations, it is important to know the impact of these problems on the postoperative result. In this prospective cohort study 60 patients older than 65 years (66.7% female, 33.3% male) who received THR were included. The cognitive function was measured preoperatively, one week and six months postoperatively by the mini-mental state test (MMSE). Shortly after surgery 4 patients (6.7%) developed postoperative cognitive dysfunction, which has recovered at six-months-follow-up. In 41 patients (68.3%) AEs were recorded. Postoperative anemia occurred as the most common AE (n=32; 53.3%). During hospital stay older patients are at an increased risk for AEs. The incidence of postoperative cognitive dysfunction was observed less often than expected. Further research is necessary to assess the effect of early interventions in case of cognitive dysfunction. With use of a simple and quickly performed test like the MMSE patients can be effectively screened for impaired cognitive function. Secure identification of those patients is mandatory to avoid complications with harmful long-term effects. PMID- 21288580 TI - The decline in coronary heart disease mortality is slowing in young adults (Australia 1976-2006): a time trend analysis. AB - BACKGROUND: To examine whether the recent flattening of mortality rates for coronary heart disease (CHD) observed among young adults in the UK and the US is also occurring in the Australian population. METHODS: Mortality data from 1976 to 2006 were used to calculate overall age-adjusted and age-specific mortality rates for Australian adults aged >= 25 years. Joinpoint regression was fitted to estimate the annual change and detect points in time where significant changes in the trends occur. RESULTS: Between 1976 and 2006 age-adjusted CHD mortality rates declined by 73% in men and 70% in women. A steady decline continued in older groups. Beginning in 1991, a slowing of the fall in mortality rates was observed in younger men, and CHD mortality rates were essentially flat in men 25-34 years. Among men aged 35-44, a reduction of the decline in CHD mortality was observed from 1992, and likewise in men aged 45-54 years from 1994. Very similar patterns were observed in women with significant slowdowns starting in 1980, 1988 and 1991 for those aged 25-34 years, 35-44 years and 45-54 years respectively. CONCLUSIONS: In Australian men and women aged 25-54 years, the CHD mortality decline has slowed since the early 1990s. The most likely explanations for reduction of the CHD mortality decline are attenuations or reversal of the earlier declines in major traditional risk factors (tobacco smoking, serum cholesterol, blood pressure) and diabetes mellitus. PMID- 21288581 TI - A tale of two coronaries. PMID- 21288582 TI - CA-125 and heart failure. PMID- 21288583 TI - Network analysis of cattle and pig movements in Sweden: measures relevant for disease control and risk based surveillance. AB - Registration of cattle and pig movements is mandatory in Sweden and all registered movements between farms in the years 2006-2008 were investigated using network analysis. The networks were analysed as monthly and yearly networks, separately per species and with the two species together. Measures that have been previously discussed in relation to outbreaks and disease control were calculated; moreover a measure of the ingoing infection chain was constructed. The ingoing infection chain captures ingoing contacts through other holdings, taking the temporal aspect and sequence of the movements into account. The distribution of the contacts among the holdings was skewed. Many farms had few or no contacts, while others had many, a pattern which has also been described from other countries. The cattle network and the combined network showed a recurring seasonal pattern, while this was not seen in the pig network. The in-degree was not equivalent to the ingoing infection chain; there were holdings with limited direct contacts, but a large number of indirect contacts. The ingoing infection chain could be a useful measure when setting up strategies for disease control and for risk based surveillance as it identifies holdings with many contacts through live animal movements and thus at potentially higher risk for introduction of contagious diseases. PMID- 21288584 TI - A comparison of pooled and individual bird sampling for detection of Salmonella in commercial egg laying flocks. AB - The objective of this study was to determine the sensitivity of culturing pooled samples containing varying numbers of individual droppings for detection of Salmonella in commercial egg-laying flocks relative to the within-flock prevalence. A laboratory experiment was performed to directly measure the effect of diluting positive with negative faeces on the sensitivity of detection, and thus provide priors for a Bayesian model of pooled sampling. Pooled samples made up of different numbers of individual faecal droppings were collected from 20 flocks, and in addition bulked faeces and dust were also sampled using an in house method that involved collecting 10 dust and 10 faeces samples into jars with buffered peptone water. The results from these flocks were analysed using Bayesian methods for diagnostic test evaluation in the absence of a gold standard, and the sensitivity of each pooled sample type was estimated relative to the within-flock prevalence. The sensitivity of pooled samples depended on the within-flock prevalence, and increased as the prevalence increased. The sensitivity of pooled sampling tended to increase with the number of droppings in the pool, and overall there was a higher proportion of positive samples from the pools of 20, 60 and the in-house faeces pooling method compared to the pools of 10, 5 and the individual droppings. Dust samples were more sensitive than the faeces samples, and so the inclusion of dust in sampling schemes is recommended. PMID- 21288585 TI - The impact of emergency birth control on teen pregnancy and STIs. AB - We use panel data from local authorities in England between 1998 and 2004 to examine the differential impact of increased access for teenagers to emergency birth control (EBC) at pharmacies on teenage pregnancies and sexually transmitted infections (STIs). We estimate both difference-in-difference (DD) and the more robust difference-in-difference-in-differences (DDD) models. The DD estimates provide some evidence that pharmacy EBC schemes are associated with higher teenage conception rates, but this result is not upheld in the DDD models. In contrast both the DD and DDD models provide consistent evidence that pharmacy EBC schemes are associated with higher teenage STI rates. PMID- 21288586 TI - The effect of job loss on overweight and drinking. AB - This paper examines the impact of job loss due to business closings on body mass index (BMI) and alcohol consumption. We suggest that the ambiguous findings in the extant literature may be due in part to unobserved heterogeneity in response and in part due to an overly broad measure of job loss that is partially endogenous (e.g., layoffs). We improve upon this literature using: exogenously determined business closings, a sophisticated estimation approach (finite mixture models) to deal with complex heterogeneity, and national, longitudinal data from the Health and Retirement Study. For both alcohol consumption and BMI, we find evidence that individuals who are more likely to respond to job loss by increasing unhealthy behaviors are already in the problematic range for these behaviors before losing their jobs. These results suggest the health effects of job loss could be concentrated among "at risk" individuals and could lead to negative outcomes for the individuals, their families, and society at large. PMID- 21288587 TI - A novel synonymous substitution in the GCK gene causes aberrant splicing in an Italian patient with GCK-MODY phenotype. AB - GCK gene analysis in an Italian MODY patient revealed a novel synonymous substitution in exon 4 (c.459T>G; p.Pro153Pro) resulting in an aberrant transcript lacking the last eight codons of the same exon. Our findings emphazise the importance of not underestimating synonymous variations when screening for disease-causing mutations. PMID- 21288589 TI - Mismatch between diabetes diagnosis in primary care and recommended diagnostic criteria. PMID- 21288588 TI - Polymorphisms in fatty acid binding protein 5 show association with type 2 diabetes. AB - Genes for the fatty acid binding proteins (FABP) family encode small 14-15 kDa cytosolic proteins and can be regulated during type 2 diabetes mellitus (T2DM) and obesity. This study compared association of single nucleotide polymorphisms (SNPs) in FABP1-5 with T2DM in different ethnic groups. Associations with T2DM of SNPs in these proteins were assessed in African American (AA), non-Hispanic White (NHW), and Hispanic American (HA) individuals. A total of 650 DNA samples were genotyped; control samples were obtained from Coriell's North American Human Variation Panel Repository (NAHVP) of apparently healthy individuals and T2DM cases were taken from the American Diabetes Association GENNID Study. The rs454550 SNP of FABP5 showed a significant association with T2DM in NHW (OR: 9.03, 95% CI: 1.13-71.73, p=0.014). Our analysis also identified a new FABP5 SNP (nSNP) that showed a significant association with T2DM in NHW (OR: 0.44, 95% CI: 0.19-0.99, p=0.045) and AA (OR: 0.17, 95% CI: 0.03-0.80, p=0.016). The Ala54Thr FABP2 polymorphism was significantly associated with T2DM in HA individuals only (OR: 1.85, 95% CI: 1.05-3.27, p=0.032). All other FABP SNPs did not show association with T2DM. These findings suggest a potential distinct role(s) of SNPs in FABP5 and FABP2 genes in T2DM in different populations. PMID- 21288590 TI - Association between serum soluble TNFalpha receptors and renal dysfunction in type 2 diabetic patients without proteinuria. AB - AIM: The aim of our study was to investigate whether serum levels of soluble tumor necrosis factor alpha receptor (sTNFR) 1 and 2 are markers for renal dysfunction in type 2 diabetic patients without overt proteinuria. METHODS: Japanese type 2 diabetic patients without overt proteinuria (n = 168) enrolled in the prospective observational follow-up study in 2001 were retrospectively analyzed. At baseline, the serum levels of sTNFR1 and sTNFR2 were measured by sandwich ELISA. The associations between these markers and change in estimated glomerular filtration rate (eGFR) after 5 years were evaluated. RESULTS: The levels of sTNFR1 and sTNFR2 closely correlated. At baseline, sTNFR1 and sTNFR2 associated inversely with eGFR. After 5 years, patients with high level of both sTNFR1 and sTNFR2 showed a greater decline in eGFR (-13.8 +/- 15.5% versus -8.5 +/- 11.8%, P = 0.027) and a 4-fold higher risk for a GFR decline of >= 25% than those with high level of only one receptor or low level of both receptors. These associations were enhanced in diabetic women. CONCLUSIONS: The higher levels of sTNFR1 and sTNFR2 were associated with a greater decline in eGFR in type 2 diabetic patients without proteinuria, especially in diabetic women. PMID- 21288591 TI - Insects as innovative models for functional studies of DNA methylation. AB - The emerging field of epigenomics has the potential to bridge the gap between static genomic sequences and complex phenotypes that arise from multigenic, nonlinear and often context-dependent interactions. However, this goal can only be achieved if easily manageable experimental systems are available in which changes in epigenomic settings can be evaluated in the context of the phenotype under investigation. Recent progress in the characterization of insect DNA methylation patterns enables evaluation of the extent to which epigenetic mechanisms contribute to complex phenotypes in easily accessible organisms whose relatively small genomes are not only sparingly methylated, but the methylated sites are also found almost exclusively in gene bodies. The implementation of insect models in the study of DNA methylation will accelerate progress in understanding the functional significance of this important epigenetic mechanism in controlling gene splicing, in environmentally driven reprogramming of gene expression and in adult brain plasticity. PMID- 21288592 TI - A physiological Intensive Control Insulin-Nutrition-Glucose (ICING) model validated in critically ill patients. AB - Intensive insulin therapy (IIT) and tight glycaemic control (TGC), particularly in intensive care unit (ICU), are the subjects of increasing and controversial debate in recent years. Model-based TGC has shown potential in delivering safe and tight glycaemic management, all the while limiting hypoglycaemia. A comprehensive, more physiologically relevant Intensive Control Insulin-Nutrition Glucose (ICING) model is presented and validated using data from critically ill patients. Two existing glucose-insulin models are reviewed and formed the basis for the ICING model. Model limitations are discussed with respect to relevant physiology, pharmacodynamics and TGC practicality. Model identifiability issues are carefully considered for clinical settings. This article also contains significant reference to relevant physiology and clinical literature, as well as some references to the modeling efforts in this field. Identification of critical constant population parameters was performed in two stages, thus addressing model identifiability issues. Model predictive performance is the primary factor for optimizing population parameter values. The use of population values are necessary due to the limited clinical data available at the bedside in the clinical control scenario. Insulin sensitivity, S(I), the only dynamic, time varying parameter, is identified hourly for each individual. All population parameters are justified physiologically and with respect to values reported in the clinical literature. A parameter sensitivity study confirms the validity of limiting time-varying parameters to S(I) only, as well as the choices for the population parameters. The ICING model achieves median fitting error of <1% over data from 173 patients (N=42,941 h in total) who received insulin while in the ICU and stayed for >= 72 h. Most importantly, the median per-patient 1-h ahead prediction error is a very low 2.80% [IQR 1.18, 6.41%]. It is significant that the 75th percentile prediction error is within the lower bound of typical glucometer measurement errors of 7-12%. These results confirm that the ICING model is suitable for developing model-based insulin therapies, and capable of delivering real-time model-based TGC with a very tight prediction error range. Finally, the detailed examination and discussion of issues surrounding model based TGC and existing glucose-insulin models render this article a mini-review of the state of model-based TGC in critical care. PMID- 21288593 TI - An axisymmetric diffusion experiment for the determination of diffusion and sorption coefficients of rock samples. AB - Diffusion anisotropy is a critical property in predicting migration of substances in sedimentary formations with very low permeability. The diffusion anisotropy of sedimentary rocks has been evaluated mainly from laboratory diffusion experiments, in which the directional diffusivities are separately estimated by through-diffusion experiments using different rock samples, or concurrently by in diffusion experiments in which only the tracer profile in a rock block is measured. To estimate the diffusion anisotropy from a single rock sample, this study proposes an axisymmetric diffusion test, in which tracer diffuses between a cylindrical rock sample and a surrounding solution reservoir. The tracer diffusion between the sample and reservoir can be monitored from the reservoir tracer concentrations, and the tracer profile could also be obtained after dismantling the sample. Semi-analytical solutions are derived for tracer concentrations in both the reservoir and sample, accounting for an anisotropic diffusion tensor of rank two as well as the dilution effects from sampling and replacement of reservoir solution. The transient and steady-state analyses were examined experimentally and numerically for different experimental configurations, but without the need for tracer profiling. These experimental configurations are tested for in- and out-diffusion experiments using Koetoi and Wakkanai mudstones and Shirahama sandstone, and are scrutinized by a numerical approach to identify favorable conditions for parameter estimation. The analysis reveals the difficulty in estimating diffusion anisotropy; test configurations are proposed for enhanced identifiability of diffusion anisotropy. Moreover, it is demonstrated that the axisymmetric diffusion test is efficient in obtaining the sorption parameter from both steady-state and transient data, and in determining the effective diffusion coefficient if isotropic diffusion is assumed. Moreover, measuring reservoir concentrations in an axisymmetric diffusion experiment coupled with tracer profiling may be a promising approach to estimate of diffusion anisotropy of sedimentary rocks. PMID- 21288594 TI - Transduced PEP-1-FK506BP inhibits the inflammatory response in the Raw 264.7 cell and mouse models. AB - FK506 binding protein 12 (FK506BP) is an immunophilin that acts as a receptor for the immunosuppressant drug FK506. Although the precise action of FK506BP remains unclear, it has emerged as a potential drug target for several inflammatory diseases. This study investigated the protective effects of FK506BP on inflammation in vitro and in vivo using protein transduction. A cell-permeable expression vector PEP-1-FK506BP was constructed. Lipopolysaccharide (LPS)- or 12 O-tetradecanoylphorbol-13-acetate (TPA)-stimulated Raw 264.7 cells and ICR mice were treated with PEP-1-FK506BP. The expression of inflammatory response enzymes and cytokines was analyzed by Western blot, reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, and electrophoretic mobility shift assay. PEP-1-FK506BP efficiently transduced into Raw 264.7 cells and markedly inhibited the expression levels of cyclooxygenase-2 as well as pro inflammatory cytokines. Furthermore, transduced PEP-1-FK506BP significantly reduced activation of nuclear factor-kappa B (NF-kappaB) and phosphorylation of p38 mitogen-activated protein kinase (MAPK) in the cells, whereas PEP-1-FK506BP reduced phosphorylation of p38 and extracellular signal-regulated kinase (ERK) in the animal models. These results indicate that PEP-1-FK506BP inhibits inflammatory response cytokines and enzymes by blocking NF-kappaB and MAPK including the phosphorylation of p38 and/or ERK MAPK in vitro and in vivo, suggesting that PEP-1-FK506BP may be a therapeutic agent against inflammatory skin diseases. PMID- 21288595 TI - Hospital-wide survey of the use of central venous catheters. AB - There are few data on indications for central venous catheter (CVC) use. We conducted an observational, hospital-wide prospective cohort study to quantify the indications for catheter placement over dwell time and to investigate agreement between healthcare workers (HCWs) on CVC use. Catheter use was observed by on-site visits, HCW interviews, and screening of patient charts. A total of 378 CVCs were inserted in 292 patients, accounting for 2704 catheter-days. Of these, 93% CVCs were multilumen catheters and 70% were placed in the intensive care unit (ICU). Median dwell time (interquartile range) was 5 (2-9) days overall, and 4 (2-7) and 8 (3-15) in the ICU and non-ICU settings, respectively. The mean number of specified indications for CVC use per day was 1.7 (1.9 for ICU and 1.5 for non-ICU; P<0.001). The most frequent reason (49%) for catheter use was prolonged (>7 days) antibiotic therapy followed by parenteral nutrition (22.3%). A total of 130 catheter-days (4.8%) were unnecessary with a higher proportion in non-ICU settings (6.6%). In 94% of cases, there was agreement among HCWs on indications for CVC use. However, 35 on-site visits (8.3%) in non-ICU settings revealed that neither the nurse nor the treating physician knew why the catheter was in place. ICU catheters have a short dwell time but are utilised more often, whereas catheters in non-ICU settings show a reverse characteristic. Prevention measures targeting catheter care are more likely to be successful in non-ICU settings. PMID- 21288596 TI - Environmental survival of vancomycin-resistant Enterococcus faecium. PMID- 21288597 TI - One-year prognosis after syncope and the failure of the ROSE decision instrument to predict one-year adverse events. AB - STUDY OBJECTIVE: We investigate the incidence of adverse events at 1 year in the cohort of emergency department (ED) syncope patients enrolled in the original Risk Stratification of Syncope in the Emergency Department (ROSE) study, the time to adverse event, and the test performance of the ROSE decision instrument to detect events at 1 year. METHODS: This report details the 1-year follow-up of adult syncope patients presenting to the ED who were enrolled into the ROSE study, a single-center, prospective, observational cohort study. The primary endpoint was the combination of serious outcome and all-cause death at 1 year. Serious outcome encompassed acute myocardial infarction, life-threatening arrhythmia, need for pacemaker/implantable defibrillator, pulmonary embolus, cerebrovascular accident, intracranial or subarachnoid hemorrhage, and interventional procedure or hemorrhage requiring blood transfusion. Secondary endpoints were all-cause death and cardiovascular serious outcome at 1 year. RESULTS: One thousand forty-three patients were available for analysis; 162 patients (15.5%) had a primary outcome. Twenty-eight (17%) of these were within 24 hours, 56 (35%) were within 1 week, and 78 (48%) were within 1 month. The remaining 84 (52%) outcomes occurred between months 2 and 12. At 1 year, 71 (6.8%) patients had died and 76 (7.3%) had a cardiovascular serious outcome. The sensitivity and specificity of the ROSE decision instrument for 1-year serious outcome and all-cause death were, respectively, 71.6% (95% confidence interval [CI] 63.9% to 78.3%) and 71.1% (95% CI 67.9% to 74.0%); for 1-year all-cause death, 76.1% (95% CI 64.2% to 85.1%) and 67.4% (95% CI 64.3% to 70.3%); and for 1 year cardiovascular serious outcome, 75.0% (95% CI 63.5% to 83.9%) and 67.5% (95% CI 64.5% to 70.5%). CONCLUSION: The proportion of patients with serious outcome and all-cause death 1 year after syncope is similar to that reported in recent international syncope studies. We have defined the proportion of patients with cardiovascular serious outcome at 1 year and have shown that most events occurred in the first month, with decreased frequency of events observed after that time especially marked for cardiovascular serious outcome. More than 50% of the outcomes observed, however, occurred after the first month. The ROSE decision instrument does not perform well at predicting 1-year outcome of ED syncope patients. PMID- 21288598 TI - Effect of deferasirox on iron absorption in a randomized, placebo-controlled, crossover study in a human model of acute supratherapeutic iron ingestion. AB - STUDY OBJECTIVE: In 2005, the Food and Drug Administration approved deferasirox as an oral iron chelating agent for chronic iron overload. To determine usefulness in management of acute iron ingestion, we study the effect of orally administered deferasirox in healthy human adults. METHODS: A double-blinded, placebo-controlled, randomized, crossover study of 8 healthy human volunteers was conducted. Subjects ingested 5 mg/kg of elemental iron in the form of ferrous sulfate. One hour after iron ingestion, subjects were randomized to receive 20 mg/kg of deferasirox or placebo. Serial iron levels were then obtained. A 2-week washout was used between study arms. The paired t test was used to compare area under time-concentration curves from baseline to both 12- and 24-hour iron levels between groups. RESULTS: Baseline serum iron levels were similar in the 2 groups. Deferasirox significantly reduced serum iron area under concentration-time curves compared with placebo during both 1 to 12 hours and 1 to 24 hours (12 hour=577 MUmol-hour/L and 392 MUmol-hour/L, 95% confidence interval for the difference 15.8 to 353.0 MUmol-hour/L; 24 hour=808 MUmol-hour/L and 598 MUmol-hour/L, 95% confidence interval for difference 54.4 to 366.7 MUmol-hour/L). CONCLUSION: Orally administered deferasirox significantly reduced serum iron levels when administered 1 hour after iron ingestion during the 12- and 24-hour periods after acute ingestion of 5 mg/kg of elemental iron in healthy human volunteers. Further study is required to determine optimal dosing, but deferasirox may be an important addition to current therapy for acute iron poisoning. PMID- 21288599 TI - Influenza, hepatitis B, and tetanus vaccination coverage among health care personnel in the United States. AB - BACKGROUND: Health care personnel (HCP) are at risk for exposure to and possible transmission of vaccine-preventable diseases. Maintenance of immunity is an essential prevention practice for HCP. We assessed the recent influenza, hepatitis B, and tetanus vaccination coverage among HCP in the United States. METHODS: We analyzed data from the 2007 National Immunization Survey-Adult restricted to survey respondents aged 18 to 64 years. Influenza, hepatitis B, and tetanus vaccination coverage levels among HCP were assessed. Multivariable logistic regression was conducted to assess factors independently associated with receipt of vaccination among HCP. RESULTS: Among HCP aged 18 to 64 years, 46.7% (95% confidence interval [CI]: 39.6%-53.8%) had received influenza vaccination for the 2006-2007 season, and 70.4% (95% CI: 63.9%-76.1%) received tetanus vaccination in the past 10 years; 61.7% (95% CI: 52.5%-70.2%) had received 3 or more doses of hepatitis B vaccination among HCP aged 18 to 49 years. Multiple logistic regression analysis showed that being married was associated with influenza vaccination coverage, higher education level was associated with hepatitis B vaccination coverage, and younger age was significantly associated with tetanus vaccination among HCP. Among those HCP who did not receive influenza vaccination, the most common reason reported was respondent concerns about vaccine safety and adverse effects. CONCLUSION: By 2007, influenza and hepatitis B vaccination coverage among HCP remained well below the Healthy People 2010 objectives. Tetanus vaccination level was 70%, and this study provided a baseline data for tetanus vaccination among HCP. Innovative strategies are needed to further increase vaccination coverage among HCP. PMID- 21288600 TI - The effectiveness of sodium dichloroisocyanurate treatments against Clostridium difficile spores contaminating stainless steel. AB - BACKGROUND: Clostridium difficile is a major cause of hospital-associated infective diarrhea, and its spore form can persist for months in the hospital environment. Chlorine-based cleaning agents are recommended for eliminating this reservoir of potential infection. OBJECTIVES: To investigate the individual contributions of active chlorine, detergent and mechanical action on decontamination of a C difficile contaminated surface. METHODS: C difficile spores in test soil were dried onto stainless steel strips and exposed to sodium dichloroisocyanurate (NaDCC) or NaDCC combined with detergent (NaDCC+) or exposed to these cleaning formulations combined with wiping and/or detergent precleaning. After set contact times, remaining viable spores from the strips were recovered and enumerated by vortexing with glass beads, followed by membrane filtration. RESULTS: Compared with NaDCC, the inclusion of detergent in the NaDCC+ formulation did not improve the effectiveness of decontamination in any exposure only treatment at concentrations tested (P > .05). Combining wiping with exposure to the cleaning formulations improved decontamination effectiveness with further reductions in spore counts of 1.66- and 2.19-log(10) colony-forming units at 2 and 20 minutes, respectively, using NaDCC, and of 2.46 and 2.56 log(10) colony forming units at 2 and 20 minutes, respectively, using NaDCC+. Precleaning the strips by wiping with detergent before exposure to NaDCC was more effective than wiping with NaDCC or NaDCC+ at 10 and 20 minutes contact times. Wiping with NaDCC+ was more effective than NaDCC only at a 2-minute contact time. Wiping with detergent followed by subsequent wiping with NaDCC (1,000 ppm) was the most effective treatment tested with a 4.00-log(10) reduction observed. CONCLUSION: Rigorous precleaning with detergent and the associated physical removal of spores through the mechanical action associated with wiping are important factors in achieving effective decontamination of surfaces when using chlorine-based agents. PMID- 21288601 TI - [Obituary for doctor Victor Politano]. PMID- 21288602 TI - [Comment to "Immunohistochemical expression of microvascular density and carbonic anhidrase IX in renal carcinoma. Relation to histological type and tumoral progression"]. PMID- 21288603 TI - Synthesis and biological evaluation of 5-membered spiro heterocycle-benzopyran derivatives against myocardial ischemia. AB - The activation of ATP-sensitive potassium channels (K(ATP)), play a key role in an endogenous "self-defence" mechanism, known as ischemic preconditioning (IPC), which is fundamentally involved in the protection of the heart against the ischemia/reperfusion injury. Presently, it is widely accepted that IPC is mainly (albeit not exclusively) mediated by the activation of K(ATP) channels expressed in the mitochondrial inner membrane (mito-K(ATP)) rather than the sarcoplasmatic ones (sarc-K(ATP)). Consistently, exogenous activation of K(ATP) channels by pharmacological tools can be viewed as one of the most promising strategies for the therapy of myocardial ischemia. As part of our research program devoted to the synthesis and the evaluation of new cardioprotective agents, we extensively studied several six-membered spiro-heterocycle-benzopyran compounds endowed of a significant anti-ischemic activity. The positive results obtained, prompted us to further explore the influence on the biopharmacological effects, of the spiro substitution at C4 benzopyran nucleus by replacing the six-membered spirocycle of the most active compounds with 5-membered-one. The preliminary evaluation of the new compounds on cultured H9c2 cardiomyoblasts exposed to anoxia/reperfusion and on Langendorff-perfused rat hearts submitted to ischemia/reperfusion cycles, showed that some of them can exert a cardioprotective effect. This anti-ischemic activity was antagonized by 5-hydroxydecanoic acid, a selective blocker of mito K(ATP) channels, confirming the involvement of this channel in the cardioprotective activity. PMID- 21288604 TI - A novel artificial superoxide dismutase: non-covalent conjugation of albumin with a Mn(III) salophen type complex. AB - The approach of non-covalent conjugation has recently been used and a number of metal complexes have been encaged in a protein scaffold to form functional metallo proteins. Here we investigate a novel artificial superoxide dismutase enzyme based on the non-covalent conjugation of bovine serum albumin and the manganese(III) complex of N,N'-bis(salicylidene)-3,4-diaminobenzoic acid. We report the intriguing ability of the albumin environment to increase the SOD activity of the inorganic complex. We also determined the binding constant with BSA by CD spectroscopy. PMID- 21288605 TI - A Marriage of Convenience? A qualitative study of colleague supervision of Master's level dissertations. AB - The focus of this study is colleague supervision of Master's level dissertations. A qualitative study was undertaken and in-depth interviews with research supervisors (n=7) and students (n=7) who had experienced colleague supervision of masters' level dissertations in the previous four years were undertaken. Independent 'outsider' researchers were deployed to undertake the interviews. A thematic content analysis approach was utilised and an analogy of a 'Marriage of Convenience' was used to describe the various dimensions and significant chronological events of the student/supervisor relationship. Four data themes were identified and included: 'Match making and betrothal', 'Soul mates or not', 'Married life' and 'Giving birth'. The study's findings give rise to a number of recommendations that will be of interest to all healthcare educators who are involved in supervision of colleagues' academic research activities. PMID- 21288606 TI - The development and psychometric testing of the Satisfaction with Simulation Experience Scale. AB - AIM: This paper reports the development and psychometric testing of the Satisfaction with Simulation Experience Scale, an instrument designed to measure and compare differences in satisfaction levels between nursing students exposed to medium and high fidelity human patient simulation manikins. BACKGROUND: Student satisfaction is important to engaged and meaningful learning and it facilitates active and purposeful participation in simulation experiences. There are suggestions that student satisfaction may have some correlation with performance. Few studies have explored in a rigorous way the impact of manikin fidelity on nursing students' satisfaction with simulation experiences. METHOD: The items for the Satisfaction with Simulation Experience Scale were identified following a critical review of the literature. Content validly was established by use of an expert panel. During 2009 and 2010 the instrument was tested with second year (n=268) and third year nursing students (n=76) from one Australian university. Exploratory factor analysis with varimax rotation was used to determine construct validity and Cronbach's coefficient alpha determined the scale's internal consistency reliability. Differences in satisfaction levels between groups were analysed using an independent t test. Responses to an open ended question were categorised using thematic content analysis. RESULTS: The scale demonstrated satisfactory internal consistency (alpha 0.77). Exploratory factor analysis yielded a three-component structure termed Debriefing and Reflection, Clinical Reasoning, and Clinical Learning; each subscale demonstrated high internal consistency: 0.94; 0.86; 0.85 respectively. Mean satisfaction scores were high for each group. However, statistically significant differences were not apparent between second or third year students exposed to medium and high fidelity manikins. Content analysis identified 13 main categories including supplementing versus replacing clinical placements and the need for increased exposure to simulation sessions. CONCLUSION: The results of this study indicate that simulation is highly valued by students, irrespective of the level of fidelity. This raises questions about the value of investing in expensive simulation modalities. The Satisfaction with Simulation Experience Scale was reliable and valid for this cohort. Further research in different contexts would be valuable in extending upon this work. PMID- 21288607 TI - Third year nursing students' understanding of how to find and evaluate information from bibliographic databases and Internet sites. AB - The aim of this study was to increase undergraduate nursing students' knowledge of finding and evaluating information from selected bibliographic databases and Internet sites. A quasi-experimental design was adopted. The 2004 autumn cohort (n=480) was divided into two approximately equal groups at the beginning of their studies. One group was subjected to a greater number of assignments requiring them to find and evaluate bibliographic and Internet-based information. The assignments were spread throughout the curriculum. Questionnaires were used to collect data. The low response rate makes generalizing the findings difficult. Only small differences were demonstrated between the knowledge of the revised assignment group and that of the other students. Both groups had a poor understanding of the use of important search and evaluation techniques. The results indicate that strategies proven in one context are not necessarily as effective in a new context and that more research is needed into which learning activities best enhance the development of information literacy skills during undergraduate nursing education. PMID- 21288608 TI - A comparison of the cooperative learning and traditional learning methods in theory classes on nursing students' communication skill with patients at clinical settings. AB - The purpose of this study was to compare the effect of traditional learning and cooperative learning methods on nursing students' communication skill with patients. This was an experimental study in which 34 nursing students in their 2nd semester of program participated. They were divided randomly into two groups, a control group who were taught their medical/surgical nursing course by traditional learning method and an experimental group, who were taught the same material using cooperative learning method. Before and after the teaching intervention, the students' communication skills with patients at clinical settings were examined. The results showed that no significant difference between the two groups in students' communication skills scores before the teaching intervention, but did show a significant difference between the two groups in the interaction skills and problem follow up sub-scales scores after the teaching intervention. This study provides evidence that cooperative learning is an effective method for improving and increasing communication skills of nursing students especially in interactive skills and follow up the problems sub-scale, thereby it is recommended to increase nursing students' participation in arguments by applying active teaching methods which can provide the opportunity for increased communication skills. PMID- 21288609 TI - Pilot testing of guidelines to support good practice in the development of professional portfolios. AB - AIMS: The aims of this study were to evaluate whether the introduction of new evidence based portfolio guidelines helped students and assessors to understand the expectations for completion of a clinical practice portfolio, and whether this understanding resulted in the submission of evidence consistent with the guidelines. METHODS: New evidence based portfolio guidelines were introduced to an undergraduate BSc (Hons) Radiography (Diagnostic) programme. A total of 134 students completed 12 item questionnaires relating to using the portfolio guidelines. Semi-structured interviews were undertaken with 12 students and 5 lecturer practitioners. Documentary analysis was undertaken on 26 portfolios. RESULTS: Survey data indicated that the new guidelines increased students' understanding of portfolio evidence requirements. Statistically significant increases in scores were evident for only two out of 12 questions; these related to understanding the need for critical reflection and which elements of the portfolio would be rewarded in assessment. Survey data also indicated some dissatisfaction with the role of lecturer practitioners and clinical assessors in relation to portfolio development. Interviews provided more mixed perceptions of the contribution of enhanced guidelines and identified some reasons for dissatisfaction with the lecturer practitioner and clinical assessor role. Documentary analysis indicated that whilst the guidelines improved students' and lecturers' understanding of evidence requirements, this did not translate into portfolio evidence which matched guideline expectations. Portfolio evidence was restricted to meeting the minimum profession specific task requirements and often indicated a mis-match between guideline expectations and assessor assessment judgements. CONCLUSIONS: New evidence based guidelines improved understanding of evidence and presentation requirements for clinical practice portfolios. Consistent interpretation of portfolio guidelines however requires structured preparation and ongoing support of students, assessors and lecturers if the pedagogic aims for clinical portfolio use are to become an integral part of providing evidence of meeting professional competence requirements. PMID- 21288610 TI - Knowledge of and attitudes toward tuberculosis of Turkish nursing and midwifery students. AB - AIM: The aim of the study was to describe the level of knowledge and the attitudes of Turkish nursing and midwifery students toward tuberculosis in an attempt to understand and determine whether there is a need for improvement in nursing and midwifery education regarding tuberculosis. METHOD: The research is a descriptive study conducted at four nursing or midwifery schools in Turkey. The sample was composed of 615 students who were first-, second-, third-, or fourth year nursing and midwifery students. Data were collected using the Knowledge and Attitudes toward Treatment and Control of Tuberculosis Questionnaire. RESULTS: The level of tuberculosis knowledge was poor [7.22+/-1.92 (range: 2-9)]. The attitudes of nursing and midwifery students toward tuberculosis were generally negative. Only 5.9% of the sample would prefer to care for patients with tuberculosis. Students who received tuberculosis lectures/education had higher levels of knowledge and more positive attitudes toward tuberculosis than their peers who did not receive such education. CONCLUSION: In order to fight effectively against tuberculosis, positive attitudes toward tuberculosis must be developed among health care teams, and awareness of tuberculosis via theoretical and practical education, starting from the initial semesters of the professional education, must be increased. PMID- 21288611 TI - Influence of magnesium status and magnesium intake on the blood glucose control in patients with type 2 diabetes. AB - BACKGROUND & AIMS: This study was undertaken to assess magnesium intake and magnesium status in patients with type 2 diabetes, and to identify the parameters that best predict alterations in fasting glucose and plasma magnesium. METHODS: A cross-sectional study was carried out in patients with type 2 diabetes (n = 51; 53.6 +/- 10.5 y) selected within the inclusion factors, at the University Hospital Onofre Lopes. Magnesium intake was assessed by three 24-h recalls. Urine, plasma and erythrocytes magnesium, fasting and 2-h postprandial glucose, HbA1, microalbuminuria, proteinuria, and serum and urine creatinine were measured. RESULTS: Mean magnesium intake (9.37 +/- 1.76 mmol/d), urine magnesium (2.80 +/- 1.51 mmol/d), plasma magnesium (0.71 +/- 0.08 mmol/L) and erythrocyte magnesium (1.92 +/- 0.23 mmol/L) levels were low. Seventy-seven percent of participants presented one or more magnesium status parameters below the cut-off points of 3.00 mmol/L for urine, 0.75 mmol/L for plasma and 1.65 mmol/L for erythrocytes. Subjects presented poor blood glucose control with fasting glucose of 8.1 +/- 3.7 mmol/L, 2-h postprandial glucose of 11.1 +/- 5.1 mmol/L, and HbA1 of 11.4 +/- 3.0%. The parameters that influenced fasting glucose were urine, plasma and dietary magnesium, while plasma magnesium was influenced by creatinine clearance. CONCLUSIONS: Magnesium status was influenced by kidney depuration and was altered in patients with type 2 diabetes, and magnesium showed to play an important role in blood glucose control. PMID- 21288612 TI - Effects of a whey protein supplementation on intrahepatocellular lipids in obese female patients. AB - BACKGROUND & AIMS: High protein diets have been shown to improve hepatic steatosis in rodent models and in high-fat fed humans. We therefore evaluated the effects of a protein supplementation on intrahepatocellular lipids (IHCL), and fasting plasma triglycerides in obese non diabetic women. METHODS: Eleven obese women received a 60 g/day whey protein supplement (WPS) for 4-weeks, while otherwise nourished on a spontaneous diet, IHCL concentrations, visceral body fat, total liver volume (MR), fasting total-triglyceride and cholesterol concentrations, glucose tolerance (standard 75 g OGTT), insulin sensitivity (HOMA IS index), creatinine clearance, blood pressure and body composition (bio impedance analysis) were assessed before and after 4-week WPS. RESULTS: IHCL were positively correlated with visceral fat and total liver volume at inclusion. WPS decreased significantly IHCL by 20.8 +/- 7.7%, fasting total TG by 15 +/- 6.9%, and total cholesterol by 7.3 +/- 2.7%. WPS slightly increased fat free mass from 54.8 +/- 2.2 kg to 56.7 +/- 2.5 kg, p = 0.005). Visceral fat, total liver volume, glucose tolerance, creatinine clearance and insulin sensitivity were not changed. CONCLUSIONS: WPS improves hepatic steatosis and plasma lipid profiles in obese non diabetic patients, without adverse effects on glucose tolerance or creatinine clearance. TRIAL NUMBER: NCT00870077, ClinicalTrials.gov. PMID- 21288613 TI - Fibula raspatory: a new tool for harvesting microvascular fibular transplants. PMID- 21288614 TI - Polymorphous low grade adenocarcinoma: case series and review of surgical management. AB - PURPOSE: The aim of the present study was to review the published data regarding the management of polymorphous low-grade adenocarcinoma (PLGA) and present our experience in the treatment of patients diagnosed with PLGA. MATERIALS AND METHODS: We performed a review of the published data of the treatment possibilities for PLGA, and report on a case series of 4 patients diagnosed with palatal PLGA. RESULTS: The mean age at diagnosis was 61.75 years. All cases were localized on the hard palate. The male/female ratio was 1:3. One patient had an ulcerative painful lump. In correlation with the published data, most of our patients presented initially with a diagnosis that was not conclusive for the presence of PLGA. The most common initial diagnostic findings were adenoid cystic carcinoma and pleomorphic adenoma. The treatment of choice was surgical excision of the tumor with safe margins of 1.5 cm. One patient had a positive cervical lymph node metastasis and underwent an elective neck dissection followed by radiotherapy. Local recurrence was diagnosed in 1 patient 6 years after the surgical management. Most cases were reconstructed using an obturator, except for 1 patient who underwent reconstruction using the temporalis myofascial flap. CONCLUSIONS: PLGA is a slow-growing, distinct, uncommon neoplasm of the minor salivary glands. Because it is characterized by a diverse morphologic pattern that resembles adenoid cystic carcinoma or pleomorphic adenoma, the initial diagnosis is usually inconclusive. Until a final diagnosis has been made, we believe that the reconstruction possibilities should be mainly obturators to allow a good visualization of the surgical site. The use of microvascular free flaps or rotational flaps should be reserved to patients with clearer pathologic diagnosis. PMID- 21288615 TI - Osteosarcoma of the jaws: factors influencing prognosis. AB - PURPOSE: To evaluate patient, tumor, and treatment variables associated with survival in patients with jaw osteosarcoma (JOS) and to compare survival in patients treated before 1991 with those managed with more aggressive treatment protocols since 1992. PATIENTS AND METHODS: This is a retrospective cohort study of patients with JOS treated at Massachusetts General Hospital from 1967 through 2007. Patients were divided by treatment date into Group 1, 1967 to 1991 (n = 30) and Group 2, 1992 to 2009 (n = 17). Medical records were reviewed to collect the following: demographic, radiographic, tumor-specific, treatment, and survival data. The 2 subgroups were statistically compared. RESULTS: There were 47 patients (32 males, 15 females) with a mean age of 30.9 years (range 4 to 74). Mandibular location showed a trend toward improved survival (P = .06). Average tumor size was 4.38 cm (range 0.5 to 9.0 cm). Larger tumors were associated with decreased overall survival (P = .016). Higher grade tumors had decreased overall survival (P = .01). Clear surgical margins were obtained in 67% of patients. Clear surgical margins correlated with improved survival (P = .002). Maxillary JOS constituted 83% of those with positive margins. Overall, 5-year survival was 68%. Improved 5-year survival was noted in group 2 (77%) compared with group 1 (52%) [P = .0073]. Patients who developed secondary osteosarcomas (n = 10) had 4.5-fold increased risk of death (P = .01). Recurrence was associated with 7-fold increased risk of death (P = .0008). Thirteen patients died of JOS. CONCLUSIONS: Improved survival was noted in treatment group 2. This group benefited from improved imaging, earlier diagnosis and more aggressive treatment that included improved surgical clearance. A clear survival advantage for neoadjuvant chemotherapy was not demonstrated. PMID- 21288616 TI - Coronectomy in patients with high risk of inferior alveolar nerve injury diagnosed by computed tomography. AB - PURPOSE: Previous studies have suggested coronectomy as an alternative procedure to decrease the risk of inferior alveolar nerve (IAN) injury when there are high risk findings observed on panoramic radiographs. However, the exact relation between the inferior alveolar canal and the roots is not obvious on 2-dimensional imaging. The aim of this study was to evaluate the success of coronectomy by comparing it with conventional extraction for the treatment of the patients who had clear IAN injury risks that were determined on 3 dimensions by computed tomography. PATIENTS AND METHODS: Two hundred and sixteen teeth of 124 patients were evaluated by computed tomography and 175 teeth of 120 patients were enrolled in the study. Teeth were divided into an extraction group (n = 87) and a coronectomy group (n = 88) according to the operations planned. RESULTS: The mean follow-up time of the study was 17.29 months. There were 2 patients in the extraction group who had moderate IAN injuries that resolved in 1 month. Also 1 case of dry socket was observed in the extraction group and 1 patient in the coronectomy group had minor infection 1 month postoperatively, which was treated with antibiotics and subgingival irrigations. There were 2 failed coronectomies and neither had any postoperative complications. No cases of lingual nerve injury were noted in this study. CONCLUSIONS: Coronectomy appears to be a preferable alternative with a low incidence of complications and therefore a suggested technique for the treatment of impacted mandibular molars when there is a high risk of IAN injury. PMID- 21288617 TI - [Myoplasty by reversal of the pectoris major muscle in the treatment of mediastinitis. A case report and review of the literature]. AB - Mediastinitis are among the most dreadful infectious complications following cardiac surgery. Their prognosis depends essentially on the precociousness of the diagnosis. In most of the cases, the medical treatment associated with an irrigation drainage is sufficient. But in case of severe sternal dehiscence, plastic surgery becomes necessary in order to fill up the loss with a well vascularized tissue. We report the case of a 78-year-old patient, chronic bronchitic who presented, after a coronary artery bypass, an aseptic sternal dehiscence necessitating an osteosynthesis, then a Klebsiella pneumoniae mediastinitis with an enlarged sternal necrosis which was treated by bone resection and a myoplasty via reversal of the right pectoris major muscle. The postsurgery course was favourable. Now, after one-year remote, cicatrisation is complete and we have not noticed any infectious recurrence. PMID- 21288618 TI - [About perforator flaps...20 years later]. AB - Despite the birth of reconstructive surgery 2000 years ago, the main advances in this field appeared in the second half of the 20th century. Born in Asia, it is from that same continent that the last improvement has occurred through the perforator flap concept. Combining advances in the understanding of cutaneous blood supply and advances in surgical instrumentation to optimize the reconstruction while reducing morbidity is gradually becoming a reality. Twenty years after the first perforator flap described by Koshima and Soeda, the authors review the history, the concept and nomenclature of these flaps. Furthermore, through an analyze of the international literature, the authors attempt to achieve an assessment of the reliability and morbidity of perforator flaps after 2 decades of existence. PMID- 21288620 TI - Preliminary study of the effect on the lungs due to the consumption of cocaine base paste. PMID- 21288619 TI - Nuclear translocation of the glucocorticoid receptor in fibroblasts of asthmatic patients with nasal polyposis insensitive to glucocorticoid treatment. AB - BACKGROUND: Nasal polyposis (NP) is treated with topical glucocorticoids (GC). Some patients require endoscopic nasal surgery because GC treatment is ineffective. To exert its function, the GC needs to bind with the GC receptor (GR) and the GC-GR complex moves to the cell nucleus. Our aim was to establish whether the poor response to GC is due to an alteration in the translocation of the GR to the nucleus. METHODS: We performed nasal fibroblast cell cultures from seven healthy controls and 12 patients with NP and asthma. Fibroblasts were incubated with budesonide or dexamethasone (10(-7) M) for different times (30 min to 4 h) and GR translocation was analyzed by immunocytochemistry. RESULTS: Both GC induced GR translocation in every group, doubling its concentration in the cell nucleus (30 min) compared to baseline. There were no differences in GR translocation between controls and patients, nor differences related to the severity of asthma or intolerance to non-steroidal anti-inflammatory drugs (NSAIDs). Atopic subjects showed a decrease in GR translocation with budesonide (1 h, 3 h and 4 h, P<0.05) and dexamethasone (30 min and 2 h, P<.05). CONCLUSIONS: The insensitivity to GC treatment does not appear to be due to an alteration in GR translocation to the nucleus. Neither does the severity of asthma or intolerance to NSAIDs appear to alter GR translocation. The association between atopy and the alteration in GR function deserves further investigation. PMID- 21288621 TI - Elastofibroma dorsi: an uncommon and under-diagnosed tumour. AB - Elastofibroma dorsi is a relatively rare soft-tissue tumour localized at the infra-scapular level and/or subscapular regions. It usually occurs between the fourth and seventh decade of life, and is more common in females. We reviewed sixteen elastofibromas diagnosed in 12 patients (7 females, 58.3%). Four patients had bilateral elastofibromas. The most common symptom was pain. Presumptive diagnosis was made by physical examination. Chest ultrasound, computed tomography and/or magnetic resonance imaging were performed to confirm the diagnosis. Surgery was performed under general anaesthesia. No major complications were observed. Elastofibromas are tumours of the chest wall with an uncertain impact. Surgical resection is indicated only in symptomatic patients. PMID- 21288622 TI - Guillain-Barre syndrome as an initial manifestation of small cell lung carcinoma. PMID- 21288623 TI - Out-of-hospital cardiac arrests in the older age groups in Melbourne, Australia. AB - BACKGROUND: Controversy exists around CPR in the elderly. The characteristics and outcomes of out-of-hospital cardiac arrest (OHCA) in this age group were studied in Melbourne, Australia. METHODS: The Victorian Ambulance Cardiac Arrest Registry (VACAR) was searched for all OHCAs not witnessed by Emergency Medical Services (EMS) occurring in those aged 65 years and older. RESULTS: Between 2000 and 2009 there were 30,006 OHCAs of which 9703 (32%) were in people 65-79 years of age, 6430 (21%) in octogenarians, 1530 (5%) in nonagenarian and 40 (0.1%) in centenarians. Rates of attempted resuscitation decreased with advancing age: 48% for those aged 65-79 years, 39% for octogenarians, 31% for nonagenarians and 17% for centenarians. Similarly rates of survival to hospital discharge decreased with age: 8% for those aged 65-79 years, 4% for octogenarians, 2% for nonagenarians; for 65-79 year olds, octogenarians and nonagenarians survival if in VF/VT was - 17%, 10% and 4%; asystole - 1%, 1% and 0.5%; and PEA - 6%, 3% and 3%, respectively. Multivariable logistic regression shows that between 2000 and 2009 rates of transportation with return of spontaneous circulation have improved for both shockable and non-shockable rhythms [OR 95% CI 1.07(1.04-1.10) and 1.16(1.12-1.20), respectively] but survival to hospital discharge has improved in the shockable rhythm group only [OR 1.12(1.07-1.16)]. CONCLUSION: Outcomes for OHCA with shockable rhythm have improved over the last 10 years for people aged 65 years and over. Quality of life studies should be performed to help inform the community and EMS on appropriate resuscitative efforts. PMID- 21288624 TI - Out-of-hospital airway management in the United States. AB - OBJECTIVE: Prior studies describe airway management by single EMS agencies, regions or states. We sought to characterize out-of-hospital airway management interventions, outcomes and complications across the United States. METHODS: Using the 2008 National Emergency Medical Services Information System (NEMSIS) Public-Release Data Set containing data from 16 states, we identified patients receiving advanced airway management, including endotracheal intubation (ETI), alternate airways (Combitube, Laryngeal Mask Airway (LMA), King LT, Esophageal Obturator Airway (EOA)), and cricothyroidotomy (needle and open). We examined airway management success and complications in the full cohort and in key subsets (cardiac arrest, non-arrest medical, non-arrest injury, children <10 and 10-19 years, rapid-sequence intubation (RSI), population setting and US census region). We analyzed the data using descriptive statistics. RESULTS: Among 4,383,768 EMS activations, there were 10,356 ETI, 2246 alternate airways, and 88 cricothyroidotomies. ETI success rates were: overall 6482/8418 (77.0%; 95% CI: 76.1-77.9%), cardiac arrest 3494/4482 (78.0%), non-arrest medical 616/846 (72.8%), non-arrest injury 417/505 (82.6%), children <10 years 295/397 (74.3%), children 10-19 years 228/289 (78.9%), adult 5829/7552 (77.2%), and rapid-sequence intubation 289/355 (81.4%). ETI success was success was lowest in the South US census region. Alternate airway success was 1564/1794 (87.2%). Major complications included: bleeding 84 (7.0 per 1000 interventions), vomiting 80 (6.7 per 1000) and esophageal intubation 12 (1.0 per 1000). CONCLUSIONS: In this study characterizing out-of-hospital airway management across the United States, we observed low out-of-hospital ETI success rates. These data may guide national efforts to improve the quality of out-of-hospital airway management. PMID- 21288625 TI - Type-specific human papillomavirus DNA testing with the genotyping array: a comparison of cervical and vaginal sampling. AB - OBJECTIVE: To compare the detection and typing of human papillomavirus (HPV) between vaginal and cervical specimens by using polymerase chain reaction (PCR) based reverse-blot genotyping arrays. STUDY DESIGN: Two hundred and fifty-two women were referred to colposcopy clinics because of suspicious or positive results in a community-based cervical cancer-screening program. Genital tract cells were sampled from the cervix and self-collected from the vagina and tested with the HPV Blot kit. RESULTS: The HPV Blot kit identified HPV infection in 24.7% of vaginal specimens and in 30.2% of cervical collections. Cervical sampling detected significantly more infections compared to vaginal sampling only for HPV type 52; cervical sampling also detected significantly more high-risk HPV infection overall. The sensitivities of detecting histology >= cervical intraepithelial neoplasia (CIN) grade 3 using the HPV Blot in vaginal and cervical specimens were 75.0% (95% CI, 47.6-92.7%) and 87.5% (95% CI, 61.6 98.4%), respectively (P=0.48). Both sampling methods were thus statistically effective at detecting high-grade lesions and cervical cancer (P<0.0001). CONCLUSIONS: The HPV Blot yielded similar results for both vaginal sampling and cervical sampling in the detection of CIN grade 3 or worse. These findings indicate that self-sampling for HPV testing is a viable cervical cancer screening option. PMID- 21288626 TI - Maternal characteristics largely explain poor pregnancy outcome after hyperemesis gravidarum. AB - OBJECTIVE: To describe the characteristics of women who suffer from hyperemesis gravidarum, and explore the independent effect of hyperemesis gravidarum on pregnancy outcome. STUDY DESIGN: In The Netherlands Perinatal Registry, we used all data on singleton pregnancies of at least 24 weeks and 500 g without congenital anomalies in the years 2000-2006. We examined the characteristics of women who suffered from hyperemesis gravidarum and their children. RESULTS: Women who suffered from hyperemesis gravidarum were slightly younger; more often primiparous, of lower socio-economic status, of non-Western descent and substance abusers; had more often conceived through assisted reproduction techniques and more often had pre-existing hypertension, diabetes mellitus and psychiatric diseases than women who did not suffer from hyperemesis gravidarum. Also, their pregnancies were more often complicated by hypertension and diabetes and they more often carried a female fetus. Pregnancies complicated by hyperemesis gravidarum significantly more often had an adverse outcome (prematurity or birth weight below the 10th percentile). The increased risk of adverse pregnancy outcomes after hyperemesis gravidarum was largely explained by the differences in maternal characteristics (crude OR 1.22 (95% CI 1.10-1.36), adjusted OR was 1.07 (95% CI 0.95-1.19)). CONCLUSION: Hyperemesis gravidarum is associated with adverse pregnancy outcomes. This is largely explained by differences in maternal characteristics. Given the impact of the early environment on later health (which is independent of size at birth), studies that aim to assess the long-term consequences of hyperemesis gravidarum need to be given high priority. PMID- 21288627 TI - Comparison of the efficacy of low anterior resection with primary anastomosis and Hartmann's procedure in advanced primary or recurrent epithelial ovarian cancer. AB - OBJECTIVE: We compared the efficacy between low anterior resection with primary anastomosis (LARA) and Hartmann's procedure (HP) in advanced primary or recurrent epithelial ovarian cancer (EOC). STUDY DESIGN: We reviewed medical records of 61 patients with advanced primary or recurrent EOC who underwent LARA or HP between January 1998 and August 2008. In 37 patients with primary FIGO stage III-IV EOC, 22 and 15 received LARA and HP, whereas 10 and 14 underwent LARA and HP in 24 patients with recurrent EOC. RESULTS: Postoperative complications (recto-vaginal fistula, leakage at the anastomotic site, postoperative ileus for >= 7 days, wound dehiscence, angina pectoris, acute renal failure, febrile illness, reoperation within 30 days and postoperative death), surgical outcomes (time of operation, estimated blood loss, transfusion, postoperative hospitalization and time to normal diet) were not different between LARA and HP. Progression-free survival (median, 20 vs. 17 months) and overall survivals (median, 70 vs. 36 months) in advanced primary EOC, and surgery-specific survival (median, 32 vs. 17 months) and overall survivals (median, 52 vs. 61 months) in recurrent EOC were also not different between LARA and HP (p>0.05). Moreover, the recto-sigmoid obstruction after LARA was developed in 9.1% in advanced primary EOC and 10% in recurrent EOC, and the stoma-free rates were high in LARA (90.9% in advanced primary EOC; 90% in recurrent EOC). CONCLUSIONS: LARA may be an optimal procedure for bowel surgery without differences in postoperative complication, surgical outcomes and survival when compared with Hartmann's procedure in advanced primary or recurrent EOC. Furthermore, the high stoma-free rate after LARA can improve postoperative quality of life by avoiding the permanent stoma formation. PMID- 21288628 TI - Treatment of moderate acne vulgaris using a combined oral contraceptive containing ethinylestradiol 20 MUg plus drospirenone 3mg administered in a 24/4 regimen: a pooled analysis. AB - OBJECTIVE: To investigate the effects of an ethinylestradiol (EE) 20 MUg/drospirenone (drsp) 3mg combined oral contraceptive (COC) administered in a 24/4 regimen (24 active tablets/4 inert tablets per cycle) for the treatment of moderate acne vulgaris, based on a pooled analysis of two identically designed US studies. STUDY DESIGN: Healthy females (n=893) aged 14-45 years with moderate facial acne were randomised to EE 20 MUg/drsp 3mg COC (n=451) or placebo (n=442) for six cycles. Primary outcome measures were mean percent change in acne lesion counts and the investigators' assessment of acne from baseline to endpoint. RESULTS: There were significantly greater reductions in the mean percent change from baseline to endpoint in inflammatory, non-inflammatory and total lesion counts in the EE 20 MUg/drsp 3mg 24/4 COC group compared with the placebo group (P<0.0001). The odds of women in the EE 20 MUg/drsp 3mg 24/4 COC group having 'clear' or 'almost clear' skin as rated by the investigators at endpoint were around three-fold greater than in the placebo group (odds ratio 3.41; 95% CI: 2.15-5.43; P<0.0001). CONCLUSIONS: A low-dose COC containing EE 20 MUg/drsp 3mg (24/4) more effectively reduced acne lesions than placebo and demonstrated greater improvement in the investigator global assessment of acne. PMID- 21288630 TI - Use of decision analysis interviews to support the sustainable use of the forests in Finnish Upper Lapland. AB - Controversy between alternative uses of forests in Finnish Upper Lapland has been going on for decades, and in recent years it has been escalated to a serious conflict. The core of the conflict is the adverse impacts of forestry on old forests which are important grazing areas for reindeer and which are regarded as intact nature and wilderness areas. This paper describes the experiences of applying multi-criteria decision analysis interview approach on this conflict. The approach provides tools for structuring the problem and preferences of the stakeholders as well as for analyzing the effects of different alternatives in a common framework. We focus on the practical experiences gained from the application of this approach in this context. Multi-criteria decision analysis was found to be a useful approach to evaluate the economic, ecological and cultural aspects of this intense conflict. The obtained experiences also support the view that the approach works best when tightly integrated into the planning process. PMID- 21288629 TI - Two-state displacement by the kinesin-14 Ncd stalk. AB - The nonprocessive kinesin-14 Ncd motor binds to microtubules and hydrolyzes ATP, undergoing a single displacement before releasing the microtubule. A lever-like rotation of the coiled-coil stalk is thought to drive Ncd displacements or steps along microtubules. Crystal structures and cryoelectron microscopy reconstructions imply that stalk rotation is correlated with ADP release and microtubule binding by the motor. Here we report FRET assays showing that the end of the stalk is more than ~9nm from the microtubule when wild-type Ncd binds microtubules without added nucleotide, but the stalk is within ~6nm of the microtubule surface when the microtubule-bound motor binds an ATP analogue, matching the rotated state observed in crystal structures. We propose that the stalk rotation is initiated when the motor binds to microtubules and releases ADP, and is completed when ATP binds. PMID- 21288631 TI - Changes in peak flow with decreased forestry practices: analysis using watershed runoff data. AB - The prevalence of forestry practices such as thinning and pruning have gradually decreased since the 1980s. Researchers have noted an increased flood risk with decreased forestry practices for coniferous plantations in Japan on the basis of infiltration and overland flow measurements at a plot scale (typically several square meters). However, no studies have examined changes in peak flow with decreased forestry practices at a watershed scale (typically several tens or hundreds of square kilometers) even though flood disasters generally occur at this scale in Japan. We examined changes in frequency distributions of daily precipitation (P) and runoff (Q) during the period 1979-2007 at the Terauchi watershed, where forestry practices are known to have decreased. For this purpose, we divided P and Q data into 14 and 15 classes according to the magnitude, respectively, and examined changes in the frequency for each class during the period. We observed no significant increasing trend for any P or Q class. Even when taking into account the effect of interannual variations in precipitation on the frequency for each Q class, there was no significant increasing trend in the frequencies except for two Q classes with moderate Q values. These results suggest that the increase in flood risk due to decreased forestry practices might be less than expected. PMID- 21288632 TI - An interval-based regret-analysis method for identifying long-term municipal solid waste management policy under uncertainty. AB - In this study, an interval-based regret-analysis (IBRA) model is developed for supporting long-term planning of municipal solid waste (MSW) management activities in the City of Changchun, the capital of Jilin Province, China. The developed IBRA model incorporates approaches of interval-parameter programming (IPP) and minimax-regret (MMR) analysis within an integer programming framework, such that uncertainties expressed as both interval values and random variables can be reflected. The IBRA can account for economic consequences under all possible scenarios associated with different system costs and risk levels without making assumptions on probabilistic distributions for random variables. A regret matrix with interval elements is generated based on a matrix of interval system costs, such that desired decision alternatives can be identified according to the interval minimax regret (IMMR) criterion. The results indicate that reasonable solutions have been generated. They can help decision makers identify the desired alternatives regarding long-term MSW management with a compromise between minimized system cost and minimized system-failure risk. PMID- 21288633 TI - Developing adaptive capacity within groundwater abstraction management systems. AB - Groundwater is a key resource for global agricultural production but is vulnerable to a changing climate. Given significant uncertainty about future impacts, bottom-up approaches for developing adaptive capacity are a more appropriate paradigm than seeking optimal adaptation strategies that assume a high ability to predict future risks or outcomes. This paper analyses the groundwater management practices adopted at multiple scales in East Anglia, UK, to identify wider lessons for developing adaptive capacity within groundwater management. Key elements are (1) horizontal and vertical integration within resource management; (2) making better use of water resources, at all scales, which vary in space and time; (3) embedding adaptation at multiple scales (from farm to national) within an adaptive management framework which allows strategies and management decisions to be updated in the light of changing understanding or conditions; (4) facilitating the ongoing formation through collective action of local Water Abstractor Groups; (5) promoting efficient use of scarce water resources by these groups, so as to increase their power to negotiate over possible short-term license restrictions; (6) controlling abstractions within a sustainable resource management framework, whether at national (regulatory) or at local (Abstractor Group) scales, that takes account of environmental water needs; and (7) reducing non-climate pressures which have the potential to further reduce the availability of usable groundwater. PMID- 21288634 TI - Glioblastoma multiforme in the Muir-Torre syndrome. AB - Muir-Torre syndrome (MTS) is an autosomal dominant subtype of nonpolyposis colorectal carcinoma (HNPCC) characterized by the development of sebaceous gland tumors and visceral malignancies. The most common subtype of MTS is characterized by germline mutations in mismatch repair (MMR) genes leading to microsatellite instability (MSI). Central nervous system tumors have only rarely been associated with MTS. In this report, we describe the development of a glioblastoma multiforme (GBM) in a patient with MTS. Immunohistochemical analysis of the patient's colon carcinoma and his GBM both revealed loss of the mismatch repair proteins mutS homolog 2 (MSH2) and mutS homolog 6 (MSH6). PMID- 21288635 TI - Enhancement of waste activated sludge dewaterability by electro-chemical pretreatment. AB - The potential effects of electro-chemical conditioning on sludge dewatering treatments and its mechanism were investigated in this study. Capillary suction time (CST) and specific resistance to filtration (SRF) were used to evaluate sludge dewaterability. Extracellular polymeric substance (EPS) content and sludge disintegration degree (DD(SCOD)) were also determined in an attempt to explain the observed changes in sludge dewaterability. The results indicated that application of considered low electrolysis voltages (<20 V) enhanced sludge dewaterability, while it exceeded 30 V, the dewaterability of sludge was significantly deteriorated. Also, electrolysis pretreatment slightly enhanced sludge dewaterability with short electrolysis time (<20 min), while it significantly deteriorated sludge dewaterability with long electrolysis time (>30 min). The optimal electrolysis voltage and electrolysis time to give preferable dewaterability characteristics were found to be 15-20 V, and 15-20 min, respectively, which generated sludge with optimal EPS content (15-20mg/L) and DD(SCOD) (1.3-2.0%). PMID- 21288636 TI - Effects on spermatogenesis in swiss mice of a protein isolated from the roots of Ricinus communis (Linn.) (Euphorbiaceae). AB - This study was aimed to evaluate the effect on spermatogenesis of a 62 kDa protein (Rp) isolated from 50% ethanolic extract of the root of Ricinus communis in mice. A dose response study in mice revealed that 25mg/kg body weight/day was the most effective dose. Swiss strain mature male mice of 30 days old were divided into two group namely control and Rp treated (25mg/kg body weight/day). The study showed that sperm motility and count were decreased significantly in the treated group as compared to the control. The fertility index of the treated groups was reduced by 100%. The activity of HMG Co A reductase and cholesterol were increased significantly in the treated group. The testicular activities of 3betaHSD, 17betaHSD, glucose 6-phosphate dehydrogenase and malic enzyme and the level of serum testosterone were decreased significantly in the treated group. The expression of 3betaHSD and 17betaHSD were decreased and the expression of StAR increased significantly in the treated group as compared to the control. Proteolytic digestion of the native protein with trypsin and chymotrypsin showed that the proteolytic cleavage did not affect the spermicidal action of Rp. Hence this study can be concluded that Rp impaired spermatogenesis in vivo by suppressing the production of testosterone. PMID- 21288637 TI - On the temperature dependence of flammability limits of gases. AB - Flammability limits of several combustible gases were measured at temperatures from 5 to 100 degrees C in a 12-l spherical flask basically following ASHRAE method. The measurements were done for methane, propane, isobutane, ethylene, propylene, dimethyl ether, methyl formate, 1,1-difluoroethane, ammonia, and carbon monoxide. As the temperature rises, the lower flammability limits are gradually shifted down and the upper limits are shifted up. Both the limits shift almost linearly to temperature within the range examined. The linear temperature dependence of the lower flammability limits is explained well using a limiting flame temperature concept at the lower concentration limit (LFL)--'White's rule'. The geometric mean of the flammability limits has been found to be relatively constant for many compounds over the temperature range studied (5-100 degrees C). Based on this fact, the temperature dependence of the upper flammability limit (UFL) can be predicted reasonably using the temperature coefficient calculated for the LFL. However, some compounds such as ethylene and dimethyl ether, in particular, have a more complex temperature dependence. PMID- 21288638 TI - Enhanced pervaporative desulfurization by polydimethylsiloxane membranes embedded with silver/silica core-shell microspheres. AB - Pervaporative desulfurization based on membrane technology provides a promising alternative for removal of sulfur substances (as represented by thiophene) in fluid catalytic cracking (FCC) gasoline. The present study focused on the performance enhancement of polydimethylsiloxane (PDMS) membrane by incorporation of core-shell structured silver/silica microspheres. A silane coupling agent, N [3-(trimethoxysily)propyl]-ethylenediamine (TSD), was used to chelate the Ag(+) via its amino groups and attach the silver seeds onto the silica surface via condensation of its methoxyl groups. The resultant microspheres were characterized by Zeta-positron annihilation lifetime spectroscopy (ZetaPALS), inductively coupled plasmaoptical emission spectrophotometer (ICP), transmission electron microscopy (TEM), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). The Ag(+)/SiO(2)-PDMS composite membranes were prepared by blending PDMS with the as-synthesized silver/silica microspheres. PALS analysis was used to correlate the apparent fractional free volume with permeation flux. The sorption selectivity towards thiophene was enhanced after incorporation of silver/silica microspheres due to the pi-complexation between the silver on the microsphere surface and the thiophene molecules. The pervaporative desulfurization performance of the composite membrane was investigated using thiophene/n-octane mixture as a model gasoline. The composite membrane exhibited an optimum desulfurization performance with a permeation flux of 7.76 kg/(m(2)h) and an enrichment factor of 4.3 at the doping content of 5%. PMID- 21288639 TI - Removals of fly ash and NO in a fluidized-bed reactor with CuO/activated carbon catalysts. AB - This study investigates the effects of fly ash compositions (SiO(2) and Al(2)O(3)), particle sizes (4-10 MUm and 40 MUm), and concentrations on the simultaneous removals of fly ash and NO using a fluidized-bed catalyst reactor. Experimental results show that the removal efficiencies of fly ash and NO at particle concentrations of 968-11,181 mg m(-3) are 71-97% and 42-57%, respectively. SiO(2) particles have more influences than Al(2)O(3) particles on the performances of fluidized-bed CuO/AC catalyst. As the concentration of fine particle increases, the pores and active sites on catalyst surface are obstructed and therefore the activities of catalysts are depressed. PMID- 21288640 TI - ETBE (ethyl tert butyl ether) and TAME (tert amyl methyl ether) affect microbial community structure and function in soils. AB - Ethyl tert butyl ether (ETBE) and tert amyl methyl ether (TAME) are oxygenates used in gasoline in order to reduce emissions from vehicles. The present study investigated their impact on a soil microflora that never was exposed to any contamination before. Therefore, soil was artificially contaminated and incubated over 6 weeks. Substrate induced respiration (SIR) measurements and phospholipid fatty acid (PLFA) analysis indicated shifts in both, microbial function and structure during incubation. The results showed an activation of microbial respiration in the presence of ETBE and TAME, suggesting biodegradation by the microflora. Furthermore, PLFA concentrations decreased in the presence of ETBE and TAME and Gram-positive bacteria became more dominant in the microbial community. PMID- 21288641 TI - Membrane solid phase microextraction with alumina hollow fiber on line coupled with ICP-OES for the determination of trace copper, manganese and nickel in environmental water samples. AB - A novel alumina hollow fiber was synthesized by sol-gel template method and was characterized by scanning electron microscopy, N(2) adsorption technique and X ray diffraction. With the use of prepared alumina hollow fiber as extraction membrane, a new method of flow injection (FI)-membrane solid phase microextraction (MSPME) on-line coupled to inductively coupled plasma-optical emission spectrometry (ICP-OES) was developed for simultaneous determination of trace metals (Cu, Mn and Ni) in environmental water samples. The adsorption capacities of the alumina hollow fiber for Cu, Mn and Ni were found to be 6.6, 8.7 and 13.3 mg g(-1), respectively. With a preconcentration factor of 10, the limits of detection (LODs) for Cu, Mn and Ni were found to be 0.88, 0.61 and 0.38 ng mL(-1), respectively, and the relative standard deviations (RSDs) were ranging from 6.2 to 7.9% (n = 7, c = 10 ng mL(-1)). To validate the accuracy, the proposed method was applied to the analysis of certified reference material GSBZ50009-88 environmental water and the determined values are in good agreement with the certified values. The developed method was also employed for the analysis of Yangtze River water and East Lake water, and the recoveries for the spiked samples were in the range of 87.4-110.2%. PMID- 21288642 TI - Reprint of: High current liquid metal ion source using porous tungsten multiemitters. AB - We recently developed an indium Liquid-Metal-Ion-Source that can emit currents from sub-MUA up to several mA. It is based on a porous tungsten crown structure with 28 individual emitters, which is manufactured using Micro-Powder Injection Molding (MUPIM) and electrochemical etching. The emitter combines the advantages of internal capillary feeding with excellent emission properties due to micron size tips. Significant progress was made on the homogeneity of the emission over its current-voltage characteristic as well as on investigating its long-term stability. This LMIS seems very suitable for space propulsion as well as for micro/nano manufacturing applications with greatly increased milling/drilling speeds. This paper summarizes the latest developments on our porous multiemitters with respect to manufacturing, emission properties and long-term testing. PMID- 21288643 TI - Atomic-scale distribution of impurities in CuInSe2-based thin-film solar cells. AB - Atom Probe Tomography was employed to investigate the distribution of impurities, in particular sodium and oxygen, in a CuInSe(2)-based thin-film solar cell. It could be shown that sodium, oxygen, and silicon diffuse from the soda lime glass substrate into the CuInSe(2) film and accumulate at the grain boundaries. Highly dilute concentrations of sodium and oxygen were measured in the bulk. Selenium was found to be depleted at the grain boundaries. These observations could be confirmed by complementary energy dispersive X-ray spectroscopy studies. Our results support the model proposed by Kronik et al. (1998) [1], which explains the enhanced photovoltaic efficiency of sodium containing CuInSe(2) solar cells by the passivation of selenium vacancies at grain boundaries. PMID- 21288644 TI - Atom-probe for FinFET dopant characterization. AB - With the continuous shrinking of transistors and advent of new transistor architectures to keep in pace with Moore's law and ITRS goals, there is a rising interest in multigate 3D-devices like FinFETs where the channel is surrounded by gates on multiple surfaces. The performance of these devices depends on the dimensions and the spatial distribution of dopants in source/drain regions of the device. As a result there is a need for new metrology approach/technique to characterize quantitatively the dopant distribution in these devices with nanometer precision in 3D. In recent years, atom probe tomography (APT) has shown its ability to analyze semiconductor and thin insulator materials effectively with sub-nm resolution in 3D. In this paper we will discuss the methodology used to study FinFET-based structures using APT. Whereas challenges and solutions for sample preparation linked to the limited fin dimensions already have been reported before, we report here an approach to prepare fin structures for APT, which based on their processing history (trenches filled with Si) are in principle invisible in FIB and SEM. Hence alternative solutions in locating and positioning them on the APT-tip are presented. We also report on the use of the atom probe results on FinFETs to understand the role of different dopant implantation angles (10 degrees and 45 degrees ) when attempting conformal doping of FinFETs and provide a quantitative comparison with alternative approaches such as 1D secondary ion mass spectrometry (SIMS) and theoretical model values. PMID- 21288646 TI - Advances in the biology of malignant pleural mesothelioma. AB - Malignant pleural mesothelioma is a highly aggressive cancer with a very poor prognosis. Although the mechanism of carcinogenesis is not fully understood, approximately 80% of malignant pleural mesothelioma can be attributed to asbestos fiber exposure. This disease is largely unresponsive to conventional chemotherapy or radiotherapy, and most patients die within 10-17 months of their first symptoms. Currently, malignant pleural mesothelioma therapy is guided by clinical stage and patient characteristics rather than by the histological or molecular features of the tumor. Several molecular pathways involved in malignant pleural mesothelioma have been identified; these include cell cycle regulation, apoptosis, growth factor pathways, and angiogenesis. Unfortunately, several agents targeting these processes, including erlotinib, gefitinib, and imatinib, have proven ineffective in clinical trials. A greater understanding of the molecular pathways involved in malignant pleural mesothelioma is needed to develop better diagnostics, therapeutics, and preventative measures. Moreover, understanding the biological basis of mesothelioma progression may facilitate personalized treatment approaches, and early identification of poor prognostic indicators may help reduce the heterogeneity of the clinical response. This paper reviews advances in the molecular biology of malignant pleural mesothelioma in terms of pathogenesis, the major molecular pathways and the associated therapeutic strategies, and the roles of biomarkers. PMID- 21288647 TI - Id1: a novel therapeutic target for patients with atherosclerotic plaque rupture. AB - Plaque neovascularization and inflammation are responsible for plaque destabilization and rupture. However, the precise triggers for inflammation and neovascularization in atherosclerosis are largely unknown. Id1 (inhibitor of DNA binding) protein is a helix-loop-helix transcription factor and plays an important role in angiogenesis and inflammation. The expression of Id1 can be up regulated by plaque formation factors such as vascular endothelial growth factor (VEGF), hypoxia, NAD(P)H oxidase, and TNF-alpha. Moreover, Id1 is critical to endothelial progenitor cell (EPC) population formation and angiogenesis. Evidence from diverse sources has suggested that Id1 may affect plaque destabilization through angiogenesis and inflammation. Herein we hypothesize that Id1 is an important protein for the development and progression of atherosclerotic plaque destabilization and hence blocking the expression of Id1 may serve as new targets for antiatherogenic therapy. PMID- 21288648 TI - Severity in phenotypic expression of homozygous sickle cell disease (Hb.SS)--does hypermelanotic or hypomelanotic skin status of affected patients play a role? AB - Abnormal hemoglobin distribution on global map, of which hemoglobin S (Hb.S) accounted for about 80% of the disorders resulting from them are more prevalent in the tropics and sub-tropics. Homozygous sickle cell disease (Hb.SS) is the most common and most severe form of sickle cell disease (SCD) in phenotypic expression. The prevalence and severity in phenotypic expression of SCD had been noted to decrease farther away from the equatorial region, with prevalence rate of sickle cell trait of about 2% and less than 1% in North African coast and South Africa, respectively, compared to about 10-40% in the equatorial region. Controlling for human migration, the distribution of prevalence and severity of SCD tend to correspond with the degree of pigmentation of skin color on global map with areas of hyperpigmentation having the likelihood of higher prevalence and severity, while areas of hypopigmentation are characterized by the reverse. This distribution had been observed to correspond with skin color variation on global map based on Von Luschan's chromatic scale. Empirical observation had also shown that individual homozygous SCD patients who are lighter in skin color tend to manifest a less severe phenotypic expression of the disease condition when compared to those with darker skin color using the yard stick of frequency in sickle cell crises. The hypothesis is; would hypermelanotic or hypomelanotic skin status of individual homozygous SCD patient, if measured objectively by assessing the types and quantity of melanin in individual patient, influence the severity in phenotypic expression of SCD in affected patients. Oculocutaneous albinism (OCA) which is characterized by hypomelanosis is an inherited autosomal recessive disorder like SCD. OCA is also common in the tropics and sub-tropics like SCD. It had been reported that OCA does occur co-morbidly with homozygous SCD. Comparing a group of patients with co-morbid OCA and homozygous SCD with another group with SCD, who do not have OCA on severity of phenotypic expression of SCD could provide a feasible means of testing the hypothesis. If future carefully controlled studies confirm the hypothesis of influence of hypermelanotic or hypomelanotic skin status of the individual patients on severity in phenotypic expression of homozygous SCD, genetic and pharmacological interventions aimed at regulation of melanin production may play a role in alleviating the severity in phenotypic expression of SCD in affected patients. PMID- 21288649 TI - Could hydroxyethyl starch be a therapeutic option in management of acute aluminum phosphide toxicity? AB - Acute aluminum phosphide poisoning is a serious toxicity and results in high mortality rate despite the progress of critical care. After ingestion, phosphine gas is released and absorbed quickly, causing systemic poisoning and cell hypoxia. Excessive thirst, severe hypotension, arrhythmias, tachypnea, and severe metabolic acidosis are the common clinical manifestations. We think acute metabolic response which characteristically occurs in severe injury also happens in aluminum phosphide poisoning. Necropsy examinations indicate congestion in almost all vital organs because of leakage of fluids from intravascular to extravascular space. The most favorable type of fluid for intravascular volume resuscitation persists and is disputed. Colloids remain in the intravascular space rather than crystalloids, and provide more rapid hemodynamic stabilization. Furthermore, hydroxyethyl starch solution may have other benefits e.g. it can reduce the extra vascular leak of albumin and fluids from an endothelial injury site. As refractory hypotension and cardiovascular collapse, because leakage of fluids from intravascular to extravascular space are common cause of death in this toxicity, we propose that hydroxyethyl starch can dominate this refractory hypotension and consequently acute metabolic response. PMID- 21288650 TI - Concerns about targeting cancer stem cell for cancer therapy. PMID- 21288651 TI - Diabetes might adversely affect expression and function of interstitial cells in the urinary bladder and urethra in humans: a new mechanism in the development of diabetic lower urinary dysfunction? AB - Diabetes is an important disease affecting many people worldwide which causes significant morbidity. In the lower urinary tract (LUT), diabetes causes LUT dysfunction in humans by leading to neuropathic bladder. In addition, diabetes can lead to functional and anatomical abnormalities of the external urethral sphincter. Diabetes was suggested to cause these complications by affecting autonomic or peripheral nerves or both. Cells having similar characteristics with interstitial cells of Cajal that are present in the gastrointestinal system have also been described in the human urinary tract. Interstitial cells (ICs) in the urinary tract were suggested to function as pacemaker cells, stretch or chemical sensors that might trigger detrusor contractions which work with close relationship with the nerves. In the human urethra, ICs were suggested to control the frequency of tonic contractions of the urethral smooth muscle. Therefore, ICs seem be playing a very important role in LUT function in humans. The hypothesis in this paper suggests that diabetes might also adversely affect IC expression and IC function in the human LUT which might play a significant role in the development of diabetic LUT dysfunction. A search of the English literature was performed by using Medline/PubMed in order to search this hypothesis and no particular study was found in humans. The information and evidence obtained following the investigation of this hypothesis might uncover the possible underlying mechanism of decreased IC expression or function in addition to neuropathy in the development of diabetic LUT dysfunction. Currently, no specific medical drug treatment or preventive measure exists targeting the cellular components of the LUT (i.e. ICs and nerves) which are in fact responsible for a normally functioning LUT. If the expression and distribution of ICs are adversely affected in the LUT of patients with diabetes, specific drugs might be developed as targeted therapy stimulating IC function which could then be used to treat diabetic LUT dysfunction and benefit many diabetic patients worldwide. Moreover, having the knowledge of the IC expression and distribution status at the level of the LUT in patients with diabetes could be a possible prognostic factor for the clinicians indicating the risk of future LUT deterioration. Therefore, targeted therapy might also be used as to prevent the development of LUT dysfunction in this patient group. PMID- 21288652 TI - Could thiamine pyrophosphate be a regulator of the nitric oxide synthesis in the endothelial cell of diabetic patients? AB - Thiamine (Vitamin B1) is considered an essential micronutrient for humans; its deficient intake brings about the Wernicke-Korsakoff syndrome (encephalopathy and psychosis) or beriberi (a neurological and cardiovascular disease). Once thiamine enters the cells it is phosphorylated by thiamine pyrophosphokinase (TPPK), and converted into the coenzyme thiamine pyrophosphate (TPP), the active form of thiamine. TPP is a relevant cofactor for transketolase (TK), alpha-ketoglutarate dehydrogenase (alphaKDH), and pyruvate dehydrogenase (PDH), all these enzymes are fundamental for glucose metabolism. Diabetes mellitus (DM), however, is considered both a deficient thiamine and deficient energy state, as a consequence of the limited TPP synthesis. Recent evidences have shown that the administration of thiamine or lipid-soluble derivatives, such as benfotiamine (developed to improve the bioavailability of thiamine), has positive effects in the diabetic patient (after thiamine is transformed into TPP). For this reason, administration of supplements with TPP in the diabetic patients is recommended to avoid complications, like neuropathy and nephropathy. It has been suggested that these beneficial effects are a consequence of the activation of TK (pentose pathway) or the PDH complex in mitochondria. Nitric oxide (NO) is synthesized by the endothelial cell and is also an important element for the viability and functionality of this cell type. However, in the DM patient, a deficient synthesis of NO has been reported. It is relevant to mention that recent evidences have led to propose mitochondrial activity as an important regulator of nitric oxide synthesis (ON). We consider that the exogenous administration of TPP facilitates the utilization of this molecule, regulating some metabolic processes such as phosphorylation of thiamine by TPPK, energy consumption (ATP), as well as mitochondrial activity, inducing eventually NO synthesis. If this is confirmed, the administration of TPP to the diabetic patient would provide additional protection to endothelial cells, reducing the risk of vascular damage, to which the diabetic patient is highly susceptible. PMID- 21288653 TI - Does neurotrophic factor benefit to PD therapy via co-function with ubiquitin proteasome system? AB - Parkinson's disease (PD) is a common progressive neurodegenerative disorder whose core symptoms are tremor, bradykinesia, rigidity, and postural instability. Currently available treatment of PD is mainly based on dopamine replacement strategy to provide relief of motor symptoms, but cannot halt or reverse the degenerative processes of disease. Considerable in vitro and in vivo studies have found that neurotrophic factor (NTF) has neuroprotective or even neurorestorative properties on dopaminergic (DA) system, promoting them become promising candidates for the treatment of PD. However, the precise mechanism of NTF's effect in PD remains to be elucidated. Though the etiopathogenesis of PD has remained elusive, recently, compelling evidence has converged to suggest that failure of the ubiquitin-proteasome system (UPS) to degrade unwanted proteins may underlie nigralstrital degeneration and Lewy body (LB) formation which occurs in PD. In support of this, proteasome inhibitor has been successfully induced a PD modal both in vivo and in vitro. Many NTFs have been proved to possess definitely a therapy effect in a PD animal modal. Whether NTF can co-function with UPS that accomplishes the aim to protect and reserve dopaminergic neurons' function from neurotoxicity injury induced by proteasome inhibitor? If this hypothesis could be confirmed, it will represent a valuable advancement in the study of PD. Moreover, investigation of the functional link between UPS and NTF should also provide useful information for understanding the pathogenesis of PD. PMID- 21288654 TI - True recurrence versus new primary: an analysis of ipsilateral breast tumor recurrences after breast-conserving therapy. AB - PURPOSE: Ipsilateral breast tumor recurrence (IBTR) can occur in 5-20% of women with early-stage breast cancer treated with breast-conserving therapy. Two entities of IBTR have been described: true recurrence (TR), suggested to be regrowth of disease at the tumor bed, and new primary (NP), distinct from the index lesion in histology and location. This study compared survival outcomes between two patient cohorts classified clinically as having either TR or NP. METHODS AND MATERIALS: Between 1989 and 1999, 6,020 women were referred to the BC Cancer Agency with newly diagnosed pT1-2, N0-1, M0 invasive breast cancer, treated with breast-conserving surgery. Of these, 289 patients had pathologically confirmed IBTR. Retrospective analysis was performed, and a set of decision rules was applied to classify cases as TR or NP based on change in histology, grade, hormone receptor status, and tumor location. Of 289 patients, 129 (45%) were classified as having TR and 139 (48%) as having NP; 21 (7%) were unclassified. RESULTS: The distributions of age at diagnosis, age at recurrence, and histopathologic factors were similar in the TR and NP cohorts (all p > 0.05). The mean time to recurrence was shorter in TR patients than in NP patients (4.8 years vs. 6.3 years, p = 0.001). Treatment of the IBTR did not differ between the two groups. In the TR and NP cohorts, breast cancer-specific survival was 55.7% vs. 61.3% (p = 0.93), and overall survival was 43.7% vs. 54.8% (p = 0.53). CONCLUSIONS: Time to recurrence is significantly shorter in patients with IBTR classified as true recurrence compared to new primary. Non-statistically significant trends for less favorable survival were observed for patients with TR. Further investigation of the hypothesis that TR and NP tumors are distinct entities with different survival prognoses will require standardized pathology review and molecular analyses. PMID- 21288655 TI - Progressive muscle atrophy and weakness after treatment by mantle field radiotherapy in Hodgkin lymphoma survivors. AB - PURPOSE: To describe the damage to the muscles and propose a pathophysiologic mechanism for muscle atrophy and weakness after mantle field radiotherapy in Hodgkin lymphoma (HL) survivors. METHODS AND MATERIALS: We examined 12 patients treated by mantle field radiotherapy between 1969 and 1998. Besides evaluation of their symptoms, the following tests were performed: dynamometry; ultrasound of the sternocleidomastoid, biceps, and antebrachial flexor muscles; and needle electromyography of the neck, deltoid, and ultrasonographically affected arm muscles. RESULTS: Ten patients (83%) experienced neck complaints, mostly pain and muscle weakness. On clinical examination, neck flexors were more often affected than neck extensors. On ultrasound, the sternocleidomastoid was severely atrophic in 8 patients, but abnormal echo intensity was seen in only 3 patients. Electromyography of the neck muscles showed mostly myogenic changes, whereas the deltoid, biceps, and antebrachial flexor muscles seemed to have mostly neurogenic damage. CONCLUSIONS: Many patients previously treated by mantle field radiotherapy develop severe atrophy and weakness of the neck muscles. Neck muscles within the radiation field show mostly myogenic damage, and muscles outside the mantle field show mostly neurogenic damage. The discrepancy between echo intensity and atrophy suggests that muscle damage is most likely caused by an extrinsic factor such as progressive microvascular fibrosis. This is also presumed to cause damage to nerves within the radiated field, resulting in neurogenic damage of the deltoid and arm muscles. PMID- 21288656 TI - Chest wall toxicity after stereotactic body radiotherapy for malignant lesions of the lung and liver. AB - PURPOSE: To quantify the frequency of rib fracture and chest wall (CW) pain and identify the dose-volume parameters that predict CW toxicity after stereotactic body radiotherapy (SBRT). METHODS AND MATERIALS: The records of patients treated with SBRT between 2000 and 2008 were reviewed, and toxicity was scored according to Common Terminology Criteria for Adverse Events v3.0 for pain and rib fracture. Dosimetric data for CW and rib were analyzed and related to the frequency of toxicity. The risks of CW toxicity were then further characterized according to the median effective concentration (EC(50)) dose-response model. RESULTS: A total of 347 lesions were treated with a median follow-up of 19 months. Frequency of Grade I and higher CW pain and/or fracture for CW vs. non-CW lesions was 21% vs. 4%, respectively (p < 0.0001). A dose of 50 Gy was the cutoff for maximum dose (Dmax) to CW and rib above which there was a significant increase in the frequency of any grade pain and fracture (p = 0.03 and p = 0.025, respectively). Volume of CW receiving 15 Gy - 40 Gy was highly predictive of toxicity (R(2) > 0.9). According to the EC(50) model, 5 cc and 15 cc of CW receiving 40 Gy predict a 10% and 30% risk of CW toxicity, respectively. CONCLUSION: Adequate tumor coverage remains the primary objective when treating lung or liver lesions with SBRT. To minimize toxicity when treating lesions in close proximity to the CW, Dmax of the CW and/or ribs should remain <50 Gy, and <5 cc of CW should receive >= 40 Gy. PMID- 21288658 TI - Childhood predictors of first chance to use and use of cannabis by young adulthood. AB - AIMS: To prospectively examine the linkage between childhood antecedents and progression to early cannabis involvement as manifest in first chance to try it and then first onset of cannabis use. METHODS: Two consecutive cohorts of children entering first grade of a public school system of a large mid-Atlantic city in the mid 1980s (n=2311) were assessed (mean age 6.5 years) and then followed into young adulthood (15 years later, mean age 21) when first chance to try and first use were assessed for 75% (n=1698) of the original sample. Assessments obtained at school included standardized readiness scores (reading; math) and teacher ratings of behavioral problems. Regression and time to event models included covariates for sex, race, and family disadvantage. RESULTS: Early classroom misconduct, better reading readiness, and better math readiness predicted either occurrence or timing of first chance to try cannabis, first use, or both. Higher levels of childhood concentration problems and lower social connectedness were not predictive. CONCLUSIONS: Childhood school readiness and behavioral problems may influence the risk for cannabis smoking indirectly via an increased likelihood of first chance to use. Prevention efforts that seek to shield youths from having a chance to try cannabis might benefit from attention to early predictive behavioral and school readiness characteristics. When a youth's chance to try cannabis is discovered, there are new windows of opportunity for prevention and intervention. PMID- 21288659 TI - Cigarette, marijuana, and alcohol use and prior drug treatment among newly homeless young adults in New York City: Relationship to a history of foster care. AB - BACKGROUND: This study examined whether a history of foster care was associated with the risk for substance use among newly homeless young adults, controlling for demographics and other risk factors. METHODS: Multiple logistic regression analyses, adjusted for controls, among consecutive admissions of 424 newly homeless young adults (18-21 years), determined the association between foster care and substance use. RESULTS: A history of foster care was reported by 35% of the sample. Alcohol, marijuana, and cigarettes were the most frequently used substances. After adjusting for demographics, childhood emotional, physical, and sexual abuse, prior arrest, unemployment, lack of high school diploma, and family drug use, homeless young adults with histories of foster care were: three times as likely to smoke cigarettes (AOR=3.09); more than three times as likely to use marijuana (AOR=3.30); and almost nine times as likely to have been in drug treatment (AOR=8.81) than those without such histories. CONCLUSIONS: It is important to screen homeless young adults who exited foster care for substance use, particularly cigarettes and marijuana. Risk reduction interventions should be targeted and tailored to their substance prevention needs. PMID- 21288660 TI - Sponsorship and service as mediators of the effects of Making Alcoholics Anonymous Easier (MAAEZ), a 12-step facilitation intervention. AB - A recent trial (n=508) of "Making Alcoholics Anonymous Easier" (MAAEZ), a group format 12-step facilitation program, showed that MAAEZ participants had increased odds of abstinence (OR=1.58; p=0.063). Effects were especially marked in several subgroups, including those with more prior AA/NA/CA exposure, and those with severe psychiatric problems. This paper examines whether the effects of MAAEZ were explained by higher engagement in particular Alcoholics Anonymous (AA) and other 12-step organization activities. Mediation analyses were performed, estimating MAAEZ effects attributable to AA/NA/CA meeting attendance, overall AA/NA/CA involvement, having a sponsor, and engaging in 12-step service. The only variable that appeared to mediate MAAEZ effects in the sample overall was doing service at either 6 months or at both 6 and 12 months. Among those with high prior AA/NA/CA attendance, both having a sponsor and doing service emerged as mediators, with having a sponsor explaining approximately 25% of the MAAEZ effect. Doing service also partially explained the MAAEZ effect among those with high psychiatric severity. Results highlight the value of studying specific AA/NA/CA activities as mediators of treatment effects, and demonstrate the importance of exploring subgroups when trying to understand treatment mechanisms. Findings also suggest that treatment programs should emphasize specific activities for particular clients. For example, individuals may have attended many AA/NA/CA meetings, but never known how to ask for a sponsor or get involved in service; doing service may represent a non-threatening way of connecting with 12-step members for clients with psychiatric problems such as social anxiety. PMID- 21288661 TI - Alcohol consumption associated with collegiate American football pre-game festivities. AB - Internationally, sporting events represent a specific context in which heavy episodic drinking is common. The current study assessed determinants of heavy episodic drinking among tailgaters (i.e., individuals engaging in pre-game social festivities) prior to American football games at two large universities. A total of 466 individuals at two universities completed a short interview and provided a breathalyzer sample to estimate breath alcohol content (BrAC) during the tailgating window (150min prior to and 10min after the start of the game). The plurality of participants, 48.5% at the southeastern university (School1) and 58.8% at the midwestern university (School2), engaged in heavy episodic drinking. Only 54 individuals (11.6%) from the combined sample at both universities abstained from alcohol (confirmed via BrAC). In total, 40.2% of participants at School1 and 31.9% at School2 produced breath samples over the legal limit for driving (i.e., BrAC=0.08 or higher). In site-specific regression analyses, younger ages, males, and non-students at School1, and younger ages and non-game attendance at School2 were associated with self-reported heavy episodic drinking and higher levels of estimated BrAC (p<0.05). Given the widespread participation in heavy episodic drinking among both students and non-students in this sample, public health interventions should be implemented both on- and off-campus to promote safety and to discourage heavy episodic drinking at American football games and other high-profile sporting events. PMID- 21288662 TI - Heterogeneity in the composition of marijuana seized in California. AB - BACKGROUND: Marijuana contains multiple cannabinoids. Most attention is given to delta-9-tetrahydrocannabinol (THC) which produces euphoria and in some cases anxiety and panic reactions. Research suggests that another cannabinoid, cannabidiol (CBD), may offset some of these effects. Thus, there is growing interest in the health consequences of the THC to CBD ratio for marijuana. METHODS: Using data from over 5000 marijuana samples in California from 1996 to 2008, we examine changes in the median THC-level, median CBD-level, and median THC:CBD-ratio. RESULTS: The median THC-level and median THC:CBD-ratio have dramatically increased for seizures in California, particularly north of the Mexican border. CONCLUSION: Research on the consequences of the THC:CBD ratio should continue, especially as more attention is devoted to thinking about how to regulate marijuana for medical and recreational use. Researchers should also consider the lack of uniformity in the chemical composition of marijuana when evaluating its health effects. PMID- 21288663 TI - Resisting temptation: decreasing alcohol-related affect and drinking behavior by training response inhibition. AB - According to dual-process models, excessive alcohol use emerges when response inhibition ability is insufficient to inhibit automatic impulses to drink alcohol. This study examined whether strengthening response inhibition for alcohol-related cues decreases alcohol intake. Fifty-two heavy drinking students were randomly assigned to one of two conditions: In the beer/no-go condition, participants performed a go/no-go task that consistently paired alcohol-related stimuli with a stopping response, to increase response inhibition for alcohol related stimuli. In the beer/go condition, in contrast, participants were always required to respond to alcohol-related stimuli during the go/no-go task. Before and after the go/no-go manipulation, we measured weekly alcohol intake and implicit attitudes toward alcohol. In addition, we measured alcohol consumption during a taste test immediately after the go/no-go manipulation. Following the manipulation, participants in the beer/no-go condition demonstrated significantly increased negative implicit attitudes toward alcohol, and a significant reduction in weekly alcohol intake, while participants in the beer/go condition showed a non-significant increase in implicit positive attitudes toward alcohol and a significant increase in weekly alcohol intake. This study demonstrates that repeatedly stopping prepotent responses toward alcohol-related stimuli can be an effective strategy to reduce excessive alcohol use. PMID- 21288664 TI - The 'broken' attachment between parents and preterm infant: how and when to intervene. PMID- 21288665 TI - Probiotics use in preterm neonates: what further evidence is needed? PMID- 21288666 TI - Effects of maternal and dietary selenium (Se-enriched yeast) on the expression of p34(cdc2) and CyclinB1 of germ cells of their offspring in goats. AB - The aim of the study was to evaluate the effect of selenium on the expression of p34(cdc2) and CyclinB1 (two components of MPF regulating cell cycle) of germ cells of their offspring in goats. A herd of 119 Taihang Black Goats, which was randomly divided into 4 treatments, received experimental diet with different Se levels (from Se-enriched yeast) for 174d. The four treatments, fed with a basal diet, were supplemented with 0 (control), 0.5, 2 and 4 mgkg-1 DM Se. Testis samples were collected from the young male goats of each treatment group at the end of the study (30d after weaning) for mRNA expression using real-time PCR and for protein expression by immunohistochemistry assay. Results show that a significant decrease was observed in mRNA expression of p34(cdc2) and CyclinB1 in the testis of Se-deficient (Group 1) and Se-excess (Group 4) animals compared with that in Groups 2 and 3. However, no significant changes were found in mRNA expression of p34(cdc2) between Se-deficient (Group 1) and Se-excess (Group 4). Also the immunohistochemistry assay detected similar results of protein expression of these two genes. These results suggest, that maternal and dietary Se-induced oxidative stress can modulate the mRNA and protein expression of the cell cycle related genes (p34(cdc2) and CyclinB1) in the testis of their offspring. In addition, Se deficiency and Se excess could prevent the completion of the cell cycle. PMID- 21288667 TI - Production of interspecies handmade cloned embryos by nuclear transfer of cattle, goat and rat fibroblasts to buffalo (Bubalus bubalis) oocytes. AB - The possibility of producing interspecies handmade cloned (iHMC) embryos by nuclear transfer from donor cells of cattle, goat and rat using buffalo oocytes as recipient cytoplasts was explored. Zona-free buffalo oocytes were enucleated by protrusion cone-guided bisection with a microblade. After electrofusion with somatic cells, reconstructed oocytes were activated by calcimycin A23187, treated with 6-dimethylaminopurine and were cultured in K-RVCL-50(r) medium for 8 days. Although the cleavage rate was not significantly different when buffalo, cattle, goat or rat cells were used as donor nuclei (74.6 +/- 3.8, 82.8 +/- 5.3, 86.0 +/- 4.9 and 82.3 +/- 3.6%, respectively), the blastocyst rate was significantly higher (P<0.01) for buffalo (51.4 +/- 2.6) than for cattle (3.5 +/- 1.0) or the goat (2.2 +/- 0.9), whereas none of the embryos crossed the 32-cell stage when rat cells were used. However, the total cell number was similar for buffalo buffalo (175.0 +/- 5.07) and cattle-buffalo embryos (178.0 +/- 11.84). Following transfer of 3 buffalo-buffalo embryos each to 6 recipients, 3 were found to be pregnant, though the pregnancies were not carried to full term. These results suggest that interspecies blastocyst stage embryos can be produced by iHMC using buffalo cytoplasts and differentiated somatic cells from cattle and goat and that the source of donor nucleus affects the developmental competence of interspecies embryos. PMID- 21288668 TI - Influence of anaesthetic drugs on the epididymal sperm quality in domestic cats. AB - The present study investigated the effect of different anaesthetic agents commonly used in cats on the fresh and frozen-thawed epididymal sperm. Seventeen male domestic cats were castrated using pentobarbital, ketamine HCl or isoflurane. Sperm samples were recovered from epididymides and evaluated before and after freezing, determining the vigor, motility, morphology, acrosome status, sperm viability and functional membrane integrity. Fresh epididymal sperm was influenced by the drugs used, noting that motility features, i.e. vigor (p<=0.05) and progressive motility (p<=0.05), were higher for the inhalation anaesthetic while the others did not showed statistical differences. In frozen-thawed sperm samples, cats treated with barbiturics showed lower values for acrosome status (p<=0.05) and integrity and functionality of membrane (p<=0.05 and p<=0.01, respectively) than in the others groups. Results suggested that drugs used for castration in cats could affect the sperm quality and this should be considered when implementing sperm cryopreservation in the feline. PMID- 21288669 TI - Effect of some permeating cryoprotectants on CASA motility results in cryopreserved bull spermatozoa. AB - Computer-assisted sperm analyzers (CASA) have become the standard tool for evaluating sperm motility because they provide objective results for thousands of mammalian spermatozoa. Mammalian spermatozoa experience osmotic stress when the glycerol is added to the cells prior to freezing and removal from the cells after thawing. In order to minimize osmotic damage, cryoprotectants having lower molecular weights and greater membrane permeability than glycerol, were evaluated to determine their effectiveness for cryopreserving bull spermatozoa. The aim of this study was to compare the cryopreservation effects of low molecular weight cryoprotectants (ethylene glycol and methanol) to glycerol, on post-thaw CASA sperm parameters. Bull semen was diluted with tris-egg yolk extender containing 3% glycerol, 3, 2 and 1% ethylene glycol or 3, 2 and 1% methanol. Bull semen was frozen in 0.5 straws. Bull spermatozoa exhibited higher percentages (p<0.01) for total (Mot, 72.4%) and progressively (Prog, 29.5%) motilities when frozen in extender containing 3% glycerol compared to 3, 2 and 1% ethylene glycol or 3, 2 and 1% methanol. In conclusion, no advantages were found in using ethylene glycol or methanol to replace glycerol in bull semen freezing. Glycerol provided the best sperm characteristics for bull spermatozoa after freezing and thawing. The possibility of using ethylene glycol or methanol as permeating cryoprotectants for bull semen deserves further investigation, and these cryoprotectants should also be evaluated in extenders that contain disaccharides or cholesterol. PMID- 21288670 TI - Implications of dimorphism, population variation, and secular change in estimating population affinity in the Iberian Peninsula. AB - Morphometric cranial variation among Spanish samples was compared to a 19th century Portuguese sample using both traditional and three-dimensional approaches. The Spanish samples included the regional 19th century Oloriz collection and the local 16-17th century Villanubla and Vallolid sample from northwestern Spain. Results suggest moderate variation among the samples and suggest that varying patterns of regional variation, sexual dimorphism and secular change represent important factors to be considered in the evaluation of population affinity using craniometric approaches. PMID- 21288671 TI - Reversing microcrystalline tests--an analytical approach to recycling of microcrystals from drugs of abuse. AB - A combined analysis of microcrystalline tests followed by LC-MS or GC-MS analysis is described. Microcrystalline tests are shown to be non-destructive as addition products formed were easily dissociated after the application of an appropriate solvent. Subsequent analysis of the sample was done to quantify the recovery of the drug. Examples were performed using the date rape drug gamma-hydroxybutyrate (GHB) and the synthetic opioid methadone. PMID- 21288672 TI - Facial reconstruction: soft tissue thickness values for South African black females. AB - In forensic science, investigators frequently have to deal with unidentified skeletonised remains. When conventional methods of identification are unsuccessful, forensic facial reconstruction (FFR) may be used, often as a last resort, to assist the process. FFR relies on the relationships between the facial features, subcutaneous soft tissues and underlying bony structure of the skull. The aim of this study was to develop soft tissue thickness (STT) values for South African black females for application to FFR, to compare these values to existing literature or databases and to add these values to existing population data. Computerised tomography scanning was used to determine average population specific STT values at 28 facial landmarks of 154 black females. Descriptive statistics are provided for these STT values, which were also compared to those reported in three other comparable databases. Many of these STT values are significantly different from those reported for comparable groups, suggesting that individuals from different geographical areas have unique facial features thus requiring population-specific STT values. Repeatability tests indicated that most measurements could be recorded with a high degree of reliability. PMID- 21288673 TI - Factors affecting clinicians' decision as to whether to prescribe psychotropic medications or not in treatment of tic disorders. AB - Using clinical data, a retrospective investigation was carried out to elucidate factors and/or symptom severity affecting the clinicians' decision-making as to whether or not psychotropic medications should be prescribed for tic disorders. For this purpose, medical records on a total of 75 patients with tic disorders were collected and scrutinized. Of the total, 36 patients were found to have been given psychotropics on their first visit to our facility. With respect to the total scores of motor tics on the YGTSS, vocal tics on the YGTSS, the GAF score and age, the subjects were divided into two groups one with psychotropic medications prescribed and the other without any psychotropic medication at the first examination and compared by use of t-test. With respect to comorbid neuropsychiatric disorders and the sex, the two groups were compared using Chi square test. To see which one of factors had influenced the treating clinicians' decision to use or not to use psychotropic drugs at the first examination, analyses were made using the logistic regression model with those factors assigned for covariants and the prescription or no-prescription of psychotropic medications for dependent variables. Analyses using a logistic regression model revealed that vocal tics (p<0.01) and age (p<0.05) had significant correlations with the use or non-use of psychotropic drugs. This finding suggested that the severity degree of vocal tics might play the most important role as a factor that affects the clinicians' initial treatment plan with or without psychotropic drugs. And clinicians tend to avoid a drug therapy on younger children. PMID- 21288674 TI - Blended learning in radiology: is self-determined learning really more effective? AB - OBJECTIVE: To investigate whether there are differences in learning outcomes after the application of self-determined (intrinsic motivation) or mandatory (extrinsic motivation) use of e-learning units in an undergraduate radiology internship. METHODS: 96 medical students undergoing a one-week radiology internship were included in this study. Ten electronic cases (e-cases) were created for a blended learning approach. The e-learning environment was accessed on a self-determined (group B; n=32) or a mandatory basis (group C; n=32). A group without access to the e-learning environment served as control group (group A; n=32). Usage parameters of the e-cases were recorded. Results of a pre- and post-course assessment were used to quantitatively analyze learning outcomes. RESULTS: In group B 19/32 (59%) students processed at least one e-case, while in group C all students processed at least one e-case. There was a trend towards a higher improvement in knowledge in students exposed to a blended learning approach (group B: 13.7%; group C: 15.4%) than in the control group (group A: 8.5%; p=0.5356). Group C processed (p=0.0093) and passed (p=0.0078) significantly more e-cases, than with group B. There were no significant differences in the mean time per e-case and the total time on e-cases between both groups. CONCLUSION: Extrinsic motivation results in a more extensive use of e-learning units in an undergraduate radiology internship when compared with intrinsic motivation. The choice of the teaching strategy has a bigger influence on learning outcomes than the type of motivation, highlighting the need for qualified medical teachers. PMID- 21288675 TI - Hepatocellular carcinoma with marginal superparamagnetic iron oxide uptake on T2* weighted magnetic resonance imaging: histopathologic correlation. AB - PURPOSE: To evaluate the characteristics of hepatocellular carcinomas (HCCs) with marginal superparamagnetic iron oxide (SPIO) uptake on T2*-weighted MRI. MATERIALS AND METHODS: The study group consisted of 73 patients with 83 surgically resected HCCs. Preoperative SPIO-enhanced MRI studies were retrospectively reviewed. Marginal SPIO uptake was considered positive if a rim like or band-like low intensity area was present on SPIO-enhanced T2*-weighted images. The prevalence of marginal SPIO uptake was evaluated. Pathological specimens with hematoxylin and eosin staining and immunohistochemical staining of CD68 were reviewed in HCCs with marginal SPIO uptake and 33 HCCs without marginal SPIO uptake (control group). RESULTS: Ten of 83 (12%) HCCs showed marginal SPIO uptake. All HCCs were hypervascular, and only one nodule showed a nodule-in nodule appearance on imaging findings. The pathology specimens suggested possible causes of marginal SPIO uptake, including marginal macrophage infiltration in moderately or poorly differentiated HCC (n=4), residual normal hepatic tissue at the marginal area of confluent multinodular or single nodular with extranodular growth type HCC (n=3), and a well-differentiated HCC component in nodule-in nodule type HCC (n=3). Marginal macrophage infiltration was not seen in the control group. CONCLUSION: SPIO-enhanced MRI may be able to demonstrate marginal macrophage infiltration in HCC. PMID- 21288676 TI - Omental vascular pedicle sign: multidetector CT finding useful for diagnosis of an omental mass. AB - OBJECTIVE: To describe multidetector CT findings of "omental vascular pedicle" sign. MATERIALS AND METHODS: "Omental vascular pedicle" sign was defined as dilated omental vein associated with a mass located in omentum and was observed in 7 patients (5 women, 2 men). Mean age was 45 years. CT examinations and patient records were retrospectively reviewed. CT images were obtained by 16-MDCT (n = 1) and 64-dual source MDCT (n = 6). Curved planar and volume rendered images were reconstructed from axial images. Diameter of omental vein and drainage site were recorded. Images were evaluated by 2 radiologists in consensus. RESULTS: Pathologic diagnosis of patients with "omental vascular pedicle sign" was omental angiosarcoma (n = 1), endometrial adenocarcinoma (n = 2), ovarian serous adenocarcinoma (n = 2), mixed gonadal tumor (n = 1), malignant peripheral sheath tumor (n = 1). In 5 patients, omental vein drained into splenic vein and in 2 patients it drained into right gastroepiploic vein. Mean size of omental masses associated with omental vascular pedicle was 7.1 * 4.5 cm (range 15 * 11 cm to 2.7 * 1.6 cm). Mean diameter of omental vein was 3.1mm (range 6-1.5mm). Diameter of the omental vein increased with the increasing size of omental masses and Pearson's correlation coefficient was 0.99. CONCLUSION: "Omental vascular pedicle sign" can be helpful to objectively diagnose omental masses in patients with primary and metastatic omental tumors. PMID- 21288677 TI - Applications of whole-cell matrix-assisted laser-desorption/ionization time-of flight mass spectrometry in systematic microbiology. AB - In the last few years matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) has been increasingly studied and applied for the identification and typing of microorganisms. Very recently, MALDI-TOF MS has been introduced in clinical routine microbiological diagnostics with marked success, which is remarkable considering that not long ago the technology was generally seen as being far from practical application. The identification of microbial isolates by whole-cell mass spectrometry (WC-MS) is being recognized as one of the latest tools forging a revolution in microbial diagnostics, with the potential of bringing to an end many of the time-consuming and man-power intensive identification procedures that have been used for decades. Apart from applications of WC-MS in clinical diagnostics, other fields of microbiology also have adopted the technology with success. In this article, an over-view of the principles of MALDI-TOF MS and WC-MS is presented, highlighting the characteristics of the technology that allow its utilization for systematic microbiology. PMID- 21288678 TI - Isolation and structure elucidation of major alkaline degradant of ezetimibe. AB - This work presents the isolation and characterization of the alkaline degradant of Ezetimibe. Ezetimibe, a selective inhibitor of intestinal cholesterol absorption, was subjected to alkaline degradation. Ezetimibe was reacted with 0.1M methanolic sodium hydroxide solution for 10min at 80 degrees C to yield alkaline degradant to an extent of 90% of initial amount of the drug taken. This degradant was detected by high performance liquid chromatography (HPLC) at relative retention time (RRT) of 1.48 with respect to Ezetimibe. HPLC method involved an isocratic elution on a Waters Symmetry C(8) 150mm*4.6mm, 5MUm column using ammonium acetate buffer (pH 4.5, 50mM) - acetonitrile (50:50, v/v) as the mobile phase at a flow rate of 1.0mL/min and UV detection at 242nm. The degradant was isolated by preparative HPLC. Purity of the isolated solid was found to be more than 99%. Structure of alkaline degradant was confirmed by LC-MS, (1)H and (13)C NMR and IR spectroscopy. On the basis of spectral data, the structure of the degradant was confirmed as 5-(4-fluorophenyl)-2-[(4-fluorophenyl amino)-(4 hydroxyphenyl)methyl]-pent-4-enoic acid. The route for the formation of this degradant is also proposed. Determining the structures of degradation products arouse during stress testing can be useful for preclinical discovery efforts. PMID- 21288679 TI - 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American Stroke Association, American Association of Neuroscience Nurses, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Congress of Neurological Surgeons, Society of Atherosclerosis Imaging and Prevention, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, Society for Vascular Medicine, and Society for Vascular Surgery. PMID- 21288680 TI - 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American Stroke Association, American Association of Neuroscience Nurses, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Congress of Neurological Surgeons, Society of Atherosclerosis Imaging and Prevention, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, Society for Vascular Medicine, and Society for Vascular Surgery. PMID- 21288681 TI - "I wish I had a physician like that..."--the use of triangulation on the way towards a patient-centred medical education. PMID- 21288682 TI - Commentary to: medically unexplained symptoms as a threat to patients' identity? A conversation analysis of patients' reactions to psychosomatic attributions by Burbaum et al. PMID- 21288683 TI - Mass media health information: quantitative and qualitative analysis of daily press coverage and its relation with public perceptions. AB - OBJECTIVE: This paper describes the methods followed by the Pisa University OCS for collecting, storing and analyzing all health-related articles and database contents. Moreover, an example population survey on the topic of food safety based on such analysis is shown. METHODS: Articles published each day since 1999 in Italy's three most popular newspapers are collected and stored in a Data Base Text; on these articles quantitative and qualitative analyses were conducted. On the basis of these results as well as of epidemiological data, a questionnaire survey was carried out about sources of information, knowledge and risk perception of citizens regarding food safety. RESULTS: On a total of 24,434 articles on all health topics, 18% regarded food related hazards: their evolution over time showed peaks on BSE, avian flu and dioxin. A large proportion of the people surveyed declared having changed their food habits, at least temporarily, as a consequence of media information. Most get their information on food safety mainly from television. Most respondents remembered having previously heard news on BSE, avian flu and dioxin, but did not recall having heard of listeriosis, brucellosis or typhoid fever. CONCLUSIONS: Newspapers articles facing food related hazards tend to be alarming thus affecting the citizens risk perception. On the other hand people often ignore how to manage their own food safety in a practical way. PRACTICE IMPLICATIONS: Analysis of media messages can help to evaluate and correct the negative effects that may result in wrong information. PMID- 21288684 TI - Effects of induced parturition in goats on immunoglobulin G and chitotriosidase activity in colostrum and plasma and on plasma concentrations of prolactin. AB - The effect of induction of parturition with a PGF(2)alpha analog on plasma concentration of prolactin (PRL) and its effects on colostrum concentration of IgG and chitotriosidase (ChT) activity were studied in 16 pregnant Majorera goats. Treated goats, those in which parturition was induced, had greater concentrations of PRL than control goats 24 h before parturition (P < 0.05) and 48 h after parturition (P < 0.05). Control goats had greater concentrations of PRL than treated goats 96 h after parturition (P < 0.05). Plasma concentration of IgG did not differ between groups during the experimental period, but colostrum concentrations of IgG were greater in control goats than in treated goats at parturition (P < 0.05). Plasma ChT activity decreased during the period 72 h before parturition to 24 h after parturition in control and treated goats. Time evolution after partum affected the colostrum ChT activity, being greater at parturition than after parturition in both groups (P < 0.05). In summary, concentration of IgG in colostrum is slightly diminished if parturition is induced. Induction of parturition causes an early increase in PRL, which is most likely responsible for preterm suppression of IgG transport into mammary secretions. PMID- 21288685 TI - Impact on survival of the number of lymph nodes removed in patients with node negative gastric cancer submitted to extended lymph node dissection. AB - PURPOSE: This study was designed to establish whether the number of lymph nodes removed has an effect on prognosis in patients with node-negative gastric cancer. PATIENTS AND METHODS: We retrospectively analysed data of 114 consecutive patients who underwent gastrectomy and extended lymph node dissection for node negative adenocarcinoma of the stomach between 2000 and 2005. Standard survival methods and restricted cubic spline multivariable Cox regression models were applied. RESULTS: Median age was 63 years and 67 patients out of 114 (59%) were males. Median number of dissected LNs was 22 (range 2-73). Median follow-up was 76 months. Patients who had <=15 nodes removed had significantly worse distant disease-free survival, disease-free survival and overall survival at multivariable analysis than other patients. The results did not change when pT1 and pT2-3 cancer patients were analysed separately. The risk of distant metastases decreased as the number of dissected lymph nodes increased (>15). CONCLUSIONS: More extended lymph node resection offered survival benefit even in the subgroup of patients with early stage disease. Lymphadenectomy involving more than 15 lymph nodes should be performed for the treatment of node-negative gastric cancer. SYNOPSIS: The impact on survival of the number of lymph nodes removed in patients with node-negative gastric cancer has not been established. This study suggests that more extended lymph node resection offers protection, as patients who had <=15 nodes removed had significantly worse disease-free survival and overall survival at multivariate analysis than patients in whom >15 nodes were removed. PMID- 21288686 TI - Anatomic study of juxta renal aneurysms: impact on fenestrated stent-grafts. AB - BACKGROUND: Fenestrated stent-grafts allow for treatment of patients with juxtarenal aneurysms (JRA) when they present with contraindications for conventional treatment. The fenestrated module is a custom-made module, specially designed to fit a specific patient, using computed tomographic scan measurements, which entails manufacturing delay and high cost. The aim of our study was to evaluate the possibility to reproduce the interrenal aorta anatomy to design a standard fenestrated module that would fit the maximum number of patients with JRA. METHODS: On a three-dimensional working station, we analyzed 289 preoperative computed tomographic scan results of patients with JRA and who were treated with fenestrated stent-grafts comprising two fenestrations for the renal arteries and a scallop for the superior mesenteric artery (SMA). On curvilinear reconstructions, we successively measured the interrenal aorta diameter, its orientation, as well as the height of each renal ostium, taking the ostium center of the SMA as a reference mark. Later, a statistical analysis of these measures distribution was performed so as to design a fenestrated module that would fit the maximum number of patients. RESULTS: The center of the left renal artery presented with a median orientation of 82.5 degrees (range, 37.5-150) and a median distance of 9 mm (range, 0-30), in relation to the SMA ostium. The ostium center of the right renal artery presented with a median orientation of 285 degrees (range, 240-337.5) and a median distance of 8 mm (range, 3-30), in relation to the SMA ostium. By positioning the current renal fenestrations (6-mm wide), on the basis of the calculated median positions, in our series, only 20% of the patients could be treated with a standard fenestrated module. Should the diameter of these fenestrations be increased by 10 mm, it would then be possible to treat 50% of our patients. CONCLUSION: The anatomy of the interrenal aorta and its branches is quite reproducible to design standard fenestrated stent-grafts that could treat half of the patients with JRA. PMID- 21288687 TI - Endovascular and open surgical treatment of brachiocephalic arteries. PMID- 21288688 TI - The use of gadolinium for arterial interventions. AB - BACKGROUND: Gadolinium (Gd) has been traditionally used as a non-nephrotoxic alternative to iodinated contrast for digital subtraction angiography (DSA) in patients with chronic renal insufficiency. However, its use has been questioned on the basis of reports of nephrotoxicity and its recent association with nephrogenic systemic fibrosis (NSF), a potentially lethal complication. Recently available data are conflicting with respect to the true safety profile of intra arterial Gd. The purpose of this study was to examine the risk of contrast nephropathy and NSF after Gd exposure in a large population of azotemic patients undergoing DSA. METHODS: A comprehensive database encompassing data on all patients who underwent DSA between June 2003 and December 2007 at the New York Presbyterian Hospital was retrospectively reviewed. Patients receiving Gd either alone or in combination with iodinated contrast during DSA were identified and further analyzed. Acute renal failure (ARF) was defined as an elevation in serum creatinine (Cr) by >0.5 mg/dL within 48 hours of exposure. Clinical follow-up was conducted through chart reviewing as well as telephonic interviews with patients and their primary care physicians. RESULTS: A total of 153 patients underwent 179 exposures to Gd either alone (33%) or in combination (67%) with iodinated contrast. Mean follow-up duration was 27.1 months. The mean Cr level was 1.94 +/- 0.78 mg/dL and 1.96 +/- 1.1 mg/dL before and after DSA, respectively. There were 20 (11.2%) instances of ARF. The mean Cr level before DSA was higher in patients who developed ARF versus those in the non-ARF group (2.7 +/- 1.1 mg/dL vs. 1.9 +/ 0.7 mg/dL, p = 0.004). In the ARF group, 12 patients had a return to baseline renal function, four experienced irreversible renal deterioration, and four needed dialysis (4.5% incidence of irreversible renal failure). There were 19 deaths at the time of this study (12.4%). The highest risk for the development of ARF after Gd exposure occurred in patients with Cr levels of >3.0 mg/dL before DSA and in those receiving >0.4 mmol/kg of Gd. For patients who received iodinated contrast in combination with Gd, there was a trend toward a higher risk for developing ARF as compared with those receiving only Gd. Finally, there were no instances of NSF identified in any of the patients who received intra-arterial Gd. CONCLUSIONS: Although Gd has the potential to cause kidney injury similar to iodinated contrast, the risk of irreversible renal failure and the requirement for dialysis is low. Life- or limb-threatening interventions should not be avoided in this patient cohort because of preexisting elevations in Cr. These data should help guide the use of Gd in patients with chronic renal insufficiency. PMID- 21288689 TI - Effects of a mindfulness-based smoking cessation program for an adult with mild intellectual disability. AB - Smoking is a major risk factor for a number of health conditions and many smokers find it difficult to quit smoking without specific interventions. We developed and used a mindfulness-based smoking cessation program with a 31-year-old man with mild intellectual disabilities who had been a smoker for 17 years. The mindfulness-based smoking cessation program consisted of three components: intention, mindful observation of thoughts, and Meditation on the Soles of the Feet. A changing-criterion analysis showed that this man was able to fade his cigarette smoking from 12 at baseline to 0 within 3 months, and maintain this for a year. Follow-up data, collected every 3 months following the maintenance period, showed he was able to abstain from smoking for 3 years. Our study suggests that this mindfulness-based smoking cessation program merits further investigation. PMID- 21288690 TI - Image segmentation and activity estimation for microPET 11C-raclopride images using an expectation-maximum algorithm with a mixture of Poisson distributions. AB - The objective of this study was to use a mixture of Poisson (MOP) model expectation maximum (EM) algorithm for segmenting microPET images. Simulated rat phantoms with partial volume effect and different noise levels were generated to evaluate the performance of the method. The partial volume correction was performed using an EM deblurring method before the segmentation. The EM-MOP outperforms the EM-MOP in terms of the estimated spatial accuracy, quantitative accuracy, robustness and computing efficiency. To conclude, the proposed EM-MOP method is a reliable and accurate approach for estimating uptake levels and spatial distributions across target tissues in microPET (11)C-raclopride imaging studies. PMID- 21288691 TI - Characterization and chronological changes of preterm human milk gangliosides. AB - OBJECTIVE: Gangliosides are present in high concentrations in the nervous tissue, and some are observed in small amounts in many extraneural tissues and body fluids. Human milk may play important roles in energy supplementation, prophylaxis of infection, and brain development. For preterm infants, human milk gangliosides are also very important substances during the early lactation stage. However, there are no data on human milk gangliosides from mothers at preterm delivery. We investigated the characterization of gangliosides and chronologic changes in human preterm milk earlier than 30 wk of gestation from 1 to 60 d after birth. METHODS: Forty-one samples were analyzed by high-performance thin layer chromatography and a microtechnique using 1 mL of milk from each lactation and compared with 61 full-term human milk samples. RESULTS: Total lipid-bound sialic acid of human milk gangliosides after preterm delivery showed a peak concentration at 2 to 3 d postpartum and then remained at a high concentration until approximately 10 d. GD3 was the major ganglioside in the colostrum until approximately 7 to 10 d postpartum. GM3 was scarcely detected until 7 d postpartum and then increased gradually. There was no difference in the GD3 concentration per 1 mL of human milk between preterm and full-term human milk until approximately 5 to 8 d postpartum. After that time, the GD3 concentration decreased sharply. In contrast, the total concentrations of GM3 per 1 mL of human milk from mothers after preterm delivery were lower than those from mothers after full-term delivery throughout the entire period examined. CONCLUSION: This finding is essential to elucidate the composition of human milk gangliosides after preterm delivery, which may contribute to the analysis of the physiologic composition and formulation appropriate preterm infant nutrition. PMID- 21288692 TI - Resequencing and follow-up of neurexin 1 (NRXN1) in schizophrenia patients. AB - Large rare deletions in NRXN1 increase the risk for schizophrenia. The aim of the present study was to determine whether small rare sequence changes in exons and splice sites contribute to the development of schizophrenia in a high-penetrance manner. Complete coding regions and splice sites were resequenced in 94 patients and 94 controls. Among the 16 rare sequence variants, two missense substitutions (E201G and I1068V) were observed in single patients but not in controls. Investigation of DNA samples from family members and in silico analysis of possible effects on protein function produced no evidence of high-penetrance genetic effects. Follow-up genotyping of the most promising findings (E201G and I1068V) in an independent sample of >1400 patients and >1100 controls revealed no overrepresentation in patients compared to controls (E201G: 0/1 and I1068V: 0/0). Since I1068V was observed in a single patient, it is impossible to exclude the possibility that I1068V makes a minor contribution to schizophrenia susceptibility. Overall, however, the results do not suggest the existence of rare, highly penetrant NRXN1 mutations in patients with schizophrenia. PMID- 21288693 TI - Viewing the elephant from 200 feet: reconstructing the schizophrenia syndrome. PMID- 21288694 TI - Group and site differences on the California Verbal Learning Test in persons with schizophrenia and their first-degree relatives: findings from the Consortium on the Genetics of Schizophrenia (COGS). AB - Genetic studies of schizophrenia focus increasingly on putative endophenotypes because their genetic etiology may be simpler than clinical diagnosis. The Consortium on the Genetics of Schizophrenia (COGS), a multisite family study, aims to identify the genetic basis of several endophenotypes including verbal declarative memory (VDM), a neurocognitive function that shows robust impairment in schizophrenia. We present data on one type of measure of VDM, the California Verbal Learning Test, Second Edition (CVLT-II), in schizophrenia probands (n=305), their full biological siblings (n=449) and parents (n=232), and in community comparison subjects (CCS; n=509) across seven sites. Probands performed more poorly on each of five CVLT-II measures compared to related sibling and parent groups and CCS. Siblings and parents performed significantly worse than CCS on one measure (Discriminability), but with smaller effect sizes and less impairment than observed previously. The results raise questions about the homogeneity of VDM as an endophenotype, about methodological issues related to sampling, and about psychometric issues that impact the utility of the CVLT for detecting VDM deficits in nonpsychotic relatives of persons with schizophrenia. PMID- 21288695 TI - Addition of the collagen binding domain of fibronectin potentiates the biochemical availability of hepatocyte growth factor for cutaneous wound healing. PMID- 21288696 TI - When should mood stabilizers be withdrawn due to lack of efficacy? Some methodological considerations. AB - Maintenance therapy in bipolar disorder is primarily aimed at preventing recurrence of acute episodes. Clinicians often decide on the basis of their own experience whether mood stabilizer (MS) is properly satisfying the objective of preventing a relapse/recurrence. Evidence-based data seem far from clinical practice in assessing a MS efficacy, as they mainly focus on a drug's efficacy to first relapse and not considering the patient's course of illness. The problem of assessing MS's efficacy seems further complicated when considering combination therapy, which, due to lack of evidence-based data, economical aspects, attitude of clinicians and legal issues may bring to cumulative prescriptions. Nowadays, the drug therapy for a bipolar patient is usually tailored after longitudinal observation of his specific course of illness. The course of illness should be considered also when choosing practical criteria for the suspension of a MS due to lack of efficacy. The authors propose some preliminary criteria which may help clinicians evaluating whether a mood stabilizer is being useful or not, dividing possible outcomes and suggesting subsequent therapeutic steps in the optimization of a patient's treatment. PMID- 21288697 TI - Mental state attribution in schizophrenia: what distinguishes patients with "poor" from patients with "fair" mentalising skills? AB - PURPOSE: Although many patients with schizophrenia are impaired in mental states attribution abilities, a significant number perform within normal or near-normal ranges in mental state attribution tasks. No studies have analysed cognitive or behavioural differences between patients with - to some extent - preserved mental state attribution skills and those with poor mentalising abilities. MATERIAL AND METHODS: To examine characteristics of "poor" and "fair" mentalisers, 58 patients with schizophrenia performed a mental state attribution task, a test of general intelligence, and two executive functioning tests. "Poor" and "fair" mentalising skills were defined according to a median-split procedure; the median score in the patient group was also within two standard deviations of the control group. In addition, patients' social behavioural skills and psychopathological profiles were rated. RESULTS: Patients performing within normal or near normal ranges on the mental state attribution task had fewer social behavioural abnormalities than patients with poor mentalising abilities (even when controlled for intelligence), but did not differ in executive functioning. Fair mental state performers showed less disorganisation and excitement symptoms than poor performers. The degree of disorganisation mediated the influence of mental state attribution on social behavioural skills. CONCLUSIONS: Schizophrenia patients with (partially) preserved mentalising skills have fewer behavioural problems in the social domain than patients with poor mentalising abilities. Conceptual disorganisation mediates the prediction of social behavioural skills through mentalising skills, suggesting that disorganised patients may require special attention regarding social-cognitive skills training. PMID- 21288698 TI - Width of the third ventricle assessed by transcranial sonography can monitor brain atrophy in a time- and cost-effective manner--results from a longitudinal study on 500 subjects. AB - Ventricular width and its enlargement over time are discussed as promising markers for preclinical brain atrophy. The aim of our study was to define whether brain atrophy can reliably be monitored by transcranial ultrasound (TCS). In a prospective longitudinal trial over 5years, 500 healthy persons were examined by a standardized protocol with TCS in addition to an extensive cognitive testing using the Consortium to Establish a Registry of Alzheimer's Disease - Neuropsychological Testing (CERAD-NP). TCS displayed the third ventricle in 96% of all cases at the follow-up with a high intra-individual reproducibility and excellent inter-rater coefficient (0.992). The mean diameter of the third ventricle in subjects with a cognitive decline was significantly wider (6mm+/-2) than in subjects with normal cognitive testing results (4.6mm+/-1.8). We demonstrated that the width of the third ventricle, as a marker of brain atrophy can reliably be monitored by using TCS as a non-invasive, time- and cost effective method. We provide evidence that the assessed width of the third ventricle can differentiate between subjects with a normal cognitive performance and subjects with a cognitive decline. TCS may be a useful screening tool in the early diagnosis of cognitive decline. PMID- 21288699 TI - Introduction. Current progress and achievements in biointerface research in China. PMID- 21288700 TI - Surface coverage of didecyl dimethylammonium bromide on poly(lactide-co glycolide) nanoparticles. AB - Coverage of didecyl dimethylammonium bromide (DDAB) on the surface of poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) was investigated. DDAB stabilized PLGA NPs (DDAB/PLGA NPs) were prepared by emulsification-diffusion technique with high shear stress. The fabricated DDAB/PLGA NPs were ellipsoidal and positively charged. An increase in the homogenizing stirring rate and in the weight percentage of DDAB in microemulsion reduced the particle size of DDAB/PLGA NPs. When the homogenizing stirring rate increased or the DDAB level in microemulsion decreased, the zeta potential of DDAB/PLGA NPs reduced. In addition, a high homogenizing stirring rate reduced the surface coverage of DDAB on PLGA NPs. The surface coverage of DDAB on PLGA NPs enhanced with increasing the weight percentage of DDAB in microemulsion. The quantity of DDAB attached on the surface could appreciably affect the properties of DDAB/PLGA NPs. PMID- 21288701 TI - [Transient pustular eruption in neonates]. AB - Transient neonatal pustular melanosis is a common, benign, but little known dermatosis in newborns. Diagnosis of transient neonatal pustular melanosis is made clinically, by the presence of vesiculopustular and pigmented macular skin lesions. This benign spontaneously regressive dermatosis should be distinguished from several serious infectious neonatal diseases. We report a case of transient neonatal pustular melanosis and discuss the nosologic problems and differential diagnosis of this entity. PMID- 21288702 TI - [Nutrition of the preterm infant]. AB - The quality of nutritional support impacts not only the growth and quality of growth of preterm infants, but also all aspects of their development. In order to provide optimal nutrition, two main rules should be followed: optimise early parenteral nutrition and introduce appropriate enteral nutrition preferably with the mother's milk as early as possible. Recommendations have recently increased early energy and protein intake. The term "aggressive nutrition" has been introduced to qualify these changes, but we prefer the term "optimal nutrition," which more precisely reflects the physiology and needs of the preterm infant. Specific efforts should be continued to improve physician training in neonatal nutrition and to facilitate the dissemination of the most recent recommendations. Standardization of nutritional protocols in neonatal units should be promoted as a way to improve overall nutritional care. A full field of research remains open to determine the most effective nutritional strategy for preterm infants in order to maximize their growth and development. PMID- 21288703 TI - Radiotherapy planning in high-grade gliomas: a survey of current UK practice. AB - AIMS: Primary brain tumours in adults are rare, with high-grade gliomas (HGG) being the most common and most aggressive type. The clinical management of rare tumours such as HGG can be heterogeneous across different cancer centres. The aim of this survey was to determine current UK practice in the primary management of HGG, particularly in light of the improved outcomes reported recently. MATERIALS AND METHODS: In February 2009, a questionnaire was sent to 71 consultant clinical oncologists in the UK who were reported to have a neuro-oncology practice. Questions focussed on the radiotherapeutic management of HGG. RESULTS: In total, 46/71 (65%) completed questionnaires were returned; 31/46 (67%) routinely used magnetic resonance imaging/computed tomography fusion for radiotherapy planning; 34/36 (94%) routinely prescribed 60Gy in 30 fractions in a single phase; 7/36 (19%) would consider 54-55Gy in 30 fractions in selected clinical scenarios; 42/46 (91%) defined the planning target volume (PTV) as the gross tumour volume (GTV)+2-3cm margin and 42/46 (91%) outlined at least one 'organ at risk' (OAR). Accepted tolerance doses varied considerably, e.g. retina range: 30-54Gy. Sixty four per cent of clinicians (27/42) compromise the PTV and 30% (14/42) the GTV in order to keep OARs within preset tolerances. Nearly one-third (14/42) involve the patient in this decision-making process, e.g. weighing up the risk of late toxicity with the risks of reducing the dose to the PTV. CONCLUSION: The results of this survey show areas of strong agreement as well as areas of variation in clinical practice of aspects of treatment planning for HGG between UK neuro oncologists. PMID- 21288704 TI - Multimodal medical image analysis: from visualization to disease modeling. PMID- 21288705 TI - Protective effect of aqueous extract of Allium sativum against zearalenone toxicity mediated by oxidative stress. AB - Zearalenone (ZEN) is a non-steroidal estrogenic mycotoxin produced by several species of Fusarium in cereals and agricultural products. It has been implicated in several mycotoxicosis in farm animals and in humans. Several reports suggest that oxidative damage seems to be a key determinant of ZEN induced toxicity in vitro and in vivo. The aim of the current study was to evaluate the protective effects of aqueous extract of Allium sativum (AEA), against ZEN-induced cytotoxicity, reactive oxygen species (ROS) generation and DNA fragmentation in cultured Vero cells. Indeed, cytotoxicity effects were studied using MTT viability assay, ROS generation measurement and catalase activity induction. To check whether the oxidative stress induction was associated to DNA lesions, we looked for DNA fragmentation using Comet test. Our results indicated that ZEN induced several toxic effects and significant alterations mediated by oxidative stress mechanism. Treatment by ZEN combined to the lowest dose of AEA (250 MUg/ml) showed a significant reduction of ZEN induced damages for all tested markers and a noticeable reduction of DNA fragmentation. It could be concluded that A. sativum aqueous extracts is effective in the protection against ZEN hazards. This could be relevant, particularly with the emergent demand for natural products which may counteract the detrimental toxic effects mediated by oxidative stress process and therefore prevents multiple human diseases. PMID- 21288706 TI - Protein folding stress in neurodegenerative diseases: a glimpse into the ER. AB - Several neurodegenerative diseases share common neuropathology, primarily featuring the presence in the brain of abnormal protein inclusions containing specific misfolded proteins. Recent evidence indicates that alteration in organelle function is a common pathological feature of protein misfolding disorders, highlighting perturbations in the homeostasis of the endoplasmic reticulum (ER). Signs of ER stress have been detected in most experimental models of neurological disorders and more recently in brain samples from human patients with neurodegenerative disease. To cope with ER stress, cells activate an integrated signaling response termed the unfolded protein response (UPR), which aims to reestablish homeostasis in part through regulation of genes involved in protein folding, quality control and degradation pathways. Here we discuss the particular mechanisms currently proposed to be involved in the generation of protein folding stress in different neurodegenerative conditions and speculate about possible therapeutic interventions. PMID- 21288707 TI - Count, identification and antimicrobial susceptibility of bacteria recovered from dental solid waste in Brazil. AB - In Brazil, few studies on microbial content of dental solid waste and its antibiotic susceptibility are available. An effort has been made through this study to evaluate the hazardous status of dental solid waste, keeping in mind its possible role in cross-infection chain. Six samples of solid waste were collected at different times and seasons from three dental health services. The microbial content was evaluated in different culture media and atmospheric conditions, and the isolates were submitted to antibiotic susceptibility testing. A total of 766 bacterial strains were isolated and identified during the study period. Gram positive cocci were the most frequent morphotype isolated (48.0%), followed by Gram-negative rods (46.2%), Gram-positive rods (5.0%), Gram-negative-cocci (0.4%), and Gram-positive coccobacillus (0.1%). Only two anaerobic bacteria were isolated (0.3%). The most frequently isolated species was Staphylococcus epidermidis (29.9%), followed by Stenotrophomonas maltophilia (8.2%), and Enterococcus faecalis (6.7%). High resistance rate to ampicillin was observed among Gram-negative rods (59.4%) and Gram-positive cocci (44.4%). For Gram negative rods, high resistance was also noted to aztreonam (47.7%), cefotaxime (47.4%), ceftriaxone and cefazolin (43.7%), and ticarcillin-clavulanic acid (38.2%). Against Gram-positive cocci penicillin exhibit a higher resistance rate (45.0%), followed by ampicillin, erythromycin (27.2%), and tetracycline (22.0%). The present study demonstrated that several pathogenic bacteria are present in dental solid waste and can survive after 48 h from the waste generation time and harbor resistance profiles against several clinical recommended antibiotics. PMID- 21288708 TI - Comprehensive quality assessment of municipal organic waste composts produced by different preparation methods. AB - In the first part of this work, the effect of municipal organic waste (MOW) composts on plant growth was evaluated in a greenhouse trial. The treatments included soil amended with 14 different composts (prepared by shredding, adding wood shavings, cocomposting with biosolids or vermicomposting), an inorganically fertilized soil, and a control soil. All of the treatments significantly increased plant growth compared to the control, and yields of three of the amended treatments were as high as that of the inorganic fertilizer treatment. When comparing differently prepared composts to the conventional compost, it was found that cocomposting MOW with biosolids was the method which most positively influenced yields (26-41% yield increases). In the second part of this work, we evaluated the effects of the different preparation methods on compost quality, using a multivariate approach. Three main quality aspects were considered collectively in a principal component analysis: organic matter and nutrient concentrations, degradability and capacity to mineralize these nutrients, and plant growth. The model was restricted to the first and second components (PC1 and PC1) which accounted for 94% of data variance. On the resulting factorial plane, four groups were distinguished. Each of the groups was compared to the reference compost to determine quality increases or decreases. Based on this analysis, it was found that cocomposting MOW with biosolids produced the highest quality products (higher total nutrient and OM concentration, nutrient mineralization potential, and plant growth). Addition of wood shavings increased OM concentration, but reduced quality in terms of the other aspects studied. Shredding was only effective to increase product quality when it was not combined with other methods, whereas vermicomposting only increased quality when MOW was not mixed with biosolids. PMID- 21288709 TI - Environmental assessment of sewage sludge as secondary raw material in cement production--a case study in China. AB - A life cycle assessment was carried out to estimate the environmental impact of sewage sludge as secondary raw material in cement production. To confirm and add credibility to the study, uncertainty analysis was conducted. Results showed the impact generated from respiratory inorganics, terrestrial ecotoxicity, global warming, and non-renewable energy categories had an important contribution to overall environmental impact, due to energy, clinker, and limestone production stages. Also, uncertainty analysis results showed the technology of sewage sludge as secondary raw material in cement production had little or no effect on changing the overall environmental potential impact generated from general cement production. Accordingly, using the technology of sewage sludge as secondary raw material in cement production is a good choice for reducing the pressure on the environment from dramatically increased sludge disposal. In addition, increasing electricity recovery rate, choosing natural gas fired electricity generation technology, and optimizing the raw material consumption in clinker production are highly recommended to reduce the adverse effects on the environment. PMID- 21288710 TI - Comparison of coal/solid recovered fuel (SRF) with coal/refuse derived fuel (RDF) in a fluidized bed reactor. AB - An experimental study was undertaken to compare the differences between municipal solid waste (MSW) derived solid recovered fuel (SRF) (complying with CEN standards) and refuse derived fuel (RDF). Both fuels were co-combusted with coal in a 50 kW fluidized bed combustor and the metal emissions were compared. Synthetic SRF was prepared in the laboratory by grinding major constituents of MSW such as paper, plastic, textile and wood. RDF was obtained from a local mechanical treatment plant. Heavy metal emissions in flue gas and ash samples from the (coal+10% SRF) fuel mixture were found to be within the acceptable range and were generally lower than that obtained for coal+10% RDF fuel mixture. The relative distribution of heavy metals in ash components and the flue gas stream shows the presence of a large fraction (up to 98%) of most of the metals in the ash (except Hg and As). Thermo-gravimetric (TG) analysis of SRF constituents was performed to understand the behaviour of fuel mixtures in the absence and presence of air. The results obtained from the experimental study will enhance the confidence of fuel users towards using MSW-derived SRF as an alternative fuel. PMID- 21288711 TI - Oligonucleotide probes applied for sensitive enzyme-amplified electrochemical assay of mercury(II) ions. AB - We developed a novel electrochemical sensor for Hg(2+) detection using two mercury-specific oligonucleotide probes and streptavidin-horseradish peroxidase (HRP) enzymatic signal amplification. The two mercury-specific oligonucleotide probes comprised a thiolated capture probe and a biotinated signal probe. The thiolated capture probe was immobilized on a gold electrode. In the presence of Hg(2+), the thymine-Hg(2+)-thymine (T-Hg(2+)-T) interaction between the mismatched T-T base pairs directed the biotinated signal probe hybridizing to the capture probe and yielded a biotin-functioned electrode surface. HRP was then immobilized on the biotin-modified substrate via biotin-streptavidin interaction. The immobilized HRP catalyzed the oxidation of hydroquinone (H(2)Q) to benzoquinone (BQ) by hydrogen peroxide (H(2)O(2)) and the generated BQ was further electrochemically reduced at the modified gold electrode, producing a readout signal for quantitative detection of Hg(2+). The results showed that the enzyme-amplified electrochemical sensor system was highly sensitive to Hg(2+) in the concentration of 0.5 nM to 1 MUM with a detection limit of 0.3 nM, and it also demonstrated excellent selectivity against other interferential metal ions. PMID- 21288712 TI - What disorders of cortical development tell us about the cortex: one plus one does not always make two. AB - The unique size and complexity of the human cerebral cortex are achieved via a long and precisely regulated developmental process controlling neurogenesis, neuronal migration and differentiation. Traditionally, disorders of cortical development have been classified on the basis of the most obvious defects in one of these developmental steps. However, the more we learn about the cellular biological roles of genes that are essential for cortical development, the more we realize that these functions map onto molecular processes, but not so cleanly onto anatomical processes. Essential genes might be involved in both proliferation and migration as well as differentiation, reflecting roles for underlying molecular mechanisms in different phases of development and causing a stunning variety of cortical defects. PMID- 21288713 TI - Structural regulation of cullin-RING ubiquitin ligase complexes. AB - Cullin-RING ligases (CRLs) compose the largest class of E3 ubiquitin ligases. CRLs are modular, multisubunit enzymes, comprising interchangeable substrate receptors dedicated to particular Cullin-RING catalytic cores. Recent structural studies have revealed numerous ways in which CRL E3 ligase activities are controlled, including multimodal E3 ligase activation by covalent attachment of the ubiquitin-like protein NEDD8, inhibition of CRL assembly/activity by CAND1, and several mechanisms of regulated substrate recruitment. These features highlight the potential for CRL activities to be tuned in responses to diverse cellular cues, and for modulating CRL functions through small-molecule agonists or antagonists. As the second installment of a two-review series, this article focuses on recent structural studies advancing our knowledge of how CRL activities are regulated. PMID- 21288714 TI - A combined approach of experiments and computational docking simulation to the Coprinus cinereus peroxidase-catalyzed oxidative polymerization of alkyl phenols. AB - The characteristics of the oxidative polymerization of alkyl phenol derivatives catalyzed by Coprinus cinereus peroxidase (CIP) were studied qualitatively and quantitatively using a combined approach of experiments and computational docking simulations. As determined by docking study of CIP and alkyl phenols, the binding interaction was found to be important for the determination of substrate specificity. The distant binding and indirect orientation of o-isopropyl phenol and o-tertiary butyl phenol to the catalytic residue (56His) could explain the inability of CIP to polymerize these substrates. Three hydrophobic residues (156Pro, 192Leu, and 230Phe) at the entrance of the binding pocket were also found to be crucial in binding and orientation of alkyl phenols. A two-parameter QSAR equation with the binding distance and the molecular volume of the substrates was proposed and the polymerization yield was accurately predicted by two-parameter QSAR equation. PMID- 21288715 TI - Synthesis and in vitro antibacterial activity of oxazolidine LBM-415 analogs as peptide deformylase inhibitors. AB - The drug resistant bacteria pose a severe threat to human health. The increasing resistance of those pathogens to traditional antibacterial therapy renders the identification of new antibacterial agents with novel antibacterial mechanisms an urgent need. In this study, a series of (2S)-N-substituted-1 [(formyhydroxyamino)methyl]-1-oxohexyl]-2-oxazolidinecarboxamides were designed, synthesized and evaluated for in vitro antibacterial activity. Most of these compounds displayed good activities against Gram-positive organisms comparable to reference agent LBM-415. PMID- 21288716 TI - Design, synthesis and biological evaluation of novel 4-hydroxybenzene acrylic acid derivatives. AB - A series of 4-hydroxybenzene acrylic acid derivatives were designed and synthesized based on the ferulic acid of natural active ingredients. The tested compound 5a, 5f and 6a have significant anti-inflammatory activity with suppression rates of 45.29%, 44.75% and 24.11%, respectively, compared with that of indomethacin, and their cardiac toxicity was not observed. The structure function relationship shows that the p-hydroxyl group on the alpha-position benzene ring, particularly if acetylated, contributes to the considerable anti inflammatory activity; that the carboxyl group on the double bond, if esterified, also contributes to the anti-inflammatory activity; that the p-methylsulfonyl group on the other benzene ring, whose introduction is due to the COX-2 selectivity, also contributes to anti-inflammatory activity surprisingly. PMID- 21288717 TI - Scaffold oriented synthesis. Part 4: design, synthesis and biological evaluation of novel 5-substituted indazoles as potent and selective kinase inhibitors employing heterocycle forming and multicomponent reactions. AB - We report the synthesis and biological evaluation of 5-substituted indazoles as kinase inhibitors. The compounds were synthesized in a parallel synthesis fashion from readily available starting materials employing heterocycle forming and multicomponent reactions and were evaluated against a panel of kinase assays. Potent inhibitors were identified for Gsk3beta, Rock2, and Egfr. PMID- 21288718 TI - A broad spectrum anticancer nucleoside with selective toxicity against human colon cells in vitro. AB - 2',3'-Bis-O-tert-butyldimethylsilyl-5'-deoxy-5'-[N-(methylcarbamoyl)amino]-N(6) (N-phenylcarbamoyl)adenosine, a new member of the N(6),5'-bis-ureidoadenosine class of anticancer nucleosides, is found to exhibit broad spectrum antiproliferative activity. A majority of the cell lines in the NCI-60 are inhibited with an average GI(50)=3.13 MUM. Selective toxicity against human colon cancer cell lines (COLO 205, HCC-2998, HCT-116, HT29, KM12) was also exhibited (LC(50)'s=6-10 MUM). PMID- 21288719 TI - A novel MYH7 mutation links congenital fiber type disproportion and myosin storage myopathy. AB - This study aimed to identify the genetic defect in a multigenerational family presenting an autosomal dominant myopathy with histological features of congenital fiber type disproportion. Linkage analysis and genetic sequencing identified, in all affected members of the family, the c.5807A>G heterozygous mutation in MYH7, which encodes the slow/beta-cardiac myosin heavy chain. This mutation causes skeletal but not cardiac involvement. Myosin heavy chain expression pattern was also characterized by immunohistochemistry, western blot and q-PCR in muscle biopsies from two patients aged 25 and 62, respectively. While only congenital fiber type disproportion was observed in the younger patient, older patient's biopsy presented aggregates of slow myosin heavy chains, in fiber sub-sarcolemmal region. These clinico-pathologic findings suggest a novel phenotype within the emerging group of hereditary myosin myopathies, which in this family presents typical characteristics of congenital fiber type disproportion in early stages and later evolves to myosin storage myopathy. PMID- 21288720 TI - Discordance in early breast cancer for tumour grade, estrogen receptor, progesteron receptors and human epidermal receptor-2 status between core needle biopsy and surgical excisional primary tumour. AB - The aim of the present study was to compare the tumour grade, Estrogen Receptor (ER), Progesteron Receptor (PgR) and Human Epidermal Receptor-2 (HER-2) status in the core needle biopsy (CNB) with those observed in the subsequent excisional primary tumour (EPT). All patients diagnosed with an early breast cancer in our University Hospital Center between January 1, 2005 and December 31, 2006 were included but exclusion criteria of patients with large tumour requiring neoadjuvant chemotherapy and cases with more than one tumour (multicentricity/multifocality tumours). Histological tumour grade assessed according to Nottingham Grading System (SBRm), ER, Pgr and HER-2 tumoural status were assessed twice in CNB and in EPT. A total of 175 patients were assessed. The concordance between CNB and EPT for Grade, ER, PgR and HER2 status were 75.4% (p > 0.00001), 84% (p > 0.00002), 78.3% (p = 0.002) and 98.3% (p = 0.486) respectively. In conclusion CNB can be used with confidence for HER2 determination. For grade, PgR and ER due to substantial discordance results from CNB should be used with caution. PMID- 21288722 TI - The experiences of patients and their families of visiting whilst in an intensive care unit--a hermeneutic interview study. AB - AIM: The aim of this study was to interpret and understand the meanings of the lived experiences of visiting of patients in an ICU and their families. METHOD: The research design was hermeneutic, based on interviews. This study includes 12 interviews with seven patients and five relatives who had been in an ICU. The interview text was interpreted in a Gadamerian manner as different plays with actors and plots. FINDINGS: Patients' narratives could be divided into two parts; recall of real life and unreal life experiences, the unreal being more common. Relatives' narratives are described as being on stage and being backstage, i.e. in the room with the patient and outside it. CONCLUSION: The final interpretation elucidated the experience of visiting as the sudden shift between being present in real life vs. being present in the real life of unreality. It was a process whereby the patient and the family build a new understanding of life that creates a new form of interplay within the family. The pre-critical illness life is no longer there--a new life has begun. To support patients and their families in this process of change a family-centred care perspective is necessary. PMID- 21288723 TI - Effects of electrical cutaneous stimulation of hallux on walking patterns in adults. AB - Single-shock electrical stimulation of the big toe results in a 20 ms advancement of the walking cycle, lasting for 1-2 strides, when the shock is applied in early swing. During stance there is a retardation of the cycle but of similar magnitude. However unlike the complex responses reported for electrical stimulation of the sole of the foot, toe stimulation is best described as a simple withdrawal response. PMID- 21288721 TI - Evolutionary origins of STIM1 and STIM2 within ancient Ca2+ signaling systems. AB - Human stromal interaction molecule (STIM) proteins are parts of elaborate eukaryotic Ca(2+) signaling systems that include numerous plasma membrane (PM), endoplasmic reticulum (ER), and mitochondrial Ca(2+) transporters, channels and regulators. STIM2 and STIM1 function as Ca(2+) sensors with different sensitivities for ER Ca(2+). They translocate to ER-PM junctions and open PM Orai Ca(2+) influx channels when receptor-mediated Ca(2+) release lowers ER Ca(2+) levels. The resulting increase in cytosolic Ca(2+) leads to the activation of numerous Ca(2+) effector proteins that in turn regulate differentiation, cell contraction, secretion and other cell functions. In this review, we use an evolutionary perspective to survey molecular activation mechanisms in the Ca(2+) signaling system, with a particular focus on regulatory motifs and functions of the two STIM proteins. We discuss the presence and absence of STIM genes in different species, the order of appearance of STIM versus Orai, and the evolutionary addition of new signaling domains to STIM proteins. PMID- 21288724 TI - The relevance of symmetric and asymmetric cell divisions to human central nervous system diseases. AB - During development of the embryonic central nervous system (CNS), large numbers of neurons and glia are generated from the neuroepithelium and its progenitor derivatives as a result of symmetric and asymmetric cell divisions. We describe the biology of symmetric and asymmetric cell divisions in the CNS as gleaned from animal models, and discuss the relevance of these processes to human CNS development and disease. PMID- 21288725 TI - The potential antioxidant activity of 2,3-dihydroselenophene, a prototype drug of 4-aryl-2,3-dihydroselenophenes. AB - Here we present our results in palladium cross-coupling reaction of aryl boronic acids with 4-iodo-2,3-dihydroselenophene derivatives. The cross-coupled products were obtained in satisfactory yields. A dehydrogenation of 4,5-diphenyl-2,3 dihydroselenophene was activated by DDQ and the 2,3-diarylselenophene was obtained in good yield. Regarding the antioxidant activity, the selenophene derivative 3a was effective in counteracting lipid and protein oxidation as well as scavenging ABTS radical. The findings of the present study indicate that 3a is a prototype for future drug development programs to treat disorders mediated by reactive oxygen species. PMID- 21288726 TI - Structure-activity relations on [1-(3,5-difluoro-4-hydroxyphenyl)-1H-pyrrol-3 yl]phenylmethanone. The effect of methoxy substitution on aldose reductase inhibitory activity and selectivity. AB - Based on our previous work, we studied the effect of methoxy-substitution as well as the regioposition of the benzoyl-moiety of 4a [(1-(3,5-difluoro-4 hydroxyphenyl)-1H-pyrrol-3-yl)(phenyl)methanone]. On this basis, compounds 4b-c and 5a-c were synthesized and assayed for aldose and aldehyde reductase inhibitory activity. Furthermore, a 4,6-difluoro-5-hydroxyphenyl pattern (9) was studied, in order to verify the optimum position of the phenol-moiety. Compound 5b emerged as the most potent and selective inhibitor. Moreover, further assays proved 5b as a potent antioxidant and an inhibitor of sorbitol accumulation in isolated rat lenses. Combining the above attributes, 5b could serve as a lead compound targeted at long-term diabetes complications. PMID- 21288727 TI - Chisopanins A-K, 11 new protolimonoids from Chisocheton paniculatus and their anti-inflammatory activities. AB - Eleven new protolimonoids, chisopanins A-K (1-11), were isolated from the twigs of Chisocheton paniculatus, as well as thirteen known (12-24) protolimonoids. The structures were elucidated on the basis of spectroscopic analysis, X-ray crystallographic analysis, and chemical methods. Chisopanins A and B (1 and 2) possessing uncommon hemiketal tetrahydropyran ring at C-17 showed the most potent inhibitory activities on lipopolysaccharide-stimulated inflammation factor release with IC(50) values at 5.4 and 7.9 MUM for NO, and at 26.9 and 30.7 MUM for TNF-alpha, respectively. In addition, compounds 5-7, 9, 12, 13, and 20 were potent to inhibit NO production with IC(50) value lower than 10 MUM. PMID- 21288728 TI - Trace elements in wild and orchard honeys. AB - The present study aims the identification and quantification of trace elements in two types of honey samples: Orchard honey and Wild honey from mainland Portugal. Chemical elements content was assessed by Instrumental Neutron Activation Analysis (INAA). Concentrations were determinated for Ag, As, Br, Ca, Cl, Cs, Cu, Fe, K, La, Mg, Mn, Na, Rb, Sb, Sc, U, V and Zn. The nutritional values of both honey types were evaluated since this product contains some elements that are essential dietary nutrients for humans. Physical properties of the honey samples, such as electrical conductivy and pH, were assessed as well. PMID- 21288729 TI - Standardisation of (210)Pb by Cerenkov counting. AB - A standard of (210)Pb in solution was produced at the National Physical Laboratory by a novel technique combining Cerenkov counting with the established liquid scintillation efficiency tracing technique known as the CIEMAT/NIST method. Coincidence counting was applied in order to validate the measurements and the activity concentrations of the solution determined with each technique are shown to be in agreement. Radiochemical separation of the (210)Pb from its daughters was also necessary and the scheme for the separation is described. After performing this two-stage standardisation, the uncertainty was successfully lowered to 0.66% (k=1). This uncertainty is approximately a factor of four lower than previously achieved at NPL by the classical method of standardisation of radionuclides, i.e. coincidence counting. PMID- 21288730 TI - Air pollution at an urban traffic tunnel in Lisbon, Portugal: an INAA study. AB - In this study, the results of chemical concentrations inside and outside of a Lisbon (Portugal) traffic tunnel were compared, during one week. They were obtained by Instrumental Neutron Activation Analysis (INAA). The tunnel values largely exceed the Air Ambient legislated values and the Pearson Correlations Coefficients point out to soil re-suspension/dispersed road dust (As, Ce, Eu, Hf, Fe, Mo, Sc, Zn), traffic-markers (Ba, Cr), tire wear (Cr, Zn), break wear (Fe, Zn, Ba, Cu, Sb), exhaust and motor oil (Zn) and sea-spray (Br, Na). On all days these elements inside the tunnel were more enriched than outside; significant statistical differences were found for Co (p=0.005), Br (p=0.008), Zn (p=0.01) and Sb (p=0.005), while enrichment factors of As and Sc are statistically identical. The highest values were found for As, Br, Zn and Sb, for both inside and outside the tunnel. PMID- 21288731 TI - Allocation of Fe and ferric chelate reductase activities in mesophyll cells of barley and sorghum under Fe-deficient conditions. AB - Although the photosynthetic apparatus requires large amounts of Fe, the adaptive mechanisms of mesophyll cells for Fe acquisition under Fe-deficient conditions are unknown. Barley and sorghum, which are tolerant and susceptible to Fe deficiency, respectively, have similar Fe and chlorophyll contents in their leaves. However, the Fe-deficient barley photosynthetic apparatus was functional while that of sorghum was not. We show that barley preferentially allocates Fe to thylakoid membranes under Fe-deficient conditions. On the other hand, in sorghum, the proportion of leaf Fe allocated to thylakoids was not altered by Fe deficiency. The relationship between the maintenance of photosynthesis and light dependent ferric chelate reductase activity on plasma membranes and chloroplast envelopes is also discussed. PMID- 21288732 TI - The role of the pyridoxine (vitamin B6) biosynthesis enzyme PDX1 in ultraviolet-B radiation responses in plants. AB - Ultraviolet-B radiation regulates plant growth and morphology at low and ambient fluence rates but can severely impact on plants at higher doses. Some plant UV-B responses are related to the formation of reactive oxygen species (ROS) and pyridoxine (vitamin B(6)) has been reported to be a quencher of ROS. UV-B irradiation of Arabidopsis Col-0 plants resulted in increased levels of PDX1 protein, compared with UV-A-exposed plants. This was shown by immunoblot analysis using specific polyclonal antibodies raised against the recombinant PDX1.3 protein and confirmed by mass spectrometry analysis of immunoprecipitated PDX1. The protein was located mainly in the cytosol but also to a small extent in the membrane fraction of plant leaves. Immunohistochemical analysis performed in pea revealed that PDX1 is present in UV-B-exposed leaf mesophyll and palisade parenchyma but not in epidermal cells. Pyridoxine production increased in Col-0 plants exposed to 3 days of UV-B, whereas in an Arabidopsis pdx1.3 mutant UV-B did not induce pyridoxine biosynthesis. In gene expression studies performed after UV-B exposure, the pdx1.3 mutant showed elevated transcript levels for the LHCB1*3 gene (encoding a chlorophyll a/b-binding protein of the photosystem II light-harvesting antenna complex) and the pathogenesis-related protein 5 (PR-5) gene, compared with wild type. PMID- 21288733 TI - A prospective randomized controlled study to assess the effectiveness of CoSeal(r) to seal air leaks in lung surgery. AB - OBJECTIVES: Prolonged alveolar air leak is the most common complication after pulmonary surgery. We conducted an investigator-led randomized trial to evaluate the effectiveness of CoSeal(r) surgical sealant (Cohesion Technologies Inc.; manufactured and distributed by Baxter Healthcare) for the closure of alveolar air leak after anatomical pulmonary resection. METHODS: Patients undergoing primary open lobectomy, bilobectomy, or sublobar resection with a demonstrable air leak on intra-operative testing were randomized to either standard care or standard care plus application of CoSeal(r) surgical sealant to areas of air leak. A second application of CoSeal(r) was used in the treatment group if air leak persisted. Patients were allocated at the point of entry to the trial by unbiased allocation with minimization to ensure balance between the two arms with respect to age, sex, surgeon, number of segments resected, preoperative forced expiratory volume in 1s (FEV1), and grade of air leak. Kaplan-Meier analysis of air-leak duration and a log rank test were performed on an intention-to-treat basis, with observations censored at death, transfer to the intensive care unit, or discharge. RESULTS: Of the 200 patients, who entered the trial over a 24-month period, 121 with demonstrable intra-operative air leak were randomly allocated to the two groups. Data were missing for one patient in the CoSeal(r) group. In 57%, the air leak was stopped at the first application; a quarter continued to leak after the second. At 24h, there was no difference in air leak and fewer patients in the control group were leaking at 48 h postoperatively. By log rank test, the difference was not significant (p=0.09). CONCLUSIONS: Patients treated with CoSeal(r) in this study had, as a group, a longer duration of air leak and hence we cannot recommend its routine use. PMID- 21288734 TI - Fluorescence resonance energy transfer from tryptophan to folic acid in micellar media and deionised water. AB - The fluorescence resonance energy transfer (FRET) from tryptophan (Trp) to folic acid (FA) in aqueous sodiumdodecyl sulphate, cetyltrimethyl ammonium bromide, and Brij-35 as well as deionised water was investigated using steady state and time resolved fluorescence techniques. The data obtained from steady state fluorescence spectral studies and time resolved measurement indicated that the FRET from Trp to FA occurred most effectively in aqueous sodium dodecyl sulphate micellar solutions. The distance between Trp and FA were evaluated. Binding constant, number of binding sites and thermodynamic parameters were determined for Trp-FA interactions in deionised water. The values of the thermodynamic parameters suggest that the hydrophobic forces and hydrogen bonding are the key interacting forces between Trp-FA interaction. PMID- 21288735 TI - Free radicals in breast carcinogenesis, breast cancer progression and cancer stem cells. Biological bases to develop oxidative-based therapies. AB - Oxidative stress leads to lipid, carbohydrate, protein and DNA damage in biological systems and affects cell structure and function. Breast cancer cells are subjected to a high level of oxidative stress, both intracellular and extracellular. To survive, cancer cells must acquire adaptive mechanisms that counteract the toxic effects of free radicals exposure. These mechanisms may involve the activation of redox-sensitive transcription factors, increased expression of antioxidant enzymes and antiapoptotic proteins. Moreover, recent data maintain that different breast cancer cell types, show different intracellular antioxidant capacities that may determine their ability to resist radio and chemotherapy. The resistant cell type has been shown to correspond with tumor initiating cells, also known as cancer stem cells (CSCs), which are thought to be responsible for tumor initiation and metastasis. Abrogation of the above mentioned adaptive mechanisms by redox regulation in cancer cells opens a promising research line that could have significant therapeutic applications. PMID- 21288736 TI - Cord blood chemokines differentiate between spontaneous and elective preterm births in singleton pregnancies. AB - BACKGROUND: Signals originating from both maternal and fetal compartments participate in the preterm labor process. OBJECTIVE: To investigate whether cord blood immunoproteins predict spontaneous preterm labor. METHODS: Cord blood from 125 very preterm (gestational age <32weeks) singleton infants and 33 term infants was collected after birth and analyzed for 107 immunoproteins on microarrays. Immunoproteins from spontaneous preterm births (SPTB) were compared to immunoproteins from preterm births without labor. The placentas were studied for histology and immunohistochemistry. The data was modeled by classification and regression trees (CART) analysis. RESULTS: In preterm births, low CCL16 level predicted SPTB with a sensitivity of 94.7%, and specificity of 46.9%. According to logistic regression analysis, low CCL16 (OR 57.9), histologic chorioamnitis (OR 33.6), and high CCL23 (OR 44.6) were independent risk factors of SPTB. Cord blood CCL16 was higher in preterm births without labor and in term births than in SPTBs. CCL16 and its signaling receptor CCR1 were visualized in syncytiotrophoblast and cytotrophoblast cells of placental villi. CONCLUSION: Low umbilical cord blood chemokine CCL16 associates with spontaneous preterm birth. Further studies are required to show whether CCL16 is involved in spontaneous preterm labor or in placental disease necessitating elective preterm delivery. PMID- 21288737 TI - External influences on the immune system via activation of the aryl hydrocarbon receptor. AB - The aryl hydrocarbon receptor (AhR), subject of intensive research over three decades by the pharmacology/toxicology field has recently made its entry into mainstream immunology research and is set to continue to intrigue with ever more complex modes of modulating immune responses. The discovery of high and selective AhR expression on Th17 cells and its role in induction of the cytokine IL-22 attributed new immunological functions to this transcription factor and stimulated further research into physiological functions of the AhR in the immune system. A number of recent reviews have highlighted potential new avenues of research. This review addresses recent new insight into physiological roles of AhR in the immune system. PMID- 21288738 TI - Genetic predisposition to autoimmunity--what have we learned? AB - Rapid advances in genetic technologies have led to the identification of more than 85 loci that contribute to susceptibility to autoimmune diseases. These susceptibility genes are distributed throughout the innate and adaptive immune systems, indicating that dysregulations in both immune systems participate in the development of autoimmunity. A significant subset of these susceptibility genes are shared between multiple autoimmune diseases. However, the dysregulation of specific pathways, such as the pathogen recognition receptors of the innate immune system and the TNF supergene family, are significantly involved in some autoimmune diseases. Although these findings dramatically increase the details available concerning the nature of genetic predisposition to autoimmunity, a mechanistic understanding of the processes involved has not been achieved. Future studies must focus on correlating phenotypes with specific genotypes to improve our understanding of the immune processes that are dysregulated during the development of autoimmunity. PMID- 21288739 TI - Bi-allelic gene targeting in mouse embryonic stem cells. AB - The EUCOMM and KOMP programs have generated targeted conditional alleles in mouse embryonic stem cells for nearly 10,000 genes. The availability of these stem cell resources will greatly accelerate the functional analysis of genes in mice and in cultured cells. We present a method for conditional ablation of genes in ES cells using vectors and targeted clones from the EUCOMM and KOMP conditional resources. Inducible homozygous cells described here provide a precisely controlled experimental system to study gene function in a model cell. PMID- 21288740 TI - Acute effects of whole-body vibration on trunk muscles in young healthy adults. AB - Little is known about the impact of whole body vibration (WBV) training on trunk muscles. Thus, this study investigated the acute effects of WBV on back and abdominal muscle activity. Twenty-five healthy subjects (24.7 +/- 3.0 years, 17 men) conducted eight common static exercises for the back and abdominal muscles in a random order on a vibration platform, with and without vibration. Surface EMG was measured from back and abdominal muscles. Vibration-induced motion artefacts were removed from the EMG signal. Muscle activity with and without vibration was normalized to maximal voluntary contraction (MVC) and compared. The addition of vibration resulted in significant increases in muscle activity particularly in the exercises for the abdominal muscles of up to 7.2 +/- 5.5% MVC (median +/- semi-interquartile range). In the back muscles, the largest difference by adding vibration was 1.6 +/- 1.4% MVC (median +/- semi interquartile range). The results of this study indicate a low to moderate increase in trunk muscle activation due to WBV. Presumably, this effect might depend on the distance from the corresponding muscle to the vibration platform and on how much the exercise position challenges body balance. However, the relevance of these findings has to be further investigated in training studies. PMID- 21288741 TI - The dreaming brain/mind, consciousness and psychosis. AB - Several independent lines of research in neurobiology seem to support the phenomenologically-grounded view of the dreaming brain/mind as a useful model for psychosis. Hallucinatory phenomena and thought disorders found in psychosis share several peculiarities with dreaming, where internally generated, vivid sensorimotor imagery along with often heightened and incongruous emotion are paired with a decrease in ego functions which ultimately leads to a severe impairment in reality testing. Contemporary conceptualizations of severe mental disorders view psychosis as one psychopathological dimension that may be found across several diagnostic categories. Some experimental data have shown cognitive bizarreness to be equally elevated in dreams and in the waking cognition of acutely psychotic subjects and in patients treated with pro-dopaminergic drugs, independent of the underlying disorder. Further studies into the neurofunctional underpinnings of both conditions will help to clarify the use and validity of this model. PMID- 21288742 TI - Giant cell aortitis: a difficult diagnosis assessing risk for the development of aneurysms and dissections. AB - A significant location affected by giant cell (GC) arteritis is the ascending aorta, where aneurysms may develop and catastrophic ruptures and acute dissections can occur. Herein, we discuss three cases of GC aortitis discovered at pathological examination of surgically excised aortic aneurysmal tissue. There was no clinical suspicion of any underlying inflammatory process. We describe the main clinical features of the patients in conjunction with a review of the literature to identify any common clinical presentations that manifest in these patients. Giant cell aortitis in the absence of previously established GC arteritis is difficult to identify, and a careful analysis of the history and presentation along with appropriate investigations (e.g., erythrocyte sedimentation rate) may prompt the clinician to consider GC aortitis and suggest immunosuppressant therapy. PMID- 21288743 TI - Effects of tilt and glenosphere eccentricity on baseplate/bone interface forces in a computational model, validated by a mechanical model, of reverse shoulder arthroplasty. AB - HYPOTHESIS/BACKGROUND: Reverse shoulder arthroplasty is being used with greater frequency for patients with severe rotator cuff deficiency. There are several commercially available reverse shoulder devices, each with different glenosphere options. The purpose of this study was to determine: (1) forces at the baseplate bone interface in glenospheres with centers of rotation located concentrically and eccentrically to the center of the baseplate; and (2) if baseplate-bone forces can be optimized by altering tilt of the baseplate. METHODS: A validated computer model was used to compare concentric glenospheres with neutral offset to eccentrically offset glenospheres (6 mm inferior or 6 mm lateral) in 3 baseplate tilts: 15 degrees inferior, neutral, or 15 degrees superior. A baseplate, simulated bone, screws, and humeral component were modeled, and forces underneath the baseplate were calculated as the arm was abducted through 90 degrees of glenohumeral motion. RESULTS: For lateral and concentric glenospheres, inferior tilt provides the most even distribution of forces (mean difference in force between superior and inferior portions of baseplate: 11.3 N and 24.7 N, respectively) and superior tilt provides the most uneven distribution of forces (109.3 N and 78.7 N, respectively). For inferior eccentric glenospheres, inferior tilt provides the most uneven distribution of forces (58.7 N) and neutral tilt provides the most even distribution of forces (27.7 N). CONCLUSION: This is the first study to investigate force distribution under the baseplate in inferior eccentric glenospheres. Although inferior tilting of the baseplate is recommended for concentric and laterally offset glenospheres, this same recommendation may be detrimental to inferiorly offset glenospheres and warrants further investigation. PMID- 21288744 TI - Complete rupture of the supraspinatus tendon. Operative treatment with report of two successful cases. 1911. PMID- 21288745 TI - A systematic review of percutaneous mechanical thrombectomy in the treatment of deep venous thrombosis. AB - BACKGROUND: In selected cases of deep vein thrombosis (DVT), catheter-directed thrombolysis (CDT) may be superior to conventional treatment with anticoagulation alone, as it can prevent DVT recurrence and the development of post-thrombotic syndrome (PTS). Percutaneous mechanical thrombectomy (PMT) devices offer a minimally invasive adjunctive strategy and the data on these emerging technologies require review. OBJECTIVES: To review the evidence for PMT devices in DVT in terms of case selection, technical feasibility and procedural outcomes. METHODS: Medline, trial registries, conference proceedings and article reference lists were searched to identify case series reporting PMT device use. Data were extracted for review. RESULTS: 16 retrospective case series have reported the use of rheolytic, rotational, or ultrasound-assisted PMT in a total of 481 patients. No randomised trials were available. Technical success of 82-100% was reported with Grade II or III lysis in 83-100% of patients. The different devices all appeared to be safe, with no reported procedure-related deaths or strokes and <1% incidence of symptomatic PE. Bleeding complications were reported in 6/16 studies, in which 4-14% of patients required transfusion (global incidence 11/146 patients, 7.5%). CONCLUSION: PMT appears feasible and safe, though the level of evidence available is poor. Major RCTs and registry data are required to determine the economic and clinical benefit of various devices used alone or in combination, for differing thrombus characteristics and clinical scenarios. Until these data are available there is little substantial evidence to support the routine use of PMT over CDT alone. PMID- 21288746 TI - Condylar cartilaginous changes after mandibular distraction osteogenesis in rabbits. AB - OBJECTIVE: The purpose of this study was to evaluate histologic and immunohistochemical changes in the condylar articular surface in response to distraction osteogenesis (DO) of the mandibular body in rabbits. STUDY DESIGN: A unilateral osteotomy of the mandible at the premolar area was performed in 16 rabbits. The animals were divided into 4 groups based on different distraction parameters (rate and rhythm). After a 5-day latency, the mandible was lengthened by 0.5 mm daily for 6 days (group 1); 0.5 mm twice daily for 3 days (group 2); 0.5 mm once daily for 10 days (group 3); or 0.5 mm twice daily for 5 days (group 4). All 4 groups underwent a 14-day consolidation period. Four rabbits were included in the control group. The specimens were stained with hematoxylin-eosin for histologic examination. Immunohistochemical analysis was performed to evaluate the expression of growth factors. RESULTS: None of the groups demonstrated any degenerative changes in the temporomandibular joint (TMJ). On the distraction side in all groups, the histopathological examination revealed a hypertrophic thickening of the cartilage zone. Prominent endochondral ossification and high active osteoblasts were observed in groups 3 and 4. On the nondistraction side, no major changes were observed excluding the appearance of osteoclasts in groups 3 and 4. The immunohistochemical analysis revealed tenascin immunoreactivity in bone marrow mesenchymal cells on the distraction side in group 4. Connexin immunoreactivity did not display a marked change in any of the groups. Osteocalcin was observed on the distraction side in group 2, which suggested that bone formation is increased. Nitric oxide synthase 2 immunoreactivity was observed on the distraction side in group 2, which is associated with stress and inflammation. CONCLUSIONS: The results indicated that the hypertrophy of the cartilage zone and endochondral ossification became more pronounced as the extent and rate of distraction increased. PMID- 21288747 TI - Implications of global and regional patterns of highly pathogenic avian influenza virus H5N1 clades for risk management. AB - This paper analyses the publicly available data on the distribution and evolution of highly pathogenic avian influenza virus (HPAIV) H5N1 clades, whilst acknowledging the biases resulting from the non-random selection of isolates for gene sequencing. The data indicate molecular heterogeneity in the global distribution of HPAIV H5N1, in particular in different parts of East and Southeast Asia. Analysis of the temporal pattern of haemagglutinin clade data shows a progression from clade 0 (the 'dominant' clade between 1996 and 2002) to clade 1 (2003-2005) and then to clade 2.3.4 (2005 onwards). This process continuously produces variants, depending on the frequency of virus multiplication in the host population, which is influenced by geographical variation in poultry density, poultry production systems and also HPAI risk management measures such as vaccination. Increased multilateral collaboration needs to focus on developing enhanced disease surveillance and control targeted at evolutionary 'hotspots'. PMID- 21288748 TI - Is there an increased risk for drug treated attention deficit/hyperactivity disorder in children born after in vitro fertilization? AB - BACKGROUND: There is mounting evidence that children born after in vitro fertilization (IVF) run an increased risk of neurological complications and notably cerebral palsy. Whether developmental disturbances occur more often than expected is debated. AIM: To investigate the risk for ADHD in children conceived after IVF. METHODS: Children conceived after IVF and born between 1982 and 2005 were identified from all IVF clinics in Sweden. Children who developed attention deficit/hyperactivity disorder (ADHD) were identified with the use of a register over all prescribed drugs in Sweden, using prescriptions for methylphenidate or atomixetine as indicators of ADHD. Maternal and neonatal characteristics were obtained by linkage with the Medical Birth Register and relevant confounders were adjusted for using Mantel-Haenszel procedures. We studied 28 158 children born after IVF and compared them with 2 417 886 children in the population. RESULTS: After adjustment for year of birth, maternal age, parity, smoking, BMI, and maternal education and after exclusion of women who did not cohabit, a weak but statistically significant association was found with an odds ratio=1.18, 95% confidence interval 1.03-1.36. The effect was stronger in girls (OR=1.40) than boys (OR=1.11) but this difference could be random. After adjustment for length of involuntary childlessness, the OR decreased slightly and lost statistical significance. CONCLUSIONS: The study suggests a weak association between IVF and drug treated ADHD. PMID- 21288749 TI - Tritrichomonas foetus infection in purebred cats in Germany: prevalence of clinical signs and the role of co-infection with other enteroparasites. AB - The aim of this study was to determine the prevalence of Tritrichomonas foetus infection and associated clinical signs in purebred cats in Germany, to investigate the role of co-infection, and identify determinants of infection. Faecal specimens accompanied by epidemiological questionnaires were scored and collected from 230 purebred cats. Faeces were examined for trichomonads and other enteroparasites. The prevalence of T foetus was 15.7% among cats and 18.5% among catteries. An abnormal faecal score and history of diarrhoea were observed in 64% and 61% of T foetus-positive cats, respectively, and correlated significantly with infection. Co-infection, observed in 36% of T foetus-infected cats, was not associated with diarrhoea. Norwegian Forest cats were infected significantly more often than other breeds. No association was found with any environmental factors. This study demonstrated a high prevalence of symptomatic T foetus infections in purebred cats in Germany. Co-infection with other enteroparasites did not worsen clinical signs of trichomonosis. PMID- 21288750 TI - [Satisfied companion, a quality indicator in emergencies]. AB - OBJECTIVES: To determine the level of satisfaction of the accompanying person in the Emergency Department and to identify main factors that could influence satisfaction and to establish areas of improvement. METHODOLOGY: A retrospective descriptive study of family or companion of patients seen in the Emergency Department. A randomised telephone questionnaire was used. The statistics used were chi-squared for categorical variables and variance analysis for those showing a normal distribution. The analysis was made with the SPSS 16.0 programme. RESULTS: A total of 117 responses were received, from a minimum sample size of 90. The demographic characteristics of the accompanying person did not influence the evaluation of the satisfaction, unlike of other studies. The fact of accompanying the patient and receiving periodic information showed differences in overall satisfaction of the accompanying person, as well as the waiting time. A long waiting time and the lack of company were the most frequent reasons for dissatisfaction. The accompanying person emphasised the feeling of isolation of the patient, the lack of health personnel, the long wait for assistance and the location of facilities. CONCLUSIONS: Rapid assistance, facilities for the accompanying person, information, empathy and friendliness are the factors which are the most appreciated when they come to Emergency Department. PMID- 21288751 TI - Atypical nodular panniculitis. AB - Suppurative panniculitis usually occurs among immunocompromised patients and can be caused by opportunistic pathogens or by secondary infectious lesions in the context of septicemia. Herein we report the case of an 82-year-old woman with multiple red nodules on the leg caused by Pseudomonas aeruginosa, not related to a blood disseminated infection. The present case represents an unusual presentation of indolent suppurative panniculitis caused by P. aeruginosa. PMID- 21288752 TI - [Incarcerated internal hernia through a breach of the broad ligament, a case report]. AB - We report a case of 44-year-old women presented with an acute small bowel obstruction revealated by tomodensitometry. Laparotomy showed an incarcerated internal hernia through the broad ligament. We performed liberation of the ileal segment and closed the hernial orifice. The patient evolution was excellent. PMID- 21288753 TI - [Typical form of Mayer-Rokitansky-Kuster-Hauser syndrome and ectopic kidney. A rare association]. AB - The Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome is a spectrum of Mullerian anomalies characterized by congenital vaginal aplasia and absent uterus or a rudimentary one in female subjects with normal endocrine status. The ovaries and fallopian tubes are present. The prime feature is a primary amenorrhea in women presenting normally developed secondary sexual characteristics and normal external genitalia. The etiology remains unknown. This syndrome is subdivided in two types. It may be isolated (type I) or associated with other malformations (type II). Type I is less frequent than type II. We report a case of MRKH syndrome in a 21-year-old woman who presented a primary amenorrhea studied with transabdominal and pelvic ultrasonography and pelvic magnetic resonance, which demonstrated a complete agenesis of uterus, a functional cyst in the right ovary, and a left pelvic ectopic kidney. We studied the MRKH syndrome with review of the literature. PMID- 21288754 TI - [Atypical presentation of a premature ovarian failure with deletion of X chromosome]. AB - In order to illustrate a particular clinical presentation of premature ovarian failure, we report the case of a 16-year-old girl, who presented with primary amenorrhea. Physical examination discovered central obesity and an extent acanthosis nigricans in the neck and in the axillae. Pubertal stage was quoted S3P3 and external genitalia were normal. Oral glucose test revealed glucose intolerance and hormonal investigation discovered hyperinsulinemia and elevated level of FSH. Pelvic echography found infantile internal genitalia and genetic analysis discovered a deletion in the long arm of one of X chromosomes. PMID- 21288755 TI - [Pregnancy with Implanon: a report on three cases]. AB - We explored the potential causes associated with pregnancies occurring in patients using an etonogestrel contraceptive implant (Implanon). Three cases of treatment failure were reported where no predisposing factors were found (i.e. Body Mass Index, hepatic inducing therapy). Etonogestrel plasmatic detection was positive in two cases whereas in the third case with negative endocrinological makers, neither palpation nor ultrasonography identified the device. Therefore, true contraceptive failure can be considered in two of the reported cases. Furthermore, pregnancies associated with Implanon use warrant additional attention including notification to drug monitoring centers and Organon SA. PMID- 21288756 TI - [Solitary fibrous tumor of the vulva: a case report]. AB - Solitary fibrous tumors of the genital tract female are extremely rare. We reported a case of solitary fibrous tumor originating in the vulva of a 37-year old woman. The histological analysis revealed a conjunctiva tumourous proliferation, with variable cellularity, the morphology feature and the immunohistochemistry profile of which entailed us to infer on a solitary fibrous tumor. No recurrence was observed 16 months after surgery with flap reconstruction. Because of their possible pejorative evolution, it is very important to know these tumors. A long term follow-up must be advised. PMID- 21288757 TI - Thermal anemometric assessment of coronary flow reserve with a pressure-sensing guide wire: an in vitro evaluation. AB - Assessment of coronary flow reserve (CFR) with a commercially available pressure sensor-tipped guide wire using the principle of thermal anemometry could provide major clinical benefits both in determining and in distinguishing between epicardial and microvascular coronary artery disease. In constant-temperature thermal anemometry, the electrical power required to maintain an element at a constant temperature is a measure for the local shear rate. Here, the feasibility of applying this thermoconvection method to a pressure-sensing guide wire is investigated using an in vitro model. A theoretical relation between electrical power and steady shear rate based on boundary layer theory was tested in an experimental set-up. In steady flow, a reproducible relation between electrical power and shear rate was obtained with an overheat temperature of 20K, which was in good agreement with theory. The relation between shear rate and flow, however, depends on geometry of the artery and position of the guide wire inside the vessel. Although this means that this thermoconvection method is less useful for absolute flow measurements, CFR could be assessed even for unsteady flow using the steady calibration curve with a mean relative difference of (3+/-5)% compared to CFR derived from the golden standard using an ultrasonic flow measurement device. PMID- 21288758 TI - Design, construction and validation of a computer controlled system for functional loading of soft tissue. AB - Osteoarthritis is a chronic degenerative disease affecting body joints. Abnormal mechanical loading could be an initiating factor of cartilage damage, by influencing chondrocytes activity. To date, devices performing mechanical studies of viable tissues are mostly uniaxial. In this work, we developed and validated a multi-axial device for static and dynamic mechanical testing of viable soft tissues. The system, named RPETS, is composed of a motor driven indenter, moving vertically and horizontally along the bottom of a tank containing tissue samples and it can apply combined compression, sliding, and rolling on viable samples. Validation studies were performed with standard rubber and bovine nasal cartilage tissue. Static tests demonstrated that the system is comparable to existing uniaxial devices, with a maximum force control error smaller than 0.5N and a positioning resolution of 5 MUm. Dynamic tests performed with different motion profiles showed that the system can exert a load of 100N with a maximum velocity of 100mm/s maintaining the force control error within 10% of the desired value. Sinusoidal motion frequency can vary between 0.05 and 0.5Hz. In practical tests, viability staining of dynamically loaded cartilage slices showed extents of cell death to depend on the indenter velocity. PMID- 21288759 TI - A portable gait assessment tool to record temporal gait parameters in SCI. AB - BACKGROUND: The ability to objectively analyze gait in a clinical environment is challenging due to time, space and cost constraints. This study investigated the validity of a portable gait assessment tool in objectively assessing the temporal gait parameters in subjects with spinal cord injury. The portable gait assessment tool consisted of a pair of insoles instrumented with force sensing resistors that were strategically positioned over the sole of each foot. AIM: To demonstrate the validity of the gait assessment tool by assessing the change in walking ability in incomplete spinal cord injured (ISCI) subjects, who participated in a robot-assisted gait training program. METHODS: Eighteen subjects with either an acute or chronic ISCI participated in this study (age range 26-63 years). Each subject participated in a robot assisted gait training programme for 6 weeks. Assessments were performed using the gait assessment tool before during and after the intervention. RESULTS: The gait assessment tool showed greater sensitivity to the change in the subject's gait, when compared to clinical assessments such as the walking index in spinal cord injury (WISCI II). Subjects with an acute ISCI showed a statistically significant (p<0.05) change in temporal gait parameters within the first 3 weeks of training. DISCUSSION AND CONCLUSION: This study for the first time has used the gait assessment tool in an ISCI population and has demonstrated that gait parameters can be measured and changes can be quantified within a clinical environment. The statistically significant changes during the first 3 weeks of training may indicate that an effective dose of robotic training can be administered within a relatively short period in ISCI subjects during the acute phase. PMID- 21288760 TI - Specifying the self for cognitive neuroscience. AB - Cognitive neuroscience investigations of self-experience have mainly focused on the mental attribution of features to the self (self-related processing). In this paper, we highlight another fundamental, yet neglected, aspect of self experience, that of being an agent. We propose that this aspect of self experience depends on self-specifying processes, ones that implicitly specify the self by implementing a functional self/non-self distinction in perception, action, cognition and emotion. We describe two paradigmatic cases - sensorimotor integration and homeostatic regulation - and use the principles from these cases to show how cognitive control, including emotion regulation, is also self specifying. We argue that externally directed, attention-demanding tasks, rather than suppressing self-experience, give rise to the self-experience of being a cognitive-affective agent. We conclude with directions for experimental work based on our framework. PMID- 21288762 TI - Creeping baselines and adaptive resistance to antibiotics. AB - The introduction of antimicrobial drugs in medicine gave hope for a future in which all infectious diseases could be controlled. Decades later it appears certain this will not be the case, because antibiotic resistance is growing relentlessly. Bacteria possess an extraordinary ability to adapt to environmental challenges like antimicrobials by both genetic and phenotypic means, which contributes to their evolutionary success. It is becoming increasingly appreciated that adaptation is a major mechanism behind the acquisition and evolution of antibiotic resistance. Adaptive resistance is a specific class of non-mutational resistance that is characterized by its transient nature. It occurs in response to certain environmental conditions or due to epigenetic phenomena like persistence. We propose that this type of resistance could be the key to understanding the failure of some antibiotic therapy programs, although adaptive resistance mechanisms are still somewhat unexplored. Similarly, hard wiring of some of the changes involved in adaptive resistance might explain the phenomenon of "baseline creep" whereby the average minimal inhibitory concentration (MIC) of a given medically important bacterial species increases steadily but inexorably over time, making the likelihood of breakthrough resistance greater. This review summarizes the available information on adaptive resistance. PMID- 21288761 TI - Iron chaperones for mitochondrial Fe-S cluster biosynthesis and ferritin iron storage. AB - Protein controlled iron homeostasis is essential for maintaining appropriate levels and availability of metal within cells. Recently, two iron chaperones have been discovered that direct metal within two unique pathways: (1) mitochondrial iron-sulfur (Fe-S) cluster assembly and (2) within the ferritin iron storage system. Although structural and functional details describing how these iron chaperones operate are emerging, both share similar iron binding affinities and metal-ligand site structures that enable them to bind and release Fe2+ to specific protein partners. Molecular details related to iron binding and delivery by these chaperones will be explored within this review. PMID- 21288763 TI - Pervasive regulation of nucleoid structure and function by nucleoid-associated proteins. AB - Bacterial DNA is organised in a compact nucleoid body that is tightly associated with the coupled transcription and translation of mRNAs. This structure contains abundant DNA-binding proteins which perform both structural and regulatory roles, and, in Escherichia coli, serve to buffer and organise pervasive DNA superhelicity. We argue that NAPs coordinate regulation of gene expression and superhelicity at the global (or chromosomal) and at local (corresponding to promoter activity and genetic recombination) levels. PMID- 21288764 TI - Fe-S clusters, fragile sentinels of the cell. AB - Iron-sulfur (Fe-S) clusters are ubiquitous cofactors present in a myriad of proteins controlling processes as diverse as DNA replication, photosynthesis, respiration and gene regulation. Their assembly and delivery into apo-proteins are catalysed by different multi-protein systems conserved throughout prokaryotes and eukaryotes. Because so many cellular processes are dependent upon Fe-S proteins, alteration of the Fe-S clusters or of the systems that make them has profound impact on cellular physiology. The present review aims at covering and discussing those situations wherein these highly efficient redox sensitive cofactors turn from faithful sentinels into enfeebled assistants or, worse, into dangerous insiders. PMID- 21288765 TI - Structure and spectral properties of dinuclear zinc complex containing semicarbazonate ligands. AB - The dinuclear Zn(2+) complex [Zn(HSSC)OAc](2).2DMF (H(2)SSC=salicylaldehyde semicarbazone; HOAc=acetic acid; DMF=N,N-dimethylfomamide) was prepared and structurally characterized by single crystal X-ray. The basic structural unit of the complex is a dinuclear complex [Zn(HSSC)OAc](2) in which the semicarbazone ligand adopts the phenol-imine form. The deprotonated phenol group forms a one atom bridge between the two zinc centers, and both of the zinc centers are five coordinated. The local coordination environment of Zn(2+) can be approximately considered as square pyramidal. UV spectral studies show that the H(2)SSC provides strong binding of Zn(2+) in a 1:1 ratio in solution. The conditional binding constant of the complex is lgK(Zn-L)=12.89+/-0.76 in 0.05M Tris-HCl buffer at pH 7.4. The H(2)SSC exhibits an enhanced fluorescence effect by the addition of Zn(2+), and affords an excellent selectivity for Zn(2+) under physiological conditions. PMID- 21288766 TI - Electromagnetic interference of magnetic field based auto identification technologies in healthcare settings. AB - PURPOSE: Increasingly, autoidentification technology is being utilized in healthcare settings to make delivery of care cheaper, more efficient, and safer. However, the risk of electromagnetic interference (EMI) when using these autoidentification systems is not entirely clear. Thus, we sough to evaluate the likelihood of electromagnetic interference (EMI) in high technology healthcare areas with a low frequency, magnetic-field based wireless autoidentification protocol. METHODS: Thirty-two devices were tested for EMI with an autoidentification technology whose maximal magnetic field output ranged from 8 to 800mgauss between November 2008 and March 2009. Testing was performed at Mayo Clinic (Rochester, MN) and Holy Cross Hospital (Miami, FL). All tests were started from 4 feet away and devices were approached in 1 foot increments with the signal antenna. EMI was characterized as light, significant, hazardous, or none per established testing standards. Significant to hazardous EMI was considered to potentially cause significant problems with clinical management of patients. RESULTS: Of 32 devices, light to hazardous EMI was seen in 8 (25%). Hazardous EMI was seen in 2 12-lead ECG machines, significant EMI in fluoroscopy, echocardiograms, and 1 of 5 cardiac monitors, and light EMI in a defibrillator and cardiac monitor. Average magnetic field strengths experienced by the devices were similar at each distance regardless of the presence of EMI. No EMI was recorded with any device at distances greater than 4 feet, with no loss of signal fidelity at distances up to 17 feet. CONCLUSION: A low frequency, magnetic field based wireless autoidentification technology induced distance dependent EMI in healthcare settings, making implementation potentially safe at antenna distances greater than 4 feet from clinical equipment. However, implementation requires rigorous in vivo testing to ensure the antenna is located a safe distance away. PMID- 21288768 TI - Gingival and dermal fibroblasts: their similarities and differences revealed from gene expression. AB - Gene expression profiles in normal human gingival and dermal fibroblasts were investigated using DNA microarrays. Their fundamental characteristics were almost identical, but 5% of their genes were uniquely expressed. These results help us to choose an optimal cell source for effective fibroblast-based cell therapy that is dependent on differential gene expression profiles. PMID- 21288769 TI - Morpheus and kidney transplantation. PMID- 21288771 TI - The magic trick of hepatocytes: uncoupling genomic instability from cancer. PMID- 21288770 TI - Alternative memory in the CD8 T cell lineage. AB - A prominent population of innate CD8+ T cells develops in the thymus of several gene-deficient mouse strains, including Itk, KLF2, CBP and Id3. These cells have the phenotype and function of memory CD8+ T cells, without previous exposure to antigen. Surprisingly, the cytokine IL-4 plays a key role in their development. As this developmental mechanism was discovered, it came to light that innate CD8+ T cells exist also in normal mice and in humans. In this review, we discuss how these cells develop, compare and contrast them to other CD8 memory cells, and discuss their potential physiological relevance. PMID- 21288772 TI - Facioscapulohumeral muscular dystrophy and DUX4: breaking the silence. AB - Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) has an unusual pathogenic mechanism. FSHD is caused by deletion of a subset of D4Z4 macrosatellite repeat units in the subtelomere of chromosome 4q. Recent studies provide compelling evidence that a retrotransposed gene in the D4Z4 repeat, DUX4, is expressed in the human germline and then epigenetically silenced in somatic tissues. In FSHD, the combination of inefficient chromatin silencing of the D4Z4 repeat and polymorphisms on the FSHD-permissive alleles that stabilize the DUX4 mRNAs emanating from the repeat result in inappropriate DUX4 protein expression in muscle cells. FSHD is thereby the first example of a human disease caused by the inefficient repression of a retrogene in a macrosatellite repeat array. PMID- 21288773 TI - Extracellular Trypanosoma cruzi calreticulin in the host-parasite interplay. AB - Calreticulin (CRT) from vertebrates is a calcium-binding protein present mainly in the endoplasmic reticulum (ER). There, it directs the conformation of proteins and controls calcium levels. This review will focus on several extracellular roles of Trypanosoma cruzi CRT (TcCRT) in relation to its capacity to inhibit the complement system, mediate parasite infectivity, interfere with angiogenesis and, as a possible consequence, with tumor growth. The TcCRT antiangiogenic effect parallels with the capacity of T. cruzi infection to inhibit tumor development in vivo. Thus, the TcCRT, complement, and endothelial cell interactions seem to be an evolutionary adaptation to promote prolonged parasite-host relationships. PMID- 21288775 TI - ART for children: what to start and when to switch. PMID- 21288776 TI - Development of an evaluation scale for self-management behavior related to physical activity of patients with coronary heart disease. AB - BACKGROUND: To provide patients with effective self-management education that takes their lifestyle into account, medical personnel need to provide education and evaluation of self-management behaviors which patients can apply to their daily life. AIM: This study aimed to assess the reliability and validity of the evaluation scale for self-management behavior related to physical activity of patients with coronary heart disease (ES-SMBPA-CHD). METHODS AND RESULTS: Outpatients with coronary heart disease (n = 76) completed a self-administered questionnaire supported by a previous study of ours. The ES-SMBPA-CHD was divided into two domains, the first dealing with self-management behavior to enhance physical activity in daily life and the second with behavior to maintain the level of physical activity. Factor analysis showed that the first part comprised four factors and the second five. The ES-SMBPA-CHD was associated with the International Physical Activity Questionnaire (IPAQ) subscales and activity energy expenditure (measured by Lifecorder EX). Cronbach's alpha coefficient was between 0.71 and 0.90. The intraclass test-retest correlation coefficient of the subscale was between 0.75 and 0.93. CONCLUSIONS: The ES-SMBPA-CHD is reasonably reliable and valid and is expected to prove useful for the assessment of patients' self-management behavior and for individualized instruction. PMID- 21288777 TI - Paucity of genotype-phenotype correlations in STAT3 mutation positive Hyper IgE Syndrome (HIES). AB - Autosomal dominant HIES (AD-HIES) is a primary immunodeficiency caused by dominant negative mutations in STAT3 clustered in the DNA binding and SH2 domains. Although in vitro differences in mutational constructs are observed, clinical phenotypic correlates of these genetic changes have not been described. We reviewed the charts of 65 AD-HIES patients (DNA binding n=35; SH2 n=30), recorded the components of the NIH HIES clinical scoring system as well as brain and coronary artery abnormalities and analyzed data by mutation region in adults and children. Patients with SH2 domain mutations had increased frequency of high palate, broad inter-alar distance, upper respiratory tract infections and, in the pediatric sub-group, significant scoliosis. There was suggestion of increased mortality for patients with DNA binding mutations. Although subtle differences in phenotype were observed to depend on the STAT3 genotype, overall the clinical phenotypes were similar between individuals with DNA binding and SH2 domain mutations. PMID- 21288778 TI - Quality of life following epilepsy surgery for children with tuberous sclerosis complex. AB - Parents of children with tuberous sclerosis complex who underwent multistage resections for treatment of refractory seizures were offered a telephone questionnaire regarding quality of life (QOL) of child and family since surgery. Of 53 families, 39 responded. Age at epilepsy onset was birth to 3 months. Average duration of epilepsy before the first surgery was 5.1 years, and average age at surgery was 5.8. The average follow-up was 3.9. Seventy-seven percent had a >90% reduction in disabling seizures. In all outcome categories, 46-85% had at least a moderate improvement in QOL. There was a significant correlation between QOL variables and Engel outcome class. Despite the potential burden posed by the aggressive surgical approach, including multiple surgeries and long hospitalization periods, 94% of parents would choose the same course once again. We conclude that aggressive surgical treatment of tuberous sclerosis complex related refractory seizures is associated with significant control of epilepsy as well as improved QOL for the patient and family. PMID- 21288779 TI - AES 2009 Annual Course: Reoperation for medically refractory epilepsy. AB - A significant percentage of patients undergoing resective surgery for medically refractory epilepsy have persistent or recurrent disabling seizures. In these patients, the objective of seizure freedom justifies the consideration of repeat resective surgery. In this report, the available published experience with repeat resective surgery is analyzed. The reoperated patients are subdivided into three categories: patients with residual medial temporal structures, patients with an unresected or partially resected structural/mass (non-glioma) lesion and patients with non-lesional neocortical epilepsy. This analysis indicates that the chance of achieving seizure freedom is significant, although lower than with the initial surgery. The chance of significant morbidity (particularly significant neurologic deficit) is low, although higher than with the initial surgery. A proper evaluation can identify appropriate candidates for a resective reoperation. Palliative surgical options should be strongly considered for all patients, especially for those with lower chance of seizure freedom and/or elevated risk of morbidity. PMID- 21288780 TI - Gestural automatisms during syncope related to cervical malignancy. AB - Cervical malignancies are a rare but well-known cause of syncope. Gestural automatisms during syncope have only rarely been reported. We describe a patient presenting with bimanual automatisms during syncopal episodes caused by parapharyngeal carcinoma involving the right laterocervical region. Ictal phenomenology was strongly suggestive of focal seizures and only video polygraphic recording including EEG and ECG allowed the correct diagnosis to be established. Syncopal episodes ceased after partial removal of the mass. Although gestural automatisms in the context of a sudden spell with loss of consciousness are strongly suggestive of focal (mainly frontal or temporal) seizures, the diagnosis of syncope must be taken in account and confirmed or excluded by appropriate neurophysiological investigations. PMID- 21288781 TI - The first Sino-German Symposium on DNA Repair and Human Diseases. AB - The first Sino-German Symposium on DNA Repair and Human Diseases was held in the Capital Normal University, Beijing, China, from October 9th to 11th, 2010. It was initiated and organized by Xingzhi Xu and Zhao-Qi Wang with strong support from top scientists in the field from China, Germany and the United States. Financially, it was fully supported by the Sino-German Center for Science Promotion jointly founded by the National Natural Science Foundation of China (NSFC) and the Deutsche Forschungsgemeinschaft (DFG). This report summarizes 35 plenary lectures presented during this three-day symposium, with topics ranging from DNA damage checkpoint signaling, DNA repair, posttranslational protein modifications in DNA damage response (DDR) to DDR in ageing and cancer. This symposium stimulated extensive discussions on science and potential collaboration among the 230 participants. PMID- 21288782 TI - Burkholderia latens infection in cystic fibrosis. PMID- 21288783 TI - Modeling the effects of physician emigration on human development. AB - We analyzed the effects of physician emigration on human development indicators in developing countries. First, the geographical distribution of physician brain drain was documented for the period 1991-2004. Second, random and fixed effects models were employed to investigate the effects of physicians in the home countries and abroad on child mortality and vaccination rates. Third, models were estimated to investigate migration-induced incentives in the medical sector that would increase the number of physicians. The results showed positive effects of migration prospects on medical training though the magnitude was too small for generating a net brain gain. Also, infant and child mortality rates were negatively associated with the number of physicians per capita after adult literacy rates exceeded 60%. The results for DPT and measles vaccinations underscored the importance of literacy rates and physicians per capita for higher vaccination rates. From the standpoint of Millennium Development Goals, reducing medical brain drain is likely to have only small benefits for child mortality and vaccination rates. PMID- 21288784 TI - Change blindness, representations, and embodied cognition: comment on "Embodied cognition and the perception-action link" by Bridgeman and Tseng. PMID- 21288785 TI - Irregular folding of nucleosomes in the cell: comment on "Cracking the chromatin code: precise rule of nucleosome positioning" by Edward N. Trifonov. PMID- 21288774 TI - First-line antiretroviral therapy with a protease inhibitor versus non-nucleoside reverse transcriptase inhibitor and switch at higher versus low viral load in HIV infected children: an open-label, randomised phase 2/3 trial. AB - BACKGROUND: Children with HIV will be on antiretroviral therapy (ART) longer than adults, and therefore the durability of first-line ART and timing of switch to second-line are key questions. We assess the long-term outcome of protease inhibitor and non-nucleoside reverse transcriptase inhibitor (NNRTI) first-line ART and viral load switch criteria in children. METHODS: In a randomised open label factorial trial, we compared effectiveness of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a protease inhibitor versus two NRTIs plus an NNRTI and of switch to second-line ART at a viral load of 1000 copies per mL versus 30,000 copies per mL in previously untreated children infected with HIV from Europe and North and South America. Random assignment was by computer generated sequentially numbered lists stratified by age, region, and by exposure to perinatal ART. Primary outcome was change in viral load between baseline and 4 years. Analysis was by intention to treat, which we defined as all patients that started treatment. This study is registered with ISRCTN, number ISRCTN73318385. FINDINGS: Between Sept 25, 2002, and Sept 7, 2005, 266 children (median age 6.5 years; IQR 2.8-12.9) were randomly assigned treatment regimens: 66 to receive protease inhibitor and switch to second-line at 1000 copies per mL (PI-low), 65 protease inhibitor and switch at 30,000 copies per mL (PI-higher), 68 NNRTI and switch at 1000 copies per mL (NNRTI-low), and 67 NNRTI and switch at 30,000 copies per mL (NNRTI-higher). Median follow-up was 5.0 years (IQR 4.2-6.0) and 188 (71%) children were on first-line ART at trial end. At 4 years, mean reductions in viral load were -3.16 log(10) copies per mL for protease inhibitors versus -3.31 log(10) copies per mL for NNRTIs (difference -0.15 log(10) copies per mL, 95% CI -0.41 to 0.11; p=0.26), and -3.26 log(10) copies per mL for switching at the low versus -3.20 log(10) copies per mL for switching at the higher threshold (difference 0.06 log(10) copies per mL, 95% CI -0.20 to 0.32; p=0.56). Protease inhibitor resistance was uncommon and there was no increase in NRTI resistance in the PI-higher compared with the PI-low group. NNRTI resistance was selected early, and about 10% more children accumulated NRTI mutations in the NNRTI-higher than the NNRTI-low group. Nine children had new CDC stage-C events and 60 had grade 3/4 adverse events; both were balanced across randomised groups. INTERPRETATION: Good long-term outcomes were achieved with all treatments strategies. Delayed switching of protease-inhibitor-based ART might be reasonable where future drug options are limited, because the risk of selecting for NRTI and protease-inhibitor resistance is low. FUNDING: Paediatric European Network for Treatment of AIDS (PENTA) and Pediatric AIDS Clinical Trials Group (PACTG/IMPAACT). PMID- 21288786 TI - In search for theoretical physiology--a mathematical theory of living systems: comment on "Toward a mathematical theory of living systems focusing on developmental biology and evolution: a review and perspectives" by N. Bellomo and B. Carbonaro. PMID- 21288787 TI - [Kingella kingae endocarditis]. PMID- 21288788 TI - Poincare plots and tachograms reveal beat patterning in sick sinus syndrome with supraventricular tachycardia and varying AV nodal block. AB - Using 24-h ambulatory electrocardiography, the RR intervals of all beats were determined in a West Highland white terrier with sick sinus syndrome characterized by long sinus pauses, bradycardia, supraventricular tachycardia (SVT) and varying degrees of atrioventricular (AV) heart block. Distinctive patterns of bradycardia and 1:1, 2:1, 3:1, 4:1 and 5:1 AV block associated with SVT were evident in the tachogram (RR interval distribution over time) and Poincare plots (short-term heart rate variability plots of RRn versus RRn+1). These patterns differed from those of abrupt alteration in cycle length during long sinus pauses or bursts of supraventricular tachycardia. Recognition of such patterns may direct attention to time points for which close attention to the cardiac rhythm should be evaluated in the full-disclosure of the 24-h ECG recording. PMID- 21288789 TI - Ankylosis of permanent first molars: genetics or environment? A case report of a discordant twin pair. AB - The rare condition of secondary retention has been reported in the literature as being of genetic origin, with some authors suggesting an autosomal dominant pattern. We report the unusual case of two monozygotic biamniotic, bichorionic male twins, who were discordant for permanent first molar secondary retention, involving ankylosis. Twin A showed normal occlusion and eruption patterns, whereas Twin B displayed a left open bite, in relation with a totally submerged primary second molar leading to retention of the underlying premolar (35), and severe infraocclusion of the adjacent permanent molar (36). After orthodontic failure to close the open bite, ankylosis of 36 was confirmed, whereas 26 became severely infraoccluded.The mother had a history of bilateral molar ankylosis and presented reduced posterior alveolar height. Discordance in this twin pair demonstrates that environmental influences, in addition to epigenetic and local factors, may play a role in secondary retention, which is difficult to diagnose and challenging to treat. PMID- 21288791 TI - Development of a rapid, 96-well alkaline based differential DNA extraction method for sexual assault evidence. AB - We present a rapid alkaline lysis procedure for the extraction of DNA from sexual assault evidence that generates purified sperm fraction extracts that yield STR typing results similar to those obtained from the traditional organic/dithiothreitol differential extraction. Specifically, a sodium hydroxide based differential extraction method has been developed in a single-tube format and further optimized in a 96-well format. The method yields purified extracts from a small sample set (~ 2-6 swabs) in approximately 2h and from a larger sample set (up to 96 swabs) in approximately 4h. While conventional differential extraction methods require vigorous sample manipulation to remove the spermatozoa from the substrate, the method described here exploits the propensity of sperm to adhere to a substrate and does not require any manipulation of the substrate after it is sampled. For swabs, sample handling is minimized by employing a process where the tip of the swab, including the shaft, is transferred to the appropriate vessel eliminating the need for potentially hazardous scalpels to separate the swab material from the shaft. The absence of multiple handling steps allows the process to be semi-automated, however the procedure as described here does not require use of a robotic system. This method may provide forensic laboratories a cost-effective tool for the eradication of backlogs of sexual assault evidence, and more timely service to their client agencies. In addition, we have demonstrated that a modification of the procedure can be used to retrieve residual sperm-cell DNA from previously extracted swabs. PMID- 21288792 TI - Anthropometric factors and ovarian cancer risk in the Malmo Diet and Cancer Study. AB - OBJECTIVE: To examine the associations of measured anthropometric factors, including general and central adiposity, with epithelial ovarian cancer (EOC) risk in the Malmo Diet and Cancer Study. METHODS: In 93 incident EOC cases from a Swedish population-based prospective cohort study, seven anthropometric factors; height, weight, BMI, body fat percentage, waist- and hip circumference, and waist hip ratio (WHR), were categorized by tertiles of baseline anthropometric measurements and relative risks were calculated using multivariate Cox regression models. RESULTS: A high WHR (<0.77, >=0.77 to <0.81, >=0.81cm/cm) was associated with a statistically significantly lower overall risk for EOC (RR 0.60; 0.36 1.00; p-trend=0.04), particularly tumours of differentiation grades 1 and 2 (RR 0.27; 0.09-0.81; p-trend=0.03) and clinical stages 1 and 2 (RR 0.32; 0.10-0.97; p trend=0.03) and these associations were stronger in postmenopausal women. Neither height, weight, BMI, body fat percentage, waist- or hip circumference were associated with overall risk, nor with risk for different subtypes, differentiation grade or stage. CONCLUSIONS: These results demonstrate that a high WHR is associated with a decreased risk of EOC. Other anthropometric factors were not associated with EOC risk. PMID- 21288793 TI - Perilymphatic fistula of the round window. AB - OBJECTIVE: To highlight diagnostic and treatment pitfalls in perilymphatic fistula. CASE REPORTS: Two cases of round-window fistula are reported, detailing clinical aspect, treatment and outcome. The triad comprising sensorineural hearing loss, tinnitus and vertigo with associated fistula sign is classical but in fact rarely encountered. Imaging is of limited contribution, but may reveal anatomic abnormalities suggestive of perilymphatic fistula. Outcome is improved by early management, especially in case of moderate hearing loss. DISCUSSION/CONCLUSION: Diagnosis of perilymphatic fistula is challenging, but enables effective treatment. On any suspicion, surgical exploration should be undertaken, being the only reliable guide to diagnosis and etiologically adapted management. PMID- 21288794 TI - Re: cardiac imaging training for radiology trainees. PMID- 21288795 TI - Re.: Pulmonary sarcoidosis: the "great pretender". PMID- 21288796 TI - An imaging checklist for pre-FESS CT: framing a surgically relevant report. AB - The reference standard for preoperative imaging in functional endoscopic sinus surgery (FESS) is multiplanar high-resolution computed tomography (HRCT). Surgeons require a precise preoperative anatomical road map, and hence it is essential for radiologists to be familiar with the normal three-dimensional sinonasal anatomy and the normal variants encountered in this region. Sagittal imaging has recently emerged as an important tool to visualize additional details in this critical anatomical region. Radiologists also need to report these examinations with special focus on the surgeon's expectations. Constant communication between the radiologist and the surgeon helps to resolve specific issues and improve the overall quality of reports. This results in better preoperative patient counselling and in predicting postoperative improvement in clinical status. This review provides a basic structured format for reporting pre FESS CT, which can be tailored to meet individual requirements. The CT reporting format follows the order in which the sinonasal structures are approached during surgery. PMID- 21288797 TI - An unusual cause of double duct sign. Type I sphincter of Oddi dysfunction due to chronic opium addiction. PMID- 21288798 TI - "Rolling ball" in the abdomen. Mesenteric cyst in mesenterium of proximal jejunum. PMID- 21288799 TI - Human papillomavirus vaccine initiation among adolescent girls in high-risk communities. AB - BACKGROUND: We assessed human papillomavirus (HPV) vaccine uptake among adolescent girls, parents' intentions to vaccinate daughters, and barriers and facilitators of vaccination in a population at elevated risk for cervical cancer. METHODS: Between October 2007 and June 2008, telephone surveys were conducted with randomly selected parents/guardians of 11-18 year old girls attending public middle and high schools serving economically disadvantaged populations in Los Angeles County. RESULTS: We surveyed 509 predominantly Hispanic (81%) and African American (16%) parents; 71% responded in Spanish. Overall, 23% reported their daughter had received >= 1 dose of HPV vaccine. Although 93% of daughters had seen a doctor in the past year, only 30% reported that a provider recommended HPV vaccine. Characteristics positively associated with odds of having initiated HPV vaccine were having heard of the vaccine (adjusted odds ratio [aOR] 2.6), belief in vaccine effectiveness (aOR 2.9), and doctor recommendation (aOR 48.5). Negative attitudes toward HPV vaccine (aOR 0.2) and needing more information about it (aOR 0.1) were negatively associated with vaccine initiation. Of those with unvaccinated daughters (n=387), 62% said they "probably/definitely will" vaccinate within the next year and 21% were undecided or didn't know; only 11% said they definitely won't. CONCLUSIONS: About one-quarter of adolescent girls in this at-risk community had initiated HPV vaccine by mid-2008. Provider recommendation was the single most important factor associated with vaccination. Because a substantial proportion of parents remain undecided about HPV vaccine, health care providers can play a key role by providing needed information and offering HPV vaccine to all eligible adolescents. PMID- 21288801 TI - Induction of humoral immune response against PfMSP-1(19) and PvMSP-1(19) using gold nanoparticles along with alum. AB - The C-terminal 19 kDa fragment of merozoite surface protein 1(MSP-1(19)) is an important vaccine candidate but a poor immunogen with available human compatible adjuvants like alum. We have investigated if Gold Nanoparticles (GNPs) based delivery system would enhance immune response to recombinant PfMSP-1(19) and PvMSP-1(19). We found that PfMSP-1(19)/PvMSP-1(19) coated on GNPs or in alum was poorly immunogenic in mice, a robust antibody response was observed when PfMSP 1(19)/PvMSP-1(19) coated GNPs were formulated with alum. PfMSP-1(19)/PvMSP-1(19) coated GNPs strongly recognized conformation specific monoclonal antibodies showing that capping on to GNPs did not compromise with conformational integrity of these antigens, which is critical for the generation of functional antibody response. Anti-PfMSP-1(19) antibodies raised with GNP-alum formulation recognized the native protein on parasite surface and showed invasion inhibition of Plasmodium falciparum parasite in an in vitro assay. Antigen coated GNPs with alum may be useful in the development of an alternate adjuvant formulation. PMID- 21288800 TI - Stability of RNA virus attenuation approaches. AB - The greatest risk from live-attenuated vaccines is reversion to virulence. Particular concerns arise for RNA viruses, which exhibit high mutation frequencies. We examined the stability of 3 attenuation strategies for the alphavirus, Venezuelan equine encephalitis virus (VEEV): a traditional, point mutation-dependent attenuation approach exemplified by TC-83; a rationally designed, targeted-mutation approach represented by V3526; and a chimeric vaccine, SIN/TC/ZPC. Our findings suggest that the chimeric strain combines the initial attenuation of TC-83 with the greater phenotypic stability of V3526, highlighting the importance of the both initial attenuation and stability for live-attenuated vaccines. PMID- 21288802 TI - Influenza neuraminidase-inhibiting antibodies are induced in the presence of zanamivir. AB - Seasonal influenza epidemics cause illness and death each year, and the emergence of antigenically novel influenza A viruses are a continual pandemic threat. Disease and death can be averted by vaccination. The potency of killed virus vaccines is based on hemagglutinin (HA) content. However, antibodies that inhibit enzyme activity of the neuraminidase (NA) also reduce virus replication and protect against disease. Monoclonal NA-inhibiting (NI) antibodies recognize conformational epitopes, and it is anticipated that native tertiary structure is required for their induction. NA assembles as a tetramer and only this form has enzyme activity. Since small inhibitors of NA do not significantly alter conformation, we sought to determine whether neuraminidase-inhibiting (NI) antibodies would be induced by inhibitor-inactivated NA. We therefore evaluated responses of mice immunized with purified NA that was either inactivated by addition of zanamivir or denatured by heat treatment. NI antibodies were induced following immunization with NA from A/Wisconsin/67/2005 (H3N2) in which enzyme activity was inhibited by the former method but not the latter. Protection of mice against challenge with virus containing an antigenically matched NA correlated with the detection of NI antibodies in serum. Similar results were obtained when mice were immunized with whole H1N1 virus in which NA activity had been inhibited by the same two modalities. This demonstrates that native conformation of NA is necessary for induction of NI antibodies; enzyme activity provides a useful marker of intact structure, but absence of activity in NA that is correctly folded does not result in loss of immunogenicity. Thus any assay to assess potency of influenza vaccines with respect to NA content should consider the proportion of NA that is in a structurally native state. PMID- 21288803 TI - A phase III randomized, controlled study to assess the immunogenicity and tolerability of DTPw-HBV-Hib, a liquid pentavalent vaccine in Indian infants. AB - Immunogenicity and tolerability of two liquid pentavalent vaccines, Pentavac((r)) (new vaccine), and Easyfive((r)) (available in the market) was assessed in a multicentre study in India. In all, 484 infants aged 6-8 weeks were enrolled, and their blood samples were assessed prior to the first dose and one month after the third dose. A 100% seroprotection rate was achieved with both vaccines' antigens, except pertussis for which the response was 95% and 96%, respectively, for the two vaccines. A diary-based recording of adverse events showed that the two most common events were pain at the injection site and restricted limb movements and were less frequent (p<0.001) among the recipients of the new vaccine. The new vaccine meets all criteria of childhood vaccination. Its low reactogenicity and low cost are valid reasons to recommend this vaccine for general use. PMID- 21288804 TI - Long term immunity following a booster dose of the inactivated Japanese Encephalitis vaccine IXIARO(r), IC51. AB - INTRODUCTION: IXIARO (IC51), a recently approved inactivated Japanese Encephalitis vaccine, is immunogenic and safe in a 0/28 days primary immunization schedule. Neutralizing antibody titers decline with time and booster doses are likely needed to enhance persistence of immunity. OBJECTIVES: To assess the effect of a booster dose on neutralizing JE antibody titers for up to 12 months after boostering. METHODS: In this phase III trial, 198 subjects, who had received primary immunization in a preceding randomized trial, were boosted with IXIARO 15 months after the primary immunization. Neutralizing antibody titers were assessed by plaque-reduction neutralisation test, PRNT. RESULTS: Prior to the booster dose, 69.2% (137/198) of subjects had PRNT50 titers >= 1:10. One month after the booster, the rate of subjects with PRNT50 >= 1:10 (recognized as a protective titer) was 100%. This rate remained high at 98.5% at 6 and 12 months; GMTs were 22.5 before the booster and 900, 487 and 361 at 1, 6 and 12 months after the booster, respectively. CONCLUSION: A booster dose of IXIARO at 15 months after primary immunization was highly immunogenic with GMTs >5-fold higher than those seen immediately after primary immunization, and remained at high levels for at least 12 months after the booster. PMID- 21288805 TI - Control of Rhipicephalus (Boophilus) microplus infestations by the combination of subolesin vaccination and tick autocidal control after subolesin gene knockdown in ticks fed on cattle. AB - Tick subolesin was shown in immunization trials using the recombinant protein to protect hosts against tick infestations. In this study, we demonstrated that subolesin vaccination and release of ticks after subolesin knockdown by RNA interference (RNAi) could be used for the control of Rhipicephalus (Boophilus) microplus tick infestations in cattle and suggested that the combination of these methods could increase the efficacy of cattle tick control under some circumstances. The greatest tick control was obtained when both release of ticks after subolesin knockdown and vaccination were used concurrently. However, modeling results suggested that vaccine efficacy could be increased if at least 80% of the ticks infesting cattle correspond to subolesin-knockdown ticks. The results of this proof-of-concept trial demonstrated the efficacy of the sterile acarine technique (SAT) through production of subolesin-knockdown larvae by dsRNA injection into replete females for the control of R. microplus tick infestations, alone or in combination with subolesin vaccination. PMID- 21288807 TI - Product biomonitoring and responsible reporting. PMID- 21288808 TI - Climate change and human health in China. PMID- 21288809 TI - Hypoxia-inducible factor 2alpha (HIF-2alpha) heterozygous-null mice exhibit exaggerated carotid body sensitivity to hypoxia, breathing instability, and hypertension. AB - Cardiorespiratory functions in mammals are exquisitely sensitive to changes in arterial O(2) levels. Hypoxia-inducible factors (e.g., HIF-1 and HIF-2) mediate transcriptional responses to reduced oxygen availability. We demonstrate that haploinsufficiency for the O(2)-regulated HIF-2alpha subunit results in augmented carotid body sensitivity to hypoxia, irregular breathing, apneas, hypertension, and elevated plasma norepinephrine levels in adult Hif-2alpha(+/-) mice. These dysregulated autonomic responses were associated with increased oxidative stress and decreased mitochondrial electron transport chain complex I activity in adrenal medullae as a result of decreased expression of major cytosolic and mitochondrial antioxidant enzymes. Systemic administration of a membrane permeable antioxidant prevented oxidative stress, normalized hypoxic sensitivity of the carotid body, and restored autonomic functions in Hif-2alpha(+/-) mice. Thus, HIF-2alpha-dependent redox regulation is required for maintenance of carotid body function and cardiorespiratory homeostasis. PMID- 21288810 TI - Chikungunya fever: focus on peripheral markers of pathogenesis. PMID- 21288811 TI - Vivax malaria: old drug, new uses? PMID- 21288812 TI - Genotypic tests for determining coreceptor usage of HIV-1. PMID- 21288813 TI - Persistent arthralgia induced by Chikungunya virus infection is associated with interleukin-6 and granulocyte macrophage colony-stimulating factor. AB - BACKGROUND: Chikungunya virus (CHIKV) infection induces arthralgia. The involvement of inflammatory cytokines and chemokines has been suggested, but very little is known about their secretion profile in CHIKV-infected patients. METHODS: A case-control longitudinal study was performed that involved 30 adult patients with laboratory-confirmed Chikungunya fever. Their profiles of clinical disease, viral load, and immune mediators were investigated. RESULTS: When patients were segregated into high viral load and low viral load groups during the acute phase, those with high viremia had lymphopenia, lower levels of monocytes, neutrophilia, and signs of inflammation. The high viral load group was also characterized by a higher production of pro-inflammatory cytokines, such as interferon-alpha and interleukin (IL)-6, during the acute phase. As the disease progressed to the chronic phase, IL-17 became detectable. However, persistent arthralgia was associated with higher levels of IL-6 and granulocyte macrophage colony-stimulating factor, whereas patients who recovered fully had high levels of Eotaxin and hepatocyte growth factor. CONCLUSIONS: The level of CHIKV viremia during the acute phase determined specific patterns of pro-inflammatory cytokines, which were associated with disease severity. At the chronic phase, levels of IL-6, and granulocyte macrophage colony-stimulating factor found to be associated with persistent arthralgia provide a possible explanation for the etiology of arthralgia that plagues numerous CHIKV-infected patients. PMID- 21288814 TI - Immuno-epidemiologic correlates of pandemic H1N1 surveillance observations: higher antibody and lower cell-mediated immune responses with advanced age. AB - BACKGROUND: Pandemic H1N1 (pH1N1) surveillance data showed lower attack rates but higher risk of severe outcomes with advanced age. We explored immuno epidemiologic correlates of surveillance findings including humoral and cell mediated immunity (CMI). METHODS: In an age-based design, ~100 banked/residual sera per 10-year age stratum were assessed by hemagglutination inhibition (HI) and microneutralization (MN) assays for preexisting antibody to pH1N1 and recent seasonal H1N1 and H3N2 strains. In a separate birth cohort design defined by childhood influenza A/subtype priming (1919-1929: H1N1; 1945-1949: H1N1; 1958 1960: H2N2; 1969-1970: H3N2; 1978-1989: H3N2/H1N1), whole blood was collected from up to 50 volunteers per birth cohort. The ratio of Th1(IFN-gamma):Th2(IL-10) cytokine responses was evaluated in vitro. RESULTS: Antibody to seasonal viruses was highest in school-age children. Cross-reactive HI/MN antibody to pH1N1 was low among participants <70 years of age (yoa; 6%/4% >= 40), but seroprevalence increased at 70-79 yoa (27%/6%), increased even more at 80-89 yoa (65%/47%), and was highest at >=90 yoa (88%/76%). CMI to pH1N1 was evident in all 5 birth cohorts but was lower compared with seasonal strains. There was little differentiation by subtype priming, but the Th1:Th2 ratio for all viruses dropped significantly in the 2 oldest cohorts. CONCLUSIONS: Preexisting antibody may have protected the very old from pH1N1 infection, while diminished CMI may have contributed to greater severity once infected. In the young, cross-reactive pH1N1 antibody was mostly absent, while more intact CMI may have protected against severe outcomes. PMID- 21288815 TI - Deep sequencing reveals mixed infection with 2009 pandemic influenza A (H1N1) virus strains and the emergence of oseltamivir resistance. AB - Mixed infections with seasonal influenza A virus strains are a common occurrence and an important source of genetic diversity. Prolonged viral shedding, as observed in immunocompromised individuals, can lead to mutational accumulation over extended periods. Recently, drug resistance was reported in immunosuppressed patients infected with the 2009 pandemic influenza A (H1N1) virus within a few days after oseltamivir treatment was initiated. To better understand the evolution and emergence of drug resistance in these circumstances, we used a deep sequencing approach to survey the viral population from an immunosuppressed patient infected with H1N1/2009 influenza and treated with neuraminidase inhibitors. This patient harbored 3 genetic variants from 2 phylogenetically distinct viral clades of pandemic H1N1/2009, strongly suggestive of mixed infection. Strikingly, one of these variants also developed drug resistance de novo in response to oseltamivir treatment. Immunocompromised individuals may, therefore, constitute an important source of genetic and phenotypic diversity, both through mixed infection and de novo mutation. PMID- 21288816 TI - High-dose mannose-binding lectin therapy for Ebola virus infection. AB - Mannose-binding lectin (MBL) targets diverse microorganisms for phagocytosis and complement-mediated lysis by binding specific surface glycans. Although recombinant human MBL (rhMBL) trials have focused on reconstitution therapy, safety studies have identified no barriers to its use at higher levels. Ebola viruses cause fatal hemorrhagic fevers for which no treatment exists and that are feared as potential biothreat agents. We found that mice whose rhMBL serum concentrations were increased >=7-fold above average human levels survived otherwise fatal Ebola virus infections and became immune to virus rechallenge. Because Ebola glycoproteins potentially model other glycosylated viruses, rhMBL may offer a novel broad-spectrum antiviral approach. PMID- 21288817 TI - Persistent genital herpes simplex virus-2 shedding years following the first clinical episode. AB - BACKGROUND: Patients with newly acquired genital herpes simplex virus 2 (HSV-2) infection have virus frequently detected at the genital mucosa. Rates of genital shedding initially decrease over time after infection, but data on long-term viral shedding are lacking. METHODS: For this study, 377 healthy adults with history of symptomatic genital HSV-2 infection collected anogenital swabs for HSV 2 DNA polymerase chain reaction for at least 30 consecutive days. RESULTS: Time since first genital herpes episode was significantly associated with reduced genital shedding. Total HSV shedding occurred on 33.6% of days in participants <1 year, 20.6% in those 1-9 years, and 16.7% in those >=10 years from first episode. Subclinical HSV shedding occurred on 26.2% of days among participants <1 year, 13.1% in those 1-9 years, and 9.3% in those >=10 years from first episode. On days with HSV detection, mean quantity was 4.9 log10 copies/mL for those <1 year, 4.7 log10 copies/mL among those 1-9 years, and 4.6 log10 copies/mL among those >=10 years since first episode. CONCLUSIONS: Rates of total and subclinical HSV-2 shedding decrease after the first year following the initial clinical episode. However, viral shedding persists at high rates and copy numbers years after infection, and therefore may pose continued risk of HSV-2 transmission to sexual partners. PMID- 21288818 TI - Immune responses to rotavirus infection and vaccination and associated correlates of protection. PMID- 21288819 TI - The human fetal immune response to hepatitis C virus exposure in utero. AB - BACKGROUND: Although the rate of mother-to-child transmission of hepatitis C virus (HCV) is low, the effect of HCV exposure in utero on the fetal immune system is unknown. METHODS: Umbilical cord blood was obtained from 7 neonates born to HCV-seropositive, HCV RNA-positive women and 8 neonates born to HCV seronegative women. Cord blood mononuclear cells were analyzed by immunophenotyping and by intracellular cytokine staining after HCV-specific and polyclonal stimulation. Plasma was analyzed for anti-HCV immunoglobulin M (IgM), cytokine/granzyme concentrations, and indoleamine 2,3-dioxygenase (IDO) activity. RESULTS: HCV-exposed neonates had significantly lower levels of regulatory T cells expressing HLA-DR, lower CD4(+) and CD8(+) T cell activation, and lower plasma levels of pro-inflammatory markers than did controls. However, CD4(+) and CD8(+) T cells from HCV-exposed neonates had higher IFN-gamma production in response to polyclonal stimulation than did T cells from controls. IDO activity was similar between groups. No HCV-specific T cell responses or anti-HCV IgM were detected in any neonates. CONCLUSIONS: HCV-exposed neonates showed a relative suppression of immune activation and pro-inflammatory markers, which was counterbalanced by an increased production capacity for IFN-gamma. These results suggest that HCV encounters the fetal immune system in utero, and alters the balance between suppressive and pro-inflammatory responses. PMID- 21288820 TI - Methotrexate is highly potent against pyrimethamine-resistant Plasmodium vivax. AB - Resistance of vivax malaria to treatment with antifolates, such as pyrimethamine (Pyr), is spreading as mutations in the dihydrofolatereductase (dhfr) genes are selected and disseminated. We tested the antitumor drug methotrexate (MTX), a potent competitive inhibitor of dhfr, against 11 Plasmodium vivax isolates ex vivo, 10 of which had multiple dhfr mutations associated with Pyr resistance. Despite high-grade resistance to Pyr (median 50% inhibitory concentration [IC50], 13,345 nM), these parasites were all highly susceptible to MTX (median IC50, 2.6 nM). Given its potency against Pyr-resistant P. vivax, the antimalarial potential of MTX deserves further investigation. PMID- 21288821 TI - Distinct clinical and immunologic profiles in severe malarial anemia and cerebral malaria in Zambia. AB - BACKGROUND: The mechanisms of severe malarial anemia and cerebral malaria, which are extreme manifestations of Plasmodium falciparum malaria, are not fully understood. METHODS: Children aged <6 years from southern Zambia presenting to the hospital with severe malarial anemia (n = 72), cerebral malaria (n = 28), or uncomplicated malaria (n = 66) were studied prospectively. Children with overlapping severe anemia and cerebral malaria were excluded. RESULTS: Low interleukin 10 concentrations had the strongest association with severe anemia (standard beta = .61; P < .001) followed by high tumor necrosis factor alpha and sFas concentrations, low weight-for-age z scores, presence of stool parasites, and splenomegaly (standard beta = .15-.25; P <= .031); most of these factors were also associated with lower reticulocytes. Greater parasitemia was associated with higher interleukin 10 and tumor necrosis factor alpha concentrations, whereas sulfadoxizole/pyrimethamine therapy and lower weight-for-age z scores were associated with lower interleukin 10 levels. Thrombocytopenia and elevated tissue plasminogen activator inhibitor 1 levels had the strongest associations with cerebral malaria (standard beta = .37 or .36; P < .0001), followed by exposure to traditional herbal medicine and hemoglobinuria (standard beta = .21-.31; P <= .006). CONCLUSIONS: Predictors of severe malarial anemia (altered immune responses, poor nutrition, intestinal parasites, and impaired erythropoiesis) differed from those of cerebral malaria (thrombocytopenia, herbal medicine, and intravascular hemolysis). Improved preventive and therapeutic measures may need to consider these differences. PMID- 21288822 TI - Selective sweeps and genetic lineages of Plasmodium falciparum drug -resistant alleles in Ghana. AB - BACKGROUND: In 2005, Ghana adopted artemisinin-based combination therapy (ACT) for primary treatment of falciparum malaria. A comprehensive study of the drug resistance-associated mutations and their genetic lineages will lead to a better understanding of the evolution of antimalarial drug resistance in this region. METHODS: The pfcrt, pfmdr1, dhps, and dhfr mutations associated with chloroquine (CQ) and sulfadoxine-pyrimethamine (SP) resistance and the microsatellite loci flanking these genes were genotyped in Plasmodium falciparum isolates from Ghana. RESULTS: The prevalence of mutations associated with both CQ and SP resistance was high in Ghana. However, we observed a decrease in prevalence of the pfcrt K76T mutation in northern Ghana after the change in drug policy from CQ to ACT. Analysis of genetic diversity and differentiation at microsatellite loci flanking all 4 genes indicated that they have been under strong selection, because of CQ and SP use. The triple-mutant pfcrt and dhfr alleles in Ghana were derived from Southeast Asia, whereas the double-mutant dhfr, dhps, and pfmdr1 alleles were of African lineage. CONCLUSION: Because of the possible role of pfmdr1 in amodiaquine and mefloquine resistance, demonstrating selection on pfmdr1 and defining lineages of resistant alleles in an African population holds great importance. PMID- 21288823 TI - Evidence that mutant PfCRT facilitates the transmission to mosquitoes of chloroquine-treated Plasmodium gametocytes. AB - Resistance of the human malarial parasite Plasmodium falciparum to the antimalarial drug chloroquine has rapidly spread from several independent origins and is now widely prevalent throughout the majority of malaria-endemic areas. Field studies have suggested that chloroquine-resistant strains might be more infective to mosquito vectors. To test the hypothesis that the primary chloroquine resistance determinant, mutations in PfCRT, facilitates parasite transmission under drug pressure, we have introduced a mutant or wild-type pfcrt allele into the rodent model malarial parasite Plasmodium berghei. Our results show that mutant PfCRT from the chloroquine-resistant 7G8 strain has no effect on asexual blood stage chloroquine susceptibility in vivo or ex vivo but confers a significant selective advantage in competitive mosquito infections in the presence of this drug, by protecting immature gametocytes from its lethal action. Enhanced infectivity to mosquitoes may have been a key factor driving the worldwide spread of mutant pfcrt. PMID- 21288824 TI - Deep sequencing to infer HIV-1 co-receptor usage: application to three clinical trials of maraviroc in treatment-experienced patients. AB - BACKGROUND: The Maraviroc versus Optimized Therapy in Viremic Antiretroviral Treatment-Experienced Patients (MOTIVATE) studies compared maraviroc versus placebo in treatment-experienced patients with CCR5-using (R5) human immunodeficiency virus type 1 (HIV-1), screened using the original Trofile assay. A subset with non-R5 HIV infection entered the A4001029 trial. We retrospectively examined the performance of a genotypic tropism assay based on deep sequencing of the HIV env V3 loop in predicting virologic response to maraviroc in these trials. METHODS: V3 amplicons were prepared from 1827 screening plasma samples and sequenced on a Roche/454 GS-FLX to a depth of >3000 sequences/sample. Samples were considered non-R5 if >=2% of their viral population scored greater than or equal to -4.75 or <=3.5 using the PSSM(x4/R5) or geno2pheno algorithms, respectively. RESULTS: Deep sequencing identified more than twice as many maraviroc recipients as having non-R5 HIV, compared with the original Trofile. With use of genotyping, we determined that 49% of maraviroc recipients with R5 HIV at screening had a week 48 viral load <50 copies/mL versus 26% of recipients with non-R5. Corresponding percentages were 46% and 23% with screening by Trofile. In cases in which screening assays differed, median week 8 log10 copies/mL viral load decrease favored 454. Other parameters predicted by genotyping included likelihood of changing to non-R5 tropism. CONCLUSIONS: This large study establishes deep V3 sequencing as a promising tool for identifying treatment-experienced individuals who could benefit from CCR5-antagonist containing regimens. PMID- 21288825 TI - Association of pharmacogenetic markers with premature discontinuation of first line anti-HIV therapy: an observational cohort study. AB - BACKGROUND: Poor tolerance and adverse drug reactions are main reasons for discontinuation of antiretroviral therapy (ART). Identifying predictors of ART discontinuation is a priority in HIV care. METHODS: A genetic association study in an observational cohort to evaluate the association of pharmacogenetic markers with time to treatment discontinuation during the first year of ART. Analysis included 577 treatment-naive individuals initiating tenofovir (n = 500) or abacavir (n = 77), with efavirenz (n = 272), lopinavir/ritonavir (n = 184), or atazanavir/ritonavir (n = 121). Genotyping included 23 genetic markers in 15 genes associated with toxicity or pharmacokinetics of the study medication. Rates of ART discontinuation between groups with and without genetic risk markers were assessed by survival analysis using Cox regression models. RESULTS: During the first year of ART, 190 individuals (33%) stopped 1 or more drugs. For efavirenz and atazanavir, individuals with genetic risk markers experienced higher discontinuation rates than individuals without (71.15% vs 28.10%, and 62.5% vs 14.6%, respectively). The efavirenz discontinuation hazard ratio (HR) was 3.14 (95% confidence interval (CI): 1.35-7.33, P = .008). The atazanavir discontinuation HR was 9.13 (95% CI: 3.38-24.69, P < .0001). CONCLUSIONS: Several pharmacogenetic markers identify individuals at risk for early treatment discontinuation. These markers should be considered for validation in the clinical setting. PMID- 21288826 TI - Lack of detectable HIV-1-specific CD8(+) T cell responses in Zambian HIV-1 exposed seronegative partners of HIV-1-positive individuals. AB - Human immunodeficiency virus type 1 (HIV-1)-specific T cell responses were characterized in a blinded study involving infected individuals and their seronegative exposed uninfected (EU) partners from Lusaka, Zambia. HIV-1-specific T cell responses were detected ex vivo in all infected individuals and amplified, on average, 27-fold following in vitro expansion. In contrast, no HIV-1-specific T cell responses were detected in any of the EU partners ex vivo or following in vitro expansion. These data demonstrate that the detection of HIV-1-specific T cell immunity in EU individuals is not universal and that alternative mechanisms may account for protection in these individuals. PMID- 21288827 TI - Concordance of CCR5 genotypes that influence cell-mediated immunity and HIV-1 disease progression rates. AB - We used cutaneous delayed-type hypersensitivity responses, a powerful in vivo measure of cell-mediated immunity, to evaluate the relationships among cell mediated immunity, AIDS, and polymorphisms in CCR5, the HIV-1 coreceptor. There was high concordance between CCR5 polymorphisms and haplotype pairs that influenced delayed-type hypersensitivity responses in healthy persons and HIV disease progression. In the cohorts examined, CCR5 genotypes containing -2459G/G (HHA/HHA, HHA/HHC, HHC/HHC) or -2459A/A (HHE/HHE) associated with salutary or detrimental delayed-type hypersensitivity and AIDS phenotypes, respectively. Accordingly, the CCR5-Delta32 allele, when paired with non-Delta32-bearing haplotypes that correlate with low (HHA, HHC) versus high (HHE) CCR5 transcriptional activity, associates with disease retardation or acceleration, respectively. Thus, the associations of CCR5-Delta32 heterozygosity partly reflect the effect of the non-?32 haplotype in a background of CCR5 haploinsufficiency. The correlations of increased delayed-type hypersensitivity with -2459G/G-containing CCR5 genotypes, reduced CCR5 expression, decreased viral replication, and disease retardation suggest that CCR5 may influence HIV infection and AIDS, at least in part, through effects on cell-mediated immunity. PMID- 21288828 TI - Underlying mechanism of in vivo and in vitro activity of C-terminal-amidated thanatin against clinical isolates of extended-spectrum beta-lactamase-producing Escherichia coli. AB - BACKGROUND: Infections with extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) have developed resistance to current therapies. Therefore, the underlying mechanisms of in vivo and in vitro activity of C terminal-amidated thanatin (A-thanatin) against clinical isolates of ESBL-EC were studied in an attempt to resolve this problem. METHODS: A-thanatin was synthesized to determine its minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and kill curve for ESBL-EC. The hemolytic toxicity, stability, and resistance induction of A-thanatin were determined. ESBL EC-infected mice were used to determine the in vivo activity of A-thanatin. Scanning and transmission electron microscopy and fluorescence microscopy were used to study the underlying mechanism of A-thanatin. RESULTS: A-thanatin is highly effective against ESBL-EC in vitro, with MIC values <=4 MUg/mL. It has been confirmed that A-thanatin has little hemolysis and relative high stability in plasma. Excellent in vivo therapeutic effects were also observed in a septicemic animal model, with survival rates of 50.0%, 66.7%, and 91.7% in the low-dose, middle-dose, and high-dose groups, respectively. Membrane permeabilization may be a major biological action of A-thanatin. CONCLUSIONS: Because the development of multidrug resistance limits the available therapeutic options, A-thanatin may provide a novel strategy for treating ESBL-EC infection and other infections due to multidrug-resistant bacteria. PMID- 21288829 TI - Coxiella burnetii antigen-stimulated dendritic cells mediated protection against Coxiella burnetii in BALB/c mice. AB - Coxiella burnetii is the etiological agent of human Q fever. In this study, adaptive transfer of mouse bone marrow-derived dendritic cells (BMDCs) stimulated with C. burnetii antigen, phase I whole-cell antigen (PIAg), lipopolysaccharide (LPS)-removed PIAg (PIIAg), protein antigen Com1, or SecB significantly reduced coxiella burden in recipient mice compared with control mice. Mice that received PIIAg-pulsed BMDCs displayed substantially lower coxiella burden than recipient mice of PIAg-pulsed BMDCs after C burnetii challenge. The protection offered by the antigen-activated BMDCs was correlated with the increased proliferation of helper T (T(H)) T(H)1 CD4(+) cells, preferential development of T(H)17 cells, and impaired expansion of regulatory T lymphocytes. Our results suggest that PIIAg is far superior to PIAg in activating BMDCs to confer protection against C. burnetii in vivo, whereas Com1 and SecB are protective antigens because Com1- or SecB pulsed BMDCs confer partial protection. PMID- 21288830 TI - Targeting the chemokine receptor CCR5: good for HIV, what about other viruses? PMID- 21288832 TI - Human metapneumovirus infection as an emerging pathogen causing acute respiratory distress syndrome. PMID- 21288834 TI - Attribution of congenital cytomegalovirus infection to primary versus non-primary maternal infection. AB - Congenital cytomegalovirus (CMV) infection is a leading cause of developmental disabilities. In the United States during the period 1988-1994, approximately one quarter of congenital CMV infections were attributable to primary maternal infection (n = 8772), and three-quarters were attributable to non-primary maternal infection (n = 29,918). Effective prevention strategies need to be developed for both primary and non-primary maternal infections. PMID- 21288835 TI - Pandemic H1N1 influenza infection and vascular thrombosis. AB - During the summer and fall of 2009, significant thrombotic events were observed in patients infected with the pandemic H1N1 influenza A virus. In a retrospective chart review of 119 individuals admitted to the hospital with H1N1 virus infection, 7 patients (5.9%) were found to have experienced thrombotic vascular events. PMID- 21288837 TI - Implementation of cocooning against pertussis in a high-risk population. AB - BACKGROUND: In 2006, the Advisory Committee on Immunization Practices recommended tetanus, diphtheria, acellular pertussis (Tdap) vaccination of all caregivers of infants aged <1 year ("cocooning") to prevent pertussis-related complications and deaths. We implemented cocooning in a predominantly Hispanic, medically underserved, uninsured population at a Houston hospital. Phase 1 (January 2008 January 2010) provided maternal postpartum Tdap vaccine; Phase 2 (June 2009 January 2010) also vaccinated infant contacts on-site. METHODS: Pertussis education was provided to health care personnel and mothers. Standing orders for maternal postpartum Tdap vaccination were initiated. Mothers were interviewed to ascertain the number of additional infant contacts eligible to receive Tdap vaccine. Consenting eligible contacts received Tdap vaccine as soon as possible after delivery. RESULTS: From 7 January 2008 through 31 January 2010, 8334 (75%) of 11,174 postpartum women received Tdap vaccine. During Phase 2, 2969 (86%) of 3455 postpartum women were vaccinated; another 197 (6%) had previously received Tdap vaccine. Mothers were Hispanic (91.4%), black (5.4%), white (0.8%), Asian (1.4%) and other (1.0%). A median of 3 (range, 1-11) other Tdap-eligible contacts per infant were identified, and a median of 2 (range, 0-10) contacts per infant received Tdap vaccine. Of 1860 contacts vaccinated, 1813 (98%) anticipated daily infant contact. A total of 1697 (91%) received Tdap vaccine before infant hospital discharge, and 144 (8%) received Tdap vaccine within 7 days after hospital discharge. Barriers to full cocooning included the need for extended vaccination hours, visiting restrictions because of pandemic H1N1 influenza, and inaccurate recall of vaccination history. CONCLUSION: Although practical and logistical barriers exist, Tdap cocooning was well accepted by and successfully implemented in a high-risk population by using standing orders and providing vaccinations on-site. PMID- 21288838 TI - Re-evaluating the treatment of nongonococcal urethritis: emphasizing emerging pathogens--a randomized clinical trial. AB - BACKGROUND: Nongonococcal urethritis (NGU) is a common chlamydia-associated syndrome in men; however, Trichomonas vaginalis and Mycoplasma genitalium are associated with its etiology and should be considered in approaches to therapy. We sought to determine whether the addition of tinidazole, an anti-trichomonal agent, to the treatment regimen would result in higher cure rates than those achieved with treatment with doxycycline or azithromycin alone. A secondary aim was to compare the efficacy of doxycycline therapy and with that of azithromycin therapy. METHODS: Randomized, controlled, double-blinded phase IIB trial of men with NGU. Participants were randomized to receive doxycycline plus or minus tinidazole or azithromycin plus or minus tinidazole and were observed for up to 45 days. RESULTS: The prevalences of Chlamydia trachomatis, M. genitalium, and T. vaginalis were 43%, 31%, and 13%, respectively. No pathogens were identified in 29% of participants. Clinical cure rates at the first follow-up visit were 74.5% (111 of 149 patients) for doxycycline-containing regimens and 68.6% (107 of 156 patients) for azithromycin-containing regimens. By the final visit, cure rates were 49% (73 of 149 patients) for doxycycline-containing regimens and 43.6% (68 of 156 patients) for azithromycin-containing regimens. There were no significant differences in clinical response rates among the treatment arms. However, the chlamydia clearance rate was 94.8% (55 of 58 patients) for the doxycycline arm and 77.4% (41 of 53 patients) for the azithromycin arm (P = .011), and the M. genitalium clearance rate was 30.8% (12 of 39 patients) for the doxycycline arm and 66.7% (30 of 45 patients) for the azithromycin arm (P = .002). CONCLUSIONS: Addition of tinidazole to the treatment regimen did not result in higher cure rates but effectively eradicated trichomonas. Clinical cure rates were not significantly different between patients treated with doxycycline and those treated with azithromycin; however, doxycycline had significantly better efficacy against Chlamydia, whereas azithromycin was superior to doxycycline for the treatment of M. genitalium. PMID- 21288839 TI - Projected impact and cost-effectiveness of a rotavirus vaccination program in India, 2008. AB - BACKGROUND: To assess the value of rotavirus vaccination in India, we determined the potential impact and cost-effectiveness of a national rotavirus vaccination program. METHODS: We compared the national rotavirus disease and cost burden with and without a vaccination program and assessed the cost-effectiveness of vaccination. Model inputs included measures of disease and cost burden, vaccine performance, and vaccination coverage and cost. We measured the annual number of health-related events and treatment costs averted, as well as the cost effectiveness in US dollars per disability-adjusted life-year (DALY) and cost per death averted. One-way sensitivity analyses were performed by individually varying each model input. RESULTS: With use of a vaccine that has an estimated effectiveness of 50%, a rotavirus vaccination program in India would prevent ~44,000 deaths, ~293,000 hospitalizations, and ~328,000 outpatient visits annually, which would avert $20.6 million in medical treatment costs. Vaccination would be cost-saving at the GAVI Alliance price of $0.15 per dose. At $1.00 per dose, a vaccination program would cost $49.8 million, which would result in an expenditure of $21.41 per DALY averted or $662.94 per life saved. Even at $7.00 per dose, vaccination would be highly cost-effective. In sensitivity analyses, varying efficacy against severe rotavirus disease and vaccine price had the greatest impact on cost-effectiveness. CONCLUSIONS: A national rotavirus vaccination program in India would prevent substantial rotavirus morbidity and mortality and would be highly cost-effective at a range of vaccine prices. Public health officials can use this locally derived data to evaluate how this highly cost-effective intervention might fit into India's long-term health care goals. PMID- 21288840 TI - Reaching MDG 4 in India: a role for rotavirus vaccine? PMID- 21288841 TI - Conservative wait-and-see therapy versus antibiotic treatment for nontuberculous mycobacterial cervicofacial lymphadenitis in children. AB - BACKGROUND: In this explorative study, 50 children with microbiologically confirmed nontuberculous mycobacterial cervicofacial lymphadenitis were randomized to either receive antibiotic therapy or follow a conservative wait-and see approach. Our primary objective was to assess the time for all infected lymph nodes to heal in patients after the nonantibiotic, wait-and-see treatment, compared with patients after a 12-week course of clarithromycin and rifabutin. METHODS: Fifty children (19 boys and 31 girls) with a polymerase chain reaction (PCR)- or culture-confirmed diagnosis of cervicofacial nontuberculous mycobacterial infection were included in our study. Twenty-five children were randomized to receive antibiotic therapy and 25 to be given a wait-and-see approach. RESULTS: The median age of the children was 35 months (range, 14-114 months). The median time to resolution of the disease for the antibiotic group was 36 weeks, compared with 40 weeks for the wait-and-see group. Adverse effects of antibiotic therapy included gastrointestinal complaints, fever, and reversible extrinsic tooth discoloration. CONCLUSION: In children with an advanced stage of nontuberculous mycobacterial cervicofacial lymphadenitis, we observed no significant differences in median healing time between the wait-and-see group and the group receiving clarithromycin and rifabutin antibiotic therapy. PMID- 21288842 TI - A dog-associated primary pneumonic plague in Qinghai Province, China. AB - BACKGROUND: Primary pneumonic plague (PPP) caused by Yersinia pestis is the most threatening clinical form of plague. An outbreak was reported in July 2009 in Qinghai Province, China. METHODS: This outbreak was investigated by clinical, epidemiological, bacteriological, and immunological methods. Multilocus variable number tandem repeat analysis (MLVA) was used to track the source of the outbreak. RESULTS: The index case, a patient with PPP, contaminated 11 close contacts. All the 12 cases, including the index patient, experienced sudden onset of fever, headache, and productive coughing with bloody sputum. Three of them died. Nevertheless, another 61 direct and 256 indirect contacts were not infected during the 2-week quarantine. Antibodies to F1 antigen were detected in 9 survival cases, with a 4-fold increase in titers in serum samples collected at different periods. Seven strains of Y. pestis were isolated from dogs and patients. Field investigation and MLVA of the isolated strains revealed that this outbreak was started by a deceased dog. CONCLUSION: Dogs are believed to be an indicator animal for plague surveillance, but their association with PPP is rare. Our results provide evidence for this possibility, which suggests the public health significance of dogs as a source of plague. PMID- 21288843 TI - Case-control evaluation of the effectiveness of the G1P[8] human rotavirus vaccine during an outbreak of rotavirus G2P[4] infection in central Australia. AB - The human rotavirus vaccine was evaluated during an outbreak of rotavirus G2P[4] infection in central Australia. No overall protective effect against hospitalization was demonstrated, raising concerns over the durability of vaccine protection against heterotypic strains. BACKGROUND: Two and a half years after commencing routine vaccination with human rotavirus vaccine, an outbreak of rotavirus G2P[4] infection occurred in central Australia. Vaccine effectiveness against a P[8]-containing strain (G9P[8]) had been demonstrated previously in this setting. This subsequent outbreak provided the opportunity to evaluate vaccine effectiveness against hospitalizations for a non-vaccine-related genotype in the same population. METHODS: A case-control study was nested within a cohort of vaccine-eligible children listed on a population-based immunization register. Children with rotavirus-confirmed gastroenteritis were individually matched by date of birth and Indigenous status with 4 control subjects. RESULTS: Forty-one cases met the inclusion criteria, and 21 were severe cases among infants aged <12 months. Nineteen (46%) of 41 case patients had received 2 doses of human rotavirus vaccine, compared with 87 (53%) of 164 control subjects. Vaccine effectiveness against rotavirus-related hospitalization was 19% (odds ratio, .81; 95% confidence interval, .32-2.05) for 2 doses compared with none. On secondary analysis, there was evidence of a protective effect against disease complicated by acidosis in the subset of infants aged <12 months (odds ratio, .15; 95% confidence interval, .03-.84). CONCLUSIONS: Evidence was not found for an overall protective effect of human rotavirus vaccine against hospitalization for rotavirus disease in this setting. Post hoc analyses suggested a protective effect against severe disease in young infants. PMID- 21288845 TI - What is the predominant source of intravascular catheter infections? AB - The predominant source of intravascular catheter-related bloodstream infections has been a research and clinical question for more than 30 years. During that time, we've moved from the position of a single source predominating in all clinical scenarios to a more realistic appraisal that both skin at the insertion site and the catheter hub/connector (ie, an extraluminal and an intraluminal source of infection, respectively) are important and that maximally effective prevention programs must address both sources of infection. PMID- 21288846 TI - Rhinocladiella mackenziei as an emerging cause of cerebral phaeohyphomycosis in Pakistan: a case series. AB - Six cases of Rhinocladiella mackenziei cerebral phaeohyphomycosis are being reported for the first time in Pakistan. Identification was confirmed by DNA sequencing (isolates and fixed tissue). Diabetes, head trauma, immunosuppressive treatment, and postpartum state were present in 4 cases. Two survivals and 3 fatalities occurred, with 1 patient lost to follow-up. PMID- 21288844 TI - Bedbugs and infectious diseases. AB - Bedbugs are brown and flat hematophagous insects. The 2 cosmopolite species, Cimex lectularius and Cimex hemipterus, feed on humans and/or domestic animals, and recent outbreaks have been reported in occidental countries. Site assessment for bedbug eradication is complex but can be assured, despite emerging insecticide resistance, by hiring a pest-control manager. The common dermatological presentation of bites is an itchy maculopapular wheal. Urticarial reactions and anaphylaxis can also occur. Bedbugs are suspected of transmitting infectious agents, but no report has yet demonstrated that they are infectious disease vectors. We describe 45 candidate pathogens potentially transmitted by bedbugs, according to their vectorial capacity, in the wild, and vectorial competence, in the laboratory. Because of increasing demands for information about effective control tactics and public health risks of bedbugs, continued research is needed to identify new pathogens in wild Cimex species (spp) and insecticide resistance. PMID- 21288847 TI - A 20-year-old man with fever, headache, and neck stiffness. Neuroborreliosis with tick-borne relapsing fever. PMID- 21288848 TI - Influenza susceptibility, severity, and shedding in HIV-infected adults: a review of the literature. AB - Influenza is a common cause of respiratory illness in adults infected with human immunodeficiency virus (HIV), but current knowledge about seasonal and 2009 H1N1 pandemic influenza A (H1N1pdm) virus infections in HIV-infected persons is limited. In this paper, we review the existing literature regarding influenza susceptibility, severity, and shedding in HIV-infected adults. Data show HIV infection does not significantly increase susceptibility to influenza. AIDS is associated with greater seasonal influenza-related morbidity and mortality, but the risk associated with HIV infection among those with less immune suppression is largely unknown. Immunologic compromise has been shown to increase the magnitude and duration of influenza virus shedding; however, these studies are limited within HIV-infected populations. With regards to H1N1pdm, data are even more limited. Reports raise concern of increased severity among HIV-infected persons, although this may be driven by other comorbid illnesses. Prospective studies are needed among HIV-infected persons to more definitively investigate influenza susceptibility, severity, and shedding. PMID- 21288849 TI - Daptomycin nonsusceptible enterococci: an emerging challenge for clinicians. AB - Daptomycin is the only antibiotic with in vitro bactericidal activity against vancomycin-resistant Enterococcus (VRE) that is approved by the Food and Drug Administration (FDA). Data on the potential emergence of daptomycin nonsusceptibility among enterococci remain limited. We systematically reviewed the published literature for reports of isolates of enterococci that were daptomycin nonsusceptible and assessed the clinical significance and outcome of therapy. Based on susceptibility breakpoints approved by the Clinical Laboratory Standards Institute (CLSI), daptomycin has in vitro activity against >90% of enterococcal isolates. Less than 2% of enterococcal isolates were daptomycin nonsusceptible, with minimum inhibitory concentrations (MICs) >4 MUg/mL. The prevalence of nonsusceptibility of VRE isolates to daptomycin may be overestimated due to the spread of clonally related isolates in health care settings. Clinicians should be aware of the possibility of the emergence of daptomycin nonsusceptibility and should closely monitor daptomycin MICs of enterococci isolated during treatment. PMID- 21288850 TI - Incidence and impact on mortality of severe neurocognitive disorders in persons with and without HIV infection: a Danish nationwide cohort study. AB - OBJECTIVE: The risk of neurocognitive disorders in human immunodeficiency virus (HIV)-infected patients in the era of highly active antiretroviral therapy (HAART) is controversial. We aimed to compare the incidence and impact on mortality of severe neurocognitive disorders (SNCDs) in HIV-infected patients with that of the background population. METHODS: The method used was a nationwide, population-based cohort study using Danish registries. We calculated incidence rates, incidence rate ratios, mortality rate ratios, and Kaplan-Meier tables to estimate the incidence of and survival after SNCD in HIV-infected patients, compared with a general population control cohort matched by age and sex. RESULTS: We observed 32 cases of SNCDs among 4452 HIV-infected patients and 120 cases of SNCDs among 62 328 population control subjects. The overall risk of SNCD among HIV-infected patients was 1.0 case per 1000 person-years (PYR), compared with 0.23 cases per 1000 PYR for population control subjects but became 0.35 cases/1000 PYR after 2004, compared with 0.27 cases/1000 PYR in population control subjects. The absence of HAART and a low CD4 lymphocyte count increased the risk of SNCD. The mortality among HIV-infected patients with SNCD was higher than that among population controls with SNCD (median survival, 4.3 years vs 9.7 years [P = .02]). CONCLUSION: HIV-infected patients have an increased risk of SNCD, but the risk is low and has, in recent years, become comparable to that seen in the background population. In contrast, the mortality remains high among HIV-infected patients diagnosed with SNCD. PMID- 21288851 TI - Impact of antiretroviral therapy on HIV-related brain injury. PMID- 21288852 TI - Humoral response to the influenza A H1N1/09 monovalent AS03-adjuvanted vaccine in immunocompromised patients. AB - BACKGROUND: Few data are available regarding the immunogenicity and safety of the pandemic influenza vaccine in immunocompromised patients. We evaluated the humoral response to the influenza A H1N1/09 vaccine in solid-organ transplant (SOT) recipients, in patients with human immunodeficiency virus (HIV) infection, and in healthy individuals. METHODS: Patients scheduled to receive the pandemic influenza vaccine were invited to participate. All participants received the influenza A H1N1/09 AS03-adjuvanted vaccine containing 3.75 MUg of hemagglutinin. SOT recipients and HIV-infected patients received 2 doses at 3-week intervals, whereas control subjects received 1 dose. Blood samples were taken at day 0, day 21, and day 49 after vaccination. Antibody responses were measured with the hemagglutination inhibition assay (HIA) and a microneutralization assay. RESULTS: Twenty-nine SOT recipients, 30 HIV-infected patients, and 30 healthy individuals were included in the study. Seroconversion measured by HIA was observed in 15 (52%) of 29 SOT recipients both at day 21 and day 49; in 23 (77%) of 30 at day 21 and 26 (87%) of 30 at day 49 in HIV-infected patients, and in 20 (67%) of 30 at day 21 and in 23 (77%) of 30 at day 49 in control subjects (P = .12 at day 21 and P = .009 at day 49, between groups). Geometric means of antibody titers were not significantly different between groups at day 21 or at day 49. CONCLUSIONS: Influenza A H1N1/09 vaccine elicited a similar antibody response in HIV-infected individuals and in control subjects, whereas SOT recipients had an overall lower response. A second dose of the vaccine only moderately improved vaccine immunogenicity in HIV-infected patients. PMID- 21288853 TI - Evaluation of the performance characteristics of 6 rapid HIV antibody tests. AB - BACKGROUND: Since 2002, the US Food and Drug Administration has approved 6 rapid human immunodeficiency virus (HIV) tests for use in the United States. To date, there has been no direct comparison of the performance of all 6 tests. METHODS: Persons known to be HIV-infected and persons who sought HIV testing at 2 clinical sites in Los Angeles, California, were recruited for evaluation of 6 rapid HIV tests with whole blood, oral fluid, serum, and plasma specimens. Sensitivity and specificity of the rapid tests were compared with viral lysate and immunoglobulin (Ig) M-sensitive peptide HIV enzyme immunoassays (EIAs). RESULTS: A total of 6282 specimens were tested. Sensitivity was >95% and specificity was >99% for all rapid tests. Compared with the IgM-sensitive EIA, rapid tests gave false-negative results with an additional 2-5 specimens. All rapid tests had statistically equivalent performance characteristics, based on overlapping confidence intervals for sensitivity and specificity, compared with either conventional EIA. CONCLUSIONS: All 6 rapid tests have high sensitivity and specificity, compared with that of conventional EIAs. Because performance was similar for all tests and specimen types, other characteristics, such as convenience, time to result, shelf life, and cost will likely be determining factors for selection of a rapid HIV screening test for a specific application. PMID- 21288855 TI - Severe hyperferritinemia in Mycobacteria tuberculosis infection. PMID- 21288854 TI - Pooling strategies to reduce the cost of HIV-1 RNA load monitoring in a resource limited setting. AB - BACKGROUND: Quantitative human immunodeficiency virus (HIV) RNA load testing surpasses CD4 cell count and clinical monitoring in detecting antiretroviral therapy (ART) failure; however, its cost can be prohibitive. Recently, the use of pooling strategies with a clinically appropriate viral load threshold was shown to be accurate and efficient for monitoring when the prevalence of virologic failure is low. METHODS: We used laboratory request form information to identify specimens with a low pretest probability of virologic failure. Patients aged >=15 years who were receiving first-line ART had individual viral load results available were eligible. Blood plasma, dried blood spots, and dried plasma spots were evaluated. Two pooling strategies were compared: minipools of 5 samples and a 10 *10 matrix platform (liquid plasma specimens only). A deconvolution algorithm was used to identify specimens(s) with detectable viral loads. RESULTS: The virologic failure rate in the study sample was <10%. Specimens included were liquid plasma specimens tested in minipools(n = 400), of which 300 were available for testing by matrix, and specimens tested with minipools only: dried blood spots (n = 100) and dried plasma spots (n = 185). Pooling methods resulted in 30.5%-60% fewer HIV RNA tests required to screen the study sample. For plasma pooling, the matrix strategy had the better efficiency, but minipools of 5 dried blood spots had the best efficiency overall and were accurate at a >95% negative predictive value with minimal technical requirements. CONCLUSIONS: In resource constrained settings, a combination of preselection of patients with low pretest probability of virologic failure and pooled testing can reduce the cost of virologic monitoring without compromising accuracy. PMID- 21288856 TI - Non-treponemal serologic tests: a supplemental, not confirmatory testing approach. PMID- 21288858 TI - Gram stains and smartphones. PMID- 21288857 TI - Tuberculosis screening in patients starting antiretroviral therapy in sub-Saharan Africa: stretching diagnostics to the limits. PMID- 21288859 TI - Artesunate is ineffective in controlling valganciclovir-resistant cytomegalovirus infection. PMID- 21288860 TI - The EXACT-Pro: measuring exacerbations of COPD. PMID- 21288861 TI - Self-efficacy approaches to improving end-of-life care for the critically ill: ineffective, insufficient, or inconclusive? PMID- 21288862 TI - Tailoring immunosuppressive therapy for lung transplantation: moving beyond hand me-down data. PMID- 21288864 TI - Thinker's sign. PMID- 21288865 TI - An update: the predictive value of QuantiFERON-TB-Gold In-Tube assay and the tuberculin skin test. PMID- 21288866 TI - On early life risk factors for COPD. PMID- 21288868 TI - Palliative care for pulmonary patients. PMID- 21288869 TI - T cell-mediated immune deficiency or compromise in patients with CTEPH. PMID- 21288870 TI - Retraction of four articles and abstracts. PMID- 21288871 TI - Functional relevance of CpG island length for regulation of gene expression. AB - CpG islands mark CpG-enriched regions in otherwise CpG-depleted vertebrate genomes. While the regulatory importance of CpG islands is widely accepted, it is little appreciated that CpG islands vary greatly in lengths. For example, CpG islands in the human genome vary ~30-fold in their lengths. Here we report findings suggesting that the lengths of CpG islands have functional consequences. Specifically, we show that promoters associated with long CpG islands (long-CGI promoters) are distinct from other promoters. First, long-CGI promoters are uniquely associated with genes with an intermediate level of gene expression breadths. Notably, intermediate expression breadths require the most complex mode of gene regulation, from the standpoint of information content. Second, long-CGI promoters encode more RNA polymerase II (Polr2a) binding sites than other promoters. Third, the actual binding patterns of Polr2a occur in a more tissue specific manner in long-CGI promoters compared to other CGI promoters. Moreover, long-CGI promoters contain the largest numbers of experimentally characterized transcription start sites compared to other promoters, and the types of transcription start sites in them are biased toward tissue-specific patterns of gene expression. Finally, long-CGI promoters are preferentially associated with genes involved in development and regulation. Together, these findings indicate that functionally relevant variations of CpG islands exist. By investigating consequences of certain CpG island traits, we can gain additional insights into the mechanism and evolution of regulatory complexity of gene expression. PMID- 21288872 TI - Role of elongator subunit Elp3 in Drosophila melanogaster larval development and immunity. AB - The Elongator complex has been implicated in several cellular processes, including gene expression and tRNA modification. We investigated the biological importance of the Elp3 gene in Drosophila melanogaster. Deletion of Elp3 results in larval lethality at the pupal stage. During early development, larval growth is dramatically impaired, with progression to the third instar delayed for ~24 hr, and pupariation occurring only at day 14 after egg laying. Melanotic nodules appear after 4 days. Microarray analysis shows that stress response genes are induced and ecdysone-induced transcription factors are severely repressed in the mutant. Interestingly, the phenotypes of Elp3 flies are similar to those of flies lacking the domino gene, encoding a SWI/SNF-like ATP-dependent chromatin remodeling enzyme. Indeed, the gene expression profiles of these mutants are also remarkably similar. Together, these data demonstrate that Drosophila Elp3 is essential for viability, normal development, and hematopoiesis and suggest a functional overlap with the chromatin remodeler Domino. PMID- 21288873 TI - Inference of mutation parameters and selective constraint in mammalian coding sequences by approximate Bayesian computation. AB - We develop an inference method that uses approximate Bayesian computation (ABC) to simultaneously estimate mutational parameters and selective constraint on the basis of nucleotide divergence for protein-coding genes between pairs of species. Our simulations explicitly model CpG hypermutability and transition vs. transversion mutational biases along with negative and positive selection operating on synonymous and nonsynonymous sites. We evaluate the method by simulations in which true mean parameter values are known and show that it produces reasonably unbiased parameter estimates as long as sequences are not too short and sequence divergence is not too low. We show that the use of quadratic regression within ABC offers an improvement over linear regression, but that weighted regression has little impact on the efficiency of the procedure. We apply the method to estimate mutational and selective constraint parameters in data sets of protein-coding genes extracted from the genome sequences of primates, murids, and carnivores. Estimates of CpG hypermutability are substantially higher in primates than murids and carnivores. Nonsynonymous site selective constraint is substantially higher in murids and carnivores than primates, and autosomal nonsynonymous constraint is higher than X-chromsome constraint in all taxa. We detect significant selective constraint at synonymous sites in primates, carnivores, and murid rodents. Synonymous site selective constraint is weakest in murids, a surprising result, considering that murid effective population sizes are likely to be considerably higher than the other two taxa. PMID- 21288874 TI - Genetic analysis implicates the Set3/Hos2 histone deacetylase in the deposition and remodeling of nucleosomes containing H2A.Z. AB - Histone variants and histone modification complexes act to regulate the functions of chromatin. In Saccharomyces cerevisiae the histone variant H2A.Z is encoded by HTZ1. Htz1 is dispensable for viability in budding yeast, but htz1Delta is synthetic sick or lethal with the null alleles of about 200 nonessential genes. One of the strongest of these interactions is with the deletion of SET3, which encodes a subunit of the Set3/Hos2 histone deacetylase complex. Little is known about the functions of Set3, and interpreting these genetic interactions remains a highly challenging task. Here we report the results of a forward genetic screen to identify bypass suppressors of the synthetic slow-growth phenotype of htz1Delta set3Delta. Among the identified loss-of-function suppressors are genes encoding subunits of the HDA1 deacetylase complex, the SWR1 complex, the H2B deubiquitination module of SAGA, the proteasome, Set1, and Sir3. This constellation of suppressor genes is uncommon among the global set of htz1Delta synthetic interactions. BDF1, AHC1, RMR1, and CYC8 were identified as high-copy suppressors. We also identified interactions with SLX5 and SLX8, encoding the sumoylation-targeted ubiquitin ligase complex. In the context of htz1Delta set3Delta, suppressors in the SWR1 and the H2B deubiquitination complexes show strong functional similarity, as do suppressors in the silencing genes and the proteasome. Surprisingly, while both htz1Delta set3Delta and swr1Delta set3Delta have severe slow-growth phenotypes, the htz1Delta swr1Delta set3Delta triple mutant grows relatively well. We propose that Set3 has previously unrecognized functions in the dynamic deposition and remodeling of nucleosomes containing H2A.Z. PMID- 21288875 TI - The effects of weak genetic perturbations on the transcriptome of the wing imaginal disc and its association with wing shape in Drosophila melanogaster. AB - A major objective of genomics is to elucidate the mapping between genotypic and phenotypic space as a step toward understanding how small changes in gene function can lead to elaborate phenotypic changes. One approach that has been utilized is to examine overall patterns of covariation between phenotypic variables of interest, such as morphology, physiology, and behavior, and underlying aspects of gene activity, in particular transcript abundance on a genome-wide scale. Numerous studies have demonstrated that such patterns of covariation occur, although these are often between samples with large numbers of unknown genetic differences (different strains or even species) or perturbations of large effect (sexual dimorphism or strong loss-of-function mutations) that may represent physiological changes outside of the normal experiences of the organism. We used weak mutational perturbations in genes affecting wing development in Drosophila melanogaster that influence wing shape relative to a co isogenic wild type. We profiled transcription of 1150 genes expressed during wing development in 27 heterozygous mutants, as well as their co-isogenic wild type and one additional wild-type strain. Despite finding clear evidence of expression differences between mutants and wild type, transcriptional profiles did not covary strongly with shape, suggesting that information from transcriptional profiling may not generally be predictive of final phenotype. We discuss these results in the light of possible attractor states of gene expression and how this would affect interpretation of covariation between transcriptional profiles and other phenotypes. PMID- 21288876 TI - Epistasis increases the rate of conditionally neutral substitution in an adapting population. AB - Kimura observed that the rate of neutral substitution should equal the neutral mutation rate. This classic result is central to our understanding of molecular evolution, and it continues to influence phylogenetics, genomics, and the interpretation of evolution experiments. By demonstrating that neutral mutations substitute at a rate independent of population size and selection at linked sites, Kimura provided an influential justification for the idea of a molecular clock and emphasized the importance of genetic drift in shaping molecular evolution. But when epistasis among sites is common, as numerous empirical studies suggest, do neutral mutations substitute according to Kimura's expectation? Here we study simulated, asexual populations of RNA molecules, and we observe that conditionally neutral mutations--i.e., mutations that do not alter the fitness of the individual in which they arise, but that may alter the fitness effects of subsequent mutations--substitute much more often than expected while a population is adapting. We quantify these effects using a simple population-genetic model that elucidates how the substitution rate at conditionally neutral sites depends on the population size, mutation rate, strength of selection, and prevalence of epistasis. We discuss the implications of these results for our understanding of the molecular clock, and for the interpretation of molecular variation in laboratory and natural populations. PMID- 21288877 TI - A screenable in vivo assay to study proteostasis networks in Caenorhabditis elegans. AB - In eukaryotic cells, the ubiquitin/proteasome system (UPS) is a key determinant of proteostasis as it regulates the turnover of damaged proteins. However, it is still unclear how the UPS integrates intrinsic and environmental challenges to promote organismal development and survival. Here, we set up an in vivo degradation assay to facilitate the genetic identification of ubiquitin-dependent proteolysis pathways in the multicellular organism Caenorhabditis elegans. Using this assay, we found that mild induction of protein-folding stress, which is nontoxic for wild-type worms, strongly reduces ubiquitin-dependent protein turnover. Ubiquitin-mediated degradation is also reduced by metabolic stress, which correlates with life-span extension. Unlike other stress conditions, however, acute heat stress results in enhanced rather than reduced proteolysis. Intriguingly, our study provides the first evidence for the existence of tissue specific degradation requirements because loss of key regulators of the UPS, such as proteasomal subunits, causes accumulation of the model substrate, depending on the tissue type. Thus, here we establish a screenable degradation assay that allows diverse genetic screening approaches for the identification of novel cell type-specific proteostasis networks important for developmental processes, stress response, and aging, thereby substantially extending the work on recently described mechanistic UPS reporter studies. PMID- 21288878 TI - Kick-starting the ratchet: the fate of mutators in an asexual population. AB - Muller's ratchet operates in asexual populations without intergenomic recombination. In this case, deleterious mutations will accumulate and population fitness will decline over time, possibly endangering the survival of the species. Mutator mutations, i.e., mutations that lead to an increased mutation rate, will play a special role for the behavior of the ratchet. First, they are part of the ratchet and can come to dominance through accumulation in the ratchet. Second, the fitness-loss rate of the ratchet is very sensitive to changes in the mutation rate and even a modest increase can easily set the ratchet in motion. In this article we simulate the interplay between fitness loss from Muller's ratchet and the evolution of the mutation rate from the fixation of mutator mutations. As long as the mutation rate is increased in sufficiently small steps, an accelerating ratchet and eventual extinction are inevitable. If this can be countered by antimutators, i.e., mutations that reduce the mutation rate, an equilibrium can be established for the mutation rate at some level that may allow survival. However, the presence of the ratchet amplifies fluctuations in the mutation rate and, even at equilibrium, these fluctuations can lead to dangerous bursts in the ratchet. We investigate the timescales of these processes and discuss the results with reference to the genome degradation of the aphid endosymbiont Buchnera aphidicola. PMID- 21288879 TI - Comprehensive computational design of mCreI homing endonuclease cleavage specificity for genome engineering. AB - Homing endonucleases (HEs) cleave long (~ 20 bp) DNA target sites with high site specificity to catalyze the lateral transfer of parasitic DNA elements. In order to determine whether comprehensive computational design could be used as a general strategy to engineer new HE target site specificities, we used RosettaDesign (RD) to generate 3200 different variants of the mCreI LAGLIDADG HE towards 16 different base pair positions in the 22 bp mCreI target site. Experimental verification of a range of these designs demonstrated that over 2/3 (24 of 35 designs, 69%) had the intended new site specificity, and that 14 of the 15 attempted specificity shifts (93%) were achieved. These results demonstrate the feasibility of using structure-based computational design to engineer HE variants with novel target site specificities to facilitate genome engineering. PMID- 21288880 TI - Quantitative analysis of condensation/decondensation status of pDNA in the nuclear sub-domains by QD-FRET. AB - Recent studies indicate that controlling the nuclear decondensation and intra nuclear localization of plasmid DNA (pDNA) would result in an increased transfection efficiency. In the present study, we established a technology for imaging the nuclear condensation/decondensation status of pDNA in nuclear subdomains using fluorescence resonance energy transfer (FRET) between quantum dot (QD)-labeled pDNA as donor, and rhodamine-labeled polycations as acceptor. The FRET-occurring pDNA/polycation particle was encapsulated in a nuclear delivery system; a tetra-lamellar multifunctional envelope-type nano device (T MEND), designed to overcome the endosomal membrane and nuclear membrane via step wise fusion. Nuclear subdomains (i.e. heterochromatin and euchromatin) were distinguished by Hoechst33342 staining. Thereafter, Z-series of confocal images were captured by confocal laser scanning microscopy. pDNA in condensation/decondensation status in heterochromatin or euchromatin were quantified based on the pixel area of the signals derived from the QD and rhodamine. The results obtained indicate that modulation of the supra-molecular structure of polyrotaxane (DMAE-ss-PRX), a condenser that is cleaved in a reductive environment, conferred euchromatin-preferred decondensation. This represents the first demonstration of the successful control of condensation/decondensation in specific nuclear sub-domain via the use of an artificial DNA condenser. PMID- 21288881 TI - Uracils at nucleotide position 9-11 are required for the rapid turnover of miR-29 family. AB - MicroRNAs are endogenous small RNA molecules that regulate gene expression. Although the biogenesis of microRNAs and their regulation have been thoroughly elucidated, the degradation of microRNAs has not been fully understood. Here by using the pulse-chase approach, we performed the direct measurement of microRNA lifespan. Five representative microRNAs demonstrated a general feature of relatively long lifespan. However, the decay dynamic varies considerably between these individual microRNAs. Mutation analysis of miR-29b sequence revealed that uracils at nucleotide position 9-11 are required for its rapid decay, in that both specific nucleotides and their position are critical. The effect of uracil rich element on miR-29b decay dynamic occurs in duplex but not in single strand RNA. Moreover, analysis of published data on microRNA expression profile during development reveals that a substantial subset of microRNAs with the uracil-rich sequence tends to be down-regulated compared to those without the sequence. Among them, Northern blotting shows that miR-29c and fruit fly bantam possess a relatively rapid turnover rate. The effect of uracil-rich sequence on microRNA turnover depends on the sequence context. The present work indicates that microRNAs contain sequence information in the middle region besides the sequence element at both ends. PMID- 21288882 TI - VCre/VloxP and SCre/SloxP: new site-specific recombination systems for genome engineering. AB - We developed two new site-specific recombination systems named VCre/VloxP and SCre/SloxP for genome engineering. Their recognition sites are different from Cre recognition sites because VCre and SCre recombinases share less protein similarity with Cre, even though the basic 13-8-13 structures of their recognition sites are identical. Mutant VloxP and SloxP, which have the same uses as mutant loxP, were also developed. VCre/VloxP and SCre/SloxP in combination with Cre/loxP and Flp/FRT systems can serve as powerful tools for genome engineering, especially when used to genetically modify both alleles of a single gene in mouse and human cells. PMID- 21288883 TI - AG-dependent 3'-splice sites are predisposed to aberrant splicing due to a mutation at the first nucleotide of an exon. AB - In pre-mRNA splicing, a conserved AG/G at the 3'-splice site is recognized by U2AF(35). A disease-causing mutation abrogating the G nucleotide at the first position of an exon (E(+1)) causes exon skipping in GH1, FECH and EYA1, but not in LPL or HEXA. Knockdown of U2AF(35) enhanced exon skipping in GH1 and FECH. RNA EMSA revealed that wild-type FECH requires U2AF(35) but wild-type LPL does not. A series of artificial mutations in the polypyrimidine tracts of GH1, FECH, EYA1, LPL and HEXA disclosed that a stretch of at least 10-15 pyrimidines is required to ensure normal splicing in the presence of a mutation at E(+1). Analysis of nine other disease-causing mutations at E(+1) detected five splicing mutations. Our studies suggest that a mutation at the AG-dependent 3'-splice site that requires U2AF(35) for spliceosome assembly causes exon skipping, whereas one at the AG-independent 3'-splice site that does not require U2AF(35) gives rise to normal splicing. The AG-dependence of the 3'-splice site that we analyzed in disease-causing mutations at E(+1) potentially helps identify yet unrecognized splicing mutations at E(+1). PMID- 21288884 TI - Hmo1 directs pre-initiation complex assembly to an appropriate site on its target gene promoters by masking a nucleosome-free region. AB - Saccharomyces cerevisiae Hmo1 binds to the promoters of ~ 70% of ribosomal protein genes (RPGs) at high occupancy, but is observed at lower occupancy on the remaining RPG promoters. In Deltahmo1 cells, the transcription start site (TSS) of the Hmo1-enriched RPS5 promoter shifted upstream, while the TSS of the Hmo1 limited RPL10 promoter did not shift. Analyses of chimeric RPS5/RPL10 promoters revealed a region between the RPS5 upstream activating sequence (UAS) and core promoter, termed the intervening region (IVR), responsible for strong Hmo1 binding and an upstream TSS shift in Deltahmo1 cells. Chromatin immunoprecipitation analyses showed that the RPS5-IVR resides within a nucleosome free region and that pre-initiation complex (PIC) assembly occurs at a site between the IVR and a nucleosome overlapping the TSS (+1 nucleosome). The PIC assembly site was shifted upstream in Deltahmo1 cells on this promoter, indicating that Hmo1 normally masks the RPS5-IVR to prevent PIC assembly at inappropriate site(s). This novel mechanism ensures accurate transcriptional initiation by delineating the 5'- and 3'-boundaries of the PIC assembly zone. PMID- 21288885 TI - Two forms of ribosomal protein L2 of Escherichia coli that inhibit DnaA in DNA replication. AB - We purified an inhibitor of oriC plasmid replication and determined that it is a truncated form of ribosomal protein L2 evidently lacking 59 amino acid residues from the C-terminal region encoded by rplB. We show that this truncated form of L2 or mature L2 physically interacts with the N-terminal region of DnaA to inhibit initiation from oriC by apparently interfering with DnaA oligomer formation, and the subsequent assembly of the prepriming complex on an oriC plasmid. Both forms of L2 also inhibit the unwinding of oriC by DnaA. These in vitro results raise the possibility that one or both forms of L2 modulate DnaA function in vivo to regulate the frequency of initiation. PMID- 21288886 TI - A low molecular weight protein tyrosine phosphatase from Synechocystis sp. strain PCC 6803: enzymatic characterization and identification of its potential substrates. AB - The predicted protein product of open reading frame slr0328 from Synechocystis sp. PCC 6803, SynPTP, possesses significant amino acid sequence similarity with known low molecular weight protein tyrosine phosphatases (PTPs). To determine the functional properties of this hypothetical protein, open reading frame slr0328 was expressed in Escherichia coli. The purified recombinant protein, SynPTP, displayed its catalytic phosphatase activity towards several tyrosine, but not serine, phosphorylated exogenous protein substrates. The protein phosphatase activity of SynPTP was inhibited by sodium orthovanadate, a known inhibitor of tyrosine phosphatases, but not by okadaic acid, an inhibitor for many serine/threonine phosphatases. Kinetic analysis indicated that the K(m) and V(max) values for SynPTP towards p-nitrophenyl phosphate are similar to those of other known bacterial low molecular weight PTPs. Mutagenic alteration of the predicted catalytic cysteine of PTP, Cys(7), to serine abolished enzyme activity. Using a combination of immunodetection, mass spectrometric analysis and mutagenically altered Cys(7)SerAsp(125)Ala-SynPTP, we identified PsaD (photosystem I subunit II), CpcD (phycocyanin rod linker protein) and phycocyanin alpha and -beta subunits as possible endogenous substrates of SynPTP in this cyanobacterium. These results indicate that SynPTP might be involved in the regulation of photosynthesis in Synechocystis sp. PCC 6803. PMID- 21288887 TI - TGF-beta1-induced PI3K/Akt/NF-kappaB/MMP9 signalling pathway is activated in Philadelphia chromosome-positive chronic myeloid leukaemia hemangioblasts. AB - Overwhelming evidence from chronic myeloid leukaemia (CML) research indicates that patients harbour quiescent CML stem cells that are responsible for blast crisis. While the haematopoietic stem cell (HSC) origin of CML was first suggested over 30 years ago, recently CML-initiating cells beyond HSCs are also being investigated. We have previously isolated fetal liver kinase-1-positive (Flk1(+)) cells carrying the BCR/ABL fusion gene from the bone marrow of Philadelphia chromosome-positive (Ph(+)) patients with hemangioblast property. Here, we show that these cells behave abnormally comparing with the hemangioblasts in healthy donors. These Ph(+) putative CML hemangioblast up regulated TGF-beta1 and result in activating matrix metalloproteinase-9 to enhance s-KitL and s-ICAM-1 secretion. Further studies showed that phosphatidylinositol-3 kinase (PI3K)/Akt/nuclear factor-kappaB signalling pathway was involved in CML pathogenesis. These findings provide direct evidence for the first time that hemangioblasts beyond HSCs play a critical role in the progression of CML. PMID- 21288888 TI - Cleavage-site specificity of prolyl endopeptidase FAP investigated with a full length protein substrate. AB - Fibroblast activation protein (FAP) is a prolyl-cleaving endopeptidase proposed as an anti-cancer drug target. It is necessary to define its cleavage-site specificity to facilitate the identification of its in vivo substrates and to understand its biological functions. We found that the previously identified substrate of FAP, alpha(2)-anti-plasmin, is not a robust substrate in vitro. Instead, an intracellular protein, SPRY2, is cleavable by FAP and more suitable for investigation of its substrate specificity in the context of the full-length globular protein. FAP prefers uncharged residues, including small or bulky hydrophobic amino acids, but not charged amino acids, especially acidic residue at P1', P3 and P4 sites. Molecular modelling analysis shows that the substrate binding site of FAP is surrounded by multiple tyrosine residues and some negatively charged residues, which may exert least preference for substrates with acidic residues. This provides an explanation why FAP cannot cleave interleukins, which have a glutamate at either P4 or P2', despite their P3-P2-P1 sites being identical to SPRY2 or alpha-AP. Our study provided new information on FAP cleavage-site specificity, which differs from the data obtained by profiling with a peptide library or with the denatured protein, gelatin, as the substrate. Furthermore, our study suggests that negatively charged residues should be avoided when designing FAP inhibitors. PMID- 21288889 TI - Familial history of stroke is associated with acute coronary syndromes in women. AB - BACKGROUND: Stroke in female first-degree relatives (FDRs) is a powerful risk factor for ischemic stroke in women, but its association with acute coronary syndromes (ACS) is unknown. Family history (FH) of stroke is omitted from existing myocardial infarction risk prediction tools, which perform less well in women than in men. Our objective was to study the sex-of-parent and sex-of proband interactions for FH of stroke in ACS patients. METHODS AND RESULTS: In a prospective, population-based study (Oxford Vascular Study) of all patients with ACS or stroke/transient ischemic attack, FH data for stroke and myocardial infarction were analyzed by sex of proband and FDRs, and coronary angiograms were reviewed, where available; 942 of 1058 ACS probands and 1015 of 1152 stroke/transient ischemic attack probands had complete FH data; 24.1% of ACS probands and 24.3% of stroke/transient ischemic attack probands had history of stroke in >=1 FDR. Maternal stroke was more common than paternal stroke in female ACS probands (odds ration [OR], 2.53; 1.39 to 4.61) but not in male probands (OR, 0.92; 0.64 to 1.32) (difference-P=0.004). Overall, female ACS probands were more likely to have female than male FDRs with stroke (OR, 2.09; 1.29 to 3.37), whereas the opposite trend was seen in male ACS probands (OR, 0.69; 0.50 to 0.97) (difference-P=0.0002). However, there was no association between parental history of stroke and disease localization or presence of multivessel disease on coronary angiography. CONCLUSIONS: FH of stroke is as common in ACS patients as in stroke/transient ischemic attack patients and sex-of-parent/sex-of-proband interactions are similar. Stroke in female FDRs may help to identify women at increased risk of ACS as well as ischemic stroke. PMID- 21288891 TI - Characterization of complementary chromatic adaptation in Gloeotrichia UTEX 583 and identification of a transposon-like insertion in the cpeBA operon. AB - Many cyanobacteria are able to alter the pigment composition of the phycobilisome in a process called complementary chromatic adaptation (CCA). The regulatory mechanisms of CCA have been identified in Fremyella diplosiphon, which regulates both phycoerythrin and phycocyanin levels, and Nostoc punctiforme, which regulates only phycoerythrin production. Recent studies show that these species use different regulatory proteins for CCA. We chose to study the CCA response of Gloeotrichia UTEX 583 in an effort to expand our knowledge about CCA and its regulation. We found that Gloeotrichia 583 has a CCA pigment response more similar to that of N. punctiforme rather than F. diplosiphon and exhibits none of the CCA-regulated morphological responses seen in F. diplosiphon. Preliminary experiments suggest that Gloeotrichia 583 contains a homolog to the CCA photoreceptor from N. punctiforme but not the CCA photoreceptor from F. diplosiphon. Additionally, two spontaneous mutants lacking phycoerythrin production were identified. Analysis has shown that these mutants contain a transposon-like insertion in the cpeA gene, which encodes the alpha subunit of phycoerythrin. These results suggest that CCA in Gloeotrichia UTEX 583 is more similar to that of N. punctiforme than it is to F. diplosiphon, a closely related species. PMID- 21288892 TI - Structures of human Golgi-resident glutaminyl cyclase and its complexes with inhibitors reveal a large loop movement upon inhibitor binding. AB - Aberrant pyroglutamate formation at the N terminus of certain peptides and proteins, catalyzed by glutaminyl cyclases (QCs), is linked to some pathological conditions, such as Alzheimer disease. Recently, a glutaminyl cyclase (QC) inhibitor, PBD150, was shown to be able to reduce the deposition of pyroglutamate modified amyloid-beta peptides in brain of transgenic mouse models of Alzheimer disease, leading to a significant improvement of learning and memory in those transgenic animals. Here, we report the 1.05-1.40 A resolution structures, solved by the sulfur single-wavelength anomalous dispersion phasing method, of the Golgi luminal catalytic domain of the recently identified Golgi-resident QC (gQC) and its complex with PBD150. We also describe the high-resolution structures of secretory QC (sQC)-PBD150 complex and two other gQC-inhibitor complexes. gQC structure has a scaffold similar to that of sQC but with a relatively wider and negatively charged active site, suggesting a distinct substrate specificity from sQC. Upon binding to PBD150, a large loop movement in gQC allows the inhibitor to be tightly held in its active site primarily by hydrophobic interactions. Further comparisons of the inhibitor-bound structures revealed distinct interactions of the inhibitors with gQC and sQC, which are consistent with the results from our inhibitor assays reported here. Because gQC and sQC may play different biological roles in vivo, the different inhibitor binding modes allow the design of specific inhibitors toward gQC and sQC. PMID- 21288893 TI - The structure of the plakin domain of plectin reveals a non-canonical SH3 domain interacting with its fourth spectrin repeat. AB - Plectin belongs to the plakin family of cytoskeletal crosslinkers, which is part of the spectrin superfamily. Plakins contain an N-terminal conserved region, the plakin domain, which is formed by an array of spectrin repeats (SR) and a Src homology 3 (SH3), and harbors binding sites for junctional proteins. We have combined x-ray crystallography and small angle x-ray scattering (SAXS) to elucidate the structure of the central region of the plakin domain of plectin, which corresponds to the SR3, SR4, SR5, and SH3 domains. The crystal structures of the SR3-SR4 and SR4-SR5-SH3 fragments were determined to 2.2 and 2.95 A resolution, respectively. The SH3 of plectin presents major alterations as compared with canonical Pro-rich binding SH3 domains, suggesting that plectin does not recognize Pro-rich motifs. In addition, the SH3 binding site is partially occluded by an intramolecular contact with the SR4. Residues of this pseudo-binding site and the SR4/SH3 interface are conserved within the plakin family, suggesting that the structure of this part of the plectin molecule is similar to that of other plakins. We have created a model for the SR3-SR4-SR5-SH3 region, which agrees well with SAXS data in solution. The three SRs form a semi flexible rod that is not altered by the presence of the SH3 domain, and it is similar to those found in spectrins. The flexibility of the plakin domain, in analogy with spectrins, might contribute to the role of plakins in maintaining the stability of tissues subject to mechanical stress. PMID- 21288894 TI - PDE4D and PDE4B function in distinct subcellular compartments in mouse embryonic fibroblasts. AB - Signaling through cAMP regulates most cellular functions. The spatiotemporal control of cAMP is, therefore, crucial for differential regulation of specific cellular targets. Here we investigated the consequences of PDE4B or PDE4D gene ablation on cAMP signaling at a subcellular level using mouse embryonic fibroblasts. PDE4B ablation had no effect on the global or bulk cytosol accumulation of cAMP but increased both basal and hormone-dependent cAMP in a near-membrane pool. Conversely, PDE4D ablation enhanced agonist-induced cAMP accumulation in the bulk cytosol as well as at the plasma membrane. Both PDE4B and PDE4D ablation significantly modified the time course and the level of isoproterenol-induced phosphorylation of vasodilator-stimulated phosphoprotein, a membrane cytoskeletal component. A second membrane response through Toll-like receptor signaling, however, was only affected by PDE4B ablation. PDE4D but not PDE4B ablation significantly prolonged cAMP-response element-binding protein mediated transcription. These findings demonstrate that PDE4D and PDE4B have specialized functions in mouse embryonic fibroblasts with PDE4B controlling cAMP in a discrete subdomain near the plasma membrane. PMID- 21288895 TI - Structure of a Ca2+-myristoyl switch protein that controls activation of a phosphatidylinositol 4-kinase in fission yeast. AB - Neuronal calcium sensor (NCS) proteins transduce Ca2+ signals and are highly conserved from yeast to humans. We determined NMR structures of the NCS-1 homolog from fission yeast (Ncs1), which activates a phosphatidylinositol 4-kinase. Ncs1 contains an alpha-NH2-linked myristoyl group on a long N-terminal arm and four EF hand motifs, three of which bind Ca2+, assembled into a compact structure. In Ca2+-free Ncs1, the N-terminal arm positions the fatty acyl chain inside a cavity near the C terminus. The C14 end of the myristate is surrounded by residues in the protein core, whereas its amide-linked (C1) end is flanked by residues at the protein surface. In Ca2+-bound Ncs1, the myristoyl group is extruded (Ca2+ myristoyl switch), exposing a prominent patch of hydrophobic residues that specifically contact phosphatidylinositol 4-kinase. The location of the buried myristate and structure of Ca2+-free Ncs1 are quite different from those in other NCS proteins. Thus, a unique remodeling of each NCS protein by its myristoyl group, and Ca2+-dependent unmasking of different residues, may explain how each family member recognizes distinct target proteins. PMID- 21288896 TI - Modulatory ATP binding affinity in intermediate states of E2P dephosphorylation of sarcoplasmic reticulum Ca2+-ATPase. AB - The mechanism of ATP modulation of E2P dephosphorylation of sarcoplasmic reticulum Ca(2+)-ATPase wild type and mutant forms was examined in nucleotide binding studies of states analogous to the various intermediates of the dephosphorylation reaction, obtained by binding of metal fluorides, vanadate, or thapsigargin. Wild type Ca(2+)-ATPase displays an ATP affinity of 4 MUM for the E2P ground state analog, 1 MUM for the E2P transition state and product state analogs, and 11 MUM for the E2 dephosphoenzyme. Hence, ATP binding stabilizes the transition and product states relative to the ground state, thereby explaining the accelerating effect of ATP on dephosphorylation. Replacement of Phe(487) (N domain) with serine, Arg(560) (N-domain) with leucine, or Arg(174) (A-domain) with alanine or glutamate reduces ATP affinity in all E2/E2P intermediate states. Alanine substitution of Ile(188) (A-domain) increases the ATP affinity, although ATP acceleration of dephosphorylation is disrupted, thus indicating that the critical role of Ile(188) in ATP modulation is mechanistically based rather than being associated with the binding of nucleotide. Mutants with alanine replacement of Lys(205) (A-domain) or Glu(439) (N-domain) exhibit an anomalous inhibition by ATP of E2P dephosphorylation, due to ATP binding increasing the stability of the E2P ground state relative to the transition state. The ATP affinity of Ca(2)E2P, stabilized by inserting four glycines in the A-M1 linker, is similar to that of the E2P ground state, but the Ca(2+)-free E1 state of this mutant exhibits 3 orders of magnitude reduction of ATP affinity. PMID- 21288897 TI - Spectral tuning in sensory rhodopsin I from Salinibacter ruber. AB - Organisms utilize light as energy sources and as signals. Rhodopsins, which have seven transmembrane alpha-helices with retinal covalently linked to a conserved Lys residue, are found in various organisms as distant in evolution as bacteria, archaea, and eukarya. One of the most notable properties of rhodopsin molecules is the large variation in their absorption spectrum. Sensory rhodopsin I (SRI) and sensory rhodopsin II (SRII) function as photosensors and have similar properties (retinal composition, photocycle, structure, and function) except for their lambda(max) (SRI, ~560 nm; SRII, ~500 nm). An expression system utilizing Escherichia coli and the high protein stability of a newly found SRI-like protein, SrSRI, enables studies of mutant proteins. To determine the residue contributing to the spectral shift from SRI to SRII, we constructed various SRI mutants, in which individual residues were substituted with the corresponding residues of SRII. Three such mutants of SrSRI showed a large spectral blue-shift (>14 nm) without a large alteration of their retinal composition. Two of them, A136Y and A200T, are newly discovered color tuning residues. In the triple mutant, the lambda(max) was 525 nm. The inverse mutation of SRII (F134H/Y139A/T204A) generated a spectral-shifted SRII toward longer wavelengths, although the effect is smaller than in the case of SRI, which is probably due to the lack of anion binding in the SRII mutant. Thus, half of the spectral shift from SRI to SRII could be explained by only those three residues taking into account the effect of Cl(-) binding. PMID- 21288898 TI - Pancreatic cancer cells respond to type I collagen by inducing snail expression to promote membrane type 1 matrix metalloproteinase-dependent collagen invasion. AB - Pancreatic ductal adenocarcinoma (PDAC) is characterized by pronounced fibrotic reaction composed primarily of type I collagen. Although type I collagen functions as a barrier to invasion, pancreatic cancer cells have been shown to respond to type I collagen by becoming more motile and invasive. Because epithelial-mesenchymal transition is also associated with cancer invasion, we examined the extent to which collagen modulated the expression of Snail, a well known regulator of epithelial-mesenchymal transition. Relative to cells grown on tissue culture plastic, PDAC cells grown in three-dimensional collagen gels induced Snail. Inhibiting the activity or expression of the TGF-beta type I receptor abrogated collagen-induced Snail. Downstream of the receptor, we showed that Smad3 and Smad4 were critical for the induction of Snail by collagen. In contrast, Smad2 or ERK1/2 was not involved in collagen-mediated Snail expression. Overexpression of Snail in PDAC cells resulted in a robust membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14)-dependent invasion through collagen-coated transwell chambers. Snail-expressing PDAC cells also demonstrated MT1-MMP dependent scattering in three-dimensional collagen gels. Mechanistically, Snail increased the expression of MT1-MMP through activation of ERK-MAPK signaling, and inhibiting ERK signaling in Snail-expressing cells blocked two-dimensional collagen invasion and attenuated scattering in three-dimensional collagen. To provide in vivo support for our findings that Snail can regulate MT1-MMP, we examined the expression of Snail and MT1-MMP in human PDAC tumors and found a statistically significant positive correlation between MT1-MMP and Snail in these tumors. Overall, our data demonstrate that pancreatic cancer cells increase Snail on encountering collagen-rich milieu and suggest that the desmoplastic reaction actively contributes to PDAC progression. PMID- 21288899 TI - Crystal structure of a viral protease intramolecular acyl-enzyme complex: insights into cis-cleavage at the VP4/VP3 junction of Tellina birnavirus. AB - Viruses of the Birnaviridae family are characterized by their bisegmented double stranded RNA genome that resides within a single-shelled non-enveloped icosahedral particle. They infect birds, aquatic organisms, and insects. Tellina virus 1 (TV-1) is an Aquabirnavirus isolated from the mollusk Tellina tenuis. It encodes a polyprotein (NH2-pVP2-X-VP4-VP3-COOH) that is cleaved by the self encoded protease VP4 to yield capsid precursor protein pVP2, peptide X, and ribonucleoprotein VP3. Here we report the crystal structure of an intramolecular (cis) acyl-enzyme complex of TV-1 VP4 at 2.1-A resolution. The structure reveals how the enzyme can recognize its own carboxyl terminus during the VP4/VP3 cleavage event. The methyl side chains of Ala830(P1) and Ala828(P3) at the VP4/VP3 junction point into complementary shallow and hydrophobic S1 and S3 binding pockets adjacent to the VP4 catalytic residues: nucleophile Ser738 and general base Lys777. The electron density clearly shows that the carbonyl carbon of Ala830 is covalently attached via an ester bond to the Ogamma of Ser738. A highly ordered water molecule in the active site is coordinated in the proper position to act as the deacylating water. A comparative analysis of this intramolecular (cis) acyl-enzyme structure with the previously solved intermolecular (trans) acyl-enzyme structure of infectious pancreatic necrosis virus VP4 explains the narrower specificity observed in the cleavage sites of TV 1 VP4. PMID- 21288900 TI - Ectodomain shedding and autocleavage of the cardiac membrane protease corin. AB - Corin is a cardiac membrane protease that activates natriuretic peptides. It is unknown how corin function is regulated. Recently, soluble corin was detected in human plasma, suggesting that corin may be shed from cardiomyocytes. Here we examined soluble corin production and activity and determined the proteolytic enzymes responsible for corin cleavage. We expressed human corin in HEK 293 cells and detected three soluble fragments of ~180, ~160, and ~100 kDa, respectively, in the cultured medium by Western blot analysis. All three fragments were derived from activated corin molecules. Similar results were obtained in HL-1 cardiomyocytes. Using protease inhibitors, ionomycin and phorbol myristate acetate stimulation, small interfering RNA knockdown, and site-directed mutagenesis, we found that ADAM10 was primarily responsible for shedding corin in its juxtamembrane region to release the ~180-kDa fragment, corresponding to the near-entire extracellular region. In contrast, the ~160- and ~100-kDa fragments were from corin autocleavage at Arg-164 in frizzled 1 domain and Arg-427 in LDL receptor 5 domain, respectively. In functional studies, the ~180-kDa fragment activated atrial natriuretic peptide, whereas the ~160- and ~100-kDa fragments did not. Our data indicate that ADAM-mediated shedding and corin autocleavage are important mechanisms regulating corin function and preventing excessive, potentially hazardous, proteolytic activities in the heart. PMID- 21288901 TI - An infant-associated bacterial commensal utilizes breast milk sialyloligosaccharides. AB - Lactating mothers secrete milk sialyloligosaccharides (MSOs) that function as anti-adhesives once provided to the neonate. Particular infant-associated commensals, such as Bifidobacterium longum subsp. infantis, consume neutral milk oligosaccharides, although their ability to utilize acidic oligosaccharides has not been assessed. Temporal glycoprofiling of acidic HMO consumed during fermentation demonstrated a single composition, with several isomers, corresponding to sialylated lacto-N-tetraose. To utilize MSO, B. longum subsp. infantis deploys a sialidase that cleaves alpha2-6 and alpha2-3 linkages. NanH2, encoded within the HMO catabolic cluster is up-regulated during HMO fermentation and is active on sialylated lacto-N-tetraose. These results demonstrate that commensal microorganisms do utilize MSO, a substrate that may be enriched in the distal gastrointestinal tract. PMID- 21288902 TI - Galectin-8-N-domain recognition mechanism for sialylated and sulfated glycans. AB - Galectin-8 has much higher affinity for 3'-O-sulfated or 3'-O-sialylated glycoconjugates and a Lewis X-containing glycan than for oligosaccharides terminating in Galbeta1->3/4GlcNAc, and this specificity is mainly attributed to the N-terminal carbohydrate recognition domain (N-domain, CRD) (Ideo, H., Seko, A., Ishizuka, I., and Yamashita, K. (2003) Glycobiology 13, 713-723). In this study, we elucidated the crystal structures of the human galectin-8-N-domain ( 8N) in the absence or presence of 4 ligands. The apo molecule forms a dimer, which is different from the canonical 2-fold symmetric dimer observed for galectin-1 and -2. In a galectin-8N-lactose complex, the lactose-recognizing amino acids are highly conserved among the galectins. However, Arg(45), Gln(47), Arg(59), and the long loop region between the S3 and S4 beta-strands are unique to galectin-8N. These amino acids directly or indirectly interact with the sulfate or sialic acid moieties of 3'-sialyl- and 3'-sulfolactose complexed with galectin-8N. Furthermore, in the LNF-III-galectin-8N complex, van der Waals interactions occur between the alpha1-3-branched fucose and galactose and between galactose and Tyr(141), and these interactions increase the affinity toward galectin-8N. Based on the findings of these x-ray crystallographic analyses, a mutagenesis study using surface plasmon resonance showed that Arg(45), Gln(47), and Arg(59) of galectin-8N are indispensable and coordinately contribute to the strong binding of galectins-8N to sialylated and sulfated oligosaccharides. Arg(59) is the most critical amino acid for binding in the S3-S4 loop region. PMID- 21288903 TI - Substrate and metal ion promiscuity in mannosylglycerate synthase. AB - The enzymatic transfer of the sugar mannose from activated sugar donors is central to the synthesis of a wide range of biologically significant polysaccharides and glycoconjugates. In addition to their importance in cellular biology, mannosyltransferases also provide model systems with which to study catalytic mechanisms of glycosyl transfer. Mannosylglycerate synthase (MGS) catalyzes the synthesis of alpha-mannosyl-D-glycerate using GDP-mannose as the preferred donor species, a reaction that occurs with a net retention of anomeric configuration. Past work has shown that the Rhodothermus marinus MGS, classified as a GT78 glycosyltransferase, displays a GT-A fold and performs catalysis in a metal ion-dependent manner. MGS shows very unusual metal ion dependences with Mg(2+) and Ca(2+) and, to a lesser extent, Mn(2+), Ni(2+), and Co(2+), thus facilitating catalysis. Here, we probe these dependences through kinetic and calorimetric analyses of wild-type and site-directed variants of the enzyme. Mutation of residues that interact with the guanine base of GDP are correlated with a higher k(cat) value, whereas substitution of His-217, a key component of the metal coordination site, results in a change in metal specificity to Mn(2+). Structural analyses of MGS complexes not only provide insight into metal coordination but also how lactate can function as an alternative acceptor to glycerate. These studies highlight the role of flexible loops in the active center and the subsequent coordination of the divalent metal ion as key factors in MGS catalysis and metal ion dependence. Furthermore, Tyr-220, located on a flexible loop whose conformation is likely influenced by metal binding, also plays a critical role in substrate binding. PMID- 21288904 TI - Molecular basis of 1,6-anhydro bond cleavage and phosphoryl transfer by Pseudomonas aeruginosa 1,6-anhydro-N-acetylmuramic acid kinase. AB - Anhydro-N-acetylmuramic acid kinase (AnmK) catalyzes the ATP-dependent conversion of the Gram-negative peptidoglycan (PG) recycling intermediate 1,6-anhydro-N acetylmuramic acid (anhMurNAc) to N-acetylmuramic acid-6-phosphate (MurNAc-6-P). Here we present crystal structures of Pseudomonas aeruginosa AnmK in complex with its natural substrate, anhMurNAc, and a product of the reaction, ADP. AnmK is homodimeric, with each subunit comprised of two subdomains that are separated by a deep active site cleft, which bears similarity to the ATPase core of proteins belonging to the hexokinase-hsp70-actin superfamily of proteins. The conversion of anhMurNAc to MurNAc-6-P involves both cleavage of the 1,6-anhydro ring of anhMurNAc along with addition of a phosphoryl group to O6 of the sugar, and thus represents an unusual enzymatic mechanism involving the formal addition of H3PO4 to anhMurNAc. The structural complexes and NMR analysis of the reaction suggest that a water molecule, activated by Asp-182, attacks the anomeric carbon of anhMurNAc, aiding cleavage of the 1,6-anhydro bond and facilitating the capture of the gamma phosphate of ATP by O6 via an in-line phosphoryl transfer. AnmK is active only against anhMurNAc and not the metabolically related 1,6-anhydro-N acetylmuramyl peptides, suggesting that the cytosolic N-acetyl-anhydromuramyl-l alanine amidase AmpD must first remove the stem peptide from these PG muropeptide catabolites before anhMurNAc can be acted upon by AnmK. Our studies provide the foundation for a mechanistic model for the dual activities of AnmK as a hydrolase and a kinase of an unusual heterocyclic monosaccharide. PMID- 21288905 TI - CTCF promotes muscle differentiation by modulating the activity of myogenic regulatory factors. AB - CTCF nuclear factor regulates many aspects of gene expression, largely as a transcriptional repressor or via insulator function. Its roles in cellular differentiation are not clear. Here we show an unexpected role for CTCF in myogenesis. Ctcf is expressed in myogenic structures during mouse and zebrafish development. Gain- and loss-of-function approaches in C2C12 cells revealed CTCF as a modulator of myogenesis by regulating muscle-specific gene expression. We addressed the functional connection between CTCF and myogenic regulatory factors (MRFs). CTCF enhances the myogenic potential of MyoD and myogenin and establishes direct interactions with MyoD, indicating that CTCF regulates MRF-mediated muscle differentiation. Indeed, CTCF modulates functional interactions between MyoD and myogenin in co-activation of muscle-specific gene expression and facilitates MyoD recruitment to a muscle-specific promoter. Finally, ctcf loss-of-function experiments in zebrafish embryos revealed a critical role of CTCF in myogenic development and linked CTCF to broader aspects of development via regulation of Wnt signaling. We conclude that CTCF modulates MRF functional interactions in the orchestration of myogenesis. PMID- 21288906 TI - Allele-specific effects of thoracic aortic aneurysm and dissection alpha-smooth muscle actin mutations on actin function. AB - Twenty-two missense mutations in ACTA2, which encodes alpha-smooth muscle actin, have been identified to cause thoracic aortic aneurysm and dissection. Limited access to diseased tissue, the presence of multiple unresolvable actin isoforms in the cell, and lack of an animal model have prevented analysis of the biochemical mechanisms underlying this pathology. We have utilized actin from the yeast Saccharomyces cerevisiae, 86% identical to human alpha-smooth muscle actin, as a model. Two of the known human mutations, N115T and R116Q, were engineered into yeast actin, and their effect on actin function in vivo and in vitro was investigated. Both mutants exhibited reduced ability to grow under a variety of stress conditions, which hampered N115T cells more than R116Q cells. Both strains exhibited abnormal mitochondrial morphology indicative of a faulty actin cytoskeleton. In vitro, the mutant actins exhibited altered thermostability and nucleotide exchange rates, indicating effects of the mutations on monomer conformation, with R116Q the most severely affected. N115T demonstrated a biphasic elongation phase during polymerization, whereas R116Q demonstrated a markedly extended nucleation phase. Allele-specific effects were also seen on critical concentration, rate of depolymerization, and filament treadmilling. R116Q filaments were hypersensitive to severing by the actin-binding protein cofilin. In contrast, N115T filaments were hyposensitive to cofilin despite nearly normal binding affinities of actin for cofilin. The mutant-specific effects on actin behavior suggest that individual mechanisms may contribute to thoracic aortic aneurysm and dissection. PMID- 21288907 TI - Combinatorial Tau pseudophosphorylation: markedly different regulatory effects on microtubule assembly and dynamic instability than the sum of the individual parts. AB - Tau is a multiply phosphorylated protein that is essential for the development and maintenance of the nervous system. Errors in Tau action are associated with Alzheimer disease and related dementias. A huge literature has led to the widely held notion that aberrant Tau hyperphosphorylation is central to these disorders. Unfortunately, our mechanistic understanding of the functional effects of combinatorial Tau phosphorylation remains minimal. Here, we generated four singly pseudophosphorylated Tau proteins (at Thr(231), Ser(262), Ser(396), and Ser(404)) and four doubly pseudophosphorylated Tau proteins using the same sites. Each Tau preparation was assayed for its abilities to promote microtubule assembly and to regulate microtubule dynamic instability in vitro. All four singly pseudophosphorylated Tau proteins exhibited loss-of-function effects. In marked contrast to the expectation that doubly pseudophosphorylated Tau would be less functional than either of its corresponding singly pseudophosphorylated forms, all of the doubly pseudophosphorylated Tau proteins possessed enhanced microtubule assembly activity and were more potent at regulating dynamic instability than their compromised singly pseudophosphorylated counterparts. Thus, the effects of multiple pseudophosphorylations were not simply the sum of the effects of the constituent single pseudophosphorylations; rather, they were generally opposite to the effects of singly pseudophosphorylated Tau. Further, despite being pseudophosphorylated at different sites, the four singly pseduophosphorylated Tau proteins often functioned similarly, as did the four doubly pseudophosphorylated proteins. These data lead us to reassess the conventional view of combinatorial phosphorylation in normal and pathological Tau action. They may also be relevant to the issue of combinatorial phosphorylation as a general regulatory mechanism. PMID- 21288908 TI - RUNX3 maintains the mesenchymal phenotype after termination of the Notch signal. AB - Notch is a critical mediator of endothelial-to-mesenchymal transition (EndMT) during cardiac cushion development. Slug, a transcriptional repressor that is a Notch target, is an important Notch effector of EndMT in the cardiac cushion. Here, we report that the runt-related transcription factor RUNX3 is a novel direct Notch target in the endothelium. Ectopic expression of RUNX3 in endothelium induces Slug expression and EndMT independent of Notch activation. Interestingly, RUNX3 physically interacts with CSL, the Notch-interacting partner in the nucleus, and induces Slug in a CSL-dependent, but Notch-independent manner. Although RUNX3 may not be required for the initial induction of Slug and EndMT by Notch, because RUNX3 has a much longer half-life than Slug, it sustains the expression of Slug thereby maintaining the mesenchymal phenotype. CSL binds to the Runx3 promoter in the atrioventricular canal in vivo, and inhibition of Notch reduces RUNX3 expression in the cardiac cushion of embryonic hearts. Taken together, our results suggest that induction of RUNX3 may be a mechanism to maintain Notch-transformed mesenchymal cells during heart development. PMID- 21288909 TI - Structural analysis of the cancer-specific promoter in mesothelin and in other genes overexpressed in cancers. AB - Mesothelin (MSLN) may be the most "dramatic" of the tumor markers, being strongly overexpressed in nearly one-third of human malignancies. The biochemical cause is unclear. We previously ascribed this cancer-specific overexpression to an element, Canscript, residing around 50 bp 5' of the transcription start site in cancer (Hucl, T., Brody, J. R., Gallmeier, E., Iacobuzio-Donahue, C. A., Farrance, I. K., and Kern, S. E. (2007) Cancer Res. 67, 9055-9065). Herein, we found a Canscript promoter activity elevated over 100-fold in cancer cells. In addition to a highly conserved TEAD1 (TEA domain family member 1)-binding MCAT motif, nucleotide substitution revealed the consensus core sequence (WCYCCACCC) of an SP1-like motif in Canscript. The unknown transcription factor binding to the SP1-like motif may hold the key for the cancer specificity of Canscript. SP1, GLI1, and RUNX1, -2, and -3 appeared unlikely to be the direct transcription factors acting at the SP1-like motif, but KLF6 had some features of such a candidate. YAP1, a TEAD1-binding protein, appeared necessary, but not sufficient, for Canscript activity; knockdown of YAP1 by small interfering RNAs greatly reduced MSLN levels in MSLN-overexpressing cells, but overexpressing YAP1 in MSLN negative cells did not induce MSLN expression. Cansript-like sequences were found in other genes up-regulated in pancreatic cancer; reporters driven by the sequences from FXYD3, MUC1, and TIMP1 had activities more than 2 times that of the control. This suggested that the cause of MSLN overexpression might also contribute mechanistically to the overexpression of other tumor markers. PMID- 21288911 TI - Whither our police service? PMID- 21288910 TI - Functional characterization of the multidomain F plasmid TraI relaxase-helicase. AB - TraI, a bifunctional enzyme containing relaxase and helicase activities, initiates and drives the conjugative transfer of the Escherichia coli F plasmid. Here, we examined the structure and function of the TraI helicase. We show that TraI binds to single-stranded DNA (ssDNA) with a site size of ~25 nucleotides, which is significantly longer than the site size of other known superfamily I helicases. Low cooperativity was observed with the binding of TraI to ssDNA, and a double-stranded DNA-binding site was identified within the N-terminal region of TraI 1-858, outside the core helicase motifs of TraI. We have revealed that the affinity of TraI for DNA is negatively correlated with the ionic strength of the solution. The binding of AMPPNP or ADP results in a 3-fold increase in the affinity of TraI for ssDNA. Moreover, TraI prefers to bind ssDNA oligomers containing a single type of base. Finally, we elucidated the solution structure of TraI using small angle x-ray scattering. TraI exhibits an ellipsoidal shape in solution with four domains aligning along one axis. Taken together, these data result in the assembly of a model for the multidomain helicase activity of TraI. PMID- 21288912 TI - When things go wrong--understanding and learning. PMID- 21288913 TI - Science, ideology and safety regulations. PMID- 21288914 TI - Parents--why it is now legal to put your child's nappy in the dustbin. AB - BACKGROUND: Notifiable diseases in England and Wales include cholera, plague, relapsing fever, smallpox, typhus and food poisoning. S 26(1) of the Public Health (Control of Disease) Act 1984 Part II made it a criminal offence to place material which is known to have been exposed to infection from a notifiable disease or one of a number of additional diseases, and which has not been disinfected, in a dustbin. One such potential infection risk that is often placed in dustbins is the disposable nappy, particularly from children who are suffering from gastroenteritis. METHOD: A literature review was undertaken using PubMed on the relationship between nappies and the transmission of infectious disease. RESULTS: The literature review did not reveal any evidence of notifiable disease transmission through discarded nappies in dustbins. CONCLUSIONS: As a result of a recent review, Part II of the Public Health (Control of Disease) Act 1984 has now been replaced by Part IIA by virtue of the Health and Social Care Act 2008, and so s 26(1) no longer applies. This is both an evidence-based decision and more importantly, decriminalizes thousands of parents who decide to discard their baby's nappy in the dustbin. PMID- 21288915 TI - Impairment of fitness to practise. PMID- 21288916 TI - Competent minors. PMID- 21288917 TI - Cutting legal aid down to size. PMID- 21288918 TI - Can you tell me the way to ...? A critical look at the police service. PMID- 21288919 TI - Medical mishap: no fault compensation as an alternative to civil litigation - a review of 30 years' experience with the New Zealand Accident Compensation Corporation System. PMID- 21288920 TI - The present legal perspective of narcoanalysis: winds of change in India. PMID- 21288921 TI - The liability of the hospital and the forensic laboratory. PMID- 21288922 TI - Targeting anaplastic lymphoma kinase in lung cancer. AB - Several decades of cancer research have revealed a pivotal role for tyrosine kinases as key regulators of signaling pathways, controlling cell growth and differentiation. Deregulation of tyrosine kinase-mediated signaling occurs frequently in cancer and is believed to drive the initiation and progression of disease. Chromosomal rearrangements involving the tyrosine kinase anaplastic lymphoma kinase (ALK) occur in a variety of human malignancies including non small cell lung cancer (NSCLC), anaplastic large cell lymphomas, and inflammatory myofibroblastic tumors. The aberrant activation of ALK signaling leads to "oncogene addiction" and marked sensitivity to ALK inhibitors such as crizotinib (PF-02341066). This review focuses on ALK rearrangements in NSCLC, starting with the discovery of the EML4-ALK fusion oncogene, and culminating in the recent validation of ALK as a therapeutic target in patients with ALK-rearranged NSCLC. Current efforts seek to expand the role of ALK kinase inhibition in lung and other cancers and to address the molecular basis for the development of resistance. PMID- 21288923 TI - Anaphase catastrophe is a target for cancer therapy. AB - Neoplastic cells are genetically unstable. Strategies that target pathways affecting genome instability can be exploited to disrupt tumor cell growth, potentially with limited consequences to normal cells. Chromosomal instability (CIN) is one type of genome instability characterized by mitotic defects that increase the rate of chromosome mis-segregation. CIN is frequently caused by extra centrosomes that transiently disrupt normal bipolar spindle geometry needed for accurate chromosome segregation. Tumor cells survive with extra centrosomes because of biochemical pathways that cluster centrosomes and promote chromosome segregation on bipolar spindles. Recent work shows that targeted inhibition of these pathways prevents centrosome clustering and forces chromosomes to segregate to multiple daughter cells, an event triggering apoptosis that we refer to as anaphase catastrophe. Anaphase catastrophe specifically kills tumor cells with more than 2 centrosomes. This death program can occur after genetic or pharmacologic inhibition of cyclin dependent kinase 2 (Cdk2) and is augmented by combined treatment with a microtubule inhibitor. This proapoptotic effect occurs despite the presence of ras mutations in cancer cells. Anaphase catastrophe is a previously unrecognized mechanism that can be pharmacologically induced for apoptotic death of cancer cells and is, therefore, appealing to engage for cancer therapy and prevention. PMID- 21288924 TI - Targeting autophagy augments in vitro and in vivo antimyeloma activity of DNA damaging chemotherapy. AB - PURPOSE: Although autophagy occurs in most tumor cells following DNA damage, it is still a mystery how this DNA-damaging event turns on the autophagy machinery in multiple myeloma (MM) and how the functional status of autophagy impacts on its susceptibility to death in response to DNA-damaging chemotherapy. EXPERIMENTAL DESIGN: We investigate the effects of DNA damage on autophagy in MM cells and elucidate its underlying molecular mechanism. Then, we examined the impacts of pharmacologic or genetic inhibition of autophagy on DNA damage-induced apoptosis. Furthermore, the antimyeloma activity of autophagy inhibitor in combination with DNA-damaging agents was evaluated in MM xenograft models. RESULTS: We showed that DNA-damaging drugs, doxorubicin and melphalan, induce caspase-dependent apoptosis and concurrently trigger Beclin 1-regulated autophagy in human MM cell lines H929 and RPMI 8226. Mechanistically, association of autophagy execution proteins Beclin 1 with class III phosphoinositide 3-kinase, which is inhibited by Bcl-2 recruitment, contributes directly to the autophagic process. Importantly, targeting suppression of autophagy by minimally toxic concentrations of pharmacologic inhibitors (hydroxychloroquine and 3 methyladenine) or short hairpin RNAs against autophagy genes, Beclin 1 and Atg5, dramatically augments proapoptotic activity of DNA-damaging chemotherapy both in vitro using MM cell lines or purified patient MM cells and in vivo in a human plasmacytoma xenograft mouse model. CONCLUSION: These data can help unravel the underlying molecular mechanism of autophagy in DNA-damaged MM cells and also provide a rationale for clinical evaluation of autophagy inhibitors in combination with DNA-damaging chemotherapy in MM. PMID- 21288925 TI - A new mechanism for blocking myeloid-derived suppressor cells by CpG. AB - In this issue of Clinical Cancer Research, Zoglmeier and colleagues show that CpG, via the induction of IFN-alpha, matures myeloid-derived suppressor cells to abrogate immune suppression in 2 murine solid tumor models. PMID- 21288927 TI - Cancer therapy associated bone loss: implications for hip fractures in mid-life women with breast cancer. AB - PURPOSE: Aromatase inhibitors (AIs) have been recently associated with hip fractures. We present a case series of breast cancer survivors and a systematic review of bone health care in breast cancer. EXPERIMENTAL DESIGN: We completed clinical assessments and bone density testing (BMD) of hip fractures from January 2005 to December 2008. Prefracture and 12-month functional status was obtained. Systematic review included case reports and review of MEDLINE, PubMed, EMBASE, and Food and Drug Administration Adverse Event Reporting System (FDA AERS) from January 1998 to December 2008 (search terms: breast cancer, bone loss, osteopenia, osteoporosis, malignancy, cancer treatment, menopause, adriamycin, cytoxan, tamoxifen, and AIs). RESULTS: Median age was 53.5 years; five women had osteopenia, one osteoporosis. Five cases were ER (+), and received surgery, XRT chemotherapy, and anastrozole. Functional decline was noted at 12 months, with difficulty in performing heavy housekeeping, climbing stairs, and shopping. The FDA AERS database included 228 cases of fractures associated with breast cancer therapy; 77/228 (29.4%) were hip or femur fractures. Among mid-life women under the age of 64 years there were 78 fractures; 15/228 (19%) were hip and femur fractures. AIs were the most common drug class associated with fractures (n = 149, 65%). CONCLUSIONS: Cancer treatment induced bone loss results in hip fractures among mid-life women with breast cancer. Hip fractures occur at younger ages and higher BMD than expected for patients in this age group without breast cancer. Hip fractures result in considerable functional decline. Greater awareness of this adverse drug effect is needed. PMID- 21288928 TI - Effects of health policy reforms on nursing resources and patient outcomes in New Zealand. AB - Health policy reforms in New Zealand during the 1990s impacted on hospital operations, on the nursing workforce, and on patients. This study analyses changes in rates of 20 adverse patient outcomes that are potentially sensitive to nursing (OPSNs) before (1989-1993), during (1993-2000), and after (2000-2006) the policy reforms, using all New Zealand public hospital inpatient discharge data for this period. Comparisons of changes in mean annual rates across periods revealed the expected trajectory of acceleration during the reform period relative to the prereform period, and a subsequent deceleration in the postreform period. This S-shaped pattern was clearly evident in 16 of the 20 OPSNs, and partially evident in the remaining 4. These results are interpreted as evidence that the 1990s policy reforms inspired by managerialism had deleterious effects on patient outcomes, and that these effects coincided with changes in nursing resources and the work environment. PMID- 21288929 TI - Review: contaminants in heparin: review of the literature, molecular profiling, and clinical implications. AB - BACKGROUND: The contaminant isolated from contaminated heparin was oversulfated chondroitin sulfate (OSCS). Other possible contaminants should be evaluated. METHODS: Contaminants were isolated from recalled contaminated heparin and were compared to OSCS from animal sources and to heparin by-products synthetically persulfated. RESULTS: A great variability in molecular weight was observed in the isolated contaminants. Dermatan sulfate with high-molecular-weight in addition to OSCS was detected. Oversulfated chondroitin sulfate from different sources as well as heparin by-products produced activation of prekallikrein to kallikrein at variable rates as measured by the generation of kallikrein. All agents produced activation of the complement system. All compounds formed complexes with platelet factor 4 (PF4) and all produced (14)C serotonin release in the heparin-induced thrombocytopenia (HIT) analysis. The agents also exhibited variable anticoagulant responses that were mostly mediated via heparin cofactor II. CONCLUSION: These results suggest that heparin contaminants represent a heterogeneous group of oversulfated glycosaminoglycans (OSGAGs) which may mediate multiple pathophysiologic responses. PMID- 21288930 TI - Prognostic value of D-dimer in stable patients with pulmonary embolism. AB - Prognosis of pulmonary embolism (PE) based on levels of D-dimer has shown mixed results, and data on in-hospital prognosis of stable patients are sparse. We assessed in-hospital prognosis in 292 stable patients with PE based on retrospective chart review using an arbitrarily selected value of D-dimer >=5000 ng/mL as cut-off level. In-hospital mortality from PE was 0% (0 of 222) with D dimer <5000 ng/mL compared with 2.9% (2 of 70) with D-dimer >=5000 ng/mL (P = .06). In-hospital all-cause mortality was 2.3% (5 of 222) with D-dimer <5000 ng/mL compared with 2.9% (2 of 70) with D-dimer >=5000 ng/mL (NS). Markedly elevated levels of D-dimer, therefore, did not indicate a high mortality from PE or all-cause mortality during hospitalization. PMID- 21288931 TI - The use and abuse of attachment theory in clinical practice with maltreated children, part I: diagnosis and assessment. AB - Debate has ensued regarding the appropriate assessment and diagnosis for school age children who display severe behavioral problems as a result of previous abuse and neglect within the primary attachment relationship. The current nomenclature recognizes reactive attachment disorder and some clinicians have suggested broader categories of attachment disorder. These attempts at classification are often criticized on empirical grounds; however, often lost in these criticisms is the fact that that these diagnostic approaches often misapply attachment theory and research. This article summarizes the original contributions of John Bowlby and other attachment researchers to our understanding of child development, examines misguided attempts to apply attachment theory to the diagnosis and assessment of maltreated children, and offers a diagnostic conceptualization and assessment recommendations consistent with the available attachment research. PMID- 21288932 TI - The use and abuse of attachment theory in clinical practice with maltreated children, part II: treatment. AB - Recent years have witnessed a growing debate about the role of attachment theory in the treatment of maltreated children. Many professional organizations have issued statements against physically restraining children as some attachment therapists promote; however, often lost in these debates is the fundamental issue of what attachment theory and research proposes as the appropriate form of treatment. Given that these attachment therapies are often directed toward maltreated children, it becomes critical for clinicians working with abused and neglected children to understand these issues and recognize unethical and dangerous treatments. This article provides a summary of the theoretical and empirical bases for the use of attachment theory in the treatment of maltreated school-age children, an examination of the ways questionable approaches to treatment have misinterpreted and misapplied attachment theory, and a conceptualization of attachment-based intervention grounded in current theory and research. PMID- 21288933 TI - The relation between childhood maltreatment and self-injury: a review of the literature on conceptualization and intervention. AB - The following article reviews literature pertaining to the association between child maltreatment and self-injury and the ways it varies according to maltreatment type. Research supporting various mediators of the relations between different maltreatment types and self-injury is summarized. Informing mediator models, dominant theories of functionality, particularly affect regulation theories, are summarized and granted empirical support. Following from explanations of its functionality, three developmental pathways (regulatory, representational/interpersonal, and reactive/neurobiological) leading from child maltreatment to self-injury are presented within an organizational model of psychopathology. Understanding the deviations in these pathways that perpetuate self-injury helps to inform intervention approaches that forge pathways perpetuating resilience instead. Three psychosocial treatments (i.e., Dialectical Behavior Therapy [DBT], Trauma-Focused Cognitive-Behavioral Therapy [TF-CBT], and Acceptance and Commitment Therapy [ACT]) were chosen for review, based upon their accumulating evidence bases, as well as upon the relevance of their core components in correcting or compensating for trauma-related developmental deviations. PMID- 21288934 TI - Review of meta-analyses on the association between child sexual abuse and adult mental health difficulties: a systematic approach. AB - This review evaluates the quality of recent meta-analyses on child sexual abuse and adult psychopathology. Using systematic review methods, seven recently published, English-language meta-analyses met the inclusion criteria of assessing outcome of child sexual abuse. Some methodological weaknesses were identified, such as failure to assess the validity of the primary studies. Child sexual abuse was found to be a nonspecific risk factor in the development of adult mental health difficulties, but the effect sizes varied (partly related to sample type and size). No gender difference was consistently found on adult mental health difficulties but was for victims' perceived mental health consequence. Future meta-analyses need to consider their methods of assessing primary studies to allow for an evidence-based model of adult psychopathology. PMID- 21288936 TI - Parental age difference, educationally assortative mating and offspring count: evidence from a contemporary population in Taiwan. AB - Using contemporary population data from Taiwan, we examine the relationships between parental age difference, educationally assortative mating, income and offspring count. Controlling for women's reproductive value (measured by age at first birth), we find that an older husband is associated with fewer offspring, whereas a husband with similar or higher education is associated with more offspring. Concerning resources, we find that women's income is negatively associated with fertility and husband's income is positively associated with fertility among highly educated women. These results are consistent with the view that women compensate for trade-offs between education, income generation and childbearing by seeking mates with a higher status. PMID- 21288937 TI - Calling at a cost: elevated nestling calling attracts predators to active nests. AB - Begging by nestling birds has been used to test evolutionary models of signalling but theory has outstripped evidence. Eavesdropping predators potentially impose a cost on begging that ensures signal honesty, yet little experimental evidence exists for such a cost at active nests because the use of artificial nests, long playback bouts and absence of parents may have exaggerated costs. We broadcast short periods (1 h) of either nestling vocalizations or background noise at active white-browed scrubwren, Sericornis frontalis, nests. Nestlings called naturally during both treatments, allowing us to test whether elevated calling increases risk, a key but rarely tested assumption of evolutionary models. Predators visited nests exclusively during periods of elevated calling. Furthermore, playbacks affected neither adult visits nor nestling activity, suggesting that calling alone attracted predators. Adults gave alarm calls and nestlings usually called less when predators approached nests. Predation risk to broods is, therefore, likely to fluctuate substantially over short periods of time, depending on nestling hunger and whether adults or young have detected predators. This study confirms a present-day cost of nestling begging, demonstrates that this cost can be incurred over short periods and supports the importance of parent-offspring antipredator strategies in reducing predation risk. PMID- 21288938 TI - Cerebral lateralization determines hand preferences in Australian parrots. AB - Individual preference for the use of one limb over the other to explore the environment or manipulate objects is common trait among vertebrates. Here, we explore the hypothesis that limb preference is determined by the engagement of a particular cerebral hemisphere to analyse certain stimuli. We recorded the eye and foot preferences of 322 individuals from 16 species of Australian parrots while investigating potential food items. Across all species, eye preferences explained 99 per cent of the variation in foot use in Australian parrots. The vast majority of species showed significant relationships between eye and foot preferences at the population level. PMID- 21288939 TI - Variability of neural activation during walking in humans: short heels and big calves. AB - People come in different shapes and sizes. In particular, calf muscle size in humans varies considerably. One possible cause for the different shapes of calf muscles is the inherent difference in neural signals sent to these muscles during walking. In sedentary adults, the variability in neural control of the calf muscles was examined with muscle size, walking kinematics and limb morphometrics. Half the subjects walked while activating their medial gastrocnemius (MG) muscles more strongly than their lateral gastrocnemius (LG) muscles during most walking speeds ('MG-biased'). The other subjects walked while activating their MG and LG muscles nearly equally ('unbiased'). Those who walked with an MG-biased recruitment pattern also had thicker MG muscles and shorter heel lengths, or MG muscle moment arms, than unbiased walkers, but were similar in height, weight, lower limb length, foot length, and exhibited similar walking kinematics. The relatively less plastic skeletal system may drive calf muscle size and motor recruitment patterns of walking in humans. PMID- 21288940 TI - Ploidy and the evolution of parasitism. AB - Levels of parasitism are continuously distributed in nature. Models of host parasite coevolution, however, typically assume that species can be easily characterized as either parasitic or non-parasitic. Consequently, it is poorly understood which factors influence the evolution of parasitism itself. We investigate how ploidy level and the genetic mechanisms underlying infection influence evolution along the continuum of parasitism levels. In order for parasitism to evolve, selective benefits to the successful invasion of hosts must outweigh the losses when encountering resistant hosts. However, we find that exactly where this threshold occurs depends not only on the strength of selection, but also on the genetic model of interaction, the ploidy level in each species, and the nature of the costs to virulence and resistance. With computer simulations, we are able to incorporate more realistic dynamics at the loci underlying species interactions and to extend our analyses in a number of directions, including finite population sizes, multiple alleles and different generation times. PMID- 21288941 TI - Locusts use dynamic thermoregulatory behaviour to optimize nutritional outcomes. AB - Because key nutritional processes differ in their thermal optima, ectotherms may use temperature selection to optimize performance in changing nutritional environments. Such behaviour would be especially advantageous to small terrestrial animals, which have low thermal inertia and often have access to a wide range of environmental temperatures over small distances. Using the locust, Locusta migratoria, we have demonstrated a direct link between nutritional state and thermoregulatory behaviour. When faced with chronic restrictions to the supply of nutrients, locusts selected increasingly lower temperatures within a gradient, thereby maximizing nutrient use efficiency at the cost of slower growth. Over the shorter term, when locusts were unable to find a meal in the normal course of ad libitum feeding, they immediately adjusted their thermoregulatory behaviour, selecting a lower temperature at which assimilation efficiency was maximal. Thus, locusts use fine scale patterns of movement and temperature selection to adjust for reduced nutrient supply and thereby ameliorate associated life-history consequences. PMID- 21288942 TI - Constrained mate choice in social monogamy and the stress of having an unattractive partner. AB - In socially monogamous animals, mate choice is constrained by the availability of unpaired individuals in the local population. Here, we experimentally investigate the physiological stress endured by a female (the choosy sex) when pairing with a non-preferred social partner. In two experimental contexts, female Gouldian finches (Erythrura gouldiae) socially paired with poor-quality mates had levels of circulating corticosterone that were three to four times higher than those observed in females that were paired with preferred mates. The elevated level of this stress hormone in response to partner quality was observed within 12 h of the experimental introduction and maintained over a period of several weeks. Our findings demonstrate the extent of intra-individual conflict that occurs when individuals are forced to make mate-choice decisions that are not perfectly aligned with mate-choice preferences. The elevated level of corticosterone also suggests a mechanistic route through which females might adaptively manage their responses to intersexual conflict over reproductive investment. PMID- 21288943 TI - Evidence for energy savings from aerial running in the Svalbard rock ptarmigan (Lagopus muta hyperborea). AB - Svalbard rock ptarmigans were walked and run upon a treadmill and their energy expenditure measured using respirometry. The ptarmigan used three different gaits: a walking gait at slow speeds (less than or equal to 0.75 m s(-1)), grounded running at intermediate speeds (0.75 m s(-1) < U < 1.67 m s(-1)) and aerial running at high speeds (greater than or equal to 1.67 m s(-1)). Changes of gait were associated with reductions in the gross cost of transport (COT; J kg( 1) m(-1)), providing the first evidence for energy savings with gait change in a small crouched-postured vertebrate. In addition, for the first time (excluding humans) a decrease in absolute metabolic energy expenditure (rate of O(2) consumption) in aerial running when compared with grounded running was identified. The COT versus U curve varies between species and the COT was cheaper during aerial running than grounded running, posing the question of why grounded running should be used at all. Existing explanations (e.g. stability during running over rocky terrain) amount to just so stories with no current evidence to support them. It may be that grounded running is just an artefact of treadmill studies. Research investigating the speeds used by animals in the field is sorely needed. PMID- 21288944 TI - Brood parasitism selects for no defence in a cuckoo host. AB - In coevolutionary arms races, like between cuckoos and their hosts, it is easy to understand why the host is under selection favouring anti-parasitism behaviour, such as egg rejection, which can lead to parasites evolving remarkable adaptations to 'trick' their host, such as mimetic eggs. But what about cases where the cuckoo egg is not mimetic and where the host does not act against it? Classically, such apparently non-adaptive behaviour is put down to evolutionary lag: given enough time, egg mimicry and parasite avoidance strategies will evolve. An alternative is that absence of egg mimicry and of anti-parasite behaviour is stable. Such stability is at first sight highly paradoxical. I show, using both field and experimental data to parametrize a simulation model, that the absence of defence behaviour by Cape bulbuls (Pycnonotus capensis) against parasitic eggs of the Jacobin cuckoo (Clamator jacobinus) is optimal behaviour. The cuckoo has evolved massive eggs (double the size of bulbul eggs) with thick shells, making it very hard or impossible for the host to eject the cuckoo egg. The host could still avoid brood parasitism by nest desertion. However, higher predation and parasitism risks later in the season makes desertion more costly than accepting the cuckoo egg, a strategy aided by the fact that many cuckoo eggs are incorrectly timed, so do not hatch in time and hence do not reduce host fitness to zero. Selection will therefore prevent the continuation of any coevolutionary arms race. Non-mimetic eggs and absence of defence strategies against cuckoo eggs will be the stable, if at first sight paradoxical, result. PMID- 21288945 TI - Modelling the impact of local reactive school closures on critical care provision during an influenza pandemic. AB - Despite the fact that the 2009 H1N1 pandemic influenza strain was less severe than had been feared, both seasonal epidemics of influenza-like-illness and future influenza pandemics have the potential to place a serious burden on health services. The closure of schools has been postulated as a means of reducing transmission between children and hence reducing the number of cases at the peak of an epidemic; this is supported by the marked reduction in cases during school holidays observed across the world during the 2009 pandemic. However, a national policy of long-duration school closures could have severe economic costs. Reactive short-duration closure of schools in regions where health services are close to capacity offers a potential compromise, but it is unclear over what spatial scale and time frame closures would need to be made to be effective. Here, using detailed geographical information for England, we assess how localized school closures could alleviate the burden on hospital intensive care units (ICUs) that are reaching capacity. We show that, for a range of epidemiologically plausible assumptions, considerable local coordination of school closures is needed to achieve a substantial reduction in the number of hospitals where capacity is exceeded at the peak of the epidemic. The heterogeneity in demand per hospital ICU bed means that even widespread school closures are unlikely to have an impact on whether demand will exceed capacity for many hospitals. These results support the UK decision not to use localized school closures as a control mechanism, but have far wider international public health implications. The spatial heterogeneities in both population density and hospital capacity that give rise to our results exist in many developed countries, while our model assumptions are sufficiently general to cover a wide range of pathogens. This leads us to believe that when a pandemic has severe implications for ICU capacity, only widespread school closures (with their associated costs and organizational challenges) are sufficient to mitigate the burden on the worst-affected hospitals. PMID- 21288947 TI - Variation in hippocampal morphology along an environmental gradient: controlling for the effects of day length. AB - Environmental conditions may create increased demands for memory, which in turn may affect specific brain regions responsible for memory function. This may occur either via phenotypic plasticity or selection for individuals with enhanced cognitive abilities. For food-caching animals, in particular, spatial memory appears to be important because it may have a direct effect on fitness via their ability to accurately retrieve food caches. Our previous studies have shown that caching animals living in more harsh environments (characterized by low temperatures, high snow cover and short day lengths) possess more neurons within a larger hippocampus (Hp), a part of the brain involved in spatial memory. However, the relative role of each of these environmental features in the relationship is unknown. Here, we dissociate the effects of one theoretically important factor (day length) within the environmental severity/Hp relationship by examining food-caching birds (black-capped chickadee, Poecile atricapillus) selected at locations along the same latitude, but with very different climatic regimes. There was a significant difference in Hp attributes among populations along the same latitude with very different climatic features. Birds from the climatically mild location had significantly smaller Hp volumes and fewer Hp neurons than birds from the more harsh populations, even though all populations experienced similar day lengths. These results suggest that variables such as temperature and snow cover seem to be important even without the compounding effect of reduced day length at higher latitudes and suggest that low temperature and snow cover alone may be sufficient to generate high demands for memory and the hippocampus. Our data further confirmed that the association between harsh environment and the hippocampus in food-caching animals is robust across a large geographical area and across years. PMID- 21288946 TI - The evolutionary biology of child health. AB - I apply evolutionary perspectives and conceptual tools to analyse central issues underlying child health, with emphases on the roles of human-specific adaptations and genomic conflicts in physical growth and development. Evidence from comparative primatology, anthropology, physiology and human disorders indicates that child health risks have evolved in the context of evolutionary changes, along the human lineage, affecting the timing, growth-differentiation phenotypes and adaptive significance of prenatal stages, infancy, childhood, juvenility and adolescence. The most striking evolutionary changes in humans are earlier weaning and prolonged subsequent pre-adult stages, which have structured and potentiated maladaptations related to growth and development. Data from human genetic and epigenetic studies, and mouse models, indicate that growth, development and behaviour during pre-adult stages are mediated to a notable degree by effects from genomic conflicts and imprinted genes. The incidence of cancer, the primary cause of non-infectious childhood mortality, mirrors child growth rates from birth to adolescence, with paediatric cancer development impacted by imprinted genes that control aspects of growth. Understanding the adaptive significance of child growth and development phenotypes, in the context of human-evolutionary changes and genomic conflicts, provides novel insights into the causes of disease in childhood. PMID- 21288948 TI - Polyandrous females benefit by producing sons that achieve high reproductive success in a competitive environment. AB - Females of many taxa often copulate with multiple males and incite sperm competition. On the premise that males of high genetic quality are more successful in sperm competition, it has been suggested that females may benefit from polyandry by accruing 'good genes' for their offspring. Laboratory studies have shown that multiple mating can increase female fitness through enhanced embryo viability, and have exposed how polyandry influences the evolution of the ejaculate. However, such studies often do not allow for both female mate choice and male-male competition to operate simultaneously. Here, I took house mice (Mus domesticus) from selection lines that had been evolving with (polygamous) and without (monogamous) sperm competition for 16 generations and, by placing them in free-ranging enclosures for 11 weeks, forced them to compete for access to resources and mates. Parentage analyses revealed that female reproductive success was not influenced by selection history, but there was a significant paternity bias towards males from the polygamous selection lines. Therefore, I show that female house mice benefit from polyandry by producing sons that achieve increased fitness in a semi-natural environment. PMID- 21288949 TI - Sib mating without inbreeding in the longhorn crazy ant. AB - Sib matings increase homozygosity and, hence, the frequency of detrimental phenotypes caused by recessive deleterious alleles. However, many species have evolved adaptations that prevent the genetic costs associated with inbreeding. We discovered that the highly invasive longhorn crazy ant, Paratrechina longicornis, has evolved an unusual mode of reproduction whereby sib mating does not result in inbreeding. A population genetic study of P. longicornis revealed dramatic differences in allele frequencies between queens, males and workers. Mother offspring analyses demonstrated that these allele frequency differences resulted from the fact that the three castes were all produced through different means. Workers developed through normal sexual reproduction between queens and males. However, queens were produced clonally and, thus, were genetically identical to their mothers. In contrast, males never inherited maternal alleles and were genetically identical to their fathers. The outcome of this system is that genetic inbreeding is impossible because queen and male genomes remain completely separate. Moreover, the sexually produced worker offspring retain the same genotype, combining alleles from both the maternal and paternal lineage over generations. Thus, queens may mate with their brothers in the parental nest, yet their offspring are no more homozygous than if the queen mated with a male randomly chosen from the population. The complete segregation of the male and female gene pools allows the queens to circumvent the costs associated with inbreeding and therefore may act as an important pre-adaptation for the crazy ant's tremendous invasive success. PMID- 21288951 TI - Conspecifics as informers and competitors: an experimental study in foraging bumble-bees. AB - Conspecifics are usually considered competitors negatively affecting food intake rates. However, their presence can also inform about resource quality by providing inadvertent social information. Few studies have investigated whether foragers perceive conspecifics as informers or competitors. Here, we experimentally tested whether variation in the density of demonstrators ('none', 'low' and 'high'), whose location indicated flower profitability, affected decision-making of bumble-bees Bombus terrestris. Bumble-bees foraged on either 'simple' (two colours) or 'complex' (four colours) artificial floral communities. We found that conspecifics at low density may be used as sources of information in first flower choices, whereas they appeared as competitors over the whole foraging sequence. Low conspecific densities improved foragers' first-visit success rate in the simple environment, and decreased time to first landing, especially in the complex environment. High conspecific densities did not affect these behavioural parameters, but reduced flower constancy in both floral communities, which may alter the efficiency of pollinating visits. These results suggest that the balance of the costs and benefits of conspecific presence varies with foraging experience, floral community and density. Spatio-temporal scales could thus be an important determinant of social information use. This behavioural flexibility should allow bumble-bees to better exploit their environment. PMID- 21288952 TI - Oldest cingulate skulls provide congruence between morphological and molecular scenarios of armadillo evolution. AB - The cingulates of the mammalian order Xenarthra present a typical case of disagreement between molecular and morphological phylogenetic studies. We report here the discovery of two new skulls from the Late Oligocene Salla Beds of Bolivia (approx. 26 Ma), which are the oldest known well-preserved cranial remains of the group. A new taxon is described: Kuntinaru boliviensis gen. et sp. nov. A phylogenetic analysis clusters K. boliviensis together with the armadillo subfamily Tolypeutinae. These skulls document an early spotty occurrence for the Tolypeutinae at 26 Ma, in agreement with the temporal predictions of previous molecular studies. The fossil record of tolypeutines is now characterized by a unique occurrence in the Late Oligocene, and a subsequent 12 Myr lack in the fossil record. It is noteworthy that the tolypeutines remain decidedly marginal in the Late Palaeogene and Early Neogene deposits, whereas other cingulate groups diversify. Also, the anatomical phylogenetic analysis herein, which includes K. boliviensis, is congruent with recent molecular phylogenetic analyses. Kuntinaru boliviensis is the oldest confident calibration point available for the whole Cingulata. PMID- 21288953 TI - Kin selection in den sharing develops under limited availability of tree hollows for a forest marsupial. AB - Animal social behaviour is not static with regard to environmental change. Flexibility in cooperative resource use may be an important response to resource decline, mediating the impacts of resource availability on fitness and demography. In forest ecosystems, hollow trees are key den resources for many species, but are declining worldwide owing to forestry. Altered patterns of den sharing may mediate the effects of the decline of this resource. We studied den sharing interactions among hollow-dependent Australian mountain brushtail possums to investigate how spatial variation in hollow tree availability affects resource sharing and kin selection. Under reduced den availability, individuals used fewer dens and shared them less often. This suggests increased territoriality in the presence of resource competition. Further, there was a switch from kin avoidance to kin preference with decreasing hollow tree availability. This was driven primarily by a change in den sharing among siblings. The inclusive fitness benefits of den sharing with kin are likely to increase under resource-limiting conditions, but are potentially outweighed by the benefits of associating with non-relatives (avoidance of inbreeding or pathogen transmission) where dens are abundant. We discuss how predictions from social evolutionary theory can contribute to understanding animal responses to landscape change. PMID- 21288954 TI - Are rates of molecular evolution in mammals substantially accelerated in warmer environments? PMID- 21288955 TI - Orientation angle and the adhesion of single gecko setae. AB - We investigated the effects of orientation angle on the adhesion of single gecko setae using dual-axis microelectromechanical systems force sensors to simultaneously detect normal and shear force components. Adhesion was highly sensitive to the pitch angle between the substrate and the seta's stalk. Maximum lateral adhesive force was observed with the stalk parallel to the substrate, and adhesion decreased smoothly with increasing pitch. The roll orientation angle only needed to be roughly correct with the spatular tuft of the seta oriented grossly towards the substrate for high adhesion. Also, detailed measurements were made to control for the effect of normal preload forces. Higher normal preload forces caused modest enhancement of the observed lateral adhesive force, provided that adequate contact was made between the seta and the substrate. These results should be useful in the design and manufacture of gecko-inspired synthetic adhesives with anisotropic properties, an area of substantial recent research efforts. PMID- 21288956 TI - Computational modelling of mitotic exit in budding yeast: the role of separase and Cdc14 endocycles. AB - The operating principles of complex regulatory networks are best understood with the help of mathematical modelling rather than by intuitive reasoning. Hereby, we study the dynamics of the mitotic exit (ME) control system in budding yeast by further developing the Queralt's model. A comprehensive systems view of the network regulating ME is provided based on classical experiments in the literature. In this picture, Cdc20-APC is a critical node controlling both cyclin (Clb2 and Clb5) and phosphatase (Cdc14) branches of the regulatory network. On the basis of experimental situations ranging from single to quintuple mutants, the kinetic parameters of the network are estimated. Numerical analysis of the model quantifies the dependence of ME control on the proteolytic and non proteolytic functions of separase. We show that the requirement of the non proteolytic function of separase for ME depends on cyclin-dependent kinase activity. The model is also used for the systematic analysis of the recently discovered Cdc14 endocycles. The significance of Cdc14 endocycles in eukaryotic cell cycle control is discussed as well. PMID- 21288957 TI - Bio-electrospraying and aerodynamically assisted bio-jetting the model eukaryotic Dictyostelium discoideum: assessing stress and developmental competency post treatment. AB - Bio-electrospraying (BES) and aerodynamically assisted bio-jetting (AABJ) have recently been established as important novel biospray technologies for directly manipulating living cells. To elucidate their potential in medical and clinical sciences, these bio-aerosol techniques have been subjected to increasingly rigorous investigations. In parallel to these studies, we wish to introduce these unique biotechnologies for use in the basic biological sciences, for handling a wide range of cell types and systems, thus increasing the range and the scope of these techniques for modern research. Here, the authors present the analysis of the new use of these biospray techniques for the direct handling of the simple eukaryotic biomedical model organism Dictyostelium discoideum. These cells are widely used as a model for immune cell chemotaxis and as a simple model for development. We demonstrate that AABJ of these cells did not cause cell stress, as defined by the stress-gene induction, nor affect cell development. Furthermore, although BES induced the increased expression of one stress-related gene (gapA), this was not a generalized stress response nor did it affect cell development. These data suggest that these biospray techniques can be used to directly manipulate single cells of this biomedical model without inducing a generalized stress response or perturbing later development. PMID- 21288958 TI - Structure and formation of ant transportation networks. AB - Many biological systems use extensive networks for the transport of resources and information. Ants are no exception. How do biological systems achieve efficient transportation networks in the absence of centralized control and without global knowledge of the environment? Here, we address this question by studying the formation and properties of inter-nest transportation networks in the Argentine ant (Linepithema humile). We find that the formation of inter-nest networks depends on the number of ants involved in the construction process. When the number of ants is sufficient and networks do form, they tend to have short total length but a low level of robustness. These networks are topologically similar to either minimum spanning trees or Steiner networks. The process of network formation involves an initial construction of multiple links followed by a pruning process that reduces the number of trails. Our study thus illuminates the conditions under and the process by which minimal biological transport networks can be constructed. PMID- 21288959 TI - Remission is the goal for cardiovascular risk management in patients with rheumatoid arthritis: a cross-sectional comparative study. AB - OBJECTIVES: To compare markers of cardiovascular disease (CVD) risk between patients with rheumatoid arthritis (RA) in an active disease state and those with RA in remission, and to compare both groups with community controls. METHODS: 113 patients with RA and 86 community controls were assessed across a panel of biomarkers for CVD. RA in remission was defined as Clinical Disease Activity Index <=2.8. Community controls were selected at random by Statistics Norway, and controls were matched with patients in the cohorts in strata using details of age, sex and residential area. A panel of biomarkers (N-terminal pro-brain natriuretic peptide (NT-proBNP), total cholesterol, reactive hyperaemia index (RHI), pressure measurements, measures of arterial stiffness and intima-media thickness) were compared between patients with active RA and those with RA in remission. Both groups were compared with controls. In addition, biomarker levels were compared across subgroups based on anticyclic citrullinated peptide status, level of joint destruction and presence of extra-articular manifestations. RESULTS: Patients with active RA had significantly higher levels of NT-proBNP, brachial systolic pressure, augmentation index and central systolic pressure but lower cholesterol than patients in remission and controls. In addition, patients with active RA had significantly higher levels of pulse wave velocity and worse RHI than patients in remission. Comparison across other subgroups gave less consistent differentiations in levels of CVD risk markers. CONCLUSION: Patients with active RA, but not those in remission, had significantly increased levels of CVD risk markers. These results link inflammatory activity to markers of CVD risk in patients with RA and may indirectly support the notion that remission in RA confers diminished cardiovascular morbidity. PMID- 21288960 TI - High disease activity is associated with an increased risk of infection in patients with rheumatoid arthritis. AB - OBJECTIVE: To determine the relationship of disease activity to infections in patients with rheumatoid arthritis (RA). METHODS: From the CORRONA database, the incidence of physician-reported infections in RA patients on stable disease modifying antirheumatic drug, biological, and corticosteroid therapy for at least 6 months was ascertained. Two composite measures of disease activity were defined: clinical disease activity index (CDAI) and disease activity score 28 (DAS28). Incident rate ratios (IRR) were calculated using generalised estimating equation Poisson regression models adjusted for demographics, medications and clinical factors. RESULTS: Of 1 6242 RA patients, 6242 were on stable therapy for at least 6 months and were eligible for analysis. 2282 infections were reported in the cohort, followed over 7290 patient-years. After controlling for possible confounders, disease activity was associated with an increased rate of infections. Each 0.6 unit increase in DAS28 score corresponded to a 4% increased rate of outpatient infections (IRR 1.04, p=0.01) and a 25% increased rate of infections requiring hospitalisation (IRR 1.25, p=0.03). There was a dichotomy in the relationship between infections and CDAI scores. For CDAI <10 (mild disease activity) patients had a 12% increased rate of outpatient infections with each 5 unit increase in CDAI score (IRR 1.12, p=0.003). At CDAI scores >=10, there was no further increase in the rate of outpatient infections associated with higher disease activity. The relationship of CDAI to hospitalised infections showed similar trends to outpatient data but did not reach statistical significance after multivariate analysis (CDAI <10: IRR 1.56, p=0.08). CONCLUSIONS: In this large cohort of RA patients, higher disease activity was associated with a higher probability of developing infections. PMID- 21288961 TI - Prevalence of spondyloarthritis and its subtypes in southern Sweden. AB - OBJECTIVE: To estimate the prevalence of spondyloarthritis and its subtypes. METHODS: The Swedish healthcare organisation comprises a system where all inpatient and outpatient care is registered by a personal identifier. For the calendar years 2003-7, all residents aged >= 15 years in the southernmost county of Sweden (1.2 million inhabitants) diagnosed by a physician with spondyloarthritis (ankylosing spondylitis (AS), psoriatic arthritis (PsA), inflammatory arthritis associated with inflammatory bowel disease (Aa-IBD) or undifferentiated spondylarthritis (USpA)) were identified. To obtain valid point estimates of prevalence by the end of 2007, identification numbers were cross referenced with the population register to exclude patients who had died or relocated. RESULTS: The authors estimated the prevalence of spondyloarthritis (not including chronic reactive arthritis) as 0.45% (95% CI 0.44% to 0.47%). The mean (SD) age of patients with prevalent spondyloarthritis by the end of 2007 was 53 (15) years. Among the component subtypes, PsA accounted for 54% of cases, AS 21.4%, USpA 17.8% and Aa-IBD 2.3% with a prevalence of 0.25%, 0.12%, 0.10% and 0.015%, respectively. The remaining 6.4% had some form of combination of spondyloarthritis diagnoses. The prevalence of spondyloarthritis at large was about the same in men and women. However, the subtype PsA was more prevalent in women and AS was more prevalent in men. CONCLUSION: In Sweden the prevalence of spondyloarthritis leading to a doctor consultation is not much lower than rheumatoid arthritis. PsA was the most frequent subtype followed by AS and USpA, and the two most frequent subtypes PsA and AS also display some distinct sex patterns. PMID- 21288962 TI - Magnetic resonance imaging of skeletal muscles in sporadic inclusion body myositis. AB - OBJECTIVE: To analyse whether MRI of upper and lower extremity muscles in a large patient group with sporadic IBM (sIBM) is of additional value in the diagnostic work-up of sIBM. METHODS: Thirty-two sIBM patients were included. Magnetic resonance (MR) parameters evaluated in 68 muscles of upper and lower extremity were muscle atrophy, fatty infiltration and inflammation. These findings were correlated with disease duration, weakness and serum creatine kinase (sCK) levels. RESULTS: Fatty infiltration was far more common than inflammation. Muscles most frequently infiltrated with fat were the flexor digitorum profundus (FDP), anterior muscles of the upper leg and all muscles of the lower leg, preferentially the medial part of the gastrocnemius. The rectus femoris was relatively spared compared with other quadriceps muscles as well as the adductors of the upper leg. Inflammation was common in general, but individually sparse, present in 78% of the patients with a median of two inflamed muscles per patient. A statistically significant correlation was found between the amount of fatty infiltration and disease severity, disease duration and sCK. CONCLUSION: We provide a detailed description of the MRI in sIBM and show a distinct pattern of muscle involvement. Relatively severe affliction of the medial compartment of the gastrocnemius, combined with relative sparing of the rectus femoris or involvement of the FDP can be indicative of sIBM. MRI can contribute to the diagnosis in selected patients with clear clinical suspicion, but lacking the mandatory set of muscle biopsy features. PMID- 21288969 TI - Identifying and managing technical faults in the anesthesia machine: lessons learned from the Israeli Board of Anesthesiologists. AB - BACKGROUND: The potential for catastrophe resulting from anesthetic equipment failure and the failure of training programs to adequately prepare residents to detect and manage equipment failure prompted the Israel Board of Anesthesiologists to include simulation-based testing in the Objective Structured Clinical Evaluation component of the Israeli Board Examination in Anesthesiology. METHODS: We used simulation-based scenarios to measure the performance of residents while (a) checking the anesthesia machine before the first morning case, (b) checking the anesthesia machine between cases, (c) managing an oxygen pipeline failure, and (d) managing an expiratory valve failure. RESULTS: During board examination, 3 of 28 examinees failed to correctly check at least 70% of the items on the anesthesia machine checkout list before the first morning case and 3 of 30 failed to correctly check 70% of the items between cases. Although all examinees recognized inadequate oxygen cylinder pressure and a malfunctioning valve, 1 of 31 examinees failed to open the O(2) cylinder, 6 of 31 did not disconnect the anesthesia machine from the central oxygen supply, 14 of 31 could not explain how to minimize the use of oxygen, 2 of 30 failed to find the faulty valve, and 15 of 30 could not give the correct differential diagnosis. CONCLUSIONS: During simulation-based board examination most senior anesthesia residents became aware of equipment failures but many failed to correctly diagnosis and manage the failure. PMID- 21288970 TI - A low approach to interscalene brachial plexus block results in more distal spread of sensory-motor coverage compared to the conventional approach. AB - A low approach to the interscalene block (LISB) deposits local anesthetic farther caudad on the brachial plexus compared with the conventional interscalene block (ISB). We compared the efficacy of LISB and ISB in achieving anesthesia of the distal extremity in 254 patients having upper extremity surgery. The most frequent elicited motor response was the deltoid for ISB and wrist for LISB. There was significantly greater sensory-motor block of regions below the elbow with the LISB compared with ISB (P < 0.001 for both sensory and motor coverage). Our data indicate that LISB results in a higher incidence of distal elicited motor response and greater sensory-motor blockage of the wrist and hand. PMID- 21288971 TI - Language testing during awake "anesthesia" in a bilingual patient with brain lesion adjacent to Wernicke's area. AB - Awake "anesthesia" is the preferable anesthetic approach for neurosurgical procedures that require intraoperative localization of eloquent brain areas. We describe intraoperative inducible selective English aphasia in a bilingual (English and Italian) patient undergoing awake anesthesia for excision of a brain lesion adjacent to Wernicke's area with no postoperative neurological sequelae. We discuss the importance of intraoperative brain mapping and intraoperative language testing in bilingual patients to prevent iatrogenic-related morbidity. PMID- 21288972 TI - A comparison of the effects of preanesthetic administration of crystalloid versus colloid on intrathecal spread of isobaric spinal anesthetics and cerebrospinal fluid movement. AB - BACKGROUND: Movement of the cerebrospinal fluid (CSF) is one of the most important factors in determining the intrathecal spread of isobaric spinal anesthetics. Preanesthetic administration of either crystalloid or colloid immediately before spinal anesthesia (preload) may result in different CSF pulsatile movement because of their different physical properties. We examined whether preload of crystalloid versus colloid may have different effects on the intrathecal spread of isobaric spinal anesthetics as a result of their different CSF dynamics regarding its pulsatile movement. METHODS: In a clinical study of isobaric spinal anesthesia, patients were allocated into 1 of 2 groups according to preload with either crystalloid (n = 30) or colloid (n = 30) before spinal anesthesia with 0.5 isobaric tetracaine. The pulsatile movements of CSF at the L2 3 intervertebral space and midportion of the aqueduct of Sylvius were also examined by magnetic resonance images in healthy volunteers (n = 23) at 0, 30, and 60 minutes after administering either crystalloid or colloid. RESULTS: In the clinical study, the time to reach the peak sensory block level was delayed significantly in the crystalloid preload group (27.2 +/- 17.8 minutes; P < 0.01) compared with the colloid preload group (13.9 +/- 7.0 minutes). The median sensory block levels of the crystalloid preload group at 15 minutes (T10, P < 0.05) and 20 minutes (T9.5, P < 0.05) were significantly lower than those (T8, T7, respectively) of the colloid preload group. In the magnetic resonance imaging study, cranially directed CSF pulsatile movement decreased significantly at the L2-3 intervertebral intrathecal space at 30 minutes after crystalloid administration, but not after colloid administration. The CSF production rate significantly increased at 30 minutes (637 MUL/min, P < 0.05) after crystalloid preload compared with the baseline measurement (448 MUL/min), and then slightly decreased (609 MUL/min) at 60 minutes. In the colloid preload group, the CSF production rate was not statistically significant compared with the baseline measurement (464, 512, and 542 MUL/min at baseline, 30, and 60 minutes, respectively). CONCLUSIONS: Compared with a colloid preload, which may be comparable to the no-preload condition, crystalloid preload prolonged the time to reach the peak sensory block level in isobaric spinal anesthesia, which might have been caused by a significant decrease in CSF pulsatile movement. This attenuated CSF pulsatile movement in the crystalloid preload group might have resulted from significant increases of CSF production. PMID- 21288973 TI - Is a patella motor response necessary for continuous femoral nerve blockade performed in conjunction with ultrasound guidance? AB - BACKGROUND: Successful continuous femoral nerve blockade (CFNB) has been associated with the elicitation of a patella motor response during needle and catheter insertion. We evaluated whether a patella motor response is necessary when CFNB is performed in conjunction with ultrasound (US) guidance. METHODS: Ninety-eight patients undergoing CFNB (along with sciatic nerve block and spinal anesthetic) for total knee arthroplasty participated in this cohort observational study. Using out-of-plane US guidance alone, the tip of an insulated Tuohy needle was positioned superficial to the midpoint of the femoral nerve visualized in short axis. A nerve stimulator was turned on and the type of motor response (patella versus medial muscle) and minimum stimulating current from the needle were recorded. A stimulating catheter was then inserted and the type of motor response and minimum current from the catheter were recorded. Ten milliliters mepivacaine 2% was injected through the catheter. The primary outcome was sensory block defined as loss of sensation to pinprick on the anterior surface of the distal thigh measured 20 minutes after mepivacaine injection. RESULTS: Forty three patients demonstrated a patella motor response, 43 demonstrated a medial motor response, and 12 demonstrated no motor response from the catheter. The proportion of patients with sensory block differed according to motor response from the catheter (patella [98%], medial [91%], and no motor response [75%]; P = 0.02), but there was no significant difference between a patella (98%) and medial (91%) motor response from the catheter (P = 0.58). The proportion of patients with motor block 20 minutes after local anesthetic injection also differed according to motor response from the catheter (patella [95%], medial [77%], and no motor response [67%]; P = 0.03). In addition, there was a significant difference between a patella (95%) and medial (77%) motor response from the catheter (P = 0.01). The mean minimum stimulating currents did not differ between patella and medial motor responses elicited from the catheter (P = 0.06). Postoperative pain and analgesic consumption were similar regardless of the type of motor response from the catheter. CONCLUSION: Based on observational data, a patella or medial motor response from the catheter similarly results in sensory block of the anterior thigh when CFNB is performed in conjunction with out-of plane US guidance. PMID- 21288974 TI - The inhibitory effect of lidocaine on the release of high mobility group box 1 in lipopolysaccharide-stimulated macrophages. AB - BACKGROUND: High mobility group box 1 (HMGB1), a key mediator of inflammation, has been shown to inhibit phagocytosis of apoptotic cells in sepsis. Lidocaine has been proven to protect macrophages in mice with septic peritonitis by attenuating the production of cytokines. However, it is currently unknown whether lidocaine also affects HMGB1. In this study, we sought to detect the effect of lidocaine on the release of HMGB1 from RAW264.7 macrophages after lipopolysaccharide (LPS) stimulation. METHODS: The levels of HMGB1 in the supernatant of RAW264.7 cells incubated with LPS and different concentrations of lidocaine were measured by enzyme-linked immunosorbent assays. HMGB1 mRNA expression was assessed by real-time polymerase chain reaction. The immunocytochemistry was used to detect the release and translocation of HMGB1 from the nucleus to cytoplasm. Nuclear factor (NF)-kappaB levels in the nuclear fraction of RAW264.7 cells were measured with the Active Motif NF-kappaB family kit. RESULTS: We found that lidocaine suppressed the translocation of HMGB1 from the nucleus to cytoplasm and decreased the expression of HMGB1 mRNA in RAW264.7 cells induced by LPS. Furthermore, the LPS-stimulated translocation of NF-kappaB from the cytoplasm to nucleus was inhibited by lidocaine in a dose-dependent manner. CONCLUSIONS: Our data suggest that lidocaine functions as an antiinflammatory by inhibiting expression of HMGB1 mRNA, and translocating both HMGB1 and NF-kappaB from the nucleus to cytoplasm. The mechanism of these effects might be involved, at least partly, in the inhibition of the NF-kappaB signal pathway. PMID- 21288975 TI - The effects of neuropeptide S on general anesthesia in rats. AB - BACKGROUND: Neuropeptide S (NPS) and its receptor (NPSR) is a novel neuropeptide system that regulates arousal and anxiety. A link between natural sleep and general anesthesia has been suggested. Therefore, we hypothesized that the NPS neuronal system may also modulate general anesthesia. METHODS: The effects of intracerebroventricular NPS and [D-Cys(tBu)(5)]NPS, a peptide NPSR antagonist, on ketamine and thiopental anesthesia time were measured in rats. Anesthesia time was defined as the interval between the loss of righting reflex and its recovery. RESULTS: Intracerebroventricular NPS 1 to 30 nmol significantly reduced ketamine anesthesia time, showing a bell-shaped dose-response curve. [D-Cys(tBu)(5)]NPS 20 nmol antagonized NPS 1 nmol effects and was per se able to increase ketamine anesthesia time. Similar results were obtained investigating thiopental anesthesia time that was significantly reduced by NPS and prolonged by [D Cys(tBu)(5)]NPS. CONCLUSION: NPS via selective NPSR activation stimulates the wakefulness-promoting pathway, thus reducing anesthesia duration. The endogenous NPS/NPSR system seems to tonically control these pathways. PMID- 21288976 TI - Parental recall of anesthesia information: informing the practice of informed consent. AB - BACKGROUND: Informed consent is a process of sharing information that facilitates the individual patient's right to self-determination. Despite its importance in anesthesia practice, the process of informed consent is rarely audited or examined. As such, there are only limited data with respect to anesthesia consent practices, particularly within the pediatric setting. We designed this study, therefore, to examine the information that parents seek regarding their child's anesthesia, what they are told, who told them, and how much of the information they recall. METHODS: Parents of children undergoing a variety of elective surgical procedures were recruited while their child was in surgery. Parents were interviewed to determine their recall of their child's anesthetic plan, postoperative pain management, and attendant risks and benefits; and then surveyed regarding what information was sought and received, and how satisfied they were with the information. RESULTS: Two hundred sixty-three parents were included. Although the majority (96.2%) recalled receiving information about how their child's anesthesia would be administered, only 51.1% recalled being given information about the risks of anesthesia and 42.4% recalled how side effects would be managed. Composite scores for parental recall of anesthesia information were generally poor (4.9 +/- 2.5 of 10). Furthermore, 50% and 55.7% of parents had no recall of the risks or benefits of anesthesia, respectively, and 82.9% could not recall pain medication side effects. Recall of consent information provided by anesthesia providers was significantly better than when provided by surgical personnel (P < 0.01). CONCLUSIONS: Results showed that disclosure of anesthesia information to parents was often incomplete, and their recall thereof, was poor. The finding that recall of consent information provided by anesthesia providers was better than when provided by surgical personnel may serve to further the debate regarding the appropriate vehicles for anesthesia consent. PMID- 21288977 TI - Continuous cardiac output measurement with a Doppler-equipped pulmonary artery catheter. AB - BACKGROUND: We developed a Doppler-equipped pulmonary artery catheter that provides continuous measurement of the true main pulmonary blood flow velocity independent of the angle of incidence formed by the pulmonary artery catheter and the main pulmonary artery blood flow. This device uses 2 orthogonally positioned Doppler transducers that allow trigonometric correction for differences in the angle of blood flow between each transducer. We tested the accuracy of the Doppler-equipped pulmonary artery catheter by comparing its cardiac output measurements with those done by conventional techniques in animals. METHODS: The Doppler-equipped pulmonary artery catheter was evaluated in dogs. A pair of ultrasound Doppler transducers positioned at a fixed angle (90 degrees ) was mounted on the distal part of the thermodilution pulmonary artery catheter. The Doppler shifts (Deltaf1, Deltaf2) were detected by the 2 transducers sampling at 2 closely spaced points in the main pulmonary artery. The values of Deltaf1 and Deltaf2 were used to compute 2 velocity measurements. The true flow velocity of the main pulmonary artery was calculated with the following equation: V(pulm) = {(V(transducer1))(2) + (V(transducer2))(2)}(1/2) (V(pulm) = true main pulmonary artery velocity; V(transducer1) and V(transducer2) = velocity detected by transducers 1 and 2, respectively). The flow velocities were calculated by using a phase differential technique. Cardiac output was calculated as V(pulm) multiplied by a coefficient value. The coefficient value was calculated by dividing cardiac output, derived from conventional techniques, by V(pulm) at the beginning of each experiment. After thoracotomy, an electromagnetic flowprobe was placed around the main pulmonary artery in dogs. Cardiac output was simultaneously measured by the Doppler-equipped pulmonary artery catheter (CO Doppler), and the electromagnetic flowmeter (CO-EMF) or the thermodilution technique (CO-Thermo). Cardiac output was manipulated by dobutamine and propranolol. RESULTS: CO-Doppler was highly correlated with CO-EMF (y = 1.16 * 0.26, r(2) = 0.99, P < 0.001) and CO-Thermo (y = 1.24 * -0.90, r(2) = 0.85, n = 48, P < 0.001). The bias between CO-EMF and CO-Doppler was -0.02 L/min; 95% limits of agreement were -0.32 to 0.28 L/min. The percentage error was 16%. The bias between CO-Thermo and CO-Doppler was 0.18 L/min; 95% limits of agreement were -0.62 to 0.98 L/min. CONCLUSIONS: The newly developed Doppler-equipped pulmonary artery catheter with 2 orthogonally positioned Doppler transducers allowed accurate and continuous measurements of cardiac output independent of the angle of incidence formed by the pulmonary artery catheter and the main pulmonary artery blood flow. PMID- 21288978 TI - Motor vehicle accidents, suicides, and assaults in epilepsy: a population-based study. AB - BACKGROUND: The goal of our study was to compare the incidence of motor vehicle accidents (MVA), attempted or completed suicides, and injuries inflicted by others between individuals with and without epilepsy. METHODS: Individuals with and without epilepsy were identified using linked administrative databases between 1996 and 2003 in a Canadian health region with a 1.4 million population. We used a validated epilepsy case definition: anyone who had 2 physician claims, one hospitalization, or one emergency room visit coded with an International Classification of Diseases (ICD)-9-CM or ICD-10 epilepsy code any time during a 2 year period. Four subjects without epilepsy were matched to one patient with epilepsy by age (within 1 year) and sex. The incidence of MVAs, attempted or completed suicides, and inflicted injuries was assessed in 2003-2004. Outcomes were adjusted using the Elixhauser comorbidity index. RESULTS: A total of 10,240 individuals with epilepsy and 40,960 individuals without epilepsy were identified. Mean age was 39.0 +/- 21.3 years (range 0.12-99.4) and 48.5% were female. One-year odds ratios before and after adjustment for comorbidity were 1.83 (95% confidence interval [CI] 1.33-2.54) and 1.38 (95% CI 0.97-1.96) for MVAs, 4.32 (95% CI 2.79-6.69) and 1.32 (95% CI 0.81-2.15) for attempted or completed suicides, and 3.54 (95% CI 2.66-4.72) and 1.46 (95% CI 1.04-2.03) for injuries inflicted by others. CONCLUSION: In this cohort-controlled population based study, once important medical and psychiatric comorbidities were adjusted for, people with epilepsy were not more likely to attempt suicide or experience MVAs, but were still more likely to be assaulted compared to those without epilepsy. PMID- 21288979 TI - Sonographic monitoring of ventricle enlargement in posthemorrhagic hydrocephalus. AB - BACKGROUND AND OBJECTIVE: Intraventricular hemorrhage often leads to obstructive hydrocephalus, necessitating placement of extraventricular drainage to prevent increasing intracranial pressure and subsequent herniation. For clamping and removal of the drainage, repeated CT scans are required to rule out recurrent hydrocephalus. We performed a prospective observational study on the use of transcranial duplex sonography to monitor changes in width of the lateral ventricles during clamping as an alternative to CT. METHODS: Patients with hydrocephalus after intracranial or subarachnoid hemorrhage were monitored by transcranial duplex sonography (TDS). Serial examinations were carried out before and directly after placement of extraventricular or lumbar drainage as well as every 12 hours until 48 hours after removal of all drainages. Clinicians were blinded for all ultrasound results. Receiver operating characteristic analysis and calculation of the positive and negative predictive values was used to identify the optimal cutoff point in increased ventricle width that best predicted reopening of the drainage by the clinician. RESULTS: Ninety-two attempts to clamp either lumbar or extraventricular drainage were monitored in 37 patients during a 1-year period. A cutoff value for increase of ventricular width of 5.5 mm yielded high sensitivity (100%) and specificity (83%) in combination with a 100% negative predictive value for reopening of the drainage. CONCLUSIONS: TDS can be used to monitor ventricular width in experienced neurologic intensive care units. Because of its noninvasive character and suitability for bedside use, it offers a valuable alternative to repeated CT scans. PMID- 21288981 TI - TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies. AB - OBJECTIVE: To improve understanding of TRPV4-associated axonal Charcot-Marie Tooth (CMT) neuropathy phenotypes and their debated pathologic mechanism. METHODS: A total of 17 CMT2C phenotypic families with vocal cord and diaphragmatic involvement and 36 clinically undifferentiated CMT2 subjects underwent sequencing analysis of the coding region of TRPV4. Functional studies of mutant proteins were performed using transiently transfected cells for TRPV4 subcellular localization, basal and stimulated Ca(2+) channel analysis, and cell viability assay with or without channel blockade. RESULTS: Two TRPV4 mutations R232C and R316H from 17 CMT2C families were identified in the ankyrin repeat domains. The R316H is a novel de novo mutation found in a patient with CMT2C phenotype. The family with R232C mutation had individuals with and without vocal cord and diaphragm involvement. Both mutant TRPV4 proteins had normal subcellular localization in HEK293 and HeLa cells. Cells transfected with R232C and R316H displayed increased intracellular Ca(2+) levels and reversible cell death by the TRPV channel antagonist, ruthenium red. CONCLUSION: TRPV4 ankyrin domain alterations including a novel de novo mutation cause axonal CMT2. Individuals with the same mutation may have nondistinct CMT2 or have phenotypic CMT2C with vocal cord paresis. Reversible hypercalcemic gain-of-function of mutant TRPV4 instead of loss-of-function appears to be pathologically important. The reversibility of cell death by channel blockade provides an attractive area of investigation in consideration of treatable axonal degeneration. PMID- 21288980 TI - Mitochondrial DNA haplogroups and mutations in children with acquired central demyelination. AB - OBJECTIVE: We investigated mitochondrial DNA (mtDNA) variants in children with a first episode of acquired demyelinating syndromes (PD-ADS) of the CNS and their relationship to disease phenotype, including subsequent diagnosis of multiple sclerosis (MS). METHODS: This exploratory analysis included the initial 213 children with PD-ADS in the prospective Canadian Pediatric Demyelinating Study and 166 matched healthy sibling controls from the Canadian Autism Genome Project. A total of 31 single nucleotide polymorphisms (SNPs) were analyzed, including haplogroup-defining SNPs and mtDNA variants previously reported to be associated with MS. RESULTS: Primary Leber hereditary optic neuropathy (LHON) mutations and other known pathogenic mtDNA mutations were absent in both patients with pediatric acquired demyelinating syndromes and controls. The 13708A haplogroup J associated variant, previously linked to adult MS, was more frequent among subjects with PD-ADS (13.0%) compared to controls (6.2%; odds ratio [OR] 2.27; 95% confidence interval [CI] 1.06 to 4.83) and haplogroup M was associated with an earlier age at onset of PD-ADS (-1.74 years; 95% CI -3.33 to -0.07). In contrast, the haplogroup cluster UKJT, as well as 3 other SNPs, were each associated with a lower risk of PD-ADS. A total of 33 subjects with PD-ADS were diagnosed with MS during a mean follow-up period of 3.11 +/- 1.14 (SD) years. No single SNP was associated with the risk of subsequent diagnosis of MS. However, haplogroup H was associated with an increased risk of MS (OR 2.60; 95% CI 1.21 to 5.55). CONCLUSION: These data suggest an association between mtDNA variants and the risk of PD-ADS and of a subsequent MS diagnosis. Replication of these findings in an independent population of subjects with PD-ADS is required. PMID- 21288982 TI - Metabolic syndrome and cognitive decline in French elders: the Three-City Study. AB - OBJECTIVE: To examine associations between metabolic syndrome (MetS) and its individual components with risk of cognitive decline on specific cognitive functions. METHODS: Participants were 4,323 women and 2,764 men aged 65 and over enrolled in the longitudinal Three-City Study. Cognitive decline, defined as being in the worst quintile of the distribution of the difference between baseline score and either 2- or 4-year follow-up, was assessed by the Mini-Mental State Examination (MMSE, global cognitive function), the Isaacs Set Test (IST, verbal fluency), and the Benton Visual Retention Test (BVRT, visual working memory). MetS was defined by National Cholesterol Education Program-Adult Treatment Panel III criteria (at least 3 of 5 cardio-metabolic abnormalities: hypertension, high waist circumference, hypertriglyceridemia, low high-density lipoprotein [HDL] cholesterol, hyperglycemia). Proportional hazards models were adjusted for age, gender, educational level, center, baseline cognitive score, APOE4 genotype, and other potential confounders. RESULTS: MetS at baseline was associated with an increased risk of cognitive decline on MMSE (hazard ratio [HR] = 1.22 [1.08-1.37]; p = 0.001) and BVRT (HR = 1.13 [1.01-1.26]; p = 0.03) but not on IST (HR = 1.11 [0.95-1.29]; p = 0.18). Among MetS components, hypertriglyceridemia and low HDL cholesterol were significantly associated with higher decline on MMSE; diabetes, but not elevated fasting glycemia, was significantly associated with higher decline on BVRT and IST. CONCLUSIONS: MetS as a whole and several of its components had a negative impact on global cognitive decline and specific cognitive functions in older persons. PMID- 21288983 TI - TRPV4 neuropathies: calcium channel inhibition as a therapeutic target? PMID- 21288984 TI - The King-Devick test as a determinant of head trauma and concussion in boxers and MMA fighters. AB - OBJECTIVE: Sports-related concussion has received increasing attention as a cause of short- and long-term neurologic symptoms among athletes. The King-Devick (K-D) test is based on measurement of the speed of rapid number naming (reading aloud single-digit numbers from 3 test cards), and captures impairment of eye movements, attention, language, and other correlates of suboptimal brain function. We investigated the K-D test as a potential rapid sideline screening for concussion in a cohort of boxers and mixed martial arts fighters. METHODS: The K-D test was administered prefight and postfight. The Military Acute Concussion Evaluation (MACE) was administered as a more comprehensive but longer test for concussion. Differences in postfight K-D scores and changes in scores from prefight to postfight were compared for athletes with head trauma during the fight vs those without. RESULTS: Postfight K-D scores (n = 39 participants) were significantly higher (worse) for those with head trauma during the match (59.1 +/ 7.4 vs 41.0 +/- 6.7 seconds, p < 0.0001, Wilcoxon rank sum test). Those with loss of consciousness showed the greatest worsening from prefight to postfight. Worse postfight K-D scores (r(s) = -0.79, p = 0.0001) and greater worsening of scores (r(s) = 0.90, p < 0.0001) correlated well with postfight MACE scores. Worsening of K-D scores by >=5 seconds was a distinguishing characteristic noted only among participants with head trauma. High levels of test-retest reliability were observed (intraclass correlation coefficient 0.97 [95% confidence interval 0.90-1.0]). CONCLUSIONS: The K-D test is an accurate and reliable method for identifying athletes with head trauma, and is a strong candidate rapid sideline screening test for concussion. PMID- 21288985 TI - Do old HLA and mitochondrial DNA variants associate with demyelination types in young patients? PMID- 21288986 TI - Transcranial sonography for monitoring hydrocephalus: an underestimated imaging modality. PMID- 21288987 TI - Retinal vascular caliber and risk of dementia: the Rotterdam study. AB - BACKGROUND: Retinal vessels provide a unique opportunity to study both systemic and cerebrovascular disease. Smaller retinal arteriolar calibers are strongly related to hypertension, whereas larger retinal venular calibers are more related to inflammation, cerebral hypoperfusion, and cerebrovascular disease. Whether retinal vessel calibers are related to dementia remains unclear. METHODS: We investigated whether retinal arteriolar and venular calibers are associated with risk of dementia, and its subtypes Alzheimer disease (AD) and vascular dementia, in the prospective population-based Rotterdam Study. Digitized retinal images were available in 5,553 participants aged 55 years or over and dementia-free at baseline (1990-1993). Participants were re-examined in 1993-1994, 1997-1999, and 2002-2004 and were continuously monitored for development of dementia. RESULTS: During a mean follow-up of 11.6 years, 655 participants developed dementia. AD was diagnosed in 519 and vascular dementia in 73 participants. Larger venular calibers were associated with an increased risk of dementia, in particular vascular dementia (age- and sex-adjusted hazard ratio per SD increase: 1.31; 95% confidence interval 1.06-1.64), but not AD. The association remained significant after adjustment for stroke and cardiovascular risk factors. Smaller arteriolar calibers were also associated with an increased risk of vascular dementia, yet only when adjusted for venular calibers. CONCLUSIONS: Retinal venular widening is associated with an increased risk of vascular dementia. Our findings are in line with previous observations in stroke and cerebral small-vessel disease and suggest that the association between larger retinal venular calibers and dementia may reflect cerebral hypoperfusion and subsequent ischemia. PMID- 21288988 TI - HLA-DRB1 confers increased risk of pediatric-onset MS in children with acquired demyelination. AB - BACKGROUND: Multiple sclerosis (MS) in the pediatric age group is being increasingly recognized. In adults, complex interactions between genetic and environmental factors contribute to risk and the major genetic component of MS susceptibility localizes to the major histocompatibility complex (human leukocyte antigen [HLA]). Whether HLA alleles predict MS in at-risk children presenting with acquired demyelinating syndromes (ADS) of the CNS is unknown. METHODS: HLA DRB1 alleles were typed using an allele-specific PCR amplification method on samples from 266 children presenting with ADS enrolled in the prospective Canadian Pediatric Demyelinating Disease Study and from 196 healthy controls. RESULTS: Sixty-four of 266 children with ADS met established criteria for a diagnosis of MS during a mean follow-up of 3.2 +/- 1.5 years. Children harboring DRB1*15 alleles were more likely to be diagnosed with MS (chi(2) = 12.2, p < 0.001; OR = 2.7), an observation strengthened by children of European ancestry (chi(2) = 10.5, p = 0.001; OR = 3.3). DRB1*15 allele frequencies in children with ADS of European ancestry subsequently diagnosed with MS were greater than in children with monophasic ADS (chi(2) = 10.7, p = 0.001) or healthy controls (chi(2) = 12.5, p < 0.001). The proportion of children with non-European ancestry diagnosed with MS was not influenced by DRB1*15 status. CONCLUSION: DRB1*15 alleles confer increased susceptibility to pediatric-onset MS, supporting a fundamental similarity in genetic contribution to MS risk in both pediatric- and adult-onset disease. The specificity of the DRB1*15 risk allele for children with subsequent MS diagnosis, but not for all children with ADS, indicates that the risk conveyed by DRB1*15 relates to chronic CNS disease (MS), rather than acquired demyelination in general. PMID- 21288989 TI - Motor vehicle crashes, suicides, and assaults: the dangers of epilepsy? PMID- 21288990 TI - MMPI-2-RF characteristics of custody evaluation litigants. AB - The Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF) is a 338-item objective self-report measure drawn from the 567 items of the MMPI 2. Although there is a substantial MMPI-2 literature regarding child custody litigants, there has been only one previously published study using MMPI-2-RF data in this population that focused on Validity scales L-r and K-r. The current study evaluated the MMPI-2-RF results of 344 child custody litigants and showed substantial consistency between T-score elevations typically found on MMPI-2 Validity scales L and K, and comparable elevations for MMPI-2-RF validity scales L-r and K-r. Mean T-scores well within normal limits characterized results for clinical scales on both instruments. The RC scale intercorrelation patterns, and alpha coefficient values found for MMPI-2-RF scales in a custody population, were also found to be very similar to those reported for other populations. Directions for future research are presented. PMID- 21288991 TI - Measuring grief following miscarriage: psychometric properties of the Chinese version of the Perinatal Grief Scale. AB - Grief following miscarriage is a complex psychological response. This study was conducted to examine the psychometric properties of the Chinese version of the Perinatal Grief Scale (PGS). A total of 280 Chinese women completed the PGS immediately following a diagnosis of miscarriage (baseline) and were reassessed at 12 months follow-up. The factor structure of the Chinese PGS was explored. The convergent validity of the PGS was established by examining its correlations with the General Health Questionnaire-12 and Beck Depression Inventory at baseline. The reliability of the Chinese PGS was satisfactory. A two-factor structure accounting for 45% of the variance was identified. The Chinese PGS was positively correlated with General Health Questionnaire-12 and Beck Depression Inventory scores. The Chinese PGS was found to be a reliable and valid tool to measure grief following miscarriage. PMID- 21288992 TI - Assessment of five antigens from Mycobacterium tuberculosis for serodiagnosis of tuberculosis. AB - Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a major public health issue, particularly in developing countries, and thus effective diagnostic methods for TB remain a central theme in basic and clinical research. To evaluate five antigens (38-kDa protein [38kDa], Rv3621c, Rv3618, 38kDa-ESAT-6 [38E6], and Ag85B-HBHA [AH]) in serological tests for TB patients, we recruited 288 patients and 201 healthy controls. The median IgG reactivity to 38kDa, 38E6, and AH was higher than that to Rv3618 and Rv3621c in pulmonary TB. 38kDa and 38E6 provided high sensitivities in pulmonary TB but low sensitivities in extrapulmonary TB (EPTB). The specificities achieved by 38kDa and 38E6 ranged from 82.0% to 93.9% in patients with non-TB respiratory disease (PD) and in controls. 38kDa and 38E6 exhibited lower sensitivities and higher specificities than their combinations with Rv3618. These findings provide useful information on the relative importance of the above five antigens and suggest that combinations of Rv3618 with 38kDa and 38E6 can increase their sensitivities, but their specificities need to be further increased. PMID- 21288993 TI - Differential Toll-like receptor recognition and induction of cytokine profile by Bifidobacterium breve and Lactobacillus strains of probiotics. AB - The use of probiotics as a food supplement has gained tremendous interest in the last few years as beneficial effects were reported in gut homeostasis and nutrient absorption but also in immunocompromised patients, supporting protection from colonization or infection with pathogenic bacteria or fungi. As a treatment approach for inflammatory bowel diseases, a suitable probiotic strain would ideally be one with a low immunogenic potential. Insight into the immunogenicities and types of T-cell responses induced by potentially probiotic strains allows a more rational selection of a particular strain. In the present study, the bacterial strains Bifidobacterium breve (NumRes 204), Lactobacillus rhamnosus (NumRes1), and Lactobacillus casei (DN-114 001) were compared concerning their capacity to induce inflammatory responses in terms of cytokine production by human and mouse primary immune cells. It was demonstrated that the B. breve strain induced lower levels of the proinflammatory cytokine gamma interferon (IFN-gamma) than the tested L. rhamnosus and L. casei strains. Both B. breve and lactobacilli induced cytokines in a Toll-like receptor 9 (TLR9) dependent manner, while the lower inflammatory profile of B. breve was due to inhibitory effects of TLR2. No role for TLR4, NOD2, and C-type lectin receptors was apparent. In conclusion, TLR signaling is involved in the differentiation of inflammatory responses between probiotic strains used as food supplements. PMID- 21288994 TI - Characterization of a mutant Escherichia coli heat-labile toxin, LT(R192G/L211A), as a safe and effective oral adjuvant. AB - Despite the fact that the adjuvant properties of the heat-labile enterotoxins of Escherichia coli (LT) and Vibrio cholerae (CT) have been known for more than 20 years, there are no available oral vaccines containing these molecules as adjuvants, primarily because they are both very potent enterotoxins. A number of attempts with various degrees of success have been made to reduce or eliminate the enterotoxicity of LT and CT so they can safely be used as oral adjuvants or immunogens. In this report we characterize the structural, enzymatic, enterotoxic, and adjuvant properties of a novel mutant of LT, designated LT(R192G/L211A), or dmLT. dmLT was not sensitive to trypsin activation, had reduced enzymatic activity for induction of cyclic AMP in Caco-2 cells, and exhibited no enterotoxicity in the patent mouse assay. Importantly, dmLT retained the ability to function as an oral adjuvant for a coadministered antigen (tetanus toxoid) and to elicit anti-LT antibodies. In vitro and in vivo data suggest that the reduced enterotoxicity of this molecule compared to native LT or the single mutant, LT(R192G), is a consequence of increased sensitivity to proteolysis and rapid intracellular degradation in mammalian cells. In conclusion, dmLT is a safe and powerful detoxified enterotoxin with the potential to function as a mucosal adjuvant for coadministered antigens and to elicit anti-LT antibodies without undesirable side effects. PMID- 21288995 TI - A Leptospira borgpetersenii serovar Hardjo vaccine induces a Th1 response, activates NK cells, and reduces renal colonization. AB - Chronic infection of cattle with Leptospira borgpetersenii serovar Hardjo reduces animal production through reproductive failure and presents a persistent health threat to workers in the animal industry. Cattle are maintenance hosts for serovar Hardjo, and development of vaccines that establish long-term protective immunity has been problematic; induction of high titers of anti-serovar Hardjo antibody does not appear to be protective. Rather, development of an antigen specific Th1 response appears to be critical for limiting renal colonization and urinary shedding of bacteria. In this study we compared two monovalent killed bacterial cell vaccines to assess long-term (12 months) protection against live serovar Hardjo challenge. Although neither vaccine prevented infection, renal colonization and urinary shedding of bacteria were reduced compared to those of control animals. Increased proliferation of CD4(+), CD8(+), and gammadelta T cells from vaccinated, but not control, animals was detected. In addition, NK cells from vaccinated animals and from all animals following infection, when exposed to antigen ex vivo, demonstrated a gamma interferon (IFN-gamma) recall response. We propose that programming NK cells to respond quickly to L. borgpetersenii serovar Hardjo infection may be an important step toward developing protective immunity. PMID- 21288996 TI - Microneedle vaccination with stabilized recombinant influenza virus hemagglutinin induces improved protective immunity. AB - The emergence of the swine-origin 2009 influenza pandemic illustrates the need for improved vaccine production and delivery strategies. Skin-based immunization represents an attractive alternative to traditional hypodermic needle vaccination routes. Microneedles (MNs) can deliver vaccine to the epidermis and dermis, which are rich in antigen-presenting cells (APC) such as Langerhans cells and dermal dendritic cells. Previous studies using coated or dissolvable microneedles emphasized the use of inactivated influenza virus or virus-like particles as skin based vaccines. However, most currently available influenza vaccines consist of solubilized viral protein antigens. Here we test the hypothesis that a recombinant subunit influenza vaccine can be delivered to the skin by coated microneedles and can induce protective immunity. We found that mice vaccinated via MN delivery with a stabilized recombinant trimeric soluble hemagglutinin (sHA) derived from A/Aichi/2/68 (H3) virus had significantly higher immune responses than did mice vaccinated with unmodified sHA. These mice were fully protected against a lethal challenge with influenza virus. Analysis of postchallenge lung titers showed that MN-immunized mice had completely cleared the virus from their lungs, in contrast to mice given the same vaccine by a standard subcutaneous route. In addition, we observed a higher ratio of antigen specific Th1 cells in trimeric sHA-vaccinated mice and a greater mucosal antibody response. Our data therefore demonstrate the improved efficacy of a skin-based recombinant subunit influenza vaccine and emphasize the advantage of this route of vaccination for a protein subunit vaccine. PMID- 21288997 TI - Serum IgG response to Cryptosporidium immunodominant antigen gp15 and polymorphic antigen gp40 in children with cryptosporidiosis in South India. AB - The surface-associated glycopeptides gp40, one of the most polymorphic Cryptosporidium antigens, and gp15, one of the most immunodominant Cryptosporidium antigens, are putative vaccine candidates because they mediate infection in vitro and induce immune responses in vivo. We evaluated antibody responses to these antigens before and after the first episode of symptomatic cryptosporidiosis in 51 children from a birth cohort study in an area in South India where Cryptosporidium is endemic and a major cause of parasitic diarrhea. IgG levels to gp15 and to homotypic and heterotypic gp40 antigens were measured in pre- and postdiarrheal sera by enzyme-linked immunosorbent assay (ELISA). There was a significant IgG response to gp15 (P < 0.001) following the first episode of cryptosporidial diarrhea. Using a general additive model, we determined the estimated time of the peak IgG response to gp15 to be 9.3 weeks (confidence interval, 5.2 to 13.4) following the diarrheal episode. In a subset of 30 children infected with Cryptosporidium hominis subtype Ia, there was a significant difference in IgG responses to homotypic C. hominis Ia and to heterotypic Cryptosporidium parvum II gp40 antigens (P = 0.035). However, there was also a significant correlation (P = 0.001) in the responses to both antigens in individual children, suggesting that while responses are in part subtype specific, there is significant cross-reactivity to both antigens. This is the first report of the characterization of immune responses to cryptosporidiosis in Indian children and the first study to investigate human immune responses to the polymorphic gp40 antigen. However, further studies are needed to determine whether immune responses to these antigens are protective against subsequent infections. PMID- 21288998 TI - Prospective studies show that magnetic resonance angiography has high sensitivity and specificity for clinically relevant arterial steno-occlusions in adults with peripheral arterial disease symptoms. PMID- 21288999 TI - Prevalence of wasting among under 6-month-old infants in developing countries and implications of new case definitions using WHO growth standards: a secondary data analysis. AB - OBJECTIVES: To determine wasting prevalence among infants aged under 6 months and describe the effects of new case definitions based on WHO growth standards. DESIGN: Secondary data analysis of demographic and health survey datasets. SETTING: 21 developing countries. POPULATION: 15 534 infants under 6 months and 147 694 children aged 6 to under 60 months (median 5072 individuals/country, range 1710-45 398). Wasting was defined as weight-for-height z-score <-2, moderate wasting as -3 to <-2 z-scores, severe wasting as z-score <-3. RESULTS: Using National Center for Health Statistics (NCHS) growth references, the nationwide prevalence of wasting in infant under-6-month ranges from 1.1% to 15% (median 3.7%, IQR 1.8-6.5%; ~3 million wasted infants <6 months worldwide). Prevalence is more than doubled using WHO standards: 2.0-34% (median 15%, IQR 6.2 17%; ~8.5 million wasted infants <6 months worldwide). Prevalence differences using WHO standards are more marked for infants under 6 months than children, with the greatest increase being for severe wasting (indicated by a regression line slope of 3.5 for infants <6 months vs 1.7 for children). Moderate infant-6 month wasting is also greater using WHO, whereas moderate child wasting is 0.9 times the NCHS prevalence. CONCLUSIONS: Whether defined by NCHS references or WHO standards, wasting among infants under 6 months is prevalent in many of the developing countries examined in this study. Use of WHO standards to define wasting results in a greater disease burden, particularly for severe wasting. Policy makers, programme managers and clinicians in child health and nutrition programmes should consider resource and risk/benefit implications of changing case definitions. PMID- 21289000 TI - 31P-MRS demonstrates a reduction in high-energy phosphates in the occipital lobe of migraine without aura patients. AB - BACKGROUND: Differences in brain energy metabolism have been found between migraine patients and controls in previous phosphorus magnetic resonance spectroscopy ((31)P-MRS) studies, most of them emphasizing migraine with aura (MwA). The aim of this study was to verify potential changes in resting-state brain energy metabolism in patients with migraine without aura (MwoA) compared to control subjects by (31)P-MRS at 3 tesla. METHODS: Quantification was performed using the phantom replacement technique. MRS measurements were performed interictally and in the medial occipital lobe of 19 MwoA patients and 26 age matched controls. RESULTS: A significantly decreased phosphocreatine concentration ([PCr]) was found as in previous studies. While adenosine triphosphate concentration ([ATP]) was considered to be constant in previously published work, this study found a significant decrease in the measured [ATP] in MwoA patients. The inorganic phosphate ([P(i)]) and magnesium ([Mg(2+)]) concentrations were not significantly different between MwoA patients and controls. CONCLUSIONS: The altered metabolic concentrations indicate that the energy metabolism in MwoA patients is impaired, certainly in a subgroup of patients. The actual decrease in [ATP] adds further strength to the theory of the presence of a mitochondrial component in the pathophysiology of migraine. PMID- 21289001 TI - Polymorphisms in the annexin A5 gene promoter in Japanese women with recurrent pregnancy loss. AB - Recent findings have raised the possibility that polymorphisms within the annexin A5 gene (ANXA5) promoter contribute to the etiology of recurrent pregnancy loss (RPL). In our present study, 243 Japanese women who had suffered more than three fetal losses and a group of 119 fertile controls were genotyped for four ANXA5 gene promoter single-nucleotide polymorphisms (SNPs; SNP1-4: g.-467G >A, g. 448A>C, g.-422T>C, g.-373G>A) previously reported to be associated with this disorder. An additional two SNPs located within the 5'-untranslated region of the ANXA5 (SNP5 and 6: g.-302T>G, g.-1C>T) were also evaluated. Our case--control study revealed that the minor allele was significantly more frequent in the RPL group than controls for all six of these SNPs, among which SNP5 showed the highest significance (P= 0.002). As with the M2 haplotype for SNP1-4 (A-C-C-A) for a western population in previous reports, a haplotype comprising all of the minor alleles for SNP1-6 (A-C-C-A-G-T), the third major haplotype in the Japanese population, showed a significantly higher frequency in our current RPL subjects than in controls (P= 0.025). In addition, the second major haplotype (G-A-T-G-G C) was found to confer a significant risk of RPL (P= 0.036), implicating SNP5 as a major risk determinant for this disease. Our present findings support the hypothesis that genomic variations within the ANXA5 gene upstream region impact upon the disease susceptibility to RPL. Our data indicate that SNP5 is a novel risk factor for this disease in the Japanese population. PMID- 21289002 TI - Wide-ranging DNA methylation differences of primary trophoblast cell populations and derived cell lines: implications and opportunities for understanding trophoblast function. AB - Difficulties associated with long-term culture of primary trophoblasts have proven to be a major hurdle in their functional characterization. In order to circumvent this issue, several model cell lines have been established over many years using a variety of different approaches. Due to their differing origins, gene expression profiles and behaviour in vitro, different model lines have been utilized to investigate specific aspects of trophoblast biology. However, generally speaking, the molecular mechanisms underlying functional differences remain unclear. In this study, we profiled genome-scale DNA methylation in primary first trimester trophoblast cells and seven commonly used trophoblast derived cell lines in an attempt to identify functional pathways differentially regulated by epigenetic modification in these cells. We identified a general increase in DNA promoter methylation levels in four choriocarcinoma (CCA)-derived lines and transformed HTR-8/SVneo cells, including hypermethylation of several genes regularly seen in human cancers, while other differences in methylation were noted in genes linked to immune responsiveness, cell morphology, development and migration across the different cell populations. Interestingly, CCA-derived lines show an overall methylation profile more similar to unrelated solid cancers than to untransformed trophoblasts, highlighting the role of aberrant DNA methylation in CCA development and/or long-term culturing. Comparison of DNA methylation and gene expression in CCA lines and cytotrophoblasts revealed a significant contribution of DNA methylation to overall expression profile. These data highlight the variability in epigenetic state between primary trophoblasts and cell models in pathways underpinning a wide range of cell functions, providing valuable candidate pathways for future functional investigation in different cell populations. This study also confirms the need for caution in the interpretation of data generated from manipulation of such pathways in vitro. PMID- 21289004 TI - An asthmatic child with a troublesome cough. PMID- 21289006 TI - Well enough to work? PMID- 21289007 TI - We should push for evidence based sentencing in criminal justice. PMID- 21289008 TI - "Make the care of your patient your first concern". PMID- 21289009 TI - Heart heal thyself: a new direction for cardiac research. PMID- 21289010 TI - Donor countries have responsibility to root out corruption in aid flows. PMID- 21289011 TI - Transforming growth factor-beta and oxidative stress mediate tachycardia-induced cellular remodelling in cultured atrial-derived myocytes. AB - AIMS: Atrial fibrillation (AF), a common tachyarrhythmia in clinical practice, is associated with increased oxidative stress. Structural remodelling in atrial myocytes, including myofibril degradation, is an important characteristic of AF. However, the mechanism underlying AF-induced cellular structural remodelling remains unclear. The aim of this study was to investigate the role of oxidative stress and related factors in tachycardia-induced atrial structural remodelling. METHODS AND RESULTS: Cultured atrial-derived myocytes (HL-1 cell line) were subjected to electrical stimulation. Immunofluorescence and immunoblotting were used to evaluate oxidative stress, myofibril degradation, and transforming growth factor-beta (TGF-beta) expression. Tachypacing in HL-1 cells induced TGF-beta expression, pronounced oxidative stress including up-regulation of NADPH oxidases (Nox2/4), and myofibril degradation. Oxidative stress scavenger, NADPH oxidase inhibitors, and small-interfering RNAs for Nox2/4 blocked tachypacing-induced myofibril degradation, suggesting that Nox-derived oxidative stress may lead to tachycardia-induced myofibril degradation. Blockade of TGF-beta signalling by neutralizing TGF-beta antibodies attenuated myofibril loss in response to tachypacing, implicating autocrine and/or paracrine roles for TGF-beta in such effects. Tachypacing also induced the activation of p-Smad3 (an effective mediator of TGF-beta) and small-interfering RNAs for Nox2/4 attenuated its activation, supporting a crosstalk between both signalling pathways. Furthermore, TGF-beta expression, oxidative stress, and myofibril loss were greater in the atria of patients with AF than those with sinus rhythm. CONCLUSIONS: Rapid activation in atrial myocytes promotes myofibril degradation through autocrine/paracrine TGF-beta signalling and increased oxidative stress. These findings provide an important mechanistic insight into AF-related structural remodelling. PMID- 21289012 TI - Modulating fatty acid oxidation in heart failure. AB - In the advanced stages of heart failure, many key enzymes involved in myocardial energy substrate metabolism display various degrees of down-regulation. The net effect of the altered metabolic phenotype consists of reduced cardiac fatty oxidation, increased glycolysis and glucose oxidation, and rigidity of the metabolic response to changes in workload. Is this metabolic shift an adaptive mechanism that protects the heart or a maladaptive process that accelerates structural and functional derangement? The question remains open; however, the metabolic remodelling of the failing heart has induced a number of investigators to test the hypothesis that pharmacological modulation of myocardial substrate utilization might prove therapeutically advantageous. The present review addresses the effects of indirect and direct modulators of fatty acid (FA) oxidation, which are the best pharmacological agents available to date for 'metabolic therapy' of failing hearts. Evidence for the efficacy of therapeutic strategies based on modulators of FA metabolism is mixed, pointing to the possibility that the molecular/biochemical alterations induced by these pharmacological agents are more complex than originally thought. Much remains to be understood; however, the beneficial effects of molecules such as perhexiline and trimetazidine in small clinical trials indicate that this promising therapeutic strategy is worthy of further pursuit. PMID- 21289013 TI - Surveillance of congenital cytomegalovirus in the UK and Ireland. AB - OBJECTIVE: To explore the presentation and management of congenital cytomegalovirus (CMV) identified through routine clinical investigations, and ascertain outcome in early childhood. DESIGN: Active population-based surveillance. SETTING: UK and Ireland. METHODS: Infants born in 2001-2002 with confirmed or suspected congenital CMV infection were reported through the British Paediatric Surveillance Unit, and clinicians completed questionnaires on presentation, diagnosis, management and subsequent outcome. RESULTS: 86 confirmed and 70 possible cases of congenital CMV infection were reported. Over a third (27/72) of singleton infants with confirmed and 44% (27/61) with possible congenital infection were preterm (<37 weeks gestation). Among confirmed cases, 75% (64/85) presented with neonatal manifestations compatible with congenital CMV, over half (34/64) of whom had neurological signs; 17 infants were treated with gancyclovir. Among confirmed cases with information on outcome, 31% (24/78) were developing normally, 18% (14/78) had mild, 24% (19/78) moderate and 14% (11/78) severe sequelae, and 13% (10/78) had died. Median age at follow-up among survivors was 18 months (IQR 15-22 months). Children with neonatal CMV manifestations were significantly more likely than those without to have moderate or severe outcomes (including death) (60%, 36/60, vs 22%, 4/18, p=0.001). 27% of survivors (17/63) had bilateral hearing loss. CONCLUSIONS: The number of confirmed cases of diagnosed congenital CMV reported in this study was lower than expected, highlighting the need for early and appropriate investigations when congenital infection is suspected. Due to the unexpectedly high proportion of preterm infants, resulting from differential case ascertainment, it was difficult to distinguish prematurity and CMV-related symptoms. PMID- 21289014 TI - Postnatal steroids: the way forward. PMID- 21289015 TI - Management of posthaemorrhagic ventricular dilatation. AB - Intraventricular haemorrhage and posthaemorrhagic ventricular dilatation remain an important challenge in the management of prematurity and are associated with significant permanent morbidity. Progressive ventricular dilatation causes white matter injury by pressure, distortion, free radical injury and inflammation. Therapeutic interventions include serial lumbar punctures, only useful when the ventricles remain in communication with the lumbar subarachnoid space, and repeated aspiration through a ventricular access device. Reduction of cerebrospinal fluid production by acetazolamide and frusemide in a large multicentre randomised trial showed a worse outcome in the treated arm. A trial of drainage, irrigation and fibrinolytic therapy did not demonstrate a reduced need for permanent cerebrospinal fluid diversion, but did show a significant reduction in severe cognitive disability at two years. Ventriculoperitoneal shunting is indicated when the ventricles continue to enlarge at a body weight of around 2.5 kg and cerebrospinal fluid protein levels are below 1.5 g /L. This review summarises current concepts on the pathophysiology and management of posthaemorrhagic ventricular dilatation, underlining clinical challenges and ongoing research. Although the percentage of small preterm infants developing intraventricular haemorrhage (IVH) has been greatly reduced in the last three decades, increased survival of very immature infants has meant that large IVH with subsequent posthaemorrhagic ventricular dilatation is still a serious unsolved problem. PMID- 21289016 TI - A novel method for testing the veridicality of dental colour assessments. AB - The Commission Internationale de l'Eclairage (CIE) L*a*b* three-dimensional coordinates suggest strong correlations between the data of a* (red-green axis) and b* (blue-yellow axis), as both are located on the same plane in the model and should therefore show a strong dependency. In order to assess the veridicality of colour determinations, the null hypothesis of no significant changes in CIE-a*/b* coherences of dental colours following a colour or lightness change induced by external dental bleaching was tested. Values from 231 extracted anterior teeth were assessed using the digital photographic CIELAB recalculation method. Teeth were then assigned to three groups (n = 77) with contrasting baseline CIE-L* values. Group A served as the control with no alteration in dental colour. The specimens in the two other groups were altered in colour or lightness employing treatment with either 15 per cent carbamide peroxide (group B) or 38 per cent hydrogen peroxide (group C). Pearson's pairwise correlation coefficient of CIE L*; a*, CIE-L*; b*, and CIE-a*; b* were calculated for assessments at baseline (T0) and after 2 (T1), 4 (T2), 12 (T3), and 24 (T4) weeks. The correlations of a* and b* from T0 to T4, in relation to group A, were stable, with coefficients of 0.78->0.65->0.65->0.69->0.67. Bleaching-induced colour and lightness changes did not have a significant influence on the a*/b* coherences assessed. A distinctly weaker and inverse relationship was observed between L* and a* values and between L* and b* values in the groups, with correlation coefficients ranging from -0.54 to -0.12. Colour coherences detected at specific points in time were in agreement with theoretical CIE colour coherences. In order to compare the methodology of different colour analyses, the analysis of correlations between CIE-a* and -b* values is advocated as an additional routine test in future CIELAB studies. PMID- 21289017 TI - The effect of magnesium infusion on rest cramps: randomized controlled trial. AB - BACKGROUND: Rest cramps (also known as nocturnal leg cramps) are very common in a geriatric population. Oral magnesium supplements are marketed for prophylaxis of such cramps but clinical trials exploring the efficacy of oral magnesium conflict. A therapeutic trial of intravenous magnesium overcomes the limited oral bioavailability of magnesium and better assesses its therapeutic potential. METHODS: A double blind, placebo controlled randomized controlled trial was conducted on 46 community-dwelling older adult (69.3 +/- 7.7 years) rest cramp sufferers to determine whether 5 consecutive days infusion of 20-mmol (5 g) magnesium sulfate would reduce the frequency of leg cramps per week in the 30 days immediately pre and post infusions. It was also determined whether the response to treatment varied with the extent to which infused magnesium was retained (as measured by 24-hour urinary magnesium excretion). RESULTS: The study population averaged 8.0 cramps per week at baseline. The mean change in number of cramps per week, magnesium versus placebo arms, was -2.4 versus -1.7, p = .51, 95% confidence interval of the difference -3.1 to 1.7. Magnesium retention did not correlate with treatment response. CONCLUSIONS: Intravenous magnesium infusion did not reduce the frequency of leg cramps in a group of older adult rest cramp sufferers regardless of the extent to which infused magnesium was retained. Although oral magnesium is widely marketed to older adults for the prophylaxis of leg cramps, our data suggest that magnesium therapy is not indicated for the treatment of rest cramps in a geriatric population. PMID- 21289018 TI - Leukocyte telomere length and mortality in the Cardiovascular Health Study. AB - BACKGROUND: Leukocyte telomere length (LTL) is related to diseases of aging, but studies of mortality have been inconsistent. METHODS: We evaluated LTL in relation to total mortality and specific cause of death in 1,136 participants of the Cardiovascular Health Study who provided blood samples in 1992-1993 and survived through 1997-1998. LTL was measured by Southern blots of the terminal restriction fragments. Cause of death was classified by a committee of physicians reviewing death certificates, medical records, and informant interviews. RESULTS: A total of 468 (41.2%) deaths occurred over 6.1 years of follow-up in participants with mean age of 73.9 years (SD 4.7), 65.4% female, and 14.8% African American. Although increased age and male gender were associated with shorter LTLs, African Americans had significantly longer LTLs independent of age and sex (p < .001). Adjusted for age, sex, and race, persons with the shortest quartile of LTL were 60% more likely to die during follow-up than those within the longest quartile (hazard ratio: 1.61, 95% confidence interval: 1.22-2.12, p = .001). The association remained after adjustment for cardiovascular disease risk factors. Evaluations of cause of death found LTL to be related to deaths due to an infectious disease etiology (hazard ratio: 2.80, 95% confidence interval: 1.32 5.94, p = .007), whereas a borderline association was found for cardiac deaths (hazard ratio: 1.82, 95% confidence interval: 0.95-3.49, p = .07) in adjusted models. Risk estimates for deaths due to cancer, dementia, and ischemic stroke were not significant. CONCLUSION: These data weakly corroborate prior findings of associations between LTL and mortality in the elderly. PMID- 21289019 TI - Association between retinal thickness measured by spectral-domain optical coherence tomography (OCT) and rod-mediated dark adaptation in non-exudative age related maculopathy. AB - AIM: To examine associations between retinal thickness and rod-mediated dark adaptation in older adults with non-exudative age-related maculopathy (ARM) or normal macular health. METHODS: A cross-sectional study was conducted with 74 adults >= 50 years old from the comprehensive ophthalmology and retina services of an academic eye centre. ARM presence and disease severity in the enrolment eye was defined by the masked grading of stereofundus photos using the Clinical Age Related Maculopathy grading system. High-definition, spectral-domain optical coherence tomography was used to estimate retinal thickness in a grid of regions in the macula. Rod-mediated dark adaptation, recovery of light sensitivity after a photo-bleach, was measured over a 20-min period for a 500 nm target presented at 5 degrees on the inferior vertical meridian. Main outcomes of interest were retinal thickness in the macula (MUm) and parameters of rod-mediated dark adaptation (second slope, third slope, average sensitivity, final sensitivity). RESULTS: In non-exudative disease retinal thickness was decreased in greater disease severity; thinner retina was associated with reductions in average and final rod-mediated sensitivity even after adjustment for age and visual acuity. CONCLUSIONS: Impairment in rod-mediated dark adaptation in non-exudative ARM is associated with macular thinning. PMID- 21289020 TI - Adjunctive use of intravitreal dexamethasone in presumed bacterial endophthalmitis: a randomised trial. AB - AIM: To evaluate the use of intravitreal dexamethasone as adjunctive therapy in the treatment of presumed bacterial endophthalmitis. Design Prospective, double masked, randomised placebo-controlled clinical trial. METHODS: Patients with 'post cataract surgery', 'bleb-related' and 'other' endophthalmitis were grouped and randomised to receive intravitreal ceftazidime (2.225 mg/0.1 ml), vancomycin (1 mg/0.1 ml), and either dexamethasone (0.4 mg/0.1) or placebo. All underwent vitreous and aqueous sampling for microbiological analysis. Injections were repeated after 48 h if necessary. The primary outcome measure was Snellen visual acuity on presentation, within the first 14 days post injection, and at 2-4 months. RESULTS: 62 patients completed the protocol from 2001 to 2005. Thirty patients received intravitreal dexamethasone and 32 received intravitreal placebo. There was no statistically significant difference in the visual outcomes of either group with a mean 2.79 Snellen lines improvement of the intravitreal dexamethasone group versus 1.8 lines in the placebo group. Subgroup analysis suggested a clinical trend to better visual acuity in the post cataract steroid subgroup with mean 4.1 lines improvement versus 2.7 in the placebo group (p=0.33). No adverse events attributable to the dexamethasone were reported. CONCLUSIONS: Intravitreal dexamethasone appears safe and may be of benefit in post cataract surgery bacterial endophthalmitis. PMID- 21289021 TI - Gelatin foam cell blocks made from cytology fluid specimens. AB - This report describes a simple method of preparing cell blocks from fluids submitted for cytology, using croutons of gelatin foam surgical dressing material. PMID- 21289022 TI - Health-related quality of life in Indian patients with three viral sexually transmitted infections: herpes simplex virus-2, genital human papilloma virus and HIV. AB - BACKGROUND: Health-related quality of life (HRQOL) has not been studied in Indian patients with viral sexually transmitted infections (STIs): herpes simplex virus 2 (HSV-2) and genital human papilloma virus (HPV) infections. Furthermore, there is no reported study that compares HRQOL among these two viral STIs and HIV. METHODS: All consenting adults with any of the three viral infections attending a sexually transmitted disease clinic and 35 healthy controls were enrolled. HRQOL was evaluated using the WHOQOL-BREF instrument, which evaluates QOL under physical, psychological, social and environmental domains. Data concerning demographic and socioeconomic status were collected. RESULTS: There were 65 (27.3%), 60 (25.2%) and 53 (22.3%) patients with HIV, HSV-2 and HPV, respectively, and 25 (10.5%) patients with mixed infections. The WHOQOL-BREF scores of patients in different STI groups were significantly lower than those of controls. The total HRQOL scores (mean+/-SD) were 280.1+/-83.56 (among controls), 196.9+/-72.41 (genital HPV), 141.0+/-50.50 (HSV-2), 101.0+/-75.25 (HIV) and 103.4+/-47.23(mixed infection groups). Mean HRQOL scores were lowest in the physical and psychological domains. HRQOL scores were least in HIV and mixed infections groups, while patients with genital HPV infection had significantly better HRQOL scores compared to other patient groups. Higher education and socioeconomic status had a positive influence on HRQOL. CONCLUSION: Viral STIs were associated with a significant reduction in HRQOL scores. Among patient groups, the greatest impact on HRQOL was seen in those with HIV and mixed infections and the least impact seen in those with genital HPV infection. Comprehensive care including counselling services need to be implemented in STI clinics. PMID- 21289023 TI - Intrapulmonary shunting associated with sildenafil treatment in a patient with idiopathic pulmonary arterial hypertension. PMID- 21289024 TI - Rhinovirus infection liberates planktonic bacteria from biofilm and increases chemokine responses in cystic fibrosis airway epithelial cells. AB - BACKGROUND: Intermittent viral exacerbations in patients with cystic fibrosis (CF) with chronic Pseudomonas aeruginosa (PA) infection are associated with increased bacterial load. A few clinical studies suggest that rhinoviruses (RV) are associated with the majority of viral-related exacerbations in CF and require prolonged intravenous antibiotic treatment. These observations imply that acute RV infection may increase lower respiratory symptoms by increasing planktonic bacterial load. However, the underlying mechanisms are not known. METHODS: Primary CF airway epithelial cells differentiated into mucociliary phenotype were infected with mucoid PA (MPA) followed by RV and examined for bacterial density, biofilm mass, levels of chemokines and hydrogen peroxide (H2O2). The need for dual oxidase 2, a component of NADPH oxidase, in RV-induced generation of H2O2 in CF cells was assessed using gene-specific siRNA. RESULTS: Superinfection with RV increased chemokine responses in CF mucociliary-differentiated airway epithelial cells with pre-existing MPA infection in the form of biofilm. This was associated with the presence of planktonic bacteria at both the apical and basolateral epithelial cell surfaces. Further, RV-induced generation of H2O2 via dual oxidase 2 in CF cells was sufficient for dispersal of planktonic bacteria from the biofilm. Inhibition of NADPH oxidase reduced bacterial transmigration across mucociliary-differentiated CF cells and the interleukin-8 response in MPA- and RV infected cells. CONCLUSION: This study shows that acute infection with RV liberates planktonic bacteria from biofilm. Planktonic bacteria, which are more proinflammatory than their biofilm counterparts, stimulate increased chemokine responses in CF airway epithelial cells which, in turn, may contribute to the pathogenesis of CF exacerbations. PMID- 21289025 TI - A cytochemical and immunocytochemical analysis of the wall labyrinth apparatus in leaf transfer cells in Elodea canadensis. AB - BACKGROUND AND AIMS: Transfer cells are plant cells specialized in apoplast/symplast transport and characterized by a distinctive wall labyrinth apparatus. The molecular architecture and biochemistry of the labyrinth apparatus are poorly known. The leaf lamina in the aquatic angiosperm Elodea canadensis consists of only two cell layers, with the abaxial cells developing as transfer cells. The present study investigated biochemical properties of wall ingrowths and associated plasmalemma in these cells. METHODS: Leaves of Elodea were examined by light and electron microscopy and ATPase activity was localized cytochemically. Immunogold electron microscopy was employed to localize carbohydrate epitopes associated with major cell wall polysaccharides and glycoproteins. KEY RESULTS: The plasmalemma associated with the wall labyrinth is strongly enriched in light-dependent ATPase activity. The wall ingrowths and an underlying wall layer share an LM11 epitope probably associated with glucuronoarabinoxylan and a CCRC-M7 epitope typically associated with rhamnogalacturonan I. No labelling was observed with LM10, an antibody that recognizes low-substituted and unsubstituted xylan, a polysaccharide consistently associated with secondary cell walls. The JIM5 and JIM7 epitopes, associated with homogalacturonan with different degrees of methylation, appear to be absent in the wall labyrinth but present in the rest of cell walls. CONCLUSIONS: The wall labyrinth apparatus of leaf transfer cells in Elodea is a specialized structure with distinctive biochemical properties. The high level of light-dependent ATPase activity in the plasmalemma lining the wall labyrinth is consistent with a formerly suggested role of leaf transfer cells in enhancing inorganic carbon inflow. The wall labyrinth is a part of the primary cell wall. The discovery that the wall ingrowths in Elodea have an antibody-binding pattern divergent, in part, from that of the rest of cell wall suggests that their carbohydrate composition is modulated in relation to transfer cell functioning. PMID- 21289026 TI - The three-dimensional distribution of minerals in potato tubers. AB - BACKGROUND AND AIMS: The three-dimensional distributions of mineral elements in potato tubers provide insight into their mechanisms of transport and deposition. Many of these minerals are essential to a healthy human diet, and characterizing their distribution within the potato tuber will guide the effective utilization of this staple foodstuff. METHODS: The variation in mineral composition within the tuber was determined in three dimensions, after determining the orientation of the harvested tuber in the soil. The freeze-dried tuber samples were analysed for minerals using inductively coupled plasma-mass spectrometry (ICP-MS). Minerals measured included those of nutritional significance to the plant and to human consumers, such as iron, zinc, copper, calcium, magnesium, manganese, phosphorus, potassium and sulphur. KEY RESULTS: The concentrations of most minerals were higher in the skin than in the flesh of tubers. The potato skin contained about 17 % of total tuber zinc, 34 % of calcium and 55 % of iron. On a fresh weight basis, most minerals were higher in tuber flesh at the stem end than the bud end of the tuber. Potassium, however, displayed a gradient in the opposite direction. The concentrations of phosphorus, copper and calcium decreased from the periphery towards the centre of the tuber. CONCLUSIONS: The distribution of minerals varies greatly within the potato tuber. Low concentrations of some minerals relative to those in leaves may be due to their low mobility in phloem, whereas high concentrations in the skin may reflect direct uptake from the soil across the periderm. In tuber flesh, different minerals show distinct patterns of distribution in the tuber, several being consistent with phloem unloading in the tuber and limited onward movement. These findings have implications both for understanding directed transport of minerals in plants to stem-derived storage organs and for the dietary implications of different food preparation methods for potato tubers. PMID- 21289027 TI - Three-dimensional distribution of vessels, passage cells and lateral roots along the root axis of winter wheat (Triticum aestivum). AB - BACKGROUND AND AIMS: The capacity of a plant to absorb and transport water and nutrients depends on anatomical structures within the roots and their co ordination. However, most descriptions of root anatomical structure are limited to 2-D cross-sections, providing little information on 3-D spatial relationships and hardly anything on their temporal evolution. Three-dimensional reconstruction and visualization of root anatomical structures can illustrate spatial co ordination among cells and tissues and provide new insights and understanding of the interrelation between structure and function. METHODS: Classical paraffin serial-section methods, image processing, computer-aided 3-D reconstruction and 3 D visualization techniques were combined to analyse spatial relationships among metaxylem vessels, passage cells and lateral roots in nodal roots of winter wheat (Triticum aestivum). KEY RESULTS: 3-D reconstruction demonstrated that metaxylem vessels were neither parallel, nor did they run directly along the root axis from the root base to the root tip; rather they underwent substitution and transition. Most vessels were connected to pre-existent or newly formed vessels by pits on their lateral walls. The spatial distributions of both passage cells and lateral roots exhibited similar position-dependent patterns. In the transverse plane, the passage cells occurred opposite the poles of the protoxylem and the lateral roots opposite those of the protophloem. Along the axis of a young root segment, the passage cells were arranged in short and discontinuous longitudinal files, thus as the tissues mature, the sequence in which the passage cells lose their transport function is not basipetal. In older segments, passage cells decreased drastically in number and coexisted with lateral roots. The spatial distribution of lateral roots was similar to that of the passage cells, mirroring their similar functions as lateral pathways for water and nutrient transport to the stele. CONCLUSIONS: With the 3-D reconstruction and visualization techniques developed here, the spatial relationships between vessels, passage cells and lateral roots and the temporal evolution of these relationships can be described. The technique helps to illustrate synchronization and spatial co-ordination among the root's radial and axial pathways for water and nutrient transport and the interdependence of structure and function in the root. PMID- 21289028 TI - Promoting calls to a quitline: quantifying the influence of message theme, strong negative emotions and graphic images in television advertisements. AB - OBJECTIVE: To understand the relative effectiveness of television advertisements that differ in their thematic focus and portrayals of negative emotions and/or graphic images in promoting calls to a smokers' quitline. METHODS: Regression analysis is used to explain variation in quarterly media market-level per smoker calls to the New York State Smokers' Quitline from 2001 to 2009. The primary independent variable is quarterly market-level delivery of television advertisements measured by target audience rating points (TARPs). Advertisements were characterised by their overall objective--promoting cessation, highlighting the dangers of secondhand smoke (SHS) or other--and by their portrayals of strong negative emotions and graphic images. RESULTS: Per smoker call volume is positively correlated with total TARPs (p<0.001), and cessation advertisements are more effective than SHS advertisements in promoting quitline call volume. Advertisements with graphic images only or neither strong negative emotions nor graphic images are associated with higher call volume with similar effect sizes. Call volume was not significantly associated with the number of TARPs for advertisements with strong negative emotions only (p=0.71) or with both graphic images and strong emotions (p=0.09). CONCLUSIONS: Exposure to television advertisements is strongly associated with quitline call volume, and both cessation and SHS advertisements can be effective. The use of strong negative emotions in advertisements may be effective in promoting smoking cessation in the population but does not appear to influence quitline call volume. Further research is needed to understand the role of negative emotions in promoting calls to quitlines and cessation more broadly among the majority of smokers who do not call quitlines. PMID- 21289029 TI - Limitation of inverse probability-of-censoring weights in estimating survival in the presence of strong selection bias. AB - In time-to-event analyses, artificial censoring with correction for induced selection bias using inverse probability-of-censoring weights can be used to 1) examine the natural history of a disease after effective interventions are widely available, 2) correct bias due to noncompliance with fixed or dynamic treatment regimens, and 3) estimate survival in the presence of competing risks. Artificial censoring entails censoring participants when they meet a predefined study criterion, such as exposure to an intervention, failure to comply, or the occurrence of a competing outcome. Inverse probability-of-censoring weights use measured common predictors of the artificial censoring mechanism and the outcome of interest to determine what the survival experience of the artificially censored participants would be had they never been exposed to the intervention, complied with their treatment regimen, or not developed the competing outcome. Even if all common predictors are appropriately measured and taken into account, in the context of small sample size and strong selection bias, inverse probability-of-censoring weights could fail because of violations in assumptions necessary to correct selection bias. The authors used an example from the Multicenter AIDS Cohort Study, 1984-2008, regarding estimation of long-term acquired immunodeficiency syndrome-free survival to demonstrate the impact of violations in necessary assumptions. Approaches to improve correction methods are discussed. PMID- 21289030 TI - Effect of postsecondary education on the economic status of persons who are deaf or hard of hearing. AB - This article examines the effect that postsecondary education has on earnings and the duration of time spent in the Social Security disability programs for young persons who are deaf or hard of hearing. Our hypothesis is that investments in postsecondary training increase the likelihood of employment for persons who are deaf or hard of hearing and thus reduce dependency on disability-related income support programs. A longitudinal data set based upon records from the National Technical Institute for the Deaf and Social Security administrative records is used for this analysis. We find that those who graduate, even those who graduate with vocational degrees, experience significant earnings benefits and reductions in the duration of time spent on federal disability programs when compared with those who do not graduate with a degree. This finding suggests that reductions in the duration of time spent on Social Security programs are not limited to those with the highest level of scholastic aptitude and that investments in post secondary education can benefit a broad group of deaf and hard-of-hearing persons. In addition, the data show that individuals who attend college, but withdraw before graduation, fair no better economically than individuals who never attended college. PMID- 21289031 TI - The effect of timing of teriparatide treatment on the circadian rhythm of bone turnover in postmenopausal osteoporosis. AB - BACKGROUND: We hypothesized that with the administration of teriparatide (TPTD) treatment at different times, we would be able to modify the physiological circadian rhythm of bone turnover. METHODS: The concentration of serum C-terminal telopeptide of collagen type I (betaCTX), serum N-terminal propeptide of procollagen type I (P1NP), serum ionized calcium (iCa), and plasma PTH were measured every 3 h over a 24 h period in 14 postmenopausal osteoporotic women (aged 72.4+/-9.3 years) treated with 20 MUg TPTD for long term, given at different times of the day. General linear model-repeated measurements (GLM RM) were performed to analyze the circadian rhythms as well as intergroup comparisons. RESULTS: GLM-RM for both related groups showed a significant influence of time of day on all measured variables except P1NP. The analysis for each group separately provided a powerful model for betaCTX (P<0.001, eta(2)=0.496), serum iCa (P<0.001, eta(2)=0.423), plasma PTH (P<0.001, eta(2)=0.283), and serum PINP (P<0.001, eta(2)=0.248). While the evening TPTD treatment showed a marked circadian rhythm for serum betaCTX, the morning TPTD treatment rather suggested circasemidian rhythm. The P1NP rhythm followed a much smaller amplitude of the rhythm than betaCTX. Changes in serum iCa were positively related to changes in serum betaCTX (P<0.001) and negatively related to changes in PTH (P<0.001). CONCLUSION: Timing of TPTD administration may significantly change the 24 h variation in bone turnover markers as well as calcium-parathyroid axis in postmenopausal osteoporotic women. PMID- 21289032 TI - Quantitative role of LAL, NPC2, and NPC1 in lysosomal cholesterol processing defined by genetic and pharmacological manipulations. AB - Lipoprotein cholesterol taken up by cells is processed in the endosomal/lysosomal (E/L) compartment by the sequential action of lysosomal acid lipase (LAL), Niemann-Pick C2 (NPC2), and Niemann-Pick C1 (NPC1). Inactivation of NPC2 in mouse caused sequestration of unesterified cholesterol (UC) and expanded the whole animal sterol pool from 2,305 to 4,337 mg/kg. However, this pool increased to 5,408 and 9,480 mg/kg, respectively, when NPC1 or LAL function was absent. The transport defect in mutants lacking NPC2 or NPC1, but not in those lacking LAL, was reversed by cyclodextrin (CD), and the ED50 values for this reversal varied from ~40 mg/kg in kidney to >20,000 mg/kg in brain in both groups. This reversal occurred only with a CD that could interact with UC. Further, a CD that could interact with, but not solubilize, UC still overcame the transport defect. These studies showed that processing and export of sterol from the late E/L compartment was quantitatively different in mice lacking LAL, NPC2, or NPC1 function. In both npc2(-/-) and npc1(-/-) mice, the transport defect was reversed by a CD that interacted with UC, likely at the membrane/bulk-water interface, allowing sterol to move rapidly to the export site of the E/L compartment. PMID- 21289033 TI - Integrating expression profiling and whole-genome association for dissection of fat traits in a porcine model. AB - Traits related to fatness, important as economic factors in pork production, are associated with serious diseases in humans. Genetical genomics is a useful approach for studying the effects of genetic variation at the molecular level in biological systems. Here we applied a whole-genome association analysis to hepatic gene expression traits, focusing on transcripts with expression levels that correlated with fatness traits in a porcine model. A total of 150 crossbred pigs [Pietrain * (German Large White * German Landrace)] were studied for transcript levels in the liver. The 24K Affymetrix expression microarrays and 60K Illumina single nucleotide polymorphism (SNP) chips were used for genotyping. A total of 663 genes, whose expression significantly correlated with the trait "fat area," were analyzed for enrichment of functional annotation groups as defined in the Ingenuity Pathways Knowledge Base (IPKB). Genes involved in metabolism of various macromolecules and nutrients as well as functions related to dynamic cellular processes correlated with fatness traits. Regions affecting the transcription levels of these genes were mapped and revealed 4,727 expression quantitative trait loci (eQTL) at P < 10-5, including 448 cis-eQTL. In this study, genome-wide association analysis of trait-correlated expression was successfully used in a porcine model to display molecular networks and list genes relevant to fatness traits. PMID- 21289034 TI - Obliging children. AB - Children may sometimes undergo healthcare procedures that are not intended to improve their health status. Such interventions might include the use of young children as bone marrow donors or their enrolment in non-therapeutic research. One of the justifications used to legitimise these interventions is the premise that children have obligations to others; to their family in the case of related bone marrow transplantation, and to wider society in the case of non-therapeutic research. However, this 'obligation model' (the notion that children possess positive obligations to advance the health status of others) fails as a justificatory paradigm because it is based upon a confusion, identified by Hart, between two notions; that of 'being under an obligation to do something' and that of 'being obliged to do something'. Instead the 'obligation model' is a device employed to put a justificatory gloss upon a consequentialist decision-making process; removing the legitimising gloss allows for a more transparent look at the conflict between parental rights and an individual child's right to bodily integrity. PMID- 21289035 TI - Lawfulness of a randomised trial of the new community treatment order regime for England and Wales. AB - This article debates and defends the lawfulness of a randomised controlled trial of compulsory outpatient treatment under the mental health legislation for England and Wales. The trial is designed to compare the outcomes for patients of their treatment under the new Community Treatment Order (CTO) regime with their treatment under the older leave scheme - the two main forms of compulsory care in the community now authorised by the revised Mental Health Act 1983. The methods for the trial involve the random allocation of some patients between the two schemes, when they are considered by their Responsible Clinicians to be eligible for some form of compulsory outpatient care. The main question we consider is the lawfulness of that aspect of the methods. Can a carefully selected group of patients be allocated at random between the two regimes to permit an evaluation to proceed? Or would that involve some departure from the decision-making criteria specified by law? We argue that a group of patients can be identified who meet - simultaneously - the tests for treatment under both the CTO and the leave schemes. Those patients could then be allocated lawfully to treatment under either scheme. This opens the door, we argue, to their random allocation between the two schemes for the purposes of the research. In reaching this conclusion, we explain the methods and aims of the trial and closely compare the respective features of the leave and CTO regimes. PMID- 21289036 TI - Re: Ozcelik B, Kabakas F, Mersa B. Treatment of nonunion of the distal phalanx with olecranon bone graft. J Hand Surg Eur. 2009, 34: 638-42. PMID- 21289037 TI - Re: Scheer JH, Hammerby S, Adolfsson LE. Radioulnar ratio in detection of distal radioulnar joint instability associated with acute distal radius fractures. J Hand Surg Eur. 2010, 35: 730-4. PMID- 21289038 TI - Efficient phage display of intracellularly folded proteins mediated by the TAT pathway. AB - Phage display with filamentous phages is widely applied and well developed, yet proteins requiring a cytoplasmic environment for correct folding still defy attempts at functional display. To extend applicability of phage display, we employed the twin-arginine translocation (TAT) pathway to incorporate proteins fused to the C-terminal domain of the geneIII protein into phage particles. We investigated functionality and display level of fluorescent proteins depending on the translocation pathway, which was the TAT, general secretory (SEC) or signal recognition particle (SRP) pathway mediated by the TorA, PelB or DsbA signal sequences, respectively. Importantly, for green fluorescent protein, yellow fluorescent protein and cyan fluorescent protein, only TAT, but not SEC or SRP, translocation led to fluorescence of purified phage particles, although all three proteins could be displayed regardless of the translocation pathway. In contrast, the monomeric red fluorescent protein mCherry was functionally displayed regardless of the translocation pathway. Hence, correct folding and fluorophor formation of mCherry is not limited to the cytosol. Furthermore, we successfully displayed firefly luciferase as well as an 83 kDa argonaute protein, both containing free cysteines. This demonstrates broad applicability of the TAT mediated phagemid system for the display of proteins requiring cytoplasmic factors for correct folding and should prove useful for the display of proteins requiring incorporation of co-factors or oligomerization to gain function. PMID- 21289039 TI - Engineered dimer interface mutants of triosephosphate isomerase: the role of inter-subunit interactions in enzyme function and stability. AB - The role of inter-subunit interactions in maintaining optimal catalytic activity in triosephosphate isomerase (TIM) has been probed, using the Plasmodium falciparum enzyme as a model. Examination of subunit interface contacts in the crystal structures suggests that residue 75 (Thr, conserved) and residue 13 (Cys, variable) make the largest number of inter-subunit contacts. The mutants Cys13Asp (C13D) and Cys13Glu (C13E) have been constructed and display significant reduction in catalytic activity when compared with wild-type (WT) enzyme (~ 7.4 fold decrease in k(cat) for the C13D and ~ 3.3-fold for the C13E mutants). Analytical gel filtration demonstrates that the C13D mutant dissociates at concentrations <1.25 MUM, whereas the WT and the C13E enzymes retain the dimeric structure. The order of stability of the mutants in the presence of chemical denaturants, like urea and guanidium chloride, is WT > Cys13Glu > Cys13Asp. Irreversible thermal precipitation temperatures follow the same order as well. Modeling studies establish that the Cys13Asp mutation is likely to cause a significantly greater structural perturbation than Cys13Glu. Analysis of sequence and structural data for TIMs from diverse sources suggests that residues 13 and 82 form a pair of proximal sites, in which a limited number of residue pairs may be accommodated. PMID- 21289040 TI - Telemonitoring in chronic heart failure. AB - Clinical management of refractory heart failure remains challenging, with a high rate of rehospitalizations despite advances in medical and device therapy. Care can be provided in person, via telehomecare (by telephone), or telemonitoring, which involves wireless technology for remote follow-up. Telemonitoring wirelessly transmits parameters such as weight, heart rate, or blood pressure for review by health-care professionals. Cardiac implantable devices (defibrillators and cardiac resynchronization therapy) also transmit continually interrogated physiological data, such as heart rate variability or intrathoracic impedance, which may be of value to predict patients at greater risk of hospitalization for heart failure. The use of remote monitoring techniques facilitates a rapid and regular review of such data by health-care workers as part of a heart failure management programme. Current evidence supports the feasibility of such an approach but routinely assessed parameters have been shown not to impact patient outcomes. Devices that directly assess cardiac haemodynamic status through invasive measurement of pressures are currently under investigation and could potentially increase the sensitivity and specificity of predicting heart failure events. The current evidence for telemonitoring and remote monitoring, including implantable haemodynamic devices, will be reviewed. PMID- 21289041 TI - Collagenase matrix metalloproteinase-8 expressed in atherosclerotic carotid plaques is associated with systemic cardiovascular outcome. AB - AIMS: Atherosclerotic plaque rupture and subsequent thrombus formation are the major cause of acute cardiovascular events. Local plaque markers may facilitate detection of the vulnerable plaque and help identify the patient at risk for cardiovascular events. Matrix metalloproteinases (MMPs) are prevalent in the arterial wall throughout the arterial system and are associated with local plaque destabilization. We hypothesized that local MMP plaque levels are predictive for atherosclerotic cardiovascular events in other vascular territories. METHODS AND RESULTS: Atherosclerotic plaques were obtained from 543 patients undergoing carotid endarterectomy (CEA). Plaques were analysed for the presence of macrophages, lipid-core, smooth muscle cells, collagen, calcification, and presence of plaque haemorrhage. MMP-2, MMP-8, and MMP-9 levels were assessed within the plaque. Following CEA, all patients underwent follow-up during 3 years. The primary outcome was defined as the composite of vascular death, non fatal vascular event, and surgical or percutaneous vascular intervention. In contrast with MMP-2 plaque levels, MMP-8 and MMP-9 levels in the plaque were associated with an unstable carotid plaque composition and clinical presentation at baseline. Increased plaque MMP-8 level (>4.58) was associated with an increased risk for the occurrence of secondary manifestations of atherosclerotic disease during follow-up [hazard ratio = 1.76, 95% CI (1.25-2.48)] (P= 0.001), whereas plaque MMP-2 and MMP-9 levels were not predictive for systemic cardiovascular events. CONCLUSION: In contrast with MMP-2, increased carotid MMP 8 and MMP-9 plaque levels are associated with an unstable plaque phenotype. High collagenase MMP-8 levels in the carotid plaque are associated with the occurrence of systemic cardiovascular outcome during follow-up. PMID- 21289042 TI - Influenza vaccination reduces cardiovascular events in patients with acute coronary syndrome. AB - AIMS: Influenza infection has been shown to accentuate the progression of atherosclerosis and precipitate the occurrence of acute coronary syndrome (ACS). However, the protective effects of the influenza vaccine on cardiovascular events are still inconclusive. METHODS AND RESULTS: The study was a prospective randomized open with blinded endpoint (PROBE) study. The 439 patients who had been admitted due to ACS within 8 weeks were enrolled and randomly allocated to receive inactivated influenza vaccine in the vaccine group and no treatment in the control group. All patients were treated with the standard therapy including revascularization according to primary cardiologists. The primary endpoint, which was the combined major cardiovascular events, including death, hospitalization from ACS, hospitalization from heart failure, and hospitalization from stroke, occurred less frequently in the vaccine group than the control group [9.5 vs. 19.3%, unadjusted HR 0.70 (0.57-0.86), P = 0.004]. There was no significant difference in the incidence of cardiovascular death between the vaccine and control groups [2.3 vs. 5.5%, unadjusted HR 0.39 (0.14-1.12), P = 0.088]. CONCLUSION: The influenza vaccine reduced major cardiovascular events in patients with ACS. Therefore, it should be encouraged as a secondary prevention in this group of patients. PMID- 21289043 TI - Training and accreditation in cardiovascular magnetic resonance in Europe: a position statement of the working group on cardiovascular magnetic resonance of the European Society of Cardiology. PMID- 21289044 TI - Thoughts on aneuploidy. AB - Aneuploidy refers to karyotypic abnormalities characterized by gain or loss of individual chromosomes. This condition is associated with disease and death in all organisms in which it has been studied. We have characterized the effects of aneuploidy on yeast and primary mouse cells and found it to be detrimental at the cellular level. Furthermore, we find that aneuploid cells exhibit phenotypes consistent with increased energy need and proteotoxic stress. These observations, together with the finding that the additional chromosomes found in aneuploid cells are active, lead us to propose that aneuploidy causes an increased burden on protein synthesis and protein quality-control pathways and so induces an aneuploidy stress response. PMID- 21289045 TI - Structure and function of the perinucleolar compartment in cancer cells. AB - The perinucleolar compartment (PNC) is a subnuclear body that forms in cancer cells. In vivo analyses using human tumor tissues demonstrate a close correlation between PNC prevalence and disease progress in colorectal carcinoma, and a high PNC prevalence is associated with poor patient outcome. These findings are consistent with previous observations in breast cancer and cancer cell lines in vitro. The PNC is composed of thick strands that form a filamental meshwork often extending into the nucleolus. Although it appears to be electron dense as observed by transmission electron microscopy (TEM), the actual density of the structure imaged by electron spectroscopy is much lower, similar to that of the interchromatin space, and is lined with ribonucleoproteins (RNPs). In situ detections show that the PNC is highly enriched with a subset of small RNAs of polymerase III (Pol III) origins and RNA-binding proteins primarily implicated in pre-mRNA processing. A novel gel-shifting approach demonstrates that the addition of PNC-associated RNAs into HeLa cell lysates increases the mobility of polypyrimidine tract-binding (PTB) protein in a native gel electrophoresis, suggesting an interaction between these RNAs and PTB proteins. On the basis of these and other findings, we propose a working model in which novel RNPs have a key role in regulating gene expression at the PNC in cancer cells. PMID- 21289046 TI - On the connection between RNAi and heterochromatin at centromeres. AB - RNA interference (RNAi) is a conserved silencing mechanism whereby double-strand RNA induces specific down-regulation of homologous sequences. In the fission yeast Schizosaccharomyces pombe, centromeric heterochromatin assembly is an RNAi dependent process. Noncoding RNAs transcribed from pericentromeric repeat sequences are processed into short interfering RNAs (siRNAs) that direct the Argonaute-containing RNA-induced transcriptional silencing (RITS) effector complex to homologous nascent transcripts. RITS is required for H3K9 methylation by the histone methyltransferase (HMT) Clr4; conversely, H3K9 methylation can attract RITS to chromatin via binding of the chromodomain protein Chp1. This codependency has hampered dissection of the order of events and mechanisms of cross talk between the RNAi and chromatin modification machineries. To tackle this problem, we have developed systems that reconstitute heterochromatin at a euchromatic locus, using either hairpin triggers or DNA-tethered chromatin modifying complexes. These systems reveal that RNAi is sufficient to promote heterochromatin assembly in cis and that direct recruitment of the HMT Clr4 can bypass the role of RNAi in heterochromatin assembly. We have also characterized a new pathway component, Stc1, that translates the RNAi signal into chromatin marks. We discuss the implications of these findings for our understanding of the mechanism and function of RNAi-directed heterochromatin assembly at centromeres. PMID- 21289047 TI - Proteomics of isolated mitotic chromosomes identifies the kinetochore protein Ska3/Rama1. AB - Despite many decades of study, mitotic chromosomes remain poorly characterized with respect to their structure and composition. Here, we have purified mitotic chromosomes from nocodazole-treated chicken DT40 cells. These chromosomes have a 0.7:1:1 ratio of nonhistone proteins to histones to DNA. They also contain a significant content of RNAs that have yet to be characterized. Overall, the isolated chromosomes contained >4000 polypeptides, >500 of which are either novel or uncharacterized. Elsewhere, we have developed an approach for comparing the results of multiple proteomics experiments. As a validation of this approach, one of 13 novel centromere proteins identified was found to occur in a complex with the previously described proteins Ska1 and Ska2. This novel protein, now known as Ska3/Rama1, occupies a unique domain in the outer kinetochore and was revealed by RNA interference (RNAi) experiments to be essential for cell cycle progression in human cells. The approach presented here offers a powerful way to define the functional proteome of complex organelles and structures whose composition is not simple or fixed. PMID- 21289049 TI - Chromatin and alternative splicing. AB - Alternative splicing affects more than 90% of human genes. Coupling between transcription and splicing has become crucial in the complex network underlying alternative splicing regulation. Because chromatin is the real template for nuclear transcription, changes in its structure, but also in the "reading" and "writing" of the histone code, could modulate splicing choices. Here, we discuss the evidence supporting these ideas, from the first proposal of chromatin affecting alternative splicing, performed 20 years ago, to the latest findings including genome-wide evidence that nucleosomes are preferentially positioned in exons. We focus on two recent reports from our laboratories that add new evidence to this field. The first report shows that a physiological stimulus such as neuron depolarization promotes intragenic histone acetylation (H3K9ac) and chromatin relaxation, causing the skipping of exon 18 of the neural cell adhesion molecule gene. In the second report, we show how specific histone modifications can be created at targeted gene regions as a way to affect alternative splicing: Using small interfering RNAs (siRNAs), we increased the levels of H3K9me2 and H3K27me3 in the proximity of alternative exon 33 of the human fibronectin gene, favoring its inclusion into mature messenger RNA (mRNA) through a mechanism that recalls RNA-mediated transcriptional gene silencing. PMID- 21289050 TI - Inhibition of renal caveolin-1 reduces natriuresis and produces hypertension in sodium-loaded rats. AB - Renal dopamine receptor function and ion transport inhibition are impaired in essential hypertension. We recently reported that caveolin-1 (CAV1) and lipid rafts are necessary for normal D(1)-like receptor-dependent internalization of Na K-ATPase in human proximal tubule cells. We now hypothesize that CAV1 is necessary for the regulation of urine sodium (Na(+)) excretion (U(Na)V) and mean arterial blood pressure (MAP) in vivo. Acute renal interstitial (RI) infusion into Sprague-Dawley rats of 1 MUg.kg-1.min-1 fenoldopam (FEN; D(1)-like receptor agonist) caused a 0.46 +/- 0.15-MUmol/min increase in U(Na)V (over baseline of 0.29 +/- 0.04 MUmol/min; P < 0.01). This increase was seen in Na(+)-loaded rats, but not in those under a normal-sodium load. Coinfusion with beta-methyl cyclodextrin (betaMCD; lipid raft disrupter, 200 MUg.kg-1.min-1) completely blocked this FEN-induced natriuresis (P < 0.001). Long-term (3 day) lipid raft disruption via continuous RI infusion of 80 MUg.kg-1.min-1 betaMCD decreased renal cortical CAV1 expression (47.3 +/- 6.4%; P < 0.01) and increased MAP (32.4 +/- 6.6 mmHg; P < 0.001) compared with vehicle-infused animals. To determine whether the MAP rise was due to a CAV1-dependent lipid raft-mediated disruption, Na(+)-loaded rats were given a bolus RI infusion of CAV1 siRNA. Two days postinfusion, cortical CAV1 expression was decreased by 73.6 +/- 8.2% (P < 0.001) and the animals showed an increase in MAP by 17.4 +/- 2.9 mmHg (P < 0.01) compared with animals receiving scrambled control siRNA. In summary, acute kidney specific lipid raft disruption decreases CAV1 expression and blocks D(1)-like receptor-induced natriuresis. Furthermore, chronic disruption of lipid rafts or CAV1 protein expression in the kidney induces hypertension. PMID- 21289051 TI - Natural IgM antibodies are involved in the activation of complement by hypoxic human tubular cells. AB - Ischemia-reperfusion injury (IRI) has a major impact on graft survival after transplantation. Renal proximal tubular epithelial cells (PTEC) located at the corticomedullary zone are relatively susceptible to IRI and have been identified as one of the main targets of complement activation. Studies in mice have shown an important role for the alternative pathway of complement activation in renal IRI. However, it is unclear whether experimental data obtained in mice can be extrapolated to humans. Therefore, we developed an in vitro model to induce hypoxia-reoxygenation in human and mouse PTEC and studied the role of the different pathways of complement activation. Exposure of human PTEC to hypoxia followed by reoxygenation in human serum resulted in extensive complement activation. Inhibition studies using different complement inhibitors revealed no involvement of the alternative or lectin pathway of complement activation by hypoxic human PTEC. In contrast, complement activation by hypoxic murine PTEC was shown to be exclusively dependent on the alternative pathway. Hypoxic human PTEC induced classic pathway activation, supported by studies in C1q-depleted serum and the use of blocking antibodies to C1q. The activation of the classic pathway was mediated by IgM through interaction with modified phosphomonoesters exposed on hypoxic PTEC. Studies with different human sera showed a strong correlation between IgM binding to hypoxic human PTEC and the degree of complement activation. These results demonstrate important species-specific differences in complement activation by hypoxic PTEC and provide clues for directed complement inhibition strategies in the treatment and prevention of IRI in the human kidney. PMID- 21289052 TI - Bardoxolone methyl (BARD) ameliorates ischemic AKI and increases expression of protective genes Nrf2, PPARgamma, and HO-1. AB - Ischemic acute kidney injury (AKI) triggers expression of adaptive (protective) and maladaptive genes. Agents that increase expression of protective genes should provide a therapeutic benefit. We now report that bardoxolone methyl (BARD) ameliorates ischemic murine AKI as assessed by both renal function and pathology. BARD may exert its beneficial effect by increasing expression of genes previously shown to protect against ischemic AKI, NF-E2-related factor 2 (Nrf2), peroxisome proliferator-activated receptor-gamma (PPARgamma), and heme oxygenase 1 (HO-1). Although we found that BARD alone or ischemia-reperfusion alone increased expression of these genes, the greatest increase occurred after the combination of both ischemia-reperfusion and BARD. BARD had a different mode of action than other agents that regulate PPARgamma and Nrf2. Thus we report that BARD regulates PPARgamma, not by acting as a ligand but by increasing the amount of PPARgamma mRNA and protein. This should increase ligand-independent effects of PPARgamma. Similarly, BARD increased Nrf2 mRNA; this increased Nrf2 protein by mechanisms in addition to the prolongation of Nrf2 protein half-life previously reported. Finally, we localized expression of these protective genes after ischemia and BARD treatment. Using double-immunofluorescence staining for CD31 and Nrf2 or PPARgamma, we found increased Nrf2 and PPARgamma on glomerular endothelia in the cortex; Nrf2 was also present on cortical peritubular capillaries. In contrast, HO-1 was localized to different cells, i.e., tubules and interstitial leukocytes. Although Nrf2-dependent increases in HO-1 have been described, our data suggest that BARD's effects on tubular and leukocyte HO-1 during ischemic AKI may be Nrf2 independent. We also found that BARD ameliorated cisplatin nephrotoxicity. PMID- 21289053 TI - HB-EGF release mediates glucose-induced activation of the epidermal growth factor receptor in mesangial cells. AB - Glomerular matrix accumulation is a hallmark of diabetic nephropathy. We showed that transactivation of the epidermal growth factor receptor (EGFR) is an important mediator of matrix upregulation in mesangial cells (MC) in response to high glucose (HG). Here, we study the mechanism of EGFR transactivation. In primary MC, EGFR transactivation by 1 h of HG (30 mM) was unaffected by inhibitors of protein kinase C, reactive oxygen species, or the angiotensin II AT1 receptor. However, general metalloprotease inhibition, as well as specific inhibitors of heparin-binding EGF-like growth factor (HB-EGF), prevented both EGFR and downstream Akt activation. HB-EGF was released into the medium by 30 min of HG, and this depended on metalloprotease activity. One of the metalloproteases shown to cleave proHB-EGF is ADAM17 (TACE). HG, but not an osmotic control, activated ADAM17, and its inhibition prevented EGFR and Akt activation and HB-EGF release into the medium. siRNA to either ADAM17 or HB-EGF prevented HG-induced EGFR transactivation. We previously showed that EGFR/Akt signaling increases transforming growth factor (TGF)-beta1 transcription through the transcription factor activator protein (AP)-1. HG-induced AP-1 activation, as assessed by EMSA, was abrogated by inhibitors of metalloproteases, HB-EGF and ADAM17. HB-EGF and ADAM17 siRNA also prevented AP-1 activation. Finally, these inhibitors and siRNA prevented TGF-beta1 upregulation by HG. Thus, HG-induced EGFR transactivation in MC is mediated by the release of HB-EGF, which requires activity of the metalloprotease ADAM17. The mechanism of ADAM17 activation awaits identification. Targeting upstream mediators of EGFR transactivation including HB-EGF or ADAM17 provides novel therapeutic targets for the treatment of diabetic nephropathy. PMID- 21289054 TI - Inhibition of heme oxygenase augments tubular sodium reabsorption. AB - Heme oxygenase (HO) catalyzes the degradation of heme to form iron, biliverdin, and carbon monoxide (CO). The vascular actions of CO include direct vasodilation of vascular smooth muscle and indirect vasoconstriction through inhibition of nitric oxide synthase (NOS). This study was performed to examine the effects in the kidney of inhibition of heme oxygenase alone or combined with NOS inhibition. Chromium mesoporphyrin (CrMP; 45 MUmol/kg ip), a photostable HO inhibitor, was given to control rats and N(G)-nitro-l-arginine methyl ester (l-NAME)-treated hypertensive rats (50 mg.kg-1.day-1), 12 h, 4 days). In control animals, CrMP decreased CO levels, renal HO-1 levels, urine volume, and sodium excretion, but had no effect on arterial pressure, renal blood flow (RBF), plasma renin activity (PRA), or glomerular filtration rate (GFR). In l-NAME-treated hypertensive rats, CrMP decreased endogenous CO and renal HO-1 levels and had no effect on arterial pressure, RBF, or GFR but decreased sodium and water excretion in a similar manner to control animals. An increase in PRA was observed in untreated rats but not in l-NAME-infused rats, indicating that this effect is associated with an absent NO system. The results suggest that inhibition of HO promotes water and sodium excretion by a direct tubular action that is independent of renal hemodynamics or the NO system. PMID- 21289055 TI - Small interfering RNA targeting IKKbeta prevents renal ischemia-reperfusion injury in rats. AB - The transcription factor NF-kappaB has been found critical to the pathogenesis of renal ischemia-reperfusion injury, which is a major cause of acute kidney injury (AKI). Activation of NF-kappaB is dependent upon the activation of the specific inhibitory kappaB kinase (IKK) subunit IKKbeta. Here, we investigate whether small interfering RNA (siRNA) targeting IKKbeta protects rats from renal ischemia reperfusion injury in vivo. Renal ischemia-reperfusion injury was induced by clamping the renal artery for 45 min. Rats were treated before ischemia with IKKbeta siRNA or scrambled siRNA, administered by renal artery injection. Treated animals were evaluated for renal IKKbeta protein and mRNA expression, blood biochemistry, tissue histopathology, NF-kappaB/DNA binding activity, and expression of two downstream inflammatory cytokines, neutrophil gelatinase associated lipocalin (NGAL) and IL-18. A local injection of IKKbeta siRNA resulted in inhibition of renal IKKbeta gene expression, NF-kappaB/DNA binding activity, and expression of NGAL and IL-18. Rats pretreated with IKKbeta siRNA had significantly less blood urea nitrogen and serum creatinine levels and less renal tubular damage scores. Consequently, our data confirm that targeted silencing of IKKbeta using siRNA substantially diminishes kidney injury and inflammation following ischemia-reperfusion. PMID- 21289056 TI - Role of smooth muscle protein SM22alpha in glomerular epithelial cell injury. AB - Podocytes are considered terminally differentiated cells in the mature kidney under normal conditions. In the face of injury, podocytes may proceed along several possible pathways, including dedifferentiation and proliferation, persistent cell cycle arrest, hypertrophy, apoptosis, or necrosis. There is mounting evidence that transdifferentiation into a dysregulated phenotype may also be a potential cell fate. We have previously reported that the transcript of SM22alpha, an actin-binding protein considered one of the earliest markers of smooth muscle differentiation, is upregulated nearly 70-fold in glomeruli of rats with passive Heymann nephritis (PHN). In contrast, the SM22alpha transcript is absent in normal adult rat glomeruli. The purpose of this study was to define SM22alpha's expression during kidney development and its role in glomerular diseases characterized by podocyte injury and proteinuria. During glomerulogenesis and podocyte differentiation, SM22alpha was expressed in glomeruli. This expression disappeared with glomerular maturation. Along with SM22alpha induction in PHN, confirmed at both mRNA and protein levels, SM22alpha was also induced across a broad range of proteinuric diseases, including experimental animal models (puromycin aminonucleoside nephropathy, adriamycin nephropathy, passive nephrotoxic nephritis, and diet-induced obesity) and human diseases (collapsing glomerulopathy, diabetic nephropathy, classic focal segmental glomerulosclerosis, IgA nephropathy, minimal-change disease, membranous nephropathy, and membranoproliferative glomerulonephritis). Crescentic glomerulonephritis was induced in SM22alpha +/+ and SM22alpha -/- mice by intraperitoneal injection of sheep anti-rabbit glomeruli antibody 12.5 mg/20 g body wt * 2 doses (n = 12-15/group), with mice euthanized at 7 and 14 days. Compared with SM22alpha -/- mice, SM22alpha +/+ mice demonstrated worse disease by histopathological parameters. In addition, there was greater apoptosis (cleaved caspase-3 immunostaining), fewer podocytes (Wilms' tumor-1 immunostaining), and less proliferation (Ki-67 immunostaining) in diseased SM22alpha +/+ mice. Furthermore, there was decreased activation of Erk1/2 in diseased SM22alpha +/+ mice. We conclude that the de novo expression of SM22alpha in glomerular epithelial cells affects the course of crescentic glomerulonephritis. PMID- 21289057 TI - Protein kinase C-epsilon activation induces mitochondrial dysfunction and fragmentation in renal proximal tubules. AB - PKC-epsilon activation mediates protection from ischemia-reperfusion injury in the myocardium. Mitochondria are a subcellular target of these protective mechanisms of PKC-epsilon. Previously, we have shown that PKC-epsilon activation is involved in mitochondrial dysfunction in oxidant-injured renal proximal tubular cells (RPTC; Nowak G, Bakajsova D, Clifton GL Am J Physiol Renal Physiol 286: F307-F316, 2004). The goal of this study was to examine the role of PKC epsilon activation in mitochondrial dysfunction and to identify mitochondrial targets of PKC-epsilon in RPTC. The constitutively active and inactive mutants of PKC-epsilon were overexpressed in primary cultures of RPTC using the adenoviral technique. Increases in active PKC-epsilon levels were accompanied by PKC-epsilon translocation to mitochondria. Sustained PKC-epsilon activation resulted in decreases in state 3 respiration, electron transport rate, ATP production, ATP content, and activities of complexes I and IV and F(0)F(1)-ATPase. Furthermore, PKC-epsilon activation increased mitochondrial membrane potential and oxidant production and induced mitochondrial fragmentation and RPTC death. Accumulation of the dynamin-related protein in mitochondria preceded mitochondrial fragmentation. Antioxidants blocked PKC-epsilon-induced increases in the oxidant production but did not prevent mitochondrial fragmentation and cell death. The inactive PKC-epsilon mutant had no effect on mitochondrial functions, morphology, oxidant production, and RPTC viability. We conclude that active PKC-epsilon targets complexes I and IV and F(0)F(1)-ATPase in RPTC. PKC-epsilon activation mediates mitochondrial dysfunction, hyperpolarization, and fragmentation. It also induces oxidant generation and cell death, but oxidative stress is not the mechanism of RPTC death. These results show that in contrast to protective effects of PKC-epsilon activation in cardiomyocytes, sustained PKC-epsilon activation is detrimental to mitochondrial function and viability in RPTC. PMID- 21289058 TI - Transcription factor FOXL2 protects granulosa cells from stress and delays cell cycle: role of its regulation by the SIRT1 deacetylase. AB - FOXL2 is a transcription factor that is essential for ovarian function and maintenance, the germline mutations of which are responsible for the Blepharophimosis Ptosis Epicanthus-inversus Syndrome (BPES), often associated with premature ovarian failure. Recent evidence has linked FOXL2 downregulation or somatic mutation (p.Cys134Trp) to cancer, although underlying molecular mechanisms remain unclear. Using a functional genomic approach, we find that FOXL2 modulates cell-cycle regulators in a way which tends to induce G1 arrest. Indeed, FOXL2 upregulation promotes cell accumulation in G1 phase and protects cells from oxidative damage, notably by promoting oxidized DNA repair and by increasing the amounts of anti-oxidant agent glutathione. In agreement with clinical observations, we find that FOXL2-mutated versions leading to BPES along with ovarian dysfunction mostly fail to transactivate cell-cycle and DNA repair targets, whereas mutations leading to isolated craniofacial defects (and normal ovarian function) activate them correctly. Interestingly, these assays revealed a mild promoter-specific hypomorphy of the tumor-associated mutation (p.Cys134Trp). Finally, the SIRT1 deacetylase suppresses FOXL2 activity on targets linked to cell-cycle and DNA repair in a dose-dependent manner. Accordingly, we find that SIRT1 inhibition by nicotinamide limits proliferation, notably by increasing endogenous FOXL2 amount/activity. The body of evidence presented here supports the idea that FOXL2 plays a key role in granulosa cell homeostasis, the failure of which is central to ovarian ageing and tumorigenesis. As granulosa cell tumors respond poorly to conventional chemotherapy, our findings on the deacetylase inhibitor nicotinamide provide an interesting option for targeted therapy. PMID- 21289059 TI - The effects of EBV transformation on gene expression levels and methylation profiles. AB - Epstein-Barr virus (EBV) transformed lymphoblastoid cell lines (LCLs) provide a conveniently accessible and renewable resource for functional genomic studies in humans. The ability to accumulate multidimensional data pertaining to the same individual cell lines, from complete genomic sequences to detailed gene regulatory profiles, further enhances the utility of LCLs as a model system. A lingering concern, however, is that the changes associated with EBV transformation of B cells reduce the usefulness of LCLs as a surrogate model for primary tissues. To evaluate the validity of this concern, we compared global gene expression and methylation profiles between CD20+ primary B cells sampled from six individuals and six independent replicates of transformed LCLs derived from each sample. These data allowed us to obtain a detailed catalog of the genes and pathways whose regulation is affected by EBV transformation. We found that the expression levels and promoter methylation profiles of more than half of the studied genes were affected by the EBV transformation, including enrichments of genes involved in transcription regulation, cell cycle and immune response. However, we show that most of the differences in gene expression levels between LCLs and B cells are of small magnitude, and that LCLs can often recapitulate the naturally occurring gene expression variation in primary B cells. Thus, our observations suggest that inference of the genetic architecture that underlies regulatory variation in LCLs can typically be generalized to primary B cells. In contrast, inference based on functional studies in LCLs may be more limited to the cell lines. PMID- 21289060 TI - Public health, corporations and the new responsibility deal: promoting partnerships with vectors of disease? PMID- 21289061 TI - What kinds of contours bound the reach of filled-in color? AB - Is a retinal representation of an edge necessary to constrain the reach of color filling-in? If so, then color filling-in should not be constrained by illusory contours, because they do not exist at a retinal level. Alternatively, if color filling-in is constrained by contours at a perceptual level of neural representation, regardless of whether there is a retinal representation, then color filling-in should be constrained by illusory contours. To address this question, a variety of real luminance edges and illusory contours were presented under conditions designed to cause color filling-in. The results showed that illusory contours bounded the reach of color filling-in. A neural representation of a contour may first exist at a retinal level or a cortical level; in either case, the contour exists at a perceptual level and bounds color filling-in. PMID- 21289062 TI - Yeast cells can access distinct quiescent states. AB - We conducted a phenotypic, transcriptional, metabolic, and genetic analysis of quiescence in yeast induced by starvation of prototrophic cells for one of three essential nutrients (glucose, nitrogen, or phosphate) and compared those results with those obtained with cells growing slowly due to nutrient limitation. These studies address two related questions: (1) Is quiescence a state distinct from any attained during mitotic growth, and (2) does the nature of quiescence differ depending on the means by which it is induced? We found that either limitation or starvation for any of the three nutrients elicits all of the physiological properties associated with quiescence, such as enhanced cell wall integrity and resistance to heat shock and oxidative stress. Moreover, the starvations result in a common transcriptional program, which is in large part a direct extrapolation of the changes that occur during slow growth. In contrast, the metabolic changes that occur upon starvation and the genetic requirements for surviving starvation differ significantly depending on the nutrient for which the cell is starved. The genes needed by cells to survive starvation do not overlap the genes that are induced upon starvation. We conclude that cells do not access a unique and discrete G(0) state, but rather are programmed, when nutrients are scarce, to prepare for a range of possible future stressors. Moreover, these survival strategies are not unique to quiescence, but are engaged by the cell in proportion to nutrient scarcity. PMID- 21289063 TI - CDK prevents Mcm2-7 helicase loading by inhibiting Cdt1 interaction with Orc6. AB - In Saccharomyces cerevisiae cells, B-type cyclin-dependent kinases (CDKs) target two origin recognition complex (ORC) subunits, Orc2 and Orc6, to inhibit helicase loading. We show that helicase loading by ORC is inhibited by two distinct CDK dependent mechanisms. Independent of phosphorylation, binding of CDK to an "RXL" cyclin-binding motif in Orc6 sterically reduces the initial recruitment of the Cdt1/Mcm2-7 complex to ORC. CDK phosphorylation of Orc2 and Orc6 inhibits the same step in helicase loading. This phosphorylation of Orc6 is stimulated by the RXL motif and mediates the bulk of the phosphorylation-dependent inhibition of helicase loading. Direct binding experiments show that CDK phosphorylation specifically blocks one of the two Cdt1-binding sites on Orc6. Consistent with the inactivation of one Cdt1-binding site preventing helicase loading, CDK phosphorylation of ORC causes a twofold reduction of initial Cdt1/Mcm2-7 recruitment but results in nearly complete inhibition of Mcm2-7 loading. Intriguingly, in addition to being a target of both CDK inhibitory mechanisms, the Orc6 RXL/cyclin-binding motif plays a positive role in the initial recruitment of Cdt1/Mcm2-7 to the origin, suggesting that this motif is critical for the switch between active and inhibited ORC function at the G1-to-S-phase transition. PMID- 21289064 TI - Small RNA-induced mRNA degradation achieved through both translation block and activated cleavage. AB - Small RNA (sRNA)-induced mRNA degradation occurs through binding of an sRNA to a target mRNA with the concomitant action of the RNA degradosome, which induces an endoribonuclease E (RNase E)-dependent cleavage and degradation of the targeted mRNA. Because many sRNAs bind at the ribosome-binding site (RBS), it is possible that the resulting translation block is sufficient to promote the rapid degradation of the targeted mRNA. Contrary to this mechanism, we report here that the pairing of the sRNA RyhB to the target mRNA sodB initiates mRNA degradation even in the absence of translation on the mRNA target. Remarkably, even though it pairs at the RBS, the sRNA RyhB induces mRNA cleavage in vivo at a distal site located >350 nucleotides (nt) downstream from the RBS, ruling out local cleavage near the pairing site. Both the RNA chaperone Hfq and the RNA degradosome are required for efficient cleavage at the distal site. Thus, beyond translation initiation block, sRNA-induced mRNA cleavage requires several unexpected steps, many of which are determined by structural features of the target mRNA. PMID- 21289065 TI - Strange as it may seem: the many links between Wnt signaling, planar cell polarity, and cilia. AB - Cilia are important cellular structures that have been implicated in a variety of signaling cascades. In this review, we discuss the current evidence for and against a link between cilia and both the canonical Wnt/beta-catenin pathway and the noncanonical Wnt/planar cell polarity (PCP) pathway. Furthermore, we address the evidence implicating a role for PCP components in ciliogenesis. Given the lack of consensus in the field, we use new data on the control of ciliary protein localization as a basis for proposing new models by which cell type-specific regulation of ciliary components via differential transport, regulated entry and exit, or diffusion barriers might generate context-dependent functions for cilia. PMID- 21289066 TI - Elimination of a specific histone H3K14 acetyltransferase complex bypasses the RNAi pathway to regulate pericentric heterochromatin functions. AB - In Schizosaccharomyces pombe, the RNAi pathway is required for the formation of pericentric heterochromatin, proper chromosome segregation, and repression of pericentric meiotic recombination. Here we demonstrate that, when the activity of the histone H3 Lys 14 (H3K14) acetyltransferase Mst2 is eliminated, the RNAi machinery is no longer required for pericentric heterochromatin functions. We further reveal that reducing RNA polymerase II recruitment to pericentric regions is essential for maintaining heterochromatin in the absence of RNAi. PMID- 21289067 TI - Essential role for the interaction between hnRNP H/F and a G quadruplex in maintaining p53 pre-mRNA 3'-end processing and function during DNA damage. AB - Following DNA damage, mRNA 3'-end formation is inhibited, contributing to repression of mRNA synthesis. Here we investigated how DNA-damaged cells accomplish p53 mRNA 3'-end formation when normal mechanisms of pre-mRNA 3'-end processing regulation are inhibited. The underlying mechanism involves the interaction between a G-quadruplex structure located downstream from the p53 cleavage site and hnRNP H/F. Importantly, this interaction is critical for p53 expression and contributes to p53-mediated apoptosis. Our results uncover the existence of a specific rescue mechanism of 3'-end processing regulation allowing stress-induced p53 accumulation and function in apoptosis. PMID- 21289068 TI - MicroRNA-335 inhibits tumor reinitiation and is silenced through genetic and epigenetic mechanisms in human breast cancer. AB - Post-transcriptional regulators have emerged as robust effectors of metastasis and display deregulated expression through unknown mechanisms. Here, we reveal that the human microRNA-335 locus undergoes genetic deletion and epigenetic promoter hypermethylation in every metastatic derivative obtained from independent patients' malignant cell populations. Genetic deletion of miR-335 is a common event in human breast cancer, is enriched for in breast cancer metastases, and also correlates with ovarian cancer recurrence. We furthermore identify miR-335 as a robust inhibitor of tumor reinitiation. We thus implicate the miR-335 locus on 7q32.2 as the first selective metastasis suppressor and tumor initiation suppressor locus in human breast cancer. PMID- 21289069 TI - Tyrosine phosphorylation controls brassinosteroid receptor activation by triggering membrane release of its kinase inhibitor. AB - Receptor tyrosine kinases control many critical processes in metazoans, but these enzymes appear to be absent in plants. Recently, two Arabidopsis receptor kinases -BRASSINOSTEROID INSENSITIVE 1 (BRI1) and BRI1-ASSOCIATED KINASE1 (BAK1), the receptor and coreceptor for brassinosteroids--were shown to autophosphorylate on tyrosines. However, the cellular roles for tyrosine phosphorylation in plants remain poorly understood. Here, we report that the BRI1 KINASE INHIBITOR 1 (BKI1) is tyrosine phosphorylated in response to brassinosteroid perception. Phosphorylation occurs within a reiterated [KR][KR] membrane targeting motif, releasing BKI1 into the cytosol and enabling formation of an active signaling complex. Our work reveals that tyrosine phosphorylation is a conserved mechanism controlling protein localization in all higher organisms. PMID- 21289070 TI - DOT1L regulates dystrophin expression and is critical for cardiac function. AB - Histone methylation plays an important role in regulating gene expression. One such methylation occurs at Lys 79 of histone H3 (H3K79) and is catalyzed by the yeast DOT1 (disruptor of telomeric silencing) and its mammalian homolog, DOT1L. Previous studies have demonstrated that germline disruption of Dot1L in mice resulted in embryonic lethality. Here we report that cardiac-specific knockout of Dot1L results in increased mortality rate with chamber dilation, increased cardiomyocyte cell death, systolic dysfunction, and conduction abnormalities. These phenotypes mimic those exhibited in patients with dilated cardiomyopathy (DCM). Mechanistic studies reveal that DOT1L performs its function in cardiomyocytes through regulating Dystrophin (Dmd) transcription and, consequently, stability of the Dystrophin-glycoprotein complex important for cardiomyocyte viability. Importantly, expression of a miniDmd can largely rescue the DCM phenotypes, indicating that Dmd is a major target mediating DOT1L function in cardiomyocytes. Interestingly, analysis of available gene expression data sets indicates that DOT1L is down-regulated in idiopathic DCM patient samples compared with normal controls. Therefore, our study not only establishes a critical role for DOT1L-mediated H3K79 methylation in cardiomyocyte function, but also reveals the mechanism underlying the role of DOT1L in DCM. In addition, our study may open new avenues for the diagnosis and treatment of human heart disease. PMID- 21289071 TI - Chromatin remodeling complex NURF regulates thymocyte maturation. AB - The maturation of T cells requires signaling from both cytokine and T-cell receptors to gene targets in chromatin, but how chromatin architecture influences this process is largely unknown. Here we show that thymocyte maturation post positive selection is dependent on the nucleosome remodeling factor (NURF). Depletion of Bptf (bromodomain PHD finger transcription factor), the largest NURF subunit, in conditional mouse mutants results in developmental arrest beyond the CD4(+) CD8(int) stage without affecting cellular proliferation, cellular apoptosis, or coreceptor gene expression. In the Bptf mutant, specific subsets of genes important for thymocyte development show aberrant expression. We also observed defects in DNase I-hypersensitive chromatin structures at Egr1, a prototypical Bptf-dependent gene that is required for efficient thymocyte development. Moreover, chromatin binding of the sequence-specific factor Srf (serum response factor) to Egr1 regulatory sites is dependent on Bptf function. Physical interactions between NURF and Srf suggest a model in which Srf recruits NURF to facilitate transcription factor binding at Bptf-dependent genes. These findings provide evidence for causal connections between NURF, transcription factor occupancy, and gene regulation during thymocyte development. PMID- 21289072 TI - Structural and thermodynamics characters of isolated α-syn12 peptide: long time temperature replica-exchange molecular dynamics in aqueous solution. AB - The structural and thermodynamics characters of alpha-syn12 (residues 1-12 of the human alpha-synuclein protein) peptide in aqueous solution were investigated through temperature replica-exchange molecular dynamics (T-REMD) simulations with the GROMOS 43A1 force field. The two independent T-REMD simulations were completed starting from an initial conformational alpha-helix and an irregular structure, respectively. Each replica was run for 300 ns. The structural and thermodynamics characters were studied based on parameters such as distributions of backbone dihedral angles, free energy surface, stability of folded beta hairpin structure, and favorite conformations. The results showed that the isolated alpha-syn12 peptide in water adopted four different conformational states: the first state was a beta-hairpin ensemble with Turn(9-6) and four hydrogen bonds, the second state was a beta-hairpin ensemble with two turns (Turn(9-6) and Turn(5-2)) and three hydrogen bonds, the third state was a disordered structure with both Turn(8-5) and Turn(5-2), and the last state was a pi-helix ensemble. Meanwhile, we studied the free energy change of alpha-syn12 peptide from the unfolded state to the beta-hairpin state, which was in good agreement with the experiments and molecular dynamics simulations for some other peptides. We also analyzed the driving force of the peptide transition. The results indicated that the driving forces were high solvent exposure of hydrophobic Leu8 and hydrophobic residues in secondary structure. To our knowledge, this was the first report to study the isolated alpha-syn12 peptide in water by T-REMD. PMID- 21289073 TI - Metabolism and disposition of [14C]brivanib alaninate after oral administration to rats, monkeys, and humans. AB - Brivanib [(R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5 methylpyrrolo[1,2,4]triazin-6-yloxy)propan-2-ol, BMS-540215] is a potent and selective dual inhibitor of vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) signaling pathways. Its alanine prodrug, brivanib alaninate [(1R,2S)-2-aminopropionic acid 2-[4-(4-fluoro-2-methyl-1H-indol-5 yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy]-1-methylethyl ester, BMS 582664], is currently under development as an oral agent for the treatment of cancer. This study describes the in vivo biotransformation of brivanib after a single oral dose of [(14)C]brivanib alaninate to intact rats, bile duct cannulated (BDC) rats, intact monkeys, BDC monkeys, and humans. Fecal excretion was the primary route of elimination of drug-derived radioactivity in animals and humans. In BDC rats and monkeys, the majority of radioactivity was excreted in bile. Brivanib alaninate was rapidly and completely converted via hydrolysis to brivanib in vivo. The area under the curve from zero to infinity of brivanib accounted for 14.2 to 54.3% of circulating radioactivity in plasma in animals and humans, suggesting that metabolites contributed significantly to the total drug related radioactivity. In plasma from animals and humans, brivanib was a prominent circulating component. All the metabolites that humans were exposed to were also present in toxicological species. On the basis of metabolite exposure and activity against VEGF and FGF receptors of the prominent human circulating metabolites, only brivanib is expected to contribute to the pharmacological effects in humans. Unchanged brivanib was not detected in urine or bile samples, suggesting that metabolic clearance was the primary route of elimination. The primary metabolic pathways were oxidative and conjugative metabolism of brivanib. PMID- 21289074 TI - Optimal experimental design for assessment of enzyme kinetics in a drug discovery screening environment. AB - A penalized expectation of determinant (ED)-optimal design with a discrete parameter distribution was used to find an optimal experimental design for assessment of enzyme kinetics in a screening environment. A data set for enzyme kinetic data (V(max) and K(m)) was collected from previously reported studies, and every V(max)/K(m) pair (n = 76) was taken to represent a unique drug compound. The design was restricted to 15 samples, an incubation time of up to 40 min, and starting concentrations (C(0)) for the incubation between 0.01 and 100 MUM. The optimization was performed by finding the sample times and C(0) returning the lowest uncertainty (S.E.) of the model parameter estimates. Individual optimal designs, one general optimal design and one, for laboratory practice suitable, pragmatic optimal design (OD) were obtained. In addition, a standard design (STD-D), representing a commonly applied approach for metabolic stability investigations, was constructed. Simulations were performed for OD and STD-D by using the Michaelis-Menten (MM) equation, and enzyme kinetic parameters were estimated with both MM and a monoexponential decay. OD generated a better result (relative standard error) for 99% of the compounds and an equal or better result [(root mean square error (RMSE)] for 78% of the compounds in estimation of metabolic intrinsic clearance. Furthermore, high-quality estimates (RMSE < 30%) of both V(max) and K(m) could be obtained for a considerable number (26%) of the investigated compounds by using the suggested OD. The results presented in this study demonstrate that the output could generally be improved compared with that obtained from the standard approaches used today. PMID- 21289075 TI - Anandamide oxidation by wild-type and polymorphically expressed CYP2B6 and CYP2D6. AB - Anandamide is an arachidonic acid-derived endogenous cannabinoid that regulates normal physiological functions and pathophysiological responses within the central nervous system and in the periphery. Several cytochrome P450 (P450) isoforms metabolize anandamide to form hydroxylated and epoxygenated products. Human CYP2B6 and CYP2D6, which are expressed heterogeneously throughout the brain, exhibit clinically significant polymorphisms and are regulated by external factors, such as alcohol and smoking. Oxidative metabolism of anandamide by these two P450s may have important functional consequences for endocannabinoid system signaling. In this study, we investigated the metabolism of anandamide by wild type CYP2B6 (2B6.1) and CYP2D6 (2D6.1) and by their common polymorphic mutants 2B6.4, 2B6.6, 2B6.9, and 2D6.34. Major differences in anandamide metabolism by the two isoforms and their mutants were found in vitro with respect to the formation of 20-hydroxyeicosatetraenoic acid ethanolamide (20-HETE-EA) and 14,15 epoxyeicosatetraenoic acid ethanolamide (14,15-EET-EA). Pharmacological studies showed that both 20-HETE-EA and 14,15-EET-EA bind to the rat brain cannabinoid CB1 receptor with lower affinities relative to that of anandamide. In addition, both products are degraded more rapidly than anandamide in rat brain homogenates. Their degradation occurs via different mechanisms involving either fatty acid amide hydrolase (FAAH), the major anandamide-degrading enzyme, or epoxide hydrolase (EH). Thus, the current findings provide potential new insights into the actions of inhibitors FAAH and EH, which are being developed as novel therapeutic agents, as well as a better understanding of the interactions between the cytochrome P450 monooxygenases and the endocannabinoid system. PMID- 21289076 TI - Reevaluation of the microsomal metabolism of montelukast: major contribution by CYP2C8 at clinically relevant concentrations. AB - According to published in vitro studies, cytochrome P450 3A4 catalyzes montelukast 21-hydroxylation (M5 formation), whereas CYP2C9 catalyzes 36 hydroxylation (M6), the primary step in the main metabolic pathway of montelukast. However, montelukast is a selective competitive CYP2C8 inhibitor, and our recent in vivo studies suggest that CYP2C8 is involved in its metabolism. We therefore reevaluated the contributions of different cytochrome P450 (P450) enzymes, particularly that of CYP2C8, to the hepatic microsomal metabolism of montelukast using clinically relevant substrate concentrations in vitro. The effects of P450 isoform inhibitors on montelukast metabolism were examined using pooled human liver microsomes, and montelukast oxidations by human recombinant CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5 were investigated. The results verified the central role of CYP3A4 in M5 formation. The CYP2C8 inhibitors gemfibrozil 1-O-beta glucuronide and trimethoprim inhibited the depletion of 0.02 MUM montelukast and formation of M6 from 0.05 MUM montelukast more potently than did the CYP2C9 inhibitor sulfaphenazole. Likewise, recombinant CYP2C8 catalyzed montelukast depletion and M6 formation at a 6 times higher intrinsic clearance than did CYP2C9, whereas other P450 isoforms produced no M6. On the basis of depletion of 0.02 MUM montelukast, CYP2C8 was estimated to account for 72% of the oxidative metabolism of montelukast in vivo, with a 16% contribution for CYP3A4 and 12% for CYP2C9. Moreover, CYP2C8 catalyzed the further metabolism of M6 more actively than did any other P450. In conclusion, CYP2C8 plays a major role in the main metabolic pathway of montelukast at clinically relevant montelukast concentrations in vitro. PMID- 21289077 TI - Augmentation of left ventricular mechanics by recirculation-mediated AAV2/1 SERCA2a gene delivery in experimental heart failure. AB - AIMS: Down-regulation of sarcoplasmic reticulum calcium ATPase (SERCA2a) is a key molecular abnormality in heart failure (HF), which is not currently addressed by specific pharmacotherapy. We sought to evaluate, in detail, the impact of augmented SERCA2a expression on left ventricular (LV) mechanics in a large animal model of HF. METHODS AND RESULTS: Heart failure was induced in adult sheep by rapid pacing (180 b.p.m.) for 1 month, followed by delivery of adeno-associated virus (AAV) 2/1-SERCA, using a percutaneous, recirculating system for gene delivery over a 10 min period. Left ventricular mechanics was investigated by echocardiography and conductance catheter measurements in sheep receiving AAV2/1 SERCA2a after a further 4 weeks of pacing in comparison with untreated HF controls. Left ventricular function was significantly improved in the AAV2/1 SERCA2a-treated group, despite continued pacing, as measured by fractional shortening (delta absolute FS, control -4.2 +/- 1.5% vs. treatment 4.4 +/- 1.5%; P < 0.01) and conductance catheterization (delta Ees, control -1.22 +/- 0.60 vs. treatment 0.65 +/- 0.51; P < 0.05). Western blots showed an increase in SERCA protein in AAV2/1-SERCA2a-treated animals, and an analysis of gene delivery showed no evidence of regional myocardial heterogeneity in the distribution of AAV2/1-SERCA. CONCLUSION: In a large animal model, AAV2/1-mediated SERCA2a gene delivery using percutaneous, recirculating cardiac delivery leads to improved LV function. PMID- 21289078 TI - On the mechanism underlying photosynthetic limitation upon trigger hair irritation in the carnivorous plant Venus flytrap (Dionaea muscipula Ellis). AB - Mechanical stimulation of trigger hairs on the adaxial surface of the trap of Dionaea muscipula leads to the generation of action potentials and to rapid leaf movement. After rapid closure secures the prey, the struggle against the trigger hairs results in generation of further action potentials which inhibit photosynthesis. A detailed analysis of chlorophyll a fluorescence kinetics and gas exchange measurements in response to generation of action potentials in irritated D. muscipula traps was used to determine the 'site effect' of the electrical signal-induced inhibition of photosynthesis. Irritation of trigger hairs and subsequent generation of action potentials resulted in a decrease in the effective photochemical quantum yield of photosystem II (Phi(PSII)) and the rate of net photosynthesis (A(N)). During the first seconds of irritation, increased excitation pressure in photosystem II (PSII) was the major contributor to the decreased Phi(PSII). Within ~1 min, non-photochemical quenching (NPQ) released the excitation pressure at PSII. Measurements of the fast chlorophyll a fluorescence transient (O-J-I-P) revealed a direct impact of action potentials on the charge separation-recombination reactions in PSII, although the effect seems to be small rather than substantial. All the data presented here indicate that the main primary target of the electrical signal-induced inhibition of photosynthesis is the dark reaction, whereas the inhibition of electron transport is only a consequence of reduced carboxylation efficiency. In addition, the study also provides valuable data confirming the hypothesis that chlorophyll a fluorescence is under electrochemical control. PMID- 21289079 TI - ABA biosynthesis and degradation contributing to ABA homeostasis during barley seed development under control and terminal drought-stress conditions. AB - Drought is one of the most severe environmental stress factors limiting crop yield especially when occurring during anthesis and seed filling. This terminal drought is characterized by an excess production of the phytohormone abscisic acid (ABA) which plays an important role during seed development and dormancy. All the genes putatively involved in ABA biosynthesis and inactivation in barley were identified and their expression studied during plant ontogeny under standard and drought-stress conditions to learn more about ABA homeostasis and the possible mode of cross-talk between source and sink tissues. Out of 41 genes related to ABA biosynthesis and inactivation 19 were found to be differentially regulated under drought stress in both flag leaves and developing seed during seed filling. Transcripts of plastid-located enzymes are regulated similarly in flag leaf and seed under terminal drought whereas transcripts of cytosolic enzymes are differentially regulated in the two tissues. Detailed information on the expression of defined gene family members is supplemented by measurements of ABA and its degradation and conjugation products, respectively. Under drought stress, flag leaves in particular contain high concentrations of both ABA and the ABA degradation products phaseic acid (PA) and diphaseic acid (DPA); whereas, in seeds, besides ABA, DPA was mainly found. The measurements also revealed a positive correlation between ABA level and starch content in developing seeds for the following reasons: (i) genes of the ABA controlled SnRK2.6 and RCAR/PP2C mediated signal transduction pathway to the ABF transcription factor HvABI5 are activated in the developing grain under drought, (ii) novel ABA- and dehydration responsive cis-elements have been found in the promoters of key genes of starch biosynthesis (HvSUS1, HvAGP-L1) and degradation (HvBAM1) and these transcripts/activity are prominently induced in developing seeds during 12 and 16 DAF, (iii) spraying of fluridone (an ABA biosynthesis inhibitor) to drought stressed plants results in severely impaired starch content and thousand grain weight of mature seeds. PMID- 21289080 TI - Tracing the history of plant traits under domestication in cranberries: potential consequences on anti-herbivore defences. AB - The process of selecting certain desirable traits for plant breeding may compromise other potentially important traits, such as defences against pests; however, specific phenotypic changes occurring over the course of domestication are unknown for most domesticated plants. Cranberry (Vaccinium macrocarpon) offers a unique opportunity to study such changes: its domestication occurred recently, and we have access to the wild ancestors and intermediate varieties used in past crosses. In order to investigate whether breeding for increased yield and fruit quality traits may indirectly affect anti-herbivore defences, the chemical defences have been examined of five related cranberry varieties that span the history of domestication against a common folivore, the gypsy moth (Lymantria dispar). Direct defences were assessed by measuring the performance of gypsy moth caterpillars and levels of phenolic compounds in leaves, and indirect defences by assaying induced leaf volatile emissions. Our results suggest that breeding in cranberry has compromised plant defences: caterpillars performed best on the derived NJS98-23 (the highest-yielding variety) and its parent Ben Lear. Moreover, NJS98-23 showed reduced induction of volatile sesquiterpenes, and had lower concentrations of the defence-related hormone cis-jasmonic acid (JA) than ancestral varieties. However, induced direct defences were not obviously affected by breeding, as exogenous JA applications reduced caterpillar growth and increased the amounts of phenolics independent of variety. Our results suggest that compromised chemical defences in high-yielding cranberry varieties may lead to greater herbivore damage which, in turn, may require more intensive pesticide control measures. This finding should inform the direction of future breeding programmes. PMID- 21289081 TI - Transcription of platelet-derived growth factor receptor alpha in Leydig cells involves specificity protein 1 and 3. AB - Platelet-derived growth factor (PDGF) A is secreted by Sertoli cells and acts on Leydig precursor cells, which express the receptor PDGFRA, triggering their differentiation into steroidogenically active Leydig cells. There is, however, no information regarding the molecular mechanisms that govern Pdgfra expression in Leydig cells. In this study, we isolated and characterized a 2.2 kb fragment of the rat Pdgfra 5'-flanking sequence in the TM3 Leydig cell line, which endogenously expresses Pdgfra. A series of 5' progressive deletions of the Pdgfra promoter was generated and transfected in TM3 cells. Using this approach, two regions (-183/-154 and -154/-105), each conferring 46% of Pdgfra promoter activity, were identified. To better define the regulatory elements, trinucleotide mutations spanning the -154/-105 region were introduced by site directed mutagenesis in the context of the -2.2 kb Pdgfra promoter. Mutations that altered the TCCGAGGGAAAC sequence at -138 bp significantly decreased Pdgfra promoter activity in TM3 cells. Several proteins from TM3 nuclear extracts were found to bind to this G(C/A) motif in electromobility shift assay. Two of the proteins were identified as the transcription factors SP1 and SP3. Using transient transfections of TM3 Leydig cells, SP1 and SP3 were found to activate the Pdgfra promoter by threefold. The SP1/SP3-dependent activation of the Pdgfra promoter was severely blunted when the G(C/A) motif was mutated. Our study provides new insights into the regulatory mechanisms of Pdgfra transcription in Leydig cells, which includes a role for the transcription factors SP1 and SP3. PMID- 21289082 TI - Context dependence of checkpoint kinase 1 as a therapeutic target for pancreatic cancers deficient in the BRCA2 tumor suppressor. AB - Inherited mutations in the tumor suppressor BRCA2 are predisposed to pancreatic adenocarcinomas, which carry activating mutations in the KRAS oncogene in more than 95% of cases, as well as frequent TP53 inactivation. Here, we have established an RNA interference (RNAi) screen to identify genes whose depletion selectively inhibits the growth of cells lacking BRCA2, and then studied the effects of the genetic depletion or pharmacologic inhibition of 1 candidate, the checkpoint kinase 1 (CHK1), in the context of pancreatic cancer. Pharmacologic inhibition of CHK1 using small-molecule inhibitors (CHK1i) reduced cell growth in several cell lines depleted of BRCA2. Unexpectedly, these drugs did not suppress the growth of BRCA2-deficient pancreatic cancer cell lines from humans or gene targeted mice expressing active Kras and trans-dominant inhibitory mutant Trp53. Remarkably, the expression of KRAS(G12V) and TP53(G154V) in BRCA2-depleted HEK293 cells was sufficient to render them resistant to CHK1i (but not to mitomycin C or inhibitors of PARP1). CHK1i sensitivity was restored by gemcitabine, an S-phase genotoxin used to treat pancreatic adenocarcinoma. Thus, the growth-suppressive effect of CHK1 inhibition in BRCA2-mutant tumors can be opposed by concurrent KRAS activation and TP53 mutations typical of pancreatic adenocarcinoma, and CHK1i resistance in this setting can be overcome by gemcitabine. Our findings show that approaches that use potential therapeutic targets for cancer identified in synthetic lethal RNAi screens are affected by the genetic context of specific malignancies and combination therapy with other agents. This concept should be taken into account in the ongoing and future development of targeted cancer therapies. PMID- 21289083 TI - Sas-4 proteins are required during basal body duplication in Paramecium. AB - Centrioles and basal bodies are structurally related organelles composed of nine microtubule (MT) triplets. Studies performed in Caenorhabditis elegans embryos have shown that centriole duplication takes place in sequential way, in which different proteins are recruited in a specific order to assemble a procentriole. ZYG-1 initiates centriole duplication by triggering the recruitment of a complex of SAS-5 and SAS-6, which then recruits the final player, SAS-4, to allow the incorporation of MT singlets. It is thought that a similar mechanism (that also involves additional proteins) is present in other animal cells, but it remains to be investigated whether the same players and their ascribed functions are conserved during basal body duplication in cells that exclusively contain basal bodies. To investigate this question, we have used the multiciliated protist Paramecium tetraurelia. Here we show that in the absence of PtSas4, two types of defects in basal body duplication can be identified. In the majority of cases, the germinative disk and cartwheel, the first structures assembled during duplication, are not detected. In addition, if daughter basal bodies were formed, they invariably had defects in MT recruitment. Our results suggest that PtSas4 has a broader function than its animal orthologues. PMID- 21289084 TI - Coilin participates in the suppression of RNA polymerase I in response to cisplatin-induced DNA damage. AB - Coilin is a nuclear phosphoprotein that concentrates within Cajal bodies (CBs) and impacts small nuclear ribonucleoprotein (snRNP) biogenesis. Cisplatin and gamma-irradiation, which cause distinct types of DNA damage, both trigger the nucleolar accumulation of coilin, and this temporally coincides with the repression of RNA polymerase I (Pol I) activity. Knockdown of endogenous coilin partially overrides the Pol I transcriptional arrest caused by cisplatin, while both ectopically expressed and exogenous coilin accumulate in the nucleolus and suppress rRNA synthesis. In support of this mechanism, we demonstrate that both cisplatin and gamma-irradiation induce the colocalization of coilin with RPA-194 (the largest subunit of Pol I), and we further show that coilin can specifically interact with RPA-194 and the key regulator of Pol I activity, upstream binding factor (UBF). Using chromatin immunoprecipitation analysis, we provide evidence that coilin modulates the association of Pol I with ribosomal DNA. Collectively, our data suggest that coilin acts to repress Pol I activity in response to cisplatin-induced DNA damage. Our findings identify a novel and unexpected function for coilin, independent of its role in snRNP biogenesis, establishing a new link between the DNA damage response and the inhibition of rRNA synthesis. PMID- 21289085 TI - Localization of Pom121 to the inner nuclear membrane is required for an early step of interphase nuclear pore complex assembly. AB - The nuclear pore complex (NPC) is a large protein assembly that mediates molecular trafficking between the cytoplasm and the nucleus. NPCs assemble twice during the cell cycle in metazoans: postmitosis and during interphase. In this study, using small interfering RNA (siRNA) in conjunction with a cell fusion based NPC assembly assay, we demonstrated that pore membrane protein (Pom)121, a vertebrate-specific integral membrane nucleoporin, is indispensable for an early step in interphase NPC assembly. Functional domain analysis of Pom121 showed that its nuclear localization signals, which bind to importin beta via importin alpha and likely function with RanGTP, play an essential role in targeting Pom121 to the interphase NPC. Furthermore, a region of Pom121 that interacts with the inner nuclear membrane (INM) and lamin B receptor was found to be crucial for its NPC targeting. Based on these findings and on evidence that Pom121 localizes at the INM in the absence of a complete NPC structure, we propose that the nuclear migration of Pom121 and its subsequent interaction with INM proteins are required to initiate interphase NPC assembly. Our data also suggest, for the first time, the importance of the INM as a seeding site for "prepores" during interphase NPC assembly. PMID- 21289086 TI - FAK phosphorylation at Tyr-925 regulates cross-talk between focal adhesion turnover and cell protrusion. AB - Cell migration is a highly complex process that requires the coordinated formation of membrane protrusion and focal adhesions (FAs). Focal adhesion kinase (FAK), a major signaling component of FAs, is involved in the disassembly process of FAs through phosphorylation and dephosphorylation of its tyrosine residues, but the role of such phosphorylations in nascent FA formation and turnover near the cell front and in cell protrusion is less well understood. In the present study, we demonstrate that, depending on the phosphorylation status of Tyr-925 residue, FAK modulates cell migration via two specific mechanisms. FAK-/- mouse embryonic fibroblasts (MEFs) expressing nonphosphorylatable Y925F-FAK show increased interactions between FAK and unphosphorylated paxillin, which lead to FA stabilization and thus decreased FA turnover and reduced cell migration. Conversely, MEFs expressing phosphomimetic Y925E-FAK display unchanged FA disassembly rates, show increase in phosphorylated paxillin in FAs, and exhibit increased formation of nascent FAs at the cell leading edges. Moreover, Y925E-FAK cells present enhanced cell protrusion together with activation of the p130(CAS)/Dock180/Rac1 signaling pathway. Together, our results demonstrate that phosphorylation of FAK at Tyr-925 is required for FAK-mediated cell migration and cell protrusion. PMID- 21289087 TI - Functional characterization of putative cilia genes by high-content analysis. AB - Cilia are microtubule-based protrusions from the cell surface that are involved in a number of essential signaling pathways, yet little is known about many of the proteins that regulate their structure and function. A number of putative cilia genes have been identified by proteomics and comparative sequence analyses, but functional data are lacking for the vast majority. We therefore monitored the effects in three cell lines of small interfering RNA (siRNA) knockdown of 40 of these genes by high-content analysis. We assayed cilia number, length, and transport of two different cargoes (membranous serotonin receptor 6-green fluorescent protein [HTR6-GFP] and the endogenous Hedgehog [Hh] pathway transcription factor Gli3) by immunofluorescence microscopy; and cilia function using a Gli-luciferase Hh signaling assay. Hh signaling was most sensitive to perturbations, with or without visible structural cilia defects. Validated hits include Ssa2 and mC21orf2 with ciliation defects; Ift46 with short cilia; Ptpdc1 and Iqub with elongated cilia; and Arl3, Nme7, and Ssna1 with distinct ciliary transport but not length defects. Our data confirm various ciliary roles for several ciliome proteins and show it is possible to uncouple ciliary cargo transport from cilia formation in vertebrates. PMID- 21289088 TI - Class V beta-tubulin alters dynamic instability and stimulates microtubule detachment from centrosomes. AB - A multigene family produces tubulin isotypes that are expressed in a tissue specific manner, but the role of these isotypes in microtubule assembly and function is unclear. Recently we showed that overexpression or depletion of beta5 tubulin, a minor isotype with wide tissue distribution, inhibits cell division. We now report that elevated beta5-tubulin causes uninterrupted episodes of microtubule shortening and increased shortening rates. Conversely, depletion of beta5-tubulin reduces shortening rates and causes very short excursions of growth and shortening. A tubulin conformation-sensitive antibody indicated that the uninterrupted shortening can be explained by a relative absence of stabilized patches along the microtubules that contain tubulin in an assembly-competent conformation and normally act to restore microtubule growth. In addition to these changes in dynamic instability, overexpression of beta5-tubulin causes fragmentation that results from microtubule detachment from centrosomes, and it is this activity that best explains the effects of beta5 on cell division. Paclitaxel inhibits microtubule detachment, increases the number of assembly competent tubulin patches, and inhibits microtubule shortening, thus providing an explanation for why the drug can counteract the phenotypic effects of beta5 overexpression. On the basis of these observations, we propose that cells can use beta5-tubulin expression to adjust the behavior of the microtubule cytoskeleton. PMID- 21289089 TI - CD43 interaction with ezrin-radixin-moesin (ERM) proteins regulates T-cell trafficking and CD43 phosphorylation. AB - Cell polarization is a key feature of cell motility, driving cell migration to tissues. CD43 is an abundantly expressed molecule on the T-cell surface that shows distinct localization to the migrating T-cell uropod and the distal pole complex (DPC) opposite the immunological synapse via association with the ezrin radixin-moesin (ERM) family of actin regulatory proteins. CD43 regulates multiple T-cell functions, including T-cell activation, proliferation, apoptosis, and migration. We recently demonstrated that CD43 regulates T-cell trafficking through a phosphorylation site at Ser-76 (S76) within its cytoplasmic tail. Using a phosphorylation-specific antibody, we now find that CD43 phosphorylation at S76 is enhanced by migration signals. We further show that CD43 phosphorylation and normal T-cell trafficking depend on CD43 association with ERM proteins. Interestingly, mutation of S76 to mimic phosphorylation enhances T-cell migration and CD43 movement to the DPC while blocking ERM association, showing that CD43 movement can occur in the absence of ERM binding. We also find that protein kinase CTheta can phosphorylate CD43. These results show that while CD43 binding to ERM proteins is crucial for S76 phosphorylation, CD43 movement and regulation of T-cell migration can occur through an ERM-independent, phosphorylation dependent mechanism. PMID- 21289090 TI - The proteomics of quiescent and nonquiescent cell differentiation in yeast stationary-phase cultures. AB - As yeast cultures enter stationary phase in rich, glucose-based medium, differentiation of two major subpopulations of cells, termed quiescent and nonquiescent, is observed. Differences in mRNA abundance between exponentially growing and stationary-phase cultures and quiescent and nonquiescent cells are known, but little was known about protein abundance in these cells. To measure protein abundance in exponential and stationary-phase cultures, the yeast GFP fusion library (4159 strains) was examined during exponential and stationary phases, using high-throughput flow cytometry (HyperCyt). Approximately 5% of proteins in the library showed twofold or greater changes in median fluorescence intensity (abundance) between the two conditions. We examined 38 strains exhibiting two distinct fluorescence-intensity peaks in stationary phase and determined that the two fluorescence peaks distinguished quiescent and nonquiescent cells, the two major subpopulations of cells in stationary-phase cultures. GFP-fusion proteins in this group were more abundant in quiescent cells, and half were involved in mitochondrial function, consistent with the sixfold increase in respiration observed in quiescent cells and the relative absence of Cit1p:GFP in nonquiescent cells. Finally, examination of quiescent cell-specific GFP-fusion proteins revealed symmetry in protein accumulation in dividing quiescent and nonquiescent cells after glucose exhaustion, leading to a new model for the differentiation of these cells. PMID- 21289091 TI - The nucleoporin Nup88 is interacting with nuclear lamin A. AB - Nuclear pore complexes (NPCs) are embedded in the nuclear envelope (NE) and mediate bidirectional nucleocytoplasmic transport. Their spatial distribution in the NE is organized by the nuclear lamina, a meshwork of nuclear intermediate filament proteins. Major constituents of the nuclear lamina are A- and B-type lamins. In this work we show that the nuclear pore protein Nup88 binds lamin A in vitro and in vivo. The interaction is mediated by the N-terminus of Nup88, and Nup88 specifically binds the tail domain of lamin A but not of lamins B1 and B2. Expression of green fluorescent protein-tagged lamin A in cells causes a masking of binding sites for Nup88 antibodies in immunofluorescence assays, supporting the interaction of lamin A with Nup88 in a cellular context. The epitope masking disappears in cells expressing mutants of lamin A that are associated with laminopathic diseases. Consistently, an interaction of Nup88 with these mutants is disrupted in vitro. Immunoelectron microscopy using Xenopus laevis oocyte nuclei further revealed that Nup88 localizes to the cytoplasmic and nuclear face of the NPC. Together our data suggest that a pool of Nup88 on the nuclear side of the NPC provides a novel, unexpected binding site for nuclear lamin A. PMID- 21289092 TI - Mitochondrial proteomic approach reveals galectin-7 as a novel BCL-2 binding protein in human cells. AB - Although the anti-apoptotic activity of Bcl-2 has been extensively studied, its mode of action remains incompletely understood. Deciphering the network of Bcl-2 interacting factors is necessary to better understand the key function of Bcl-2 in apoptosis initiation. To identify novel Bcl-2 mitochondrial partners, we have combined a Bcl-2 immunocapture with a mass spectrometry analysis using highly pure mitochondrial fractions isolated from human cancer cells. We identified at high confidence 127 potential Bcl-2-interacting proteins. Gene ontology mining reveals enrichment for mitochondrial proteins, endoplasmic reticulum-associated proteins, and cytoskeleton-associated proteins. Importantly, we report the identification of galectin-7 (Gal7), a member of a family of beta-galactoside binding lectins that was already known to exhibit a pro-apoptotic function, as a new mitochondrial Bcl-2 interacting partner. Our data further show that endogenous Bcl-2 coimmunoprecipitates with Gal7 and that recombinant Gal7 directly interacts with recombinant Bcl-2. A fraction of Gal7 is constitutively localized at mitochondria in a Bcl-2-dependent manner and sensitizes the mitochondria to the apoptotic signal. In addition, we show that the Bcl-2/Gal7 interaction is abolished following genotoxic stress. Taken together, our findings suggest that the binding of Gal7 to Bcl-2 may constitute a new target for enhancing the intrinsic apoptosis pathway. PMID- 21289093 TI - DDR1 triggers epithelial cell differentiation by promoting cell adhesion through stabilization of E-cadherin. AB - Discoidin domain receptor 1 (DDR1) promotes E-cadherin-mediated adhesion. The underlying mechanism and its significance, however, have not been elucidated. Here we show that DDR1 overexpression augmented, whereas dominant negative mutant (DN-DDR1) or knockdown of DDR1 inhibited E-cadherin localized in cell-cell junctions in epithelial cells. DDR1 changed the localization and abundance of E cadherin, as well as epithelial plasticity, as manifested by enhancement of microvilli formation and alteration of cytoskeletal organization. DDR1 also reduced protein abundance of mesenchymal markers, whereas DN-DDR1 and sh-DDR1 showed opposite effects. These results suggest that expression of DDR1 increases epithelial plasticity. Expression of DDR1 augmented E-cadherin protein levels by decreasing its degradation rate. Photobleaching and photoconversion of E-cadherin conjugated with Eos fluorescence protein demonstrated that DDR1 increased the stability of E-cadherin on the cell membrane, whereas sh-DDR1 decreased it. Pull down assay and expression of constitutively active or dominant-negative Cdc42 showed that DDR1 stabilized E-cadherin through inactivation of Cdc42. Altogether, our results show that DDR1 promotes cell-cell adhesion and differentiation through stabilization of E-cadherin, which is mediated by Cdc42 inactivation. PMID- 21289094 TI - A decisive function of transforming growth factor-beta/Smad signaling in tissue morphogenesis and differentiation of human HaCaT keratinocytes. AB - The mechanism by which transforming growth factor-beta (TGFbeta) regulates differentiation in human epidermal keratinocytes is still poorly understood. To assess the role of Smad signaling, we engineered human HaCaT keratinocytes either expressing small interfering RNA against Smads2, 3, and 4 or overexpressing Smad7 and verified impaired Smad signaling as decreased Smad phosphorylation, aberrant nuclear translocation, and altered target gene expression. Besides abrogation of TGFbeta-dependent growth inhibition in conventional cultures, epidermal morphogenesis and differentiation in organotypic cultures were disturbed, resulting in altered tissue homeostasis with suprabasal proliferation and hyperplasia upon TGFbeta treatment. Neutralizing antibodies against TGFbeta, similar to blocking the actions of EGF-receptor or keratinocyte growth factor, caused significant growth reduction of Smad7-overexpressing cells, thereby demonstrating that epithelial hyperplasia was attributed to TGFbeta-induced "dermis"-derived growth promoting factors. Furthermore impaired Smad signaling not only blocked the epidermal differentiation process or caused epidermal-to mesenchymal transition but induced a switch to a complex alternative differentiation program, best characterized as mucous/intestinal-type epithelial differentiation. As the same alternative phenotype evolved from both modes of Smad-pathway interference, and reduction of Smad7-overexpression caused reversion to epidermal differentiation, our data suggest that functional TGFbeta/Smad signaling, besides regulating epidermal tissue homeostasis, is not only essential for terminal epidermal differentiation but crucial in programming different epithelial differentiation routes. PMID- 21289095 TI - Tissue-nonspecific alkaline phosphatase promotes axonal growth of hippocampal neurons. AB - Axonal growth is essential for establishing neuronal circuits during brain development and for regenerative processes in the adult brain. Unfortunately, the extracellular signals controlling axonal growth are poorly understood. Here we report that a reduction in extracellular ATP levels by tissue-nonspecific alkaline phosphatase (TNAP) is essential for the development of neuritic processes by cultured hippocampal neurons. Selective blockade of TNAP activity with levamisole or specific TNAP knockdown with short hairpin RNA interference inhibited the growth and branching of principal axons, whereas addition of alkaline phosphatase (ALP) promoted axonal growth. Neither activation nor inhibition of adenosine receptors affected the axonal growth, excluding the contribution of extracellular adenosine as a potential hydrolysis product of extracellular ATP to the TNAP-mediated effects. TNAP was colocalized at axonal growth cones with ionotropic ATP receptors (P2X7 receptor), whose activation inhibited axonal growth. Additional analyses suggested a close functional interrelation of TNAP and P2X7 receptors whereby TNAP prevents P2X7 receptor activation by hydrolyzing ATP in the immediate environment of the receptor. Furthermore inhibition of P2X7 receptor reduced TNAP expression, whereas addition of ALP enhanced P2X7 receptor expression. Our results demonstrate that TNAP, regulating both ligand availability and protein expression of P2X7 receptor, is essential for axonal development. PMID- 21289096 TI - Regulation of flagellar motility by the conserved flagellar protein CG34110/Ccdc135/FAP50. AB - Eukaryotic cilia and flagella are vital sensory and motile organelles. The calcium channel PKD2 mediates sensory perception on cilia and flagella, and defects in this can contribute to ciliopathic diseases. Signaling from Pkd2 dependent Ca2+ rise in the cilium to downstream effectors may require intermediary proteins that are largely unknown. To identify these proteins, we carried out genetic screens for mutations affecting Drosophila melanogaster sperm storage, a process mediated by Drosophila Pkd2. Here we show that a new mutation lost boys (lobo) encodes a conserved flagellar protein CG34110, which corresponds to vertebrate Ccdc135 (E = 6e-78) highly expressed in ciliated respiratory epithelia and sperm, and to FAP50 (E = 1e-28) in the Chlamydomonas reinhardtii flagellar proteome. CG34110 localizes along the fly sperm flagellum. FAP50 is tightly associated with the outer doublet microtubules of the axoneme and appears not to be a component of the central pair, radial spokes, dynein arms, or structures defined by the mbo waveform mutants. Phenotypic analyses indicate that both Pkd2 and lobo specifically affect sperm movement into the female storage receptacle. We hypothesize that the CG34110/Ccdc135/FAP50 family of conserved flagellar proteins functions within the axoneme to mediate Pkd2-dependent processes in the sperm flagellum and other motile cilia. PMID- 21289097 TI - RB deletion disrupts coordination between DNA replication licensing and mitotic entry in vivo. AB - The integrity of the retinoblastoma tumor suppressor (RB) pathway is critical for restraining inappropriate proliferation and suppressing tumor development in a plethora of tissues. Here adenovirus-mediated RB deletion in the liver of adult mice led to DNA replication in the absence of productive mitotic condensation. The replication induced by RB loss was E2F-mediated and associated with the induction of DNA damage and a nontranscriptional G2/M checkpoint that targeted the accumulation of Cyclin B1. In the context of RB deletion or E2F activation, there was an increase in hepatocyte ploidy that was accompanied by hyperphysiological assembly of prereplication complexes. In keeping with this dysregulation, initiation of DNA replication was readily observed in hepatocytes that were phenotypically in G2/M. Under such conditions, uncoupling of replication initiation from mitotic progression led to altered genome ploidy in the liver. Interestingly, these findings in hepatocytes were not recapitulated in the basally proliferative tissues of the gastrointestinal tract, where RB deletion, while increasing DNA replication, did not lead to a profound uncoupling from mitosis. Combined, these findings demonstrate the critical role of RB in controlling cell-cycle transitions and underscore the importance of intrinsic tissue environments in resultant phenotypes. PMID- 21289098 TI - Dual function of Rpn5 in two PCI complexes, the 26S proteasome and COP9 signalosome. AB - Subunit composition and architectural structure of the 26S proteasome lid is strictly conserved between all eukaryotes. This eight-subunit complex bears high similarity to the eukaryotic translation initiation factor 3 and to the COP9 signalosome (CSN), which together define the proteasome CSN/COP9/initiation factor (PCI) troika. In some unicellular eukaryotes, the latter two complexes lack key subunits, encouraging questions about the conservation of their structural design. Here we demonstrate that, in Saccharomyces cerevisiae, Rpn5 plays dual roles by stabilizing proteasome and CSN structures independently. Proteasome and CSN complexes are easily dissected, with Rpn5 the only subunit in common. Together with Rpn5, we identified a total of six bona fide subunits at roughly stoichiometric ratios in isolated, affinity-purified CSN. Moreover, the copy of Rpn5 associated with the CSN is required for enzymatic hydrolysis of Rub1/Nedd8 conjugated to cullins. We propose that multitasking by a single subunit, Rpn5 in this case, allows it to function in different complexes simultaneously. These observations demonstrate that functional substitution of subunits by paralogues is feasible, implying that the canonical composition of the three PCI complexes in S. cerevisiae is more robust than hitherto appreciated. PMID- 21289099 TI - Protective role of Gipie, a Girdin family protein, in endoplasmic reticulum stress responses in endothelial cells. AB - Continued exposure of endothelial cells to mechanical/shear stress elicits the unfolded protein response (UPR), which enhances intracellular homeostasis and protect cells against the accumulation of improperly folded proteins. Cells commit to apoptosis when subjected to continuous and high endoplasmic reticulum (ER) stress unless homeostasis is maintained. It is unknown how endothelial cells differentially regulate the UPR. Here we show that a novel Girdin family protein, Gipie (78 kDa glucose-regulated protein [GRP78]-interacting protein induced by ER stress), is expressed in endothelial cells, where it interacts with GRP78, a master regulator of the UPR. Gipie stabilizes the interaction between GRP78 and the ER stress sensor inositol-requiring protein 1 (IRE1) at the ER, leading to the attenuation of IRE1-induced c-Jun N-terminal kinase (JNK) activation. Gipie expression is induced upon ER stress and suppresses the IRE1-JNK pathway and ER stress-induced apoptosis. Furthermore we found that Gipie expression is up regulated in the neointima of carotid arteries after balloon injury in a rat model that is known to result in the induction of the UPR. Thus our data indicate that Gipie/GRP78 interaction controls the IRE1-JNK signaling pathway. That interaction appears to protect endothelial cells against ER stress-induced apoptosis in pathological contexts such as atherosclerosis and vascular endothelial dysfunction. PMID- 21289100 TI - Nutrient stress does not cause retrograde transport of cytoplasmic tRNA to the nucleus in evolutionarily diverse organisms. AB - Intracellular trafficking of tRNA was long thought to be a one-way trip from the site of biogenesis in the nucleus to the translation machinery in the cytoplasm. This view has recently been challenged, however, by the discovery that tRNA can move retrograde from the cytoplasm back to the nucleus in Saccharomyces cerevisiae and rat hepatoma H4IIE cells during nutrient stress and in S. cerevisiae after intron-containing pre-tRNAs are spliced in the cytoplasm. Contrary to studies reported, we present data suggesting that nutrient stress does not cause retrograde transport of cytoplasmic tRNAs to the nucleus in rat hepatoma H4IIE cells, human HeLa and HEK293 cells, and the yeasts Kluyveromyces lactis and S. cerevisiae. However, the efficiency of nuclear re-export of retrograded spliced tRNA was severely affected in S. cerevisiae and two other Saccharomyces species deprived of nutrient. Collectively, the data suggest that nutrient stress does not cause nuclear import of cytoplasmic tRNA; instead, nutrient stress specifically regulates nuclear re-export of retrograded spliced tRNAs but not nuclear export of tRNAs made from intronless pre-tRNAs in Saccharomyces species. Furthermore, we provide evidence suggesting that Mtr10p and the Gsp1pGTP/Gsp1pGDP cycle are not involved in nuclear tRNA import in S. cerevisiae during nutrient stress. PMID- 21289101 TI - Nuclear import of an intact preassembled proteasome particle. AB - The 26S proteasome is a conserved 2.5 MDa protein degradation machine that localizes to different cellular compartments, including the nucleus. Little is known about the specific targeting mechanisms of proteasomes in eukaryotic cells. We used a cell-free nuclear reconstitution system to test for nuclear targeting and import of distinct proteasome species. Three types of stable, proteolytically active proteasomes particles were purified from Xenopus egg cytosol. Two of these, the 26S holoenzyme and the 20S core particle, were targeted to the nuclear periphery but did not reach the nucleoplasm. This targeting depends on the presence of mature nuclear pore complexes (NPCs) in the nuclear envelope. A third, novel form, designated here as 20S+, was actively imported through NPCs. The 20S+ proteasome particle resembles recently described structural intermediates from other systems. Nuclear import of this particle requires functional NPCs, but it is not directly regulated by the Ran GTPase cycle. The mere presence of the associated "+" factors is sufficient to reconstitute nuclear targeting and confer onto isolated 20S core particles the ability to be imported. Stable 20S+ particles found in unfertilized eggs may provide a means for quick mobilization of existing proteasome particles into newly formed nuclear compartments during early development. PMID- 21289102 TI - Comparative evolution of photosynthetic genes in response to polyploid and nonpolyploid duplication. AB - The likelihood of duplicate gene retention following polyploidy varies by functional properties (e.g. gene ontologies or protein family domains), but little is known about the effects of whole-genome duplication on gene networks related by a common physiological process. Here, we examined the effects of both polyploid and nonpolyploid duplications on genes encoding the major functional groups of photosynthesis (photosystem I, photosystem II, the light-harvesting complex, and the Calvin cycle) in the cultivated soybean (Glycine max), which has experienced two rounds of whole-genome duplication. Photosystem gene families exhibit retention patterns consistent with dosage sensitivity (preferential retention of polyploid duplicates and elimination of nonpolyploid duplicates), whereas Calvin cycle and light-harvesting complex gene families do not. We observed similar patterns in barrel medic (Medicago truncatula), which shared the older genome duplication with soybean but has evolved independently for approximately 50 million years, and in Arabidopsis (Arabidopsis thaliana), which experienced two nested polyploidy events independent from the legume duplications. In both soybean and Arabidopsis, Calvin cycle gene duplicates exhibit a greater capacity for functional differentiation than do duplicates within the photosystems, which likely explains the greater retention of ancient, nonpolyploid duplicates and larger average gene family size for the Calvin cycle relative to the photosystems. PMID- 21289103 TI - Genetic diversity and population structure in French populations of Mycosphaerella graminicola. AB - Mycosphaerella graminicola populations were examined in France with microsatellite markers and PCR-SSCP analysis of partial actin and beta-tubulin encoding sequences. A total of 363 isolates was sampled in 2005 from 17 provinces, and genotypes from corresponding strains were characterized. Unique haplotypes comprised 84% of the population, and gene diversity was high nationwide (0.70) and locally. A moderate genetic differentiation (G(ST) = 0.18) was found and indicated that in France the M. graminicola population was more structured than in other previously studied European countries. Bayesian structure analysis identified three genetic clusters distributed among the 17 provinces. Our results highlighted the potential for the adaptation of the fungus to local conditions, leading to genetic clusters among the French population of the fungus as well as genotype flow between regional clusters. PMID- 21289104 TI - The fossil record of the Peronosporomycetes (Oomycota). AB - Evidence of fossil Peronosporomycetes has been slow to accumulate. In this review various fossils historically assigmed to the Peronosporomycets are dicussed briefly and an explanation is provided as to why the fossil record of this grouop has remained inconsistent. In recent year there has been several new reports of fossil peronosporomycetes based on structurally preserved oogonium-antheridium complexes from Derovonian and Carboniferous rocks that demonstrate the existence of these organisms as fossils and refute the long-standing assumption that they are too delicate to be preserved. Among these are serral tyoes characterized by oogonial surface members of the group. To date at last three groups of fossil vascular plants (i.e. lycophytes, ferns and seed ferns) are known to host peronosporomycetes aas endophytes; however only one form has been identified as a parasite. PMID- 21289105 TI - Diversity of culturable ericoid mycorrhizal fungi of Rhododendron decorum in Yunnan, China. AB - The diversity of ericoid mycorrhizal fungi isolated from Rhododendron decorum Franch. in Yunnan, southwestern China, was examined for the first time. In total 300 hair-root samples were collected from 13 R. decorum individuals in two adjacent wild population sites and one cultivated population site. Two hundred eighteen slow-growing isolates were obtained; the ability of some to form ericoid mycorrhiza was tested in vitro. One hundred twenty-five isolates formed hyphal structures morphologically corresponding to ericoid mycorrhiza, and these were determined by morphological and molecular means to belong to 12 fungal species. There were hardly any differences in species among the three sampled populations. The sequences of several isolates were similar to those of Oidiodendron maius and ericoid mycorrhizal fungi from Helotiales, accounting respectively for 18.4% and 24.8% of the total culturable ericoid mycorrhizal fungi assemblage. Dark septate endophytes were detected in the sampled hair roots by microscopy. PMID- 21289106 TI - The diversity of Terfezia desert truffles: new species and a highly variable species complex with intrasporocarpic nrDNA ITS heterogeneity. AB - Desert truffles belonging to Terfezia are well known mycorrhizal members of the mycota of the Mediterranean region and the Middle East. We aimed to test (i) whether the morphological criteria of Terfezia species regularly collected in Spain enable their separation and (ii) whether the previously hypothesized edaphic/biotic specificity of one group could be confirmed by study of a larger number of specimens. The species T. arenaria and T. claveryi can be identified unambiguously by morphological characters. We consider T. leptoderma as a distinct species while several lineages of similar spiny spored Terfezia truffles with cellular peridium were detected that have no obvious anatomical differences. Several species treated generally as synonyms of T. olbiensis have been described in this group, and because they cannot be unambiguously assigned to separate lineages we propose to consider the group as the T. olbiensis species complex. A high level of intrasporocarpic variation of the nrDNA ITS was detected in the T. olbiensis species complex, especially in one of its lineages. We detected no exclusive specificity to either plant associates or soil, except in T. leptoderma, which was associated with Quercus spp. and cistaceous plants on acidic soils. Nevertheless the clades showed a tendency either to associate with Quercus/Helianthemum/Cistus or Pinus hosts. Specimens having distinct anatomical features, reticulate spores and cellular peridium formed a separate group in the molecular phylogenetic analyses of nrDNA ITS and LSU regions; for these specimens we propose a new species, Terfezia alsheikhii sp. nov. PMID- 21289107 TI - Intragenomic variation in the ITS rDNA region obscures phylogenetic relationships and inflates estimates of operational taxonomic units in genus Laetiporus. AB - Regions of rDNA are commonly used to infer phylogenetic relationships among fungal species and as DNA barcodes for identification. These regions occur in large tandem arrays, and concerted evolution is believed to reduce intragenomic variation among copies within these arrays, although some variation still might exist. Phylogenetic studies typically use consensus sequencing, which effectively conceals most intragenomic variation, but cloned sequences containing intragenomic variation are becoming prevalent in DNA databases. To understand effects of using cloned rDNA sequences in phylogenetic analyses we amplified and cloned the ITS region from pure cultures of six Laetiporus species and one Wolfiporia species (Basidiomycota, Polyporales). An average of 66 clones were selected randomly and sequenced from 21 cultures, producing a total of 1399 interpretable sequences. Significant variation (>= 5% variation in sequence similarity) was observed among ITS copies within six cultures from three species clades (L. cincinnatus, L. sp. clade J, and Wolfiporia dilatohypha) and phylogenetic analyses with the cloned sequences produced different trees relative to analyses with consensus sequences. Cloned sequences from L. cincinnatus fell into more than one species clade and numerous cloned L. cincinnatus sequences fell into entirely new clades, which if analyzed on their own most likely would be recognized as "undescribed" or "novel" taxa. The use of a 95% cut off for defining operational taxonomic units (OTUs) produced seven Laetiporus OTUs with consensus ITS sequences and 20 OTUs with cloned ITS sequences. The use of cloned rDNA sequences might be problematic in fungal phylogenetic analyses, as well as in fungal bar-coding initiatives and efforts to detect fungal pathogens in environmental samples. PMID- 21289108 TI - Insights from the first putative biosynthetic gene cluster for a lichen depside and depsidone. AB - The genes for polyketide synthases (PKSs), enzymes that assemble the carbon backbones of many secondary metabolites, often cluster with other secondary pathway genes. We describe here the first lichen PKS cluster likely to be implicated in the biosynthesis of a depside and a depsidone, compounds in a class almost exclusively produced by lichen fungi (mycobionts). With degenerate PCR with primers biased toward presumed PKS genes for depsides and depsidones we identified among the many PKS genes in Cladonia grayi four (CgrPKS13-16) potentially responsible for grayanic acid (GRA), the orcinol depsidone characteristic of this lichen. To single out a likely GRA PKS we compared mRNA and GRA induction in mycobiont cultures using the four candidate PKS genes plus three controls; only CgrPKS16 expression closely matched GRA induction. CgrPKS16 protein domains were compatible with orcinol depside biosynthesis. Phylogenetically CgrPKS16 fell in a new subclade of fungal PKSs uniquely producing orcinol compounds. In the C. grayi genome CgrPKS16 clustered with a CytP450 and an o-methyltransferase gene, appropriately matching the three compounds in the GRA pathway. Induction, domain organization, phylogeny and cluster pathway correspondence independently indicated that the CgrPKS16 cluster is most likely responsible for GRA biosynthesis. Specifically we propose that (i) a single PKS synthesizes two aromatic rings and links them into a depside, (ii) the depside to depsidone transition requires only a cytochrome P450 and (iii) lichen compounds evolved early in the radiation of filamentous fungi. PMID- 21289109 TI - Exploring the fitness landscape of an RNA virus by using a universal barcode microarray. AB - Studies of viral pathogenesis have relied heavily on analyses of specific clones and their genetic determinants of virulence. It is sometimes difficult to apply this reductionist approach to the study of RNA viruses, which by virtue of their very high mutation rates, exist as a complex mixture of mutants. While quasispecies theory has provided an intellectual framework for exploring the relationship between the viral population structure and phenotype, experimental studies have been limited by the relatively poor resolution of traditional sequencing-based approaches. We have addressed this problem by developing a molecular barcoding strategy in which viral subpopulations are tagged with unique 20-nucleotide sequences. The behavior of these subpopulations can be monitored using a universal barcode microarray. We demonstrate the performance of our barcode microarray platform using poliovirus, a model RNA virus. Using this platform, we explored the fitness landscape occupied by an artificial quasispecies consisting of 48 randomly mutagenized clones. We were able to rapidly derive precise fitness measurements for a majority of these clones and identified a neutral space surrounding the wild type. The experimental paradigm presented here is readily adaptable to other viral systems and can potentially be used to track thousands of variants in a cost-effective manner. PMID- 21289110 TI - Human immunodeficiency virus type 1 and related primate lentiviruses engage clathrin through Gag-Pol or Gag. AB - The Gag-Pol polyprotein of human immunodeficiency virus type 1 (HIV-1) is not required for efficient viral particle production. However, premature termination codons in pol, particularly in the integrase (IN)-coding region, can markedly impair HIV-1 particle formation, apparently due to the premature activation of the viral protease (PR). We now report that the IN domain of Gag-Pol is required for the incorporation of clathrin into HIV-1 virions. Significantly, PR-dependent effects of point mutations in IN on particle production correlated strictly with their effects on clathrin incorporation. A possible interpretation of these findings is that certain IN mutations impair particle production in a PR dependent manner by promoting Gag-Pol dimerization, which also occludes a binding site for clathrin. Consistently with this model, the reverse transcriptase (RT) inhibitor efavirenz, which is thought to promote Gag-Pol dimerization, inhibited the incorporation of clathrin into HIV-1 virions. Clathrin-depleted cells produced normal amounts of HIV-1 virions; however, their infectivity was reduced. We also observed that HIV-2 and the simian immunodeficiency virus SIVmac interact with clathrin through one or two copies of a peptide motif in the p6 domain of Gag that resembles the clathrin box of cellular adaptor proteins. Furthermore, the substitution of the hydrophobic residues in the single clathrin box motif of SIVmac caused a replication defect in primary cells. Taken together, our results indicate that primate lentiviruses from two different subgroups functionally interact with clathrin during assembly. PMID- 21289111 TI - Interaction of Kaposi's sarcoma-associated herpesvirus ORF59 with oriLyt is dependent on binding with K-Rta. AB - Kaposi's sarcoma-associated herpesvirus (KSHV)/human herpesvirus 8 (HHV-8) displays two distinct life stages, latency and lytic reactivation. Progression through the lytic cycle and replication of the viral genome constitute an essential step toward the production of infectious virus and human disease. KSHV K-RTA has been shown to be the major transactivator required for the initiation of lytic reactivation. In the transient-cotransfection replication assay, K-Rta is the only noncore protein required for DNA synthesis. K-Rta was shown to interact with both C/EBPalpha binding motifs and the R response elements (RRE) within oriLyt. It is postulated that K-Rta acts in part to facilitate the recruitment of replication factors to oriLyt. In order to define the role of K Rta in the initiation of lytic DNA synthesis, we show an interaction with ORF59, the DNA polymerase processivity factor (PF), one of the eight virally encoded proteins necessary for origin-dependent DNA replication. Using the chromatin immunoprecipitation (ChIP) assay, both K-Rta and ORF59 interact with the RRE and C/EBPalpha binding motifs within oriLyt in cells harboring the KSHV bacterial artificial chromosome (BAC). A transient-transfection ChIP assay demonstrated that the interaction of ORF59 with oriLyt is dependent on binding with K-Rta and that ORF59 fails to bind to oriLyt in the absence of K-Rta. Also, using the cotransfection replication assay, overexpression of the interaction domain of K Rta with ORF59 has a dominant negative effect on oriLyt amplification, suggesting that the interaction of K-Rta with ORF59 is essential for DNA synthesis and supporting the hypothesis that K-Rta facilitates the formation of a replication complex at oriLyt. PMID- 21289112 TI - Influence of Gag-protease-mediated replication capacity on disease progression in individuals recently infected with HIV-1 subtype C. AB - HLA class I-mediated selection of immune escape mutations in functionally important Gag epitopes may partly explain slower disease progression in HIV-1 infected individuals with protective HLA alleles. To investigate the impact of Gag function on disease progression, the replication capacities of viruses encoding Gag-protease from 60 individuals in early HIV-1 subtype C infection were assayed in an HIV-1-inducible green fluorescent protein reporter cell line and were correlated with subsequent disease progression. Replication capacities did not correlate with viral load set points (P = 0.37) but were significantly lower in individuals with below-median viral load set points (P = 0.03), and there was a trend of correlation between lower replication capacities and lower rates of CD4 decline (P = 0.09). Overall, the proportion of host HLA-specific Gag polymorphisms in or adjacent to epitopes was negatively associated with replication capacities (P = 0.04), but host HLA-B-specific polymorphisms were associated with higher viral load set points (P = 0.01). Further, polymorphisms associated with host-specific protective HLA alleles were linked with higher viral load set points (P = 0.03). These data suggest that transmission or early HLA-driven selection of Gag polymorphisms results in reduced early cytotoxic T lymphocyte (CTL) responses and higher viral load set points. In support of the former, 46% of individuals with nonprotective alleles harbored a Gag polymorphism exclusively associated with a protective HLA allele, indicating a high rate of their transmission in sub-Saharan Africa. Overall, HIV disease progression is likely to be affected by the ability to mount effective Gag CTL responses as well as the replication capacity of the transmitted virus. PMID- 21289113 TI - Basic residues in the foamy virus Gag protein. AB - Foamy virus (FV) capsid proteins have few lysines. Basic residues are almost exclusively represented by arginines indicating positive selective pressure. To analyze the possible functions of this peculiarity, we mutated an infectious molecular clone of the prototypic FV (PFV) to harbor lysines in the Gag protein at arginine-specifying positions and analyzed various aspects of the FV replication cycle. The majority of mutants replicated equally as well in permanent cell cultures as the original wild-type (wt) virus and were genetically stable in gag upon 10 cell-free passages. With respect to the features of late reverse transcription, nucleic acid content, and infectiousness of the virion DNA genome, the majority of mutants behaved like the wt. Several mutants of PFV were ubiquitinated in Gag but unable to generate virus-like particles (VLPs) or to undergo pseudotyping by a heterologous envelope. Using primary cells, however, a replicative disadvantage of the majority of mutants was disclosed. This disadvantage was enhanced upon interferon (IFN) treatment. We found no evidence that the lysine-bearing gag mutants showed more restriction than the wt virus by tetherin (CD317) or Trim5alpha. A single lysine in PFV Gag was found to be nonessential for transient replication in permanent cell culture if replaced by an arginine residue. Upon replication in primary cells, even without IFN treatment, this mutant was severely impaired, indicating the importance of specifying at least this lysine residue in PFV Gag. The paucity of lysines in FV Gag proteins may be a consequence of preventing proteasomal Gag degradation. PMID- 21289114 TI - Single-nucleotide changes in the HIV Rev-response element mediate resistance to compounds that inhibit Rev function. AB - Previously we described the identification of two compounds (3-amino-5-ethyl-4,6 dimethylthieno[2,3-b]pyridine-2-carboxamide [103833] and 4-amino-6-methoxy-2 (trifluoromethyl)-3-quinolinecarbonitrile [104366]) that interfered with HIV replication through the inhibition of Rev function. We now describe resistant viral variants that arose after drug selection, using virus derived from two different HIV proviral clones, NL4-3 and R7/3. With HIV(NL4-3), each compound selected a different single point mutation in the Rev response element (RRE) at the bottom of stem-loop IIC. Either mutation led to the lengthening of the stem loop IIC stem by an additional base pair, creating an RRE that was more responsive to lower concentrations of Rev than the wild type. Surprisingly, wild type HIV(R7/3) was also found to be inhibited when tested with these compounds, in spite of the fact this virus already has an RNA stem-loop IIC similar to the one in the resistant NL4-3 variant. When drug resistance was selected in HIV(R7/3), a virus arose with two nucleotide changes that mapped to the envelope region outside the RRE. One of these nucleotide changes was synonymous with respect to env, and one was not. The combination of both nucleotide changes appeared to be necessary for the resistance phenotype as the individual point mutations by themselves did not convey resistance. Thus, although drug-resistant variants can be generated with both viral strains, the underlying mechanism is clearly different. These results highlight that minor nucleotide changes in HIV RNA, outside the primary Rev binding site, can significantly alter the efficiency of the Rev/RRE pathway. PMID- 21289115 TI - Interferon signaling remains functional during henipavirus infection of human cell lines. AB - Henipaviruses encode several proteins from the P gene, of which V and W have been demonstrated by gene-based transfection studies to antagonize the innate immune response, blocking both type I interferon production and signaling. This study examines the effects of henipavirus infection on the innate immune response in human cell lines. We report that henipavirus infection does not result in interferon production, with the virus antagonizing this response. In contrast to published transfection studies, our study found that the interferon signaling pathways are only partially blocked by henipavirus infection of human cell lines. PMID- 21289116 TI - Identification of human parainfluenza virus type 2 (HPIV-2) V protein amino acid residues that reduce binding of V to MDA5 and attenuate HPIV-2 replication in nonhuman primates. AB - Human parainfluenza virus type 2 (HPIV-2), an important pediatric respiratory pathogen, encodes a V protein that inhibits type I interferon (IFN) induction and signaling. Using reverse genetics, we attempted the recovery of a panel of V mutant viruses that individually contained one of six cysteine-to-serine (residues 193, 197, 209, 211, 214, and 218) substitutions, one of two paired charge-to-alanine (R175A/R176A and R205A/K206A) substitutions, or a histidine-to phenylalanine (H174F) substitution. This mutagenesis was performed using a cDNA derived HPIV-2 virus that expressed the V and P coding sequences from separate mRNAs. Of the cysteine substitutions, only C193S, C214S, and C218S yielded viable virus, and only the C214S mutant replicated well enough for further analysis. The H174F, R175A/R176A, and R205A/K206A mutants were viable and replicated well. The H174F and R205A/K206A mutants did not differ from the wild-type (WT) V in their ability to physically interact with MDA5, a cytoplasmic sensor of nonself RNA that induces type I IFN. Like WT HPIV-2, these mutants inhibited IFN-beta induction and replicated efficiently in African green monkeys (AGMs). In contrast, the C214S and R175A/R176A mutants did not bind MDA5 efficiently, did not inhibit interferon regulatory factor 3 (IRF3) dimerization or IFN-beta induction, and were attenuated in AGMs. These findings indicate that V binding to MDA5 is important for HPIV-2 virulence in nonhuman primates and that some V protein residues involved in MDA5 binding are not essential for efficient HPIV-2 growth in vitro. Using a transient expression system, 20 additional mutant V proteins were screened for MDA5 binding, and the region spanning residues 175 to 180 was found to be essential for this activity. PMID- 21289117 TI - Interaction of Autographa californica multiple nucleopolyhedrovirus cathepsin protease progenitor (proV-CATH) with insect baculovirus chitinase as a mechanism for proV-CATH cellular retention. AB - The insect baculovirus chitinase (CHIA) and cathepsin protease (V-CATH) enzymes cause terminal host insect liquefaction, enhancing the dissemination of progeny virions away from the host cadavers. Regulated and delayed cellular release of these host tissue-degrading enzymes ensures that liquefaction starts only after optimal viral replication has occurred. Baculoviral CHIA remains intracellular due to its C-terminal KDEL endoplasmic reticulum (ER) retention motif. However, the mechanism for cellular retention of the inactive V-CATH progenitor (proV CATH) has not yet been determined. Signal peptide cleavage occurs upon cotranslational ER import of the v-cath-expressed protein, and ER-resident CHIA is needed for the folding of proV-CATH. Although this implies that CHIA and proV CATH bind each other in the ER, the putative CHIA-proV-CATH interaction has not been experimentally verified. We demonstrate that the amino-terminal 22 amino acids (aa) of Autographa californica multiple nucleopolyhedrovirus (AcMNPV) preproV-CATH are responsible for the entry of proV-CATH into the ER. Furthermore, the CHIA-green fluorescent protein (GFP) and proV-CATH-red fluorescent protein (RFP) fusion proteins colocalize in the ER. Using monomeric RFP (mRFP)-based bimolecular fluorescence complementation (BiFC), we determined that CHIA and proV CATH interact directly with each other in the ER during virus replication. Moreover, reciprocal Ni/His pulldowns of His-tagged proteins confirmed the CHIA proV-CATH interaction biochemically. The reciprocal copurification of CHIA and proV-CATH suggests a specific CHIA-proV-CATH interaction and corroborates our BiFC data. Deletion of the CHIA KDEL motif allowed for premature CHIA secretion from cells, and proV-CATH was similarly prematurely secreted from cells along with DeltaKDEL-CHIA. These data suggest that CHIA and proV-CATH interact directly with each other and that this interaction aids the cellular retention of proV CATH. PMID- 21289118 TI - TRIM56 is a virus- and interferon-inducible E3 ubiquitin ligase that restricts pestivirus infection. AB - The tripartite motif (TRIM) protein family comprises more than 60 members that have diverse functions in various biological processes. Although a small number of TRIM proteins have been shown to regulate innate immunity, much remains to be learned about the functions of the majority of the TRIM proteins. Here we identify TRIM56 as a cellular protein associated with the N-terminal protease (N(pro)) of bovine viral diarrhea virus (BVDV), a pestiviral interferon antagonist which degrades interferon regulatory factor 3 (IRF3) through the proteasome. We found that TRIM56 was constitutively expressed in most tissues, and its abundance was further upregulated moderately by interferon or virus. The manipulation of TRIM56 abundance did not affect the protein turnover of N(pro) and IRF3. Rather, ectopic expression of TRIM56 substantially impaired, while knockdown of TRIM56 expression greatly enhanced, BVDV replication in cell culture. The antiviral activity of TRIM56 depended on its E3 ubiquitin ligase activity as well as the integrity of its C-terminal region but was not attributed to a general augmentation of the interferon antiviral response. Overexpression of TRIM56 did not inhibit the replication of vesicular stomatitis virus or hepatitis C virus, a virus closely related to BVDV. Together, our data demonstrate that TRIM56 is a novel antiviral host factor that restricts pestivirus infection. PMID- 21289119 TI - Characterization of the Candiru antigenic complex (Bunyaviridae: Phlebovirus), a highly diverse and reassorting group of viruses affecting humans in tropical America. AB - The genus Phlebovirus of the family Bunyaviridae consists of approximately 70 named viruses, currently assigned to nine serocomplexes (species) based on antigenic similarities. Sixteen other named viruses that show little serologic relationship to the nine recognized groups are also classified as tentative species in the genus. In an effort to develop a more precise classification system for phleboviruses, we are attempting to sequence most of the named viruses in the genus with the goal of clarifying their phylogenetic relationships. In this report, we describe the serologic and phylogenetic relationships of 13 viruses that were found to be members of the Candiru serocomplex; 6 of them cause disease in humans. Analysis of full genome sequences revealed branching inconsistencies that suggest five reassortment events, all involving the M segment, and thus appear to be natural reassortants. This high rate of reassortment illustrates the inaccuracy of a classification system based solely on antigenic relationships. PMID- 21289120 TI - The NLRP3 inflammasome detects encephalomyocarditis virus and vesicular stomatitis virus infection. AB - Inflammasomes are cytosolic protein complexes that regulate caspase-1 activation and the secretion of interleukin-1beta (IL-1beta) and IL-18. Several different inflammasome complexes have been identified, but the NLRP3 inflammasome is particularly notable because of its central role in diseases of inflammation. Recent work has demonstrated an essential role for the NLRP3 inflammasome in host defense against influenza virus. We show here that two other RNA viruses, encephalomyocarditis virus (EMCV) and vesicular stomatitis virus (VSV), activate the NLRP3 inflammasome in dendritic cells and macrophages through a mechanism requiring viral replication. Inflammasome activation in response to both viruses does not require MDA5 or RIG-I signaling. Despite the ability of the NLRP3 inflammasome to detect EMCV and VSV, wild-type and caspase-1-deficient mice were equally susceptible to infection with both viruses. These findings indicate that the NLRP3 inflammasome may be a common pathway for RNA virus detection, but its precise role in the host response may be variable. PMID- 21289121 TI - Epithelial cells lining salivary gland ducts are early target cells of severe acute respiratory syndrome coronavirus infection in the upper respiratory tracts of rhesus macaques. AB - The shedding of severe acute respiratory syndrome coronavirus (SARS-CoV) into saliva droplets plays a critical role in viral transmission. The source of high viral loads in saliva, however, remains elusive. Here we investigate the early target cells of infection in the entire array of respiratory tissues in Chinese macaques after intranasal inoculations with a single-cycle pseudotyped virus and a pathogenic SARS-CoV. We found that angiotensin-converting enzyme 2-positive (ACE2(+)) cells were widely distributed in the upper respiratory tract, and ACE2(+) epithelial cells lining salivary gland ducts were the early target cells productively infected. Our findings also have implications for SARS-CoV early diagnosis and prevention. PMID- 21289122 TI - Key genomic changes necessary for an in vivo lethal mouse marburgvirus variant selection process. AB - Marburgvirus (MARV) infections are generally lethal in humans and nonhuman primates but require in vivo lethal mouse variant selection by the serial transfer (passage) of the nonlethal virus into naive mice to propagate a lethal infection. The passage of progenitor (wild-type) MARV or Ravn virus (RAVV) from infected scid BALB/c mouse liver homogenates into immunocompetent BALB/c mice results in the selection of lethal mouse viruses from within the quasispecies sufficient to establish lethality in immunocompetent mice. Genomic analysis in conjunction with the passage history of each mutation detailed the altered primary and secondary structures of the viral genomic RNA throughout the process. Key findings included the following: (i) a VP40:D184N mutation previously identified in the lethal guinea pig MARV genome was the first mutation to occur during the passage of both the MARV and RAVV variants; (ii) there was biased hypermutagenesis in the RAVV variant genome; (iii) there were two identical mutations in lethal mouse MARV and RAVV variants, VP40:Y19H in the PPPY motif and VP40:D184N in a loop structure between the two VP40 domains; (iv) the passage of wild-type MARV and RAVV in mice resulted in the selection of viral variants from among the quasispecies with different genotypes than those of the wild-type viruses; and (v) a lethal mouse RAVV variant had different tissue tropisms distinct from those of its wild-type virus. These studies provide insights into how marburgviruses manipulate the host for enzymes, metabolites, translation regulators, and effectors of the innate immune response to serve as potential viral countermeasures. PMID- 21289123 TI - The tegument protein UL71 of human cytomegalovirus is involved in late envelopment and affects multivesicular bodies. AB - Morphogenesis of human cytomegalovirus (HCMV) is still only partially understood. We have characterized the role of HCMV tegument protein pUL71 in viral replication and morphogenesis. By using a rabbit antibody raised against the C terminus of pUL71, we could detect the protein in infected cells, as well as in virions showing a molecular mass of approximately 48 kDa. The expression of pUL71, detected as early as 48 h postinfection, was not blocked by the antiviral drug foscarnet, indicating an early expression. The role of pUL71 during virus replication was investigated by construction and analysis of a UL71 stop mutant (TBstop71). The mutant could be reconstituted on noncomplementing cells proving that pUL71 is nonessential for virus replication in human fibroblasts. However, the inhibition of pUL71 expression resulted in a severe growth defect, as reflected by an up to 16-fold reduced extracellular virus yield after a high multiplicity infection and a small-plaque phenotype. Ultrastructural analysis of cells infected with TBstop71 virus revealed an increased number of nonenveloped nucleocapsids in the cytoplasm, many of them at different stages of envelopment, indicating that final envelopment of nucleocapsids in the cytoplasm was affected. In addition, enlarged multivesicular bodies (MVBs) were found in close proximity to the viral assembly compartment, suggesting that pUL71 affects MVBs during virus infection. The observation of numerous TBstop71 virus particles attached to MVB membranes and budding processes into MVBs indicated that these membranes can be used for final envelopment of HCMV. PMID- 21289124 TI - Novel mutations in a tissue culture-adapted hepatitis C virus strain improve infectious-virus stability and markedly enhance infection kinetics. AB - Hepatitis C virus (HCV) establishes persistent infections and leads to chronic liver disease. It only recently became possible to study the entire HCV life cycle due to the ability of a unique cloned patient isolate (JFH-1) to produce infectious particles in tissue culture. However, despite efficient RNA replication, yields of infectious virus particles remain modest. This presents a challenge for large-scale tissue culture efforts, such as inhibitor screening. Starting with a J6/JFH-1 chimeric virus, we used serial passaging to generate a virus with substantially enhanced infectivity and faster infection kinetics compared to the parental stock. The selected virus clone possessed seven novel amino acid mutations. We analyzed the contribution of individual mutations and identified three specific mutations, core K78E, NS2 W879R, and NS4B V1761L, which were necessary and sufficient for the adapted phenotype. These three mutations conferred a 100-fold increase in specific infectivity compared to the parental J6/JFH-1 virus, and media collected from cells infected with the adapted virus yielded infectious titers as high as 1 * 10(8) 50% tissue culture infective doses (TCID(50))/ml. Further analyses indicated that the adapted virus has longer infectious stability at 37 degrees C than the wild type. Given that the adapted phenotype resulted from a combination of mutations in structural and nonstructural proteins, these data suggest that the improved viral titers are likely due to differences in virus particle assembly that result in significantly improved infectious particle stability. This adapted virus will facilitate further studies of the HCV life cycle, virus structure, and high-throughput drug screening. PMID- 21289125 TI - Loss of asparagine-linked glycosylation sites in variable region 5 of human immunodeficiency virus type 1 envelope is associated with resistance to CD4 antibody ibalizumab. AB - Ibalizumab (formerly TNX-355) is a first-in-class, monoclonal antibody inhibitor of CD4-mediated human immunodeficiency type 1 (HIV-1) entry. Multiple clinical trials with HIV-infected patients have demonstrated the antiviral activity, safety, and tolerability of ibalizumab treatment. A 9-week phase Ib study adding ibalizumab monotherapy to failing drug regimens led to transient reductions in HIV viral loads and the evolution of HIV-1 variants with reduced susceptibility to ibalizumab. This report characterizes these variants by comparing the phenotypic susceptibilities and envelope (env) sequences of (i) paired baseline and on-treatment virus populations, (ii) individual env clones from selected paired samples, and (iii) env clones containing site-directed mutations. Viruses with reduced susceptibility to ibalizumab were found to exhibit reduced susceptibility to the anti-CD4 antibody RPA-T4. Conversely, susceptibility to soluble CD4, which targets the HIV-1 gp120 envelope protein, was enhanced. No changes in susceptibility to the fusion inhibitor enfuvirtide or the CCR5 antagonist maraviroc were observed. Functionally, viruses with reduced ibalizumab susceptibility also displayed high levels of infectivity relative to those of paired baseline viruses. Individual env clones exhibiting reduced ibalizumab susceptibility contained multiple amino acid changes in different regions relative to the paired baseline clones. In particular, clones with reduced susceptibility to ibalizumab contained fewer potential asparagine-linked glycosylation sites (PNGSs) in variable region 5 (V5) than did paired ibalizumab susceptible clones. The reduction in ibalizumab susceptibility due to the loss of V5 PNGSs was confirmed by site-directed mutagenesis. Taken together, these findings provide important insights into resistance to this new class of antiretroviral drug. PMID- 21289126 TI - Gag localization and virus-like particle release mediated by the matrix domain of human T-lymphotropic virus type 1 Gag are less dependent on phosphatidylinositol (4,5)-bisphosphate than those mediated by the matrix domain of HIV-1 Gag. AB - The human immunodeficiency virus type 1 (HIV-1) Gag matrix (MA) domain facilitates Gag targeting and binding to the plasma membrane (PM) during virus assembly. Interaction with a PM phospholipid, phosphatidylinositol-(4,5) bisphosphate [PI(4,5)P(2)], plays a key role in these MA functions. Previous studies showed that overexpression of polyphosphoinositide 5-phosphatase IV (5ptaseIV), which depletes cellular PI(4,5)P(2), mislocalizes HIV-1 Gag to the cytosol and greatly reduces HIV-1 release efficiency. In this study, we sought to determine the role of the MA-PI(4,5)P(2) interaction in Gag localization and membrane binding of a deltaretrovirus, human T-lymphotropic virus type 1 (HTLV 1). We compared the chimeric HIV-1 Gag (HTMA), in which MA was replaced with HTLV 1 MA, with wild-type HIV-1 and HTLV-1 Gag for PI(4,5)P(2) dependence. Our results demonstrate that, unlike HIV-1 Gag, subcellular localization of and VLP release by HTLV-1 and HTMA Gag were minimally sensitive to 5ptaseIV overexpression. These results suggest that the interaction of HTLV-1 MA with PI(4,5)P(2) is not essential for HTLV-1 particle assembly. Furthermore, liposome-binding analyses showed that both HTLV-1 and HTMA Gag can bind membrane efficiently even in the absence of PI(4,5)P(2). Efficient HTLV-1 Gag binding to liposomes was largely driven by electrostatic interaction, unlike that of HIV-1 Gag, which required specific interaction with PI(4,5)P(2). Furthermore, membrane binding of HTLV-1 Gag in vitro was not suppressed by RNA, in contrast to HIV-1 Gag. Altogether, our data suggest that Gag targeting and membrane binding mediated by HTLV-1 MA does not require PI(4,5)P(2) and that distinct mechanisms regulate HIV-1 and HTLV-1 Gag membrane binding. PMID- 21289127 TI - Genome sequence of Ostreococcus tauri virus OtV-2 throws light on the role of picoeukaryote niche separation in the ocean. AB - Ostreococcus tauri, a unicellular marine green alga, is the smallest known free living eukaryote and is ubiquitous in the surface oceans. The ecological success of this organism has been attributed to distinct low- and high-light-adapted ecotypes existing in different niches at a range of depths in the ocean. Viruses have already been characterized that infect the high-light-adapted strains. Ostreococcus tauri virus (OtV) isolate OtV-2 is a large double-stranded DNA algal virus that infects a low-light-adapted strain of O. tauri and was assigned to the algal virus family Phycodnaviridae, genus Prasinovirus. Our working hypothesis for this study was that different viruses infecting high- versus low-light adapted O. tauri strains would provide clues to propagation strategies that would give them selective advantages within their particular light niche. Sequence analysis of the 184,409-bp linear OtV-2 genome revealed a range of core functional genes exclusive to this low-light genotype and included a variety of unexpected genes, such as those encoding an RNA polymerase sigma factor, at least four DNA methyltransferases, a cytochrome b(5), and a high-affinity phosphate transporter. It is clear that OtV-2 has acquired a range of potentially functional genes from its host, other eukaryotes, and even bacteria over evolutionary time. Such piecemeal accretion of genes is a trademark of large double-stranded DNA viruses that has allowed them to adapt their propagation strategies to keep up with host niche separation in the sunlit layers of the oceanic environment. PMID- 21289129 TI - Current perspectives on management of congenital jugular vein aneurysms. AB - True aneurysms of the internal jugular vein are relatively rare. This study describes 3 cases and the current management of congenital internal jugular vein aneurysms. PMID- 21289128 TI - Vif substitution enables persistent infection of pig-tailed macaques by human immunodeficiency virus type 1. AB - Among Old World monkeys, pig-tailed macaques (Pt) are uniquely susceptible to human immunodeficiency virus type 1 (HIV-1), although the infection does not persist. We demonstrate that the susceptibility of Pt T cells to HIV-1 infection is due to the absence of postentry inhibition by a TRIM5 isoform. Notably, substitution of the viral infectivity factor protein, Vif, with that from pathogenic SIVmne enabled replication of HIV-1 in Pt T cells in vitro. When inoculated into juvenile pig-tailed macaques, the Pt-tropic HIV-1 persistently replicated for more than 1.5 to 2 years, producing low but measurable plasma viral loads and persistent proviral DNA in peripheral blood mononuclear cells. It also elicited strong antibody responses. However, there was no decline in CD4(+) T cells or evidence of disease. Surprisingly, the Pt-tropic HIV-1 was rapidly controlled when inoculated into newborn Pt macaques, although it transiently rebounded after 6 months. We identified two notable differences between the Pt tropic HIV-1 and SIVmne. First, SIV Vif does not associate with Pt-tropic HIV-1 viral particles. Second, while Pt-tropic HIV-1 degrades both Pt APOBEC3G and APOBEC3F, it prevents their inclusion in virions to a lesser extent than pathogenic SIVmne. Thus, while SIV Vif is necessary for persistent infection by Pt-tropic HIV-1, improved expression and inhibition of APOBEC3 proteins may be required for robust viral replication in vivo. Additional adaptation of the virus may also be necessary to enhance viral replication. Nevertheless, our data suggest the potential for the pig-tailed macaque to be developed as an animal model of HIV-1 infection and disease. PMID- 21289130 TI - Neutrophil-lymphocyte ratio predicts medium-term survival following elective major vascular surgery: a cross-sectional study. AB - BACKGROUND: The systemic nature of atherosclerosis compromises medium-term survival following major vascular surgery. Neutrophil-lymphocyte ratio (NLR) is a simple index of systemic inflammatory burden which correlates with survival following percutaneous coronary intervention. METHODS: Patients undergoing elective major vascular surgery in 2 tertiary vascular units were identified from prospectively maintained databases. Factors associated with 2-year mortality were assessed by univariate and multivariate analyses. RESULTS: Over a 4-year period, 1021 patients underwent elective major vascular surgery (carotid endarterectomy, abdominal aortic aneurysm repair, lower limb revascularization). Two-year mortality was 11.2%. In multivariate analysis, preoperative NLR > 5 was independently associated with 2-year mortality (multivariate odds ratio [OR] 2.21; 95% confidence interval [CI] 1.22-4.01). CONCLUSION: Preoperative NLR identifies patients at increased risk of death within 2 years of major vascular surgery. This simple index may facilitate targeted preventive measures for high risk patients. PMID- 21289131 TI - Serglycin is a theranostic target in nasopharyngeal carcinoma that promotes metastasis. AB - Nasopharyngeal carcinoma (NPC) is known for its high-metastatic potential. Here we report the identification of the proteoglycan serglycin as a functionally significant regulator of metastasis in this setting. Comparative genomic expression profiling of NPC cell line clones with high- and low-metastatic potential revealed the serglycin gene (SRGN) as one of the most upregulated genes in highly metastatic cells. RNAi-mediated inhibition of serglycin expression blocked serglycin secretion and the invasive motility of highly metastatic cells, reducing metastatic capacity in vivo. Conversely, serglycin overexpression in poorly metastatic cells increased their motile behavior and metastatic capacity in vivo. Growth rate was not influenced by serglycin in either highly or poorly metastatic cells. Secreted but not bacterial recombinant serglycin promoted motile behavior, suggesting a critical role for glycosylation in serglycin activity. Serglycin inhibition was associated with reduced expression of vimentin but not other epithelial-mesenchymal transition proteins. In clinical specimens, serglycin expression was elevated significantly in liver metastases from NPC relative to primary NPC tumors. We evaluated the prognostic value of serglycin by immunohistochemical staining of tissue microarrays from 263 NPC patients followed by multivariate analyses. High serglycin expression in primary NPC was found to be an unfavorable independent indicator of distant metastasis-free and disease free survival. Our findings establish that glycosylated serglycin regulates NPC metastasis via autocrine and paracrine routes, and that it serves as an independent prognostic indicator of metastasis-free survival and disease-free survival in NPC patients. PMID- 21289132 TI - Temporally selective processing of communication signals by auditory midbrain neurons. AB - Perception of the temporal structure of acoustic signals contributes critically to vocal signaling. In the aquatic clawed frog Xenopus laevis, calls differ primarily in the temporal parameter of click rate, which conveys sexual identity and reproductive state. We show here that an ensemble of auditory neurons in the laminar nucleus of the torus semicircularis (TS) of X. laevis specializes in encoding vocalization click rates. We recorded single TS units while pure tones, natural calls, and synthetic clicks were presented directly to the tympanum via a vibration-stimulation probe. Synthesized click rates ranged from 4 to 50 Hz, the rate at which the clicks begin to overlap. Frequency selectivity and temporal processing were characterized using response-intensity curves, temporal-discharge patterns, and autocorrelations of reduplicated responses to click trains. Characteristic frequencies ranged from 140 to 3,250 Hz, with minimum thresholds of -90 dB re 1 mm/s at 500 Hz and -76 dB at 1,100 Hz near the dominant frequency of female clicks. Unlike units in the auditory nerve and dorsal medullary nucleus, most toral units respond selectively to the behaviorally relevant temporal feature of the rate of clicks in calls. The majority of neurons (85%) were selective for click rates, and this selectivity remained unchanged over sound levels 10 to 20 dB above threshold. Selective neurons give phasic, tonic, or adapting responses to tone bursts and click trains. Some algorithms that could compute temporally selective receptive fields are described. PMID- 21289133 TI - Muscle short-range stiffness can be used to estimate the endpoint stiffness of the human arm. AB - The mechanical properties of the human arm are regulated to maintain stability across many tasks. The static mechanics of the arm can be characterized by estimates of endpoint stiffness, considered especially relevant for the maintenance of posture. At a fixed posture, endpoint stiffness can be regulated by changes in muscle activation, but which activation-dependent muscle properties contribute to this global measure of limb mechanics remains unclear. We evaluated the role of muscle properties in the regulation of endpoint stiffness by incorporating scalable models of muscle stiffness into a three-dimensional musculoskeletal model of the human arm. Two classes of muscle models were tested: one characterizing short-range stiffness and two estimating stiffness from the slope of the force-length curve. All models were compared with previously collected experimental data describing how endpoint stiffness varies with changes in voluntary force. Importantly, muscle properties were not fit to the experimental data but scaled only by the geometry of individual muscles in the model. We found that force-dependent variations in endpoint stiffness were accurately described by the short-range stiffness of active arm muscles. Over the wide range of evaluated arm postures and voluntary forces, the musculoskeletal model incorporating short-range stiffness accounted for 98 +/- 2, 91 +/- 4, and 82 +/- 12% of the variance in stiffness orientation, shape, and area, respectively, across all simulated subjects. In contrast, estimates based on muscle force-length curves were less accurate in all measures, especially stiffness area. These results suggest that muscle short-range stiffness is a major contributor to endpoint stiffness of the human arm. Furthermore, the developed model provides an important tool for assessing how the nervous system may regulate endpoint stiffness via changes in muscle activation. PMID- 21289134 TI - Specializations of a pheromonal glomerulus in the Drosophila olfactory system. AB - Insect pheromonal glomeruli are thought to track the fine spatiotemporal features of one or a few odorants to aid conspecific localization. However, it is not clear whether they function differently from generalist glomeruli, which respond to many odorants. In this study, we test how DA1, a model pheromonal glomerulus in the fruit fly, represents the spatial and temporal properties of its input, compared with other glomeruli. We combine calcium imaging and electrical stimulation in an isolated brain preparation for a simultaneous, unbiased comparison of the functional organization of many glomeruli. In contrast to what is found in other glomeruli, we find that ipsilateral and contralateral stimuli elicit distinct spatial patterns of activity within DA1. DA1's output shows a greater preference for ipsilateral stimuli in males than in females. DA1 experiences greater and more rapid inhibition than other glomeruli, allowing it to report slight interantennal delays in stimulus onset in a "winner-take-all" manner. DA1's ability to encode spatiotemporal input features distinguishes it from other glomeruli in the fruit fly antennal lobe but relates it to pheromonal glomeruli in other insect species. We propose that DA1 is specialized to help the fly localize and orient with respect to pheromone sources. PMID- 21289135 TI - Keep your eyes on the ball: smooth pursuit eye movements enhance prediction of visual motion. AB - Success of motor behavior often depends on the ability to predict the path of moving objects. Here we asked whether tracking a visual object with smooth pursuit eye movements helps to predict its motion direction. We developed a paradigm, "eye soccer," in which observers had to either track or fixate a visual target (ball) and judge whether it would have hit or missed a stationary vertical line segment (goal). Ball and goal were presented briefly for 100-500 ms and disappeared from the screen together before the perceptual judgment was prompted. In pursuit conditions, the ball moved towards the goal; in fixation conditions, the goal moved towards the stationary ball, resulting in similar retinal stimulation during pursuit and fixation. We also tested the condition in which the goal was fixated and the ball moved. Motion direction prediction was significantly better in pursuit than in fixation trials, regardless of whether ball or goal served as fixation target. In both fixation and pursuit trials, prediction performance was better when eye movements were accurate. Performance also increased with shorter ball-goal distance and longer presentation duration. A longer trajectory did not affect performance. During pursuit, an efference copy signal might provide additional motion information, leading to the advantage in motion prediction. PMID- 21289136 TI - Behavioral correlates of human hippocampal delta and theta oscillations during navigation. AB - Previous rodent studies demonstrate movement-related increases in theta oscillations, and recent evidence suggests that multiple navigationally relevant variables are reflected in this activity. Human invasive recordings have revealed movement-related modulations in delta and theta activity, although it is unclear whether additional behavioral variables are responsible for modulating this neural activity during navigation. We tested the role of delta and theta oscillations during navigation by addressing whether spatial-related processing, in addition to speed and task variables, modulates delta and theta activity. Recording from 317 hippocampal intracranial electrodes in 10 patients undergoing seizure monitoring, we observed increasing delta and theta power with increasing virtual speed at significantly more electrodes than would be expected by chance, replicating previous findings in nonhuman mammals. Delta and theta power were more consistently modulated, however, as a function of spatial view, including when subjects looked at stores in the virtual environment both to find a relevant goal or for spatial updating. A significantly larger proportion of electrodes showed view-related effects than speed-related modulations. Although speed, task, and spatial view affected delta and theta activity, individual electrodes were most frequently modulated by only one variable, rather than a combination of variables. These electrodes likely sampled independent delta and theta generators, which reflected movement-related and allocentric processing, respectively. These results extend previous findings in nonhuman mammals and humans, expanding our knowledge of the role of human hippocampal low-frequency oscillations in navigation. PMID- 21289137 TI - Kinetic modeling of Nav1.7 provides insight into erythromelalgia-associated F1449V mutation. AB - Gain-of-function mutations of the voltage-gated sodium channel (VGSC) Na(v)1.7 have been linked to human pain disorders. The mutation F1449V, located at the intracellular end of transmembrane helix S6 of domain III, induces the inherited pain syndrome erythromelalgia. A kinetic model of wild-type (WT) and F1449V Na(v)1.7 may provide a basis for predicting putative intraprotein interactions. We semiautomatically constrained a Markov model using stochastic search algorithms and whole cell patch-clamp recordings from human embryonic kidney cells transfected with Na(v)1.7 and its F1449V mutation. The best models obtained simulated known differences in action potential thresholds and firing patterns in spinal sensory neurons expressing WT and F1449V. The most suitable Markov model consisted of three closed, one open, and two inactivated states. The model predicted that the F1449V mutation shifts occupancy of the closed states closer to the open state, making it easier for the channel pore to open. It also predicted that F1449V's second inactivated state is more than four times more likely to be occupied than the equivalent state in WT at hyperpolarized potentials, although the mutation still lowered the firing threshold of action potentials. The differences between WT and F1449V were not limited to a single transition. Thus a point mutation in position F1449, while phenotypically most probably affecting the activation gate, may also modify channel functions mediated by structures in more distant areas of the channel protein. PMID- 21289139 TI - Path shape impacts the extent of CA1 pattern recurrence both within and across environments. AB - Similarities and differences in the visual content, scale, and shape of environmental boundaries for two environments have been extensively examined for their impact on the recurrence of spatially specific hippocampal firing patterns across environments and across multiple regions of a single environment. Although the shapes of paths taken through an environment are known to impact hippocampal firing patterns within any single region of a single environment, it is not known to what extent path shape and scale can impact firing pattern recurrence across two environments and across multiple regions of a single environment. This question was addressed in the present work where the spatial firing patterns of hippocampal CA1 neurons were examined as rats traversed differently shaped spiral paths centered on the same position within a visually observable curtained enclosure. On such tracks, firing fields for CA1 neurons were found to recur across multiple subregions of a single path and across similarly positioned regions of different paths. Both within and across different spiral tracks, the extent of such pattern recurrence was strongly influenced by similarity in the specific sequences of movement directions and locomotor behaviors engendered by different path shapes. The findings demonstrate that the shapes of paths taken through an environment can robustly and dynamically alter both the scale of spatially specific CA1 firing fields and the extent to which they recur across environments. PMID- 21289138 TI - Parasagittally aligned, mGluR1-dependent patches are evoked at long latencies by parallel fiber stimulation in the mouse cerebellar cortex in vivo. AB - The parallel fibers (PFs) in the cerebellar cortex extend several millimeters along a folium in the mediolateral direction. The PFs are orthogonal to and cross several parasagittal zones defined by the olivocerebellar and corticonuclear pathways and the expression of molecular markers on Purkinje cells (PCs). The functions of these two organizations remain unclear, including whether the bands respond similarly or differentially to PF input. By using flavoprotein imaging in the anesthetized mouse in vivo, this study demonstrates that high-frequency PF stimulation, which activates a beamlike response at short latency, also evokes patches of activation at long latencies. These patches consist of increased fluorescence along the beam at latencies of 20-25 s with peak activation at 35 s. The long-latency patches are completely blocked by the type 1 metabotropic glutamate receptor (mGluR(1)) antagonist LY367385. Conversely, the AMPA and NMDA glutamate receptor antagonists DNQX and APV have little effect. Organized in parasagittal bands, the long-latency patches align with zebrin II-positive PC stripes. Additional Ca(2+) imaging demonstrates that the patches reflect increases in intracellular Ca(2+). Both the PLCbeta inhibitor U73122 and the ryanodine receptor inhibitor ryanodine completely block the long-latency patches, indicating that the patches are due to Ca(2+) release from intracellular stores. Robust, mGluR(1)-dependent long-term potentiation (LTP) of the patches is induced using a high-frequency PF stimulation conditioning paradigm that generates LTP of PF-PC synapses. Therefore, the parasagittal bands, as defined by the molecular compartmentalization of PCs, respond differentially to PF inputs via mGluR(1) mediated release of internal Ca(2+). PMID- 21289140 TI - Detection of the glmM gene in Helicobacter pylori isolates with a novel primer by PCR. AB - A novel reverse primer (GLM MR1) was designed for detection of the glmM gene in Helicobacter pylori by PCR. The percentage of amplification in clinical isolates using GLM MR1 was 100% for detection of the glmM gene and 86.36% for the ureA gene. The primer designed is useful for the identification of H. pylori. PMID- 21289141 TI - First report of Atopobium vaginae bacteremia with fetal loss after chorionic villus sampling. AB - Infectious complications after chorionic villus sampling (CVS) are rare (<0.1%) but can lead to maternal sepsis and spontaneous abortion. We report the first bacteremia with Atopobium vaginae and suggest A. vaginae to be a pathogenic microorganism that can lead to intrauterine infection and fetal death following CVS. PMID- 21289142 TI - Mutation detection and accurate diagnosis of extensively drug-resistant tuberculosis: report from a tertiary care center in India. AB - We screened and spoligotyped 150 consecutive phenotypically confirmed extensively drug-resistant Mycobacterium tuberculosis (XDR-TB) isolates (January 2008 to March 2009) for rifampin, isoniazid, fluoroquinolone, and aminoglycoside resistance targeting rpoB, inhA, katG, gyrA, gyrB, and rrs. Mutations predominant among XDR-TB were S315T (katG) (100% of isolates), S531L (rpoB) (97% of isolates), D94G (gyrA) (53% of isolates), and A1401G (rrs) (71% of isolates). Spoligotyping revealed 62% of the isolates to be Beijing. PMID- 21289143 TI - Use of the accessory genome for characterization and typing of Acinetobacter baumannii. AB - Outbreak strains of Acinetobacter baumannii are highly clonal, and cross infection investigations can be difficult. We sought targets based on AbaR resistance islands and on other genes found in some, but not all, sequenced isolates of A. baumannii among a set of clinical isolates (n = 70) that included multiple representatives of a number of pulsed-field gel electrophoresis (PFGE) defined types. These included representatives that varied in their profiles at two variable-number tandem repeat (VNTR) loci, which can provide discrimination within a PFGE cluster. Detection, or not, of each element sought provided some degree of discrimination among the set, with the presence or absence of genes coding for a phage terminase (ACICU_02185), a sialic acid synthase (ACICU_00080), a polysaccharide biosynthesis protein (AB57_0094), aphA1, bla(TEM), and integron associated orfX (Kyoto Encyclopedia of Genes and Genomes [KEGG] no. K03830) proving the most helpful in discriminating between closely related isolates in our panel. The results support VNTR data in describing distinct populations of highly similar isolates. Such analysis, in combination with other typing methods, can inform epidemiological investigations and provide additional characterization of isolates. Most genotypes carrying bla(OXA-23-like) were PCR positive for a yeeA-bla(OXA-23) fragment found in an AbaR4-type island, suggesting that this is widespread. PMID- 21289144 TI - Evaluation of twelve real-time reverse transcriptase PCR primer-probe sets for detection of pandemic influenza A/H1N1 2009 virus. AB - Real-time reverse transcriptase PCR (rRT-PCR) assays have greatly contributed to the detection, control, and prevention of the pandemic influenza A/H1N1 2009 virus. To improve the rRT-PCR assays for detection of pandemic influenza A/H1N1 2009 virus, we evaluated the sensitivity, specificity, and performance of 12 rRT PCR primer-probe sets [SW (a) to SW (l)] using a panel of virus strains and clinical specimens. These primer-probe sets were derived from published work and designed for detecting the hemagglutinin (HA) or the neuraminidase (NA) gene of the pandemic influenza A/H1N1 2009 virus. A primer-probe set, SW (CDC), developed by the Centers for Disease Control and Prevention (U.S. CDC) to target the HA gene of pandemic influenza A/H1N1 2009 virus, was used as a referee method. Our results demonstrated that although all primer-probe sets in this study had as high as 98.4 to 100% in silico coverage, some of the primer-probe sets had better specificity, sensitivity, and amplification efficiency than others. Two primer probe sets, SW (h) and SW (l), which target the NA gene of pandemic influenza A/H1N1 2009 virus, were highly sensitive (10(4) copies/reaction), had high detection rates (56/60, P = 0.134, and 59/60, P = 1.000), and showed ideal specificity compared with SW (CDC). In addition, a cocktail of primer-probe sets targeted to the HA and NA genes displayed higher detection sensitivity than primer-probe sets targeting HA or NA alone, indicating that for practical applications, a combination of primer-probes targeting HA and NA genes is the best option for the detection of pandemic influenza A/H1N1 2009 virus. PMID- 21289145 TI - Performance of the Abbott RealTime HIV-1 viral load assay is not impacted by integrase inhibitor resistance-associated mutations. AB - The Abbott RealTime HIV-1 viral load assay uses primers and probes targeted to integrase, which is also the target of integrase inhibitors such as raltegravir. Viral loads of 42 raltegravir-susceptible and 40 raltegravir-resistant specimens were determined using RealTime HIV-1 and Roche Monitor (v1.5). The differences in viral load measurements between assays were comparable in the two groups, demonstrating that the RealTime HIV-1 assay can tolerate raltegravir-selected mutations. PMID- 21289146 TI - Chronic Q fever-related dual-pathogen endocarditis: case series of three patients. AB - Following Coxiella burnetii infection, there is a 1 to 5% risk of chronic Q fever. Endocarditis, mycotic aneurysm, and vascular prosthesis infection are common manifestations. We present three patients with endocarditis by C. burnetii concomitant with another bacterial pathogen. Chronic Q fever should therefore be considered in all endocarditis patients in regions where Q fever is endemic. PMID- 21289147 TI - Discovery and phylogenetic analysis of novel members of class b enterotoxigenic Escherichia coli adhesive fimbriae. AB - Enterotoxigenic Escherichia coli (ETEC) is recognized to be a common cause of acute watery diarrhea in children from developing countries. Colonization factors (CFAs) have been identified predominantly in ETEC isolates secreting heat-stable enterotoxin (ST) or cosecreting ST with a heat-labile toxin (LT). We hypothesized that LT-only-secreting ETEC produces unique colonization factors not previously described in ST and LTST-secreting ETEC. A set of degenerate primers based on nucleotide sequence similarities between the major structural genes of CS20 (csnA), CS18 (fotA), CS12 (cswA), and porcine antigen 987 (fasA) was developed and used to screen a collection of 266 LT-secreting ETEC isolates in which no known CFA was detected. PCR-amplified products of different molecular masses were obtained from 49 (18.4%) isolates. Nucleotide sequence analysis of the PCR amplicons followed by GenBank nucleotide BLASTn analysis revealed five novel DNA sequences; translated amino acid BLASTx analysis confirmed sequence similarity to class 1b major structural proteins encoded by csnA, fotA, and fasA. Strains expressing the novel CFAs were phylotyped and analyzed using multilocus sequence typing (MLST; Achtman scheme), and the types detected were compared to those of a collection of archived global E. coli strains. In conclusion, application of the degenerate primer sets to ETEC isolates from surveillance studies increased the total number of ETEC isolates with detectable CFAs by almost 20%. Additionally, MLST analysis suggests that for many CFAs, there may be a requirement for certain genetic backgrounds to acquire and maintain plasmids carrying genes encoding CFAs. PMID- 21289148 TI - Detection of rapidly growing mycobacteria in routine cultures of samples from patients with cystic fibrosis. AB - Rapidly growing mycobacteria (RGM) are respiratory pathogens in patients with cystic fibrosis (CF), but detection generally requires specialized cultures for acid-fast bacilli (AFB; AFB cultures). We determined that RGM could be recovered from routine cultures of samples from patients with CF by extending incubation of the Burkholderia cepacia selective agar (BCSA) from 5 to 14 days. To explore the impact of this modification, we compared results from routine and AFB cultures of samples from CF patients for 2 years before (4,212 samples by routine culture, 1,810 samples by AFB culture, 670 patients) and 2 years after (4,720 samples by routine culture, 2,179 samples by AFB culture, 695 patients) the change. Clinical relevance was assessed with samples from a subgroup of 340 patients followed regularly throughout both periods. Extending incubation of BCSA enhanced RGM recovery from routine cultures (0.7% before, 2.8% after; P < 0.001); recovery from AFB cultures was unchanged (5.5% before, 5.7% after). Estimates of RGM detection sensitivity by culture or patient-based methods ranged from ~65 to 75% for routine cultures (nonsignificantly lower than the ~80 to 85% for AFB cultures) and were adversely affected by coculture with mold or nonpseudomonal, nonfermenting Gram-negative rods. In the after period, 16 CF patients met the criteria for RGM infection by routine culture, including 4 who did not meet the criteria for RGM infection by AFB culture. We conclude that a simple methodological change enhanced recovery of RGM from routine cultures. The modified culture method could be utilized to improve screening for RGM in CF patients or as a simpler method to follow patients with known RGM infection. However, this method should be used cautiously in patients with certain coinfections. PMID- 21289149 TI - Rapid identification of gram-negative bacteria with and without CTX-M extended spectrum beta-lactamase from positive blood culture bottles by PCR followed by microchip gel electrophoresis. AB - We evaluated the usefulness of PCR analysis of the 16S-23S rRNA gene internal transcribed spacer (ITS) and the CTX-M extended-spectrum beta-lactamase (ESBL) followed by microchip gel electrophoresis (MGE) for direct identification and CTX M detection of Gram-negative bacteria (GNB) from positive blood culture bottles. Of 251 GNB isolated from blood cultures containing a single bacterium, 225 (90%) were correctly identified at the species level directly from positive blood culture bottles by comparing the ITS-PCR patterns of the sample strain with those of the control strains. There were no cases of incorrect identification. Limitations encountered included the inability to detect mixed cultures (four bottles) as well as some species (Enterobacter species and Klebsiella oxytoca) demonstrating identical ITS-PCR patterns. A total of 109 ESBL-producing isolates from various clinical materials obtained between January 2005 and December 2008 were examined for bla(CTX-M), bla(SHV), and bla(TEM) genes by PCR and sequences of PCR products. CTX-M ESBL was detected in 105 isolates, and SHV ESBL was detected in two isolates. The remaining two isolates (K. oxytoca) were shown to harbor bla(OXY.) Twenty (19%) of 104 Escherichia coli isolates from blood cultures were suspected to produce ESBL by the combination disk method, and these isolates were shown to harbor CTX-M ESBL by PCR-MGE. The results were obtained within 1.5 h at a calculated cost of $6.50 per specimen. In conclusion, simultaneous detection of ITS length polymorphisms and bla(CTX)-(M) by single PCR followed by MGE is useful for rapid, cost-effective, and reliable species-level identification of CTX-M ESBL-producing GNB responsible for bloodstream infections. PMID- 21289150 TI - Cultivable anaerobic microbiota of severe early childhood caries. AB - Severe early childhood caries (ECC), while strongly associated with Streptococcus mutans using selective detection (culture, PCR), has also been associated with a widely diverse microbiota using molecular cloning approaches. The aim of this study was to evaluate the microbiota of severe ECC using anaerobic culture. The microbial composition of dental plaque from 42 severe ECC children was compared with that of 40 caries-free children. Bacterial samples were cultured anaerobically on blood and acid (pH 5) agars. Isolates were purified, and partial sequences for the 16S rRNA gene were obtained from 5,608 isolates. Sequence-based analysis of the 16S rRNA isolate libraries from blood and acid agars of severe ECC and caries-free children had >90% population coverage, with greater diversity occurring in the blood isolate library. Isolate sequences were compared with taxon sequences in the Human Oral Microbiome Database (HOMD), and 198 HOMD taxa were identified, including 45 previously uncultivated taxa, 29 extended HOMD taxa, and 45 potential novel groups. The major species associated with severe ECC included Streptococcus mutans, Scardovia wiggsiae, Veillonella parvula, Streptococcus cristatus, and Actinomyces gerensceriae. S. wiggsiae was significantly associated with severe ECC children in the presence and absence of S. mutans detection. We conclude that anaerobic culture detected as wide a diversity of species in ECC as that observed using cloning approaches. Culture coupled with 16S rRNA identification identified over 74 isolates for human oral taxa without previously cultivated representatives. The major caries-associated species were S. mutans and S. wiggsiae, the latter of which is a candidate as a newly recognized caries pathogen. PMID- 21289151 TI - Evaluation of the Cepheid Xpert MTB/RIF assay for direct detection of Mycobacterium tuberculosis complex in respiratory specimens. AB - A total of 217 specimens submitted for routine smear and culture from three different sites within the western United States were used to evaluate the GeneXpert MTB/RIF assay (for research use only) (Cepheid, Sunnyvale, CA). Overall agreement compared to culture was 89% (98% for smear positives and 72% for smear negatives) for detection of Mycobacterium tuberculosis. PMID- 21289152 TI - Imipenem disc for detection of KPC carbapenemase-producing Enterobacteriaceae in clinical practice. AB - The global spread of class A-carbapenemase-producing Enterobacteriaceae has made the development of a simple test a desirable goal. A disc diffusion test using imipenem was 100% sensitive and 96% specific in identifying carbapenemase producing organisms, potentially reducing or eliminating the need for the relatively labor-intensive modified Hodge test. PMID- 21289153 TI - Improved method for rapid and efficient determination of genome replication and protein expression of clinical hepatitis B virus isolates. AB - Different hepatitis B virus (HBV) genotypes and variants are associated with different clinical outcomes and/or response to antiviral therapy, yet the comparison of the in vitro replication capacity of a large number of clinical isolates remains technically challenging and time-consuming. Although the full length HBV genome can be amplified from high-titer blood samples by PCR using High Fidelity(plus) DNA polymerase and primers targeting the conserved precore region, the HBV clones thus generated are replication deficient due to the inability to generate the terminally redundant pregenomic RNA essential for genome replication. The transfection experiment is further complicated by PCR errors and the presence of viral quasispecies. A previous study found that the precise removal of non-HBV sequence by SapI digestion led to HBV replication in transfected cells, possibly due to low-level genome circularization by a cellular enzyme. We released HBV genome from the cloning vector using BspQI, an inexpensive isoschizomer of SapI, and increased the efficiency of genome replication by an extra step of in vitro DNA ligation. The uncut plasmid DNA can be used for transfection if the sole purpose is to study envelope protein expression. We found significant PCR errors associated with the High Fidelity(plus) DNA polymerase, which could be greatly diminished using Phusion DNA polymerase or masked by the use of a clone pool. The reduced PCR error and modified enzymatic steps prior to transfection should facilitate a more widespread functional characterization of clinical HBV isolates, while the clone pool approach is useful for samples with significant sequence heterogeneity. PMID- 21289154 TI - Evaluation of four commercial rapid immunochromatographic assays for detection of Cryptosporidium antigens in stool samples: a blind multicenter trial. AB - In a multicenter study, potassium dichromate-preserved stools from patients infected with Cryptosporidium parvum (n = 20), C. hominis (n = 20), and other Cryptosporidium species (n = 10) and 60 controls were examined using four immunochromatographic assays. Assay sensitivity ranged between 50.1% and 86.7% for C. parvum and C. hominis but was <35% for other species. PMID- 21289155 TI - Validation of 24-hour posaconazole and voriconazole MIC readings versus the CLSI 48-hour broth microdilution reference method: application of epidemiological cutoff values to results from a global Candida antifungal surveillance program. AB - We performed 24- and 48-h MIC determinations of posaconazole and voriconazole against more than 16,000 clinical isolates of Candida species. By using the 24- and 48-h epidemiological cutoff values (ECVs), the categorical agreement between the 24-h and reference 48-h broth microdilution results ranged from 97.1% (C. parapsilosis and voriconazole) to 99.8% (C. krusei and voriconazole), with 0.0 to 2.9% very major discrepancies (VMD). The essential agreement (within 2 log(2) dilutions) between the 24- and 48-h results was 99.6% for both posaconazole and voriconazole. The MIC results obtained for both posaconazole and voriconazole after only 24 h of incubation may be used to determine the susceptibilities of Candida spp. to these important antifungal agents. The applications of ECVs to this large collection of Candida isolates suggests the potential to develop 24-h species-specific clinical breakpoints for both posaconazole and voriconazole. PMID- 21289156 TI - Combining culture techniques for Bartonella: the best of both worlds. AB - In this study we compared some common Bartonella culturing methodologies using four diverse species causing human illnesses. Based on a review of the literature, we focused on three major inconsistencies between protocols: base medium, cell coculture, and temperature. Our data showed that Bartonella tamiae demonstrated temperature-dependent growth limitations between common culturing conditions only 2 degrees C apart. Additionally, growth of B. quintana was significantly enhanced by the presence of mammalian cell coculture under mammalian cell culture conditions; however, when the medium was modified to incorporate insect cell culture-based medium, coculturing with mammalian cells was no longer needed. In this study, we were able to overcome these temperature- and cell-dependent limitations and accommodate all of the strains tested by combining mammalian cell culture-based medium with insect cell culture-based medium. PMID- 21289157 TI - Old World hantaviruses do not produce detectable amounts of dsRNA in infected cells and the 5' termini of their genomic RNAs are monophosphorylated. AB - dsRNA and 5'-triphosphate RNA are considered critical activators of the innate immune response because of their interaction with pattern recognition receptors. It has been reported that no dsRNA is detected in negative-sense RNA virus infected cells and that Hantaan virus (HTNV) genomic RNA bears a 5' monophosphate group. In this paper we examine the 5' termini of genomic RNAs of and dsRNA production by two major groups of Old World hantaviruses. No detectable amounts of dsRNA were found in infected cells. Also, the genomic RNAs of these hantaviruses bear a 5' monophosphate group and therefore are unable to trigger interferon induction. Taken together with the earlier data on HTNV, these results suggest that in addition to the dsRNA and genomic RNA, which may be only minimally involved in the induction of innate immunity, other cellular signalling pathways may also be involved and that these await further investigation. PMID- 21289158 TI - HEPES inhibits the conversion of prion protein in cell culture. AB - HEPES is a well-known buffering reagent used in cell-culture medium. Interestingly, this compound is also responsible for significant modifications of biological parameters such as uptake of organic molecules, alteration of oxidative stress mechanisms or inhibition of ion channels. While using cell culture medium supplemented with HEPES on prion-infected cells, it was noticed that there was a significant concentration-dependent inhibition of accumulation of the abnormal isoform of the prion protein (PrP(Sc)). This effect was present only in live cells and was thought to be related to modification of the PrP environment or biology. These results could modify the interpretation of cell culture assays of prion therapeutic agents, as well as of previous cell biology results obtained in the field using HEPES buffers. This inhibitory effect of HEPES could also be exploited to prevent contamination or propagation of prions in cell culture. PMID- 21289159 TI - ADAR2 editing enzyme is a novel human immunodeficiency virus-1 proviral factor. AB - The adenosine deaminases acting on RNA (ADAR) enzymes catalyse conversion of adenosine to inosine in dsRNA. A positive effect of ADAR1 on human immunodeficiency virus type 1 (HIV-1) replication has recently been reported. Here, we show that another ADAR enzyme, ADAR2, positively affects the replication process of HIV-1. We found that, analogously to ADAR1, ADAR2 enhances the release of progeny virions by an editing-dependent mechanism. However, differently from the ADAR1 enzyme, ADAR2 does not increase the infectious potential of the virus. Importantly, downregulation of ADAR2 in Jurkat cells significantly impairs viral replication. Therefore, ADAR2 shares some but not all proviral functions of ADAR1. These results suggest a novel role of ADAR2 as a viral regulator. PMID- 21289160 TI - Preclinical efficacy studies of influenza A haemagglutinin precursor cleavage loop peptides as a potential vaccine. AB - A universal influenza vaccine that does not require annual reformulation would have clear advantages over the currently approved seasonal vaccine. In this study, we combined the mucosal adjuvant alpha-galactosylceramide (alphaGalCer) and peptides designed across the highly conserved influenza precursor haemagglutinin (HA(0)) cleavage loop as a vaccine. Peptides designed across the HA(0) of influenza A/H3N2 viruses, delivered to mice via the intranasal route with alphaGalCer as an adjuvant, provided 100 % protection following H3N2 virus challenge. Similarly, intranasal inoculation of peptides across the HA(0) of influenza A/H5N1 with alphaGalCer completely protected mice against heterotypic challenge with H3N2 virus. Our data suggest that these peptide vaccines effectively inhibited subsequent influenza A/H3N2 virus replication. In contrast, only 20 % of mice vaccinated with alphaGalCer-adjuvanted peptides spanning the HA(0) of H5N1 survived homologous viral challenge, possibly because the HA(0) of this virus subtype is cleaved by intracellular furin-like enzymes. Results of these studies demonstrated that HA(0) peptides adjuvanted with alphaGalCer have the potential to form the basis of a synthetic, intranasal influenza vaccine. PMID- 21289161 TI - Inactivation of hantaviruses by N-ethylmaleimide preserves virion integrity. AB - Thiol groups of cysteine residues are crucial for the infectivity of various enveloped viruses, but their role in the infectivity of viruses of the family Bunyaviridae has thus far not been studied. This report shows that thiol groups are essential to the infectivity of hantaviruses. Alkylation of the thiol functional groups using the membrane-permeable compound N-ethylmaleimide (NEM) and membrane-impermeable compound 5,5'-dithio-bis-(2-nitrobenzoic acid) (DTNB) showed NEM to be a highly effective inactivator of Puumala and Tula hantaviruses. The NEM-inactivated hantavirus maintained the buoyant density of the wild-type virus. Furthermore, the antigenicity of glycoproteins and the cell attachment capacity of virions were retained at NEM concentrations that totally abolished virus infectivity. These results signified preservation of virion integrity following inactivation with NEM, making chemically inactivated virions valuable research antigens. It was demonstrated with biotin-conjugated maleimide, a mechanistic analogue of NEM, that all the structural proteins of hantavirus were sensitive towards thiol alkylation. In contrast to hantaviruses, NEM did not abolish Uukuniemi phlebovirus infectivity to the same extent. This indicates differences in the use of free thiols in virus entry among members of the family Bunyaviridae. PMID- 21289163 TI - Sleep selectively enhances memory expected to be of future relevance. AB - The brain encodes huge amounts of information, but only a small fraction is stored for a longer time. There is now compelling evidence that the long-term storage of memories preferentially occurs during sleep. However, the factors mediating the selectivity of sleep-associated memory consolidation are poorly understood. Here, we show that the mere expectancy that a memory will be used in a future test determines whether or not sleep significantly benefits consolidation of this memory. Human subjects learned declarative memories (word paired associates) before retention periods of sleep or wakefulness. Postlearning sleep compared with wakefulness produced a strong improvement at delayed retrieval only if the subjects had been informed about the retrieval test after the learning period. If they had not been informed, retrieval after retention sleep did not differ from that after the wake retention interval. Retention during the wake intervals was not affected by retrieval expectancy. Retrieval expectancy also enhanced sleep-associated consolidation of visuospatial (two dimensional object location task) and procedural motor memories (finger sequence tapping). Subjects expecting the retrieval displayed a robust increase in slow oscillation activity and sleep spindle count during postlearning slow-wave sleep (SWS). Sleep-associated consolidation of declarative memory was strongly correlated to slow oscillation activity and spindle count, but only if the subjects expected the retrieval test. In conclusion, our work shows that sleep preferentially benefits consolidation of memories that are relevant for future behavior, presumably through a SWS-dependent reprocessing of these memories. PMID- 21289164 TI - Separate visual signals for saccade initiation during target selection in the primate superior colliculus. AB - The primary function of the superior colliculus (SC) is to orient the visual system toward behaviorally relevant stimuli defined by features such as color. However, a longstanding view has held that visual activity in the SC arises exclusively from achromatic pathways. Recently, we reported evidence that the primate SC is highly sensitive to signals originating from chromatic pathways, but these signals are delayed relative to luminance signals (White et al., 2009). Here, we describe a functional consequence of this difference in visual arrival time on the processes leading to target selection and saccade initiation. Two rhesus monkeys performed a simple color-singleton selection task in which stimuli carried a chromatic component only (target and distractors were isoluminant with the background, but differed in chromaticity) or a combined chromatic-achromatic component (36% luminance contrast added equally to all stimuli). Although visual responses were delayed in the chromatic-only relative to the combined chromatic achromatic condition, SC neurons discriminated the target from distractors at approximately the same time provided stimulus chromaticity was held constant. However, saccades were triggered sooner, and with more errors, with the chromatic achromatic condition, suggesting that luminance signals associated with these stimuli increased the probability of triggering a saccade before the target color was adequately discriminated. These results suggest that separate mechanisms may independently influence the saccadic command in the SC, one linked to the arrival time of pertinent visual signals, and another linked to the output of the visual selection process. PMID- 21289165 TI - What does local functional hyperemia tell about local neuronal activation? AB - In the brain, neuronal activation triggers a local increase in cerebral blood flow, a response named functional hyperemia. The extent to which functional hyperemia faithfully reports brain activation, spatially or temporally, remains a matter of debate. Here, we used the olfactory bulb glomerulus as a neurovascular model and two-photon microscopy imaging to investigate the correlation between calcium signals in glutamatergic terminals of olfactory sensory neurons and local vascular responses. We find that, depending on odor stimulation intensity, vascular responses are differently coupled to calcium signals. Upon moderate odor stimulation, glomerular vascular responses increase accordingly with calcium signals. In contrast, in silent glomeruli neighboring strongly activated ones and in glomeruli adapting upon high odor stimulation, vascular responses are independent of or negatively coupled to presynaptic calcium signals, respectively. Hence, functional hyperemia, a key signal used in functional imaging, can be, at times, an unreliable marker of local brain activation. PMID- 21289166 TI - The anterior piriform cortex is sufficient for detecting depletion of an indispensable amino acid, showing independent cortical sensory function. AB - Protein synthesis requires a continuous supply of all of the indispensable (essential) amino acids (IAAs). If any IAA is deficient, animals must obtain the limiting amino acid by diet selection. Sensing of IAA deficiency requires an intact anterior piriform cortex (APC), but does it act alone? Shortly after rats begin eating an IAA-deficient diet, the meal ends and EPSPs are activated in the APC; from there, neurons project to feeding circuits; the meal ends within 20 min. Within the APC in vivo, uncharged tRNA activates the general amino acid control non-derepressing 2 (GCN2) enzyme system increasing phosphorylation of eukaryotic initiation factor (P-eIF2alpha), which blocks general protein synthesis. If this paleocortex is sufficient for sensing IAA depletion, both neuronal activation and P-eIF2alpha should occur in an isolated APC slice. We used standard techniques for electrophysiology and immunohistochemistry. After rats ate IAA-devoid or -imbalanced diets, their depleted slices responded to different stimuli with increased EPSP amplitudes. Slices from rats fed a control diet were bathed in artificial CSF replete with all amino acids with or without the IAA, threonine, or a tRNA synthetase blocker, l-threoninol, or its inactive isomer, d-threoninol. Thr depletion in vitro increased both EPSP amplitudes and P eIF2alpha. l (but not d)-threoninol also increased EPSP amplitudes relative to control. Thus, we show independent excitation of the APC with responses parallel to those known in vivo. These data suggest a novel idea: in addition to classical processing of peripheral sensory input, direct primary sensing may occur in mammalian cortex. PMID- 21289167 TI - Micro-opioid receptor activation in the basolateral amygdala mediates the learning of increases but not decreases in the incentive value of a food reward. AB - The decision to perform, or not perform, actions known to lead to a rewarding outcome is strongly influenced by the current incentive value of the reward. Incentive value is largely determined by the affective experience derived during previous consumption of the reward-the process of incentive learning. We trained rats on a two-lever, seeking-taking chain paradigm for sucrose reward, in which responding on the initial seeking lever of the chain was demonstrably controlled by the incentive value of the reward. We found that infusion of the MU-opioid receptor antagonist, CTOP (d-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr-NH(2)), into the basolateral amygdala (BLA) during posttraining, noncontingent consumption of sucrose in a novel elevated-hunger state (a positive incentive learning opportunity) blocked the encoding of incentive value information normally used to increase subsequent sucrose-seeking responses. Similar treatment with delta [N, N diallyl-Tyr-Aib-Aib-Phe-Leu-OH (ICI 174,864)] or kappa [5'-guanidinonaltrindole (GNTI)] antagonists was without effect. Interestingly, none of these drugs affected the ability of the rats to encode a decrease in incentive value resulting from experiencing the sucrose in a novel reduced-hunger state. However, the MU agonist, DAMGO ([d-Ala2, NMe-Phe4, Gly5-ol]-enkephalin), appeared to attenuate this negative incentive learning. These data suggest that upshifts and downshifts in endogenous opioid transmission in the BLA mediate the encoding of positive and negative shifts in incentive value, respectively, through actions at MU-opioid receptors, and provide insight into a mechanism through which opiates may elicit inappropriate desire resulting in their continued intake in the face of diminishing affective experience. PMID- 21289168 TI - Human basal ganglia and the dynamic control of force during on-line corrections. AB - Natural movements are corrected in part by the generation of submovements, occurring early in a movement such that they amend an ongoing action. Submovements are associated with activity of the basal ganglia, implying a role for the structures in error correction. In parallel, the basal ganglia are linked to the generation and control of force amplitude, change, and duration. Here, we tested whether activity in human basal ganglia is associated with submovements generally, or was specific to a condition where the submovements only occurred in the face of unexpected proprioceptive error. Submovements were induced by introducing unexpected and variable viscous loads (augmenting the need for trial specific grip forces) or by reducing target size (augmenting the need for visually guided on-line control) in a one-dimensional target-capture task. In both cases, subjects compensated for the increased task difficulty by generating corrective submovements, which were closely matched in frequency and type. Activity in the internal segment of the globus pallidus and subthalamic nucleus correlated strongly with the number of submovements during the viscous challenge but not with the target challenge. The effects could not be explained by kinematic differences, i.e., movement amplitude or average number of submovements. The results support a specific role for the basal ganglia in error correction under conditions of variable load where there is a need for the dynamic control of force within an ongoing movement. PMID- 21289169 TI - Dopamine-mediated reinforcement learning signals in the striatum and ventromedial prefrontal cortex underlie value-based choices. AB - A large body of evidence exists on the role of dopamine in reinforcement learning. Less is known about how dopamine shapes the relative impact of positive and negative outcomes to guide value-based choices. We combined administration of the dopamine D(2) receptor antagonist amisulpride with functional magnetic resonance imaging in healthy human volunteers. Amisulpride did not affect initial reinforcement learning. However, in a later transfer phase that involved novel choice situations requiring decisions between two symbols based on their previously learned values, amisulpride improved participants' ability to select the better of two highly rewarding options, while it had no effect on choices between two very poor options. During the learning phase, activity in the striatum encoded a reward prediction error. In the transfer phase, in the absence of any outcome, ventromedial prefrontal cortex (vmPFC) continually tracked the learned value of the available options on each trial. Both striatal prediction error coding and tracking of learned value in the vmPFC were predictive of subjects' choice performance in the transfer phase, and both were enhanced under amisulpride. These findings show that dopamine-dependent mechanisms enhance reinforcement learning signals in the striatum and sharpen representations of associative values in prefrontal cortex that are used to guide reinforcement based decisions. PMID- 21289170 TI - Mechanism of spontaneous activity in afferent neurons of the zebrafish lateral line organ. AB - Many auditory, vestibular, and lateral-line afferent neurons display spontaneous action potentials. This spontaneous spiking is thought to result from hair-cell glutamate release in the absence of stimuli. Spontaneous release at hair-cell resting potentials presumably results from Ca(V)1.3 L-type calcium channel activity. Here, using intact zebrafish larvae, we recorded robust spontaneous spiking from lateral-line afferent neurons in the absence of external stimuli. Consistent with the above assumptions, spiking was absent in mutants that lacked either Vesicular glutamate transporter 3 (Vglut3) or Ca(V)1.3. We then tested the hypothesis that spontaneous spiking resulted from sustained Ca(V)1.3 activity due to depolarizing currents that are active at rest. Mechanotransduction currents (I(MET)) provide a depolarizing influence to the resting potential. However, following block of I(MET), spontaneous spiking persisted and was characterized by longer interspike intervals and increased periods of inactivity. These results suggest that an additional depolarizing influence maintains the resting potential within the activation range of Ca(V)1.3. To test whether the hyperpolarization activated cation current, I(h) participates in setting the resting potential, we applied I(h) antagonists. Both ZD7288 and DK-AH 269 reduced spontaneous activity. Finally, concomitant block of I(MET) and I(h) essentially abolished spontaneous activity, ostensibly by hyperpolarization outside of the activation range for Ca(V)1.3. Together, our data support a mechanism for spontaneous spiking that results from Ca(2+)-dependent neurotransmitter release at hair-cell resting potentials that are maintained within the activation range of Ca(V)1.3 channels through active I(MET) and I(h). PMID- 21289171 TI - Sensory neuropathy attributable to loss of Bcl-w. AB - Small fiber sensory neuropathy is a common disorder in which progressive degeneration of small-diameter nociceptors causes decreased sensitivity to thermal stimuli and painful sensations in the extremities. In the majority of patients, the cause of small fiber sensory neuropathy is unknown, and treatment options are limited. Here, we show that Bcl-w (Bcl-2l2) is required for the viability of small fiber nociceptive sensory neurons. Bcl-w(-/-) mice demonstrate an adult-onset progressive decline in thermosensation and a decrease in nociceptor innervation of the epidermis. This denervation occurs without cell body loss, indicating that lack of Bcl-w results in a primary axonopathy. Consistent with this phenotype, we show that Bcl-w, in contrast to the closely related Bcl-2 and Bcl-xL, is enriched in axons of sensory neurons and that Bcl-w prevents the dying back of axons. Bcl-w(-/-) sensory neurons exhibit mitochondrial abnormalities, including alterations in axonal mitochondrial size, axonal mitochondrial membrane potential, and cellular ATP levels. Collectively, these data establish bcl-w(-/-) mice as an animal model of small fiber sensory neuropathy and provide new insight regarding the role of Bcl-w and of mitochondria in preventing axonal degeneration. PMID- 21289172 TI - Memory retrieval and the passage of time: from reconsolidation and strengthening to extinction. AB - An established memory can be made transiently labile if retrieved or reactivated. Over time, it becomes again resistant to disruption and this process that renders the memory stable is termed reconsolidation. The reasons why a memory becomes labile after retrieval and reconsolidates still remains debated. Here, using inhibitory avoidance learning in rats, we provide evidence that retrievals of a young memory, which are accompanied by its reconsolidation, result in memory strengthening and contribute to its overall consolidation. This function associated to reconsolidation is temporally limited. With the passage of time, the stored memory undergoes important changes, as revealed by the behavioral outcomes of its retrieval. Over time, without explicit retrievals, memory first strengthens and becomes refractory to both retrieval-dependent interference and strengthening. At later times, the same retrievals that lead to reconsolidation of a young memory extinguish an older memory. We conclude that the storage of information is very dynamic and that its temporal evolution regulates behavioral outcomes. These results are important for potential clinical applications. PMID- 21289173 TI - Heparan sulphate proteoglycan and the low-density lipoprotein receptor-related protein 1 constitute major pathways for neuronal amyloid-beta uptake. AB - Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder in which the aggregation and deposition of amyloid-beta (Abeta) peptides in the brain are central to its pathogenesis. In healthy brains, Abeta is effectively metabolized with little accumulation. Cellular uptake and subsequent degradation of Abeta is one of the major pathways for its clearance in the brain. Increasing evidence has demonstrated significant roles for the low-density lipoprotein receptor-related protein 1 (LRP1) in the metabolism of Abeta in neurons, glia cells, and along the brain vasculatures. Heparan sulfate proteoglycan (HSPG) has also been implicated in several pathogenic features of AD, including its colocalization with amyloid plaques. Here, we demonstrate that HSPG and LRP1 cooperatively mediate cellular Abeta uptake. Fluorescence-activated cell sorter and confocal microscopy revealed that knockdown of LRP1 suppresses Abeta uptake, whereas overexpression of LRP1 enhances this process in neuronal cells. Heparin, which antagonizes HSPG, significantly inhibited cellular Abeta uptake. Importantly, treatment with heparin or heparinase blocked LRP1-mediated cellular uptake of Abeta. We further showed that HSPG is more important for the binding of Abeta to the cell surface than LRP1. The critical roles of HSPG in cellular Abeta binding and uptake were confirmed in Chinese hamster ovary cells genetically deficient in HSPG. We also showed that heparin and a neutralizing antibody to LRP1 suppressed Abeta uptake in primary neurons. Our findings demonstrate that LRP1 and HSPG function in a cooperative manner to mediate cellular Abeta uptake and define a major pathway through which Abeta gains entry to neuronal cells. PMID- 21289174 TI - Ablation of CBP in forebrain principal neurons causes modest memory and transcriptional defects and a dramatic reduction of histone acetylation but does not affect cell viability. AB - Rubinstein-Taybi syndrome (RSTS) is an inheritable disease associated with mutations in the gene encoding the CREB (cAMP response element-binding protein) binding protein (CBP) and characterized by growth impairment, learning disabilities, and distinctive facial and skeletal features. Studies in mouse models for RSTS first suggested a direct role for CBP and histone acetylation in cognition and memory. Here, we took advantage of the genetic tools for generating mice in which the CBP gene is specifically deleted in postmitotic principal neurons of the forebrain to investigate the consequences of the loss of CBP in the adult brain. In contrast to the conventional CBP knock-out mice, which exhibit very early embryonic lethality, postnatal forebrain-restricted CBP mutants were viable and displayed no overt abnormalities. We identified the dimer of histones H2A and H2B as the preferred substrate of the histone acetyltransferase domain of CBP. Surprisingly, the loss of CBP and subsequent histone hypoacetylation had a very modest impact in the expression of a number of immediate early genes and did not affect neuronal viability. In addition, the behavioral characterization of these mice dissociated embryonic and postnatal deficits caused by impaired CBP function, narrowed down the anatomical substrate of specific behavioral defects, and confirmed the special sensitivity of object recognition memory to CBP deficiency. Overall, our study provides novel insights into RSTS etiology and clarifies some of the standing questions concerning the role of CBP and histone acetylation in activity-driven gene expression, memory formation, and neurodegeneration. PMID- 21289175 TI - Anti-ganglioside antibody-mediated activation of RhoA induces inhibition of neurite outgrowth. AB - Anti-ganglioside antibodies (Abs) are strongly associated with axonal forms of Guillain Barre syndrome (GBS). Some studies indicate that these Abs, including those with GD1a reactivity, are associated with poor prognosis and/or incomplete recovery. We recently demonstrated that a disease-relevant anti-ganglioside Ab with GD1a reactivity inhibits axon regeneration after PNS injury in an animal model (Lehmann et al., 2007). An implication of these findings is that anti-GD1a Abs can mediate inhibition of axon regeneration and limit recovery in some patients with GBS. The downstream inhibitory intracellular signaling that mediates anti-ganglioside Ab-induced axon inhibition remains unclear. In the current study, we show that disease-relevant and GBS patient's anti-ganglioside Abs can inhibit neurite outgrowth in dissociated primary neuronal cultures. Activation of small GTPase RhoA and its key downstream effector Rho kinase (ROCK) are critical mediators of growth cone and neurite outgrowth inhibition. Therefore, we examined the role of these intracellular signaling molecules in our primary neuronal cultures by molecular and pharmacologic approaches. Our results show that the Ab-mediated inhibition of neurite outgrowth involves the activation of RhoA and ROCK pathway and this activation is through the engagement of specific cell-surface gangliosides by Abs. In summary, these studies directly link patient autoantibodies to an intracellular inhibitory signaling pathway involved in anti-ganglioside Ab-mediated inhibition of neurite outgrowth. PMID- 21289176 TI - Wnt signaling regulates neuronal differentiation of cortical intermediate progenitors. AB - Cortical intermediate progenitors (IPs) comprise a secondary neuronal progenitor pool that arises from radial glia (RG). IPs are essential for generating the correct number of cortical neurons, but the factors that regulate the expansion and differentiation of IPs in the embryonic cortex are essentially unknown. In this study, we show that the Wnt-beta-catenin pathway (canonical Wnt pathway) regulates IP differentiation into neurons. Upregulation of Wnt-beta-catenin signaling by overexpression of Wnt3a in the neocortex induced early differentiation of IPs into neurons and the accumulation of these newly born neurons at the subventricular zone/intermediate zone border. Long-term overexpression of Wnt3a led to cortical dysplasia associated with the formation of large neuronal heterotopias. Conversely, downregulation of Wnt-beta-catenin signaling with Dkk1 during mid and late stages of neurogenesis inhibited neuronal production. Consistent with previous reports, we show that Wnt-beta-catenin signaling also promotes RG self-renewal. Thus, our findings show differential effects of the Wnt-beta-catenin pathway on distinct groups of cortical neuronal progenitors: RG self-renewal and IP differentiation. Moreover, our findings suggest that dysregulation of Wnt signaling can lead to developmental defects similar to human cortical malformation disorders. PMID- 21289177 TI - Tau protein is required for amyloid {beta}-induced impairment of hippocampal long term potentiation. AB - Amyloid beta (Abeta) and tau protein are both implicated in memory impairment, mild cognitive impairment (MCI), and early Alzheimer's disease (AD), but whether and how they interact is unknown. Consequently, we asked whether tau protein is required for the robust phenomenon of Abeta-induced impairment of hippocampal long-term potentiation (LTP), a widely accepted cellular model of memory. We used wild-type mice and mice with a genetic knock-out of tau protein and recorded field potentials in an acute slice preparation. We demonstrate that the absence of tau protein prevents Abeta-induced impairment of LTP. Moreover, we show that Abeta increases tau phosphorylation and that a specific inhibitor of the tau kinase glycogen synthase kinase 3 blocks the increased tau phosphorylation induced by Abeta and prevents Abeta-induced impairment of LTP in wild-type mice. Together, these findings show that tau protein is required for Abeta to impair synaptic plasticity in the hippocampus and suggest that the Abeta-induced impairment of LTP is mediated by tau phosphorylation. We conclude that preventing the interaction between Abeta and tau could be a promising strategy for treating cognitive impairment in MCI and early AD. PMID- 21289178 TI - Disrupting function of FK506-binding protein 1b/12.6 induces the Ca2+ dysregulation aging phenotype in hippocampal neurons. AB - With aging, multiple Ca(2+)-associated electrophysiological processes exhibit increased magnitude in hippocampal pyramidal neurons, including the Ca(2+) dependent slow afterhyperpolarization (sAHP), L-type voltage-gated Ca(2+) channel (L-VGCC) activity, Ca(2+)-induced Ca(2+) release (CICR) from ryanodine receptors (RyRs), and Ca(2+) transients. This pattern of Ca(2+) dysregulation correlates with reduced neuronal excitability/plasticity and impaired learning/memory and has been proposed to contribute to unhealthy brain aging and Alzheimer's disease. However, little is known about the underlying molecular mechanisms. In cardiomyocytes, FK506-binding protein 1b/12.6 (FKBP1b) binds and stabilizes RyR2 in the closed state, inhibiting RyR-mediated Ca(2+) release. Moreover, we recently found that hippocampal Fkbp1b expression is downregulated, whereas Ryr2 and Frap1/Mtor (mammalian target of rapamycin) expression is upregulated with aging in rats. Here, we tested the hypothesis that disrupting FKBP1b function also destabilizes Ca(2+) homeostasis in hippocampal neurons and is sufficient to induce the aging phenotype of Ca(2+) dysregulation in young animals. Selective knockdown of Fkbp1b with interfering RNA in vitro (96 h) enhanced voltage-gated Ca(2+) current in cultured neurons, whereas in vivo Fkbp1b knockdown by microinjection of viral vector (3-4 weeks) dramatically increased the sAHP in hippocampal slice neurons from young-adult rats. Rapamycin, which displaces FKBP1b from RyRs in myocytes, similarly enhanced VGCC current and the sAHP and also increased CICR. Moreover, FKBP1b knockdown in vivo was associated with upregulation of RyR2 and mTOR protein expression. Thus, disruption of FKBP1b recapitulated much of the Ca(2+)-dysregulation aging phenotype in young rat hippocampus, supporting a novel hypothesis that declining FKBP function plays a major role in unhealthy brain aging. PMID- 21289179 TI - Dynamic changes in superior temporal sulcus connectivity during perception of noisy audiovisual speech. AB - Humans are remarkably adept at understanding speech, even when it is contaminated by noise. Multisensory integration may explain some of this ability: combining independent information from the auditory modality (vocalizations) and the visual modality (mouth movements) reduces noise and increases accuracy. Converging evidence suggests that the superior temporal sulcus (STS) is a critical brain area for multisensory integration, but little is known about its role in the perception of noisy speech. Behavioral studies have shown that perceptual judgments are weighted by the reliability of the sensory modality: more reliable modalities are weighted more strongly, even if the reliability changes rapidly. We hypothesized that changes in the functional connectivity of STS with auditory and visual cortex could provide a neural mechanism for perceptual reliability weighting. To test this idea, we performed five blood oxygenation level-dependent functional magnetic resonance imaging and behavioral experiments in 34 healthy subjects. We found increased functional connectivity between the STS and auditory cortex when the auditory modality was more reliable (less noisy) and increased functional connectivity between the STS and visual cortex when the visual modality was more reliable, even when the reliability changed rapidly during presentation of successive words. This finding matched the results of a behavioral experiment in which the perception of incongruent audiovisual syllables was biased toward the more reliable modality, even with rapidly changing reliability. Changes in STS functional connectivity may be an important neural mechanism underlying the perception of noisy speech. PMID- 21289180 TI - Auditory cortex encodes the perceptual interpretation of ambiguous sound. AB - The confounding of physical stimulus characteristics and perceptual interpretations of stimuli poses a problem for most neuroscientific studies of perception. In the auditory domain, this pertains to the entanglement of acoustics and percept. Traditionally, most study designs have relied on cognitive subtraction logic, which demands the use of one or more comparisons between stimulus types. This does not allow for a differentiation between effects due to acoustic differences (i.e., sensation) and those due to conscious perception. To overcome this problem, we used functional magnetic resonance imaging (fMRI) in humans and pattern-recognition analysis to identify activation patterns that encode the perceptual interpretation of physically identical, ambiguous sounds. We show that it is possible to retrieve the perceptual interpretation of ambiguous phonemes-information that is fully subjective to the listener-from fMRI measurements of brain activity in auditory areas in the superior temporal cortex, most prominently on the posterior bank of the left Heschl's gyrus and sulcus and in the adjoining left planum temporale. These findings suggest that, beyond the basic acoustic analysis of sounds, constructive perceptual processes take place in these relatively early cortical auditory networks. This disagrees with hierarchical models of auditory processing, which generally conceive of these areas as sets of feature detectors, whose task is restricted to the analysis of physical characteristics and the structure of sounds. PMID- 21289182 TI - Absence of large-scale dendritic plasticity of layer 5 pyramidal neurons in peri infarct cortex. AB - When stroke or traumatic brain injury lead to cortical damage, how do surviving neurons rewire the brain to restore lost functionalities? Several Golgi studies have argued for de novo growth and branching of dendrites of pyramidal neurons in the spared hemisphere, but the results could not always be replicated. Functional brain imaging studies in humans and rodents suggest that significant neuronal plasticity occurs in areas surrounding the cortical lesion, but whether dendritic rearrangements occur there has been less well studied, especially after stroke. We used in vivo two-photon microscopy in adult mice expressing green fluorescent protein to monitor longitudinally the length and branch complexity of entire apical dendritic arbors from layer 5 pyramidal neurons distributed over a large peri-infarct cortex region after middle cerebral artery occlusion. We find no evidence of growth of dendrites or addition of new branches to their arbors over a period of 3 months after stroke. Instead, we observed a two-step pruning process: an initial decrease in dendritic length, followed by a loss of dendritic branches. Importantly, the shortening of branch tips reflected a general shrinkage in the dendritic apical tree, suggesting that mechanical forces attributable to the involution of the infarct contributed to the changes in dendritic length. These results help resolve a long-standing debate regarding the role of large-scale dendritic plasticity of pyramidal neurons in functional recovery after cortical injury. PMID- 21289181 TI - Thermoregulatory phenotype of the Trpv1 knockout mouse: thermoeffector dysbalance with hyperkinesis. AB - This study aimed at determining the thermoregulatory phenotype of mice lacking transient receptor potential vanilloid-1 (TRPV1) channels. We used Trpv1 knockout (KO) mice and their genetically unaltered littermates to study diurnal variations in deep body temperature (T(b)) and thermoeffector activities under basal conditions, as well as thermoregulatory responses to severe heat and cold. Only subtle alterations were found in the basal T(b) of Trpv1 KO mice or in their T(b) responses to thermal challenges. The main thermoregulatory abnormality of Trpv1 KO mice was a different pattern of thermoeffectors used to regulate T(b). On the autonomic side, Trpv1 KO mice were hypometabolic (had a lower oxygen consumption) and hypervasoconstricted (had a lower tail skin temperature). In agreement with the enhanced skin vasoconstriction, Trpv1 KO mice had a higher thermoneutral zone. On the behavioral side, Trpv1 KO mice preferred a lower ambient temperature and expressed a higher locomotor activity. Experiments with pharmacological TRPV1 agonists (resiniferatoxin and anandamide) and a TRPV1 antagonist (AMG0347) confirmed that TRPV1 channels located outside the brain tonically inhibit locomotor activity. With age (observed for up to 14 months), the body mass of Trpv1 KO mice exceeded that of controls, sometimes approaching 60 g. In summary, Trpv1 KO mice possess a distinct thermoregulatory phenotype, which is coupled with a predisposition to age-associated overweight and includes hypometabolism, enhanced skin vasoconstriction, decreased thermopreferendum, and hyperkinesis. The latter may be one of the primary deficiencies in Trpv1 KO mice. We propose that TRPV1-mediated signals from the periphery tonically suppress the general locomotor activity. PMID- 21289183 TI - SDF1 regulates leading process branching and speed of migrating interneurons. AB - Cell migration is required for normal embryonic development, yet how cells navigate complex paths while integrating multiple guidance cues remains poorly understood. During brain development, interneurons migrate from the ventral ganglionic eminence to the cerebral cortex within several migratory streams. They must exit these streams to invade the cortical plate. While SDF1 (stromal cell derived factor-1) signaling is necessary for normal interneuron stream migration, how they switch from tangential stream migration to invade the cortical plate is unknown. Here, we demonstrate that SDF1 signaling reduces interneuron branching frequency by reducing cAMP levels via a G(i) signaling pathway using an in vitro mouse explant system, resulting in the maintenance of stream migration. Blocking SDF1 signaling or increasing branching frequency results in stream exit and cortical plate invasion in mouse brain slices. These data support a novel model to understand how migrating interneurons switch from tangential migration to invade the cortical plate in which reducing SDF signaling increases leading process branching and slows the migration rate, permitting migrating interneurons to sense cortically directed guidance cues. PMID- 21289184 TI - Selective toxicity by HDAC3 in neurons: regulation by Akt and GSK3beta. AB - Although it is well established that pharmacological inhibitors of classical histone deacetylases (HDACs) are protective in various in vivo models of neurodegenerative disease, the identity of the neurotoxic HDAC(s) that these inhibitors target to exert their protective effects has not been resolved. We find that HDAC3 is a protein with strong neurotoxic activity. Forced expression of HDAC3 induces death of otherwise healthy rat cerebellar granule neurons, whereas shRNA-mediated suppression of its expression protects against low potassium-induced neuronal death. Forced expression of HDAC3 also promotes the death of rat cortical neurons and hippocampally derived HT22 cells, but has no effect on the viability of primary kidney fibroblasts or the HEK293 and HeLa cell lines. This suggests that the toxic effect of HDAC3 is cell selective and that neurons are sensitive to it. Neurotoxicity by HDAC3 is inhibited by treatment with IGF-1 as well as by the expression of a constitutively active form of Akt, an essential mediator of IGF-1 signaling. Protection against HDAC3-induced neurotoxicity is also achieved by the inhibition of GSK3beta, a kinase inhibited by Akt that is widely implicated in the promotion of neurodegeneration in experimental models and in human pathologies. HDAC3 is directly phosphorylated by GSK3beta, suggesting that the neuronal death-promoting action of GSK3beta could be mediated through HDAC3 phosphorylation. In addition to demonstrating that HDAC3 has neurotoxic effects, our study identifies it as a downstream target of GSK3beta. PMID- 21289185 TI - Influence of GABAAR monoliganded states on GABAergic responses. AB - To reach the open state, the GABA(A) receptor (GABA(A)R) is assumed to bind two agonist molecules. Although it is currently believed that GABA(A)R could also operate in the monoliganded state, the gating properties of singly bound GABA(A)R are poorly understood and their physiological role is still obscure. In the present study, we characterize for the first time the gating properties of singly bound GABA(A)Rs by using a mutagenesis approach and we propose that monoliganded GABA(A)R contribute in shaping synaptic responses. At saturating GABA concentrations, currents mediated by recombinant GABA(A)Rs with a single functional binding site display slow onset, fast deactivation kinetics, and slow rate of desensitization-resensitization. GABA(A)Rs with two binding sites activated by brief pulses of subsaturating GABA concentrations (in the range of the GABA concentration profile in the synaptic cleft) could also mediate fast deactivating currents, displaying deactivation kinetics similar to those mediated by GABA(A)Rs with a single functional binding site. Model simulations of receptors activated by realistic synaptic GABA waves revealed that a considerable proportion of GABA(A) receptors open in the monoliganded state during synaptic transmission, therefore contributing in shaping IPSCs. PMID- 21289186 TI - Horizontal cell feedback without cone type-selective inhibition mediates "red green" color opponency in midget ganglion cells of the primate retina. AB - The distinctive red-green dimension of human and nonhuman primate color perception arose relatively recently in the primate lineage with the appearance of separate long (L) and middle (M) wavelength-sensitive cone photoreceptor types. "Midget" ganglion cells of the retina use center-surround receptive field structure to combine L and M cone signals antagonistically and thereby establish a "red-green, color-opponent" visual pathway. However, the synaptic origin of red green opponency is unknown, and conflicting evidence for either random or L versus M cone-selective inhibitory circuits has divergent implications for the developmental and evolutionary origins of trichromatic color vision. Here we directly measure the synaptic conductances evoked by selective L or M cone stimulation in the midget ganglion cell dendritic tree and show that L versus M cone opponency arises presynaptic to the midget cell and is transmitted entirely by modulation of an excitatory conductance. L and M cone synaptic inhibition is feedforward and thus occurs in phase with excitation for both cone types. Block of GABAergic and glycinergic receptors does not attenuate or modify L versus M cone antagonism, discounting both presynaptic and postsynaptic inhibition as sources of cone opponency. In sharp contrast, enrichment of retinal pH-buffering capacity, to attenuate negative feedback from horizontal cells that sum L and M cone inputs linearly and without selectivity, completely abolished both the midget cell surround and all chromatic opponency. Thus, red-green opponency appears to arise via outer retinal horizontal cell feedback that is not cone type selective without recourse to any inner retinal L versus M cone inhibitory pathways. PMID- 21289187 TI - CRMP5 (collapsin response mediator protein 5) regulates dendritic development and synaptic plasticity in the cerebellar Purkinje cells. AB - Collapsin response mediator protein 5 (CRMP5) is one of the CRMP members that expresses abundantly in the developing brain. To examine the in vivo function of CRMP5, we generated crmp5-deficient (crmp5(-/-)) mice. Anti-calbindin immunofluorescence studies of crmp5(-/-) mice revealed aberrant dendrite morphology; specifically, a decrease in the size of soma and diameter of primary dendrite of the cerebellar Purkinje cells at postnatal day 21 (P21) and P28, but not at P14. Coincidentally, CRMP5 is detected in Purkinje cells at P21 and P28 from crmp5(+/-) mice. In cerebellar slices of crmp5(-/-) mice, the induction of long-term depression of excitatory synaptic transmission between parallel fibers and Purkinje cells was deficient. Given that brain-derived neurotrophic factor (BDNF) plays major roles in dendritic development, we tried to elucidate the possible roles of CRMP5 in BDNF signaling. The effect of BDNF to induce dendritic branching was markedly attenuated in cultured crmp5(-/-) neurons. Furthermore, CRMP5 was tyrosine phosphorylated when coexpressed with neurotrophic tyrosine kinase receptor type 2 (TrkB), a receptor for BDNF, in HEK293T cells. These findings suggest that CRMP5 is involved in the development, maintenance and synaptic plasticity of Purkinje cells. PMID- 21289188 TI - Posterior medial frontal cortex activity predicts post-error adaptations in task related visual and motor areas. AB - As Seneca the Younger put it, "To err is human, but to persist is diabolical." To prevent repetition of errors, human performance monitoring often triggers adaptations such as general slowing and/or attentional focusing. The posterior medial frontal cortex (pMFC) is assumed to monitor performance problems and to interact with other brain areas that implement the necessary adaptations. Whereas previous research showed interactions between pMFC and lateral-prefrontal regions, here we demonstrate that upon the occurrence of errors the pMFC selectively interacts with perceptual and motor regions and thereby drives attentional focusing toward task-relevant information and induces motor adaptation observed as post-error slowing. Functional magnetic resonance imaging data from an interference task reveal that error-related pMFC activity predicts the following: (1) subsequent activity enhancement in perceptual areas encoding task-relevant stimulus features; (2) activity suppression in perceptual areas encoding distracting stimulus features; and (3) post-error slowing-related activity decrease in the motor system. Additionally, diffusion-weighted imaging revealed a correlation of individual post-error slowing and white matter integrity beneath pMFC regions that are connected to the motor inhibition system, encompassing right inferior frontal gyrus and subthalamic nucleus. Thus, disturbances in task performance are remedied by functional interactions of the pMFC with multiple task-related brain regions beyond prefrontal cortex that result in a broad repertoire of adaptive processes at perceptual as well as motor levels. PMID- 21289189 TI - Cortical connections of area V6Av in the macaque: a visual-input node to the eye/hand coordination system. AB - The goal of the present study was to elucidate the corticocortical afferent connections of area V6Av, the ventral subregion of area V6A, using retrograde neuronal tracers combined with physiological and cytoarchitectonic analyses in the macaque monkey. The results revealed that V6Av receives many of its afferents from extrastriate area V6, and from regions of areas V2, V3, and V4 subserving peripheral vision. Additional extrastriate visual projections originate in dorsal stream areas MT and MST. Area V6Av does not receive projections directly from V1; such connections were only observed when the injection sites crossed into area V6. The strongest parietal lobe afferents originate in fields V6Ad, PGm, MIP (medial intraparaietal), and PG, with frontal lobe afferents originating from the frontal eye field, caudal area 46, and the rostral subdivision of the dorsal premotor area (F7). A comparison of their respective connections supports the view that V6Av is functionally distinct from adjacent areas (V6 and V6Ad). The strong afferents from V6 and other extrastriate areas are consistent with physiological data that suggest that V6Av is primarily a visual area, supporting the notion that V6Av is part of a dorsomedial cortical network performing fast form and motion analyses needed for the visual guidance of action. PMID- 21289190 TI - Calcitonin gene-related peptide in the bed nucleus of the stria terminalis produces an anxiety-like pattern of behavior and increases neural activation in anxiety-related structures. AB - Calcitonin gene-related peptide (CGRP) evokes anxiety-like responses when infused into the lateral ventricle of rats. Because the bed nucleus of the stria terminalis (BNST) lies immediately adjacent to the lateral ventricle, is rich in CGRP receptors, and has itself been implicated in anxiety, we evaluated the hypothesis that these effects are attributable to stimulation of CGRP receptors within the BNST itself. Bilateral intra-BNST, but not dorsal, CGRP infusions (0, 200, 400, 800 ng/side) enhanced startle amplitude in a dose-dependent manner, and produced an anxiety-like response on the elevated plus maze. Intra-BNST infusion of the CGRP antagonist, alphaCGRP(8-37), blocked the effect of CGRP on startle, and also blocked startle potentiation produced by exposure to trimethylthiazoline (a component of fox feces that induces anxiety-like behavior in rats). Intra BNST, but not dorsal, CGRP infusions also increased c-Fos immunoreactivity in a number of anxiety-related brain areas (central nucleus of the amygdala, locus ceruleus, ventrolateral septal nucleus, paraventricular hypothalamic nucleus, lateral hypothalamus, lateral parabrachial nucleus, dorsal raphe nucleus, and nucleus accumbens shell), all of which receive direct projections from the BNST. Together, the results indicate that the activation of BNST CGRP receptors is both necessary and sufficient for some anxiety responses and that these effects may be mediated by activation of a wider network of BNST efferent structures. If so, inhibition of CGRP receptors may be a clinically useful strategy for anxiety reduction. PMID- 21289191 TI - Arrestin in ciliary invertebrate photoreceptors: molecular identification and functional analysis in vivo. AB - Arrestin was identified in ciliary photoreceptors of Pecten irradians, and its role in terminating the light response was established electrophysiologically. Downstream effectors in these unusual visual cells diverge from both microvillar photoreceptors and rods and cones; the finding that key regulatory mechanisms of the early steps of visual excitation are conserved across such distant lineages of photoreceptors underscores that a common blueprint for phototransduction exists across metazoa. Arrestin was detected by Western blot analysis of retinal lysates, and localized in ciliary photoreceptors by immunostaining of whole-eye cryosections and dissociated cells. Two arrestin isoforms were molecularly identified by PCR; these present the canonical N- and C-arrestin domains, and are identical at the nucleotide level over much of their sequence. A high degree of homology to various beta-arrestins (up to 70% amino acid identity) was found. In situ hybridization localized the two transcripts within the retina, but failed to reveal finer spatial segregation, possibly because of insufficient differences between the riboprobes. Intracellular dialysis of anti arrestin antibodies into voltage-clamped ciliary photoreceptors produced a gradual slow-down of the photocurrent falling phase, leaving a tail that decayed over many seconds after light termination. The antibodies also caused spectrally neutral flashes to elicit prolonged aftercurrents in the absence of large metarhodopsin accumulation; such aftercurrents could be quenched by chromatic illumination that photoconverts metarhodopsin back to rhodopsin. These observations indicate that the antibodies depleted functionally available arrestin, and implicate this molecule in the deactivation of the photoresponse at the rhodopsin level. PMID- 21289192 TI - Superior facial expression, but not identity recognition, in mirror-touch synesthesia. AB - Simulation models of expression recognition contend that to understand another's facial expressions, individuals map the perceived expression onto the same sensorimotor representations that are active during the experience of the perceived emotion. To investigate this view, the present study examines facial expression and identity recognition abilities in a rare group of participants who show facilitated sensorimotor simulation (mirror-touch synesthetes). Mirror-touch synesthetes experience touch on their own body when observing touch to another person. These experiences have been linked to heightened sensorimotor simulation in the shared-touch network (brain regions active during the passive observation and experience of touch). Mirror-touch synesthetes outperformed nonsynesthetic participants on measures of facial expression recognition, but not on control measures of face memory or facial identity perception. These findings imply a role for sensorimotor simulation processes in the recognition of facial affect, but not facial identity. PMID- 21289193 TI - Suppressor of fused controls mid-hindbrain patterning and cerebellar morphogenesis via GLI3 repressor. AB - Sonic Hedgehog and its GLI transcriptional effectors control foliation complexity during cerebellar morphogenesis by promoting granule cell precursor proliferation. Here, we reveal a novel contribution of Sonic Hedgehog-GLI signaling to cerebellar patterning and cell differentiation by generating mice with targeted deletion of Suppressor of Fused (SuFu), a regulator of Sonic Hedgehog signaling, in the mid-hindbrain. Postnatal SuFu-deficient mice exhibit impaired motor coordination and severe cerebellar mispatterning. SuFu conditional knock-out embryos display abnormal mid-hindbrain morphology associated with misexpression of Fgf8, and delayed differentiation and abnormal migration of major cerebellar cell types. Sonic Hedgehog is ectopically expressed in the external granule layer and Hedgehog signaling is upregulated. While expression of full-length GLI transcriptional activators downstream of Hedgehogs is markedly reduced, a processed form of GLI3, a transcriptional repressor, is essentially lost. Genetic expression of a Gli3 allele encoding GLI3 repressor in SuFu deficient mice largely rescues abnormal cerebellar patterning and cell differentiation observed in mice with SuFu deficiency alone. Together, our data demonstrate that SuFu controls cerebellar patterning and cell differentiation in a GLI3 repressor-dependent manner. PMID- 21289194 TI - Sphingolipid storage affects autophagic metabolism of the amyloid precursor protein and promotes Abeta generation. AB - Deposition of amyloid beta peptides (Abetas) in extracellular amyloid plaques within the human brain is a hallmark of Alzheimer's disease (AD). Abeta derives from proteolytic processing of the amyloid precursor protein (APP) by beta- and gamma-secretases. The initial cleavage by beta-secretase results in shedding of the APP ectodomain and generation of APP C-terminal fragments (APP-CTFs), which can then be further processed within the transmembrane domain by gamma-secretase, resulting in release of Abeta. Here, we demonstrate that accumulation of sphingolipids (SLs), as occurs in lysosomal lipid storage disorders (LSDs), decreases the lysosome-dependent degradation of APP-CTFs and stimulates gamma secretase activity. Together, this results in increased generation of both intracellular and secreted Abeta. Notably, primary fibroblasts from patients with different SL storage diseases show strong accumulation of potentially amyloidogenic APP-CTFs. By using biochemical, cell biological, and genetic approaches, we demonstrate that SL accumulation affects autophagic flux and impairs the clearance of APP-CTFs. Thus, accumulation of SLs might not only underlie the pathogenesis of LSDs, but also trigger increased generation of Abeta and contribute to neurodegeneration in sporadic AD. PMID- 21289195 TI - The distinct role of medium spiny neurons and cholinergic interneurons in the D2/A2A receptor interaction in the striatum: implications for Parkinson's disease. AB - A(2A) adenosine receptor antagonists are currently under investigation as potential therapeutic agents for Parkinson's disease (PD). However, the molecular mechanisms underlying this therapeutic effect is still unclear. A functional antagonism exists between A(2A) adenosine and D(2) dopamine (DA) receptors that are coexpressed in striatal medium spiny neurons (MSNs) of the indirect pathway. Since this interaction could also occur in other neuronal subtypes, we have analyzed the pharmacological modulation of this relationship in murine MSNs of the direct and indirect pathways as well in striatal cholinergic interneurons. Under physiological conditions, endogenous cannabinoids (eCBs) play a major role in the inhibitory effect on striatal glutamatergic transmission exerted by the concomitant activation of D(2) DA receptors and blockade of A(2A) receptors in both D(2)- and D(1)-expressing striatal MSNs. In experimental models of PD, the inhibition of striatal glutamatergic activity exerted by D(2) receptor activation did not require the concomitant inhibition of A(2A) receptors, while it was still dependent on the activation of CB(1) receptors in both D(2)- and D(1)-expressing MSNs. Interestingly, the antagonism of M1 muscarinic receptors blocked the effects of D(2)/A(2A) receptor modulation on MSNs. Moreover, in cholinergic interneurons we found coexpression of D(2) and A(2A) receptors and a reduction of the firing frequency exerted by the same pharmacological agents that reduced excitatory transmission in MSNs. This evidence supports the hypothesis that striatal cholinergic interneurons, projecting to virtually all MSN subtypes, are involved in the D(2)/A(2A) and endocannabinoid-mediated effects observed on both subpopulations of MSNs in physiological conditions and in experimental PD. PMID- 21289196 TI - Maternal influenza viral infection causes schizophrenia-like alterations of 5 HT2A and mGlu2 receptors in the adult offspring. AB - Epidemiological studies indicate that maternal influenza viral infection increases the risk for schizophrenia in the adult offspring. The serotonin and glutamate systems are suspected in the etiology of schizophrenia, as well as in the mechanism of action of antipsychotic drugs. The effects of hallucinogens, such as psilocybin and mescaline, require the serotonin 5-HT(2A) receptor, and induce schizophrenia-like psychosis in humans. In addition, metabotropic glutamate receptor mGlu(2/3) agonists show promise as a new treatment for schizophrenia. Here, we investigated the level of expression and behavioral function of 5-HT(2A) and mGlu(2) receptors in a mouse model of maternal influenza viral infection. We show that spontaneous locomotor activity is diminished by maternal infection with the mouse-adapted influenza A/WSN/33 (H1N1) virus. The behavioral responses to hallucinogens and glutamate antipsychotics are both affected by maternal exposure to influenza virus, with increased head-twitch response to hallucinogens and diminished antipsychotic-like effect of the glutamate agonist. In frontal cortex of mice born to influenza virus-infected mothers, the 5-HT(2A) receptor is upregulated and the mGlu(2) receptor is downregulated, an alteration that may be involved in the behavioral changes observed. Additionally, we find that the cortical 5-HT(2A) receptor-dependent signaling pathways are significantly altered in the offspring of infected mothers, showing higher c-fos, egr-1, and egr-2 expression in response to the hallucinogenic drug DOI. Identifying a biochemical alteration that parallels the behavioral changes observed in a mouse model of prenatal viral infection may facilitate targeting therapies for treatment and prevention of schizophrenia. PMID- 21289197 TI - Leptin-receptor-expressing neurons in the dorsomedial hypothalamus and median preoptic area regulate sympathetic brown adipose tissue circuits. AB - Brown adipose tissue (BAT) thermogenesis is critical to maintain homoeothermia and is centrally controlled via sympathetic outputs. Body temperature and BAT activity also impact energy expenditure, and obesity is commonly associated with decreased BAT capacity and sympathetic tone. Severely obese mice that lack leptin or its receptor (LepRb) show decreased BAT capacity, sympathetic tone, and body temperature and thus are unable to adapt to acute cold exposure (Trayhurn et al., 1976). LepRb-expressing neurons are found in several hypothalamic sites, including the dorsomedial hypothalamus (DMH) and median preoptic area (mPOA), both critical sites to regulate sympathetic, thermoregulatory BAT circuits. Specifically, a subpopulation in the DMH/dorsal hypothalamic area (DHA) is stimulated by fever-inducing endotoxins or cold exposure (Dimicco and Zaretsky, 2007; Morrison et al., 2008). Using the retrograde, transsynaptic tracer pseudorabies virus (PRV) injected into the BAT of mice, we identified PRV-labeled LepRb neurons in the DMH/DHA and mPOA (and other sites), thus indicating their involvement in the regulation of sympathetic BAT circuits. Indeed, acute cold exposure induced c-Fos (as a surrogate for neuronal activity) in DMH/DHA LepRb neurons, and a large number of mPOA LepRb neurons project to the DMH/DHA. Furthermore, DMH/DHA LepRb neurons (and a subpopulation of LepRb mPOA neurons) project and synaptically couple to rostral raphe pallidus neurons, consistent with the current understanding of BAT thermoregulatory circuits from the DMH/DHA and mPOA (Dimicco and Zaretsky, 2007; Morrison et al., 2008). Thus, these data present strong evidence that LepRb neurons in the DMH/DHA and mPOA mediate thermoregulatory leptin action. PMID- 21289198 TI - Rescue of progranulin deficiency associated with frontotemporal lobar degeneration by alkalizing reagents and inhibition of vacuolar ATPase. AB - Numerous loss-of-function mutations in the progranulin (GRN) gene cause frontotemporal lobar degeneration with ubiquitin and TAR-DNA binding protein 43 positive inclusions by reduced production and secretion of GRN. Consistent with the observation that GRN has neurotrophic properties, pharmacological stimulation of GRN production is a promising approach to rescue GRN haploinsufficiency and prevent disease progression. We therefore searched for compounds capable of selectively increasing GRN levels. Here, we demonstrate that four independent and highly selective inhibitors of vacuolar ATPase (bafilomycin A1, concanamycin A, archazolid B, and apicularen A) significantly elevate intracellular and secreted GRN. Furthermore, clinically used alkalizing drugs, including chloroquine, bepridil, and amiodarone, similarly stimulate GRN production. Elevation of GRN levels occurs via a translational mechanism independent of lysosomal degradation, autophagy, or endocytosis. Importantly, alkalizing reagents rescue GRN deficiency in organotypic cortical slice cultures from a mouse model for GRN deficiency and in primary cells derived from human patients with GRN loss-of-function mutations. Thus, alkalizing reagents, specifically those already used in humans for other applications, and vacuolar ATPase inhibitors may be therapeutically used to prevent GRN-dependent neurodegeneration. PMID- 21289199 TI - Cocaine-induced plasticity in the nucleus accumbens is cell specific and develops without prolonged withdrawal. AB - Cocaine induces plasticity at glutamatergic synapses in the nucleus accumbens (NAc). Withdrawal was suggested to play an important role in the development of this plasticity by studies showing that some changes only appear several weeks after the final cocaine exposure. In this study, the requirement for prolonged withdrawal was evaluated by comparing the changes in glutamatergic transmission induced by two different noncontingent cocaine treatments: a short treatment followed by prolonged withdrawal, and a longer treatment without prolonged withdrawal. Recordings were performed from mouse medium spiny neurons (MSNs) in the NAc at the same time after the first cocaine injection under both treatments. A similar increase in the frequency of glutamate-mediated miniature EPSCs was observed in D(1)-expressing MSNs after both cocaine treatments, demonstrating that prolonged withdrawal was not required. Furthermore, larger AMPA receptor-to NMDA receptor ratios, higher spine density, and enlarged spine heads were observed in the absence of withdrawal after a long cocaine treatment. These synaptic adaptations expressed in D(1)-containing MSNs of the NAc core were not further enhanced by protracted withdrawal. In conclusion, a few repeated cocaine injections are enough to trigger adaptations at glutamatergic synapses in D(1) expressing MSNs, which, although they take time to develop, do not require prolonged cocaine withdrawal. PMID- 21289200 TI - Gateways of ventral and dorsal streams in mouse visual cortex. AB - It is widely held that the spatial processing functions underlying rodent navigation are similar to those encoding human episodic memory (Doeller et al., 2010). Spatial and nonspatial information are provided by all senses including vision. It has been suggested that visual inputs are fed to the navigational network in cortex and hippocampus through dorsal and ventral intracortical streams (Whitlock et al., 2008), but this has not been shown directly in rodents. We have used cytoarchitectonic and chemoarchitectonic markers, topographic mapping of receptive fields, and pathway tracing to determine in mouse visual cortex whether the lateromedial field (LM) and the anterolateral field (AL), which are the principal targets of primary visual cortex (V1) (Wang and Burkhalter, 2007) specialized for processing nonspatial and spatial visual information (Gao et al., 2006), are distinct areas with diverse connections. We have found that the LM/AL border coincides with a change in type 2 muscarinic acetylcholine receptor expression in layer 4 and with the representation of the lower visual field periphery. Our quantitative analyses also show that LM strongly projects to temporal cortex as well as the lateral entorhinal cortex, which has weak spatial selectivity (Hargreaves et al., 2005). In contrast, AL has stronger connections with posterior parietal cortex, motor cortex, and the spatially selective medial entorhinal cortex (Haftig et al., 2005). These results support the notion that LM and AL are architecturally, topographically, and connectionally distinct areas of extrastriate visual cortex and that they are gateways for ventral and dorsal streams. PMID- 21289201 TI - Subregional specification of embryonic stem cell-derived ventral telencephalic tissues by timed and combinatory treatment with extrinsic signals. AB - During early telencephalic development, the major portion of the ventral telencephalic (subpallial) region becomes subdivided into three regions, the lateral (LGE), medial (MGE), and caudal (CGE) ganglionic eminences. In this study, we systematically recapitulated subpallial patterning in mouse embryonic stem cell (ESC) cultures and investigated temporal and combinatory actions of patterning signals. In serum-free floating culture, the dorsal-ventral specification of ESC-derived telencephalic neuroectoderm is dose-dependently directed by Sonic hedgehog (Shh) signaling. Early Shh treatment, even before the expression onset of Foxg1 (also Bf1; earliest marker of the telencephalic lineage), is critical for efficiently generating LGE progenitors, and continuous Shh signaling until day 9 is necessary to commit these cells to the LGE lineage. When induced under these conditions and purified by fluorescence-activated cell sorter, telencephalic cells efficiently differentiated into Nolz1(+)/Ctip2(+) LGE neuronal precursors and subsequently, both in culture and after in vivo grafting, into DARPP32(+) medium-sized spiny neurons. Purified telencephalic progenitors treated with high doses of the Hedgehog (Hh) agonist SAG (Smoothened agonist) differentiated into MGE- and CGE-like tissues. Interestingly, in addition to strong Hh signaling, the efficient specification of MGE cells requires Fgf8 signaling but is inhibited by treatment with Fgf15/19. In contrast, CGE differentiation is promoted by Fgf15/19 but suppressed by Fgf8, suggesting that specific Fgf signals play different, critical roles in the positional specification of ESC-derived ventral subpallial tissues. We discuss a model of the antagonistic Fgf8 and Fgf15/19 signaling in rostral-caudal subpallial patterning and compare it with the roles of these molecules in cortical patterning. PMID- 21289202 TI - A human model of selenium that integrates metabolism from selenite and selenomethionine. AB - Selenium (Se) metabolism is affected by its chemical form in foods and by its incorporation (specific vs. nonspecific) into multiple proteins. Modeling Se kinetics may clarify the impact of form on metabolism. Although the kinetics of Se forms have been compared in different participants, or the same participants at different times, direct comparisons of their respective metabolism in the same participants have not been made. The aim of this study was to simultaneously compare kinetics of absorbed Se from inorganic selenite (Sel) and organic selenomethionine (SeMet) in healthy participants (n = 31). After oral administration of stable isotopic tracers of each form, urine and feces were collected for 12 d and blood was sampled over 4 mo. Tracer enrichment was determined by isotope-dilution-GC-MS. Using WinSAAM, a compartmental model was fitted to the data. Within 30 min of ingestion, Se from both forms entered a common pool, and metabolism was similar for several days before diverging. Slowly turning-over pools were required in tissues and plasma for Se derived from SeMet to account for its 3-times-higher incorporation into RBC compared with Se from Sel; these presumably represent nonspecific incorporation of SeMet into proteins. Pool sizes and transport rates were determined and compared by form and gender. The final model consisted of 11 plasma pools, 2 pools and a delay in RBC, and extravascular pools for recycling of Se back into plasma. This model will be used to evaluate changes in Se metabolism following long-term (2 y) Se supplementation. PMID- 21289203 TI - Dietary acid load is not associated with lower bone mineral density except in older men. AB - High dietary acid load may be detrimental to bone mineral density (BMD), although sufficient calcium intake might neutralize this effect. In observational studies, the association between BMD and dietary acid load, estimated by net endogenous acid production (NEAP) and potential renal acid load (PRAL), has been inconsistent, and the potential modifying effect of calcium intake has not been assessed. We therefore examined the cross-sectional associations of estimated NEAP and PRAL with BMD in the Framingham Osteoporosis Study. We hypothesized that higher estimated NEAP and PRAL would be associated with lower BMD, but only among those with total calcium intake < 800 mg/d. BMD of the femoral neck and lumbar spine was measured, and estimated NEAP and PRAL were calculated via FFQ among 1069 Framingham Original (1988-1989, 1992-1993; 62% women, mean age 76 y) and 2919 Offspring (1996-2001; 56% women, mean age 60 y) cohort participants. Cohort- and sex-specific ANCOVA was used to calculate multivariable-adjusted mean BMD for estimated NEAP and PRAL quartiles. Assuming no uncontrolled confounding, estimated NEAP, but not PRAL, was inversely associated with femoral neck BMD (P trend = 0.04) in Original cohort men, whereas neither was associated with lumbar spine BMD. Estimated NEAP and PRAL were not associated with BMD at any site among Original cohort women or Offspring cohort men and women. There were no significant interactions between either estimated NEAP or PRAL and total calcium intake. These results suggest that, with a possible exception of older men, dietary acid load does not have a measureable negative effect on bone health, regardless of total calcium intake. PMID- 21289204 TI - Enhanced amino acid sensitivity of myofibrillar protein synthesis persists for up to 24 h after resistance exercise in young men. AB - We aimed to determine whether an exercise-mediated enhancement of muscle protein synthesis to feeding persisted 24 h after resistance exercise. We also determined the impact of different exercise intensities (90% or 30% maximal strength) or contraction volume (work-matched or to failure) on the response at 24 h of recovery. Fifteen men (21 +/- 1 y, BMI = 24.1 +/- 0.8 kg . m(-2)) received a primed, constant infusion of l-[ring-(13)C(6)]phenylalanine to measure muscle protein synthesis after protein feeding at rest (FED; 15 g whey protein) and 24 h after resistance exercise (EX-FED). Participants performed unilateral leg exercises: 1) 4 sets at 90% of maximal strength to failure (90FAIL); 2) 30% work matched to 90FAIL (30WM); or 3) 30% to failure (30FAIL). Regardless of condition, rates of mixed muscle protein and sarcoplasmic protein synthesis were similarly stimulated at FED and EX-FED. In contrast, protein ingestion stimulated rates of myofibrillar protein synthesis above fasting rates by 0.016 +/- 0.002%/h and the response was enhanced 24 h after resistance exercise, but only in the 90FAIL and 30FAIL conditions, by 0.038 +/- 0.012 and 0.041 +/- 0.010, respectively. Phosphorylation of protein kinase B on Ser473 was greater than FED at EX-FED only in 90FAIL, whereas phosphorylation of mammalian target of rapamycin on Ser2448 was significantly increased at EX-FED above FED only in the 30FAIL condition. Our results suggest that resistance exercise performed until failure confers a sensitizing effect on human skeletal muscle for at least 24 h that is specific to the myofibrillar protein fraction. PMID- 21289205 TI - Differential expression of novel adiponectin receptor-1 transcripts in skeletal muscle of subjects with normal glucose tolerance and type 2 diabetes. AB - OBJECTIVE: Adiponectin receptor-1 (AdipoR1) expression in skeletal muscle has been suggested to play an important role in insulin resistance and diabetes. We aimed at evaluating the presence of novel AdiopR1 splice variants in human muscle and their regulation under physiological and pathophysiological states. RESEARCH DESIGN AND METHODS: AdipoR1 5'UTR mRNA transcripts, predicted from bioinformatics data, were evaluated in fetal and adult human tissues. Expression and function of the identified transcripts were assessed in cultured human skeletal muscle cells and in muscle biopsies obtained from individuals with normal glucose tolerance (NGT) and type 2 diabetes (n = 49). RESULTS: Screening of potential AdipoR1 5'UTR splice variants revealed a novel highly abundant muscle transcript (R1T3) in addition to the previously described transcript (R1T1). Unlike R1T1, R1T3 expression was significantly increased during fetal development and myogenesis, paralleled with increased AdipoR1 protein expression. The 5'UTR of R1T3 was found to contain upstream open reading frames that repress translation of downstream coding sequences. Conversely, AdipoR1 3'UTR was associated with enhanced translation efficiency during myoblast-myotube differentiation. A marked reduction in muscle expression of R1T3, R1T1, and R1T3-to-R1T1 ratio was observed in individuals with type 2 diabetes compared with expression levels of NGT subjects, paralleled with decreased expression of the differentiation marker myogenin. Among NGT subjects, R1T3 expression was positively correlated with insulin sensitivity. CONCLUSIONS: These results indicate that AdipoR1 receptor expression in human skeletal muscle is subjected to posttranscriptional regulation, including alternative splicing and translational control. These mechanisms play an important role during myogenesis and may be important for whole-body insulin sensitivity. PMID- 21289206 TI - RIG-I- and MDA5-initiated innate immunity linked with adaptive immunity accelerates beta-cell death in fulminant type 1 diabetes. AB - OBJECTIVE: The contribution of innate immunity responsible for aggressive beta cell destruction in human fulminant type 1 diabetes is unclear. RESEARCH DESIGN AND METHODS: Islet cell expression of Toll-like receptors (TLRs), cytoplasmic retinoic acid-inducible gene I (RIG-I)-like receptors, downstream innate immune markers, adaptive immune mediators, and apoptotic markers was studied in three autopsied pancreata obtained 2 to 5 days after onset of fulminant type 1 diabetes. RESULTS: RIG-I was strongly expressed in beta-cells in all three pancreata infected with enterovirus. Melanoma differentiation-associated gene-5 was hyperexpressed in islet cells, including beta- and alpha-cells. TLR3 and TLR4 were expressed in mononuclear cells that infiltrated islets. Interferon (IFN) alpha and IFN-beta were strongly expressed in islet cells. Major histocompatibility complex (MHC)-class I, IFN-gamma, interleukin-18, and CXC motif ligand 10 were expressed and colocalized in affected islets. CD11c+ MHC class II+ dendritic cells and macrophage subsets infiltrated most islets and showed remarkable features of phagocytosis of islet cell debris. CD4+ forkhead box P3+ regulatory T cells were not observed in and around the affected islets. Mononuclear cells expressed the Fas ligand and infiltrated most Fas-expressing islets. Retinoic acid-receptor responder 3 and activated caspases 8, 9, and 3 were preferentially expressed in beta-cells. Serum levels of IFN-gamma were markedly increased in patients with fulminant type 1 diabetes. CONCLUSIONS: These findings demonstrate the presence of specific innate immune responses to enterovirus infection connected with enhanced adoptive immune pathways responsible for aggressive beta-cell toxicity in fulminant type 1 diabetes. PMID- 21289207 TI - INF2 is another piece of the jigsaw puzzle for FSGS. PMID- 21289208 TI - Macrophages in kidney repair and regeneration. PMID- 21289209 TI - Identification of a major chronic renal failure susceptibility locus in mice: perhaps EGFR determines what happens to eGFR. PMID- 21289210 TI - Atrial fibrillation in dialysis patients: a neglected comorbidity. PMID- 21289211 TI - Mortality risk in dialysis patients with naturally higher hemoglobins. PMID- 21289212 TI - Performance measurement in chronic kidney disease. AB - Do Americans receive high-value health care? Value only improves by advancing key indicators in one of two directions: increasing quality, decreasing cost, or both. In the face of unyielding mortality rates and the relentless expense of end stage renal disease, government agencies and professional organizations are now focusing on new quality measures for patients with advancing chronic kidney disease. These performance measures are in early stages of refinement but reflect efforts of payers to slow the incidence of progressive renal disease across the population. To improve quality of care, one must study the performance measures themselves and determine how to capture the necessary data efficiently, identify the appropriate patients for measurement, and assign accountability to providers. Here, we discuss the challenges of doing this well. PMID- 21289213 TI - The emergence of TH17 cells as effectors of renal injury. AB - IL-17-producing Th17 effector cells directly induce renal inflammation by activating neutrophils or by participating in macrophage-mediated tissue injury. Th17 cells and cytokines participate in human and experimental renal disease, especially in proliferative glomerulonephritis where Th17 effector cells are active. Although growing evidence suggests Th17 cells are particularly relevant to effector responses involving neutrophils, there are still important questions to address before the complete functions of Th17 cells in renal disease are understood fully. PMID- 21289214 TI - Predominance of intraglomerular T-bet or GATA3 may determine mechanism of transplant rejection. AB - The transcription factors T-bet and GATA3 determine the differentiation of helper T cells into Th1 or Th2 cells, respectively. An altered ratio of their relative expression promotes the pathogenesis of certain immunological diseases, but whether this may also contribute to the pathogenesis of antibody-mediated rejection (ABMR) versus T cell-mediated rejection (TCMR) is unknown. Here, we characterized the intragraft expression of T-bet and GATA3 and determined the correlation of their levels with the presence of typical lesions of ABMR and TCMR. We found a predominant intraglomerular expression of T-bet in patients with ABMR, which was distinct from that in patients with TCMR. In ABMR, interstitial T bet expression was typically located in peritubular capillaries, although the overall quantity of interstitial T-bet was less than that observed in TCMR. The expression of intraglomerular T-bet correlated with infiltration of CD4+ and CD8+ lymphocytes, which express T-bet, as well as intraglomerular CD68+ monocyte/macrophages, which do not express T-bet. The predominance of intraglomerular T-bet expression relative to GATA3 expression associated with poor response to treatment with bolus steroid. In summary, predominance of intraglomerular T-bet expression correlates with antibody-mediated rejection and resistance to steroid treatment. PMID- 21289215 TI - The tuberin/mTOR pathway promotes apoptosis of tubular epithelial cells in diabetes. AB - Apoptosis contributes to the development of diabetic nephropathy, but the mechanism by which high glucose (HG) induces apoptosis is not fully understood. Because the tuberin/mTOR pathway can modulate apoptosis, we studied the role of this pathway in apoptosis in type I diabetes and in cultured proximal tubular epithelial (PTE) cells exposed to HG. Compared with control rats, diabetic rats had more apoptotic cells in the kidney cortex. Induction of diabetes also increased phosphorylation of tuberin in association with mTOR activation (measured by p70S6K phosphorylation), inactivation of Bcl-2, increased cytosolic cytochrome c expression, activation of caspase 3, and cleavage of PARP; insulin treatment prevented these changes. In vitro, exposure of PTE cells to HG increased phosphorylation of tuberin and p70S6K, phosphorylation of Bcl-2, expression of cytosolic cytochrome c, and caspase 3 activity. High glucose induced translocation of the caspase substrate YY1 from the cytoplasm to the nucleus and enhanced cleavage of PARP. Pretreatment the cells with the mTOR inhibitor rapamycin reduced the number of apoptotic cells induced by HG and the downstream effects of mTOR activation noted above. Furthermore, gene silencing of tuberin with siRNA decreased cleavage of PARP. These data show that the tuberin/mTOR pathway promotes apoptosis of tubular epithelial cells in diabetes, mediated in part by cleavage of PARP by YY1. PMID- 21289216 TI - The GDNF target Vsnl1 marks the ureteric tip. AB - Glial cell line-derived neurotrophic factor (GDNF) is indispensable for ureteric budding and branching. If applied exogenously, GDNF promotes ectopic ureteric buds from the Wolffian duct. Although several downstream effectors of GDNF are known, the identification of early response genes is incomplete. Here, microarray screening detected several GDNF-regulated genes in the Wolffian duct, including Visinin like 1 (Vsnl1), which encodes a neuronal calcium-sensor protein. We observed renal Vsnl1 expression exclusively in the ureteric epithelium, but not in Gdnf-null kidneys. In the tissue culture of Gdnf-deficient kidney primordium, exogenous GDNF and alternative bud inducers (FGF7 and follistatin) restored Vsnl1 expression. Hence, Vsnl1 characterizes the tip of the ureteric bud epithelium regardless of the inducer. In the tips, Vsnl1 showed a mosaic expression pattern that was mutually exclusive with beta-catenin transcriptional activation. Vsnl1 was downregulated in both beta-catenin-stabilized and beta-catenin-deficient kidneys. Moreover, in a mouse collecting duct cell line, Vsnl1 compromised beta catenin stability, suggesting a counteracting relationship between Vsnl1 and beta catenin. In summary, Vsnl1 marks ureteric bud tips in embryonic kidneys, and its mosaic pattern demonstrates a heterogeneity of cell types that may be critical for normal ureteric branching. PMID- 21289217 TI - Distinct macrophage phenotypes contribute to kidney injury and repair. AB - The ischemically injured kidney undergoes tubular cell necrosis and apoptosis, accompanied by an interstitial inflammatory cell infiltrate. In this study, we show that iNos-positive proinflammatory (M1) macrophages are recruited into the kidney in the first 48 hours after ischemia/reperfusion injury, whereas arginase 1- and mannose receptor-positive, noninflammatory (M2) macrophages predominate at later time points. Furthermore, depletion of macrophages before ischemia/reperfusion diminishes kidney injury, whereas depletion at 3 to 5 days after injury slows tubular cell proliferation and repair. Infusion of Ifngamma stimulated, bone marrow-derived macrophages into macrophage-depleted mice at the time of kidney reperfusion restored injury to the level seen without macrophage depletion, suggesting that proinflammatory macrophages worsen kidney damage. In contrast, the appearance of macrophages with the M2 phenotype correlated with the proliferative phase of kidney repair. In vitro studies showed that IFNgamma stimulated, proinflammatory macrophages begin to express markers of M2 macrophages when cocultured with renal tubular cells. Moreover, IL-4-stimulated macrophages with an M2 phenotype, but not IFNgamma-stimulated proinflammatory macrophages, promoted renal tubular cell proliferation. Finally, tracking fluorescently labeled, IFNgamma-stimulated macrophages that were injected after injury showed that inflammatory macrophages can switch to an M2 phenotype in the kidney at the onset of kidney repair. Taken together, these studies show that macrophages undergo a switch from a proinflammatory to a trophic phenotype that supports the transition from tubule injury to tubule repair. PMID- 21289218 TI - Circulating nonphosphorylated carboxylated matrix gla protein predicts survival in ESRD. AB - The mechanisms for vascular calcification and its associated cardiovascular mortality in patients with ESRD are not completely understood. Dialysis patients exhibit profound vitamin K deficiency, which may impair carboxylation of the calcification inhibitor matrix gla protein (MGP). Here, we tested whether distinct circulating inactive vitamin K-dependent proteins associate with all cause or cardiovascular mortality. We observed higher levels of both desphospho uncarboxylated MGP (dp-ucMGP) and desphospho-carboxylated MGP (dp-cMGP) among 188 hemodialysis patients compared with 98 age-matched subjects with normal renal function. Levels of dp-ucMGP correlated with those of protein induced by vitamin K absence II (PIVKA-II; r = 0.62, P < 0.0001). We found increased PIVKA-II levels in 121 (64%) dialysis patients, indicating pronounced vitamin K deficiency. Kaplan-Meier analysis showed that patients with low levels of dp-cMGP had an increased risk for all-cause and cardiovascular mortality. Multivariable Cox regression confirmed that low levels of dp-cMGP increase mortality risk (all cause: HR, 2.2; 95% CI, 1.1 to 4.3; cardiovascular: HR, 2.7; 95% CI, 1.2 to 6.2). Furthermore, patients with higher vascular calcification scores showed lower levels of dp-cMGP. In 17 hemodialysis patients, daily supplementation with vitamin K2 for 6 weeks reduced dp-ucMGP levels by 27% (P = 0.003) but did not affect dp-cMGP levels. In conclusion, the majority of dialysis patients exhibit pronounced vitamin K deficiency. Lower levels of circulating dp-cMGP may serve as a predictor of mortality in dialysis patients. Whether vitamin K supplementation improves outcomes requires further study. PMID- 21289219 TI - Energy, evolution, and human diseases: an overview. AB - In the symposium entitled "Transcriptional controls of energy sensing," the authors presented recent advances on 1) AMP kinase, an intracellular energy sensor; 2) PGC-1alpha (peroxisome proliferator-activated receptor gamma co activator 1alpha), a transcriptional co-activator that has powerful effects on mitochondria; 3) methylation and demethylation in response to metabolic fluctuations; and 4) FGF21 (fibroblast growth factor 21) as an emerging hormone like intercellular metabolic coordinator. This introduction places these advances within a broad overview of energy sensing and energy balance, with a focus on human evolution and disease. Four key elements of human biology are analyzed: 1) elevated body temperature; 2) complex prolonged reproductive pathways; 3) emergence of 4 large, well-defined fat depots, each with its own functional role; and 4) an immune system that is often up-regulated by nutrition-related signals, independent of the actual presence of a pathogen. We propose that an overactive immune system, including the "metabolic syndrome," was adopted evolutionarily in the distant past to help hold out against unconquerable infections such as tuberculosis, malaria, and trypanosomiasis. This immune activation is advantageous in the absence of other disease management methods, especially under conditions in which life expectancy is short. The inflammation has become a major agent of pathology in wealthy populations in whom the pathogens are a minor threat and life expectancy is long. The "Conclusions" section sketches cautiously how understanding the molecules involved in energy sensing and energy balance may lead to specific therapies for obesity and diabetes and for their complications. PMID- 21289220 TI - Serum peptide YY in response to short-term overfeeding in young men. AB - BACKGROUND: Peptide YY (PYY), a gut hormone that inhibits appetite, has been linked to the development of obesity. OBJECTIVE: This study investigated the nutritional regulation of PYY after 7 d of overfeeding (70% above normal energy requirements) in normal-weight, overweight, and obese men. DESIGN: Sixty-nine men (aged 19-29 y) participated in the study. We analyzed the relation between fasting serum PYY before and after a 7-d overfeeding challenge in normal-weight, overweight, and obese men. In addition, we analyzed PYY with obesity-related phenotypes including weight, percentage body fat (measured by dual-energy X-ray absorptiometry), body mass index (BMI), total cholesterol, HDL, LDL, glucose, insulin, insulin resistance, and beta cell function evaluated by the homeostasis model assessment of insulin resistance (HOMA-IR) and beta cell function (HOMA beta) at baseline and in response to the energy surplus. RESULTS: Fasting serum PYY concentrations at baseline were not significantly different between the normal-weight, overweight, and obese subjects on the basis of dual-energy X-ray absorptiometry or BMI. Although the PYY concentration significantly increased due to overfeeding, no differences were observed between adiposity statuses. In addition, basal PYY was negatively correlated with the changes of total cholesterol, HDL, and LDL in normal weight. In addition, the increase in PYY after overfeeding was positively correlated with HDL cholesterol and glucose in normal-weight subjects. CONCLUSIONS: Our findings suggest that fasting PYY concentrations are not associated with adiposity status. Moreover, the 7-d overfeeding challenge significantly increased fasting PYY, which is likely a protective response to the positive energy balance. PMID- 21289221 TI - Regulation of PGC-1alpha, a nodal regulator of mitochondrial biogenesis. AB - Mechanisms responsible for energy management in the cell and in the whole organism require a complex network of transcription factors and cofactors. Peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) has emerged as a master regulator of mitochondrial biogenesis and function, thus becoming a crucial metabolic node. We present an overview of the mechanisms by which PGC-1alpha is regulated, including the transcriptional regulation of PGC 1alpha expression and the fine-tuning of its final activity via posttranslational modifications. PMID- 21289222 TI - DNA methylation in metabolic disorders. AB - DNA methylation is a major epigenetic modification that controls gene expression in physiologic and pathologic states. Metabolic diseases such as diabetes and obesity are associated with profound alterations in gene expression that are caused by genetic and environmental factors. Recent reports have provided evidence that environmental factors at all ages could modify DNA methylation in somatic tissues, which suggests that DNA methylation is a more dynamic process than previously appreciated. Because of the importance of lifestyle factors in metabolic disorders, DNA methylation provides a mechanism by which environmental factors, including diet and exercise, can modify genetic predisposition to disease. This article considers the current evidence that defines a role for DNA methylation in metabolic disorders. PMID- 21289223 TI - Baseline leptin and leptin reduction predict improvements in metabolic variables and long-term fat loss in obese children and adolescents: a prospective study of an inpatient weight-loss program. AB - BACKGROUND: It is unclear whether high plasma leptin in obese individuals represents leptin resistance or whether individuals with marked reductions in leptin concentrations in response to weight loss may be at greater risk of regaining weight. Moreover, whether changes in leptin predict metabolic improvements during weight loss is uncertain. OBJECTIVE: The objective was to prospectively examine associations between plasma leptin, body fat, and weight and metabolic risk factors in obese children during weight loss. DESIGN: In obese children and adolescents [n = 203; mean age: 14.1 y, >98th body mass index (BMI) percentile for age and sex] participating in a 2-mo inpatient weight-loss program, we measured changes in body composition (by dual-energy X-ray absorptiometry), plasma leptin, insulin, and lipids. After discharge, anthropometric measures and plasma leptin were remeasured at 6 (n = 139) and 12 (n = 100) mo. RESULTS: During the 2-mo program, mean (+/-SD) weight and fat loss were 13.9 +/- 4.0 kg and 9.2 +/- 2.5 kg, respectively; and mean plasma leptin decreased by 76%. Weight and fat loss were sustained, and no significant differences in BMI-SD score (SDS) or body composition were found between 12 and 2 mo. Baseline leptin was a negative predictor for percentage fat loss at 2, 6, and 12 mo (P < 0.05). The percentage change in leptin during the 2-mo intervention positively correlated with the relative change in fasting insulin, the relative change in LDL cholesterol at 2 mo, percentage fat loss, and change in BMI-SDS at 2 and 6 mo (P < 0.02). CONCLUSIONS: Even in obese children with strongly elevated baseline leptin, large leptin reductions that predict short- and long-term loss of body fat and improvements in lipids and insulin sensitivity can be achieved. Thus, increased plasma leptin in obese children may not necessarily reflect leptin resistance; many children appear to remain leptin sensitive at this age. PMID- 21289224 TI - Anthocyanin analysis in banana fruit--a mistake. PMID- 21289225 TI - Hidden vegetables: an effective strategy to reduce energy intake and increase vegetable intake in adults. AB - BACKGROUND: The overconsumption of energy-dense foods leads to excessive energy intakes. The substitution of low-energy-dense vegetables for foods higher in energy density can help decrease energy intakes but may be difficult to implement if individuals dislike the taste of vegetables. OBJECTIVE: We investigated whether incorporating pureed vegetables to decrease the energy density of entrees at multiple meals reduced daily energy intakes and increased daily vegetable intakes. DESIGN: In this crossover study, 20 men and 21 women ate ad libitum breakfast, lunch, and dinner in the laboratory once a week for 3 wk. Across conditions, entrees at meals varied in energy density from standard versions (100% condition) to reduced versions (85% and 75% conditions) by the covert incorporation of 3 or 4.5 times the amount of pureed vegetables. Entrees were accompanied by unmanipulated side dishes. Participants rated their hunger and fullness before and after meals. RESULTS: Subjects consumed a consistent weight of foods across conditions of energy density; thus, the daily energy intake significantly decreased by 202 +/- 60 kcal in the 85% condition (P < 0.001) and by 357 +/- 47 kcal in the 75% condition (P < 0.0001). Daily vegetable consumption significantly increased from 270 +/- 17 g of vegetables in the 100% condition to 487 +/- 25 g of vegetables in the 75% condition (P < 0.0001). Despite the decreased energy intake, ratings of hunger and fullness did not significantly differ across conditions. Entrees were rated as similar in palatability across conditions. CONCLUSIONS: Large amounts of pureed vegetables can be incorporated into various foods to decrease the energy density. This strategy can lead to substantial reductions in energy intakes and increases in vegetable intakes. This trial was registered at clinicaltrials.gov as NCT01165086. PMID- 21289226 TI - Daily consumption of vitamin D- or vitamin D + calcium-fortified yogurt drink improved glycemic control in patients with type 2 diabetes: a randomized clinical trial. AB - BACKGROUND: Low serum concentrations of 25-hydroxyvitamin D [25(OH)D] have been associated with impaired glucose tolerance and diabetes. OBJECTIVE: This study aimed to compare the effects of daily intake of vitamin D- or vitamin D(3) + calcium-fortified yogurt drink on glycemic status in subjects with type 2 diabetes (T2D). DESIGN: Ninety diabetic subjects were randomly allocated to 3 groups to consume plain yogurt drink (PY; containing no vitamin D and 150 mg Ca/250 mL), vitamin D-fortified yogurt drink (DY; containing 500 IU vitamin D(3) and 150 mg Ca/250 mL), or vitamin D + calcium-fortified yogurt drink (DCY; containing 500 IU vitamin D(3) and 250 mg Ca/250 mL) twice per day for 12 wk. Fasting serum glucose (FSG), glycated hemoglobin (Hb A(1c)), homeostasis model assessment of insulin resistance (HOMA-IR), serum lipid profile, and percentage fat mass (FM) were assessed before (baseline) and after the intervention. RESULTS: In both the DY and DCY groups, mean serum 25(OH)D(3) improved (+32.8 +/- 28.4 and +28.8 +/- 16.1 nmol/L, respectively; P < 0.001 for both), but FSG [-12.9 +/- 33.7 mg/dL (P = 0.015) and -9.6 +/- 46.9 mg/dL (P = 0.035)], Hb A(1c) [-0.4 +/- 1.2% (P < 0.001) and -0.4 +/- 1.9% (P < 0.001)], HOMA-IR [-0.6 +/- 1.4 (P = 0.001) and -0.6 +/- 3.2 (P < 0.001)], waist circumference (-3.6 +/- 2.7 and -2.9 +/- 3.3; P < 0.001 for both), and body mass index [in kg/m(2); -0.9 +/- 0.6 (P < 0.001) and -0.4 +/- 0.7 (P = 0.005)] decreased significantly more than in the PY group. An inverse correlation was observed between changes in serum 25(OH)D(3) and FSG (r = -0.208, P = 0.049), FM (r = -0.219, P = 0.038), and HOMA-IR (r = 0.219, P = 0.005). CONCLUSION: Daily intake of a vitamin D-fortified yogurt drink, either with or without added calcium, improved glycemic status in T2D patients. This trial was registered at clinicaltrials.gov as NCT01229891. PMID- 21289227 TI - Lack of association between 25(OH)D levels and incident type 2 diabetes in older women. AB - OBJECTIVE: To examine whether lower serum levels of serum 25-hydroxyvitamin (OH) D [25(OH)D] are associated with increased risk of developing type 2 diabetes. RESEARCH DESIGN AND METHODS: A post hoc analysis of three nested case-control studies of fractures, colon cancer, and breast cancer that measured serum 25(OH)D levels in women participating in the Women's Health Initiative (WHI) Clinical Trials and Observational Study who were free of prevalent diabetes at baseline. Diabetes was defined as self-report of physician diagnosis or receiving insulin or oral hypoglycemic medication. We used inverse probability weighting to make the study population representative of the WHI population as a whole. Weighted logistic regression models compared 25(OH)D levels (divided into quartiles, clinical cut points [<50, 50-<75, >= 75 nmol/L], or as a continuous variable) using the distribution of control subjects and adjusted for multiple confounding factors. RESULTS: Of 5,140 women (mean age 66 years) followed for an average of 7.3 years, 317 (6.2%) developed diabetes. Regardless of the cut points used or as a continuous variable, 25(OH)D levels were not associated with diabetes incidence in either age or fully adjusted models. Nor was any relationship found between 25(OH)D and incident diabetes when evaluated by strata of BMI, race/ethnicity, or randomization status in the Calcium Vitamin D trial. CONCLUSIONS: Lower serum 25(OH)D levels were not associated with increased risk of developing type 2 diabetes in this racially and ethnically diverse population of postmenopausal women. PMID- 21289228 TI - Dietary salt intake and mortality in patients with type 2 diabetes. AB - OBJECTIVE: Many guidelines recommend that patients with type 2 diabetes should aim to reduce their intake of salt. However, the precise relationship between dietary salt intake and mortality in patients with type 2 diabetes has not been previously explored. RESEARCH DESIGN AND METHODS: Six hundred and thirty-eight patients attending a single diabetes clinic were followed in a prospective cohort study. Baseline sodium excretion was estimated from 24-h urinary collections (24hU(Na)). The predictors of all-cause and cardiovascular mortality were determined by Cox regression and competing risk modeling, respectively. RESULTS: The mean baseline 24hU(Na) was 184 +/- 73 mmol/24 h, which remained consistent throughout the follow-up (intraindividual coefficient of variation [CV] 23 +/- 11%). Over a median of 9.9 years, there were 175 deaths, 75 (43%) of which were secondary to cardiovascular events. All-cause mortality was inversely associated with 24hU(Na), after adjusting for other baseline risk factors (P < 0.001). For every 100 mmol rise in 24hU(Na), all-cause mortality was 28% lower (95% CI 6-45%, P = 0.02). After adjusting for the competing risk of noncardiovascular death and other predictors, 24hU(Na) was also significantly associated with cardiovascular mortality (sub-hazard ratio 0.65 [95% CI 0.44-0.95]; P = 0.03). CONCLUSIONS: In patients with type 2 diabetes, lower 24-h urinary sodium excretion was paradoxically associated with increased all-cause and cardiovascular mortality. Interventional studies are necessary to determine if dietary salt has a causative role in determining adverse outcomes in patients with type 2 diabetes and the appropriateness of guidelines advocating salt restriction in this setting. PMID- 21289229 TI - Hemoglobin A1c as a predictor of incident diabetes. AB - OBJECTIVE: Several studies have suggested that HbA(1c) levels may predict incident diabetes. With new recommendations for use of HbA(1c) in diagnosing diabetes, many patients with HbA(1c) results below the diagnostic threshold will be identified. Clinicians will need to categorize risk for a subsequent diabetic diagnosis in such patients. The objective of this study was to determine the ability of HbA(1c) to predict the incidence of a diabetic diagnosis. RESEARCH DESIGN AND METHODS: We performed a historical cohort study using electronic medical record data from two Department of Veterans Affairs Medical Centers. Patients (n = 12,589) were identified with a baseline HbA(1c) <6.5% between January 2000 and December 2001 and without a diagnosis of diabetes. Patients (12,375) had at least one subsequent follow-up visit. These patients were tracked for 8 years for a subsequent diagnosis of diabetes. RESULTS: During an average follow-up of 4.4 years, 3,329 (26.9%) developed diabetes. HbA(1c) >= 5.0% carried a significant risk for developing diabetes during follow-up. When compared with the reference group (HbA(1c) <4.5%), HbA(1c) increments of 0.5% between 5.0 and 6.4% had adjusted odds ratios of 1.70 (5.0-5.4%), 4.87 (5.5-5.9%), and 16.06 (6.0 6.4%) (P < 0.0001). Estimates of hazard ratios similarly showed significant increases for HbA(1c) >= 5.0%. A risk model for incident diabetes within 5 years was developed and validated using HbA(1c), age, BMI, and systolic blood pressure. CONCLUSIONS: The incidence of diabetes progressively and significantly increased among patients with an HbA(1c) >= 5.0%, with substantially expanded risk for those with HbA(1c) 6.0-6.4%. PMID- 21289230 TI - Impaired endothelial function in preadolescent children with type 1 diabetes. AB - OBJECTIVE: We evaluated the prevalence of endothelial dysfunction as measured by flow-mediated dilatation (FMD) of the brachial artery and carotid intima-media thickness (c-IMT) in relationship to vascular inflammatory biomarkers in preadolescent children with type 1 diabetes. RESEARCH DESIGN AND METHODS: We studied 21 type 1 diabetic children (aged 8.3 +/- 0.3 years with diabetes duration of 4.3 +/- 0.4 years) and 15 group-matched healthy siblings (aged 7.6 +/ 0.3 years). Fasting plasma glucose (FPG), lipid profile, HbA(1c), high sensitivity C-reactive protein (hs-CRP), fibrinogen, homocysteine, and erythrocyte (red blood cell [RBC]) folate were evaluated in all subjects. Each subject underwent c-IMT and brachial artery FMD percentage (FMD%) measurements using high-resolution vascular ultrasound. RESULTS: Type 1 diabetic children had higher FPG (173.4 +/- 7.9 mg/dL vs. 81.40 +/- 1.7 mg/dL; P < 0.0001), HbA(1c) (8.0 +/- 0.2% vs. 5.0 +/- 0.1%; P < 0.0001), and hs-CRP (1.8 +/- 0.3 vs. 0.70 +/- 0.2; P = 0.017) than control children without significant differences in BMI, homocysteine, and fibrinogen levels; RBC folate content; and c-IMT between the groups. Children with type 1 diabetes had lower FMD% than control children (7.1 +/- 0.8% vs. 9.8 +/- 1.1%; P = 0.04), whereas c-IMT did not differ between groups. CONCLUSIONS: Preadolescent children with type 1 diabetes and mean diabetes duration of 4 years displayed evidence of low-intensity vascular inflammation and attenuated FMD measurements. These data suggest that endothelial dysfunction and systemic inflammation, known harbingers of future cardiovascular risk, are present even in preadolescent children. PMID- 21289231 TI - Self-monitoring of blood glucose: the use of the first or the second drop of blood. AB - OBJECTIVE: There is no general agreement regarding the use of the first or second drop of blood for glucose monitoring. This study investigated whether capillary glucose concentrations, as measured in the first and second drops of blood, differed >= 10% compared with a control glucose concentration in different situations. RESEARCH DESIGN AND METHODS: Capillary glucose concentrations were measured in two consecutive drops of blood in the following circumstances in 123 patients with diabetes: without washing hands, after exposing the hands to fruit, after washing the fruit-exposed hands, and during application of different amounts of external pressure around the finger. The results were compared with control measurements. RESULTS: Not washing hands led to a difference in glucose concentration of >= 10% in the first and in the second drops of blood in 11% and 4% of the participants, respectively. In fruit-exposed fingers, these differences were found in 88% and 11% of the participants, respectively. Different external pressures led to >= 10% differences in glucose concentrations in 5-13% of the participants. CONCLUSIONS: We recommend washing the hands with soap and water, drying them, and using the first drop of blood for self-monitoring of blood glucose. If washing hands is not possible, and they are not visibly soiled or exposed to a sugar-containing product, it is acceptable to use the second drop of blood after wiping away the first drop. External pressure may lead to unreliable readings. PMID- 21289232 TI - Inflammatory genes in epicardial fat contiguous with coronary atherosclerosis in the metabolic syndrome and type 2 diabetes: changes associated with pioglitazone. AB - OBJECTIVE: To determine changes in gene expression in epicardial adipose tissue (EAT) associated with coronary atherosclerosis (CAD) and effects of pioglitazone therapy. RESEARCH DESIGN AND METHODS: Genes were quantified by RT-PCR in EAT and thoracic subcutaneous adipose tissue (SAT) obtained during surgery in CAD patients with metabolic syndrome (MS) or type 2 diabetes and control subjects with minimal or no CAD and no MS or type 2 diabetes. RESULTS: Increased expression of interleukin-1 receptor antagonist (IL-1Ra) and IL-10, a trend for higher IL-1beta, and no change in peroxisome proliferator-activated receptor gamma (PPARgamma) was found in EAT from MS or type 2 diabetes. Only PPARgamma mRNA was reduced in SAT. Pioglitazone therapy in type 2 diabetes was associated with decreased expression of IL-1beta, IL-1Ra, and IL-10 in EAT; decreased IL-10 in SAT; and increased PPARgamma in SAT. CONCLUSIONS: In MS and type 2 diabetes with CAD, proinflammatory and anti-inflammatory genes were differentially increased in EAT and selectively reduced in association with pioglitazone treatment. PMID- 21289233 TI - Substance use in college students with ADHD. AB - OBJECTIVE: The college years represent a developmental transition during which the initiation and escalation of heavy drinking set the stage for lifelong difficulties with alcohol and other drugs. Evidence from studies of adolescents and young adults with ADHD suggests that college students with the disorder may be uniquely vulnerable to alcohol- and drug-related problems. However, no studies have examined substance use in college students with ADHD. METHOD: Tobacco, alcohol, illicit drug use, and associated impairment were examined in 91 college students with (n = 53) and without (n = 38) ADHD. RESULTS: ADHD was associated with increased frequency of tobacco use, higher rates of dangerous or hazardous patterns of alcohol use, and higher levels of impairment related to marijuana and nonmarijuana illicit drug use, independent of conduct disorder history. CONCLUSION: These findings suggest that college students with ADHD may be at elevated risk for problematic patterns of substance use. PMID- 21289234 TI - How oppositionality, inattention, and hyperactivity affect response to atomoxetine versus methylphenidate: a pooled meta-analysis. AB - OBJECTIVE: To assess how threshold oppositional defiant disorder (ODD), inattention, and hyperactivity-impulsivity affect the response to atomoxetine versus methylphenidate. METHOD: Systematic review of randomized controlled trials (RCTs; >=6 weeks follow-up). The primary measure was core symptom response->=40% reduction in ADHD Rating Scale-IV-Parent Version: investigator administered and scored total or domain subscores, as appropriate. RESULTS: Data from 1,391 children and adolescents (823 atomoxetine, 568 methylphenidate; 7 RCTs) were meta analyzed. The mean difference in response rates for patients with ODD was 0.6% (95% confidence interval [CI] = -11.9%-13.1%). The "without ODD" patient group showed significant between-trial heterogeneity (p < .001). Response rate differences for patients meeting the threshold for inattention or hyperactivity impulsivity were -3.1% (95% CI = -11.5%-5.3%) and -4.9% (95% CI = -14.3%-4.4%), respectively. CONCLUSIONS: Meeting the threshold criteria for oppositionality, inattention, or hyperactivity-impulsivity did not alter core ADHD symptom response to atomoxetine versus methylphenidate, which was equivalent. PMID- 21289235 TI - The positive illusory bias: does it explain self-evaluations in college students with ADHD? AB - OBJECTIVE: To evaluate whether the positive illusory bias explains the self evaluations of driving and work behaviors in college students with ADHD. METHOD: A total of 103 students with ADHD were compared to a sample of 94 students without ADHD. Both groups completed self-reports of their specific driving and work behaviors and then rated their overall, global performance in each area. Three specific-to-global change scores were obtained (one measuring work and two measuring driving) that were thought to be measures of the positive illusory bias. These specific-to-global change scores were analyzed using chi-square to evaluate differences between participants with and without ADHD. RESULTS: The participants with ADHD were significantly more likely than the participants without ADHD to engage in the positive illusory bias on two of the three work and driving ratings. CONCLUSION: College students with ADHD demonstrate self evaluations that appear to reflect the positive illusory bias and that may be related to their academic functioning in the college setting and willingness to receive treatment. PMID- 21289236 TI - The relationship between ADHD symptoms and competence as reported by both self and others. AB - OBJECTIVE: This study examines the relative relationships of self- and other reports of adult ADHD symptoms to important life competencies, and also investigates whether self- and other-reports of ADHD symptoms are differentially associated with interrater differences in reports of competence. METHOD: A total of 91 women completed a self-perception questionnaire assessing competence. Other individuals who knew the women well completed the same questionnaire with regard to the women. The women's ADHD symptoms were also rated by themselves and others. RESULTS: Regressions of self- and other-reports of ADHD symptoms on competence scores suggest that other-reports of ADHD symptoms are more valid than self reports. Also, correlations between reports of ADHD symptoms and interrater differences in rated competence were consistent with a positive illusory bias among women with high ADHD symptoms. CONCLUSION: Other-reports of ADHD symptoms may be better associated with an individual's competence than self-reports. PMID- 21289237 TI - Blood flow index using near-infrared spectroscopy and indocyanine green as a minimally invasive tool to assess respiratory muscle blood flow in humans. AB - Near-infrared spectroscopy (NIRS) in combination with indocyanine green (ICG) dye has recently been used to measure respiratory muscle blood flow (RMBF) in humans. This method is based on the Fick principle and is determined by measuring ICG in the respiratory muscles using transcutaneous NIRS in relation to the [ICG] in arterial blood as measured using photodensitometry. This method is invasive since it requires arterial cannulation, repeated blood withdrawals, and reinfusions. A less invasive alternative is to calculate a relative measure of blood flow known as the blood flow index (BFI), which is based solely on the NIRS ICG curve, thus negating the need for arterial cannulation. Accordingly, the purpose of this study was to determine whether BFI can be used to measure RMBF at rest and during voluntary isocapnic hyperpnea at 25, 40, 55, and 70% of maximal voluntary ventilation in seven healthy humans. BFI was calculated as the change in maximal [ICG] divided by the rise time of the NIRS-derived ICG curve. Intercostal and sternocleidomastoid muscle BFI were correlated with simultaneously measured work of breathing and electromyography (EMG) data from the same muscles. BFI showed strong relationships with the work of breathing and EMG for both respiratory muscles. The coefficients of determination (R(2)) comparing BFI vs. the work of breathing for the intercostal and sternocleidomastoid muscles were 0.887 (P < 0.001) and 0.863 (P < 0.001), respectively, whereas the R(2) for BFI vs. EMG for the intercostal and sternocleidomastoid muscles were 0.879 (P < 0.001) and 0.930 (P < 0.001), respectively. These data suggest that the BFI closely reflects RMBF in conscious humans across a wide range of ventilations and provides a less invasive and less technically demanding alternative to measuring RMBF. PMID- 21289238 TI - Imbalance of central nitric oxide and reactive oxygen species in the regulation of sympathetic activity and neural mechanisms of hypertension. AB - Nitric oxide (NO) and reactive oxygen species (ROS) play important roles in blood pressure regulation via the modulation of the autonomic nervous system, particularly in the central nervous system (CNS). In general, accumulating evidence suggests that NO inhibits, but ROS activates, the sympathetic nervous system. NO and ROS, however, interact with each other. Our consecutive studies and those of others strongly indicate that an imbalance between NO bioavailability and ROS generation in the CNS, including the brain stem, activates the sympathetic nervous system, and this mechanism is involved in the pathogenesis of neurogenic aspects of hypertension. In this review, we focus on the role of NO and ROS in the regulation of the sympathetic nervous system within the brain stem and subsequent cardiovascular control. Multiple mechanisms are proposed, including modulation of neurotransmitter release, inhibition of receptors, and alterations of intracellular signaling pathways. Together, the evidence indicates that an imbalance of NO and ROS in the CNS plays a pivotal role in the pathogenesis of hypertension. PMID- 21289239 TI - Rapid transitions among functional states support efficient osmoregulatory acclimation: focus on "Functional plasticity of mitochondrion-rich cells in the skin of euryhaline medaka larvae (Oryzias latipes) subjected to salinity changes". PMID- 21289240 TI - Stimulation of human whole-body energy expenditure by salsalate is fueled by higher lipid oxidation under fasting conditions and by higher oxidative glucose disposal under insulin-stimulated conditions. AB - OBJECTIVE: Nonsteroidal antiinflammatory drugs appear to improve insulin sensitivity and are currently tested in clinical trials. Salsalate, however, may blunt mitochondrial function, an unwarranted side effect for type 2 diabetics. We examined the effect of salsalate on ex vivo mitochondrial function and lipid induced insulin resistance. DESIGN: In a crossover design, nine volunteers underwent a hyperinsulinemic-euglycemic clamp with simultaneous infusion of glycerol (control), Intralipid, or Intralipid preceded by 4 d of salsalate (4000 mg Disalsid). Oxidative glucose disposal and nonoxidative glucose disposal (NOGD), metabolic flexibility, energy expenditure (EE), and ex vivo muscle mitochondrial function were measured. RESULTS: Lipid infusion reduced insulin stimulated glucose disposal by approximately 40%, glucose oxidation (CHOox) by approximately 50%, and NOGD by approximately 35%. Lipid-induced whole-body insulin resistance and decreased NOGD were not ameliorated by salsalate. However, salsalate repressed lipid-induced reduction in CHOox and reduced insulin clearance, resulting in higher insulin levels under basal as well as under clamp conditions (~25 and ~39%, respectively). Intriguingly, EE was higher after administration of salsalate (~18 and ~16% under basal and clamp conditions, respectively) and was fueled by increased fat oxidation in the basal state and increased CHOox upon insulin stimulation. Salsalate did not affect mitochondrial function and coupling. CONCLUSION: We conclude that salsalate failed to improve whole-body insulin sensitivity but increased basal fat oxidation and insulin stimulated CHOox, indicating improved metabolic flexibility. The beneficial effects of salsalate on CHOox can be attributed to elevated insulin levels. Mitochondrial respirometry revealed no indications that the changes in substrate selection and EE could be attributed to changes in skeletal muscle mitochondrial capacity or mitochondrial coupling. PMID- 21289241 TI - Chronically increased S6K1 is associated with impaired IRS1 signaling in skeletal muscle of GDM women with impaired glucose tolerance postpartum. AB - CONTEXT: The rapidly increasing prevalence of gestational diabetes mellitus (GDM) globally places a growing population at risk for developing type 2 diabetes mellitus (T2DM), particularly those with persistent impaired glucose tolerance (IGT) postpartum. OBJECTIVE: We sought to 1) identify dynamic insulin signaling abnormalities in vivo in a prospective, longitudinal study of GDM women compared to weight-matched pregnant controls both antepartum and postpartum; and 2) determine abnormalities that might distinguish GDM women who normalize their glucose tolerance postpartum from those with persistent IGT. DESIGN: Skeletal muscle biopsies were obtained before and after a 75-g glucose load in nine overweight to obese GDM women and 10 weight-matched pregnant controls antepartum and postpartum. Postpartum biopsies were collected in five weight-matched GDM women with IGT (GDM/IGT). RESULTS: GDM women had decreased skeletal muscle insulin-stimulated insulin receptor and insulin receptor substrate 1 (IRS1) tyrosine activation and reduced IRS1, concomitant with increased basal IRS1 serine phosphorylation and basal p70 S6-kinase (S6K1) activation, which resolved postpartum. However, GDM/IGT subjects had a persistent impairment in IRS1 activation and increased S6K1 phosphorylation compared to GDM subjects with normal glucose tolerance. CONCLUSIONS: This study reveals that women with GDM demonstrate impaired IRS1 signaling associated with increased S6K1 activation in skeletal muscle in vivo. This defect is maintained postpartum in GDM/IGT subjects, despite similar body weights and cytokine levels. Given that GDM women with persistent IGT are at a high risk of developing T2DM, understanding how the nutrient-sensitive mammalian target of rapamycin/S6K1 pathway is chronically activated in GDM may lead to important therapies that could prevent the progression to T2DM. PMID- 21289242 TI - Progressive hyperglycemia across the glucose tolerance continuum in older obese adults is related to skeletal muscle capillarization and nitric oxide bioavailability. AB - CONTEXT: Reduced tissue nutrient exposure may aid in the progression of glucose intolerance. OBJECTIVE: The aim of the study was to examine peripheral tissue glucose disposal in relation to muscle capillarization and plasma nitric oxide bioavailability. DESIGN: Participants were carefully matched for age, adiposity, and lipid status and stratified into normal (n = 20), impaired (n = 20), and type 2 diabetic (n = 20) glucose-tolerant groups. SETTING: The study was conducted in an outpatient setting at a Clinical Research Unit. PARTICIPANTS: Older, obese men and women (n = 60; age, 65 +/- 1 yr; body mass index, 32.7 +/- 0.5 kg/m(2)) participated in the study. INTERVENTION: We performed a cross-sectional study. MAIN OUTCOME MEASURES: Body composition, energy metabolism, aerobic fitness (maximum oxygen consumption), insulin sensitivity (glucose clamp), vastus lateralis muscle morphology, and plasma nitric oxide were assessed. RESULTS: Although subjects were identical with respect to age, body composition, energy expenditure, and lipid status, insulin-stimulated glucose disposal and maximum oxygen consumption showed progressive decline with increasing glucose intolerance. Muscle fiber type composition and mitochondrial density were not different between groups. However, capillary density markedly declined with advancing glucose intolerance (1.86 +/- 0.31, 1.70 +/- 0.28, 1.42 +/- 0.24 capillary/fiber; P < 0.05), a trend that was mirrored by fasting plasma nitric oxide concentrations (26.3 +/- 3.6, 19.8 +/- 2.3, 15.2 +/- 2.1 MUmol/liter; P < 0.05). Furthermore, skeletal muscle capillary density correlated with insulin sensitivity (r = 0.65; P < 0.001). CONCLUSIONS: Impaired muscle capillarization and reduced nutrient exposure to the metabolizing tissue may play a major role in the progression of insulin resistance across the glucose tolerance continuum, independent of age, adiposity, lipid status, and resting energy metabolism. These data also highlight plasma nitric oxide as a potential surrogate marker of these impairments and may be indicative of the progression toward type 2 diabetes. PMID- 21289243 TI - Pregnancy does not accelerate corticotroph tumor progression in Nelson's syndrome. AB - CONTEXT: Pituitary surgery is the first line of treatment for Cushing's disease; when surgery fails, bilateral adrenalectomy may be proposed, particularly for women with a desire for pregnancy. Little is known about the impact of pregnancy on corticotroph tumor progression after bilateral adrenalectomy. OBJECTIVE: The aim was to evaluate the impact of pregnancy on corticotroph tumor progression after bilateral adrenalectomy in Cushing's disease and to assess maternal and pregnancy outcomes. DESIGN: We conducted a retrospective cohort study. SETTING: Patients who became pregnant after bilateral adrenalectomy were followed in a single center. PATIENTS: Twenty pregnancies from 11 patients with Cushing's disease were treated by bilateral adrenalectomy and no pituitary irradiation. MEASUREMENTS: Corticotroph tumor progression was assessed by serial pituitary magnetic resonance imaging and plasma ACTH measurements before, during, and after pregnancy. Comparisons were performed using paired Wilcoxon rank tests. Data on maternal and neonatal outcomes were recorded by correspondence from patients and obstetricians. RESULTS: Corticotroph tumor progression occurred in eight of 17 pregnancies, and ACTH increased in eight of 10 pregnancies. However, rates of increase during or after pregnancy were not faster than those observed before pregnancy. Maternal complications occurred in four pregnancies from two patients, including gestational hypertension in three and gestational diabetes mellitus in three. Among these four pregnancies, three had a favorable outcome, and one led to an in utero death after eclampsia, due to loss to follow-up. No other maternal or fetal complications were reported. CONCLUSION: Pregnancy does not accelerate corticotroph tumor progression after bilateral adrenalectomy. Pregnancy is manageable, provided the patients can be followed closely. PMID- 21289244 TI - Somatic mutation and germline sequence abnormalities in CDKN1B, encoding p27Kip1, in sporadic parathyroid adenomas. AB - CONTEXT: Typical nonfamilial (sporadic) parathyroid adenomas are common endocrine tumors for which no predisposing germline DNA variants and only a few clonally altered genes that drive parathyroid tumorigenesis have been identified. CDKN1B, encoding cyclin-dependent kinase inhibitor p27(kip1), has recently been implicated in a multiple endocrine tumor phenotype in rats and, rarely, in a human familial MEN1 (multiple endocrine neoplasia type 1)-like disorder. OBJECTIVE: We sought to determine whether mutation of CDKN1B might contribute to the development of common sporadic parathyroid adenomas. PATIENTS AND DESIGN: We sequenced the CDKN1B gene in 86 parathyroid adenomas from patients with typical, sporadic presentations of primary hyperparathyroidism. Identified alterations were categorized as somatic or germline, and their functional consequences were examined. RESULTS: CDKN1B sequence abnormalities were identified in four parathyroid adenomas. Acquired biallelic alteration of CDKN1B, resulting from somatic mutation plus loss of heterozygosity, was detected in one tumor. Germline origin was documented in two cases despite nonfamilial presentations. None of the observed alterations were found in 240 CDKN1B alleles from normal individuals, nor among more than 2,000 previously reported alleles. Most identified variants reduced p27(kip1) protein levels or altered in vitro stability. CONCLUSIONS: In typical, sporadic parathyroid adenomas, CDKN1B mutation can be somatic and clonal, indicative of a directly conferred selective advantage in parathyroid tumorigenesis. Additionally, the identification of germline CDKN1B variants in patients with sporadic presentations provides evidence for CDKN1B as a susceptibility gene in the development of typical parathyroid adenomas. PMID- 21289245 TI - 1,25-Dihydroxyvitamin D3 reduces TGF-beta3-induced fibrosis-related gene expression in human uterine leiomyoma cells. AB - BACKGROUND: Uterine leiomyomas (fibroids) are the most common benign estrogen dependent tumors of premenopausal women. TGF-beta3 up-regulates the synthesis of many of extracellular matrix proteins that are associated with tissue fibrosis. OBJECTIVE: To examine the effect of 1,25-dihydroxyvitamin D(3) (vitamin D(3)) on TGF-beta3-induced fibrosis-related protein expression in immortalized human uterine leiomyoma (HuLM) cells. METHODS: HuLM cells were treated with TGF-beta3 with or without vitamin D(3). Western blot analyses were employed to test the effect of vitamin D(3) on TGF-beta3-induced protein expression of collagen type 1, fibronectin, and plasminogen activator inhibitor-1 proteins. Western blots as well as immunofluorescence analyses were used to verify the effect of vitamin D(3) on TGF-beta3-induced Smad activation involved in extracellular matrix protein synthesis and deposition, which ultimately lead to tissue fibrosis. RESULTS: We observed that TGF-beta3 induced fibronectin and collagen type 1 protein expression in HuLM cells, and that effect was suppressed by vitamin D(3). TGF-beta3 also induced protein expression of plasminogen activator inhibitor-1, an important TGF-beta target, in HuLM cells, which was also inhibited by vitamin D(3). Additionally, TGF-beta3 induced phosphorylation of Smad2 as well as nuclear translocation of Smad2 and Smad3 in HuLM cells, whereas vitamin D significantly reduced all these TGF-beta3-mediated effects. Therefore, our results suggest that vitamin D(3) has consistently reduced TGF-beta3 effects that are involved in the process of fibrosis in human leiomyoma cells. CONCLUSION: Vitamin D(3) is an antifibrotic factor that might be potentially useful as a novel therapeutic for nonsurgical treatment of benign uterine fibroids. PMID- 21289246 TI - Effects of two selective serotonin reuptake inhibitor antidepressants, sertraline and escitalopram, on aldosterone/renin ratio in normotensive depressed male patients. AB - BACKGROUND: Plasma aldosterone to renin ratio (ARR) is the most popular screening test for primary aldosteronism (PAL). Certain medications are known to cause false-negative or -positive ARRs by affecting renin and aldosterone levels. There are no previously published data on the effects of antidepressants on ARR. METHODS: Normotensive, depressed male patients (n = 26) underwent measurement (seated, midmorning) of plasma aldosterone, direct renin concentration (DRC), renin activity (PRA), electrolytes and creatinine and urinary aldosterone, cortisol, electrolytes, and creatinine at baseline and after 2 and 6 wk treatment with sertraline (n = 14) or escitalopram (n = 12). RESULTS: For both antidepressants, treatment was associated with rises in aldosterone [sertraline: baseline, mean +/- sd, 243 +/- 34; 2 wk, 256 +/- 33; 6 wk, 267 +/- 34 pmol/liter (P < 0.01 by ANOVA); escitalopram, 261 +/- 36, 269 +/- 38, 282 +/- 40 pmol/liter (P < 0.05)], DRC [19.5 +/- 2.2, 33.5 +/- 2.0, 39.0 +/- 2.4 mU/liter (P < 0.001); 24.5 +/- 2.4, 34.0 +/- 2.7, 42.8 +/- 2.4 mU/liter (P < 0.001)], and PRA [2.24 +/- 0.21, 2.58 +/- 0.26, 4.68 +/- 0.42 ng/ml . h (P < 0.001); 4.31 +/- 0.22, 5.57 +/- 0.36, 6.42 +/- 0.53 ng/ml . h (P < 0.001)]. ARR fell significantly whether calculated using DRC [sertraline, 13.7 +/- 2.2, 7.5 +/- 0.7, 6.8 +/- 0.7 (P < 0.001); escitalopram, 11.5 +/- 1.9, 8.0 +/- 1.1, 6.6 +/- 1.0 (P < 0.001)], or PRA [116.6 +/- 15.8, 108.4 +/- 15.6, 60.4 +/- 6.2 (P < 0.001); 61.2 +/- 8.1, 50.0 +/- 7.7, 45.6 +/- 6.0 (P < 0.01)]. CONCLUSION: Selective serotonin reuptake inhibitor antidepressants can significantly reduce ARR and therefore potentially increase the risk of false-negative results when screening for PAL. Further studies in hypertensive patients, including patients with confirmed PAL, are required. PMID- 21289247 TI - Postnatal decrease in circulating insulin-like growth factor-I and low brain volumes in very preterm infants. AB - CONTEXT: IGF-I and IGF binding protein-3 (IGFBP-3) are essential for growth and maturation of the developing brain. OBJECTIVE: The aim of this study was to evaluate the association between postnatal serum concentrations of IGF-I and IGFBP-3 and brain volumes at term in very preterm infants. DESIGN: Fifty-one infants with a mean (sd) gestational age (GA) of 26.4 (1.9) wk and birth weight (BW) of 888 (288) g were studied, with weekly blood sampling of IGF-I and IGFBP-3 from birth until 35 gestational weeks (GW) and daily calculation of protein and caloric intake. Magnetic resonance images obtained at 40 GW were segmented into total brain, cerebellar, cerebrospinal fluid, gray matter, and unmyelinated white matter volumes. MAIN OUTCOME MEASURES: We evaluated brain growth by measuring brain volumes using magnetic resonance imaging. RESULTS: Mean IGF-I concentrations from birth to 35 GW correlated with total brain volume, unmyelinated white matter volume, gray matter volume, and cerebellar volume [r = 0.55 (P < 0.001); r = 0.55 (P < 0.001); r = 0.44 (P = 0.002); and r = 0.58 (P < 0.001), respectively]. Similar correlations were observed for IGFBP-3 concentrations. Correlations remained after adjustment for GA, mean protein and caloric intakes, gender, severe brain damage, and steroid treatment. Protein and caloric intakes were not related to brain volumes. Infants with BW small for GA had lower mean concentrations of IGF-I (P = 0.006) and smaller brain volumes (P = 0.001-0.013) than infants with BW appropriate for GA. CONCLUSION: Postnatal IGF-I and IGFBP-3 concentrations are positively associated with brain volumes at 40 GW in very preterm infants. Normalization of the IGF-I axis, directly or indirectly, may support normal brain development in very preterm infants. PMID- 21289248 TI - Limited value of ovarian function markers following orthotopic transplantation of ovarian tissue after gonadotoxic treatment. AB - CONTEXT: In young women, some treatments for cancer or other conditions (such as sickle cell anemia) may give rise to primary ovarian insufficiency. Ovarian transplantation is one of the available options for fertility preservation, with highly variable pregnancy rates. OBJECTIVE: The objective of the study was to investigate markers of ovarian reserve and ovarian function in women up to 7 yr after orthotopic ovarian transplantation. Secondary objectives were to assess the relationship between markers of ovarian reserve and pregnancy rate along with the duration of ovarian function. DESIGN: This was a prospective cohort study in 10 women, with a mean follow-up of 2.5 yr. SETTING: The study was conducted at a university hospital in Brussels, Belgium. PATIENTS: Patients included 10 women who were about to receive or had previously received gonadotoxic treatment. In seven women cryopreservation of ovarian tissue was performed before starting treatment. Subsequently autografts were orthotopically transplanted in these women. Three women, who had already developed primary ovarian insufficiency due to treatment, underwent orthotopic transplantation of ovarian allograft tissue originating from their human leukocyte antigen-compatible sisters. MAIN OUTCOME MEASURES: Serum concentrations of FSH, LH, estradiol, inhibin B, and anti Mullerian hormone (AMH) were measured. RESULTS: On average, first menses took place after 4.7 months. Duration of graft functioning varied from 2 to more than 60 months. FSH concentrations remained elevated, whereas estradiol levels normalized and AMH was low to undetectable. Inhibin B varied among women and was not associated with the duration of ovarian function (hazard ratio 0.966, 95% confidence interval 0.881-1.059). Two spontaneous pregnancies occurred. Endocrine characteristics were not significantly different in these women. CONCLUSIONS: Low AMH and inhibin B concentrations may suggest decreased ovarian reserve in women after ovarian transplantation. AMH and inhibin B levels may not be associated with the duration of ovarian graft function or probability to achieve a pregnancy. PMID- 21289249 TI - Evaluation of ergocalciferol or cholecalciferol dosing, 1,600 IU daily or 50,000 IU monthly in older adults. AB - CONTEXT: Whether ergocalciferol (D(2)) and cholecalciferol (D(3)) are equally effective to increase and maintain serum 25-hydroxyvitamin D [25(OH)D] concentration is controversial. OBJECTIVE: The aim of the study was to evaluate the effect of daily and once monthly dosing of D(2) or D(3) on circulating 25(OH)D and serum and urinary calcium. DESIGN, SETTING AND PARTICIPANTS: In a university clinical research setting, 64 community dwelling adults age 65+ were randomly assigned to receive daily (1,600 IU) or once-monthly (50,000 IU) D(2) or D(3) for 1 yr. MAIN OUTCOME MEASURES: Serum 25(OH)D, serum calcium, and 24-h urinary calcium were measured at months 0, 1, 2, 3, 6, 9, and 12. Serum PTH, bone specific alkaline phosphatase, and N-telopeptide were measured at months 0, 3, 6, and 12. RESULTS: Serum 25(OH)D was less than 30 ng/ml in 40% of subjects at baseline; after 12 months of vitamin D dosing, levels in 19% of subjects (n = 12, seven receiving daily doses and five monthly doses) remained low, despite compliance of more than 91%. D(2) dosing increased 25(OH)D(2) but produced a decline (P < 0.0001) in 25(OH)D(3). Substantial between-individual variation in 25(OH)D response was observed for both D(2) and D(3). The highest 25(OH)D observed was 72.5 ng/ml. Vitamin D administration did not alter serum calcium, PTH, bone-specific alkaline phosphatase, N-telopeptide, or 24-h urine calcium. CONCLUSIONS: Overall, D(3) is slightly, but significantly, more effective than D(2) to increase serum 25(OH)D. One year of D(2) or D(3) dosing (1,600 IU daily or 50,000 IU monthly) does not produce toxicity, and 25(OH)D levels of less than 30 ng/ml persist in approximately 20% of individuals. Substantial between individual response to administered vitamin D(2) or D(3) is observed. PMID- 21289250 TI - Progestogen-only contraceptives and the risk of acute myocardial infarction: a meta-analysis. AB - CONTEXT: The association between combined oral contraceptives (OC) and the risk of myocardial infarction (MI) has been intensively studied, and conclusions are controversial. While progestogen-only contraceptives (POC) are commonly used worldwide, their impact on cardiovascular diseases is poorly investigated and remains unclear. OBJECTIVE: We carried out a meta-analysis based on EMBASE- and MEDLINE-referenced literature corresponding to OC marketed since 1960. METHODS: Eligible articles published in English language describing OC or POC use and MI outcome were reviewed, and relevant ones were extracted. All types of POC and route of administration were considered. RESULTS: Six case-control studies were identified. The combined odds ratio showed no increase in the MI risk with POC use (odds ratio = 1.07; 95% confidence interval, 0.62-1.84). This result was similar according to the route of administration, including implant, injectable, and oral POC. CONCLUSION: Data from observational studies suggest no increase in risk of MI with POC use. However, these results are based on limited data. Further investigations are needed, especially among women at high MI risk. PMID- 21289251 TI - A resveratrol and polyphenol preparation suppresses oxidative and inflammatory stress response to a high-fat, high-carbohydrate meal. AB - BACKGROUND: High-fat, high-carbohydrate (HFHC) meals are known to induce oxidative and inflammatory stress, an increase in plasma endotoxin concentrations, and an increase in the expression of suppressor of cytokine signaling-3 (SOCS-3). HYPOTHESIS: The intake of a nutritional supplement containing resveratrol and muscadine grape polyphenols reduces HFHC meal-induced oxidative and inflammatory stress and stimulates the activity of the antioxidant transcription factor, NF-E2-related factor-2 (Nrf-2), and its downstream targets. METHODS: Ten normal, healthy subjects were given a 930-kcal HFHC meal either with placebo or with the supplement. Indices of oxidative stress, inflammation, Nrf-2 binding activity, the concentrations of endotoxin (lipopolysaccharide) and lipoprotein binding protein (LBP), and the expression of toll-like receptor 4 (TLR-4), CD14, IL-1beta, TNFalpha, SOCS-3, Keap-1, NAD(P)H:quinone oxidoreductase 1 (NQO-1), and GST-P1 were measured. RESULTS: The intake of the supplement suppressed the meal-induced elevations of plasma endotoxin and LBP concentrations, the expression of p47(phox), TLR-4, CD14, SOCS-3, IL-1beta, and Keap-1, while enhancing Nrf-2 binding activity and the expression of NQO-1 and GST-P1 genes. CONCLUSION: A supplement containing resveratrol and muscadine polyphenols suppresses the increase in oxidative stress, lipopolysaccharide and LBP concentrations, and expression of TLR-4, CD14, IL-1beta and SOCS-3 in mononuclear cells after an HFHC meal. It also stimulates specific Nrf-2 activity and induces the expression of the related antioxidant genes, NQO-1 and GST-P1. These results demonstrate the acute antioxidant and antiinflammatory effects of resveratrol and polyphenolic compounds in humans in the postprandial state. PMID- 21289253 TI - Dissecting the workforce and workplace for clinical endocrinology, and the work of endocrinologists early in their careers. AB - CONTEXT: The United States lacks timely reliable mechanisms for assessing the professional work of subspecialty physicians. OBJECTIVE: The aim was to use early career members of The Endocrine Society as a model to estimate subspecialty physician involvement in patient care, teaching, research, and administration among clinical, academic, federal, and pharmaceutical/biotech workplaces and to assess the workforce for research within individual workplaces. METHODS: Physicians joining The Endocrine Society from 1991-2005 and residing in North America were invited to complete a Web-based survey. This report relies on 817 early-career endocrinologists or 29.6% of eligible respondents. RESULTS: Respondents from all types of workplaces engaged in patient care, teaching, research, and administration. The time committed to the four tasks, however, differed significantly among workplaces. Research (basic, translational, disease, patient, population, and prevention) was accomplished within all workplaces, but the scope and scale of investigative work was employer dependent. Recipients of National Institutes of Health K08/23 awards succeeded in receiving federal research project grants (P < 0.001). Respondents associated research with lowered incomes, a perception validated by an estimated drop in annual earnings of 2.8% per half-day spent on research (P < 0.001). Women in academic settings earned less than men (P < 0.01) and were less likely to occupy tenure-eligible positions (P < 0.01). CONCLUSIONS: Web-based surveys offer a simple tool for estimating the work of subspecialty physicians and provide a framework for improving biomedical investigation. Several interventions should be considered for endocrinology: recruit physicians from underrepresented demographic groups, increase K08/23 awards, incentivize investigative careers, and improve the national infrastructure for biomedical research. PMID- 21289254 TI - Effect of bariatric surgery-induced weight loss on SR-BI-, ABCG1-, and ABCA1 mediated cellular cholesterol efflux in obese women. AB - AIM: We tested the hypothesis that quantitative changes in high-density lipoprotein (HDL) particles weight loss induced by Roux-en-Y bypass (RYGBP) in morbidly obese subjects might be associated with improved functionality of these particles in the reverse cholesterol transport pathway. METHODS AND RESULTS: Thirty-four morbidly obese women were recruited and followed up before and 6 months after RYGBP. After surgery, along with a major weight loss (-20%; P < 0.0001), we observed a significant increase in HDL mass concentration (+14%; P < 0.04), reflecting a specific increase in large HDL2 subfraction levels (+42%; P < 0.01), whereas those of HDL3 remained unchanged. Cholesterol ester transfer protein activity decreased significantly (-15%; P < 0.0001). Efflux capacity of total plasma increased significantly via both scavenger receptor class B type I (SR-BI) (+58%; P < 0.0001) and ATP binding cassette G1 (ABCG1) (+26%; P < 0.0001) pathways. Such enhanced capacity resulted from increased capacity of HDL2 particles to mediate cholesterol efflux through the SR-BI pathway (+56%, P < 0.001) and from the increase plasma level of cholesteryl ester-rich HDL2 particles for the ABCG1 pathway. CONCLUSION: RYGBP-induced weight loss results in improvement in atherogenic lipid profile including a shift toward a more cardioprotective HDL subfraction profile. In addition, our in vitro studies demonstrated an increased in plasma efflux capacity via both SR-BI and ABCG1 after surgery. PMID- 21289252 TI - Inhibition of the Ras/Raf/MEK/ERK and RET kinase pathways with the combination of the multikinase inhibitor sorafenib and the farnesyltransferase inhibitor tipifarnib in medullary and differentiated thyroid malignancies. AB - PURPOSE: Ras/Raf/MAPK kinase/ERK and rearranged in transformation (RET) kinase pathways are important in thyroid cancer. We tested sorafenib, a B-Raf, RET, and vascular endothelial growth factor receptor kinase inhibitor, combined with tipifarnib, a farnesyltransferase inhibitor that inactivates Ras and other farnesylated proteins. PATIENTS AND METHODS: We treated 35 patients with differentiated thyroid cancer (DTC) and medullary thyroid cancer (MTC) in a phase I trial. Sorafenib and tipifarnib were given for 21 d with 7 d rest in each 28-d cycle. RESULTS: We enrolled 22 patients with metastatic DTC (16 papillary, five follicular, and one poorly differentiated) and 13 patients with MTC, of whom 15 with DTC and 10 with MTC reached first restaging. When tissue was available, eight of 15 DTC patients (53%) had B-Raf mutations; eight of 13 MTC (61.5%) patients had RET mutations. MTC partial response rate was 38% (five of 13) (duration = 9+, 12, 13, 16+, and 34+ months), stable disease of at least 6 months was 31% (four of 13). The DTC partial response rate was 4.5% (one of 22), and stable disease of at least 6 months was 36% (eight of 22). Median progression free survival for all 35 patients was 18 months (95% confidence interval, 14.6 to not reached months). Median overall survival has not been reached, with a median follow-up of 24 months with 80% overall survival. Grade 1-2 toxicities were mainly rash, fatigue, and diarrhea. The most common grade 3-4 toxicities were rash, rise in amylase/lipase, and fatigue. CONCLUSIONS: Inhibiting the Ras/Raf/MAPK kinase/ERK and RET kinase pathways with sorafenib and tipifarnib is well tolerated and active against thyroid cancer. PMID- 21289255 TI - Higher serum free testosterone concentration in older women is associated with greater bone mineral density, lean body mass, and total fat mass: the cardiovascular health study. AB - CONTEXT: The physiological importance of endogenous testosterone (T) in older women is poorly understood. OBJECTIVE: The aim of the study was to determine the association of higher total and free T levels with bone mineral density (BMD), lean body mass, and fat mass in elderly women. DESIGN: Total and free T were measured using sensitive assays in 232 community-dwelling women aged 67-94 yr who were enrolled in the Cardiovascular Health Study and had dual-energy x-ray absorptiometry scans. Cross-sectional analyses were performed to examine associations between total and free T and BMD and body composition. RESULTS: In adjusted models, total T was directly associated with BMD at the lumbar spine (P = 0.04) and hip (P = 0.001), but not body composition outcomes, in all women, and after excluding estrogen users and adjusting for estradiol (P = 0.04 and 0.01, respectively). Free T was positively related to hip BMD, lean body mass, and body fat (all P < 0.05), with more than 10% differences in each outcome between women at the highest and lowest ends of the free T range, with attenuation after excluding estrogen users and adjusting for estradiol. CONCLUSIONS: In the setting of the low estradiol levels found in older women, circulating T levels were associated with bone density. Women with higher free T levels had greater lean body mass, consistent with the anabolic effect of T, and, in contrast to men, greater fat mass. Mechanistic studies are required to determine whether a causal relationship exists between T, bone, and body composition in this population and the degree to which any T effects are estrogen-independent. PMID- 21289256 TI - Impaired CRH and urocortin expression and function in eutopic endometrium of women with endometriosis. AB - CONTEXT: Women with endometriosis have altered endometrial function. CRH and urocortin (Ucn) are neuropeptides produced by human endometrium and modulate endometrial decidualization. OBJECTIVE: To evaluate endometrial mRNA expression of CRH and Ucn, their role in in vitro decidualization of cultured human endometrial stromal cells (HESCs) in patients with endometriosis, and the role of CRH receptors (CHR-Rs). DESIGN: Obstetrics and Gynecology, University of Siena. PATIENTS: Endometrial specimens were obtained from patients with and without endometriosis. INTERVENTIONS: Endometrial biopsy obtained at both phases of menstrual cycle. In vitro decidualization of HESCs collected from endometriosis or control was done in the presence of CRH, Ucn, or CRH receptor type 1 (CRH-R1, antalarmin) or type 2 (CRH-R2, astressin 2b) antagonists. OUTCOME MEASURES: Endometrial mRNA expression of CRH and Ucn during endometrial cycle; prolactin, CRH-R1, and CRH-R2 mRNA expression during in vitro decidualization. RESULTS: In healthy women CRH and Ucn expression were significantly higher (P < 0.05) in secretory than in proliferative phase; no differences were observed in endometriotic women. During in vitro decidualization, prolactin mRNA expression and release in endometriosis was lower than in control (P < 0.001). CRH and Ucn were able to significantly increase (P < 0.01) prolactin release only in control group; moreover, in this group antalarmin reduced prolactin release (P < 0.01). CRH-R1 mRNA expression increased during in vitro decidualization of HESCs in control (P < 0.01) but not in endometriosis. CONCLUSIONS: Women with endometriosis show an impaired endometrial expression of CRH and Ucn mRNA, and these neuropeptides are no more active in modulating the in vitro decidualization of HESCs, associated with a reduced expression of CRH-R1 mRNA. PMID- 21289257 TI - Correlation of plasma copeptin and vasopressin concentrations in hypo-, iso-, and hyperosmolar States. AB - BACKGROUND: Copeptin, the C-terminal moiety of provasopressin, is cosecreted with vasopressin. Copeptin may be a useful parameter to characterize disorders of water homeostasis and can be readily measured in plasma or serum. However, it is unknown to date how circulating copeptin and vasopressin levels correlate at different plasma osmolalites. OBJECTIVE: To correlate plasma copeptin with plasma osmolality and vasopressin concentrations in healthy subjects during iso-, hypo-, and hyperosmolar states. METHODS: Plasma osmolalities, copeptin, and vasopressin levels were measured in 20 volunteers at baseline, after an oral water load, and during and after iv infusion of 3% saline. Correlation coefficients were determined between plasma osmolalites and copeptin and vasopressin concentrations, as well as between vasopressin and copeptin concentrations. RESULTS: Median plasma osmolalities decreased from 290 mOsm/kg (range, 284-302) at baseline to 281 (273-288) mOsm/kg after water load and rose to 301 (298-307) mOsm/kg after hypertonic saline. Median plasma copeptin concentrations decreased from 3.3 (1.1-36.4) pm at baseline to 2.0 (0.9-10.4) pm after water load and increased to 13.6 (3.7-43.3) pm after hypertonic saline. Vasopressin and copeptin concentrations correlated with plasma osmolality (Spearman's rank correlation coefficient 0.49 and 0.77, respectively). There was a close correlation of vasopressin and copeptin concentrations (Spearman's rank correlation coefficient 0.8). CONCLUSION: Plasma vasopressin and copeptin correlate strongly over a wide range of osmolalities in healthy individuals. Therefore, the measurement of copeptin, which remains stable for several days, is a useful alternative to vasopressin measurements and will likely facilitate the differential diagnosis of disorders of water metabolism. PMID- 21289258 TI - Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass. AB - CONTEXT: Denosumab treatment for 24 months increased bone mineral density (BMD) and reduced bone turnover markers (BTM) in postmenopausal women. OBJECTIVE: The aim was to determine the effects of prior denosumab or placebo injections on BMD, BTM, and safety over 24 months after treatment discontinuation. DESIGN: We conducted an off-treatment extension of a phase 3, randomized, double-blind, parallel-group study. PARTICIPANTS: A total of 256 postmenopausal women with a mean age of 59 yr and a mean lumbar spine T-score of -1.61 at randomization participated in the study. INTERVENTIONS: Participants received placebo or 60 mg denosumab every 6 months for 24 months, followed by 24 months off treatment. MAIN OUTCOME MEASURES: We measured the percentage changes in BMD and BTM, and evaluated safety. RESULTS: Of the 256 participants enrolled in the posttreatment phase, 87% completed the study. During 24 months of denosumab treatment, BMD increased (lumbar spine, 6.4%; total hip, 3.6%; 1/3 radius, 1.4%), and BTM decreased (serum C-terminal telopeptide of type 1 collagen, 63%; and N-terminal propeptide of type 1 procollagen, 47%), compared with placebo. After discontinuation, BMD declined, but the previously treated denosumab group maintained higher BMD than the previously treated placebo group at these sites (P <= 0.05). Final BMD at month 48 strongly correlated with month 0 BMD. After denosumab discontinuation, BTM increased above baseline within 3 months (serum C terminal telopeptide of type 1 collagen) or 6 months (N-terminal propeptide of type 1 procollagen) and returned to baseline by month 48. Adverse event rates during the off-treatment phase were similar between groups. CONCLUSIONS: In postmenopausal women with low BMD, the effects of 60 mg denosumab treatment for 24 months on BMD and BTM are reversible upon discontinuation, reflecting its biological mechanism of action. Residual BMD measurements remained above those of the group previously treated with placebo. PMID- 21289259 TI - Increased transactivation associated with SOX3 polyalanine tract deletion in a patient with hypopituitarism. AB - BACKGROUND AND AIMS: Correct gene dosage of SOX3 is critical for the development of the hypothalamo-pituitary axis. Both overdosage of SOX3, as a result of gene duplication, and loss of function resulting from expansion of the first polyalanine (PA) tract are associated with variable degrees of hypopituitarism, with or without mental retardation. The aim of this study was to further investigate the contribution of SOX3 in the etiology of hypopituitarism and the mechanisms involved in the phenotypic variability. METHODS: We screened 154 patients with congenital hypopituitarism and an undescended posterior pituitary for mutations in SOX3 and variability in the length of the first PA tract. In addition, 300 patients with variable septooptic dysplasia were screened for variability of the PA tract. RESULTS: We report a novel 18-base pair deletion (p.A243_A248del6, del6PA) in a female patient with hypopituitarism resulting in a 2-fold increase in transcriptional activation in vitro, compared with wild-type SOX3. We also identified a previously reported seven-alanine expansion (p.A240_A241ins7, +7PA) in two male siblings with isolated GH deficiency and a distinct phenotype, in addition to the nonsynonymous variant p.R5Q in an unrelated individual; this appears to have no functional effect on the protein. In contrast to +7PA, del6PA maintained its ability to repress beta-catenin mediated transcription in vitro. CONCLUSION: This is the first study to report that PA tract deletions associated with hypopituitarism have functional consequences in vitro, possibly due to increased activation of SOX3 target genes. In addition, we have expanded the phenotypic spectrum associated with PA tract expansion (+7PA) mutations to include panhypopituitarism or isolated GH deficiency, with or without mental retardation. PMID- 21289260 TI - Insulin- and leptin-mediated control of aquaglyceroporins in human adipocytes and hepatocytes is mediated via the PI3K/Akt/mTOR signaling cascade. AB - OBJECTIVE: Glycerol constitutes an important metabolite for the control of lipid accumulation and glucose homeostasis. The impact of obesity and obesity associated type 2 diabetes as well as the potential regulatory role of insulin and leptin on aquaglyceroporins (AQP) 3, 7, and 9 were analyzed. RESEARCH DESIGN AND METHODS: The tissue distribution and expression of AQP in biopsies of omental and sc adipose tissue as well as liver were analyzed in lean and obese Caucasian volunteers (n = 63). The effect of insulin (1, 10, and 100 nmol/liter) and leptin (0.1, 1, and 10 nmol/liter) on the expression of the glycerol channels was determined in vitro in human omental adipocytes and HepG2 hepatocytes. The translocation of AQP in response to insulin and isoproterenol was analyzed by immunocytochemistry. RESULTS: In addition to the well-known expression of AQP7 in adipose tissue, AQP3 and AQP9 were also expressed in both omental and sc adipose tissue. Obese type 2 diabetes patients showed higher expression of AQP in visceral adipose tissue and lower expression of AQP7 in sc adipose tissue and hepatic AQP9. The staining of AQP9 in the plasma membrane of adipocytes was reinforced by insulin, whereas isoproterenol induced the translocation of AQP3 and AQP7 from the lipid droplets to the plasma membrane. Insulin up-regulated all AQP, whereas leptin up-regulated AQP3 and down-regulated AQP7 and AQP9 in adipocytes and hepatocytes. These effects were abrogated by both the phosphatidylinositol 3-kinase inhibitor wortmannin and the mammalian target of rapamycin inhibitor rapamycin. CONCLUSIONS: Our findings show, for the first time, that insulin and leptin regulate the AQP through the phosphatidylinositol 3 kinase/Akt/mammalian target of rapamycin pathway in human visceral adipocytes and hepatocytes. AQP3 and AQP7 may facilitate glycerol efflux from adipose tissue while reducing the glycerol influx into hepatocytes via AQP9 to prevent the excessive lipid accumulation and the subsequent aggravation of hyperglycemia in human obesity. PMID- 21289261 TI - Progesterone prevents sleep disturbances and modulates GH, TSH, and melatonin secretion in postmenopausal women. AB - CONTEXT: A number of neuroactive progesterone metabolites produce sedative-like effects. However, the effects of progesterone administration on sleep are not well characterized. OBJECTIVE: To investigate the effects of a 3-wk progesterone administration on sleep architecture and multiple hormonal profiles. SUBJECTS: Eight healthy postmenopausal women, 48-74 yr old, without sleep complaints or vasomotor symptoms. None was on hormone replacement therapy. They did not take any medication for >= 2 months. DESIGN: Randomized, double-blind, placebo controlled study. For 3 wk, subjects took daily at 2300 h a capsule of either 300 mg of progesterone or placebo. Sleep was polygraphically recorded during the last two nights, and blood samples were obtained at 15-min intervals for 24 h. RESULTS: During the first night (no blood sampling), sleep was similar in both conditions. Under placebo, blood sampling procedure was associated with marked sleep disturbances, which were considerably reduced under progesterone treatment: mean duration of wake after sleep onset was 53% lower, slow-wave sleep duration almost 50% higher, and total slow-wave activity (reflecting duration and intensity of deep sleep) almost 45% higher under progesterone than under placebo (P <= 0.05). Nocturnal GH secretion was increased, and evening and nocturnal TSH levels were decreased under progesterone (P <= 0.05). CONCLUSIONS: Progesterone had no effect on undisturbed sleep but restored normal sleep when sleep was disturbed (while currently available hypnotics tend to inhibit deep sleep), acting as a "physiologic" regulator rather than as a hypnotic drug. Use of progesterone might provide novel therapeutic strategies for the treatment of sleep disturbances, in particular in aging where sleep is fragmented and of lower quality. PMID- 21289262 TI - Fertility and ovarian function in high-dose estrogen-treated tall women. AB - BACKGROUND/OBJECTIVE: High-dose estrogen treatment to reduce final height of tall girls has been shown to interfere with fertility. Ovarian function has not been studied. We therefore evaluated fertility and ovarian function in tall women who did or did not receive such treatment in adolescence. METHODS: This was a retrospective cohort study of 413 tall women aged 23-48 yr, of whom 239 women had been treated. A separate group of 126 fertile, normoovulatory volunteers aged 22 47 yr served as controls. RESULTS: Fertility was assessed in 285 tall women (157 treated, 128 untreated) who had attempted to conceive. After adjustment for age, treated women were at increased risk of experiencing subfertility [odds ratio (OR) 2.29, 95% confidence interval (CI) 1.38-3.81] and receiving infertility treatments (OR 3.44, 95% CI 1.76-6.73). Moreover, fecundity was notably affected because treated women had significantly reduced odds of achieving at least one live birth (OR 0.26, 95% CI 0.13-0.52). Remarkably, duration of treatment was correlated with time to pregnancy (r = 0.23, P = 0.008). Ovarian function was assessed in 174 tall women (119 treated, 55 untreated). Thirty-nine women (23%) exhibited a hypergonadotropic profile. After adjusting for age category, treated women had significantly higher odds of being diagnosed with imminent ovarian failure (OR 2.83, 95% CI 1.04-7.68). Serum FSH levels in these women were significantly increased, whereas antral follicle counts and serum anti-Mullerian hormone levels were decreased. CONCLUSION: High-dose estrogen-treated tall women are at risk of subfertility in later life. Their fecundity is significantly reduced. Treated women exhibit signs of accelerated ovarian aging with concomitant follicle pool depletion, which may be the basis of the observed subfertility. PMID- 21289263 TI - The effect of very-low-calorie diet on mRNA expression of inflammation-related genes in subcutaneous adipose tissue and peripheral monocytes of obese patients with type 2 diabetes mellitus. AB - CONTEXT: Low-grade inflammation links obesity, type 2 diabetes mellitus (T2DM), and cardiovascular diseases. OBJECTIVE: To explore the expression profile of genes involved in inflammatory pathways in adipose tissue and peripheral monocytes (PM) of obese patients with and without T2DM at baseline and after dietary intervention. DESIGN: Two-week intervention study with very-low-calorie diet (VLCD). SETTING: University hospital. PATIENTS: Twelve obese females with T2DM, 8 obese nondiabetic females (OB) and 15 healthy age-matched females. INTERVENTION: Two weeks of VLCD (2500 kJ/d). MAIN OUTCOME MEASURES: Metabolic parameters, circulating cytokines, hormones, and mRNA expression of 39 genes in sc adipose tissue (SCAT) and PM. RESULTS: Both T2DM and OB group had significantly increased serum concentrations of circulating proinflammatory factors (C-reactive protein, TNFalpha, IL-6, IL-8), mRNA expression of macrophage antigen CD68 and proinflammatory chemokines (CCL-2, -3, -7, -8, -17, -22) in SCAT and complementary chemokine receptors (CCR-1, -2, -3, -5) and other proinflammatory receptors (toll-like receptor 2 and 4, TNF receptor superfamily 1A and 1B, IL-6R) in PM, with OB group showing less pronounced chemoattracting and proinflammatory profile compared to T2DM group. In T2DM patients VLCD decreased body weight, improved metabolic profile, and decreased mRNA expression of up-regulated CCRs in PM and chemokines [CCL 8, chemokine (C-X-C motif) ligand 10] in SCAT. VLCD markedly increased mRNA expression of T-lymphocyte attracting chemokine CCL-17 in SCAT. CONCLUSION: Obese patients with and without T2DM have increased mRNA expression of chemotactic and proinflammatory factors in SCAT and expression of corresponding receptors in PM. Two weeks of VLCD significantly improved this profile in T2DM patients. PMID- 21289264 TI - Enhancer of zeste homolog 2 overexpression has a role in the development of anaplastic thyroid carcinomas. AB - CONTEXT: Enhancer of zeste homolog 2 (EZH2) is a histone lysine methyltransferase belonging to the polycomb group protein family. Overexpression of EZH2 has been found in several human malignancies including hematological and solid tumors. OBJECTIVES: In this study we investigated the expression levels of EZH2 and its polycomb group protein partners in thyroid carcinoma tissues with different degrees of malignancy to identify potential new therapeutic targets for anaplastic thyroid carcinoma (ATC). RESULTS: We show that high EZH2 expression levels are characteristic of undifferentiated ATC, whereas no significant changes were observed in well-differentiated papillary and follicular thyroid carcinomas as compared with normal thyroid. Knockdown of EZH2 in ATC cell lines results in cell growth inhibition, loss of anchorage-independent growth, migration, and invasion properties. Moreover, we demonstrate that EZH2 directly controls differentiation of ATC cells by silencing the thyroid specific transcription factor paired-box gene 8 (PAX8). CONCLUSIONS: EZH2 is specifically overexpressed in ATC, and it directly contributes to transcriptional silencing of PAX8 gene and ATC differentiation. PMID- 21289265 TI - Angiotensin-converting enzyme insertion/deletion polymorphism and severe hypoglycemia complicating type 2 diabetes: the Fremantle Diabetes Study. AB - AIMS/HYPOTHESES: The aim of this study was to determine whether the angiotensin converting enzyme (ACE) gene I/D polymorphisms independently predict severe hypoglycemia in community-dwelling type 2 patients. METHODS: Six hundred and two patients who were ACE genotyped at baseline and assessed in 1998 were followed up to the end of June 2006. Severe hypoglycemia was defined as that requiring documented health service use as the primary diagnosis. Cox proportional hazards modeling was used to determine the predictors of first episode and zero-inflated negative binomial regression modeling identified predictors of frequency. RESULTS: Forty-nine patients (8.1%) experienced 63 episodes of severe hypoglycemia. After adjusting for previously identified significant independent predictors of time to first episode, both ACE DD genotype and ACE inhibitor therapy, but not their interaction, added to the model [hazard ratio (95% confidence interval): 2.34 (1.29-4.26), P = 0.006, and 1.77 (0.99-3.13), P = 0.052, respectively]. Similarly, after adjusting for previously identified risk factors for multiple episodes of severe hypoglycemia, ACE DD genotype was independently associated with increased risk [incidence relative risk (95% confidence interval): 1.80 (1.00-3.24), P = 0.050]. CONCLUSIONS/INTERPRETATION: ACE DD genotype was associated with an approximately 2-fold increased risk of the first episode of severe hypoglycemia and its subsequent frequency in well characterized patients with type 2 diabetes. Consistent with previous case control studies, ACE inhibitor therapy was a weak predictor of severe hypoglycemia. ACE I/D genotyping might provide useful adjunctive prognostic information when intensive glycemic control measures are contemplated. PMID- 21289266 TI - The effect of gonadotropin withdrawal and stimulation with human chorionic gonadotropin on intratesticular androstenedione and DHEA in normal men. AB - INTRODUCTION: Concentrations of intratesticular (IT) testosterone (T) are known to be 100-200 times those of serum T; however, the IT concentrations of T's precursors, their testicular to serum gradients, gonadotropin dependence, and response to stimulation with human chorionic gonadotropin (hCG) have not been studied in detail. We hypothesized that serum and IT androstenedione (ADD) and IT dehydroepiandrosterone (DHEA) would be significantly suppressed by the administration of a GnRH antagonist and increased when stimulated by hCG, without a similar suppression of serum DHEA. METHODS: We suppressed gonadotropins in 23 normal men with the GnRH antagonist acyline and randomly assigned them to one of four doses of hCG, 0, 15, 60, or 125 IU sc every other day for 10 d. Blood and IT fluid for the measurement of serum and IT hormones were obtained at baseline and after 10 d of treatment. RESULTS: Baseline IT ADD [median (25th, 75th percentile)] was 629 (308, 860) nmol/liter, and IT DHEA was 564 (411, 879) nmol/liter, which were 175 and 27 times higher than their respective serum concentrations. IT ADD and IT DHEA were suppressed by 98 and 82%, respectively, by acyline and significantly increased with hCG administration. Likewise, serum ADD was suppressed by 50%, but serum DHEA was unchanged. DISCUSSION: ADD and DHEA are highly concentrated within the human testes compared with serum. Serum and IT ADD and IT DHEA are markedly suppressed with GnRH administration and stimulated by hCG, but serum DHEA is not, suggesting that most circulating DHEA is not of testicular origin. PMID- 21289267 TI - The Akt-specific inhibitor MK2206 selectively inhibits thyroid cancer cells harboring mutations that can activate the PI3K/Akt pathway. AB - CONTEXT: The phosphoinositide 3-kinase (PI3K)/Akt pathway is widely postulated to be an effective therapeutic target in thyroid cancer. OBJECTIVE: The aim of the study was to test the therapeutic potential of the novel Akt inhibitor MK2206 for thyroid cancer. DESIGN: We examined the effects of MK2206 on thyroid cancer cells with respect to the genotypes of the PI3K/Akt pathway. RESULTS: Proliferation of thyroid cancer cells OCUT1, K1, FTC133, C643, Hth7, and TPC1, which harbored PIK3CA, PTEN, Ras, or RET/PTC mutations that could activate the PI3K/Akt pathway, was potently inhibited by MK2206 with IC(50) values mostly below or around 0.5 MUm. In contrast, no potent inhibition by MK2206 was seen in most of the Hth74, KAT18, SW1736, WRO, and TAD2 cells that did not harbor mutations in the PI3K/Akt pathway. The inhibition efficacy was also genetic-selective. Specifically, the average inhibition efficacies were 59.2 +/- 11.3 vs. 36.4 +/- 8.8% (P = 0.005) at 1 MUm MK2206 and 64.4 +/- 11.5 vs. 38.5 +/- 18.9% (P = 0.02) at 3 MUm MK2206 for cells with mutations vs. cells without. The SW1736 cell, lacking mutations in the PI3K/Akt pathway, had minimal response to MK2206, but transfection with exogenous PIK3CA mutants, PIK3CA H1047R and E545K, significantly increased its sensitivity to MK2206. MK2206 also completely overcame the feedback activation of Akt from temsirolimus-induced mammalian target of rapamycin suppression, and the two inhibitors synergistically inhibited thyroid cancer cell growth. CONCLUSIONS: Our study demonstrates a genetic selectivity of MK2206 in inhibiting thyroid cancer cells by targeting the PI3K/Akt pathway, supporting a clinical trial in thyroid cancer. PMID- 21289268 TI - An endocrinologist's guide to the clock. AB - CONTEXT: It has long been recognized that a "biological clock" residing in the suprachiasmatic nucleus controls circadian or daily variations in physiological processes. Old observations are now being revisited after the discovery of the cellular mechanism of timekeeping, the molecular clock, an autoregulatory feedback loop of transcription factors that cycles over a period of approximately 24 h. Its functioning or breakdown impinges upon the physiology and pathophysiology of numerous systems, including the endocrine system and metabolism. Here we provide an introduction to those aspects of the clock most relevant to the endocrinologist. EVIDENCE ACQUISITION: Articles were identified by searching PubMed using the search terms "circadian" and "clock" and refining results to include articles relating to endocrinology and metabolism. EVIDENCE SYNTHESIS: We discuss current understanding of the mechanisms through which hormonal and metabolic axes fall under the influence of the circadian clock. Of particular interest is the complex interaction of genetic and environmental factors in determining health or disease states. CONCLUSIONS: Research into the molecular clock provides a novel window onto endocrine and metabolic disease. These advances present new avenues for diagnostic and therapeutic strategies. PMID- 21289269 TI - Neonatal hyperparathyroidism with a heterozygous calcium-sensing receptor (CASR) R185Q mutation: clinical benefit from cinacalcet. AB - Neonatal hyperparathyroidism can be caused by a heterozygous inactivating mutation in the calcium-sensing receptor. Calcimimetics, allosteric activators of the calcium-sensing receptor, may provide an effective means of reducing PTH secretion in such patients. OBJECTIVE/PATIENT: The objective of the study was to identify the molecular defect and to monitor the postnatal course of a 1-wk-old infant with elevated blood ionized calcium, serum PTH, and alkaline phosphatase and low calcium excretion. The parents were normocalcemic. METHODS: CASR gene mutation analysis was performed on genomic DNA of the proband and her parents. The infant was treated initially with pamidronate and then cinacalcet. RESULTS: A heterozygous mutation (R185Q, CGA > CAA) in exon 4 of the CASR gene was identified in the proband. The CASR gene of both parents was normal. At 1 wk of age, iv fluids and furosemide were initiated, but hypercalcemia, hyperparathyroidism, and low calcium excretion persisted. At 2 wk of age, a single iv dose of pamidronate resulted in hypocalcemia and further increase in PTH levels, but hypercalcemia recurred within 1 wk. At 3 wk of age, a single oral dose of cinacalcet resulted in decreased PTH levels at 2 h; blood-ionized calcium reached a nadir at 10 h. Three days later daily cinacalcet was initiated, resulting in normalization of ionized calcium. The suppression of serum PTH and reduction in total serum calcium was maintained long term. CONCLUSIONS: In neonatal hyperparathyroidism secondary to presumed de novo heterozygous CASR mutation, treatment with cinacalcet decreases PTH secretion and serum calcium levels and mitigates the need for parathyroidectomy. PMID- 21289270 TI - Osteoporosis medication and reduced mortality risk in elderly women and men. AB - CONTEXT: Osteoporotic fractures are associated with premature mortality. Antiresorptive treatment reduces refracture but mortality reduction is unclear. OBJECTIVE: The objective of the study was to examine the effect of osteoporosis treatment [bisphosphonates (BP), hormone therapy (HT), and calcium +/- vitamin D only (CaD)] on mortality risk. DESIGN: This was a prospective cohort study (April 1989 to May 2007). SETTING: The study was conducted with community-dwelling elderly (aged 60+ yr) subjects in Dubbo, a semiurban city, Australia. SUBJECTS: Subjects included 1223 and 819 women and men in the Dubbo Osteoporosis Epidemiology Study. MAIN OUTCOME MEASURE: Mortality according to treatment group was recorded. RESULTS: There were 325 (BP, n = 106; HT, n = 77; CaD, n = 142) women and 37 men (BP, n = 15; CaD, n = 22) on treatment. In women, mortality rates were lower with BP 0.8/100 person-years (0.4, 1.4) and HT 1.2/100 person years (0.7, 2.1) but not CaD 3.2/100 person-years (2.5, 4.1) vs. no treatment 3.5/100 person-years (3.1, 3.8). Accounting for age, fracture occurrence, comorbidities, quadriceps strength, and bone mineral density, mortality risk remained lower for women on BP [hazard ratio (HR) 0.3 (0.2, 0.6)] but not HT [HR 0.8 (0.4, 1.8)]. For 429 women with fractures, mortality risk was still reduced in the BP group [adjusted HR 0.3 (0.2, 0.7)], not accounted for by a reduction in subsequent fractures. In men, lower mortality rates were observed with BP but not CaD [BP 1.0/100 person-years (0.3, 3.9) and CaD 3.1/100 person-years (1.5, 6.6) vs. no treatment 4.3/100 person-years (3.9, 4.8)]. After adjustment, mortality was similar, although not significant [HR 0.5 (0.1, 2.0)]. CONCLUSIONS: Osteoporosis therapy appears to reduce mortality risk in women and possibly men. PMID- 21289271 TI - Humanizing animal models: a key to autoimmune diabetes treatment. AB - Preclinical evaluation of antibody-based immunotherapies for the treatment of type 1 diabetes (T1D) in animal models is often hampered by the fact that the human antibody drug does not cross-react with its mouse counterpart. In this issue of Science Translational Medicine, researchers describe a new mouse model that expresses the human isoform of a molecule targeted by T1D antibody therapies that are currently being tested in clinical trials--the human epsilon chain of the CD3 complex expressed on T cells. Anti-CD3 is capable of reducing insulin needs in individuals with recently diagnosed T1D; however, the precise underlying mechanisms of action and the minimal effective dose have been difficult to define. The new humanized mouse model will be instrumental in optimizing anti-CD3 based therapies and accelerating their clinical realization. PMID- 21289272 TI - Human CD3 transgenic mice: preclinical testing of antibodies promoting immune tolerance. AB - Monoclonal antibodies have proven to be potent agents to promote immunological tolerance in animal models of autoimmune disease and transplantation. However, optimal clinical application and pharmaceutical development have been limited by the species specificity of therapeutic antibodies, as well exemplified in the case of anti-CD3 antibodies. Compelling evidence in the nonobese diabetic (NOD) mouse, recently translated to clinical autoimmune insulin-dependent diabetes, demonstrates that a short CD3 antibody treatment effectively and durably controls disease progression. We established transgenic mice expressing the human epsilon chain of the CD3 complex bred onto the NOD background. These mice developed a high incidence of spontaneous autoimmune diabetes and harbored T cells sensitive both in vitro and in vivo to anti-human CD3 antibodies. Treatment of diabetic transgenic mice with otelixizumab, an anti-human CD3 antibody that has proven effective in the clinic, resulted in durable disease remission dependent on transferable T cell-mediated tolerance. This model should enable the evaluation of anti-human CD3 antibodies to determine their potential clinical utility. PMID- 21289273 TI - Readily available tissue-engineered vascular grafts. AB - Autologous or synthetic vascular grafts are used routinely for providing access in hemodialysis or for arterial bypass in patients with cardiovascular disease. However, some patients either lack suitable autologous tissue or cannot receive synthetic grafts. Such patients could benefit from a vascular graft produced by tissue engineering. Here, we engineer vascular grafts using human allogeneic or canine smooth muscle cells grown on a tubular polyglycolic acid scaffold. Cellular material was removed with detergents to render the grafts nonimmunogenic. Mechanical properties of the human vascular grafts were similar to native human blood vessels, and the grafts could withstand long-term storage at 4 degrees C. Human engineered grafts were tested in a baboon model of arteriovenous access for hemodialysis. Canine grafts were tested in a dog model of peripheral and coronary artery bypass. Grafts demonstrated excellent patency and resisted dilatation, calcification, and intimal hyperplasia. Such tissue engineered vascular grafts may provide a readily available option for patients without suitable autologous tissue or for those who are not candidates for synthetic grafts. PMID- 21289274 TI - Risk factors for syndesmotic and medial ankle sprain: role of sex, sport, and level of competition. AB - BACKGROUND: Syndesmotic and medial ankle sprains constitute up to 15% of all ankle sprains in athletic populations and can result in significant time lost to injury and long-term disability. PURPOSE: The objective of this study was to estimate the rate of syndesmotic and medial ankle sprain injuries and identify risk factors associated with these injuries within the physically active cadet population at the United States Military Academy (USMA). STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: The Cadet Illness and Injury Tracking System (CIITS) database at USMA was queried for all ankle injuries between 2005 and 2009. Sex, level of competition, and exposure to sport were among risk factors analyzed. RESULTS: Among 20 336 person-years, 1206 cadets sustained ankle sprain. Syndesmotic (6.7%) and medial (5.1%) ankle sprains had an incidence rate (IR) of 4.8 and 3.5 per 1000 person-years, respectively. Compared with women, men were 3 times more likely to experience medial ankle sprain (IR ratio [IRR] 3.37; 95% confidence interval [CI]: 1.05, 10.74], but there was no difference in rate of syndesmotic sprains by sex (IRR 1.06; 95% CI: 0.58, 1.95). Athletics accounted for 81% of syndesmotic sprains and 64% of medial sprains. Sprint football (52.3), team handball (men's, 34.7), soccer (men's, 30.5; women's, 6.5), and basketball (men's, 24.8; women's, 6.7) had the highest syndesmotic IR per 100 000 athlete exposures. Medial sprain IR was highest in men's rugby (16.6) and gymnastics (14.0). When analyzed by athlete-exposure, male intercollegiate athletes had a greater risk of syndesmotic sprain than their female counterparts (3.53; 95% CI: 1.26, 9.83). Furthermore, intercollegiate level of competition had an increased risk of syndesmotic sprain when compared with intramural level (IRR 2.41; 95% CI: 1.03, 5.65). CONCLUSION: Male athletes have an over threefold greater risk of medial ankle sprain. Male sex and higher level of competition are risk factors for syndesmotic ankle sprain during athletics. PMID- 21289275 TI - Effect of complications after minimally invasive surgical repair of acute achilles tendon ruptures: report on 211 cases. AB - BACKGROUND: Complications of acute Achilles tendon rupture treatment are considered to negatively influence outcome, but the relevance of these effects is largely unknown. PURPOSE: The Achilles Tendon Total Rupture Score (ATRS) was used to determine level of disability in patients with minimally invasive surgical Achilles tendon rupture repair with a complicated postoperative course. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: The charts of 340 consecutive patients treated for an acute Achilles tendon rupture by minimally invasive surgical repair were reviewed. Complications were categorized as rerupture, severe wound infection, sural nerve injury, and other. Level of disability was evaluated by the 10-item ATRS with a sum score of minimum 0 to maximum 100 points. RESULTS: A total of 211 patients returned a completed questionnaire: mean follow-up was 6.2 years (range, 3-10 years). Mean ATRS for all 211 patients was 84 (95% confidence interval: 82, 87). The mean ATRS for the 135 (64%) uncomplicated cases was 89 of 100 points, 71 points for the 17 (8%) patients with a rerupture (95% confidence interval: 63, 79; P < .0001), 79 points for the 41 patients (19%) with a sural nerve injury (95% confidence interval: 74, 85; P = .0008), and 75 points for the 17 patients (8%) with another complication (95% confidence interval: 67, 83; P = .001). Of these other complications, 13 patients (6%) suffered a wound-healing complication considered minor. Their average ATRS score was 80 points (95% confidence interval: 71, 88.7; P = .0445). One patient suffered a severe wound infection as well, scoring 28 of 100 points. Rerupture significantly increased the risk of quitting or changing sport participation on the long term. CONCLUSION: Long-term outcome after minimally invasive Achilles tendon rupture repair is excellent. Rerupture and severe wound infection are the most important complications with lasting negative effect on outcome. It justifies the use of rerupture as a relevant outcome measure in treatment evaluation. PMID- 21289276 TI - Sequential volume reduction with capsular plications: relationship between cumulative size of plications and volumetric reduction for multidirectional instability of the shoulder. AB - PURPOSE: To quantify the relationship between the amount of shoulder capsule imbricated with a simple stitch and the degree of glenohumeral volume reduction in a multidirectional instability model. Secondary purposes were to identify the number of arthroscopic plication stitches required to reduce the shoulder volume equal to that of an open lateral-based inferior capsular shift and to compare volume reductions between suture anchor and suture-only capsular plication stitches. STUDY DESIGN: Controlled laboratory study. METHODS: Twelve fresh-frozen cadaveric shoulders (mean age, 64.4 years) were dissected to the level of the rotator cuff. A viscous liquid was injected into each joint, and measurements were taken before and after six 1-cm arthroscopic capsular plication stitches were performed. The sizes of the capsular plications were measured to quantify the amount of capsule imbricated with each simple stitch. A repeated random intercept regression model was fitted for each outcome, with significance set at P = .05. RESULTS: There was a near-linear relationship, with each 1 cm of total plication equaling 10% volume reduction up to 4.0 cm. After this, each additional 1-cm plication stitch resulted in 2% to 6% more reduction (mean, 4%). Five simple plication stitches reduced the volume by 52% in the suture anchor group and 49% in the suture-only group. The suture anchor achieved 3% greater volumetric reduction than the suture-only plication stitches, but this effect was not statistically significant (P = .06). Conclusion/ CLINICAL RELEVANCE: A 1-cm capsular plication stitch results in a roughly 10% volume reduction of the glenohumeral joint. Five simple capsular plication stitches result in a volume reduction equivalent to an open lateral-based capsular shift. PMID- 21289277 TI - Long-term assessment of posterolateral ligament femoral-fibular reconstruction in chronic multiligament unstable knees. AB - BACKGROUND: The authors previously reported the initial results of a femoral fibular posterolateral reconstruction in which an Achilles tendon allograft was passed through a fibular tunnel adjacent to the anatomical fibular attachment site of the fibular collateral ligament and a femoral tunnel anterior and posterior to its femoral attachment site. PURPOSE: To compare the short-term results (mean, 3.5 years) to the long-term results (mean, 14 years) of posterolateral femoral-fibular knee ligament reconstructions in regard to restoration of posterolateral knee stability. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: The authors report on 21 patients who underwent a posterolateral femoral-fibular reconstruction after sustaining multiligament ruptures with chronic instability. The results were determined by a comprehensive knee examination, stress radiographs, standing posteroanterior radiographs, knee arthrometer testing, the Cincinnati Knee Rating System, and the International Knee Documentation Committee rating system. RESULTS: In the short-term analysis, the posterolateral reconstruction restored normal or nearly normal lateral joint opening and external tibial rotation according to International Knee Documentation Committee criteria in 16 of 21 patients (76%), whereas the other 5 were deemed early failures. Fourteen of these patients were followed 10.0 to 19.4 years postoperatively. Retention of normal or nearly normal lateral joint opening and external tibial rotation was found, and there were no significant differences between evaluations for symptoms, sports and daily activity functions, overall knee ratings, and knee ligament function. At the long-term follow-up evaluation, 71% had no symptoms with low-impact sports. However, concurrent arthritis affected 14% who had symptoms with sports (but no symptoms with daily activities) and 14% who had symptoms with daily activities. CONCLUSION: The long-term success rate of the femoral-fibular procedure in restoring posterolateral stability warrants consideration of this procedure, particularly in acute cases or when operative time is prolonged and a more simplified procedure is indicated. PMID- 21289278 TI - Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome. AB - Point mutations of the NADP(+)-dependent isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) occur early in the pathogenesis of gliomas. When mutated, IDH1 and IDH2 gain the ability to produce the metabolite (R)-2-hydroxyglutarate (2HG), but the downstream effects of mutant IDH1 and IDH2 proteins or of 2HG on cellular metabolism are unknown. We profiled >200 metabolites in human oligodendroglioma (HOG) cells to determine the effects of expression of IDH1 and IDH2 mutants. Levels of amino acids, glutathione metabolites, choline derivatives, and tricarboxylic acid (TCA) cycle intermediates were altered in mutant IDH1- and IDH2-expressing cells. These changes were similar to those identified after treatment of the cells with 2HG. Remarkably, N-acetyl-aspartyl-glutamate (NAAG), a common dipeptide in brain, was 50-fold reduced in cells expressing IDH1 mutants and 8.3-fold reduced in cells expressing IDH2 mutants. NAAG also was significantly lower in human glioma tissues containing IDH mutations than in gliomas without such mutations. These metabolic changes provide clues to the pathogenesis of tumors associated with IDH gene mutations. PMID- 21289279 TI - Inhibition of the interactions between eukaryotic initiation factors 4E and 4G impairs long-term associative memory consolidation but not reconsolidation. AB - Considerable evidence indicates that the general blockade of protein synthesis prevents both the initial consolidation and the postretrieval reconsolidation of long-term memories. These findings come largely from studies of drugs that block ribosomal function, so as to globally interfere with both cap-dependent and independent forms of translation. Here we show that intra-amygdala microinfusions of 4EGI-1, a small molecule inhibitor of cap-dependent translation that selectively disrupts the interaction between eukaryotic initiation factors (eIF) 4E and 4G, attenuates fear memory consolidation but not reconsolidation. Using a combination of behavioral and biochemical techniques, we provide both in vitro and in vivo evidence that the eIF4E-eIF4G complex is more stringently required for plasticity induced by initial learning than for that triggered by reactivation of an existing memory. PMID- 21289280 TI - Activity-dormancy transition in the cambial meristem involves stage-specific modulation of auxin response in hybrid aspen. AB - The molecular basis of short-day-induced growth cessation and dormancy in the meristems of perennial plants (e.g., forest trees growing in temperate and high latitude regions) is poorly understood. Using global transcript profiling, we show distinct stage-specific alterations in auxin responsiveness of the transcriptome in the stem tissues during short-day-induced growth cessation and both the transition to and establishment of dormancy in the cambial meristem of hybrid aspen trees. This stage-specific modulation of auxin signaling appears to be controlled via distinct mechanisms. Whereas the induction of growth cessation in the cambium could involve induction of repressor auxin response factors (ARFs) and down-regulation of activator ARFs, dormancy is associated with perturbation of the activity of the SKP-Cullin-F-box(TIR) (SCF(TIR)) complex, leading to potential stabilization of repressor auxin (AUX)/indole-3-acetic acid (IAA) proteins. Although the role of hormones, such as abscisic acid (ABA) and gibberellic acid (GA), in growth cessation and dormancy is well established, our data now implicate auxin in this process. Importantly, in contrast to most developmental processes in which regulation by auxin involves changes in cellular auxin contents, day-length-regulated induction of cambial growth cessation and dormancy involves changes in auxin responses rather than auxin content. PMID- 21289281 TI - Leading the dog of selection by its mutational nose. PMID- 21289282 TI - Reverse and flick: Hybrid locomotion in bacteria. PMID- 21289283 TI - RNAi screen of the protein kinome identifies checkpoint kinase 1 (CHK1) as a therapeutic target in neuroblastoma. AB - Neuroblastoma is a childhood cancer that is often fatal despite intense multimodality therapy. In an effort to identify therapeutic targets for this disease, we performed a comprehensive loss-of-function screen of the protein kinome. Thirty kinases showed significant cellular cytotoxicity when depleted, with loss of the cell cycle checkpoint kinase 1 (CHK1/CHEK1) being the most potent. CHK1 mRNA expression was higher in MYC-Neuroblastoma-related (MYCN) amplified (P < 0.0001) and high-risk (P = 0.03) tumors. Western blotting revealed that CHK1 was constitutively phosphorylated at the ataxia telangiectasia response kinase target site Ser345 and the autophosphorylation site Ser296 in neuroblastoma cell lines. This pattern was also seen in six of eight high-risk primary tumors but not in control nonneuroblastoma cell lines or in seven of eight low-risk primary tumors. Neuroblastoma cells were sensitive to the two CHK1 inhibitors SB21807 and TCS2312, with median IC(50) values of 564 nM and 548 nM, respectively. In contrast, the control lines had high micromolar IC(50) values, indicating a strong correlation between CHK1 phosphorylation and CHK1 inhibitor sensitivity (P = 0.0004). Furthermore, cell cycle analysis revealed that CHK1 inhibition in neuroblastoma cells caused apoptosis during S-phase, consistent with its role in replication fork progression. CHK1 inhibitor sensitivity correlated with total MYC(N) protein levels, and inducing MYCN in retinal pigmented epithelial cells resulted in CHK1 phosphorylation, which caused growth inhibition when inhibited. These data show the power of a functional RNAi screen to identify tractable therapeutical targets in neuroblastoma and support CHK1 inhibition strategies in this disease. PMID- 21289284 TI - Ammonia synthons for the multicomponent assembly of complex gamma-lactams. AB - The synthesis of gamma-lactams that are unsubstituted at the 1-position (nitrogen) as well as their subsequent N-functionalization is reported. A recently discovered four-component reaction (4CR) is employed with either an ammonia precursor or a protected form of ammonia that can be deprotected in a subsequent synthetic step. These methods represent the first multicomponent assembly of complex lactam structures that are unsubstituted at nitrogen. In addition, two methods for the introduction of nitrogen substituents that are not possible through the original 4CR are reported. X-ray crystallographic analysis of representative structures reveals conformational changes in the core structure that will enable future deployment of this chemistry in the design and synthesis of diverse collections of lactams suitable for the discovery of new biological probes. PMID- 21289285 TI - Angiotensin II-induced vascular endothelial dysfunction through RhoA/Rho kinase/p38 mitogen-activated protein kinase/arginase pathway. AB - Enhanced vascular arginase activity impairs endothelium-dependent vasorelaxation by decreasing l-arginine availability to endothelial nitric oxide (NO) synthase, thereby reducing NO production. Elevated angiotensin II (ANG II) is a key component of endothelial dysfunction in many cardiovascular diseases and has been linked to elevated arginase activity. We determined signaling mechanisms by which ANG II increases endothelial arginase function. Results show that ANG II (0.1 MUM, 24 h) elevates arginase activity and arginase I expression in bovine aortic endothelial cells (BAECs) and decreases NO production. These effects are prevented by the arginase inhibitor BEC (100 MUM). Blockade of ANG II AT(1) receptors or transfection with small interfering RNA (siRNA) for Galpha12 and Galpha13 also prevents ANG II-induced elevation of arginase activity, but siRNA for Galphaq does not. ANG II also elevates active RhoA levels and induces phosphorylation of p38 MAPK. Inhibitors of RhoA activation (simvastatin, 0.1 MUM) or Rho kinase (ROCK) (Y-27632, 10 MUM; H1152, 0.5 MUM) block both ANG II-induced elevation of arginase activity and phosphorylation of p38 MAPK. Furthermore, pretreatment of BAECs with p38 inhibitor SB-202190 (2 MUM) or transfection with p38 MAPK siRNA prevents ANG II-induced increased arginase activity/expression and maintains NO production. Additionally, inhibitors of p38 MAPK (SB-203580, 5 MUg.kg(-1).day(-1)) or arginase (ABH, 8 mg.kg(-1).day(-1)) or arginase gene knockout in mice prevents ANG II-induced vascular endothelial dysfunction and associated enhancement of arginase. These results indicate that ANG II increases endothelial arginase activity/expression through Galpha12/13 G proteins coupled to AT(1) receptors and subsequent activation of RhoA/ROCK/p38 MAPK pathways leading to endothelial dysfunction. PMID- 21289286 TI - S1P2 receptor regulation of sphingosine-1-phosphate effects on conventional outflow physiology. AB - Elevated intraocular pressure is the main risk factor in primary open-angle glaucoma, involving an increased resistance to aqueous humor outflow in the juxtacanalicular region of the conventional outflow pathway which includes the trabecular meshwork (TM) and the inner wall of Schlemm's canal (SC). Previously, sphingosine-1-phosphate (S1P) was shown to decrease outflow facility in porcine and human eyes, thus increasing outflow resistance and intraocular pressure. Owing to S1P's known effect of increasing barrier function in endothelial cells and the robust expression of the S1P1 receptor on the inner wall of SC, we hypothesized that S1P1 receptor activation promotes junction formation and decreases outflow facility. The effects of subtype-specific S1P receptor compounds were tested in human and porcine whole-eye perfusions and human primary cultures of SC and TM cells to determine the receptor responsible for S1P effects on outflow resistance. The S1P1-specific agonist SEW2871 failed to both mimic S1P effects in paired human eye perfusions, as well as increase myosin light chain (MLC) phosphorylation in cell culture, a prominent outcome in S1P-treated SC and TM cells. In contrast, the S1P2 antagonist JTE-013, but not the S1P1 or S1P1,3 antagonists, blocked the S1P-promoted increase in MLC phosphorylation. Moreover, JTE-013 prevented S1P-induced decrease in outflow facility in perfused human eyes (P < 0.05, n = 6 pairs). Similarly, porcine eyes perfused with JTE-013 + S1P did not differ from eyes with JTE-013 alone (P = 0.53, n = 3). These results demonstrate that S1P2 , and not S1P1 or S1P3, receptor activation increases conventional outflow resistance and is a potential target to regulate intraocular pressure. PMID- 21289287 TI - Protein composition and function of red and white skeletal muscle mitochondria. AB - Red and white muscles are faced with very different energetic demands. However, it is unclear whether relative mitochondrial protein expression is different between muscle types. Mitochondria from red and white porcine skeletal muscle were isolated with a Percoll gradient. Differences in protein composition were determined using blue native (BN)-PAGE, two-dimensional differential in gel electrophoresis (2D DIGE), optical spectroscopy, and isobaric tag for relative and absolute quantitation (iTRAQ). Complex IV and V activities were compared using BN-PAGE in-gel activity assays, and maximal mitochondrial respiration rates were assessed using pyruvate (P) + malate (M), glutamate (G) + M, and palmitoyl carnitine (PC) + M. Without the Percoll step, major cytosolic protein contamination was noted for white mitochondria. Upon removal of contamination, very few protein differences were observed between red and white mitochondria. BN PAGE showed no differences in the subunit composition of Complexes I-V or the activities of Complexes IV and V. iTRAQ analysis detected 358 mitochondrial proteins, 69 statistically different. Physiological significance may be lower: at a 25% difference, 48 proteins were detected; at 50%, 14 proteins were detected; and 3 proteins were detected at a 100%. Thus any changes could be argued to be physiologically modest. One area of difference was fat metabolism where four beta oxidation enzymes were ~25% higher in red mitochondria. This was correlated with a 40% higher rate of PC+M oxidation in red mitochondria compared with white mitochondria with no differences in P+M and G+M oxidation. These data suggest that metabolic demand differences between red and white muscle fibers are primarily matched by the number of mitochondria and not by significant alterations in the mitochondria themselves. PMID- 21289288 TI - Tropomyosin variants describe distinct functional subcellular domains in differentiated vascular smooth muscle cells. AB - Tropomyosin (Tm) is known to be an important gatekeeper of actin function. Tm isoforms are encoded by four genes, and each gene produces several variants by alternative splicing, which have been proposed to play roles in motility, proliferation, and apoptosis. Smooth muscle studies have focused on gizzard smooth muscle, where a heterodimer of Tm from the alpha-gene (Tmsm-alpha) and from the beta-gene (Tmsm-beta) is associated with contractile filaments. In this study we examined Tm in differentiated mammalian vascular smooth muscle (dVSM). Liquid chromatography-tandem mass spectrometry (LC MS/MS) analysis and Western blot screening with variant-specific antibodies revealed that at least five different Tm proteins are expressed in this tissue: Tm6 (Tmsm-alpha) and Tm2 from the alpha-gene, Tm1 (Tmsm-beta) from the beta-gene, Tm5NM1 from the gamma-gene, and Tm4 from the delta-gene. Tm6 is by far most abundant in dVSM followed by Tm1, Tm2, Tm5NM1, and Tm4. Coimmunoprecipitation and coimmunofluorescence studies demonstrate that Tm1 and Tm6 coassociate with different actin isoforms and display different intracellular localizations. Using an antibody specific for cytoplasmic gamma-actin, we report here the presence of a gamma-actin cortical cytoskeleton in dVSM cells. Tm1 colocalizes with cortical cytoplasmic gamma-actin and coprecipitates with gamma-actin. Tm6, on the other hand, is located on contractile bundles. These data indicate that Tm1 and Tm6 do not form a classical heterodimer in dVSM but rather describe different functional cellular compartments. PMID- 21289289 TI - Full-length cardiac Na+/Ca2+ exchanger 1 protein is not phosphorylated by protein kinase A. AB - The cardiac Na(+)/Ca(2+) exchanger 1 (NCX1) is an important regulator of intracellular Ca(2+) homeostasis and cardiac function. Several studies have indicated that NCX1 is phosphorylated by the cAMP-dependent protein kinase A (PKA) in vitro, which increases its activity. However, this finding is controversial and no phosphorylation site has so far been identified. Using bioinformatic analysis and peptide arrays, we screened NCX1 for putative PKA phosphorylation sites. Although several NCX1 synthetic peptides were phosphorylated by PKA in vitro, only one PKA site (threonine 731) was identified after mutational analysis. To further examine whether NCX1 protein could be PKA phosphorylated, wild-type and alanine-substituted NCX1-green fluorescent protein (GFP)-fusion proteins expressed in human embryonic kidney (HEK)293 cells were generated. No phosphorylation of full-length or calpain- or caspase-3 digested NCX1-GFP was observed with purified PKA-C and [gamma-(32)P]ATP. Immunoblotting experiments with anti-PKA substrate and phosphothreonine-specific antibodies were further performed to investigate phosphorylation of endogenous NCX1. Phospho-NCX1 levels were also not increased after forskolin or isoproterenol treatment in vivo, in isolated neonatal cardiomyocytes, or in total heart homogenate. These data indicate that the novel in vitro PKA phosphorylation site is inaccessible in full-length as well as in calpain- or caspase-3 digested NCX1 protein, suggesting that NCX1 is not a direct target for PKA phosphorylation. PMID- 21289290 TI - Modulation of sarcoplasmic reticulum Ca2+ release in skeletal muscle expressing ryanodine receptor impaired in regulation by calmodulin and S100A1. AB - In vitro, calmodulin (CaM) and S100A1 activate the skeletal muscle ryanodine receptor ion channel (RyR1) at submicromolar Ca(2+) concentrations, whereas at micromolar Ca(2+) concentrations, CaM inhibits RyR1. One amino acid substitution (RyR1-L3625D) has previously been demonstrated to impair CaM binding and regulation of RyR1. Here we show that the RyR1-L3625D substitution also abolishes S100A1 binding. To determine the physiological relevance of these findings, mutant mice were generated with the RyR1-L3625D substitution in exon 74, which encodes the CaM and S100A1 binding domain of RyR1. Homozygous mutant mice (Ryr1(D/D)) were viable and appeared normal. However, single RyR1 channel recordings from Ryr1(D/D) mice exhibited impaired activation by CaM and S100A1 and impaired CaCaM inhibition. Isolated flexor digitorum brevis muscle fibers from Ryr1(D/D) mice had depressed Ca(2+) transients when stimulated by a single action potential. However, during repetitive stimulation, the mutant fibers demonstrated greater relative summation of the Ca(2+) transients. Consistently, in vivo stimulation of tibialis anterior muscles in Ryr1(D/D) mice demonstrated reduced twitch force in response to a single action potential, but greater summation of force during high-frequency stimulation. During repetitive stimulation, Ryr1(D/D) fibers exhibited slowed inactivation of sarcoplasmic reticulum Ca(2+) release flux, consistent with increased summation of the Ca(2+) transient and contractile force. Peak Ca(2+) release flux was suppressed at all voltages in voltage-clamped Ryr1(D/D) fibers. The results suggest that the RyR1 L3625D mutation removes both an early activating effect of S100A1 and CaM and delayed suppressing effect of CaCaM on RyR1 Ca(2+) release, providing new insights into CaM and S100A1 regulation of skeletal muscle excitation-contraction coupling. PMID- 21289291 TI - Hypoxia inhibits hepcidin expression in HuH7 hepatoma cells via decreased SMAD4 signaling. AB - Hepcidin negatively regulates systemic iron homeostasis in response to inflammation and elevated serum iron. Conversely, hepcidin expression is diminished in response to hypoxia, oxidative stress, and increased erythropoietic demand, though the molecular intermediates involved are incompletely understood. To address this, we have investigated hypoxic hepcidin regulation in HuH7 hepatoma cells either cultured alone or cocultured with activated THP-1 macrophages. HuH7 hepcidin mRNA expression was determined using quantitative polymerase chain reaction (Q-PCR). Hepcidin promoter activity was measured using luciferase reporter constructs containing a 0.9 kb fragment of the wild-type human hepcidin promoter, and constructs containing mutations in bone morphogenetic protein (BMP)/SMAD4, signal transducer and activator of transcription 3 (STAT3), CCAAT/enhancer-binding protein (C/EBP), and E-box responsive elements. Hepatic expression of bone morphogenetic proteins BMP2 and BMP6 and the BMP inhibitor noggin was determined using Q-PCR, and the protein expression of hemojuvelin (HJV), pSMAD 1/5/8, and SMAD4 was determined by western blotting. Following exposure to hypoxia or H(2)O(2), hepcidin mRNA expression and promoter activity increased in HuH7 cells monocultures but were decreased in HuH7 cells cocultured with THP-1 macrophages. This repression was attenuated by mutation of the BMP/SMAD4-response element, suggesting that modulation of SMAD signaling mediated the response to hypoxia. No changes in hepatocyte BMP2, BMP6 or noggin mRNA, or protein expression of HJV or pSMAD 1/5/8 were detected. However, treatment with hypoxia caused a marked decrease in nuclear and cytosolic SMAD4 protein and SMAD4 mRNA expression in cocultured HuH7 cells. Together these data indicate that hypoxia represses hepcidin expression through inhibition of BMP/SMAD signaling. PMID- 21289292 TI - BAX supports the mitochondrial network, promoting bioenergetics in nonapoptotic cells. AB - The dual functionality of the tumor suppressor BAX is implied by the nonapoptotic functions of other members of the BCL-2 family. To explore this, mitochondrial metabolism was examined in BAX-deficient HCT-116 cells as well as primary hepatocytes from BAX-deficient mice. Although mitochondrial density and mitochondrial DNA content were the same in BAX-containing and BAX-deficient cells, MitoTracker staining patterns differed, suggesting the existence of BAX dependent functional differences in mitochondrial physiology. Oxygen consumption and cellular ATP levels were reduced in BAX-deficient cells, while glycolysis was increased. These results suggested that cells lacking BAX have a deficiency in the ability to generate ATP through cellular respiration. This conclusion was supported by detection of reduced citrate synthase activity in BAX-deficient cells. In nonapoptotic cells, a portion of BAX associated with mitochondria and a sequestered, protease-resistant form was detected. Inhibition of BAX with small interfering RNAs reduced intracellular ATP content in BAX-containing cells. Expression of either full-length or COOH-terminal-truncated BAX in BAX-deficient cells rescued ATP synthesis and oxygen consumption and reduced glycolytic activity, suggesting that this metabolic function of BAX was not dependent upon its COOH-terminal helix. Expression of BCL-2 in BAX-containing cells resulted in a subsequent loss of ATP measured, implying that, even under nonapoptotic conditions, an antagonistic interaction exists between the two proteins. These findings infer that a basal amount of BAX is necessary to maintain energy production via aerobic respiration. PMID- 21289293 TI - Src kinase pathway is involved in NFAT5-mediated S100A4 induction by hyperosmotic stress in colon cancer cells. AB - S100A4 is associated with the progression of many types of cancers as well as several nonmalignant conditions. However, how it is regulated by intracellular signaling and/or at the transcriptional level has not been extensively studied. We recently demonstrated that S100A4 is partially regulated by nuclear factor in activated T cell 5 (NFAT5) downstream of integrin alpha6beta4. NFAT5 is a mammalian osmotic regulator. To study the regulation of S100A4 by NFAT5 in a more readily inducible model, colon cancer cells were subjected to hyperosmotic stress. We found that S100A4 is induced in a subset of colon cancer cell lines, and the ability to induce S100A4 depends on the methylation status of S100A4. The osmotic stress response elements were identified in the first intron region of S100A4 by S100A4 luciferase reporter assays. Depletion of NFAT5 by small interfering RNA abolished S100A4 induction. Furthermore, chromatin immunoprecipitation assays showed that NFAT5 is induced to bind to the first intron region. Inhibition of Src kinase pathways reduced S100A4 induction by affecting NFAT5 transactivation and protein levels. The 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to study the function of S100A4 induction in colon cancer cells under the condition of hyperosmotic stress; the results suggest that S100A4 induction contributes to cell survival. In conclusion, this study demonstrates that hyperosmotic stress induces S100A4 through NFAT5, and Src and chromatin remodeling are involved. In addition, the induction of S100A4 contributes to cell survival. Given that the gastrointestinal tract is periodically exposed to hyperosmotic stress, this study may uncover a novel signaling pathway that could contribute to GI cancer progression. PMID- 21289294 TI - ERK and Akt signaling pathways function through parallel mechanisms to promote mTORC1 signaling. AB - The mammalian target of rapamycin (mTOR) is a protein kinase that, when present in a complex referred to as mTOR complex 1 (mTORC1), acts as an important regulator of growth and metabolism. The activity of the complex is regulated through multiple upstream signaling pathways, including those involving Akt and the extracellular-regulated kinase (ERK). Previous studies have shown that, in part, Akt and ERK promote mTORC1 signaling through phosphorylation of a GTPase activator protein (GAP), referred to as tuberous sclerosis complex 2 (TSC2), that acts as an upstream inhibitor of mTORC1. In the present study we extend the earlier studies to show that activation of the Akt and ERK pathways acts in a synergistic manner to promote mTORC1 signaling. Moreover, we provide evidence that the Akt and ERK signaling pathways converge on TSC2, and that Akt phosphorylates residues on TSC2 distinct from those phosphorylated by ERK. The results also suggest that leucine-induced stimulation of mTORC1 signaling occurs through a mechanism distinct from TSC2 and the Akt and ERK signaling pathways. Overall, the results are consistent with a model in which Akt and ERK phosphorylate distinct sites on TSC2, leading to greater repression of its GAP activity, and consequently a magnified stimulation of mTORC1 signaling, when compared with either input alone. The results further suggest that leucine acts through a mechanism distinct from TSC2 to stimulate mTORC1 signaling. PMID- 21289295 TI - A histidine-rich motif mediates mitochondrial localization of ZnT2 to modulate mitochondrial function. AB - Female reproductive tissues such as mammary glands, ovaries, uterus, and placenta are phenotypically dynamic, requiring tight integration of bioenergetic and apoptotic mechanisms. Mitochondrial zinc (Zn) pools have emerged as a central player in regulating bioenergetics and apoptosis. Zn must first be imported into mitochondria to modulate mitochondrion-specific functions; however, mitochondrial Zn import mechanisms have not been identified. Here we documented that the Zn transporter ZnT2 is associated with the inner mitochondrial membrane and acts as an auxiliary Zn importer into mitochondria in mammary cells. We found that attenuation of ZnT2 expression significantly reduced mitochondrial Zn uptake and total mitochondrial Zn pools. Moreover, expression of a ZnT2-hemagglutinin (HA) fusion protein was localized to mitochondria and significantly increased Zn uptake and mitochondrial Zn pools, directly implicating ZnT2 in Zn import into mitochondria. Confocal microscopy of truncated and point mutants of ZnT2-green fluorescent protein (GFP) fusion proteins revealed a histidine-rich motif ((51)HHXH(54)) in the NH(2) terminus that is important for mitochondrial targeting of ZnT2. More importantly, the expansion of mitochondrial Zn pools by ZnT2 overexpression significantly reduced ATP biogenesis and mitochondrial oxidation concurrent with increased apoptosis, suggesting a functional role for ZnT2-mediated Zn import into mitochondria. These results identify the first Zn transporter directly associated with mitochondria and suggest that unique secretory tissues such as the mammary gland require novel mechanisms to modulate mitochondrion-specific functions. PMID- 21289296 TI - A lipid-modified estrogen derivative that treats breast cancer independent of estrogen receptor expression through simultaneous induction of autophagy and apoptosis. AB - It is a challenge to develop a universal single drug that can treat breast cancer at single- or multiple-stage complications, yet remains nontoxic to normal cells. The challenge is even greater when breast cancer-specific, estrogen-based drugs are being developed that cannot act against multistaged breast cancer complications owing to the cells differential estrogen receptor (ER) expression status and their possession of drug-resistant and metastatic phenotypes. We report here the development of a first cationic lipid-conjugated estrogenic derivative (ESC8) that kills breast cancer cells independent of their ER expression status. This ESC8 molecule apparently is nontoxic to normal breast epithelial cells, as well as to other noncancer cells. ESC8 induces apoptosis through an intrinsic pathway in ER-negative MDA-MB-231 cells. In addition, ESC8 treatment induces autophagy in these cells by interfering with the mTOR activity. This is the first example of an estrogen structure-based molecule that coinduces apoptosis and autophagy in breast cancer cells. Further in vivo study confirms the role of this molecule in tumor regression. Together, our results open new perspective of breast cancer chemotherapy through a single agent, which could provide the therapeutic benefit across all stages of breast cancer. PMID- 21289297 TI - The incorporation of 5-fluorouracil into RNA affects the ribonucleolytic activity of the exosome subunit Rrp6. AB - 5-Fluorouracil (5FU) is a fluoropyrimidine used for the treatment of solid tumors. 5FU is a precursor of dTTP and UTP during biogenesis, and it interferes with both DNA and RNA metabolism. The RNA exosome, a multisubunit complex with ribonucleolytic activity, has been identified as one of the targets of 5FU in yeast. Studies in human cells have shown that the catalytic subunit of the nuclear exosome, Rrp6, is specifically targeted. Here, we have investigated the direct effect of 5FU on the activity of Rrp6 in Drosophila S2 cells, and we have identified two aspects of Rrp6 function that are altered by 5FU. First, gel filtration analysis revealed that the repertoire of multimolecular complexes that contain Rrp6 is modified by exposure to 5FU, which is consistent with the proposal that incorporation of 5FU into RNA leads to the sequestration of Rrp6 in ribonucleoprotein complexes. Second, the incorporation of 5FU into RNA renders the RNA less susceptible to degradation by Rrp6, as shown by Rrp6 activity assays in vitro. Our results imply that aberrant transcripts synthesized in 5FU-treated cells cannot be turned over efficiently by the surveillance machinery. Together with previous results on the mechanisms of action of 5FU, our findings suggest that the cytotoxicity of 5FU at the RNA level is the result of at least three different effects: the increased levels of retroviral transcripts with mutagenic potential, the reduced synthesis of ribosomes, and the inhibition of the nuclear RNA surveillance pathways. Drugs that reinforce any of these effects may boost the cytotoxicity of 5FU. PMID- 21289298 TI - Rural/urban variations in diabetes self-care and quality of care in a national sample of US adults with diabetes. AB - PURPOSE: The purpose of this study was to examine differences in diabetes self care and provider-based quality-of-care indicators between rural and urban dwellers in a nationally representative sample of adults with diabetes. METHODS: Data were analyzed on 52,817 individuals with type 2 diabetes from the 2007 Behavioral Risk Factor Surveillance Survey. Rural and urban residence was based on metropolitan statistical area. Self-care behaviors (nutrition, physical activity, self-monitoring) and quality-of-care indicators (clinical visits, glycemic control, preventive measures) were self-reported. Logistic regression analyses were done using STATA 10 to assess the independent effect of rural/urban residence on self-care and each quality measure and to account for the complex survey design. RESULTS: Rural residents comprised 21% of the sample and were less likely to receive diabetes education (57% vs 51%, P < .001). The final adjusted model showed that foot self-checks (odds ratio, 1.42; 95% confidence interval, 1.27-1.59) and blood glucose testing at least once daily (odds ratio, 1.14; 95% confidence interval, 1.02-1.26) were significantly higher among rural individuals. Provider-based quality of care was not significantly different by rural/urban residence. CONCLUSION: Contrary to what has been reported, there were no significant differences in diabetes quality of care between rural and urban dwellers. In addition, rural dwellers appeared to have better self-care behaviors than urban dwellers. Further research is needed to clarify the reasons for these findings. PMID- 21289299 TI - Risk of lymphoproliferative malignancy in relation to small intestinal histopathology among patients with celiac disease. AB - BACKGROUND: Celiac disease is associated with an increased risk of malignant lymphomas. The risk of lymphoproliferative malignancies in patients with small intestinal inflammation without villous atrophy and in patients with latent celiac disease is unknown. METHODS: We performed a cohort study using duodenal and jejunal biopsy data that were collected from all 28 Swedish pathology departments (July 1969 to February 2008). We identified two population-based cohorts composed of 28,989 individuals with biopsy-verified celiac disease (villous atrophy, Marsh stage 3) and 13,140 individuals with small intestinal inflammation without villous atrophy (Marsh 1 + 2) and a regional cohort of 3711 individuals with latent celiac disease (positive celiac disease serology and normal mucosa). Cancer data were obtained by linkage to the National Cancer Registry. We used Cox regression to estimate hazard ratios (HRs) for lymphoproliferative malignancy and any solid cancer among the three cohorts compared with a total of 227,911 age- and sex-matched reference individuals. RESULTS: Although biopsy-verified celiac disease and intestinal inflammation were associated with lymphoproliferative malignancy (for celiac disease, HR = 2.82; 95% confidence interval [CI] = 2.36 to 3.37, n = 193; for inflammation, HR = 1.81; 95% CI = 1.42 to 2.31, n = 89), latent celiac disease was not associated with lymphoproliferative malignancy (HR = 0.97; 95% CI = 0.44 to 2.14, n = 7). The absolute rates of lymphoproliferative malignancies among persons with celiac disease, small intestinal inflammation, and latent celiac disease were 70.3 per 100,000 person-years, 83.4 per 100,000 person-years, and 28.0 per 100,000 person years, respectively. Compared with individuals with celiac disease, individuals with small intestinal inflammation or latent celiac disease were at a statistically significantly lower risk of lymphoproliferative malignancy. Risk of any solid cancer was not increased beyond the first year of follow-up in any cohort. Celiac disease was associated with Hodgkin lymphoma and both T-cell and B cell non-Hodgkin lymphomas. CONCLUSION: The risk of lymphoproliferative malignancy in celiac disease is dependent on small intestinal histopathology, with no increased risk in latent celiac disease. PMID- 21289300 TI - Re: Association of meat and fat intake with liver disease and hepatocellular carcinoma in the NIH-AARP cohort. PMID- 21289301 TI - Coronin 1-mediated naive T cell survival is essential for the development of autoimmune encephalomyelitis. AB - Autoimmune encephalomyelitis is a disease of the CNS that can develop when an initial peripheral inflammatory stimulus is followed by infiltration and reactivation of T lymphocytes in the CNS. We report a crucial role for coronin 1, which is essential for maintenance of the naive T cell pool, for the development of murine experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. In the absence of coronin 1, immunization with myelin oligoglycoprotein (MOG(35-55)) peptide largely failed to induce EAE symptoms, despite normal mobilization of leukocyte subsets in the blood, as well as effector cytokine expression comparable with wild-type T cells on polyclonal stimulation. Susceptibility of coronin 1-deficient mice to EAE induction was restored by transfer of wild-type CD4(+) T cells, suggesting that the observed resistance of coronin 1-deficient mice to EAE development is T cell intrinsic. Importantly, although coronin 1-deficient regulatory T cells (Tregs) showed a suppressor activity comparable with wild-type Tregs, Treg depletion failed to restore EAE development in coronin 1-deficient animals. These results suggest a hitherto unrecognized role of naive T cells in the development of autoimmune encephalomyelitis and reveal coronin 1 as a crucial modulator of EAE induction. PMID- 21289302 TI - Human TMEM30a promotes uptake of antitumor and bioactive choline phospholipids into mammalian cells. AB - Antitumor alkylphospholipids initiate apoptosis in transformed HL-60 and Jurkat cells while sparing their progenitors. 1-O-Alkyl-2-carboxymethyl-sn-glycero-3 phosphocholine (Edelfosine) like other short-chained phospholipids--inflammatory platelet-activating factor (PAF) and apoptotic oxidatively truncated phospholipids--are proposed to have intracellular sites of action, yet a conduit for these choline phospholipids into mammalian cells is undefined. Edelfosine is also accumulated by Saccharomyces cerevisiae in a process requiring the membrane protein Lem3p, and the human genome contains a Lem3p homolog TMEM30a. We show that import of choline phospholipids into S. cerevisiae DeltaLem3 is partially reconstituted by human TMEM30a and by Lem3p-TMEM30a chimeras, showing the proteins are orthologous. TMEM30a-GFP chimeras expressed in mammalian cells localized in plasma membranes, as well as internal organelles, and ectopic TMEM30a expression promoted uptake of exogenous choline and ethanolamine phospholipids. Short hairpin RNA knockdown of TMEM30a reduced fluorescent choline phospholipid and [(3)H]PAF import. This knockdown also reduced mitochondrial depolarization from exogenous Edelfosine or the mitotoxic oxidatively truncated phospholipid azelaoyl phosphatidylcholine, and the knockdown reduced apoptosis in response to these two phospholipids. These results show that extracellular choline phospholipids with short sn-2 residues can have intracellular roles and sites of metabolism because they are transport substrates for a TMEM30a phospholipid import system. Variation in this mechanism could limit sensitivity to short chain choline phospholipids such as Edelfosine, PAF, and proapoptotic phospholipids. PMID- 21289303 TI - Local inactivation of sphingosine 1-phosphate in lymph nodes induces lymphopenia. AB - Sphingosine 1-phosphate (S1P) initiates T and B cell exit from lymphoid tissues by activating the S1P(1) receptor on lymphocytes. To define the mechanistic details of this ligand-receptor interaction, the biological activity of the S1P blocking Ab Sphingomab was investigated. Treatment of mice with Sphingomab resulted in blood B and T cell lymphopenia. Although Sphingomab blocked S1P(1) mediated calcium flux and receptor downregulation by S1P in vitro, plasma from Sphingomab-treated mice demonstrated a 4-fold increase in S1P concentration and largely retained its stimulating activity on S1P receptors. Plasma-borne S1P was obviously not sufficiently inactivated by Sphingomab to account for the observed lymphopenia. Therefore, we addressed the local S1P-blocking activity of Sphingomab in spleen and peripheral lymph nodes (pLNs) as a potential cause of PBL depletion. Transwell chemotaxis assays revealed the migration of freshly isolated splenocytes, but not pLN cells to S1P. However, chemotaxis of pLN cells was regained after culture in S1P-low medium, and pLN cells isolated from Sphingomab-treated mice also revealed enhanced chemotaxis to S1P, indicating substantial local inactivation of S1P in pLN after Sphingomab treatment. We conclude that treatment with the S1P-blocking Ab Sphingomab induces lymphopenia by inactivating S1P locally in pLN and not systemically in plasma. Consequently, the presence of local S1P amounts in secondary lymphoid organs contributes to B and T cell egress. PMID- 21289304 TI - OX40 complexes with phosphoinositide 3-kinase and protein kinase B (PKB) to augment TCR-dependent PKB signaling. AB - T lymphocyte activation requires signal 1 from the TCR and signal 2 from costimulatory receptors. For long-lasting immunity, growth and survival signals imparted through the Akt/protein kinase B (PKB) pathway in activated or effector T cells are important, and these can be strongly influenced by signaling from OX40 (CD134), a member of the TNFR superfamily. In the absence of OX40, T cells do not expand efficiently to Ag, and memory formation is impaired. How most costimulatory receptors integrate their signals with those from Ag through the TCR is not clear, including whether OX40 directly recruits PKB or molecules that regulate PKB. We show that OX40 after ligation by OX40L assembled a signaling complex that contained the adapter TNFR-associated factor 2 as well as PKB and its upstream activator phosphoinositide 3-kinase (PI3K). Recruitment of PKB and PI3K were dependent on TNFR-associated factor 2 and on translocation of OX40 into detergent-insoluble membrane lipid microdomains but independent of TCR engagement. However, OX40 only resulted in strong phosphorylation and functional activation of the PI3K-PKB pathway when Ag was recognized. Therefore, OX40 primarily functions to augment PKB signaling in T cells by enhancing the amount of PI3K and PKB available to the TCR. This highlights a quantitative role of this TNFR family second signal to supplement signal 1. PMID- 21289305 TI - Computational and experimental analysis reveals a requirement for eosinophil derived IL-13 for the development of allergic airway responses in C57BL/6 mice. AB - Eosinophils are found in the lungs of humans with allergic asthma, as well as in the lungs of animals in models of this disease. Increasing evidence suggests that these cells are integral to the development of allergic asthma in C57BL/6 mice. However, the specific function of eosinophils that is required for this event is not known. In this study, we experimentally validate a dynamic computational model and perform follow-up experimental observations to determine the mechanism of eosinophil modulation of T cell recruitment to the lung during development of allergic asthma. We find that eosinophils deficient in IL-13 were unable to rescue airway hyperresponsiveness, T cell recruitment to the lungs, and Th2 cytokine/chemokine production in DeltadblGATA eosinophil-deficient mice, even if Th2 cells were present. However, eosinophil-derived IL-13 alone was unable to rescue allergic asthma responses in the absence of competence of other IL-13 producing cells. We further computationally investigate the role of other cell types in the production of IL-13, which led to the various predictions including early and late pulses of IL-13 during airway hyperresponsiveness. These experiments suggest that eosinophils and T cells have an interdependent relationship, centered on IL-13, which regulates T cell recruitment to the lung and development of allergic asthma. PMID- 21289306 TI - Development of tumor-infiltrating CD8+ T cell memory precursor effector cells and antimelanoma memory responses are the result of vaccination and TGF-beta blockade during the perioperative period of tumor resection. AB - A main goal of cancer immunology research is the formation of Ag-specific memory T cell immunity capable of activation upon tumor re-encounter. The requirements necessary to overcome the inhibitory signals present in the tumor microenvironment and form such memory T cell responses are unknown. In contrast to previous studies targeting tumors expressing highly immunogenic model Ags, we demonstrate that alleviating tumor-induced suppression along with vaccination against authentic Ags during the perioperative period provides long-lasting protection against a highly suppressive and poorly immunogenic melanoma. In this study, we employed DNA vaccination with an immunologically optimized mouse melanoma-shared Ag, Trp1ee/ng, combined with systemic TGF-beta blockade during the perioperative period of primary tumor resection, to confer protection against B16 melanoma, and against JBRH, an independently derived melanoma unrelated to B16. Importantly, we demonstrate that correlative to memory responses, perioperative immunotherapy increases the formation of tumor-infiltrating and tumor-reactive CD8(+) T cells expressing low levels of the transcription factor T bet, defined as memory precursor effector cells. We show that conditions for an immunologically fertile environment are met when TGF-beta blockade and vaccination are applied during the perioperative period of primary tumor resection. These findings address limitations of current CD8(+) T cell immunotherapies against cancer by generating effective CD8(+) T cell memory recall responses. PMID- 21289307 TI - Lentiviral gene transfer regenerates hematopoietic stem cells in a mouse model for Mpl-deficient aplastic anemia. AB - Thpo/Mpl signaling plays an important role in the maintenance of hematopoietic stem cells (HSCs) in addition to its role in megakaryopoiesis. Patients with inactivating mutations in Mpl develop thrombocytopenia and aplastic anemia because of progressive loss of HSCs. Yet, it is unknown whether this loss of HSCs is an irreversible process. In this study, we used the Mpl knockout (Mpl(-/-)) mouse model and expressed Mpl from newly developed lentiviral vectors specifically in the physiologic Mpl target populations, namely, HSCs and megakaryocytes. After validating lineage-specific expression in vivo using lentiviral eGFP reporter vectors, we performed bone marrow transplantation of transduced Mpl(-/-) bone marrow cells into Mpl(-/-) mice. We show that restoration of Mpl expression from transcriptionally targeted vectors prevents lethal adverse reactions of ectopic Mpl expression, replenishes the HSC pool, restores stem cell properties, and corrects platelet production. In some mice, megakaryocyte counts were atypically high, accompanied by bone neo-formation and marrow fibrosis. Gene-corrected Mpl(-/-) cells had increased long-term repopulating potential, with a marked increase in lineage(-)Sca1(+)cKit(+) cells and early progenitor populations in reconstituted mice. Transcriptome analysis of lineage(-)Sca1(+)cKit(+) cells in Mpl-corrected mice showed functional adjustment of genes involved in HSC self-renewal. PMID- 21289308 TI - Evi1 represses PTEN expression and activates PI3K/AKT/mTOR via interactions with polycomb proteins. AB - Evi1 (ecotropic viral integration site 1) is essential for proliferation of hematopoietic stem cells and implicated in the development of myeloid disorders. Particularly, high Evi1 expression defines one of the largest clusters in acute myeloid leukemia and is significantly associated with extremely poor prognosis. However, mechanistic basis of Evi1-mediated leukemogenesis has not been fully elucidated. Here, we show that Evi1 directly represses phosphatase and tensin homologue deleted on chromosome 10 (PTEN) transcription in the murine bone marrow, which leads to activation of AKT/mammalian target of rapamycin (mTOR) signaling. In a murine bone marrow transplantation model, Evi1 leukemia showed modestly increased sensitivity to an mTOR inhibitor rapamycin. Furthermore, we found that Evi1 binds to several polycomb group proteins and recruits polycomb repressive complexes for PTEN down-regulation, which shows a novel epigenetic mechanism of AKT/mTOR activation in leukemia. Expression analyses and ChIPassays with human samples indicate that our findings in mice models are recapitulated in human leukemic cells. Dependence of Evi1-expressing leukemic cells on AKT/mTOR signaling provides the first example of targeted therapeutic modalities that suppress the leukemogenic activity of Evi1. The PTEN/AKT/mTOR signaling pathway and the Evi1-polycomb interaction can be promising therapeutic targets for leukemia with activated Evi1. PMID- 21289309 TI - RNAi screen of the druggable genome identifies modulators of proteasome inhibitor sensitivity in myeloma including CDK5. AB - The molecular target(s) cooperating with proteasome inhibition in multiple myeloma (MM) remain unknown. We therefore measured proliferation in MM cells transfected with 13 984 small interfering RNAs in the absence or presence of increasing concentrations of bortezomib. We identified 37 genes, which when silenced, are not directly cytotoxic but do synergistically potentiate the growth inhibitory effects of bortezomib. To focus on bortezomib sensitizers, genes that also sensitized MM to melphalan were excluded. When suppressed, the strongest bortezomib sensitizers were the proteasome subunits PSMA5, PSMB2, PSMB3, and PSMB7 providing internal validation, but others included BAZ1B, CDK5, CDC42SE2, MDM4, NME7, RAB8B, TFE3, TNFAIP3, TNK1, TOP1, VAMP2, and YY1. The strongest hit CDK5 also featured prominently in pathway analysis of primary screen data. Cyclin dependent kinase 5 (CDK5) is expressed at high levels in MM and neural tissues with relatively low expression in other organs. Viral shRNA knockdown of CDK5 consistently sensitized 5 genetically variable MM cell lines to proteasome inhibitors (bortezomib and carfilzomib). Small-molecule CDK5 inhibitors were demonstrated to synergize with bortezomib to induce cytotoxicity of primary myeloma cells and myeloma cell lines. CDK5 regulation of proteasome subunit PSMB5 was identified as a probable route to sensitization. PMID- 21289310 TI - Increased HIV-specific CD8+ T-cell cytotoxic potential in HIV elite controllers is associated with T-bet expression. AB - Recent data suggest that CD8+ T-cell effector activity is an important component in the control of HIV replication in elite controllers (ECs). One critical element of CD8+ T-cell effector function and differentiation is the T-box transcription factor T-bet. In the present study, we assessed T-bet expression, together with the effector proteins perforin, granzyme A (Grz A), granzyme B (Grz B), and granulysin, in HIV-specific CD8+ T cells from ECs (n = 20), chronically infected progressors (CPs; n = 18), and highly active antiretroviral therapy (HAART)-suppressed individuals (n = 19). Compared with the other cohort groups, HIV-specific CD8+ T cells among ECs demonstrated a superior ability to express perforin and Grz B, but with no detectable difference in the levels of Grz A or granulysin. We also observed higher levels of T-bet in HIV-specific CD8+ T cells from ECs, with an ensuing positive correlation between T-bet and levels of both perforin and Grz B. Moreover, HIV-specific CD8+ T cells in ECs up-regulated T-bet to a greater extent than CPs after in vitro expansion, with concomitant up regulation of perforin and Grz B. These results suggest that T-bet may play an important role in driving effector function, and its modulation may lead to enhanced effector activity against HIV. PMID- 21289311 TI - Comment on "Therapeutic targeting of Syk in autoimmune diabetes". PMID- 21289312 TI - Glatiramer acetate treatment of multiple sclerosis: an immunological perspective. AB - Glatiramer acetate (GA) has been used as an immunomodulatory agent for the treatment of relapsing-remitting multiple sclerosis (MS) in the United States since 1996. It is currently one of two first-line agents for use in the treatment of relapsing-remitting MS. GA was the first agent to be used in the treatment of MS that was developed using the animal model of MS called experimental autoimmune encephalomyelitis. In this commentary, we examine the development of GA as a treatment for MS and discuss its mechanism of action as suggested by recent studies using modern immunologic methods. PMID- 21289313 TI - NK cells and immune "memory". AB - Immunological memory is a hallmark of the adaptive immune system. However, the ability to remember and respond more robustly against a second encounter with the same pathogen has been described in organisms lacking T and B cells. Recently, NK cells have been shown to mediate Ag-specific recall responses in several different model systems. Although NK cells do not rearrange the genes encoding their activating receptors, NK cells experience a selective education process during development, undergo a clonal-like expansion during virus infection, generate long-lived progeny (i.e., memory cells), and mediate more efficacious secondary responses against previously encountered pathogens--all characteristics previously ascribed only to T and B cells in mammals. This review describes past findings leading up to these new discoveries, summarizes the evidence for and characteristics of NK cell memory, and discusses the attempts and future challenges to identify these long-lived memory NK cell populations in humans. PMID- 21289314 TI - Apolipoprotein E and peptide mimetics modulate inflammation by binding the SET protein and activating protein phosphatase 2A. AB - The molecular mechanism by which apolipoprotein E (apoE) suppresses inflammatory cytokine and NO production is unknown. Using an affinity purification approach, we found that peptide mimetics of apoE, derived from its receptor binding domain residues 130-150, bound to the SET protein, which is a potent physiological inhibitor of protein phosphatase 2A (PP2A). Both holo-apoE protein and apoE mimetic peptides bound to the C-terminal region of SET, which is then associated with an increase in PP2A-mediated phosphatase activity. As physiological substrates for PP2A, the LPS-induced phosphorylation status of signaling MAPK and Akt kinase is reduced following treatment with apoE-mimetic peptides. On the basis of our previous report, in which apoE-mimetic peptides reduced I-kappaB kinase and NF-kappaB activation, we also demonstrate a mechanism for reduced production of inducible NO synthase protein and its NO product. These data provide evidence for a novel molecular mechanism by which apoE and apoE-mimetic peptides antagonize SET, thereby enhancing endogenous PP2A phosphatase activity, which reduces levels of phosphorylated kinases, signaling, and inflammatory response. PMID- 21289315 TI - Retraction: The IL-15Ralpha chain signals through association with Syk in human B cells. PMID- 21289316 TI - Retraction: Mast cells express novel functional IL-15 receptor alpha isoforms. PMID- 21289317 TI - Retraction: Extracellular ATP induces cytokine expression and apoptosis through P2X7 receptor in murine mast cells. PMID- 21289318 TI - Infectious Diseases Society unveils MRSA treatment guidelines. PMID- 21289319 TI - Heart groups release partial update to atrial fibrillation guidelines. PMID- 21289320 TI - Concierge desk, call center help military outpatient pharmacy improve service. PMID- 21289321 TI - Common mistakes of pharmacy job seekers. PMID- 21289322 TI - Iloperidone: Does it have a meaningful place in therapy? PMID- 21289324 TI - Iloperidone: A new drug for the treatment of schizophrenia. AB - PURPOSE: The pharmacology, pharmacokinetics, pharmacogenomics, clinical efficacy, and safety and tolerability profile of iloperidone for the treatment of schizophrenia are reviewed. SUMMARY: Iloperidone is an atypical antipsychotic that recently received marketing approval from the Food and Drug Administration for the acute treatment of schizophrenia. Iloperidone is a pure antagonist and the first antipsychotic to have pharmacogenomic studies indicate predictive response based on six identified polymorphisms. Pharmacokinetic studies have determined that iloperidone is well absorbed orally, with a bioavailability of 96%. Phase II and III clinical trials have shown iloperidone to improve symptoms of schizophrenia, based on the Positive and Negative Symptom Scale, Brief Psychiatric Rating Scale, and Clinical Global Impressions-Severity scores (p < 0.05). Iloperidone has established tolerability at recommended dosages of up to 24 mg daily; however, the dosage must be slowly increased over seven days, and twice-daily administration is required to avoid orthostatic hypotension. The most common adverse effects associated with iloperidone were dizziness, dry mouth, fatigue, nasal congestion, orthostatic hypotension, somnolence, tachycardia, and weight gain. Safety studies have also found that iloperidone increases the risk of Q-Tc interval prolongation, similar to that seen with ziprasidone. Minimal changes in glucose and lipid abnormalities were seen in short-term (4- and 6 week) and long-term (52-week) studies, indicating a low chance of metabolic disturbance with iloperidone. CONCLUSION: Iloperidone may be a viable and safe option for the treatment of schizophrenia in adult patients, especially for patients who cannot tolerate other antipsychotic agents. However, iloperidone lacks a clear benefit over other antipsychotic agents. PMID- 21289325 TI - Calcium supplementation in postmenopausal women to reduce the risk of osteoporotic fractures. AB - PURPOSE: The most recent large-scale studies evaluating the effects of calcium supplementation for prevention of osteoporosis-related fractures in postmenopausal women are reviewed. SUMMARY: Osteoporosis is a very common disease associated with significant morbidity and mortality. For many years, use of a calcium supplement (preferably in combination with vitamin D to optimize calcium absorption) has been recommended for postmenopausal women to decrease fracture risk. However, five large-scale, randomized, controlled trials have called into question the benefits of calcium in reducing fracture risk, and four of the studies indicated that calcium users may be at increased risk for renal stones and gastrointestinal problems. However, all five studies had one or more important limitations, including possible selection bias and study participants' relatively high baseline calcium intake and generally low adherence to treatment regimens. Moreover, in some of the studies, vitamin D was not included in the treatment protocol or was not used at levels sufficient to optimize calcium absorption. In three of the five trials, subgroup analysis of the most treatment adherent participants indicated significant reductions in osteoporotic fracture risk with calcium supplement use. CONCLUSION: Results of recent clinical trials indicate that calcium supplementation does not significantly reduce fracture risk in postmenopausal women. However, evidence from the same studies suggests that beneficial effects on fracture risk may be seen in women who are adherent to therapy. Postmenopausal women should continue calcium supplementation to reduce osteoporosis risk. PMID- 21289326 TI - Eradication of Pseudomonas aeruginosa in an adult patient with cystic fibrosis. AB - PURPOSE: The use of a continuous infusion of a beta-lactam antibiotic in combination with high-dose, extended-interval amino-glycoside therapy for eradication of Pseudomonas aeruginosa in an adult patient with cystic fibrosis (CF) is reported. SUMMARY: Testing of an expectorated sputum sample taken during routine evaluation of a 32-year-old woman with CF isolated P. aeruginosa; the patient's medical record indicated no prior episodes of P. aeruginosa colonization. In an initial attempt to eradicate the organism, the woman received outpatient therapy with oral ciprofloxacin twice daily combined with an aminoglycoside (tobramycin solution) by nebulization twice daily. After a culture four weeks later again isolated P. aeruginosa, the patient was hospitalized, and i.v. antimicrobial therapy was initiated. The inpatient treatment regimen consisted of continuous-infusion cefepime 6 g (100 mg/kg/24 hr) and i.v. tobramycin 700 mg (12 mg/kg/24 hr), with both drugs administered via a peripherally inserted central catheter, for two weeks. A bronchoalveolar lavage fluid culture performed two months after completion of the i.v. antimicrobial regimen, as well as several sputum cultures obtained during the subsequent three years, tested negative for P. aeruginosa. CONCLUSION: The administration of continuous-infusion cefepime and high-dose, extended-interval tobramycin led to the successful eradication of P. aeruginosa in an adult patient with CF. PMID- 21289327 TI - Intraoperative anaphylaxis associated with bacitracin irrigation. AB - PURPOSE: Three cases of severe anaphylactic reactions associated with prophylactic bacitracin irrigation during cardiac procedures are describe. SUMMARY: In all three cases, bacitracin irrigation was concentrated at 50,000 units per 10 mL and applied directly to the pacemaker pocket. The first case described involved an 88-year-old woman undergoing pacemaker insertion to correct bradycardia. Within 10 minutes of bacitracin irrigation, she lost consciousness and developed apnea, diffuse erythema, and hypotension. In the second case, a 69 year-old man receiving a cardiac resynchronization defibrillator implant developed apnea, hypotension, decreased pulse, erythema of the extremities, and a maculopapular rash within 15 minutes of bacitracin administration. The third case involved an 83-year-old woman undergoing a dual pacemaker battery change; she became agitated and was noted to have hypotension, anxiety, and other symptoms 8 minutes after bacitracin irrigation. Two of the three cases involved apnea and loss of consciousness, and all three patients developed erythema or rash. Application of the adverse drug reaction probability scale developed by Naranjo et al. yielded a score of 3 (indicating a possible adverse reaction to bacitracin) in all three cases. As in other published reports of anaphylactic reactions associated with bacitracin irrigation, development of hypotension within 15 minutes of bacitracin administration was the first sign of an adverse reaction in these cases. CONCLUSION: Three patients developed severe adverse reactions after prophylactic bacitracin irrigation, two during pacemaker insertions and one during a cardiac resynchronization defibrillator implantation. PMID- 21289328 TI - Effect of serum sodium concentration and tolvaptan treatment on length of hospitalization in patients with heart failure. AB - PURPOSE: The effect of serum sodium concentration and tolvaptan treatment on length of stay (LOS) in patients hospitalized with heart failure (HF) was evaluated. METHODS: Data for this study were derived from a large, international, Phase III trial of patients hospitalized for HF. Two distinct post hoc analyses were performed, analyzing the association between serum sodium concentration and index hospitalization LOS in normonatremic patients and hyponatremic patients treated with placebo plus standard of care versus tolvaptan. Analysis of covariance models were constructed to adjust for potential variation in care delivery and adjusted for hyponatremia status or treatment. RESULTS: Patients with a baseline serum sodium concentration of <135 meq/L who received placebo had an adjusted mean LOS that was 3.06 days longer than did normonatremic patients (p < 0.001). More severely hyponatremic patients had an adjusted mean LOS 5.18 days longer than did normonatremic patients (p < 0.001). In an analysis of all hyponatremic patients, those receiving tolvaptan had an adjusted mean LOS that was 1.72 days shorter than patients receiving placebo, though this difference was not significant. In more severely hyponatremic patients (serum sodium concentration of <130 meq/L), patients treated with tolvaptan had an adjusted mean LOS 2.12 days shorter than those receiving placebo, but this difference was not significant. CONCLUSION: A secondary analysis of a large, international, Phase III trial of patients hospitalized for HF demonstrated that comorbid hyponatremia was associated with a significant increase in hospital LOS. Treatment of hyponatremia with tolvaptan was associated with reductions in LOS that were not significant. PMID- 21289329 TI - Integrating medication therapy management in the primary care medical home: A review of randomized controlled trials. AB - PURPOSE: Randomized controlled trials (RCTs) that evaluated the effect of medication therapy management (MTM) on patient outcomes in the primary care medical home were reviewed to determine how these services may be integrated into the primary care medical home. METHODS: A literature search was conducted to identify RCTS published between 1989 and 2009 that evaluated the impact of MTM services on patient outcomes. To qualify as MTM services, the interventions had to include both a review of medication therapy and patient interactions, including educating patients about drug therapy, identifying potential barriers to medication adherence, and helping patients manage their diseases. The internal validity of the studies was evaluated using previously published criteria. The description, specification, and appropriateness of study objectives, study population, intervention, randomization, blinding, outcome measures, statistical analysis, and conclusions were evaluated. RESULTS: A total of 1795 publications were identified, but only 8 met the inclusion criteria. These studies targeted patients with specific medical conditions or patients with multiple medications without specifying a medical condition. The interventions varied in intensity (i.e., frequency and length of patient contact), ranging from a single patient contact in a community pharmacy setting to multiple visits with an ambulatory care pharmacist practicing in a collaborative care model. Two of the 8 studies obtained expected results. These studies targeted patients with unrealized therapeutic goals, and the interventions involved collaboration between pharmacists and physicians and extensive patient follow-up. CONCLUSION: Of 1795 publications identified, 8 were RCTs meeting selection criteria for evaluation of the effect of MTM services on patient outcomes. Two service elements that benefit patient care were identified: (1) selecting patients with specific therapeutic problems and (2) implementing MTM services that involve timely communication with primary care providers to discuss therapeutic problems, along with routine patient follow-up to support medication adherence to changes in therapy. PMID- 21289330 TI - Effects of therapeutic drug monitoring criteria in a computerized prescriber order-entry system on the appropriateness of vancomycin level orders. AB - PURPOSE: The effects of therapeutic drug monitoring (TDM) criteria in a computerized prescriber-order-entry (CPOE) system on the appropriateness of orders for vancomycin levels were evaluated. METHODS: Vancomycin TDM criteria were developed and implemented in a CPOE system. These criteria were displayed via a pop-up alert message when vancomycin levels were ordered and included directions for appropriate timing and justification for routine monitoring. Data for two groups of adult inpatients who had vancomycin levels ordered before and after criteria implementation were compared. Medical records were retrospectively reviewed for these patients to collect information regarding patient demographics, vancomycin dosage and indication, concurrent antibiotics and nephrotoxic agents during vancomycin therapy, length of stay, duration of vancomycin therapy, and number of vancomycin levels drawn. The primary outcome was the percent change in appropriate vancomycin levels ordered after criteria implementation. RESULTS: A total of 200 patients were analyzed, 100 in each group. The percentage of appropriate orders for vancomycin levels significantly increased after criteria implementation (from 58% to 68%, p = 0.02). The greatest effect on appropriateness occurred with the first level ordered (52% versus 70% in the preimplementation and postimplementation groups, respectively; p = 0.01). The majority of inappropriate levels were due to improper timing of sample collections, accounting for 55% of the inappropriate levels evaluated. CONCLUSION: A significant increase in the number of appropriately ordered and drawn serum vancomycin levels occurred after implementation of TDM criteria in the hospital's CPOE system. The majority of orders that were deemed inappropriate were due to improper timing of laboratory collection. PMID- 21289331 TI - The expectation conundrum: Reflections from a residency class. PMID- 21289332 TI - Meta-data analysis as a strategy to evaluate individual and common features of proteomic changes in breast cancer. AB - BACKGROUND: Individual differences among breast tumours in patients is a significant challenge for the treatment of breast cancer. This study reports a strategy to assess these individual differences and the common regulatory mechanisms that may underlie breast tumourigenesis. MATERIALS AND METHODS: The two-step strategy was based firstly on a full-scale proteomics analysis of individual cases, and secondly on the analysis of common features of the individual proteome-centred networks (meta-data). RESULTS: Proteomic profiling of human invasive ductal carcinoma tumours was performed and each case was analysed individually. Analysis of primary datasets for common cancer-related proteins identified keratins. Analysis of individual networks built with identified proteins predicted features and regulatory mechanisms involved in each individual case. Validation of these findings by immunohistochemistry confirmed the predicted deregulation of expression of CK2alpha, PDGFRalpha, PYK and p53 proteins. CONCLUSION: Meta-data analysis allowed efficient evaluation of both individual and common features of the breast cancer proteome. PMID- 21289333 TI - BRAF p.Val600Glu (V600E) somatic mutation is mainly associated with MSS phenotype in metastatic colorectal cancer. AB - BACKGROUND: Oncogenic activation of EGF-signalling pathway is central to the progression of colorectal cancer. The use of mutations of the KRAS codons 12 and 13 as a selection biomarker for anti-endothelial growth factor receptor (EGFR) monoclonal antibody treatment is at present the first major step towards individualised treatment for patients with metastatic colorectal cancer. The impact of BRAF V600E mutation is not well documented. PATIENTS AND METHODS: A total of 803 metastatic cancer samples from colorectal cancer patients were explored for KRAS exon 2 and BRAF exon 15 mutations. BRAF mutated samples were characterized for mismatch repair function. RESULTS: Overall, 344 tumours were mutated, with 34 of them involving BRAF mutations (8 of microsatellite instability type). No specificity was found according to gender, age at diagnosis and tumour localisation. CONCLUSION: A complete analysis of KRAS, BRAF and PIK3CA status may identify approximately 10-15% additional patients who are unlikely to respond an EGFR-targeted monoclonal antibody and who may benefit from prospective and specific new biomarker-driven studies. PMID- 21289334 TI - Tocotrienol-treated MCF-7 human breast cancer cells show down-regulation of API5 and up-regulation of MIG6 genes. AB - BACKGROUND: Tocotrienols belong to the vitamin E family and have multiple anticancer effects, such as antiproliferative, antioxidant, pro-apoptosis and antimetastatic. This study aimed to identify the genes that are regulated in human breast cancer cells following exposure to various isomers of vitamin E as these may be potential targets for the treatment of breast cancer. MATERIALS AND METHODS: Gene expression profiling was performed with MCF-7 cells at inhibitory conditions of IC(50) using Illumina's Sentrix Array Human-6 BeadChips. The expression levels of selected differentially expressed genes were verified by quantitative real-time-PCR (qRT-PCR). RESULTS: The treatment with tocotrienol rich palm oil fraction (TRF), alpha-tocopherol and isomers of tocotrienols (alpha, gamma, and delta) altered the expression of several genes that code for proteins involved in the regulation of immune response, tumour growth and metastatic suppression, apoptotic signalling, transcription, protein biosynthesis regulation and many others. CONCLUSION: Treatment of human MCF-7 cells with tocotrienol isomers causes the down-regulation of the API5 gene and up-regulation of the MIG6 gene and the differential expression of other genes reported to play a key role in breast cancer biology. PMID- 21289335 TI - Ionizing radiation affects epidermal growth factor receptor signalling and metalloproteinase secretion in glioma cells. AB - BACKGROUND: The effect of different doses of X(-)rays on apoptosis, proliferation, epidermal growth factor receptor (EGFR) and matrix metalloproteinase (MMP-2) expression was investigated in a human glioblastoma cell line. MATERIALS AND METHODS: The cell line LN18 was irradiated at room temperature with doses ranging from 0.5 to 15 Gy using 6 MV X(-)rays. Apoptosis was assessed using the annexin V binding assay, proliferation by the methyl tetrazolium (MTT) assay and MMP-2 secretion with zymography. The levels of phosphorylated (pEGFR) were estimated using a commercially available ELISA kit. RESULTS: Cell proliferation decreased in a dose-dependent manner, while apoptosis was increased after radiation. Doses below 2 Gy did not affect proliferation or apoptosis. MMP-2 levels were increased 48 h after radiation in a dose-dependent manner. In contrast, EGFR signaling was significantly activated 15 min after radiation in a dose-dependent manner. CONCLUSION: Ionizing radiation activates EGFR signalling and enhances MMP-2 secretion, suggesting that the molecular pathways involved may contribute to the invasiveness and malignant behaviour of glioma cells and help to explain the response of gliomas to ionizing radiation. PMID- 21289336 TI - Parthenolide, an NF-kappaB inhibitor, suppresses tumor growth and enhances response to chemotherapy in gastric cancer. AB - AIM: This study evaluated the sesquiterpene lactone parthenolide, an inhibitor of transcription factor nuclear factor-kappaB (NF-kappaB), in the treatment of gastric cancer in vitro and in vivo. MATERIALS AND METHODS: In vitro, the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed to evaluate the effect of parthenolide on growth inhibition and chemosensitization to antitumor drugs of three gastric cancer cell lines (MKN-28, MKN-45 and MKN 74). Microarray analysis was performed to identify genes which were up- or down regulated on the treatment of parthenolide. The isobologram analysis was introduced to evaluate the synergic effect of parthenolide on antitumor drugs. In vivo, the effect of parthenolide was investigated in a mouse peritoneal dissemination model with and without chemotherapy. RESULTS: Parthenolide significantly inhibited cell growth in three gastric cancer cell lines. The phosphorylation of NF-kappaB was down-regulated by the treatment of parthenolide. The synergic effect of parthenolide was confirmed in combination with paclitaxel and cisplatin. In the peritoneal dissemination model, parthenolide significantly suppressed the disseminated nodules as a single agent and also enhanced chemosensitivity to paclitaxel. Furthermore, the combined therapy of parthenolide and paclitaxel significantly contributed to prolonging the survival duration. CONCLUSION: The NF-kappaB inhibitor, parthenolide, may enhance chemosensitivity to paclitaxel in the treatment of patients with gastric cancer. PMID- 21289337 TI - A tour across vast health policy terrain. PMID- 21289338 TI - Despite tight budgets, boosting US Health workforce may be policy that is 'just right'. AB - The challenge of tackling the nation's physician and nurse shortage will require federal funding and, perhaps, creative solutions from Congress and the White House. PMID- 21289339 TI - The $16,819 pay gap for newly trained physicians: the unexplained trend of men earning more than women. AB - Prior research has suggested that gender differences in physicians' salaries can be accounted for by the tendency of women to enter primary care fields and work fewer hours. However, in examining starting salaries by gender of physicians leaving residency programs in New York State during 1999-2008, we found a significant gender gap that cannot be explained by specialty choice, practice setting, work hours, or other characteristics. The unexplained trend toward diverging salaries appears to be a recent development that is growing over time. In 2008, male physicians newly trained in New York State made on average $16,819 more than newly trained female physicians, compared to a $3,600 difference in 1999. PMID- 21289340 TI - Nurses' widespread job dissatisfaction, burnout, and frustration with health benefits signal problems for patient care. AB - Job dissatisfaction among nurses contributes to costly labor disputes, turnover, and risk to patients. Examining survey data from 95,499 nurses, we found much higher job dissatisfaction and burnout among nurses who were directly caring for patients in hospitals and nursing homes than among nurses working in other jobs or settings, such as the pharmaceutical industry. Strikingly, nurses are particularly dissatisfied with their health benefits, which highlights the need for a benefits review to make nurses' benefits more comparable to those of other white-collar employees. Patient satisfaction levels are lower in hospitals with more nurses who are dissatisfied or burned out-a finding that signals problems with quality of care. Improving nurses' working conditions may improve both nurses' and patients' satisfaction as well as the quality of care. PMID- 21289341 TI - Performance-based payment incentives increase burden and blame for hospital nurses. AB - We interviewed hospital leaders and unit nurses in twenty-five hospitals between June and October 2008 to explore the effect of performance-based incentives. Interviewees expressed favorable impressions of the impact that incentive policies have on quality and safety. However, they raised concerns about the policies' effects on the nurse workforce. Their concerns included the belief that performance-based incentives would increase both the burden and the blame for nurses without corresponding improvements in staffing levels, work environment, salaries, or turnover. To maximize the intended policy impact without jeopardizing the workforce that holds the key to their adoption, we recommend that policy makers invest in implementation support, redesign hospital incentives to reward teamwork, and involve nursing leaders in the design of future incentive policies. PMID- 21289342 TI - Seniors' perceptions of health care not closely associated with physician supply. AB - We conducted a national random survey of Medicare beneficiaries to better understand the association between the supply of physicians and patients' perceptions of their health care. We found that patients living in areas with more physicians per capita had perceptions of their health care that were similar to those of patients in regions with fewer physicians. In addition, there were no significant differences between the groups of patients in terms of numbers of visits to their personal physician in the previous year; amount of time spent with a physician; or access to tests or specialists. Our results suggest that simply training more physicians is unlikely to lead to improved access to care. Instead, focusing health policy on improving the quality and organization of care may be more beneficial. PMID- 21289343 TI - Issues in health reform: how changes in eligibility may move millions back and forth between medicaid and insurance exchanges. AB - The Affordable Care Act will extend health insurance coverage by both expanding Medicaid eligibility and offering premium subsidies for the purchase of private health insurance through state health insurance exchanges. But by definition, eligibility for these programs is sensitive to income and can change over time with fluctuating income and changes in family composition. The law specifies no minimum enrollment period, and subsidy levels will also change as income rises and falls. Using national survey data, we estimate that within six months, more than 35 percent of all adults with family incomes below 200 percent of the federal poverty level will experience a shift in eligibility from Medicaid to an insurance exchange, or the reverse; within a year, 50 percent, or 28 million, will. To minimize the effect on continuity and quality of care, states and the federal government should adopt strategies to reduce the frequency of coverage transitions and to mitigate the disruptions caused by those transitions. Options include establishing a minimum guaranteed eligibility period and "dually certifying" some plans to serve both Medicaid and exchange enrollees. PMID- 21289344 TI - Transforming a traditional safety net into a coordinated care system: lessons from healthy San Francisco. AB - Since 2007, San Francisco, California, has transformed its traditional safety-net health care "system"-in reality, an amalgam of a public hospital, private nonprofit hospitals, public and private clinics, and community health centers into a comprehensive health care program called Healthy San Francisco. The experience offers lessons in how other local safety-net systems can prepare for profound changes under health reform. By July 2010, 53,546 adults had enrolled (70-89 percent of uninsured adults in San Francisco), and satisfaction is high (94 percent). Unnecessary emergency department visits were less common among enrollees (7.9 percent) than among Medicaid managed care recipients (15 percent). These findings indicate that other safety-net systems would do well to invest in information technology, establish primary care homes, increase coordination of care, and improve customer service as provisions of the national health care reform law phase in. PMID- 21289346 TI - Lack of access due to costs remains a problem for some in Massachusetts despite the state's health reforms. AB - Did the Massachusetts health reforms, which provided near-universal insurance coverage, also address problems of unmet need resulting from the cost of care and of inadequate preventive care for diverse patient groups? We found that nearly a quarter of adults who were in fair or poor health reported being unable to see a doctor because of cost during the implementation of the reforms. We also found that state residents earning less than $25,000 per year were much less likely than higher earners to receive screening for cardiovascular disease and cancer. The state needs to implement new strategies to build on the promise of universal coverage and address specific needs of vulnerable populations, such as limiting out-of-pocket spending for this group. Also, more data are needed on the social determinants of health to identify specific barriers related to cost and access for vulnerable groups that general insurance reforms may not address. PMID- 21289347 TI - A new independent authority is needed to issue National Health Care guidelines. AB - Health experts emphasize that getting doctors to follow clinical guidelines can save both lives and money. Less attention has been paid to how the guidelines are developed and the variability in the recommendations they include. We examined the quality and content of screening guidelines as a proxy for guidelines in general and found that the source of the guidelines affects their quality. Guidelines with inconsistent recommendations are unlikely to serve patients or physicians well. The creation of an independent organization that would work with multiple stakeholders to develop guidelines holds the potential to improve their quality. PMID- 21289348 TI - Many physicians are willing to use patients' electronic personal health records, but doctors differ by location, gender, and practice. AB - Electronic personal health records could become important tools for patients to use in managing and monitoring their health information and communicating with clinicians. With the emergence of new products and federal incentives that might indirectly encourage greater use of personal health records, policy makers should understand the views of physicians on using these records. In a national survey of physicians in 2008-09, we found that although 64 percent have never used a patient's electronic personal health record, 42 percent would be willing to try. Strikingly, rural physicians expressed much more willingness to use such records compared to urban or suburban physicians. Female physicians were significantly less willing to use these tools than their male peers (34 percent versus 46 percent). Physicians broadly have concerns about the impact on patients' privacy, the accuracy of underlying data, their potential liability for tracking all of the information that might be entered into a personal health record, and the lack of payment to clinicians for using or reviewing these patient records. PMID- 21289349 TI - Lesson from Canada's Universal Care: socially disadvantaged patients use more health services, still have poorer health. AB - Lower socioeconomic status is commonly related to worse health. If poor access to health care were the only explanation, universal access to care should eliminate the association. We studied 14,800 patients with access to Canada's universal health care system who were initially free of cardiac disease, tracking them for at least ten years and seven months. We found that socially disadvantaged patients used health care services more than did their counterparts with higher incomes and education. We also found that service use by people with lower incomes and less education had little impact on their poorer health outcomes, particularly mortality. Countries contemplating national health insurance cannot rely on universal health care to eliminate historical disparities in outcomes suffered by disadvantaged groups. Universal access can only reduce these disparities. Our findings suggest the need to introduce large-scale preventive strategies early in patients' lives to help change unhealthy behavior. PMID- 21289350 TI - Changes In US spending on Mental Health And Substance Abuse Treatment, 1986-2005, and implications for policy. AB - The United States invests a sizable amount of money on treatments for mental health and substance abuse: $135 billion in 2005, or 1.07 percent of the gross domestic product. We provide treatment spending estimates from the period 1986 2005 to build understanding of past trends and consider future possibilities. We find that the growth rate in spending on mental health medications-a major driver of mental health expenditures in prior years-declined dramatically. As a result, mental health and substance abuse spending grew at a slightly slower rate than gross domestic product in 2004 and 2005, and it continued to shrink as a share of all health spending. Of note, we also find that Medicaid's share of total spending on mental health grew from 17 percent in 1986 to 27 percent in 2002 to 28 percent in 2005. The recent recession, the full implementation of federal parity law, and such health reform-related actions as the planned expansion of Medicaid all have the potential to improve access to mental health and substance abuse treatment and to alter spending patterns further. Our spending estimates provide an important context for evaluating the effect of those policies. PMID- 21289351 TI - New Jersey's efforts to improve postpartum depression care did not change treatment patterns for women on medicaid. AB - Identification and treatment of postpartum depression are the increasing focus of state and national legislation, including portions of the Affordable Care Act. Some state policies and proposals are modeled directly on programs in New Jersey, the first state to require universal screening for postpartum depression among mothers who recently delivered babies. We examined the impact of these policies on a particularly vulnerable population, Medicaid recipients, and found that neither the required screening nor the educational campaign that preceded it was associated with improved treatment initiation, follow-up, or continued care. We argue that New Jersey's policies, although well intentioned, were predicated on an inadequate base of evidence and that efforts should now be undertaken to build that base. We also argue that to improve detection and treatment, policy makers contemplating or implementing postpartum depression mandates should consider additional measures. These could include requiring mechanisms to monitor and enforce the screening requirement; paying providers to execute screening and follow-up; and preliminary testing of interventions before policy changes are enacted. PMID- 21289352 TI - Misuse of the FDA's humanitarian device exemption in deep brain stimulation for obsessive-compulsive disorder. AB - Deep brain stimulation-a novel surgical procedure-is emerging as a treatment of last resort for people diagnosed with neuropsychiatric disorders such as severe obsessive-compulsive disorder. The US Food and Drug Administration granted a so called humanitarian device exemption to allow patients to access this intervention, thereby removing the requirement for a clinical trial of the appropriate size and statistical power. Bypassing the rigors of such trials puts patients at risk, limits opportunities for scientific discovery, and gives device manufacturers unique marketing opportunities. We argue that Congress and federal regulators should revisit the humanitarian device exemption to ensure that it is not used to sidestep careful research that can offer valuable data with appropriate patient safeguards. PMID- 21289353 TI - Medicare's policy on carotid stents limited use to hospitals meeting quality guidelines yet did not hurt disadvantaged. AB - Medicare began covering the use of carotid stents to treat arterial blockages in 2005 under an innovative policy requiring hospitals to meet quality-of-care benchmarks before seeking reimbursement. By restricting carotid stent provision to a smaller subset of US hospitals than those typically adopting new cardiovascular technologies, this policy could have disproportionately reduced the availability of this technology for minority, low-income, and rural patients. Such patients are often served by hospitals less able than others to meet increasingly stringent quality requirements. However, our analysis of hospitals that provided stents during 2005-07 demonstrated that although 21-38 percent fewer hospitals offered stents than offered other types of interventional cardiovascular procedures, such as heart bypass grafts, stents were no less available in localities with substantial poor, black, or rural populations than they were in other areas. Our study provides important evidence that the carotid stent coverage policy met its goal of limiting the adoption of the technology by hospitals that weren't well prepared to provide it-while still maintaining equitable availability of the technology. Therefore, it may be a useful model for future Medicare coverage decisions. PMID- 21289354 TI - Nearly half of families in high-deductible health plans whose members have chronic conditions face substantial financial burden. AB - High-deductible health plans-typically with deductibles of at least $1,000 per individual and $2,000 per family-require greater enrollee cost sharing than traditional plans. But they also may provide more affordable premiums and may be the lowest-cost, or only, coverage option for many families with members who are chronically ill. We surveyed families with chronic conditions in high-deductible plans and families in traditional plans to compare health care-related financial burden-such as experiencing difficulty paying medical or basic bills or having to set up payment plans. Almost half (48 percent) of the families with chronic conditions in high-deductible plans reported health care-related financial burden, compared to 21 percent of families in traditional plans. Almost twice as many lower-income families in high-deductible plans spent more than 3 percent of income on health care expenses as lower-income families in traditional plans (53 percent versus 29 percent). As health reform efforts advance, policy makers must consider how to modify high-deductible plans to reduce the financial burden for families with chronic conditions. PMID- 21289355 TI - What are the respective roles of the public and private sectors in pharmaceutical innovation? AB - What are the respective roles of the public and private sectors in drug development? This question is at the heart of some policy proposals, such as those that would give the government a share of profits from drugs at least partly developed with federal research dollars. This paper provides empirical data on these issues, using information included in the patents on drugs approved between 1988 and 2005. Overall, we find that direct government funding is more important in the development of "priority-review" drugs-sometimes described as the most innovative new drugs-than it is for "standard-review" drugs. Government funding has played an indirect role-for example, by funding basic underlying research that is built on in the drug discovery process-in almost half of the drugs approved and in almost two-thirds of priority-review drugs. Our analyses should help inform thinking about the returns on public research funding-a topic of long-standing interest to economists, policy makers, and health advocates. PMID- 21289356 TI - A simulation shows that early treatment of chronic hepatitis B infection can cut deaths and be cost-effective. AB - Chronic hepatitis B affects between 800,000 and two million people in the United States and causes 4,000 deaths each year. Yet the costs and benefits of treatment have not been fully evaluated. Using a model that simulates disease progression, we compare treatment programs for hepatitis B that start at an early stage of the disease to treatment that begins at a late stage. Our analysis concludes that early hepatitis B care can improve health, reduce premature deaths, and prevent expensive complications, making it highly cost-effective in the long term. Our results demonstrate the importance of screening for hepatitis B among at-risk groups and then linking screening to treatment. They also illustrate how predictive models can be used to evaluate strategies for improving access to care. PMID- 21289357 TI - Applying comparative effectiveness research to public and population health initiatives. AB - Comparative effectiveness research to date has focused primarily on the diagnosis and treatment of diseases and injuries in individuals. Yet the greatest drivers of people's overall health are found in their social and physical environments. We recommend that the comparative effectiveness research agenda focus on the public health issues responsible for the greatest overall illness and death levels, such as programs to increase high school graduation rates, which are strongly associated with improvements in long-term illness and death rates. In so doing, the agenda should spotlight efforts to address widely recognized social and environmental determinants of health, such as improving access to early childhood development programs and education, as well as interventions aimed at affecting climate change and addressing behavioral risk factors such as smoking. We also urge federal health agencies to invest in further development of methods to compare public health interventions and to use those methods to conduct the studies. PMID- 21289358 TI - Surrendering the keys: a doctor tries to get an impaired elderly patient to stop driving. AB - In the interest of public safety, the author argues for a vastly improved policy framework to help get dangerous older drivers off the road. PMID- 21289361 TI - Revitalizing pharmaceutical innovation for global health. PMID- 21289362 TI - State-sponsored public reporting of hospital quality. PMID- 21289364 TI - Identification of a subpopulation of metastatic breast cancer patients with very high HER2 expression levels and possible resistance to trastuzumab. AB - BACKGROUND: Patients with metastatic breast cancer (MBC) overexpressing HER2 (human epidermal growth factor receptor 2) are currently selected for treatment with trastuzumab, but not all patients respond. PATIENTS AND METHODS: Using a novel assay, HER2 protein expression (H2T) was measured in formalin-fixed, paraffin-embedded primary breast tumors from 98 women treated with trastuzumab based therapy for MBC. Using subpopulation treatment effect pattern plots, the population was divided into H2T low (H2T < 13.8), H2T high (H2T >= 68.5), and H2T intermediate (13.8 <= H2T < 68.5) subgroups. Kaplan-Meier (KM) analyses were carried out comparing the groups for time to progression (TTP) and overall survival (OS). Cox multivariate analyses were carried out to identify correlates of clinical outcome. Bootstrapping analyses were carried out to test the robustness of the results. RESULTS: TTP improved with increasing H2T until, at the highest levels of H2T, an abrupt decrease in the TTP was observed. KM analyses demonstrated that patients with H2T low tumors [median TTP 4.2 months, hazard ratio (HR) = 3.7, P < 0.0001] or H2T high tumors (median TTP 4.6 months, HR = 2.7, P = 0.008) had significantly shorter TTP than patients whose tumors were H2T intermediate (median TTP 12 months). OS analyses yielded similar results. CONCLUSIONS: MBC patients with very high levels of H2T may represent a subgroup with de novo resistance to trastuzumab. These results are preliminary and require confirmation in larger controlled clinical cohorts. PMID- 21289365 TI - Unity is strength: one, two, or more drugs against advanced pancreatic cancer? PMID- 21289366 TI - Long-term toxic effects of adjuvant chemotherapy in breast cancer. AB - Breast cancer is the most common malignant tumor affecting women. Adjuvant systemic therapies have been shown to have a significant impact on reducing the risk for breast cancer recurrence and overall mortality. Chemotherapy remains an important and frequently used treatment option in the adjuvant setting, and the associated short-term adverse events are very well described. However, there is insufficient information regarding the long-term sequelae of most chemotherapeutic agents. In this review, we describe different potential long term adverse events associated with adjuvant chemotherapy in breast cancer, with a particular focus on long-term cardiac toxicity, secondary leukemia, cognitive function, and neurotoxicity. In addition, we discuss the effect of adjuvant chemotherapy on fertility and sexual function of young breast cancer patients. These adverse events are frequently overshadowed by the well-demonstrated clinical efficacy and/or reassuring short-term safety profiles of the different chemotherapy regimens commonly used today. We believe that a proper understanding and appreciation of these adverse events will enable us to refine our strategies for managing breast cancer. The fact that adjuvant chemotherapy is often given to patients who might not really need it urges us to consider the whole spectrum of chemotherapy risks versus benefits to maximize benefit without compromising quality of life. PMID- 21289367 TI - A prospective dose-finding trial using a modified continual reassessment method for optimization of fludarabine plus melphalan conditioning for marrow transplantation from unrelated donors in patients with hematopoietic malignancies. AB - BACKGROUND: Because of the less graft-facilitating effect by bone marrow (BM), we need to assess a dosage of conditioning more accurately particularly in combination with reduced-intensity conditioning. Thus we examined that modified continual reassessment method (mCRM) is applicable for deciding appropriate conditioning of allogeneic BM transplantation. PATIENTS AND METHODS: The conditioning regimen consisted of i.v. fludarabine (125 mg/m2) plus an examination dose of i.v. melphalan. The primary endpoint was a donor-type T-cell chimerism at day 28 with successful engraftment defined as >90% donor cells. Five patients per dose level were planned to be accrued and chimerism data were used to determine the next dose. RESULTS: Seventeen patients were enrolled at doses between 130 and 160 mg/m2. The dose was changed from 160 to 130 mg/m(2) (second level) after five full-donor chimerisms. With one patient of 0% chimera in the second level, the dose was increased to 135 mg/m2 (third level). Following five full-donor chimerisms in the third level, the study was complete as projected. CONCLUSIONS: mCRM was shown to be a relevant method for dose-finding of conditioning regimen. The melphalan dose of 135 mg/m2 was determined as the recommended phase II dose to induce initial full-donor chimerism. PMID- 21289368 TI - Impact of neutropenia on the outcomes of critically ill patients with cancer: a matched case-control study. AB - BACKGROUND: The prognostic effect of neutropenia in cancer patients admitted to intensive care units (ICUs) was addressed exclusively in cohort studies with conflicting results. Our aim was to address this question using a matched case control study. PATIENTS AND METHODS: Ninety-four neutropenic patients and 94 non neutropenic controls were matched for age, cancer type, Simplified Acute Physiology Score II, Sequential Organ Failure Assessment score, and need for mechanical ventilation and vasopressors. Conditional logistic regression was used to identify factors associated with hospital mortality. RESULTS: The ICU (66% versus 66%, P = 0.999) and hospital (73% versus 78%, P = 0.611) mortality rates were similar in neutropenic and non-neutropenic patients. Adjusting for the type of admission and length of hospital stay before ICU admission, the characteristics associated with increased mortality were the severity of acute disease and organ failures, compromised performance status and sepsis diagnosis. The impact of both previous chemotherapy and neutropenia on the outcomes was not significant. CONCLUSIONS: Using a matched case-control study design, our results provide additional evidence that the presence of neutropenia is no longer associated with worse outcomes in critically ill patients with cancer. Moreover, our results also corroborate that recent exposure to chemotherapy is not associated with increased risk for death. PMID- 21289369 TI - Comparison of RECIST and Choi criteria for computed tomographic response evaluation in patients with advanced gastrointestinal stromal tumor treated with sunitinib. AB - BACKGROUND: Controversies exist about computed tomography (CT) response evaluation criteria for patients with gastrointestinal stromal tumor (GIST). PATIENTS AND METHODS: Fifty-one patients with advanced GIST treated second line with sunitinib were evaluated with contrast-enhanced CT every 3 months. Response was rated according to RECIST and Choi criteria. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier analysis. RESULTS: According to RECIST, patients were categorized as complete response (CR; n = 0; 0%), partial remission (PR; n = 1; 2.0%), stable disease (SD; n = 37; 72.5%), and progressive disease (PD; n = 13; 25.5%) at 3 months. When Choi criteria were applied responses were CR (n = 0; 0%), PR (n = 16; 31.4%), SD (n = 21; 41.1%), and PD (n = 14; 27.5%). Despite these discrepancies, patients rated as SD with RECIST and PR as well as SD according to Choi criteria displayed similar PFS (41.3, 40.7, and 41.3 weeks, respectively) and OS (100.4, 91.6, and 108.0 weeks, respectively). Patients with PD had significantly shorter PFS (10.1 weeks for both criteria) and OS (29.1 weeks for RECIST; 28.9 weeks for Choi) regardless of the response classification applied. CONCLUSION: In contrast to absence of progression, discrimination of PR from SD with Choi criteria was of no predictive value. PMID- 21289370 TI - Rampant gene loss in the underground orchid Rhizanthella gardneri highlights evolutionary constraints on plastid genomes. AB - Since the endosymbiotic origin of chloroplasts from cyanobacteria 2 billion years ago, the evolution of plastids has been characterized by massive loss of genes. Most plants and algae depend on photosynthesis for energy and have retained ~110 genes in their chloroplast genome that encode components of the gene expression machinery and subunits of the photosystems. However, nonphotosynthetic parasitic plants have retained a reduced plastid genome, showing that plastids have other essential functions besides photosynthesis. We sequenced the complete plastid genome of the underground orchid, Rhizanthella gardneri. This remarkable parasitic subterranean orchid possesses the smallest organelle genome yet described in land plants. With only 20 proteins, 4 rRNAs, and 9 tRNAs encoded in 59,190 bp, it is the least gene-rich plastid genome known to date apart from the fragmented plastid genome of some dinoflagellates. Despite numerous differences, striking similarities with plastid genomes from unrelated parasitic plants identify a minimal set of protein-encoding and tRNA genes required to reside in plant plastids. This prime example of convergent evolution implies shared selective constraints on gene loss or transfer. PMID- 21289371 TI - Oral administration of penta-O-galloyl-beta-D-glucose suppresses triple-negative breast cancer xenograft growth and metastasis in strong association with JAK1 STAT3 inhibition. AB - There is an urgent clinical need for chemotherapeutic and chemopreventive drugs for triple-negative breast cancer (TNBCa). Extending on our recent work, we hypothesize that the herbal compound 1,2,3,4,6-penta-O-galloyl-beta-D-glucose (PGG) can inhibit the growth and metastasis of TNBCa xenograft and target Janus activated kinase (JAK)-signal transducer and activator of transcription (STAT) 3 signaling axis. Daily oral gavage of 10 mg PGG/kg body wt decreased MDA-MB-231 xenograft weight by 49.3% (P < 0.01) at 40 days postinoculation, whereas weekly intraperitoneal injections of Taxol at the same dosage resulted in a 21.4% reduction (P > 0.1). PGG treatment also decreased the incidence of lung metastasis. Immunohistochemical staining detected decreased Ki-67 (proliferation) index and increased terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (apoptosis) index in PGG-treated and Taxol-treated xenografts. However, the CD34 (angiogenesis) index was decreased only in PGG treated xenografts along with decreased phospho-STAT3. In cell culture of MDA-MB 231 cells, PGG decreased pSTAT3 and its downstream target proteins, decreased its upstream kinase pJAK1 and induced the expression of SHP1, a JAK1 upstream tyrosine phosphatase, within as early as 1 h of exposure. The phosphatase inhibitor pervanadate reversed the PGG-induced downregulation of pSTAT3 and caspase activation. Orally administered PGG can inhibit TNBCa growth and metastasis, probably through anti-angiogenesis, antiproliferation and apoptosis induction. Mechanistically, PGG-induced inhibition of JAK1-STAT3 axis may contribute to the observed in vivo efficacy and the effects on the cellular processes. PMID- 21289372 TI - Does easily learned mean easily remembered?: it depends on your beliefs about intelligence. AB - Because numerous studies have shown that feelings of encoding fluency are positively correlated with judgments of learning, a single dominant heuristic, easily learned = easily remembered (ELER), has been posited to explain how people interpret encoding fluency when assessing their own memory. However, the inferences people draw from feelings of encoding fluency may vary with their beliefs about why information is easy or effortful to encode. We conducted two experiments in which participants studied word lists and then predicted their future recall of those items. Results revealed that subjects who viewed intelligence as fixed, and who tended to interpret effortful encoding as indicating that they had reached the limits of their ability, used the ELER heuristic to make judgments of learning. However, subjects who viewed intelligence as malleable, and who tended to interpret effortful encoding as indicating greater engagement in learning, did not use the ELER heuristic and at times predicted greater memory for items that they found more effortful to learn. PMID- 21289375 TI - Reinforcement learning in children with FASD. AB - BACKGROUND: It is often said that children with Fetal Alcohol Spectrum Disorder (FASD) have difficulty learning from reinforcement. However, there is little empirical evidence to support or deny this claim. OBJECTIVES: To examine reinforcement learning in children with FASD, specifically: (1) the rate of learning from reinforcement; and (2) the impact of concreteness of the reinforcer. METHODS: Participants included 18 children with FASD (IQ >= 70), ages 11-17, and 18 age- and sex-matched controls. Participants each completed a novel reinforcement learning discrimination task that involved visual probabilistic learning (70% contingent feedback). The task was completed twice, once with tokens, and once with points (counterbalanced). RESULTS: The control group demonstrated significantly stronger overall reinforcement learning, although rates of improvement and effect of concreteness of the reinforcer (tokens vs. points) were not different between groups. The FASD group's responses were more likely to be guided by the most recent information, rather than based on integration of reward status over multiple trials. CONCLUSIONS: Reinforcement learning does not appear to occur in a functionally different manner in children with FASD, but does take longer, and is more impacted by recent reward than an integration of overall reinforcement information. Children with FASD without an intellectual disability may be able to learn from reinforcement given sufficient consistent repetition. However, other failures associated with learning difficulties such as the complexity of the material, transfer of learning, or impulsivity were not addressed in this study. PMID- 21289374 TI - A prospective, multicentre, observational cohort study of analgesia and outcome after pneumonectomy. AB - BACKGROUND: Meta-analysis and systematic reviews of epidural compared with paravertebral blockade analgesia techniques for thoracotomy conclude that although the analgesia is comparable, paravertebral blockade has a better short term side-effect profile. However, reduction in major complications including mortality has not been proven. METHODS: The UK pneumonectomy study was a prospective observational cohort study in which all UK thoracic surgical centres were invited to participate. Data presented here relate to the mode of analgesia and outcome. Data were analysed for 312 patients having pneumonectomy at 24 UK thoracic surgical centres in 2005. The primary endpoint was a major complication. RESULTS: The most common type of analgesia used was epidural (61.1%) followed by paravertebral infusion (31%). Epidural catheter use was associated with major complications (odds ratio 2.2, 95% confidence interval 1.1-3.8; P=0.02) by stepwise logistic regression analysis. CONCLUSIONS: An increased incidence of clinically important major post-pneumonectomy complications was associated with thoracic epidural compared with paravertebral blockade analgesia. However, this study is unable to provide robust evidence to change clinical practice for a better clinical outcome. A large multicentre randomized controlled trial is now needed to compare the efficacy, complications, and cost-effectiveness of epidural and paravertebral blockade analgesia after major lung resection with the primary outcome of clinically important major morbidity. PMID- 21289376 TI - Severe bullous hypersensitivity reactions after exposure to carbamazepine in a Han-Chinese child with a positive HLA-B*1502 and negative in vitro toxicity assays: evidence for different pathophysiological mechanisms. AB - BACKGROUND: Drug hypersensitivity syndrome (DHS) can present in several clinical forms ranging from simple maculopapular skin rash to severe bullous reactions and multi-system dysfunction. Genetic analysis of DHS patients has revealed a striking association between carbamazepine (CBZ)-induced severe bullous reactions, such as Steven-Johnson Syndrome, and toxic epidermal necrolysis in individuals from Southeast Asia who carry a specific HLA allele (HLA-B*1502). This ethnic-specific relationship with a disease phenotype has raised the question of the commonality of the pathogenesis mechanisms of these diseases. The aim of this study was to investigate the genetic and metabolic bases of DHS development to help predict patient susceptibility. METHOD: A case of carbamazepine-induced Steven-Johnson Syndrome reaction in a HLA-B*1502 positive child of Han Chinese origin, a carbamazepine-induced DHS case in a Caucasian patient and 3 healthy controls were investigated. We performed two types of in vitro toxicity assay, the lymphocyte toxicity assay (LTA) and the novel in vitro platelet toxicity assay (iPTA) on cells taken from the Chinese child 3 and 9 months after recovery from the reaction and from two healthy volunteers. We also tested the Caucasian patient, who developed CBZ-induced DHS, 3 months after the reaction. RESULTS: Both LTA and iPTA tests were negative 3 and 9 months after the reaction on samples from the Chinese child whereas the tests were positive in the Caucasian patient. CONCLUSION: These results strongly suggest more than one mechanistic pathway for different CBZ-induced hypersensitivity reactions in patients with different ethnic backgrounds. PMID- 21289377 TI - Perpetuating fears: bias against the null hypothesis in fetal safety of drugs as expressed in scientific citations. AB - BACKGROUND: Bias against negative studies (i.e., those showing no issues with fetal safety of drugs) may cause distorted interpretation with apparently safe drugs being labeled as teratogenic, causing women to terminate pregnancy or not to treat serious medical conditions. OBJECTIVE: To investigate whether "positive" studies, claiming teratogenic effects of drugs, which were later shown to be safe, have been cited more often than "negative" studies on the same topic. METHODS: We reviewed published studies on the fetal safety of 6 drugs, which were the focus of appreciable controversy over the last 5 decades (oral contraceptives, bendectin(r), benzodiazepines, paroxetine, ACE inhibitors and statins). While initial highly publicized papers claimed teratogenic effects, these were subsequently contradicted by large numbers of "negative" studies. We compared medical citation patterns of the "positive" vs. "negative" papers related to these 6 drugs.Results"Positive" papers were 70% more likely to be cited than "negative" articles (median 39 vs. 23, p=0.04). In multivariate linear regression, "positivity" of results (p=0.04), the number of years since publication (p=0.01) and journal citation impact (p<0.001) all independently predicted the total number of medical citations. CONCLUSIONS: We documented bias against the null hypothesis in medical citations of fetal drug safety. Acknowledging this source of bias is critical in trying to avert the distortion of the medical knowledge created by it. PMID- 21289378 TI - Executive functioning and working memory deficits on the CANTAB among children with prenatal alcohol exposure. AB - BACKGROUND: Children with prenatal alcohol exposure (PAE) and Fetal Alcohol Spectrum Disorders (FASD) display numerous neuropsychological impairments, including deficits on measures of executive functioning (EF) and working memory. OBJECTIVES: The goal of this project was to examine whether children with PAE and FASD demonstrate EF and working memory deficits on the CANTAB(r) (a computerized neuropsychological test). METHODS: Twenty-four children with PAE and 26 control children were tested on the CANTAB(r). RESULTS: Children with PAE demonstrated deficits in the areas of executive functioning, working memory, and attention. Among the PAE group, those with FASD were specifically impaired on working memory capacity. CONCLUSIONS: The CANTAB(r) is a useful tool for detecting neurobehavioral deficits in children with PAE. PMID- 21289379 TI - Prevalance and determinants of antidepressant use among Canadian Forces members experiencing major depressive episodes. AB - BACKGROUND: Major depression affects a significant proportion of individuals including those serving in the military; but, there is less information on the pharmacological treatment they receive. OBJECTIVES: We assessed the prevalence and determinants of past year antidepressant use among regular and reservist members of the Canadian Forces who have experienced major depressive episodes in the past 12 months. METHODS: The 2002 Canadian Community Health Survey Cycle 1.2 Canadian Forces Supplement (CCHS1.2-CFS) surveyed 8441 active members of the Canadian Forces. Individuals who reported experiencing major depressive episodes (MDE) in the past 12 months, according to the definition of the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV), were examined with data from the CCHS1.2-CFS. Regression models assessed sociodemographic determinants and service factors of antidepressant use employing appropriate weights and bootstrapping variance estimation methods. RESULTS: Overall, 7.4% of members of the Canadian Forces experienced MDE in the past 12 months, and of those only 32.1% reported to have taken an antidepressant. Significant predictors of antidepressant use were marital status i.e. married/common law (OR=3.6, 95%CI 2.0-6.4), widowed/separated/divorced (OR=4.0, 95%CI 2.0-8.4), and being in both combat and peacekeeping missions (OR=2.2, 95%CI 1.3-3.8). CONCLUSION: Findings highlight the characteristics that predispose individuals in the Canadian Forces with MDE to use antidepressant, and serves as a baseline to determine the effectiveness of ongoing programs for diagnosis, treatment and prevention of major depression. Continued research involving the Canadian Forces will foster better understanding of mental health outcomes and effective interventions to improve care. PMID- 21289380 TI - Retrograde flexible ureteroscopy: reshaping the upper urinary tract endourology. AB - Introduction of retrograde flexible ureteroscopy represented a leap forward in upper urinary tract endourology. Nowadays, areas of the pyelocaliceal system accessible otherwise only by percutaneous or open surgery, can be approached in a retrograde fashion, using the anatomical pathways. The flexible ureteroscopes evolved from the limited deflectable first generation ones to the digital very maneuverable models. The ancillary instruments and the energy sources underwent a similar evolution. Flexible ureteroscopy is a very useful investigative method, especially in patients with equivocal data provided by the imaging. Introduction of this procedure decreased significantly the number of cases with so called "essential" hematuria. The conservatively treated upper urinary tract tumors can be also followed-up more efficiently, the recurrence being identified before becoming radiological obvious. Initially reserved only for diagnostic purposes, flexible ureteropyeloscopy may be used also in the treatment of various pathological conditions of the upper urinary tract such as lithiasis, stenosis, tumors, pyelocaliceal abnormalities etc. However, technical limitations regarding the visibility and access are still influencing the outcome of the method. The characteristics of the available flexible endoscope, and how they are influenced by the used energy sources and ancillary instruments is crucial for achieving the best performances. Also the particularities of the lesion and upper urinary tract anatomy have a significant impact over the flexible ureteroscopic approach. Despite the already achieved efficacy, the technological progress may still allow various improvements of the method, including robotic flexible ureteroscopy. PMID- 21289381 TI - [Retrograde flexible ureteroscopy: endourologic remodeling of the upper urinary tract]. PMID- 21289382 TI - Photodynamic diagnosis in urology: state of the art. AB - High grade NMIBC remains a treatment challenge for urologists. WLC is widely regarded as the gold standard for detection and TUR. PDD may offer superiority to WLC in terms of detection, recurrence free survival and overall cost, but the current data must be scrutinized closely. Nearly all trials comparing PDD to WLC have shown an advantage in overall tumor detection with photodynamics and thus may lead to better treatment strategies in these patients. This review will focus on the results of a multitude of studies where PDD in combination with various photosensitizers was employed in the diagnosis and treatment of bladder cancer. The equipment, techniques and cost of these modalities will also be discussed. PMID- 21289383 TI - [Photodynamic diagnosis in urology: current status]. PMID- 21289384 TI - Obesity modifies prostatic specific antigen in men over 45 years. AB - OBJECTIVES: To determine whether lower serum prostate-specific antigen (PSA) concentration in obese men is caused by plasma hemodilution and/or decreased serum testosterone levels. METHODS: A sample of 413 men, from 45 to 75 years old, were randomly selected for the study among those who participated in prostate cancer screening at 2 urban urology practices in Argentina and Puerto Rico. Weight, height, serum testosterone and total PSA concentration were determined. Body mass index (BMI), body surface, plasma volume, and PSA mass were calculated. Prostate volume was estimated by transrectal ultrasound using the prolate ellipsoid formula. RESULTS: Mean age was 59 years old (range, 45 to 75) and mean BMI was 28.8 kg/m2 (range, 24 to 46). Mean serum PSA concentration was 1.43 ng/ml in normal weight patients (n=68), 1.4 ng/ml in overweight patients (n=222), 1.05 ng/ml in obese patients (n=114), and 0.85 ng/ml in morbidly obese patients (n=9). BMI was directly correlated with plasma volume (r= 0.687; p= 0.001) and inversely correlated with serum PSA concentration (r= -0.235; P= 0.001). PSA mass tended to be lower in obese and morbidly obese patients (P= 0.0063)compared to normal weight and overweight subjects. Serum testosterone concentration (P= 0.91) and prostate volume (P= 0.068) were similar among all BMI groups. CONCLUSIONS: Obese men had lower serum PSA concentrations than normal weight men mainly due to plasma hemodilution. PSA mass tended to be lower in obese patients, but it is unlikely a consequence of lower serum testosterone concentrations. PMID- 21289385 TI - Evaluation of the significance of radiographic density and size of calculi in the incidence and clinical manifestations of postlithotripsy renal hematomas. AB - OBJECTIVES: The present study is a continuation of an earlier article published on the incidence, clinical manifestations, treatment and risk factors associated with postlithotripsy renal hematomas (1). To assess the possible influence of the size and radiodensity of kidney stones on the incidence and clinical behavior of renal postlithotripsy hematomas. METHODS: Observational prospective study of 324 renal units in the same number of patients undergoing extracorporeal renal lithotripsy. The variables "calculus size" and "radiographic calculus density" were evaluaArch. ted statistically by means of the IPSS 0.15 program on the basis of 42 postlithotripsy hematomas diagnosed and grouped according to their clinical behavior. RESULTS: Higher incidence of hematomas was observed in hiperdense calculi (25%) versus medium density calculi (7,4%), this difference was significant in the asymptomatic hematoma group. CONCLUSIONS: Calculus size was unrelated to the incidence of renal hematoma, but there was a significant association between renal hematoma and radiographic calculus density, probably due to the relation of radiographic density to chemical composition and, ultimately, to hardness and ultrastructure. Ultrastructure is yet another factor, among others, to be taken into account as a potential conditioning factor for this complication. PMID- 21289386 TI - Percutaneous radiofrequency ablation of renal tumors in solitary kidney patients. AB - OBJECTIVES: In solitary kidney patients with renal cell carcinoma (RCC), radiofrequency ablation (RFA) could be effective in achieving complete tumor necrosis without increasing the risk of complications or renal failure. To analyze the outcomes of a group of solitary kidney patients treated for RCC by RFA considering tumor size and location, renal function involvement and complications. METHODS: A transversal retrospective study was performed, in which we selected 11 solitary kidney patients with 19 tumors in total treated by RFA for one or more renal tumors. A CT protocol was used for follow up. It included unenhanced series and contrast enhanced series at 1 month, 3-6 months, 12 months and yearly after RFA. Serum creatinine levels of each patient, pre RFA and within the first 48 hours after RFA, were collected. RESULTS: Complete ablation was achieved in 17 tumors (89.4%) after one or two RFA sessions. 100% of exophytic and parenchymal tumors, and 3 cm size or smaller, were completely ablated. Renal failure, immediate complications or more than 24 hours hospitalization were not observed in 10 (90.1%) of our patients. CONCLUSIONS: RFA treatment for RCC in solitary kidney patients has a high success rate; it does not affect renal function and achieves complete initial tumor necrosis, especially in exophytic, parenchymal and 3 cm or smaller lesions. PMID- 21289387 TI - Rectoprostatic fistula: unusual presentation of a prostatic abscess. AB - OBJECTIVE: To present the case and iconography of a rectoprostatic fistula as a form of presentation of a prostatic abscess and to review the literature on the diagnosis and treatment of this pathology. METHODS: 69-year-old male with multiple pathologic conditions who presents an orifice in the prostatic fossa on digital rectal examination in the scenario of a urinary tract infection with fever. CT scan and colonoscopy showed a prostatic abscess fistulizing to rectum. RESULTS: Due to spontaneous drainage of the abscess, conservative treatment with intravenous fluid therapy and antibiotics was chosen. CONCLUSIONS: Prostatic abscess is often difficult to diagnose because of its low prevalence and unspecific symptomatology. Since the introduction of antibiotics, cases in which abscess fistulas or opens spontaneously to neighboring structures like urethra or rectum have decreased. PMID- 21289388 TI - Prostatic abscess: diagnosis and treatment of an infrequent urological entity. AB - OBJECTIVE: To report two cases of prostatic abscess of difficult management and review the literature on diagnosis and management of this entity. METHODS /RESULTS: We describe two patients with prostatic abscess. The first one, a 73 year-old diabetic male, was treated using a more passive approach with percutaneous transrectal drainage; after a slow response, the patient passed away due to sepsis. The second case was a 59-year-old male who experienced a negative clinical response to antibiotic treatment. While under antibiotic ambulatory care the patient was treated with a transurethral resection of the prostate, which yielded a successful outcome. CONCLUSION: Prostatic abscess is a rare entity that affects individuals experiencing weakness and can be a serious condition. Measures taken to arrive at a resolution must be rapid and appropriate. PMID- 21289389 TI - Spontaneous resolution of ureterovaginal fistula. AB - OBJECTIVE: We report one case of a spontaneous resolution of a uretero-vaginal fistula, and we review the current diagnostic and therapeutic features of this condition in the literature. METHODS: We present the case of a 41-year-old woman who, during the late postoperative period of a radical hysterectomy, presented episodes of daily and nocturnal incontinence with episodic flank pain compatible with uretero-vaginal fistula. RESULTS: One month after diagnosis the patient does not report incontinence during day or night, and the lumbar pain has disappeared. An intravenous urography shows that there has been a spontaneous resolution of the uretero-vaginal fistula. CONCLUSIONS: Spontaneous resolution of a uretero vaginal fistula is rare. Most fistulas require endourological or surgical treatment. PMID- 21289390 TI - Mobility of a 5|7 defect in carbon nanotubes. AB - The movement of a 5|7 defect in the plastic deformations of a carbon nanotube (CNT) plays the role of dislocation glide in the plastic deformations of metals. This work is concerned with the atomic shift mechanism of the 5|7 defect and the energy barrier when the CNT is subjected to tensile loading. Action-derived molecular dynamics (ADMD) is applied to find the minimum energy path and the energy barrier. It is found that the tensile loads make it easy for the 5|7 defect to glide, and lower the energy barrier. The minimum load level that makes a 5|7 defect glide freely with no energy barrier in the presence of an adatom is obtained. PMID- 21289391 TI - Strain engineering of thermal conductivity in graphene sheets and nanoribbons: a demonstration of magic flexibility. AB - Graphene is an outstanding material with ultrahigh thermal conductivity. Its thermal transfer properties under various strains are studied by reverse nonequilibrium molecular dynamics. Based on the unique two-dimensional structure of graphene, the distinctive geometries of graphene sheets and graphene nanoribbons with large flexibility and their intriguing thermal properties are demonstrated under strains. For example, the corrugation under uniaxial compression and helical structure under light torsion, as well as tube-like structure under strong torsion, exhibit enormously different thermal conductivity. The important robustness of thermal conductivity is found in the corrugated and helical configurations of graphene nanoribbons. Nevertheless, thermal conductivity of graphene is very sensitive to tensile strain. The relationship among phonon frequency, strain and thermal conductivity are analyzed. A similar trend line of phonon frequency dependence of thermal conductivity is observed for armchair graphene nanoribbons and zigzag graphene nanoribbons. The unique thermal properties of graphene nanoribbons under strains suggest their great potentials for nanoscale thermal managements and thermoelectric applications. PMID- 21289392 TI - An improved AFM cross-sectional method for piezoelectric nanostructures properties investigation: application to GaN nanowires. AB - We present an improved atomic force microscopy (AFM) method to study the piezoelectric properties of nanostructures. An AFM tip is used to deform a free standing piezoelectric nanowire. The deflection of the nanowire induces an electric potential via the piezoelectric effect, which is measured by the AFM coating tip. During the manipulation, the applied force, the forcing location and the nanowire's deflection are precisely known and under strict control. We show the measurements carried out on intrinsic GaN and n-doped GaN-AlN-GaN nanowires by using our method. The measured electric potential, as high as 200 mV for n doped GaN-AlN-GaN nanowire and 150 mV for intrinsic GaN nanowire, have been obtained, these values are higher than theoretical calculations. Our investigation method is exceptionally useful to thoroughly examine and completely understand the piezoelectric phenomena of nanostructures. Our experimental observations intuitively reveal the great potential of piezoelectric nanostructures for converting mechanical energy into electricity. The piezoelectric properties of nanostructures, which are demonstrated in detail in this paper, represent a promising approach to fabricating cost-effective nano generators and highly sensitive self-powered NEMS sensors. PMID- 21289393 TI - Lithographical gap-size engineered nanoarrays for surface-enhanced Raman probing of biomarkers. AB - Engineered gold nanostructured arrays with feature separation in the sub-10-nm range were fabricated and used for highly sensitive surface enhanced Raman scattering (SERS) detection of biomarkers. Nanostructuring is achieved by combining electron beam lithography with the so-called shadow evaporation technique which involves a two-step Au vapor deposition through a suspended Ge mask while the substrate is tilted in opposite directions. This results in a regular triangular surface pattern with extremely small gap distances that allow positive enhancement of the local electric fields by enabling improvements in the electromagnetic coupling between adjacent nanoparticles. The resulting SERS active surfaces are suitable for the realization of reference procedures for quantifying marker molecules like urea or creatinine at physiologically relevant concentrations. PMID- 21289394 TI - Oxidative fabrication of patterned, large, non-flaking CuO nanowire arrays. AB - We report a simple and fast approach to fabricate large, non-flaking arrays of CuO nanowires by oxidizing thin copper substrates in air. Oxidative CuO nanowire growth is commonly accompanied by oxide layer flaking due to stress at the copper copper oxide interface. Using thin substrates is shown to prevent this flaking by introducing favourable material thickness ratios in the samples after oxidation. Additionally, thin foils allow larger scale topographic patterns to be transferred from an underlying mould to realize non-flat, nanowire-decorated surfaces. Further patterning is possible by electrodeposition of a nickel layer, which restricts nanowire growth to specific areas of the sample. PMID- 21289395 TI - Antifungal activity of ZnO nanoparticles--the role of ROS mediated cell injury. AB - Metal oxide nanoparticles have marked antibacterial activity. The toxic effect of these nanoparticles, such as those comprised of ZnO, has been found to occur due to an interaction of the nanoparticle surface with water, and to increase with a decrease in particle size. In the present study, we tested the ability of ZnO nanoparticles to affect the viability of the pathogenic yeast, Candida albicans (C. albicans). A concentration-dependent effect of ZnO on the viability of C. albicans was observed. The minimal fungicidal concentration of ZnO was found to be 0.1 mg ml(-1) ZnO; this concentration caused an inhibition of over 95% in the growth of C. albicans. ZnO nanoparticles also inhibited the growth of C. albicans when it was added at the logarithmic phase of growth. Addition of histidine (a quencher of hydroxyl radicals and singlet oxygen) caused reduction in the effect of ZnO on C. albicans depending on its concentration. An almost complete elimination of the antimycotic effect was achieved following addition of 5 mM of histidine. Exciting the ZnO by visible light increased the yeast cell death. The effects of histidine suggest the involvement of reactive oxygen species, including hydroxyl radicals and singlet oxygen, in cell death. In light of the above results it appears that metal oxide nanoparticles may provide a novel family of fungicidal compounds. PMID- 21289396 TI - The fabrication of nanoporous Pt-based multimetallic alloy nanowires and their improved electrochemical durability. AB - A general approach for the fabrication of nanoporous Pt-based multimetallic alloy nanowires is reported, which involves electrodeposition of corresponding precursor alloys into porous anodic alumina templates, followed by a mild dealloying process. Nanoporous ternary PtCoNi and PtCoAu as well as quaternary PtRuCoNi nanowires were successfully fabricated, and their microstructure and composition were examined by transmission electron microscopy. Electrochemical tests showed that these porous nanowires exhibit higher electrochemically active surface area and much improved durability compared to commercially available Pt black, and may find potential applications in electrocatalysis and electrochemical sensing. PMID- 21289397 TI - Optical absorption characteristic of highly ordered and dense two-dimensional array of silicon nanodiscs. AB - We created a two-dimensional array of sub-10 nm Si-nanodiscs (Si-NDs), i.e. a 2D array of Si-NDs, with a highly ordered arrangement and dense NDs by using a new top-down technique comprising advanced damage-free neutral-beam (NB) etching and a bio-template (iron oxide core) as a uniform sub-10 nm etching mask. The bandgap energy (E(g)) of the fabricated 2D array of Si-NDs can be simply controlled from 2.2 to 1.3 eV by changing the ND thickness from 2 to 12 nm. Due to weak quantum confinement existing in the diameter direction resulting from the sub-10 nm Si-ND diameter, even though the thickness of the Si-ND is much larger than the Bohr radius of Si, E(g) is still larger than the 1.1 eV E(g) of bulk Si. Si-ND not only has wide controllable E(g) but also a high absorption coefficient due to quantum confinement in three dimensions. This new technique is a promising candidate for developing new nanostructures and could be integrated into the fabrication of nanoelectronic devices. PMID- 21289398 TI - Friction-formed liquid droplets. AB - The formation of nanoscale liquid droplets by friction of a solid is observed in real-time. This is achieved using a newly developed in situ transmission electron microscope (TEM) triboprobe capable of applying multiple reciprocating wear cycles to a nanoscale surface. Dynamical imaging of the nanoscale cyclic rubbing of a focused-ion-beam (FIB) processed Al alloy by diamond shows that the generation of nanoscale wear particles is followed by a phase separation to form liquid Ga nanodroplets and liquid bridges. The transformation of a two-body system to a four-body solid-liquid system within the reciprocating wear track significantly alters the local dynamical friction and wear processes. Moving liquid bridges are observed in situ to play a key role at the sliding nanocontact, interacting strongly with the highly mobile nanoparticle debris. In situ imaging demonstrates that both static and moving liquid droplets exhibit asymmetric menisci due to nanoscale surface roughness. Nanodroplet kinetics are furthermore dependent on local frictional temperature, with solid-like surface nanofilaments forming on cooling. TEM nanotribology opens up new avenues for the real-time quantification of cyclic friction, wear and dynamic solid-liquid nanomechanics, which will have widespread applications in many areas of nanoscience and nanotechnology. PMID- 21289399 TI - Hybrid InAs nanowire-vanadium proximity SQUID. AB - We report the fabrication and characterization of superconducting quantum interference devices (SQUIDs) based on InAs nanowires and vanadium superconducting electrodes. These mesoscopic devices are found to be extremely robust against thermal cycling and to operate up to temperatures of ~ 2.5 K with reduced power dissipation. We show that our geometry allows one to obtain nearly symmetric devices with very large magnetic field modulation of the critical current. All these properties make these devices attractive for sensitive magnetometry applications and quantum circuit implementation. PMID- 21289400 TI - Fabrication and nano-imprintabilities of Zr-, Pd- and Cu-based glassy alloy thin films. AB - With the aim of investigating nano-imprintability of glassy alloys in a film form, Zr(49)Al(11)Ni(8)Cu(32), Pd(39)Cu(29)Ni(13)P(19) and Cu(38)Zr(47)Al(9)Ag(6) glassy alloy thin films were fabricated on Si substrate by a magnetron sputtering method. These films exhibit a very smooth surface, a distinct glass transition phenomenon and a large supercooled liquid region of about 80 K, which are suitable for imprinting materials. Moreover, thermal nano-imprintability of these obtained films is demonstrated by using a dot array mold with a dot diameter of 90 nm. Surface observations revealed that periodic nano-hole arrays with a hole diameter of 90 nm were successfully imprinted on the surface of these films. Among them, Pd-based glassy alloy thin film indicated more precise pattern imprintability, namely, flatter residual surface plane and sharper hole edge. It is said that these glassy alloy thin films, especially Pd-based glassy alloy thin film, are one of the promising materials for fabricating micro-machines and nano devices by thermal imprinting. PMID- 21289401 TI - Stacked GaAs quantum dots fabricated by refilling of self-organized nanoholes: optical properties and post-growth annealing. AB - We study the photoluminescence and impact of post-growth annealing of stacked, strain-free GaAs quantum dots fabricated by refilling of self-organized nanoholes using molecular beam epitaxy. Temperature- and power-dependent photoluminescence studies reveal an excellent optical quality of the quantum-dot stack. After high temperature post-growth annealing only slight blueshifts and an increase in full width at half-maximum of the photoluminescence peak are observed, indicating very high-temperature stability and crystalline quality of the stacked GaAs quantum dot structure. PMID- 21289402 TI - Preparation and characterization of chrysotile for use as nanofiller in polyolefins. AB - Chrysotile was treated using three methods to reduce its toxicity and prepare it for use as nanofiller in olefin polymerization. In two of the treatments chrysotile was leached with hydrochloric acid at different concentrations, 0.1 and 3.0 M, and subsequently subjected to thermal treatment. In the third method the chrysotile was only exposed to a thermal treatment at 800 degrees C. The treated chrysotiles were characterized by BET, SEM-EDX, XRD, TEM and DRIFTS. The dilute acid treatment was the most efficient and gave a material with a nanotube morphology, with reduced toxicity, high aspect ratio and high concentrations of isolated OH groups. All the treatments gave particles with nanometric dimensions interesting for use as nanofillers in nanocomposites and also as support for catalysts. PMID- 21289403 TI - Control of luminescence emitted by Cd 1-x Mn x S nanocrystals in a glass matrix: x concentration and thermal annealing. AB - Cd(1-x)Mn(x)S nanocrystals (NCs) were successfully grown in a glass matrix and investigated by photoluminescence (PL), electron paramagnetic resonance (EPR) and magnetic force microscopy (MFM). We verified that the luminescent properties of these NCs can be controlled both by changing the x concentration and by thermal annealing of the samples. The EPR and PL data showed that the characteristic emission of Mn(2+) ions ((4)T(1)-(6)A(1)) is only observed when this magnetic impurity is substitutionally incorporated in the Cd(1-x)Mn(x)S NC core (site S(I)). Besides, it was observed that the emission ((4)T(1)-(6)A(1)) suppression, caused by the Mn(2+) ion presence near the surface (site S(II)) of the Cd(1 x)Mn(x)S NCs, is independent of the host material. The MFM images also confirmed the high quality of the Cd(1 - x)Mn(x)S NC samples, showing a uniform distribution of total magnetic moments in the nanoparticles. PMID- 21289404 TI - Controlled synthesis of core-shell iron-silica nanoparticles and their magneto dielectric properties in polymer composites. AB - Low loss core-shell iron-silica nanocomposites with improved magneto-dielectric properties at radio frequencies (1 MHz-1 GHz) were successfully fabricated. A new simple method was developed to synthesize metallic iron (Fe) nanoparticles with uniform size distribution in an aqueous environment at room temperature. Citric acid and oleic acid served as surface-capping agents to control the particle size of the synthesized Fe nanoparticles. Smaller Fe nanoparticles with narrower particle size distribution were obtained as the concentration ratio of iron ions to carboxylic acid groups decreased. The Fe nanoparticles were subsequently coated with silica (SiO(2)) layers to prevent the iron cores oxidizing. Polymer composites were prepared by incorporating Fe@SiO(2) nanoparticles with polydimethylsiloxane (PDMS) elastomers. Experimental results showed that the dielectric permittivity (epsilon) and magnetic permeability (MU) of the polymer composite increased with increasing amount of Fe@SiO(2) nanoparticle doping. The dielectric loss (tandelta) was near 0.020 at a frequency of 1 GHz. PMID- 21289405 TI - Microstructure and optical properties of Ag-doped ZnO nanostructures prepared by a wet oxidation doping process. AB - Silver-doped zinc oxide (Ag:ZnO) nanostructures were prepared by a facile and efficient wet oxidation method. This method included two steps: metallic Zn thin films mixed with Ag atoms were prepared by magnetron sputtering as the precursors, and then the precursors were oxidized in an O(2) atmosphere with water vapour present to form Ag:ZnO nanostructures. By controlling the oxidation conditions, pure ZnO and Ag:ZnO nanobelts/nanowires with a thickness of ~ 20 nm and length of up to several tens of microns were synthesized. Scanning electron microscopy, transmission electron microscopy, cathodoluminescence and low temperature photoluminescence (PL) measurements were adopted to characterize the microstructure and optical properties of the prepared samples. The results indicated that Ag doping during magnetron sputtering was a feasible method to tune the optical properties of ZnO nanostructures. For the Ag:ZnO nanostructures, the intensity of ultraviolet emission was increased up to three times compared with the pure ones. The detailed PL intensity variation with the increasing temperature is also discussed based on the ionization energy of acceptor in ZnO induced by Ag dopants. PMID- 21289406 TI - Magnetism in oxidized graphenes with hydroxyl groups. AB - The magnetic properties of three oxidized graphene structures with hydroxyl groups (cases A, B and C) have been investigated through spin-polarized density functional theory. The results reveal that in a graphene hexagonal ring structure, chemical bond formation by two non-neighbored hydroxyl-bonded carbon atoms with one carbon atom between (case B) can cause unpaired spins to produce a magnetic moment of 1.2 MU(B), while chemical bond formation by two neighbored hydroxyl-bonded carbon atoms (case A) or non-neighbored hydroxyl-bonded carbon atoms with two carbon atoms between (case C) cannot generate unpaired spins for nonmagnetic states. These magnetic oxidized graphenes have great promise for new spintronics. This work provides fundamentals to controllably synthesize or/and oxidized graphene with hydroxyl groups at specific carbon positions for magnetic properties. PMID- 21289407 TI - Optimized network of multi-walled carbon nanotubes for chemical sensing. AB - This work reports the design of a resistive gas sensor based on 2D mats of multi walled carbon nanotubes (MWCNTs) grown by aerosol-assisted chemical vapour deposition. The sensor sensitivity was optimized using chlorine as analyte by tuning both CNT network morphology and CNT electronic properties. Optimized devices, operating at room temperature, have been calibrated over a large range of concentration and are shown to be sensitive down to 27 ppb of chlorine. The as grown MWCNT response is compared with responses of 2000 degrees C annealed CNTs, as well as of nitrogen-doped CNTs and CNTs functionalized with polyethyleneimine (PEI). Under chlorine exposure, the resistance decrease of as-grown and annealed CNTs is attributed to charge transfer from chlorine to CNTs and demonstrates their p-type semiconductor behaviour. XPS analysis of CNTs exposed to chlorine shows the presence of chloride species that confirms electron charge transfer from chlorine to CNTs. By contrast, the resistance of nitrogen-doped and PEI functionalized CNTs exposed to chlorine increases, in agreement with their n-type semiconductor nature. The best response is obtained using annealed CNTs and is attributed to their higher degree of crystallinity. PMID- 21289408 TI - The role of surface charge on the uptake and biocompatibility of hydroxyapatite nanoparticles with osteoblast cells. AB - The objective of this study is to evaluate the effect of hydroxyapatite (HAP) nanoparticles with different surface charges on the cellular uptake behavior and in vitro cell viability and proliferation of MC3T3-E1 cell lines (osteoblast). The nanoparticles' surface charge was varied by surface modification with two carboxylic acids: 12-aminododecanoic acid (positive) and dodecanedioic acid (negative). The untreated HAP nanoparticles and dodecanoic acid modified HAP nanoparticles (neutral) were used as the control. X-ray diffraction (XRD) revealed that surface modifications by the three carboxylic acids did not change the crystal structure of HAP nanoparticles; Fourier transform infrared spectroscopy (FT-IR) confirmed the adsorption and binding of the carboxylic acids on the HAP nanoparticles' surfaces; and zeta potential measurement confirmed that the chemicals successfully modified the surface charge of HAP nanoparticles in water based solution. Transmission electron microscopy (TEM) images showed that positively charged, negatively charged and untreated HAP nanoparticles, with similar size and shape, all penetrated into the cells and cells had more uptake of HAP nanoparticles with positive charge compared to those with negative charge, which might be attributed to the attractive or repulsive interaction between the negatively charged cell membrane and positively/negatively charged HAP nanoparticles. The neutral HAP nanoparticles could not penetrate the cell membrane due to their larger size. MTT assay and LDH assay results indicated that as compared with the polystyrene control, greater cell viability and cell proliferation were measured on MC3T3-E1 cells treated with the three kinds of HAP nanoparticles (neutral, positive, and untreated), among which positively charged HAP nanoparticles showed the strongest improvement for cell viability and cell proliferation. In summary, the surface charge of HAP nanoparticles can be modified to influence the cellular uptake of HAP nanoparticles and the different uptake also influences the behavior of cells. These in vitro results may also provide useful information for investigations of HAP nanoparticle applications in gene delivery and intracellular drug delivery. PMID- 21289409 TI - Electronic transport in conducting polymer nanowire array devices. AB - We report on the temperature dependent conductivity and current-voltage (I-V) properties of novel polyaniline nanowire array devices. Below 60 K, I-V measurements show a transition to non-linear behaviour, leading to the onset at 30 K of a threshold voltage, for potentials below which little current flows. By considering an intrinsic morphology of small conducting regions separated by tunnel junctions, we show that charging of the conducting regions leads to Coulomb blockade effects that can account for this behaviour. PMID- 21289410 TI - Low energy focused ion beam milling of silicon and germanium nanostructures. AB - In this paper focused ion beam milling of very shallow nanostructures in silicon and germanium by low energy Ga( + ) ions is studied with respect to ion beam and scanning parameters. It has been found that, using low energy ions, many scanning artefacts can be avoided and, additionally, some physical effects (e.g. redeposition and ion channelling) are significantly suppressed. The structures milled with low energy ions suffer less subsurface ion beam damage (amorphization, formation of voids) and are thus more suitable for selected applications in nanotechnology. PMID- 21289411 TI - Dielectrophoretic self-assembly of polarized light emitting poly(9,9 dioctylfluorene) nanofibre arrays. AB - Conjugated polymer based 1D nanostructures are attractive building blocks for future opto-electronic nanoscale devices and systems. However, a critical challenge remains the lack of manipulation methods that enable controlled and reliable positioning and orientation of organic nanostructures in a fast, reliable and scalable manner. To address this challenge, we explore dielectrophoretic assembly of discrete poly(9,9-dioctylfluorene) nanofibres and demonstrate site selective assembly and orientation of these fibres. Nanofibre arrays were assembled preferentially at receptor electrode edges, being aligned parallel to the applied electric field with a high order parameter fit (~ 0.9) and exhibiting an emission dichroic ratio of ~ 4.0. As such, the dielectrophoretic method represents a fast, reliable and scalable self-assembly approach for manipulation of 1D organic nanostructures. The ability to fabricate nanofibre arrays in this manner could be potentially important for exploration and development of future nanoscale opto-electronic devices and systems. PMID- 21289412 TI - [Animal models for bone and joint disease. Ovariectomized and orchidectomized animals]. AB - Ovariectomized (OVX) animal is a typical experimental model for investigation of postmenopausal osteoporosis due to estrogen deficiency in women. Recently, both OVX mouse and OVX rat are commonly used for the evaluation of bone tissues in the animal model. OVX mouse is appropriate for the study of pathogenesis of postmenopausal osteoporosis, since various gene knockout mice are available for the experiments. OVX rat model is widely used for the evaluation and development of new drug compounds for postmenopausal osteoporosis treatments. On the other hand, orchidectomized (ORX) animal model is excellent in the study of osteoporosis due to androgen deficiency in men. Both OVX and ORX animal exhibits marked bone loss with increased bone resorption. We focused on the feature and evaluation technique for bone tissues in OVX and ORX animals. PMID- 21289413 TI - [Animal models for bone and joint disease. Low calcium diet-induced rat model of osteoporosis]. AB - Amount of daily calcium (Ca) intake have direct impact on bone metabolism, because of an important mineral component of bone. Two months rearing with less than 0.3% Ca diet clarified effectiveness for a rat model of osteoporosis, resulted in a significant decrease in BMD and bone strength. Besides low Ca diet associated with ovariectomy also induced significant decrease in BMC and BMD in such a short-term. Otherwise precaution for assessment as to an experimental objective ought to be deliberated depend on which part of bone should be evaluated and how long rats should be reared. PMID- 21289414 TI - [Animal models for bone and joint disease. Animal models of immobilization and unloading]. AB - Animal models of immobilization and unloading mimic the situation of lack of mechanical stimulation on the limb. Immobilization or unloading of the hindlimb for one or two weeks rapidly reduces tibial trabecular bone volume by approximately 50% of the baseline level. We should pay attention on the fact that the subsequent results after immobilization or unloading significantly depend on the strains of the mice. Here, we describe the practical technique for preparing animal models and the obtained results concerning the mechanism of bone loss and articular degeneration due to immobilization or unloading. PMID- 21289415 TI - [Animal models for bone and joint disease. Bone disease of osteoprotegerin deficient mouse]. AB - Osteoprotegerin (OPG) acts as a decoy receptor for the receptor activator of the nuclear factor kappa B (RANK) ligand (RANKL) , preventing its association with RANK and inhibiting osteoclastogenesis. Therefore, mice homozygous for targeted disruption of the OPG gene reveal stimulated bone resorption and bone formation, resulting in enhanced bone remodeling. The OPG deficient (OPG( - / - )) mouse showed the diturbed distribution of collagen fibers and complex meshwork of cement lines, which implies weakened strength of OPG( - / - ) bone against mechanical stress. In addition, the abnormally promoted remodeling of the OPG( - / - ) bone caused the disorganized distribution of osteocyte lacunar canalicular system (OLCS) . Histochemical assessment revealed the markedly reduced synthesis of sclerostin in the OPG( - / - ) OLCS while the synthesis of dentin matrix protein-1 was not extremely affected by the OPG deficiency. Taken together, OPG deficient mouse appears to be a valid model for extremely-stimulated bone remodeling, and would provided important clues for better understanding for activities of bone cells in a pathological state in bone. PMID- 21289416 TI - [Animal models for bone and joint disease. RANKL-injected bone loss model]. AB - Discovery of the osteoclast differentiation factor RANKL (receptor activator of NF-kappaB ligand) has opened a new era in the understanding of mechanisms in osteoclast differentiation over the last decade. The discovery results in the development of a fully human anti-RANKL neutralizing monoclonal antibody (called denosumab) and denosumab has been approved for the treatment of osteoporosis in Europe and the US. Here I review a novel rapid bone loss model with GST (glutathione-S-transferase) -RANKL. Pharmacologic studies of candidates for the treatment of osteoporosis with this model can be done in short periods such as 3 days and a couple of weeks although it took several months in the conventional methods with ovariectomized (OVX) -rats. This model also is useful for the rapid analyses in the functions of osteoclasts in vivo . I am expecting the RANKL induced bone loss model to be the gold standard in the animal osteoporosis model as well as OVX-rats in the near future. PMID- 21289417 TI - [Animal models for bone and joint disease. Genetic analysis of low BMD in SAMP6 mice]. AB - We performed the whole-genome scan for quantitative trait loci (QTLs) in SAMP6 mice that exhibits a significantly low peak bone mass. We found two significant loci on Chrs 11 and 13 (designated Pbd1 and Pbd2, respectively) and one suggestive locus on Chr X (designated Pbd3 ) that were linked to the bone mass. Next, we clarified that Pbd1 is related to the bone geometry, Pbd2 to the formation of bone before maturation, and Pbd3 to the bone loss after maturation. In particular, we showed that secreted frizzled-related protein 4 (Sfrp4) encoded by a gene within the Pbd2 locus on Chr 13 was responsible, at least in part, for the lower bone mineral density (BMD) in the SAMP6 mice, by inhibiting the proliferation of osteoblasts. PMID- 21289418 TI - [Animal models for bone and joint disease. Rodent models of natural aging]. AB - This review summarizes changes in bone mass and metabolism during natural aging of C57BL/6J mice and F344/N rats, as models of senile osteoporosis. The effects of caloric restriction, an evolutionally conserved remedy known to slow aging process and counter age-related disorders, on bone metabolism are also discussed. PMID- 21289419 TI - [Animal models for bone and joint disease. The genetically-modified mice as a tool for osteoporosis research]. AB - Recent advances of molecular genetics made it possible to generate genetically modified mice. Furthermore, the discovery and application of Cre-loxP recombination system into mouse genetics led to study the function of a gene in a tissue-specific manner. Analyses of these mutant mice advanced our understanding of the molecular physiology and pathophisiology of skeletal tissue. PMID- 21289420 TI - [Animal models for bone and joint disease. Animal fracture model and fracture healing process]. AB - We described how to make our rat femoral fracture model. Based on our results using this model, we reviewed radiological, histological and mechanical fracture healing process. Fracture healing is completed by not only bone union of fracture site but restoration of original bony shape and bone quality due to progression of callus remodeling. PMID- 21289421 TI - [Animal models for bone and joint disease. Assessment of bone mass, structure and strength in rat and mouse models - focus on micro-computed tomography study -]. AB - In the assessment of quality of bone in animal models, it is required to know the differences in bone mineral density, bone structure and strength from the human bones. "Guidelines for Assessment of Bone Microstructure in Rodents Using Micro Computed Tomography" has been published (2010 JBMR). For a good use of micro-CT for animal studies, the important items are explained in this article, (1) Imaging acquisition : sample preparation and positioning, X-ray scan conditions, voxel size/image resolution, region of interest (2) Image processing : filtration, segmentation (3) Terminology and algorithm of trabecular (bone volume fraction, trabecular number/thickness/separation, structure model index, connectivity, degree of anisotropy) and cortical (cross-sectional area, cortical thickness) bone morphometry. PMID- 21289422 TI - [Animal models for bone and joint disease. CIA, CAIA model]. AB - The collagen-induced arthritis (collagen-induced arthritis, CIA) is an autoimmune arthritis that resembles rheumatoid arthritis (RA) in many ways, therefore it has been used most commonly as a model of RA. CIA is induced by immunization with an emulsion of complete Freund's adjuvant (CFA) and type II collagen (C II ) . Collagen antibody-induced arthritis (CAIA) is induced by the administration of a cocktail of monoclonal antibodies recognizing conserved epitopes located within the CB11 fragment. CAIA offers several advantages over CIA, including rapid disease onset, high uptake rate, and the capacity to use genetically modified mice, such as transgenics and knockouts. PMID- 21289423 TI - [Animal models for bone and joint disease. K/BxN mice - serum transferred arthritis -]. AB - K/BxN mice spontaneously develop severe symmetrical polyarthritis, and serum from these mice induces a similar arthritis in a wide range of mouse strains, due to autoantibodies recognizing glucose-6-phosphate isomerase (GPI) . K/BxN mice and their serum have been used for investigating the development of arthritis, particularly used for analyzing how autoantibody recognizing GPI directly induce systemic arthritis. This section summarizes the mechanisms of autoimmune arthritis of K/BxN mice, and discusses future direction. PMID- 21289424 TI - [Animal models for bone and joint disease. Osteoimmunology and animal models for rheumatoid arthritis]. AB - Bone homeostasis is maintained by not only bone cells but also by various types of cells. Particularly, the skeletal system has an apparent relationship with the immune system, in that immune cells are generated in the bone marrow and that osteoclasts which play a crucial role in bone destruction differentiate from monocyte/macrophage lineage cells. In addition, investigation into rheumatoid arthritis (RA) has highlighted the relevance of the interplay between the bone and immune systems and promoted a new research field of 'osteoimmunology'. Here, we summarize how various animal models for RA contributed, and can contribute to the progress in osteoimmunology and increasing understanding of RA development and treatment. PMID- 21289425 TI - [Animal models for bone and joint disease. Osteoarthritis development in experimental mouse models induced by mechanical stress]. AB - Little is known about molecular mechanism underlying osteoarthrits. Our mouse genetics approaches by mechanical stress induced OA models found that the proteinases produced during the endochondral ossification process cause cartilage degradation at the center of the joint and osteophyte formation at the periphery. At the periphery, vascularity is accessible from the synovium or tendon, which completes endochondral ossification and forms osteophytes, just as it does at the embryonic and growth plate cartilage. However, in the center, the vascularity is not accessible from the edge, so that it may end up with cartilage degradation without being replaced by bone. Molecules related to the endochondral ossification will be a therapeutic target of osteoarthritis, so our experimental mouse models are useful tools for elucidation of the molecular mechanisms. PMID- 21289426 TI - [Animal models for bone and joint disease. Mouse models develop spontaneous osteoarthritis]. AB - Osteoarthritis (OA) is a major joint disorder that significantly decreases the quality of life of elderly. Animal models, especially mice, have contributed in studies on a number of diseases. Among mice develop OA spontaneously, genetically modified and naturally mutated mice have been reported. STR/ort is a well recognized model, which pronounces natural onset OA. Here we introduce the several models possessed spontaneous OA with focusing the feature and utilization of STR/ort. PMID- 21289427 TI - [Animal models for bone and joint disease. ttw (tiptoe walking), a model mouse of OPLL (ossification of the posterior longitudinal ligament of the spine)]. AB - ttw (tiptoe walking), a known model mouse of OPLL (ossification of the posterior longitudinal ligament of the spine) is reviewed. ttw is a natural mutant which shows generalized ectopic calcification followed by ossification in the Achiles tendon, ear and spinal ligaments, etc. The trait is caused by a homozygous nonsense mutation in the gene for NPPS (nucleotide pyrophosphatase) , a cell membrane enzyme that produces pyrophosphate. Its pathomechanism is the decrease of extracellular pyrophosphate due to insufficiency of NPPS. ttw is a excellent model for ectopic calcification and ossification. Several interesting genes related to ectopic calicification have been identified by studies using this mouse. PMID- 21289428 TI - Single-neuron encoding of surprise in auditory processing. PMID- 21289429 TI - Neural coding of temporal information and its topography in the auditory cortex. PMID- 21289430 TI - Optineurin, a multifunctional protein involved in glaucoma, amyotrophic lateral sclerosis and antiviral signalling. PMID- 21289431 TI - Science literacy and natural history museums. AB - It appears that developed countries, such as the US, the UK and Italy, are losing the race against irrationalism and arbitrary thinking in regard to nature and human interactions. The incidence of misguided beliefs and the detachment from and, in some cases, outright hostility toward science are on the rise. Paradoxically, this is probably the period in the history of advanced countries in which increasing public and personal efforts have been directed toward the dissemination of scientific knowledge to increase public understanding of science. This article vindicates the role of natural history museums in consolidating rational and critical scientific thinking while briefly examining scientific illiteracy in developed countries. It also discusses methods to improve the involvement of natural history museums in the promotion of rational thinking, the only appropriate avenue for objective knowledge. PMID- 21289432 TI - What history tells us. XXII. The French neo-Lamarckians. PMID- 21289433 TI - Evidence for functional interaction of plasma membrane electron transport, voltage-dependent anion channel and volume-regulated anion channel in frog aorta. AB - Frog aortic tissue exhibits plasma membrane electron transport (PMET) owing to its ability to reduce ferricyanide even in the presence of mitochondrial poisons, such as cyanide and azide. Exposure to hypotonic solution (108 mOsmol/kg H2O) enhanced the reduction of ferricyanide in excised aortic tissue of frog. Increment in ferricyanide reductase activity was also brought about by the presence of homocysteine (100 microM dissolved in isotonic frog Ringer solution), a redox active compound and a potent modulator of PMET. Two plasma-membrane-bound channels, the volume-regulated anion channel (VRAC) and the voltage-dependent anion channel (VDAC), are involved in the response to hypotonic stress. The presence of VRAC and VDAC antagonists-tamoxifen, glibenclamide, fluoxetine and verapamil, and 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS), respectively-inhibited this enhanced activity brought about by either hypotonic stress or homocysteine. The blockers do not affect the ferricyanide reductase activity under isotonic conditions. Taken together, these findings indicate a functional interaction of the three plasma membrane proteins, namely, ferricyanide reductase (PMET), VDAC and VRAC. PMID- 21289434 TI - Demonstration of a visual cell-based assay for screening glucose transporter 4 translocation modulators in real time. AB - Insulin-stimulated translocation of glucose transporter 4 (GLUT4) to cell membrane leading to glucose uptake is the rate-limiting step in diabetes. It is also a defined target of antidiabetic drug research. Existing GLUT4 translocation assays are based on time-consuming immunoassays and are hampered by assay variability and low sensitivity. We describe a real-time, visual, cell-based qualitative GLUT4 translocation assay using CHO-HIRc-myc-GLUT4eGFP cells that stably express myc- and eGFP-tagged GLUT4 in addition to human insulin receptor (HIRc). GLUT4 translocation is visualized by live cell imaging based on GFP fluorescence by employing a cooled charge-coupled device camera attached to a fluorescent microscope. This video imaging method and further quantitative analysis of GLUT4 on the cell membrane provide rapid and foolproof visual evidence that this method is suitable for screening GLUT4 translocation modulators. PMID- 21289435 TI - Antibacterial abietane-type diterpenoid, taxodone from Metasequoia glyptostroboides Miki ex Hu. AB - In an attempt to isolate bioactive constituents, ethyl acetate cone extract of Metasequoia glyptostroboides was subjected to a column chromatographic analysis that resulted in isolation of an abietane-type diterpenoid, taxodone. Its structure was elucidated by spectroscopic means. Further, taxodone showed potential antibacterial effect as diameters of zones of inhibition against foodborne pathogenic bacteria, such as Listeria monocytogenes ATCC 19166, Salmonella typhimurium KCTC 2515, S. enteritidis KCTC 2021, Escherichia coli ATCC 8739, E. coli O157:H7 ATCC 43888, Enterobacter aerogenes KCTC 2190, Staphylococcus aureus ATCC 6538 and S. aureus KCTC 1916, were found in the range of 9.4 to 14.2 mm. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values of taxodone against the employed bacterial pathogens were found in the range of 250 to 1000 and 250 to less than 2000 microg/ml, respectively. Also the compound had a strong antibacterial effect on the viable counts of the tested bacteria. These findings indicate that the bioactive compound taxodone present in M. glyptostroboides could be used as an antibacterial agent in food industry to inhibit the growth of certain important foodborne pathogens. PMID- 21289436 TI - Translocations used to generate chromosome segment duplications in Neurospora can disrupt genes and create novel open reading frames. AB - In Neurospora crassa, crosses between normal sequence strains and strains bearing some translocations can yield progeny bearing a duplication (Dp) of the translocated chromosome segment. Here, 30 breakpoint junction sequences of 12 Dp generating translocations were determined. The breakpoints disrupted 13 genes (including predicted genes), and created 10 novel open reading frames. Insertion of sequences from LG III into LG I as translocation T(UK8-18) disrupts the eat-3 gene, which is the ortholog of the Podospora anserine gene ami1. Since ami1 homozygous Podospora crosses were reported to increase the frequency of repeat induced point mutation (RIP), we performed crosses homozygous for a deficiency in eat-3 to test for a corresponding increase in RIP frequency. However, our results suggested that, unlike in Podospora, the eat-3 gene might be essential for ascus development in Neurospora. Duplication-heterozygous crosses are generally barren in Neurospora; however, by using molecular probes developed in this study, we could identify Dp segregants from two different translocation-heterozygous crosses, and using these we found that the barren phenotype of at least some duplication-heterozygous crosses was incompletely penetrant. PMID- 21289437 TI - Replacement of the C-terminal tetrapeptide (314 PAPV 317 to 314 SSSM 317) in interferon regulatory factor-2 alters its N-terminal DNA-binding activity. AB - Interferon regulatory factor-2 (IRF-2) is an important transcription factor involved in cell growth regulation, immune response and cancer. IRF-2 can function as a transcriptional repressor and activator depending on its DNA binding activity and protein-protein interactions. We compared the amino acid sequences of IRF-2 and found a C-terminal tetrapeptide (314PAPV317) of mouse IRF 2 to be different (314SSSM317) from human IRF-2. Recombinant GST-IRF-2 with 314PAPV317 (wild type) and 314SSSM317 (mutant) expressed in Escherichia coli were assessed for DNA-binding activity with 32P-(GAAAGT) 4 by electrophoretic mobility shift assay (EMSA). Wild type- and mutant GST-IRF-2 showed similar expression patterns and immunoreactivities but different DNA-binding activities. Mutant (mt) IRF-2 formed higher-molecular-mass, more and stronger DNA-protein complexes in comparison to wild type (wt) IRF-2. Anti-IRF-2 antibody stabilized the DNA protein complexes formed by both wt IRF-2 and mt IRF-2, resolving the differences. This suggests that PAPV and SSSM sequences at 314-317 in the C terminal region of mouse and human IRF-2 contribute to conformation of IRF-2 and influence DNA-binding activity of the N-terminal region, indicating intramolecular interactions. Thus, evolution of IRF-2 from murine to human genome has resulted in subtle differences in C-terminal amino acid motifs, which may contribute to qualitative changes in IRF-2-dependent DNA-binding activity and gene expression. PMID- 21289438 TI - Proteomic analysis of cell lines to identify the irinotecan resistance proteins. AB - Chemotherapeutic drug resistance is a frequent cause of treatment failure in colon cancer patients. Several mechanisms have been implicated in drug resistance. However, they are not sufficient to exhaustively account for this resistance emergence. In this study, two-dimensional gel electrophoresis (2-DE) and the PDQuest software analysis were applied to compare the differential expression of irinotecan-resistance-associated protein in human colon adenocarcinoma LoVo cells and irinotecan-resistant LoVo cells (LoVo/irinotecan). The differential protein dots were excised and analysed by ESI-Q-TOF mass spectrometry (MS). Fifteen proteins were identified, including eight proteins with decreased expression and seven proteins with increased expression. The identified known proteins included those that function in diverse biological processes such as cellular transcription, cell apoptosis, electron transport/redox regulation, cell proliferation/differentiation and retinol metabolism pathways. Identification of such proteins could allow improved understanding of the mechanisms leading to the acquisition of chemoresistance. PMID- 21289439 TI - Antimycobacterial activity of two natural alkaloids, vasicine acetate and 2 acetyl benzylamine, isolated from Indian shrub Adhatoda vasica Ness. leaves. AB - In folk medicine, Adhatoda vasica Ness. (Acanthaceae) is used to treat asthma and cough. The leaves of A. vasica were powdered and extracted with hexane, ethyl acetate and methanol. The hexane extract showed 97 percent reduction in colony forming units (CFU) at 100 microg/ml. The hexane extract was subjected to column chromatography. Two natural compounds, vasicine acetate and 2-acetyl benzylamine, were isolated from it. They were bioassayed against Mycobacterium tuberculosis. The two compounds showed strong antimycobacterial activity. Vasicine acetate and 2-acetyl benzylamine isolated from hexane extract of A. vasica leaves, significantly inhibited M. tuberculosis and one multi-drug-resistant (MDR) strain and one sensitive strain at 200 and 50 microg/ml, respectively. Our study demonstrated that both the compounds, vasicine acetate and 2-acetyl benzylamine, could be evaluated further for developing a drug to control M. tuberculosis. PMID- 21289440 TI - Temporal phase relation of circadian neural oscillations as the basis of testicular maturation in mice: a test of a coincidence model. AB - To study the underlying mechanism of gonadal growth during the attainment of puberty and to test a coincidence model, 7 experimental groups of 2-week-old male mice, Mus musculus, were administered the serotonin precursor, 5 hydroxytryptophan, followed by the dopamine precursor, L-dihydroxyphenylalanine at hourly intervals of 6, 7, 8, 9, 10, 11 and 12 h (5 mg/100 g body weight per day for 13 days). At 11 days post-treatment, a suppression of gonadal activity was seen in the 7-h mice and a maximum suppression in the 8-h mice, along with a significantly increased degree of gonadal development in the 12-h mice, as compared with the controls. In addition to its known regulation of seasonal gonadal cycles, the relative position of two circadian neural oscillations may also affect the rate of gonadal development during the attainment of puberty in mice. Moreover, the present study provides an experimental paradigm to test the coincidence model of circadian oscillations. PMID- 21289441 TI - Guanidination of notexin alters its membrane-damaging activity in response to sphingomyelin and cholesterol. AB - To elucidate the contribution of phospholipase A 2 (PLA2) activity of notexin to its ability to perturb membranes, comparative studies on the interaction of notexin and guanidinated notexin (Gu-notexin) with egg yolk phosphatidylcholine (EYPC), EYPC/egg yolk sphingomyelin (EYSM) and EYPC/EYSM/cholesterol vesicles were conducted. EYSM notably reduced the membrane-damaging activity of notexin against EYPC vesicles, but had an insignificant influence on that of Gu-notexin. Unlike the effects noted with notexin, inactivation of PLA 2 activity by EDTA led to a reduction in the ability of Gu-notexin to induce EYPC/EYSM vesicle leakage and to increase Gu-notexin-induced membrane permeability of EYPC/EYSM/cholesterol vesicles. The geometrical arrangement of notexin and Gu-notexin in contact with either EYPC/EYSM vesicles or EYPC/EYSM/cholesterol vesicles differed. Moreover, global conformation of notexin and Gu-notexin differed in either Ca2+-bound or metal-free states. These results indicate that notexin and Gu-notexin could induce membrane permeability without the involvement of PLA 2 activity, and suggest that guanidination alters the membrane-bound mode of notexin on damaging phospholipid vesicles containing sphingomyelin and cholesterol. PMID- 21289442 TI - The effect of contaminants on the adhesion of the spatulae of a gecko. AB - Many researchers have reported that the robust adhesion that enables geckos to move quickly and securely across a range of vertical and horizontal surfaces is provided by the hierarchical structure of their feet (i.e. lamellae, setae, spatulae, etc.). Maintaining this robust adhesion requires an intimate contact between the terminal tips of the spatulae and the surface. The aim of this study was to investigate the effect on the adhesive properties of the spatulae when a particle becomes trapped at the contact surface. Using the Johnson, Kendall and Roberts (JKR) theory, a model was constructed to assist in the analysis of the interactions between the spatula tip, the particle and the surface. The results showed that the keratin (the natural material of the spatula) provides a robust system for adhesion even when there is a particle in the contact area, and the effective contact area of spatulae will be 80%. When the particle is significantly harder than the surface, the adhesion properties of the contact surface influenced by the particle will be more obvious. The results also reveal that the generated adhesion is considerably higher when the spatula is in contact with a softer surface, such as wood or concrete, rather than a hard surface, such as glass or SiO2. PMID- 21289443 TI - Molecular variability analyses of Apple chlorotic leaf spot virus capsid protein. AB - The complete sequences of the coat protein (CP) gene of 26 isolates of Apple chlorotic leaf spot virus (ACLSV) from India were determined. The isolates were obtained from various pome (apple, pear and quince) and stone (plum, peach, apricot, almond and wild Himalayan cherry) fruit trees. Other previously characterized ACLSV isolates and Trichoviruses were used for comparative analysis. Indian ACLSV isolates among themselves and with isolates from elsewhere in the world shared 91-100% and 70-98% sequence identities at the amino acid and nucleotide levels, respectively. The highest degree of variability was observed in the middle portion with 9 amino acid substitutions in contrast to the N terminal and C-terminal ends, which were maximally conserved with only 4 amino acid substitutions. In phylogenetic analysis no reasonable correlation between host species and/or geographic origin of the isolates was observed. Alignment with capsid protein genes of other Trichoviruses revealed the TaTao ACLSV peach isolate to be phylogenetically closest to Peach mosaic virus, Apricot pseudo chlorotic leaf spot virus and Cherry mottle leaf virus. Recombination analysis (RDP3 ver.2.6) done for all the available ACLSV complete CP sequences of the world and Indian isolates indicate no significant evidence of recombination. However, one recombination event among Indian ACLSV-CP isolates was detected. To the best of our knowledge, this is the first report of complete CP sequence variability study from India and also the first evidence of homologous recombination in ACLSV. PMID- 21289444 TI - Self-organizing maps: a tool to ascertain taxonomic relatedness based on features derived from 16S rDNA sequence. AB - Exploitation of microbial wealth, of which almost 95% or more is still unexplored, is a growing need. The taxonomic placements of a new isolate based on phenotypic characteristics are now being supported by information preserved in the 16S rRNA gene. However, the analysis of 16S rDNA sequences retrieved from metagenome, by the available bioinformatics tools, is subject to limitations. In this study, the occurrences of nucleotide features in 16S rDNA sequences have been used to ascertain the taxonomic placement of organisms. The tetra- and penta nucleotide features were extracted from the training data set of the 16S rDNA sequence, and was subjected to an artificial neural network (ANN) based tool known as self-organizing map (SOM), which helped in visualization of unsupervised classification. For selection of significant features, principal component analysis (PCA) or curvilinear component analysis (CCA) was applied. The SOM along with these techniques could discriminate the sample sequences with more than 90% accuracy, highlighting the relevance of features. To ascertain the confidence level in the developed classification approach, the test data set was specifically evaluated for Thiobacillus, with Acidiphilium, Paracocus and Starkeya, which are taxonomically reassigned. The evaluation proved the excellent generalization capability of the developed tool. The topology of genera in SOM supported the conventional chemo-biochemical classification reported in the Bergey manual. PMID- 21289445 TI - Male mate location behaviour and encounter sites in a community of tropical butterflies: taxonomic and site associations and distinctions. AB - Male mate location behaviour and encounter sites have been studied in 72 butterfly species at Nagpur, India, and related to taxonomy, morphology, habitat and population parameters. Species can be placed in three broad classes of mate location behaviour: invariant patrolling, invariant perching, and perch-patrol, the latter associated with increasing site fidelity, territorial defence and male assemblages. Significant taxonomic differences occur, closely related species tending to share mate location behaviours. Morphological differences are found with heavier and larger butterflies displaying greater site fidelity and territorial defence, and differences occur between individuals of species which both perch and patrol. Invariant patrolling is particularly associated with tracks through vegetation, host planttrack distributions, and high female to male numbers observed on transects; invariant perching is linked more to edge features than patrolling, and to lower population counts on transects. Species which perch patrol, defend territories and establish male assemblages are associated with more complex vegetation structures, and have encounter sites at vegetation edges, landforms and predictable resource (host plant) concentrations. Attention is drawn to the importance of distinctive mate encounter sites for the conservation of butterfly species' habitats. PMID- 21289446 TI - Epigenetic modulation of host: new insights into immune evasion by viruses. AB - Viruses have evolved with their hosts, which include all living species. This has been partly responsible for the development of highly advanced immune systems in the hosts. However, viruses too have evolved ways to regulate and evade the host's immune defence. In addition to mutational mechanisms that viruses employ to mimic the host genome and undergo latency to evade the host's recognition of the pathogen, they have also developed epigenetic mechanisms by which they can render the host's immune responses inactive to their antigens. The epigenetic regulation of gene expression is intrinsically active inside the host and is involved in regulating gene expression and cellular differentiation. Viral immune evasion strategies are an area of major concern in modern biomedical research. Immune evasion strategies may involve interference with the host antigen presentation machinery or host immune gene expression capabilities, and viruses, in these manners, introduce and propagate infection. The aim of this review is to elucidate the various epigenetic changes that viruses are capable of bringing about in their host in order to enhance their own survivability and pathogenesis. PMID- 21289448 TI - Heel pain: hands-on physical therapy and stretching prove effective for treating heel pain. PMID- 21289447 TI - Glycan changes: cancer metastasis and anti-cancer vaccines. AB - Complex carbohydrates, which are major components of the cell membrane, perform important functions in cell-cell and cell-extracellular matrix interactions, as well as in signal transduction. They comprise three kinds of biomolecules: glycoproteins, proteoglycans and glycosphingolipids. Recent studies have also shown that glycan changes in malignant cells take a variety of forms and mediate key pathophysiological events during the various stages of tumour progression. Glycosylation changes are universal hallmarks of malignant transformation and tumour progression in human cancer, which take place on the whole cells or some specific molecules. Accordingly, those changes make them prominent candidates for cancer biomarkers in the meantime. This review mainly focuses on the correlation between glycosylation and the metastasis potential of tumour cells from comprehensive aspects to further address the vital roles of glycans in oncogenesising. Moreover, utilizing these glycosylation changes to ward off tumour metastasis by means of anti-adhesion approach or devising anti-cancer vaccine is one of promising targets of future study. PMID- 21289449 TI - Patellofemoral joint forces and stress during forward step-up, lateral step-up, and forward step-down exercises. AB - STUDY DESIGN: Controlled laboratory study using a repeated-measures design. OBJECTIVE: To quantify patellofemoral joint reaction force (PFJRF) and stress (PFJS) during forward step-up (FSU), lateral step-up (LSU), and forward step-down (FSD) exercises. BACKGROUND: Although FSU, LSU, and FSD exercises are commonly used in patellofemoral joint rehabilitation programs, the influence of these stepping tasks on patellofemoral joint kinetics has not been quantified. METHODS: Three-dimensional lower extremity kinematics and kinetics and electromyographic (EMG) data were obtained from 20 healthy adults during their performance of FSU, LSU, and FSD exercises. The step height for each participant was adjusted to permit a standardized knee flexion angle of 45 degrees . A previously described biomechanical model of the patellofemoral joint was used to quantify PFJRF and PFJS during each task. Peak PFJRF and PFJS during the concentric and eccentric phases of each step task were compared using a 2-factor analysis of variance (ANOVA). RESULTS: When collapsed across concentric and eccentric phases, peak PFJS was significantly greater during the FSD (mean +/- SD, 13.8 +/- 0.4 MPa) compared to the LSU (11.5 +/- 0.8 MPa; P<.001) and FSU (11.2 +/- 0.6 MPa; P = .002) exercises. Peak PFJRF also was significantly greater during the FSD (51.1 +/- 2.7 N/kg) compared to the LSU (44.1 +/- 3.4 N/kg; P<.001) and FSU (43.6 +/- 2.3 N/kg; P = .023) exercises. CONCLUSION: In selecting exercises that promote lower extremity muscle strengthening while minimizing patellofemoral joint loading, LSU and FSU should be considered over FSD exercises, if the same step height is used. PMID- 21289450 TI - Activation of selected shoulder muscles during unilateral wall and bench press tasks under submaximal isometric effort. AB - STUDY DESIGN: Controlled laboratory study. OBJECTIVE: To assess the activation of 7 shoulder muscles under 2 closed kinetic chain (CKC) tasks for the upper extremity using submaximal isometric effort, thus providing relative quantification of muscular isometric effort for these muscles across the CKC exercises, which may be applied to rehabilitation protocols for individuals with shoulder weakness. BACKGROUND: CKC exercises favor joint congruence, reduce shear load, and promote joint dynamic stability. Additionally, knowledge about glenohumeral and periscapular muscle activity elicited during CKC exercises may help clinicians to design protocols for shoulder rehabilitation. METHODS: Using surface electromyography, activation level was measured across 7 shoulder muscles in 20 healthy males, during the performance of a submaximal isometric wall press and bench press. Signals were normalized to the maximal voluntary isometric contraction, and, using paired t tests, data were analyzed between the exercises for each muscle. RESULTS: Compared to the wall press, the bench press elicited higher activity for most muscles, except for the upper trapezius. Levels of activity were usually low but were above 20% maximal voluntary isometric contraction for the serratus anterior on both tasks, and for the long head triceps brachii on the bench press. CONCLUSIONS: Both the bench press and wall press, as performed in this study, led to relatively low EMG activation levels for the muscles measured and may be considered for use in the early phases of rehabilitation. PMID- 21289451 TI - The effect of cyclic loading simulating oscillatory joint mobilization on the posterior capsule of the glenohumeral joint: a cadaveric study. AB - STUDY DESIGN: Experimental laboratory design. OBJECTIVES: To examine the effect of force and repetition during oscillatory joint mobilizations on the posterior capsule of the glenohumeral joint. BACKGROUND: The optimal external force and frequency to be used during joint mobilization to elongate the posterior capsule of the glenohumeral joint has yet to be identified. METHODS: Twenty-one posterior capsules were harvested from fresh-frozen shoulders. A cyclic loading test simulating oscillatory posterior joint mobilization on the shoulder specimens was performed with a material testing machine. The specimens were assigned to 3 different loading groups simulating joint mobilization in the toe (5 N), transition (20 N), and beginning of the linear regions (40 N) of the load displacement curve. Displacement of the humeral head at an applied load of 5 N was recorded at the 1st, 100th, 200th, 300th, 400th, 500th, and 600th cycles and at 1 hour after completion of the cyclic loading. Furthermore, stiffness was calculated after the 1st and 600th cycles and 1 hour after testing. RESULTS: Humeral head displacement was significantly greater for the 100th to 600th cycle, compared to the 1st cycle, for all 3 loading groups. Significant increases in displacement and stiffness were observed between the 1st cycle and 1 hour after completion of the cyclic tests for both the 20-N and 40-N loading groups. CONCLUSION: While oscillatory joint mobilization to a force of 5 N resulted in temporary elongation of the posterior capsule, mobilization to loads of 20 and 40 N resulted in sustained elongation of the capsule for up to 1 hour. Our findings also suggest that mobilization up to loads that represent the beginning of the linear region of the load displacement curve could be performed without serious damage to the posterior capsule. PMID- 21289452 TI - Clinical tests to diagnose lumbar segmental instability: a systematic review. AB - STUDY DESIGN: Systematic literature review. OBJECTIVES: To evaluate the diagnostic accuracy of clinical tests used to diagnose patients with structural lumbar segmental instability (LSI). BACKGROUND: Patients with structural LSI represent an important, identifiable subgrouping of individuals with low back pain. Numerous clinical tests have been proposed to diagnose structural LSI; however, data on the diagnostic accuracy of these tests have not yet been evaluated through a systematic review of the literature. METHODS: A systematic review was conducted in 6 electronic databases for diagnostic accuracy studies, published between January 1950 and March 2010, that evaluated clinical tests against radiological diagnosis of structural LSI. The diagnostic accuracy of the clinical tests from the retrieved articles was independently evaluated, reviewed, and quality scored using the QUADAS tool. RESULTS: Four articles and a total of 11 clinical tests used in the diagnosis of structural LSI met the study inclusion criteria. The majority of tests had high specificity but low sensitivity, with positive likelihood ratios ranging from very small to moderate. QUADAS scores ranged from 16 to 25 out of a possible 26. The passive lumbar extension test was the most accurate clinical test, with high sensitivity (84%), specificity (90%), and a positive likelihood ratio of 8.8 (95% CI: 4.5, 17.3), indicating that this clinical test may be useful in the differential diagnosis of structural LSI. CONCLUSION: This systematic review found that the majority of clinical tests routinely employed to diagnose structural LSI demonstrated only limited ability to do so. The results do, however, indicate that the passive lumbar extension test may be useful in orthopaedic clinical practice to diagnose structural LSI. Additional research is required to further validate its use for diagnosing structural LSI in all populations of those with low back pain. LEVEL OF EVIDENCE: Diagnosis, level 2a. PMID- 21289453 TI - Lower trapezius muscle strength in individuals with unilateral neck pain. AB - STUDY DESIGN: Descriptive and within-subject comparative study. OBJECTIVES: To examine lower trapezius muscle strength in individuals with unilateral neck pain. BACKGROUND: Previous research has established the presence of reduced cervical flexor, extensor, and rotator muscle strength in individuals with neck pain. Some authors have suggested that individuals with neck pain have limited strength of the lower trapezius muscle, yet no research has investigated this claim. METHODS: Twenty-five individuals with unilateral neck pain participated in this study. Participants completed the Northwick Park Neck Pain Questionnaire (NPQ) as a measure of disability. Side of neck pain, duration of neck pain, and hand dominance were recorded. Lower trapezius muscle strength was assessed bilaterally in each participant, using a handheld dynamometer. RESULTS: A significant difference in lower trapezius strength was found between sides (P<.001), with participants demonstrating an average of 3.9 N less force on the side of neck pain. The tested levels of association between NPQ score and percent strength deficit (r = -0.31, P = .13), and between symptom duration and percent strength deficit (r = -0.25, P = .22), were not statistically significant. No significant association was found between hand dominance and side of stronger lower trapezius (P = .59). CONCLUSION: The results of this study demonstrate that individuals with unilateral neck pain exhibit significantly less lower trapezius strength on the side of neck pain compared to the contralateral side. This study suggests a possible association between lower trapezius muscle weakness and neck pain. PMID- 21289454 TI - The relationships between inter-recti distance measured by ultrasound imaging and abdominal muscle function in postpartum women: a 6-month follow-up study. AB - STUDY DESIGN: A prospective longitudinal study. BACKGROUND: Diastasis recti abdominis (DRA) is defined as an increase in the inter-recti distance (IRD), or width of the linea alba. It is a common occurrence in women postpartum. Little information exists on the short- and long-term recovery of IRD and the relationship between changes in IRD and the functional performance of the abdominal muscles. OBJECTIVES: To investigate the natural recovery of IRD and abdominal muscle strength and endurance in women between 7 weeks and 6 months postpartum, and to examine the relationship between IRD and abdominal muscle function. METHODS: Forty postpartum (25-37 years of age) and 20 age-matched, nulliparous females participated. IRD was measured at 4 locations (upper and lower margin of the umbilical ring, and 2.5 cm above and below the umbilical ring) with a 7.5-MHz linear ultrasound transducer. Trunk flexion and rotation strength and endurance were measured with manual muscle testing and curl-ups. Evaluation was conducted at 4 to 8 weeks and 6 to 8 months after childbirth in postpartum women, and only once for the nulliparous female controls. RESULTS: During follow-up, the IRD at 2.5 cm above the umbilical ring and at the upper margin of the umbilical ring decreased (P = .013 and P = .002, respectively). The strength and static endurance of the abdominal muscles improved over time (P<.05). A negative correlation between IRD and abdominal muscle function at 7 weeks and 6 months postpartum was found (r = 0.34 to 0.51; P<.05, except for trunk flexion strength at 6 months postpartum [P = .064]). In addition, IRD changes between 7 weeks and 6 months postpartum were correlated with improvement in trunk flexion strength (Spearman rho = 0.38, P = .040). At 6 months after childbirth, postpartum women had greater mean ? SD IRDs at all 4 locations (from cranial to caudal: 1.80 +/- 0.72, 2.13 +/- 0.65, 1.81 +/- 0.62, and 1.16 +/- 0.58 cm) than those of nulliparous females (0.85 +/- 0.26, 0.99 +/- 0.31, 0.65 +/- 0.23, and 0.43 +/- 0.17 cm) (all P<.001). All abdominal strength and endurance measurements were less than those of nulliparous females (all P<.001). CONCLUSIONS: The IRD and abdominal muscle function of postpartum women improved but had not returned to normal values at 6 months after childbirth. Future research is essential to explore the need for intervention and, if needed, the effectiveness of specific intervention to reduce the size of IRD in postpartum women. PMID- 21289455 TI - Selective strength loss and decreased muscle activity in hamstring injury. AB - STUDY DESIGN: Cross-sectional, controlled laboratory study. OBJECTIVES: To determine whether thigh muscle isokinetic torque patterns and activity, measured by electromyography (EMG), of individuals with hamstring injury differ from control individuals. BACKGROUND: Neuromuscular control during thigh muscle strength assessment following hamstring injuries has not been reported. METHODS: Fifteen athletes with prior hamstring injury (hamstring-injured group [HG]) were compared to 15 uninjured athletes (control group [CG]). The injuries were incurred 6 weeks to 12 months prior to participation, and all injured athletes had returned to at least partial training. Participants performed 5 isokinetic concentric extensor, concentric flexor, and eccentric flexor torque tests at 60 degrees /s in the seated position. Peak torque was determined for each contraction type, as well as average torque for each of 4 time-based movement quartiles. EMG root-mean-squares were calculated in these movement quartiles for the biceps femoris and medial hamstrings. RESULTS: No significant differences were found for peak torque for all contractions, when comparing HG injured and uninjured sides to CG bilateral averages. The HG injured limb eccentric flexor torque was significantly lower in the fourth quartile (approximately 25 degrees to 5 degrees knee flexion, hamstring lengthened range) compared to the CG bilateral average (P = .025). Eccentric flexor biceps femoris and hamstrings EMG root-mean-squares of the HG injured and the uninjured sides were significantly lower in the second to fourth quartiles (towards the lengthened range), compared to the CG bilateral averages (P<.05). CONCLUSION: Decreased strength and EMG activation in a lengthened hamstrings range for the athletes with prior hamstring injury suggested a change in neuromuscular control. Lengthened range assessment of isokinetic eccentric flexor torque may be useful for the assessment of athletes with a prior injury; however, results should be confirmed with prospective studies. PMID- 21289457 TI - Five-position grip strength measures in individuals with clinical depression. AB - STUDY DESIGN: Case-control study. OBJECTIVES: To compare the results of 5 position grip strength testing between a group of individuals newly diagnosed with clinical depression and a group of age-matched and sex-matched individuals without depression. BACKGROUND: Clinicians often employ 5-position (or 5-rung) grip strength dynamometry as a measure of sincerity of effort. However, patients with clinical depression are known to show altered performance on motor skill tests. Therefore, the results of 5-position grip strength dynamometry in the clinically depressed may be subject to misinterpretation. METHODS: Consecutive patients newly diagnosed with clinical depression (n = 45) and age- and sex matched individuals without clinical depression (n = 45) were recruited over a 3 month period. Each group underwent identical 5-position grip strength testing of both hands. Measures were analyzed using a statistical analysis method based on an 8.5-lb (3.83-kg) SD cutoff and visual analysis of force curve plots by clinicians naive to the participants' diagnosis. RESULTS: Participants with clinical depression had an SD equal to or less than 8.5 lb in 60 of 90 hands tested, while the participants in the control group had an SD equal to or less than 8.5 lb in 1 of 90 hands. Clinicians who analyzed force plots considered participants with depression to have exerted "limited effort" in 70% of cases and those who were not depressed to have exerted limited effort in 18% of cases. CONCLUSION: A high percentage of individuals diagnosed with clinical depression produced statistical and graphical representations of 5-position grip strength measures that suggested poor volitional effort, which is often interpreted as lack of sincerity of effort. Clinicians unaware of the presence of clinical depression in patients could misinterpret the results of 5-position grip strength testing in this population. PMID- 21289456 TI - Utilization of modified NFL combine testing to identify functional deficits in athletes following ACL reconstruction. AB - STUDY DESIGN: Case control. OBJECTIVES: To use modified NFL Combine testing methodology to test for functional deficits in athletes following anterior cruciate ligament (ACL) reconstruction following return to sport. BACKGROUND: There is a need to develop objective, performance-based, on-field assessment methods designed to identify potential lower extremity performance deficits and related impairments in this population. METHODS: Eighteen patients (mean +/- SD age, 16.9 +/- 2.1 years; height, 170.0 +/- 8.7 cm; body mass, 71.9 +/- 21.8 kg) who returned to their sport within a year following ACL reconstruction (95% CI: 7.8 to 11.9 months from surgery) participated (ACLR group). These individuals were asked to bring 1 or 2 teammates to serve as control participants, who were matched for sex, sport, and age (n = 20; mean +/- SD age, 16.9 +/- 1.1 years; height, 169.7 +/- 8.4 cm; body mass, 70.1 +/- 20.7 kg). Functional performance was tested using the broad jump, vertical jump, modified long shuttle, modified pro shuttle, modified agility T-test, timed hop, triple hop, single hop, and crossover hop tests. A 1-way multivariate analysis of variance (MANOVA) was used to evaluate group differences for dependent performance variables. RESULTS: The functional performance measurements of skills requiring bilateral involvement of both lower extremities showed no group differences between the ACLR and control groups (P>.05). An overall group difference (P = .006) was observed for the combined limb symmetry index (LSI) measures. However, the modified double-limb performance tasks (long shuttle, modified agility T-test, and pro shuttle) were not, independently, sufficiently sensitive to detect limb deficits in individuals with ACL reconstruction. Conversely, the LSI on the distance measures of the single-limb performance tasks all provided moderate to large effect sizes to differentiate between the ACLR and control groups, as the individuals who had ACL reconstruction demonstrated involved limb deficits on all measures (P<.05). Finally, the LSI for the timed hop test was not different between groups (P>.05). CONCLUSIONS: These findings indicate that, while unilateral deficits are present in individuals following ACL reconstruction, they may not be evident during bipedal performance or during modified versions of double-limb performance activities. Isolation of the involved limb with unilateral hopping tasks should be used to identify deficits in performance. PMID- 21289458 TI - Cross-cultural adaptation and validation of the VISA-P questionnaire for German speaking patients with patellar tendinopathy. AB - STUDY DESIGN: Clinical measurement study. OBJECTIVES: To cross-culturally adapt and validate the Victorian Institute of Sports Assessment Patellar Tendinopathy Questionnaire (VISA-P) for German-speaking patients. BACKGROUND: Like most questionnaires, the VISA-P was developed for English-speaking patients. There is a need to adapt the scale for German-speaking patients and thereby add to the total body of psychometric evidence relating to this instrument. METHODS: The VISA-P questionnaire was translated and cross-culturally adapted into German (VISA-P-G) in 6 steps: translation, synthesis, back translation, expert committee review, pretesting, and advisory committee appraisal. The psychometric properties of the VISA-P-G were determined using 23 patients with patellar tendinopathy and 57 active healthy persons (32 sport students and 25 basketball players). Reliability was evaluated by applying the questionnaire twice within a week to all 80 participants. Known group validity was calculated using a 1-way analysis of variance. Additionally, VISA-P-G results were correlated with the Blazina classification system for patellar tendinopathy, using the Spearman rank correlation coefficient. VISA-P-G ratings from the present study groups were further compared with respective data published in the original English, Dutch, and Swedish versions by a 2-sample t test. Internal consistency for the individual items of the questionnaire was determined within the patient group using a Cronbach alpha. RESULTS: Test-retest revealed excellent reliability for the patient and the asymptomatic control group (ICC = 0.88 and 0.87, respectively). Internal consistency for the patients was 0.88. Concurrent validity was almost perfect (rho = -0.81; P<.001). CONCLUSION: The VISA-P-G is a reliable and valid questionnaire for the self-assessment of pain, symptoms, and function in German-speaking patients with patellar tendinopathy. Its psychometric properties are comparable with the original English and international adaptations (Swedish, Dutch, and Italian). PMID- 21289459 TI - The short-term effects of treating plantar fasciitis with a temporary custom foot orthosis and stretching. AB - STUDY DESIGN: Prospective single-group cohort study. OBJECTIVES: To identify the effectiveness of a temporary custom foot orthosis (TCFO), followed by a stretching program, for the treatment of plantar fasciitis (PF). BACKGROUND: PF, a common cause of heel pain, often leads to disability. Optimal treatment for this often challenging clinical condition is still unknown. METHODS: Fifteen individuals with PF were recruited from the general public. All participants received a TCFO and were instructed to wear it for 2 weeks while weight bearing. Following the initial 2 weeks, participants were weaned off of the TCFO and instructed to begin a daily stretching program. Follow-up appointments occurred at 2, 4, and 12 weeks. The primary outcome measures included first-step heel pain via numeric pain rating scale (NPRS), the Foot and Ankle Ability Measure activities of daily living subscale (FAAM-A), and the Foot and Ankle Ability Measure sports subscale (FAAM-S). Secondary outcome included the global rating of change (GRC) score. RESULTS: Individuals with a primary complaint of plantar foot pain entered and completed this study. Repeated-measures ANOVAs for the NPRS, FAAM-A, and FAAM-S showed statistically significant changes (P<.001). Post hoc analysis using paired t tests demonstrated statistically and clinically significant change at all follow-up times, compared to the initial intervention (P<.001). Mean GRC scores at 2, 4, and 12 weeks were 4.4, 4.5, and 4.2, respectively. CONCLUSION: In treating PF, a TCFO used for 2 weeks, followed by a stretching program, provided preliminary evidence that first-step heel pain and foot and ankle function improve in the short term and up to 12 weeks. LEVEL OF EVIDENCE: Therapy, level 2b. PMID- 21289460 TI - Using outcome measure results to facilitate clinical decisions the first year after total hip arthroplasty. AB - STUDY DESIGN: Variable-occasion, repeated-measures design. OBJECTIVES: To model change in lower extremity functional status of patients 1 year after total hip arthroplasty (THA), using the Lower Extremity Functional Scale (LEFS) and the 6 minute walk test (6MWT), and, secondarily, to provide clinicians with useful data to guide practice. BACKGROUND: Given the prevalence of THA and current resource pressures, standardized outcome measures play an important role in providing physical therapists with objective knowledge about postoperative recovery and prognosis. METHODS: Seventy-five patients, with a mean age of 61 years and a diagnosis of hip osteoarthritis, consented to participate in the study. Assessments were conducted preoperatively and at multiple time points for up to 65 weeks postoperatively. Recovery was modeled using a nonlinear robust regression analysis for clustered data. The predictive ability of age, body mass index, and preoperative score was explored. RESULTS: Gender-based recovery curves were generated to depict the rate and amount of change in LEFS scores and 6MWT distances over the first year. Preoperative baseline 6MWT distance was the only covariate predictive of postarthroplasty 6MWT distances for both males and females. None of the covariates examined were significantly associated with postarthroplasty LEFS scores. CONCLUSION: Although there were variations in the recovery curves by measure, general patterns were noted. There was a rapid increase in both self-reported and physical performance measure scores for 12 to 15 weeks. Thereafter, we observed a slowing of recovery, with a plateau at 30 to 35 weeks for the 6MWT and later for the LEFS. These data can be used to make evidence-based decisions regarding prognosis and to guide the setting of measurable treatment goals. LEVEL OF EVIDENCE: Prognosis, level 1b. PMID- 21289461 TI - Cardiac-troponin-guided heart failure management: is it possible in clinical practice? PMID- 21289463 TI - More fundamental and practical indices based on the data analysis of NIPPON DATA 80 might be needed for clinical settings. PMID- 21289464 TI - Characterization and in vitro culture of male germ cells from developing bovine testis. AB - The transition from male primitive germ cells (gonocytes) to type A spermatogonia in the neonatal testis is the initial process and a crucial process in spermatogenesis. However, in large domestic animals, the physiological and biochemical characteristics of germ cells during the developmental processes remain largely unknown. In this study, we characterized bovine germ cells in the developing testis from the neonatal stage to the adult stage. The binding of the lectin Dolichos biflorus agglutinin (DBA) and the expression of ubiquitin carboxyl-terminal hydrolase 1 (UCHL1) were restricted to gonocytes in the neonatal testis and spermatogonia in the adult testis. Gonocytes also expressed a germ cell marker (VASA) and stem cell markers (NANOG and OCT3/4), while the expressions of these markers in the adult testis were restricted to differentiated spermatic cells and were rarely expressed in spermatogonia. We subsequently utilized these markers to characterize gonocytes and spermatogonia after culture in vitro. Spermatogonia that were collected from the adult testis formed colonies in vitro only for one week. On the other hand, gonocytes from the neonatal testis could proliferate and form colonies after every passage for 1.5 months in culture. These colonies retained undifferentiated states of gonocytes as confirmed by the expression of both germ cell and stem cell markers. Moreover, a transplantation assay using immunodeficient mice testes showed that long-term cultured cells derived from gonocytes were able to colonize in the recipient testis. These results indicated that bovine gonocytes could maintain germ cell and stem cell potential in vitro. PMID- 21289465 TI - Vitrification of fully grown and growing porcine oocytes using germinal vesicle transfer. AB - The survival rate of vitrified germinal vesicle (GV) stage porcine oocytes is very low, and it is not known if the vitrification damages the nucleus, cytoplasm or both. We have evaluated the eventual GV or cytoplasmic damage in fully grown (FG) and growing vitrified oocytes. Fifty-five percent of nonvitrified FG cumulus denuded oocytes reached the metaphase II (MII) stage in culture. When growing oocytes from preantral (PA) and early antral (EA) follicles were matured in vitro, almost all oocytes were arrested at the GV stage (GV stage: PA 88.9 and EA 79.5%, respectively). When fresh GVs from FG, PA and EA oocytes were transferred into fresh enucleated FG oocytes and matured in vitro, some of them reached the MII stage (MII stage: FG/FG 57.5%, PA/FG 9.3% and EA/FG 35.3%, respectively). The maturation rate of vitrified FG oocytes was only 6.1% but increased dramatically when vitrified GVs from FG, PA and EA oocytes were transferred into fresh enucleated FG oocytes (MII stage: VitFG/FG 43.9%, VitPA/FG 7.1% and VitEA/FG 26.3%, respectively). These results were not significantly different from those for the nonvitrified groups (MII stage: FG/FG 57.5%, PA/FG 9.3% and EA/FG 35.3%, respectively). We activated the reconstructed oocytes that received fresh or vitrified GVs (FG/FG, EA/FG, VitFG/FG and VitEA/FG) and examined their embryonic development. Cleaved embryos (nonvitrified groups 13.0-61.8%, vitrified groups 33.3-40.0%) and blastocysts (nonvitrified groups 0.0-18.2%, vitrified groups 0.0 2.9%) were obtained after activation. These results demonstrate that vitrified porcine GVs maintain maturational and developmental competence and that vitrification predominantly damages the cytoplasm. PMID- 21289466 TI - Epigenetically immature oocytes lead to loss of imprinting during embryogenesis. AB - Loss of imprinting (LOI) is occasionally observed in human imprinting disorders. However, the process behind the LOI is not fully understood. To gain a better understanding, we produced embryos and pups from mouse oocytes that lacked a complete methylation imprint using a method that involved transferring the nuclei of growing oocytes into the cytoplasm of enucleated fully grown oocytes following in vitro fertilization (IVF). We then analyzed the imprinting statuses. Our findings show that the incomplete methylation imprint derived from growing oocytes results in epigenetic mosaicism or a loss of methylation imprint (LOM) at maternal alleles in embryos. In some embryos, both hypo- and hypermethylated maternal Kcnq1ot1 alleles were detected, whereas either hypo- or hypermethylated maternal Kcnq1ot1 alleles were detected in others. Such tendencies were also observed at the Igf2r and Mest loci. Gene expression levels of imprinted genes were linked with their methylation statuses in some but not all embryos. Possible explanations of the inconsistency between the data from DNA methylation and gene expression include epigenetic mosaicism in embryos. Pups were successfully produced from growing oocytes at a quite low frequency. They exhibited an obese phenotype and LOI with respect to Igf2r, Snrpn and Mest. Our finding suggests the possibility that LOI/LOM at maternal alleles in human concepti could be derived from epigenetically immature/mutated oocytes. PMID- 21289467 TI - Upregulation of P-glycoprotein activity in porcine oocytes and granulosa cells during in vitro maturation. AB - Multidrug resistance P-glycoprotein (Pgp), coded by the multidrug resistance type I (MDR1/ABCB1) gene, is an energy-dependent efflux pump and functions in systemic detoxification processes. In the present study, the expression and development of Pgp were evaluated in the porcine oocyte during in vitro maturation to compare with the expression of Pgp in cultured granulosa cells. As revealed by Western blotting using anti-human Pgp antibody, a single band of Pgp with an apparent molecular size of 170 kDa was detected in the germinal vesicle stage oocytes. The surface of GV oocyte was positively labeled by immunostaining. In the second metaphase oocyte after culture in the maturation medium containing porcine follicular fluid and human chorionic gonadotropin, the level of Pgp was increased. The elevation of the oocyte Pgp level was associated with increased activity of rhodamine 6G efflux from the oocyte, and its efflux was suppressed by verapamil, an inhibitor of Pgp. Removal of porcine follicular fluid from the maturation medium resulted in little alteration of the oocyte Pgp level. Expression of Pgp was also elevated in cultured porcine granulosa cells during cell maturation when stimulated with follicle-stimulating hormone or luteinizing hormone for 24-48 h. Collectively, the present results indicate that the transporting activity of P-glycoprotein upregulates in porcine oocytes and granulosa cells during exposure to gonadotropins or prior to ovulation. PMID- 21289468 TI - The use of embryonic stem cell derived bioactive material as a new protein supplement for the in vitro culture of bovine embryos. AB - Embryonic stem (ES) cells are expanded versions of the inner cell mass cells that compose the early mammalian blastocyst. Components derived from ES cells may contain various bioactive materials (BM) helpful for early preimplantation embryo growth. In this study, we examined the effect of human ES cell derived BM (hES BM) on in vitro culture of bovine embryos. When bovine parthenogenetic day 2 embryos were cultured in 10% hES-BM, a significantly higher embryo development rate (44.3%) and increased cell numbers were observed relative to control medium containing 3 mg/ml BSA (19.5%; P<0.01). Among the various concentrations (5, 10 and 15%) and days of treatment (2 or 4 days) tested, 10% hES-BM treatment for 4 days provided the best culture environment to support the growth of bovine embryos in vitro (P<0.05). Little difference was observed between 10% hES-BM and 10% FBS treatment in the examined parthenogenetic or in vitro fertilized embryos, although the hES-BM group developed at a slightly better rate. However, the ICM cell numbers were significantly higher in the hES-BM group in irrespective of embryo origin (P<0.05). In addition, the relative levels of pluripotency (Oct4, * 1.8 fold; Nanog. * 3.3 fold), embryogenesis (Stat3, * 2.8 fold; FGF4, * 18.8 fold; E-cad, * 2.0 fold) and growth (Glut5, * 2.6 fold) genes were significantly higher in the 10% hES-BM group than in the 10% FBS group (P<0.05), while the levels of other genes (Bax, Bcl2, MnSOD and Connexin43) were not different. This is the first report examining the positive effects of hES-BM on bovine embryo development in vitro. Based on our results, we conclude that hES-BM can be used as a new protein supplement for bovine preimplantation embryo development. PMID- 21289469 TI - A feline hemoplasma, 'Candidatus Mycoplasma haemominutum', detected in dog in Japan. AB - We examined for 'Candidatus Mycoplasma haemominutum' infection in 167 blood samples collected from domestic dogs between 2008 and 2009 in the Tohoku area, Japan, and found 5 (3.0%) were positive by PCR assay. This is the first demonstration of 'Candidatus Mycoplasma haemominutum', a feline haemotropic mycoplasma, in the dogs raised in Japan. PMID- 21289470 TI - Evaluation of the reverse transcription loop-mediated isothermal amplification (RT-LAMP) as a screening method for the detection of influenza viruses in the fecal materials of water birds. AB - Migratory water birds are a natural reservoir for influenza A viruses. Viruses replicate in the intestines of ducks and are shed with the fecal materials. Virus isolation from collected fecal materials, therefore, is an integral part of the surveillance of avian influenza in water birds. In the present study, reverse transcription loop-mediated isothermal amplification (RT-LAMP) was assessed for its usefulness in detecting the RNA of influenza A viruses in fecal materials. It was found that, RT-LAMP specifically and sensitively detects the matrix gene of influenza A viruses. Influenza A viruses were isolated from the fecal materials in which viral RNA were detected by RT-LAMP in 35 min. The present findings indicate that RT-LAMP is useful as a high throughput screening method for field samples prior to virus isolation, allowing the processing of hundreds of samples per day. PMID- 21289471 TI - Proventricular dilatation disease associated with avian bornavirus infection in a Citron-crested Cockatoo that was born and hand-reared in Japan. AB - A 5-month-old female Citron-crested Cockatoo (Cacatua sulphurea citrinocristata) that was born and hand-reared in Japan died with suspected proventricular dilatation disease (PDD). Macroscopic and microscopic examinations of the bird revealed characteristic features of PDD, i.e., distention of the proventriculus and infiltration of lymphocytes and plasma cells in ganglia of various organs and in central and peripheral nerves. A linkage of this PDD case to infection with avian bornavirus (ABV) was documented by RT-PCR amplification of the virus genomes from the affected bird. Phylogenetic analysis revealed that the ABV identified in this study clustered into the genotype 2, which is one of the dominant ABV genotypes worldwide. To the best of our knowledge, this is the first report of a natural case of PDD associated with ABV infection in Japan. PMID- 21289472 TI - Importance of bringing dogs in contact with children during their socialization period for better behavior. AB - Much attention has been given to the role that dogs play in the social, physical, and psychological development of children. Furthermore, dogs are now playing a new important role in animal-assisted education (AAE). However, some dogs have difficulty getting along with children. The aim of this study was to demonstrate how dogs' contact with children during and after their socialization period influenced their responses toward children. In total, 31 pet dogs were divided into three groups. Group 1 dogs had been in contact with children during the canine socialization period (between 3 and 12 weeks of age); Group 2 dogs had been in contact with children after this socialization period; Group 3 dogs seldom had contact with children. As soon as a child entered the room, the dog was presented three stimuli by the child over the course of several intervals. The dogs' responses were evaluated by analyzing behavior and heart rates. The dogs that had been in contact with children during their socialization period did not show aggressive behavior or excited behavior toward the child in our test. Moreover, their heart rates were significantly decreased even during the last stimulus, which involved the child running around the dog while calling its name. This study suggested that the dogs having contact with children during socialization period might not show inappropriate responses toward children and could be suitable for taking part in AAE. PMID- 21289473 TI - Effect of protein malnutrition on the skin epidermis of hairless mice. AB - The purpose of this study was to evaluate the effect of protein malnutrition on the skin epidermis of mice. A low protein diet induced thinning of the skin epidermis, a decrease of cell proliferative activity in epidermal cells and a decrease of stratum corneum hydration. Dityrosine was immunostained in the cytoplasm of epidermal cells in the low protein diet group. Plasma advanced oxidation protein product (AOPP) levels were significantly more increased in the low protein diet group than in the control diet group. These results suggest that protein malnutrition adversely affects the structure and water barrier and reservoir functions of the skin epidermis, and these pathological changes are associated with the expressions of protein oxidation markers, dityrosine and AOPP. PMID- 21289474 TI - Dimethylnitrosamine-induced liver fibrosis and recovery in NOD/SCID mice. AB - There is a need for a new liver fibrosis model of immunodeficient mice to study the effects of cell therapy on liver disease because there are not many animal models available to study the effects of cell therapy. In this study, we induced liver fibrosis using dimethylnitrosamine (DMN) in NOD/SCID mice to create an animal model for liver disease. DMN (5 mg/kg, i.p.) was injected intraperitoneally for three consecutive days per week for 6 or 8 weeks, and the mice were sacrificed at weeks 0, 4 and 8 after the last DMN injection. The 6-week DMN-treated group gradually recovered from serum biochemical changes, histopathological toxic effects and lesions in the liver at weeks 4 and 8 after the last DMN injection. However, the progression of liver fibrosis and toxic levels were maintained in the 8-week DMN-treated group at week 4 after the last DMN injection. The increases in iron and extracellular matrix (collagen) in the DMN-treated group were confirmed by Prussian blue (PB) and Masson's trichrome (MT) staining, respectively. Additionally, activation of hepatic stellate cells was observed by alpha smooth muscle actin (alpha-SMA) immunostaining and western blot. In conclusion, treatment of NOD/SCID mice with 5 mg/kg of DMN for 8 weeks can be used to induce an appropriate animal model of disease for liver fibrosis. This model may be useful for evaluation of the efficacy and safety of cell therapies such as human mesenchymal stem cell therapy. PMID- 21289475 TI - Differential virulence of Candida albicans and C. dubliniensis: A role for Tor1 kinase? AB - Candida albicans and Candida dubliniensis are two very closely related species of pathogenic yeast. C. albicans is the most prevalent species in the human gastrointestinal tract and is responsible for far more opportunistic infections in comparison with C. dubliniensis. This disparity is likely to be due to the reduced ability of C. dubliniensis to undergo the yeast to hypha transition, a change in morphology that plays an important role in C. albicans virulence. We have recently shown that hypha formation by C. dubliniensis is specifically repressed by nutrients at alkaline pH. In this article, we present new data showing that this can be partly reversed by treatment with rapamycin, an inhibitor of the nutrient sensing kinase Tor1 (Target Of Rapamycin). We also provide a speculative model to describe why C. albicans filaments more efficiently in nutrient rich environments, citing recently described data on Mds3, a pH responsive regulator of Tor1 kinase activity. PMID- 21289476 TI - Ethanol-mediated long-lasting adaptations of the NR2B-containing NMDA receptors in the dorsomedial striatum. AB - We recently found that ethanol-induced long-term facilitation (LTF) of NMDAR activity is mediated by NR2B-NMDARs and is observed in the dorsomedial striatum (DMS) but not in the dorsolateral striatum (DLS). We also showed that repeated administration of ethanol causes a long-lasting increase in NMDAR activity in the DMS, resulting from ethanol-mediated Fyn phosphorylation of NR2B subunits. In this addendum, we report that the different sensitivity of NMDARs to ethanol between the DMS and DLS is not attributed to the abundance of synaptic NR2B NMDARs or differences in Fyn levels. We further show that LTF is specific for NR2B-, but not NR2A-NMDARs, and that the duration of the in vivo ethanol-mediated increase in NMDAR activity is associated with the period of ethanol exposure, but not with alteration in NR1 or NR2A protein levels. Together, these results suggest that upregulation of NR2B-NMDAR activity by ethanol is selective and that ethanol's effect on NMDAR activity is gradual and cumulative. PMID- 21289478 TI - Renal replacement therapy review: past, present and future. AB - Support of renal function in modern times encompasses a wide array of methods and clinical scenarios, from the ambulatory patient to the critically ill. The ability to safely and routinely deliver ongoing organ support in the outpatient setting has until recently separated renal replacement therapy from other organ support. Renal replacement therapy (RRT) can be applied intermittently or continuously using extracorporeal (hemodialysis) or paracorporeal (peritoneal dialysis) methods. The purpose of this article is to familiarize the reader with the history, physiology, mode, dose, equipment and future of renal replacement therapy and not to detail the technical methods employed for blood purification. PMID- 21289479 TI - Artificial lung basics: fundamental challenges, alternative designs and future innovations. AB - There exists a growing demand for new technology that can take over the function of the human lung, from assisting an injured or recently transplanted lung to completely replacing the native organ. Many obstacles must be overcome to achieve the lofty goals and expectations of such a device. An artificial lung must be able to sustain the gas exchange requirements of a normal functioning lung. Pursuant to this purpose, the device must maintain appropriate blood pressure, decrease injury to blood cells and minimize clotting and immunologic response. Attachment methods vary, and ideally researchers want to find a way that minimizes bodily trauma, maximizes gas exchange and utilizes the inherent properties of the native lung. The currently proposed methods include the parallel, in-series and venous double-lumen cannula configurations. For the time being, current research focuses on the extracorporeal (i.e., outside the body) placement, but ultimate long-term goals look toward total implantation. PMID- 21289480 TI - Can technological solutions for diabetes replace islet cell function? AB - The central objective of diabetes research and management is to restore the deficient secretion of insulin, thereby restoring a state of euglycemia and minimizing short- and long-term risks associated with poor glucose control. The development of the artificial pancreas seeks to imitate the action of the pancreatic beta cell by employing closed-loop control to respond to glycemic excursions by appropriately infusing appropriate amounts of insulin. This article examines progress towards implementing an artificial pancreas in the context of the pancreatic islet as the ideal model for controlling blood glucose. Physiologic insulin secretion will form our foundation for considering the technical design elements relevant to electromechanically imitating the beta cell. The most recent clinical trials using closed-loop control are reviewed and this modality is compared to other curative approaches including islet cell transplantation and preservation. Finally, the potential of the artificial pancreas as a method to adequately reestablish euglycemia is considered. PMID- 21289481 TI - The artificial endothelium. AB - As the world of critical care medicine advances, extracorporeal therapies (ECC) have become commonplace in the management of the high risk intensive care patient. ECC encompasses a wide variety of technologies from hemodialysis, continuous renal replacement therapy (CRRT) and plasmapheresis, to cardiopulmonary bypass (CPB), extracorporeal life support (ECLS) and hepatic support. The development of internal man made organs is the next step with ventricular assist devices and artificial lungs. As we advance the technologies with smaller devices, and more intricate circuitry, we lack the keystone necessary to control the blood-biomaterial interface. For the last 50 years much has been learned about surface induced thrombosis and attempts have been made to prevent it with alternative systemic anticoagulation, circuitry surface modifications, or a combination of both. Despite these efforts, systemic or regional anticoagulation remain necessary for both laboratory and clinical application of ECC. As such, the development of an endothelial-like, biomimetic surface to reduce or perhaps even eliminate the blood activation/thrombus formation events that occur upon exposure to artificial surfaces is paramount. PMID- 21289482 TI - Mechanical circulatory support. PMID- 21289483 TI - MiR-145 inhibits cell proliferation of human lung adenocarcinoma by targeting EGFR and NUDT1. AB - MicroRNAs (miRNAs) are emerging as important modulators in cellular pathways and they appear to play a key role in tumorigenesis. MiR-145 is downregulated in several human malignancies, including lung cancer, but the responsible molecular mechanisms remain unclear. We previously reported that restoration of hsa-miR-145 inhibits cancer cell growth in lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutation. This study showed that hsa-miR-145 targets EGFR and nucleoside diphosphate linked moiety X-type motif 1 (NUDT1 or MTH1) in lung adenocarinoma cells. The mRNA expressions of EGFR and NUDT1 were significantly downregulated after miR-145 transfection in human lung adenocarcinoma cells. Our results demonstrated miR-145 in the negative regulation of EGFR and NUDT1 expressions at both mRNA and protein levels. Further analysis showed that miR-145 has the ability to inhibit cell proliferation on transfected lung adenocarcinoma cells over three time points (24, 48 and 72 hours). Upregulation of miR-145 appeared to be an important gene regulation mechanism for the proliferation of lung adenocarcinoma cells and it correlated strongly with the downregulation of EGFR and NUDT1. Interestingly, our study revealed that the altered proliferation in lung cancer cells is not accompanied by changes in apoptosis. Our findings provided new insight into the complex regulating pathway comprising of miR-145, EGFR, NUDT1 and other unknown factors which function in cell proliferation but not in apoptosis. Understanding miR-145's targets and its regulating pathways may lead to new therapeutic strategies for lung adenocarcinoma. PMID- 21289484 TI - Coding region: the neglected post-transcriptional code. AB - The control of mammalian mRNA turnover and translation has been linked almost exclusively to specific cis-elements within the 5'- and 3'-untranslated regions (UTRs) of the mature mRNA. However, instances of regulated turnover and translation via cis-elements within the coding region (CR) of mRNAs are accumulating. Here, we describe the regulation of post-transcriptional fate through trans-binding factors (RNA-binding proteins and microRNAs) that function via CR sequences. We discuss how the CR enriches the post-transcriptional control of gene expression, and predict that new high-throughput technologies will enable a more mainstream study of CR-governed gene regulation. PMID- 21289485 TI - Smad-mediated miRNA processing: a critical role for a conserved RNA sequence. AB - microRNAs (miRNAs) are short, 21-24 nucleotide (nt), non-coding RNAs that post transcriptionally regulate the expression of messenger RNAs (mRNAs). Through the regulation of their cognate mRNAs, miRNAs control diverse aspects of biology, including development, cellular differentiation, proliferation, metabolism, and death. Thus, miRNAs play a critical role in the determination of normal cellular physiology and misexpression of miRNAs leads to pathological responses. Understanding the mechanisms that control miRNA expression is an important step forward as novel functions of miRNAs continue to be uncovered. In addition to transcriptional regulation, multiple pathways of post-transcriptional modulation of miRNA expression have been uncovered. In this review we discuss the role of the Smads in the regulation of miRNA processing in response to Transforming Growth Factor-beta stimulation. PMID- 21289486 TI - Determinants of intracellular RNA pharmacokinetics: Implications for RNA-based immunotherapeutics. AB - RNAs with optimized properties are increasingly investigated as a tool to deliver the genetic information of complete antigens into professional antigen-presenting dendritic cells for HLA haplotype-independent antigen-specific vaccination against cancer. As the dose of the antigen and duration of its presentation are critical factors for generating strong and sustained antigen-specific immune responses, improvement of the immunobioavailability of RNA-based vaccines has been a recurrent subject of research. Substantial increase of the amount of antigen produced from RNA can be achieved by optimizing RNA stability and translational efficiency. Both features are determined by cis-acting elements in the RNA, namely the 5' cap, the poly(A) tail, and the sequence of the coding and non-coding regions, which interact with corresponding trans-acting factors. This article summarizes recent developments in identifying optimized RNA for expression of foreign proteins in dendritic cells, as well as their implications for immunotherapy based on antigen-encoding RNA. PMID- 21289487 TI - The eukaryotic RNA exosome: same scaffold but variable catalytic subunits. AB - The RNA exosome is a versatile ribonucleolytic protein complex that participates in a multitude of cellular RNA processing and degradation events. It consists of an invariable nine-subunit core that associates with a variety of enzymatically active subunits and co-factors. These contribute to or even provide the catalytic activity and substrate specificity of the complex. The S. cerevisiae exosome has been intensively studied since its discovery in 1997 and thus serves as the archetype of eukaryotic exosomes. Notably, its catalytic potential, derived exclusively from associated subunits, differs between the nuclear and cytoplasmic versions of the complex. The same holds true for other eukaryotes, however, recent discoveries from various laboratories including our own have revealed that there are variations on this theme. Here, we review the latest findings concerning catalytic subunits of eukaryotic exosomes, and we discuss the apparent need for differential composition and subcellular distribution of exosome variants. PMID- 21289488 TI - Subcellular localization of RNA degrading proteins and protein complexes in prokaryotes. AB - The archaeal exosome is a prokaryotic protein complex with RNA processing and degrading activities. Recently it was shown that the exosome is localized at the periphery of the cell in the thermoacidophilic archaeon Sulfolobus solfataricus. This localization is most likely mediated by the archaeal DnaG protein and depends on (direct or indirect) hydrophobic interactions with the membrane. A localization of RNA degrading proteins and protein complexes was also demonstrated in several bacteria. In bacteria a subcellular localization was also shown for substrates of these proteins and protein complexes, i.e. chromosomally encoded mRNAs and a small RNA. Thus, despite the missing compartmentalization, a spatial organization of RNA processing and degradation exists in prokaryotic cells. Recent data suggest that the spatial organization contributes to the temporal regulation of these processes. PMID- 21289489 TI - Assembly, disassembly and recycling: the dynamics of exon junction complexes. AB - Efficient gene expression requires that, during their lifetime, mRNAs associate with different sets of RNA binding proteins to form messenger ribonucleoprotein particles (mRNPs). The protein components of mRNPs are essential for the correct post-transcriptional function and regulation of mRNAs. mRNPs are constitutively remodeled during the maturation of the mRNA in the nucleus and downstream steps in the cytoplasm, and can also change depending on the cellular environment. Here we review the current understanding of the biochemical and structural aspects of a central mRNP component and regulator, the exon junction complex (EJC). PMID- 21289490 TI - PPR proteins network as site-specific RNA editing factors in plant organelles. AB - RNA editing in flowering plant mitochondria targets several hundred C nucleotides mostly in mRNAs to be altered to U. Several nuclear encoded genes have been recently identified predominantly in Arabidopsis thaliana which code for proteins involved in specific RNA editing events in plastids or mitochondria. These nuclear genes code for proteins characterized by a stretch of 4-20 repeats of 34 36 amino acids each, accordingly classified as pentatricopeptide repeat (PPR) proteins. These repeats most likely participate in recognizing and binding the specific nucleotide motifs around editing sites which have been defined as essential cis-elements. All of the RNA editing PPR proteins contain at their C termini an extension of as yet unclear function, the E domain, and some of these are further extended by another domain which terminates with the triplet DYW. While the E domain seems to be always required for their function in RNA editing, the DYW domain can sometimes be removed. At some editing sites a given PPR protein seems to be required, while at others their function can at least partially be compensated by presumably other PPR proteins. These observations suggest that the PPR proteins may act in a complex network to define and to target RNA editing sites. PMID- 21289491 TI - The intestinal factor Tff3 and a miRNA network regulate murine caloric metabolism. AB - Genetic impairment of the genes coding for three mammalian trefoil peptides resulted in severe gastrointestinal malfunctions. The trefoil peptides also appear involved in caloric metabolism. Monitoring global miRNA expression of Tff3 deficient mice points to an interplay of Tff3 with a miRNA regulatory network. We identified 21 miRNAs that were deregulated when compared to the wild type strain. In silico evaluation indicated that the majority of the 21 miRNA were connected with the metabolic pathway "glycolysis/gluconeogenesis'' (p=0.032), a signaling pathway including nine target genes Aldh9a1, Aldh2, Pck1, Aldoc, Pgam2, Pck2, Adh4, Adh5, and Fbp1. Association of Tff3 with this metabolic pathway is further supported by the observation that the body mass of adult Tff3 KO mice (five months) showed a clearly reduced weight. Furthermore, the majority of the identified 21 miRNA genes are localized on murine chromosomes 2 and 5 in three clusters (2A1, 2B, 5B3) suggesting a coordinated expression control and function. PMID- 21289492 TI - Initiation of the yeast G0 program requires Igo1 and Igo2, which antagonize activation of decapping of specific nutrient-regulated mRNAs. AB - Growth factors and essential nutrients are key controllers of eukaryotic cell proliferation. In their absence, cells may enter into a quiescent (G0) state. In yeast, nitrogen and/or carbon limitation causes downregulation of the conserved TORC1 and PKA signaling pathways and consequently activation of Rim15, a member of the PAS protein kinase family. Rim15 orchestrates the initiation of the G0 program in part by coordinating transcription of Msn2/4- and/or Gis1-dependent genes with posttranscriptional protection of the corresponding mRNAs via direct phosphorylation of Igo1/2. Here, we show that several factors including Ccr4, the Lsm-Pat1 complex, and Dhh1, which are implicated in mRNA decapping activation, participate in the decay of specific mRNAs during initiation of the G0 program when Igo1/2 are absent. Accordingly, Igo1/2 likely play a key role in preventing the decapping and subsequent 5'-3' degradation of a set of nutrient-regulated mRNAs that are critical for cell differentiation and chronological life span. PMID- 21289493 TI - Patterns of height changes in anterior and posterior cervical disc regions affects the contact loading at posterior facets during moderate and severe disc degeneration: a poroelastic C5-C6 finite element model study. AB - STUDY DESIGN: Biomechanical roles of anterior and posterior portions of the disc (AD and PD, respectively) in governing posterior facets (PF) behavior of a C5-C6 motion segment. OBJECTIVE: To understand how height patterns (loss and gain) at AD and PD affects the PF contact loading during moderate and severe grades of cervical disc degeneration (DD). SUMMARY OF BACKGROUND DATA: PF overloading and degeneration after degenerative disc height loss is a clinical concern. This may occur because of a decrease in facet joints space, causing elevated PF contact forces. During a physiologic motion, axial disc height patterns at AD and PD affects the spacing and overlapping of articulating PF surfaces. The question arises as to what percentage of deformation and/or elongation at AD and PD is contributing to a corresponding increase and/or decrease in PF contact loading. METHODS: A poroelastic, three-dimensional finite element model of a C5-C6 segment with a normal (grade I) disc was used after validation. Two degenerated disc models were developed from the normal disc model: moderate (combined effect of Thompson disc grades II and III) and severe (combined effect of Thompson disc grades IV and V). The models were analyzed under compression, flexion, and extension. Height patterns (loss and gain) at AD and PD, and PF loading were calculated for each model. RESULTS: PF loading increased with PD height loss, and further increased with AD height gain. In moderate DD, PF loading was more affected by PD height loss than AD height gain, whereas in severe DD, it was more affected by AD height gain than PD height loss. CONCLUSION: The current study conclusions suggest a possible mechanism for PF loading through loss and gain in the AD and PD heights during moderate and severe grades of DD. Further cervical spine based biomechanical investigations are suggested to verify our findings. PMID- 21289494 TI - A case-control study of robotic radical hysterectomy and pelvic lymphadenectomy using 3 robotic arms compared with abdominal radical hysterectomy in cervical cancer. AB - OBJECTIVE: The purpose of this study was to compare surgical outcomes of robotic radical hysterectomy (RRH) using 3 robotic arms with those of abdominal radical hysterectomy (ARH) in the treatment of early-stage cervical cancer. METHODS: Thirty-two patients with stage IA2-IIB cervical carcinoma according to the International Federation of Gynecology and Obstetrics underwent RRH between June 2006 and February 2009. Patient outcomes were compared with those of a historic cohort of 32 patients who underwent ARH, who were matched for age, stage according to the International Federation of Gynecology and Obstetrics, and type of radical surgery. RESULTS: All RRHs were completed robotically with no conversions to laparotomy. Robotic radical hysterectomy showed favorable outcomes over ARH in terms of the mean length of hospital stay (11.6 vs 16.9 days, P < 0.001) and the mean estimated blood loss (220 vs 531 mL, P = 0.002). The mean operating time and the number of lymph node retrievals were comparable. There were no significant differences in the incidence of postoperative complications between the 2 groups. The mean follow-up time was 15.3 months, and 2 patients in the RRH group had recurrences. CONCLUSIONS: Robotic radical hysterectomy and pelvic lymphadenectomy using 3 robotic arms is feasible and preferable over ARH for the treatment of cervical cancer patients. Prospective randomized trials should be completed to confirm the potential benefits associated with RRH. PMID- 21289495 TI - Perinatal hypoxia enhances cyclic adenosine monophosphate-mediated BKCa channel activation in adult murine pulmonary artery. AB - Exposure to perinatal hypoxia results in alteration of the adult pulmonary circulation, which is linked among others to alterations in K(+) channels in pulmonary artery (PA) smooth muscle cells. In particular, large conductance Ca(2+)-activated K(+) (BK(Ca)) channels protein expression and activity were increased in adult PA from mice born in hypoxia compared with controls. We evaluated long-term effects of perinatal hypoxia on the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway-mediated activation of BK(Ca) channels, using isoproterenol, forskolin, and dibutyryl-cAMP. Whole-cell outward current was higher in pulmonary artery smooth muscle cells from mice born in hypoxia compared with controls. Spontaneous transient outward currents, representative of BK(Ca) activity, were present in a greater proportion in pulmonary artery smooth muscle cells of mice born in hypoxia than in controls. Agonists induced a greater relaxation in PA of mice born in hypoxia compared with controls, and BK(Ca) channels contributed more to the cAMP/PKA-mediated relaxation in case of perinatal hypoxia. In summary, perinatal hypoxia enhanced cAMP-mediated BK(Ca) channels activation in adult murine PA, suggesting that this pathway could be a potential target for modulating adult pulmonary vascular tone after perinatal hypoxia. PMID- 21289496 TI - Moderators of weight-based stigmatization among youth who are overweight and non overweight: the role of gender, race, and body dissatisfaction. AB - OBJECTIVE: : To identify demographic correlates and moderators of weight-based stigmatization in a diverse sample of children and adolescents. METHOD: : A total of 157 children/adolescents aged 7 to 17 years and their parents participated in this study, and the following measurements were used: demographic questionnaire, child weight and height, figure ranking weight-based stigmatization, and body dissatisfaction. RESULTS: : Weight-based stigmatization was greater among younger children and females. Gender moderated the relationship between age and weight based stigmatization, with significant differences in endorsement of weight bias between child and adolescent females. Gender also moderated the relationship between race and weight-based stigmatization, with African-American females endorsing significantly lower levels of weight-based stigmatization than white females. Body dissatisfaction moderated the relationship between degree of overweight and weight-based stigmatization and served as a protective buffer from endorsement of weight-based stigmatization among children with greater degree of overweight but low body dissatisfaction. CONCLUSION: : Weight-based stigmatization is prevalent, with certain age groups and populations at particular risk for its endorsement. Identification of correlates and moderators of weight-based stigmatization can inform the design of effective interventions to reduce its profound negative impact on children who are overweight or obese. PMID- 21289497 TI - Parent picture-book reading to infants in the neonatal intensive care unit as an intervention supporting parent-infant interaction and later book reading. AB - OBJECTIVES: To examine the effects of a parent book reading intervention in the neonatal intensive care unit (NICU) on parent-infant interaction and on the incidence of parents reading to their infants 3 months post-NICU discharge. METHODS: A nonrandomized, participant blinded intervention study using a historical control group (CG) was conducted. The intervention group (IG: n = 59) consisted of parents of infants admitted to the NICU after the introduction of the parent reading program. The CG (n = 57) consisted of parents of infants discharged from the NICU in the 3-month period before the introduction of the reading program. Questionnaires were mailed to participants 3 months after their infant's discharge and completed verbally, over the telephone. Groups were compared on parenting activities and reading. In addition, a thematic analysis of qualitative descriptive data provided insight into the parents' experiences with reading to their infants. RESULTS: Sixty-nine percent of IG parents reported that reading helped them feel closer to their baby, and 86% reported it was enjoyable. Parents reported an increased sense of control and normalcy and increased intimacy with their infant. Twice as many parents in the IG reported reading 3 or more times a week to their infants (55.9% IG; 23.3% CG). CONCLUSION: Study results support the use of a parent book-reading intervention in the NICU to enhance parent-infant interactions and promote reading. PMID- 21289499 TI - Gender differences in orthostatic hypotension. AB - Orthostatic hypotension is a decrease in systolic blood pressure of more than 20 mm Hg or a decrease in diastolic blood pressure of at least 10 mm Hg, within 3 minutes of changing from a supine to an upright position. The typical clinical presentation of orthostatic hypotension includes dizziness, syncope, blurry vision and loss of balance. Symptoms may be more frequent in women, but the complicating roles played by comorbid factors and the estrogen mechanisms are not well understood. Women have a more active parasympathetic system, higher estrogen levels and a lower center of gravity. Thus, women less effectively compensate for the drop of blood pressure in response to positional change. An understanding of these mechanisms contributing to orthostatic hypotension may improve diagnosis and treatment of the problem. PMID- 21289500 TI - Differentiation of human mesenchymal stem cells: the potential mechanism for estrogen-induced preferential osteoblast versus adipocyte differentiation. AB - INTRODUCTION: Bone marrow-derived mesenchymal stem cells (MSCs) are capable of differentiating into osteoblasts and adipocytes. This critical balance between osteoblast and adipocyte differentiation plays a significant role in maintaining normal bone homeostasis. In osteoporosis, a metabolic bone disease seen mainly in postmenopausal women because of estrogen deficiency, the concomitant occurrence of increased bone marrow adipocyte production with diminished production of osteoblasts, points to the potential role of estrogen in shifting the balance of MSC differentiation. METHODS: We established an in vitro differentiation model of isolated human MSCs (hMSCs) and examined the role of distinct estrogen signaling pathways in regulating the differentiation of hMSCs. RESULTS: Estrogen promoted the differentiation of hMSCs to osteoblasts in contrast to adipocytes, the former of which was mediated through the PI3K/SSH1L but not the mitogen-activated protein kinase pathway. CONCLUSION: This study provides a novel mechanistic understanding of estrogen-related osteoporosis and identifies potential targets for antiosteoporosis therapies. PMID- 21289501 TI - Impact of vitamin D in the treatment of tuberculosis. AB - Tuberculosis (TB) is a major global health problem and often coincides with nutritional deficiency. In fact, vitamin D deficiency has been reported among TB patients, and vitamin D receptor polymorphisms are associated with susceptibility to Mycobacterium tuberculosis. High doses of vitamin D were widely used to treat TB patients in the preantibiotic era. This approach was successful: vitamin D can suppress intracellular growth of M tuberculosis in vitro. Vitamin D also induced the expression of cathelicidin, which is involved in the first line of defense in TB patients. Thus, vitamin D may have a role in TB treatment, and further investigation is needed. PMID- 21289502 TI - Traumatic chyle leak: a rare complication of left internal jugular venous cannulation. AB - A traditional method for internal jugular vein catheterization has been through the transjugular approach. These days, ultrasound-guided cannulation is the preferred mode because of the higher success and lower complication rates. Complications associated with the transjugular approach include neck hematoma caused by carotid artery puncture, pleural puncture leading to pneumothorax and air embolism. Thoracic duct injury is a rare complication of left internal jugular vein catheterization. This complication occurred in one of the patients in whom ultrasound-guided left internal jugular vein catheterization was used. The anatomical basis of this injury is discussed here. PMID- 21289503 TI - Transthoracic echocardiogram is a useful tool in the hemodynamic assessment of patients with chest trauma. AB - INTRODUCTION: The utility of transthoracic echocardiogram (TTE) in patients on the trauma service is not well defined. The aim of this study was to evaluate the frequency of abnormal echocardiographic findings that would aid in the assessment and management of cardiovascular hemodynamics in patients with chest trauma. METHODS: A retrospective analysis of all patients who had a TTE on the trauma service at a level 1 trauma center during a 12-month period was performed. RESULTS: There were 94 patients in the study. TTE was performed after cardiac surgery in 5 patients. One of the 5 patients with prior cardiac surgery was excluded from the study because of poor quality images, and each of the remaining 4 patients showed significant TTE abnormalities. Of the 89 patients without prior cardiac surgery, 38 (43%) had significant TTE findings although 32 (84%) of them had no known history of cardiac abnormalities. A decreased left ventricular ejection fraction (<50%) was found in 18% of all patients, and half of them were hemodynamically unstable. Significant valvular regurgitation or stenosis was found in 31 patients, pulmonary hypertension in 25 patients, left ventricular wall motion abnormalities in 12 patients and pericardial effusion in 11 patients. CONCLUSION: Significant echocardiographic abnormalities are detected by TTE in patients with chest trauma. Such findings can be used in the hemodynamic assessment and management of unstable patients during their hospitalization and in planning long-term follow-up and management of these patients after discharge from the hospital. PMID- 21289504 TI - Incidence and outcome of healthcare-associated Acinetobacter baumannii in chronically ventilated patients in a tertiary care hospital in Taiwan. AB - INTRODUCTION: Most studies related to healthcare-associated infection with Acinetobacter baumannii (HAIA) are on acutely ventilated patients. Little is known regarding the incidence and outcomes of HAIA in chronically ventilated patients. METHODS: A retrospective study of chronically ventilated patients covering the period May 2002 to May 2008 was conducted to determine the incidence of patients with HAIA. The Cox proportional hazard model was used to estimate differences in the 30-day mortality between those with and those without HAIA by case-control study after controlling for confounders. RESULTS: Of 240 patients who were chronically ventilated for 49,207 days, 78 (32.5%) acquired HAIA at a rate of 1.59/1,000 patient day. The central venous catheter-related bloodstream infections rate was 8.78 per 1,000 catheter days; the ventilator-associated pneumonia rate was 1.26 per 1,000 ventilator days; and the catheter-associated urinary tract infections rate was 0.17 per 1,000 catheter days. Fifty (64.1%) HAIA and 58 (64.4%) non-HAIA patients were treated well and survived without ICU admission. After univariate and multivariate analyses, prolonged ventilation days (odds ratio: 3.4; 95% confidence interval: 1.7-6.1; P = 0.01] and inappropriate empiric antibiotics within 48 hours (odds ratio: 7.9; 95% confidence interval: 3.9-9.8; P = 0.02) were independent factors that predicted the 30-day mortality of HAIA among chronically ventilated patients. CONCLUSIONS: Although chronically ventilated patients with HAIA have longer ventilator days, higher antibiotics resistance, and high rate per 100 patients of ventilator-associated pneumonia, most patients are treated well. Compared with patients without HAIA, prolonged ventilation days and inappropriate empiric antibiotics within 48 hours are independent factors of the 30-day mortality. PMID- 21289505 TI - Pathologic evaluation of gallbladder in patients who underwent cholecystectomy and hepatic resection for hepatocellular carcinoma. AB - INTRODUCTION: The purpose of this study was to describe the pathologic findings of the gallbladder in patients who underwent simultaneous cholecystectomy and hepatectomy for hepatocellular carcinoma in Taiwan. METHODS: This was a hospital based retrospective study. The authors analyzed the medical records of all subjects with hepatocellular carcinoma who were initially treated by hepatic resection and cholecystectomy at 1 medical center in Taiwan from 1995 to 2008. Totally, 549 subjects were enrolled in this study. RESULTS: There were 428 men (78.0%) and 121 women (22.0%). The mean age was 55.6 +/- 13.2 years (range, 15-88 years). Among the 549 subjects with hepatocellular carcinoma, only 1 patient (0.2%) had gallbladder metastasis. The prevalence of gallstones was 9.3%; the prevalence of cholesterolosis of the gallbladder was 6.6%; and the prevalence of cholesterol polyp of the gallbladder was 0.9%. CONCLUSIONS: The prevalence of metastasis from hepatocellular carcinoma to the gallbladder is low. Other lesions inside the gallbladder among patients with hepatocellular carcinoma are benign and they do not always require cholecystectomy. PMID- 21289506 TI - Myelomatous orbital and intracranial involvement. PMID- 21289507 TI - Abdominal and pelvic coccidioidomycosis. AB - Coccidioidomycosis is a fungal infection endemic to the Southwestern United States that has a clinical presentation resembling community-acquired pneumonia. Disease occurs after inhalation of airborne arthroconidia. Dissemination to a variety of organ systems via hematogenous spread from a primary pulmonary focus may then occur. Coccidioidomycosis rarely involves the abdominal cavity. The authors review the spectrum of abdominal and pelvic presentations of coccidioidomycosis and report 6 unusual cases, including acute appendicitis, hepatitis and adnexal masses. Pathologists played a critical role in the diagnosis of these presentations by recognizing spherules in tissue. In only 2 of the cases were Coccidioides species cultured. PMID- 21289508 TI - Hypopituitarism caused by neurocysticercosis. AB - Although neurocysticercosis is pleomorphic in its presentation, neurocysticercosis of the pituitary gland and hypothalamus is so uncommon that less than 10 cases have been reported in the literature. Hypopituitarism as a complication of neurocysticercosis is exceedingly rare with only 2 cases described in the literature. Herein, the authors describe a case of neurocysticercosis causing hypopituitarism in a young patient and mimicking a pituitary adenoma. Clinical experience with management of these cases is lacking, and there are no studies confirming the efficacy of cysticidal drugs in intrasellar or suprasellar cysts. Because most of single enhancing cystic lesions may disappear spontaneously and risk may outweigh the benefit of treatment, conservative management may be indicated in these cases. PMID- 21289509 TI - Postoperative bleeding in an elderly patient from acquired factor V inhibitor: rapid response to immunosuppressive therapy. AB - Acquired factor V inhibitor is a rare but potentially life-threatening hemorrhagic disorder caused by the development of autoantibodies directed against coagulation factor V. The management of acute bleeding and inhibitor eradication is the mainstay of the treatment. The authors report a case of a 79-year-old man who underwent right hip arthroplasty and postoperatively, when on Coumadin for deep venous thrombosis prophylaxis, developed bleeding from the surgical site with a hematoma and abnormal coagulation parameters. Further workup revealed an acquired factor V inhibitor. The approach to treat this rare and challenging disorder is discussed. The patient responded rapidly with disappearance of factor V inhibitor titers after initiation of treatment with rituximab, prednisone and cyclophosphamide. PMID- 21289510 TI - Impaired fasting glucose association with mortality in nondiabetic patients on maintenance peritoneal dialysis. AB - INTRODUCTION: The aim of this study was to investigate clinical significance of impaired fasting glucose (IFG) in nondiabetic patients on maintenance peritoneal dialysis (PD). METHODS: In total, 362 maintenance PD patients were enrolled and followed up for 2-years. According to 1997 definitions, patients were divided into 3 groups: diabetic (n = 85), nondiabetic with IFG (n = 62) and nondiabetic with normal fasting glucose levels (n = 215). After basal data were collected for cross-sectional analyses, mortality and cause of death were recorded for longitudinal analyses. RESULTS: After adjusting for related variables by multivariate logistic regression analysis, IFG was found to be positively associated with age but negatively associated with normalized protein nitrogen appearance and transferrin saturation in nondiabetic maintenance PD patients. Thirty nondiabetic patients had died after the 2-year follow-up. Cox multivariate analysis showed that age (hazard ratio: 1.037; 95% confidence interval: 1.002 1.073; P = 0.036) and presence of IFG (hazard ratio: 2.719; 95% confidence interval: 1.082-6.833; P = 0.033) were significant risk factors for all-cause 2 year mortality in nondiabetic maintenance PD patients. CONCLUSIONS: IFG, a preventable and treatable condition, was associated with all-cause 2-year mortality in nondiabetic maintenance PD patients. PMID- 21289511 TI - Switching to black rice diets modulates low-density lipoprotein oxidation and lipid measurements in rabbits. AB - The effect of white and black rice consumption on lipid profile, hydroperoxides, thiobarbituric reactive substances and oxidized low-density lipoprotein (LDL) induced by hypercholesterolemia was investigated in 24 male rabbits; a purified normal diet (NC, n = 6), a high fat/cholesterol (1.0 g/100 g) diet (PC group, n = 6), a high fat/cholesterol diet with 25 g/100 g white ground rice (PCWR group, n = 6), 25 g/100 g black ground rice (PCBR group, n = 6) for 10 weeks. Blood samples were collected for lipid measurements. Results indicate that serum high density lipoprotein-cholesterol was higher (P < 0.05) in the PCBR compared with the PC and PCWR groups. Hydroperoxides and thiobarbituric reactive substances were significantly lower (P < 0.05) in the PCBR compared with PCWR and PC groups. Cyanidin-3-glucoside (Cy-3-Glu) and peonidin-3-glucoside have been tested in vitro against copper-mediated low-density lipoprotein. Cy-3-Glu was excelled peonidin-3-glucoside by increasing the lag time of NC from 80 to 500 minutes in the presence of 2.0 MUM of Cy-3-Glu. Hierarchically, black rice rabbits group was given the best results compared with other groups. The results may be indicating to a suggested mechanism (anthocyanins protection; Cy-3-Glu) of the cardioprotective effect of black rice. PMID- 21289512 TI - Ovarian malignancies incidentally diagnosed during cesarean section: analysis of 13 cases. AB - INTRODUCTION: To describe and analyze the clinicopathologic characteristics of ovarian malignancies discovered at cesarean section (CS). METHODS: A retrospective study based on clinical histories from 13 patients diagnosed concurrently with CS at our hospital from January 1991 to December 2008. RESULTS: The incidence of ovarian malignancies diagnosed during CS was 0.21 in 1000 CS. Histopathologic categories included malignant germ cell tumor (2, 15.38%), invasive epithelial carcinoma (3, 23.08%) and low-malignant potential tumor (8, 61.54%). All patients were clinically asymptomatic and diagnosed in stage I. Ovarian masses were detected by ultrasound in only 5 patients before surgery, but no malignancy was indicated. Tumor sizes ranged from 2.5 to 30 cm. Six malignancies were diagnosed by paraffin section after surgery, and of these, 2 patients received second surgery for tumor staging. Conservative surgical treatment was performed on 12 patients. Three patients received adjuvant chemotherapy. All patients are currently in complete remission. No maternal and fetal complication related to surgery was observed. CONCLUSIONS: Ultrasound in the first trimester is recommended to rule out the adnexal mass. Frozen section is indicated for any suspicion. Conservative therapy could be applied to most patients with good prognosis if the patient was chosen carefully. PMID- 21289513 TI - How does a simple enquiry compare to a detailed family history questionnaire to identify coronary heart disease or diabetic familial risk? AB - PURPOSE: To examine whether a simple enquiry can provide similar family history information compared with a detailed questionnaire for coronary heart disease or diabetes. METHODS: Data from two randomized controlled trials were extracted that assess the clinical value of using family history information for either coronary heart disease (ISRCTNI17943542) or diabetes risk assessment (NTR1938) in a community-based population. Outcome measures were percentage agreement, sensitivity, and specificity of self-reported family history for coronary heart disease and diabetes by means of a simple enquiry, when compared with a detailed questionnaire. RESULTS: Agreement between both family history tools was 76.8% for first-degree relatives with coronary heart disease, and 89.2% and 87.6% for first and second-degree relatives with diabetes, respectively. The sensitivity was 44.2% for first-degree relatives with coronary heart disease, 81.9% for first degree relatives with diabetes, and 35.4% for second-degree relatives with diabetes. Specificity was 89.3%, 97.0%, and 94.5%, respectively. CONCLUSION: Compared with a detailed questionnaire, the simple enquiry correctly identified the majority of individuals classified as having no significant family history but missed a significant proportion of individuals with positive family history. Incorrect classification of family history, in particular the high false-negative rate, has implications on the utility of a simple enquiry in identifying familial risk in clinical practice. PMID- 21289514 TI - Copy number variation in the dosage-sensitive 16p11.2 interval accounts for only a small proportion of autism incidence: a systematic review and meta-analysis. AB - PURPOSE: Autism is one of the most heritable complex disorders, but the genetic etiology of autism spectrum disorders is unexplained in ~ 90% of cases. Highly penetrant microdeletions and microduplications of 16p11.2 contribute to the pathogenesis of autism spectrum disorder, but the extent to which these variants account for the total burden of idiopathic autism spectrum disorders has not been systematically investigated. METHODS: A systematic literature review and meta analysis were performed to determine the prevalence of these variants among individuals diagnosed with autism spectrum disorders. A planned subgroup analysis was conducted to assess prevalence differences between sporadic and familial autism spectrum disorder cases. RESULTS: In the combined analysis of 3613 idiopathic autism spectrum disorder cases from seven studies, the meta-analytic prevalence of these microdeletions and microduplications was 0.76% (95% CI, 0.51 1.12%). When stratified by copy number variant-type, the prevalence of microdeletions was 0.50% (95% CI, 0.31-0.82%) and the prevalence of microduplications was 0.28% (95% CI, 0.14-0.56%). Sporadic autism spectrum disorder cases showed only a slightly higher prevalence than familial cases. CONCLUSION: The number needed to test to identify one such variant is 132 patients (95% CI, 89-198). Such information, especially as it pertains to diagnostic yield in genetic testing, should prove useful to clinicians considering chromosomal microarray analysis in subjects with autism spectrum disorders. PMID- 21289515 TI - von Willebrand disease. AB - von Willebrand disease is a common inherited bleeding disorder characterized by excessive mucocutaneous bleeding. Characteristic bleeding symptoms include epistaxis, easy bruising, oral cavity bleeding, menorrhagia, bleeding after dental extraction, surgery, and/or childbirth, and in severe cases, bleeding into joints and soft tissues. There are three subtypes: types 1 and 3 represent quantitative variants and type 2 is a group of four qualitative variants: (1) type 2A-characterized by defective von Willebrand factor-dependent platelet adhesion because of decreased high-molecular-weight von Willebrand factor multimers, (2) type 2B-caused by pathologically increased von Willebrand factor platelet interactions, (3) type 2M-caused by decreased von Willebrand factor platelet interactions not based on the loss of high-molecular-weight multimers, and (4) type 2N-characterized by reduced binding of von Willebrand factor to factor VIII. The diagnosis of von Willebrand disease requires specialized assays of von Willebrand factor and/or molecular genetic testing of von Willebrand factor. Severe bleeding episodes can be prevented or controlled with intravenous infusions of virally inactivated plasma-derived clotting factor concentrates containing both von Willebrand factor and factor VIII. Depending on the von Willebrand disease type, mild bleeding episodes usually respond to intravenous or subcutaneous treatment with desmopressin, a vasopressin analog. Other treatments that can reduce symptoms include fibrinolytic inhibitors and hormones for menorrhagia. PMID- 21289516 TI - Standards of care: are they being used? AB - Electronic access to standards of care is viewed as a promising strategy for increasing evidence-based practice. Before determining whether electronic access to standards will increase nurses' use of standards of care, data on their current rate of utilization are needed. Using 2 standards of care, Fluid Volume Excess and Manic Behavior, we used retrospective chart reviews to gather baseline information. Insights from these findings are presented. PMID- 21289517 TI - Aromatase inhibitor exemestane has antiproliferative effects on human mesothelioma cells. AB - PURPOSE: The aim of this study was to investigate the expression and biological activity of aromatase (CYP19A1) in malignant mesothelioma (MM). EXPERIMENTAL DESIGN: We found CYP19A1 in five human MM cell lines using reverse transcription polymerase chain reaction and Western immunoblots and in a group of samples from patients with MM by immunohistochemistry. Aromatization activity was determined in MM cells by enzyme-linked immunosorbent assay as a measure of estradiol (E2) product, in basal condition and after addition of cytokine, prostaglandin-E2, and epidermal growth factor to MM cells. Treatment of MM cells with exemestane, a CYP19A1 inhibitor, was assessed by cell proliferation kit, cell cycle analysis, and Western blot for caspase, poly(ADP-ribose)polymerase, Bcl-xL, and v-akt murin thymoma viral oncogene homolog (Akt). RESULTS: Biological activity of CYP19A1, already present in basal condition, was increased in MPP89 and Ist-Mes1 cells after treatment with cytokine, in all MM cells on prostaglandin-E2 treatment, and in MPP89, Ist-Mes2, and Ist-Mes1 after addition of epidermal growth factor. Treatment of MM cells with exemestane led to significant reduction of tumor cell growth, perturbation of cell cycle, caspase activation, poly(ADP ribose)polymerase cleavage, and down-regulation of phosphorylation of Akt and Bcl xL. In tumor tissues, we found a cytoplasmic localization of CYP19A1. By univariate analysis, overall survival resulted to be strongly influenced by high CYP19A1 expression (p = 0.001). CONCLUSION: These findings show that CYP19A1 is present in MM and that cell growth can be down-regulated by exemestane. As Akt pathway and Bcl-xL are implicated in conferring resistance to conventional chemotherapy, exemestane could open new treatment strategies to be associated with standard therapy for patients afflicted with MM. PMID- 21289518 TI - Expression of excision repair cross-complementation group 1, breast cancer susceptibility 1, and beta III-tubulin in thymic epithelial tumors. AB - BACKGROUND: We investigated the clinical significance of excision repair cross complementation group 1 (ERCC1), breast cancer susceptibility 1 (BRCA1), and class III beta-tubulin (TUBB3) expression in thymic epithelial tumors. METHOD: Fifty-six patients with thymic epithelial tumors were included in this study. Tumors sections were stained by immunohistochemistry for ERCC1, BRCA1, TUBB3, microvessel density, and p53. RESULTS: ERCC1, BRCA1, and TUBB3 were expressed in 48%, 50%, and 27%, respectively. The expression of ERCC1, BRCA1, and TUBB3 was significantly correlated with the grade of malignancy in thymic epithelial tumors. These biomarkers were closely associated with p53 and microvessel density and were a prognostic marker for predicting poor outcome. We also found that overexpression of ERCC1 and TUBB3 was associated with resistance to platinum- and taxane-based chemotherapy. CONCLUSION: An expression of ERCC1, BRCA1, and TUBB3 was correlated strongly with each other and was significantly associated with a poor outcome in thymic epithelial tumors. High-ERCC1 and TUBB3 expressions might be associated with resistance to platinum- and taxane-based chemotherapy, respectively. PMID- 21289519 TI - p63 and p73 isoform expression in non-small cell lung cancer and corresponding morphological normal lung tissue. AB - BACKGROUND: The TP73 and TP63 genes are members of the p53 tumor suppressor family and are expressed in different N-terminal isoforms either with proapoptotic (transactivation domain, TA) and antiapoptotic (N-terminally truncated, DeltaN) function. Unlike p53, the role of p73 and p63 in tumor is controversial. It has been recently hypothesized that altered DeltaN:TA expression ratio, rather than single isoform overexpression, plays a role in the pathogenesis of many diseases, including lung cancer. METHODS: Isoform-specific, real-time polymerase chain reaction and immunohistochemistry analysis on matched cancer and corresponding normal tissues from surgically resected non-small cell lung cancers (NSCLCs) have been performed aiming to explore the expression levels of each p63 and p73 N-terminal isoforms and their DeltaN:TA expression ratio. RESULTS: For both p63 and p73, a N-terminal isoform-specific modulation that alter DeltaN:TA isoform balance was identified. In particular, DeltaNp63 isoform was significantly up-modulated, whereas TAp63 was slightly down-modulated in NSCLC specimens. Likewise, Delta2p73 and Delta2/3p73 were up-modulated, whereas DeltaNp73 and DeltaN'p73 isoforms were down-modulated. Moreover, a higher TAp63 and DeltaN'p73 transcripts expression, detected in the normal tissue surrounding the tumors, correlates with poor patient outcome, representing independent prognostic factors for overall survival (DeltaN'p73: p = 0.049, hazard ratio = 3.091, 95% confidence interval = 1.005-9.524 and TAp63: p = 0.001, hazard ratio = 8.091, 95% confidence interval = 2.254-29.05). CONCLUSION: Our findings suggest that p63 and p73 altered DeltaN:TA expression ratio occurs in NSCLC likely contributing to the molecular pathogenesis of this tumor. PMID- 21289520 TI - Phase II trial of induction gemcitabine and carboplatin followed by conformal thoracic radiation to 74 Gy with weekly paclitaxel and carboplatin in unresectable stage III non-small cell lung cancer. AB - INTRODUCTION: The survival for patients with locally advanced, unresectable non small cell lung cancer receiving standard of care concomitant chemoradiation remains disappointingly low. A reduction in both local and distant recurrence is needed to improve patients' outcome. Performing molecular studies on serially collected tumor specimens may result in a better selection of therapeutic options. METHODS: We conducted a phase II single-institution trial of two cycles of induction chemotherapy with gemcitabine and carboplatin followed by high-dose conformal radiation concomitant with weekly paclitaxel and carboplatin in 39 patients. The trial required a dedicated tumor biopsy before treatment initiation. In addition, tumor biopsies were requested, if safely feasible, before initiation of chemoradiation and 2 months after completion all therapy. RESULTS: Induction chemotherapy was well tolerated, and 38 patients proceeded with chemoradiation. The mean delivered radiation dose was 70.2 Gy, 23 patients received the full dose of 74 Gy, and 19 patients completed all treatment on schedule without dose reductions or delays. Median overall and progression-free survivals were 22.7 and 14.3 months, respectively. A total of 82 procedures, including 46 transthoracic core needle biopsies, were performed. Thirteen patients had all three serial tumor biopsies. Three of these procedures resulted in complications that required an intervention; all for the treatment of a biopsy induced pneumothorax. CONCLUSIONS: We conclude that induction gemcitabine/carboplatin followed by concurrent paclitaxel/carboplatin with conformal radiation to 74 Gy is safe and tolerable with promising efficacy. We demonstrated that dedicated and serial tumor collections are safe, feasible, and acceptable for patients with non-small cell lung cancer. PMID- 21289521 TI - Multicenter phase II trial of Motexafin gadolinium and pemetrexed for second-line treatment in patients with non-small cell lung cancer. AB - BACKGROUND: Motexafin gadolinium (MGd) disrupts redox-dependent pathways by inhibiting oxidative stress-related proteins leading to apoptosis. MGd selectively targets tumor cells, disrupting energy metabolism and repair mechanisms, rendering cells more prone to apoptosis. Preclinical studies with MGd and pemetrexed show significant tumor growth delay in lung cancer cell lines. METHODS: Patients with non-small cell lung cancer, Eastern Cooperative Oncology Group performance status 0 to 1, who had received one previous platinum containing regimen and normal organ function were treated with MGd 15 mg/kg and pemetrexed 500 mg/m q21days. Patients were allowed to receive more than one regimen if the initial treatment was in the adjuvant or curative setting and administered >12 months earlier. The primary end point was to demonstrate a 40% rate of 6-month progression free survival (PFS). RESULTS: Seventy-two patients (30 women, 42 men), performance status 0/1 (30/42), and a median age of 63 years were enrolled. Most patients (96%) were current or former smokers. All histologic types were represented (squamous/adenocarcinoma/other: 28%, 42%, 31%). Number of prior regimens: 1: 69%; 2: 26%, and >2: 4%. Median number of cycles administered was (range) 2 (1-12). TOXICITY: grade 3/4 neutropenia was noted in 8.3% with febrile neutropenia in 1.4%, thrombocytopenia in 8.3%, fatigue in 9.7%, and pneumonia in 11.1%. There were no complete responses, 8.1% had partial response, 56.5% had stable disease, and 35.5% had progressive disease as their best response. Twenty-three percent of patients were progression free at 6 months and the median PFS was 2.6 months with an overall survival of 8.1 months. CONCLUSIONS: The combination of MGd and pemetrexed was well tolerated with toxicity similar to that of pemetrexed alone. However, the study did not achieve its end point of 40% 6-month PFS. The response rate, PFS, and overall survival did not seem markedly different than prior phase II and phase III studies of pemetrexed alone. Consequently, there are no further plans for development of this combination. PMID- 21289522 TI - Double-blind, placebo-controlled, randomized phase 2 study of the proapoptotic agent AT-101 plus docetaxel, in second-line non-small cell lung cancer. AB - BACKGROUND: AT-101 is an inhibitor of Bcl-2 family proteins including Bcl-2, Bcl xL, Mcl-1, and Bcl-w. In vivo and in vitro studies have exhibited broad activity of AT-101, including synergy with docetaxel in non-small cell lung cancer tumor models. METHODS: We conducted a prospective, randomized (1:1), double-blind, placebo-controlled phase 2 study. Eligible patients must have received one prior chemotherapeutic regimen for advanced or metastatic non-small cell lung cancer and may also have received therapy with an epidermal growth factor receptor inhibitor. Patients received AT-101 (40 mg b.i.d. * 3 days) or placebo in combination with docetaxel (75 mg/m on day 1) every 21 days. The primary endpoint was progression-free survival (PFS) as determined by independent review; other endpoints include overall survival and PFS by investigator determination. Approximately 102 patients were planned to provide 70 events (80% power, hazard ratio [HR] of 0.6, one-sided alpha of 0.1). RESULTS: : One hundred six patients were assigned to treatment and 105 patients received at least one dose of AT-101 or placebo. Baseline factors were balanced between treatment groups: median age 59 years; 77% men, and 79% current or former smokers. Ninety-three percent of patients had distant metastatic disease at randomization and 56% squamous histology. The most frequently reported adverse events were fatigue (18%), anemia (18%), and dyspnea (18%). No statistically significant differences in serious adverse events were observed between AT-101 and placebo; grade 1/2 headaches appeared more frequently with AT-101 (9% versus 0%) and neutropenia was reported more frequently in the docetaxel plus placebo arm compared with docetaxel plus AT 101 (17% versus 8%). Unlike trials with continuous daily dosing of AT-101, no cases of small bowel obstruction were reported. The response rate and median PFS were not different between the arms by independent review, PFS 7.5 weeks for docetaxel plus AT-101 and 7.1 weeks for docetaxel plus placebo arms (HR, 1.04; p = 0.57). The median overall survival was 7.8 months for docetaxel plus AT-101 versus 5.9 months for docetaxel plus placebo (HR, 0.82; p = 0.21). CONCLUSIONS: The primary endpoint of improved PFS for AT-101 plus docetaxel was not met. AT 101 plus docetaxel was well tolerated with an adverse event profile indistinguishable from the base docetaxel regimen. AT-101 is the first oral, pan Bcl-2 family inhibitor to exhibit a possible survival benefit in a randomized study. PMID- 21289523 TI - Screening-detected lung cancers: is systematic nodal dissection always essential? AB - BACKGROUND: To address whether systematic lymph node dissection is always necessary in early lung cancer, we identified factors predicting nodal involvement in a screening series and applied them to nonscreening-detected cancers. METHODS: In the 97 patients with clinical T1-2N0M0 lung cancer (<3 cm), enrolled in the Continuous Observation of Smoking Subjects computed tomography (CT) screening study, who underwent curative resection with radical mediastinal lymph node dissection, we examined factors associated with hilar extrapulmonary and mediastinal nodal involvement. Nodule size plus positive/negative positron emission tomography (PET)-CT (usually as maximum standard uptake value [maxSUV]) were subsequently evaluated retrospectively for their ability to predict nodal involvement in 193 consecutive patients with nonscreening-detected clinical stage I lung cancer. RESULTS: Among Continuous Observation of Smoking Subjects patients, 91 (94%) were pN0, and six (6.2%) were pN+. All patients with maxSUV <2.0 (p = 0.08) or pathological nodule <=10 mm (p = 0.027) were pN0 (62 cases). Nodal metastases occurred in 6 cases among the 29 (17%) patients with lung nodule >10 mm and maxSUV >=2.0 (p = 0.002 versus the other 62 cases). In the nonscreening series, 42 of 43 cases with negative PET-CT (usually maxSUV <2.0) or nodule <=10 mm were pN0; 33 of 149 (22%) cases with positive PET-CT (usually maxSUV >= 2.0) and nodule >10 mm were pN+ (p = 0.001 versus the 43 cases). CONCLUSIONS: This limited experience suggests that in early-stage clinically N0 lung cancers with maxSUV <2.0 or pathological nodule size <=10 mm, systematic nodal dissection can be avoided as the risk of nodal involvement is very low. PMID- 21289524 TI - Effect of moderate-intensity exercise on oxidative stress indices in metabolically healthy obese and metabolically unhealthy obese phenotypes in postmenopausal women: a pilot study. AB - OBJECTIVE: The aim of this work was to determine whether the level of oxidative stress induced by moderate-intensity exercise depends on obesity phenotypes: metabolically healthy but obese (MHO) and non-metabolically healthy obese (at risk obesity; non-MHO). METHODS: We performed the study on 161 postmenopausal women aged 50 to 60 years. A metabolically healthy nonobese (MH-NO) group (n = 73), an MHO group (n = 27), and a non-MHO group (n = 61) exercised on a cycloergometer for 30 minutes at 50% of their peak oxygen consumption and were evaluated for oxidative status by determination of thiobarbituric acid-reactive substances (TBARS) and serum antioxidant activity (AS). RESULTS: No difference was found in AS between the MH-NO group and the MHO group. The AS of the non-MHO group was significantly lower than that of the MH-NO group (P < 0.05) and that of the MHO group (P = 0.011). The insulin resistance index homeostasis model assessment was the only biochemical parameter that correlated with AS. After exercise, a significant increase in the TBARS concentration in all tested groups of women was observed, but differences in the increment of TBARS level between groups were not found. CONCLUSIONS: Antioxidant status in obese postmenopausal women depends on obesity phenotypes and is higher for women with the MHO than those with the non-MHO phenotype. Independently of obesity phenotype, obese postmenopausal women exposed to moderate-intensity exercise seem to be at similar risk for oxidative stress compared with their nonobese counterparts. We suggest that homeostasis model assessment be taken into account when planning physical exercise for obese people. PMID- 21289525 TI - Effects of bazedoxifene in nonflushing postmenopausal women: a randomized phase 2 trial. AB - OBJECTIVE: Phase 3 studies of postmenopausal women with or at risk for osteoporosis reported that, compared with placebo, bazedoxifene increased the incidence of hot flushes. The current study evaluated the vasomotor effects of bazedoxifene in healthy nonflushing postmenopausal women. METHODS: In this phase 2 study, nonflushing postmenopausal women (n = 494) were randomized to daily treatment with bazedoxifene 5, 10, or 20 mg; raloxifene 60 mg; or placebo for 12 weeks. The primary endpoint was the percentage of women reporting hot flushes at any time during the study; secondary endpoints included the mean number and severity of hot flushes and the mean number of days with hot flushes. Effects on bone turnover markers and lipid parameters were also evaluated. RESULTS: Over the 12-week study, 25.5% of placebo-treated women reported hot flushes. The incidence of hot flushes with bazedoxifene 5, 10, and 20 mg and raloxifene 60 mg was 26.0%, 33.7%, 27.6%, and 21.4%, respectively, with no significant differences from that with placebo. The active treatment groups showed no significant differences from placebo in the mean number or severity of hot flushes during week 12 or any 4 week period. Bazedoxifene and raloxifene showed beneficial effects on lipid parameters and markers of bone turnover. All doses of bazedoxifene were generally well tolerated and did not increase endometrial thickness, vaginal bleeding, or breast pain compared with placebo over 12 weeks of therapy. CONCLUSIONS: Data from this phase 2 clinical trial suggest that bazedoxifene does not increase the incidence of hot flushes relative to placebo in nonflushing postmenopausal women. PMID- 21289526 TI - Intrapancreatic nerve invasion as a predictor for recurrence after pancreaticoduodenectomy in patients with invasive ductal carcinoma of the pancreas. AB - BACKGROUND: Neural invasion is a distinct route for the spread of pancreatic carcinoma. However, the clinicopathologic significance of neural invasion, with particular reference to intrapancreatic nerve invasion, remains to be elucidated. METHODS: One hundred fifty-three patients who underwent pancreaticoduodenectomy for invasive ductal carcinoma of the pancreas between 2004 and 2008 were retrospectively examined. The clinical and histopathologic factors, including intrapancreatic nerve invasion, were analyzed in these patients. The relationships between the degree of intrapancreatic nerve invasion and disease free survival, as well as various histopathologic factors, were investigated. RESULTS: There were significant differences in the degree of intrapancreatic nerve invasion with regard to disease-free survival (P < 0.001). A lack of lymph node metastases (P = 0.001), lower incidence of intrapancreatic nerve invasion (P = 0.001), and negative surgical margin (P = 0.011) significantly increased the disease-free survival. The tumor stage was not associated with intrapancreatic nerve invasion (P = 0.255). However, a larger tumor size (P = 0.024), a higher incidence of lymphatic invasion (P = 0.036), and the presence of extrapancreatic nerve plexus invasion (P < 0.001) were identified as independent factors associated with a higher incidence of intrapancreatic nerve invasion. CONCLUSIONS: Intrapancreatic nerve invasion may be useful as a predictor for recurrence after pancreaticoduodenectomy in patients with invasive ductal carcinoma of the pancreas. PMID- 21289527 TI - Natural history of branch duct intraductal papillary mucinous neoplasms of the pancreas: a multicenter study in Japan. AB - OBJECTIVE: The aim of this study was to evaluate the long-term follow-up results of patients with branch duct intraductal papillary mucinous neoplasms (BD-IPMNs) without mural nodules (MNs) at 10 representative institutions in Japan. METHODS: We analyzed 349 follow-up BD-IPMN patients who had no MNs on endoscopic ultrasonography at initial diagnosis. RESULTS: Observation periods ranged from 1 to 16.3 years (median, 3.7 years). Sixty-two (17.8%) patients exhibited disease progression during follow-up. Twenty-two underwent surgery, leading to a pathological diagnosis of carcinoma in 9 and adenoma in 13. Although the remaining 287 (82.2%) showed no changes, 7 underwent surgery because of symptoms (n = 2), choice (n = 2), or development of pancreatic ductal adenocarcinoma (n = 3); all of them were diagnosed pathologically as adenomas. Of the 29 patients undergoing surgery, all 9 with carcinoma exhibited signs of progression, such as increased main pancreatic duct diameter and/or appearance of MNs. Pancreatic ductal adenocarcinomas and additional BD-IPMNs developed in 7 (2.0%) and 13 (3.7%), respectively. Overall, 320 (91.7%) patients were followed without surgery. CONCLUSIONS: Most BD-IPMN patients who had no MNs on endoscopic ultrasonography could be managed without surgery. However, careful attention should be paid to disease progression and the development of pancreatic ductal adenocarcinomas during follow-up. PMID- 21289528 TI - Preprotachykinin-A gene deletion regulates hydrogen sulfide-induced toll-like receptor 4 signaling pathway in cerulein-treated pancreatic acinar cells. AB - OBJECTIVE: This study aimed to determine the effect of hydrogen sulfide (H2S) on Toll-like receptor 4 (TLR4)-mediated innate immune signaling in acute pancreatitis (AP) via substance P. METHODS: Male Swiss mice were treated with hourly intraperitoneal injections of cerulein (50 MUg/kg) for 10 hours. dl propargylglycine ([PAG] 100 mg/kg, intraperitoneally), an inhibitor of H2S formation, was administered 1 hour after the induction of AP. Pancreatic acinar cells from male preprotachykinin-A gene-knockout mice (PPTA) and their wild-type counterparts were incubated with or without cerulein (10 M for 60 minutes). To better understand the effect of H2S in inflammation, acinar cells were stimulated with cerulein after addition of H2S donor, sodium hydrosulfide. In addition, cerulein-treated pancreatic acinar cells were pretreated with PAG (30 MUM) for 1 hour. RESULTS: The H2S inhibitor PAG eliminated TLR4, interleukin 1 receptor associated kinase 4, tumor necrosis factor receptor-associated factor 6, and nuclear factor-kappaB (NF-kappaB) levels in in vitro and in vivo models of cerulein-induced AP. PPTA gene deletion reduced TLR4, myeloid differentiation factor 88, interleukin 1 receptor-associated kinase 4, tumor necrosis factor receptor-associated factor 6, and NF-kappaB in cerulein-treated pancreatic acinar cells, whereas administration of sodium hydrosulfide resulted in a further rise in TLR4 and NF-kappaB levels in cerulein-treated pancreatic acinar cells. CONCLUSION: The present findings show for the first time that in AP, H2S may up regulate the TLR4 pathway and NF-kappaB via substance P. PMID- 21289529 TI - Comparison of pandemic and seasonal influenza in the pediatric emergency department. AB - BACKGROUND: Emergency department (ED) presentation of pediatric pandemic H1N1 (pH1N1) infection is not well characterized. Our objective was to describe the clinical manifestations of pH1N1 in the pediatric ED. We also compared these characteristics to seasonal influenza A, and explored risk factors for pH1N1 hospitalization. METHODS: We conducted a retrospective cohort study at a pediatric hospital in Quebec City, Canada. Subjects were ED patients aged 0 to 17 years with laboratory-confirmed pH1N1 (April-July 2009) or seasonal influenza A (June 2006-March 2009). Clinical and laboratory data were analyzed by univariate and multivariate log-binomial regression. RESULTS: A total of 127 pH1N1 cases and 110 seasonal influenza cases were identified. pH1N1 patients were older (9.5 vs. 5.6 years; P < 0.0001) and presented more rapidly (2.8 vs. 3.5 days; P = 0.02). Clinical manifestations were similar, although gastrointestinal findings were less frequent in pH1N1 (relative risk [RR]: 0.49; 95% confidence interval [CI]: 0.37-0.65). Hospitalization risk was similar (RR: 1.12; 95% CI: 0.81-1.55), but hospitalized pH1N1 subjects were more frequently diagnosed with pneumonia (RR: 2.41; 95% CI: 1.16-5.00). In a multivariable model, age <2 years was independently associated with pH1N1 hospitalization (RR: 3.17; 95% CI: 1.78 5.65), whereas the absence of significant comorbidities decreased its risk (RR: 0.51; 95% CI: 0.31-0.85). CONCLUSIONS: After adjustment for age and delay to presentation, clinical manifestations and 21-day outcomes of pediatric pH1N1 were similar to those of seasonal influenza. pH1N1 patients with previously established risk factors for severe seasonal influenza experienced increased hospitalization risk. Our results suggest that pH1N1 clinical diagnosis and management in the pediatric ED can be performed in a manner similar to seasonal influenza. PMID- 21289530 TI - Healthcare-associated versus community-associated infective endocarditis in children. AB - BACKGROUND: Infective endocarditis (IE) in children is continuously changing in regard to underlying conditions, predisposing factors, etiologic agents, clinical manifestations, treatment, and outcome. We describe current characteristics and compare healthcare-associated and community-associated disease. PATIENTS AND METHODS: All children (<18 years) who were treated at our center between January 1992 through June 2004 and met the Duke criteria for definite or possible IE were included. Demographic, clinical, and laboratory data were collected. Cases were categorized as healthcare- or community-associated. RESULTS: A total of 50 children with IE were identified (51 events; 0.32/1000 hospitalizations). Twenty children (41%) had an isolated congenital heart disease, 13 (25%) had an underlying chronic disease, 9 (18%) were previously healthy, and 8 (16%) were preterm. Mortality rate was 12% (6/51). Compared with the community-associated cases (21/51, 41%), the healthcare-associated cases (30/51, 59%) showed female preponderance, younger age, 1.7-fold longer hospitalization, 1.6-fold longer time to pathogen eradication, and 3.4-fold higher mortality. The leading causes of healthcare-associated IE were Candida sp (8/30, 27%), coagulase-negative staphylococci (6/30, 20%), and Gram-negative bacilli (5/30, 16%). By contrast, the leading causes of community-associated IE were viridans streptococci (8/21, 38%) and Staphylococcus aureus (4/21, 19%). CONCLUSIONS: A high proportion of pediatric IE is healthcare-associated that occurs in younger and sicker children. Healthcare-associated IE differs from community-associated IE in the patients' age, causative pathogens, and mortality. These trends and the different etiologies may affect future antibiotic management of this important pediatric infection. PMID- 21289531 TI - Immunogenicity and safety of an investigational fully liquid hexavalent combination vaccine versus licensed combination vaccines at 6, 10, and 14 weeks of age in healthy South African infants. AB - BACKGROUND: Assessment of primary vaccination of a new fully liquid, hexavalent investigational DTaP-IPV-Hep B-PRP-T vaccine (Hexaxim) in South African infants. METHODS: Infants were randomized to the following at 6, 10, and 14 weeks of age (Expanded Program on Immunization schedule): DTaP-IPV-Hep B-PRP-T (Group 1; N = 286); DTwP-Hib, hepatitis B, and OPV vaccines (Group 2; N = 286); or DTaP-IPV-Hep B-PRP-T vaccine with hepatitis B vaccine at birth (Group 3; N = 143). Antibody titers were measured before vaccination (pertussis toxoid, filamentous hemagglutinin) and postprimary vaccination (all valences). Noninferiority analyses were performed for Group 1 versus Group 2 for seroprotection rates. Safety was evaluated from parental reports. RESULTS: Noninferiority (Group 1 minus Group 2) was demonstrated for anti-HBs, -PRP, -diphtheria, -tetanus, and polio 1, 2, 3 (lower 95% confidence interval for the difference was -8.20 to 3.46). Anti-HBs antibody titers >=10 mIU/mL and anti-PRP >=0.15 MUg/mL were >=95.4% in each group. Seroprotection rates were also high for the other antigens. Seroconversion rates (4-fold increase from pre- to postvaccination) were 93.6%, 83.2%, and 95.1% in Groups 1, 2, and 3, respectively, for anti pertussis toxoid and 93.1%, 57.7%, and 90.0% for anti-filamentous hemagglutinin. Anti-HBs GMTs were 330, 148, and 1913 mIU/mL for Groups 1, 2, and 3, respectively. Reactogenicity was similar in each group. Fever >=39.0 degrees C occurred in 1.7%, 0.4%, and 0.0% of infants in Groups 1, 2, and 3, respectively; no extensive limb swelling, hypotonic-hyporesponsive episodes, or vaccine-related serious adverse events were reported. CONCLUSIONS: The new, fully liquid, investigational hexavalent vaccine in the Expanded Program on Immunization schedule, with/without hepatitis B at birth, is highly immunogenic and safe compared with control vaccines, warranting further development. PMID- 21289532 TI - Mood disorders and their pharmacological treatment during pregnancy: is the future child affected? AB - Nearly half the US population will meet criteria for a neuropsychiatric disorder at some point in their lives, and 1 in 17 has a seriously debilitating illness. Although not all affected adults had an identified disorder as a child, increasingly these psychopathologies are conceptualized as the late-stage culmination of aberrant developmental processes shaped by a complex interplay of genes and experience, including experiences in utero. Decades of studies with pregnant animals demonstrate that stress-elicited perturbations in maternal biology affect offspring neurodevelopment. Studies of stress in pregnant women largely mirror these findings. Pregnant women with anxiety and/or depression experience greater life stress, and illness-related alterations in their neurobiology, with a potential to impact fetal neurobehavioral development via associated changes in the intrauterine environment and/or pharmacologic interventions. This article critically reviews findings on child development (including fetal neurobehavior) related to maternal depression, anxiety, and pharmacological treatments, primarily selective serotonin reuptake inhibitors (SSRIs). The hypothesis under review is that, in addition to genetics and characteristics of the postnatal environment, the familial transmission of risk for neuropsychiatric disorders involves a "third path"-prenatal exposure to psychiatric illness and its treatment. PMID- 21289533 TI - Sensory processing in autism: a review of neurophysiologic findings. AB - Atypical sensory-based behaviors are a ubiquitous feature of autism spectrum disorders (ASDs). In this article, we review the neural underpinnings of sensory processing in autism by reviewing the literature on neurophysiological responses to auditory, tactile, and visual stimuli in autistic individuals. We review studies of unimodal sensory processing and multisensory integration that use a variety of neuroimaging techniques, including electroencephalography (EEG), magnetoencephalography (MEG), and functional MRI. We then explore the impact of covert and overt attention on sensory processing. With additional characterization, neurophysiologic profiles of sensory processing in ASD may serve as valuable biomarkers for diagnosis and monitoring of therapeutic interventions for autism and reveal potential strategies and target brain regions for therapeutic interventions. PMID- 21289534 TI - Preterm birth and childhood psychiatric disorders. AB - Epidemiologic studies have, for many years, identified preterm birth as a significant risk factor for psychiatric disorders. There has been a recent resurgence of interest in neurobehavioral outcomes after preterm birth. In this article, we review clinical cohort studies of the prevalence, etiology, and risk factors for psychiatric sequelae in ex-preterm children. Studies using diagnostic psychiatric evaluations are few in number but typically report a 3- to 4-fold increased risk for disorders in middle childhood. Our review of studies reveals a "preterm behavioral phenotype" characterized by an increased risk for symptoms and disorders associated with inattention, anxiety, and social difficulties. The most contemporary studies have also reported a markedly increased prevalence of autism spectrum disorders (ASD) in preterm populations. Our examination of the correlates and comorbidities of psychiatric disorders is indicative of a different causative pathway that may be associated with altered brain development after preterm birth. Despite the low population attributable risk, the frequency of these symptoms and disorders means that psychiatric screening is likely to be beneficial in this vulnerable population. PMID- 21289535 TI - Genetic influences on social cognition. AB - Human social behavior develops under the influence of genetic, environmental, and cultural factors. Social cognition comprises our ability to understand and respond appropriately to other people's social approaches or responses. The concept embraces self-knowledge and theory of mind, or the ability to think about emotions and behavior from the perspective of another person. The neuropeptides oxytocin (OT) and vasopressin (AVP) are now known to play an important role, affecting individual differences in parenting behavior, social recognition, and affiliative behaviors. The processes of social cognition are also supported by reward circuitry, underpinned by the dopaminergic neurotransmitter system. Reward processes build social relationships, in parenting and pair-bonding, and influence social interactions that require trust, or display altruism. The impact of emotional regulation upon social behavior, including mood and anxiety, is also mediated through the serotonergic system. Variation in activity of serotonergic networks in the brain influences emotional responsivity, including subjective feelings, physiological responses, emotional expressions, and the tendency to become engaged in action as a consequence of a feeling state. Genetic variation in the receptors associated with OT, AVP, dopamine, and serotonin has been intensively studied in humans and animal models. Recent findings are building an increasingly coherent picture of regulatory mechanisms. PMID- 21289536 TI - Mitochondrial dysfunction can connect the diverse medical symptoms associated with autism spectrum disorders. AB - Autism spectrum disorder (ASD) is a devastating neurodevelopmental disorder. Over the past decade, evidence has emerged that some children with ASD suffer from undiagnosed comorbid medical conditions. One of the medical disorders that has been consistently associated with ASD is mitochondrial dysfunction. Individuals with mitochondrial disorders without concomitant ASD manifest dysfunction in multiple high-energy organ systems, such as the central nervous, muscular, and gastrointestinal (GI) systems. Interestingly, these are the identical organ systems affected in a significant number of children with ASD. This finding increases the possibility that mitochondrial dysfunction may be one of the keys that explains the many diverse symptoms observed in some children with ASD. This article will review the importance of mitochondria in human health and disease, the evidence for mitochondrial dysfunction in ASD, the potential role of mitochondrial dysfunction in the comorbid medical conditions associated with ASD, and how mitochondrial dysfunction can bridge the gap for understanding how these seemingly disparate medical conditions are related. We also review the limitations of this evidence and other possible explanations for these findings. This new understanding of ASD should provide researchers a pathway for understanding the etiopathogenesis of ASD and clinicians the potential to develop medical therapies. PMID- 21289537 TI - The quantitative nature of autistic social impairment. AB - Autism, like intellectual disability, represents the severe end of a continuous distribution of developmental impairments that occur in nature, that are highly inherited, and that are orthogonally related to other parameters of development. A paradigm shift in understanding the core social abnormality of autism as a quantitative trait rather than as a categorically defined condition has key implications for diagnostic classification, the measurement of change over time, the search for underlying genetic and neurobiologic mechanisms, and public health efforts to identify and support affected children. Here, a recent body of research in genetics and epidemiology is presented to examine a dimensional reconceptualization of autistic social impairment-as manifested in clinical autistic syndromes, the broader autism phenotype, and normal variation in the general population. It illustrates how traditional categorical approaches to diagnosis may lead to misclassification of subjects (especially girls and mildly affected boys in multiple-incidence autism families), which can be particularly damaging to biological studies and proposes continued efforts to derive a standardized quantitative system by which to characterize this family of conditions. PMID- 21289538 TI - Structural MRI in autism spectrum disorder. AB - Magnetic resonance (MR) examination provides a powerful tool for investigating brain structural changes in children with autism spectrum disorder (ASD). We review recent advances in the understanding of structural MR correlates of ASD. We summarize findings from studies based on voxel-based morphometry, surface based morphometry, tensor-based morphometry, and diffusion-tensor imaging. Finally, we discuss diagnostic models of ASD based on MR-derived features. PMID- 21289539 TI - The link between perinatal glucocorticoids exposure and psychiatric disorders. AB - The perinatal period is particularly sensitive to a variety of insults during which stress-regulating systems can be permanently altered and psychopathologies ensue. The programming of physiological, endocrinological, and behavioral functions by perinatal adversities is mediated by altered levels of glucocorticoids or the hypothalamic-pituitary-adrenal axis activity in either the mother or offspring. In this article, I review the integrated data from human studies and from animal models that suggest the programming effects of perinatal glucocorticoids exposure. Finally, the concept of developmental origins of psychiatric disorders is discussed. PMID- 21289540 TI - Schizophrenia and autism: both shared and disorder-specific pathogenesis via perinatal inflammation? AB - Prenatal exposure to infection and subsequent inflammatory responses have been implicated in the etiology of schizophrenia and autism. In this review, we summarize current evidence from human and animal studies supporting the hypothesis that the pathogenesis of these two disorders is linked via exposure to inflammation at early stages of development. Moreover, we propose a hypothetical model in which inflammatory mechanisms may account for multiple shared and disorder-specific pathological characteristics of both entities. In essence, our model suggests that acute neuroinflammation during early fetal development may be relevant for the induction of psychopathological and neuropathological features shared by schizophrenia and autism, whereas postacute latent and persistent inflammation may contribute to schizophrenia- and autism-specific phenotypes, respectively. PMID- 21289541 TI - Theory of mind and neurodevelopmental disorders of childhood. AB - To a large extent, the human infant is socialized through the acquisition of a specific cognitive mechanism known as theory of mind (ToM), a term which is currently used to explain a related set of intellectual abilities that enable us to understand that others have beliefs, desires, plans, hopes, information, and intentions that may differ from our own. Various neurodevelopmental disorders, such as autism spectrum disorders, attention deficit hyperactivity disorder, developmental language disorders, and schizophrenia, as well as acquired disorders of the right brain (and traumatic brain injury) impair ToM. ToM is a composite function, which involves memory, joint attention, complex perceptual recognition (such as face and gaze processing), language, executive functions (such as tracking of intentions and goals and moral reasoning), emotion processing-recognition, empathy, and imitation. Hence, ToM development is dependent on the maturation of several brain systems and is shaped by parenting, social relations, training, and education; thus, it is an example of the dense interaction that occurs between brain development and (social) environment. PMID- 21289542 TI - Modeling autistic features in animals. AB - A variety of features of autism can be simulated in rodents, including the core behavioral hallmarks of stereotyped and repetitive behaviors, and deficits in social interaction and communication. Other behaviors frequently found in autism spectrum disorders (ASDs) such as neophobia, enhanced anxiety, abnormal pain sensitivity and eye blink conditioning, disturbed sleep patterns, seizures, and deficits in sensorimotor gating are also present in some of the animal models. Neuropathology and some characteristic neurochemical changes that are frequently seen in autism, and alterations in the immune status in the brain and periphery are also found in some of the models. Several known environmental risk factors for autism have been successfully established in rodents, including maternal infection and maternal valproate administration. Also under investigation are a number of mouse models based on genetic variants associated with autism or on syndromic disorders with autistic features. This review briefly summarizes recent developments in this field, highlighting models with face and/or construct validity, and noting the potential for investigation of pathogenesis, and early progress toward clinical testing of potential therapeutics. Wherever possible, reference is made to reviews rather than to primary articles. PMID- 21289543 TI - Animal models of human anxiety disorders: reappraisal from a developmental psychopathology vantage point. AB - We are witnessing a tremendous expansion of strategies and techniques that derive from basic and preclinical science to study the fine genetic, epigenetic, and proteomic regulation of behavior in the laboratory animal. In this endeavor, animal models of psychiatric illness are becoming the almost exclusive domain of basic researchers, with lesser involvement of clinician researchers in their conceptual design, and transfer into practice of new paradigms. From the side of human behavioral research, the growing interest in gene-environment interplay and the fostering of valid endophenotypes are among the few substantial innovations in the effort of linking common mental disorders to cutting-edge clinical research questions. We argue that it is time for cross-fertilization between these camps. In this article, we a) observe that the "translational divide" can and should-be crossed by having investigators from both the basic and the clinical sides cowork on simpler, valid "endophenotypes" of neurodevelopmental relevance; b) emphasize the importance of unambiguous physiological readouts, more than behavioral equivalents of human symptoms/syndromes, for animal research; c) indicate and discuss how this could be fostered and implemented in a developmental framework of reference for some common anxiety disorders and ultimately lead to better animal models of human mental disorders. PMID- 21289544 TI - Neurobiology of attention deficit/hyperactivity disorder. AB - Attention deficit/hyperactivity disorder (ADHD), a prevalent neurodevelopmental disorder, has been associated with various structural and functional CNS abnormalities but findings about neurobiological mechanisms linking genes to brain phenotypes are just beginning to emerge. Despite the high heritability of the disorder and its main symptom dimensions, common individual genetic variants are likely to account for a small proportion of the phenotype's variance. Recent findings have drawn attention to the involvement of rare genetic variants in the pathophysiology of ADHD, some being shared with other neurodevelopmental disorders. Traditionally, neurobiological research on ADHD has focused on catecholaminergic pathways, the main target of pharmacological treatments. However, more distal and basic neuronal processes in relation with cell architecture and function might also play a role, possibly accounting for the coexistence of both diffuse and specific alterations of brain structure and activation patterns. This article aims to provide an overview of recent findings in the rapidly evolving field of ADHD neurobiology with a focus on novel strategies regarding pathophysiological analyses. PMID- 21289545 TI - Diagnosis and management of seroma following breast augmentation: an update. AB - This article is an update to the decision and management algorithms for management of periprosthetic space infection or seroma following breast augmentation, originally published in "Decision and Management Algorithms to Address Patient and Food and Drug Administration Concerns Regarding Breast Augmentation and Implants," published in the October 2004 issue of this Journal. This update specifically addresses additional diagnosis and management alternatives for management of seroma in breast augmentation patients that may relate to lymphoproliferative disorders or anaplastic large cell lymphoma. PMID- 21289546 TI - Converting SRS-24, SRS-23, and SRS-22 to SRS-22r: establishing conversion equations using regression modeling. AB - STUDY DESIGN: Cross-sectional mail questionnaire. OBJECTIVE: Assess the feasibility of translating total and domain scores from Scoliosis Research Society (SRS)-24, SRS-23, and SRS-22 to SRS-22r. SUMMARY OF BACKGROUND DATA: Three successive editions of the original SRS-24 health-related quality-of-life questionnaire have resulted from efforts to improve its psychometric properties and validate its use in patients down to 10 years of age. This resulted in the need to establish, if possible, conversion equations to the last and most thoroughly validated version, SRS-22r. METHODS: A consolidated questionnaire of 49 questions that incorporated the various questions in the four questionnaires was mailed to a consecutive series of 235 patients who had received primary posterior or anterior instrumentation and arthrodesis to treat adolescent idiopathic scoliosis. Regression modeling was used to establish conversion equations from the SRS-24, SRS-23, and SRS-22 to the SRS-22r. RESULTS: One hundred twenty-one of the 235 patients (51%), aged 23.3 +/- 4.52 years (range 14.2-34.6 years), returned the questionnaire at 8.6 +/- 4.00 years (range 2.3 15.9 years) following surgery. Estimation of SRS-22r questionnaire and nonmanagement domains total scores and mean scores from SRS-22 and SRS-23 scores is excellent (R2 scores of 0.97-0.99) and good for SRS-24 scores (R2 scores of 0.80-0.82, improving to 0.86 and 0.87 after minimal domain reconfiguration). Estimation of SRS-22r individual domain total scores and mean scores from SRS-22 and SRS-23 is good to excellent (R2 scores of 0.81-0.99). Minimal domain reconfiguration improves conversion from SRS-24 pain from R2 = 0.71 to 0.76, which are both fair; SRS-24 function from R2 = 0.69 and 0.74 to 0.83, from poor and fair to good; and SRS-24 satisfaction/dissatisfaction with management from R2 = 0.64 to 0.80, from poor to good. Conversion of SRS-24 self-image is poor (R2 = 0.60) despite the correlation being statistically significant. CONCLUSION: With one exception, SRS-24, SRS-23, and SRS-22 questionnaire, nonmanagement domains, and individual domain total scores and mean scores can be translated to SRS-22r scores with fair to excellent accuracy, which is further improved in some instances by minimal domain reconfigurations. The sole exception is SRS-24 self image, which translates poorly. PMID- 21289549 TI - Long-term magnetic resonance imaging follow-up demonstrates minimal transitional level lumbar disc degeneration after posterior spine fusion for adolescent idiopathic scoliosis. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To describe long-term clinical and imaging results focusing on the uninstrumented lumbar spine after posterior spinal fusion for adolescent idiopathic scoliosis. SUMMARY OF BACKGROUND DATA: Although previous studies found rates of low back pain after long fusion for adolescent idiopathic scoliosis which are comparable to rates found in the general population, many surgeons believe that the long lever arm associated with the fusion mass will result in increased stress at uninstrumented caudal intervertebral discs and accelerated degenerative changes. METHODS: This is a retrospective chart and imaging review of adolescent idiopathic scoliosis patients treated with posterior fusion and segmental instrumentation. Patients completed follow-up examination, outcome questionnaires, radiographs, and magnetic resonance (MR) imaging. MR images were scored for evidence of degeneration of lumbar discs below the level of the fusion. RESULTS: Twenty patients participated in the study, providing 90 discs below fusions for evaluation. The average follow-up was 11.8 years. The distal level of fixation was at L1 on average. The major curve averaged 55 degrees +/- 11 degrees before surgery and was corrected to 25 degrees +/- 10 degrees at follow-up. Follow-up MR imaging demonstrated new disc pathology in 85% of patients enrolled. Only one patient demonstrated significant degenerative disc disease at the junctional level, whereas most pathology was seen at the L5-S1 disc. The average Pfirrmann grade at uninstrumented levels deteriorated from 1.1 before surgery to 1.8 at follow-up. The greatest degree of degeneration was seen at the L5-S1 disc space where average degenerative scores increased from 1.2 before surgery to 2.3 after surgery. Three patients with severe disc disease were taking nonsteroidal anti inflammatory drugs for pain, but no narcotics. Only mild scoliosis research society (SRS) and Oswestry changes were noted in this severe degeneration group. CONCLUSION: Despite demonstrating an accelerated rate of L5-S1 disc degeneration, our study group has good functional scores and maintenance of correction over 10 years postfusion. In this long-term MR imaging follow-up study, disc degeneration was found remote to the lowest instrumented vertebra. PMID- 21289550 TI - Clinical characteristics, pain, and disability in relation to alar ligament MRI findings. AB - STUDY DESIGN: Cross-sectional study. OBJECTIVE: To evaluate the association between degree of signal changes in the alar ligaments on MRI with respect to pain and disability. SUMMARY OF BACKGROUND DATA: Conflicting evidence exists whether areas of high-signal intensity in the alar ligaments on MRI are associated with pain and disability. METHODS: A cross-sectional designed study of 173 subjects including a group with persistent whiplash associated disorder (WAD) Grade II after a car accident (n = 59), a group with chronic nontraumatic neck pain (n = 57) and a group without neck pain or previous neck trauma (n = 57). To assess pain and disability, all participants filled in the Brief Pain Inventory (BPI-intensity and BPI-interference), the European Quality of Life (EQ-5D and EQ VAS) and the Hospital Anxiety and Depression Rating Scale (HADS). High-resolution proton-weighted MR images in three planes were evaluated by two experienced neuroradiologists who were blinded to patient history and group allocation. The alar ligaments were evaluated according to a 4-point grading scale; 0 = low signal intensity throughout the entire cross-section area, 1 = high-signal intensity in one third or less, 2 = high-signal intensity in one third to two thirds, and 3 = high-signal intensity in two thirds or more of the cross-section area. RESULTS: With respect to BPI and HADS, the scores were highest in the WAD group, intermediate in the chronic nontraumatic neck pain group, and lowest among controls. EuroQol scores were lowest in the WAD group, intermediate in the chronic nontraumatic neck pain group, and highest among controls (P < 0.001). There was, however, no significant correlation between the alar ligament changes and measures for pain and disability. CONCLUSION: The previously reported assumption that changes in the alar ligaments detected on MRI are associated with pain and disability is not supported by this study. The diagnostic value and the clinical relevance of MR-detectable areas of high intensity in the alar ligaments remain questionable. PMID- 21289551 TI - Assessment of association between low back pain and paraspinal muscle atrophy using opposed-phase magnetic resonance imaging: a population-based study among young adults. AB - STUDY DESIGN: A cross-sectional imaging study of young adults. OBJECTIVE: To evaluate whether severity of low back symptoms predicts atrophy in the paraspinal muscles of young adults. SUMMARY OF BACKGROUND DATA: Although an increased fat content of the lumbar muscles has been observed among adults with chronic LBP, there is limited knowledge of this association in younger populations. METHODS: The population-based study sample consisted of 554 subjects (321 females and 233 males) from the 1986 Northern Finland Birth Cohort. Latent Class Analysis (LCA) was used to cluster the subjects according to the low back symptoms and functional limitations at 18, 19, and 21 years. The mean age of the subjects at the time of the MRI (magnetic resonance imaging) was 21 years (range, 20-23). Muscle atrophy was evaluated by assessing the fat content of the paraspinal muscles using Opposed-Phase MRI. The cross-sectional areas (CSAs) of the erector spinae and multifidus muscles were also measured. RESULTS: LCA analysis produced five clusters differing in symptoms, ranging from a cluster (n = 65) in which subjects had high likelihood of symptoms and functional limitations at all time points, to a cluster (n = 165) with no pain ever. The fat content of the multifidus muscles was significantly higher among women than men (14.0% vs. 5.3%, P < 0.001), but it was not significantly associated with symptom severity. The CSA of both erector spinae and multifidus muscles were significantly larger among men than women (P < 0.001 in all of the muscles), but were not associated with pain severity. CONCLUSION: Low back symptoms and functional limitations over a 3 year period were not associated with increased fat content or a reduction in the cross-sectional area of lumbar paraspinal muscles among young adults. PMID- 21289552 TI - Direct posterior c1 lateral mass screws compression reduction and osteosynthesis in the treatment of unstable jefferson fractures. AB - STUDY DESIGN: Technical case report. OBJECTIVE: To investigate a new concept and surgical technique in the treatment of unstable Jefferson fractures, which preserves the motion of upper cervical spine, avoiding fusion. SUMMARY OF BACKGROUND DATA: The management of unstable Jefferson fractures remains controversial. Conservative treatment usually involves a long time of immobilization in halo vest, whereas surgical intervention generally performs fusion, eliminating the range of motion of upper cervical spine. METHODS: Two patients with unstable Jefferson fractures were surgically treated via direct posterior C1 lateral mass screws compression reduction and osteosynthesis technique, aiming at restoring the C0-C2 height and maintaining the vertical ligamentous tension for C0-C1-C2 complex stability despite the incompetent transverse ligament, achieving physiologic repair instead of traditional fusion. The clinical and radiographic results were documented. RESULTS: The postoperative CT showed that C1 lateral mass screws were well positioned. At 1-year follow-up, plain radiographs, and CT scan revealed no implant failure, good cervical alignment, and bony healing of the fractures; no C1-C2 instability was observed on the flexion-extension radiographs. The patients were completely pain-free, with full range of motion of the cervical spine. CONCLUSION: The ideal treatment of unstable Jefferson fractures is expected to preserve the function of C0-C1-C2. Unstable Jefferson fractures involve the concomitant failure of the vertical ligamentous tension because of the loss of C0-C2 height. Reduction of the displaced lateral masses to restore the C0-C2 height and maintain the ligamentous tension is the key to the surgery. Direct posterior C1 lateral mass screws compression reduction and osteosynthesis is a valid technique, avoiding fusion of upper cervical spine. PMID- 21289553 TI - Decrease of self-concept in adolescent patients with mild to moderate scoliosis after conservative treatment. AB - STUDY DESIGN: Comparative study. OBJECTIVE: To analyze the effect of conservative treatment on self-concept in patients with mild to moderate scoliosis. SUMMARY OF BACKGROUND DATA: The choice of surgery or conservative treatment in adolescent idiopathic scoliosis is usually done on the basis of the magnitude of the initial Cobb angle in these patients. However, mental effect of the therapy choice should be considered. METHODS: Between August 2006 and December 2008, 65 patients with adolescent idiopathic scoliosis were selected for this study. Twenty-two patients with Cobb angles between 20 degrees and 40 degrees received conservative treatment, 18 patients with Cobb angles between 40 degrees and 50 degrees received conservative treatment, and 25 patients with Cobb angles between 40 degrees and 50 degrees received surgical treatment. All subjects were required to fill the Children's Self-Concept Scale at the beginning of the study and at the follow-up visit 1 year later. Scores on this scale were compared among the three different groups, and between the initial visit and the follow-up visit in each group. RESULTS: At the initial test, the total self-concept score was significantly higher in the group of patients with Cobb angles between 20 degrees and 40 degrees than in the two groups with Cobb angles between 40 degrees and 50 degrees . At the follow-up visit, the total self-concept score had increased significantly in the surgically treated group (Cobb angle between 40 degrees and 50 degrees ), however, it had decreased in the two conservatively treated groups. No significant difference was seen between the two conservatively treated groups in the amount by which the self-concept score had decreased at follow-up. CONCLUSION: In terms of mental health, conservative treatment is not ideal for patients with mild to moderate scoliosis, and in particular, it is not conducive to mental health in patients with Cobb angles between 40 degrees and 50 degrees . PMID- 21289554 TI - Middle-term results of a prospective comparative study of anterior decompression with fusion and posterior decompression with laminoplasty for the treatment of cervical spondylotic myelopathy. AB - STUDY DESIGN: A clinical prospective study. OBJECTIVE: To assess whether clinical and radiologic outcomes differ between anterior decompression and fusion (ADF) and laminoplasty (LAMP) in the treatment of cervical spondylotic myelopathy (CSM). SUMMARY OF BACKGROUND DATA: No reports to date have accurately and prospectively compared middle-term clinical outcomes after anterior and posterior decompression for CSM. METHODS: We prospectively performed LAMP (n = 50) in 1996, 1998, 2000, and 2002, and ADF (n = 45) in 1997, 1999, 2001, and 2003. The Japanese Orthopedic Association (JOA) score, recovery rate, and each item of the JOA score were evaluated. For radiographic evaluation, the lordotic angle and range of motion (ROM) at C2-C7 and residual anterior compression to the spinal cord (ACS) after LAMP on magnetic resonance imaging were investigated. RESULTS: Eighty-six patients (ADF n = 39; LAMP n = 47) could be followed for more than 5 years (follow-up rate 91.5%). Demographics were similar between the two groups. The mean JOA score and recovery rate in the ADF group were superior to those in the LAMP group from 2-year data collected after surgery. However, LAMP was safer and less invasive than ADF with respect to physical status and complications in the perioperative period. For individual items of the JOA score, the ADF group showed significantly more improvement of upper extremity motor function than the LAMP group (P < 0.05). There was a significant difference in maintenance of the lordotic angle in the ADF group compared with the LAMP group despite no difference in ROM.The LAMP group was divided into two subgroups: (1) LAMP(+) (n = 16) comprising patients who had ACS at 2 years after surgery, and (2) LAMP(-) (n = 31) comprising patients without ACS. Recovery rate differed significantly between the LAMP(+) and LAMP(-) groups despite there being no difference between the LAMP(-) and ADF groups. CONCLUSION: The recovery rate of the JOA score in the ADF group was better than that in the LAMP group. The clinical outcomes after LAMP could be influenced by ACS. PMID- 21289555 TI - Effect of hyperbaric oxygenation on intervertebral disc degeneration: an in vitro study with human lumbar nucleus pulposus. AB - STUDY DESIGN: An in vitro study with degenerated human lumbar intervertebral disc specimens cultured under hyperbaric oxygenation (HBO). OBJECTIVE: To observe the changes in interleukin (IL)-1beta, prostaglandin (PG)-E2, nitric oxide (NO), cell growth, and apoptosis of the human nucleus pulposus cell (NPC) after HBO. SUMMARY OF BACKGROUND DATA: Intervertebral disc degeneration has been demonstrated as related to IL-1beta, PG-E2, NO, and O2 concentration but the actual mechanism is not clear. HBO also has also been reported in the literature to influence changes in IL-1beta, prostaglandin E2, NO, and O2 concentration. However, the direct effect of HBO on the disc cells has not been previously reported. METHODS: We collected 12 human lumbar degenerated disc specimens and evaluated the effects of HBO on the cultured NPCs. The amounts of IL-1beta, PG-E2, and NO in the conditioned medium were quantified by enzyme-linked immunosorbent assay and high performance liquid chromatography. Cell growth was measured by increase in cell number. Cell viability and proteoglycan content were evaluated by histologic study using safranin O staining. In situ analysis of apoptosis was performed using Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. RESULTS: Our data indicated that HBO treatment inhibited IL-1beta, PG E2, and NO production but increased cell number and matrix synthesis of cultured NPCs. TUNEL staining showed that HBO treatment suppressed the apoptosis of cultured NPCs. CONCLUSION: HBO provides a potential treatment modality for disc degeneration. PMID- 21289556 TI - Managing nonspecific low back pain: do nonclinical patient characteristics matter? AB - STUDY DESIGN: A fully blocked experimental design using clinical vignettes to query primary care physicians on prescription for management of acute nonspecific low back pain. OBJECTIVE: To identify how nonclinical patient factors, specifically sex, patient presentation, and socioeconomic status, influence physician treatment recommendations for assessing and treating acute nonspecific low back pain. SUMMARY OF BACKGROUND DATA: Adherence to evidence-based practice guidelines for nonspecific low back pain remains inconsistent. Therefore, it is important to understand what factors guide physician management of these cases. METHODS: One vignette and questionnaire was distributed to primary care and emergency department clinical physicians during meetings at five teaching hospitals. The questionnaire asked for diagnostic and treatment recommendations including specific tests, medications, therapeutic procedures, activity, referral to other services, and patient education for the case represented in the vignette. RESULTS: Subjects included 284 physicians and approximately 75% had less than 5 years of clinical practice experience. Multivariate logistic regression showed seven significant associations of patient factors with treatment recommendations for acute nonspecific low back pain (one sex, two socioeconomic status, and four patient presentation; P < 0.05). CONCLUSION: All three assessed nonclinical factors influenced physician decisions regarding diagnostic and treatment recommendations for acute nonspecific low back pain. Patient presentation, suggestive of a patient's emotional state, was shown to be the most influential. PMID- 21289557 TI - Intradural cervical disc herniation: report of two cases and review of the literature. AB - STUDY DESIGN: Case report and review of the literature. OBJECTIVE: To report two additional cases with intradural cervical herniation and review the pertinent literature. SUMMARY OF BACKGROUND DATA: Intradural cervical disc herniation is rare and a total of 22 cases were reported in 2007. In searching the world literature on this topic, we found 27 cases of intradural cervical disc herniation in all. METHODS: Clinical history, physical examination, and radiographic findings of two patients with intradural cervical disc herniation were described, and corpectomy was performed in both cases. A review of the literature was completed. RESULT: The outcome of one case was gratifying, and at a 36-month follow-up, nearly a full recovery was obtained. But the other's condition was disappointing, whose postoperative MRI demonstrated high signal intensity in the spinal cord and adhesion of spinal cord to the posterior margin at C4 level. CONCLUSION: Intradural cervical disc herniation is relatively rare, and the two additional cases updated the number of this condition to 29. It remains difficult to definitively diagnose the disease before surgery, but some indirect signs may indicate the cases. Corpectomy under a microscope as the first option in treatment of this disease is recommended once it is highly diagnosed. The pathogenesis of intradural cervical disc herniation remains to be further investigated. We presume that biochemical factors may play an important role in the pathogenesis. PMID- 21289558 TI - Acute infrarenal aortic thrombosis presenting with flaccid paraplegia. AB - STUDY DESIGN: This study is a case report. OBJECTIVE: To report a case of a patient with paraplegia and low back pain, who was diagnosed with acute infrarenal aortic thrombosis. SUMMARY OF BACKGROUND DATA: There have been few reports in the literature regarding acute aortic thrombosis presenting with paraplegia. METHODS: A 56-year-old man was referred to our emergency department with flaccid paraplegia and low back pain. Clinical examination and imaging revealed acute infrarenal aortic thrombosis, with lower limb ischemia. The patient underwent transcutaneous embolectomy. RESULTS: Despite successful revascularization, the patient finally died because of development of revascularization syndrome. CONCLUSION: Acute aortic occlusion is a catastrophic event and may present with paraplegia, because of acute spinal cord ischemia. This can mislead the clinician to a wrong diagnosis and delay initiation of definite treatment. PMID- 21289559 TI - Computed tomographic artifact suggesting cervical facet subluxation. AB - STUDY DESIGN: A case report with review of the literature on the cause of computed tomographic (CT) artifacts and recommendations for identification of such artifacts. OBJECTIVE: To describe the presentation of a patient with a CT scan suggesting a cervical facet dislocation that ultimately proved to be artifactual. SUMMARY OF BACKGROUND DATA: CT scanning is routinely used in the detection of cervical spine injuries. This technique has a reported sensitivity of 98%, although specificity has proved more difficult to estimate. CT artifacts such as the case reported here is a significant cause of a decrease in specificity for this technique. METHODS: A 30-year-old woman with a history of a cervical fracture developed severe neck pain without neurologic deficit after trauma to the back of her neck. CT scans were obtained and reviewed at a local secondary level hospital. A cervical fracture dislocation was diagnosed and cervical spinal injury protocols were initiated and the patient transferred to authors', tertiary level institution for surgical management. A repeat CT scan showed her cervical spine to be in normal alignment. RESULTS: A movement artifact in the patient's original CT scans was misinterpreted as a unilateral facet fracture subluxation at C5-C6. There are two clues that in hindsight indicate that this finding was artifactual; an ill-defined tracheal margin in contrast with the sharply defined margin above and below the level of the artifact and a double bone margin seen on axial sections at the level of the artifact. CONCLUSION: Motion artifacts are an important cause in the reduction in specificity of CT scans and can be easily missed. It is important to be aware of the indicators of motion artifacts to reduce the risk of unnecessary treatments. PMID- 21289560 TI - Treatment of irreducible old atlantoaxial subluxation with cable-dragged reduction and cantilever beam internal fixation. AB - STUDY DESIGN: Retrospective case series study of surgical outcome for 21 atlantoaxial subluxation patients treated with a new technique, called cable dragged reduction/cantilever beam internal fixation. Surgery was performed by a single surgeon. OBJECTIVE: To describe and evaluate the cable-dragged reduction/cantilever beam internal fixation technique for the treatment for old atlantoaxial subluxation irreducible by traction. SUMMARY OF BACKGROUND DATA: Management of old atlantoaxial subluxation has always been a difficult task. A more effective way to achieve surgical reduction is needed. MATERIALS AND METHODS: Twenty one patients, aged 31.6 +/- 13.3 years (range, 11-67 years), 17 men and four women, with atlantoaxial subluxation that failed to be reduced after 10 to 111 days in traction, underwent posterior cable-dragged reduction/cantilever beam internal fixation surgery. Frankel classification of neural function before surgery was the following: Frankel B, four patients; Frankel C, five patients; Frankel D, four patients; and Frankel E, eight patients. Plain radiographs, computed tomographic three-dimensional reconstructive images and magnetic resonance images of the cervical spine were obtained at 3, 6, and 12 months after surgery, and each year thereafter. No patient was lost to follow-up, and the follow-up time ranged from 6 months to 4 years. Rate of reduction and C1~3 fusion, as well as improvement of neural function, were recorded and analyzed. RESULTS: The average follow-up period was 13.2 months. Radiographic evaluation of the group at follow-up showed 16 complete and five partial reductions, and satisfactory decompression and C1~3 fusion in all cases. Neural function at the end of the follow-up was Frankel B still in one patient, Frankel C in seven patients, and Frankel E in 13 patients. CONCLUSION: Cable-dragged reduction/cantilever beam internal fixation is almost as effective for reduction as anterior release but is less invasive and risky. It has similar operative time and blood loss to occipitocervical fusion but avoids arthrodesis of occipitoatlantal joint. It is also suitable for patients with severe myelopathy before surgery. Its major disadvantage is that C3, which is left free in the traditional atlantoaxial fusion surgery, has to be involved in fusion. And it is suitable only for patients with intact posterior arches in C1. PMID- 21289561 TI - The natural history of cardiac and pulmonary function decline in patients with duchenne muscular dystrophy. AB - STUDY DESIGN: Retrospective review of scoliosis progression, pulmonary and cardiac function in a series of patients with Duchenne Muscular Dystrophy (DMD). OBJECTIVE: To determine whether operative treatment of scoliosis decreases the rate of pulmonary function loss in patients with DMD. SUMMARY OF BACKGROUND DATA: It is generally accepted that surgical intervention should be undertaken in DMD scoliosis once curve sizes reach 35 degrees to allow intervention before critical respiratory decline has occurred. There are conflicting reports, however, regarding the effect of scoliosis stabilization on the rate of pulmonary function decline when compared to nonoperative cohorts. METHODS: We reviewed spinal radiographs, echocardiograms, and spirometry, hospital, and operative records of all patients seen at our tertiary referral center from July 1, 1992 to June 1, 2007. Data were recorded to Microsoft Excel (Microsoft, Redmond, WA) and analyzed with SAS (SAS Institute, Cary, NC) and R statistical processing software (www.r-project.org). RESULTS: The percent predicted forced vital capacity (PPFVC) decreased 5% per year before operation. The mean PPFVC was 54% (SD = 21%) before operation with a mean postoperative PPFVC of 43% (SD = 14%). Surgical treatment was associated with a 12% decline in PPFVC independent of other treatment variables. PPFVC after operation declined at a rate of 1% per year and while this rate was lower, it was not significantly different than the rate of decline present before operation (P = 0.18). Cardiac function as measured by left ventricular fractional shortening declined at a rate of 1% per year with most individuals exhibiting a left ventricular fractional shortening rate of more than 30 before operation. CONCLUSION: Operative treatment of scoliosis in DMD using the Luque Galveston method was associated with a reduction of forced vital capacity related to operation. The rate of pulmonary function decline after operation was not significantly reduced when compared with the rate of preoperative forced vital capacity decline. PMID- 21289562 TI - Manual and computerized measurement of sagittal vertebral inclination in computed tomography images. AB - STUDY DESIGN: Sagittal vertebral inclination (SVI) was systematically evaluated in computed tomography (CT) images by three observers using six manuals and two computerized measurements. OBJECTIVE: To analyze and compare manual and computerized measurements of SVI in CT images. SUMMARY OF BACKGROUND DATA: A number of methods were proposed to measure SVI in lateral radiographic projections in the form of spinal curvature or segmental angulation. A systematic analysis of the manual and computerized measurements in sagittal CT cross sections has not been performed yet. METHODS: SVI was measured in CT images for 28 vertebrae independently by three observers. Manual measurements were obtained in sagittal cross-sections by manually identifying the vertebral body corners, which defined the lines of SVI (superior and inferior tangents, anterior and posterior tangents, mid-endplate and mid-wall lines) against reference horizontal or vertical lines. Computerized measurements were obtained by manually identifying the vertebral centroids, which initialized the automated method that evaluated SVI by searching for the planes of maximal symmetry of vertebral bodies in two dimensions and in three dimensions. RESULTS: The midwall lines proved to be the most reproducible and reliable manual measurements (1.0 degrees and 1.4 degrees standard deviations [SD]). The computerized measurements in three dimensions were more reproducible and reliable (0.9 degrees and 1.3 degrees SD) and also most consistent with the midwall lines (2.1 degrees SD and 1.7 degrees mean absolute difference). CONCLUSIONS: The manual measurements based on mid-wall lines and the computerized measurements in three dimensions yielded the lowest intraobserver and interobserver variability of SVI. However, in terms of speed and operator friendliness, the computerized measurements may represent an adequate alternative to manual measurements. PMID- 21289563 TI - Centroid method: reliable method to determine the coronal curvature of scoliosis: a case control study comparing with the Cobb method. AB - STUDY DESIGN: Observational study with three examiners. OBJECTIVE: To compare the reliability of the Cobb and centroid methods. SUMMARY OF BACKGROUND DATA: The Cobb method is considered to be the gold standard in scoliosis measurement despite its low reliability. In adolescent idiopathic scoliosis (AIS) patients, the centroid method can be a good method for measuring scoliosis. METHODS: Sixty whole spine postero-anterior radiographs were collected to compare the reliability of the Cobb and centroid methods in AIS patients. Sixty radiographs were measured twice by each of the three examiners using the two measurement methods. The data were analyzed statistically to determine the inter- and intraobserver reliability. RESULT: In comparisons of inter- and intraobserver reliability of all 60 radiographs, the inter- and intraclass coefficients (ICCs) were higher in the centroid (>0.969) than in the Cobb method (>0.832), although both were in the excellent range. The mean absolute difference (MAD) values were higher in the Cobb method (<7.15 degrees vs. <3.75 degrees ), and >5 degrees in five comparisons. Regarding measures of mismatched radiograms, the inter- and intraobserver MAD values were higher in the Cobb method (<9.81 degrees vs. <3.82 degrees ), and >5 degrees in six comparisons. And, the ICCs were higher in the centroid method (>0.972) than the Cobb method (>0.758). In immature radiograms, the ICCs were higher in the centroid (>0.973) than in the Cobb method (>0.764), even though it was in the excellent range. And, the inter- and intraobserver MAD values were higher in the Cobb method (<8.49 degrees vs. <3.99 degrees ), and >5 degrees in seven comparisons. CONCLUSION: The centroid method is more reliable for measuring scoliosis in AIS than the Cobb method, and it can substitute the Cobb method, which showed high variability. PMID- 21289565 TI - Posterior C2 instrumentation: accuracy and complications associated with four techniques. AB - STUDY DESIGN: Retrospective review of a single tertiary care spine database to identify patients with C2 instrumentation between January 2001 and September 2008. OBJECTIVE: (1) Evaluate a large series of posterior C2 screws to determine accuracy by computed tomography (CT) scan, (2) assess dimensions of "safe bony windows" with CT, and (3) assess perioperative complication rate related to errant screw placement. SUMMARY OF BACKGROUND DATA: The variable C2 anatomy can make instrumentation challenging and prone to potentially severe complications. New techniques have expanded available options. METHODS: Clinical data were obtained from the medical record. Radiographic analyses included preoperative and postoperative CT scans to quantify the patients' bone and to classify accuracy of instrumentation. Screws were graded using the following definitions: RESULTS: Seven hundred and thirty-six screws in 383 patients were identified. Fifty-five patients were excluded because of lack of data leaving 328 patients (188 male patients, 140 female patients) with 633 screws. Three hundred and thirty-nine pedicle, 154 transarticular, 63 laminar, and 77 short pars screws were placed, and of the 509 screws with postoperative CT scans, accuracy rates (Types I and II) were 98.8%, 98.5%, 100%, and 94.6%, respectively. Eight were unacceptably placed: two medially and six encroaching on the vertebral artery foramen. One patient had a vertebral artery occlusion and another had a dissection. There were no neurologic injuries. Mean CT measurements of pedicle height, axial width, and laminar width were 8.1, 5.8, and 5.7 mm respectively, with males having significantly larger pedicle height (P<0.001), pedicle width (P<0.001), and laminar width (P<0.022). CONCLUSION: We show a lower than previously reported incidence of complications associated with posterior C2 screw placement. The multiple techniques of posterior C2 fixation available allow for flexibility in determining ideal technique. PMID- 21289566 TI - Neurological complications of cervical laminoplasty for patients with ossification of the posterior longitudinal ligament-a multi-institutional retrospective study. AB - STUDY DESIGN: Retrospective multi-institutional study. OBJECTIVE: To investigate the incidence of neurological deficits after cervical laminoplasty for ossification of the posterior longitudinal ligament (OPLL). SUMMARY OF BACKGROUND DATA: According to analysis of long-term results, laminoplasty for cervical OPLL has been reported as a safe and effective alternative procedure with few complications. However, perioperative neurological complication rates of laminoplasty for cervical OPLL have not been well described. METHODS: Subjects comprised 581 patients (458 men and 123 women; mean age: 62 +/- 10 years; range: 30-86 years) who had undergone laminoplasty for cervical OPLL at 27 institutions between 2005 and 2008. Continuous-type OPLL was seen in 114, segmental-type in 146, mixed-type in 265, local-type in 24, and not judged in 32 patients. Postoperative neurological complications within 2 weeks after laminoplasty were analyzed in detail. Cobb angle between C2 and C7 (C2/C7 angle), maximal thickness, and occupying rate of OPLL were investigated. Pre- and postoperative magnetic resonance imaging was performed on patients with postoperative neurological complications. RESULTS: Open-door laminoplasty was conducted in 237, double-door laminoplasty in 311, and other types of laminoplasty in 33 patients. Deterioration of lower-extremity function occurred after laminoplasty in 18 patients (3.1%). Causes of deterioration were epidural hematoma in 3, spinal cord herniation through injured dura mater in 1, incomplete laminoplasty due to vertebral artery injury while making a trough in 1, and unidentified in 13 patients. Prevalence of unsatisfactory recovery not reaching preoperative level by 6-month follow-up was 7/581 (1.2%). Mean occupying rate of OPLL for patients with deteriorated lower-extremity function was 51.2 +/- 13.6% (range, 21.0% 73.3%), significantly higher than the 42.3 +/- 13.0% for patients without deterioration. OPLL thickness was also higher in patients with deterioration (mean, 6.6 +/- 2.2 mm) than in those without deterioration (mean, 5.7 +/- 2.0 mm). No significant difference in C2/C7 lordotic angle was seen between groups. CONCLUSION: Although most neurological deterioration can be expected to recover to some extent, the frequency of short-term neurological complications was higher than the authors expected. PMID- 21289567 TI - Progressive vertebral body osteolysis after cervical disc arthroplasty. AB - STUDY DESIGN: Case report. OBJECTIVE: To review the management of a patient with progressive osteolysis of the vertebral body after undergoing cervical arthroplasty for management of a refractory radiculopathy. SUMMARY OF BACKGROUND DATA: Since the Food and Drug Administration's (FDA) approval of cervical arthroplasty devices in 2007, many surgeons have incorporated this technology into clinical practice. As arthroplasty becomes more widespread, complications unique to this technology are inevitable. To date, only a limited number of complications have been reported in the literature suggesting the safety of this device. To the authors' knowledge, this report represents the first complication of osteolysis from a keel based arthroplasty device. METHODS: A 30-year-old man underwent an uneventful C5-C6 total disc arthroplasty with initial benefit. Progressively worsening neck pain prompted repeat imaging at 9 and 15 months, which showed a progressive osteolytic process in the vicinity of the keel of the superior alloy endplate. This necessitated exploration of the surgical site, explantation of the implant and conversion of the disc arthroplasty to an arthrodesis. RESULTS: Examination of the osteolytic area did not reveal any gross abnormalities. Testing of the device by the manufacturer did not reveal any defects. A comprehensive infectious workup was negative. The osteolytic process halted after the explantation of the device. A bony arthrodesis was achieved at 6 months and the patient remains symptom free 29 months after the initial procedure and 14 months after the revision. CONCLUSION: This report illustrates an exceptional case of a progressive osteolysis with a keel based arthroplasty device. An immune mediated osteolytic process appears to be a plausible explanation for the clinical symptoms and radiographic progression seen in this case. Given the years of use of the ProDisc-C since its FDA approval in 2007, complications with this device are rare. This represents the first reported case of osteolysis from such an implant. PMID- 21289568 TI - Influence of interpersonal geometrical variation on spinal motion segment stiffness: implications for patient-specific modeling. AB - STUDY DESIGN: A validated finite element model of an L3-L4 motion segment is used to analyze the effects of interpersonal differences in geometry on spinal stiffness. OBJECTIVE: The objective of this study is to determine which of the interpersonal variations of the geometry of the spine have a large effect on spinal stiffness. This will improve patient-specific modeling. SUMMARY OF BACKGROUND DATA: The parameters that define the geometry of a motion segment are vertebral height, disc height, endplate width, endplate depth, spinous process length, transverse process width, nucleus size, lordosis angle, facet area, facet orientation, and the cross-sectional areas of the ligaments. All these parameters differ between patients. The influence of each parameter on spinal stiffness is largely unknown and such knowledge would greatly help in patient-specific modeling of the spine. METHODS: The range of interpersonal variation of each of the geometric parameters was set at mean+/-2SD (covering 95% of the population). Subsequently, we determined the effect of each of these ranges on the bending stiffness in flexion, extension, axial rotation, and lateral bending. RESULTS: Disc height had the largest influence; a maximal disc height reduced the spinal stiffness to 75-86% of the mean motion segment stiffness, and a minimal disc height increased the spinal stiffness to 154-226% of the mean motion segment stiffness. Lordosis angle, transversal and longitudinal facet angle, endplate depth, and area of the capsular ligament also had a substantial influence (>5%) on the stiffness, but considerable less than the influence of the disc height. Ligament areas, nucleus size, spinous process length, and length of processes are of negligible effect (<2%) on the stiffness. CONCLUSION: The disc height should be accurately determined in patients to estimate the spinal stiffness. Ligament areas, nucleus size, spinous process length, and transverse process width do not need patient-specific modeling. PMID- 21289569 TI - Disc strain and resulting positive mRNA expression from application of a noninvasive treatment. AB - STUDY DESIGN: Bovine caudal intervertebral discs were exposed to a noninvasive vibrating intervention for 10 minutes at amplitudes of 0 or 0.5 to 5 g and frequencies of 0, 16, 50 to 80, and a combined 16+50 to 80 Hz treatment. Expression of mRNA for aggrecan, collagen type I, collagen type II, biglycan, decorin, and versican were assayed. OBJECTIVE: To determine if the intervention is effective in altering intervertebral disc gene expression. SUMMARY OF BACKGROUND DATA: Studies have variously suggested either an increased risk of disc degeneration with vibrations, no effect, analgesic effect, or even positive effects within certain loading parameters. The KKT intervention is in clinical use for spinal ailment pain reduction. METHODS: The intervention was applied in a clinic emulation set-up. Gene expression in the nucleus pulposus was assessed using real-time RT-PCR and SYBR Green chemistry. RESULTS: Expression of mRNAs for aggrecan, collagen type II, and versican were significantly effected by the intervention. Collagen type I, biglycan, and decorin were uneffected. CONCLUSION: Expression of the extracellular matrix genes were significantly up-regulated when vibrated with the intervention under specific loading patterns, indicating a potential therapeutic stimulus. Further studies on the protein-level and long term effects are warranted. Previous studies have indicated a mixed effect of vibrations in the human spine. In this study, a clinical intervention using vibrations was applied to bovine intervertebral discs, and gene expression in the nucleus pulposus was measured. Several extracellular matrix genes were up regulated, suggesting a potential therapeutic effect. PMID- 21289570 TI - Symptomatic idiopathic noncommunicating intradural arachnoid cyst of the S1 nerve root: a case report. AB - STUDY DESIGN: A case report of a rare symptomatic, idiopathic, noncommunicating intradural arachnoid cyst (IAC) of the proximal part of the S1 nerve root (NR). OBJECTIVE: To discuss the possible pathophysiology, clinical and magnetic resonance imaging (MRI) presentation, intraoperative findings, and follow-up of IAC of the proximal part of the S1 NR. SUMMARY OF BACKGROUND DATA: Rare variety of the Nabors's Type 3 spinal IAC. The etiopathogenesis are uncertain. Surgical NR decompression with extirpation of the cyst is the treatment of choice. METHODS: A 37-year-old woman clinically presented as monoradiculopathy with a 9 month history of progressive, posture-dependent radicular pain, paresthesia and hypoesthesia in the right S1 dermatome, and mild weakness of the ipsilateral plantar flexors. Magnetic resonance imaging (MRI) showed a noncommunicating IAC of the proximal part of the S1 NR on the right side. Surgical exploration through the ipsilateral L5-S1 hemilaminectomy was performed with microsurgical arachnolysis of the compressed and stretched S1 NR fascicles that surrounded the cyst, during which the cyst spontaneously collapsed. The remnant of the cyst wall was extirpated and histopathology confirmed the diagnosis. RESULTS: After surgery an excellent clinical outcome was archived: the leg pain was no longer present and the paraesthesia, hypoesthesia, and motor weakness were resolved within 3 months. At 12 months of follow-up, the patient continues to be completely asymptomatic with no evidence of recurrence on MRI. CONCLUSION: A rare case of symptomatic, idiopathic, noncommunicating IAC of the proximal part of the S1 NR has been presented. Early recognition and treatment resulted in complete symptom resolution, with preservation of the full working capacity and good quality of life. Isolated monoradiculopathy with progressive, posture-dependent radicular pain seem to be typical clinical findings for such a lesion. Attending physicians should always be mindful of this fact in the total clinical evaluation of such cases. PMID- 21289571 TI - ICG videography facilitates interpretation of vascular supply and anatomical landmarks in intramedullary spinal lesions: two case reports. AB - STUDY DESIGN: This is an illustration of two case reports. OBJECTIVE: We present two cases where intradural indocyanine-green (ICG) videography facilitated interpretation of vascular supply patterns and anatomic landmarks in intramedullary spinal lesions. SUMMARY OF BACKGROUND DATA: ICG videography is a new, complimentary imaging method, that is routinely employed in the context of vascular neurosurgical procedures and has recently been described to facilitate localization of intradural spinal lesions before dural opening. Its role in the setting of intramedullary lesions is less well defined. METHODS: Two cases are presented. The first patient (case 1) had a small, diffuse, intramedullary lesion of unknown etiology who was referred for additional work-up and surgery. The second patient had presented with progressive paraparesis and ataxia due to an extensive intradural lesion, and he was referred for resection of the tumor.Routine exposure of the spinal cord via (hemi-)laminectomy and durotomy was followed by ICG videography (injection of intravenous indocyanine green, visualization with operating microscope in combination with an additional fluorescent light source) to guide the surgical strategy. RESULTS: In case 1, ICG videography helped to delineate the anatomic midline for optimization of myelotomy. In case 2, imaging was able to identify arterial feeders of the highly vascularized lesion and simplified safe removal of the lesion. CONCLUSION: ICG videography may represent a useful adjunct for optimization of surgical approach and strategy in intramedullary spinal tumors in selected cases. The anatomic midline can be safely identified in cases where usual landmarks are distorted, and better interpretation of supply patterns in highly vascularized lesions may increase safety of resection. PMID- 21289572 TI - Os odontoideum complicating craniovertebral junction tuberculosis: a case report. AB - STUDY DESIGN: A case report and review of literature. OBJECTIVE: To present a rare case of os odontoideum complicating craniovertebral junction (CVJ) tuberculosis (TB) and discuss the treatment outcome. SUMMARY OF BACKGROUND DATA: CVJ is a rare site of predilection for Mycobacterium tuberculosis. The treatment protocol for this entity has periodically undergone swings between conservative treatment and radical surgery. To the best of our knowledge, os odontoideum complicating TB of this region has not been reported before in the literature. METHODS: We report on a 17-year-old patient with CVJ TB in setting of dystopic os odontoideum. The patient presented with fever, cervical pain and weakness of all the four limbs, and was treated with antitubercular chemotherapy along with cervical traction, followed by halo-vest. RESULTS: Patient made uneventful recovery with conservative form of treatment and was asymptomatic at 36 months of follow-up. CONCLUSION: This case has the originality of being the first report of CVJ TB with dystopic os odontoideum. High index of suspicion by the clinician must be practiced to make the appropriate diagnosis. PMID- 21289573 TI - Internal construct validity of the Swiss Spinal Stenosis questionnaire: Rasch analysis of a disease-specific outcome measure for lumbar spinal stenosis. AB - STUDY DESIGN: Rasch analysis of an outcome tool using data from questionnaires completed by patients with lumbar spinal stenosis. OBJECTIVE: To evaluate the psychometric properties of the Swiss Spinal Stenosis questionnaire using the Rasch measurement model. SUMMARY OF BACKGROUND DATA: Lumbar spinal stenosis (LSS) is a common cause of low back pain and leg symptoms in older patients. The SSS questionnaire was devised as a condition-specific outcome measure for patients with LSS. It comprises two subscales; one to measure symptom severity and another to measure physical functioning. The SSS is commonly used in trials for patients with LSS but has not, to our knowledge, been subjected to rigorous modern psychometric analysis methods. METHODS: Data from a total of 190 SSS assessments in 98 people with LSS were fitted to the Rasch measurement model. This method was used to examine the validity of the item scoring functions, the presence of item bias or differential item functioning and the fit of data to model expectations. In addition, the analysis was used to assess whether or not the item set in each scale formed a unidimensional scale to provide a valid summed score. RESULTS: The symptom severity scale and the physical function scale of the SSS were found to be reliable and well targeted to the study population. However, the symptom severity scale was found to be multidimensional; three items focused on pain and four items on neuroischemic symptoms. The physical function scale performed well as a unidimensional scale, but needed to be modified by excluding one item in order for it to fit the Rasch model. CONCLUSION: Development of a more robust measurement tool for this patient group may be warranted. A new tool may need to include three scales to measure the separate domains of pain severity, neuroischemic symptom severity, and physical function. PMID- 21289574 TI - Late prevertebral abscess after anterior cervical fusion. AB - STUDY DESIGN: We present a unique case of a 54-year-old woman who developed a prevertebral abscess 2 years after anterior cervical fusion in the absence of previously reported risk factors for late infection. The literature relevant to this topic is reviewed. OBJECTIVE: To report a rare complication of a commonly performed surgery. SUMMARY OF BACKGROUND DATA: Anterior cervical discectomy and fusion (ACDF) is one of the most commonly performed spinal surgeries. The complication rate is relatively low; the risk of infection is only 0.1% to 1.6%. In the late postoperative setting, more than 6 months, wound infections are very rare and are often associated with an esophageal perforation secondary to hardware migration. METHODS: We present a rare complication of a deep wound infection in a 54-year-old woman 2 years after an anterior cervical fusion. On serial radiograph imaging after surgery, the surgical level demonstrated progressive fusion. At 2 years, however, the patient presented with acute dysphagia. Computed tomography (CT) of the neck with contrast demonstrated a rim enhancing prevertebral mass, which was treated with wound exploration and debridement. Direct laryngoscopy at the time of surgery did not demonstrate a breach in the esophageal mucosa and inspection of the esophagus during surgery did not reveal a diverticulum, tear, or breach in the esophagus. RESULTS: After surgical exploration and debridement the patient was placed on a 6-week course of antibiotics. Her dysphagia improved significantly after debridement of the prevertebral abscess. CONCLUSION: Late occurring, deep wound infections are a rare complication of anterior cervical fusion. Dysphagia in the late postoperative setting should be considered carefully and evaluated for esophageal perforation or deep wound infection. PMID- 21289575 TI - The volumetric analysis of cement in vertebroplasty: relationship with clinical outcome and complications. AB - STUDY DESIGN: Prospective study. OBJECTIVE: The aim of this study was to demonstrate the safe range of cement volume during percutaneous vertebroplasty. SUMMARY OF BACKGROUND DATA: A few clinical reports have addressed the relationship between cement volume and clinical outcome. However, the weakness of these studies was that subjects included were not homogeneous. No study in the clinical setting has confirmed results from biomechanical and computational studies. METHODS: We examined 96 patients with single compression fractures who underwent percutaneous vertebroplasty and postoperative three-dimensional CT scan within a week between June 2006 and April 2009. The volume and fraction were measured by a CT volumetry program. Relationships between predictors and volumetric data, outcome, leakage, intraverterbal vacuum cleft (IVVC), and subsequent fracture were examined. Relationships between volumetric data and outcome, leakage, IVVC, and subsequent fracture were analyzed with stratification by the treated level. Receiver-operator characteristic (ROC) curves were plotted to acquire cut-off values of volumetric data. RESULTS: Seventy-three patients (76%) were female, and the mean age was 76.3 +/- 8.4 years (range 53-97). The mean duration of follow-up was 11 months (range 6-21). Locations were as follows: T4-T10 9, T11-L1-L57, and L2-L4 30. Seventy-eight patients (81%) reported a favorable outcome. Fractured body volume (FBV) and the level treated were associated with fraction, which had an influence on outcome. The fraction of the favorable group was significantly higher. Cut-off values to acquire a favorable outcome were 11.64% (P = 0.026) on the T4-L4 level and 3.35 cm (P = 0.059), 11.65% (P = 0.059) on the T11-L1 level. Group with intradiscal leakage had a smaller volume than nonleakage group on the L2-L4 level (3.86 cm vs. 5.65 cm, P = 0.002). There were no relationships of volumetric data with epidural leakage and pulmonary embolism. The presence of IVVC increased volume on the T4-L4 and L2-L4 level (P < 0.03). Larger volume increased significantly the incidence of adjacent fracture on the L2-L4 level. The significant cut-off volume to avoid adjacent fracture was 4.90 cm on the ROC curve. CONCLUSION: It is suggested that fraction is superior to volume for predicting outcome on the T11-L1 level and an amount of cement should be determined in terms of FBV and fraction according to the treated level. A lower fraction than required for the restoration of mechanical property was enough to obtain pain relief. Intradiscal leakage on the L2-L4 level may be inevitable to obtain appropriate mechanical properties in the case of severe endplate breakdown connected with the disc space. Smaller volume is needed to avoid an adjacent fracture on the L2-L4 level. Although we did not know the reason why there was a difference among the treated level groups, one thing that is certain is the fact that level-specific approaches may be necessary for good outcome in terms of volume, fraction and FBV. PMID- 21289576 TI - The Scoliosis Research Society Health-Related Quality of Life (SRS-30) age-gender normative data: an analysis of 1346 adult subjects unaffected by scoliosis. AB - STUDY DESIGN: Prospective, cross-sectional study. OBJECTIVE: To determine Scoliosis Research Society (SRS)-30 health-related quality of life (HRQOL) reference values by age and gender in an adult population unaffected by scoliosis thereby allowing clinicians and investigators to compare individual and/or groups of spinal deformity patients to their generational peers. SUMMARY OF BACKGROUND DATA: Normative data are collected to establish means and standard deviations of health-related quality of life outcomes representative of a population. The SRS HRQOL questionnaire has become the standard for determining and comparing treatment outcomes in spinal deformity practices. With the establishment of adult SRS-30 HRQOL population values, clinicians, and investigators now have a reference for interpretation of individual scores and/or the scores of subgroups of adult patients with spinal deformities. METHODS: The SRS-30 HRQOL was issued prospectively to 1346 adult volunteers recruited from across the United States. Volunteers self-reported no history of scoliosis or prior spine surgery. Domain medians, means, confidence intervals, percentiles, and minimum/maximum values were calculated for six generational age-gender groups: male/female; 20-39, 40 59, and 60-80 years of age. RESULTS: Median and mean domain values ranged from 4.1 to 4.6 for all age-gender groups. The older the age-gender group, the lower (worse) the reported domain median and mean scores. The only exception was the mental health domain scores in the female groups which improved slightly. Males reported higher (better) scores than females but only the younger males were significantly higher in all domains than their female counterparts. In addition, all male groups reported higher Mental Health domain scores than their female counterparts (P=0.003). CONCLUSION: This study reports population medians, means, standard deviations, percentiles, and confidence intervals for the domains of the SRS-30 HRQOL instrument. Clinicians must be mindful of age-gender differences when assessing deformity populations. Generational decreases noted in the older adult volunteer scores may provide a basis for future investigators to interpret observed score decreases in patient cohorts at long-term follow-up. PMID- 21289577 TI - The effect of tethered cord release on coronal spinal balance in tight filum terminale. AB - STUDY DESIGN: A retrospective review of coronal spine balance after tethered cord release for children with tight filum terminale. OBJECTIVE: To understand the effects of untethering on coronal spine balance for these patients. SUMMARY OF BACKGROUND DATA: In patients with tight filum terminale, the spinal cord is tethered by a thickened filum with a low conus medullaris but without other forms of spinal dysraphism. There have not been studies examining the effects of spinal cord untethering on coronal spinal alignment in children with tight filum terminale. METHODS: Forty-five consecutive pediatric patients with tight filum terminale who had undergone untethering were evaluated. Their presenting signs and symptoms, pre- and postsurgery imagings, and clinical courses were reviewed for scoliosis progression. RESULTS: Twenty-six girls and 19 boys underwent tethered cord release at a mean age of 4.5 years. The prevalence of coronal spinal malalignment, manifesting as scoliosis, before the untethering procedure was 31% (14 of 45). During the follow-up period, nine patients had coronal spinal alignment that worsened>10 degrees (five patients eventually underwent surgical fusion), two patients had spinal alignment that improved, and five patients' curves stabilized after untethering surgery. Therefore, at the end of the follow up period, 9 of 45 patients (20%) had worsened coronal spinal alignment. In the multivariate analysis, patients who presented with a Cobb angle greater than 35 degrees were most likely to progress (P=0.002, odds ratio=21). There was no operative morbidity or mortality associated with scoliosis surgery. CONCLUSION: A significant number of children with tight filum terminale were found to present with scoliosis. In patients with less severe curves, tethered cord release may halt scoliosis progression. PMID- 21289578 TI - Navigated percutaneous lumbosacral interbody fusion: a feasibility study with three-dimensional surgical simulation and cadaveric experiment. AB - STUDY DESIGN: A feasibility study with three-dimensional surgical simulation and cadaveric experiment. OBJECTIVE: To verify the feasibility of a new navigated surgical method for lumbosacral interbody fusion. SUMMARY OF BACKGROUND DATA: The advances in surgical navigation have opened new possibilities for lumbosacral interbody fusion procedure. We designed a novel navigated surgical method that enables lumbosacral discectomy and bone grafting to be performed percutaneously and safely. METHODS: First, to prove that the newly designed surgical method is feasible from an anatomic perspective, the new method, navigated percutaneous lumbosacral interbody fusion (NPLSIF), was simulated on the three-dimensional models of lumbosacral spine. The three-dimensional models were established using the computed tomographic (CT) data of 60 patients. Feasibility could be verified if both working corridor and S1 pedicle screw could be accommodated in sacral ala without overlapping and without penetrating either the spinal canal or the anterior or upper sacral wall. Second, to verify the feasibility of the NPLSIF procedure in reality, cadaveric experiment was performed. Two cadavers were included; one was a 67-year-old male, and the other a 65-year-old female. CT scanning was performed with an intraoperative CT scanner before surgery, after the discectomy and after bone grafting. These three series of CT images were compared to evaluate the efficacy of the NPLSIF procedure. After the procedures, the lumbosacral spines were separated from the cadaver trunks in the department of anatomy. The lumbosacral disc of one cadaver was bisected coronally, while the lumbosacral disc of the other cadaver was bisected sagittally. The internal view of the lumbosacral discs helped to further evaluate the efficacy of the NPLSIF procedures. RESULTS: In the three-dimensional surgical simulation experiment, the feasibility of the NPLSIF procedure was verified in every case. In the cadaveric experiment, the NPLSIF procedures were successfully executed. The surgical procedure on the first cadaver took 3 hours. After improving the workflow and having gained some experience, the procedure on the second cadaver took 1.5 hours. On the navigation workstation, the preoperative plan was completed in 3 to 5 minutes and each intraoperative CT scanning took 30 seconds. The quality of the intraoperative CT images was comparable to that of normal CT images. CT images and the internal view of the lumbosacral discs showed that the NPLSIF procedures had yielded satisfactory discectomy and endplate preparation. CONCLUSION: The feasibility of NPLSIF was verified by the means of three-dimensional surgical simulation and cadaveric experiment. Clinical studies are needed to further investigate the efficacy and efficiency of NPLSIF in clinical practice. PMID- 21289579 TI - Bilateral pars fractures complicating long fusion to L5 in a patient with rheumatoid arthritis. AB - STUDY DESIGN: Case report. OBJECTIVE: To report bilateral pars fractures at L5 complicating a long fusion for adult idiopathic scoliosis in a patient with rheumatoid arthritis. SUMMARY OF BACKGROUND DATA: To our knowledge, there are no reports in the literature regarding bilateral pars fractures at the end instrumented vertebrae of a long fusion at the lumbosacral junction, nor reports that have evaluated long spinal deformity corrections in patients with rheumatoid arthritis. The question of ending a long fusion at L5 or S1 is controversial, and a review is presented. METHODS: We present the patient's history, physical examination, and radiographic findings; describe the surgical treatment and long term follow-up; and provide a literature review. RESULTS: Bilateral pars fractures at the end instrumented vertebrae of a long construct (T4-L5) that we discovered were subsequently revised by extension of the fusion to the sacrum. Anterior structural support at L5-S1 was also provided. At the latest follow-up (46 months), the patient has had no recurrence of her symptoms. Her radiographs showed a stable construct without loss of alignment in the sagittal or coronal planes. Her rheumatoid arthritis continues to be treated with biologic, disease modifying antirheumatic drugs. CONCLUSION: To our knowledge, this is the first report of the treatment and long-term outcome of a patient with rheumatoid arthritis and bilateral pars fractures at the end instrumented vertebrae (L5) of a long deformity correction construct. PMID- 21289580 TI - An acute cervical epidural hematoma as a complication of dry needling. AB - STUDY DESIGN: A retrospective case report. OBJECTIVE: The objective of this article is to report an unusual complication of dry needling. SUMMARY OF BACKGROUND DATA: Epidural hematomas after dry needling are quite unusual and only a few cases of epidural hematoma after acupuncture have been reported in the literature. We are presenting the first report of acute cervical epidural hematoma after dry needling. METHODS: A 58-year-old woman presented with quadriparesis and neck pain. Magnetic resonance imaging of the spine revealed a hyperintense mass in the T2-weighted magnetic resonance image at the C2-T2 level, which proved to be an epidural hematoma. RESULTS: Symptoms related to the epidural hematoma resolved after decompression. CONCLUSION: Though rare, epidural hematomas are a possible complication when applying needling therapies. Therapists need to have precise knowledge of human anatomy, especially in the region where he or she will puncture. Continuous attention must be paid throughout the whole procedure. PMID- 21289581 TI - Disc replacement adjacent to cervical fusion: a biomechanical comparison of hybrid construct versus two-level fusion. AB - STUDY DESIGN: A cadaveric biomechanical study. OBJECTIVE: To investigate the biomechanical behavior of the cervical spine after cervical total disc replacement (TDR) adjacent to a fusion as compared to a two-level fusion. SUMMARY OF BACKGROUND DATA: There are concerns regarding the biomechanical effects of cervical fusion on the mobile motion segments. Although previous biomechanical studies have demonstrated that cervical disc replacement normalizes adjacent segment motion, there is a little information regarding the function of a cervical disc replacement adjacent to an anterior cervical decompression and fusion, a potentially common clinical application. METHODS: Nine cadaveric cervical spines (C3-T1, age: 60.2 +/- 3.5 years) were tested under load- and displacement-control testing. After intact testing, a simulated fusion was performed at C4-C5, followed by C6-C7. The simulated fusion was then reversed, and the response of TDR at C5-C6 was measured. A hybrid construct was then tested with the TDR either below or above a single-level fusion and contrasted with a simulated two-level fusion (C4-C6 and C5-C7). RESULTS: The external fixator device used to simulate fusion significantly reduced range of motion (ROM) at C4 C5 and C6-C7 by 74.7 +/- 8.1% and 78.1 +/- 11.5%, respectively (P < 0.05). Removal of the fusion construct restored the motion response of the spinal segments to their intact state. Arthroplasty performed at C5-C6 using the porous coated motion disc prosthesis maintained the total flexion-extension ROM to the level of the intact controls when used as a stand-alone procedure or when implanted adjacent to a single-level fusion (P > 0.05). The location of the single-level fusion, whether above or below the arthroplasty, did not significantly affect the motion response of the arthroplasty in the hybrid construct. Performing a two-level fusion significantly increased the motion demands on the nonoperated segments as compared to a hybrid TDR-plus fusion construct when the spine was required to reach the same motion end points. The spine with a hybrid construct required significantly less extension moment than the spine with a two-level fusion to reach the same extension end point. CONCLUSION: The porous-coated motion cervical prosthesis restored the ROM of the treated level to the intact state. When the porous-coated motion prosthesis was used in a hybrid construct, the TDR response was not adversely affected. A hybrid construct seems to offer significant biomechanical advantages over two-level fusion in terms of reducing compensatory adjacent-level hypermobility and also loads required to achieve a predetermined ROM. PMID- 21289582 TI - A safe controlled instrumented reduction technique for cervical osteotomy in ankylosing spondylitis. AB - STUDY DESIGN: A retrospective review of clinical and radiologic outcome in 13 consecutive patients with Ankylosing Spondylitis (AS) who underwent cervical osteotomy for correction of fixed cervicothoracic kyphotic deformity (CTKD) using an innovative technique. OBJECTIVE: To report further refinements to an existing technique for instrumented reduction of cervical osteotomy and assess the safety and efficacy of this procedure in 13 patients. SUMMARY OF BACKGROUND DATA: Cervical osteotomy in AS has been used for correction of CTKD, but is associated with significant risks. We have previously reported a novel technique to perform this procedure safely. Even with this technique, there was a small risk of subluxation, and this risk has been further reduced with our new technique. METHODS: Between 1993 and 2008, the senior author (SMHM) performed cervical osteotomy for severe CTKD in 13 AS patients. There were 11 male and two female patients, the average age being 56 (40-74) years. The main surgical indication was restricted frontal visual field. The average symptom duration was 2.7 (1-5) years. All patients had a general anesthetic and underwent cervical osteotomy and instrumentation from C3 to T5 in prone position. RESULTS: The average duration of surgery was 4.7 (3-6.5) hours. The calculated blood loss was 1938 mL (1000-3600). The mean follow-up period was 6.5 (1.5-16) years. The mean preoperative chin brow vertical angle was found to be 54 degrees (20 degrees -70 degrees ). After surgery, this improved to 7 degrees (2 degrees -12 degrees ). The preoperative kyphotic angle measured was 19.2 degrees (14 degrees -28 degrees ). This improved after surgery to -34 degrees (-21 degrees to -39 degrees ). There were no instances of a neurologic deficit. At a mean follow-up of 6.5 years (18 months 6 yr), no instances of loss of correction or implant failure were noted. CONCLUSION: This innovative new technique provides for a safe, controlled reduction for cervical osteotomy for fixed cervicothoracic kyphosis in AS. The technique reliably renders rigid immobilization that obviates the risk of intra- and postoperative junctional subluxation, eliminates the need for postoperative halo-vest immobilization, and achieves satisfactory fusion. PMID- 21289583 TI - Spinal cord intramedullary pressure in cervical kyphotic deformity: a cadaveric study. AB - STUDY DESIGN: In vitro cadaveric study of cervical spinal cord intramedullary pressure (IMP) in kyphotic deformity. OBJECTIVE: To define the relationship between cervical spinal kyphotic deformity and spinal cord IMP. SUMMARY OF BACKGROUND DATA: Previous studies of asymptomatic volunteers have revealed that the greatest variation in regional sagittal neutral upright spinal alignment occurs in the cervical spine with "normal" alignment ranging up to +15 to +20 degrees kyphosis. We sought to determine whether IMP changes in response to increasing cervical kyphosis. METHODS: In eight fresh-frozen cadavers, a progressive kyphotic deformity was created. Cadavers were positioned sitting with cervical lordosis, with head stabilized using a skull clamp. The C1 posterior arch was removed, dura was opened, and three pressure sensors were advanced caudally to C7, C4-C5, and C2 within the cord parenchyma. A stepwise kyphotic deformity was then induced by sequentially releasing and retightening the skull clamp while distracting posterior short segment rods and closing anterior segmental osteotomies. After each step, fluoroscopic images and pressure measurements were obtained. The C2-C7 Gore angle and horizontal displacement of the odontoid plumb line relative to C7 (C2-C7 sagittal vertical axis [SVA]) were measured. RESULTS: Minor IMP increases of 2 to 5 mm Hg were observed at one or more spinal cord levels in one of eight cadavers when the Gore angle was <+7.5 degrees and in three of eight cadavers when the Gore angle was >+7.5 degrees and <+21 degrees . At Gore angles exceeding +21 degrees , change in pressure (DeltaIMP) progressively increased at one or more spinal cord levels in eight of eight cadavers. Gore angles ranging from +21 degrees to +78 degrees resulted in statistically significant increases in IMP ranging to >50 mm Hg, as did C2-C7 SVA >+75 mm. DeltaIMP did not correlate with segmental spinal canal diameter (stenosis). CONCLUSION: Cervical lordosis and kyphosis less than +7.5 degrees resulted in no meaningful increase in IMP. Minor cervical kyphosis measuring +7.5 degrees to +21 degrees resulted in 2 to 5 mm Hg increases in IMP. As the cervical kyphotic deformity exceeded +21 degrees , IMP increased significantly. DeltaIMP with spinal alignment may help to explain the wide range of "normal" cervical neutral upright sagittal alignment in studies of asymptomatic individuals and may help further define cervical kyphotic deformity. PMID- 21289584 TI - Endoscope-assisted surgery of spinal intradural adhesions in the presence of cerebrospinal fluid flow obstruction. AB - STUDY DESIGN: Prospective cohort study. OBJECTIVE: To investigate whether the adjunctive use of endoscopy of the subarachnoid space (arachnoscopy) can improve the success of microsurgery for spinal arachnoid adhesions. SUMMARY OF BACKGROUND DATA: Intradural adhesions that obstruct pulsatile cerebrospinal fluid (CSF) flow are a typical spinal cause of syringomyelia. Phase-contrast magnetic resonance imaging (MRI) allows CSF flow obstructions to be reliably localized. The treatment of choice is the microsurgical removal of CSF flow obstructions caused by adhesions. Microsurgery, however, does not lend itself to assessments of further adhesions beyond the borders of the exposed area. In this study, we therefore investigated whether endoscopic assistance allows adhesions in the vicinity of the exposed area to be detected. METHODS: From 2006 to 2009, a single neurosurgeon performed 27 consecutive microsurgical procedures with endoscopic assistance in 25 patients with spinal arachnoid adhesions. A MurphyScope endoscope was used for this purpose. CSF flow was studied before and after surgery in all patients using phase-contrast MRI in the region of the craniocervical junction, the cervical spine, the thoracic spine, and the lumbar spine. RESULTS: In all 27 procedures, CSF flow obstructions were detected at the level identified by phase-contrast MRI. In 25 procedures, image quality was sufficient for an inspection of the adjacent subarachnoid space. In six cases, the surgeon detected further adhesions that obstructed CSF flow in the adjacent subarachnoid space not visualized with the microscope. In all cases, these adhesions were identified and removed during microsurgery.Postoperative MRI scans demonstrated free CSF flow in all patients and a decrease in syrinx size in six patients. CONCLUSION: Arachnoscopy is a helpful adjunct to microsurgery and can be performed safely and easily. It allows the surgeon to detect further adhesions in the subarachnoid space, which would remain undetected by microscopy alone. PMID- 21289585 TI - Comparative assessment of sacral screw loosening augmented with PMMA versus a calcium triglyceride bone cement. AB - STUDY DESIGN: A calcium triglyceride bone cement (CTBC) was compared with the gold-standard polymethylmethacrylate (PMMA) to assess the stability of augmented sacral screw fixation under cyclic loading. OBJECTIVE: To determine whether CTBC augmentation of a pedicle screw would provide a similar level of fixation in the S1 pedicles compared with PMMA augmentation. SUMMARY OF BACKGROUND DATA: Numerous studies have shown the advantages of using PMMA to augment screw fixation; however, its biomechanical properties are not ideal. CTBC offers potential benefits such as being low exothermic, a modulus of elasticity closer to bone, and the potential for osteoconductivity, but its comparative performance in this situation has not been previously evaluated. METHODS: Six cadaveric sacra were used in this study; 3.0 mL volumes of PMMA (Simplex P) and CTBC (KryptoniteTM Bone Cement) were injected into contralateral screw tracts, with the screw immediately inserted after cement injection. After a 12-hour setting period, the sacrum was potted in a custom fixture and mounted to the frame of a materials testing machine. Alternating flexion and extension bending moments were applied at 1 Hz. Flexion moments were applied starting at 0.5 Nm and increased by 1 Nm after every 1000 cycles until the screw had reached 6 degrees of rotation relative to its starting position. Extension moments were maintained at 0.5 Nm. Screw rotation relative to bone was determined in real time by a custom optical tracking system and was analyzed using two-way repeated-measures analyses of variance (ANOVAs) and post hoc Student-Newman-Keuls tests (alpha = 0.05). RESULTS: To reach 6 degrees of screw rotation, the PMMA-augmented screw required more loading cycles (15,464 +/- 2526 vs. 10,277 +/- 1762 cycles; P = 0.006) and a larger applied moment (15.3 +/- 2.2 vs. 10.5 +/- 1.7 Nm; P = 0.010) than CTBC augmented screw. CONCLUSION: The PMMA augmentation provided increased resistance to cyclic loading compared with the CTBC augmentation for sacral pedicle screw fixation, but both augmentations well exceeded previously published findings for nonaugmented screws. PMID- 21289586 TI - Anatomical feasibility of pediatric cervical pedicle screw insertion by computed tomographic morphometric evaluation of 376 pediatric cervical pedicles. AB - STUDY DESIGN: Prospective analysis of computed tomographic images of 376 normal pediatric cervical pedicles. OBJECTIVE: To study the normal cervical pedicle morphometrics, the changes in pedicle morphology with skeletal growth, and the possibility of pedicle screw insertion. SUMMARY OF BACKGROUND DATA: Although the usage of cervical pedicle screws in adults has become established, the feasibility of its application in children has not been studied. There are no in vivo studies that define the normal pediatric cervical pedicle morphometrics and its changes with growth and development of the child. METHODS: A total of 376 normal pediatric cervical spine pedicles of 30 children (mean age = 6.7 +/- 3.9 years) were analyzed for pedicle width (PW), pedicle height (PH), pedicle length (PL), pedicle axis length (PAL), transverse pedicle angle (TPA), and sagittal pedicle angle (SPA). The study population was categorized into three age groups (A: <5 years, B: 5-10 years, and C >10 years). The mean values of these parameters in the different age groups and the possibility of application cervical pedicle screws were studied. RESULTS.: The mean PW was lowest in the C3 vertebra and increased distally to be widest at C7. Sixty percent of C3 pedicles had a width less than 4 mm making screw passage risky and unsafe. With growth, the PW increased at all levels but this increase was significant only up to the age of 10 years. More than 75% of adult pedicle dimensions were achieved by 5 years of age. The mean PL at all levels remained the same with no significant increase with growth. However, the PAL showed continuous increase with growth similar to PW. The PAL also showed an increase from C3 to C7. The PH was always more than the PW at any level. Mild insignificant asymmetry was present between the right and left side pedicles in all values. CONCLUSION: With growth, there was a gradual increase in PW, PH, and PAL but was mainly before the age of 10 years. Majority of C3 pedicles were thin making screw fixation unsafe. However, at all other levels, the pedicle morphometrics per se were adequate and do not restrict safe application of 3-mm cervical pedicle screw. PMID- 21289587 TI - Tranexamic acid reduces perioperative blood loss in cervical laminoplasty: a prospective randomized study. AB - STUDY DESIGN: A prospective randomized comparative study. OBJECTIVE: To evaluate the effect of tranexamic acid (TXA) on decreasing perioperative blood loss in cervical laminoplasty, in which the surgical procedure is identical in all cases. SUMMARY OF BACKGROUND DATA: TXA, an inhibitor of fibrinolysis, has proven to be effective in reducing perioperative blood loss in patients undergoing total hip and knee arthroplasty. However, only a limited number of well-controlled spinal surgery trials have been conducted due to heterogeneity in the performed surgical procedures. METHODS: Forty consecutive patients with cervical compressive myelopathy were prospectively randomized into groups that received 15 mg/kg body weight of TXA or placebo intravenously before the skin incision was made. "French door" cervical laminoplasty from C3 to C6 was performed for all patients by using a consistent procedure. Intraoperative and postoperative blood loss was compared between the groups. The surgery and follow-up were conducted at a single institution. RESULTS: There were no statistically significant differences between the TXA and control groups in terms of age, sex, body mass index, and operating time. Intraoperative blood loss in the TXA group (49.1 +/- 30.6 mL) was not significantly different from that in the control group (63.4 +/- 53.0 mL, P = 0.30). However, in the TXA group, postoperative blood loss during the first 16 hours was reduced by 37% as compared to the control group (132.0 +/- 45.3 vs. 211.0 +/- 41.5 mL; P < 0.01). The total blood loss (intraoperative plus postoperative blood loss during the first 40 hours) in the TXA group (264.1 +/- 75.1 mL) was significantly lower than that in the control group (353.9 +/- 60.8 mL, P < 0.01). No thromboembolic events or complications occurred in either group. CONCLUSION: TXA significantly reduced perioperative blood loss, primarily through a reduction in postoperative blood loss, in cervical laminoplasty. PMID- 21289588 TI - Penetrating injury of rectum and vertebral body by steel bar causing cauda equina syndrome. AB - STUDY DESIGN: Case report. OBJECTIVE: To report an extremely rare case of combined penetrating injury to rectum and vertebral body by steel bar causing cauda equina syndrome. SUMMARY OF BACKGROUND DATA: Only one similar case has been reported. Our case was more severe and posed more challenges to physicians. METHODS: A 37-year-old male had a penetrating rectal injury by a long steel bar as a result of a falling accident. He was firstly treated with removal of the bar, debridement, and fecal diversion. Spine and cauda equina injuries were found the second day by lumbar and sacral CT. Because of infection after the first surgery, decompressive surgery was performed 2 months from injury. Cerebrospinal fluid fistula happened on the 12th day after surgery which was managed by debridement, irrigation and drainage, suture of the leaking skin and combined use of antibiotics. RESULTS: When being discharged, he could ambulate independently but could not control his voiding. The colostomy and urinary canal was preserved during the follow-up. CONCLUSION: Steel bar penetrating injury of rectum and vertebral body can be severe and cause complex injuries. Complications included infection and cerebrospinal fluid fistula. Thorough history and physical examination and CT and MRI inspection are very important for timely diagnosis and early treatment of spine and cauda equina injuries. Dural tear should be carefully inspected and repaired during posterior lumbar decompression surgery. Cooperation of experienced surgeons from orthopedics and gastrointestinal department is needed to give the patient the most appropriate treatment and improve prognosis. PMID- 21289590 TI - The access randomized clinical trial of public versus private physiotherapy for low back pain. AB - STUDY DESIGN: Pragmatic randomized clinical trial. OBJECTIVE: This study investigated differences in the clinical outcomes of public physiotherapy (public PT) versus private physiotherapy (private PT) for general practitioner-referred patients with acute and chronic low back pain (LBP). SUMMARY OF BACKGROUND DATA: Health care setting (i.e., public or private) has been found to influence the course and clinical outcome of common diseases. Despite the international burden of LBP, the effect of health care setting on clinical outcomes has not been investigated in this population. METHODS: One hundred sixty consenting patients, who were referred for physiotherapy for LBP by their general practitioner, completed the Roland Morris Disability Questionnaire (primary outcome), Short Form 36 v2, Fear Avoidance Beliefs Questionnaire, Back Beliefs Questionnaire, EuroQol EQ5D, and Patient Satisfaction Questionnaires. The patients were stratified (acute LBP: <= 3 months, n = 55; chronic LBP: > 3 months, n = 105), randomly allocated to receive public PT (n = 3 hospitals) or private PT (n = 12 clinics), and followed up at 3, 6, and 12 months postrandomization. RESULTS: Repeated measures analysis of variance showed significant improvement over time for 9 predominantly biomedical outcomes: (i) Roland Morris Disability Questionnaire at 3 and 6 months, (ii) Short-Form 36 v2 Physical Component Score, Bodily Pain, Role Physical, General Health, Vitality, EQ5D visual analogue scale, and weighted health index scores at 3 months, and (iii) the Back Beliefs Questionnaire at 6 months. The remaining 7 biopsychosocial outcomes showed no change over time, and the "between within" repeated measures analysis of variance showed no significant differences between groups over time for any outcome measures (P > 0.05). Independent samples t tests found no significant differences between groups in the mean changes in outcome measures from baseline at 12 months, apart from SF-36 v2 Role Physical (mean difference, 95% CI = 5.64 [0.860 10.428]; t = 2.337; P = 0.021) in favor of the private PT group. There were significantly higher levels of satisfaction with outcome of treatment in the private PT group (median [IQR]: public PT: 5.0 [2.0]; private PT: 6.0 [2.0]; Mann Whitney U test = 1324.50; P = 0.020), but no differences in satisfaction with treatment or global perceived improvement (P > 0.05). The private PT group had a significantly shorter waiting time (mean difference = 39.79 days; 95% CI: 26.88 52.69; t = 6.121; P < 0.001) and treatment duration (mean difference: 23.48 days; 95% CI: 7.43-39.52; t = 2.909; P = 0.005) than public PT. Participants in both groups were treated with advice/education, manipulative therapy, and exercise therapy, with minimal use of cognitive behavioral approaches in either group. Physiotherapists in the private PT group had significantly more experience and more postgraduate qualifications than the public PT group (P < 0.005). CONCLUSION: Despite differences between public and private PT regarding waiting times for treatment and therapist experience, there were no significant differences between groups in the majority of clinical outcome measure scores at follow-up, apart from SF-36 Role Physical and satisfaction with treatment outcome in favor of the private PT group. PMID- 21289591 TI - Can magnetic resonance imaging reflect the prognosis in patients of cervical spinal cord injury without radiographic abnormality? AB - STUDY DESIGN: This is a prospective imaging study of adult patients with cervical spinal cord injury without radiographic abnormality (SCIWORA). OBJECTIVE: The purpose of this study was to investigate the occurrence rate of intramedullary high-signal intensity (increased signal intensity [ISI]) and prevertebral hyperintensity (PVH) in patients with SCIWORA, and examine their relationship to symptom severity and surgical outcome. SUMMARY OF BACKGROUND DATA: SCIWORA is accompanied by the presence of neurologic symptoms in the absence of positive radiographic findings before the emergence of magnetic resonance imaging (MRI). There are few reports regarding the image features on MRI in these patients. METHODS: One-hundred consecutive patients with SCIWORA who had undergone expansive laminoplasty were enrolled. There were 79 men and 21 women; the mean age was 55 years (range, 16-87 years). All patients underwent functional x-ray and MRI in the acute phase. On MR T2-weighted imaging sagittal view, occurrence of ISI and PVH was evaluated. Range of ISI and PVH was measured relative to C3 vertebral height. Japanese Orthopaedic Association (JOA) scoring system for cervical myelopathy (JOA score), it's recovery rate, and ASIA impairment scale were used to evaluate neurological status. RESULTS: ISI was observed in 92 patients and PVH in 90 patients on MRI preoperatively. The range of ISI and PVH tended to increase with scores on the preoperative ASIA scale. ISI and PVH were seen in all patients with ASIA A and B. There was a significant negative correlation between the range of ISI and preoperative JOA score. A significant negative correlation between the range of ISI and recovery rate of JOA score was also seen. CONCLUSION: ISI and PVH occurred in more than 90% of patients with SCIWORA. The range of ISI significantly reflected symptom severity and prognosis for neurologic outcome. PMID- 21289592 TI - Differences in damage to CGRP immunoreactive sensory nerves after two lumbar surgical approaches: investigation using humans and rats. AB - STUDY DESIGN: Immunohistochemical study. OBJECTIVE: To evaluate invasive surgical approaches by analyzing the number of sensory nerve fibers at 2 back muscle sites in rats and humans and the number of injured nerve fibers innervating these 2 sites after muscle injury in rats. SUMMARY OF BACKGROUND DATA.: Several minimally invasive approaches have recently become popular in the treatment of lumbar spine disorders. Minimally invasive surgery (MIS) is not invasive to back muscle and is thought to reduce low back pain. Muscle damage has been generally evaluated by magnetic resonance imaging (MRI); however, damage to sensory nerve fibers in and around back muscle that is directly related to pain has apparently not been explored. METHODS: Human muscle at L4-L5 was obtained from the paraspinous process (during a midline approach) and from paraspinal back muscle (during a Wiltse paraspinal approach) (n = 10 each). The muscle was sectioned and immunostained for calcitonin gene-related peptide (CGRP). To detect dorsal root ganglion (DRG) neurons innervating back muscle in rats, Fluoro-Gold (FG) was applied to the same 2 sites on the lower back muscle at L4-L5 (only application, n = 12; application of FG + muscle injury, n = 12). DRGs were harvested and immunostained for CGRP and activating transcription factor-3 (ATF-3: marker for nerve injury). The numbers of FG-labeled CGRP-immunoreactive or FG-labeled ATF-3 immunoreactive DRG neurons innervating the 2 sites were counted and compared. RESULTS: CGRP-immunoreactive sensory nerve fibers were found at the 2 sites. The average number of CGRP-immunoreactive sensory nerve fibers in muscle obtained in a midline approach was significantly higher than that in muscle obtained in a Wiltse paraspinal approach (P < 0.01). The numbers of FG-labeled CGRP- and ATF-3 immunoreactive DRG neurons innervating paraspinous process muscle were significantly greater than those innervating paraspinal back muscle in rats (P < 0.01). CONCLUSION: There are more CGRP-immunoreactive sensory nerve fibers and DRG neurons innervating muscle in the midline approach area than in the Wiltse paraspinal approach area in humans and rats. There are more ATF-3-immunoreactive DRG neurons innervating muscle in the midline approach area than in the Wiltse paraspinal approach area after muscle injury in rats. This result may show the differences in sensory nerve injury during the 2 surgical approaches. PMID- 21289593 TI - Exhaled breath condensate pH in lung transplant recipients with bronchiolitis obliterans syndrome. AB - BACKGROUND: Assessment of exhaled breath condensate (EBC) pH is a promising method for investigating airway pathology. However, inaccurate measurement techniques may bias pH readings. In this longitudinal study, we tested whether development of bronchiolitis obliterans syndrome (BOS) in lung transplant recipients is associated with acidification of EBC. METHODS: EBC was collected in 15 patients with BOS and 16 stable BOS-free patients during routine clinical visits. From nine BOS patients, samples were collected before and after the onset of BOS, as well. Twenty healthy nontransplant subjects served as controls. EBC pH was measured by the carbon dioxide gas standardization method. RESULTS: EBC pH in patients with and without BOS and controls was similar (BOS group: 6.40+/-0.04, BOS-free group: 6.45+/-0.03; controls: 6.39+/-0.02; P>0.05). In patients who developed BOS during the follow-up, EBC pH before and after the onset of BOS was comparable (pre-BOS: 6.41+/-0.04 vs. post-BOS: 6.41+/-0.04; P>0.05). Coefficient of variation for repeated pH measurements in controls and subjects with and without BOS was 2.3%+/-0.3%, 2.0%+/-0.3%, and 1.7%+/-0.2%, respectively (P>0.05). Similarly, the limits of agreement for between-visit variability determined by the Bland-Altman test were comparable among the study groups. CONCLUSIONS: These data suggest that assessment of EBC pH is of limited value for the diagnosis of BOS. PMID- 21289594 TI - Effect of immunosuppression for first kidney or kidney/pancreas transplant on sensitization at the time of second transplant. AB - BACKGROUND: Previously transplanted patients are more likely to be sensitized, leading to prolonged waitlist times and decreased graft survival. This analysis of the United Network for Organ Sharing kidney/pancreas transplant database investigates factors at the time of first transplant associated with increased sensitization in patients undergoing second transplantation. METHODS: Records of nonsensitized patients (panel reactive antibodies [PRA] <20%) receiving a primary transplant in 1999 or later were analyzed to determine whether immunosuppressive agents at the time of first transplant were associated with a change in PRA from first to second transplant. Variables included gender, race, human leukocyte antigen (HLA) mismatch, rabbit antithymocyte globulin (RATG), interleukin-2 receptor antagonists, tacrolimus (FK), cyclosporine A (CSA), and mycophenolate mofetil/sodium (MMF). RESULTS: For the primary endpoint of increase in PRA greater than or equal to 20%, African Americans (AA) versus non-AA (OR 2.63, P<0.0001) and HLA nonzero mismatch versus zero mismatch (OR 2.90, P<0.0001) were associated with increased sensitization. The effect of immunosuppressive regimen depended on race and HLA status. In non-AAs/HLA mismatch (1-6), interleukin-2 receptor antagonists versus RATG (OR 1.40, P=0.001), CSA versus FK (OR 1.69, P<0.001) and no MMF versus MMF (OR 1.39, P<0.001) were also associated with increased sensitization. In AAs/HLA mismatch (1-6), no induction versus RATG (OR 1.59, P=0.031) and CSA versus FK (OR 1.68, P=0.006) were associated with increased sensitization. CONCLUSIONS: These data suggest a reduced risk of sensitization at the time of second transplant when using more potent immunosuppression with RATG, FK, and MMF for nonsensitized primary kidney or kidney/pancreas transplant patients. These effects seem to be related to race and HLA mismatch. PMID- 21289595 TI - The instant blood-mediated inflammatory reaction characterized in hepatocyte transplantation. AB - BACKGROUND: Hepatocyte transplantation (HcTx) has proven to be a safe procedure, although the functional results have been unsatisfactory, probably due to insufficient engraftment or a loss of transplanted mass or function. In this study, we investigate whether hepatocytes in contact with blood induce an inflammatory reaction leading to, similar to what happens in clinical islet transplantation, an instant blood-mediated inflammatory reaction (IBMIR) resulting in an early loss of transplanted cells. METHODS: By using an experimental model that mimics the portal vein blood flow, we could study different parameters reflecting the effects on the innate immunity elicited by hepatocytes in contact with ABO-matched human blood. RESULTS: We report that all aspects of the IBMIR such as platelet and granulocyte consumption, coagulation, and complement activation were demonstrated. Addition of various specific inhibitors of coagulation allowed us to clearly delineate the various stages of the hepatocyte-triggered IBMIR and show that the reaction was triggered by tissue factor. Analysis of a case of clinical HcTx showed that hepatocyte-induced IBMIR also occurs in vivo. Both the inflammatory and the coagulation aspects were controlled by low-molecular-weight dextran sulfate. CONCLUSION: Isolated hepatocytes in contact with blood induce the IBMIR in vitro, and there are indications that these events are also relevant in vivo. According to these findings, HcTx would benefit from controlling a wider range of signals from the innate immune system. PMID- 21289596 TI - ISN Forefronts Symposium 2010 in Sylt, Germany: 'Induction and Resolution of Renal Inflammation'. AB - The International Society of Nephrology (ISN) Forefronts Symposium 'Induction and Resolution of Renal Inflammation' took place in May 2010 on the Island of Sylt, Germany. The program included basic and clinical aspects of inflammation with a special focus on human and experimental glomerulonephritis. Distinguished scientists from different fields of inflammation research reported their recent discoveries and discussed emerging topics including the role of resolution for inflammatory processes; the 'new and old' cellular players of innate immunity and their mediators; the fundamental role of T-cell subtypes and chemokines; new aspects of B cell-mediated immune responses; and finally the potential implication of results from basic science for human inflammatory renal disease. PMID- 21289597 TI - Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes. A collaborative meta-analysis of general and high-risk population cohorts. AB - Both a low estimated glomerular filtration rate (eGFR) and albuminuria are known risk factors for end-stage renal disease (ESRD). To determine their joint contribution to ESRD and other kidney outcomes, we performed a meta-analysis of nine general population cohorts with 845,125 participants and an additional eight cohorts with 173,892 patients, the latter selected because of their high risk for chronic kidney disease (CKD). In the general population, the risk for ESRD was unrelated to eGFR at values between 75 and 105 ml/min per 1.73 m(2) but increased exponentially at lower levels. Hazard ratios for eGFRs averaging 60, 45, and 15 were 4, 29, and 454, respectively, compared with an eGFR of 95, after adjustment for albuminuria and cardiovascular risk factors. Log albuminuria was linearly associated with log ESRD risk without thresholds. Adjusted hazard ratios at albumin-to-creatinine ratios of 30, 300, and 1000 mg/g were 5, 13, and 28, respectively, compared with an albumin-to-creatinine ratio of 5. Albuminuria and eGFR were associated with ESRD, without evidence for multiplicative interaction. Similar associations were found for acute kidney injury and progressive CKD. In high-risk cohorts, the findings were generally comparable. Thus, lower eGFR and higher albuminuria are risk factors for ESRD, acute kidney injury and progressive CKD in both general and high-risk populations, independent of each other and of cardiovascular risk factors. PMID- 21289598 TI - Lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease. A collaborative meta-analysis of kidney disease population cohorts. AB - We studied here the independent associations of estimated glomerular filtration rate (eGFR) and albuminuria with mortality and end-stage renal disease (ESRD) in individuals with chronic kidney disease (CKD). We performed a collaborative meta analysis of 13 studies totaling 21,688 patients selected for CKD of diverse etiology. After adjustment for potential confounders and albuminuria, we found that a 15 ml/min per 1.73 m2 lower eGFR below a threshold of 45 ml/min per 1.73 m2 was significantly associated with mortality and ESRD (pooled hazard ratios (HRs) of 1.47 and 6.24, respectively). There was significant heterogeneity between studies for both HR estimates. After adjustment for risk factors and eGFR, an eightfold higher albumin- or protein-to-creatinine ratio was significantly associated with mortality (pooled HR 1.40) without evidence of significant heterogeneity and with ESRD (pooled HR 3.04), with significant heterogeneity between HR estimates. Lower eGFR and more severe albuminuria independently predict mortality and ESRD among individuals selected for CKD, with the associations stronger for ESRD than for mortality. Thus, these relationships are consistent with CKD stage classifications based on eGFR and suggest that albuminuria provides additional prognostic information among individuals with CKD. PMID- 21289599 TI - Chronic sphingosine 1-phosphate 1 receptor activation attenuates early-stage diabetic nephropathy independent of lymphocytes. AB - Sphingosine 1-phosphate (S1P), a pleiotropic lipid mediator, binds to five related G-protein-coupled receptors to exert its effects. As S1P1 receptor (S1P1R) activation blocks kidney inflammation in acute renal injury, we tested whether activation of S1P1Rs ameliorates renal injury in early-stage diabetic nephropathy (DN) in rats. Urinary albumin excretion increased in vehicle-treated diabetic rats (single injection of streptozotocin), compared with controls, and was associated with tubule injury and increased urinary tumor necrosis factor alpha (TNF-alpha) at 9 weeks. These effects were significantly reduced by FTY720, a non-selective, or SEW2871, a selective S1P1R agonist. Interestingly, only FTY720 was associated with reduced total lymphocyte levels. Albuminuria was reduced by SEW2871 in both Rag-1 (T- and B-cell deficient) and wild-type diabetic mice after 6 weeks, suggesting that the effect was independent of lymphocytes. Another receptor, S1P3R, did not contribute to the FTY720-mediated protection, as albuminuria was also reduced in diabetic S1P3R knockout mice. Further, both agonists restored WT-1 staining along with podocin and nephrin mRNA expression, suggesting podocyte protection. This was corroborated in vitro, as SEW2871 reduced TNF-alpha and vascular endothelial growth factor mRNA expression in immortalized podocytes grown in media containing high glucose. Whether targeting kidney S1P1Rs will be a useful therapeutic measure in DN will need direct testing. PMID- 21289600 TI - Influence of cocaine history on the behavioral effects of Dopamine D(3) receptor selective compounds in monkeys. AB - Although dopamine D(3) receptors have been associated with cocaine abuse, little is known about the consequences of chronic cocaine on functional activity of D(3) receptor-preferring compounds. This study examined the behavioral effects of D(3) receptor-selective 4-phenylpiperazines with differing in vitro functional profiles in adult male rhesus monkeys with a history of cocaine self administration and controls. In vitro assays found that PG 619 (N-(3-hydroxy-4-(4 (2-methoxyphenyl)piperazin-1-yl)butyl)-4-(pyridin-2-yl)benzamide HCl) was a potent D(3) antagonist in the mitogenesis assay, but a fully efficacious agonist in the adenylyl cyclase assay, NGB 2904 (N-(4-(4-(2,3-dichlorophenyl)piperazin-1 yl)butyl)-9H-fluorene-2-carboxamide HCl) was a selective D(3) antagonist, whereas CJB 090 (N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-4-(pyridin-2 yl)benzamide HCl) exhibited a partial agonist profile in both in vitro assays. In behavioral studies, the D(3) preferential agonist quinpirole (0.03-1.0 mg/kg, i.v.) dose-dependently elicited yawns in both groups of monkeys. PG 619 and CJB 090 elicited yawns only in monkeys with an extensive history of cocaine, whereas NGB 2904 did not elicit yawns, but did antagonize quinpirole and PG 619-elicited yawning in cocaine-history monkeys. In another experiment, doses of PG 619 that elicited yawns did not alter response rates in monkeys self-administering cocaine (0.03-0.3 mg/kg per injection). Following saline extinction, cocaine (0.1 mg/kg) and quinpirole (0.1 mg/kg), but not PG 619 (0.1 mg/kg), reinstated cocaine seeking behavior. When given before a cocaine prime, PG 619 decreased cocaine elicited reinstatement. These findings suggest that (1) an incongruence between in vitro and in vivo assays, and (2) a history of cocaine self-administration can affect in vivo efficacy of D(3) receptor-preferring compounds PG 619 and CJB 090, which appear to be dependent on the behavioral assay. PMID- 21289601 TI - Pharmacologically induced alcohol craving in treatment seeking alcoholics correlates with alcoholism severity, but is insensitive to acamprosate. AB - Modulation of alcohol craving induced by challenge stimuli may predict the efficacy of new pharmacotherapies for alcoholism. We evaluated two pharmacological challenges, the alpha(2)-adrenergic antagonist yohimbine, which reinstates alcohol seeking in rats, and the serotonergic compound meta chlorophenylpiperazine (mCPP), previously reported to increase alcohol craving in alcoholics. To assess the predictive validity of this approach, the approved alcoholism medication acamprosate was evaluated for its ability to modulate challenge-induced cravings. A total of 35 treatment seeking alcohol dependent inpatients in early abstinence were randomized to placebo or acamprosate (2997 mg daily). Following two weeks of medication, subjects underwent three challenge sessions with yohimbine, mCPP or saline infusion under double blind conditions, carried out in counterbalanced order, and separated by at least 5 days. Ratings of cravings and anxiety, as well as biochemical measures were obtained. In all, 25 subjects completed all three sessions and were included in the analysis. Cravings were modestly, but significantly higher following both yohimbine and mCPP challenge compared with saline infusion. The mCPP, but not yohimbine significantly increased anxiety ratings. Both challenges produced robust ACTH, cortisol and prolactin responses. There was a significant correlation between craving and the degree of alcoholism severity. Acamprosate administration did not influence craving. Both yohimbine and mCPP challenges lead to elevated alcohol craving in a clinical population of alcoholics, and these cravings correlate with alcoholism severity. Under the experimental conditions used, alcohol cravings induced by these two stimuli are not sensitive to acamprosate at clinically used doses. PMID- 21289602 TI - Peripheral nerve injury leads to working memory deficits and dysfunction of the hippocampus by upregulation of TNF-alpha in rodents. AB - Patients with chronic pain usually suffer from working memory deficits, which may decrease their intellectual ability significantly. Despite intensive clinical studies, the mechanism underlying this form of memory impairment remains elusive. In this study, we investigated this issue in the spared nerve injury (SNI) model of neuropathic pain, a most common form of chronic pain. We found that SNI impaired working memory and short-term memory in rats and mice. To explore the potential mechanisms, we studied synaptic transmission/plasticity in hippocampus, a brain region critically involved in memory function. We found that frequency facilitation, a presynaptic form of short-term plasticity, and long-term potentiation at CA3-CA1 synapses were impaired after SNI. Structurally, density of presynaptic boutons in hippocampal CA1 synapses was reduced significantly. At the molecular level, we found that tumor necrosis factor-alpha (TNF-alpha) increased in cerebrospinal fluid, in hippocampal tissue and in plasma after SNI. Intracerebroventricular or intrahippocampal injection of recombinant rat TNF mimicked the effects of SNI in naive rats, whereas inhibition of TNF-alpha or genetic deletion of TNF receptor 1 prevented both memory deficits and synaptic dysfunction induced by SNI. As TNF-alpha is critical for development of neuropathic pain, we suggested that the over-production of TNF-alpha following peripheral nerve injury might lead to neuropathic pain and memory deficits, simultaneously. PMID- 21289603 TI - Ethanol affects striatal interneurons directly and projection neurons through a reduction in cholinergic tone. AB - The acute effects of ethanol on the neurons of the striatum, a basal ganglia nucleus crucially involved in motor control and action selection, were investigated using whole-cell recordings. An intoxicating concentration of ethanol (50 mM) produced inhibitory effects on striatal large aspiny cholinergic interneurons (LAIs) and low-threshold spike interneurons (LTSIs). These effects persisted in the presence of tetrodotoxin and were because of an increase in potassium currents, including those responsible for medium and slow afterhyperpolarizations. In contrast, fast-spiking interneurons (FSIs) were directly excited by ethanol, which depolarized these neurons through the suppression of potassium currents. Medium spiny neurons (MSNs) became hyperpolarized in the presence of ethanol, but this effect did not persist in the presence of tetrodotoxin and was mimicked and occluded by application of the M1 muscarinic receptor antagonist telenzepine. Ethanol effects on MSNs were also abolished by 100 MUM barium. This showed that the hyperpolarizations observed in MSNs were because of decreased tonic activation of M1 muscarinic receptors, resulting in an increase in Kir2 conductances. Evoked GABAergic responses of MSNs were reversibly decreased by ethanol with no change in paired-pulse ratio. Furthermore, ethanol impaired the ability of thalamostriatal inputs to inhibit a subsequent corticostriatal glutamatergic response in MSNs. These results offer the first comprehensive description of the highly cell type-specific effects of ethanol on striatal neurons and provide a cellular basis for the interpretation of ethanol influence on a brain area crucially involved in the motor and decisional impairment caused by this drug. PMID- 21289604 TI - Nicotine-mediated activation of dopaminergic neurons in distinct regions of the ventral tegmental area. AB - Nicotine activation of nicotinic acetylcholine receptors (nAChRs) within the dopaminergic (DAergic) neuron-rich ventral tegmental area (VTA) is necessary and sufficient for nicotine reinforcement. In this study, we show that rewarding doses of nicotine activated VTA DAergic neurons in a region-selective manner, preferentially activating neurons in the posterior VTA (pVTA) but not in the anterior VTA (aVTA) or in the tail VTA (tVTA). Nicotine (1 MUM) directly activated pVTA DAergic neurons in adult mouse midbrain slices, but had little effect on DAergic neurons within the aVTA. Quantification of nAChR subunit gene expression revealed that pVTA DAergic neurons expressed higher levels of alpha4, alpha6, and beta3 transcripts than did aVTA DAergic neurons. Activation of nAChRs containing the alpha4 subunit (alpha4(*) nAChRs) was necessary and sufficient for activation of pVTA DAergic neurons: nicotine failed to activate pVTA DAergic neurons in alpha4 knockout animals; in contrast, pVTA alpha4(*) nAChRs were selectively activated by nicotine in mutant mice expressing agonist hypersensitive alpha4(*) nAChRs (Leu9'Ala mice). In addition, whole-cell currents induced by nicotine in DAergic neurons were mediated by alpha4(*) nAChRs and were significantly larger in pVTA neurons than in aVTA neurons. Infusion of an alpha6(*) nAChR antagonist into the VTA blocked activation of pVTA DAergic neurons in WT mice and in Leu9'Ala mice at nicotine doses, which only activate the mutant receptor indicating that alpha4 and alpha6 subunits coassemble to form functional receptors in these neurons. Thus, nicotine selectively activates DAergic neurons within the pVTA through alpha4alpha6(*) nAChRs. These receptors represent novel targets for smoking-cessation therapies. PMID- 21289605 TI - Amelioration of the cardiovascular effects of cocaine in rhesus monkeys by a long acting mutant form of cocaine esterase. AB - A long-acting mutant form of a naturally occurring bacterial cocaine esterase (T172R/G173Q CocE; double mutant CocE (DM CocE)) has previously been shown to antagonize the reinforcing, convulsant, and lethal effects of cocaine in rodents. However, the effectiveness and therapeutic characteristics of DM CocE in nonhuman primates, in a more clinically relevant context, are unknown. The current studies were aimed at (1) characterizing the cardiovascular effects of cocaine in freely moving rhesus monkeys, (2) evaluating the capacity of DM CocE to ameliorate these cocaine-induced cardiovascular effects when administered 10 min after cocaine, and (3) assessing the immunological responses of monkeys to DM CocE following repeated administration. Intravenous administration of cocaine produced dose dependent increases in mean arterial pressure (MAP) and heart rate (HR) that persisted throughout the 2-h observation period following a dose of 3.2 mg/kg cocaine. Cocaine failed to produce reliable changes in electrocardiograph (ECG) parameters, body temperature, and locomotor activity. DM CocE produced a rapid and dose-dependent amelioration of the cardiovascular effects, with saline-like MAP measures restored within 5-10 min, and saline-like HR measures restored within 20-40 min of DM CocE administration. Although administration of DM CocE produced increases in anti-CocE antibodies, they did not appear to have a neutralizing effect on the capacity of DM CocE to reverse the cardiovascular effects of cocaine. In conclusion, these findings in monkeys provide strong evidence to suggest that highly efficient cocaine esterases, such as DM CocE, can provide a potential therapeutic option for treatment of acute cocaine intoxication in humans. PMID- 21289606 TI - Effect of modafinil on learning and task-related brain activity in methamphetamine-dependent and healthy individuals. AB - Methamphetamine (MA)-dependent individuals exhibit deficits in cognition and prefrontal cortical function. Therefore, medications that improve cognition in these subjects may improve the success of therapy for their addiction, especially when cognitive behavioral therapies are used. Modafinil has been shown to improve cognitive performance in neuropsychiatric patients and healthy volunteers. We therefore conducted a randomized, double-blind, placebo-controlled, cross-over study, using functional magnetic resonance imaging, to examine the effects of modafinil on learning and neural activity related to cognitive function in abstinent, MA-dependent, and healthy control participants. Modafinil (200 mg) and placebo were administered orally (one single dose each), in counterbalanced fashion, 2 h before each of two testing sessions. Under placebo conditions, MA dependent participants showed worse learning performance than control participants. Modafinil boosted learning in MA-dependent participants, bringing them to the same performance level as control subjects; the control group did not show changes in performance with modafinil. After controlling for performance differences, MA-dependent participants showed a greater effect of modafinil on brain activation in bilateral insula/ventrolateral prefrontal cortex and anterior cingulate cortices than control participants. The findings suggest that modafinil improves learning in MA-dependent participants, possibly by enhancing neural function in regions important for learning and cognitive control. These results suggest that modafinil may be a suitable pharmacological adjunct for enhancing the efficiency of cognitive-based therapies for MA dependence. PMID- 21289607 TI - Huperzine A activates Wnt/beta-catenin signaling and enhances the nonamyloidogenic pathway in an Alzheimer transgenic mouse model. AB - Huperzine A (HupA) is a reversible and selective inhibitor of acetylcholinesterase (AChE), and it has multiple targets when used for Alzheimer's disease (AD) therapy. In this study, we searched for new mechanisms by which HupA could activate Wnt signaling and reduce amyloidosis in AD brain. A nasal gel containing HupA was prepared. No obvious toxicity of intranasal administration of HupA was found in mice. HupA was administered intranasally to beta-amyloid (Abeta) precursor protein and presenilin-1 double-transgenic mice for 4 months. We observed an increase in ADAM10 and a decrease in BACE1 and APP695 protein levels and, subsequently, a reduction in Abeta levels and Abeta burden were present in HupA-treated mouse brain, suggesting that HupA enhances the nonamyloidogenic APP cleavage pathway. Importantly, our results further showed that HupA inhibited GSK3alpha/beta activity, and enhanced the beta-catenin level in the transgenic mouse brain and in SH-SY5Y cells overexpressing Swedish mutation APP, suggesting that the neuroprotective effect of HupA is not related simply to its AChE inhibition and antioxidation, but also involves other mechanisms, including targeting of the Wnt/beta-catenin signaling pathway in AD brain. PMID- 21289609 TI - Rheumatoid arthritis in 2010: from the gut to the joint. PMID- 21289608 TI - Prenatal exposure to nicotine impairs performance of the 5-choice serial reaction time task in adult rats. AB - Cigarette smoking is associated with a wide variety of adverse reproductive outcomes, including increased infant mortality and decreased birth weight. Prenatal exposure to tobacco smoke, of which nicotine is a major teratogenic component, has also been linked to the acceleration of the risk for different psychiatric disorders, including conduct disorder and attention deficit hyperactivity disorder (ADHD). Whether this increased risk is influenced by the direct effects of gestational nicotine exposure on the developing fetus remains uncertain. In this study we provide experimental evidence for the effects of prenatal nicotine exposure on measures of attention and impulsivity in adult male rats. Offspring of females exposed during pregnancy to 0.06 mg/ml nicotine solution as the only source of water (daily consumption: 69.6+/-1.4 ml/kg; nicotine blood level: 96.0+/-31.9 ng/ml) had lower birth weight and delayed sensorimotor development measured by negative geotaxis, righting reflex, and grip strength. In the 5-choice serial reaction time test, adult rats showed increased numbers of anticipatory responses and omissions errors, more variable response times, and lower accuracy with evidence of delayed learning of the task demands when the 1 s stimulus duration was introduced. In contrast, prenatal nicotine exposure had no effect on exploratory locomotion or delay-discounting test. Prenatal nicotine exposure increased expression of the D5 dopamine receptor gene in the striatum, but did not change expression of other dopamine-related genes (DRD4, DAT1, NR4A2, and TH) in either the striatum or the prefrontal cortex. These data suggest a direct effect of prenatal nicotine exposure on important aspects of attention, inhibitory control, or learning later in life. PMID- 21289610 TI - Osteoarthritis in 2010: New takes on treatment and prevention. PMID- 21289611 TI - Gout in 2010: progress and controversies in treatment. PMID- 21289612 TI - Spondyloarthropathies in 2010: new insights into therapy-TNF blockade and beyond. PMID- 21289613 TI - Osteoporosis in 2010: building bones and (safely) preventing breaks. PMID- 21289614 TI - Autoinflammation in 2010: expanding clinical spectrum and broadening therapeutic horizons. PMID- 21289615 TI - Conservative biomechanical strategies for knee osteoarthritis. AB - Knee osteoarthritis (OA) is one of the most prevalent forms of this disease, with the medial compartment most commonly affected. The direction of external forces and limb orientation during walking results in an adduction moment that acts around the knee, and this parameter is regarded as a surrogate measure of medial knee compression. The knee adduction moment is intimately linked with the development and progression of knee OA and is, therefore, a target for conservative biomechanical intervention strategies, which are the focus of this Review. We examine the evidence for walking barefoot and the use of lateral wedge insoles and thin-soled, flexible shoes to reduce the knee adduction moment in patients with OA. We review strategies that directly affect the gait, such as walking with the foot externally rotated ('toe-out gait'), using a cane, lateral trunk sway and gait retraining. Valgus knee braces and muscle strengthening are also discussed for their effect upon reducing the knee adduction moment. PMID- 21289616 TI - Adenovirus type 5 induces vitamin A-metabolizing enzymes in dendritic cells and enhances priming of gut-homing CD8 T cells. AB - Protective immunity at the gut-associated mucosal tissue is induced primarily by oral/rectal immunization owing to the need for targeting antigen to the gut resident dendritic cells (DCs). In this study we show that an adenovirus type 5 (Ad5)-based human immunodeficiency virus type 1 vaccine can prime a durable antigen-specific CD8 T-cell response in the gut following intramuscular (IM) immunization in mice. The ability of Ad5 to prime gut-homing CD8 T cells in vivo was associated with Ad5-induced expression of retinal dehydrogenase (RALDH) enzymes in conventional DCs. The Ad5-mediated induction of RALDH did not require signaling through Toll-like receptors, DNA-dependent activator of interferon regulatory factors and several mitogen-activated protein kinases, or replication capacity of the virus, but was dependent on nuclear factor-kappaB and granulocyte macrophage colony-stimulating factor. These results provide an innate mechanism through which Ad5-stimulated DCs prime gut-homing CD8 T cells and have implications for the development of novel mucosal adjuvants for subunit vaccines administered via the IM route. PMID- 21289618 TI - Can modeling of health outcomes facilitate regulatory decision making? The benefit-risk tradeoff for rosiglitazone in 1999 vs. 2007. AB - Rosiglitazone was initially approved for type 2 diabetes monotherapy. We tested health-outcomes modeling as an aid to regulatory decision making by quantifying the incremental net benefit (INB) value of rosiglitazone (relative to a comparator), both at the time of first approval (1999) and at the FDA advisory committee review (2007). Using 1999 data, rosiglitazone was projected to provide an additional 0.639 years of life (0.373 quality-adjusted life years (QALYs)) relative to placebo but a loss of 0.312 years (0.173 QALYs) relative to glyburide, with uncertainty in reduction of hemoglobin A(1c) (HbA(1c)) level having the greatest impact on the benefit-risk profile. By 2007, rosiglitazone was projected to provide an additional 0.222 years (0.091 QALYs) vs. glyburide and 0.026 years vs. metformin (0.009 QALYs). Modeling suggested that the use of rosiglitazone as monotherapy was not initially warranted, given the uncertainty with regard to benefit. Despite similar net benefit (NB) as metformin shown in postmarketing data, residual cardiovascular (CV) concerns did not support the use of rosiglitazone as first-line therapy. We adapted a mathematical diabetes model to estimate NB and uncertainty of diabetes monotherapy. PMID- 21289617 TI - Bile retinoids imprint intestinal CD103+ dendritic cells with the ability to generate gut-tropic T cells. AB - Small intestinal lamina propria (SI-LP) CD103(+) dendritic cells (DCs) are imprinted with an ability to metabolize vitamin A (retinol), a property underlying their enhanced capacity to induce the gut-homing receptors CC chemokine receptor-9 and alpha4beta7 on responding T cells. In this study, we demonstrate that imprinting of CD103(+) DCs is itself critically dependent on vitamin A and occurs locally within the small intestine (SI). The major vitamin A metabolite retinoic acid (RA) induced retinol-metabolizing activity in DCs both in vitro and in vivo, suggesting a direct role for RA in this process. Consistent with this, SI-LP CD103(+) DCs constitutively received RA signals in vivo at significantly higher levels than did colonic CD103(+) DCs. Remarkably, SI CD103(+) DCs remained imprinted in mice depleted of dietary but not of systemic retinol. We found that bile contained high levels of retinol, induced RA receptor dependent retinol-metabolizing activity in bone marrow-derived DCs, and imprinted these cells with the ability to generate gut-tropic T cells. Taken together, these results suggest a novel and unexpected role for bile in SI-LP CD103(+) DC imprinting. PMID- 21289619 TI - Cardiovascular pharmacogenomics of adrenergic receptor signaling: clinical implications and future directions. AB - G-protein-coupled receptors (GPCRs) are the targets for many drugs, and genetic variation in coding and noncoding regions is apparent in many such receptors. In this superfamily, adrenergic receptors (ARs) were among the first in which single nucleotide polymorphisms (SNPs) were discovered, and studies including in vitro mutagenesis, genetically modified mouse models, human ex vivo and in vitro studies and pharmacogenetic association studies were conducted. The signal transduction in these receptors includes amplification steps, desensitization, crosstalk, and redundancies, enabling potential mitigation of the size of the clinical effect for a single variant in a single gene. Nevertheless, convincing evidence has emerged that several variants have an impact on therapy, with certain caveats as to how the results are to be interpreted. Here we review these results for selected ARs and associated regulatory kinases relative to the pharmacogenomics of beta-blocker treatment for hypertension and heart failure. We emphasize the linking of clinical results to molecular mechanisms, discuss study design limitations, and offer some recommendations for future directions. PMID- 21289620 TI - Subjective and physiological effects after controlled Sativex and oral THC administration. AB - Sativex is a cannabis-plant extract delivering nearly 1:1 Delta(9) tetrahydrocannabinol (THC) and cannabidiol (CBD) by oromucosal spray. It has been suggested that CBD attenuates THC-induced tachycardia, anxiety, and euphoria. In this study, pharmacodynamic effects were compared over 10.5 h in nine cannabis smokers randomly assigned to receive placebo, 5 and 15 mg oral synthetic THC, and low (5.4 mg THC, 5.0 mg CBD) and high (16.2 mg THC, 15.0 mg CBD) doses of Sativex. At therapeutic doses, no substantial CBD-induced modulation of THC's effects was evident. Oral THC and Sativex produced similar, clinically insignificant increases in heart rate, anxiety, and "good drug effects" with no serious adverse events. Oral and oromucosal THC have slower absorption, lower rate of THC delivery to the brain, and fewer associated adverse events as compared with smoked cannabis. These results indicate that Sativex has a pharmacodynamic safety profile comparable to that of oral THC at low, therapeutic doses. PMID- 21289621 TI - Effects of KCNQ1 polymorphisms on the therapeutic efficacy of oral antidiabetic drugs in Chinese patients with type 2 diabetes. AB - The aim of this study was to explore the impact of KCNQ1 variants on the responses to oral antidiabetic drugs in a Chinese study population. A 48-week randomized pharmacogenetics study compared the effects of repaglinide and rosiglitazone in 209 newly diagnosed patients with type 2 diabetes. In the repaglinide cohort, individuals who were rs2237892 TT homozygotes exhibited lower 2-h glucose levels and significantly higher cumulative attainment rates of target 2-h glucose levels (P(log-rank) = 0.0383) than the C allele carriers; patients with a greater number of rs2237892 C alleles showed larger augmentations in both fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR) (P = 0.0166 and 0.0026, respectively); moreover, the rs2237895 C allele was also associated with greater increments in both fasting insulin and HOMA-IR (P = 0.0274 and 0.0259, respectively). In contrast, only an association between rs2237897 and decrease in 2-h glucose levels was detected in the rosiglitazone cohort (P = 0.0321). Our results indicated that KCNQ1 polymorphisms are associated with repaglinide efficacy, and might also be associated with rosiglitazone response, in Chinese patients with type 2 diabetes. PMID- 21289622 TI - Pharmacogenomics of the RNA world: structural RNA polymorphisms in drug therapy. AB - The use of pharmacogenomic biomarkers can enhance treatment outcomes. Regulatory polymorphisms are promising biomarkers that have proven difficult to uncover. They come in two flavors: those that affect transcription (regulatory single nucleotide polymorphisms (rSNPs)) and those that affect RNA functions such as splicing, turnover, and translation (termed structural RNA SNPs (srSNPs)). This review focuses on the role of srSNPs in drug metabolism, transport, and response. An understanding of the nature and diversity of srSNPs and rSNPs enables clinical scientists to evaluate genetic biomarkers. PMID- 21289623 TI - ABCB1 single-nucleotide polymorphisms determine tacrolimus response in patients with ulcerative colitis. AB - Tacrolimus (Tac) is effective in the treatment of steroid-refractory ulcerative colitis (UC); however, nonresponse and unpredictable side effects are major limitations. Because Tac response in patients who have undergone solid-organ transplantation has been associated with the presence of variants in CYP3A and ABCB1, we elucidated the contributions of CYP3A4*1B and CYP3A5*3 and of ABCB1 1236C>T, 2677G>T,A, and 3435C>T polymorphisms to Tac response in 89 patients with UC. Short-term remission and response were achieved in 61 and 14% of the patients, respectively, and were associated with colectomy-free survival. In a linear logistic regression model, patients with homozygous variants for one of the three ABCB1 alleles showed significantly higher short-term remission rates as compared with those of other genotypes. The effects held true after multivariate analysis including multiple comparisons and were more pronounced after correction for dose-adjusted Tac blood trough levels. We suggest that ABCB1, but not CYP3A5, may predict short-term remission of Tac in steroid-refractory UC. PMID- 21289624 TI - SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression. AB - Effective clinical management of prostate cancer (PCA) has been challenged by significant intratumoural heterogeneity on the genomic and pathological levels and limited understanding of the genetic elements governing disease progression. Here, we exploited the experimental merits of the mouse to test the hypothesis that pathways constraining progression might be activated in indolent Pten-null mouse prostate tumours and that inactivation of such progression barriers in mice would engender a metastasis-prone condition. Comparative transcriptomic and canonical pathway analyses, followed by biochemical confirmation, of normal prostate epithelium versus poorly progressive Pten-null prostate cancers revealed robust activation of the TGFbeta/BMP-SMAD4 signalling axis. The functional relevance of SMAD4 was further supported by emergence of invasive, metastatic and lethal prostate cancers with 100% penetrance upon genetic deletion of Smad4 in the Pten-null mouse prostate. Pathological and molecular analysis as well as transcriptomic knowledge-based pathway profiling of emerging tumours identified cell proliferation and invasion as two cardinal tumour biological features in the metastatic Smad4/Pten-null PCA model. Follow-on pathological and functional assessment confirmed cyclin D1 and SPP1 as key mediators of these biological processes, which together with PTEN and SMAD4, form a four-gene signature that is prognostic of prostate-specific antigen (PSA) biochemical recurrence and lethal metastasis in human PCA. This model-informed progression analysis, together with genetic, functional and translational studies, establishes SMAD4 as a key regulator of PCA progression in mice and humans. PMID- 21289625 TI - Three-dimensional atomic imaging of crystalline nanoparticles. AB - Determining the three-dimensional (3D) arrangement of atoms in crystalline nanoparticles is important for nanometre-scale device engineering and also for applications involving nanoparticles, such as optoelectronics or catalysis. A nanoparticle's physical and chemical properties are controlled by its exact 3D morphology, structure and composition. Electron tomography enables the recovery of the shape of a nanoparticle from a series of projection images. Although atomic-resolution electron microscopy has been feasible for nearly four decades, neither electron tomography nor any other experimental technique has yet demonstrated atomic resolution in three dimensions. Here we report the 3D reconstruction of a complex crystalline nanoparticle at atomic resolution. To achieve this, we combined aberration-corrected scanning transmission electron microscopy, statistical parameter estimation theory and discrete tomography. Unlike conventional electron tomography, only two images of the target--a silver nanoparticle embedded in an aluminium matrix--are sufficient for the reconstruction when combined with available knowledge about the particle's crystallographic structure. Additional projections confirm the reliability of the result. The results we present help close the gap between the atomic resolution achievable in two-dimensional electron micrographs and the coarser resolution that has hitherto been obtained by conventional electron tomography. PMID- 21289626 TI - Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. AB - Induced pluripotent stem cells (iPSCs) offer immense potential for regenerative medicine and studies of disease and development. Somatic cell reprogramming involves epigenomic reconfiguration, conferring iPSCs with characteristics similar to embryonic stem (ES) cells. However, it remains unknown how complete the reestablishment of ES-cell-like DNA methylation patterns is throughout the genome. Here we report the first whole-genome profiles of DNA methylation at single-base resolution in five human iPSC lines, along with methylomes of ES cells, somatic cells, and differentiated iPSCs and ES cells. iPSCs show significant reprogramming variability, including somatic memory and aberrant reprogramming of DNA methylation. iPSCs share megabase-scale differentially methylated regions proximal to centromeres and telomeres that display incomplete reprogramming of non-CG methylation, and differences in CG methylation and histone modifications. Lastly, differentiation of iPSCs into trophoblast cells revealed that errors in reprogramming CG methylation are transmitted at a high frequency, providing an iPSC reprogramming signature that is maintained after differentiation. PMID- 21289627 TI - Kidney function in patients undergoing coronary revascularization. PMID- 21289628 TI - Potential impact of renin-angiotensin system inhibitors and calcium channel blockers on plasma high-molecular-weight adiponectin levels in hemodialysis patients. AB - Although metabolic syndrome confers an increased risk of cardiovascular disease in the general population, little is known about the alteration of abdominal adiposity and its association with adipocytokines in hemodialysis patients. We investigated the plasma high-molecular-weight (HMW) adiponectin level and its relationship to visceral fat area (VFA) and various markers of atherosclerosis in hemodialysis patients. In a cross-sectional study, conventional cardiovascular risk factors, plasma total and HMW adiponectin, the number of components of the metabolic syndrome and, using computed tomography, the distribution of abdominal adiposity were assessed in 144 hemodialysis patients (90 men and 54 women; mean age, 60.7 years) and 30 age- and sex-matched patients with chronic kidney disease (CKD). Plasma HMW adiponectin levels in hemodialysis patients were significantly higher than those in patients with CKD, negatively associated with VFA and serum triglycerides and positively associated with plasma total adiponectin, as well as the HMW-to-total adiponectin ratio in men and women (all P < 0.05) in a simple regression analysis. In a multiple regression analysis, VFA was a significant determinant of HMW adiponectin in hemodialysis patients. Furthermore, after adjustment for classical risk factors, HMW adiponectin levels were significantly higher in patients undergoing treatment with renin-angiotensin system inhibitors or calcium channel blockers compared with patients not undergoing such treatment. This study shows that plasma HMW adiponectin levels were negatively associated with VFA and positively associated with treatment with blockade of the renin angiotensin system and of the calcium channel. Therefore, these drugs might be effective for improving adipocytokine-related metabolic abnormalities in hemodialysis patients. PMID- 21289629 TI - beta-Adrenergic receptor gene polymorphism is a genetic risk factor for cardiovascular disease: a cohort study with hypertensive patients. AB - Single-nucleotide polymorphisms (SNPs) of the beta-adrenergic receptor (betaADR) subtypes are related to hypertension and obesity. This hospital-based cohort study with hypertensive patients evaluated five betaADR SNPs in association with cardiovascular events. The cohort included 357 hypertensive patients (male = 181; mean age = 61.5 +/- 11.8 years) seen between January 1998 and June 2004. The SNPs (Ser49Gly and Arg389Gly for beta(1)ADR; Gly16Arg and Glu27Gln for beta(2)ADR; Trp64Arg for beta(3)ADR) were identified by PCR. We used Kaplan-Meier curves to assess the prognostic effect of these SNPs on cardiovascular disease (CVD). The SNP frequencies were Ser/Ser:Ser/Gly:Gly/Gly = 243:104:10; Arg/Arg:Arg/Gly:Gly/Gly = 256:95:6; Gly/Gly:Gly/Arg:Arg/Arg = 71:201:85; Gln/Gln:Glu/Gln = 308:49; and Trp/Trp:Trp/Arg:Arg/Arg = 265:89:3. A total of 17 stroke and 15 coronary artery disease cases were recorded. By Kaplan-Meier analysis, the Ser/Ser SNP in Ser49Gly (P = 0.0398), the Glu/Gln SNP in Glu27Gln (P = 0.0390) and the Trp/Trp SNP in Trp64Arg (P = 0.0132) were associated with lower event-free CVD survival (log-rank, Mantel-Cox model). A Cox proportional hazards model revealed that only the Trp/Trp SNP (P = 0.0321) and age (P = 0.0186) were independently related to lower event-free survival for CVD, adjusted for gender, diabetes, dyslipidemia, blood pressure, body mass index, medication and hypertensive complications. Combination Kaplan-Meier analysis of these three positive SNPs indicated a higher frequency of CVD among patients with the combination of Ser/Ser in Ser49Gly of beta(1), Glu/Gln in Glu27Gln of beta(2) and Trp/Trp in Trp64Arg of beta(3) (P = 0.0209). These three SNPs, especially the Trp64Arg SNP of beta(3)ADR, might be risk factors for CVD in hypertensive patients. PMID- 21289630 TI - MicroRNA-141 confers resistance to cisplatin-induced apoptosis by targeting YAP1 in human esophageal squamous cell carcinoma. AB - MicroRNAs (miRNAs) are endogenous non-coding RNAs that function as negative regulators of gene expression. Alterations in miRNA expression have been shown to affect tumor growth and response to chemotherapy. In this study, we explored the possible role of miRNAs in cisplatin resistance in esophageal squamous cell carcinoma (ESCC). First we assessed the sensitivity of nine human ESCC cell lines (KYSE series) to cisplatin using an in vitro cell viability assay, and then we compared the miRNA profiles of the cisplatin-sensitive and -resistant cell lines by miRNA microarray analysis. The two groups showed markedly different miRNA expression profiles, and 10 miRNAs were found to be regulated differentially between the two groups. When miR-141, which was the most highly expressed miRNA in the cisplatin-resistant cell lines, was expressed ectopically in the cisplatin sensitive cell lines, cell viability after cisplatin treatment was increased significantly. Furthermore, we found that miR-141 directly targeted the 3' untranslated region of YAP1, which is known to have a crucial role in apoptosis induced by DNA-damaging agents, and thus downregulated YAP1 expression. Our study highlights an important regulatory role for miR-141 in the development of cisplatin resistance in ESCC. PMID- 21289631 TI - Gene therapy moves forward in 2010. PMID- 21289634 TI - Is human cell therapy research caught in a mousetrap? PMID- 21289635 TI - Direct conversion of skin cells into blood: alchemy or science? PMID- 21289636 TI - Solving the problem of gamma-retroviral vectors containing long terminal repeats. PMID- 21289637 TI - AAV6-mediated gene silencing fALS short. PMID- 21289638 TI - eNOS-uncoupling in age-related erectile dysfunction. AB - Aging is associated with ED. Although age-related ED is attributed largely to increased oxidative stress and endothelial dysfunction in the penis, the molecular mechanisms underlying this effect are not fully defined. We evaluated whether endothelial nitric oxide synthase (eNOS) uncoupling in the aged rat penis is a contributing mechanism. Correlatively, we evaluated the effect of replacement with eNOS cofactor tetrahydrobiopterin (BH(4)) on erectile function in the aged rats. Male Fischer 344 'young' (4-month-old) and 'aged' (19-month old) rats were treated with a BH(4) precursor sepiapterin (10 mg/kg intraperitoneally) or vehicle for 4 days. After 1-day washout, erectile function was assessed in response to electrical stimulation of the cavernous nerve. Endothelial dysfunction (eNOS uncoupling) and oxidative stress (thiobarbituric acid reactive substances, TBARS) were measured by conducting western blot in penes samples. Erectile response was significantly reduced in aged rats, whereas eNOS uncoupling and TBARS production were significantly increased in the aged rat penis compared with young rats. Sepiapterin significantly improved erectile response in aged rats and prevented increase in TBARS production, but did not affect eNOS uncoupling in the penis of aged rats. These findings suggest that aging induces eNOS uncoupling in the penis, resulting in increased oxidative stress and ED. PMID- 21289639 TI - IL-23-mediated epidermal hyperplasia is dependent on IL-6. AB - Psoriasis is a chronic inflammatory skin disease primarily driven by Th17 cells. IL-23 facilitates the differentiation and induces complete maturation of Th17 cells. Lesional psoriatic skin has increased levels of IL-23 and recent studies show that intradermal injections of IL-23 induce a psoriasis-like skin phenotype in mice. We have now characterized the IL-23-induced skin inflammation in mice at the molecular level and found a significant correlation with the gene expression profile from lesional psoriatic skin. As observed in psoriasis, the pathogenesis of the IL-23-induced skin inflammation in mice is driven by Th17 cells. We demonstrate a dramatic upregulation of IL-6 mRNA and protein after intradermal injections of IL-23 in mice. Using IL-6(-/-) mice we show that IL-6 is essential for development of the IL-23-elicited responses. Despite producing high levels of IL-22, IL-6(-/-) mice were unable to express the high-affinity IL-22 receptor chain and produced minimal IL-17A in response to intradermal injections of IL-23. In conclusion, we provide evidence for the critical role played by IL-6 in IL-23 induced skin inflammation and show that IL-6 is required for expression of IL 22R1A. PMID- 21289640 TI - Full sequencing of the FLG gene in Italian patients with atopic eczema: evidence of new mutations, but lack of an association. PMID- 21289641 TI - Topical cholecystokinin depresses itch-associated scratching behavior in mice. AB - Cholecystokinin (CCK) serves as a gastrointestinal hormone and also functions as a neuropeptide in the central nervous system (CNS). CCK may be a downregulator in the CNS, as represented by its anti-opioid properties. The existence of CCK in the peripheral nervous system has also been reported. We investigated the suppressive effects of various CCKs on peripheral pruritus in mice. The clipped backs of ICR mice were painted with CCK synthetic peptides and injected intradermally with substance P (SP). The frequency of SP-induced scratching was reduced significantly by topical application of sulfated CCK8 (CCK8S) and CCK7 (CCK7S), but not by nonsulfated CCK8, CCK7, or CCK6. Dermal injection of CCK8S also suppressed the scratching frequency, suggesting that dermal cells as well as epidermal keratinocytes (KCs) are the targets of CCKs. As determined using real time PCR, mRNA for CCK2R, one of the two types of CCK receptors, was expressed highly in mouse fetal skin-derived mast cells (FSMCs) and moderately in ICR mouse KCs. CCK8S decreased in vitro compound 48/80-promoted degranulation of FSMCs with a transient elevation of the intracellular calcium concentration. These findings suggest that CCK may exert an antipruritic effect via mast cells and that topical CCK may be clinically useful for pruritic skin disorders. PMID- 21289642 TI - Dimethylfumarate inhibits angiogenesis in vitro and in vivo: a possible role for its antipsoriatic effect? AB - The fumaric acid esters (FAEs) have been used for the oral treatment of psoriasis for some 50 years. Given that a persistent and maintained angiogenesis is associated with several cutaneous diseases, including psoriasis, we sought in our study to gain further insight into their mechanism of action by investigating whether FAEs are able to interfere with angiogenesis mechanisms. Our results demonstrate that dimethylfumarate (DMF) inhibits certain functions of endothelial cells, namely, differentiation, proliferation, and migration. This activity was not exhibited by similar concentrations of monomethylfumarate or fumaric acid. Our data indicate that DMF inhibits the growth of transformed and nontransformed cells in a dose-dependent manner. The growth-inhibitory effect exerted by this compound on proliferating endothelial cells could be due, at least in part, to an induction of apoptosis. Inhibition by DMF of the mentioned essential steps of in vitro angiogenesis is consistent with the observed inhibition of in vivo angiogenesis, substantiated using chick chorioallantoic membrane and live fluorescent zebrafish embryo neovascularization assays. The antiangiogenic activity of DMF may contribute to the antipsoriatic, antitumoral, and antimetastatic activities of this compound and suggests its potential in the treatment of angiogenesis-related malignancies. PMID- 21289643 TI - c-Jun promotes whereas JunB inhibits epidermal neoplasia. AB - Deregulation of the activator protein 1 (AP1) family gene regulators has been implicated in a wide range of diseases, including cancer. In this study we report that c-Jun was activated in human squamous cell carcinoma (SCC) and coexpression of c-Jun with oncogenic Ras was sufficient to transform primary human epidermal cells into malignancy in a regenerated human skin grafting model. In contrast, JunB was not induced in a majority of human SCC cells. Moreover, exogenous expression of JunB inhibited tumorigenesis driven by Ras or spontaneous human SCC cells. Conversely, the dominant-negative JunB mutant (DNJunB) promoted tumorigenesis, which is in contrast to the tumor-suppressor function of the corresponding c-Jun mutant. At the cellular level, JunB induced epidermal cell senescence and slowed cell growth in a cell-autonomous manner. Consistently, coexpression of JunB and Ras induced premature epidermal differentiation concomitant with upregulation of p16 and filaggrin and downregulation of cyclin D1 and cyclin-dependent kinase 4 (CDK4). These findings indicate that JunB and c Jun differentially regulate cell growth and differentiation and induce opposite effects on epidermal neoplasia.JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article, please go to http://www.nature.com/jid/journalclub. PMID- 21289644 TI - Left atrial diameter, flow-mediated dilation of brachial artery and target organ damage in Chinese patients with hypertension. AB - To investigate the relationship between left atrial (LA) size, endothelial dysfunction and different markers of target organ damage (TOD), we measured left atrial diameter (LAD) and endothelial function in hypertensive patients with or without TOD. In this study, 197 patients with hypertension were divided into four groups as follows: no TOD (Group I, n=40), one TOD (Group II, n=76), two TOD (Group III, n=46) and >=3 TOD (Group IV, n=35). Endothelial function was assessed by endothelium-dependent vasodilatation (flow-mediated dilation, FMD) of the brachial artery. We also assessed serum creatinine, the urinary albumin creatinine ratio (UACR), the intima-media thickness (IMT) of the common carotid, carotid to femoral pulse wave velocity (cf-PWV) and left ventricular mass index (LVMI). Our results were as follows: LA size was increased in 50.8% of patients and was associated with the number of TOD. LAD was larger in the patient groups with >=3 TOD as compared with patients with two TOD, one TOD and no TOD. FMD was lower in patients with LAD enlargement. LAD exhibited significant relationships with serum creatinine, UACR, cf-PWV, IMT and LVMI. In stepwise multivariate regression analysis, LVMI (beta=0.37, P<0.001), BMI (beta=0.33, P<0.001), duration of hypertension (beta=0.20, P=0.001) and FMD (beta=-0.17, P=0.006) were the independent predictors of LAD. FMD significantly correlated with LAD (beta= 0.26, P=0.001), male sex (beta=-0.23, P=0.004) and pulse pressure (PP) (beta= 0.16, P<0.05). In conclusions, enlargement of LAD may be an important predictor of endothelial dysfunction and may be considered to be an indicator for evaluating TOD in hypertensive patients. PMID- 21289645 TI - Family history of diabetes modifies the effect of blood pressure for incident diabetes in Middle Eastern women: Tehran Lipid and Glucose Study. AB - Elevated blood pressure (BP) may lead to incident diabetes. However, data about the effect of different BP components on incident diabetes in Middle Eastern women is lacking. We evaluated systolic BP (SBP), diastolic BP (DBP), pulse pressure (PP) and mean arterial pressure (MAP) as independent predictors of diabetes in Iranian women. We performed a population-based prospective study among 3028 non-diabetic women, aged >=20 years. Odds ratios (ORs) of diabetes were calculated for every 1 s.d. increase in SBP, DBP, PP and MAP. During ~6 years of follow-up, 220 women developed diabetes. There were significant interactions between family history of diabetes and SBP, PP and MAP (P<=0.01) in predicting incident diabetes. In women without a family history of diabetes, all BP components were significantly associated with diabetes in the age-adjusted model; the risk factor-adjusted ORs were significant (P<0.05) for SBP, PP and MAP (1.30, 1.34 and 1.27, respectively) with similar predictive ability (area under the receiver operating characteristic curve ~83%). In women with family history of diabetes, in the age-adjusted model, SBP, DBP and MAP were associated with diabetes; in multivariable model, they were not independent predictors of diabetes. In conclusion, in women without family history of diabetes, SBP, PP and MAP, were independent predictors of diabetes with almost similar predictive ability; hence, in the evaluation of the risk of BP components for prediction of diabetes, the presence of family history of diabetes should be considered. PMID- 21289646 TI - Perception of uncontrolled blood pressure and behaviours to improve blood pressure: findings from the 2009 Survey on Living with Chronic Diseases in Canada. AB - Individuals with hypertension should lower and maintain their blood pressure levels through lifestyle modification and/or pharmacotherapy. To determine whether perception of blood pressure control is related to behaviours and intentions for improving blood pressure, data from 6142 Canadians age 20+ years with self-reported hypertension were analysed. Relationships between perception of control, current behaviours for blood pressure control and intentions to improve these behaviours were examined. Although individuals who reported uncontrolled blood pressure were equally likely to report engaging in lifestyle behaviours for blood pressure control, they were more likely to indicate an intention to improve their health, compared with those who reported well controlled/low blood pressure. These individuals were also less likely to report having enough information to control their blood pressure. In addition, they were less likely to report having been advised to take antihypertensive medication, and to be taking and adhering to medications. Individuals who perceive their blood pressure as uncontrolled have intentions to make health-enhancing changes but may lack the information to do so. The study highlights the potential need for programmes/services to help those with uncontrolled blood pressure make lifestyle changes and/or take appropriate medication. PMID- 21289647 TI - Metabolic syndrome and microalbuminuria predict renal outcome in non-diabetic patients with primary hypertension: the MAGIC study. AB - Metabolic syndrome (MS) has recently been shown to be a forerunner of chronic kidney disease (CKD). Microalbuminuria (MA) is associated with both MS and CKD. This study aimed to prospectively investigate the relationship among MA, MS and renal outcome in non-diabetic patients with primary hypertension. A total of 790 hypertensive patients enrolled in the MAGIC study between 1993 and 1997 (mean age 49.3+/-10.7 years) were included in the analysis. Renal outcome was defined as the first hospitalization with a diagnosis of CKD. At baseline, 146 (19%) and 60 (7.6%) patients met MS and MA criteria, respectively. A total of 20 patients (2.5%) concomitantly showed MS and MA. After a median follow-up of 11.6 years (interquartile range 3.2 years), renal end point was reached in 15.8% of patients with MS and in 8.9% of those without it (P=0.0087). The incidence of renal events increased progressively starting from patients with neither MS nor MA, to patients with only one of these abnormalities and then to those with both. Significant interaction was observed between MS and MA. Patients with concomitant occurrence of MS and MA at baseline showed a greater than fivefold risk of renal outcome, as compared with patients with neither of these two risk factors (hazard ratio 5.46; 95% confidence interval 2.34-12.75). This risk became even higher when data were adjusted for potential confounders. MS and MA are independent and interactive predictors of renal outcome in non-diabetic patients with primary hypertension. PMID- 21289648 TI - Is capillary rarefaction an independent risk marker for cardiovascular disease in South Asians? PMID- 21289649 TI - Measles virus fusion shifts into gear. AB - In this issue, two papers present contrasting models for the machinations of the measles virus attachment protein. Here we discuss how these reports illuminate possible intersubunit motions made by the protein as it drives the fusion of viral and cellular membranes during infection and further our understanding of this global scourge. PMID- 21289650 TI - Location, location, location: a crystal-clear view of autotaxin saturating LPA receptors. AB - The interaction of autotaxin with its substrates leads to the production of lysophosphatidic acids (LPA), bioactive lipids with an emerging prominent role in inflammation and cancer. Two papers in this issue tell the previously unknown story of autotaxin, from substrate discrimination to highly efficient local delivery of LPA to target receptors. PMID- 21289652 TI - Global distribution patterns of distinct clades of the photosynthetic picoeukaryote Ostreococcus. AB - Ostreococcus is a marine picophytoeukaryote for which culture studies indicate there are 'high-light' and 'low-light' adapted ecotypes. Representatives of these ecotypes fall within two to three 18S ribosomal DNA (rDNA) clades for the former and one for the latter. However, clade distributions and relationships to this form of niche partitioning are unknown in nature. We developed two quantitative PCR primer-probe sets and enumerated the proposed ecotypes in the Pacific Ocean as well as the subtropical and tropical North Atlantic. Statistical differences in factors such as salinity, temperature and NO(3) indicated the ecophysiological parameters behind clade distributions are more complex than irradiance alone. Clade OII, containing the putatively low-light adapted strains, was detected at warm oligotrophic sites. In contrast, Clade OI, containing high-light adapted strains, was present in cooler mesotrophic and coastal waters. Maximal OI abundance (19 555+/-37 18S rDNA copies per ml) was detected in mesotrophic waters at 40 m depth, approaching the nutricline. OII was often more abundant at the deep chlorophyll maximum, when nutrient concentrations were significantly higher than at the surface (stratified euphotic zone waters). However, in mixed euphotic zone water columns, relatively high numbers (for example, 891+/-107 18S rDNA copies per ml, Sargasso Sea, springtime) were detected at the surface. Both Clades OI and OII were found at multiple euphotic zone depths, but co-occurrence at the same geographical location appeared rare and was detected only in continental slope waters. In situ growth rate estimates using these primer-probes and better comprehension of physiology will enhance ecological understanding of Ostreococcus Clades OII and OI which appear to be oceanic and coastal clades, respectively. PMID- 21289654 TI - Bring Back the Future: What's in Store for 1981? PMID- 21289655 TI - Fluoridation and the physician. PMID- 21289653 TI - A critical evaluation of the creatinine correction approach: can it underestimate intakes of phthalates? A case study with di-2-ethylhexyl phthalate. AB - The creatinine correction approach has been used to estimate daily intake for contaminants whose primary route of elimination is through urine. This method is challenged using the phthalate di-2-ethylhexyl phthalate (DEHP) as an example. An alternate prediction approach based on human experimental metabolism and urinary excretion data on DEHP was developed. This alternate model was developed from urine measurements of four metabolites of DEHP from two individuals partaking in different experiments, for up to 44 h after known exposures. Particular attention was paid to the changing ratios of the metabolites over time: they took a certain form when exposure was in the "near" (the past few hours) versus the "distant" (24 h or more) past. The creatinine correction approach was applied to measurements of the same four metabolites from 18 individuals in the National Health And Nutrition Evaluation Survey (NHANES) 2003/2004. The alternate model was also applied to these individuals, and the results were compared. Predictions using the two methods were similar or the creatinine correction predicted higher concentrations when the ratio suggested that the DEHP exposure was "near" in time, but the alternate approach predicted intakes that were an order of magnitude higher when the ratios suggested that the intake was "distant". As much as 25% of all NHANES measurements contain metabolites whose key ratio suggest that exposure was "distant". Uncertainties notwithstanding, the analysis in this article suggests that the creatinine correction approach should be used cautiously for DEHP and possibly other contaminants with similar exposure characteristics: rapid metabolism with metabolite urine elimination half-lives on the order of hours, and exposure patterns that may not be continuous and ongoing. PMID- 21289656 TI - [Not Available]. PMID- 21289657 TI - [Not Available]. PMID- 21289658 TI - Another doctor's bag. PMID- 21289660 TI - Addition. PMID- 21289659 TI - Academic family medicine. PMID- 21289662 TI - Famli. PMID- 21289661 TI - Who's in bed with whom? PMID- 21289663 TI - Blood lead levels. PMID- 21289664 TI - Prescribing in family practice: a method of data collection. AB - Data collected from prescriptions in family practice are useful for interpractice comparison because these data are more precise than morbidity data. Interpractice comparisons of prescribing are an attractive alternative for continuing medical education.Drug prescribing patterns are influenced by the characteristics of the practice population, physician factors and external factors. Any review of prescribing patterns must control as many of these variables as possible to be accurate and useful.This article describes methods of data collection and calculation of prescribing rates in a 32 physician teaching practice and discusses current problems of interpractice comparisons. PMID- 21289665 TI - Corynebacterium vaginale: a neglected pathogen in family practice. AB - In an urban practice, 76 cases of Corynebacterium vaginale infection were discovered in a two year period. In retrospect, eight percent of the female patients in the practice had this organism. Most of these women were symptomatic and 45% had atypical Pap smears. Sulfa vaginal cream was found to be ineffective in six of nine cases. Various oral antibiotic treatments of both partners were compared. A ten day course of metronidazole was found to give the best result. Metronidazole in one dose, ampicillin and tetracycline were found to be less effective. PMID- 21289666 TI - The role of immittance audiometry in detecting middle ear disease. AB - IMMITTANCE AUDIOMETRY IS AN OBJECTIVE TECHNIQUE WHICH EVALUATES MIDDLE EAR FUNCTION BY THREE PROCEDURES: static immittance, tympanometry, and the measurement of acoustic reflex threshold sensitivity. This article discusses the technique's ability to identify middle ear effusion, the single leading ear disease in children.A comparison of immittance screening and traditional pure tone audiometry was conducted on 311 school aged children. The results of this study reveal the superiority of immittance audiometry in detecting middle ear pathology. PMID- 21289667 TI - Semen analysis in the investigation of infertility. AB - Following a complete history and physical examination, the next step in investigating the male partner of an infertile couple will be to order semen analyses. Even with optimum collection and processing, wide laboratory errors may occur. When the clinician receives a report, interpretation is beset with pitfalls. This article describes the collection and processing of semen samples and discusses how best the information can be used by the practicing clinician. PMID- 21289668 TI - A lump in the neck. AB - A lump in the neck presents the physician with a stimulating diagnostic challenge. Management of such a patient requires thoughtful analysis of the clinical findings. Investigation should result in an expeditious diagnosis with a minimum of morbidity, inconvenience and hospitalization. Diagnostic tools available today make some of these idealistic goals attainable but do not substitute for sound clinical judgment. This article reports our rationale in managing patients who have a cervical mass. PMID- 21289669 TI - Bedside diagnosis of dizziness. AB - Dizziness, a common presenting symptom in the family physician's office, can present diagnostic problems. The landmark in diagnosis is the presence or absence of vertigo, which can be established by very simple methods, described in this article. PMID- 21289670 TI - Senile dementia and family medicine. AB - Senile dementia is an increasingly important disease in family medicine, because our population is growing old. Dementia can have many causes, some of which are reversible. Its definition varies with time, discipline, and country. Correctly diagnosing reversible dementing processes as early as possible may lead to reversal of an otherwise devastating process. This article discusses definition and diagnosis of senile dementia. PMID- 21289671 TI - Single-dose antibiotic treatment: a new approach to lower urinary tract infections in primary care. AB - Uncomplicated lower urinary tract infections are a common entity in family practice, yet their treatment is often unsatisfactory. Symptoms do not correlate well with bacteriology. Many patients are treated in the absence of bacteriological diagnosis. In those with known disease, compliance with therapy may be limited. These problems may be avoided by recourse to effective single dose therapy with amoxicillin or trimethoprim-sulfamethoxazole. PMID- 21289672 TI - As it Happened: A Disease in Evolution. AB - In family practice the physician has a continuous relationship with his patient, which gives him a chance to observe a disease from the early stages to the full blown clinical picture. This case presents one such instance, where the disease picture was very unclear to begin with, but as time went on, the real problem came into focus. PMID- 21289674 TI - Should patients, not doctors, be opted in or out? PMID- 21289673 TI - Predischarge conference in a family medicine residency program. AB - A predischarge family conference is an important adjunct in providing better patient management and improved patient compliance, besides being a valuable learning experience for residents. It helps house staff evaluate what the patient and family understand about the illness. The conference also helps assess the emotional effect of the illness on the patient and family. Decreased morbidity and fewer readmissions are predicted in programs where active predischarge planning is an integral component. PMID- 21289675 TI - Children, automobiles, hospitals and governments. PMID- 21289676 TI - Birth Control is a Labor-Saving Device Part 2. PMID- 21289677 TI - [Not Available]. PMID- 21289678 TI - [Not Available]. PMID- 21289679 TI - Certification and CFPC Membership. PMID- 21289680 TI - The doctor's bag. PMID- 21289681 TI - The doctor's bag. PMID- 21289682 TI - Purple bag syndrome. PMID- 21289683 TI - Training for rural practice. PMID- 21289684 TI - FPs' logic. PMID- 21289685 TI - Efficacy of Influenza Inoculation: Intradermal versus Subcutaneous Route. AB - Intradermal injection of antigen can theoretically produce the same antibody response as 10-20% of the volume required for subcutaneous injection. This paper demonstrates equal efficacy of intradermal injection of Fluviral vaccine as compared to subcutaneous injection in an ambulatory geriatric population. There was no difference in adverse reactions between the two groups. A significant portion of both groups did not develop protective HAI antibody level to or more than 1/40. PMID- 21289686 TI - Prevention of ill health. AB - The purpose and possibilities of prevention in the workplace are described. A problem solving approach begins by identifying physical, chemical or organizational factors in the work environment and personal health factors in the individual worker. Consulting experts may be required to assist in the process. Methodical assessment of the value of collecting data or of intervention policies will be required as increasing emphasis is placed on the development of truly effective preventive health policies. Major success so far must be credited to engineering and industrial hygiene endeavors. However, the occupational health professional is the only member of the team with knowledge of individual workers' health and who can thus render appropriate advice. With the employment of handicapped, disabled or recently ill workers, the physician's role will become increasingly important in the prevention of ill health at work. PMID- 21289687 TI - [Not Available]. AB - Following the Task Force on the Periodic Health Examination, the authors review the chief preventable pathology and outline norms for the nature and frequency of preventive procedures. They propose a systematic program of prevention and screening of the adult. In order to accomplish this, the initial evaluation of the patient must include the search for risk factors and these are included in the problem list. Finally, tables provide simple and efficient modes of applying this program, which also constitutes a useful research tool. PMID- 21289688 TI - Are your patients protected from rubeola? AB - Patients have a 95% chance of being protected from rubeola if they received the proper vaccine, stored and handled in the correct manner, at the appropriate age. An increase in measles in teenagers is more likely due to technical problems (the vaccine, storage, handling, and age of administration) than to waning immunity. Provincial governments should follow the U.S. lead and mount programs to eradicate measles, just as we have done with smallpox. For patients whose immune status is unknown, serology should be done and only the susceptibles vaccinated. PMID- 21289689 TI - Preventive medicine and the family. AB - Studies have demonstrated the links between the family system and illness, emphasizing the importance of prevention on a family level for physical as well as psychological illness. Brief preventive counselling on routine visits is possible if the physician knows the family well and understands the principles of the family as a system. Periods of high risk when illness and family dysfunction increase in incidence are the normal "crises" of the family life cycle, medical crises of illness, hospitalization and death, and non-medical crises. High-risk families should be identified; secondary prevention is an important role for the family physician who sees family problems at a much earlier stage than the psychiatrist or marital or family therapist. PMID- 21289690 TI - On motor vehicle accidents and prevention. AB - Motor vehicle accidents, a modern epidemic, cause sudden unexpected loss and personal disasters. They challenge the physician in many ways but the ultimate challenge is how to prevent them. A rational approach requires good data and analysis together with realistic practical measures aimed at minimizing high risk situations. Physicians can contribute in many ways towards better public awareness of the problem and how to solve it. PMID- 21289691 TI - Prevention of eye injuries. AB - In Canada 30,000 people are registered as blind; in one third of these, blindness might have been avoided. Prevention is the key to reducing the number of eye injuries and blind eyes. The role of the family physician in early identification of treatable conditions and in the education of patients is discussed, but responsibility for prevention belongs to all physicians. The success of prevention is seen in the great reduction in eye injuries in industry and sports since eye protectors have been commonly used. However, many dangers to the eyes are either not recognized or are not taken seriously enough. This paper discusses some of the common causes of serious eye injuries in the home, in sports and in industry. PMID- 21289692 TI - Resolving the sore throat dilemma. AB - Many physicians ignore the traditional dictum that throat culture is the only tool of value in assessing sore throat. A review of the literature supports this skepticism. Evidence indicates that clinical assessment has been underestimated and the significance of positive culture exaggerated.An approach to managing pharyngitis utilizing the combined strengths of throat culture and clinical assessment is proposed. This approach avoids needless cultures, minimizes unnecessary antibiotic use, achieves prompt clinical improvement in patients whose symptoms are most severe and reduces the risk of long term morbidity from rheumatic heart disease to negligible levels. PMID- 21289693 TI - Dependence among physicians. AB - This paper reports some of the things we have learned about doctors who misuse alcohol and drugs, and what has been accomplished over the past three years by the Project for Doctors on Chemicals, a joint program of the Donwood Institute in Toronto, the Addiction Research Foundation of Ontario, and the College of Physicians and Surgeons of Ontario. PMID- 21289694 TI - 'Innocent' neonatal inclusion conjunctivitis: parental origins and complications. AB - Family physicians must be familiar with the origins and complications of inclusion conjunctivitis caused by Chlamydia trachomatis, since this infection can lead to pneumonia or otitis media in infants. Because nongonococcal and postgonococcal urethritis in men is frequently chlamydial in origin, these men comprise a source of infection for women who eventually become mothers. These women may harbor the organism asymptomatically in their genital tracts before passing it on to their offspring during birth. Diagnosis and treatment of this infection is now recommended not only for neonates but also for the mother and her sexual partner. PMID- 21289695 TI - Acute renal failure induced by semi-synthetic penicillins. AB - Two cases of acute reversible renal failure caused by semi-synthetic penicillins (cloxicillin and ampicillin) are reported. The natural history is slow and incomplete recovery of renal function. Evidence suggests that corticosteroids shorten the recovery phase and restore renal function to normal. It is recommended that steroids should be used in treatment of this condition except where steroids are contraindicated. PMID- 21289696 TI - Caring for the dying patient at home. AB - Because of documented shortcomings and deficiencies in the provision of medical care to the terminally ill in hospitals, terminal care in the home setting presents an attractive alternate in selected instances. This article reviews one such circumstance and offers guidelines to family physicians who may hesitate to assume responsibility for patients who wish to die in the comfort of their homes. Knowledge of, and access to, community resources is essential to provision of effective care. PMID- 21289697 TI - Teaching community medicine to undergraduates: the role of student projects. AB - The community medicine primary care clerkship at the University of Manitoba integrates didactic elements, clinical placements and student projects in teaching community medicine. The clinical clerkship is undertaken in a variety of community settings and emphasizes ambulatory care. The rotation for each student is eight weeks, six of which are spent in the clinical clerkship, bracketed by two weeks of community medicine. Student research projects allow medical students to become familiar with the principles of population-based and community-oriented medicine as applied in clinical practice. Evaluation of 156 projects completed during the first two years of the program indicates that a wide range of community-based health problems were identified and a variety of methodological approaches applied. PMID- 21289698 TI - Reactions to the report of the canadian task force on the periodic health examination. PMID- 21289699 TI - Enfants, automobiles, hopitaux et gouvernements. PMID- 21289700 TI - [Not Available]. PMID- 21289701 TI - 'Real world' medicine. PMID- 21289702 TI - Prevention. PMID- 21289703 TI - Prevention. PMID- 21289704 TI - Prevention. PMID- 21289705 TI - Prevention. PMID- 21289706 TI - Asymmetrical feet. PMID- 21289707 TI - Prevention. PMID- 21289708 TI - 'Must' reading. PMID- 21289709 TI - Rational prescribing. PMID- 21289710 TI - Current indications for coronary arteriography. AB - Coronary arteriography is not necessary in all patients with angina pectoris. Angiography is indicated to define coronary anatomy in patients who have persistent angina despite full medication. It is also indicated in patients with a markedly positive stress test, unstable angina pectoris, positive stress test following myocardial infarction, variants of angina, ventricular aneurysm complications, and in the young coronary patient. Coronary arteriography may clarify the diagnosis in patients with chest pain of uncertain origin.The family physician should counsel the patient about risk factors, initiate medical therapy, and psychologically prepare the patient for potential cardiac investigations.Although coronary angiography has inherent risks, complications may occur which are a result of the natural course of the patient's coronary disease. PMID- 21289711 TI - Mitral valve prolapse or, what to ignore in cardiology. AB - The presence of an isolated midsystolic click and/or late systolic murmur in an otherwise healthy young individual is a totally benign entity and represents a normal variation of mitral valve motion and function. There exists a very small subset of patients with mitral prolapse easily identified by certain clinical characteristics, who have distinct pathologic changes in their mitral valve leaflets and supporting structures. (Can Fam Physician 1981; 27:631-634). PMID- 21289712 TI - Cardiac murmurs in childhood. AB - Innocent heart murmurs can be identified and distinguished from organic murmurs using only clinical skills. Pulmonary flow murmurs may be differentiated from those of atrial septal defect or pulmonary stenosis by the behavior of the second heart sound, parasternal vibratory murmurs from ventricular septal defect, aortic stenosis and mitral regurgitation by their length and radiation, venous hums from patent ductus arteriosus by maneuvers designed to obliterate the hum, and supraclavicular arterial murmurs from carotid artery bruit, aortic stenosis and coarctation by similar maneuvers and blood pressure recordings. The article outlines the points of differentiation in order to arrive at a firm diagnosis and obviate concern and unnecessary referrals. PMID- 21289713 TI - Pericarditis. AB - The autopsy frequency of pericarditis is two to six percent excluding uremic pericarditis and pericarditis secondary to myocardial infarction. The hospital incidence in adults is about one per 1000 admissions.(7,8)Pericarditis is easily overlooked as a cause of chest pain, particularly if the pain is atypical and not too bothersome to the patient. Consideration of pericarditis in the differential diagnosis of chest pain, careful auscultation for a pericardial friction rub and the use of ultrasound to confirm pericardial effusion will increase the frequency of diagnosis. While the prognosis in viral pericarditis is usually excellent, caution is indicated in advice and follow up because of the frequency of recurrences, the possibility of irreversible myocardial damage and the occasional development of constriction. Etiologic factors other than acute viral infection must always be considered. PMID- 21289714 TI - Refractory heart failure. AB - WHEN A PATIENT WITH CONGESTIVE HEART FAILURE IS NOT RESPONDING OR DETERIORATING WITH TREATMENT, THE FOLLOWING QUESTIONS MUST BE ASKED: 1. Are the symptoms due to heart failure or an associated condition? 2. Has maximum therapy been administered? 3. What is the cause of the heart failure and is there a condition which is amenable to specific therapy? 4. Are there associated conditions which may be responsible for the poor response to treatment? 5. Is the patient a candidate for vasodilator therapy? In spite of all efforts there are some patients who will remain with intractable heart failure, but many with so called refractory failure can be improved when the above points are carefully considered. PMID- 21289715 TI - A nurse associate in a department of family medicine: developing a role definition. AB - The activities of a nurse associated with a family practice were documented and categorized into functional activities to give a role description. Over two years, the mean distribution of her time has spent in well child care (28.6%), pre- and postnatal care (14.7%), health education and counselling (9.6%), liaison (2.6%), student education (23.7%) and practice management (20.8%). Two important conclusions are that her major role is in preventive care and health promotion, complementary to the role of the physician, and that her clientele is the receptive young expanding family and those with impending problems related to health hazards of lifestyles.The major problem is the lack of an adequate system of financial remuneration for preventive care(1) within a family medicine setting. PMID- 21289716 TI - The wisdom tooth. AB - Physicians may often wonder about the basis on which dentists advocate removal of third molars. This article outlines indications for removal and for leaving the tooth in place. It also describes postoperative experiences according to the nature of the extractions. PMID- 21289717 TI - Severe hepatic necrosis associated with methyldopa. AB - Family physicians should carefully follow their patients receiving methyldopa for liver toxicity. Methyldopa is commonly used in treating hypertension and its hepatotoxic potential is frequently overlooked. This point is illustrated in the following case report involving a 45-year-old black female. The patient had been receiving oral methyldopa for 7.5 months prior to hospitalization for control of severe hypertension. Methyldopa was discontinued on her second hospital day when her liver tests were found to be abnormal. She developed progressive liver failure and lapsed into hepatic coma. Subsequently, her liver biopsy showed severe hepatic necrosis. She slowly improved with medical management. Her liver tests returned to normal; she resumed work and at 14 months follow up her liver biopsy showed no evidence of chronic active liver disease. Monitoring for methyldopa toxicity as outlined in this article could have prevented this costly and near lethal side effect. PMID- 21289718 TI - What do family practice residents do in prevention and counselling? AB - A study was undertaken to measure what family practice residents do in prevention and counselling during routine check-ups on adults. A series of Health Monitoring and Promotion (HMP) measures were used to assess the content of the check-up. The residents were given a sheet of guidelines in an attempt to augment performance of the HMP measures. Using one-way glass, 353 patient encounters were observed. Analysis of 171 encounters before and 182 encounters after the introduction of the guidelines showed that the guidelines positively influenced the residents' behavior by increasing the number of HMP measures performed. Preventive items of a physical nature were carried out 61.2% of the time before the introduction of the guidelines and 69.7% after, with more pronounced improvement when dealing with the 18-39 age group and among men. Similar changes occurred on historical items of a preventive type, but history-taking from women was more positively influenced. Preventive counselling was carried out 20% of the time and was uninfluenced by the guidelines. There was a high level of breast and testicle examination, but a low level of teaching self-examination. Counselling on retirement, lifestyle, 'passages' and similar issues was uninfluenced by the instrument. PMID- 21289719 TI - A program of faculty development in family medicine. AB - This article describes one teacher's experience in a program of faculty development offered by the University of Western Ontario, Department of Family Medicine. Faculty development is summarized according to faculty's four roles: clinician, teacher, administrator and researcher. Emphasis is put on self-growth and development. The difficulties encountered after a sabbatical leave are briefly discussed. PMID- 21289720 TI - Professional education and the national cancer institute of Canada. PMID- 21289721 TI - [Not Available]. PMID- 21289722 TI - [Not Available]. PMID- 21289723 TI - Maternal death study. PMID- 21289724 TI - Abuse of medical skills. PMID- 21289725 TI - Toxoplasmosis in pregnancy. PMID- 21289726 TI - Vitamin a Acid. PMID- 21289727 TI - Spinal manipulation. PMID- 21289728 TI - Acid indigestion. PMID- 21289729 TI - Acupuncture for non-articular rheumatism. PMID- 21289731 TI - To see or not to see: a study of after hours telephone calls in a residency program. AB - This study examined the influence of patient, resident, and environmental variables on the management of after-hours telephone calls. Twenty-one family medicine residents participated in the study; 299 telephone calls in a one-month period at three teaching units were analyzed.A number of variables were found to influence the decision to manage patients on the phone or see them in the office, emergency room or home. Older patients were more likely to be seen at home, and pediatric problems were more likely to be managed on the phone or in the office. There was no relationship between the disposition of the call and the resident's educational level; however, married residents with children were more likely to manage patients on the phone. Measures of the resident's and patient's emotional state at beginning and end of the call were significantly related to patient management. PMID- 21289732 TI - Teaching the principles of family medicine. AB - NINE PRINCIPLES OF FAMILY MEDICINE CAN BE DESCRIBED: an open-ended commitment to patients; an understanding of the context of illness; the use of all visits for preventive purposes; the view of the practice as a population at risk; the use of a community-wide network of supports; the sharing with patients of the same habitat; the care of patients in office, home and hospital; a recognition of the subjective aspects of medicine; and an awareness of the need to manage resources. PMID- 21289733 TI - Teaching the behavioral sciences in family medicine. AB - This article addresses the need to develop behavioral science training programs in Canadian family practice residencies. Guidelines for establishing such programs are described, emphasizing teaching goals, structures, and methodologies. Faculty development and the evaluation of program effectiveness are also discussed. A current, ongoing program is presented to illustrate one approach to integrating the behavioral sciences in a family medicine centre. PMID- 21289734 TI - The family express: trouble on the line? AB - In a recent study, residents completing training in family medicine manifested a surprising degree of diversity in their interpretations of the place of 'family' in practice, had a unique way of relating to their professional role, and expressed a high degree of uncertainty about future careers. Utilizing results from earlier research on professional socialization, explanations for these findings are sought in the structure of the program and characteristics of the staff. PMID- 21289735 TI - Through the looking glass: history-taking revisited. AB - Traditional teaching of history-taking stops short of assisting the learner to evaluate the doctor-patient relationship, and incorporate this into clinical decision making. The evolution of specific programs in interviewing skills is reviewed, emphasizing the content and process of the medical interview and newer teaching methods being used in these programs. Improved methods of evaluating the effectiveness of these programs, including increased patient and physician satisfaction, will form part of the future direction of residency programs in family medicine. (Can Fam Physician 1981; 27:827-830). PMID- 21289736 TI - Learning continuity of care. AB - CONTINUITY OF CARE HAS FOUR DIMENSIONS: chronological, geographical, interdisciplinary and interpersonal. This article reviews ways in which these dimensions are currently being taught, and summarizes strategies by which teaching can be made more effective. (Can Fam Physician 1981; 27:831-833). PMID- 21289737 TI - Teaching analytical skills. AB - The maintenance of individual practice quality requires that the family physician continually evaluate and improve his performance, selectively using new information. This means that the physician must possess certain basic analytical abilities. The minimum skills necessary for critical appraisal are outlined in the CFPC's educational objectives. These objectives are used as a background to discuss curriculum content and teaching methods. Despite obstacles, there is a growing stimulus to expand teaching and learning in this area. Faculty development may be an essential first step. PMID- 21289739 TI - Clonorchis sinensis infestation: a case report. AB - A young female refugee from Indochina suffered recurring episodes of upper abdominal pain for several months before developing acute cholangitis and pancreatitis, associated with the presence of ova of Clonorchis sinensis in her stool. Microscopy of her stools was negative for this parasite on several previous occasions. The attention of all family physicians caring for 'boat people' is drawn to the possibility of disease developing after arrival in Canada, despite screening on arrival. PMID- 21289738 TI - Screening females for gonorrhea. AB - Routine culturing for gonorrhea in low incidence populations is not indicated, as shown by examples from the literature and the authors' own practice. An alternate approach to detection of gonorrhea is recommended which involves assessment of risk based on routine gynecologic functional enquiry. PMID- 21289740 TI - The role of family medicine in the health science centre. AB - The evolution of training in family medicine has passed through several controversial phases to its current position within academic medicine. Many controversies still exist; this article defines them in the areas of education, service and research, gives some reasons why they exist, and offers conclusions on the benefits of having a family practice unit in a health science centre. PMID- 21289742 TI - [Not Available]. PMID- 21289741 TI - Obstetrics from the primary care perspective. PMID- 21289743 TI - Measles. PMID- 21289745 TI - Preventing children's accidents. PMID- 21289744 TI - Freebies. PMID- 21289746 TI - Hypothermia in hamilton: searching for a syndrome. AB - The purpose of this study was to examine the incidence of accidental hypothermia in people 65 years and older who were residing at home or were seen in emergency rooms of the four Hamilton hospitals between January 1 and March 31, 1980. For the purpose of this study, accidental hypothermia was defined as a rectal temperature or a core body temperature below 35 degrees C. Persons with temperatures below 35.5 degrees C were considered "at risk" of becoming hypothermic. Special low reading thermometers were supplied to professionals taking part in this study. No cases at risk of, or having, hypothermia were found at home. Nine people were found to be at risk and seven were found to be hypothermic in the emergency room group. None of these manifested the classical signs of hypothermia. PMID- 21289747 TI - Infant feeding and illness on an Indian reservation. AB - In 1978, the prevalence of breast-feeding in Caughnawaga was 45%. This study examined some of the differences between mothers who breast-fed and those who bottle-fed, and documented infectious illnesses in the first year of life. Bottle fed babies had five times more episodes of infectious illnesses in their first year of life than those babies exclusively breast-fed for three months. PMID- 21289748 TI - Outcome of high-risk pregnancies in a community health centre. AB - The REACH community health centre in the east end of Vancouver serves a socially disadvantaged community of diverse ethnic origins. Nurse-practitioner and family physician teams provide antenatal care with appropriate support from nutritionist and clinical pharmacist. Well-baby care and developmental assessment are primarily carried out by the nurse-practitioners. Most infants are born at a family-centred hospital obstetrical unit. We reviewed 85 high risk pregnancies receiving prenatal care at REACH Centre and delivering between January 1976 January 1978. Obstetric outcome was comparable to other reports, in spite of a high-risk population. Anesthetic and analgesic use were lower than other reports. Fifty-two of the children were assessed by physical examination and Denver Developmental Screening Testing between 12-30 months of age. No previously unrecognized abnormalities were discovered. Fifty-one of them were functioning appropriately for age, and one child demonstrated marked speech delay. Immunization status was complete in 48/52 children (92%). This study suggests that high-risk pregnancies can be managed effectively in a family practice setting. PMID- 21289749 TI - Exercise and pregnancy. AB - Evidence is beginning to appear that complications of pregnancy are fewer in the athlete than the non-athlete. Studies show that after childbirth, sports performance improves in a majority of women. A few activities could prove hazardous to the woman and her fetus. In view of the increased participation of women in sports and recreation, it is imperative that the benefits as well as the dangers are considered and discussed as part of prenatal care. PMID- 21289750 TI - Fathers and childbearing: new dimensions. AB - The father has a new emerging role in pregnancy and childbirth. If he becomes an active, involved participant in pregnancy, labor, and birth, he will likely become more involved in fathering his child and will take on a more nurturing, child care role. Engrossment or father-infant interaction immediately postpartum has implications for the future father-child relationship. The paper discusses such implications and presents suggestions for enhancing the father's involvement in pregnancy and childbirth. PMID- 21289751 TI - Having a baby today: how changing attitudes challenge the doctor. AB - Although having a baby today is safer, more comfortable and more controlled than ever before, changes in society's expectations have resulted in considerable dissatisfaction for both childbearing women and physicians. The apparent conflict can be resolved by open minded, clear and precise communication, and by our recognition of a woman's right to choose what we may not think is right for her. PMID- 21289752 TI - Prenatal care for the 80s. AB - Despite improvements in the last decade, Canada's perinatal mortality rate is still higher than those of many other developed countries. Consumer expectations have increased not only for a good outcome, but also a more personal and humane process. The physician has to make a decision to be involved in prenatal care. Appropriate steps are suggested for initial assessment, genetic evaluation, and ongoing prenatal care. PMID- 21289753 TI - Pregnancy and the working mother. AB - Many women of childbearing age are in the workforce. Pregnant women wishing to continue working often seek the advice of their physician. The advice should be based on an understanding of the physiological changes of pregnancy and current information about industrial hazards. A thorough review and periodic reassessment of the woman's job, including exposure to physical or chemical hazards, is necessary. Certain pregnancy complications may require cessation of work. Collaboration with other health professionals may prove useful in identifying the worker's special needs in order to ensure safety for mother and child. PMID- 21289754 TI - Alternative birthing. AB - This paper deals with the concept of alternative birthing. The reasons for home births versus hospital births are discussed. A general model of an alternative birthing centre (ABC) is described. Some concepts common to alternative birthing are discussed, followed by a discussion of problems involved in initiating an alternative birthing centre. The article concludes that hospital-based alternative birthing centres are an ideal vehicle for modern healthy obstetrics. PMID- 21289755 TI - The effects of medication during pregnancy. AB - Each pregnant woman takes an average of four or five different drugs during her pregnancy and an undetermined number of other agents. What role drugs may play in the overall problem of fetal wastage is difficult to estimate; this concern raises the question of a proper risk/benefit ratio for both mother and fetus in administering any drug to the pregnant woman. Maternal indications for drug administration may outweigh the fetal risk. PMID- 21289756 TI - Breast-feeding in French Canadian Women. AB - Over half the women studied at this centre who attempted breast-feeding had switched to bottle-feeding by six weeks postpartum. More educated or wealthy women fared no better than their less favored counterparts. Only those who had been breast-fed by their mothers were more likely to continue. Poor information and a disapproval of breast-feeding were reported by the breast-feeding women. Self-help groups should be promoted to give the support and information needed for mothers to continue breast-feeding. PMID- 21289757 TI - The electronic fetal monitor: should every mother have one? AB - In little more than a decade, the use of electronic fetal monitoring has become standard obstetric practice. Increasingly it is being suggested that all labors should be monitored electronically, and that such universal monitoring will result in improved neonatal outcome. This paper reviews the evidence in what has been termed "the fetal monitoring debate",(1) concluding that there is no indication for monitoring low risk labors, and that in fact too many-rather than too few-labors are being monitored. PMID- 21289758 TI - Family practice history: bloodletting. AB - For 2000 years bloodletting was an accepted form of treatment. During this time, the indications and philosophical basis for lancing, cupping, and the application of leeches evolved in conjunction with advances in anatomy and physiology. In the late 19th century discoveries by tissue pathologists using new diagnostic techniques undermined earlier dogma and bloodletting quickly became a highly suspect form of treatment. PMID- 21289759 TI - Respect for the disabled. PMID- 21289760 TI - Wheelchairs of the mind. PMID- 21289761 TI - [Not Available]. PMID- 21289762 TI - [Not Available]. PMID- 21289763 TI - Birth control editorial sparks controversy. PMID- 21289764 TI - Birth control editorial sparks controversy. PMID- 21289765 TI - Influence of physician gender on amitriptyline prescribing. AB - A study was conducted between January 15, 1978 and January 15, 1979 at the Ottawa Civic Hospital Family Medicine Centre, to determine if there were differences in patterns of prescribing amitriptyline to depressed patients because of the patients' and physicians' gender.Male physicians prescribed amitriptyline less frequently to males than females once depression was diagnosed. No such difference was found in female physician prescribing of amitriptyline. PMID- 21289766 TI - Physical dependence on diazepam. AB - This article describes several cases of withdrawal symptoms following diazepam therapy which suggest physical dependence following usual therapeutic dosage. PMID- 21289767 TI - Understanding depression. AB - To understand the effects of depression on a patient's life, the physician must be aware how depression manifests itself. Somatic tension, strategies to relieve discomfort and social withdrawal must be recognized as symptoms of depression. An awareness of life situations which can give rise to these symptoms, as well as the effect of the physician's own reactions to the patient's depression, are helpful. PMID- 21289769 TI - Clinical diagnosis of anxiety. AB - Although anxiety constitutes the chief symptom of neuroses and functional psychoses, there is little agreement on its definition. This article reviews such definitions, the epidemiology of anxiety, and distinguishes between anxiety, depression and stress. PMID- 21289768 TI - Psychopharmacological management of post-myocardial depression and anxiety. AB - Anxiety and depression are frequently associated with myocardial infarction and may play an important role in subsequent morbidity and mortality. The few clinical trials assessing the benefits of psychopharmacogical or non-drug psychological interventions for such patients have been encouraging, but hardly conclusive. Rational management is possible only with adequate delineation of the patients at high risk, the disorders they suffer, and the properties of therapeutic agents employed. PMID- 21289770 TI - Principles of antidepressant use. AB - Depression is a disabling illness which tends to be undiagnosed and undertreated. Antidepressants are a specific treatment for this condition, but their effective use requires considerable judgment, knowledge and skill. Many drugs are available, although with a few exceptions there are no substantial differences in their overall efficacy in equivalent doses. Shades of clinical judgment dictate the use of one preparation over the other. In any case, physicians should become thoroughly familiar with several of these agents. A fair trial of treatment requires therapeutic doses for at least three to four weeks. These drugs have a low safety margin and elderly patients are especially at risk for the cardiac, anticholinergic and CNS side effects. Duration of treatment is decided empirically. The successful chemotherapy of depression is one of the most gratifying experiences in medicine. PMID- 21289772 TI - Diagnosis on a plate: an unusual case. AB - This case study illustrates how important it is for physicians to be good detectives, to follow the clues and to recognize the culprit when it is presented on a plate. The patient in question endured many costly investigations including hospitalization, only to make the diagnosis herself at a later date. PMID- 21289771 TI - The Overutilization of X-rays. AB - Within 20 years of Roentgen's discovery of X-rays in 1895, it became apparent that large doses of radiation damaged human tissue.(1) Yet the medical profession continues to contribute to the overutilization of X-rays, occasionally spending health care dollars to subject our patients to a health risk. This paper discusses the evidence to support the claim that X-rays are overutilized, and offers recommendations to rectify the situation. PMID- 21289773 TI - Current clinical findings on monosodium glutamate. AB - Monosodium glutamate (MSG) is a common and widely used food additive which has been passed as GRAS (generally recognized as safe) by the American Food and Drug Administration. However, it may have a significant adverse effect on certain individuals; the physician must be able to recognize the symptoms of MSG sensitivity, otherwise known as "Chinese Restaurant Syndrome". This article reviews current findings on MSG. PMID- 21289774 TI - Ten years as a family medicine teacher. AB - This article summarizes impressions after ten years of fulltime teaching in a department of family medicine. Both positive and negative experiences are assessed, including views on teaching, medical school admissions, and the acceptance of training in family medicine. Concern is expressed for the longterm future of family medicine residency programs. PMID- 21289775 TI - What Are the Most Effective Forms of CME? PMID- 21289776 TI - Terry Fox: Heroes Aren't Saints. PMID- 21289777 TI - Facing the psychological dimension of diabetes. PMID- 21289778 TI - [Not Available]. PMID- 21289779 TI - [Not Available]. PMID- 21289781 TI - Prevention. PMID- 21289780 TI - CFPC income survey. PMID- 21289782 TI - New Sri Lanka medical college. PMID- 21289783 TI - Aspirin: a trademark. PMID- 21289784 TI - Screening females for gonorrhea. PMID- 21289785 TI - When the patient knows best. PMID- 21289786 TI - Monitoring adverse drug reactions: a preliminary study. AB - The feasibility of family physicians functioning as monitors of adverse drug reactions (ADR) was examined over one month in ten practices. This was done as a preliminary trial, before attempting to use the 200 family physicians of the National Reporting System of the College of Family Physicians of Canada to monitor ADRs on a national basis. Both of these trials were designed to examine the feasibility of family physicians acting as prospective monitors of ADRs in newly marketed drugs and to identify a drug group suitable for monitoring. This study examined the detection of ADRs, prescribing and practice profiles. No firm conclusion could be reached as to the value of family doctors monitoring ADRs. This study supports the evidence that older patients receive more drugs and are at even greater risk of an ADR. Antibiotics, cardiovascular, anti-inflammatory or antidepressant drugs are suggested as those most suitable for prospective monitoring in a family practice setting. PMID- 21289787 TI - Helping diabetic patients learn. AB - Family physicians can be highly effective in helping diabetic patients learn about their disease. Educational principles should be followed. It is essential to motivate the patient, the family doctor, the nurse and the receptionist to be knowledgeable and responsible about diabetes. Individualized, Socratic probing to find out what has been learned and to provide feedback should characterize the educational dialogue. Learning resources, particularly pamphlets and books, should be provided for patients to meet individual educational needs. Every family practice should have an effective appointment and follow up system. Newer knowledge about nutrition and home blood sugar monitoring makes education of diabetic patients even more worth while. PMID- 21289788 TI - Diabetes update. AB - This paper summarizes the new classification of diabetes mellitus (and other categories of glucose intolerance) and presents some clinically important aspects of the new insulins. The new classification promises to bring to the field considerable uniformity, previously lacking. The five clinical classes are: Type I (insulin-dependent diabetes mellitus, IDDM), Type II (non-insulin-dependent, NIDDM), "other types", gestational diabetes (GDM) and impaired glucose tolerance (IGT). The two statistical risk classes are: previous abnormality of glucose tolerance (Prev AGT) and potential abnormality of glucose tolerance (Pot AGT). These are mutually exclusive classes. Criteria recommended for use by clinicians and researchers are presented in detail, as well as information on the oral glucose test and normal glucose tolerance. Particular attention is drawn to the differences in glucose metabolism (tolerance) characteristics in non-pregnant adults, children and pregnant females. The new insulins are so called because of increased purity achieved by new purification methods. They are not new formulations or types of insulin. Contamination of insulin preparations by other hormones or compounds (e.g. glucagon, pro-insulin, pancreatic polypeptide) is now at a very low level. PMID- 21289789 TI - Quo vadis family medicine? AB - Originally presented as the first George McQuitty Memorial Lecture in Calgary, this article reviews the progress of family medicine since the inception of the first residency training programs in 1966, and speculates on its future. PMID- 21289790 TI - A Family Physician's Approach to Acne. AB - Because of the potential for permanent physical and psychological sequelae, acne vulgaris should be regarded as a true disease-not the "normal" physiologic response one might infer from its near universal prevalence in adolescence. Effective therapy reduces pilosebaceous unit obstruction, minimizes secondary inflammation, and lessens the chance of significant scarring. This article reviews current therapeutic modalities, and suggests a sequence for implementation of specific agents. PMID- 21289791 TI - Symptoms and stress: how we can be misled. AB - The stressful life which some patients live may lead us astray in attempting to diagnose a medical condition. A case history is presented of such a patient, who placed so much emphasis on his stressful lifestyle that several physicians responsible for his care missed the diagnosis. PMID- 21289792 TI - Parathyroid hyperplasia and endocrine malignancy: the fourth episode. AB - A case of parathyroid hyperplasia was presented in this journal in 1978, at which time I noted that continuous monitoring of the patient would be necessary. This article is a follow up report of the same case, showing how decisions affecting a patient's wellbeing must be based on many factors besides the condition. PMID- 21289793 TI - Some principles of evaluation for family medicine teachers. AB - The purpose of this paper is to show that evaluation is not an isolated facet of the educational process; on the contrary, it is part of a cyclical system. Evaluation is something from which many teachers and students shy away needlessly. This article outlines some positive steps towards making evaluation a sharing of information between teacher and learner. PMID- 21289794 TI - Should family physicians do refractions? PMID- 21289795 TI - [Not Available]. PMID- 21289796 TI - Where is the 'family' in family medicine? PMID- 21289797 TI - Exercise and constipation. PMID- 21289798 TI - Foreign bodies in the eyes, ears, nose and throat. AB - This article outlines the presenting problems of foreign bodies in the eyes, ears, nose and throat, describing diagnostic signs associated with each common type of foreign body presentation and the methods involved in removal. Equipment and supplies for the average emergency room are listed according to location of the foreign body. PMID- 21289799 TI - Diagnostic du vertige. AB - In cases of vertigo, the history is the most important diagnostic element. Questioning must be directed towards obtaining the most pertinent and precise answers possible. A classification based on the duration of vertigo, together with the physiopathology, is suggested. PMID- 21289800 TI - [Not Available]. AB - The Speech and Hearing Department of the University of Montreal, in conjunction with 'l'Unite de medecine familiale de Verdun' set up a pilot project grouping family doctors, audiologists and speech pathologists. Information was exchanged on speech and language problems in children, stuttering, voice disorders, aphasia and hearing problems in children and adults. We emphasized the importance of early detection of these problems, of adequate information to the patient and his family and referral to the speech pathologist or to the audiologist. The results of this experience showed the importance of close collaboration between family doctors and communication specialists. PMID- 21289801 TI - Screening for hearing loss in children. AB - Hearing loss in infants has severe, lifelong consequences. The critical period for speech and language development is from birth to age two, so every effort must be made to diagnose hearing problems early. Several simple screening and testing procedures can be carried out in a normal office visit. The use of a 'high risk registry' is advocated for newborns. Parents are usually the first to suspect a problem. Believe the parents... get the child tested. PMID- 21289802 TI - Diagnosis of a mass in the neck. AB - A mass in the neck can occur because of developmental factors, lymphadenopathy, salivary gland disease, or neuromas. It is important to examine areas other than the neck in assessing these masses, most of which can be diagnosed by a good history/physical examination and simple laboratory tests, described here. PMID- 21289803 TI - Otitis media in children. AB - Acute otitis media is one of the commonest diseases of childhood. Most cases are due to Streptococcus pneumoniae and can be treated safely with penicillin. However, Hemophilus influenzae is also common, particularly under the age of five. In many areas it is increasingly resistant to ampicillin and should be treated with a trimethoprim-sulfamethoxazole preparation (Bactrim, Septra). The new agent, cefaclor (Ceclor) may prove to be a valid alternative. In the first few months of life, special problems include difficulty in recognition, a greater frequency of atypical organisms including Escherichia coli, and associated serious systemic illnesses. Recurrent suppurative otitis media (three or more episodes of acute otitis media in a six month period) is an indication for prophylactic antimicrobial therapy.The most common complication of acute otitis media is persistence of effusion. Risk factors include resistance of the organism(s) to the initial antimicrobial agent and the presence of coexisting allergy. Tympanostomy tubes and adenoidectomy should be considered in selected cases. A key to successful treatment is careful follow up after each episode to assure the restoration of normal hearing. PMID- 21289804 TI - The child with delayed language: assessment and management. AB - Speech and language disorders are the most common developmental problems among preschool children. Early detection and remediation of delayed language development are important in helping the child establish appropriate social behavior and acquire additional information about the world through the use of language.The major reasons for delayed language acquisition are mixed developmental delay, hearing loss, psychosocial factors, behavioral disturbance, specific language disorder, and major physical handicap. Assessment and management are outlined here by case presentations and discussions. The family physician can play a key role as part of a team of professionals concerned with language delay. (Can Fam Physician 1981; 27:1405-1412). PMID- 21289805 TI - Pre-hospital emergency care and the family physician. AB - Advances in resuscitation and arrhythmia control that are now readily available in most hospitals have made little impact on community mortality from acute myocardial infarction and other causes of sudden unexpected death. Most deaths occur before the victim can obtain conventional medical aid, and are due to potentially correctable lethal arrhythmias. Pre-hospital emergency care systems provide the advantages of modern methods of arrhythmia control and resuscitation directly and rapidly to the victim in the community. Advanced resuscitation is medical practice, so these systems require medical supervision and control. Potential roles for family physicians in organizing pre-hospital care are described. PMID- 21289806 TI - Status epilepticus or what? AB - This case report describes a man who had two grand mal seizures, each one followed by a lengthy period of unconsciousness during which he was extremely restless, with violent uncoordinated movements. This was probably a form of status epilepticus conforming to a diagnosis of grand mal seizure, followed by a complex partial seizure, but was similar to what has been described as post epileptic mania or delirium. A brief historical perspective is included together with a resume of the differential diagnosis of adult onset epilepsy. PMID- 21289807 TI - Process rather than product in the patient-physician relationship. PMID- 21289809 TI - [Not Available]. PMID- 21289808 TI - Whither the CMA? PMID- 21289810 TI - Diazepam. PMID- 21289811 TI - 1980 cut-off date. PMID- 21289812 TI - Torture. PMID- 21289813 TI - Drugs vs. diet. PMID- 21289814 TI - Anxiety. PMID- 21289815 TI - Dementia and vitamin B(12) deficiency. PMID- 21289816 TI - Hong Kong directory. PMID- 21289817 TI - Hoarding in the aged. AB - Hoarding has been observed in residents of a geriatric centre. The incidence varies from 11-13% on the standard and chronic nursing care floors to 53% on the special care floors.The activity was largely unobtrusive, but in some instances constituted an irritant or offensive activity towards fellow residents and others. Consequences can be serious when potentially harmful agents such as chemicals are inadvertently acquired. Hoarding of medication can likewise cause complications. Loss appears to be an important factor in the psychodynamics of hoarding. Insights into this behavior trait should bring tolerance of its presence and preventive action directed against the associated hazards. PMID- 21289818 TI - Dealing with confusion in the elderly. AB - Elderly patients with established brain failure present the family doctor with problems of longterm management for which there are, at best, limited pharmacologic solutions. An organized plan of management developed jointly with the significant other(s) will help achieve treatment objectives. By assessing the patient's physical and mental function, it is possible to work out appropriate changes in the living environment and behavioral interventions which will help retard deterioration, maintain and conserve function and reduce the confusion and distress felt by all parties. Though initially it may be more time consuming for the doctor to take on this leadership and coordination, the recurrent and frustrating crises over the long haul may well be reduced. Certainly patient care will be improved. PMID- 21289819 TI - Pressure sores: an age-old problem of the aged. AB - The most frequently cited and/or best-designed studies of pressure sore prevention and treatment in the last 25 years are almost all uncontrolled. These studies are critically reviewed. An appropriate methodology for evaluating the effectiveness of decubitus ulcer management, based on data and experience, is outlined. A suggested treatment protocol is described. PMID- 21289820 TI - Hypertension in the elderly. AB - The elderly differ biologically from young and middle-aged adults. We cannot assume that hypertension has the same significance in the elderly or that treatment outcomes will be similar. Evidence concerning the risks of hypertension and benefits of antihypertensive therapy in the elderly is reviewed and the implications for patient management are outlined. There are hazards to antihypertensive therapy; an approach to treatment is presented. PMID- 21289821 TI - Placement of the elderly. AB - Placement of the elderly involves the person, family, treating professionals and those professionals who will provide future care. It must be based on accurate assessment of the person's abilities, interests and care needs. It requires knowledge of possible community support services and residential care facilities. The person must recognize, accept and adjust to the care needs and as far as possible, be allowed the final decision on placement. This requires that he or she be fully informed and given time to consider. There is often competition for resources; a system is needed to ensure identification of the optimal resource for each individual, equitable access to resources according to a recognized priority rating, and a certainty that every person will find a place appropriate to his need. PMID- 21289822 TI - Rehabilitation of the elderly stroke patient. AB - AGE ALONE DOES NOT AFFECT THE OUTCOME OF REHABILITATION: approximately 75% of stroke patients are 65 years or over, yet 95% of these patients can be helped. Rehabilitation involves physiologic care, specific therapies, cognitive retraining, family and patient education, plus support and follow up. The process should be started early, pursued aggressively and monitored by follow-up visits for an indefinite period. PMID- 21289823 TI - Depressive illness in old age. AB - Depression in the elderly is increasingly common, resulting in significant morbidity and mortality. Elderly patients may present with symptoms of hypochondriasis or dementia, thus masking depression and making diagnosis difficult. Treatment consists of many modalities, including alleviation of precipitating factors (such as physical illness or medications), the use of tricyclic antidepressants, supportive psychotherapy and utilization of community support systems. PMID- 21289824 TI - Arterial blood gases: a clinical review for family physicians. AB - Armed with just a few concepts and an arterial blood gas report, the family physician should be able to discuss the patient's acid-base balance and oxygenation in relation to his ventilation. Observed deficiencies can then be grouped into those caused by defective ventilation, gas exchange pathology in the lungs, and metabolic factors, thus facilitating more effective therapy.Example problems are provided for self-assessment. Proposed answers are discussed, allowing for differences in altitude. PMID- 21289825 TI - The management of neuroleptic-induced CNS effects. AB - Basal ganglia side effects caused by the neuroleptic drugs include the acute extrapyramidal syndromes (dystonias, akathisia and parkinsonism) and tardive dyskinesia. These may be ignored, misdiagnosed or mistreated by the patient or physician. Because the neuroleptics are effective in the treatment and secondary prevention of serious psychiatric disorders such as schizophrenia, it is important that neurological side effects be anticipated and appropriately managed. This increases patient compliance and enhances the therapeutic relationship. Patients should be examined frequently and systematically for basal ganglia side effects. (Can Fam Physician 1981; 27:1615-1624). PMID- 21289826 TI - Generalism: the discipline of family medicine. AB - The term 'discipline', as applied to family medicine, is widely used, yet poorly understood. The dictionary definitions of discipline as "a branch of knowledge or learning; training that develops self-control, character, or orderliness and efficiency" are related in this article to the personal discipline of family physicians. This discipline requires a commitment to whole person medicine, learning and growth; it is both efficient and humane. PMID- 21289827 TI - 'Just a GP' Corresponds With the College's President. PMID- 21289829 TI - [Not Available]. PMID- 21289828 TI - [Not Available]. PMID- 21289830 TI - Certification overdefended? PMID- 21289831 TI - More on diazepam. PMID- 21289832 TI - Breech delivery: a 12-year survey in a family practice. AB - The obstetric and perinatal records of 156 breech deliveries over 12 years in a family practice were analyzed and mortality and morbidity statistics extracted. There were 90 singleton, mature babies, without congenital abnormality, delivered vaginally. Of these, 28 babies were located, matched with a control group, physically examined, and given developmental assessment, IQ and psychological testing. There were no differences between the groups. PMID- 21289833 TI - Normal and abnormal behavior in early childhood. AB - Evaluation of normal and abnormal behavior in the period to three years of age involves many variables. Parental attitudes, determined by many factors such as previous childrearing experience, the bonding process, parental psychological status and parental temperament, often influence the labeling of behavior as normal or abnormal. This article describes the forms of crying, sleep and wakefulness, and affective responses from infancy to three years of age. PMID- 21289834 TI - Breaking away: adolescent behavior in context. AB - Studies of adolescence in the family context suggest that rebellion is more the exception than the rule. The transition from childhood to adulthood includes the resolution of the tasks of sexual, educational, and work identity, as well as gradual emancipation from parental control. Serious behavioral problems of the teenager reflect failure in these tasks and/or breakdown of family values. Management includes respect, not necessarily acceptance, for the adolescent and his family's values, the democratic setting of limits, and encouragement of parental harmony. PMID- 21289835 TI - In the family way: transition to parenthood. AB - The birth of the first child, awaited eagerly or anxiously, is a normal life event bringing its own set of stresses and strains, which couples do not often anticipate. The family doctor can use the opportunity afforded by prenatal and postnatal visits to do some preventive medicine and assist the new family through this transition. The family physician needs to be aware of the stresses of parenthood on him or herself. Family medicine training programs should adapt to support residents at the time they become new parents. PMID- 21289836 TI - The reconstituted family. AB - The reconstituted or step-family is becoming more prevalent. The physician who cares for families should be acquainted with the different aspects of such family structure and family functioning. This will enable professionals to better understand and assist their patients, by anticipating the different stresses related to the new family formation, and supporting their adaptation. PMID- 21289837 TI - Preparation for death. AB - Preparation for death is a physical, psychosocial and spiritual process needing the active participation of both patient and physician. Physicians' denial of death leads to unrelieved symptoms, inappropriate treatment, and poor communication in the care of the terminally ill. This paper discusses strategies to minimize the effect of denial describing a goal-setting approach to terminal care and the use of quality of life indices. Several principles are presented on how to tell bad news to patients. PMID- 21289838 TI - The role of family physicians in 'empty nest' transitions. AB - This article discusses changes which occur during a patient's adjustment to the post-parental period. The 'empty nest', while marked by turmoil during the transition period, does not constitute a crisis nor produce an enduring maladjustment. Rather, for the majority, it is a positive experience. The family physician's role in education and intervention, including a counselling role, are described. Two brief case histories are presented to illustrate the interaction between empty nest issues, individual psychopathology and relationship problems. PMID- 21289839 TI - Teaching family theory and family counselling in canadian medical schools. AB - A survey of Canada's medical schools and family practice residencies, conducted in 1979-80 to determine the extent and quality of teaching in family assessment and counselling, showed that many programs are not accomplishing their objectives in this area. Recommendations are made on the basis of the information collected. PMID- 21289840 TI - Canadian family physician: a new year, a new direction. PMID- 21289841 TI - [Not Available]. PMID- 21289842 TI - [Not Available]. PMID- 21289844 TI - Not 'Just a GP'-A Respected Practitioner. PMID- 21289843 TI - Just Another GP Writes to the College. PMID- 21289845 TI - Opportunities in the stock market. PMID- 21289846 TI - Utilization of ontario health care services by southeast asian refugees. AB - Despite claims that southeast Asian refugees might swamp the health care system, a sample of 135 refugee patients in the Kingston, ON., area showed no significant difference in utilization rates from a control group-after the first six months. Before that time, refugees' utilization rates were significantly higher. During the first six months the commonest diagnosis for refugees was parasitic disease; for controls, upper respiratory infection. After that time, refugees' illness patterns matched those of controls. These findings suggest that sudden free access to western medical care does not establish a longterm pattern of high utilization. PMID- 21289847 TI - Epidemiology of tuberculosis in remote native communities. AB - The incidence and mortality rates of tuberculosis among Indians living in the Sioux Lookout Zone in northwestern Ontario have declined over the past two decades. This 70-case series within the period 1975-1979 documents age-sex distribution, community distribution, sites of disease, signs and symptoms, bacteriologic status, X-ray findings, drug resistance and relapse rates, and effect of vaccination and chemoprophylaxis. Such information can also be used to evaluate the health care delivery system in general and the TB control program in particular. There are several policy implications in case-finding, treatment and prevention, especially in a setting such as the Sioux Lookout Zone, where both preventive and curative services are organized and delivered by the same agency. PMID- 21289848 TI - Prostaglandin inhibitors: rational therapy for dysmenorrhea. AB - Dysmenorrhea affects at least 50% of women at some time in their lives. Painful contractions of the uterine muscle (similar to labor pains) are triggered by increased endometrial synthesis of prostaglandins, which appear in elevated amounts in the plasma and menstrual fluid of women with dysmenorrhea. Non steroidal anti-inflammatory drugs, which have been used for years in arthritis, are effective prostaglandin inhibitors. Taken by mouth at the onset of menstruation, they can relieve dysmenorrhea in the majority of cases. This is a major advantage for women in whom oral contraceptives are not indicated. PMID- 21289849 TI - Drug treatment of cardiac failure. AB - Treatment of cardiac failure should first be aimed at reversing or ameliorating the underlying pathological processes. This review highlights the common problems and pitfalls in the use of digoxin, diuretics and vasodilators in patients with cardiac failure. PMID- 21289850 TI - Abnormal involuntary movements: side-effect of neuroleptic drugs. AB - Neuroleptics are antipsychotic drugs. In addition to their antipsychotic properties, many physicians use them as anti-anxiety or antiemetics. Indeed, most patients referred to psychiatrists would have been given one, or a combination, of these drugs. Physicians should therefore be aware of their side-effects. Abnormal involuntary movements, now recognized as side-effects of neuroleptics, are broadly classified as acute early occurring movement disorders and late appearing movement disorders. The clinical description, early recognition, pathophysiology, prevention and treatment of these side-effects are reviewed and judicious use of these drugs advocated. PMID- 21289851 TI - [Not Available]. AB - OUR EXPERIENCE HAS SHOWN THAT DETERMINING AN EFFECTIVE DAILY DOSE OF THEOPHYLLINE MEANS CONSIDERING SUCH FACTORS AS: age, patient's ideal weight, available pharmaceutical format, cost, frequency of administration, nicotine intake, coffee intake, diet and lifestyle. Cardiac and/or renal insufficiency and hepatic disorder are also factors affecting treatment with theophylline. We have therefore created a guide to daily dosage, taking all these factors into account. This helps both prescriber and pharmacist on instituting or evaluating theophylline treatment in an otherwise normal individual. This article presents the guide and explains the adjustment of dose in adult smokers, those with cardiac or renal insufficiency, and those with hepatic disorders. PMID- 21289852 TI - Well child care in family medicine: part 1: physical examination, developmental assessment and evaluation of parenting skills. AB - The periodic health examination of the well child offers an opportunity for examining the child, immunizing the child against infectious disease, counselling the parents about adequate nutrition and evaluating parenting skills. Part 1 of this article outlines the criteria used in physical examination and developmental assessment, and counselling on parenting. Part 2 will deal with immunization and counselling on nutrition. PMID- 21289853 TI - The content of family practice: do we need more studies? AB - Having an accurate job description of family physicians is important to a number of audiences. There is a tendency to produce another content profile of family practice in response to every specific request for an accurate job description, rather than examining the existing profiles. We analyzed the amount of similarity and therefore redundancy in currently available profiles of family practice. Our findings indicate remarkable consistency across profile studies. We conclude that there is no need to continue producing profiles of family practice unless something significant occurs in the medical environment to suggest there might be a change in the profile. PMID- 21289854 TI - Presentation and management of bipolar affective disorders in primary care. AB - The author reviews four case summaries of patients presenting to her family practice within a 12 month period. Each patient presented unique features, which on careful history review, fit the pattern of bipolar affective disorder, the features of which are described. Management of these patients includes mandatory psychiatric consultation and lithium for treatment of acute mania, and prophylaxis of mania and depression. Guidelines for lithium therapy are presented.The family physician is in an ideal position to detect bipolar illness and to manage patients once stabilized on longterm lithium therapy. PMID- 21289856 TI - In silico genotyping of the maize nested association mapping population. AB - Nested Association Mapping (NAM) has been proposed as a means to combine the power of linkage mapping with the resolution of association mapping. It is enabled through sequencing or array genotyping of parental inbred lines while using low-cost, low-density genotyping technologies for their segregating progenies. For purposes of data analyses of NAM populations, parental genotypes at a large number of Single Nucleotide Polymorphic (SNP) loci need to be projected to their segregating progeny. Herein we demonstrate how approximately 0.5 million SNPs that have been genotyped in 26 parental lines of the publicly available maize NAM population can be projected onto their segregating progeny using only 1,106 SNP loci that have been genotyped in both the parents and their 5,000 progeny. The challenge is to estimate both the genotype and genetic location of the parental SNP genotypes in segregating progeny. Both challenges were met by estimating their expected genotypic values conditional on observed flanking markers through the use of both physical and linkage maps. About 90%, of 500,000 genotyped SNPs from the maize HapMap project, were assigned linkage map positions using linear interpolation between the maize Accessioned Gold Path (AGP) and NAM linkage maps. Of these, almost 70% provided high probability estimates of genotypes in almost 5,000 recombinant inbred lines. PMID- 21289857 TI - Pseudarthrosis after disruption of an incomplete luno-triquetral coalition: a case report. AB - Whilst bony luno-triquetral coalitions are known to be asymptomatic, fibro cartilage unions can cause ulnar-sided wrist pain. The purpose is to present the rare case of painful pseudarthrosis after traumatic disruption of an incomplete luno-triquetral coalition. Recommendations for proper diagnosis and treatment options will be discussed. The case of a 35-year-old male patient is reported, where disruption of a fibro-cartilaginous luno-triquetral coalition resulted in a painful pseudarthrosis. Luno-triquetral fusion with a corticocancellous wedge from the iliac crest and a Herbert screw was undertaken. Using this method pain was relieved but resulted in minor loss of range of motion. We recommend luno triquetral fusion in the rare case of fracture or pseudarthrosis of a luno triquetral coalition. The use of a corticocancellous wedge should be considered depending on gap formation after resection of the pseudarthrosis. PMID- 21289858 TI - The spectrum of use of rituximab in chronic lymphocytic leukemia. AB - The monoclonal chimeric anti-CD20 antibody, rituximab, has considerably improved therapeutic outcome in B-cell chronic lymphocytic leukemia. Rituximab has limited clinical activity when used as a single agent. The combination of the monoclonal antibody with fludarabine-based regimens clearly demonstrated, in Phase II and randomized trials, an increase in clinical efficacy in previously untreated and pretreated patients. Furthermore the addition of rituximab enabled the eradication of minimal residual disease, which is correlated with the prognosis in a high proportion of patients. Although the combination of rituximab with fludarabine-based regimens increased myelosuppression and immunosuppression, incidence of infections did not increase. The benefit of adding rituximab to other purine analogs or other chemotherapeutic combination regimens has also been explored. Moreover there could be a role for achieving better quality of responses with the combination of different monoclonal antibodies, considering that they target different antigens and exert different mechanism of action. Although the role of rituximab as maintenance therapy in low grade non-Hodgkin's lymphomas has been determined, the benefit and optimal schedule in chronic lymphocytic leukemia are still under investigation. This review brings together knowledge of the pharmacokinetics, mechanism of action and clinical use of rituximab in chronic lymphocytic leukemia. PMID- 21289855 TI - Advances in structure elucidation of small molecules using mass spectrometry. AB - The structural elucidation of small molecules using mass spectrometry plays an important role in modern life sciences and bioanalytical approaches. This review covers different soft and hard ionization techniques and figures of merit for modern mass spectrometers, such as mass resolving power, mass accuracy, isotopic abundance accuracy, accurate mass multiple-stage MS(n) capability, as well as hybrid mass spectrometric and orthogonal chromatographic approaches. The latter part discusses mass spectral data handling strategies, which includes background and noise subtraction, adduct formation and detection, charge state determination, accurate mass measurements, elemental composition determinations, and complex data-dependent setups with ion maps and ion trees. The importance of mass spectral library search algorithms for tandem mass spectra and multiple stage MS(n) mass spectra as well as mass spectral tree libraries that combine multiple-stage mass spectra are outlined. The successive chapter discusses mass spectral fragmentation pathways, biotransformation reactions and drug metabolism studies, the mass spectral simulation and generation of in silico mass spectra, expert systems for mass spectral interpretation, and the use of computational chemistry to explain gas-phase phenomena. A single chapter discusses data handling for hyphenated approaches including mass spectral deconvolution for clean mass spectra, cheminformatics approaches and structure retention relationships, and retention index predictions for gas and liquid chromatography. The last section reviews the current state of electronic data sharing of mass spectra and discusses the importance of software development for the advancement of structure elucidation of small molecules. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12566-010-0015-9) contains supplementary material, which is available to authorized users. PMID- 21289859 TI - Survivin-T34A: molecular mechanism and therapeutic potential. AB - The inhibitor of apoptosis protein survivin's threonine 34 to alanine (T34A) mutation abolishes a phosphorylation site for p34(cdc2)-cyclin B1, resulting in initiation of the mitochondrial apoptotic pathway in cancer cells; however, it has little known direct effects on normal cells. The possibility that targeting survivin in this way may provide a novel approach for selective cancer gene therapy has yet to be fully evaluated. Although a flurry of work was undertaken in the late 1990s and early 2000s, only minor advances on this mutant have recently taken place. We recently described that cells generated to express a stable form of the mutant protein released this survivin-T34A to the conditioned medium. When this conditioned medium was collected and deposited on naive tumor cells, conditioned medium T34A was as effective as some chemotherapeutics in the induction of tumor cell apoptosis, and when combined with other forms of genotoxic stressors potentiated their killing effects. We hope with this review to revitalize the T34A field, as there is still much that needs to be investigated. In addition to determining the therapeutic dose and the duration of drug therapy required at the disease site, a better understanding of other key factors is also important. These include knowledge of target cell populations, cell-surface receptors, changes that occur in the target tissue at the molecular and cellular level with progression of the disease, and the mechanism and site of therapeutic action. PMID- 21289860 TI - Acceptance of Swedish e-health services. AB - OBJECTIVE: To investigate older people's acceptance of e-health services, in order to identify determinants of, and barriers to, their intention to use e health. METHOD: Based on one of the best-established models of technology acceptance, Technology Acceptance Model (TAM), in-depth exploratory interviews with twelve individuals over 45 years of age and of varying backgrounds are conducted. RESULTS: This investigation could find support for the importance of usefulness and perceived ease of use of the e-health service offered as the main determinants of people's intention to use the service. Additional factors critical to the acceptance of e-health are identified, such as the importance of the compatibility of the services with citizens' needs and trust in the service provider. Most interviewees expressed positive attitudes towards using e-health and find these services useful, convenient, and easy to use. CONCLUSION: E-health services are perceived as a good complement to traditional health care service delivery, even among older people. These people, however, need to become aware of the e-health alternatives that are offered to them and the benefits they provide. PMID- 21289861 TI - Physiotherapeutic management strategies for the treatment of cystic fibrosis in adults. AB - Physiotherapy has long been considered a cornerstone of condition management for people with cystic fibrosis (CF). The presentation of CF has changed over time with an increased life expectancy and increased expectations of people with CF to have a complete lifestyle. In turn, the scope of strategies used in physiotherapy for CF have also changed dramatically over the years, moving away from routine postural drainage and manual techniques toward an individualized regimen including the choice of many different forms of airway clearance, such as both independent and assisted, exercise, treatments to promote continence and good posture, inhalation therapy, oxygen, and noninvasive ventilation. This article describes the techniques and overall strategies used by physiotherapists in helping people with CF to manage the symptoms and progression of their condition. PMID- 21289862 TI - Reorientation to more health promotion in health services - a study of barriers and possibilities from the perspective of health professionals. AB - AIM: The objective of this study is to analyze the commitment to a more health promoting health service and to illuminate important barriers for having a health promoting role in daily practice, among Swedish health care professionals. MATERIAL AND METHOD: Out of a total of 3751 health professionals who are working daytime in clinical practice in the province of Vasterbotten, 1810 were invited to participate in a survey. The health professionals represented eight different occupational groups: counselors, dieticians, midwives, nurses, occupational therapists, physical therapists, psychologists, and physicians. A questionnaire that operationalized perceptions found in a previous qualitative study was mailed to residential addresses of the participants. RESULTS: The majority believed that health services play a major role in long-term health development in the population and saw a need for health orientation as a strategy to provide more effective health care. Willingness to work more in health promotion and disease prevention was reported significantly more often by women than men, and by primary health care personnel compared to hospital personnel. Among the professional groups, psychologists, occupational therapists, and physiotherapists most frequently reported willingness. The most common barriers to health promotion roles in daily practice were reported to be heavy workload, lack of guidelines, and unclear objectives. CONCLUSIONS: This study found strong support for reorientation of health services in the incorporation of a greater health promotion. A number of professions that are not usually associated with health promotion practices are knowledgeable and wish to focus more on health promotion and disease prevention. Management has a major role in creating opportunities for these professionals to participate in health promotion practices. Men and physicians reported less positive attitudes to a more health-promoting health service and often possess high positions of power. Therefore, they may play an important role in the process of change toward more health promotion in health services. PMID- 21289863 TI - Hourly-block and standard patient scheduling systems at two private hospitals in Alexandria. AB - INTRODUCTION: Patient appointment systems are of great importance for efficiently managing outpatient clinics as well as patient satisfaction as an indirect indicator for quality care rendered. PURPOSE: To describe the hourly block and standard sequential scheduling appointment systems at two different hospitals, as well as to assess the patients' opinions regarding their waiting time in both systems. STUDY SETTINGS: The study was conducted at ENT (Ear, Nose, and Throat) clinics in two of the biggest and reputable private hospitals in Alexandria. Hospital A follows the standard appointment system and Hospital B follows the hourly block appointment system. STUDY DESIGN: A cross-sectional descriptive study was designed to compare the two settings. RESULTS: For new cases, the mean time was longer for the standard system with regards to access time (12.2 +/- 5.9) days, while the mean time was longer in the hourly block system with regards to punctuality, waiting time, and consultation time (28.5 +/- 12.3, 27.5 +/- 17.1, and 14.5 +/- 9.0 minutes, respectively). For return cases, the mean time was longer for the standard system with regards to access and punctuality times (14.5 +/- 6.1 days and 48.9 +/- 27.0 minutes, respectively), while the highest mean times in the hourly block system were for waiting and consultation (19.4 +/- 6.9 and 12.3 +/- 3.9 minutes, respectively). Most of the patients in both systems preferred the standard appointment system to the hourly block system (73.3% for Hospital A and 55.0% for Hospital B). CONCLUSION: Every health care organization should know how to choose the most appropriate method of appointment system and how best to organize it to meet the needs of its patients. Patient scheduling is an important tool for efficient outpatient department management as well as rationally operating outpatient resources and critical areas like physician productivity, patient satisfaction, and practice profits. PMID- 21289864 TI - An updated review of current concepts in the management of carotid stenosis. AB - Several large randomized clinical trials in North America and Europe concluded over a decade ago that carotid endarterectomy plus medical management was significantly better than medical management alone for stroke prevention in either symptomatic or asymptomatic patients with severe carotid stenosis. Percutaneous carotid angioplasty now represents yet another treatment option that currently appears to have a higher risk than endarterectomy in symptomatic patients as well as in those who are 70 years of age or older. For these reasons, there is a consensus that angioplasty should be used cautiously in such patients and probably remains most appropriate either in the context of ongoing randomized trials or for patients who are at a higher-than-average risk for conventional surgical treatment. PMID- 21289866 TI - A Rationale and Outline for an Undergraduate Course on the Philosophy and History of Science for Life Science Students. AB - There are compelling reasons for teaching a philosophy of science course to undergraduate life science students. The main reason is to help them understand that modern science is not based upon a single, consistent philosophical system; nor is it based upon common sense, or a method, set of rules or formulas that can be used to make unerring predictions. Rather, science is a dynamic process that is constantly being modified and refined to reflect and encompass an ever expanding set of hypotheses, observations, and theories. To illustrate these points, we developed a course that examined the history and philosophical underpinnings of modern science, and we discussed famous experiments that challenged the prevailing norm and led to Kuhnian revolutions in scientific thought. Building upon this knowledge, students investigated how different philosophical systems address controversial social issues in the biological sciences. They examined the teaching of intelligent design and creationism in public schools, the implications of legalized abortion and physician-assisted suicide, the potential impact of DNA fingerprinting on human rights and racism, the promise and pitfalls of stem cell research, and the neurobiological basis of consciousness and its relevance to mental health therapies and the animal rights movement. We believe undergraduate life science students should be exposed to these issues and have an opportunity to develop informed opinions about them before they graduate from college. Exploration of such topics will help them become better prepared for the inevitable public debates that they will face as science educators, researchers, and leaders of society. PMID- 21289865 TI - Anterior thalamic lesions produce chronic and profuse transcriptional de regulation in retrosplenial cortex: A model of retrosplenial hypoactivity and covert pathology. AB - Anterior thalamic lesions are thought to produce 'covert pathology' in retrosplenial cortex, but the causes are unknown. Microarray analyses tested the hypothesis that thalamic damage causes a chronic, hypo-function of metabolic and plasticity-related pathways (Experiment 1). Rats with unilateral, anterior thalamic lesions were exposed to a novel environment for 20 minutes, and granular retrosplenial tissue sampled from both hemispheres 30 minutes, 2h, or 8h later. Complementary statistical approaches (analyses of variance, predictive patterning and gene set enrichment analysis) revealed pervasive gene expression differences between retrosplenial cortex ipsilateral to the thalamic lesion and contralateral to the lesion. Selected gene differences were validated by QPCR, immunohistochemistry (Experiment 1), and in situ hybridisation (Experiment 2). Following thalamic lesions, the retrosplenial cortex undergoes profuse cellular transcriptome changes including lower relative levels of specific mRNAs involved in energy metabolism and neuronal plasticity. These changes in functional gene expression may be largely driven by decreases in the expression of multiple transcription factors, including brd8, c-fos, fra-2, klf5, nfix, nr4a1, smad3, smarcc2, and zfp9, with a much smaller number (nfat5, neuroD1, RXRgamma) showing increases. These findings have implications for conditions such as diencephalic amnesia and Alzheimer's disease, where both anterior thalamic pathology and retrosplenial cortex hypometabolism are prominent. PMID- 21289867 TI - Violent Victimization and Perpetration: Joint and Distinctive Implications for Adolescent Development. AB - To date few reports have provided direct comparison of psychosocial vulnerability and resources among youth with victimization and perpetration histories. Within a racially diverse, high-risk adolescent sample (n = 849), this study undertakes MANCOVA tests on a multidimensional set of risk and protective factors contrasting youth with histories of 1) neither violent victimization nor perpetration, 2) victimization only , 3) both perpetration only, and 4) both victimization and perpetration. All three violence-affected groups reported elevated risk and diminished protection, with perpetrating victims demonstrating the greatest psychosocial impairment. Detailed contrasts among the youth group profiles provide insights regarding overlapping and distinct developmental etiologies and implications for preventive and remedial intervention. PMID- 21289868 TI - Achieving accurate radiochromic optical-CT imaging when using a polychromatic light source. AB - Optical-CT performed with a broad spectrum light source can lead to inaccurate reconstructed attenuation coefficients (and hence dose) due to 'spectral warping' as the beam passes through the dosimeter. Some wavelengths will be attenuated more strongly than others depending on the absorption spectrum of the radiochromic dosimeter. A simulation was run to characterize the error introduced by the spectrum warping phenomena. Simulations of a typical dosimeter and delivered dose (6cm diameter, 2 Gy irradiation) showed reconstructed attenuation coefficients can be in error by >12% when compared to those obtained from a monochromatic scan. A method to correct for these errors is presented and preliminary data suggests that with the correction, polychromatic imaging can yield imaging results equal in accuracy to those of monochromatic imaging. The advantage is that polychromatic imaging may be less sensitive to prominent schlerring artefacts that are often observed in telecentric optical-CT scanning systems with tight bandwidth filters applied. PMID- 21289869 TI - Health Care Disparities and Diabetes Care: Practical Considerations for Primary Care Providers. AB - Disparities in diabetes care are prevalent in the United States. This article provides an overview of these disparities and discusses both potential causes and efforts to address them to date. The authors focus the discussion on aspects relevant to the patient-provider dyad and provide practical considerations for the primary care provider's role in helping to diminish and eliminate disparities in diabetes care. PMID- 21289870 TI - Investigations on the Q and CT Bands of Cytochrome c Submonolayer Adsorbed on an Alumina Surface Using Broadband Spectroscopy with Single-Mode Integrated Optical Waveguides. AB - In this work, we report experimental results on the molar absorptivity of cytochrome c adsorbed at different submonolayer levels onto an aluminum oxide waveguide surface; our data show a clear dependence of the protein optical properties on its surface density. The measurements were performed using the broadband, single-mode, integrated optical waveguide spectroscopic technique, which is an extremely sensitive tool able to reach submonolayer levels of detection required for this type of studies. This investigation focuses on the molar absorptivity at the Q-band (centered at 525 nm) and, for the first time to our knowledge, the weak charge transfer (CT) band (centered at 695 nm) of surface adsorbed cyt c. Polarized light in the spectral region from 450 to 775 nm was all coupled into an alumina thin film, which functioned as a single-mode planar optical waveguide. The alumina thin-film waveguide used for this work had a thickness of 180 nm and was deposited on a glass substrate by the atomic layer deposition process. The protein submonolayer was formed on the alumina waveguide surface through electrostatic adsorption from an aqueous buffer solution at neutral pH. The optical properties of the surface-adsorbed cyt c were investigated for bulk protein concentrations ranging from 5 nM to 8200 nM in the aqueous buffer solution. For a protein surface density of 2.3 pmol/cm(2), the molar absorptivity measured at the charge transfer band was 335 M(-1) cm(-1), and for a surface density of 15 pmol/cm(2) was 720 M(-1) cm(-1), which is much closer to the value of cyt c dissolved in an aqueous neutral buffer (830 M(-1) cm(-1)). The modification of the protein molar absorptivity and its dependence on the surface density can most likely be attributed to conformational changes of the surface-adsorbed species. PMID- 21289871 TI - MicroRNA-based Cancer Therapeutics: Big Hope from Small RNAs. AB - Tremendous progress has been made during the last few years in identification of novel tumor-associated microRNAs and experimental validation of their cancer relevant gene targets. Indeed, these small non-coding RNAs are now known to modulate many biological pathways related to cancer progression, metastasis and therapy-resistance. Therefore, modulating miRNA functions may provide novel therapeutic opportunities for cancer treatment. This article reviews recent literature on the role of miRNAs in cancer with an emphasis on their potential as cancer therapeutics. PMID- 21289872 TI - Levodopa enhances reward learning but impairs reversal learning in Parkinson's disease patients. PMID- 21289873 TI - Quantitative neuroimaging and the prediction of rehabilitation outcome following traumatic brain injury. PMID- 21289874 TI - Specific immunotherapy (SIT) in the treatment of allergic rhinitis. AB - SCIENTIFIC BACKGROUND: Allergic rhinitis (AR) exhibits a prevalence of approx. 20% in Germany and causes enormous costs in the health care system. Specific immunotherapy (SIT) is considered to be the only potentially causal therapy for AR and mainly administered by two routes, subcutaneous (SCIT) and sublinguale (SLIT). SIT promises a reduction of symptoms and the need for medication in patients with AR. RESEARCH QUESTIONS: The question arises, to what extent is SIT effective and cost effective in the treatment of AR and which ethical-social and legal aspects have to be considered regarding its application. METHODS: The literature search was accomplished in the electronic data bases MEDLINE, EMBASE etc. in February 2008. The medical evaluation was based on systematic reviews of blinded, randomised controlled studies (RCT). The economic evaluation included health-economic studies on the basis of RCT. Additionally, it was also searched for publications explicitly addressing ethical-social and legal aspects of the use of SIT. RESULTS: MEDICAL EVALUATION: Two reviews on SCIT and three on SLIT were included in the medical evaluation. For the evaluation of SIT with grass pollen results for short and medium-term effects are considered from several studies, for SIT with other seasonal allergens (e. g. tree pollen) and with house dust mite allergens from clearly fewer studies and for SIT with other perennial allergens only from a few. The reviews report a significant reduction of the symptom and medication score in favour of SCIT with seasonal allergens and recognise the effectiveness at least for grass pollen allergens. Also for other seasonal allergens SCIT is appraised as effective. The reviews about SLIT determine a significant reduction of the symptom and the medication score in favour of SLIT vs. placebo in short and medium term follow-up in evaluations across all allergens. The subgroup analyses show a significant reduction of the symptom and medication score only in favour of SLIT with seasonal allergens. HEALTH ECONOMIC EVALUATION: Four publications about two health economic studies are identified, one of these publications on Alutard-SQ((r)) injections (SCIT) and three on GRAZAX((r)) tablets (SLIT). The studies provide more (on Alutard SQ((r))) or less (on GRAZAX((r))) robust information, but no evidence on cost effectiveness of these SIT administration forms in patients with AR. DISCUSSION: The topic of the report is very broad, so that the evidence is summarised using systematic reviews. In particular the statistic heterogeneity of the studies found in the reviews considerably limits the strength of the findings. The included health economic studies show different methodical flaws, the largest potential bias is the projection of the magnitude of the medium-term clinical effects on the time period of nine years. CONCLUSIONS: The effectiveness of SIT in patients with AR is not equally proven for all SIT administration forms and allergens. For SCIT and SLIT with grass pollen allergens short and medium-term effectiveness can be regarded as proven. These therapy forms should be used if the indication is appropriate and if no contraindications are present. Also SCIT and SLIT with other seasonal allergens such as tree pollen allergens can be an effective treatment option, but used with a certain restraint due to insufficient data especially in the case of SLIT. For SIT with house dust mite allergens and further perennial allergens no consistent proof of effectiveness are to be determined from the available information. Further research addressing non-grass pollen-associated SIT, allergen and manufacturer specific evaluations as well as asthma prevention is needed. Due to the lack of evidence the use of SIT can not be seen proven as cost effective. To provide such evidence further health economic studies with a long term follow-up are needed. The informed consent of the patients is an important ethical requirement within the use of SIT. PMID- 21289875 TI - The impact of microsurgery, stereotactic radiosurgery and radiotherapy in the treatment of meningiomas depending on different localizations. AB - SCIENTIFIC BACKGROUND: Meningiomas are the most common benign intracranial neoplasms with a slow growth presented as the intracranial lesion. These tumors are without any symptoms for a long time. At the time of diagnosis it is frequently an asymptomatic tumor. In that case the therapist may well suggest a wait-and-see strategy. The therapy of meningiomas focuses firstly on the microsurgical treatment. Volume reduction can be achieved immediately after treatment. Stereotactic radiosurgery is an important non-invasive treatment option for recurrent tumors or meningiomas with partial resection. The technical equipment for the stereotactic radiosurgery is a cost intensive investment. In this context the high precision of the intervention, presented as a low invasiveness of the treatment, is an important factor. The aim of this assessment is to identify the chances and limitations of the diverse treatment options and to estimate their outcome for different localisations of meningiomas. METHODS: In December 2007 a systematic literature search was conducted using the most relevant medical databases. The whole strategy and the used search terms were documented. The literature search was supplemented with an internet and literature based hand search on law, ethics and economics. Primary studies and systematic reviews which report relevant outcomes are included in this analysis. The current assessment is based on the available evidence that was found at the time of the literature search. RESULTS: A total of 31 publications for the medical focus of assessment and three reports from the economical hand search were included. In general, it is not possible to identify neither randomised clinical trials or prospective, contrasting cohort studies nor studies summarising results from such studies. The results presented in the literature published by surgeons strongly vary regarding localisation of meningiomas. Publications not differentiating between the localisation of meningiomas indicate a progression free survival rate of five years in 77 to 97% of the cases after complete surgical resection of the tumor, in 18 to 70% of the cases after subtotal resection and for patients who had undergone surgical resection and a combined radiotherapeutical treatment of their meningiomas a five year progression free survival rate between 82 and 97%. Other treatment options like hormone therapy or treatments to stop tumor growth had been used unsuccessfully so far. Based on the results presented regarding economic evaluation, costs resulting from radiosurgical treatment are lower in contrast to costs resulting from surgical resection. However, it has to be taken into account that costs resulting from radiosurgical treatment strongly depend on the number of patients treated in total with the radiosurgical equipment. CONCLUSION: Due to the strong dependencies between the results from surgical therapy and the localisation of the tumor, it is only possible to derive recommendations on whether or not to perform the surgical therapy with respect to the localisation of the tumor. Only for patients with tumors with a spinal localisation or WHO Grade I meningiomas with a cortical localisation, primary treatment with by means of microsurgery can be suggested. For all other localisations of the tumor, alternative treatment by radiosurgery should be discussed. From the literature identified, a clear recommendation of one or the other therapy however can not be deduced. Thus, there is a strong need for randomised clinical trials or prospective or contrasting cohort studies, which compare rigorously microsurgery with radiosurgery concerning different localisations of tumors. PMID- 21289876 TI - New-onset diabetes and antihypertensive treatment. AB - INTRODUCTION: Chronic diseases substantially contribute to the continuous increase in health care expenditures, including type-2 diabetes mellitus as one of the most expensive chronic diseases. Arterial hypertension presents a risk factor for the development of type-2 diabetes mellitus. Numerous analyses have demonstrated that antihypertensive therapies promote the development of type-2 diabetes mellitus. Studies indicate, that the application of angiotensin converting enzyme (ACE) inhibitors and angiotensin-receptor-blockers (ARB) lead to less new-onset diabetes compared to beta-blockers, diuretics and placebo. Given that beta-blockers and diuretics impair the glucose metabolism, the metabolic effects of different antihypertensive drugs should be regarded; otherwise not only the disease itself, but also antihypertensive therapies may promote the development of new-onset diabetes. Even though, the cost of ACE inhibitors and ARB are higher, the use in patients with metabolic disorders could be cost-effective in the long-term if new-onset diabetes is avoided. OBJECTIVES: To evaluate which class of antihypertensive agents promote the development or the manifestation of type-2 diabetes mellitus. How high is the incidence of new-onset diabetes during antihypertensive therapy and how is treatment-induced type-2 diabetes mellitus evaluated clinically? Which agents are therefore cost-effective in the long term? Which ethical, social or legal aspects should be regarded? METHODS: A systematic literature review was conducted including clinical trials with at least ten participants which reported new-onset diabetes in the course of antihypertensive treatment. The trials had to be published after 1966 (after 2003 for economic publications) in English or German. RESULTS: A total of 34 clinical publications meet the inclusion criteria. Of these, eight publications focus on the development of diabetes mellitus under treatment with diuretic and/or beta blockers, six publications focused on ACE inhibitors alone or in combination with calcium-channel-blockers, ten publications on ARB and/or ACE inhibitors with respect to their effects on new-onset diabetes or their preventive aspects. Furthermore, five publications investigate the role of calcium-channel antagonists in the development of diabetes, and five publications indicate the development of new-onset diabetes with different antihypertensive agents amongst each other or in comparison to no antihypertensive treatment. The clinical trials show a significant difference in the development of new-onset diabetes. Therapies with diuretics and/or beta-blockers result in a higher incidence of new-onset diabetes. ARB as well as ACE inhibitors have a preventive effect and calcium channel-blockers show a neutral position regarding the development of new-onset diabetes. Two publications report on economic results. The first one evaluates the cost-effectiveness of ARB alone or in combination with calcium-channel blockers in comparison to diuretics alone or in combination with beta-blockers. The second publication compares economic outcomes of calcium-channel-blockers and beta-blockers considering the development of new-onset diabetes. Treatment with the ARB candesartan lead to savings in total costs of 549 US-Dollar per patient and in incremental costs of 30,000 US-Dollar per diabetes mellitus avoided. In the second publication, costs to the amount of 18,965 Euro in Great Britain and 13,210 Euro in Sweden are quoted for an avoided event. The treatment with calcium channel-blockers compared to beta-blockers is proven to be more cost-effective. No publications were identified regarding ethical, social and legal aspects. DISCUSSION: The available meta-analyses allow for a high clinical evidence level. A few studies vary in terms of diabetes definition and study duration. In most of the trials, the incidence of new-onset diabetes is not an endpoint. The evaluation of treatment-induced diabetes mellitus cannot be conducted, due to the lack of sufficient results in the identified literature. The two economic studies do not address all the objectives sufficiently. Ethical, social and legal aspects are discussed but not analysed systematically. CONCLUSION: Based on these studies, sufficient evidence to confirm the presumption that diuretics and/or beta-blockers promote the development of new-onset diabetes compared to other antihypertensive agents, especially in patients who are predisposed, is presented with this report. Trials reflecting the clinical relevance of treatment-induced diabetes mellitus compared to existing diabetes mellitus regarding cardiovascular outcomes are required. Also health economic evaluations considering the development of new-onset diabetes should be conducted for the different classes of antihypertensive agents. PMID- 21289877 TI - Medical and health economic evaluation of prevention- and control measures related to MRSA infections or -colonisations at hospitals. AB - INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA) are dangerous agents of nosocomial infections. In 2007 the prevalence of MRSA is 20.3% in Germany (Oxacilline-resistance according to EUCAST-criteria [EUCAST = European Committee on Antimicrobial Susceptibility Testing]). OBJECTIVES: Which measurements are effective in the prevention and control of MRSA-infections in the hospital?How effective are contact precautions, screening, decolonisation, education and surveillance?Which recommendations can be given to health care politics on the basis of cost-effectiveness studies?Have there been any adverse effects on patients and clinical staff?What kind of liability problems exist? METHODS: Based on a systematic review of the literature studies are included which have been published in German or English language since 2004. RESULTS: 1,508 articles have been found. After having surveyed the full text, 33 medical, eight economic and four ethical/juridical studies are included for the Health Technology Assessment (HTA) report. The key result of the HTA report is that different measurements are effective in the prevention and control of MRSA infections in hospitals, though the majority of the studies has a low quality. Effective are the conduction of differentiated screening measurements if they take into account the specific endemic situation, the use of antibiotic-control programs and the introduction and control of hygienic measurements. The break even point of preventive and control measurements cannot be defined because the study results differ too much. In the future it has to be more considered that MRSA-infections and contact precautions lead to a psycho-social strain for patients. DISCUSSION: It is hardly possible to describe causal efficacies because in the majority of the studies confounders are not sufficiently considered. In many cases bundles of measurements have been established but not analyzed individually. The internal and external validity of the studies is too weak to evaluate single interventions. Hygienic measurements prove to be effective in combination with other measurements. But it cannot be said which of the single measurements (gloves, washing hands, wearing gowns or masks) has the strongest effect on the reduction of MRSA. It is irritating that there are high differences in the compliance concerning hand hygiene between different studies. A general decolonisation is questionable for different reasons: first because of the side effects for patients, second because of the high rate of spontaneous remissions in the untreated control group, third because of the differentiated process from colonisation to infection. Severalfold Hawthorne effects have been reported. One of them is that the competition between hospitals to reduce MRSA-rates leads already to a reduction. CONCLUSIONS: It is evident that selective screening programs of risk patients considering the particular MRSA-prevalence are of use. The application of rapid tests seems to be only recommendable for risk patients and a high MRSA-prevalence. The improvement of the compliance of hand hygiene should be the basis of any prevention strategy. Training of staff members (with feedback mechanisms) is effective to improve compliance and to optimise the use of antibiotics. Antibiotic management programs are effective as well. Obviously multimodal approaches can lead to overadditive effects. Therefore the catalogue of preventive and control measurements has to be further evaluated. Good cost efficacy studies are missing in Germany. The psychosocial effects of MRSA infections are not researched in Germany. There is only punctual information on the risk management of hospitals. PMID- 21289878 TI - Decision-analytic modeling to evaluate the long-term effectiveness and cost effectiveness of HPV-DNA testing in primary cervical cancer screening in Germany. AB - BACKGROUND: Persistent infections with high-risk types of human papillomavirus (HPV) are associated with the development of cervical neoplasia. Compared to cytology HPV testing is more sensitive in detecting high-grade cervical cancer precursors, but with lower specificity. HPV based primary screening for cervical cancer is currently discussed in Germany. Decisions should be based on a systematic evaluation of the long-term effectiveness and cost-effectiveness of HPV based primary screening. RESEARCH QUESTIONS: What is the long-term clinical effectiveness (reduction in lifetime risk of cervical cancer and death due to cervical cancer, life years gained) of HPV testing and what is the cost effectiveness in Euro per life year gained (LYG) of including HPV testing in primary cervical cancer screening in the German health care context? How can the screening program be improved with respect to test combination, age at start and end of screening and screening interval and which recommendations should be made for the German health care context? METHODS: A previously published and validated decision-analytic model for the German health care context was extended and adapted to the natural history of HPV infection and cervical cancer in order to evaluate different screening strategies that differ by screening interval, and tests, including cytology alone, HPV testing alone or in combination with cytology, and HPV testing with cytology triage for HPV-positive women. German clinical, epidemiological and economic data were used. In the absence of individual data, screening adherence was modelled independently from screening history. Test accuracy data were retrieved from international meta-analyses. Predicted outcomes included reduction in lifetime-risk for cervical cancer cases and deaths, life expectancy, lifetime costs, and discounted incremental cost effectiveness ratios (ICER). The perspective of the third party payer and 3% annual discount rate were adopted. Extensive sensitivity analyses were performed in order to evaluate the robustness of results and identify areas of future research. RESULTS: In the base case analysis screening resulted in a 53% to 97% risk reduction for cervical cancer with a discounted ICER between 2,600 Euro/LYG (cytology alone every five years) and 155,500 Euro/LYG (Annual cytology age 20 to 29 years, and annual HPV age 30 years and older). Annual cytology, the current recommended screening strategy in Germany, was dominated. In sensitivity analyses variation in the relative increase in the sensitivity of HPV testing as compared to cytology, HPV test costs, screening adherence, HPV incidence, and annual discount rate influenced the ICER results. Variation in the screening start age also influenced the ICER. All cytology strategies were dominated by HPV screening strategies, when relative sensitivity increase by HPV testing compared to cytology was higher (scenario analysis with data for test accuracy from German studies). HPV testing every one, two or three years was more effective than annual cytology. With increased screening adherence a longer screening interval and with low screening adherence a shorter interval would be more cost-effective. With a reduction in HPV incidence of more than 70% triennial HPV screening in women aged 30 years and older (and biennial Pap screening in women aged 20 to 29 years) is cost-effective. The discounted ICER increases with increasing annual discount rate. Increasing screening start age to 25 years had no relevant loss in effectiveness but resulted in lower costs. An optimal strategy may be biennial HPV testing age 30 years and older with biennial cytology at age 25 to 29 years (ICER of 23,400 Euro/LYG). CONCLUSIONS: Based on these results, HPV-based cervical cancer screening is more effective than cytology and could be cost effective if performed at intervals of two years or greater. Increasing the age at screening start to 25 years causes no relevant loss in effectiveness but saves resources. In the German context an optimal screening strategy could be biennial HPV testing at age 30 years and older with biennial cytology at the age of 25 to 29 years. An extension to a three-yearly screening interval requires substantially improved screening adherence or a higher relative increase in the sensitivity of HPV testing as compared to cytology. The implementation of an organised screening program for quality-controlled introduction of HPV-screening and -vaccination with continued systematic outcome evaluation is recommended. PMID- 21289879 TI - Dental indications for the instrumental functional analysis in additional consideration of health-economic aspects. AB - BACKGROUND: Besides clinical and radiological examination instrumental functional analyses are performed as diagnostic procedures for craniomandibular dysfunctions. Instrumental functional analyses cause substantial costs and shows a considerable variability between individual dentist practices. OBJECTIVES: On the basis of published scientific evidence the validity of the instrumental functional analysis for the diagnosis of craniomandibular dysfunctions compared to clinical diagnostic procedures; the difference of the various forms of the instrumental functional analysis; the existence of a dependency on additional other factors and the need for further research are determined in this report. In addition, the cost effectiveness of the instrumental functional analysis is analysed in a health-policy context, and social, legal and ethical aspects are considered. METHODS: A literature search is performed in over 27 databases and by hand. Relevant companies and institutions are contacted concerning unpublished studies. The inclusion criteria for publications are (i) diagnostic studies with the indication "craniomandibular malfunction", (ii) a comparison between clinical and instrumental functional analysis, (iii) publications since 1990, (iv) publications in English or German. The identified literature is evaluated by two scientists regarding the relevance of content and methodical quality. RESULTS: The systematic database search resulted in 962 hits. 187 medical and economic complete publications are evaluated. Since the evaluated studies are not relevant enough to answer the medical or health economic questions no study is included. DISCUSSION: The inconsistent terminology concerning craniomandibular dysfunctions and instrumental functional analyses results in a broad literature search in databases and an extensive search by hand. Since no relevant results concerning the validity of the instrumental functional analysis in comparison to the clinical functional analysis are found, it is impossible to make relevant statements concerning the underlying research questions. CONCLUSION: Studies comparing the instrumental functional analysis to the clinical functional analysis for the diagnosis of craniomandibular dysfunctions are missing. So far the instrumental functional analysis is not systematically and independently validated in comparison to the clinical functional analysis as the reference standard. It is uncertain, whether conducting an instrumental functional analysis with a clinical functional analysis for the diagnostics of craniomandibular dysfunctions is recommendable. Further research is strongly recommended. PMID- 21289880 TI - Comparison of tools for assessing the methodological quality of primary and secondary studies in health technology assessment reports in Germany. AB - HEALTH CARE POLICY BACKGROUND: Findings from scientific studies form the basis for evidence-based health policy decisions. SCIENTIFIC BACKGROUND: Quality assessments to evaluate the credibility of study results are an essential part of health technology assessment reports and systematic reviews. Quality assessment tools (QAT) for assessing the study quality examine to what extent study results are systematically distorted by confounding or bias (internal validity). The tools can be divided into checklists, scales and component ratings. RESEARCH QUESTIONS: What QAT are available to assess the quality of interventional studies or studies in the field of health economics, how do they differ from each other and what conclusions can be drawn from these results for quality assessments? METHODS: A systematic search of relevant databases from 1988 onwards is done, supplemented by screening of the references, of the HTA reports of the German Agency for Health Technology Assessment (DAHTA) and an internet search. The selection of relevant literature, the data extraction and the quality assessment are carried out by two independent reviewers. The substantive elements of the QAT are extracted using a modified criteria list consisting of items and domains specific to randomized trials, observational studies, diagnostic studies, systematic reviews and health economic studies. Based on the number of covered items and domains, more and less comprehensive QAT are distinguished. In order to exchange experiences regarding problems in the practical application of tools, a workshop is hosted. RESULTS: A total of eight systematic methodological reviews is identified as well as 147 QAT: 15 for systematic reviews, 80 for randomized trials, 30 for observational studies, 17 for diagnostic studies and 22 for health economic studies. The tools vary considerably with regard to the content, the performance and quality of operationalisation. Some tools do not only include the items of internal validity but also the items of quality of reporting and external validity. No tool covers all elements or domains. Design-specific generic tools are presented, which cover most of the content criteria. DISCUSSION: The evaluation of QAT by using content criteria is difficult, because there is no scientific consensus on the necessary elements of internal validity, and not all of the generally accepted elements are based on empirical evidence. Comparing QAT with regard to contents neglects the operationalisation of the respective parameters, for which the quality and precision are important for transparency, replicability, the correct assessment and interrater reliability. QAT, which mix items on the quality of reporting and internal validity, should be avoided. CONCLUSIONS: There are different, design-specific tools available which can be preferred for quality assessment, because of its wider coverage of substantive elements of internal validity. To minimise the subjectivity of the assessment, tools with a detailed and precise operationalisation of the individual elements should be applied. For health economic studies, tools should be developed and complemented with instructions, which define the appropriateness of the criteria. Further research is needed to identify study characteristics that influence the internal validity of studies. PMID- 21289881 TI - Invasive home mechanical ventilation, mainly focused on neuromuscular disorders. AB - INTRODUCTION AND BACKGROUND: Invasive home mechanical ventilation is used for patients with chronic respiratory insufficiency. This elaborate and technology dependent ventilation is carried out via an artificial airway (tracheal cannula) to the trachea. Exact numbers about the incidence of home mechanical ventilation are not available. Patients with neuromuscular diseases represent a large portion of it. RESEARCH QUESTIONS: Specific research questions are formulated and answered concerning the dimensions of medicine/nursing, economics, social, ethical and legal aspects. Beyond the technical aspect of the invasive home, mechanical ventilation, medical questions also deal with the patient's symptoms and clinical signs as well as the frequency of complications. Economic questions pertain to the composition of costs and the differences to other ways of homecare concerning costs and quality of care. Questions regarding social aspects consider the health-related quality of life of patients and caregivers. Additionally, the ethical aspects connected to the decision of home mechanical ventilation are viewed. Finally, legal aspects of financing invasive home mechanical ventilation are discussed. METHODS: Based on a systematic literature search in 2008 in a total of 31 relevant databases current literature is viewed and selected by means of fixed criteria. Randomized controlled studies, systematic reviews and HTA reports (health technology assessment), clinical studies with patient numbers above ten, health-economic evaluations, primary studies with particular cost analyses and quality-of-life studies related to the research questions are included in the analysis. RESULTS AND DISCUSSION: Invasive mechanical ventilation may improve symptoms of hypoventilation, as the analysis of the literature shows. An increase in life expectancy is likely, but for ethical reasons it is not confirmed by premium-quality studies. Complications (e. g. pneumonia) are rare. Mobile home ventilators are available for the implementation of the ventilation. Their technical performance however, differs regrettably. Studies comparing the economic aspects of ventilation in a hospital to outpatient ventilation, describe home ventilation as a more cost-effective alternative to in-patient care in an intensive care unit, however, more expensive in comparison to a noninvasive (via mask) ventilation. Higher expenses arise due to the necessary equipment and the high expenditure of time for the partial 24-hour care of the affected patients through highly qualified personnel. However, none of the studies applies to the German provisionary conditions. The calculated costs strongly depend on national medical fees and wages of caregivers, which barely allows a transmission of the results. The results of quality-of-life studies are mostly qualitative. The patient's quality of life using mechanical ventilation is predominantly considered well. Caregivers of ventilated patients report positive as well as negative ratings. Regarding the ethical questions, it was researched which aspects of ventilation implementation will have to be considered. From a legal point of view the financing of home ventilation, especially invasive mechanical ventilation, requiring specialised technical nursing is regulated in the code of social law (Sozialgesetzbuch V). The absorption of costs is distributed to different insurance carriers, who often, due to cost pressures within the health care system, insurance carriers, who consider others and not themselves as responsible. Therefore in practice, the necessity to enforce a claim of cost absorption often arises in order to exercise the basic right of free choice of location. CONCLUSION: Positive effects of the invasive mechanical ventilation (overall survival and symptomatic) are highly probable based on the analysed literature, although with a low level of evidence. An establishment of a home ventilation registry and health care research to ascertain valid data to improve outpatient structures is necessary. Gathering specific German data is needed to adequately depict the national concepts of provision and reimbursement. A differentiation of the cost structure according to the type of chosen outpatient care is currently not possible. There is no existing literature concerning the difference of life quality depending on the chosen outpatient care (homecare, assisted living, or in a nursing home specialised in invasive home ventilation). Further research is required. For a so called participative decision - made by the patient after intense counselling - an early and honest patient education pro respectively contra invasive mechanical ventilation is needed. Besides the long term survival, the quality of life and individual, social and religious aspects have also to be considered. PMID- 21289882 TI - Differential diagnostic of the burnout syndrome. AB - INTRODUCTION: There is no consistent definition of burnout. It is neither a defined diagnosis in ICD-10 nor in DSM-IV. Yet it is diagnosed by office-based doctors and clinicians. Mainly due to reimbursement reasons, diagnoses like depression are used instead of burnout diagnoses. Therefore burnout has a very high individual, social and economic impact. OBJECTIVES: How is burnout diagnosed? Which criteria are relevant? How valid and reliable are the used tools?What kind of disorders in case of burnout are relevant for a differential diagnosis?What is the economic effect of a differential diagnosis for burnout?Are there any negative effects of persons with burnout on patients or clients?Can stigmatization of burnout-patients or -clients be observed? METHODS: Based on a systematic literature research in 36 databases, studies in English or German language, published since 2004, concerning medical and differential diagnoses, economic impact and ethical aspects of burnout, are included and evaluated. RESULTS: 852 studies are identified. After considering the inclusion and exclusion criteria and after reviewing the full texts, 25 medical and one ethical study are included. No economic study met the criteria. The key result of this report is that so far no standardized, general and international valid procedure exists to obtain a burnout diagnosis. At present, it is up to the physician's discretion to diagnose burnout. The overall problem is to measure a phenomenon that is not exactly defined. The current available burnout measurements capture a three dimensional burnout construct. But the cutoff points do not conform to the standards of scientifically valid test construction. It is important to distinguish burnout from depression, alexithymia, feeling unwell and the concept of prolonged exhaustion. An intermittent relation of the constructs is possible. Furthermore, burnout goes along with various ailments like sleep disturbance. Through a derogation of work performance it can have also negative effects on significant others (for example patients). There is no evidence for stigmatization of persons with burnout. DISCUSSION: The evidence of the majority of the studies is predominantly low. Most of the studies are descriptive and explorative. Self-assessment tools are mainly used, overall the Maslach Burnout Inventory (MBI). Objective data like medical parameters, health status, sick notes or judgements by third persons are extremely seldomly included in the studies. The sample construction is coincidental in the majority of cases, response rates are often low. Almost no longitudinal studies are available. There are insufficient results on the stability and the duration of related symptoms. The ambiguity of the burnout diagnosis is regularly neglected in the studies. CONCLUSIONS: The authors conclude, that (1) further research, particularly high quality studies are needed, to broaden the understanding of the burnout syndrome. Equally (2) a definition of the burnout syndrome has to be found which goes beyond the published understanding of burnout and is based on common scientific consent. Furthermore, there is a need (3) for finding a standardized, international accepted and valid procedure for the differentiated diagnostics of burnout and for (4) developing a third party assessment tool for the diagnosis of burnout. Finally, (5) the economic effects and implication of burnout diagnostics on the economy, the health insurances and the patients have to be analysed. PMID- 21289883 TI - Prevention of infection after knee arthroplasty. AB - SCIENTIFIC BACKGROUND: Man-made joints (joint endoprostheses), including knee endoprostheses, are used in some irreversible diseases of the human joints. The implantation of joint endoprostheses (arthroplasty) is associated with an increased risk for infection. To prevent infections, different interventions without and with the use of antibiotics (hygiene procedures and antibiotic prophylaxis) are used. The benefits of these interventions are not clear yet. RESEARCH QUESTIONS: The presented report addresses the questions regarding the medical effectiveness, the cost-effectiveness as well as the ethical, social and legal aspects related to the use of interventions to prevent infections after knee arthroplasty. METHODS: A systematic literature search is conducted in the medical electronic databases MEDLINE, EMBASE, SciSearch etc. in June 2009 and has been completed by a hand search. The analysis includes publications which describe and/or evaluate clinical data from randomized controlled trials (RCT), systematic reviews of RCT, registers of endoprostheses or databases concerning interventions to prevent infections after knee arthroplasty. The conducted literature search also aims to identify health-economic studies and publications dealing explicitly with ethical, social or legal aspects in the use of interventions to prevent infections after knee arthroplasty. The synthesis of information from different publications has been performed qualitatively. RESULTS: The systematic literature search yields 1,030 hits. Based on the predefined inclusion and exclusion criteria a total of ten publications is included in the analysis. The presented report does not find evidence of the effectiveness of different hygiene interventions with a high evidence level. Most of the unspecific interventions are recommended on the basis of results from non RCT, from studies for other clinical indications and/or for clinically not relevant endpoints, as well as on the basis of expert opinions. The evidence of the effectiveness of intravenous prophylaxis with antibiotics in knee arthroplasty on a high level of evidence is also missing. The recommendations use evidence on the intravenous antibiotic prophylaxis transferred from RCT in hip arthroplasty to the arthroplasty of all joints including knee replacement. Moreover, no evidence is found for differences in the effectiveness between various antibiotics in knee arthroplasty. The presented report finds strong hints for the effectiveness of antibiotics in cement in addition to the intravenous prophylaxis; however, evidence of the effectiveness may be accepted only for operating rooms without clean-air measures. DISCUSSION: The conclusiveness of the results from non-RCT and from studies for clinically non-relevant endpoints is relatively low. The determined evidence from studies for other clinical indications may be generally transferred to knee replacement operations. CONCLUSIONS: No proposal to change the recommendations of the Robert Koch Institute with respect to hygiene interventions and intravenous antibiotic prophylaxis can be made from the presented analysis. Also, no recommendations on the selection of certain antibiotic can be derived from the analysed data. The use of antibiotics in cement in addition to the intravenous prophylaxis may be generally recommended. The cost-effectiveness of different interventions to prevent infections in knee arthroplasty remains unclear. There are no signs for concern regarding any ethical, social and/or legal consequences in the use of interventions to prevent infections in knee arthroplasty. PMID- 21289884 TI - Outpatient pulmonary rehabilitation - rehabilitation models and shortcomings in outpatient aftercare. AB - BACKGROUND: The chronic obstructive pulmonary disease (COPD) and the bronchial asthma are widespread diseases. They need long-lasting and sustainable rehabilitation. OBJECTIVES: The goal of this HTA is to describe the present supply and the economic relevance of out-patient pulmonary rehabilitation in conjunction with its social aspects. A further target is to derivate options for actions in the health-care system and possible research necessities. METHODS: Relevant publications are identified by means of a structured search in 37 database accessed through the German Institute of Medical Documentation and Information (DIMDI). In addition a manual search of identified reference lists has been done. The present report includes German and English literature published from 2004 to 2009. The methodological quality was assessed by two independent researchers according to pre-defined quality criteria of evidence based medicine. RESULTS: Among 860 publications 31 medical studies, four economic studies and 13 ethical studies meet the inclusion criteria. The studies cover rehabilitation programmes in 19 countries. The majority of them has a high level of evidence (1A to 2C). The pulmonary rehabilitation programmes differ by the setting (in-patient, out-patient, in-home, community-based), by the length of intervention (from two weeks to 36 months), by the way and the frequency of intervention and by the duration of the follow-up treatment. Overall out-patient rehabilitation programmes achieve the same positive effects for COPD patients as in-patient programmes do. This is especially true for physical performance and health related quality of life. There are only a few studies dealing with asthma. Therefore, valid statements cannot be given. The results for cost-effectiveness are not distinct enough. DISCUSSION: Goals of pulmonary rehabilitation like prevention and adequate treatment of acute exacerbations, the minimisation of hospitalisation and the reduction of mortality are attained in out-patient as well as in in-patient pulmonary rehabilitation. Regarding the best frequency of training units per week or the duration and the content of a unit further research is needed. Final results for the ideal length of an in-patient rehabilitation are still missing. None of the studies deals with the analysis of the different treatment forms of a COPD which are frequently defined by an alteration of in-patient and out-patient treatments and participation in sports clubs or self-help groups. There are some other limitations of the studies. The results concerning self-management programmes are not distinct. (Self-) Selection leads to high drop-out rates. Many studies have only small sample sizes. Confounder and long-time effects are seldom researched, relevant economic evaluations do not exist The improvement of health related quality of life is primarily obtained by an improved disease management than by an improvement of a medical parameter. CONCLUSION: Out-patient pulmonary rehabilitation is as effective as in-patient pulmonary rehabilitation. But there is a critical shortage of out-patient pulmonary rehabilitation supply in Germany. Domains for further research are the evaluation of models for integrated care, the length, frequency and content of training programmes, psychiatric assessments and the cost-effectiveness of out-patient pulmonary rehabilitation. PMID- 21289885 TI - The importance of growth factors for the treatment of chronic wounds in the case of diabetic foot ulcers. AB - INTRODUCTION: Ulcers as a result of diabetes mellitus are a serious problem with an enormous impact on the overall global disease burden due to the increasing prevalence of diabetes. Because of long hospital stays, rehabilitation, often required home care and the use of social services diabetic foot complications are costly. Therapy with growth factors could be an effective and innovative add-on to standard wound care. RESEARCH QUESTIONS: What is the benefit of therapies with growth factors alone or in combination with other technologies in the treatment of diabetic foot ulcer assessed regarding medical, economical, social, ethical and juridical aspects? METHODS: We systematically searched relevant databases limited to English and German language and publications since 1990. Cost values were adjusted to the price level of 2008 and converted into Euro. A review and an assessment of the quality of publications were conducted following approved methodical standards conforming to evidence-based medicine and health economics. RESULTS: We identified 25 studies (14 randomized controlled trials (RCT), nine cost-effectiveness analyses, two meta-analyses). The RCT compared an add-on therapy to standard wound care with standard wound care/placebo alone or extracellular wound matrix: in six studies becaplermin, in two rhEGF, in one bFGF, and in five studies the metabolically active skin grafts Dermagraft and Apligraf. The study duration ranged from twelve to 20 weeks and the study population included between 17 to 382 patients, average 130 patients. The treatment with becaplermin, rhEGF and skin implants Dermagraft and Apligraf showed in eight out of 13 studies an advantage concerning complete wound closure and the time to complete wound healing. Evidence for a benefit of treatment with bFGF could not be found. In four out of 14 studies the proportion of adverse events was 30% per study group with no difference between the treatment groups. The methodological quality of the studies was affected by significant deficiencies. The results showed becaplermin being cost-effective whereas no obvious statement can be made regarding Dermagraft and Apligraf because of diverging cost bases and incremental cost-effectiveness ratios. DISCUSSION: Differences in standard wound care are complicating the comparison of study results. Taking into consideration the small to very small sample sizes and other methodological flaws with high potential of bias, the validity of the results with regard to effectiveness and cost-effectiveness has to be considered limited. The duration of treatment and follow-up examinations is not long enough to assess the sustainability of the intervention and the surveillance of ulcer recurrences or treatment related adverse events like the development of malignancy. CONCLUSIONS: There are indications of an advantage for the add-on therapy with growth factors in diabetic foot ulcers concerning complete wound closure and the time to complete wound healing. Further more studies of high methodological quality with adequate sample sizes and sufficient follow-up periods are necessary also investigating patient-relevant parameters like the health-related quality of life, the acceptance and tolerance of the intervention in addition to clinical outcomes. PMID- 21289886 TI - Effectiveness of pharmaceutical therapy of ADHD (Attention-Deficit/Hyperactivity Disorder) in adults - health technology assessment. AB - BACKGROUND: Attention-Deficit/Hyperactivity Disorder (ADHD) is a mental disorder. Symptoms include hyperactivity, lack of attentiveness, and frivolousness. This disorder always begins in childhood, but can remain through adulthood. ADHD affects all areas of life and limits the quality of life due to its symptoms and the high rate of associated disorders that can develop. An established form of therapy is using stimulant medications, most commonly, containing Methylphenidate as the active ingredient. However, in Germany this ingredient is not approved for adults suffering from ADHD. Therefore, many adults cannot obtain appropriate medication to treat this disorder. OBJECTIVE: The following report (Health Technology Assessment [HTA]) examines the effectiveness and cost-effectiveness of the medical treatment of ADHD in adults as well as the ethical, social and legal aspects thereof. METHODS: In August 2009, a systematic literature search is performed in all relevant scientific databases. The selected citations fulfill predetermined inclusion criteria. The data in the publications is then systematically extracted, reviewed and assessed. A manual search of citations is conducted as well. RESULTS: NINETEEN STUDIES FULFILL THE INCLUSION CRITERIA: nine randomised controlled studies (RCT), five meta-analyses, three economic studies and two studies relevant to the legal aspects of the HTA. All RCT reveal that adult patients who receive medication containing a stimulant (Methylphenidate and Amphetamine) and Atomoxetine, see a reduction of ADHD symptoms compared to the placebo-treated patients. The drug response rate among the control group ranges from 7 to 42%; in the treatment group from 17 to 59.6%. The meta-analyses confirm the findings of the RCT. In light of the control group, it can be ascertained that there are higher annual costs (both direct and indirect) for patients with ADHD. The average annual medical expenses for an adult with ADHD were 1,262 $ in 1998 and 1,673 $ in 2001 (the converted and inflation-adjusted rate for 2009: between 1,270 and 1,619 Euro). The use of stimulants use may impair the patient's ability to drive, travel or do sports. No relevant studies can be identified concerning the ethical, social and/or legal aspects of stimulant medication for ADHD patients. DISCUSSION/CONCLUSION: Medical treatment, particularly including Methylphenidate and Atomoxetine, proves to have a positive effect. In order to attain an optimal drug response, dosing must be determined on an individual basis. There is a need of high-quality studies that directly compare various agents - an aspect which is relevant to medical effectiveness of a therapy. No definite statement can be made about the cost-effectiveness of the medical treatment of ADHD in adults. More health economic studies are therefore required. Apart from the unquestionable mental indication, it is already recommended by health economic reasons to establish the conditions for an adequate treatment with these medicaments also for adults. PMID- 21289887 TI - Surgery of pulmonary aspergillomas in immunocompromised patients. AB - INTRODUCTION: Pulmonary aspergillosis is a devastating complication in immunocompromised patients. Timing of surgery is controversial and depends on the patients' general condition. METHODS: From 2000 to 2007, 16 patients (mean age 47 years, range 20-64) underwent surgery for pulmonary aspergillosis. All patients were receiving immunosuppressive drugs due to chemotherapy of hematological malignancies, ten with additional bone marrow or stem cell transplantation. Perioperatively, aspergillosis was treated with antifungal agents. If granulocyte numbers in the peripheral blood was below 1.0x10(9)/l, granulocyte stimulating factor and granulocyte transfusions were administered perioperatively. RESULTS: Four patients underwent lobectomy and wedge resections of the same lung, one patient bilobectomy, two patients lobectomy, eight patients wedge resections of one lung, and one patient wedge resections of both lungs. All patients survived surgery without major complications. Five patients were bone marrow or stem cell transplanted 1, 2, 3, 7 and 10 months after surgery. Three of them died due to recurrence of the underlying malignancy. All other patients are alive and free of fungal disease. CONCLUSIONS: Timing of surgery in the context of antifungal therapy and adequate numbers of granulocytes and platelets in the peripheral blood appear essential for successful surgical therapy and avoidance of major complications. PMID- 21289888 TI - Concepts of care for people with dementia. AB - INTRODUCTION: Today there are approximately one million people with dementia in Germany. If current demographic trends continue, this number is likely to rise substantially in the coming years. In the older population, dementia is the most frequent reason for long-term care. Because most forms of dementia cannot be cured, the aim of treatment is to delay disease progression and to maintain functioning and quality of life. RESEARCH QUESTIONS: What is the evidence on different approaches to the long-term usual care of patients with dementia in terms of common endpoints such as quality of life, and social behaviour? How is the cost-effectiveness of these concepts to be evaluated? Which ethical, social, or legal issues are discussed in this context? METHODS: Based on a systematic literature review, we include randomized, controlled studies that had at least 30 participants and investigated one or more of the following approaches of dementia care: validation therapy/emotion-oriented usual care, ergotherapy, sensory stimulation, relaxation techniques, reality orientation therapy, and reminiscence therapy. Studies had to be published after 1996 (after 1990 for the economic part) in English or German. RESULTS: A total of 20 studies meet the inclusion criteria. Of these, three focus on validation therapy/emotion-oriented usual care, five on ergotherapy, seven on different kinds of sensory stimulation, two on reality orientation, two on reminiscence therapy, and one on a type of relaxation technique. There are no significant differences between the intervention and control groups in two of the three studies on validation therapy or emotion-oriented usual care, in two of the five studies on ergotherapy, in three of the seven studies on sensory stimulation, in both of the two studies on reminiscence therapy, and in the one study on relaxation. In the remaining ten studies, seven report some positive results in favour of the respective interventions, and three studies (ergotherapy, aroma therapy, and music/massage) report positive effects with respect to all of the endpoints measured. Six publications present economic results for usual-care-concepts. One study reports additional costs of 16 GBP (24.03 Euro (2006)) per patient per week for occupational therapie. Two publications declare incremental cost of 24.30 USD (25.62 Euro (2006)) per mini-mental-state-examination-(MMSE)-point gained per month respectively 1,380,000 ITL (506.21 Euro (2006)) per MMSE-point gained. Two publications focus on mixed interventions. One study reports the additional costs of an activity program (1.13 USD (1.39 Euro (2006)) per day per patient) and the other additional time for the usual care for mobile demented patients (average of 45 minutes per day per patient). WITH RESPECT TO ETHICAL AND SOCIAL ASPECTS THE DISCUSSION FOCUSSES ON THE PROBLEM OF AUTONOMY: dementia does not necessarily mean inability to decide over the participtation in studies. Legal questions address the financial situation of patients, the organisation of their care and the legal representation of dementia patients. DISCUSSION: Only a few studies on the nursing interventions considered in this report are methodologically robust. Most of the studies have a small number of participants and show substantial differences in terms of their inclusion criteria, implementation, and endpoints. THIS HETEROGENEITY IS REFLECTED IN THE RESULTS: in half of the studies, the interventions have no positive effects compared to the control group. The other half of the studies reports some positive effects with regard to specific endpoints. All of the economic studies are, from a methodologial and a thematic standpoint, not suitable to answer the questions raised. Ethical, social and legal aspects are discussed but not systematically analysed. CONCLUSION: The studies conducted to date do not provide sufficient evidence of neither efficacy nor cost-effectiveness for any of the nursing interventions considered in the present HTA. However, lack of evidence does not mean lack of efficacy. Instead, more methodologically sound studies are needed. Particullary desireable are studies reflecting the framework of dementia care in Germany. This holds also for the healtheconomic evaluations of the chosen interventions. PMID- 21289889 TI - Effectiveness and efficiency of CT-colonography compared to conventional colonoscopy for the early detection and diagnosis of colorectal cancer. AB - HEALTH POLITICAL BACKGROUND: Colorectal cancer (CC) is the second most common cancer and cause of cancer death for both men and women in Germany. Various methods for early detection of CC exist, including conventional coloscopy which is reimbursed within the scope of cancer screening, as well as computertomography coloscopy (CTC) which is currently not reimbursed. SCIENTIFIC BACKGROUND: CTC is a mere diagnostic procedure which has a lower risk of perforation than conventional coloscopy. However, as it is an x-ray procedure, it exposes the patient to radiation. Conventional coloscopy is considered the gold standard due to its high sensitivity and specificity for locating adenomas. Furthermore, it offers the advantage that in addition to extended diagnostic measures therapeutic measures can be undertaken during the procedure. RESEARCH QUESTIONS: This HTA report aims to evaluate the effectiveness and efficiency of CTC in comparison to conventional coloscopy in the early detection and diagnosis of colorectal cancer and/or its precursors and which ethical and legal aspects have to be considered. METHODS: The systematic literature search (27 international literature data bases) yielded a total of 1,713 abstracts. After a two-step selection process 36 publications remained to be assessed. RESULTS: The results regarding the effectivity of CTC in diagnosis and screening for colorectal cancer and/or its precursors are partly promising, however, they are very heterogeneous. Therefore, regarding its sensitivity and specificity, CTC cannot be considered an equivalent alternative to conventional coloscopy for diagnosis and screening. The heterogeneity of results is due to technical (device type, settings), patient dependent (preparation) and operator dependent (training) factors. No economic results for a comparison of the procedures for diagnosis exist. Regarding the cost-effectiveness of a CTC-screening, international model calculations are available. According to this calculation, the CTC-screening is cost-effective compared to the option 'no screening'; however, conventional coloscopy-screening is generally more cost-effective. DISCUSSION: If modern CTC-devices are used with adequate technical settings, software, appropriate patient preparation and training of the operator, better results regarding sensitivity can be expected. Basically, the fact that no therapeutic measures (polypectomy) can be taken during CTC compared to conventional coloscopy needs to be considered. Unanswered medical questions pertain to the interval of examinations for screening (considering the radiation exposure), the approach to small polyps and the significance of flat and depressed lesions. Regarding its cost-effectiveness, conventional coloscopy-screening results in greater health benefits and lower costs than CTC-screening in most model calculations. These results cannot be applied to Germany directly. An important ethical aspect is the consideration of patient preferences regarding the procedures. Legal aspects concern the stipulation and maintenance of quality standards. CONCLUSIONS: At this time, a clear endorsement of CTC as an alternative procedure for diagnosis and screening to the current gold standard conventional coloscopy cannot be given. On the basis of the available literature this holds true for both the medical as well as the economic assessment. However, despite the numerous studies and analyses on this topic, this assessment is afflicted with uncertainties. Due to the rapid development of CTC, short term revisions of these research questions are needed. PMID- 21289890 TI - Medical and health economic assessment of radiosurgery for the treatment of brain metastasis. AB - BACKGROUND: Radiotherapy for patients suffering from malignant neoplasms has developed greatly during the past decades. Stereotactic radiosurgery (SRS) is one important radiotherapeutic option which is defined by a single and highly focussed application of radiation during a specified time interval. One of its important indications is the treatment of brain metastases. OBJECTIVES: The objective of this HTA is to summarise the current literature concerning the treatment of brain metastasis and to compare SRS as a single or additional treatment option to alternative treatment options with regard to their medical effectiveness/efficacy, safety and cost-effectiveness as well as their ethical, social and legal implications. METHODS: A structured search and hand search of identified literature are performed from January 2002 through August 2007 to identify relevant publications published in English or German. Studies targeting patients with single or multiple brain metastases are included. The methodological quality of included studies is assessed according to quality criteria, based on the criteria of evidence based medicine. RESULTS: Of 1,495 publications 15 medical studies meet the inclusion criteria. Overall study quality is limited and with the exception of two randomized controlleed trials (RCT) and two meta-analyses only historical cohort studies are identified. Reported outcome measures are highly variable between studies. Studies with high methodological quality provide evidence, that whole-brain radiotherapy (WBRT) in addition to SRS and SRS in addition to WBRT is associated with improved local tumour control rates and neurological function. However, only in patients with single brain metastasis, RPA-class 1 (RPA = Recursive partitioning analysis) and certain primary tumour entities, this combination of SRS and WBRT is associated with superior survival compared to WBRT alone. Studies report no significant differences in adverse events between treatment groups. Methodologically less rigorous studies provide no conclusive evidence with regard to medical effectiveness and safety, comparing SRS to WBRT, neurosurgery (NS) or hypofractionated radiotherapy (HCSRT). The quality of life is not investigated in any of the studies. Within the searched databases a total of 320 economic publications are identified. Five publications are eligible for this report. The five reports have a quiet variable quality. Concerning the economic efficiency of alternative equipment, while assuming equal effectiveness, the calculations show, that economic efficiency depends to a large extend on the number of patients treated. In case the two alternative equipments are used solely for SRS, the Gamma Knife might be more cost-efficient. Otherwise an adapted linear accelerator is most likely to be beneficial because of its flexibility. One Health Technology Assessment (HTA) states, that the cost for a Gamma Knife and a dedicated linear accelerator are comparable, while an adapted version is cheaper. No reports concerning ethical, legal and social aspects are identified. DISCUSSION: Overall, quantity and quality of identified studies is limited. However, the identified studies indicate that the prognosis of patients with brain metastases is despite highly developed and modern treatment regimes still limited. Conclusive evidence with regard to the effectiveness of identified interventions is only available for the combined treatment of SRS and WBRT compared to SRS or WBRT alone. Furthermore, there is insufficient evidence to compare SRS with WBRT, NS or HCSRT. The efficiency of the different equipments depends to a great extent on the number and the indications of the patients treated. If dedicated systems are used to their full capacity, there is some evidence for superior cost effectiveness. If more treatment flexibility is required, adapted systems seem to be advantageous. However, equal treatment effectiveness is a necessary assumption for these conclusions. The need for a treatment precision can influence the purchase decision. No reports concerning more recent therapeutic alternatives are currently available. CONCLUSION: Combination of SRS and WBRT is associated with improved local tumour control and neurological function compared to SRS or WBRT alone. However, only for patients with single metastasis there is strong evidence that this results in improved survival compared to WBRT alone. Methodologically rigorous studies are warranted to investigate SRS compared to WBRT and NS and to investigate the quality of life in patients undergoing these treatment regimes. Concerning the type of equipment used, economic efficiency depends to a great extend on the capacity at which the system can be used. Dedicated systems might be favourable for a high number of patients, while lower patient counts probably favour adapted systems with their superior treatment flexibility. Using the equipment at its full capacity may result in a limited number of machines, what in turn may give rise to the question of an equal and easy access to this technology. Studies focusing on the comparative effectiveness and cost effectiveness of different treatment options and their combinations, especially for the German setting, are warranted. PMID- 21289891 TI - Human papillomavirus (HPV) vaccination for the prevention of HPV 16/18 induced cervical cancer and its precursors. AB - INTRODUCTION: Essential precondition for the development of cervical cancer is a persistent human papillomavirus (HPV) infection. The majority - approximately 70% - of cervical carcinomas is caused by two high-risk HPV types (16 and 18). Recently, two vaccines have been approved to the German market with the potential to induce protection against HPV 16 and HPV 18 among additional low-risk virus types. OBJECTIVES: To analyse whether HPV vaccination is effective with regard to the reduction of cervical cancer and precursors of cervical carcinoma (CIN), respectively? Does HPV vaccination represent a cost-effective alternative or supplement to present screening practice? Are there any differences concerning cost-effectiveness between the two available vaccines? Should HPV vaccination be recommended from a health economic point of view? If so, which recommendations can be conveyed with respect to a (re)organization of the German vaccination strategy? Which ethical, social and legal implications have to be considered? METHODS: Based on a systematic literature review, randomized controlled trials (RCT) looking at the effectiveness of HPV vaccination for the prevention of cervical carcinoma and its precursors - cervical intraepithelial neoplasia - have been identified. In addition, health economic models were identified to address the health economic research questions. Quality assessment of medical and economic literature was assured by application of general assessment standards for the systematic and critical appraisal of scientific studies. RESULTS: Vaccine efficacy in prevention of CIN 2 or higher lesions in HPV 16 or HPV 18 negative women, who received all vaccination doses, ranges between 98% and 100%. Side effects of the vaccination are mainly associated with injection site reactions (redness, turgor, pain). No significant differences concerning serious complications between the vaccination- and the placebo-groups were reported. Results of base case scenarios in the identified health economic modeling analyses range from approximately 3,000 Euro to 40,000 Euro per additional QALY (QALY = Quality-adjusted life year) and approximately 9,000 Euro to 65,000 Euro per additional life year (LYG), respectively. DISCUSSION: The included studies show that both available HPV vaccines are effective in preventing HPV 16 and HPV 18 infections and probable resulting premalignant lesions of the cervix. However, the duration of protection is currently unclear. With regard to side effects, the vaccination can be considered as secure. Nevertheless, the number of cases within the clinical studies is not sufficient to determine the occurrence of rarely occurring (severe) adverse events in a reliable way. A reduction in the incidence and induced mortality through cervical cancer in Germany is not only depending on the vaccine's clinical efficacy. Effects of the new technology on the overall participation rate in screening programs and the resulting vaccination rate and immunization status are also important factors. The results of identified health economic models vary substantially due to the heterogeneity of methodological approaches as well as chosen input parameters. However, almost all model-based analyses reached the conclusion that the implementation of a vaccination with lifelong protection can be considered as cost-effective, if the present screening practice continues. A comparison of the two vaccines shows, that the cost effectiveness ratios are more favorable with the quadrivalent vaccine than with the bivalent alternative when considering QALY as primary outcome parameter. The reason for this finding might be that in the case of the quadrivalent vaccine the prevention of genital warts can also be incorporated into the analysis. Variations of the duration of protection as well as the discounting rate were identified as the primary influencing factors of cost-effectiveness results. CONCLUSION: Implementation of HPV vaccination might lead to a reduction of cervical cancer in immunized women. However, uptake of immunization should be accompanied by further studies in order to assess long-term effectiveness and safety aiming at an optimization of possible implementation processes. High numbers of participants are of particular importance regarding immunization. This has to be backed up by programs to optimize early detection - as this affects even those women who already underwent immunization. Since cost-effectiveness evidence might be significantly affected by the unclear duration of protective benefits, a final verdict on the vaccination's cost-effectiveness in the German setting is not possible. Hence, risk-sharing-agreements between third-party payers and manufacturers would pose an option to balance the consequences of uncertainty towards the duration of protection on cost-effectiveness. PMID- 21289892 TI - Overweight prevention in adolescents and children (behavioural and environmental prevention). AB - HEALTH POLITICAL BACKGROUND: In 2006, the prevalence of overweight and adiposity among children and adolescents aged three to 17 years is 15%, 6.3% (800,000) of these are obese. SCIENTIFIC BACKGROUND: Obese children and adolescents have an increased body fat ratio. The reasons for overweight are - among others - sociocultural factors, and a low social status as determined by income and educational level of the parents. The consequences of adiposity during childhood are a higher risk of metabolic and cardiovascular diseases and increased mortality in adulthood. Possible approaches to primary prevention in children and adolescents are measures taken in schools and kindergarten, as well as education and involvement of parents. Furthermore, preventive measures geared towards changing environmental and living conditions are of particular importance. RESEARCH QUESTIONS: What is the effectiveness and efficiency of different measures and programs (geared towards changing behaviour and environmental and living conditions) for primary prevention of adiposity in children and adolescents, with particular consideration of social aspects? METHODS: The systematic literature search yielded 1,649 abstracts. Following a two-part selection process with predefined criteria 31 publications were included in the assessment. RESULTS: The majority of interventions evaluated in primary studies take place in schools. As the measures are mostly multi-disciplinary and the interventions are often not described in detail, no criteria of success for the various interventions can be extrapolated from the reviews assessed. An economic model calculation for Australia, which compares the efficiency of different interventions (although on the basis of low evidence) comes to the conclusion that the intervention with the greatest impact on society is the reduction of TV ads geared towards children for foods and drinks rich in fat and sugar. There is a significant correlation between adiposity and socioeconomic deprivation. The lack of interventions (especially preventive measures geared towards changing environmental and living conditions) and studies focusing on this population group is noticeable. DISCUSSION: There are only a few primary studies of high quality on adiposity prevention in children and adolescents. Especially studies which compare different measures are lacking. This holds also true for the economic analysis, which seems logical insofar, as the basis for economic analyses are usually primary studies (preferably randomized controlled trials (RCT)) due to their evidence level). Studies on interventions geared towards changing environmental and living conditions and towards specific population groups (i. e. the socially disadvantaged) are hardly available. CONCLUSIONS: There are hardly any primary studies of high quality on adiposity prevention in children and adolescents, especially studies which compare different measures are lacking. Interventions geared towards specific population groups (particularly for the socioeconomically disadvantaged) are specifically underrepresented. Establishing such studies is an essential requirement of adiposity prevention. Recommended are a combination of measures geared towards changing environmental and living conditions and towards specific population groups. Furthermore, it is recommended to systematically register future programs (preferably online) in order to be able to draft criteria of success. PMID- 21289893 TI - Prognostic value, clinical effectiveness and cost-effectiveness of high sensitivity C-reactive protein as a marker in primary prevention of major cardiac events. AB - BACKGROUND: In a substantial portion of patients (= 25%) with coronary heart disease (CHD), a myocardial infarction or sudden cardiac death without prior symptoms is the first manifestation of disease. The use of new risk predictors for CHD such as the high-sensitivity C-reactive Protein (hs-CRP) in addition to established risk factors could improve prediction of CHD. As a consequence of the altered risk assessment, modified preventive actions could reduce the number of cardiac death and non-fatal myocardial infarction. RESEARCH QUESTION: Does the additional information gained through the measurement of hs-CRP in asymptomatic patients lead to a clinically relevant improvement in risk prediction as compared to risk prediction based on traditional risk factors and is this cost-effective? METHODS: A literature search of the electronic databases of the German Institute of Medical Documentation and Information (DIMDI) was conducted. Selection, data extraction, assessment of the study-quality and synthesis of information was conducted according to the methods of evidence-based medicine. RESULTS: Eight publications about predictive value, one publication on the clinical efficacy and three health-economic evaluations were included. In the seven study populations of the prediction studies, elevated CRP-levels were almost always associated with a higher risk of cardiovascular events and non-fatal myocardial infarctions or cardiac death and severe cardiovascular events. The effect estimates (odds ratio (OR), relative risk (RR), hazard ratio (HR)), once adjusted for traditional risk factors, demonstrated a moderate, independent association between hs-CRP and cardiac and cardiovascular events that fell in the range of 0.7 to 2.47. In six of the seven studies, a moderate increase in the area under the curve (AUC) could be detected by adding hs-CRP as a predictor to regression models in addition to established risk factors though in three cases this was not statistically significant. The difference [in the AUC] between the models with and without hs CRP fell between 0.00 and 0.023 with a median of 0.003. A decision-analytic modeling study reported a gain in life-expectancy for those using statin therapy for populations with elevated hs-CRP levels and normal lipid levels as compared to statin therapy for those with elevated lipid levels (approximately 6.6 months gain in life-expectancy for 58 year olds). Two decision-analytic models (three publications) on cost-effectiveness reported incremental cost-effectiveness ratios between Euro 8,700 and 50,000 per life year gained for the German context and between 52,000 and 708,000 for the US context. The empirical input data for the model is highly uncertain. CONCLUSION: No sufficient evidence is available to support the notion that hs-CRP-values should be measured during the global risk assessment for CAD or cardiovascular disease in addition to the traditional risk factors. The additional measurement of the hs-CRP-level increases the incremental predictive value of the risk prediction. It has not yet been clarified whether this increase is clinically relevant resulting in reduction of cardiovascular morbidity and mortality. For people with medium cardiovascular risk (5 to 20% in ten years) additional measurement of hs-CRP seems most likely to be clinical relevant to support the decision as to whether or not additional statin therapy should be initiated for primary prevention. Statin therapy can reduce the occurrence of cardiovascular events for asymptomatic individuals with normal lipid and elevated hs-CRP levels. However, this is not enough to provide evidence for a clinical benefit of hs-CRP-screening. The cost-effectiveness of general hs CRP-screening as well as screening among only those with normal lipid levels remains unknown at present. PMID- 21289894 TI - Computerized Physician Order Entry - effectiveness and efficiency of electronic medication ordering with decision support systems. AB - HEALTH POLITICAL BACKGROUND: Computerized physician order entry (CPOE) systems are software to electronically enter medication orders. They can be equipped with tools for decision support (CDS). In Germany, various vendors offer such systems for hospitals and physicians' offices. These systems have mostly been developed during the last five to ten years. SCIENTIFIC BACKGROUND: CPOE-systems exist since the 1970's. Usually, clinical decision support is integrated into the CPOE to avoid errors. RESEARCH QUESTIONS: This HTA-report aims to evaluate the effectiveness and efficiency of CPOE-/CDS-systems and their ethical, social and legal aspects. METHODS: The systematic literature search (27 international data bases) yielded 791 abstracts. Following a two-part selection process, twelve publications were included in the assessment. RESULTS: All reviews and studies included in the present report show that the use of CPOE-/CDS-systems can lead to a reduction of medication errors. Minor errors can be eliminated almost completely. The effect of CPOE-/CDS-systems on the rate of adverse drug events (ADE) is evaluated in only two primary studies with conflicting results. It is difficult to compare the results of economical studies because they evaluate different settings, interventions and time frames. In addition, the documentation often is not fully transparent. All four studies included measure costs and effects from the perspective of a hospital or hospital affiliation. Concerning social aspects, the literature points at changes regard competing interests of technology and humans that result from the implementation of CPOE-systems. The experience of institutions in which the implementation of CPOE-systems leads to problems showed that the importance of considering the socio-organisational context had partly been underestimated. DISCUSSION: CPOE-/CDS-systems are able to reduce the rate of medication errors when ordering medications. The adherence to guidelines, communication, patient care and personnel satisfaction can also be affected positively. However, the literature also reports negative effects, as through the use of CPOE-/CDS-systems new errors can be generated. This makes continuous revisions of the system, as well as data-updates necessary. Concerning the cost-benefit-ratio from the hospital perspective, the two qualitatively best economic studies show contradictory results. Therefore, a positive cost-benefit ratio for individual hospitals cannot be assumed, particularly as the study results cannot be generalized. CONCLUSIONS: If the implementation of CPOE-/CDS systems is well planned and conducted, the system adapted to the needs of the institution and continuously reviewed, and data used are updated on a regular basis, the rate of medication ordering errors can be reduced considerably by using CPOE-/CDS-systems. However, it is not clear how this results in a reduction of ADE. Prospective, systematic multi-centre evaluation-studies with clear methodology are needed, which include an analysis of the user-friendliness and of social and technical aspects of the system. Such studies should evaluate the impact a CPOE-/CDS-system has on ADE-rates and mortality. A detailed description of the system used and of the hospital evaluated is essential. If possible, costs and cost effects should be surveyed and documented transparently. PMID- 21289895 TI - Effectiveness and cost-efficiency of phosphate binders in hemodialysis. AB - HEALTH POLITICAL BACKGROUND: In 2006, the prevalence of chronic renal insufficiency in Germany was 91,718, of which 66,508 patients were on dialysis. The tendency is clearly growing. SCIENTIFIC BACKGROUND: Chronic renal insufficiency results in a disturbance of the mineral balance. It leads to hyperphosphataemia, which is the strongest independent risk factor for mortality in renal patients. Usually, a reduction in the phosphate intake through nutrition and the amount of phosphate filtered out during dialysis are not sufficient to reduce the serum phosphate values to the recommended value. Therefore, phosphate binders are used to bind ingested phosphate in the digestive tract in order to lower the phosphate concentration in the serum. Four different groups of phosphate binders are available: calcium- and aluminium salts are the traditional therapies. Sevelamer and Lanthanum are recent developments on the market. In varying doses, all phosphate binders are able to effectively lower phosphate concentrations. However, drug therapies have achieved recommended phosphate levels in only 50 percent of patients during the last years. RESEARCH QUESTIONS: How effective and efficient are the different phosphate binders in chronic renal insufficient patients? METHODS: The systematic literature search yielded 1,251 abstracts. Following a two-part selection process with predefined criteria 18 publications were included in the assessment. RESULTS: All studies evaluated conclude that serum phosphate, serum calcium and intact parathyroid hormone can be controlled effectively with all phosphate binders. Only the number of episodes of hypercalcaemia is higher when using calcium-containing phosphatebinders compared to Sevelamer and Lanthanum. Regarding the mortality rate, the cardiovascular artery calcification and bone metabolism no definite conclusions can be drawn. In any case, the amount of calcification at study start seems to be crucial for the further development of the cardiovascular calcification. Economic studies show higher costs for Sevelamer and Lanthanum compared to calcium containing phosphate binders. DISCUSSION: Only a few well documented primary studies on the effectiveness of phosphate binders are available. Particularly long-term studies with a robust study design and transparent documentation are lacking. Ten of the eleven primary studies included in this report were conducted in only 539 patients from five patient collectives. CONCLUSIONS: From a medical point of view, Sevelamer shows some superiority over calcium-containing phosphate binders based on the current data, at least for special indications. The validity of the present Health Technology Assessment (HTA) report is significantly limited due to the limited number of available publications, the low sample size of treated patients, as well as the fact that the majority of studies are based on the same patient collectives. Prospective long-term studies not funded by the industry with adequate sample sizes and comparable study designs are called for to make authoritative statements regarding the medical effectiveness and safety of Sevelamer and Lanthanum, as well as regarding their economic efficiency. PMID- 21289896 TI - Indirect comparisons of therapeutic interventions. AB - HEALTH POLITICAL BACKGROUND: The comparison of the effectiveness of health technologies is not only laid down in German law (Social Code Book V, S 139 and S 35b) but also constitutes a central element of clinical guidelines and decision making in health care. Tools supporting decision making (e. g. Health Technology Assessments (HTA)) are therefore in need of a valid methodological repertoire for these comparisons. SCIENTIFIC BACKGROUND: Randomised controlled head-to-head trials which directly compare the effects of different therapies are considered the gold standard methodological approach for the comparison of the efficacy of interventions. Because this type of trial is rarely found, comparisons of efficacy often need to rely on indirect comparisons whose validity is being controversially debated. RESEARCH QUESTIONS: RESEARCH QUESTIONS FOR THE CURRENT ASSESSMENT ARE: Which (statistical) methods for indirect comparisons of therapeutic interventions do exist, how often are they applied and how valid are their results in comparison to the results of head-to-head trials? METHODS: In a systematic literature research all medical databases of the German Institute of Medical Documentation and Information (DIMDI) are searched for methodological papers as well as applications of indirect comparisons in systematic reviews. Results of the literature analysis are summarized qualitatively for the characterisation of methods and quantitatively for the frequency of their application. The validity of the results from indirect comparisons is checked by comparing them to the results from the gold standard - a direct comparison. Data sets from systematic reviews which use both direct and indirect comparisons are tested for consistency by of the z-statistic. RESULTS: 29 methodological papers and 106 applications of indirect methods in systematic reviews are being analysed. Four methods for indirect comparisons can be identified: Unadjusted indirect comparisons include, independent of any comparator, all randomised controlled trials (RCT) that provide a study arm with the intervention of interest. Adjusted indirect comparisons and metaregression analyses include only those studies that provide one study arm with the intervention of interest and another study arm with a common comparator. While the aforementioned methods use conventional metaanalytical techniques, Mixed treatment comparisons (MTC) use Bayesian statistics. They are able to analyse a complex network of RCT with multiple comparators simultaneously. During the period from 1999 to 2008 adjusted indirect comparisons are the most commonly used method for indirect comparisons. Since 2006 an increase in the application of the more methodologically challenging MTC is being observed. For the validity check 248 data sets, which include results of a direct and an indirect comparison, are available. The share of statistically significant discrepant results is greatest in the unadjusted indirect comparisons (25,5% [95% CI: 13,1%; 38%]), followed by metaregression analyses (16,7% [95% CI: -13,2%; 46,5%]), adjusted indirect comparisons (12,1% [95% CI: 6,1%; 18%]) and MTC (1,8% [95% CI: -1,7%; 5,2%]). Discrepant results are mainly detected if the basic assumption for an indirect comparison - between study homogeneity - does not hold. However a systematic over- or underestimation of the results of direct comparisons by any of the indirectly comparing methods was not observed in this sample. DISCUSSION: The selection of an appropriate method for an indirect comparison has to account for its validity, the number of interventions to be compared and the quality as well as the quantity of available studies. Unadjusted indirect comparisons provide, contrasted with the results of direct comparisons, a low validity. Adjusted indirect comparisons and MTC may, under certain circumstances, give results which are consistent with the results of direct comparisons. The limited number of available reviews utilizing metaregression analyses for indirect comparisons currently prohibits empirical evaluation of this methodology. CONCLUSIONS/RECOMMENDATIONS: Given the main prerequisite - a pool of homogenous and high-quality RCT - the results of head-to head trials may be pre-estimated by an adjusted indirect comparison or a MTC. In the context of HTA and guideline development they are valuable tools if there is a lack of a direct comparison of the interventions of interest. PMID- 21289897 TI - Behavioural and skill-based early interventions in children with autism spectrum disorders. AB - INTRODUCTION: Autism spectrum disorders (ASD) comprise typical or infantile autism (Kanner syndrome), Asperger's disorder and atypical autism or pervasive developmental disorder - not otherwise specified. The syndrome is characterized by deficits in (1) verbal and nonverbal communication, (2) reciprocal social interaction and (3) repetitive patterns of behaviour, interests and activities. Early behavioural interventions are based on learning theory and behaviour therapy. They take into account specific deficits in perception, emotional reactions, social interaction and communication. In Germany, these comprehensive models are not widely evaluated and implemented. RESEARCH QUESTIONS: What are the clinical effectiveness and safety of early behavioural or skills-based early interventions in autism compared to other interventions or to treatment as usual?What are specific factors responsible for the effectiveness?What are the cost-effectiveness and cost consequences of different early interventions in autism?Which legal, social and ethical aspects are relevant with regard to the implementation of the respective interventions in persons with autism? METHODS: Following a systematic review of the literature, controlled studies on early behavioural or skills-based interventions published since 2000 in English or German with children until the age of twelve are included and critically appraised. Studies must have at least ten participants per intervention group. RESULTS: In total, 15 publications based on 14 studies, eight systematic reviews and one health economic study are included. Most studies evaluate early interventions based upon the Lovaas model (Early intensive behavioural treatment (EIBT), Applied behavioural analysis (ABA)). Other evaluate pragmatic interventions or interventions based on other theoretical models like specific parent interventions, responsive education and prelinguistic milieu teaching, joint attention, symbolic play, and picture exchange communication system. Behaviour analytic interventions referring to the Lovaas model remain the most empirically evaluated early interventions in autism. Preschool children with autism can achieve improvements in cognitive and functional domains when treated within behavioural interventions with a frequency of at least 20 hours per week. It is not clear which is the minimum duration of effective interventions, and which active components are necessary for the effectiveness. There was no high quality evidence for other comprehensive early interventions. The identified health economic study is not suitable to evaluate the cost-effectiveness or cost consequences of early interventions. No publications concerning legal, ethical or social aspects were identified. The financial situation of persons with autisms and their families will be improved through the implementation of the "Pflege Weiterententwicklungsgesetz" (Pf-WG). Further questions concern the organisation of care and the legal representation of autistic patients. Ethical questions arise mainly in the context of the equal supply of care to each individual patient in all regions of the country and the situation of the caregivers. DISCUSSION: There are only a few studies with high methodology evaluating early interventions in children with autism. Most studies have a short duration with a lack of blinded outcome assessment in many cases. The lack of high quality comparative studies does not allow answering questions of comparative effectiveness of early interventions in autism. It can be concluded that interventions referring to the Lovaas model seem to have the highest effectiveness. This seems to be especially true when they are run clinic-based. However, there was no solid evidence with regard to factors responsible for the effectiveness of programms according to the ABA model. With regard to communication improvement, a systematic parent training seems to be superior to treatment as usual where a mixture of therapeutic elements is used. As well for clinical and health economic studies there is a substantial problem of generalisability into the German context. The identified health economic study is not suitable to evaluate the cost-effectiveness or cost consequences of early interventions. CONCLUSION: Based on the available studies, there is no sufficient evidence for any of the evaluated behavioural early intervention programmes. Studies suggest that preschool children with autism in behavioural intervention programmes with a frequency of at least 20 hours per week can achieve improvements in cognitive and functional domains. There is no evidence that in a substantial portion of the children a normal development can be achieved by early interventions. Most research evidence is available for ABA. A minimal necessary intensity of interventions to achieve positive outcomes cannot be derived from literature. There are no valid statements possible as to cost-effectiveness or consequences of these interventions. Effective early interventions may reduce total autism costs in the long run. This may be achieved when the initial high treatment expenditures are more than compensated later if persons with this disorder have better social functioning. PMID- 21289898 TI - Assessments tools for risk prediction of cardiovascular diseases. AB - SCIENTIFIC BACKGROUND: Cardiovascular diseases have an enormous epidemiological and economic importance. For the selection of persons with increased total cardiovascular risk for individual-targeted (e. g. drug-based) prevention interventions different risk prognosis instruments (equations, point scores and table charts) were derived from studies or databases. The transferability of these prognostic instruments on the populations not examined in these data sources as well as their comparability are not clear. RESEARCH QUESTIONS: The evaluation addresses the questions on the existence of instruments for risk prediction of cardiovascular diseases, their transferability and comparability. METHODS: A systematic literature search was performed in the medical electronic databases in April 2008 beginning from 2004 and was completed with a hand search. Publications on the prognostic instruments for cardiovascular diseases as well as publications addressing external validity and/or comparing prognostic instruments were included in the evaluation. RESULTS: The systematic lierature search yielded 734 hits. Three systematic reviews, 38 publications with descriptions of prognostic instruments and 29 publications with data on the validity of the prognosis instruments were identified. Most risk prognosis instruments are based on the Framingham cohort of the USA. Only the PROCAM study is completely based on the German reference population. Almost all prognostic instruments use the variables sex, age, smoking, different parameters of the lipid status and of the blood pressure. Different cardiovascular events are considered to be an end parameter in the prognosis instruments. The time span for predicted events in the studies mostly comprises ten years. Data on calibration of the prognosis instruments (a quotient of the predicted by the observed risk) are presented in nearly half of the studies on the validation, however in no study from Germany. Only single studies find the levels of calibration between 0.9 and 1.1. Many studies on the transferability of the prognosis instruments show a value of the discrimination (correct differentiation of persons with different risk levels, best value 1.0) between 0.7 and 0.8, few studies between 0.8 and 0.9 and no study over 0.9. The studies addressing the discrimination of the prognostic instruments on the German population almost always find values between 0.7 and 0.8. The comparison of the validity of different risk prognosis instruments shows a trend for a better calibration and a better discrimination for the prognosis instruments examined on the derivation and/or validation cohorts of one of the compared prognostic instruments. Comparing the prognostic instruments on other cohorts, the newly derived Framingham prognostic instruments show a better discrimination in comparison with previously derived instruments. No studies exists comparing different prognostic instruments on the German population. DISCUSSION: The geographic variance of the cardiovascular morbidity and mortality supposed to be the most important factor limiting the transferability of the prognostic instruments. An appropriate recalibration is considered to be an approach for the improvement of the transferability. CONCLUSIONS: The identified instruments for the risk prediction of cardiovascular diseases are insufficiently validated on the German population. Their use can lead to false risk estimation for a single person. Therefore, the existing prognostic instruments should be used for the informed decision-making and for the therapy selection in Germany only with critical caution. PMID- 21289899 TI - Use of Surrogate end points in HTA. AB - The different actors involved in health system decision-making and regulation have to deal with the question which are valid parameters to assess the health value of health technologies.So called surrogate endpoints represent in the best case preliminary steps in the casual chain leading to the relevant outcome (e. g. mortality, morbidity) and are not usually directly perceptible by patients. Surrogate endpoints are not only used in trials of pharmaceuticals but also in studies of other technologies. Their use in the assessment of the benefit of a health technology is however problematic.IN THIS REPORT WE INTEND TO ANSWER THE FOLLOWING RESEARCH QUESTIONS: Which criteria need to be fulfilled for a surrogate parameter to be considered a valid endpoint? Which methods have been described in the literature for the assessment of the validity of surrogate endpoints? Which methodological recommendations concerning the use of surrogate endpoints have been made by international HTA agencies? Which place has been given to surrogate endpoints in international and German HTA reports?For this purpose, we choose three different approaches. Firstly, we conduct a review of the methodological literature dealing with the issue of surrogate endpoints and their validation. Secondly, we analyse current methodological guidelines of HTA agencies members of the International network of agencies for Health Technology Assessment (INAHTA) as well as of agencies concerned with assessments for reimbursement purposes. Finally, we analyse the outcome parameter used in a sample of HTA reports available for the public.The analysis of methodological guidelines shows a very cautious position of HTA institutions regarding the use of surrogate endpoints in technology assessment. Surrogate endpoints have not been prominently used in HTA reports. None of the analysed reports based its conclusions solely on the results of surrogate endpoints. The analysis of German HTA reports shows a similar pattern.The validation of a surrogate endpoint requires extensive research, including randomized controlled trials (RCT) assessing clinical relevant endpoints. The validity of a surrogate parameter is rather technology-specific than disease-specific. Thus - even in the case of apparently similar technologies - it is necessary to validate the surrogate for every single technology (i. e. for every single active agent).The use of surrogate endpoints in the assessment of the benefit of health technologies is still to be seen very critically. PMID- 21289900 TI - Arthroplasty register for Germany. AB - SCIENTIFIC BACKGROUND: The annual number of joint replacement operations in Germany is high. The introduction of an arthroplasty register promises an important contribution to the improvement of the quality of patient's care. RESEARCH QUESTIONS: The presented report addresses the questions on organization and functioning, benefits and cost-benefits as well as on legal, ethical and social aspects of the arthroplasty registers. METHODS: A systematic literature search was conducted in September 2008 in the medical databases MEDLINE, EMBASE etc. and was complemented with a hand search. Documents describing arthroplasty registers and/or their relevance as well as papers on legal, ethical and social aspects of such registers were included in the evaluation. The most important information was extracted and analysed. RESULTS: Data concerning 30 arthroplasty registers in 19 countries as well as one international arthroplasty register were identified. Most of the arthroplasty registers are maintained by national orthopedic societies, others by health authorities or by their cooperation. Mostly, registries are financially supported by governments and rarely by other sources. The participation of the orthopedists in the data collection process of the arthroplasty registry is voluntary in most countries. The consent of the patients is usually required. The unique patient identification is ensured in nearly all registers. Each data set consists of patient and clinic identification numbers, data on diagnosis, the performed intervention, the operation date and implanted prostheses. The use of clinical scores, patient-reported questionnaires and radiological documentation is rare. Methods for data documentation and transfer are paper form, electronic entry as well as scanning of the data using bar codes. The data are mostly being checked for their completeness and validity. Most registers offer results of the data evaluation to the treating orthopedists and/or hospitals, provide annual reports and publish scientific articles and/or presentations. The effects of the arthroplasty registers on clinical practice and on health political decisions in the time after the introduction of these registers are documented in some countries. The influence on cost savings for health services is also reported. DISCUSSION: The most important legal and ethical aspect is the patient's data protection and, therefore, the requirement of patient's consent. The involvement of the physicians in the data collection process is a further organisational and legal challenge. The 100% data collection, which is the aim of the registers due to their definition, should not cause disadvantages for certain groups of patients. CONCLUSION: The arthroplasty registers have a large medical and health-economic potential. Aspects of the patient's data protection and the guaranteed financial support of the registers should be clarified before the introduction of a register. PMID- 21289901 TI - Efficacy and cost-effectiveness of the 13C-urea breath test as the primary diagnostic investigation for the detection of Helicobacter pylori infection compared to invasive and non-invasive diagnostic tests. AB - BACKGROUND: Helicobacter pylori (H. pylori) is one of the most common bacterial infections in humans. There is a risk factor for gastric or duodenal ulcers, gastric cancer and MALT (Mucosa Associated Lymphoid Tissue)-Lymphomas. There are several invasive and non-invasive methods available for the diagnosis of H. pylori. The (13)C-urea breath test is a non-invasive method recommended for monitoring H. pylori eradication therapy. However, this test is not yet used for primary assessment of H. pylori in Germany. OBJECTIVES: What are the clinical and health economic benefits of the (13)C-urea breath test in the primary assessment of H. pylori compared to other invasive and non-invasive methods? METHODS: A systematic literature search including a hand search was performed for studies investigating test criteria and cost-effectiveness of the (13)C-urea breath test in comparison to other methods used in the primary assessment of H. pylori. Only studies that directly compared the (13)C-urea breath test to other H. pylori tests were included. For the medical part, biopsy-based tests were used as the gold standard. RESULTS: 30 medical studies are included. Compared to the immunoglobulin G (IgG) test, the sensitivity of the (13)C-urea breath test is higher in twelve studies, lower in six studies and one study reports no differences. The specificity is higher in 13 studies, lower in three studies and two studies report no differences. Compared to the stool antigen test, the sensitivity of the (13)C-urea breath test is higher in nine studies, lower in three studies and one study reports no difference. The specificity is higher in nine studies, lower in two studies and two studies report no differences. Compared to the urease test, the sensitivity of the (13)C-urea breath test is higher in four studies, lower in three studies and four studies report no differences. The specificity is higher in five studies, lower in five studies and one study reports no difference. Compared to histology, the sensitivity of the (13)C-urea breath test is higher in one study and lower in two studies. The specificity is higher in two studies and lower in one study. One study each compares the (13)C-urea breath test to the (14)C-urea breath test and the polymerase chain reaction (PCR) test, respectively, and reports no difference in sensitivity and specificity with the (14)C-urea breath test, and lower sensitivity and higher specificity compared to PCR. The statistical significance of these differences is described for six of the 30 studies. Nine health economic evaluations are included in the Health Technology Assessment (HTA) report. Among these studies, the test-and-treat strategy using the (13)C-urea breath test is compared to test-and-treat using serology in six analyses and to test and treat using the stool antigen test in three analyses. Thereby, test-and-treat using the breath test is shown to be cost-effective over the serology based strategy in three models and is dominated by a test-and-treat strategy using the stool antigen test in one model. A cost-effectiveness comparison between the urea breath test approach and the empirical antisecretory therapy is carried out in four studies. Of these, two studies report that the strategy using the urea breath test is cost-effective over the empirical antisecretory therapy. In two studies, test-and-treat using the (13)C-urea breath test is compared to the empirical eradication therapy and in five studies to endoscopy-based strategies. The breath test approach dominates endoscopy in two studies and is dominated by this strategy in one study. DISCUSSION: All included medical and economic studies are limited to a greater or lesser extent. Additionally, the results of the studies are heterogeneous regarding medical and economic outcomes respectively. Thus, the majority of the medical studies do not report the statistical significance of the differences in sensitivity and specificity. In direct comparisons the (13)C- urea breath test shows higher sensitivity and specificity than the IgG and stool antigen tests. In comparison to the urease test, results for sensitivity are inconsistent, and the specificity is slightly higher for the (13)C-urea breath test. There are not enough results for comparisons between the (13)C-urea breath test and the (14)C-urea breath test, histology and PCR to describe tendencies. The included economic studies suggest that the test-and treat strategy using the (13)C-urea breath test is cost-effective compared to test-and-treat using serology as well as empirical antisecretory therapies. Due to a lack of valid studies, it is not possible to assess the breath test approach in comparison to test-and-treat using the stool antigen test and the empirical eradication therapy respectively, regarding the cost-effectiveness. The results of economic analyses comparing test-and-treat using the breath test to endoscopy strategies are too heterogeneous to draw any conclusions. Overall, none of the included economic models is able to completely capture the complexity of managing patients with dyspeptic complaints. CONCLUSIONS/RECOMMENDATIONS: Based on available medical and economic studies, there is no sufficient evidence to recommend test and-treat using (13)C-urea breath testing for the detection of H. pylori infection as the standard procedure for the management of uninvestigated dyspepsia in the German health care system. In addition, it must be considered that the DVGS guidelines of the Deutsche Gesellschaft fur Verdauungs- und Stoffwechselkrankheiten (DVGS) recommend endoscopy based methods for the management of patients with dyspeptic complaints. PMID- 21289902 TI - Methods for assessment of innovative medical technologies during early stages of development. AB - Conventional Health Technology Assessment (HTA) is usually conducted at a point in time at which the development of the respective technology may no longer be influenced. By this time developers and/or purchasers may have misinvested resources. Thus the demand for Technology Assessment (TA) which incorporates appropriate methods during early development stages of a technology becomes apparent. Against this health political background, the present report describes methods for a development-accompanying assessment of innovative medical technologies. Furthermore, international research programmes set out to identify or apply such methods will be outlined. A systematic literature search as well as an extensive manual literature search are carried out in order to obtain literature and information. The greatest units of the identified methods consist of assessment concepts, decision support methods, modelling approaches and methods focusing on users and their knowledge. Additionally, several general purpose concepts have been identified. The identified research programmes INNO HTA and MATCH (Multidisciplinary-Assessment-of-Technology-Centre-for-Healthcare) are to be seen as pilot projects which so far have not been able to generate final results. MATCH focuses almost entirely on the incorporation of the user perspective regarding the development of non-pharmaceutical technologies, whereas INNO-HTA is basically concerned with the identification and possible advancement of methods for the early, socially-oriented technology assessment. Most references offer only very vague descriptions of the respective method and the application of greatly differing methods seldom exceeds the character of a pilot implementation. A standardisation much less an institutionalisation of development-accompanying assessment cannot be recognized. It must be noted that there is no singular method with which development-accompanying assessment should be carried out. Instead, a technology and evaluation specific method selection seem to be necessary as medical innovations are diverse and none of the methods are exhaustive. Because of a variety of issues (e. g. ideal time of evaluation, lack of data and uncertainty of data) a development-accompanying assessment should not replace a comprehensive HTA, but rather form a possible preceding step in a multi-staged HTA-process. A final appraisal of the methods for development accompanying assessment cannot be made based on the available sources. However, the present review may serve as a starting point for further development and application of these methods as well as further examination of the concept of development-accompanying assessment. There is a substantial need for further research concerning the application, validation and comparison of the various methods for development-accompanying assessment. PMID- 21289903 TI - Evaluation of medical and health economic effectiveness of non-pharmacological secondary prevention of coronary heart disease. AB - BACKGROUND: Coronary heart disease (CHD) is a common and potentially fatal malady with a life time prevalence of over 20%. For Germany, the mortality attributable to chronic ischemic heart disease or acute myocardial infarction is estimated at 140,000 deaths per year. An association between prognosis of CHD and lifestyle risk factors has been consistently shown. To positively influence lifestyle risk factors in patients with CHD, non-pharmaceutical secondary prevention strategies are frequently recommended and implemented. OBJECTIVES: The aim of this HTA (HTA = Health Technology Assessment) is to summarise the current literature on strategies for non-pharmaceutical secondary prevention in patients with CHD and to evaluate their medical effectiveness/efficacy and cost-effectiveness as well as the ethical, social and legal implications. In addition, this report aims to compare the effectiveness and efficacy of different intervention components and to evaluate the generalisability with regard to the German context. METHODS: Relevant publications were identified by means of a structured search of databases accessed through the German Institute of Medical Documentation and Information (DIMDI). In addition, a manual search of identified reference lists was conducted. The present report includes German and English literature published between January 2003 and September 2008 targeting adults with CHD. The methodological quality of included studies was assessed according to pre-defined quality criteria, based on the criteria of evidence based medicine. RESULTS: Among 9,074 publications 43 medical publications met the inclusion criteria. Overall study quality is satisfactory, but only half the studies report overall mortality or cardiac mortality as an outcome, while the remaining studies report less reliable outcome parameters. The follow-up duration varies between twelve and 120 months. Although overall effectiveness of non-pharmaceutical secondary prevention programs shows considerable heterogeneity, there is evidence for the long-term effectiveness concerning mortality, recurrent cardiac events and quality of life. Interventions based on exercise and also multicomponent interventions report more conclusive evidence for reducing mortality, while interventions focusing on psychosocial risk factors seem to be more effective in improving quality of life. Only two studies from Germany fulfill the methodological criteria and are included in this report. Additionally, 25 economic publications met the inclusion criteria. Both, quantity and quality of publications dealing with combined interventions are higher compared with those investigating single component interventions. However, there are difficulties in transferring the international results into the German health care system, because of its specific structure of the rehabilitation system. While international literature mostly shows a positive cost-effectiveness ratio of combined programs, almost without exception, studies investigate out-of hospital or home-based programs. The examination of publications evaluating the cost effectiveness of single interventions merely shows a positive trend of exercise based and smoking cessation programs. Due to a lack of appropriate studies, no conclusive evidence regarding psychosocial and dietary interventions is available. Altogether eleven publications concerned with ethical or social issues of non-pharmacological secondary prevention strategies are included. These studies are relatively confirm the assumption that patients with a lower socioeconomic background reflect a population at increased risk and therefore have specific needs to participate in rehabilitation programs. However, there currently remains uncertainty, whether these patients participate in rehabilitation more or less often. As barriers, which deter patients from attending, aspects like a lack of motivation, family commitments or the distance between home and rehabilitation centres are identified. Psychological factors like anxiety, depression and uncertainty as well as physical constraints are also pointed out. DISCUSSION: Non-pharmacological secondary preventive strategies are safe and effective in improving mortality, morbidity and quality of life in patients with CHD. Because of the small number of reliable studies with long term follow up over 60 months, sustainability of observed intervention effects has to be regarded with caution. Due to a lack of suitable studies, it was not possible to determine the effectiveness of interventions in important patient subgroups as well as the comparative effectiveness of different intervention strategies, conclusively. Future research should, amongst others, attempt to investigate these questions in methodologically rigorous studies. With regard to the cost effectiveness of non-pharmacological interventions, overall, international studies show positive results. However, there are considerable limitations due to the qualitative and quantitative deficiencies of identified studies. The special characteristics of the German rehabilitation system with its primarily inpatient offers result in further difficulties, when trying to transfer international study results to the German health care system. Both, studies demonstrating the cost-effectiveness of inpatient programs and those investigating the cost effectiveness of single interventions are currently not available. To examine the German rehabilitation programs concerning their efficiency and their potential for optimisation, there is a need for further research. Concerning social and ethical issues, a lack of studies addressing the structure of rehabilitation participants in Germany is striking. The same applies to studies examining the reasons for none participation in non-pharmacological secondary prevention programs. Evidence regarding these questions would provide an informative basis for optimising rehabilitation programs in Germany. CONCLUSION: Non pharmacological secondary prevention interventions are safe and able to reduce mortality from CHD and cardiac events, as well as to imporve patient's quality of life. Nevertheless, there is considerable need for research; especially the effectiveness of interventions for important subgroups of CHD patients has to be evaluated. In addition to intervention effectiveness, there is also some evidence that interventions generate an appropriate cost-effectiveness ratio. However, future research should investigate this further. The same applies to the sustainability of secondary prevention programs and patient's reasons for not attending them. PMID- 21289904 TI - Surgical resection and survival of patients with unsuspected single node positive lung cancer (NSCLC) invading the descending aorta. AB - BACKGROUND: Surgical treatment of non-small cell lung cancer (NSCLC) with aortic invasion is still debated. METHODS: Thirteen patients with locally advanced (T4) NSCLC and invasion of the descending aorta underwent pneumonectomy (n=9) or lobectomy (n=4) together with aorta en bloc resection and reconstruction (n=8) or subadventitial dissection (n=5), complete lymph node dissection, and had microscopic unsuspected node metastasis at N1 (n=5) and N2/3 (n=8) levels of whom 12 received radiation therapy. Clamp-and-sew was used to resect and reconstruct the aorta. RESULTS: Operative mortality and morbidity rate was 0% and 23%, respectively. Four patients died of systemic tumor relapse and 2 of local recurrence. Six patients were alive after a median follow-up of 40 months (range 15-125 months). Overall 5-year survival rate was 45%. Median survival time and 5 year survival rate of patients after aortic resection was 35 months and 67%, respectively, and was 17 months and 0%, respectively, after aortic subadventi tial dissection (p=0.001). N1 and N2 nodal status adversely affected survival, but survival difference was not significant (N1 versus N2/3; 52% versus 39% at 5 years; p=0.998). CONCLUSIONS: Aortic resection with single station node positive T4 lung cancer can achieve long-term survival. The data indicate that aortic resection-reconstruction is associated with better outcome than subadventitial dissection. PMID- 21289905 TI - Thoracoscopic versus open lobectomy debate: the pro argument. AB - INTRODUCTION: Controversy persists about the role of VATS lobectomy for patients with lung cancer. This is particularly true in Europe, where VATS (video assisted thoracic surgery) lobectomy is performed for lung cancer less often than in the USA or Japan. This article reviews existing data comparing the results of VATS vs. open lobectomy for the treatment of lung cancer in order to provide a scientific basis for a rational assessment of this issue. METHODS: The review of the data presented here draws heavily from a 2007 metaanalysis by Cheng et al. [1] published in 2007, as it employed rigorous methodology in performing a systematic review and metaanalysis, and involved a detailed analysis of many major and minor endpoints on an intent to treat basis. This included 36 trials, three of them randomized, and 3589 patients, reported between 1995 and 2007. Summary results for individual endpoints are shown as a mean value with 95% confidence intervals (CI). These values are taken from the summary results of the Forrest plots in the source article. Dichotomized variables are expressed as an Odds Ratio, with values <1 being in favor of VATS lobectomy. Continuous variables are reported as weighted mean differences. RESULTS: The operative time for a VATS lobectomy was statistically longer, but only by 16 minutes. The conversion rate from VATS to open was 6%. There was no significant difference in the rates of major bleeding, blood transfusion or re-operation. VATS lobectomy was associated with a significantly lower rate of complications in general and pulmonary complications in particular. Postoperative pain was reduced, functional outcome was better, whereas overall quality of life was not. Mediastinal staging was equal with regard to the number of nodes or the number of nodal stations sampled. The ability of patients to receive adjuvant chemotherapy was improved following VATS. There was no difference in survival at 1 and 3 years for lung cancer (all stages combined). There was no difference in survival at 5 years for each tumor stage, and no difference in the rate of deaths at maximal follow-up. CONCLUSION: The data suggests that VATS lobectomy for NSCLC is safe, results in fewer complications, less pain, and more rapid return of normal functioning. There appears to be either no difference or a slight benefit in long term survival after VATS lobectomy. These conclusions are demonstrated by a comprehensive, rigorous metaanalysis of the controlled clinical trials, but are weakened by the fact that most of the studies were not randomized. However, because a large randomized trial is not likely to ever be conducted, this represents the best assessment of the value of VATS lobectomy that is available. PMID- 21289906 TI - Morbidity and mortality after pneumonectomy in smokers with NSCLC. AB - OBJECTIVE: Perioperative morbidity and mortality in patients receiving pneumonectomy because of non-small cell lung cancer (NSCLC) remains quite high. The aim of this study is to identify risk factors to minimize perioperative mortality and morbidity. PATIENTS AND METHOD: The results of 156 Patients who received pneumonectomy between 1995 and 2004 were reviewed retrospectively. All patients had stage I or II NSCLC. In 81 cases a right sided and in 75 a left sided pneumonectomy was performed. Cardiopulmonary function tests were sufficient for pneumonectomy. RESULTS: Overall perioperative 30-day mortality was 7.1% (n=11), in hospital mortality 8.3% (n=13). The cause was sepsis in 6 cases, cardiac failure in 4 cases, and respiratory insufficiency in 3 cases. In univariable and multivariable regression analysis considering mortality, none of the prognostic factors reached significance. The odds ratio for postoperative death was 1.6 fold for smokers in comparison to non smokers. Complications after pneumonectomy were seen in 34.6%, with arrhythmia in 16.0%, sepsis in 1.9% and bronchopleural fistula (BPF) occurring in 6.4%. Smoking and intraoperative blood loss >500 ml were highly significant perioperative risk factors. CONCLUSION: Smoking until operation and intraoperative blood loss were independent postoperative risk factors leading to complications after pneumonectomy for NSCLC. The risk for complications was 2.8-fold higher for smokers. PMID- 21289907 TI - Health Technology Assessment of laparoscopic compared to conventional surgery with and without mesh for incisional hernia repair regarding safety, efficacy and cost-effectiveness. AB - INTRODUCTION: Incisional hernias are a common complication following abdominal surgery and they represent about 80% of all ventral hernia. In uncomplicated postoperative follow-up they can develop in about eleven percent of cases and up to 23% of cases with wound infections or other forms of wound complications. Localisation and size of the incisional hernia can vary according to the causal abdominal scar. Conservative treatment (e. g. weight reduction) is only available to relieve symptoms while operative treatments are the only therapeutic treatment option for incisional hernia. Traditionally, open suture repair was used for incisional hernia repair but was associated with recurrence rates as high as 46%. To strengthen the abdominal wall and prevent the development of recurrences the additional implantation of an alloplastic mesh is nowadays commonly used. Conventional hernia surgery as well as minimally invasive surgery, introduced in the early 90s, make use of this mesh-technique and thereby showed marked reductions in recurrence rates. However, there are possible side effects associated with mesh-implantation. Therefore recommendations remain uncertain on which technique to apply for incisional hernia repair and which technique might, under specific circumstances, be associated with advantages over others. OBJECTIVES: The goal of this HTA-Report is to compare laparoscopic incisional hernia repair (LIHR) and conventional incisional hernia repair with and without mesh-implantation in terms of their medical efficacy and safety, their cost effectiveness as well as their ethical, social und legal implications. In addition, this report aims to compare different techniques of mesh-implantation and mesh-fixation as well as to identify factors, in which certain techniques might be associated with advantages over others. METHODS: Relevant publications were identified by means of a structured search of databases accessed through the German Institute of Medical Documentation and Information (DIMDI) as well as by a manual search. The former included the following electronic resources: SOMED (SM78), Cochrane Library - Central (CCTR93), MEDLINE Alert (ME0A), MEDLINE (ME95), CATFILEplus (CATLINE) (CA66), ETHMED (ED93), GeroLit (GE79), HECLINET (HN69), AMED (CB85), CAB Abstracts (CV72), GLOBAL Health (AZ72), IPA (IA70), Elsevier BIOBASE (EB94), BIOSIS Previews (BA93), EMBASE (EM95), EMBASE Alert (EA08), SciSearch (IS90), Cochrane Library - CDSR (CDSR93), NHS-CRD-DARE (CDAR94), NHS-CRD-HTA (INAHTA) as well as NHSEED (NHSEED). The present report includes German and English literature published until 31.08.2005. The search parameters can be found in the appendix. No limits were placed on the target population. The methodological quality of the included clinical studies was assessed using the criteria recommended by the "Scottish Intercollegiate Guidelines Network Grading Review Group". Economic studies were evaluated by the criteria of the German Scientific Working Group Technology Assessment for Health Care. RESULTS: The literature search identified 17 relevant medical publications. One of these studies compared laparoscopic and conventional surgery with and without mesh for incisional hernia repair, while 16 studies compared laparoscopic and conventional surgery with mesh for incisional hernia repair. Among these studies were 14 primary studies (one randomised controlled trial (RCT), two systematic reviews and one HTA-Report. The only study comparing laparoscopic and conventional surgery without mesh found substantial differences in terms of baseline characteristics between treatment groups. The outcome parameters showed decreased recurrence rates for the laparoscopic repair and similar safety of the procedures. Studies comparing laparoscopic and conventional surgery with mesh found similar outcome in terms of medical efficacy and safety. However, there was a trend towards lower recurrence rates, length of hospital stay, and postoperative pain as well as decreased complication rates for laparoscopic repair in the majority of studies. The impact of the technique of mesh implantation and -fixation as well as the impact of certain factors on the choice of technique has not been systematically assessed in any of the studies. DISCUSSION: All identified studies suffer from significant methodological weaknesses, such as differences between treatment groups, mainly due to the non randomised study design, small treatment groups causing low case numbers and lack of statistical power as well as the neglect of important risk factors or adjustment for those. Therefore, no conclusive differences could be identified concerning compared operative techniques, mesh-implantation and -fixation techniques or certain risk factors. Only the comparison of laparoscopic and conventional technique with mesh provides some evidence for a trend towards similar or slightly improved outcome in terms of medical efficacy and safety for the laparoscopic technique. However, there is still a great need for further research to investigate these questions. Basically, there is no full economic evaluation focussing on the relevant alternatives. Cost compareisons were available, even though only briefly attached to clinical research results. None of the studies primarily aimed to investigate costs or even cost-effectiveness. CONCLUSION: When deciding on the choice of operative technique for incisional hernia repair, surgeons take various considerations into account, including patient characteristics, hernia characteristics and their own experience. The studies included in this HTA did not provide conclusive evidence to answer the research questions. Nonetheless, laparoscopic surgery demonstrated a trend towards similar or slightly improved outcome following incisional hernia repair. However, for more conclusive recommendations on the choice of operative technique, high quality trials are required From the economic perspective, alternative methods are not yet assessed. Only five of the studies involve a cost analysis, though in an insufficient manner. None of the studies identified were laid out as a health economic evaluation. Hence, further research is strongly recommended. PMID- 21289908 TI - Oral health with fixed appliances orthodontics. AB - Orthodontic treatment represents an important fraction in dental interventions. According to other medical methods the question for scientific evidence for the effectiveness of these treatments arises. The question of the effectiveness is connected with the question what is understood as an effect. In principle, the effect of the intervention is understood on the basis of the occlusion or dental health, what disregards further functions of oral health. The generalization to oral health is therefore a necessary consideration in science now. If one appreciates this further development, then there is no one single randomised study available which examines the long-term effect of the orthodontic intervention or for the effects on the oral health.The question, whether the application of a fixed appliance in an orthodontic treatment causes a long-term improvement in oral health, cannot be answered at the present time. The scientific status is the definition of oral health at present. Also the question, whether in the long run the dental health can be improved by fixed appliances cannot be answered with a quality usually achieved by evidence-based medicine. Whether correction of a dental malposition is an effective prerequisite for the preservation of the natural teeth, cannot be answered. There is no generalizing study with sufficient scientific background for Europe or Germany to this topic. The risk for caries cannot be quantified. Caries is identified as a central topic in general but due to numerous factors influencing the risk it is not quantified. The question of the indications is completely open from the scientific literature. For the question of the therapy need or therapy priority some indexes were developed, which lead to a quantification. These indices however are fundamentally criticised by recent research in their meaning and the empirical relevance.There is an impression that there exists a big gap between the practical application and the scientific investigation of this effectiveness of fixed appliances or orthodontic treatment in general. There is much research in the area of diagnostics or further development of appliances or techniques done, however extremely few in the area of need for intervention, analysis of the sustainability; influence factors on the success, like caries or quantification of side effects e. g. root resorption. This research to evaluate the indications is completely lacking, also the required evaluation parameters (e. g. means long term dental maintenance). This gap is in this respect dubious since a link of determining the demand (inducing demand) and supply in Central European health systems is economically given. This enables to create a possibility for a so called supply induced demand. To get rid of discussions that the professional work of orthodontics can be near to induced demand or unnecessary indications, research of this topic is quite essential. This requires much stronger information for indications. This can improve confidence for patients and insurance companies. Existing indices like the Index of Treatment Need (IOTN) seem to be of academic interest without practice importance for daily work. The question which indications can be regarded as scientifically proven for the intervention must be given big attention immediately. The individual and subjective assessment of the orthodontist (whose experience is not doubted) has to be considered as not sufficient. The scientific background is absolutely necessary due to ethic reasons for the patient, economic reasons for the social insurance system or financiers and also for the orthodontists to evaluative and legitimates the treatment. Well coordinated research with the goal of collecting specific data is urgently required for individual therapeutic processes with appropriate design. The study quality is also an essential topic. It is unacceptable at the beginning of the 21st century with the background of the evidence based medicine, that studies are published with enormous methodological errors. Orthodontics deserves a well discussed scientific position to prove the enormous individual success and to demonstrate the effectiveness of the developed treatments. PMID- 21289909 TI - Pharmacogenomics Bias - Systematic distortion of study results by genetic heterogeneity. AB - BACKGROUND: Decision analyses of drug treatments in chronic diseases require modeling the progression of disease and treatment response beyond the time horizon of clinical or epidemiological studies. In many such models, progression and drug effect have been applied uniformly to all patients; heterogeneity in progression, including pharmacogenomic effects, has been ignored. OBJECTIVE: We sought to systematically evaluate the existence, direction and relative magnitude of a pharmacogenomics bias (PGX-Bias) resulting from failure to adjust for genetic heterogeneity in both treatment response (HT) and heterogeneity in progression of disease (HP) in decision-analytic studies based on clinical study data. METHODS: We performed a systematic literature search in electronic databases for studies regarding the effect of genetic heterogeneity on the validity of study results. Included studies have been summarized in evidence tables. In the case of lacking evidence from published studies we sought to perform our own simulation considering both HT and HP. We constructed two simple Markov models with three basic health states (early-stage disease, late-stage disease, dead), one adjusting and the other not adjusting for genetic heterogeneity. Adjustment was done by creating different disease states for presence (G+) and absence (G-) of a dichotomous genetic factor. We compared the life expectancy gains attributable to treatment resulting from both models and defined pharmacogenomics bias as percent deviation of treatment-related life expectancy gains in the unadjusted model from those in the adjusted model. We calculated the bias as a function of underlying model parameters to create generic results. We then applied our model to lipid-lowering therapy with pravastatin in patients with coronary atherosclerosis, incorporating the influence of two TaqIB polymorphism variants (B1 and B2) on progression and drug efficacy as reported in the DNA substudy of the REGRESS trial. RESULTS: We found four studies that systematically evaluated heterogeneity bias. All of them indicated that there is a potential of heterogeneity bias. However, none of these studies explicitly investigated the effect of genetic heterogeneity. Therefore, we performed our own simulation study. Our generic simulation showed that a purely HT-related bias is negative (conservative) and a purely HP-related bias is positive (liberal). For many typical scenarios, the absolute bias is smaller than 10%. In case of joint HP and HT, the overall bias is likely triggered by the HP component and reaches positive values >100% if fractions of "fast progressors" and "strong treatment responders" are low. In the clinical example with pravastatin therapy, the unadjusted model overestimated the true life-years gained (LYG) by 5.5% (1.07 LYG vs. 0.99 LYG for 56-year-old men). CONCLUSIONS: We have been able to predict the pharmacogenomics bias jointly caused by heterogeneity in progression of disease and heterogeneity in treatment response as a function of characteristics of patients, chronic disease, and treatment. In the case of joint presence of both types of heterogeneity, models ignoring this heterogeneity may generate results that overestimate the treatment benefit. PMID- 21289910 TI - Behaviour therapy for obesity treatment considering approved drug therapy. AB - INTRODUCTION: Obesity is a worldwide health problem whose prevalence is on the increase. Many obesity-associated diseases require intensive medical treatment and are the cause of a large proportion of health-related expenditures in Germany. Treatment of obesity includes nutritional, exercise and behaviour therapy, usually in combination. The goal of behaviour therapy for obesity is to bring about a long-term alteration in the eating and exercise habits of overweight and obese individuals. Under certain circumstances, drug treatment may be indicated. OBJECTIVES: What is the effectiveness of behaviour therapy for obesity considering approved drugs reduce weight under medical, economic, ethical social and legal aspects? METHODS: A systematic review was conducted using relevant electronic literature databases. Publications chosen according to predefined criteria are evaluated by approved methodical standards of the evidence-based medicine systematically and qualitatively. RESULTS: In total 18 studies, included one HTA and one meta-analysis could be identified according to the predefined inclusion criteria. Three studies compare behaviour therapy to other therapy forms (advice or instruction on nutritional changes, physical activity or a combination of the two), six studies evaluate different forms of behaviour therapy, four studies and four studies compare behaviour therapies mediated by Internet or telephone. Three studies could be identified examining the effect of the combination of behaviour and drug therapy. Furthermore one HTA and one meta-analysis could be included in the evaluation. The behaviour therapy in comparison with other therapy forms reveals a higher effectiveness. In comparison of the different therapeutic approaches of the behaviour therapy intensive behaviour therapy forms and group therapy show a higher effectiveness. Studies related to behaviour therapy based on media support demonstrate a weight reduction both through the interventions of media alone as well as through the intervention of media in conjunction with personal support within the groups. However, analyses of the inter-group comparisons offer no statistically significant difference. However, analyses of the inter-group comparisons offer no statistically significant difference. Comparative analyses confirm the effectiveness of behaviour therapy in combination with additional drug treatment when compared to behaviour therapy alone. In all the studies presented here, relevant changes in weight of -5% to -10% are only partially achieved. High weight losses of less than -10% were found among the intervention group in two of the studies. One study reported a weight loss of -11.4% with the "group therapy" intervention method, while another study reported a weight loss of -11.2% with the "behaviour therapy plus drug treatment" intervention method. Studies with a subsequent follow-up period indicate a clear weight loss at the end of the intervention followed by a renewed weight gain towards the end of the follow-up period. For the evaluation of economic, social-ethical or legal aspects we could not identify any studies. DISCUSSION: A comparative assessment among the studies proved difficult due to their heterogeneous nature. Little conformity can be detected in either the contents of the behaviour therapy or in the treatment plans. The length of the follow-up periods also varies from study to study. Many studies only analyze weight changes within one group or for the entire study population. However, the results of these analyses all indicate a significant weight loss at the end of the intervention. CONCLUSION: Some effects of behaviour therapy on a reduction in weight can be shown. However, relevant weight changes of -5% to -10% are only achieved to a certain extent. The extremely heterogeneous nature of the interventions makes a comparison of the study results very difficult. A trend can be detected indicates that those treatments which offer drug treatment in addition to behaviour therapy are more effective than behaviour therapy alone. For the verification of long-term successes of a behaviour therapy too few data are available. PMID- 21289911 TI - The treatment of Parkinson's disease with dopamine agonists. AB - Parkinson's disease is a chronic degenerative organic disease with unknown causes. A disappearance of cells with melanin in the substantia nigra is considered as biological artefact of the disease, which causes a degenerative loss of neurons in the corpus striatum of mesencephalon. This structure produces also the transmitter substance dopamine. Due to this disappearance of cells dopamine is not produced in a sufficient quantity which is needed for movement of the body.The questions of this report are concerned the efficiency and safety of a treatment with dopamine agonists. Furthermore the cost-effectiveness is investigated as well as ethic questions. The goal is to give recommendation for the use of dopamine agonists to the German health system.A systematic literature search was done. The identified studies have different methodological quality and investigate different hypothesis and different outcome criteria. Therefore a qualitative method of information synthesis was chosen.Since the introduction of L-Dopa in the 1960's it is considered as the most effective substance to reduce all the cardinal symptoms of Parkinson disease. This substance was improved in the course of time. Firstly some additional substances were given (decarbonxylase inhibitors, catechol-o-transferase inhibitors (COMT-inhibitors), monoaminoxydase inhibitors (MAO-inhibitors) and NMDA-antagonists (N-Methyl-d-aspartat antagonists).In the practical therapy of Parkinson dopamine agonists play an important role, because they directly use the dopamine receptors. The monotherapy of Parkinson disease is basically possible and is used in early stages of the disease. Clinical practise has shown, that an add on therapy with dopamine agonists can led to a reduction of the dose of L-dopa and a reduction of following dyskinesia.The studies for effectiveness include studies for the initial therapy, monotherapy and add-on-therapy. Basically there is a good effectiveness of dopamine agonists the reduce dyskinesia and this differences are statistically significant. The effect of dopamine agonists is weaker then levodopa generally. The initial therapy with dopamine agonists can postpone the use of levodopa medication or keep the dose small for a longer period of time. There are more other side effects to levodopa, these are not statistically significant. The idea, which strategy for the treatment should be chosen is dependent of several factors and has to be evaluated with the individual patient. An important criterion is the age of the patient at the beginning of the treatment. For younger patients (under 65 years) the risk of developing motoric fluctuation and dyskinesia is much higher and therefore it is proposed to use levodopa at later stages. The evidence of the evaluated studies show a good effectiveness with the therapy of Parkinson disease as monotherapy of younger patients or as additional medication to levodopa as well as older patients with progressive stages of this disease. In these groups of patients there is a positive cost-benefit ratio. PMID- 21289912 TI - Evaluation of medical and health economic effectiveness of bariatric surgery (obesity surgery) versus conservative strategies in adult patients with morbid obesity. AB - BACKGROUND: Obesity with its associated medical, psychological, social, and economic complications is considered a chronic, multifactorial disorder. Given the magnitude of the challenge obesity, there is a clear need for preventive as well as therapeutic measures and strategies on an individual and a public health level. OBJECTIVES: The goal of this health technology assessment (HTA)-report is to summarise the current literature on bariatric surgery, to evaluate their medical effectiveness/efficacy and cost-effectiveness as well as the ethical, social and legal implications of these procedures in comparison to conventional therapies and compared to each other. METHODS: Relevant publications are identified by means of a structured search of databases accessed on 13.11.2006 and an update conducted on 12.11.2007. In addition, a manual search of identified reference lists is conducted. The present report includes German and English literature published since 2001 and targeting adult subjects with morbid obesity (body mass index (BMI) >=40 kg/m2 or BMI >=35 kg/m2 with severe comorbidities). The methodological quality of studies included is assessed according to pre defined quality criteria by two independent scientists. RESULTS: Among 5910 retrieved publications, 25 medical articles, as well as seven health economic studies meet the inclusion criteria. The medical studies show a superior weight loss following bariatric surgery compared to conventional therapy. Malabsorptive procedures lead to a more profound weight loss than purely restrictive procedures. Weight reduction in general is accompanied by a reduced frequency of comorbidities (mostly diabetes type 2). The evidence is not sufficient to quantify these effects for individual procedures or to assess long-term outcomes. However, recent studies show a profound survival benefit for surgically treated patients up to a period of eleven years. The economic studies illustrate that bariatric surgery is cost-effective compared to no treatment or conservative treatment. The comparison between surgical therapies does not allow to draw any conclusions on cost-effectiveness. Appropriate studies/surveys, which are concerned with ethical, legal and social aspects, are not available. DISCUSSION: Concerning clinical outcomes as well as cost-effectiveness, there is a lack of high quality studies. Clinical effectiveness and safety as well as cost effectiveness of bariatric procedures in the short- and medium-term course are agreed on, but long-term evaluations that focus not exclusively on weight loss, but also on comorbidities and patient relevant outcomes such as quality of life, are needed. Also within the economic views are missing long-term evaluation particularly for the German health care system. CONCLUSION: Based upon the available literature the short- and medium-term effectiveness of bariatric procedures on weight loss, comorbidities, e. g. diabetes, and mortality can be assumed and also seems to be cost-effective. No recommendation can be given with respect to the choice of a certain bariatric procedure or to the selection of particular groups of patients. PMID- 21289913 TI - Measurement of fractional flow reserve to guide decisions for percutaneous coronary intervention. AB - BACKGROUND: Coronary artery disease (CAD) is one of the leading causes of premature death in Germany. Percutaneous coronary interventions (PCI) are frequently performed in patients with angiographically intermediate stenoses. However, the necessity of PCI has not been proven for all patients. Pressure based fractional flow reserve (FFR) is an invasive test that can be used to assess the functional significance of intermediate coronary stenoses in order to guide decisions on PCI. OBJECTIVES: This health technology assessment (HTA) aims to evaluate (1) the diagnostic accuracy, (2) the risk-benefit trade-off and (3) the long-term cost-effectiveness of FFR measurement to guide the decision on PCI in patients with stable angina pectoris and intermediate coronary stenoses. METHODS: We performed a literature search in medical and HTA databases. We used the DIMDI instruments (DIMDI = Deutsches Institut fur Medizinische Dokumentation und Information/German Institute for Medical Information and Documentation) to assess study quality and to extract and summarize the information in evidence tables. We performed a meta-analysis to calculate the pooled overall estimate for sensitivity and specificity of FFR with 95% confidence intervals (95% CI). Individual studies' case numbers were used as weights. The influence of single studies and important covariates on the results was tested in sensitivity analyses. We developed the German Coronary Artery Disease Outcome Model (German CADOM), a decision-analytic Markov model, to estimate the long-term effectiveness and cost-effectiveness of FFR measurement in the context of the German healthcare system. RESULTS: Our literature search identified twelve studies relevant to this HTA-report including ten diagnostic accuracy studies of FFR measurement, one randomized clinical trial (RCT) investigating the clinical benefits of this technique as well as one economic evaluation. Pooled estimates for sensitivity and specificity were 81.7% (95% CI: 77.0-85.7%) and 78.7% (95% CI: 74.3-82.7%). Sensitivity analyses indicated robust results. The RCT investigating the efficacy of an FFR-based treatment strategy provided evidence of the advantages of this strategy for patients with respect to freedom from angina and major adverse cardiac events. The published cost-effectiveness study demonstrates that the FFR based strategy is cost-saving in the US context. Based on our own decision analysis for the German context, the FFR-based strategy improves (quality adjusted) life-expectancy when compared to universal PCI and is cost-effective in the German healthcare context. This HTA is limited by the use of poor gold standards in several of the included diagnostic studies as well as the ongoing advance of technology and treatment options in interventional cardiology. Results of the decision analysis are limited by the necessary underlying assumptions and the uncertainty regarding long-term mortality reduction associated with PCI. Further research should focus on the acquisition of long-term data for disease progression in patients with and without functional coronary stenoses as well as the benefits and risks of PCI. CONCLUSIONS: Based on actual evidence and our decision analysis, the use of FFR measurement to guide the decision on PCI should lead to better short- and long-term clinical outcomes in patients with stable angina and single-vessel disease without documented myocardial ischemia and it should provide a cost-effective use of resources in the German healthcare system. FFR measurement should be introduced in routine clinical practice. However, appropriate reimbursement strategies are necessary to avoid wrong incentives. PMID- 21289914 TI - Intravascular brachytherapy for peripheral vascular disease. AB - SCIENTIFIC BACKGROUND: Percutaneous transluminal angioplasties (PTA) through balloon dilatation with or without stenting, i.e. vessel expansion through balloons with or without of implantation of small tubes, called stents, are used in the treatment of peripheral artery occlusive disease (PAOD). The intravascular vessel irradiation, called intravascular brachytherapy, promises a reduction in the rate of repeated stenosis (rate of restenosis) after PTA. RESEARCH QUESTIONS: The evaluation addresses questions on medical efficacy, cost-effectiveness as well as ethic, social and legal implications in the use of brachytherapy in PAOD patients. METHODS: A systematic literature search was conducted in August 2007 in the most important medical electronic databases for publications beginning from 2002. The medical evaluation included randomized controlled trials (RCT). The information synthesis was performed using meta-analysis. Health economic modeling was performed with clinical assumptions derived from the meta-analysis and economical assumptions derived from the German Diagnosis Related Groups (G-DRG 2007). RESULTS: MEDICAL EVALUATION : Twelve publications about seven RCT on brachytherapy vs. no brachytherapy were included in the medical evaluation. Two RCT showed a significant reduction in the rate of restenosis at six and/or twelve months for brachytherapy vs. no brachytherapy after successful balloon dilatation, the relative risk in the meta-analysis was 0.62 (95% CI: 0.46 to 0.84). At five years, time to recurrence of restenosis was significantly delayed after brachytherapy. One RCT showed a significant reduction in the rate of restenosis at six months for brachytherapy vs. no brachytherapy after PTA with optional stenting, the relative risk in the meta-analysis was 0.76 (95% CI: 0.61 to 0.95). One RCT observed a significantly higher rate of late thrombotic occlusions after brachytherapy in the subgroup of stented patients. A single RCT for brachytherapy vs. no brachytherapy after stenting did not show significant results for the rate of restenosis at six months. Both, early and late thrombotic occlusions appeared more frequently in the brachytherapy group. HEALTH ECONOMIC EVALUATION : Additional costs of brachytherapy were estimated to be 1,655 or 1,767 Euro according to the used G-DRG. The incremental cost-effectiveness ratio per avoided restenosis was calculated to be 8,484 Euro or 9,058 Euro for brachytherapy use after successful balloon dilatation, 19,027 Euro or 20,314 Euro for brachytherapy after PTA with optional stenting and -39,646 Euro or -48,330 Euro for brachytherapy after stenting. DISCUSSION: Partially poor performing and reporting quality of the RCT exacerbate the interpretation and the transferability of the study results. The used methodical approach enables the highest evidence level for the determined results and presents a good approximation of the current brachytherapy related costs for the German health care system. CONCLUSIONS: Brachytherapy after successful balloon dilatation in PAOD can be recommended from a medical point of view for the reduction of the rate of restenosis at one year. However from a health economic view the answer is not yet clear. Based on the current data the use of brachytherapy after stenting in PAOD cannot be recommended neither from a medical nor from a health economic point of view. The informed consent of the patients is an important ethical aspect in the use of brachytherapy. PMID- 21289915 TI - Interferons and natalizumab for multiple sclerosis. AB - Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system which is accompanied by considerable disability and high costs. This report summarises the evidence on effectiveness and costs of beta-interferons and natalizumab in the treatment of multiple sclerosis.The review included systematic reviews and randomised controlled trials (with an observation time of at least one year) in patients with MS which assessed outcome parameters such as progression, exacerbations and adverse effects. An extensive literature search included databases such as MEDLINE, EMBASE, the Cochrane Library and various HTA databases. Studies were selected according to predefined criteria, their quality was assessed according to criteria defined prospectively, and data were summarised systematically in tables. Cost-effectiveness evaluations were also included.Two systematic reviews and 24 randomised controlled trials of beta interferon therapy were included, as well as three trials on the effectiveness of natalizumab. A total of 22 cost-effectiveness analyses for interferons were included, whereas no economic evaluations for natalizumab were identified.Use of interferon beta-1a or interferon beta-1b after a first demyelinating event led to a reduction of the conversion to definite MS during an observation time of two to three years. In relapsing remitting MS, interferon beta-1a reduced progression. The effects of interferon beta-1b on progression are unclear. Interferon beta-1a and interferon beta-1b reduced in some but not all studies outcomes relating to exacerbations. In direct comparison trials, interferon beta-1b (Betaferon((r)) or Betaseron((r))) and interferon beta-1a (Rebif((r)), higher dosage of 44 ug three subcutaneous injections per week) proved superior to interferon beta-1a (Avonex((r)), 30 ug per week intramuscular) with respect to exacerbation outcomes. For secondary progressive MS, only one of five studies found a reduced progression with interferon beta-1a and only a part of the studies found an improvement with respect to outcomes relating to exacerbations. For primary progressive MS no advantage of therapy with beta-interferons was found with respect to patient-related outcomes. Beta-interferons showed characteristic and frequently occurring adverse effects, including reactions at the injection site and flu-like symptoms. A large proportion of patients stop interferon therapy because of adverse events. The other main reason for stopping therapy is the felt ineffectiveness of the treatment when patients experience a new exacerbation while on treatment. Many patients produce interferon-neutralising antibodies during therapy. The ultimate effect of neutralising antibodies on the efficacy of interferon treatment is unclear.In patients with relapsing remitting (and partially with secondary progressive) MS, treatment with natalizumab led to a reduction of progression and of exacerbation rates. However, a number of cases of progressive multifocal leucoencephalopathy have been reported after natalizumab therapy. These raise serious concerns about patient safety. Reliable data on the long term effectiveness of beta-interferons or natalizumab are not yet available.The absolute cost of interferon therapy is high and the available, international cost-effectiveness analyses indicate a high cost for achieving moderate benefits in quality of life. Further research is needed to provide specific cost-effectiveness estimates for Germany. PMID- 21289916 TI - Effectiveness and cost-effectiveness of behavioural strategies in the prevention of cigarette smoking. AB - BACKGROUND: The hazardous health effects of smoking and second hand smoke have been confirmed in numerous studies. For Germany, the mortality attributable to smoking is estimated at 110,000 to 140,000 deaths per year, associated with annual smoking-related costs of 17 to 21 billion euro. Because the majority of smokers initiate this habit early in life, behavioural preventive strategies usually tried to prevent the uptake of smoking among children and youths. OBJECTIVES: The goal of this HTA is to summarise the current literature on behavioural strategies for smoking prevention and to evaluate their medical effectiveness/efficacy and cost-effectiveness as well as the ethical, social and legal implications of smoking prevention programs. In addition, this report aims to compare the effectiveness and efficacy of different intervention components and to evaluate the reliability of results in the German context. METHODS: Relevant publications were identified by means of a structured search of databases accessed through the German Institute of Medical Documentation and Information (DIMDI). In addition a manual search of identified reference lists was conducted. The present report includes German and English literature published between August 2001 and August 2006 targeting youths up to 18 years old. The methodological quality of included studies was assessed according to pre defined quality criteria, based on the criteria of evidence-based medicine. RESULTS: Among 3,580 publications 37 medical studies met the inclusion criteria. Overall study quality was satisfactory but only half the studies reported smoking uptake as an outcome, while the remaining studies reported alternative outcome parameters. The follow-up duration varied between twelve and 120 months. Although overall effectiveness of prevention programs showed considerable heterogeneity, there was evidence for the long-term effectiveness of behavioural smoking prevention programs. However, the reduction in smoking rates was only moderate. Community and multisectorial interventions reported more conclusive evidence for reductions in smoking rates, while the evidence for school-based programs alone was inconclusive. Only one study from Germany fulfilled the methodological criteria and was included in this report. Three included economic studies focused on school-based interventions. Study results suggested, that the cost effectiveness of school-based behavioural interventions is positive. DISCUSSION: Behavioural preventive strategies were effective to delay or decrease uptake of smoking behaviour among children and youth. The effect size, however, was only moderate. Similar to previous research, there was no conclusive evidence for the long-term effectiveness of school-based interventions, whereas community and multisectorial interventions provided more conclusive evidence. However, sustainability of intervention effects has to be regarded with caution. In addition, there is evidence that findings from international studies can be adapted to the German situation and that intervention effectiveness is comparable. The available evidence regarding the cost-effectiveness of school based interventions is not sufficient to draw reliable conclusions. CONCLUSION: Behavioural preventive strategies can be effective in the prevention of smoking among children and youths. It seems advisable, though, to incorporate community strategies in addition to school-based strategies in order to improve their effectiveness. Future research should, amongst others, attempt to investigate the effectiveness of specific intervention components and the cost-effectiveness in methodologically high-quality studies. PMID- 21289917 TI - Longevity of dental amalgam in comparison to composite materials. AB - HEALTH POLITICAL BACKGROUND: Caries is one of the most prevalent diseases worldwide. For (direct) restaurations of carious lesions, tooth-coloured composite materials are increasingly used. The compulsory health insurance pays for composite fillings in front teeth; in posterior teeth, patients have to bear the extra cost. SCIENTIFIC BACKGROUND: Amalgam is an alloy of mercury and other metals and has been used in dentistry for more than one hundred and fifty years. Composites consist of a resin matrix and chemically bonded fillers. They have been used for about fifty years in front teeth. Amalgam has a long longevity; the further development of composites has also shown improvements regarding their longevity. RESEARCH QUESTIONS: This HTA-report aims to evaluate the longevity (failure rate, median survival time (MST), median age) of direct amalgam fillings in comparison to direct composite fillings in permanent teeth from a medical and economical perspective and discusses the ethical, legal and social aspects of using these filling materials. METHODS: The systematic literature search yielded a total of 1,149 abstracts. After a two-step selection process based on defined criteria 25 publications remained to be assessed. RESULTS: The medical studies report a longer longevity for amalgam fillings than for composite fillings. However, the results of these studies show a large heterogeneity. No publication on the costs or the cost-effectiveness of amalgam and composite fillings exists for Germany. The economic analyses (NL, SWE, GB) report higher costs for composite fillings when longevity is assumed equal (for an observation period of five years) or longer for amalgam compared to composite fillings. These higher costs are due to the higher complexity of placing composite fillings. DISCUSSION: Due to different study designs and insufficient documentation of study details, a comparison of different studies on longevity of direct amalgam and composite fillings in posterior teeth is difficult. Apart from the difficulties in conducting a randomized, controlled long-term study comparing the longevity of direct fillings, the fact that composites and adhesives used in a study have often already been replaced by the next generation of the product at the time of study publication presents an additional problem. Not only the filling material, but also patient parameters and local, intraoral factors (e. g. localisation of the filling) as well as the treating dentist have an impact on the longevity of dental fillings. In evaluating economic studies, one has to refer to the heterogeneity of data on longevity in the medical evaluation. The only effect parameter used in the studies is longevity, other aspects (e. g. long-term functionality) are only referred to in discussions. Extensive counselling of patients regarding the selection of the appropriate filling material is important. CONCLUSIONS: Amalgam fillings show a longer longevity than composite fillings. Two out of six systematic reviews conclude that the expected survival time of composite fillings can be comparable to amalgam fillings. However, these conclusions are based on the results of short-term studies which usually overestimate the longevity of filling materials. From an economic standpoint, amalgam is the more economic filling material compared to direct composite fillings in posterior teeth when considering longevity as the only result parameter. Other aspects than longevity need to be considered in individually choosing the appropriate dental filling material. For future studies aiming to compare the longevity of amalgam and composite fillings, a sufficient sample size and study period, preferably in the setting of a private dental practice, should be aimed for. An evaluation of the cost-effectiveness of amalgam and composite fillings should take the functionality of teeth over a longer time period into account, as well as patients' preferences. The rapid development of composite materials and adhesives make short term revisions of these conclusions necessary. PMID- 21289918 TI - Drug-eluting stents vs. coronary artery bypass-grafting in coronary heart disease. AB - BACKGROUND: Coronary artery bypass graft (CABG) and percutaneous revascularisations with implantation of drug-eluting stents (DES) are important treatment methods in coronary heart disease (CHD). RESEARCH QUESTIONS: The evaluation addresses questions on medical efficacy, health economic parameters as well as ethic, social and legal implications in the use of DES vs. CABG in CHD patients. METHODS: A systematic literature search was conducted in December 2006 in the most important electronic databases beginning from 2004. Register data and controlled clinical studies were included in the evaluation. Additionally, a health economic modelling was conducted. RESULTS: MEDICAL EVALUATION : The literature search yielded 2,312 hits. 14 publications about six controlled clinical studies and five publications about two registers were included into the evaluation. Register data showed low mortality (0.2% to 0.7%) and low rates of myocardial infarction (0.5% to 1.4%) during hospital stay. In patients with stenosis of the left anterior descending coronary artery one study showed in several analyses a significantly higher rate of reinterventions and a significantly higher rate of repeated angina pectoris for DES up to two years after the implantation (16.8% vs. 3.6% and 35% vs. 8%). In patients with left main coronary artery stenosis two studies revealed a significantly higher survival without myocardial infarction and stroke for DES up to one year (96% vs. 79% and 95% vs. 91%) and two studies a significantly higher rate of revascularisations up to two years (20% vs. 4% and 25% vs. 5%) after the primary intervention. In patients with multivessel disease, one study found a significantly higher mortality and myocardial infarction rate for CABG at one year (2.7% vs. 1.0% and 4.2% vs. 1.3%). The rate of revascularisations was significantly higher in two studies up to two years after DES implantation (8.5% vs. 4.2% and 14.2% vs. 5.3%). The rate at repeated angina pectoris was significantly higher in one study in DES patients during two-years follow-up (28% vs. 12%). HEALTH ECONOMIC EVALUATION: The one-year total costs per patient after CABG were calculated to be 13,373 euro and after DES 10,443 euro, leading to a difference of 2,930 euro in favour of DES implantation. The three-year total costs per patient after CABG were estimated to be 13,675 euro and after DES 10,989 euro, showing a cost difference of 2,686 euro in favour of DES implantation. In the performed sensitivity analyses no break even point was reached. DISCUSSION: Existing data should be viewed only as limited evidence for possible medical and health economic effects. CONCLUSIONS: There is limited evidence for the possible advantage of DES vs. CABG with respect to mortality and the rate of myocardial infarction in some indications as well as disadvantages with regard to the rate of revascularisations and the rate of repeated angina pectoris. Moreover there is also a limited evidence for possible economic advantage of DES vs. CABG in multivessel disease. Existing data should be proven in long-term follow-up and in randomised studies. PMID- 21289919 TI - Thoracic aortic aneurysm presenting with dysphagia: a fatal delay in diagnosis. AB - Extrinsic oesophageal compression leading to dysphagia is a recognised but uncommon sole presentation of thoracic aortic aneurysms. This has been referred to as Dysphagia Aortica, and is a late presentation of large thoracic aneurysms, or a symptom of impending aorto-oesophageal fistula. We present the case of a 67 year old woman who presented repeatedly with dysphagia and weight loss over a 3 month period to specialists in three different disciplines. Eventually, a type II thoraco-abdominal aortic aneurysm causing extrinsic compression of the oesophagus was discovered. When dealing with patients who present with dysphagia, if no other cause is discovered, a thoracic aortic aneurysm should form part of the differential diagnosis, as this is potentially curable, and delays in diagnosis and treatment predispose to rupture and death. PMID- 21289920 TI - Full-thickness chest wall resection for locally recurrent breast cancer. AB - AIM: In spite of available recommendations, therapeutic procedures of locally recurrent breast cancer are very different. In a retrospective study, the possibilities and results of complete, full-thickness chest wall resection are presented. METHODS: Between 1985 and 2004, 51 women underwent complete, full thickness chest wall resection with primary coverage. Primary surgical therapy of breast cancer had been mastectomy in 88%. Median age of patients undergoing surgery for a local recurrence was 57 (29 - 81) years. The median interval between surgery of the primary tumour and of the local recurrence was 70.3 (10.7 327.2) months; median follow-up was 29.4 (1.8 - 230.9) months. 40 (78.4%) patients required rib resections, 15 (29.4%) of them in combination with partial sternal resection. In 4 (7.8%) patients complete and in 7 (13.7%) patients partial sternal resection without additional rib resection were performed.Coverage was mainly realized using latissimus dorsi myocutaneous flaps (n=44; 86.3%). Survival rates were calculated by means of the Kaplan-Meier method, the relative risk using univariate and multivariate Cox-regression analysis. RESULTS: In the total collective, cumulative 5-, 10- and 15-year survival (YS) rates were 39%, 31% and 23%, respectively, median survival 46.4 months. R0 resection was associated with a 5-YS of 42%. Prognostic factors were age at the time of primary surgery, disease-free interval and tumour invasion of bony structures. Mortality was 2%, morbidity 35%. CONCLUSION: Full-thickness chest wall resection of locally recurrent breast cancer is possible in almost any patient when performed by a team of thoracic and plastic surgeons. Only radical resection provides good long-term results with low mortality and morbidity. PMID- 21289921 TI - Systematic Video-Assisted Mediastinoscopic Lymphadenectomy (VAMLA). AB - Accurate mediastinal lymph node dissection during thoracotomy is mandatory for staging and for adjuvant therapy in lung cancer. Pre-therapeutic staging for neoadjuvant therapy or for video assisted thoracoscopic resection of lung cancer is achieved usually by CT-scan and mediastinoscopy. However, these methods do not reach the accuracy of open nodal dissection. Therefore we developed a technique of radical video-assisted mediastinoscopic lymphadenectomy (VAMLA). This study was designed to show that VAMLA is feasible and that radicality of lymphadenectomy is comparable to the open procedure.In a prospective study all VAMLA procedures were registered and followed up in a database. Specimens of VAMLA were analysed by a single pathologist. Lymph nodes were counted and compared to open lymphadenectomy. The weight of the dissected tissue was documented. In patients receiving tumour resection subsequently to VAMLA, radicality of the previous mediastinoscopic dissection was controlled during thoracotomy.37 patients underwent video-assisted mediastinoscopy from June 1999 to April 2000. Mean duration of anaesthesia was 84.6 (SD 35.8) minutes.In 7 patients radical lymphadenectomy was not intended because of bulky nodal disease or benign disease. The remaining 30 patients underwent complete systematic nodal dissection as VAMLA.18 patients received tumour resection subsequently (12 right- and 6 left-sided thoracotomies). These thoracotomies allowed open re-dissection of 12 paratracheal regions, 10 of which were found free of lymphatic tissue. In two patients, 1 and 2 left over paratracheal nodes were counted respectively. 10/18 re-dissected subcarinal regions were found to be radically dissected by VAMLA. In 6 patients one single node and in the remaining 2 cases 5 and 8 nodes were found, respectively. However these counts also included nodes from the ipsilateral main bronchus. None of these nodes was positive for tumour.Average weight of the tissue that was harvested by VAMLA was 10.1 g (2.2-23.7, SD 6.3). An average number of 20.5 (6-60, SD 12.5) nodes per patient were counted in the specimens. This is comparable to our historical data from open lymphadenectomy.One palsy of the recurrent nerve in a patient with extensive preparation of the nerve and resection of 11 left-sided enlarged nodes was the only severe complication in this series.VAMLA seems to accomplish mediastinal nodal dissection comparable to open lymphadenectomy and supports video assisted surgery for lung cancer. In neoadjuvant setting a correct mediastinal N-staging is achieved. PMID- 21289922 TI - GMS-HTA: Information out of the world of HTA - up-to-date, comprehensive and valid. PMID- 21289923 TI - The impact of HTA reports on health policy: a systematic review. AB - RESEARCH QUESTION: The objective of health technology assessment (HTA) is to support decision-making in the health sector by assessing health technologies systematically under medical, economic, social, and ethical aspects. The present study aims at identifying ways of enabling the impact of HTA on decision-making processes in the German health sector. The authors formulate three research questions: (1) Can methods be identified that allow a valid assessment of the impact of HTA reports on the decision-making processes? (2) Has been shown an impact of HTA reports on decision-making processes in the health sector? (3) Which are the factors responsible for a high or a low impact of HTA? METHODS: The authors include studies that present a methodology to assess the impact of HTA, that investigate the impact of HTA on decision-making processes, or study the factors that might enhance or hinder the impact of HTA. Medical and social science electronic databases, lists of publications and projects of the European, North American, Canadian, and Australian HTA agencies, as well as the bibliography of the identified articles and documents are looked through. The writers do a handsearch of the International Journal of Technology Assessment in Health Care and contact 64 HTA agencies by a letter, requesting information on investigations that might not have been published. RESULTS: Abstracts from about 5,000 articles are read. 57 articles are ordered as full-text, 43 are finally included and 14 excluded. (1) In eight studies interviews with decision-makers are used to elicit the information, in three studies document analysis is employed, and in six surveys the results rely only on the observations and interpretations of the authors. One study analyses service data and in nine examinations more than one of the methods listed above are employed. Only in two studies pre-defined indicators were used and only in one clinical trial a prospective design is chosen. (2) In nine studies the impact of a population of HTA reports is analysed: Among these, seven find that more than 70% of the reports have an impact on the decision-making process, in one study 50% of the reports have none or only a minimal impact. In one study on the impact of 50 short HTA reports, it is found that they contribute valuable information but do not influence decisions. However, because of methodological flaws the evidence base for these results is rather limited. Most of the conclusions presented in the publications are based on the appraisal of the authors who are often related to the program of which the impact has been "evaluated". (3) The writers divide the factors that are identified as modifying the degree of impact of the HTA reports in two groups: context factors and factors that are connected to the developing process, the subject, the format, the content, or the quality of the reports. However, the relevance of these factors has to be assessed with caution: none of the publications has the relevance for a primary research question and in none of the studies is the relevance of the factors investigated in a prospective and systematic manner. CONCLUSION: There is little experience with study designs or methods that allow a valid assessment of the impact of HTA reports on the decision-making process in the health sector. However, some approaches, such as the use of pre-defined indicators, were identified that should be pursued and elaborated in further studies. Due to the lack of a developed methodology only limited conclusions related to the impact of HTA reports can be drawn. Among the studies that show a relevant impact, most are methodological. However, results from qualitative studies caution against assuming a causal relationship where a mere coincidence between the recommendations of an HTA report and health policy is identified. In order to produce evidence-based conclusions regarding the impact of HTA reports, validated indicators should be used. Study design should also aim at controlling for other influencing factors. None of the studies explicitly aim at examining the role of the factors that might be responsible for a low or high impact of the HTA reports. The non-systematic retrospective analyses do not allow reliable conclusions regarding the relevance of these factors. Therefore the factors identified here should only serve for hypothesis formation. On the basis of these studies it is not possible to give evidence based recommendations on the way how to increase the impact of HTA on decision making in Germany. Instead a concept for evaluation should be developed that combines quantitative and qualitative methods and considers the following questions:(1) What kind of impact should be measured? (2) Which are the target groups and at which level of the health system are they located? (3) Which are the outcome parameters and how can they be measured? (4) Which are the potential impact enhancing or limiting factors? PMID- 21289924 TI - Using decision-analytic modelling to transfer international evidence from health technology assessment to the context of the German health care system. AB - The objective of this Health Technology Assessment (HTA) methods report was to examine and to assess decision analysis (DA) as a method to transfer and adapt international scientific evidence in HTA to the German health care context. Furthermore, we sought to develop a systematic framework to facilitate the selection, transfer, adaptation, and synthesis of these data in German HTA projects.In this report, we review and summarise the concepts and methods of DA; present potential areas of applications, and provide a basis for the critical assessment of decision-analytic studies. The two main methods of DA, decision trees and Markov models, as well as various approaches to sensitivity analyses are described. Examples of typical situations for the use of DA in scientific evidence transfer are described, and a list of main health care domains and parameters in evidence transfer is presented. Finally, we developed a framework to transfer and apply international evidence to the national health care context. The strengths and limitations of the decision-analytic approach are critically examined.In summary, this HTA report describes different situations, in which decision-analytic models can be useful, and demonstrates the utility of DA in transferring and applying international evidence to the national health care context. We developed a systematic instrument to transfer international evidence to the context of other countries and successfully applied this instrument in two German HTA projects. The use of this instrument is recommended in further HTA projects dealing with the application of international evidence to the German health care context. The use of decision-analytic models to transfer international evidence is endorsed. However, the limitations of DA should be clearly stated discussed transparently in all HTA reports. PMID- 21289925 TI - Determination of albuminuria in the urine of diabetics for prevention and control of diabetic nephropathy. AB - THE ISSUE: Diabetes has become the main cause of endstage renal disease. The costs for the treatment of diabetic patients with endstage renal disease have increased in the last years and have become a relevant economic topic of the health service. The first unspecific predictor of a diabetic nephropathy is an albuminuria. The screening for diabetic nephropathy uses microalbuminuria as a proof. OBJECTIVES: What significance does the determination of albuminuria have on the precaution and course-control of the diabetic nephropathy?a) in type 1 diabetic patientsb) in type 2 diabetic patientsWhich is an appropriate time to determine the albuminuria for the purpose of precaution and course-control of the diabetic nephropathy?a) in type 1 diabetic patientsb) in type 2 diabetic patientsWhich method of testing is most effective concerning economic and medical aspects? METHODS: Published literature from 1998 up to 2004 was identified by searching in the most important databases. Most of the guidelines were found by hand searching in the internet. RESULTS: Of 2,792 citation titles and abstracts examined, 274 articles were retrieved for full-text review. Five metaanalyses and reviews, one review about clearing of guidelines (regarding 18 international guidelines) and four guidelines met the inclusion criteria for screening for microalbuminuria and type 1 diabetes. Seven metaanalyses, one HTA report, one review about clearing of guidelines (regarding 17 international guidelines), and seven guidelines met the inclusion criteria for screening for microalbuminuria and type 2 diabetes. At the moment, the determination of albuminuria still has a great significance because it is recommended in most published literature and guidelines. The time to determine the albuminuria depends on the age of the patients and their type of diabetes. Type 2 diabetic patients should start the determination when the diabetes is diagnosed whereas the determination is recommended five years later when type 1 diabetic patients are concerned. Most guidelines recommend a screening for microalbuminuria every year. DISCUSSION AND CONCLUSION: All guidelines and most of the literature recommend this screening. However, these recommendations are only based on expert consensus. The specificity of this screening is rather low. False positive tests in type 2 diabetic patients will cause psychological problems. A positive test leads to the recommendation to achieve "normal blood pressure" and "normoglycaemia" - but this applies to each diabetic patient. Based on these facts, the screening for albuminuria in type 1 or type 2 diabetes patients cannot be recommended as long as benefit has not been demonstrated by large, clinical, controlled trials. Without an evidence of the benefit, this screening cannot be economic. PMID- 21289926 TI - Effectiveness and cost-effectiveness of general immunisation of infants and young children with the heptavalent conjugated pneumococcal vaccine. AB - BACKGROUND: The European Agency for the Evaluation of Medicinal Products (EMEA) granted market authorisation to the heptavalent pneumococcal vaccine Prevenar (Wyeth) in the year 2001. The indication of Prevenar is the active immunisation of infants and young children under the age of two against invasive disease caused by Streptococcus pneumonia serotypes 4, 6B, 9V, 14, 18C, 19F and 23F. At the time of this study the German vaccination scheme advises the immunisation with Prevenar only for children at high risk. OBJECTIVES: The objective of the study is first to determine the efficacy and effectiveness of the immunisation of all children with the heptavalent conjugated pneumococcal vaccine in Germany and second, whether a general recommendation for vaccination of all children would be cost-effective. METHODS: A systematic literature search was performed in 29 relevant databases for the period of January 1999 to June 2004. Thus 1,884 articles were identified which were then assessed according to predefined selection criteria. RESULTS: There is evidence for the medical effectiveness of Prevenar against invasive pneumococcal disease caused by the covered serotypes from a major double-blinded RCT undertaken in California. The vaccine shows lower values of effectiveness against otitis media and pneumonia. The values for effectiveness of the vaccine in Germany are below the data for California because of the different incidence of Serotypes. The cost-effectiveness rates for an immunisation of all children with Prevenar vary across different countries. One reason - besides different Health Systems - can be seen in the uncertainty about the duration of protection, another in the assumption on regional serotype coverage of the vaccine. From the healthcare payers' perspective a general vaccination of all children in Germany is not cost-effective, from a societal perspective the benefits from vaccination could prevail the cost. The actual price of the vaccine (if financed by the Healthcare Payer, 2004) has dropped and is lower than the assumed price in the German cost-effectiveness study. This fact could raise the cost-effectiveness-ratio of a general immunisation. DISCUSSION: The low evidence of information on the herd immunity effect of pneumococcal immunisation, the occurrence on serotype-replacement phenomenon and the effects on the prevalence of antibiotic-resistant strains shall be considered when deciding whether the pneumococcal vaccination for all infants and young children should be added to the German vaccination scheme. There is also little information on the duration of vaccine effectiveness and regional effectiveness because of different serotype incidence. The economic models thus incorporate some uncertainties. CONCLUSION: At present, relatively few pneumococcal strains in Germany show antibiotic resistance. This situation shall further be observed while improving the data evidence for future decisions (epidemiologic data of incidence of pneumococcal diseases and serotyping of pneumococcal bacteria). From the economic perspective no distinct recommendation to add the conjugated vaccination for all children to the German vaccination scheme can be given. This situation may change if the price for the vaccine further decreases. Furthermore a future cost-effectiveness analysis for Germany should incorporate the effects of the replacement phenomenon, the herd immunisation effects and the effects of the vaccination on the antibiotic-resistant pneumococcal strains. PMID- 21289927 TI - Coated stents to prevent restenosis in coronary heart disease. AB - BACKGROUND: In-stent-restenosis (ISR) is considered to be an essential limiting factor of stenting in coronary heart disease (CHD). The development of coated stents has raised expectations on substantial lowering restenosis after stenting with decreasing the rate of restenosis and a reduction in the rate of clinical events. OBJECTIVES: The present analysis addresses the questions on medical effectiveness and cost-effectiveness of the use of various coated stent types in CHD. METHODS: The literature was searched in December 2004 in the most relevant medical and economic databases. The medical evaluation was conducted on the basis of published RCT. The data from the studies regarding various angiographic, sonographic and clinical endpoints were checked for methodical quality and summarised in meta-analyses. Within the scope of economic evaluation the primary studies were analysed and modelling was performed, applying clinical effect estimates from the meta-analyses of the medical evaluation and current estimates of German costs. RESULTS: MEDICAL EVALUATION: Ten different stenttypes were used in the included 26 RCT. The results for heparin, silicon-carbide, carbon and PTFE coated stenttypes could not reveal any significant differences between the medical effectiveness of coated and uncoated stents. The application of sirolimus, paclitaxel, everolimus and 7-hexanoyltaxol eluting stents showed a significant lower restenosis at 6-9 months with decrease in the rate of restenosis for polymer-based sirolimus, paclitaxel and 7-hexanoyltaxol eluting stents. In contrast, the use of gold-coated and actinomycin-D eluting stents was associated with a significantly higher restenosis. The polymer-based sirolimus and paclitaxel eluting stents also showed a significant and considerable reduction in the rate of repeated percutaneous revascularisations at 6-12 months (3.5% vs. 19.7%; p<0.0001, RR=0.19 [95%CI: 0.11; 0.33] and 3.5% vs. 12.2%; p<0.0001, RR=0.30 [95%CI: 0.20; 0.43]) and an equivalent reduction in the rate of combined events. The 7-hexanoyltaxol-eluting stents caused, however, a significant increase of stent thrombosis as well as of myocardial infarctions. ECONOMIC EVALUATION: The allocation to polymer-based sirolimus and paclitaxel eluting stents resulted in incremental costs (compared with uncoated stents) of approximately 1,421 ? and 1,234 ? per patient, taking in account expected revascularisations during the first year after implantation. The mean incremental cost-effectiveness-ratios per avoided revascularisation was 8,881 ? and 13,711 ?, respectively. The "break-even"-prices for these stenttypes in the used model were 707 ? and 551 ?, and the "break-even"-risks for ISR after stenting with uncoated stent, was 76% and 65%, respectively. The use of the other evaluated coated stents seems not to be cost-effective. DISCUSSION: The absolute effects and cost savings for patient groups with a higher risk of restenosis could be considerably higher than for patient groups with a lower risk of restenosis. The transferability of the results from the present analysis to other (sub) populations and technology modifications is limited. The direct comparability of the results for sirolimus and paclitaxel eluting stents is also restricted. CONCLUSIONS: From a medical point of view the use of polymer-based sirolimus or paclitaxel eluting stents can be recommended. The use of gold coated, 7 hexanoyltaxol and actinomycin-D eluting stents is in contrast not recommendable. From an economical point of view and on the basis of current stent prices the polymer-based eluting sirolimus and paclitaxel stents should primarily be recommended for patients with a higher risk of restenosis. PMID- 21289928 TI - Minimally invasive surgical procedures for the treatment of lumbar disc herniation. AB - INTRODUCTION: In up to 30% of patients undergoing lumbar disc surgery for herniated or protruded discs outcomes are judged unfavourable. Over the last decades this problem has stimulated the development of a number of minimally invasive operative procedures. The aim is to relieve pressure from compromised nerve roots by mechanically removing, dissolving or evaporating disc material while leaving bony structures and surrounding tissues as intact as possible. In Germany, there is hardly any utilisation data for these new procedures - data files from the statutory health insurances demonstrate that about 5% of all lumbar disc surgeries are performed using minimally-invasive techniques. Their real proportion is thought to be much higher because many procedures are offered by private hospitals and surgeries and are paid by private health insurers or patients themselves. So far no comprehensive assessment comparing efficacy, safety, effectiveness and cost-effectiveness of minimally-invasive lumbar disc surgery to standard procedures (microdiscectomy, open discectomy) which could serve as a basis for coverage decisions, has been published in Germany. OBJECTIVE: Against this background the aim of the following assessment is: Based on published scientific literature assess safety, efficacy and effectiveness of minimally-invasive lumbar disc surgery compared to standard procedures. To identify and critically appraise studies comparing costs and cost-effectiveness of minimally-invasive procedures to that of standard procedures. If necessary identify research and evaluation needs and point out regulative needs within the German health care system. The assessment focusses on procedures that are used in elective lumbar disc surgery as alternative treatment options to microdiscectomy or open discectomy. Chemonucleolysis, percutaneous manual discectomy, automated percutaneous lumbar discectomy, laserdiscectomy and endoscopic procedures accessing the disc by a posterolateral or posterior approach are included. METHODS: In order to assess safety, efficacy and effectiveness of minimally invasive procedures as well as their economic implications systematic reviews of the literature are performed. A comprehensive search strategy is composed to search 23 electronic databases, among them MEDLINE, EMBASE and the Cochrane Library. Methodological quality of systematic reviews, HTA reports and primary research is assessed using checklists of the German Scientific Working Group for Health Technology Assessment. Quality and transparency of cost analyses are documented using the quality and transparency catalogues of the working group. Study results are summarised in a qualitative manner. Due to the limited number and the low methodological quality of the studies it is not possible to conduct metaanalyses. In addition to the results of controlled trials results of recent case series are introduced and discussed. RESULTS: The evidence-base to assess safety, efficacy and effectiveness of minimally-invasive lumbar disc surgery procedures is rather limited: PERCUTANEOUS MANUAL DISCECTOMY: Six case series (four after 1998)AUTOMATED PERCUTANEOUS LUMBAR DISCECTOMY: Two RCT (one discontinued), twelve case series (one after 1998)CHEMONUCLEOLYSIS: Five RCT, five non-randomised controlled trials, eleven case seriesPERCUTANEOUS LASERDISCECTOMY: One non-randomised controlled trial, 13 case series (eight after 1998)ENDOSCOPIC PROCEDURES: Three RCT, 21 case series (17 after 1998) There are two economic analyses each retrieved for chemonucleolysis and automated percutaneous discectomy as well as one cost-minimisation analysis comparing costs of an endoscopic procedure to costs for open discectomy. Among all minimally invasive procedures chemonucleolysis is the only of which efficacy may be judged on the basis of results from high quality randomised controlled trials (RCT). Study results suggest that the procedure maybe (cost)effectively used as an intermediate therapeutical option between conservative and operative management of small lumbar disc herniations or protrusions causing sciatica. Two RCT comparing transforaminal endoscopic procedures with microdiscectomy in patients with sciatica and small non-sequestered disc herniations show comparable short and medium term overall success rates. Concerning speed of recovery and return to work a trend towards more favourable results for the endoscopic procedures is noted. It is doubtful though, whether these results from the eleven and five years old studies are still valid for the more advanced procedures used today. The only RCT comparing the results of automated percutaneous lumbar discectomy to those of microdiscectomy showed clearly superior results of microdiscectomy. Furthermore, success rates of automated percutaneous lumbar discectomy reported in the RCT (29%) differ extremely from success rates reported in case series (between 56% and 92%). The literature search retrieves no controlled trials to assess efficacy and/or effectiveness of laser-discectomy, percutaneous manual discectomy or endoscopic procedures using a posterior approach in comparison to the standard procedures. Results from recent case series permit no assessment of efficacy, especially not in comparison to standard procedures. Due to highly selected patients, modi-fications of operative procedures, highly specialised surgical units and poorly standardised outcome assessment results of case series are highly variable, their generalisability is low. The results of the five economical analyses are, due to conceptual and methodological problems, of no value for decision-making in the context of the German health care system. DISCUSSION: Aside from low methodological study quality three conceptual problems complicate the interpretation of results. Continuous further development of technologies leads to a diversity of procedures in use which prohibits generalisation of study results. However, diversity is noted not only for minimally-invasive procedures but also for the standard techniques against which the new developments are to be compared. The second problem refers to the heterogeneity of study populations. For most studies one common inclusion criterion was "persisting sciatica after a course of conservative treatment of variable duration". Differences among study populations are noted concerning results of imaging studies. Even within every group of minimally-invasive procedure, studies define their own in- and exclusion criteria which differ concerning degree of dislocation and sequestration of disc material. There is the non-standardised assessment of outcomes which are performed postoperatively after variable periods of time. Most studies report results in a dichotomous way as success or failure while the classification of a result is performed using a variety of different assessment instruments or procedures. Very often the global subjective judgement of results by patients or surgeons is reported. There are no scientific discussions whether these judgements are generalisable or comparable, especially among studies that are conducted under differing socio-cultural conditions. Taking into account the weak evidence-base for efficacy and effectiveness of minimally-invasive procedures it is not surprising that so far there are no dependable economic analyses. CONCLUSIONS: Conclusions that can be drawn from the results of the present assessment refer in detail to the specified minimally-invasive procedures of lumbar disc surgery but they may also be considered exemplary for other fields where optimisation of results is attempted by technological development and widening of indications (e.g. total hip replacement). Compared to standard technologies (open discectomy, microdiscectomy) and with the exception of chemonucleolysis, the developmental status of all other minimally-invasive procedures assessed must be termed experimental. To date there is no dependable evidence-base to recommend their use in routine clinical practice. To create such a dependable evidence-base further research in two directions is needed: a) The studies need to include adequate patient populations, use realistic controls (e.g. standard operative procedures or continued conservative care) and use standardised measurements of meaningful outcomes after adequate periods of time. b) Studies that are able to report effectiveness of the procedures under everyday practice conditions and furthermore have the potential to detect rare adverse effects are needed. In Sweden this type of data is yielded by national quality registries. On the one hand their data are used for quality improvement measures and on the other hand they allow comprehensive scientific evaluations. Since the year of 2000 a continuous rise in utilisation of minimally-invasive lumbar disc surgery is observed among statutory health insurers. Examples from other areas of innovative surgical technologies (e.g. robot assisted total hip replacement) indicate that the rise will probably continue - especially because there are no legal barriers to hinder introduction of innovative treatments into routine hospital care. Upon request by payers or providers the "Gemeinsamer Bundesausschuss" may assess a treatments benefit, its necessity and cost-effectiveness as a prerequisite for coverage by the statutory health insurance. In the case of minimally-invasive disc surgery it would be advisable to examine the legal framework for covering procedures only if they are provided under evaluation conditions. While in Germany coverage under evaluation conditions is established practice in ambulatory health care only ("Modellvorhaben") examples from other European countries (Great Britain, Switzerland) demonstrate that it is also feasible for hospital based interventions. (ABSTRACT TRUNCATED) PMID- 21289929 TI - Sonographic diagnosis of "acute abdomen" in children and adults. AB - INTRODUCTION: The acute abdomen is the main term for an at first unclear emergency situation of the abdominal cavity. The acute abdomen belongs to the three most important reasons for the admission of patients into the emergency room. Further, this illness ranks 40% of all consultations in the ambulant care sector. The acute abdomen requires an early and direct diagnosis because of its potential of having a life threatening differential diagnosis. This HTA report aimed to assess the ultrasound diagnosis of the acute abdomen considering children and adults. This will be done from a medical and economic perspective. The differential diagnosis respectively the cause of the acute abdomen binds high direct treatment costs, especially in the stationary sector. Ultrasound diagnosis is a procedure that plays a big part in the differential diagnosis process and it is widely used in practise. Other research methods of diagnosing acute abdominal illness are: clinical examinations with inspection and palpation, surgical exploration and laparocopy as well as computer tomography and x-ray examination. OBJECTIVES: The main objective of this HTA report is to assess what significance sonography should have within the examination strategy of the acute abdomen from the medical and economical view. Second, this HTA report will evaluate under which circumstances the ultrasonographic diagnosis of the acute abdomen, considering medical and economical quality classifications, is the alternative of choice to comparable diagnostic measures. METHODS: The target population this HTA report is aimed at are children and adults with acute abdomen or embedded differential diagnosis. A systematic literature search was conducted covering all relevant medical and HTA-databases. Furthermore, handsearch was conducted inside of the known data bases of HTA-institutions as well as from medical and economical journals. The following databases were searched in cooperation with DIMDI to identify relevant literature: Biosis-Previews (BA93), Biotechnobase (ET80), Cab-Health (AZ72), Elsevier Biobase (EB94), EMBASE (EM74), Embase Alert (EA08), Ethmed (ED93), Euroethics (EU93), Gerolit (GE79), Heclinet (HN69), IHTA ( HT83), IPA (IA70), MEDLINE (ME90, Medline Alert (MEOA) and SciSearch (IS74). The search parameters were orientated by the embedded differential diagnosis's as well as diagnostic measures considering the acute abdomen. The bibliographic search covered the period from 1990 to 2003. The relevant languages are English, German in connection to French. The evaluation of the information has been graduated. It must be clear that the abstract follows the topic of the acute abdomen. The as such identified literature will be structured by its methodological quality and relevance. This will be analysed and later valued after it is clear that the minimum requirements are met. RESULTS: The identified and assessed primary studies, reviews and metaanalytic studies demonstrated the medical effectiveness as well as the economical efficiency of the sonographical diagnosis for individual questions or indications. The evaluated papers of the target population 'children' demonstrated that sonography resp. ultrasound as the basic examination is recommended for children with acute abdominal pain. DISCUSSION: The identified studies have not used an extensive setting of the ultrasound diagnosis of the acute abdomen. Instead they focus only on small sections, orientated on certain indications. Blinded medical studies have not been identified. Also, there is no health-economics study that evaluated the diagnostic measures by comparing all available technologies. Altogether, the identified and assessed publications show that sonography is an alternative of choice considering particular questions in comparison to other diagnostic measures of analyzing the acute abdomen. A general deflected dominance from the sonography facing the computer tomography for instance can not be seen as the result of this structured review of the published literature. CONCLUSION: During a structured examination strategy, e.g. guidelines, sonography of children has become the diagnostic method of choice. Taking up sonography as a primary diagnostic evaluation into the guidelines of the analysis of the considered literature is recommended. The usage of already existing ultrasound systems is also recommended. Seeing that existing publications of this subject are scarce, it is not possible to prognose the economical effects of an obligatory primary sonographical diagnostic. PMID- 21289930 TI - Methods for the comparative evaluation of pharmaceuticals. AB - POLITICAL BACKGROUND: As a German novelty, the Institute for Quality and Efficiency in Health Care (Institut fur Qualitat und Wirtschaftlichkeit im Gesundheitswesen; IGWiG) was established in 2004 to, among other tasks, evaluate the benefit of pharmaceuticals. In this context it is of importance that patented pharmaceuticals are only excluded from the reference pricing system if they offer a therapeutic improvement. The institute is commissioned by the Federal Joint Committee (Gemeinsamer Bundesausschuss, G-BA) or by the Ministry of Health and Social Security. The German policy objective expressed by the latest health care reform (Gesetz zur Modernisierung der Gesetzlichen Krankenversicherung, GMG) is to base decisions on a scientific assessment of pharmaceuticals in comparison to already available treatments. However, procedures and methods are still to be established. RESEARCH QUESTIONS AND METHODS: This health technology assessment (HTA) report was commissioned by the German Agency for HTA at the Institute for Medical Documentation and Information (DAHTA@DIMDI). It analysed criteria, procedures, and methods of comparative drug assessment in other EU-/OECD countries. The research question was the following: How do national public institutions compare medicines in connection with pharmaceutical regulation, i.e. licensing, reimbursement and pricing of drugs? Institutions as well as documents concerning comparative drug evaluation (e.g. regulations, guidelines) were identified through internet, systematic literature, and hand searches. Publications were selected according to pre-defined inclusion and exclusion criteria. Documents were analysed in a qualitative matter following an analytic framework that had been developed in advance. Results were summarised narratively and presented in evidence tables. RESULTS AND DISCUSSION: Currently licensing agencies do not systematically assess a new drug's added value for patients and society. This is why many countries made post-licensing evaluation of pharmaceuticals a requirement for reimbursement or pricing decisions. Typically an explicitly designated drug review body is involved. In all eleven countries included (Austria, Australia, Canada, Switzerland, Finland, France, the Netherlands, Norway, New Zealand, Sweden, and the United Kingdom) a drug's therapeutic benefit in comparison to treatment alternatives is leading the evaluation. A medicine is classified as a therapeutic improvement if it demonstrates an improved benefit-/risk-profile compared to treatment alternatives. However, evidence of superiority to a relevant degree is requested. Health related quality of life is considered as the most appropriate criterion for a drug's added value from patients' perspective. Review bodies in Australia, New Zealand, and the United Kingdom have committed themselves to include this outcome measure whenever possible. Pharmacological or innovative characteristics (e.g. administration route, dosage regime, new acting principle) and other advantages (e.g. taste, appearance) are considered in about half of the countries. However, in most cases these aspects rank as second line criteria for a drug's added value. All countries except France and Switzerland perform a comparative pharmacoeconomic evaluation to analyse costs caused by a drug intervention in relation to its benefit (preferably by cost utility analysis). However, the question if a medicine is cost effective in relation to treatment alternatives is answered in a political and social context. A range of remarkably varying criteria are considered. Countries agree that randomised controlled head to-head trials (head-to-head RCT) with a high degree of internal and external validity provide the most reliable and least biased evidence of a drug's relative treatment effects (as do systematic reviews and meta-analyses of these RCT). Final outcome parameters reflecting long-term treatment objectives (mortality, morbidity, quality of life) are preferred to surrogate parameters. Following the concept of community effectiveness, drug review institutions also explicitly favour RCT in a "natural" design, i.e. in daily routine and country specific care settings. The countries' requirements for pharmacoeconomic studies are similar despite some methodological inconsistencies, e.g. concerning cost calculation. Outcomes of clinical and pharmacoeconomic analyses are largely determined by the choice of comparator. Selecting an appropriate comparative treatment is therefore crucial. In theory, the best or most cost effective therapy is regarded as appropriate comparator for clinical and economic studies. Pragmatically however, institutions accept that the drug is compared to the treatment of daily routine or to the least expensive therapy. If a pharmaceutical offers several approved indications, in some countries all of them are assessed. Others only evaluate a drug's main indication. Canada is the only country which also considers a medicine's off-label use. It is well known that clinical trials and pharmacoeconomic studies directly comparing a drug with adequate competitors are lacking - in quantitative as well as in qualitative terms. This is specifically the case before or shortly after marketing authorisation. Yet there is the need to support reimbursement or pricing decisions by scientific evidence. In this situation review bodies are often forced to rely on observational studies or on other internally less valid data (including expert and consensus opinions). As a second option they use statistical approaches like indirect adjusted comparisons (in Australia and the United Kingdom) and, commonly, economic modelling. However, there is consensus that results provided by these techniques need to be verified by valid head-to-head comparisons as soon as possible. CONCLUSIONS: In the majority of countries reimbursement and pricing decisions are based on systematic and evidence-based evaluation comparing a drug's clinical and economic characteristics to daily treatment routine. However, further evaluation criteria, requirements and specific methodological issues still lack internationally consented standards. PMID- 21289931 TI - Cognitive training for dementia. AB - The aim of the HTA report is to evaluate the effectiveness of cognitive training methods to treat cognitive disorders of dementia and other diseases with cognitive deficits. For this purpose, a systematic literature search was carried out first based on the DIMDI superbase retrieval. The identified publications were judged and selected by two independent, methodically competent experts. 33 publications were included in the report.Based on the studies for a normal cognitive development in old age a theory that healthy older people have a considerable capacity reserve for an improved performance in abstract abilities of thinking can be assumed. The first symptoms for older people at risk for dementia are a reduced cognitive capacity reserve. Cognitive training methods therefore focus abilities of abstract memory.APART FROM TYPES OF DEMENTIA ANOTHER TWO GROUPS OF DISEASES WITH COGNITIVE DEFICITS WERE INCLUDED IN THE HTA REPORT: cerebral lesions and schizophrenic psychoses.Studies with mild as well as forms of dementia heavy forms including the Alzheimer disease were included. The described training methods were very heterogeneous with regard to their contents, the temporal sequence and the outcome parameter. The studies were methodically partly contestable. Approximately a third of the studies of all publications could show improvements in the cognitive achievements by the training.Three studies concerning cognitive training methods in case of cerebral lesions were included. All three studies demonstrated a significant improvement in the training group in some outcome parameters.Special cognitive training methods were used for the treatment of cognitive deficits at schizophrenic psychoses. The neurocognitive training (NET), the "Cognitive Remediation Therapy" as well as the strategic training with coaching proved to be effective. The studies, however, were hardly comparable and very heterogeneous in detail.Summarising the cognitive training methods in case of severe dementia by reality orientation training (ROT) show selected success. In case of cerebral lesions in combination with schizophrenic psychoses successes could be proved in some parameters by applied cognitive training.Considering the heterogenity and the methodical deficiencies of the included studies it can be recommended, to carry out coordinated further studies with the goal to identify the success parameters of cognitive training methods and work out the relevant factors of effectiveness. PMID- 21289932 TI - Hypertension guidelines and their effects on the health system. AB - INTRODUCTION: Hypertension guidelines, which have existed for many years and primarily used in the USA, Canada and Great Britain, are now becoming an issue in Germany. Strong efforts are presently underway for a German version comparable to the guidelines developed for the mentioned countries. The development of guidelines is a part of the implementation system of guidelines in Germany. It covers the mode of operation of the AWMF (work community of the scientific medical subject companies) with the clearinghouse for guidelines (CLA) and the cooperation with the centre for medical quality (AZQ). In the HTA report the real use of the hypertension guidelines shall be investigated for Germany from the development trends and further possibilities of use according to a medical applicability. Economic issues and an optimisation of use are also discussed. QUESTION: THE FOLLOWING QUESTIONS SHALL BE ANSWERED IN PARTICULAR: How much are the guidelines used concerning hypertension? Can effects (or their influence) be established on the medical procedures? Are there statements available about costs and cost effectiveness? Are there recommendations for further use? METHODOLOGY: To answer these questions, a comprehensive literature search was done. No empirical investigation was carried out. From this enquiry 206 articles were checked in detail but not all of them were available in full text. Only those publications which directly dealt with high blood pressure guidelines or articles with a direct reference to the topic have been considered in the HTA report. Publications concerning screening or methods of prevention, medical studies of the hypertension syndrome without a direct reference to guidelines and publications concerned with putting guidelines into action were excluded. RESULTS: After an analysis of the selected literature addressing the topic of hypertension guidelines, it was evident that the use of these guidelines cannot be gathered from existing literature at the present time. One can assume from international studies with analogical reasoning that these are confessed and have a high level of acceptance in the medical community. Unfortunately the actual usage is not represented satisfactorily in the scientific literature. The effects of the guidelines on the medical procedures seem to be very strongly individual and the analyses to the compliance show at least an observable effect within the last few years. No publications could be found for the cost effectiveness of the guidelines. The actual compliance with guidelines seems to be in relation with the duration of the professional practice. It seems the shorter the professional practice takes place, the stronger the guidelines are adhered. DISCUSSION: At present, there are only a few notes for the German health service regarding the actual effect of the hypertonus guidelines. However, the reason is not that the effect would not be possibly strong but at the methodical challenge to evaluate the sustaining effects of the application of the hypertonus guidelines. For this reason the literature is very rare regarding this topic. For Germany it can be derived by analogical reasoning from foreign studies that guidelines will facilitate a more and more essential contribution to the design of the health system. Considering that primarily younger physicians accepted guidelines mode, the further construction, update and implementation of guidelines are essential, particularly with regard to the quality assurance. Straight guidelines can express a standard of the quality of a health system as a benchmark. The existence of guidelines or the lack thereof is considered also as a quality indicator of a health system at the organisation for economic cooperation and development (OECD). CONCLUSION: Guidelines should be evaluated - especially the hypertonus guideline. Also further development and implementation should be emphasised. Methodically oriented work to the approach is pretty recent. It is undeniable that guidelines represent a very essential and important contribution for the successful dealing with significant morbidity problems in a health system. The fact that primarily younger doctors more frequently adopt, employ and adhere to guidelines leads to the assumption that expected sustainability for practical use will increase. Furthermore intensified use of guidelines can be considered in the "mainstream" of the development of the public health system also in an international perspective. Not one single publication contradicts that a further acquirement, update and distribution of guidelines for the use of practices is necessary. The importance of the guideline is also not questioned in any article. PMID- 21289933 TI - Influence of tumor necrosis factor alpha in rheumatoid arthritis. AB - OBJECTIVE: Rheumatoid arthritis (RA) is the most prevalent inflammatory rheumatic disorder. It is a chronic and incurable disease that leads to painful inflammation, often irreversible joint damage, and eventually to functional loss. Conventional treatment is based on unspecific immunosuppressive agents, e.g. Methotrexate, Azathioprin or Gold. However, the longterm outcomes of these approaches have been poor with frequently ongoing inflammatory disease activity, functional decline, and temporary or permanent work disability. More recently, antagonists of the human cytokine Tumor Necrosis Factor alpha (TNF-alpha) have been introduced that are potent suppressors of inflammatory processes. Infliximab is a chimeric antibody against TNF-alpha. Etanercept is a soluble human TNF-alpha receptor. The report assesses the efficacy of TNF-alpha-antagonists to down regulate inflammation, improve functional status and prevent joint damage in RA with particular regard to the following indications: Treatment of severe, refractory and ongoing disease activity despite adequate use of conventional antirheumatic agents; and treatment of early RA before conventional treatment failure has been demonstrated. METHODS: A systematic review of the literature is been performed using established electronic databases. The literature search is supplemented by a hand search of journals and publications relevant to RA, reviews of websites of national and international rheumatologic expert societies, as well as contacts to manufacturers. A priori defined inclusion and exclusion criteria are used for literature selection. Analysis and evaluation of included publications are based on standardised criteria sets and checklists of the German Scientific Working Group for Technology Assessment in Health Care. RESULTS: Health Technology Assessment reports and metaanalyses cannot be identified. A total of 12 clinical trials are analysed, as well as national and international expert recommendations and practice guidelines. Numerous non-systematic reviews are found and analysed for additional sources of information that is not identified through the systematic search. Case reports and safety assessements are considered as well. A total of 137 publications is included. The primary outcome measures in clinical trials are suppression of inflammatory disease activity and slowing of structural joint damage. Clinical response is usually measured by standardised response criteria that allow a semi-quantitative classification of improvement from baseline by 20%, 50%, or 70%. In patients with RA refractory to conventional treatment, TNF-alpha-antagonists are unequivocally superior to Methotrexate with regard to disease activity, functional status and prevention of structural damage. In patients with early RA, TNF-alpha-antagonists show a more rapid onset of anti-inflammatory effects than Methotrexate. However, differences in clinical response rates and radiologic progression disappear after a few months of treatment and are no longer statistically significant. Serious adverse events are rare in clinical trials and do not occur significantly more often than in the control groups. However, case reports and surveillance registries show an increased risk for serious infectious complications, particularly tuberculosis. Expert panels recommend the use of TNF-alpha antagonists in patients with active refractory RA after failure of conventional treatment. Studies that compare Infliximab and Etanercept are lacking. There are no pharmacoeconomic studies although decision analytic models of TNF-alpha antagonists for the treatment of RA exist. Based on the results of the models, a combination therapy with Hydroxychloroquin (HCQ), Sulfaslazin (SASP) and Methotrexate as well as Etanercept/Methotrexate can be considered a cost effective treatment for Methotrexate-resistant RA. CONCLUSIONS: TNF-alpha antagonists are clearly effective in RA patients with no or incomplete response to Methotrexate and superior to continuous use of Methotrexate. It refers to both, reduction of inflammatory disease activity including pain relief and improved functional status, and prevention of structural joint damage. Therefore, TNF-alpha-antagonism is an important new approach in the treatment of RA. There is still insufficient evidence that early use of TNF-alpha-antagonists in RA prior to standard agents is beneficial and further studies have to be awaited. An analytic model suggests that TNF-alpha-antagonists are, due to their clinical effectiveness in patients with no or incomplete response to Methotrexate, a cost effective alternative to common therapies chosen in the subpopulations of patients. Nevertheless, it has to be borne in mind that the acquisition costs of TNF-alpha-antagonists lead to high incremental costs and C/E ratios, which exceed the common frame of assessing the cost-effectiveness of medical methods and technologies. Hence, society's willingness-to-pay is the critical determinant in the question whether TNF-alpha-antagonists shall be reimbursed or not, or to define criteria for reimbursement. Changes in the quality of life attributable to the use of TNF-alpha-antagonists in RA have not yet been assessed which might assist the decision making. With respect of the questions mentioned above and the potential financial effect of a systematic use of TNF-alpha-antagonists in the treatment of RA, we come to the conclusion that TNF-alpha-antagonists should not introduced as a standard benefit reimbursed by the statutory health insurers in Germany. PMID- 21289934 TI - Screening on urogenital Chlamydia trachomatis. AB - INTRODUCTION: Around 92 million urogenital infections are caused yearly by Chlamydia trachomatis worldwide [1].The overall incidence of sexually transmitted diseases is increasing, as shown by the increases in the number of reported cases of syphilis and gonorrhea [2]. Chlamydia trachomatis infections are associated with various serious diseases in women, men and newborns, which could be, at least partially, avoided by means of early diagnosis and therapy. The Federal Joint Committee - responsible for decision-making concerning the benefit package of the German Social Health Insurance - has publicly announced the starting of deliberations on the issue of screening for Chlamydia trachomatis. RESEARCH QUESTIONS: The leading question to be answered is whether screening for Chlamydia trachomatis should be included in the German benefit basket. The aim of this report is to provide a summary of the available evidence concerning the issue of screening for Chlamydia trachomatis. METHODS: The summary of published scientific evidence, including HTA reports, systematic reviews, guidelines and primary research is represented. The synthesis follows the structure given by the criteria of Wilson and Jungner [3] for the introduction of screening in a population: relevance of the condition, availability of an adequate test, effectiveness of screening, acceptance of the programme, and economical issues. A literature search was conducted for each aspect of the synthesis and the evidence has been summarised in evidence tables. RESULTS: We identified five HTA reports from three European agencies [4], [5], [6], [7] and one from the USA [8]. In addition, we identified four guidelines from Northamerica[9], [10], [11], [12] and one from Europe [13]. A total of 56 primary research publications were included: relevance of the disease (n=26), availability of test (n=1), effectiveness of screening (n=11), acceptance of the programme (n=11), economical issues (n=7). DISCUSSION: The main limitation of this report is that we relied only on published results. Most of research has been conducted in countries other than Germany. The fulfilment of the criteria for introduction of screening depends on contextual factors. More data from Germany are needed in order to answer the main questions concerning acceptance, use of selection criteria to identify subgroups and economical aspects of screening for Chlamydia trachomatis in Germany. CONCLUSIONS: The criteria for introduction of screening for Chlamydia trachomatis are partially fulfilled. The available evidence indicates that the success of a screening programme for Chlamydia trachomatis will depend on the implementation of strategies for uptake enhancement and probably on the participation of men as well. A pilot project should be conducted in order to assess cost-effectiveness, acceptance and feasibility of different screening strategies in Germany. On the light of the available evidence, the inclusion of screening for Chlamydia trachomatis in the benefit basket without embedding it in a multifaceted programme targeting primary prevention of sexually transmitted diseases and participation in screening cannot be recommende. PMID- 21289935 TI - Validity and cost-effectiveness of methods for screening of primary open angle glaucoma. AB - HEALTH POLITICAL BACKGROUND: About 950,000 people are affected by glaucoma in Germany, about 50% of which are undiagnosed. The German Ophthalmological Society and the German Association of Ophthalmologists recommend a screening for glaucoma according to their guidelines. The Federal Joint Committee disapproved a glaucoma screening program on expense of the compulsory health insurance in 2004. SCIENTIFIC BACKGROUND: Primary open angle glaucoma is diagnosed by evaluation of the optic disc, the retinal fibre layer and the visual field. The main examinations are ophthalmoscopy, scanning laser polarimetry, confocal scanning laser ophthalmoscopy, retinal thickness analysis and optical coherence tomography. Scotomas are diagnosed by perimetry (standard automated perimetry, short wavelength automated perimetry and frequency doubling perimetry). The intraocular pressure is the most important treatable risk factor and is measured by (contact or non-contact) tonometry. RESEARCH QUESTIONS: The aim of this HTA report is to investigate the diagnostic validity and cost effectiveness of diagnostic techniques or combinations of these methods with respect to the use in a screening setting in Germany. METHODS: A systematic literature research was performed in 35 international databases and yielded 2602 articles. Overall 57 publications were included for assessment, according to predefined selection criteria. RESULTS: The 55 medical articles deal mainly with frequency doubling perimetry, confocal scanning laser ophthalmoscopy and scanning laser polarimetry. Few articles cover short wavelength automated perimetry, tonometry and ophalmocopic evaluations by ophthalmologists. The quality of the papers is generally low, as far as the evidence in respect of screening is concerned. No single method exists with both, high sensitivity and high specificity for screening purpose. Data are also not sufficient to recommend combinations of methods. Only two economic models on cost-effectivenes of screening investigations could be identified. No economic evaluations of the most recent methods can be found in the published literature. A British cost-effectiveness analysis calculates cost per true positives and favours a combination of ophthalmoscopy, tonometry and perimetry either for people at high risk for glaucoma or for the total population as an initial examination. A Canadian HTA report models the cost per year of blindness avoided. The report concludes that because of a high degree of uncertainty with respect to the benefits and the high costs involved, the setting-up of a glaucoma-screening program cannot be supported. DISCUSSION: The literature shows that combinations of methods have to be used for screening of glaucoma in order to get reasonable values of sensitivity and specificity. Presently no combination of methods and no algorithm can be presented for glaucoma screening with sufficient evidence. Also no conclusions about cost-effectiveness for Germany can be made based on the available literature. CONCLUSIONS: In order to find the optimal combination of methods for glaucoma-screening, population-based studies have to be performed. Therefore also no final conclusions can be drawn with respect to cost effectiveness of glaucoma-screening methods. The economic evaluation of a clinical effective screening-method should consider the effects of blindness avoided, as well as effects on the prevention of visual impairment. PMID- 21289936 TI - Evaluation of optical coherence tomography in the diagnosis of age related macula degeneration compared with fluorescence angiography. AB - BACKGROUND: In industrialised nations age-related macular degeneration (AMD) is the most common cause of blindness and severe visual impairment. AMD is a disease of the retina characterized by the accumulation of metabolic products in the macula. In early stages drusen and pigment disorders occur, in late stages a dry form is distinguished from the exsudative form with choroidal neovascularisation. AMD causes vision disorders such as blurred vision of the central part of the visual field, leading finally to a dark spot. Several therapies are available for the exsudative form, however an exact diagnosis is partially essential. The gold standard for the diagnosis of AMD is fluorescein angiography (FA), an invasive investigation with intravenous application of a dye. Optical coherence tomography (OCT) is a more recent non-invasive procedure. OBJECTIVES: The aim of this HTA report is to investigate the efficacy and efficiency of OCT compared to FA. Ethical, societal and legal aspects are also considered. METHODS: A systematic literature search was performed in 34 international databases which yielded 2324 articles. Eight publications were included for assessment, according to predefined selection criteria. RESULTS: The number of studies investigating OCT compared to FA in patients with AMD is presently very limited and the quality of the studies is generally low. The number of investigated patients is below 35 in four publications and in only one publication it is above 100. Moreover in most of the articles very selected patient groups are studied. Economic studies concerning the efficiency of OCT compared to FA cannot be identified. DISCUSSION: Even though the patient groups investigated and the objectives of the studies are very heterogenous, all publications uniformly show that OCT cannot replace FA. However, OCT yields additional diagnostic findings and may verify unclear findings of FA. Therefore the application of OCT in addition to FA is useful in many cases. With regard to costs German patients on average currently have to pay more for performing OCT than for performing FA. CONCLUSION: Future studies have to show whether OCT may give diagnostic information essential for therapeutic decisions in addition to FA and whether it can replace FA in selected cases. The number of patients included in these studies should be high enough to answer relevant questions with sufficient statistical power. An economic model calculation can be built upon the resulting findings. PMID- 21289937 TI - Hormones for therapy of climacteric afflictions. AB - BACKGROUND: In Western countries hormone replacement therapy (HT) is widely used in the treatment of climacteric women who are affected with hot flashes and night sweats. Besides, long-term HT was frequently used to manage the higher risks for osteoporosis and heart attack in postmenopause. Estrogens alone or combined with progestin feature most frequently in HT. OBJECTIVES: This HTA report addresses the questions on medical efficacy and cost-effectiveness of HT as a treatment of hot flashes and night sweats as well as in the primary prevention of osteoporosis and cardiovascular disease in postmenopause in general healthy women. METHODS: The literature search for articles published after 1998 was conducted in March 2004 in standard medical and economic databases. The analysis included randomised controlled trials, systematic reviews, meta-analysis and economic evaluations considering relevant clinical endpoints in English or German language. The quality of the studies was assessed using checklists corresponding to the study type. RESULTS: HT is highly effective in treating hot flashes in climacteric women. The question of economical efficiency cannot be answered due to the scarce database. As the positive effects (lower risk for fractures and endometrial cancer) do not outweigh the negative effects (higher risk for breast cancer and general cardiovascular risk) estrogen-progestin combination HT cannot be recommended for primary prevention of osteoporosis and cardiovascular disease in postmenopausal women. DISCUSSION: The observation period of most of the studies regarding therapy of hot flashes and night sweats were too short to evaluate possible risks of long-term HT. The economic publications assessing HT for this indication varied vastly in terms of applied methods and were not carried out with respect to the German health care system. CONCLUSIONS: HT can be recommended in the short-term treatment of hot flashes and night sweats in climacteric women. To explore the economic effects of HT for this indication for Germany, studies constructed with respect to the German health care system are desirable. PMID- 21289938 TI - Long term substitution treatment (maintenance treatment) of opioid dependent persons. AB - HEALTH POLITICAL BACKGROUND: Methadone substitution treatment in Germany is introduced in 1988 in the framework of a scientific pilot study in North Rhein Westphalia. Recent statistics show that by now a broad offer of substitution treatment exists. From 1 June 2002 to 31 December 2003 113,000 substitution treatments have been recorded as being started of which around 56,000 have been recorded as ongoing treatments by 1 December 2003. SCIENTIFIC BACKGROUND: Substitution treatment (treatment of opioid-dependent persons using substitution substances) is one part of addiction treatment. Its goals are harm reduction and the stabilisation of opioid dependent persons. Integration of opioid-dependent persons in a treatment-setting, reduction of consumption of psychoactive substances, reduction of risk behaviour (primarily related to infectious diseases), decrease of mortality and improvements concerning the social, psychic and physic situation are seen as a success of substitution treatment as maintenance therapy. RESEARCH QUESTIONS: The aim of this HTA report is to investigate which indicators can be used to evaluate the effectiveness of substitution treatment. Based on these indicators an evaluation of the medical, social and economical benefit of substitution treatment - also in relation to abstinence oriented treatment - is carried out. METHODS: A systematic literature search was performed in 31 international databases which yielded 2451 articles with publication date between 1995 and February 2005. RESULTS: After a twofold selection process 32 publications were included for assessment and 276 publications were used as background literature. Despite serious restrictions due to selection bias and dropout in most studies focusing on substitution treatment, reduction of consumption of illegal opioids, reduction of risk behaviour, criminal behaviour, mortality and incidence of HIV can be seen as an empirically proven success of substitution treatment. Concerning the improvement of life and health situation the results of the studies are contradictory. The results show that retention rate of substitution treatment is higher than retention rate of abstinence oriented treatment. Regarding economical aspects substitution treatment is efficient in avoiding secondary illnesses (infections) and decreasing criminality. From the perspective of medical ethics substitution treatment as well as medical prescription of heroin is in principle acceptable. DISCUSSION AND CONCLUSIONS: Based on these results, it can be recommended that substitution treatment in principle should be made available for all opioid dependent persons. The decision whether substitution treatment or another treatment (e. g. abstinence oriented treatment) is more promising has to take into account the individual situation of the client. In addition a combination of substitution treatment and abstinence oriented treatment might be promising although there is a lack of studies about this approach. In any case the decision concerning a certain form of treatment should leave aside pseudo-moralic concerns and should be made on the base of established medical ethic principles - like the interest of the patient - taking into account the specific situation of the client. PMID- 21289939 TI - Efficacy and effectiveness of recombinant human activated protein C in severe sepsis of adults. AB - INTRODUCTION: Sepsis is defined as an invasion of microorganisms and/or their toxins into the blood associated the reaction of the organism to this invasion. Severe sepsis is a major cost driver in intensive care medicine. In Germany, prevalence data was assessed in the context of the German Prevalence Study. Severe sepsis has a prevalence of 35% in German intensive care units. RESEARCH QUESTIONS: THE FOLLOWING QUESTIONS WERE ANALYSED: is Drotrecogin alfa (activated) (DAA) effective in the treatment of patients with severe sepsis and a mixed risk of death, both in all patients and in different subgroups? Is DAA effective in the treatment of patients with severe sepsis and low risk of death? Is DAA cost effective in the treatment of patients with severe sepsis compared to placebo? METHODS: Only studies with adult patients are included. There are no other exclusion criteria. A systematic literature search is performed by the German Institute of Medical Documentation and Information (DIMDI). The literature search yielded as a total of 847 hits. After screening of the abstracts, 165 medical and 101 economic publications were chosen for full text appraisal. RESULTS: Therapy with DAA appears to be cost effective in reducing 28-day-mortality in patients with severe sepsis and a high risk of death. A high risk of death is indicated by the presence of multiorgan failure (>=2) and/or an APACHE-II-Score >=25. Therapy with DAA is not associated with a long-term reduction of mortality at later follow-up assessments. Therapy with DAA is not associated with a long-term reduction of mortality at later follow-up assessments. Therapy with DAA is cost effective in patients with multiorgan failure and/or an APACHE II Score (>=25). In patients with a lower risk of death, DAA is not cost-effective. Costs associated with bleeding events have been rarely included in cost calculations. DISCUSSION: DAA appears to reduce mortality in patients with severe sepsis and a high risk of death, but not in patients with a low risk of death. Bleeding events and mortality are considerable higher in studies in the usual care setting compared to clinical trials. In a number of subgroup analyses, both retrospectively and prospectively performed, DAA was not significantly associated with improved survival. The role of concurrent therapy with heparin is unclear, as DAA was only effective in reducing mortality in patients without heparin. There was no significant long-term survival benefit associated with DAA beyond the initial 28 days. Also, there is a lack of studies assessing prospectively functional ability, health-related quality of life, and morbidity in the long term. In the subgroup of patients with a high risk of death, therapy with DAA ranges at the top level of generally accepted costs per LYG or QALY, in the subgroup of patients with low risk of death, cost effectiveness ratios were higher than those accepted for resource allocation. CONCLUSION: Due to the lack of effectiveness of DAA in patients with severe sepsis and a low risk of death as well as with regard to the high bleeding rates in the usual care setting, indication for DAA therapy. In those subgroups with no significant survival benefit, prospective studies with adequate sample size are needed. With regard to the heterogeneity of severe sepsis, comorbidity and concurrent medication have to be taken into account in further studies. Studies with alternative study designs, for example studies comparing heparin alone or in combination with DAA to placebo, as well as studies conducted by different researchers are needed. Costs induced by bleeding events should also be taken into account in future studies, as bleeding events are the major complica-tion associated the DAA therapy. PMID- 21289940 TI - Benefits and risks of hormonal contraception for women. AB - SCIENTIFIC BACKGROUND: A large proportion of women of reproductive age in Germany use various methods of pregnancy prevention (contraception), among them various hormone-based methods. Hormonal contraceptives may be divided into combined estrogen-progestogen contraceptives (pills, skin patches, vaginal rings), progestogen-only contraceptives (pills, injections, implants, hormone spirals) and emergency contraceptives. RESEARCH QUESTIONS: The evaluation addressed the question of benefits and risks of hormonal contraceptives, their economic effects as well as their ethical-social and legal implications. METHODS: A systematic literature search was conducted in April 2006 starting from 2000. The evaluation is primarily based on systematic reviews. RESULTS: In perfect use, all hormonal contraceptives excluding emergency contraceptives proved to be the most effective reversible contraceptive methods (rate of unintended pregnancies 0.05% to 0.3%). However, the typical use of oral contraceptives, injections, skin patches, and vaginal rings, which also considers possible application errors, showed a lower contraceptive efficacy (rate of unintended pregnancies 3% to 8%). It was lower than that of copper spirals. The risk of venous thromboembolism increased three to six times in users of hormonal contraceptives, the risks of stroke and myocardial infarction two to three times. The risk declined after discontinuation of use. The effects were estrogen-dose and progestogen-type dependent. The use of hormonal contraceptives showed a relative risk of ovarian and endometrial carcinomas of approximately 0.5 or 0.7, of breast and cervical cancer of approximately 1.2 or 1.6. The effect remained several years after discontinuation of use. The results concerning hepatocellular carcinoma suggested a carcinogenic effect. In women with acne, an improvement due to use of hormonal contraceptives was proven. Cervical chlamydial infections were more frequent in users of hormonal contraception. Headache appeared mostly only at the beginning of the use of combined oral contraceptives. Progestogen-only contraceptives worsened the results of the glucose tolerance test. A review of low evidence reported further risks of hormonal contraceptives (concerning menstrual problems, ovarian cysts, bone density, thyroid diseases and rheumatoid arthritis) as well as further benefits (concerning blood pressure and Crohn's disease). Hormonal spirals were shown to be more effective than spirals which do not release hormones. In emergency contraception, Levonorgestrel was more effective than the Yuzpe method. Most other proven differences between hormonal contraceptives were related to menstrual problems. After spirals with or without hormone release, the other hormonal contraceptives were shown in typical use to be the second most cost effective reversible methods of contraception. DISCUSSION: The addressed questions could be answered only on relatively low evidence level, partly only for applications with estrogen doses which are not used in Germany any more. The transferability of the results of the analysed primary health-economics studies on the current situation in Germany is limited (clinical assumptions from out dated information sources of low evidence levels, cost assumptions from the American health system). CONCLUSIONS: In perfect use, hormonal contraceptives have to be classified as the most effective reversible contraceptive methods. For the individual decision concerning the use of hormonal contraception, benefits should be related to the additional risks. Alternative methods such as spirals should be prioritised if perfect use seems to be impossible. In this case, spirals are also preferable from health-economics perspective. No ethical-social or legal conclusions can be derived from the available data. PMID- 21289941 TI - Review on the medical and health economic evidence for an inclusion of colposcopy in primary screening programs for cervical cancer. AB - INTRODUCTION: With 3.2% of all cancer cases in 2002, cervical carcinoma is the tenth most common cancer in Germany and causes 1.8% of all cancer deaths in women in Germany. To date diagnosis in Germany solely has been based on cervical cytology which has been criticised due to its low sensitivity and consequently high rate of false negative results. OBJECTIVES: How does colposcopy compare to cytological tests in terms of sensitivity and specificity, and what may be the effects of changes in screening for cervical carcinoma in Germany? Is there health economic evidence that may foster an inclusion of colposcopy into national screening programms? METHODS: A systematic literature review was performed, including studies that compared colposcopy to cervical cytology in terms of sensitivity and specificity. In addition, a systematic review of the relevant health economic literature was performed to analyse cost-effectiveness issues relevant to the German setting. RESULTS: A total of four studies fulfilled the inclusion criteria, of which only two were of high methodologic quality. In all studies, the sensitivity of colposcopy was lower than that of cytology. In three studies the specificity of colposcopy was lower than that of cytology, in one study specificity of colposcopy and cytology was similar. No health economic data suggesting positive effects of adding colposcopy in primary screening could be identified. DISCUSSION: Only few studies have compared the test criteria of colposcopy with those of cytology for screening in cervical cancer. In all studies, sensitivity of colposcopy was even lower than the sensitivity of cytology, which has been critisized because of its low sensitivity. CONCLUSION: Based on the present data, an inclusion of colposcopy in primary cervical cancer screening programmes can not be recommended. PMID- 21289942 TI - Assessment of effectiveness and cost-effectiveness of HPV testing in primary screening for cervical. AB - INTRODUCTION: The introduction of a screening programme for cervical carcinoma in Germany has led to a significant reduction in incidence of the disease. To date, however, diagnosis in Germany has been based solely on cervical cytology, which has been criticised because of a low sensitivity and consequently high rate of false negative results. Because an infection with the human papillomavirus (HPV) previously was found to be a necessary aetiological factor in the development of cervical cancer, there has been some discussion that HPV testing should be included in cervical cancer screening. OBJECTIVES: How do HPV tests compare to cytological tests in terms of sensitivity and specificity, and what are the effects of screening for cervical carcinoma in Germany? Is there health economic evidence that may foster an inclusion of HPV testing into national screening programms? METHODS: A systematic literature review was performed, including studies that compared the HPV test to cervical cytology in terms of sensitivity and specificity in the diagnosis of CIN 2+ (CIN=Cervical Intraepithelial Neoplasia). In addition, a systematic review of the relevant health economic literature was performed to analyze cost-effectiveness in the German setting. RESULTS: A total of 24 studies fulfilled the inclusion criteria. One study consisted of three substudies. Hence, results of 26 comparisons of HPV and cytology are reported. In 25 of these, the HPV test was more sensitive than cytology, whereas cytology had better specificity in 21 studies. The combination of HPV test and cytology increased sensitivity. Variability in results was considerably larger for cytology than for HPV testing. Results of the economic meta-analysis suggest that in health care settings with already established PAP screening programms, cost-effectiveness strongly depends on screening intervals. In analyses comparing HPV screening to conventional PAP screening with two-yearly intervals, only 25% of the HPV strategies were found to be cost-effective, whereas in comparison with one-, three-, and five-yearly PAP screening, the percentage of overall cost-effective HPV strategies was 83%, 55%, and 92%, respectively. Results for annual screening intervals are based on the assumption of complete screening compliance, which has to be further evaluated in decision analyses in the future adapting to the German health care setting. DISCUSSION: Including HPV testing in screening procedures for cervical carcinoma could lead to a reduction in false positive results. Doing so would involve one of the following approaches: a) combining the HPV test with cytology, or b) using cytology as triage in HPV-positive women. The most appropriate interval between screening tests and the best age to start or stop screening remains to be determined. At this point a formal health economic decision analyses may help in resolving those questions, additionally incorporating compliance and adherence within different screening scenarios. CONCLUSION: Considering medical evidence weighing the question whether HPV testing should be implemented into screening routine may not be if but how to do so. Open questions remain in setting the length of optimal screening intervals, the age range in which to screen, and the combination or sequence of existing cytology and HPV testing. Answers to those questions will be gathered in the very near future through large international clinical trials. Cost-effectiveness of implementing HPV testing is likely to exist in the management of borderline or unclear smears in triage treatment as well as in certain scenarios of primary screening within the German health care setting. PMID- 21289943 TI - Corticosteroid therapy in the treatment of pediatric patients with atopic dermatitis. AB - HEALTH POLITICAL BACKGROUND: In developed countries 2.5% of the population - mainly children - are affected by atopic dermatitis. During the past few years its prevalence amongst school children has risen decisively and now lies between 8% to 16%. It is the most frequent chronic skin disease amongst school-aged children. SCIENTIFIC BACKGROUND: Current methods of treating atopic dermatitis among children focus on containing and preventing the illness's further progression. Preventing dry skin, relieving symptoms (such as pruritis and inflammation of the skin) and identifying and avoiding provocating factors are elementary goals of treatment. Successful treatment can substantially increase the children's quality of life. Possible therapies of children affected by atopic dermatitis include both topically and systemically applied pharmaceuticals. During the past ten years the use of corticosteroids has been the standard topical anti-inflammatory therapy in case of aggravating inflammations. In 2002 a new group of pharmaceutical substances (topical calcineurin inhibitors tacrolimus and pimecrolimus) was authorised in Germany for topical anti-inflammatory treatment of patients. Because of its high prevalence atopic dermatitis represents a major expense factor to the German health care system. In 1999 the costs of the treatment of atopic dermatitis with corticosteroids in Germany amounted to 230 million Euro. If other direct costs for the treatment are included, for example hospitalisation or doctor appointments, the total costs amount to 3.57 billion Euro. RESEARCH QUESTION: How effective and efficient are topical anti-inflammatory treatments of children with atopic dermatitis? METHODS: A systematic literature search was performed in 35 international databases which yielded 1335 articles. Following a two-part selection process according to predefined criteria 24 publications were included in the assessment. RESULTS: Of 19 randomised controlled clinical trials, which were included in the assessment, only two evaluated the effect of topical corticosteroids in comparison to tacrolimus, which is one of the calcineurin inhibitors. Both studies show that tacrolimus is more effective than hydrocortisone acetate in children with moderate to severe atopic dermatitis. No study was found that directly compares corticosteroids with pimecrolimus in the treatment of paediatric patients with atopic dermatitis. However, two trials show that an intermittent treatment with pimecrolimus can reduce the need for topical corticosteroids. Two publications focusing on the costs of atopic dermatitis, provide model calculations comparing the use of topical corticosteroids and calcineurin inhibitors. The calculations show that the treatment with topical corticosteroids is inferior to the treatment with pimecrolimus in children with mild to moderate atopic dermatitis. Furthermore the treatment with tacrolimus appears to be more expensive however also more effective in comparison to topical corticosteroids. DISCUSSION: During the past five decades topical corticosteroids have represented the first choice therapy when it comes to atopic dermatitis. Their effectiveness has been proven by several studies. Amongst newer generations of topical corticosteroids the occurrence of adverse side effects seems to be less frequent. Due to the fact that they have only recently been authorised experience with tacrolimus and pimecrolimus is limited. So far the only adverse side effect of the calcineurin inhibitors appears to be a burning sensation of the skin. One point for discussion concerns the economical aspects of the treatment of atopic dermatitis. The cost-effectiveness of pimecrolimus has been based on the calculated costs per quality-adjusted life year, which were lower than the frequently hawked value of 50,000 USD. It is up to policy makers to decide on the actual value of a quality adjusted life year. CONCLUSIONS/RECOMMENDATIONS: From a medical as well as an economical viewpoint, there appears to be insufficient evidence stating that inflammatory steroid-free substances are more effective and/or efficient than topical corticosteroids. Based on the results of the studies that have been included in this assessment therapies based on calcineurin inhibitors seem to constitute a good alternative in case a child is unresponsive or intolerable to topical corticosteroids and for the treatment of intertriginous areas. PMID- 21289944 TI - Ventricular assist devices for heart failure. AB - BACKGROUND: Heart failure is a clinical syndrome of major epidemiological and economical importance. In Germany as in other industrialised countries it is one of the leading causes of mortality, morbidity and disability. For patients not responding to medical therapies ventricular assist devices are used as bridge to transplant, bridge to recovery or as destination therapy alternative to transplantation. RESEARCH QUESTIONS: This report aims to present the actual evidence on clinical effectiveness, psychological and social aspects and economical aspects of left ventricular assist devices. METHODS: We conducted a systematic research of the literature in different databases (EMBASE, MEDLINE, Cochrane Library). The included studies were assessed by two reviewers and were presented in tables and in a narrative form. We also conducted a survey among hospitals using the technology. RESULTS AND DISCUSSION: We included 40 references, six of them were HTA-reports. LVAD patients as bridge to transplant had better survival rates and a better quality of life as compared to medical therapy. Mechanical assistance was associated with frequent and often serious adverse events which were often the cause of death. There were numerous psychological and psychiatric problems. CONCLUSIONS/RECOMMENDATIONS: LVAD showed to be clinically effective, however with high complications rate and seriousness of them. The use of technology is very costly. Cost-effective should be analysed for Germany. There is a need to further develop the technology before it can contribute seriously to a reduction of the need for heart transplantation. PMID- 21289945 TI - The role of Homocysteine as a predictor for coronary heart disease. AB - BACKGROUND AND OBJECTIVE: There is an ongoing debate on the role of the cytotoxic aminoacid homocysteine as a causal risk factor for the development of coronary heart disease. Results from multiple case control-studies demonstrate, that there is a strong association between high plasma levels of homoysteine and prevalent coronary heart disease, independent of other classic risk factors. Furthermore, results from interventional studies point out that elevated plasma levels of homocysteine may effectively be lowered by the intake of folic acid and B vitamins. In order to use this information for the construction of a new preventive strategy against coronary heart disease, more information is needed: first, whether homocysteine actually is a causal risk factor with relevant predictive properties and, second, whether by lowering elevated homocysteine plasma concentrations cardiac morbidity can be reduced. Currently in Germany the determination of homocysteine plasma levels is reimbursed for by statutory health insurance in patients with manifest coronary heart disease and in patients at high risk for coronary heart disease but not for screening purposes in asymptomatic low risk populations. Against this background the following assessment sets out to answer four questions: Is an elevated homocysteine plasma concentration a strong, consistent and independent (of other classic risk factors) predictor for coronary heart disease?Does a therapeutic lowering of elevated homoysteine plasma levels reduce the risk of developing coronary events?What is the cost-effectiveness relationship of homocysteine testing for preventive purposes?Are there morally, socially or legally relevant aspects that should be considered when implementing a preventive strategy as outlined above? METHODS: In order to answer the first question, a systematic overview of prospective studies and metaanalyses of prospective studies is undertaken. Studies are included that analyse the association of homocysteine plasma levels with future cardiac events in probands without pre-existing coronary heart disease or in population-based samples. To answer the second question, a systematic overview of the literature is prepared, including randomised controlled trials and systematic reviews of randomised controlled trials that determine the effectiveness of homocysteine lowering therapy for the prevention of cardiac events. To answer the third question, economic evaluations of homocysteine testing for preventive purposes are analysed. Methodological quality of all materials is assessed by widely accepted instruments, evidence was summarized qualitatively. RESULTS: For the first question eleven systematic reviews and 33 single studies (prospective cohort studies and nested case control studies) are available. Among the studies there is profound heterogeneity concercing study populations, classification of exposure (homocysteine measurements, units to express "elevation"), outcome definition and measurement, as well as controlling for confounding (qualitatively and quantitatively). Taking these heterogeneities into consideration, metaanalysis of single patient data with controlling for multiple confounders seems to be the only adequate method of summarizing the results of single studies. The only available analysis of this type shows, that in otherwise healthy people homocysteine plasma levels are only a very weak predictor of future cardiac events. The predictive value of the classical risk factors is much stronger. Among the studies that actively exclude patients with pre-existing coronary heart disease, there are no reports of an association between elevated homocysteine plasma levels and future cardiac events. Eleven randomized controlled trials (ten of them reported in one systematic review) are analysed in order to answer the second question. All trials include high risk populations for the development of (further) cardiac events. These studies also present with marked clinical heterogeneity: primarily concerning the average homocysteine plasma levels at baseline, type and mode of outcome measurement and as study duration. Except for one, none of the trials shows a risk reduction for cardiac events by lowering homocysteine plasma levels with folate or B vitamins. These results also hold for predefined subgroups with markedly elevated homocysteine plasma levels. In order to answer the third questions, three economic evaluations (modelling studies) of homocysteine testing are available. All economic models are based on the assumption that lowering homocysteine plasma levels results in risk reduction for cardiac events. Since this assumption is falsified by the results of the interventional studies cited above, there is no evidence left to answer the third question. Morally, socially or legally relevant aspects of homocysteine assessment are currently not being discussed in the scientific literature. DISCUSSION AND CONCLUSION: Many currently available pieces of evidence contradict a causal role of homocysteine in the pathogenesis of coronary heart disease. Arguing with the Bradford-Hill criteria at least the criterion of time-sequence (that exposure has to happen before the outcome is measured), the criterion of a strong and consistent association and the criterion of reversibility are not fulfilled. Therefore, homocysteine may, if at all, play a role as a risk indicator but not as risk factor. Furthermore, currently available evidence does not imply that for the prevention of coronary heart disease, knowledge of homocysteine plasma levels provides any information that supersedes the information gathered from the examination of classical risk factors. So, currently for the indication of prevention, there is no evidence that homocysteine testing provides any benefit. Against this background there is also no basis for cost-effectiveness calculations. Further basic research should clarify the discrepant results of case control studies and prospective studies. Maybe there is a third parameter (confounder) associated with homocysteine metabolism as well with coronary heart disease. Further epidemiological research could elucidate the role of elevated homocysteine plasma levels as a risk indicator or prognostic indicator in patients with pre-existing coronary heart disease taking into consideration the classical risk factors. PMID- 21289946 TI - The Measels-Mumps-Rubella Vaccination from a health political and economical point of view. AB - INTRODUCTION: Measels, Mumps and Rubella (MMR) are highly contagious infectious diseases which may lead to severe complications. These diseases are vaccine preventable. The present Health Technology Assessment report (report on technological consequences, HTA report) was commissioned by the German Institute of Medical Documentation and Information (DIMDI) and addresses various aspects of the MMR vaccination, the key question being how the MMR immunisation coverage rate can be increased in Germany. OBJECTIVES: The objectives of this report were to describe the benefits of the MMR vaccination for Germany and to analyse how the desired MMR immunisation coverage of >95% can be achieved. METHODS: A systematic literature search was performed in 29 literature data bases. Particularly for epidemiological data and information on vaccination programs, this systematic search was supplemented by an extensive hand search, written and oral enquiries, as well as interviews with experts. A total of 200 texts were used to prepare this report. RESULTS: At 92.5% (as of 2004) based on the whole of Germany, the current immunisation coverage for measles in children is above the weighted EC-15-average of 90.67%. Statements can only be made regarding the probability of illness for measles, as no data is available for mumps and rubella. With 2.8 infections (per 100,000 residents) in 2006, Germany has not achieved the WHO target. Of cases submitted to the laboratory, only 32% were validated by diagnostic laboratory findings and 45% confirmed clinical epidemiologically. There are only few economic analyses of vaccination programs in Germany. In international publications, mainly measels are validated economically. An analysis of the cost of measles for Germany shows potential cost savings. Unfortunately, no complete economic evaluation (cost-effectiveness, cost benefit, or cost-utility analyses) for MMR vaccination has been performed for Germany. Analyses conducted in the US and a model calculation for a hypothetical Western-European country show a considerable cost saving potential for society in general as well as for the health care system. INTERVENTIONS TO INCREASE THE IMMUNISATION RATE WERE CATEGORIZED IN THREE MAIN GROUPS ACCORDING TO THEIR GOALS: interventions increasing the demand for vaccinations, those improving access to vaccination services and those aiming at the providers (e.g. physicians) of vaccinations. DISCUSSION: Various studies concluded that reminders to clients, provided in written, electronic or oral form, are a highly recommendable intervention. Provider based interventions were also strongly advised. DESPITE EFFORTS MADE DURING THE PAST YEARS TO ACHIEVE HERD IMMUNITY IN GERMANY, SOME DEFICITS REMAIN: i. e. there are still ample regional differences between and within German federal states. CONCLUSIONS: In the authors' opinion, a key point in increasing immunisation coverage is the development of a binding vaccination program for Germany with regionally differentiated immunisation targets. During the development of such a program, special emphasis should be placed on determining responsibilities of the federal government, the Laender and health insurance funds (e. g. in the case of a measles outbreak). PMID- 21289947 TI - Procedures and Criteria for the regulation of innovative non-medicinal technologies into the benefit catalogue of solidly financed health care insurances. AB - Because great interest in an efficient range of effective medicinal innovations and achievements has arisen, many countries have introduced procedures to regulate the adoption of innovative non-medicinal technologies into the benefit catalogue of solidly financed health care insurances. With this as a background, this report will describe procedures for the adoption of innovative non-medicinal technologies by solidly financed health care insurances in Germany, England, Australia and Switzerland. This report was commissioned by the German Agency for Health Technology Assessment at the German Institute for Medical Documentation and Information.In order to find the relevant literature and information, systematic literature research, a hand search and a written survey were carried out. All the selected documents (chosen according to defined criteria for inclusion and exclusion) were qualitatively evaluated, summarized and presented on a chart using a framework developed for this purpose. All the countries in this report require that some innovative non-medicinal technologies undergo evaluation by a central governing body. This evaluation is a prerequisite for adoption into the benefit catalogue. The process of evaluation can differ (e. g. the people and institutions concerned, the division of the synthesis of evidence and overall evaluation, processing the evidence). Similarities do exist, such as the size and composition of the governing bodies or the overreaching criteria according to which institutions must make their recommendations. This is how all the countries examined in this report determine how the benefits and effectiveness of the innovations, as well as their cost-effectiveness, can be chosen as criteria for the evaluation. Furthermore, there are many criteria which differ from country to country (social and ethical aspects, possible effects on the health system, etc.) and which are also relevant to an evaluation. The preferred types of clinical studies for these evaluations are randomized controlled trials. However, all institutions do allow for other types of evidence (e. g. expert opinion) when no other study types of a higher evidence level are available. In addition, all the countries are willing to allow unpublished or confidential information (e. g. from manufacturers) to be included in an evaluation. It is important to remember that the decisions made by the central governing bodies do not necessarily become conditions for the introduction of innovative non-medicinal technologies. There is a host of other requirements which determine how these innovations can be introduced. This means that a large number of non-medicinal technologies make it into the medical care system via these other decision-making processes. Often, these innovations are unevaluated and differ from region to region. Every country has established a system of observation and registration for medicinal products. These systems are meant to document any incidents with the innovations and to confer responsibility on certain organizations. All in all, no country has a central authority which systematically investigates the effects of newly introduced innovative non medicinal technologies on medical care in general. However, Australia and England both carry out a review of innovations in some areas (e. g. by means of special commissions). In principle, the starting point for improving regulations of innovative non-medicinal technologies lies in the extension of transparency, the shortening of decision-making time (especially the central decision-making processes), the further development of evaluation methods, more flexibility and increased capacity in the governing bodies' decision-making processes and also, if needed, in the creation of a single authority to act as contact for people who are interested in introducing an innovation into the benefit catalogue.More research is required, especially in the area of decentralized decision-makers and how they actually decide whether or not to introduce innovative technologies into the core care system (methods, criteria, etc.). In view of this, it would also be interesting to see how the application of innovations actually happens in practice once their adoption has been approved by the corresponding governing bodies. PMID- 21289948 TI - Interventions for enhancing medication compliance/adherence with benefits in treatment outcomes. AB - SCIENTIFIC BACKGROUND: Poor compliance or adherence in drug therapy can cause increased morbidity, mortality and enormous costs in the healthcare system (in Germany annually approximately 10 billion euros). Different methods are used for enhancing the compliance or adherence. RESEARCH QUESTIONS: The evaluation addresses the questions about existence, efficacy, cost-benefit relation as well as ethical-social and juridical implications of strategies for enhancing compliance or adherence in drug therapy with concomitant improvements in treatment outcomes. METHODS: A systematic literature search was conducted in the medical, also health economic relevant, literature databases in January 2007, beginning from 2002. Systematic reviews on the basis of (randomised controlled trials (RCT) concerning interventions to enhance compliance or adherence with regard to treatment outcomes as well as systematic reviews of health economic analyses were included in the evaluation. Additionally, it was also searched for publications which primarily considered ethical-social and juridical aspects of these interventions for the German context. RESULTS: One systematic review with data for 57 RCT was included in the medical evaluation and one systematic review with data for six studies into the health economic evaluation. No publication primary concerning ethical-social or juridical implications could be identified. A significant positive effect on the treatment outcome was reported for 22 evaluated interventions. For many interventions the results can be classified as reliable: counseling with providing an information leaflet and compliance diary chart followed by phone consultation for helicobacter pylori positive patients, repeated counseling for patients with acute asthma symptoms, telephone calls to establish the level of compliance and to make recommendations based on that for the therapy of cardiovascular diseases, calls of an automated telephone system with phone counseling in problem cases for diabetics, different family based interventions including repeated family counseling, education and "culturally modified family therapy" in patients with schizophrenia, repeated "compliance therapy" sessions for patients with acute psychosis. For other interventions the results should be viewed with more concern (because of the poor methodical quality of the underlying studies). The effect size of the interventions can not be estimated from the available data. From the available data, no reliable results can be provided concerning the cost-benefit relation of these strategies. DISCUSSION: Many of the reported studies had a poor reporting and methodological quality. The reliability of the conclusions of the studies is restricted because of methodical shortcomings. Efficacy and cost estimates determined in the health economic studies are not transferable to the current situation in Germany. It has been discussed recently that the compliance or adherence enhancing interventions can restrict the autonomy and the privacy of the patients. CONCLUSIONS: In drug therapy some compliance or adherence enhancing interventions with concomitant positive effect on the treatment outcome may be used. The cost-benefit relation of these interventions is to be estimated. Using these interventions the patient's autonomy and privacy are to be restricted as few as possible. PMID- 21289949 TI - Lymphomas presenting as chest wall tumors. AB - Four cases of thoracic lymphoma mimicking chest wall tumors are presented. As resection is not the treatment of first choice in lymphomas, pretherapeutical evaluation of chest wall tumors should include a thoroughly staging and a biopsy for histopathological diagnosis. Chest wall destruction due to an anterior mediastinal mass, or a chest wall tumor associated with mediastinal lymph node enlargement, could be suspicious of thoracic lymphoma. Lymphoma with chest wall involvement mostly turns out to be Hodgkin's disease or large B-cell lymphoma. Stage and histopathological diagnosis have major impact on treatment and prognosis. Therapy is chemotherapy or chemo-radiation. PMID- 21289950 TI - Benign mesenchymoma of the mediastinum: a report and review of the literature. AB - Benign mesenchymoma is a rare type of germ cell tumour. An extensive literature search revealed only one described case of mediastinal mesenchymoma in Europe and three cases in Asia. We describe our recent experience of a mediastinal mesenchymoma and present the fascinating imaging and operative findings. The preoperative diagnosis of these lesions remains difficult and therefore surgical resection is recommended. PMID- 21289951 TI - Carcinoid lung tumors: long-term results from 111 resections. AB - OBJECTIVE: Carcinoids are rare neuroendocrine tumors of the bronchial system. Only recently, the histological classification was standardized, and there are varying opinions about the extent of surgical resection. This research reports on the long-term results of 111 consecutive patients, who underwent surgery in a department for thoracic surgery. METHODS: Between 1/1988 and 2/2001, 111 consecutive pulmonary resections were conducted in patients with bronchial carcinoids. Retrospectively, researchers obtained clinical and surgical data and re-classified all histological specimen according to the WHO classification of 1999. Information regarding long-term results was obtained by using data obtained during follow-up visits and by talking to the patient on the phone. RESULTS: 97 patients with typical and 14 with atypical carcinoids were identified. The preoperative diagnosis of typical or atypical carcinoid had been correct in 56 patients (50.5%). Surgical procedures included 79 lobectomies, 16 bilobectomies, 8 pneumonectomies, 5 segmental resections, 2 sleeve resections of the main bronchus without parenchymal resection and one exploratory thoracotomy. Mediastinal lymphadenectomies were performed on 105 patients (94.6%). Postoperative staging revealed 91 patients (81.2%) in UICC stage I, 12 (10.8%) in stage II, 7 in stage III and one in stage IV. 97 (87.4%) typical and 14 (12.6%) atypical carcinoids were classified. 30-day mortality was 1.8% (n=2). Mean follow up was 73.4 months. The total cohort showed a 5-year survival rate of 94% and a 10-year survival rate of 82%. In patients with typical and atypical carcinoids, the 5-year survival rates were 94% and 82%, respectively (n.s.), and the 10-year survival rates were 92% and 62%, respectively (p<0.01). The 5- (10-) year survival rate without lymph node involvement was 96% (85%), with N1 involvement 88% (65%), with N2 involvement 67% (no 10-year survival). CONCLUSIONS: Patients with bronchial carcinoids who underwent a radical oncological resection with mediastinal lymphadenectomy have very good survival chances. There are no prospective randomized studies evaluating the surgical procedures as they relate to the classification. Since a preoperative diagnosis cannot clearly determine if the lymph nodes are involved and what histology type the physician dealing with, a limited resections without lymphadenectomy is insufficient. It is absolutely necessary to conduct retrospective and multi-center studies on the prognostic importance of lymph node involvement and on the impact of adjuvant therapies. PMID- 21289952 TI - Cavernous sinus syndrome caused by a metastasis of a thymic carcinoid tumor. AB - Thymic carcinoid tumors belong to the group of mediastinal tumors, but are quite rare and usually carry a very poor prognosis. This report illustrates a case in which a thymic carcinoid tumor that had led to cavernous sinus syndrome was treated successfully. This is the first case report of a thymic carcinoid to metastasize to the cavernous sinus. PMID- 21289953 TI - Elastic robust intramedullary nailing for forearm fracture in children. AB - BACKGROUND: Forearm fractures are the most common fractures in children (23% of all fractures). Basically there are two treatment options available for diaphyseal forearm fractures in children: closed reduction with cast immobilisation (conservative therapy) and the elastic stable intramedullary nailing (ESIN). Treatment decision is influenced by the doctor's estimation of fracture instability. Stable fractures can be treated conservatively whereas instable forearm shaft fractures can be treated according the following three treatment strategies: conservative therapy in an outpatient settingconservative therapy in the operating room in attendance to change to ESIN in case that no stabilisation can be achieved with cast immobilisationimmediate treatment with ESIN in the operating room. OBJECTIVES: Aim of this Health Technology Assessment (HTA) report is to assess and report the published evidence concerning effectiveness and cost-effectiveness of ESIN as a treatment option for diaphyseal forearm fractures in children and to identify future research need. Important parameters for the assessment of effectiveness are objective parameters (axis deviation, losses of motion, and numbers of reductions in case of redislocations) and subjective parameters (pain or impairment in quality of life). Furthermore, a health economic evaluation shall be done which refers to the costs of the different therapy strategies. METHODS: An extensive, systematic literature search in medical, economic, and HTA literature databases was performed. Relevant data were extracted and synthesised. RESULTS: Three cohort studies and seven case series have been identified. Controlled clinical studies, systematic reviews and/or HTA reports that gave evidence to answer the own study question have not been found. The identified studies partly differed in respect of defined indication for ESIN, study population and treatment strategies. For that reason comparability of results was limited. In the majority of cases the publications reported a successful consolidation of fractures treated with ESIN. The cohort studies reported no differences in mobility after treatment with ESIN compared to patients who were treated conservatively. No publications that argue health economic aspects of the ESIN in children could be identified in the literature search. A cost data assessment conducted by the authors of this report showed that ESIN is associated with higher costs compared to the other treatment strategies (without considering long term costs due to reduction in case of redisplacement). CONCLUSIONS: Little evidence for a dominance of ESIN in treating forearm shaft fractures of children compared to conservative therapy could be found. Accomplishment of ESIN without complications causes more costs than conservative therapy both in outpatient and in inpatient setting. However, if fracture stabilisation cannot be achieved by conservative therapy, further interventions will be necessary. They will result in a burden for the patients and higher costs. PMID- 21289954 TI - Endodontic treatment of molars. AB - OBJECTIVE: Commissioned by the German Institute of Medical Documentation and Information (DIMDI) the Austrian Health Institute (OBIG) prepared a HTA report on the long-term effectiveness of endodontic treatment (root canal treatment, RCT) of molars. The focus is to examine factors influencing the outcome of endodontic treatment and showing their impact on long-term results. Additionally, economic aspects of root canal treatment in Germany are discussed. METHODOLOGY: By performing a systematic literature search in 29 databases (e.g. MEDLINE), the Cochrane Library and by hand searching two peer-reviewed endodontic journals the authors could identify 750 relevant articles, of which finally 18 qualified for assessment. RESULTS: The findings show that the most relevant factor influencing the long-term outcome of endodontic treatment is the preoperative status of a tooth. The lowest success rates are reported for molars with a preoperative devital or necrotic pulp and persisting periapical lesions (so called periapical disease). DISCUSSION: Even if there is no positive selection of patients and the RCT is performed by a normal dentist rather than an endodontist - a fact which is very common - long-term success rates of more then 90% are possible. The overall success rates for endodontic treatment of molars therefore seem to be similar to those of other tooth-types. CONCLUSIONS: Especially primary, conventional (i.e. non-surgical) root canal treatment is an effective and efficient therapy for endodontically ill molars, especially if no large periapical lesion persists. Nonetheless, a long term successful endodontic therapy requires a thorough assessment of the pre-operative status of the molar and treatment according to established guidelines. PMID- 21289955 TI - Value of intensified nursing. AB - The concept "intensified nursing" is mentioned in differentiation to concepts of "nursing care" or "nursing" which intensifies resources or patient contact. Especially psychic and social needs of patients are very appreciated in nursing. A similar type of nursing is known under the concept "advanced nursing practice" (ANP) which means, that a specialised, academically trained nurse offers an extended nursing care in which a focus on the published knowledge of evidence based research is made.From the thin literature to this topic a selection of predetermined topics was analysed where at least two articles with a sufficient high methodical quality were available. The selected topic groups were: "Infant and paediatric nursing", "gerontology" and "oncology". Generally the five publications concerning infant and paediatric nursing could conclusive show a benefit of intensified nursing. Further research is still needed to prove intensified nursing care. Two publications could be found to the gerontological intensified nursing; both used an extended nursing model and an enlarged use of resources. Both studies demonstrated a measurable success in the applied parameters. Two studies also could be analysed in the oncological field in which successes were also provable by the applied parameters. The success was given especially in a higher patient satisfaction, one study showed an improved scheduling (time planning) of nurses.There was not one article concerning economic questions of intensified nursing care. It has to be taken into account that the financial resources have to be used effectively also in nursing nowadays. It has to be assumed that the costs are driven by increased use of resources. Savings can be achieved, however, in the form of avoided therapies and days in hospital by intensified nursing. The intensified nursing can be considered as similar cost-effective as conventional models of nursing.Ethically it is necessary to consider that the possibilities of the intensified nursing should be exhausted as much as possible for the patients. The daily work is limited, due to restrictions of resource. This means a conflict for nurses between knowledge and the predefined resource requirements which often leaded to overtaxing and dissatisfaction. It is desirable that decision makers of the health policy appreciate the evidence and promote intensified nursing care models.Nursing science has to do special research to prove the meaning and effectiveness of intensified nursing and establish this in the health care delivery system. PMID- 21289956 TI - Monitoring heart functions using telemetry. AB - HEALTH-ECONOMIC BACKGROUND: The conditions for area-wide utilisation of telemedicine on national and European levels have to be developed. Before the nation-wide implementation in Germany can take place, the effectiveness of the structures and services of telemedicine has to be verified under everyday conditions. The utilisation of telemedicine has been assessed in recent HTA reports that cover the existing scientific knowledge. This article also reports on the future role telemedicine could play in the telemetric monitoring of heart function. GENERAL BACKGROUND: With telemonitoring it is possible to keep body function data under continuous surveillance. This is especially useful for high risk patients. Telemetry is the term used for the transfer of measured values from the sensor to the surveillance control point. Telemetric monitoring is well suited for measuring cardiac function parameters without investing a lot of time and effort. RESULTS: Telemedicine is well accepted by the patients. It has been indicated that the implementation of telemedicine reduces both the number of hospitalisations and the duration of hospitalisation. Treatment costs are accordingly reduced. With an early diagnosis, the therapy can be optimised precociously. Considering acute medical care, a diagnosis prior to hospitalisation can lead to a reduction in the time interval between admittance and the start of therapy. Considering preventive medical care, the continuous surveillance enables a timely diagnosis. The quality of life of the patient is hereby significantly enhanced. CONCLUSION: Telemetric monitoring can be applied in many areas of health care and be of positive assistance, within the single therapeutic strategies, to patients with acute and chronic cardiac illnesses. The integration of information- and communication systems available for the health sector can significantly support patient orientated medical care. This has been indicated in numerous studies/trials. Telemedicine supports the renunciation of a centralised medical care system, where the patient has to seek for consultancy, towards a patient orientated system, where expert advice (by means of care-taking networks) is transferred to the patient. PMID- 21289957 TI - Bypass materials in vascular surgery. AB - INTRODUCTION: Arteriosclerotic changes can lead to circulatory disturbances in various areas of the human vascular system. In addition to pharmacological therapy and the management of risk factors (e. g. hypertension, diabetes, lipid metabolism disorders, and lifestyle), surgical interventions also play an important role in the treatment of arteriosclerosis. Long-segment arterial occlusions, in particular, can be treated successfully with bypass sur-gery. A number of different materials are available for this type of operation, such as autologous vein or pros-thetic grafts comprised of polytetrafluoroethylene (PTFE) or Dacron((r)). Prosthetic materials are used especially in the treatment of peripheral artery disease, such as in aortoiliac or femoropopliteal bypass surgery. The present report will thus focus on this area in order to examine the effectiveness of different bypass materials. Among the efforts being made to refine the newly introduced DRG system in Germany, analysing the different bypass materials used in vascular surgery is particularly important. Indeed, in its current version the German DRG system does not distinguish between bypass materials in terms of reimbursement rates. Differences in cost structures are thus of especial interest to hospitals in their budget calculations, whereas both private and statutory health insurance funds are primarily interested in long term results and their costs. OBJECTIVES: The goal of this HTA is to compare the different bypass materials used in vascular surgery in terms of their medical efficiency and cost-effectiveness, as well as with regard to their ethical, social and legal implications. In addition, this report aims to point out the areas in which further medical, epidemiological and health economic research is still needed. METHODS: Relevant publications were identified by means of a structured search of databases accessed through the German Institute of Medical Documentation and Information (DIMDI), as well as by a manual search. The for-mer included the following electronic resources: SOMED (SM78), Cochrane Library - Central (CCTR93), MEDLINE Alert (ME0A), MEDLINE (ME95), CATFILEplus (CATLINE) (CA66), ETHMED (ED93), GeroLit (GE79), HECLINET (HN69), AMED (CB85), CAB Abstracts (CV72), GLOBAL Health (AZ72), IPA (IA70), El-sevier BIOBASE (EB94), BIOSIS Previews (BA93), EMBASE (EM95), EMBASE Alert (EA08), SciSearch (IS90), Cochrane Library - CDSR (CDSR93), NHS-CRD-DARE (CDAR94), NHS-CRD-HTA (INAHTA), and NHS-EED (NHSEED). The present report included German and English literature published between the years 1999 and 2004. A list of the search parameters can be found in the appendix. No limits were placed on the target population, and the methodical quality of the included studies was determined using standardised checklists. RESULTS: THE STUDIES INCLUDED IN THIS HEALTH TECHNOLOGY ASSESSMENT COMPARED THE FOLLOWING BYPASS MATERIALS: autologous vein, human umbilical vein (HUV) and synthetic materials such as PTFE or Dacron((r)). Both the systematic reviews and the randomised controlled trials comparing autologous vein grafts to other bypass materials come to the conclusion that autologous vein is superior to all other materials. From a medical viewpoint, there are no clear differences between the various synthetic materials. To date, the subject of bypass materials in vascular surgery has not been addressed comprehensively from an economic point of view. Indeed, we were able to identify only one publication that compared the cost of various bypass materials. The remaining health economic studies did not compare costs, cost effectiveness, or quality of life associated with the use of various bypass materials. DISCUSSION: When deciding which bypass material to use, vascular surgeons take a number of medical considerations into account, including the bypass area, the availability of autologous vein, the amount of operation time available, and the health status of the patient. The studies included in this health technology assessment demonstrate that autologous vein is usually the preferred material for bypass grafts. In contrast, comparisons of various synthetic materials did not show any specific differences. It remains to be seen whether studies on newly developed synthetic materials will show these to have any particular advantages. The randomised controlled trials included in the present report were limited by a number of methodological weaknesses, such as different methods for determining patency rates, sample size and power problems, the interpretation of non-significant results, and a lack of consideration of additional factors. From an economic point of view, there is still great need for further research, and we have attempted to describe a number of pressing questions for health economic studies in the present report. PMID- 21289958 TI - Therapy of moderate and severe psoriasis. AB - OBJECTIVE AND METHODS: This health technology assessment (HTA) report synthesises systematically randomized controlled studies (RCT) on the therapy of moderate and severe psoriasis vulgaris which were published between 1999 and 2004; it includes some important clinical studies which have been published after 2004 and thus updates the English HTA report by Griffiths et al. [1]. The major objective is the evaluation of the medical effectiveness of different therapeutical approaches and the cost effectiveness with relevance for Germany. RESULTS: The major conclusions from the results of medical RCT on moderate and severe psoriasis vulgaris are: Oral fumarates are effective in the treatment of moderate to severe psoriasis vulgaris. However, fumarates quiet frequently cause moderate side effects. Cyclosporine and methotrexate are both effective in the treatment of severe psoriasis vulgaris. Both substances have a different spectrum of side effects which may limit the individual applicability. Acetritin is only moderately effective in the treatment of severe psoriasis of the plaque type. Calcipotriol or UV-radiation used at the same time can increase the clinical effectiveness of acetritin. Systemic PUVA, balneo-PUVA and UVB therapy are all effective for the treatment of severe psoriasis. The combination of UV therapy with vitamin D3 analogues or with topical steroids is more effective than the treatment with UV radiation alone. Saltwater baths increase the effectiveness of UVB therapy. No RCT on the therapeutical effects of topical tar or of dithranol in combination with UV therapy have been published so far. A continuous therapy with PUVA should not be applied due to its proven photocarcinogenicity. Three substances from the group of biologicals (Efalizumab, Etanercept, and Infliximab) are now available in Europe and a further substance (Alefacept) is available in the USA for the treatment of moderate to severe psoriasis. All biologicals have been effective in placebo controlled studies. The substances differ in the times until a clinical effect is observable, in the spectrum of side effects and in their efficiency on psoriasis arthritis. From health-economic studies considering both costs and clinical efficiency oral fumarates appear to be superior to acitretin or cyclosporine (although cyclosporine appears to be more effective in severe psoriasis). From the health economic view methotrexate is equivalent with UVB or PUVA and superior to cyclosporine. The therapy options UVB, UVB plus calcipotriol and PUVA are equivalent and superior to balneo-phototherapy. Biologicals are cost intensive and should be used when other approaches are not sufficient or are not applicable due to their side effects. The HTA report summarizes some health-economic studies on dithranol, on calcipotriol and on the combination with tar and UV light. No RCT have been published for the treatment of severe psoriasis with these agents alone but it appears to be certain that these substances are effective in severe psoriasis as well. DISCUSSION: The spectrum of therapeutical options has fortunately increased during the last years. It must be emphasized that a number of therapeutical procedures exist which are not discussed in detail in this HTA. This is due to the search strategy of literature: Only RCT performed with patients with moderate and/or severe psoriasis vulgaris were included into this evaluation. This led to the exclusion of a number of substances which are traditionally used alone or in combination for the treatment of moderate or severe psoriasis vulgaris (e.g. dithranol, salicyc acid, tar, corticosteroids and topical retinoids). Moreover, other approaches which include neither drugs nor UV light are not discussed in this HTA although the authors believe in the importance of psychotherapeutical interventions, educational approaches and combined medical and non-medical approaches in rehabilitational medicine in the management of psoriasis vulgaris. The transferability of the health economic evaluations is strongly limited by the fact that all included health economic evaluations except one were not aligned to a German setting. A future research question will be the evaluation of the duration of remission and relapse ratios in the context of different therapy options of moderate and severe psoriasis. Moreover, the consideration of combined outcomes such as the improvement of psoriatic symptoms and the decrease of symptoms in accompanying psoriasis arthritis represents a future requirement of health assessment. CONCLUSIONS: From the clinical point of view it is positive that the spectrum of therapeutic procedures for a chronic severe skin disease has increased continuously during the last years. In cases of individual contraindications or individual inefficacies it is now possible to try alternative approaches. Moreover the risk of long-term side effects can be reduced by changing the therapeutical procedure after some time (so-called rotation therapy). The therapeutical algorithm for severe psoriasis vulgaris now includes photo(chemo-)therapy in combination with topical substances, oral fumaric acid esters, retinoids (in combination with phototherapy or topical substances), methotrexate, cylosporine and the new biologics. Future studies should address therapeutical approaches which can not easily be studied by RCT, e.g. physical, balneological, climate approaches, educational programs and complex rehabilitation therapy which all may have positive effects on individuals with severe psoriasis. As in medical therapy management of moderate and severe psoriasis the economic evaluation also points out the way of a strategic therapy concept which corresponds to a large extent to the algorithm in medical practice. PMID- 21289959 TI - Extracorporal hemodialysis with acute or decompensated chronical hepatic failure. AB - BACKGROUND: Conventional diagnostic procedures and therapy of acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) focus on to identify triggering events of the acute deterioration of the liver function and to avoid them. Further objectives are to prevent the development respectively the progression of secondary organ dysfunctions or organ failure. Most of the times the endocrinological function of the liver can to a wide extent be compensated, but the removal of toxins can only marginally be substituted by conventional conservative therapy. To improve this component of the liver function is the main objective of extracorporal liver support systems. The following principles of liver support systems can be differentiated: Artificial systems, bioartifical systems and extracorporal liver perfusion systems. This HTA report focuses on artificial systems (e.g. BioLogic-DT/-DTPF, MARS, Prometheus), because only these approaches currently are relevant in the German health care system. In 2004 a category "Extracorporal liver assist device" was introduced in the list of "additional payments" in the German DRG-system, which makes reimbursement for hospitals using the technology in inpatient care possible, based on an hospital's individual contract with statutory sickness funds. OBJECTIVES: To report the present evidence and future research need on medical efficacy and economic effectiveness of extracorporal liver support devices for treatment of patients with ALF or ACLF based on published literature data. Are artificial liver support systems efficient and effective in the treatment of ALF or ACLF? METHODS: An extensive, systematic literature search in medical, economic, and HTA literature data bases was performed. Relevant data were extracted and synthesised. RESULTS: Relevant controlled trials were detected for BioLogic-DT and MARS. No randomised controlled trial on Prometheus was found. None of the included studies on BioLogic-DT showed advantages of the technology compared with standard conventional therapy concerning survival, clinical scores or clinical surrogate parameter like laboratory tests of liver function. Some studies reported complications and side effects of BioLogic-DT. All studies were methodologically insufficient. Concerning the use of MARS overall five studies - three of them randomised - were identified. Two studies reported a significant higher 30d survival after MARS compared to controls, one study showed a non-significant trend to a better survival probability after one year. The studies showed statistically significant advantages in severity of hepatic encephalopathy, routine lab tests and hemodynamic parameter of the MARS group. None of the studies reported relevant complications or side effects. Although the methodological quality of the studies is seen as slightly better than in the studies on BioLogic-DT, there are methodological limitations: The largest sample size of the randomised trials was twelve patients per group and the study population was highly selected. Because of the methodological limitations the results can hardly be generalised. Only two economic publications presenting analyses of MARS could be de-tected. One publication shows major methodological mistakes which make a further interpretation of the results impossible. The other publication presents an incremental cost-effectiveness of MARS of 29,719 EUR per life year gained after one year from a payer's perspective (German statutory sickness fund, neglecting the intervention costs because of lacking reimbursement at this time), respectively 79,075 EUR per life year gained from a societal perspective. Including health related quality of life aspects the incremental costs per QALY (Quality adjusted life years) gained were calculated to be 44,784 EUR from a payer's perspective respectively 119,162 EUR from a societal perspective. The authors state that prolonging the time horizon of the calculations would improve cost-effectiveness ratios. The limitations of the study design also limit the scientific evidence of the results. CONCLUSION: The results of the detected publications do not give any evidence for a positive medical efficacy of BioLogic-DT. Concerning MARS there is some evidence for positive effects on 30d-survival, clinical parameter, and some lab tests, although the evidence is limited by the small number of studies and their methodological weakness. The currently strongly limited evidence shows a trend to an acceptable cost-effectiveness of MARS, although the results are based on only one non-randomised trial. To give valid recommendations concerning the medical efficacy as well as the cost-effectiveness of artificial liver support systems further studies are necessary. PMID- 21289960 TI - Platelet aggregation inhibitors in primary and secondary prevention of ischemic stroke. AB - BACKGROUND: The ischaemic stroke (IS) is one of the most frequent cause of death in Germany. Besides of non-drug many drug-based interventions are used in primary or secondary prevention of IS, among them the thrombocyte aggregation inhibitors (TAI). OBJECTIVES: The evaluation addresses the questions on medical efficacy and cost-effectiveness of the TAI administration in the prevention of IS as compared to the management of risk factors alone as well as to the use of anticoagulant drugs. METHODS: The literature search for articles published after 1997 was conducted in December 2003 in the most important medical and economic databases. The medical analysis was performed on the basis of the most up-to date meta analyses of randomised controlled trials (RCT) as well as of new published RCT. The data from the studies for stroke, bleeding complications as well as for the combined endpoint "severe vascular events" (SVE: death or stroke or myocardial infarction) were summarised in meta-analyses. In order to include grey literature contact has been taken up with the pharmaceutical manufacturers of TAI. Results are presented in a descriptive way. RESULTS: The medical analysis included data from 184 RCT (vs. placebo) and from 22 RCT (vs. anticoagulant drugs). The absolute reduction of IS (4.8% vs. 6.6%; p<0,00001) and SVE (10.0% vs. 12.4%; p<0,00001) were definitely higher than the absolute increase of bleeding complications (1.6% vs. 0.9%; p<0,00001), but relatively similar to this absolute increase in a subpopulation with a low risk for SVE. With regard to the stroke prevention, evidence of efficacy could be yielded for acetylsalicil acid (ASA), dipyridamole, cilostazol, ridogrel and the combination ASA with dipyridamole. ASA is less effective than anticoagulants in the prevention of ischaemic stroke in atrial fibrillation, however, it causes fewer bleeding complications. Low dosed ASA can be considered cost-effective in secondary prevention of ischemic stroke, which is not the case for clopridogrel. Dipyridamole/ASA being more effective compared with ASA alone is connected with higher acquisition costs. DISCUSSION: The exclusive consideration of stroke prevention is limited, as well as physicians by allocation to TAI expect to avoid all thrombotic events. Since no pharmacoeconomic studies exist for the German context, the economic assessment had to be based on international evidence. CONCLUSIONS: From the medical point of view, TAI may be recommended for primary and secondary prevention of IS in patients with a high risk of severe vascular events and with low risk for bleeding complications. ASA may be also administered in patients with atrial fibrillation in case of contraindication to anticoagulation drugs. From the health economic point of view a systematic primary prophylaxis of IS with ASA cannot be recommended, whereas in secondary prophylaxis savings can be made. Neither the use of Dipyridamole/ASS nor Clopidogrel is advisable for a systematic secondary prophylaxis of IS. PMID- 21289961 TI - The use of statins in primary prevention. AB - BACKGROUND: The use of statins in secondary prevention of cardiovascular events is well established. However, there is ongoing discussion about the use of statins in the context of primary prevention. Moreover statins - besides cholesterol-lowering effects - are assumed to have pleiotropic effects. Positive impacts on diseases like stroke, Alzheimer's disease or osteoporosis are discussed but still have to be proven. OBJECTIVES: The aim of this report is first to investigate the efficacy and effectiveness of statins in primary prevention of cardiovascular and non-cardiovascular events and second to examine the economic implications for Germany - particularly in comparison to existing prevention programs. Finally ethical questions are considered. METHODS: A systematic literature search was performed for the period between 1998 and 2004 which yielded 3704 abstracts. Overall 43 articles were included for assessment and 167 for background information, according to predefined selection criteria. RESULTS: Most studies within the context of primary prevention describe significant risk reductions with regard to cardiovascular events; yet no significant results according to the reduction of the overall mortality rate can be seen. With respect to stroke, osteoporosis and Alzheimer's disease results are inconsistent. Regarding cost-effectiveness of primary prevention with statins results turn out to be inconsistent as well or even negative for populations with low to moderate risk. For groups with high cardiovascular risk the intervention is mostly assessed to be cost-effective. No cost-effectiveness study for Germany was found. According to a rough estimate of future expenses statin drug expenses of the German legal health insurance might increase at least by 50% in the case of an enlargement of the group of recipients. DISCUSSION: To thoroughly estimate the cost-effectiveness of the use of statins in primary prevention in Germany a model calculation including all relevant parameters has to be done. Moreover - from the economic as well as from the ethic point of view - one of the most important issues in primary prevention therapy is the question of compliance. The amount of risk reduction seen in primary prevention studies can be achieved only if patients as well as doctors follow therapeutic instructions and medical guidelines (as for example the guidelines of the "Adult Treatment Panel III", the "European guidelines on cardiovascular disease prevention in clinical practice" or the guidelines of the German Association of Cardiology and of the "Arzneimittelkommission der deutschen Arzteschaft fur Koronare Herzkrankheit"). CONCLUSION: For (primary) prevention of cardiovascular diseases the use of statins as suggested in guidelines is recommended - provided that these guidelines are scientifically evaluated at regular intervals. Regarding stroke, osteoporosis and Alzheimer's disease definite conclusions cannot be drawn at present. Particular attention has to be paid to the problem of compliance both in statin-therapy as well as in alternative therapies. The cost-effectiveness of primary prevention with statins mainly depends on the development of statin prices. PMID- 21289962 TI - Computed tomography for the measurement of coronary calcification in asymptomatic risk patients. AB - BACKGROUND: In 2003 nearly 20% of deaths in Germany were caused by coronary heart disease (CHD). Risk models are used to estimate the ten-year-risk of a coronary event. Coronary calcification may be seen as an additional risk factor. The amount of calcium is correlated with atherosclerotic lesions, but there is no direct correlation with the probability of a plaque rupture. Coronary calcification may be measured either by electron beam computed tomography (EBCT) or multi-detector computed tomography (MDCT). OBJECTIVES: The aim of this HTA report is to investigate the diagnostic validity and cost effectiveness of computed tomography techniques in measuring coronary calcification of asymptomatic risk patients. Ethical aspects are discussed. METHODS: A systematic literature research was performed in 35 international databases which yielded 1080 articles. Overall 43 publications were included for assessment, according to predefined selection criteria. RESULTS: Measuring coronary calcification offers additional information compared with traditional risk factors. Yet at present it cannot be said - according to published literature - which population groups gain most. For determining adequate calcium score thresholds standardisation for age and sex is important. When comparing the reference standard EBCT with MDCT results are inconsistent and depend on the calcium-score value as well as on the scoring method. EBCT as a triage instrument in diagnosing CHD appears to be cost effective. Yet it is rather not cost-effective as a refinement tool for risk stratification. DISCUSSION: Most of the literature was published in the United States and discusses the use of EBCT as well as (traditional) risk stratification by the Framingham Score. Regarding coronary calcification measured by MDCT (which is more widespread in Germany than EBCT) and a risk model applicable for European populations clear recommendations based on published literature cannot be made at present. CONCLUSION: In conclusion measuring coronary calcification is a promising tool for improving risk stratification with established risk models. Nevertheless many questions remain concerning the targeted use in medical practice, particularly regarding European populations. Therefore also no final conclusions can be drawn with respect to cost-effectiveness. The evaluation of diagnostic procedures measuring other parameters than coronary calcium with regard to CHD risk stratification, compared to EBCT or MDCT, is not part of this report. PMID- 21289963 TI - Prevention of relapsing backache. AB - BACKGROUND: The condition of non-specific back pain is characterized by high prevalence, non satisfactory therapeutic options and severe socioeconomic consequences. Therefore prevention seems an attractive option to downsize the problem. However, the construction of effective preventive measures is complicated by the obscure aetiology of the condition, the multidimensionality of risk and prognostic factors (bio psychosocial model!) and the variability of its natural as well as clinical course. This led to the development of a wide variety of preventive measures: e. g. exercise programs, educational measures (including back school), ergonomic modification of the work environment, mechanical supports (e. g. back belts) as well as multidisciplinary interventions. For two reasons the workplace seems to be a suitable setting for prevention. First, because a number of strong risk factors are associated with working conditions and second, because it allows addressing a large proportion of the adult population. Against this background the assessment at hand sets out to answer the following questions: What is the amount and methodological quality of the available scientific literature on the effectiveness of back pain prevention in the workplace environment? What are effective measures for the prevention of back pain and its consequences in the workplace environment and how effective are they? Is back pain prevention in the workplace environment cost-effective? Is there a need for more research? As primary outcomes for effectiveness the assessment will focus on time lost from work and the frequency and duration of episodes with back pain. The preventive measures assessed belong to the following categories: exercise programs, educational and information measures, multidimensional interventions, back belts, lifting teams and ergonomic interventions. METHODS: The assessment is based on a systematic review of the published literature according to the methodological requirements of DAHTA. Proceedings of the electronic literature searches are documented in the appendix. In addition references of review articles were searched. Methodological quality of publications (systematic reviews, HTA reports) was assessed using the checklists developed by the German Scientific Working Group for Technology Assessment in Health Care (GSWGTAHC) or with the Jadad-Score (controlled trials) respectively. Due to the large number of relevant publications the assessment is mainly based on data reported by systematic reviews and supplemented by the results of newer trials. A separate economic assessment was not performed because of the low amount of available data. An assessment of ethical, legal and social impact was omitted due to resource constraints. RESULTS: For preventive interventions based on exercise programs most of the analysed trials demonstrate some effectiveness. Due to the heterogeneity of the programs it is not possible to conclude whether positive effects are associated with a special type, duration or intensity of exercise. For purely educational measures or information strategies applied in a workplace setting the available trials were not able to demonstrate effectiveness. Back school programs, which in addition to theoretical instructions offer intensive exercising may in the short term, be successful in reducing the incidence of new episodes of back pain. Some trials in high risk groups demonstrate effectiveness of multidimensional interventions on time lost from work. These programs include education and exercise as well as cognitive behavioural interventions to change pain perception. The assessment of the benefits of back belts for the prevention of back pain is based on results of high quality efficacy as well as effectiveness trials. Their results imply for the otherwise healthy working population no protective effect of back belts on time lost from work due to back pain, on the incidence of painful episodes or on days with impairment by back pain. So far there are no data from controlled trials that demonstrate the effectiveness of "lifting teams" in nursing care to prevent back pain or its consequences. However, results from uncontrolled pilot studies indicate a potential for effectiveness. Among "ergonomic interventions" three different approaches have to be distinguished: interventions addressing changes of the workplace setting, interventions addressing the individual's behaviour and combined interventions. Studies evaluating the effectiveness of setting interventions (modification of the physical workplace environment, changes of production processes, organisational changes) yield no dependable results. This conclusion is not based on indifferent trial results but rather on the lack of methodologically sound studies. Results from studies on ergonomic interventions addressing the individual confirm the conclusions drawn for exercise and educational measures. The most marked results are found in trials that examine the effectiveness of combined interventions in high risk groups and contain a strong participatory component. Hardly any of the trials studying the effects of ergonomic interventions satisfied methodological quality criteria that are accepted standard for clinical or public health intervention studies. There were no data allowing firm conclusions on the cost-effectiveness of interventions from any of the categories. DISCUSSION: The significance of the results of the assessment at hand is strongly limited by the comprehensiveness of the questions addressed. Reviewing the literature on the basis of (even systematic) review articles impairs the differentiated examination of the role of target groups, program contents, application and duration, effect sizes and context factors. While the methodological quality of the review articles is quite high, the quality of individual trials (even those included in the review papers) is highly variable. While most trials examining preventive interventions addressed at individuals satisfy at least some methodological requirements many studies dealing with setting interventions do not. CONCLUSIONS: In conclusion, sound scientific evidence for the effectiveness and cost-effectiveness of back pain prevention in the workplace environment is still quite scarce. Further research should include: The development of interventions guided by the bio psychosocial model of back pain aetiology that combines individual prevention as well as measures addressing the workplace environment.The integration of results from basic ergonomic research into prevention concepts and the conduct of trials focussing outcomes with relevance to health.at the workplace setting. The conduct of qualitative studies to identify factors that impair the effectiveness of prevention programs (e. g. motivation, compliance, people skills).The integration of cost-effectiveness evaluations into all interventional studies. PMID- 21289964 TI - Orchiectomy versus medical therapy with LH-RH analogues for the treatment of advanced prostatic carcinoma. AB - BACKGROUND: In Germany prostatic cancer is the most frequent cancer in men. The therapy of advanced prostatic cancer has changed significantly from the sub capsulate and / or total orchiectomy to the medical LH-RH analogues therapy during the last ten years, which has considerable effects on results and on costs. Both treatment procedures are based on a slowing down regulation of the growth of the hormone sensitive, neoplastic prostatic cells by the withdrawal of testosterone, which is clinically accompanied by a slowed tumor progression. OBJECTIVES: This health technology assessment depicts and evaluates international data of medical effectiveness and efficiency of orchiectomy and medical therapy with LH-RH-analogues in patients with advanced prostate cancer. METHODS: A systematic, diversified literature analysis in the common medical, economic and HTA data bases and further media was conducted. RESULTS: Five identified, randomized and controlled studies concerning the application of LH-RH analogues showed the same medical effectiveness of orchiectomy and treatment with LH-RH analogues. Four different studies regarding the quality of life revealed no significant difference between the treatment with LH-RH analogues and the therapy with orchiectomy. Dealing with health economic aspects seven cost-minimizing studies and one cost effectiveness study could be identified. All cost-minimizing studies show methodological restrictions. In general all studies draw the conclusion that the treatment of advanced prostatic cancer with orchiectomy is the most cost effective method, if one assumes a remaining life expectancy of more than one year. CONCLUSIONS: According to available studies, there is clear evidence for the equivalent effectiveness of LH-RH analogues and orchiectomy. Until now the studies - due to immense methodological restrictions - could not supply sufficient scientific evidence concerning the aspects of quality of life. In cases of a remaining life expectancy of more than one year, the orchiectomy is the more cost-effective alternative of therapy. PMID- 21289965 TI - Antioxidative vitamines for prevention of cardiovascular disease for patients after renal transplantation and patients with chronic renal failure. AB - INTRODUCTION: The mortality from cardiovascular disease in patients with chronic renal failure is much higher than in the general population. In particular, patients with chronic renal failure with replacement therapies (dialysis patients and patients with renal transplantation) show both increased traditional risk factors and risk factors due to the dysfunction of the renal system. In combination with necessary medication for renal insufficiency oxidative stress is elevated. Progression of atherosclerosis is promoted due to increased oxidation of lipids and endothelium damage. This link between lipid oxidation and artherogenesis provides the rationale for the supposed beneficial effect of supplementation with antioxidative vitamins (vitamin A, C and E). Such an effect could not be demonstrated for patients with a history of cardiovascular disease and without kidney diseases. However, in high risk patients with chronic renal failure and renal replacement therapies this could be different. OBJECTIVES: The objective of this systematic literature review was to assess the clinical effectiveness and cost-effectiveness of supplementation with antioxidative vitamins A, C or E to reduce cardiovascular events in patients with chronic kidney diseases, dialysis-requiring patients and patients after a renal transplantation with or without cardiovascular diseases. METHODS: A systematic literature review was conducted with documented search and selection of the literature, using a priori defined inclusion and exclusion criteria as well as a documented extraction and assessment of the literature according to the methods of evidence-based medicine. RESULTS: 21 publications met the inclusion criteria for the evaluation of clinical effectiveness. No study could be identified for the economic evaluation. Two studies (four publications) analysed the effect of oral supplementation on the secondary prevention of clinical cardiovascular endpoints. Studies analysing the effect on patients without a history of cardiovascular disease could not be identified. 17 studies analysed the effect of oral supplementation or infusion with antioxidative vitamins or the supplementation with dialysis membranes coated with vitamin E on intermediate outcomes like oxidative stress or vessel parameters. The two randomized clinical trials analysing the effect of orally supplemented vitamin E on clinical endpoints in patients with mild-to-moderate renal insufficiency and for haemodialysis patients respectively reported different results. After 4.5 years supplementation with a daily dose of 400 IU vitamin E renal insufficiency patients showed neither a beneficial nor a harmful effect on a combined event rate of myocardial infarction, stroke or death by cardiovascular causes. The second study reported a 50% risk reduction (RR=0.46, 95%-KI: 0.27-0.78, p=0.014) on the combined event rate of fatal myocardial infarction, nonfatal myocardial infarction, stroke, peripheral vascular disease or unstable angina pectoris in the study arm with vitamin E-Supplementation of 800 IU daily. In 16 of 17 studies with intermediate endpoints the supplementation with vitamins was associated with a change of one or several of the examined endpoints in the expected direction. This means that the concentrations of the markers for oxidative stress decreased in the Vitamin E-group, the progression of aortic calcification (only one study) was reduced, the intima media thickness decreased and the lipid profile improved. No studies regarding costs or cost-effectiveness were identified. DISCUSSION: A possible explanation for the different results in the two studies with clinical endpoints may be due to the different study populations with different risk profiles, to different dosage during the intervention or to variation by chance. Due to the absence of clinically meaningful endpoints, the relevance of studies analysing the effect of antioxidative vitamins on intermediate endpoints like oxidative stress markers is basically limited to show single intermediate steps of the postulated biological effect mechanisms by which a potentially preventive effect could possibly be mediated. The mainly unsatisfactory planning and reporting quality of the 17 identified studies and a possible "publication bias" are further limitations. CONCLUSION: The available evidence is not sufficient to support or to reject an effect of antioxidative vitamins on secondary prevention for cardiovascular disease for patients with chronic renal insufficiency or renal replacement therapy. There is a lack of randomized, placebo-controlled studies with a sufficient number of cases and clinical endpoints of cardiovascular disease, on the effect of antioxidative vitamins either orally applied or given by vitamin E-modified dialysers. No data are available about supplementation with antioxidative vitamins for primary prevention of cardiovascular disease. Therefore the current evidence does not allow to draw conclusions concerning this subject either. As opposed to patients with a history of cardiovascular disease without kidney diseases where there is enough evidence to exclude a beneficial effect on secondary prevention of cardiovascular disease for patients with chronic renal insufficiency and renal replacement therapy this question remains unanswered. Conclusions about costs and cost-effectiveness also cannot be drawn. PMID- 21289966 TI - Bypass operation at the beating heart in comparison to the operation with support of the heart-lung machine. AB - The coronary Bypass operation at the beating heart ("off-pump surgery") is a new procedure which promises advantages in comparison to the established procedure with uses a heart-lung machine ("on-pump-surgery"). In the presented HTA report cardiac surgery the question is investigated, whether there are advantages of the off-pump-surgery in comparison to the on-pump-surgery regarding medical effectiveness, safety as well as cost effectiveness. At the beginning a systematic literature search was done, the articles were classified according to the hierarchy of evidence. There are partly considerable different groups of patients included in the different studies as well as quite different outcome parameters. The quality of the studies in detail, where at least two groups are compared was generally very good.The studies results show more or less equivalent results in the comparison of the two operation techniques. Concluding neither a clinical superiority nor an inferiority on the basis of the present available studies can therefore be proven (off-pump Coronary Artery Bypass; OPCAB) or the conventional bypass operation with use of the heart-lung machine (Coronary Artery Bypass Graft; CABG can).The diagnostic criteria of a patient who is allocated to the one or other operating technique are important. Due to technical reasons the majority of patients with the necessity of a bypass operation con only be treated by CABG, (on-pump-surgery). These criteria for the allocation of operation techniques should be the important components of optimization considerations. PMID- 21289967 TI - Interventions for increasing uptake in screening programmes. AB - INTRODUCTION: Opportunities for the early detection of disease are not sufficiently being taken advantage of. Specific interventions could increase the uptake of prevention programmes. A comprehensive analysis of effectiveness and cost-effectiveness of these interventions with reference to Germany is still needed. OBJECTIVES: This report aimed to describe and assess interventions to increase uptake in primary and secondary prevention and to explore the assessment of their cost-effectiveness. METHODS: 29 scientific databases were systematically searched in a wide strategy. Additional references were located from bibliographies. All published systematic reviews and primary studies were assessed for inclusion without language restrictions. Teams of two reviewers identified the literature, extracted data and assessed the quality of the publications independently. RESULTS: Four HTA reports and 22 systematic reviews were identified for the medical evaluation covering a variety of interventions. The economic evaluation was based on two HTA-reports, one meta-analysis and 15 studies. The evidence was consistent for the effectiveness of invitations and reminders aimed at users, and for prompts aimed at health care professionals. These interventions were the most commonly analysed. (Financial) Incentives for users and professionals were identified in a small number of studies. Limited evidence was available for cost-effectiveness showing incremental costs for follow-up reminders and invitations by telephone. Evidence for ethical, social and legal aspects pointed to needs in vulnerable populations. DISCUSSION: The material was heterogeneous regarding interventions used, study populations and settings. The majority of references originated from the United States and focused on secondary prevention. Approaching all target groups by invitations and reminders was recommended to increase uptake in prevention programmes in general. CONCLUSIONS: Further research should aim to focus on primary prevention. Future research should also focus on specific interventions aiming to include vulnerable target groups and individuals, who have not previously made use of opportunities for prevention. PMID- 21289968 TI - Therapy of unspecific tinnitus without organic cause. AB - INTRODUCTION: There is a variety of medical and non-medical therapies in practice, which were not evaluated regarding its effectiveness by any systematic evidence oriented investigation. A number of therapies of medical and non-medical type try to treat the different types of tinnitus. The evidence in the scientific literature also had to be cleared in the field of diagnosis and classification as well as medical/psychiatric/psychological procedures of existing medical therapy. QUESTION: The HTA report had to investigate the following questions: Which evidence do diagnostic methods in recognition of tinnitus have? Which types of therapy show medical effectiveness at the acute or chronic tinnitus without an organic cause? Which consequences (need for further research, future procedures) can be drawn? METHODOLOGY: In the following databases "tinnitus" was searched according to the search string: HTA97; INAHTA; CDAR94; CDSR93; CCTR93; ME66; ME0A; HT83; SM78; CA66; CB85; BA70; BA93; EM74; IS74; ET80; EB94; IA70; AZ72; CV72; GE79; EU93; HN69; ED93; EA08 RESULT: 1932 studies, unsorted after assessment in accordance with EBM criterions, selection: 409 studies. Due to the completely heterogeneous representation modes of the therapeutic approaches at the treatment of the chronic tinnitus no quantitative synthesis method could be performed. Therefore the methodology of a qualitative overview has been carried out. RESULTS: The diagnostic confirmation of the non-specific tinnitus without organic cause meets with the problem of the assurance of the diagnosis tinnitus. According to the current opinion the stepwise diagnostics is carried out also in the case of the so called subjective tinnitus. Nothing can be said about the evidence of these procedures since no publication was found about that. A study concerning the evidence of the diagnostic questionnaires from Goebel and Hiller [1] comes to the end that the tinnitus questionnaire frequently used (TF) [2] is the best evaluated procedure. The number of therapies which treat tinnitus is exceptionally high and makes clear, that the search for "the" tinnitus therapy is still going on. According to the current knowledge tinnitus genesis is multifactorial and therefore there can't be any standard therapy for tinnitus. The following seven categories can be distinguished: AD 1: MACHINE-AIDED ACOUSTIC THERAPIES From many studies regarding machine-aided acoustic therapy of tinnitus only two showed an evidence degree that allows scientifically correct statements about the effectiveness of these procedures. Selectively significant improvements could be shown in the comparison with a placebo (apparatus switched off) a superiority of tinnitus-maskers. AD 2: ELECTROSTIMULATION In an application study of electro-stimulation the results were not evaluated statistically, but it was described descriptively that a successful medical treatment can be expected in about 50% of the cases. AD 3: PSYCHOLOGICAL THERAPY PROCEDURES Hypnosis did not show positive effectiveness. With regard to biofeedback it can be concluded that this method can be effective in individual cases, however regarded as unreliable from missing reproducibility. Neurobiofeedback could prove that it had a positive therapeutic effect. From eight controlled studies to relaxation techniques and cognitive behaviour therapy four studies showed a therapeutic effectiveness and four failed. Combined therapies proved generally to be more effective than individual types. The behaviour medical psychotherapy could show a positive therapy effect. In a study with cognitive therapy and relaxation (three groups, a passive relaxation, an active relaxation and a cognitive therapy) short-term successes could be stated (for one month), however, the parameters of success returned on the initial value after four months. Also only coincidental and short term successes could be achieved with cognitive behaviour therapy training, autogenic training and structured group psychotherapy. AD 4: TINNITUS RETRAINING THERAPY (TRT) Unfortunately, the published results of the TRT are methodically frequently bad and scientific of a poor value. Many of the studies presented until now regarding tinnitus retraining therapy are not informative in their scientific context. In a study with 95 patients with a chronic tinnitus TRT could show a significant, more than six months lasting stable success by comparison to a combination of TET with group behaviour therapy (improvement be achieved around at least ten points in the tinnitus questionnaire (TF)). AD 5: PHARMACOLOGICAL THERAPIES Rheological drugs (medicines for hemodilution) could not show any statistically significant effect in the treatment of tinnitus. Studies to the medical treatment with tocainides (lidocaine) showed repeatable positive effects on tinnitus in higher dosages (as of 1.2 mg/day). Lamotrigine as a medicine had an effect positively only at with a small fraction of patients. Two studies with GABA receptor agonists could not prove therapeutic effects for tinnitus. Undesired side-effects were observed. Injections with Carvoverine (a glutamate antagonist) achieved significantly successes with a special form of tinnitus, the "Cochlear-synaptic tinnitus (CST)". A tricyclic antidepressant (Amitriptilin) could prove superiority against placebo. This effect could be confirmed in another study. However Clonazepame (a benzodiazepine), could not achieve any improvement. Short-term improvements were achieved with other benzodiazepines (Clonazepame, Diazepam, Flurazepame, Oxacepame and Alprazolame). A German retrospective study suggests a graded pharmacological therapy by means of rheological infusion therapy, applications of neurotransmitters, and injections of lidocaine. This method achieved a disappearance or a recovery of the complaints at 95.3% of the acute and 26.7% of the chronic cases. AD 6: SURGICAL PROCEDURES The effects of the operative excision of the stapes (stapedectomy) showed significant effects concerning tinnitus. This method is a routine operation to recover hearing, effects on tinnitus were observed only coincidently. There are generally high frequencies of improvements of tinnitus after cochlea implantations; however the risk of deterioration is present with this method. AD 7: OTHER AND ALTERNATIVE THERAPY PROCEDURES The hyperbaric oxygen therapy can be considered successful after acute events with tinnitus. The therapy should be started in the first month after appearance of the tinnitus. The methods transcranial-, electromagnetic and transcutaneous nerve stimulations did not show any significant effects on tinnitus. Also low laser medical treatment showed disappointing effects. The "pneumatic external contra-pulsation" is described as an unproblematic usable procedure by the authors of the examination, but 10% of the patients had to stop the medical treatment because of complications associated with the medical treatment. Acupuncture showed significant improvements in comparison to medical treatment. The effectiveness of this therapy could not be reproduced in another study. Five other studies between 1993 and 1999 also did not show any therapeutic effect of this method. Gingko Biloba preparations did not show any positive effects in large-scale studies on tinnitus. DISCUSSION: Neither the diagnostic procedures nor the therapeutic methods or the individual therapies reach a usual scientific level in medicine. Unsolved problems concerning insurance, economic as well as legal problems have resulted for the patients and for caring stuff from this unsatisfactory situation. Numerous competitive tinnitus emergence models led to an incredible creativity in trying out different therapy approaches. No convergence of the therapy procedures can be seen within the last decades of tinnitus research, contrariwise there is always more and more "creativity" of new approaches. Priority has to be given to find the cause of tinnitus since therapies are a consequence of a better understanding of these symptoms that evidence oriented investigations on an usual scientific level can be started. CONCLUSION: The innumerable therapeutic approaches, seeming completely incoherent to their effects should be coordinated on the meaningfulness, on the success parameters and with patient safety in light of the most plausible explanation models for non specific chronic Tinnitus. To this the facilities of competence centres or related science- directing facilities are recommendable. Examinations which are carried out also with small numbers show often methodical insufficiencies. It is necessary that minimal requirements on a scientifically clinical experiment, such as design, case number calculation, analytic statistics, control group, are fulfilled. It is recommendable, that further research has to be promoted regarding tinnitus causes that a coordinated evidence-orientated treatment will be developed. PMID- 21289969 TI - Mistletoe treatments for minimising side effects of anticancer chemotherapy. AB - BACKGROUND: More than 200,000 persons died in 2002 in Germany as a consequence of cancer diseases. Cancer (ICD-9: 140-208, ICD-10: C00-C97) accounted for 28% of all male deaths and for 22% of all female deaths. Cancer treatment consists on surgery, radio- and chemotherapy. During chemotherapy patients may experience a wide variety of toxic effects (including life-threatening toxicity) which require treatment. The type and the intensity of chemotherapy toxicity are one of the limiting factors in cancer treatment. Toxic effects are also one of the factors affecting health related quality of life (HRQOL) during chemotherapy. Mistletoe extracts belong to the group of so called "unconventional methods" and are used in Germany as complementary cancer treatments. It has been postulated that the addition of mistletoe to chemotherapeutical regimes could help reduce chemotherapy-induced toxicity and enhance treatment tolerability. The German social health insurance covers the prescription of ML I standardized mistletoe extracts when those are prescribed as palliative cancer treatments with the aim of improving HRQOL. RESEARCH QUESTIONS: Does the addition of mistletoe to chemotherapeutical regimes reduce their toxicity?Does the addition of mistletoe to chemotherapeutical regimes contribute to improve quality of life?Has the addition of mistletoe to chemotherapeutical regimes any effects on survival?Has the addition of mistletoe to chemotherapeutical regimes any effects on tumor remission? METHODS: WE CONDUCTED A SYSTEMATIC LITERATURE SEARCH IN FOLLOWING DATABASES: The Cochrane Library, DIMDI Superbase and Dissertation Abstracts. We included systematic reviews and randomized controlled trials (RCT). Appraisal of literature was done by two authors independently. Checklists were used to guide literature appraisal. The Jadad-Score was used to score quality of RCT. Evidence was summarized in tables and in narrative form. RESULTS AND DISCUSSION: The literature search yielded 437 potentially relevant papers. A total of 94 papers was retrieved. Of them, 48 were potentially relevant for answering the research questions and 46 for background information. In this report we summarize the results from three systematic reviews, five published RCT and two unpublished RCT. A protocol of an ongoing systematic review from the Cochrane Collaboration was also identified. The information gathered from the systematic reviews was insufficient to answer the research questions. The relevant studies identified and synthetised in these reviews were appraised and extracted again. In addition, a set of recently published RCT was identified and included in these report. None of the RCT defined frequency or severity of chemotherapy associated toxic effects as its primary outcome. Some of the RCT reported, however, rates of toxic effects or parameters related to toxicity. The results are inconsistent among the RCT ranging from no effect on to positive effects (i. e. reduction) on chemotherapy toxicity. RCT with treatment toxicity as primary outcome are needed to answer the question of whether the addition of mistletoe extracts to chemotherapy regimes can help reducing treatment toxicity. HRQOL was the primary outcome in four RCT. The addition of mistletoe to chemotherapy showed to have a positive effect on HRQOL of women treated for breast cancer. CONCLUSIONS: The available evidence does not allow giving a conclusive answer to the question of whether the addition of mistletoe to chemotherapeutical regimes can reduce the toxicity of the latter. RCT are needed in which the primary outcome is treatment toxicity. The addition of standardised mistletoe extract to chemotherapeutical regimes in the treatment of women with breast cancer can lead to improvements in HRQOL. In the light of the results from RCT the coverage of mistletoe in cancer treatment should be restricted in Germany to the latter indication. PMID- 21289970 TI - Therapy of atopic eczema. AB - OBJECTIVES: Major objective is the evaluation of the medical effectiveness of different therapeutical approaches and the cost effectiveness with relevance for Germany. METHODS: This health technology assessment (HTA) evaluates systemically randomized controlled studies (RCT) on the therapy of atopic dermatitis which were published between 1999 and 2004. Further it includes some important clinical studies which have been published after 2004 and other updates the English HTA report by Hoare et al. [1]. RESULTS: Topical corticosteroids and topical calcineurin-inhibitors are the principal substances which are currently used for anti-inflammatory therapy in atopic dermatitis. These substances have shown a significant therapeutic efficacy in controlled studies. In newer controlled studies no difference was observable when corticosteroids were applied once or more than once daily onto the skin. Moreover, there is now one controlled study available which points to the fact that an interval therapy with a stronger topical corticosteroid over a limited time (some weeks) may lower the risk of recurrent flares of atopic dermatitis. Both topical calcineurin-inhibitors pimecrolimus and tacrolimus have shown a significant therapeutical efficacy in a number of placebo-controlled prospective studies. The wealth of data is high for these substances. Both substances have been shown to be efficient in infants, children and adult patients with atopic dermatitis. The importance of a so-called basic therapy with emollients which have to be adapted to the current status of skin is generally accepted in clinical practice. Controlled studies show the efficacy of "basic therapy" - although the level of evidence is quite low for this approach. The skin of patients with atopic dermatitis is colonized in the majority with Staphylococcus aureus, a gram-positive bacterium. Therefore, a therapeutical approach for the treatment of atopic dermatitis is the anti bacterial or anti-septic treatment of the skin. Due to the lack of randomized controlled studies there is still not certain proof that antimicrobial or anti septic treatment of non-infected eczematous skin is efficient for the treatment of atopic dermatitis. A reduction of Staphylococcus aureus is observable during an anti-inflammatory treatment of the skin with topical corticosteroids and/or the topical calcineurin-inhibitor tacrolimus. Antihistaminic drugs which are orally applied in atopic dermatitis may support the therapy of the itching skin disease. One controlled study showed a rapid reduction of itch during the use of a non-sedating antihistaminic drug. There are, however, no controlled studies which show the efficacy of antihistaminic drugs on the skin condition in atopic dermatitis. Dietetic restrictions should be applied only after a specific allergological diagnostic clarification. The "gold standard" is still a (blinded) oral provocation test which has to show an influence of a given food on the skin condition. There is sufficient evidence that there is no general dietetic approach which shows efficacy in atopic dermatitis. The treatment of patients with lactobacillae is still controversially discussed. Available studies which showed an efficacy show methodological weaknesses so that this approach can not be generally recommended for clinical practice at the time now. Approaches reducing house dust mite in the surroundings of patients with atopic dermatitis can have an effect on the skin condition so that at least in mite sensitized patients this approach appears to be reasonable. The specific immunotherapy with house dust mite showed clinical efficacy in a controlled study and in some open studies. The education of patients with atopic dermatitis or their parents is a further efficient approach in the management of this chronic skin disease. Interdisciplinary approaches in patients' education containing also psychological elements appear to be an attractive new approach for the treatment of atopic dermatitis. Phototherapy is a further possibility of intervention in atopic dermatitis in adolescent or adult patients. The available evidence points to the fact that UVB radiation (both small and broad spectrum), UVA-1 radiation and balneo-phototherapy are efficient therapeutical options for atopic dermatitis. The systemic treatment with the immunosuppressive substance cyclosporine A is efficient in the treatment of severe atopic dermatitis. Cyclosoprine A is approved for the treatment of adult patients with this skin disease. The immunosuppressive substance azathioprine showed a high clinical efficacy in two controlled studies for severe atopic dermatitis in adults. There are still controversial results for the application of antagonists to leucotriens in the treatment of atopic dermatitis: in some open studies a therapeutical efficacy was described which was, however, not reproducible in a newer controlled study. The phosphodiesterase-4-inhibitor cipamphyllin was efficient in the treatment of atopic dermatitis in a controlled study but weaker than a topical class II (i. e. moderate strength) corticosteroide. The HTA assessment further describes so called complementary therapeutical approaches which have either not properly been studied in controlled clinical trials or which have been shown to be of no value for the treatment of atopic dermatitis. Altogether six full health-economic evaluations were found which did not cover the whole therapy spectrum of atopic dermatitis. The choice of the most cost effective treatment option of topic corticosteroids depends less on application frequency, but rather on the drug price and more used or unused quantity of the standard packages, so even smallest improvements justify a more frequent application. The results from health economic evaluations of calcineurin-inhibitors are not reliable. The therapy of severe atopic dermatitis in adults with ciclosporin shows comparable cost effectiveness in comparison to UVA/UVB therapy. DISCUSSION: The spectrum of therapeutical procedures has increased for atopic dermatitis but is still not sufficient. The spectrum of established substances is much smaller compared to psoriasis, another chronic and common inflammatory skin disease. There is need for the development new substances which can be applied topically and which are aimed to treat atopic dermatitis in early childhood. Another need for new developments can be found for the treatment of severe atopic dermatitis in adults. CONCLUSIONS: The spectrum of therapeutical procedures has increased for atopic dermatitis but is still not sufficient. The spectrum of established substances is much smaller compared to psoriasis, another chronic and common inflammatory skin disease. There is need for the development new substances which can be applied topically and which are aimed to treat atopic dermatitis in early childhood. Another need for new developments can be found for the treatment of severe atopic dermatitis in adults. Due to lack of health economic evaluations therapy decisions in the treatment of atopic dermatitis must take place on the basis of clinical decision criteria. The prescription of topic corticosteroids should prefer low priced drugs. Reliable statements about the cost effectiveness of the new calcineurin-inhibitors tacrolimus and pimecrolimus. PMID- 21289971 TI - Screening of the hearing of newborns - Update. AB - INTRODUCTION: Permanent congenital bilateral hearing loss (CHL) of moderate or greater degree (>=40 dB HL) is a rare disease, with a prevalence of about 1 to 3 per 1000 births. However, it is one of the most frequent congenital diseases. Reliance on physician observation and parental recognition has not been successful in the past in detecting significant hearing loss in the first year of life. With this strategy significant hearing losses have been detected in the second year of life. With two objective technologies based on physiologic response to sound, otoacoustic emissions (OAE) and auditory brainstem response (ABR) hearing screening in the first days of life is made possible. OBJECTIVES: The objective of this health technology assessment report is to update the evaluation on clinical effectiveness and cost-effectiveness of newborn hearing screening programs. Universal newborn hearing screening (UHNS) (i), selective screening of high risk newborns (ii), and the absence of a systematic screening program are compared for age at identification and age at hearing aid fitting of children with hearing loss. Secondly the potential benefits of early intervention are analysed. Costs and cost-effectiveness of newborn hearing screening programs are determined. This report is intended to make a contribution to the decision making whether and under which conditions a newborn hearing screening program should be reimbursed by the statutory sickness funds in Germany. METHODS: This health technology assessment report updates a former health technology assessment (Kunze et al. 2004 [1]). A systematic review of the literature was conducted, based on a documented search and selection of the literature using predefined inclusion and exclusion criteria and a documented extraction and appraisal of the included studies. To assess the cost-effectiveness of the different screening strategies in Germany the decision analytic Markov state model which had been developed in our former health technology assessment report was updated. RESULTS: Universal newborn hearing screening programs are able to substantially reduce the age at identification and the age at intervention of children with CHL to six months of age in the German health care setting. High coverage rates, low fail rates and - if tracking systems are implemented - high follow-up-rates to diagnostic evaluation for test positives were achieved. New publications on potential benefits of early intervention could not be retrieved. For a final assessment of cost-effectiveness of newborn hearing screening evidence based long term data are lacking. Decision analytic models with lifelong time horizon assuming that early detection results in improved language abilities and lower educational costs and higher life time productivity showed a potential of UNHS for long term cost savings compared to selective screening and no screening. For the short-term cost-effectiveness with a time horizon up to diagnostic evaluation more evidence based data are available. The average costs per case diagnosed range from 16,000 EURO to 33,600 EURO in Germany and hence are comparable to the cost of other implemented newborn screening programs. Empirical data for cost of selective screening in the German health care setting are lacking. Our decision analytic model shows that selective screening is more cost-effective but detects only 50% of all cases of congenital hearing loss. DISCUSSION: There is good evidence that UNHS-Programs with appropriate quality management can reduce the age at start of intervention below six months. Up to now there is no indication of considerable negative consequences of screening for children with false positive test results and their parents. However, it is more difficult to prove the efficacy of early intervention to improve long-term outcomes. Randomized clinical trials of the efficacy of early intervention for children with CHL hearing losses are inappropriate because of ethical reasons. Prospective cohort studies with long-term outcomes of rare diseases are costly, take a long time and simultaneously substantial benefits of early intervention for language development seem likely. CONCLUSIONS: A UNHS-Program should be implemented in Germany and be reimbursed by the statutory sickness funds. To achieve high coverage and because of better conditions for obtaining low false positive rates UNHS should be performed in hospital after birth. For outpatient deliveries additionally screening measures in an outpatient setting must be provided. PMID- 21289972 TI - What effects has the cataract surgery on the development and progression of Age Related Macular Degeneration (AMD)? AB - BACKGROUND: The cataract (Cataracta senilis) is the most frequent eye disease of elderly people worldwide. In Germany, the cataract operation - with currently 450,000 interventions each year the most frequent operation in ophthalmology - can be seen as routine surgery. The age related macular degeneration (AMD) is a further one of the most common, age-related eye diseases and the most frequent cause of blindness of elderly people in industrial nations. Due to demographic changes an increasing number of patients will suffer from cataract and AMD at the same time. This coincidence leads to a greater interest in the question of a mutual influence of both diseases, respectively their therapies, on each other. OBJECTIVES: The aim of this report was the evaluation of the medical and health economic effects of cataract operations on the development and progression of an age related macular degeneration (AMD). It was differentiated between first manifestations of AMD, progression of early stages of AMD and influence on further impairment in late stages of AMD. METHODS: The relevant publications for this report were identified by DIMDI via structured database enquiry as well as common, self-made enquiry and were evaluated, based on the criteria of evidence based medicine. The present report included German and English literature published since 1983. RESULTS: The database enquiry generated a record of 2769 issue-related publications. Eight medical publications were eligible for analysis in the course of the present HTA report. No relevant studies on health economical, ethical, social or legal issues could be included. Three epidemiological cohort studies provided some evidence for a promoting influence of cataract extractions on the progression of early types of AMD. Two of the epidemiological studies assessed the risk of first manifestation of AMD after cataract extraction. Both came up with up with increased incidences that did not reach statistical significance despite a large number of participants. Only one out of two clinical studies looked at further impairment in late stages of AMD and could not find an interrelation with cataract extraction. Thus the available evidence was not sufficient to come to a conclusion on the contribution of cataract extractions to the first manifestation of AMD and to the further impairment in late stages. DISCUSSION: The presentation of the evaluated literature made clear that only a small number of publications dealt with the development of age related macula degeneration in consequence of a cataract extraction. The overall scientific level of evidence of these articles was not very high. Therefore it was not possible to obtain a well-defined conclusion on the effect of a cataract extraction on the development or progression of an age related macula degeneration. CONCLUSION: Additional well conducted clinical trials, that offer a sufficient number of patients, length of study period and adequate control for confounding variables like age and severity of cataract, are urgently needed. Health economic, ethical, social and legal aspect of the problem could and should be investigated after clarification of the mentioned medical issues. PMID- 21289973 TI - Laparoscopic vs. open appendectomy: systematic review of medical efficacy and health economic analysis. AB - SCIENTIFIC BACKGROUND: Appendicitis is an inflammation of the appendix of the blind intestine. Appendicitis remains the most frequent cause for an acute abdomen. Both interventions, the open surgical (through opening of the abdominal cavity) as well as the laparoscopic approach (via insertion of an optic system and instruments into the abdominal cavity through three small incisions), are used for the excision of the inflamed appendix (appendectomy). RESEARCH QUESTIONS: The performed evaluation addresses questions on the medical effectiveness of the use of laparoscopic appendectomy in comparison with the classical open appendix excision as well as on its cost-effectiveness based on the German health system. METHODS: A literature search was conducted in October 2005 in the most important medical electronic databases. The medical analysis was performed on the basis of the most up to date systematic review (basic review) of randomized controlled studies (RCT), newly published RCT and on our own quantitative information synthesis of all studies as well as of selected methodologically high-value RCT. In the health economic analysis, relevant publications were evaluated and cost differences of both interventions were calculated. RESULTS: One systematic review and 56 primary studies were included in the medical evaluation, 24 of these studies were included in the conducted subanalysis on the basis of methodologically high-value studies. In total, a relation of three avoided wound infections per one additional intraabdominal abscess has to be expected by the use of laparoscopic appendectomy in com-parison with the open operation. Diagnostic laparoscopy reduces the rate of unclear diagnoses within the scope of planned appendectomy in fertile women. By routine, leaving the macroscopically bland appendix in situ, the rate of negative appendectomy is reduced significantly and profound. The results speak for a small advantage of the laparoscopic appendec-tomy with regard to pain intensity, the time until reintroduction of liquid and solid diet, time until first stool as well as for a slightly better cosmetic result and slightly better quality of life. In the contemporary practice in Germany, a longer operation time, a reduced length of hospital stay and a similar time to return to work have to be expected by the use of laparoscopic appendectomy in comparison with open appendectomy. In the current health care situation in Germany, the use of laparoscopic appendectomy is associated with additional operation costs of approximately 150 to 200 Euro compared with the open appendectomy. By approximately 200 Euro costs savings due to the shorter length of hospital stay, the total (direct and indirect) costs of in-patient care of both interventions seem to be similar. Due to similar indirect costs, the total costs of both interventions lie also in the same range and the incremental cost-effectiveness ratio of both technologies are driven to zero. DISCUSSION: The use of the results of the performed medical analysis in the cost calculations supports the conclusions of the health-economic evaluation on the same evidence level as in the medical analysis. CONCLUSIONS: Laparoscopic appendectomy shows both small advantages (diagnostics, wound infections, pain intensity, cosmetic result and quality of life) and disadvantages (intraabdominal abscesses) when compared with open appendectomy. From a health-economic view, laparoscopic and open appendectomies are generally similar with respect to the direct in-patient and indirect costs. Therefore, the decision between the two alternatives should be made by the physicians individually. PMID- 21289974 TI - The development of General Thoracic Surgery. PMID- 21289975 TI - Pyothorax-associated lymphoma (PAL): report and review of a rare entity. AB - Pyothorax-associated lymphoma (PAL) is a rare haematological malignancy often associated with artificial pneumothorax due to the treatment of pulmonary tuberculosis. A 76 year old man with chronic tube-drained pyothorax and a history of artificial pneumothorax for pulmonary tuberculosis was admitted to our hospital because of progressive right thoracic pain, weight loss, and pyrexia. After clinical examination and imaging processes a chest wall tumour anterior on the right side was diagnosed as well as a persisting pyothorax. Surgery was performed to resect the tumour and drain the pleural cavity. A diagnosis of a high grade B-cell lymphoma was established after histological examination of the surgical biopsy. Epstein-Barr virus (EBV) was identified in the tumour by immunocytochemical and molecular methods. Additional gastric involvement of B cell lymphoma could be diagnosed by gastroscopy because of postoperative gastrointestinal bleeding. The patient received chemotherapy with 2 courses of cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP). The response was favourable initially, but 2 months later the patient died because of lymphoma progression.Most cases of PAL have been described by Japanese investigators and only a few cases are reported in Western countries. To the best of our knowledge this case of PAL is the first to be documented in Germany.Awareness of this rare entity, together with diligent histological examination, in patients with chronic pyothorax are essential for a correct diagnosis and correct early treatment. PMID- 21289976 TI - Effective screen for amyloid beta aggregation inhibitor using amyloid beta conjugated gold nanoparticles. AB - The abnormal aggregation of amyloid beta (Abeta) and its subsequent intra- and extracellular accumulation constitute the disease-causing cascade of Alzheimer's disease (AD). The detection of Abeta aggregates and senile plaque formation, however, is nearly impossible during early pathogenesis, and the absence of a convenient screen to validate the activity of Abeta aggregation regulators impedes the development of promising drug targets and diagnostic biomarkers for AD. Here, we conjugated amyloid beta42 (Abeta42) peptide to gold nanoparticles (AuNPs) to visualize Abeta42 aggregation via Abeta42 aggregation-induced AuNP precipitation. AuNP-Abeta42 precipitate was quantified by optical density measurements of supernatants and thioflavin T binding assay. Transmission electron microscopy (TEM) analysis also showed reduced interparticle distance of AuNPs and confirmed the Abeta42 aggregation-induced AuNP precipitation. Transthyretin, a widely known Abeta aggregation inhibitor, limited AuNP-Abeta42 precipitation by preventing Abeta42 aggregation. Finally, according to TEM analysis, Abeta42-conjugated AuNPs treated with blood-driven serum revealed the differentiated aggregation patterns between normal and AD. These findings may open a scientific breakthrough in finding a possible diagnostic and prognostic tool for neurodegenerative diseases involving abnormal protein aggregation as their key pathogenesis processes. PMID- 21289977 TI - Evaluation of the interaction between calcifying nanoparticles and human dental pulp cells: a preliminary investigation. AB - Calcifying nanoparticles (CNPs, previously called nanobacteria) are self propagating, cultivable macromolecular complexes. Their extraordinary characteristic is that they can aggregate carbonate apatite on their envelope from soluble calcium and phosphorus at physiologic concentrations and display cytotoxic effects on murine and human fibroblast cell lines. The question arises whether CNPs contribute to the degeneration of pulp tissue and thus result in clinically significant human dental pulp stones as nidies. This study evaluates CNPs' effects upon human dental pulp cells (HDPCs, the host cells in pulp tissue). We observed the ultrastructural variation of HDPCs attacked by CNPs. The spatial relationship of HDPCs and CNPs after coculture was also identified by immunofluorescence staining. Furthermore, it was verified by MTT viability assay that CNPs isolated from dental pulp stones exerted cytotoxic effect on HDPCs. Therefore, it could be concluded that the existence of CNPs might interfere with the normal physiologic function of the cells, and that might lead to dental pulp calcification. Elucidation of the cytotoxic characteristics of CNPs may offer a new perspective for understanding the etiology of human dental pulp stones. PMID- 21289978 TI - Treatment of Parkinson's disease: nanostructured sol-gel silica-dopamine reservoirs for controlled drug release in the central nervous system. AB - INTRODUCTION: We have evaluated the use of silica-dopamine reservoirs synthesized by the sol-gel approach with the aim of using them in the treatment of Parkinson's disease, specifically as a device for the controlled release of dopamine in the striatum. Theoretical calculations illustrate that dopamine is expected to assume a planar structure and exhibit weak interactions with the silica surface. METHODS: Several samples were prepared by varying the wt% of dopamine added during the hydrolysis of tetraethyl orthosilicate. The silica dopamine reservoirs were characterized by N(2) adsorption, scanning and transmission electron microscopy, and Fourier transform infrared spectroscopy. The in vitro release profiles were determined using ultraviolet visible absorbance spectroscopy. The textural analyses showed a maximum value for the surface area of 620 m(2)/g nanostructured silica materials. The stability of dopamine in the silica network was confirmed by infrared and (13)C-nuclear magnetic resonance spectroscopy. The reservoirs were evaluated by means of apomorphine-induced rotation behavior in hemiparkisonian rats. RESULTS: The in vitro dopamine delivery profiles indicate two regimes of release, a fast and sustained dopamine delivery was observed up to 24 hours, and after this time the rate of delivery became constant. Histologic analysis of formalin-fixed brains performed 24-32 weeks after reservoir implantation revealed that silica-dopamine implants had a reddish-brown color, suggesting the presence of oxidized dopamine, likely caused by the fixation procedure, while implants without dopamine were always translucent. CONCLUSION: The major finding of the study was that intrastriatal silica-dopamine implants reversed the rotational asymmetry induced by apomorphine, a dopamine agonist, in hemiparkinsonian rats. No dyskinesias or other motor abnormalities were observed in animals implanted with silica or silica-dopamine. PMID- 21289980 TI - Stability and antimicrobial effect of amikacin-loaded solid lipid nanoparticles. AB - Solid lipid nanoparticles (SLNs) of amikacin were designed in this study for pulmonary delivery to reduce the dose or its administration intervals leading to reduction of its toxicities especially in long term treatment. Nanoparticles of amikacin were prepared from cholesterol by solvent diffusion technique and homogenization. The size, zeta potential, loading efficiency, and release profile of the nanoparticles were studied. The conventional broth macrodilution tube method was used to determine the minimum inhibitory concentration (MIC) and minimum bacteriostatic concentration (MBC) of amikacin SLNs with respect to Pseudomonas aeruginosa in vitro. To guarantee the stability of desired SLNs, they were lyophilized using cryoprotectants. Results showed that considering the release profile of amikacin from the studied nanocarrier, MIC and MBC of amikacin could be about two times less in SLNs of amikacin compared to the free drug. Therefore, fewer doses of amikacin in SLNs can clear the infection with less adverse effects and more safety. Particle size enlargement after lyophilization of desired SLNs after two months storage was limited in comparison with non lyophilized particles, 996 and 194 nm, respectively. Zeta potential of lyophilized particles was increased to +17 mV from +4 mV before lyophilization. Storage of particles in higher temperature caused accelerated drug release. PMID- 21289981 TI - Selective axonal growth of embryonic hippocampal neurons according to topographic features of various sizes and shapes. AB - PURPOSE: Understanding how surface features influence the establishment and outgrowth of the axon of developing neurons at the single cell level may aid in designing implantable scaffolds for the regeneration of damaged nerves. Past studies have shown that micropatterned ridge-groove structures not only instigate axon polarization, alignment, and extension, but are also preferred over smooth surfaces and even neurotrophic ligands. METHODS: Here, we performed axonal outgrowth competition assays using a proprietary four-quadrant topography grid to determine the capacity of various micropatterned topographies to act as stimuli sequestering axon extension. Each topography in the grid consisted of an array of microscale (approximately 2 MUm) or submicroscale (approximately 300 nm) holes or lines with variable dimensions. Individual rat embryonic hippocampal cells were positioned either between two juxtaposing topographies or at the borders of individual topographies juxtaposing unpatterned smooth surface, cultured for 24 hours, and analyzed with respect to axonal selection using conventional imaging techniques. RESULTS: Topography was found to influence axon formation and extension relative to smooth surface, and the distance of neurons relative to topography was found to impact whether the topography could serve as an effective cue. Neurons were also found to prefer submicroscale over microscale features and holes over lines for a given feature size. CONCLUSION: The results suggest that implementing physical cues of various shapes and sizes on nerve guidance conduits and other advanced biomaterial scaffolds could help stimulate axon regeneration. PMID- 21289982 TI - Novel peptide-dendrimer conjugates as drug carriers for targeting nonsmall cell lung cancer. AB - Phage display technology has been demonstrated to be a powerful tool for screening useful ligands that are capable of specifically binding to biomarkers on the surface of tumor cells. The ligands found by this technique, such as peptides, have been successfully applied in the fields of early cancer diagnostics and chemotherapy. In this study, a novel nonsmall cell lung cancer targeting peptide (LCTP, sequence RCPLSHSLICY) was screened in vivo using a Ph.D. C7C(TM) phage display library. In order to develop a universal tumor-targeting drug carrier, the LCTP and fluorescence-labeled molecule (FITC) were conjugated to an acetylated polyamidoamine (PAMAM) dendrimer of generation 4 (G4) to form a PAMAM-Ac-FITC-LCTP conjugate. The performance of the conjugate was first tested in vitro. In vitro results of cell experiments analyzed by flow cytometry and inverted fluorescence microscopy indicated that PAMAM-Ac-FITC-LCTP was enriched more in NCI-H460 cells than in 293T cells, and cellular uptake was both time- and dose-dependent. The tissue distribution of the conjugate in athymic mice with lung cancer xenografts was also investigated to test the targeting efficiency of PAMAM-Ac-FITC-LCTP in vivo. The results showed that LCTP can effectively facilitate the targeting of PAMAM-Ac-FITC-LCTP to nonsmall cell lung cancer cells and tumors. These results suggest that the LCTP-conjugated PAMAM dendrimer might be a promising drug carrier for targeted cancer diagnosis and treatment. PMID- 21289983 TI - Preparation of silver nanoparticles in virgin coconut oil using laser ablation. AB - Laser ablation of a silver plate immersed in virgin coconut oil was carried out for fabrication of silver nanoparticles. A Nd:YAG laser at wavelengths of 1064 nm was used for ablation of the plate at different times. The virgin coconut oil allowed formation of nanoparticles with well-dispersed, uniform particle diameters that were stable for a reasonable length of time. The particle sizes and volume fraction of nanoparticles inside the solutions obtained at 15, 30, 45 min ablation times were 4.84, 5.18, 6.33 nm and 1.0 * 10(-8), 1.6 * 10(-8), 2.4 * 10(-8), respectively. The presented method for preparation of silver nanoparticles in virgin coconut oil is environmentally friendly and may be considered a green method. PMID- 21289984 TI - Improved antigen cross-presentation by polyethyleneimine-based nanoparticles. AB - PURPOSE: In the development of therapeutic vaccines against cancer, it is important to design strategies for antigen cross-presentation to stimulate cell mediated immune responses against tumor antigens. METHODS: We developed a polyethyleneimine (PEI)-based protein antigen delivery system to promote cross presentation through the major histocompatibility complex (MHC) I pathway using ovalbumin (OVA) as a model antigen. PEIs formed nanoparticles with OVA by electrostatic interactions, as demonstrated by electrophoresis analysis, scanning electron microscopy, and photon correlation spectroscopy analysis. RESULTS: The nanoparticles were used to stimulate mouse bone marrow-derived dendritic cells in vitro and resulted in significantly more OVA(257-264)/MHC I complex presentation on dendritic cell surfaces. The activated dendritic cells interacted specifically with RF33.70 to stimulate interleukin-2 secretion. The cross-presentation promoting effect was more prominent in dendritic cells that had been cultured for longer periods of time (13 days). Further studies comparing the antigen presentation efficacies by other polyanionic agents, such as PLL or lysosomotropic agents, suggested that the unique "proton sponge effect" of PEI facilitated antigen escape from the endosome toward the MHC I pathway. CONCLUSION: Such a PEI-based nanoparticle system may have the potential to be developed into an effective therapeutic vaccine delivery system. PMID- 21289985 TI - Novel free paclitaxel-loaded poly(L-gamma-glutamylglutamine)-paclitaxel nanoparticles. AB - The purpose of this study was to develop a novel formulation of paclitaxel (PTX) that would improve its therapeutic index. Here, we combined a concept of polymer PTX drug conjugate with a concept of polymeric micelle drug delivery to form novel free PTX-loaded poly(L-gamma-glutamylglutamine) (PGG)-PTX conjugate nanoparticles. The significance of this drug formulation emphasizes the simplicity, novelty, and flexibility of the method of forming nanoparticles that contain free PTX and conjugated PTX in the same drug delivery system. The results of effectively inhibiting tumor growth in mouse models demonstrated the feasibility of the nanoparticle formulation. The versatility and potential of this dual PTX drug delivery system can be explored with different drugs for different indications. Novel and simple formulations of PTX-loaded PGG-PTX nanoparticles could have important implications in translational medicines. PMID- 21289986 TI - Polyurethane/fluor-hydroxyapatite nanocomposite scaffolds for bone tissue engineering. Part I: morphological, physical, and mechanical characterization. AB - In this study, new nano-fluor-hydroxyapatite (nFHA)/polyurethane composite scaffolds were fabricated for potential use in bone tissue engineering. Polyester urethane samples were synthesized from polycaprolactone, hexamethylene diisocyanate, and 1,4-butanediol as chain extender. Nano fluor-hydroxyapatite (nFHA) was successfully synthesized by sol-gel method. The solid-liquid phase separation and solvent sublimation methods were used for preparation of the porous composites. Mechanical properties, chemical structure, and morphological characteristics of the samples were investigated by compressive test, Fourier transform infrared, and scanning electron microscopy (SEM) techniques, respectively. The effect of nFHA powder content on porosity and pore morphology was investigated. SEM images demonstrated that the scaffolds were constituted of interconnected and homogeneously distributed pores. The pore size of the scaffolds was in the range 50-250 MUm. The result obtained in this research revealed that the porosity and pore average size decreased and compressive modulus increased with nFHA percentage. Considering morphological, physical, and mechanical properties, the scaffold with a higher ratio of nFHA has suitable potential use in tissue regeneration. PMID- 21289987 TI - Self-assembled rosette nanotubes for incorporating hydrophobic drugs in physiological environments. AB - Rosette nanotubes (RNTs) are novel, biomimetic, injectable, self-assembled nanomaterials. In previous studies, materials coated with RNTs have significantly increased cell growth (eg, osteoblasts, chondrocytes, and endothelial cells) due to the favorable cellular environment created by RNTs. It has also been suggested that the tubular RNT structures formed by base stacking and hydrophobic interactions can be used for drug delivery, and this possibility has not been studied to date. Here we investigated methods to load and deliver tamoxifen (TAM, a hydrophobic anticancer drug) using two different types of RNTs: single- base RNTs and twin-base RNTs. Drug-loaded RNTs were characterized by nuclear magnetic resonance spectroscopy, diffusion-ordered nuclear magnetic resonance spectroscopy (DOSY NMR), and ultraviolet-visible (UV-Vis) spectroscopy at different ratios of twin-base RNTs to TAM. The results demonstrated successful incorporation of hydrophobic TAM into RNTs. Importantly, because of the hydrophilicity of the outer surface of the RNTs, TAM-loaded RNTs were dissolved in water, and thus have great potential to deliver hydrophobic drugs in various physiological environments. The results also showed that twin-base RNTs further improved TAM loading. Therefore, this study demonstrated that hydrophobic pharmaceutical agents (such as TAM), once considered hard to deliver, can be easily incorporated into RNTs for anticancer treatment purposes. PMID- 21289988 TI - Association between dental pulp stones and calcifying nanoparticles. AB - The etiology of dental pulp stones, one type of extraskeletal calcification disease, remains elusive to date. Calcifying nanoparticles (CNPs), formerly referred to as nanobacteria, were reported to be one etiological factor in a number of extraskeletal calcification diseases. We hypothesized that CNPs are involved in the calcification of the dental pulp tissue, and therefore investigated the link between CNPs and dental pulp stones. Sixty-five freshly collected dental pulp stones, each from a different patient, were analyzed. Thirteen of the pulp stones were examined for the existence of CNPs in situ by immunohistochemical staining (IHS), indirect immunofluorescence staining (IIFS), and transmission electron microscope (TEM). The remaining 52 pulp stones were used for isolation and cultivation of CNPs; the cultured CNPs were identified and confirmed via their shape and growth characteristics. Among the dental pulp stones examined in situ, 84.6% of the tissue samples staines positive for CNPs antigen by IHS; the corresponding rate by IIFS was 92.3 %. In 88.2% of the cultured samples, CNPs were isolated and cultivated successfully. The CNPs were visible under TEM as 200-400 nm diameter spherical particles surrounded by a compact crust. CNPs could be detected and isolated from a high percentage of dental pulp stones, suggesting that CNPs might play an important role in the calcification of dental pulp. PMID- 21289989 TI - Thiolated chitosan nanoparticles for enhancing oral absorption of docetaxel: preparation, in vitro and ex vivo evaluation. AB - The aim of this study was to prepare and evaluate mucoadhesive core-shell nanoparticles based on copolymerization of thiolated chitosan coated on poly methyl methacrylate cores as a carrier for oral delivery of docetaxel. Docetaxel loaded nanoparticles with various concentrations were prepared via a radical emulsion polymerization method using cerium ammonium nitrate as an initiator. The physicochemical properties of the obtained nanoparticles were characterized by: dynamic light-scattering analysis for their mean size, size distribution, and zeta potential; scanning electron microscopy and transmission electron microscopy for surface morphology; and differential scanning calorimetry analysis for confirmation of molecular dispersity of docetaxel in the nanoparticles. Nanoparticles were spherical with mean diameter below 200 nm, polydispersity of below 0.15, and positive zeta potential values. The entrapment efficiency of the nanoparticles was approximately 90%. In vitro release studies showed a sustained release characteristic for 10 days after a burst release at the beginning. Ex vivo studies showed a significant increase in the transportation of docetaxel from intestinal membrane of rat when formulated as nanoparticles. Cellular uptake of nanoparticles was investigated using fluoresceinamine-loaded nanoparticles. Docetaxel nanoparticles showed a high cytotoxicity effect in the Caco-2 and MCF-7 cell lines after 72 hours. It can be concluded that by combining the advantages of both thiolated polymers and colloidal particles, these nanoparticles can be proposed as a drug carrier system for mucosal delivery of hydrophobic drugs. PMID- 21289990 TI - Enhanced laser thermal ablation for the in vitro treatment of liver cancer by specific delivery of multiwalled carbon nanotubes functionalized with human serum albumin. AB - The main goal of this investigation was to develop and test a new method of treatment for human hepatocellular carcinoma (HCC). We present a method of carbon nanotube-enhanced laser thermal ablation of HepG2 cells (human hepatocellular liver carcinoma cell line) based on a simple multiwalled carbon nanotube (MWCNT) carrier system, such as human serum albumin (HSA), and demonstrate its selective therapeutic efficacy compared with normal hepatocyte cells. Both HepG2 cells and hepatocytes were treated with HSA-MWCNTs at various concentrations and at various incubation times and further irradiated using a 2 W, 808 nm laser beam. Transmission electron, phase contrast, and confocal microscopy combined with immunochemical staining were used to demonstrate the selective internalization of HSA-MWCNTs via Gp60 receptors and the caveolin-mediated endocytosis inside HepG2 cells. The postirradiation apoptotic rate of HepG2 cells treated with HSA-MWCNTs ranged from 88.24% (for 50 mg/L) at 60 sec to 92.34% (for 50 mg/L) at 30 min. Significantly lower necrotic rates were obtained when human hepatocytes were treated with HSA-MWCNTs in a similar manner. Our results clearly show that HSA MWCNTs selectively attach on the albondin (aka Gp60) receptor located on the HepG2 membrane, followed by an uptake through a caveolin-dependent endocytosis process. These unique results may represent a major step in liver cancer treatment using nanolocalized thermal ablation by laser heating. PMID- 21289991 TI - The protective effects of cerium oxide nanoparticles against hepatic oxidative damage induced by monocrotaline. AB - OBJECTIVE: The objective of the present study was to determine the ability of cerium oxide (CeO(2)) nanoparticles to protect against monocrotaline (MCT) induced hepatotoxicity in a rat model. METHOD: Twenty male Sprague Dawley rats were arbitrarily assigned to four groups: control (received saline), CeO(2) (given 0.0001 nmol/kg intraperitoneally [IP]), MCT (given 10 mg/kg body weight IP as a single dose), and MCT + CeO(2) (received CeO(2) both before and after MCT). Electron microscopic imaging of the rat livers was carried out, and hepatic total glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GPX), glutathione S-transferase (GST), superoxide dismutase (SOD), and catalase (CAT) enzymatic activities were quantified. RESULTS: Results showed a significant MCT induced decrease in total hepatic GSH, GPX, GR, and GST normalized to control values with concurrent CeO(2) administration. In addition, MCT produced significant increases in hepatic CAT and SOD activities, which also ameliorated with CeO(2). CONCLUSIONS: These results indicate that CeO(2) acts as a putative novel and effective hepatoprotective agent against MCT-induced hepatotoxicity. PMID- 21289992 TI - Mental strain among staff at medical rehabilitation clinics in Germany. AB - OBJECTIVES: The aim of the study is to compare the frequency of mental strain effects on employees in somatic and psychosomatic rehabilitation clinics as well as between the different occupational groups. Associations between mental strain effects and working conditions, cooperation in the team and employee satisfaction are also investigated. METHODS: The present study is cross-sectional with a descriptive-explorative design. It is composed of a survey with standardized questionnaires (Human Service Workload, Questionnaire on Teamwork and Questionnaire on Staff Satisfaction in Medical Rehabilitation) and global items, and was conducted among all employees of twelve rehabilitation teams (five somatic and seven psychosomatic rehabilitation clinics (n=549)). The response rate of the survey averaged 45% (n=252). RESULTS: One in four participants reported being emotionally exhausted. There were significantly more emotionally exhausted employees working in the psychosomatic (31%) than in the somatic rehabilitation clinics (16%) (X(2)=7.403, df=1, p<0.05), with physicians most frequently reporting emotional exhaustion (45%). The negative appraisal of mental strain effects is accompanied by negative values for cooperation in the team and employee satisfaction (r=-.38 to r=-.50, p<.001). There were mostly high correlations (r=-.503 to r=-.609) between the working conditions and the mental strain effects (emotional exhaustion, intrinsic motivation, dissatisfaction). CONCLUSIONS: The results clearly show that the employees in medical rehabilitation clinics have a high stress level at work, a situation which is also known in other health care organizations. Observations of strong associations between cooperation in the team and strain effects confirm the positive impact of social support in the daily work routine. Correlation between the subjective appraisal of working conditions and the impact of strain is mostly high. It can be assumed that the strain effects can be influenced positively with supportive team and human resource development (person-related interventions) and interventions that enhance working conditions (condition-related interventions). PMID- 21289994 TI - Polyacrylate adsorbents for the selective adsorption of cholesterol-rich lipoproteins from plasma or blood. AB - Polyacrylate (PAA) adsorbents selectively bind low density lipoproteins (LDL) from human plasma and blood, whereas very low density lipoproteins (VLDL) are only minimally adsorbed. The adsorption of cholesterol-rich lipoproteins to PAA adsorbents is related to the molecular weight (mw) of the polyanion ligand. Ca(++) and Mg(++) inhibit the binding of LDL to PAA adsorbents. The chemical composition of the organic hardgels of the adsorbents does not have an influence on adsorption. The selective adsorption of LDL to PAA adsorbents can be explained to result from their low negative surface charge density and the specific colloid chemical properties of the surface-bound PAA, which do not prevent LDL from binding to charge-like domains of the ligand. By contrast, VLDL and high density lipoproteins (HDL) are repelled from the adsorbents due to their higher negative surface charge density. PMID- 21289995 TI - Treatment of heart failure at home. AB - AIM: An alternative for treatment and control of patients aged 80 years and more suffering from heart failure. INTRODUCTION: It is known that a substantial proportion the elderly suffer from heart failure. Patients of advanced age do prefer to be treated at home. They find it a burden to go the hospital and being examined. At the same time it is known that treatment for heart failure in this advanced age is more difficult and less evidence-based as in younger years. PRACTICE: A nurse practitioner working for the family practice examined and controlled 63 elderly over 80 at home by visiting them and controlling them with a limited number of examinations. We saw them every three months and controlled weight, blood pressure, condition, shortness of breath, edema of the ankles, enlargement of the liver, BNP, Hb, Creatinine. If necessary we controlled diet, and changed medication. RESULTS: It was able to stabilize the condition and to prevent hospital admission. The quality of life was improved, the satisfaction of the patients much better and the mortality of heart failure minimized. In this way we were able to give an alternative to hospital heart failure policlinics for a group of elderly, who are not easy movable any more. PMID- 21289996 TI - Consensus group sessions: a useful method to reconcile stakeholders' perspectives about network performance evaluation. AB - BACKGROUND: Having a common vision among network stakeholders is an important ingredient to developing a performance evaluation process. Consensus methods may be a viable means to reconcile the perceptions of different stakeholders about the dimensions to include in a performance evaluation framework. OBJECTIVES: To determine whether individual organizations within traumatic brain injury (TBI) networks differ in perceptions about the importance of performance dimensions for the evaluation of TBI networks and to explore the extent to which group consensus sessions could reconcile these perceptions. METHODS: We used TRIAGE, a consensus technique that combines an individual and a group data collection phase to explore the perceptions of network stakeholders and to reach a consensus within structured group discussions. RESULTS: One hundred and thirty-nine professionals from 43 organizations within eight TBI networks participated in the individual data collection; 62 professionals from these same organisations contributed to the group data collection. The extent of consensus based on questionnaire results (e.g. individual data collection) was low, however, 100% agreement was obtained for each network during the consensus group sessions. The median importance scores and mean ranks attributed to the dimensions by individuals compared to groups did not differ greatly. Group discussions were found useful in understanding the reasons motivating the scoring, for resolving differences among participants, and for harmonizing their values. CONCLUSION: Group discussions, as part of a consensus technique, appear to be a useful process to reconcile diverging perceptions of network performance among stakeholders. PMID- 21289997 TI - Types of treatment collaboration between conventional and alternative practitioners-results from a research project at a Danish MS hospital. AB - INTRODUCTION: More than 50% of People with Multiple Sclerosis (PwMS) in Denmark use alternative treatment. Most of them combine alternative and conventional treatment, but PwMS often find that they engage in parallel courses of treatment between which there is no dialogue, coordination or synergy. For this reason the Danish Multiple Sclerosis Society conducted a research project to develop and examine different models for collaboration between conventional and alternative treatment providers. METHODS: The empirical material consisted of 10 individual interviews with practitioners, a group interview with practitioners, a group interview with professional staff at the Danish Multiple Sclerosis hospital that provided the organisational framework for the project, interviews with 59 patients and written responses from participating treatment providers in connection with 29 practitioner-researcher seminars held during the period 2004 2010. RESULTS: Collaboration between researchers and the treatment team resulted in the development and examination of several models which describe the strengths and weaknesses of various types of collaboration. The models show that the various types of collaboration place different requirements on the degree of 1) mutual acknowledgement and understanding among practitioners and 2) flexibility and resources in the organizational framework. The analyses also point to the fact that the degree of patient activity must be considered in relation to a given type of collaboration. DISCUSSION: The relationship between integration and pluralism can contribute to a fruitful discussion in regards to the value of treatment collaboration. In addition to the many positive perspectives that characterise integration of different treatment modalities the project points to the importance of not overlooking the opportunities, values and potential inherent in a pluralistic ideal in the form of patients' own active efforts and the dynamism that can arise when the patient becomes a co-informant, co coordinator and/or co-integrator. PMID- 21289998 TI - It's good to talk: social network analysis as a method for judging the strength of integrated care. PMID- 21289999 TI - Mental health network governance: comparative analysis across Canadian regions. AB - OBJECTIVE: Modes of governance were compared in ten local mental health networks in diverse contexts (rural/urban and regionalized/non-regionalized) to clarify the governance processes that foster inter-organizational collaboration and the conditions that support them. METHODS: Case studies of ten local mental health networks were developed using qualitative methods of document review, semi structured interviews and focus groups that incorporated provincial policy, network and organizational levels of analysis. RESULTS: Mental health networks adopted either a corporate structure, mutual adjustment or an alliance governance model. A corporate structure supported by regionalization offered the most direct means for local governance to attain inter-organizational collaboration. The likelihood that networks with an alliance model developed coordination processes depended on the presence of the following conditions: a moderate number of organizations, goal consensus and trust among the organizations, and network level competencies. In the small and mid-sized urban networks where these conditions were met their alliance realized the inter-organizational collaboration sought. In the large urban and rural networks where these conditions were not met, externally brokered forms of network governance were required to support alliance based models. DISCUSSION: In metropolitan and rural networks with such shared forms of network governance as an alliance or voluntary mutual adjustment, external mediation by a regional or provincial authority was an important lever to foster inter-organizational collaboration. PMID- 21290000 TI - The organisation of interagency training to safeguard children in England: a case study using realistic evaluation. AB - BACKGROUND: Joint training for interagency working is carried out by Local Safeguarding Children Boards in England to promote effective local working to safeguard and promote the welfare of children. PURPOSE: This paper reports on the findings of the outputs and outcomes of interagency training to safeguard children in eight Local Safeguarding Children Boards. METHODS: A review of Local Safeguarding Children Board documentation, observations of Local Safeguarding Children Board training sub-group meetings and a series of interviews with training key stakeholders in each Local Safeguarding Children Board were used to assess how partner agencies in the Local Safeguarding Children Boards carried out their statutory responsibilities to organise interagency training. 'Realistic Evaluation' was used to evaluate the mechanisms by which a central government mandate produced particular inter-agency training outputs (number of courses, training days) and joint working outcomes (effective partnerships), within particular Local Safeguarding Children Board contexts. RESULTS: The 'mandated partnership' imposed on Local Safeguarding Children Boards by central government left little choice but for partner agencies to work together to deliver joint training, which in turn affected the dynamics of working partnerships across the various sites. The effectiveness of the training sub group determined the success of the organisation and delivery of training for joint working. Despite having a central mandate, Local Safeguarding Children Boards had heterogeneous funding and training arrangements. These resulted in significant variations in the outputs in terms of the number of courses per 'children in need' in the locality and in the cost per course. CONCLUSIONS: Interagency training which takes account of the context of the Local Safeguarding Children Board is more likely to produce better trained staff, effective partnership working, and lead to better integrated safeguarding children services. PMID- 21290001 TI - Integrating care for people with depression: developments in the Netherlands. AB - INTRODUCTION: In this article we describe the history and present state of integrated care for people with depression in the Netherlands. The central question is: what are the developments in integrated care for people with depression in the Netherlands? METHODS: WE DESCRIBE THESE DEVELOPMENTS FROM THE ROLE OF AN OBSERVER, AND MAKE USE OF SEVERAL SOURCES: important Dutch policy documents and research documents, our own national survey carried out in 2007, a number of reports and project descriptions and searches in PubMed and Google. Also key people were contacted to supply additional information. RESULTS: In the Netherlands two separate phases can be distinguished within integrated care for people with depression. From the beginning of the 1990s, specialized secondary Mental Health Care (MHC) began to develop care programmes, including programmes for people with depression. The implementation of these care programmes has taken years. Mass usage of care programmes only went ahead once the large-scale mergers between ambulatory and clinical MHC organizations around 2000 had taken effect. An analysis of these programmes shows, that they did not lead to integration with primary care. This changed in the second phase from around 2000. Then attention was directed more towards strengthening the GP within the treatment of depression, collaboration between primary and specialized care and the development of collective integrated care packages. DISCUSSION: We relate these developments to projects in other countries and discuss the scientific basis by using evidence of international literature reviews and metastudies. Some general recommendations are given about functional costing, the physical presence of MHC specialists in the primary care sector and the use of a common national standard for both primary care and specialized MHC. PMID- 21290002 TI - Integrated care as a scientific discipline: the need for more theory and new analytical methods. PMID- 21290003 TI - Ladies and gentlemen! PMID- 21290005 TI - Patient factors influencing the effect of surgeon-performed ultrasound on the acute abdomen. AB - PURPOSE: To evaluate the effect of surgeon-performed ultrasound on acute abdomen in specific patient subgroups regarding the diagnostic accuracy and further management. METHODS: Eight hundred patients attending the emergency department at Stockholm South General Hospital, Sweden, for abdominal pain, were randomized to either receive or not receive surgeon-performed ultrasound as a complement to routine management. Patients were divided into subgroups based on patient characteristics, symptoms or first preliminary diagnosis set at the emergency department before randomization. Outcomes measured were diagnostic accuracy, admission rate and requests for further examinations. Timing of surgery was evaluated for patients with peritonitis. RESULTS: Increased diagnostic accuracy was seen in patients with body mass index > 25, elevated C-reactive protein, peritonitis, age 30-59 years and/or upper abdominal pain. Decreased need for further examinations and/or fewer admissions were seen in all groups except in patients with a preliminary diagnosis of appendicitis. Among patients with non specific abdominal pain, admission frequency was decreased with 14% when ultrasound was used (P = 0.007). Among patients with peritonitis, requiring surgery, 61% in the ultrasound group were admitted for surgery directly from the emergency department compared to 19% in the control group. CONCLUSION: In different ways, surgeon-performed ultrasound is helpful for the majority of patients admitted to the emergency department for abdominal pain. Taking into account other shown benefits and the lack of adverse effects, we find the method worth consideration for routine implementation. PMID- 21290004 TI - Cladistic analysis of olfactory and vomeronasal systems. AB - Most tetrapods possess two nasal organs for detecting chemicals in their environment, which are the sensory detectors of the olfactory and vomeronasal systems. The seventies' view that the olfactory system was only devoted to sense volatiles, whereas the vomeronasal system was exclusively specialized for pheromone detection was challenged by accumulating data showing deep anatomical and functional interrelationships between both systems. In addition, the assumption that the vomeronasal system appeared as an adaptation to terrestrial life is being questioned as well. The aim of the present work is to use a comparative strategy to gain insight in our understanding of the evolution of chemical "cortex." We have analyzed the organization of the olfactory and vomeronasal cortices of reptiles, marsupials, and placental mammals and we have compared our findings with data from other taxa in order to better understand the evolutionary history of the nasal sensory systems in vertebrates. The olfactory and vomeronsasal cortices have been re-investigated in garter snakes (Thamnophis sirtalis), short-tailed opossums (Monodelphis domestica), and rats (Rattus norvegicus) by tracing the efferents of the main and accessory olfactory bulbs using injections of neuroanatomical anterograde tracers (dextran-amines). In snakes, the medial olfactory tract is quite evident, whereas the main vomeronasal recipient structure, the nucleus sphaericus is a folded cortical-like structure, located at the caudal edge of the amygdala. In marsupials, which are acallosal mammals, the rhinal fissure is relatively dorsal and the olfactory and vomeronasal cortices relatively expanded. Placental mammals, like marsupials, show partially overlapping olfactory and vomeronasal projections in the rostral basal telencephalon. These data raise the interesting question of how the telencephalon has been re-organized in different groups according to the biological relevance of chemical senses. PMID- 21290006 TI - How to pitch the "perfect game". PMID- 21290007 TI - Dermabond efficacy in total joint arthroplasty wounds. AB - The goals of wound closure are a low infection rate and timely healing. Total joint arthroplasty (TJA) requires mobile recovery, and, therefore, a high-tension wound care environment. We conducted a study to compare the efficacy of high viscosity Dermabond (Ethicon, Somerville, New Jersey) and the efficacy of surgical staples in healing high-tension, mobile surgical sites of TJA. Of 236 total knee arthroplasties and 223 total hip arthroplasties (459 surgeries total), 250 were performed with Dermabond and 209 with staples. According to chi2 analysis, case and control infection rates were equivalent. Signs of acute inflammation (redness, drainage, dehiscence) also were statistically equivalent. Absence of staples accounted for a significant decrease in tape blisters and skin abscesses. Dermabond is superior to staples in high-tension wound care. PMID- 21290008 TI - Minimally invasive total knee arthroplasty: pitfalls and complications. AB - Despite reports of complications, there has been tremendous interest in using minimally invasive surgery (MIS) for total knee arthroplasty (TKA). Over the past 10 years, we have used an MIS approach for all TKAs. In the study described here, we examined the complications of the first 1000 of these TKAs. These cases involved a minimal incision (mean, 10 cm), a quadriceps muscle-sparing approach, and a non-patellar-everting technique. The complications assessed included manipulations, reoperations, and component revisions. We also analyzed for deviations in radiographic alignment or radiographic failures. There were 45 clinical complications-25 manipulations under anesthesia, 12 arthroscopic procedures for painful patellofemoral crepitus (mostly for an initially nonvisualized retained lateral band), and 8 operative explorations for various component problems. Radiographically, there were 3 impending component failures-2 tibial and 1 femoral. Excluding manipulations, there was a significant decrease in operative complication rate from the first 200 cases (6.0%) to the next 800 cases (1.0%), with overall complication rates similar to those of a control cohort treated with traditional surgical techniques. From this analysis, the major concern was potential tibial component loosening, which may be related to decreased exposure and possibly poor cement pressurization. Despite the low complication rate, this study yielded insights into further potential improvements in using this MIS technique for TKAs. PMID- 21290009 TI - Patellofemoral arthroplasty versus total knee arthroplasty in patients with isolated patellofemoral osteoarthritis. AB - We identified all patients at our institution who underwent patellofemoral arthroplasty (PFA) or total knee arthroplasty (TKA) as treatment for isolated patellofemoral arthritis (PA) between January 2003 and December 2005. Twenty three PFA and 22 TKA patients met inclusion criteria. Mean age was 60 years and 69 years, respectively (P = .01). Mean follow-up was 29 months (range, 24 to 49 months) in the PFA group and 27 months (range, 24 to 33 months) in the TKA group. Mean postoperative Knee Society Clinical Rating System scores were 89 and 90 in the PFA and TKA cohorts, respectively. Mean UCLA scores were 6.6 and 4.2, respectively (P<.0001). Mean blood loss (P = .03) and hospital stay (P = .001) were significantly lower among PFA patients. Linear regression analysis showed that blood loss, hospital stay, and functional outcomes were not affected by age as an independent variable. No significant complications occurred in the PFA group. There was one deep vein thrombosis in the TKA group. We conclude that PFA yields clinical outcomes comparable to that of TKA as treatment for isolated PA and may be a less invasive option for this select subgroup of patients. PMID- 21290010 TI - Perioperative bridging anticoagulation therapy in at-risk patients undergoing elective arthroplasty surgery. AB - We investigated the efficacy and safety of a standardized periprocedural anticoagulation bridging regimen that was instituted for patients who were on long-term oral anticoagulation therapy and were admitted for elective lower limb arthroplasty. Over a 3-month period, from March to June 2007, 15 inpatients who required temporary interruption of oral anticoagulation therapy in order to undergo elective orthopedic surgery were included in the study. All patients had bridging anticoagulation therapy instituted as per a standardized hospital protocol adapted from a British Orthopaedic Association publication. Patients were followed up prospectively during their inpatient stay. One operation was canceled, and 1 operating theatre list was rescheduled to delay a procedure because of nonadherence to the protocol. There were 2 cases of excessive surgical wound bruising, which caused additional morbidity and delayed discharge. One patient died from a cause unrelated to anticoagulation. Lack of proper knowledge of the bridging therapy protocol and improper communication between the medication prescribing and dispensing staff were the most important areas of concern. Given our study results, we believe that patient information and staff education are the key elements in successful implementation of a perioperative bridging anticoagulation protocol in elective arthroplasty. PMID- 21290011 TI - Surface roughness of femoral head prostheses after dislocation. AB - The effects of damaged femoral heads on long-term wear in total hip arthroplasties are not well known. In the study reported here, we compared the surface roughness of dislocated femoral heads, retrieved at time of revision, with that of heads revised for reasons other than dislocation. The dislocated heads, including 6 cobalt-chrome (Co-Cr), 2 oxidized zirconium, and 2 alumina (ceramic) heads, were compared with nondislocated Co-Cr and ceramic heads. Scratch marks on the dislocated Co-Cr and alumina heads were considerably smaller and shallow than those on the dislocated oxidized zirconium heads. Mean surface roughness of the dislocated heads was 368 nm (Co-Cr), 376 nm (alumina), and 2137 nm (oxidized zirconium). On the contrary, the mean surface roughness for nondislocated Co-Cr and alumina heads was 307.44 nm (outlier excluded) and 138.8 nm, respectively. Our data suggest that increased surface damage and roughness can occur after dislocation. PMID- 21290012 TI - "Peel the onion" to avoid common mistakes with a hospital's offer of an electronic medical records system. PMID- 21290013 TI - Clinical results of a modular neck hip system: hitting the "bull's-eye" more accurately. AB - In this article, we present 2-year clinical results of a modular neck tapered hip stem, based on 634 patients from a 2-center study. Nearly half of the patients in this series required use of a head center location offered by the modular neck stem but not available in a nonmodular stem with an identical body. The modular neck enabled femoral-first preparation, which facilitates establishing the desired total version of the reconstruction. No fractures of a stem or modular neck occurred, and there were no dissociations of the head-neck junction. There were no complications or revisions related to the femoral implant. Optimal leg length, femoral offset, and total version are goals in hip arthroplasty. Neck modularity improves the ability to re-create the head center to achieve these goals and to hit the "bull's-eye" in total hip arthroplasty. PMID- 21290014 TI - A modular hip system for simplification of revision hip arthroplasty. AB - Revision femoral arthroplasty can be a daunting task. Historical success with a host of different reconstructive options has previously been reported. The Zimmer Modular Revision (ZMR(r)) system provides a complete armamentarium for the revision setting. For lesser femoral defects, the modular ZMR system can be used to create a custom preassembled implant. For more difficult situations, the implant can be sequentially assembled in vivo. The ZMR system can thus separate the tasks of revision femoral surgery so that the surgeon does not have to manage all issues at once. Fixation, length, offset, and implant version can all be handled independently to allow a safe, easy, and reproducible reconstruction in all settings. PMID- 21290015 TI - Use of the Fitmore(r) hip stem bone-preserving system for the minimally invasive anterior-supine approach in hip replacement. AB - Total hip arthroplasty through a single-incision anterior approach is a minimally invasive surgical (MIS) technique that allows component placement without violation of the posterior hip capsule or "hip deltoid." This allows faster recovery without dislocation precautions. The Fitmore(r) hip stem (Zimmer, Warsaw, Ind) is a bone-conserving stem designed for use in MIS techniques. The technique described here is a single-incision anterior approach with the Fitmore system using a special orthopedic table. PMID- 21290016 TI - Extensive tumoral calcinosis in a patient with systemic sclerosis. AB - Tumoral calcinosis, a rare disease manifesting with periarticular, calcified masses in soft tissues, can be either primary or secondary to a disease, such as systemic sclerosis. In the case reported here, a patient diagnosed with systemic sclerosis presented with hard calcified masses that involved the shoulders and hips. PMID- 21290017 TI - Familial tumoral calcinosis. PMID- 21290018 TI - How outcomes can affect cost: the importance of defining patient- relevant and proxy outcome measurements. PMID- 21290019 TI - Technique of reduction and fixation of unicondylar medial Hoffa fracture. AB - Coronal fractures of the medial femoral condyle (Hoffa fractures) are rare. Articular surface communication is common, and reduction can be difficult. For this injury, an extensile medial subvastus approach can be used to obtain adequate visualization, accurate reduction, and fixation. A case series of these injuries and this treatment method supports this management strategy. PMID- 21290020 TI - Evaluation of reliability of the Mason classification for radial head fractures. AB - In the study reported here, we sought to determine the interobserver reliability and the intraobserver reproductibility of the Mason classification. We also evaluated the effect of having an external rotation oblique view on agreement in radiographic readings. Four readers reviewed 50 radial head fracture radiographs approximately 2 months apart. Half the radiographs had an anteroposterior view and a lateral view; the other half had an additional external rotation oblique view. There was a trend toward improved interobserver agreement in the 3-view radiographs. Three of the 4 readers demonstrated substantial intraobserver reproducibility, which was noted to be higher when 3 views were available. PMID- 21290021 TI - Inferior vena cava filter placement in orthopedic surgery. AB - Inferior vena cava (IVC) filters were developed for the treatment of venous thromboembolism but in high-risk patients are often used for prophylaxis instead. In the study reported here, we reviewed all the orthopedic surgery cases in which IVC filters were used at our institution in 2005. Charts were analyzed and patients contacted by telephone for long-term follow-up. IVC filters were used in 90 (0.96%) of the 9,348 inpatient orthopedic surgeries. Sixty-one percent of filters were placed for prophylaxis, though only 42% of patients with prophylactic filters had a contraindication to anticoagulation. Eighty-one percent of patients with prophylactic filters who received anticoagulation received warfarin. Ratios of prophylactic-to-treatment filters were 3.25 for fracture surgeries, 2.1 for arthroplasties, and 0.89 for spine surgeries. Five percent of patients with prophylactic filters developed deep vein thrombosis. Fifty-two percent of filters were retrievable, but only 40% of those were removed a mean of 5.1 months (SD, 3.9 months) after placement. Filter removal was associated with complications in 11% of patients, and in another 10% the filter could not be removed. Forty-one patients were contacted a mean of 21 months (SD, 3 months) after filter placement. Only 32% of those who still had filters were on anticoagulation at follow-up. PMID- 21290022 TI - Distal humerus internal fixation: a biomechanical comparison of 90 degrees and parallel constructs. AB - The optimal plating configuration for open reduction and internal fixation of complex distal humerus fractures is controversial. We evaluated cyclic fatigue performance and biomechanical stiffness in a cadaveric model of distal humerus fractures: precontoured nonlocking parallel plates versus a 90 degrees nonlocking construct. A paired design was used, and 8 matched pairs of cadaveric arms were evaluated for bone density and plated. An osteotomy gap was created to simulate comminution, and constructs were randomized to anteroposterior, mediolateral, and torsional stiffness testing. Finally, 350 N was applied cyclically until deformation was permanent, Although there was a trend toward more stiffness of the parallel construct in anteroposterior, mediolateral, and torsional testing, it was not significant (P>.05). Likewise, there was no significant difference in number of cycles to failure (P>.05). Given these results, we suggest that it is reasonable to use a 90 degrees construct or a parallel construct for internal fixation of distal humerus fractures. However, our findings are consistent with a trend in the biomechanical literature supporting use of a parallel construct. PMID- 21290023 TI - Floating patella: combined quadriceps tendon, retinacula, and patellar tendon ruptures in a high-performance elite athlete. AB - Simultaneous quadriceps and patellar tendon rupture is rare. To our knowledge, we present the first known case of simultaneous quadriceps tendon, patella tendon, and retinacula rupture in the ipsilateral knee of a high-performance elite athlete. This disabling injury in the active person results in an inability to actively obtain and maintain full knee extension. When the tendons do not heal properly, at the correct length and tension, knee range of motion and strength can become significantly altered, leading to early fatigue, patellofemoral pain, and possibly instability, preventing return to preinjury status. Immediate surgical repair is recommended for optimal return of knee function and power. PMID- 21290024 TI - Management of elderly patients with hip fractures and cardiac rhythm devices. AB - The annual incidence of hip fractures in the United States is expected to double by the year 2050. An additional challenge is that comorbidities are common in elderly patients. As indications for implantation of cardiac rhythm devices continue to broaden, the number of elderly patients with a pacemaker or an implantable cardioverter-defibrillator seen in the orthopedic surgeon's practice is likely to increase. We review the unique properties and functions of the most commonly implanted cardiac rhythm devices, provide an algorithm to assist the surgeon in gathering important patient information and developing perioperative approaches to treatment, and detail potential intraoperative complications and their prevention. PMID- 21290025 TI - Overview of the GLOBAL Orthopaedic Registry (GLORY). PMID- 21290026 TI - Orthopaedic practice in total hip arthroplasty and total knee arthroplasty: results from the Global Orthopaedic Registry (GLORY). AB - The Global Orthopaedic Registry (GLORY) offers global and country-specific insights into the management of patients undergoing total hip arthroplasty and total knee arthroplasty by drawing on data, from June 2001 to December 2004, of 15,020 patients in 13 countries. GLORY achieved a 70% follow-up rate at 3 and/or 12 months, allowing longer-term findings to be reported. This paper reports data from GLORY on patient demographics, surgical approaches to patient management, selection of implants, anesthetic and analgesic practices, blood management, length of hospital stay, and patient disposition at discharge. Some aspects of orthopedic practice differ between countries. There was notable variation in the choice and selection of prosthesis, fixation of implants, length of hospital stay, and discharge disposition. PMID- 21290027 TI - Practice patterns in the use of venous thromboembolism prophylaxis after total joint arthroplasty--insights from the Multinational Global Orthopaedic Registry (GLORY). AB - The Global Orthopaedic Registry (GLORY) offers insights into multinational practice patterns of venous thromboembolism (VTE) prophylaxis in orthopedic surgery, based on data from 15,020 patients undergoing primary total knee arthroplasty or primary total hip arthroplasty from 2001 to 2004. Registry data show that the first choice for in-hospital VTE prophylaxis was low-molecular weight heparin. Multimodal prophylaxis was common. Warfarin was more widely used in the USA than elsewhere in the world. GLORY data suggest that real-world practice often fails to meet the standards for prophylaxis recommended in the American College of Chest Physicians evidence-based guidelines, particularly in the USA. However, many US orthopedic surgeons may follow other practice guidelines, causing an underestimation of prophylaxis us in this study. Warfarin in the USA often failed to achieve recommended target International Normalized Ratio (INR) values. This paper reviews the GLORY practice findings in light of the contemporary literature on best practices for VTE prophylaxis in orthopedic patients. PMID- 21290028 TI - Complications and functional outcomes after total hip arthroplasty and total knee arthroplasty: results from the Global Orthopaedic Registry (GLORY). AB - The Global Orthopaedic Registry (GLORY) has been designed to monitor a broad range of complications and outcomes that occur following total hip arthroplasty (THA) and total knee arthroplasty (TKA). GLORY provides global 'real-world' data, in contrast to the data generated by the controlled conditions of clinical trials. The results to date show an overall incidence of both in-hospital and post-discharge complications of approximately 7% in THA patients and 8% in TKA patients. The most common in-hospital complications in THA patients are fractures (0.6%) and deep-vein thrombosis (DVT) (0.6%), whereas in TKA patients DVT (1.4%) and cardiac events (0.8%) are most common. The most common post-discharge complications in both THA and TKA patients are reoperation due to bleeding, wound necrosis, wound infection, or other causes; and DVT. Bleeding complications were less common than other adverse events in both groups (in-hospital rates of 0.48% and 0.83%, respectively). Functional outcomes improved after surgery in both groups, as expected. Younger patients and patients who had been discharged directly to their homes seemed to have the greatest improvement in functional outcome after surgery. PMID- 21290029 TI - Lessons learned from the global orthopaedic registry: study design, current practice patterns, and future directions. PMID- 21290030 TI - Arthroscopic treatment of localized pigmented villonodular synovitis: long-term functional results. AB - Pigmented villonodular synovitis (PVNS) is a proliferative disorder that may lead to joint destruction and activity limitation. We conducted a retrospective study to determine the long-term results of localized PVNS (LPVNS) treated with arthroscopic excision, specifically with respect to postoperative activity level and symptom resolution. We reviewed the cases of 11 patients who had been treated with arthroscopic excision and partial synovectomy of LPVNS and been followed up for a mean of 112 months. Preoperative and postoperative Ogilvie-Harris scores, Tegner activity level scores, and UCLA activity level scores were calculated to determine disease-specific and general functional outcomes, respectively. We noted 2 cases in which posteromedial lesions recurred, moderate resolution of preoperative symptoms in most cases, and 2 cases in which the patient developed secondary osteoarthritis requiring surgical intervention. Arthroscopic excision of LPVNS can improve symptoms with a return to preoperative activity levels, but patients may develop secondary osteoarthritis after treatment, as noted in long term follow-up. PMID- 21290031 TI - Total hip and total knee arthroplasties: trends and disparities revisited. AB - Total joint arthroplasties are recognized as being effective in the treatment of joint disease and making a significant difference in patients' quality of life. Understanding the trends and disparities in use of these procedures is important for policy decisions. However, research on these issues has been limited because of the suboptimal samples used. To study trends and racial and economic disparities associated with total hip and total knee arthroplasties, we used a large national database, Nationwide Inpatient Sample, 1996-2005, which may be best suited for elucidating trends and disparities in treatment use. Primary and revision hip and knee arthroplasties were the primary outcomes. Rates of use were computed by count per 100,000 persons in the population. Logistic regression was used to examine the associations between disparity factors and each outcome, where regressors included age, sex, race, regional income, hospital characteristics, payer, comorbidities, and obesity. Between 1996 and 2005, primary arthroplasty rates have increased, but revision rates only minimally. Racial disparities were larger than income disparities. Our study also revealed that racial disparities were not confined to the elderly or to low-income populations. This may mean that there is an unmet need for these medical procedures among racial minorities. PMID- 21290033 TI - Controlled syntheses of cubic and hexagonal ZnIn2S4 nanostructures with different visible-light photocatalytic performance. AB - Cubic ZnIn(2)S(4) nanoparticles and hexagonal ZnIn(2)S(4) flower-like microspheres were controlled synthesized via a facile hydrothermal method by simply changing the metal precursors. The as-prepared samples were characterized by XRD, SEM, TEM and UV-vis DRS. It was found that the metal precursors influenced the final ZnIn(2)S(4) polymorphs, i.e., metal nitrates led to the formation of cubic ZnIn(2)S(4), while metal chlorides resulted in the formation of the hexagonal phase. The formation processes of the cubic ZnIn(2)S(4) nanoparticles and hexagonal ZnIn(2)S(4) flower-like microspheres were investigated and the mechanism of the phase formation was proposed. Although both cubic and hexagonal ZnIn(2)S(4) polymorphs exhibited photocatalytic activity for the degradation of methyl orange (MO) under visible light irradiation, the photocatalytic performances over cubic and hexagonal ZnIn(2)S(4) were different. PMID- 21290032 TI - Fluorescent DNA-based enzyme sensors. AB - Fluorescent sensors that make use of DNA structures have become widely useful in monitoring enzymatic activities. Early studies focused primarily on enzymes that naturally use DNA or RNA as the substrate. However, recent advances in molecular design have enabled the development of nucleic acid sensors for a wider range of functions, including enzymes that do not normally bind DNA or RNA. Nucleic acid sensors present some potential advantages over classical small-molecule sensors, including water solubility and ease of synthesis. An overview of the multiple strategies under recent development is presented in this critical review, and expected future developments in microarrays, single molecule analysis, and in vivo sensing are discussed (160 references). PMID- 21290034 TI - Emerging trends in metalloprotein inhibition. AB - Numerous metalloproteins are important therapeutic targets that are gaining increased attention in the medicinal and bioinorganic chemistry communities. This Perspective article describes some emerging trends and recent findings in the area of metalloprotein inhibitor discovery and development. In particular, increasing recognition of the importance of the metal-ligand interactions in these systems calls for more input and consideration from the bioinorganic community to address questions traditionally confined to the medicinal chemistry community. PMID- 21290035 TI - Synthesis of arabinofuranose branched galactofuran tetrasaccharides, constituents of mycobacterial arabinogalactan. AB - Mycolyl-arabinogalactan (mAG) complex is a major component of the cell wall of Mycobacterium tuberculosis, the causative agent of tuberculosis disease. Due to the essentiality of the cell wall for mycobacterium viability, knowledge of the biosynthesis of the arabinogalactan is crucial for the development of new therapeutic agents. In this context, we have synthesized two new branched arabinogalactafuranose tetrasaccharides, decenyl beta-D-Galf-(1->5)-beta-D-Galf (1->6)[alpha-D-Araf(1->5)]-beta-D-Galf (1) and decenyl beta-D-Galf-(1->6)-[alpha D-Araf-(1->5)]-beta-D-Galf-(1->5)-beta-D-Galf (2), as interesting tools for arabinofuranosyl transferase studies. The aldonolactone strategy for the introduction of the internal d-Galf was employed, allowing the construction of oligosaccharides from the non-reducing to the reducing end. Moreover, a one-pot procedure was developed for the synthesis of trisaccharide lactone 21, precursor of 2, which involved a glycosylation-deprotection-glycosylation sequence, through the use of TMSOTf as catalyst of the trichloroacetimidate method as well as promoter of TBDMS deprotection. PMID- 21290036 TI - The molecular level modification of surfaces: from self-assembled monolayers to complex molecular assemblies. AB - The modification of surfaces with self-assembled monolayers (SAMs) containing multiple different molecules, or containing molecules with multiple different functional components, or both, has become increasingly popular over the last two decades. This explosion of interest is primarily related to the ability to control the modification of interfaces with something approaching molecular level control and to the ability to characterise the molecular constructs by which the surface is modified. Over this time the level of sophistication of molecular constructs, and the level of knowledge related to how to fabricate molecular constructs on surfaces have advanced enormously. This critical review aims to guide researchers interested in modifying surfaces with a high degree of control to the use of organic layers. Highlighted are some of the issues to consider when working with SAMs, as well as some of the lessons learnt (169 references). PMID- 21290037 TI - Synthesis, structures and optical properties of trisilasumanene and its related compounds. AB - Novel trisilasumanenes that have no substituents on the exo carbon atoms, silicon analogues of sumanene, were prepared via repetitive lithiations of triphenylene followed by introduction of silicon functionalities. The optical properties of these trisilasumanenes and their related compounds were investigated by UV-vis and fluorescence spectroscopy. PMID- 21290041 TI - Influence of the chelate effect on the electronic structure of one-electron oxidized group 10 metal(II)-(disalicylidene)diamine complexes. AB - The neutral and one-electron oxidized group 10 metal, Ni(II), Pd(II) and Pt(II), six-membered chelate Salpn (Salpn = N,N'-bis(3,5-di-tert-butylsalicylidene)-1,3 propanediamine) complexes have been investigated and compared to the five membered chelate Salen (N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2 ethanediamine) and Salcn (N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexane (1R,2R)-diamine) complexes. Reaction of the Salpn complexes with 1 equivalent of AgSbF(6) affords the oxidized complexes which exist as ligand radical species in solution and in the solid state. The solid state structures of the oxidized complexes have been determined by X-ray crystal structure analysis. While the Ni and Pt analogues exhibit an essentially symmetric coordination sphere contraction upon oxidation, the oxidized Pd derivative exhibits an asymmetric metal binding environment demonstrating at least partial ligand radical localization. In comparison to the oxidized Salen and Salcn complexes, the propyl backbone of the Salpn complexes leads to a larger deviation from a planar geometry in the solid state. The electronic structure of the oxidized Salpn complexes was further probed by UV-vis-NIR measurements, electrochemistry, EPR spectroscopy, and theoretical calculations. The intense NIR band for the one-electron oxidized Salpn complexes shifts to lower energy in comparison to the 5-membered chelate analogues, which is attributed to lower metal d(xz) character in the beta-LUMO for the Salpn series. The reactivity of the one-electron oxidized Salpn complexes with exogenous ligands was also studied. In the presence of pyridine, the oxidized Ni analogue exhibits a shift in the locus of oxidation to a Ni(III) species. The oxidized PtSalpn complex rapidly decomposes in the presence of pyridine, even at low temperature. Interestingly, electronic and EPR spectroscopy suggests that the addition of pyridine to the oxidized Pd analogue results in initial dissociation of the phenoxyl radical ligand, likely due to the increased flexibility of the propyl backbone. PMID- 21290042 TI - Surfactant-assisted, shape-controlled synthesis of gold nanocrystals. AB - The shape control of gold nanocrystals has attracted extensive research interest because of their unique shape-dependent properties and widespread applications. Surfactants have been frequently used in the shape-controlled synthesis of gold nanocrystals in solution. In this feature article, we summarize some of the emerging colloidal approaches towards shape-tailored gold nanocrystals with the assistance of surfactants, focusing on the roles played by surfactants in shape control. We start with a discussion on the general strategies in shape control of gold nanocrystals, which include adsorbate-directed synthesis, seed-mediated synthesis, template-assisted synthesis, and the control of growth kinetics. Then, we highlight some recent progress in the gold nanocrystal synthesis assisted by single surfactants, mixed surfactants, supramolecular surfactants, as well as metal-surfactant complex templates, which is followed by a brief description of the potential applications of shaped gold nanocrystals in catalysis and molecular sensing. PMID- 21290043 TI - Scattering methods applied to soft matter. PMID- 21290044 TI - Stream water nutrient enrichment in a mixed-use watershed. AB - Eutrophic conditions, in both saline and freshwater systems, result from nutrient export from upstream watersheds. The objective of this study was to quantify the surface runoff losses of nitrate-nitrogen (NO3-N), total nitrogen (TN), dissolved reactive phosphorus (DRP), and total phosphorus (TP) resulting from prevailing practices on a managed golf course. Inflow and outflow discharge waters on a sub area of Northland Country Club (NCC) located in Duluth, Minnesota were measured for both quantity and quality from April through November from 2003 to 2008. Nutrient losses were detectable throughout the year, had a seasonal trend, and routinely exceeded recommended levels to minimize eutrophication. The median outflow TN concentration (1.04 mg L-1) was significantly greater (p < 0.05) than the median inflow (0.81 mg L-1) concentration. Similarly, the median outflow TP concentration (0.03 mg L-1) was significantly greater (p < 0.05) than the median inflow concentration (0.02 mg L-1). Maximum recorded concentrations during the study period were 1.9 mg L-1 NO3-N, 3.93 mg L-1 TN, 0.34 mg L-1 DRP, and 1.11 mg L-1 TP. Mean annual export coefficients at NCC were 0.7 kg ha-1 NO3-N (1.7% of applied), 4.43 kg ha-1 TN (10.7% of applied), 0.14 kg ha-1 DRP (2.6% of applied), and 0.25 kg ha-1 TP (4.6% of applied). The findings of this study highlight the need for adopting conservation practices aimed at reducing offsite nutrient transport. PMID- 21290045 TI - High-speed droplet generation on demand driven by pulse laser-induced cavitation. AB - We report on a pulse laser-driven droplet generation (PLDG) mechanism that enables on-demand droplet generation at rates up to 10,000 droplets per second in a single-layer PDMS-based microfluidic device. Injected droplet volumes can be continuously tuned between 1 pL and 150 pL with less than 1% volume variation. PMID- 21290046 TI - Laser-induced alignment and anti-alignment of rotationally excited molecules. AB - We numerically investigate the post-pulse alignment of rotationally excited diatomic molecules upon nonresonant interaction with a linearly polarized laser pulse. In addition to the simulations, we develop a simple model which qualitatively describes the shape and amplitude of post-pulse alignment induced by a laser pulse of moderate power density. In our treatment we take into account that molecules in rotationally excited states can interact with a laser pulse not only by absorbing energy but also by stimulated emission. The extent to which these processes are present in the interaction depends, on the one hand, on the directionality of the molecular angular momentum (given by the M quantum number), and on the other hand on the ratio of transition frequencies and pulse duration (determined by the J number). A rotational wave packet created by a strong pulse from an initially pure state contains a broad range of rotational levels, over which the character of the interaction can change from non-adiabatic to adiabatic. Depending on the laser pulse duration and amplitude, the transition from the non-adiabatic to the adiabatic limit proceeds through a region with dominant rotational heating, or alignment, for short pulses and a large region with rotational cooling, and correspondingly preferred anti-alignment, for longer pulses. PMID- 21290047 TI - Pore size analysis of >250,000 hypothetical zeolites. AB - Computational methods have been used in the past to generate large libraries of hypothetical zeolite structures, but to date analysis of these structures has typically been limited to relatively simple physical properties such as density. We use efficient methods to analyze the adsorption and diffusion properties of simple adsorbate molecules in a library of >250,000 hypothetical silica zeolites that was generated previously by Deem and co-workers (J. Phys. Chem. C, 2009, 113, 21353). The properties of this library of materials are compared to the complete set of ~190 zeolites that have been identified experimentally. Our calculations provide information on the largest cavities available in each material for adsorption, and the size of the largest molecules that can diffuse through each material. For a subset of ~8000 materials, we computed the Henry's constant and diffusion activation energy for adsorbed CH(4) and H(2). We show that these calculations provide a useful screening tool for considering large collections of nanocrystalline materials and choosing materials with particular promise for more detailed modeling. PMID- 21290048 TI - Ionic and mass transport in micro-nanofluidic devices: a matter of volumic surface charge. AB - The shape and the surface charge of microchannels are critical parameters for ionic and mass transport in microfluidic systems. A great number of studies and developments have been carried out in order to optimize these features separately. We propose to consider them together within a new fundamental parameter for microfluidics, that we named the Volumic Surface Charge (VSC), which is the ratio of the surface charge to the section height in planar microchannels. The non-linear effects induced by rapid VSC variations can result in selective preconcentration processes, which can be used for a simultaneous preconcentration and separation of biomolecules within simple straight channels. In this review, we first present 3 different techniques that we developed to tune the VSC either by surface chemical patterning, integration of polarisable interfaces or geometrical constrictions. The proof of concept of the selective preconcentration using VSC variations will be presented on the basis of experimental results obtained with fluorescent probes and numerical simulations. PMID- 21290049 TI - DNA hybridization enhancement using piezoelectric microagitation through a liquid coupling medium. AB - In conventional DNA microarray hybridization, delivery of target cDNAs to surface bounded probes depends solely on diffusion, which is notoriously slow, and thus typically requires 6-20 h to complete. In this study, piezoelectric microagitation through a liquid coupling medium is employed to enhance DNA hybridization efficiency and the results are compared with the standard static hybridization method. DNA hybridization was performed in a sealed aluminium chamber containing DNA microarray glass chip, coupling medium and piezoelectric transducers. 3*SSC (Saline Sodium Citrate) was used as a coupling medium to prevent overheating of the piezoelectric transducers and to effectively transmit ultrasonic wave to the glass chip. Flow visualization using fluidic dye and velocimetry (PTV) technique was applied to observe fluid transport in the hybridization chamber. It was revealed that the dye solution was homogeneously distributed within 10 min under dynamic agitation while it took over 1 h to reach the same level of homogeneity in static condition. Plasmodium falciparum DNA microarrays and total RNA extracted from parasite cells were used as a model for DNA microarray experiments. It was found that the required hybridization time may be substantially reduced from 16 h to 4 h by the use of dynamic hybridization scheme. With the same hybridization time of 16 h, dynamic hybridization resulted in higher fluorescent signals of ~33% and ~24% compared to static hybridization in Cy3 and Cy5 channels, respectively. Additionally, good/effective spots, some of which were not formed by static method, were enhanced and distributed more uniformly over the microarray. Therefore, the developed dynamic hybridization with integrated piezoelectric microagitation platform is highly promising for DNA analysis in molecular biology and medical applications. PMID- 21290050 TI - A new diversity oriented and metal-free approach to highly functionalized 3H pyrimidin-4-ones. AB - A new synthesis of 3H-pyrimidin-4-ones, characterized by four different sets of decorations, is presented. The strategy is based on the synthetic elaboration of readily available alpha-substituted beta-ketoesters that, upon transformation into the corresponding acyl enamines, have been cyclized to give 6H-1,3-oxazin-6 ones. These reactive intermediates have been in turn cleanly converted into highly functionalized pyirimidinones, by treatment with an appropriate primary amine. The whole sequence does not need the use of any metal mediator or catalyst. PMID- 21290054 TI - Correlation of p16(INK4A) expression and HPV copy number with cellular FTIR spectroscopic signatures of cervical cancer cells. AB - Cervical cancer, a potentially preventable disease, has its main aetiology in infection by high risk human papillomavirus (HR-HPV). Approaches to improving cervical cancer screening and diagnostic methodologies include molecular biological analysis, targeting of biomarker proteins, but also exploration and implementation of new techniques such as vibrational spectroscopy. This study correlates the biomarker protein p16(INK4A) expression levels dependent on HPV copy number with the infrared absorption spectral signatures of the cervical cancer cell lines, HPV negative C33A, HPV-16 positive SiHa and CaSki and HPV-18 positive HeLa. Confocal fluorescence microscopy demonstrated that p16(INK4A) is expressed in all investigated cell lines in both nuclear and cytoplasmic regions, although predominantly in the cytoplasm. Flow cytometry was used to quantify the p16(INK4A) expression levels and demonstrated a correlation, albeit nonlinear, between the reported number of integrated HPV copies and p16(INK4A) expression levels. CaSki cells were found to have the highest level of expression, HeLa intermediate levels, and SiHa and C33A the lowest levels. FTIR spectra revealed differences in nucleic acid, lipid and protein signatures between the cell lines with varying HPV copy number. Peak intensities exhibited increasing tendency in nucleic acid levels and decreasing tendency in lipid levels with increasing HPV copy number, and although they were found to be nonlinearly correlated with the HPV copy number, their dependence on p16(INK4A) levels was found to be close to linear. Principal Component Analysis (PCA) of the infrared absorption spectra revealed differences between nuclear and cytoplasmic spectroscopic signatures for all cell lines, and furthermore clearly differentiated the groups of spectra representing each cell line. Finally, Partial Least Squares (PLS) analysis was employed to construct a model which can predict the p16(INK4A) expression level based on a spectral fingerprint of a cell line, demonstrating the diagnostic potential of spectroscopic techniques. PMID- 21290055 TI - Development of a novel single sensor multiplexed marker assay. AB - There is an increasing desire to measure multiple analytes simultaneously for disease management and detection. However, in the case of invasive devices, it would be better to obtain one small sample and immediately be able to detect the analytes rapidly, as in the case of self-monitoring blood glucose, without the need for additional steps, arrays, or reagents. Electrochemical impedance spectroscopy is used to measure the interaction between ultralow levels of analyte and molecular recognition element in a label-free and rapid manner. Gold nanoparticles were attached to antibodies against interleukin-12 and tumor necrosis factor-alpha, typical inflammatory markers found with near overlapping responses, on an impedance spectroscopy based biosensor. Cross-reactivity and specificity of tuned antibodies were verified using ELISA. Impedance frequency was quantified by concentration gradients of marker against the device. The natural impedance frequency for interleukin-12 (5.00 Hz) was tuned to a lower frequency four Hertz away from one another for better signal processing. This was accomplished without significantly altering the lower limits of detection (<4 pg ml(-1) and ~60 pg ml(-1) for interleukin-12 and tumor necrosis factor-alpha, respectively), no cross-reactivity and specificity as determined by ELISAs. With modeling the nanoscale effects and further development, a larger tuning will be possible for making a better multiplexed sensor. Although interleukin-12 and TNF alpha equivalent circuit calculations were modeled here, a sensor with the potential to measure multiple markers at once might offer a solution on the sensor front for simplified management of conditions such as diabetes, where both glucose and hemoglobin A1c values could be obtained. PMID- 21290056 TI - Critical behavior of confined supramolecular soft materials on a microscopic scale. AB - The formation of fiber networks and the resulting rheological properties of supramolecular soft materials are dramatically influenced when the volume of the system is reduced to a threshold. Unlike un-confined systems, the formation of fiber networks under volume confinement is independent of temperature and solute concentration. PMID- 21290057 TI - Colorimetric response to anions by a "robust" copper(II) complex of a [9]aneN3 pendant arm derivative: CN- and I- selective sensing. AB - The 1 : 1 complex [Cu(L)](BF(4))(2).MeCN (1) of the tetradentate ligand 1-(2 quinolinylmethyl)-1,4,7-triazacyclononane (L) selectively changes its colour in the presence of CN(-) in H(2)O and MeCN (without undergoing decomplexation from the macrocyclic ligand). The same complex in MeCN assumes different colours in the presence of CN(-) or I(-). PMID- 21290058 TI - Size-dependent interaction of Au nanoparticles and graphene sheet. AB - We report enhancement of the mechanical stability of graphene through a one-step method to disperse gold nanoparticles on the pristine graphene without any added agent. PMID- 21290059 TI - Porous metal-organic frameworks as platforms for functional applications. AB - Metal-organic frameworks (MOFs), also known as coordination polymers, have emerged as a new class of crystalline porous materials, which are constructed from metal ions or metal ion clusters and bridging organic linkers. MOFs have tunable pores and functionalities, and usually exhibit very high surface areas. The potential applications of porous MOFs cover a broad range of fields and most of their applications are related to pore sizes, shapes and structures/environments. In this feature article, we provide an overview of the recent developments of porous MOFs as platforms in the functional applications of sorption and separation, heterogeneous catalysis, as supports/host matrices for metal nanoparticles, and as templates/nanoreactors for new material preparation. PMID- 21290060 TI - Thermoreversible formation and negative thermal expansion of supramacromolecular assemblies of unimolecular micelles in solution. AB - We report the thermoreversible formation of superstructural assemblies of unimolecular micelles in solution displaying negative thermal expansion behaviour. PMID- 21290061 TI - Synthesis and efficient circularly polarized light emission of an optically active hyperbranched poly(fluorenevinylene) derivative. AB - An optically active, hyperbranched poly(fluorenevinylene) derivative was synthesized by polymerization of (-)-2,4,7-tris(bromomethyl)-9-neomenthyl-9 pentylfluorene. A spin-coated film sample of the polymer exhibited efficient circularly polarized light (CPL) emission in the visible range of 400-700 nm on photo excitation even without annealing processes leading to chain ordering. PMID- 21290062 TI - Monitoring the effect of a control pulse on a conical intersection by time resolved photoelectron spectroscopy. AB - We have previously shown how femtosecond angle- and energy-resolved photoelectron spectroscopy can be used to monitor quantum wavepacket bifurcation at an avoided crossing or conical intersection and also how a symmetry-allowed conical intersection can be effectively morphed into an avoided crossing by photo-induced symmetry breaking. The latter result suggests that varying the parameters of a laser to modify a conical intersection might control the rate of passage of wavepackets through such regions, providing a gating process for different chemical products. In this paper, we show with full quantum mechanical calculations that such optical control of conical intersections can actually be monitored in real time with femtosecond angle- and energy-resolved photoelectron spectroscopy. In turn, this suggests that one can optimally control the gating process at a conical intersection by monitoring the photoelectron velocity map images, which should provide far more efficient and rapid optimal control than measuring the ratio of products. To demonstrate the sensitivity of time-resolved photoelectron spectra for detecting the consequences of such optical control, as well as for monitoring how the wavepacket bifurcation is affected by the control, we report results for quantum wavepackets going through the region of the symmetry-allowed conical intersection between the first two (2)A' states of NO(2) that is transformed to an avoided crossing. Geometry- and energy-dependent photoionization matrix elements are explicitly incorporated in these studies. Time-resolved photoelectron angular distributions and photoelectron images are seen to systematically reflect the effects of the control pulse. PMID- 21290063 TI - Structures of manganese polysulfides: mass-selected photodissociation and density functional calculations. AB - Manganese polysulfide cations, MnS(x)(+) (x = 1-10), were studied with mass selected photodissociation experiments and density functional calculations. We found that MnS(+), MnS(2)(+) and MnS(3)(+) undergo dissociation at 355 nm by loss of S, S(2) and S(3), respectively. The dissociation of larger clusters is relatively complex because of the existence of multiple isomers and multiple dissociation channels. The geometric structures of the low-lying isomers found by theoretical calculations are consistent with the dissociation channels observed in the experiments. The dissociation of MnS(x)(+) clusters occurs mainly by breaking of the Mn-S bonds since they are weaker than the S-S bonds. PMID- 21290064 TI - Application of a battery of biomarkers in mussel digestive gland to assess long term effects of the Prestige oil spill in Galicia and the Bay of Biscay: lysosomal responses. AB - In order to assess the long-term lysosomal responses to the Prestige oil spill (POS), mussels, Mytilus galloprovincialis, were collected in 22 localities from Galicia and the Bay of Biscay (North Iberian peninsula) in July, and September 2003, April, July, and October 2004-2005 and April 2006. Lysosomal membrane stability (labilisation period, LP) and lysosomal structural changes (lysosomal volume density, Vv(L) and lysosomal surface-to-volume ratio, S/V(L)) were measured as general stress biomarkers. The most remarkable long-term effects after the POS were drastic changes in lysosomal size (lysosomal enlargement) and membrane stability (extremely low LP values) up to April-04. Later on, a recovery trend was envisaged all along the studied area after July-04, albeit membrane stability continued to be below 20 min throughout the studied period up to April 06, which indicates a "distress-to-moderate-stress" condition. Lysosomal Response Index (LRI) revealed that environmental stress was more marked in Galicia than in the Bay of Biscay, mainly in the first sampling year, although a "moderate-to high-stress" condition persisted until July-05. Overall, although lysosomal size returned to reference values, membrane stability was not fully recovered indicating a stress situation throughout the studied period. PMID- 21290065 TI - Application of a battery of biomarkers in mussel digestive gland to assess long term effects of the Prestige oil spill in Galicia and Bay of Biscay: tissue-level biomarkers and histopathology. AB - In order to assess the biological effects of the Prestige oil spill (POS), mussels, Mytilus galloprovincialis, were collected in 22 localities along the North coast of the Iberian Peninsula over 3 years (April 2003-April 2006). Different tissue-level biomarkers including cell type composition (volume density of basophilic cells, Vv(BAS)) in digestive gland epithelium, structural changes of digestive alveoli (mean luminal radius to mean epithelial thickness, MLR/MET) and histopathological alterations (prevalence and intensity) of the digestive gland were analysed. Severe alterations in the general condition of the digestive gland tissue were observed all over the study area up to 2004-2005. High Vv(BAS) values were recorded mainly in Galicia but also to a lesser extent in the Bay of Biscay in 2003-2004. Atrophy of the digestive alveoli, measured in terms of MLR/MET, was detected all along the studied area up to 2006. Inflammatory responses cannot be related to pollution due to the POS: (a) prevalence and intensity of focal hemocytic infiltration were higher in the Bay of Biscay than in Galicia but they did not show a clear temporal trend; (b) high intensities of brown cell aggregates were only sporadically recorded; and (c) granulocytomas were more frequently recorded in the Bay of Biscay than in Galicia and especially in localities (i.e. Arrigunaga) subjected to chronic pollution. Likewise, Marteilia, trematodes, intracellular ciliates, unidentified eosinophilic bodies, R/CLO and Mytilicola did not follow any recognisable pattern that could be associated to the POS. In contrast, high Nematopsis intensities recorded in several localities in 2003 might suggest some response of local interest after the POS (i.e., in combination with particular factors/conditions). More data at a regional scale are needed before histopathology may provide a reliable ecosystem health assessment but the present results suggest that the approach is worthwhile. Overall, although Vv(BAS) returned to reference values by 2004-2005, MLR/MET values indicated that the mussel health condition was affected during the whole study period up to April 2006. PMID- 21290066 TI - Construction of spirolactones with concomitant formation of the fused quaternary centre--application to the synthesis of natural products. AB - Polycyclic structures fused at a central carbon are of great interest due to their appealing conformational features and their structural implications in biological systems. Although progress in the development of synthetic methodologies towards such structures has been impressive, the stereoselective construction of such quaternary stereocentres remains a significant challenge in the total synthesis of natural products. This review highlights the progress in the formation of 1-oxaspiro[4.n]alkan-2-ones (2<=n<=7) with concomitant formation of the quaternary spiro centre. PMID- 21290067 TI - Synthesis, biology and clinical significance of pentacyclic triterpenes: a multi target approach to prevention and treatment of metabolic and vascular diseases. AB - This review (with 335 references cited) is devoted to pentacyclic triterpenes. The total synthesis, semi-synthesis, structural modification, and metabolic behavior of naturally occurring pentacyclic triterpenes are described. We also cover the in vivo evidence, mechanistic studies, and clinical significance of pentacyclic triterpenes as multi-target therapeutic agents for the prevention and treatment of metabolic and vascular diseases. PMID- 21290069 TI - A new heterogeneous catalyst for epoxidation of alkenes via one-step post functionalization of IRMOF-3 with a manganese(II) acetylacetonate complex. AB - A manganese(II) acetylacetonate complex has been immobilized to the metal-organic framework IRMOF-3 through a one-step post-synthetic route for the first time, providing an effective and recyclable heterogeneous catalyst for epoxidation of alkenes. PMID- 21290068 TI - Chemical synthesis and biological evaluation of gallidermin-siderophore conjugates. AB - The lantibiotic gallidermin was modified at lysine residues by regioselective attachment of derivatives of pyochelin, agrobactin and desferrioxamine B with the objective of having siderophore receptors of Gram-negative bacteria transport the antibiotic-iron chelator conjugate through the outer membrane. All of the conjugates retained activity against the Gram-positive indicator strain, Lactococcus lactis subsp. cremoris HP. However, testing of the conjugates against several Gram-negative strains yielded unexpected results. Bacteria treated with 100 MUM of the conjugates complexed with Fe(3+) grew better than bacteria grown in iron-free media but worse than bacteria grown in the same media supplemented with 10 MUM FeCl(3). Although these findings indicate that the conjugates are unable to inhibit the growth of Gram-negative bacteria, they indicate penetration of the outer membrane and provide structure-activity information for design of other lantibiotic conjugates. The synthetic strategy is applicable for linking biomarkers or fluorescence probes to gallidermin for studies on its localization and mode of action. As there are many lantibiotics that operate with unknown mechanisms of action, this chemical approach provides a means to modify such peptides with biomarkers for biological investigations. PMID- 21290070 TI - Copper(II) enhances membrane-bound alpha-synuclein helix formation. AB - Interactions of copper and membranes with alpha-synuclein have been implicated in pathogenic mechanisms of Parkinson's disease, yet work examining both concurrently is scarce. We have examined the effect of copper(ii) on protein/vesicle binding and found that both the copper(ii) affinity and alpha helical content are enhanced for the membrane-bound protein. PMID- 21290071 TI - Substrate specificity of Rv3378c, an enzyme from Mycobacterium tuberculosis, and the inhibitory activity of the bicyclic diterpenoids against macrophage phagocytosis. AB - The Rv3378c gene product from Mycobacterium tuberculosis encodes a diterpene synthase to produce tuberculosinol (3), 13R-isotuberculosinol (4a), and 13S isotuberculosinol (4b) from tuberculosinyl diphosphate (2). The product distribution ratios are 1 : 1 for 3 to 4 and 1 : 3 for 4a to 4b. The substrate specificity of the Rv3378c-encoded enzyme was examined. The 3 labdadienyl diphosphates, copalyl diphosphate (CDP) (7), ent-CDP (8), and syn-CDP (9), underwent the conversion reaction, with good yields (67-78%). Copalol (23) and manool (24) were produced from 7, ent-copalol (25) and ent-manool (26) from 8, and syn-copalol (27) and vitexifolin A (28) from 9. The ratio of 23 to 24 was 40 : 27, that of 25:26 was 22 : 50, and that of 27:28 was 16 : 62. Analysis on a GC MS chromatograph equipped with a chiral column revealed that 24, 26, and 28 consisted of a mixture of 13R- (a) and 13S-stereoisomers (b) in the following ratio: ca. 1 : 1 for 24a to 24b, ca. 1 : 5 for 26a to 26b, and ca. 1 : 19 for 28a to 28b. The structures of these products indicate that the reactions of the 3 CDPs proceeded in the same fashion as that of 2. This is the first report on the enzymatic synthesis of natural diterpenes manool, ent-manool, and vitexifolin A. Both Rv3377c and Rv3378c genes are found in virulent Mycobacterium species, but not in avirulent species. We found that 3 and 4 inhibited the phagocytosis of opsonized zymosan particles by human macrophage-like cells. Interestingly, the inhibitory activity was synergistically increased by the coexistence of 3 and 4b. Other labdane-related diterpenes, 13-16 and 23-28, had little or no inhibitory activity. This synergistic inhibition by 3 and 4 may provide further advantage to the impairment of phagocyte function, which might contribute to pathogenicity of M. tuberculosis. PMID- 21290072 TI - N-fused carbazole-zinc porphyrin-free-base porphyrin triad for efficient near-IR dye-sensitized solar cells. AB - N-fused carbazole-zinc porphyrin-free-base porphyrin triad featuring an ethynyl linkage was synthesized; efficient sensitization as long as 900 nm was demonstrated and an overall light-to-electricity conversion efficiency of 5.21% was achieved under AM 1.5 G one sun illumination. PMID- 21290073 TI - Fabrication of nanostructured metal nitrides with tailored composition and morphology. AB - Unprecedented multi-channel TiN micro/nanotubes as well as various metal nitride nanofibers, including TiN, VN, NbN and ternary metal nitride nanofibers, were fabricated by a template free electrospinning method combined with post nitridation. PMID- 21290074 TI - Halogen bonded complexes between volatile anaesthetics (chloroform, halothane, enflurane, isoflurane) and formaldehyde: a theoretical study. AB - The structures and intermolecular interactions in the halogen bonded complexes of anaesthetics (chloroform, halothane, enflurane and isoflurane) with formaldehyde were studied by ab initio MP2 and CCSD(T) methods. The CCSD(T)/CBS calculated binding energies of these complexes are between -2.83 and -4.21 kcal mol(-1). The largest stabilization energy has been found for the C-Br...O bonded halothane...OCH(2) complex. In all complexes the C-X bond length (where X = Cl, Br) is slightly shortened, in comparison to a free compound, and an increase of the C-X stretching frequency is observed. The electrostatic interaction was excluded as being responsible for the C-X bond contraction. It is suggested that contraction of the C-X bond length can be explained in terms of the Pauli repulsion (the exchange overlap) between the electron pairs of oxygen and halogen atoms in the investigated complexes. This is supported by the DFT-SAPT results, which indicate that the repulsive exchange energy overcompensates the electrostatic one. Moreover, the dispersion and electrostatic contributions cover about 95% of the total attraction forces, in these complexes. PMID- 21290075 TI - Preparation of ideal molecular junctions: depositing non-invasive gold contacts on molecularly modified silicon. AB - Recent advances in creating rectifying gold|monolayer|silicon (Au-M-Si) junctions (namely, molecular silicon diodes) are reviewed. It is known that direct deposition of gold contacts onto molecular monolayers covalently bonded to silicon surfaces causes notable disruption to the junction structure, resulting in deteriorated performance and poor reproducibility that are unsuitable for practical applications. In the past few years, several new experimental approaches have been explored to minimize or eliminate such damage, including the "indirect" evaporation method and the pre-deposition of a protective "non penetrating" metal. To enhance the interactions at the gold-monolayer interface, head-groups that allow bonding to gold are used to maintain the monolayer integrity. Construction of the device via flip-chip lamination and the modified polymer-assisted lift-off techniques also prohibits monolayer damage. Refining the fabrication and design techniques towards reliable molecular junctions is crucial if they are to be used in nanoelectronics for the purpose of miniaturization. PMID- 21290077 TI - Spectral interpretation of thermally irreversible recovery of poly(N isopropylacrylamide-co-acrylic acid) hydrogel. AB - The thermally induced volume phase transition process of poly(N isopropylacrylamide-co-acrylic acid) (PNIPAM-co-AA) hydrogel is studied using FT IR spectroscopy in combination with the perturbation correlation moving window (PCMW) technique and two-dimensional correlation spectroscopy (2Dcos) analysis. According to PCMW spectra analysis, an elevation of volume phase transition temperature (VPTT) due to an extra equilibrium of repulsive electrostatic interactions of acrylic acid moieties in hydrogel from 34 degrees C to ca. physiological temperature (37 degrees C) is determined. 2Dcos helps us to conclude that the dehydration of hydrogel responds earlier in the process of network collapse than hydrogen bond variations of AA and NIPAM moieties during heating, while the hydrogen bonds of NIPAM and AA moieties change before the network swelling in the cooling process. Furthermore, relatively stable inner hydrogen bonds of AA moieties restrict the complete expansion of PNIPAM-co-AA hydrogel, resulting in a unique irreversible recovery during cooling. PMID- 21290076 TI - An inkjet-printed microfluidic device for liquid-liquid extraction. AB - A microfluidic device for liquid-liquid extraction was quickly produced using an office inkjet printer. An advantage of this method is that normal end users, who are not familiar with microfabrication, can produce their original microfluidic devices by themselves. In this method, the printer draws a line on a hydrophobic and oil repellent surface using hydrophilic ink. This line directs a fluid, such as water or xylene, to form a microchannel along the printed line. Using such channels, liquid-liquid extraction was successfully performed under concurrent and countercurrent flow conditions. PMID- 21290078 TI - Photodissociation dynamics of the tert-butyl radical via photofragment translational spectroscopy at 248 nm. AB - The photodissociation dynamics of the tert-butyl radical (t-C(4)H(9)) were investigated using photofragment translational spectroscopy. The tert-butyl radical was produced from flash pyrolysis of azo-tert-butane and dissociated at 248 nm. Two distinct channels of approximately equal importance were identified: dissociation to H + 2-methylpropene, and CH(3) + dimethylcarbene. Neither the translational energy distributions that describe these two channels nor the product branching ratio are consistent with statistical dissociation on the ground state, and instead favor a mechanism taking place on excited state surfaces. PMID- 21290079 TI - Natural products and Chagas' disease: a review of plant compounds studied for activity against Trypanosoma cruzi. AB - Here, we review studies that have investigated the activity of plant-derived compounds against Trypanosoma cruzi, the etiologic agent of Chagas' disease. In the last decade, more than 300 species belonging to almost 100 families have been evaluated for activity, and here we describe the compounds isolated; 85 references are cited. PMID- 21290080 TI - Differential separation of protein mixtures using convective assembly and label free detection with surface enhanced Raman scattering. AB - Differential separation and label-free detection of proteins using SERS from their mixtures after a convective assembly process is reported. Binary and ternary mixtures of proteins are mixed with AgNPs and assembled into ordered structures. The spectra acquired from the assembled area indicate that the proteins are differentially distributed. PMID- 21290081 TI - Rationally fabricating hollow particles of complex oxides by a templateless hydrothermal route: the case of single-crystalline SrHfO3 hollow cuboidal nanoshells. AB - Based on the theory of sol-gel science, perovskite SrHfO(3) hollow cuboidal particles with tunable sizes were rationally synthesized by templateless hydrothermal reactions in KOH solutions. The concentrated KOH solution not only elevated the supersaturation of the reactants to promote the grain growth of SrHfO(3) but also controlled the aggregated particle sizes by compressing the electrical double layers of the primary particulates. The following Ostwald ripening process produced hollow particles with sizes ranging from submicrometer to hundred nanometre. The HRTEM image and SAED pattern revealed the single crystal nature of each hollow cuboidal nanoshell. The KOH concentration and reaction time related experiments confirmed that the formation of SrHfO(3) hollow cuboidal nanoshell was driven by the Ostwald ripening process and followed our assumption. The particles experienced solid, core-shell and hollow morphologies as the reaction proceeded. Also, the formation of SrHfO(3) hollow cuboidal nanoshells favored high reaction temperature which initiated and accelerated the ripening process. The as-prepared hollow cuboidal nanoshells displayed blue light emission under UV laser excitation at room temperature. After calcination, the photoluminescence intensity declined due to the improvement of crystallinity. PMID- 21290082 TI - A facile route for the preparation of nanoparticles of the spin-crossover complex [Fe(Htrz)2(trz)](BF4) in xerogel transparent composite films. AB - Films and monoliths containing the spin crossover complex [Fe(Htrz)(2)(trz)](BF(4)) (trz = 1,2,4-triazole) as nanoparticles have been obtained. The dispersion and consecutive inclusion of the Fe complex in a silica matrix prepared from tetramethoxysilane or tetraethoxysilane afford monoliths or films with a violet colour at room temperature, which turns white above 380 K. This change of colour is reversible. This thermochromic behaviour has been characterized by measuring the magnetic properties together with thermogravimetric studies and Raman spectroscopy, the result of which all demonstrate that both films and monoliths undergo a spin crossover. Microscopy studies confirm the occurrence of the Fe complex as nanoparticles, in both the monoliths and the films. The facile synthesis of these materials as nanoparticles in transparent films should open the possibility of the synthesis of high quality films. PMID- 21290083 TI - Shift and night work and long working hours--a systematic review of safety implications. AB - OBJECTIVE: In order to devise effective preventive strategies, it is important to study workplace stressors that might increase the risk of workplace accidents - both affecting workers themselves as well as causing harm to third-parties. The aim of this report is to provide a systematic, updated overview and scientific review of empirical research regarding accidents in relation to long work hours and shift work, primarily based on epidemiological studies. METHODS: The search for articles was part of a large review study on the effects of work hours on various health outcomes, safety, and performance. The search strategy included 5 international scientific databases, and nearly 7000 articles were initially identified using our search string. Following the application of inclusion and exclusion criteria, 443 publications were found and evaluated using a pre-defined scoring system. Of these, 43 concerned safety and accidents but only 14 were considered to be of high quality (total score 2 or 3 on a scale from 0-3) and therefore used for this study. RESULTS: Both shift work and long working hours present a substantial and well-documented detrimental effect on safety - all the studies that are included in this review have one or more significant findings in this respect. The trends are quite coherent although the increases in accident rates are mostly from 50% to 100%. In epidemiological terms, this may be seen as rather small differences. The use of such data is therefore only of importance if the accident incidence is high or if accidents may have large effects. CONCLUSIONS: The findings are most relevant to safety-critical activities such as the transport and health sectors. Work periods >8 hours carry an increased risk of accidents that cumulates, so that the increased risk of accidents at around 12 hours is twice the risk at 8 hours. Shift work including nights carries a substantial increased risk of accidents, whereas "pure" night work may bring some protection against this effect due to resynchronization. The evaluated studies give no clear indications of any age or gender being specifically susceptible or protected against the effects of work times scheduling on accident risk. PMID- 21290084 TI - Difficulty to identify sentinel lymph nodes with computed tomography-lymphography in patients with cutaneous melanoma. PMID- 21290085 TI - Skin problems of the stump in lower limb amputees: 1. A clinical study. AB - Use of a prosthesis in lower limb amputees can lead to skin problems of the amputation stump. However, little is known about the epidemiology and type of problems experienced. We conducted a cross-sectional survey consisting of a questionnaire and a clinical assessment of the amputation stump. The aims of the study were to estimate the prevalence of skin problems of the amputation stump, to evaluate the impact of these skin problems and to evaluate differences between clinically observed skin problems and skin problems reported by the amputee. Participants (n = 124) were recruited from among lower limb amputees who visited an orthopaedic workshop. The prevalence of skin problems was 36%. Problems identified were: reduction in prosthesis use, and reduction in walking distance without a break. Significantly more skin problems were reported than observed (p = 0.011). Cold skin and excessive perspiration in particular were significantly more reported than observed. PMID- 21290086 TI - Serious adverse events reporting on systemic terbinafine: a Danish register-based study. PMID- 21290087 TI - Psychosocial stress and coping in alopecia areata: a questionnaire survey and qualitative study among 45 patients. AB - The controversial role of psychosocial stress in alopecia areata has been discussed widely, but there has been little research into patients' subjective stress experiences and coping. The aim of this study was to explore general and specific coping strategies in alopecia areata and to assess the role of psychosocial stress in the onset and course of alopecia areata from the patient's viewpoint. Forty-five patients conducted measurements of general coping strategies and body image. Qualitative data analysis was performed referring to interviews of stress experiences before the onset of alopecia areata, stress reactivity, subjective disease models, consequences of alopecia areata and illness-related coping strategies. Patients do not have dysfunctional coping strategies in general, but they benefit from advantageous strategies in terms of better alopecia areata-specific coping and course of disease after 6 months. Psychological interventions in alopecia areata should focus on training general and alopecia areata-specific coping competences and regulating negative emotionality and insecurity, particularly at the first onset of alopecia areata. PMID- 21290088 TI - Suppressing tumourigenicity of prostate cancer cells by inhibiting osteopontin expression. AB - Expression of osteopontin (OPN) is increased in prostate cancer cells. The possibility of utilising the increased OPN as a target to suppress the tumourigenicity was investigated in this study. Small interference RNAs against OPN were transfected into highly malignant DU145 prostate cancer cells, which express high level of OPN prior to the transfections, to establish OPN-suppressed clones. Compared with the control transfectants generated by scrambled RNA, suppressed expression of OPN significantly inhibited cell invasiveness and anchorage-independent growth. Similar results were obtained from in vivo experiments. OPN-suppressed transfectants produced significant reductions in average sizes of subcutaneous tumours after inoculation into nude mice. When the levels of OPN measured in transfectants before injection were related to tumour sizes, the reduction in tumour sizes was not propotionally related to the inhibition in OPN-levels. However, when the levels of OPN were analysed in the tumour tissues, it was found that the reduced OPN expression levels were significantly associated with the reducing tumour sizes. These results showed that changes in OPN levels had occurred after the transfectants were inoculated in mice. This study suggested while OPN can be an effective target for therapeutic suppression of prostate cancer, more effective way than RNAi is needed to inhibit OPN expression. PMID- 21290089 TI - Characterization of cytarabine-resistant leukemic cell lines established from five different blood cell lineages using gene expression and proteomic analyses. AB - Cytarabine (ara-C) is the key drug for treatment of acute myeloid leukemia. Since intracellular cytarabine triphosphate (ara-CTP) is an active metabolite of ara-C, factors that reduce the amount of ara-CTP are known to induce drug resistance. However, these factors do not fully explain the development of resistance to ara C. The present study was conducted to search for new candidate ara-C resistance factors, including those that are unrelated to ara-CTP production. For this purpose, we newly established five ara-C-resistant leukemic clones from different blood cell lineage leukemic cell lines (HL-60, K562, CEM, THP1 and U937). The resistant subclones were 5-58-fold more ara-C-resistant than their parental counterparts. All of the ara-C-resistant subclones, except for ara-C-resistant CEM cells, displayed alteration of ara-CTP-related factors such as ara-C membrane transport capacity, deoxycytidine kinase activity or cytosolic nucleotidase II activity. To identify new candidate factors, we used two comprehensive approaches: DNA microarray and proteome analyses. The DNA microarray analysis revealed eight genes (C19orf2, HSPA8, LGALS1, POU4F3, PSAP, AKT1, MBC2 and CACNA2D3) that were altered in all five ara-C-resistant lines compared to parental cells. Both proteome and DNA microarray analyses further detected a reduced protein level of stathmin1 in the ara-C-resistant CEM subclone compared to its parental line. Thus, the present findings suggested the involvement of novel multiple mechanisms in mediating the ara-C resistance of leukemic cells. The role of some of these molecules in resistance is still unclear. PMID- 21290090 TI - Oncogenic role of p53 is suppressed by si-RNA bicistronic construct of uPA, uPAR and cathepsin-B in meningiomas both in vitro and in vivo. AB - Meningiomas are the most commonly occurring intracranial tumors and account for approximately 15-20% of central nervous system tumors. Patients whose tumors recur after surgery and radiation therapy have limited therapeutic options. It has also been reported recently that radiation triggers DNA repair, cell survival and cell proliferation, and reduces apoptosis via the induction of cellular protective mechanisms. Earlier studies have reported that proteases such as uPA, uPAR and cathepsin B play important roles in tumor progression. In the present study, we attempted to determine the effectiveness of two bicistronic siRNA constructs pUC (uPAR/cathepsin B) and pU2 (uPA/uPAR) either alone or in combination with radiation, both in in vitro and in vivo models. Transfection of a plasmid vector expressing double-stranded RNA for uPA, uPAR and cathepsin B significantly induced the sub-G0-G1 cell population by the mitochondrial intrinsic apoptotic pathway. Results showed that pUC efficiently enhanced sub-G0 G1 phases compared to pU2 and was more effective. Interestingly, we observed that in IOMM-Lee cell lines, combined treatment of radiation with pUC and pU2 is more effective in comparison to SF-3061 and MN cell lines. We showed that apoptosis caused by these bicistronic constructs involves Bcl-2, Bcl-xL, p53 inactivation, cytochrome c release from mitochondria and caspase-9 activation, followed by the activation of caspase-3. We also determined that apoptosis caused by pUC and pU2 involves a mechanism which includes inactivation of p53 by its translocation from nucleus to cytoplasm as confirmed by immunofluorescence, which shows the oncogenic potential of p53 in meningiomas. However, the simultaneous RNAi mediated targeting of uPAR and cathepsin B (pUC), in combination with irradiation, has greater potential application for the treatment of human meningioma in comparison to pU2 by decreasing p53 expression both in vitro and in vivo. PMID- 21290091 TI - Reactive oxygen species (ROS) accumulation induced by mononaphthalimide spermidine leads to intrinsic and AIF-mediated apoptosis in HeLa cells. AB - Developing polyamine conjugates having the potential of transporting naphthalimide selectively into tumor cells is attractive. However, the evaluation of their cytotoxic mechanism has not been comprehensive. This study focused on the effects of mononaphthalimide spermidine (MNISpd) conjugate on apoptosis induction and the relationship between MNISpd-induced apoptosis and reactive oxygen species (ROS) in HeLa cells. Our findings indicated that 9 uM MNISpd induced apoptosis in HeLa cells during a 48-h period. MNISpd induced apoptosis in HeLa cells following cytochrome c release, elevation of caspase 3/9 activity, apoptosis-inducing factor (AIF) translocation and up-/down-regulation of Bax/Bcl 2 protein expression, respectively, and these effects were completely antagonized by pre-incubation with 10 mM NAC for 2 h. MNISpd induced significant ROS accumulation following up-regulation of polyamine oxidase (PAO) activity and complex variations in glutathione levels. It is concluded that MNISpd-induced apoptosis is related to intrinsic caspase-dependent and AIF-mediated caspase independent apoptosis pathways in HeLa cells. MNISpd-induced apoptosis correlates to MNISpd-induced ROS production resulting from GSH (reduced form of glutathione) pool depletion, and PAO is likely to be the source of ROS. PMID- 21290092 TI - [Merkel cell carcinoma: a highly aggressive tumor with possible viral etiology]. AB - Merkel cell carcinoma (MCC) or neuroendocrine carcinoma of the skin, is a rare and highly aggressive tumor which typically develops in chronically sun-damaged skin in aged or immunosuppressed patients. The clinical course is characterized by early local recurrence and lymphatic metastases. The current discussion on the etiology of MCC is dominated by the recently discovered Merkel cell polyoma virus (MCPyV). Apparently, MCPyV infection takes place early in life and the virus can also be found in healthy tissue. Possibly, a mutation of the viral genome is responsible for the development of the tumor. The 5 year survival rate of patients with primary MCC is only 30-40% after surgical therapy alone but can increase to about 75% after additional adjuvant radiotherapy. In cases with lymphatic or distant metastases various chemotherapy protocols in addition to operative and radiation therapy analogous to those for small cell lung cancer therapy have been found to be effective. Nevertheless, very high recurrence rates are typical in patients with distant metastases. Thus, MCC is regarded as chemosensitive but not chemocurable.Patients with MCC should be treated with an aggressive but individually adapted concept. The consequent integration of radiotherapy into the therapeutic approach can improve the prognosis. PMID- 21290093 TI - [Laparoscopic splenectomy for sclerosing angiomatoid nodular transformation]. AB - Sclerosing angiomatoid nodular transformation (SANT) is a benign lesion of the spleen which can be cured by splenectomy. In the literature about 45 cases have been reviewed. Although it is defined by the morphological details, data regarding surgical therapy are scarce. To the best of our knowledge, a laparoscopic approach has not been published before. We investigated in one case of SANT the feasibility of a laparoscopic approach. Histological investigations confirmed the diagnosis of a SANT which was resected in toto. This report shows that the laparoscopic splenectomy is a feasible, safe and effective method for treatment of SANT. PMID- 21290094 TI - [Quality of life after prostate cancer in members of support groups: first results of the HAROW retro study]. AB - BACKGROUND: The HAROW project was founded by the Stiftung Mannergesundheit to have a closer look at the situation of patients who suffer from prostate cancer, especially focusing on their situation regarding supply and services. METHODS: In the current study 504 members of support groups were asked about their health related quality of life (QOL). Standardized questionnaires were used to ensure the validation. Both the diagnosis and initial therapy dated back at least 12 months. The EORTC QLQ-C30 as well as the prostate-specific module (PSM) were used as questionnaires. RESULTS: Various forms of therapies proved to have different impacts on QOL. Patients with a combined hormonal therapy and radiation therapy evaluated their QOL worse than others with different forms of therapies. Patients with cured tumors reported significantly better data than those in the middle of therapy or the uncured. CONCLUSION: The data even indicate that their QOL is similar to people living under normal circumstances and health situations. Particular characteristics however exist on specific scales. Patients attending support groups show surprisingly high values for QOL. PMID- 21290095 TI - [The work of the Cochrane Collaboration in urology]. AB - The Cochrane Collaboration collects medical information from clinical trials and presents the results as systematic reviews. The aim of these evidence-based publications is to enable medical decisions which are based on the best available evidence and to improve knowledge transfer in healthcare decisions. Accurately developed systematic reviews identify relevant clinical trials, evaluate their quality, abstract the results and are being published in an increasing frequency in professional urological journals. The Cochrane Library provides, with diverse databases, a quick overview of the best available evidence in urology. The quality of systematic reviews depends on the quality of the included studies. A checklist provided by the PRISMA statement could help authors and thereby readers to improve methodology and recommendations in evidence-based urology. PMID- 21290096 TI - Alcohol misuse among partners: a potential effect modifier in the relationship between physical intimate partner violence and postpartum depression. AB - PURPOSE: This study evaluated if the probability of postpartum depression (PPD) increases with an upward gradient of physical intimate partner violence (IPV) during pregnancy and whether substance use by any member of the couple modifies this relationship. METHODS: The sample comprised 811 randomly selected mothers of children under 5 months old attending primary health services of Rio de Janeiro, Brazil. The Revised Conflict Tactics Scale (CTS2) gauged physical IPV, and the Edinburgh Postnatal Depression Scale (EPDS) assessed PPD. A hierarchical logistic regression model was employed to deal with confounding. Specific interaction terms between physical IPV and alcohol misuse or use of illicit drugs were also tested. RESULTS: Physical IPV during pregnancy was reported by 37.8% of respondents and 24.3% were presumably depressed (EPDS score >= 12). Interaction between physical IPV and partners' alcohol misuse was statistically significant (p = 0.026). Although there was a significant increase in PPD with just one act of physical IPV in the absence of a partners' alcohol misuse, mounting acts did not have any further influence. Conversely, when partners misused alcohol, the probability progressively and steeply increased from two acts onwards, reaching almost sevenfold by six cumulative physical IPV events as opposed to none. CONCLUSIONS: The results reinforce the relevance of physical IPV as a risk factor to PPD. They also suggest that context matters, partners' alcohol misuse acting as an important effect modifier. These evidences justify tailored preventive, screening and intervention procedures for IPV and alcohol misuse during pregnancy and the postpartum period. PMID- 21290097 TI - Mental health service utilization for psychiatric disorders among Latinos living in the United States: the role of ethnic subgroup, ethnic identity, and language/social preferences. AB - PURPOSE: To examine aspects of Latino experience in the US as predicting service utilization for mood, anxiety, and substance disorders. METHODS: Latino participants 18 and older in the NESARC (N = 6,359), a US national face to face survey. Outcomes were lifetime service utilization for DSM-IV lifetime mood/anxiety or substance disorders, diagnosed via structured interview (AUDADIS IV). Main predictors were ethnic subgroup, ethnic identity, linguistic/social preferences, nativity/years in the US, and age at immigration. RESULTS: Higher levels of Latino ethnic identity and Spanish language/Latino social preferences predicted lower service utilization for mood disorders [ethnic identity OR = 0.52, language/social OR = 0.44] and anxiety disorders [ethnic identity OR = 0.67, language/social OR = 0.47], controlling for ethnic subgroup, disorder severity, time spent in the US, and economic and practical barriers Service utilization for alcohol/drug disorders was low across all Latino subgroups, without variation by examined predictors. CONCLUSION: Ethnic/cultural factors are strong determinants of service utilization for mood/anxiety, but not substance use disorders among Latinos in the US strategies to increase service utilization among Latinos with psychiatric disorders should be disorder specific, and recognize the role of ethnicity and identity as important components of a help seeking model. PMID- 21290098 TI - Special distribution of polybrominated diphenyl ethers in brain tissues of free range domestic hens and ducks from a village near an electronic waste recycling site in South China. AB - The rural village, Taizhou of Zhejiang Province, had been exposed to e-waste recycling for years, the polybrominated diphenyl ether (PBDE) levels in hens and ducks were high. The concentration of ?PBDEs in the brain was the lowest among tissues of individual hens and ducks after correction for the respective lipid content. Also, the concentration ratio of BDE-153 versus BDE-154 (153/154) of brain was the highest among tissues of individual hens and ducks. Our results indicate that the hindrance of blood-brain barrier to compounds, such as high molecular weight and non-planar conformation (steric hindrance), contributed to the low concentration of PBDEs in the brain tissue of hens and ducks, especially in cases exposed to high levels of PBDE. PMID- 21290099 TI - Effects of nitrite and toxic Microcystis aeruginosa PCC7806 on the growth of freshwater rotifer Brachionus calyciflorus. AB - Over the last two centuries, anthropogenic activities have increased the nitrogen amount in aquatic ecosystems, which has resulted in increased occurrences of blooms of cyanobacteria. This study investigated the effects of nitrite and the cyanobacterium Microcystis aeruginosa on population growth in the rotifer Brachionus calyciflorus. The rotifer was treated for 12 days with nitrite alone (medium containing 0, 3, 6, 10 mg NO (2)(-) -N L(-1)), M. aeruginosa alone (medium containing 0 mg NO(2)(-)-N L(-1) + 5.0 * 10(5) cell ml(-1) M. aeruginosa precultured at 0, 3, 6, 10 mg NO(2)(-)-N L(-1)), and nitrite in combination with M. aeruginosa (medium containing 3, 10 mg NO(2)(-)-N L(-1) + 5.0 * 10(5) cell ml( 1) M. aeruginosa precultured at corresponding nitrite concentrations). We observed that a nitrite concentration of 10 mg NO(2)(-)-N L(-1) markedly inhibited the growth of B. calyciflorus; however, rotifer growth declined slightly in the presence of M. aeruginosa precultured at 6 mg NO(2)(-)-N L(-1). Furthermore, reduced population growth of B. calyciflorus was observed when it was treated with both nitrite and M. aeruginosa compared to nitrite alone or M. aeruginosa alone. These results suggested that a high tolerance of B. calyciflorus to nitrite levels may be attributed to the absence of specific respiratory structures and pigments; and that the increased toxicity of nitrite in combination with M. aeruginosa may have been due to increased production of microcystin. It is also possible that nitrite and microcystin could act in a synergistic way in causing toxicity. PMID- 21290100 TI - Concentrations of gaseous elemental mercury in ambient air within an academic chemistry building. AB - Gaseous elemental mercury (GEM) concentrations were determined within an academic chemistry building by cold vapor atomic fluorescence spectrometry. Concentrations varied depending on the room activity, with night time and weekend levels the lowest and most stable (typically between 10 and 20 ng/m(3)), and daytime weekday levels the highest (averaging about 3-5 times higher). Laboratory air exhibited daytime concentration spikes as high as 1,600 ng/m(3). Office levels were similar to weekend laboratory concentrations, suggesting a general building-wide mercury background. However, concentration spikes suggest GEM levels may be exacerbated by foot traffic which may cause motion-induced wafting from higher concentration areas. Based on current regulations the GEM levels do not present a health hazard. PMID- 21290101 TI - Organochlorine pesticide gradient levels among maternal adipose tissue, maternal blood serum and umbilical blood serum. AB - The objective of the present study was to determine levels and calculate ratios of copartition coefficients among organochlorine pesticides beta-HCH, pp'DDE, op'DDT and pp'DDT in maternal adipose tissue, maternal blood serum and umbilical blood serum of mother-infant pairs from Veracruz, Mexico. Organochlorine pesticides were analyzed in 70 binomials: maternal adipose tissue, maternal serum and umbilical cord serum samples, using gas chromatography with electron capture detection (GC-ECD). The results were expressed as mg/kg on fat basis. p,p'-DDE was the major organochlorine component, detected in every maternal adipose tissue (0.770 mg/kg), maternal serum sample (5.8 mg/kg on fat basis) and umbilical cord blood sample (6.9 mg/kg on fat basis). p,p'-DDT was detected at 0.101 mg/kg, 2.2 mg/kg and 5.9 mg/kg respectively, according to the order given above. beta-HCH was detected at 0.027 mg/kg, 4.2 mg/kg and 28.0 mg/kg respectively. op'DDT was detected only in maternal adipose tissue at 0.011 mg/kg. The copartition coefficients among samples identify significant increases in concentrations from adipose tissue to maternal blood serum and to umbilical blood serum. The increase indicated that maternal adipose tissue released organochlorine pesticides to blood serum and that they are carried over to umbilical cord blood. PMID- 21290102 TI - Residue and dissipation dynamics of flusilazole in apple and soil. AB - A simple, quick and reliable residue analytical method for flusilazole in apple and soil was developed in this study. The samples were extracted with acetonitrile and determined by liquid chromatography with UV detection. The LOQ of the method was 0.02 mg/kg. The dissipation dynamic and final residues of flusilazole in apple and soil were studied using field trial method. The results of residual dynamics experiment showed that after the apple was treated by flusilazole at treble of recommended high dosage (3.75 g/kg H(2)O), the half-life times of flusilazole in apple and soil were 4.23-7.77 days and 3.04-5.14 days, respectively. Residues of flusilazole in apple at harvest time were all below 0.05 mg/kg at both recommended high dosage and 1.5 times of recommended high dosage. PMID- 21290103 TI - Year in review in Intensive Care Medicine 2010: III. ARDS and ALI, mechanical ventilation, noninvasive ventilation, weaning, endotracheal intubation, lung ultrasound and paediatrics. PMID- 21290104 TI - Injection treatment for chronic midportion Achilles tendinopathy: do we need that many alternatives? PMID- 21290105 TI - Surgical results of 5th metatarsal stress fracture using modified tension band wiring. AB - PURPOSE: The purpose of this study was to evaluate the surgical results of modified tension band wiring using two cortical screws for the treatment of fifth metatarsal stress fractures. METHODS: Forty-two patients with Torg's type I and II fifth metatarsal stress fractures treated using the modified tension band wiring technique from 2005 to 2008 were evaluated retrospectively. All of the patients were elite athletes. RESULTS: The mean length of follow-up was 26 +/- 16 months (12-62 months). All patients were able to return to their previous levels of sporting activity. The mean time to union as determined by CT was 75 +/- 25 days (40-150 days). However, during follow-up, there were 4 delayed unions, 1 nonunion, and 4 refractures. CONCLUSION: The described modified tension band wiring technique is a good alternative method for the surgical treatment of Torg's type I and II fifth metatarsal stress fractures. LEVEL OF EVIDENCE: Case series with no comparison group, retrospective case series, Level IV. PMID- 21290106 TI - Repair of horizontal meniscal cleavage tears with exogenous fibrin clots. AB - PURPOSE: A novel indication and technique using exogenous fibrin clots to repair horizontal cleavage tears of the meniscus is presented. METHODS: Vertical sutures were placed on the meniscus using FasT-Fix (Smith & Nephew Endoscopy, Andover, MA, USA), and exogenous fibrin clots were inserted within the cleft to promote healing and to preserve function. RESULTS: Repeat arthroscopy showed healing and closure of the cleft of the meniscus without affecting the articular cartilage. Three medial and six lateral menisci were treated, and all of the patients showed improvements in their functional scores and their quality of life. CONCLUSIONS: It appears that the exogenous fibrin clots act as a scaffold to promote the healing process and that growth factors in the fibrin clots had a beneficial effect on meniscal healing. This procedure should be considered to treat degenerative menisci for which repair options have been limited until now. LEVEL OF EVIDENCE: IV. PMID- 21290107 TI - Secondary patellar resurfacing in the treatment of patellofemoral pain after total knee arthroplasty. AB - PURPOSE: This paper reports a prospective review of patients who, between 2004 and 2007, underwent secondary patellar resurfacing (SPR) due to anterior knee pain after a primary total knee arthroplasty (TKA). The aim was to evaluate the clinical outcomes obtained with the SPR and to compare them with radiological findings. METHODS: A total of twenty-seven consecutive patients met the inclusion criteria. There were twenty-three (85%) women and four (15%) men with a median age of 70 years. The patients were evaluated before and after the surgery with the same functional scores and radiological parameters. Bone scintigraphy was also used in the assessment, and a CT-scan was performed in order to evaluate the femoral component rotation. The median time between TKA and SPR was 18 months. RESULTS: With a median follow-up of 23 months, seventeen patients (63%) reported a clear subjective improvement after SPR, and patellofemoral scores (primary outcome measure), KSS and WOMAC (secondary outcome measures) showed a statistically significant improvement following the procedure. There were no significant changes after SPR in the Insall-Salvati ratio, the lateral patellar displacement or the lateral patellar tilt. The mean time between TKA and SPR had no statistically significant effect on outcome. The bone scintigraphy revealed increased patellar uptake in seven cases, but this was not related to subsequent improvement after SPR. Rotational computed tomography showed a median internal rotation of the femoral component of 1o. The complications observed were a patellar component loosening and an acute post-infection. CONCLUSION: No clinical or radiological parameter was found to be related to the final outcome after SPR. There was a discrepancy between functional scale scores and the patient's subjective satisfaction. PMID- 21290108 TI - The anterior trochlear line as a reference for femoral component positioning in total knee arthroplasty. AB - PURPOSE: A new radiographic method using the anterior and posterior femoral condyles as a landmark to determine the rotational alignment of the femoral component in TKA had been developed. METHODS: The new radiograph presents an axial view of the distal femur. The patients were asked to lie in the supine position and flex the knee approximately 120 degrees to 130 degrees . Radiographs were applied at an inclination angle of 20 degrees to 30 degrees . The condylar twist angle (CTA), the external rotational angle between the posterior condylar (PC) line and the clinical transepicondylar axis (TEA), and the trochlear line angle (TLA), and the internal rotational angle between the anterior trochlear line and the clinical TEA were measured. Images were taken of 129 knees in 87 patients with osteoarthritis of the knee. The measurement values obtained using our method with those obtained using 3D reconstructed images from a 3-dimensional helical CT system (n = 35) were compared. RESULTS: The average CTA was 5.7 degrees +/- 2.8 degrees and the average TLA was -5.6 degrees +/- 3.2 degrees . The CTA was negatively correlated with the tibiofemoral angle (TFA). The average TLA was positively correlated with the TFA. The average difference between the TLA values obtained with this view and those obtained using the 3D-CT was 0.5 degrees +/- 1.6 degrees . The relationship between the radiograph and 3D-CT in TLA was higher than that in CTA. CONCLUSIONS: This radiographic technique allows easy and simultaneous measurement of the CTA and TLA and may provide an alternative method for assessing the TEA of the femur during preoperative planning for TKA. PMID- 21290109 TI - Anterior cruciate ligament reconstruction improves the metabolic energy cost of level walking at customary speeds. AB - PURPOSE: The metabolic energy cost of walking is altered by pathological changes in gait. It is thought that anterior cruciate ligament (ACL) deficiency alters the energy requirement for level walking through its effect on gait pattern. In this study, it is hypothesised that the metabolic energy cost of walking would improve after ACL reconstruction. METHODS: Eight patients who were undergoing ACL reconstruction for an isolated rupture were included in this prospective study. Clinical examinations, Lysholm scores and metabolic tests were performed preoperatively and at 3, 6 and 12 months after ACL reconstruction using autologous quadruple hamstring tendons. For the metabolic evaluation, net oxygen cost was calculated while walking on a treadmill at 50-, 70- and 90-m/min velocities. A two-way factorial ANOVA was performed in order to evaluate the primary effects and interactions of the time point and velocity variables on net oxygen cost. RESULTS: All patients had positive Lachman and anterior drawer tests preoperatively that became negative postoperatively and remained negative until the last follow-up point. The mean preoperative Lysholm score was 66, whereas the mean postoperative follow-up scores were 85, 91 and 94, respectively. The interaction between follow-up time point and velocity was not significant. Regardless of the selected velocity, the net oxygen cost was lower than that at preoperative levels at each postoperative time point (p < 0.05). CONCLUSION: The results of the present study indicate that the energy cost of level walking in chronic ACL-deficient patients improves after ACL reconstruction. Cause-effect based studies with correlation evaluations that compare kinetic, kinematic and electromyographic data and metabolic cost calculations should facilitate more accurate analyses. LEVEL OF EVIDENCE: Therapeutic study, Level 4. PMID- 21290110 TI - Reliability of tunnel angle in ACL reconstruction: two-dimensional versus three dimensional guide technique. AB - PURPOSE: To compare the reliability of tibial tunnel position and angle produced with a standard ACL guide (two-dimensional guide) or Howell 65 degrees Guide (three-dimensional guide) in the coronal and sagittal planes. In the sagittal plane, the dependent variables were the angle of the tibial tunnel relative to the tibial plateau and the position of the tibial tunnel with respect to the most posterior aspect of the tibia. In the coronal plane, the dependent variables were the angle of the tunnel with respect to the medial joint line of the tibia and the medial and lateral placement of the tibial tunnel relative to the most medial aspect of the tibia. METHODS: The position and angle of the tibial tunnel in the coronal and sagittal planes were determined from anteroposterior and lateral radiographs, respectively, taken 2-6 months postoperatively. The two-dimensional and three-dimensional guide groups included 28 and 24 sets of radiographs, respectively. Tibial tunnel position was identified, and tunnel angle measurements were completed. Multiple investigators measured the position and angle of the tunnel 3 times, at least 7 days apart. RESULTS: The angle of the tibial tunnel in the coronal plane using a two-dimensional guide (61.3 +/- 4.8 degrees ) was more horizontal (P < 0.05) than tunnels drilled with a three dimensional guide (64.7 +/- 6.2 degrees ). The position of the tibial tunnel in the sagittal plane was more anterior (P < 0.05) in the two-dimensional (41.6 +/- 2.5%) guide group compared to the three-dimensional guide group (43.3 +/- 2.9%). CONCLUSION: The Howell Tibial Guide allows for reliable placement of the tibial tunnel in the coronal plane at an angle of 65 degrees . Tibial tunnels were within the anatomical footprint of the ACL with either technique. Future studies should investigate the effects of tibial tunnel angle on knee function and patient quality of life. LEVEL OF EVIDENCE: Case-control retrospective comparative study, Level III. PMID- 21290112 TI - "Intersection syndrome" of the foot: treated by endoscopic release of master knot of Henry. AB - Intersection syndrome of the forearm is a painful condition in the area where the muscle bellies of the abductor pollicis longus and extensor pollicis brevis cross the common wrist extensors. A similar case of the foot with marked fibrosis at the interconnection of flexor hallucis longus and flexor digitorum tendons is reported and the fibrous interconnection was extended proximally. This was successfully treated with endoscopic release of the master knot of Henry. PMID- 21290111 TI - Prediction of range of motion 2 years after mobile-bearing total knee arthroplasty: PCL-retaining versus PCL-sacrificing. AB - PURPOSE: This study evaluated the changes in the range of motion (ROM) with time postoperatively. METHOD: The pre- and intraoperative ROM was compared with the ROM 3, 6, 12, and 24 months postoperatively to clarify the effects of posterior cruciate ligament-retaining (PCLR) and posterior cruciate ligament-sacrificing (PCLS) prostheses on the ROM. The changes in the ROM in PCLR (n = 57) and PCLS (n = 51) mobile-bearing total knee arthroplasties for osteoarthritis patients for whom complete data were available were examined. RESULTS: No significant difference was seen between the two prostheses at any time point. Nevertheless, the ROM 24 months after PCLR and PCLS prostheses could be predicted statistically from the ROM after 6 and 3 months, respectively. CONCLUSION: This study showed the effects of retention of the PCL and the degree of its functional recovery on postoperative ROM for the two prostheses. PMID- 21290113 TI - A prospective randomized comparison of irradiated and non-irradiated hamstring tendon allograft for ACL reconstruction. AB - PURPOSE: To analyze the outcome of arthroscopic anterior cruciate ligament reconstruction with irradiated versus non-irradiated hamstring tendon allograft. METHODS: All hamstring tendon allografts were obtained from a single certified tissue bank, and the irradiated allografts were sterilized with 2.5 Mrad of irradiation prior to distribution. A total of 78 patients who met the inclusion and exclusion criteria of the study were prospectively randomized consecutively into two groups (Non-ir-Allo vs. Ir-Allo). All the operations were done by the same senior surgeon. Before surgery and at follow-up, patients were evaluated by the same observer according to clinical evaluations including the Lachman test, ADT, pivot shift test, varus/valgus stress test, the instrumented KT-2000 arthrometer testing, vertical jump test, one-leg hop test, ROM of knee, Cincinnati knee score, IKDC Subjective Knee Form, Tegner activity score, modified Lysholm knee scoring scale, and the standard knee ligament evaluation form of the IKDC. RESULTS: Of these patients, 69 (Non-ir-Allo 38, Ir-Allo 31) were available for full evaluation. When compared the Ir-Allo group with Non-ir-Allo group at the final follow-up by Lachman test, ADT, pivot shift test, and KT-2000 arthrometer testing, statistically significant differences were found (P < 0.05). Most importantly, 84% of patients in the Non-ir-Auto group and just only 32% in the Ir-Allo group had a side-to-side difference of less than 3 mm according to KT 2000. The anterior and rotational stability decreased significantly in the Ir Allo group. According to the overall IKDC, functional, subjective evaluations, and activity level testing, no statistically significant differences were found between the two groups (n.s.). As to the osteoarthritis (OA) rate, for the Non-ir Allo group, there was no significant difference (n.s.) in development of OA between the operated knee and contralateral knee at the final follow-up. While for the Ir-Allo group, significant difference (P < 0.05) was found in development of OA between the operated knee and contralateral knee. There was statistical difference (P < 0.05) between the Non-ir-Allo and Ir-Allo groups when comparing the development of OA of the operated knees at the final follow-up. CONCLUSION: There was a significant difference in knee stability between the two groups (in favor of Non-ir-Allo), but no differences in functional scores should be pointed out clearly. LEVEL OF EVIDENCE: I. PMID- 21290114 TI - The effects of the synovium on chondrocyte growth: an experimental study. AB - PURPOSE: The objective of this study was to evaluate the effects of synovium on the proliferation of the cartilage tissue and chondrocytes using a rabbit knee model as an in vivo synovial culture medium. METHODS: Twelve New Zealand rabbits were used as the animal model in this investigation. Standard size chondral and osteochondral cartilage grafts were taken from, respectively, the left and right knees of all the animals. Two groups of 6 animals were formed: in Group I (synovium group), grafts were placed into the synovial tissue and in group II (patellar tendon group) behind the patellar tendon of the corresponding knees. After 4 months, samples were collected and evaluated macroscopically by measuring their dimensions (vertical = D1, horizontal = D2, and depth = D3) and volumes, and histologically by counting the chondrocyte number using camera lucida method. RESULTS: Macroscopically, the increase in average D1, D2, and D3 measurements and volume in the osteochondral specimens were significantly higher compared to the chondral specimens in both groups (P < 0.05). However, no significant difference was observed between the two groups in terms of macroscopic values. Histologically, the mean chondrocyte counts in osteochondral and chondral specimens for Group I (synovium) were 20.2 and 18.1, and for Group II (patellar tendon) were 18.7 and 15.6, respectively. The mean number of chondrocytes was found to be significantly higher in osteochondral specimens than that of chondral specimens in either group (P < 0.05). Overall average chondrocyte count was significantly higher for Group I compared to Group II (P < 0.05). CONCLUSION: Transplantation of the cartilage grafts into the synovial tissue in rabbit knees significantly enhanced the chondrocyte production compared with the group where the grafts were transplanted into intra-articular patellar tendon. The results of this study indicate that native synovial tissue may have the potential to be used as an in vivo culture medium for osteochondral tissue growth. PMID- 21290115 TI - A new "double-pulley" dual-row technique for arthroscopic fixation of bony Bankart lesion. AB - The double-row technique is a new concept for arthroscopic treatment of bony Bankart lesion in shoulder instability. It presents a new and reproducible technique for arthroscopic fixation of bony Bankart fragments with suture anchors. This technique creates double-mattress sutures which compress the fragment against its bone bed and restores better bony anatomy of the anterior glenoid rim with stable and non-tilting fixation that may improve healing. PMID- 21290116 TI - Comparison between hamstring autograft and free tendon Achilles allograft: minimum 2-year follow-up after anterior cruciate ligament reconstruction using EndoButton and Intrafix. AB - PURPOSE: This study is to compare the clinical and radiographic results of anterior cruciate ligament (ACL) reconstruction with four-stranded autogenous hamstring tendon and two-stranded free tendon Achilles allograft fixed with EndoButton in the femoral tunnel and Intrafix in the tibial tunnel. MATERIALS AND METHODS: 106 patients diagnosed with ACL rupture underwent ACL reconstruction. Autogenous hamstring tendon was used in 33 patients (group I) and free tendon Achilles allografts were used in 32 patients (group II). Median age was 23 years old (20-51) in group I and 22 years old (20-55) in group II. Range of motion, Lachman test, Pivot shift test, IKDC score, Lysholm score and side-to-side difference (SSD) were evaluated preoperatively and at the last follow-up. Tegner activity scale was evaluated before injury and at the last follow-up. RESULTS: The mean follow-up periods were 28.1 months in group I and 31.6 months in group II. Range of motion of the knee was not different from that of the unaffected side in most cases except one flexion deficit in group I and three in group II (n.s.). One in group I and three in group II showed grade two or three laxity on Lachman test at the last follow-up. One in group I and three in group II showed clear positive results on Pivot shift test at the last follow-up. Thirty in group I and 26 in group II were classified to IKDC A or B at the last follow-up (n.s.). Median Lysholm scores were 98 (85-100) in group I and 99 (85-100) in group II at the last follow-up (n.s.). Median Tegner activity scales were 6 (5-9) in group I and 6 (4-9) in group II at the last follow-up (n.s.). The mean SSD at the last follow-up were 1.4 +/- 2.0 mm in group I and 1.9 +/- 2.4 mm in group II (n.s.). CONCLUSION: Clinical and radiological outcomes of ACL reconstruction with two stranded free tendon Achilles allograft were comparable to those of four-stranded autogenous hamstring tendon. This technique is reasonable to accomplish good results without some weaknesses when using allograft with bone block. LEVEL OF EVIDENCE: Therapeutic randomized controlled prospective study, Level I. PMID- 21290117 TI - Intra-operative four-stranded hamstring tendon graft diameter evaluation. AB - PURPOSE: To evaluate whether clinical factors enable prediction of the diameter of hamstring tendons harvested for anterior cruciate ligament (ACL) reconstruction. METHODS: Eighty patients were submitted for reconstruction of the ACL with hamstring tendons in a quadruple manner. During surgery the diameter of the graft was measured. The variables analyzed were: age, gender, weight, height, operated side, dominant side, leg length, thigh length, thigh diameter, body mass index (BMI), and sports activity. The data was collected pre-operatively and correlated with the diameter of the graft. RESULTS: The diameter of the graft was strongly related to gender, height, leg length, thigh length, weight, and thigh diameter. Women presented significantly smaller graft diameter than men; as well as weight, height, leg length, and thigh length. Men with height equal to or greater than 1.80 m showed average graft diameter greater than the total group, and greater percentage of 9 mm grafts. CONCLUSION: The diameter of the hamstring graft is significantly associated to weight, height, leg length, thigh length, thigh diameter, and gender. The variable that had most influence was height, followed by gender and leg length. The variables BMI, age, sports activity, and dominant side did not present correlation. Tendon diameter was larger in men than in women. Men with a height equal to or greater than 1.80 m had a higher prevalence of 9 mm grafts and had a larger average tendon diameter. LEVEL OF EVIDENCE: Prospective cross sectional collection of data, Level IV. PMID- 21290118 TI - Intraarticular stabilization following anterior cruciate ligament injury in children and adolescents. AB - PURPOSE: Significant controversy exists regarding the potential harm to the growth plate following reconstruction of the anterior cruciate ligament in skeletally immature patients. This study was performed to evaluate the results of a transepiphyseal replacement of the anterior cruciate ligament in skeletally immature patients. METHODS: Ninety-four skeletally immature patients (56 male and 38 female) with median age 13.7 years (range, 11.6-15.9 years) who underwent arthroscopic transphyseal reconstruction of anterior cruciate ligament with four strand medial hamstring autograft between 1999 and 2006 were reviewed. All patients had been followed up until skeletal maturity was confirmed. RESULTS: The average follow-up was 38 months (range 24-60 months). Neither leg length discrepancy nor angular deformities were noted on radiological or clinical measurement. Two patients had radiographic evidence of mild arthrosis at final follow-up. New traumatic injuries occurred in 4 patients, in whom surgical revision was performed. Ligament laxity testing with a KT 1000/2000 arthrometer showed no significant difference between the normal and the operated legs. At follow-up, the median Lysholm score was 89 (range 77-100), and the median Tegner activity score was increased from 3 to 6. The International Knee Documentation Committee score was A in 79 patients (84%) and B in 6 patients (6%) and C in 9 patients (9%). Of the 94 patients, 73 (78%) returned to their similar preoperative sport activities and 90% returned to their preoperative level of daily activities. CONCLUSIONS: ACL reconstruction with medial hamstring autograft via transepiphyseal drilling and grafting yielded satisfactory clinical results with no growth defects in skeletally immature patient. The preliminary results of this series demonstrated that this surgical technique can be performed in prepubescent patients with efficacy and safety. LEVEL OF EVIDENCE: IV. PMID- 21290119 TI - Distinct DNA methylation patterns of lysophosphatidic acid receptor genes during rat hepatocarcinogenesis induced by a choline-deficient L-amino acid-defined diet. AB - Altered expressions of lysophosphatidic acid (LPA) receptor genes have been reported in tumor cells of human and rats. Recently, we detected the frequent mutations of LPA receptor-1 (LPA1) gene in rat hepatocellular carcinomas (HCCs) induced by a choline-deficient L-amino acid-defined (CDAA) diet. In this study, the DNA methylation patterns of LPA receptor genes and their expression levels during rat hepatocarcinogenesis induced by the CDAA diet were investigated. Six week-old F344 male rats were continuously fed with the CDAA diet, and animals were then killed at 7 days and 2, 12, 20, and 75 weeks, respectively. Genomic DNAs were extracted from livers and HCCs for the assessment of methylation status by bisulfite sequencing, comparing to normal livers. The livers of rats fed the CDAA diet were unmethylated in LPA1 and LPA2 genes as well as normal livers. In LPA3 gene, although normal livers were unmethylated, the livers at 7 days and 2 and 12 weeks weakly or moderately methylated and those at 20 weeks markedly methylated. Moreover, 4 HCCs were completely methylated in LPA3 gene. Expression levels of LPA receptor genes in the livers of rats fed the CDAA diet and HCCs were correlating with DNA methylation status. These results indicate that DNA methylation status of the LPA3 gene was disturbed in the livers of rats fed the CDAA diet and established HCCs, suggesting that alterations of the LPA receptor genes might be involved during rat hepatocarcinogenesis induced by the CDAA diet. PMID- 21290120 TI - Mercury biomagnification in the aquaculture pond ecosystem in the Pearl River Delta. AB - This is the first study to investigate the rate of mercury (Hg) biomagnification in the aquaculture pond ecosystem of the Pearl River Delta (PRD), China, by analyzing total mercury (THg) and methyl mercury (MeHg) concentrations in various species of fish at different trophic levels (TLs). Species representing a gradient of trophic positions in the aquaculture pond food chains were chosen for analyzing THg and MeHg concentrations. In this study, there were two kinds of the aquaculture pond food chains: (1) omnivorous (fish feeds, zooplankton, grass carp [Ctenopharyngodon idellus], and bighead carp [Aristichthys nobilis]) and (2) predatory (zooplankton, mud carp [Cirrhina molitorella], and mandarin fish [Siniperca kneri]). Bighead carp and mandarin fish had the highest MeHg and THg concentrations, i.e., an order of magnitude higher than other species, in their respective food chains. More than 90% of the THg concentrations detected in bighead carp, mandarin fish, and mud carp were in the methylated form. In this study, %MeHg increased with TLs and MeHg concentrations, reflecting that MeHg is the dominant chemical species of Hg accumulated in higher concentrations in biota, especially biota associated with higher TLs in the food chains. The trophic magnification factors were 2.32 and 2.60 for MeHg and 1.94 and 2.03 for THg in omnivorous and predatory food chains, respectively, in PRD. Hg concentrations in fish tissue correlated to Hg levels in the ambient environment, and sediment seemed to be the major source for Hg accumulated in fish. In addition, feeding habit also affected Hg accumulation in different fish species. Four significant linear relationships were obtained between log-THg and delta(15)N and between log-MeHg and delta(15)N. The slope of the regression equations, as biomagnification power, was smaller in magnitude compared with those reported for temperate and arctic marine and freshwater ecosystems, indicating that THg and MeHg biomagnifications were lower in this PRD subtropical aquaculture pond ecosystem. This was probably due to low Hg bioavailability at lower TLs as well as individual feeding behavior of fish. PMID- 21290121 TI - Use of small angle neutron scattering to study the interaction of angiotensin II with model membranes. AB - Understanding biological processes assumes a detailed understanding of the interaction of all involved molecules. Here the effect of the peptide hormone angiotensin II (Ang II), an agonist of the angiotensin receptors, on the structure of unilamellar and multilamellar dimyristoyl phosphatidylcholine vesicles was studied by small angle neutron scattering, dynamic light scattering and differential scanning calorimetry. The calorimetry data indicate a weak interaction of Ang II with the surface of the membrane bilayer, as the pretransition persists during all experiments, and the main transition is only slightly shifted towards higher temperatures. From the SANS data we were able to confirm the calorimetric data and verify the interaction of the hormone with the membrane surface. At low temperatures, when the lipid molecules are in the gel phase, more precisely in the ripple phase, the peptide penetrates in the head group core, but due to the close packing of the acyl chains, the hydrophobic region is not affected. In a temperature region below but close to the region of the phase transition, the hydrophibic core starts to be affected by the peptide, and the same is true for the fluid phase. Upon binding of the peptide, the thickness of the head group increases, and the scattering length density of the head group starts to rise with increasing peptide concentrations. This interaction and binding to the membrane surface may be relevant for the relocation, binding and reconstitution of the angiotensin receptors into the membrane. Second, the peptide adsorption to the membrane surface may contribute to the binding of Ang II in the active site of the receptor. PMID- 21290122 TI - NMR and protein structure in drug design: application to cyclotides and conotoxins. AB - Nuclear magnetic resonance spectroscopy (NMR) is a powerful technique for determining the structures, dynamics and interactions of molecules, and the derived information can be useful in drug design applications. This article gives a brief overview of the role of NMR in drug design and illustrates this role with examples studied in our laboratory in recent years on disulfide-rich peptides, including cyclotides and conotoxins. Cyclotides are head-to-tail cyclized proteins from plants that are exceptionally stable and hence make useful templates for the stabilization of bioactive peptide epitopes as well as potential leads for anti-HIV drugs. Natural cyclotides target cell membranes, so understanding cyclotide-membrane interactions is useful in applying cyclotides in drug design applications. NMR studies of these interactions are described in this article. Conotoxins are disulfide-rich peptides, from the venoms of marine cone snails, which are of pharmaceutical interest because they potently interact with a range of ion channels, transporters and other receptor sites implicated in disease states. Chemically re-engineering conotoxins to give them a cyclic backbone has been used to engender them with improved biopharmaceutical properties, such as are observed in cyclotides. PMID- 21290123 TI - Risk factors for and long-term outcomes of anastomotic leakage after colorectal cancer surgery. PMID- 21290124 TI - Extravascular submucosal coil migration after transcatheter arterial embolization for a massively bleeding duodenal ulcer. PMID- 21290125 TI - Endovascular management of thoracic aortic aneurysms. AB - The overall survival of patients with thoracic aortic aneurysm (TAA) has improved significantly in the past few years. Endovascular treatment, proposed as an alternative to surgery, has been considered a therapeutic innovation because of its low degree of invasiveness, which allows the treatment of even high-surgical risk patients with limited complications and mortality. A major limitation is the lack of adequate evidence regarding long-term benefit and durability because follow-up has been limited to just a few years even in the largest series. The combination of endovascular exclusion with visceral branch revascularization for the treatment of thoraco-abdominal aortic aneurysms involving the visceral aorta has also been attempted. As an alternative, endografts with branches represent a technological evolution that allows treatment of complex anatomy. Even if only small numbers of patients and short follow-up are available, this technical approach, which has with limited mortality (<10%) and paraplegia rates, to expand endovascular treatment to TAA seems feasible. With improved capability to recognize proper anatomy and select clinical candidates, the choice of endovascular stent-graft placement may offer a strategy to optimize management and improve prognosis. PMID- 21290126 TI - Foam sclerotherapy using polidocanol (aethoxysklerol) for preoperative portal vein embolization in 16 patients. AB - PURPOSE: To evaluate the clinical safety and effectiveness of foam sclerotherapy using polidocanol for preoperative portal vein embolization (PVE) before hemihepatectomy of the liver. MATERIALS AND METHODS: From March 2006 to October 2008, foam sclerotherapy using polidocanol was performed in 16 patients (male-to female ratio of 12:4, age range 48-75 years [mean 62]) for PVE. Patients were diagnosed with Klatskin tumor (n = 13), gallbladder (GB) cancer (n = 2), or hepatocellular carcinoma (HCC) (n = 1). The foam was composed of a 1:2:1 ratio of 3% polidocanol (Aethoxysklerol; Kreussler Pharma, Wiesbaden, Germany), room air, and contrast media (Xenetix 350; Guerbet, Aulnay-Sous-Bois, France). The total amount of polidocanol used (2 to 8 mL [mean 4.6]) varied according to the volume of the target portal vein. We calculated the volume of future liver remnant (FLR) before and after PVE and evaluated complications associated with the use of polidocanol foam sclerotherapy for PVE. RESULTS: Technical success was achieved in all patients. All patients were comfortable throughout the procedure and did not experience pain during sclerotherapy. No periprocedural morbidity or mortality occurred. Patients underwent a liver dynamic computed tomography (CT) scan 2-4 weeks after PVE. FLR increased significantly after PVE using polidocanol foam from 19.3% (range 16-35%) before PVE to 27.8% (range 23-42%) after PVE (p = 0.001). All patients were operable for hemihepatectomy of the liver and achieved effective resection. CONCLUSION: Foam sclerotherapy using polidocanol is clinically safe and effective for preoperative PVE. PMID- 21290127 TI - Dual sinoatrial node arteries. PMID- 21290128 TI - Signal propagation of the MAPK cascade in Xenopus oocytes: role of bistability and ultrasensitivity for a mixed problem. AB - The MAPK signaling cascade is nowadays understood as a network module highly conserved across species. Its main function is to transfer a signal arriving at the plasma membrane to the cellular interior. Current understanding of 'how' this is achieved involves the notions of ultrasensitivity and bistability which relate to the nonlinear dynamics of the biochemical network, ignoring spatial aspects. Much less, indeed, is so far known about the propagation of the signal through the cytoplasm. In this work we formulate, starting from a Michaelis-Menten model for the MAPK cascade in Xenopus oocytes, a reaction-diffusion model of the cascade. We study this model in one space dimension. Basing ourselves on previous general results on reaction diffusion models, we particularly study for our model the conditions for signal propagation. We show that the existence of a propagating front depends sensitively on the initial and boundary conditions at the plasma membrane. Possible biological consequences of this finding are discussed. PMID- 21290129 TI - Resolution of adalimumab-induced psoriasis after vitamin D deficiency treatment. AB - Tumoral necrosis factor alpha blockers are very efficient in the treatment of many inflammatory systemic diseases, including rheumatoid arthritis and psoriasis. However, a paradoxical arouse of psoriasiform lesions may occur in a few patients taking anti-TNFalpha. The etiology of this rare side effect is still a mystery, and its treatment may be difficult. The authors report the resolution of adalimumab-induced psoriasis in a woman with rheumatoid arthritis after the use of high vitamin D(3) doses for the treatment of vitamin D deficiency. This is the first report of resolution of anti-TNFalpha-induced psoriasiform lesions by high doses of vitamin D(3) in a patient with rheumatoid arthritis and vitamin D deficiency. This case raises interesting questions on the role of vitamin D deficiency in the pathogenesis of this side effect and on the possible usefulness of high-dose vitamin D(3) in its treatment. PMID- 21290130 TI - Involvement of soluble receptor activator of nuclear factor-kappaB ligand (sRANKL) in collagenase-induced murine osteoarthritis and human osteoarthritis. AB - Joint destruction and excessive bone formation are associated with high expression of soluble receptor activator of nuclear factor-kappaB ligand (sRANKL). This study was undertaken to investigate the role of sRANKL in collagenase-induced osteoarthritis (CIOA) in mice and in patients with osteoarthritis (OA). The initial phase of CIOA was associated with severe proteoglycan depletion, decreased collagen density, and up-regulation of bone morphogenetic protein (BMP)-2. At the late stage of CIOA, bone remodeling was related with increased BMP2 and RANKL expression in the joints, high sRANKL, and decreased number of activated neutrophils in synovium. CIOA mice showed elevated plasma level of sRANKL but low RANKL expression on blood neutrophils. The percentage of RANKL-positive blood neutrophils was higher in patients with OA than in healthy individuals. Our data indicate that increased local and systemic levels of soluble RANKL might be indicative for OA disorders in mouse and human. PMID- 21290131 TI - New standardization of checking the vesicourethral anastomosis for tightness following radical prostatectomy with dynamic transrectal ultrasound: can this new technique replace the traditional postoperative cystogram? AB - PURPOSE: Urinary extravasation at the anastomosis is common after radical prostatectomies. Nevertheless, no data exist referring to the optimal date of catheter removal at the time of expected complete tightness of the leakage. Thus, we developed over the last 10 years a standardized concept to check the anastomosis, evaluating urinary extravasation using a dynamic transrectal ultrasound (dTRUS). METHODS: From 1999 to 2008, 1,479 radical prostatectomies have been performed. For complete tightness, 752 could be evaluated using the standardized concept of checking the anastomosis. The first 250 patients have been evaluated by cystogram and dTRUS and the following 502 patients only by dTRUS postoperatively. The date of checking the anastomosis was determined by the urine color. RESULTS: Urinary extravasation could be detected 4-8 days postoperatively in 41% (n = 308), 9-12 days in 16% (n = 120), 13-20 days in 8% (n = 60), and in no patient after 21 days. The coefficient of correlation comparing dTRUS versus cystogram was r = 0.99, P < 0.05. The measured volume of urinary extravasation after 4-8 days postoperatively was 15 ml (3-49 ml) using dTRUS and 16 ml (3-45 ml) using cystogram. After 9-20 days, the volume was determined as 9 ml (3-24 ml) by dTRUS and 9 ml (4-23 ml) by cystogram. The macroscopic evaluation of the urinary color was very well correlated with the likelihood of extravasation being still present. When the urine was cloudy or colored by old blood, extravasation was present in 96.9% of the patients. Microscopic evaluation like leukocyturia or hematuria of the urine on the same day shows specificity in only 34.3%. CONCLUSIONS: Following radical prostatectomy, the urine color is essential to assess the chance of a persisting leakage at the anastomosis. The method of dTRUS can replace the cystogram in checking for complete healing of the anastomosis, thus decreasing the exposure to X-rays of the patient of about 60 cGy/cm(2). PMID- 21290132 TI - A case of giant cell arteritis with massive pericardial effusion. AB - Giant cell arteritis (GCA) is a chronic inflammatory disease of the medium and large blood vessels. The early symptoms of this disease are nonspecific, and pericardial effusion is a rare manifestation of GCA. Recently, we investigated a case of GCA in which massive pericardial effusion was the initial symptom, and active aortitis was observed on positron emission tomography with fluorine-18 fluorodeoxyglucose. These observations indicated that pericardial effusion could occur in patients with GCA. PMID- 21290133 TI - Chinese pediatric and adolescent primary tracheobronchial tumors: a hospital based study. AB - OBJECTIVES: To investigate the clinical characteristics and treatment outcomes in Chinese pediatric and adolescent patients with primary tracheobronchial tumors by focusing upon the exploration of prognostic factors. METHODS: A retrospective review of medical records collected from January 1996 through June 2009 was conducted within a single institution, inclusive of the total 19 treated pediatric and adolescent patients (3 benign tumors, 16 malignant tumors). A parallel comparison of adult cases with tracheobronchial tumor was performed to the pediatric and adolescent cases. RESULTS: The chart review of pediatric and adolescent case reports revealed 19 cases with primary tracheobronchial tumors. Final pathologic diagnosis included 14 (73.68%) mucoepidermoid carcinoma (ME), 2 (10.53%) carcinoid tumor, 2 (10.53%) papillomatosis and 1 (5.26%) neurofibroma. Median age upon diagnosis was 12 years (range 4-18 years). Chest imaging revealed common abnormal radiographic atelectasis (12/19). Patients with localized disease received surgical tumor resection. There were a total of 8 (42.1%) sleeve resections, 4 (21.1%) resection of anatomically related lung parenchyma (1 bilateral lobectomies, 2 lobectomies, 1 pneumonectomy) and 7 local tumor resections. No surgery-related deaths or complications were observed. 16 patients (84.2%) remained disease free with a median follow-up of 70.5 months (range 44 168 months). CONCLUSIONS: Our hospital data indicated a high incidence of ME, presenting the difference in the incidence rates between Chinese and western populations. Sleeve lobectomy provides efficient treatment with excellent prognosis among Chinese pediatric and adolescent patients. PMID- 21290134 TI - Body-image, self-concept and mental exposure in patients with pectus excavatum. AB - BACKGROUND: Pectus excavatum is the most common congenital anomaly of the sternum and anterior chest wall, which occurs about 3-4 times more often in boys than girls [1]. Although most patients do not report physical symptoms as cardiovascular and respiratory problems, they show a loss of self-esteem and a poor self-image. There exist very rare data about psychological state before the OP compared with data afterwards. OBJECTIVE: This study was conducted to examine psychological changes in body-image, self-concept and mental exposure in patients with pectus excavatum, who had undergone the Nuss procedure. METHODS: Seventeen patients (13 male, 4 female), who underwent 2003 a comprehensive psychological investigation, have been tested again in 2007 by means of the identical questionnaires to get postoperative data: OPE-FB (Wallisch; Operation-Expectation Questionnaire), FKKS (Deusinger; Frankfurter Body Concept Scales) and SCL-90-R (Derogatis; Symptom Checklist Revised). The mean age at the second time of investigation was 19.6 years (SD = 2.5). The patients were classified into two groups based on a lower (n = 10) and a higher (n = 7) severity index of PE. Parents or a parent person were interviewed about the topics of OPE-FB by a structured interview. Data were analyzed using Mann-Whitney U test and Wilcoxon test. Interview data were evaluated with a content analysis. RESULTS: Nearly all patient's expectations in regard to the beneficial effect of the surgical procedure-investigated with the OPE-FB preoperatively-have been confirmed postoperatively. In patients with a lower severity index impairment in general interest in sports and improvements in self-assurance, health, self-acceptance of one's body and acceptance of one's body by others can be reported. Data from SCL 90-R, measuring mental exposure, had normal range. Interviews with relatives showed, that the external attribution could emphasize patient's data from the OPE FB. CONCLUSIONS: The long-time follow-up can make us sure, that the Nuss procedure as a physical treatment has positive effects on physical as well as psychological aspects of young adults. The patient's confidence with the cosmetic result was very high, which reflects the excellent effects of the minimal invasive repair according to Nuss. PMID- 21290135 TI - Therapeutic effects of vitamin A on experimental cholestatic rats with hepatic fibrosis. AB - PURPOSE: The aim of this study is to investigate the role of hepatic stellate cells (HSCs) and the effect of vitamin A administration on liver damage induced by bile duct ligation (BDL) and administration of CCl(4). METHODS: Two types of animal model were used; one was BDL as a model of biliary atresia, the other was CCl(4)-induced hepatic fibrosis. Pathological changes of the liver with or without administration of vitamin A were compared by light and electron microscopy with focusing on HSCs in each experimental group. Immunohistochemical examination was performed with anti-keratinocyte growth factor (KGF), anti-alpha smooth muscle actin (alpha-SMA), and anti-glial fibrillary acidic protein (GFAP) antibodies, as markers of fibrosis. RESULTS: On light microscopic findings, periportal inflammation with bile ductular proliferation was obvious in BDL group and pericentral necrosis with fatty degeneration was observed in CCl(4) group, both of which were ameliorated by subcutaneous injection of vitamin A. Electron microscopy showed lipid droplets were almost depleted in the HSCs treated with BDL or CCl(4), which improved with vitamin A administration. Immunohistochemistry demonstrated that enhanced expression of all three fibrotic markers in the BDL group was diminished by vitamin A administration. CONCLUSIONS: Although most of our data are qualitative observation, vitamin A may ameliorate hepatic fibrosis in the BDL model by restoring vitamin A in the HSCs. PMID- 21290136 TI - Laparoscopic versus open inguinal herniotomy in infants and children: a meta analysis. AB - PURPOSE: To undertake a meta-analysis of comparative data of laparoscopic versus open inguinal herniotomy in infants and children. METHODS: We searched MEDLINE, EMBASE, and The Cochrane Central Controlled Trials Registry for relevant randomized controlled trials and observational studies comparing laparoscopic with open inguinal hernia repair in children aged less than 19 years. RESULTS: Data on 2,699 children were identified from 10 comparative studies. Laparoscopic techniques were associated with a trend towards higher recurrence rate (OR = 1.81; 95% CI 0.89-3.67; p = 0.10), longer operative time for unilateral repairs (WMD = 10.23; 95% CI 8.82-11.64; p < 0.00001), and may be shorter operative time for bilateral repairs (WMD = -4.54; 95% CI -11.63 to 2.55; p = 0.21). There was a significant reduction in developing a contralateral metachronous inguinal hernia in the laparoscopic group (OR = 0.37; 95% CI 0.20-0.67; p = 0.001). CONCLUSIONS: Laparoscopic inguinal herniotomy is significantly associated with longer operative time for unilateral cases and a reduction in metachronous hernia development. There was a trend towards higher recurrence rate for laparoscopic repairs and shorter operative time for bilateral cases. A well conducted randomized controlled trial is warranted to compare both approaches. PMID- 21290137 TI - Laparoscopic exploration of the common bile duct to relieve choledocholithiasis in children. AB - PURPOSE: The optimal method of managing paediatric choledocholithiasis is controversial. Endoscopic retrograde cholangiopancreatography (ERCP) and sphincterotomy are effective in adults; however, the long-term outcome in the paediatric population is unknown. We report our experience with laparoscopic common bile duct (CBD) exploration to relieve choledocholithiasis in children and propose a management algorithm. METHODS: A retrospective chart review of 124 children, who underwent cholecystectomy over 5 years was conducted. Data collected included age at onset, duration of symptoms, length of stay, method of relieving choledocholithiasis and postoperative outcome. RESULTS: Mean age was 12.5 years (range 10-14 years). 102 cholecystectomies were performed laparoscopically. Following intraoperative cholangiogram (IOC), choledocholithiasis was identified in eight patients. In three cases, the CBD was flushed with normal saline via a 5F ureteral catheter successfully relieving the obstruction. In three cases, a Dormia basket was used to break down the stone. Two cases required postoperative ERCP and sphincterotomy to successfully extract the stones. All children were symptom-free at follow-up with no complications reported to date. CONCLUSION: Laparoscopic CBD exploration with Dormia basket or saline flushes to relieve choledocholithiasis is a safe and effective alternative in children. If unsuccessful, ERCP and sphincterotomy can be performed in centres with adequate resources and expertise. PMID- 21290138 TI - Treatment of venous malformations with ethanolamine oleate: a descriptive study of 83 cases. AB - PURPOSE: To evaluate the outcome and complications of sclerotherapy with injection ethanolamine oleate for the treatment of venous malformations (VMs). METHODS: Eighty-three patients' (39 males and 44 females) age ranging from 3 months to 21 years with 85 lesions were followed clinically for about 1 year following treatment with injection of ethanolamine oleate. The cases were enrolled between January 2006 and December 2009. The amount of ethanolamine oleate per treatment session ranged from 0.50 to 10 ml, and maximum dose was 0.40 ml per kg body weight. All patients were evaluated after 8 weeks of last injection session. All of the treatment sessions were performed on a day-case basis. RESULTS: Eighty-five lesions have under gone 201 sclerotherapy sessions with 39 requiring one, 27 requiring two and 19 lesions requiring more than two sessions. Sclerotherapy with ethanolamine oleate provided complete resolution of symptoms in 79 lesions and significant improvement of 6 lesions. There is no recurrence of studied patients. All patients experienced pain and swelling to a variable degree for short duration. Skin sloughed out in four patients which were healed spontaneously. No other complications were observed in our study. CONCLUSION: The treatment of VMs with injection ethanolamine oleate is safe and effective. PMID- 21290139 TI - Increased cutaneous oxygen availability by topical application of hydrogen peroxide cream enhances the photodynamic reaction to topical 5-aminolevulinic acid-methyl ester. AB - Topical 5-aminolevulinic acid (ALA) and methyl aminolevulinate (MAL) photodynamic therapy (PDT) of skin lesions is an accepted treatment for skin tumours but success rates need improvement. The effectiveness of PDT is influenced by availability of oxygen. The aim of this study was to demonstrate, in normal skin, whether a decrease in skin oxygen tension reduces the photodynamic reaction (PDR); and whether the addition of topical hydrogen peroxide can reverse the effect. Topical MAL and red light were administered to the inner forearms of 40 healthy volunteers. Skin oxygen availability was lowered during the illumination phase of the PDT, by applying blanching pressure with a plastic slide. Topical hydrogen peroxide was applied under the pressure slide, immediately prior to illumination, to reverse the effect. Erythema was assessed by naked eye and laser Doppler perfusion imaging (LDPI), at baseline and at 1, 5, 24 and 48 h following illumination. Decreasing oxygen availability by pressure altered the PDR with a larger number of subjects (17.5%) not demonstrating any visible erythema at any time point after plastic slide pressure compared to a PDR Control site (7.5%). The addition of topical hydrogen peroxide during pressure application, restored the number of subjects showing no visible erythema compared to that of PDR Control. LDPI data showed that there was a decrease in mean perfusion after plastic slide pressure when comparing the change from baseline to 24 h (P < 0.05) with the PDR Control. The addition of hydrogen peroxide not only restored but also increased the mean perfusion compared to that of PDR Control when comparing the change from baseline to 5 h and the change from baseline to 24 h (P < 0.001). Increasing oxygen availability increased the PDR in normal skin. The possibility that addition of topical hydrogen peroxide to PDT protocols for non-melanoma skin cancer may increase reactivity and, thus, be relevant for outcomes warrants further study. PMID- 21290140 TI - A comparison of misoprostol, controlled-release dinoprostone vaginal insert and oxytocin for cervical ripening. AB - OBJECTIVE: We compared the safety and effectiveness of oxytocin, dinoprostone and misoprostol for cervical priming. STUDY DESIGN: A total of 218 patients were enrolled to receive between one and three treatments according to physicians' options. The end points were: (1) vaginal delivery or Bishop score >= 8 at the end of 12 h, (2) vaginal delivery by 12 h or difference >= 4 between the initial and 12th hour Bishop scores. Statistical analyses were performed with ANOVA, Krustal Wallis, Scheffe, chi2, Fisher, Advanced chi2, and Kolmogorov-Smirnov tests. Tukey's HSD was used as a post hoc test. RESULTS: Misoprostol showed statistical significance for the rate of vaginal delivery <12 h, >= 8 Bishop score at the end of 12 h, and cervical change of >= 4 Bishop scores within 12 h (p = 0.013). CONCLUSIONS: Comparison between cases Bishop score <4 showed that misoprostol is more effective than dinoprostone and oxytocin. Considering Bishop score = 0 cases we calculated no statistical significance. PMID- 21290141 TI - Evaluation of the feasibility of the vidian neurectomy using computed tomography. AB - For around 50 years, various approaches to the vidian neurectomy have been advocated. This indicates that there is no single surgical technique that is superior to all others. In this report, we analyze the included angle between the posterior end of middle turbinate and the anterior opening of the vidian canal. The aim of this paper is to use preoperative CT scanning to find a key anatomical structure to predict the feasibility of the vidian neurectomy. A retrospective research was performed. A total of 63 patients with 106 endoscopic vidian neurectomies between September 2006 and April 2010 were selected. The study population included 50 men and 13 women, with a mean age of 28. A paranasal sinus CT scan was obtained and analyzed. The included angle was measured and compared to the operating success rates. In the successful group (78 sides, 73.58%), the included angle from axial and coronal CT imaging was 30.2 +/- 4.9 degrees and 26.4 +/- 9.1 degrees , respectively. In the 28 failed sides (26.42%), the value was 33.8 +/- 4.8 degrees and 44.3 +/- 8.1 degrees , respectively. Statistical analysis confirmed that the difference between those two groups was significant (P < 0.05). The present study reports the relationship between the vidian canal and the middle turbinate, which is represented by their included angle. The findings support the decision to intervene the surgical side with a smaller angle, because of the significantly higher success rate. PMID- 21290142 TI - Parent of origin effect and allelic expression imbalance of the serotonin transporter in bipolar disorder and suicidal behaviour. AB - Suicide and suicidal behaviour are a major health concern worldwide particularly in patients with mood disorders. Family, adoption and twin studies show that genetics influences suicidal behaviour. The serotonin transporter (5HTT) plays an important role in the pathophysiology of mood disorders and may also be involved in suicidal behaviour since 5HTT binding is decreased in the brain of suicide completers. Because the effect of genomic imprinting in the 5HTT gene on suicidal behaviour has not been investigated, we analysed the parent-of-origin effect (POE) of four 5HTT markers and the differential expression of the 5HTT G2651T (rs1042173) alleles in suicide attempters affected by bipolar disorder. We performed a family based association study and ETDT/QTDT analyses of the rs25531, HTTLPR, VNTR-2 and G2651T polymorphisms in 312 nuclear families with at least one subject affected by bipolar disorder. The main outcomes investigated in this study are bipolar disorder diagnosis, suicide attempts, suicidal behaviour severity and age at onset of bipolar disorder. We also compared the allele specific mRNA levels in lymphoblastoid cells from 13 bipolar suicide attempters and 8 bipolar non-suicide attempters. Allele 2651T was transmitted significantly more often to bipolar patients (P = 0.042). There was no significant difference between maternal and paternal transmission ratios. Furthermore, there was no significant difference in the ratio of T/G-specific mRNA expression between bipolar attempters and non-attempters. These data do not support a role for differential allelic expression of 5HTT for suicidal behaviour in bipolar disorder. Small sample size and the fact that RNA was obtained from lymphoblastoid cell lines were some of the limitations of this study. PMID- 21290143 TI - BDNF serum levels, but not BDNF Val66Met genotype, are correlated with personality traits in healthy subjects. AB - Consisting evidence in animal models has suggested that alterations in brain derived neurotrophic factor (BDNF) brain expression and release are involved in the pathogenesis of mental illnesses, such as, mood, anxiety, and eating disorders. This hypothesis is supported by data emerging from biochemical studies on serum BDNF levels and genetic studies on the functional polymorphism Val66Met in the BDNF gene in patients and control subjects. Anxiety-related personality traits are associated with several mental disorders. However, they are also measurable in non-affected subjects and, so, may represent a useful "endophenotype" to study the biological correlation of the vulnerability factors in the general population. In this study, we analyzed putative correlations in subjects unaffected by mental disorders between personality traits, serum BDNF levels (N = 107), and the BDNF Val66Met genotype (N = 217). Furthermore, we tested the possible interactions between these variables. A significant correlation has been observed between high scores of harm avoidance (HA) measured by the temperament and character inventory (TCI), and low BDNF serum concentration (r = -0.253, P = 0.009). In addition, an association has been evidenced between low BDNF levels in serum and the BDNF Val/Val genotype (P = 0.021). By analyzing putative concomitant effects of different variables on HA scores in a regression model, we observed a significant correlation only with BDNF serum concentrations (P = 0.022). The study results suggest that a decrease in serum BDNF concentrations may represent a biochemical marker associated with anxiety personality traits also retrievable in the general population. PMID- 21290144 TI - Anti-N-methyl-D-aspartate receptor encephalitis associated with carcinosarcoma with neuroendocrine differentiation of the uterus. PMID- 21290145 TI - The effect of acute exercise on endothelial progenitor cells is attenuated in chronic heart failure. AB - Exercise training improves endothelial function in patients with chronic heart failure (CHF) through functional enhancement of circulating angiogenic cells and increased numbers of circulating endothelial progenitor cells (EPC). In contrast to healthy subjects, an immediate effect of acute exercise on CD34(+)/KDR(+) EPC is absent in CHF. Whether this reflects an attenuated or rather delayed mobilization, is addressed in the present study by measuring CD34(+)/KDR(+) EPC over a longer time period post-exercise. Seven CHF patients and eight healthy subjects (HS; 4 young and 4 age-matched subjects) underwent graded exercise testing (GXT). Venous blood was sampled before and 10, 30, and 60 min, 2, 4, 8, 12, 24 and 48 h following GXT to determine numbers of circulating CD34(+)/KDR(+) EPC (flow cytometry) and serum levels of stromal cell-derived factor (SDF)-1alpha (ELISA). In both HS groups, CD34(+)/KDR(+) EPC numbers increased within 10 min following GXT and remained elevated for up to 2 h. In CHF patients, the initial increase was small and normalized within 30 min. Evolution of CD34(+)/KDR(+) EPC numbers over time following GXT overall was attenuated in CHF versus HS (p = 0.036). Exercise considerably influenced SDF-1alpha levels over time (p = 0.0008), without a relation to the changes in CD34(+)/KDR(+) EPC. The immediate effect of acute exercise on CD34(+)/KDR(+) EPC numbers is not delayed, but significantly attenuated in CHF patients compared to HS. PMID- 21290146 TI - PRBP plays a role in plastid ribosomal RNA maturation and chloroplast biogenesis in Nicotiana benthamiana. AB - In the present study, we investigated protein characteristics and physiological functions of PRBP (plastid RNA-binding protein) in Nicotiana benthamiana. PRBP fused to green fluorescent protein (GFP) localized to the chloroplasts. Recombinant PRBP proteins bind to single-stranded RNA in vitro, but not to DNA in a double- or a single-stranded form. Virus-induced gene silencing (VIGS) of PRBP resulted in leaf yellowing in N. benthamiana. At the cellular level, PRBP depletion disrupted chloroplast biogenesis: chloroplast number and size were reduced, and the thylakoid membrane was poorly developed. In PRBP-silenced leaves, protein levels of plastid-encoded genes were significantly reduced, whereas their mRNA levels were normal regardless of their promoter types indicating that PRBP deficiency primarily affects translational or post translational processes. Depletion of PRBP impaired processing of the plastid encoded 4.5S ribosomal RNA, resulting in accumulation of the larger precursor rRNAs in the chloroplasts. In addition, PRBP-deficient chloroplasts contained significantly reduced levels of mature 4.5S and 5S rRNAs in the polysomal fractions, indicating decreased chloroplast translation. These results suggest that PRBP plays a role in chloroplast rRNA processing and chloroplast development in higher plants. PMID- 21290147 TI - Genome-wide analysis of auxin response factor (ARF) gene family from tomato and analysis of their role in flower and fruit development. AB - Auxin response transcription factors have been widely implicated in auxin mediated responses during various developmental processes ranging from root and shoot development to flower and fruit development in plants. In order to use them for improvement of agronomic traits related to fruit, we need to have better understanding of their role during fruit development. In this study, 17 SlARF genes have been identified from tomato (Solanum lycopersicum), using various publically available tomato EST databases. Phylogenetic analysis of the 23 AtARF and 17 SlARF proteins results in formation of three major classes and a total of 14 sister pairs, including seven SlARF-AtARF, four SlARF-SlARF and three AtARF AtARF sister pairs, providing insights into various orthologous relationships between AtARFs and SlARFs. Further, search for orthologs of these SlARFs resulted in identification of nine, ten, four and three ARF genes from potato, tobacco, N. benthemiana and pepper, respectively. A phylogenetic analysis of these genes, along with their orthologs from Solanaceae species, suggests the presence of a common set of the ARF genes in this family. Comparison of the expression of these SlARF genes in wild type and rin mutant provides an insight into their role during different stages of flower and fruit development. This study suggests that ARF genes may play diverse role during flower and fruit development. Comprehensive data generated here will provide a platform for identification of ARF genes and elucidation of their function during reproductive development stages in Solanaceae in general and fruit development in tomato, in particular. PMID- 21290148 TI - Water-use strategies of six co-existing Mediterranean woody species during a summer drought. AB - Drought stress is known to limit plant performance in Mediterranean-type ecosystems. We have investigated the dynamics of the hydraulics, gas exchange and morphology of six co-existing Mediterranean woody species growing under natural field conditions during a drought that continued during the entire summer. Based on the observed minimum leaf water potentials, our results suggest that the six co-existing species cover a range of plant hydraulic strategies, from isohydric to anisohydric. These differences are remarkable since the selected individuals grow within several meters of each other, sharing the same environment. Surprisingly, whatever the leaf water potentials were at the end of the dry period, stomatal conductance, photosynthesis and transpiration rates were relatively similar and low across species. This result contradicts the classic view that anisohydric species are able to maintain gas exchange for longer periods of time during drought stress. None of the plants showed the expected structural acclimation response to the increasing drought (reduction of leaf-to sapwood area ratio), thereby rejecting the functional equilibrium hypothesis for our study system. Instead, three of the six species increased photosynthetic area at the branch level. The observed dissimilar patterns of gas exchange, hydraulics and morphology across species seem to be equally successful given that photosynthesis at the leaf level was maintained at similar rates over the whole dry period. PMID- 21290149 TI - Dominance and species co-occurrence in highly diverse ant communities: a test of the interstitial hypothesis and discovery of a three-tiered competition cascade. AB - The role of competitive exclusion is problematic in highly diverse ant communities where exceptional species richness occurs in the face of exceptionally high levels of behavioural dominance. A possible non-niche-based explanation is that the abundance of behaviourally dominant ants is highly patchy at fine spatial scales, and subordinate species act as insinuators by preferentially occupying these gaps--we refer to this as the interstitial hypothesis. To test this hypothesis, we examined fine-scale patterns of ant abundance and richness according to a three-tiered competition hierarchy (dominants, subdominants and subordinates) in an Australian tropical savanna using pitfall traps spaced at 2 m intervals. Despite the presence of gaps in the fine-scale abundance of individual species, the combined abundance of dominant ants (species of Iridomyrmex, Papyirus and Oecophylla) was relatively uniform. There was therefore little or no opportunity for subordinate species to preferentially occupy gaps in the foraging ranges of dominant species, and we found no relationship between the abundance of dominant ants and nondominant species richness at fine spatial scales. However, we found a negative relationship between subdominant and subordinate ants, a negative relationship between dominant and subdominant ants, and a positive relationship between dominant and subordinate ants. These results suggest that dominant species actually promote species richness by neutralizing the effects of subdominant species on subordinate species. Such indirect interactions have very close parallels with three-tiered trophic cascades in food webs, and we propose a "competition cascade" where the interactions are through a competition rather than trophic hierarchy. PMID- 21290150 TI - Comparison of inpatient treatment costs after balloon kyphoplasty and non surgical treatment of vertebral body compression fractures. AB - We performed an analysis of following costs after primary conservative or operative treatment with balloon kyphoplasty (BKP) in osteoporotic vertebral fractures. Patients with primary osteoporotic vertebral fractures treated with BKP or conservatively from discharge year 2002-2005 were retrospectively assessed regarding the following hospital treatment in any hospital in Austria from 2002 to 2006. A statistical record linkage between the hospital data and the mortality registry of Statistic Austria was performed. The data search was restricted to ICD-10 and procedures according to the Austrian catalogue of procedures defined as "spine relevant". Number of readmissions, length of hospital stay and DRG related costs were calculated for the surgical and conservative group separately. 324.5 years (mean 2.93 +/- 1.40, conservative group) and 343.6 (mean 2.56 +/- 0.96, BKP group) of 110 conservative patients and 134 BKP patients were analyzed. There was no statistical difference of the mortality rate with 9 patients (6.7%, BKP) and 11 patients (9.9%, conservative). The number of readmissions was 1.62 times higher (P = 0.039), the length of stay 1.09 times higher (P = 0.046) in the conservative group. No difference in the DRG scores were found (P = 0.11). In conclusion, patients with osteoporotic vertebral fractures showed in the following years after BKP fewer hospital readmissions and shorter hospital stays but no difference in DRG scores in comparison to conservatively treated patients. PMID- 21290151 TI - Biopterin levels in the cerebrospinal fluid of patients with PARK8 (I2020T). AB - PARK8 is the most common form of familial Parkinson's disease (PD). We measured biopterin and monoamine metabolite levels in the cerebrospinal fluids of 7 PARK8 patients (I2020T mutation in leucine-rich repeat kinase 2), 2 asymptomatic mutation carriers, and 21 sporadic PD patients. The biopterin levels in PARK8 patients were significantly higher than those in sporadic PD patients, although the symptoms were comparable in both groups, suggesting that PARK8 patients exhibit parkinsonian symptoms with higher biopterin levels than sporadic PD patients. PMID- 21290152 TI - Course of NTX changes under continuous bisphosphonate treatment in cases of NTX over-reduction due to long-term treatment with bisphosphonates. AB - BACKGROUND: It has recently been suggested that long-term continuous treatment with bisphosphonates can eventually result in skeletal harm. We reported that the level of urinary cross-linked N-telopeptide of type I collagen (NTX) was over reduced in 11 of 87 (12.7%) patients receiving long-term therapy with bisphosphonates. In this case, it is inconclusive whether treatment with bisphosphonates should be continued or not after over-reduction of bone resorption markers. In this study, we demonstrated changes in NTX levels in 13 patients who consented to continue treatment with bisphosphonates even after the over-reduction of NTX levels. MATERIALS AND METHODS: We investigated 13 osteoporosis patients who wanted to continue taking bisphosphonates even after an over-reduction of their NTX levels (less than 9.3 nmolBCE/mmol Cr) caused by the long-term treatment had been recognized. We measured NTX and serum alkaline phosphatase (ALP) levels, and lumbar bone mineral density (BMD). Measurements were made at 12, 24 and 36 months before and after the recognition of NTX over reduction. RESULTS: Mean NTX levels at 42, 36, 24 and 12 months prior to recognition of NTX over-reduction (42.6 +/- 38.5, 31.9 +/- 16.4, 25.0 +/- 10.2 and 20.4 +/- 9.5 nmolBCE/mmol Cr, respectively) decreased incrementally. In contrast, mean NTX levels at 6, 12, 24 and 36 months (16.0 +/- 4.6, 19.6 +/- 11.9, 16.8 +/- 6.4 and 18.2 +/- 5.9 nmolBCE/mmol Cr, respectively) after NTX over reduction (8.7 +/- 0.9 nmolBCE/mmol Cr) returned to within the reference range. Mean ALP levels did not reveal significant change and stayed within the reference range (110-370 IU/l) during the total course of bisphosphonate treatment. Mean BMD values had a tendency to increase throughout the entire period of bisphosphonate treatment. CONCLUSION: The NTX levels in all 13 cases returned to within the reference range even when bisphosphonate treatment was continued after the over-reduction of NTX levels because of long-term bisphosphonate treatment, and continued treatment was not observed to cause atypical fractures of the femur in any of the patients. PMID- 21290153 TI - Pubic/ischial stress fractures after eccentric rotational acetabular osteotomy. AB - BACKGROUND: Although there have been several reports on the complications of periacetabular osteotomy, stress fractures occurring in the pubic and ischial bones are less well recognised. The purpose of this study was to analyse the incidence of stress fracture, factors and treatment outcomes of stress fractures in the pubic/ischial bone after eccentric rotational acetabular osteotomy (ERAO). MATERIALS AND METHODS: We examined 340 hips of 290 patients (male 35 hips, female 305 hips; mean age 42 years) with whom it was possible to conduct a minimum of 1 year of follow-up observations after ERAO. The following items were investigated: presence of a pubic/ischial stress fracture after surgery; gender; age; bilateral or unilateral osteoarthritis; height, weight and body mass index; preoperative and final stages of osteoarthritis of the hip; preoperative and final center-edge (CE) angle, acetabular head index and minimum joint space; preoperative and final Japan Orthopaedic Association score; and presence of a pubic discontinuity. We then compared cases with pubic/ischial stress fracture (fractured group) with those with no fracture (nonfractured group). For the fractured group, we also investigated the onset time of the fracture. RESULTS: The fractured group consisted entirely of women with a mean age of 47 years, and comprised 10 (2.9%) of the 340 patient hips examined. A statistically significant difference was observed between the two groups in pubic discontinuities (fractured group 8/10, nonfractured group 16/330; P < 0.0001) and postoperative CE angle (fractured group; 43 degrees , nonfractured group; 36 degrees , P = 0.0338) according to univariate analysis. However, only the pubic discontinuity rate differed significantly between the groups according to multivariate analysis (P < 0.0001). In all cases, a pubic/ischial stress fracture occurred within 3 months after surgery, and all cases had bony union. Recurrent fracture occurred in only one hip. There was no difference in the clinical outcomes of the fractured and nonfractured groups at the time of final follow-up. CONCLUSIONS: The patients with pubic discontinuities were significantly more susceptible to a pubic/ischial stress fracture after ERAO. The presence of a pubic/ischial stress fracture did not influence the clinical outcome. PMID- 21290154 TI - Are family variables associated with ADHD, inattentive type? A case-control study in schools. AB - Attention-deficit/hyperactivity disorder (ADHD) seems to be associated with significant psychosocial adversity. However, few studies assessed the role of environmental, social and interpersonal factors specifically in ADHD, inattentive type (ADHD-I). Thus, this study aims to investigate whether family environment risk factors are associated with ADHD-I. In a case-control study, we assessed a non-referred sample of 100 children and adolescents with ADHD-I and 100 non-ADHD controls (6-18 years old). They were systematically evaluated through structured diagnostic interviews. The following family adversity measures were used: Rutter's family adversity index (marital discord, low social class, large family size, paternal criminality, maternal mental disorder), Family Environment Scale (FES) (subscores of cohesion, expressiveness and conflict) and Family Relationship Index (FRI) (based on the subscores above). After adjusting for confounding factors (social phobia and maternal history of ADHD), the odds ratio (OR) for ADHD-I increased as the number of Rutter's indicators increased. Families of children with lower FES cohesion subscores presented higher OR for ADHD-I (OR 1.24; 95% confidence interval 1.05-1.45). Lower levels of FRI, a general index of family relationship, were also related to higher risk of ADHD-I (OR 1.11; 95% confidence interval 1.03-1.21). Our findings suggest that family adversity (in general), low family cohesion and low FRI (in particular) are associated with an increase in the risk for ADHD-I. However, the cross-sectional nature of the study limits our ability to infer causality. PMID- 21290155 TI - Pouch of Douglas pelvic hernia: a rare entity managed laparoscopically. AB - Pouch of Douglas hernias are uncommon forms of pelvic hernia. They are most commonly seen in multiparous, elderly women and those having undergone previous pelvic surgery (Stamatiou et al. in Am Surg 76(5):474-479, 2010). Herein, we present a case of a 77-year-old female presenting with groin pain due to a Pouch of Douglas hernia. She had no previous abdominal or pelvic surgery. This was repaired via a trans-abdominal pre-peritoneal approach and the patient's symptoms resolved. To our knowledge, this is the first case report in the literature of an idiopathic Pouch of Douglas hernia managed laparoscopically. PMID- 21290156 TI - Laparoscopic totally extra-peritoneal inguinal hernia repair: 9 year's experience. AB - PURPOSE: Major innovations continue to occur in the operative techniques used in hernia operations. Laparoscopic totally extra-peritoneal (TEP) hernia repair is the latest addition to the long list of operations used for hernia repair. The objectives of this study were to assess the safety and efficacy of this relatively new procedure and to discuss various technical aspects to make the procedure easy to learn. METHODS: Patients who underwent elective inguinal hernia repair from January 2000 to December 2008 were included in this ongoing prospective clinical study. Patient demographic data, operative records, perioperative findings, postoperative morbidity and outpatient follow-up of TEP repairs were studied. RESULTS: Out of 1,814 hernia operations, 1,539 (84.84%) were performed by laparoscopic TEP repair and 275(15.16%) were operated by Lichtenstein repair. There were 19 conversions from attempted TEP to open surgeries. Mean operative time for unilateral TEP repair was 28 +/- 7 min and for bilateral repair 36 +/- 8 min The incidence of intra-operative complications was 2.98%. Overall morbidity rate was 8.57%. The usual hospital stay was 36 h. The recurrence rate in first 3 years was 8.00%, the next 3 years, 2.05% and in the last 3 years, 0.67%. The longest interval between operation and recurrence was 48 months. CONCLUSIONS: Laparoscopic TEP repair is an excellent mode of treatment in the era of laparoscopic surgery. If the standard technique now established is followed, the procedure is easy to learn for a laparoscopic surgeon, the overall morbidity and complications are fewer in number and severity, and recurrence rates are lower. PMID- 21290157 TI - Unusual cause of cerebral vasospasm after pituitary surgery. AB - Cerebral vasospasm (CVS) was described in patients after trans-sphenoidal pituitary surgery due to intra-operative trauma of arteries or blood clots around the arteries of Willis' circle. We consider that in the two presented cases the main cause of CVS in early postoperative period was meningitis. Two patients with pituitary adenomas were operated with trans-sphenoidal approach. CVS developed in early postoperative period. Meningitis was revealed in both cases. CVS regressed only after successful treatment of meningitis. In the first case empiric antibiotic therapy was ineffective and CVS remained until Klebsiella pneumonia was detected in CSF and specific therapy was performed. In the second case empiric therapy was effective and CVS vasospasm regressed in 12 days. These cases show that meningitis can be a leading cause of CVS in early postoperative period in trans-sphenoidal pituitary surgery. Adequate treatment of meningitis shortens duration of CVS in these patients. PMID- 21290158 TI - Obsessive-compulsive disorder: a new risk factor for Alzheimer disease? AB - We describe a case of a 75-year-old woman referred to the Memory Clinic of the neurological Department of Charles Nicolle Hospital, Tunis, for cognitive decline and behavioral disturbances. Her past medical history was marked by severe obsessive-compulsive disorder (OCD) with contamination obsessions and washing compulsions. She has a family history for OCD and/or of dementia in 15 members. Clinical features, along with neuropsychological findings and Brain imaging were in favor of Alzheimer disease (AD). The present report is the first family study reporting the possible association of OCD and AD. The glutamatergic dysfunction may be a common pathophysiology of OCD and AD explaining this association. PMID- 21290159 TI - Unusual segmental narrowing of spinal cord responsible for child paraparesis. AB - We describe a 7-year-old girl with spastic paraparesis. Her clinical condition was due to a unusual segmental thoracic narrowing of spinal cord. We show the imaging of her spinal cord, we compare her condition with the few similar cases from the literature and we try to suppose an aetiology. PMID- 21290160 TI - Somatic and autonomic small fiber neuropathy induced by bortezomib therapy: an immunofluorescence study. AB - Bortezomib is a new chemotherapeutic agent approved for the treatment of relapsed/refractory and newly diagnosed multiple myeloma. One of the major side effects of bortezomib is a peripheral length-dependent sensory axonal neuropathy and, less frequently, a small fiber neuropathy. Autonomic symptoms like postural dizziness, syncope, diarrhoea, ileus, impotence and urinary disturbances have been reported, nevertheless, autonomic neuropathy has never been characterized. We describe by means of immunofluorescence, the involvement of autonomic skin nerve fibers in three patients with small fiber neuropathy induced by bortezomib treatment. PMID- 21290161 TI - Fluctuating frontal lobe dysfunction in a patient with moyamoya disease. PMID- 21290162 TI - Associations between problematic mobile phone use and psychological parameters in young adults. AB - OBJECTIVES: This study aims to address possible associations between excessive or dysfunctional use of mobile phones and certain psychological variables. METHODS: Our study focuses on Problematic Mobile Phone Use (PU) in 196 young adults. A survey was arranged to measure PU, daily mobile phone use in minutes, use of short message service (SMS) and also included psychological and health variables (e.g., chronic stress, depression). RESULTS: Statistic analysis indicates that chronic stress, low emotional stability, female gender, young age, depression, and extraversion are associated with PU. CONCLUSIONS: Future research needs to clarify the causality of these findings and should also intend to develop concepts for a more meaningful use of mobile phone and related technologies. PMID- 21290163 TI - HDAC2 and TXNL1 distinguish aneuploid from diploid colorectal cancers. AB - DNA aneuploidy has been identified as a prognostic factor for epithelial malignancies. Further understanding of the translation of DNA aneuploidy into protein expression will help to define novel biomarkers to improve therapies and prognosis. DNA ploidy was assessed by image cytometry. Comparison of gel electrophoresis-based protein expression patterns of three diploid and four aneuploid colorectal cancer cell lines detected 64 ploidy-associated proteins. Proteins were identified by mass spectrometry and subjected to Ingenuity Pathway Analysis resulting in two overlapping high-ranked networks maintaining Cellular Assembly and Organization, Cell Cycle, and Cellular Growth and Proliferation. CAPZA1, TXNL1, and HDAC2 were significantly validated by Western blotting in cell lines and the latter two showed expression differences also in clinical samples using a tissue microarray of normal mucosa (n=19), diploid (n=31), and aneuploid (n=47) carcinomas. The results suggest that distinct protein expression patterns, affecting TXNL1 and HDAC2, distinguish aneuploid with poor prognosis from diploid colorectal cancers. PMID- 21290164 TI - The structure of the Klf4 DNA-binding domain links to self-renewal and macrophage differentiation. AB - Krueppel-like factor 4 (Klf4) belongs to the Sp/Klf family of zinc-finger transcription factors and is indispensable for terminal maturation of epithelial tissues. Furthermore, it is part of a small set of proteins that are used to generate pluripotent embryonic stem cells from differentiated tissues. Herein, we describe that a Klf4 zinc-finger domain mutant induces self-renewal and block of maturation, while wild-type Klf4 induces terminal macrophage differentiation. Moreover, we present the crystal structure of the zinc-finger domain of Klf4 bound to its target DNA, revealing that primarily the two C-terminal zinc-finger motifs are required for site specificity. Lack of those two zinc fingers leads to deficiency of Klf4 to induce macrophage differentiation. The first zinc finger, on the other hand, inhibits the otherwise cryptic self-renewal and block of differentiation activity of Klf4. Our data show that impairing the DNA binding could potentially contribute to a monocytic leukemia. PMID- 21290165 TI - Trehalose accumulation from cassava starch and release by a highly thermosensitive and permeable mutant of Saccharomycopsis fibuligera. AB - Highly thermosensitive and permeable mutants are the mutants from which intracellular contents can be released when they are incubated both in low osmolarity water and at non-permissive temperature (usually 37 degrees C). After mutagenesis by using nitrosoguanidine, a highly thermosensitive and permeable mutant named A11-b was obtained from Saccharomycopsis fibuligera A11-12, a trehalose overproducer in which the acid protease gene has been disrupted. Of the total trehalose, 73.8% was released from the mutant cells suspended in distilled water after they had been treated at 37 degrees C overnight. However, only 10.0% of the total trehalose was released from the cells of S. fibuligera A11-12 treated under the same conditions. The cell volume of the mutant cells suspended in distilled water and treated at 37 degrees C overnight was much bigger than that of S. fibuligera A11-12 treated under the same conditions. The cell growth and trehalose accumulation of the mutant were almost the same as those of S. fibuligera A11-12 during the cultivation at the flask level and in a 5-l fermentor. Both could accumulate around 28.0% (w/w) trehalose from cassava starch. After purification, the trehalose crystal from the aqueous extract of the mutant was obtained. PMID- 21290166 TI - Retinal disorders in northern Brazilian patients treated with chloroquine assessed by multifocal ERG. AB - The effects of chloroquine intake on the retinal function in a Brazilian population of patients were assessed by multifocal electroretinography. Twenty four randomly chosen eyes of patients treated with chloroquine for rheumatoid arthritis and systemic lupus erythematosus were examined using multifocal electroretinography (mfERG). Control measurements were acquired from 21 randomly chosen eyes of age-matched healthy subjects. None of the study participants had an inherited retinal disease or a Snellen visual acuity reduced to less than 20/40. In patients and control subjects, cumulative chloroquine dose, total daily dose, duration of treatment, retinal examination, visual field defects, visual acuity, and the mfERG were assessed. The average amplitudes and implicit times of the N1, P1, and P2 components of the mfERGs were measured in the central hexagon (R1) and in five rings (R2-R6). The values measured in patients and normal subjects were compared. The P1 amplitudes in R2 were significantly decreased in the patients. In addition, the amplitudes of N1 and N2 in R1 were significantly smaller in the patients. The implicit times of none of the components were significantly different between patients and controls. The response amplitude was not significantly correlated with cumulative dose and duration of intake. There was no correlation with retinal appearance, visual field, and visual acuity. In agreement with earlier data, the central mfERG amplitudes were decreased in chloroquine patients indicating functional alterations in the retina. These changes are also present in a Brazilian population suggesting that the effects of chloroquine are general and that genetic background and life circumstances probably have, if at all, only little effect. PMID- 21290167 TI - Corrosion protection of low-carbon steel using exopolysaccharide coatings from Leuconostoc mesenteroides. AB - Corrosion of metals is a serious and challenging problem faced worldwide by industry. Purified Leuconostoc mesenteroides exopolysaccharide (EPS) coatings, cast from aqueous solution, inhibited the corrosion of low-carbon steel as determined by electrochemical impedance spectroscopy (EIS). There were two different corrosion behaviors exhibited when EPS films from different strains were cast onto the steel. One EPS coating reacted immediately with the steel substrate to form an iron (III) oxide layer ("rust") during the drying process while another did not. The samples that did not flash corrode had higher corrosion inhibition and formed an iron (II) passivation layer during EIS testing that persisted after the cells were disassembled. Corrosion inhibition was strain specific as polysaccharides with similar structure did not have the same corrosion potential. PMID- 21290168 TI - Production of biologically active human thioredoxin 1 protein in lettuce chloroplasts. AB - The production of human therapeutic proteins in plants provides opportunities for low-cost production, and minimizes the risk of contamination from potential human pathogens. Chloroplast genetic engineering is a particularly promising strategy, because plant chloroplasts can produce large amounts of foreign target proteins. Oxidative stress is a key factor in various human diseases. Human thioredoxin 1 (hTrx1) is a stress-induced protein that functions as an antioxidant against oxidative stress, and overexpression of hTrx1 has been shown to suppress various diseases in mice. Therefore, hTrx1 is a prospective candidate as a new human therapeutic protein. We created transplastomic lettuce expressing hTrx1 under the control of the psbA promoter. Transplastomic plants grew normally and were fertile. The hTrx1 protein accumulated to approximately 1% of total soluble protein in mature leaves. The hTrx1 protein purified from lettuce leaves was functionally active, and reduced insulin disulfides. The purified protein protected mouse insulinoma line 6 cells from damage by hydrogen peroxide, as reported previously for a recombinant hTrx1 expressed in Escherichia coli. This is the first report of expression of the biologically active hTrx1 protein in plant chloroplasts. This research opens up possibilities for plant-based production of hTrx1. Considering that this expression host is an edible crop plant, this transplastomic lettuce may be suitable for oral delivery of hTrx1. PMID- 21290169 TI - In vitro dissolution and corrosion study of calcium phosphate coatings elaborated by pulsed electrodeposition current on Ti6Al4V substrate. AB - Calcium-deficient hydroxyapatite (Ca-def-HAP) coatings on titanium alloy (Ti6Al4V) substrates are elaborated by pulsed electrodeposition. In vitro dissolution/precipitation process is investigated by immersion of the coated substrate into Dulbecco's Modified Eagle Medium (DMEM) from 1 h to 28 days. Calcium and phosphorus concentrations evolution in the biological liquid are determined by Induced Coupled Plasma-Atomic Emission Spectroscopy (ICP-AES) for each immersion time. Physical and chemical characterizations of the coating are performed by scanning electron microscopy (SEM) associated to Energy Dispersive X ray Spectroscopy (EDXS) for X-ray microanalysis. Surface modifications are investigated by an original method based on the three-dimensional reconstruction of SEM images (3D-SEM). Moreover, corrosion measurements are carried out by potentiodynamic polarization experiments. The results show that the precipitation rate of the Ca-def HAP coating is more pronounced in comparison with that of stoichiometric hydroxyapatite (HAP) used as reference. The precipitated bone-like apatite coating is thick, homogenous and exhibits an improved link to the substrate. Consequently, the corrosion behaviour of the elaborated prosthetic material is improved. PMID- 21290170 TI - Hollow hydroxyapatite microspheres as a device for controlled delivery of proteins. AB - Hollow hydroxyapatite (HA) microspheres were prepared by reacting solid microspheres of Li(2)O-CaO-B(2)O(3) glass (106-150 MUm) in K(2)HPO(4) solution, and evaluated as a controlled delivery device for a model protein, bovine serum albumin (BSA). Reaction of the glass microspheres for 2 days in 0.02 M K(2)HPO(4) solution (pH = 9) at 37 degrees C resulted in the formation of biocompatible HA microspheres with a hollow core diameter equal to 0.6 the external diameter, high surface area (~100 m(2)/g), and a mesoporous shell wall (pore size ~ 13 nm). After loading with a solution of BSA in phosphate-buffered saline (PBS) (5 mg BSA/ml), the release kinetics of BSA from the HA microspheres into a PBS medium were measured using a micro bicinchoninic acid (BCA) protein assay. Release of BSA initially increased linearly with time, but almost ceased after 24-48 h. Modification of the BSA release kinetics was achieved by modifying the microstructure of the as-prepared HA microspheres using a controlled heat treatment (1-24 h at 600-900 degrees C). Sustained release of BSA was achieved over 7-14 days from HA microspheres heated for 5 h at 600 degrees C. The amount of BSA released at a given time was dependent on the concentration of BSA initially loaded into the HA microspheres. These hollow HA microspheres could provide a novel inorganic device for controlled local delivery of proteins and drugs. PMID- 21290171 TI - Lineage-based primary muscle fiber type diversification independent of MEF2 and NFAT in chick embryos. AB - Differences in primary avian skeletal muscle fiber types are based on myoblast cell lineages and independent of innervation. To understand the basis for this mode of myogenesis, embryonic myoblasts specifically committed to the formation of either fast or fast/slow muscle fiber types were isolated, characterized, and examined for their capacities to transcriptionally regulate the slow myosin heavy chain 2 (MyHC2) gene. Myogenic basic helix-loop-helix protein binding sites within the slow MyHC2 promoter were mutated and did not direct fast versus fast/slow muscle fiber type development. Using promoter analyses coupled with overexpression studies and transcriptional sensors, the roles of Nuclear Factor of Activated T cells (NFATc1), and MEF2A in regulation of the slow MyHC2 gene were determined. MEF2A activated the slow MyHC2 promoter in both fast and fast/slow primary muscle fibers. In contrast, NFATc1 repressed promoter activity. These results do not support the roles of MEF2 and NFAT as direct regulators of primary muscle fiber type differences. Rather, the results reflect intrinsic differences in the modes of regulation of the slow MyHC2 gene in primary muscle fiber types. PMID- 21290172 TI - Spatial analysis of preterm birth demonstrates opportunities for targeted intervention. AB - To develop a specific, targeted intervention strategy for reducing preterm birth through use of geographic analysis. We utilized Hamilton County, Ohio vital records and Census data from 2003 to 2006. Spatial scanning statistics allowed determination of the prevalence of preterm birth for any geographical point. Attributable risk calculations demonstrated heterogeneity of risk factors within areas of high or low preterm birth prevalence. Three geographically separate areas with high preterm birth proportions (>16%) had differing primary risk factors for preterm birth, including short interpregnancy interval, previous preterm birth, and low prepregnancy weight, despite similarities in demographics and physical location. Primary risk factors also differed when comparing areas with high and low preterm birth proportions, with diabetes and smoking having primary associations in the lower risk areas. Each local region of high preterm birth proportion as well as those with average or low proportion displayed distinct hierarchies of attributable risk. The heterogeneous distribution of preterm birth proportion within an urban county is complex and requires location specific analysis to develop targeted interventions. PMID- 21290173 TI - Pediatric poisonings and risk markers for hospital admission in a major emergency department in Romania. AB - To identify the prevalence, characteristics, and risk markers for childhood poisonings treated in the emergency department of a large Romanian hospital. Trauma registry data using ICD-10 codes and case summaries were studied to identify poisonings among children aged 0-18. Multivariate logistic regression identified factors associated with hospital admission. Between 1999 and 2003, 1,173 pediatric trauma cases were seen in the emergency department; 437 (37.3%) were treated for poisoning, including medication (35%), alcohol (26%), chemical products (19%), and carbon monoxide (14%). Half of all poisonings were unintentional, primarily affecting children < 10 years. Half were intentional, mainly affecting children 10-18. Females were three times more likely than males to have documented suicidal intent (P < .0001). Over 30% of suicide attempts were among children ages 10-14 (P < .0001). We report significantly increased adjusted odds ratios (P < .05) of hospital admission for children 10-18, and for chemical substance poisoning, and suicidal intent. Pediatric poisoning is a serious public health issue in Romania, and we suggest these findings are relevant across other eastern European countries with limited resources. Poisonings result in morbidity and hospital admissions, yet there are few prevention resources available. Health education programs and consumer product safety policies are needed in Romania and eastern Europe. PMID- 21290174 TI - Atypical brain responses to reward cues in autism as revealed by event-related potentials. AB - Social motivation deficit theories suggest that children with autism do not properly anticipate and appreciate the pleasure of social stimuli. In this study, we investigated event-related brain potentials evoked by cues that triggered social versus monetary reward anticipation in children with autism. Children with autism showed attenuated P3 activity in response to cues associated with a timely reaction to obtain a reward, irrespective of reward type. We attribute this atypical P3 activity in response to reward cues as reflective of diminished motivated attention to reward signals, a possible contributor to reduced social motivation in autism. Thus, our findings suggest a general reward processing deficit rather than a specific social reward dysfunction in autism. PMID- 21290175 TI - Blame, symbolic stigma and HIV misconceptions are associated with support for coercive measures in urban India. AB - This study was designed to examine the prevalence of stigma and its underlying factors in two large Indian cities. Cross-sectional interview data were collected from 1,076 non-HIV patients in multiple healthcare settings in Mumbai and Bengaluru, India. The vast majority of participants supported mandatory testing for marginalized groups and coercive family policies for PLHA, stating that they "deserved" their infections and "didn't care" about infecting others. Most participants did not want to be treated at the same clinic or use the same utensils as PLHA and transmission misconceptions were common. Multiple linear regression showed that blame, transmission misconceptions, symbolic stigma and negative feelings toward PLHA were significantly associated with both stigma and discrimination. The results indicate an urgent need for continued stigma reduction efforts to reduce the suffering of PLHA and barriers to prevention and treatment. Given the high levels of blame and endorsement of coercive policies, it is crucial that such programs are shaped within a human rights framework. PMID- 21290176 TI - Socioeconomic inequalities in attending the mass screening for breast cancer in the south of the Netherlands--associations with stage at diagnosis and survival. AB - The associations of socioeconomic status (SES) and participation in the breast cancer screening program, as well as consequences for stage of disease and prognosis were studied in the Netherlands, where no financial barriers for participating or health care use exist. From 1998 to 2005, 1,067,952 invitations for biennial mammography were sent to women aged 50-75 in the region covered by the Eindhoven Cancer Registry. Screening attendance rates according to SES were calculated. Tumor stage and survival were studied according to SES group for patients diagnosed with breast cancer between 1998 and 2006, whether screen detected, interval carcinoma or not attended screening at all. Attendance rates were rather high: 79, 85 and 87% in women with low, intermediate and high SES (p < 0.001), respectively. Compared to the low SES group, odds ratios for attendance were 1.5 (95%CI:1.5-1.6) for the intermediate SES group and 1.8 (95%CI:1.7-1.8) for the high SES group. Moreover, women with low SES had an unfavorable tumor node-metastasis stage compared to those with high SES. This was seen in non attendees, among women with interval cancers and with screen-detected cancers. Among non-attendees and interval cancers, the socioeconomic survival disparities were largely explained by stage distribution (48 and 35%) and to a lesser degree by therapy (16 and 16%). Comorbidity explained most survival inequalities among screen-detected patients (23%). Despite the absence of financial barriers for participation in the Dutch mass-screening program, socioeconomic inequalities in attendance rates exist, and women with low SES had a significantly worse tumor stage and lower survival rate. PMID- 21290177 TI - Factor analysis of a modified version of the California Brief Multicultural Competence Scale with minority pharmacy students. AB - While most of the more frequently used self-report measures of cultural competence in health professionals are targeted to practicing physicians and mental health providers from the majority-white population, no measures have been specifically developed for minority pharmacy students. With the objective to find a suitable tool to be used for curriculum development in cultural competence, this study applied a modified version of the California Brief Multicultural Competence Scale (CBMCS) to 467 pharmacy students at the Xavier University of Louisiana, a Historically Black University. Confirmatory and exploratory factor analyses were conducted to examine if the CBMCS factor structure was replicated using a modified tool and a different population and Cronbach alphas were calculated to determine internal consistency reliability. The CBMCS's original factor structure was not replicated, perhaps because of modifications introduced in the original tool or because of differences between the sample population in this study (minority pharmacy students) and the population used in the original CBMCS study (majority-white mental health providers). However, results show that a modified factor structure fits the data well. The primary difference between the factors found in this study and the CBMCS factors is the appearance of a new factor composed of three items related to interpersonal and racial dynamics, which includes racial discrimination, white privilege, and power imbalance. The significant relationships (p < 0.001) found between respondents' race and these three items suggest that the wording in these items should be modified when the respondents do not belong to the majority population. Results imply that racism, prejudice and bias are not just issues of the majority-white health providers and point to the need for more racially diverse samples. The unique results in this study advance research on racial dynamics and self-assessment of cultural competence of minority health professionals. PMID- 21290178 TI - In search of HPA axis dysregulation in child and adolescent depression. AB - Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in adults with major depressive disorder is among the most consistent and robust biological findings in psychiatry. Given the importance of the adolescent transition to the development and recurrence of depressive phenomena over the lifespan, it is important to have an integrative perspective on research investigating the various components of HPA axis functioning among depressed young people. The present narrative review synthesizes evidence from the following five categories of studies conducted with children and adolescents: (1) those examining the HPA system's response to the dexamethasone suppression test (DST); (2) those assessing basal HPA axis functioning; (3) those administering corticotropin releasing hormone (CRH) challenge; (4) those incorporating psychological probes of the HPA axis; and (5) those examining HPA axis functioning in children of depressed mothers. Evidence is generally consistent with models of developmental psychopathology that hypothesize that atypical HPA axis functioning precedes the emergence of clinical levels of depression and that the HPA axis becomes increasingly dysregulated from child to adult manifestations of depression. Multidisciplinary approaches and longitudinal research designs that extend across development are needed to more clearly and usefully elucidate the role of the HPA axis in depression. PMID- 21290179 TI - Natural history and outcome of hepatic vascular malformations in a large cohort of patients with hereditary hemorrhagic teleangiectasia. AB - BACKGROUND: Hereditary hemorrhagic telangiectasia is a genetic disease characterized by teleangiectasias involving virtually every organ. There are limited data in the literature regarding the natural history of liver vascular malformations in hemorrhagic telangiectasia and their associated morbidity and mortality. AIM: This prospective cohort study sought to assess the outcome of liver involvement in hereditary hemorrhagic telangiectasia patients. METHODS: We analyzed 16 years of surveillance data from a tertiary hereditary hemorrhagic telangiectasia referral center in Italy. We considered for inclusion in this study 502 consecutive Italian patients at risk of hereditary hemorrhagic telangiectasia who presented at the hereditary hemorrhagic telangiectasia referral center and underwent a multidisciplinary screening protocol for the diagnosis of hereditary hemorrhagic telangiectasia. Of the 502 individuals assessed in the center, 154 had hepatic vascular malformations and were the subject of the study; 198 patients with hereditary hemorrhagic telangiectasia and without hepatic vascular malformations were the controls. Additionally, we report the response to treatment of patients with complicated hepatic vascular malformations. RESULTS: The 154 patients were included and followed for a median period of 44 months (range 12-181); of these, eight (5.2%) died from VM-related complications and 39 (25.3%) experienced complications. The average incidence rates of death and complications were 1.1 and 3.6 per 100 person-years, respectively. The median overall survival and event-free survival after diagnosis were 175 and 90 months, respectively. The rate of complete response to therapy was 63%. CONCLUSIONS: This study shows that substantial morbidity and mortality are associated with liver vascular malformations in hereditary hemorrhagic telangiectasia patients. PMID- 21290180 TI - Elevated levels of circulating angiotensin converting enzyme in patients with hepatoportal sclerosis. AB - BACKGROUND AND AIMS: Hepatoportal sclerosis (HPS) is a clinicopathologic condition that is clinically characterized by portal hypertension (varices and portosystemic collateral vessels), splenomegaly and pancytopenia, in the absence of cirrhosis. Although the etiology is obscure, a number of theories such as immunologic and vascular endothelial cellular abnormalities have been put forward to explain the underlying pathophysiology. Angiotensin-converting enzyme (ACE), an important molecule of the renin-angiotensin system (RAS), is also known as a regulatory molecule in systemic and portal circulation in distinct disorders. The aim of the present study was to investigate the possible role of the ACE in the context of RAS in HPS pathogenesis. MATERIALS AND METHODS: The study was conducted on 30 HPS patients (16 men, 14 women; median age 36 years, range 18-63) and 20 healthy controls. The clinical features of HPS patients including demographics, laboratory, and ultrasonography findings were summarized. Serum ACE levels were measured by using commercially available kits. RESULTS: Serum median ACE levels were 36 (8-174) U/l and 16 (8-43) U/l for the HPS patients and controls, respectively. Serum ACE levels were significantly higher in patients with HPS compared to the control group (P < 0.05). CONCLUSION: ACE in the context of RAS may be associated with pathological endothelial occlusive events in the microenvironment of the portal circulation in HPS. Revealing the interactions between circulating and local RAS within the hepatic microenvironment would enlighten the biologic basis and clinical management of liver diseases. PMID- 21290181 TI - Subtypes of irritable bowel syndrome based on abdominal pain/discomfort severity and bowel pattern. AB - INTRODUCTION: Irritable bowel syndrome (IBS) has traditionally been classified by stooling pattern (e.g., diarrhea-predominant). However, other patterns of symptoms have long been recognized, e.g., pain severity. Our objective was to examine the utility of subtyping women with IBS based on pain/discomfort severity as well as predominant bowel pattern. METHODS: Women (n = 166) with IBS completed interviews, questionnaires, and kept a diary for 28 days. Rome II questionnaire items eliciting the past year recall of hard and loose stools, and frequency and severity of abdominal pain or discomfort were used to classify participants into six subtypes-three bowel pattern categories by two pain/discomfort severity categories. Concordance of these subtypes with corresponding diary items was examined. Analysis of variance (ANOVA) tested the relationship of bowel pattern and pain categories to measures of quality of life and symptoms. RESULTS: There is moderate congruence of the retrospective classification of bowel pattern and pain/discomfort severity subtypes with prospectively reported stool frequency and consistency and pain severity. Quality of life, impact of IBS on work and daily activities, and cognitive beliefs about IBS differed significantly based on abdominal pain/discomfort category but not on predominant bowel pattern. There is evidence of an interaction, with the effect of pain severity being strong in the IBS-diarrhea and IBS-mixed groups, but this was absent in the IBS-constipation group. Similar results hold for most diary symptoms, except for those directly related to bowel pattern. CONCLUSIONS: Overall, the distress of IBS is more strongly related to the severity of abdominal pain/discomfort than is the predominant stool pattern in patients with IBS. Categorizing IBS patients by abdominal pain/discomfort severity in conjunction with predominant bowel pattern may be useful to clinicians and researchers in developing more effective management. PMID- 21290182 TI - Dietary treatment of phenylketonuria: the effect of phenylalanine on reaction time. AB - There is no evidence that high phenylalanine (Phe) levels have irreversible effects on the adult brain. Many adults with phenylketonuria (PKU) no longer follow a protein-restricted diet. Neuropsychological studies have shown that reaction time in adults with PKU is slower than controls. There are no data to show that this is directly related to Phe levels. Another way to assess reaction time is to measure saccadic latency. We have used a portable, head-mounted saccadometer to measure latency in the outpatient setting. Patients with PKU were split into three groups: off-diet (Phe >1,200 MUmol/l), on-diet (Phe < 800 MUmol/l) and maternal diet (Phe 100-400 MUmol/l ). Reciprocal median latency (RML) was compared between groups. Latency was significantly slower in patients who were off-diet than in patients on-diet, on a maternal diet or in normal controls. Reaction times in both diet-treated groups were not significantly different from normal controls. In 16 women planning pregnancy we obtained values before and after they commenced the maternal diet. Stricter control of Phe levels resulted in a significant improvement in reaction times. We conclude that saccadometry is useful in monitoring PKU patients. Adult patients with PKU not on a protein-restricted diet have significantly slower reaction times than controls. In addition, off-diet patients have significantly slower reaction times than on diet. Paired data show that effects of Phe levels on reaction time are reversible. PMID- 21290183 TI - Evaluation of high density lipoprotein as a circulating biomarker of Gaucher disease activity. AB - Circulating biomarkers are important surrogates for monitoring disease activity in type I Gaucher disease (GD1). We and others have reported low high-density lipoprotein (HDL) in GD1. We assessed HDL cholesterol as a biomarker of GD1, with respect to its correlation with indicators of disease severity and its response to imiglucerase enzyme replacement therapy (ERT). In 278 consecutively evaluated GD1 patients, we correlated HDL cholesterol, chitotriosidase, and angiotensin converting enzyme (ACE) with indicators of disease severity. Additionally, we measured the response of these biomarkers to ERT. HDL cholesterol was negatively correlated with spleen volume, liver volume, and GD severity score index; the magnitude of this association of disease severity with HDL cholesterol was similar to that for ACE and for chitotriosidase. Within individual patients monitored over many years, there was a strikingly strong correlation of HDL with liver and spleen volumes; there was a similarly strong correlation of chitotriosidase and ACE with disease severity in individual patients monitored serially over many years (chitotriosidase r = 0.96 to 0.98, ACE r = 0.88 to 0.94, and HDL r = -0.84 to -0.94, p < 0.001). ERT for 3 years resulted in a striking increase of HDL while serum levels of chitotriosidase and ACE decreased. Our results reveal markedly low HDL cholesterol in untreated GD1, a correlation with indicators of disease severity in GD1, and a rise towards normal after ERT. These findings suggest HDL cholesterol merits inclusion within the "biomarker basket" for monitoring of patients with GD1. PMID- 21290184 TI - Features and outcome of galactokinase deficiency in children diagnosed by newborn screening. AB - Galactokinase deficiency (GALK-D), an autosomal recessive disorder in the Leloir pathway, results in accumulation of galactose, galactitol, and galactonate and leads to early onset of juvenile bilateral cataract. Highest incidence of GALK-D is found in Romani populations. The migration wave due to the Yugoslavian civil war has changed the spectrum of inborn errors of metabolism within Europe. Hence, newborn screening (NBS) in the Berlin region, performed from 1991 until 2010 in 683,675 neonates, revealed an increased incidence of GALK-D of 1:40,000, comparable to that of galactose-1-phosphate-uridyltransferase deficiency. A total of 44% of GALK-D patients were of Romani origin. All patients of Bosnian or Serbian origin were homozygous for the Romani founder mutation p.P28T. Detection of GALK-D by NBS and early start of galactose-restricted diet resulted in regression or prevention of cataracts. Slight cataracts without visual impairment occurred in 50% of the patients, 56% of whom were noncompliant. Further clinical symptoms, e.g., hypoglycemia, mental retardation, microcephaly, and failure to thrive, were associated with noncompliance. With treatment, galactose in blood decreased from 8,892 +/- 5,243 to 36.5 +/- 49.3 MUmol/l, galactose in urine from 31,820 +/- 32,103 to 30.0 +/- 36.1 MUmol/mmol creatinine, galactitol in RBC from 1,584 +/- 584 to 12.3 +/- 9.4 MUmol/l, and galactitol in urine from 11,724 +/- 4,496 to 236 +/- 116 MUmol/mmol creatinine. This is the first presentation of outcome and clinical features in GALK-D patients diagnosed by NBS. As our data suggest, GALK-D should be considered for inclusion in NBS in populations expected to have substantial numbers of GALK-D carriers, e.g., Yugoslavian immigrants. PMID- 21290185 TI - Advances and challenges in the treatment of branched-chain amino/keto acid metabolic defects. AB - Disorders of branched-chain amino/keto acid metabolism encompass diverse entities, including maple syrup urine disease (MSUD), the 'classical' organic acidurias isovaleric acidemia (IVA), propionic acidemia (PA), methylmalonic acidemia (MMA) and, among others, rarely described disorders such as 2 methylbutyryl-CoA dehydrogenase deficiency (MBDD) or isobutyryl-CoA dehydrogenase deficiency (IBDD). Our focus in this review is to highlight the biochemical basis underlying recent advances and ongoing challenges of long-term conservative therapy including precursor/protein restriction, replenishment of deficient substrates, and the use of antioxidants and anaplerotic agents which refill the Krebs cycle. Ongoing clinical assessments of affected individuals in conjunction with monitoring of disease-specific biochemical parameters remain essential. It is likely that mass spectrometry-based 'metabolomics' may be a helpful tool in the future for studying complete biochemical profiles and diverse metabolic phenotypes. Prospective studies are needed to test the effectiveness of adjunct therapies such as antioxidants, ornithine-alpha-ketoglutarate (OKG) or creatine in addition to specialized diets and to optimize current therapeutic strategies in affected individuals. With the individual life-time risk and degree of severity being unknown in asymptomatic individuals with MBDD or IBDD, instructions regarding risks for metabolic stress and fasting avoidance along with clinical monitoring are reasonable interventions at the current time. Overall, it is apparent that carefully designed prospective clinical investigations and multicenter cohort-controlled trials are needed in order to leverage that knowledge into significant breakthroughs in treatment strategies and appropriate approaches. PMID- 21290186 TI - Parenting a child with phenylketonuria or galactosemia: implications for health related quality of life. AB - Parents of children with chronic disorders have an impaired health-related quality of life (HRQoL) compared to parents of healthy children. Remarkably, parents of children with a metabolic disorder reported an even lower HRQoL than parents of children with other chronic disorders. Possibly, the uncertainty about the course of the disease and the limited life expectancy in many metabolic disorders are important factors in the low parental HRQoL. Therefore, we performed a cross-sectional study in parents of children with phenylketonuria (PKU, OMIM #261600) and galactosemia (OMIM #230400), metabolic disorders not affecting life expectancy, in order to investigate their HRQoL compared to parents of healthy children and to parents of children with other metabolic disorders. A total of 185 parents of children with PKU and galactosemia aged 1-19 years completed two questionnaires. Parents of children with PKU or galactosemia reported a HRQoL comparable to parents of healthy children and a significantly better HRQoL than parents of children with other metabolic disorders. Important predictors for parental mental HRQoL were the psychosocial factors emotional support and loss of friendship. As parental mental functioning influences the health, development and adjustment of their children, it is important that treating physicians also pay attention to the wellbeing of the parents. The insight that emotional support and loss of friendship influence the HRQoL of the parents enables treating physicians to provide better support for these parents. PMID- 21290187 TI - Language production and working memory in classic galactosemia from a cognitive neuroscience perspective: future research directions. AB - Most humans are social beings and we express our thoughts and feelings through language. In contrast to the ease with which we speak, the underlying cognitive and neural processes of language production are fairly complex and still little understood. In the hereditary metabolic disease classic galactosemia, failures in language production processes are among the most reported difficulties. It is unclear, however, what the underlying neural cause of this cognitive problem is. Modern brain imaging techniques allow us to look into the brain of a thinking patient online - while she or he is performing a task, such as speaking. We can measure indirectly neural activity related to the output side of a process (e.g. articulation). But most importantly, we can look into the planning phase prior to an overt response, hence tapping into subcomponents of speech planning. These components include verbal memory, intention to speak, and the planning of meaning, syntax, and phonology. This paper briefly introduces cognitive theories on language production and methods used in cognitive neuroscience. It reviews the possibilities of applying them in experimental paradigms to investigate language production and verbal memory in galactosemia. PMID- 21290188 TI - In vitro antioxidant activity of aged extracts of some Italian Allium species. AB - Antioxidant activity of fresh Allium sativum L. (garlic) is well known and is mainly due to unstable and irritating organosulphur compounds. Fresh garlic extracted over a prolonged period (up to 20 months) produces odourless aged garlic extract (AGE) containing stable and water soluble organosulphur compounds that prevent oxidative damage by scavenging free radicals. The aim of this study was to investigate the in vitro antioxidant activity of aged (up to 20 months) 15% hydroethanolic extracts of different parts (bulbs, bulblets, flower bulblets, flowers, and leaves) of three Allium spontaneous species which are endemic for Italian flora: Allium neapolitanum Cyr., Allium subhirsutum L., Allium roseum L. and to compare it with the in vitro antioxidant activity of aged 15% hydroethanolic extracts of bulbs and leaves of garlic. The antioxidant potential of aged extracts of all species has been evaluated using two different spectrophotometric assays: 2,2-diphenylpicrylhydrazyl (DPPH) test and the ferric reducing/antioxidant power (FRAP) assay. Furthermore the polyphenol content was determined. The aged extracts obtained from the leaves showed the best antioxidant activity, followed by flowers and then by bulbs in both used tests, while flower bulblets and bulblets exhibited lower results or no activity. The polyphenol content was generally directly correlated with antioxidant/antiradical activity. This study confirms the data obtained in previous researches, the wild type species of Allium and in particular organs other than bulbs are more active and efficacious than garlic bulb. Surely leaves of these Allium spp. deserve special attention. PMID- 21290189 TI - How do medical device manufacturers' websites frame the value of health innovation? An empirical ethics analysis of five Canadian innovations. AB - While every health care system stakeholder would seem to be concerned with obtaining the greatest value from a given technology, there is often a disconnect in the perception of value between a technology's promoters and those responsible for the ultimate decision as to whether or not to pay for it. Adopting an empirical ethics approach, this paper examines how five Canadian medical device manufacturers, via their websites, frame the corporate "value proposition" of their innovation and seek to respond to what they consider the key expectations of their customers. Our analysis shows that the manufacturers' framing strategies combine claims that relate to valuable socio-technical goals and features such as prevention, efficiency, sense of security, real-time feedback, ease of use and flexibility, all elements that likely resonate with a large spectrum of health care system stakeholders. The websites do not describe, however, how the innovations may impact health care delivery and tend to obfuscate the decisional trade-offs these innovations represent from a health care system perspective. Such framing strategies, we argue, tend to bolster physicians' and patients' expectations and provide a large set of stakeholders with powerful rhetorical tools that may influence the health policy arena. Because these strategies are difficult to counter given the paucity of evidence and its limited use in policymaking, establishing sound collective health care priorities will require solid critiques of how certain kinds of medical devices may provide a better (i.e., more valuable) response to health care needs when compared to others. PMID- 21290190 TI - The influence of psychosocial factors on quality of life among women with pain: a prospective study in Sweden. AB - OBJECTIVES: To identify/quantify predictors of QOL among women with pain over time. METHODS: The study comprised 2,300 women aged 18-64 years with and without pain. A longitudinal panel survey with two waves of measurement, 1 year apart, by means of questionnaires was used. Multiple linear regression analyses were used to identify and quantify predictors of QOL. RESULTS: After controlling for socio demographics, physical health, and baseline pain parameters, QOL, psychological factors, and pain-related disability at base line, as well as their changer scores, predicted differential aspects of social, psychological, and physical QOL, respectively, over time. Aspects of social support were central for the social dimension of QOL and to a lower degree for the psychological dimension. Change scores of burnout and distress were related to all dimensions of QOL. CONCLUSIONS: QOL seems to be a rather stable characteristic influenced not only by pain but also related to psychosocial factors over time. Addressing such factors seems central in treatment interventions aiming at improving QOL among individuals with pain. PMID- 21290191 TI - The World Health Organization Quality of Life Scale Brief Version: a validation study in patients with schizophrenia. AB - PURPOSE: The World Health Organization Quality of Life Scale Brief Version (WHOQOL-BREF) is used for patients with schizophrenia although no validation is available. This work addresses this issue by dealing with its psychometric properties in a clinical sample of patients with schizophrenia. METHODS: Two hundred forty-one patients from 10 Adult Mental Health Care Centers (AMHCC) meeting the following inclusion criteria were included: (1) International Classification of Diseases-10 or ICD-10 diagnosis of schizophrenia, (2) Global Assessment of Functioning scores or GAF <= 50, 3) Illness duration of more than 2 years and (4) Clinical stability at assessment time. Patients were evaluated at baseline and at one-year follow-up regarding quality of life (QOL), clinical variables and other psychosocial measures. RESULTS: Internal consistency was excellent for the total WHOQOL-BREF (0.88 at baseline and 0.89 at follow-up) and adequate (0.65-0.78 at baseline; 0.66-0.79 at one-year follow-up) for the WHOQOL BREF domains. Correlations between WHOQOL-BREF scores and those of global functioning, psychiatric symptoms, disability and social support ranged between small and large. There were significant differences between groups of patients with schizophrenia in the WHOQOL-BREF. Patients who were anxious, disabled, lacked social support and used more social services scored significantly lower in some or all WHOQOL-BREF domains. Changes in WHOQOL-BREF scores were positively associated with changes over time in global functioning, social support and use of health services, and negatively with psychiatric symptoms and disability (correlation coefficients between small and moderate). After one-year follow-up, patients improved in overall functioning and there was a decrease in psychiatric symptoms. CONCLUSIONS: This study shows that the WHOQOL-BREF has good reliability and validity, and suggests that it is suitable for the assessment of QOL in patients with schizophrenia. PMID- 21290192 TI - Aberrant expression and mutation-inducing activity of AID in human lung cancer. AB - BACKGROUND: Activation-induced cytidine deaminase (AID) is expressed in B lymphocytes and triggers antibody diversification. Recent reports have indicated that the constitutive expression of AID in mice causes not only lymphomas, but also cancers of some organs including the lung, prompting us to investigate the expression and effect of AID on human lung cancer. MATERIALS AND METHODS: We examined AID mRNA expression in 17 lung cancer cell lines and 51 primary lung cancers using a quantitative RT-PCR analysis. Next, we established H1299 lung cancer cells stably overexpressing AID and performed a supF forward mutation assay. We then examined AID protein expression and p53 mutation in 129 primary lung cancers by an immunohistochemical analysis and PCR-SSCP and sequencing analyses, respectively. RESULTS: Aberrant mRNA expression of AID was detected in 29% (5 of 17) of the lung cancer cell lines and 31% (16 of 51) of the primary lung cancers. AID-overexpressing H1299 clones showed a 5.0- to 6.1-fold higher mutation frequency than an empty vector-transfected H1299 clone, and about half of the AID-induced mutations were base substitutions, indicating that AID induces gene mutations in lung cancer cells. Furthermore, an association was found between the AID protein expression level and the p53 mutation status in an analysis of 129 primary lung cancers. A further expression analysis revealed that a portion of AID is localized at the centrosomes. CONCLUSION: Our current findings suggest that the aberrant expression of AID may be involved in a subset of human lung cancers as a result of its mutation-inducing activity. PMID- 21290193 TI - Does a supplementary preoperative breast MRI in patients with invasive lobular breast cancer change primary and secondary surgical interventions? AB - BACKGROUND: We evaluated whether a supplementary preoperative breast MRI in patients with invasive lobular breast cancer (ILC) has changed number and methods of primary and number of secondary surgical interventions. MATERIALS AND METHODS: This was a retrospective controlled single-center analysis of 178 ILC patients. The 2 study groups consisted of 92 patients with breast MRI (MRI group) and of 86 patients without breast MRI (non-MRI group). We investigated the primary and final surgical procedures and factors that influenced the number of secondary surgical interventions. RESULTS: A total of 40 primary mastectomies (38%) have been performed in the MRI group, compared with 27 (30%) in the non-MRI group (P = .119).There have been more bilateral surgical interventions in the MRI group (14 vs 3 patients; P = .002). The 2 groups did not differ with respect to secondary surgery rates (P = .429). The MRI and non-MRI group were significantly different with respect to age and breast density (P = .003 and P = .002). Yet, both variables seemed not to influence secondary surgery rates (P = .516 and P = .788, respectively). CONCLUSIONS: The implementation of preoperative breast MRI tended to result in more primary mastectomies and bilateral surgeries and did not seem to decrease the secondary surgery rate. PMID- 21290194 TI - Loss of sympathetic nerve fibers around intratumoral arterioles reflects malignant potential of gastric cancer. AB - BACKGROUND: The role and clinical significance of the alteration of sympathetic nerve fibers (SNF) was assessed in gastric cancer. Loss of nerve fibers in malignant tumors has previously been described; however, how dysfunction of the nervous system is involved in cancer progression has not been clarified in clinical studies. MATERIALS AND METHODS: The distribution of SNF was examined in 82 surgically resected gastric cancer specimens with immunohistochemical staining of tyrosine hydroxylase (TH), and the association with clinicopathological findings as well as the clinical outcome of the patients was retrospectively evaluated. RESULTS: Arterioles in the normal gastric wall were totally covered with SNF, while the immunoreactivity to TH was markedly reduced around arterioles in cancer tissue. The degree of loss of SNF was significantly correlated with the depth of invasion (P < .0001) and lymph node metastasis (P < .0001) as well as microvessel density (MVD) (P = .0043). Moreover, patients who had tumors with marked loss of SNF showed a markedly worse clinical outcome, with an independent association by multivariate analysis. CONCLUSIONS: Loss of periarteriolar SNF is associated with aggressive phenotype of gastric cancer possibly through enhanced angiogenesis and thus could be a useful marker to predict the clinical outcome. PMID- 21290195 TI - OSNA-based novel molecular testing for lymph node metastases in colorectal cancer patients: results from a multicenter clinical performance study in Japan. AB - BACKGROUND: Lymph node (LN) metastasis in colorectal cancer (CRC) is a critical factor in making accurate prognoses and therapeutic decisions. This study evaluated the clinical performance of the one-step nucleic acid amplification (OSNA) assay in accurately diagnosing LN metastases in CRC patients through the specific detection of cytokeratin 19 mRNA levels in LNs. METHODS: The OSNA assay was performed on 121 LNs dissected from early-stage CRC patients (pStage 0 or I) or from patients with benign colorectal disease (study 1). Separately, 385 LNs were dissected from 85 CRC patients (any stage); the OSNA assay was performed on half of each LN, and the results were compared with histopathological examination in 2-mm intervals of the other LN half (study 2). RESULTS: In study 1, all 121 histopathologically negative LNs were also negative by the OSNA assay (concordance rate for metastasis negative: 1.0, 95% confidence interval [95% CI]: 0.976-1.0). In study 2, the concordance rate between the OSNA assay and the 2-mm interval histopathological examination was 0.971 (95% CI: 0.950-0.984), with a sensitivity of 0.952 (95% CI: 0.881-0.987) and a specificity of 0.977 (95% CI: 0.953-0.991). CONCLUSIONS: The OSNA assay provided a judgment performance equivalent to a 2-mm-interval histopathological examination, a more detailed assay than the common pathological examination. Therefore, the OSNA assay is considered a new molecular examination method for the diagnosis of LN metastases in CRC patients in clinical settings. PMID- 21290196 TI - Overexpression of metastasis-associated protein 1 is significantly correlated with tumor angiogenesis and poor survival in patients with early-stage non-small cell lung cancer. AB - BACKGROUND: The aims of this work are to detect the expression levels of metastasis-associated protein 1 (MTA1) in patients with early-stage non-small cell lung cancer (NSCLC), and to investigate the relationship of MTA1 protein with clinicopathologic factors, tumor angiogenesis, and prognosis. METHODS: One hundred and two patients with pathologic stage I NSCLC who successfully underwent curative surgical resection were enrolled in this study. Immunohistochemical staining for MTA1 and CD34 was performed using the streptavidin-peroxidase method, and intratumoral microvessel density (MVD) was recorded by counting CD34 positive immunostained endothelial cells. All statistical analyses were performed with SPSS statistical software to determine the effects of MTA1 protein on clinicopathologic factors, tumor angiogenesis, and prognosis. RESULTS: MTA1 protein overexpression was detected in 41 cases and was significantly associated with MVD (P = 0.008). MTA1 protein overexpression and high MVD were significantly associated with tumor relapse (P = 0.004 and 0.007) and poor 5-year disease-free survival (P = 0.001 and 0.004). Patients with MTA1 protein overexpression and high MVD had significantly poor overall survival (P = 0.005 and 0.043) and disease-specific survival (P = 0.006 and 0.031) at 5 years after operation. Multivariate analysis demonstrated that MTA1 protein overexpression was an independent prognosticator for unfavorable disease-free, overall, and disease specific survival (P = 0.011, 0.024, and 0.046). CONCLUSIONS: MTA1 protein overexpression is common in early-stage NSCLC and is significantly associated with tumor angiogenesis and poor survival. These findings suggest that MTA1 may have clinical potential as a promising predictor to identify individuals with poor prognostic potential and as a possible novel target molecule of antiangiogenic therapy for patients with early-stage NSCLC. PMID- 21290197 TI - An iatrogenic complication of internal jugular vein catheterization for hemodialysis. AB - BACKGROUND: Central venous catheterization is increasingly performed as a temporary vascular access for hemodialysis therapy in developing countries and it can be associated with serious complications. Iatrogenic common carotid artery jugular vein arteriovenous fistula is a rare but serious complication of internal jugular vein catheterization for hemodialysis access. Few cases of such complication of uremic patients on hemodialysis have been reported in the literature. AIM: To report a case of iatrogenic common carotid artery-jugular vein arteriovenous fistula caused by internal jugular vein catheterization of a hemodialysis patient and its surgical repair. RESULT: The iatrogenic arteriovenous fistula was repaired. CONCLUSION: Acquaintance of anatomical landmarks, careful preparation, experience of the physician and the ultrasound guidance are important factors to reduce the risk of complications during internal jugular vein catheterization. Surgical repair should be performed earlier in order to avoid the development of other serious complications. PMID- 21290198 TI - What has happened to people affected by thalidomide 50 years on? AB - INTRODUCTION: There have been reports of thalidomide-affected people suffering a deterioration in their disability over time [1, 2]. This study assessed changes in disabilities among thalidomide-affected people in the Irish population. METHODS: A questionnaire, assessing musculo-skeletal health, quality-of-life, general health and illness intrusiveness was sent to 26 people affected by thalidomide in the Republic of Ireland. RESULTS: Seventeen (65%) responded. Six (35%) respondents were not working as a result of their disability. Eleven (65%) reported a worsening of their disability over time, with nine of them reporting the deterioration as moderate to severe. The impact of this decline was measured by respondents in terms of ability to perform daily tasks, emotional health and finances (due to extra costs related to clothing, transport, housing alterations and heating). CONCLUSION: There is a need to continually review the physical, psychological and social needs of thalidomide survivors in order to ensure optimum care is made available. PMID- 21290199 TI - Analysis of structural and molecular events associated with adult rat optic chiasm and nerves demyelination and remyelination: possible role for 3rd ventricle proliferating cells. AB - Multiple sclerosis frequently affects the optic apparatus, particularly optic chiasm and nerves. Here, we have reported the structural and molecular characteristics of remyelination in the adult rat optic chiasm and nerves. Moreover, considering the proximity of optic chiasm and 3rd ventricle, we have tried to determine if proliferating cells residing in 3rd ventricle region are able to migrate in response to experimental demyelination of the optic chiasm. Following local demyelination by lysolecithin, remyelination pattern in longitude of optic chiasm and proximal nerves was investigated using myelin staining and marker genes expression. Furthermore, cell tracing was carried out using BrdU labeling of proliferating cells prior to gliotoxin injection. Morphometric analysis revealed that demyelination was considerable on days 7 and 14 and an incomplete remyelination occurred on day 28 post-lesion. Interestingly, myelin repair was more evident in the caudal part of chiasm, compared to rostral part and proximal optic nerves. Following chiasm and nerve demyelination, trains of BrdU+ cells were seen near the 3rd ventricle which subsequently moved to lesion site. Nestin was significantly up-regulated in 3rd ventricle surroundings. At the lesion site, Nogo-A gene expression was significantly decreased on days 7 and 14 post lesion, while Olig2, nestin, and GFAP expression was increased on day 7. The changes were then reversed by the time. Myelin repair in optic chiasm seems to be mediated by endogenous progenitors and stem cells. Adult 3rd ventricle proliferating cells may play a role in this context by mobilization into the demyelinated chiasm. PMID- 21290200 TI - Right ventricular function predicts cardiovascular events in outpatients with stable cardiovascular diseases: preliminary results. AB - Right ventricular (RV) function impacts the outcome in cardiac and pulmonary diseases such as heart failure, pulmonary hypertension, myocardial infarction, valvular, and congenital heart diseases. To our knowledge, simultaneous evaluation of left ventricular (LV) and RV systolic and diastolic echocardiographic indices in outpatients with clinically stable cardiovascular diseases has never been performed. Thus, we designed a prospective cohort study to define the prognostic power of these parameters. One hundred and sixty-three patients were submitted to transthoracic echocardiography with multiparametric and tissue Doppler evaluation of the following indices: ejection fraction, MAPSE, TAPSE, RV presystolic peak, LV and RV diastolic function, pulmonary artery systolic pressure, and functional mitral regurgitation. All these parameters and clinical variables (age, sex, and prior cardiovascular events) were entered in a multivariable Cox regression model. The primary end point was the occurrence of major cardiovascular events (MACEs) during the follow-up period. Twenty-one MACEs were observed; in the final multivariable Cox regression model only prior cardiovascular events (B 1.305, p 0.004, 95% CI 1.523-8.933), age (B 0.067, p 0.005, 95% CI 1.020-1.121), and TAPSE (B -1.065, p 0.026, 95% CI 0.135-0.883) were associated with MACEs. TAPSE, a simple and reproducible echocardiographic index, may be viewed as an early echocardiographic marker of heart involvement in atherosclerosis. We believe that TAPSE may be useful in clinical practice for risk stratification. PMID- 21290201 TI - Hypertonic versus normal saline as initial fluid bolus in pediatric septic shock. AB - OBJECTIVE: To compare the efficacy of 3% saline and 0.9% saline infusion as initial resuscitative fluid therapy in children with septic shock. METHODS: Sixty children between 2 to 12 years of age with septic shock were randomized to receive normal saline or 3% saline as initial resuscitative fluid. Fluid resuscitation was done with 0.9% saline in boluses of 20 ml/kg, each bolus over a duration of 15 min with a maximum of 2 boluses. Fluid resuscitation with 3% saline was given as a single bolus of 15 ml/kg over 30 min. After initial fluid bolus completion, if hemodynamic stability was not achieved then further fluid boluses of 0.9% saline were given in volumes of 5-10 ml/kg guided by CVP. RESULTS: There were 30 patients in both the groups. Both the groups were identical with respect to age, gender, primary diagnosis, laboratory parameters, initial hemodynamic parameters and PRISM score at time of admission. The amount of total fluid bolus required for resuscitation was approximately half in the group who received 3% saline as compared to the group who received 0.9% saline. The use of vasopressor drugs, shock reversal time, ICU stay and mortality rate were similar in both the groups. No adverse effects related to fluid therapy were observed in any of the groups. CONCLUSIONS: Both normal saline and hypertonic saline were equally effective as resuscitation fluid with respect to restoration of hemodynamic stability, average duration of ICU stay and mortality. Hypertonic saline appears to be a promising fluid for resuscitation of septic shock. PMID- 21290202 TI - Clear cell carcinoma and clear cell odontogenic carcinoma: a comparative clinicopathologic and immunohistochemical study. AB - Clear cell carcinoma or hyalinizing clear cell carcinoma (CCC) and clear cell odontogenic carcinoma (CCOC) are rare, low-grade and typically indolent malignancies that can be diagnostically challenging. In this study the clinicopathologic, histologic, and immunohistochemical features of 17 CCCs and 12 CCOCs are examined. The differential diagnosis of clear cell malignancies in the head and neck is discussed. The relationship of CCCs and CCOCs to other clear cell tumors on the basis of their immunohistochemical staining patterns is postulated. PMID- 21290203 TI - Does perception of usefulness of arthroscopic simulators differ with levels of experience? AB - BACKGROUND: Some commercial simulators are available for training basic arthroscopic skills. However, it is unclear if these simulators allow training for their intended purposes and whether the perception of usefulness relates to level of experience. QUESTIONS/PURPOSES: We addressed the following questions: (1) Do commercial simulators have construct (times to perform tasks) and face validity (realism), and (2) is the perception of usefulness (educational value and user-friendliness) related to level of experience? METHODS: We evaluated two commercially available virtual reality simulators (Simulators A and B) and recruited 11 and nine novices (no arthroscopies), four and four intermediates (one to 59 arthroscopies), and seven and nine experts (> 60 arthroscopies) to test the devices. To assess construct validity, we recorded the median time per experience group for each of five repetitions of one identical navigation task. To assess face validity, we used a questionnaire to judge up to three simulator characteristic tasks; the questionnaire asked about the realism, perception of educational value, and perception of user-friendliness. RESULTS: We observed partial construct validity for Simulators A and B and considered face validity satisfactory for both simulators for simulating the outer appearance and human joint, but barely satisfactory for the instruments. Simulators A and B had equal educational value according to the participants. User-friendliness was judged better for Simulator B although both were graded satisfactory. The perception of usefulness did not differ with level of experience. CONCLUSIONS: Our observations suggest training on either simulator is reasonable preparation for real-life arthroscopy, although there is room for improvement for both simulators. PMID- 21290204 TI - Healing of long-term frozen orthotopic bone allografts is not affected by MHC differences between donor and recipient. AB - BACKGROUND: The use of bone grafting in orthopaedic surgery has increased dramatically in recent years. However, the degree to which immune responses are important for the survival of the allograft is not fully understood. In particular it remains unclear whether differences in the major histocompatibility complex (MHC) influence incorporation of bone allografts and their subsequent biologic performance. QUESTIONS/PURPOSES: Therefore, we asked whether isolated mismatch for MHC antigens of deep frozen bone allografts in the long-term causes (1) immune reactions, and whether these reactions have any effect on (2) morphologic features of the graft, (3) radiographic graft healing, and (4) graft strength. METHODS: We used an established orthotopic tibial segment transplantation technique that allows determination of mechanical strength, histologic evaluation, and immune responses. Tibial segments that had been deep frozen at -80 degrees C for 1 year were transplanted into 24 PVG (RT1 (c)) rats from either 12 syngeneic donors or 12 MHC congenic donors PVG.1U (RT1 (u)). We determined immune responses using an indirect Coombs reaction and determined graft healing radiographically and mechanically after 6 months. RESULTS: We detected no alloantibody production to graft MHC-I antigens, and found no differences between syngeneic and MHC mismatched grafts in terms of remodeling with host bone, graft healing, and mechanical strength. CONCLUSIONS: Mismatches for MHC antigens do not seem to play a decisive role in healing of long-term, deep-frozen bone allografts. PMID- 21290205 TI - Letter to the editor: Cams and pincer impingement are distinct, not mixed: the acetabular pathomorphology of femoroacetabular impingement. PMID- 21290206 TI - Beyond stenosis: further progress in multi-modal evaluation of carotid disease. PMID- 21290207 TI - A transesophageal echocardiography examination clarifies the cause of cardiovascular collapse during scoliosis surgery in a child. AB - PURPOSE: The prone position is required for posterior spinal fusion surgery and may be associated with cardiovascular changes, including a decrease in venous return and cardiac index. We report a case of a patient who developed cardiovascular collapse, increased central venous pressure (CVP), and massive bleeding during posterior spinal fusion surgery. A transesophageal echocardiography examination (TEE) documented a right ventricular outflow tract (RVOT) obstruction associated with the use of transverse bolsters. CLINICAL FEATURES: We describe a case of a healthy 14-yr-old male with idiopathic scoliosis who developed severe intraoperative cardiovascular instability and massive bleeding. The surgery was suspended, and the patient was transferred to the intensive care unit. The patient subsequently underwent TEE in the supine and prone positions. The echocardiogram appeared normal in the supine position; however, in the prone position with transverse bolsters, we identified a significant decrease in the diameter of the RVOT that worsened with pressure applied against the thoracic spine. The central venous pressure increased from 10 24 mmHg simultaneously. We found appreciably less impact to the RVOT, RV size and flow, and CVP (10 to 14 mmHg) using longitudinal bolsters both with and without pressure to the back. This position was recommended for the patient's reoperation, which was uneventful. CONCLUSION: A TEE confirmed a RVOT obstruction in the prone position that was associated, in this case, with the use of transverse bolsters. The RVOT obstruction was explained by the chest deformity, compliant chest cage, bolstering, and pressure applied to the patient's back by the surgeon. This positional RVOT obstruction may explain the increase in the CVP and the secondary massive bleeding during the first operation. The TEE was useful to diagnose the patient's condition and to guide his positioning for the second operation. PMID- 21290208 TI - Ethnic differences in leaving home: timing and pathways. AB - The dynamics of leaving home for youth from migrant families in the Netherlands are examined using individual administrative data on the 1977 and 1983 birth cohorts for the period 1999-2004. A competing-risks approach is applied to distinguish leaving home for union formation, to live independently, and to share with others. Migrant youth, and particularly Turkish and Moroccan youth, leave home at a significantly younger age than Dutch youth, given the relevant background variables. This is remarkable, given the older ages at which young people in the origin countries leave the parental home. The result may be seen as evidence of how the potential effects of cultural norms are counter-affected by other factors, such as the facilities of the welfare state and the awkward position of migrant youth between two cultures. Considering the pathways out of home, the analysis largely confirms the expected pattern: Turkish and Moroccan youth leave home more often for union formation and particularly marriage, while this pathway is of minor importance for Dutch youth at early ages. PMID- 21290209 TI - In thyroid cancer cell lines expression of periostin gene is controlled by p73 and is not related to epigenetic marks of active transcription. AB - BACKGROUND: Periostin expression is a feature of the epithelial-mesenchymal transition, which occurs during cancer progression. Previous reports indicate that periostin expression is related to tumour aggressiveness. METHODS: In order to identify mechanisms regulating periostin expression in thyroid cancer, a panel of continuous thyroid cancer cell lines was investigated. Levels of posttranslational modifications of the H3 histone were investigated by chromatin immunoprecipitation. Moreover, treatment of cell lines with deacetylase inhibitors and transfection experiments were performed. RESULTS: Our insights show that levels of H3 histone acetylated at lysines 9 and 14 (which are epigenetic marks of active transcription) are not related to periostin mRNA levels. Moreover, treatment of WRO and FRO thyroid cancer cell lines with the deacetylase inhibitor tricostatin A (TSA) or suberoylanilide hydroxamic acid (SAHA) increases levels of acetylated H3 histone to periostin promoter however, unpredictably, reduces periostin mRNA levels. Interestingly, treatment of WRO cells with either TSA or SAHA increases levels of the H3 histone trimethylated at lysine 4, which is a different epigenetic mark of active transcription. Instead, data obtained by cell transfection indicate that DeltaNp73, a member of p53 family selectively expressed in thyroid carcinomas, plays a role in activating periostin gene expression. CONCLUSIONS: Levels of epigenetic marks of active transcription do not contribute to regulation of periostin gene expression. The DeltaNp73 effects suggest a novel molecular mechanism involved in thyroid cancer progression. PMID- 21290210 TI - Chemotherapeutic agents in low noncytotoxic concentrations increase immunogenicity of human colon cancer cells. AB - BACKGROUND: We have recently reported that chemotherapeutic agents in ultra low noncytotoxic concentrations may block the ability of tumor cells to suppress functional activation of dendritic cells (DCs). METHODS: HCT-116 human colon cancer cells were treated with 0.5 nM paclitaxel (PAC) or 2 nM doxorubicin (DOX) with the aim of defining the immunogenic changes induced by ultra low noncytotoxic concentrations of antineoplastic chemotherapeutic agents. Genetic alterations were screened by DNA microarray that revealed increased expression of genes involved in antigen processing and presentation, including the heat-shock protein, calmodulin, and proteasome 26 genes. As the proteins encoded by these genes are involved in the cytosolic route of antigen processing machinery, we next evaluated whether PAC and DOX in noncytotoxic concentrations changed expression of MHC class I antigen processing machinery (APM) components in three different colon cancer cell lines. RESULTS: Our results showed that PAC and DOX increased the intracellular expression of APM proteins, including calmodulin, LMP2, LMP7, TAP1 and tapasin. The biological significance of modulation of antigen processing and presentation proteins in tumor cells by ultra low nontoxic concentrations of chemotherapeutic drugs was revealed when non-treated and treated tumor cells were used as a source of tumor antigens for the generation of tumor-specific cytotoxic T cells (CTLs) in vitro. We demonstrated that (i) DCs that engulf tumor cells pretreated with noncytotoxic concentrations of chemotherapeutic agents induced CTLs with a higher cytotoxic potential than DCs loaded with nontreated tumor cells, and (ii) CTLs induced by tumor lysate-pulsed DCs killed live tumor cells more efficiently if these tumor cells were pretreated with noncytotoxic concentrations of chemotherapeutic drugs. CONCLUSIONS: These results demonstrate that chemomodulation of human tumor cells with noncytotoxic concentrations of chemotherapeutic agents increases tumor immunogenicity and results in the generation of more efficient DC vaccines and CTLs, which can be used for cell-based anticancer immunotherapies. PMID- 21290211 TI - Establishment and characterization of six human lung cancer cell lines: EGFR, p53 gene mutations and expressions of drug sensitivity genes. AB - BACKGROUND: Six human lung cancer cell lines (SNU-371, SNU-963, SNU-1327, SNU 1330, SNU-2292 and SNU-2315) were newly established through primary cell cultures. These cell lines were derived from a pulmonary blastoma, a small cell lung cancer, three adenocarcinomas and a squamous cell carcinoma of the lung of six Korean lung cancer patients. METHODS: The histopathology of the primary tumors and their in vitro growth characteristics were described. DNA fingerprinting analysis and genetic alterations in the p53, beta-catenin, TGFbetaRII, K-ras and EGFR genes were conducted. mRNA expressions levels of E cadherin, COX-2, MDR1, MXR, CGA, synatophysin and TTF1 genes were investigated and sensitivity to anticancer drugs was screened. RESULTS: Five cell lines grew as adherent cells and one cell line grew as floating aggregates. All lines were free of mycoplasma or bacteria and were proven unique by DNA fingerprinting analysis. A significant polymorphism at codon 72 (Arg to Pro) of the p53 gene was found in one line (SNU-1327) and a mutation at codon 176 was found in SNU-2292. No mutations in the K-ras, beta-catenin and TGF-betaRII genes were observed. E cadherin was not expressed in SNU-371 and COX-2 was overexpressed in SNU-1330, SNU-2292 and SNU-2315 cell lines. MDR1 was overexpressed in SNU-371 and SNU-2292 cell lines and MXR was overexpressed in SNU-1327 cell line. Interestingly, the SNU-371 cell line derived from a pulmonary blastoma and which overexpressed MDR1 displayed cross resistance for several anticancer drugs. Neuroendocrine markers, chromogranin A and synaptophysin, were overexpressed in the small cell lung cancer cell line, SNU-963 and thyroid transcription factor-1 was also over expressed in this cell line. Two mutations (p.Glu746_Ser752delinsVal and p.Glu746_Ala750del) in exon 19 of EGFR were found in SNU-1330 and SNU-2315 cell lines, respectively. CONCLUSION: These well-characterized lung cancer cell lines may be useful tools for investigations of the biological characteristics of lung cancers, particularly for investigations related to mutations of EGFR. PMID- 21290213 TI - Gold-catalyzed cycloadditions involving allenes: mechanistic insights from theoretical studies. AB - Allenes, owing to their special structural characteristics related to the presence of two pi bonds in a formally strained manner, are particularly prone to undergo gold-activated reactions, particularly cycloaddition processes. Theoretical studies based on DFT calculations have been very useful to explain observed reactivities and advance mechanistic proposals. PMID- 21290212 TI - Effect of BIBF 1120 on reversal of ABCB1-mediated multidrug resistance. AB - BACKGROUND: The overexpression of ATP-binding cassette (ABC) transporters is one of the main causes of multi-drug resistance (MDR) which represents a major obstacle to the success of cancer chemotherapy. In this study, we examined the effect of BIBF 1120, an inhibitor of vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors (PDGFRs) and fibroblast growth factor receptors (FGFRs) tyrosine kinases, on the reversal of multidrug resistance in vitro. METHODS: The doxorubicin and rhodamine 123 retention assay was performed by flowcytometry. Western blot were employed to identify ABCB1 expression level and the effect of BIBF 1120 on the blockade of Akt and ERK1/2 phosphorylation. The expression of mdr1 mRNA was determined by RT-PCR analysis. The ATPase activity of ABCB1 was investigated using Pgp-GloTM assay systems. RESULTS: BIBF 1120 significantly enhanced the cytotoxicity of doxorubicin and paclitaxel and increased the accumulation of ABCB1 substrates in ABCB1 overexpressing cancer cells, whereas it had no effect on the parental cells. On the other hand, BIBF 1120 did not alter the cytotoxicity of non-ABCB1 substrates and was unable to reverse ABCC1 or ABCG2-mediated MDR. Furthermore, BIBF 1120 inhibited the ATPase activity of ABCB1 in a concentration-dependent manner. However, no detectable alteration on the expression level of mdr1 mRNA or ABCB1 protein was identified in ABCB1-overexpressing cancer cells by different treatments of BIBF 1120. Interestly, total and phosphorylated forms of AKT and ERK1/2 were not inhibited by BIBF 1120 at the reversal concentrations. CONCLUSION: Our results suggest that BIBF 1120 is capable of overcoming ABCB1 mediated drug resistance by inhibiting ABCB1 function, which may have clinical significance for BIBF 1120 combinational treatment of certain resistant cancers. PMID- 21290214 TI - Activation of allenes by gold complexes: a theoretical standpoint. AB - This review provides an insight into the activation of allenes by gold complexes toward nucleophilic attack. The various possible geometries of allene-gold species, from eta(2)-allenes to eta(1) allylic cations, are described. From the data collected in the literature, it is clear that all of these intermediates have been met during computational analysis of reaction mechanisms. While some retain the stereochemical information of the starting optically active allenes, others may lose it by planarization. To shed light on that matter, the factors governing axial-to-center chirality transfer are described. Some concepts are illustrated by selected examples of catalytic transformations, the mechanisms of which have been studied computationally. PMID- 21290215 TI - N-heterocyclic carbene complexes of au, pd, and pt as effective catalysts in organic synthesis. AB - N-Heterocyclic carbenes (NHC) have been developed in the last 20 years as effective alternatives to classical tertiary phosphines in transition metal catalyzed transformations. The rapid development of this area is a result of synergistic interactions between experimental and computational chemists. Indeed, computer modeling has proven extremely useful in rationalizing large amount of experimental data, and thus has permitted to accelerate the pace at which this chemistry has been developed. In this review, we will discuss catalytic transformations involving NHC-containing gold, platinum, and palladium complexes. Particular attention is drawn to the fundamental insights that computational chemistry provided to rationalize mechanistic aspects of these processes. PMID- 21290216 TI - Structure, bonding, and reactivity of reactant complexes and key intermediates. AB - Complexes of Pt and Au (gold(III) and cationic gold(I)) have shown an exceptional ability to promote a variety of organic transformations of unsaturated precursors due to their peculiar Lewis acid properties: the alkynophilic character of these soft metals and the pi-acid activation of unsaturated groups promotes the intra- or intermolecular attack of a nucleophile. In this chapter we summarize the computational data reported on the structure, bonding, and reactivity of the reactant pi-complexes and also on the key intermediate species. PMID- 21290217 TI - Programmable one-pot glycosylation. AB - In oligosaccharide synthesis, protecting groups, possible participating groups, promoters/catalysts, reaction conditions, and donor leaving groups and acceptors must all be carefully designed in order to generate the correct regio- and stereochemistry for the new glycosidic bond. Programmable one-pot synthesis has been developed to address the above problems. This strategy is based on the sequential use of thioglycoside building blocks to form glycosidic bonds based on the reactivity difference of the building blocks. The activation of the anomeric leaving group can be attenuated through modification of the protecting group strategy and neighboring group participation. This reactivity-based strategy has been applied to one-pot glycosylation reactions where a series of building blocks with identical leaving groups react sequentially in one vessel without laborious intermediate purification steps. It provides rapid access to oligosaccharides with a wide-range of molecular diversity. In this chapter we outline the recent development of this strategy that can be applied to synthesize a wide variety of oligosaccharides and glycoconjugates that are associated with infectious diseases or carbohydrate-based cancer antigens. PMID- 21290218 TI - Advancing biopharmaceutical process development by system-level data analysis and integration of omics data. AB - Development of efficient bioprocesses is essential for cost-effective manufacturing of recombinant therapeutic proteins. To achieve further process improvement and process rationalization comprehensive data analysis of both process data and phenotypic cell-level data is essential. Here, we present a framework for advanced bioprocess data analysis consisting of multivariate data analysis (MVDA), metabolic flux analysis (MFA), and pathway analysis for mapping of large-scale gene expression data sets. This data analysis platform was applied in a process development project with an IgG-producing Chinese hamster ovary (CHO) cell line in which the maximal product titer could be increased from about 5 to 8 g/L.Principal component analysis (PCA), k-means clustering, and partial least-squares (PLS) models were applied to analyze the macroscopic bioprocess data. MFA and gene expression analysis revealed intracellular information on the characteristics of high-performance cell cultivations. By MVDA, for example, correlations between several essential amino acids and the product concentration were observed. Also, a grouping into rather cell specific productivity-driven and process control-driven processes could be unraveled. By MFA, phenotypic characteristics in glycolysis, glutaminolysis, pentose phosphate pathway, citrate cycle, coupling of amino acid metabolism to citrate cycle, and in the energy yield could be identified. By gene expression analysis 247 deregulated metabolic genes were identified which are involved, inter alia, in amino acid metabolism, transport, and protein synthesis. PMID- 21290219 TI - Overview on the lower urinary tract. AB - This chapter overviews our current knowledge on the subject of the urinary tract, whose fundamental role is to transport urine from the kidneys and then store it at low pressure in the lower urinary tract until it can be voided at a socially convenient time. Current understanding of lower urinary tract function and dysfunction is summarized, with reference to anatomy, innervation, and function. The importance of the neurological system in the normal function of the lower urinary tract is emphasized, with a brief overview of the consequence of neural injury at different levels within the central nervous system. The role of urodynamics in the evaluation of lower urinary tract symptoms is discussed with particular reference to the currently recommended terminology advocated by the International Continence Society and The International Urogynaecological Association. PMID- 21290220 TI - Animal models in overactive bladder research. AB - Overactive bladder syndrome (OAB) is a symptom-based diagnosis characterised by the presence of urinary urgency. It is highly prevalent and overlaps with the presence of bladder contractions during urine storage, which characterises the urodynamic diagnosis of detrusor overactivity. Animal models are needed to understand the pathophysiology of OAB, but the subjective nature of the symptom complex means that interpretation of the findings in animals requires caution. Because urinary urgency cannot be ascertained in animals, surrogate markers such as frequency, altered toileting areas, and non-micturition contractions have to be used instead. No model can recapitulate the subjective, objective, and related factors seen in the clinical setting. Models used include partial bladder outlet obstruction, the spontaneous hypertensive rat, the hyperlipidaemic rat, various neurological insults and some gene knock-outs. Strengths and weaknesses of these models are discussed in the context of the inherent difficulties of extrapolating subjective symptoms in animals. PMID- 21290222 TI - Animal models for benign prostatic hyperplasia. AB - Although the etiology of benign prostatic hyperplasia (BPH) is unknown, various animal models have been used for several decades to identify potential therapeutic approaches. These models can be divided into those measuring smooth muscle tone and those measuring cellular proliferation. Animal models have played an important role in the development of the two drug classes currently approved for the treatment of BPH: the alpha-adrenoceptor antagonists and the steroid 5 alpha-reductase inhibitors. However, models measuring prostatic tone have not been particularly useful in the identification of new alpha-adrenoceptor antagonists having advantages over currently available drugs, and it is not certain that reduction of prostatic smooth muscle tone is responsible for the relief of BPH symptoms. A further limitation with BPH models is that prostatic hyperplasia similar to the human condition does not occur spontaneously or cannot be induced in any suitable animal species. The identification of a more useful BPH model is focused on cellular mechanisms of prostatic growth, looking similarities between humans and experimental animals. PMID- 21290223 TI - Use of functional imaging to monitor central control of voiding in humans. AB - Bladder problems are frequently disorders of control, which is exercised from the brain. In such disorders, brain responses to bladder events are abnormal; therapy is accompanied by regional changes that may be measured by functional imaging and used to monitor the effect of treatment. The regional responses may be understood in terms of a tentative model of the bladder control system. The model helps also to interpret alterations in brain behavior (as imaged by functional scanning) that occur when afferent signals from bladder or urethra are changed experimentally or by an underlying disorder or treatment, for example, overactive bladder (urge/urgency incontinence). Successful treatment may either increase the ability to cope with the problem or may be curative. The direction of treatment induced change of abnormal brain responses can distinguish these two possibilities and shed light on the therapeutic mechanism. In addition, brain activity in regions such as insula or dorsal anterior cingulate cortex may be regarded as a proxy for sensations such as desire to void or urgency, which are otherwise difficult to define or measure. Monitoring of brain responses in these regions offers an obvious way to test the effect of drugs. PMID- 21290221 TI - Animal models of stress urinary incontinence. AB - Stress urinary incontinence (SUI) is a common health problem significantly affecting the quality of life of women worldwide. Animal models that simulate SUI enable the assessment of the mechanism of risk factors for SUI in a controlled fashion, including childbirth injuries, and enable preclinical testing of new treatments and therapies for SUI. Animal models that simulate childbirth are presently being utilized to determine the mechanisms of the maternal injuries of childbirth that lead to SUI with the goal of developing prophylactic treatments. Methods of assessing SUI in animals that mimic diagnostic methods used clinically have been developed to evaluate the animal models. Use of these animal models to test innovative treatment strategies has the potential to improve clinical management of SUI. This chapter provides a review of the available animal models of SUI, as well as a review of the methods of assessing SUI in animal models, and potential treatments that have been tested on these models. PMID- 21290224 TI - Neuroanatomy of the lower urinary tract. AB - The lower urinary tract (LUT), which consists of the urinary bladder and its outlet, the urethra, is responsible for the storage and periodic elimination of bodily waste in the form of urine. The LUT is controlled by a complex set of peripheral autonomic and somatic nerves, which in turn are controlled through neural pathways in the spinal cord and brain. This influence of the central nervous system allows for the conscious control of the bladder, allowing the individual to choose an appropriate place to urinate. Defects in the CNS pathways that control the LUT can lead to incontinence, an embarrassing condition that affects over 200 million people worldwide. As a first step in understanding the neural control of the bladder, we will discuss the neuroanatomy of the LUT, focusing first on the peripheral neural pathways, including the sensory pathways that transmit information on bladder filling and the motoneurons that control LUT muscle contractility. We will also discuss the organization of the central pathways in the spinal cord and brainstem that are responsible for coordinating bladder activity, promoting continuous storage of urine except for a few short minutes per day when micturition takes place. To conclude, we will discuss current studies underway that aim to elucidate the higher areas of the brain that control the voluntary nature of micturition in higher organisms. PMID- 21290225 TI - Anatomy and histology of the lower urinary tract. AB - The function of the lower urinary tract is basically storage of urine in the bladder and the at-will periodic evacuation of the stored urine. Urinary incontinence is one of the most common lower urinary tract disorders in adults, but especially in the elderly female. The urethra, its sphincters, and the pelvic floor are key structures in the achievement of continence, but their basic anatomy is little known and, to some extent, still incompletely understood. Because questions with respect to continence arise from human morbidity, but are often investigated in rodent animal models, we present findings in human and rodent anatomy and histology. Differences between males and females in the role that the pelvic floor plays in the maintenance of continence are described. Furthermore, we briefly describe the embryologic origin of ureters, bladder, and urethra, because the developmental origin of structures such as the vesicoureteral junction, the bladder trigone, and the penile urethra are often invoked to explain (clinical) observations. As the human pelvic floor has acquired features in evolution that are typical for a species with bipedal movement, we also compare the pelvic floor of humans with that of rodents to better understand the rodent (or any other quadruped, for that matter) as an experimental model species. The general conclusion is that the "Bauplan" is well conserved, even though its common features are sometimes difficult to discern. PMID- 21290226 TI - Neurophysiology of the lower urinary tract. AB - The lower urinary tract (LUT) has two functions: (1) the storage of waste products in the form of urine and (2) the elimination of those wastes through micturition. The LUT operates in a simple "on-off" fashion, either storing urine or releasing it during voiding. While this activity may seem simple, micturition is controlled by a complex set of peripheral neurons that are, in turn, coordinated by cell groups in the spinal cord, brainstem, and brain. When this careful coordination is interrupted, the control of the bladder is lost, resulting in incontinence or retention of urine. The purpose of this chapter is to review how the neural systems coordinating the activity of the lower urinary tract form neural circuits that are responsible for either maintaining continence (the storage reflex) or inducing micturition (the voiding reflex). We will also discuss the brain centers that enable higher organisms to voluntarily choose the time and place for voiding. Finally, we will discuss how defects in the pathways controlling micturition can lead to urinary incontinence and which treatments may normalize LUT function. PMID- 21290227 TI - Afferent mechanism in the urinary tract. AB - Much of the current research on lower urinary tract dysfunction is focused on afferent mechanisms. The main goals are to define and modulate the signaling pathways by which afferent information is generated and conveyed to the central nervous system. Alterations in bladder afferent mechanisms are a potential source of voiding dysfunction and an emerging source of drug targets. Even some established drug therapies such as muscarinic receptor antagonists, as well as emerging therapies such as botulinum toxin type-A, may act partly through afferent mechanisms. This review presents up-to-date findings on the localization of afferent fiber types within the bladder wall, afferent receptors and transmitters, and how these may communicate with the urothelium, interstitial cells, and detrusor smooth muscle to regulate micturition in normal and pathological bladders. Peripheral and central mechanisms of afferent sensitization and myogenic mechanisms that lead to detrusor overactivity, overactive bladder symptoms, and urgency sensations are also covered as well as new therapeutic approaches and new and established methods of measuring afferent activity. PMID- 21290228 TI - Urothelial signaling. AB - The urinary bladder "mucosa" or innermost portion of the bladder is composed of transitional epithelium, basement membrane, and the lamina propria. This chapter reviews the specialized anatomy of the bladder epithelium (urothelium) and speculates on possible communication mechanisms from urothelial cells to various cell types within the bladder wall. For example, beyond serving as a simple barrier, there is growing evidence that the urinary bladder urothelium exhibits specialized sensory properties and plays a key role in the detection and transmission of both physiological and nociceptive stimuli. Findings from a number of studies suggest that the urothelium exhibits both "sensor" (expressing receptors/ion channels capable of responding to thermal, mechanical, and chemical stimuli) and "transducer" (ability to release chemicals) properties. Thus, urothelial cells exhibit the ability to sense changes in their extracellular environment including the ability to respond to chemical, mechanical, and thermal stimuli that may communicate the state of the urothelial environment to the underlying nervous and muscular systems. PMID- 21290229 TI - Interstitial cells of Cajal in the urinary tract. AB - The study of novel interstitial cells in the tissues of the urinary tract has defined advances in the field in the last decade. These intriguing cells belong to the same family as the better known interstitial cells of Cajal (ICC) of the gastrointestinal tract, and their discovery has been interpreted to suggest that pacemaker cells may be present in the urinary tract, driving the spontaneous or myogenic activity of the neighboring smooth muscle. This scenario may be true for the urethra where ICC have been described as "loose pacemakers" providing multiple, random inputs to modulate urethral smooth muscle activity. However, there is a paucity of direct evidence available to support this hypothesis in the bladder (where the smooth muscle cells are spontaneously active) or the renal pelvis (where atypical smooth muscle cells are the pacemakers), and it now seems more likely that urinary tract ICC act as modulators of smooth muscle activity.Interestingly, the literature suggests that the role of urinary tract ICC may be more apparent in pathophysiological conditions such as the overactive bladder. Several reports have indicated that the numbers of ICC present in overactive bladder tissues are greater than those from normal tissues; moreover, the contractility of tissues from overactive bladders in vitro appears to be more sensitive to the Kit antagonist, glivec, than those from normal bladder. Future research on urinary tract ICC in the short to medium term is likely to be dynamic and exciting and will lead to increasing our understanding of the roles of these cells in both normal and dysfunctional bladder. PMID- 21290230 TI - Potential applications of gene therapy/transfer to the treatment of lower urinary tract diseases/disorders. AB - Identification of molecular targets for novel therapeutics is a natural consequence of the age of molecular and personalized medicine. How this information is leveraged and applied to the treatment of functional diseases/disorders of the lower urinary tract will determine if this field of medicine can keep pace with technological developments and patient expectations for improved therapies. In this regard, therapeutic improvements for the treatment of lower urinary tract diseases and disorders have been largely incremental over the past 30 years. The goal of this report is to review the evidence pointing toward the enormous potential of gene therapy/transfer to provide a paradigm shift from palliative to curative therapeutic solutions for lower urinary tract diseases/disorders. In fact, it seems clear that gene therapy represents a biotechnology approach particularly suitable to applications in the lower urinary tract. Although much more research is required, ample preclinical evidence already indicates that, for example, gene therapy can favorably impact/alter virtually every aspect of bladder physiology/function. In short, further investigations and continued applications of gene therapy to the treatment of lower urinary tract diseases/disorders seems a prudent step toward potentially marked and more durable therapeutic improvements. PMID- 21290231 TI - Specific pharmacokinetic aspects of the urinary tract. AB - This chapter reviews the evidence for "specific" pharmacokinetics playing a role in currently marketed drugs intended to treat lower urinary tract (LUT) symptoms. Principles of drug targeting include intrinsic properties of drugs or organs as well as drug formulations to modify drug release or to create confinement of drug presence. Prodrugs and specific formulations to deliver high drug concentrations at the site(s) of action as well as other ways to manipulate drug distribution to achieve enrichment in target tissues are considered. In overactive bladder (OAB), specific formulations for oxybutynin have been introduced to reduce the level of side effects of the active drug. Extended release tablet formulations and a topical gel formulation have been introduced, with efficacy similar to immediate release (IR) tablets, but with a reduction in anticholinergic adverse effects. However, these modifications have not led to outstanding performance parameters compared to other anticholinergic drugs marketed as IR formulations. Urinary excretion is discussed as potential mechanism for targeting LUT symptoms, but no strong indications appear to exist that this mechanism would contribute for currently available drugs. Intravesical administration of drugs is not a preferred option and only considered for drugs like botulinum toxin, where the inconvenient application compensates for a reasonable degree of long-term efficacy in severe refractory OAB. Alpha acid glycoprotein binding is discussed as a potential factor to influence drug tissue distribution, and it is concluded that there is reasonable evidence that for tamsulosin this mechanism is responsible for the difference in free fraction of the drug observed in plasma and prostate, which could contribute to its relative absence of blood pressure effects in patients with LUT symptoms related to benign prostate hyperplasia (LUTS-BPH). The principle of irreversible inhibition of type II 5alpha-reductase as a tool to develop drugs to reduce prostatic levels of dihydrotestosterone is employed by both dutasteride and finasteride for treatment of LUTS-BPH. Of the mechanisms discussed, the principles employed for the 5alpha-reductase blockers and tamsulosin in this respect can be considered relatively specific for its urological indication. PMID- 21290232 TI - alpha(1)-Adrenoceptors in the urinary tract. AB - alpha(1)-Adrenoceptors have been identified and characterized extensively by functional, radioligand-binding, and molecular biological techniques. Molecular clones have been isolated for three alpha(1)-subtypes (alpha(1a), alpha(1b), and alpha(1d)), and these subtypes are also functionally characterized. alpha(1) Adrenoceptors are present in the prostate, urethra, bladder (urothelium, smooth muscle, and afferent nerves), ureter, vas deferens, peripheral ganglia, nerve terminals, vascular tissues, and central nervous system (CNS), and they could all potentially influence overall urinary function and contribute to both the therapeutic and adverse effects of alpha(1)-adrenoceptor antagonists in patients with benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). This review aimed to discuss the relevant physiological and pharmacological roles and molecular biology of alpha(1)-adrenoceptor subtypes in the prostate, urethra, bladder, ureter, and CNS. PMID- 21290233 TI - beta-Adrenergic Receptor Subtypes in the Urinary Tract. AB - Within the urinary tract, beta-adrenergic receptors (AR) are found largely on smooth muscle cells but are also present, at least in the bladder, in the urothelium and on afferent nerves. Our understanding of beta-AR subtype expression and function is hampered by a lack of well-validated tools, particularly with regard to beta(3)-AR. Moreover, the beta-AR subtypes involved in a specific function may differ between species. In the ureter, beta-AR can modulate pacemaker activity and smooth muscle tone involving multiple subtypes. In the human bladder, beta-AR promote urine storage. Bladder smooth muscle relaxation primarily involves beta(3)-AR, and the agonists selective for this subtype are in clinical development to treat bladder dysfunction. While prostate and urethra also express beta-AR, the overall physiological role in these tissues remains unclear. PMID- 21290234 TI - Muscarinic acetylcholine receptors in the urinary tract. AB - Muscarinic receptors comprise five cloned subtypes, encoded by five distinct genes, which correspond to pharmacologically defined receptors (M(1)-M(5)). They belong to the family of G-protein-coupled receptors and couple differentially to the G-proteins. Preferentially, the inhibitory muscarinic M(2) and M(4) receptors couple to G(i/o), whereas the excitatory muscarinic M(1), M(3), and M(5) receptors preferentially couple to G(q/11). In general, muscarinic M(1), M(3), and M(5) receptors increase intracellular calcium by mobilizing phosphoinositides that generate inositol 1,4,5-trisphosphate (InsP3) and 1,2-diacylglycerol (DAG), whereas M(2) and M(4) receptors are negatively coupled to adenylyl cyclase. Muscarinic receptors are distributed to all parts of the lower urinary tract. The clinical use of antimuscarinic drugs in the treatment of detrusor overactivity and the overactive bladder syndrome has focused interest on the muscarinic receptors not only of the detrusor, but also of other components of the bladder wall, and these have been widely studied. However, the muscarinic receptors in the urethra, prostate, and ureter, and the effects they mediate in the normal state and in different urinary tract pathologies, have so far not been well characterized. In this review, the expression of and the functional effects mediated by muscarinic receptors in the bladder, urethra, prostate, and ureters, under normal conditions and in different pathologies, are discussed. PMID- 21290235 TI - Modulation of urinary bladder innervation: TRPV1 and botulinum toxin A. AB - The persisting interest around neurotoxins such as vanilloids and botulinum toxin (BoNT) derives from their marked effect on detrusor overactivity refractory to conventional antimuscarinic treatments. In addition, both are administered by intravesical route. This offers three potential advantages. First, intravesical therapy is an easy way to provide high concentrations of pharmacological agents in the bladder tissue without causing unsuitable levels in other organs. Second, drugs effective on the bladder, but inappropriate for systemic administration, can be safely used as it is the case of vanilloids and BoNT. Third, the effects of one single treatment might be extremely longlasting, contributing to render these therapies highly attractive to patients despite the fact that the reasons to the prolonged effect are still incompletely understood. Attractive as it may be, intravesical pharmacological therapy should still be considered as a second line treatment in patients refractory to conventional oral antimuscarinic therapy or who do not tolerate its systemic side effects. However, the increasing off label use of these neurotoxins justifies a reappraisal of their pharmacological properties. PMID- 21290236 TI - Ion channel modulators and urinary tract function. AB - The membrane potential fulfils an important role in initiating smooth muscle contraction, through its depolarization and the subsequent influx of Ca(2+) through voltage-gated Ca(2+) channels. Changes in membrane potential can also coordinate contraction across great distances, utilizing the speed of electrical current flow through gap junctions. Hence, regulating membrane potential can greatly influence smooth muscle function. In this chapter, we will consider the influence of ion channels, as dynamic gatekeepers of membrane permeability, on urogenital function. Through their ability to act as key regulators of both the resting membrane potential and its dynamic changes, they provide important pharmacological targets for influencing urogenital function.Urogenital smooth muscle and urothelia contain a diverse range of molecularly and functionally distinct K(+) channels, which are key to regulating the resting membrane and for re-establishing the normal membrane potential following both active and passive changes. The voltage-gated Ca(2+) channels are key to initiating contraction and causing rapid depolarization, supplemented in some smooth muscles by rapid Na(+) conductances. The Cl(-) channels, often assumed to be passive, can actively change the membrane potential, and hence, cellular function, because Cl(-) is not usually at its equilibrium potential. The useful ways in which these ion channels can be targeted therapeutically in the ureter, bladder and urethra are discussed, focussing particularly on treatments for ureteric obstruction and detrusor overactivity. Current treatments for many urinary tract disorders, particularly the overactive bladder, are complicated by side effects. While ion channels have traditionally been considered as poor therapeutic targets by the pharmaceutical industry, our increasing knowledge of the molecular diversity of K(+) and Cl(-) channels gives new hope for more narrowly focused drug targeting, while the exciting discoveries of active currents in interstitial cells give us a new set of cellular targets for drugs. PMID- 21290238 TI - Cannabinoids: potential targets for bladder dysfunction. AB - Cannabinoids are the active chemical components of Cannabis sativa (marijuana). The medical use of cannabis goes back over 5,000 years. Cannabinoids produce a very wide array of central and peripheral effects, some of which may have beneficial clinical applications. The discovery of cannabinoid receptors has spawned great interest within the pharmaceutical industry with the hopes of capitalizing on the beneficial effects of cannabis without the unwanted psychotropic effects on the central and peripheral nervous system. This chapter presents an overview of the pharmacology of cannabinoids and their derivatives. It reviews the current literature on central and peripheral cannabinoid receptors as related to effects on the lower urinary tract and the role of these receptors in normal and abnormal urinary tract function. An objective evaluation of the published results of clinical trials of cannabis extracts for the treatment of bladder dysfunction resulting from multiple sclerosis is also presented. It is clear that cannabinoid receptors are present in the lower urinary tract as well as spinal and higher centers involved in lower urinary tract control. Systemic cannabinoids have effects on the lower urinary tract that may be able to become clinically useful; however, a much greater understanding of the mechanisms of cannabinoid receptors in control of the human lower urinary tract is necessary to facilitate development of novel cannabinoid drugs for treatment of pelvic disorders. PMID- 21290239 TI - Vasopressin receptors in voiding dysfunction. AB - Arginine vasopressin (AVP), also known as vasopressin or anti-diuretic hormone, is a neuropeptide produced in the hypothalamus. It is primarily responsible for osmoregulation and thus maintains body fluid homeostasis. It is also a potent vasoconstrictor, may have a role in higher cognitive functions and affects metabolism. All the biological and cellular effects of vasopressin are mediated by the interaction of this hormone with three G-protein-coupled receptors - V(1a), V(1b) and V(2).Urological applications are based on the rationale that V(2) receptors mediate water conservation and increase urine osmolality. Due to their anti-diuretic properties mediated by the V(2) receptors, synthetic vasopressin agonists, such as desmopressin, are now commonly used for the treatment of nocturnal polyuria, central diabetes insipidus and nocturnal enuresis and potentially in urinary incontinence. Desmopressin has been licenced worldwide for haematological indications of haemophilia and von Willebrand disease. Vasopressin receptor antagonists correct hyponatremia by blocking the activation of the V(2) receptor and induce a free water diuresis without an accompanying natriuresis or kaliuresis; an effect termed 'aquaresis'. Interfering with vasopressin signalling by administering vasopressin antagonists may have clinical benefits in acute and chronic heart failure. PMID- 21290237 TI - Neuropeptides in lower urinary tract function. AB - Numerous neuropeptide/receptor systems including vasoactive intestinal polypeptide, pituitary adenylate cyclase-activating polypeptide, calcitonin gene related peptide, substance P, neurokinin A, bradykinin, and endothelin-1 are expressed in the lower urinary tract (LUT) in both neural and nonneural (e.g., urothelium) components. LUT neuropeptide immunoreactivity is present in afferent and autonomic efferent neurons innervating the bladder and urethra and in the urothelium of the urinary bladder. Neuropeptides have tissue-specific distributions and functions in the LUT and exhibit neuroplastic changes in expression and function with LUT dysfunction following neural injury, inflammation, and disease. LUT dysfunction with abnormal voiding, including urinary urgency, increased voiding frequency, nocturia, urinary incontinence, and pain, may reflect a change in the balance of neuropeptides in bladder reflex pathways. LUT neuropeptide/receptor systems may represent potential targets for therapeutic intervention. PMID- 21290240 TI - ATP and P2X purinoceptors in urinary tract disorders. AB - The pharmacological concept of specifically targeting purinoceptors (receptors for ATP and related nucleotides) has emerged over the last two decades in the quest for novel, differentiated therapeutics. Investigations from many laboratories have established a prominent role for ATP in the functional regulation of most tissue and organ systems, including the urinary tract, under normal and pathophysiological conditions. In the particular case of the urinary tract, ATP signaling via P2X1 receptors participates in the efferent control of detrusor smooth muscle excitability, and this function may be heightened in disease and aging. Perhaps of greater interest, ATP also appears to be involved in bladder sensation, operating via activation of P2X3-containing receptors on sensory afferent neurones, both on peripheral terminals within the urinary tract tissues (e.g., ureters, bladder) and on central synapses in the dorsal horn of the spinal cord. Such findings are based on results from classical pharmacological and localization studies in nonhuman and human tissues, gene knockout mice, and studies using recently identified pharmacological antagonists some of which have progressed as candidate drug molecules. Based on recent advances in this field, it is apparent that the development of selective antagonists for these receptors will occur that could lead to therapies offering better relief of storage, voiding, and sensory symptoms for patients, while minimizing the systemic side effects that curb the clinical effectiveness of current urologic medicines. PMID- 21290241 TI - Cyclic nucleotide metabolism including nitric oxide and phosphodiesterase-related targets in the lower urinary tract. AB - The clinical data on the use of the orally active phosphodiesterase (PDE) type 5 inhibitors sildenafil (VIAGRATM), vardenafil (LEVITRATM), and tadalafil (CIALISTM) for the treatment of male erectile dysfunction have boosted research activities on the physiology and pharmacology of the organs of the lower urinary tract (LUT). This includes both intracellular signal transduction in the prostate, urinary bladder (detrusor), and urethra, as well as central brain and spinal cord pathways controlling the function of the LUT. Such efforts provided the basis for the development of new therapeutic modalities into the management of dysfunctions/ syndromes of the LUT, some of which are already offered to the patients. The pharmacological treatment of the overactive bladder and the so called benign prostatic syndrome, including LUT symptomatology and bladder outlet obstruction secondary to benign prostatic enlargement, has primarily focused on selective, orally available drugs acting by influencing intracellular regulatory mechanisms. These agents are regarded efficacious, have a fast onset of drug action in the target tissue and an improved effect-to-side-effect ratio. Better understanding of the functional significance of proteins related to cyclic nucleotide-dependent pathways, such as nitric oxide synthase, cytosolic and membrane-bound guanylyl cyclases, PDE isoenzymes and cyclic AMP- and cyclic GMP binding protein kinases, the relative distribution in tissues of the LUT, and the consequences for urogenital function, seems to be of particular interest in order to identify new or more selective pharmacological approaches to manage disorders of the LUT. The present review focuses on cyclic nucleotide-related targets involved in the control of the function of the bladder, prostate, and urethra and the significance of those proteins in the process of evolving new pharmacological options for the treatment of LUT symptoms secondary to benign prostatic hyperplasia as well as dysfunctions of the storage and voiding capability of the urinary bladder. PMID- 21290242 TI - Rho-kinase, a common final path of various contractile bladder and ureter stimuli. AB - Normal urinary bladder function is based on the proper contraction and relaxation of smooth muscle (SM), which constitutes the majority of the bladder wall. The contraction and relaxation of all SM involves a phosphorylation-dephosphorylation pathway involving the enzymes smooth muscle myosin light chain kinase (SMMLCK) and smooth muscle myosin light chain phosphatase (SMMLCP), respectively. Although originally thought to function just as a passive opposition to SMMLCK-driven SM contraction, it is now clear that SMMLCP activity is under an extremely complex molecular regulation via which SMMLCP inhibition can induce "calcium sensitization." This review provides a thorough summary of the literature regarding the molecular regulation of the SMMLCP with a focus on one of its major inhibitory pathways that is RhoA/Rho-kinase (ROK) including its activation pathways, effector molecules, and its roles in various pathological conditions associated with bladder dysfunction. Newly emerging roles of ROK outside of SM contractility are also discussed. It is concluded that the RhoA/ROK pathway is critical for the maintenance of basal SM tone of the urinary bladder and serves as a common final pathway of various contractile stimuli in rabbits, rats, mice, and pigs as well as humans. In addition, this pathway is upregulated in response to a number of pathological conditions associated with bladder SM dysfunction. Similarly, RhoA/Rho-kinase signaling is essential for normal ureteral function and development and is upregulated in response to ureteral outlet obstruction. In addition to its critical role in bladder SM function, a role of ROK in the urothelium is also beginning to emerge as well as roles for ROK in bladder infection and invasion and metastasis of bladder cancer. PMID- 21290243 TI - Integration of visual and auditory information for hand actions: preliminary evidence for the contribution of natural sounds to grasping. AB - When we reach out to grasp objects, vision plays a major role in the control of our movements. Nevertheless, other sensory modalities contribute to the fine tuning of our actions. Even olfaction has been shown to play a role in the scaling of movements directed at objects. Much less is known about how auditory information might be used to program grasping movements. The aim of our study was to investigate how the sound of a target object affects the planning of grasping movements in normal right-handed subjects. We performed an experiment in which auditory information could be used to infer size of targets when the availability of visual information was varied from trial to trial. Classical kinematic parameters (such as grip aperture) were measured to evaluate the influence of auditory information. In addition, an optimal inference modeling was applied to the data. The scaling of grip aperture indicated that the introduction of sound allowed subjects to infer the size of the object when vision was not available. Moreover, auditory information affected grip aperture even when vision was available. Our findings suggest that the differences in the natural impact sounds of objects of different sizes being placed on a surface can be used to plan grasping movements. PMID- 21290244 TI - Accelerated disease progression in prostate cancer and bone metastases with platelet-derived growth factor receptor inhibition: observations with tandutinib. AB - BACKGROUND: Activated platelet-derived growth factor receptor (p-PDGFR) is frequently expressed in bone metastases of castration-resistant prostate cancer (CRPC). Phase II study of tandutinib was conducted to assess the effects of a continuously administered highly potent PDGFR inhibitor in this disease state. METHODS: Men with progressive CRPC, bone metastases, and prior taxane chemotherapy were treated with oral tandutinib 500 mg twice daily until disease progression under a two-stage design with the 8-week freedom-from-progression (FFP) rate as the primary endpoint. The trial was designed to have 87% power to reject a null FFP rate of 10% when the true rate was 33% (type I error rate = 0.02). Secondary endpoints included tumor expression of p-PDGFR, bone marker (urine N-telopeptide, serum bone-specific alkaline phosphatase) kinetics, in vivo monitoring of PDGFR inhibition in peripheral blood leukocytes, and correlation with survival. RESULTS: Among 18 patients registered (aged 47-81, median 66 years), 15 were evaluable for efficacy. Five of 6 evaluable tumors were p-PDGFR positive. Mean urine N-telopeptide declined from 123.7 (baseline) to 41.0 (Cycle 2 Day 1) nmol/mmol Cr (P = 0.012). Probability of decrease in peripheral blood leukocyte p-PDGFR >0.5 versus <0.5 was associated with progression-free survival of 6 versus 8 weeks (P = 0.03, log-rank) and overall survival, 26.6 versus 42.9 weeks, respectively (P = 0.09, log-rank). CONCLUSIONS: In vivo PDGFR inhibition with tandutinib correlated with accelerated disease progression. This observation raises the hypothesis that PDGF contributes to the homeostasis of bone metastases from prostate cancer. PMID- 21290245 TI - Metronomic docetaxel chemotherapy inhibits angiogenesis and tumor growth in a gastric cancer model. AB - PURPOSE: Low-dose metronomic (LDM) chemotherapy represents a new strategy to treat solid tumors by stronger antiangiogenic activity and less side effects. The aim of the study is to rationally develop a docetaxel metronomic regimen in preclinical settings of gastric cancer. METHODS: In vitro cell proliferation, apoptosis, and thrombospondin-1/vascular endothelial growth factor (TSP-1/VEGF) expression analyses were performed on human umbilical vein endothelial cells (HUVECs) and gastric cancer (BGC-823) cells exposed for 144 h to metronomic concentrations of docetaxel. BGC-823 human gastric cancer xenograft model was used, and tumor growth and side effects were closely monitored. Quantitative real time PCR was used to determine TSP-1/VEGF mRNA levels in tumor samples. Expression of VEGF and CD31 was observed by immunohistochemistry. RESULTS: Our results indicated that LDM docetaxel preferentially inhibited HUVEC cell proliferation and induced HUVEC apoptosis. Docetaxel significantly increased TSP 1 expression and secretion in HUVEC cells whereas the expression and secretion of VEGF significantly decreased in BGC-823 cells. LDM docetaxel significantly inhibited BGC-823 tumor growth in the absence of toxicity, which was accompanied by decreases in microvessel density (MVD) and VEGF and increases in TSP-1 gene expression in tumor tissues. CONCLUSIONS: In vitro results show the antiangiogenic properties of LDM docetaxel. In vivo, LDM docetaxel treatment is effective against gastric tumor and microvessel growth without toxic effect on nude mice. PMID- 21290246 TI - A phase I study of combination therapy with S-1 and irinotecan in patients with previously untreated metastatic or recurrent colorectal cancer. AB - BACKGROUND: To investigate the combination of S-1 and irinotecan (CPT-11) as an alternative to infusional 5-fluorouracil/leucovorin plus CPT-11, we performed a phase I trial to determine the maximum tolerated dose, recommended dose (RD), and dose-limiting toxicities (DLTs) in patients with metastatic or recurrent colorectal cancer. PATIENTS AND METHODS: S-1 and CPT-11 doses were escalated using a standard 3 + 3 design. S-1 was administered orally at 70 mg/m(2) (levels 1-3) or 80 mg/m(2) (levels 4 and 5) for 14 consecutive days followed by 1-week rest. CPT-11 was administered intravenously on day 1, at 175 mg/m(2) (level 1), 200 mg/m(2) (level 2), 225 mg/m(2) (levels 3 and 4), or 250 mg/m(2) (level 5). Treatment was repeated every 3 weeks, unless disease progression or severe toxicities were observed. RESULTS: Twenty-three patients were treated. One patient at each of levels 2 and 4 developed a DLT, grade 3 ileus, and grade 3 diarrhea, respectively. At both levels, an additional three patients did not experience DLTs. At level 5, two of five patients experienced DLTs, including grade 3 enteritis and grade 4 neutropenia for more than 5 days. The RD was determined at level 4 (80 mg/m(2) S-1 and 225 mg/m(2) CPT-11). An objective response was observed in 7 of 17 patients with measurable disease: 2 of 5 at level 2; 3 of 4 at level 4; and 2 of 4 at level 5. CONCLUSIONS: The RDs of CPT-11 and S-1 were determined as 225 and 80 mg/m(2), respectively, and further phase II trials are warranted. PMID- 21290247 TI - A prognostic model in patients who receive chemotherapy for metastatic or recurrent gastric cancer: validation and comparison with previous models. AB - PURPOSE: To make up for the limitations of previous prognostic models, we developed and validated a model in patients with metastatic or recurrent gastric adenocarcinoma (AGC), and to compare with previous models. METHODS: A total of 2,805 patients received chemotherapy for AGC in Asan Medical Center between January 2000 and December 2008 and were randomly split into training and validation sets of 1,870 and 935 patients, respectively. A prognostic model was developed from the training set. RESULTS: The median follow-up duration was 26.5 months (range, 10.8-116.3), during which time 2,495 patients (88.9%) died. Eight factors associated with poor prognosis were identified by multivariate analysis: ECOG performance status >=2 (2 points), no gastrectomy, peritoneal metastasis, bone metastasis (2 points), lung metastasis, alkaline phosphatase > 120 IU/l, albumin < 3.3 g/dL, and total bilirubin > 1.2 mg/dL. A prognostic model was developed by dividing patients into good (0-1 points), moderate (2-3), and poor (>=4) risk groups. The overall survival (OS) curves for three risk groups differed significantly for both the training and the validation sets (P < 0.001 each). In the training set, the median OS for the three risk groups was 14.0, 9.4, and 5.1 months, respectively. Application of three previous prognostic models to our validation set showed that the four models, including ours, had similar ability to predict survival outcomes (c-statistics, 0.5520-0.5836). CONCLUSION: Validation and comparison of prognostic models indicated that our model was as effective as the previous models to stratify the patients with AGC. PMID- 21290248 TI - Pharmacokinetics of cyclophosphamide enantiomers in patients with breast cancer. AB - PURPOSE: Adjuvant chemotherapy with cyclophosphamide (CYC) is used for the treatment of breast cancer. CYC is used as a racemic mixture, although preclinical data have demonstrated differences in the efficacy and toxicity of its enantiomers, with (S)-(-)-CYC exhibiting a higher therapeutic index. The present study investigated the enantioselectivity and influence of CYP2B6, CYP2C9, CYP2C19, and CYP3A on the kinetic disposition of CYC in patients with breast cancer. METHODS: Fifteen patients previously submitted to removal of the tumor and treated with racemic CYC (900 or 1,000 mg/m(2)) and epirubicin were included in the study. The in vivo activity of CYP3A was evaluated using midazolam as a marker drug. Serial blood samples were collected up to 24 h after administration of the first cycle of CYC. RESULTS: The kinetic disposition of CYC was enantioselective in patients with breast cancer, with plasma accumulation of the (S)-(-)-CYC enantiomer (AUC 195.0 vs. 174.8 MUg h/mL) due to the preferential clearance of the (R)-(+)CYC enantiomer (5.1 vs. 5.7 L/h). Clearance of either CYC enantiomer did not differ between the CYP2B6, CYP2C9, and CYP2C19 genotypes or as a function of the in vivo activity of CYP3A evaluated by midazolam clearance. CONCLUSIONS: The pharmacokinetics of CYC is enantioselective in patients with breast cancer concomitantly treated with epirubicin and ondansetron. Genotyping or phenotyping did not contribute to adjustment of the CYC dose regimen in patients included in this study. PMID- 21290249 TI - Hepatic expression of the GH/JAK/STAT/IGF pathway, acute-phase response signalling and complement system are affected in mouse offspring by prenatal and early postnatal exposure to maternal high-protein diet. AB - PURPOSE: Effects of pre- and early postnatal exposure to maternal high-protein diets are not well understood. Transcription profiling was performed in male mouse offspring exposed to maternal high-protein diet during pregnancy and/or lactation to identify affected hepatic molecular pathways. METHODS: Dams were fed isoenergetic diets with control (20% w/w) or high protein levels (40%). The hepatic expression profiles were evaluated by differential microarray analysis 3 days (d3) and 3 weeks (d21) after birth. Offspring from three different high protein dietary groups, HP (d3, high-protein diet during pregnancy), HPHP (d21, high-protein diet during pregnancy and lactation) and CHP (d21, control diet during pregnancy and high-protein diet during lactation), were compared with age matched offspring from dams fed control diet. RESULTS: Offspring body and liver mass of all high-protein groups were decreased. Prenatal high-protein diet affected hepatic expression of genes mapping to the acute response/complement system and the GH/JAK/STAT/IGF signalling pathways. Maternal exposure to high protein diet during lactation affected hepatic gene expression of the same pathways but additionally affected genes mapping to protein, fatty acid, hexose and pyruvate metabolism. CONCLUSIONS: (1) Genes of the acute response/complement system and GH/JAK/STAT/IGF pathways were down-regulated in offspring of dams exposed to high-protein diets during pregnancy and/or lactation. (2) Genes related to nutrient and energy metabolism, however, were only affected when high protein diet was administered during lactation. (3) Modulation of the GH/JAK/STAT/IGF pathway might be responsible for reduced body and liver masses by maternal high-protein diet. PMID- 21290250 TI - Fibulin-5 expression in the human placenta. AB - Fibulin-5 is a secreted extracellular matrix glycoprotein and displays a diverse panel of biological functions, which can be segregated into elastogenic as well as extra-elastogenic functions. While elastogenic functions of fibulin-5 include essential roles in early steps of elastic fibre assembly, extra-elastogenic functions are widespread. Depending on the cell type used, fibulin-5 mediates cell adherence via a subset of integrins, antagonizes angiogenesis and inhibits migration as well as proliferation of endothelial and smooth muscle cells. In this study, we focused on the spatiotemporal expression of fibulin-5 in the human placenta. With progressing gestation, placental fibulin-5 expression increased from first trimester towards term. At term, placental fibulin-5 mRNA expression is lower when compared with other well-vascularized organs such as lung, kidney, heart, uterus and testis. In first trimester, placenta immunohistochemistry localized fibulin-5 in villous cytotrophoblasts and extravillous cytotrophoblasts of the proximal cell column. In term placenta, fibulin-5 was detected in the endothelial basement membrane and adventitia-like regions of vessels in the chorionic plate and stem villi. Cell culture experiments with the villous trophoblast-derived cell line BeWo showed that fibulin-5 expression was downregulated during functional differentiation and intercellular fusion. Moreover, cultivation of BeWo cells under low oxygen conditions impaired intercellular fusion and upregulated fibulin-5 expression. The spatiotemporal shift from the trophoblast compartment in first trimester to the villous vasculature at term suggests a dual role of fibulin-5 in human placental development. PMID- 21290251 TI - Insulin resistance, low-grade inflammation and type 1 diabetes mellitus. AB - To assess the relationships between insulin resistance and low-grade inflammation in subjects with type 1 diabetes mellitus (T1DM) who do not have clinical macrovascular complications. A total of 120 subjects diagnosed with T1DM 14 years before were evaluated for the following: (1) sex, age, body mass index, waist-to hip ratio (WHR), blood pressure, smoking, alcohol intake, insulin dose, HbA1c and lipid profile; (2) microvascular complications; (3) plasma concentrations of soluble fractions of tumour necrosis factor-alpha receptors type 1 and 2, interleukin-6, adiponectin, leptin and high-sensitivity C-reactive protein (hs CRP); and (4) insulin resistance (estimation of the glucose disposal rate-eGDR). Those subjects with an eGDR below the median of the same sex group were classified as insulin resistant and the others as insulin sensitive. Insulin resistant men, compared to the insulin-sensitive, had higher WHR (0.89 +/- 0.08 vs. 0.83 +/- 0.05; P < 0.01), higher systolic [121 (118-125) vs. 114 (108-120) mmHg; P = 0.01] and diastolic [73 (66-80) vs. 67 (70-73) mmHg; P = 0.02] blood pressures, higher HbA1c values [8.7 (8.1-9.9) vs. 7.5 (7.2-8.0) %; P < 0.01] and higher hs-CRP concentrations [1.16 (0.61-3.20) vs. 0.49 (0.31-0.82) mg/dl; P = 0.01], but no other significant differences between groups were found. Insulin resistant women had higher WHR and HbA1c values, compared to the insulin sensitive, but they did not have any other differences. In men, hs-CRP correlated significantly with WHR and HbA1c (r = 0.363; P = 0.016 and r = 0.317; P = 0.036, respectively), after adjusting for age, alcohol intake, smoking and microvascular complications. Insulin-resistant men with T1DM have an increase in plasma concentrations of hs-CRP. Central obesity and HbA1c are its main determinants. PMID- 21290252 TI - Lack of association of apoE epsilon4 allele with insulin resistance. AB - ApoE is a polymorphic protein involved in the metabolism of plasma lipoproteins; the epsilon4 allele was shown to be associated with coronary and aortic atherosclerosis in age-dependent fashion mediated by unknown mechanisms. This study was undertaken to assess whether the apoE isoforms in humans were associated with normal glucose tolerance and with metabolic and inflammatory risk factors of CVD. ApoE genotype was assessed in 365 individuals. Of those, 309 were studied in the postabsorptive conditions and 142 of them also underwent a 3h OGTT; 56 additional subjects were studied by means of the insulin clamp in combination with [6,6-2H2] glucose infusion. ApoE genotype frequencies were similar to those previously reported and were not influenced by age and BMI. Fasting plasma glucose, insulin, FFA, the lipid profile, surrogate markers (HOMA IR, OGTT-derived index) as well as the clamp-derived parameters or insulin sensitivity and insulin secretion were not different by apoE genotypes. Serum adipokines concentrations (leptin, adiponectin, resistin) and markers of inflammation (serum fasting hsCRP and MCP1/CCL2) were also not different by apoE genotypes. In the subgroup of young epsilon4 carriers which underwent the clamp procedure, a higher fasting endogenous glucose production was detected. ApoE genotype was not associated with insulin resistance or altered insulin secretion, and no abnormalities in the typical circulating endocrine, metabolic, and inflammatory features of the insulin resistance syndrome were detected. PMID- 21290253 TI - Exploring the disparities of regional health care expenditures in Switzerland: some empirical evidence. AB - This study investigates the determinants of regional variations in health care expenditures (HCE) in Switzerland, since there are significant differences between cantons per capita HCE. The empirical analysis contributes to the discussion on the outcome of federalism in the Swiss health care system by improving the understanding of the determinants of the differences in HCE. Our econometric estimations indicate that HCE are significantly related to the density of specialist physicians, density of dispensing doctors, per capita income, proportion of managed care, medical and technological progress and socio economic factors. Due to the presumptive importance of the organisation of ambulatory care, we suggest policy makers should particularly concentrate on promoting the supply of managed care models in Switzerland. Supporting the development of managed care may help to countervail some of the influences which tend to lead to higher cantonal health expenditures. PMID- 21290254 TI - Relationship between peripheral arterial reactive hyperemia and residual platelet reactivity after 600 mg clopidogrel. AB - Clopidogrel reduces long-term ischemic events in patients with acute coronary syndrome or stable angina (SA) undergoing percutaneous coronary intervention (PCI). Endothelial function improvement has been proposed, among other factors, for this beneficial effect of clopidogrel, but whether this might be associated to its anti-platelet action remains unclear. We tested the hypothesis that clopidogrel improvement of peripheral vascular endothelial function might be associated with inhibition of platelet aggregation. Endothelial function was evaluated before and at least 12 h after 600 mg clopidogrel in 43 SA pts undergoing elective PCI by: (a) reactive hyperemia peripheral arterial tonometry (measuring the Endoscore); (b) circulating endothelial microparticles (EMPs). Response to clopidogrel was measured with point-of-care VerifyNow P2Y12 assay and expressed as platelet reaction unit (PRU) and percent platelet inhibition (%PI). High platelet reactivity after clopidogrel was defined as PRU >= 240. Endothelial function improved after clopidogrel in 20 pts. Changes in Endoscore (Delta Endoscore) were significantly correlated with both PRU (r = -0.61, P < 0.001) and %PI (r = 0.57, P < 0.001). Endoscore significantly increased after clopidogrel in pts with PRU < 240 (0.38 +/- 0.26 to 0.57 +/- 0.33, P < 0.001), but did not in pts with PRU >= 240 (0.53 +/- 0.31 to 0.40 +/- 0.37, P = 0.12). EMPs were also significantly reduced in pts with PRU < 240 (222 [140-593] to 142 [83-371]/MUl, P = 0.001), while no changes were observed in pts with PRU >= 240 (256 [178-531] to 388 [238-499]/MUl, P = 0.55). In patients with stable coronary artery disease, a single 600 mg clopidogrel loading dose improves vascular endothelial function. This improvement is associated with optimal platelet inhibition and it is not observed in patients with post-clopidogrel high platelet reactivity. PMID- 21290256 TI - Misogyny, acculturation, and ethnic identity: relation to rape-supportive attitudes in Asian American college men. AB - Asian Americans have been understudied with respect to sexuality and rape and its contributory factors. Some attitudinal research has shown that Asian American college males tend to hold more rape-supportive beliefs than their White counterparts. Generally, this research treats ethnicity as a proxy for culture rather than examining specific facets of culture per se. The current study incorporated measures of misogynistic beliefs, acculturation, and ethnic identity to investigate these ethnic differences in rape-supportive attitudes. White (n = 222) and Asian American (n = 155) college men read an acquaintance rape vignette and evaluated it on four judgments: how much they blamed the perpetrator and the victim, how credible they viewed the victim's refusal, and to what degree they defined the event as rape. Consistent with previous research, Asian American men made more rape-supportive judgments than Whites. This relationship was partially mediated by misogynistic beliefs for all judgments except the extent to which they defined the vignette as rape. Among Asian Americans, acculturation was negatively associated with all four rape vignette judgments above and beyond generational status, and ethnic identity was positively associated with two of the four judgments above and beyond acculturation and generational status. These findings suggest that cultural constructs are relevant to understanding rape supportive attitudes among Asian American men, and may be useful for promoting culturally enhanced theoretical models of rape and sexual assault prevention efforts, as well as a deeper understanding of cultural influences on sexuality. PMID- 21290255 TI - Age-concordant and age-discordant sexual behavior among gay and bisexual male adolescents. AB - There is evidence that risks for HIV and sexually transmitted infections among adolescent females are higher for those with older male sexual partners. Yet, little empirical research has been conducted with male adolescents who engage in sexual activity with older men. In this article, we summarize in a number of ways the range of sexual activity reported by an ethnically diverse sample of 200 gay and bisexual male youth (15-22 years old) in Chicago and Miami. A general pattern of progression from oral sex with men to both receptive and insertive anal sex with men appeared to characterize the sample during their adolescence. Further, there appeared to be a high degree of "versatile" positioning among the sexually active gay and bisexual young men, in both age-discrepant and age-concordant dyads. Risk analysis revealed having primarily age-concordant partners to be a significant predictor of sexual risk behavior. HIV risk among young gay and bisexual men engaging in sexual activity with older men may occur not only within a distinct biological context from their heterosexual counterparts, but also in a social context that may not as rigidly bound to traditional assumptions about age, gender, and power. The significant associations among participants with partners who were the same age and the risk behavior measures in this analysis have implications for HIV prevention efforts. PMID- 21290257 TI - Evaluation of sexual function in men with orchialgia. AB - This study examined the effect of chronic scrotal pain on sexual function using the International Index of Erectile Function (IIEF). We enrolled 50 patients with symptoms consistent with orchialgia and 50 control subjects without orchialgia, who were healthy, sexually active, married, and age-matched. Both groups were evaluated using the IIEF questions for sexual function, and quality of life was investigated using the abbreviated version of the World Health Organization Quality of Life Questionnaire. A significant difference was found in the values of orgasmic function, intercourse satisfaction, sexual desire, overall sexual satisfaction, and total IIEF scores between the patient and control groups; however, there were no significant group differences in the IIEF scores related to erectile function. In the patient group, 39 of 50 subjects reported decreased sexual desire and satisfaction due to a decrease in frequency of sexual activities. Thus, investigation of sexual function was essential for these patients in order to determine the adequate management and treatment of chronic orchialgia. PMID- 21290258 TI - Is hypersexuality dimensional? Evidence for the DSM-5 from general population and clinical samples. AB - Hypersexual Disorder is currently being considered for inclusion in the DSM-5. To inform this process, we investigated the latent structure of the hypersexuality construct using Meehl's (1995) taxometric method. Data on sexual interests and behaviors were obtained from 2,101 general population males and females in Sweden and 716 male sex offenders from the United States. Taxometric analyses of self report indicators of hypersexuality supported a dimensional interpretation of latent structure in both samples. These findings suggest that individual differences in hypersexuality are quantitative (matter of degree) rather than qualitative (difference in kind) in nature, at least when self-report data were used. This is another way of saying that hypersexuality is organized along a continuum of increasing sexual frequency and preoccupation, with clinical cases of hypersexuality falling at the upper end of the continuum or dimension. We conclude that the proposed inclusion of Hypersexual Disorder in the DSM-5 should acknowledge the lack of non-arbitrary breaks in the latent symptoms continuum which runs from very low to very high engagement in sexual behavior and preoccupation. The diagnostic threshold should therefore be decided from an analysis of external data on severity, comorbidity, and prognosis for individuals with sub-threshold and full diagnoses, respectively. Additionally, dimensional assessment of Hypersexual Disorder should be part of clinical diagnostic practice. PMID- 21290259 TI - Associations between online pornography and sexual behavior among adolescents: myth or reality? AB - This study aimed to compare the sexual behavior of adolescents who were or were not exposed to online pornography, to assess to what extent the willingness of exposure changed these possible associations, and to determine the profiles of youths who were exposed to online pornography. Data were drawn from the 2002 Swiss Multicenter Adolescent Survey on Health, a self-administered cross sectional, paper and pencil questionnaire. From the 7529 adolescents aged 16-20 years, 6054 (3283 males) used the Internet during the previous month and were eligible for our study. Males were divided into three groups (wanted exposure, 29.2%; unwanted exposure, 46.7%; no exposure, 24.1%) whereas females were divided into two groups (exposure, 35.9%; no exposure, 64.1%). The principal outcome measures were demographic characteristics, Internet use parameters and risky sexual behaviors. Risky sexual behaviors were not associated with online pornography exposure in any of the groups, except that males who were exposed (deliberately or not) had higher odds of not having used a condom at last intercourse. Bi/homosexual orientation and Internet use parameters were not associated either. Additionally, males in the wanted exposure group were more likely to be sensation-seekers. On the other hand, exposed girls were more likely to be students, higher sensation-seekers, early maturers, and to have a highly educated father. We conclude that pornography exposure is not associated with risky sexual behaviors and that the willingness of exposure does not seem to have an impact on risky sexual behaviors among adolescents. PMID- 21290260 TI - High-throughput pyrosequencing of the chloroplast genome of a highly neutral lipid-producing marine pennate diatom, Fistulifera sp. strain JPCC DA0580. AB - The chloroplast genome of the highly neutral-lipid-producing marine pennate diatom Fistulifera sp. strain JPCC DA0580 was fully sequenced using high throughput pyrosequencing. The general features and gene content were compared with three other complete diatom chloroplast genomes. The chloroplast genome is 134,918 bp with an inverted repeat of 13,330 bp and is slightly larger than the other diatom chloroplast genomes due to several low gene-density regions lacking similarity to the other diatom chloroplast genomes. Protein-coding genes were nearly identical to those from Phaeodactylum tricornutum. On the other hand, we found unique sequence variations in genes of photosystem II which differ from the consensus in other diatom chloroplasts. Furthermore, five functional unknown ORFs and a putative serine recombinase gene, serC2, are located in the low gene density regions. SerC2 was also identified in the plasmids of another pennate diatom, Cylindrotheca fusiformis, and in the plastid genome of the diatom endosymbiont of Kryptoperidinium foliaceum. Exogenous plasmids might have been incorporated into the chloroplast genome of Fistulifera sp. by lateral gene transfer. Chloroplast genome sequencing analysis of this novel diatom provides many important insights into diatom evolution. PMID- 21290261 TI - The interrelationship between the lower oxygen limit, chlorophyll fluorescence and the xanthophyll cycle in plants. AB - The lower oxygen limit (LOL) in plants may be identified through the measure of respiratory gases [i.e. the anaerobic compensation point (ACP) or the respiratory quotient breakpoint (RQB)], but recent work shows it may also be identified by a sudden rise in dark minimum fluorescence (F(o)). The interrelationship between aerobic respiration and fermentative metabolism, which occur in the mitochondria and cytosol, respectively, and fluorescence, which emanates from the chloroplasts, is not well documented in the literature. Using spinach (Spinacia oleracea), this study showed that F(o) and photochemical quenching (q(P)) remained relatively unchanged until O(2) levels dropped below the LOL. An over reduction of the plastoquinone (PQ) pool is believed to increase F(o) under dark + anoxic conditions. It is proposed that excess cytosolic reductant due to inhibition of the mitochondria's cytochrome oxidase under low-O(2), may be the primary reductant source. The maximum fluorescence (F(m)) is largely unaffected by low-O(2) in the dark, but was severely quenched, mirroring changes to the xanthophyll de-epoxidation state (DEPS), under even low-intensity light (~4 MUmol m(-2) s(-1)). In low light, the low-O(2)-induced increase in F(o) was also quenched, likely by non-photochemical and photochemical means. The degree of quenching in the light was negatively correlated with the level of ethanol fermentation in the dark. A discussion detailing the possible roles of cyclic electron flow, the xanthophyll cycle, chlororespiration and a pathway we termed 'chlorofermentation' were used to interpret fluorescence phenomena of both spinach and apple (Malus domestica) over a range of atmospheric conditions under both dark and low-light. PMID- 21290262 TI - Angiogenesis in meningiomas. AB - Neoangiogenesis has been correlated to biological aggressiveness and an adverse clinical course of several neoplasias. Its prognostic role in meningiomas appears to be controversial. Nonetheless, if adequately quantified with specific markers and appropriate scoring methods, angiogenesis seems to be significantly associated with a high growth fraction, development of recurrences and shorter overall survival of meningiomas. As a consequence, neoangiogenesis may represent a target for therapies aimed at reducing the growth of inoperable meningiomas or recurrence risk of totally resected tumors. Even more significantly, the identification of the factors that mediate angiogenesis in meningiomas could help us to determine appropriate novel anti-angiogenic therapies for these tumors. Herein the methods for quantification of angiogenesis as well as its regulating factors in meningiomas are reviewed. PMID- 21290263 TI - Current strategy for triple-negative breast cancer: appropriate combination of surgery, radiation, and chemotherapy. AB - Triple-negative breast cancer (TNBC) often grows rapidly and has poor outcomes, with a high recurrence rate and a short interval between recurrence and death. New molecular-targeted therapies are being developed, but cannot be used at present. Other strategies for the management of TNBC are needed. TNBC is characterized by an expanding growth pattern without extensive intraductal spread and is a good candidate for breast-conserving therapy (BCT) with sufficient margins. The local recurrence rate after BCT is not high as those of other subtypes of breast cancer. In contrast, the regional recurrence rate is higher in TNBC than in other subtypes. Sentinel node biopsy and axillary resection should therefore be performed with the upmost caution. Radiation therapy has been shown to be useful for the management of TNBC. Radiation therapy of the chest wall after mastectomy and the regional area as well as the breast after breast conserving surgery should be considered. Chemotherapy is the only systemic treatment available for TNBC. In our hospital, a combination of cyclophosphamide, epirubicin, and 5-fluorouracil (FEC) followed by docetaxel (DTX) or DTX followed by FEC has been used to treat tumors more than 2 cm in diameter or node-positive breast cancer. Neoadjuvant chemotherapy with these regimens has produced pathological complete response (pCR) rates higher than 20% in patients with TNBC, regardless of the specific order of agents. Tumors tend to shrink towards their center and can be a good indication for BCT. After 3 years, a pCR is associated with good outcomes, whereas a non-pCR sometimes results in distant recurrence, even when residual tumor is minimal. Patients should be closely observed during neoadjuvant chemotherapy. If there is any evidence of tumor progression, the chemotherapeutic regimen should be modified or surgery performed, without losing the opportunity to administer potentially effective treatment. Several studies indicate that neoadjuvant chemotherapy with platinum-based regimens is effective for TNBC and is thus an important treatment option. We have used regimens combining epirubicin and cyclophosphamide (EC) to treat tumors 1-2 cm in diameter without node metastasis, and 2 of 21 patients presented with distant metastases (disease-free interval, 2 and 5 years). We have not used systemic therapy to treat tumors 1 cm or less in diameter without node metastasis, and all 8 patients are alive without recurrence for more than 4 years. After distant recurrence in patients with TNBC, the same chemotherapeutic agents as those used for other subtypes of breast cancer are recommended, but the response is often disappointing, leading to poor outcomes. TNBC presents with different clinical features from other subtypes. The treatment strategy should be selected according to the characteristics of the specific subtype of breast cancer. PMID- 21290264 TI - Anastrozole can cause severe hypercalcaemia mimicking primary hyperparathyroidism. AB - A 65-year-old woman on anastrozole treatment because of a recurrent breast cancer developed hypercalcaemia and increased parathyroid hormone (PTH) levels 21/2 years after start of the treatment. A diagnosis of hyperparathyroidism was suspected and the patient underwent neck surgery, but only normal parathyroid glands were found. Postoperatively, the hypercalcaemia as well as the PTH level continued to rise, and 9 months after exploration of the parathyroids her calcium level was extremely high (adjusted serum calcium = 3.39 mmol/l). Anastrozole was then withheld, and within 2 weeks the severe hypercalcaemic state turned into hypocalcaemia. A month later, anastrozole treatment was started again, and after 6 weeks her calcium and PTH values had returned to extremely high levels. After withdrawal of anastrozole, calcium and PTH concentrations again fell toward normal values. The urinary excretion of calcium was very low during anastrozole treatment and high after cessation of the drug. The mechanism(s) by which anastrozole can cause hypercalcaemia are unknown. However, it might be hypothesised that anastrozole, directly or indirectly, interferes with the calcium-sensing receptors known to be present on the cell surface of both parathyroid and renal tubular cells. PMID- 21290265 TI - Alteration of immunohistochemical biomarkers between pre- and post-chemotherapy: hormone receptors, HER2 and Ki-67. AB - The immunohistochemical (IHC) biomarkers of breast cancer, especially hormone receptors and HER2, are very important because the pharmacological therapeutic strategy is generally decided by biomarker expression patterns. Biomarkers are examined on pre-chemotherapeutic biopsy materials from patients in whom neoadjuvant chemotherapy is planned. Statistically significant changes between pre- and post-chemotherapeutic markers have been reported; however, the alterations in biomarkers are poorly understood. Fluctuation of the Ki-67 labeling index (LI) between pre- and post-neoadjuvant therapy is associated with chemotherapeutic effects and with the prognosis of patients. It has been shown that IHC evaluation of Ki-67 LI is useful as a predictive and a prognostic factor. There are issues to be considered surrounding the use of the IHC Ki-67 LI in routine practice, including the standardization of staining procedures and a cutoff point for Ki-67 LI detection. The current understanding of IHC evaluation of biomarkers for breast cancer under neoadjuvant chemotherapy is reviewed based on the literature. PMID- 21290266 TI - [Quality control in medicine]. PMID- 21290267 TI - [What is evidence-based concerning quality management? Thoughts about an apparently simple question]. AB - Quality management has become more important due to the growing pressure for change within the healthcare sector. Responsible for this are driving forces that include not only competition and legislation, but also society. Therefore, quality management has developed especially in the direction of structural organization, process orientation, and professionalism. However, there is a lack of information concerning the scientific, evidence-based evaluation of activities, measures, and projects. Current studies and data are not able to answer questions concerning a strong correlation between quality management activities and treatment effects, and the influence on the whole system remains open. The reason for this is the complexity of the different dynamic factors influencing the benefit assessment. Single investigations can only indicate specific aspects of the multifaceted term quality analysis. There is a high demand for scientific and proven methods as well as for the understanding that scientifically established answers can only be given to well-defined and specific questions. PMID- 21290268 TI - [Assessing the quality of quality indicators]. AB - Quality in healthcare is not directly observable and measurable. Quality indicators serve as a tool for operationalizing quality of care. Different quality measures are required depending on the purpose, context, and audience concerned. The methodological quality of the indicators themselves has to be critically assessed. Various quality requirements for indicators have been published and can be described based on the steps of the developmental process. Importance, scientific acceptability, usability, and feasibility are reported as basic criteria for assessment. The QUALIFY instrument offers a standardized approach for assessing quality indicators and reflects best current practice. Measuring quality through indicators is no end in itself. The effect of measurement on motivating quality improvement must be evaluated in future studies. PMID- 21290269 TI - [From clinical practice guidelines towards quality assurance]. AB - Clinical practice guidelines have been introduced to assist decision making at the bedside of individual patients. Guidelines are also increasingly regarded as being an indispensable part of professional quality systems. Guidelines are important tools to improve knowledge-management, processes and outcomes in healthcare. They aim to assist professional and patient decisions especially in those areas of healthcare where considerable variation or potential for improvement exist and they can provide a foundation for assessing and evaluating the quality and effectiveness of healthcare in terms of measuring processes and outcomes. Quality indicators or performance measures based on guideline recommendations are necessary to evaluate the usefulness of guidelines and the appropriateness of healthcare delivery. Guideline recommendations are the tools for healthcare professionals to develop strategies for quality improvement in case deviations from desired processes or outcomes are identified by the measurement of quality indicators. PMID- 21290270 TI - [Pay for performance (P4P). Long-term effects and perspectives]. AB - After 10 years of experience and research, a wide array of results on evaluation and long-term effects of pay for performance (P4P) programs have been published. These data do not only give insight into most of the problems of implementation, but also into aspects which, in part, may attenuate the high expectations at the beginning of the discussion. P4P programs exhibit a ceiling effect, some improvements are reversed after incentives are cancelled, and improvements show opportunity costs as absent improvements for indicators, which are not object to financial incentives (in some cases for the same disease). These observations can be explained by the hypothesis that P4P programs have characteristics of fee-for service reimbursement, if symmetric information is available for insurance and provider. P4P programs are local instruments. While integration of healthcare is considered as an important issue, they should be combined with programs and incentives which foster further vertical and horizontal integration. For Germany, further research in the implementation and effects of P4P programs is necessary. PMID- 21290272 TI - [Quality assurance and quality management in medical rehabilitation]. AB - External quality assurance in medical rehabilitation is characterized by the programs of Germany's two largest providers of rehabilitation (the German pension insurance and the statutory health insurance). The programs were developed with considerable input from scientific institutes. Their strengths lie in measuring several relevant dimensions of quality, the comprehensive implementation for nearly all illnesses treated, integration of the patient perspective, and realization of prospective study designs with follow-up. Weaknesses include low relevance for patient allocation and compensation, the absence of systematic evaluations, and a lack of published patient information on the results of the quality measurements. Internal quality management in medical rehabilitation is regulated by sweeping legal guidelines. Since 2009, a statutory agreement has been in effect which includes a provision that all inpatient rehabilitation centers must be certified by October 2012. Areas for potential improvements in internal quality management processes include an improved theoretical basis, higher specificity for rehabilitation, and a more transparent, methodically improved structure of certification procedures. PMID- 21290271 TI - [Measures to enhance patient safety. Importance of efficiency evaluation]. AB - Over the last 10 years, there has been increasing awareness of medical errors and harm to patients in healthcare. There is now widespread acceptance of the problem of medical harm and a determination to tackle major patient safety problems. Safety is defined as freedom from accidental injury. Thus, clinical risk management has been increasingly requested by professionals and their professional organizations to make healthcare safer. Clinical risk management is one of a number of organizational systems or processes aimed to improve the quality of healthcare, but one which is primarily concerned with creating and maintaining safe systems of care. A definition of this form--identifying, analyzing, and controlling risks--fits more comfortably with the culture and mission of healthcare organizations and is more likely to achieve the support and involvement of clinical professionals because it better reflects their purpose and values. Patient safety needs to become embedded in the culture of healthcare, not just in the sense of individual high standards, but a widespread acceptance of understanding of risk and safety and the need of everyone to actively promote patient safety. Measures taken to enhance patient safety encompass a wide range of activities with regard to the errors in the process of medication, to surgical errors and surgical outcome ("safer surgery saves lives"), and to hospitalism and hospital-acquired infections taking into consideration adherence to hand hygiene. An evaluation of the added value to patient safety, when processes are systematically changed and the patients become involved in making healthcare safer, is needed. PMID- 21290273 TI - [Quality management in ambulatory care nursing and inpatient nursing in Germany. Specifics and current trends]. AB - In principle, quality management in nursing care follows the concepts used in medicine. Occasionally, professionals develop quality requirements and pursue quality improvements by using various tools. Specific features in Germany's nursing care are related to the binding character of seven so-called expert standards and to mandatory, external quality assessments that began in 2009 and will be conducted and published yearly. Preliminary results of these assessments show that both home health agencies and nursing homes provide on average good quality nursing care. However, assessments also revealed a huge demand for improvements concerning the quality criteria and the procedures used to calculate the results. Currently, nursing scientists, providers of care, and long-term care insurance companies are controversially discussing that matter. PMID- 21290274 TI - [Structures and quality assurance of preventive care and health promotion in Germany]. AB - In order to identify requirements of quality assurance in this field, a general description of prevention, health promotion and education is outlined, based upon healthcare supply analyses and 158 interviews with experts. Prominent features are, among others, a distinctive heterogeneity and complexity of settings, suppliers, and interventions; supply of coverage is below public health criteria (needs); weak outcome evaluation; competition among suppliers, providers, and political agencies and decision makers; need for intra- and intersectoral coordination; the lack of evidence-based healthcare planning; and hurdles for quality assurance. A structural taxonomy of quality assurance systems is then developed, consisting of three dimensions: validity (quality of information), regularity, and degree of commitment and obligation. In terms of these dimensions, important systems of quality assurance in prevention, health promotion and education in Germany are analyzed. A number of different systems and approaches can be found. However, most of them share questionable validity, regularity, and degree of obligation. Increased commitment on behalf of providers, suppliers, and political institutions and decision makers for the quality of preventive interventions is inevitable in order to raise the performance of prevention and health promotion in Germany to their potential effectiveness. PMID- 21290275 TI - [Quality management for preventing healthcare-acquired infections. The importance of surveillance]. AB - Healthcare acquired (nosocomial) infections are one of the most frequent complications of medical care. The management to prevent such nosocomial infections is a typical example of the use of the general principles of quality management in healthcare institutions: each institution should compare their own nosocomial infection rates for defined patient risk groups with reference data and identify problems concerning specific infection types or units/departments. This comparison should stimulate a careful analysis of the process of care and the options to improve the situation. Structured interventions, such as the introduction of bundles of infection control measures or checklists, are very helpful to increase compliance with infection control measures and to decrease nosocomial infection rates. However, often only interventions individually designed according to the specific needs in a particular unit/department are successful to improve infection rates. Therefore, the employment of experienced infection control personnel and surveillance strategies designed according to the specific needs of the institution are key elements of a good infection control management within healthcare institutions. PMID- 21290276 TI - [Lifestyle modification programs protecting cardiovascular health in Germany and Sweden. A qualitative interview study]. AB - A large amount of evidence, including neurohumoral, inflammatory, and metabolic physiological adaptations, emphasize the importance of the individual lifestyle as a public health concern. The related burden of chronic diseases in the European Union, which could be minimized by appropriate lifestyles, requires consistent transfer of evidence-based prevention guidelines. Due to the epidemiologic importance of cardiovascular diseases and innovative health promoting strategies in Sweden, a comparative analysis between German and Swedish practices preventing cardiovascular events in high-risk populations is presented in this paper. This qualitative analysis demonstrates that lifestyle-related risk and protective factors based on smoking, physical activity, nutrition, and psychosocial determinants are of growing importance in cardiac death prevention. Especially in Sweden, behavioral prevention is joined by condition prevention. In Germany, intersectoral rehabilitation concepts improve patient adherence to behavioral recommendations but interdisciplinary communication between different health experts needs to be improved. The health-promoting hospital composes a health professional's interface, which is based on the understanding that behavioral risk factors are not only highly interrelated, but also require sophisticated healthcare delivery to optimize health management effectiveness. PMID- 21290277 TI - [Who enrolls in a general practitioner model? The behavioral model of health services use and general practitioner-centered care in Germany]. AB - Since July 2009, statutory health insurance companies in Germany are obliged to offer a so-called general practitioner model. By strengthening the general practitioner's position, these models should optimize healthcare especially for people with higher demands for health services. So far, little is known about which patients participate in the model. Our study's aim was to describe correlates of enrollment based on the behavioral model of health services use. The data were obtained from the Robert Koch Institute's 2006 telephone health survey. Variables influencing enrollment in the general practitioner models were determined through logistic regression models. Main indicators for enrollment were age above 60 years, lower social status, lower income status, and living in less populated areas. Insured persons with a higher demand for medical services were more often enrolled in general practitioner models. Most of them had consulted their general practitioner very frequently even before the general practitioner model was introduced. PMID- 21290278 TI - [Shortage and need of physicians in Germany? Questions addressed to health services research]. AB - The problem of shortage of physicians has been discussed controversially in Germany for years, and the different positions of the interest groups involved have not been resolved. The question of the present and anticipated future requirement of physicians is central for an appropriate and necessary medical care of the population. In the analysis, supply and demand of medical care have to be distinguished. Relatively reliable data do exist for the supply of physicians; however, the changing number of working hours that male and--in particular female--physicians are willing to contribute should be taken into consideration. Reliable data for the future demand are presently not available. Several variables (e.g., demography, disease spectrum of an aging society, medical progress, the changing rules of working hours, and the shift of medical care between hospital and practice care) depend on future developments. Considering the existing serious indicators of a growing shortage of physicians, it is recommended to put more effort into the scientific investigation of these factors. More profound data should improve the basis for decisions in health and education politics. PMID- 21290279 TI - [Measles in 2010. Knowledge and vaccination status of medical students]. AB - OBJECTIVES: In 2002, the WHO Regional Office for Europe developed a strategic plan for measles in the WHO European Region. WHO recommends that at least 95% of children receive two doses of measles vaccine. This plan targeted the elimination of measles for the year 2010 and is supported by the Federal Republic of Germany. METHODS: Questionnaire survey, serological tests and check-up of the certificates of vaccination were offered to second year medical students of Goethe University Frankfurt/Main, Germany. RESULTS: Only 62.3% of medical students had received two doses of measles vaccine. Serological data showed that 23.1% were not immune against measles. Important gaps of knowledge were identified in the knowledge test of the survey; less than one third of the students (n=95/324) were able to answer more than 50% of the questions correctly. DISCUSSION: The suboptimum measles-vaccination coverage shows that the goal of eliminating measles will not be met across Europe by the target year 2010. Both occupational and public health measures need to make sure that vaccination programs should achieve a minimum of 95% coverage with two doses. In addition, the obligation to notify the authorities even of suspected cases serve the same purpose and measures to improve the knowledge of medical students are required. Consequent surveillance systems are necessary to investigate chains of measles infections. Healthcare workers play a decisive role in this issue. PMID- 21290280 TI - [Fourth report on the amendment to the guidelines for the hygienic assessment of organic coatings in contact with drinking water (Coating guideline)]. PMID- 21290281 TI - [Fifth report on the amendment to the guidelines for hygienic assessment of lubricants in contact with drinking water (sanitary lubricants) [Lubricant guideline]]. PMID- 21290282 TI - [Revised case definitions for the submission of evidence of dengue virus and norovirus and morbidity or death from dengue fever and norovirus gastroenteritis.]. PMID- 21290283 TI - [Classification of water-polluting substances]. PMID- 21290287 TI - Structural biology of TRP channels. AB - Structural studies on TRP channels, while limited, are poised for a quickened pace and rapid expansion. As of yet, no high-resolution structure of a full length TRP channel exists, but low-resolution electron cryomicroscopy structures have been obtained for 4 TRP channels, and high-resolution NMR and X-ray crystal structures have been obtained for the cytoplasmic domains, including an atypical protein kinase domain, ankyrin repeats, coiled coil domains and a Ca(2+)-binding domain, of 6 TRP channels. These structures enhance our understanding of TRP channel assembly and regulation. Continued technical advances in structural approaches promise a bright outlook for TRP channel structural biology. PMID- 21290289 TI - Natural product ligands of TRP channels. AB - Natural product ligands have contributed significantly to the deorphanisation of TRP ion channels. Furthermore, natural product ligands continue to provide valuable leads for the identification of ligands acting at "orphan" TRP channels. Additional naturally occurring modulators at TRP channels can be expected to be discovered in future, aiding in our understanding of not only their pharmacology and physiology, but also the therapeutic potential of this fascinating family of ion channels. PMID- 21290288 TI - Functional and structural studies of TRP channels heterologously expressed in budding yeast. AB - The transient receptor potential (TRP) superfamily is one of the largest families of cation channels. The metazoan TRP family has been subdivided into major branches: TRPC, TRPA, TRPM, TRPP, TRPV, TRPML, and TRPN, while the TRPY family is found in fungi. They are involved in many physiological processes and in the pathogenesis of various disorders. An efficient high-yield expression system for TRP channels is a necessary step towards biophysical and biochemical characterization and structural analysis of these proteins, and the budding yeast, Saccharomyces cerevisiae has proven to be very useful for this purpose. In addition, genetic screens in this organism can be carried out rapidly to identify amino acid residues important for function and to generate useful mutants. Here we present an overview of current developments towards understanding TRP channel function and structure using Saccharomyces cerevisiae as an expression system. In addition, we will summarize recent progress in understanding gating mechanisms of TRP channels using endogenously expressing TRPY channels in S. cerevisiae, and insights gained from genetic screens for mutants in mammalian channels. The discussion will focus particular attention of the use of cryo-electron microscopy (cryo-EM) to determine TRP channel structure, and outlines a "divide and concur" methodology for combining high resolution structures of TRP channel domains determined by X-ray crystallography with lower resolution techniques including cryo-EM and spectroscopy. PMID- 21290290 TI - Synthetic modulators of TRP channel activity. AB - In humans, 27 TRP channels from 6 related families contribute to a broad spectrum of cellular functions, such as thermo-, pressure-, volume-, pain- and chemosensation. Pain and inflammation-inducing compounds represent potent plant and animal defense mechanisms explaining the great variety of the naturally occurring, TRPV1-, TRPM8-, and TRPA1-activating ligands. The discovery of the first vanilloid receptor (TRPV1) and its involvement in nociception triggered the euphoria and the hope in novel therapeutic strategies treating pain, and this clear-cut indication inspired the development of TRPV1-selective ligands. On the other hand the nescience in the physiological role and putative clinical indication hampered the development of a selective drug in the case of the other TRP channels. Therefore, currently only a handful of mostly un-selective blocker is available to target TRP channels. Nevertheless, there is an ongoing quest for new, natural or synthetic ligands and modulators. In this chapter, we will give an overview on available broad-range blocker, as well as first TRP channel selective compounds. PMID- 21290291 TI - Study of TRP channels by automated patch clamp systems. AB - Ion channels are responsible for the permeation of ions across the membrane and their central role in cellular physiology is well established. Historically, the direct study of ion channels has been considered technically challenging. As such, a significant barrier to drug discovery for ion channels has been the low throughput of high quality electrophysiological data. The emergence of automated high throughput platforms for studying ion channel kinetics and pharmacology has lowered this barrier. Ion channels are now recognized as increasingly important drug targets and a diverse range of ion channels are implicated in a variety of drug discovery and cardiac safety assessment programs. The TRP (Transient Receptor Potential) superfamily of ion channels play a crucial role in a broad range of sensory functions including vision, taste, olfaction, hearing, touch, pain and thermosensation. Many of the TRP channels are polymodal in their activation and deactivation mechanisms and even with conventional patch clamp electrophysiology, the TRP channels are considered to be a very complex target class. Here we present an update on the significant progress made on the TRP receptor assays with the available automated patch clamp systems. PMID- 21290292 TI - TRPC2: of mice but not men. AB - Relatively little is known in regard to the physiological significance of TRPC2 and its regulation or interaction with other calcium regulating signalling molecules. In rodents, however, the importance of TRPC2 is indisputable. In mice, transcripts for TRPC2 have been found in testis, sperm, in neurons in the vomeronasal organ, and both in the dorsal root ganglion and in the brain. In rats, TRPC2 is thought to be expressed exclusively in the vomeronasal organ. In mice, TRPC2 is of importance in regulating both sexual and social behaviour. In sperm, TRPC2 is of importance in the acrosome reaction. This review will summarize the known physiological effects of TRPC2 channels, and the regulation of the function of the channel. In addition, some new preliminary data on the role of TRPC2 in rat thyroid cells will be presented. PMID- 21290293 TI - TRPM1: new trends for an old TRP. AB - TRPM1, initially named Melastatin, is the founding member of the TRPM subfamily of Transient Receptor Potential (TRP) ion channels. Despite sustained efforts, the molecular properties and physiological functions of TRPM1 remained elusive until recently. New evidence has uncovered novel TRPM1 splice variants and revealed that TRPM1 is critical for a non-selective cation conductance in melanocytes and retinal bipolar cells. Functionally, TRPM1 has been shown to mediate retinal ON bipolar cell transduction and suggested to regulate melanocyte pigmentation. Notably, TRPM1 mutations have also been associated with congenital stationary night blindness in humans. This review will summarize and discuss our present knowledge of TRPM1: its discovery, expression, regulation, and proposed functions in skin and eye. PMID- 21290294 TI - The non-selective monovalent cationic channels TRPM4 and TRPM5. AB - Transient Receptor Potential (TRP) proteins are non-selective cationic channels with a consistent Ca(2+)-permeability, except for TRPM4 and TRPM5 that are not permeable to this ion. However, Ca(2+) is a major regulator of their activity since both channels are activated by a rise in internal Ca(2+). Thus TRPM4 and TRPM5 are responsible for most of the Ca(2+)-activated non-selective cationic currents (NSC(Ca)) recorded in a large variety of tissues. Their activation induces cell-membrane depolarization that modifies the driving force for ions as well as activity of voltage gated channels and thereby strongly impacts cell physiology. In the last few years, the ubiquitously expressed TRPM4 channel has been implicated in insulin secretion, the immune response, constriction of cerebral arteries, the activity of inspiratory neurons and cardiac dysfunction. Conversely, TRPM5 whose expression is more restricted, has until now been mainly implicated in taste transduction. PMID- 21290295 TI - TRPM7, the Mg(2+) inhibited channel and kinase. AB - TRPM7 is a ubiquitously expressed nonselective cation channel fused to a C terminal alpha kinase. TRPM7 current is typically small at physiological magnesium concentrations, but large outwardly rectifying currents develop in low magnesium extracellular solution when cells are dialyzed with magnesium free solutions during whole-cell patch clamp recordings. In addition to regulation by magnesium, TRPM7 current is potentiated by low extracellular pH and inhibited by depletion of phosphatidylinositol 4,5-bisphosphate (PIP(2)) during phospholipase C mediated signaling events. A diverse body of literature has implicated TRPM7 in fundamental cellular processes including death, survival, proliferation, cell cycle progression, magnesium homeostasis and responses to shear stress and oxidative stress. Global deletion of TRPM7 in mouse results in embryonic lethality and a thymocyte-restricted conditional knockout exhibits defective thymopoeisis, suggesting a role for TRPM7 in development and organogenesis. In disease states, TRPM7 has been linked to Guamanian amyotrophic lateral sclerosis and parkinsonian dementia (ALS/PD), various forms of neoplasia, hypertension and delayed neuronal death following cerebral ischemia. PMID- 21290296 TI - TRPM8 in health and disease: cold sensing and beyond. AB - This review focuses on TRPM8, one of the approximately 30 members of the diverse family of transient receptor potential (TRP) ion channels. Initially identified from the prostate, TRPM8 has been studied more extensively in the sensory system and is best established as a major transducer of environmental cold temperatures. An increasing body of evidence suggests that it may also be an important player in various chronic conditions, such as inflammatory/neuropathic pain and prostate cancer. Small molecule compounds that selectively modulate TRPM8 are beginning to emerge and will be critically valuable for better understanding the role of this channel in both physiological and pathological states, on which the prospects of TRPM8 as a viable therapeutic target rest. PMID- 21290297 TI - TRPML1. AB - TRPML1 (or mucolipin 1) is the first member of the TRP family of ion channels that was found to function in the lower portions of the endocytic pathway. Mutations in the gene coding for TRPML1 (MCOLN1) cause the lysosomal storage disease mucolipidosis type IV (MLIV). TRPML1 localization in the lysosomes and the similarity of mucolipidosis type IV phenotype to lysosomal storage diseases whose origin has been directly linked to lysosomal dysfunction, suggest that TRPML1 activity drives some vitally important processes within the endocytic machinery. The specific aspect(s) of TRPML1 activity that make it indispensable for the proper function of the endocytic pathway as well as the specific aspect(s) of the endocytic activity that depend on TRPML1 are currently being discussed. Among the candidates are: membrane fusion within the lower portion of the endocytic pathway possibly mediated by Ca(2+) release through TRPML1, or regulation of lysosomal ion homeostasis (pH or Fe content) by TRPML1. In addition to delineating the mechanisms of MLIV pathogenesis, identifying the role of TRPML1 in the endocytic pathway will lead to important developments in our understanding of the endocytic pathway and, due to the neurodegenerative nature of MLIV, of the integrative function of the cell. Moreover, molecular modulators of TRPML1 function may lead to novel approaches to modulating biological processes that depend on the endocytic pathway such as growth factor signaling. The present review will focus on the recent developments in identifying the TRPML1 function. PMID- 21290298 TI - TRPML2 and the evolution of mucolipins. AB - TRPML2, the polypeptide product of the gene Trpml2 (aka Mcoln2), is a member of the TRPML or mucolipin branch of the TRP super family of ion channels. Although no known agonists have been discovered, the wild type channel gives basal currents when heterologously expressed in Drosophila (S2) cells and is constitutively active in mammalian cells when bearing a cell degeneration causing, proline to alanine substitution in the fifth trans-membrane domain. TRPML2 forms channels that are inwardly rectifying and permeable to Ca(+2), Na(+), and Fe(+2). Localization studies indicate TRPML2 is present in lysosomes, late endosomes, recycling endosomes and, at a lower level, the plasma membrane. Tissue and organ distribution of TRPML2 is solely reported through RT-PCR and it is uncertain which cell types express this channel. However, various studies suggest that lymphoid cells express TRPML2. Although the function of TRPML2 is not known, distribution and channel properties suggest it could play roles in calcium release from endolysosomes, perhaps to mediate calcium-dependent events such as vesicle fusion, or to release calcium from intracellular acidic stores. However, TRPML2 may also function in the plasma membrane and its abundance in vesicles of the endocytic pathaway might occur because its presence in the cell surface is regulated by endocytosis and exocytosis. An evolutionary analysis of Trpml2 and its relatives reveals that vertebrate and invertebrate chordates have only one Trpml gene, that Trpml1 and Trpml2 are common to vertebrates, and that Trpml3 is only found in tetrapods. Ray-finned fishes contain another isoform, which we term Trpml4 or Mcoln4 (and its product TRPML4). Trpml2 is next to Trpml3 in all tetrapod genomes except that of the frog Xenopus tropicalis and of the domesticated pig, which seems to lack most of the Trpml3 gene. This close linkage across species implies that it is maintained by selective pressure and suggests that the regulation of both genes is interdependent. PMID- 21290299 TI - The TRPML3 channel: from gene to function. AB - TRPML3 is a transient receptor potential (TRP) channel that is encoded by the mucolipin 3 gene (MCOLN3), a member of the small mucolipin gene family. Mcoln3 shows a broad expression pattern in embryonic and adult tissues that includes differentiated cells of skin and inner ear. Dominant mutant alleles of murine Mcoln3 cause embryonic lethality, pigmentation defects and deafness. The TRPML3 protein features a six-transmembrane topology and functions as a Ca(2+) permeable inward rectifying cation channel that is open at sub-physiological pH and closes as the extracytosolic pH becomes more acidic. TRPML3 localizes to the plasmamembrane and to early- and late-endosomes as well as lysosomes. Recent advances suggest that TRPML3 may regulate the acidification of early endosomes, hence playing a critical role in the endocytic pathway. PMID- 21290300 TI - TRPV5 and TRPV6 in transcellular Ca(2+) transport: regulation, gene duplication, and polymorphisms in African populations. AB - TRPV5 and TRPV6 are unique members of the TRP super family. They are highly selective for Ca(2+) ions with multiple layers of Ca(2+)-dependent inactivation mechanisms, expressed at the apical membrane of Ca(2+) transporting epithelia, and robustly responsive to 1,25-dihydroxivitamin D(3). These features are well suited for their roles as Ca(2+) entry channels in the first step of transcellular Ca(2+) transport pathways, which are involved in intestinal absorption, renal reabsorption of Ca(2+), placental transfer of Ca(2+) to fetus, and many other processes. While TRPV6 is more broadly expressed in a variety of tissues such as esophagus, stomach, small intestine, colon, kidney, placenta, pancreas, prostate, uterus, salivary gland, and sweat gland, TRPV5 expression is relatively restricted to the distal convoluted tubule and connecting tubule of the kidney. There is only one TRPV6-like gene in fish and birds in comparison to both TRPV5 and TRPV6 genes in mammals, indicating TRPV5 gene was likely generated from duplication of TRPV6 gene during the evolution of mammals to meet the needs of complex renal function. TRPV5 and TRPV6 are subjected to vigorous regulations under physiological, pathological, and therapeutic conditions. The elevated TRPV6 level in malignant tumors such as prostate and breast cancers makes it a potential therapeutic target. TRPV6, and to a lesser extent TRPV5, exhibit unusually high levels of single nucleotide polymorphisms (SNPs) in African populations as compared to other populations, indicating TRPV6 gene was under selective pressure during or after humans migrated out of Africa. The SNPs of TRPV6 and TRPV5 likely contribute to the Ca(2+) conservation mechanisms in African populations. PMID- 21290301 TI - The TRPV5 promoter as a tool for generation of transgenic mouse models. AB - The transient receptor potential vanilloid 5 (TRPV5) is a Ca(2+) channel, which is expressed in renal late distal convoluted tubules (DCT2s) and connecting tubules (CNTs). These tubules play a major role in hormone controlled renal Ca(2+) reabsorption, and thereby in body Ca(2+) homeostasis, as well as urinary excretion of other electrolytes, including Na(+) and K(+). DCT2 and CNT are difficult to distinguish from the surrounding structures and thereby to study by direct functional methods. We developed a transgenic mouse model expressing enhanced green fluorescent protein (EGFP) driven by the TRPV5 promoter to identify these specific tubules. Expression of EGFP in the DCT2 and CNT allows the isolation of pure DCT2 and CNT populations for proteomic and physiological analyses. The TRPV5 promoter is also useful for generating conditional knockout mouse models in a cell-specific manner. TRPV5 promoter driven Cre recombinase expression will be useful for inducing DCT2 and CNT specific gene silencing of various channels, pumps, carriers, and receptors. In this chapter, we describe the strategy for developing transgenic mouse lines involving the TRPV5 promoter, provide a description of extensive validation of these mouse lines, and discuss possible uses and limitations. PMID- 21290302 TI - TRPP channels and polycystins. AB - The founding member of the TRPP family, TRPP2, was identified as one of the disease genes causing autosomal dominant polycystic kidney disease (ADPKD). ADPKD is the most prevalent, potentially lethal, monogenic disorder in humans, with an average incidence of one in 400 to one in 1,000 individuals worldwide. Here we give an overview of TRPP ion channels and Polycystin-1 receptor proteins focusing on more recent studies. We include the Polycystin-1 family since these proteins are functionally linked to TRPP channels. PMID- 21290303 TI - TRP channels in yeast. AB - Microbes have made numerous contributions to the study of biology and medicine. Those contributions also include many original discovery's in the study of ion channels often thought as the province of neuroscientists or cardiophysiologists. Yeast have long been used as a model organism and TRP channel genes and their transmembrane products touted as the "vanguards of the sensory system" can be identified in the genomes of many yeasts. This article aims to review the study of these TRP channels in yeast their discovery, electrophysiological properties and physiological function. PMID- 21290305 TI - Investigations of the in vivo requirements of transient receptor potential ion channels using frog and zebrafish model systems. AB - Transient Receptor Potential (TRP) channels are cation channels that serve as cellular sensors on the plasma membrane, and have other less-well defined roles in intracellular compartments. The first TRP channel was identified upon molecular characterization of a fly mutant with abnormal photoreceptor function. More than 20 TRP channels have since been identified in vertebrates and invertebrate model systems, and these are divided into subfamilies based on structural similarities. The biophysical properties of TRP channels have primarily been explored in tissue culture models. The in vivo requirements for TRPs have been studied in invertebrate models like worm and flies, and also in vertebrate models, primarily mice and rats. Frog and zebrafish model systems offer certain experimental advantages relative to mammalian systems, and here a selection of papers which capitalize on these advantages to explore vertebrate TRP channel biology are reviewed. For instance, frog oocytes are useful for biochemistry and for electrophysiology, and these features were exploited in the identifcation TRPC1 as a candidate vertebrate mechanoreceptor. Also, the spinal neurons from frog embryos can be readily grown in culture. This feature was used to establish a role for TRPC1 in axon pathfinding in these neurons, and to explore how TRPC1 activity is regulated in this context. Zebrafish embryos are transparent making them well suited for in vivo imaging studies. This quality was exploited in a study in which the trpc2 gene promoter was used to label and trace the axon pathway of a subset of olfactory sensory neurons. Another experimental advantage of zebrafish is the speed and low cost of manipulating gene expression in embryos. Using these methods, it has been shown that TRPN1 is necessary for mechanosensation in zebrafish hair cells. Frogs and fish genomes have been mined to make inferences regarding evolutionary diversification of the thermosensitive TRP channels. Finally, TRPM7 is required for early morphogenesis in mice but not in fish; the reason for this difference is unclear, but it has caused zebrafish to be favored for exploration of TRPM7's role in later events in embryogenesis. The special experimental attributes of frogs and zebrafish suggest that these animals will continue to play an important role as models in future explorations of TRP channel biology. PMID- 21290304 TI - C. elegans TRP channels. AB - Transient receptor potential (TRP) channels represent a superfamily of cation channels found in all eukaryotes. The C. elegans genome encodes seventeen TRP channels covering all of the seven TRP subfamilies. Genetic analyses in C. elegans have implicated TRP channels in a wide spectrum of behavioral and physiological processes, ranging from sensory transduction (e.g. chemosensation, touch sensation, proprioception and osmosensation) to fertilization, drug dependence, organelle biogenesis, apoptosis, gene expression, and neurotransmitter/hormone release. Many C. elegans TRP channels share similar activation and regulatory mechanisms with their vertebrate counterparts. Studies in C. elegans have also revealed some previously unrecognized functions and regulatory mechanisms of TRP channels. C. elegans represents an excellent genetic model organism for the study of function and regulation of TRP channels in vivo. PMID- 21290306 TI - TRP channels in parasites. AB - A wide range of single- and multi-cellular parasites infect humans and other animals, causing some of the most prevalent and debilitating diseases on the planet. There have been virtually no published studies on the TRP channels of this diverse group of organisms. However, since many parasite genomes have been sequenced, it is simple to demonstrate that they are present in all parasitic metazoans and that sequences related to the yeast trp are present in many protozoans, including all the kinetoplastids. We compared the TRP genes of three species of animal and plant parasitic nematode to those of C. elegans and found that the parasitic species all had fewer such genes. These differences may reflect the phylogenetic distance between the species studied, or may be due to loss of specific gene functions following the evolution of the parasitic lifestyle. Other helminth groups, the trematodes and cestodes, seem to possess many TRPC and TRPM genes, but lack TRPV and TRPN. Most ectoparasites are insects or arachnids. We compared the TRP genes of a plant parasitic aphid and an animal parasite louse and tick with those of Drosophila. Again, all the parasitic species seemed to have fewer types of TRP channel, though the difference was less marked than for the nematodes. The aphid lacks TRPP and TRPML channel genes, whereas the tick lacked those encoding TRPVs. Again, these differences may reflect adaptation to parasitism, and could enable TRP channels to be targeted in the development of novel antiparasitic drugs. PMID- 21290307 TI - Receptor signaling integration by TRP channelsomes. AB - Homologues of transient receptor potential (TRP) genes encode a variety of cation channels, most of which conduct Ca(2+) across the plasma membrane. TRP proteins interact with a variety of proteins and other biologically important factors, such as second messengers, and thereby form "channelsomes", most of which function as Ca(2+) signalsomes. Activation mechanisms and final outputs are exquisitely incorporated in the signaling system of TRP channelsomes. In this study, we discuss the channelsomes of TRPC3, TRPC5, and TRPM2, which show unique molecular interactions and modulations of activation. Comparative studies of these specific TRP channelsomes should aid the determination of general rules that govern the formation and regulation of channelsomes and signalsomes. PMID- 21290308 TI - Gating mechanisms of canonical transient receptor potential channel proteins: role of phosphoinositols and diacylglycerol. AB - Canonical transient receptor potential (TRPC) Ca(2+)-permeable channels are members of the mammalian TRP super-family of cation channels, and have the closest homology to the founding members, TRP and TRPL, discovered in Drosophila photoreceptors. The TRPC subfamily is composed of 7 subunits (C1-C7, with TRPC2 a pseudogene in humans), which can all combine with one another to form homomeric and heteromeric structures. This review focuses on mechanisms involved in opening TRPC channels (i.e. gating mechanisms). It initially describes work on the involvement of phosphatidylinositol-4,5-bisphosphate (PIP(2)) and diacylglycerol (DAG) in gating TRP and TRPL channels in Drosophila, and then discusses evidence that similar gating mechanisms are involved in opening mammalian TRPC channels. It concludes that there are two common activation pathways of mammalian TRPC channels. Non-TRPC1-containing channels are opened by interactions between DAG, the direct activating ligand, and PIP(2), which acts as a physiological antagonist at TRPC proteins. Competitive interactions between an excitatory effect of DAG and an inhibitory action of PIP(2) can also be modulated by IP(3) acting via an IP(3) receptor-independent mechanism. In contrast TRPC1-containing channels are gating by PIP(2), which requires PKC-dependent phosphorylation of TRPC1 proteins. PMID- 21290309 TI - The TRPC ion channels: association with Orai1 and STIM1 proteins and participation in capacitative and non-capacitative calcium entry. AB - Transient receptor potential (TRP) proteins are involved in a large number of non selective cation channels that are permeable to both monovalent and divalent cations. Two general classes of receptor-mediated Ca(2+) entry has been proposed: one of then is conduced by receptor-operated Ca(2+) channels (ROC), the second is mediated by channels activated by the emptying of intracellular Ca(2+) stores (store-operated channels or SOC). TRP channels have been presented as subunits of both ROC and SOC, although the precise mechanism that regulates the participation of TRP proteins in these Ca(2+) entry mechanisms remains unclear. Recently, TRPC proteins have been shown to associate with Orai1 and STIM1 in a dynamic ternary complex regulated by the occupation of membrane receptors in several cell models, which might play an important role in the function of TRPC proteins. The present review summarizes the current knowledge concerning the association of TRP proteins with Orai and STIM proteins and how this affects the participation of TRP proteins in store-operated or receptor-operated Ca(2+) entry. PMID- 21290310 TI - Contribution of TRPC1 and Orai1 to Ca(2+) entry activated by store depletion. AB - Store-operated Ca(2+) entry (SOCE) is activated in response to depletion of the ER-Ca(2+) stores by the ER Ca(2+) sensor protein, STIM1 which oligomerizes and moves to ER/PM junctional domains where it interacts with and activates channels involved in SOCE. Two types of channel activities have been described. I(CRAC), via Ca(2+) release-activated Ca(2+) (CRAC) channel, which displays high Ca(2+) selectivity and accounts for the SOCE and cell function in T lymphocytes, mast cells, platelets, and some types of smooth muscle and endothelial cells. Orai1 has been established as the pore-forming component of CRAC channels and interaction of Orai1 with STIM1 is sufficient for generation of the CRAC channel. Store depletion also leads to activation of relatively non-selective cation currents (referred to as I(SOC)) that contribute to SOCE in several other cell types. TRPC channels, including TRPC1, TRPC3, and TRPC4, have been proposed as possible candidate channels for this Ca(2+) influx. TRPC1 is the best characterized channel in this regard and reported to contribute to endogenous SOCE in many cells types. TRPC1-mediated Ca(2+) entry and cation current in cells stimulated with agonist or thapsigargin are inhibited by low [Gd(3+)] and 10-20 MUM 2APB (conditions that block SOCE). Importantly, STIM1 also associates with and gates TRPC1 via electrostatic interaction between STIM1 ((684)KK(685)) and TRPC1 ((639)DD(640)). Further, store depletion induces dynamic recruitment of a TRPC1/STIM1/Orai1 complex and knockdown of Orai1 completely abrogates TRPC1 function. Despite these findings, there has been much debate regarding the activation of TRPC1 by store depletion as well as the role of Orai1 and STIM1 in SOC channel function. This chapter summarizes recent studies and concepts regarding the contributions of Orai1 and TRPC1 to SOCE. Major unresolved questions regarding functional interaction between Orai1 and TRPC1 as well as possible mechanisms involved in the regulation of TRPC channels by store depletion will be discussed. PMID- 21290311 TI - Primary thermosensory events in cells. AB - Temperature sensing is essential for the survival of living organisms. Since thermal gradients are almost everywhere, thermoreception could represent one of the oldest sensory transduction processes that evolved in organisms. There are many examples of temperature changes affecting the physiology of living cells. Almost all classes of biological macromolecules in a cell (nucleic acids, lipids, proteins) can serve as a target of the temperature-related stimuli. This review is devoted to some common features of different classes of temperature-sensing molecules as well as molecular and biological processes involved in thermosensation. Biochemical, structural and thermodynamic approaches are discussed in order to overview the existing knowledge on molecular mechanisms of thermosensation. PMID- 21290312 TI - Thermo-TRP channels: biophysics of polymodal receptors. AB - In this chapter we discuss the polymodal activation of thermo-TRP channels using as exemplars two of the best characterized members of this class of channels: TRPM8 and TRPV1. Since channel activation by temperature is the hallmark of thermo-TRP channels, we present a detailed discussion on the thermodynamics involved in the gating processes by temperature, voltage, and agonists. We also review recently published data in an effort to put together all the pieces available of the amazing puzzle of thermo-TRP channel activation. Special emphasis is made in the structural components that allow the channel-forming proteins to integrate such diverse stimuli, and in the coupling between the different sensors and the ion conduction pathway. We conclude that the present data is most economically explained by allosteric models in which temperature, voltage, and agonists act separately to modulate channel activity. PMID- 21290313 TI - Complex regulation of TRPV1 and related thermo-TRPs: implications for therapeutic intervention. AB - The capsaicin receptor TRPV1 (Transient Receptor Potential, Vanilloid family member 1), the founding member of the heat-sensitive TRP ("thermo-TRP") channel family, plays a pivotal role in pain transduction. There is mounting evidence that TRPV1 regulation is complex and is manifest at many levels, from gene expression through post-translational modification and formation of receptor heteromers to subcellular compartmentalization and association with regulatory proteins. These mechanisms are believed to be involved both in disease-related changes in TRPV1 expression, and the long-lasting refractory state, referred to as "desensitization", that follows TRPV1 agonist treatment. The signaling cascades that regulate TRPV1 and related thermo-TRP channels are only beginning to be understood. Here we review our current knowledge in this rapidly changing field. We propose that the complex regulation of TRPV1 may be exploited for therapeutic purposes, with the ultimate goal being the development of novel, innovative agents that target TRPV1 in diseased, but not healthy, tissues. Such compounds are expected to be devoid of the side-effects (e.g. hyperthermia and impaired noxious heat sensation) that plague the clinical use of existing TRPV1 antagonists. PMID- 21290314 TI - Voltage sensing in thermo-TRP channels. AB - Membrane voltage, ligand binding, mechanical force and temperature can all induce conformational changes that open ion channel pores. A key question in understanding ion channel function is how the protein domains involved in sensing stimuli (sensors) communicate with the pore to gate its opening and closing. TRP channels are considered six-transmembrane cation-permeable channels, distant relatives of voltage-gated potassium channels (Kv), which are known to be activated by membrane depolarization. Understanding the molecular nature of thermo-TRP channel gating offers a fair challenge to biophysicists. This chapter will summarize our present knowledge on the effect of voltage and temperature during thermo-TRP channel activation. PMID- 21290315 TI - TRP channels as mediators of oxidative stress. AB - The transient receptor potential (TRP) protein superfamily is a diverse group of cation-permeable channels expressed in mammalian cells, which is divided into six subfamilies based on sequence identity. Three subfamilies have members with roles in oxidative stress: the TRPC subfamily characterized by receptor operated calcium entry channels; the TRPM subfamily with a number of members involved in cell proliferation and death; and the TRPV subfamily which is activated by chemical, mechanical, and physical stimuli. The TRPC members TRPC3 and TRPC4 can serve as subunits of a redox-sensitive ion channel in native aortic endothelial cells. The TRPM family member TRPM2 has a number of physiologic isoforms expressed in many cell types and responds to stimuli including oxidative stress, TNFalpha, and beta-amyloid peptide. The important role of TRPM2 isoforms in cell proliferation and oxidant-induced cell death has been well established using divergent cell systems and techniques including overexpression, channel depletion or inhibition, and calcium chelation. TRPM7 has been shown to be involved in Ca(2+) influx and anoxic cell death in cortical neurons. In these cells and in B cells, precise expression of TRPM7 is necessary for cell survival. TRPV1 is involved in oxidant stress-induced pain and in neuronal injury, contributing to diabetic sensory neuropathy. Future studies will likely identify additional channels involved in oxidant injury, as well as better define mechanisms through which these channels are regulated and mediate their effects. Therapeutic approaches to modulate activation of specific TRP channels are likely to have an important impact in reducing tissue damage in a number of diseases resulting from oxidant stress including ischemia/reperfusion injury and diabetes. PMID- 21290316 TI - Regulation of TRP signalling by ion channel translocation between cell compartments. AB - The TRP (transient receptor potential) family of ion channels is a heterogeneous family of calcium permeable cation channels that is subdivided into seven subfamilies: TRPC ("Canonical"), TRPV ("Vanilloid"), TRPM ("Melastatin"), TRPA ("Ankyrin"), TRPN ("NOMPC"), TRPP ("Polycystin"), and TRPML ("Mucolipin"). TRP mediated ion currents across the cell membrane are determined by the single channel conductance, by the fraction of activated channels, and by the total amount of TRP channels present at the plasma membrane. In many cases, the amount of TRP channels at the plasma membrane is altered in response to physiological stimuli by translocation of channels to and from the plasma membrane. Regulated translocation has been described for channels of the TRPC, TRPV, TRPM, and TRPA family and is achieved by vesicular transport of these channels along cellular exocytosis and endocytosis pathways. This review summarizes the stimuli and signalling cascades involved in the translocation of TRP channels and highlights interactions of TRP channels with proteins of the endocytosis and exocytosis machineries. PMID- 21290318 TI - TRP channels and neural persistent activity. AB - One of the integrative properties of the nervous system is its capability to, by transient motor commands or brief sensory stimuli, evoke persistent neuronal changes, mainly as a sustained, tonic action potential firing. This neural activity, named persistent activity, is found in a good number of brain regions and is thought to be a neural substrate for short-term storage and accumulation of sensory or motor information [1]. Examples of this persistent neural activity have been reported in prefrontal [2] and entorhinal [3] cortices, as part of the neural mechanisms involved in short-term working memory [4]. Interestingly, the general organization of the motor systems assumes the presence of bursts of short lasting motor commands encoding movement characteristics such as velocity, duration, and amplitude, followed by a maintained tonic firing encoding the position at which the moving appendage should be maintained [5, 6]. Generation of qualitatively similar sustained discharges have also been found in spinal and supraspinal regions in relation to pain processing [7, 8]. Thus, persistent neural activity seems to be necessary for both behavioral (positions of fixation) and cognitive (working memory) processes. Persistent firing mechanisms have been proposed to involve the participation of a non-specific cationic current (CAN current) mainly mediated by activation of TRPC channels. Because the function and generation of persistent activity is still poorly understood, here we aimed to review and discuss the putative role of TRP-like channels on its generation and/or maintenance. PMID- 21290317 TI - Emerging roles of canonical TRP channels in neuronal function. AB - Ca(2+) signaling in neurons is intimately associated with the regulation of vital physiological processes including growth, survival and differentiation. In neurons, Ca(2+) elicits two major functions. First as a charge carrier, Ca(2+) reveals an indispensable role in information relay via membrane depolarization, exocytosis, and the release of neurotransmitters. Second on a global basis, Ca(2+) acts as a ubiquitous intracellular messenger to modulate neuronal function. Thus, to mediate Ca(2+)-dependent physiological events, neurons engage multiple mode of Ca(2+) entry through a variety of Ca(2+) permeable plasma membrane channels. Here we discuss a subset of specialized Ca(2+)-permeable non selective TRPC channels and summarize their physiological and pathological role in the context of excitable cells. TRPC channels are predominately expressed in neuronal cells and are activated through complex mechanisms, including second messengers and store depletion. A growing body of evidence suggests a prime contribution of TRPC channels in regulating fundamental neuronal functions. TRPC channels have been shown to be associated with neuronal development, proliferation and differentiation. In addition, TRPC channels have also been suggested to have a potential role in regulating neurosecretion, long term potentiation, and synaptic plasticity. During the past years, numerous seminal discoveries relating TRPC channels to neurons have constantly emphasized on the significant contribution of this group of ion channels in regulating neuronal function. Here we review the major groundbreaking work that has uniquely placed TRPC channels in a pivotal position for governing neuronal Ca(2+) signaling and associated physiological responses. PMID- 21290319 TI - Role of TRP channels in pain sensation. AB - It is crucial for a living organism to recognize and discern potentially harmful noxious stimuli from innocuous stimuli to avoid hazards in the environment. However, unnecessary or exaggerated nociception is at best unpleasant and often compromises the quality of life. In order to lessen the intensity of nociception or eliminate the pathological pain, it is important to understand the nature of nociception and the mechanisms of hyperalgesia or allodynia. Transient receptor potential (TRP) channels play central roles in nociception under physiological and pathological conditions including inflammation and neuropathy. In this chapter, we will highlight the enormous progress in understanding the role of TRP channels in nociception. We will mainly focus on two TRP channels (TRPV1 and TRPA1) that have been particularly implicated in transducing signals associated with pain sensation, and briefly discuss the role of TRPM8, TRPV3 and TRPV4. We will stress debatable issues that needed to be resolved and provide perspectives for the future studies. PMID- 21290320 TI - TRPV1: a therapy target that attracts the pharmaceutical interests. AB - TRPV1 is a non-selective cation channel gated by noxious heat, vanilloids and extracellular protons, and act as an important signal integrator in sensory nociceptors. Because of its integrative signaling properties in response to inflammatory stimuli, TRPV1 antagonists are predicted to inhibit the sensation of ongoing or burning pain that is reported by patients suffering from chronic pain, therefore offering an unprecedented advantage in selectively inhibiting painful signaling from where it is initiated. In this chapter, we firstly summarize the physiological and pathological roles of TRPV1 and then describe the pharmacology of TRPV1 agonists and antagonists. Finally, we give an update and the status on TRPV1 therapies that have progressed into clinical trials. PMID- 21290321 TI - Expression and function of TRP channels in liver cells. AB - The liver plays a central role in whole body homeostasis by mediating the metabolism of carbohydrates, fats, proteins, drugs and xenobiotic compounds, and bile acid and protein secretion. Hepatocytes together with endothelial cells, Kupffer cells, smooth muscle cells, stellate and oval cells comprise the functioning liver. Many members of the TRP family of proteins are expressed in hepatocytes. However, knowledge of their cellular functions is limited. There is some evidence which suggests the involvement of TRPC1 in volume control, TRPV1 and V4 in cell migration, TRPC6 and TRPM7 in cell proliferation, and TRPPM in lysosomal Ca(2+) release. Altered expression of some TRP proteins, including TRPC6, TRPM2 and TRPV1, in tumorigenic cell lines may play roles in the development and progression of hepatocellular carcinoma and metastatic liver cancers. It is likely that future experiments will define important roles for other TRP proteins in the cellular functions of hepatocytes and other cell types of which the liver is composed. PMID- 21290322 TI - Expression and physiological roles of TRP channels in smooth muscle cells. AB - Smooth muscles are widely distributed in mammal body through various systems such as circulatory, respiratory, gastro-intestinal and urogenital systems. The smooth muscle cell (SMC) is not only a contractile cell but is able to perform other important functions such as migration, proliferation, production of cytokines, chemokines, extracellular matrix proteins, growth factors and cell surface adhesion molecules. Thus, SMC appears today as a fascinating cell with remarkable plasticity that contributes to its roles in physiology and disease. Most of the SMC functions are dependent on a key event: the increase in intracellular calcium concentration ([Ca(2+)](i)). Calcium entry from the extracellular space is a major step in the elevation of [Ca(2+)](i) in SMC and involves a variety of plasmalemmal calcium channels, among them is the superfamily of transient receptor potential (TRP) proteins. TRPC (canonical), TRPM (melastatin), TRPV (vanilloid) and TRPP (polycystin), are widely expressed in both visceral (airways, gastrointestinal tract, uterus) and vascular (systemic and pulmonary circulation) smooth muscles. Mainly, TRPC, TRPV and TRPM are implicated in a variety of physiological and pathophysiological processes such as: SMC contraction, relaxation, growth, migration and proliferation; control of blood pressure, arterial myogenic tone, pulmonary hypertension, intestinal motility, gastric acidity, uterine activity during parturition and labor. Thus it is becoming evident that TRP are major element of SMC calcium homeostasis and, thus, appear as novel drug targets for a better management of diseases originating from SMC dysfunction. PMID- 21290323 TI - TRPM channels in the vasculature. AB - Recent studies show that mammalian melastatin TRPM nonselective cation channels (TRPM1-8), members of the largest and most diverse TRP subfamily, are widely expressed in the endothelium and vascular smooth muscles. When activated, these channels similarly to other TRPs permit the entry of sodium, calcium and magnesium, thus causing membrane depolarisation. Although membrane depolarisation reduces the driving force for calcium entry via TRPMs as well as other pathways for calcium entry, in smooth muscle myocytes expressing voltage-gated Ca(2+) channels the predominant functional effect is an increase in intracellular Ca(2+) concentration and myocyte contraction. This review focuses on several best documented aspects of vascular functions of TRPMs, including the role of TRPM2 in oxidant stress, regulation of endothelial permeability and cell death, the connection between TRPM4 and myogenic response, significance of TRPM7 for magnesium homeostasis, vessel injury and hypertension, and emerging evidence that the cold and menthol receptor TRPM8 is involved in the regulation of vascular tone. PMID- 21290325 TI - TRP channels in skeletal muscle: gene expression, function and implications for disease. AB - Besides the well known voltage-gated Ca(2+) channels skeletal muscle fibres contain several non-voltage gated Ca(2+) conducting cation channels. They have been physiologically characterized as stretch activated, store operated and Ca(2+) leak channels. TRP channels are good candidates to account for these sarcolemmal channels and Ca(2+) influx pathways or at least contribute to the responsible macromolecular complexes. Several members of the TRPC, TRPV and TRPM subfamilies of TRP channels are expressed in skeletal muscle as shown by RT-PCR, Western blot and immunohistochemistry. The most prominent and consistently found are TRPC1, C3, C4 and C6, TRPV2 and V4 as well as TRPM4 and M7. However, the precise function of individual channels is largely unknown. Linking physiologically characterized channels of the muscle fibre membrane to TRP channel proteins has been a major challenge during the last years. It has been successful only in a few cases and is complicated by the fact that some channels have dual functions in cultured, immature muscle cells and adult fibres. The best characterized TRP channel in skeletal muscle is TRPC1, a small-conductance channel of the sarcolemma. It is needed for Ca(2+) homeostasis during sustained contractile muscle activity. In addition to certain physiological functions TRP channels seem to be involved in the pathomechanisms of muscle disorders. There is a broad body of evidence that dysregulation of Ca(2+) conducting channels plays a key role in the pathomechanism of Duchenne muscular dystrophy. Lack of the cytoskeletal protein dystrophin or delta-sarcoglycan, seems to disturb the function of one or several Ca(2+) channels of the muscle fibre membrane, leading to pathological dystrophic changes. Almost 10 different TRP channels have been detected in skeletal muscle. They seem to be involved in muscle development, Ca(2+) homeostasis, Ca(2+) signalling and in disease progression of certain muscle disorders. However, we are still at the beginning of understanding the impact of TRP channel functions in skeletal muscle. PMID- 21290324 TI - Molecular expression and functional role of canonical transient receptor potential channels in airway smooth muscle cells. AB - Multiple canonical or classic transient receptor potential (TRPC) molecules are expressed in animal and human airway smooth muscle cells (SMCs). TRPC3, but not TRPC1, is a major molecular component of native non-selective cation channels (NSCCs) to contribute to the resting [Ca(2+)](i) and muscarinic increase in [Ca(2+)](i) in freshly isolated airway SMCs. TRPC3-encoded NSCCs are significantly increased in expression and activity in airway SMCs from ovalbumin sensitized/challenged "asthmatic" mice, whereas TRPC1-encoded channel activity, but not its expression, is largely augmented. The upregulated TRPC3- and TRPC1 encoded NSCC activity both mediate "asthmatic" membrane depolarization in airway SMCs. Supportively, tumor necrosis factor-alpha (TNFalpha), an important asthma mediator, increases TRPC3 expression, and TRPC3 gene silencing inhibits TNFalpha mediated augmentation of acetylcholine-evoked increase in [Ca(2+)](i) in passaged airway SMCs. In contrast, TRPC6 gene silencing has no effect on 1-oleoyl-2-acetyl sn-glycerol (OAG)-evoked increase in [Ca(2+)](i) in primary isolated cells. These findings provide compelling information indicating that TRPC3-encoded NSCCs are important for physiological and pathological cellular responses in airway SMCs. However, continual studies are necessary to further determine whether, which, and how TRPC-encoded channels are involved in cellular responses in normal and diseased (e.g., asthmatic) airway SMCs. PMID- 21290326 TI - TRP channels in vascular endothelial cells. AB - Endothelial cells regulate multiple vascular functions, such as vascular tone, permeability, remodeling, and angiogenesis. It is known for long that cytosolic Ca(2+) level ([Ca(2+)](i)) and membrane potential of endothelial cells are crucial factors to initiate the signal transduction cascades, leading to diverse vascular functions. Among the various kinds of endothelial ion channels that regulate ion homeostasis, transient receptor potential (TRP) channels emerge as the prime mediators for a diverse range of vascular signaling. The characteristics of TRP channels, including subunit heteromultimerization, diverse ion selectivity, and multiple modes of activation, permit their versatile functional roles in vasculatures. Substantial amount of evidence demonstrates that many TRP channels in endothelial cells participate in physiological and pathophysiological processes of vascular system. In this article, we summarize the recent findings of TRP research in endothelial cells, aiming at providing up to-date information to the researchers in this rapidly growing field. PMID- 21290327 TI - TRP channels in the cardiopulmonary vasculature. AB - Transient receptor potential (TRP) channels are expressed in almost every human tissue, including the heart and the vasculature. They play unique roles not only in physiological functions but, if over-expressed, also in pathophysiological disease states. Cardiovascular diseases are the leading cause of death in the industrialized countries. Therefore, TRP channels are attractive drug targets for more effective pharmacological treatments of these diseases. This review focuses on three major cell types of the cardiovascular system: cardiomyocytes as well as smooth muscle cells and endothelial cells from the systemic and pulmonary circulation. TRP channels initiate multiple signals in all three cell types (e.g. contraction, migration) and are involved in gene transcription leading to cell proliferation or cell death. Identification of their genes has significantly improved our knowledge of multiple signal transduction pathways in these cells. Some TRP channels are important cellular sensors and are mostly permeable to Ca(2+), while most other TRP channels are receptor activated and allow for the entry of Na(+), Ca(2+) and Mg(2+). Physiological functions of TRPA, TRPC, TRPM, TRPP and TRPV channels in the cardiovascular system, dissected by down-regulating channel activity in isolated tissues or by the analysis of gene-deficient mouse models, are reviewed. The involvement of TRPs as homomeric or heteromeric channels in pathophysiological processes in the cardiovascular system like heart failure, cardiac hypertrophy, hypertension as well as edema formation by increased endothelial permeability will be discussed. PMID- 21290328 TI - TRP channels of islets. AB - In the normal human body pancreatic beta-cells spend most of the time in a READY mode rather than in an OFF mode. When in the READY mode, normal beta-cells can be easily SWITCHED ON by a variety of apparently trivial stimuli. In the READY mode beta-cells are highly excitable because of their high input resistance. A variety of small depolarizing currents mediated through a variety of cation channels triggered by a variety of chemical and physical stimuli can SWITCH ON the cells. Several polymodal ion channels belonging to the transient receptor potential (TRP) family may mediate the depolarizing currents necessary to shift the beta cells from the READY mode to the ON mode. Thanks to the TRP channels, we now know that the Ca(2+)-activated monovalent cation selective channel described by Sturgess et al. in 1986 (FEBS Lett 208:397-400) is TRPM4, and that the H(2)O(2) activate non-selective cation channel described by Herson and Ashford, in 1997 (J Physiol 501:59-66) is TRPM2. Glucose metabolism generates heat which appears to be a second messenger sensed by the temperature-sensitive TRP channels like the TRPM2 channel. Global knock-out of TRPM5 channel impairs insulin secretion in mice. Other TRPs that may be involved in the regulation of beta-cell function include TRPC1, TRPC4, TRPM3, TRPV2 and TRPV4. Future research needs to be intensified to study the molecular regulation of the TRP channels of islets, and to elucidate their roles in the regulation of human beta-cell function, in the context of pathogenesis of human islet failure. PMID- 21290329 TI - Multiple roles for TRPs in the taste system: not your typical TRPs. AB - The peripheral taste system is contained within taste buds located in the oral cavity. These taste buds are comprised of a heterogeneous group of taste receptor cells that use multiple signaling pathways to transduce chemical taste stimuli into an output signal that is sent to the brain. Salty and sour taste involve the detection of charged ions that directly interact with receptors to cause cell depolarization while bitter, sweet and umami taste stimuli activate G-protein coupled receptors and their second messenger pathways. The roles of TRP channels in these different signaling pathways are not well characterized and to date, only three TRP channels have been identified in taste receptor cells. This book chapter discusses the current understanding of how the three known TRP channels function in peripheral taste cell signaling: TRPM5, TRPV1, and the heterodimer PKD1L3/PKD2L1. PMID- 21290330 TI - Roles of transient receptor potential proteins (TRPs) in epidermal keratinocytes. AB - Epidermal keratinocytes are the epithelial cells of mammalian skin. At the basal layer of the epidermis, these cells proliferate strongly, and as they move towards the skin surface, differentiation proceeds. At the uppermost layer of the epidermis, keratinocytes undergo apoptosis and die, forming a thin, water impermeable layer called the stratum corneum. Peripheral blood vessels do not reach the epidermis, but peripheral nerve fibers do penetrate into it. Until recently, it was considered that the main role of epidermal keratinocytes was to construct and maintain the water-impermeable barrier function. However, since the functional existence of TRPV1, which is activated by heat and low pH, in epidermal keratinocytes was identified, our understanding of the role of keratinocytes has changed enormously. It has been found that many TRP channels are expressed in epidermal keratinocytes, and play important roles in differentiation, proliferation and barrier homeostasis. Moreover, because TRP channels expressed in keratinocytes have the ability to sense a variety of environmental factors, such as temperature, mechanical stress, osmotic stress and chemical stimuli, epidermal keratinocytes might form a key part of the sensory system of the skin. The present review deals with the potential roles of TRP channels expressed in epidermal keratinocytes and focuses on the concept of the epidermis as an active interface between the body and the environment. PMID- 21290331 TI - TRP channels in urinary bladder mechanosensation. PMID- 21290332 TI - The role of trp ion channels in testicular function. AB - Transient receptor potential (TRP) proteins are homologues of Drosophila transient receptor potential ion channels first identified in the photo receptors and reported to be involved in calcium entry following calcium store depletion during photo transduction. TRP is a large super family divided in several families including the TRPC (Canonical) family, the TRPV (Vanilloid) family, the TRPM (Melastatin) family, the TRPP (Polycystin) family, the TRPML (Mucolipin) family, the TRPA (Ankyrin) family, and the TRPN (NOMPC) family. TRP proteins are six transmembrane ion channels and act as components of multimeric complexes which allow cation entry either after internal calcium depletion or in response to receptor stimulation. TRP ion channels have been reported to act as molecular sensors of environment. Trp genes are expressed in a wide range of tissues including testis. In addition to this TRP proteins have also been detected in mature sperm from a number of species including humans. TRP may be involved in regulating calcium dependent functions of sperm including motility, capacitation, and acrosome reaction. Here we review the available information about TRP proteins reported in the sperm, as well as in other cells/tissue systems. PMID- 21290333 TI - TRP channels in female reproductive organs and placenta. AB - TRP channel proteins are widely expressed in female reproductive organs. Based on studies detecting TRP transcripts and proteins in different parts of the female reproductive organs and placenta they are supposed to be involved in the transport of the oocyte or the blastocyte through the oviduct, implantation of the blastocyte, development of the placenta and transport processes across the feto-maternal barrier. Furthermore uterus contractility and physiological processes during labour and in mammary glands seem to be dependant on TRP channel expression. PMID- 21290334 TI - Oncogenic TRP channels. AB - Ion channels and notably TRP channels play a crucial role in a variety of physiological functions and in addition these channels have been also shown associated with several diseases including cancer. The process of cancer initiation and progression involves the altered expression of one or more of TRP proteins, depending on the nature of the cancer. The most clearly described role in pathogenesis has been evidenced for TRPM8, TRPV6 and TRPM1 channels. The increased expression of some other channels, such as TRPV1, TRPC1, TRPC6, TRPM4, and TRPM5 has also been demonstrated in some cancers. Further investigations are required to precise the role of TRP channels in cancer development and/or progression and to specifically develop further knowledge of TRP proteins as discriminative markers and prospective targets for pharmaceutical intervention in treating cancer. PMID- 21290335 TI - TRPV channels in tumor growth and progression. AB - Transient receptor potential (TRP) channels affect several physiological and pathological processes. In particular, TRP channels have been recently involved in the triggering of enhanced proliferation, aberrant differentiation, and resistance to apoptotic cell death leading to the uncontrolled tumor invasion. About thirty TRPs have been identified to date, and are classified in seven different families: TRPC (Canonical), TRPV (Vanilloid), TRPM (Melastatin), TRPML (Mucolipin), TRPP (Polycystin), and TRPA (Ankyrin transmembrane protein) and TRPN (NomPC-like). Among these channel families, the TRPC, TRPM, and TRPV families have been mainly correlated with malignant growth and progression. The aim of this review is to summarize data reported so far on the expression and the functional role of TRPV channels during cancer growth and progression. TRPV channels have been found to regulate cancer cell proliferation, apoptosis, angiogenesis, migration and invasion during tumor progression, and depending on the stage of the cancer, up- and down-regulation of TRPV mRNA and protein expression have been reported. These changes may have cancer promoting effects by increasing the expression of constitutively active TRPV channels in the plasma membrane of cancer cells by enhancing Ca(2+)-dependent proliferative response; in addition, an altered expression of TRPV channels may also offer a survival advantage, such as resistance of cancer cells to apoptotic-induced cell death. However, recently, a role of TRPV gene mutations in cancer development, and a relationship between the expression of specific TRPV gene single nucleotide polymorphisms and increased cancer risk have been reported. We are only at the beginning, a more deep studies on the physiopathology role of TRPV channels are required to understand the functional activity of these channels in cancer, to assess which TRPV proteins are associated with the development and progression of cancer and to develop further knowledge of TRPV proteins as valuable diagnostic and/or prognostic markers, as well as targets for pharmaceutical intervention and targeting in cancer. PMID- 21290336 TI - The role of transient receptor potential channels in respiratory symptoms and pathophysiology. AB - The Transient Receptor Potential channels constitute a superfamily of ion channels that is unmatched in its functional diversity. Recent research employing pharmacological and genetic methods has demonstrated that these channels are widely distributed within the respiratory tract, where they may mechanistically link noxious irritant exposures and inflammation to heightened airway reflex sensitivity, pathological remodeling and airflow limitation. Herein, we summarize the state of the art in this rapidly expanding area, emphasizing the known roles of Transient Receptor Potential channels in airway sensory nerves in addition to highlighting their roles in non-excitable cells. PMID- 21290337 TI - TRP channels and psychiatric disorders. AB - Depression and schizophrenia are major psychiatric disorders that cause much human suffering. Current treatments have major limitations and new drug targets are eagerly sought. Study of transient receptor potential (TRP) channels in these disorders is at an early stage and the potential of agents that activate or inhibit these channels remains speculative. The findings that TRPC6 channels promote dendritic growth and are selectively activated by hyperforin, the key constitutent of St John's wort, suggest that TRPC6 channels might prove to be a new target for antidepressant drug development. There is now considerable evidence that TRPV1 antagonists have anxiolytic activity but there is no direct evidence that they have antidepressant activity. There is also no direct evidence that TRP channels play a role in schizophrenia. However, the findings that TRPC channels are involved in neuronal development and fundamental synaptic mechanisms, and that TRPV1 channels play a role in central dopaminergic and cannabinoid mechanisms is suggestive of potential roles of these channels in schizophrenia. Investigation of TRP channels in psychiatric disorders holds the promise of yielding further understanding of the aetiology of psychiatric disorders and the development of new drug treatments. PMID- 21290338 TI - Transient receptor potential genes and human inherited disease. AB - Transient receptor potential (TRP) genes have been implicated in a wide array of human disorders, from cancers to bipolar disorder. The extraordinary range of diseases in whose pathogenesis they may play a role exemplifies the equally broad range of functions of the TRP proteins. TRP proteins primarily form homomeric or heteromeric channels in the cell membrane but there may also be intracellular non channel functions for TRPs. Mutations in TRP genes have been causally associated with at least 12 hereditary human diseases. This chapter aims to summarise those associations and focuses on the following diseases: focal segmental glomerulosclerosis; polycystic kidney disease; brachyolmia; spondylometaphyseal dysplasia; metatropic dysplasia; hereditary motor and sensory neuropathy; spinal muscular atrophy; congenital stationary night blindness; progressive familial heart block; hypomagnesaemia; and mucolipidosis. There appears to be very little to connect these disorders except the involvement of a TRP gene but by understanding more about the genes involved in diseases, we understand more about disease biology and about the function of those genes causally associated. This feedback loop of information will serve to enhance our knowledge of disease and elucidate basic gene and protein function of the TRPs. PMID- 21290340 TI - Immunoexpression and clinical significance of the PTEN and MLH1 proteins in endometrial carcinomas. AB - Carcinogenesis is a multistep process resulting from mutations in genes controlling the cellular growth, differentiation, apoptosis, and genome integrity maintenance. We investigated relationships between the PTEN and MLH1 immunoreactivity in the cancer cells and the histological subtypes of endometrial carcinoma as well as the survival times of the affected women. The PTEN and MLH1 protein immunoexpression was also examined separately in both clinicopathological groups of endometrial carcinoma. We estimated the practical use of the proteins as diagnostic and predictive markers. The histoclinical analysis was performed on 104 patients. The follow-up in all the cases was well known. To assess the expression of both proteins in the cancer cells we adopted a semiquantitative immunohistochemical analysis. We proved that the incidence of the PTEN and MLH1 nuclear positive cells was significantly higher in the serous type than in the endometrioid one. We also demonstrated a strong correlation between both cytoplasmic and nuclear PTEN immunoexpression and the survival times in the entire cohort. In conclusion, the PTEN and MLH1 immunohistochemical analysis broadens the microscopic diagnosis of the endometrial carcinomas. However, the PTEN and MLH1 antibodies tests cannot determine the recognition of the cancer, and they should not be regarded as independent prognostic factors. PMID- 21290341 TI - Analysis of PI3K/AKT/mTOR signalling pathway in high risk neuroblastic tumours. AB - Neuroblastoma (NB) represents one of the most common paediatric tumours. Despite advance in NB research and treatment, the outcome of the patients from the high risk group remains poor. PI3K/AKT/mTOR signalling pathway which is involved in oncogenesis and cancer progression of many tumours, in parallel constitutes the target for the biologically based oncological therapy. In this study we analyzed the status of PI3K/AKT/mTOR signalling route in the primary tumour tissue samples from a group of 39 high-risk NB. The pathway activation state was assessed immunohistochemically using antibodies with specificity towards PI3Kp85, PI3Kp110, phospho-AKT, phospho-mTOR, phospho-p70S6K and phospho-4EBP1. Moreover, expression of PTEN, bcl2 and cyclin D1 was examined. We found that most of tumours were positive for PI3Kp85 and PI3Kp110, as well as for p-AKT, p-mTOR and its downstream effectors p-p70S6K and p-4EBPI. PTEN was expressed in all cases, bcl2 and cyclin D1 staining was found in more than 90% of examined NB. Statistical analysis revealed that p-AKT expression was correlated with p-mTOR and strong cyclin D1 labelling. Furthermore, high expression of p-4EBP1 was significantly associated with p-p70S6K expression, high cyclin D1 and lower differentiation of the tumour. PI3K/AKT/mTOR signalling pathway activation is a common event in high-risk NB and it seems that this group of patients may benefit from targeted therapy with kinase inhibitors. PMID- 21290342 TI - Simultaneous assessment of p53 and MDM2 expression in leukemic cells in response to initial prednisone therapy in children with acute lymphoblastic leukemia. AB - Ineffective apoptosis is one of main causes of a treatment failure in childhood acute lymphoblastic leukemia (ALL). p53 plays a crucial role in triggering apoptosis of ALL in response to prednisone treatment. MDM2 is the endogenous inhibitor of apoptosis that downregulates the functional activity of p53 protein. This study is aimed to evaluate changes in MDM2 and p53 expression in peripheral blood mononuclear cells collected from children with ALL prior to and after 6 and 12 h of prednisone administration in relation to early treatment response. The study comprised 35 children with newly diagnosed ALL, subdivided into good (n = 24) and poor (n = 11) early treatment responders. MDM2 - associated APC fluorescence and p53 - associated FITC fluorescence were measured by the laser scanning cytometer. In the group of poor responders, p53 and MDM2 fluorescence were significantly higher than in the group of good responders. In the group of good early treatment responders, a statistically significant rise of p53 fluorescence measured in the nucleus and in the cytoplasm 12 h after prednisone administration as well as increase in MDM2 fluorescence measured in the cytoplasm 6 and 12 h after prednisone administration were seen. These data suggest that pretreatment overexpression of MDM2 protein may contribute to poor early treatment response. PMID- 21290343 TI - Genetics polymorphism in DNA repair genes by base excision repair pathway (XRCC1) and homologous recombination (XRCC2 and RAD51) and the risk of breast carcinoma in the Polish population. AB - Background : Several polymorphisms in the DNA repair gene have been extensively studied in the association with various human cancers such as breast cancer. Material and methods : We investigated the association of polymorphisms in the DNA repair genes XRCC1-Arg399Gln, XRCC2-Arg188His and RAD51-135G/C with the breast cancer risk. Genotypes were determined by PCR-RFLP assays in 220 patients with breast cancer and 220 age-matched healthy controls. Results : Our results demonstrated a significant positive association between the XRCC1 399Gln/Gln homozygous genotype and breast carcinoma, with an adjusted odds ratio (OR) of 2.08 [1.08-3.98]. The 399Gln allele variant was also associated with type I breast cancer (OR = 1.41 [0.98-2.01], p = 0.034). The distributions of genotypes and alleles of the genes XRCC2 and RAD51 polymorphism were not significantly associated with the different stages of breast carcinoma (p > 0.05). Conclusion : These results suggest that 399Gln allele of XRCC1 Arg399Gln may be a risk factor for breast cancer in the Polish population. PMID- 21290344 TI - Increased interleukin 6 and tumour necrosis factor alpha expression in the infrapatellar fat pad of the knee joint with the anterior knee pain syndrome: a preliminary report. AB - The pathway of pain in the anterior knee pain syndrome remains unclear. It has been hypothesized that some biochemical mediators of inflammation, such as cytokines contribute to the process. The objective of this work was to evaluate the synovial membrane and the infrapatellar fat pad expression of the inflammatory mediators and potentially chondrodestructive cytokines interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-alpha) in the anterior knee pain syndrome, and to determine whether the cytokine expression counterpart with/corresponds to the amount of chondral damage in this syndrome. Ten consecutive patients with the anterior knee pain syndrome (group I) participated in the study. Patients with a history of trauma were excluded from this group. For comparison we used 10 patients with anterior cruciate ligament rupture or meniscal lesion with no history of pain in the anterior compartment (group II). Immunohistochemical techniques using a polyclonal rabbit anti-human antibody to IL-6 and a monoclonal mouse anti-human antibody to TNF-alpha were employed. The results show a statistically significant higher expression of IL-6 in infrapatellar fat pad (p < 0.05) as well as TNF-alpha in the infrapatellar fad pad and the synovium (p < 0.03, and p < 0.02, respectively) in group I as compared to control subjects. There is no any difference in the amount of chondral damage present in group I as compared to group II. The results of this study provide the immunohistochemical evidence suggesting that the anterior knee pain syndrome could be characterized by infrapatellar fat pad and synovial inflammation variations without the articular cartilage loss. PMID- 21290345 TI - Immunoexpression of CAS protein is augmented in high grade serous ovarian tumors. AB - Ovarian cancer is one of the most important causes of death from gynecological malignancies in Poland. Recent investigations took a note of possible relationship between tumor histological grading and immunoexpression of apoptosis and proliferation related proteins in serous ovarian cancers. The aim of the study was to assess the immunoexpression of CAS protein in serous ovarian tumors of different histological grade, as well as to find possible relationships between this immunoexpression and tumor proliferation activity expressed by immuneexpression of Ki-67 protein. The analysis comprised of 66 women diagnosed and treated for malignant epithelial ovarian tumors. The immunoexpression of CAS protein was assessed semiquantitatively whereas immunoexpression of Ki-67 was performed using computer image analysis system. On immunohistochemical examinations it was found a significantly higher immunoexpression of both examined proteins in invasive serous ovarian cancers than in cystadenomas. Also, the significant positive correlation has been shown between immunoexpression of Ki-67 and CAS protein in particular group of tumors. In conclusion, our data suggest that increased immunoexpression of CAS protein in serous ovarian tumors may be useful in identifying the patients with more aggressive disease. PMID- 21290346 TI - Investigations into human tracheal cartilage osseocalcineus metaplasia IV. Morphokinesis of tracheal cartilage retrograde lesions during the process of aging. AB - We determined the frequency of occurrence and dynamism of the mentioned retrograde lesions. The investigated material comprised 371 cartilages collected from 95 male tracheas (mean age: 56 +/- 13 years), and 279 cartilages collected from 70 female tracheas (mean age: 65.3 +/- 14 years) during the process of aging. The dynamism proved non-homogenous with a visible gender difference. The empirical regression curves often crossed each other. Some of the presented curves in female patients were observed beginning two decades after that of male patients, and at lower levels. Thus, it seems hard to conclude that some processes considering tracheal cartilage morphokinesis always precede others. PMID- 21290347 TI - Patient with rheumatoid arthritis and acute renal failure: a case report and review of literature. AB - Rheumatoid arthritis (RA) is an autoimmune disease also known as an example of connective tissue disease. There are no case-controlled studies to determine the frequency of renal disease in RA. Most of patients present slow progression of chronic kidney disease while acute renal failure is uncommon in rheumatoid arthritis. We report a case of a 40-year-old woman with established medical history of RA who presented with abrupt onset of severe hypertension with rapidly growing serum creatinine concentration and oliguria. Renal biopsy revealed oedematous intimal thickening of vessels and ischemic changes in glomeruli, and nonspecific lesions in tubules and interstitium. These pathological findings were consistent with the scleroderma nephropathy. Additionally, we provided a brief literature overview on coincidence of hypertension and different types of connective tissue diseases. PMID- 21290348 TI - Histoclinical study of nephroblastoma in relation to current and previous SIOP Classification of Renal Tumors of Childhood. AB - Histological classifications are essential for prognosis in children malignancies. Currently, the histological type of tumor is one of the main prognostic factors in this group. We investigated histoclinical features of nephroblastoma in relation to SIOP 93-01 and SIOP 2001 Classifications of Renal Tumors of Childhood. We examined all the routinely available histological features and histological nephroblastoma types and investigated their influence on patients' survival with the use of log-rank test and Kaplan-Meier method. The results of statistical analysis indicated that SIOP 93-01 more precisely separated nephroblastoma types according to their biology and malignant potential. We also observed that epithelial type of nephroblastoma showed a mixture of results typical for both intermediate and high risk tumors. What is more, we noticed statistically important correlations between developmental defects found in patients with nephroblastoma and tumor volume and the course of disease. PMID- 21290349 TI - Subcutaneous fat necrosis of the newborn - a case report and review of literature. PMID- 21290350 TI - what is your diagnosis? PMID- 21290351 TI - [The IC3D classification of the corneal dystrophies]. AB - BACKGROUND: The recent availability of genetic analyses has demonstrated the shortcomings of the current phenotypic method of corneal dystrophy classification. Abnormalities in different genes can cause a single phenotype, whereas different defects in a single gene can cause different phenotypes. Some disorders termed corneal dystrophies do not appear to have a genetic basis. PURPOSE: The purpose of this study was to develop a new classification system for corneal dystrophies, integrating up-to-date information on phenotypic description, pathologic examination, and genetic analysis. METHODS: The International Committee for Classification of Corneal Dystrophies (IC3D) was created to devise a current and accurate nomenclature. RESULTS: This anatomic classification continues to organize dystrophies according to the level chiefly affected. Each dystrophy has a template summarizing genetic, clinical, and pathologic information. A category number from 1 through 4 is assigned, reflecting the level of evidence supporting the existence of a given dystrophy. The most defined dystrophies belong to category 1 (a well-defined corneal dystrophy in which a gene has been mapped and identified and specific mutations are known) and the least defined belong to category 4 (a suspected dystrophy where the clinical and genetic evidence is not yet convincing). The nomenclature may be updated over time as new information regarding the dystrophies becomes available. CONCLUSIONS: The IC3D Classification of Corneal Dystrophies is a new classification system that incorporates many aspects of the traditional definitions of corneal dystrophies with new genetic, clinical, and pathologic information. Standardized templates provide key information that includes a level of evidence for there being a corneal dystrophy. The system is user-friendly and upgradeable and can be retrieved on the website www.corneasociety.org/ic3d . PMID- 21290352 TI - [Integration of self-help associations into the health services system- developments and perspectives]. AB - The concept of a special label for "self-help-friendly" institutions was first developed for hospitals. A demonstration project (funded by the BKK BV, the German Federal Association of Company Health Insurance Funds) was launched in Hamburg. Between 2004 and 2007 quality criteria were developed and put into practice. Shortly thereafter, a group of experienced self-help supporters started to integrate self-help friendliness into quality management systems for ambulatory care. Recently similar developments have been initiated in the Public Health Services. After an introduction on the origins and political context of these new developments we present in this article the efforts and experiences in the 3 mentioned areas of the health-care system. It can be shown that user-based quality standards are becoming more and more common in quality development processes of the health-care services. In the last part we introduce the national "Network Self-Help-Friendliness in the Health Services--Together for Self-Help and Patient Orientation" as the new structure for further implementation, and give hints that the organised self-help is facing completely new challenges. PMID- 21290353 TI - [Changes in mental health care by a regional budget--results of a pilot project in schleswig-holstein (Germany)]. AB - OBJECTIVES: In a region of Schleswig-Holstein, a regional budget was used to investigate which structural changes could be brought about by a financial plan which enables (clinical) treatment that defies rigid financial limits and makes flexible treatment in various settings possible. METHODS: Since 2003 in a region in Schleswig-Holstein (Steinburg) a financing system has been tested in cooperation with all health insurances. It is no longer based on days of treatment or individual treated cases, instead a budget has been made available for the setting of interdisciplinary psychiatric and pyschotherapeutic management. RESULTS: In 5 years, the number of inpatient treatment places in the care region was reduced considerably. The length of stay per patient and year decreased by 25%. Day care and outpatient treatment offers were expanded substantially and new treatment concepts were established. The quality of treatment remained safeguarded. CONCLUSIONS: A regional budget is suitable for bringing about fundamental changes in terms of content and structure in psychiatric care. The result is clearly improved flexibility as compared to previous care structures; incentives for disorders are reduced. The principle "outpatient before inpatient" is strengthened. The financial plan can be transposed onto other regions, whereby modifications according to the structure of the care region may be necessary. PMID- 21290354 TI - Teaching reflection: Speech & language therapy students using visual clues for reflection. AB - INTRODUCTION: Reflection is an essential tool for the development of professional behaviour. Central to all reflection methods is language, either written or spoken. As the use of language is not easy for all students, especially those learning in a language other than their native tongue, it is essential that teachers use alternative methods to stimulate reflection. AIM: To identify the benefits that speech and language therapy students perceive in an educational approach that combines pictures and drawings as a stimulus for reflecting on professional experiences. METHOD: During an international course twenty-two students of various nationalities participated in a two-hour session and reflected on professional experiences. To stimulate reflection, drawings and pictures were used. All the students were asked to evaluate this educational approach by responding to five open-ended questions. Their responses were coded and analyzed. RESULTS: Students' comments fell into three categories of perceived benefits: (1) educational approach benefits; (2) personal benefits; and (3) professional benefits. Almost all the students reported that the nature of the reflection exercises helped them verbalize their experiences after the profession related exercises. CONCLUSION: This study provides evidence that visualizing as a first step towards verbalizing experiences can foster learning through reflection. It provides students with greater opportunities to verbalize awareness, especially within a group of students who may have difficulty expressing themselves in a non-native language. PMID- 21290355 TI - Transfer of medical students' clinical skills learned in a clinical laboratory to the care of real patients in the clinical setting: the challenges and suggestions of students in a developing country. AB - CONTEXT: Recent studies indicate that medical students may face problems applying clinical skills taught in a skills laboratory setting when they enter their clerkships. This study explores these problems in the context of a developing country, and explores students' suggestions for improving clinical skills training. METHODS: Focus groups discussions (FGDs) were organized with students who had just entered their clerkships. Transcripts of FGDs were digested according to the inductive content analysis protocol. RESULTS: Clerkship students said to have encountered significant problems when they had to perform clinical skills on patients for the first time, in particular with respect to invasive clinical procedures. Differences in context between skills laboratory and clinic, inadequate supervision and unpredictable responses by patients were most common reasons given. Students suggested creating opportunities to practice clinical skills on patients before entering the clerkships. CONCLUSION: Early in their clerkships students may face significant problems when they have to apply skills learned in the skills laboratory on actual patients. Particularly in developing countries, opportunities may exist to follow up on our students' suggestion to arrange for skills training of pre-clinical students in clinical settings. PMID- 21290356 TI - Factors associated with attrition and success in a worksite wellness telephonic health coaching program. AB - OBJECTIVES: This study identifies factors associated with attrition and improvements in body mass index (BMI) in a telephonic health coaching program. METHODS: A cohort study design was used with 6,129 employees aged 21-88 years, enrolled in telephonic health coaching sometime during 2002 through 2008. RESULTS: Attrition through 3, 6 and 12 months of follow-up was 13%, 17% and 36%, respectively. Those currently making changes in physical activity or nutrition had the highest BMI (kg/m2), lowest levels of exercise and the poorest overall health at baseline. They were also most likely to continue with health coaching through 12 months. Those not ready to make changes at this time or having maintained an appropriate level of physical activity or nutrition for more than six months were least likely to continue with health coaching through 12 months. They also had the lowest BMI, highest levels of exercise and the best overall health. Among those continuing with health coaching through 12 months, the percent decrease in BMI between baseline and 12 months was: 1.5% for normal weight, 2.7% for overweight, 4.1% for class I & II obesity and 7.2% for class III obesity; 4.3% for high confidence to lose weight, 3.5% for medium confidence to lose weight and 3.1% for low confidence to lose weight; and 3.8% for very good or good general health, 4.5% for average general health and 6.8% for poor/very poor general health. CONCLUSIONS: Attrition in the telephonic health coaching program is greatest among those least in need of behavior change. Of those who continued in the program, the greatest decrease in BMI occurred in those in greatest need for behavior change. KEYWORDS: Behavior change, BMI, interactive health coaching, readiness to change, self-efficacy, weight. PMID- 21290357 TI - Innovative method of needs assessment for faculty development programs in a Gulf medical school. AB - BACKGROUND: Faculty development lays the foundation for the quality enhancement in medical education. However, programs are not always based on the needs of the participants, and there is dearth of information on methods to derive faculty's needs. The Medical Education Unit at the University of Dammam, Saudi Arabia, carried out an innovative method to identify and prioritize faculty needs in order to plan future activities. METHODS: A questionnaire was designed, pilot tested and administered to all faculty members (N=200). The respondents rated the perceived importance (high, moderate, low) and their performance (good, average, poor) on twelve competencies described in the literature. The ratings of perceived importance - high/moderate, and self-rated performance- average/poor, were summed up to determine priority rankings for continuing education. The respondents' rating of various continuing education activities, their willingness to participate and commit time, and their suggestions for strengthening faculty development were also analyzed. RESULTS: All the twelve competencies were perceived as 'highly important' by the subjects. They felt most confident in teaching in large and small groups, attitudes and ethical values, and decision making skills. The competencies prioritized as "gaps" were knowing how to develop learning resources, plan curriculum, evaluate courses and conduct research. The prioritized activities were specialized courses, orientation workshops for the new faculty, and training in educational research skills. This implied a multi phased approach to faculty development. A majority (62.4%) were willing to devote 2.2 hours per week to faculty development. Respondents suggested initiatives that should be undertaken by the Medical Education Unit and the broader institution. CONCLUSION: We demonstrated a participatory approach to needs assessment by identifying the gaps between "perceived importance" and "self-rated performance", as criteria for determining priorities. Findings also demonstrated the need for adopting a comprehensive approach to faculty development in which both departmental and organizational initiatives are required. Our findings are applicable to the Gulf Region context and our methodology can be applied anywhere. PMID- 21290358 TI - A systematic review of collaborative models for health and education professionals working in school settings and implications for training. AB - CONTEXT: Collaborative engagement between education and health agencies has become requisite since the establishment of school inclusion policies in many developed countries. For the child with healthcare needs in an educational setting, such collaboration is assumed to be necessary to ensure a coordinated and holistic approach. However, it is less clear how this is best achieved. OBJECTIVES: This secondary research aimed to answer the questions: what are the reported models of best practice to support the collaboration between education and health staff and what are the implications for training strategies at an undergraduate and postgraduate level to affect these models? METHODS: Systematic review of current literature, with narrative summary. FINDINGS: Models of interaction and teamwork are well-described, but not necessarily well-evaluated, in the intersection between schools and health agencies. They include a spectrum from consultative to collaborative and interactive teaming. It is suggested that professionals may not be adequately skilled in, or knowledgeable about, teamwork processes or the unique roles each group can play in collaborations around the health needs of school children. DISCUSSION AND CONCLUSION: There is a need for robust primary research into the questions identified in this paper, as well as a need for educators and health professionals to receive training in interprofessional teamwork and collaboration beyond their traditional domains. It is suggested such training needs to occur at both the undergraduate and postgraduate levels. PMID- 21290359 TI - Evaluation of the content validity, internal consistency and stability of an instrument designed to assess the HIV/AIDS knowledge of university students. AB - OBJECTIVE: This study evaluated the content validity, internal consistency and stability of a questionnaire designed to assess the HIV/AIDS knowledge of young adults. METHODS: The questionnaire was administered on two occasions, within two week intervals, to 219 university students in the USA (n=66), Turkey (n=53) and South Africa (n=100). The psychometric instrument contained demographic information questions and 45 knowledge questions regarding the HIV virus, ways of transmitting it, symptoms of HIV/AIDS infection and methods of prevention. Factor analysis was conducted to assess construct validity; Cronbach alphas and Pearson's product moment correlation (r) were calculated to evaluate internal consistency and stability, respectively. RESULTS: The 45 knowledge questions produced a Kaiser-Meyer-Olkin (measure of sampling adequacy) value of 0.8133 and loaded on three factors with an overall Cronbach's alpha of 0.861. The r for the individual knowledge question was greater than 0.50 and the overall knowledge score was "almost perfect" (0.91; p<.001). For participating students from the USA, Turkey and South Africa, their r for the overall knowledge score was 0.80 (p<.001), 0.83 (p<.001) and 0.93 (p<.001), respectively. CONCLUSIONS: Our findings revealed that the instrument is highly stable and internally consistent. The availability of this instrument may enhance HIV intervention studies internationally. PMID- 21290360 TI - Simulation for teaching normal delivery and shoulder dystocia to midwives in training. AB - INTRODUCTION AND OBJECTIVE: The cognitive impact of using simulation sessions in midwifery training has not been the subject of previous research. The aim of this study was to compare the effect on students' knowledge of a simulation session versus an image-based lecture, for teaching routine management of normal delivery and resolution of shoulder dystocia to midwives in training. METHODS: Sixty students were enrolled three weeks after a "labour and delivery" class, and randomly assigned to two groups. Ten were subsequently excluded as they were not able to attend the whole session and/or did not complete the tests. In the simulation group (n=26), students were divided into pairs and attended a 30 minute hands-on session in the simulation centre. In the lecture group (n=24), students participated in a 30-minute image-based interactive lecture. A ten question multiple-choice test was taken before (pre-test) and after (post-test) both sessions, to evaluate students' knowledge of labour and delivery and shoulder dystocia. Learner satisfaction was evaluated by adding a six question Likert scale questionnaire to the post-test. Independent t-test, paired samples t test, and Mann-Whitney test were used for statistical analysis, setting significance at p<0.05. RESULTS: The simulation group showed a significantly higher mean post-test score (6.38 vs. 5.16; p=0.003) and a significantly greater inter-test score progression (p<0.0001). Overall learner satisfaction was also higher in this group (p=0.0001). CONCLUSIONS: A significantly higher short-term reinforcement of knowledge and greater learner satisfaction was obtained using simulation sessions compared to image-based lectures when teaching routine management of normal delivery and resolution of shoulder dystocia to midwives in training. PMID- 21290361 TI - Listening styles of undergraduate health students. AB - BACKGROUND: Concerns about poor communication in the medical and other healthcare professions are common in the empirical literature, with studies showing direct relationships between practitioners' effective listening and patients' satisfaction and less risk of litigation. Furthermore, people do not simply listen or not listen, rather they adopt particular listening styles, making the understanding and investigation of practitioner communication a complex topic. The objective of this study was to identify the listening styles of undergraduate health science students enrolled at one Australian university. METHODS: A cross sectional study using a paper-based version of the Listening Styles Profile (LSP 16) was administered to a cohort of students enrolled in undergraduate education programs in eight different health disciplines: emergency health (paramedics), nursing, midwifery, occupational therapy, physiotherapy, nursing/emergency health dual degree, health science and nutrition and dietetics. The LSP-16 is a validated and reliable scale that assesses participants' preferences for each of four distinct listening style constructs. There were 1459 health students eligible for inclusion in the study. Ethics approval was granted. RESULTS: A total of 860 students participated in the study (response rate of 58%), of whom 87.2% (n=750) were female. Across the group, a strong preference was shown for the People Listening Style (LS), which is a listening style characterised by a concern for people's feelings and emotions. Otherwise, an unexpected amount of homogeneity in preferred listening style was found within the group of health science students. Female students reported a slightly stronger preference for the People LS, whereas males reported slightly stronger preferences for the Action LS and Content LS. There were no statistical differences in preference for LS by students' age or year level of undergraduate enrolment. CONCLUSION: The health professional student participants of this study reported a preference for a range of listening styles, which is appropriate for many healthcare settings. However, a strong preference for the People LS and a moderate preference for the Content LS were evident. This study should be replicated with practicing professionals to establish if the demands of the workplace affect practitioners' listening style(s). PMID- 21290362 TI - On-line capacity-building program on "analysis of data" for medical educators in the South Asia region: a qualitative exploration of our experience. AB - BACKGROUND AND OBJECTIVE: In medical education, using the World Wide Web is a new approach for building the capacity of faculty. However, there is little information available on medical education researchers' needs and their collective learning outcomes in such on-line environments. Hence, the present study attempted: 1)to identify needs for capacity-building of fellows in a faculty development program on the topic of data analysis; and 2) to describe, analyze and understand the collective learning outcomes of the fellows during this need-based on-line session. MATERIALS AND METHODS: The present research is based on quantitative (on-line survey for needs assessment) and qualitative (contents of e-mails exchanged in listserv discussion) data which were generated during the October 2009 Mentoring and Learning (M-L) Web discussion on the topic of data analysis. The data sources were shared e-mail responses during the process of planning and executing the M-L Web discussion. Content analysis was undertaken and the categories of discussion were presented as a simple non hierarchical typology which represents the collective learning of the project fellows. RESULTS: We identified the types of learning needs on the topic 'Analysis of Data' to be addressed for faculty development in the field of education research. This need-based M-L Web discussion could then facilitate collective learning on such topics as 'basic concepts in statistics', tests of significance, Likert scale analysis, bivariate correlation, and simple regression analysis and content analysis of qualitative data. CONCLUSIONS: Steps like identifying the learning needs for an on-line M-L Web discussion, addressing the immediate needs of learners and creating a flexible reflective learning environment on the M-L Web facilitated the collective learning of the fellows on the topic of data analysis. Our outcomes can be useful in the design of on-line pedagogical strategies for supporting research in medical education. PMID- 21290363 TI - Training workshops in problem-based learning: changing faculty attitudes and perceptions in a Pakistani medical college. AB - BACKGROUND: Problem-based learning (PBL) has over the years become a learning strategy established for teaching students in medicine. In order to use PBL as a teaching tool, faculty must be familiar with PBL and comfortable with the role transition from 'teacher' to 'facilitator'. This transition is critical for the success of PBL. This article describes the faculty development process undertaken in Pakistan at the onset of introduction of PBL in the curriculum. METHODS: At the Foundation University Medical College (FUMC), we initiated a faculty development program in PBL. The program consisted of two-day, hands-on facilitator training workshops conducted five times over the year and led by in house faculty. A total of 180 faculty members completed these workshops. The workshops consisted of interactive sessions on the philosophy of PBL, small group dynamics, the role of the facilitator, an introduction to case design, wrap-up PBL sessions and assessment in PBL. Participants were provided with pre-workshop reading material in the form of 'PBL Handbooks', which contained details of the PBL process and specific responsibilities of the facilitator. Participants were also given a chance to experience the role of the facilitator by facilitating the faculty-learner group through a PBL session and receiving feedback. A retrospective pre-post survey was conducted to gauge changes in participants' perceptions of PBL. RESULTS: The faculty reported a significant increase in their regard for PBL as an instructional paradigm (p=<0.001). They also generally became more interested in empowering students with self-directed learning using PBL as a teaching tool and showed a greater desire to be facilitators (p=<0.001). CONCLUSION: This evaluation reveals that facilitator training workshops can help not just to improve the facilitation skills of participants but also to stimulate interest amongst faculty to use PBL in the curriculum. Such workshops can be run in Pakistan at minimal cost: the only cost we incurred was for photocopying the reading material. How much difficulty the faculty will actually have serving as facilitator in the PBL process will only become evident when they lead PBL groups over the coming year. PMID- 21290364 TI - The Thai-Australian Health Alliance: developing health management capacity and sustainability for primary health care services. AB - CONTEXT: There have been recent calls for a renewed worldwide focus on primary health care. The Thai-Australian Health Alliance addresses this call by developing health care management capability in primary health care professionals in rural Thailand. OBJECTIVES: This paper describes the history and current activities of the Thai-Australian Health Alliance and its approaches to developing health care management capacity for primary care services through international collaborations in research, education and training over a sustained time period. METHODS: The Alliance's approach is described herein as a distributed network of practices with access to shared knowledge through collaboration. Its research and education approaches involve action research, multi-methods projects, and evaluative studies in the context of workshops and field studies. WHO principles underpin this approach, with countries sharing practical experiences and outcomes, encouraging leadership and management resource networks, creating clearing houses/knowledge centres, and harmonising and aligning partners with their country's health systems. FINDINGS: Various evaluations of the Alliance's activities have demonstrated that a capacity building approach that aligns researchers, educators and health practitioners in comparative and reflective activities can be effective in transferring knowledge and skills among a collaboration's partners. Project participants, including primary health care practitioners, health policy makers and academics embraced the need to acquire management skills to sustain primary care units. Participants believe that the approaches described herein were crucial to developing the management skills needed of health care professionals for rural and remote primary health care. The implementation of this initiative was challenged by pre existing low opinions of the importance of the management role in health care, but with time the Alliance's activities highlighted for all the importance of health care management. Acceptance of its activities and goals are evidenced by the establishment of a Centre of Leadership Expertise in Health Management and the endorsement of the Phitsanulok Declaration by more than 470 primary health care practitioners, academics and policy makers. DISCUSSION AND CONCLUSION: Problems with the primary health care delivery system in rural Thailand continue, but the Alliance has successfully implemented a cross cultural strategic collaboration through a continuity of activities to augment practice management capacities in primary care practices. PMID- 21290365 TI - Longitudinal development of medical students' communication skills in interpreted encounters. AB - OBJECTIVE: Describe longitudinal skill development of medical students for the interpreted encounter. METHOD: Two successive classes of students (n=92 and 100) participated in standardized clinical stations testing general communication skills and skills for working with interpreters at the end of their second year and after completing clinical clerkships during their third year. Performance was rated by standardized patients, interpreters and students using validated scales. ANALYSIS: Analysis of individual matched paired data was performed for each scale item using the Wilcoxon signed-rank test. Pairwise correlation was used to compare global scores of the standardized patient and standardized interpreter with student self-ratings. RESULTS: Over one year students' (n=124-168) performance worsened in behaviors for 'managing the encounter' (per interpreters' ratings) or remained unchanged (per patients' ratings). By patients' ratings, performance scores in general communication remained high. Students rated themselves as significantly improved in five of eight skills for working with interpreters despite a lack of external evidence of improvement from patient or interpreter. Students showed a trend toward underestimating their own global skills at baseline and overestimating them in comparison with the interpreters' global ratings. DISCUSSION: Students' general communication skills remained excellent over one year of training but some skills for working with interpreters worsened. Over time students showed a pattern of overrating their own skills compared with trained observers. Faculty who teach students should focus on specific behaviors that are most likely to decay without reinforcement and practice. PMID- 21290366 TI - The use of cynical humor by medical staff: implications for professionalism and the development of humanistic qualities in medicine. AB - Humor and laughter in medicine has received much attention in the medical literature. The use of humor by medical students, residents and medical personnel is not uncommon. Laughter can be therapeutic, for patients and practitioners alike. However, when inappropriately directed towards patients humor can be seen as unprofessional, disrespectful and dehumanizing. How physicians interpret their day-to-day professional experiences, and when and how they use humor is influenced by the perspective that is taken, the social distance from the event, culture and context. Some argue that social and physical distance makes it more acceptable to laugh and joke about patients, but not everyone agrees. To laugh with and not at others is the appropriate use of humor in medicine. To cry against the suffering of others and the injustice behind that suffering and not with them in their agony and frustration is the appropriate response to tragedy. PMID- 21290367 TI - [Latent tuberculosis]. PMID- 21290369 TI - [Intima lesion of the brachial artery after traumatic dislocation of the elbow]. PMID- 21290370 TI - ["Ovomaltine protects the heart, a valuable aid to drug therapy"]. PMID- 21290371 TI - [Vacuum-therapy of chronic wounds in long-term care institutions]. AB - Negative pressure wound therapy is still mainly used in hospitals. By the introduction of the diagnosis related groups the average length of stay in hospitals is expected to be reduced even more. Therefore, the question arises whether the Negative pressure wound therapy in nursing homes should be applied, too, because they often provide the continuity of care in elderly patients after treatment in a hospital. Based on the literature, the authors formulate recommendations for the use of Negative pressure wound therapy in nursing homes. PMID- 21290372 TI - [Needlestick-injuries among health care professionals: guidelines and reality]. AB - Health care workers are at increased risk of exposure to contaminated infectious body fluids. Guidelines exist regarding prevention of exposure and measures to take if an exposure has occurred. The goal is to evaluate the potential risk for infections with HIV, HCV and HBV rapidly, and, if necessary, to initiate an early treatment. Morbidity and the related costs may thus be lowered. The practical application of such guidelines is not always simple and will be discussed in our article. PMID- 21290373 TI - [Personalized medicine]. AB - Molecular and cell biology have revolutionized not only diagnosis, therapy and prevention of human diseases but have also greatly contributed to the understanding of their pathogenesis. Based on modern molecular and biochemical methods it is possible to identify on the one hand point mutations and single nucleotide polymorphisms. On the other hand, using high throughput array technologies, it is possible to analyze thousands of genes simultaneously, resulting in an individual gene or gene expression profile (signature). These data increasingly allow to define the individual risk for a given disease and to predict the individual prognosis of a disease as well as the efficacy of therapeutic strategies (personalized medicine). In this review recent advances of predictive medicine and its clinical relevance will be addressed. PMID- 21290374 TI - [Septic arthritis in children]. PMID- 21290375 TI - [White small finger in a 45 year old teacher]. AB - We report the case of a 45 year old teacher with a digital ischemia of the small finger of the right hand. Non invasive diagnostics showed a hypothenar hammer syndrome caused by repetitive trauma due to mechanical working, use of a classical espresso machine and playing drums. Diagnostics, etiology and therapeutic options are discussed. PMID- 21290376 TI - [Not Available]. PMID- 21290377 TI - [Not Available]. PMID- 21290379 TI - [CME ultrasound diagnosis 38. Cavernous transformation of the portal vein in primary portal vein thrombosis]. PMID- 21290380 TI - [Physician picture puzzle. A portrait]. PMID- 21290381 TI - [Physician art column. The sensuality of the pure idea]. PMID- 21290382 TI - Performance of a cutinase membrane reactor for the production of biodiesel in organic media. AB - The enzymatic transesterification of oils with an alcohol, using recombinant cutinase of Fusarium solani pisi microencapsulated in sodium bis(2-ethylhexyl) sulfosuccinate (AOT)/isooctane reversed micelles, was performed in a membrane bioreactor (MBR). A tubular ceramic membrane with a nominal molecular weight cut off of 15,000 Da was used to retain the enzyme, and characterized in terms of rejection coefficients of the reaction components by transmission experiments. The performance of the MBR in a total recirculation-batch mode was compared with results obtained in a stirred batch tank reactor. The continuous operation of the MBR was also evaluated and the influence of the alcohol type and permeate flow rate on conversion degree and productivity (up to 500 g(product) /day/g(enzyme) was attained) were analyzed. Cutinase wild type and mutant T179C were tested for this process and the high long-term operational stability of the cutinase mutant demonstrated its potential as biocatalyst for the enzymatic continuous production of biodiesel. PMID- 21290383 TI - Integration of a microbial fuel cell with activated sludge process for energy saving wastewater treatment: taking a sequencing batch reactor as an example. AB - In the research and application of microbial fuel cell (MFC), how to incorporate MFCs into current wastewater infrastructure is an importance issue. Here, we report a novel strategy of integrating an MFC into a sequencing batch reactor (SBR) to test the energy production and the chemical oxygen demand (COD) removal. The membrane-less biocathode MFC is integrated with the SBR to recover energy from the aeration in the form of electricity and thus reduce the SBR operation costs. In a lab-scale integrated SBR-MFC system, the maximum power production of the MFC was 2.34 W/m(3) for one typical cycle and the current density reached up to 14 A/m(3) . As a result, the MFC contributed to the 18.7% COD consumption of the integrated system and also recovered energy from the aeration tank with a volume fraction of only 12% of the SBR. Our strategy provides a feasible and effective energy-saving and -recovering solution to upgrade the existing activated sludge processes. PMID- 21290384 TI - Prospective study of biliary cytology in suspected perihilar cholangiocarcinoma. AB - BACKGROUND: The diagnostic value of biliary cytology for hilar bile duct stricture is uncertain. This study prospectively examined three methods for the evaluation of biliary cytology in a consecutive group of patients. METHODS: Preoperative bile sampling by aspiration through a drainage catheter (aspiration samples), saline flush through a drainage catheter (saline samples) or direct sampling from a drainage bag (bag samples) was performed in consecutive patients with suspected perihilar cholangiocarcinoma who underwent resection after endoscopic nasobiliary drainage or percutaneous transhepatic biliary drainage. All bile sampling was performed three times on separate days. The accuracy of cytology in the diagnosis of carcinoma was determined. RESULTS: Of 100 consecutive patients with hilar strictures, 97 had histologically proven cholangiocarcinoma. The proportion of these 97 patients who had a positive finding on cytology in at least one of three sampling sessions was 55 per cent for aspiration samples, 48 per cent for bag samples and 38 per cent for saline samples (P = 0.021, aspiration versus saline). Tumour length correlated significantly with overall positivity. For aspiration samples, sensitivity was 55 per cent, specificity was 100 per cent and accuracy 56.0 per cent. CONCLUSION: For biliary cytology, sampling by catheter aspiration is more effective than catheter flushing or sampling from a drainage bag. Repeated sampling increases sensitivity. Biliary cytology has modest diagnostic yield, but is easy to perform, highly specific, and can provide a definitive diagnosis. PMID- 21290385 TI - Nanoparticle formation and growth during in vitro dissolution of ketoconazole solid dispersion. AB - The aim of this study is to examine the physical mechanisms during the dissolution of a solid dispersion, so as to provide further understanding behind the enhanced dissolution properties. X-ray amorphous solid dispersions of ketoconazole (KC), a poorly aqueous soluble drug, were prepared by melt extrusion with polyvinlypyrrolidone 17 (PVP 17) and PVP-vinyl acetate (PVP-VA64) copolymer. Prior to dissolution, Raman mapping showed a fully homogeneous spatial distribution of KC in polymer and possible drug dispersion at molecular level, whereas Fourier transform infrared spectroscopy revealed no drug-polymer chemical interaction. During in vitro dissolution test, a burst release followed by a gradual decline in dissolution could be explained by the release of KC in molecular form followed by formation of drug nanoparticles and their subsequent growth to micron size range as shown by dynamic light scattering analysis. Observations using transmission electron microscopy and cryogenic scanning electron microscopy provided support to the suggested mechanisms. The results suggested that the release of KC from the solid dispersions was carrier controlled initially, and PVP 17 PF is more efficient in inhibiting particle growth as compared with PVP-VA64. The particle growth inhibition during dissolution may be an important consideration to achieve the full benefits of dissolution enhancement of solid dispersions. PMID- 21290386 TI - Negative dielectrophoresis-based particle separation by size in a serpentine microchannel. AB - Dielectrophoresis has been widely used to focus, trap, concentrate, and sort particles in microfluidic devices. This work demonstrates a continuous separation of particles by size in a serpentine microchannel using negative dielectrophoresis. Depending on the magnitude of the turn-induced dielectrophoretic force, particles travelling electrokinetically through a serpentine channel either migrate toward the centerline or bounce between the two sidewalls. These distinctive focusing and bouncing phenomena are utilized to implement a dielectrophoretic separation of 1 and 3 MUm polystyrene particles under a DC-biased AC electric field of 880 V/cm on average. The particle separation process in the entire microchannel is simulated by a numerical model. PMID- 21290387 TI - Continuous-time random walk models of DNA electrophoresis in a post array: part II. Mobility and sources of band broadening. AB - Using the two-state, continuous-time random walk model, we develop expressions for the mobility and the plate height during DNA electrophoresis in an ordered post array that delineate the contributions due to (i) the random distance between collisions and (ii) the random duration of a collision. These contributions are expressed in terms of the means and variances of the underlying stochastic processes, which we evaluate from a large ensemble of Brownian dynamics simulations performed using different electric fields and molecular weights in a hexagonal array of 1 MUm posts with a 3 MUm center-to-center distance. If we fix the molecular weight, we find that the collision frequency governs the mobility. On the contrary, the average collision duration is the most important factor for predicting the mobility as a function of DNA size at constant Peclet number. The plate height is reasonably well described by a single post rope-over-pulley model, provided that the extension of the molecule is small. Our results only account for dispersion inside the post array and thus represent a theoretical lower bound on the plate height in an actual device. PMID- 21290388 TI - Recent developments in electrophoretic separations on microfluidic devices. AB - Research combining the areas of separation science and microfluidics has gained popularity, driven by the increasing need to create portable, fast, and low analyte-consumption devices. Much of this research has focused on the developments in electrophoretic separations, which use the electrokinetic properties of analytes to overcome many of the problems encountered during system scale-down. In addition, new physical phenomenon can be exploited on the microscale not available in standard techniques. In this study, the innovative developments, including electrophoretic concentration, sample preparation/conditioning, and separation on-chip are reviewed, along with some introductory discussions, from January 2008 to July 2010. PMID- 21290389 TI - Accuracy and sensitivity of the determination of rate constants of interconversion in achiral and chiral environments by dynamic enantioselective electrophoresis. AB - The method for determination of rate constants of interconversion of enantiomers in chiral and achiral environments of a dynamic enantioseparation system was investigated in order to reveal its accuracy, sensitivity and robustness. Two significantly different enantioseparation systems were selected, one with a single (well-defined) chiral selector (CS) and the second with a mixture of CSs, and the rate constants of interconversion for these two systems were compared statistically. While the rate constants of interconversion in the chiral environment were found to be significantly different, the rate constants in achiral environment were confirmed to be statistically the same. The accuracy of the method was independent of experimental conditions. Influence of a CS and temperature on the rate of interconversion were discussed within the scope of determined thermodynamic parameters and statistical evaluation. A certain temperature may exist at which two different types of CSs influence the rate of interconversion equally while the extent of their influence may largely differ at other temperatures. PMID- 21290390 TI - AC field induced-charge electroosmosis over leaky dielectric blocks embedded in a microchannel. AB - An effective electrical boundary condition is formulated to describe AC field driven induced-charge electrokinetic (ICEK) phenomena at the interface between a liquid and a leaky dielectric solid. Since most materials in reality possess finite dielectric and conductive properties, i.e. leaky dielectric, the present boundary condition can be used to describe the induced zeta potential on a leaky dielectric surface with consideration of both bond charges (due to polarization) and free charges (due to conduction). Two well-known limiting cases, i.e. the perfectly dielectric and the perfectly conducting wall boundary conditions can be recovered from the present formulation. Utilizing the derived boundary condition, we obtain analytical solutions in closed form for the AC field-driven induced charge electroosmosis (ICEO) over two symmetric leaky dielectric blocks embedded in the walls of an infinitely long microchannel. Two important factors for the induced zeta potential are identified to respectively account for the polarization charges and the free charges, and their effects on AC field-driven ICEO oscillating flow patterns are analyzed. It is found that the flow patterns exhibit two counter-rotating vortices, which can be deformed, relocated, eliminated and even reverse their rotating directions. It is very promising that such temporary evolution of flow patterns can possibly induce chaotic advection which can enhance microfluidic mixing. PMID- 21290391 TI - Regulation of the retention factor for weak acids in micellar electrokinetic chromatography with cationic surfactant via variation of the chloride concentration. AB - For tetradecyltrimethylammonium bromide in boric acid/borate or acetic acid/acetate buffer and NaCl or CaCl2 as the added salt, it is investigated whether the retention behaviour of weak acids in MEKC with cationic surfactant can be modelled by assuming for the deprotonated species predominantly electrostatic interaction with the micelles acting as a pseudostationary ion exchanger. The retention of (partially) charged solutes by oppositely charged micelles is analyzed by applying the classical theory of IEC (plotting lg k against lg(c(Cl-)) assuming a fixed concentration of ion-exchange sites. When plotting the absolute slopes of the regression lines against the absolute effective charge numbers of the analytes, correlation coefficients of 0.968-0.998 were obtained. It is shown that the dependence of the retention factor on the concentration of chloride (the competing ion) in the separation electrolyte and on the degree of dissociation of the analyte corresponds to what would be expected for mixed-mode retention (hydrophobic and ion-exchange interaction) on a pseudostationary ion-exchanger. PMID- 21290392 TI - Phototherapy for chronic rhinosinusitis. AB - OBJECTIVES: Near-infrared laser illumination (NILI), with or without photo activated (PA) agents, has bactericidal and wound healing promoting effects. NILI may have a potential role managing chronic rhinosinusitis (CRS). METHODS: A prospective randomized study with 23 symptomatic post-surgical CRS patients with positive cultures was conducted. Two groups (GR1 and GR2) were treated with NILI. Objective nasal endoscopic scoring (NES) was elaborated. GR1 was treated with a 940 nm laser, while GR2 was treated with a topical PA agent, indocyanine-green, followed with 810 nm laser. SNOT20 scores, NES, and cultures were obtained prior to illumination. Saccharin test was performed 1 week following treatment. RESULTS: Some cultures remained positive through treatment, with Staph. aureus predominating. Both therapy arms demonstrated clinical efficacy. The SNOT20 score change was 0.9, 0.8 for GR1 and GR2, respectively (P < 0.05). Improvement (P < 0.05) was observed based on NES. No significant difference was observed between two treatment groups. All passed the saccharin test. Therapeutic effect was sustained for a minimum of 2 months. Side effects were minimal. CONCLUSIONS: NILI was objectively and subjectively beneficial in managing CRS, safe, reproducible, sustained and appeared not to interfere with ciliary motility. CRS exacerbation was avoided without using antibiotics or steroids. PMID- 21290393 TI - Short laser pulse-induced irreversible photothermal effects in red blood cells. AB - BACKGROUND AND OBJECTIVES: Photothermal (PT) responses of individual red blood cells (RBC) to short laser pulses may depend upon PT interactions at microscale. STUDY DESIGN/MATERIALS AND METHODS: A sequence of identical short laser pulses (0.5 and 10 nanoseconds, 532 nm) was applied to individual RBCs, and their PT properties were analyzed at microscale in real time after each single pulse. RESULTS: PT interactions in RBC were found to be localized to sub-micrometer zones associated with Hb that may be responsible for overheating and evaporation at higher optical energies. At sub-ablative energies, a single short laser pulse induced irreversible changes in the optical properties of RBC that stimulated the transition from a heating-cooling response to ablative evaporation in individual erythrocytes during their exposure to subsequent, but identical pulses. CONCLUSION: The PT response of RBCs to short laser pulses of specific energy includes localized irreversible modifications of cell structure, resulting in three different effects: thermal non-ablative response, ablative evaporation, and residual thermal response. PMID- 21290394 TI - Normal ranges of fetal nasal bone length during the second trimester in an Iranian population. AB - OBJECTIVE: To provide a normal reference range for nasal bone length (NBL) during the second trimester of pregnancy in an Iranian population. METHODS: This cross sectional study was performed on 3201 fetuses at 15 to 28 weeks of gestational age (GA). Both singleton and twin fetuses were evaluated. The relationship between NBL and GA was determined and percentile values for each gestational week were provided. RESULTS: NBL measurement was obtained in 98% of singleton and 96% of twin fetuses. There was a linear relationship between GA and NBL both in singleton (R(2) = 0.62) and in twin (R(2) = 0.74) fetuses. There was no significant difference between twins regarding NBL (p = 0.18). CONCLUSION: We have provided the normal reference range for NBL during the second trimester in an Iranian population. NBL in singleton and twin fetuses is similar and there is no significant difference between twins regarding NBL. PMID- 21290395 TI - Umbilical cord insertion into the lower segment of the uterus at 11 to 13 weeks' gestation is associated with maternal serum PAPP-A. AB - OBJECTIVES: To evaluate whether the location of the placental cord insertion (CI) at 11 to 13 weeks' gestation affects the maternal serum pregnancy-associated plasma protein-A (PAPP-A). METHODS: Cohort study was conducted in patients who underwent the first trimester screening including nuchal translucency and blood test. We additionally documented the CI site. The thickness of the placenta under the CI and the minimum distance on the uterine wall between the internal cervical os and the CI (Dis) were measured. The subjects were divided into two groups. Below the tenth percentile in multiples of median (MoM) of Dis were defined as cases in which CI was located on the lower uterine segment (low CI) and the others were defined as controls. RESULTS: A total of 117 subjects were analyzed. The thickness of the placenta (r = 0.237, p = 0.010) and Dis (r = 0.243, p = 0.008) was correlated with the crown-rump length (CRL). The maternal serum PAPP-A MoM in the low CI group was lower than in controls (0.76 +/- 0.34 vs 1.16 +/- 0.55; p = 0.009), whereas the other ultrasonographic measurements and maternal demographics were not different between the two groups. CONCLUSION: CI on the lower segment of the uterus is associated with low maternal serum PAPP-A MoM levels. PMID- 21290396 TI - Signalling pathways and the host-parasite relationship: putative targets for control interventions against schistosomiasis: signalling pathways and future anti-schistosome therapies. AB - A better understanding of how schistosomes exploit host nutrients, neuro endocrine hormones and signalling pathways for growth, development and maturation may provide new insights for improved interventions in the control of schistosomiasis. This paper describes recent advances in the identification and characterisation of schistosome tyrosine kinase and signalling pathways. It discusses the potential intervention value of insulin signalling, which may play an important role in glucose uptake and carbohydrate metabolism in schistosomes, providing the nutrients essential for parasite growth, development and, notably, female fecundity. Significant progress has also been made in the characterisation of other schistosome growth factor receptors, such as transforming growth factor beta receptor and epidermal growth factor receptor, and in our understanding of their roles in the host-parasite molecular dialogue and parasite development. The use of parasite signal transduction components as novel vaccine or drug targets may prove invaluable in prevention, treatment and control strategies to combat schistosomiasis. PMID- 21290397 TI - How will fish that evolved at constant sub-zero temperatures cope with global warming? Notothenioids as a case study. AB - Current climate change has raised concerns over the fate of the stenothermal Antarctic marine fauna (animals that evolved to live in narrow ranges of cold temperatures). The present paper focuses on Notothenioidei, a taxonomic group that dominates Antarctic fish. Notothenioids evolved in the Southern Ocean over the last 20 million years, providing an example of a marine species flock with unique adaptations to the cold at morphological, physiological and biochemical levels. Their phenotypic modifications are often accompanied by 'irreversible' genomic losses or gene amplifications. On a micro-evolutionary scale, relatively 'shallow' genetic variation is observed, on account of past fluctuations in population size, and a significant genetic structure is evident, suggesting low population connectivity. These features suggest that Antarctic fish might have relatively little potential to adapt to global warming, at least at a genetic level. The extent of their phenotypic plasticity, which is evident to some degree, awaits further research. PMID- 21290398 TI - The free-radical damage theory: Accumulating evidence against a simple link of oxidative stress to ageing and lifespan. AB - Recent work on a small European cave salamander (Proteus anguinus) has revealed that it has exceptional longevity, yet it appears to have unexceptional defences against oxidative damage. This paper comes at the end of a string of other studies that are calling into question the free-radical damage theory of ageing. This theory rose to prominence in the 1990s as the dominant theory for why we age and die. Despite substantial correlative evidence to support it, studies in the last five years have raised doubts over its importance. In particular, these include studies of mice with the major antioxidant genes knocked out (both singly and in combination), which show the expected elevation in oxidative damage but no impact on lifespan. Combined, these findings raise fundamental questions over whether the free-radical damage theory remains useful for understanding the ageing process, and variation in lifespan and life histories. PMID- 21290399 TI - Of circles, forks and humanity: Topological organisation and replication of mammalian mitochondrial DNA. AB - The organisation of mammalian mitochondrial DNA (mtDNA) is more complex than usually assumed. Despite often being depicted as a simple circle, the topology of mtDNA can vary from supercoiled monomeric circles over catenanes and oligomers to complex multimeric networks. Replication of mtDNA is also not clear cut. Two different mechanisms of replication have been found in cultured cells and in most tissues: a strand-asynchronous mode involving temporary RNA coverage of one strand, and a strand-coupled mode rather resembling conventional nuclear DNA replication. In addition, a recombination-initiated replication mechanism is likely to be associated with the multimeric mtDNA networks found in human heart. Although an insight into the general principles and key factors of mtDNA organisation and maintenance has been gained over the last few years, there are many open questions regarding replication initiation, termination and physiological factors determining mtDNA organisation and replication mode. However, common themes in mtDNA maintenance across eukaryotic kingdoms can provide valuable lessons for future work. PMID- 21290400 TI - Smoothing across time in repeated cross-sectional data. AB - Repeated cross-sectional samples are common in national surveys of health like the National Health Interview Survey (NHIS). Because population health outcomes generally evolve slowly, pooling data across years can improve the precision of current-year annual estimates of disease prevalence and other health outcomes. Pooling over time is particularly valuable in health disparities research, where outcomes for small groups are often of interest and pooling data across groups would bias disparity estimates. State-space modeling and Kalman filtering are appealing choices for smoothing data across time. However, filtering can be problematic when few time points are available, as is common with annual cross sectional data. Problems arise because filtering relies on estimated variance components, which can be biased and imprecise when estimated with small samples, especially when estimated in tandem with linear trends. We conduct a simulation study showing that even when trends and variance components are estimated poorly, smoothing with these estimates can improve the mean squared error (MSE) of estimated health states for multiple racial/ethnic groups when the variance components are estimated with the pooled sample. We consider frequentist estimators with no trends, one common trend across groups, and separate trends for every group, as well as shrinkage estimators of trends through a Bayesian model. We show that the Bayesian model offers the greatest improvement in MSE, and that Bayesian Information Criterion (BIC)-based model averaging of the frequentist estimators with different trend assumptions performs nearly as well. We present empirical examples using the NHIS data. PMID- 21290401 TI - Health indicators: eliminating bias from convenience sampling estimators. AB - Public health practitioners are often called upon to make inference about a health indicator for a population at large when the sole available information are data gathered from a convenience sample, such as data gathered on visitors to a clinic. These data may be of the highest quality and quite extensive, but the biases inherent in a convenience sample preclude the legitimate use of powerful inferential tools that are usually associated with a random sample. In general, we know nothing about those who do not visit the clinic beyond the fact that they do not visit the clinic. An alternative is to take a random sample of the population. However, we show that this solution would be wasteful if it excluded the use of available information. Hence, we present a simple annealing methodology that combines a relatively small, and presumably far less expensive, random sample with the convenience sample. This allows us to not only take advantage of powerful inferential tools, but also provides more accurate information than that available from just using data from the random sample alone. PMID- 21290402 TI - Optimizing the response to surveillance alerts in automated surveillance systems. AB - Although much research effort has been directed toward refining algorithms for disease outbreak alerting, considerably less attention has been given to the response to alerts generated from statistical detection algorithms. Given the inherent inaccuracy in alerting, it is imperative to develop methods that help public health personnel identify optimal policies in response to alerts. This study evaluates the application of dynamic decision making models to the problem of responding to outbreak detection methods, using anthrax surveillance as an example. Adaptive optimization through approximate dynamic programming is used to generate a policy for decision making following outbreak detection. We investigate the degree to which the model can tolerate noise theoretically, in order to keep near optimal behavior. We also evaluate the policy from our model empirically and compare it with current approaches in routine public health practice for investigating alerts. Timeliness of outbreak confirmation and total costs associated with the decisions made are used as performance measures. Using our approach, on average, 80 per cent of outbreaks were confirmed prior to the fifth day of post-attack with considerably less cost compared to response strategies currently in use. Experimental results are also provided to illustrate the robustness of the adaptive optimization approach and to show the realization of the derived error bounds in practice. PMID- 21290403 TI - An integrated approach for fusion of environmental and human health data for disease surveillance. AB - This paper describes the problem of public health monitoring for waterborne disease outbreaks using disparate evidence from health surveillance data streams and environmental sensors. We present a combined monitoring approach along with examples from a recent project at the Johns Hopkins University Applied Physics Laboratory in collaboration with the U.S. Environmental Protection Agency. The project objective was to build a module for the Electronic Surveillance System for the Early Notification of Community-based Epidemics (ESSENCE) to include water quality data with health indicator data for the early detection of waterborne disease outbreaks. The basic question in the fused surveillance application is 'What is the likelihood of the public health threat of interest given recent information from available sources of evidence?' For a scientific perspective, we formulate this question in terms of the estimation of positive predictive value customary in classical epidemiology, and we present a solution framework using Bayesian Networks (BN). An overview of the BN approach presents advantages, disadvantages, and required adaptations needed for a fused surveillance capability that is scalable and robust relative to the practical data environment. In the BN project, we built a top-level health/water-quality fusion BN informed by separate waterborne-disease-related networks for the detection of water contamination and human health effects. Elements of the art of developing networks appropriate to this environment are discussed with examples. Results of applying these networks to a simulated contamination scenario are presented. PMID- 21290404 TI - Variable selection using the optimal ROC curve: an application to a traditional Chinese medicine study on osteoporosis disease. AB - In biomedical studies, there are multiple sources of information available of which only a small number of them are associated with the diseases. It is of importance to select and combine these factors that are associated with the disease in order to predict the disease status of a new subject. The receiving operating characteristic (ROC) technique has been widely used in disease classification, and the classification accuracy can be measured with area under the ROC curve (AUC). In this article, we combine recent variable selection methods with AUC methods to optimize diagnostic accuracy of multiple risk factors. We first describe one new and some recent AUC-based methods for effectively combining multiple risk factors for disease classification. We then apply them to analyze the data from a new clinical study, investigating whether a combination of traditional Chinese medicine symptoms and standard Western medicine risk factors can increase discriminative accuracy in diagnosing osteoporosis (OP). Based on the results, we conclude that we can make a better diagnosis of primary OP by combining traditional Chinese medicine symptoms with Western medicine risk factors. PMID- 21290405 TI - Test and power considerations for multiple endpoint analyses using sequentially rejective graphical procedures. AB - A variety of powerful test procedures are available for the analysis of clinical trials addressing multiple objectives, such as comparing several treatments with a control, assessing the benefit of a new drug for more than one endpoint, etc. However, some of these procedures have reached a level of complexity that makes it difficult to communicate the underlying test strategies to clinical teams. Graphical approaches have been proposed instead that facilitate the derivation and communication of Bonferroni-based closed test procedures. In this paper we give a coherent description of the methodology and illustrate it with a real clinical trial example. We further discuss suitable power measures for clinical trials with multiple primary and/or secondary objectives and use a generic example to illustrate our considerations. PMID- 21290406 TI - Estimation of reliability in a three-factor model. AB - Reliability measures have been well studied over many years. Such measures have been thoroughly studied for two-factor models. Motivated by a medical research problem, point and confidence interval estimates of the intraclass correlation coefficient are extended to models containing three crossed random factors subjects, raters, and occasions. The estimation is conducted using both analysis of variance and Monte Carlo Markov chain methods. PMID- 21290407 TI - gamma-Aminobutyric acid type B receptor changes in the rat striatum and substantia nigra following intrastriatal quinolinic acid lesions. AB - Changes in the regional distribution of the metabotropic GABA type B receptors (GABA(B)) were investigated in a rat model of Huntington's disease. Animals received a unilateral intrastriatal injection of quinolinic acid (QA), and GABA(B) immunoreactivity was monitored 3, 11, and 21 days postinjection in the striatum and substantia nigra (SN). Two antibodies, recognizing either the GABA(B1) or the GABA(B2) receptor subtypes, were used. QA injection rapidly induced a protracted increase in GABA(B1) or GABA(B2) immunoreactivity in the lesioned striatum, despite the neuronal loss. In the SN, a continuous increase in GABA(B1) and GABA(B2) immunoreactivity was observed at all time points in the ipsilateral pars reticulata (SNr), whereas the pars compacta (SNc) was unaffected by this phenomenon. This increase was supported by a densitometric analysis. At day 21 postlesion induction, intensely labeled stellate cells and processes were found in the ipsilateral SNr, in addition to immunoreactive neurons. Double labeling of GABA(B1) and glial fibrillary acidic protein (GFAP) showed that the stellate cells were reactive astrocytes. Hence, part of the sustained increase in GABA(B) immunoreactivity that takes place in the SNr and possibly the striatum may be ascribed to reactive astrocytes. It is suggested that GABA(B) receptors are up-regulated in these reactive astrocytes and that agonists might influence the extent of this astroglial reaction. PMID- 21290408 TI - Regulation of cytokine expression by Schwann cells in response to alpha2 macroglobulin binding to LRP1. AB - Binding of activated alpha(2)-macroglobulin (alpha(2)M) to LDL receptor-related protein-1 (LRP1) in Schwann cells activates ERK/MAP kinase and Akt and thereby promotes cell survival and migration. The goal of this study was to determine whether alpha(2)M binding to LRP1 regulates expression of cytokines and chemokines. To assess the LRP1 response selectively, we studied primary cultures of rat Schwann cells. In a screening assay that detects 84 gene products, monocyte chemoattractant protein-1 (MCP-1/CCL2) mRNA expression was increased more than 13-fold in Schwann cells treated with activated alpha(2)M. The effects of alpha(2)M on MCP-1 expression were selective, because expression of the general proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) was not induced. We confirmed that alpha(2)M selectively induces expression of MCP-1 and not TNF-alpha in single-target qPCR assays. MCP-1 protein accumulated at increased levels in conditioned medium of alpha(2)M-treated cells. LRP1 was necessary for induction of MCP-1 expression, as determined in experiments with the LRP1 antagonist receptor-associated protein, a mutated form of full-length alpha(2)M that does not bind LRP1, and in studies with Schwann cells in which LRP1 was silenced. Inhibiting ERK/MAP kinase activation blocked expression of MCP 1. These studies support a model in which LRP1 regulates multiple aspects of Schwann cell physiology in the response to PNS injury. PMID- 21290409 TI - Neurotoxic properties of the anabolic androgenic steroids nandrolone and methandrostenolone in primary neuronal cultures. AB - Anabolic-androgenic steroid (AAS) abuse is associated with multiple neurobehavioral disturbances. The sites of action and the neurobiological sequels of AAS abuse are unclear at present. We investigated whether two different AASs, nandrolone and methandrostenolone, could affect neuronal survival in culture. The endogenous androgenic steroid testosterone was used for comparison. Both testosterone and nandrolone were neurotoxic at micromolar concentrations, and their effects were prevented by blockade of androgen receptors (ARs) with flutamide. Neuronal toxicity developed only over a 48-hr exposure to the steroids. The cell-impermeable analogues testosterone-BSA and nandrolone-BSA, which preferentially target membrane-associated ARs, were also neurotoxic in a time-dependent and flutamide-sensitive manner. Testosterone-BSA and nandrolone BSA were more potent than their parent compounds, suggesting that membrane associated ARs were the relevant sites for the neurotoxic actions of the steroids. Unlike testosterone and nandrolone, toxicity by methandrostenolone and methandrostenolone-BSA was insensitive to flutamide, but it was prevented by the glucocorticoid receptor (GR) antagonist RU-486. Methandrostenolone-BSA was more potent than the parent compound, suggesting that its toxicity relied on the preferential activation of putative membrane-associated GRs. Consistently with the evidence that membrane-associated GRs can mediate rapid effects, a brief challenge with methandrostenolone-BSA was able to promote neuronal toxicity. Activation of putative membrane steroid receptors by nontoxic (nanomolar) concentrations of either nandrolone-BSA or methandrostenolone-BSA became sufficient to increase neuronal susceptibility to the apoptotic stimulus provided by beta-amyloid (the main culprit of AD). We speculate that AAS abuse might facilitate the onset or progression of neurodegenerative diseases not usually linked to drug abuse. PMID- 21290410 TI - Involvement of interleukin-1 in lipopolysaccaride-induced microglial activation and learning and memory deficits. AB - We have developed an animal model of learning and memory impairment associated with activation of microglia in the mouse brain. Injection of lipopolysaccharide into the CA1 region of the mouse hippocampus resulted in an increased production of inflammatory cytokines, such as interleukin-1beta. Immunostaining for interleukin-1beta revealed an increase in the signal at 6 hr after lipopolysaccharide injection. Immunopositive cells for interleukin-1beta were colocalized with those immunopositive for CD11b. When subacute lipopolysaccharide treatment (20 MUg/2 MUl/injection, bilaterally for 5 consecutive days) was performed, long-term activation of microglia and learning and memory deficits as evaluated using a step-through passive avoidance test were observed in the wild type mice. Gene expression of the N-methyl-D-aspartate receptor NR1 and NR2A subunits was also decreased by the lipopolysaccharide treatment. In contrast, activation of microglia and the associated behavioral deficits were not observed in mice lacking interleukin-1alpha and -1beta following the subacute lipopolysaccharide treatment, together with little change in the gene expression of NR1 and NR2A subunits. However, the subacute lipopolysaccharide treatment produced almost similar changes in those parameters in the tumor necrosis factor alpha knockout mice as in the wild-type animals. The injection of interleukin 1beta neutralizing antibody with lipopolysaccharide for 5 consecutive days resulted in the improvement of lipopolysaccharide-induced learning and memory deficits. These findings suggest that the expression of interleukin-1 plays an important role in lipopolysaccharide-induced activation of microglia and the associated functional deficits in learning and memory. PMID- 21290411 TI - Different spatial and temporal protein expressions of repulsive guidance molecule a and neogenin in the rat optic nerve after optic nerve crush with and without lens injury. AB - The failure of lesioned mammalian CNS neurons to regenerate their axons remains a challenge. Evidence is emerging that repulsive proteins contribute to this failure. The repulsive guidance molecule A (RGMA) induces growth cone collapse in vitro, accumulates in the scar after spinal cord injury, and is up-regulated in glaucoma. In this study, we evaluated the spatial and temporal localization pattern of RGMA and its receptor neogenin in the optic nerve after optic nerve crush (ONC) without or with lens injury (LI) at up to nine time points (6 hr to 20 days) postsurgery by performing immunohistochemistry and Western blots. We found RGMA at the crush site (CS) and in the developing scar of ONC rats at every time point investigated, whereas it was absent in the CS of ONC + LI rats. Independent of the model, many cells were RGMA(+) in the ON: nerve fibers, blood vessels, astrocytes, oligodendrocytes, some microglia, some macrophages, and the sheath of the ON. Western blots showed a significantly lowered amount of RGMA in ONC + LI animals at 2, 4, and 6 days after crush compared with ONC animals. Furthermore, LI in sham-operated animals showed an increase of RGMA in six of eight time points compared with the sham-operated animals. Moreover, the effects of LI on the morphology of the ON were characterized at a level of detail never reported before. Our results show that RGMA is present and might contribute to the inhibitory environment in the ON, especially in and around the CS after ONC. PMID- 21290412 TI - Calpeptin attenuated apoptosis and intracellular inflammatory changes in muscle cells. AB - In idiopathic inflammatory myopathies (IIMs), extracellular inflammatory stimulation is considered to induce secondary intracellular inflammatory changes including expression of major histocompatibility complex class-I (MHC-I) and to produce a self-sustaining loop of inflammation. We hypothesize that activation of calpain, a Ca(2+) -sensitive protease, bridges between these extracellular inflammatory stress and intracellular secondary inflammatory changes in muscle cells. In this study, we demonstrated that treatment of rat L6 myoblast cells with interferon-gamma (IFN-gamma) caused expression of MHC-I and inflammation related transcription factors (phosphorylated-extracellular signal-regulated kinase 1/2 and nuclear factor-kappaB). We also demonstrated that treatment with tumor necrosis factor-alpha (TNF-alpha) induced apoptotic changes and activation of calpain and cyclooxygenase-2. Furthermore, we found that posttreatment with calpeptin attenuated the intracellular changes induced by IFN-gamma or TNF-alpha. Our results indicate that calpain inhibition attenuates apoptosis and secondary inflammatory changes induced by extracellular inflammatory stimulation in the muscle cells. These results suggest calpain as a potential therapeutic target for treatment of IIMs. PMID- 21290413 TI - Trimethyltin initially activates the caspase 8/caspase 3 pathway for damaging the primary cultured cortical neurons derived from embryonic mice. AB - The organotin trimethyltin (TMT) is well known to cause neuronal damage in the central nervous system. To elucidate the mechanisms underlying the toxicity of TMT toward neurons, we prepared primary cultures of neurons from the neocortex of mouse embryos. A continuous exposure to TMT produced a decrease in cell viability as well as an increase in the number of cells with nuclear condensation/shrinkage at the exposure time window up to 24 hr. In addition to the events at the early time window, lactate dehydrogenase released was significantly elevated at the later exposure time from 36 to 48 hr. With a 3-hr exposure to TMT, a significant increase was observed in the activity of caspase 8, but not in that of caspase 9. TMT exposure produced no elevation in the level of cytochrome c released from mitochondria until 12 hr of exposure, with a significant facilitation of cytochrome c release at the exposure times of 16 and 24 hr. After the activation of caspase 8 by TMT exposure, caspase 3 activation and nuclear translocation of caspase-activated DNase were caused by exposure for 6 hr or longer. However, nuclear DNase II was elevated at the later time window of exposure. A caspase inhibitor completely prevented TMT from damaging the cells in any time window. Taken together, our data are the first demonstration that TMT toxicity is initially caused by activation of the caspase 8/caspase 3 pathway for nuclear translocation of DNases in cortical neurons in primary culture. PMID- 21290414 TI - Differential effects of the HESR/HEY transcription factor family on dopamine transporter reporter gene expression via variable number of tandem repeats. AB - The 3'-untranslated region (UTR) of the human dopamine transporter (DAT1) gene contains a variable number of tandem repeats (VNTR) domain, which is thought to be associated with dopamine-related psychiatric disorders, personality, and behavior. However, the molecular and neuronal functions of polymorphisms within the VNTR domain are unknown. We previously identified the transcription factor HESR1 (HEY1) as a VNTR-binding protein. Hesr1 knockout mice exhibit DAT up regulation in the brain and low levels of spontaneous activity. Other members of the HESR (HEY) family, including HESR2 (HEY2) and 3 (HEYL), have similar DNA binding domains. In this study, we analyzed the effects of HESR1, -2, and -3 on DAT1 expression in human neuroblastoma SH-SY5Y cells using luciferase reporter assays. We found that the VNTR domain played an inhibitory role in DAT1 reporter gene expression and that HESR1 and -2 inhibited expression via both the core promoter and the VNTR. The inhibitory effects of HESR family members on DAT reporter gene expression differed depending on the number of repeats in the VNTR domain. We also found that each Hesr was expressed in the dopaminergic neurons in the mouse midbrain. These results suggest that the HESR family is involved in DAT expression via the VNTR domain. PMID- 21290415 TI - The morphology of neoptile feathers: ancestral state reconstruction and its phylogenetic implications. AB - Avian neoptile feathers are defined as the first feather generation, which covers the chick after hatching, and usually described as simple structures consisting of numerous downy barbs which are radially symmetrically arranged and come together in a short calamus. In contrast, in some birds (e.g., Anas platyrhynchos, Dromaius novaehollandiae) the neoptile feathers have a prominent rhachis, and therefore display clear bilateral symmetry. Because the symmetrical variety found in neoptile feathers is poorly understood, their morphology was studied in a more comprehensive and phylogenetic approach. Neoptile body feathers from over 22 bird species were investigated using light microscopy, SEM, and MicroCT. Characters such as an anterior-posterior axis, a central rhachis, medullary cells, and structure of the calamus wall were defined and mapped onto recent phylogenetic hypotheses for extant birds. It can be shown that bilaterally symmetric neoptile feathers (with a solid calamus wall) were already present in the stem lineage of crown-group birds (Neornithes). In contrast, simple radially symmetric neoptile feathers (with a fragile calamus wall) are an apomorphic character complex for the clade Neoaves. The simple morphology of this feather type may be the result of a reduced period of development during embryogenesis. To date, embryogenesis of neoptile feathers from only a few bird species was used as a model to reconstruct feather evolution. Because this study shows that the morphology of neoptile feathers is more diverse and even shows a clear phylogenetic signal, it is necessary to expand the spectrum of "model organisms" to species with bilaterally symmetric neoptile feathers and compare differences in the frequency of feather development from a phylogenetic point of view. PMID- 21290416 TI - Chondrogenesis of the limbs and mesopodial ossification of Podocnemis expansa Schweigger, 1812 (Testudines: Podocnemidae). AB - We address the chondrogenic formation of the limbs and the mesopodial ossification pattern of the Pleurodira Podocnemis expansa, to resolve the homology of these elements as well as the pattern of connection of the autopodial elements and the origin of the digital arch. Embryos and juveniles of P. expansa were cleared and stained for cartilage and bone. The fore- and hind-limbs were also studied histologically. We describe the development of the stylopodium and zeugopodium originating from a Y-shaped cartilaginous condensation, and the differentiation of the primary axis and the digital arch in the initial stages of limb development. The most pronounced changes were observed in the chondrogenic pattern and ossification of the mesopodium, although development of the digits is similar and we found no ontogenetic reduction such as that described for other Testudines. In this study, as in previous research involving several groups of reptilian sauropsids, we found an inconsistent pattern between the chondrogenic formation and mesopodial ossification of the limbs, indicating that these developmental events are dissociated. In summary, the chondrogenic and ossification sequences of these elements do not follow the same pattern. In addition, the differences found between P. expansa and other species to which it was compared clearly indicate that these events follow more than one pattern in Testudines. PMID- 21290417 TI - Dry under water: comparative morphology and functional aspects of air-retaining insect surfaces. AB - Superhydrophobic surfaces prevent certain body parts of semiaquatic and aquatic insects from getting wet while submerged in water. The air layer on these surfaces can serve the insects as a physical gill. Using scanning electron microscopy, we investigated the morphology of air-retaining surfaces in five insect species with different levels of adaptation to aquatic habitats. We found surfaces with either large and sparse hairs (setae), small and dense hairs (microtrichia), or hierarchically structured surfaces with both types of hairs. The structural parameters and air-film persistence of these surfaces were compared. Air-film persistence varied between 2 days in the beetle Galerucella nymphaea possessing only sparse setae and more than 120 days in the bugs Notonecta glauca and Ilyocoris cimicoides possessing dense microtrichia (up to 6.6 * 10(6) microtrichia per millimeter square). From our results, we conclude that the density of the surface structures is the most important factor that affects the persistence of air films. Combinations of setae and microtrichia are not decisive for the overall persistence of the air film but might provide a thick air store for a short time and a thin but mechanically more stable air film for a long time. Thus, we assume that a dense cover of microtrichia acts as a "backup system" preventing wetting of the body surface in case the air-water interface is pressed toward the surface. Our findings might be beneficial for the development of biomimetic surfaces for long-term air retention and drag reduction under water. In addition, the biological functions of the different air retention capabilities are discussed. PMID- 21290418 TI - Scanning electron microscopy of the placental interface in the viviparous lizard Sceloporus jarrovi (Squamata: Phrynosomatidae). AB - Placental membranes mediate maternal-fetal exchange in all viviparous reptilian sauropsids. We used scanning electron microscopy to examine the placental interface in the mountain spiny lizard, Sceloporus jarrovi (Phrynosomatidae). From the late limb bud stage until birth, the conceptus is surrounded by placental membranes formed from the chorioallantois and yolk sac omphalopleure. The chorioallantois lies directly apposed to the uterine lining with no intervening shell membrane. Both fetal and maternal sides of the chorioallantoic placenta are lined by continuous layers of flattened epithelial cells that overlie dense capillary networks. The chorioallantoic placenta shows specializations that enhance respiratory exchange, as well as ultrastructural evidence of maternal secretion and fetal absorption. The yolk sac placenta contains enlarged fetal and maternal epithelia with specializations for histotrophic nutrient transfer. This placenta lacks intrinsic vascularity, although the vascular allantois lies against its inner face, contributing to an omphallantoic placenta. In a specialized region at the abembryonic pole, uterine and fetal tissues are separated by a compact mass of shed shell membrane, yolk droplets, and cellular debris. The omphalopleure in this region develops elongate folds that may contribute to sequestration and absorption of this material. Fetal membrane morphogenesis and composition in S. jarrovi are consistent with those of typical squamates. However, this species exhibits unusual placental specializations characteristic of highly placentotrophic lizards. PMID- 21290419 TI - Catch-up and targeted growth following variable duration protein restriction: effects on bone and body mass. AB - Protein malnutrition leads to growth retardation that can be reversed through catch-up growth, once normative nutrition is restored. Because growth is a dynamic process, catch-up capacity is likely influenced by the maturity of the animal and/or the duration of the insult, in addition to the type of insult experienced. We compared length of malnutrition, sexual dimorphism, body mass, and skeletal growth. Eighty Rattus norvegicus were divided into 10 treatment groups (five diets; male and female) and followed for more than 1 year. At weaning, animals were placed on either a control or low-protein isocaloric diet. Three experimental groups were switched to the control diet at 40, 60, or 90 days. Beginning with 21 days of age, animals were weighed daily and radiographed throughout the study. To determine the presence of catch-up growth, growth rates (GRs) were calculated (linear regression) for 20-day time spans before and after diet changes and compared among treatment groups. Targeted growth was measured as final size or as the coefficient of variation with age. These results show that 1) protein-restricted animals experience catch-up growth with dietary rehabilitation; 2) for females, catch-up GRs are proportional to GRs in control animals at the same age as the timing of dietary rehabilitation but not for males; and 3) targeted growth was observed in some, but not all, aspects of anatomy. The length of the tibia and humerus was indistinguishable from controls, regardless of length of malnutrition or gender, whereas the ulna and male body mass exceeded control sizes. Although most measures decreased in variation with ontogeny, the tibia failed to do so. These results support a complex biological regulation of catch-up and targeted growth. The implications for selection are that flexible and responsive developmental trajectories may have an advantage over those programed into a single size. PMID- 21290420 TI - Angioarchitecture of the bovine spermatic cord. AB - We described the topography and morphometry of the testicular artery, pampiniform plexus veins, and indirect connections between them in the spermatic cord of the bull. Sixty microcorrosive casts of bovine spermatic cords were analyzed macroscopically, by stereomicroscopy, and by scanning electron microscopy. The average size of the testicles was 94.6 * 49.7 * 54.7 mm. The testicular artery formed a superiorly pointed cone-like structure with its base fixed to the proximal part of the gonad. The artery gave off one or two branches to the head of epididymis and to the deferens duct. The pampiniform plexus originated from intra-tunical veins. Veins of the pampiniform plexus were of smaller diameter but larger number than intra-tunical ones. The density of the veins of the pampiniform plexus was 9.37 +/- 1.07 mm(-2) . The testicular vein began 90-121 mm above the superior pole of the testis. In 2.9% of specimens, the testicular vein was doubled. Numerous anastomoses among veins of pampiniform plexus were observed. Additionally, indirect anastomoses between the testicular artery and pampiniform plexus veins formed by the capillary network of the vasa vasorum of the testicular artery were visualized by scanning electron microscopy. In all cases, narrowings in the casts of the precapillary vessel were observed. We also documented the vasa vasorum of the testicular artery in bulls. The density of these vessels was 22.87 +/- 11.48 mm(-2) . The indirect arteriovenous connections together with the presence of circular constrictions of the lumen in precapillary vessels may play a role in testicular blood flow regulation. PMID- 21290421 TI - Homologies of the branchial arch muscles in Zacco platypus (Teleostei: Cypriniformes: Cyprinidae): evidence from innervation pattern. AB - Homologies of the branchial arch muscles in the cyprinid Zacco platypus are assessed based on their innervation. Muscles serving the first gill arch are innervated by branches of the glossopharyngeal (IX) nerve and those serving other arches by the vagal (X) nerve. Absence of the levator posterior is confirmed. Five pairs of muscles originating from the cranium and inserted onto the specialized 5th ceratobranchial, all unique to cyprinids, are innervated by the 4th branchial trunks of X, indicating that all pairs are derivatives of the sphincter oesophagi, involving reorganization from intrinsic to extrinsic elements. Homologies of some ventral branchial muscles are also discussed and the criteria for homology improved by clarifying the innervation pattern. PMID- 21290422 TI - Evaluation of polyhydroxybenzophenones as alpha-glucosidase inhibitors. AB - This experiment was designed to synthesize 18 kinds of polyhydroxybenzophenones by using Friedel-Crafts reaction, and to measure the inhibitory activity on alpha glucosidase with p-nitrophenyl-beta-D-galactopyranoside (PNPG) as a substrate. Here, acarbose (IC(50) = 1674.75 umol L(-1) ) was used as the reference inhibitor. The results demonstrated that most of the target compounds had remarkable inhibitory activities on alpha-glucosidase. Among all these compounds, 2,4,4',6-butahydroxydiphenylketone (11) was found to be the most potent alpha glucosidase inhibitor with an IC(50) value of 10.62 umol L(-1) . In addition, we found these compounds were competitive inhibitors through the kinetic analysis. The results suggested that such compounds might be utilized for the development of new candidates for diabetes treatment. PMID- 21290423 TI - Synthesis and anti-hepatitis B virus activity of a novel class of thiazolylbenzimidazole derivatives. AB - Recently, heterocyclic benzimidazole derivatives have been investigated and validated as a promising class of antiviral agents. In this paper, a series of novel thiazolylbenzimidazole derivatives was synthesized and evaluated for their anti-hepatitis B virus (HBV) activity and cytotoxicity on the HepG2.2.15 cell line. Afterwards, the preliminary structure-activity relationship (SAR) was discussed. Compound 8b, with IC(50) = 1.1 uM and SI > 90.9, was the most promising compound and could be selected as a benchmark compound for further investigation. PMID- 21290424 TI - Synthesis, antimicrobial and anticancer activity of new thiosemicarbazone derivatives. AB - Thiosemicarbazones of p-aminobenzoic acid (PABA) were synthesized and tested for their antimicrobial and anticancer activity. Hydroxamate derivatives 4a-4l were found to have better antimicrobial and anticancer activity than their acid counterpart. Compound 4d was found to have good antimicrobial activity against Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, Vibrio cholerae, and Bacillus subtilis with IC(50) value of about 1 uM. Compound 4f showed potent antifungal activity against Candida albicans (IC(50) = 1.29 uM) and compound 4h showed potent anticancer activity (IC(50) = 0.07 uM). PMID- 21290425 TI - Synthesis and antimicrobial activity of some new N-substituted quinoline derivatives of 1H-pyrazole. AB - A new series of 32 derivatives of 4-pyrazolyl-N-(hetero)arylquinoline 5a-p and 6a p were synthesized by a one-pot base-catalyzed cyclocondensation reaction of 1 phenyl-3-(hetero)aryl-pyrazole-4-carbaldehyde 1a-h, malononitrile 2, and 3 (hetero)aryl-5,5-disubstitutedcyclohex-2-enone 3a-b or 4a-b, respectively. All the synthesized compounds were characterized by elemental analysis, FT-IR, (1) H NMR, and (13) C-NMR spectral data. All the synthesized compounds were screened, against six bacterial pathogens, namely Bacillus subtilis, Clostridium tetani, Streptococcus pneumoniae, Salmonella typhi, Vibrio cholerae, Escherichia coli, and antifungal activity, against two fungal pathogens Aspergillus fumigatus and Candida albicans, using broth microdilution MIC method. Some of the compounds were found to be more or equipotent against most of the employed strains than commercially available drugs as evident from the screening data. PMID- 21290426 TI - In-vitro antiproliferative activity of benzopyranone derivatives in comparison with standard chemotherapeutic drugs. AB - The cytotoxic activities of five new benzopyranone derivatives containing basic amino side chain are described. Their cytotoxicities against ER(+) MCF-7 and ER( ) MDA-MB-231 human breast cancer cell lines, and Ishikawa human endometrial cell line were determined after 72 h drug exposure employing CellTiter-Glo assay at concentrations ranging from 0.01-1.0 * 10(5) nM. The antiproliferative activities of these compounds were compared to tamoxifen (TAM), 4-hydroxytamoxifen (4-OHT, active metabolite of tamoxifen), and raloxifene (RAL). In-vitro results indicated that compounds 9, 10, 12, and 13 were more potent than TAM against the human breast cancer cell lines with IC(50) < 20 uM. The in-silico structure-activity relationships of these compounds and their binding mode within the estrogen receptor (ER) binding site using AutoDock vina are discussed. PMID- 21290427 TI - Design, synthesis and evaluation of cytotoxicity of novel chromeno[4,3 b]quinoline derivatives. AB - In the present work 15 new 1,4-dihydropyridines (DHPs) bearing a coumarin ring were synthesized and assessed on 4 different human cancer cell lines (HeLa, K562, LS180, and MCF-7). Although, all the derivatives were inactive on LS180 cell line, the results on other cells showed that these compounds had weak to moderate antitumoral activities and their IC(50) ranged from 25 to >100 uM. Among the synthesized compounds, 7-(2-nitrophenyl)-8,9,10,12-tetrahydro-7H-chromeno[4,3 b]quinoline-6,8-dione (6a) demonstrated the highest activity (IC(50) range in different cell lines: 25.4-58.6 uM). Furthermore, the calcium channel antagonist activity of the derivatives, an undesired effect when these compounds are used as antitumoral agents, was much lower than nifedipine, a reference antagonist. In conclusion, this group of compounds seems to have promising biological properties and further investigation on this group could potentially lead to the discovery of cytotoxic agents with low calcium channel blocking activity. PMID- 21290428 TI - Synthesis, antihypertensive activity, and 3D-QSAR studies of some new p hydroxybenzohydrazide derivatives. AB - p-Hydroxybenzohydrazide 2 on treatment with aromatic/aliphatic aldehyde followed by cyclization with carbon disulphide afforded compounds 4a-4n. Also, compound 2 by treatment of substituted isothiocyanate followed by the treatment of chloroacetic acid yields the corresponding compounds 6a-6i. All the test compounds were assayed for antihypertensive activity by non-invasive blood pressure measurement and invasive blood pressure measurement methods. The test compounds showed significant antihypertensive activity. The intact compounds were subjected to 3D-QSAR studies. The 3D-QSAR analysis was carried out by PHASE program and a statistically reliable model with good predictive power (r(2) = 0.98, q(2) = 0.74) was achieved. The 3D-QSAR plots illustrated insights into the structure-activity relationship of these compounds which may aid in the design of potent p-hydroxybenzohydrazide derivatives as antihypertensive agents. PMID- 21290429 TI - NMR QSAR model for the analysis of 4-(5-arylamino-1,3,4-thiadiazol-2-yl)benzene 1,3-diols. AB - We have developed a NMR data quantitative structure-activity relationship NMR QSAR model based on (1)H- and (13)C-NMR experimental spectral data of 4-(5 arylamino-1,3,4-thiadiazol-2-yl)benzene-1,3-diols. Compounds show in-vitro antiproliferative activity against some human cancer cell lines. Two-parameter equations obtained by the multiple linear regression procedure showed that chemical shifts of the protons of hydroxyl groups and carbon atoms of the 1,3,4 thiadiazole ring are the decisive descriptors of inhibition interactions of the compounds. The models gave leave-one-out (LOO) cross-validation ranges from 78% to 93%. The obtained NMR-QSAR equations provide a rapid, reliable, and simple way for predicting the antiproliferative activity of N-substituted 4-(5-amino-1,3,4 thiadiazol-2-yl)benzene-1,3-diols. PMID- 21290430 TI - 4,5-Diaryl-3-aminopyrazole derivatives as analogs of Combretastatin A-4: synthesis and biological evaluation. AB - A series of cis-restricted 4,5-diaryl-3-aminopyrazole derivatives were synthesized and tested for their cytotoxic activity in vitro against five human cancer cell lines (K562, ECA-109, A549, SMMC-7721, and PC-3). Compounds 5a, 5b, 5d, and 6b showed potent cytotoxicity against all tested cell lines. Primary mechanism research on compound 5a indicated that it was a potent inhibitor of tubulin polymerization, arresting cell cycle in G(2)/M phase. The docking research showed the conformation of 5a overlaps well with CA-4 in the crystallized protein complex, suggesting the 4,5-diaryl-3-aminopyrazoles were good mimics of CA-4. PMID- 21290431 TI - Aminocarbonyl arylvinylbenzamides as gastric sparing anti-inflammatory agents. AB - Some (E/Z)-aminocarbonyl arylvinylbenzamides (B1-B15) were synthesized, evaluated for anti-inflammatory activity and ulcerogenic tendency, and their effect on gastro-intestinal motility in the rats was studied. These benzamides comprising of aliphatic unsaturated region situated between two amide linkages were synthesized by nucleophilic ring opening of appropriate azlactones (AZ1-AZ4) by suitable amines. The characterization of newly synthesized benzamides was performed by IR, (1)H- and (13)C-NMR, mass and elemental analysis. Amongst the tested compounds, benzamide B1, B2, B4, B5, and B13 were able to produce comparable or superior anti-inflammatory activity at 10 and 20 mg/kg p.o. dose with respect to standard diclofenac in carrageenan induced rat paw edema model with lessened propensity to cause gastro-intestinal hypermotility and were found to have nil tendencies to generate gastric ulcers. PMID- 21290433 TI - Society for Urodynamics and Female Urology, 2011 Winter Meeting, March 1-5, 2011, Phoenix, Arizona. Abstracts. PMID- 21290434 TI - Single molecule electronic devices. AB - Single molecule electronic devices in which individual molecules are utilized as active electronic components constitute a promising approach for the ultimate miniaturization and integration of electronic devices in nanotechnology through the bottom-up strategy. Thus, the ability to understand, control, and exploit charge transport at the level of single molecules has become a long-standing desire of scientists and engineers from different disciplines for various potential device applications. Indeed, a study on charge transport through single molecules attached to metallic electrodes is a very challenging task, but rapid advances have been made in recent years. This review article focuses on experimental aspects of electronic devices made with single molecules, with a primary focus on the characterization and manipulation of charge transport in this regime. PMID- 21290435 TI - Novel and efficient copper-catalysed synthesis of nitrogen-linked medium-ring biaryls. AB - Herein, a new copper-catalysed strategy for the synthesis of rare nitrogen-linked seven-, eight- and nine-membered biaryl ring systems is described. It is proposed that the reaction proceeds through a highly activated intramolecularly co ordinated copper catalyst. The process is technically simple, proceeds under relatively mild conditions, displays a broad substrate scope and forms biologically valuable products that are difficult to synthesise by other methods. We envisage that this methodology will prove useful in a wide synthetic context, with possible applications in both target-oriented and diversity-oriented synthesis. PMID- 21290437 TI - Haloperoxidase activity of oxovanadium(V) thiobisphenolates. AB - By employing the 2,2'-thiobis(2,4-di-tert-butylphenolate) ligand ((S)L(2-)) a novel oxovanadium(V) complex, (PPh(4))(2)[(S)LV(O)(MU(2)-O)(2)V(O)(S)L] (1), was synthesised that exhibits haloperoxidase activity: on addition of H(2)O(2) a sequence of successive peroxide formation and intramolecular thioether oxidation events (sulfoxide and sulfone) led to a mixture of five products, which were all identified unambiguously, partly through an independent synthesis and characterisation. It was shown that internal thioether oxidation proceeds through peroxide formation, but the sulfoxidation of external thioether functions requires further activation of the peroxide function by protons or alkyl cations. Consistently, the employment of tBuOOH instead of H(2)O(2) led to a very active system for the catalytic sulfoxidation of thioethers. PMID- 21290436 TI - Molybdenum-catalyzed asymmetric allylic alkylation of 3-alkyloxindoles: reaction development and applications. AB - We report a full account of our work towards the development of Mo-catalyzed asymmetric allylic alkylation reactions with 3-alkyloxindoles as nucleophiles. The reaction is complementary to the Pd-catalyzed reaction with regard to the scope of oxindole nucleophiles. A number of 3-alkyloxindoles were alkylated successfully under mild conditions to give products with excellent yields and good-to-excellent enantioselectivities. Applications of this method to the preparation of indoline alkaloids such as (-)-physostigmine, ent-(-) debromoflustramine B, and the indolinoquinoline rings of communesin B are reported. PMID- 21290438 TI - Synthesis and characterization of near-infrared absorbing benzannulated aza BODIPY dyes. AB - A series of novel aza-diisoindolmethine dyes 9 with six different aryl and heteroaryl groups at the indole moiety have been synthesized by the addition of aryl Grignard compounds to phthalodinitrile and subsequent reaction with formamide. A plausible reaction mechanism, through a Leuckart-Wallach-type reduction has been confirmed by means of DFT calculations of the related transition and intermediate states. The corresponding boron difluoride complexes (10) of 9 were prepared in a subsequent reaction step and the spectroscopic and electrochemical properties of 9 and 10 have been investigated both experimentally and theoretically. The aza-diisoindolmethines 9 exhibit an absorption maximum in the range from 615 to 720 nm, whereas the complexes 10 show a bathochromically shifted absorption maximum between 681 and 793 nm. Measurements of 9 and 10 by cyclic voltammetry display fully reversible redox waves for the reduction and oxidation with higher potentials for 10. From the measured redox potentials, the HOMO and LUMO energy levels were calculated for 9 and 10. The frontier orbital energies, the energies of the absorption bands, as well as the orbitals involved in the absorption process were calculated with DFT and compared to the measured results of 9 and 10. The absorption maximum can be related to an intense HOMO LUMO transition and the more-pronounced stabilization of the LUMO upon complexation is the origin of the bathochromic shift of the absorption. Additionally, single-crystal structures for two species, 10 d and 10 f, are reported. PMID- 21290439 TI - Broadening deoxysugar glycodiversity: natural and engineered transaldolases unlock a complementary substrate space. AB - The majority of prokaryotic drugs are produced in glycosylated form, with the deoxygenation level in the sugar moiety having a profound influence on the drug's bioprofile. Chemical deoxygenation is challenging due to the need for tedious protective group manipulations. For a direct biocatalytic de novo generation of deoxysugars by carboligation, with regiocontrol over deoxygenation sites determined by the choice of enzyme and aldol components, we have investigated the substrate scope of the F178Y mutant of transaldolase B, TalB(F178Y), and fructose 6-phosphate aldolase, FSA, from E. coli against a panel of variously deoxygenated aldehydes and ketones as aldol acceptors and donors, respectively. Independent of substrate structure, both enzymes catalyze a stereospecific carboligation resulting in the D-threo configuration. In combination, these enzymes have allowed the preparation of a total of 22 out of 24 deoxygenated ketose-type products, many of which are inaccessible by available enzymes, from a [3*8] substrate matrix. Although aliphatic and hydroxylated aliphatic aldehydes were good substrates, D-lactaldehyde was found to be an inhibitor possibly as a consequence of inactive substrate binding to the catalytic Lys residue. A 1 hydroxy-2-alkanone moiety was identified as a common requirement for the donor substrate, whereas propanone and butanone were inactive. For reactions involving dihydroxypropanone, TalB(F178Y) proved to be the superior catalyst, whereas for reactions involving 1-hydroxybutanone, FSA is the only choice; for conversions using hydroxypropanone, both TalB(F178Y) and FSA are suitable. Structure-guided mutagenesis of Ser176 to Ala in the distant binding pocket of TalB(F178Y), in analogy with the FSA active site, further improved the acceptance of hydroxypropanone. Together, these catalysts are valuable new entries to an expanding toolbox of biocatalytic carboligation and complement each other well in their addressable constitutional space for the stereospecific preparation of deoxysugars. PMID- 21290440 TI - A new phase in the binary iron nitrogen system?--The prediction of iron pernitride, FeN2. AB - Among numerous different AB(2) structures with the hypothetical composition FeN(2), the structures lying lowest in energy have been determined by a series of density-functional electronic-structure calculations. The most likely FeN(2) phase crystallizing in the space group R3m must be considered an iron pernitride incorporating binuclear N-N units (d=1.275 A) with an anionic charge of 2-. This high-pressure magnetic phase with a bulk modulus of about 192 GPa and an iron saturation moment of approximately 1.68 MU(B) should already form at a pressure of 17 GPa at an assumed reaction temperature of 1000 K. Besides bonding Fe-N interactions, antibonding N-N and Fe-Fe interactions exist in the crystal structure. PMID- 21290441 TI - The protective effect and action mechanism of Vaccinium myrtillus L. on gastric ulcer in mice. AB - Vaccinium myrtillus L. anthocyanoside (VMA) is used as a folk medicine to treat diseases related to gastric ulcers in northern Europe. However, the effects of VMA and its detailed mechanism on gastric ulcer have not been investigated sufficiently. Therefore, the aim of the present study was to investigate the protective effects of VMA on gastric mucosal damage in a murine gastric ulcer model. First the effects of VMA on ethanol-induced gastric ulcers in mice were investigated. Then, the levels of lipid peroxide in murine stomach homogenates were measured to investigate the antioxidative effects of VMA. In addition, the free radical scavenging activity of VMA and its main anthocyanidins were evaluated by electron spin resonance measurement. Oral administration of VMA (10, 30 and 100 mg/kg) significantly protected gastric mucosa against HCl/ethanol induced gastric ulcers. Furthermore, VMA inhibited lipid peroxide levels in a concentration-dependent manner and showed high scavenging activity against the superoxide anion radical (.O(2) (-) ) and the hydroxyl radical (.OH). Anthocyanidins also showed scavenging activity against the .O(2) (-) , while only delphinidin showed high scavenging activity against the .OH. These findings indicate that the protective effects of VMA on HCl/ethanol-induced gastric mucosal injury may be partially due to the antiperoxidative effects of anthocyanidins. PMID- 21290442 TI - Quercetin inhibits alpha-MSH-stimulated melanogenesis in B16F10 melanoma cells. AB - Quercetin is known to inhibit tyrosinase activity and melanin production in melanocytes. However, several reports suggest that quercetin has different and opposite effects on melanogenesis. This study examined the precise effects of quercetin on melanogenesis using cell-free assay systems and melanocytes. Quercetin inhibited the monophenolase and diphenolase activities of tyrosinase, and melanin synthesis in cell-free assay systems. Quercetin induced mild stimulation of the tyrosinase activity and dihydroxyphenylalaminechrome tautomerase (TRP-2) expression but only at low concentrations (<20 MUm) in B16F10 melanoma cells. In contrast, the addition of 50 MUm quercetin to the cells led to a significant decrease in the activity and synthesis of tyrosinase, as well as a decrease in the expression of tyrosinase-related protein-1 and TRP-2 proteins, regardless of the presence or absence of alpha-melanocyte stimulating hormone (alpha-MSH). Quercetin also reduced the intracellular cAMP and the phosphorylated protein kinase A levels in alpha-MSH-stimulated B16F10 cells. Moreover, quercetin (20 MUm) diminished the expression and activity of tyrosinase, and melanin content in cultured normal human epidermal melanocytes. These effects were not related to its cytotoxic action. Although the in vivo effects of quercetin are still unclear, these results suggest that quercetin could play important roles in controlling melanogenesis. PMID- 21290443 TI - Structural determination of cerebrosides isolated from Asterias amurensis starfish eggs using high-energy collision-induced dissociation of sodium-adducted molecules. AB - Six cerebrosides were isolated from the eggs of the starfish Asterias amurensis using solvent extraction, silica gel column chromatography, and reversed-phase high-performance liquid chromatography. This study demonstrated that the structures of cerebrosides could be completely characterized, based on their sodium-adducted molecules, using fast atom bombardment (FAB) tandem mass spectrometry. The high-energy collision-induced dissociation of the sodium adducted molecule, [M + Na](+), of each cerebroside molecular species generated abundant ions, providing information on the compositions of the 2-hydroxy fatty acids and long-chain sphingoid bases, as well as the sugar moiety polar head group. Each homologous ion series along the fatty acid and aliphatic chain of the sphingoid base was useful for locating the double-bond positions of both chains and the methyl branching position of the long-chain base. The N-fatty acyl portions were primarily long-chain saturated or monoenoic acids (C16 to C24) with an alpha-hydroxy group. The sphingoid long-chain base portions were aliphatic chains (C18 or C22) with two or three degrees of unsaturation and with or without methyl branching. PMID- 21290444 TI - Inter-laboratory calibration of new silver orthophosphate comparison materials for the stable oxygen isotope analysis of phosphates. AB - Stable oxygen isotope compositions (delta(18)O values) of two commercial and one synthesized silver orthophosphate reagents have been determined on the VSMOW scale. The analyses were carried out in three different laboratories: lab (1) applying off-line oxygen extraction in the form of CO(2) which was analyzed on a dual inlet and triple collector isotope ratio mass spectrometer, while labs (2) and (3) employed an isotope ratio mass spectrometer coupled to a high-temperature conversion/elemental analyzer (TC/EA) where Ag(3)PO(4) samples were analyzed as CO in continuous flow mode. The delta(18)O values for the proposed new comparison materials were linked to the generally accepted delta(18)O values for Vennemann's TU-1 and TU-2 standards as well as for Ag(3)PO(4) extracted from NBS120c. The weighted average delta(18)O(VSMOW) values for the new comparison materials UMCS 1, UMCS-2 and AGPO-SCRI were determined to be + 32.60 (+/- 0.12), + 19.40 (+/- 0.12) and + 14.58 (+/- 0.13)0/00, respectively. PMID- 21290445 TI - Analysis of bioactive eicosanoids in equine plasma by stable isotope dilution reversed-phase liquid chromatography/multiple reaction monitoring mass spectrometry. AB - Oxidative metabolites of arachidonic acid (AA) are implicated in inflammation. Thus, we evaluated cycloxygenases (COXs) and lipoxygenases (LOs) mediated metabolism of AA to eicosanoids in equine plasma. Eicosanoids were extracted from plasma by two liquid-liquid extraction (LLE) steps; first was by chloroform/isopropanol and second by methyl-tert-butyl ether. For identification and quantification of 25 eicosanoids, a highly specific, selective and sensitive stable isotope dilution liquid chromatography (LC) multiple reaction monitoring (MRM) mass spectrometric (MS) method was developed. To avoid artifact formation of eicosanoids, deferoxamine was added to plasma to chelate residual transition metal ions. The calibration curve showed excellent linearity within 0.1 to 10 ng/mL. Slopes of the calibration curves generated by adding known quantities of eicosanoids in plasma were higher than those prepared in methanol/mobile phase A. Addition of deferoxamine decreased the slope of calibration curves generated using plasma. Limit of detection (LOD) was 1-10 pg on-column for 25 different eicosanoids. Inter-day accuracy was 86-111%, whereas intra-day accuracy was from 88-110%, and precision did not exceed 15% for all quality control (QC) samples. To evaluate the formation of eicosanoids, AA was exogenously added or endogenous AA was released from esterified lipids by calcium ionophore (CI) A23187 treatment of equine whole blood. Pre-treatment of equine whole blood with dexamethasone (DEX) significantly inhibited AA or CI A23187- mediated formation of eicosanoids. The validated method is now employed in studies undertaken to better understand the mechanism of action and pharmacokinetics/pharmacodynamics of eicosanoids after administration of glucocorticoids to horses. This method is reliably reproducible. PMID- 21290446 TI - Measurement of 13C and 15N isotope labeling by gas chromatography/combustion/isotope ratio mass spectrometry to study amino acid fluxes in a plant-microbe symbiotic association. AB - We have developed a method based on a double labeling with stable isotopes and gas chromatography/combustion/isotope ratio mass spectrometry (GC/C/IRMS) analyses to study amino acid exchange in a symbiotic plant-microbe association. Isotopic precision was studied for 21 standards including 15 amino acid derivatives, three N-protected amino acid methyl esters, three amines and one international standard. High correlations were observed between the delta(13)C and delta(15)N values obtained by GC/C/IRMS and those obtained by an elemental analyzer (EA) coupled to an isotope ratio mass spectrometer (R(2) = 0.9868 and 0.9992, respectively). The mean precision measured was 0.040/00 for delta(13)C and 0.280/00 for delta(15)N (n = 15). This method was applied in vivo to the symbiotic relationship between alfalfa (Medicago sativa L.) and N(2)-fixing bacteria. Plants were simultaneously labeled over 10 days with (13)C-depleted CO(2) ((12)CO(2)), which was assimilated through photosynthesis by leaves, and (15)N(2) fixed via nodules. Subsequently, the C and N isotope compositions (i.e. delta(13)C and delta(15)N) of free amino acids were analyzed in leaves and nodules by GC/C/IRMS. The method revealed the pattern of C and N exchange between leaves and nodules, highlighting that gamma-aminobutanoic acid and glycine may represent an important form of C transport from leaves to the nodules. The results confirmed the validity, reliability and accuracy of the method for assessing C and N fluxes between plants and symbiotic bacteria and support the use of this technique in a broad range of metabolic and fluxomic studies. PMID- 21290447 TI - Hydrogen isotope correction for laser instrument measurement bias at low water vapor concentration using conventional isotope analyses: application to measurements from Mauna Loa Observatory, Hawaii. AB - The hydrogen and oxygen isotope ratios of water vapor can be measured with commercially available laser spectroscopy analyzers in real time. Operation of the laser systems in relatively dry air is difficult because measurements are non linear as a function of humidity at low water concentrations. Here we use field based sampling coupled with traditional mass spectrometry techniques for assessing linearity and calibrating laser spectroscopy systems at low water vapor concentrations. Air samples are collected in an evacuated 2 L glass flask and the water is separated from the non-condensable gases cryogenically. Approximately 2 uL of water are reduced to H(2) gas and measured on an isotope ratio mass spectrometer. In a field experiment at the Mauna Loa Observatory (MLO), we ran Picarro and Los Gatos Research (LGR) laser analyzers for a period of 25 days in addition to periodic sample collection in evacuated flasks. When the two laser systems are corrected to the flask data, they are strongly coincident over the entire 25 days. The delta(2)H values were found to change by over 2000/00 over 2.5 min as the boundary layer elevation changed relative to MLO. The delta(2)H values ranged from -106 to -3320/00, and the delta(18)O values (uncorrected) ranged from -12 to -500/00. Raw data from laser analyzers in environments with low water vapor concentrations can be normalized to the international V-SMOW scale by calibration to the flask data measured conventionally. Bias correction is especially critical for the accurate determination of deuterium excess in dry air. PMID- 21290448 TI - Charging megadalton poly(ethylene oxide)s by electrospray ionization. A charge detection mass spectrometry study. AB - Ions from compounds of megadalton (MDa) molecular weight were produced in an electrospray ionization source from solutions of poly(ethylene oxide) (PEO) samples with average molecular weights ranging from 1,000,000 to 7,000,000 Da. Charge detection mass spectrometry (CDMS) has been used to determine the mass of the MDa PEOs. Simultaneous measurement of the charge and velocity of individual ions allows the mass determination of the ion, after calibration of the instrument with independent samples. In addition to the mass spectra, CDMS generates charge-versus-mass plots, which allow investigation of the charging of electrosprayed ions over a broad range of masses. The experimental charging capacity of MDa PEOs is compared with a simple model based on the affinity of alkali cations for oxygen sites and on the electrostatic potential energy of the charged polymer. The charging capacity of PEOs was also investigated as a function of the concentration of and the type of alkali ions. PMID- 21290449 TI - A method for analyzing the delta18O of resin-extractable soil inorganic phosphate. AB - Improved tools for tracing phosphate transformations in soils are much needed, and can lead to a better understanding of the terrestrial phosphorus cycle. The oxygen stable isotopes in soil phosphate are still not exploited in this regard. Here we present a method for measuring the oxygen stable isotopes in a fraction of the soil phosphate which is rapidly available to plants, the resin-extractable P. This method is based on extracting available phosphate from the soil with anion-exchange membranes, soil organic matter removal by a resin, purification by precipitation as cerium phosphate, and finally precipitation as silver phosphate. The purified silver phosphate samples are then measured by a high-temperature elemental analyzer (HT-EA) coupled in continuous flow mode to an isotope ratio mass spectrometer. Testing the method with Mediterranean and semi-arid soils showed no artifacts, as well as good reproducibility in the same order as that of the HT-EA analytical uncertainty (0.30/00). PMID- 21290450 TI - Quantitative profiling of SiGe/Si superlattices by time-of-flight secondary ion mass spectrometry: the advantages of the extended Full Spectrum protocol. AB - The abundance of work on SiGe-based devices demonstrates the importance of the compositional characterization of such materials. However, Secondary Ion Mass Spectrometry (SIMS) characterization of SiGe layers often suffers from matrix effects due to the non-linear variation of ionization yields with Ge content. Several solutions have been proposed in order to overcome this problem, each having its own limitations such as a restricted germanium concentration range, or a weak sensitivity to dopants or impurities. Here, we studied the improvements brought by an alternative protocol: the extended Full Spectrum protocol, which states proportionality between the composition of the secondary ion beam and that of the actual material. Previous studies on this protocol showed that it was extremely precise and reproducible for Ge quantification in a permanent regime, because of minimized matrix effects. In this study we thus investigated its accuracy for the simultaneous quantitative depth profiling of both matrix elements (Si, Ge) and impurities (B, C or P) in strained SiGe/Si superlattices by comparing results with those from more classic protocols. The profiles provided by the extended Full Spectrum protocol were found to be accurate, and to exhibit better properties than classic protocols in terms of signal/noise ratio and signal stability, along with a slight enhancement in depth resolution. PMID- 21290451 TI - Piperazines for peptide carboxyl group derivatization: effect of derivatization reagents and properties of peptides on signal enhancement in matrix-assisted laser desorption/ionization mass spectrometry. AB - Piperazine-based derivatives, including 1-(2-pyridyl)piperazine (2-PP), 1-(2 pyrimidyl)piperazine (2-PMP), 1-(4-pyridyl)piperazine (4-PP), and 1-(1-methyl-4 piperidinyl)piperazine (M-PP), were used for the derivatization of carboxyl groups on peptides with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 1-hydroxy-7-azabenzotriazole (HOAt) as coupling reagents, and trifluoroacetic acid (TFA) as activator. Taking synthetic peptides RVYVHPI (RI-7) and APGDRIYVHPF (AF-11) as samples, the yields of derivatized peptides by 2-PP, 2-PMP and 4-PP were higher than 94%. The effect of piperazine derivatives on the signals of tryptic digests of alpha-transferrin and bovine serum albumin (BSA) was investigated, and it was found that peptides derivatized by 2-PP and 2 PMP exhibited obviously improved ionization efficiency. Furthermore, comparison of identified peptides before and after derivatization showed that peptides with low molecular weight (MW) and high pI value were preferably detected after derivatization. In addition, after derivatization with 2-PP and 2-PMP, protein myelin basic protein S, 20 kDa protein, and histone H were confidently identified from the tryptic digests of two fractions of rat brain protein separated by reversed-phase high-performance liquid chromatography (HPLC), indicating the potential application of 2-PP and 2-PMP for the highly sensitive determination of peptides in comprehensive proteome analysis. PMID- 21290452 TI - Study of the desorption/ionization mechanism in electrospray droplet impact secondary ion mass spectrometry. AB - Electrospray droplet impact (EDI) secondary ion mass spectrometry (SIMS) is a desorption/ionization technique for mass spectrometry in which highly charged water clusters produced from an atmospheric-pressure electrospray are accelerated in vacuum by several kV and impact on the sample deposited on the metal substrate. The abundances of the secondary ions for C(60) and amino acids are measured as a function of the acceleration voltage of the primary charged water droplets. Two desorption/ionization mechanisms are suggested in the EDI ionization processes: low-energy and high-energy regimes. In the low-energy regime, the excess charges in the primary droplets play a role in the formation of secondary ions. In the high-energy regime, samples are ionized by the supersonic collision of the primary droplets with the sample. The yield of secondary ions increases by about three orders of magnitude with increase in the acceleration voltage of the primary droplets from 1.75 kV to 10 kV. PMID- 21290453 TI - delta15N natural abundance in permafrost soil indicates impact of fire on nitrogen cycle. AB - The impact of fire on the nitrogen (N) cycle of natural ecosystems is arguable. Here we report and interpret an observation from boreal ecosystems in the Lena River basin, Sakha Republic (Yakutia), Russian Federation. Different types of permafrost soil (0-30 cm depth) were sampled along transects (60-150 m length) from the forest edge towards the centre of four separate thermokarst depressions under grassland. The average values of delta(15)N were remarkably similar within three transects, but differed systematically between them. Three findings point towards fire being the cause of the observed pattern. First, the spatial extent of systematic differences in soil delta(15)N coincides with the extent of typical fire scars in the region. Second, soil enrichment in (15)N is larger in the proximity of settlements, where fire is generally more frequent than in more remote places. Third, there is a significant positive correlation between delta(15)N values and the ratio of black C to total N. These findings point towards fire having a marked impact on soil delta(15)N and, accordingly, on the N cycle of this cold and dry ecosystem. PMID- 21290455 TI - Cation-pi interactions in gas-phase complexes formed by benzo-crown ethers and alkali metal cations. PMID- 21290454 TI - Absorption and translocation of nitrogen in rhizomes of Leymus chinensis. AB - Leymus chinensis is a dominant species in the Inner Mongolia steppe, northern China. Plant growth in northern China grassland is often limited by low soil nitrogen availability. The objective of this study is to investigate whether rhizomes of Leymus chinensis are involved in the contribution of N uptake. The N concentration, (15)N concentration and (15)N proportion in roots, rhizomes and shoots after 48 h exposure of roots (L(root)) and rhizomes (L(rhizo)) separately and roots and rhizomes together (L(r+r)) to 0.1 mM (15)NH (4)(15)NO(3) solution were measured using root-splitting equipment and stable isotope ((15)N) techniques, respectively. The N content and dry mass were not affected by the labeling treatment. In contrast, the (15)N concentration in shoots, rhizomes and roots was significantly increased by the labeling in rhizomes, indicating that the inorganic nitrogen was absorbed via rhizomes from the solution and can be transported to other tissues, with preference to shoots rather than roots. Meanwhile, the absolute N absorption and translocation among compartments were also calculated. The N absorption via rhizomes was much smaller than via roots; however, the uptake efficiency per surface unit via rhizomes was greater than via roots. The capacity and high efficiency to absorb N nutrient via rhizomes enable plants to use transient nutrient supplies in the top soil surface. PMID- 21290456 TI - Analysis of delta15N values in mollusk shell organic matrix by elemental analysis/isotope ratio mass spectrometry without acidification: an evaluation and effects of long-term preservation. PMID- 21290457 TI - Assessment of the effect of haematocrit-dependent arterial input functions on the accuracy of pharmacokinetic parameters in dynamic contrast-enhanced MRI. AB - The detection and prognosis of prostate cancer in its early stages are critically important. It is therefore essential to improve the existing dynamic contrast enhanced MRI (DCE MRI) techniques commonly used for the assessment of the tumour vascular environment. The goal of this study was to describe a method for the estimation of the arterial input function (AIF) in DCE MRI by measuring R(2) * values in the femoral artery of patients with early-stage prostate cancer. The calculation of contrast agent concentrations was based on calibration curves determined in whole blood samples for a range of normal haematocrit (HCT) values (HCT = 0.35-0.525). Individual AIFs corrected for HCT were compared with individual AIFs calibrated with a mean whole blood [R(2)*-Gd-DTPA-BMA] [Gd-DTPA BMA, gadolinium diethylenetriaminepentaacetate-bis(methylamide) (gadodiamide)] curve at an assumed HCT = 0.44, as well as a population AIF at an assumed HCT = 0.45. The area under the curve of the first-pass bolus ranged between 0.6 min mM at HCT = 0.53 and 1.3 min mM at HCT = 0.39. Significant differences in magnitude at peak contrast agent concentrations (HCT = 0.36, [Gd-DTPA-BMA](max) = 9 +/- 0.4 mM; HCT = 0.46, [Gd-DTPA-BMA](max) = 4.0 +/- 0.2 mM) were found. Using model based simulations, the accuracy of the kinetic parameters estimated using individual AIFs corrected for HCT demonstrated that, for the use of individual calibration curves with HCT values differing by more than 10%, K(trans) and k(ep) values were largely underestimated (up to 60% difference for K(trans)). Moreover, blood volume estimates were severely underestimated. Estimates of kinetic parameters in early-stage prostate cancer patients demonstrated that the efflux rate constant (k(ep)) was influenced significantly by the definition of AIF. Regardless of whether an individually calibrated AIF or a population AIF (average of all individually calibrated AIFs) was used, pixel-by-pixel mapping of k(ep) and v(b) in the prostate gland appeared to be more sensitive than with the usual biexponential approach. PMID- 21290458 TI - Reproducibility of prefrontal gamma-aminobutyric acid measurements with J-edited spectroscopy. AB - gamma-Aminobutyric acid (GABA) is the chief inhibitory neurotransmitter of the human brain, and GABA-ergic dysfunction has been implicated in a variety of neuropsychiatric disorders. Recent MRS techniques have allowed the quantification of GABA concentrations in vivo, and could therefore provide biologically relevant information. Few reports have formally characterized the reproducibility of these techniques, and differences in field strength, acquisition and processing parameters may result in large differences in measured GABA values. Here, we used a J-edited, single-voxel spectroscopy method of measurement of GABA + macromolecules (GABA + ) in the anterior cingulate cortex (ACC) and right frontal white matter (rFWM) at 3 T. We measured the coefficient of variation within subjects (CVw) and intra-class correlation coefficients on two repeated scans obtained from 10 healthy volunteers with processing procedures developed in-house for the quantification of GABA + and other major metabolites. In addition, by segmenting the spectroscopic voxel into cerebrospinal fluid, gray matter and white matter, and employing a linear regression technique to extrapolate metabolite values to pure gray and white matter, we determined metabolite differences between gray and white matter in ACC and rFWM. CVw values for GABA + /creatine, GABA + /H(2) O, GABA + , creatine, partially co-edited glutamate + glutamine (Glx)/creatine, partially co-edited Glx and N-acetylaspartic acid (NAA)/creatine were all below 12% in both ACC and rFWM. After extrapolation to pure gray and pure white matter, CVw values for all metabolites were below 16%. We found metabolite ratios between gray and white matter for GABA + /creatine, GABA + , creatine, partially co-edited Glx and NAA/creatine to be 0.88 +/- 0.21 (standard deviation), 1.52 +/- 0.32, 1.77 +/- 0.4, 2.69 +/- 0.74 and 0.70 +/- 0.05, respectively. This study validates a reproducible method for the quantification of brain metabolites, and provides information on gray/white matter differences that may be important in the interpretation of results in clinical populations. PMID- 21290459 TI - (1)H-MRS can detect aberrant glycosylation in tumour cells: a study of the HeLa cell line. AB - Glycosylation is the most abundant and diverse form of post-translational modification of proteins. Two types of glycans exist in glycoproteins: N-glycans and O-glycans often coexisting in the same protein. O-glycosylation is frequently found on secreted or membrane-bound mucins whose overexpression and structure alterations are associated with many types of cancer. Mucins have several cancer associated structures, including high levels of Lewis antigens characterized by the presence of terminal fucose. The present study deals with the identification of MR signals from N-acetylgalactosamine and from fucose in HeLa cells by detecting a low-field signal in one-dimensional (1D) spectra assigned to the NH of N-acetylgalactosamine and some cross peaks assigned to fucose in two dimensional (2D) spectra. The increase of Golgi pH by treatment with ammonium chloride allowed the N-acetylgalactosamine signal assignment to be confirmed. Behaviour of MR peak during cell growth and comparison with studies from literature taken together made it possible to have more insight into the relationship between aberrantly processed mucin and the presence of non-processed N-acetylgalactosamine residues in HeLa cells. Fucose signals, tentatively ascribed to residues bound to galactose and to N-acetylglucosamine, are visible in both intact cell and perchloric acid spectra. Signals assigned to fucose bound to galactose are more evident in ammonium chloride-treated cells where structural changes of mucin-related Lewis antigens are expected as a result of the higher Golgi pH. A common origin for the N-acetylgalactosamine and fucose resonances attributing them to aberrantly processed mucin can be inferred from the present results. PMID- 21290462 TI - Quantum of dots. PMID- 21290463 TI - Helping flow cytometry communities grow. PMID- 21290464 TI - An improved technique for calculating relative response in cellular proliferation experiments. AB - Investigating the response of cells to specific agonists may involve the use of cell tracking dyes to assess the extent of stimulated proliferation, frequently reported as the proliferation index (PI). Calculation of PI uses a model for cell division that expects the cell number to double as cells proliferate through each successive generation. It is often useful to compare the PI of a stimulated control population with that of a population in the presence of some agent, whether chemical, pharmacologic, or cellular. For such comparison studies, the nature of the metric being used must be taken into account to accurately assess the extent of inhibition. Specifically, the metric used in ModFit LT (Verity Software House, Topsham, ME) and in FCS Express (De Novo Software, Los Angeles, CA) uses a metric with a lower limit of unity, whereas the metric used in FlowJo (Treestar, Ashland, OR) has a lower limit of zero. For studies involving cell proliferation comparisons using tracking dye dilution, a new equation is proposed as the appropriate calculation to use when determining the percent of relative response based on proliferation index values for a metric whose lower limit is unity. PMID- 21290465 TI - Optimizing the setup of a flow cytometric cell sorter for efficient quantitative sorting of long filamentous cyanobacteria. AB - Heterogeneity within natural phytoplankton communities makes it very difficult to analyze parameters at the single-cell level. Flow cytometric sorting is therefore a useful tool in aquatic sciences, as it provides material for post-sort analysis and culturing. Sorting subpopulations from natural communities, however, often requires handling morphologically diverse and complex particles with various abundances. Long particles, such as filament-forming cyanobacteria (>100-MUm long), prove very difficult to handle. These potentially toxic organisms are widespread in eutrophic systems and have important ecological consequences. Being able to sort filamentous cyanobacteria efficiently and as viable cells is therefore highly desirable when studying factors associated with their toxicity and occurrence. This unconventional sorting requires extensive user experience and special instrument setup. We have investigated the effect of hydrodynamic and electromechanical components of a flow cytometer, and sorting protocol on the quantitative sorting efficiency of these long particles using two filamentous cyanobacterial strains with average lengths of ~100 and ~300 MUm. Sorting efficiency ranged from 9.4 to 96.0% and was significantly affected by filament length, sorting envelope, drop delay (dd), and for the long species also by tip size, but not by cycle time. Filaments survived sorting and were not damaged. The optimal settings found for the modular MoFlo(r) cell-sorter to sort the filaments were a 100-MUm flow tip at 30 psi (207 kPa) with a three-droplet envelope in Enrich mode while using an extended analysis time of 17.6 MUs and an intermediate plate charge and deflection percentage combination of 3,000 V/60%, combined with a dd 0 for the cultures with 100-MUm filaments and dd +1 for the culture with 300 MUm filaments. To the best of our knowledge, the filaments up to 1063.5 MUm sorted in this study are the longest ever sorted. PMID- 21290466 TI - Long-term time series analysis of quantum dot encoded cells by deconvolution of the autofluorescence signal. AB - The monitoring of cells labeled with quantum dot endosome-targeted markers in a highly proliferative population provides a quantitative approach to determine the redistribution of quantum dot signal as cells divide over generations. We demonstrate that the use of time-series flow cytometry in conjunction with a stochastic numerical simulation to provide a means to describe the proliferative features and quantum dot inheritance over multiple generations of a human tumor population. However, the core challenge for long-term tracking where the original quantum dot fluorescence signal over time becomes redistributed across a greater cell number requires accountability of background fluorescence in the simulation. By including an autofluorescence component, we are able to continue even when this signal predominates (i.e., >80% of the total signal) and obtain valid readouts of the proliferative system. We determine the robustness of the technique by tracking a human osteosarcoma cell population over 8 days and discuss the accuracy and certainty of the model parameters obtained. This systems biology approach provides insight into both cell heterogeneity and division dynamics within the population and furthermore informs on the lineage history of its members. PMID- 21290467 TI - Analysis of quantum dot fluorescence stability in primary blood mononuclear cells. AB - A quantitative assessment of fluorescence signal generation and persistence in blood cells, measured at multiple points over a time course, is presented. Quantum dots (QDs) are inorganic fluorophores that are photostable and nonmetabolized and so can provide quantitative measures of cell biology over multiple cell generations. However, if the potential of these nanoparticles for long-term reporting is to be realized, an understanding of the stability of their fluorescence in living cells is essential. CdTe/ZnS and CdSe/ZnS core/shell dots with peak emission wavelengths of 705 nm and 585 nm, respectively, were loaded, via endocytosis into mononuclear cells extracted from primary blood and flow cytometry used to measure the average fluorescence intensity per cell within populations >104. Time-based study showed a saturation-limited uptake of QDs with a characteristic time of 20 min and a maximum fluorescence signal that is linearly proportional to dot solution concentration. The fluorescence signal decreases after attachment and internalization within cells and is accurately described by a biexponential decay with a rapid initial decay followed by a much slower signal loss with characteristic times of 435 and 7,000 min respectively. Comparison with control samples indicates that interaction with the culture media is a major contributory factor to the initial signal decay. These results provide phenomenological descriptions of the evolving QD fluorescence within live cells with associated analytical equations that allow quantitative assessment of QD based assays. PMID- 21290468 TI - Hyperthermia alters the interaction of proteins of the Mre11 complex in irradiated cells. AB - Radiosensitization of mammalian cells by heat is believed to involve the inhibition of repair of DNA double-strand breaks (DSBs). The Mre11 complex (composed of Mre11, Rad50, and Nbs1) is involved in DSB repair and forms foci at sites of radiation-induced DSBs. Heat induces the translocation of a significant amount of Mre11, Rad50, and Nbs1 from the nucleus to the cytoplasm, but little is known about how heat affects the integrity of the proteins still remaining in nuclei, or alters kinetics of formation/disappearance of DNA repair foci in heated, irradiated cells. Here, we show that hyperthermia alters the interaction between proteins of the Mre11 complex in irradiated human melanoma cells and inhibits the formation of repair foci. At various times after X-irradiation and/or heating (2 h at 41.5 or 42.5 degrees C), the cells were fixed and stained for Mre11, Rad50, and Nbs1. Colocalization of proteins and formation and disappearance of nuclear foci in heated and/or irradiated cells, determined using confocal microscopy, were compared. In heated, irradiated cells, focus formation was inhibited for 2-8 h, and colocalization of the proteins of the Mre11 complex was reduced for 12-24 h post-treatment. Colocalization was recovered in irradiated cells within 24 h after heating at 41.5 degrees C, but was inhibited longer after heating at 42.5 degrees C. The decreased colocalization in heated, irradiated cells suggests that there is a decrease in protein interaction, and Mre11 complexes in nuclei disassemble after heating. Such changes could be involved, at least in part, in heat radiosensitization and inhibition of DSB repair. Also, the kinetics of disassembly and reassembly of Mre11 complexes appears to be dependent upon treatment temperature. PMID- 21290469 TI - Miniaturizing bromodeoxyuridine incorporation enables the usage of flow cytometry for cell cycle analysis of adherent tissue culture cells for high throughput screening. AB - Analysis of cell cycle progression by 5-bromo-2'-deoxyuridine (BrdU) incorporation is commonly used for evaluating the mode of action of anticancer drugs, but usually requires a high number of cells and large amounts of monoclonal antibodies. In addition, manual sample handling is not suitable for high throughput. To circumvent these limitations, we have developed a miniaturized method to measure BrdU incorporation into DNA directly in 96-wells plates. Adherent cells were grown in 96-well plates in the absence or presence of compounds of interest. After BrdU pulse labeling or pulse chase, cells were harvested, transferred to polymerase chain reaction (PCR) V-bottom plates, and fixed by adding methanol. DNA denaturation was performed directly in the plates by heat using a PCR thermocycler. BrdU incorporation was detected by indirect immunocytochemical staining, and cellular DNA was counterstained using propidium iodide. Samples were acquired by a BD FACSCalibur with BD Multiwells Auto sampler or BD HTS. We defined a dynamic range of the optimal cell number, for which cells maintained exponential growth up to 72 h. The assay was robust up to 30,000 cells per well. BrdU dot plots of cell cycle phases showed an excellent separation of cell populations, and DNA histograms showed a low coefficient of variation. Thermal denaturation was suitable for 96-well plates to detect BrdU incorporation with a good signal-to-noise ratio, and cluster analysis allowed fingerprint readouts for drug sensitivity and mechanism of action as exemplified for paclitaxel and doxorubicin. This method provided rapid high-throughput BrdU/DNA content analysis with high accuracy and reproducibility, accompanied by a reduction in reagent consumption. A critical step was identified as the standardization of DNA denaturation using a PCR thermocycler. Here,we show some applications of this method for cell cycle studies in drug discovery. PMID- 21290470 TI - Proinflammatory activation pattern of human umbilical vein endothelial cells induced by IL-1beta, TNF-alpha, and LPS. AB - Endothelial cells play a critical role in inflammation by responding to several endogenous and exogenous proinflammatory stimuli. The three most studied factors that provide inflammatory signals to endothelial cells are lipopolysaccharide (LPS), tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1beta; however, their effects on endothelial cells were thoroughly compared at the level of gene expression only. Therefore, our aim was to assess the differences in the signaling pathways, adhesion molecules, and cytokines induced by proinflammatory factors in human umbilical vein endothelial cells (HUVEC). In this study, we demonstrated that signaling of LPS was less effective than that of IL-1beta, and was significantly slower than that ofTNF-alpha and IL-1beta, which can be partially explained by the special localization of Toll-like receptor 4 (TLR4). We showed that TLR4 is mainly localized in Golgi apparatus in HUVEC. The proinflammatory capacity of TNF-alpha was similar to that of IL-1beta in inducing NF-kappaB nuclear translocation, while IL-1beta was the strongest activator of MAPK pathways. Moreover, expression of E-selectin, IL-6, and IL-8 was induced most efficiently by IL-1beta, while LPS and TNF-alpha had less effect, whereas we did not find such a difference in ICAM-1 and MCP-1 expression. Due to the higher induction of E-selectin and IL-8, IL-1beta might have more important role in neutrophil recruitment than LPS and TNF-alpha. By above-mentioned parameters we identified a signaling and expression pattern for the three proinflammatory molecules. This pattern illustrates how complex a proinflammatory process can be, and may enable us to predict and compare the pathomechanism of various inflammatory diseases. PMID- 21290471 TI - Flow cytometric analysis of the uptake of low-density lipoprotein by endothelial cells in microfluidic channels. AB - Acceptance of microfluidic technology in everyday laboratory practice by biologists is still low. One of the reasons for this is that the technology combines poorly with standard cell biological and biochemical analysis tools. Flow cytometry is an example of a conventional analytical tool that is considered to be incompatible with microfluidic technology and its inherent small sample sizes. In this study, it is shown that properly designed microfluidic devices contain cell populations that are large enough to be analyzed by flow cytometry. To illustrate this, the uptake of fluorescent human low-density lipoprotein (LDL) by human endothelial cells that were cultured in a microfluidic channel was analyzed. It was found that the uptake of LDL by the cells increased linearly over time. Moreover, the uptake decreased when cells were pretreated with fluid shear stress inside the microfluidic devices. This study shows that microfluidic technology can be combined with conventional flow cytometry, while retaining the advantages of working with microfluidics such as low reagent use and dynamic cell culture conditions. This approach of combining microfluidic technology with conventional laboratory tools may contribute to greater acceptance of microfluidic devices in biological research. PMID- 21290473 TI - A method of quantifying cell sorting yield in "real time". AB - Cell sorting flow cytometers sort cells by applying electrical charges to a stream that forms liquid droplets containing the cells at a set time after sample interrogation. The correct time to apply these charges is determined based on calibration beads and automated technology. The central tenet of this method is that beads accurately indicate the yield of cells sorted using the same instrument parameters. HEK293T cells were incubated with AccudropTM calibration beads. Cell incorporation of beads by phagocytosis was confirmed by imaging cytometry. Cells containing beads were analyzed and sorted on unmodified commercially available cell sorters that have automated technology for setting drop delay times. Based on cell sorter drop delay times optimized using beads, sorting experiments demonstrate that yield can be assessed in real time using bead loaded cells and existing technology. Here, data presented show that cells have lower sorting yields than indicated using beads. Further, this data show clear trends related to nozzle tip diameter and sorting yield. The present study demonstrates a method to quantify yield "on the fly" during cell sorting, that is separated from drop charge counts and removes the variables associated with yield assessment from collection tubes. These data have implications for the expected recovery of cells from sorting experiments. PMID- 21290472 TI - Improved detection of nicotinamide adenine dinucleotide phosphate oscillations within human neutrophils. AB - Kinetic studies of nicotinamide adenine dinucleotide phosphate autofluorescence have been conducted in adherent neutrophils using an improved microscopic photometry system incorporating low noise excitation and detection systems. Dynamic autofluorescence oscillations were found with periods ranging from ~4 min to ~10 s. The largest portion of the population of oscillating neutrophils (32%) had periods near 2 min. The next largest group at 25% exhibited periods of 1 min or less. These oscillations could not be accounted for by instrument artifacts, cell shape changes away from the focal plane, or other factors. They disappeared when detergent was added to oscillating cells. Higher-frequency oscillations disappeared as cells changed shape, indicating a correlation between these two processes. This approach provides a reliable method to monitor this cellular property. PMID- 21290474 TI - A simple method to sort ESC-derived adipocytes. AB - Because of the increasing incidence of worldwide obesity, cell culture models which enable the study of adipose tissue development are of particular importance. The murine embryonic stem cell (ESC) line CGR8 differentiates into adipocytes with a differentiation efficiency of up to 15%. A critical step for the analysis of stem cell-derived adipogenesis is the reliable separation of adipocytes. Here we report on how to (i) gently separate the cells of embryoid bodies (EBs) and (ii) identify and sort adipocytes from the rest of the heterogeneous cell mixture. Up to the present, no adipocyte specific surface marker is known for fluorescence activated cell sorting (FACS). After separation we employed two independently existing FACS methods for adipocyte cell sorting. These methods are based on Nile red staining and granularity. For stem cell derived adipocytes only the combination of both methods led to a reliable, efficient, and highly reproducible FACS analysis, as shown by the presence and absence of adipocyte specific markers in positively and negatively sorted cells. PMID- 21290475 TI - Epigenetic profile of developmentally important genes in bovine oocytes. AB - Assisted reproductive technologies are associated with an increased incidence of epigenetic aberrations, specifically in imprinted genes. Here, we used the bovine oocyte as a model to determine putative epigenetic mutations at three imprinted gene loci caused by the type of maturation, either in vitro maturation (IVM) in Tissue Culture Medium 199 (TCM) or modified synthetic oviduct fluid (mSOF) medium, or in vivo maturation. We applied a limiting dilution approach and direct bisulfite sequencing to analyze the methylation profiles of individual alleles (DNA molecules) for H19/IGF2, PEG3, and SNRPN, which are each associated with imprinting defects in humans and/or the mouse model, and are known to be differentially methylated in bovine embryos. Altogether, we obtained the methylation patterns of 203 alleles containing 4,512 CpG sites from immature oocytes, 213 alleles with 4,779 CpG sites from TCM-matured oocytes, 215 alleles/4,725 CpGs in mSOF-matured oocytes, and 78 alleles/1,672 CpGs from in vivo-matured oocytes. The total rate of individual CpGs and entire allele methylation errors did not differ significantly between the two IVM and the in vivo group, indicating that current IVM protocols have no or only marginal effects on these critical epigenetic marks. Furthermore, the mRNA expression profiles of the three imprinted genes and a panel of eight other genes indicative of oocyte competence were determined by quantitative real-time PCR. We found different mRNA expression profiles between in vivo-matured oocytes versus their in vitro-matured counterparts, suggesting an influence on regulatory mechanisms other than DNA methylation. PMID- 21290476 TI - Spatiotemporal changes in cell adhesiveness during vertebrate limb morphogenesis. AB - During vertebrate limb development, various molecules are expressed in the presumptive limb field or the limb bud in a spatiotemporal-specific manner. The combination of these molecules regulates cellular properties that affect limb initiation and its morphogenesis, especially cartilage formation. Cell adhesiveness of the limb mesenchyme is a key factor in the regulation of cell distribution. Differential adhesiveness of mesenchymal cells is first observed between cells in the presumptive limb field and flank region, and the adhesiveness of the cells in the limb field is higher than that of cells in the flank region. In the limb bud, the adhesiveness of mesenchymal cells shows spatiotemporal difference, which reflects the positional identity of the cells. Position-dependent cell adhesiveness is also observed in blastema cells of the regenerating limb. Therefore, local changes in cell adhesiveness are observed during limb development and regeneration, suggesting significant roles for cell adhesiveness in limb morphogenesis. PMID- 21290477 TI - Looking proximally and distally: 100 years of limb regeneration and beyond. AB - The experimental study of amphibian limb regeneration spans most of the 20th century and the first decade of the 21st century. We first review the major questions investigated over this time span: (1) the origin of regeneration blastema cells, the mechanism of tissue breakdown that liberates cells from their tissue organization to participate in blastema formation, (3) the mechanism of dedifferentiation of these cells, (4) how the blastema grows, (5) how the blastema is patterned to restore the missing limb structures, and (6) why adult anurans, birds and mammals do not have the regenerative powers of urodele salamanders. We then look forward in a perspective to discuss the many unanswered questions raised by investigations of the past century, what new approaches can be taken to answer them, and what the prospects are for translation of basic research on limb regeneration into clinical means to regenerate human appendages. PMID- 21290478 TI - Essential role of clusterin in pancreas regeneration. AB - Based on our previous observations that clusterin induction accompanies pancreas regeneration in the rat, we sought to determine if regeneration might be impaired in mice that lacked clusterin. We studied the impact of absent clusterin on morphogenic and functional features of regenerating pancreas. Clusterin induction was accompanied in the regenerating pancreas by a robust development of new lobules with ductules, acini, and endocrine islets in wild type after partial pancreatectomy. In clusterin knock-out mice, however, pancreatectomy resulted in a poor formation of regenerating lobule. In particular, regeneration of beta cells was also significantly reduced and was associated with persistent hyperglycemia. Duct cells obtained from pancreatectomized clusterin knock-out mice exhibited impaired beta-cell formation in vitro; this was restored by administration of exogenous clusterin. We suggest that clusterin plays a critical role to promote both exocrine and endocrine regeneration following pancreas injury, as well as for in vitro beta-cell regeneration. PMID- 21290479 TI - Teacher knowledge of basic language concepts and dyslexia. AB - Roughly one-fifth of the US population displays one or more symptoms of dyslexia: a specific learning disability that affects an individual's ability to process written language. Consequently, elementary school teachers are teaching students who struggle with inaccurate or slow reading, poor spelling, poor writing, and other language processing difficulties. Findings from studies have indicated that teachers lack essential knowledge needed to teach struggling readers, particularly children with dyslexia. However, few studies have sought to assess teachers' knowledge and perceptions about dyslexia in conjunction with knowledge of basic language concepts related to reading instruction. Thus, the purpose of the present study was to examine elementary school teachers' knowledge of basic language concepts and their knowledge and perceptions about dyslexia. Findings from the present study indicated that teachers, on average, were able to display implicit skills related to certain basic language concepts (i.e. syllable counting), but failed to demonstrate explicit knowledge of others (i.e. phonics principles). Also, teachers seemed to hold the common misconception that dyslexia is a visual processing deficit rather than phonological processing deficit. PMID- 21290480 TI - De novo collagenous cuffitis. PMID- 21290481 TI - Lymphomas in two IBD patients treated with anti-TNF-alpha mono or combination therapy: is hepatosplenic lymphoma really the "old maid"? PMID- 21290482 TI - Treatment of thromboembolism in IBD: more questions than answers. PMID- 21290483 TI - Altered O-glycosylation profile of MUC2 mucin occurs in active ulcerative colitis and is associated with increased inflammation. AB - BACKGROUND: The MUC2 mucin organizes the two mucus layers in the colon. This mucin carries a large number of O-glycans that are assumed to be attachment sites for the commensal flora found in the outer mucus layer. METHODS: Single biopsies from the sigmoid colon of controls (25) and patients with inactive (13) or active (15) ulcerative colitis (UC) were collected during routine colonoscopy. The insoluble MUC2 mucin was prepared and separated by gel electrophoresis, its relative amount estimated, its O-glycans released, and glycans analyzed by novel sensitive glycomics chromatography / mass spectrometry providing information on glycan structures and relative abundances. The glycosylation pattern was related to the degree of mucosal inflammation and clinical severity of the disease. RESULTS: The relative abundance of MUC2 showed high individual variability. Two major glycan profiles were found; a normal pattern in the control and inactive UC patients and an aberrant profile in patients with active colitis with an increase in a subset of the smaller glycans and a decrease of several complex glycans. The magnitude of this phenomenon was significantly related to both the degree of inflammation in the biopsies and also to some extent the severity of disease course. The aberrant profile was further shown to be reversible upon remission. CONCLUSIONS: In the majority of the active UC patients MUC2 mucin has an altered glycan profile as compared to inactive UC and control patients. Patients with strong alterations in the glycan pattern tended to have a more severe disease course. PMID- 21290484 TI - Hookworm products ameliorate dextran sodium sulfate-induced colitis in BALB/c mice. AB - BACKGROUND: Several lines of evidence have shown that helminthiasis can significantly reduce disease severity in animal models of intestinal inflammation, airway inflammation/hyperreactivity, diabetes, and multiple sclerosis. Identification and characterization of helminth-derived immunomodulatory molecules that contribute to anticolitis effects could lead to new therapeutic approaches in inflammatory bowel diseases (IBDs) without the need for helminth infection. We evaluated the therapeutic potential of adult human hookworm, Ancylostoma ceylanicum, crude (Aw) and excreted/secreted (ES) products on dextran sulfate sodium (DSS)-induced colitis in BALB/c mice. METHODS: Colitis was induced by 5% DSS oral administration for 7 days. Clinical disease severity was monitored daily during concomitant intraperitoneal treatment with helminth derived products. Additionally, several pathways of immunological modulation induced by A. ceylanicum products (MPO, EPO, Th1, Th2, and Th17 cytokine responses) in the inflamed intestinal microenvironment were assessed. Finally, the histopathological profile of the colon was characterized. RESULTS: Hookworm products are able to modulate the potent proinflammatory response induced by DSS, mainly through the downregulation of Th1 and Th17 cytokines. These proteins also reduce clinical and colonic microscopic inflammation scores as well as EPO and MPO activity. CONCLUSIONS: Ancylostoma ceylanicum Aw and ES mediators have an important therapeutic potential in experimental colitis in mice, which may provide a more socially acceptable form of therapy for patients with IBDs as opposed to using living worms. Our results support the urgency of further isolation and recombinant expression of active hookworm products responsible for the beneficial effects on colitis. PMID- 21290488 TI - Protecting-group-free total syntheses: a challenging approach. PMID- 21290489 TI - Molecule-constructed microporous materials: long under our noses, increasingly on our tongues, and now in our bellies. PMID- 21290490 TI - 9-Fluorenylmethoxycarbonyl-based solid-phase synthesis of peptide alpha thioesters. AB - Peptide thioesters play a key role in convergent protein synthesis strategies such as native chemical ligation, traceless Staudinger ligation, and Ag(+) mediated thioester ligation. The Boc-based solid-phase synthesis provides a very reliable access to peptide thioesters. However, the acid lability of many peptide modifications and the requirements of most parallel peptide synthesizers call for the milder Fmoc-based solid-phase synthesis. The Fmoc-based synthesis of peptide thioesters is more cumbersome and typically proceeds with lower yields than the synthesis of peptide acids and peptide amides. The success of native chemical ligation and related technologies has sparked intensive research effort devoted to the development of new methods. The recent progress in this rapidly expanding field is reviewed. PMID- 21290491 TI - Nanoparticles in biological systems. AB - Understanding the behavior of nanoparticles in biological systems opens up new directions for medical treatments and is essential for the development of safe nanotechnology. This Review discusses molecules and nanoparticles when in contact with cells or whole organisms, with a focus on inorganic materials. The interaction of particles with biology unravels a series of new mechanisms not found for molecules: altered biodistribution, chemically reactive interfaces, and the combination of solid-state properties and mobility. Externally guided movement of medicaments by using functional nanomagnets brings mechanics into drug design. In subsequent sections, the role of inertness and bioaccumulation is discussed in regard to the long-term safety of nanoparticles. PMID- 21290492 TI - Nanotoxicology: an interdisciplinary challenge. AB - The increasing consumption of products containing nanomaterials that can be currently observed and forecasts of new developments and applications fan the fear of individuals and organizations regarding new risks to health. Considering experiences gained from previous technology developments, such fears are not completely unfounded. But are they really justified? And is it justified, moreover, to speak of "nanotoxicology" as a new discipline? This Review seeks to cast light on the phenomena that may occur as nanoobjects interact with cells, tissues, and organisms. Furthermore, we will demonstrate that the many data made available on the biological effects of nanomaterials do not always come from studies that can be considered reliable. We will point out the aspect of reliability with specific examples from the literature and will not address specific (nano)materials. In particular, inadequate methods will be described together with recommendations how to avoid this in the future, thereby contributing to a sustainable improvement of the available data. PMID- 21290493 TI - Plasmonic enhancement of photoinduced uphill electron transfer in a molecular monolayer system. PMID- 21290494 TI - Control of the chirality and helicity of oligomers of serinol nucleic acid (SNA) by sequence design. PMID- 21290495 TI - Synthesis of metallophthalocyanine covalent organic frameworks that exhibit high carrier mobility and photoconductivity. PMID- 21290496 TI - Architecture-dependent distribution of mesopores in steamed zeolite crystals as visualized by FIB-SEM tomography. PMID- 21290497 TI - Supramolecular architecture with a cavitand-capsule chimera. PMID- 21290498 TI - Conformation of a seven-helical transmembrane photosensor in the lipid environment. PMID- 21290499 TI - Using pH value to control intermolecular electronic decay. PMID- 21290500 TI - Design, synthesis, and electrochemistry of room-temperature ionic liquids functionalized with propylene carbonate. PMID- 21290502 TI - Tailored anisotropic magnetic chain structures hierarchically assembled from magnetoresponsive and fluorescent components. PMID- 21290501 TI - Direct monitoring of the inhibition of protein-protein interactions in cells by translocation of PKCdelta fusion proteins. PMID- 21290503 TI - Fast and efficient fluorination of small molecules by SF4(2+). PMID- 21290504 TI - Fluorescence imaging of azobenzene photoswitching in vivo. PMID- 21290505 TI - Membrane-bound stable glycosyltransferases: highly oriented protein immobilization by a C-terminal cationic amphipathic peptide. PMID- 21290506 TI - Photoconductivity of pea-pod-type chains of gold nanoparticles encapsulated within dielectric amyloid protein nanofibrils of alpha-synuclein. PMID- 21290507 TI - The vinyl moiety as a handle for regiocontrol in the preparation of unsymmetrical 2,3-aliphatic-substituted indoles and pyrroles. PMID- 21290508 TI - Quantification of protein sulfenic acid modifications using isotope-coded dimedone and iododimedone. PMID- 21290510 TI - Stereodivergent synthesis of substituted N,O-containing bicyclic compounds by sequential addition of nucleophiles to N-alkoxybicyclolactams. PMID- 21290511 TI - Stable iso-osmabenzenes from a formal [3+3] cycloaddition reaction of metal vinylidene with alkynols. PMID- 21290509 TI - Synthesis of highly functionalized cyclohexenone rings: rhodium-catalyzed 1,3 acyloxy migration and subsequent [5+1] cycloaddition. PMID- 21290512 TI - Iridium-mediated borylation of benzylic C-H bonds by borohydride. PMID- 21290513 TI - Large-scale synthesis and characterization of the size-dependent thermoelectric properties of uniformly sized bismuth nanocrystals. PMID- 21290514 TI - Acid-base interaction between transition-metal hydrides: dihydrogen bonding and dihydrogen evolution. PMID- 21290515 TI - Noncovalent modification of carbon nanotubes with pyrene-functionalized nickel complexes: carbon monoxide tolerant catalysts for hydrogen evolution and uptake. PMID- 21290516 TI - Indium-catalyzed heteroaryl-heteroaryl bond formation through nucleophilic aromatic substitution. PMID- 21290517 TI - One-pot formation of C-C and C-N bonds through palladium-catalyzed dual C-H activation: synthesis of phenanthridinones. PMID- 21290518 TI - Facile catalytic hydrosilylation of pyridines. PMID- 21290519 TI - Chromatographic separation of highly soluble diamond nanoparticles prepared by polyglycerol grafting. PMID- 21290520 TI - One-pot synthesis of alpha-amino acids from imines through CO2 incorporation: an alternative method for Strecker synthesis. PMID- 21290521 TI - Formation of linear supramolecular polymers that is driven by C-H???pi interactions in solution and in the solid state. PMID- 21290522 TI - Concise total syntheses of variecolortides A and B through an unusual hetero Diels-Alder reaction. PMID- 21290523 TI - Selective NIR chromophores: bis(pyrrolopyrrole) cyanines. PMID- 21290524 TI - Highly enantioselective synthesis of alpha-amino acid derivatives by an NHC catalyzed intermolecular Stetter reaction. PMID- 21290525 TI - Diversity-oriented synthesis of polycyclic scaffolds by modification of an anodic product derived from 2,4-dimethylphenol. PMID- 21290526 TI - Siamese-twin porphyrin: a pyrazole-based expanded porphyrin providing a bimetallic cavity. PMID- 21290527 TI - A biomimetic iron catalyst for the epoxidation of olefins with molecular oxygen at room temperature. PMID- 21290528 TI - Generation, reactivity towards hydrocarbons, and electronic structure of heteronuclear vanadium phosphorous oxygen cluster ions. PMID- 21290529 TI - An organometallic nanosized capsule consisting of cyclo-P5 units and copper(I) ions. PMID- 21290530 TI - A model of the [FeFe] hydrogenase active site with a biologically relevant azadithiolate bridge: a spectroscopic and theoretical investigation. PMID- 21290533 TI - An enzymatic route to sunscreens. PMID- 21290534 TI - Universal sensing by transduction of antibody binding with backscattering interferometry. PMID- 21290535 TI - A novel organometallic ReI complex with favourable properties for bioimaging and applicability in solid-phase peptide synthesis. AB - Organometallic complexes possess great potential for imaging applications in biology, due to their kinetic stability and often favourable intrinsic properties. In this work we present a new class of Re(I) -tricarbonyl complexes with a substituted bis(phenanthridinylmethyl)amine (bpm) ligand. The complex Re(CO)(3) (R-bpm) could be conveniently prepared by microwave synthesis from [Re(CO)(3)(H(2)O)(3) ]Br and a suitably substituted bis(phenanthridinylmethyl)amine (R-bpm). Complex 5, with R=CH(2)-CO(2)-CH(3) , was characterized by a single-crystal X-ray structure. Complex 6 (R=CH(2) C(6)H(4)-CO(2)H) was used in solid-phase peptide synthesis (SPPS) to label the neurotensin(8-13) (NT) fragment N-terminally. The complexes show luminescence emission with large Stokes shifts (lambda(ex) =350 nm, lambda(em) =570 nm). Cellular uptake and intracellular localization studies in several cell lines demonstrate the utility of the new Re(CO)(3) (R-bpm) complexes for fluorescence imaging and reveal significant differences between the simple methyl ester 5 and the NT bioconjugate 7. PMID- 21290536 TI - Implantation of post-translational tyrosylprotein sulfation into a prokaryotic expression system. PMID- 21290537 TI - Enzyme-catalyzed substrate attachment to phage surfaces for the selection of catalytic activities. PMID- 21290538 TI - Dissecting cell signaling pathways with genetically encoded 3-iodo-L-tyrosine. PMID- 21290539 TI - Internal and global protein motion assessed with a fusion construct and in-cell NMR spectroscopy. PMID- 21290540 TI - A two-photon turn-on probe for lipid rafts with minimum internalization. PMID- 21290541 TI - Rebeccamycin and staurosporine biosynthesis: insight into the mechanisms of the flavin-dependent monooxygenases RebC and StaC. PMID- 21290542 TI - Cyclic RGD beta-lactam peptidomimetics induce differential gene expression in human endothelial cells. PMID- 21290543 TI - Bacterial inclusion bodies of Alzheimer's disease beta-amyloid peptides can be employed to study native-like aggregation intermediate states. AB - The structures of oligomeric intermediate states in the aggregation process of Alzheimer's disease beta-amyloid peptides have been the subject of debate for many years. Bacterial inclusion bodies contain large amounts of small heat shock proteins (sHSPs), which are highly homologous to those found in the plaques of the brains of Alzheimer's disease patients. sHSPs break down amyloid fibril structure in vitro and induce oligomeric assemblies. Prokaryotic protein overexpression thus mimics the conditions encountered in the cell under stress and allows the structures of Abeta aggregation intermediate states to be investigated under native-like conditions, which is not otherwise technically possible. We show that IB40/IB42 fulfil all the requirements to be classified as amyloids: they seed fibril growth, are Congo red positive and show characteristic beta-sheet-rich CD spectra. However, IB40 and IB42 are much less stable than fibrils formed in vitro and contain significant amounts of non-beta-sheet regions, as seen from FTIR studies. Quantitative analyses of solution-state NMR H/D exchange rates show that the hydrophobic cores involving residues V18-F19-F20 adopt beta-sheet conformations, whereas the C termini adopt alpha-helical coiled coil structures. In the past, an alpha-helical intermediate-state structure has been postulated, but could not be verified experimentally. In agreement with the current literature, in which Abeta oligomers are described as the most toxic state of the peptides, we find that IB42 contains SDS-resistant oligomers that are more neurotoxic than Abeta42 fibrils. E. coli inclusion bodies formed by the Alzheimer's disease beta-amyloid peptides Abeta40 and Abeta42 thus behave structurally like amyloid aggregation intermediate states and open the possibility of studying amyloids in a native-like, cellular environment. PMID- 21290544 TI - A G-quadruplex aptamer inhibits the phosphatase activity of oncogenic protein Shp2 in vitro. AB - Shp2 is a member of the protein tyrosine phosphatase (PTP) family, which regulates a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. Using a recombinant Shp2-GST protein as the target and GST as a counter target, we have identified two classes of single-stranded DNA aptamers that selectively bind to Shp2 with a K(d) in the nanomolar range. Structural studies of the most abundant sequence in the enriched library, HJ24, revealed a parallel G-quadruplex as the core binding domain. Furthermore, this aptamer was found to be an effective inhibitor of Shp2 phosphatase, an effect which was readily reversed by using the cDNA of HJ24. In view of these characteristics, this aptamer has the potential to be used for further development of Shp2 assays and therapeutics for the treatment of Shp2 dependent cancers and other diseases. PMID- 21290545 TI - Cleavage of functionalized DNA containing 5-modified pyrimidines by type II restriction endonucleases. AB - A series of six pyrimidine-modified dNTPs--5-ethynyl-, 5-phenyl-, and 5-(3 nitrophenyl)deoxycitidine and -deoxyuridine triphosphates--were prepared and incorporated by primer extension with Vent (exo-)polymerase to specific DNA sequences within or next to the recognition sequences of selected restriction endonucleases. The cleavage of these pyrimidine-modified DNA sequences by 13 restriction enzymes was then studied. Whereas the presence of any modified C within the target sequence completely prevented any restriction cleavage, most enzymes tolerated the presence of 5-ethynylU and two of them even the presence of 5-phenyl- and 5-(3-nitrophenyl)U. Modifications outside the recognition sequence were tolerated except in the case of phenyl derivatives with the PvuII enzyme. 5 EthynylC was used for protection of the recognition sequence from cleavage in the presence of the second unmodified copy of the same sequence that was cleaved. PMID- 21290546 TI - Neuronal differentiation of C17.2 neural stem cells induced by a natural flavonoid, baicalin. AB - Natural medicinal materials are a significant resource for the identification of compounds with specific biological properties. In this study, we employed multipotent C17.2 neural stem cells as a model for screening natural compounds that possess neural differentiation-inducing properties. We show here for the first time that, out of the 67 compounds tested, the flavonoid baicalin is a potent differentiation-inducing agent. Baicalin increased the number of cells bearing extended neurites and the expression levels of a number of neuronal markers. Importantly, baicalin promoted the expression of several key neurogenic transcriptional factors. Moreover, we demonstrated that baicalin enhanced the phosphorylation/activation of Erk1/2. Inhibition of Erk1/2 activation by the MEK inhibitor U0126 attenuated the neuronal differentiation-inducing effect of baicalin. Taken together, our findings suggest that baicalin induces neuronal differentiation of C17.2 neural stem cells and that this is mediated by activation of Erk1/2. Our work lays the foundation for exploring baicalin for the promotion of neural regeneration after injury or disease. PMID- 21290547 TI - Synthesis, evaluation, and mechanism of N,N,N-trimethyl-D-glucosamine-(1->4) chitooligosaccharides as selective inhibitors of glycosyl hydrolase family 20 beta-N-acetyl-D-hexosaminidases. AB - GH20 beta-N-acetyl-D-hexosaminidases are enzymes involved in many vital processes. Inhibitors that specifically target GH20 enzymes in pests are of agricultural and economic importance. Structural comparison has revealed that the bacterial chitindegrading beta-N-acetyl-D-hexosaminidases each have an extra +1 subsite in the active site; this structural difference could be exploited for the development of selective inhibitors. N,N,Ntrimethyl-D-glucosamine (TMG) chitotriomycin, which contains three GlcNAc residues, is a natural selective inhibitor against bacterial and insect beta-N-acetyl-D-hexosaminidases. However, our structural alignment analysis indicated that the two GlcNAc residues at the reducing end might be unnecessary. To prove this hypothesis, we designed and synthesized a series of TMG-chitotriomycin analogues containing one to four GlcNAc units. Inhibitory kinetics and molecular docking showed that TMG (GlcNAc)(2), is as active as TMG-chitotriomycin [TMG-(GlcNAc)(3)]. The selective inhibition mechanism of TMG-chitotriomycin was also explained. PMID- 21290548 TI - NMR studies of DOXP reductoisomerase and its inhibitor complex. AB - 1-Deoxy-D-xylulose 5-phosphate (DOXP) reductoisomerase (EC1.1.1.267) catalyses the second step of the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway of isoprenoid biosynthesis. The enzyme is used by most bacteria, apicomplexan parasites and the plastids of plants, but not by humans, and therefore represents an attractive target for antibacterial, antiparasitic and herbicidal compounds. Fosmidomycin, an inhibitor of DXR, has been found to be active against bacterial infections and malaria in early clinical studies. Here, we report sample optimisation, partial backbone assignment and secondary-structure prediction of E. coli DXR by heteronuclear NMR analysis for further NMR-aided drug discovery. Perdeuterated (15)N,(13)C-labelled samples were prepared under oxygen exclusion in the presence of Mg(2+), NADPH and the inhibitor FR-900098, a close derivative of fosmidomycin. (1)H and (15)N backbone assignment was achieved for 44 % of the primary structure, and (13)C backbone assignment was achieved for 50 % of the primary structure. Comparison with previously solved crystal structures revealed that the assigned fragments were located mainly in helical regions on the solvent exposed surface of the enzyme. Torsion angle likelihood obtained from shift and sequence similarity (TALOS) was used for secondary structure prediction, resulting in agreement with eight available crystal structures; deviations could be observed for the catalytic loop region. PMID- 21290549 TI - Identification of a napsamycin biosynthesis gene cluster by genome mining. AB - Napsamycins are potent inhibitors of bacterial translocase I, an essential enzyme in peptidoglycan biosynthesis, and are classified as uridylpeptide antibiotics. They comprise an N-methyl diaminobutyric acid, an ureido group, a methionine and two non-proteinogenic aromatic amino acid residues in a peptide backbone that is linked to a 5'-amino-3'-deoxyuridine by an unusual enamide bond. The napsamycin gene cluster was identified in Streptomyces sp. DSM5940 by using PCR probes from a putative uridylpeptide biosynthetic cluster found in S. roseosporus NRRL15998 by genome mining. Annotation revealed 29 hypothetical genes encoding for resistance, regulation and biosynthesis of the napsamycins. Analysis of the gene cluster indicated that the peptide core structure is assembled by a nonlinear non ribosomal peptide synthetase (NRPS)-like mechanism that involves several discrete single or didomain proteins. Some genes could be assigned, for example, to the synthesis of the N-methyl diaminobutyric acid, to the generation of m-tyrosine and to the reduction of the uracil moiety. The heterologous expression of the gene cluster in Streptomyces coelicolor M1154 resulted in the production of napsamycins and mureidomycins as demonstrated by LC-ESI-MS and MS/MS analysis. The napsamycin gene cluster provides a molecular basis for the detailed study of the biosynthesis of this class of structurally unusual compounds. PMID- 21290551 TI - Systematic screening for catalytic promiscuity in 4-oxalocrotonate tautomerase: enamine formation and aldolase activity. AB - The enzyme 4-oxalocrotonate tautomerase (4-OT) is part of a catabolic pathway for aromatic hydrocarbons in Pseudomonas putida mt-2, where it catalyzes the conversion of 2-hydroxy-2,4-hexadienedioate(1) to 2-oxo-3-hexenedioate(2). 4-OT is a member of the tautomerase superfamily, a group of homologous proteins that are characterized by a beta-alpha-beta structural fold and a catalytic amino terminal proline. In the mechanism of 4-OT, Pro1 is a general base that abstracts the 2-hydroxyl proton of 1 for delivery to the C-5 position to yield 2. Here, 4 OT was explored for nucleophilic catalysis based on the mechanistic reasoning that its Pro1 residue has the correct protonation state (pK(a) ~6.4) to be able to act as a nucleophile at pH 7.3. By using inhibition studies and mass spectrometry experiments it was first demonstrated that 4-OT can use Pro1 as a nucleophile to form an imine/enamine with various aldehyde and ketone compounds. The chemical potential of the smallest enamine (generated from acetaldehyde) was then explored for further reactions by using a small set of selected electrophiles. This systematic screening approach led to the discovery of a new promiscuous activity in wild-type 4-OT: the enzyme catalyzes the aldol condensation of acetaldehyde with benzaldehyde to form cinnamaldehyde. This low level aldolase activity can be improved 16-fold with a single point mutation (L8R) in 4-OT's active site. The proposed mechanism of the reaction mimicks that used by natural class-I aldolases and designed catalytic aldolase antibodies. An important difference, however, is that these natural and designed aldolases use the primary amine of a lysine residue to form enamines with carbonyl substrates, whereas 4-OT uses the secondary amine of an active-site proline as the nucleophile catalyst. Further systematic screening of 4-OT and related proline based biocatalysts might prove to be a useful approach to discover new promiscuous carbonyl transformation activities that could be exploited to develop new biocatalysts for carbon-carbon bond formation. PMID- 21290552 TI - Culprit or multivessel treatment for STEMI: the opinion of a repented principal investigator. PMID- 21290553 TI - Unfractionated versus low-molecular-weight heparin for primary angioplasty-More data suggesting to go low. PMID- 21290554 TI - Optimizing the impact of primary percutaneous coronary intervention in acute myocardial infarction. PMID- 21290555 TI - How to manage no reflow phenomenon with local drug delivery via a rapid exchange catheter. AB - We describe two cases of no reflow phenomenon in the setting of primary PCI for ST elevation myocardial infarction successfully managed with intracoronary vasodilator therapy via a ClearwayTM balloon catheter, where vasodilator therapy via the guiding catheter had been ineffective. Traditionally, if not given via the guiding catheter, vasodilators have been administered via an over-the-wire balloon catheter, which can be cumbersome and time consuming. The Clearway catheter is a rapid exchange balloon catheter affording rapid delivery of vasodilators to the distal infarct related artery without risk of loss of wire position. (c) 2010 Wiley-Liss, Inc. PMID- 21290556 TI - Think globally: Cath locally. PMID- 21290557 TI - Ventricular septal defect closure in a small children with the Amplatzer Duct Occluder II. AB - Transcatheter technique for muscular ventricular septal defect closure remains challenging, particularly in small patients. We report the successful use of the low profile Amplatzer Duct Occluder II for multiple ventricular septal defect closure in an infant with D-transposition of the great arteries, status postpulmonary artery banding. The multiple apical ventricular septal defects were successfully closed with two Amplatzer Duct Occluder II and one Amplatzer Muscular Ventricular Septal Defect Occluder during two interventional catheterizations. The patient subsequently underwent successful surgical repair. PMID- 21290558 TI - Techniques for successful leak repair. PMID- 21290559 TI - Transplant renal artery stenosis: what lessons should we learn? PMID- 21290560 TI - Mutual exchange promotes progress together. PMID- 21290561 TI - Migration of fractured renal artery stent. AB - An 80-year-old man received stent implantation for severe stenosis of the right renal artery. During the procedure, the proximal edge of the stent was successfully positioned at the ostium of the renal artery. After 6 months, follow up renal angiography showed transverse stent fracture without restenosis. The proximal part of the fractured stent had moved and protruded into the abdominal aorta. Three years later, the proximal part of the fractured stent had migrated from the renal artery to the wall of infrarenal aorta. This is the first reported case of stent migration of the renal artery caused by a complete transverse stent fracture. PMID- 21290562 TI - Oral clefts and maternal biomarkers of folate-dependent one-carbon metabolism in Utah. AB - BACKGROUND: Maternal folate intake and related biomarkers have been inconsistently associated with a risk of oral clefts. METHODS: Maternal concentrations of plasma folate (PF) and erythrocyte folate (EF), plasma pyridoxal-5'-phosphate (PLP; active vitamin B(6) ) and total plasma homocysteine (tHcy) were measured in a Utah study with 347 cases and 469 controls. RESULTS: Risk of all clefts combined, including cleft lip with or without cleft palate (CL/P) and cleft palate only (CP), was 65% lower in the highest versus lowest PF quartile (odds ratio [OR], 0.35; 95% confidence interval [CI], 0.23-0.53; p-trend < 0.001). Results remained significant in the subgroups with isolated CL/P and CP (p-trend < 0.001 in each). EF results were similar. In the highest versus lowest PLP quartile, risk of CP with other malformations was lower (OR, 0.25; 95% CI, 0.07-0.95); however, no other associations were significant for PLP or tHcy. Differences in mean biomarker levels between cases and controls widened with an increasing interval between delivery and maternal blood collection. Decreased cleft risk with increasing quartiles of PF, EF, and PLP and decreasing tHcy was more apparent in mothers with a longer versus shorter interval between the index child delivery and blood collection. CONCLUSION: Low maternal blood folate concentration was associated with an increased risk of clefts, and the differences in mean case and control PF, EF, PLP, and tHcy concentrations widened over time. Additional mechanistic studies are warranted to elucidate whether an acquired or inherited disorder of folate metabolism plays a role in the etiology of clefts. PMID- 21290563 TI - Functional effects of genetic polymorphisms in the N-acetyltransferase 1 coding and 3' untranslated regions. AB - BACKGROUND: The functional effects of N-acetyltransferase 1 (NAT1) polymorphisms and haplotypes are poorly understood, compromising the validity of associations reported with diseases, including birth defects and numerous cancers. METHODS: We investigated the effects of genetic polymorphisms within the NAT1 coding region and the 3'-untranslated region (3'-UTR) and their associated haplotypes on N- and O-acetyltransferase catalytic activities, and NAT1 mRNA and protein levels following recombinant expression in COS-1 cells. RESULTS: 1088T>A (rs1057126; 3' UTR) and 1095C>A (rs15561; 3'-UTR) each slightly reduced NAT1 catalytic activity and NAT1 mRNA and protein levels. A 9-bp (TAATAATAA) deletion between nucleotides 1065 and 1090 (3'-UTR) reduced NAT1 catalytic activity and NAT1 mRNA and protein levels. In contrast, a 445G>A (rs4987076; V149I), 459G>A (rs4986990; T153T), and 640T>G (rs4986783; S214A) coding region haplotype present in NAT1*11 increased NAT1 catalytic activity and NAT1 protein, but not NAT1 mRNA levels. A combination of the 9-bp (TAATAATAA) deletion and the 445G>A, 459G>A, and 640T>G coding region haplotypes, both present in NAT1*11, appeared to neutralize the opposing effects on NAT1 protein and catalytic activity, resulting in levels of NAT1 protein and catalytic activity that did not differ significantly from the NAT1*4 reference. CONCLUSIONS: Because 1095C>A (3'-UTR) is the sole polymorphism present in NAT1*3, our data suggest that NAT1*3 is not functionally equivalent to the NAT1*4 reference. Furthermore, our findings provide biologic support for reported associations of 1088T>A and 1095C>A polymorphisms with birth defects. PMID- 21290565 TI - Comment on maternal alcohol consumption--Re: "Cryptorchidism and hypospadias as a sign of testicular dysgenesis syndrome: environmental connection". PMID- 21290564 TI - Association of common variants in ERBB4 with congenital left ventricular outflow tract obstruction defects. AB - BACKGROUND: The left ventricular outflow tract (LVOT) defects aortic valve stenosis (AVS), coarctation of the aorta (COA), and hypoplastic left heart syndrome (HLHS) represent an embryologically related group of congenital cardiovascular malformations. They are common and cause substantial morbidity and mortality. Prior evidence suggests a strong genetic component in their causation. METHODS: We selected NRG1, ERBB3, and ERBB4 of the epidermal growth factor receptor (EGFR) signaling pathway as candidate genes for investigation of association with LVOT defects based on the importance of this pathway in cardiac development and the phenotypes in knockout mouse models. Single nucleotide polymorphism (SNP) genotyping was performed on 343 affected case-parent trios of European ancestry. RESULTS: We identified a specific haplotype in intron 3 of ERBB4 that was positively associated with the combined LVOT defects phenotype (p=0.0005) and in each anatomic defect AVS, COA, and HLHS separately. Mutation screening of individuals with an LVOT defect failed to identify a coding sequence or splice site change in ERBB4. RT-PCR on lymphoblastoid cells from LVOT subjects did not show altered splice variant ratios among those homozygous for the associated haplotype. CONCLUSION: These results suggest ERBB4 is associated with LVOT defects. Further replication will be required in separate cohorts to confirm the consistency of the observed association. PMID- 21290567 TI - Importance of including all pregnancy outcomes to reduce bias in epidemiologic studies of neural tube defects--Texas, 1999 to 2005. AB - BACKGROUND: Neural tube defects (NTDs) often result in fetal death or elective termination; therefore, not all cases are captured in typical hospital-based surveillance. We examined sociodemographic differences among pregnancy outcomes to assess sources of bias in NTD surveillance and research. METHODS: We used 1999 to 2005 Texas Birth Defects Registry data, a population-based active surveillance system, and calculated crude and adjusted prevalence ratios (aPRs). We then assessed the association of anencephaly and spina bifida with the selected characteristics, stratified by pregnancy outcomes (fetal death, elective termination, or live birth). RESULTS: Data were available for 1852 NTD cases (anencephaly, 677; spina bifida, 954; and encephalocele, 221), resulting in 1211 live births, 236 fetal deaths, and 405 elective terminations. For both anencephaly and spina bifida, a significant excess of Hispanic mothers was observed among live-birth cases (aPRs=1.2-2.4), but not among mothers experiencing other pregnancy outcomes. Mothers of anencephaly cases resulting in a non-live birth were more likely to be adolescents (aPRs=2.4-2.7 for ages<20 years old vs. ages 25-29 years old), but this pattern was not observed for live birth cases. A trend of increasing anencephaly risk with increasing parity was demonstrated only among fetal-death cases. For spina bifida, mothers of fetal death (but not live-birth) cases were less likely to live along the Texas-Mexico border (aPR=0.30). CONCLUSIONS: Demographic differences across NTD pregnancy outcomes exist and are a potential source of bias. Inclusion of all pregnancy outcomes in NTD surveillance is vital in NTD monitoring and research. PMID- 21290568 TI - Dynamics of Polycomb and Trithorax activities during development. AB - Dynamic changes in gene expression are tightly controlled during development, as a single totipotent zygote gives rise to distinct cell lineages. The establishment and maintenance of these diverse transcriptional programs rely on changes of chromatin state, mainly through histone modifications. Polycomb and Trithorax complexes participate in setting apart active and inactive genes by respectively repressing and activating key developmental regulators in different cell types. Over the last decade, our understanding of the biochemical mechanisms underlying their activities has greatly improved, but the signals targeting these proteins to specific regions of the genome are still poorly understood, particularly in vertebrates. Recent findings highlight the highly dynamic activities of Polycomb and Trithorax complexes in vivo. Surprisingly, although their role in transcriptional regulation is deeply conserved during evolution, the time sequence in which they act seems to vary across species. PMID- 21290569 TI - Comparative study between tissue-engineered periosteum and structural allograft in rabbit critical-sized radial defect model. AB - The purpose of this study was to compare the efficacy of tissue-engineered periosteum (TEP) to allgeneic bone in repairing segmental bone defect. TEP was fabricated with osteoinduced rabbit bone marrow mesenchymal stem cells (MSCs) and porcine small intestinal submucosa (SIS). Allogrfats were cryopreserved radial segments of New Zealand Rabbits. Forty-eight radial critical-sized defects (CSD) were bilaterally produced in 24 rabbits. The defects were divided into three groups, group A, TEP implantation, group B, SIS implantation, and group C allograft. Bone defect reconstruction was kinetically analyzed at 4, 8, and 12 weeks by radiographic and histological scoring system. In group A, bone defects were radiographically and histologically healed with mature cortex and marrow cavity by 12 weeks, while none of the defects healed in group B. Group C showed a slow process of creeping substitution with lymphocyte infiltration. Statistical comparison confirmed that group A had a more efficient and rapid bone defect reparation as well as remodelling than Group B and C. In conclusion, TEP is superior to structural allograft in reconstruction of allogenic segmental bone defect. Pure SIS cannot guide bone regeneration in this rabbit model. PMID- 21290570 TI - Osteogenic differentiation of human adipose-derived stem cells induced by osteoinductive calcium phosphate ceramics. AB - Microstructure is indispensable for the osteoinduction of calcium phosphate ceramics. To study how microstructure takes its role and explore the mechanism of the osteoinduction, we evaluated attachment, proliferation, alkaline phosphatase (ALP)/DNA, protein/DNA, and mineralization of human adipose-derived stem cells cultured on two kinds of biphasic calcium phosphate (BCP) ceramic discs with the same chemistry and dimension, but different microporosity and surface area. BCP-A had been found osteoinductive in vivo while BCP-B was not. During the conventional culture, ALP/DNA and protein/DNA of the cell on BCP-A with larger surface area were significantly higher than those of the cells on BCP-B. With the adsorption of the proteins in culture medium with 50% fetal bovine serum (FBS) in advance, the increments of the ALP/DNA and protein/DNA for the BCP-A were found respectively significantly more than the increments of those for BCP-B, suggesting that the larger amount of protein adsorbed on the BCP-A was crucial. More results showed that ALP/DNA and protein/DNA of the cells on the two kinds of discs presoaked in culture medium having additional rhBMP-2 were found to be both higher than those of the cells on the discs resoaked in culture medium with 50% FBS, and that those values for BCP-A increased much more. Furthermore, larger mineral content was found on BCP-A than on BCP-B at day 7. The results indicated that by increasing microporosity and thus surface areas, osteoinductive calcium phosphate ceramics concentrate more proteins, including bone-inducing proteins, and thereafter stimulate inducible cells in soft tissues to form inductive bone. PMID- 21290571 TI - Hyaluronic acid nanofiber wound dressing--production, characterization, and in vivo behavior. AB - Hyaluronic acid (HA) was electrospun. The effects of flow rate, spin length, and the applied voltage on the diameter of the HA nanofibers were analyzed. The average thickness of the webs was 0.041 cm. The air permeability of sterilized HA nanofiber wound dressing was much higher than that of gauze with Vaseline. The degree of crystallinity of HA nanofibers was characterized using powder X-ray technique and was found to be 20.6%. A preclinical study was conducted to compare healing of wounds covered by an adhesive bandage, a sterilized solid HA, gauze with Vaseline, an antibiotic dressing, and a sterilized HA nanofiber wound dressing. Results of the two methods of appraisal showed that the sterilized HA nanofiber wound dressing was the best type of dressing out of the five types of dressings compared. PMID- 21290572 TI - Microstructure and drug-release studies of sirolimus-containing poly(lactide-co glycolide) films. AB - Sirolimus-containing poly(lactide-co-glycolide) (PLGA) films were prepared by solution casting and removing the residual solvent, 1,4-dioxane, by liquid and supercritical carbon dioxide (CO(2) ) extraction. The effect of lactide:glycolide ratio, stereochemistry of PLGA, and extraction condition (i.e., temperature and pressure) on the polymer and drug morphologies was studied using wide-angle X-ray scattering and differential scanning calorimetry. The polymer and drug crystallinity increased after liquid and supercritical CO(2) extraction, and the level of drug crystallinity within the film depended on the extraction conditions. Generally, higher levels of drug crystallinity were observed in the films with amorphous polymer matrices, and the drug crystallinity increased with temperature and pressure of the extraction conditions. In vitro drug elution from these films was studied using a USP 4 apparatus. Polymer crystallinity was found to be the determining factor for drug release, whereby films with higher polymer crystallinity eluted less drug compared to films with amorphous polymer matrices. PMID- 21290573 TI - Silver/hydroxyapatite composite coatings on porous titanium surfaces by sol-gel method. AB - Hydroxyapatite (HA) coatings loaded with nanosilver particles is an attractive method to impart the HA coating with antibacterial properties. Producing Ag/HA coatings on porous Ti substrates have been an arduous job since commonly used line-of-sight techniques are not able to deposit uniform coatings on the inner pore surfaces of the porous Ti. In this study, porous Ti scaffolds with high porosity and interconnected structures were prepared by polymer impregnating method. A sol-gel process was used to produce uniform Ag/HA composite coatings on the surfaces of porous Ti substrates. Ca(NO(3) )(2) .4H(2) O and P(2) O(5) in an ethyl alcohol based system was selected to prepare the sol, which ensured the homogeneous distribution of Ag in the sol. The characterization revealed that silver particles uniformly distributed in the coatings without agglomeration. High antibacterial ratio (>95%), against E. coli and S. albus was expressed by the silver-containing coatings (Ag/HA 0.8 and 1.6 wt %). The biocompatibility of the Ag/HA 0.8 surfaces was as good as that of pure HA surface, as revealed by culturing osteoblasts on them. The results indicated that Ag/HA 0.8 had the good balance between the biocompatibility and antibacterial properties of the coatings. PMID- 21290574 TI - Dysregulation of monocytic cytokine secretion by endodontic sealers. AB - Recent studies have reported that sealers may alter the secretion of specific cytokines from THP1 monocytic cells in vitro. In this study, a cytokine array was used to determine if endodontic sealers changed secretion of 42 cytokines. White mineral trioxide aggregate (WMTA), MTA preparation (CS), AH-Plus (AHP), and Pulp Canal Sealer (PCS) were mixed, allowed to set for 72 h, then "aged" in buffered saline for 12 weeks. Aged specimens were placed in direct contact with THP1 for 72 h and their cytotoxicity (MTT assay) was assessed. Materials that were not severely toxic were then exposed to THP1 with or without lipolysaccharide (LPS), and the culture medium was assayed for cytokine secretion. Secretion of cytokines was quantified using infrared scanning (Odyssey((r))); replicate pairs were averaged. PCS severely suppressed MTT activity and was not assessed for its influence on cytokine secretion. WMTA, CS, and AHP induced a broad-based increase in cytokine secretion (>20% vs. Teflon controls), but AHP induced the greatest increase (>100% in 17 of 42 cytokines). The effects of the sealers on LPS activated THP1 were biphasic, with some increases and decreases cytokine secretion of >20%, but few larger effects. This work shows endodontic sealers may alter the secretion of a broad cross section of cytokines from monocytic cells. PMID- 21290575 TI - Development of a biodegradable tissue adhesive based on functionalized 1,2 ethylene glycol bis(dilactic acid). II. AB - In body regions where damage and bleeding must be avoided, a substitute for mechanical tissue fixation by sutures or staplers is needed. Since tissue adhesives provide easy and fast handling they are a promising alternative. The present study reports the development and analysis of a tissue adhesive that consists of two adhesive components: hexamethylene diisocyanate (HDI) functionalized 1,2-ethylene glycol bis(dilactic acid) (ELA-NCO) and chitosan chloride. This composition was chosen based on preliminary studies on several chain elongation agents. The present study evaluates this adhesive system by IR spectroscopy, tensile tests, and gel point measurements in comparison to fibrin glue. The system's in vitro biocompatibility was tested with mouse fibroblasts (L929) according to ISO 10993-5. Furthermore, an implantation study was performed in SPF-Wistar rats. The adhesive strength of manually applied mixtures or mixtures applied by double chamber syringes with a mixing extruder was determined to be significantly higher than that of fibrin glue on bovine muscle tissue at 37 degrees C. Tensile strength increased further when exposure time of the adhesive was increased from 10 min to 48 h. The rheological gel point determination showed that the mixture of ELA-NCO/DMSO and chitosan chloride offers a time window large enough to readjust the fused joint during surgery, as opposed to fibrin glue. Additionally, the in vitro and in vivo biocompatibility studies of the adhesive system revealed no toxic effects on the surrounding tissue. PMID- 21290576 TI - Understanding preventable hospital readmissions: masqueraders, markers, and true causal factors. PMID- 21290577 TI - Unplanned transfers to a medical intensive care unit: causes and relationship to preventable errors in care. AB - BACKGROUND: Unplanned intensive care unit (ICU) transfers may result from errors in care but the frequency of their occurrence, and whether these transfers might be prevented, has not been investigated. OBJECTIVE: To determine why unplanned transfers occur, what fraction results from errors in care, whether they are preceded by changes in clinical status and if so, whether earlier or different responses might prevent the transfers. DESIGN: Retrospective study. SETTING: University-affiliated hospital. PATIENTS: All patients 18 to 89 years with unplanned transfers to the medical ICU from June 1, 2005 to May 30, 2006. INTERVENTION: None. MEASUREMENTS: Demographics, admission and transfer diagnoses, clinical triggers preceding the transfer, mortality, judgment by three reviewers about cause of transfer and whether it could have been prevented. RESULTS: A total of 152 patients had unplanned transfers. The most common reasons were worsening of the problem for which the patient was admitted (48%) and development of a new problem (39%). Errors in care accounted for 29 transfers (19%), 15 of which were due to incorrect triage at the time of admission, and 14 due to iatrogenic errors. Of the 14 iatrogenic errors, the investigators determined that eight transfers might have been prevented by an earlier intervention. Agreement among the three reviewers was moderate to almost perfect (kappa 0.55-0.90). CONCLUSIONS: Although 19% of unplanned transfers to medical ICUs are associated with errors in care, almost 80% of these seem to be preventable. Most of the preventable errors resulted from inappropriate admission triage. PMID- 21290579 TI - Intra-hospital transfers to a higher level of care: contribution to total hospital and intensive care unit (ICU) mortality and length of stay (LOS). AB - BACKGROUND: Patients who experience intra-hospital transfers to a higher level of care (eg, ward to intensive care unit [ICU]) are known to have high mortality. However, these findings have been based on single-center studies or studies that employ ICU admissions as the denominator. OBJECTIVE: To employ automated bed history data to examine outcomes of intra-hospital transfers using all hospital admissions as the denominator. DESIGN: Retrospective cohort study. SETTING: A total of 19 acute care hospitals. PATIENTS: A total of 150,495 patients, who experienced 210,470 hospitalizations, admitted to these hospitals between November 1st, 2006 and January 31st, 2008. MEASUREMENTS: Predictors were age, sex, admission type, admission diagnosis, physiologic derangement on admission, and pre-existing illness burden; outcomes were: 1) occurrence of intra-hospital transfer, 2) death following admission to the hospital, 3) death following transfer, and 4) total hospital length of stay (LOS). RESULTS: A total of 7,868 hospitalizations that began with admission to either a general medical surgical ward or to a transitional care unit (TCU) had at least one transfer to a higher level of care. These hospitalizations constituted only 3.7% of all admissions, but accounted for 24.2% of all ICU admissions, 21.7% of all hospital deaths, and 13.2% of all hospital days. Models based on age, sex, preadmission laboratory test results, and comorbidities did not predict the occurrence of these transfers. CONCLUSIONS: Patients transferred to higher level of care following admission to the hospital have excess mortality and LOS. PMID- 21290580 TI - Scheduled admissions and high occupancy at a children's hospital. AB - BACKGROUND: High hospital occupancy is a challenge for quality of care and access, while low levels of occupancy may be inefficient in terms of resource utilization. Variability from scheduling decisions may affect occupancy and be amenable to alteration. OBJECTIVE: Describe variability in admission, discharge, and occupancy patterns at a large children's hospital and assess the relationship between scheduled admissions and occupancy. DESIGN: Retrospective administrative data analysis. SETTING: One urban, tertiary-care children's hospital. PATIENTS: A total of 22,310 consecutive patients admitted from July 1, 2007 to June 30, 2008. MEASUREMENTS: Admission-discharge-transfer (ADT) data for 1 fiscal year were abstracted for analysis of admission and occupancy patterns. RESULTS: Among 22,310 admissions, 78% were coded as emergent and 22% as scheduled. Variation in admission volume by day of week was high for scheduled admissions (coefficient of variation [CV] 65.3%), while it was more consistent for emergent admissions (CV 12.0%). For patients with length of stay (LOS) <= 7 days (84%), Mondays and Tuesdays generated 45.2% of scheduled patient hours. Wednesdays and Thursdays had the highest frequency of high occupancy. CONCLUSIONS: Scheduled admissions contribute significantly to variability in occupancy and risk of mid-week crowding. Predictable patterns of admissions lead to high occupancy on some days and unused capacity on others, which can be addressed with proactive management of admissions (eg, greater use of unused capacity on weekends and in summer). Hospitals interested in optimizing patient flow should assess their admission and occupancy patterns. Further studies should link variation in occupancy to outcomes including quality of care, educational activities, and staff satisfaction. PMID- 21290581 TI - The ritual: death pronouncement. AB - BACKGROUND: Death pronouncement comes infrequently for the pediatrician. The place of death for most children is in the hospital. For hospitalists and pediatric intensivists in the neonatal intensive care or pediatric intensive care units, death pronouncement is not uncommon. For hospitalist physicians, the call to attend a code or to pronounce a death may come on any given shift and from almost anywhere in the hospital. CONCLUSION: A demonstrative case is provided, followed by key concepts for practice and for educating trainees. PMID- 21290582 TI - In the face of it all. PMID- 21290583 TI - Pregabalin-induced trismus in a leukemia patient. PMID- 21290584 TI - Reflections on Haiti: the role of hospitalists in disaster response. PMID- 21290585 TI - Preparation and properties of nano-hydroxyapatite/PCL-PEG-PCL composite membranes for tissue engineering applications. AB - Nano-hydroxyapatite (n-HA)/poly(epsilon-caprolactone)-poly(ethylene glycol) poly(epsilon-caprolactone) (PCL-PEG-PCL, PCEC) composite membranes were prepared by solvent casting and evaporation method. The structure and properties of the membranes were investigated by Fourier transform infrared spectroscopy (FT-IR), X ray diffraction (XRD), scanning electron microscopy (SEM), water contact angle measurements, in vitro hydrolytic degradation, mechanical test, and cell culture. The effect of n-HA content on physical-chemical properties of the n-HA/PCEC composite membranes was studied. The results showed that the shape and size of micropores of the composite membranes changed with n-HA content increased; the tensile strength decreased with the increase of n-HA content. The osteoblast cell was cultured on the membranes, good cell attachment and growth manner were observed after postseeding for 1 day. MTT assays showed that the n-HA/PCEC membranes had no negative effect on the cell viability and proliferation. These results suggested that the obtained n-HA/PCEC composite membranes in this study might have prospective applications in tissue engineering field. PMID- 21290586 TI - Optically based-indentation technique for acute rat brain tissue slices and thin biomaterials. AB - Currently, micro-indentation testing of soft biological materials is limited in its capability to test over long time scales due to accumulated instrumental drift errors. As a result, there is a paucity of measures for mechanical properties such as the equilibrium modulus. In this study, indentation combined with optical coherence tomography (OCT) was used for mechanical testing of thin tissue slices. OCT was used to measure the surface deformation profiles after placing spherical beads onto submerged test samples. Agarose-based hydrogels at low-concentrations (w/v, 0.3-0.6%) and acute rat brain tissue slices were tested using this technique over a 30-min time window. To establish that tissue slices maintained cell viability, allowable testing times were determined by measuring neuronal death or degeneration as a function of incubation time with Fluor-Jade C (FJC) staining. Since large deformations at equilibrium were measured, displacements of surface beads were compared with finite element elastic contact simulations to predict the equilibrium modulus, MU(infinity) . Values of MU(infinity) for the low-concentration hydrogels ranged from 0.07 to 1.8 kPa, and MU(infinity) for acute rat brain tissue slices was 0.13 +/- 0.04 kPa for the cortex and 0.09 +/- 0.015 kPa for the hippocampus (for Poisson ratio = 0.35). This indentation technique offers a localized, real-time, and high resolution method for long-time scale mechanical testing of very soft materials. This test method may also be adapted for viscoelasticity, for testing of different tissues and biomaterials, and for analyzing changes in internal structures with loading. PMID- 21290587 TI - Preliminary in vivo study of apatite and laminin-apatite composite layers on polymeric percutaneous implants. AB - A polymeric material coated with a hydroxyapatite (HA) layer would be useful as a flexible percutaneous device with good biocompatibility and resistance to bacterial infection. We have recently developed a simple, safe, and mild coating process to form an HA layer on the surfaces of polymeric materials. In this study, our coating process was applied to an ethylene-vinyl alcohol copolymer film. The resulting HA-coated film was percutaneously implanted in the scalp of a rat to examine the stability and biocompatibility of the HA layer. From the results of histological analysis, the HA layer remained undissolved on the film surface under the skin tissue even 3 days after implantation. Owing to the good biocompatibility of HA, the HA-coated film suppressed a host's foreign-body response and integrated with the surrounding skin tissue for as long as 14 days, in a similar fashion to a conventional percutaneous device composed of ceramic HA. Immobilization of a cell adhesion protein, laminin, into the HA layer was found to improve the adhesion strength between the film and the surrounding skin tissue without compromising good biocompatibility of HA. Our coating process to form HA and laminin-HA composite layers would be useful in fabricating polymeric percutaneous devices with a reduced risk of bacterial infection, although further in vivo studies are required. PMID- 21290588 TI - Bacterial cellulose as a potential vascular graft: Mechanical characterization and constitutive model development. AB - Bacterial cellulose (BC) is a polysaccharide produced by Acetobacter Xylinum bacteria with interesting properties for arterial grafting and vascular tissue engineering including high-burst pressure, high-water content, high crystallinity, and an ultrafine highly pure fibrous structure similar to that of collagen. Given that compliance mismatch is one of the main factors contributing to the development of intimal hyperplasia in vascular replacement conduits, an in depth investigation of support mechanical properties of BC is required to further supporting its use in cardiovascular-grafting applications. The aim of this study was to mechanically characterize BC and also study its potential to accommodate vascular cells. To achieve these aims, inflation tests and uniaxial tensile tests were carried out on BC samples. In addition, dynamic compliance tests were conducted on BC tubes, and the results were compared to that of arteries, saphenous vein, expanded polytetrafluoroethylene, and Dacron grafts. BC tubes exhibited a compliance response similar to human saphenous vein with a mean compliance value of 4.27 * 10(-2) % per millimeter of mercury over the pressure range of 30-120 mmHg. In addition, bovine smooth muscle cells and endothelial cells were cultured on BC samples, and histology and fluorescent imaging analysis were carried out showing good adherence and biocompatibility. Finally, a method to predict the mechanical behavior of BC grafts in situ was established, whereby a constitutive model for BC was determined and used to model the BC tubes under inflation using finite element analysis. PMID- 21290589 TI - Integration of cellulases into bacterial cellulose: Toward bioabsorbable cellulose composites. AB - Cellulose biodegradation resulting from enzymolysis generally occurs in nature rather than in the human body because of the absence of cellulose degrading enzymes. In order to achieve in-vivo degradation in human body for in-vivo tissue regeneration applications, we developed a bioaborbable bacterial cellulose (BBC) material, which integrates one or more cellulose degrading enzymes (cellulases), and demonstrated its degradability in vitro using buffers with pH values relevant to wound environments. We introduced a double lyophilizing process to retain the microstructure of the bacterial cellulose as well as the activity of embedded enzymes allowing for long-term storage of the material, which only requires hydration before use. Enzymes and their combinations have been examined to optimize the in-vitro degradation of the BBC material. In-vitro studies revealed that acidic cellulases from Trichoderma viride showed reasonable activity for pH values ranging from 4.5 to 6.0. A commercial cellulase (cellulase-5000) did not show good activity at pH 7.4, but its degrading ability increased when used in conjunction with a beta-glucosidase from Bacillus subtilis or a beta-glucosidase from Trichoderma sp. Given the harmless glucose product of the enzymatic degradation of cellulose, the BBC material may be ideal for many wound care and tissue engineering applications for the bioabsorbable purpose. PMID- 21290590 TI - In situ formation of silver nanoparticles in photocrosslinking polymers. AB - Nanocomposites of cross-linked methacrylate polymers with silver nanoparticles have been synthesized by coupling photoinitiated free radical polymerization of dimethacrylates with in situ silver ion reduction. A polymerizable methacrylate bearing a secondary amino functional group was used to increase the solubility of the silver salt in the hydrophobic resin system. Fourier transform infrared spectroscopy (FTIR) revealed that the silver ion reduction had no significant effect on the degree of vinyl conversion of the methacrylate. X-ray photoelectron spectroscopy (XPS) measurements showed an increased silver concentration at the composite surface compared to the expected concentration based on the total amount of silver salt added. Furthermore, the surface silver concentration leveled off when the silver salt mass fractions were 0.08% or greater. Composites with low concentrations of silver salt (< 0.08% by mass) exhibited comparable mechanical properties to those containing no silver. Transmission electron microscopy (TEM) confirmed that the silver nanoparticles formed within the polymer matrix were nanocrystalline in nature and primarily ~ 3 nm in diameter, with some large particle aggregates. Composites containing silver nanoparticles were shown to reduce bacterial colonization with as little as 0.03% (by mass) silver salt, while additional amounts of silver salt did not further decrease their surface colonization. With a substantial effect on bacterial growth and minimal effects on mechanical properties, the in situ formation of silver nanoparticles within methacrylate materials is a promising technique for synthesizing antibacterial nanocomposites for biomedical applications. PMID- 21290591 TI - In vitro assessment of strength, fatigue durability, and disassembly of Ti6Al4V and CoCrMo necks in modular total hip replacements. AB - Modularity in total hip replacement offers advantages with regard to biomechanical adjustments and leg lengths. Recently, modular femoral necks were introduced as an added advantage to head modularity permitting further adjustments in femoral version as well as offset and ease of revision. Currently, most necks are made of Ti6Al4V for which cases of in vivo fractures and inseparable neck-stem junctions have been reported. Therefore, we investigated CoCrMo head-Ti6Al4V stem hip replacements with necks made of CoCrMo as an alternative to Ti6Al4V. We compared the two materials with respect to (1) compressive load bearing capacity; (2) fatigue durability; and (3) component distraction. We performed in vitro fatigue-pull-off, microscopy, fatigue durability and compression investigations. The CoCrMo neck showed a load bearing capacity of 18 kN, 38% higher than 13 kN for the Ti6Al4V neck. A fatigue load of 11.2 kN for 1 million cycle failure was achieved with CoCrMo translating into nearly 1000 times longer fatigue life compared to Ti6Al4V necks. The neck-stem distraction force showed large statistical variation and was similar for both neck materials. Overall, the results suggest a superiority of CoCrMo over Ti6Al4V as neck material with regard to mechanical behavior. However, the corrosion behavior was not appropriately assessed and necessitates additional investigations. PMID- 21290592 TI - In vivo biological performance of a novel highly bioactive glass-ceramic (Biosilicate(r)): A biomechanical and histomorphometric study in rat tibial defects. AB - This study aimed to investigate bone responses to a novel bioactive fully crystallized glass-ceramic of the quaternary system P(2)O(5)-Na(2)O-CaO-SiO(2) (Biosilicate(r)). Although a previous study demonstrated positive effects of Biosilicate(r) on in vitro bone-like matrix formation, its in vivo effect was not studied yet. Male Wistar rats (n = 40) with tibial defects were used. Four experimental groups were designed to compare this novel biomaterial with a gold standard bioactive material (Bioglass(r) 45S5), unfilled defects and intact controls. A three-point bending test was performed 20 days after the surgical procedure, as well as the histomorphometric analysis in two regions of interest: cortical bone and medullary canal where the particulate biomaterial was implanted. The biomechanical test revealed a significant increase in the maximum load at failure and stiffness in the Biosilicate(r) group (vs. control defects), whose values were similar to uninjured bones. There were no differences in the cortical bone parameters in groups with bone defects, but a great deal of woven bone was present surrounding Biosilicate(r) and Bioglass(r) 45S5 particulate. Although both bioactive materials supported significant higher bone formation; Biosilicate(r) was superior to Bioglass(r) 45S5 in some histomorphometric parameters (bone volume and number of osteoblasts). Regarding bone resorption, Biosilicate(r) group showed significant higher number of osteoclasts per unit of tissue area than defect and intact controls, despite of the non-significant difference in the osteoclastic surface as percentage of bone surface. This study reveals that the fully crystallized Biosilicate(r) has good bone-forming and bone bonding properties. PMID- 21290593 TI - Correlating hypoxia with insulin secretion using a fluorescent hypoxia detection system. AB - A common obstacle to the survival of encapsulated tissue is oxygen insufficiency. This appears particularly true of encapsulated pancreatic beta-cells. Our work investigates a fluorescent hypoxia detection system for early recognition of hypoxic stress in encapsulated pancreatic tissue. Murine insulinoma (MIN6) cells were engineered to produce a red fluorescent protein under the control of hypoxia inducible-factor-1. Aggregates of these cells were encapsulated in poly(ethylene glycol) hydrogels at densities of 200,000, 600,000, and 1 million cells per capsule then incubated in either a 1% or 20% oxygen environment. Cell function was evaluated by daily measurement of glucose-stimulated insulin secretion. Encapsulated cells were also fluorescently imaged periodically over 72 h for expression of the marker signal. Results indicate that oxygen insufficiency severely impacts insulin release from MIN6 cells, and that large aggregates are especially vulnerable to oxygen limitations. Our marker was found to be successfully indicative of hypoxia and could be used as a predictor of subsequent insulin release. Further work will be required to fully characterize signal dynamics and to evaluate in vivo efficacy. The method presented here represents a unique and valuable approach to detecting hypoxic stress in living tissues which may prove useful to a variety of fields of biological research. PMID- 21290594 TI - Porous hydroxyapatite and gelatin/hydroxyapatite microspheres obtained by calcium phosphate cement emulsion. AB - Hydroxyapatite and hybrid gelatine/hydroxyapatite microspheres were obtained through a water in oil emulsion of a calcium phosphate cement (CPC). The setting reaction of the CPC, in this case the hydrolysis of alpha-tricalcium phosphate, was responsible for the consolidation of the microspheres. After the setting reaction, the microspheres consisted of an entangled network of hydroxyapatite crystals, with a high porosity and pore sizes ranging between 0.5 and 5 MUm. The size of the microspheres was tailored by controlling the viscosity of the hydrophobic phase, the rotation speed, and the initial powder size of the CPC. The incorporation of gelatin increased the sphericity of the microspheres, as well as their size and size dispersion. To assess the feasibility of using the microspheres as cell microcarriers, Saos-2 cells were cultured on the microspheres. Fluorescent staining, SEM studies, and LDH quantification showed that the microspheres were able to sustain cell growth. Cell adhesion and proliferation was significantly improved in the hybrid gelatin/hydroxyapatite microspheres as compared to the hydroxyapatite ones. PMID- 21290595 TI - A pH-sensitive chitosan-tripolyphosphate hydrogel beads for controlled glipizide delivery. AB - A chitosan(CS)-tripolyphosphate (TPP) hydrogel bead was prepared by the ionic gelation method for the controlled delivery of glipizide. The structure and surface morphology of the beads were characterized by FT-IR and SEM, separately. Factors influencing the swelling behavior of the hydrogel beads were also investigated, such as CS concentration (X(1)), TPP concentration (X(2)), the weight ratio of drug to polymer (X(3)), crosslinking time (X(4)), and the volume ratio of CS to TPP (X(5)). In addition, the swelling property and the delivery behavior of the hydrogel bead was studied as well. With decreasing of pH value, the swelling ratio of the bead was increasing. The swelling ratio of hydrogel bead at pH 1.5 was relatively high, while this value was low at pH 6.8. The amount of glipizide released from the hydrogel bead at pH 1.5 was about 90%, while this value approached 36% at pH 6.8. The results clearly suggested that the CS-TPP hydrogel beads were used as a pH-sensitive controlled release system for the delivery of glipizide. PMID- 21290597 TI - Intact mammalian cell function on semiconductor nanowire arrays: new perspectives for cell-based biosensing. AB - Nanowires (NWs) are attracting more and more interest due to their potential cellular applications, such as delivery of compounds or sensing platforms. Arrays of vertical indium-arsenide (InAs) NWs are interfaced with human embryonic kidney cells and rat embryonic dorsal root ganglion neurons. A selection of critical cell functions and pathways are shown not to be impaired, including cell adhesion, membrane integrity, intracellular enzyme activity, DNA uptake, cytosolic and membrane protein expression, and the neuronal maturation pathway. The results demonstrate the low invasiveness of InAs NW arrays, which, combined with the unique physical properties of InAs, open up their potential for cellular investigations. PMID- 21290598 TI - Structured graphene devices for mass transport. AB - The reversible atomic-mass transport along graphene devices has been achieved. The motion of Al and Au in the form of atoms or clusters is driven by applying an electric field between the metal electrodes that contact the graphene sheet. It is shown that Al moves in the direction of the applied electric field whereas Au tends to diffuse in all directions. The control of the motion of Al is further demonstrated by achieving a 90 degrees turn, using a graphene device patterned in a crossroads configuration. The controlled motion of Al is attributed to the charge transfer from Al onto the graphene so that the Al is effectively charged and can be accelerated by the applied electric field. To get further insight into the actuation mechanism, theoretical simulations of individual Al and Au impurities on a perfect graphene sheet were performed. The direct (electrostatic) force was found to be ~1 pN and dominant over the wind force. These findings hold promise for practical use in future mass transport in complex circuits. PMID- 21290599 TI - Ball-milling modification of single-walled carbon nanotubes: purification, cutting, and functionalization. AB - Single-walled carbon nanotubes (SWNTs) can be successfully cut with relatively homogeneous sizes using a planetary mill. The optimized conditions produce highly dispersible SWNTs that can be efficiently functionalized in a variety of synthetic ways. As clearly shown by Raman spectroscopy, the milling/cutting procedure compares very favorably with the most common way of purifying SWNTs, namely, treatment with strong oxidizing acids. Moreover a similar milling process can be used to functionalize and cut pristine SWNTs by one-step nitrene chemistry. PMID- 21290600 TI - Ultrafast large-area micropattern generation in nonabsorbing polymer thin films by pulsed laser diffraction. AB - An ultrafast, parallel, and beyond-the-master micropatterning technique for ultrathin (30-400 nm) nonabsorbing polymer films by diffraction of laser light through a 2D periodic aperture is reported. The redistribution of laser energy absorbed by the substrate causes self-organization of polymer thin films in the form of wrinklelike surface relief structures caused by localized melting and freezing of the thin film. Unlike conventional laser ablation and laser writing processes, low laser fluence is employed to only passively swell the polymer as a pre-ablative process without loss of material, and without absorption/reaction with incident radiation. Self-organization in the thin polymer film, aided by the diffraction pattern, produces microstructures made up of thin raised lines. These regular microstructures have far more complex morphologies than the mask geometry and very narrow line widths that can be an order of magnitude smaller than the openings in the mask. The microstructure morphology is easily modulated by changing the film thickness, aperture size, and geometry, and by changing the diffraction pattern. PMID- 21290601 TI - Location of biomarkers and reagents within agarose beads of a programmable bio nano-chip. AB - The slow development of cost-effective medical microdevices with strong analytical performance characteristics is due to a lack of selective and efficient analyte capture and signaling. The recently developed programmable bio nano-chip (PBNC) is a flexible detection device with analytical behavior rivaling established macroscopic methods. The PBNC system employs ~300 MUm-diameter bead sensors composed of agarose "nanonets" that populate a microelectromechanical support structure with integrated microfluidic elements. The beads are an efficient and selective protein-capture medium suitable for the analysis of complex fluid samples. Microscopy and computational studies probe the 3D interior of the beads. The relative contributions that the capture and detection of moieties, analyte size, and bead porosity make to signal distribution and intensity are reported. Agarose pore sizes ranging from 45 to 620 nm are examined and those near 140 nm provide optimal transport characteristics for rapid (<15 min) tests. The system exhibits efficient (99.5%) detection of bead-bound analyte along with low (~2%) nonspecific immobilization of the detection probe for carcinoembryonic antigen assay. Furthermore, the role analyte dimensions play in signal distribution is explored, and enhanced methods for assay building that consider the unique features of biomarker size are offered. PMID- 21290602 TI - Enhancement of cellulolytic enzyme activity by clustering cellulose binding domains on nanoscaffolds. AB - Cellulose, one of the most abundant carbon resources, is degraded by cellulolytic enzymes called cellulases. Cellulases are generally modular proteins with independent catalytic and cellulose-binding domain (CBD) modules and, in some bacteria, catalytic modules are noncovalently assembled on a scaffold protein with CBD to form a giant protein complex called a cellulosome, which efficiently degrades water-insoluble hard materials. In this study, a catalytic module and CBD are independently prepared by recombinant means, and are heterogeneously clustered on streptavidin and on inorganic nanoparticles for the construction of artificial cellulosomes. Heteroclustering of the catalytic module with CBD results in significant improvements in the enzyme's degradation activity for water-insoluble substrates. In particular, the increase of CBD valency in the cluster structure critically enhances the catalytic activity by improving the affinity for substrates, and clustering with multiple CBDs on CdSe nanoparticles generates a 7.2-fold increase in the production of reducing sugars relative to that of the native free enzyme. The multivalent design of substrate-binding domain on clustered cellulases is important for the construction of the artificial cellulosome, and the nanoparticles are an effective scaffold for increasing the valence of CBD in clustered cellulases. A new design is proposed for artificial cellulosomes with multiple CBDs on noncellulosome-derived scaffold structures. PMID- 21290603 TI - Orthogonal array design for the optimization of ionic liquid-based dispersive liquid-liquid microextraction of benzophenone-type UV filters. AB - In the present study, dispersive liquid-liquid microextraction (DLLME) using an ionic liquid (IL) as the extractant was successfully developed to extract four benzophenone-type UV filters from the different water matrices. Orthogonal array experimental design (OAD), based on five factors and four levels (L(16)(4(5))), was employed to optimize IL-dispersive liquid-liquid microextraction procedure. The five factors included pH of sample solution, the volume of IL and methanol addition, extraction time and the amount of salt added. The optimal extraction condition was as follows. Sample solution was at a pH of 2.63 in the presence of 60 mg/mL sodium chloride; 30 MUL IL and 15 MUL methanol were used as extractant and disperser solvent, respectively; extraction was achieved by vortexing for 4 min. Using high-performance liquid chromatography-UV analysis, the limits of detection of the target analytes ranged between 1.9 and 6.4 ng/mL. The linear ranges were between 10 or 20 ng/mL and 1000 ng/mL. This procedure afforded a convenient, fast and cost-saving operation with high extraction efficiency for the model analytes. Spiked waters from two rivers and one lake were examined by the developed method. For the swimming pool water, the standard addition method was employed to determine the actual concentrations of the UV filters. PMID- 21290604 TI - Ionic liquid stationary phases for gas chromatography. AB - This article provides a summary of the development of ionic liquids as stationary phases for gas chromatography beginning with early work on packed columns that established details of the retention mechanism and established working methods to characterize selectivity differences compared with molecular stationary phases through the modern development of multi-centered cation and cross-linked ionic liquids for high-temperature applications in capillary gas chromatography. Since there are many reviews on ionic liquids dealing with all aspects of their chemical and physical properties, the emphasis in this article is placed on the role of gas chromatography played in the design of ionic liquids of low melting point, high thermal stability, high viscosity, and variable selectivity for separations. Ionic liquids provide unprecedented opportunities for extending the selectivity range and temperature-operating range of columns for gas chromatography, an area of separation science that has otherwise been almost stagnant for over a decade. PMID- 21290606 TI - Proteomics reviews 2011. PMID- 21290607 TI - Molecular logic gate arrays. AB - Chemists are now able to emulate the ideas and instruments of mathematics and computer science with molecules. The integration of molecular logic gates into small arrays has been a growth area during the last few years. The design principles underlying a collection of these cases are examined. Some of these computing molecules are applicable in medical- and biotechnologies. Cases of blood diagnostics, 'lab-on-a-molecule' systems, and molecular computational identification of small objects are included. PMID- 21290608 TI - The legacy of fossil fuels. AB - Currently, over 80% of the energy used by mankind comes from fossil fuels. Harnessing coal, oil and gas, the energy resources contained in the store of our spaceship, Earth, has prompted a dramatic expansion in energy use and a substantial improvement in the quality of life of billions of individuals in some regions of the world. Powering our civilization with fossil fuels has been very convenient, but now we know that it entails severe consequences. We treat fossil fuels as a resource that anyone anywhere can extract and use in any fashion, and Earth's atmosphere, soil and oceans as a dump for their waste products, including more than 30 Gt/y of carbon dioxide. At present, environmental legacy rather than consistence of exploitable reserves, is the most dramatic problem posed by the relentless increase of fossil fuel global demand. Harmful effects on the environment and human health, usually not incorporated into the pricing of fossil fuels, include immediate and short-term impacts related to their discovery, extraction, transportation, distribution, and burning as well as climate change that are spread over time to future generations or over space to the entire planet. In this essay, several aspects of the fossil fuel legacy are discussed, such as alteration of the carbon cycle, carbon dioxide rise and its measurement, greenhouse effect, anthropogenic climate change, air pollution and human health, geoengineering proposals, land and water degradation, economic problems, indirect effects on the society, and the urgent need of regulatory efforts and related actions to promote a gradual transition out of the fossil fuel era. While manufacturing sustainable solar fuels appears to be a longer-time perspective, alternatives energy sources already exist that have the potential to replace fossil fuels as feedstocks for electricity production. PMID- 21290609 TI - Reactive adsorption of NO2 at ambient conditions on iron-containing polymer-based porous carbons. AB - Adsorption of NO(2) and retention of NO (the product of NO(2) reduction by carbon) on iron-containing materials prepared from polystyrenesulfonic acid-co maleic acid iron salt were studied. The surface of the materials was characterized using nitrogen adsorption, XRD, scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy-dispersive X-ray (EDX), and FTIR spectroscopy, and thermogravimetric analysis (TGA). The results showed the positive effects of the pore volume and well-dispersed iron species (Fe(2)O(3), FeSO(4), and FeS) on the performance of carbons as NO(2) adsorbents at room temperature. The retention of NO(2) on the carbon surface takes place either through its reduction to NO by carbon and/or by Fe(2)O(3), FeSO(4), and FeS, or through its reaction with Fe(2)O(3) and/or Fe(OH)(3), leading to the formation of Fe(NO(3))(3). The retention of NO is enhanced on carbons containing iron in the form of alpha-FeOOH, alpha-Fe(2)O(3), or gamma-FeOOH. The best performance was found on the carbon with alpha-Fe(2)O(3). Dispersion and the particle size of iron compounds on the carbon surface affect both the adsorption/reduction process of NO(2) and the retention process of NO. PMID- 21290610 TI - Regulatory volume decrease and P receptor signaling in fish cells: mechanisms, physiology, and modeling approaches. AB - For animal cell plasma membranes, the permeability of water is much higher than that of ions and other solutes, and exposure to hyposmotic conditions almost invariably causes rapid water influx and cell swelling. In this situation, cells deploy regulatory mechanisms to preserve membrane integrity and avoid lysis. The phenomenon of regulatory volume decrease, the partial or full restoration of cell volume following cell swelling, is well-studied in mammals, with uncountable investigations yielding details on the signaling network and the effector mechanisms involved in the process. In comparison, cells from other vertebrates and from invertebrates received little attention, despite of the fact that e.g. fish cells could present rewarding model systems given the diversity in ecology and lifestyle of this animal group that may be reflected by an equal diversity of physiological adaptive mechanisms, including those related to cell volume regulation. In this review, we therefore present an overview on the most relevant aspects known on hypotonic volume regulation presently known in fish, summarizing transporters and signaling pathways described so far, and then focus on an aspect we have particularly studied over the past years using fish cell models, i.e. the role of extracellular nucleotides in mediating cell volume recovery of swollen cells. We, furthermore, present diverse modeling approaches developed on the basis of data derived from studies with fish and other models and discuss their potential use for gaining insight into the theoretical framework of volume regulation. PMID- 21290611 TI - Development of the genital duct system in the protandrous black porgy, Acanthopagrus schlegeli. AB - Protandrous black porgies, Acanthopagrus schlegeli, have a striking life cycle, which includes early sex differentiation, bisexual gonads, and a male-to-female sex change at three years of age. We found novel features of and insights into the development of the genital duct system in relation to the gonadal stage during early gonadal development and natural sex change. We found that the genital ducts developed at 16-20 weeks of age during sex differentiation. The gonad developed "ovarian cavity cracks" and became "four-stranded" during the first prespawning period and then proceeded to the development of genital ducts before 1 year of age. Two ovarian cavities of the paired gonads combined, developed, and extended caudally to form the oviduct, making up the inner duct of the genital ducts. The testicular main cavities also extended and fused together to form the outer duct of the genital duct system, that is, the sperm duct. The coexistence of an outer sperm duct and an inner oviduct constituted a unique "double cannula genital duct" structure. Gradually the inferior walls of the oviduct intermingled with those of the sperm duct, and the circular lumen of the sperm duct changed into an "M-shaped canal." Finally, the sperm duct and oviduct separated completely at the distal part of genital duct system. During natural sex change, the male reproductive passage regressed and degenerated and was replaced by connective tissue. The oviduct arrested as a blunt end during male phase and, finally, extended and connected to the genital pore during the female phase. PMID- 21290612 TI - Occipital ossification of balaenopteroid mysticetes. AB - The bones of the posterior portion of the mammalian skull often exhibit incomplete ossification of the joints between the bones at the time of birth, with complete ossification at some point after birth. The sequence of ossification of these joints in mysticetes can be used to characterize the relative age in the calf and early juvenile ontogenetic stages. This study examined occipital joints ossification of 38 dry prepared neonate specimens in four mysticete species from two families (Eschrichtiidae: Eschrichtius robustus; Balaenopteridae: Balaenoptera acutorostrata, Balaenoptera physalus, and Megaptera novaeangliae). Each of the joints responsible for the fusion of the occiput were examined and rated for degree of ossification. The cranial ossification analysis indicates that E. robustus calves have open occipital joints until ~6 months of age and are born at a less mature stage than closely related balaenopterids. All of the species followed the same sequence of ossification: basioccipital/exoccipital joint, followed by the basioccipital/basisphenoid joint, and completed by the supraoccipital/exoccipital joint. PMID- 21290613 TI - Toward comprehensive analysis of the galectin network in chicken: unique diversity of galectin-3 and comparison of its localization profile in organs of adult animals to the other four members of this lectin family. AB - Characterization of all members of a gene family established by gene divergence is essential to delineate distinct or overlapping expression profiles and functionalities. Their activity as potent modulators of diverse physiological processes directs interest to galectins (endogenous lectins with beta-sandwich fold binding beta-galactosides and peptide motifs), warranting their study with the long-term aim of a comprehensive analysis. The comparatively low level of complexity of the galectin network in chicken with five members explains the choice of this organism as model. Previously, the three proto-type chicken galectins CG-1A, CG-1B, and CG-2 as well as the tandem-repeat-type CG-8 had been analyzed. Our study fills the remaining gap to determine gene structure, protein characteristics and expression profile of the fifth protein, that is, chimera type chicken galectin-3 (CG-3). Its gene has a unique potential to generate variants: mRNA production stems from two promoters, alternative splicing of the form from the second transcription start point (tsp) can generate three mRNAs. The protein with functional phosphorylation sites in the N-terminus generated by transcription from the first tsp (tsp1CG-3) is the predominant CG-3 type present in adult tissues. Binding assays with neoglycoproteins and cultured cells disclose marked similarity to properties of human galectin-3. The expression and localization profiles as well as proximal promoter regions have characteristic features distinct from the other four CGs. This information on CG-3 completes the description of the panel of CGs, hereby setting the stage for detailed comparative analysis of the entire CG family, e.g., in embryogenesis. PMID- 21290614 TI - Use of two sulfonthalein dyes in the extraction-free spectrophotometric assay of tramadol in dosage forms and in spiked human urine based on ion-pair reaction. AB - Tramadol is a centrally acting analgesic used in the prevention and treatment of moderate to severe pain. Two sensitive, selective, and rapid spectrophotometric methods are described for the determination of tramadol in its dosage forms and in spiked human urine. The methods are based on formation of yellow ion-pairs between tramadol and two sulfonthalein dyes; bromocresol purple (BCP) and bromocresol green (BCG) in dichloromethane medium followed by absorbance measurement at 400 and 410 nm, respectively. Under the optimum conditions, tramadol could be assayed in the concentration ranges, 1-15 and 1-16 ug ml(-1) with correlation coefficient greater than 0.999 in both cases. The molar absorptivity values are calculated to be 1.84 * 10(4) and 1.97 * 10(4) l mol(-1) cm(-1) for BCP and BCG methods, respectively; and the corresponding Sandell sensitivity values are 0.0143 and 0.0134 ug cm(-2). The limits of detection (LOD) and quantification (LOQ) have also been reported. The stoichiometry of the reaction was found to be 1:1 in both cases and the conditional stability constant (K(f)) values of the ion pairs have been calculated. The within-day and between day RSD were 0.9-1.96% and 1.56-3.21%, respectively. The methods were successfully applied to the determination of tramadol in tablets and injections and also in spiked human urine with good recoveries. The procedures are simple, accurate, and suitable for quality control application. PMID- 21290615 TI - Risk factors for current wheezing and its phenotypes among elementary school children. AB - BACKGROUND: Accumulating evidence suggests, asthma includes many phenotypes with varying clinical and prognostic features. Epidemiological surveys documented a number of environmental risk factors for the development of asthma and interestingly these differ between and within countries, suggesting that the differences may be related with the different distribution of asthma phenotypes. This study aimed to investigate risk factors of current wheezing (CW) and different wheezing phenotypes in elementary school children. METHODS: Six thousand nine hundred sixty-three 9- to 11-year-old children of a previous multicenter survey where the methodology of the International Study of Asthma and Allergies in Childhood (ISAAC) Phase-II was used were analyzed. Wheezing phenotypes were defined as wheezing with rhinitis (RW), wheezing with rhinoconjunctivitis (RCW), atopic wheezing (AW), non-atopic wheezing (NAW), and frequent wheezing (FW) (>=4/year wheezing episodes). RESULTS: The prevalence of CW was 15.8% and among these, 22.4%, 67.3%, 45.9%, 20.5%, and 79.5% were classified as FW, RW, RCW, AW, and NAW, respectively. History of parental asthma/allergic rhinitis, coexistence of other allergic diseases, presence of mold and dampness in the house lived during the first year of life and maternal smoking in pregnancy were found to be risk factors for most phenotypes (odds ratio (OR) ranged from 1.43 to 3.56). Number of household in the last year (OR = 1.14), prematurity (OR = 2.08), and duration of breastfeeding (OR = 1.02) per additional month were found to be risk factor for FW, AW, and RCW, respectively. CONCLUSION: Beside common risk factors for the development of asthma and its phenotypes, certain risk factors appeared to play a role in the development of phenotypic characteristics of asthma. These findings support our hypothesis that each phenotype has not only different clinical characteristics but also has different roots. PMID- 21290616 TI - Determination of yeast viability during a stress-model alcoholic fermentation using reagent-free microscopy image analysis. AB - A dedicated microscopy imaging system including automated positioning, focusing, image acquisition, and image analysis was developed to characterize a yeast population with regard to cell morphology. This method was used to monitor a stress-model alcoholic fermentation with Saccharomyces cerevisiae. Combination of dark field and epifluorescence microscopy after propidium iodide staining for membrane integrity showed that cell death went along with important changes in cell morphology, with a cell shrinking, the onset of inhomogeneities in the cytoplasm, and a detachment of the plasma membrane from the cell wall. These modifications were significant enough to enable a trained human operator to make the difference between dead and viable cells. Accordingly, a multivariate data analysis using an artificial neural network was achieved to build a predictive model to infer viability at single-cell level automatically from microscopy images without any staining. Applying this method to in situ microscope images could help to detect abnormal situations during a fermentation course and to prevent cell death by applying adapted corrective actions. PMID- 21290617 TI - Use of a centrifugal bioreactor for cartilaginous tissue formation from isolated chondrocytes. AB - Although a centrifugal bioreactor (CCBR) supports high-density mammalian suspension cell cultures by balancing drag, buoyancy, and centrifugal forces, to date anchorage-dependent cultures have not been tried. Also, steady or intermittent hydrostatic pressures of 8 to 500 kPa, and shears of 0.02 to 1.4 N/m(2) can be simultaneously applied in the CCBR. This article demonstrates the use of a CCBR to stimulate chondrogenesis in a high-density culture. At 3 weeks, histological results show even distribution of glycosaminoglycan (GAG) and collagen, with 1,890 +/- 270 cells/mm(2) cell densities that exceed those of 1,470 +/- 270 in pellet cultures. Analysis of collagen content reveals similar levels for all treatment groups; 6.8 +/- 3.5 and 5.0 +/- 0.4 MUg collagen/MUg DNA for 0.07 and 0.26 MPa CCBR cultures, respectively, in contrast to 6.6 +/- 1.9 values for control pellet cultures. GAG levels of 5.6 +/- 1.5 and 4.1 +/- 0.9 MUg GAG /MUg DNA are present for cultures stressed at 0.07 and 0.26 MPa, respectively, in comparison to control pellet cultures at the 8.4 +/- 0.9 level. Although results to date have not revealed mechanical stress combinations that stimulate chondrogenesis over unstressed controls, system advantages include continuous culture at cell densities above those in the pellet, precise medium control, the ability to independently vary multiple mechanical stresses over a broad range, and the flexibility for integration of scaffold features for future chondrogenesis stimulation studies. PMID- 21290789 TI - Clinical roundtable monograph. Current management and treatment of T-cell lymphoma: A multidisciplinary approach. PMID- 21290790 TI - Melanoma and viagra: an unexpected connection. PMID- 21290791 TI - Needs of women with breast cancer as communicated to physicians on the Internet. AB - PURPOSE: With improved access to health information via the Internet, an increasing number of women with breast cancer are using this venue to obtain information about their illness and treatment from physicians. This study aims to identify the needs of women with breast cancer who communicate with physicians on the Internet. METHODS: From a total of 4,424 requests posted by Korean women with breast cancer to a physician run Internet Q&A board during 2003 to 2007, we sampled 1,355 representative requests according to different type of online user identification and analyzed these using a qualitative content analytic approach to identify the nature of the requests. RESULTS: The vast majority of women (93.5%) used the online Q&A board to seek informational support from physicians. They requested information across a broad range of topics, including treatment (38.4% of requests), physical condition (31.7%), and lifestyle/self-care (24%).Women at different disease stages made requests indifferent informational domains. Few (<5%) postings were direct requests for emotional support, but emotional requests were often embedded within informational requests. Over 63% of requests expressed concern and worry, and about 75% of the requests included at least one emotional expression. There was no difference by type of online user identification with respect to the subject and purpose of the requests. CONCLUSIONS: Korean women with breast cancer expressed diverse needs related to their physical and psychological conditions in their online requests to physicians via a Q&A board. While future research should establish and evaluate the role of internet communications for cancer management,we conclude that an online Q&A board can be a valuable tool in assisting breast cancer patients in managing their physical and psychosocial needs as well as communicating these needs to physicians. PMID- 21290792 TI - Reform programme. What Dorrell says matters, and his message to the NHS is clear. PMID- 21290793 TI - Commissioning. PCT talent to be assigned to consortia. PMID- 21290795 TI - Andrew Murrison on the military covenant. PMID- 21290794 TI - Dorrell: the 'main game' is delivering efficiency. PMID- 21290796 TI - Our lives in the detectives' hands. PMID- 21290797 TI - GP commissioning. Making a difference. PMID- 21290798 TI - Service integration. Bringing it all back home. PMID- 21290799 TI - Efficiency. PCTs make slow progress with QIPP. PMID- 21290800 TI - Transforming community services. PCTs step closer to deciding fate of their provider arms. PMID- 21290801 TI - Paul Corrigan on the pace of evolution. PMID- 21290802 TI - I feel like we're being watched. PMID- 21290803 TI - Pathology. Get the test value for your money. PMID- 21290804 TI - Principles of patient assessment. PMID- 21290805 TI - Male intermittent self catheterisation. PMID- 21290806 TI - Problem solving. PMID- 21290807 TI - Irregular practices. Wide variations found in use of heart implants. PMID- 21290808 TI - WHIO unites key stakeholders in effort to improve health care quality, safety, affordability. PMID- 21290809 TI - Allocations. SHAs to retain 2 per cent of PCT cash to pay for change. PMID- 21290810 TI - White Paper. Key details added to reform plan. PMID- 21290811 TI - Commissioning. DH figures show pathfinder GPs are set to bust budgets. PMID- 21290812 TI - John Deffenbaugh on a survival plan for non-foundations. PMID- 21290813 TI - The big chill will hit medics too. PMID- 21290814 TI - Circle prize for inspiring innovation. The outstanding ideas that will transform healthcare. PMID- 21290815 TI - Wellbeing at work. Aiming for that personal podium. PMID- 21290816 TI - Human resources. Don't forget the carrots. PMID- 21290817 TI - The politics of partnerships: a study of police and housing collaboration to tackle anti-social behaviour on Australian public housing estates. AB - This paper draws on the findings from a research project on partnership arrangements between the police and housing departments on three Australian public housing estates to tackle problems associated with illicit drug activity and anti-social behaviour (ASB). The analysis focused on the setting up of the partnerships and the interactions that followed from these institutional arrangements. The assumption that informs the paper is that when studying partnerships there is a need for a more critically framed analysis. The temptation to posit "a successful model" of what partnership entails and then to judge practices in relation to this model is considerable, but it inevitably falls into the trap of constructing a narrative of partnership success or failure in terms of individual agency (that is, the degree of commitment from individuals). The analysis undertaken in this paper has therefore sought to fathom a more complex set of organizational processes. Rather than confine the discussion to issues of success and failure, the study foregrounds the subjective accounts of individuals who work within partnership and the constraints they encounter. The paper therefore makes explicit the cultural tensions within and across agencies, contestation as to the extent of the policy "problem," and the divergent perspectives on the appropriate modes of intervention. PMID- 21290818 TI - Acting discursively: the development of UK organic food and farming policy networks. AB - This paper documents the early evolution of UK organic food and farming policy networks and locates this empirical focus in a theoretical context concerned with understanding the contemporary policy-making process. While policy networks have emerged as a widely acknowledged empirical manifestation of governance, debate continues as to the concept's explanatory utility and usefulness in situations of network and policy transformation since, historically, policy networks have been applied to "static" circumstances. Recognizing this criticism, and in drawing on an interpretivist perspective, this paper sees policy networks as enacted by individual actors whose beliefs and actions construct the nature of the network. It seeks to make links between the characteristics of the policy network and the policy outcomes through the identification of discursively constructed "storylines" that form a tool for consensus building in networks. This study analyses the functioning of the organic policy networks through the discursive actions of policy-network actors. PMID- 21290819 TI - [DNA polymerases beta and lambda, and their roles in the DNA replication and repair]. AB - One of the key stages of life of a cell is genome duplication. The main enzymes which lead this process are DNA-dependent DNA polymerases. At the moment, 19 DNA polymerases with striking properties are listed in the eukaryotic cells. Mitochondrial DNA polymerase gamma from A family and most of the nuclear enzymes from B family are high fidelity DNA polymerases which are participate in genome DNA replication process as well as in DNA repair. Among the other 1 5 proteins, the D N A polymerases belonging to the X and Y families have a special place. They participate in a different repair processes such as base excision repair and non-homologous end joining. Moreover, some of them play a specific role in the replication of the damaged DNA templates. This process is referred as translesion synthesis or TLS. The DNA polymerases beta and lambda members of X family are enclosed in polyfunctional enzymes, and their properties and functions will be discussed in this review. PMID- 21290820 TI - [Chromatin structure and transcription regulation in Saccharomyces cerevisiae]. AB - Nucleosome organization of eukaryotic chromatin determines the DNA availability for regulatory factors during transcription. Nucleosome positioning at promoters is an important factor effecting gene expression. Recent studies showed that yeast promoters can be divided in two groups with the different chromatin organization. It has become clear that genes with the similar chromatin structure in promoters are regulated by the same mechanisms. In this review, using Saccharomyces cerevisiae as example, we discuss interplay between chromatin structure and transcription, dynamic changes in chromatin during transcription and a role of various factors (histone chaperones, remodeling complexes, histone variant H2A.Z) in these processes. PMID- 21290821 TI - [Polymorphism in the human 2'-5'-oligoadenylate synthetase genes (OAS), associated with predisposition to severe forms of tick-borne encephalitis, in populations from North Eurasia]. AB - 2'-5'-oligoadenylate synthetases are a family of interferon-induced enzymes which play an important role in the antiviral defense in mammals. In human genome three genes encoding functional synthetases (OAS1, OAS2 and OAS3) form a cluster. Previously we found that particular genotypes and/or alleles of five single nucleotide polymorphisms (SNPs) located within OAS2 and OAS3 genes are associated with predisposition to severe forms of tick-borne encephalitis (TBE) in Russian population. In current study we investigated the distribution of three of that SNPs (OAS3rs2285932 (C/T Ile438Ile), OAS3rs2072136 (G/A, Ser567Ser) and OAS2 rs15895 (G/A, Trp720Ter relative to p71 isoform)) in seven populations from North Eurasia: Caucasians (Russians and Germans (from Altai region)), Central Asian Mongoloids (Altaians, Khakasses, Tuvinians and Shorians) and Arctic Mongoloids (Chukchi). Differences between populations in genotype, allele and haplotype frequencies and in linkage disequilibrium structure for these SNPs were detected. We found that these frequencies correlate with the ethnicity of the populations and with their supposed differential exposure to TBE virus. Particularly, the lowest frequencies of G/G genotype for OAS3 gene rs2072136 SNP (that according to our previously obtained data is associated with predisposition to severe forms of TBE) were found in Altaians, Khakasses, Tuvinians and Shorians who may highly contact with TBE virus in places of their habitation. Thus, data obtained allow to suppose that TBE virus might act as a selection factor for particular OAS genes variants in Central Asian Mongoloids. PMID- 21290822 TI - [The phylogeny of Schistidium (Bryophyta, Grimmiaceae) based on primary and secondary structure study of nuclear rDNA internal transcribed spacers]. AB - The phylogeny of Schistidium (Bryophyta, Grimmiaceae) was studied on the basis of nucleotide sequences of internal transcribed spacers ITS1-2 of nuclear DNA and trnT-trnD region of chloroplast DNA. The consistency of phylogenetic trees constructed from nuclear and chloroplast sequences was shown. A basal grade and two large clades were resolved on the phylogenetic trees. Morphological characteristics specific for these clades were described. ITS1 and ITS2 secondary structures of Schistidium species were modeled using thermodynamic criteria. Four different structures of the longest ITS1 hairpin were identified. Possible paths of Schistidium evolution were considered based on the four types of ITS1 secondary structure and phylogenetic trees. PMID- 21290823 TI - [The protein complex Ppz1p/Hal3p and nonsense suppression efficiency in the yeast Saccharomyces cerevisiae]. AB - It is known that nonsense suppression efficiency in yeast is controlled both genetically and epigenetically. As many components of translation machinery are represented by phosphoproteins, it depends, in particular, on the activity of kinases and phosphatases. The Ppz1p/Hal3p complex is among them. In this complex, the Ppz1p phosphatase is a catalytic subunit and Hal3p negatively regulates its function. The aim of this work was to study mechanisms which relate the activity of Ppz1p/Hal3p complex to nonsense suppression efficiency. In this study we used a genetic approach consisting of the analysis of nonsense suppression phenotype of strains over-expressing HAL3 or PPZ1 genes and also bearing deletions or mutant alleles of genes which presumably could participate in the manifestation of these over-expressions. We have shown that Hal3p inhibits not only Ppz1p, but also the homologous phosphatase Ppz2p. Our data indicate that Ppz2p is also involved in the control of nonsense suppression efficiency. In the course of search for Ppz1p target protein, it was shown that Ppz1p dephosphorylates at least two proteins participating in translation. Moreover, Ppz1p affects nonsense suppression efficiency not only due to its phosphatase activity but also due to another mechanism triggered by its interaction with Hsp70 chaperones. PMID- 21290824 TI - [Mitochondrial genetic apparatus functioning in mice spleen cells under radiation induced apoptosis]. AB - An important role of mitochondria in the process of programmed cell death is widely accepted now. There is a set of nuclear-encoded mitochondrial proteins involved in this process. Apart from this, a mitochondrion contains its own genetic apparatus comprising mtDNA and replication, transcription, and translation systems. However, a mechanism of mitochondria genetic information realization under apoptosis-inducing conditions has been understood poorly. Here, using the real-time PCR technique the number of mitochondrial genes and their transcripts in mouse spleen cells after whole-body X-ray irradiation at the dosage of 10 Gy has been evaluated. During 5 h after the irradiation a nuclear DNA was subjected to fragmentation, whereas mtDNA remained intact. Moreover, in the course of time after irradiation the number of mtDNA copies increased threefold. A process of mtDNA transcription was more susceptible to the irradiation: in 1 h after exposure the number of ND2, ND4 and CYTB gene transcripts were sharply decreased. In 24 and 72 h after the irradiation the amount of ND2 and ND4 transcripts was restored to the control values, while the CYTB one remained low; the number of ATP6 transcripts was compared with the control within the whole period of observation. The difference in levels of mRNAs for the genes transcribed under the control of the same promoter for mice to be grown both under normal conditions and after x-ray irradiation allows us to propose the existing a posttranscriptional mechanism which regulates expression of mitochondrial genes and provides different recovery rates for different mitochondrial transcripts at the development of apoptosis. PMID- 21290825 TI - [Production of the recombinant human bone morphogenetic protein-2 in Escherichia coli and testing of its biological activity in vitro and in vivo]. AB - Bone morphogenetic protein-2 (rhBMP-2) represents the osteoinductive protein factor which plays a dominant role in growth and regeneration of a bone tissue. In clinical practice the bone grafting materials on the basis of rhBMP-2 are widely applied; the Russian analogues of similar materials are not produced. The fragment of the bmp2gene coding for a mature protein was cloned in Escherichia coli. The effective overproducing strain of rhBMP-2 was created on a basis of the E. coli BL21 (DE3). The rhBMP-2 production was about 25% of total cell protein. The biologically active dimeric form of rhBMP-2 was obtained by isolation and purification of protein from inclusion bodies with subsequent refolding. The rhBMP-2 sample with more than 80% of the dimeric form was obtained, which is able to interact with specific antibodies to BMP-2. Biological activity of the received rhBMP-2 samples was shown in the in vitro experiments by induction of alkaline phosphatase synthesis in C2C12 and C3H10T1/2 cell cultures. On model of the ectopic osteogenesis it was shown that received rhBMP-2 possesses biological activity in vivo, causing tissue calcification in the place of an injection. The protein activity in vivo depends on way of protein introduction and characteristics of protein sample: rhBMP-2 may be introduced in an acid or basic buffer solution, with or without the carrier. The offered method of rhBMP-2 isolation and purification results in increasing common protein yield as well as the maintenance of biologically active dimeric form in comparison with the analogues described in the literature. PMID- 21290826 TI - [The interaction of NS3 protein of hepatitis C virus with polymethylen derivatives of nucleic bases]. AB - NS3 protein of hepatitis C virus plays the key role in the virus functioning. It possesses three enzymatic activities, namely protease activity, associated with N terminal domain of the protein, and helicase/NTPase activities specific for C terminal domain. Here, the effect of some polimethylenic derivatives of the nucleic bases on helicase and ATPase enzyme activities has been studied. Several of compounds tested displayed inhibitory activity towards NS3 helicase. However, most compounds demonstrated strong activating effect on ATPase activity of the enzyme as well as several other ATPases. The ATPase activating mechanism was not described earlier. The activation potency of the compounds depended on substrate/activator concentration ratio, and was maximal at the 1000:1. The activation mechanism scheme that allows us to explain phenomena observed is proposed. PMID- 21290827 TI - [Modeling spatial structures of variola and cowpox virus TNF-binding CrmB proteins bound to murine or human TNF]. AB - Orthopoxviruses bear in their genomes several genes coding for homologous secreted proteins able to bind tumor necrosis factor. Different species of the genus possess different sets of these tumor necrosis factor-binding proteins. Viriola virus encodes the only one of them named CrmB. Despite sharing high sequence identity, CrmB proteins belonging to distinct orthopoxviral species were shown to significantly differ by their physico-chemical and biological properties. We modeled spatial structures of tumor necrosis factor receptor domains of variola and cowpox virus CrmB proteins bound to either murine, or human or mutated human tumor necrosis factor. In the sequence of last the arginine residue at position 31 is substituted with glutamine that is characteristic for murine tumor necrosis factor. Theoretical analysis of modeled ligand-receptor complexes revealed that the least stable should be the complex of cowpox virus CrmB with human tumor necrosis factor, and that arginine to glutamine substitution at position 31 should significantly stabilize binding of corresponding human tumor necrosis factor mutant to cowpox virus CrmB. Experimental evaluation of recombinant variola and cowpox virus CrmB efficiencies in inhibiting cytotoxic effect of all these tumor necrosis factors have approved our predictions. PMID- 21290828 TI - [NMR structure and dynamics of the chimeric protein SH3-F2]. AB - For the further elucidation of structural and dynamic principles of protein self organization and protein-ligand interactions the design of new chimeric protein SH3-F2 was made and genetically engineered construct was created. The SH3-F2 amino acid sequence consists of polyproline ligand mgAPPLPPYSA, GG linker and the sequence of spectrin SH3 domain circular permutant S19-P20s. Structural and dynamics properties of the protein were studied by high-resolution NMR. According to NMR data the tertiary structure of the chimeric protein SH3-F2 has the topology which is typical of SH3 domains in the complex with the ligand, forming polyproline type II helix, located in the conservative region of binding in the orientation II. The polyproline ligand closely adjoins with the protein globule and is stabilized by hydrophobic interactions. However the interaction of ligand and the part of globule relative to SH3 domain is not too large because the analysis of protein dynamic characteristics points to the low amplitude, high frequency ligand tumbling in relation to the slow intramolecular motions of the main globule. The constructed chimera permits to carry out further structural and thermodynamic investigations of polyproline helix properties and its interaction with regulatory domains. PMID- 21290829 TI - [Optimization of the methods for small peptide solution structure determination by NMR spectroscopy]. AB - NMR spectroscopy was recognized as a method of protein structure determination in solution. However, determination of the conformation of small peptides, which undergo fast molecular motions, remains a challenge. This is mainly caused by impossibility to collect required quantity of the distance and dihedral angle restraints from NMR spectra. At the same time, short charged peptides play an important role in a number of biological processes, in particular in pathogenesis of neurodegenerative diseases including Alzheimer's disease. Therefore development of a method for structure calculation of small peptides in a water environment using the most realistic force fields seems to be of current importance. Such algorithm has been developed using the Amber-03 force field and software package Gromacs after updating its program code. The algorithm of calculation has been verified on a model peptide for which the solution structure is known, and on the metal binding fragment of rat beta-amyloid for which structure has been determined by alternative methods. The developed algorithm substantially increases quality of structures, in particular Ramachandran plot statistics, and decreases RMSD of coordinates of atoms inside calculated family. The described protocol of calculation can be used for determination of conformation of short peptides, and also for structure optimization of larger proteins containing poorly structured fragments. PMID- 21290830 TI - [Dysphagia after stroke treated with acupuncture or electric stimulation: a randomized controlled trial]. AB - OBJECTIVE: To compare the therapeutic effects between acupuncture and electric stimulation on post-stroke dysphagia on the basis of rehabilitation training. METHODS: Ninety-seven patients with post-stroke dysphagia were randomly divided into an acupuncture group (group A, n = 32), an electric stimulation group (group B, n = 35) and a rehabilitation training group (group C, n = 30). In group C, the conventional therapy (conventional therapy of neurologic internal medicine and rehabilitation training) was applied. In group A, the combination of conventional therapy and acupuncture was applied. The acupoints of Fengchi (GB 20), Futu (LI 18), three-needles on the forehead, etc. were selected. In group B, the combination of conventional therapy and electric stimulation was adopted. Watian drinking water experiment, stethocatharsis function scoring and video fluoroscopic swallowing study (VFSS) were used to evaluate swallowing function of patients. RESULTS: After treatment, the total effective rate was 96.95 (31/32) in group A and was 94.3% (33/35) in group B, which was superior to that of 66.7% (20/30) in group C (P < 0.01). After treatment, the swallowing function in group A, group B and group C were all improved significantly as compared with that before treatment (all P < 0.05). After treatment, the effects in group A and B were superior to that in group C (both P < 0.05). CONCLUSION: The therapeutic effect of the combination of either acupuncture or electric stimulation with rehabilitation training is better than that of simple rehabilitation training. The efficacy on dysphagia is equal between acupuncture and electric stimulation. PMID- 21290831 TI - [Brain arousal dysfunction in severe craniocerebral injury treated with acupuncture]. AB - OBJECTIVE: To explore the early rehabilitation effect of acupuncture on brain arousal in severe craniocerebral injury. METHODS: One hundred and two cases of severe craniocerebral injury were randomly divided into an observation group and a control group, 51 cases in each one. Based on the conventional nursing care in neurological external medicine, in observation group, acupuncture was applied at Shuigou (GV 26), Neiguan (PC 6) and Sanyinjiao (SP 6) mainly. In control group, functional electric stimulation was applied at stimulate the affected muscles of the upper limbs. Thirty days later, the lucid rate from coma, lucid interval and clinical efficacy were compared between two groups. RESULTS; The lucid rate from coma was 82.4% (42/51) in observation group, which was higher than 56.9% (29/51) in control group (P < 0.01). The lucid interval in observation group was shortened remarkably as compared with control group (P < 0.01), and the clinical efficacy was superior apparently to that in control group (P < 0.01). CONCLUSION: On the basis of conventional treatment, acupuncture intervention at early stage can accelerate the recovery of brain arousal function in patients with severe craniocerebral injury. PMID- 21290832 TI - [Clinical observation on acupoint irradiation with combined laser or red light on patients with knee osteoarthritis of yang deficiency and cold coagulation type]. AB - OBJECTIVE: To explore the effects of combined laser on patients with knee osteoarthritis (OA) of yang deficiency and cold coagulation type. METHODS: Forty one cases with knee OA of yang deficiency and cold coagulation type were randomly divided into a combined laser group (n = 22) and a red light group (n = 19), with combined laser and red light irradiation on Dubi (ST 35) and Neixiyan (EX-LE 4), respectively. They were treated for 6 weeks. The scores of Western Ontario and McMaster Universities' Osteoarthritis Index (WOMAC VA3. 1) were used for assessment of therapeutic effects. RESULTS: After treatment for 2 weeks and 6 weeks, the WOMAC scores significantly decreased in the two groups as compared with those before treatment (P < 0.05, P < 0.01 and P < 0.001). The mean improvement rate of WOMAC scores in the combined laser group was better than those in the red light group. CONCLUSION: Combined laser irradiation can improve the pain, stiffness and functional limitation of patients with knee OA of yang deficiency and cold coagulation type. PMID- 21290833 TI - [Comparative observation on hip osteoarthritis treated with electroacupuncture and medication]. AB - OBJECTIVE: To observe the differences of effect of electroacupuncture and medication on hip osteoarthritis. METHODS: Sixty cases were randomly divided into an electroacupuncture group and a medication group, 30 cases in each one. In electroacupuncture group, electroacupuncture was applied at Biguan (ST 31), Juliao (GB 29), Zuwuli (LR 10) and Yinlian (LR 11). In medication group, Diclofenac Sodium was prescribed for oral administration. One month after treatment, Visual Analogue Scale (VAS) and Harris score were compared between two groups. RESULTS: VAS scores were 67.83 +/- 8.48 and 55.83 +/- 9.66 before and after treatment in electroacupuncture group, and were 68.67 +/- 8.09 and 61.50 +/ 7.78 in medication group separately. VAS pain scores after treatment were reduced remarkably in two groups (both P < 0.001), but the score was reduced much more remarkably in electroacupuncture group as compared with medication group. In electroacupuncture group, after treatment, Harris total score, the single scores of joint pain, function and motion range increased apparently as compared with those before treatment (all P < 0.001). In medication group, after treatment, Harris total score and pain score increased remarkably as compared with those before treatment (both P < 0.001). Harris total score, pain score and function score after treatment in electroacupuncture group increased much more remarkably as compared with those in medication group (all P < 0.05). CONCLUSION: Electroacupuncture can treat effectively hip osteoarthritis, relieve joint pain and improve joint function. The efficacy of it is superior to that of oral administration of Diclofenac Sodium. PMID- 21290834 TI - [Clinical observation on pricking blood along meridians combined with electroacupuncture for treatment of prolapse of lumbar intervertebral disc]. AB - OBJECTIVE: To observe the therapeutic effects on pricking blood along meridians combined with electroacupuncture for treatment of prolapse of lumbar intervertebral disc. METHODS: One hundred cases were randomly divided into an observation group (50 cases) and a control group (50 cases). The observation group was treated with pricking blood along meridians combined with electroacupuncture. The main points for pricking blood were collaterals with blood stasis around Weizhong (BL 40) on the affected side, and collaterals with blood stasis on corresponding meridians such as Foot Shaoyang Meridian, Foot Taiyang Meridian and Foot Yangming Meridian according to body parts syndrome differentiation could also be used. The points for electroacupuncture included Ashi point (1 cun away from the spinal space of segmental lesions), Dachangshu (BL 25), Guanyuanshu (BL 26), Zhibian (BL 54), Huantiao (GB 30) and so on. The control group was only treated with electroacupuncture and treatment was same as the observation group. The therapeutic effects and scores of Visual Analogue Scale (VAS) of two groups were compared. RESULTS: The cured rate of observation group (68.0%, 34/50) was higher than that of control group (46.0%, 23/50, P < 0.05). The cured and markedly effective rate of observation group (92.0%, 46/50) was also higher than that of control group (74.0%, 37/50, P < 0.05). The scores of VAS after treatment in both groups decreased obviously (both P < 0.01), and the decreasing degree of VAS in observation group was more obvious than that in control group (P < 0.01). CONCLUSION: Pricking blood along meridians combined with electroacupuncture has outstanding effect for treatment of prolapse of lumbar intervertebral disc. PMID- 21290835 TI - [Comparison of therapeutic effects of peripheral facial paralysis in acute stage by different interventions]. AB - OBJECTIVE: To compare the therapeutic effects of peripheral facial paralysis in acute stage by different interventions and explore the better treatments of peripheral facial paralysis. METHODS: One hundred and thirty one cases of Bell's facial paralysis were randomly divided into three groups. In acupuncture group (44 cases), Dicang (ST 4), Jiache (ST 6), Hegu (LI 4), Yangbai (GB 14) and Taiyang (EX-HN 5), etc. were applied; in electroacupuncture group (45 cases), the selection of acupoints and needling method were same as those in acupuncture group, and the electroacupuncture therapy was applied on Dicang (ST 4), Xiaguan (ST 7), Yangbai (GB 14) and Taiyang (EX-HN 5) in acute stage; in medication and acupuncture group (42 cases), Prednisone and Acyclovir were taken by oral administration, Vitamin B1 and Vitamin B12, were applied by intramuscular injection in acute stage, and acupuncture was applied by the way which was same as that in acupuncture group during quiescent and recovery stages. The curative effects were evaluated by House-Brackmann Grading Scale, and the failed rates were observed by follow-up after one and three months. RESULTS: The cured and markedly effective rates were 79.6% (35/44), 93.4% (42/45) and 78.6% (33/42) respectively in acupuncture group, electroacupuncture group and medication and acupuncture group, and the result in electroacupuncture group was superior to those in acupuncture group and medication and acupuncture group (P < 0.05). The cured rates above tympanichord were 54.2% (13/24), 85.2% (23/27) and 48.0% (12/25) in acupuncture group, electroacupuncture group and medication and acupuncture group, and the result in electroacupuncture group was superior to those in acupuncture group and medication and acupuncture group (P < 0.01). There was no significant differences of cured rates below tympanichord among three groups (P > 0.05); and the failed rate in electroacupuncture group was much lower than those in acupuncture group and medication and acupuncture group by follow-up after one and three months (all P < 0.01). CONCLUSION: The peripheral facial paralysis is effectively treated by electroacupuncture in acute stage, and it suggests that electroacupuncture should be applied early during the acupuncture treatment of peripheral facial paralysis. PMID- 21290836 TI - [Efficacy observation on acupoint catgut embedding therapy combined medication for treatment of chronic urticaria induced by Helicobacter pylori infection]. AB - OBJECTIVE: To observe the efficacy of acupoint catgut embedding therapy combined medication on chronic urticaria induced by Helicobacter pylori (HP) infection. METHODS: Ninety-two cases were randomly divided into 3 groups, named a medication group (group A, 31 cases), an acupoint catgut embedding group (group B, 30 cases) and a medication combined acupoint catgut embedding group (group C, 31 cases). In group A, the medication was administered orally for antihistamine and anti-HP infection. In group B, catgut embedding was applied on Quchi (LI 11), Xuehai (SP 10), Zusanli (ST 36), etc. In group C, acupoint catgut embedding therapy was applied in combination with medication (medication as group A, acupoint catgut embedding as group B). After 3-month treatment, the efficacy, recurrence rate and HP negative rate were compared among 3 groups. RESULTS: Separately, the effective rates of group A, B, C were 61.3% (19/31), 53.3% (16/30) and 90.3% (28/31); the recurrence rates were 27.3% (3/11), 33.3% (3/9) and 5.9% (1/17); and HP negative rates were 31.3% (10/31), 26.7% (9/30) and 77.4% (24/31). The clinical efficacy and HP negative rate in group C were superior to those in group A and B (P < 0.01, P < 0.05). CONCLUSION: Acupoint catgut embedding therapy combined medication is significant in efficacy and low in recurrence rate in treatment of chronic urticaria caused by HP infection. PMID- 21290837 TI - [Application of cerebral function imaging in research on the acupoints specificity]. AB - To explore the effect of cerebral function imaging in research on the acupoints specificity. Relevant literatures are retrieved and their results are compared. The results reveals as the follows: (1) Acupuncture can ameliorate cerebral blood flow hypoperfusion in patients with cerebrovascular disease, which maybe one of the mechanisms of acupuncture effect; (2) Acupuncture treatment has selectivity regulation role, which is related to the state of body and brain; (3) Cerebral function imaging can draw a clear distinction between therapeutic effect and placebo effect of acupuncture; (4) The points have specificity on the brain activation, but the outcomes are not exactly the same under different experimental conditions. Cerebral function imaging can be used to exploring acupoints specificity. Due to many interference factors which influence the accuracy of experiment, the subsequent experimental design have to be improved in the days ahead so as to make the results more cogent and rigorous. PMID- 21290838 TI - [Morphologic characteristics and clinical significance of Neiguan (PC 6)]. AB - OBJECTIVE: To provide appropriate needling angle and depth for the acupuncture and acupoint injection at Neiguan (PC 6), and to avoid damaging nerves and vessels so as to produce its maximum effect. METHODS: Thirty adults' upper-limb samples were used to dissect and observe the referred hierarchical structure and adjoining crucially nerves and vessels in needling Neiguan (PC 6) according to the national standard Acupoint Location (GB 12346-90). RESULTS: In this punctuation region, there are three parts rich in connective tissues containing the nerves and blood vessels. The surface part is between the skin and the musculus flexor digitorum superficialis and it is the tissue which contains medial and lateral antebrachial cutaneous nerve and its nutrient artery. The middle part is between the musculus flexor digitorum superficialis and the flexor digitorum profundus muscle and contains the median nerve, its palmar branch of and artery. The deep part is between the pronator quadratus muscle and the interosseous membrane and contains the anterior interosseous nerve. When perpendicular needling, the depth of needling the body from skin to the superficial surface of the musculus flexor digitorum superficialis and to the superficial surface of the flexor digitorum profundus muscle is (6.68 +/- 0.64) mm and (12.37 +/- 0.87) mm respectively. The depth of needling the body from skin to the superficial surface of the pronator quadratus muscle and to the superficial surface of the anterior interosseous terminal branch of the nerves is (17.83 +/- 1.00) mm and (30.87 +/- 1.85) mm respectively, and the proportional cun is (2.20 +/- 0.14) cm. The ulnaris cord of median nerves are located at the radial of the needle. The deep layers could touch the anterior interosseous nerve ending. CONCLUSION: Perpendicularly needling Neiguan (PC 6) for 3 fen (6.68 mm), 5 fen (12.37 mm) and 1.4 cun (30.87 mm) will stimulate the nervus vascularis of the rich part of surface, middle and deep connective tissues respectively and produce the acupuncture effect. During the acupoint injection, perforating the needle perpendicularly at the middle point of the two tendons or deviating slightly to the direction of tendon of palmaris longus can avoid the damage of the median nerve cord. PMID- 21290839 TI - [Effects of electroacupuncture on expression of Abeta positive cells of the hippocampus and SOD activity in rats with streptozocin-Alzheimer's disease]. AB - OBJECTIVE: To investigate the possible mechanism of the electroacupuncture for improvement of learning and memory in rats of Alzheimer's disease (AD). METHODS: Sixty Wistar rats were randomly divided into a normal group, a normal saline group, a model group, a western medication group and an electroacupuncture group, 12 rats in each group. The AD rat model was established by injecting Streptozocin (STZ) into lateral cerebral ventricle, except the rats in the normal saline group injecting Normal Saline with the same dose and in normal group with no injection. The western medication group was treated with intragastric administration of Memantine, and in the electroacupuncture group, the electroacupuncture was given at "Baihui" (GV 20), "Dazhui" (CV 14), "Taixi" (KI 3), "Shenshu" (BL 23), "Zusanli" (ST 36), once each day, 7 days for a course, and lasted for 4 courses. The other three groups were fed in routine way and without any treatment. The learning and memory ability was assessed by Morris water maze and the expression of Abeta positive cells of the hippocampus and superoxide dismutase (SOD) activity were determined by immunohistochemistry and visible spectrophotometer colorimetry. RESULTS: Compared with the normal group and the normal saline group, the Abeta protein expression was significantly increased in the model group (both P < 0.01), and the SOD activity was obviously decreased (both P < 0.01). After treatment, as compared with the model group, the Abeta protein expression was significantly decreased (both P < 0.01), and the SOD activity was obviously increased (both P < 0.01) in the electroacupuncture group and western medication group. CONCLUSION: Electroacupuncture treatment can reduce the Abeta protein expression and increase the SOD activity of the hippocampus so as to improve learning and memory ability in the AD rats. PMID- 21290840 TI - [Effects of gap junction blocking on the oxygen partial pressure in acupoints of the bladder meridian]. AB - OBJECTIVE: To explore the relation between gap junction and meridian phenomenon. METHODS: The oxygen partial pressure in acupoints [see text for formula] and in their corresponding non-acupoints of the Bladder Meridian was observed with the needle-type tissue oxygen tension sensor in the gap junction blocking goats by 1 Heptanol injection and the Connexin 43 (Cx43) gene knockout mice. RESULTS: (1) The oxygen partial pressure in acupoints of Bladder Meridian on goats was higher than that in non-acupoints after 1-Heptanol injection with significant differences between them (both P < 0.01). (2) The oxygen partial pressure in acupoints of Bladder Meridian on goats increased significantly after injecting 1 Heptanol as compare with that either injecting normal saline or injecting nothing with significant differences between them (all P < 0.01). (3) The oxygen partial pressure in acupoints of the Bladder Meridian was significantly higher than that in the non-acupoint controls in Cx43 wild type (WT) mice (all P < 0.01). In Cx43 heterozygote (HT) mice, the oxygen partial pressure between acupoints and non acupoint controls showed no significant differences (all P > 0.05). (4) In acupoints, the oxygen partial pressure in Cx43 WT mice was significantly higher than that in Cx43 HT mice (all P < 0.05), while in the corresponding non acupoints, this difference had no statistically significant (all P > 0.05). CONCLUSION: Gap junction maybe the essential factor in signal transduction of acupuncture. PMID- 21290841 TI - [Application of acupuncture-assisted anesthesia in prostate biopsy via the perineum]. AB - OBJECTIVE: To explore acupuncture-assisted anesthesia in transrectal ultrasound guided prostate biopsy via the perineum. METHODS: One hundred and five cases of prostate biopsy were randomly divided into two groups. For 51 cases in observation group (group A), the periprostatic nerve plexus block and acupuncture on bilateral Zusanli (ST 36) were applied. For 54 cases in control group (group B), the simple periprostatic nerve plexus block was adopted. Visual Analogue Score (VAS) was used to evaluate the pain extent after biopsy and blood pressure and heart rate were monitored before, during and after operation, separately. RESULTS: VAS scores were 0.9 +/- 0.8 and 2.8 +/- 1.0 in group A and group B, separately, indicating statistical significant difference in comparison (P < 0.01). Additionally, in group B, blood pressure and heart rate during and after operation were higher remarkably than those before operation (all P < 0.05). Moreover, in group B, blood pressure during operation and heart rate during and after operation were all higher apparently than those in group A (all P < 0.05). CONCLUSION: Acupuncture-assisted anesthesia alleviates apparently pain and discomforts during transrectal ultrasound guided prostate biopsy via the perineum in patients and ensures the stability of blood pressure and heart rate. PMID- 21290842 TI - [Essentials of the treatment based on syndrome differentiation belonging to the meridian theory by professor Wang Ju-yi]. AB - This paper states the essentials of the treatment based on syndrome differentiation practiced by professor WANG Ju-yi's and his experience in clinic. The understanding of basic theory is a key for clinical practices using meridian theory. Based on the understanding of mutual transformations among six meridians, six qi, six zang, and six fu, the theory of meridians and collaterals can be applied to daily acupuncture clinical practices. Doctors should follow the processes of observing meridian, inspection of meridian, selection meridian, selection acupoints in the clinical practices. This paper lists the clinical examples of treating patients with thalamic lesion by using the method of diagnosis and examination practiced by professor WANG Ju-yi's. PMID- 21290843 TI - [SHI Xue-min's idea of acupuncture treatment on acute syndromes and intractable diseases]. AB - Under the guidance of traditional acupuncture theory and modern medical knowledge, with long-term clinical practice, professor SHI Xue-min, academician of the Chinese Academy of Engineering, has made new recognitions on the concept of Shen (mind or vitality, a general term for life processes of the human body, referring to mentality, consciousness and thinking) and the brain, established the ideas of "Xingshen" (to cause resuscitation), "Tiaoshen" (to regulate the function of mental activity) and "Anshen" (to tranquilize the mind), promoted the application of the above ideas into acupuncture treatment on acute syndromes and intractable diseases, which is approved to have significant effect. The article dedicats to introduce professor SHI's experiences of using his idea of mental regulation with the combination of standard quantitative manipulations to treat acute, severe and intractable diseases such as stroke, central respiratory failure, angina pectoris, temporary syncope, pseudobular palsy, vascular dementia and dysuria. PMID- 21290844 TI - [Acupuncture treatment on ophthalmic diseases]. AB - Clinical experiences of acupuncture treatment on ophthalmic diseases over the years are summarized and analyzed to study the therapeutic capacity of acupuncture. Ophthalmic disorders are categorized into diseases with acupuncture treatment as the predominant or supplementary therapy, or as the therapeutic or prevention regimen. At the same time, various treating courses are designed for different phases of the diseases. And effects of acupuncture on different categories of ophthalmic disorders are discussed so as to improve the level of clinical application of acupuncture. PMID- 21290845 TI - [Research prospect for sensing needle in Chinese medicine]. AB - The domestic and abroad research literatures on sensing needle in Chinese medicine in recent years are retrieved. The design principle and application situation of calcium sensing needle, temperature sensing needle, pH sensing needle and oxygen partial pressure sensing needle are summarized. The findings suggest that the sensing needle can be used in the measurements of in vivo, location positioning, fixed-point, real time, and dynamic state with little or no damage to the human body. It can be used as a transducer or a device for treatment. This paper proposes that the sensing needle can be used in the measurements in clinical practices of western medicine; it will facilitate the development of Chinese and western integrative medicine. PMID- 21290846 TI - [Concept and terminology study on Xiahe points (lower confluent point)]. AB - The six points on the foot yang channels with the main indications of disorders of six fu organs are named as he points in ancient time, while as Xiahe points in modern times. Both of the names share the Chinese character of He, which confounded with He (sea) point of the five shu points. The related ancient literatures, modern compiled textbooks and dictionaries are studied, and the original meaning and paraphrase of the name are analyzed so as to make clear the concept of the so-called Xiahe points and standardized its name. And it is held that the terminology of Xiahe points is inappropriate with the definition unclear and the concept indistinct. In the Internal classic, Xiahe points is also named as he points following the He (sea) points of the five shu points, and there was no proper name for the points at that time. The meaning of "he" in Xiahe points are different from the meaning of "He" in He (sea) points. And the article proposes that Xiahe points should be replaced as Liu fu Xiashu (lower shu points of six fu organs) or redefined with other names. PMID- 21290847 TI - [Characteristics of the guidelines of acupuncture clinical practices]. AB - Based on the optimum clinical evidence, consulting the international guide, the outstanding guidelines of acupuncture clinical practices is formulated in order to promote the process of acupuncture modernization and internationalization. According to consensus of experts, using the questionnaire method, integrating the characteristics and requirements for acupuncture clinical practices, the guidelines reflect the characteristics of acupuncture, for instance, applicability, inheritance, holism, and the discipline characteristics. Thus, the guidelines will standardize the treatments in acupuncture clinical practices, strengthen medical service quality management, control medical costs, and promote the process of acupuncture modernization and internationalization. PMID- 21290848 TI - [Contributions of professor Yang Chang-sen to modern acupuncture-moxibustion theory]. AB - Professor YANG Chang-sen, devoted himself entirely to the clinical practice, education and research of modern acupuncture-moxibustion for over 50 years, has made great contribution to the construction and development of the theoretical system of the science. His main achievements includes constructing and perfecting acupuncture-moxibustion module in differentiation of syndromes, editing textbooks such as Zhenjiuxue Jiangyi (Teaching Materials of Acupuncture-Moxibustion) and Zhenjiu Zhi-liaoxue (Acupuncture Therapeutics) from innovational viewpoints, explaining the reducing and reinforcing manipulations of acupuncture therapy systematically and historically, exploring means of high-level personnel cultivation and insisting to carry out acupuncture-moxibustion academic research in clinical practice. PMID- 21290849 TI - [History and progress of study on electrical properties of acupoints at home and abroad]. AB - Ninety articles on electrical properties of acupoints and 38 closely related articles with the time raged from 1950s' till present were retrieved and studied from Pubmed, CNKI and VIP databases. Conclusions indicate that most of the low resistance points or high potential points of the skin are in accordance with acupoints. However, not every acupoint shows the property of low-resistance or high potential feature. The electrical properties of acupoints vary with the physiological and pathological changes of the human body. And the electrical properties of acupoints which share the same name on the affected meridians located symmetrically on bilateral sides of the body were in a condition of imbalance. However, the result of measurement can be affected by the type of apparatus, intensity, size and number of the electrode etc. Therefore, the future study should be focused on the reaction laws of electrical properties of acupoints under physiological and pathological conditions through selection of different resistance measurement apparatus and strictly control of the impacting factors during the researching process. PMID- 21290850 TI - [Emotion regulation strategies and aggressive behavior of preschool children]. AB - The present study (N = 193) examined use of emotional regulation strategies in physically and relationally aggressive preschool children (mean age: 55 months), compared to non-aggressive peers. To assess emotion regulation, we conducted a structured videotaped behavioral observation of a situation where frustration was elicited. Afterwards, regulation strategies were analyzed in seven categories. Physical and relational aggression was rated by preschool teachers. Cut-off scores were used to classify children as relationally or physically aggressive. Results show that physically aggressive children focused their attention on frustrating stimulus and used venting and cognitive verbalization more often than non-physically aggressive children. Relationally aggressive children used venting more often than non-relationally aggressive children. Findings suggest that aggressive children would benefit from training in emotion regulation. PMID- 21290851 TI - [Hamburg model-project for minors who are at risk for sexual offending: co operation between the institutions in Hamburg, Germany]. AB - When children and adolescents show deviant sexual behavior, co-operation between institutions of the youth welfare service is necessary in order to prevent further assaults. As a part of the Hamburg model project for minors who are at risk for sexual offending we evaluated the existing case-unspecific co-operation between the city's institutions. Selection of the sample resulted in a diagram of co-operation between institutions that have or might have contact to sexual deviant children or juveniles. By analyzing 147 online-surveys, comprising quantitative as well as qualitative questions, revealed a comprehensive system rich in resources but only little case-unspecific cooperation. Highest average rating in co-operation was given to the non-governmental institutions and the police. The inquiry of reasons for the co-operation indicated a demand for specialized diagnostics and advice. Positively evaluated were an efficient and fast processing, an unbureaucratic handling of the case and constant availability. Pointed out negatively were "not-reacting", trivializing and a lack of capacities. In order to improve the level of information and the range of intervention programs, training of professionals in school and the youth welfare service is needed. PMID- 21290852 TI - [The function of music in the context of non-suicidal self injury]. AB - Music and non-suicidal self injury (NSSI) are both of extraordinary importance for adolescents with respect to expressing emotions, and demonstrating protest. Nevertheless, little is known about the interrelation between these phenomena, in particular about the function of music in the context of NSSI. The aim of our study was to investigate the connections between music and auto-aggressive behaviour and suicidality in adolescents. We developed a specific questionnaire for this purpose, which was used together with a self-reporting depression inventory in 40 subjects in a child and adolescent psychiatric clinic. We enrolled inpatients between 13 and 18 years who had presented with NSSI and/or suicidality during the last three months. Music proved to be very important to the patients and seemed to have an emotionally elevating function. Moreover, music was in some cases an integral part of the NSSI-scenario, but also was used to inhibit autoaggressive tendencies. In a qualitative analysis, it could be demonstrated that music and lyrics are associated with affect regulation, anti dissociation and interpersonal influence. Music seems to fulfil similar self regulatory functions as have been described for NSSI and can thus be considered, as a substitute to have a protective effect. There were no indications that specific music preferences are directly linked to NSSI or suicidality. PMID- 21290853 TI - [Overweight and obesity in childhood and adolescence]. AB - Firstly, essential developmental aspects of the focused periods of life, namely childhood and adolescence, are discussed. Furthermore, different issues of overweight and obesity in childhood and adolescence are highlighted. Besides the definition and the assessment, possibilities of classification and epidemiological aspects are of interest. Physical and psychiatric consequences, which can be associated with obesity are also presented. In the context of a model of multifactorial genesis of obesity, different causing and maintaining factors are described. In addition to genetic and biological risk factors, the significance of several psychosocial factors is illustrated. Finally, the focus is on the therapy of obesity in childhood and adolescence. PMID- 21290854 TI - [Early oral feeding versus classic oral feeding after appendicectomy for acute appendicitis]. AB - The appendectomies for acute appendicitis are the most frequent surgical interventions (43.6%) in our service. The recent studies demonstrated the feasibility and the economical gain of the early oral feeding vs. classic oral feeding, after elective digestive surgery. We wanted to spread these results therefore to the appendectomy for acute appendicitis. It is about a prospective survey carrying on 110 patients also left in two groups, and comparing the classic postoperative oral feeding vs. the early postoperative oral feeding on one year. The two groups were comparable and the studied parameters were : the length of the postoperative ileus, the hospitable morbidity, the length of the hospitalization and the cost of the hold in charge. The length of the postoperative ileus was not different in the two groups as well as the morbidity. The difference of the median length of hospitalization in the two groups was not meaningful. The cost of the hold in charge was meaningfully more elevated in the group with classic postoperative feeding. In conclusion, the early postoperative oral feeding in our survey doesn't reduce the length of the postoperative ileus and don't drag a morbidity anymore that the classic oral feeding. However if it doesn't shorten the length of the hospitalization, it drags a reduction of the cost of the hold in charge. There is a gain therefore precociously to nourish the patients after appendectomy for acute appendicitis. PMID- 21290855 TI - [Health problems in textile industry in Democratic Republic of Congo]. AB - The objective of this work was to highlight the influence of the occupational conditions on the textile sector workers' health in Democratic Republic of Congo (DRC). We conduct an exploratory cross-sectional study of two populations within a plant located at the North of the DRC: workers (N=114) and executive or employees (N=96). Our total sample data (N=210) were collected by a questionnaire focused on the procedures, the exposures and the effects on health. Odds ratio (OR) and confidence interval at 95% were estimated. For each significant diseases symptom, a regression model has been achieved in order to estimate OR adjusted for association of disease symptoms and occupational statute. Workers compared to employees present high frequencies and exposure rates for many diseases symptoms. These OR are respectively for cough (OR = 5.1; IC: 2.93-10.68); respiratory difficulty (OR = 2.9; IC: 1.42-6.42) thoracic pain (OR = 2.6; IC: 1.31-5.24); fever (OR = 2.4; IC: 1.27-4.50); upper limbs pain (OR = 4.8; IC: 2.55-8.80); neck shoulder pain (OR = 3.8; IC: 2.02-7.31); ocular diseases (OR = 2.2; IC: 1.17 3.89) and cutaneous diseases (OR = 2.5; IC: 1.18-5.46). The OR related to the libido loss is highest (OR = 5.5; IC: 2.84-10.71). In the other hand, the OR of the neuropsychics disorders are lower than 1 in this comparison and are respectively of 0.5 (0.28-0.95) for tiredness; 0.2 (0.08-0.28) for the lack of concentration and 0.07 (0.04-0.18) for the stress. In conclusion, the frequencies and high OR observed attest differences of the health issues between the workers and employees whose causes could be under the live and work conditions. These results should be confronted with those of other studies in health at the work. PMID- 21290856 TI - [The use of platelet concentrates: platelet-rich plasma (PRP) and platelet-rich fibrin (PRF) in bone reconstruction prior to dental implant surgery]. AB - The autologous platelet concentrates--Platelet-Rich Plasma (PRP) and Platelet Rich Fibrin (PRF)--are used in various medical fields, particularly in oral and maxillofacial surgery. These concentrates contain high levels of growth factors, including the 3 isomers of PDGF (platelet-derived growth factor), 2 of the numerous transforming growth factors (TGF-beta), the insulinlike growth factor (IGF), the epithelial growth factor (EGF) and the vascular endothelial growth factor (VEGF), which are the key elements in wound healing, particularly in bone regeneration. Platelet concentrates are easy to apply in clinical practice and offer potential benefits including rapid wound healing and bone regeneration, and can therefore be considered to be new therapeutic adjuvants. In dental implant surgery they are used in bone reconstruction prior or concomitant to implant procedures, and also for dental extraction socket preservation. Their use result in enhanced bone graft density and maturation. A literature review on the use of PRP/PRF in maxillofacial and dental implant surgery is proposed. PMID- 21290857 TI - [Dysphagia and recurrent esophageal stenosis associated with intramural pseudodiverticulosis of the esophagus. A case report]. AB - Intramural pseudodiverticulosis of the esophagus is a rare benign disease of the eosphageal wall, with dilation of the submucosal glands, and the predominant symptom is dysphagia. This disorder may be associated with gastroesophageal reflux, motility disorders, candidiasis and alcoholism. Inflammation, resulting in periductal fibrosis and compression of the duct orifices, may be a causative factor. Good and long-lasting therapeutic success can be achieved by bouginage of the stenosis with concomitant treatment of the associated esophageal diseases. Esophageal intramural pseudodiverticulosis is a differential diagnosis in cases of dyspagia and/or esophageal strictures if no other causes are found. PMID- 21290858 TI - [Progressive pseudorheumatoid chondrodysplasia. Case report]. AB - We present the case of a 17-year-old patient suffering from progressive pseudorheumatoid chondrodysplasia from whom 2 total hip prostheses and 2 total knee prostheses were necessary. We have to do with a recessive autosomal genetic disorder characterized by a lysis of the articular cartilage. This leads to an early degeneration of the joints. The clinic is mainly characterized by various complaints such as joint pain, stiffness, limitation or swelling causing a significant motor disability from childhood. The first joints affected are situated in the hands, later followed by the hips, elbows and knees. The X-rays show severe, multifocal articular degenerative modifications which are unusual for the age. The genetic mutation concerns the WISP 3 gene actively expressed by articular chondrocytes and located on chromosome 6. The differential diagnosis is done with a series of rheumatologic disorders in children and autoimmune diseases. We mainly retain the juvenile rheumatoid arthritis. A symptomatic medical treatment can be undertaken first. However, given the evolving nature of the pathology, a joint replacement surgery is needed once the child's growth is finished (second decade of life). PMID- 21290859 TI - [Bithalamic lesion. Report of a case]. PMID- 21290860 TI - [A Belgian medical board during World War II or the bad outcome of the law concerning the "Board of Medical Doctors" from 1938 (third part)]. PMID- 21290861 TI - [Complete destruction of the sino-nasal structures]. PMID- 21290862 TI - [The 11th Meeting on emergencies and severe complications in cancer patients ]. PMID- 21290863 TI - [The urologist at the center of the expected progress on the management of localized prostate cancer!]. PMID- 21290864 TI - [Prostate cancer screening: utility, goals and perspectives in 2010]. AB - According to recent results of a sub-group of 20,000 patients from the ERSPC study, prostate cancer screening significantly increases disease specific survival for men with a life expectancy of 15 years. However presently, only 20% of prostate biopsies lead to the diagnosis of cancer. This low yield may be increased by using new tools on their way to validation, such as the blood and urinary markers p2-PSA and PCA3, so as MRI and tridimensional computerized echography. Finally, the tumours detected must be managed with subtlety, since a third of them are not overtly aggressive clinically. Hence, a significant proportion of such tumours may not need immediate curative intent treatment, and can be followed up in an active surveillance protocol. PMID- 21290865 TI - [Role of the urologist in the screening of bone diseases]. AB - During their lifetime, 20% of men will suffer from a fracture secondary to osteoporosis, and morbidity and mortality of a hip fracture in men are more severe than in women. Despite these facts, there are only few studies on osteoporosis in men. Hyopgonadism is a known risk factor for bone mineral density decrease. Hypogonadism can be found in patients diagnosed with prostate cancer who are receiving androgen deprivation therapy, but can also be discovered in patients with male infertility or erectile dysfunction. Urologists have central role in men's health aftercare, and therefore have key role in the screening and in the multidisciplinary treatment of osteoporosis and osteopenia. PMID- 21290866 TI - [Medical therapy for ureteral stones: high versus low fluid intake]. AB - The mainstays of renal colic medical treatment are first to provide efficient pain relief, and second to facilitate migration of the ureteral stone or dissolve it. In the ambulatory setting, non steroidal anti-inflammatory drugs are the treatment of choice of pain relief. To facilitate stone migration, the debate between hydric restriction and hyperhydration remains somewhat open. Besides that, alpha-blockers and anti-calcic agents appear to speed up stone explusion, whereas stone chemolysis acts on a longer time scale. PMID- 21290867 TI - [Fluorescence guided endoscopy: improvement in the management of bladder cancer]. AB - White-light cystoscopy and cytology are the standard tools to diagnose bladder cancer. White-light cystoscopy is excellent to detect macroscopic exophytic tumors, but its sensitivity is poor for flat tumors such as carcinoma in situ. Use of fluorescence cystoscopy during transurethral bladder resection improve tumor detection, particulary for carcinoma in situ. Fluorescence cystoscopy reduce residual tumor rate, especially for voluminous and multifocal tumors with consecutive lower recurrence. Fluorescence is now recommended to diagnose and treat bladder cancer. PMID- 21290868 TI - [Renal mass biopsy: usefulness and indications]. AB - Whereas renal biopsy is routinely performed in nephrology for the management of renal failure or follow-up of kidney grafts, it has historically been seldom used in urology for the work-up of kidney tumours because of its low yield. Since a few years however, some authors recommend to biopsy select renal lesions to improve their diagnosis and management. Indeed, biopsy technique has evolved, leading to better tissue sampling. Moreover, the risk of tumoral seeding of the needle tract has proven to be negligeable. Renal biopsy appears now to be useful for managing atypical solid renal lesions, those < or =3 cm, possible neoplastic lesions in solitary kidneys, bilateral renal tumours, putative renal metastasis, so as lesions in functionally deficient kidneys. PMID- 21290869 TI - [Benefits of ultrasonography in kidney and testicular-sparing surgery]. AB - Renal and testicular cancers account for 4% and 1% of all malignancies, respectively. Their prevalence has increased over the past years and is related to the widespread use of medical imaging and the incidental findings of small asymptomatic tumors on computed tomography scanners and ultrasounds examinations. The urologist faces the dilemma of overtreating benign asymptomatic lesions with radical surgery. Therefore, organ-sparing surgery was developed. Recent studies have shown that recurrence rates are often similar between organ-sparing and radical surgery for small kidney or testicular tumors. However, the risk of positive surgical margins consecutive to organ-sparing surgery remains a matter of debate. This article discusses the role of ex-vivo peroperative ultrasonography in predicting negative surgical margins during kidney- and testicular-sparing surgery. PMID- 21290870 TI - [Being the sibling of a child suffering from cancer: a support group]. AB - This paper offers a reflection on the family life and that of the siblings of a child with cancer. We will present our intervention model developed jointly by the pediatric oncology and the pediatric psychiatry units at the University Hospital CHUV in Lausanne. It is known that siblings show difficulties in dealing with the ambivalent emotions triggered by the sickness of a brother or sister. Their defence mechanisms can be heavy and may have consequences on the child's psycho-affective development and on the dynamics of the whole family. Speech groups allow the siblings to unfold an experience which is often irrepresentable. They also permit remobilization of affects frozen by the illness. This model used since 2006 in our unit responds to the wish to improve the quality of care of heavily sick children. PMID- 21290871 TI - [Assisted suicide and the death certificate: what is the role of the physician?]. PMID- 21290872 TI - [AIDS: an embarrassing preventive trial in homosexual men]. PMID- 21290873 TI - [Euthanasia: the girl, love, death (3)]. PMID- 21290874 TI - [From Black Venus and Georges Cuvier (3) ]. PMID- 21290875 TI - [Health systems: praise of hybridization ]. PMID- 21290876 TI - [Ultrasonographic diapeutics of the hepatic abscess. Possibilities and achievements]. AB - Transcutaneous interventions (TI) under ultrasonographic control were applied in 163 patients (the main group) for primary pyogenic hepatic abscess (PPHA). For comparative group 31 patients were included, in whom an operative intervention was done (disclosure, sanation and external drainage of the focal lesions). While treating PPHA in 91 patients the TI punctures under ultrasonographic control were made and in 72--transcutaneous drainage was performed. The puncture treatment appeared effective in 88 (96.7%) patients, drainage--in 70 (97.2%), summarized efficacy of TI had constituted 96.9%. The morbidity ratio after miniinvasive treatment of PPHA was lesser than after routine operative treatment. The TI application for PPHA is an effective method of the patients treatment, not dependent on their foci size and the patient general state, it permit to lower morbidity, lethality and period of hospitalization significantly, and to improve the results meaningfully. TI under ultrasonographic control constitutes the method of choice in PPHA treatment, excluding posttraumatic abscesses, chronic hepatic abscesses and intracavitary sequesteres presence. PMID- 21290877 TI - [Comparative estimation of the results of open and endoscopic thoracic sympathectomy in the treatment of Raynaud's phenomenon]. AB - Comparative analysis of thoracic sympathectomy efficacy, performed for Raynaud's phenomenon (RP), was accomplished, concerning application either endoscopic or open method. In 62 patients, suffering RP, open or endoscopic thoracic sympathectomy was done in surgical and vascular departments in 1997-2007 yrs. In 32 (51.61%) patients there was performed endoscopic thoracic sympathectomy, in 30 (48.39%)--upper thoracic sympathectomy, using extrapleural supraclavicular access, according to V. N. Klimenko. Immediate results of upper thoracic sympathectomy did not differ trustworthy depending on any method or access. Late follow-up results of upper thoracic sympathectomy were worse than immediate results by 28%--in endoscopic variant and by 43% --in the open one. The positive results rate after endoscopic thoracic sympathectomy have exceeded that after conducting the open one by 15.18%. PMID- 21290878 TI - [The structure of microflora in ulcerative-necrotic lesions in patients with diabetic foot syndrome]. AB - The results of dynamic microbiological investigation, conducted in 37 patients, suffering diabetic foot syndrome (DFS) during 2008-2009 yrs period, were presented. There were 103 investigations made and 169 species of microorganisms revealed. The microflora structure of surgical infection in patients with DFS was presented by S. aureus (42.85%), P. aeruginosa (32.09%), E. coli (7.66%), S. pyogenes (7.16%), Enterobacteriaceae aerogenes (6.3%), E fecales (1.97%), E. cloacae (1.97%). S. aureus have shown resistance towards ceftriaxone (66.7%), lincomycine (75%), cyprofloxacine (58.3%); P. aeruginosa--towards cephoperazone (100%), amicacine (66.6%), vancomycine (89.9%), cyprofloxacine (87.8%), imipenem (87.8%). Enterobacteriaceae are resistant towards cefuroxym (60%) and amicacine (80%). PMID- 21290879 TI - [Surgical treatment of mediastinal tumors and central forms of pulmonary cancer, using the method of artificial blood circulation]. AB - The epidemiological data were presented, concerning the mediastinal tumors and central pulmonary cancer spread among population of Ukraine, and the pulmonary cancer classification. The methods of surgical correction, which are applied in the clinic and include the extended lymph node dissection performance, were depicted. It is frequently impossible to perform the lymph nodes dissection without doing median sternotomy and manipulations on the main vessels--without artificial blood circulation using. PMID- 21290880 TI - [Diagnostic and prognostic value of determination of the endogenic intoxication and functional activity of neutrophils indices in odontogenic phlegmon]. AB - There were studied up the peripheral blood indices in 109 patients, suffering odontogenic phlegmon (OPH), coexistant with severe and of medium severity systemic inflammatory response syndrome (SIRS). In the patients with OPH and severe SIRS (with the complicated course), the blood neutrophils indices, concerning endogenic intoxication and functional activity, differ essentially from those parameters, present in patients, suffering noncomplicated course of the disease. PMID- 21290881 TI - [Chronic inguinal pain syndrome: modern view on the problem]. PMID- 21290882 TI - [Chronic osteomyelitis of the lower extremities: etiology, pathogenesis, principles of treatment]. PMID- 21290883 TI - [Treatment or recurrent perforation and fistulas of the eventrated intestine on the disseminated endometriosis background]. PMID- 21290884 TI - [Observation of botulism, complicated by hemorrhage from upper region of the digestive tract]. PMID- 21290885 TI - [Prominent Russian surgeon of the XVIIIth century Iakov Sapolovich (to the 250th birthday anniversary)]. PMID- 21290886 TI - Pioneers, cowboys, and desperados: a brief history of pediatric surgical innovation. PMID- 21290887 TI - Clinical images: The iron salute: a sign of hemochromatosis. PMID- 21290888 TI - [Guillain-Barre syndrome and the influenza virus]. PMID- 21290889 TI - [Diagnostic strategy in infective endocarditis with negative cultures]. PMID- 21290890 TI - [Environmental decontamination with UV radiation]. PMID- 21290891 TI - [Rapid diagnosis of respiratory viruses with LuminexTM versus real time PCR]. PMID- 21290892 TI - Molecular characterisation of Australasian isolates of aquatic birnaviruses. AB - An aquatic birnavirus, first isolated in Australia from farmed Atlantic salmon in Tasmania in 1998, has continued to be re-isolated on an infrequent but regular basis. Due to its low pathogenicity, there has been little urgency to undertake a comprehensive characterisation of this aquatic birnavirus. However, faced with possible incursions of any new aquatic birnaviruses, specific identification and differentiation of this virus from other, pathogenic, aquatic birnaviruses such as infectious pancreatic necrosis virus (IPNV) are becoming increasingly important. The present study determined the nucleic acid sequence of the aquatic birnavirus originally isolated in 1998, as well as a subsequent isolate from 2002. The sequences of the VP2 and VP5 genes were compared to that of other aquatic birnaviruses, including non-pathogenic aquatic birnavirus isolates from New Zealand and pathogenic infectious pancreatic necrosis virus isolates from North America and Europe. The deduced amino acid (aa) sequences indicate that the Australian and New Zealand isolates fall within Genogroup 5 together with IPNV strains Sp, DPL, Fr10 and N1. Thus, Genogroup 5 appears to contain aquatic birnavirus isolates from quite diverse host and geographical ranges. Using the sequence information derived from this study, a simple diagnostic test has been developed that differentiates the current Australian isolates from all other aquatic birnaviruses, including the closely related isolates from New Zealand. PMID- 21290893 TI - Physicochemical properties of double-stranded RNA used to discover a reo-like virus from blue crab Callinectes sapidus. AB - Mortality among blue crab Callinectes sapidus in soft shell production facilities is typically 25% or greater. The harvest, handling, and husbandry practices of soft shell crab production have the potential to spread or exacerbate infectious crab diseases. To investigate the possible role of viruses in soft shell crab mortalities, we took advantage of the physicochemical properties of double stranded RNA (dsRNA) to isolate a putative virus genome. Further characterization confirmed the presence of a reo-like virus that possesses 12 dsRNA genome segments. The virus was present in >50% of dead or dying soft shell crabs, but fewer than 5% of healthy hard crabs. Injection of the virus caused mortality and resulted in the appearance of viral RNA and virus inclusions in hemocytes. The genome of the virus was partially sequenced and the information used to develop a reverse transcription polymerase chain reaction (RT-PCR) assay that is able to detect the virus genome in as little as 7.5 pg of total RNA. The molecular tools developed during this study will allow us to quantify prevalence of the blue crab reo-like virus in captive (soft shell facilities, aquaculture operations) and wild populations and facilitate understanding of the role this virus has in blue crab life history. PMID- 21290894 TI - Development of PCR assays to detect iridovirus infections among captive and wild populations of Missouri River sturgeon. AB - The Missouri River sturgeon iridovirus (MRSIV) is an important factor contributing to losses during the hatchery rearing of juvenile pallid Scaphirhynchus albus and shovelnose S. platorynchus sturgeon. As the virus has not been isolated in cell culture, current detection procedures rely upon a combination of light and electron microscopy. Detection of characteristic virus infected cells in the integument, usually of the fins, in hematoxylin and eosin (H&E)-stained tissue sections provides a presumptive finding. Confirmation requires observation by electron microscopy of characteristic doubly enveloped hexagonal virions of the appropriate size in the host cell cytoplasm. To improve these diagnostic procedures, a conventional polymerase chain reduction (PCR) assay was developed as a sensitive and specific method for detection of MRSIV DNA as found in numerous tissues of both naturally and experimentally infected pallid and shovelnose sturgeon. Sequences of amplicons obtained from testing of wild caught shovelnose sturgeon and juvenile pallid sturgeon during hatchery outbreaks were identical, suggesting that the viruses found in both sturgeon are similar or closely related. In addition, a TaqMan PCR was developed that allowed estimates of the concentrations of MRSIV DNA present in the tissues of pallid and shovelnose sturgeon during acute and persistent infection. These new PCR assays are improved methods to detect MRSIV, but equally importantly, they provide insights into to the biology of the agent for more effective management of viral diseases in captive and wild Missouri River sturgeon populations. PMID- 21290895 TI - Chronic and persistent viral hemorrhagic septicemia virus infections in Pacific herring. AB - Chronic viral hemorrhagic septicemia virus (VHSV) infections were established in a laboratory stock of Pacific herring Clupea pallasii held in a large-volume tank supplied with pathogen-free seawater at temperatures ranging from 6.8 to 11.6 degrees C. The infections were characterized by viral persistence for extended periods and near-background levels of host mortality. Infectious virus was recovered from mortalities occurring up to 167 d post-exposure and was detected in normal-appearing herring for as long as 224 d following initial challenge. Geometric mean viral titers were generally as high as or higher in brain tissues than in pools of kidney and spleen tissues, with overall prevalence of infection being higher in the brain. Upon re-exposure to VHSV in a standard laboratory challenge, negligible mortality occurred among groups of herring that were either chronically infected or fully recovered, indicating that survival from chronic manifestations conferred protection against future disease. However, some survivors of chronic VHS infections were capable of replicating virus upon re exposure. Demonstration of a chronic manifestation of VHSV infection among Pacific herring maintained at ambient seawater temperatures provides insights into the mechanisms by which the virus is maintained among populations of endemic hosts. PMID- 21290896 TI - Previously unrecognised division within Moritella viscosa isolated from fish farmed in the North Atlantic. AB - Previously undocumented phenotypical and genetic variation was identified amongst isolates of Moritella viscosa collected from various geographical locations and from different fish species. The studied isolates could be split into 2 major phenotypically and genetically different clusters, one of which was consistent with the species type strain (NCIMB 13548). Isolates consistent with the type strain originated exclusively from Atlantic salmon farmed in Norway, Scotland and the Faroe Isles, although a single isolate from farmed Norwegian cod clustered closely with this group. The 'variant' cluster comprised isolates originating from Norwegian farmed rainbow trout, Icelandic farmed rainbow trout and salmon, Canadian farmed (Atlantic) salmon, Icelandic lumpsucker and only exceptionally from Norwegian salmon. With the exception of the single aforementioned cod isolate, all isolates from Norwegian farmed cod belonged to the variant cluster. Phenotypically, the clusters could be absolutely separated only by elevated haemolytic activity in the variant strain, although approximately half of these isolates also produced acid from mannose, in contrast to the typical (type) strain. While 16S rRNA gene sequencing was unable to separate the 2 clusters, Western blot analyses, plasmid profile analysis, pulsed field gel electrophoresis and gyrB gene sequence analysis produced clusters consistent with the phenotypic data. Macroscopically and histologically the disease in rainbow trout caused by the variant strain was consistent with that previously described in Atlantic salmon. The results of the present study may indicate a degree of host specificity of the typical strain for Atlantic salmon. PMID- 21290897 TI - Mortality threshold for juvenile Chinook salmon Oncorhynchus tshawytscha in an epidemiological model of Ceratomyxa shasta. AB - The myxozoan parasite Ceratomyxa shasta is a significant pathogen of juvenile Chinook salmon Oncorhynchus tshawytscha in the Klamath River, California, USA. This parasite requires 2 hosts to complete its life cycle: a freshwater polychaete (Manayunkia speciosa) and a salmonid. The complex life cycle and large geographic area where infection occurs make it difficult to monitor and manage ceratomyxosis. We present a model for ceratomyxosis-induced mortality in O. tshawytscha, from which parameters important to the persistence of C. shasta are identified. We also experimentally quantify specific parameters from the model and identify a mortality threshold (a critical parameter), by naturally exposing native O. tshawytscha to C. shasta in the Klamath River. The average percent mortality that resulted from these experimental challenges ranged from 2.5 to 98.5% over an exposure dose of 4.4 to 612 x 10(6) parasites. This experiment identified a non-linear mortality threshold of 7.7 +/- 2.1 x 10(4) actinospores fish(-1) for Chinook salmon from the Iron Gate Hatchery on the Klamath River. Below this threshold no mortality occurred and above it mortality increased dramatically, thus providing a target by which to reduce parasitism in emigrating juvenile O. tshawytscha. PMID- 21290898 TI - Helminth community structure of Scinax nasicus (Anura: Hylidae) from a South American subtropical area. AB - The main goal of this study was to evaluate the relative influence of season, year of study, host body size, and host sex on abundance of helminth species parasitic in the frog Scinax nasicus. A total of 273 frogs was collected between December 2004 and November 2006 over all seasons in Corrientes City, Province of Corrientes, Argentina. Helminth community included 21 taxa, and was dominated particularly by larval trematodes. Infected frogs harboured a maximum of 7 species. Host sex and season played no significant effect in determining infracommunity parasite species abundance. Similarly, species richness was similar for both host sexes, and across time (year and season). However, occurrence of the parasites Opisthogonimus sp. 2 and Travtrema aff. stenocotyle greatly varied over time. Host body size was the main factor for determining infrapopulation structure of Centrorhynchus sp. Species richness was significantly and positively correlated with host body size. Strong associations were observed mainly between metacercariae of some species. The transmission strategies of parasites suggest that this hylid acquires infections by ingestion of infective larvae and through direct contact with larval parasites from aquatic and terrestrial habitats. PMID- 21290900 TI - Embracing change--delivering optimized prevention as a team. PMID- 21290899 TI - Novel recombinant monoclonal antibodies for vitellogenin assays in cyprinid fish species. AB - Various polyclonal and monoclonal antibodies have been developed for vitellogenin (Vtg) bioassays in different aquatic species. Preparation of these reagents is time-consuming and expensive. In the present study, a phage-displayed, recombinant, single-chain variable fragment (scFv) format antibody library was constructed using splenic mRNA from non-immunized mice. After 3 rounds of panning, 3 scFv antibodies with specificity for the highly conserved N-terminal region of cyprinid fish Vtg were isolated. One of these, antibody H4, bound purified Vtg from common carp Cyprinus carpio, zebrafish Danio rerio and Chinese rare minnow Gobiocypris rarus with similar affinities and detected Vtg in zebrafish plasma samples. This study provides a simple, low cost Vtg bioassay for plasma samples from a variety of cyprinid fish. PMID- 21290901 TI - Caries control from cradle to grave. AB - Caries is a ubiquitous, natural process occurring in the biofilm. The interaction of the biofilm with the dental tissues may result in a caries lesion, the reflection of the process being the consequence that can be seen. However, lesion formation and progression are not inevitable because the process in the biofilm can be controlled by plaque control, fluoride and a sensible diet. This paper summarizes caries control in note form and it questions how these measures are to be carried out under the current Unit of Dental Activity payment system used within the NHS Dental Services in England and Wales. CLINICAL RELEVANCE: Caries control is the non-operative management of the ubiquitous, natural process in the biofilm so that lesions do not form, or established lesions are arrested. This paper seeks to present these caries control measures in note form as checklists to aid the dental team. PMID- 21290902 TI - Water fluoridation as a public health measure. AB - Water fluoridation schemes have been used as dental public health measures for over 50 years. This second paper in a series of three aims to provide a background to the history of water fluoridation schemes and the evidence base that led to their implementation. The article will also discuss the processes and chemicals involved in fluoridation during water treatment. CLINICAL RELEVANCE: This article aims to provide a summary for general practitioners of the history and evidence base for water fluoridation, to enable them to understand the role of water fluoridation in caries prevention and to be able to answer non-clinical questions raised by patients. PMID- 21290903 TI - Pharmacology and the elderly. AB - This paper describes the impact of ageing on an individual's ability to process drugs. It considers adverse drug reactions in the elderly and discusses prescribing for the older dental patient. CLINICAL RELEVANCE: Many older dental patients will be suffering from medical conditions or taking prescribed or non prescribed drugs. These can influence the impact of drugs prescribed by dentists. PMID- 21290904 TI - The role of the dentist in sleep disorders. AB - Snoring and sleep apnoea are common. The demand for sleep medicine services has increased exponentially since the recognition of sleep apnoea as a disease in the 1960s. The involvement of dentists in the treatment of sleep apnoea has increased. This article provides an overview of the disorders and options for management. CLINICAL RELEVANCE: It is important that dentists are aware of the problem of sleep disorders and the potential they have to help in their management. PMID- 21290905 TI - Revisiting the principles of partial denture design. AB - Dentists may find partial denture design difficult. This is often due to lack of educational experience. Removable partial dentures (RPDs) are one-off prosthodontic solutions that require proper assessment, planning and preparation, combined with effective design. This article revisits the principles of RPD design. CLINICAL RELEVANCE: One in six people in Britain have some form of RPD. Many of these are unworn. For future well-being of patients, improvement in RPD provision is essential. PMID- 21290906 TI - An unusual dental anomaly in a hypodontia patient. AB - Hypodontia is the most common developmental dental anomaly known in humans. It is often associated with other dental anomalies such as disturbances in eruption, peg lateral incisors and taurodontism. This case report describes a ten-year-old female with hypodontia and a very unusual conical-shaped mandibular right central incisor, which has not previously been reported in the literature. The case highlights the importance of prompt referral to an interdisciplinary team so joint decisions on management can ensure an optimal outcome with the corresponding improvement in quality of life. CLINICAL RELEVANCE: Hypodontia and other developmental dental disorders are common and their early recognition and prompt referral is important. PMID- 21290907 TI - Dental care professionals: their training and clinical practice in the UK. AB - Since the event of compulsory registration, Dental Care Professionals now make up approximately 60% of the dental workforce. This article outlines training for all groups of Dental Care Professionals and discusses their clinical practice, emphasizing the importance of their involvement in the delivery of holistic patient care. CLINICAL RELEVANCE: To promote understanding of training and the current roles and responsibilities of the wider dental team. PMID- 21290908 TI - Dental decisions--an emotional experience? AB - This article discusses the psychological literature on emotion, highlighting the effect of emotion on decision-making. This is applied to the example of dentistry. CLINICAL RELEVANCE: This article explores how the everyday decisions of both the patient and the dentist are influenced by their emotions. PMID- 21290909 TI - Cross cultural adaptation of oral health-related quality of life measures. AB - Oral Health-Related Quality of Life (OHRQOL) is the shift in the perception of health from merely the absence of disease and infirmity to complete physical, mental and social well-being. The impact of health on the quality of life has received more attention in recent years in both general and oral health. OHRQOL assessments are used in oral health research, surveys and studies evaluating the outcome of oral care. If researchers have no appropriate health-related quality of life (HRQOL) measure in their own language, they have two options: to develop a new measure or to modify a measure that has previously been validated in another language which is known as a cross-cultural adaptation process. The aim of this study is to provide guidance on how to adapt an existing measure of Oral Health-Related Quality of Life (OHRQOL) for a different culture. CLINICAL RELEVANCE: It is important that dental professionals should have sufficient knowledge about Oral Health-Related Quality of Life in order to make sure that providing the treatment focuses on the patient rather than the disease. In addition, information about a patient's OHRQOL will make decisions on treatment plans which are more likely to influence clinical outcomes. PMID- 21290910 TI - Faster is not always better! PMID- 21290911 TI - Comprehending the condition, causes, controversies, control and consequences. 2. Main risk factors and epidemiology. PMID- 21290912 TI - Physical signs for the general dental practitioner. Case 80. Livedo reticularis. PMID- 21290913 TI - The future of nursing. PMID- 21290914 TI - Change is coming. PMID- 21290915 TI - Clinical and cost effectiveness of guidelines to prevent intravascular catheter related infections in patients on hemodialysis. AB - Sepsis is the second leading cause of death in patients with end stage renal disease (ESRD) on hemodialysis (HD). The average cost to the healthcare system for catheter-related infections (CRI) ranges from $4000 to $80,235 for each occurrence. CRI is a significant health problem leading to increased hospitalizations, morbidity, mortality, and a financial burden to the healthcare system. The purpose of this study was to evaluate the clinical and cost effectiveness of implementing published guidelines that pertain to patients on HD. Adult patients receiving long-term HD through a tunneled and cuffed HD catheter in an outpatient dialysis setting were studied. One-hundred and eighty seven patients on HD were instituted on published guidelines (chlorhexidine to clean the exit site and HD catheters/hubs, hand washing, aseptic technique with site/dressing changes/placing patients on HD, setting up an infrastructure to support monitoring CRI) and prospectively followed from May 2009 to April 2010. Comparison was made to a retrospective cohort of 198 patients on HD from May 2008 to April 2009 in the same unit using standard care (sodium hypochlorite to clean the exit site; povidone iodine to clean the HD catheter hubs). A t-test analysis compared the two groups for differences. The number of infections decreased from 1.7 to 0.2 per 1000 catheter days during a 12-month period (p = 0.005). The number needed to prevent one adverse outcome of a CRI was 22 patients, with a relative risk of 0.11 and relative risk reduction of 89% in the treated group. The return on investment for implementing the program was 169% in one year, and the break-even point occurred within the first quarter. The projected annual savings in one dialysis unit was $141,606 using the project hospital's data and $179,010 using national data. CRI in patients on HD are preventable. The analysis revealed a significant reduction in CRI by implementing published guidelines with a significant cost savings to the healthcare system. PMID- 21290916 TI - Peginesatide: a potential erythropoiesis stimulating agent for the treatment of anemia of chronic renal failure. AB - Erythropoiesis stimulating agents (ESAs) have revolutionized the management of anemia of chronic kidney disease (CKD). Peginesatide is an investigational pegylated, peptide-based, once-monthly ESA for increasing and maintaining hemoglobin (Hb). In phase 2 studies, peginesatide increases and maintains target Hb levels in patients with CKD, both those on hemodialysis and those not on hemodialysis; phase 3 trials have recently been completed. This article discusses unmet needs in the management of anemia of CKD, presents peginesatide attributes, reviews the results of select peginesatide clinical studies, and discusses the potential value of peginesatide as an alternative anemia management option. PMID- 21290917 TI - Frequency, severity, and distress of dialysis-related symptoms reported by patients on hemodialysis. AB - The purpose of this study was to determine which symptoms are the most reported occur most frequently, have the greatest severity, and cause the most bother for patients on hemodialysis (HD), and to determine if the symptoms experienced differ between the first (HD1) and second (HD2) treatments of the week. An observational, comparative design was used to determine participants' HD symptoms experienced on HD1 and HD2, and the effect of the symptom experience on quality of life (QOL). One hundred subjects were recruited from five dialysis centers. The adapted Dialysis Frequency, Severity, and Symptom Burden Index (DFSSBI) and the Medical Outcomes Study Short Form 36 (MOS SF 36) were administered (N = 99) on HD1 and the DFSSBI again on HD2. Data were analyzed for significance among symptom experience test scores in relation to HD1 and HD2, QOL, and gender and age. Of 31 symptoms assessed respondents reported an average of 9.77 symptoms on HD1 and 7.51 symptoms on HD2. Overall, more symptoms were reported and were more frequent, severe, and bothersome on HD1 when the level of metabolic waste is highest. The most reported symptoms included tiredness, dry skin, difficulty falling asleep, itching, numbness/tingling, difficulty staying asleep, decreased interest in sex, and bone/joint pain. Females scored consistently higher than males in the four symptom dimensions. Respondents reported about the same as the population norm (50) on the physical component summary score of the MOS SF 36 and higher than the norm (65.23) on the mental component summary score. The study found patients on HD experience multiple symptoms that can be frequent, severe, and bothersome. Interventions should be developed and tested to reduce symptom bother and improve QOL. PMID- 21290918 TI - Peritoneal dialysis survival in relation to patient body size and peritoneal transport characteristics. AB - This study compares patient and technique survival on continuous ambulatory peritoneal dialysis (CAPD) and other peritoneal dialysis (PD) modalities in relation to body size indicators, race, sex, and peritoneal transport characteristics. Data were abstracted from a PD adequacy database, with 354 patients subjected to analysis. Transfers between PD modalities were almost exclusively from CAPD to various offshoots of PD, mostly due to inadequate dialysis or inadequate ultrafiltration. Survival analysis showed better technique survival for other PD modalities compared to CAPD when body mass index was less than 25 kg/m2, body surface area (BSA) was less than 1.9 m2, total body water was less than 39 L, and the dialysate-to-plasma ratio of creatinine at four hours was less than 0.65 by the peritoneal equilibration test (PET). There were no differences found in relation to gender, race, or PET ratio of dialysate glucose at four hours to dialysate glucose at time zero. In other PD modalities, no differences in technique and patient survival were found in regard to the same parameters, with the exception of better technique survival in males with a BSA over 1.9 m2. In conclusion, CAPD technique survival is better in the small patient with below average peritoneal transport characteristics. In other PD modalities, survival is not related to anthropometric indices or peritoneal transport characteristics. PMID- 21290919 TI - Pregnancy and dialysis: an overview. AB - The occurrence of pregnancy in women with chronic kidney disease undergoing dialysis is still uncommon; however, women in this population do become pregnant and need management by renal and high-risk obstetric teams to promote best outcomes. This article discusses recommendations for medical considerations, the dialysis regimen, medications used, medical nutrition therapy, and the assessment of dry weight gain. Most recommendations are based upon case experience. PMID- 21290920 TI - An arteriovenous fistula (AVF) functionality quality improvement tracking tool- developed and implemented to improve newly placed AVF utilization rates and patient outcomes. AB - The authors developed a reporting tool to assist hemodialysis clinicians to track new arteriovenous fistulas (AVFs), their maturation, and use. The tool identifies impediments to timely use (6 weeks/42 days) of AVFs. The use of this tool in nine dialysis units with high gaps between AVF placement and usage reduced the gap from 19.5% to 13.5% and reflected a reduction in the percentage of AVFs in place but not in use from 31.4% to 23.2%. PMID- 21290921 TI - Sharing secrets of the hemodialysis club. PMID- 21290922 TI - Psychometric properties of the Arabic version of the Depressive Cognition Scale in first-year adolescent Egyptian nursing students. AB - BACKGROUND: Identifying depressive cognitions in adolescent nursing students can be an important step to prevent the development of clinical depression, which is positively associated with suicide. PURPOSE: This study focused on the psychometric testing of the Arabic version of the Depressive Cognition Scale (A DCS) among 170 first-year adolescent Egyptian nursing students. METHODS: The questionnaire was assessed for internal consistency, homogeneity, and construct validity using factor analysis and convergent validity. RESULTS: Cronbach's alpha for (A-DCS) was .86. The homogeneity of the instrument was supported by item-to total correlations between .30 and .70. Factor extraction generated only one factor with eigenvalues greater than 1, which is consistent with the English version. The (A-DCS) total score had a strong significant correlation with the Alienation Scale scores (r = .51, p < .01), indicating convergent validity. CONCLUSION: This scale has the potential to become a useful screening tool for depressive cognitions among Egyptian nursing students. PMID- 21290923 TI - Factor analyses of condom attitudes, norms, and self-efficacy measures in diverse samples. AB - Measurement of condom attitudes, norms, and self-efficacy is variable, reducing research generalizability. The purpose of this study was to assess reliability and construct validity of measures of condom attitudes, norms, and self-efficacy across 3,989 youth. Data were collected at computer kiosks and on the Internet. Analyses included internal consistency reliability assessments and exploratory and confirmatory factor analyses of three constructs in a 32-item a priori instrument. Reliability estimates ranged between 0.68 and 0.89, and goodness of fit indices all exceeded 0.90. Factor analysis results supported the compatibility of the items from the three subscales with their conceptual domains. Final scales include measures of positive and negative outcome expectancies related to condom use, peer and partner condom norms, self-efficacy for condom negotiation, and self-efficacy for condom use. These measures of condom attitudes, norms, and self-efficacy can be employed for assessments to improve standardization of measures and generalizability of research, particularly related to HIV prevention. PMID- 21290924 TI - The nursing incivility scale: development and validation of an occupation specific measure. AB - This article describes the development of the Nursing Incivility Scale (NIS), which is designed to assess hospital nurses' experiences with incivility according to specific sources-physicians, coworkers, patients, and direct supervisors. The NIS was developed using focus groups with nurses at a hospital in the midwestern United States and validated during a second survey administered to 163 hospital nurses. Exploratory factor analysis revealed that the NIS items grouped according to a priori scale construction. All subscales showed acceptable reliability and demonstrated acceptable convergent and discriminant validity with other variables. The results indicate that the NIS has good psychometric qualities and can be used by hospitals and health care administrators to assess the prevalence of incivility. PMID- 21290925 TI - Lessons learned in instrument pilot testing with Mexican American caregivers of elders. AB - Given the fast-growing Mexican American (MA) population, it is common for investigators to be pressured into using Spanish translated instruments developed for English-speaking populations. However, these translated instruments may have limited relevance for data collection without adequate assessment and vetting. The purpose of this paper is to present lessons learned from the pilot testing of instruments designed for use with Mexican Americans. Pilot testing of two instruments was conducted with 22 Mexican American family caregivers of older adults. Issues that emerged were classified into three categories instrumentation, methodology, and demographic data. Within the area of instrumentation, six issues were identified-level of abstraction, concreteness, pronoun use, clarity, exclusiveness, and response format. Methodological concerns were focused on test-retest administration and inclusion criteria. Issues within the demographic data were concerned with marital status, country of birth, household size and income, and validity of self-rated scales. By addressing those concerns, investigators may be more likely to have culturally sensitive measures and greater generalization to relevant MA populations. PMID- 21290926 TI - Review of scales of parenting confidence. AB - Interest in the measurement of parenting confidence in research and clinical contexts has grown considerably in recent decades, particularly in the area of health care. Psychometric and technical characteristics of scales assessing this construct suitable for the parents of children aged 0-12 years were reviewed in this research. In so doing, information is provided that will assist clinicians and researchers in selecting a measure suitable to their needs. Thirty-six instruments assessing parenting confidence were located. Two dominant approaches to item selection were evident: (1) general items suitable for a range of child ages, or (2) task-specific items suitable for parents of a child of a particular age. Psychometrically, most scales possessed adequate reliability data, although validity data for many scales was limited. In addition, only two of the instruments, both with general items, had stratified normative data. Scales appropriate for a range of research purposes and some clinical applications are available. Further research is necessary to provide normative data for task specific parenting confidence scales. PMID- 21290927 TI - Young adult sibling relations: the effects of perceived parental favoritism and narcissism. AB - The present study examined predictors of siblings' relations in 202 young adults (aged 21-32 years), who completed the Adult Sibling Relationship Questionnaire and the Narcissistic Personality Inventory. Results indicate that warmth between siblings is explained by gender (with women feeling closer), perceived paternal favoritism, low levels of narcissism, and an interaction suggesting that paternal favoritism moderates the link between narcissism and sibling warmth. Conflict between siblings was explained by gender (sisters), age, parental favoritism, high levels of narcissism, extreme levels of similarity or dissimilarity between siblings, and interactions indicating that older age is a predictor of conflict between siblings among women but not among men. The impact of parental favoritism and narcissism on sibling relationships in young adulthood was discussed. PMID- 21290928 TI - Evaluating the college sophomore problem: the case of personality and politics. AB - College sophomores feature prominently in social scientific research but are frequently criticized for providing unrepresentative, invalid, and unreliable data. Using the case of personality and politics, the present authors evaluated those critiques, concluding that college sophomores are not representative of the general adult population on all 5 factors of personality. Despite this limitation, analyses show that the relationship between personality and political opinions is virtually identical for college students and a comparison group of adults. Further, a range of reliability statistics suggests that college students provide reliable data on personality. College students are not a panacea for the problems of participant recruiting, but they should not be discounted as unreliable and invalid, either. In many cases, the so-called "college-sophomore problem" is not a problem. PMID- 21290929 TI - Insight, rumination, and self-reflection as predictors of well-being. AB - Dispositional private self-focused attention variables such as insight, internal self-awareness (ISA), and self-reflectiveness (SR) have been found to relate to well-being. The present study sought to determine which dispositional private self-focused attention variables have the most predictive power for subjective well-being as measured by the Satisfaction With Life Scale (E. Diener, R. A. Emmons, R. J. Larsen, & S. Griffin, 1985) and for a eudaemonic form of well-being as measured by the Psychological Well-Being Scale (C. D. Ryff, 1989). A total of 121 college student participants completed an online version of the Self Consciousness Scale-Revised, the Rumination-Reflection Questionnaire, the Self Reflection and Insight Scale, the Satisfaction With Life Scale, and the Psychological WellBeing Scale. Results of a multivariate regression analysis using the Self-Consciousness Scale-Revised's (M. F. Scheier & C. S. Carver, 1985) subfactors of SR and ISA, the Rumination-Reflection Questionnaire's (P. D. Trapnell & J. D. Campbell, 1999) subscales of Rumination and Reflection, and the Self-Reflection and Insight Scale's (A. M. Grant, J. Franklin, & P. Langford, 2002) Self-Reflection and Insight subscales revealed that the Insight subscale was the only statistically significant predictor (a positive predictor) for all 6 dimensions of psychological well-being. Insight was also the only significant positive predictor for satisfaction with life. The Rumination subscale was a significant negative predictor for 3 dimensions of psychological well-being, and the Reflection subscale was a significant positive predictor for 1 dimension. Implications of dispositional self-awareness variables and their relation to dimensions of well-being are discussed. PMID- 21290930 TI - The relationship between preretirement occupation and older adults' life satisfaction and self-rated health. AB - Pensioners currently compose nearly 20% of the British population; men and women can expect to spend an average of about 17 years and 19 years in retirement, respectively. The present study aimed to investigate the roles of preretirement occupation and self-rated health (SRH) on the attainment of life satisfaction in retired people. A total of 121 community-dwelling men and women (M age = 75.8 years, SD = 7.1) completed a survey to assess life satisfaction, self-rated health, retirement stress, retirement adjustment, and recollected aspects of preretirement occupation. Results revealed positive and significant correlations between scores on a life satisfaction measure and SRH, retirement stress, and retirement adjustment (all ps < .001). Path analysis indicated that aspects of previous employment that may predict an adverse influence on current life satisfaction and that engagement in voluntary work appears to have benefits for both life satisfaction and SRH. The authors conclude that many of the adverse effects of preretirement occupation can be helped or avoided through suitable retirement preparation and training. PMID- 21290931 TI - Ovipositional behavior in the context of mass rearing of Anopheles arabiensis. AB - Large-scale production of mosquitoes is a key factor for a successful sterile insect technique program. A manageable mass-production cage must contain appropriate features for adult resting, mating, feeding, and ovipositional activities. In order to maximize egg collections, tests were conducted to determine the physical characteristics of ovipositional sites for caged Anopheles arabiensis. Effects of texture, shade, height, and shape of the ovipositional container on female behavior were investigated. Results indicate a strong preference for oviposition on humid substrates over free-standing water. The shade and texture of the cup's walls also influenced site choice, with black rough inner vertical walls of the cup resulting in the largest number of eggs. Ovipositional sites with square shape were preferred rather than circular cups, and in the square cups, >60% of the eggs were laid in the corners. Height also affected oviposition, as An. arabiensis significantly favored the lowest sites even though some oviposition occurred at higher sites. Based on this study and from available literature, we determined the characteristics of an artificial ovipositional site that includes all these characteristics, which will yield large numbers of eggs required for mass production of this species. PMID- 21290932 TI - The effects of moisture on ovipositional responses and larval eclosion of Aedes albopictus. AB - Moisture plays a major role in the dynamics of mosquito populations, especially those breeding in container habitats. Despite this importance, the role of moisture conditions as they affect oviposition and egg development in Aedes vectors remains largely unexplored. We investigated the effect of exposing gravid female Aedes albopictus mosquitoes and their eggs to different moisture levels (MLs) for various periods on oviposition and hatching. Overall, high-moisture substrates (HMSs; 66% and 72%) provided better environments for egg laying. The timing of initial egg laying was far longer at the lowest substrate moisture level (LSML, 25% and 41.2%) than at HMSs. The numbers of eggs laid were much lower in the drier environments. At LSMLs, gravid females retained increasing numbers of mature eggs until death, and egg retention decreased gradually with increasing ML. The HMSs also provided better environments for larval eclosion. The numbers of eggs hatched were lower at the LSML than the HSML environment. No egg hatching occurred after 1 h exposure to moisture. However, egg hatching occurred by installment, with spontaneous hatching (SH) increasing gradually with increasing ML. High-moisture conditions combined with long exposure (30 h and 48 h) favored SH. These results suggest that Ae. albopictus females can respond to better moisture conditions for increased success of embryonation and larval eclosion. This information may be useful in the colonization of floodwater Aedes species. PMID- 21290933 TI - An in vitro assay for testing mosquito repellents employing a warm body and carbon dioxide as a behavioral activator. AB - We describe here an in vitro behavioral assay for testing mosquito repellents applied in a dose-based manner to a warm body (34 degrees C) in test cages. The system was used to assess the sensitivity of 4-6-day-old Anopheles gambiae to the insect repellent diethyl methyl benzamide (deet). These tests were made in the absence and presence of additional carbon dioxide (CO2) applied as a pulse to activate mosquitoes in the cages. In the absence of the CO2 pulse the mosquitoes hardly responded to the warm body. Increasing the CO2 level in the cage by 1,000 parts per million caused a 25-fold increase in the number of landings by mosquitoes on the warm body in 2-min tests. This mosquito activation allowed the measurement of a significant reduction in the number of landings to bite on the warm body with increasing doses of deet (0.4 to 3.8 microg/cm2). An asymptotic nonlinear model fitted to the repellency data in the presence of CO2 allowed estimation of the effective dose of deet that reduced landings to bite by 50% (ED50) at 0.95 microg/cm2 (5 nmol/cm2) and the corresponding ED95 at 4.12 microg/cm2 (21.5 nmol/cm2). This in vitro bioassay has the advantage of permitting a fast throughput of test products under standardized conditions and is suitable for screenings designed for the purpose of discovering lead products with as yet unknown human toxicological and dermatological profiles. PMID- 21290934 TI - Efficacy of alpha-cypermethrin and lambda-cyhalothrin applications to prevent Aedes breeding in tires. AB - The efficacy of alpha-cypermethrin (Cyperthor) and lambda-cyhalothrin (Demand) to prevent mosquito larval colonization of water-containing receptacles was investigated using 2 differing applications in disused car tires in Darwin, Australia. Insecticide treatments were applied uniformly to the inside surfaces of 2 categories of tires: 1) dry tires that were partially filled with water 24 h after spraying and 2) wet tires partially filled with water prior to spraying. All mosquito larvae, pupae, and dead adults were collected from the treatment and control tires weekly over the 24-wk study period and were later identified to species in the laboratory. Control tires were colonized by Aedes notoscriptus in wk 2 and by Culex quinquefasciatus in wk 4. Aedes notoscriptus failed to colonize any alpha-cypermethrin-treated tires until wk 22 and did not colonize any lambda cyhalothrin-treated tires during the 24-wk trial. Culex quinquefasciatus colonized alpha-cypermethrin and lambda-cyhalothrin-treated tires from wk 11 and wk 15, respectively. These results indicate both insecticides using either application method can prevent colonization of Ae. notoscriptus for at least 20 wk and demonstrate great potential for the prevention of breeding in receptacles for other receptacle-breeding Aedes species, such as the dengue vectors, Ae. aegypti and Ae. albopictus. PMID- 21290935 TI - Laboratory evaluation of insecticide-treated sugar baits for control of phlebotomine sand flies (Diptera: Psychodidae). AB - The purpose of this study was to evaluate the use of boric acid, imidacloprid, ivermectin, or abamectin incorporated into sugar baits as oral toxicants for adult phlebotomine sand flies. Variable toxicity of insecticide-sugar bait solutions to adult male and female sand flies was demonstrated, based on male female median lethal concentration values of 0.10-0.08, 6.13-9.53, and 9.03-18.11 mg/liter of imidacloprid, ivermectin, and abamectin, respectively. Complete control of sand flies could not be achieved with as high as 40 g/liter of boric acid in sugar bait solution; concentrations >40 g/liter were found repellent to the sand flies. Uranine O (a fluorescent tracer dye that can be used to measure the ingestion of sugar baits by sand flies) did not interact negatively with imidacloprid, ivermectin, or abamectin when it was combined with the insecticides in a sugar bait. Also, incorporation of imidacloprid, ivermectin, or abamectin into sugar baits did not reduce the effect whether adult male and female sand flies fed on these sugar baits. We propose that imidacloprid, ivermectin, or abamectin could be used to control adult sand fly populations with targeted use of insecticide-treated sugar baits. PMID- 21290936 TI - Organophosphate resistance in Trinidad and Tobago strains of Aedes aegypti. AB - Aedes aegypti larvae from 8 sites in Trinidad and 1 in Tobago were assayed against temephos, malathion, and fenthion using the Centers for Disease Control and Prevention time-mortality-based bioassay method. Resistance ratios (RRs) and resistance thresholds (RTs) for each insecticide were calculated in relation to the Caribbean Epidemiology Center reference susceptible strain. Results showed that the Haleland Park and Tobago strains were susceptible to fenthion and malathion, respectively (RRs < 1), while the San Fernando strain had a high RR (33.92) to malathion. All other strains had low-level resistance to fenthion and malathion. Resistance to temephos was more intense with 4 strains showing high level resistance. The established RT was 60 min for fenthion, 75 min for bendiocarb, and 120 min for temephos and malathion. At the RTs, all Trinidad strains were resistant to temephos (11.50-74.50% mortality), 7 resistant to fenthion (21.25-78.75% mortality), and 5 resistant to malathion (56.25-77.50% mortality). The other strains were incipiently resistant (80-97% mortality). Despite the discrepancies between the RR levels and RT status, it is evident that the organophosphate insecticide resistance is prevalent in Trinidad and Tobago populations of Ae. aegypti. These results suggest that operational failure could soon occur and alternative strategies should be developed and implemented to reduce the probability of further selection pressure on resistant Ae. aegypti populations in Trinidad and Tobago. PMID- 21290937 TI - Filtration effects due to bioassay cage design and screen type. AB - The use of bioassay cages in the efficacy assessment of pesticides, application techniques, and technologies is common practice using numerous cage designs, which vary in both shape and size as well as type of mesh. The objective of this work was to examine various cage shapes and mesh types for their filtration effects on air speed, spray droplet size, and spray volume. Reductions in wind speed and droplet size seen inside the cages were measured by placing cages in a low-speed wind tunnel at air speeds of 0.5 m/sec, 1 m/sec, 2 m/sec, and 4 m/sec and cage face orientations (relative to the air stream) of 0 degrees, 10 degrees, 22.5 degrees, and 45 degrees. Reduction in spray volume inside a select number of cages was also evaluated under similar conditions. Generally, greater air speed reductions were seen at lower external air speeds with overall reductions ranging from 30% to 88%, depending on cage type and tunnel air speed. Cages constructed with screens of lower porosities and smaller cylindrical-shaped cages tended to provide greater resistance to air flow and spray volume. Overall, spray droplet size inside the cages was minimally reduced by 0-10%. There was a 32-100% reduction in concentration of the spray volume applied relative to that recovered inside the bioassay cages, depending on the cage geometry and screening material used. In general, concentration reductions were greatest at lower air speeds and for cages with lower porosity screens. As a result of this work, field researchers involved in assessing the efficacy of vector control applications will have a better understanding of the air speed and spray volume entering insect bioassay cages, relative to the amount applied, resulting in better recommended application techniques and dosage levels. PMID- 21290938 TI - Impact of electrostatic and conventional sprayers characteristics on dispersion of barrier spray. AB - A study was conducted to analyze the performance of 3 electrostatic (Electrolon BP-2.5, Spectrum Electrostatic 4010, and Spectrum Electrostatic head on a Stihl 420) and 2 conventional (Buffalo Turbine CSM2 and Stihl 420) sprayers for barrier sprays to suppress an adult mosquito population in an enclosed area. Sprayer characteristics such as charge-mass ratio, air velocity, flow rate, and droplet spectra were measured while spraying water. Dispersion of the spray cloud from these sprayers was determined using coverage on water-sensitive cards at various heights (0.5 m, 1.0 m, 1.5 m, 2.0 m, 2.5 m, and 3.0 m) and depths (1 m, 3 m, and 5 m) into the under-forest vegetation while spraying bifenthrin (Talstar 7.9% AI; FMC Corporation, Philadelphia, PA) at the rate of 21.8 ml/300 m of treated row. The charge-mass ratio data show that Electrostatic head on a Stihl 420 did not impart enough charge to the droplets to be considered as an electrostatic sprayer. In general, the charged spray cloud moved down toward the ground. The Electrolon BP 2.5 had significantly lower spray coverage on cards, indicating lack of spray dispersion. This sprayer had the lowest air velocity and did not have the air capacity needed to deliver droplets close to the target for electrostatic force to affect deposition. The analysis shows that these 2 sprayers are not a suitable choice for barrier sprays on vegetation. The results indicate that the Buffalo Turbine is suitable for barriers wider than 3 m, and the Spectrum 4010 and Stihl 420 are suitable for 1-3-m-wide barriers. PMID- 21290939 TI - Anopheles belenrae, a potential vector of Plasmodium vivax in the Republic of Korea. AB - The malarial parasite, Plasmodium vivax, was detected in 4 species of Anopheles (Hyrcanus Group) mosquitoes, namely An. kleini, An. pullus, An. belenrae, and An. sinensis, from Gyeonggi Province, Republic of Korea (ROK). This study confirmed that An. belenrae was infected by P. vivax, and implicated this species as a potential vector of vivax malaria in the ROK. PMID- 21290940 TI - Larvicidal activity of the extract of seaweed, Caulerpa scalpelliformis, against Culex pipiens. AB - The larvicidal efficacy of the acetone extract of the thalli of Caulerpa scalpelliformis var. denticulata was determined against late 2nd to early 3rd instars of Culex pipiens at concentrations ranging from 100 to 2,000 parts per million (ppm). At 1,200 ppm, the extract caused >70% larval mortality at 24-, 48 , and 72-h exposure. The LC50 (lethal concentration) and LC90 values of C. scalpelliformis were 338.91 and 1,891.31 ppm, respectively. Our data showed that this species of seaweed contains components with larvicidal properties against mosquitoes. PMID- 21290941 TI - In vitro and in vivo effects of West Nile virus propagated in cells of different passage. AB - Tissue cultures are used to propagate viruses for use in mosquito infection studies and to detect live virus in field-collected specimens. Microscopic evaluation of cytopathic effects is used to visualize virus presence. In this study, both low-passage (LP; n = 35) and high-passage (HP; n = 218) lines of African green monkey kidney (Vero) cells were infected with West Nile virus, and virus growth kinetics were quantitated over different incubation periods (IPs) (2, 6, 10, 24, 48, 72, and 96 h postinfection). Virus titers were significantly (P < 0.05) higher in the HP compared with LP line 24, 48, and 96 h postinfection. No differences were observed in plaque morphology between the LP and HP lines. Culex pipiens quinquefasciatus were fed infectious blood meals created using supernatant from the 2 lines and maintained at 28 degrees C for a 12-day IP. Although the virus dose was higher (P < 0.05) in the HP compared with the LP line, there were no significant differences in mosquito infection or dissemination rates at the end of the IP. The significance of these observations for assessing virus presence and pathogenicity is discussed. PMID- 21290942 TI - Circadian activity of Lutzomyia shannoni (Diptera: Psychodidae) during late season population peaks. AB - The phlebotomine sand fly, Lutzomyia shannoni (Dyar), is considered both zoophillic and anthropophillic and may be a potential vector of human and livestock pathogens. While the known range of this species in North America has recently been expanded, many aspects of its natural history, which are fundamental components for assessments of disease risk or development of integrated pest management programs for the vector, remain unclear. One is the time of day when individuals are active and searching for blood meals. Through the use of a rotating trap mechanism, male L. shannoni were found to be active earlier in the evening (1-4 h after sunset), whereas the majority of female activity occurred after midnight. PMID- 21290943 TI - Potential for stable flies and house flies (Diptera: Muscidae) to transmit Rift Valley fever virus. AB - Rift Valley fever (RVF), a disease of ruminants and humans, has been responsible for large outbreaks in Africa that have resulted in hundreds of thousands of human infections and major economic disruption due to loss of livestock and to trade restrictions. As indicated by the rapid spread of West Nile viral activity across North America since its discovery in 1999 and the rapid and widespread movement of chikungunya virus from Africa throughout the Indian Ocean Islands to Asia and Europe, an introduced exotic arbovirus can be rapidly and widely established across wide geographical regions. Although RVF virus (RVFV) is normally transmitted by mosquitoes, we wanted to determine the potential for this virus to replicate in 2 of the most globally distributed and common higher flies: house flies, Musca domestica, and stable flies, Stomoxys calcitrans. Neither species supported the replication of RVFV, even after intrathoracic inoculation. However, S. calcitrans was able to mechanically transmit RVFV to susceptible hamsters (Mesocricetus auratus) after probing on infected hamsters with high viral titers. Therefore, S. calcitrans, because of its close association with domestic animals that serve as amplifying hosts of RVFV, should be considered a possible mechanical vector of RVFV, and it may contribute to the rapid spread of a RVF outbreak. Other Stomoxys species present in Africa and elsewhere may also play similar roles. PMID- 21290944 TI - Evaluation of octenol and Lurex as baits in Mosquito Magnet Pro traps to collect vector mosquitoes in China. AB - The effectiveness of the attractants 1-octen-3-ol (octenol) and L-lactic acid (Lurex) on the collection of Aedes albopictus, Culex tritaeniorhynchus, Cx. pipiens pallens, and Anopheles sinensis was first evaluated in Mosquito Magnet Pro traps in Yamenkou and Badachu residential areas, Beijing City, and Lishui area, Zhejiang Province, China. The Mosquito Magnet Pro traps baited with octenol collected significantly more Ae. albopictus, Cx. tritaeniorhynchus, and An. sinensis, but fewer Cx. pipiens pallens than collection by the traps alone. There were no significant differences in the numbers of Cx. pipiens pallens, Cx. tritaeniorhynchus, and An. sinensis collected by Mosquito Magnet Pro traps baited with Lurex compared to the traps alone, but the Mosquito Magnet Pro traps baited with Lurex collected significantly more Ae. albopictus than the number collected by the traps alone at 2 areas in Beijing. PMID- 21290945 TI - Restrictive collaboration: the Alabama Nurse Practitioner. PMID- 21290946 TI - Tourette's syndrome. PMID- 21290947 TI - An inspiring first visit to West Africa. PMID- 21290948 TI - Stress care: turning failure into triumph. PMID- 21290949 TI - Health literacy: more than just the three Rs. PMID- 21290950 TI - Creating a lasting impression of a short life. Bereavement coordinators at SickKids facilitate "good deaths" by focusing on the needs of families. PMID- 21290951 TI - Workplace change: the good, the bad and the ugly. PMID- 21290952 TI - A team designed to meet patients' needs. PMID- 21290953 TI - Revisioning transition-to-practice issues. PMID- 21290954 TI - Please get your dirty hands off me! PMID- 21290955 TI - How the health care reform law affects APRNs. PMID- 21290956 TI - Reflections on Haiti and its resilient people. PMID- 21290957 TI - Reflections on nursing in a juvenile detention center. PMID- 21290958 TI - Safe after 60. PMID- 21290959 TI - Caregiver and nurse hopes for recovery of patients with acquired brain injury. AB - From the moment an adolescent with acquired brain injury (ABI) is admitted to the hospital, his or her caregiver develops hopes for the recovery and future of the patient; however, rehabilitation nurses have reported that these hopes are not always congruent with the nurse's observations of the adolescent's progression. The purpose of this study was threefold: (1) explore the caregiver's hope for recovery of his or her family member who has experienced an ABI, (2) compare the nurse's hopes for the patient with ABI to those of the caregiver, and (3) identify what caregivers and nurses do to maintain hope for recovery during the rehabilitation process. This qualitative study validated that in some cases there was a disconnect between caregivers' and nurses' hopes for recovery. Four themes related to the caregiver's maintenance of hope were identified: "the importance of family," "taking one day at a time," "knowing the patient better," and "spiritual strength brings me through." Enhancing the perceptual congruence between nurse and caregiver hope during rehabilitation will ultimately improve patient outcomes. PMID- 21290960 TI - Great rehabilitation nurses combine art and science to create magic. PMID- 21290961 TI - Delegation knowledge and practice among rehabilitation nurses. AB - Delegation is an essential process that allows nurses to function more effectively and efficiently. The Association of Rehabilitation Nurses' (ARN) Southeast Texas Chapter research committee developed a survey to study registered nurses (RN) practices and knowledge of delegation to unlicensed assistive personnel. State boards of nursing determine delegation practices, so the survey was sent only to Texas ARN members. Benners' Novice to Expert theory was used to study delegation practices based on years of experience, certification, and education. Survey Monkey was used with a questionnaire developed by the research committee. Descriptive statistics analyzed data from the survey's 73 respondents, and chi-square measured significance of differences based on years of experience and certification (yes or no). Data show that delegation knowledge does not necessarily translate to practice, especially when looking at specific tasks performed by certified rehabilitation registered nurses (CRRNs) and non-CRRNs. The data support continued study of this important issue; 93.7% of respondents say delegation requires further discussion. PMID- 21290962 TI - Nurses with sensory disabilities: their perceptions and characteristics. AB - A survey design was used to explore the perceptions and characteristics of registered nurses (RNs) with sensory disabilities and their risk for leaving their jobs. An earlier study found that nurses with disabilities are leaving nursing and that employers do not appear to support these nurses. Work instability and the mismatch between a nurse's perceptions of his or her ability and the demands of their work increase risk for job retention problems. This study's convenience sample of U.S. RNs had hearing, vision, or communication disabilities. Participants completed a demographic form, three U.S. Census questions, and the Nurse-Work Instability Survey. Hospital nurses were three times more likely to be at risk for retention problems. Nurses with hearing disabilities were frustrated at work. Hearing difficulties increased with years spent working as a nurse. Many nurses with sensory disabilities have left nursing. Early intervention may prevent work instability and increase retention, and rehabilitation nurses are ideally positioned to lead early intervention programs. PMID- 21290964 TI - Hanhart syndrome. AB - We report on a male infant with Hanhart Syndrome. It is classified in "oromandibular limb hypogenesis syndromes" which are a group of rare conditions involving congenital malformations of tongue, mandible, and limbs. PMID- 21290963 TI - Improving physical activity and function in overweight and obese older adults with osteoarthritis of the knee: a feasibility study. AB - Osteoarthritis of the knee, a prevalent condition in older adults, can impact physical function and ability to perform physical activity. This randomized controlled trial examined the effects of a 6-month self-efficacy-based, individually delivered, lower-extremity exercise and fitness walking intervention with 6-month follow-up on physical activity and function. The 26 subjects were mostly older (M = 63.2 years, SD = 9.8), White (83%), obese (BMI M = 33.3, SD = 6.0) women (96%). Physical activity was measured by diaries. Physical function was measured by the 6-minute walk, Short Physical Performance Battery (SPPB), and WOMAC Physical Function subscale. Exercise self-efficacy was assessed by a questionnaire. Results showed significant increases in self-reported performance of lower-extremity exercise and participation in fitness walking distance in the 6-minute walk, and SPPB scores from baseline to 6-month follow-up with a trend for improvement in self-efficacy. Results suggest that the intervention was feasible, acceptable, and improved physical activity and function. PMID- 21290965 TI - Clinical delineation of a patient with trisomy 1q32.qter and monosomy 5p resulting from a familial translocation 1;5. AB - We describe a patient who had multiple malformations including ventriculomegaly, colpocephaly, corpus callosum, cerebellum and vermix hypoplasia, optic nerve hypoplasia, corneal opacity and congenital heart disease in whom a trisomy 1q32 qter and monosomy 5p derived from a t(1;5)mat was diagnosed by karyotype and FISH analysis. This trisomy/monosomy association has not been previously reported. The familial analysis of the translocation was carried out in four generations and its implications on the phenotype of the patient and genetic counseling are discussed. PMID- 21290966 TI - Hopelessness of mothers who have children with Down syndrome. AB - This study was conducted to determine hopelessness status of mothers who have children with Down syndrome. Beck Hopelessness Scale was used in this restrictive type study. The average value of mothers enrolled in the study was detected as 8.29 +/- 2.49. Age, education level, socio-economical status, work and the problems between parents were also examined and it was found that there is a relationship between the education level, socio-economical status, the problems between parents and the hopelessness scale (p < 0.01). Consequently, it is apparent that the mothers who have children with Down syndrome need social and psychological support to overcome their feelings of hopelessness. PMID- 21290967 TI - A case of lower mesodermal defects sequence. AB - Here, we describe a stillborn fetus who had lower mesodermal defects sequence associated with craniorachischisis, anencephaly, bilateral pulmonary hypoplasia. PMID- 21290968 TI - Medical problems in children with Down syndrome in the Erzurum area of Turkey. AB - Down syndrome (DS) is diagnosed in approximately 1 Per 800 live births and is the most common known genetic cause of medical problems. To determine the prevalence of common medical problems in children with DS, a study was conducted between December 2003 and March 2010 in the Erzurum Nenehatun Obstetrics and Gynecology Hospital. 107 children with DS were entered into a retrospective observational study. Case notes were reviewed to obtain details regarding complications of children with DS. Medical problems such as cardiac, gastrointestinal, respiratory, sensory, orthopaedic anomalies, endocrine disorders, and obesity occur more frequently in children with DS. Clinicians should be aware of the risk of problems in children with DS. PMID- 21290969 TI - The case of an infertile male with an uncommon reciprocal X-autosomal translocation: how does this affect male fertility? AB - Infertility is defined as the inability to conceive after one year of regular unprotected intercourse. Constitutional numerical and/or structural chromosomal aberrations like sex-chromosome aberrations are one of the possible factors involved in fertility problems. Reciprocal translocations between an X-chromosome and an autosome are rarely seen in men. Male carriers of an X-autosome translocation are invariably sterile, regardless of the position of the breakpoint in the X-chromosome. Breakpoints in autosomal chromosomes could also be involved in male infertility. In this paper, we describe a 31-year-old male with azoospermia. GTG banding with high resolution multicolor-banding (MCB) techniques revealed a karyotype 46,Y,t(X;1)(p22.3;q25), and we discuss how the breakpoint of this translocation could affect male infertility. As a conclusion, cytogenetic evaluation of infertile subjects with azoospermia should be considered in the first place before in vitro fertilisation procedures are planned. PMID- 21290970 TI - Fryns syndrome with atypical findings--with large midline cleft on forehead but normal cranial MRI findings. AB - We report a newborn with Fryns syndrome and atypical findings like a large midline cleft on forehead. Abnormal findings included congenital left diaphragmatic hernia, prominent forehead, hypertelorism, broad nasal bridge, anteverted nostrils, cleft palate, low set ears, tapered fingers, macrocephaly, congenital heart defect, midline defects and renal anomalies. This is the first case that has a midline cleft on forehead with normal cranial MRI findings. PMID- 21290971 TI - Variegated-like mosaicism and ring syndrome in a r(4) boy. Appraisal of 38 patients with a fairly complete ring 4. AB - A 13-month-old boy with normal development and growth failure of prenatal onset but no other physical stigmata had a 46,XY,r(4)(p1 6.3q35).ish (4psubtel-, WHS1+, 4qsubtel+, pantel-) de novo karyotype. The analysis of 50-106 metaphases from each of four lymphocyte cultures (three of 72 h including one without colchicine and one of 96 h) revealed a dynamic mosaicism in 22-36% of cells. We did not observe a normal cell line. Hypoploidies (excluding ring losses) were observed in 2-7% of metaphases from colchicine-arrested cultures whereas tetraploidies were observed in 2-12% of metaphases from all four lymphocyte cultures. Further FISH studies were carried out on interphase nuclei from uncultured buccal cells and lymphocytes using two alphoid (CEP 1 and 9), a dual CEP X/SRY, and (in the former only) a subtel 4p probes. We scored 70-131 nuclei per assay and found apparent heteroploidies in approximately 1-47% of cells for CEP 1, CEP 9, subtel 4p, and SRY but not for CEP X. The patient's phenotype was typical of the ring syndrome and comparable to 9/37 previous r(4) cases. Moreover, all 38 patients were alive at the time of reporting and none has developed cancer. The 2-7% rate of hypodiploid cells in colchicine-arrested cultures and the approximately 1-47% rate of apparent heteroploidies in nuclei of uncultured cells evoke the in vitro and in vivo findings in patients with mosaic variegated aneuploidy (MVA). We conclude that our observation highlights the clinical and cytogenetical overlapping between the ring syndrome and the MVA syndrome; the crucial difference is the high risk of cancer related to BUB1B mutations in the latter. PMID- 21290972 TI - Educational-support groups for BRCA mutation carriers satisfy need for information but do not affect emotional distress. AB - INTRODUCTION: Due to high cancer risks, women carrying a BRCA 1/2 mutation face a complex choice between breast and ovarian cancer surveillance and prophylactic surgery. The aim of this study is to evaluate educational-support groups, which are offered to facilitate mutual support between BRCA mutation carriers and to provide adequate information. METHODS: Female BRCA mutation carriers were approached by a social worker after genetic test disclosure and offered participation in educational-support groups. Data regarding emotional well-being, breast cancer risk knowledge and perception, cancer risk management behaviour and family communication were collected both before (T1) and after group participation (T2). RESULTS: Of the 34 participants, mean levels of negative mood states at T1 were significantly higher compared to those of a norm group (depression p < 0.001, anger p < 0.001, fatigue p = 0.04, tension p = 0.03) and remained high at T2. Self-perceived breast cancer risk and frequency of cancer thoughts were high both at T1 and T2. Breast cancer risk knowledge was accurate both at T1 and T2; women either followed current surveillance advices or obtained prophylactic surgery. Communication with the family of origin was significantly reduced at T2 compared to T1 (p = 0.02). At T2, all women indicated that group participation highly met their needs of BRCA-related information to support their decision-making processes regarding cancer surveillance or prophylactic surgery. CONCLUSION: After following an educational support group female BRCA mutation carriers were able to make cancer risk management decisions but still reported high levels of emotional distress while family communication appeared diminished. PMID- 21290973 TI - Genetic alterations in gastric precancerous lesions. AB - To investigate the occurrence of 17p (p53) loss of heterozygosity (LOH) and increased 4N or aneuploidy in gastric precancerous lesions (GPL), and their association with Helicobacter pylori (H pylori) infection. A total of 78 gastric mucosal biopsy specimens, including 10 normal mucosa and 68 gastric precancerous lesions [chronic atrophic gastritis (CAG, n = 20), intestinal metaplasia (IM, n = 12), low grade dysplasia (LGD, n = 15), and high grade dysplasia (HGD, n = 21)] were studied using PCR and flow cytometry. A modified Giemsa staining technique was used to detect H pylori. The study was performed in Erzurum Numune Hospital between 2007 and 2009. 17p (p53) LOH was observed in (1/20) 5% of CAG, in (2/12) 16% of IM, in (3/15) 20% of LGD and in (11/21) 53% of HGD. There was correlation between prevalence of 17p (p53) LOH and histological type of GPL (P = 0.004). Similarly, increased 4N or aneuploidy was detected in (1/20) 5% of CAG, in (1/12) 8% of IM, in (2/15) 13% of LGD and in (9/21) 43% of HGD. The correlation was found between aneuploidy and histological type of GPL (P = 0.009). However, there was no correlation between presence of H pylori infection in histological type of GPL (P = 0.921). On the other hand, a significant association was found between increased 4N or aneuploidy and 17p (p53) LOH in all of GPL (P = 0.0001). However, there was no statistically significant association between H pylori infection and 17p (p53) LOH or increased 4N/aneuplody in GPL. 17p (p53) LOH and increased 4N or aneuploidy are closely related to the early stages of gastric carcinogenesis. PMID- 21290974 TI - Prenatal diagnosis of partial monosomy 1q (1q42.3-qter) associated with hydrocephalus and corpus callosum agenesis. PMID- 21290975 TI - A 5.3-Mb duplication of 9p12 --> p13.1 characterized by array CGH in a female infant with developmental delay. PMID- 21290976 TI - Screening for the M694V mutation of the familial Mediterranean fever (FMF) gene in 604 French patients. PMID- 21290977 TI - A new association or coincidence: achondroplasia and unilateral renal agenesis. PMID- 21290978 TI - Reply to Dundar et. al. why a causal association between classical euchromatic variants of chromosome 9 and multiple miscarriages is unlikely. PMID- 21290979 TI - An in vitro comparative study determining bactericidal activity of stabilized chlorine dioxide and other oral rinses. AB - OBJECTIVE: The study was conducted to determine the bactericidal activity of a stabilized chlorine dioxide oral rinse (CloSYS Oral Rinse) compared to products currently available on the market. METHODS: Oral bacteria associated with gingivitis and periodontitis were exposed to rinses for one minute and five minutes. The numbers of colony forming units per milliliter (CFU/ml) were measured prior to and following exposure to determine the bactericidal activity. RESULTS: As expected, Listerine and Crest Pro-Health demonstrated complete kill on all bacteria exposed within one minute. Breath Rx exhibited the weakest levels of bactericidal effects overall. CloSYS and chlorhexidine rinses proved identical 100% kills against the periodontal pathogens at five minutes; in some cases, CloSYS oral rinse achieved a higher kill at the one-minute mark over the chlorhexidine rinse. CONCLUSION: The results demonstrated that CloSYS Oral Rinse has potential for providing a therapeutic benefit, making it an attractive option to induce compliance in patients concerned about taste and tooth discoloration during oral health therapy. PMID- 21290980 TI - An in vitro investigation of two currently marketed dentin tubule occlusion dentifrices. AB - OBJECTIVE: The objective of this study was to evaluate the relative level of dentin tubule occlusion afforded by two dentifrices specifically developed to occlude dentin tubules, following finger-applied dab-on application and by repeated brushing, in a longitudinal acid-challenge-based dentin disk model. The impact of a dietary acid alone (grapefruit juice) on the level of dentin tubule occlusion conferred by each product following dab-on application was also explored in a separate short-term stand-alone exploratory dentin disk-based in vitro study. METHODS: For the longitudinal study, 120 bovine dentin discs, polished and etched in citric acid for two minutes to provide a smooth dentin surface with patent tubules, were divided into three treatment groups and subjected to a finger application of the dentifrice only, or a combination of finger application and brushing. Prior to and between treatments, the dentin samples were stored in saliva (for > 60 minutes). The test products were an 8% w/w strontium acetate dentifrice (currently marketed as Sensodyne Rapid Relief), an arginine-based dentifrice (marketed as Colgate Sensitive Pro-Relief), and deionized water. For the exploratory acid resistance study, 24 dentin samples were divided into two treatment groups. Treatment consisted of a single dab-on application with the test dentifrices to the hydrated surface of dentin, followed by exposure to either a 30-second or 10-minute grapefruit juice acid challenge. For both models, at the end of each treatment period, the samples were removed for scanning electron microscopy analysis and graded on a categorical visual scale. All data were analyzed statistically by unpaired t-test comparison. RESULTS: In the longitudinal (four-day) model, the strontium acetate-based dentifrice occluded dentin tubules significantly better than the currently marketed arginine-based dentifrice post-dab-on treatment and grapefruit juice challenge (p < 0.0001). At all other time points, the strontium acetate dentifrice demonstrated significantly better occlusion than the arginine-based dentifrice (p < or = 0.0001). In the exploratory acid resistance model, the level of occlusion observed for the strontium acetate dentifrice was statistically significantly greater when compared to the arginine dentifrice following 10 second and 10-minute (p < 0.0001) exposures to grapefruit juice. CONCLUSION: A strontium acetate dentifrice is observed to deliver statistically significantly greater levels of dentin tubule occlusion when compared to the arginine dentifrice following dab-on and brushing application under dietary acid-challenge conditions in this in vitro model. This study suggests that the arginine containing dentifrice may be more susceptible to acid-mediated dissolution than the strontium-based dentifrice under the conditions employed in this in vitro model. PMID- 21290981 TI - Abrasion, polishing, and stain removal characteristics of various commercial dentifrices in vitro. AB - OBJECTIVE: To evaluate, using conventional in vitro procedures, the abrasivity, enamel polishing properties, and stain removal effectiveness of various commercial dentifrices that have a variety of compositions and are marketed for cleaning, whitening, and/or polishing capabilities, and to examine their relationships between stain removal and abrasivity. METHODS: The Relative Dentin Abrasivity (RDA) method was used to measure abrasivity, and the Pellicle Cleaning Ratio (PCR) procedure was used to evaluate stain removal performance. A Cleaning Efficiency Index (CEI) was calculated using the RDA and PCR values. Enamel polish was determined on bovine enamel specimens using a reflectometer. All treatments were performed on a V-8 cross-brushing machine using aqueous dentifrice slurries and standard nylon-bristle toothbrushes. A total of 26 dentifrices, purchased at retail, were tested against the American Dental Association (ADA) calcium pyrophosphate reference standard. RESULTS: All dentifrices removed extrinsic stain and produced some dentin abrasion, but scores ranged widely between products (from 36 to 269 for RDA and from 25 to 138 for PCR). The majority of dentifrices contained hydrated silicas, and those with high PCR scores often, but not always, had higher RDA values. Products containing other abrasives (e.g., dicalcium phosphate, sodium bicarbonate, and calcium carbonate) generally had lower RDA values and usually lower PCR scores. There were exceptions (e.g., refined kaolin clay) that had high PCR scores and low RDA values, resulting in higher CEI values. Similarly, brushing with all dentifrices significantly increased reflectance readings of acid-dulled teeth, but polish scores also were highly variable among products (ranging from 38 to 97). The polish scores of dentifrices containing hydrated silica varied extensively (ranging from 38 to 80), and the scores of products containing other abrasives fell within this same range, except for dentifrices containing either Fuller's earth (86) or kaolin (97). CONCLUSION: With only a few exceptions, dentifrices marketed as "whitening" products were generally more abrasive to dentin, especially for those containing silicas. Similarly, aside from two non-silica products, those dentifrices advertised for polishing ability generally were no more effective than other products. The relationship between stain-removal ability and abrasivity of dentifrices was not necessarily direct. PMID- 21290982 TI - The plaque removal efficacy of a novel power brush head. AB - OBJECTIVE: To assess the plaque removal efficacy of an oscillating/rotating power toothbrush with novel brush head (Oral-B Precision Clean) in comparison to an American Dental Association (ADA) reference manual toothbrush. METHODS: This was a replicate-use, single-brushing, two-treatment, examiner-blind, randomized, four period (visit) study with a crossover design. At each visit, subjects disclosed their plaque with disclosing solution for one minute, and an examiner performed a baseline (pre-brushing) plaque examination (Rustogi, et al. Modification of the Navy Plaque Index). Subjects were then instructed to brush for two minutes (according to manufacturer's instructions) with their assigned power toothbrush or as they normally do with the ADA manual brush under supervision, after which they again disclosed their plaque and were given a post-brushing plaque examination. RESULTS: Both the power brush and manual brush showed statistically significant plaque reductions from baseline for the whole mouth, along the gingival margin, and on approximal surfaces. The power brush showed statistically significant advantages (p < 0.001) over the manual brush in plaque reduction for whole mouth (28.8%), gingival margin (44.3%), and approximal surfaces (20.7%). CONCLUSION: The oscillating/rotating power toothbrush with a novel brush head showed statistically significantly superior plaque reduction (whole mouth, gingival margin, and approximal surfaces) compared to a manual toothbrush. PMID- 21290983 TI - Short-term germ-killing effect of sugar-sweetened cinnamon chewing gum on salivary anaerobes associated with halitosis. AB - OBJECTIVE: The present study investigated the short-term germ-killing effect of sugar-sweetened cinnamon chewing gum on total and H2S-producing salivary anaerobes. METHODS: Fifteen healthy adult subjects were recruited in the double blind, crossover clinical study. The three test chewing gums included: 1) sugared chewing gum containing cinnamic aldehyde and natural flavors (CinA+); 2) sugared chewing gum without cinnamic aldehyde but with natural flavors (CinA-); and 3) non-sugared chewing gum base (GB) without any flavors and without cinnamic aldehyde. A three-day "washout" period followed each treatment. Each subject chewed gum under supervision for 20 minutes at 60 chews/minute. Unstimulated whole saliva samples were collected before the subjects chewed the gum and at 20 minutes after expectoration of the gum. All saliva samples were serially diluted, plated on blood agar or agar plates that select for bacteria producing H2S, incubated anaerobically for three days, and enumerated for viable colony counts of total and H2S-producing salivary anaerobes. RESULTS: Significant reductions in total salivary anaerobes (p < 0.01) and H2S-producing salivary anaerobes (p < 0.01) were observed 20 minutes after subjects chewed the CinA+ gum. The chewing of CinA- gum also significantly reduced total salivary anaerobes (p < 0.05) and H2S-producing salivary anaerobes (p < 0.05). However, no statistically significant difference in germ-killing effect was detected between the CinA+ and CinA- gums, although there was a numeric difference. The chewing of a gum base (GB) alone did not result in a significant reduction in the total or H2S producing salivary anaerobes (p > 0.05). CONCLUSION: The commercially available sugar-sweetened cinnamon chewing gum may benefit halitosis by reducing volatile sulfur compounds producing anaerobes in the oral cavity. PMID- 21290984 TI - Stigma. PMID- 21290985 TI - From sequence to consequence. PMID- 21290986 TI - Management of HIV-associated lymphomas. PMID- 21290987 TI - Acute myeloid leukemia in the elderly. PMID- 21290988 TI - Pesticides and non-Hodgkin lymphoma: an overview for the clinician. PMID- 21290989 TI - Chronic lymphocytic leukemia: something old, something new and something borrowed... PMID- 21290990 TI - Adenosquamous cell carcinoma of the gallbladder. PMID- 21290991 TI - Primary care physicians' role in promoting children's oral health. PMID- 21290992 TI - A prescription for atonement. PMID- 21290993 TI - Dr. Richard Singer: a master number cruncher. PMID- 21290994 TI - A brief historical sketch of the Association of Life Insurance Medical Directors of America (ALIMDA), the predecessor of the American Academy of Insurance Medicine (AAIM). AB - This is a brief historical sketch of ALIMDA, the name of our professional organization when it was founded at a meeting of a few medical directors in New York City in 1898. The principal source for its contents is based on recollections of my own experience with ALIMDA/AAIM since I first became a member after appointment as an Assistant Medical Director of the company then known as New England Mutual Life Insurance Company, in Boston, in 1952. I was never an officer of ALIMDA or AAIM, but I attended most of its meetings, and I was involved in our mortality research activites. PMID- 21290995 TI - Albumin and all-cause mortality risk in insurance applicants. AB - OBJECTIVE: Determine the relationship between albumin levels and all-cause mortality in life insurance applicants. METHOD: By use of the Social Security Death Master File, mortality was determined in 1,704,566 insurance applicants for whom blood samples were submitted to Clinical Reference Laboratory. There were 53,211 deaths observed in this healthy adult population during a median follow-up of 12 years. Results were stratified by 6 age-sex groups: females: ages 20 to 49, 50 to 69 and 70+; and males: ages 20 to 49, 50 to 69 and 70+. The middle 50% of albumin values specific to each group was used as the reference band for that group. The mortality in bands representing other percentiles of albumin values higher and lower than the middle 50% were compared to the mortality in the reference band for each age-sex group. The highest percentile bands represent the lowest albumin values. RESULTS: Relative risk exceeded 150% of each age- and sex specific reference band for all groups between the 90th and 95th percentile of albumin values. This translates into 150% risk thresholds at approximately 3.8 mg/dL for all females and for males 70+, and 4.1 mg/dL for males ages 20 to 69. Conversely, the highest 25% of albumin values were associated with approximately a 20% reduction in risk in males and a variable 10% reduction in risk in females when compared to the middle 50% of albumin values. Excluding those with total cholesterol < or = 160 mg/dL, or with AST, GGT or alkaline phosphatase elevations, had little impact on relative risk except at the lowest 0.5% of albumin values. CONCLUSION: When stratified by age and sex, albumin discriminated between all-cause mortality risks in healthy adults at all ages and across a wide range of values independent of other laboratory tests. PMID- 21290996 TI - Life risk assessment in cancer: a guide to using the surveillance, epidemiology, and end results (SEER) program. AB - A guide to the use of SEER data to analyze cancer survival using the SEER*Stat software package is presented. Relative and cause-specific survival techniques are demonstrated via examples, and the strengths and weaknesses of these approaches are explored. PMID- 21290997 TI - Hereditary neuropathy. AB - A 58-year-old male presented with a history of slowly progressive bilateral hand weakness manifested by decreased grip strength and pinch strength associated with some pain in the first metacarpal-carpal joints with atrophy of the muscles of the web space. An evaluation based on history, physical exam, and judicious diagnostic testing yielded a finding of motor and sensory peripheral polyneuropathy and a working diagnosis of hereditary nerve pressure palsy syndrome (HNPP) or hereditary neuropathy with liability to pressure palsies. The clinical findings and diagnostic tests for sensory and motor peripheral neuropathy are discussed. The case details over time, hereditary features, and the natural history of this disorder lead to a favorable clinical and insurance medicine prognosis. PMID- 21290998 TI - Early repolarization ECG pattern--still a benign finding? AB - A life insurance applicant with an early repolarization pattern on his electrocardiogram (ECG) previously assessed as a standard risk, wishes to increase the amount of his coverage. The risk assessment implications of recent studies of early repolarization ECG patterns are reviewed. PMID- 21290999 TI - Ramsay Hunt syndrome. AB - Ramsay Hunt syndrome is a rare viral infection of the facial nerve causing otalgia, hearing loss, tinnitus, vertigo, and paresis. PMID- 21291000 TI - Putting the lid on chemical burns. PMID- 21291001 TI - Fall protection for wood pole climbing. PMID- 21291002 TI - Encouraging wellness for fun & profit. PMID- 21291003 TI - Push harder. The AHA's new 2010 guidelines focus on chest compressions. PMID- 21291004 TI - Survivor spreads the word on AEDs. PMID- 21291005 TI - Better identification of fire hazards needed. PMID- 21291006 TI - Noise control: how to plan for OSHA's new interpretation. PMID- 21291007 TI - Building in-house capability. PMID- 21291008 TI - Enlist the power of setting expectations. PMID- 21291009 TI - Patient's page. Dental products for home use. PMID- 21291010 TI - What to expect when you search for a practice location. PMID- 21291011 TI - What to expect when you sign your dental office lease. PMID- 21291012 TI - What to expect during build-out of your dental office. PMID- 21291013 TI - Substantial consumption of fluoride increases risk of mild fluorosis. PMID- 21291014 TI - Community water fluoridation: back to the future. PMID- 21291015 TI - Prevention--not just for teeth but for your practice, too! PMID- 21291016 TI - New House member has long term care roots. PMID- 21291017 TI - Industry perception needs rehab. AHCA chair advocates for an image campaign. PMID- 21291018 TI - Ramping up for higher acuity. Nursing facilities respond to the need for reducing hospitalizations. PMID- 21291020 TI - MDS 3.0 news from the frontlines. PMID- 21291019 TI - Learning from adverse events. PMID- 21291021 TI - Design for living. PMID- 21291022 TI - Pilot scale testing of a new configuration of the membrane aerated biofilm reactor (MABR) to treat high-strength industrial sewage. AB - An alternative design of the membrane aerated biofilm reactor (MABR) was developed to overcome some of the current technical and economical limitations preventing full scale applications of the process. The ZeeLung system uses a new dense hollow-fibre membrane with an unprecedented thin diameter. Two pilot units treating a synthetic high-strength industrial wastewater (4700 mgCOD/L, 145 mgTKN/L) operated successfully for 16 months. They performed simultaneous COD removal, nitrification and denitrification. The very high specific surface area (810 m2/m3) allowed the surface loading rate to be kept low enough (3.6 gCOD/(m2.d)) to maintain a relatively thin biofilm (200 to 350 microm) and use low-pressure air (41 kPa) instead of high-pressure pure oxygen. Intermittent air and liquid mixing at high frequency and low shear were compared: they were equally effective in enhancing substrate transfer, but failed to stabilize biofilm accumulation. Air sparging additionally prevented the acidification of the bulk by stripping CO2. PMID- 21291023 TI - Effect of surfactants on sorption and desorption of phenanthrene onto black carbon. AB - Sorption and desorption of phenanthrene onto black carbon extracted from sediment were studied in the presence of a cationic surfactant (cetyltrimethylammonium bromide [CTAB]), an anionic surfactant (sodium dodecylbenzene sulfonate [SDBS]), and a nonionic surfactant (Triton X-100 [TX100]), to examine the role of surfactants in sorption and desorption. Nonlinearity of the sorption isotherms increased in the presence of surfactants. The CTAB enhanced the sorption capacity and irreversibility of phenanthrene on black carbon. However, the presence of SDBS reduced the sorption capacity and desorption hysteresis. Unlike CTAB and SDBS, the influence of TX100 on sorption was concentration-dependent. Low levels of TX100 increased sorption, as a result of the sorption of TX100 on the black carbon surface. High levels of TX100 led to a decrease in sorption because of the solubilization of phenanthrene in TX100 solution. Our results may help to understand the different effects of surfactants on the distribution and transport of polycyclic aromatic hydrocarbons in the environment. PMID- 21291024 TI - Deodorization and dewatering of biosolids by using dimethyl ether. AB - We proposed a method for the deodorising and dewatering of biosolids. In the proposed method, liquefied dimethyl ether (DME) was used as an extractant for odorous components and water. We developed a bench-scale experiment to almost completely deodorize and dewater biosolids by using liquefied DME at room temperature. The deodorized and dewatered biosolids have sufficient caloric density and can be used as a carbon neutral fuel. PMID- 21291025 TI - The effect of degree of recycle on the nitrifier growth rate. AB - The nitrifier maximum specific growth rate, mu(A),max, is a critical parameter for the design and performance of nitrifying activated sludge systems. Although many investigations studied mu(A),max, only a few have dealt with the effect of the reactor configuration on this important kinetic parameter. Bench- and full scale trials were devised to study the effect of the internal mixed-liquor recycle (IMLR) on the nitrifier growth rate constant. The nitrifier growth rate constant for an existing activated sludge plant was determined at different operational conditions using the high food-to-microorganism ratio (F/M) test and by process model calibration. Overall, the results obtained during this study indicate that high IMLR values have a negative effect on mu(A),max. Based on the results obtained during this investigation, a 15% decrease in mu(A),max was observed at an IMLR of 4Q or higher. It is surmised that, at high IMLRs, the reactor behavior shifts from a plug-flow configuration to a "quasi" complete-mix configuration, influencing either the species selection in activated sludge population or at least the adaptation of specific species. These results have a tremendous effect on the design of activated sludge processes that incorporate IMLR for denitrification, such as the Bardenpho, Modified Ludzack-Ettinger (MLE), University of Cape Town (UCT), and Phoredox or anaerobic-anoxic-aerobic (A2/O) processes. PMID- 21291026 TI - Factorial experimental designs for enhancement of concurrent poly(hydroxyalkanoate) production and brewery wastewater treatment. AB - The influence of four main process parameters--solids retention time (SRT), hydraulic retention time (HRT), anoxic-oxic cycling, and carbon-to-nitrogen ratio (C/N ratio)--on poly(hydroxyalkanoate) (PHA) production, while treating brewery wastewater, was studied. Two sets of two-level, three-factor experimental designs were implemented to (1) determine the effects and interactions among process parameters, (2) assess their significance to PHA production, and (3) approximate optimal operational conditions. The HRT and SRT were found to be the crucial operational parameters affecting PHA production. The highest PHA content of 55% (on a cell-weight basis) was produced at a 4-day HRT and 4-day SRT, whereas a maximum PHA concentration of 907 mg/L was obtained at a 2-day HRT and 12-day SRT. The effect of anoxic conditions on PHA production was insignificant. The C/N ratio played a more important role in the PHA concentration in the system than in the PHA content in the biomass. PMID- 21291027 TI - Digestion performance of various combinations of thermophilic and mesophilic sludge digestion systems. AB - Various combinations of single- and multi-stage anaerobic and aerobic-anaerobic digestion systems were studied to evaluate their solids reduction potential with capabilities to control sulfur-based biosolids odor compounds. All the multi stage digestion systems removed more volatile solids than the single-stage anaerobic digestion systems, even at the same overall retention time. However, digestion systems with mesophilic digestion as the final stage showed a much lower headspace organic sulfur content in the dewatered biosolids than the systems with thermophilic digestion as the final stage. This observation leads to the conclusion that placing a mesophilic anaerobic digestion system at the end of multi-stage digestion systems will enable greater sulfur-based odor reduction from dewatered biosolids with greater solid reduction than single-stage mesophilic or thermophilic digestion systems. PMID- 21291028 TI - Optimal design of regional wastewater pipelines and treatment plant systems. AB - This manuscript describes the application of a genetic algorithm model for the optimal design of regional wastewater systems comprised of transmission gravitational and pumping sewer pipelines, decentralized treatment plants, and end users of reclaimed wastewater. The algorithm seeks the diameter size of the designed pipelines and their flow distribution simultaneously, the number of treatment plants and their size and location, the pump power, and the required excavation work. The model capabilities are demonstrated through a simplified example application using base runs and sensitivity analyses. Scaling of the proposed methodology to real life wastewater collection and treatment plants design problems needs further testing and developments. The model is coded in MATLAB using the GATOOL toolbox and is available from the authors. PMID- 21291029 TI - Treatment of distillery wastewater by the nano-scale zero-valent iron and the supported nano-scale zero-valent iron. AB - The treatment of wastewater from the distillery industry was carried out by using nano-scale- and supported nano-scale zero-valent iron at a laboratory scale and ambient temperature. Effects of dilution, pH, mixing rate, zero-valent iron dosage, and amount of support for the zero-valent iron were investigated. All parameters had a significant effect on the removal efficiency of all investigated pollutants. Increasing the number of dilutions and the nano-scale zero-valent iron dosage led to the increase of removal efficiency of pollutants. Higher removal efficiency was achieved in an acidic initial pH of wastewater. The reduction of all pollutants was limited by the kinetics of the pollutant destruction/reduction by nano-scale zero-valent iron particles at a mixing rate greater than 170 rpm. At optimum condition, greater than 95, 94, and 64% of color, chemical oxygen demand, and biochemical oxygen demand were removed, respectively, within 6 hours. Additionally, the presence of a support had a significant effect on pollutant removal. PMID- 21291030 TI - Reasons for poststerilization hysterosalpingography noncompliance in a clinic population. AB - OBJECTIVE: Although hysterosalpingography (HSG) is required 12 weeks after hysteroscopic sterilization, HSG compliance in our clinic population is remarkably low. We were interested in determining the reason(s) for HSG noncompliance in this urban-based patient population. STUDY DESIGN: University Health Center patients who underwent hysteroscopic sterilization between January 1, 2006, and December 31, 2007, and who did not complete HSG were contacted by telephone to elicit the reason(s) for lack of follow-up. RESULTS: Fifty-two patients qualified for inclusion in this study. Consent was obtained from all 14 patients accessible by telephone. Of note, 63.5% of patient-provided phone numbers were not in service at the time contact was attempted (n = 33). Patient reported reasons for HSG noncompliance included insurance issues (n = 5), failure to remember to schedule HSG (n = 4), HSG scheduling difficulties (n = 2),failure to be informed about the need for HSG (n = 2), and prolonged postoperative vaginal bleeding (n =1). CONCLUSION: Reasons for poststerilization HSG noncompliance varied. However, an insurance issue was the most frequently reported reason for noncompliance. not recalling the need to schedule HSG was another common reason for noncompliance. Approaches to increase compliance with poststerilization HSG are needed, particularly in an urban-based, clinic population. PMID- 21291031 TI - Ketorolac-mepivacaine lower uterine block for in-office endometrial ablation: a randomized, controlled trial. AB - OBJECTIVE: To investigate the effectiveness of a nonsteroidal antiinflammatory drug (NSAID) administered in combination with a local anesthetic as a deep paracervical block for in-office endometrial ablations. STUDY DESIGN: Double blind, placebo-controlled, randomized trial. Patients received either sublingual ketorolac (30 mg/1 mL) or a mepivacaine-only paracervical injection (standard group) or received sublingual saline (1 mL) and a ketorolac (30 mg/1 mL) mepivacaine paracervical block (NSAID group)for Gynecare Thermachoice III ablation (Ethicon, Inc., Somerville, New Jersey). All received sublingual ketorolac/placebo and 1 mg alprazolam sublingually 20 minutes preprocedure. Primary outcome was intraoperative pain control measured by 100 mm visual analogue scale. Secondary outcomes were postablation pain control (visual analogue scale [VAS]), postoperative use of narcotic analgesics and patient satisfaction in the first 24 hours (not satisfied, satisfied or very satisfied). RESULTS: Twenty patients were randomized into each group. No statistically significant difference was noted in overall intraoperative VAS score (p = 0.81), but there was a significant reduction in postoperative VAS (p = 0.01). There was less need for postoperative analgesic use in the first 24 hours (p = 0.02) in the NSAID group. More patients were "very satisfied" in the NSAID group. CONCLUSION: Injectable ketorolac-mepivacaine anesthetic solution functions well as a deep paracervical block for in-office gynecologic procedures, with better postoperative pain control than mepivacaine-alone protocols. PMID- 21291032 TI - Classification and management of cervical ectopic pregnancies: experience at a single institution. AB - OBJECTIVE: To classify cervical ectopic pregnancies including previous cesarean section scar pregnancies and to describe the management of cervical ectopic pregnancies. STUDY DESIGN: This was a retrospective analysis of all cervical ectopic pregnancies, including previous cesarean scar pregnancies, diagnosed at the Korea University Guro Hospital, Seoul, Korea, between January 1997 and October 2009 using transvaginal ultrasound. Clinical and demographic data were recorded in all cases. The pregnancies were categorized into three groups and subclassified into five types on the basis of transvaginal ultrasound and history of a previous cesarean delivery. The management of cervical pregnancies included medical treatment such as systemic methotrexate (single dose or multiple doses) or intraamniotic methotrexate and surgical treatment such as dilation and curettage (D&C), laparoscopic exploration and hysterectomy. RESULTS: Forty cervical ectopic pregnancies including previous cesarean section scar pregnancies were diagnosed. Cesarean section scar-related pregnancy (intramural type and nonintramural type) and cesarean section scar-unrelated pregnancy accounted for 10, 12 and 18 cases, respectively. D&C was performed in 21 patients and was successful in all cases except one. The success rate of medical treatment was 61.5% (8/13). Nine patients (22.5%) required a blood transfusion, and a total hysterectomy was performed in five patients (12.5%). CONCLUSION: Cervical ectopic pregnancies were classified, including previous cesarean scar pregnancies, into five types based on the findings of transvaginal ultrasound and history of a previous cesarean delivery. PMID- 21291033 TI - Screening practices for postpartum depression among various health care providers. AB - OBJECTIVE: To assess the frequency with which health care providers screen for postpartum depression (PPD), assess attitudes towards routine screening and identify barriers to screening. STUDY DESIGN: Eighty-two providers (recruited via electronic mailing lists, postal mailings and colleague referrals) completed a survey designed for this study. RESULTS: Sixty-one percent of participants endorsed routine screening for PPD. Differences in frequency of screening among obstetricians, nurses and midwives were not detected. Only 17% of participants reported using a screening instrument; 74% of participants favored a clinical interview, which did not necessarily correspond to DSM criteria for depression. Of participants who do not routinely screen all patients, 15% report intending to screen, but are sometimes unable to complete screening due to a lack of time or other reason. Mean self-reported knowledge of PPD did not differ among those participants who endorsed routine screening versus those who did not. CONCLUSION: Many providers from the current sample report screening for PPD; sometimes screening efforts may be incomplete and there are identified barriers to screening. Implications for clinical practice remain unclear. While a number of effective screening instruments exist, additional research is needed to evaluate where screening should occur and how to manage positive screens. PMID- 21291034 TI - Effect of high-dose estrogen in luteal phase support on live birth rates after assisted reproduction treatment cycles. AB - OBJECTIVE: The role of estrogen administration for luteal phase support (LPS) after assisted reproductive technologies treatment is not well established. While most studies report ineffectiveness of doses up to 4 mg/day, a small randomized, controlled trial suggested improved clinical outcome with higher dosage of 6 mg/day. The present pilot trial assessed effectiveness of 6 mg/day estrogen in addition to progesterone administration for LPS. STUDY DESIGN: Randomized, controlled trial. Sixty women undergoing assisted reproduction treatment were randomly allocated to receive progesterone vaginal gel with or without 6 mg/day 17beta-estradiol (E2) orally starting from the embryo transfer day. RESULTS: Embryo implantation rates were 33.33% and 28.9% in the control and E2 groups, respectively (p = 0.64). There were 11 (36.7%) live births in the control group, while there were 10 (33.3%) live births in the E2 group (p = 0.79). CONCLUSION: Our results do not suggest a beneficial effect of orally administered estrogen as adjuncts to progesterone for luteal support when administered to all patients in an unselective manner, even in a dose of 6 mg/day. PMID- 21291035 TI - Mitochondria DNA deletion and copy numbers of cumulus cells associated with in vitro fertilization outcomes. AB - OBJECTIVE: Mitochondria are important organelles in cell biology. We aimed to study the effects of mitochondrial DNA variations in cumulus cells (CCs) upon in vitro fertilization and embryo transfer (IVF-ET) outcomes. STUDY DESIGN: A total of 51 women undergoing IVF-ET were recruited for the study. The CCs were collected during oocyte retrievals. Mitochondria DNA 4977-bp deletion (dmtDNA delta5Kb) and copy numbers (MCN) of CCs were analyzed by polymerase chain reaction. The relationships of dmtDNA-delta5Kb and MCN with patients' age, embryo qualities and pregnancy rates (PRs) were detected and compared. RESULTS: PRs were positively correlated with younger age, better transferred embryo qualities and lower dmtDNA-delta5Kb ratios in CCs. The dmtDNA-delta5Kb status was positively associated with older age and higher MCN but was not associated with embryo morphologic scoring. The dmtDNA-delta5Kb ratios of transferred embryos in pregnancy and nonpregnancy groups were 0% and 10.4%, respectively. The dmtDNA delta5Kb in > or = 34-year-old and <34-year-old groups were 6.9% and 3.2%, respectively. CONCLUSION: The dmtDNA-delta5Kb and MCN statuses of CCs are negatively associated with PRs, which might be potential tools for oocyte evaluation and embryo selections during IVF-ET. PMID- 21291036 TI - Randomized, controlled trial of a normal pregnancy virtual patient to teach medical students counseling skills. AB - OBJECTIVE: To determine whether medical students using the Normal Pregnancy Virtual Patient program (Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, Massachusetts) have better knowledge and skills in obstetric counseling than traditional clerkship students. STUDY DESIGN: We performed a randomized, controlled trial of 23 students at Harvard Medical School to determine whether participation in a virtual patient program improves medical student knowledge and skills in obstetric counseling. Students were randomized to the obstetrics/gynecology clerkship (n = 11) or the clerkship plus Normal Pregnancy Virtual Patient (n = 12) in 2006-2008. Students interviewed a standardized patient at the end of the clerkship. Two blinded physicians reviewed the videotaped interview and used a standardized checklist to assess knowledge and counseling skills in preconception, breastfeeding, genetics, postpartum counseling, and overall performance. RESULTS: Stratified analyses indicated the virtual patient group provided significantly better preconception counseling than controls (p = 0.002). Overall, students who completed the Virtual Patient program scored higher than those in traditional clerkship alone, though not significantly (26.0 vs. 22.0, p = 0.25). The study may not have had sufficient numbers of students enrolled to detect a significant difference. CONCLUSION: The use of a virtual patient program in obstetrics improves medical students' preconception counseling skills. PMID- 21291037 TI - Effect of controlled ovarian hyperstimulation treatment on cardiac function. AB - OBJECTIVE: To evaluate the effects of controlled ovarian hyperstimulation (COH) treatment on cardiac functions using tissue Doppler imaging (TDI). STUDY DESIGN: Twenty-one patients aged 22-35 years were enrolled to COH cycles. Each subject underwent a conventional transthoracic echocardiographic examination that included an assessment of cardiac function. Measurements were taken twice--the first on the second day of the cycle and the second on the day when human chorionic gonadotropin was administered. Twenty-one healthy women were chosen for the control group. RESULTS: The COH treatment did not cause favorable cardiac function changes. The parameters showing the left ventricular diastolic function such as early diastolic peak flow velocity (E), late diastolic peak flow velocity (A), mitral E/A ratios, mitral E wave, deceleration time (DT), lateral isovolumic relaxation time (IVRT), and left ventricular myocardial performance index (LVMPI) were not changed. The COH treatment did not affect the right ventricular diastolic functions such as tricuspid valve E wave, DT, right ventricular (RV) IVRT, or right ventricular myocardial performance index (RVMPI). Concurrently, the COH treatment showed no effects on the right and left ventricular systolic functions. CONCLUSION: TDI findings reveal no effects of the COH treatment on cardiac function. PMID- 21291038 TI - Controlled ovarian hyperstimulation and gestational surrogacy in a patient with lung transplant: a case report. AB - BACKGROUND: Cystic fibrosis (CF) is one of the most common genetic disorders that can often lead to chronic pulmonary disease. Patients with respiratory failure due to CF may achieve a good quality of life after lung transplant, and many will desire to have children. CASE: A 26-year-old, nulliparous female with CF and double lung transplant presented for fertility treatment. She was successfully treated with controlled ovarian hyperstimulation and gestational surrogacy. CONCLUSION: Controlled ovarian hyperstimulation and gestational surrogacy is a safe option for patients with lung transplant to have a genetic child. PMID- 21291039 TI - Emergent thermal balloon ablation for acute uterine hemorrhage: a report of 2 cases. AB - BACKGROUND: The management of acute, recalcitrant uterine hemorrhage has traditionally included gynecologic dilation and curettage, uterine balloon tamponade or emergent hysterectomy. These options were considered after failed medical therapy (intravenous estrogen, oral contraceptives or intramuscular progestins). The advent of global endometrial ablation devices now allow for an in-office treatment modality for these patients. CASES: Two cases of thermal balloon ablation to treat recalcitrant uterine bleeding are reported from an inner city obstetrics and gynecology practice. No further vaginal bleeding was noted up to eight weeks posttherapy, with an increase in hemoglobin in each patient. Each patient avoided emergent hysterectomy and/or blood transfusion. CONCLUSION: Office-based Thermachoice III ablation provides an alternative to traditional management of the acutely bleeding patient without the need for hospital admission. PMID- 21291040 TI - Urethral condyloma accuminata causing bladder outlet obstruction in pregnancy: a case report. AB - BACKGROUND: Condyloma accuminata represents the most common sexually transmitted disease in the United States. Pregnancy can lead to enlargement of existing lesions or development of new lesions. CASE: A 31-year-old woman presented at 28 weeks' gestation with a complaint of difficulty voiding due to an obstructing urethral mass. In the weeks preceding presentation voiding had become progressively more difficult, leading to Valsalva voiding, the use of the Crede maneuver and the sensation of incomplete emptying. Excision in the office setting resulted in complete resolution of her symptoms with return to normal voiding. CONCLUSION: Resection of obstructive urethral condyloma can be a safe and effective treatment for bladder outlet obstruction during pregnancy with rapid return to normal voiding. PMID- 21291041 TI - Primary sclerosing cholangitis in pregnancy refractory to ursodeoxycholic acid treatment: a case report. AB - BACKGROUND: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease associated with fibrosis and inflammation of the bile ducts. Its complications include symptoms from pruritis and fatigue to dominant strictures, cholangiocarcinoma and liver failure necessitating liver transplant. Due to its predominance in young males, little is reported regarding PSC and pregnancy. CASE: We report a case of a pregnant woman with PSC whose symptoms were initially unresponsive to the traditional treatment of ursodeoxycholic acid (UDCA) early in her pregnancy but subsequently did well using high dose steroids for the duration of her pregnancy. CONCLUSION: With close management, successful pregnancy outcomes seem possible with patients with PSC, even when diagnosed multiple years prior to pregnancy, if not with UDCA, then possibly with steroid treatment. PMID- 21291043 TI - There's no place like home for the holidays. PMID- 21291042 TI - Rattlesnake bites in pregnant women. AB - OBJECTIVE: To determine the number of rattlesnake bites in pregnant women reported to U.S. poison centers and evaluate whether differences in management, treatments, or outcomes exist between pregnant and non-pregnant female bite victims. STUDY DESIGN: Review was conducted of the database of the American Association of Poison Control Centers (AAPCC). Exposures coded as rattlesnake bites between 2001 and 2007 were included for all reproductive-age women (15-45 years). RESULTS: Sixty-one poison control centers reported a total of 8,413 rattlesnake bites, with 767 (9.1%) involving reproductive-age women. Of these, 11 (1.4%) were pregnant. There were no significant differences between pregnant and nonpregnant victims with regard to rates of hospital admission, antivenom administration, or overall outcome codes. There were no adverse reactions to antivenom in pregnant women and no maternal deaths or fetal losses while in the hospital or during the period of poison center follow-up. CONCLUSION: This rare condition is associated with favorable short-term pregnancy outcomes in the AAPCC database. In the absence of definitive evidence, we recommend standard management, including antivenom when indicated and extended fetal monitoring. PMID- 21291044 TI - Parental perceptions of risk and protective factors associated with the adaptation of siblings of children with cystic fibrosis. AB - When a child is diagnosed with a chronic, life-threatening illness, there is a significant impact on the healthy siblings. Few studies have addressed the adaptation of well siblings in diagnoses other than cancer. The purpose of this descriptive correlational study was to examine the relationships between the risk and protective factors that affect the psychological adaptation of healthy siblings of a child with cystic fibrosis. Findings from this study suggest family environment, especially parental stress and perceived social support, may affect the adaptation of the well sibling. Adolescent well siblings were more at risk for environmental influences than their younger counterparts. PMID- 21291045 TI - Adolescent self-efficacy and resilience in participants attending A diabetes camp. AB - Adolescents with type 1 diabetes mellitus (T1DM) often speak of the importance of attending a diabetes camp. In an effort to identify the effect of a diabetes camp on participants, a descriptive comparative pilot study was undertaken. Adolescents 10 to 16 years of age with T1DM attending a residential diabetes camp (N = 81) were recruited to explore the concept of self-efficacy and resilience, two possible mediators influenced by attending camp. Overall, self-efficacy and resilience scores were moderately high. No differences were detected in outcome measures for gender or mode of insulin therapy; however, African Americans scored significantly higher for diabetes self-efficacy and resilience. Subjects living with one parent had poorer glycosylated hemoglobin (HgbA1C) but scored better in resilience. No association for years of camp attendance and study outcomes were identified. Diabetes camp is an important experience for adolescents living with T1DM, and continued exploration of the influence of diabetes camp is warranted. PMID- 21291046 TI - The experience of therapeutic support groups by siblings of children with cancer. AB - When a child is diagnosed with cancer, the whole family, including siblings, lives in fear of how the cancer will affect the sick child and how it will influence other family members. The aim of this article is to describe the experiences expressed by the siblings in a support group environment when their families have or have had a child diagnosed with cancer. Fifteen siblings 8 to 19 years of age with a brother or sister who was receiving treatment for or had died from cancer were interviewed after participating in therapeutic support groups. These interviews were conducted two weeks after the last group interaction and were analyzed using qualitative content analysis. Regardless of gender and age, the siblings felt a sense of belonging and comfort by being in a group, which they appreciated. They were able to share their experiences and help each other with advice and encouragement. They all drew strength from each other. A therapeutic support group for siblings of children with cancer is beneficial. Follow-up interviews with the siblings indicated they found the groups helpful in coping with their situation. PMID- 21291047 TI - Coping interventions for parents of children newly diagnosed with cancer: an evidence review with implications for clinical practice and future research. AB - There are approximately 12,000 children diagnosed with cancer every year in the U.S. The diagnosis of childhood cancer has an impact on the entire family. Parents of children newly diagnosed with cancer often exhibit symptoms of stress, depression, and anxiety. In addition, children diagnosed with cancer often exhibit behavioral changes during and after treatment. Although numerous studies have demonstrated the adverse impact of the cancer diagnosis on the parents and children, few studies have been conducted on interventions designed to facilitate parental coping and mental health outcomes. The purpose of this evidence review was to determine the impact of psychosocial interventions on the mental health/coping outcomes of parents of children diagnosed with cancer. A synthesis of the current literature from the search demonstrates an urgent need for larger, theory-based, randomized controlled trials with attention control groups for parents of children newly diagnosed with cancer to improve their children's coping/mental health outcomes as well as their own. PMID- 21291048 TI - Obesity in children with Down syndrome: background and recommendations for management. AB - Children with Down syndrome have a higher risk for developing obesity. The primary care provider can assist the family in preventing or managing obesity by recognizing the physiological and behavioral factors that place children and adolescents with Down syndrome at increased risk to become obese, and establishing a screening and management plan early to prevent or treat excess weight gain. By using adapted strategies, the negative physiological and psychological outcomes associated with obesity may be lessened or avoided in this specific population. PMID- 21291049 TI - Impact of pediatric nurses' uniforms on perceptions of nurse professionalism. AB - This study examined the impact of nursing pants uniform color and style on perceptions of professionalism. Pediatric patients 7 to 17 years of age and their adult visitors were surveyed at two midwestern health care centers. Participants viewed eight photographs of the same RN in different uniforms. Adult participants rated each photograph for 10 image traits using a modified nurse image scale (MNIS). Pediatric participants rated each photograph for five image traits using the nurse image scale for children (NISC). Pediatric participant median sum scores for the eight uniforms were similar, despite clear preferences for boldly printed top and pressed blue or white-pant uniforms (22% each). Adult participant median sum scores were similar for six of the eight uniforms, but two had significantly lower scores (p < 0.001). Pediatric patients' and visitors' uniform preferences are not related to perceptions of professionalism. PMID- 21291050 TI - Combat high mortality rate by going home. PMID- 21291051 TI - Massachusetts, the health care reform microcosm: has it worked? PMID- 21291052 TI - How will the mid-term elections impact ESRD? PMID- 21291053 TI - Budget pressures affecting kidney patients and providers. PMID- 21291054 TI - Comparative effectiveness of active oral vitamin D agents in patients on peritoneal dialysis. AB - Comparative Effectiveness Research (CER) has become positioned to inform health care decision-making with passage of the health care reform law, "Patient Protection and Affordability Care Act of 2010". As the name suggests, CER attempts to understand the relative efficacy between two therapies to allow clinicians, health care providers, and others to make rational decisions when evaluating therapeutic options. This is particularly relevant in the nephrology community as the dawn of bundled payments approaches. The current evidence base for CER studies is especially curtailed as a result of limited head-to-head clinical trials in patients with end-stage renal disease. Specifically, CER for available oral vitamin D agents approved for use in ESRD is lacking. The inclusion of oral vitamin D in the bundled payment system in 2011 may lead more clinicians to examine which oral vitamin D analog to prescribe to their patients, making this an especially timely topic. PMID- 21291055 TI - Academic and clinical research collaboration. Part 3: Challenges for the clinician and researcher. PMID- 21291056 TI - A vision for future health care: where nurses lead the change. PMID- 21291057 TI - Improving retention, confidence, and competence of new graduate nurses: results from a 10-year longitudinal database. AB - Developing competent and confident new graduate nurses who remain with their hospitals is a major challenge. A structured evidence-based RN residency was developed and implemented in hospitals across the United States. Outcomes data were collected from over 6000 new graduate nurses who completed the RN residency over a 10-year period. The results indicate an accelerated increase in competence and self-confidence and a significant decrease in turnover intent and actual turnover. This study provides persuasive evidence that both new graduate nurses and their organizations benefit from the implementation of a structured, clinical immersion RN residency. PMID- 21291058 TI - The sustainability budgeting model: multiplemode flexible budgeting using sustainability as the synthesizing criterion. AB - The Sustainability Budgeting Model (SBM) is presented in the context of a department of nursing of a major hospital. If successfully incorporated in the department of nursing, the SBM can easily be moved into the larger hospital context. The SBM was designed recognizing the three necessary components underlying all budgeting models. The SBM incorporates the inherent variability of the resource inflows and outflows and in that sense is robust; it is recommended these resource flows be calibrated for the various time horizons using the standard Present Value model so as to provide comparability across projects. Most importantly, the SBM focuses on financial sustainability considering all the relevant costs--variable and fixed--and so speaks to long-term coordinated planning and continuation of desired patient services. PMID- 21291059 TI - Evaluation of an intervention on socio cultural communication skills of international nurses. AB - International nurses face a myriad of challenges in their transition, adaptation, and integration into the U.S. health care environment. This pilot intervention study examined socio-cultural competence regarding communication in a sample of international nurses working in two community hospitals in southern Nevada. Significant improvement in communication behaviors of the sampled international nurses with regard to socio-cultural skills of communication after the workshop intervention were not found. Similarly, there were no remarkable differences in standardized patient comments for most items on the checklist. However, the sampled international nurses demonstrated some highly desirable qualities such as being very personable, caring, and compassion that appeared to lay a foundation for an effective nurse-patient relationship. PMID- 21291060 TI - Complex home care: part III--economic impact on family caregiver quality of life and patients' clinical outcomes. AB - Family caregivers perform a significant role in the care of patients with chronic illnesses and prescribed life-long complex home care treatments. Both quantitative and qualitative data from this study suggest the mental health burdens and financial costs of home parenteral nutrition (HPN) caregiving are extensive. In this study, the variability in HPN out-of-pocket expenses and the uncertainty of incurring such extensive costs created additional financial worries within already stressed families. Based on these data, interventions to improve caregivers' sleepiness, depression, and physical health could be hypothesized to improve both patients' and caregivers' quality of life and reduce the frequency of patients' catheter-related infections. These specific nursing interventions also could improve caregiver health and subsequently reduce the costs of caregivers' health care. PMID- 21291061 TI - For health care reform to survive we must stick to the facts. PMID- 21291062 TI - Doing what only you can do: the challenge to the promoted leader. AB - An offer of an executive-level promotion is not without risk. The transition to an effective executive is a continual journey, not a destination. Designing a roadmap with effective skills and strategies will help make your professional and personal life journey more rewarding and successful. PMID- 21291063 TI - Nursing and technology: a love/hate relationship. AB - The fundamental value of information technology in clinical settings is no longer in question, as clinicians enter and retrieve information in order to deliver care and the benefit of ubiquitous availability to clinical data using computers cannot be overplayed. The question now is how to increase adoption, improve productivity, and support transformational changes in health care delivery. It is important to get the interplay between people, process, and technology right for successful implementations which support care transformation. We must lead projects with the clinical practice changes being enabled by the technology, and then ensure the technology supports the practice change. Nurse leaders must consider letting the quality improvement process drive and define when and how technology is used, running our projects as practice changes and not IT implementations, with nursing sponsors owning the projects and leading the charge. PMID- 21291064 TI - Evolution of the chronic care role of the registered nurse in primary care. AB - High-quality, accessible, and efficient primary care is needed as the U.S. health care system undergoes significant change. Advancing the role of registered nurses in the primary care setting is important to the solution. A large academic health center implemented five initiatives to improve the care of chronically ill patients through the expanded role of RNs in the context of the health care team. Role evolution of nurses in the pilots required some continuing education and some additional nursing support to release the pilot nurses from their usual duties. These strategies allowed the nurses to apply interventions that enhanced the coordination of care and promoted patient self-management skills. Some short term improvements in health status were realized and barriers to self-care were identified and resolved. PMID- 21291065 TI - When caring stops, staffing doesn't really matter. AB - How well do we understand the people side of staffing, and do we recognize the importance therein? Delivering care without caring is simply wrong. Health care leaders must take this concern seriously and find ways to invest in and set up structures that support healthy processing, by individual caregivers, of the many emotional situations that are a natural part of care delivery. Individual care provides must take responsibility for their own well-being and make choices that promote self-care. We must find more ways to recognize and address the needs of care providers who are facing emotional burnout or compassion fatigue, as they are both a threat to their own health and a potential risk to the patients and organizations they serve. PMID- 21291066 TI - Enhancing board effectiveness. AB - Like any other job, board work is associated with specific competencies. Competencies are the combination of knowledge, skills, personal characteristics, and behaviors needed to perform a job or task effectively. Boards are only as strong as their weakest member. Board education should focus on improving the knowledge and skills of the board and individual members and on overall board performance. Assessment of individual board member performance is designed to evaluate the trustee's knowledge of board roles and responsibilities and the expectations of board members. Board effectiveness is built through competency based board member recruitment and selection; board member education and development; and evaluation of board, board member, and meeting performance. PMID- 21291067 TI - Wellness, inside and out. PMID- 21291068 TI - Caseload assignments--an ever-present topic. PMID- 21291069 TI - A new year. A new resolution for your school health curriculum. PMID- 21291070 TI - School nurse research networks. A win-win for nurse educators. PMID- 21291071 TI - How can I help the student who is returning to school after a brain injury. AB - The school nurse plays an important role in helping students with a brain injury be successful in school by advocating for the student in the classroom, providing case management and helping families access appropriate resources. PMID- 21291072 TI - Becoming a special needs school nurse in a typical school nurse world. A personal perspective. PMID- 21291073 TI - H1N1 and the role of the Rhode Island certified school nurse-teachers. PMID- 21291074 TI - Stress, coping, and diabetes support groups. PMID- 21291075 TI - How can social media help support my role as the health expert in my school? PMID- 21291076 TI - A dozen tips to being the best you in the new year and beyond. PMID- 21291077 TI - Preventing bullycides: the school nurse's role in breaking the link between victimization of sexual minority youth and suicide. PMID- 21291078 TI - Tar wars: a tobacco-free education program for 4th and 5th graders. PMID- 21291079 TI - Tomorrow's SMILES gives hope to teens with extreme dental needs. PMID- 21291080 TI - GKAS gives school nurses something to smile about. PMID- 21291081 TI - Health Information Technology for Economic and Clinical Health Act: modifications to the HIPAA privacy, security, and enforement rules (Document ID HSS-OCR-2010 0016-001). PMID- 21291082 TI - NASN position statement: caseload assignments. AB - It is the position of the National Association of School Nurses (NASN) that schools should employ professionally prepared Registered Nurses, to conduct and supervise school health programs which address the variety of health problems experienced by school children. NASN recommends a formula-based approach with minimum ratios of nurses-to-students depending on the needs of the student populations as follows: 1:750 for students in the general population, 1:225 in the student populations requiring daily professional school nursing services or interventions, 1:125 in student populations with complex health care needs, and 1:1 may be necessary for individual students who require daily and continuous professional nursing services. Other factors that should be considered in the formula-based approach are number of students on free or reduced lunch, number of students with a medical home, and average number of emergency services per year. PMID- 21291083 TI - Soda tax a good idea. PMID- 21291084 TI - Dental health aide therapists: we can do better. PMID- 21291085 TI - Dental benefit plans: read them carefully. PMID- 21291086 TI - The ADA: back on track and moving forward. PMID- 21291087 TI - Older male vs. younger female: a lawsuit waiting to happen. PMID- 21291088 TI - Facts about the Special Committee on Peer Review/Care and Well-Being. PMID- 21291089 TI - Plan to fail? The secret to a successful associate buy-in. PMID- 21291090 TI - British study suggests genetic link to tooth decay. PMID- 21291091 TI - The new ADA codes and proper billing. PMID- 21291092 TI - A new era in Michigan politics. PMID- 21291093 TI - Infant oral health examinations: attitudes and professional behavior of general and pediatric dentists in Michigan and pediatric dentists in the U.S. AB - Caries in young children in the United States has increased since 1988. Infant oral health examinations (IOHE) provide opportunities to educate parents about preventing caries in young children. The objective is to explore attitudes and behavior concerning IOHE among general and pediatric dentists in Michigan and pediatric dentists in the remaining 49 U.S. states. METHODS: Survey data were collected from 137 general and 45 pediatric dentists in Michigan and 2,112 pediatric dentists outside of Michigan. RESULTS: General dentists had more negative attitudes towards IOHE than pediatric dentists in Michigan and other U.S. states. Only 41 percent of general dentists vs. 84 percent and 89 percent of pediatric dentists in Michigan and other states performed IOHE (p<.001). While general dentists who performed IOHE had better attitudes towards IOHE than their non-IOHE-performing colleagues, they engaged less in prevention directed activities compared to pediatric dentists. CONCLUSIONS: It is crucial to engage increasing numbers of general dentists in a preventive approach to treating young children. PMID- 21291094 TI - 'Caring Hands Day' at Lansing's Care Free Clinic. PMID- 21291095 TI - Cognitive dissonance and ethics. PMID- 21291096 TI - When dentists do drugs. PMID- 21291097 TI - Advancing forensic psychiatry in Jamaica. PMID- 21291098 TI - Investigation of CTLA-4 and CD28 gene polymorphisms in patients with diabetes mellitus type 2 using PCR-RFLP in a Turkish population. AB - OBJECTIVE: The aim of this study is to investigate whether specific polymorphisms in the CTLA-4 and CD28 gene are associated with Type 2 diabetes mellitus (T2DM). METHODS: Blood samples were collected from 241 individuals (72 patients with T2DM and 169 healthy individuals) and DNA was isolated. A polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method was used to detect the frequencies of CTLA-4 NM_005214.3:c.49A > G and c.-319C > T, and CD28 NM_006139.1:c.534+17T > C polymorphisms in T2DM patients in the Sanliurfa Population. RESULTS: The data suggested that body mass index (BMI), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-c) and haemoglobin A1c (HbA1c) were significantly higher in T2DM patients than in the control individuals (p < 0.05). No significant differences were observed for the frequencies of c.49A > G, c.-319C > T genotype and allele of CTLA-4 gene and c.534+17T > C of the CD28 gene in T2DM patients compared to healthy individuals (p > 0.05). CONCLUSION: The CTLA-4 gene c.49A > G and c.-319C > T and CD28 gene c.534+ 17T > C polymorphisms did not represent an important risk factor for this disease in a group of the Turkish population. PMID- 21291099 TI - The emergence of qnr-mediated quinolone resistance among Enterobacteriaceae in Jamaica. AB - OBJECTIVE: Quinolone resistance is usually caused by various chromosomal mutations, but has been more recently associated with plasmids which carry the qnr determinant. The aim of this study is to investigate the prevalence of qnr genes in clinical isolates of Enterobacteriaceae in Jamaica. METHODS: A total of 255 non-duplicate fluoroquinolone-resistant Enterobacteriaceae clinical isolates, comprising 232 Escherichia coli, 20 Klebsiella species and three Enterobacter spp were collected between October 2007 and November 2008 from hospitalized patients in Jamaica. The presence of the qnr gene was screened by PCR using specific primers for qnrA, qnrB and qnrS in extracted plasmid DNA. RESULTS: Eighty-three (32.5%) of these isolates were qnr-positive, of which 47.0% housed the qnrA gene only, 1.2% qnrB and 9.6% qnrS only. Another 36.1% possessed both qnrA and qnrS genes. Approximately 30% of the quinolone-resistant E coli isolates harboured the qnr gene while 50% Klebsiella spp and all Enterobacter spp were positive. CONCLUSION: The emergence of qnr-mediated quinolone resistance among clinical Enterobacteriaceae isolates is described for the first time in Jamaica. PMID- 21291100 TI - An extract of neem leaves reduces anxiety without causing motor side effects in an experimental model. AB - Anxiety modulation often requires pharmaceutical intervention, and though effective in the short-term, benzodiazepines may cause impaired motor function. As a potential alternative, anxiety-modulating effects of a neem leaf (Azadirachta indica, A Juss) extract were investigated using ethological analysis of rat behaviour on an elevated X maze and compared with diazepam treatment. Sexually immature female Sprague-Dawley rats received 0.07 or 7 mg/kg neem leaf steroidal extract, a sham injection, a 1% DMSO/saline vehicle, 2 mg/kg diazepam or no treatment one hour prior to a recorded five-minute exploration of the elevated X maze. Neem matched diazepam in anxiety reduction as both treatments caused a decrease in per cent protected stretched-attend postures (PPSAP). Neem treatment had no effect on closed arm entries or total rears, distinguishing it pharmacologically from diazepam which resulted in a predictable decrease in those locomotor measures. Whereas both neem and diazepam reduced anxiety in complex ethological behavioural indices, only neem produced anxiolysis without motor deficiency. PMID- 21291101 TI - The antibacterial activities of mikanolide and its derivatives. AB - OBJECTIVE: The sesquiterpene, mikanolide, was found to possess antibacterial activity. As a result, a structure-activity relationship study was carried out on mikanolide and eleven of its derivatives. METHODS: Mikanolide and two of its derivatives were isolated from organic extract of Mikania micrantha using chromatographic methods. Nine additional derivatives were synthesized and all were investigated for their antibacterial activity against the Gram positive pathogen Staphylococcus aureus and beta haemolytic Streptococcus group A (BHSA) as well as the Gram negative Escherichia coli using the disk diffusion assay. RESULTS: The investigation revealed that only four of the derivatives displayed antibacterial activity and only pathogens Staphylococcus aureus and beta haemolytic Streptococcus group A were susceptible at a concentration of 100 microg per disk. However there was an increase in activity for three of the derivatives in comparison to mikanolide. CONCLUSION: This study underscores the potential for phytochemicals from locally available plants to be further investigated and developed as antibacterial agents. PMID- 21291102 TI - An evaluation of the diagnostic utility of anthropometric and body composition cut-off values in assessing elevated fasting blood sugar and blood pressure. AB - OBJECTIVE: High blood pressure and diabetes mellitus account for over 50% of annual visits to health facilities in Trinidad and Tobago. This study investigates the ability of various absolute and relative body composition variables to predict elevated fasting blood sugar (FBS) and blood pressure (BP). SUBJECTS AND METHODS: Participants had overnight fasting finger-stick blood glucose analysed with a hand-held automated glucometer (Basic One-touch Ultra). Two blood pressure tests were taken on the right arm after ten minutes of rest in the sitting position using an automated blood pressure (Omron HEM 712C). Participation in the study was voluntary. Waist, height and weight circumferences were measured using standard procedure. Percentage body fat (%BF) was measured with a foot-to-foot bioelectric body fat analyser (Tanita UM026). RESULTS: One hundred and fifty-seven persons (90 females and 67 males) participated in the investigation. Approximately 23% of participants had BP, FBS and waist circumference levels that were above recommended cut-offs. In correlation, analyses controlling for ethnicity and age-adjusted FBS were significantly positively correlated with waist circumference, BMI, weight, fat mass and %BF. Receiver-operator curve analyses suggest that cut-off values based on BMI, waist circumference and waist-height ratio were significant predictors of elevated FBS among females while those based on waist circumference and %BF were significant predictors of elevated FBS among males. CONCLUSION: The findings suggest similar predictive ability among the various absolute and relative body composition measures in predicting FBS and BP. PMID- 21291103 TI - The epidemiology of diabetes mellitus in Jamaica and the Caribbean: a historical review. AB - Epidemiological studies on diabetes mellitus (DM) have been conducted in the Caribbean for more than four decades. In Jamaica, the estimated prevalence of DM among adults ranged from 1.3% in 1960 to 17.9% in 1995. Part of the variation in estimates has been due to the differing age groups that have been studied. The 2007-8 Jamaica Health and Lifestyle Survey (JHLS-2) reported prevalence estimates of 7.9% for diabetes mellitus and 2.8% for impaired fasting glucose in persons 15 74 years old. Across the Caribbean, the overall prevalence of diabetes mellitus is estimated at about 9%. In addition to the high burden of prevalent diabetes, there is also a high burden of complications. In Barbados, the incidence of diabetic foot complications has been found to be second only to a population of Native Americans in Najavo. The Barbados Eye Study revealed that among persons 40 84 years old in Barbados, 28.5% had evidence of diabetic retinopathy on fundus photographs. Regionally, the impact of DM on cardiovascular diseases (CVD) has not been adequately reported. With regards to diabetes care, poor control rates and inadequate surveillance for complications have been reported in Barbados, Trinidad and Tobago, Tortola and Jamaica. The JHLS-2 showed that while more than 70% of persons with diabetes were aware of the condition less than 50% were under control. In light of the expected increase in the number of people with diabetes mellitus, healthcare planners and researchers will need to redouble their efforts to both prevent as well as limit the impact of diabetes mellitus and its complications in Caribbean populations. PMID- 21291104 TI - Prevalence of the metabolic syndrome in Jamaican adults and its relationship to income and education levels. AB - OBJECTIVE: To estimate the prevalence of the metabolic syndrome in Jamaican adults and to evaluate its association with socio-economic status (SES). METHODS: A cross-sectional analysis was performed using data from a cohort study of persons, 25-74 years old, living in St Catherine, Jamaica, and who were evaluated between 1993 and 2001. Participants completed an interviewer administered questionnaire and had blood pressure and anthropometric measurements performed by trained observers. Venous blood was collected for measurement of fasting glucose and lipids. The metabolic syndrome was defined using the International Diabetes Federation (IDF) and American Heart Association/National Heart Lung and Blood Institute (AHA/NHLBI) criteria. Income and education were used as markers of SES. RESULTS: Data from 1870 participants (717 males 1153 females) were analysed. Prevalence of the metabolic syndrome was 21.1% (95% CI 19.2, 22.9%) using IDF criteria and 18.4% (95% CI 16.6, 20.2%) using the AHA/NHLBI criteria. Prevalence was higher among females (27.6% [IDF], 23.0% [AHA]) compared to males (10.6% [IDF], 11.0% [AHA]). The prevalence of the metabolic syndrome increased with age. Compared to males with primary/lower education, those with secondary and tertiary education had higher odds of having the metabolic syndrome after adjusting for age; odds ratio 3.12 (1.54, 6.34) and 2.61 (1.33, 5.11) respectively. High income was also associated with increased odds of having the metabolic syndrome among males, OR = 6.0 (2.22, 16.19) adjusting for age-group. There were no significant associations among women. CONCLUSION: The metabolic syndrome is common in Jamaica. Clinicians should look for this syndrome in their patients and take steps to treat the abnormalities identified. PMID- 21291105 TI - An assessment of adolescent satisfaction with reproductive primary healthcare services in the Eastern Cape Province, South Africa. AB - OBJECTIVE: To assess adolescents' satisfaction with reproductive health services in Mdantsane Township, Eastern Cape Province, South Africa. METHOD: A structured questionnaire was used to assess the levels of participants' satisfaction with reproductive health services. The sample consisted of 200 adolescents within the ages of 16 to 19 years. A response of "yes" indicated that the person was satisfied with the specific item, while a response of "no" indicated dissatisfaction with that item. A spreadsheet was developed to analyse data obtained and 95% was used as a cut off rate to define an appropriate level of client satisfaction. RESULTS: Results indicated that adolescents were dissatisfied with reproductive health delivery at Mdantsane Township. Satisfaction responses on accessibility and confidentiality of services, options available to participants as well as staff friendliness fell below the stated cut off rate of 95%. From each item, the number of responses of satisfaction on reproductive health delivery at the primary health clinic was mostly below 89%. CONCLUSION: In general, participants in this survey were dissatisfied with reproductive health services at the clinics at Mdantsane Township in the Eastern Cape Province. PMID- 21291106 TI - Fundamental issues in forensic semen detection. AB - Sperm detection can be an important factor in confirming sexual assault in cases of rape. A large number of cases received in a forensic laboratory involve sexual offenses, making it necessary to examine exhibits for the presence of seminal stains. The objective of this paper is to provide an overview of the most important methods and tests used in the identification of spermatozoa or constituents of seminal fluid during the investigation of alleged sexual assault cases in forensic medical practice. Furthermore, this paper focusses on the basic knowledge that is necessary to the graduate students who wish to specialize in forensic sciences. PMID- 21291107 TI - Preparing medical graduates to practise in a changing environment: complementary/alternative medicine in the medical undergraduate curriculum of the University of the West Indies. PMID- 21291108 TI - Is Free Running Asthma Screening Test still useful? AB - OBJECTIVE: The aim of this study is to evaluate the usefulness of Free Running Asthma Screening Test (FRAST) as a method that may help the diagnosis of exercise induced bronchospasm (EIB) in children from a rural area and to compare the results with their history of asthma. METHODS: A FRAST challenge took place at 9 schools. It lasted for 6 minutes and pupils performed it properly with the help of an athlete. The best out of three Peak Expiratory Flow Rate (PEFR) efforts was recorded before and after challenge, using a mini-Wright peak-flow-meter. A more than 15% drop in PEFR was considered an indication of EIB. A questionnaire defining asthmatic symptoms had been distributed and already completed by their parents. RESULTS: The exercise was successfully performed by 268 children. Eleven children presented a fall of PEFR of at least 15%, five or ten minutes after the exercise; among these, only three boys had a history of asthma, while the remaining 8 children were undiagnosed. No difference regarding age, gender or locations' altitude was found. CONCLUSION: FRAST can be of great use in the diagnosis of EIB in areas that lack proper tools and specialized personnel. A poor correlation between self-reported symptoms and the results of exercise challenges was confirmed. PMID- 21291109 TI - Significance of mutation in the D-loop region in cervical cancer. AB - AIM: To investigate the mutation in the D-loop region of mitochondrial DNA in cervical cancer and its influence on the changes of reactive oxygen species (ROS) and cell cycle. METHODS: The D-loop region was amplified by PCR and sequenced. Reactive oxygen species and cell cycle were detected by flow cytometry in 40 specimens from cervical cancer and adjacent normal tissues. According to the sequence results, gastric cancer tissue was divided into mutation group and control group. Reactive oxygen species, apoptosis and proliferation in the two groups were compared. RESULTS: Among the 40 cervical cancer specimens, 21 mutations were identified in 12 patients, the mutation rate being 30%. There were four microsatellite instabilities in the mutations. No mutation was found in the adjacent tissues. Reactive oxygen species, apoptosis and proliferation in the mutation group were all significantly higher than those in the control group. CONCLUSION: Mutation in the D-loop region plays a role in the genesis and development of cervical cancer. PMID- 21291110 TI - Perinatal factors in students admitted to the University of the West Indies data from the Jamaican Perinatal Study. AB - OBJECTIVE: To compare perinatal and social factors in students admitted to The University of the West Indies (UWI), Kingston, Jamaica, at age 18 years with those in the rest of the Jamaican Perinatal Cohort. METHOD: The Jamaican Perinatal Survey recorded demographic and perinatal details in 10 527 or 97% of births in Jamaica in September and October 1986. Eighteen years later 140 of these were admitted to the UWI in Kingston, Jamaica. The perinatal features of these UWI students have been compared with the rest of the Perinatal Survey Cohort. RESULTS: Mothers of UWI students were older (p < 0.001), more likely to be married at the time of birth (p < 0.001), had earlier and more complete antenatal care (p < 0.05) and greater educational achievement at time of pregnancy (p < 0.001). These mothers of UWI students were also more likely to have diabetes (p < 0.01), operative deliveries (p < 0.01) and to attend private hospitals (p < 0.01). The UWI students had fewer siblings by their mothers (p < 0.05), were less likely to be low birthweight babies (p = 0.035) and more likely to be full-term (37-42 weeks) than lower gestational age (p = 0.005). Differences in Apgar scores did not reach statistical significance. CONCLUSIONS: The students of the University of the West Indies were more likely to come from smaller families with features indicative of a better quality of life. They were also of higher birthweight and tended to be full-term. The lack of association of Apgar scores with educational attainment is noteworthy. PMID- 21291111 TI - The feasibility of using magnetic nanoparticles modified as gene vector. AB - OBJECTIVE: To evaluate the feasibility of using magnetic nanoparticles (MNPs) as gene vector and the effect of magnetic field on efficiency of transfection. METHODS: Magnetic nanoparticles were prepared by controlling some chemical reaction parameters through a partially reduction precipitation method with ferric chloride aqueous solution as precursor material. The surface of particles was modified by polyethyleneimine (PEI) agents. The appearance, the size distribution, structure and phase constitute of MNPs were characterized by Transmission electron microscope (TEM), X-ray diffraction (XRD); the potential of absorbing DNA of MNPs was analysed by electrophoresis. Transfection was determined by delivering reporter gene, PGL2-control encoding luciferase, to different cell lines using MNPs-PLL as vector. The effect of magnetic field on the efficiency of transfection was determined using Nd-Fe-B permanent magnet. RESULTS: Foreign gene could be delivered to various cell lines by MNPs-PLL and expressed with high efficiency but the transfection efficiency and time course varied in the different cell lines studied. Magnetic field could enhance the efficiency of transfection by 5-10 fold. CONCLUSION: MNPs- PLL can be used as a novel non-viral gene vector in vitro, which offers a basis for gene delivery in vivo. PMID- 21291112 TI - Juvenile polyposis syndrome. AB - Juvenile polyposis syndrome (JPS) is rare and is present when there are multiple juvenile polyps in the gastrointestinal tract, usually the colon. The importance of this condition is the association with the development of colorectal and upper gastrointestinal cancer at a young age. We report the case of a 21-year old male with a two-year history of intermittent rectal bleeding and anal protrusion. Colonoscopy revealed multiple pedunculated cherry red polyps mainly in the left colon. Histology confirmed juvenile polyps. Juvenile polyposis syndrome should be considered in young patients with colonic symptoms, especially rectal bleeding. It is important to distinguish between patients with JPS and patients with an isolated harmatomatous juvenile polyp. PMID- 21291113 TI - The prevalence of Helicobacter pylori infection in patients undergoing upper gastrointestinal endoscopy in the Turks and Caicos Islands. AB - BACKGROUND: Helicobacter pylori infection remains a common problem and previous studies in the Caribbean revealed infection in over 50% of patients undergoing upper endoscopy. OBJECTIVE: The present study determined the prevalence of H pylori infection in patients undergoing upper gastrointestinal endoscopy in the Turks and Caicos Islands over a two- year interval. METHODS: All patients with upper gastrointestinal symptoms requiring endoscopy were evaluated clinically and H pylori testing performed histologically. RESULTS: There were 57 patients (21 males, 36 females) with a mean age of 43 years. Twenty-six patients presented with gastroesophageal reflux, 17 with upper abdominal pain, 10 with dyspepsia and 4 with upper gastrointestinal bleeding. H pylori infection was present in 24 patients (42%) and negative in 33 (58%). Upper gastrointestinal endoscopy was normal in 27 patients, 13 (54%) were H pylori positive and 14 (43%) negative. Antral gastritis was present in 13 patients, 7 (54%) were H pylori positive and 6 (46%) negative. Duodenal ulcer was present in 6 (33% H pylori positive) and gastric ulcer in 5 patients (40% H pylori positive). Distal oesophagitis was present in 5 patients (all negative for H pylori) and gastric carcinoma in 1 (H pylori positive). CONCLUSION: In patients with dyspepsia, 60% were positive for H pylori. H pylori infection was common in the patients in this study with gastrointestinal symptoms. However, the prevalence in endoscopic patients and peptic ulcer disease is lower than in other reports from the Caribbean. PMID- 21291114 TI - Characteristics, complications and outcome of patients treated with automated peritoneal dialysis at the Peritoneal Dialysis Unit, University Hospital of the West Indies. AB - OBJECTIVE: To characterize and evaluate complications and outcomes of the patients treated with automated peritoneal dialysis (PD) at the University Hospital of the West Indies (UHWI), Jamaica. METHOD: Retrospective data were collected from peritoneal dialysis patients' case files retrieved from the medical records department of UHWI. Demographic data (age, gender address, marital status), year of dialysis commencement, cause of end stage renal disease (ESRD), haemoglobin, serum electrolytes, serology, blood pressure readings, medications used, blood transfusion and erythropoietin use were collated. Complications such as infections (pneumonia, catheter-related infections), cardiac related disorders (congestive cardiac failure, acute coronary syndrome, pericarditis/pericardial effusion), cerebrovascular diseases, renal osteodystrophy, complications of the procedure and of end stage renal disease (ESRD), outcome and cause of death were retrieved from patients' case files for analysis. RESULTS: There were 202 patients receiving peritoneal dialysis between September, 1999 and December 2008. Data on 190 were analysed. The case files of 12 patients were not included because of incomplete data. The ages of the studied PD patients ranged between 33 and 65 years. The mean haemoglobin was 7.4 g/dL, serum calcium of 2.1 mmol/L, serum phosphate of 1.9 mmol/L and calcium/phosphate product of 4.1mmol2/L2. The serum albumin was 32 g/L and serum total cholesterol/HDL ratio of 5.3. Most patients were from Kingston and St Andrew (56.8%), St Catherine (18.9%) and Clarendon (7.4%). Hypertension (27.9%), chronic glomerulonephritis (17.9%) and diabetes mellitus (17.4%) were the commonest causes of ESRD. There were 70.5% unmarried persons and 81.6% of patients were unemployed. HIV, Hepatitis B and Hepatitis C seropositivity were discovered in 4.1%, 1.1 and 0.5% of patients respectively. Only 20% of the patients used erythropoietin and of this 92% used it less than 50% of the prescribed frequency. Infections (43.2%) such as pneumonia, peritonitis, catheter tunnel infection, exit site infection and cardiac related complications (37.4%) such as congestive cardiac failure, acute coronary syndrome, pericarditis/pericardial effusion were the most frequently encountered complications. Forty-one per cent of patients were transferred to haemodialysis mainly on account of inadequate dialysis clearance. Sepsis (42%) such as pneumonia, urinary tract infection, peritonitis and cardiac related causes (31%) such as congestive cardiac failure and acute coronary syndrome were the two major causes of death. Of those who died of sepsis, 45.2% had pneumonia. Only 9.5% (4/42) of patients had confirmed peritonitis during their illness. CONCLUSION: Infection and cardiovascular disease were common complications observed in this study. Therefore intensive management of risk factors (hypertension, diabetes and dyslipidaemia) and prompt recognition of infection is hereby recommended. Early recognition and appropriate management of sepsis in peritoneal dialysis patients should be initially based on standard protocol. The use of erythropoietin in peritoneal dialysis patients will enhance better management of anaemia and improve quality of life. PMID- 21291115 TI - Clinicopathological features of atypical nephrotic syndrome in Jamaican children. AB - OBJECTIVES: To document the histopathological spectrum of atypical nephrotic syndrome in Jamaican children and to make clinicopathological correlations which will assist physicians in identifying patients needing nephrology consultation. METHODS: This was a retrospective review of renal biopsy data of Jamaican children who were referred to the University Hospital of the West Indies and the Bustamante Hospital for Children between January 1985 and December 2008. The study population consisted of children < 12 years old with atypical nephrotic syndrome. RESULTS: Biopsies were done in 157 children--85 males and 72 females (mean age 8.91 +/- 3.44 years). Indications for biopsy were steroid resistance (35%), frequent relapses (8.9%) and other atypical presentations (56.1%). Overall, mesangial proliferative glomerulonephritis (MesGN) was the commonest histology (49/157, 31.2%), followed by minimal change disease (MCD) (36/157, 22.9%) and diffuse proliferative glomerulonephritis (DPGN) (26/157, 16.6%). Infection was present in 38/157 (24%) cases. Diffuse proliferative glomerulonephritis was the predominant type associated with streptococcal infection (52.9%) while Hepatitis B was seen in 83% of cases of membranous nephropathy. CONCLUSION: Mesangial proliferative glomerulonephritis is the commonest histology seen in Jamaican children with atypical nephrotic syndrome. Most membranous nephropathy is Hepatitis B related. Hypertension with hypocomplementaemia, renal failure and anaemia are features of more serious renal disease (eg membranoproliferative glomerulonephritis and crescentic nephritis) rather than MCNS and should warrant urgent nephrology consultation for renal biopsy. PMID- 21291116 TI - Renal biopsy findings in Jamaican children. AB - OBJECTIVE: To document the histological findings in Jamaican children undergoing renal biopsy in order to determine the relative prevalence of varying types of glomerular disease in the island. METHODS: This study analyses retrospectively the renal histology in all Jamaican children less than age 12 years undergoing their first adequate renal biopsy between January 1985 and December 2008. Clinicopathological data were obtained solely from the histology reports from the University Hospital of the West Indies where all paediatric renal biopsies are processed. RESULTS: Of the 270 children, aged 1 month to 11 years (mean 7.58 years), 147 [58.1%] were males. The commonest indications for renal biopsy were nephrotic syndrome (57.4%) and glomerulonephritis (30%). Most biopsied children (260/270) had glomerular disease. The predominant glomerulonephritides were diffuse proliferative glomerulonephritis (DPGN) (27.7%) and mesangial proliferative glomerulonephritis (MesGN) (25.5%). Glomerular disease was idiopathic in 136/260 (53%) but was infection-associated in 32.3% (84 cases) of which Poststreptococcal glomerulonephritis (PSGN) was the commonest (75%)- predominantly DPGN (74.6%). Hepatitis B followed at 15.5% (13/84) manifested as membranous nephropathy in 83.3% (10/12). In patients with SS disease, DPGN was the commonest histology (47.4%). Systemic lupus erythematosus accounted for 5% of all renal biopsies. Over time, PSGN occurred less frequently, with a parallel reduction in DPGN and MesGN. CONCLUSION: In Jamaican children, DPGN is the commonest nephritis. Membranous nephropathy is primarily due to Hepatitis B. The commonest histology in SS disease is DPGN. The role of infection in the pathogenesis of renal disease in Jamaican children is probably underestimated. PMID- 21291117 TI - Mycophenolate mofetil in minimal change nephrosis. PMID- 21291118 TI - The importance of bone biomarkers in the diagnosis of renal osteodystrophy. AB - OBJECTIVE: To evaluate the association of serum biochemical markers in patients with chronic kidney disease (CKD) in Jamaica for early detection of renal osteodystrophy (ROD). METHODS: The study contained two groups: CKD group (221) which consisted of adult patients, from dialysis units and renal clinics, with stage III to V CKD. The control group (237) had adult individuals, from the medical outpatient clinics, with mild and controlled chronic diseases and absence of renal failure. The patients in the study were between 18-80 years of age and gave informed consent to participate in the study. The differences in distribution of demographic, clinical and pathologic variables between the two groups were evaluated. Pearson's chi-squared test and Spearman' rho correlation coefficient test was used, with p < 0.01 considered statistically significant. Data analysis was conducted using the statistical package for the social sciences (SPSS) version 17.0. RESULTS: Among the 221 CKD patients in the study, 174 (78.7%) had ROD based on serum intact parathyroid hormone (iPTH) levels. The majority of patients in the control group did not have bone disease ie 95-96%. The majority of CKD patients (70.0%) had high-turnover (HTO) bone disease compared to 29.3% of patients with low-turnover (LTO) bone disease. Dialysis patients who had HTO bone disease compared with those with LTO had significantly higher levels of iPTH and total serum alkaline phosphatase (ALP). A similar relationship was observed among CKD patients not on dialysis. There was a significant individual variation in bone turnover biochemical markers. A total of 237 patients were recruited in the control group. Based on the levels of iPTH and tALP six of them were found to have bone disease. The majority of these patients with bone disease were diabetic (83.3%) while the other patient had cancer (16.7%). The six patients in the control group with bone disease were within the age cohort of 64-80 years, most of whom were 78 years old. CONCLUSION: A combination of serum biochemical markers might predict underlying renal osteodystrophy better that would individual biochemical markers. A predictive model using bone histology and biochemical markers can be developed in the future. PMID- 21291119 TI - A case of lupus-associated pancreatitis in Jamaica. AB - Pancreatitis complicating a diagnosis of systemic lupus erythematosus (SLE) is rarely reported in the literature and there are no known published cases thus far in the Caribbean. A 50-year old female diagnosed with SLE and discoid lupus erythematosus (DLE) since 1990, presented in February, 2009, to the University Hospital of the West Indies (UHWI), Kingston, Jamaica, with symptoms suggestive of lupus pancreatitis. Serum amylase level was 2341 IU/L and serum lipase was 203 IU/L. Pancreatitis has a 3-8% rate of occurrence in adult patients with SLE. Aetiology and management of this entity remains controversial in these cases, but one must bear the diagnosis in mind, when faced with a SLE patient presenting with abdominal pain, vomiting and diarrhoea. PMID- 21291121 TI - Effective prevention measures based on aspects of traffic fatality rates are needed in Thailand. PMID- 21291120 TI - The report on the current state of activities of palliative care teams and further enhancement of those activities: a summary based on previous reports. PMID- 21291123 TI - Nurses as primary care providers get new backing, old opposition. PMID- 21291122 TI - Urgent importance of various suicide prevention measures among the elderly in South Korea. PMID- 21291124 TI - Expanded role for pharmacists tested. PMID- 21291125 TI - 'Freeze the pay on specialists'. PMID- 21291126 TI - Plans confront specialty pharmacy's escalating costs in variety of ways. PMID- 21291127 TI - Is'mobile health' revolution made for managed care? PMID- 21291128 TI - Health insurers need social media presence. PMID- 21291130 TI - 5010 compliance effort keeps eye on deadlines. PMID- 21291129 TI - What do you do about ER costs? PMID- 21291131 TI - How the doughnut hole affects prescription fulfillment decisions involving cardiovascular medications for Medicare Part D enrollees. AB - PURPOSE: The unsupplemented Medicare Part D prescription drug benefit does not provide coverage for stand-alone prescription drug plan (PDP) beneficiaries within the coverage gap (often called a doughnut hole) in Medicare Part D. DESIGN: We evaluated whether the doughnut hole was a factor in altering prescription fulfillment decisions regarding cardiovascular medications in Part D beneficiaries. METHODOLOGY: We investigated 500 Medicare Part D members' pharmacy adjudication records (all prescription transactions) for one full year from a blinded, national Part D HMO pharmacy database. We selected 250 stand-alone PDP beneficiaries without coverage in the doughnut hole and 250 Medicare Advantage Prescription Drug (MA-PD) plan beneficiaries whose prescription coverage did not lapse in the doughnut hole by way of random stratified sampling and analyzed the records using multinomial logistic regression for their prescription fulfillment decision endpoints of filling, delaying, switching, or stopping their medications. FINDINGS: Of stand-alone PDP beneficiaries, 16.8% delayed medication, 12.4% switched medication, 10.4% both delayed and stopped medication, and 9.6% stopped at least one medication. Part D enrollees who entered the doughnut hole are 1.5 times as likely to delay their cardiovascular prescriptions (OR = 1.54, 95% CI 0.924, 2.562), 1.5 times as likely to switch and delay their cardiovascular prescriptions (OR = 1.52, 95% CI 0.532, 4.332), and 2.3 times as likely to delay and stop their cardiovascular prescriptions than beneficiaries with coverage through the doughnut hole period (OR = 2.30, 95% CI 1.134, 4.673). CONCLUSIONS: For cardiovascular medications, the presence of a doughnut hole affects the prescription fulfillment decisions made by Part D beneficiaries. PMID- 21291132 TI - In 2011, a third fewer nationwide Medicare PDPs. PMID- 21291133 TI - Highmark's P4P program uses 2 different approaches. PMID- 21291135 TI - MA plans to limit members' out-of-pocket expenses. PMID- 21291134 TI - Telescope placed in eye improves central vision. PMID- 21291136 TI - New grad or unemployed? Don't get rusty while waiting. PMID- 21291137 TI - Consulting can help your pocket and your patients. PMID- 21291138 TI - Healthcare reform is good for NPs, PAs and patients. PMID- 21291139 TI - Atrial fibrillation. A concise update on treatment. PMID- 21291140 TI - Cultural issues in diabetes. Dietary counseling for black patients. PMID- 21291141 TI - Gestational diabetes. Current management strategies for a 'growing' problem. PMID- 21291142 TI - Rehydration and refeeding after diarrheal illness. Say no to sports drinks and BRAT. PMID- 21291143 TI - Complex regional pain syndrome. Triggered by injury. PMID- 21291144 TI - Think thyroid. Connecting an assortment of symptoms leads to a hypothyroidism diagnosis. PMID- 21291145 TI - Type 2 diabetes: a family affair. PMID- 21291146 TI - Holiday foods on a budget. PMID- 21291147 TI - National Diabetes Month: headlines from 2010. PMID- 21291148 TI - New tools 2010. PMID- 21291149 TI - What your doctor is reading. PMID- 21291150 TI - Green bean casserole. PMID- 21291151 TI - Intuitive eating: enjoy your food, respect your body. PMID- 21291152 TI - Vegetarian frozen entrees. PMID- 21291153 TI - How much do you know about MRSA? PMID- 21291154 TI - Coping with painful neuropathy. PMID- 21291155 TI - Biological and cultural factors in applied experimental psychology. Introduction. PMID- 21291156 TI - Adaptive memory: nature's criterion and the functionalist agenda. AB - Memory researchers traditionally ignore function in favor of largely structural analyses. For example, it is well known that forming a visual image improves retention, and various proximate mechanisms have been proposed to account for the advantage (e.g., elaboration of the memory trace), but next to nothing is known about why memory evolved such sensitivities. Why did nature craft a memory system that is sensitive to imagery or the processing of meaning? Functional analyses are critical to progress in memory research for two main reasons: First, as in applied research, functional analyses provide the necessary criteria for measuring progress; second, there are good reasons to believe that modern cognitive processes continue to bear the imprint of ancestral selection pressures (i.e., cognitive systems are functionally designed). We review empirical evidence supporting the idea that memory evolved to enhance reproductive fitness; as a consequence, to maximize retention in basic and applied settings it is useful to develop encoding techniques that are congruent with the natural design of memory systems. PMID- 21291158 TI - Cross-modal congruency benefits for combined tactile and visual signaling. AB - This series of experiments tested the assimilation and efficacy of tactile messages that were created based on five common military arm and hand signals. We compared the response times and accuracy rates for these tactile representations against responses to equivalent visual representations of the same messages. Experimentally, such messages were displayed in either tactile or visual forms alone, or using both modalities in combination. There was a performance benefit for concurrent message presentations, which showed superior response times and improved accuracy rates when compared with individual presentations in either modality alone. Such improvement was due largely to a reduction in premotor response time. These improvements occurred equally in military and nonmilitary samples. Potential reasons for this multimodal facilitation are discussed. On a practical level, these results confirm the utility of tactile messaging to augment visual messaging, especially in challenging and stressful environments where visual messaging is not feasible or effective. PMID- 21291157 TI - Translating cognitive neuroscience to the driver's operational environment: a neuroergonomic approach. AB - Neuroergonomics provides a multidisciplinary translational approach that merges elements of neuroscience, human factors, cognitive psychology, and ergonomics to study brain structure and function in everyday environments. Driving safety, particularly that of older drivers with cognitive impairments, is a fruitful application domain for neuroergonomics. Driving makes demands on multiple cognitive processes that are often studied in isolation and so presents a useful challenge in generalizing findings from controlled laboratory tasks to predict safety outcomes. Neurology and the cognitive sciences help explain the mechanisms of cognitive breakdowns that undermine driving safety. Ergonomics complements this explanation with the tools for systematically exploring the various layers of complexity that define the activity of driving. A variety of tools, such as part task simulators, driving simulators, and instrumented vehicles, provide a window into cognition in the natural settings needed to assess the generalizability of laboratory findings and can provide an array of potential interventions to increase driving safety. PMID- 21291159 TI - Universal and culture-specific effects of display-control compatibility. AB - Research on compatibility of displays and controls has been a staple of basic and applied experimental psychology since the work by Paul Fitts and colleagues in the 1950s. Compatibility is often defined in terms of natural response tendencies, and many behavioral studies have been conducted examining various determinants of compatibility effects. Some compatibility phenomena are universal because of constant properties of the physical environments in which people live. Others, often called population stereotypes (Loveless, 1962), are specific to particular cultural groups due to experience with unique display-control relations. Determining which compatibility phenomena are universal and which are limited to certain populations is necessary for knowing how widely various compatibility principles can be expected to hold for performance. In this article we examine the universal and cultural aspects of display-control compatibility with an emphasis on implications for understanding human performance in general and for applying the knowledge to design of interfaces that will be maximally compatible with the characteristics of the intended users. PMID- 21291160 TI - The influence of surface color information and color knowledge information in object recognition. AB - In order to clarify whether the influence of color knowledge information in object recognition depends on the presence of the appropriate surface color, we designed a name-object verification task. The relationship between color and shape information provided by the name and by the object photo was manipulated in order to assess color interference independently of shape interference. We tested three different versions for each object: typically colored, black and white, and nontypically colored. The response times on the nonmatching trials were used to measure the interference between the name and the photo. We predicted that the more similar the name and the photo are, the longer it would take to respond. Overall, the color similarity effect disappeared in the black-and-white and nontypical color conditions, suggesting that the influence of color knowledge on object recognition depends on the presence of the appropriate surface color information. PMID- 21291161 TI - Evidence of mnemonic ability selectively affecting truthful and deceptive response dynamics. AB - In the executive model of deception, the telling of a lie necessitates the inhibition of a veridical prepotent response (the truth), and such inhibition incurs a temporal penalty, manifest as a longer response time. If memory processes are engaged in generating such truths, then memory function should affect truthful and deceptive response times. To investigate this we examined the relationship between performance on a semantic knowledge deception task and a test of verbal memory in 40 college students. We found that verbal memory performance differentially affects the temporal parameters of truth and deception. PMID- 21291162 TI - The effect of number of options on choices involving delayed causation. AB - A video game was adapted to investigate the effect of the number of alternatives on causal judgment in a complex environment involving targets with delayed outcomes. Participants were presented with groups of potential targets. Each target (the candidate cause) fired at random relative to the others, with one target in each group causing a delayed explosion (the effect).The participants were tasked with discriminating which of the potential targets was producing the effect. Experiment 1 revealed a main effect of delay on discriminability but no effect of the number of alternatives. However, latencies did increase as the number of alternatives increased, suggesting that discriminability was maintained by compensating with longer observation times. But, a similar increase in latency for longer delays did not offset the detrimental impact of an increase in cause effect delay. Experiment 2 replicated the outcome under conditions in which participants were always required to observe for 16 s before making a decision; under the most difficult conditions, however, the limited viewing time started to reveal an effect of the number of alternatives on the participants' ability to discriminate a true cause from foils. Evidence suggests that participants' decisions were determined primarily by differences in the number of cause-effect contiguities experienced for the true cause versus the foils. PMID- 21291163 TI - An investigation into differences between the structure of temperament and the structure of personality. AB - This article analyzes the differences between an activity-specific temperament model and the Big Five personality model using the Structure of Temperament Questionnaire--Compact (STQ-77). The STQ-77 has 3 emotionality scales and 9 scales assessing 3 dynamic aspects (arousal, lability, and sensory sensitivity) in 3 areas of activity (physical, verbal-social, and mental). The results of administration of the Russian STQ-77, NEO-FFI, and SSS-V to 174 Russian participants showed how components of temperament can represent the traits described in the Big Five model. The confirmatory factor analysis of the English STQ-77 and the results of a study involving a prolonged word classification task with 221 Canadian participants showed the benefits of the activity-specific approach, separating temperament traits in three areas of activity. Such specificity of temperament traits differentiates them from personality traits. PMID- 21291164 TI - Health, human rights and global security: exploring connections. PMID- 21291165 TI - The Treaty on the Non-Proliferation of Nuclear Weapons (NPT) Review Conference: success is in the eye of the beholder. PMID- 21291166 TI - Human rights and humanitarian assistance: helping health professionals lead the way in Haiti and beyond. PMID- 21291167 TI - The quest for human responsibilities to complement human rights. PMID- 21291168 TI - Pre- and post-displacement stressors and time of migration as related to self rated health among Iraqi immigrants and refugees in Southeast Michigan. AB - The objective of this study was to determine whether perceived health status of Iraqi immigrants and refugees residing in the United States was related to pre migration environmental stress, current unemployment, and if they had emigrated before or after the 1991 Gulf War. A random sample of Iraqis residing in Southeast Michigan, US, was interviewed using an Arab language structured survey. The main outcome measure was self-rated health (SRH). Major predictors included socioeconomics, employment status, pre-migration environmental stress, and health disorders. Path analysis was used to look at mediating effects between predictors and SRH. We found that SRH was significantly worse among participants that had left Iraq after the 1991 Gulf War. Unemployment and environmental stress exposure were inversely related to SRH. There was a direct path between Gulf War exposure and poor health. In addition, there were indirect paths mediated through psychosomatic and psychiatric disorders to SRH. Another path went from Gulf War exposure, via environmental stress and somatic health to poor health. Unemployment had a direct path, as well as indirect paths mediated through psychiatric and psychosomatic disorders, to poor self-rated health. In conclusion, these results suggest that pre- as well as post-migration factors, and period of migration, affect health. PMID- 21291169 TI - Government gas vans and school gas chambers: preparedness and paranoia in Britain, 1936-1941. AB - In 1936 the Air Raid Precautions department of the British Home Office instigated a training programme in which members of the public, including school students, were systematically exposed to tear gas. Based around fixed and mobile gas chambers, this training aimed to educate the public in the value and efficacy of their gas masks. Drawing on documentary and oral historical sources, this paper examines the discrepancies between the stated form and aims of these tests, and their practical applications, including some excessively brutal training practices. In the last part of the paper I consider these variations in the context of both the gas panic and the moral panic about children's behaviour in wartime. PMID- 21291170 TI - Transmembrane topology of mammalian planar cell polarity protein Vangl1. AB - Vangl1 and Vangl2 are membrane proteins that play an important role in neurogenesis, and Vangl1/Vangl2 mutations cause neural tube defects in mice and humans. At the cellular level, Vangl proteins regulate the establishment of planar cell polarity (PCP), a process requiring membrane assembly of asymmetrically distributed multiprotein complexes that transmit polarity information to neighboring cells. The membrane topology of Vangl proteins and the protein segments required for structural and functional aspects of multiprotein membrane PCP complexes is unknown. We have used epitope tagging and immunofluorescence to establish the secondary structure of Vangl proteins, including the number, position, and polarity of transmembrane domains. Antigenic hemagglutinin A (HA) peptides (YYDVPDYS) were inserted in predicted intra- or extracellular loops of Vangl1 at positions 18, 64, 139, 178, 213, and 314, and individual mutant variants were stably expressed at the membrane of MDCK polarized cells. The membrane topology of the exofacial HA tag was determined by a combination of immunofluorescence in intact (extracellular epitopes) and permeabilized (intracellular epitopes) cells and by surface labeling. Results indicate that Vangl proteins have a four-transmembrane domain structure with the N-terminal portion (HA18 and HA64) and the large C-terminal portion (HA314) of the protein being intracellular. Topology mapping and hydropathy profiling show that the loop delineated by TMD1-2 (HA139) and TMD3-4 (HA213) is extracellular while the segment separating predicted TMD2-3 (HA178) is intracellular. This secondary structure reveals a compact membrane-associated portion with very short predicted extra- and intracellular loops, while the protein harbors a large intracellular domain. PMID- 21291171 TI - Facile fabrication of branched gold nanoparticles by reductive hydroxyphenol derivatives. AB - In nature, polyphenol is one of the most important chemicals in many reductive biological reactions widely found in plants and animals. In this study, we demonstrated that hydroxyphenol compounds and their derivatives could be used as versatile reducing agents for facile one-pot synthesis of gold nanoparticles with diverse morphological characters by reducing precursor Au(III) ions into a gold crystal structure via a biphasic kinetically controlled reduction process. We found that the biphasic reduction of hydroxyphenols generated single-crystalline branched gold nanoparticles having high-index facets on their surface. The kinetically controlled self-conversion of hydroxyphenols to quinones was mainly responsible for the generation of morphologically different branches on the gold nanoparticles. Different hydroxyphenol derivatives with additional functional groups on the aromatic ring could produce totally different nanostructures such as nanoprisms, polygonal nanoparticles, and nanofractals possibly by inhibiting the self-conversion or by inducing self-polymerization. In addition, polymeric hydroxyphenol derivatives generated stably polymer-coated spherical gold nanoparticles with controlled size, usefully applicable for biomedical applications. PMID- 21291172 TI - Cycloisomerization of bifunctionalized allenes: synthesis of 3(2H)-furanones in water. AB - A simple protocol for the efficient synthesis of 3(2H)-furanones by cycloisomerization of allenic hydroxyketones is described. This transformation is achieved in water and in the absence of any expensive metal catalysts. PMID- 21291173 TI - Ag(I)-catalyzed regioselective ring-opening of N-tosylaziridine and N tosylazetidine with S-, O-, and N-nucleophiles and tethered dinucleophiles. AB - [Ag(COD)(2)]PF(6) catalyzes the ring-opening of N-tosylaziridines and -azetidines with alcohols, amines, thiols, and related tethered 1,2-ethane dinucleophiles. Initial rate studies and DFT-based evaluation of stepwise energetics suggest an inverse relationship between the nucleophilic reactivity of a heteroatom donor and its binding affinity to cationic Ag(I). PMID- 21291175 TI - Comparison between the efficiencies of sub-2 MUm C18 particles packed in narrow bore columns. AB - The chromatographic performance of two types of core-shell particles and two fully porous particles packed in 2.1 ID * 50 mm columns was investigated. Comparisons of the performances of the EiS-150-C(18) to that of the Kinetex-1.7 MUm-C(18), Acquity-BEH-1.7 MUm-C(18), and Zorbax-XDB-1.8 MUm-C(18) are made and discussed. The physical factors that govern the performance of these columns, such as particle size distribution and column external, total, and particle porosity of the C(18) packing materials were among the prime foci of investigation. The differences in the mass transfer behavior measured using naphtho[2,3-a]pyrene between these columns provides an indication of improved performance of the new EiS-150-C(18) column. The minimum reduced height equivalent to a theoretical plate (HETP) value for the EiS-150-C(18), h(min) = 1.95, was achieved and was comparable to that obtained from the C(18) phases of the Kinetex (h(min) = 2.53), the Acquity (h(min) = 2.26), and the Zorbax (h(min) = 2.57) columns. This study reveals the importance of the dimension of the shell thickness in controlling the performance of columns packed with shell particles in narrow bore columns. PMID- 21291174 TI - A machine learning-based method to improve docking scoring functions and its application to drug repurposing. AB - Docking scoring functions are notoriously weak predictors of binding affinity. They typically assign a common set of weights to the individual energy terms that contribute to the overall energy score; however, these weights should be gene family dependent. In addition, they incorrectly assume that individual interactions contribute toward the total binding affinity in an additive manner. In reality, noncovalent interactions often depend on one another in a nonlinear manner. In this paper, we show how the use of support vector machines (SVMs), trained by associating sets of individual energy terms retrieved from molecular docking with the known binding affinity of each compound from high-throughput screening experiments, can be used to improve the correlation between known binding affinities and those predicted by the docking program eHiTS. We construct two prediction models: a regression model trained using IC(50) values from BindingDB, and a classification model trained using active and decoy compounds from the Directory of Useful Decoys (DUD). Moreover, to address the issue of overrepresentation of negative data in high-throughput screening data sets, we have designed a multiple-planar SVM training procedure for the classification model. The increased performance that both SVMs give when compared with the original eHiTS scoring function highlights the potential for using nonlinear methods when deriving overall energy scores from their individual components. We apply the above methodology to train a new scoring function for direct inhibitors of Mycobacterium tuberculosis (M.tb) InhA. By combining ligand binding site comparison with the new scoring function, we propose that phosphodiesterase inhibitors can potentially be repurposed to target M.tb InhA. Our methodology may be applied to other gene families for which target structures and activity data are available, as demonstrated in the work presented here. PMID- 21291176 TI - Serial line scan encoding imaging cytometer for both adherent and suspended cells. AB - We present a new design of an imaging cytometer for high content bioanalysis, which is equipped with a low-cost linear complementary metal oxide semiconductor (CMOS) imager (running at >=40kHz). The fluorescent signals are encoded in a series of line scans across the cellular body, while it streams through a precisely defined line-shaped focus spot. This bioanalysis platform enables the concurrent collection of multiple fluorescence channels, while maintaining both high resolution and excellent throughput (1000 cells/s). We develop several image processing routines for the on-the-fly quantitative analysis of subcellular structures. Finally, we characterize our prototype system by imaging both adherent cells (plate format) and suspended cells (microfluidics format). PMID- 21291177 TI - Synchrotron UV-visible multispectral luminescence microimaging of historical samples. AB - UV-visible luminescence techniques are fre-quently used for the study of cultural heritage materials, despite their limitations for identification and discrimination in the case of complex heterogeneous materials. In contrast to tabletop setups, two methods based on the vacuum ultraviolet (VUV)-UV-visible emission generated at a bending magnet of a synchrotron source are described. The main advantages of the source are the extended wavelength range attained, the continuous tunability of the source, and its brightness, leading to a submicrometer lateral resolution. Raster-scanning microspectroscopy and full field microimaging were implemented and tested at the DISCO beamline (synchrotron SOLEIL, France). Investigative measurements were performed on a sample from a varnished musical instrument and a paint sample containing the pigment zinc white (ZnO) in order to illustrate some of the challenges analyzing heterogeneous cultural heritage cross-section samples with the novel imaging approach. The data sets obtained proved useful for mapping organic materials at the submicrometer scale and visualizing heterogeneities of the semiconductor pigment material. We propose and discuss the combined use of raster-scanning microspectroscopy and full-field microimaging in an integrated analytical methodology. Synchrotron UV luminescence appears as a novel tool for identification of craftsmen's and artists' materials and techniques and to assess the condition of artifacts, from the precise identification and localization of luminescent materials. PMID- 21291178 TI - Microfluidic electrochemical aptameric assay integrated on-chip: a potentially convenient sensing platform for the amplified and multiplex analysis of small molecules. AB - Aptamers are artificial oligonucleotides that have been widely employed to design biosensors (i.e., aptasensors). In this work, we report a microfluidic electrochemical aptamer-based sensor (MECAS) by constructing Au-Ag dual-metal array three-electrode on-chip for multiplex detection of small molecules. In combination with the microfluidic channels covering on the glass chip, different targets are transported to the Au electrodes integrated on different positions of the chip. These electrodes are premodified by different kinds of aptamers, respectively, to fabricate different sensing interfaces which can selectively capture the corresponding target. It is an address-dependent sensing platform; thus, with the use of only one electrochemical probe, multitargets can be recognized and detected according to the readout on a corresponding aptamer modified electrode. In the sensing strategy, the electrochemical probe, [Ru(NH(3))(6)](3+) (RuHex), which can quantitatively bind to surface-confined DNA via electrostatic interaction, was used to produce chronocoulometric signal; Au nanoparticles (AuNPs) were used to improve the sensitivity of the sensor by amplifying the detection signals. Moreover, the sensing interface fabrication, sample incubation, and electrochemical detection were all performed in microfluidic channels. By using this detection chip, we achieved the multianalysis of two model small molecules, ATP, and cocaine, in mixed samples within 40 min. The detection limit of ATP was 3 * 10(-10) M, whereas the detection limit of cocaine was 7 * 10(-8) M. This Au-Ag dual metal electrochemical chip detector integrated MECAS was simple, sensitive, and selective. Also it is similar to a dosimeter which accumulates signal upon exposure. It held promising potential for designing electrochemical devices with high throughput, high automation, and high integration in multianalysis. PMID- 21291179 TI - MPIC: a high-throughput analytical method for multiple DNA targets. AB - We describe the development of a novel combined approach for high-throughput analysis of multiple DNA targets based on multiplex Microdroplet PCR Implemented Capillary gel electrophoresis (MPIC), a two-step PCR amplification strategy. In the first step, the multiple target DNAs are preamplified using bipartite primers attached with universal tail sequences on their 5'-ends. Then, the preamplified templates are compartmentalized individually in the microdroplet of the PCR system, and multiple targets can be amplified in parallel, employing primers targeting their universal sequences. Subsequently, the resulting multiple products are analyzed by capillary gel electrophoresis (CGE). Using genetically modified organism (GMO) analysis as a model, 24 DNA targets can be simultaneously detected with a relative limit of detection of 0.1% (w/w) and absolute limit of detection of 39 target DNA copies. The described system provides a promising alternative for high-throughput analysis of multiple DNA targets. PMID- 21291180 TI - Kinetics and thermodynamics of biotinylated oligonucleotide probe binding to particle-immobilized avidin and implications for multiplexing applications. AB - In this work, the kinetics and dissociation constant for the binding of a biotin modified oligonucleotide to microparticle-immobilized avidin were measured. Avidin has been immobilized by both covalent coupling and bioaffinity capture to a surface prefunctionalized with biotin. The measured rate and equilibrium dissociation constants of avidin immobilized by these different methods have been compared with those for nonimmobilized avidin. We found that immobilization resulted in both a decrease in the rate of binding and an increase in the rate of dissociation leading to immobilized complexes having equilibrium dissociation constants of 7 +/- 3 * 10(-12) M, higher than the value measured for the complex between biotin-modified oligonucleotide and nonimmobilized avidin and approximately 4 orders of magnitude larger than values for the wild-type avidin biotin complex. Immobilized complex half-lives were found to be reduced to 5 days, which resulted in biotin ligands migrating between protein attached to different particles. Different immobilization methods showed little variation in complex stability but differed in total binding and nonspecific biotin-modified oligonucleotide binding. These findings are critical for the design of multiplexed assays where probe molecules are immobilized to biosensors via the avidin-biotin interaction. PMID- 21291181 TI - On the possible "supersolid" character of parahydrogen clusters. AB - We present results of a theoretical study of structural and superfluid properties of parahydrogen (p-H(2)) clusters comprising 25, 26, and 27 molecules at low temperature. The microscopic model utilized here is based on the Silvera-Goldman pair potential. Numerical results are obtained by means of quantum Monte Carlo simulations, making use of the continuous-space worm algorithm. The clusters are superfluid in the low temperature limit, but display markedly different physical behaviors. For N = 25 and 27, superfluidity at low temperature arises as clusters melt, that is, become progressively liquid-like as a result of quantum effects. On the other hand, for N = 26, the cluster remains rigid and solid-like. We argue that the cluster (p-H(2))(26) can be regarded as a mesoscopic "supersolid". This physical picture is supported by results of simulations in which a single p-H(2) molecule in the cluster is isotopically substituted. PMID- 21291182 TI - Density of states and wave function localization in disordered conjugated polymers: a large scale computational study. AB - We present large-scale calculations of electronic structure of strongly disordered conjugated polymers. The calculations have been performed using the density functional theory based charge patching method for the construction of single-particle Hamiltonian and the overlapping fragments method for the efficient diagonalization of that Hamiltonian. We find that the hole states are localized due to the fluctuations of the electrostatic potential and not by the breaks in the conjugation of the polymer chain. The tail of the density of hole states exhibits an exponentially decaying behavior. The main features of the electronic structure of the system can be described by an one-dimensional nearest neighbor tight-binding model with a correlated Gaussian distribution of on-site energies and constant off-site coupling elements. PMID- 21291183 TI - Interionic interactions of binary gels consisting of pyrrolidinium-based zwitterionic compounds and lithium salts. AB - We demonstrated thermal transitions and physical gelation of binary ionic salts through interionic interactions, which consist of pyrrolidinium-N propanesulfonate zwitterionic compound (PyrZIC) and lithium bis(trifluorosulfonyl)imide (LiTFSI). The transition behaviors of binary ionic gels were attributed to conformational changes in the cations and anions of PyrZIC and LiTFSI as analyzed by density functional theory (DFT), principal component analysis (PCA), and two-dimensional infrared correlation spectroscopy (2D IR COS). Furthermore, the geometries of binary PyrZIC-LiTFSI systems were strongly influenced by the electrostatic interactions between two ionic salts. The different dynamic processes in the PyrZIC- and LiTFSI-rich phases, which are classified by the transition point of PCA plots, were induced by the conformational changes in the respective interaction fields, as shown by 2D correlation spectra. In particular, LiTFSI-rich binary gels revealed characteristic four-leaf-clover and butterfly patterns under their unique chemical circumstances, which were different from those of PyrZIC-rich gels. Consequently, these computational and experimental investigations provide an analytical tool to understand the physical phenomenon and interactions occurring in the unveiled and complicated systems. PMID- 21291184 TI - Deconstructing the excited-state dynamics of beta-carotene in solution. AB - The femtosecond to nanosecond dynamics of the all-trans beta-carotene carotenoid dissolved in 3-methylpentane is characterized and dissected with excitation wavelength and temperature-dependent ultrafast dispersed transient absorption signals. The kinetics measured after red-edge (490 nm) and blue-edge (400 nm) excitation were contrasted under fluid solvent (298 K) and rigid glass (77 K) conditions. In all four measured data sets, the S* population kinetics was resolved prompting the development of a modified multicompartment model. The temperature-dependent and excitation wavelength-dependent S* quantum yield is ascribed to a competition of population surmounting a weak (55 cm(-1)) energy barrier on the S(2) state to favor S(1) generation and rapid internal conversion that favors S* generation. When cooled from room temperature to 77 K, the S* decay time scale shifted significantly from 30 to 400 ps, which is ascribed to small-scale structural relaxation with a 115 cm(-1) energy barrier. For the first time under low-energy excitation conditions, the triplet state is observed and confirmed to not originate from S* or S(1), but from S(2). The interconnectivity of the S* and S(1) populations is discussed, and no observed population flow is resolved between S* and S(1). Comparison of samples obtained from different laboratories with different purity levels demonstrates that sample contamination is not the primary origin of the S* state. PMID- 21291185 TI - Low-frequency modes of aqueous alkali halide solutions: an ultrafast optical Kerr effect study. AB - A detailed picture of aqueous solvation of ions is central to the understanding of diverse phenomena in chemistry and biology. In this work, we report polarization resolved THz time domain measurements of the Raman spectral density of a wide range of aqueous salt solutions. In particular, the isotropic Raman spectral density reveals the frequency of the hydrogen bond formed between the halide ion and water. The frequency of this mode is measured for the series Cl( ), Br(-), and I(-) as a function of concentration, cation size, and charge. The frequencies extrapolated to zero concentration permit an estimation of the force constant of the mode, which is found to decrease with increasing halide mass and to be similar to the force constant associated with the water-water hydrogen bond. This result is consistent with recent calculations. The extrapolation of the frequency of the chloride hydrogen bond to zero concentration reveals a dependence of the frequency on the nature of the cation. This is ascribed to an interaction between the solvated anion and cation even at the lowest concentration studied here (<0.15 M). It is suggested that this behavior reflects the influence of the electric field of the cation on the hydrogen bond of an adjacent anion. Such interactions should be taken into account when modeling experimental data recorded at concentrations of ions in excess of 0.1 M. These measurements of the isotropic Raman spectral density are compared with those for the anisotropic response, which reflects the frequencies of the full range of hydrogen bonds in aqueous salt solutions. The anisotropic spectral density recovered can be modeled in terms of a concentration-dependent population of water-water H-bonds with a frequency unaffected by the ions, the halide-water hydrogen bonds, and a low-frequency collision-induced contribution. PMID- 21291186 TI - Infrared spectroscopy of Li(+)(CH4)1Ar(n), n = 1-6, clusters. AB - Infrared predissociation (IRPD) spectra of Li(+)(CH(4))(1)Ar(n), n = 1-6, clusters are reported in the C-H stretching region from 2800 to 3100 cm(-1). The Li(+) electric field perturbs CH(4) lifting its tetrahedral symmetry and gives rise to multiple IR active modes. The observed bands arise from the totally symmetric vibrational mode, v(1), and the triple degenerate vibrational mode, v(3). Each band is shifted to lower frequency relative to the unperturbed CH(4) values. As the number of argon atoms is increased, the C-H red shift becomes less pronounced until the bands are essentially unchanged from n = 5 to n = 6. For n = 6, additional vibrational features were observed which suggested the presence of an additional conformer. By monitoring different photodissociation loss channels (loss of three Ar or loss of CH(4)), one conformer was uniquely associated with the CH(4) loss channel, with two bands at 2914 and 3017 cm(-1), values nearly identical to the neutral CH(4) gas-phase v(1) and v(3) frequencies. With supporting ab initio calculations, the two conformers were identified, both with a first solvent shell size of six. The major conformer had CH(4) in the first shell, while the conformer exclusively present in the CH(4) loss channel had six argons in the first shell and CH(4) in the second shell. This conformer is +11.89 kJ/mol higher in energy than the minimum energy conformer at the MP2/aug-cc-pVDZ level. B3LYP/6-31+G* level vibrational frequencies and MP2/aug-cc-pVDZ level single-point binding energies, D(e) (kJ/mol), are reported to support the interpretation of the experimental data. PMID- 21291187 TI - Practical calculation of molecular acidity with the aid of a reference molecule. AB - A set of linear free energy models are presented for determining the pK(a) values of amines, alcohols, and carboxylic acids. Models are determined from a series of pK(a) predictors, taken both from traditional natural atomic orbital analysis (NAO) and from a novel approach introduced here of using a reference molecule: an ammonium ion for amines and a hydrogen sulfide molecule for alcohols and carboxylic acids. Using these reference molecules, we calculate the barrier to proton transfer and show that a number of properties associated with the transition state are correlated with the pK(a). By considering 38 predictors, we obtain a four-variable model for amines and a three-variable model for oxygen containing compounds. The model for amines is based on 145 compounds and has a root mean squared error (RMSE) of 0.45 and R(2) = 0.98. The oxygen set has 48 molecules: RMSE = 0.26, and R(2) = 0.993. Similar, linear, and multilinear models are constructed after separating the sets into chemically similar categories: alcohols, carboxylic acids, and primary, secondary, tertiary, and aromatic amines. This separation gives simpler models with relatively low RMSE values, where the most important predictor of the pK(a) is the difference in energy between transferring the proton from the reference molecular base to the conjugate acid from the data set. PMID- 21291188 TI - Role of nearby charges on the electronic structure of pi-conjugated molecules: symmetric versus asymmetric charge distributions in oligo(p-phenyleneethynylene). AB - Oligo(p-phenyleneethynylene)s (OPEs) are conjugated oligomers of great interest within materials science and molecular electronics on account of their highly applicable electronic and optical properties. Here we use gas-phase action spectroscopy to elucidate how the intrinsic electronic properties of these chromophores are affected by nearby charges. An OPE3 chromophore with two nearby ammonium groups was synthesized. This molecule and a related OPE3 with only one amine protonation site were transferred to the gas phase by electrospray ionization and subjected to action spectroscopy. Ions were bunched in a 14-pole ion trap, accelerated to 50-keV kinetic energies, mass-to-charge selected by a magnet, and photoexcited in a crossed-beam configuration. Fragment ions were finally mass-analyzed by an electrostatic analyzer. The setup enables photodissociation mass spectrometry and action spectroscopy on the microsecond time scale. The gas-phase absorption of the mono- and dication was measured and compared to that of neutral chromophores in solution. Similar absorption was found for neutral chromophores (in solution) and the dication (in gas phase or solution), whereas the monocation absorbs at lower energies in the gas phase. Simple electrostatic considerations lead to an energy difference like the one found from the experiment. The work presented here addresses how the electronic properties of a pi-conjugated system are affected by nearby charges, a question of fundamental interest in, for example, molecular electronics. PMID- 21291189 TI - Unveiling electronic transitions in three novel chiral azo-compounds using linear and nonlinear circular dichroism: a theoretical-experimental study. AB - Herein, we report on the experimental and theoretically study of the linear absorption, electronic circular dichroism (ECD) spectra, as well as the two photon absorption circular-linear dichroism measurements of three different chiral azo derivatives in dimethylsulfoxide solution. Using potential energy surfaces and frontier orbital analysis, we established the most stable conformation for each molecule and elucidated their different electronic transitions. Our theoretical calculations allowed us to unambiguously identify the spectral position of such transitions and correlate them with the spectral profiles observed in the two-photon absorption spectra. To further elucidate the characteristics of the main electronic transitions in terms of spectral shape and position, we carried out measurements of the polarization dependent two-photon absorption cross sections and determined the two-photon circular-linear dichroism spectra of these azo dyes. PMID- 21291190 TI - Photochemistry and vibrational spectra of matrix-isolated methyl 4-chloro-5 phenylisoxazole-3-carboxylate. AB - Methyl 4-chloro-5-phenylisoxazole-3-carboxylate (MCPIC) has been synthesized, isolated in low temperature argon and xenon matrices, and studied by FTIR spectroscopy. The characterization of the low energy conformers of MCPIC was made by undertaking a systematic investigation of the DFT(B3LYP)/6-311++G(d,p) potential energy surface of the molecule. The theoretical calculations predicted the existence of three low energy conformers. Two of them (I and II) were observed experimentally in the cryogenic matrices. The third one (III) was found to be converted into conformer II during deposition of the matrices, a result that is in agreement with the predicted low III -> II energy barrier (<0.3 kJ mol(-1)). In situ UV irradiation (lambda > 235 nm) of matrix-isolated MCPIC yielded as final photoproduct the corresponding oxazole (methyl 4-chloro-5-phenyl 1,3-oxazole-2-carboxylate). Identification of the azirine and nitrile-ylide intermediates in the spectra of the irradiated matrices confirmed their mechanistic relevance in the isoxazole -> oxazole photoisomerization. PMID- 21291191 TI - Reaction of HOD+ with NO2: effects of OD and OH stretching, bending, and collision energy on reactions on the singlet and triplet potential surfaces. AB - Integral cross sections and product recoil velocity distributions were measured for the reaction of HOD(+) with NO(2), in which the HOD(+) reactant was prepared in its ground state and with mode-selective excitation in the 001 (OH stretch), 100 (OD stretch), and 010 (bend) modes. In addition, we measured the 300 K thermal kinetics in a selected ion flow tube reactor and report product branching ratios different from previous measurements. Reaction is found to occur on both the singlet and triplet surfaces with near-unit efficiency. At 300 K, the product branching indicates that triplet -> singlet transitions occur in about 60% of triplet-coupled collisions, which we attribute to long interaction times mediated by complexes on the triplet surface. Because the collision times are much shorter in the beam experiments, the product distributions show no signs of such transitions. The dominant product on the singlet surface is charge transfer. Reactions on the triplet surface lead to NO(+), NO(2)H(+), and NO(2)D(+). There is also charge transfer, producing NO(2)(+) (a(3)B(2)); however, this triplet NO(2)(+) mostly predissociates. The NO(2)H(+)/NO(2)D(+) cross sections peak at low collision energies and are insignificant above ~1 eV due to OH/OD loss from the nascent product ions. The effects of HOD(+) vibration are mode-specific. Vibration inhibits charge transfer, with the largest effect from the bend. The NO(2)H(+)/NO(2)D(+) channels are also vibrationally inhibited, and the mode dependence reveals how energy in different reactant modes couples to the internal energy of the product ions. PMID- 21291192 TI - U(VI) uranyl cation-cation interactions in framework germanates. AB - The isomorphous compounds NH(4)[(UO(6))(2)(UO(2))(9)(GeO(4))(GeO(3)(OH))] (1), K[(UO(6))(2)(UO(2))(9)(GeO(4))(GeO(3)(OH))] (2), Li(3)O[(UO(6))(2)(UO(2))(9)(GeO(4))(GeO(3)(OH))] (3), and Ba[(UO(6))(2)(UO(2))(9)(GeO(4))(2)] (4) were synthesized by hydrothermal reaction at 220 degrees C. The structures were determined using single crystal X-ray diffraction and refined to R(1) = 0.0349 (1), 0.0232 (2), 0.0236 (3), 0.0267 (4). Each are trigonal, P(3)1c. 1: a = 10.2525(5), c = 17.3972(13), V = 1583.69(16) A(3), Z = 2; 2: a = 10.226(4), c = 17.150(9), V = 1553.1(12) A(3), Z = 2; 3: a = 10.2668(5), c = 17.0558(11), V = 1556.94(15) A(3), Z = 2; 4: a = 10.2012(5), c = 17.1570(12), V = 1546.23(15) A(3), Z = 2. There are three symmetrically independent U sites in each structure, two of which correspond to typical (UO(2))(2+) uranyl ions and the other of which is octahedrally coordinated by six O atoms. One of the uranyl ions donates a cation-cation interaction, and accepts a different cation-cation interaction. The linkages between the U-centered polyhedra result in a relatively dense three-dimensional framework. Ge and low valence sites are located within cavities in the framework of U-polyhedra. Chemical, thermal, and spectroscopic characterizations are provided. PMID- 21291193 TI - Nitrate ion photolysis in thin water films in the presence of bromide ions. AB - Nitrate ions commonly coexist with halide ions in aged sea salt particles, as well as in the Arctic snowpack, where NO(3)(-) photochemistry is believed to be an important source of NO(y) (NO + NO(2) + HONO + ...). The effects of bromide ions on nitrate ion photochemistry were investigated at 298 +/- 2 K in air using 311 nm photolysis lamps. Reactions were carried out using NaBr/NaNO(3) and KBr/KNO(3) deposited on the walls of a Teflon chamber. Gas phase halogen products and NO(2) were measured as a function of photolysis time using long path FTIR, NO(y) chemiluminescence and atmospheric pressure ionization mass spectrometry (API-MS). Irradiated NaBr/NaNO(3) mixtures show an enhancement in the rates of production of NO(2) and Br(2) as the bromide mole fraction (chi(NaBr)) increased. However, this was not the case for KBr/KNO(3) mixtures where the rates of production of NO(2) and Br(2) remained constant over all values of chi(KBr). Molecular dynamics (MD) simulations show that the presence of bromide in the NaBr solutions pulls sodium toward the solution surface, which in turn attracts nitrate to the interfacial region, allowing for more efficient escape of NO(2) than in the absence of halides. However, in the case of KBr/KNO(3), bromide ions do not appreciably affect the distribution of nitrate ions at the interface. Clustering of Br(-) with NO(3)(-) and H(2)O predicted by MD simulations for sodium salts may facilitate a direct intermolecular reaction, which could also contribute to higher rates of NO(2) production. Enhanced photochemistry in the presence of halide ions may be important for oxides of nitrogen production in field studies such as in polar snowpacks where the use of quantum yields from laboratory studies in the absence of halide ions would lead to a significant underestimate of the photolysis rates of nitrate ions. PMID- 21291194 TI - Role of anions and reaction conditions in the preparation of uranium(VI), neptunium(VI), and plutonium(VI) borates. AB - U(VI), Np(VI), and Pu(VI) borates with the formula AnO(2)[B(8)O(11)(OH)(4)] (An = U, Np, Pu) have been prepared via the reactions of U(VI) nitrate, Np(VI) perchlorate, or Pu(IV) or Pu(VI) nitrate with molten boric acid. These compounds are all isotypic and consist of a linear actinyl(VI) cation, AnO(2)(2+), surrounded by BO(3) triangles and BO(4) tetrahedra to create an AnO(8) hexagonal bipyramidal environment. The actinyl bond lengths are consistent with actinide contraction across this series. The borate anions bridge between actinyl units to create sheets. Additional BO(3) triangles and BO(4) tetrahedra extend from the polyborate layers and connect these sheets together to form a three-dimensional chiral framework structure. UV-vis-NIR absorption and fluorescence spectroscopy confirms the hexavalent oxidation state in all three compounds. Bond-valence parameters are developed for Np(VI). PMID- 21291195 TI - Computational characterization of the substrate-binding mode in coproporphyrinogen III oxidase. AB - Oxygen-dependent coproporphyrinogen III oxidase catalyzes the sequential decarboxylation of the propionate substituents present on the A and B rings of coproporphyrinogen III in the heme biosynthetic pathway. Although extensive experimental investigation of this enzyme has already afforded many insights into its reaction mechanism, several key features (such as the substrate binding mode, the characterization of the active site, and the initial substrate protonation state) remain poorly described. The molecular dynamics simulations described in this paper enabled the determination of a very promising substrate binding mode and the extensive characterization of the enzyme active site. The proposed binding mode is fully consistent with the known selectivity of the active site toward substituted tetrapyrroles and explains the lack of activity of the H131A, R135A, D274A, and R275A mutants and the reasons behind the nonoccurrence of catalysis on the C and D rings of the tetrapyrrole. An important role in this binding mode is fulfilled by G276, as its carbonyl oxygen intervenes in the substrate anchoring by hydrogen bonding its ring D pyrrole NH group. The presence of this interaction (which is only possible with the protonated NH pyrrole group) and the absence of positively charged side chains close to the pyrrole nitrogen (which might stabilize the N-deprotonated pyrrole postulated in some mechanistic proposals) show that the pyrrole ring is very unlikely to undergo deprotonation during the catalytic cycle and allow the discrimination between the previously postulated mechanistic proposals. PMID- 21291196 TI - Quantum dot size dependent J-V characteristics in heterojunction ZnO/PbS quantum dot solar cells. AB - The current-voltage (J-V) characteristics of ZnO/PbS quantum dot (QD) solar cells show a QD size-dependent behavior resulting from a Schottky junction that forms at the back metal electrode opposing the desirable diode formed between the ZnO and PbS QD layers. We study a QD size-dependent roll-over effect that refers to the saturation of photocurrent in forward bias and crossover effect which occurs when the light and dark J-V curves intersect. We model the J-V characteristics with a main diode formed between the n-type ZnO nanocrystal (NC) layer and p-type PbS QD layer in series with a leaky Schottky-diode formed between PbS QD layer and metal contact. We show how the characteristics of the two diodes depend on QD size, metal work function, and PbS QD layer thickness, and we discuss how the presence of the back diode complicates finding an optimal layer thickness. Finally, we present Kelvin probe measurements to determine the Fermi level of the QD layers and discuss band alignment, Fermi-level pinning, and the V(oc) within these devices. PMID- 21291197 TI - Effect of core diameter, surface coating, and PEG chain length on the biodistribution of persistent luminescence nanoparticles in mice. AB - A growing insight toward optical sensors has led to several major improvements in the development of convenient probes for in vivo imaging. Efficient optical detection using quantum dots (QDs) as well as near-infrared organic dyes relies on several key driving principles: the ability to lower background absorption or autofluorescence from tissue, a good photostability of the probe, and a high quantum yield. In this article, we report the real-time biodistribution monitoring of lanthanide-doped persistent luminescence nanoparticles (PLNP), emitting in the near-infrared window, in healthy and tumor-bearing mice. We focused on the influence of hydrodynamic diameter, ranging from 80 to 180 nm, and polyethylene glycol (PEG) surface coating on the behavior of our probes. Tissue distribution was found to be highly dependent on surface coverage as well as core diameter. The amount of PLNP in the blood was highly increased for small (d < 80 nm) and stealth particles. On the opposite, PEG shield molecular weight, ranging from 5 to 20 kDa, had only negligible influence on the in vivo biodistribution of our silicate-based material. PMID- 21291198 TI - Controlled modulation of electronic properties of graphene by self-assembled monolayers on SiO2 substrates. AB - In this study, with self-assembled monolayers (SAMs) of aminopropyl-, ammoniumpropyl-, butyl-, and 1H,1H,2H,2H-perfluorooctyltriethoxysilanes deposited in-between graphene and the SiO(2) substrate, a controlled doping of graphene was realized with a threshold voltage ranging from -18 to 30 V. In addition, the SAMs are covalently bonded to the SiO(2) surface rather than the graphene surface, thereby producing minimal effects on the mobility of the graphene. Finally, it is more stable than conventional noncovalent dopants. PMID- 21291199 TI - Ratiometric fluorescent chemosensor for silver ion at physiological pH. AB - Bis-pyrene derivative 1, bearing two pyrene and pyridine groups, was synthesized as a ratiometric fluorescent chemosensor for Ag(+) in aqueous solution. Fluorescent chemosensor 1 displayed a selective ratiometric change with Ag(+), which was attributed to the excimer-monomer emissions of pyrenes. A mechanism for the binding mode was proposed based on fluorescence changes, NMR experiments, and theoretical calculations. PMID- 21291200 TI - Role of the uranyl oxo group as a hydrogen bond acceptor. AB - Density functional theory calculations have been used to evaluate the geometries and energetics of interactions between a number of uranyl complexes and hydrogen bond donor groups. The results reveal that although traditional hydrogen bond donors are repelled by the oxo group in the [UO(2)(OH(2))(5)](2+) species, they are attracted to the oxo groups in [UO(2)(OH(2))(2)(NO(3))(2)](0), [UO(2)(NO(3))(3)](-), and [UO(2)Cl(4)](2-) species. Hydrogen bond strength depends on the equatorial ligation and can exceed 15 kcal mol(-1). The results also reveal the existence of directionality at the uranyl oxo acceptor, with a weak preference for linear U?O---H angles. PMID- 21291201 TI - Synthesis and functionalization of heteroatom-bridged bicyclocalixaromatics, large molecular triangular prisms with electron-rich and -deficient aromatic interiors. AB - The synthesis and functionalization of oxygen and nitrogen atom bridged bicyclocalixaromatics of triangular prism structures are reported. By means of a fragment coupling approach, molecular triangular prisms of electron-rich and electron-deficient aromatic interiors were prepared using 1,3,5-tri(p hydroxyphenyl)benzene and 2,4,6-tri(p-aminophenyl)triazine as base units and chlorotriazines as pillars. Aromatic nucleophilic substitution reaction of chlorotriazine moieties with functionalized amines led to triangular prisms with functionalizations on the peripheral edge positions, while functionalized triangular prisms on the vertex nitrogen positions were obtained using 2,4,6 tri[(p-allylamino)phenyl]triazine derivative as a starting material. Symmetrical and distorted molecular triangular prisms in the solid state were revealed by X ray crystallography. As evidenced by NMR spectroscopic data, however, all cage molecules synthesized most probably adopted highly symmetric triangular prism structures in solution phase. The functionalized shape-persistent triangular prism structures might find applications in molecular recognition and in the construction of higher and more sophisticated molecular architectures in supramolecular chemistry. PMID- 21291202 TI - Highly selective insertion of arynes into a C(sp)-O(sp3) sigma bond. AB - Arynes react with ethoxyacetylene to afford 2-ethoxyethynylaryl derivatives through a highly chemo- and regioselective formal insertion of the aryne into the C(sp)-O(sp(3)) bond of the alkyne. Computational studies suggest that the reaction does not proceed through a mechanism initiated by the nucleophilic addition of the oxygen atom to the aryne as previously proposed but by the addition of the triple bond of the alkyne to the aryne. PMID- 21291203 TI - Graft copolymer-templated mesoporous TiO(2) films micropatterned with poly(ethylene glycol) hydrogel: novel platform for highly sensitive protein microarrays. AB - In this study, we describe the use of organized mesoporous titanium oxide (TiO(2)) films as three-dimensional templates for protein microarrays with enhanced protein loading capacity and detection sensitivity. Multilayered mesoporous TiO(2) films with high porosity and good connectivity were synthesized using a graft copolymer consisting of a poly(vinyl chloride) (PVC) backbone and poly(oxyethylene methacrylate) (POEM) side chains as a structure-directing template. The average pore size and thickness of the TiO(2) films were 50-70 nm and 1.5 MUm, respectively. Proteins were covalently immobilized onto mesoporous TiO(2) film via 3-aminopropyltriethoxysilane (APTES), and protein loading onto TiO(2) films was about four times greater than on planar glass substrates, which consequently improved the protein activity. Micropatterned mesoporous TiO(2) substrates were prepared by fabricating poly(ethylene glycol) (PEG) hydrogel microstructures on TiO(2) films using photolithography. Because of non adhesiveness of PEG hydrogel towards proteins, proteins were selectively immobilized onto surface-modified mesoporous TiO(2) region, creating protein microarray. Specific binding assay between streptavidin/biotin and between PSA/anti-PSA demonstrated that the mesoporous TiO(2)-based protein microarrays yielded higher fluorescence signals and were more sensitive with lower detection limits than microarrays based on planar glass slides. PMID- 21291204 TI - Enantioselective synthesis of a GPR40 agonist AMG 837 via catalytic asymmetric conjugate addition of terminal alkyne to alpha,beta-unsaturated thioamide. AB - A concise enantioselective synthetic route to a potent GPR40 agonist AMG 837 is described. The crucial catalytic asymmetric conjugate addition of terminal alkyne was promoted by a soft Lewis acid/hard Bronsted base cooperative catalyst, allowing efficient construction of the requisite stereogenic center. The thioamide functional group is key to both activation in asymmetric alkynylation and facile transformation into carboxylic acid. PMID- 21291205 TI - Palladium-catalyzed highly regio- and stereoselective synthesis of 4-alkylidene 4H-3,1-benzoxazines from N-acyl-o-alkynylanilines. AB - The highly regio- and stereoselective 6-exo-dig mode cyclization of N-acyl-o alkynylanilines producing 4-alkylidene-3,1-benzoxazines occurred unpredictably by use of a proper catalyst [Pd(OAc)(2)] and an effective additive (acetic acid) under suitable reaction conditions. PMID- 21291208 TI - High photocatalytic activity of ZnO-carbon nanofiber heteroarchitectures. AB - One-dimensional ZnO-carbon nanofibers (CNFs) heteroarchitectures with high photocatalytic activity have been successfully obtained by a simple combination of electrospinning technique and hydrothermal process. The as-obtained products were characterized by field-emission scanning electron microscopy (FE-SEM), energy-dispersive X-ray (EDX) spectroscopy, transmission electron microscopy (TEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), and IR spectrum. The results revealed that the secondary ZnO nanostructures were successfully grown on the primary CNFs substrates without aggregation. And, the coverage density of ZnO nanoparticles coating on the surface of the CNFs could be controlled by simply adjusting the mass ratio of zinc acetate to CNFs in the precursor during the hydrothermal process for the fabrication of ZnO-CNFs heterostructures. The obtained ZnO-CNFs heteroarchitectures showed high photocatalytic property to degrade rhodamine B (RB) because of the formation of heteroarchitectures, which might improve the separation of photogenerated electrons and holes. Moreover, the ZnO-CNFs heteroarchitectures could be easily recycled without the decrease in photocatalytic activity due to their one dimensional nanostructural property. PMID- 21291209 TI - Silicification of peptide-coated silver nanoparticles--A Biomimetic soft chemistry approach toward chiral hybrid core-shell materials. AB - Silica and silver nanoparticles are relevant materials for new applications in optics, medicine, and analytical chemistry. We have previously reported the synthesis of pH responsive, peptide-templated, chiral silver nanoparticles. The current report shows that peptide-stabilized nanoparticles can easily be coated with a silica shell by exploiting the ability of the peptide coating to hydrolyze silica precursors such as TEOS or TMOS. The resulting silica layer protects the nanoparticles from chemical etching, allows their inclusion in other materials, and renders them biocompatible. Using electron and atomic force microscopy, we show that the silica shell thickness and the particle aggregation can be controlled simply by the reaction time. Small-angle X ray scattering confirms the Ag/peptide@silica core-shell structure. UV-vis and circular dichroism spectroscopy prove the conservation of the silver nanoparticle chirality upon silicification. Biological tests show that the biocompatibility in simple bacterial systems is significantly improved once a silica layer is deposited on the silver particles. PMID- 21291210 TI - Palladium-catalyzed 1,1-aryloxygenation of terminal olefins. AB - This paper describes the 1,1-arylacetoxylation of diverse alpha-olefins using organostannanes and hypervalent iodine oxidants. The reaction provides a convergent approach for generating a C-C and a C-O bond as well as a new stereocenter in a single catalytic transformation. PMID- 21291211 TI - Structural basis of telomeric RNA quadruplex--acridine ligand recognition. AB - Human telomeric DNA is now known to be transcribed into noncoding RNA sequences, termed TERRA. These sequences, which are believed to play roles in the regulation of telomere function, can form higher-order quadruplex structures and may themselves be the target of therapeutic intervention. The crystal structure of a TERRA quadruplex-acridine small-molecule complex at a resolution of 2.60 A, is reported here and contrasts remarkably with the structure of the analogous DNA quadruplex complex. The bimolecular RNA complex has a parallel-stranded topology with propeller-like UUA loops. These loops are held in particular conformations by multiple hydrogen bonds involving the O2' hydroxyl groups of the ribonucleotide sugars and play an active role in binding the acridine molecules to the RNA quadruplex. By contrast, the analogous DNA quadruplex complex has simpler 1:1 acridine binding, with no loop involvement. There are significant loop conformational changes in the RNA quadruplex compared to the native TERRA quadruplex (Collie, G. W.; Haider, S. M.; Neidle, S.; Parkinson, G. N. Nucleic Acids Res. 2010, 38, 5569 - 5580), which have implications for the future design of small molecules targeting TERRA quadruplexes, and RNA quadruplexes more generally. PMID- 21291212 TI - Finite temperature properties of clusters by replica exchange metadynamics: the water nonamer. AB - We introduce an approach for the accurate calculation of thermal properties of classical nanoclusters. On the basis of a recently developed enhanced sampling technique, replica exchange metadynamics, the method yields the true free energy of each relevant cluster structure, directly sampling its basin and measuring its occupancy in full equilibrium. All entropy sources, whether vibrational, rotational anharmonic, or especially configurational, the latter often forgotten in many cluster studies, are automatically included. For the present demonstration, we choose the water nonamer (H(2)O)(9), an extremely simple cluster, which nonetheless displays a sufficient complexity and interesting physics in its relevant structure spectrum. Within a standard TIP4P potential description of water, we find that the nonamer second relevant structure possesses a higher configurational entropy than the first, so that the two free energies surprisingly cross for increasing temperature. PMID- 21291213 TI - Sc2C2@C80 rather than Sc2@C82: templated formation of unexpected C2v(5)-C80 and temperature-dependent dynamic motion of internal Sc2C2 cluster. AB - Unambiguous X-ray crystallographic results of the carbene adduct of Sc(2)C(82) reveal a new carbide cluster metallofullerene with the unexpected C(2v)(5)-C(80) cage, that is, Sc(2)C(2)@C(2v)(5)-C(80). More interestingly, DFT calculations and NMR results disclose that the dynamic motion of the internal Sc(2)C(2) cluster depends strongly on temperature. At 293 K, the cluster is fixed inside the cage with two nonequivalent Sc atoms on the mirror plane, thereby leading to C(s) symmetry of the whole molecule. However, when the temperature increases to 413 K, the (13)C and (45)Sc NMR spectra show that the cluster rotates rapidly inside the C(2v)(5)-C(80) cage, featuring two equivalent Sc atoms and weaker metal-cage interactions. PMID- 21291214 TI - Icosahedral Pt-centered Pt13 and Pt19 carbonyl clusters decorated by [Cd5(MU Br)5Br(5-x)(solvent)x]x+ rings reminiscent of the decoration of Au-Fe-CO and Au thiolate nanoclusters: a unifying approach to their electron counts. AB - The new [Pt(13)(CO)(12){Cd(5)(MU-Br)(5)Br(2)(dmf)(3)}(2)](2-) and [Pt(19)(CO)(17){Cd(5)(MU-Br)(5)Br(3)(Me(2)CO)(2)}{Cd(5)(MU Br)(5)Br(Me(2)CO)(4)}](2-) clusters have been obtained in good yields by reaction of [Pt(12)(CO)(24)](2-) with CdBr(2).H(2)O in dmf at 90 degrees C and structurally characterized by X-ray diffraction. Their structures consist of a Pt centered Pt(13)(CO)(12) icosahedron and a Pt(19)(CO)(17) interpenetrated double icosahedron, respectively, decorated by two Cd(5)(MU-Br)(5)Br(5-x)(solvent)(x) rings. Their surface decoration may be related to that of Au-Fe-CO clusters as well as to the staple motifs stabilizing gold-thiolates nanoclusters. An oversimplified and unifying approach to interpret their electron count is suggested. PMID- 21291215 TI - Reactivity of metallic nitride endohedral metallofullerene anions: electrochemical synthesis of a Lu3N@Ih-C80 derivative. AB - Electrochemically generated Lu(3)N@I(h)-C(80) dianions react with the electrophile, PhCHBr(2), to produce a methano derivative of Lu(3)N@I(h) C(80)(CHC(6)H(5)) (1) with high regioselectivity. The compound was characterized by MALDI-TOF, NMR, and UV-vis-NIR absorption spectroscopy. Electrochemical characterization of this Lu(3)N@I(h)-C(80)(CHC(6)H(5)) derivative showed the typical irreversible reductive behavior of the pristine Lu(3)N@I(h)-C(80), similar to those observed for Bingel adducts of Lu(3)N@I(h)-C(80). Using the same conditions, the reaction between Sc(3)N@I(h)-C(80) dianions and PhCHBr(2) was conducted for comparison. Unexpectedly, no nucleophilic reaction was observed, indicating that Sc(3)N@I(h)-C(80) dianions are not reactive toward the electrophile. Theoretical studies for both dianionic Lu(3)N@I(h)-C(80) and Sc(3)N@I(h)-C(80) showed that the HOMO is more highly localized on the fullerene cage for [Lu(3)N@I(h)-C(80)](2-) and more localized on the inside cluster for [Sc(3)N@I(h)-C(80)](2-), providing an explanation for the drastically different reactivities observed. PMID- 21291216 TI - Redox-neutral atom-economic rhodium-catalyzed coupling of terminal alkynes with carboxylic acids toward branched allylic esters. AB - A new method for the preparation of a wide range of branched allylic esters from terminal alkynes that proceeds via a redox-neutral propargylic CH activation employing a rhodium(I)/DPEphos catalyst is reported. PMID- 21291217 TI - Specific and nonspecific metal ion-nucleotide interactions at aqueous/solid interfaces functionalized with adenine, thymine, guanine, and cytosine oligomers. AB - This article reports nonlinear optical measurements that quantify, for the first time directly and without labels, how many Mg(2+) cations are bound to DNA 21 mers covalently linked to fused silica/water interfaces maintained at pH 7 and 10 mM NaCl, and what the thermodynamics are of these interactions. The overall interaction of Mg(2+) with adenine, thymine, guanine, and cytosine is found to involve -10.0 +/- 0.3, -11.2 +/- 0.3, -14.0 +/- 0.4, and -14.9 +/- 0.4 kJ/mol, and nonspecific interactions with the phosphate and sugar backbone are found to contribute -21.0 +/- 0.6 kJ/mol for each Mg(2+) ion bound. The specific and nonspecific contributions to the interaction energy of Mg(2+) with oligonucleotide single strands is found to be additive, which suggests that within the uncertainty of these surface-specific experiments, the Mg(2+) ions are evenly distributed over the oligomers and not isolated to the most strongly binding nucleobase. The nucleobases adenine and thymine are found to bind only three Mg(2+) ions per 21-mer oligonucleotide, while the bases cytosine and guanine are found to bind eleven Mg(2+) ions per 21-mer oligonucleotide. PMID- 21291218 TI - Stereoconvergent synthesis of chiral allylboronates from an E/Z mixture of allylic aryl ethers using a 6-NHC-Cu(I) catalyst. AB - We present a 6-NHC-Cu(I) complex that provides alpha-substituted allylboronates using allylic aryl ether substrates. The method was discovered by comparison of the chemoselectivities exhibited by complexes 1a, 1b, 2, and 3. We observed that 1a preferentially reacts with electron-rich alkenes over electron-deficient alkenes. Development of an asymmetric method revealed that 1b reacts with both the E and Z isomers to provide the same absolute configuration without showing E Z isomerization. This stereoconvergent reaction occurs with high yields (av 86%), high S(N)2' selectivity (>99:1), and high ee (av 94%) and exhibits wide functional-group tolerance using pure E or Z isomer or E/Z alkene mixtures. The stereoconvergent feature enables the use of many different olefination strategies for substrate production, including cross-metathesis. Chiral allylboronates could be purified by silica gel chromatography and stored in the freezer without decomposition. PMID- 21291219 TI - 17beta-estradiol-linked nitro-L-arginine as simultaneous inducer of apoptosis in melanoma and tumor-angiogenic vascular endothelial cells. AB - Aggressive melanoma is commonly associated with rapid angiogenic growth in tumor mass, tumor cells acquiring apoptosis resistance, inhibition of cellular differentiation etc. Designing a single anticancer molecule which will target all these factors simultaneously is challenging. In the pretext of inciting anticancer effect through inhibiting nitric oxide synthase (NOS) via estrogen receptors (ER) in ER-expressing skin cancer cells, we developed an estrogen linked L-nitro-arginine molecule (ESAr) for inciting anticancer effect in melanoma cells. ESAr showed specific anticancer effect through diminishing aggressiveness and metastatic behavior in melanoma cells and tumor. In comparison, ESAr showed significantly higher antiproliferative effect than parent molecule L-nitroarginine methyl ester (L-NAME, a NOS inhibitor) through induction of prominent apoptosis in melanoma cells. ESAr-pretreated aggressive melanoma cells could not form tumor possibly because of transformation/differentiation into epithelial-type cells. Furthermore, its antiangiogenic effect was demonstrated through ESAr-induced antiproliferation in HUVEC cells and apoptosis induction in tumor-associated vascular endothelial cells, thereby significantly restricting severe growth in melanoma tumor. The targeting moiety, estrogen, at the therapeutic concentration of ESAr has apparently no effect in tumor-growth reduction. Albeit, no specific NOS-inhibition was observed, but ESAr could simultaneously induce these three cancer-specific antiaggressiveness factors, which the parent molecule could not induce. Our data rationalize and establish a new use of estrogen as a ligand for potentially targeting multiple cellular factors for treating aggressive cancers. PMID- 21291220 TI - Role of polyplex intermediate species on gene transfer efficiency: polyethylenimine-DNA complexes and time-resolved fluorescence spectroscopy. AB - Polyethylenimine (PEI) is a cationic DNA condensing polymer that facilitates gene transfer into the mammalian cells. The highest gene transfer with branched PEI is obtained at high nitrogen/phosphate (N/P) ratios with free PEI present. The small molecular weight PEI alone is not able to mediate DNA transfection. Here, we used recently developed time-resolved fluorescence spectroscopic method to study the mechanism of PEI-DNA complex formation and to investigate how free PEI, mean molecular weight, and branching of PEI affect the complexes. Analysis of fluorescence lifetimes and time-resolved spectra revealed that for both linear and branched high-molecular-weight PEI the complexation takes place in two steps, but the small-molecular-weight branched PEI complexed DNA at a single step. According to the binding constants obtained from time-resolved spectroscopic measurements, the affinity of N/P complexation per nitrogen atom is highest for LPEI and weakest for BPEI, whereas SPEI-DNA complexation showed intermediate values. Thus, the binding constant alone does not give adequate measure for transfection efficiency. On the other hand, the presence of intermediate states during the polyplex formation seems to be favorable for the gene transfection. Free PEI had no impact on the physical state of PEI-DNA complexes, even though it was essential for gene transfection in the cell culture. In conclusion, the molecular size and topology of PEI have direct influence on the DNA complexation but the free PEI does not. Free PEI must facilitate transfection at the cellular level and not via indirect effects on the PEI-DNA complexes. PMID- 21291221 TI - Clay nanopaper with tough cellulose nanofiber matrix for fire retardancy and gas barrier functions. AB - Nacre-mimicking hybrids of high inorganic content (>50 wt %) tend to show low strain-to-failure. Therefore, we prepared clay nanopaper hybrid composite montmorillonite platelets in a continuous matrix of nanofibrillated cellulose (NFC) with the aim of harnessing the intrinsic toughness of fibrillar networks. Hydrocolloid mixtures were used in a filtration approach akin to paper processing. The resulting multilayered structure of the nanopaper was studied by FE-SEM, FTIR, and XRD. Uniaxial stress-strain curves measured in tension and thermal analysis were carried out by DMTA and TGA. In addition, fire retardance and oxygen permeability characteristics were measured. The continuous NFC matrix is a new concept and provides unusual ductility to the nanocomposite, allowing inorganic contents as high as 90% by weight. Clay nanopaper extends the property range of cellulose nanopaper and is of interest in self-extinguishing composites and in oxygen barrier layers. PMID- 21291222 TI - Comment on "Principal role of the stepwise aggregation mechanism in ionic surfactant solutions near the critical micelle concentration. Molecular dynamics study". PMID- 21291223 TI - Excess charge density and its relationship with surface tension increment at the air-electrolyte solution interface. AB - The adsorption isotherms of probe cationic molecules were measured at various electrolyte solution interfaces by resonant second harmonic generation. The excess charge density was obtained by analyzing the isotherms; it increases with square root of the bulk electrolyte concentration. Its value is ion-specific and the amount of probe molecular adsorption follows the Hofmeister series. By calculating the pressure anisotropy at the interface, it is found that the ratio of surface tension increment to the bulk electrolyte concentration decreases with the square of the excess charge density. This is in good agreement with the experimental observations. PMID- 21291224 TI - H/D isotope effects in protein thermal denaturation: the case of bovine serum albumin. AB - The present work investigates the effects of H/D isotopic substitution on the structural and thermodynamic stability of bovine serum albumin (BSA) in aqueous solution over the temperature range of 5-90 degrees C. Using far-ultraviolet circular dichroism, we have compared protein unfolding pathways in H(2)O and D(2)O. Our results show that BSA possesses similar conformations in H(2)O and D(2)O at temperatures below 50 degrees C but follows different unfolding pathways at higher temperatures. The presence of D(2)O retards the occurrence of irreversible thermal denaturation in BSA, as evidenced by a higher onset temperature of 58 degrees C, in contrast to 50 degrees C in H(2)O. D(2)O exhibits a protective effect on the domain structure during the early stages of domain denaturation. Following incubation at 90 degrees C over a period of minutes, D(2)O causes a rapid aggregation of BSA molecules. This behavior is not observed in H(2)O solutions. Meanwhile, H/D substitution does not influence the reversible structural transformation of the protein in a significant manner. Partly renatured BSA in H(2)O and D(2)O undergoes very similar reversible structural transformations during a second heating cycle. PMID- 21291225 TI - Catalytic roles of active-site residues in 2-methyl-3-hydroxypyridine-5 carboxylic acid oxygenase: an ONIOM/DFT study. AB - The catalytic mechanism of 2-methyl-3-hydroxypyridine-5-carboxylic acid (MHPC) oxygenase (MHPCO) has been systematically studied using DFT and ONIOM(DFT:MM) methods. MHPCO catalyzes the hydroxylation and subsequent ring-opening of the aromatic substrate MHPC to give the aliphatic product alpha-(N acetylaminomethylene)succinic acid (AAMS). Our calculations show that the active site residues Arg211 and Tyr223 have a minor effect on the reaction, while the peptide bond of Pro295-Ala296, the side chain of Tyr82 and several crystal water molecules affect the reaction energy profile considerably. Both DFT and ONIOM calculations show that the ring-opening pathway B, in which an epoxy transition state is formed, is more favored than the direct C2-C3 cleavage pathway A. Different QM/MM partitioning schemes have been used to study the enzymatic reaction, and the results show that both the reaction barriers for the hydroxylation and the ring-opening pathways are sensitive to the QM/MM partitioning. PMID- 21291226 TI - Modeling the nanophase structural dynamics of phenylated sulfonated poly ether ether ketone ketone (Ph-SPEEKK) membranes as a function of hydration. AB - Solvated phenylated sulfonated poly ether ether ketone ketone (Ph-SPEEKK) membranes in the presence of hydronium ions were modeled by classical molecular dynamics simulations. The characterization of the nanophase structure and dynamics of such membranes was carried out as a function of the water content lambda, where lambda is the number of water molecules per sulfonate group, for lambda values of 3.5, 6, 11, 25, and 40. Analysis of pair correlation functions supports the experimental observation of membrane swelling upon hydration as well the increase in water and hydronium ion diffusion with increasing lambda. Whereas the average number of hydrogen bonds between hydronium ions and sulfonate groups is dramatically affected by the hydration level, the average lifetime of the hydrogen bonds remains essentially constant. The membrane is found to be relatively rigid, and its overall flexibility shows little dependence on water content. Compared with Nafion, water and ion diffusion coefficients are considerably smaller at lower hydration levels and room temperature. However, at higher lambda values of 25 and 40, these coefficients are comparable to those in Nafion at a lambda value of 16. This study also shows that water diffusion in Ph SPEEKK membranes at low hydration levels can be significantly improved by raising the temperature with important implications for proton conductivity. PMID- 21291227 TI - Bioaugmentation and adsorption treatment of coking wastewater containing pyridine and quinoline using zeolite-biological aerated filters. AB - Bioaugmented zeolite-biological aerated filters (Z-BAFs), i.e. adding isolated degrading bacteria into the BAFs with zeolite as fillings, were designed to treat coking wastewater containing high concentrations of pyridine and quinoline and to explore the bacterial community of biofilm on the zeolite surface. The investigation was carried out for 91 days of column operation and the treatment of pyridine, quinoline, total organic carbon (TOC), and ammonium was shown to be highly efficient by bioaugmentation and adsorption. Biomass determination and bacterial diversity detection based on 16S rDNA and rRNA techniques supported the treatment data and indicated that bioaugmentation could recover the bacterial richness and diversity from pyridine and quinoline loading shocks. However, bioaugmentation accelerated the shift of the bacterial community structure resulting in a more distinct difference from the starting community. Clone library analysis revealed that pyridine and quinoline were more harmful to Bacterodietes among all ingenious bacteria, and bioaugmentation promoted the growth of Planctomycetes in the biofilm. Moreover, the introduced bacteria did not remain dominant in the bioaugmented biofilm, indicating the indigenous degrading bacteria played the most significant role in the treatment. This bioaugmented Z-BAF method was shown to be an alternative technology for the treatment of wastewater containing pyridine and quinoline or other N-heterocyclic aromatic compounds. PMID- 21291228 TI - Effects of humic substances on precipitation and aggregation of zinc sulfide nanoparticles. AB - Nanoparticulate metal sulfides such as ZnS can influence the transport and bioavailability of pollutant metals in anaerobic environments. The aim of this work was to investigate how the composition of dissolved natural organic matter (NOM) influences the stability of zinc sulfide nanoparticles as they nucleate and aggregate in water with dissolved NOM. We compared NOM fractions that were isolated from several surface waters and represented a range of characteristics including molecular weight, type of carbon, and ligand density. Dynamic light scattering was employed to monitor the growth and aggregation of Zn-S-NOM nanoparticles in supersaturated solutions containing dissolved aquatic humic substances. The NOM was observed to reduce particle growth rates, depending on solution variables such as type and concentration of NOM, monovalent electrolyte concentration, and pH. The rates of growth increased with increasing ionic strength, indicating that observed growth rates primarily represented aggregation of charged Zn-S-NOM particles. Furthermore, the observed rates decreased with increasing molecular weight and aromatic content of the NOM fractions, while carboxylate and reduced sulfur content had little effect. Differences between NOM were likely due to properties that increased electrosteric hindrances for aggregation. Overall, results of this study suggest that the composition and source of NOM are key factors that contribute to the stabilization and persistence of zinc sulfide nanoparticles in the aquatic environment. PMID- 21291229 TI - Formation and stability of atmospherically relevant isoprene-derived organosulfates and organonitrates. AB - Isoprene is the precursor for number of alcohol, organosulfate, and organonitrate species observed in ambient secondary organic aerosol (SOA). Recent laboratory and field work has suggested that isoprene-derived epoxides may be crucial intermediates that can explain the existence of these compounds in SOA. To confirm this hypothesis, the specific hydroxy epoxides observed in gas phase isoprene photooxidation experiments (as well as several other related species) were synthesized and the bulk phase aqueous reactions of these species in the presence of sulfate and nitrate were studied via nuclear magnetic resonance (NMR) techniques. The results indicate that both primary and tertiary organosulfates and organonitrates are efficiently formed from the potential SOA reactions of isoprene-derived epoxides. However, the tertiary organonitrates are shown to undergo rapid nucleophilic substitution reactions (in which nitrate is substituted for by water or sulfate) over the whole range of SOA pH, while the tertiary organosulfates are found to undergo a much slower acid-dependent hydrolysis reaction. The primary organonitrates and organosulfates under study were found to be stable against nucleophilic substitution reactions, even at low pH. This finding provides a potential explanation for the fact that organosulfates are more commonly detected in ambient SOA than are organonitrates. PMID- 21291230 TI - Identifying the causes of sediment-associated toxicity in urban waterways of the Pearl River Delta, China. AB - Twenty-one sediments collected in urban waterways of the Pearl River Delta (PRD) in China were screened for acute toxicity using Chironomus dilutus in addition to being examined for potential contributors of sediment toxicity, including 19 organochlorine, five organophosphate, and nine pyrethroid insecticides, 28 polycyclic aromatic hydrocarbons, 27 polychlorinated biphenyls, 15 polybrominated diphenyl ethers, 12 metals, and ammonia. Fifteen of the 21 sediments exhibited acute toxicity to C. dilutus, with 33% of the samples exhibiting 100% mortality. This is one of the first studies in China which directly correlates a broad range of sediment-associated contaminants to ecological effects measured by bioassays. A toxic unit approach showed that pyrethroids contributed most to the observed toxicity; as cypermethrin alone was predicted to cause significant mortality in about half of the sites. Specific toxicity identification evaluation analysis confirmed pyrethroid toxicity. Other contaminants may also be supplemental contributors at a few sites. The current study suggests that pyrethroids are the principal cause of contamination and that future risk assessment and mitigation efforts in this area should focus primarily on pyrethroids but should not disregard other contaminants as potential risk is evident. PMID- 21291231 TI - Using two-dimensional correlation dynamic mechanical spectroscopy to detect different modes of molecular motions in the glass-rubber transition region in polyisobutylene. AB - In this Article, we report the first study of the molecular dynamics in the glass rubber transition region in polyisobutylene by 2D correlation dynamic mechanical spectroscopy (2DC-DMS). With the help of the high resolution and high sensitivity of the technique, the sub-Rouse modes are independently separated from the Rouse modes and local segmental motion (LSM). According to the positions and widths of autopeaks of three modes of molecular motions, the loss tangent peak is resolved into three peaks by nonlinear fitting method. Moreover, the glass-rubber transition region is divided into three regions. 2DC-DMS has been demonstrated to be a powerful tool for studying the molecular motions with different time/length scales. PMID- 21291232 TI - Brominated flame retardants in seawater and atmosphere of the Atlantic and the Southern Ocean. AB - Seawater and air samples were collected aboard the FS Polarstern during the cruises ANT-XXV/1 + 2 in the Atlantic and Southern Ocean in 2008. The particulate and dissolved phase in water and particulate and gaseous phase in air were analyzed separately for nine polybrominated diphenyl ethers (PBDEs) and six non PBDE brominated flame retardants (BFRs). Air concentrations of 2,3-dibromopropyl 2,4,6-tribromophenyl ether (DPTE) and hexabromobenzene (HBB) in the gaseous and particulate phase (median = 0.56 pg m(-3) for DPTE and 0.92 pg m(-3) for HBB) were comparable to ?(9)PBDEs (1.0 pg m(-3)). Pentabromotoluene (PBT) was detectable in ~30% of the gaseous phase samples, whereas concentration of 2,4,6 tribromophenyl allylether (ATE), hexachlorocyclopentenyl-dibromocyclooctane (HCDBCO) and 2-ethyl-1-hexyl 2,3,4,5-tetrabromobenzoate (EHTBB) were below their method detection limits. DPTE, and PBDEs were also found in seawater at low pg per liter levels. Elevated seawater concentrations of PBDEs and DPTE were measured in the English Channel and close to South African coast. Concentrations of DPTE, BDE-47, and BDE-99 in the atmosphere generally decreased from Europe toward the Southern Ocean, whereas no latitudinal trend was observed in seawater. Air-water exchange gradients suggested net deposition dominates for all selected substances. The medians of net deposition fluxes for the air-water gas exchange were 83, 21, 69, 20, and 781 pg m(-2) day(-1) for BDE-47, BDE-100, BDE-99, DPTE, and HBB, whereas medians of dry deposition fluxes were 2.0, 0.3, 1.2, 1.0, and 0.5 pg m(-2) day(-1) for BDE-47, BDE-100, BDE-99, DPTE, and HBB. Overall, these results highlight the important role of the long-range atmospheric transport of PBDE and non-PBDE BFRs to remote regions. PMID- 21291233 TI - Comparison of lipid content and Fatty Acid composition in the edible meat of wild and cultured freshwater and marine fish and shrimps from china. AB - The lipid content and fatty acid composition in the edible meat of twenty-nine species of wild and cultured freshwater and marine fish and shrimps were investigated. Both the lipid content and fatty acid composition of the species were specified due to their unique food habits and trophic levels. Most of the marine fish demonstrated higher lipid content than the freshwater fish, whereas shrimps had the lowest lipid content. All the marine fish and shrimps had much higher total n-3 PUFA than n-6 PUFA, while most of the freshwater fish and shrimps demonstrated much lower total n-3 PUFA than n-6 PUFA. This may be the biggest difference in fatty acid composition between marine and freshwater species. The cultured freshwater fish demonstrated higher percentages of total PUFA, total n-3 PUFA, and EPA + DHA than the wild freshwater fish. Two freshwater fish, including bighead carp and silver carp, are comparable to the marine fish as sources of n-3 PUFA. PMID- 21291234 TI - Antioxidant potential of rat plasma by administration of freeze-dried jaboticaba peel (Myrciaria jaboticaba Vell Berg). AB - The effect of the intake of freeze-dried jaboticaba peel powder on the antioxidant potential of rats' blood plasma was investigated in two experiments. In the first, 35 male rats, divided into 5 groups, received 7 mg of anthocyanins/100 g of body weight, by gavage. The blood was withdrawn 0, 30, 60, and 120 min after gavage. The antioxidant capacity was evaluated in plasma by ORAC and TEAC. There was no significant difference in the plasmatic antioxidant potential among the groups. In the second experiment, 40 male rats were divided into 4 groups that consumed, respectively, 0, 1, 2, and 4% of freeze-dried jaboticaba peel powder added to their diet. An increase in the plasmatic antioxidant potential was observed for groups that received 1 and 2% of jaboticaba peel powder (1.7 times by TEAC method and 1.3 times by ORAC); however, the group that received 4% of the powder did not show antioxidant effects according to the methods used. PMID- 21291235 TI - Fluorinated N,N-dialkylaminostilbenes for Wnt pathway inhibition and colon cancer repression. AB - Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the United States. CRC is initiated by mutations of the tumor suppressor gene, adenomatous polyposis coli (APC), or beta-catenin gene. These mutations stabilize beta-catenin and constitutively activate Wnt/beta-catenin target genes, such as c Myc and cyclin D1, ultimately leading to cancer. Naturally occurring stilbene derivatives, resveratrol and pterostilbene, inhibit Wnt signaling and repress CRC cell proliferation but are ineffective at concentrations less than 10 MUM. To understand the structure--activity relationship within these stilbene derivatives and to develop more efficacious Wnt inhibitors than these natural products, we synthesized and evaluated a panel of fluorinated N,N-dialkylaminostilbenes. Among this panel, (E)-4-(2,6-difluorostyryl)-N,N-dimethylaniline (4r) inhibits Wnt signaling at nanomolar levels and inhibits the growth of human CRC cell xenografts in athymic nude mice at a dosage of 20 mg/kg. These fluorinated N,N dialkylaminostilbenes appear to inhibit Wnt signaling downstream of beta-catenin, probably at the transcriptional level. PMID- 21291236 TI - Sensitive and versatile detection of the fouling process and fouling propensity of proteins on polyvinylidene fluoride membranes via surface-enhanced Raman spectroscopy. AB - Membrane fouling is the major drawback of membrane-based technologies because it will lead to severe flux declines and the need to clean or replace the fouled membrane. A technique capable of early diagnosis, process monitoring, and evaluation of the role of different foulants playing in the fouling process is crucial for the fouling control. We develop surface-enhanced Raman spectroscopy (SERS) as a new and versatile tool to investigate the fouling process of protein on PVDF (polyvinylidene fluoride) membranes as well as the fouling propensity of three different proteins. We optimized the aggregation level and volume of SERS active Ag sol and the spectra acquisition method combined with a statistical analysis method to ensure a high detection sensitivity, signal uniformity, and stability. We then used SERS for the early diagnosis of the fouling process and determining when the membrane pores would be blocked. The fouled area was visualized by a combination of the silver staining and Raman mapping. The fouling propensity of different proteins was studied by comparing the relative SERS band intensities of different proteins on a glass slide and after membrane filtration. Compared with fluorescence-based techniques, the narrow, well-resolved Raman band, especially the use of the same excitation line and laser power, endows SERS the ability to compare the fouling propensity in a very simple way. PMID- 21291237 TI - Repellent activity of essential oils and some of their individual constituents against Tribolium castaneum herbst. AB - A tool for integrated pest management is the use of essential oils (EOs) and plant extracts. In this study, EOs from Tagetes lucida , Lepechinia betonicifolia , Lippia alba , Cananga odorata , and Rosmarinus officinalis , species grown in Colombia, were analyzed by gas chromatography-mass spectrometry. These oils as well as several of their constituents were tested for repellent activity against Tribolium castaneum , using the area preference method. The main components (>10%) found in EOs were methylchavicol, limonene/alpha-pinene, carvone/limonene, benzyl acetate/linalool/benzyl benzoate, and alpha-pinene, for T. lucida, L. betonicifolia, L. alba, C. odorata, and R. officinalis, respectively. All EOs were repellent, followed a dose-response relationship, and had bioactivity similar to or better than that of commercial compound IR3535. EOs from C. odorata and L. alba were the most active. Compounds from EOs, such benzyl benzoate, beta myrcene, and carvone, showed good repellent properties. In short, EOs from plants cultivated in Colombia are sources of repellents against T. castaneum. PMID- 21291238 TI - Carbonic anhydrase activators: gold nanoparticles coated with derivatized histamine, histidine, and carnosine show enhanced activatory effects on several mammalian isoforms. AB - Lipoic acid moieties were attached to amine or amino acids showing activating properties against the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1). The obtained lipoic acid conjugates of histamine, L-histidine methyl ester, and L carnosine methyl ester were attached to gold nanoparticles (NPs) by reaction with Au(III) salts in reducing conditions. The CA activators (CAAs)-coated NPs showed low nanomolar activation (K(A)s of 1-9 nM) of relevant cytosolic, membrane-bound, mitochondrial, and transmembrane CA isoforms, such as CA I, II, IV, VA, VII, and XIV. These NPs also effectively activated CAs ex vivo, in whole blood experiments, with an increase of 200-280% of the CA activity. This is the first example of enzyme activation with nanoparticles and may lead to biomedical applications for conditions in which the CA activity is diminished, such as aging, Alzheimer's disease, or CA deficiency syndrome. PMID- 21291239 TI - Construction of a well-defined multifunctional dendrimer for theranostics. AB - A dendrimer-based building block for theranostics was designed. The multifunctional dendrimer is polyamide-based and contains nine azide termini, nine amine termini, and fifty-four terminal acid groups. Orthogonal functionalization of the multifunctional dendrimer with a near-infrared (NIR) cyanine dye afforded the final dendrimer that shows fluorescence in the NIR region and no toxicity toward T98G human cells. The synthetic strategy described here might be promising for fabricating the next generation of materials for theranostics. PMID- 21291240 TI - Species-specific differences and structure-activity relationships in the debromination of PBDE congeners in three fish species. AB - Previous studies have suggested that there may be species-specific differences in the metabolism of polybrominated diphenyl ethers (PBDEs) among different fish species. In this study, we investigated the in vitro hepatic metabolism of eleven individual PBDE congeners (tri- through decaBDEs) in three different fish species: rainbow trout (Oncorhynchus mykiss), common carp (Cyprinus carpio), and Chinook salmon (O. tschwatcha). In addition, we evaluated the influence of PBDE structural characteristics (i.e., bromine substitution patterns) on metabolism. Six of the eleven congeners we evaluated, BDEs 99, 153, 183, 203, 208, and 209, were metabolically debrominated to lower brominated congeners. All of the congeners that were metabolized contained at least one meta-substituted bromine. Metabolites were not detected for congeners without one meta-substituted bromine (e.g., BDEs 28, 47, and 100). Metabolite formation rates were generally 10 to 100 times faster in carp than in trout and salmon. BDEs 47, 49, 101, 154, and 183 were the major metabolites observed in all three species with the exception of BDE 47, which was only detected in carp. Carp demonstrated a preference toward meta-debromination, while trout and salmon debrominated meta- and para-bromine atoms to an equal extent. We compared glutathione-S-transferase (GST) and deiodinase (DI) activity among all three species as these enzyme systems have been hypothesized to play a role in PBDE debromination in teleosts. Carp exhibited a preference for meta-deiodination of the thyroid hormone thyroxine, which was consistent with the preference for meta-debromination of PBDEs observed in carp. PMID- 21291242 TI - Potential of wastewater-treating anaerobic granules for biomethanation of synthesis gas. AB - Gasification of biomass produces a mixture of gas (mainly carbon monoxide (CO), carbon dioxide (CO(2)), and hydrogen (H(2))) called synthesis gas, or syngas, by thermal degradation without combustion. Syngas can be used for heat or electricity production by thermochemical processes. This project aims at developing an alternative way to bioupgrade syngas into biogas (mainly methane), via anaerobic fermentation. Nonacclimated industrial granular sludge to be used as reactor inoculum was initially evaluated for mesophilic carboxydotrophic methanogenesis potential in batch tests at 4 and 8 mmol CO/g VSS.d, in the absence and presence of H(2) and CO(2), respectively. Granular sludge was then introduced into a 30 L gas-lift reactor and supplied with CO, to study the production of methane and other metabolites, at different gas dilutions as well as feeding and recirculation rates. A maximal CO conversion efficiency of 75%, which was gas-liquid mass transfer limited, occurred at a CO partial pressure of 0.6 atm combined with a gas recirculation ratio of 20:1. The anaerobic granule potential for methanogenesis from CO was likely hydrogenotrophic, combined with CO-dependent H(2) formation, either under mesophilic or thermophilic conditions. Thermophilic conditions provide the anaerobic granules with a CO-bioconversion potential significantly larger (5-fold) than under mesophilic conditions, so long as the gas-liquid transfer is alleviated. PMID- 21291243 TI - Photopatterning of cell-adhesive-modified poly(ethyleneimine) for guided neuronal growth. AB - We describe photopatterning technique that employs the photodegradation of cell adhesive-modified poly(ethyleneimine) (m-PEI) to fabricate precise micropatterns on the indium tin oxide (ITO) substrate for guided neuronal growth. The photodegradation of m-PEI coated on hydroxyl group-terminated ITO substrate created micropatterns over a large area through deep UV irradiation. The photopatterned m-PEI layer can effectively guide neurite outgrowth and control neurite extensions from individual neurons. PMID- 21291244 TI - Evolutionary screening of collagen-like peptides that nucleate hydroxyapatite crystals. AB - The biogenesis of inorganic/organic composite materials such as bone typically involves the process of templated mineralization. Biomimetic synthesis of bone like materials therefore requires the development of organic scaffolds that mediate mineralization of hydroxyapatite (HAP), the major inorganic component of bone. Using phage display, we identified a 12-residue peptide that bound to single-crystal HAP and templated the nucleation and growth of crystalline HAP mineral in a sequence- and composition-dependent manner. The sequence responsible for the mineralizing activity resembled the tripeptide repeat (Gly-Pro-Hyp) of type I collagen, a major component of bone extracellular matrix. Using a panel of synthetic peptides, we defined the structural features required for mineralizing activity. The results support a model for the cooperative noncovalent interaction of the peptide with HAP and suggest that native collagen may have a mineral templating function in vivo. We expect this short HAP-binding peptide to be useful in the synthesis of three-dimensional bone-like materials. PMID- 21291245 TI - Copolymer hydrogels of acrylic acid and a nonionic surfmer: pH-induced switching of transparency and volume and improved mechanical stability. AB - Copolymer hydrogels were prepared from an aqueous micellar solution of the nonionic surfactant monomer (surfmer) omega-methoxy poly(ethylene oxide)40undecyl alpha-methacrylate (PEO-R-MA-40) and acrylic acid (AA) in a one-step reaction using gamma-irradiation. The hydrogels were transparent if the polymerization was carried out at pH >= 4, whereas turbid gels were obtained if the polymerization was carried out at lower pH. Exposure of the turbid gels to an aqueous solution of pH 11 led to swelling and clearing, whereas subsequent exposure to pH 1 had the reverse effect. Clear gels prepared at pH 4 became turbid, if exposed to an aqueous solution of lower pH and became clear again if reswollen at higher pH. The pH at which clouding set in increased with the amount of surfmer copolymerized in the gel. Pure poly(acrylic acid) (P-AA) hydrogels did not show any changes in transparency if the pH was varied. The presence of surfmer led to more pronounced shrinking and swelling, especially if the gels were prepared at pH 4. The mechanical stability of P-AA and copolymer hydrogels was studied using elongational flow measurements. The presence of surfmer led to increased mechanical stability of the hydrogels. The increase originates from copolymerized micellar aggregates acting as additional, stable cross-linking units in the gel. The true stress at break of copolymer hydrogels prepared at pH 2.4 (or 4) was 5.5 (or 3.4) times larger than for surfmer-free P-AA gels. Possible origins for the higher stability such as complex formation between P-AA and oxyethylene segments of copolymerized PEO-R-MA-40 are discussed. PMID- 21291246 TI - Does participating in physical activity in outdoor natural environments have a greater effect on physical and mental wellbeing than physical activity indoors? A systematic review. AB - Our objective was to compare the effects on mental and physical wellbeing, health related quality of life and long-term adherence to physical activity, of participation in physical activity in natural environments compared with physical activity indoors. We conducted a systematic review using the following data sources: Medline, Embase, Psychinfo, GreenFILE, SportDISCUS, The Cochrane Library, Science Citation Index Expanded, Social Sciences Citation Index, Arts and Humanities Citation Index, Conference Proceedings Citation Index--Science and BIOSIS from inception to June 2010. Internet searches of relevant Web sites, hand searches of relevant journals, and the reference lists of included papers and other review papers identified in the search were also searched for relevant information. Controlled trials (randomized and nonrandomized) were included. To be eligible trials had to compare the effects of outdoor exercise initiatives with those conducted indoors and report on at least one physical or mental wellbeing outcome in adults or children. Screening of articles for inclusion, data extraction, and quality appraisal were performed by one reviewer and checked by a second with discrepancies resolved by discussion with a third if necessary. Due to the heterogeneity of identified studies a narrative synthesis was performed. Eleven trials (833 adults) were included. Most participants (6 trials; 523 adults) were young students. Study entry criteria and methods were sparsely reported. All interventions consisted of a single episode of walking or running indoors with the same activity at a similar level conducted outdoors on a separate occasion. A total of 13 different outcome measures were used to evaluate the effects of exercise on mental wellbeing, and 4 outcome measures were used to assess attitude to exercise. Most trials (n = 9) showed some improvement in mental wellbeing on one or other of the outcome measures. Compared with exercising indoors, exercising in natural environments was associated with greater feelings of revitalization and positive engagement, decreases in tension, confusion, anger, and depression, and increased energy. However, the results suggested that feelings of calmness may be decreased following outdoor exercise. Participants reported greater enjoyment and satisfaction with outdoor activity and declared a greater intent to repeat the activity at a later date. None of the identified studies measured the effects of physical activity on physical wellbeing or the effect of natural environments on exercise adherence. The hypothesis that there are added beneficial effects to be gained from performing physical activity outdoors in natural environments is very appealing and has generated considerable interest. This review has shown some promising effects on self-reported mental wellbeing immediately following exercise in nature which are not seen following the same exercise indoors. However, the interpretation and extrapolation of these findings is hampered by the poor methodological quality of the available evidence and the heterogeneity of outcome measures employed. The review demonstrates the paucity of high quality evidence on which to base recommendations and reveals an undoubted need for further research in this area. Large, well designed, longer term trials in populations who might benefit most from the potential advantages of outdoor exercise are needed to fully elucidate the effects on mental and physical wellbeing. The influence of these effects on the sustainability of physical activity initiatives also awaits investigation. PMID- 21291247 TI - Inhibitory activity of natural occurring antioxidants on Thiyl radical-induced trans-arachidonic acid formation. AB - trans-Fatty acids in humans not only may be obtained exogenously from food intake but also could be generated endogenously in tissues. The endogenous generation of trans-fatty acids, especially in the cell membranes induced by radical stress, is an inevitable source for the living species. Thiyl radicals generated from thiols act as the catalyst for the cis-trans isomerization of fatty acids. Arachidonic acid (5c,8c,11c,14c-20:4) with only two of the four double bonds deriving from linoleic acid in the diet can be used to differentiate the exogenous or endogenous formation of double bonds. The aim of this study is to evaluate the effective compounds in preventing thiyl radical-induced trans-arachidonic acid formation during UV irradiation in vitro. The trans-arachidonic acids were found to be 75% after 30 min UV irradiation of all-cis-arachidonic acid. Myricetin, luteolin, and quercetin had the highest thiyl radical scavenging activities, whereas sesamol, gallic acid, and vitamins A, C, and E had the lowest. The structures of flavonoids with higher thiyl radical scavenging activities were a 3',4'-o-dihydroxyl group in the B ring and a 2,3-double bond combined with a 4 keto group in the C ring. These effective compounds found in the present work may be used as lead compounds for the potential inhibitors in the formation of trans fatty acids in vivo. PMID- 21291248 TI - LEED, energy savings, and carbon abatement: related but not synonymous. PMID- 21291249 TI - A concise synthesis of paucifloral F and related indanone analogues via palladium catalyzed alpha-arylation. AB - A concise approach to synthesize paucifloral F was developed via a stereoselective palladium-catalyzed alpha-arylation reaction. The approach has also been applied in the synthesis of indanone analogues of Paucifloral F. PMID- 21291250 TI - High activity carbide supported catalysts for water gas shift. AB - Nanostructured carbides are refractory materials with high surface areas that could be used as alternatives to the oxide materials that are widely used as support materials for heterogeneous catalysts. Carbides are also catalytically active for a variety of reactions, offering additional opportunities to tune the overall performance of the catalyst. In this paper we describe the synthesis of molybdenum carbide supported platinum (Pt/Mo(2)C) catalysts and their rates for the water gas shift reaction. The synthesis method allowed interaction of the metal precursor with the native, unpassivated support. The resulting materials possessed very high WGS rates and atypical Pt particle morphologies. Under differential conditions, rates for these catalysts were higher than those for the most active oxide-supported Pt catalysts and a commercial Cu-Zn-Al catalyst. Experimental and computational results suggested that active sites on the Pt/Mo(2)C catalysts were located on the perimeter of the Pt particles and that strong interactions between Pt and the Mo(2)C surface gave rise to raft-like particles. PMID- 21291251 TI - Vesicle and stable monolayer formation from simple "click" chemistry adducts in water. AB - Click chemistry has been successfully extended into the field of molecular design of novel amphiphatic adducts. After their syntheses and characterizations, we have studied their aggregation properties in aqueous medium. Each of these adducts forms stable suspensions in water. These suspensions have been characterized by dynamic light scattering (DLS) studies and transmission electron microscopy (TEM). The presence of inner aqueous compartments in such aggregates has been demonstrated using dye (methylene blue) entrapment studies. These aggregates have been further characterized using X-ray diffraction (XRD), which indicates the existence of bilayer structures in them. Therefore, the resulting aggregates could be described as vesicles. The temperature-induced order-to disorder transitions of the vesicular aggregates and the accompanying changes in their packing and hydration have been examined using high-sensitivity differential scanning calorimetry, fluorescence anisotropy, and generalized polarization measurements using appropriate membrane-soluble probe, 1,6 diphenylhexatriene, and Paldan, respectively. The findings of these studies are consistent with each other in terms of the apparent phase transition temperatures. Langmuir monolayer studies confirmed that these click adducts also form stable monolayers on buffered aqueous subphase at the air-water interface. PMID- 21291252 TI - Rational concept to recognize/extract single-walled carbon nanotubes with a specific chirality. AB - Single-walled carbon nanotubes (SWNTs) have remarkable and unique electronic, mechanical, and thermal properties, which are closely related to their chiralities; thus, the chirality-selective recognition/extraction of the SWNTs is one of the central issues in nanotube science. However, any rational materials design enabling one to efficiently extract/solubilize pure SWNT with a desired chirality has yet not been demonstrated. Herein we report that certain chiral polyfluorene copolymers can well-recognize SWNTs with a certain chirality preferentially, leading to solubilization of specific chiral SWNTs. The chiral copolymers were prepared by the Ni(0)-catalyzed Yamamoto coupling reaction of 2,7 dibromo-9,9-di-n-decylfluorene and 2,7-dibromo-9,9-bis[(S)-(+)-2 methylbutyl]fluorene comonomers. The selectivity of the SWNT chirality was mainly determined by the relative fraction of the achiral and chiral side groups. By a molecular mechanics simulation, the cooperative interaction between the fluorene moiety, alkyl side chain, and graphene wall were responsible for the recognition/dissolution ability of SWNT chirality. This is a first example describing the rational design and synthesis of novel fluorene-based copolymers toward the recognition/extraction of targeted (n, m) chirality of the SWNTs. PMID- 21291253 TI - Accurate distance determination of nucleic acids via Forster resonance energy transfer: implications of dye linker length and rigidity. AB - In Forster resonance energy transfer (FRET) experiments, the donor (D) and acceptor (A) fluorophores are usually attached to the macromolecule of interest via long flexible linkers of up to 15 A in length. This causes significant uncertainties in quantitative distance measurements and prevents experiments with short distances between the attachment points of the dyes due to possible dye-dye interactions. We present two approaches to overcome the above problems as demonstrated by FRET measurements for a series of dsDNA and dsRNA internally labeled with Alexa488 and Cy5 as D and A dye, respectively. First, we characterize the influence of linker length and flexibility on FRET for different dye linker types (long, intermediate, short) by analyzing fluorescence lifetime and anisotropy decays. For long linkers, we describe a straightforward procedure that allows for very high accuracy of FRET-based structure determination through proper consideration of the position distribution of the dye and of linker dynamics. The position distribution can be quickly calculated with geometric accessible volume (AV) simulations, provided that the local structure of RNA or DNA in the proximity of the dye is known and that the dye diffuses freely in the sterically allowed space. The AV approach provides results similar to molecular dynamics simulations (MD) and is fully consistent with experimental FRET data. In a benchmark study for ds A-RNA, an rmsd value of 1.3 A is achieved. Considering the case of undefined dye environments or very short DA distances, we introduce short linkers with a propargyl or alkenyl unit for internal labeling of nucleic acids to minimize position uncertainties. Studies by ensemble time correlated single photon counting and single-molecule detection show that the nature of the linker strongly affects the radius of the dye's accessible volume (6-16 A). For short propargyl linkers, heterogeneous dye environments are observed on the millisecond time scale. A detailed analysis of possible orientation effects (kappa(2) problem) indicates that, for short linkers and unknown local environments, additional kappa(2)-related uncertainties are clearly outweighed by better defined dye positions. PMID- 21291254 TI - Silver- and gold-mediated domino transformation: a strategy for synthesizing benzo[e]indolo[1,2-a]pyrrolo/pyrido[2,1-c][1,4]diazepine-3,9-diones. AB - We reported a strategy for the synthesis of fused heterocyclic compounds benzo[e]indolo[1,2-a]pyrrolo/pyrido[2,1-c][1,4]diazepine-3,9-diones via an AgSbF(6)/gold-complex catalyzed one-pot cascade transformation. The strategy is tolerant of a broad range of substrates and affords a series of intriguing fused diazepinedione heterocycles. PMID- 21291255 TI - Ferromagnetic FePt-nanoparticles/polycation hybrid capsules designed for a magnetically guided drug delivery system. AB - The present Article describes the synthesis of ferromagnetic capsules approximately 330 nm in diameter with a nanometer-thick shell to apply to magnetic carriers in a magnetically guided drug delivery system. The magnetic shell of 5 nm in thickness is a nanohybrid, composed of ordered alloy FePt nanoparticles of approximately 3-4 nm in size and a polymer layer of a cationic polyelectrolyte, poly(diaryldimethylammonium chloride) (PDDA). The magnetic capsules have an excellent capacity for carrying medical drugs and genes. Surface modified silica particles with PDDA were used as a template for the capsules. FePt nanoparticles were deposited on the PDDA-modified silica particles through a polyol method followed by dissolving the silica particles with a NaOH solution, resulting in the formation of the magnetic capsules as the final product. A three dimensional hollow structure is maintained by the nanohybrid shell. The FePt nanoparticles/PDDA nanohybrid shell also exhibits a ferromagnetic feature at room temperature because the FePt nanoparticles of an ordered-alloy phase are formed with the aid of PDDA despite the small size (3-4 nm). PMID- 21291256 TI - Stable protein-repellent zwitterionic polymer brushes grafted from silicon nitride. AB - Zwitterionic poly(sulfobetaine acrylamide) (SBMAA) brushes were grafted from silicon-rich silicon nitride (SixN4, x > 3) surfaces by atom transfer radical polymerization (ATRP) and studied in protein adsorption experiments. To this aim ATRP initiators were immobilized onto SixN4 through stable Si-C linkages via three consecutive reactions. A UV-induced reaction of 1,2-epoxy-9-decene with hydrogen-terminated SixN4 surfaces was followed by conversion of the epoxide with 1,2-ethylenediamine resulting in primary and secondary amine-terminated surfaces. A reaction with 2-bromoisobutyryl bromide led to ATRP initiator-covered surfaces. Zwitterionic polymer brushes of SBMAA were grown from these initiator-coated surfaces (thickness ~30 nm), and the polymer-coated surfaces were characterized in detail by static water contact angle measurements, X-ray photoelectron spectroscopy (XPS), and an atomic force microscope (AFM). The adsorption of proteins onto zwitterionic polymer coated surfaces was evaluated by in situ reflectometry, using a fibrinogen (FIB) solution of 0.1 g.L(-1), and compared to hexadecyl-coated SixN4 surfaces (C16-SixN4), uncoated air-based plasma oxidized SixN4 surfaces (SiOy-SixN4), and hexa(ethylene oxide)-coated SixN4 surfaces (EO6 SixN4). Excellent protein repellence (>99%) was observed for these zwitterionic polymer-coated SixN4 surfaces during exposure to FIB solution as compared to C16 SixN4 surfaces. Furthermore, the stability of these zwitterionic polymer-coated SixN4 surfaces was surveyed by exposing the surfaces for 1 week to phosphate buffered saline (PBS) solution at room temperature. The zwitterionic polymer coated SixN4 surfaces before and after exposure to PBS solution were characterized by XPS, AFM, and water contact angle measurements, and their protein-repelling properties were evaluated by reflectometry. After exposure to PBS solution, the zwitterionic polymer coating remained intact, and its thickness was unchanged within experimental error. No hydrolysis was observed for the zwitterionic polymer after 1 week exposure to PBS solution, and the surfaces still repelled 98% FIB as compared to C16-SixN4 surfaces, demonstrating the long term efficiency of these easily prepared surface coatings. PMID- 21291257 TI - New isotherm for multisite occupancy adsorption of long, straight rigid rods. AB - The adsorption of long, straight rigid rods of length k (k-mers) on 2D lattices is described by using a new theoretical approach based on a generalization of the classical Guggenheim-DiMarzio approximation. In this scheme, the Helmholtz free energy and its derivatives are written in terms of the order parameter delta, which characterizes the nematic phase occurring in the system at intermediate densities. Then, using the principle of minimum free energy with delta as a parameter, the main adsorption properties are calculated. Comparisons with Monte Carlo simulations are performed in order to test the validity of the theoretical model. The obtained results indicate that the new thermodynamic description is significantly better than the existing theoretical models developed to treat the polymer adsorption problem. PMID- 21291258 TI - Effects of receptor binding on plasma half-life of bifunctional transferrin fusion proteins. AB - In contrast to the wide applications of recombinant bifunctional fusion proteins in clinical usage, the systematic study for the pharmacokinetics (PK) of bifunctional fusion proteins is left blank. In this report, recombinant fusion proteins consisting of transferrin (Tf) and growth hormone (GH) or granulocyte colony-stimulating factor (G-CSF) have been constructed as a model for studying the PK of bifunctional fusion proteins. The results showed that the insertion of different linkers between the two protein domains altered the binding affinities of the fusion proteins to both domain receptors, and that the fusion proteins' plasma half-lives were greatly affected. A strong correlation between GH receptor binding affinity and plasma half-life of GH-Tf fusion proteins was observed. In addition, we demonstrated that the intracellular processing after receptor binding plays an important role in determining the half-life of fusion proteins. While the binding of the GH domain to the GH receptor will lead to endocytosis and lysosomal degradation in target cells, binding of the Tf domain to the Tf receptor may recycle the fusion protein and prolong its plasma half-life. To further confirm the effects of receptor binding on plasma half-life, G-CSF-Tf bifunctional fusion proteins with the same three linkers as GH-Tf were evaluated. While the 3 fusion proteins showed a similar G-CSF receptor binding affinity, the G-CSF-Tf fusion protein with the higher Tf receptor binding affinity exhibited longer plasma half-life. The linker insertion further demonstrated the involvement of Tf in recycling and prolonging plasma half-life. Based on our results, a model was developed to summarize the factors in determining the PK of bifunctional fusion proteins. Our findings are useful for predicting the plasma half-lives, as well as for improving the pharmacokinetic profiles of therapeutic bifunctional fusion proteins by applying linker technology. PMID- 21291259 TI - On the Munn-Silbey approach to polaron transport with off-diagonal coupling and temperature-dependent canonical transformations. AB - Improved results using a method similar to the Munn-Silbey approach have been obtained on the temperature dependence of transport properties of an extended Holstein model incorporating simultaneous diagonal and off-diagonal exciton phonon coupling. The Hamiltonian is partially diagonalized by a canonical transformation, and optimal transformation coefficients are determined in a self consistent manner. Calculated transport properties exhibit substantial corrections on those obtained previously by Munn and Silbey for a wide range of temperatures thanks to a numerically exact evaluation and an added momentum dependence of the transformation matrix. Results on the diffusion coefficient in the moderate and weak coupling regime show distinct band-like and hopping-like transport features as a function of temperature. PMID- 21291260 TI - Enhanced stereoselectivity of a Cu(II) complex chiral auxiliary in the synthesis of Fmoc-L-gamma-carboxyglutamic acid. AB - L-gamma-Carboxyglutamic acid (Gla) is an uncommon amino acid that binds avidly to mineral surfaces and metal ions. Herein, we report the synthesis of N-alpha-Fmoc L-gamma-carboxyglutamic acid gamma,gamma'-tert-butyl ester (Fmoc-Gla(O(t)Bu)(2) OH), a suitably protected analogue for Fmoc-based solid-phase peptide synthesis. The residue was synthesized using a novel chiral Cu(II) complex, whose structure based design was inspired by the blue copper protein rusticyanin. The five coordinate complex is formed by Shiff base formation between glycine and the novel ligand (S)-2-(N-(2-methylthio)benzylprolyl)aminobenzophenone in the presence of copper. Michael addition of di-tert-butyl methylenemalonate to the alpha-carbon of the glycine portion of the complex occurs in a diastereoselective fashion. The resulting (S,S)-complex diastereomer can be easily purified by chromatography. Metal complex decomposition followed by Fmoc protection affords the enantiomerically pure amino acid. With the use of this novel chiral complex, the asymmetric synthesis of Fmoc-Gla(O(t)Bu)(2)-OH was completed in nine steps from thiosalicylic acid in 14.5% overall yield. PMID- 21291261 TI - An advanced lithium ion battery based on high performance electrode materials. AB - In this paper we report the study of a high capacity Sn-C nanostructured anode and of a high rate, high voltage Li[Ni(0.45)Co(0.1)Mn(1.45)]O(4) spinel cathode. We have combined these anode and cathode materials in an advanced lithium ion battery that, by exploiting this new chemistry, offers excellent performances in terms of cycling life, i.e., ca. 100 high rate cycles, of rate capability, operating at 5C and still keeping more than 85% of the initial capacity, and of energy density, expected to be of the order of 170 Wh kg(-1). These unique features make the battery a very promising energy storage for powering low or zero emission HEV or EV vehicles. PMID- 21291262 TI - Asymmetric total synthesis of danicalipin A and evaluation of biological activity. AB - Asymmetric total synthesis of danicalipin A was achieved. The synthesis was characterized by diastereoselective introduction of chlorine atoms. Biological activities with synthetic danicalipin A, its enantiomer, and racemate were also evaluated toward brine shrimp. Both enantiomers of danicalipin A showed almost the same activity. PMID- 21291264 TI - Direct observation of triple ions in aqueous solutions of nickel(II) sulfate: a molecular link between the gas phase and bulk behavior. AB - Electrospray ionization of an aqueous solution of nickel(II) sulfate provides direct experimental evidence for the formation of triple ions of the type [Ni(2)(SO(4))(H(2)O)(n)](2+) and [Ni(SO(4))(2)](2-), whose existence in aqueous solution has previously been proposed based on relaxation spectroscopy [Chen et al. J. Sol. Chem. 2005, 34, 1045]. Formally, these triple ions are formed by aggregation of the solvated ions Ni(2+) and SO(4)(2-), respectively, with the neutral ion pair NiSO(4). In addition, also higher adducts are observed, e.g. the "pentuple ions" [Ni(3)(SO(4))(2)(H(2)O)(n)](2+) (n = 7-9) and [Ni(2)(SO(4))(3)](2 ), of which the dicationic is extensively hydrated, whereas the anionic is not. The structures of the dinuclear nickel clusters are derived from ab initio calculations and their infrared spectra are compared with experimental data obtained for the gaseous ions [Ni(2)SO(4)(H(2)O)(5)](2+) and [Ni(2)(SO(4))(3)](2 ), respectively. The calculations show that the structures are crucially controlled by the degree of solvation of nickel ion. Explicit consideration of solvating water molecules within the first coordination sphere suggest that the dicationic triple ion [Ni(2)SO(4)](aq)(2+) is bent and thus bears a permanent dipole moment, whereas the [Ni(SO(4))(2)](aq)(2-) dianion tends to be quasi linear. The experimental and theoretical data for the gaseous ions thus support the elegant, but indirect, deductions previously made based on solution-phase studies. PMID- 21291265 TI - Molecular dynamics study and electronic structure evolution of a DNA duplex d(CCCGATCGGG)2. AB - The molecular dynamics simulations and electronic structure evolution of a A-DNA decamer, d(CCCGATCGGG)(2), in the presence and absence of [Co(NH(3))(6)](3+) ions have been investigated. In both cases, the results of 2.5 ns MD simulation indicate a A-DNA->B-DNA transition. Ab initio DFT calculations were performed on a series of conformations representing the A->B transitions to reveal the dynamical behavior of the electronic structure of the decamer. The results suggest that the conformational parameters as well as the surrounding environment have no direct correlation with the electronic structures. Instead, the thermal fluctuations play an important role in the electronic structure of the present DNA system. PMID- 21291263 TI - Substrate specificity of protein tyrosine phosphatases 1B, RPTPalpha, SHP-1, and SHP-2. AB - We determined the substrate specificities of the protein tyrosine phosphatases (PTPs) PTP1B, RPTPalpha, SHP-1, and SHP-2 by on-bead screening of combinatorial peptide libraries and solution-phase kinetic analysis of individually synthesized phosphotyrosyl (pY) peptides. These PTPs exhibit different levels of sequence specificity and catalytic efficiency. The catalytic domain of RPTPalpha has very weak sequence specificity and is approximately 2 orders of magnitude less active than the other three PTPs. The PTP1B catalytic domain has modest preference for acidic residues on both sides of pY, is highly active toward multiply phosphorylated peptides, but disfavors basic residues at any position, a Gly at the pY-1 position, or a Pro at the pY+1 position. By contrast, SHP-1 and SHP-2 share similar but much narrower substrate specificities, with a strong preference for acidic and aromatic hydrophobic amino acids on both sides of the pY residue. An efficient SHP-1/2 substrate generally contains two or more acidic residues on the N-terminal side and one or more acidic residues on the C-terminal side of pY but no basic residues. Subtle differences exist between SHP-1 and SHP-2 in that SHP-1 has a stronger preference for acidic residues at the pY-1 and pY+1 positions and the two SHPs prefer acidic residues at different positions N terminal to pY. A survey of the known protein substrates of PTP1B, SHP-1, and SHP 2 shows an excellent agreement between the in vivo dephosphorylation pattern and the in vitro specificity profiles derived from library screening. These results suggest that different PTPs have distinct sequence specificity profiles and the intrinsic activity/specificity of the PTP domain is an important determinant of the enzyme's in vivo substrate specificity. PMID- 21291267 TI - Ultrahigh mobility in polymer field-effect transistors by design. AB - In this article, the design paradigm involving molecular weight, alkyl substituents, and donor-acceptor interaction for the poly[2,6-(4,4-bis-alkyl-4H cyclopenta[2,1-b;3,4-b']-dithiophene)-alt-4,7-(2,1,3-benzothiadiazole)] (cyclopentadithiophene-benzothiadiazole) donor-acceptor copolymer (CDT-BTZ) toward field-effect transistors (FETs) with ultrahigh mobilities is presented and discussed. It is shown that the molecular weight plays a key role in improving hole mobilities, reaching an exceptionally high value of up to 3.3 cm(2) V(-1) s( 1). Possible explanations for this observation is highlighted in conjunction with thin film morphology and crystallinity. Hereby, it is found that the former does not change, whereas, at the same time, crystallinity improved with ever growing molecular weight. Furthermore, other important structural design factors such as alkyl chain substituents and donor-acceptor interaction between the polymer backbones potentially govern intermolecular stacking distances crucial for charge transport and hence for device performance. In this aspect, for the first time we attempt to shed light onto donor-acceptor interactions between neighboring polymer chains with the help of solid state nuclear magnetic resonance (NMR). On the basis of our results, polymer design principles are inferred that might be of relevance for prospective semiconductors exhibiting hole mobilities even exceeding 3 cm(2) V(-1) s(-1). PMID- 21291268 TI - The Japanese mutant Abeta (DeltaE22-Abeta(1-39)) forms fibrils instantaneously, with low-thioflavin T fluorescence: seeding of wild-type Abeta(1-40) into atypical fibrils by DeltaE22-Abeta(1-39). AB - The DeltaE693 (Japanese) mutation of the beta-amyloid precursor protein leads to production of DeltaE22-Abeta peptides such as DeltaE22-Abeta(1-39). Despite reports that these peptides do not form fibrils, here we show that, on the contrary, the peptide forms fibrils essentially instantaneously. The fibrils are typical amyloid fibrils in all respects except that they cause only low levels of thioflavin T (ThT) fluorescence, which, however, develops with no lag phase. The fibrils bind ThT, but with a lower affinity and a smaller number of binding sites than wild-type (WT) Abeta(1-40). Fluorescence depolarization confirms extremely rapid aggregation of DeltaE22-Abeta(1-39). Size exclusion chromatography (SEC) indicates very low concentrations of soluble monomer and oligomer, but only in the presence of some organic solvent, e.g., 2% (v/v) DMSO. The critical concentration is approximately 1 order of magnitude lower for DeltaE22-Abeta(1 39) than for WT Abeta(1-40). Several lines of evidence point to an altered structure for DeltaE22-Abeta(1-39) compared to that of WT Abeta(1-40) fibrils. In addition to differences in ThT binding and fluorescence, PITHIRDS-CT solid-state nuclear magnetic resonance (NMR) measurements of DeltaE22-Abeta(1-39) are not compatible with the parallel in-register beta-sheet generally observed for WT Abeta(1-40) fibrils. X-ray fibril diffraction showed different D spacings: 4.7 and 10.4 A for WT Abeta(1-40) and 4.7 and 9.6 A for DeltaE22-Abeta(1-39). Equimolar mixtures of DeltaE22-Abeta(1-39) and WT Abeta(1-40) also produced fibrils extremely rapidly, and by the criteria of ThT fluorescence and electron microscopic appearance, they were the same as fibrils made from pure DeltaE22 Abeta(1-39). X-ray diffraction of fibrils formed from 1:1 molar mixtures of DeltaE22-Abeta(1-39) and WT Abeta(1-40) showed the same D spacings as fibrils of the pure mutant peptide, not the wild-type peptide. These findings are consistent with extremely rapid nucleation by DeltaE22-Abeta(1-39), followed by fibril extension by WT Abeta(1-40), and "conversion" of the wild-type peptide to a structure similar to that of the mutant peptide, in a manner reminiscent of the prion conversion phenomenon. PMID- 21291269 TI - Discovery of a potential allosteric ligand binding site in CDK2. AB - Cyclin-dependent kinases (CDKs) are key regulatory enzymes in cell cycle progression and transcription. Aberrant activity of CDKs has been implicated in a number of medical conditions, and numerous small molecule CDK inhibitors have been reported as potential drug leads. However, these inhibitors exclusively bind to the ATP site, which is largely conserved among protein kinases, and clinical trials have not resulted in viable drug candidates, attributed in part to the lack of target selectivity. CDKs are unique among protein kinases, as their functionality strictly depends on association with their partner proteins, the cyclins. In an effort to identify potential target sites for disruption of the CDK-cyclin interaction, we probed the extrinsic fluorophore 8-anilino-1 naphthalene sulfonate (ANS) with human CDK2 and cyclin A using fluorescence spectroscopy and protein crystallography. ANS interacts with free CDK2 in a saturation-dependent manner with an apparent K(d) of 37 MUM, and cyclin A displaced ANS from CDK2 with an EC(50) value of 0.6 MUM. Co-crystal structures with ANS alone and in ternary complex with ATP site-directed inhibitors revealed two ANS molecules bound adjacent to one another, away from the ATP site, in a large pocket that extends from the DFG region above the C-helix. Binding of ANS is accompanied by substantial structural changes in CDK2, resulting in a C-helix conformation that is incompatible for cyclin A association. These findings indicate the potential of the ANS binding pocket as a new target site for allosteric inhibitors disrupting the interaction of CDKs and cyclins. PMID- 21291270 TI - Synthesis of enantiomerically pure P-stereogenic diphosphacrowns and their palladium complexes. AB - A practical synthetic route for enantiomerically pure P-stereogenic diphosphacrowns was developed by using a P-stereogenic bisphosphine as a chiral building block. Their molecular structures were confirmed by NMR spectroscopy and X-ray crystallography. Complexation of the diphosphacrowns with palladium was carried out, and the corresponding palladium complexes were obtained. The P stereogenic diphosphacrowns were applicable to the chiral ligand for the asymmetric 1,4-addition of arylboronic acids to alpha,beta-unsaturated ketone catalyzed by palladium. This reaction proceeded smoothly to afford the corresponding 1,4-addition products in high yield with good enantioselectivities. PMID- 21291271 TI - An unusual cell penetrating peptide identified using a plasmid display-based functional selection platform. AB - Cell penetrating peptides (CPPs) have tremendous potential for use in gene and drug delivery applications. The selection of new CPPs with desired capabilities from randomized peptide libraries is challenging, since the CPP phenotype is a complex selection target. Here we report the discovery of an unusual new CPP from a randomized peptide library using a functional selection system based on plasmid display (PD). After four rounds of screening of a 14-mer peptide library over PC12 cells, several peptides were identified and tested for their ability to deliver the green fluorescent protein (GFP). One peptide (SG3) exhibited a cell penetrating phenotype; however, unlike other well-known CPPs such as TAT or Penetratin, the newly identified peptide was not highly cationic. The PD protocol necessitated the addition of a cationic lipid (Lipofectamine2000), and in the presence of this compound, the SG3 peptide significantly outperformed the well known TAT CPP in the delivery of GFP to PC12 cells and primary astrocytes. When the SG3 peptide was fused to the pro-apoptotic BH3 peptide from the Bak protein, significant cell death was induced in cultured primary astrocytes, indicating relevant, intracellular delivery of a functional cargo. The PD platform is a useful method for identifying functional new CPPs from randomized libraries with unique delivery capabilities. PMID- 21291272 TI - Dynamic and reversible self-assembly of photoelectrochemical complexes based on lipid bilayer disks, photosynthetic reaction centers, and single-walled carbon nanotubes. AB - An aqueous solution containing photosynthetic reaction centers (RCs), membrane scaffold proteins (MSPs), phospholipids, and single-walled carbon nanotubes (SWCNTs) solubilized with the surfactant sodium cholate (SC) reversibly self assembles into a highly ordered structure upon dialysis of the latter. The resulting structure is photoelectrochemically active and consists of 4-nm-thick lipid bilayer disks (nanodisks, NDs) arranged parallel to the surface of the SWCNT with the RC housed within the bilayer such that its hole injecting site faces the nanotube surface. The structure can be assembled and disassembled autonomously with the addition or removal of surfactant. We model the kinetic and thermodynamic forces that drive the dynamics of this reversible self-assembly process. The assembly is monitored using spectrofluorimetry during dialysis and subsequent surfactant addition and used to fit a kinetic model to determine the forward and reverse rate constants of ND and ND-SWCNT formation. The calculated ND and ND-SWCNT forward rate constants are 79 mM(-1) s(-1) and 5.4 * 10(2) mM(-1) s(-1), respectively, and the reverse rate constants are negligible over the dialysis time scale. We find that the reaction is not diffusion-controlled since the ND-SWCNT reaction, which consists of entities with smaller diffusion coefficients, has a larger reaction rate constant. Using these rate parameters, we were able to develop a kinetic phase diagram for the formation of ND-SWCNT complexes, which indicates an optimal dialysis rate of approximately 8 * 10(-4) s(-1). We also fit the model to cyclic ND-SWCNT assembly and disassembly experiments and hence mimic the thermodynamic forces used in regeneration processes detailed previously. Such forces may form the basis of both synthetic and natural photoelectrochemical complexes capable of dynamic component replacement and repair. PMID- 21291273 TI - Stabilization of engineered zero-valent nanoiron with Na-acrylic copolymer enhances spermiotoxicity. AB - Studies were carried out to assess the effects of stabilized (i.e., coated with organic polyacrylic stabilizer) and nonstabilized forms of zero-valent nanoiron (nZVI) on the development of Mytilus galloprovincialis embryos following 2 h exposure of the sperm prior to in vitro fertilization. Both forms of nZVI caused serious disruption of development, consisting of 30% mortality among spermatozoa with subsequent 20% decline in fertilization success, and delay in development, i.e., over 50% of the larvae were suspended in the trochophore stage. Significant DNA damage was also detected in sperm exposed to the highest exposure concentrations (10 mg L(-1)). Distinct dose response to the two different types of nZVI observed are linked to aggregation behavior that is controlled by the surface stabilizers. This work reports on conventional biomarkers (for membrane integrity, genotoxicity, and developmental toxicity) applied for the rapid assessment of toxicity of nZVI, which are able to detect surface property-related effects to meet the requirements of risk assessments for nanotechnology. The study highlights the potential ecotoxicological impact of an environmentally relevant engineered nanoparticle. Implications of the NOM-nZVI interactions regarding soil and groundwater remediation and wastewater treatment are discussed. PMID- 21291274 TI - Recycling MgOH2 nanoadsorbent during treating the low concentration of CrVI. AB - Investigations about how to recycle the deactivated nanomaterials are well needed. This work was designed to explore the recycling strategy of Mg(OH)(2) nanoadsorbent during treating low concentration of Cr(VI) solution as an example. It was demonstrated that a reversible route between Cr-adsorbed nano-Mg(OH)(2) and Cr-desorbed bulk-MgCO(3) . 3H(2)O can be established by using CO(2) as a phase transformation medium. In each adsorption-desorption cycle, Cr(VI) solution with initial concentration of 10 mg . L(-1) could be enriched over 40 times. An aggregation-induced rapid phase transformation mechanism from nano-Mg(OH)(2) to bulk-MgCO(3) . 3H(2)O was discovered, which was one of the critical factors to ensure the disposing efficiency of this environmental-friendly Cr(VI) disposal system. A pilot-scale experiment was conducted with this strategy to deal with 50 L Cr(VI)-containing simulated industrial wastewater. The enrichment of Cr(VI) and the recycle of nano-Mg(OH)(2) can be successfully achieved simultaneously. PMID- 21291275 TI - Cloning and elucidation of the FR901464 gene cluster revealing a complex acyltransferase-less polyketide synthase using glycerate as starter units. AB - FR901464, an antitumor natural product, represents a new class of potent anticancer small molecules targeting spliceosome and inhibiting both splicing and nuclear retention of pre-mRNA. Herein we describe the biosynthetic gene cluster of FR901464, identified by degenerate primer PCR amplification of a gene encoding the 3-hydroxy-3-methylglutaryl-CoA synthase (HCS) postulated to be involved in the biosynthesis of a beta-branched polyketide from Pseudomonas sp. No. 2663. This cluster consists of twenty open reading frames (ORFs) and was localized to 93-kb DNA segment, and its involvement in FR901464 biosynthesis was confirmed by gene inactivation and complementation. FR901464 is biosynthesized by a hybrid polyketide synthase (PKS)/nonribosomal peptide synthetase (NRPS), HCS, and acyltransferases (AT)-less system. The PKS/NRPS modules feature unusual domain organization including multiple domain redundancy, inactivation, and tandem. Biochemical characterization of a glyceryl transferase and an acyl carrier protein (ACP) in the start module revealed that it incorporates D-1,3 bisphosphoglycerate, which is dephosphorylated and transferred to ACP as the starter unit. Furthermore, an oxidative Baeyer-Villiger reaction followed by chain release was postulated to form a pyran moiety. On the basis of in silico analysis and genetic and biochemical evidances, a biosynthetic pathway for FR901464 was proposed, which sets the stage to further investigate the complex PKS biochemically and engineer the biosynthetic machinery for the production of novel analogues. PMID- 21291276 TI - Photocatalytic patterning and modification of graphene. AB - TiO(2)-based photocatalysis has been widely used to decompose various organic pollutants for the purpose of environmental protection. Such a "green" photochemical process can ultimately degrade organic compounds into CO(2) and H(2)O under ambient conditions. We demonstrate here its extended application on the engineering of single- or few-layer graphene. Using a patterned TiO(2) photomask, we have achieved various photochemical tailorings of graphene, including ribbon cutting, arbitrary patterning on any substrate, layer-by-layer thinning, and localized graphene to graphene oxide conversion. UV-visible spectroscopic studies indicate that the photogenerated, highly reactive .OH radicals work as sharp chemical scissors. Being a solution-free, cost-effective, scalable, and easy handling technique, the presented photocatalytic patterning and modification approach allows for the versatile design and fabrication of graphene-based devices and circuits, compatible with current microelectronic technology, as demonstrated by this fabricated all-carbon field effect transistor (FET) array. PMID- 21291277 TI - Screen-printable silver pastes with metallic nano-zinc and nano-zinc alloys for crystalline silicon photovoltaic cells. AB - Silver metallization pastes for crystalline silicon PV cells containing nanosized metallic zinc were found to be superior to commercial pastes containing micrometer-sized metallic zinc and micrometer sized zinc oxide in terms of efficiency and firing window. Efficiency performance decreases as the size of the particles increases: nano-Zn > 3.6 MUm Zn > 4.4 MUm Zn. Advanced electron microscopy techniques were used to investigate the interfacial microstructure between the front-side contact and the Si emitter of nanosized zinc additive based cells fired at temperatures from below to above optimal. These microstructural observations confirmed the possibility of a tunneling mechanism of current flow (a "nano-Ag colloid assisted tunneling" model) in the absence of Ag crystallites. Contact resistance maps were used to guide sampling, leading to a better understanding of the relationship between microstructure and contact resistance. Low contact resistance and higher cell efficiency, especially at under- and overfiring temperature conditions, are due to more uniform silicon nitride etching obtained through the use of nanosized metallic zinc additives. PMID- 21291278 TI - Polymorphism in self-assembled AB6 binary nanocrystal superlattices. AB - We report the formation and systematic struc-tural characterization of a new AB(6) polymorph with the body-centered cubic (bcc) symmetry in binary nanocrystal superlattices (BNSLs). The bcc-AB(6) phase, lacking any atomic analogue, is isomorphic to certain alkali-metal intercalation compounds of fullerene C(60) (e.g., K(6)C(60)). On the basis of the space-filling principle, we further tailor the relative phase stability of the two AB(6) polymorphs-CaB(6) and bcc-AB(6) from coexistence to phase-pure bcc-AB(6), highlighting the entropic effect as the main driving-force of the self-organization of BNSLs. We also discuss the implication of surface topology studies and the observation of twinning and preferential orientation in bcc-AB(6) on the growth mechanism of BNSLs. Furthermore, the connection between the bcc-AB(6) phase and the (3(2).4.3.4) Archimedean tiling shows the promise of further exploration on the structural diversity (both periodic and aperiodic) in this emerging class of metamaterials. The identification and the ability to tune the relative phase stability of polymorphic structures provide a unique opportunity to engineer the interparticle coupling through controlled clustering and/or interconnectivity of sublattice in BNSLs with identical stoichiometry. PMID- 21291279 TI - Interface enhancement of glass fiber reinforced vinyl ester composites with flame synthesized carbon nanotubes and its enhancing mechanism. AB - Interface enhancement with carbon nanotubes (CNTs) provides a promising approach for improving shock strength and toughness of glass fiber reinforced plastic (GFRP) composites. The effects of incorporating flame-synthesized CNTs (F-CNTs) into GFRP were studied, including on hand lay-up preparation, microstructural characterization, mechanical properties, fracture morphologies, and theoretical calculation. The experimental results showed that: (1) the impact strength of the GFRP modified by F-CNTs increased by more than 15% over that of the GFRP modified by CNTs from chemical vapor deposition; and (2) with the F-CNT enhancement, no interfacial debonding was observed at the interface between the fiber and resin matrix on the GFRP fracture surface, which indicated strong adhesive strength between them. The theoretical calculation revealed that the intrinsic characteristics of the F-CNTs, including lower crystallinity with a large number of defects and chemical functional groups on the surface, promoted their surface activity and dispersibility at the interface, which improved the interfacial bond strength of GFRP. PMID- 21291280 TI - Hydrophobically modified dendrons: developing structure-activity relationships for DNA binding and gene transfection. AB - This paper develops a structure-activity relationship understanding of the way in which surfactant-like dendrons with hydrophilic spermine surface groups and a variety of lipophilic units at their focal points can self-assemble and subsequently bind to DNA with high affinity. The choice of functional group at the focal point of the dendron and the high tunability of the molecular structure have a very significant impact on DNA binding. Mesoscale modeling of the mode of dendron self-assembly provides a direct insight into how the mode of self assembly exerts its effect on the DNA binding process. In particular, the hydrophobic unit controls the number of dendrons in the self-assembled micellar structures, and hence their diameters and surface charge density. The DNA binding affinity correlates with the surface charge density of the dendron aggregates. Furthermore, these structure-activity effects can also be extended to cellular gene delivery, as surface charge density plays a role in controlling the extent of endosomal escape. It is reported that higher generation dendrons, although binding DNA less strongly than the self-assembling lower generation dendrons, are more effective for transfection. The impact of the lipophilic group at the focal point is less significant for the DNA binding ability of these larger dendrons, which is predominantly controlled by the spermine surface groups, but it does modify the levels of gene transfection. Significant synergistic effects on gene delivery were observed when employing combinations of the dendrons and polyethyleneimine (PEI, 25 kDa), with transfection becoming possible at low loading levels where the two components would not transfect individually, giving practically useful levels of gene delivery. PMID- 21291281 TI - Manipulating molecular quantum states with classical metal atom inputs: demonstration of a single molecule NOR logic gate. AB - Quantum states of a trinaphthylene molecule were manipulated by putting its naphthyl branches in contact with single Au atoms. One Au atom carries 1-bit of classical information input that is converted into quantum information throughout the molecule. The Au-trinaphthylene electronic interactions give rise to measurable energy shifts of the molecular electronic states demonstrating a NOR logic gate functionality. The NOR truth table of the single molecule logic gate was characterized by means of scanning tunnelling spectroscopy. PMID- 21291282 TI - Highly ordered nanoporous template from triblock copolymer. AB - Silica nanoporous templates from poly(1,4-isoprene)-block-polystyrene-block poly(2-vinyl pyridine) (IS2VP) were prepared. The films of IS2VP spin-coated from toluene showed a dimple-type structure with short-range lateral order. When the films were exposed to a mixed solvent vapor of toluene/hexane, a highly ordered and oriented core-shell structure, consisting of an outer shell of PI, a middle shell of PS, and a core of P2VP, was obtained. The PI was degraded by UV-ozone treatment and removed. A film of polydimethylsiloxane (PDMS) was spin coated onto the remaining film with dimple-type structures and, upon heating, was drawn into the interstitial regions by capillary action. Exposure to oxygen plasma converted the PDMS into silica and degraded all other remaining polymers. This led to highly ordered and oriented nanoporous silica that could be used as an etching mask for transfer of the pattern or templates for metal loading. PMID- 21291283 TI - Synthesis and characterization of boron azadipyrromethene single-wall carbon nanotube electron donor-acceptor conjugates. AB - The preparation of a novel donor-acceptor material, consisting of a red/near infrared (NIR) absorbing boron azadipyrromethene donor covalently attached to a highly functionalized single-wall carbon nanotube (SWNT) acceptor, which bears great potential in the field of organic photovoltaics, has been demonstrated. Both purification and covalent functionalization of SWNTs have been demonstrated using a number of complementary characterization techniques, including atomic force microscopy, Raman, X-ray photoelectron spectroscopy (XPS), Fourier transform infrared, and NIR-photoluminescence spectroscopy, and a functionalization density of approximately 1 donor molecule per 100 SWNT atoms has been estimated by XPS. The redox behavior of the fluorophore has been investigated by electrochemistry and spectroelectrochemistry as well as by pulse radiolysis. The donor-acceptor properties of the material have been characterized by means of various spectroscopic techniques, such as UV-vis NIR absorption spectroscopy, steady-state and time-resolved fluorescence spectroscopy, and time resolved transient absorption spectroscopy. Charge transfer from the photoexcited donor to the SWNT acceptor has been confirmed with a radical ion pair state lifetime of about 1.2 ns. PMID- 21291284 TI - A conserved surface loop in type I dehydroquinate dehydratases positions an active site arginine and functions in substrate binding. AB - Dehydroquinate dehydratase (DHQD) catalyzes the third step in the biosynthetic shikimate pathway. We present three crystal structures of the Salmonella enterica type I DHQD that address the functionality of a surface loop that is observed to close over the active site following substrate binding. Two wild-type structures with differing loop conformations and kinetic and structural studies of a mutant provide evidence of both direct and indirect mechanisms of involvement of the loop in substrate binding. In addition to allowing amino acid side chains to establish a direct interaction with the substrate, closure of the loop necessitates a conformational change of a key active site arginine, which in turn positions the substrate productively. The absence of DHQD in humans and its essentiality in many pathogenic bacteria make the enzyme a target for the development of nontoxic antimicrobials. The structures and ligand binding insights presented here may inform the design of novel type I DHQD inhibiting molecules. PMID- 21291285 TI - Definition of the extracellular proteome of pathogenic-phase Histoplasma capsulatum. AB - The dimorphic fungal pathogen Histoplasma capsulatum causes respiratory and systemic disease. Within the mammalian host, pathogenic Histoplasma yeast infect, replicate within, and ultimately kill host phagocytes. Surprisingly, few factors have been identified that contribute to Histoplasma virulence. To address this deficiency, we have defined the constituents of the extracellular proteome using LC-MS/MS analysis of the proteins in pathogenic-phase culture filtrates of Histoplasma. In addition to secreted Cbp1, the extracellular proteome of pathogenic Histoplasma yeast consists of 33 deduced proteins. The proteins include glycanases, extracellular enzymes related to oxidative stress defense, dehydrogenase enzymes, chaperone-like factors, and five novel culture filtrate proteins (Cfp's). For independent verification of proteomics-derived identities, we employed RNA interference (RNAi)-based depletion of candidate factors and showed loss of specific proteins from the cell-free culture filtrate. Quantitative RT-PCR revealed the expression of 10 of the extracellular factors was particularly enriched in pathogenic yeast cells as compared to nonpathogenic Histoplasma mycelia, suggesting that these proteins are linked to Histoplasma pathogenesis. In addition, Histoplasma yeast express these factors within macrophages and during infection of murine lungs. As extracellular proteins are positioned at the interface between host and pathogen, the definition of the pathogenic-phase extracellular proteome provides a foundation for the molecular dissection of how Histoplasma alters the host-pathogen interaction to its advantage. PMID- 21291286 TI - Epigenetic changes in individuals with arsenicosis. AB - Inorganic arsenic (iAs) is an environmental toxicant currently poisoning millions of people worldwide, and chronically exposed individuals are susceptible to arsenicosis or arsenic poisoning. Using a state-of-the-art technique to map the methylomes of our study subjects, we identified a large interactome of hypermethylated genes that are enriched for their involvement in arsenic associated diseases, such as cancer, heart disease, and diabetes. Notably, we have uncovered an arsenic-induced tumor suppressorome, a complex of 17 tumor suppressors known to be silenced in human cancers. This finding represents a pivotal clue in unraveling a possible epigenetic mode of arsenic-induced disease. PMID- 21291287 TI - Structure-activity analysis of diffusible lipid electrophiles associated with phospholipid peroxidation: 4-hydroxynonenal and 4-oxononenal analogues. AB - Electrophile-mediated disruption of cell signal-ing is involved in the pathogenesis of several diseases including atherosclerosis and cancer. Diffusible and membrane bound lipid electrophiles are known to modify DNA and protein substrates and modulate cellular pathways including ER stress, antioxidant response, DNA damage, heat shock, and apoptosis. Herein we report on a structure activity relationship for several electrophilic analogues of 4-hydroxynonenal (HNE) and 4-oxononenal (ONE) with regard to toxicity and anti-inflammatory activity. The analogues studied were the oxidation products of HNE and ONE, HNEA/ONEA, the in vivo hydrolysis products of oxidized phosphatidylcholine, COOH HNE/COOH-ONE, and their methyl esters, COOMe-HNE/ONE. The reactivity of each compound toward N-acetylcysteine was determined and compared to the toxicity toward a human colorectal carcinoma cell line (RKO) and a human monocytic leukemia cell line (THP-1). Further analysis was performed in differentiated THP 1 macrophages to assess changes in macrophage activation and pro-inflammatory signaling in response to each lipid electrophile. HNE/ONE analogues inhibited THP 1 macrophage production of the pro-inflammatory cytokines, IL-6, IL-1beta, and TNFalpha, after lipopolysaccharide (LPS)/IFNgamma activation. Inhibition of cytokine production was observed at submicromolar concentrations of several analogues with as little as 30 min of exposure. Phagocytosis of fluorescent beads was also inhibited by lipid electrophile treatment. Lipid electrophiles related to HNE/ONE are both toxic and anti-inflammatory, but the anti-inflammatory effects in human macrophages are observed at nontoxic concentrations. Neither toxicity nor anti-inflammatory activity are strongly correlated to the reactivity of the model nucleophile, N-acetylcysteine. PMID- 21291288 TI - Single strand break in DNA coupled to the O-P bond cleavage. A computational study. AB - In the present study, we consider the formation of a single strand break (SSB) in DNA via an alternative mechanism involving O-P bond splitting that was observed as a minor route to DNA damage induced by low-energy electrons (LEEs) or gamma radiation. We postulate and characterize, at the B3LYP/6-31++G(**) level, a path that starts with LEE attachment to the nucleotide of thymine resulting in a stable valence radical anion localized on pyrimidine. In the next step, a proton is attached to the C5 position of thymine, producing a neutral monohydroradical of this nucleotide. This event triggers the subsequent intramolecular transfer of a sugar hydrogen atom from C3' or C5' to the C6 site of thymine. In the final elemental reaction, O-P bond dissociation takes place, which yields the phosphoryl radical and a cyclic ketone or aldehyde. Identification of the latter species as well as 5,6-dihydropyrimidines in DNA solutions irradiated with ionizing radiation could provide experimental confirmation of the suggested mechanism. PMID- 21291289 TI - Synthesis and unique catalytic performance of single-site Ti-containing hierarchical macroporous silica with mesoporous frameworks. AB - Single-site Ti-containing hierarchical macroporous silica with mesoporous frameworks (Ti-MMS) was successfully prepared by a solvent evaporation method using organic surfactant and poly(methyl methacrylate) (PMMA) colloidal crystals as the template. The formation of a well-defined macroporous structure composed of mesoporous silica walls was characterized by SEM and TEM observations. The successful incorporation of tetrahedrally coordinated Ti oxide moieties within their frameworks was also confirmed by spectroscopic techniques such as UV-vis and XAFS measurements. Comparative studies revealed that Ti-MMS exhibited higher catalytic activities for the epoxidation of linear alpha-olefin compared to Ti containing mesoporous silica without macropores (Ti-MS). The reaction rate was significantly enhanced on Ti-MMS depending on increases in the alkyl chain length of linear alpha-olefins. It was also found that Ti-MMS showed good catalytic performance in the selective epoxidation of methyl oleate, which is a kind of unsaturated fatty acid methyl ester (FAME), under acid-free reaction conditions with tert-butylhydroperoxide (TBHP) because of the advantages of the combination of hierarchical macroporous and mesoporous structures. PMID- 21291290 TI - Cost-effectiveness of 70-gene MammaPrint signature in node-negative breast cancer. AB - OBJECTIVE: To evaluate the cost-effectiveness of 70-gene MammaPrint signature (Agendia Inc, Huntington Beach, CA) vs Adjuvant! Online software (AS) (http://www.adjuvantonline.com) in patients 60 years or younger with early-stage breast cancer. STUDY DESIGN: Cost-effectiveness and cost-utility analyses from a US payer perspective. METHODS: A Markov model with 3 health states was constructed. In the base case model, risk classification and patient outcomes were based on a 70-gene signature validation study. Efficacy of chemotherapy was derived from a published meta-analysis of clinical trials. An alternative model using data from AS and from the Surveillance, Epidemiology and End Results registry was built to examine the external validity of the base case model. The incremental benefits, costs, and cost-effectiveness of treatment guided by 70 gene signature were calculated. RESULTS: In the base case model, 70-gene signature reclassified 29% of patients and spared 10% of patients from chemotherapy. Compared with the AS strategy, the 70-gene signature strategy was associated with $1440 higher total cost per patient and with 0.14 additional life year or 0.15 additional quality-adjusted life-year. Overall, the incremental cost effectiveness ratios were approximately $10,000 per life-year or quality-adjusted life-year in the base case model and $700 in the alternative model. The model results were sensitive to estrogen receptor status, the proportion of patients classified as high risk vs low risk, and the overall survival in each risk group. CONCLUSION: A 70-gene signature is likely to be a cost-effective strategy to guide adjuvant chemotherapy treatment in younger patients with early-stage breast cancer. PMID- 21291291 TI - Nurse practitioner comanagement for patients in an academic geriatric practice. AB - OBJECTIVE: To determine whether nurse practitioner (NP) comanagement can improve the quality of care for 5 chronic conditions in an academic geriatrics practice. STUDY DESIGN AND METHODS: From September 2006 to September 2007, 18 primary care geriatricians were divided into an intervention group that could refer patients to an NP for comanagement of dementia, depression, falls, heart failure, and/or urinary incontinence, or a control group that indicated which patients would have been referred to the NP for these conditions. The NP used structured visit notes to guide care delivery for the 5 conditions concordant with Assessing Care of Vulnerable Elders-3 (ACOVE-3) quality indicators. We reviewed charts to determine adherence to recommended processes of care. RESULTS: A total of 200 patients (108 intervention, 92 control) were eligible for at least 1 process of care recommended by ACOVE-3 for the 5 conditions. Patients' mean (SD) age was 85 years (7 years), 67% were women, and patients were eligible for a mean (SD) of 6.9 (4.4) processes of care. Intervention patients were eligible for more care processes than controls (7.8 vs 5.9 processes per patient; P = .002). Quality of care was higher for patients in the intervention group compared with the control group (54% vs 34% of care processes completed; P <.001). The adjusted absolute difference between intervention and control groups in care processes completed was 20% (95% confidence interval = 13%, 27%). CONCLUSION: NP comanagement of 5 chronic conditions was associated with higher quality of care, even in a practice of geriatricians. PMID- 21291292 TI - Prescribing by physician assistants and nurse practitioners. PMID- 21291293 TI - "Under the radar": nurse practitioner prescribers and pharmaceutical industry promotions. AB - OBJECTIVE: To assess nurse practitioners' interactions with pharmaceutical industry promotional activities and their perception of information reliability and self-reported prescribing behaviors. STUDY DESIGN: Self-administered online survey. METHODS: A nationally randomized sample of nurse practitioner prescribers was surveyed. Eligibility criteria included current clinical practice and licensure to prescribe medications in their state of practice. RESULTS: A total of 263 responses were analyzed. Almost all respondents (96%) reported regular contact with pharmaceutical sales representatives, and most (71%) reported receiving information on new drugs directly from pharmaceutical sales representatives some or most of the time. A large portion (66%) dispensed drug samples regularly to their patients, and 73% believed that samples were somewhat or very helpful in learning about new drugs. Eighty-one percent of respondents thought that it was ethically acceptable to give out samples to anyone, and 90% believed that it was acceptable to attend lunch and dinner events sponsored by the pharmaceutical industry. Almost half (48%) stated that they were more likely to prescribe a drug that was highlighted during a lunch or dinner event. Most respondents stated that it was ethically acceptable for speakers to be paid by industry. CONCLUSIONS: Nurse practitioner prescribers had extensive contact with pharmaceutical industry promotional activities such as pharmaceutical representative contact, receipt of drug samples, and regular attendance at industry-sponsored meal events and continuing education programs. They reported that industry interface with nurse practitioner prescribers in the form of sponsored meals, education events, and paid speakers was ethically acceptable. PMID- 21291294 TI - Gastroduodenal mucosa in microscopic colitis. AB - BACKGROUND: We have assessed gastroduodenal, endoscopical and histopathological findings in a series of patients with microscopic colitis (MC). METHODS: We studied 75 patients with MC, 27 with collagenous colitis (CC) and 48 with lymphocytic colitis (LC), and 60 controls. Data of endoscopical findings were collected and biopsies were assessed. RESULTS: Helicobacter pylori infection rate was 15% in MC and 28% in the controls (p = 0.088). Age at diagnosis of MC was higher in H. pylori positive than negative patients (63.4 +/- 9.6 vs. 54.4 +/- 13.1 years; p = 0.034). Gastric endoscopic erosions were more prevalent in CC than in LC (25.9% vs. 6.2%; p = 0.030) and associated with thick body glands and antral predominance of gastritis in H. pylori positive patients. Rates of focal gastritis (5.6% vs. 6.9%) and lymphocytic gastritis (5.6% vs. 10%) were similar in MC and controls. LC was associated with gastric epithelial lymphocytosis and lymphocytic gastritis. Fifteen patients (20%) had celiac disease. CONCLUSIONS: Unlike LC, CC is associated with endoscopic erosions, likely related with the high acid secretion capacity as indicated by the ample body glands and antral predominance of gastritis in H. pylori associated cases of CC. The presence of some divergent gastroduodenal features in LC and CC, and in comparison with those reported in inflammatory bowel disease (IBD), supports the concept that these two conditions differ not only from IBD but also from each other. The findings also suggest the presence of pathogenetic links between colorectal and gastroduodenal abnormalities. PMID- 21291295 TI - Differential regulation of T and B lymphocytes by PD-1 and SOCS-1 signaling in hepatitis C virus-associated non-Hodgkin's lymphoma. AB - HCV infection is associated with immune dysregulation and B cell Non-Hodgkins lymphoma (HCV-NHL). We have previously shown in vitro that HCV core protein differentially regulates T and B cell functions through two negative signaling pathways, programmed death-1 (PD-1) and suppressor of cytokine signaling-1 (SOCS 1). In this report, we performed a detailed immunologic analysis of T and B cell functions in the setting of HCV-NHL. We observed that T cells isolated from patients with HCV-NHL exhibited an exhausted phenotype including decreased expression of viral-specific and non-specific activation markers; whereas B cells exhibited an activated phenotype including over-expression of cell activation markers and immunoglobulins compared to healthy subjects. Individuals with HCV alone or NHL alone exhibited abnormal T and B cell phenotypes, but to a lesser extent compared to HCV-NHL. This differential activation of T and B lymphocytes was inversely associated with the expression of PD-1 and SOCS-1. Interestingly, blocking PD-1 during TCR activation inhibited SOCS-1 gene expression, suggesting that these regulatory pathways are linked in T cells. Importantly, blocking PD-1 also restored the impaired T cell functions observed in the setting of HCV-NHL. These results support a coordinated mechanism by which HCV might cause immune dysregulation that is associated to HCV-NHL. PMID- 21291296 TI - Results of spectral-domain optical coherence tomography by preferential hyperacuity perimeter in patients after idiopathic epiretinal membrane surgery. AB - PURPOSE: To evaluate spectral-domain optical coherence tomography (OCT) findings based on preferential hyperacuity perimeter (PHP) in patients after idiopathic epiretinal membrane surgery. METHODS: Forty eyes of 40 patients undergoing surgery for idiopathic epiretinal membrane were included in the study. The best corrected visual acuity, PHP, Amsler grid test, and OCT were assessed 3 months after surgery. RESULTS: Patients were classified based on the defect of hyperacuity by PHP, as follows: hyperacuity defect (n = 18 eyes) and hyperacuity intact (n = 22 eyes). There was no difference in age, gender, duration of symptoms, and visual acuity. The average macular thickness and inner nuclear layer thickness in the hyperacuity defect group was thicker than the hyperacuity intact group (P = 0.041 and P = 0.045, respectively). A disrupted photoreceptor layer was more common in the hyperacuity defect group compared with the hyperacuity intact group (P = 0.001). CONCLUSION: With regard to metamorphopsia, a hyperacuity defect after epiretinal membrane surgery was associated with inner nuclear layer edema and photoreceptor disarrangement. PMID- 21291297 TI - Therapeutic efficacy of intranasally delivered mesenchymal stem cells in a rat model of Parkinson disease. AB - Safe and effective cell delivery remains one of the main challenges in cell-based therapy of neurodegenerative disorders. Graft survival, sufficient enrichment of therapeutic cells in the brain, and avoidance of their distribution throughout the peripheral organs are greatly influenced by the method of delivery. Here we demonstrate for the first time noninvasive intranasal (IN) delivery of mesenchymal stem cells (MSCs) to the brains of unilaterally 6-hydroxydopamine (6 OHDA)-lesioned rats. IN application (INA) of MSCs resulted in the appearance of cells in the olfactory bulb, cortex, hippocampus, striatum, cerebellum, brainstem, and spinal cord. Out of 1 * 106 MSCs applied intranasally, 24% survived for at least 4.5 months in the brains of 6-OHDA rats as assessed by quantification of enhanced green fluorescent protein (EGFP) DNA. Quantification of proliferating cell nuclear antigen-positive EGFP-MSCs showed that 3% of applied MSCs were proliferative 4.5 months after application. INA of MSCs increased the tyrosine hydroxylase level in the lesioned ipsilateral striatum and substantia nigra, and completely eliminated the 6-OHDA-induced increase in terminal deoxynucleotidyl transferase (TdT)-mediated 2'-deoxyuridine, 5' triphosphate (dUTP)-biotin nick end labeling (TUNEL) staining of these areas. INA of EGFP-labeled MSCs prevented any decrease in the dopamine level in the lesioned hemisphere, whereas the lesioned side of the control animals revealed significantly lower levels of dopamine 4.5 months after 6-OHDA treatment. Behavioral analyses revealed significant and substantial improvement of motor function of the Parkinsonian forepaw to up to 68% of the normal value 40-110 days after INA of 1 * 106 cells. MSC-INA decreased the concentrations of inflammatory cytokines-interleukin-1beta (IL-1beta), IL-2, -6, -12, tumor necrosis factor (TNF), interferon-gamma (IFN-gamma, and granulocyte-macrophage colony-stimulating factor (GM-CSF)-in the lesioned side to their levels in the intact hemisphere. IN administration provides a highly promising noninvasive alternative to the traumatic surgical procedure of transplantation and allows targeted delivery of cells to the brain with the option of chronic application. PMID- 21291298 TI - AmI in good care? Developing design principles for ambient intelligent domotics for elderly. AB - The combination of ambient intelligence (AmI) and domotics has the potential to respond to elderly people's desire to live independent from extensive forms of care. Their slow adoption of technological aids shows reluctance, though. This article investigates their motivations to adopt ambient intelligent domotics, and proposes design principles specifically based on their preferences and experiences. Respondents appeared to be more acceptive of tangible problems they expected with AmI domotics than intangible ones. In addition, their opinions seemed to be profoundly influenced by the way they perceived their psychological quality of life, while their physical conditions did not seem to have noticeable impacts. PMID- 21291299 TI - The impact of an integrated hospital-community medical information system on quality of care and medical service utilisation in primary-care clinics. AB - BACKGROUND: In 2005, an innovative system of hospital-community, on-line medical records (OFEK) was introduced in Clalit Health Services (CHS). GOALS: To examine OFEK's use and impact on quality indicators and medical-service utilisation in CHS primary-care clinics. METHODS: Examining the frequency of OFEK's use with its own track-log data; comparing 'before' and 'after' quality indicators and service utilisation of experimental versus control clinics. RESULTS: Use of OFEK increased by hundreds of percent between 2005 and 2006, continued rising at a slower rate in 2007 and decreased slightly in 2008. At clinics in catchment areas of hospitals using OFEK extensively, OFEK reduced the number of imaging tests and, to a lesser extent, laboratory testing and improved several quality measures. An examination of all clinics in the catchment areas and in the study revealed a much weaker impact. CONCLUSIONS: OFEK's introduction affected a number of outcome measures - some, significantly - in medical and financial terms. Its increased use at additional clinics may exert a stronger impact there, too. The study contributes to the development of measures to examine the impact of such systems, which can be used to assess a broad range of Health Information Technology (HIT) systems. PMID- 21291300 TI - Estimating the success of e-health collaborative services: the THEMIS framework. AB - This study proposes a prototype framework (THEMIS) for estimating algebraically the success (S) of the electronic health collaborative services (e-HCS) and examines two hypotheses: first, that the S estimation of an e-HCS, developed by a third-party vendor, demands a 'shrunk formative model' and second that causal relationships between the involved dimensions (FFP, CO, COSTS) do exist, and their parameters affect the S - from weakly to strongly and vice-versa. A formative model was shrunk to generate three causal dimensions ('Collaborators Objections', 'Costs', 'Fitness for Purpose'). Then, the new framework (THEMIS) was enriched with a causal loop diagram, a prototype scoring method, (termed 'polarisation method') and 42 questions. In order to investigate the feasibility of the THEMIS framework, we estimated the S of 15 e-HCSs and the algebraic outcomes (E(S)) were compared - one by one - with usage categories produced by a commercial software. Our findings supported the initial hypotheses. The S was estimated with accuracy; for the e-HCSs with a weak E(S) the commercial software verified that they remained idle several times during the 11-month evaluation period, whereas the e-HCS with a strong E(S) the commercial software verified that they were used frequently. Frameworks, such as the one proposed, which are based on both qualitative and quantitative methods, may provide significant support on the S estimation field. PMID- 21291301 TI - A cadaveric study of the morphometric and geometric relationships of the orbital apex. AB - INTRODUCTION: To define the morphometric and geometric relationships which exist at the orbital apex. MATERIALS AND METHODS: Forty-seven orbits from twenty-four formalin-fixed Caucasian cadavers were exenterated and the relevant sutures, fissures and foramina identified. Measurements were taken from the optic canal to anatomical landmarks located along the medial wall, inferior wall and lateral wall of each orbit. Based on the mean results the geometric angles between the different anatomical structures were calculated and used to create three dimensional models. RESULTS: The mean distances from the midpoint of the optic canal to the superior orbital fissure, inferior orbital fissure and anterior ethmoidal foramen were 10.22 mm, 29.56 mm and 21.65 mm, respectively. The mean distances from the anterior ethmoidal foramen to the superior and inferior orbital fissures were 24.27 mm and 31.93 mm, respectively. The mean distance between the tips of the superior and inferior orbital fissures was 27.70 mm. The mean distances directly from the tips of the superior and inferior orbital fissures and the anterior ethmoidal foramen to the orbital rim were 39.23 mm, 17.11 mm and 18.94 mm, respectively. These values were used to calculate geometric values and create three-dimensional models. DISCUSSION: The orbital apex is a congested structure and the practicing orbital surgeon must have an intimate knowledge of its contents. We have presented novel data, which in conjunction with radiology may be used as both a navigational aid to plan orbital surgery and to guide the surgeon intraoperatively to assess proximity to key anatomical structures. PMID- 21291302 TI - A new technique of alfentanil-induced conscious sedation for oculoplastic surgery. AB - This technique describes a new painless method of injecting local anaesthetic in a highly pain-sensitive area of the body-around the eyes. We describe how a new technique using a bolus of intravenous alfentanil can help alleviate patient discomfort during the injection of the local anaesthetic and also reduce the amount of local anaesthetic injected. This also helps oculoplastic surgeons to work in a relaxed environment, whilst still utilizing the efficiencies that are provided by an ambulatory day surgery unit. PMID- 21291303 TI - Bilateral orbital haematomas in an anticoagulated patient with severe H1N1 influenza. AB - A previously healthy woman was admitted to the intensive care unit (ICU) with severe H1N1 influenza. She had prolonged hospital stay due to multiple complications of critical illness, including pelvic deep vein thrombosis (DVT), which was treated with subcutaneous enoxaparin. The patient was referred to the ophthalmology service for bilateral proptosis. On examination, she had bilateral tense proptosis, worse on the left side with exposure keratopathy. Laboratory tests showed that she had thrombocytopenia and raised activated partial thromboplastin time (APTT). A CT scan revealed well-circumscribed soft tissue density lesions in the superolateral orbits and was reported as bilateral lacrimal gland enlargement. However, based on a clinical suspicion of subperiosteal hematoma collection, a diagnostic tap was performed. Following aspiration of six mls of dark blood from the left superior orbit, there was a reduction of proptosis with improvement in chemosis and resolution of exposure keratopathy. Enoxaparin is one of several antithrombotic agents which are increasingly being used for DVT prophylaxis in severely compromised patients. Furthermore, ICU patients ventilated for prolonged periods are at risk of developing chemosis and exposure keratopathy. Thus, the clinician should maintain a high index of suspicion in identifying subperiosteal hematomas, when managing such cases. The spontaneous bilateral vision threatening subperiosteal hematoma was probably caused by a combination of enoxaparin therapy and prolonged ventilation. PMID- 21291304 TI - Detection, characterization, and spontaneous differentiation in vitro of very small embryonic-like putative stem cells in adult mammalian ovary. AB - The present study was undertaken to detect, characterize, and study differentiation potential of stem cells in adult rabbit, sheep, monkey, and menopausal human ovarian surface epithelium (OSE). Two distinct populations of putative stem cells (PSCs) of variable size were detected in scraped OSE, one being smaller and other similar in size to the surrounding red blood cells in the scraped OSE. The smaller 1-3 MUm very small embryonic-like PSCs were pluripotent in nature with nuclear Oct-4 and cell surface SSEA-4, whereas the bigger 4-7 MUm cells with cytoplasmic localization of Oct-4 and minimal expression of SSEA-4 were possibly the tissue committed progenitor stem cells. Pluripotent gene transcripts of Oct-4, Oct-4A, Nanog, Sox-2, TERT, and Stat-3 in human and sheep OSE were detected by reverse transcriptase-polymerase chain reaction. The PSCs underwent spontaneous differentiation into oocyte-like structures, parthenote like structures, embryoid body-like structures, cells with neuronal-like phenotype, and embryonic stem cell-like colonies, whereas the epithelial cells transformed into mesenchymal phenotype by epithelial-mesenchymal transition in 3 weeks of OSE culture. Germ cell markers like c-Kit, DAZL, GDF-9, VASA, and ZP4 were immuno-localized in oocyte-like structures. In conclusion, as opposed to the existing view of OSE being a bipotent source of oocytes and granulosa cells, mammalian ovaries harbor distinct very small embryonic-like PSCs and tissue committed progenitor stem cells population that have the potential to develop into oocyte-like structures in vitro, whereas mesenchymal fibroblasts appear to form supporting granulosa-like somatic cells. Research at the single-cell level, including complete gene expression profiling, is required to further confirm whether postnatal oogenesis is a conserved phenomenon in adult mammals. PMID- 21291305 TI - The development of an instrument to measure factors that influence self-perceived dignity. AB - BACKGROUND: Preserving dignity can be considered as a goal of palliative care. To provide dignity-conserving care, it is relevant to identify the factors that influence a patient's self-perceived dignity. This study aims to develop an instrument to measure factors affecting self-perceived dignity that has good content validity and is appropriate for use in practice. METHODS: Data were collected in the Advance Directives Cohort Study. In 2008, the cohort received a questionnaire with 31 items that might influence one's self-perceived dignity. For a subsample of people with poor health (n = 292), we analyzed which items could be removed because of the mean scores for presence of the item and its influence on dignity. RESULTS: The 31 items fell into four domains: evaluation of self in relation to others, functional status, mental state, and care and situational aspects. Mean scores for presence and influence on dignity showed large differences and were not correlated. Six items were scarcely present and did not substantially affect self-perceived dignity. Because three of these were expected to influence dignity in other settings, only three items could be removed and two items could be combined into one. After calculating correlations between conceptually similar items, one extra item could be removed. CONCLUSION: Reducing the instrument to 26 items and dichotomizing the answer option for presence increases its feasibility for use in practice. The instrument offers an important step to better understanding the phenomenon of self-perceived dignity by gaining information directly from patients. PMID- 21291307 TI - Accounting for the Down syndrome advantage? AB - The authors examined factors that could explain the higher levels of psychosocial well being observed in past research in mothers of individuals with Down syndrome compared with mothers of individuals with other types of intellectual disabilities. The authors studied 155 mothers of adults with Down syndrome, contrasting factors that might validly account for the ?Down syndrome advantage? (behavioral phenotype) with those that have been portrayed in past research as artifactual (maternal age, social supports). The behavioral phenotype predicted less pessimism, more life satisfaction, and a better quality of the mother?child relationship. However, younger maternal age and fewer social supports, as well as the behavioral phenotype, predicted higher levels of caregiving burden. Implications for future research on families of individuals with Down syndrome are discussed. PMID- 21291309 TI - Secondary conditions in people with developmental disability. AB - The authors investigated secondary conditions in people with developmental disabilities in terms of (a) the average number of conditions experienced and overall health and independence, (b) their degree and nature, and (c) gender differences. Information was obtained by a questionnaire completed by the caregivers for 659 people with developmental disabilities. Participants experienced an average of 11.3 secondary conditions. Secondary conditions causing significant limitations were reading difficulties, communication, physical fitness-conditioning, personal hygiene-appearance, weight, dental and oral hygiene, and memory problems. Some gender differences emerged in overall health scores and limitations due to secondary conditions. PMID- 21291308 TI - Exploring the adult life of men and women with fragile X syndrome: results from a national survey. AB - Using data from a national family survey, the authors describe the adult lives (i.e., residence, employment, level of assistance needed with everyday life, friendships, and leisure activities) of 328 adults with the full mutation of the FMR1 gene and identify characteristics related to independence in these domains. Level of functional skills was the strongest predictor of independence in adult life for men, whereas ability to interact appropriately was the strongest predictor for women. Co-occurring mental health conditions influenced independence in adult life for men and women, in particular, autism spectrum disorders for men and affect problems for women. Services for adults with fragile X syndrome should not only target functional skills but interpersonal skills and co-occurring mental health conditions. PMID- 21291310 TI - Peer-related social competence of young children with Down syndrome. AB - The peer-related social competence of children with Down syndrome was examined in an observational study. Dyadic interactions with peers of children with Down syndrome were compared with the dyadic interactions of matched groups of typically developing children and with playmates differing in both familiarity and social skills. Results suggested that both risk and protective factors influenced the peer interactions of children with Down syndrome. Recommendations are made for applying contemporary models of peer-related social competence to etiologic subgroups to better understand the mechanisms involved and to provide direction for the design of intervention programs. PMID- 21291311 TI - Examining the function of problem behavior in fragile X syndrome: preliminary experimental analysis. AB - Fragile X syndrome is the most common inherited cause of intellectual and developmental disability. The influence of environmental variables on behaviors associated with the syndrome has received only scant attention. The current study explored the function served by problem behavior in fragile X syndrome by using experimental functional analysis methodology with 8 children with fragile X. No child met criteria for attention-maintained problem behavior, 5 children met criteria for escape-maintained problem behavior, and 4 children met criteria for tangible-maintained problem behavior. Results are discussed and compared with previous findings on the function of problem behavior in fragile X syndrome, and implications for intervention are discussed. It is noted that the external validity of these findings is limited by the small sample size. PMID- 21291312 TI - Marital satisfaction and parenting experiences of mothers and fathers of adolescents and adults with autism. AB - The association of marital satisfaction with parenting burden and quality of the parent?child relationship was examined in 91 married mothers and fathers of co residing adolescents and adults with autism spectrum disorders. Within-couple differences between mothers and fathers in how child characteristics related to these parenting experiences were also evaluated. Multilevel modeling was used to control for the dependency in couple data. Marital satisfaction was an important predictor of parenting experiences, particularly for fathers. Mothers reported feeling closer to their son or daughter than did fathers. Fathers' parenting experiences were more strongly impacted by child characteristics than were mothers' parenting experiences. Results emphasized the connection between the marital relationship and parenting experiences and overlapping but unique experiences of mothers and fathers. PMID- 21291315 TI - Can Innate, modular "foundations" explain morality? Challenges for Haidt's Moral Foundations Theory. AB - Jonathan Haidt's Moral Foundations Theory is an influential scientific account of morality incorporating psychological, developmental, and evolutionary perspectives. The theory proposes that morality is built upon five innate "foundations," each of which is believed to have been selected for during human evolution and, subsequently, tuned-up by learning during development. We argue here that although some general elements of Haidt's theory are plausible, many other important aspects of his account are seriously flawed. First, innateness and modularity figure centrally in Haidt's account, but terminological and conceptual problems foster confusion and ambiguities. Second, both the theory's proposed number of moral foundations and its taxonomy of the moral domain appear contrived, ignoring equally good candidate foundations and the possibility of substantial intergroup differences in the foundations' contents. Third, the mechanisms (viz., modules) and categorical distinctions (viz., between foundations) proposed by the theory are not consilient with discoveries in contemporary neuroscience concerning the organization, functioning, and development of the brain. In light of these difficulties, we suggest that Haidt's theory is inadequate as a scientific account of morality. Nevertheless, the theory's weaknesses are instructive, and hence, criticism may be useful to psychologists, neuroscientists, and philosophers attempting to advance theories of morality, as well as to researchers wishing to invoke concepts such as innateness and modularity more generally. PMID- 21291314 TI - Cortical mechanisms of cognitive control for shifting attention in vision and working memory. AB - Organisms operate within both a perceptual domain of objects and events, and a mnemonic domain of past experiences and future goals. Each domain requires a deliberate selection of task-relevant information, through deployments of external (perceptual) and internal (mnemonic) attention, respectively. Little is known about the control of attention shifts in working memory, or whether voluntary control of attention in these two domains is subserved by a common or by distinct functional networks. We used human fMRI to examine the neural basis of cognitive control while participants shifted attention in vision and in working memory. We found that these acts of control recruit in common a subset of the dorsal fronto-parietal attentional control network, including the medial superior parietal lobule, intraparietal sulcus, and superior frontal sulcus/gyrus. Event-related multivoxel pattern classification reveals, however, that these regions exhibit distinct spatio-temporal patterns of neural activity during internal and external shifts of attention, respectively. These findings constrain theoretical accounts of selection in working memory and perception by showing that populations of neurons in dorsal fronto-parietal network regions exhibit selective tuning for acts of cognitive control in different cognitive domains. PMID- 21291316 TI - Cord blood CD133 cells define an OV6-positive population that can be differentiated in vitro into engraftable bipotent hepatic progenitors. AB - Cell therapy represents the most promising alternative strategy for end-stage liver diseases and hepatic progenitors are the best candidates. We have identified a reservoir of immature hepatic precursors within human cord blood, which can derive engraftable bipotent progenitors. We isolated a stem cell subset CD133+/CD34+/OV6(low) expressing a surface-marker profile consistent with that of fetal liver cells. Upon induction of hepatic commitment by a medium containing cytokines and factors involved in vivo oval-cell activation, a heterogeneous cell population displaying characteristics of functional oval-cell-like bipotent hepatic progenitors was obtained. The cells expressed markers of hepatocytes and cholangiocytes and were highly enriched in OV6, c-Met, c-Kit, and Thy-1. They also displayed liver functional activity as glycogen storage, urea production, albumin secretion, and inducible CyP2B6 activity. When injected into liver damaged severe-combined immunodeficient mice, induced bipotent hepatic progenitors appropriately engrafted livers of recipient animals, where they formed clusters of human-derived cells expressing human leucocyte antigen-class I, Hep-Par1, and OV6 antigens. Human-specific albumin, alpha-fetoprotein, and cytokeratin 19 were also expressed. In transplanted animals, AST serum levels showed a significative reduction with regard to controls. This human model for in vitro progenitor-cell activation may provide a powerful tool for elucidating the pathways and synergies that regulate this complex process and can represent a valuable source, exploitable for liver cell-based therapies and regenerative medicine. PMID- 21291317 TI - Maternal stress retards fetal development in mice with transcriptome-wide impact on gene expression profiles of the limb. AB - The environment of a pregnant mother has a life-long impact on later life of offspring. Maternal stress is known to cause low birth weight and programs several physiological dysfunctions in offspring. However, the direct effects of maternal stress on the developing fetus remain largely unknown. The present study focused on the effect of chronic maternal stress on the developmental program and its molecular mechanisms. Pregnant mice were given 6-hour immobilization stress every day from 8.5 days post coitum. Fetal body weight was significantly decreased by maternal stress throughout development. Importantly, developmental events were retarded in the stressed fetuses. Around embryonic day 13.5 (E13.5), the developmental increment of somite numbers was delayed, although this difference recovered by E15.5. Limb bud formation and regression of interdigital webbing were also retarded by approximately 0.5 days. Subsequently, transcriptomes of developing limbs were analyzed by cDNA microarrays. Approximately, one-tenth of detected transcripts were significantly influenced by maternal stress. Q-PCR AQ analyses further demonstrated that the expression of a subset of limb development-associated genes, including Igf1, Aldh1a2, and Acta1, was changed in the stressed fetus. In conclusion, our findings suggest that maternal stress can retard limb and somite development in mice, with profound impacts on the developmental genetic program of limb. PMID- 21291318 TI - Regulatory interactions of stress and reward on rat forebrain opioidergic and GABAergic circuitry. AB - Palatable food intake reduces stress responses, suggesting that individuals may consume such ?comfort? food as self-medication for stress relief. The mechanism by which palatable foods provide stress relief is not known, but likely lies at the intersection of forebrain reward and stress regulatory circuits. Forebrain opioidergic and gamma-aminobutyric acid ergic signaling is critical for both reward and stress regulation, suggesting that these systems are prime candidates for mediating stress relief by palatable foods. Thus, the present study (1) determines how palatable ?comfort? food alters stress-induced changes in the mRNA expression of inhibitory neurotransmitters in reward and stress neurocircuitry and (2) identifies candidate brain regions that may underlie comfort food mediated stress reduction. We used a model of palatable ?snacking? in combination with a model of chronic variable stress followed by in situ hybridization to determine forebrain levels of pro-opioid and glutamic acid decarboxylase (GAD) mRNA. The data identify regions within the extended amygdala, striatum, and hypothalamus as potential regions for mediating hypothalamic-pituitary-adrenal axis buffering following palatable snacking. Specifically, palatable snacking alone decreased pro-enkephalin-A (ENK) mRNA expression in the anterior bed nucleus of the stria terminalis (BST) and the nucleus accumbens, and decreased GAD65 mRNA in the posterior BST. Chronic stress alone increased ENK mRNA in the hypothalamus, nucleus accumbens, amygdala, and hippocampus; increased dynorphin mRNA in the nucleus accumbens; increased GAD65 mRNA in the anterior hypothalamus and BST; and decreased GAD65 mRNA in the dorsal hypothalamus. Importantly, palatable food intake prevented stress-induced gene expression changes in subregions of the hypothalamus, BST, and nucleus accumbens. Overall, these data suggest that complex interactions exist between brain reward and stress pathways and that palatable snacking can mitigate many of the neurochemical alterations induced by chronic stress. PMID- 21291319 TI - Adrenal gland responses to lipopolysaccharide after stress and ethanol administration in male rats. AB - All forms of stress, including restraint stress (RS) and lipopolysaccharide (LPS) administration, activate the hypothalamic-pituitary-adrenal (HPA) axis. LPS binds to a recognition protein (CD14) and toll-like receptor 2/4 in different cells and tissues, including the adrenal gland, to induce the production of cytokines and cause upregulation of cyclooxygenase and nitric oxide synthase (NOS) enzymes. Acute ethanol exposure activates the HPA axis, but in some conditions prolonged administration can dampen this activation as well as decrease the inflammatory responses to LPS. Therefore, this study was designed to evaluate the adrenal response to a challenge dose of LPS (50 MUg/kg) injected i.p., after submitting male rats to RS, twice a day (2 h each time) for 5 days and/or ethanol administration (3 g/kg) by gavage also for 5 days, twice daily. At the end of the experiment, plasma corticosterone concentrations and adrenal gland content of prostaglandin E (PGE) and NOS activity were measured as stress mediators. The results showed that repetitive ethanol administration attenuated the adrenal stress response to LPS challenge alone and after RS, by preventing the increase in plasma corticosterone concentrations and by decreasing the PGE content and NOS activity in the adrenal gland. Therefore, we conclude that moderate alcohol consumption could attenuate the effects of psychophysical stress and impair an inflammatory response. PMID- 21291320 TI - Genetic polymorphisms of p53 codon 72 and bladder cancer susceptibility: a hospital-based case-control study. AB - BACKGROUND: p53 is one of the most widely investigated molecular markers in bladder cancer and its polymorphisms have been related to individual cancer risks. The objective of this study was to explore the association of p53 codon 72 polymorphism with susceptibility and clinicopathologic characteristics of bladder cancer in a Chinese population. METHODS: We investigated the impact of p53 codon 72 polymorphism in a hospital-based case-control study of bladder cancer. We tested peripheral blood samples from 120 patients with bladder cancer and 120 healthy individuals of similar age and from the same geographical region. The polymorphisms were analyzed using polymerase chain reaction-restriction fragment length polymorphism assay. RESULTS: There was an association between smoking status and bladder cancer (odds ratio [OR] = 2.25; 95% confidence interval [95% CI] = 1.31, 3.87; p = 0.003). Patients with bladder cancer had a significantly lower frequency of Arg/Arg (OR = 0.53; 95% CI = 0.31, 0.89; p = 0.02) and Arg allele (OR = 0.66; 95% CI = 0.45, 0.95; p = 0.03) than controls. Patients with invasive bladder cancer had a significantly lower frequency of Arg/Arg (OR = 0.29; 95% CI = 0.10, 0.88; p = 0.03) than those with superficial bladder cancer. When stratifying by the grade and histological type of bladder cancer, we found no statistical association. CONCLUSIONS: These data suggest that the p53 codon 72 Arg/Arg genotype and Arg allele are associated with a lower risk of bladder cancer in Chinese population. PMID- 21291321 TI - Wolman disease (LIPA p.G87V) genotype frequency in people of Iranian-Jewish ancestry. AB - Wolman disease (WD) is a rare inherited condition caused by lysosomal acid lipase (LAL) deficiency first described in Iranian-Jewish (IJ) children. Newborns with WD are healthy and active, but soon the infant develops symptoms of severe malnutrition in the first few months of life, and often dies before the age of 1 year. Harmful amounts of lipids accumulate in the spleen, liver, bone marrow, intestine, adrenal glands, and lymph nodes. Although worldwide incidence is estimated at 1/350,000 newborns, WD occurs at higher than expected frequency in the IJ community of the Los Angeles area. As a validation study, we analyzed 162 DNA specimens of IJ origin by automated sequencing. For LIPA p.G87V (ggc>gtc, alternative numbering p.G66V), a heterozygous frequency of 5/162 (3.086%) was discovered. Thus, we estimate that as high as 1 in 4200 newborns of IJ couples may be at risk. Additional studies are required to confirm and further validate the higher frequencies seen in our sample pool, and to determine if people of IJ and even possibly Middle Eastern descent are at a higher risk for WD. PMID- 21291322 TI - Assessment of bioactivity of a recombinant chicken interferon-gamma expressed using a baculovirus expression system. AB - The full-length coding sequence of chicken interferon-gamma (ChIFN-gamma) was cloned into a baculovirus nonfusion vector, pFastBacDual, and expressed in Sf21 insect cells. Recombinant ChIFN-gamma (rChIFN-gamma) protein was found to be expressed both intracellularly as well as in the culture supernatants. The affinity-purified rChIFN-gamma contained 14, 17, and 28 kDa proteins, possibly representing both glycosylated and nonglycosylated protein forms of ChIFN-gamma. The bioactivity of rChIFN-gamma was confirmed in vitro by production of nitric oxide in a chicken macrophage cell line (HD11) and antiviral activity against vesicular stomatitis virus in primary chicken embryonic fibroblast cells. Further, HD11 cells stimulated with rChIFN-gamma showed significant upregulation of inducible nitric oxide synthases, IFN-gamma, interleukin-1beta, interleukin 12p35, signal transducers and activators of transcription 1, class II, major histocompatibility complex, transactivator, and major histocompatibility complex II-beta chain (BL-B) transcripts. In conclusion, the present study provides information on the ability of functionally active rChIFN-gamma expressed in a baculovirus system in inducing significant transcriptional upregulation of various immune system-related genes, including those that encode cytokines, antigen-presenting molecules, and transcription factors involved in the major histocompatibility complex and IFN-signaling pathway. PMID- 21291323 TI - A randomized trial of interleukin-2 during withdrawal of antiretroviral treatment. AB - In HIV-infected individuals on antiretroviral treatment with viral suppression, structured treatment interruptions are designed to allow exposure to endogenous HIV antigens and to thereby boost HIV-specific immunity. AIDS Clinical Trials Group A5132 was an exploratory 2-arm randomized trial that evaluated two 4-week treatment interruptions in combination with 2 strategies for administering interleukin-2 (IL-2): 2.0 million international units of IL-2 subcutaneously daily during the final 2 weeks of treatment interruption and the first week of treatment reinitiation (arm A), or 4.5 million international units of IL-2 subcutaneously twice a day during the first 5 days of treatment reinitiation (arm B). Twenty-one subjects with HIV-1 RNA <50 copies/mL and CD4+ T cell counts >=300 (median 615) cells/mm(3) were randomized. The primary endpoint was the viral setpoint measured 11-12 weeks after a third treatment interruption (observed for 7 Arm A and 9 Arm B). The median HIV-1 RNA setpoints were 4.3 and 4.5 log(10) copies/mL for Arm A and Arm B, respectively; there was no evidence of a difference between arms (P = 0.50, rank-sum test, worst rank for unobserved viral setpoint). The current study, the first to evaluate IL-2 during repeated short term treatment interruptions, revealed no evidence for augmentation of HIV immunity. Viral setpoints were similar to historical controls, emphasizing the need for new strategies to enhance HIV-specific immunity. PMID- 21291324 TI - The kinase activity of interleukin-1 receptor-associated kinase 2 is essential for lipopolysaccharide-mediated cytokine and chemokine mRNA stability and translation. AB - Interleukin-1 receptor-associated kinase 2 (IRAK2) has been shown to be essential for lipopolysaccharide (LPS)-mediated posttranscriptional control of cytokine and chemokine production. In this study, we investigated the role of IRAK2 kinase activity in LPS-mediated posttranscriptional control by reconstituting IRAK2 deficient macrophages with either wild-type or kinase-inactive IRAK2. Compared with wild-type IRAK2 (IRAK2-WT) macrophages, kinase-inactive IRAK2 (IRAK2-KD) macrophages show reduced cytokine and chemokine mRNA stability and translation in response to LPS. Further, LPS-treated IRAK2-KD macrophages also show reduced activation of MKK3/6, MNK1, and eIF4E and attenuated toll-like receptor 4-induced tristetraprolin modification and stabilization. Taken together, these results suggest that the kinase activity of IRAK2 is required for the optimal activation of mitogen-activated protein kinase signaling, which regulates cytokine and chemokine production at posttranscriptional levels. PMID- 21291325 TI - Allergen-specific transforming growth factor-beta-producing CD19+CD5+ regulatory B-cell (Br3) responses in human late eczematous allergic reactions to cow's milk. AB - CD19(+)CD5(+) regulatory B cells produce transforming growth factor beta (TGF beta) in both mouse and human B-cell leukemias. In this study, TGF-beta was uniquely produced by normal human regulatory B cells. TGF-beta-producing regulatory B-cell (Br3) responses were characterized through allergic responses to cow's milk. In total, 10 subjects allergic to milk and 13 milk-tolerant subjects were selected following double-blinded, placebo-controlled food challenges. Their peripheral blood mononuclear cells were stimulated in vitro with casein. Following allergen stimulation, the percentage of Br3s among CD5(+) B cells decreased from 11.5% +/- 13.7% to 8.0% +/- 9.6% (P = 0.042, n = 5) in the milk-allergy group and increased from 14.7% +/- 15.6% to 18.9% +/- 20.1% (P = 0.006, n = 7) in the milk-tolerant group. However, the numbers of Br3s increased only in the milk-tolerant group, from 1,954 +/- 1,058 to 4,548 +/- 1,846 per well (P = 0.026), whereas the numbers of Br3s in the milk-allergy group were unchanged [2,596 +/- 823 to 2,777 +/- 802 per well (P = 0.734)]. The numbers of apoptotic events were similar to the numbers of total Br3 responses. The percentage of non TGF-beta-producing CD5(+) B cells with apoptotic changes increased from 13.4% +/- 17.1% to 16.4% +/- 20.3% (P = 0.047, n = 5) in the milk-allergy group and remained unchanged [from 9.9% +/- 11.9% to 9.3% +/- 11.4% (P = 0.099, n = 7)] in the milk-tolerant group. Using carboxyfluorescein succinimidyl ester labeling, we observed that the percentage of proliferating Br3s among CD5(+) B cells was unchanged [from 6.1% +/- 2.8% to 6.4% +/- 2.9% (P = 0.145)] in the milk-allergy group and increased from 6.8% +/- 3.9% to 10.2% +/- 5.3% (P = 0.024) in the milk tolerant group. In conclusion, Br3s proliferated in response to allergen stimulation in the milk-tolerant group and not in the milk-allergy group. TGF beta-producing regulatory B cells (Br3) may be involved in allergy tolerance by negatively regulating the immune system with TGF-beta, and this negative regulation may be controlled by apoptosis. PMID- 21291326 TI - Resident perceptions of palliative care training in the emergency department. AB - OBJECTIVES: To characterize the level of formal training and perceived educational needs in palliative care of emergency medicine (EM) residents. METHODS: This descriptive study used a 16-question survey administered at weekly resident didactic sessions in 2008 to EM residency programs in New York City. Survey items asked residents to: (1) respond to Likert-scaled statements about the role of palliative care in the emergency department (ED); (2) quantify their level of formal training and personal comfort in symptom management, discussion of bad news and prognosis, legal issues, and withdrawing/withholding therapy; and (3) express their interest in future palliative care training. RESULTS: Of 228 total residents, 159 (70%) completed the survey. Of those surveyed, 50% completed some palliative care training before residency; 71.1% agreed or strongly agreed that palliative care was an important competence for an EM physician. However, only 24.3% reported having a "clear idea of the role of palliative care in EM." The highest self-reported level of formal training was in the area of advanced directives or legal issues at the end of life; the lowest levels were in areas of patient management at the end of life. The highest level of self-reported comfort was in giving bad news and the lowest was in withholding/withdrawing therapy. A slight majority of residents (54%) showed positive interest in receiving future training in palliative care. CONCLUSIONS: New York City EM residents reported palliative care as an important competency for emergency medicine physicians, yet also reported low levels of formal training in palliative care. The majority of residents surveyed favored additional training. PMID- 21291327 TI - Listening to the voiceless patient: case reports in assisted communication in the intensive care unit. AB - Communication problems experienced by nonspeaking, critically ill patients in the Intensive Care Unit (ICU) have serious implications for the physical and psychological well-being of patients and the quality of their care. These problems are most profound for those with prolonged critical illnesses who are at the highest risk of dying. Recently, speech language pathologist (SLP) services have been used to provide augmentative and alternative communication (AAC) assistance to this vulnerable group of patients, their caregivers, and medical staff. Here we present three clinical cases that illustrate the application of AAC strategies across different levels of illness severity and communication impairment for nonspeaking patients in the ICU. Both high-tech communication devices with voice output and low-tech options were used for each patient according to their motor and cognitive abilities. To accommodate fluctuations in patient status and communication needs, multiple AAC strategies were integrated into the communication repertoire and tailored for each case. Medical personnel involved in these cases attributed enhanced communication efficiency, improved ventilator weaning trials, and increased patient engagement to the AAC techniques. This approach has the potential to improve symptom communication and to ease suffering for seriously ill ICU patients with speech limitations. PMID- 21291328 TI - Naproxen test for neoplastic fever may reduce suffering. AB - Abstract Neoplastic fever (NF) is a paraneoplastic syndrome that is encountered in a significant proportion of patients with cancer. We present the case of a 37 year old female with matastatic renal transitional cell carcinoma. She was hospitalized with fever, constitutional symptoms, and worsening performance status. There was no identifiable infection source. In the third week of hospitalization, she was started on naproxen, resulting in complete lysis of fever, control of constitutional symptoms and improvement in performance status. She was discharged the next day and died of advanced disease within two months. Workup of NF can lead to unnecessary and prolonged hospitalization in patients near the end of their life, resulting in significant suffering. While it is important to rule out infection, an early trial of naproxen is inexpensive and, in patients who can tolerate NSAIDs, may provide good control for NF. PMID- 21291329 TI - Applying motivational interviewing techniques to palliative care communication. AB - Palliative care relies heavily on communication. Although some guidelines do address difficult communication, less is known about how to handle conversations with patients who express ambivalence or resistance to such care. Clinicians also struggle with how to support patient autonomy when they disagree with patient choices. Motivational Interviewing (MI) techniques may help address these responses. Specifically, MI techniques such as reflective statements and summarizing can help reduce a patient's resistance, resolve patient ambivalence, and support patient autonomy. Not all the MI techniques are applicable, however, in part because palliative care clinicians do not guide patients to make particular choices but, instead, help patients make choices that are consistent with patient values. Some elements from MI can be used to improve the quality and efficacy of palliative care conversations. PMID- 21291330 TI - Lipoprotein-associated phospholipase A2 activity predicts progression of subclinical coronary atherosclerosis. AB - BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a lipoprotein associated enzyme that cleaves oxidized phosphatidylcholines, generating pro atherosclerotic lysophosphatidylcholine and oxidized free fatty acids. Lp-PLA2 is independently associated with cardiovascular disease (CVD) in a variety of populations. Coronary calcium is a measure of subclinical CVD, and progression of coronary calcification predicts future CVD events. In type 1 diabetes there is an increase in coronary calcium and CVD despite a favorable lipid profile. Levels of Lp-PLA2 in type 1 diabetes are not known, nor is the relationship between Lp-PLA2 and progression of coronary calcification. METHODS: The Coronary Artery Calcification in Type 1 Diabetes study measured coronary calcium by electron-beam computed tomography twice over a 2.6 +/- 0.3-year interval. Lp-PLA2 mass and activity were measured at baseline (n = 1,097 subjects, 506 with and 591 without type 1 diabetes). RESULTS: In type 1 diabetes Lp-PLA2 mass was marginally higher (285 +/- 79 vs. 278 +/- 78 ng/mL, P = 0.1), and Lp-PLA2 activity was significantly lower (137 +/- 30 vs. 146 +/- 36 nmol/min/mL, P < 0.0001) than in those without diabetes. There was a greater proportion of those with progression of coronary calcification in type 1 diabetes compared with those without diabetes (24% vs. 10%, P < 0.0001). Lp-PLA2 activity was independently associated with progression of coronary calcification in multivariate analysis (4th quartile verses bottom three quartiles, odds ratio = 1.77 [1.08-2.91], P = 0.02). LpPLA2 mass was not significantly associated with progression of coronary calcification in this cohort (P = 0.09). CONCLUSIONS: Lp-PLA2 activity predicts progression of subclinical atherosclerosis in individuals with and without type 1 diabetes. PMID- 21291331 TI - Performance of a new reusable insulin pen. AB - BACKGROUND: The aim of this multinational (Canada, France, Germany, United Kingdom, and United States), task and interview-based study was to compare the ease of use and performance of the ClikSTAR(r) (sanofi-aventis, Paris, France) insulin pen with other commonly used reusable pens based on participant and interviewer assessments. METHODS: People with diabetes (n = 654) were asked to demonstrate four pens consecutively-ClikSTAR, Lilly Luxura (r) (Eli Lilly, Indianapolis, IN), and NovoPen (r) 3 and 4 (Novo Nordisk, Bagsvaerd, Denmark) according to the respective instruction manuals. The endpoint was assessed by a rating from the participants and the interviewer. While the participants focused on the pen's ease of use, the interviewer considered the participants' difficulty in preparing and delivering a 40-unit dose and their requirement for help. RESULTS: Twenty percent of U.S. participants and 24% of participants from the other countries had type 1 diabetes. Approximately 50% of participants in each group had prior insulin pen experience. A higher proportion of participants, including those with dexterity or visual impairments, reported ClikSTAR as easier to use than other pens (P < 0.05). Participants using ClikSTAR did not experience any difficulty in completing the tasks. The proportion of participants not requiring help in completing the tasks with ClikSTAR was rated as numerically higher than, or similar to, that observed with Lilly Luxura or NovoPen 3 or 4 (75%, 74%, 62%, and 65%, respectively). According to participants, ClikSTAR and NovoPen 4 emerged as the most highly rated pens. CONCLUSIONS: In comparison with other pens, ClikSTAR was significantly easier to use, which, when taken together with overall performance, meets the need of people with diabetes. PMID- 21291332 TI - The ability of different areas of the skin to absorb heat from a locally applied heat source: the impact of diabetes. AB - BACKGROUND: When heat is applied to the skin, heat is conducted away because of the latent heat transfer properties of the skin and an increase in skin circulation, but little attention has been paid to the heat transfer properties of skin in different areas of the body and in people with diabetes. research design: Thirty subjects in the age range of 20-75 years had a thermode (44 degrees C) applied to the skin of their arm, leg, foot, and back for 6 min to assess the heat transfer characteristics of skin in these four areas of the body. Skin blood flow and skin temperature were monitored over the 6-min period. RESULTS: For the younger subjects, blood flow was not statistically different in response to heat in three areas of the body, starting at less than 200 flux measured by a laser Doppler imager and ending at approximately 1,200 flux after heat exposure. The foot had higher resting blood flow and higher blood flow in response to heat. Temperature and the rate of rise of temperature were also not different in any of the areas. The heat added to raise temperature, however, varied by body region. The arm required the least, whereas the leg and foot required the most. For the older group and subjects with diabetes, the heat required for any region of the body was much less to achieve the same increase in skin temperature, and blood flows were also much less; the subjects with diabetes showed the least blood flow and required the fewest calories to heat the skin. Whereas the foot required the greatest number of calories to heat the tissue in younger and older subjects, in subjects with diabetes, the foot took proportionally fewer calories. CONCLUSION: Thus, specific areas of the body are damaged more by diabetes than other areas. PMID- 21291333 TI - Comparable efficacy and safety of insulin glulisine and insulin lispro when given as part of a Basal-bolus insulin regimen in a 26-week trial in pediatric patients with type 1 diabetes. AB - BACKGROUND: We compared the efficacy and safety of insulin glulisine with insulin lispro as part of a basal-bolus regimen in children and adolescents with type 1 diabetes. METHODS: Overall, 572 children and adolescents (4-17 years old) using insulin glargine or neutral protamine Hagedorn insulin as basal insulin were enrolled in a 26-week, multicenter, open, centrally randomized, parallel-group, noninferiority study. Subjects were randomized to receive glulisine (n = 277) or lispro (n= 295) 0-15 min premeal. RESULTS: Baseline-to-endpoint hemoglobin A1c changes were similar between the two insulins: adjusted mean change (glulisine vs. lispro), 0.10% versus 0.16%; between-treatment difference (glulisine-lispro), &minsu;0.06, 95% confidence interval (-0.24; 0.12); and prespecified noninferiority margin, 0.4%. Overall, for all age groups together, the percentage of patients achieving American Diabetes Association age-specific A1c targets at endpoint was significantly higher (P = 0.039) with glulisine (38.4%) versus lispro (32.0%). From Month 4 to endpoint, both "all" and "severe" symptomatic hypoglycemia rates were similar (3.10 vs. 2.91 and 0.06 vs. 0.07 events/patient month, respectively). Frequency and type of adverse events, serious adverse events, or hypoglycemia reported as serious adverse events were similar between both groups. CONCLUSIONS: Glulisine was as effective as lispro in baseline-to endpoint A1c change, and both treatments were similarly well tolerated. PMID- 21291334 TI - Calculating the mean amplitude of glycemic excursion from continuous glucose monitoring data: an automated algorithm. AB - BACKGROUND: Glycemic variability is currently under scrutiny as a possible predictor of the complications of diabetes. The manual process for estimating a now classical measure of glycemic variability, the mean amplitude of glycemic excursion (MAGE), is both tedious and prone to error, and there is a special need for an automated method to calculate the MAGE from continuous glucose monitoring (CGM) data. METHODS: An automated algorithm for identifying the peaks and nadirs corresponding to the glycemic excursions required for the MAGE calculation has been developed. The algorithm takes a column of timed glucose measurements and generates a plot joining the peaks and nadirs required for estimating the MAGE. It returns estimates of the MAGE for both upward and downward excursions, together with several other indices of glycemic variability. RESULTS: Details of the application of the algorithm to CGM data collected over a 48-h period are provided, together with graphical illustrations of the intermediate stages in identifying the peaks and nadirs required for the MAGE. Application of the algorithm to 104 CGM datasets (92 from children with diabetes and 12 from controls) generated plots that, on visual inspection, were all found to have identified the peaks, nadirs, and excursions correctly. CONCLUSIONS: The proposed algorithm eliminates the tedium and/or errors of manually identifying and measuring countable excursions in CGM data in order to estimate the MAGE. It can also be used to calculate the MAGE from "sparse" blood glucose measurements, such as those collected in home blood glucose monitoring. PMID- 21291335 TI - Comparing the efficacy of alpha-glucosidase inhibitors in suppressing postprandial hyperglycemia using continuous glucose monitoring: a pilot study-the MAJOR study. AB - BACKGROUND: This study aimed to compare glucose variability in patients given the alpha-glucosidase inhibitors miglitol and acarbose using continuous glucose monitoring (CGM). METHODS: Ten type 2 diabetes patients were hospitalized for 4 days, and their glucose levels were measured using CGM. Patients were given miglitol (50 mg) or acarbose (100 mg) before each meal on Day 2, and vice versa on Day 3, in a randomized crossover design. The patients had three identical test meals on Days 2 and 3. The CGM data were used to compare each parameter for glycemic variability after each of the three meals. RESULTS: No significant differences were observed between miglitol treatment or acarbose treatment in regard to the range of increase in glucose levels from baseline to peak, time to peak postprandial glucose levels from the preprandial period, and area under the curve for glycemic variability from the preprandial period to 3 h after each meal. However, the range of increase in glucose levels at 30 min (0.4 vs. 30.7 mg/dL, P < 0.0001) and 60 min (32.8 vs. 67.5 mg/dL, P <0.0001) after lunch and 30, 60, and 90 min after dinner (3.3 vs. 22.2 mg/dL, P = 0.0249; 36.6 vs. 67.5 mg/dL, P < 0.0001; and 60.5 vs. 81.6 mg/dL, P = 0.0073, respectively) was significantly smaller in miglitol treatment compared with acarbose treatment. CONCLUSIONS: In a pilot study with a crossover design in 10 type 2 diabetes patients, it was shown that although there was no significant difference in glucose variability with miglitol or acarbose after a fat-rich diet, glucose increases was significantly reduced with miglitol after a meal comprising typical Japanese diet 60-90 min postprandially. PMID- 21291336 TI - Impact of an alerting clinical decision support system for glucose control on protocol compliance and glycemic control in the intensive cardiac care unit. AB - BACKGROUND: Glycemic control in patients with acute cardiac conditions is a clinical challenge but may substantially improve patient outcome. The aim of the current study was to evaluate the effect of implementing an automated version of an existing insulin protocol for glucose regulation in the Intensive Cardiac Care Unit (ICCU) on compliance with the protocol and achievement of glycemic targets. METHODS: During an 11-month period, data of 667 patients with two or more glucose measurements were evaluated, 425 before and 242 after implementation of the clinical decision support system (CDSS) for glucose control at the Erasmus Medical Center ICCU (Rotterdam, The Netherlands). RESULTS: After implementation, compliance with the advised measurement time increased from 40% to 52% (P < 0.001), and compliance regarding insulin dosage increased from 49% to 61% (P < 0.001). Also, more patients had a mean glucose level within the target range of 81-126 mg/dL (31% vs. 43% [P = 0.01]). Monthly evaluation identified reasons for protocol noncompliance (e.g., nutritional status and time of day) and will be used to improve the existing CDSS. CONCLUSIONS: The CDSS implementation of an insulin protocol in an ICCU improved compliance, identified targets for further improvement of the protocol, and resulted in improved glucose regulation after implementation. PMID- 21291337 TI - The use of a computer program to calculate the mean amplitude of glycemic excursions. AB - BACKGROUND: The mean amplitude of glycemic excursions (MAGE), traditionally estimated with a graphical approach, is often used to characterize glycemic variability. Here, we tested a proposed software program for calculating MAGE. METHODS: Development and testing of the software was based on retrospective analyses of 72-h continuous glucose monitoring profile data collected during two different clinical studies involving 474 outpatients (458 with type 2 and 16 with type 1 diabetes) in three cohorts (two type 2 diabetes and one type 1 diabetes), using the CGMS(r) GoldTM (Medtronic MiniMed, Northridge, CA). Correlation analyses and a Bland-Altman procedure were used to compare the results of MAGE calculations performed using the developed computer program (MAGE(C)) and the original method (MAGE(O)). RESULTS: Close linear correlations between MAGE(C) and MAGE(O) were documented in the two type 2 and the type 1 diabetes cohorts (r = 0.954, 0.962, and 0.951, respectively; P < 0.00001 for all), as was the absence of any systematic error between the two calculation methods. Comparison of the two indices revealed no within-group differences but did show differences among the various antihyperglycemic treatments (P < 0.0001). In each of the study cohorts, MAGE(C) correlated strongly with the SD (r = 0.914-0.943), moderately with the mean of daily differences (r = 0.688-0.757), and weakly with glycosylated hemoglobin A1c and mean sensor glucose (r= 0.285 and r = 0.473, respectively). CONCLUSIONS: The proposed computerized calculation of MAGE is a practicable method that may provide an efficient tool for assessing glycemic variability. PMID- 21291338 TI - Identification of lily pollen 14-3-3 isoforms and their subcellular and time dependent expression profile. AB - 14-3-3 proteins are major regulators in plant development and physiology including primary metabolism and signal transduction pathways, typically via a phosphorylation-dependent interaction with a target protein. Four full-length 14 3-3 isoforms were identified in pollen grains of Lilium longiflorum by screening of a cDNA library and RACE (rapid amplification of cDNA ends)-PCR. Mass spectrometry analysis of partially purified 14-3-3s confirmed the presence of the four isoforms but also indicated the presence of additional, less abundant 14-3-3 isoforms in lily pollen. Separation of partially purified 14-3-3 proteins by two dimensional gel electrophoresis resulted in nine spots that mainly contained the four major 14-3-3 isoforms. In a first step to examine putative physiological roles of specific 14-3-3 isoforms, their subcellular expression profile during pollen germination and tube growth was monitored using a characterized set of antibodies against 14-3-3 proteins with distinct crossreactivity. The abundance profile of 14-3-3 proteins associated with the cytosol, endomembranes (tonoplast, endoplasmic reticulum, Golgi, mitochondria) and plasma membrane showed high spatial-temporal dynamics. This indicates different targets of 14-3-3 proteins at different organelles and time points during pollen germination and growth. PMID- 21291339 TI - Measuring elderly dysphagic patients' performance in eating--a review. AB - PURPOSE: This review aims to identify psychometrically robust assessment tools suitable for measuring elderly dysphagic patients' performance in eating for use in clinical practice and research. METHOD: Electronic databases, related citations and references were searched to identify assessment tools integrating the complexity of the eating process. Papers were selected according to criteria defined a priori. Data were extracted regarding characteristics of the assessment tools and the evidence of reliability, validity and responsiveness. Quality appraisal was undertaken using developed criteria concerning the study design, the statistics used for the psychometric evaluation and the reported values. RESULTS: Eight of fourteen identified assessment tools met the inclusion criteria. Three assessment tools were specific to dementia, two were specific to stroke and three targeted a range of neurological and geriatric conditions. The rigor of the assessment tools' psychometric properties varied from no evidence available to excellent evidence. Only two assessment tools were rated adequate to excellent. CONCLUSION: 'The Minimal Eating Observation Form-Version II' to be used for screening and 'The McGill Ingestive Skills Assessment' to be used for treatment planning and monitoring appeared to be psychometrically robust for clinical practice and research. However, further research on their psychometric properties is needed. PMID- 21291340 TI - Community-based rehabilitation programme as a model for task-shifting. AB - This article explores some of the implications of a non-governmental organisation (NGO) initiated community-based rehabilitation (CBR) programme, for HIV-related task-shifting programmes which have been recommended by the World Health Organisation (WHO) as an important aspect of HIV prevention, treatment and care programmes. The CBR programme is run by multi-skilled community rehabilitation facilitators (CRFs) in a low income, rural context in KwaZulu-Natal, South Africa, and explicitly recognises the multiple facets of disability. As such, the programme focuses on both the physical and social aspects of living with disabilities. A qualitative approach was used to conduct this study, and semi structured interviews were conducted with beneficiaries of the programme (n = 35), home and community-based care givers (HCBCs) (n = 13), and managers (n = 2). A focus group discussion was conducted with CRFs (n = 5). We found that the CBR programme successfully delivered rehabilitation services at a community level and that multi-skilled CRFs are an effective means of implementing CBR programmes in low-income rural areas. The developmental focus of the programme created a range of benefits for people with disabilities, including: physical rehabilitation, emotional support and counselling, access to grants, social inclusion and accessing assistive devices. Central to the programme's success was the maintenance of relationships and partnerships at different levels in the community, these included relationships between HCBCs and CRFs, between CRFs and therapists, and between the NGO and the various participants in the programme. However, the NGO struggled to maintain a partnership with the relevant government departments and this had important implications for the programmes sustainability. In conclusion, we argue that this programme's use of multi skilled mid-level workers who have undergone effective training programmes in CBR demonstrates that a wide range of rehabilitation activities can be effectively undertaken at a community level, and that this programme provides an important example of how the WHO's task-shifting guidelines for HIV treatment, care and prevention can be implemented. PMID- 21291341 TI - In silico site of metabolism prediction of cytochrome P450-mediated biotransformations. AB - INTRODUCTION: Preclinical research involves the in vitro monitoring of metabolic stability to deliver compounds with improved ADME profiles. Prediction of the metabolically vulnerable points can substantially help in analyzing CYP-mediated metabolism data and support optimization efforts in drug discovery programs. Moreover, fast and reliable in silico predictions could accelerate the characterization of in vitro/in vivo metabolites. AREAS COVERED: This paper reviews in silico methods available for CYP-mediated site of metabolism (SOM) prediction. Comprehensive and practical knowledge in this field can guide the identification of best practice and may inspire ideas for the development of novel approaches. EXPERT OPINION: Comparison of the efficacy of SOM prediction methodologies revealed the general dependency on the studied isoform and substrate set. Increasing knowledge on P450 X-ray structures, on biotransformations and on the mechanistic details of the catalytic cycle revolutionized the prediction of SOM. Although no ultimate solution exits, combined methods covering both steric and electronic effects are preferred on most of the pharmaceutically relevant isoforms. PMID- 21291342 TI - Severe fetal valproate syndrome: combination of complex cardiac defect, multicystic dysplastic kidney, and trigonocephaly. AB - Valproic acid (VPA) is a teratogenic drug used in pregnant women for the treatment of epilepsy and mood disorders. Fetal valproate syndrome (FVS) is characterized by a number of abnormalities associated with VPA exposure in utero including neural tube defects, congenital heart defects, limb defects, genitourinary defects, brain, eye and respiratory anomalies, and abdominal wall defects. Complex cardiac defect and trigonocephaly have rarely been reported and multicystic dysplastic kidney has never been detected in FVS. We here report a female infant who was born to a mother with a history of low-dose VPA monotherapy (250 mg/day) during pregnancy and who had presented with a combination of unilateral multicystic dysplastic kidney, multicomplex cardiac defect including severe coarctation of aorta, Ebstein anomaly, secundum atrial septal defect, mesocardia along with trigonocephaly due to metopic craniosynostosis, typical facial appearance and limb defects. To our knowledge, this is the first case presented with multicystic dysplastic kidney, complex cardiac defect, trigonocephaly and other limb and facial defects because of exposure to very low dose VPA monotherapy (250 mg/day) in utero. We conclude that VPA must be used very cautiously in pregnant women even as monotherapy and in low doses to prevent major congenital defects. PMID- 21291343 TI - An anthropological analysis of the perspectives of Somali women in the West and their obstetric care providers on caesarean birth. AB - We explored the perceptions of 39 Somali women and 62 obstetric care providers in London in relation to caesarean birth, as borne out of a paradox we recognised from evidence-based information about the Somali group. Socio-cultural factors potentially leading to adverse obstetric outcome were identified using in-depth and focus group interviews with semi-structured, open-ended questions. A cultural anthropology model, the emic/etic model, was used for analysis. Somali women expressed fear and anxiety throughout the pregnancy and identified strategies to avoid caesarean section (CS). There was widespread, yet anecdotal, awareness among obstetric care providers about negative Somali attitudes. Caesarean avoidance and refusal were expressed as being highly stressful among providers, but also as being the responsibility of the women and families. For women, avoiding or refusing caesarean was based on a rational choice to avoid death and coping with adverse outcome relied on fatalistic attitudes. Motivation for the development of preventive actions among both groups was not described, which lends weight to the vast distinction and lack of correspondence in identified perspectives between Somali women and UK obstetric providers. Early booking and identification of women likely to avoid caesarean is proposed, as is the development of preventive strategies to address CS avoidance. PMID- 21291344 TI - Re-evaluation of the role of image guidance in minimally invasive pituitary surgery: benefits and outcomes. AB - OBJECTIVE: To evaluate the utility of performing endonasal transsphenoidal pituitary surgery with computer-based neuronavigation, and to examine the efficacy of computer-based neuronavigation compared to fluoroscopy. PATIENTS: We conducted a retrospective review of patients who underwent pituitary surgery between September 1998 and September 2008. Of 120 consecutive patients, 70 met inclusion criteria and were fully examined. The inclusion criteria were that patients had undergone endonasal transsphenoidal pituitary surgery performed by the same neurosurgeon at the same institution. Nineteen of the patients were treated using intraoperative fluoroscopy and 48 were treated using the BrainLAB VectorVision neuronavigation system. Preparation times, surgical times and associated complications were analyzed. RESULTS: Our results indicate that image guidance reduces the overall operating room time and complication rate. Average preparation time for fluoroscopy and computer-based neuronavigation was 70.3 and 67.3 min, respectively (p = 0.3299). Average surgical time with fluoroscopy and BrainLAB was 131 and 107.9 min, respectively (p = 0.0079). The results were also analyzed with regard to other parameters such as associated complications, age and diagnoses. CONCLUSION: Computer guided endoscopic endonasal transsphenoidal surgery provides a three-dimensional image to the surgeon, allowing for greater visual accuracy and surgical precision and a faster procedure without radiation exposure or the need for additional personnel. PMID- 21291345 TI - Reliability of frames of reference used for tibial component rotation in total knee arthroplasty. AB - This study evaluated seven different frames of reference used for tibial component rotation in total knee arthroplasty (TKA) to determine which ones showed good reliability between bone specimens. An optoelectronic system based around a computer-assisted surgical navigation system was used to measure and locate 34 individual anatomical landmarks on 40 tibias. Each particular frame of reference was reconstructed from a group of data points taken from the surface of each bone. The transverse axis was used as the baseline to which the other axes were compared, and the differences in angular rotation between the other six reference frames and the transverse axis were calculated. There was high variability in the tibial rotational alignment associated with all frames of reference. Of the references widely used in current TKA procedures, the tibial tuberosity axis and the anterior condylar axis had lower standard deviations (6.1 degrees and 7.3 degrees , respectively) than the transmalleolar axis and the posterior condylar axis (9.3 degrees for both). In conclusion, we found high variability in the frames of reference used for tibial rotation alignment. However, the anterior condylar axis and transverse axis may warrant further tests with the use of navigation. Combining different frames of reference such as the tibial tuberosity axis, anterior condylar axis and transverse axis may reduce the range of errors found in all of these measurements. PMID- 21291346 TI - Sitagliptin and metformin--novel combination therapy. AB - INTRODUCTION: The historical background of the discovery of incretins became of particular interest when insulin response was found to be much more pronounced when glucose was given orally, rather than intravenously. The robust insulin secretion seen in response to oral glucose, as opposed to intravenous glucose, is due to incretin hormones. Since the discovery of incretins, the significance of sitagliptin and metformin combination therapy has become an essential strategy in combating diabetes. The use of combination therapy such as sitagliptin and metformin in achieving the desired level of glycemia in patients with diabetes is very important and is an additional armamentarium in the fight against diabetes. AREAS COVERED: This article reviews the history of incretins, the pathophysiology of diabetes and the use of sitagliptin and metformin combination therapy. EXPERT OPINION: Achieving optimum blood glucose control is crucial in avoiding or at least delaying the progression of complications related to diabetes. Recently, it has become very clear that treatment with a single antidiabetic agent is often not successful in achieving glycemic control. Thus, many patients with type 2 diabetes require multiple combinations. Using sitagliptin and metformin combination therapy is an ideal strategy in the treatment of diabetes. PMID- 21291347 TI - Targets of chymase inhibitors. AB - INTRODUCTION: Chymase converts angiotensin I to angiotensin II and it can also convert precursors of TGF-beta and MMP-9 to their active forms. Therefore, diseases related to angiotensin II TGF-beta, and MMP-9 could potentially be treated with chymase inhibitors. AREAS COVERED: This review discusses the appropriate targets and safety of chymase inhibitors. Six diseases with notable mortality or morbidity as targets of chymase inhibitors are focused on; abdominal aortic aneurysms (AAAs), nephropathy and retinopathy, cardiomyopathy, nonalcoholic steatohepatitis (NASH), organ fibrosis and intestinal diseases. EXPERT OPINION: If chymase inhibition proves to be a useful strategy for the attenuation of angiotensin II, TGF-beta and MMP-9 in vivo, the application of chymase inhibitors is likely to become widespread in various diseases in the clinical setting. Chymase inhibitors are anticipated not to interfere with the homeostasis of resting tissues, that is, those not affected by injury or inflammation. PMID- 21291348 TI - The pharmacotherapy of overactive bladder. AB - Urinary urgency is the key symptom of overactive bladder (OAB) and often forces patients to modify their lifestyle or daily routine. The impact of OAB on quality of life is significant. Antimuscarinics, an established pharmaceutical treatment for OAB, were originally thought to affect parasympathetic efferents to the bladder; however, there is increasing evidence of an important effect on afferent pathways. Dry mouth and constipation are the most common undesirable events resulting from the use of these agents. Imipramine, a tricyclic antidepressant, is a useful drug for the treatment of OAB, especially when combined with antimuscarinic agents, although this has not been adequately assessed as yet. One result of research in this field is the upcoming introduction of beta-3 agonists in the treatment of OAB. Botulinum toxin, a minimally invasive medical treatment, represents a new era for the treatment of refractory OAB. Despite the fact that this is currently an off-label treatment, it actually represents a widespread alternative method of therapy when conventional medical treatment fails. Pharmacotherapy will continue to play a major role in the treatment of OAB in the future. PMID- 21291349 TI - Highlight: dipeptidyl peptidase 4 and related proteins. PMID- 21291350 TI - Crucial roles of NGF in dorsal horn plasticity in partially deafferentated cats. AB - Though exogenous nerve growth factor (NGF) has been implicated in spinal cord plasticity, whether endogenous NGF plays a crucial role has not been established in vivo. This study investigated first the role of endogenous NGF in spinal dorsal horn (DH) plasticity following removal of L1-L5 and L7-S2 dorsal root ganglions (DRGs) in cats. Co-culture of chick embryo DRG with DH condition media, protein band fishing by cells as well as western blot showed that NGF could promote neurite growth in vitro. Immunohistochemistry and in situ hybridization technique revealed an increase in the NGF and NGF mRNA immunoreactive cells in the DH after partial deafferentation. Lastly, after blocking with NGF antibody, choleragen subunit B horseradish peroxidase (CB-HRP) tracing showed a reduction in the neuronal sprouting observed in the DH. Our results demonstrated that in the cat, endogenous NGF plays a crucial role in DH plasticity after partial deafferentation. PMID- 21291351 TI - Effect of exercise on bone and articular cartilage in heterozygous manganese superoxide dismutase (SOD2) deficient mice. AB - Reactive oxygen species (ROS) are involved in both bone and cartilage physiology and play an important role in the pathogenesis of osteoporosis and osteoarthritis. The present study investigated the effect of running exercise on bone and cartilage in heterozygous manganese superoxide dismutase (SOD2) deficient mice. It was hypothesized that exercise might induce an increased production of ROS in these tissues. Heterozygous SOD2-deficient mice should exhibit an impaired capability to compensate, resulting in an increased oxidative stress in cartilage and bone. Thirteen female wild type and 20 SOD2(+/-) mice (aged 16 weeks) were randomly assigned to a non-active wild type (SOD2(+/+)Con, n = 7), a trained wild type (SOD2(+/+)Run, n = 6), a non-active SOD2(+/-) (SOD2(+/ )Con, n = 9) and a trained SOD2(+/-) (SOD2(+/-)Run, n = 11) group. Training groups underwent running exercise on a treadmill for 8 weeks. In SOD2(+/-) mice elevated levels of 15-F(2t)-isoprostane and nitrotyrosine were detected in bone and articular cartilage compared to wild type littermates. In osteocytes the elevated levels of these molecules were found to be reduced after exercise while in chondrocytes they were increased by aerobic running exercise. The observed changes in oxidative and nitrosative stress did neither affect morphological, structural nor mechanical properties of both tissues. These results demonstrate that exercise might protect bone against oxidative stress in heterozygous SOD2 deficient mice. PMID- 21291352 TI - 8-Hydroxyguanine levels and repair capacity during mouse embryonic stem cell differentiation. AB - To evaluate the defence capacities of embryonic stem (ES) cells against gene impairment, this study measured the levels of 8-hydroxyguanine (8-OH-Gua), a well known marker of oxidative stress in DNA, and its repair capacity during differentiation. Undifferentiated ES cells (EB3) were cultured without leukaemia inhibitory factor (LIF) for 0, 4 and 7 days and are referred to as ES-D0, ES-D4 and ES-D7, respectively. These three cell lines were treated with 300 MUM hydrogen peroxide (H(2)O(2)) for 48 and 72 h. After treatment, the amounts of 8 OH-Gua in the cells were determined by the high-performance liquid chromatography (HPLC)-electrochemical detector (ECD) method. The levels of 8-OH-Gua in ES-D7 treated with H(2)O(2) were higher than those in ES-D0 and ES-D4, suggesting that the DNA in the undifferentiated cells was protected against gene impairment, as compared to that in the differentiated cells. To examine the repair capacity for 8-OH-Gua, this study analysed the expression of 8-OH-Gua repair-associated genes, 8-oxoguanine DNA glycosylase 1 (OGG1), MutY homolog (MUTYH) and Mut T homolog 1 (MTH1), in ES-D0, ES-D4 and ES-D7. The mRNA levels of MUTYH and MTH1 showed no significant change, whereas OGG1 mRNA was significantly decreased in ES-D7 treated with H(2)O(2). Moreover, it was observed that ES-D7 treated with H(2)O(2) readily underwent apoptosis, in comparison to its undifferentiated counterparts, ES-D0 and ES-D4. Taken together, ES cells are more resistant to DNA oxidative stresses than differentiated cells. PMID- 21291353 TI - Alrp, a survival factor that controls the apoptotic process of regenerating liver after partial hepatectomy in rats. AB - Augmenter of Liver Regeneration (Alrp) enhances, through unknown mechanism/s, hepatocyte proliferation only when administered to partially hepatectomized (PH) rats. Liver resection, besides stimulating hepatocyte proliferation, induces reactive oxygen species (ROS), triggering apoptosis. To clarify the role of Alrp in the process of liver regeneration, hepatocyte proliferation, apoptosis, ROS induced parameters and morphological findings of regenerating liver were studied from PH rats Alrp-treated for 72 h after the surgery. The same parameters, evaluated on regenerating liver from albumin-treated PH rats, were used as control. The results demonstrated that Alrp administration induces the anti apoptotic gene expression, inhibits hepatocyte apoptosis and reduces ROS-induced cell damage. These and similar data from in vitro studies and the presence of 'Alrp homologous proteins' in viruses as well as in mammals (i) allow to hypothesize that Alrp activity/ies may not be exclusive for regenerating liver and (ii) suggest the use of Alrp in the treatment of oxidative stress-related diseases. PMID- 21291354 TI - Interactions of nanoparticles with plasma proteins: implication on clearance and toxicity of drug delivery systems. AB - INTRODUCTION: Intravenously injected nanoparticles, like any other foreign pathogen that enters the body, encounter multiple lines of defense intended to neutralize and eliminate the invading substance. Adsorption of plasma proteins on the nanoparticle surface is the first barrier of defense, which could lead to physical changes in the formulation, such as aggregation and charge neutralization, biochemical activation of defense cascades, and trigger elimination by multiple types of phagocytic cell. AREAS COVERED: In this review, recent knowledge on the mechanisms that govern the interactions of nanoparticles (micelles, liposomes, polymeric and inorganic nanoparticles) with plasma proteins is discussed. In particular, the role of the nanoparticle surface properties and protective polymer coating in these interactions is described. The mechanisms of protein adsorption on different nanoparticles are analyzed and the implications on the clearance, toxicity and efficacy of drug delivery are discussed. The review provides readers with the biological insight into the plasma/blood interactions of nanoparticles. EXPERT OPINION: The immune recognition of nanoparticles can seriously affect the drug delivery efficacy and toxicity. There is at present not enough knowledge on the mechanisms that dictate the nanoparticle immune recognition and stability in the biological milieu. Understanding the mechanisms of recognition will become an important part of nanoparticle design. PMID- 21291355 TI - Optimization of lentiviral vectors generation for biomedical and clinical research purposes: contemporary trends in technology development and applications. AB - Classical non-viral methods of gene transfer, such as chemical transfection, have met with limited success of instillation of genetic material into non proliferating cells in vitro. Among the different kinds of viral vectors, Lentiviral vectors (LVs) have emerged as robust and versatile tool for ex vivo and in vivo gene delivery into multiple cell types including non-dividing cells such as neurons. The capacity of LVs to maintain stable, long-term transgene expression and the substantial flexibility in the design of the expression cassettes account for their increasing use in various pre-clinical and clinical applications. Additionally, LVs have been hugely successful in reprogramming induced pluripotent stem cells (iPSCs). Recent development using LVs in conjunction with a Cre-Lox based reversible system has opened up many new possibilities towards therapeutic application of iPSC technology in various clinical settings. Moreover, improvements in term of biosafety and efficacy, achieved either by modifying the vector design or by involving integration deficient LVs (IDLVs), have important implications for adoption of LV as the vector of choice for clinical trials. Several human gene therapy clinical trials evaluating the use of LVs for treatment: of human diseases such as Parkinson's disease, beta-thalassemia, X-linked adrenoleukodystrophy (ALD), and AIDS are currently ongoing. This review will describe the state of the art achieved by LV technology, its impact on biomedical research, and implications to human clinical trials as therapeutic gene delivery vehicle for a wide range of infectious and genetic diseases. PMID- 21291356 TI - Therapies for neurological disease in the mucopolysaccharidoses. AB - Intravenous enzyme replacement therapy has been developed as a viable treatment for most of the somatic pathologies associated with the mucopolysaccharide storage disorders. However, approximately two thirds of individuals affected by a mucopolysaccharide storage disorder also display neurological disease, in these instances intravenous enzyme replacement therapy is not viable as the blood-brain barrier severely limits enzyme distribution from the peripheral circulation into the central nervous system. Accordingly, much research is now focussed on developing therapies that specifically address neurological disease, or somatic and neurological disease in combination. Therapies designed to address the underlying cause of central nervous system pathology, that is the lysosomal storage itself, can be broadly divided into two groups, those that continue the rationale of enzyme replacement, and those that address the supply side of the storage equation; that is the production of storage material. Enzyme replacement can be further divided by technology (principally direct enzyme replacement, gene replacement and cell transplantation). Here we review the current state of the art for these strategies and suggest possible future directions for research in this field. In particular, we suggest that any one approach in itself is unlikely to be as efficacious as a carefully considered combination therapy, be it a combination of some sort of enzyme replacement with substrate deprivation, or a combination of two different replacement technologies or strategies. PMID- 21291357 TI - Retinal ganglion cell gene therapy and visual system repair. AB - Recent clinical trials have shown that the use of replication deficient viral vectors to genetically modify cells in the retina can be of therapeutic benefit in the treatment of certain inherited degenerative conditions that compromise photoreceptor, and hence visual, function. This review is focussed primarily on the use of recombinant adeno-associated viral (rAAV) vectors to target neurons in inner retina, specifically retinal ganglion cells (RGCs). Genetic modification of RGCs may be of value in various ophthalmic conditions in which there is documented loss of RGCs or damage to their centrally projecting axons. Such conditions include glaucoma, optic neuritis, vascular disruption or trauma, and neurological degenerative conditions such as Alzheimer's disease. Furthermore, because the retina and optic nerve (ON) form part of the CNS, the visual system is a useful experimental model in which to study the molecular and cellular mechanisms that underlie degenerative as well as regenerative responses of adult CNS neurons after injury. Gene therapy studies from a number of laboratories are first reviewed, involving not only rAAV-based treatments but also application of lentiviral and adenoviral vectors. Recent work from our own laboratory is then summarized, in which intravitreal injection of rAAV2 serotype vectors is used to introduce growth promoting genes into injured RGCs. rAAV encoding a secretable form of ciliary neurotrophic factor (CNTF) has proved to be particularly effective in promoting RGC survival and axon regeneration after optic nerve crush or after transection followed by a peripheral nerve autograft. In the latter situation we have found that RGCs and their regenerated axons are maintained for at least 15 months after the initial injury. We have also combined rAAV gene therapy with pharmacotherapy to determine if cAMP elevation and additional intravitreal injections of growth factors can act synergistically with vector based delivery of growth-promoting genes. PMID- 21291358 TI - Gene therapy approaches for neuroprotection and axonal regeneration after spinal cord and spinal root injury. AB - Recent understanding in pathophysiological mechanisms of spinal cord and spinal root injuries has facilitated the development of new strategies to promote neural repair. Gene therapy approaches have been viewed as the ideal means to achieve long-term local delivery of therapeutic molecules in the central nervous system (CNS). Ex vivo gene delivery offers the additional advantage of providing cellular support for regenerating axons. In this review, we summarize the studies on viral vector-mediated gene delivery to spinal cord in animal models, both in vivo and ex vivo. Most of the studies reported so far are aimed at delivery of various growth factors, such as neurotrophins and neuropoietic cytokines. Other molecules tested include those that interfere with intracellular processes to prevent cell death, or increase intrinsic regenerating state of injured neurons, or modify the CNS environment to make it permissive for axon growth. Several different combinatorial strategies involving gene delivery are also discussed as it has been recognized that successful neural repair may require the synergistic actions of multiple therapeutic managements. PMID- 21291359 TI - Cell adhesion molecules in gene and cell therapy approaches for nervous system repair. AB - The inability of the central nervous system (CNS) to efficiently repair damages results in severe functional impairment after trauma or neurodegenerative/demyelinating diseases. Regeneration failure is attributed to inhibitory molecules creating a nonpermissive environment for axonal regrowth, and dictates the necessity for the development of novel therapeutic strategies. An emerging approach for improving regeneration is the use of gene therapy to manipulate cell adhesion molecule expression in experimental animal models of degeneration. Alternatively, cell transplantation to replace lost neurons and the grafting of myelinating cells to repair demyelinating lesions are promising approaches for treating CNS injuries and demyelination. Schwann cells (SCs), oligodendrocyte progenitors, olfactory ensheathing cells and embryonic and neural stem cells have been shown to form myelin after transplantation into the demyelinated CNS. The repair capacity of the peripheral nervous system (PNS) is much higher, but there is still a limit to the amount of nerve loss that can be bridged after injury, and longer nerve gaps call for the use of conduits populated with living cells. In both cases, the interaction of grafted cells with the host environment is of paramount importance for the incorporation and functional integration of these cells and the manipulation of cell adhesion molecules is an attractive approach towards achieving this goal. In this review we summarize data from the recent literature regarding the manipulation of cell adhesion molecule expression towards CNS and PNS repair and discuss the prospects for future therapeutic applications. PMID- 21291360 TI - Gene therapy for the peripheral nervous system: a strategy to repair the injured nerve? AB - Peripheral nerve injury in humans often leads to incomplete functional recovery. In this review we discuss the potential for gene therapy to be used as a strategy alongside surgical repair techniques for the study of peripheral nerve regeneration in rodent models and with a view to its eventual use for the promotion of successful regeneration in the clinic. Gene therapy vectors based on herpes simplex virus, adenovirus, lentivirus and adeno-associated virus have been developed to deliver genes to the neurons of the peripheral nervous system, i.e. primary sensory neurons in the dorsal root ganglia and primary motor neurons. Adenoviral and lentiviral vectors have also been used to transduce Schwann cells and fibroblasts in the injured nerve. We present an overview of these vectors, their application so far in the peripheral nervous system, their potential as vectors for enhancing peripheral nerve repair, and the successful interventions that have been demonstrated in animal models. We also discuss some of the limitations of current vectors and how they may be overcome. While the technology for gene delivery is approaching a state of readiness for clinical translation, the current range of therapeutic genes for the repair of the traumatically injured peripheral nerve is mostly limited to neurotrophic factors delivered to neurons, Schwann cells or possibly the target organs. Finally, therefore, we consider what type of therapeutic transgene may be desirable to enhance nerve regeneration in the future. PMID- 21291361 TI - Chemopreventive properties and molecular mechanisms of the bioactive compounds in Hibiscus sabdariffa Linne. AB - Hibiscus sabdariffa Linne is a traditional Chinese rose tea and has been effectively used in folk medicines for treatment of hypertension, inflammatory conditions. H. sabdariffa aqueous extracts (HSE) were prepared from the dried flowers of H. sabdariffa L., which are rich in phenolic acids, flavonoids and anthocyanins. In this review, we discuss the chemopreventive properties and possible mechanisms of various H. sabdariffa extracts. It has been demonstrated that HSE, H. sabdariffa polyphenol-rich extracts (HPE), H. sabdariffa anthocyanins (HAs), and H. sabdariffa protocatechuic acid (PCA) exert many biologic effects. PCA and HAs protected against oxidative damage induced by tert butyl droperoxide (t-BHP) in rat primary hepatocytes. In rabbits fed cholesterol and human experimental studies, these studies imply HSE could be pursued as atherosclerosis chemopreventive agents as they inhibit LDL oxidation, foam cell formation, as well as smooth muscle cell migration and proliferation. The extracts also offer hepatoprotection by influencing the levels of lipid peroxidation products and liver marker enzymes in experimental hyperammonemia. PCA has also been shown to inhibit the carcinogenic action of various chemicals in different tissues of the rat. HAs and HPE were demonstrated to cause cancer cell apoptosis, especially in leukemia and gastric cancer. More recent studies investigated the protective effect of HSE and HPE in streptozotocin induced diabetic nephropathy. From all these studies, it is clear that various H. sabdariffa extracts exhibit activities against atherosclerosis, liver disease, cancer, diabetes and other metabolic syndromes. These results indicate that naturally occurring agents such as the bioactive compounds in H. sabdariffa could be developed as potent chemopreventive agents and natural healthy foods. PMID- 21291362 TI - Promising targets for anti-hepatitis C virus agents. AB - Hepatitis C virus (HCV) infection is a serious global health problem, with 3-4 million new cases reported each year. Chronic HCV infection places 170 million people at risk of developing liver cirrhosis and hepatocellular carcinoma. However, difficulties in preparing HCV particles in vitro have delayed development of effective anti-HCV therapies. In 2005, Wakita et al. developed an in vitro method to prepare HCV particles, thereby enabling researchers to better understand the mechanism of HCV infection. Other recent advances include development of a virus-free system for evaluating HCV replication and the identification of HCV receptors, such as claudin-1 and occludin, that may serve as targets for anti-HCV drugs. In this review, we discuss recent findings in HCV infection research, including discovery of new potential targets for anti-HCV therapy. PMID- 21291363 TI - Adalimumab in Crohn's disease: tips and tricks after 5 years of clinical experience. AB - INTRODUCTION: Three anti TNF-alpha agents have currently been approved for the treatment of moderate-to-severe or complicated Crohn's disease (CD): infliximab, certolizumab and adalimumab. Infliximab is effective in CD, but for reasons linked to its chimeric structure, response to treatment may be lost overtime and as a result, it can sometimes be unable to provide long term durable treatment of CD. Adalimumab, a fully human anti TNF-alpha antibody, demonstrates similar treatment efficacy as infliximab and certolizumab, and can easily be self administered at home. AIM AND METHODS: A literature search in the Cochrane, MEDLINE, PUBMED, Ovid MEDLINER(r) and EMBASE databases has been performed on the efficacy, safety and the impact adalimumab has on the quality of life and natural history of CD. Abstracts presented at the DDW, UEGW and ECCO Congresses have also been reviewed as well as references from review articles, meta-analysis studies and published RCTs. RESULTS: Adalimumab induced remission of CD in 64% of patients, and maintained remission in more than 80% of initial responders. Adalimumab did not significantly increase the risk of adverse events compared with conventional medication up to 3 years of follow-up. Adalimumab reduces more than 50% the risk for hospitalisation and surgery due to CD. It is also effective for fistula closure, for the healing of the mucosa, and improving quality of life. CONCLUSION: Adalimumab is effective in the induction and maintenance of clinical remission in CD and is generally well tolerated. It has been proved to have a positive impact by improving quality of life of patients, and reducing the need for hospitalisation and surgery due to CD. According to the European Crohn's and Colitis Organisation (ECCO), infliximab or adalimumab can be used for the treatment of fistulizing CD. PMID- 21291364 TI - Lactoferrin: a biologically active molecule for bone regeneration. AB - Lactoferrin, a member of the "Siderophilin" family, is an iron binding glycoprotein. Lactoferrin is produced by various exocrine glands in our body and is abundantly present in milk and colostrums. The uniqueness of lactoferrin as a skeletal regenerative molecule lies in its ability to favorably modulate the responses of the various cell types involved in musculoskeletal regeneration. Lactoferrin exhibits pleiotropic functions and recent studies indicate that lactoferrin promotes the proliferation and differentiation of osteoblast cells and inhibits osteoclast-mediated bone resorption. Human lactoferrin is also known to promote neovascularization. This review aims to summarize the most recent studies on lactoferrin focusing on its anabolic effect to bone tissue and the ability to modulate immune responses with specific focus on osteoimmunology. PMID- 21291365 TI - Is androstadienone a putative human pheromone? AB - On the basis of different evidences, androstadienone, a steroid compound produced in the armpit, has been proposed as a human pheromone, although its physiological levels appear too low to induce a response under experimental conditions. For this reason, the majority of researchers in this area puts into question the "legitimacy" of androstadienone, and prefers to consider the axillary extracts in its entirety, like a sort of "medicinal tea", the components of which still remain to be identified, but that taken together may induce a response, or function as a carrier of other active substances. Another option is that androstadienone acts with varying degrees of potency and, at lower concentrations, according to the context and to specific behavioral situations. The aim of this paper is to review all relevant data regarding androstadienone, in order to ascertain whether it may be considered a physiological pheromone and, as such, a possible target of future modulators of some human behaviors. PMID- 21291366 TI - Neuroprotective actions of flavonoids. AB - The experimental evidences accumulated during last years point out a relevant role of oxidative stress in neurodegeneration. As anti-cellular oxidative stress agents flavonoids can act either as direct chemical antioxidants, the classic view of flavonoids as antioxidants, or as modulators of enzymes and metabolic and signaling pathways leading to an overshot of reactive oxygen species (ROS) formation, a more recently emerging concept. Flavonoids, a large family of natural antioxidants, undergo a significant hepatic metabolism leading to flavonoid-derived metabolites that are also bioactive as antioxidant agents. The development of more efficient flavonoid's based anti-oxidative stress therapies should also take into account their bioavailability in the brain using alternate administration protocols, and also that the major ROS triggering the cellular oxidative stress are not the same for all neurodegenerative insults and diseases. On these grounds, we have reviewed the reports on neuroprotection by different classes of flavonoids on cellular cultures and model animals. In addition, as they are now becoming valuable pharmacological drugs, due to their low toxicity, the reported adverse effects of flavonoids in model experimental animals and humans are briefly discussed. PMID- 21291367 TI - Structure-based approach for the discovery of novel selective estrogen receptor modulators. AB - In the last twenty years the efforts to design and optimize new drugs have been based on the three dimensional structure of the selected target proteins. In this regard, useful information has been achieved mainly by protein crystallography, which has recently turned from a low into a high-throughput process thanks to the improvement in robot technologies, automation procedure and the use of synchrotron radiation facilities [1-3]. This review examines the impact of Structure Based Drug Design (SBDD) on the discovery of ligands as the selective estrogen receptor modulators (SERMs) of the Estrogen Receptor (ER)alpha, which is involved in the regulation of several physiological and pathological processes. PMID- 21291368 TI - Novel trends in the treatment of cardiovascular disorders: site- and event- selective adenosinergic drugs. AB - This review focuses on the potential role of site- and event-selective adenosinergic drugs in the treatment of cardiovascular diseases. Adenosine is released from the myocardium and vessels in response to various forms of stress and acts on four receptor subtypes (A1, A2A, A2B and A3). Adenosine is an important endogenous substance with important homeostatic activity in the regulation of cardiac function and circulation. Adenosine receptors are also involved in the modulation of various cellular events playing crucial role in physiological and pathological processes of the cardiovascular system. These actions are associated to activation of distinct adenosine receptor subtypes, therefore drugs targeting specific adenosine receptors might be promising therapeutic tools in treatment of several disorders including various forms of cardiac arrhythmia, myocardial ischemia-reperfusion injury, angina pectoris, chronic heart failure, etc. Recently, in addition to subtype-specific adenosine receptor agonists and antagonists, a number of substances that enhance adenosine receptor activation locally at the site where the release of endogenous adenosine is the most intensive have been developed. Thus global actions of adenosine receptor agonists and antagonists, as well as desensitization or down-regulation following chronic administration of these orthosteric compounds can possibly be avoided. We discuss the chemical, pharmacological and clinical features of these compounds: (1) inhibitors of membrane adenosine transporters (NBTI, dipyridamole), (2) inhibitors of adenosine deaminase (coformycin, EHNA), (3) inhibitors of adenosine kinase (tubercidin, aristeromycin), (4) inhibitors of AMP deaminase (GP3269), (5) activators of 5'-nucleotidase (methotrexate), (6) adenosine regulators (acadesine) and (7) allosteric adenosine receptor modulators (PD81723, LUF6000). The development of this type of substances might offer a novel therapeutic approach for treating cardiovascular diseases in the near future. PMID- 21291369 TI - Lycopene and cardiovascular diseases: an update. AB - Cardiovascular disease (CVD) is the leading cause of death in Western societies and accounts for up to a third of all deaths worldwide. In comparison to the Northern European or other Western countries, the Mediterranean area has lower rates of mortality from cardiovascular diseases and cancer, and this is attributed, at least in part, to the so-called Mediterranean diet, which is rich in plantderived bioactive phytochemicals. Identification of the active constituents of the Mediterranean diet is therefore crucial to the formulation of appropriate dietary guidelines. Lycopene is a natural carotenoid found in tomato, an essential component of the Mediterranean diet, which, although belonging to the carotenoid family, does not have pro-vitamin A activity but many other biochemical functions as an antioxidant scavenger, hypolipaemic agent, inhibitor of pro-inflammatory and pro-thrombotic factors, thus potentially of benefit in CVD. In particular, the review intends to conduct a systematic analysis of the literature (epidemiological studies and interventional trials) in order to critically evaluate the association between lycopene (or tomato products) supplementation and cardiovascular diseases and/or cardiovascular disease risk factors progression, and to prepare provision of evidence-based guidelines for patients and clinicians. Several reports have appeared in support of the role of lycopene in the prevention of CVD, mostly based on epidemiological studies showing a dose-response relationship between lycopene and CVD. A less clear and more complex picture emerges from the interventional trials, where several works have reported conflicting results. Although many aspects of lycopene in vivo metabolism, functions and clinical indications remain to be clarified, supplementation of low doses of lycopene has been already suggested as a preventive measure for contrasting and ameliorating many aspects of CVD. PMID- 21291370 TI - Phenolic compounds from plants as nitric oxide production inhibitors. AB - Nitric oxide (NO) is a diatomic free radical produced from L-arginine by constitutive and inducible nitric oxide synthase (cNOS and iNOS) in numerous mammalian cells and tissues. Nitric oxide (NO), superoxide (O2-) and their reaction product peroxynitrite (ONOO-) may be generated in excess during the host response against viral and antibacterial infections and contribute to some pathogenesis by promoting oxidative stress, tissue injury and, even, cancer. Oxidative damage, caused by action of free radicals, may initiate and promote the progression of a number of chronic diseases, including cancer, cardiovascular diseases, Alzheimer's disease, diabetes and inflammation. The mechanism of inflammation injury is attributed, in part, to release of reactive oxygen species from activated neutrophils and macrophages. ROS propagate inflammation by stimulating release of mediators such as NO and cytokines. The interest of the research is motivated by the current need to find new substances of natural origin which have demonstrated effectiveness in the described fields of application and low degree of toxicity for humans. Natural products provide a vast pool of NO inhibitors that can possibly be developed into clinical products. This article reviews some plenolic secondary metabolites from plants with NO inhibitory properties and their structure-activity relationship studies that can be focused for drug development programs. PMID- 21291371 TI - In silico methods to assist drug developers in acetylcholinesterase inhibitor design. AB - Alzheimer's disease (AD) is a neurodegenerative disease characterized by a low acetylcholine (ACh) concentration in the hippocampus and cortex. ACh is a neurotransmitter hydrolyzed by acetylcholinesterase (AChE). Therefore, it is not surprising that AChE inhibitors (AChEIs) have shown better results in the treatment of AD than any other strategy. To improve the effects of AD, many researchers have focused on designing and testing new AChEIs. One of the principal strategies has been the use of computational methods (structural bioinformatics or in silico methods). In this review, we summarize the in silico methods used to enhance the understanding of AChE, particularly at the binding site, to design new AChEIs. Several computational methods have been used, such as docking approaches, molecular dynamics studies, quantum mechanical studies, electronic properties, hindrance effects, partition coefficients (Log P) and molecular electrostatic potentials surfaces, among other physicochemical methods that exhibit quantitative structure-activity relationships. PMID- 21291372 TI - Resveratrol, a phytochemical inducer of multiple cell death pathways: apoptosis, autophagy and mitotic catastrophe. AB - Cancers are the largest cause of mortality and morbidity in industrialized countries. In the field of the medicinal chemistry of natural products, numerous studies have reported interesting properties of trans-resveratrol as a chemopreventing agent against cancers, inflammation, and viral infection. Tumor growth inhibition has been linked to the ability of resveratrol to arrest cell cycle progression and to trigger cell death. This review focuses on the pathways that mediate resveratrol-induced cell death. Resveratrol impacts on the mitochondrial functions (respiratory chain, oncoproteins, gene expression, etc), in which p53 protein can be involved and its acetylated or phosphorylated forms. This polyphenol also affects death receptor distribution in ceramide-enriched membrane platforms which serve to trap and cluster receptor molecules, and facilitates the formation of a death-inducing signaling complex in the cell. To induce apoptosis, resveratrol also activates the ceramide / sphingomyelin pathway, which promotes ceramide generation and the downstream activation of kinase cascades. Resveratrol can activate alternative pathways to cell death such as those leading to autophagy, senescence or mitotic catastrophe. Furthermore, numerous attempts have been made using resveratrol analogs to improve the molecule's ability to block cell proliferation and induce cell death. Moreover, structural modification of natural phenolics is expected to produce analogs that may be useful tools to study the structure-activity relationships. Lastly, in various cancer types, resveratrol behaves as a chemosensitizer that lowers the threshold of cell death induction by classical anticancer agents and counteracts tumor cell chemoresistance. PMID- 21291373 TI - Peptide-based subunit nanovaccines. AB - Classical vaccines incorporating live or attenuated microorganisms possess several disadvantages and cannot be applied against cancer and some pathogens. Modern vaccines utilizing immunogenic subunits derived from a particular pathogen are able to overcome these obstacles but need a specific delivery system for their efficacy. Nanotechnology has opened a new window into these delivery methodologies. A nano-sized formulation of subunit vaccines has been proven to be very effective in inducing cellular and humoral immune responses. Here, we review a number of peptide vaccine delivery strategies based on nanoparticles composed of polymers, peptides, lipids, and inorganic materials. PMID- 21291374 TI - Cancer, signal transduction and nanotechnology. AB - Understanding the mechanisms underlying different cellular signaling pathways implicated in the pathogenesis of cancer are leading to the identification of novel drug targets as well as novel drug candidates. Multiple targeted therapeutics that modulate aberrant molecular pathways have already reached the clinic. However, targeted therapeutics can exert mechanism-driven side effects as a result of the implication of the molecular target in normal physiological functions besides tumorigenesis. We hypothesize that targeted therapeutics can be optimized by merging them with nanotechnology, which offers the potential for preferential targeting to the tumor, resulting in increased intratumoral concentrations of the active agent with reduced distribution to other parts of the body. This review will address some of the emerging concepts that integrate these two disciplines to engineer novel nanovectors that target different signaling pathways. PMID- 21291375 TI - Part II: targeted particles for imaging of anticancer immune responses. AB - The interaction of dendritic cells (DCs) and T cells has been the cornerstone of approaches to cancer immunotherapy. Antitumoral immune responses can be elicited by delivering cancer antigens to DCs. As antigen presenting cells, these DCs activate cancer antigen specific T cells. Whereas the first part of the review discusses methods for delivery of cancer vaccines to DCs, in this part the focus is on the potential role of nanoscopic devices for molecular imaging of these immune responses. Nanoscopic devices could potentially deliver tracking molecules to DCs, enabling monitoring of DCs and/or T cell activation and tumoricidal activity during immunotherapy, using non-invasive imaging modalities such as nuclear imaging (single photon emission computed tomography (SPECT), positron emission tomography (PET)), magnetic resonance imaging (MRI) and optical imaging. PMID- 21291376 TI - Regulating nanomedicine - can the FDA handle it? AB - There is enormous excitement and expectation surrounding the multidisciplinary field of nanomedicine - the application of nanotechnology to healthcare - which is already influencing the pharmaceutical industry. This is especially true in the design, formulation and delivery of therapeutics. Currently, nanomedicine is poised at a critical stage. However, regulatory guidance in this area is generally lacking and critically needed to provide clarity and legal certainty to manufacturers, policymakers, healthcare providers as well as public. There are hundreds, if not thousands, of nanoproducts on the market for human use but little is known of their health risks, safety data and toxicity profiles. Less is known of nanoproducts that are released into the environment and that come in contact with humans. These nanoproducts, whether they are a drug, device, biologic or combination of any of these, are creating challenges for the Food and Drug Administration (FDA), as regulators struggle to accumulate data and formulate testing criteria to ensure development of safe and efficacious nanoproducts (products incorporating nanoscale technologies). Evidence continues to mount that many nanoproducts inherently posses novel size-based properties and toxicity profiles. Yet, this scientific fact has been generally ignored by the FDA and the agency continues to adopt a precautionary approach to the issue in hopes of countering future potential negative public opinion. As a result, the FDA has simply maintained the status quo with regard to its regulatory policies pertaining to nanomedicine. Therefore, there are no specific laws or mechanisms in place for oversight of nanomedicine and the FDA continues to treat nanoproducts as substantially equivalent ("bioequivalent") to their bulk counterparts. So, for now nanoproducts submitted for FDA review will continue to be subjected to an uncertain regulatory pathway. Such regulatory uncertainty could negatively impact venture funding, stifle nanomedicine research and development (R&D) and erode public acceptance of nanoproducts. The end-result of this could be a delay or loss of commercialized nanoproducts. Whether the FDA eventually creates new regulations, tweaks existing ones or establishes a new regulatory center to handle nanoproducts, for the time being it should at least look at nanoproducts on a case-by-case basis. The FDA should not attempt regulation of nanomedicine by applying existing statutes alone, especially where scientific evidence suggests otherwise. Incorporating nanomedicine regulation into the current regulatory scheme is a poor idea. Regulation of nanomedicine must balance innovation and R&D with the principle of ensuring maximum public health protection and safety. PMID- 21291377 TI - Biphasic vesicles for topical delivery of interferon alpha in human volunteers and treatment of patients with human papillomavirus infections. AB - PURPOSE. Topical biphasic vesicle delivery system encapsulating interferon alpha (IFN alpha) was developed as an alternative to injections used to treat human papillomavirus (HPV) infections. METHODS. Biphasic lipid vesicles encapsulating increasing doses of IFN alpha (biphasic IFN alpha) were characterized for encapsulation efficiency, size, zeta potential and vesicle structure by centrifugation, dynamic light scattering, confocal microscopy and small-angle x ray scattering. Biphasic IFN-alpha delivery into human skin in vivo and topical efficacy in patients with genital warts were evaluated. RESULTS. Average encapsulation efficiency of IFN alpha was 81-91%. The average particle size was 1000-1100 nm and zeta potential +70 to +78 mV. After application of 5, 15 and 40MU/g biphasic IFN alpha formulation in a topical patch on the upper inner arm in healthy volunteers, skin IFN alpha levels increased to 120+/-30, 380+/-60 and 400+/-80 IU/mg protein in skin homogenates (n=5, 5, and 7), respectively. Topical application of biphasic IFN alpha (1 MU/dose) twice daily for two weeks in a pilot study with 12 patients with external condylomata acuminata resulted in a decrease in lesion size, in 2',5'-oligoadenylate synthetase activity and in tissue viral load. CONCLUSIONS. Biphasic vesicles delivered clinically significant levels of IFN alpha across intact human skin and elicited marked therapeutic effect in patients. PMID- 21291378 TI - Nanomedicine: a new frontier in cancer therapeutics. AB - Nanotechnology is a cutting edge and rapidly evolving technology in medicine. The potential of nanomedicine in cancer therapy is infinitely promising due to the fact that novel developments are constantly being explored. This is particularly the case in the use of nanoparticles in both tumor diagnosis, as well as treatment. This article will attempt to describe some recent advances using nanoparticle drug delivery system in cancer therapy. The evolution history, the challenges and the role of nanoparticles in cancer drug delivery will briefly be discussed together with additional opportunities in cancer therapy. An overall understanding of these issues will help with further advancement of designing better drug delivery system that can be applied clinically. PMID- 21291379 TI - Amino acid-substituted gemini surfactant-based nanoparticles as safe and versatile gene delivery agents. AB - Gene based therapy represents an important advance in the treatment of diseases that heretofore have had either no treatment or cure. To capitalize on the true potential of gene therapy, there is a need to develop better delivery systems that can protect these therapeutic biomolecules and deliver them safely to the target sites. Recently, we have designed and developed a series of novel amino acid-substituted gemini surfactants with the general chemical formula C(12)H(25) (CH(3))(2)N(+)-(CH(2))(3)-N(AA)-(CH(2))(3)-N(+) (CH(3))(2)-C(12)H(25) (AA= glycine, lysine, glycyl-lysine and, lysyl-lysine). These compounds were synthesized and tested in rabbit epithelial cells using a model plasmid and a helper lipid. Plasmid/gemini/lipid (P/G/L) nanoparticles formulated using these novel compounds achieved higher gene expression than the nanoparticles containing the parent unsubstituted compound. In this study, we evaluated the cytotoxicity of P/G/L nanoparticles and explored the relationship between transfection efficiency/toxicity and their physicochemical characteristics (such as size, binding properties, etc.). An overall low toxicity is observed for all complexes with no significant difference among substituted and unsubstituted compounds. An interesting result revealed by the dye exclusion assay suggests a more balanced protection of the DNA by the glycine and glycyl-lysine substituted compounds. Thus, the higher transfection efficiency is attributed to the greater biocompatibility and flexibility of the amino acid/peptide-substituted gemini surfactants and demonstrates the feasibility of using amino acid-substituted gemini surfactants as gene carriers for the treatment of diseases affecting epithelial tissue. PMID- 21291380 TI - CH(50): a revisited hemolytic complement consumption assay for evaluation of nanoparticles and blood plasma protein interaction. AB - The use of nanoparticles as platforms or vehicles for applications in nanomedicine, such as drug delivery and medical imaging, has been widely reported in the literature. A key area of potential improvement in the development and implementation of nanoparticles is the design of surface treatments to maximize residence time in the bloodstream. Major obstacles to the prolonged circulation of nanoparticles include complement activation and opsonization, both of which contribute to the removal of foreign matter from the vasculature. A greater understanding of the mechanisms through which nanoparticles interact with the complement system of innate immunity may be necessary in future endeavours to optimize nanoparticle design. The range of experimental techniques available for measuring complement interaction is presented. In particular, an in vitro hemolytic complement consumption assay called the CH(50) method is compared with alternative complement measurement techniques and cellular uptake studies in order to demonstrate its effectiveness as a quantitative evaluation of overall complement interaction. Moreover, establishing the usefulness of CH(50) results as predictors of in vivo behaviour is identified as a critical area for future research. PMID- 21291381 TI - Non-viral nucleic acid delivery: key challenges and future directions. AB - Gene therapy holds the promise of correcting a genetic defect. It can be achieved with the introduction of a normal wild-type transgene into specific cells of the patient where the endogenous gene is underexpressing or by the introduction of a therapeutic agent, such as, antisense oligonucleotides (AON) or small interfering RNA (siRNA) to inhibit transcription and/or translation of an overexpressing endogenous gene or a cancer causing oncogene. Gene therapy has been utilized for vaccination and for the treatment of several diseases, such as, cancer, viral infections and dermatological diseases. However, there are many hurdles to overcome in developing effective gene-based therapeutics, including cellular barriers, enzymatic degradation and rapid clearance after administration. Successful transfer of nucleic acids (e.g. plasmid DNA, AON, siRNA, small hairpin RNA and micro RNA) into cells usually relies on the use of efficient carriers, commonly viral or non-viral vectors. Presently, viral vectors are more efficient than non-viral systems. However, immunogenicity, inflammatory reactions and problems associated with scale-up limit their clinical use. The ideal carriers for gene delivery should be safe and yet ensure that the DNA/RNA survives the extra- and intracellular environment and efficiently transfer to the appropriate cellular compartments. This review discusses some of the strategies that have been employed to overcome the barriers towards successful gene delivery. PMID- 21291382 TI - M cells prefer archaeosomes: an in vitro/in vivo snapshot upon oral gavage in rats. AB - The archaeolipids (lipids extracted from archaebacterias) are non saponificable molecules that form self sealed mono or bilayers (archaeosomes-ARC). Different to liposomes with bilayers made of conventional glycerophospholipids, the bilayer of ARC posses a higher structural resistance to physico chemical and enzymatic degradation and surface hydrophobicity. In this work we have compared the binding capacity of ARC exclusively made of archaeols containing a minor fraction of sulphoglycophospholipids, with that of liposomes in gel phase on M-like cells in vitro. The biodistribution of the radiopharmaceutical (99m)Tc-DTPA loaded in ARC vs that of liposomes upon oral administration to Wistar rats was also determined. The fluorescence of M-like cells upon 1 and 2h incubation with ARC loaded with the hydrophobic dye Rhodamine-PE (Rh-PE) and the hydrophilic dye pyranine (HPTS) dissolved in the aqueous space, was 4 folds higher than upon incubation with equally labeled liposomes. Besides, 15% of Rh-PE and 13 % of HPTS from ARC and not from liposomes, were found in the bottom wells, a place that is equivalent to the basolateral pocket from M cells. This fact suggested the occurrence of transcytosis of ARC. Finally, 4 h upon oral administration, ARC were responsible for the 22.3 % (3.5 folds higher than liposomes) shuttling of (99m)Tc-DTPA to the blood circulation. This important amount of radioactive marker in blood could be a consequence of an extensive uptake of ARC by M cells in vivo, probably favored by their surface hydrophobicity. Taken together, these results suggested that ARC, proven their adjuvant capacity when administered by parenteral route and high biocompatibility, could be a suitable new type of nanoparticulate material that could be used as adjuvants by the oral route. PMID- 21291383 TI - Nanotechnology enables superior medical therapies. PMID- 21291384 TI - Understanding the use of immunosuppressive agents in the clinical management of IBD. AB - The advent of the biological era has seen many improvements in the management of inflammatory bowel disease (IBD). These agents, however, are not a ubiquitous panacea as they are neither universally available nor are they universally efficacious in the short or long-term. There is, therefore, still a need for other therapies and it is important to remember about the medications that have been effective in the past. The use of azathioprine and 6-mercoptopurine has been the mainstay of long-term therapy for many IBD patients for many years. Their role as steroid sparing agents and in the maintenance of remission is well recognized, and with the advent of metabolite testing their use has been refined. Methotrexate is a second line immunomodulator with less impressive data but still with observed benefits in Crohn's disease (CD) and two newer immunosuppressive agents, mycophenylate mofetil and tacrolimus have sparked some interest as they appear to be efficacious in some patients. As IBD is a chronic incurable condition that primarily presents in young patients, the treating clinician's goal is to induce and maintain long-term remission. So when one agent is ineffective, or unavailable, other agents need to be considered. This review aims to provide clinicians with practical and up to date knowledge about the use of the immunomodulators in the management of IBD, which is vital in order to offer the best management for their patients. PMID- 21291385 TI - Inhibition of human serine racemase, an emerging target for medicinal chemistry. AB - Proteins of glutamatergic NMDA receptor signaling pathways have been studied as targets for intervention in a variety of neuropathological conditions, including neurodegenerations, epilepsy, neuropathic pain, drug addiction, and schizophrenia. High activity NMDA-blocking agents have been designed to treat some of these disorders; however, their effect is often compromised by undesirable side effects. Therefore, alternative ways of modulating NMDA receptor function need to be sought after. The opening of the NMDA receptor ion channel requires occupation of two distinct binding sites, the glutamate site and the glycine site. It has been shown that D-serine, rather than glycine, can trigger the physiological NMDA receptor function. D-serine is a product of the activity of a specific enzyme, serine racemase (SR), which was identified a decade ago. SR has therefore emerged as a new potential target for the NMDA-receptor-based diseases. There is evidence linking increased levels of D-Ser to amyotrophic lateral sclerosis and Alzheimer's disease and decreased concentrations of D serine to schizophrenia. SR is a pyridoxal-5'-phosphate dependent enzyme found in the cytosol of glial and neuronal cells. It is activated by ATP, divalent cations like Mg(2+) or Ca(2+), and reducing agents. This paper reviews the present literature on the activity and inhibition of mammalian SRs. It summarizes approaches that have been applied to design SR inhibitors and lists the known active compounds. Based on biochemical and docking analyses, i) we delineate for the first time the ATP binding site of human SR, and ii) we suggest possible mechanisms of action for the active compounds. In the end, we discuss the SR features that make the discovery of its inhibitors a challenging, yet very important, task of medicinal chemistry. PMID- 21291386 TI - Phosphatidylinositol 3-kinase isoforms as novel drug targets. AB - Phosphatidylinositol 3-kinases (PI3Ks) are key molecules in the signal transduction pathways initiated by the binding of extracellular signals to their cell surface receptors. The PI3K family of enzymes comprises eight catalytic isoforms subdivided into three classes and control a variety of cellular processes including proliferation, growth, apoptosis, migration and metabolism. Deregulation of the PI3K pathway has been extensively investigated in connection to cancer, but is also involved in other commonly occurring diseases such as chronic inflammation, autoimmunity, allergy, atherosclerosis, cardiovascular and metabolic diseases. The fact that the PI3K pathway is deregulated in a large number of human diseases, and its importance for different cellular responses, makes it an attractive drug target. Pharmacological PI3K inhibitors have played a very important role in studying cellular responses involving these enzymes. Currently, a wide range of selective PI3K inhibitors have been tested in preclinical studies and some have entered clinical trials in oncology. However, due to the complexity of PI3K signaling pathways, developing an effective anti cancer therapy may be difficult. The biggest challenge in curing cancer patients with various signaling pathway abnormalities is to target multiple components of different signal transduction pathways with mechanism-based combinatorial treatments. In this article we will give an overview of the complex role of PI3K isoforms in human diseases and discuss their potential as drug targets. In addition, we will describe the drugs currently used in clinical trials, as well as promising emerging candidates. PMID- 21291389 TI - The ryanodine receptor: a pivotal Ca2+ regulatory protein and potential therapeutic drug target. AB - The ryanodine receptor (RyR) calcium release channel is an essential intracellular ion channel that is central to Ca(2+) signaling and contraction in the heart and skeletal muscle. The rapid release of Ca(2+) from the internal sarcoplasmic reticulum Ca(2+) stores through the RyR during excitation contraction coupling is facilitated by the unique arrangement of the surface and sarcoplasmic reticulum membrane systems. Debilitating and sometimes fatal skeletal and cardiomyopathies result from changes in RyR activity that disrupt normal Ca(2+) signaling. Such changes can be caused by point mutations in many different regions of the RyR protein or acquired as a result of stress associated with exercise, heart failure, age or drugs. In general, both inherited and acquired changes include an increase in RyR channel activity. Because of its central function, the RyR is a potential therapeutic target for the inherited disorders and many of the acquired disorders. The RyR is currently used as a therapeutic target in malignant hyperthermia where dantrolene is effective and to relieve ventricular arrhythmia, with the use of JTV519 and flecainide. These drugs show that the RyR is a valid therapeutic target, but have side effects that prevent their chronic use. Thus there is an urgent need for the development of skeletal and cardiac specific drugs to treat these diverse muscle disorders. In this review, we discuss the mutations that cause skeletal myopathies and cardiac arrhythmias and how these mutations pinpoint residues within the RyR protein that are functionally significant and might be developed as targets for therapeutic drugs. PMID- 21291388 TI - Triple threat: the Na+/Ca2+ exchanger in the pathophysiology of cardiac arrhythmia, ischemia and heart failure. AB - The Na(+)/Ca(2+) exchanger (NCX) is the main Ca(2+) extrusion mechanism of the cardiac myocyte and thus is crucial for maintaining Ca(2+) homeostasis. It is involved in the regulation of several parameters of cardiac excitation contraction coupling, such as cytosolic Ca(2+) concentration, repolarization and contractility. Increased NCX activity has been identified as a mechanism promoting heart failure, cardiac ischemia and arrhythmia. Transgenic mice as well as pharmacological interventions have been used to support the idea of using NCX inhibition as a future pharmacological strategy to treat cardiovascular disease. PMID- 21291390 TI - Targeting calcium and the mitochondria in prevention of pathology in the heart. AB - Calcium is a key determinant of cardiac excitation, contraction and relaxation. Cardiac excitation and contraction is powered by ATP that is synthesized within mitochondria via a calcium-dependent process known as oxidative phosphorylation. During this process oxygen molecules within the mitochondria are converted to superoxide. Under physiological conditions, low levels of ROS are required to maintain normal cellular function. This is achieved as a result of a balance between ROS formation and amelioration by antioxidants. Uninhibited increases in ROS production lead to oxidative stress. Large increases in ROS are associated with damage to mitochondria, DNA, proteins and lipids. In the heart this ultimately leads to apoptosis and loss of myocytes. However sub-lethal increases in ROS can activate hypertrophic signaling kinases and transcription factors including NFAT, CaMK and serine-threonine and tyrosine kinases. Calcium is also an important signaling molecule and a mediator of hypertrophic signaling pathways. ROS and calcium appear to participate as partners in pathological remodeling but their interaction and early mechanisms associated with the development of cardiac hypertrophy are poorly understood. An increase in cytoplasmic calcium can potentiate cellular oxidative stress via effects on mitochondrial metabolism. In addition oxidative stress can regulate the function of calcium channels and transporters. We discuss the evidence for calcium transporting proteins and the mitochondria in oxidative stress responses and propose sites to target in the prevention of cardiac hypertrophy. PMID- 21291387 TI - Properties and therapeutic potential of transient receptor potential channels with putative roles in adversity: focus on TRPC5, TRPM2 and TRPA1. AB - Mammals contain 28 genes encoding Transient Receptor Potential (TRP) proteins. The proteins assemble into cationic channels, often with calcium permeability. Important roles in physiology and disease have emerged and so there is interest in whether the channels might be suitable therapeutic drug targets. Here we review selected members of three subfamilies of mammalian TRP channel (TRPC5, TRPM2 and TRPA1) that show relevance to sensing of adversity by cells and biological systems. Summarized are the cellular and tissue distributions, general properties, endogenous modulators, protein partners, cellular and tissue functions, therapeutic potential, and pharmacology. TRPC5 is stimulated by receptor agonists and other factors that include lipids and metal ions; it heteromultimerises with other TRPC proteins and is involved in cell movement and anxiety control. TRPM2 is activated by hydrogen peroxide; it is implicated in stress-related inflammatory, vascular and neurodegenerative conditions. TRPA1 is stimulated by a wide range of irritants including mustard oil and nicotine but also, controversially, noxious cold and mechanical pressure; it is implicated in pain and inflammatory responses, including in the airways. The channels have in common that they show polymodal stimulation, have activities that are enhanced by redox factors, are permeable to calcium, and are facilitated by elevations of intracellular calcium. Developing inhibitors of the channels could lead to new agents for a variety of conditions: for example, suppressing unwanted tissue remodeling, inflammation, pain and anxiety, and addressing problems relating to asthma and stroke. PMID- 21291391 TI - Calcium regulatory proteins as therapeutic targets. PMID- 21291392 TI - Structural insight into the crucial role of ligand chirality in the activation of PPARs by crystallographic methods. AB - Peroxisome Proliferator-Activated Receptors (PPARs) are ligand-activated transcription factors that govern lipid and glucose homeostasis playing a central role in cardiovascular disease, obesity, and diabetes. These receptors show a high degree of stereoselectivity towards several classes of drugs. This review provides an overview of most papers reporting the influence of stereochemistry on PPAR activation. Some cases in which chirality is a crucial point in determining the PPAR binding mode are reviewed and discussed with the aim to show how enantiomeric recognition originates at the molecular level. The structural characterization by crystallographic methods of complexes formed by PPARs with their ligands turns out to be an essential tool to explain receptor stereoselectivity. PMID- 21291393 TI - Selectivity filters to edit out deleterious side effects in kinase inhibitors. AB - As the molecular etiology of cancer unravels, revealing the heterogeneous nature of the malignancy, multi-target drug treatments are more frequently advocated. Such therapeutic avenues often target kinases, the basic signal transducers in the cell. Because kinases share common evolutionary backgrounds, they also share many structural attributes, making it difficult for molecular targeted therapy to distinguish between paralogs. Thus, kinase inhibitors (KIs) tend to have undesired cross-reactivities, resulting in potentially lethal side effects. The health risks are obviously higher in these multi-pronged treatments when contrasted with the effects of more selective therapeutic agents. Using a nonconserved physicochemical biomarker, we present a rationally designed molecular filter that enables the control of specificity and the development of adjuvant drugs to edit out the side effects of the primary therapeutic agent. These editors work by overlapping therapeutically with the primary drug in cancer cells, while interfering with toxicity-related signaling pathways recruited by the primary drug in off-target cells. We then examine the possible application of these filtering methods to specifically target kinases when they present idiosyncratic cancer-related mutations. Such applications open the door to engineer personalized drugs tailored to the genetic makeup of the patient. These various methods of enhancing efficacy and safety show some degree of modularity, allowing drug designers to utilize multiple techniques and various drug combinations to create the safest and most powerful treatment for any given therapeutic scenario. PMID- 21291395 TI - Stereochemistry at the forefront in the design and discovery of novel anti tuberculosis agents. AB - Today, 75% of new drugs introduced to the market are single enantiomers and new techniques in asymmetric synthesis and chiral separation expedites chiral drug discovery and development worldwide. The enantiomers of a chiral drug present unique chemical and pharmacological behaviors in a chiral environment, such as the human body, in which the stereochemistry of chiral drugs determines their pharmacokinetic, pharmacodynamic, and toxicological actions. Thus, it is imperative that only the pure and therapeutically active isomer be prepared and marketed. Tuberculosis (TB), a highly contagious and airborne disease that is caused by infection with Mycobacterium tuberculosis (Mtb), currently represents one of the most threatening health problems globally. The emergence of multidrug resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB), as well as HIV co-infection along with a lengthy treatment regimen, highlights an urgent need for the development of new anti-TB agents. Currently, new chiral anti-TB agents are being developed from some well-known anti-TB agents, high throughput screening (HTS) hits, and natural products. This review will focus on the reported chiral anti-TB agents together with the clinical importance of their chirality and stereochemistry. PMID- 21291394 TI - Chiral kinase inhibitors. AB - Small molecule kinase inhibitors are important tools for studying cellular signaling pathways, phenotypes and are, occasionally, useful clinical agents. With stereochemistry pervasive throughout the molecules of life it is no surprise that a single stereocenter can bestow a ligand with distinct binding affinities to various protein targets. While the majority of small molecule kinase inhibitors reported to date are achiral, a number of asymmetric compounds show great utility as tools for probing kinase-associated biomolecular events as well as promising therapeutic leads. The mechanism by which chirality is introduced varies but includes screening of chiral libraries, incorporation of chiral centers during optimization efforts and the rational installation of a chiral moiety as guided by structural and modeling efforts. Here we discuss several advanced chiral small molecule kinase inhibitors where stereochemistry plays an important role in terms of potency and selectivity. PMID- 21291396 TI - Structural requirements to obtain highly potent and selective 18 kDa Translocator Protein (TSPO) Ligands. AB - The (18 kDa) Translocator Protein (TSPO), was initially identified in 1977 as peripheral binding site for the benzodiazepine diazepam and named "Peripheral type benzodiazepine receptor (PBR)". It is an evolutionarily well-conserved protein particularly located at the outer/inner mitochondrial membrane contact sites, in closely association with the 32 kDa voltage-dependent anion channel (VDAC) and the 30 kDa adenine nucleotide translocase (ANT), thus forming the mitochondrial permeability transition pore (MPTP). TSPO is ubiquitary expressed in peripheral tissues (steroid producing tissues, liver, heart, kidney, lung, immune system) and in lower levels in the central nervous system, where it is mainly located in glial cells, and in neurons. TSPO is involved in a variety of biological processes such as cholesterol transport, steroidogenesis, calcium homeostasis, lipid metabolism, mitochondrial oxidation, cell growth and differentiation, apoptosis induction, and regulation of immune functions. In the last decade, many studies have reported that TSPO basal expression is altered in a number of human pathologies, such as cancer and neurodegenerative disorders (Huntington's and Alzheimer's diseases), as well as in various forms of brain injury and inflammation and anxiety. Consequently, TSPO has not only been suggested as a promising drug target for a number of therapeutic applications (anticonvulsant, anxiolytic, immunomodulating, etc.), but also as valid diagnostic marker for related-disease state and progression, prompting the development of specific labelled ligands as powerful tools for imaging techniques. A number of structurally different classes of ligands have been reported, showing high affinity and selectivity towards TSPO. Indeed, most of these ligands have been designed starting from selective CBR ligands which were structurally modified in order to shift their affinity towards TSPO. Extensive structure-activity relationship studies were performed allowing to hypothesize various TSPO pharmacophore models. The purpose of this paper is to highlight the structural requirements needed to obtain TSPO ligands with high affinity and selectivity. PMID- 21291397 TI - The importance of stereochemistry on the actions of vitamin D. AB - The seco-steroid hormone 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)] is the most potent natural metabolite of vitamin D(3) and regulates primarily calcium and phosphate homeostasis, but also as a regulator of specific differentiation and of the immune system. Most, if not all, of the biological actions of 1alpha,25(OH)(2)D(3) are mediated through its specific receptor, the vitamin D receptor (VDR), which is a member of the nuclear receptor superfamily acting as a ligand-dependent transcription factor with coactivators. 1alpha,25(OH)(2)D(3) has significant therapeutic potential in the treatment of osteoporosis, rickets, secondary hyperparathyroidism, psoriasis, and renal osteodystrophy. However, the use of 1alpha,25(OH)(2)D(3) itself is limited because it induces significant hypercalcemia. Vitamin D is a highly flexible molecule and a very large number of analogs have been synthesized by industry and academia in an attempt to provide beneficial therapeutic agents with low calcemic activity. Chemical modifications of every portion of the vitamin D(3) molecule (the A, C, and D rings, the 17beta-aliphatic side chain, and the 5,6,7,8-diene moiety) have been reported, with the most of the interesting analogs resulting from a combination of several modifications. The three-dimensional structure of both rat and human VDR-LBD have provided significant information for our understanding of the structure-function relationship (SFR) of vitamin D and some synthetic analogs. In this review, we focus on the current understanding of the relationship between selected stereochemical modifications of key structural components (i.e. A-ring, CD-ring and Side-chain) of the 1alpha,25(OH)(2)D(3) molecule and their effect on biological potency and selectivity. Based on current information, suggestions for the structure-based design of therapeutically valuable vitamin D analogs will conclude the review. PMID- 21291398 TI - Numerical descriptors for the characterization of chiral compounds and their applications in modeling biological and toxicological activities. AB - Due to the advancement in chiral synthesis and separation technology and the new regulatory policies for chiral pharmaceuticals several manufacturers are replacing the previously marketed racemate chemicals with single enantiomeric products, the so called chiral switch. Though 25% of agrochemicals are chiral in nature, most of them are sold as racemates or enantiomer enriched products. Chiral pesticides and some of the pharmaceuticals reach the human food chain as pollutants. Stereoisomers (enantiomers and diastereoisomers) not only differ from one another in their medicinal effects, but also in their phramacokinectic (adsorption, distribution, biotransformation and excretion) profiles and toxicological properties. Several recent attempts have been reported in the literature on developing mathematical models to predict the properties of chiral molecules from structure and such methods utilized numerical characterization. A comparison of different mathematical approaches on the numerical characterization of molecules with chiral center(s) and a brief background on the importance of stereochemistry in pharmacology, agrochemistry and environmental toxicology is presented. PMID- 21291399 TI - The significance of chirality in drug design and development. AB - Proteins are often enantioselective towards their binding partners. When designing small molecules to interact with these targets, one should consider stereoselectivity. As considerations for exploring structure space evolve, chirality is increasingly important. Binding affinity for a chiral drug can differ for diastereomers and between enantiomers. For the virtual screening and computational design stage of drug development, this problem can be compounded by incomplete stereochemical information in structure libraries leading to a "coin toss" as to whether or not the "ideal" chiral structure is present. Creating every stereoisomer for each chiral compound in a structure library leads to an exponential increase in the number of structures resulting in potentially unmanageable file sizes and screening times. Therefore, only key chiral structures, enantiomeric pairs based on relative stereochemistry need be included, and lead to a compromise between exploration of chemical space and maintaining manageable libraries. In clinical environments, enantiomers of chiral drugs can have reduced, no, or even deleterious effects. This underscores the need to avoid mixtures of compounds and focus on chiral synthesis. Governmental regulations emphasizing the need to monitor chirality in drug development have increased. The United States Food and Drug Administration issued guidelines and policies in 1992 concerning the development of chiral compounds. These guidelines require that absolute stereochemistry be known for compounds with chiral centers and that this information should be established early in drug development in order that the analysis can be considered valid. From exploration of structure space to governmental regulations it is clear that the question of chirality in drug design is of vital importance. PMID- 21291400 TI - Glutamate receptor agonists: stereochemical aspects. AB - The neurotransmitter (S)-glutamate [(S)-Glu] is responsible for most of the excitatory neurotransmission in the central nervous system. The effect of (S)-Glu is mediated by both ionotropic and metabotropic receptors. Glutamate receptor agonists are generally alpha-amino acids with one or more stereogenic centers due to strict requirements in the agonist binding pocket of the activated state of the receptor. By contrast, there are many examples of achiral competitive antagonists. The present review addresses how stereochemistry affects the activity of glutamate receptor ligands. The review focuses mainly on agonists and discusses stereochemical and conformational considerations as well as biostructural knowledge of the agonist binding pockets, which is useful in the design of glutamate receptor agonists. Examples are chosen to demonstrate how stereochemistry not only determines how the agonist binding pocket is filled, but also how it affects the conformational space of the ligand and in this way restricts the recognition of various glutamate receptors, ultimately leading to selectivity. PMID- 21291401 TI - Effect of stereochemistry in medicinal chemistry and drug discovery. PMID- 21291402 TI - Does more MnSOD mean more hydrogen peroxide? AB - Superoxide dismutases (SODs) are a family of important antioxidant enzymes that catalyze the conversion of superoxide to hydrogen peroxide and oxygen. Hydrogen peroxide is then detoxified by a host of antioxidant enzymes. A common misconception is that the increased MnSOD levels will result in increased hydrogen peroxide levels. Herein we offer some potential reasons for this confusion, as well as some potential resolutions. Data are offered that demonstrate the ability of MnSOD, in the presence of nitric oxide, to utilize hydrogen peroxide to produce superoxide and the more toxic oxidant, peroxynitrite. PMID- 21291404 TI - PRL-3, an emerging marker of carcinogenesis, is strongly associated with poor prognosis. AB - PRL-3 protein belongs to the family of protein tyrosine phosphatases with unique COOH-terminal prenylation motif, which determines the functions of this protein and its location in the cell. Numerous research studies revealed that apart from performing the poorly investigated physiological role, PRL-3 takes part in the process of carcinogenesis. Specifically, it is involved in reconstructing of the cytoskeleton, regulating adhesion and cell cycle of the cancer cells, and in epithelial-mesenchymal transition. Through these mechanisms PRL-3 protein participates in invasion, migration, metastasis and angiogenesis. Numerous studies indicate that PRL-3 expression is particularly important in colorectal, as well as in gastric, ovarian and breast carcinomas. Recently, several studies on PRL-3 protein in other types of cancer have been published. They reveal a significant role of this protein in the process of angiogenesis and metastasis. It has been proven that a higher expression of PRL-3 correlates with tumor progression and its severity. While the degree of overexpression of PRL-3 varies in different types of tumors, most research shows that in the metastases of these tumors, whether to the lymph nodes or to other organs, the level of expression is extremely high. Overexpression of PRL-3 protein was repeatedly confirmed in metastases, but not with primary tumors. PRL-3 seems to be an adequate marker in diagnosing the stage of tumor advancement for various types of carcinomas, especially for colorectal carcinoma investigated thoroughly in this study. PRL-3 overexpression predicts poor prognosis in patients with various carcinomas and is a promising target in the cancer treatment. PMID- 21291403 TI - Cellular redox modulator, ortho Mn(III) meso-tetrakis(N-n-hexylpyridinium-2 yl)porphyrin, MnTnHex-2-PyP(5+) in the treatment of brain tumors. AB - Despite intensive efforts to improve multimodal treatment of brain tumor, survival remains limited. Current therapy consists of a combination of surgery, irradiation and chemotherapy with predisposition to long-term complications. Identifying novel targeted therapies is therefore at the forefront of brain tumor research. This study explores the utility of a manganese porphyrin in a brain tumor model. The compound used is ortho isomer, mangnese(III) meso-tetrakis(N-n hexylpyridinium-2-yl)porphyrin, MnTnHex-2-PyP(5+). It is a powerful SOD mimic and peroxynitrite scavenger and a potent modulator of redox-based cellular transcriptional activity, able to suppress excessive immune and inflammatory responses and in turn proliferative pathways. It is further one of the most lipophilic compound among cationic Mn(III) N-alkylpyridylporphyrins, and thus accumulates predominantly in mitochondria relative to cytosol. In mitochondria, MnTnHex-2-PyP(5+) mimics our key antioxidant system, mitochondrial superoxide dismutase, MnSOD, whose overexpression has been widely shown to suppress tumor growth. Importantly, MnTnHex-2-PyP(5+) crosses blood brain barrier in sufficient amounts to demonstrate efficacy in treating CNS injuries. For those reasons we elected to test its effects in inhibiting brain tumor growth. This study is the first report of the antitumor properties of MnTnHex-2-PyP(5+) as a single agent in adult and pediatric glioblastoma multiforme (D-54 MG, D-245 MG, D-256 MG, D 456 MG) and pediatric medulloblastoma (D-341 MED), and is the first case where a redox-able metal complex has been used in glioma therapy. When given subcutaneously to mice bearing subcutaneous and intracranial xenografts, MnTnHex 2-PyP(5+) caused a significant (P <= 0.001) growth delay in D 245 MG, D-256 MG, D 341 MED, and D-456 MG tumors. Growth delay for mice bearing subcutaneous xenografts ranged from 3 days in D-54 MG to 34 days in D-341 MED. With mice bearing intracranial xenografts, MnTnHex-2-PyP(5+) increases median survival by 33% in adult glioblastoma multiforme (D-256 MG; p<= 0.001) and 173% in pediatric medulloblastoma (D-341 MED, <0.001). The beneficial effects of MnTnHex-2-PyP(5+) are presumably achieved either (1) indirectly via elimination of signaling reactive oxygen and nitrogen species (in particular superoxide and peroxynitrite) which in turn would prevent activation of transcription factors; or (2) directly by coupling with cellular reductants and redox-sensitive signaling proteins. The former action is antioxidative while the latter action is presumably pro oxidative in nature. Our findings suggest that the use of Mn porphyrin-based SOD mimics, and in particular lipophilic analogues such as MnTnHex-2-PyP(5+), is a promising approach for brain tumor therapy. PMID- 21291405 TI - SHP-1 in cell-cycle regulation. AB - The reversible phosphorylation of tyrosine residues in proteins, which is governed by the balanced action of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), is a key element of the signaling pathways that are involved in the control of cell proliferation. Deregulation of either of these key regulators leads to abnormal cell signaling, which is largely associated with human pathologies including cancer. This review focuses on recent studies on the role of the protein tyrosine phosphatase SHP-1 on cell-cycle regulation and its possible roles in tumour onset and progression. SHP-1 is a PTP with two SH2 domains that is expressed in haematopoietic cells and, moderately, in many other cell types, especially malignant epithelial cells. SHP-1 regulates cell proliferation, whether it is by controlling mitogenic pathways activated by receptors with tyrosine kinase activity, or by regulating components of the cell cycle machinery such as CDK2, p27 and cyclin D1. Since several inhibitors targeting SHP-1 have demonstrated their value in cancer treatment, this phosphatase has been proposed as a therapeutic target for this pathology. PMID- 21291407 TI - Multifunctional porous silicon for therapeutic drug delivery and imaging. AB - Major challenges in drug formulation are the poor solid state stability of drug molecules, poor dissolution/solubility and/or poor pharmacokinetic properties (bioavailability), which may lead to unreliable in vitro-in vivo (IVIV) correlation. To improve current therapeutical strategies, novel means to deliver poorly water soluble active pharmaceutical ingredients, as well as to target them to specific sites or cells in the body are needed. Biomedical applications of porous silicon (PSi) have been actively investigated during the last 10 years, especially in the areas of drug delivery and imaging, due to the biocompatibility and biodegradability of PSi materials, which makes them a potential candidate for controlled drug release. In addition, the unique pore sizes and easily functionalized surface properties of PSi materials allow high drug payloads and controlled kinetics from the drug release formulations. Modification of the PSi surface properties also facilitates biofunctionalization of the surface and the possibility to attach targeting moieties (e.g., antibodies and peptides), thus enabling effective targeting of the payload. In this review, we briefly address the production methodologies of PSi, and we will mainly present and discuss several examples about the biocompatibility of PSi, the most recent in vitro and in vivo applications of PSi as a carrier in drug/protein/peptide delivery and tissue engineering, as well as PSi as a platform for drug targeting and imaging. PMID- 21291406 TI - Evolving therapies and FAK inhibitors for the treatment of cancer. AB - Despite advances in medical and surgical therapy, cancer kills more than half a million people in the United States annually, and the majority of these patients succumb to metastatic disease. The traditional approach to treating systemic disease has been the use of cytotoxic chemotherapy. However, chemotherapy is rarely curative and toxicity is often dose limiting. In addition, the effects of chemotherapy are nonspecific, targeting both malignant and normal tissues. As a result, recent efforts increasingly have focused on developing agents that target specific molecules in tumor cells in order to both improve efficacy and limit toxicity. This review summarizes the history and current use of targeted molecular therapy for cancer, with a special emphasis on recently developed inhibitors of Focal Adhesion Kinase (FAK). PMID- 21291408 TI - Silica materials in drug delivery applications. AB - In this review article we collect and analyse preparation, chemistry and properties of silica materials relevant for drug delivery applications. We review some of the most relevant milestones in the research of silica materials for implantable, oral, intravenous and dermal drug delivery systems. Preparation, chemistry and drug delivery characteristics of fumed silica nanoparticles (oral and dermal delivery route), silica xerogels (implant delivery), mesoporous silica materials (implant and oral delivery) and mesoporous silica spheres (intravenous delivery) with particular emphasis on their role in anticancer therapy and the design of stimuli responsive drug delivery systems are analysed. Recent progress in the research of silica materials for controlled drug delivery, namely, biocompatibility aspects, research on hybrid materials, anticancer and stimuli responsive mesoporous silica materials are particularly emphasized. PMID- 21291409 TI - 20 years of lipid nanoparticles (SLN and NLC): present state of development and industrial applications. AB - In 1990, the lipid nanoparticles were invented in the laboratories, the first patent filings took place in 1991. The lipid nanoparticles were developed as alternative to traditional carriers such as polymeric nanoparticles and liposomes. After 20 years of lipid nanoparticles, the present state of development is reviewed - academic progress but also the development state of pharmaceutical products for the benefit of patients. Meanwhile many research groups are active worldwide, their results are reviewed which cover many different administration routes: dermal and mucosal, oral, intravenous/parenteral, pulmonary but also ocular. The lipid nanoparticles are also used for peptide/protein delivery, in gene therapy and various miscellaneous applications (e.g. vaccines). The questions of large scale production ability, accepted regulatory status of excipients, and - important for the public perception - lack of nanotoxicity are discussed, important pre-requisites for the use of each nanocarrier in products. Identical to the liposomes, the lipid nanoparticles entered first the cosmetic market, product examples are presented. Presently the pharmaceutical product development focuses on products for unmet needs and on niche products with lower development costs (e.g. ocular delivery), which can be realized also by smaller companies. A pharmaceutical perspective for the future is given, but also outlined the opportunities for non-pharmaceutical use, e.g. in nutraceuticals. PMID- 21291410 TI - Stressors, academic performance, and learned resourcefulness in baccalaureate nursing students. AB - High stress levels in nursing students may affect memory, concentration, and problem-solving ability, and may lead to decreased learning, coping, academic performance, and retention. College students with higher levels of learned resourcefulness develop greater self-confidence, motivation, and academic persistence, and are less likely to become anxious, depressed, and frustrated, but no studies specifically involve nursing students. This explanatory correlational study used Gadzella's Student-life Stress Inventory (SSI) and Rosenbaum's Self Control Scale (SCS) to explore learned resourcefulness, stressors, and academic performance in 53 baccalaureate nursing students. High levels of personal and academic stressors were evident, but not significant predictors of academic performance (p = .90). Age was a significant predictor of academic performance (p = < .01) and males and African-American/Black participants had higher learned resourcefulness scores than females and Caucasians. Studies in larger, more diverse samples are necessary to validate these findings. PMID- 21291411 TI - A Markov-chain model for the analysis of high-resolution enzymatically 18O labeled mass spectra. AB - The enzymatic 18O-labeling is a useful quantification technique to account for between-spectrum variability of the results of mass spectrometry experiments. One of the important issues related to the use of the technique is the problem of incomplete labeling of peptide molecules, which may result in biased estimates of the relative peptide abundance. In this manuscript, we propose a Markov-chain model, which takes into account the possibility of incomplete labeling in the estimation of the relative abundance from the observed data. This allows for the use of less precise but faster labeling strategies, which should better fit in the high-throughput proteomic framework. Our method does not require extra experimental steps, as proposed in the approaches developed by Mirgorodskaya et al. (2000), Lopez-Ferrer et al. (2006) and Rao et al. (2005), while it includes the model proposed by Eckel-Passow et al. (2006) as a special case. The method estimates information about the isotopic distribution directly from the observed data and is able to account for biases induced by the different sulphur content in peptides as reported by Johnson and Muddiman (2004). The method is integrated in a statistically sound framework and allows for the calculation of the errors on the parameter estimates based on model theory. In this manuscript, we describe the methodology in a technical matter and assess the properties of the algorithm via a thorough simulation study. The method is also tested on a limited dataset; more intense validation and investigation of the operational characteristics is being scheduled. PMID- 21291412 TI - Repeated measures semiparametric regression using targeted maximum likelihood methodology with application to transcription factor activity discovery. AB - In longitudinal and repeated measures data analysis, often the goal is to determine the effect of a treatment or aspect on a particular outcome (e.g., disease progression). We consider a semiparametric repeated measures regression model, where the parametric component models effect of the variable of interest and any modification by other covariates. The expectation of this parametric component over the other covariates is a measure of variable importance. Here, we present a targeted maximum likelihood estimator of the finite dimensional regression parameter, which is easily estimated using standard software for generalized estimating equations. The targeted maximum likelihood method provides double robust and locally efficient estimates of the variable importance parameters and inference based on the influence curve. We demonstrate these properties through simulation under correct and incorrect model specification, and apply our method in practice to estimating the activity of transcription factor (TF) over cell cycle in yeast. We specifically target the importance of SWI4, SWI6, MBP1, MCM1, ACE2, FKH2, NDD1, and SWI5. The semiparametric model allows us to determine the importance of a TF at specific time points by specifying time indicators as potential effect modifiers of the TF. Our results are promising, showing significant importance trends during the expected time periods. This methodology can also be used as a variable importance analysis tool to assess the effect of a large number of variables such as gene expressions or single nucleotide polymorphisms. PMID- 21291413 TI - Learning monotonic genotype-phenotype maps. AB - Evolutionary escape of pathogens from the selective pressure of immune responses and from medical interventions is driven by the accumulation of mutations. We introduce a statistical model for jointly estimating the dynamics and dependencies among genetic alterations and the associated phenotypic changes. The model integrates conjunctive Bayesian networks, which define a partial order on the occurrences of genetic events, with isotonic regression. The resulting genotype-phenotype map is non-decreasing in the lattice of genotypes. It describes evolutionary escape as a directed process following a phenotypic gradient, such as a monotonic fitness landscape. We present efficient algorithms for parameter estimation and model selection. The model is validated using simulated data and applied to HIV drug resistance data. We find that the effect of many resistance mutations is non-linear and depends on the genetic background in which they occur. PMID- 21291414 TI - A comparison of multifactor dimensionality reduction and L1-penalized regression to identify gene-gene interactions in genetic association studies. AB - Recently, the amount of high-dimensional data has exploded, creating new analytical challenges for human genetics. Furthermore, much evidence suggests that common complex diseases may be due to complex etiologies such as gene-gene interactions, which are difficult to identify in high-dimensional data using traditional statistical approaches. Data-mining approaches are gaining popularity for variable selection in association studies, and one of the most commonly used methods to evaluate potential gene-gene interactions is Multifactor Dimensionality Reduction (MDR). Additionally, a number of penalized regression techniques, such as Lasso, are gaining popularity within the statistical community and are now being applied to association studies, including extensions for interactions. In this study, we compare the performance of MDR, the traditional lasso with L1 penalty (TL1), and the group lasso for categorical data with group-wise L1 penalty (GL1) to detect gene-gene interactions through a broad range of simulations. We find that each method has both advantages and disadvantages, and relative performance is context dependent. TL1 frequently over fits, identifying false positive as well as true positive loci. MDR has higher power for epistatic models that exhibit independent main effects; for both Lasso methods, main effects tend to dominate. For purely epistatic models, GL1 has the best performance for lower minor allele frequencies, but MDR performs best for higher frequencies. These results provide guidance of when each approach might be best suited for detecting and characterizing interactions with different mechanisms. PMID- 21291415 TI - Accuracy and computational efficiency of a graphical modeling approach to linkage disequilibrium estimation. AB - We develop recent work on using graphical models for linkage disequilibrium to provide efficient programs for model fitting, phasing, and imputation of missing data in large data sets. Two important features contribute to the computational efficiency: the separation of the model fitting and phasing-imputation processes into different programs, and holding in memory only the data within a moving window of loci during model fitting. Optimal parameter values were chosen by cross-validation to maximize the probability of correctly imputing masked genotypes. The best accuracy obtained is slightly below than that from the Beagle program of Browning and Browning, and our fitting program is slower. However, for large data sets, it uses less storage. For a reference set of n individuals genotyped at m markers, the time and storage required for fitting a graphical model are approximately O(nm) and O(n+m), respectively. To impute the phases and missing data on n individuals using an already fitted graphical model requires O(nm) time and O(m) storage. While the times for fitting and imputation are both O(nm), the imputation process is considerably faster; thus, once a model is estimated from a reference data set, the marginal cost of phasing and imputing further samples is very low. PMID- 21291416 TI - Learning from past treatments and their outcome improves prediction of in vivo response to anti-HIV therapy. AB - Infections with the human immunodeficiency virus type 1 (HIV-1) are treated with combinations of drugs. Unfortunately, HIV responds to the treatment by developing resistance mutations. Consequently, the genome of the viral target proteins is sequenced and inspected for resistance mutations as part of routine diagnostic procedures for ensuring an effective treatment. For predicting response to a combination therapy, currently available computer-based methods rely on the genotype of the virus and the composition of the regimen as input. However, no available tool takes full advantage of the knowledge about the order of and the response to previously prescribed regimens. The resulting high-dimensional feature space makes existing methods difficult to apply in a straightforward fashion. The machine learning system proposed in this work, sequence boosting, is tailored to exploiting such high-dimensional information, i.e. the extraction of longitudinal features, by utilizing the recent advancements in data mining and boosting. When applied to predicting the latest treatment outcome for 3,759 treatment-experienced patients from the EuResist integrated database, sequence boosting achieved superior performance compared to SVMs with RBF kernels. Moreover, sequence boosting allows an easy access to the discriminative treatment information. Analysis of feature importance values provided by our model confirmed known facts regarding HIV treatment. For instance, application of potent and recently licensed drugs was beneficial for patients, and, conversely, the patient group that was subject to NRTI mono-therapies in the past had poor treatment perspectives today. Furthermore, our model revealed novel biological insights. More precisely, the combination of previously used drugs with their in vivo response is more informative than the information of previously used drugs alone. Using this information improves the performance of systems for predicting therapy outcome. PMID- 21291417 TI - A three component latent class model for robust semiparametric gene discovery. AB - We propose a robust model for discovering differentially expressed genes which directly incorporates biological significance, i.e., effect dimension. Using the so-called c-fold rule, we transform the expressions into a nominal observed random variable with three categories: below a fixed lower threshold, above a fixed upper threshold or within the two thresholds. Gene expression data is then transformed into a nominal variable with three levels possibly originated by three different distributions corresponding to under expressed, not differential, and over expressed genes. This leads to a statistical model for a 3-component mixture of trinomial distributions with suitable constraints on the parameter space. In order to obtain the MLE estimates, we show how to implement a constrained EM algorithm with a latent label for the corresponding component of each gene. Different strategies for a statistically significant gene discovery are discussed and compared. We illustrate the method on a little simulation study and a real dataset on multiple sclerosis. PMID- 21291418 TI - Log-linear modelling of protein dipeptide structure reveals interesting patterns of side-chain-backbone interactions. AB - It has long been known that the amino-acid sequence of a protein determines its 3 dimensional structure, but accurate ab initio prediction of structure from sequence remains elusive. We gain insight into local protein structure conformation by studying the relationship of dihedral angles in pairs of residues in protein sequences (dipeptides). We adopt a contingency table approach, exploring a targeted set of hypotheses through log-linear modelling to detect patterns of association of these dihedral angles in all dipeptides considered. Our models indicate a substantial association of the side-chain conformation of the first residue with the backbone conformation of the second residue (side-to back interaction) as well as a weaker but still significant association of the backbone conformation of the first residue with the side-chain conformation of the second residue (back-to-side interaction). To compare these interactions across different dipeptides, we cluster the parameter estimates for the corresponding association terms. This reveals a striking pattern. For the side-to back term, all dipeptides which have the same first residue jointly appear in distinct clusters whereas for the back-to-side term, we observe a much weaker pattern. This suggests that the conformation of the first residue affects the conformation of the second. PMID- 21291419 TI - Cytosolic lysine residues enhance anterograde transport and activation of the erythropoietin receptor. AB - Lysine residues are key residues in many cellular processes, in part due to their ability to accept a wide variety of post-translational modifications. In the present study, we identify the EPO-R [EPO (erythropoietin) receptor] cytosolic lysine residues as enhancers of receptor function. EPO-R drives survival, proliferation and differentiation of erythroid progenitor cells via binding of its ligand EPO. We mutated the five EPO-R cytosolic lysine residues to arginine residues (5KR EPO-R), eliminating putative lysine-dependent modifications. Overexpressed 5KR EPO-R displayed impaired ubiquitination and improved stability compared with wt (wild-type) EPO-R. Unexpectedly, fusion proteins consisting of VSVGtsO45 (vesicular stomatitis virus glycoprotein temperature-sensitive folding mutant) with wt or 5KR EPO-R cytosolic domains demonstrated delayed glycan maturation kinetics upon substitution of the lysine residues. Moreover, VSVG-wt EPO-R, but not VSVG-5KR EPO-R, displayed endoplasmic reticulum-associated ubiquitination. Despite similar cell-surface EPO-binding levels of both receptors and the lack of EPO-induced ubiquitination by 5KR EPO-R, the lysine-less mutant produced weaker receptor activation and signalling than the wt receptor. We thus propose that EPO-R cytosolic lysine residues enhance receptor function, most probably through ubiquitination and/or other post-translational modifications. PMID- 21291420 TI - SUMO2 and SUMO3 transcription is differentially regulated by oxidative stress in an Sp1-dependent manner. AB - Protein SUMOylation (SUMO is small ubiquitin-related modifier) is a dynamic process that is strictly regulated under physiological and pathological conditions. However, little is known about how various intra- or extra-cellular stimuli regulate expression levels of components in the SUMO system. SUMO isoforms SUMO2 and SUMO3 can rapidly convert to be conjugated in response to a variety of cellular stresses. Owing to the limitations of sequence homology, SUMO2 and SUMO3 cannot be differentiated between and are thus referred to as SUMO2/3. Whether these two isoforms are regulated in distinct manners has never been addressed. In the present paper we report that the expression of SUMO3, but not SUMO2, can be down-regulated at the transcription level by cellular oxidative stress. In the present study, we checked SUMO2 and SUMO3 mRNA levels in cells exposed to various doses of H2O2 and in cells bearing different levels of ROS (reactive oxygen species). We found an inverse relationship between SUMO3 transcription and ROS levels. We characterized a promoter region specific for the mouse Sumo3 gene that is bound by the redox-sensitive transcription factor Sp1 (specificity protein 1) and demonstrated oxidation of Sp1, as well as suppression of Sp1-DNA binding upon oxidative stress. This revealed for the first time that the expression of SUMO2 and SUMO3 is regulated differently by ROS. These findings may enhance our understanding about the regulation of SUMOylation and also shed light on the functions of Sp1. PMID- 21291421 TI - Purification and characterization of a Ca(2+)-dependent novel lectin from Nymphaea nouchali tuber with antiproliferative activities. AB - A lectin (termed NNTL) was purified from the extracts of Nymphaea nouchali tuber followed by anion-exchange chromatography on DEAE-cellulose, hydrophobic chromatography on HiTrap Phenyl HP and by repeated anion-exchange chromatography on HiTrap Q FF column. The molecular mass of the purified lectin was 27.0 +/- 1.0 kDa, as estimated by SDS/PAGE both in the presence and in the absence of 2 mercaptoethanol. NNTL was an o-nitrophenyl beta-D-galactopyranoside sugar specific lectin that agglutinated rat, chicken and different groups of human blood cells and exhibited high agglutination activity over the pH range 5-9 and temperatures of 30-60 degrees C. The N-terminal sequence of NNTL did not show sequence similarity with any other lectin and the amino acid analysis revealed that NNTL was rich in leucine, methionine and glycine residues. NNTL was a glycoprotein containing 8% neutral sugar and showed toxicity against brine shrimp nauplii with an LC(50) value of 120 +/- 29 MUg/ml and exerted strong agglutination activity against four pathogenic bacteria (Bacillus subtilis, Sarcina lutea, Shigella shiga and Shigella sonnei). In addition, antiproliferative activity of this lectin against EAC (Ehrlich ascites carcinoma) cells showed 56% and 76% inhibition in vivo in mice at 1.5 and 3 mg.kg(-1).day( 1) respectively. NNTL was a divalent ion-dependent glycoprotein, which lost its activity markedly in the presence of denaturants. Furthermore, measurement of fluorescence spectra in the presence and absence of urea and CaCl(2) indicated the requirement of Ca(2+) for the stability of NNTL. PMID- 21291422 TI - Synergy of isoflurane preconditioning and propofol postconditioning reduces myocardial reperfusion injury in patients. AB - Either isoflurane preconditioning or high-dose propofol treatment has been shown to attenuate myocardial IRI (ischaemia/reperfusion injury) in patients undergoing CABG (coronary artery bypass graft) surgery. It is unknown whether isoflurane and propofol may synergistically attenuate myocardial injury in patients. The present study investigated the efficacy of IsoPC (isoflurane preconditioning), propofol treatment (postconditioning) and their synergy in attenuating postischaemic myocardial injury in patients undergoing CABG surgery using CPB (cardiopulmonary bypass). Patients (n = 120) selected for CABG surgery were randomly assigned to one of four groups (n = 30 each). After induction, anaesthesia was maintained either with fentanyl and midazolam (control; group C); with propofol at 100 MUg x kg(-1) of body weight x min(-1) before and during CPB followed by propofol at 60 MUg x kg(-1) of body weight x min(-1) for 15 min after aortic declamping (group P); with isoflurane 1-1.5% end tidal throughout the surgery (group I) or with isoflurane 1-1.5% end tidal before CPB and switching to propofol at 100 MUg x kg( 1) of body weight x min(-1) during CPB followed by propofol at 60 MUg x kg(-1) of body weight x min(-1) for 15 min after aortic declamping (group IP, i.e. IsoPC plus propofol postconditioning). A joint isoflurane and propofol anaesthesia regimen synergistically reduced plasma levels of cTnI (cardiac troponin I) and CK MB (creatine kinase MB) and f-FABP (heart-type fatty acid-binding protein) (all P < 0.05 compared with control, group P or group I) and facilitated postoperative myocardial functional recovery. During reperfusion, myocardial tissue eNOS (endothelial NO synthase) protein expression in group IP was significantly higher, whereas nitrotyrosine protein expression was lower than those in the control group. In conclusion, a joint isoflurane preconditioning and propofol anaesthesia regimen synergistically attenuated myocardial reperfusion injury in patients. PMID- 21291423 TI - Geographical, urban/rural and socioeconomic variations in nonmelanoma skin cancer incidence: a population-based study in Ireland. AB - BACKGROUND: Nonmelanoma skin cancer (NMSC) is the most common cancer in white populations worldwide. International comparisons in incidence are limited because few registries collect comprehensive population-based data. OBJECTIVES: We describe spatial, urban/rural and socioeconomic variations in NMSC incidence in Ireland, overall and for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) separately. Methods NMSC cases (n=47 347) diagnosed during 1994-2003 were extracted from the National Cancer Registry. Each case was allocated to a small area (electoral district, ED) based on address at diagnosis. Standardized incidence ratios (SIRs) were calculated and smoothed using a Bayesian conditional autoregressive model. Associations between disease and census-derived area-based socioeconomic factors (unemployment, employment type, early school leavers, deprivation category, population density) were investigated using negative binomial regression. RESULTS: The spatial and socioeconomic distributions differed by subtype, suggesting aetiological differences. For BCC, areas of higher risk were concentrated around the main cities, with small patches on the south and west coast. Higher risks for SCC were seen in the north-east, on the south, mid and north-west coast. BCC risk in males and females, and SCC in males, was significantly higher in those living in the least deprived areas. Risk of BCC and SCC in females was higher in the most densely populated areas. CONCLUSIONS: We observed striking geographical variation in NMSC incidence, which cannot be satisfactorily explained on the basis of known risk factors. Differences by deprivation category and population density may reflect better access to cancer surveillance or care, as well as differences in risk factor exposure. PMID- 21291425 TI - Raising healthy children: translating child development research into practice. PMID- 21291426 TI - Science does not speak for itself: translating child development research for the public and its policymakers. AB - Science has an important role to play in advising policymakers on crafting effective responses to social problems that affect the development of children. This article describes lessons learned from a multiyear, working collaboration among neuroscientists, developmental psychologists, pediatricians, economists, and communications researchers who are engaged in the iterative construction of a core story of development, using simplifying models (i.e., metaphors) such as "brain architecture,""toxic stress," and "serve and return" to explain complex scientific concepts to nonscientists. The aim of this article is to stimulate more systematic, empirical approaches to the task of knowledge transfer and to underscore the need to view the translation of science into policy and practice as an important academic endeavor in its own right. PMID- 21291427 TI - Intergenerational transmission of adaptive functioning: a test of the interactionist model of SES and human development. AB - The interactionist model (IM) of human development (R. D. Conger & M. B. Donellan, 2007) proposes that the association between socioeconomic status (SES) and human development involves a dynamic interplay that includes both social causation (SES influences human development) and social selection (individual characteristics affect SES). Using a multigenerational data set involving 271 families, the current study finds empirical support for the IM. Adolescent personality characteristics indicative of social competence, goal-setting, hard work, and emotional stability predicted later SES, parenting, and family characteristics that were related to the positive development of a third generation child. Processes of both social selection and social causation appear to account for the association between SES and dimensions of human development indicative of healthy functioning across multiple generations. PMID- 21291428 TI - Double jeopardy: poorer social-emotional outcomes for children in the NICHD SECCYD experiencing home and child-care environments that confer risk. AB - Using data from the National Institute of Child Health and Human Development Early Child Care Research Network (NICHD SECCYD), the authors examined whether interactions between home and child-care quality affect children's social emotional adjustment at 24, 36, and 54 months (N = 771). Triadic splits on quality of home and child care were used to examine children in specific ecological niches, with a focus on those who experience the double jeopardy of poor quality home and child-care environments. Children in this niche exhibited the highest levels of mother-reported problem behavior and the lowest levels of prosocial behavior. However, there was evidence that children from lower quality home environments were able to benefit from the compensatory influence of high quality child care. These results suggest policies aimed at the cross-context influences of protective and risky settings. PMID- 21291429 TI - Maternal employment, work schedules, and children's body mass index. AB - Previous work has shown that mothers' employment is associated with increases in children's body mass index (BMI), a measure of weight for height. Nonstandard work (working evenings or nights, weekends, or an irregular shift) may also be associated with children's BMI. This article examines the association between maternal work and children's BMI and considers the influence of mothers' nonstandard work schedules. Using data from school-age children (approximately 8 to 12 years) in the NICHD's Study of Early Child Care and Youth Development (N = 990), this study found that an increase in the total time a mother is employed is associated with an increase in her child's BMI; additionally, the association between maternal employment and children's weight is much stronger at 6th grade relative to younger ages. There was no evidence that maternal or home characteristics or children's time use mediated these associations, nor was there any evidence that nonstandard work was associated with children's BMI. Implications for policy and future research are discussed. PMID- 21291430 TI - Media as social partners: the social nature of young children's learning from screen media. AB - Television has become a nearly ubiquitous feature in children's cultural landscape. A review of the research into young children's learning from television indicates that the likelihood that children will learn from screen media is influenced by their developing social relationships with on-screen characters, as much as by their developing perception of the screen and their symbolic understanding and comprehension of information presented on screen. Considering the circumstances in which children under 6 years learn from screen media can inform teachers, parents, and researchers about the important nature of social interaction in early learning and development. The findings reviewed in this article suggest the social nature of learning, even learning from screen media. PMID- 21291431 TI - Revisiting the impact of part-time work on adolescent adjustment: distinguishing between selection and socialization using propensity score matching. AB - The impact of part-time employment on adolescent functioning remains unclear because most studies fail to adequately control for differential selection into the workplace. The present study reanalyzes data from L. Steinberg, S. Fegley, and S. M. Dornbusch (1993) using multiple imputation, which minimizes bias in effect size estimation, and 2 types of propensity score matching, to account for selection effects. In this sample (N = 1,792; Grades 10-11, M = 16.26), youth who begin working more than 20 hr per week evince declines in school engagement and increases in substance use and delinquency compared with youth who remain unemployed. Conversely, working 20 hr or less a week has negligible effects, positive or negative, on academic, psychological, or behavioral outcomes. PMID- 21291432 TI - Assessing the effects of a work-based antipoverty program for parents on youth's future orientation and employment experiences. AB - The impacts of New Hope, a 3-year work-based antipoverty program to increase parent employment and reduce poverty, on youth ages 9-19 (N = 866) were assessed 5 years after parents left the program. New Hope had positive effects on the future orientation and employment experiences of boys, especially African American boys. Compared to boys in control group families, boys in program group families were less cynical about work, less pessimistic about their employment prospects, and more involved in employment and career preparation. They also worked for longer periods during the school year than did control group boys. Comparable effects were not found for girls. The developmental significance of the findings, possible processes that led to the impacts, and the policy implications of the findings are discussed. PMID- 21291433 TI - The ABCs of family mealtimes: observational lessons for promoting healthy outcomes for children with persistent asthma. AB - Family mealtimes have the potential to promote healthy child development. This observational study of 200 family mealtimes examined the relation between child health in a group of children (ages 5 to 12) with persistent asthma and 3 dimensions of mealtime interaction: Action, Behavior Control, and Communication. Percent time spent in Action and Positive Communication varied by asthma severity, child quality of life, and sociodemographic variables. Positive communication during mealtimes predicted child quality of life. Significant interactions between demographic variables and behavior control suggested that higher levels of behavior control affected child quality of life in the context of lower maternal education. Guidance is offered for practitioners and policy makers toward promoting healthy family mealtimes as a public health priority. PMID- 21291434 TI - Parents as moderators of the impact of school norms and peer influences on aggression in middle school students. AB - This study examined parenting variables as protective factors to reduce the influence of school and peer risk factors on adolescents' aggression. Five waves of data spanning 3 years were collected from 5,581 students at 37 schools who began the 6th grade in 2001 or 2002. Class-level and perceived school norms supporting aggression, delinquent peer associations, parental support for fighting and support for nonviolence, and parental involvement were each associated with physical aggression across all waves. Each parenting variable moderated 1 or more risk factors, with the magnitude of many effects varying by gender and decreasing over time. Implications for the role parents may play in reducing the impact of school and peer risk factors for aggression are discussed. PMID- 21291435 TI - Intergenerational continuity in child maltreatment: mediating mechanisms and implications for prevention. AB - In the interest of improving child maltreatment prevention, this prospective, longitudinal, community-based study of 499 mothers and their infants examined (a) direct associations between mothers' experiences of childhood maltreatment and their offspring's maltreatment, and (b) mothers' mental health problems, social isolation, and social information processing patterns (hostile attributions and aggressive response biases) as mediators of these associations. Mothers' childhood physical abuse--but not neglect--directly predicted offspring victimization. This association was mediated by mothers' social isolation and aggressive response biases. Findings are discussed in terms of specific implications for child maltreatment prevention. PMID- 21291436 TI - Accumulating evidence for parent-child interaction therapy in the prevention of child maltreatment. AB - In a randomized controlled trial, the effectiveness of Parent-Child Interaction Therapy (PCIT) and correlates of maltreatment outcomes were examined. Mothers (N = 150) had a history or were at high risk of maltreating their children. After 12 weeks and compared to waitlist, PCIT mothers were observed to have improved parent-child interactions and reported better child behavior and decreased stress. At PCIT completion, improvements continued and mothers reported less child abuse potential and had improved maternal sensitivity. Also, PCIT completers were less likely to be notified to child welfare than noncompleters. Finally, those families not notified post-PCIT showed greater reductions in child abuse potential and improvements in observed sensitivity during treatment. Implications for theory and practice are discussed. PMID- 21291437 TI - A randomized controlled trial of Child FIRST: a comprehensive home-based intervention translating research into early childhood practice. AB - This randomized, controlled trial was designed to document the effectiveness of Child FIRST (Child and Family Interagency, Resource, Support, and Training), a home-based, psychotherapeutic, parent-child intervention embedded in a system of care. Multirisk urban mothers and children, ages 6-36 months (N = 157) participated. At the 12-month follow-up, Child FIRST children had improved language (odds ratio [OR] = 4.4) and externalizing symptoms (OR= 4.7) compared to Usual Care children. Child FIRST mothers had less parenting stress at the 6-month follow-up (OR = 3.0), lower psychopathology symptoms at 12-month follow-up (OR = 4.0), and less protective service involvement at 3 years postbaseline (OR = 2.1) relative to Usual Care mothers. Intervention families accessed 91% of wanted services relative to 33% among Usual Care. Thus, Child FIRST is effective with multirisk families raising young children across multiple child and parent outcomes. PMID- 21291438 TI - An ecological approach to promoting early adolescent mental health and social adaptation: family-centered intervention in public middle schools. AB - This study examined the impact of the Family Check-Up (FCU) and linked intervention services on reducing health-risk behaviors and promoting social adaptation among middle school youth. A total of 593 students and their families were randomly assigned to receive either the intervention or middle school services as usual. Forty-two percent of intervention families engaged in the service and received the FCU. Using complier average causal effect analyses, engagement in the intervention moderated intervention outcomes. Families who engaged in the intervention had youth who reported lower rates of antisocial behavior and substance use over time than did a matched control sample. Results extend previous research indicating that a family-centered approach to supporting youth in the public school setting reduced the growth of antisocial behavior, alcohol use, tobacco use, and marijuana use throughout the middle school years. PMID- 21291439 TI - Remission of depression in parents: links to healthy functioning in their children. AB - This study examined whether improvement in parents' depression was linked with changes in their children's depressive symptoms and functioning. Participants were 223 parents and children ranging in age from 7 to 17 years old (M = 12.13, SD =2.31); 126 parents were in treatment for depression and 97 parents were nondepressed. Children were evaluated 6 times over 2 years. Changes in parents' depressive symptoms predicted changes in children's depressive symptoms over and above the effect of time; children's symptoms significantly predicted parents' symptoms. Trajectories of children's depressive symptoms differed significantly for children of remitted versus nonremitted depressed parents, and these differences were significantly predicted by their parents' level of depression. The relation between parents' and children's depressive symptoms was partially mediated by parental acceptance. PMID- 21291440 TI - Protecting children from the consequences of divorce: a longitudinal study of the effects of parenting on children's coping processes. AB - This study examines whether intervention-induced changes in mother-child relationship quality and discipline led to short-term (6 months) and long-term (6 years) changes in children's coping processes in a sample of 240 youth aged 9-12 years when assessed initially. Data were from a randomized, experimental trial of a parenting-focused preventive intervention designed to improve children's postdivorce adjustment. Three-wave prospective mediational analyses revealed that intervention-induced improvements in relationship quality led to increases in coping efficacy at 6 months and to increases in coping efficacy and active coping at 6 years. Tests of the mediated effects were significant for all 3 indirect paths. Results are discussed in terms of pathways to adaptive coping and implications for the implementation of preventive interventions targeting coping. PMID- 21291441 TI - Promoting effective parenting practices and preventing child behavior problems in school among ethnically diverse families from underserved, urban communities. AB - This study examines the efficacy of ParentCorps among 4-year-old children (N = 171) enrolled in prekindergarten in schools in a large urban school district. ParentCorps includes a series of 13 group sessions for parents and children held at the school during early evening hours and facilitated by teachers and mental health professionals. ParentCorps resulted in significant benefits on effective parenting practices and teacher ratings of child behavior problems in school. Intervention effects were of similar magnitude for families at different levels of risk and for Black and Latino families. The number of sessions attended was related to improvements in parenting. Study findings support investment in and further study of school-based family interventions for children from underserved, urban communities. PMID- 21291442 TI - Adolescents' development of skills for agency in youth programs: learning to think strategically. AB - This research examines how youth in arts and leadership programs develop skills for organizing actions over time to achieve goals. Ethnically diverse youth (ages 13-21) in 11 high-quality urban and rural programs were interviewed as they carried out projects. Qualitative analyses of 712 interviews with 108 youth yielded preliminary grounded theory about youth's development of strategic thinking, defined as use of dynamic systems reasoning to anticipate real-word scenarios and plan work. Strategic thinking appeared to develop through youth's creative engagement with tactical challenges in the work and feedback from the work's outcomes. Program advisors supported this development by giving youth control and by providing nondirective assistance when needed. PMID- 21291443 TI - Understanding bullying and victimization during childhood and adolescence: a mixed methods study. AB - In the present study, quantitative and qualitative data are presented to examine individual and contextual predictors of bullying and victimization and how they vary by age and gender. Two waves of survey data were collected from 2,678 elementary, middle, and high school youth attending 59 schools. In addition, 14 focus groups were conducted with 115 youth who did not participate in the survey. Changes in both bullying and victimization were predicted across gender and age by low self-esteem and negative school climate, with normative beliefs supporting bullying predicting increases in bullying only. Focus group comments provided insights into the dynamics of bullying, highlighting its connection to emergent sexuality and social identity during adolescence. Findings are discussed in terms of their implications for preventive antibullying interventions in schools. PMID- 21291444 TI - A large-scale evaluation of the KiVa antibullying program: grades 4-6. AB - This study demonstrates the effectiveness of the KiVa antibullying program using a large sample of 8,237 youth from Grades 4-6 (10-12 years). Altogether, 78 schools were randomly assigned to intervention (39 schools, 4,207 students) and control conditions (39 schools, 4,030 students). Multilevel regression analyses revealed that after 9 months of implementation, the intervention had consistent beneficial effects on 7 of the 11 dependent variables, including self- and peer reported victimization and self-reported bullying. The results indicate that the KiVa program is effective in reducing school bullying and victimization in Grades 4-6. Despite some evidence against school-based interventions, the results suggest that well-conceived school-based programs can reduce victimization. PMID- 21291445 TI - The effects of the fast track preventive intervention on the development of conduct disorder across childhood. AB - The impact of the Fast Track intervention on externalizing disorders across childhood was examined. Eight hundred-ninety-one early-starting children (69% male; 51% African American) were randomly assigned by matched sets of schools to intervention or control conditions. The 10-year intervention addressed parent behavior-management, child social cognitive skills, reading, home visiting, mentoring, and classroom curricula. Outcomes included psychiatric diagnoses after grades 3, 6, 9, and 12 for conduct disorder, oppositional defiant disorder, attention deficit hyperactivity disorder, and any externalizing disorder. Significant interaction effects between intervention and initial risk level indicated that intervention prevented the lifetime prevalence of all diagnoses, but only among those at highest initial risk, suggesting that targeted intervention can prevent externalizing disorders to promote the raising of healthy children. PMID- 21291446 TI - Mentoring in schools: an impact study of big brothers big sisters school-based mentoring. AB - This random assignment impact study of Big Brothers Big Sisters School-Based Mentoring involved 1,139 9- to 16-year-old students in 10 cities nationwide. Youth were randomly assigned to either a treatment group (receiving mentoring) or a control group (receiving no mentoring) and were followed for 1.5 school years. At the end of the first school year, relative to the control group, mentored youth performed better academically, had more positive perceptions of their own academic abilities, and were more likely to report having a "special adult" in their lives. However, they did not show improvements in classroom effort, global self-worth, relationships with parents, teachers or peers, or rates of problem behavior. Academic improvements were also not sustained into the second school year. PMID- 21291447 TI - CSRP's Impact on low-income preschoolers' preacademic skills: self-regulation as a mediating mechanism. AB - Based on theoretically driven models, the Chicago School Readiness Project (CSRP) targeted low-income children's school readiness through the mediating mechanism of self-regulation. The CSRP is a multicomponent, cluster-randomized efficacy trial implemented in 35 Head Start-funded classrooms (N = 602 children). The analyses confirm that the CSRP improved low-income children's self-regulation skills (as indexed by attention/impulse control and executive function) from fall to spring of the Head Start year. Analyses also suggest significant benefits of CSRP for children's preacademic skills, as measured by vocabulary, letter-naming, and math skills. Partial support was found for improvement in children's self regulation as a hypothesized mediator for children's gains in academic readiness. Implications for programs and policies that support young children's behavioral health and academic success are discussed. PMID- 21291448 TI - Age 26 cost-benefit analysis of the child-parent center early education program. AB - Using data collected up to age 26 in the Chicago Longitudinal Study, this cost benefit analysis of the Child-Parent Centers (CPC) is the first for a sustained publicly funded early intervention. The program provides services for low-income families beginning at age 3 in 20 school sites. Kindergarten and school-age services are provided up to age 9 (third grade). Findings from a complete cohort of over 1,400 program and comparison group participants indicated that the CPCs had economic benefits in 2007 dollars that exceeded costs. The preschool program provided a total return to society of $10.83 per dollar invested (18% annual return). The primary sources of benefits were increased earnings and tax revenues and averted criminal justice system costs. The school-age program had a societal return of $3.97 per dollar invested (10% annual return). The extended intervention program (4-6 years) had a societal return of $8.24 (18% annual return). Estimates were robust across a wide range of analyses including Monte Carlo simulations. Males, 1-year preschool participants, and children from higher risk families derived greater benefits. Findings provide strong evidence that sustained programs can contribute to well-being for individuals and society. PMID- 21291449 TI - The impact of enhancing students' social and emotional learning: a meta-analysis of school-based universal interventions. AB - This article presents findings from a meta-analysis of 213 school-based, universal social and emotional learning (SEL) programs involving 270,034 kindergarten through high school students. Compared to controls, SEL participants demonstrated significantly improved social and emotional skills, attitudes, behavior, and academic performance that reflected an 11-percentile-point gain in achievement. School teaching staff successfully conducted SEL programs. The use of 4 recommended practices for developing skills and the presence of implementation problems moderated program outcomes. The findings add to the growing empirical evidence regarding the positive impact of SEL programs. Policy makers, educators, and the public can contribute to healthy development of children by supporting the incorporation of evidence-based SEL programming into standard educational practice. PMID- 21291450 TI - Context matters in child and family policy. AB - The traditional model of translation from basic laboratory science to efficacy trials to effectiveness trials to community dissemination has flaws that arise from false assumptions that context changes little or matters little. One of the most important findings in developmental science is that context matters, but this fact is not sufficiently taken into account in many translation efforts. Studies reported in this special issue highlight both the potential of systematic interventions in parenting, peer relations, and social-cognitive skills training, and the problems that will be encountered in trying to bring these interventions to a community context. It is advocated that developmental scientists start from within the community context itself so that translation to policy is only a small step. It is also advocated that this research be conducted through rigorous community randomized controlled trials. PMID- 21291452 TI - PTEN in colorectal cancer: a report on two Cowden syndrome patients. AB - Heterozygous germline PTEN mutations cause Cowden syndrome. The risk of colorectal cancer in Cowden patients, however, remains a matter of debate. We describe two patients presenting with colorectal cancer at a young age (28 and 39 years) and dysmorphisms fitting the Cowden spectrum. Heterozygous germline mutations in PTEN were found in both patients. Moreover, analysis of the resected colorectal cancer specimens revealed loss of heterozygosity at the PTEN locus with retention of the mutated alleles, and greatly reduced or absent PTEN expression. Histologically and molecularly, the tumours showed resemblance with sporadic colorectal cancers, although they had prominent fibrotic stroma. Our data indicate that PTEN loss was involved in carcinogenesis in the two patients, supporting that colorectal cancer is part of the Cowden syndrome-spectrum. This is in line with data on sporadic colorectal cancer, mice studies and emerging epidemiological data on Cowden syndrome. Although the exact role of germline PTEN mutations in the carcinogenesis of colorectal cancer remains unclear, we think that Cowden syndrome should be in the differential diagnosis of colorectal cancer certainly in view of the possible prognostic and therapeutic consequences. Prospective follow-up and surveillance of PTEN mutation carriers from the age of 25 to 30 years in a study setting should clarify this issue. PMID- 21291453 TI - High frequency of SH3TC2 mutations in Czech HMSN I patients. AB - Charcot-Marie-Tooth (CMT) neuropathy type 4C (CMT4C) is an autosomal recessive (AR), demyelinating neuropathy with early spine deformities caused by mutations in the SH3TC2 gene. To determine the spectrum of SH3TC2 mutations in the Czech population, the entire coding region of SH3TC2 was sequenced in 60 unrelated Czech patients. The prevalent mutation was shown to be the p.Arg954Stop. Therefore, 412 additional patients referred for CMT testing were tested for the presence of p.Arg954Stop only. Of 60 patients in whom the SH3TC2 gene was sequenced, at least one mutation was detected in 13 (21.7%) patients and biallelic pathogenic mutations were detected in 7 (11.6%) patients. Of the 412 patients tested for p.Arg954Stop, the mutation was found in 8 patients (1.94%), 6 were homozygous and 2 were heterozygous. The second causative mutation was detected by sequencing in one of the patients but not in the other. Nine novel sequence variants were detected. Their pathogenicity was further tested in silico and in control samples. Mutations in the SH3TC2 gene are a frequent cause of demyelinating hereditary neuropathy among Czech patients. In total, at least one mutation was found in 21 unrelated patients. CMT4C seems to be the most frequent type of AR CMT and one of the most frequent of all CMT types. Mutation p.Arg954Stop is highly prevalent in the Czech population. Patients with demyelinating neuropathy along with non-dominant mode of inheritance and negative for CMT1A/hereditary neuropathy with liability to pressure palsy should be tested for the presence of the p.Arg954Stop mutation or other mutations in the SH3TC2 gene. PMID- 21291454 TI - Identification of 11 novel mutations in 49 Korean patients with mucopolysaccharidosis type II. AB - Mucopolysaccharidosis type II (MPS II) or Hunter syndrome is a rare lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS). As MPS II is X-linked, patients are usually males with heterogeneous mutations ranging from point mutations to gross deletions and recombination. In 2003, we reported a mutation analysis of 25 patients with MPS II. In this study, 31 mutations in another 49 Korean patients (45 families) with MPS II are reported: 12 missense, nine deletions, four splicing, two nonsense, two insertions, one deletion/insertion, and IDS-IDS2 recombination mutations. Among these mutations, 11 were novel ones (4 missense mutations: Ser61Pro, Pro97Arg, Pro228Ala, and Pro261Ala; 5 deletions: c.344delA, c.420delG, c.768delT, c.1112delC and c.1402delC; 1 deletion/insertion: c.1222delinsTA; and 1 insertion mutation: c.359_360insATCC). The IDS-IDS2 recombination mutations were most frequently observed; all patients with this mutation had the severe MPS II phenotype. However, most of the patients (5/7) with the G374G splicing mutation had an attenuated phenotype, except for two sibling cases with the severe phenotype. Except for a few recurrent mutations such as the G374G, R443X, L522P, and recombination mutations, each patient had a unique individual mutation. Therefore, careful interpretation of genotype-phenotype correlations is warranted. PMID- 21291455 TI - X-linked dominant Charcot-Marie-Tooth disease with connexin 32 (Cx32) mutations in Koreans. AB - X-linked dominant Charcot-Marie-Tooth disease (CMTX) is an inherited peripheral neuropathy, caused mainly by a mutation of connexin 32 (Cx32) gene. We performed a mutation analysis of Cx32 by direct sequencing of the coding sequence, then identified 23 mutations from 28 Korean CMTX families. Nine mutations were not reported previously: Gly5Ser, Ser26fs, Val37Leu, Thr86Ile, Val152fs, Phe153Cys, Asp178X, Ala197Val, and Ile214Asn. The extracellular 2 (EC2) domain of Cx32 protein was the hot spot mutation domain in 44% of Koreans. Transmembrane domain 4 was rarely affected in Koreans (4%), compared with 14% of Europeans. The EC1 and intracellular domain was not affected in Koreans, although they were frequently affected in Europeans. This study revealed that the frequencies of CMTX with Cx32 mutations are specific to different ethnic groups. The frequency of CMTX (5.3%) caused by Cx32 mutation in Koreans is similar to those in Asians but lower than those in Europeans. This study suggests differences between CMTX patients with Cx32 mutations and ethnic background. PMID- 21291456 TI - Exome sequencing expedites disease gene discovery. PMID- 21291457 TI - Does physiotherapeutic intervention affect motor outcome in high-risk infants? An approach combining a randomized controlled trial and process evaluation. AB - AIM: The aim of this study was to examine the effects of intervention in infants at risk of developmental disorders on motor outcome, as measured by the Infant Motor Profile (IMP) and using the combined approach of a randomized controlled trial and process evaluation. METHOD: At a corrected age of 3 months, 46 infants (20 males, 26 females) recruited from the neonatal intensive care unit at the University Medical Centre Groningen (median birthweight 1210 g, range 585-4750 g; median gestational age 30 wks, range 25-40 wks) were included on the basis of definitely abnormal general movements. Exclusion criteria were severe congenital disorders and insufficient understanding of the Dutch language. The infants were assigned to either the family-centred COPing with and CAring for Infants with Special Needs (COPCA) intervention group (n=21; 9 males, 12 females) or the traditional infant physiotherapy (TIP) intervention group (n=25; 11 males, 14 females) for a period of 3 months. Three infants assigned to the TIP group (one male, two females) did not receive physiotherapy. IMP scores were measured by blinded assessors at 3, 4, 5, 6, and 18 months. At each age, the infants were neurologically examined. Physiotherapeutic sessions at 4 and 6 months were videotaped. Quantified physiotherapeutic actions were correlated with IMP scores at 6 and 18 months. RESULTS: The IMP scores of both the COPCA and TIP groups before, during, and after the intervention did not differ. Some physiotherapeutic actions were associated with IMP outcomes; the associations differed for infants who developed cerebral palsy (n=10) and those who did not (n=33). INTERPRETATION: At randomized controlled trial level, the scores of both the TIP and COPCA groups did not differ in effect on motor outcome, as measured with the IMP. The analysis of physiotherapeutic actions revealed associations between these actions and IMP outcomes. However, the small sample size of this study precludes pertinent conclusions. PMID- 21291458 TI - Getting our services right for children and young people. PMID- 21291459 TI - Have school-age cognitive outcomes improved for preterm infants in the last decade of neonatal care? PMID- 21291460 TI - Metabolic testing in children with cerebral palsy: less doing and more thinking? PMID- 21291461 TI - The effect of early confirmation of hearing loss on the behaviour in middle childhood of children with bilateral hearing impairment. PMID- 21291462 TI - Distribution of motor types in cerebral palsy: how do registry data compare? PMID- 21291463 TI - Physiotherapy in high-risk infants--a motor learning facilitator or not? PMID- 21291464 TI - Effects of leg muscle botulinum toxin A injections on walking in children with spasticity-related cerebral palsy: a systematic review. AB - AIM: To assess treatment effects of botulinum toxin type A (BoNT-A) on walking of children with leg spasticity due to cerebral palsy (CP) compared with usual care. METHOD: We systematically searched the databases CINAHL, Cochrane, PEDro, EMBASE, and PubMed from July 1993 until July 2009 and additionally screened reference lists. Randomized controlled trials assessing functional outcomes on walking of children with CP were included. The intervention had to contain BoNT-A into the lower limb and be compared with usual care. The methodological quality and clinical relevance were independently assessed by two of the authors (UCR, CHGB). If statistical pooling was not feasible, we performed a best-evidence synthesis. RESULTS: Eight trials were included. Trials comparing BoNT-A plus usual care or physiotherapy versus usual care or physiotherapy alone showed moderate evidence for functional outcomes at 2 to 6, 12, and 24 weeks follow-up in favour of BoNT A. Studies comparing BoNT-A versus casting showed strong evidence for no difference in effects between these interventions. A limitation of our review was the exclusion of studies not published in English, Dutch, or German. The heterogeneity of the included studies, especially for outcome measures and follow up assessments, prompted us to refrain from statistical pooling, which might also be considered a limitation. INTERPRETATION: The use of BoNT-A with usual care or physiotherapy seems to improve walking of children with CP, but results should be appraised carefully owing to the limited quality of included trials. PMID- 21291465 TI - The association of genetic polymorphisms with cerebral palsy: a meta-analysis. AB - AIM: The aim of our meta-analysis was to summarize quantitatively the association of genetic polymorphisms with cerebral palsy (CP). METHOD: We identified 16 studies on the association of genetic polymorphisms with CP in Pubmed, Elsevier Science Direct, Chinese Biomedical Literature Database, Chinese National Knowledge Infrastructure, and Wanfang. Eleven of these studies (involving a total of 2533 cases and 4432 controls) were used in the current meta-analysis. A study was included if (1) it was published up to September 2010 and (2) it was a case control study. We excluded one study of family members because the analysis was based on linkage considerations. Meta odds ratios and 95% confidence intervals based on fixed-effects models or random-effects models were dependent on Cochran's Q statistic. We examined the relationship between alleles, as well as genotypes and susceptibility to CP. RESULTS: Meta-analysis was performed for 17 genetic polymorphisms: apolipoprotein E (epsilon2,epsilon3,epsilon4), methylenetetrahydrofolate reductase (MTHFR) (rs1801133), coagulation factor II (rs1799963]), coagulation factor V (rs6025), coagulation factor VII (rs5742910/rs6046), interleukin-6 (IL-6) (rs1800795), endothelial nitric oxide (rs1800779/rs1799983/rs3918226), fibrinogen beta-polypeptide (rs1800790), plasminogen activator inhibitor 1 (rs1799768/rs7242), TNF-beta lymphotoxin alpha precursor (rs1041981), adducin 1 (alpha) (rs4961), ADRB2 (rs1042714), and tumour necrosis factor alpha (rs1800629). We found a significant association between CP and IL-6 (rs1800795) [C vs G: odds ratio (OR) 1.79, 95% confidence interval (CI) 1.44-2.22, p<0.001; CC+GC vs GG: OR 1.72, 95% CI 1.29-2.29, p=0.002; CC vs GG+GC: OR 2.17, 95% CI 1.52-3.09, p<0.001], but no other genetic polymorphisms. INTERPRETATION: This meta-analysis demonstrated that CP is associated with the genetic polymorphism IL-6 (rs1800795). PMID- 21291466 TI - Should children with cerebral palsy and normal imaging undergo testing for inherited metabolic disorders? AB - AIM: For the 9% to 16% of children with cerebral palsy (CP) who have normal brain imaging, further testing for metabolic and/or genetic conditions has been recommended. This study aimed to identify a cohort of children with CP with normal magnetic resonance imaging (MRI), clinically review and describe the cases, and assess the value of testing for inherited metabolic disorders in these children. METHOD: Children with congenital CP born from 1999 to 2005 were selected from a population register. Normal MRI reports were identified and the scans reassessed. Children whose scans were performed before 18 months were excluded, as were children with spastic CP (Gross Motor Function Classification System [GMFCS] level I). The remainder were reviewed clinically and offered investigations. RESULTS: Of 730 children identified, 515 had available imaging and 54 were confirmed as normal. Cases with non-spastic CP and those with milder clinical severity were more likely to have normal imaging. Twenty-three children (17 males, six females; mean age 6 y 11 mo, SD 1 y 10 mo, range 3 y 0 mo to 10 y 0 mo) were reviewed clinically and offered investigations. Twelve children had spasticity (11 with diplegia, one quadriplegia), three had dyskinesia, five ataxia, and three hypotonia. Two children functioned in GMFCS level I, 11 in level II, seven in level III and three in level IV. Four children with spasticity had unusual features. No alternative diagnoses were made. INTERPRETATION: Although important to consider in individual cases, comprehensive metabolic testing failed to clarify the aetiology of CP further in this large cohort of children with normal MRIs, even those with atypical features. PMID- 21291468 TI - Suicide by cop among female subjects in officer-involved shooting cases. AB - An analysis of suicide by cop (SBC) among female subjects in a large sample (n = 707) of officer-involved shootings (OIS) is reported. Women represented 3% of the total sample (n = 21) and 5% (n = 12) of the 256 SBC cases. Therefore, 57% of the women (n = 12) were classified as SBC, and 81% of the women (n = 17) behaviorally evidenced some suicidal motivation. The results underscore that when a female subject becomes involved in a situation leading to an OIS, there is a very high likelihood that she is motivated to be intentionally killed. She is almost guaranteed to have a diagnosed mental disorder, has been prescribed psychiatric medications, and is abusing a substance at the time, most likely alcohol. Nevertheless, she also poses a serious risk of injury to both police officers and civilians during the encounter and will possess a firearm half the time. The wish for suicide is often precipitated by serious relationship issues. Comparisons are made to the male subjects in our previous study. PMID- 21291469 TI - Phencyclidine: a 5-year retrospective review from the New York City Medical Examiner's Office. AB - We report here a 5-year retrospective review of autopsy cases from the New York City Medical Examiner's Office that demonstrated phencyclidine (PCP) in the blood. There were a total of 138 cases. There were 52 deaths because of mixed drug intoxication: the blood PCP concentrations in these cases ranged from <1 to 598 ng/mL. There were 80 violent deaths in which PCP was quantified in the blood but was unrelated to the cause of death. There were five nonviolent deaths in which PCP exclusively was detected. In four of these, there were preexisting medical conditions that could also have contributed to death. In these, the highest PCP concentration was 361.3 ng/mL, a concentration lower than seven of the individuals in our violent death category. This suggests that lower concentrations may be fatal with comorbid conditions. PMID- 21291470 TI - Trends in suicide by carbon monoxide inhalation in King County, Washington: 1996 2009. AB - Carbon monoxide (CO) inhalation is one of the leading methods of suicide in the United States. A sharp increase in suicide by inhaling the CO produced from burning charcoal has been reported in parts of Asia; however, the incidence of this method has not been determined in a U.S. population. Thus, we determined trends of CO suicide in the ethnically diverse population of King County, Washington, U.S.A. During the period 1996-2009, we identified 158 cases of suicide by CO poisoning, with 125 because of automotive exhaust, 26 because of charcoal burning, and seven from other CO sources. While historical U.S. data indicate >99% of CO suicides in the United States occurring by automobile exhaust inhalation, in the most recent years analyzed, c. 40% of CO-related suicides in King County, Washington, were because of charcoal burning, indicating a possible shift in suicide trends that warrants further scrutiny in additional populations. PMID- 21291471 TI - A female mass murder. AB - A case study of a 44-year-old woman who committed a mass murder is presented. Following a chronic course of psychotic deterioration, and a likely diagnosis of paranoid schizophrenia that remained untreated, she returned to her workplace after 3 years from her termination and killed seven people and herself. Her history is reconstructed through investigation of primary and secondary source materials. Although there are very few female mass murderers in recorded criminal history, this case is quite similar to the known research on mass murderers in general. Such individuals often have a psychotic disorder evident in violent and paranoid delusions, show a deteriorating life course before the mass murder, intentionally plan and prepare for their assault, and methodically kill as many individuals as possible before taking their own lives. They typically do not directly threaten the target beforehand, but do leak their intent to third parties--however, in this case, leakage and other obvious warning behaviors did not occur. Such acts are impossible to predict but depend on threat management and target security for risk mitigation. PMID- 21291472 TI - Characteristics of young suicides by violent methods in rural China. AB - Suicide is one of the most common public health problems in the world. Information on 392 completed suicides aged 15-34 years were consecutively collected from 16 counties in three provinces of China. Information on each suicide was obtained from two informants. The results showed ingesting pesticides or other poisons (73.5%) and hanging (10.5%) were the two most common methods of suicide. Suicides happened more in autumn (30.10%) or summer (27.29%), nighttime (68.3%), and at home (73.6%). However, suicides with violent methods were more common in winter and spring and outside of home. Season (autumn or summer), place (at home), and pesticide stored in home were negatively while depression was positively associated with violent methods of suicide. Characteristics of the suicides by violent methods are different from those by nonviolent methods. Investigations into the methods of rural young suicides are necessary for suicide prevention in China. PMID- 21291473 TI - S100B alters neuronal survival and dendrite extension via RAGE-mediated NF-kappaB signaling. AB - S100B is a soluble protein secreted by astrocytes that exerts pro-survival or pro apoptotic effects depending on the concentration reached in the extracellular millieu. The S100B receptor termed RAGE (for receptor for advanced end glycation products) is highly expressed in the developing brain but is undetectable in normal adult brain. In this study, we show that RAGE expression is induced in cortical neurons of the ischemic penumbra. Increased RAGE expression was also observed in primary cortical neurons exposed to excitotoxic glutamate (EG). S100B exerts effects on survival pathways and neurite extension when the cortical neurons have been previously exposed to EG and these S100B effects were prevented by anti-RAGE blocking antibodies. Furthermore, nuclear factor kappa B (NF-kappaB) is activated by S100B in a dose- and RAGE-dependent manner and neuronal death induced by NF-kappaB inhibition was prevented by S100B that restored NF-kappaB activation levels. Together, these findings suggest that excitotoxic damage can induce RAGE expression in neurons from ischemic penumbra and demonstrate that cortical neurons respond to S100B through engagement of RAGE followed by activation of NF-kappaB signaling. In addition, basal NF-kappaB activity in neurons is crucial to modulate the extent of pro-survival or pro-death S100B effects. PMID- 21291474 TI - Quantitative targeted absolute proteomics of human blood-brain barrier transporters and receptors. AB - We have obtained, for the first time, a quantitative protein expression profile of membrane transporters and receptors in human brain microvessels, that is, the blood-brain barrier (BBB). Brain microvessels were isolated from brain cortexes of seven males (16-77 years old) and protein expression of 114 membrane proteins was determined by means of a liquid chromatography-tandem mass spectrometric quantification method using recently established in-silico peptide selection criteria. Among drug transporters, breast cancer resistance protein showed the most abundant protein expression (8.14 fmol/MUg protein), and its expression level was 1.85-fold greater in humans than in mice. By contrast, the expression level of P-glycoprotein in humans (6.06 fmol/MUg protein) was 2.33-fold smaller than that of mdr1a in mice. The organic anion transporters reported in rodent BBB, that is, multidrug resistance-associated protein, organic anion transporter and organic anion-transporting polypeptide family members, were under limit of quantification in humans, except multidrug resistance-associated protein 4 (0.195 fmol/MUg protein). Among detected transporters and receptors for endogenous substances, the glucose transporter 1 level was similar to that of mouse, while the L-type amino acid transporter 1 level was fivefold smaller than that of mouse. These findings should be useful for understanding human BBB function and its differences from that in mouse. PMID- 21291475 TI - Proteomic analysis of cPKCbetaII-interacting proteins involved in HPC-induced neuroprotection against cerebral ischemia of mice. AB - Hypoxic preconditioning (HPC) initiates intracellular signaling pathway to provide protection against subsequent cerebral ischemic injuries, and its mechanism may provide molecular targets for therapy in stroke. According to our study of conventional protein kinase C betaII (cPKCbetaII) activation in HPC, the role of cPKCbetaII in HPC-induced neuroprotection and its interacting proteins were determined in this study. The autohypoxia-induced HPC and middle cerebral artery occlusion (MCAO)-induced cerebral ischemia mouse models were prepared as reported. We found that HPC reduced 6 h MCAO-induced neurological deficits, infarct volume, edema ratio and cell apoptosis in peri-infarct region (penumbra), but cPKCbetaII inhibitors Go6983 and LY333531 blocked HPC-induced neuroprotection. Proteomic analysis revealed that the expression of four proteins in cytosol and eight proteins in particulate fraction changed significantly among 49 identified cPKCbetaII-interacting proteins in cortex of HPC mice. In addition, HPC could inhibit the decrease of phosphorylated collapsin response mediator protein-2 (CRMP-2) level and increase of CRMP-2 breakdown product. TAT-CRMP-2 peptide, which prevents the cleavage of endogenous CRMP-2, could inhibit CRMP-2 dephosphorylation and proteolysis as well as the infarct volume of 6 h MCAO mice. This study is the first to report multiple cPKCbetaII-interacting proteins in HPC mouse brain and the role of cPKCbetaII-CRMP-2 in HPC-induced neuroprotection against early stages of ischemic injuries in mice. PMID- 21291476 TI - Bisphosphonates and osteonecrosis of the jaw: proceedings of an international conference. AB - There has been an upsurge of multidisciplinary research since the adoption of a standardized definition of osteonecrosis of the jaw (ONJ) and the first bisphosphenate-related ONJ conference in 2007 held at the New York Academy of Sciences. This series of papers revisits topics presented at the conference in addition to covering recent advances in the history, mechanisms, clinical management, and prevention of bisphosphonate-related ONJ. PMID- 21291477 TI - The impact of bisphosphonates on oral health: lessons from the past and opportunities for the future. AB - Osteonecrosis of the jaw (ONJ), a challenging medical condition seen primarily among intravenous bisphosphonate (BP) users, is characterized by exposed necrotic bone that persists for more than eight weeks. While rare among people with osteoporosis treated with oral BPs, ONJ has captured the public's attention and caused significant distress. For many, the risk-benefit scale has conceptually changed, tipping steeply toward risk, while for others the benefit of increased bone mass still outweighs the possibility of ONJ. While more than seven years have passed since the first cases were published, the scientific and medical communities are not yet ready to address with certainty the issue of causal inference, nor do they have any concrete recommendations for risk assessment or management of ONJ. Equally important, the dental literature has been skewed by the perceived risk associated with prolonged use of BPs and has neglected to explore how the antiosteoclastic activity of BPs may be utilized to improve dental outcomes. This article reviews critically the current state of knowledge about the impact of bisphosphonates on oral health. Using the principles of epidemiology, the article identifies scientific gains, research challenges, and future research opportunities on the topic. PMID- 21291479 TI - Rapid and simple detection of the invA gene in Salmonella spp. by isothermal target and probe amplification (iTPA). AB - AIMS: Salmonella spp. are an important cause of food-borne infections throughout world, and the availability of rapid and simple detection techniques is critical for the food industry. Salmonella enterica serovars Enteritidis and Typhimurium cause the majority of human gastroenteritis infections, and there are a reported 40,000 cases of salmonellosis in the United States each year. METHODS AND RESULTS: A novel rapid and simple isothermal target and probe amplification (iTPA) assay that rapidly amplifies target DNA (Salmonella invA gene) using a FRET-based signal probe in an isothermal environment was developed for detection Salmonella spp. in pre-enriched food samples. The assay was able to specifically detect all of 10 Salmonella spp. strains without detecting 40 non-Salmonella strains. The detection limit was 4 x 101 CFU per assay. The iTPA assay detected at an initial inoculum level of <10 CFU in the pre-enriched food samples (egg yolk, chicken breast and peanut butter). CONCLUSIONS: This detection system requires only a water bath and a fluorometer and has great potential for use as a hand-held device or point-of-care-testing diagnostics. The iTPA assay is sensitive and specific and has potential for rapid screening of Salmonella spp. by food industry. PMID- 21291478 TI - Potential pathophysiological mechanisms in osteonecrosis of the jaw. AB - Bisphosphonates are used in the treatment of hypercalcemia of malignancy, skeletal complications associated with metastastic bone disease, Paget's disease, and osteoporosis. Osteonecrosis of the jaw (ONJ) is a recently described clinical condition that has been associated with the use of nitrogen-containing bisphosphonates. Reports describing this entity first appeared in the literature in 2003. While there have been significant numbers of case reports and a limited number of retrospective and prospective studies examining risk factors associated with ONJ, the pathophysiology of this condition remains elusive. In this review, we explore proposed mechanisms underlying ONJ development and identify potential areas for future investigation. PMID- 21291480 TI - Silica-immobilized Methylobacterium sp. NP3 and Acinetobacter sp. PK1 degrade high concentrations of phenol. AB - AIMS: To immobilize Methylobacterium sp. NP3 and Acinetobacter sp. PK1 to silica and determine the ability of the immobilized bacteria to degrade high concentrations of phenol. METHODS AND RESULTS: The phenol degradation activity of suspended and immobilized Methylobacterium sp. NP3 and Acinetobacter sp. PK1 bacteria was investigated in batch experiments with various concentrations of phenol. The bacterial cells were immobilized by attachment to or encapsulation in silica. The encapsulated bacteria had the highest phenol degradation rate, especially at initial phenol concentrations between 7500 and 10000 mg l(-1) . Additionally, the immobilized cells could continuously degrade phenol for up to 55 days. CONCLUSIONS: The encapsulation of a mixed culture of Methylobacterium sp. NP3 and Acinetobacter sp. PK1 is an effective and easy technique that can be used to improve bacterial stability and phenol degradation. SIGNIFICANCE AND IMPACT OF THE STUDY: Wastewater from various industries contains high concentrations of phenol, which can cause wastewater treatment failure. Silica immobilized bacteria could be applied in bioreactors to initially remove the phenol, thereby preventing phenol shock loads to the wastewater treatment system. PMID- 21291481 TI - Inhibitory effects of gossypol-related compounds on growth of Aspergillus flavus. AB - AIMS: The objective of this study was to test a series of gossypol-related compounds for growth inhibition against Aspergillus flavus. METHODS AND RESULTS: A series of chiral and achiral gossypol derivatives, some natural products of the cotton plant and others prepared by synthesis from gossypol, were incorporated into agar plates to follow the rate of A. flavus isolate AF13 colony growth. All tested compounds exhibited some growth inhibition against this organism. The synthetic compounds, gossypolone and apogossypolone, exhibited greater activity than either racemic or chiral gossypol. Methylated derivatives (i.e. 6-methoxy and 6,6'-dimethoxy derivatives) generally exhibited less activity than the nonmethylated parent compounds. The (-)-optical form of gossypol was found to be slightly more active than the (+)-optical form, and this trend was observed regardless of the presence of methoxy groups at the 6-position. Growth inhibition of gossypolone and apogossypolone was concentration dependent. For gossypolone, the 50% effective dose was 90 MUg ml-1 of medium (165 MUmol l-1). For apogossypolone, the most active compound in the study, the 50% effective dose was 19 MUg ml-1 (38.7 MUmol l-1). The presence of gossypol-related terpenoids appeared to stimulate production of A. flavus sclerotia, although replicate variability was so large that it was not possible to determine a significant correlation between the mass of sclerotia formed and compound growth inhibition. CONCLUSIONS: The quinone derivatives of gossypol, gossypolone and apogossypolone demonstrated significant fungal growth inhibitory activity against A. flavus. SIGNIFICANCE AND IMPACT OF THE STUDY: These gossypol derivatives may provide a new class of fungicide for use against the mycotoxigenic fungus A. flavus. PMID- 21291482 TI - Subconjunctival mycetoma caused by Scedosporium apiospermum infection in a horse. AB - An 11-year-old American Saddlebred gelding was presented for evaluation of a nonpainful subconjunctival mass involving the lateral canthus of the left eye. Other findings included a central corneal scar and a small central cataract of the lens in the left eye. Fine-needle aspiration of the mass was performed and cytologic examination revealed marked pyogranulomatous inflammation with intralesional fungal hyphae, consistent with mycetoma. The fungal structures were elongated and characterized by nonstaining walls; several bulbous yeast-like structures were also observed. The mycetoma was surgically removed and submitted for histopathologic examination and fungal culture. The histopathologic diagnosis was subconjunctival phaeohyphomycosis. Scedosporium apiospermum was identified based on macroscopic and microscopic features of the organism in culture. Scedosporium spp. have been reported as causes of mycetomatous and nonmycetomatous infections in both immunocompromised and immunocompetent people and animals. S. apiospermum and Pseudallescheria boydii, which is its teleomorphic counterpart, have been implicated as potentially emerging human and veterinary pathogens. Timely diagnosis is essential as the organism is often resistant to commonly used antifungal drugs. This report provides a detailed cytologic description of the organism and recent information on the taxonomy of this fungus and the diagnostic peculiarities of this particular infection. PMID- 21291483 TI - Glanzmann thrombasthenia in a 17-year-old Peruvian Paso mare. AB - A 17-year-old Peruvian Paso mare was evaluated for bilateral epistaxis that had been present for at least 3 years. The mare had mild anemia, platelet count within the reference interval, unremarkable coagulation times, and a negative Coggins test. On endoscopic examination, structural abnormalities were not observed in the nasal cavities, pharynx, larynx, trachea, or either guttural pouch, but petechiation was noted in the nasal mucosa. Additional tests revealed prolonged cutaneous bleeding time, normal concentration of von Willebrand factor antigen, an abnormal clot retraction test, and failure of plalelet aggregation in response to agonists, suggesting a functional disorder of platelets. Genetic analysis indicated the horse was homozygous for a 10-base-pair deletion that included the last 3 base pairs of exon 11 and the first 7 base pairs of intron 11 of the gene encoding glycoprotein IIb. The diagnosis was Glanzmann thrombasthenia (GT) caused by a structural defect in glycoprotein IIb. GT is an autosomal recessive disorder caused by a defect in the glycoprotein IIb-IIIa complex on platelet surfaces. Separate genes encode each glycoprotein, and mutations in either gene can result in GT. This case of GT is unique given the age of the mare at the time of diagnosis. We conclude that GT, although an inherited disorder, should be considered in horses with suspected dysfunctional platelets, regardless of age. PMID- 21291484 TI - What is your diagnosis? Cutaneous mass in the mammary region of a dog. Acantholytic squamous cell carcinoma (ASCC). PMID- 21291485 TI - Idiopathic solitary cutaneous xanthoma in a dog. AB - A 6-year-old female spayed Boxer mix dog was presented with multiple cutaneous masses, one of which was determined to be a xanthoma. Fine-needle aspirates of this mass revealed large round cells that were consistent with macrophages. These macrophages had lightly basophilic cytoplasm that was filled with many clear circular spaces that varied in size. The nuclei of these cells displayed mild anisokaryosis with condensed chromatin and lacked prominent nucleoli. The cytologic interpretation was lipid-laden histiocytic inflammation most consistent with a cutaneous xanthoma, which was confirmed histologically. Mild hypertriglyceridemia and persistent moderate hypercholesterolemia were present. After ruling out other causes of hyperlipidemia, we concluded that the dog likely had idiopathic hyperlipidemia with secondary xanthoma formation. PMID- 21291486 TI - What is your diagnosis? Cerebrospinal fluid from a dog. Eosinophilic pleocytosis due to protothecosis. PMID- 21291487 TI - Cytologic patterns of lymphadenopathy in canine monocytic ehrlichiosis. AB - BACKGROUND: Recognition of different cytologic patterns in lymph nodes (LNs) from dogs with canine monocytic ehrlichiosis (CME) and noninfectious causes of lymphoid reactivity may have diagnostic utility. OBJECTIVES: The aims of the present study were to compare cytologic patterns in LNs of dogs with different phases of CME, to investigate the association of cytologic pattern and presence of Ehrlichia spp. morulae, and to compare patterns of lymphoid reactivity between dogs with CME and those with noninfectious causes of lymphoid hyperplasia. METHODS: Cytologic preparations of LNs from 35 dogs with nonmyelosuppressive CME (group A), 16 dogs with myelosuppressive CME (group B), 26 dogs with noninfectious diseases (group C), and 15 healthy dogs (group D) were evaluated. Percentages of lymphocyte types, plasma cells, macrophages, neutrophils, and eosinophils were determined. Samples from dogs in groups A and B were evaluated for the presence of morulae. RESULTS: Cytologic abnormalities in LNs were recorded in 54% of dogs in group A, 88% in group B, 39% in group C, and 0% in group D and were more frequent (P=.02) in dogs with myelosuppressive CME than those with nonmyelosuppressive CME. Plasma cell hyperplasia was more frequent in CME than in noninfectious diseases (P=.03). An association between the presence of cytologic abnormalities and morulae in group A dogs was not found. CONCLUSIONS: Dogs with myelosuppressive CME have more lymphoid cytologic abnormalities than dogs with nonmyelosuppressive CME. LN plasmacytosis is the major pattern of lymphadenopathy in dogs with CME and is found more frequently in dogs with CME than in dogs with noninfectious causes of lymphadenopathy. PMID- 21291488 TI - Serum alpha-1-acid glycoprotein concentrations in 26 dogs with pyometra. AB - BACKGROUND: The acute phase protein, alpha-1-acid glycoprotein (AGP), has been proposed to have a role in immunomodulation and to be a nonspecific antimicrobial agent. We suggest that AGP may be increased in dogs with pyometra and possibly to a greater extent in dogs also manifesting signs of systemic inflammatory response syndrome (SIRS). OBJECTIVES: Our objectives were to evaluate serum AGP concentrations in dogs diagnosed with pyometra compared with clinically healthy female dogs and to determine if AGP concentrations were correlated with severity of disease. METHODS: Twenty-six dogs with pyometra and 18 clinically healthy intact female dogs were included in this prospective study. A diagnosis of pyometra was verified by histopathologic examination after ovariohysterectomy in the pyometra group. A commercially available single radial immunodiffusion test was used for AGP analysis. Clinical findings, laboratory variables, and hospitalization times were compared. RESULTS: Mean AGP concentration in dogs with pyometra (1943 +/- 913 mg/L, mean +/- SD), was significantly higher (P<.001) than in healthy dogs (495 +/- 204 mg/L). Mean AGP concentration in dogs in the pyometra group with (n=18) or without (n=8) SIRS did not differ. Animals with a prolonged hospital stay had higher AGP concentrations. CONCLUSIONS: Pyometra was associated with increased serum concentrations of the acute phase protein AGP. AGP concentrations were associated with severity of disease as measured by duration of hospitalization. As AGP binds basic drugs, further studies of its pharmacokinetic and pharmacodynamic propreties in cases of pyometra may be of clinical interest. PMID- 21291489 TI - What is your diagnosis? Lymphadenopathy in a cow with severe anemia. Bovine trypanosomiasis. PMID- 21291490 TI - Paraneoplastic leukocytosis in a dog with a renal carcinoma. AB - A 7-year-old male German Shepherd dog in poor body condition had a 3-month history of intermittent hematuria. Nonregenerative anemia, mild leukocytosis, marked hypoalbuminemia, and hematuria were observed. Subsequently, marked neutrophilia and moderate monocytosis were noted; anemia, hypoalbuminemia, and hematuria persisted; and the dog developed disseminated intravascular coagulation. Ultrasonographic examination of the abdomen revealed the presence of an enlarged and irregularly shaped right kidney with a large area of cavitation, and a nephrectomy was performed 30 days after initial examination. Cytologic examination of fine-needle aspirates and imprints of the right kidney revealed a neoplastic cell population suggestive of renal carcinoma. The histopathologic diagnosis was chromophobic cystic-papillary renal carcinoma. The tumor cells expressed granulocytic/macrophage-colony-stimulating factor (GM-CSF), detected by immunohistochemical staining, and elaboration of GM-CSF by the tumor may have mediated the leukocytosis in this dog. Following excision of the tumor, neutrophil and monocyte counts were only mildly increased. The dog died 135 days after initial presentation, and a necropsy was not permitted. Paraneoplastic neutrophilic leukocytosis is an uncommon finding and may be caused by elaboration of CSF by neoplastic cells. PMID- 21291491 TI - Desensitization of depolarization-mediated contractile pathways does not necessarily regulate receptor-mediated excitation-contraction coupling in longitudinal smooth muscle of guinea pig ileum. AB - 1. Activation of G(q) protein-coupled receptors, such as muscarinic M(3) and histamine H(1) receptors, induces smooth muscle contraction through activation of voltage-dependent Ca channels. 2. To evaluate roles of depolarization-mediated contractile pathways in the desensitization of receptor-mediated contraction, we compared the development of carbachol-induced desensitization to receptor agonists, carbachol and histamine, and to receptor-bypassed stimulation of voltage-dependent Ca channels with depolarizing high K in longitudinal smooth muscle of guinea pig ileum. 3. Under Ca-containing physiological conditions, pretreatment with 10(-4) mol/L carbachol for 15 s-30 min induced desensitization to carbachol as well as to high K, whereas contractile responses to histamine remained normal. 4. In contrast, under Ca-free conditions containing 0.2 mmol/L EGTA, carbachol pretreatment induced desensitization to high K in a manner similar to that induced under Ca-containing physiological conditions, whereas contractile responses to carbachol and histamine remained normal. 5. Thus, it was shown that contractile responses to carbachol and histamine were not necessarily desensitized, even under conditions where contractile responses to high K were desensitized. These results suggest that desensitization of depolarization mediated contractile pathways might not necessarily regulate excitation contraction coupling through muscarinic M(3) and histamine H(1) receptors in longitudinal smooth muscle of guinea pig ileum. PMID- 21291492 TI - Activation of peroxisome proliferator-activated receptor-gamma downregulates soluble epoxide hydrolase in cardiomyocytes. AB - 1. The antidiabetic agents, thiazolidinediones (TZD), ligands for peroxisome proliferator-activated receptor-gamma (PPARgamma), have been reported to reduce cardiac hypertrophy. However, the underlying mechanism is still elusive. 2. We previously reported that soluble epoxide hydrolase (sEH) was specifically upregulated by angiotensin-II (AngII), which directly mediated AngII-induced cardiac hypertrophy. In the present study, we examined the role of sEH in PPARgamma inhibiting AngII-induced cardiac hypertrophy. 3. The protein level of sEH was elevated in the left ventricle of AngII-infused Sprague-Dawley rats. Administration of the TZD rosiglitazone decreased this induction. In vitro, AngII upregulated the expression of sEH and hypertrophy markers, including atrial natriuretic factor and beta-myosin heavy chain, in rat neonatal cardiomyocytes and H9c2 cells, which was attenuated by rosiglitazone and pioglitazone. An elevated level of sEH was also found in the left ventricle of heterozygous PPARgamma-deficient mice. The effect of TZD on sEH level could be reversed by treatment with the PPARgamma antagonists, GW9662 and BADGE, which suggests PPARgamma activation. In elucidating the mechanisms by which PPARgamma inhibited AngII-induced sEH expression, we found that rosiglitazone inhibited AngII-induced sEH promoter activity in H9c2 cells. In contrast, the activity of the human sEH 3'UTR was not affected by AngII and TZD. 4. Our results suggest that the protective role of PPARgamma activation in AngII-induced cardiac hypertrophy is, at least in part, through downregulating sEH. PMID- 21291493 TI - MicroRNA-375 promotes 3T3-L1 adipocyte differentiation through modulation of extracellular signal-regulated kinase signalling. AB - 1. Adipocyte hypertrophy and hyperplasia are important processes in the development of obesity. To understand obesity and its associated diseases, it is important to elucidate the molecular mechanisms governing adipogenesis. MicroRNA 375 has been shown to inhibit differentiation of neurites, and participate in the regulation of insulin secretion and blood homeostasis. However, it is unknown whether miR-375 plays a role in adipocyte differentiation. 2. To investigate the role of miR-375 in adipocyte differentiation, we compared the miR-375 expression level between 3T3-L1 pre-adipocytes and adipocytes using miRNA microarray and quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) analysis. Furthermore, we evaluated the effects of overexpression or inhibition of miR-375 on 3T3-L1 adipocyte differentiation. 3. In the present study, we found that miR-375 expression was increased after induction of adipogenic differentiation. Overexpression of miR-375 enhanced 3T3-L1 adipocyte differentiation, as evidenced by its ability to increase mRNA levels of both CCAAT/enhancer binding protein-alpha (C/EBPalpha) and peroxisome proliferator activated receptor-gamma (PPARgamma2), and induction of adipocyte fatty acid binding protein (aP2) and triglyceride (TG) accumulation. Furthermore, we found overexpression of miR-375 suppressed phosphorylation levels of extracellular signal-regulated kinases 1/2 (ERK1/2). In contrast, anti-miR-375 increased ERK1/2 phosphorylation levels and inhibited mRNA expression of C/EBPalpha, PPARgamma2 and aP2 in 3T3-L1 adipocyte, accompanied by decreased adipocyte differentiation. 4. Taken together, these data suggest that miR-375 promotes 3T3-L1 adipocyte differentiation, possibly through modulating the ERK-PPARgamma2-aP2 pathway. PMID- 21291494 TI - Comparative and evolutionary analysis of plasmid pREN isolated from Lactobacillus rennini, a novel member of the theta-replicating pUCL287 family. AB - Here, we describe plasmid pREN of Lactobacillus rennini ACA-DC 1534, isolated from traditional Kopanisti cheese. pREN is a circular molecule of 4371 bp. Orf calling revealed a novel repA-orf2 operon with the deduced product of orf2 showing no similarity to other known proteins. Downstream of this operon, a gene cluster encoding different mobilization proteins, namely mobC, mobA1, mobA2 and mobB, was detected. Based on the sequence of the origin of replication (ori) and the similarity pattern of RepA, pREN was placed in the pUCL287 family of theta replicating plasmids. Multiple sequence alignment demonstrated for the first time the degree of conservation in the pUCL287 oris. Our analysis supported that the identified conserved repeats could drive similar secondary structures in the oris of all plasmids. Furthermore, comparative mapping of pREN with its related plasmids (i.e. pLB925A03 and pLJ42) showed that they retain a unique combination in the architecture of their replication and mobilization elements within the pUCL287 family. Phylogenetic analysis also established that these plasmids have undergone a modular evolutionary process in order to acquire their mob genes. Research on plasmids from uncommon lactic acid bacteria will expand our appreciation for their divergence and will aid their rational selection for biotechnological applications. PMID- 21291495 TI - Relationship between heat-induced fibrillogenicity and hemolytic activity of thermostable direct hemolysin and a related hemolysin of Vibrio parahaemolyticus. AB - The formation of nonspecific ion channels by small oligomeric amyloid intermediates is toxic to the host's cellular membranes. Thermostable direct hemolysin (TDH) and TDH-related hemolysin (TRH) are major virulence factors of Vibrio parahaemolyticus. We have previously reported the crystal structure of TDH tetramer with the central channel. We have also identified the molecular mechanism underlying the paradoxical responses to heat treatment of TDH, known as the Arrhenius effect, which is the reversible amyloidogenic property. In the present report, we describe the biophysical properties of TRH, which displays 67% amino acid similarity with TDH. Molecular modeling provided a good fit of the overall structure of TDH and TRH. Size-exclusion chromatography, ultracentrifugation, and transmission electron microscopy revealed that TRH formed tetramer in solution. These toxins showed similar hemolytic activity on red blood cells. However, TRH had less amyloid-like structure than TDH analyzed by thioflavin T-binding assay and far-UV circular dichroism spectra. These data indicated that amyloidogenicity upon heating is not essential for the membrane disruption of erythrocytes, but the maintenance of tetrameric structure is indispensable for the hemolytic activity of the TDH and TRH. PMID- 21291496 TI - Morphology and laccase production of white-rot fungi grown on wheat bran flakes under semi-solid-state fermentation conditions. AB - In this paper, we studied the laccase production and the growth morphology of different white-rot fungi, i.e. Pleurotus ostreatus, Trametes pubescens, Cerrena unicolor and Trametes versicolor, cultured under semi-solid-state fermentation conditions using wheat bran flakes as a natural low-cost support substrate. Trametes versicolor exhibited the highest laccase activity per gram of total dry matter, followed by P. ostreatus (63.5 and 58.2Ug(-1) , respectively). In addition, they showed a time profile of laccase production that was quite similar. Growth morphology was studied using environmental microscopic images and analyzed by discrete Fourier transformation-based software to determine the mean diameter of the hyphae, the number of hypha layers and the global micromorphology. The four strains exhibited different micromorphologies of growth. Pleurotus ostreatus presented narrow hyphae, which formed many thick clumps, T. pubescens and T. versicolor showed clumps of different sizes and C. unicolor showed thick hyphae that formed larger clumps, but in less amounts. PMID- 21291497 TI - Cutaneous tuberculosis mimicking erysipelas of the lower leg in a heart transplant recipient. PMID- 21291498 TI - Decision tables and rule engines in organ allocation systems for optimal transparency and flexibility. AB - Organ allocation systems have become complex and difficult to comprehend. We introduced decision tables to specify the rules of allocation systems for different organs. A rule engine with decision tables as input was tested for the Kidney Allocation System (ETKAS). We compared this rule engine with the currently used ETKAS by running 11,000 historical match runs and by running the rule engine in parallel with the ETKAS on our allocation system. Decision tables were easy to implement and successful in verifying correctness, completeness, and consistency. The outcomes of the 11,000 historical matches in the rule engine and the ETKAS were exactly the same. Running the rule engine simultaneously in parallel and in real time with the ETKAS also produced no differences. Specifying organ allocation rules in decision tables is already a great step forward in enhancing the clarity of the systems. Yet, using these tables as rule engine input for matches optimizes the flexibility, simplicity and clarity of the whole process, from specification to the performed matches, and in addition this new method allows well controlled simulations. PMID- 21291499 TI - Epigallocatechin-3-gallate protects kidneys from ischemia reperfusion injury by HO-1 upregulation and inhibition of macrophage infiltration. AB - Epigallocatechin-3-gallate (EGCG) shows diverse chemical and biological activities. We investigated the effects of EGCG in a rat renal ischemia reperfusion (I/R) injury model. Sprague-Dawley rats received intraperitoneal injection of 50 mg/kg EGCG 48 h, 24 h, and 30 min prior to I/R injury. The animals were subjected to left renal occlusion for 45 min. EGCG treatment suppressed the peak in serum creatinine. EGCG-treated kidneys showed significantly less tubular damage and a decreased number of apoptotic cells. The I/R-induced elevation in the renal MDA level was significantly decreased in the EGCG group. Reverse-transcriptase polymerase chain reaction showed that EGCG significantly decreased the expression of MHC class II, TLR2, TLR4, MCP-1, IL-18, TGF-beta1, procollagen Ia1, TIMP-1, and Kim-1. ED-1 staining showed reduced macrophage infiltration and alpha-SMA staining revealed less interstitial expression. Heme oxygenase-1 (HO-1) expression in I/R kidneys was upregulated in the EGCG group based on the results of both RT-PCR and Western blotting analysis. Blockade of HO-1 gene induction by SnPP increased renal tubular damage and macrophage infiltration. These findings suggest that EGCG protects the kidneys against I/R injury by reducing macrophage infiltration and decreasing renal fibrosis. These beneficial effects may be mediated, in part, by augmentation of the HO-1 gene. PMID- 21291500 TI - Major histocompatibility complex heterozygosity enhances reproductive success. AB - We investigated how heterozygosity at the major histocompatibility complex (MHC) affects fitness in wild-derived (F2) house mice (Mus musculus musculus). To compare and control for potential confounding effects from close inbreeding and genome-wide heterozygosity, we used mice that were systematically outbred. We assessed how heterozygosity at MHC and background loci (using 15 microsatellite markers on 11 different chromosomes) affects individual survival and reproductive success (RS) in large, semi-natural population enclosures. We found that overall heterozygosity significantly increased RS, and this correlation was entirely explained by heterozygosity at two MHC loci. Moreover, we found that the effects of MHC heterozygosity depend on the level of background heterozygosity, and the benefits of maximal MHC heterozygosity show a curvilinear effect with increasing background heterozygosity. The enhanced RS from MHC heterozygosity was not because of increased survival, and although MHC heterozygosity was correlated with body mass, body mass did not correlate with RS when heterozygosity is controlled. Breeders were more MHC heterozygous than nonbreeders for both sexes, indicating that MHC heterozygosity enhanced fecundity, mating success or both. Our results show that (i) MHC heterozygosity enhances fitness among wild, outbred as well as congenic laboratory mice; (ii) heterozygosity-fitness correlations can potentially be explained by a few loci, such as MHC; (iii) MHC heterozygosity can increase fitness, even without affecting survival, by increasing mating and RS; and (iv) MHC effects depend on background genes, and maximal MHC heterozygosity is most beneficial at intermediate or optimal levels of background heterozygosity. PMID- 21291501 TI - Molecular mechanism of co-translational protein targeting by the signal recognition particle. AB - The signal recognition particle (SRP) is a key component of the cellular machinery that couples the ongoing synthesis of proteins to their proper localization, and has often served as a paradigm for understanding the molecular basis of protein localization within the cell. The SRP pathway exemplifies several key molecular events required for protein targeting to cellular membranes: the specific recognition of signal sequences on cargo proteins, the efficient delivery of cargo to the target membrane, the productive unloading of cargo to the translocation machinery and the precise spatial and temporal coordination of these molecular events. Here we highlight recent advances in our understanding of the molecular mechanisms underlying this pathway, and discuss new questions raised by these findings. PMID- 21291502 TI - The recycling endosome protein Rab17 regulates melanocytic filopodia formation and melanosome trafficking. AB - Rab GTPases including Rab27a, Rab38 and Rab32 function in melanosome maturation or trafficking in melanocytes. A screen to identify additional Rabs involved in these processes revealed the localization of GFP-Rab17 on recycling endosomes (REs) and melanosomes in melanocytic cells. Rab17 mRNA expression is regulated by microphthalmia transcription factor (MITF), a characteristic of known pigmentation genes. Rab17 siRNA knockdown in melanoma cells quantitatively increased melanosome concentration at the cell periphery. Rab17 knockdown did not inhibit melanosome maturation nor movement, but it caused accumulation of melanin inside cells. Double knockdown of Rab17 and Rab27a indicated that Rab17 acts on melanosomes downstream of Rab27a. Filopodia are known to play a role in melanosome transfer, and in Rab17 knockdown cells filopodia formation was inhibited. Furthermore, we show that stimulation of melanoma cells with alpha melanocyte-stimulating hormone induces filopodia formation, supporting a role for filopodia in melanosome release. Cell stimulation also caused redistribution of REs to the periphery, and knockdown of additional RE-associated Rabs 11a and 11b produced a similar accumulation of melanosomes and melanin to that seen after loss of Rab17. Our findings reveal new functions for RE and Rab17 in pigmentation through a distal step in the process of melanosome release via filopodia. PMID- 21291503 TI - Sed4p stimulates Sar1p GTP hydrolysis and promotes limited coat disassembly. AB - The coat protein complex II (COPII) generates transport vesicles that mediate protein export from the endoplasmic reticulum (ER). The first step of COPII vesicle formation involves conversion of Sar1p-GDP to Sar1p-GTP by guanine nucleotide-exchange factor (GEF) Sec12p. In Saccharomyces cerevisiae, Sed4p is a structural homolog of Sec12p, but no GEF activity toward Sar1p has been found. Although the role of Sed4p in COPII vesicle formation is implied by the genetic interaction with SAR1, the molecular basis by which Sed4p contributes to this process is unclear. This study showed that the cytoplasmic domain of Sed4p preferentially binds the nucleotide-free form of Sar1p and that Sed4p binding stimulates both the intrinsic and Sec23p GTPase-activating protein (GAP) accelerated GTPase activity of Sar1p. This stimulation of Sec23p GAP activity by Sed4p leads to accelerated dissociation of coat proteins from membranes. However, Sed4p binding to Sar1p occurs only when cargo is not associated with Sar1p. On the basis of these findings, Sed4p appears to accelerate the dissociation of the Sec23/24p coat from the membrane, but the effect is limited to Sar1p molecules that do not capture cargo protein. We speculate that this restricted coat disassembly may contribute to the concentration of specific cargo molecules into the COPII vesicles. PMID- 21291504 TI - Escherichia coli producing CNF1 toxin hijacks Tollip to trigger Rac1-dependent cell invasion. AB - Rho GTPases, which are master regulators of both the actin cytoskeleton and membrane trafficking, are often hijacked by pathogens to enable their invasion of host cells. Here we report that the cytotoxic necrotizing factor-1 (CNF1) toxin of uropathogenic Escherichia coli (UPEC) promotes Rac1-dependent entry of bacteria into host cells. Our screen for proteins involved in Rac1-dependent UPEC entry identifies the Toll-interacting protein (Tollip) as a new interacting protein of Rac1 and its ubiquitinated forms. We show that knockdown of Tollip reduces CNF1-induced Rac1-dependent UPEC entry. Tollip depletion also reduces the Rac1-dependent entry of Listeria monocytogenes expressing InlB invasion protein. Moreover, knockdown of Tollip, Tom1 and clathrin, decreases CNF1 and Rac1 dependent internalization of UPEC. Finally, we show that Tollip, Tom1 and clathrin associate with Rac1 and localize at the site of bacterial entry. Collectively, these findings reveal a new link between Rac1 and Tollip, Tom1 and clathrin membrane trafficking components hijacked by pathogenic bacteria to allow their efficient invasion of host cells. PMID- 21291505 TI - Neonatal outcomes of twins according to birth order, presentation and mode of delivery: a systematic review and meta-analysis. AB - BACKGROUND: The optimal mode of delivery for twins is undetermined. OBJECTIVE: To review literature regarding the neonatal outcomes following twin delivery. DATA SOURCES: Searches were conducted in PubMed, Medline, Embase, Cochrane library and reference lists. SELECTION CRITERIA: Studies selection criteria were: both twins alive at labour, outcomes stratified for birth order, presentation, planned and actual delivery mode. Eighteen articles were included in the meta-analysis (39, 571 twin sets). DATA COLLECTION AND ANALYSIS: The Meta-analysis of Observational Studies in Epidemiology guidelines were followed. Interstudy heterogeneity (I(2) ) was tested. A fixed model was generated whenever I(2)<25%. Pooled odds ratios (OR) with 95% CI were computed. Intergroup comparison was significant if 95% CI did not encompass 1. The first and second twins were indicated as Twin A (TA) and Twin B (TB), respectively. MAIN RESULTS: Neonatal morbidity was lower in TA than TB (3.0 versus 4.6%; OR 0.53; 95% CI 0.39-0.70). TA experienced neonatal death less often than TB (0.3 versus 0.6%; OR 0.55; 95% CI 0.38-0.81). No differences were noted between vertex and non-vertex and attempted vaginal delivery versus planned caesarean section in either TA or TB. In TA, neonatal morbidity was lower after vaginal delivery (1.1%) than caesarean section (2.2%; OR 0.47; 95% CI 0.27 0.82). Neonatal death was not associated with actual delivery mode. In TB, morbidity following combined delivery (19.8%) was higher than after vaginal delivery (9.5%; OR 0.55; 95% CI 0.41-0.74) or caesarean section (9.8%; OR 0.47; 95% CI 0.43-0.53). When outcomes were stratified for both presentation and delivery mode, mortality rate was lower after vaginal delivery than caesarean section for both vertex and nonvertex TB. AUTHOR'S CONCLUSION: An attempt at vaginal delivery should be considered in twin pregnancies with vertex/vertex presentation. PMID- 21291507 TI - Three-dimensional ultrasound fetal lung volumes and infant respiratory outcome: a prospective observational study. AB - OBJECTIVE: To determine if fetal lung volumes (FLVs), determined by three dimensional rotational ultrasound and virtual organ computer-aided analysis software (vocal), correlated with neonatal respiratory outcomes in surviving infants who had a high risk [fetuses with congenital diaphragmatic hernia (CDH)], lower risk [fetuses with anterior wall defects (AWDs)] and no risk (controls) of abnormal antenatal lung growth. DESIGN: Prospective observational study. SETTING: Tertiary fetal medicine and neonatal intensive care units. POPULATION: Sixty fetuses (25 with CDH, 25 with AWDs and ten controls). METHODS: FLVs were measured and expressed as the percentage of the observed compared with the expected for gestational age. MAIN OUTCOME MEASURES: Neonatal respiratory outcome was determined by the duration of supplemental oxygen, mechanical ventilation and dependencies, and assessment of lung volume using a gas dilution technique to measure functional residual capacity (FRC). RESULTS: The infants with CDH had lower FLV results than both the infants with AWDs (P=0.05) and the controls (P<0.05). The infants with CDH had longer durations of mechanical ventilation (P<0.001) and supplementary oxygen (P<0.001) dependence, compared with infants with AWDs. The infants with CDH had a lower median FRC than both the infants with AWDs (P<0.001) and the controls (P<0.001). FLV results correlated significantly with the durations of dependency on ventilation (r= -0.744, P<0.01) and oxygen (r= -0.788, P<0.001), and with FRC results (r=0.429, P=0.001). CONCLUSIONS: These results suggest that FLVs obtained using three-dimensional rotational ultrasound might be useful in predicting neonatal respiratory outcome in surviving infants who had varying risks of abnormal lung growth. Larger and more comprehensive studies are needed to clarify the role that lung volume measurements have in assessing lung function and growth. PMID- 21291508 TI - Recurrence risk and prediction of a delivery under 34 weeks of gestation after a history of a severe hypertensive disorder. AB - OBJECTIVE: The aim of this study was to report outcomes of the subsequent pregnancy after early-onset pre-eclampsia in a first pregnancy (index), and to evaluate the potential risk factors for recurrence of pre-eclampsia and preterm delivery. DESIGN: We performed a retrospective cohort study of all women who developed early-onset pre-eclampsia (delivery before 34 weeks of gestation) in their first pregnancy between January 1996 and December 2004 in two perinatal centres with regional function. All patients were included consecutively. Information was retrieved on the course of subsequent pregnancies. SETTING: Two tertiary centres with regional function. POPULATION: Women with a delivery under 34 weeks due to a hypertensive disorder (N=380). MAIN OUTCOME MEASURES: We determined the absolute risk of recurrence of an adverse outcome, defined as a hypertensive complication resulting in delivery before 34 weeks of gestation. The available clinical parameters were evaluated as predictors for recurrence using logistic regression analysis. RESULTS: We identified 380 patients, of whom 46 were lost to follow-up. In total, 123 patients refrained from subsequent pregnancy (79 [64%] from fear of recurrence). Of the 211 patients with a subsequent pregnancy, 36 (17%, 95% CI 12-22%) had a recurrent delivery before 34 weeks of gestation, 30 (14%, 95% CI 9.5-19%) delivered between 34 and 37 weeks of gestation, and 145 (69%, 95% CI 62-75%) delivered later than 37 weeks of gestation. Of this last group, only 67 (32%, 95% CI 25-38%) pregnancies were completely uneventful. Chronic hypertension, maximum diastolic blood pressure, caesarean delivery and level of 24-h proteinuria were independent predictors for an adverse pregnancy outcome. CONCLUSIONS: Women that had early severe pre eclampsia in their first pregnancy have a 17% risk of recurrence, with a delivery before 34 weeks of gestation. Only 32% had a completely uneventful pregnancy. PMID- 21291506 TI - The Early External Cephalic Version (ECV) 2 Trial: an international multicentre randomised controlled trial of timing of ECV for breech pregnancies. AB - OBJECTIVE: To investigate whether initiating external cephalic version (ECV) earlier in pregnancy might increase the rate of successful ECV procedures, and be more effective in decreasing the rate of non-cephalic presentation at birth and of caesarean section. DESIGN: An unblinded multicentred randomised controlled trial. SETTING: A total of 1543 women were randomised from 68 centres in 21 countries. POPULATION: Women with a singleton breech fetus at a gestational age of 33(0/7) weeks (231 days) to 35(6/7) weeks (251 days) of gestation were included. METHODS: Participants were randomly assigned to having a first ECV procedure between the gestational ages of 34(0/7) (238 days) and 35(6/7) weeks of gestation (early ECV group) or at or after 37(0/7) (259 days) weeks of gestation (delayed ECV group). MAIN OUTCOME MEASURES: The primary outcome was the rate of caesarean section; the secondary outcome was the rate of preterm birth. RESULTS: Fewer fetuses were in a non-cephalic presentation at birth in the early ECV group (314/765 [41.1%] versus 377/768 [49.1%] in the delayed ECV group; relative risk [RR] 0.84, 95% CI 0.75, 0.94, P=0.002). There were no differences in rates of caesarean section (398/765 [52.0%] versus 430/768 [56.0%]; RR 0.93, 95% CI 0.85, 1.02, P=0.12) or in risk of preterm birth (50/765 [6.5%] versus 34/768 [4.4%]; RR 1.48, 95% CI 0.97, 2.26, P=0.07) between groups. CONCLUSION: External cephalic version at 34-35 weeks versus 37 or more weeks of gestation increases the likelihood of cephalic presentation at birth but does not reduce the rate of caesarean section and may increase the rate of preterm birth. PMID- 21291509 TI - Clinical efficiency in a simulated emergency and relationship to team behaviours: a multisite cross-sectional study. AB - OBJECTIVE: To identify specific aspects of teamworking associated with greater clinical efficiency in simulated obstetric emergencies. DESIGN: Cross-sectional secondary analysis of video recordings from the Simulation & Fire-drill Evaluation (SaFE) randomised controlled trial. SETTING: Six secondary and tertiary maternity units. SAMPLE: A total of 114 randomly selected healthcare professionals, in 19 teams of six members. METHODS: Two independent assessors, a clinician and a language communication specialist identified specific teamwork behaviours using a grid derived from the safety literature. MAIN OUTCOME MEASURES: Relationship between teamwork behaviours and the time to administration of magnesium sulfate, a validated measure of clinical efficiency, was calculated. RESULTS: More efficient teams were likely to (1) have stated (recognised and verbally declared) the emergency (eclampsia) earlier (Kendall's rank correlation coefficient tau(b) = -0.53, 95% CI from -0.74 to -0.32, P=0.004); and (2) have managed the critical task using closed-loop communication (task clearly and loudly delegated, accepted, executed and completion acknowledged) (tau(b) = 0.46, 95% CI 0.17-0.74, P=0.022). Teams that administered magnesium sulfate within the allocated time (10 minutes) had significantly fewer exits from the labour room compared with teams who did not: a median of three (IQR 2-5) versus six exits (IQR 5-6) (P=0.03, Mann-Whitney U-test). CONCLUSIONS: Using administration of an essential drug as a valid surrogate of team efficiency and patient outcome after a simulated emergency, we found that more efficient teams were more likely to exhibit certain team behaviours relating to better handover and task allocation. PMID- 21291510 TI - Trans-obturator tape compared with tension-free vaginal tape in the surgical treatment of stress urinary incontinence: a cost utility analysis. AB - OBJECTIVE: To conduct an economic evaluation of the use of trans-obturator tape (TOT) compared with tension-free vaginal tape (TVT) in the surgical treatment of stress urinary incontinence (SUI) in women. DESIGN: Cost utility analysis from public-payer perspective, conducted alongside a randomised clinical trial (RCT). SETTING: Health services provided in Alberta, Canada. POPULATION: A total of 194 women who participated in the RCT, followed to 1 year from surgery. METHODS: Data collected on all women in the RCT, over 12 months following surgery. Comparisons undertaken between RCT groups for cost and quality-adjusted life-years (QALYs). Multiple imputation used for the 10% missing data. Bootstrapping used to account for sampling uncertainty. One-way sensitivity analysis conducted for productivity loss due to time away from work. MAIN OUTCOME MEASURES: Utility--15D questionnaire was used to calculate QALYs. Costs over 12 months--from trial data, health provider and provincial ministry of health. RESULTS: The TOT group had a non-significant average saving of $1133 (95% CI -2793; 442), with no difference in average QALYs between groups (95% CI -0.02; 0.01). TOT was cost-saving in over 80% of bootstrapping replications, over a wide range of willingness-to-pay. CONCLUSION: The bootstrapping replication results suggest that TOT could be cost effective compared with TVT in the treatment of SUI. However, these results must be confirmed by longer-term assessment of clinical and economic outcomes, because of concern that surgical tape palpable at 12 months may lead to vaginal erosion and further treatment. PMID- 21291511 TI - Maternal birth characteristics and perinatal mortality in twin offspring. An intergenerational population-based study in Norway, 1967-2008. AB - OBJECTIVE: To investigate the relationship between maternal preterm birth and fetal growth in one generation and perinatal mortality of twin offspring in the next generation. DESIGN: Population-based cohort study. SETTING: The Medical Birth Registry of Norway from 1967 to 2008. POPULATION: Linked generational data with 9426 mother-twin pair units. METHODS: Twin offspring were linked to their mothers by means of the unique national identification numbers. MAIN OUTCOME MEASURES: Perinatal mortality in twin offspring. RESULTS: The twin prevalence was not dependent on the mother's gestational age at birth, but increased with increasing birthweight in term mothers. Maternal gestational age was strongly and inversely associated with a risk of perinatal death in one or both of her twin offspring. Compared with term mothers, preterm mothers born at 27-31 and 32-34 weeks had relative risks (RRs) for perinatal loss of 3.83 [95% confidence interval (CI), 1.56-9.36] and 2.41 (95% CI, 1.29-4.50), respectively. This effect was even stronger after the use of assisted reproductive technologies (ART), with a significant interaction between maternal gestational age and ART (P = 0.03). Further, term mothers with birthweight-by-gestational age Z-scores of -2 or less had more than twice the risk of a perinatal loss in their twin offspring relative to mothers with the most favourable birthweight Z-scores (1-1.99) [RR, 2.42 (95% CI, 1.37-4.29)]. CONCLUSIONS: Women born preterm had an increased risk of perinatal mortality in their twin offspring, particularly after ART treatment. The same was true for women who were growth restricted at term. A twin pregnancy is a high-risk pregnancy in general, but even more so if the mother herself was born preterm or was growth restricted at birth. PMID- 21291512 TI - Update on cosmeceuticals. AB - As youth and perception of beauty are considered to be of great importance, an increasing number of new cosmeceuticals have been developed in recent years. This article will briefly present the problems of distinguishing cosmetics, cosmeceuticals or drugs and describe important new developments in raw materials, carrier systems and ingredients from the dermatological point of view. Especially active ingredients against skin-aging, here in particular antioxidants and cell regulators, are reviewed. Important parameters for the quality of cosmetics and cosmeceuticals are evidence-based in-vivo and in-vitro efficacy as well as scientifically proven wanted and unwanted effects. PMID- 21291513 TI - Emerging targets for the treatment of obesity. PMID- 21291514 TI - Structural variation in the chicken genome identified by paired-end next generation DNA sequencing of reduced representation libraries. AB - BACKGROUND: Variation within individual genomes ranges from single nucleotide polymorphisms (SNPs) to kilobase, and even megabase, sized structural variants (SVs), such as deletions, insertions, inversions, and more complex rearrangements. Although much is known about the extent of SVs in humans and mice, species in which they exert significant effects on phenotypes, very little is known about the extent of SVs in the 2.5-times smaller and less repetitive genome of the chicken. RESULTS: We identified hundreds of shared and divergent SVs in four commercial chicken lines relative to the reference chicken genome. The majority of SVs were found in intronic and intergenic regions, and we also found SVs in the coding regions. To identify the SVs, we combined high-throughput short read paired-end sequencing of genomic reduced representation libraries (RRLs) of pooled samples from 25 individuals and computational mapping of DNA sequences from a reference genome. CONCLUSION: We provide a first glimpse of the high abundance of small structural genomic variations in the chicken. Extrapolating our results, we estimate that there are thousands of rearrangements in the chicken genome, the majority of which are located in non-coding regions. We observed that structural variation contributes to genetic differentiation among current domesticated chicken breeds and the Red Jungle Fowl. We expect that, because of their high abundance, SVs might explain phenotypic differences and play a role in the evolution of the chicken genome. Finally, our study exemplifies an efficient and cost-effective approach for identifying structural variation in sequenced genomes. PMID- 21291515 TI - Superior canal dehiscence in a patient with three failed stapedectomy operations for otosclerosis: a case report. AB - INTRODUCTION: This case illustrates that superior semicircular canal dehiscence syndrome can be associated with a "pseudo"-conductive hearing loss, a symptom that overlaps with the clinical appearance of otosclerosis. CASE PRESENTATION: We present the case of a 48-year-old German Caucasian woman presenting with hearing loss on the left side and vertigo. She had undergone three previous stapedectomies for hearing improvement. Reformatted high-resolution computed tomographic scanning and the patient's history confirmed the diagnosis of concurrent canal dehiscence syndrome. CONCLUSION: Failure of hearing improvement after otosclerosis surgery may indicate an alternative underlying diagnosis which should be explored by further appropriate evaluation. PMID- 21291516 TI - Hormonal status in protracted critical illness and in-hospital mortality. AB - INTRODUCTION: The aim of this study was to determine the relationship between hormonal status and mortality in patients with protracted critical illness. METHODS: We conducted a prospective observational study in four medical and surgical intensive care units (ICUs). ICU patients who regained consciousness after 7 days of mechanical ventilation were included. Plasma levels of insulin like growth factor 1 (IGF-1), prolactin, thyroid-stimulating hormone, follicle stimulating hormone, luteinizing hormone, estradiol, progesterone, testosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS) and cortisol were measured on the first day patients were awake and cooperative (day 1). Mean blood glucose from admission to day 1 was calculated. RESULTS: We studied 102 patients: 65 men and 37 women (29 of the women were postmenopausal). Twenty-four patients (24%) died in the hospital. The IGF-1 levels were higher and the cortisol levels were lower in survivors. Mean blood glucose was lower in women who survived, and DHEA and DHEAS were higher in men who survived. CONCLUSIONS: These results suggest that, on the basis of sex, some endocrine or metabolic markers measured in the postacute phase of critical illness might have a prognostic value. PMID- 21291517 TI - Reducing the environmental impact of trials: a comparison of the carbon footprint of the CRASH-1 and CRASH-2 clinical trials. AB - BACKGROUND: All sectors of the economy, including the health research sector, must reduce their carbon emissions. The UK National Institute for Health Research has recently prepared guidelines on how to minimize the carbon footprint of research. We compare the carbon emissions from two international clinical trials in order to identify where emissions reductions can be made. METHODS: We conducted a carbon audit of two clinical trials (the CRASH-1 and CRASH-2 trials), quantifying the carbon dioxide emissions produced over a one-year audit period. Carbon emissions arising from the coordination centre, freight delivery, trial related travel and commuting were calculated and compared. RESULTS: The total emissions in carbon dioxide equivalents during the one-year audit period were 181.3 tonnes for CRASH-1 and 108.2 tonnes for CRASH-2. In total, CRASH-1 emitted 924.6 tonnes of carbon dioxide equivalents compared with 508.5 tonnes for CRASH 2. The CRASH-1 trial recruited 10,008 patients over 5.1 years, corresponding to 92 kg of carbon dioxide per randomized patient. The CRASH-2 trial recruited 20,211 patients over 4.7 years, corresponding to 25 kg of carbon dioxide per randomized patient. The largest contributor to emissions in CRASH-1 was freight delivery of trial materials (86.0 tonnes, 48% of total emissions), whereas the largest contributor in CRASH-2 was energy use by the trial coordination centre (54.6 tonnes, 30% of total emissions). CONCLUSIONS: Faster patient recruitment in the CRASH-2 trial largely accounted for its greatly increased carbon efficiency in terms of emissions per randomized patient. Lighter trial materials and web based data entry also contributed to the overall lower carbon emissions in CRASH 2 as compared to CRASH-1. TRIAL REGISTRATION NUMBERS: CRASH-1: ISRCTN74459797CRASH-2: ISRCTN86750102. PMID- 21291518 TI - Ovarian cryopreservation after laparoscopic ovariectomy using the Endo-GIA stapling device and LAPRO-clip absorbable ligating clip in a woman: a case report. AB - INTRODUCTION: Several options are available for preserving fertility before cytotoxic treatment, including ovarian tissue cryopreservation. Most reported surgical techniques include electrocoagulation. Our hypothesis is that avoidance of electrocoagulation may decrease ovarian cortex injury during cryopreservation procedures. CASE PRESENTATION: We report a laparoscopic technique of whole-ovary removal without coagulation using Endo-GIA forceps and clips. Laparoscopic ovariectomy was performed for cryopreservation in a 37-year-old Caucasian woman with breast cancer and for whom chemotherapy was planned. The procedure was completed quickly and without complication. This Endo-GIA procedure was of short duration with a short period of ischemia before freezing. CONCLUSION: Laparoscopic ovariectomy using the Endo-GIA stapling device procedure without coagulation may diminish ovary injury before ovarian cryopreservation. PMID- 21291519 TI - Serum antibodies against genitourinary infectious agents in prostate cancer and benign prostate hyperplasia patients: a case-control study. AB - BACKGROUND: Infection plays a role in the pathogenesis of many human malignancies. Whether prostate cancer (PCa) - an important health issue in the aging male population in the Western world - belongs to these conditions has been a matter of research since the 1970 s. Persistent serum antibodies are a proof of present or past infection. The aim of this study was to compare serum antibodies against genitourinary infectious agents between PCa patients and controls with benign prostate hyperplasia (BPH). We hypothesized that elevated serum antibody levels or higher seroprevalence in PCa patients would suggest an association of genitourinary infection in patient history and elevated PCa risk. METHODS: A total of 434 males who had undergone open prostate surgery in a single institution were included in the study: 329 PCa patients and 105 controls with BPH. The subjects' serum samples were analysed by means of enzyme-linked immunosorbent assay, complement fixation test and indirect immunofluorescence for the presence of antibodies against common genitourinary infectious agents: human papillomavirus (HPV) 6, 11, 16, 18, 31 and 33, herpes simplex virus (HSV) 1 and 2, human cytomegalovirus (CMV), Chlamydia trachomatis, Mycoplasma hominis, Ureaplasma urealyticum, Neisseria gonorrhoeae and Treponema pallidum. Antibody seroprevalence and mean serum antibody levels were compared between cases and controls. Tumour grade and stage were correlated with serological findings. RESULTS: PCa patients were more likely to harbour antibodies against Ureaplasma urealyticum (odds ratio (OR) 2.06; 95% confidence interval (CI) 1.08-4.28). Men with BPH were more often seropositive for HPV 18 and Chlamydia trachomatis (OR 0.23; 95% CI 0.09-0.61 and OR 0.45; 95% CI 0.21-0.99, respectively) and had higher mean serum CMV antibody levels than PCa patients (p = 0.0004). Among PCa patients, antibodies against HPV 6 were associated with a higher Gleason score (p = 0.0305). CONCLUSIONS: Antibody seropositivity against the analyzed pathogens with the exception of Ureaplasma does not seem to be a risk factor for PCa pathogenesis. The presence or higher levels of serum antibodies against the genitourinary pathogens studied were not consistently associated with PCa. Serostatus was not a predictor of disease stage in the studied population. PMID- 21291520 TI - Fused eco29kIR- and M genes coding for a fully functional hybrid polypeptide as a model of molecular evolution of restriction-modification systems. AB - BACKGROUND: The discovery of restriction endonucleases and modification DNA methyltransferases, key instruments of genetic engineering, opened a new era of molecular biology through development of the recombinant DNA technology. Today, the number of potential proteins assigned to type II restriction enzymes alone is beyond 6000, which probably reflects the high diversity of evolutionary pathways. Here we present experimental evidence that a new type IIC restriction and modification enzymes carrying both activities in a single polypeptide could result from fusion of the appropriate genes from preexisting bipartite restriction-modification systems. RESULTS: Fusion of eco29kIR and M ORFs gave a novel gene encoding for a fully functional hybrid polypeptide that carried both restriction endonuclease and DNA methyltransferase activities. It has been placed into a subclass of type II restriction and modification enzymes--type IIC. Its MTase activity, 80% that of the M.Eco29kI enzyme, remained almost unchanged, while its REase activity decreased by three times, concurrently with changed reaction optima, which presumably can be caused by increased steric hindrance in interaction with the substrate. In vitro the enzyme preferentially cuts DNA, with only a low level of DNA modification detected. In vivo new RMS can provide a 102 fold less protection of host cells against phage invasion. CONCLUSIONS: We propose a molecular mechanism of appearing of type IIC restriction-modification and M.SsoII-related enzymes, as well as other multifunctional proteins. As shown, gene fusion could play an important role in evolution of restriction-modification systems and be responsible for the enzyme subclass interconversion. Based on the proposed approach, hundreds of new type IIC enzymes can be generated using head to-tail oriented type I, II, and III restriction and modification genes. These bifunctional polypeptides can serve a basis for enzymes with altered recognition specificities. Lastly, this study demonstrates that protein fusion may change biochemical properties of the involved enzymes, thus giving a starting point for their further evolutionary divergence. PMID- 21291522 TI - Does undertaking an intercalated BSc influence first clinical year exam results at a London medical school? AB - BACKGROUND: Intercalated BScs (iBScs) are an optional part of the medical school curriculum in many Universities. Does undertaking an iBSc influence subsequent student performance? Previous studies addressing this question have been flawed by iBSc students being highly selected. This study looks at data from medical students where there is a compulsory iBSc for non-graduates. Our aim was to see whether there was any difference in performance between students who took an iBSc before or after their third year (first clinical year) exams. METHODS: A multivariable analysis was performed to compare the third year results of students at one London medical school who had or had not completed their iBSc by the start of this year (n = 276). A general linear model was applied to adjust for differences between the two groups in terms of potential confounders (age, sex, nationality and baseline performance). RESULTS: The results of third year summative exams for 276 students were analysed (184 students with an iBSc and 92 without). Unadjusted analysis showed students who took an iBSc before their third year achieved significantly higher end of year marks than those who did not with a mean score difference of 4.4 (0.9 to 7.9 95% CI, p = 0.01). (overall mean score 238.4 "completed iBSc" students versus 234.0 "not completed", range 145.2 - 272.3 out of 300). There was however a significant difference between the two groups in their prior second year exam marks with those choosing to intercalate before their third year having higher marks. Adjusting for this, the difference in overall exam scores was no longer significant with a mean score difference of 1.4 (-4.9 to +7.7 95% CI, p = 0.66). (overall mean score 238.0 " completed iBSc" students versus 236.5 "not completed"). CONCLUSIONS: Once possible confounders are controlled for (age, sex, previous academic performance) undertaking an iBSc does not influence third year exam results. One explanation for this confounding in unadjusted results is that students who do better in their second year exams are more likely to take an iBSc before their third year. PMID- 21291521 TI - The effect of progesterone replacement on gene expression in the corpus luteum during induced regression and late luteal phase in the bonnet monkey (Macaca radiata). AB - BACKGROUND: In higher primates, although LH/CG play a critical role in the control of corpus luteum (CL) function, the direct effects of progesterone (P4) in the maintenance of CL structure and function are unclear. Several experiments were conducted in the bonnet monkey to examine direct effects of P4 on gene expression changes in the CL, during induced luteolysis and the late luteal phase of natural cycles. METHODS: To identify differentially expressed genes encoding PR, PR binding factors, cofactors and PR downstream signaling target genes, the genome-wide analysis data generated in CL of monkeys after LH/P4 depletion and LH replacement were mined and validated by real-time RT-PCR analysis. Initially, expression of these P4 related genes were determined in CL during different stages of luteal phase. The recently reported model system of induced luteolysis, yet capable of responsive to tropic support, afforded an ideal situation to examine direct effects of P4 on structure and function of CL. For this purpose, P4 was infused via ALZET pumps into monkeys 24 h after LH/P4 depletion to maintain mid luteal phase circulating P4 concentration (P4 replacement). In another experiment, exogenous P4 was supplemented during late luteal phase to mimic early pregnancy. RESULTS: Based on the published microarray data, 45 genes were identified to be commonly regulated by LH and P4. From these 19 genes belonging to PR signaling were selected to determine their expression in LH/P4 depletion and P4 replacement experiments. These 19 genes when analyzed revealed 8 genes to be directly responsive to P4, whereas the other genes to be regulated by both LH and P4. Progesterone supplementation for 24 h during the late luteal phase also showed changes in expression of 17 out of 19 genes examined. CONCLUSION: These results taken together suggest that P4 regulates, directly or indirectly, expression of a number of genes involved in the CL structure and function. PMID- 21291523 TI - Hypothermia does not increase the risk of infection: a case control study. AB - INTRODUCTION: Hypothermia may improve outcome in patients after traumatic brain injury, especially when hypothermia is maintained for more than 48 hours. In the acute phase, patients with severe brain injury are more vulnerable to infections. Prolonged hypothermic treatment may further enhance the risk of infection. Selective decontamination of the digestive tract (SDD) reduces the risk of respiratory tract infections. The aim of this study was to investigate the incidence of infections in patients treated with hypothermia and normothermia while receiving SDD. METHODS: In this retrospective case control study 35 patients treated with prolonged hypothermia (cases) were identified and 169 patients with severe brain injury were included (controls). Propensity score matching was performed to correct for differences in baseline characteristics and clinical parameters. Primary outcome was the incidence of infection. The secondary endpoints were the micro-organisms found in the surveillance cultures and infection. In addition, a number of clinical characteristics were assessed. RESULTS: The demographic and clinical data indicated that the cases and controls were well matched. The overall risk of infection during ICU stay was 20% in the hypothermia groups versus 34.4% in the normothermia group (P = 0.388). Pneumonia was diagnosed in 11.4% of patients in both groups (P = 1.000). The incidence of meningitis, wound infection, bacteremia, and urinary tract infection was low and comparable between the groups. SDD surveillance cultures indicated a higher colonization with gram-negative bacteria in the rectal samples of the hypothermia patients. CONCLUSIONS: Hypothermia does not increase the risk of infection in patients treated with SDD. PMID- 21291524 TI - Stochastic adaptation and fold-change detection: from single-cell to population behavior. AB - BACKGROUND: In cell signaling terminology, adaptation refers to a system's capability of returning to its equilibrium upon a transient response. To achieve this, a network has to be both sensitive and precise. Namely, the system must display a significant output response upon stimulation, and later on return to pre-stimulation levels. If the system settles at the exact same equilibrium, adaptation is said to be 'perfect'. Examples of adaptation mechanisms include temperature regulation, calcium regulation and bacterial chemotaxis. RESULTS: We present models of the simplest adaptation architecture, a two-state protein system, in a stochastic setting. Furthermore, we consider differences between individual and collective adaptive behavior, and show how our system displays fold-change detection properties. Our analysis and simulations highlight why adaptation needs to be understood in terms of probability, and not in strict numbers of molecules. Most importantly, selection of appropriate parameters in this simple linear setting may yield populations of cells displaying adaptation, while single cells do not. CONCLUSIONS: Single cell behavior cannot be inferred from population measurements and, sometimes, collective behavior cannot be determined from the individuals. By consequence, adaptation can many times be considered a purely emergent property of the collective system. This is a clear example where biological ergodicity cannot be assumed, just as is also the case when cell replication rates are not homogeneous, or depend on the cell state. Our analysis shows, for the first time, how ergodicity cannot be taken for granted in simple linear examples either. The latter holds even when cells are considered isolated and devoid of replication capabilities (cell-cycle arrested). We also show how a simple linear adaptation scheme displays fold-change detection properties, and how rupture of ergodicity prevails in scenarios where transitions between protein states are mediated by other molecular species in the system, such as phosphatases and kinases. PMID- 21291525 TI - Augmentation of arginase 1 expression by exposure to air pollution exacerbates the airways hyperresponsiveness in murine models of asthma. AB - BACKGROUND: Arginase overexpression contributes to airways hyperresponsiveness (AHR) in asthma. Arginase expression is further augmented in cigarette smoking asthmatics, suggesting that it may be upregulated by environmental pollution. Thus, we hypothesize that arginase contributes to the exacerbation of respiratory symptoms following exposure to air pollution, and that pharmacologic inhibition of arginase would abrogate the pollution-induced AHR. METHODS: To investigate the role of arginase in the air pollution-induced exacerbation of airways responsiveness, we employed two murine models of allergic airways inflammation. Mice were sensitized to ovalbumin (OVA) and challenged with nebulized PBS (OVA/PBS) or OVA (OVA/OVA) for three consecutive days (sub-acute model) or 12 weeks (chronic model), which exhibit inflammatory cell influx and remodeling/AHR, respectively. Twenty-four hours after the final challenge, mice were exposed to concentrated ambient fine particles plus ozone (CAP+O3), or HEPA-filtered air (FA), for 4 hours. After the CAP+O3 exposures, mice underwent tracheal cannulation and were treated with an aerosolized arginase inhibitor (S boronoethyl-L-cysteine; BEC) or vehicle, immediately before determination of respiratory function and methacholine-responsiveness using the flexiVent(r). Lungs were then collected for comparison of arginase activity, protein expression, and immunohistochemical localization. RESULTS: Compared to FA, arginase activity was significantly augmented in the lungs of CAP+O3-exposed OVA/OVA mice in both the sub-acute and chronic models. Western blotting and immunohistochemical staining revealed that the increased activity was due to arginase 1 expression in the area surrounding the airways in both models. Arginase inhibition significantly reduced the CAP+O3-induced increase in AHR in both models. CONCLUSIONS: This study demonstrates that arginase is upregulated following environmental exposures in murine models of asthma, and contributes to the pollution-induced exacerbation of airways responsiveness. Thus arginase may be a therapeutic target to protect susceptible populations against the adverse health effects of air pollution, such as fine particles and ozone, which are two of the major contributors to smog. PMID- 21291526 TI - Synergistic antitumor effect of AAV-mediated TRAIL expression combined with cisplatin on head and neck squamous cell carcinoma. AB - BACKGROUND: Adeno-associated virus-2 (AAV-2)-mediated gene therapy is quite suitable for local or regional application in head and neck cancer squamous cell carcinoma (HNSCC). However, its low transduction efficiency has limited its further development as a therapeutic agent. DNA damaging agents have been shown to enhance AAV-mediated transgene expression. Cisplatin, one of the most effective chemotherapeutic agents, has been recognized to cause cancer cell death by apoptosis with a severe toxicity. This study aims to evaluate the role of cisplatin in AAV-mediated tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression and the effect on HNSCC both in vitro and in vivo. METHODS: Five human HNSCC cell lines were treated with recombinant soluble TRAIL (rsTRAIL) and infected with AAV/TRAIL to estimate the sensitivity of the cancer cells to TRAIL-induced cytotoxicity. KB cells were infected with AAV/EGFP with or without cisplatin pretreatment to evaluate the effect of cisplatin on AAV-mediated gene expression. TRAIL expression was detected by ELISA and Western blot. Cytotoxicity was measured by MTT assay and Western blot analysis for caspase-3 and -8 activations. Following the in vitro experiments, TRAIL expression and its tumoricidal activity were analyzed in nude mice with subcutaneous xenografts of HNSCC. RESULTS: HNSCC cell lines showed different sensitivities to rsTRAIL, and KB cells possessed both highest transduction efficacy of AAV and sensitivity to TRAIL among five cell lines. Preincubation of KB cells with subtherapeutic dosage of cisplatin significantly augmented AAV-mediated transgene expression in a heparin sulfate proteoglycan (HSPG)-dependent manner. Furthermore, cisplatin enhanced the killing efficacy of AAV/TRAIL by 3-fold on KB cell line. The AAV mediated TRAIL expression was observed in the xenografted tumors and significantly enhanced by cisplatin. AAV/TRAIL suppressed the tumors growth and cisplatin augmented the tumoricidal activity by two-fold. Furthermore, Combination treatment reduced cisplatin-caused body weight loss in nude mice. CONCLUSION: The combination of AAV-mediated TRAIL gene expression and cisplatin had synergistic therapeutic effects on head and neck cancers and reduced the potential toxicity of cisplatin. These findings suggest that the combination of AAV/TRAIL and cisplatin may be a promising strategy for HNSCC therapy. PMID- 21291527 TI - Dot1 binding induces chromatin rearrangements by histone methylation-dependent and -independent mechanisms. AB - BACKGROUND: Methylation of histone H3 lysine 79 (H3K79) by Dot1 is highly conserved among species and has been associated with both gene repression and activation. To eliminate indirect effects and examine the direct consequences of Dot1 binding and H3K79 methylation, we investigated the effects of targeting Dot1 to different positions in the yeast genome. RESULTS: Targeting Dot1 did not activate transcription at a euchromatic locus. However, chromatin-bound Dot1 derepressed heterochromatin-mediated gene silencing over a considerable distance. Unexpectedly, Dot1-mediated derepression was established by both a H3K79 methylation-dependent and a methylation-independent mechanism; the latter required the histone acetyltransferase Gcn5. By monitoring the localization of a fluorescently tagged telomere in living cells, we found that the targeting of Dot1, but not its methylation activity, led to the release of a telomere from the repressive environment at the nuclear periphery. This probably contributes to the activity-independent derepression effect of Dot1. CONCLUSIONS: Targeting of Dot1 promoted gene expression by antagonizing gene repression through both histone methylation and chromatin relocalization. Our findings show that binding of Dot1 to chromatin can positively affect local gene expression by chromatin rearrangements over a considerable distance. PMID- 21291528 TI - Using Mitrofanoff's principle and Monti's technique as a surgical option for bladder augmentation with a continent stoma: a case report. AB - INTRODUCTION: Hydronephrosis, reflux and renal failure are serious complications that occur in patients with neurogenic bladder associated with myelomeningocele. When the bladder compliance is lost, it is imperative to carry out surgery aimed at reducing bladder storage pressure. An ileocystoplasty, and for patients not suitable for intermittent catheterization, using the Mitrofanoff principle to form a continent stoma and the subsequent closure of the bladder neck, can be used. We report here, for the first time to the best of our knowledge, an association between two previously described techniques (the Mitrofanoff principle and the technique of Monti), that can solve the problem of a short appendix in obese patients. CASE PRESENTATION: A 33-year-old male Caucasian patient with myelomeningocele and neurogenic bladder developed low bladder compliance (4.0 mL/cm H2O) while still maintaining normal renal function. A bladder augmentation (ileocystoplasty) with continent derivation principle (Mitrofanoff) was performed. During surgery, we found that the patient's appendix was too short and was insufficient to reach the skin. We decided to make an association between the Mitrofanoff conduit and the ileal technique of Monti, through which we performed an anastomosis of the distal stump of the appendix to the bladder (with an antireflux valve). Later, the proximal stump of the appendix was anastomosed to an ileal segment of 2.0 cm that was open longitudinally and reconfigured transversally (Monti technique), modeled by a 12-Fr urethral catheter, and finally, the distal stump was sutured at the patient's navel.After the procedure, a suprapubic cystostomy (22 Fr) and a Foley catheter (10 Fr) through the continent conduit were left in place. The patient had recovered well and was discharged on the tenth day after surgery. He remained with the Foley catheter (through the conduit) for 21 days and cystostomy for 30 days. Six months after surgery he was continent with good bladder compliance without reflux and fully adapted to catheterization through the navel. CONCLUSION: The unpublished association between the Mitrofanoff and Monti techniques is feasible and a very useful alternative in urologic cases of derivation continent in which the ileocecal appendix is too short to reach the skin (i.e., in obese patients). PMID- 21291529 TI - The prolyl hydroxylase enzymes are positively associated with hypoxia-inducible factor-1alpha and vascular endothelial growth factor in human breast cancer and alter in response to primary systemic treatment with epirubicin and tamoxifen. AB - INTRODUCTION: The purpose of the present study was to investigate the relationship of expression of hypoxia inducible factor (HIF)-1alpha-modifying enzymes prolyl hydroxylase (PHD)1, PHD2 and PHD3 to response of tumours and survival in breast cancer patients enrolled in a phase II trial of neoadjuvant anthracycline and tamoxifen therapy. METHODS: The expression of PHD1, PHD2 and PHD3 together with HIF-1alpha and the HIF-inducible genes vascular endothelial cell growth factor (VEGF) and carbonic anhydrase IX were assessed by immunohistochemistry using a tissue microarray approach in 211 patients with T2-4 N0-1 breast cancer enrolled in a randomised trial comparing single-agent epirubicin versus epirubicin and tamoxifen as the primary systemic treatment. RESULTS: PHD1, PHD2 and PHD3 were detected in 47/179 (26.7%), 85/163 (52.2%) and 69/177 (39%) of tumours at baseline. PHD2 and PHD3 expression was moderate/strong whereas PHD1 expression was generally weak. There was a significant positive correlation between HIF-1alpha and PHD1 (P = 0.002) and PHD3 (P < 0.05) but not PHD2 (P = 0.41). There was a significant positive relationship between VEGF and PHD1 (P < 0.008) and PHD3 (P = 0.001) but not PHD2 (P = 0.09). PHD1, PHD2 and PHD3 expression was significantly increased after epirubicin therapy (all P < 0.000) with no significant difference in PHD changes between the treatment arms. There was no significant difference in response in tumours that expressed PHDs and PHD expression was not associated with survival. CONCLUSIONS: Although expression of the PHDs was not related to response or survival in patients receiving neoadjuvant epirubicin, our data provide the first evidence that these enzymes are upregulated on therapy in breast cancer and that the biological effects independent of HIF make them therapeutic targets. PMID- 21291530 TI - Does the socioeconomic context explain both mortality and income inequality? Prospective register-based study of Norwegian regions. AB - BACKGROUND: Studies from various countries have observed worse population health in geographical areas with more income inequality. The psychosocial interpretation of this association is that large income disparities are harmful to health because they generate relative deprivation and undermine social cohesion. An alternative explanation contends that the association between income inequality and ill health arises because the underlying social and economic structures will influence both the level of illness and disease and the size of income differences. This paper examines whether the observed association between mortality and income inequality in Norwegian regions can be accounted for by the socioeconomic characteristics of the regions. METHODS: Norwegian register data covering the entire population were utilised. An extensive set of contextual and individual predictors were included in multilevel Poisson regression analyses of mortality 1994-2003 among 1.6 millions individuals born 1929-63, distributed across 35 residential regions. RESULTS: Mean income, composition of economic branches, and percentage highly educated in the regions were clearly connected to the level of income inequality. These social and economic characteristics of the regions were also markedly related to regional mortality levels, after adjustment for population composition, i.e., the individual-level variables. Moreover, regional mortality was significantly higher in regions with larger income disparities. The regions' social and economic structure did not, however, account for the association between regional income inequality and mortality. A distinct independent effect of income inequality on mortality remained after adjustment for regional-level social and economic characteristics. CONCLUSIONS: The results indicate that the broader socioeconomic context in Norwegian regions has a substantial impact both on mortality and on the level of income disparities. However, the results also suggest, in a way compatible with the psychosocial interpretation, that on top of the general socioeconomic influences, a higher level of income inequality adds independently to higher mortality levels. PREVIOUS PUBLICATION: This article is a reworked version of the study 'Er inntektsforskjeller dodelige?' [Are income inequalities lethal?] which was published in Norwegian in Tidsskrift for velferdsforskning [Journal for welfare research], Vol. 13 (4), 2010. PMID- 21291531 TI - Carney-Complex: multiple resections of recurrent cardiac myxoma. AB - We report a case of a female patient who was operated at the third relapse of an atrial myxoma caused by Carney complex. The difficult operation was performed without any complications despite extensive adhesions caused by the previous operations. The further inpatient course went without complications and the patient was discharged to the consecutive treatment on the 9th postoperative day. The echocardiographic finding postoperative showed no abnormalities. PMID- 21291532 TI - A case report of male breast cancer in a very young patient: what is changing? AB - Male breast cancer accounts for 1% of all breast cancer cases, and men tend to be diagnosed at an older age than women (mean age is about 67 years). Several risk factors have been identified, such as genetic and hormonal abnormalities. The present study reported the case of a 25-year-old man who was diagnosed with an advanced invasive ductal carcinoma; however, he did not have any important risk factors. Even though more data is emerging about this disease, more efforts to understand risk factors, treatment options and survival benefits are needed. In this case, we discussed the risk factors as well as the impaired fertility associated with breast cancer therapies. PMID- 21291533 TI - Thermostability in endoglucanases is fold-specific. AB - BACKGROUND: Endoglucanases are usually considered to be synergistically involved in the initial stages of cellulose breakdown-an essential step in the bioprocessing of lignocellulosic plant materials into bioethanol. Despite their economic importance, we currently lack a basic understanding of how some endoglucanases can sustain their ability to function at elevated temperatures required for bioprocessing, while others cannot. In this study, we present a detailed comparative analysis of both thermophilic and mesophilic endoglucanases in order to gain insights into origins of thermostability. We analyzed the sequences and structures for sets of endoglucanase proteins drawn from the Carbohydrate-Active enZymes (CAZy) database. RESULTS: Our results demonstrate that thermophilic endoglucanases and their mesophilic counterparts differ significantly in their amino acid compositions. Strikingly, these compositional differences are specific to protein folds and enzyme families, and lead to differences in intramolecular interactions in a fold-dependent fashion. CONCLUSIONS: Here, we provide fold-specific guidelines to control thermostability in endoglucanases that will aid in making production of biofuels from plant biomass more efficient. PMID- 21291534 TI - Preserved acute pain and impaired neuropathic pain in mice lacking protein interacting with C Kinase 1. AB - Protein interacting with C Kinase 1 (PICK1), a PDZ domain-containing scaffolding protein, interacts with multiple different proteins in the mammalian nervous system and is believed to play important roles in diverse physiological and pathological conditions. In this study, we report that PICK1 is expressed in neurons of the dorsal root ganglion (DRG) and spinal cord dorsal horn, two major pain-related regions. PICK1 was present in approximately 29.7% of DRG neurons, most of which were small-less than 750 MUm(2) in cross-sectional area. Some of these PICK1-positive cells co-labeled with isolectin B4 or calcitonin-gene related peptide. In the dorsal horn, PICK1 immunoreactivity was concentrated in the superficial dorsal horn, where it was prominent in the postsynaptic density, axons, and dendrites. Targeted disruption of PICK1 gene did not affect basal paw withdrawal responses to acute noxious thermal and mechanical stimuli or locomotor reflex activity, but it completely blocked the induction of peripheral nerve injury-induced mechanical and thermal pain hypersensitivities. PICK1 appears to be required for peripheral nerve injury-induced neuropathic pain development and to be a potential biochemical target for treating this disorder. PMID- 21291535 TI - Interactions among oscillatory pathways in NF-kappa B signaling. AB - BACKGROUND: Sustained stimulation with tumour necrosis factor alpha (TNF-alpha) induces substantial oscillations--observed at both the single cell and population levels--in the nuclear factor kappa B (NF-kappa B) system. Although the mechanism has not yet been elucidated fully, a core system has been identified consisting of a negative feedback loop involving NF-kappa B (RelA:p50 hetero-dimer) and its inhibitor I-kappa B-alpha. Many authors have suggested that this core oscillator should couple to other oscillatory pathways. RESULTS: First we analyse single cell data from experiments in which the NF-kappa B system is forced by short trains of strong pulses of TNF-alpha. Power spectra of the ratio of nuclear-to cytoplasmic concentration of NF-kappa B suggest that the cells' responses are entrained by the pulsing frequency. Using a recent model of the NF-kappa B system due to Caroline Horton, we carried out extensive numerical simulations to analyze the response frequencies induced by trains of pulses of TNF-alpha stimulation having a wide range of frequencies and amplitudes. These studies suggest that for sufficiently weak stimulation, various nonlinear resonances should be observable. To explore further the possibility of probing alternative feedback mechanisms, we also coupled the model to sinusoidal signals with a wide range of strengths and frequencies. Our results show that, at least in simulation, frequencies other than those of the forcing and the main NF-kappa B oscillator can be excited via sub- and superharmonic resonance, producing quasiperiodic and even chaotic dynamics. CONCLUSIONS: Our numerical results suggest that the entrainment phenomena observed in pulse-stimulated experiments is a consequence of the high intensity of the stimulation. Computational studies based on current models suggest that resonant interactions between periodic pulsatile forcing and the system's natural frequencies may become evident for sufficiently weak stimulation. Further simulations suggest that the nonlinearities of the NF-kappa B feedback oscillator mean that even sinusoidally modulated forcing can induce a rich variety of nonlinear interactions. PMID- 21291536 TI - The impact of maternal HIV infection on cord blood lymphocyte subsets and cytokine profile in exposed non-infected newborns. AB - BACKGROUND: Children born to HIV+ mothers are exposed intra-utero to several drugs and cytokines that can modify the developing immune system, and influence the newborn's immune response to infections and vaccines. We analyzed the relation between the distribution of cord blood lymphocyte subsets and cytokine profile in term newborns of HIV+ mothers using HAART during pregnancy and compared them to normal newborns. METHODS: In a prospective, controlled study, 36 mother-child pairs from HIV+ mothers and 15 HIV-uninfected mothers were studied. Hematological features and cytokine profiles of mothers at 35 weeks of pregnancy were examined. Maternal and cord lymphocyte subsets as well as B-cell maturation in cord blood were analyzed by flow cytometry. The non-stimulated, as well as BCG and PHA-stimulated production of IL2, IL4, IL7, IL10, IL12, IFN-gamma and TNF alpha in mononuclear cell cultures from mothers and infants were quantified using ELISA. RESULTS: After one year follow-up none of the exposed infants became seropositive for HIV. An increase in B lymphocytes, especially the CD19/CD5+ ones, was observed in cord blood of HIV-exposed newborns. Children of HIV+ hard drug using mothers had also an increase of immature B-cells. Cord blood mononuclear cells of HIV-exposed newborns produced less IL-4 and IL-7 and more IL 10 and IFN-gamma in culture than those of uninfected mothers. Cytokine values in supernatants were similar in infants and their mothers except for IFN-gamma and TNF-alpha that were higher in HIV+ mothers, especially in drug abusing ones. Cord blood CD19/CD5+ lymphocytes showed a positive correlation with cord IL-7 and IL 10. A higher maternal age and smoking was associated with a decrease of cord blood CD4+ cells. CONCLUSIONS: in uninfected infants born to HIV+ women, several immunological abnormalities were found, related to the residual maternal immune changes induced by the HIV infection and those associated with antiretroviral treatment. Maternal smoking was associated to changes in cord CD3/CD4 lymphocytes and maternal hard drug abuse was associated with more pronounced changes in the cord B cell line. PMID- 21291537 TI - Evidence for somatic gene conversion and deletion in bipolar disorder, Crohn's disease, coronary artery disease, hypertension, rheumatoid arthritis, type-1 diabetes, and type-2 diabetes. AB - BACKGROUND: During gene conversion, genetic information is transferred unidirectionally between highly homologous but non-allelic regions of DNA. While germ-line gene conversion has been implicated in the pathogenesis of some diseases, somatic gene conversion has remained technically difficult to investigate on a large scale. METHODS: A novel analysis technique is proposed for detecting the signature of somatic gene conversion from SNP microarray data. The Wellcome Trust Case Control Consortium has gathered SNP microarray data for two control populations and cohorts for bipolar disorder (BD), cardiovascular disease (CAD), Crohn's disease (CD), hypertension (HT), rheumatoid arthritis (RA), type-1 diabetes (T1D) and type-2 diabetes (T2D). Using the new analysis technique, the seven disease cohorts are analyzed to identify cohort-specific SNPs at which conversion is predicted. The quality of the predictions is assessed by identifying known disease associations for genes in the homologous duplicons, and comparing the frequency of such associations with background rates. RESULTS: Of 28 disease/locus pairs meeting stringent conditions, 22 show various degrees of disease association, compared with only 8 of 70 in a mock study designed to measure the background association rate (P < 10-9). Additional candidate genes are identified using less stringent filtering conditions. In some cases, somatic deletions appear likely. RA has a distinctive pattern of events relative to other diseases. Similarities in patterns are apparent between BD and HT. CONCLUSIONS: The associations derived represent the first evidence that somatic gene conversion could be a significant causative factor in each of the seven diseases. The specific genes provide potential insights about disease mechanisms, and are strong candidates for further study. PMID- 21291538 TI - Increased susceptibility of 129SvEvBrd mice to IgE-Mast cell mediated anaphylaxis. AB - BACKGROUND: Experimental analyses have identified strain-dependent factors that regulate susceptibility to anaphylaxis in mice. We assessed the susceptibility of the widely used 129SvEvBrd (also known as 129S5) mouse strain to IgE/mast cell mediated anaphylaxis as compared to BALB/c. Mice were subjected to passive and oral Ovalbumin [OVA]-induced active anaphylaxis. Tissue mast cell, plasma histamine, total IgE and OVA-specific IgE levels and susceptibility to histamine i.v infusion were assessed. Bone marrow mast cell (BMMC)s were examined for FcepsilonRI, c-kit, degranulation efficiency, proliferation, apoptosis and cytokine profile. RESULTS: 129S5 mice had significantly increased susceptibility to passive and oral OVA-induced active anaphylaxis. Increased susceptibility to anaphylaxis was associated with increased homeostatic mast cell levels but not OVA-specific IgE or IgG1 levels. In vitro analyses of BMMCs revealed no difference in FcepsilonRI and c-Kit expression, however, 129S5 BMMCs possessed greater proliferative capacity and reduced caspase-3-mediated apoptosis. IgE-BMMC degranulation assays demonstrated no difference in degranulation efficiency. Furthermore, 129S5 mice possessed increased sensitivity to histamine-induced hypothermia. CONCLUSIONS: We conclude that 129S5 mice have increased susceptibility to anaphylaxis as compared to BALB/c strain and their increased susceptibility was associated with altered mast cell proliferation and homeostatic tissue levels and responsiveness to histamine. Given the wide spread usage of the 129SvEvBrd strain of mice in experimental gene targeting methodology, these data have important implications for studying IgE-reactions in mouse systems. PMID- 21291539 TI - Another tool in the genome-wide association study arsenal: population-based detection of somatic gene conversion. AB - The hunt for the genetic contributors to complex disease has used a number of strategies, resulting in the identification of variants associated with many of the common diseases affecting society. However most of the genetic variants detected to date are single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) and fall far short of explaining the full genetic component of any given disease. An as yet untapped genomic mechanism is somatic gene conversion and deletion, which could be complicit in disease risk but has been challenging to detect in genome-wide datasets. In a recent publication in BMC Medicine by Kenneth Ross, the author uses existing datasets to look at somatic gene conversion and deletion in human disease. Here, we describe how Ross's recent efforts to detect such occurrences could impact the field going forward. PMID- 21291540 TI - Antibodies of IgG, IgA and IgM isotypes against cyclic citrullinated peptide precede the development of rheumatoid arthritis. AB - INTRODUCTION: We and others have previously shown that antibodies against cyclic citrullinated proteins (anti-CCP) precede the development of rheumatoid arthritis (RA) and in a more recent study we reported that individuals who subsequently developed RA had increased concentrations of several cytokines and chemokines years before the onset of symptoms of joint disease. Here we aimed to evaluate the prevalence and predictive values of anti-CCP antibodies of IgG, IgM and IgA isotype in individuals who subsequently developed RA and also to relate these to cytokines and chemokines, smoking, genetic factors and radiographic score. METHODS: A case-control study (1:4 ratio) was nested within the Medical Biobank and the Maternity cohorts of Northern Sweden. Patients with RA were identified from blood donors predating the onset of disease by years. Matched controls were selected randomly from the same registers. IgG, IgA and IgM anti-CCP2 antibodies were determined using EliA anti-CCP assay on ImmunoCAP 250 (Phadia AB, Uppsala, Sweden). RESULTS: Of 86 patients with RA identified as blood donors prior to the onset of symptoms, samples were available from 71 for analyses. The median (Q1 to Q3) predating time was 2.5 years (1.1 to 5.9 years). The sensitivity of anti-CCP antibodies in the pre-patient samples was 35.2% for IgG, 23.9% for IgA, and 11.8% for IgM. The presence of IgG and IgA anti-CCP antibodies was highly significant compared with controls. IgG and IgA anti-CCP2 predicted RA significantly in conditional logistic regression models odds ratio (OR) = 94.1, 95% confidence interval (CI) 12.7 to 695.4 and OR = 11.1, 95% CI 4.4 to 28.1, respectively, the IgM anti-CCP showed borderline significance OR = 2.5 95% CI 0.9 to 6.3. Concentrations of all anti-CCP isotypes increased the closer to the onset of symptoms the samples were collected with an earlier and higher increase for IgG and IgA compared with IgM anti-CCP. IgA and IgG anti-CCP positive individuals had different patterns of up-regulated chemokines and also, smoking brought forward the appearance of IgA anti-CCP antibodies in pre-RA individuals. CONCLUSIONS: Anti-CCP2 antibodies of both the IgG and IgA isotypes pre-dated the onset of RA by years; also, both IgG and IgA anti-CCP2 antibodies predicted the development of RA, with the highest predictive value for IgG anti-CCP2 antibodies. PMID- 21291542 TI - Patients' perspectives on self-testing of oral anticoagulation therapy: content analysis of patients' internet blogs. AB - BACKGROUND: Patients on oral anticoagulant therapy (OAT) require regular testing of the prothrombin time (PT) and the international normalised ratio (INR) to monitor their blood coagulation level to avoid complications of either over or under coagulation. PT/INR can be tested by a healthcare professional or by the patient. The latter mode of the testing is known as patient self-testing or home testing. The objective of this study was to elicit patients' perspectives and experiences regarding PT/INR self-testing using portable coagulometer devices. METHODS: Internet blog text mining was used to collect 246 blog postings by 108 patients, mainly from the USA and the UK. The content of these qualitative data were analysed using XSight and NVivo software packages. RESULTS: The key themes in relation to self-testing of OAT identified were as follows: Patient benefits reported were time saved, personal control, choice, travel reduction, cheaper testing, and peace of mind. Equipment issues included high costs, reliability, quality, and learning how to use the device. PT/INR issues focused on the frequency of testing, INR fluctuations and individual target (therapeutic) INR level. Other themes noted were INR testing at laboratories, the interactions with healthcare professionals in managing and testing OAT and insurance companies' involvement in acquiring the self-testing equipment. Social issues included the pain and stress of taking and testing for OAT. CONCLUSIONS: Patients' blogs on PT/INR testing provide insightful information that can help in understanding the nature of the experiences and perspectives of patients on self-testing of OAT. The themes identified in this paper highlight the substantial complexities involved in self-testing programmes in the healthcare system. Thus, the issues elicited in this study are very valuable for all stakeholders involved in developing effective self-testing strategies in healthcare that are gaining considerable current momentum particularly for patients with chronic illness. PMID- 21291541 TI - Lymphocyte deficiency limits Epstein-Barr virus latent membrane protein 1 induced chronic inflammation and carcinogenic pathology in vivo. AB - BACKGROUND: The importance of the malignant cell environment to its growth and survival is becoming increasingly apparent, with dynamic cross talk between the neoplastic cell, the leukocyte infiltrate and the stroma. Most cancers are accompanied by leukocyte infiltration which, contrary to an anticipated immuno protective role, could be contributing to tumour development and cancer progression. Epstein-Barr virus (EBV) associated cancers, including nasopharyngeal carcinoma and Hodgkin's Disease, show a considerable leukocyte infiltration which surrounds the neoplastic cells, raising the questions as to what role these cells play in either restricting or supporting the tumour and what draws the cells into the tumour. In order to begin to address this we have studied a transgenic model of multistage carcinogenesis with epithelial expression of the EBV primary oncoprotein, latent membrane protein 1 (LMP1). LMP1 is expressed particularly in the skin, which develops a hyperplastic pathology soon after birth. RESULTS: The pathology advances with time leading to erosive dermatitis which is inflamed with a mixed infiltrate involving activated CD8+ T cells, CD4+ T-cells including CD4+/CD25+/FoxP3+ Treg cells, mast cells and neutrophils. Also significant dermal deposition of immunoglobulin-G (IgG) is observed as the pathology advances. Along with NF-kappaB activation, STAT3, a central factor in inflammation regulation, is activated in the transgenic tissue. Several inflammatory factors are subsequently upregulated, notably CD30 and its ligand CD153, also leukocyte trafficking factors including CXCL10, CXCL13, L selectin and TGFbeta1, and inflammatory cytokines including IL-1beta, IL-3 and the murine IL-8 analogues CXCL1, CXCL2 and CXCL5-6, amongst others. The crucial role of mature T- and/or B-lymphocytes in the advancing pathology is demonstrated by their elimination, which precludes mast cell infiltration and limits the pathology to an early, benign stage. CONCLUSIONS: LMP1 can lead to the activation of several key factors mediating proliferation, angiogenesis and inflammation in vivo. With the initiation of an inflammatory programme, leukocyte recruitment follows which then itself contributes to the progressing pathology in these transgenic mice, with a pivotal role for B-and/or T-cells in the process. The model suggests a basis for the leukocyte infiltrate observed in EBV-associated cancer and its supporting role, as well as potential points for therapeutic intervention. PMID- 21291543 TI - GCOD - GeneChip Oncology Database. AB - BACKGROUND: DNA microarrays have become a nearly ubiquitous tool for the study of human disease, and nowhere is this more true than in cancer. With hundreds of studies and thousands of expression profiles representing the majority of human cancers completed and in public databases, the challenge has been effectively accessing and using this wealth of data. DESCRIPTION: To address this issue we have collected published human cancer gene expression datasets generated on the Affymetrix GeneChip platform, and carefully annotated those studies with a focus on providing accurate sample annotation. To facilitate comparison between datasets, we implemented a consistent data normalization and transformation protocol and then applied stringent quality control procedures to flag low quality assays. CONCLUSION: The resulting resource, the GeneChip Oncology Database, is available through a publicly accessible website that provides several query options and analytical tools through an intuitive interface. PMID- 21291544 TI - Differential gene expression in liver and small intestine from lactating rats compared to age-matched virgin controls detects increased mRNA of cholesterol biosynthetic genes. AB - BACKGROUND: Lactation increases energy demands four- to five-fold, leading to a two- to three-fold increase in food consumption, requiring a proportional adjustment in the ability of the lactating dam to absorb nutrients and to synthesize critical biomolecules, such as cholesterol, to meet the dietary needs of both the offspring and the dam. The size and hydrophobicity of the bile acid pool increases during lactation, implying an increased absorption and disposition of lipids, sterols, nutrients, and xenobiotics. In order to investigate changes at the transcriptomics level, we utilized an exon array and calculated expression levels to investigate changes in gene expression in the liver, duodenum, jejunum, and ileum of lactating dams when compared against age-matched virgin controls. RESULTS: A two-way mixed models ANOVA was applied to detect differentially expressed genes. Significance calls were defined as a p < 0.05 for the overall physiologic state effect (lactation vs. control), and a within tissue pairwise comparison of p < 0.01. The proportion of false positives, an estimate of the ratio of false positives in the list of differentially expressed genes, was calculated for each tissue. The number of differentially expressed genes was 420 in the liver, 337 in the duodenum, 402 in the jejunum, and 523 in the ileum. The list of differentially expressed genes was in turn analyzed by Ingenuity Pathways Analysis (IPA) to detect biological pathways that were overrepresented. In all tissues, sterol regulatory element binding protein (Srebp)-regulated genes involved in cholesterol synthesis showed increased mRNA expression, with the fewest changes detected in the jejunum. We detected increased Scap mRNA in the liver only, suggesting an explanation for the difference in response to lactation between the liver and small intestine. Expression of Cyp7a1, which catalyzes the rate limiting step in the bile acid biosynthetic pathway, was also significantly increased in liver. In addition, decreased levels of mRNA associated with T-cell signaling were found in the jejunum and ileum. Several members of the Solute Carrier (SLC) and Adenosine Triphosphate Binding Cassette (ABC) superfamilies of membrane transporters were found to be differentially expressed; these genes may play a role in differences in nutrient and xenobiotic absorption and disposition. mRNA expression of SLC39a4_predicted, a zinc transporter, was increased in all tissues, suggesting that it is involved in increased zinc uptake during lactation. Microarray data are available through GEO under GSE19175. CONCLUSIONS: We detected differential expression of mRNA from several pathways in lactating dams, including upregulation of the cholesterol biosynthetic pathway in liver and intestine, consistent with Srebp activation. Differential T-Cell signaling in the two most distal regions of the small intestine (ileum and jejunum) was also noted, as well as differential expression of transporters that likely play a key role in nutrient uptake. PMID- 21291545 TI - Nuclear receptors from the ctenophore Mnemiopsis leidyi lack a zinc-finger DNA binding domain: lineage-specific loss or ancestral condition in the emergence of the nuclear receptor superfamily? AB - BACKGROUND: Nuclear receptors (NRs) are an ancient superfamily of metazoan transcription factors that play critical roles in regulation of reproduction, development, and energetic homeostasis. Although the evolutionary relationships among NRs are well-described in two prominent clades of animals (deuterostomes and protostomes), comparatively little information has been reported on the diversity of NRs in early diverging metazoans. Here, we identified NRs from the phylum Ctenophora and used a phylogenomic approach to explore the emergence of the NR superfamily in the animal kingdom. In addition, to gain insight into conserved or novel functions, we examined NR expression during ctenophore development. RESULTS: We report the first described NRs from the phylum Ctenophora: two from Mnemiopsis leidyi and one from Pleurobrachia pileus. All ctenophore NRs contained a ligand-binding domain and grouped with NRs from the subfamily NR2A (HNF4). Surprisingly, all the ctenophore NRs lacked the highly conserved DNA-binding domain (DBD). NRs from Mnemiopsis were expressed in different regions of developing ctenophores. One was broadly expressed in the endoderm during gastrulation. The second was initially expressed in the ectoderm during gastrulation, in regions corresponding to the future tentacles; subsequent expression was restricted to the apical organ. Phylogenetic analyses of NRs from ctenophores, sponges, cnidarians, and a placozoan support the hypothesis that expansion of the superfamily occurred in a step-wise fashion, with initial radiations in NR family 2, followed by representatives of NR families 3, 6, and 1/4 originating prior to the appearance of the bilaterian ancestor. CONCLUSIONS: Our study provides the first description of NRs from ctenophores, including the full complement from Mnemiopsis. Ctenophores have the least diverse NR complement of any animal phylum with representatives that cluster with only one subfamily (NR2A). Ctenophores and sponges have a similarly restricted NR complement supporting the hypothesis that the original NR was HNF4-like and that these lineages are the first two branches from the animal tree. The absence of a zinc finger DNA-binding domain in the two ctenophore species suggests two hypotheses: this domain may have been secondarily lost within the ctenophore lineage or, if ctenophores are the first branch off the animal tree, the original NR may have lacked the canonical DBD. Phylogenomic analyses and categorization of NRs from all four early diverging animal phyla compared with the complement from bilaterians suggest the rate of NR diversification prior to the cnidarian bilaterian split was relatively modest, with independent radiations of several NR subfamilies within the cnidarian lineage. PMID- 21291546 TI - Concurrent cisplatin, continuous infusion fluorouracil and radiotherapy followed by tailored consolidation treatment in non metastatic anal squamous cell carcinoma. AB - BACKGROUND: To evaluate efficacy and feasibility of chemo-radiotherapy in patients with non-metastatic anal squamous-cell-cancer. METHODS: TNM staged anal squamous-cell cancer patients were treated with pelvic radiotherapy concomitant to continuous infusion fluorouracil plus cisplatin for at least 2 cycles. In T3 T4 or any T - N+ tumours or in "slow-responder" cases, 1-2 chemotherapy courses were subsequently administered. Tumour assessment was performed at baseline and 6 8 weeks after radiotherapy to evaluate response. RESULTS: 29 patients were enrolled: 4 males, 25 females; median age 57 years; baseline T1/T2/T3/T4 2/12/7/8; N involvement 17. Median dose pelvic radiotherapy was 59.4 Gy (range: 54-74). In 5 patients 2 chemotherapy courses, in 12 patients three and in 12 patients four courses were performed. At first evaluation, 27 CR (93.1%; 95% CI: 78% - 98%) and 2 SD were observed. Main grade (G) 3 toxic events were neutropenia (8%), diarrhoea (8%) and dermatitis (62%). Most frequent late events G3-G4 occurred in 14 patients: proctitis (5), dermatitis (4), bladder dysfunctions (2), sexual dysfunctions (9), lower extremity venous thromboses (2), dysuria (1), stenosis (1) and tenesmus (1). Five patients reported G1 leucopoenia. The rate of colostomy was 14%. After a median follow up of 42 months (range: 4-81), 20 patients are still alive without relapse and 3 died due to PD. The estimated 7 year DFS was 83.4% (C.I.: 68.3%-98.5%) and the estimated 7-year OS was 85.7% (C.I.: 70% - 100%). The 1-year and the estimated 7-year colostomy-free survivals were 85.9% (C.I.: 73.1% - 98.7%). CONCLUSIONS: Concurrent cisplatin plus fluorouracil and radiotherapy is associated with favourable local control rates and acute toxicity. Future investigations will be directed towards research into molecular biomarkers related to disease progression and resistance to chemo radiotherapy and to the evaluation of new cytotoxic agents or targeted drugs, such as anti-epidermal growth factor receptor, concomitant to RT and to determining the role of intensity-modulated radiotherapy. PMID- 21291547 TI - Avipoxviruses: infection biology and their use as vaccine vectors. AB - Avipoxviruses (APVs) belong to the Chordopoxvirinae subfamily of the Poxviridae family. APVs are distributed worldwide and cause disease in domestic, pet and wild birds of many species. APVs are transmitted by aerosols and biting insects, particularly mosquitoes and arthropods and are usually named after the bird species from which they were originally isolated. The virus species Fowlpox virus (FWPV) causes disease in poultry and associated mortality is usually low, but in flocks under stress (other diseases, high production) mortality can reach up to 50%. APVs are also major players in viral vaccine vector development for diseases in human and veterinary medicine. Abortive infection in mammalian cells (no production of progeny viruses) and their ability to accommodate multiple gene inserts are some of the characteristics that make APVs promising vaccine vectors. Although abortive infection in mammalian cells conceivably represents a major vaccine bio-safety advantage, molecular mechanisms restricting APVs to certain hosts are not yet fully understood. This review summarizes the current knowledge relating to APVs, including classification, morphogenesis, host-virus interactions, diagnostics and disease, and also highlights the use of APVs as recombinant vaccine vectors. PMID- 21291548 TI - The effects of attention capacity on dynamic balance control following concussion. AB - The purpose of this study was to examine how individuals modulate attention in a gait/cognition dual task during a 4-week period following a concussion. Ten individuals suffering from a grade 2 concussion and 10 matched controls performed a single task of level walking, a seated auditory Stroop task and a simultaneous auditory Stroop and walking task. Reaction time and accuracy were measured from the Stroop task. Dynamic balance control during gait was measured by the interaction (displacement and velocity) between the center of mass (CoM) and center of pressure (CoP) in the coronal and sagittal planes. Concussed individuals shifted from conservative control of balance (shorter separation between CoM and CoP) immediately after injury to normal balance control over 28 days post-injury. Immediately after injury, correlations analyses using each subject on each testing day as a data point showed that there was a spectrum of deficient performance among concussed individuals on the first testing day. Within a testing session, deficiencies in reaction time of processing involved in the Stroop task were commonly seen with reduce dynamic balance control. However, the prioritization was not always towards the same task between trials. There were no correlations in the control group. Information provided in this study would enhance our understanding of the interaction between attention and gait following concussion. PMID- 21291550 TI - The unique resistance and resilience of the Nigerian West African Dwarf goat to gastrointestinal nematode infections. AB - BACKGROUND: West African Dwarf (WAD) goats serve an important role in the rural village economy of West Africa, especially among small-holder livestock owners. They have been shown to be trypanotolerant and to resist infections with Haemonchus contortus more effectively than any other known breed of goat. METHODS: In this paper we review what is known about the origins of this goat breed, explain its economic importance in rural West Africa and review the current status of our knowledge about its ability to resist parasitic infections. CONCLUSIONS: We suggest that its unique capacity to show both trypanotolerance and resistance to gastrointestinal (GI) nematode infections is immunologically based and genetically endowed, and that knowledge of the underlying genes could be exploited to improve the capacity of more productive wool and milk producing, but GI nematode susceptible, breeds of goats to resist infection, without recourse to anthelmintics. Either conventional breeding allowing introgression of resistance alleles into susceptible breeds, or transgenesis could be exploited for this purpose. Appropriate legal protection of the resistance alleles of WAD goats might provide a much needed source of revenue for the countries in West Africa where the WAD goats exist and where currently living standards among rural populations are among the lowest in the world. PMID- 21291549 TI - Unified treatment algorithm for the management of crotaline snakebite in the United States: results of an evidence-informed consensus workshop. AB - BACKGROUND: Envenomation by crotaline snakes (rattlesnake, cottonmouth, copperhead) is a complex, potentially lethal condition affecting thousands of people in the United States each year. Treatment of crotaline envenomation is not standardized, and significant variation in practice exists. METHODS: A geographically diverse panel of experts was convened for the purpose of deriving an evidence-informed unified treatment algorithm. Research staff analyzed the extant medical literature and performed targeted analyses of existing databases to inform specific clinical decisions. A trained external facilitator used modified Delphi and structured consensus methodology to achieve consensus on the final treatment algorithm. RESULTS: A unified treatment algorithm was produced and endorsed by all nine expert panel members. This algorithm provides guidance about clinical and laboratory observations, indications for and dosing of antivenom, adjunctive therapies, post-stabilization care, and management of complications from envenomation and therapy. CONCLUSIONS: Clinical manifestations and ideal treatment of crotaline snakebite differ greatly, and can result in severe complications. Using a modified Delphi method, we provide evidence informed treatment guidelines in an attempt to reduce variation in care and possibly improve clinical outcomes. PMID- 21291551 TI - Dietary intakes in people with irritable bowel syndrome. AB - BACKGROUND: Irritable Bowel Syndrome (IBS) is a functional bowel disorder characterised by episodes of abdominal pain associated with altered bowel habits. Many IBS sufferers believe that diet may play a role in triggering these episodes and may avoid certain foods. However relatively few studies have undertaken a dietary assessment in IBS sufferers to examine the wider impact of the condition upon diet. METHODS: 104 individuals with IBS were recruited and asked to complete a validated food frequency questionnaire (FFQ). The data were analysed against Dietary Reference Values for food energy and nutrients for the United Kingdom and observed intakes for the general population and for differences between IBS subtypes and the UK population. RESULTS: The data show that the dietary intakes of this population of IBS sufferers met the UK Dietary Reference Values. The average energy intake of the population exceeded the Estimated Average Requirements of the UK population and the balance of macronutrients was favourable. Intakes of selected micronutrients significantly exceeded the reference nutrient intakes. There were no differences between IBS subtypes. CONCLUSIONS: The IBS subpopulation appear to have an adequate and balanced macronutrient intake with no evidence of inadequate micronutrient intake. PMID- 21291552 TI - Vaccination with live attenuated simian immunodeficiency virus causes dynamic changes in intestinal CD4+CCR5+ T cells. AB - BACKGROUND: Vaccination with live attenuated SIV can protect against detectable infection with wild-type virus. We have investigated whether target cell depletion contributes to the protection observed. Following vaccination with live attenuated SIV the frequency of intestinal CD4+CCR5+ T cells, an early target of wild-type SIV infection and destruction, was determined at days 3, 7, 10, 21 and 125 post inoculation. RESULTS: In naive controls, modest frequencies of intestinal CD4+CCR5+ T cells were predominantly found within the LPL TTrM-1 and IEL TTrM-2 subsets. At day 3, LPL and IEL CD4+CCR5+ TEM cells were dramatically increased whilst less differentiated subsets were greatly reduced, consistent with activation-induced maturation. CCR5 expression remained high at day 7, although there was a shift in subset balance from CD4+CCR5+ TEM to less differentiated TTrM-2 cells. This increase in intestinal CD4+CCR5+ T cells preceded the peak of SIV RNA plasma loads measured at day 10. Greater than 65.9% depletion of intestinal CD4+CCR5+ T cells followed at day 10, but overall CD4+ T cell homeostasis was maintained by increased CD4+CCR5- T cells. At days 21 and 125, high numbers of intestinal CD4+CCR5- naive TN cells were detected concurrent with greatly increased CD4+CCR5+ LPL TTrM-2 and IEL TEM cells at day 125, yet SIV RNA plasma loads remained low. CONCLUSIONS: This increase in intestinal CD4+CCR5+ T cells, following vaccination with live attenuated SIV, does not correlate with target cell depletion as a mechanism of protection. Instead, increased intestinal CD4+CCR5+ T cells may correlate with or contribute to the protection conferred by vaccination with live attenuated SIV. PMID- 21291553 TI - The evolution of farnesoid X, vitamin D, and pregnane X receptors: insights from the green-spotted pufferfish (Tetraodon nigriviridis) and other non-mammalian species. AB - BACKGROUND: The farnesoid X receptor (FXR), pregnane X receptor (PXR), and vitamin D receptor (VDR) are three closely related nuclear hormone receptors in the NR1H and 1I subfamilies that share the property of being activated by bile salts. Bile salts vary significantly in structure across vertebrate species, suggesting that receptors binding these molecules may show adaptive evolutionary changes in response. We have previously shown that FXRs from the sea lamprey (Petromyzon marinus) and zebrafish (Danio rerio) are activated by planar bile alcohols found in these two species. In this report, we characterize FXR, PXR, and VDR from the green-spotted pufferfish (Tetraodon nigriviridis), an actinopterygian fish that unlike the zebrafish has a bile salt profile similar to humans. We utilize homology modelling, docking, and pharmacophore studies to understand the structural features of the Tetraodon receptors. RESULTS: Tetraodon FXR has a ligand selectivity profile very similar to human FXR, with strong activation by the synthetic ligand GW4064 and by the primary bile acid chenodeoxycholic acid. Homology modelling and docking studies suggest a ligand binding pocket architecture more similar to human and rat FXRs than to lamprey or zebrafish FXRs. Tetraodon PXR was activated by a variety of bile acids and steroids, although not by the larger synthetic ligands that activate human PXR such as rifampicin. Homology modelling predicts a larger ligand-binding cavity than zebrafish PXR. We also demonstrate that VDRs from the pufferfish and Japanese medaka were activated by small secondary bile acids such as lithocholic acid, whereas the African clawed frog VDR was not. CONCLUSIONS: Our studies provide further evidence of the relationship between both FXR, PXR, and VDR ligand selectivity and cross-species variation in bile salt profiles. Zebrafish and green-spotted pufferfish provide a clear contrast in having markedly different primary bile salt profiles (planar bile alcohols for zebrafish and sterically bent bile acids for the pufferfish) and receptor selectivity that matches these differences in endogenous ligands. Our observations to date present an integrated picture of the co-evolution of bile salt structure and changes in the binding pockets of three nuclear hormone receptors across the species studied. PMID- 21291554 TI - Increased creatinine clearance in polytrauma patients with normal serum creatinine: a retrospective observational study. AB - INTRODUCTION: The aim of this study, performed in an intensive care unit (ICU) population with a normal serum creatinine, was to estimate urinary creatinine clearance (CLCR) in a population of polytrauma patients (PT) through a comparison with a population of non trauma patients (NPT). METHODS: This was a retrospective, observational study in a medical and surgical ICU in a university hospital. A total of 284 patients were consecutively included. Two different groups were studied: PT (n = 144) and NPT (n = 140). Within the second week after admission to the ICU, renal function was assessed using serum creatinine, 24 h urinary CLCR . RESULTS: Among the 106 patients with a CLCR above 120 mL minute( 1) 1.73 m(-2), 79 were PT and 27 NPT (P < 0.0001). Only 63 patients had a CLCR below 60 mL minute(-1) 1.73 m(-2) with 15 PT and 48 NPT (P < 0.0001). Patients with CLCR greater than 120 mL minute(-1). 1.73 m(-2) were younger, had a lower SAPS II score and a higher male ratio as compared to those having CLCR lower than 120 mL minute(-1). 1.73 m(-2). Through a logistic regression analysis, age and trauma were the only factors independently correlated to CLCR. CONCLUSIONS: In ICU patients with normal serum creatinine, CLCR, is higher in PT than in NPT. The measure of CLCR should be proposed as routine for PT patients in order to adjust dose regimen, especially for drugs with renal elimination. PMID- 21291555 TI - Musculoskeletal comorbidities in cardiovascular disease, diabetes and respiratory disease: the impact on activity limitations; a representative population-based study. AB - BACKGROUND: The purpose of this study was to quantify the contribution of comorbidity to activity limitations in populations with chronic cardiovascular disease, diabetes or respiratory disease (index conditions), with emphasis on musculoskeletal comorbidity (arthritis or back problems). METHODS: Analysis of the 2005 Canadian Community Health Survey 3.1 (age 20+ years, n = 115,915). Prevalence ratios for activity limitations in people with the index conditions and co-occurring musculoskeletal disease, adjusted for age, gender, and socioeconomic factors, were used to estimate population associated fractions (PAF). RESULTS: Comorbid arthritis and back problems significantly increased the risk of activity limitations across all index conditions with prevalence ratios of 1.60 and 1.46 for cardiovascular disease, 1.51 and 1.36 for diabetes, and 1.38 and 1.44 for respiratory disease for arthritis and back problems respectively. Arthritis and back problems accounted for at least 13% and 9% of activity limitations in the index populations. CONCLUSIONS: While chronic musculoskeletal conditions are not always considered priorities in chronic disease prevention, they account for a substantial proportion of activity restrictions seen in people with cardiovascular disease, diabetes and respiratory disease, with implications for prevention and control strategies. PMID- 21291556 TI - Obesity resistant mechanisms in the Lean polygenic mouse model as indicated by liver transcriptome and expression of selected genes in skeletal muscle. AB - BACKGROUND: Divergently selected Lean and Fat mouse lines represent unique models for a polygenic form of resistance and susceptibility to obesity development. Previous research on these lines focused mainly on obesity-susceptible factors in the Fat line. This study aimed to examine the molecular basis of obesity resistant mechanisms in the Lean line by analyzing various fat depots and organs, the liver transcriptome of selected metabolic pathways, plasma and lipid homeostasis and expression of selected skeletal muscle genes. RESULTS: Expression profiling using our custom Steroltalk v2 microarray demonstrated that Lean mice exhibit a higher hepatic expression of cholesterol biosynthesis genes compared to the Fat line, although this was not reflected in elevation of total plasma or liver cholesterol. However, FPLC analysis showed that protective HDL cholesterol was elevated in Lean mice. A significant difference between the strains was also found in bile acid metabolism. Lean mice had a higher expression of Cyp8b1, a regulatory enzyme of bile acid synthesis, and the Abcb11 bile acid transporter gene responsible for export of acids to the bile. Additionally, a higher content of blood circulating bile acids was observed in Lean mice. Elevated HDL and upregulation of some bile acids synthesis and transport genes suggests enhanced reverse cholesterol transport in the Lean line--the flux of cholesterol out of the body is higher which is compensated by upregulation of endogenous cholesterol biosynthesis. Increased skeletal muscle Il6 and Dio2 mRNA levels as well as increased activity of muscle succinic acid dehydrogenase (SDH) in the Lean mice demonstrates for the first time that changes in muscle energy metabolism play important role in the Lean line phenotype determination and corroborate our previous findings of increased physical activity and thermogenesis in this line. Finally, differential expression of Abcb11 and Dio2 identifies novel strong positional candidate genes as they map within the quantitative trait loci (QTL) regions detected previously in crosses between the Lean and Fat mice. CONCLUSION: We identified novel candidate molecular targets and metabolic changes which can at least in part explain resistance to obesity development in the Lean line. The major difference between the Lean and Fat mice was in increased liver cholesterol biosynthesis gene mRNA expression, bile acid metabolism and changes in selected muscle genes' expression in the Lean line. The liver Abcb11 and muscle Dio2 were identified as novel positional candidate genes to explain part of the phenotypic difference between the Lean and Fat lines. PMID- 21291558 TI - Methodology in conducting a systematic review of systematic reviews of healthcare interventions. AB - BACKGROUND: Hundreds of studies of maternity care interventions have been published, too many for most people involved in providing maternity care to identify and consider when making decisions. It became apparent that systematic reviews of individual studies were required to appraise, summarise and bring together existing studies in a single place. However, decision makers are increasingly faced by a plethora of such reviews and these are likely to be of variable quality and scope, with more than one review of important topics. Systematic reviews (or overviews) of reviews are a logical and appropriate next step, allowing the findings of separate reviews to be compared and contrasted, providing clinical decision makers with the evidence they need. METHODS: The methods used to identify and appraise published and unpublished reviews systematically, drawing on our experiences and good practice in the conduct and reporting of systematic reviews are described. The process of identifying and appraising all published reviews allows researchers to describe the quality of this evidence base, summarise and compare the review's conclusions and discuss the strength of these conclusions. RESULTS: Methodological challenges and possible solutions are described within the context of (i) sources, (ii) study selection, (iii) quality assessment (i.e. the extent of searching undertaken for the reviews, description of study selection and inclusion criteria, comparability of included studies, assessment of publication bias and assessment of heterogeneity), (iv) presentation of results, and (v) implications for practice and research. CONCLUSION: Conducting a systematic review of reviews highlights the usefulness of bringing together a summary of reviews in one place, where there is more than one review on an important topic. The methods described here should help clinicians to review and appraise published reviews systematically, and aid evidence-based clinical decision-making. PMID- 21291557 TI - Porcine dentin sialoprotein glycosylation and glycosaminoglycan attachments. AB - BACKGROUND: Dentin sialophosphoprotein (Dspp) is a multidomain, secreted protein that is critical for the formation of tooth dentin. Mutations in DSPP cause inherited dentin defects categorized as dentin dysplasia type II and dentinogenesis imperfecta type II and type III. Dentin sialoprotein (Dsp), the N terminal domain of dentin sialophosphoprotein (Dspp), is a highly glycosylated proteoglycan, but little is known about the number, character, and attachment sites of its carbohydrate moieties. RESULTS: To identify its carbohydrate attachment sites we isolated Dsp from developing porcine molars and digested it with endoproteinase Glu-C or pronase, fractionated the digestion products, identified fractions containing glycosylated peptides using a phenol sulfuric acid assay, and characterized the glycopeptides by N-terminal sequencing, amino acid analyses, or LC/MSMS. To determine the average number of sialic acid attachments per N-glycosylation, we digested Dsp with glycopeptidase A, labeled the released N-glycosylations with 2-aminobenzoic acid, and quantified the moles of released glycosylations by comparison to labeled standards of known concentration. Sialic acid was released by sialidase digestion and quantified by measuring beta-NADH reduction of pyruvic acid, which was generated stoichiometrically from sialic acid by aldolase. To determine its forms, sialic acid released by sialidase digestion was labeled with 1,2-diamino-4,5 methyleneoxybenzene (DMB) and compared to a DMB-labeled sialic acid reference panel by RP-HPLC. To determine the composition of Dsp glycosaminoglycan (GAG) attachments, we digested Dsp with chondroitinase ABC and compared the chromotagraphic profiles of the released disaccharides to commercial standards. N glycosylations were identified at Asn37, Asn77, Asn136, Asn155, Asn161, and Asn176. Dsp averages one sialic acid per N-glycosylation, which is always in the form of N-acetylneuraminic acid. O-glycosylations were tentatively assigned at Thr200, Thr216 and Thr316. Porcine Dsp GAG attachments were found at Ser238 and Ser250 and were comprised of chondroitin 6-sulfate and chondroitin 4-sulfate in a ratio of 7 to 3, respectively. CONCLUSIONS: The distribution of porcine Dsp posttranslational modifications indicate that porcine Dsp has an N-terminal domain with at least six N-glycosylations and a C-terminal domain with two GAG attachments and at least two O-glycosylations. PMID- 21291559 TI - BYPASS1: synthesis of the mobile root-derived signal requires active root growth and arrests early leaf development. AB - BACKGROUND: The Arabidopsis bypass1 (bps1) mutant root produces a biologically active mobile compound that induces shoot growth arrest. However it is unknown whether the root retains the capacity to synthesize the mobile compound, or if only shoots of young seedlings are sensitive. It is also unknown how this compound induces arrest of shoot growth. This study investigated both of these questions using genetic, inhibitor, reporter gene, and morphological approaches. RESULTS: Production of the bps1 root-synthesized mobile compound was found to require active root growth. Inhibition of postembryonic root growth, by depleting glutathione either genetically or chemically, allowed seedlings to escape shoot arrest. However, the treatments were not completely effective, as the first leaf pair remained radialized, but elongated. This result indicated that the embryonic root transiently synthesized a small amount of the mobile substance. In addition, providing glutathione later in vegetative development caused shoot growth arrest to be reinstated, revealing that these late-arising roots were still capable of producing the mobile substance, and that the older vegetative leaves were still responsive. To gain insight into how leaf development responds to the mobile signal, leaf development was followed morphologically and using the CYCB1,1::GUS marker for G2/M phase cells. We found that arrest of leaf growth is a fully penetrant phenotype, and a dramatic decrease in G2/M phase cells was coincident with arrest. Analyses of stress phenotypes found that late in development, bps1 cotyledons produced necrotic lesions, however neither hydrogen peroxide nor superoxide were abundant as leaves underwent arrest. CONCLUSIONS: bps1 roots appear to require active growth in order to produce the mobile bps1 signal, but the potential for this compound's synthesis is present both early and late during vegetative development. This prolonged capacity to synthesize and respond to the mobile compound is consistent with a possible role for the mobile compound in linking shoot growth to subterranean conditions. The specific growth-related responses in the shoot indicated that the mobile substance prevents full activation of cell division in leaves, although whether cell division is a direct response remains to be determined. PMID- 21291560 TI - Does prenatal micronutrient supplementation improve children's mental development? A systematic review. AB - BACKGROUND: Although maternal nutrient status influences all aspects of fetal development including the brain, the impact of micronutrient supplementation on the baby's mental function is a topic of debate. This systematic review assesses the effect of single and multiple micronutrient supplementation during pregnancy on offspring mental development. METHODS: Eleven electronic literature databases were searched using key terms of various combinations and filter string terms. Reference lists of articles selected for review were scanned for citations fitting the same inclusion criteria. Each stage of the literature retrieval and review process was conducted independently by two reviewers. The CONSORT checklist was used to assess study quality. RESULTS: A total of 1316 articles were retrieved from the electronic database search, of which 18 met the inclusion criteria and were evaluated. The selected studies were randomized controlled trials published from 1983 to 2010, with high variance in sample size, intervention type, and outcome measures. The median CONSORT score was 15 (range 12 - 19). Due to inconsistent interventions and outcome measures among the studies, no conclusive evidence was found that enhancing the intrauterine environment through micronutrient supplementation was associated with child mental development in a number of dimensions. There was some evidence to support n-3 fatty acids or multi-micronutrients having some positive effect on mental development, but the evidence for single nutrients was much weaker. CONCLUSIONS: The study of children's mental outcomes as a function of prenatal supplementation is still relatively new, but the results of this systematic review suggest that further work with multiple micronutrients and/or n-3 fatty acids should be conducted. PMID- 21291561 TI - Protein S blocks the extrinsic apoptotic cascade in tissue plasminogen activator/N-methyl D-aspartate-treated neurons via Tyro3-Akt-FKHRL1 signaling pathway. AB - BACKGROUND: Thrombolytic therapy with tissue plasminogen activator (tPA) benefits patients with acute ischemic stroke. However, tPA increases the risk for intracerebral bleeding and enhances post-ischemic neuronal injury if administered 3-4 hours after stroke. Therefore, combination therapies with tPA and neuroprotective agents have been considered to increase tPA's therapeutic window and reduce toxicity. The anticoagulant factor protein S (PS) protects neurons from hypoxic/ischemic injury. PS also inhibits N-methyl-D-aspartate (NMDA) excitotoxicity by phosphorylating Bad and Mdm2 which blocks the downstream steps in the intrinsic apoptotic cascade. To test whether PS can protect neurons from tPA toxicity we studied its effects on tPA/NMDA combined injury which in contrast to NMDA alone kills neurons by activating the extrinsic apoptotic pathway. Neither Bad nor Mdm2 which are PS's targets and control the intrinsic apoptotic pathway can influence the extrinsic cascade. Thus, based on published data one cannot predict whether PS can protect neurons from tPA/NMDA injury by blocking the extrinsic pathway. Neurons express all three TAM (Tyro3, Axl, Mer) receptors that can potentially interact with PS. Therefore, we studied whether PS can activate TAM receptors during a tPA/NMDA insult. RESULTS: We show that PS protects neurons from tPA/NMDA-induced apoptosis by suppressing Fas-ligand (FasL) production and FasL-dependent caspase-8 activation within the extrinsic apoptotic pathway. By transducing neurons with adenoviral vectors expressing the kinase deficient Akt mutant AktK179A and a triple FKHRL1 Akt phosphorylation site mutant (FKHRL1-TM), we show that Akt activation and Akt-mediated phosphorylation of FKHRL1, a member of the Forkhead family of transcription factors, are critical for FasL down-regulation and caspase-8 inhibition. Using cultured neurons from Tyro3, Axl and Mer mutants, we show that Tyro3, but not Axl and Mer, mediates phosphorylation of FHKRL1 that is required for PS-mediated neuronal protection after tPA/NMDA-induced injury. CONCLUSIONS: PS blocks the extrinsic apoptotic cascade through a novel mechanism mediated by Tyro3-dependent FKHRL1 phosphorylation which inhibits FasL-dependent caspase-8 activation and can control tPA-induced neurotoxicity associated with pathologic activation of NMDA receptors. The present findings should encourage future studies in animal stroke models to determine whether PS can increase the therapeutic window of tPA by reducing its post-ischemic neuronal toxicity. PMID- 21291562 TI - Pharmacokinetics of phenoxodiol, a novel isoflavone, following intravenous administration to patients with advanced cancer. AB - BACKGROUND: Phenoxodiol is a novel isoflavone currently being studied in clinical trials for the treatment of cancer. This study reports the pharmacokinetics of phenoxodiol in patients with cancer. METHODS: The pharmacokinetics of phenoxodiol was studied following a single intravenous (iv) bolus dose and during a continuous intravenous infusion. Three men with prostate cancer and 3 women with breast cancer received IV bolus phenoxodiol (5 mg/kg) and plasma was sampled for free and total phenoxodiol levels. On a separate occasion 5 of the same patients received a continuous intravenous infusion of phenoxodiol (2 mg/kg/h) and plasma was again sampled for free and total phenoxodiol levels. Phenoxodiol was measured using gradient HPLC with ultraviolet detection. RESULTS: Following bolus injection, free and total phenoxodiol appeared to follow first order pharmacokinetics. The elimination half-lives for free and total phenoxodiol were 0.67 +/- 0.53 h and 3.19 +/- 1.93 h, respectively, while the total plasma clearance rates were 2.48 +/- 2.33 L/h and 0.15 +/- 0.08 L/h, respectively. The respective apparent volumes of distribution were 1.55 +/- 0.69 L/kg and 0.64 +/- 0.51 L/kg. During continuous intravenous infusion, free phenoxodiol accumulated rapidly to reach a mean concentration at steady state of 0.79 +/- 0.14 MUg/ml after 0.87 +/- 0.18 h. The apparent accumulation half-life of free phenoxodiol was 0.17 +/- 0.04 h while the plasma clearance during continuous infusion was 1.29 +/- 0.23 L/h. CONCLUSIONS: Phenoxodiol has a short plasma half-life, particularly in the free form, leading to a rapid attainment of steady state levels during continuous intravenous infusion. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12610000334000. PMID- 21291563 TI - Nutrition of preterm infants in relation to bronchopulmonary dysplasia. AB - BACKGROUND: The pathogenesis of bronchopulmonary dysplasia (BPD) is multifactorial. In addition to prenatal inflammation, postnatal malnutrition also affects lung development. METHODS: A retrospective study was performed to analyse during the first two weeks of life the total, enteral and parenteral nutrition of premature infants (<31 weeks, birth weight <=1500 g) born between 08/04 and 12/06. RESULTS: Ninety-five premature infants were analysed: 26 with BPD (27 +/- 1 weeks) and 69 without BPD (28 +/- 1 weeks). There was no statistical significant difference in the total intake of fluids, calories, glucose or protein and weight gain per day in both groups. The risk of developing BPD was slightly increased in infants with cumulative caloric intake below the minimal requirement of 1230 kcal/kg and a cumulative protein intake below 43.5 g/kg. Furthermore, the risk of developing BPD was significantly higher when infants had a cumulative fluid intake above the recommended 1840 ml/kg. In infants who developed BPD, the enteral nutrition was significantly lower than in non-BPD infants [456 ml/kg (IQR 744, 235) vs. 685 (IQR 987, 511)]. Infants who did not develop BPD reached 50% of total enteral feeding significantly faster [9.6 days vs. 11.5]. CONCLUSIONS: Preterm infants developing BPD received less enteral feeding, even though it was well compensated by the parenteral nutrient supply. Data suggest that a critical minimal amount of enteral feeding is required to prevent development of BPD; however, a large prospective clinical study is needed to prove this assumption. PMID- 21291564 TI - The effects of centralised and specialised combined pharmacological and psychological intervention compared with decentralised and non-specialised treatment in the early course of severe unipolar and bipolar affective disorders- design of two randomised clinical trials. AB - BACKGROUND: In unipolar, and bipolar affective disorders, there is a high risk of relapse that increases as the number of episodes increases. Naturalistic follow up studies suggest that the progressive development of the diseases is not prevented with the present treatment modalities. It is not known whether centralised and specialised secondary care intervention initiated early after the onset of the diseases can prevent the progression and thereby improve the prognosis. METHODS: Two randomised clinical multi-centre trials comparing a centralised and specialised outpatient intervention program consisting of combined pharmacological and psychological intervention with standard decentralised psychiatric treatment. Patients discharged from their first, second, or third hospitalisation due to a manic episode or bipolar disorder (trial 1) or to a single depressive episode or recurrent depressive disorder (trial 2) were randomised. Central randomization for both trials were stratified for the number of hospitalisations and treatment centre. The primary outcome measure for the two trials is time to re-hospitalisation with an affective episode. DISCUSSION: These trials are the first to evaluate the effect of a centralised and specialised intervention in patients with early severe affective disorders. The trials used a pragmatic design comparing a specialised mood disorder clinic intervention with decentralised, non-specialised standard psychiatric treatment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00253071. PMID- 21291565 TI - Incidence of hepatitis-C among HIV infected men who have sex with men (MSM) attending a sexual health service: a cohort study. AB - BACKGROUND: We aimed to determine the incidence of Hepatitis C (HCV) infection among HIV-infected men who have sex with men (MSM) attending a Sexual Health Centre. METHODS: A retrospective cohort study was carried out among HIV-infected MSM seen at least once between February 2002 and March 2010. The analysis was restricted to MSM who had had a negative HCV antibody test at least 6 months after their diagnosis for HIV. Duration of follow up was taken from the date of HIV diagnosis to the first positive or last negative HCV antibody test. RESULTS: During the time 1445 HIV-infected men attended the clinic of whom 1065 (74%) were MSM. Of these, 869 (82%) were tested for HCV at any time after HIV diagnosis. Of these 869, 69% (620) tested HCV negative at least 6 months after their HIV diagnosis. These 620 men had a mean age of 34 years (range 17-72) at HIV diagnosis and a total of 4,359 person years (PY) of follow up. There were 40 incident cases of HCV, of which 16 were in injecting drug users (IDU) and 24 in non-IDU. The overall incidence of HCV among HIV-infected MSM was 0.9/100 PY (95% CI 0.6-1.2). The incidence among HIV-infected IDU was 4.7/100 PY (95% CI 2.7-7.5) while the incidence among HIV-infected non-IDU was 0.6/100 PY (95% CI 0.4-0.8) (hazard ratio of 8.7 and 95% CI 4.6-16.6, P < 0.001).The majority (78%) were tested for HCV because they developed abnormal liver transaminases (n = 31) or hepatitis symptoms (n = 2), while others (n = 7) were identified through routine HCV testing. CONCLUSION: A considerable proportion of HIV-positive MSM who did not inject drugs contracted HCV, presumably via sexual transmission and the main trigger for investigation was abnormal liver transaminases. PMID- 21291566 TI - Accurate statistics for local sequence alignment with position-dependent scoring by rare-event sampling. AB - BACKGROUND: Molecular database search tools need statistical models to assess the significance for the resulting hits. In the classical approach one asks the question how probable a certain score is observed by pure chance. Asymptotic theories for such questions are available for two random i.i.d. sequences. Some effort had been made to include effects of finite sequence lengths and to account for specific compositions of the sequences. In many applications, such as a large scale database homology search for transmembrane proteins, these models are not the most appropriate ones. Search sensitivity and specificity benefit from position-dependent scoring schemes or use of Hidden Markov Models. Additional, one may wish to go beyond the assumption that the sequences are i.i.d. Despite their practical importance, the statistical properties of these settings have not been well investigated yet. RESULTS: In this paper, we discuss an efficient and general method to compute the score distribution to any desired accuracy. The general approach may be applied to different sequence models and and various similarity measures that satisfy a few weak assumptions. We have access to the low-probability region ("tail") of the distribution where scores are larger than expected by pure chance and therefore relevant for practical applications. Our method uses recent ideas from rare-event simulations, combining Markov chain Monte Carlo simulations with importance sampling and generalized ensembles. We present results for the score statistics of fixed and random queries against random sequences. In a second step, we extend the approach to a model of transmembrane proteins, which can hardly be described as i.i.d. sequences. For this case, we compare the statistical properties of a fixed query model as well as a hidden Markov sequence model in connection with a position based scoring scheme against the classical approach. CONCLUSIONS: The results illustrate that the sensitivity and specificity strongly depend on the underlying scoring and sequence model. A specific ROC analysis for the case of transmembrane proteins supports our observation. PMID- 21291567 TI - Iron bioavailibity from a tropical leafy vegetable in anaemic mice. AB - Telfairia occidentalis is a vegetable food crop that is indigenous to West Africa. The leaves and seeds are the edible parts of the plant and are used in everyday meals by incorporation into soups and stews. Previous studies have attributed improved haematological indices to the vegetable and have advocated the use of T. occidentalis in the treatment of anemia. This study investigates the ameliorative effects of T. occidentalis when compared to FeSO4 as a reference salt in anaemic mice. It also compares the bioavailability of test iron and hepatic hepcidin expression for the estimation of iron absorption in the mice. Non-haem iron was determined in the liver of mice after the experimental feeding treatments. Hepcidin mRNA expression was carried out by quantitative RT-PCR. Administration of T. occidentalis leaves led to a modest increase in haemoglobin (Hb) levels in anaemic mice that were comparable to the Hb repletion in anaemic mice given FeSO4. Hepatic iron increase in the mice given either T. occidentalis or FeSO4 led to a corresponding enhancement of hepcidin mRNA expression. Induced hepcidin mRNA expression was enhanced by the addition of ascorbic acid to the test dose of iron. Hepatic hepcidin mRNA expression was found to be responsive to increase in the relative bioavailability of iron from test diets. PMID- 21291568 TI - We should not be complacent about our population-based public health response to the first influenza pandemic of the 21st century. AB - BACKGROUND: More than a year after an influenza pandemic was declared in June 2009, the World Health Organization declared the pandemic to be over. Evaluations of the pandemic response are beginning to appear in the public domain. DISCUSSION: We argue that, despite the enormous effort made to control the pandemic, it is now time to acknowledge that many of the population-based public health interventions may not have been well considered. Prior to the pandemic, there was limited scientific evidence to support border control measures. In particular no border screening measures would have detected prodromal or asymptomatic infections, and asymptomatic infections with pandemic influenza were common. School closures, when they were partial or of short duration, would not have interrupted spread of the virus in school-aged children, the group with the highest rate of infection worldwide. In most countries where they were available, neuraminidase inhibitors were not distributed quickly enough to have had an effect at the population level, although they will have benefited individuals, and prophylaxis within closed communities will have been effective. A pandemic specific vaccine will have protected the people who received it, although in most countries only a small minority was vaccinated, and often a small minority of those most at risk. The pandemic vaccine was generally not available early enough to have influenced the shape of the first pandemic wave and it is likely that any future pandemic vaccine manufactured using current technology will also be available too late, at least in one hemisphere. SUMMARY: Border screening, school closure, widespread anti-viral prophylaxis and a pandemic-specific vaccine were unlikely to have been effective during a pandemic which was less severe than anticipated in the pandemic plans of many countries. These were cornerstones of the population-based public health response. Similar responses would be even less likely to be effective in a more severe pandemic. We agree with the recommendation from the World Health Organisation that pandemic preparedness plans need review. PMID- 21291569 TI - Evaluation of chronic lymphocytic leukemia by BAC-based microarray analysis. AB - BACKGROUND: Chronic lymphocytic leukemia (CLL) is a highly variable disease with life expectancies ranging from months to decades. Cytogenetic findings play an integral role in defining the prognostic significance and treatment for individual patients. RESULTS: We have evaluated 25 clinical cases from a tertiary cancer center that have an established diagnosis of CLL and for which there was prior cytogenetic and/or fluorescence in situ hybridization (FISH) data. We performed microarray-based comparative genomic hybridization (aCGH) using a bacterial artificial chromosome (BAC)-based microarray designed for the detection of known constitutional genetic syndromes. In 15 of the 25 cases, aCGH detected all copy number imbalances identified by prior cytogenetic and/or FISH studies. For the majority of those not detected, the aberrations were present at low levels of mosaicism. Furthermore, for 15 of the 25 cases, additional abnormalities were detected. Four of those cases had deletions that mapped to intervals implicated in inherited predisposition to CLL. For most cases, aCGH was able to detect abnormalities present in as few as 10% of cells. Although changes in ploidy are not easily discernable by aCGH, results for two cases illustrate the detection of additional copy gains and losses present within a mosaic tetraploid cell population. CONCLUSIONS: Our results illustrate the successful evaluation of CLL using a microarray optimized for the interrogation of inherited disorders and the identification of alterations with possible relevance to CLL susceptibility. PMID- 21291570 TI - Swine-origin influenza a outbreak 2009 at Shinshu University, Japan. AB - BACKGROUND: A worldwide outbreak of swine flu H1N1 pandemic influenza occurred in April 2009. To determine the mechanism underlying the spread of infection, we prospectively evaluated a survey implemented at a local university. METHODS: Between August 2009 and March 2010, we surveyed 3 groups of subjects: 2318 children in six schools attached to the Faculty of Education, 11424 university students, and 3344 staff members. Subjects with influenza-like symptoms who were diagnosed with swine flu at hospitals or clinics were defined as swine flu patients and asked to make a report using a standardized form. RESULTS: After the start of the pandemic, a total of 2002 patients (11.7%) were registered in the survey. These patients included 928 schoolchildren (40.0%), 1016 university students (8.9%), and 58 staff members (1.7%). The incidence in schoolchildren was significantly higher than in the other 2 groups (P < 0.0001) but there were no within group differences in incidence rate between males and females. During the period of the survey, three peaks of patient numbers were observed, in November 2009, December 2009, and January 2010. The first peak consisted mainly of schoolchildren, whereas the second and third peaks included many university students. Staff members did not contribute to peak formation. Among the university students, the most common suspected route of transmission was club activity. Interventions, such as closing classes, schools, and clubs, are likely to affect the epidemic curves. CONCLUSION: Schoolchildren and university students are vulnerable to swine flu, suggesting that avoidance of close contact, especially among these young people, may be effective way in controlling future severe influenza pandemics, especially at educational institutions. PMID- 21291571 TI - Enzymatic analysis of the effect of naturally occurring Leu138Pro mutation identified in SHV beta-lactamase on hydrolysis of penicillin and ampicillin. AB - BACKGROUND: The aim of this study was to analyze the significance of leucine to proline substitution at position 138(Leu138Pro) on the hydrolysis of penicillin and ampicillin that we identified in the blaSHV gene of clinical Escherichia coli swine isolate. RESULTS: Kinetic analysis of the mutant proteins showed that K(m) value of the purified L138P mutant was comparatively higher than SHV-1, SHV-33 and SHV-33(L138P) enzyme for penicillin and ampicillin. Docking simulation of the SHV-1 and SHV-(L138P) enzymes also confirmed that beta-lactamases preferred penicillin to ampicillin and the SHV-1 had a higher binding affinity for antibiotics compared to the SHV-(L138P) and other mutants. CONCLUSIONS: Our result demonstrated that L138P has a reduced role in penicillin and ampicillin hydrolyzing properties of SHV beta-lactamases. These naturally occurring mutations rendering reduced function of the existing protein could trigger the emergence or acquisition of more effective alternative mechanisms for beta-lactam hydrolysis. PMID- 21291573 TI - [A baby with an abdomen full of balls]. AB - A 2-day-old girl with an urethrorectal fistula as part of an anorectal septum malformation showed intra-abdominal densities in the colon on radiologic examination, due to calcified meconium balls. This calcification is caused by the presence of urine in the intestinal tract and therefore confirms the presence of an urethrorectal fistula. PMID- 21291574 TI - [Franciscus Donders (1818-1889): ophthalmologist and physiologist]. AB - In the 19th century Donders was one of the few Dutch physicians who had an international reputation. Initially a military physician, in 1842 he was appointed as a teacher of anatomy, histology and physiology at the academy in Utrecht at which he had been trained. Five years later, Utrecht University appointed him as professor extraordinarius. Donders was among the first to use Von Helmholtz' ophthalmoscope (1851) and treated increasing numbers of patients with an eye disease. In 1864 he published a widely acclaimed treatise on disorders of refraction and accommodation. In 1862 he was appointed full professor of physiology in Utrecht. Subsequently he published on a variety of physiological subjects. PMID- 21291572 TI - A quality metric for homology modeling: the H-factor. AB - BACKGROUND: The analysis of protein structures provides fundamental insight into most biochemical functions and consequently into the cause and possible treatment of diseases. As the structures of most known proteins cannot be solved experimentally for technical or sometimes simply for time constraints, in silico protein structure prediction is expected to step in and generate a more complete picture of the protein structure universe. Molecular modeling of protein structures is a fast growing field and tremendous works have been done since the publication of the very first model. The growth of modeling techniques and more specifically of those that rely on the existing experimental knowledge of protein structures is intimately linked to the developments of high resolution, experimental techniques such as NMR, X-ray crystallography and electron microscopy. This strong connection between experimental and in silico methods is however not devoid of criticisms and concerns among modelers as well as among experimentalists. RESULTS: In this paper, we focus on homology-modeling and more specifically, we review how it is perceived by the structural biology community and what can be done to impress on the experimentalists that it can be a valuable resource to them. We review the common practices and provide a set of guidelines for building better models. For that purpose, we introduce the H-factor, a new indicator for assessing the quality of homology models, mimicking the R-factor in X-ray crystallography. The methods for computing the H-factor is fully described and validated on a series of test cases. CONCLUSIONS: We have developed a web service for computing the H-factor for models of a protein structure. This service is freely accessible at http://koehllab.genomecenter.ucdavis.edu/toolkit/h-factor. PMID- 21291575 TI - [New antithrombotics for atrial fibrillation]. AB - Cerebral infarction is the most serious complication of atrial fibrillation. Coumarin derivatives (vitamin K antagonists) counteract systemic thromboembolism and reduce the risk of stroke by more than 60%, but carry a risk of serious bleeding. Antiplatelet therapy and subcutaneous low-molecular-weight heparin are as yet not sufficiently effective and are associated with a bleeding risk similar to vitamin K antagonists. Vitamin K antagonists require intensive INR monitoring to ensure efficacy and safety. In the past decade, oral agents have been developed that directly inhibit the activity of thrombin (factor IIa) and of activated factor X (Xa), which is the first compound in the final common pathway of the coagulation cascade. These do require INR monitoring and have rapid onset and offset of action. The first results with thrombin blockers, such as dabigatran, look promising in efficacy and safety and Xa inhibitors are currently under investigation in atrial fibrillation in 3 large clinical trials. Long-term safety of the new agents in patients with atrial fibrillation has not yet been determined. PMID- 21291576 TI - [Transfusion policy in trauma involving massive blood loss]. AB - Severe haemorrhage is a significant cause of death in trauma patients. In the case of massive blood loss a combination of coagulation defects, acidosis and hypothermia arise, which are accompanied by high morbidity and mortality rates unless properly corrected. Research in wounded military showed that a high ratio of fresh frozen plasma to packed red blood cells (FFP:PRBC) seemed to have a positive effect on survival. These studies do not provide a definition of the ideal ratio FFP:PRBC; the ratio in which a positive effect is seen varies from 1:1 to 1:3. Unnecessary FFP transfusions in trauma patients without imminent severe haemorrhage increase the risk of complications such as multi-organ failure and acute respiratory distress syndrome. Additional research is required into the accuracy of diagnosis of acute coagulation disorders. PMID- 21291577 TI - [Volume replenishment in haemorrhage: caution advised]. AB - Acute haemorrhage is a frequent problem in medicine. Patients with acute bleeding may present with signs of hypotension and reduced organ perfusion. The physician's reflex action is often to treat such patients with intravenous volume replenishment using colloid or cristalloid liquids. Intravenous volume replenishment has, however, a downside: it increases the tendency to bleed and therefore can increase blood loss. Previous clinical observations and experimental animal and human studies addressing volume replenishment in haemorrhagic shock have repeatedly shown that accepting hypotension favourably affects prognosis. However, relevant practice guidelines, such as for gastrointestinal bleeding, usually advise liberal intravenous volume replenishment if hypotension is present. In this article we advocate caution when considering intravenous blood volume adjustment in haemorrhage. PMID- 21291578 TI - [Audit of severe acute maternal morbidity (SAMM) in the Netherlands]. AB - OBJECTIVE: To describe the audit of severe acute maternal morbidity in the Netherlands, indicating the audit procedure and possible points for improvement. DESIGN: Descriptive audit investigation. METHODS: Eight audit meetings were held concerning cases of severe acute maternal morbidity selected from a prospective, population-based, cohort investigation at all 98 obstetric departments in the Netherlands. Before the start of each meeting, details of the cases were sent to panel members for individual analysis. During the plenary meeting the findings were discussed, and more detailed information was available if required from the patient dossier. Substandard care was identified on the basis of the opinion of the majority of panel members. RESULTS: Substandard care was identified in almost 80% of the SAMM cases discussed. Specific recommendations were formulated concerning the procedure of audit and also concerning local and national implementation of guidelines. CONCLUSION: Audit merits an important place both nationally and locally in Dutch obstetric practice. Quality improvement is generally possible without large changes to the system, specifically by optimising existing guidelines and putting them into practice. PMID- 21291579 TI - [Thrombinoscopy: measuring thrombin generation]. AB - A test is needed of which the score is low in case of haemorrhagic tendency and high in case of thrombotic tendency. Emerging evidence shows that thrombin generation is a promising candidate. Recently it became possible to measure the course in thrombin concentration in clotting blood or blood plasma in an simple way suitable for application in a routine clinical setting. It appears that the amount of thrombin developing in clotting blood or blood plasma is a better measure for thrombotic- or haemorrhagic tendency than any variant of the clotting time and that thrombin generation is a universal test for the effect of antithrombotic drugs. PMID- 21291580 TI - [The oldest painting of an anatomy lesson]. AB - The Amsterdam Historical Museum has a large collection of paintings of anatomy lessons, painted when surgeons followed the popular sixteenth century trend for group portraits. The very first, a painting of an anatomy lesson given by Sebastiaen Egbertsz de Vrij, was painted by Aert Pietersz in 1601-1603. PMID- 21291581 TI - [A complication of coronary angiography in a female patient with systemic sclerosis]. AB - Systemic sclerosis is an autoimmune connective tissue disorder characterized by microvascular obliterations of the skin, lungs, and heart. Pulmonary hypertension is a potentially life-threatening complication of systemic sclerosis and coronary angiography is indicated for diagnosing this complication. A 79-year-old woman, who suffered from systemic sclerosis and Raynaud's syndrome, presented with a cold, painful, ulcerated right hand. It appeared that arterial occlusion of the radial artery had occurred following coronary angiography. Symptoms initially worsened, but improved following treatment with bosentan. This complication could have been avoided by performing the coronary angiography via the femoral artery. This case study emphasises the importance of taking medical history and comorbidities into account when carrying out invasive diagnostic procedures. PMID- 21291582 TI - [There is something coming out of the anus of my child]. AB - The diagnosis of anal protrusions in children may be difficult, because the protrusion often occurs only after defaecation, and is usually invisible during the consultation. We present three cases of children with rectal prolapse (4-year old boy), polyp (4-year-old boy), and external haemorrhoids (3-year-old boy), respectively. In each case, the diagnosis could be made after parents had sent a picture of the phenomenon. The first patient recovered after laxative therapy, the second after polypectomy, and in the third patient, the haemorrhoid persisted, despite laxative therapy and physiotherapy. PMID- 21291583 TI - [The audit: a vital but limited measuring instrument]. AB - An audit is an instrument to improve quality of care. It primarily does this by revealing the extent to which medical professionals do not follow existing protocols for patient care. However, it should not replace robust research into new forms of care. Most audits are, in effect, no more than a series of cases of poor outcomes and cannot yield rigorous evidence. In an audit, Van Dillen et al. (2010) report 17 cases of postpartum hemorrhage (PPH) and eclampsia after home births and births started under midwifery care. They show that in 76% of these cases the care by the midwife and/or obstetrician did not follow existing Dutch practice guidelines or consensus. They make recommendations for changes in care, including the introduction of misoprostol in primary care and transfer to hospital if the placenta has not been delivered within half an hour. Although PPH and eclampsia are rare in Dutch primary obstetric care, midwives and obstetricians should make a better effort to adhere to practice guidelines aimed at delivering the best pregnancy and birth care. However, new forms of care should first be researched for effectiveness in lowering maternal morbidity, side effects and costs, before they can be implemented in practice. PMID- 21291584 TI - Zoonoses in the bedroom. AB - In most industrialized countries, pets are becoming an integral part of households, sharing human lifestyles, bedrooms, and beds. The estimated percentage of pet owners who allow dogs and cats on their beds is 14%-62%. However, public health risks, including increased emergence of zoonoses, may be associated with such practices. PMID- 21291585 TI - Hepatitis E virus and neurologic disorders. AB - Information about the spectrum of disease caused by hepatitis E virus (HEV) genotype 3 is emerging. During 2004-2009, at 2 hospitals in the United Kingdom and France, among 126 patients with locally acquired acute and chronic HEV genotype 3 infection, neurologic complications developed in 7 (5.5%): inflammatory polyradiculopathy (n = 3), Guillain-Barre syndrome (n = 1), bilateral brachial neuritis (n = 1), encephalitis (n = 1), and ataxia/proximal myopathy (n = 1). Three cases occurred in nonimmunocompromised patients with acute HEV infection, and 4 were in immunocompromised patients with chronic HEV infection. HEV RNA was detected in cerebrospinal fluid of all 4 patients with chronic HEV infection but not in that of 2 patients with acute HEV infection. Neurologic outcomes were complete resolution (n = 3), improvement with residual neurologic deficit (n = 3), and no improvement (n = 1). Neurologic disorders are an emerging extrahepatic manifestation of HEV infection. PMID- 21291586 TI - Human infections with non-O157 Shiga toxin-producing Escherichia coli, Switzerland, 2000-2009. AB - We characterized 97 non-O157 Shiga toxin (stx)-producing Escherichia coli strains isolated from human patients during 2000-2009 from the national reference laboratory in Switzerland. These strains belonged to 40 O:H serotypes; 4 serotypes (O26:H11/H-, O103:H2, O121:H19, and O145:H28/H-) accounted for 46.4% of the strains. Nonbloody diarrhea was reported by 23.2% of the patients, bloody diarrhea by 56.8%. Hemolytic uremic syndrome developed in 40.0% of patients; serotype O26:H11/H- was most often associated with this syndrome. Forty-five (46.4%) strains carried stx2 genes only, 36 strains (37.1%) carried stx1, and 16 (16.5%) strains carried stx1 and stx2. Genes encoding enterohemolysin and intimin were detected in 75.3% and 70.1% of the strains, respectively. Resistance to >=1 antimicrobial agent was present in 25 isolates. High genetic diversity within strains indicates that non-O157 stx-producing E. coli infections in Switzerland most often occurred as single cases. PMID- 21291587 TI - Severe cases of pandemic (H1N1) 2009 in children, Germany. AB - In a hospital-based observational study in Germany, we investigated children admitted to pediatric intensive care units and deaths caused by confirmed pandemic (H1N1) 2009 to identify risk factors and outcomes in critically ill children. Ninety-three children were eligible for our study, including 9 with hospital-acquired infections. Seventy-five percent had underlying chronic medical conditions; neurodevelopmental disorders were most prevalent (57%). The proportion of patients having >=1 risk factor increased with age in years (odds ratio 1.21, p = 0.007). Of 15 deaths, 11 occurred in a pediatric intensive care unit (case-fatality rate 12%, 95% confidence interval 6%-21%). Only 9% of the children had been vaccinated against pandemic (H1N1) 2009; all survived. Our results stress the role of underlying risk factors, especially neurodevelopmental disorders, and the need for improving preventive measures to reduce severe disease and adverse outcomes of pandemic (H1N1) 2009 in children. PMID- 21291588 TI - Risk factors for Cryptococcus gattii infection, British Columbia, Canada. AB - To determine whether particular environmental, medical, or behavioral risk factors existed among Cryptcoccus gattii-infected persons compared with the general population, we conducted a sex-matched case-control study on a subset of case-patients in British Columbia (1999-2001). Exposures and underlying medical conditions among all case-patients (1999-2007) were also compared with results of provincial population-based surveys and studies. In case-control analyses, oral steroids (matched odds ratio [MOR] 8.11, 95% confidence interval [CI] 1.74 37.80), pneumonia (MOR 2.71, 95% CI 1.05-6.98), and other lung conditions (MOR 3.21, 95% CI 1.08-9.52) were associated with infection. In population comparisons, case-patients were more likely to be >=50 years of age (p<0.001), current smokers (p<0.001), infected with HIV (p<0.001), or have a history of invasive cancer (p<0.001). Although C. gattii is commonly believed to infect persons with apparently healthy immune systems, several immunosuppressive and pulmonary conditions seem to be risk factors. PMID- 21291589 TI - Possible increased pathogenicity of pandemic (H1N1) 2009 influenza virus upon reassortment. AB - Since emergence of the pandemic (H1N1) 2009 virus in April 2009, three influenza A viruses-seasonal (H3N2), seasonal (H1N1), and pandemic (H1N1) 2009-have circulated in humans. Genetic reassortment between these viruses could result in enhanced pathogenicity. We compared 4 reassortant viruses with favorable in vitro replication properties with the wild-type pandemic (H1N1) 2009 virus with respect to replication kinetics in vitro and pathogenicity and transmission in ferrets. Pandemic (H1N1) 2009 viruses containing basic polymerase 2 alone or in combination with acidic polymerase of seasonal (H1N1) virus were attenuated in ferrets. In contrast, pandemic (H1N1) 2009 with neuraminidase of seasonal (H3N2) virus resulted in increased virus replication and more severe pulmonary lesions. The data show that pandemic (H1N1) 2009 virus has the potential to reassort with seasonal influenza viruses, which may result in increased pathogenicity while it maintains the capacity of transmission through aerosols or respiratory droplets. PMID- 21291590 TI - Common reservoirs for Penicillium marneffei infection in humans and rodents, China. AB - Human penicilliosis marneffei is an emerging infectious disease caused by the fungus Penicillium marneffei. High prevalence of infection among bamboo rats of the genera Rhizomys and Cannomys suggest that these rodents are a key facet of the P. marneffei life cycle. We trapped bamboo rats during June 2004-July 2005 across Guangxi Province, China, and demonstrated 100% prevalence of infection. Multilocus genotypes show that P. marneffei isolates from humans are similar to those infecting rats and are in some cases identical. Comparison of our dataset with genotypes recovered from sites across Southeast Asia shows that the overriding component of genetic structure in P. marneffei is spatial, with humans containing a greater diversity of genotypes than rodents. Humans and bamboo rats are sampling an as-yet undiscovered common reservoir of infection, or bamboo rats are a vector for human infections by acting as amplifiers of infectious dispersal stages. PMID- 21291591 TI - Phocine distemper virus in seals, east coast, United States, 2006. AB - In 2006 and 2007, elevated numbers of deaths among seals, constituting an unusual mortality event, occurred off the coasts of Maine and Massachusetts, United States. We isolated a virus from seal tissue and confirmed it as phocine distemper virus (PDV). We compared the viral hemagglutinin, phosphoprotein, and fusion (F) and matrix (M) protein gene sequences with those of viruses from the 1988 and 2002 PDV epizootics. The virus showed highest similarity with a PDV 1988 Netherlands virus, which raises the possibility that the 2006 isolate from the United States might have emerged independently from 2002 PDVs and that multiple lineages of PDV might be circulating among enzootically infected North American seals. Evidence from comparison of sequences derived from different tissues suggested that mutations in the F and M genes occur in brain tissue that are not present in lung, liver, or blood, which suggests virus persistence in the central nervous system. PMID- 21291592 TI - Leptospirosis in Hawaii, USA, 1999-2008. AB - Although infrequently diagnosed in the United States, leptospirosis is a notable reemerging infectious disease throughout developing countries. Until 1995, when the disease was eliminated from the US list of nationally notifiable diseases, Hawaii led the nation in reported annual incidence rates. Leptospirosis remains a notifiable disease in Hawaii. To ascertain the status of leptospirosis in Hawaii since the most recent US report in 2002, we reviewed 1999-2008 data obtained from case investigation reports by the Hawaii State Department of Health. Of the 345 case reports related to in-state exposures, 198 (57%) were laboratory confirmed. Our findings indicate a change in seasonal disease occurrence from summer to winter and in the infective serogroup from Icterohemorrhagiae to Australis. Also, during the past 20 years, recreational exposures have plateaued, while occupational exposures have increased. Ongoing surveillance is needed to clarify and track the dynamic epidemiology of this widespread zoonosis. PMID- 21291593 TI - Next-generation sequencing of Coccidioides immitis isolated during cluster investigation. AB - Next-generation sequencing enables use of whole-genome sequence typing (WGST) as a viable and discriminatory tool for genotyping and molecular epidemiologic analysis. We used WGST to confirm the linkage of a cluster of Coccidioides immitis isolates from 3 patients who received organ transplants from a single donor who later had positive test results for coccidioidomycosis. Isolates from the 3 patients were nearly genetically identical (a total of 3 single-nucleotide polymorphisms identified among them), thereby demonstrating direct descent of the 3 isolates from an original isolate. We used WGST to demonstrate the genotypic relatedness of C. immitis isolates that were also epidemiologically linked. Thus, WGST offers unique benefits to public health for investigation of clusters considered to be linked to a single source. PMID- 21291594 TI - Arbovirus prevalence in mosquitoes, Kenya. AB - Few studies have investigated the many mosquito species that harbor arboviruses in Kenya. During the 2006-2007 Rift Valley fever outbreak in North Eastern Province, Kenya, exophilic mosquitoes were collected from homesteads within 2 affected areas: Gumarey (rural) and Sogan-Godud (urban). Mosquitoes (n = 920) were pooled by trap location and tested for Rift Valley fever virus and West Nile virus. The most common mosquitoes trapped belonged to the genus Culex (75%). Of 105 mosquito pools tested, 22% were positive for Rift Valley fever virus, 18% were positive for West Nile virus, and 3% were positive for both. Estimated mosquito minimum infection rates did not differ between locations. Our data demonstrate the local abundance of mosquitoes that could propagate arboviral infections in Kenya and the high prevalence of vector arbovirus positivity during a Rift Valley fever outbreak. PMID- 21291595 TI - New Delhi metallo-beta-lactamase from traveler returning to Canada. AB - An Escherichia coli isolate with New Delhi metallo-beta-lactamase was isolated from a patient with pyelonephritis and prostatitis who returned to Canada after recent hospitalization in India. The patient was successfully treated with ertapenem and fosfomycin. This patient highlights the role of international travel in the spread of antimicrobial drug resistance and blaNDM-1. PMID- 21291596 TI - School closures and student contact patterns. AB - To determine how school closure for pandemic (H1N1) 2009 affected students' contact patterns, we conducted a retrospective questionnaire survey at a UK school 2 weeks after the school reopened. School closure was associated with a 65% reduction in the mean total number of contacts for each student. PMID- 21291597 TI - Unusual transmission of Plasmodium falciparum, Bordeaux, France, 2009. AB - Plasmodium falciparum malaria is usually transmitted by mosquitoes. We report 2 cases in France transmitted by other modes: occupational blood exposure and blood transfusion. Even where malaria is not endemic, it should be considered as a cause of unexplained acute fever. PMID- 21291598 TI - Transmission of Armillifer armillatus ova at snake farm, The Gambia, West Africa. AB - Visceral pentastomiasis caused by Armillifer armillatus larvae was diagnosed in 2 dogs in The Gambia. Parasites were subjected to PCR; phylogenetic analysis confirmed relatedness with branchiurans/crustaceans. Our investigation highlights transmission of infective A. armillatus ova to dogs and, by serologic evidence, also to 1 human, demonstrating a public health concern. PMID- 21291599 TI - Characteristics of patients with oseltamivir-resistant pandemic (H1N1) 2009, United States. AB - During April 2009-June 2010, thirty-seven (0.5%) of 6,740 pandemic (H1N1) 2009 viruses submitted to a US surveillance system were oseltamivir resistant. Most patients with oseltamivir-resistant infections were severely immunocompromised (76%) and had received oseltamivir before specimen collection (89%). No evidence was found for community circulation of resistant viruses; only 4 (unlinked) patients had no oseltamivir exposure. PMID- 21291600 TI - Primary amebic meningoencephalitis caused by Naegleria fowleri, Karachi, Pakistan. AB - We report 13 cases of Naegleria fowleri primary amebic meningoencephalitis in persons in Karachi, Pakistan, who had no history of aquatic activities. Infection likely occurred through ablution with tap water. An increase in primary amebic meningoencephalitis cases may be attributed to rising temperatures, reduced levels of chlorine in potable water, or deteriorating water distribution systems. PMID- 21291601 TI - Alert system to detect possible school-based outbreaks of influenza-like illness. AB - To evaluate the usefulness of school absentee data in identifying outbreaks as part of syndromic surveillance, we examined data collected from public schools in Miami-Dade County, Florida, USA. An innovative automated alert system captured information about school-specific absenteeism to detect and provide real-time notification of possible outbreaks of influenza-like illness. PMID- 21291602 TI - New avian influenza virus (H5N1) in wild birds, Qinghai, China. AB - Highly pathogenic avian influenza virus (H5N1) (QH09) was isolated from dead wild birds (3 species) in Qinghai, China, during May-June 2009. Phylogenetic and antigenic analyses showed that QH09 was clearly distinguishable from classical clade 2.2 viruses and belonged to clade 2.3.2. PMID- 21291603 TI - Blastomycosis in man after kinkajou bite. AB - We report transmission of Blastomyces dermatitidis fungal infection from a pet kinkajou to a man. When treating a patient with a recalcitrant infection and a history of an animal bite, early and complete animal necropsy and consideration of nonbacterial etiologies are needed. PMID- 21291604 TI - Novel HIV-1 recombinant forms in antenatal cohort, Montreal, Quebec, Canada. AB - Near full-length genomes of 4 unclassified HIV-1 variants infecting patients enrolled in an antenatal cohort in Canada were obtained by sequencing. All 4 variants showed original recombination profiles, including A1/A2/J, A1/D, and A1/G/J/CRF11_cpx structures. Identification of these variants highlights the growing prevalence of unique recombinant forms of HIV-1 in North America. PMID- 21291605 TI - Eschar-associated spotted fever rickettsiosis, Bahia, Brazil. AB - In Brazil, Brazilian spotted fever was once considered the only tick-borne rickettsial disease. We report eschar-associated rickettsial disease that occurred after a tick bite. The etiologic agent is most related to Rickettsia parkeri, R. africae, and R. sibirica and probably widely distributed from Sao Paulo to Bahia in the Atlantic Forest. PMID- 21291606 TI - Pandemic (H1N1) 2009-associated pneumonia in children, Japan. AB - To describe clinical aspects of pandemic (H1N1) 2009 virus-associated pneumonia in children, we studied 80 such children, including 17 (21%) with complications, who were admitted to 5 hospitals in Japan during August-November 2009 after a mean of 2.9 symptomatic days. All enrolled patients recovered (median hospitalization 6 days). Timely access to hospitals may have contributed to favorable outcomes. PMID- 21291607 TI - Oseltamivir-resistant pandemic (H1N1) 2009 virus, Mexico. AB - During May 2009-April 2010, we analyzed 692 samples of pandemic (H1N1) 2009 virus from patients in Mexico. We detected the H275Y substitution of the neuraminidase gene in a specimen from an infant with pandemic (H1N1) 2009 who was treated with oseltamivir. This virus was susceptible to zanamivir and resistant to adamantanes and oseltamivir. PMID- 21291608 TI - Comparison of pandemic (H1N1) 2009 and seasonal influenza viral loads, Singapore. AB - Mean viral loads for patients with pandemic (H1N1) 2009 were ~1 log10 times lower than those for patients with seasonal influenza within the first week after symptom onset. Neither pandemic nor seasonal influenza viral loads correlated with clinical severity of illness. No correlation was found between viral loads and concurrent illness. PMID- 21291609 TI - Pandemic (H1N1) 2009, Abu Dhabi, United Arab Emirates, May 2009-March 2010. AB - To ascertain characteristics of pandemic (H1N1) 2009 virus infection, we reviewed medical records for all suspected or confirmed cases reported in Abu Dhabi during May 2009-March 2010. Overall case-fatality rate was 1.4/100,000 population. Most patients who died had >=1 risk factor, and female decedents were considerably younger than male decedents. PMID- 21291610 TI - Usefulness of published PCR primers in detecting human rhinovirus infection. AB - We conducted a preliminary comparison of the relative sensitivity of a cross section of published human rhinovirus (HRV)-specific PCR primer pairs, varying the oligonucleotides and annealing temperature. None of the pairs could detect all HRVs in 2 panels of genotyped clinical specimens; >1 PCR is required for accurate description of HRV epidemiology. PMID- 21291611 TI - Surveillance for West Nile virus in dead wild birds, South Korea, 2005-2008. AB - To investigate the possibility of West Nile virus (WNV) introduction into South Korea, the National Veterinary Research and Quarantine Service has conducted nationwide surveillance of WNV activity in dead wild birds since 2005. Surveillance conducted during 2005-2008 found no evidence of WNV activity. PMID- 21291612 TI - Hantavirus infection in Istanbul, Turkey. PMID- 21291613 TI - Maternal-fetal transmission of Cryptococcus gattii in harbor porpoise. PMID- 21291614 TI - New Delhi metallo-beta-lactamase, Ontario, Canada. PMID- 21291615 TI - Genetic detection of dobrava/belgrade virus, bulgaria. PMID- 21291616 TI - A226V strains of Chikungunya virus, Reunion Island, 2010. PMID- 21291617 TI - Segniliparus rugosus-associated bronchiolitis in California sea lion. PMID- 21291618 TI - Orbiviruses in Rusa deer, Mauritius, 2007. PMID- 21291619 TI - No xenotropic murine leukemia virus-related virus detected in fibromyalgia patients. PMID- 21291620 TI - Clonal spread of Streptococcus pyogenes emm44 among homeless persons, Rennes, France. PMID- 21291621 TI - Surface layer protein A variant of Clostridium difficile PCR-ribotype 027. PMID- 21291622 TI - Introduction of Japanese encephalitis virus genotype I, India. PMID- 21291623 TI - Dengue virus serotype 3 subtype III, Zhejiang Province, China. PMID- 21291624 TI - European subtype tick-borne encephalitis virus in Ixodes persulcatus ticks. PMID- 21291625 TI - Rickettsia aeschlimannii in Hyalomma marginatum ticks, Germany. PMID- 21291626 TI - Dogs as reservoirs for Leishmania braziliensis. PMID- 21291627 TI - Pandemic (H1N1) 2009 and HIV co-infection. PMID- 21291629 TI - A systematic review and economic evaluation of the use of tumour necrosis factor alpha (TNF-alpha) inhibitors, adalimumab and infliximab, for Crohn's disease. AB - BACKGROUND: Crohn's disease (CD) is a severe, lifelong disease characterised by inflammation of the gastrointestinal mucosa. The impact on patients and society is high as ill health can be lifelong and can negatively affect patients' quality of life. Costs to the NHS are high, particularly for patients needing hospitalisation. Conventional treatment pathways are complex. More recently, a group of drugs called tumour necrosis factor (TNF) inhibitors (anti-TNF-alpha agents) have been evaluated for their effectiveness in CD. One of these, infliximab, is currently recommended by the National Institute for Health and Clinical Excellence (NICE; 2002) for patients with severe, active CD where patients are refractory to or intolerant of conventional treatment. OBJECTIVES: To investigate whether there is evidence for greater clinical effectiveness or cost-effectiveness for either adalimumab or infliximab. DATA SOURCES: Cochrane Library (Cochrane Central Register of Controlled Trials) 2007 Issue 2; MEDLINE (Ovid) 2000 to May/June 2007; MEDLINE In-Process & Other Non-Indexed Citations (Ovid) 4 June and 26 June 2007; EMBASE (Ovid) 2000 to May/June 2007. The European Medicines Agency, the US Food and Drug Administration and other relevant websites. REVIEW METHODS: Standard systematic review methods were used for study identification and selection, data extraction and quality assessment. Only randomised controlled trials (RCTs) comparing adalimumab or infliximab with standard treatment (placebo), RCTs comparing adalimumab with infliximab, or RCTs comparing different dosing regimens of either adalimumab or infliximab in adults and children with moderate-to-severe active CD intolerant or resistant to conventional treatment were eligible for inclusion. A systematic review of published studies on the cost and cost-effectiveness of adalimumab and infliximab was undertaken. The economic models of cost-effectiveness submitted by the manufacturers of both drugs were critically appraised and, where appropriate, rerun using parameter inputs based on the evidence identified by the authors of the technology asessment report. A de novo Markov state transition model was constructed to calculate the incremental cost-effectiveness ratio for adalimumab and infliximab therapy compared with standard care. RESULTS: Based on 11 trials, there was evidence from both induction and maintenance trials that both adalimumab and infliximab therapy were beneficial compared with placebo (standard care) for adults with moderate-to-severe CD and, for infliximab, for adults with fistulising CD; results were statistically significant for some time points. Between 6% and 24% (adalimumab), and 21% and 44% (infliximab) more patients achieved remission with anti-TNF-alpha antibodies than with placebo in the induction trials. Between 24% and 29% (adalimumab), and 14% and 24% (infliximab) more patients achieved remission with anti-TNF-alpha antibodies in the two large maintenance trials at reported follow-up. In fistulising CD, between 29% and 42% (induction trial) and 23% (maintenance trial) more patients achieved a > 50% reduction in fistulas with infliximab than with placebo at reported follow-up. There was no direct evidence to show that 'responders' were more likely to benefit from treatment than 'non-responders' in the longer term. Few differences were found between treatment and standard care arms for selected adverse events, though high proportions of scheduled crossovers resulted in a lack of a true placebo group in most of the maintenance trials. No published studies on the cost effectiveness of adalimumab were identified. The four independently funded studies identified for infliximab suggested high cost-effectiveness ratios [all above L50,000/quality-adjusted life-year (QALY) for non-fistulising disease and all above L100,000/QALY for fistulising disease]. A budget impact assessment suggested that total cost to the NHS in England and Wales for induction in severe disease only could range between L17M and L92M and for maintenance for 1 year between L140M and L200M. LIMITATIONS: Regarding clinical effectiveness, there were concerns about the trial design and lack of clarity, which may have affected interpretation of results. None of the trials matched exactly the licence indications or NICE guidance, which specify the use of these drugs in patients with 'severe' disease. All trials were multicentre, and applicability to UK populations, particularly in terms of standard care being provided and in terms of patients having failed or having become intolerant to conventional treatment, was uncertain. The published economic models relied heavily on little information and data from small samples. CONCLUSIONS: Anti-TNF therapy with adalimumab or infliximab may have a beneficial effect compared with standard care on outcome measures for induction and maintenance. The findings were that for induction, both adalimumab and infliximab are cost-effective (dominant relative to standard care) in the management of severe CD, and adalimumab (but not infliximab) is cost effective for moderate CD, according to limits generally accepted by NICE. On the basis of the analysis presented here, neither drug is likely to be cost-effective as maintenance therapy for moderate or severe disease. Perhaps, most importantly, the analysis reflected the fact that a substantial number of patients would achieve remission under standard care and that the incidence of relapse among those in remission was such that maintenance therapy would have to show greater effectiveness than at present and/or be much less costly than it currently is in order to reach the levels of generally accepted cost-effectiveness. Any future trials need to be designed to meet the particular challenges of measuring and quantifying benefit in this patient group. FUNDING: The research was funded by the HTA programme on behalf of NICE. PMID- 21291630 TI - Expression and significance of FOXM1 in human cervical cancer: a tissue micro array study. AB - OBJECTIVE: This study was designed to investigate the expression and significance of the Forkhead Box M1 (FOXM1) transcription factor in human cervical cancer. METHODS: The expression of FOXM1 protein was assessed in tissue microarrays containing 102 cervical cancer tissues by the Streptavidin-Peroxidase (SP) immunohistochemistry technique. The relationship between FOXM1 protein and clinico-pathological features (pathological stages, pathological types, TNM stage) was analyzed. RESULTS: FOXM1 protein was located in the cytoplasma and/or nucleus. The overall expression of FOXM1 in the cytoplasm and nucleus was not associated with T stages (P=0.217) or lymph node status (P=0.313). The nuclear expression of FOXM1 protein was not associated with T stage (P=0.508) or lymph node status (P=0.345). Elevated translocation and activity of FOXM1 were discovered with a secondary analysis that showed that the differences of the nuclear expression of FOXM1, among different pathological stages, were statistically significant (P < 0.05). The nuclear expression of FOXM1 in low differential cervical cancer tissues was significantly higher than in high differential cervical cancer tissues (P < 0.05). CONCLUSION: The overexpression of FOXM1 protein in cervical cancer maybe associated with the progression of cervical cancer, and could be a potentially novel tumor marker useful for diagnosis and therapy of cervical cancer. PMID- 21291631 TI - The relationship between lipoprotein(a) and coronary artery disease, as well as its variable nature following myocardial infarction. AB - PURPOSE: The present study aimed to investigate the relationship between the severity of coronary artery disease (CAD) and level of Lipoprotein (LP)(a). METHODS: The study included 52 CAD patients and a control group consisting of 38 individuals. The patients were classified into three groups based on the clinical form of CAD (stable angina pectoris, SAP, unstable angina pectoris, UAP, and myocardial infarction,MI), and were further divided into three groups based on CAD severity (1-, 2- and 3-vessel). Serum Lp(a) levels were monitored 4, 8, and 24 h, 10 and 30 days following acute MI in 18 patients. RESULTS: Based on regression analysis, Lp(a) was not correlated with other lipoproteins or with risk factors of CAD, such as body mass index, smoking, family history, diabetes, age, gender, and hypertension (r = 0.08-0.22). 72% of the patients in the CAD group and 24% of the control group had an Lp(a) level > 30 mg dL(-1) (P = 0.004), and Lp(a) levels were higher in 3-vessel patients than in 2-vessel and 1-vessel CAD patients (86% vs. 68%, P = 0.02 and 86% vs. 62%, P=0.01, respectively). Serum Lp(a) levels were higher in the UAP and MI groups than in the SAP group (48 +/- 44.7 mg dL(-1), 49 +/- 36.1 mg dL(-1) and 31.2 +/- 22.3 mg dL(-1), respectively, P=0.02). Lp(a) levels increased after acute MI, and reached peak levels 10 days post-MI (41% increase, P=0.001) and remained considerably elevated (18%) 30 days post-MI (P=0.01). CONCLUSION: Serum Lp(a) was higher in the UAP and MI patients in comparison with the SAP patients, and was higher in 3-vessel CAD in comparison with 1- and 2-vessel CAD patients. PMID- 21291632 TI - Use of complementary and alternative medicine in a pediatric population in southern Turkey. AB - PURPOSE: The use of complementary and alternative medicine (CAM) in children is becoming increasingly acceptable and popular. The aim of this questionnaire-based study was to determine the prevalence, patterns of use, types, perceived effectiveness and associated factors of CAM in children. METHODS: Parents of children (n= 268) who attended the Pediatric Outpatient Department of the Faculty of Medicine at Gaziantep University in June and July 2008 were asked to complete a questionnaire. RESULTS: The prevalence of CAM use, at least once in the previous year, was 58.6%. The most commonly used CAM modality was herbal preparations (82.7%), which were used to treat cough (42.0%), diarrhea (30.0%) and gas (colic) pains (34.4%). These products were recommended by the respondents' mother/mother-in-law (52.5%), neighbors (20.0%), friends (14.7%) and doctors (12.8%). Only 31.6% (61) of these parents informed their doctor about their use of CAM to treat their children. Thirty-eight percent (n=102) of the participants stated that they preferred to use CAM modalities rather than referring to a doctor when their child was sick. While most of the families (57.7 %) stated that the method they used was "slightly" useful, 18.6% of them stated the method to be "fairly" useful. The parental use of CAM and the educational level of the parents were among the factors of affecting the use of CAM in children. No correlation was found between the use of CAM and the sex, social security status, income level and other sociodemographic properties of the respondents. CONCLUSION: This study showed that a great majority of parents of children in this population used CAM modalities and that herbal products were preferred. Most parents did not inform their physicians of their use of CAM. In the light of these findings, pediatricians should be prepared to discuss alternative therapies with parents, since talking about CAM may be helpful in minimizing associated risks. PMID- 21291633 TI - The biomarker N-terminal pro-brain natriuretic peptide and liver diseases. AB - PURPOSE: NT-proBNP has emerged as a powerful diagnostic and prognostic biomarker in heart disease. Studies showed that NT-proBNP is a sensitive biomarker for identifying patients with heart failure caused by hepatitis C virus (HCV) related myocarditis. The purpose of this study was to evaluate the correlation between the serum concentration of NT-proBNP and hepatitis virus infection/liver disease. METHODS: 223 serum samples from blood donors (aged 19~50 years old) were collected as a control group, and 644 samples were obtained from patients infected by hepatitis viruses including 493 HBV: 364 chronic hepatitis (CH), 86 hepatocellular carcinoma (HCC) and 43 liver cirrhosis (LC) and 151 HCV (85 CH, 14 HCC, 52 LC). All samples were assayed with an Elecsys immunoassay analyzer for NT proBNP concentration. RESULTS: The mean concentration of NT-proBNP in the control group was 21.77 pg/ml and showed no significant variation with either age or gender. Both the mean value and the rate of abnormality of NT-proBNP were significantly higher for the HBV- and HCV-infected groups in comparison with the control group. The mean NT-proBNP value (380.24 pg/ml) and abnormality rate (38.41%) in the HCV group were higher than that of the HBV group. For samples from patients with HBV/HCV-related hepatic disease/pathology, the mean NT-proBNP value (517.19 pg/ml/597.18 pg/ml) were the highest in the liver cirrhosis group. CONCLUSIONS: Hepatic pathologic lesions, particularly cirrhosis, may contribute to the elevation of NT-proBNP in subjects with HBV/HCV infection. PMID- 21291634 TI - Pandrug-resistant isolate of Klebsiella pneumoniae causes less damage than drug susceptible isolates in a rabbit model. AB - PURPOSE: Bacterial infections induce a series of inflammatory responses and lead to longer hospital stays and increased mortality. In clinical work, we often find that infections caused by drug-susceptible isolates have a worse outcome than those caused by pandrug-resistant isolates. To goal of this study was to assess the impact of drug resistant in a rabbit model of Klebsiella pneumoniae infection. METHODS: This study used a rabbit model of experimental bacteremia, challenged by susceptible (A), multidrug-resistant (B) and pandrug-resistant (C) isolates of Klebsiella pneumoniae. Mimimal inhibitory concentrations (MIC), leukocyte, TNFalpha, IL-17, and HMGB-1 levels and survival times were measured. RESULTS: Mean survival times after challenge by isolates A, B and C were 10.5 +/- 3.63, 12.7 +/- 2.31 and 13.9 +/- 0.32 days, respectively. Leukocytes levels after challenge with isolate C were lower compared with those after challenge with isolate A (p = 0.002). Blood counts of the offending pathogens and concentrations of TNFalpha, IL-17, and HMGB-1 were higher in the group challenged by isolate A in comparison with isolate B or C. Tissue bacterial load after animal death was significantly higher in rabbits of group A in comparison with isolates B and C. CONCLUSION: Bacteremia induced by pandrug-resistant isolates is accompanied by less damage compared with bacteremia by drug-susceptible isolates. Rabbits infected with a pandrug-resistant isolate of K. pneumoniae survived longer and had a lower inflammatory response than did animals infected with drug-susceptible isolates. PMID- 21291635 TI - LYVE-1 enhances the adhesion of HS-578T cells to COS-7 cells via hyaluronan. AB - PURPOSE: Lymphatic vessel endothelial hyaluronan receptor (LYVE-1), a specific molecular marker for lymph systems, has only one known ligand, hyaluronan (HA). Many studies have reported that HA, on the surface of tumor cells, is associated with the metastatic behavior of cancer cells. The interaction of LYVE-1 with HA may facilitate tumor cell attachment and enhance dissemination of tumor cells to lymph nodes. The aim of this study was to explore the biological function of LYVE 1 and to determine whether the interaction between LYVE-1 and HA was directly involved in the adhesion of tumor cells to lymphatic vessels. METHODS: COS-7 cells were transfected with cDNA encoding LYVE-1 and expressed LYVE-1 assembled exogenously added HA. A high HA-expressing breast cancer cell line, HS-578T, was chosen to be the upper layer of cells that adhered to a lower layer of COS-7(LYVE 1(+)), COS-7(pEGFP-N1), or COS-7 cells for the adhesion analyses. The mechanism of adhesion was investigated by an experiment in which the HA on the surface of HS-578T cells was digested by Streptomyces hyaluronidase before the HS-578T cells were allowed to adhere to COS-7(LYVE-1(+)) cells. RESULTS: Results showed that more adhesion was observed between HS-578T and COS-7(LYVE-1(+)) cells, while less adhesion was observed between HS-578T cells and either COS-7(pEGFP-N1) or COS-7 cells (p < 0.01). Decreased HA on the HS-578T cell surface could reduce the adhesion of HA-578T cells to COS-7(LYVE-1(+)) cells suggesting that this adhesion might be mediated through HA. CONCLUSION: Our results suggest that LYVE-1 allows the adhesion of tumor cells through the interaction of HA on the tumor cell membrane with LYVE-1. PMID- 21291636 TI - Continuous infusion of 5-FU with split-dose cisplatin: an effective treatment for advanced squamous-cell carcinoma of the head and neck. AB - PURPOSE: The purpose of this study was to determine if a combination chemotherapy, using continuous intravenous infusion of fluorouracil (5-FU) in combination with split-dose cisplatin, in patients with recurrent or metastatic head and neck squamous-cell could improve previously reported clinical outcomes. METHODS: Forty-two patients with recurrent or metastatic head and neck squamous cell cancer were treated by cisplatin (25 mg/m(2)/day on days 1-3) and 5-FU (750 mg/m(2)/day for 120 hours; continuous intravenous infusion on days 1 through 5) with a cycle that repeated every 3 weeks. RESULTS: Of the 42 patients, 8 (19.1%) showed complete response and 12 (28.5%) demonstrated a partial response, giving an overall response rate of 47.6%. Response rates were significantly different for patients undergoing initial treatment vs. re-treatment:73.6% (14/19) vs. 25.9% (6/23), respectively (chi(2)=9.45, P < 0.05). Median time to progression was 7.2 months and median overall survival was 13.7 months. The 1 year survival was 57.1%. Toxicity mainly included myelo-suppression, mucositis, nausea and vomiting. CONCLUSION: Chemotherapy with 5-FU by continuous intravenous infusion in combination with split-dose cisplatin is effective with a tolerable toxicity profile in patients with recurrent, or metastatic squamous-cell carcinoma of head and neck. The overall response was significantly higher in patients undergoing initial treatment in comparison with patients undergoing re-treatment after relapse. PMID- 21291637 TI - Dimethyl fumarate. PMID- 21291638 TI - Teaching interventions in contact dermatitis. AB - Prevention of occupational contact dermatitis is of utmost significance for both insurers and legislators because it can preserve the individual's ability to work and result in decreased costs for public health. In the last 20 years, many concepts for educational interventions and a multitude of teaching aids have been developed by insurance associations and public institutions from different countries (eg, the United States, Sweden, Denmark, Switzerland, and Germany). For didactic purposes, terms of different levels of prevention have been inaugurated in northern Europe in the context of occupational dermatology. This review presents different educational interventions in the fields of primary, secondary, and tertiary prevention as well as evaluation studies of these measures, especially among health care workers, hairdressers, metalworkers, and bakers' apprentices. Special emphasis is put on the prevention of allergic contact dermatitis. PMID- 21291639 TI - Patch-testing with hairdressing chemicals. AB - BACKGROUND: Hairdressing chemicals may be associated with allergic contact dermatitis. OBJECTIVE: To review our experience of patch-testing with hairdressing chemicals. METHODS: We reviewed results from patients who underwent patch testing with our standard allergen series (including 15 hairdressing chemicals) and a supplementary "hairdresser series" (18 additional hairdressing chemicals) at Mayo Clinic (Rochester, MN; Scottsdale, AZ; and Jacksonville, FL) from January 1, 2000, through December 31, 2008. RESULTS: Two hundred ten patients (mean age, 53.8 years [SD, 16.9 yr]; female, 94.8%) were patch-tested. The most common sites of dermatitis were the scalp, face, and hands. Patients had widely varying occupations. The most common occupations were cosmetologist (10.5%), housewife (9.5%), and beautician (5.2%); 14.3% were retired. The hairdresser series detected 13 additional patients with allergies (6.4%; 204 patients tested with both series) who would not have been detected with the standard allergen series alone. The highest allergic patch-test rates in the supplemental hairdresser series were with ammonium persulfate (14.4%), 4 aminoazobenzene (13.4%), and pyrogallol (9.1%). CONCLUSIONS: Patch-testing with hairdressing-specific chemicals (standard series plus supplemental hairdresser series) was appropriate for numerous clinical situations and was not limited to patients in hair care occupations. The supplemental hairdresser series helped identify more patients than would have been identified with the standard series alone. PMID- 21291640 TI - Correlation between stated and measured concentrations of acrylate and methacrylate allergens in patch-test preparations. AB - BACKGROUND: Contact allergy to acrylates and methacrylates is not uncommon. The allergy is confirmed by patch-testing patients with commercial patch-test preparations. OBJECTIVE: To investigate acrylate and methacrylate allergens used for patch testing in nine different dermatology departments from Europe, America, Asia, and Australia. METHODS: The acrylate and methacrylate (methyl methacrylate, 2-hydroxypropyl acrylate, 2-hydroxyethyl methacrylate, ethylene glycol dimethacrylate, and triethylene glycol diacrylate) allergen samples were analyzed with high-performance liquid chromatography to measure the allergen content. RESULTS: Variation in measured versus stated concentrations was seen in these samples. The ratio of measured to stated concentrations ranged from 0.11 to 1.1. Only 22 (63%) of 35 samples were within the arbitrary acceptable limits of 80 to 120% of the stated concentrations. CONCLUSION: The results may have implications for individual diagnosis and prevention and when test results from various centers are compared. PMID- 21291641 TI - Patch testing with uranyl acetate in veterans exposed to depleted uranium during the 1991 Gulf war and the Iraqi conflict. AB - BACKGROUND: The Depleted Uranium Follow-Up Program is a clinical surveillance program run by the Baltimore Veterans Affairs Medical Center since 1993 for veterans of the Gulf and Iraqi wars who were exposed to depleted uranium (DU) as a result of "friendly-fire" incidents. OBJECTIVES AND METHODS: In 2009, 40 veterans from this cohort were screened for skin reactivity to metals by patch testing with extended metal series and uranyl acetate (0.25%, 2.5%, and 25%). A control arm comprised 46 patients without any known occupational exposures to DU who were seen at the University of Maryland Dermatology Clinic for evaluation of allergic contact dermatitis. RESULTS: Excluding irritant reactions, no patch-test reactions to uranyl acetate were observed in the participants. Irritant reactions to DU were more common in the clinic cohort, likely reflective of the demographic differences between the two arms of the study. Biologic monitoring of urine uranium concentrations in the DU program participants with 24-hour urine samples showed evidence of percutaneous uranium absorption from the skin patches. CONCLUSION: We conclude that dermatitis observed in a subset of the veterans was unrelated to their military DU exposure. Our data suggest that future studies of skin testing with uranyl acetate should utilize 0.25%, the least irritating concentration. PMID- 21291642 TI - Atopic dermatitis in adults. AB - Atopic dermatitis (AD) is a chronically relapsing eczematous disease, more common in infants and children than in adults and very rare after midlife. The diagnosis of AD is not always easy in adults, especially when the extension of lesions is limited and their distribution atypical. The aim of this study was to investigate epidemiologic and clinical features of adult AD. The medical files of 332 consecutive AD patients were reviewed to ascertain family and personal history of atopy, age at onset, morphology and localization sites of AD lesions, serum total immunoglobulin E levels, skin prick-test and patch-test results. The present study has show that the disease is more frequent in females and during the third decade of life, starts after the 18th year in slightly fewer than half the patients (47.6%), is prevalently localized in the limb flexures, eyelids, and perioral region, but also in the forehead, cheeks, and anterolateral region of the neck, where it is mainly mild to moderate. AD is of the intrinsic type in 30.4% of cases. Positive patch-test reactions to chemical allergens have been observed in 23.8% of patients. These are very important, because they may influence the occupational choices and the development of hand dermatitis. PMID- 21291643 TI - Dimethyl fumarate: a human health hazard. PMID- 21291644 TI - Pruritus ani as a manifestation of systemic contact dermatitis: resolution with dietary nickel restriction. AB - Pruritus ani is a common distressing problem with numerous possible causes. When locally applied agents trigger irritation or allergic response, skin changes of dermatitis usually accompany the itch. Focal pruritus in the absence of dermatitis is not generally considered to be a manifestation of contact allergy. Furthermore, focal pruritus is not listed among the possible diverse presentations of the systemic delivery of a proven contact allergen. We report a case of a gentleman with a 1.5-year history of treatment-resistant pruritus ani. When patch testing revealed a positive reaction to nickel sulfate, he admitted to daily peanut butter consumption. His symptoms resolved with dietary nickel restriction. Patch testing may be useful in patients with pruritus of the anogenital region, not only to elucidate potential contact exposures contributing to the symptom but also to suggest possible dietary precipitants. PMID- 21291645 TI - Allergic contact dermatitis from cetyl alcohol. PMID- 21291646 TI - Bunga Pad-induced ankle dermatitis in a figure skater. PMID- 21291647 TI - Allergic contact dermatitis from methylchloroisothiazolinone, with acute exanthematous pustulosis-like histopathologic changes. PMID- 21291649 TI - Tenascin-C expression in papulosquamous disorders other than psoriasis in pediatric patients: an epiphenomenon? AB - BACKGROUND: Tenascin-C is a large extracellular matrix protein that is expressed in the basal membrane zone during embryonic development, tissue repair, and oncogenesis. In vitro studies suggest that proliferating epithelium induces the production of tenascin-C by mesenchymal cells. OBJECTIVE: Our goal was to compare the expression of tenascin-C in psoriasis with other papulosquamous disorders of the skin in pediatric patients. METHODS: The study was conducted on skin biopsy samples of 37 patients with psoriasis or other papulosquamous disorders. Of the 37 skin biopsy samples, 17 (45.9%) were diagnosed as psoriasis and 20 (54.1%) were diagnosed as other papulosquamous disorders histopathologically, and the expression of tenascin-C was evaluated immunohistochemically. RESULTS: Tenascin-C expression was seen in the dermis of lesional tissues or epidermal keratinocytes in 1 (5.8%) of the 17 biopsy samples diagnosed as psoriasis and 15 (75.0%) of the 20 biopsy samples diagnosed as other papulosquamous disorders (p = .001). CONCLUSION: Tenascin-C expression was not found to be a staining characteristic of psoriasis lesions. But the significant staining intensity of the tenascin-C expression in other papulosquamous disorders suggests that tenascin-C expression might be an epiphenomenon in the papulosquamous disorders other than psoriasis immunohistochemically. PMID- 21291650 TI - Dermatologic manifestations of Sjogren syndrome. AB - BACKGROUND: Sjogren syndrome (SS) is a chronic autoimmune inflammatory disease that involves primarily the exocrine glands, resulting in their functional impairment. SS typically presents as dry eyes (xerophthalmia) and dry mouth (xerostomia). This process can manifest either as the independent phenomenon of primary SS or as secondary SS when found in the context of another autoimmune process, most commonly rheumatoid arthritis or systemic lupus erythematosus. Nearly half of the patients with SS develop cutaneous manifestations, which may include dry skin (xeroderma), palpable and nonpalpable purpura, and/or urticaria like lesions. These cutaneous manifestations have been underemphasized because they are often overshadowed by the more prominent sicca symptoms. However, certain skin findings are of paramount clinical and prognostic importance as they confer an increased risk for the development of life-threatening conditions, including multisystem vasculitis and non-Hodgkin lymphoma.OBJECTIVE AND CONCLUSIONS:In this review, the cutaneous manifestations of primary SS are discussed, with an emphasis on those findings that portend an increased risk of mortality. PMID- 21291651 TI - Pretibial angioplasia: a novel entity encompassing the clinical features of necrobiosis lipoidica and the histopathology of venous insufficiency. AB - BACKGROUND: Necrobiosis lipoidica (NL) presents clinically as waxy yellow-brown plaques, commonly on the shins. Venous insufficiency also involves the legs; however, it has distinct clinical and pathologic features. OBJECTIVE: We present a series of eight patients who had lesions that clinically resembled NL but on pathology showed features resembling venous insufficiency. METHODS: Between 1997 and 2008, eight patients were identified at St. Paul's Hospital, Vancouver, to have had skin lesions clinically diagnosed as NL, or a similar morphologic entity, but showing histopathologic features resembling venous insufficiency on biopsy. The clinical records and pathology reports of these patients were reviewed. RESULTS: The patients' ages ranged from 39 to 73 years. Only one patient was female. Members of the group held diagnoses of diabetes, renal failure, or venous or arterial disease. All patients had lesions on the legs, most on the anterior aspect. The clinical diagnosis was generally NL; other clinical impressions included lichen planus, morphea, and Kaposi sarcoma. All patients had features on pathology resembling venous insufficiency and no features of NL. CONCLUSION: We propose that this unique combination of clinical features of NL and histopathologic features resembling venous insufficiency represents a novel entity for which we propose the name pretibial angioplasia. PMID- 21291652 TI - Short-scar surgical approach for the treatment of glomus tumor of the digit. AB - BACKGROUND: A glomus tumor is a biologically benign neoplasm. The traditional surgical approach to treat this tumor boasts the lowest recurrence rates but may cause nail deformities. OBJECTIVE: A short-scar surgical approach was applied, with the aim of preserving the aesthetics of the nail. METHODS: Between January 1999 and January 2009, 25 patients who underwent surgery for a glomus tumor were included in the study. All patients underwent radical resection with three different surgical approaches based on the location of the tumor. RESULTS: All patients who were operated on had complete regression of pain immediately after surgery and at postsurgery follow-ups. CONCLUSION: The treatment of glomus tumors consists of surgical excision, which is successful if properly executed. Excision of sensitive afferent nervous fibers is a prerequisite to achieve regression of pain. A short-scar surgical approach ensures complete eradication of the tumor and preservation of nail aesthetics. PMID- 21291653 TI - Health-related quality of life in patients with psoriasis. AB - BACKGROUND: Psoriasis is a chronic skin disease that has a significant impact on patients' lives. OBJECTIVE: The purpose of the study was to assess factors that might influence the health-related quality of life (HRQoL) of patients with psoriasis. METHODS: We conducted a cross-sectional study of 110 outpatients with psoriasis. To assess the HRQoL, The Short Form 36 Health Survey (SF-36) and Skindex-29 were administered. Stressful life events during the last 12 months were assessed with Paykel's Interview for Recent Life Events. RESULTS: HRQoL was significantly more impaired in older patients, those with age at onset of 40 years or more, who had a positive family history and who experienced stressful life events in the 12 months preceding the interview. Sex and clinical severity were not significantly related to patients' HRQoL. CONCLUSION: Psoriasis patients have poorer HRQoL than the general population. This study supports the decision to use both generic and skin-specific instruments to assess the impact of psoriasis on HRQoL. PMID- 21291654 TI - Long-term prognosis and comorbidities associated with psoriasis in the Newfoundland and Labrador founder population. AB - BACKGROUND: Psoriasis is a common chronic immune-mediated inflammatory disorder of the skin with several associated comorbidities. OBJECTIVE: To assess the prevalence of comorbidities in a cohort of psoriasis patients within the Canadian province of Newfoundland and Labrador (NL). METHODS: This cross-sectional observational study investigated hospital-coded comorbidities associated with psoriasis in comparison to the general NL hospitalized population. RESULTS: Patients died significantly younger than the general population, with patients having an earlier disease onset (<= 25 years) dying at a younger age than those with a later onset (> 25 years; 59.3 vs 71.2; p = .001). Patients were hospitalized more frequently for several system disorders than the general population, and a potential association was observed between prognostic factors such as age at onset, disease severity, and HLA-Cw6 genotype and certain comorbid conditions. CONCLUSION: This study supports an association between psoriasis and other conditions, such as circulatory and endocrine diseases. PMID- 21291655 TI - Practical techniques to enhance the safety of health care workers in office-based surgery. AB - BACKGROUND: Office-based surgery is commonly practiced in different specialties for a variety of procedures. During these procedures, the health care worker (HCW) is exposed to a large number of pathogens that can be bloodborne, including the hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV). These pathogens can be transmitted through needlesticks or sharp injuries to intact skin or by backsplash of contaminated body fluids onto mucous membranes or injured skin. OBJECTIVES AND CONCLUSIONS: This article reviews the published techniques designed to protect the HCW from such hazards. These techniques are classified into preoperative, intraoperative, and postoperative. Preoperative measures include general protective measures, organization of the surgical field, and consideration of alternative treatments in high-risk patients. Intraoperative techniques deal with safe handling and transferring of sharp instruments, working without using sharps, and protection from backspray injuries. Postoperative measures address proper disposal of used sharps. PMID- 21291656 TI - Bullous scabies simulating pemphigoid. AB - BACKGROUND: Scabies is a contagious infestation affecting subjects of all ages, races, and social conditions. OBJECTIVE: We report a case of a 79-year-old man who developed a bullous pemphigoid-like eruption. He presented to our unit 4 months after the onset of symptoms. An autoimmune bullous disease was suspected. Direct immunofluorescence on a skin specimen and anti-desmoglein 1, anti desmoglein 3, and anti-bullous pemphigoid antigen 180 were negative. Surprisingly, the histology of a skin lesion demonstrated the presence of scabies, which was successfully treated with benzyl benzoate 20%. CONCLUSION: The diagnosis of bullous scabies should be considered for any bullous eruptions accompanied by papules and itching resistant to steroid treatment and with negative immunopathologic findings. PMID- 21291657 TI - Pyogenic granuloma of the foot with satellitosis: a role for conservative management. AB - BACKGROUND: Pyogenic granuloma (PG) with satellitosis is a rare phenomenon that typically occurs in children and teenagers. It can be seen after excision or trauma to the original lesion. OBJECTIVE: The aim is to review an atypical case of PG with satellitosis and to highlight a conservative approach to management. METHODS: This article includes a case report of a 48-year-old woman developing PG with satellitosis in her right foot and includes a review of the literature. RESULTS: There are few cases of PG with satellitosis in the literature. Our patient differs from most given her age and the location of the lesions. She was managed differently with a conservative observational approach, and, over time, her symptoms abated. CONCLUSION: PG with satellitosis can occur in varying patient populations with varying presentations. Although several treatment options exist, managing patients conservatively should be considered an approach to management. Early investigations should be conducted to rule out more sinister items in the differential diagnosis. PMID- 21291658 TI - An approach to the treatment of vulvar lymphedema. PMID- 21291659 TI - Gourmet clinical pearls. PMID- 21291660 TI - Metabolic syndrome in subjects at high risk for type 2 diabetes: the genetic, physiopathology and evolution of type 2 diabetes (GENFIEV) study. AB - BACKGROUND AND AIM: We evaluated the relationship between insulin resistance (IR) and insulin secretion with the metabolic syndrome (MS) in 885 subjects (377 men/508 women, age 49+/-11 years, BMI 29+/-5.2kgm(-2)) at risk of diabetes enrolled in the genetics, pathophysiology and evolution of type 2 diabetes (GENFIEV) study. METHODS AND RESULTS: All subjects underwent a 75-g oral glucose tolerance test (OGTT) for the estimation of plasma levels of glucose and C peptide, as well as fasting insulin and lipid profile. IR was arbitrarily defined as HOMA-IR value above the 75th centile of normal glucose tolerance (NGT) subjects. Overall MS prevalence (National Cholesterol Treatment Panel-Adult Treatment Panel (NCEP-ATPIII) criteria) was 33%, 19% in subjects with NGT, 42% in impaired fasting glucose (IFG), 34% in impaired glucose tolerance (IGT), 74% in IFG+IGT subjects, and 56% in newly diagnosed diabetic patients. Prevalence was slightly higher with IDF criteria. MS prevalence was >50% in subjects with 2h glucose >7.8mmoll(-1), independently of fasting plasma glucose. IR prevalence was higher in subjects with MS than in those without (63% vs. 23%; p<0.0001) and increased from 54% to 73% and 88% in the presence of three, four or five traits, respectively. IR occurred in 42% of subjects with non-diabetic alterations of glucose homeostasis, being the highest in those with IFG+IGT (IFG+IGT 53%, IFG 45%, IGT 38%; p<0.0001). Individuals with MS were more IR irrespective of glucose tolerance (p<0.0001) with no difference in insulinogenic index. Hypertriglyceridaemia (OR: 3.38; Confidence Interval, CI: 2.294.99), abdominal obesity (3.26; CI: 2.18-4.89), hyperglycaemia (3.02; CI: 1.80-5.07) and hypertension (1.69; CI: 1.12-2.55) were all associated with IR. CONCLUSIONS: These results show that in subjects with altered glucose tolerance (in particular IFG+IGT) MS prevalence is high and is generally associated to IR. Some combinations of traits of MS may significantly contribute to identify subjects with IR. PMID- 21291662 TI - News from the national lipid association. PMID- 21291661 TI - From the Editor-in-Chief. PMID- 21291663 TI - In memorium: David Kritchevsky. PMID- 21291664 TI - High-density lipoprotein and transport of cholesterol and triglyceride in blood. AB - High-density lipoproteins (HDL) contain approximately 25% of the cholesterol and <5% of the triglyceride in the plasma of human blood. However, the dynamic exchange of lipids and lipid-binding proteins is not revealed by simply considering the mass of material at any point in time. HDL are the most complex of lipoprotein species with multiple protein constituents, which facilitate cholesterol secretion from cells, cholesterol esterification in plasma, and transfer of cholesterol to other lipoproteins and to the liver for excretion. They also play a major role in triglyceride transport by providing for activation of lipoprotein lipase, exchange of triglyceride among the lipoproteins, and removal of triglyceride rich remnants of chylomicrons and very-low-density lipoproteins after lipase action. In addition, antioxidative enzymes and phospholipid transfer proteins are important components of HDL. Many of the proteins of HDL are exchangeable with other lipoproteins, including chylomicrons and very-low-density lipoproteins. The constantly changing content of lipids and apolipoproteins in HDL particles generate a series of structures that can be analyzed by using separation techniques that depend on size or charge of the particles. Interaction of these various structures can be very different with cell surfaces depending on the size or apolipoprotein content. A series of different transport proteins preferentially exchange lipids with specific structures among the HDL but interact poorly or not at all with others. The role of these differing forms of HDL and their interactions with cells and other lipoprotein species in plasma is the subject of intense study stimulated by the potential for reducing atherogenesis. The strength of this is only partially indicated by the correlation of higher total levels of the HDL particles with reduced incidence of vascular disease in various clinical trials and epidemiological studies. PMID- 21291665 TI - Intrinsic enzymes of high-density lipoprotein. AB - Several lines of evidence are available to support the protective effects of high density lipoproteins (HDL) on atherosclerosis. The exact mechanisms by which HDL protects against atherosclerotic disease development are not understood. In addition to its role in the reverse transport of cholesterol from the peripheral sites to the liver for excretion, HDL also carries a number of enzymes that contribute to the remodeling of plasma lipoproteins and to the protection of other lipoproteins against oxidative modification. Many of these enzymes can play a role in determining the composition of circulating HDL, while others appear to affect specific biologic activities associated with HDL. It is not clear whether the concentrations of HDL particles or the activities associated with this class of particles are more important. One of the problems is that HDL constitutes a heterogeneous population of particles, and analytical tools to characterize the various subpopulations are not widely available. In this article, we will review the enzymes that are associated with plasma HDL and possible mechanisms as to how these may contribute to the protective properties of HDL in humans. PMID- 21291666 TI - Familial occurrence of abnormalities of high-density lipoprotein cholesterol. AB - In families, well-known monogenic high-density lipoprotein cholesterol (HDL-C) disorders characterized by extreme HDL-C levels on both ends of the continuum occur in multiple HDL pathways and can confer increased risk for atherosclerotic disease. Polygenic HDL-C variants have been more difficult to identify. In many family and twin studies in different populations, HDL-C levels have been shown to be highly heritable, explaining, on average, between 40% and 60% of between individual variation. This review of abnormal HDL in families addresses known monogenic HDL disorders and HDL-C heritability in the general population, and presents novel data on the heritability of HDL-C in families with a history of premature coronary artery disease. We conclude that levels of HDL-C and HDL abnormalities are largely under genetic control and environmental and behavioral factors alone have only a modest impact. While rare, monogenic disorders offer considerable insight into the genetics of HDL regulation. Moderate to high heritability estimates across different family populations suggest that future genetic studies will be successful in identifying HDL genetic trait loci and that translational studies will ultimately lead to therapies that optimize the cardiovascular protective benefits of HDL. PMID- 21291667 TI - Severe acquired (secondary) high-density lipoprotein deficiency. AB - Decreased high-density lipoprotein cholesterol (HDL-C) levels have been designated a major risk factor for cardiovascular disease, and there is considerable interest in identifying individuals with these abnormalities for appropriate management. Although low HDL-C may result from genetic factors, it is estimated that approximately 50% of cases may be secondary to other abnormal or disease states or to their treatment. Very low HDL-C levels, arbitrarily defined as <20 mg/dL, are uncommon, and are best known to result from major genetic mutations of key steps in HDL metabolism. Less well-described are secondary forms of severe HDL-C deficiency, which need to be distinguished from the primary causes. In this review, causes of severe acquired HDL-C deficiency are identified from the literature and are reviewed extensively. These include moderate to severe hypertriglyceridemia, critical illness, androgenic anabolic steroids, and acquired lecithin cholesteryl acyl transferase deficiency and liver disease. A relatively new entity referred to as the "disappearing HDL syndrome" was coined to describe the fairly rapid development of severe HDL-C deficiency in ambulant subjects with previously normal HDL-C and triglyceride levels. This may occur with peroxisome proliferation-activated receptor agonist treatment or in patients with benign or malignant paraproteinemias. Case discussions from our clinical experience are provided to illustrate to the practitioner the clinical context in which these severe acquired deficiencies of HDL occur. PMID- 21291668 TI - High-density lipoprotein associations with coronary heart disease: Does measurement of cholesterol content give the best result? AB - The protective role played by high-density lipoprotein (HDL) in atherogenesis is well-accepted, as is the significant inverse association of HDL cholesterol (HDL C) with coronary heart disease (CHD) risk. What remains controversial is whether we are using the best measure(s) of HDL to identify and manage HDL-related cardiovascular risk. Measuring particle number has been postulated to offer additional and possibly more specific information regarding risk. Although HDL-C is thought to indicate the quantity of circulating HDL particles, it is underappreciated that the amount of cholesterol carried inside lipoprotein particles is highly variable among individuals with the same HDL-C. Numerous trials have investigated the relations of CHD with various measures of HDL other than those based on cholesterol content of the particles present. Studies regarding the association of alternate measures of HDL with CHD risk have been mixed, possibly due to diversity in clinical characteristics accompanying low HDL C states, variability in cholesterol content of HDL particles, and substantial inter-correlations of HDL with other lipoprotein particles. Additional research is needed to assess the clinical settings in which individual HDL tests, after multivariate adjustment for confounding factors, provide superior independent prediction of CHD events beyond HDL-C. Such studies show promise in defining measures of particle number that will prove useful in future strategies to enhance management of CHD risk and assess response to therapy at an individual patient level. PMID- 21291669 TI - Effects of lifestyle interventions on high-density lipoprotein cholesterol levels. AB - This review summarizes intervention studies that evaluated the effects of lifestyle behaviors on high-density lipoprotein-cholesterol (HDL-C) levels. Current diet and lifestyle recommendations beneficially affect HDL-C. Individual lifestyle interventions that increase HDL-C include: a healthful diet that is low (7-10% of calories) in saturated fat and sufficient in unsaturated fat (15-20% of calories), regular physical activity, attaining a healthy weight, with moderate alcohol consumption, and cessation of cigarette smoking. Combining a healthy diet with weight loss and physical activity can increase HDL-C 10% to 13%. When combined with interventions that beneficially affect other cardiovascular disease risk factors, this increase in HDL-C is expected to contribute to a overall reduction in cardiovascular disease risk. PMID- 21291670 TI - Effect of drugs on high-density lipoprotein. AB - The National Cholesterol Education Program Adult Treatment Panel III found evidence for raising high-density lipoprotein cholesterol (HDL-C) to reduce coronary artery disease (CAD) events supports use of HDL-C to help modify low density lipoprotein cholesterol (LDL-C)-lowering goals, but not to establish new HDL-C-focused treatment recommendations. However, the HDL-C-raising clinical trials provide important lessons to help guide clinical management of dyslipidemic patients. The fibrate outcome trials demonstrate that these drugs reduce CAD events, but not death. Their greatest benefit is in patients with atherogenic dyslipidemia characterized by high triglycerides, small LDL particles, and low HDL-C. Unfortunately, there is no information on whether these drugs extend risk reduction when added to a statin. The niacin outcome trials also demonstrate a reduction in CAD events, both with niacin monotherapy and in combination with a statin. Unfortunately, most of the trials are too small to address the impact of niacin on mortality. In the clinic, statins are most useful for their LDL-C-lowering efficacy, although their modest HDL-C-raising effects can be important in CAD risk reduction. In most cases, other therapies will need to be added to a statin to augment HDL-C-raising, and the most effective drug for achieving this is niacin. The greatest challenge with the use of niacin is managing the vasodilatory side effects, but this can be effectively done in the majority of patients. Fibrates can also be added to a statin for management of atherogenic dyslipidemia. These drugs are among the most effective triglyceride lowering drugs, and they also increase HDL-C levels, but not as much as niacin. The biggest concern with combining a fibrate with a statin is the enhanced risk of severe muscle toxicity, but this appears to be a problem unique to gemfibrozil, and not fenofibrate. In the research center, new approaches are under development for enhancing the availability of apolipoprotein A-I (ApoA-I) and nascent HDL particles to promote enhanced reverse cholesterol transport, increasing the production of transport molecules, in particular, ATP-binding cassette A-I, to facilitate delivery of cholesterol within the macrophage cell to the cell surface, where it can be taken up by nascent HDL particles for transport to the liver, and inhibiting the cholesteryl ester transport protein to promote retention of cholesteryl esters within the HDL core for delivery back to the liver. In addition, new insights into the role of prostaglandin D(2) in the niacin flush and discovery of the niacin receptor has led to a search for a more efficacious and "flushless" niacin. PMID- 21291671 TI - Should both HDL-C and LDL-C be targets for lipid therapy? A review of current evidence. AB - The current guidelines for treatment of high-risk of lipid disorders do not specify a therapeutic target level of high-density lipoprotein cholesterol (HDL C) for prevention of vascular disease in high-risk populations. However, there is a substantial body of evidence from basic science and epidemiologic studies and from clinical trials, providing the strong, consistent message that raising HDL-C by therapeutic means will effectively and independently reduce cardiovascular risk. This review summarizes epidemiologic evidence and the results of a meta analysis of 23 published, prospective, randomized, placebo-controlled clinical trials. It focuses on the effects of lipid therapies on coronary stenosis progression, as measured by quantitative arteriography and/or, on clinical cardiovascular endpoints. Among the seven drug/treatment classes into which individual study results were categorized and averaged, reduction in stenosis progression and reduction in clinical events are both very highly correlated with the composite lipid variable (%DeltaHDL-C - %Delta low-density lipoprotein cholesterol [LDL-C]; where %Delta is percent change relative to the placebo group response). This holds true for all lipid drug classes or combinations of lipid drug therapy, with the exception of the unexpectedly anomalous effects of the torcetrapib-atorvastatin combination. There is a strong and consistent body of evidence that therapeutic HDL-C-raising is at least as effective as comparable percentages of LDL-C-lowering for reduction of atherosclerosis progression or clinical cardiovascular events over a broad range of risk levels. Adoption of this strategy into guidelines probably awaits results of at least one large controlled HDL-C-raising clinical trial, of which two are ongoing and one other is planned. PMID- 21291672 TI - News from the national lipid association. PMID- 21291673 TI - From the Editor-in-Chief. PMID- 21291674 TI - Introduction: John Gofman and the early years at the Donner Laboratory. PMID- 21291675 TI - The serum lipoprotein transport system in health, metabolic disorders, atherosclerosis and coronary heart disease. PMID- 21291677 TI - News from the national lipid association. PMID- 21291676 TI - From the Editor-in-Chief. PMID- 21291678 TI - Impact of exercise on blood lipids and lipoproteins. AB - Abnormal blood lipids are a significant cardiovascular health risk. Drug therapy and diet continue to be standard management strategies. However, considerable evidence supports physical activity and exercise as having a positive impact on abnormal lipids and such are often recommended as adjunctive interventions. The purpose of this review is to clarify the mechanisms by which exercise facilitates favorable changes in levels of blood lipids and lipoproteins. Studies relative to the effects of exercise on blood lipid levels are notable: The impact of exercise on high-density lipoproteins (HDL-C) is best studied and specify effects of intensity and amount of exercise as well as a genetic influence. Exercise also exerts an effect on HDL-C maturation and composition, cholesterol efflux, and cholesterol delivery to receptors (reverse cholesterol transport). Positive effects of exercise are also seen with blood triglycerides (TG), but little specific effect is seen on low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC). Abundant evidence supports the benefits of exercise on levels of certain blood lipids (namely HDL-C and TG). Although standard management of abnormal blood lipids is drug therapy and diet, it seems prudent to incorporate aerobic exercise as an important component of a healthy lifestyle. In certain individuals, drug therapy may be decreased in dosage or perhaps discontinued in the patient who is "exercise trained," especially if there is associated weight loss. PMID- 21291679 TI - Implications of recent statin trials for primary care practice. AB - 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) are the first-line treatment for dyslipidemia and the results of large statin trials have a significant impact on guidelines for cardiovascular disease (CVD) management, such as those set by the National Cholesterol Education Program Adult Treatment Panel. The benefit of statin therapy in CVD prevention has traditionally been demonstrated in clinical trials by the superior efficacy of statins vs placebo in lowering low-density lipoprotein cholesterol (LDL-C) and preventing hard coronary heart disease (CHD) outcomes including myocardial infarction and CHD death. However, due to earlier and improved treatment of CVD, the clinical manifestations of atherosclerosis are changing and other forms of CVD are now thought to predominate (such as revascularization and stroke). These changes in how CVD manifests in the patient population may have consequences for selection of endpoints when designing future clinical trials. Recent statin trials have also demonstrated the early and improved clinical benefit of lowering LDL-C beyond traditional goals with intensive statin therapy vs more moderate lipid lowering therapy. This review assesses the impact of early statin trials on current CVD management guidelines, summarizes results of recent landmark statin trials, and evaluates the potential implications of these studies for future clinical trials and CVD management guidelines. PMID- 21291680 TI - The role of nicotinic acid metabolites in flushing and hepatotoxicity. AB - Flushing and hepatotoxicity are important adverse effects of nicotinic acid. This article reviews the role of metabolism of nicotinic acid in the production of these side effects. The suggestion that nicotinic acid (NUA) formation produces flushing is traced to a correlation of flushing with NUA C(max) (maximal concentration) and the observation that aspirin inhibits NUA formation and flushing. The former does not establish causation and the latter can be explained by inhibition of prostaglandin formation. Recent characterization of the GPR109A receptor that mediates prostaglandin release by Langerhans cells to produce flushing has shown nicotinic acid, not NUA, is responsible. The suggestion that nicotinamide metabolites produce hepatotoxicity is not supported by any data. The mechanism of hepatotoxicity is unknown and a toxic metabolite of nicotinic acid has not been identified. Different nicotinic acid formulations produce different metabolite patterns due to nonlinear pharmacokinetics, but there is no evidence that these differences have any clinical importance. PMID- 21291681 TI - Atherosclerosis and teen eating study. AB - BACKGROUND: Low-density lipoprotein, high-density lipoprotein, serum triglyceride concentrations, blood pressure, obesity, and blood glucose are all known to contribute to risk for development of atherosclerosis. Research demonstrates that dietary modifications, which reduce saturated fat intake, impact the likelihood of development of atherosclerosis. OBJECTIVE: The Atherosclerosis and Teen Eating Study was designed to determine whether a short-term health educational program, complemented by availability of alternative low-fat school lunches, could result in favorable changes to healthier eating patterns. Additionally, the study was designed to measure whether changes in eating behaviors were sufficient to result in risk-factor reduction. METHODS: The 6-week study consisted of a defined educational curriculum in addition to the availability of alternative low-fat cafeteria meals. Six 1-hour educational sessions on heart-healthy nutrition and exercise were presented over a period of 2 weeks. Self-perceived nutritional intake was assessed at baseline and the conclusion of the trial via a documented method, the Eating Pattern Assessment Tool. Routine laboratory work and blood pressure were measured at baseline and conclusion of the study. RESULTS: Eating Pattern Assessment Tool score decreased by 14 points (P < 0.001), indicating a significant fall in fat consumption. Fasting glucose and diastolic blood pressure were also reduced. Mean fasting glucose decreased by 3.1 mg/dL (P = 0.041) and mean diastolic blood pressure fell by 6.6 mmHg (P < 0 .001). The percentage reduction in low-density lipoprotein, the primary endpoint, showed a trend downward but did not achieve statistical significance (P = 0.075). CONCLUSION: School-based educational programs and improved choice of foods focused on cardiovascular risk reduction have the capacity to positively influence eating patterns and risk factors associated with future development of atherosclerosis. PMID- 21291682 TI - Primary care physician treatment of low HDL: Rational approach or Pandora's Box? AB - BACKGROUND: Guidelines for treating high low-density lipoproteins are clear, whereas guidelines for treating low high-density lipoproteins (HDL) are less so. Physicians approach to treating low HDL cholesterol is not known. OBJECTIVE: To determine primary care physicians approach to managing low HDL. METHODS: Three thousand, nine-hundred and nineteen surveys were mailed to all primary care physicians in the State of Indiana, asking questions regarding demographics, case studies to assess the provider's approach to managing low HDL, and direct questions regarding management of HDL levels and general lipid knowledge questions. RESULTS: Seven-hundred and eighty-one surveys were returned, for a response rate of 19.9%. Fifty-eight percent of participants would initiate HDL raising therapy after achieving the appropriate low-density lipoprotein cholesterol goal. The approaches used to raise HDL included lifestyle changes (diet, exercise, smoking cessation) (85%), niacin (83%), fibric acid derivative (61%), and alcohol (31%). Reasons inhibiting initiating therapy for raising HDL included concern over side effects (56%), perceived lack of effectiveness of currently available drugs (24%), lack of clear guidelines (22%), and lack of evidenced-based trials demonstrating benefit of raising HDL (14%). For men, 40% of physicians use 40 mg/dL as a cutoff for initiating HDL-raising therapy, while 25% using a cutoff of 35 mg/dL. For women, 24% use a cutoff of 50 mg/dL for initiating HDL-raising therapy, while 12% use 45 mg/dL as a cutoff. CONCLUSIONS: The majority of primary care physicians in the State of Indiana treated low HDL with appropriate approaches, although use of alcohol to raise HDL raises concerns. PMID- 21291683 TI - Pilot study of combined therapy with omega-3 fatty acids and niacin in atherogenic dyslipidemia. AB - BACKGROUND: Niacin and omega-3 fatty acids (omega-3 FA) are both nutrients that reduce serum triglyceride and raise high-density lipoprotein cholesterol (HDL-C) levels when used at pharmacological doses. The possibility that these two agents, given in combination, might have additive effects on these lipid parameters has not been examined previously. In addition, the combination might prevent the rise in low-density lipoprotein (LDL)-C levels frequently seen with omega-3 FA treatment. OBJECTIVE: To determine the effect of therapy of niacin and omega-3 FA alone and in combination versus placebo on lipid parameters in subjects with atherogenic dyslipidemia. METHODS: In a pilot parallel group study, we studied 29 patients with atherogenic dyslipidemia who were assigned to either dual placebo (n = 7), omega-3 FA (3.4 g/d; n = 8), crystalline niacin (3 g/d; n = 7), or the combination (n = 7) for 12 weeks. Fasting lipid profiles were assessed before and after treatment. RESULTS: Changes in serum triglyceride levels from baseline were 10%, -2%, -17%, and -52%, respectively, while HDL-C concentrations rose by 4%, 10%, 18%, and 33%, respectively. Both of these results were statistically significantly different for combination therapy compared to changes with placebo and omega-3 FA monotherapy (analysis of variance with Tukey's post-hoc test). No statistically significant changes were seen for LDL-C. Addition of omega-FA to niacin had no effect on niacin-induced flushing. CONCLUSION: From this small pilot study, we conclude that combined therapy with niacin and omega-3 FA has beneficial effects on triglyceride and HDL-C levels, and use of these two agents in combination prevents the omega-3 FA-induced rise in LDL-C. Larger studies of this combination therapy are clearly warranted in patient populations with atherogenic dyslipidemia to assess not only lipid effects, but also potential coronary heart disease benefits. PMID- 21291684 TI - From the Editor-in-Chief. PMID- 21291685 TI - News from the National Lipid Association Dr. John Gofman named NLA lifetime member. PMID- 21291686 TI - Making a case for quantitative assessment of cardiovascular risk. AB - Cardiovascular disease (CVD) causes nearly one third of all deaths worldwide. Estimates of the cumulative effects of the most common cardiovascular risk factors indicate that >30% of the chronic care burden of CVD and >50% of deaths from CVD are attributable to modifiable risk factors, such as cigarette smoking, elevated low-density lipoprotein cholesterol, low levels of high-density lipoprotein cholesterol, diabetes mellitus, and hypertension. While a significant percentage of patients present with one or more of these risk factors, health care practitioners encounter great difficulty in achieving long-term patient adherence to risk-factor modification interventions. More accurate stratification of death and disability risk across age, gender, and ethnic categories-and more comprehensible quantification of the magnitude and timeframe of the impact of risk-factor modification on such risks-will likely be useful to patients and health care practitioners in the implementation of more effective strategies. There is a need to study which risk-assessment methodologies, which depictions of short- and long-term risk, and which intervention modalities will have the greatest possible impact on patients' understanding of risk factors and risk modification behaviors. PMID- 21291687 TI - Nutritional and exercise aspects of cognitive impairment. AB - According to recent evidence, our aging society is in the early phases of an epidemic of cognitive decline. Accordingly, efforts directed at reducing the risk of Alzheimer's disease and dementia will be an important goal of health care efforts. While there are a paucity of successful treatment options currently available, diet and other lifestyle changes can play an important role in such an approach. Epidemiologic data have been conflicting in relation to the benefit of vitamins C and E, and some individual foods. This review will examine the role of the Mediterranean diet, as well as individual dietary components, including fruits, vegetables, antioxidants, fish, docosahexaenoic acid, and fat intake. The role of exercise in maintaining normal weight and reducing risk factors may provide additional protection. There is a need for well-designed prospective, randomized controlled trials in the future to improve the currently available database and to document the efficacy and cost-effectiveness of specific interventions, providing for development of preventive guidelines in this area. PMID- 21291688 TI - Revisiting niacin: reviewing the evidence. AB - Atherogenic dyslipidemia, defined by a cluster of lipoprotein abnormalities, including low high-density lipoprotein cholesterol (HDL-C) and elevated serum triglycerides, represents an important potential target for reducing cardiovascular risk. This has paved the way for revisiting niacin as a therapy in preventing progression of atherosclerosis. Niacin remains the safest and most effective agent for raising HDL-C and is a logical choice to target atherogenic dyslipidemia. While the clinical efficacy of niacin has been known for many years, it is only with development of newer formulations, which have lower side effect profiles and improved compliance, that the potential for this agent been fully realized. In this review, we will examine some of the reasons that niacin can have important implications for reducing progression of atherosclerosis. We will first examine the different formulations and their variability, not only in side-effect profiles, but also in clinical efficacy. We will then consider the theoretical evidence for the benefit of HDL-raising produced by niacin on atherosclerotic progression. Finally, we will review clinical data suggesting the benefit of niacin on cardiovascular outcomes. PMID- 21291689 TI - Diagnosis of type III hyperlipoproteinemia from plasma total cholesterol, triglyceride, and apolipoprotein B. AB - OBJECTIVE: Our objective was to develop a simple algorithm that could be applied in routine clinical practice to diagnose type III hyperlipoproteinemia based on plasma total cholesterol, triglyceride and apolipoprotein (Apo) B. METHODS: Analysis of plasma lipid, lipoprotein lipid, and apolipoprotein data from 1771 patients in a tertiary care lipid clinic, from whom all data had been collected prospectively by standardized methods. Of the 1771, based on the Fredrickson classification, 16 had type I hyperlipoproteinemia, 736 type IIa hyperlipoproteinemia, 371 type IIb hyperlipoproteinemia, 38 type III hyperlipoproteinemia, 509 type IV hyperlipoproteinemia, and 101 type V hyperlipoproteinemia. RESULTS: Mean plasma ApoB was highest in type IIb (1.53 +/- 0.36 g/L), borderline high (1.1 +/- 0.23 g/L) in type IV, normal in type III and type V (1.04 +/- 0.21 g/L and 0.96 +/- 0.40 g/L, respectively) and low in type I (0.48 +/- 0.16 g/L). In type III hyperlipoproteinemia, very low-density lipoprotein ApoB (ie, d<1.006 g/mL) accounted for 42.3% of total ApoB, a value that was substantially higher than in any of the other dyslipoproteinemias. The total cholesterol (TC)/ApoB ratio was similar in the uncommon dyslipoproteinemias type I, III, and V hyperlipoproteinemia (10.5 +/- 4.8, 8.7 +/- 1.8, 10.3 +/- 7.7, respectively)-and much higher than in the common dyslipoproteinemias-type IIa, IIb, and type IV hyperlipoproteinemia (5.0 +/- 0.4, 4.6 +/- 0.4, 4.9 +/- 1.1, respectively). Notwithstanding that the TC/ApoB area under the curve-receiver operating characteristic (AUC-ROC) was very high (0.93), it did not discriminate among the uncommon dyslipoproteinemias. However, the triglyceride (TG)/ApoB ratio was much higher in type I (42.4 +/- 28.8) and type V (25.6 +/- 30.2) than in type III (5.8 +/- 3.2). All cases of type III had a TC/ApoB ratio >6.2 and a TG/ApoB ratio of <10.0. Using these cutpoints, there were also no false positives. Based on the TC/ApoB ratio and the TG/ApoB ratio, the AUC-ROC was 0.99. CONCLUSIONS: These data indicate that type III hyperlipoproteinemia can be reliably diagnosed based on plasma cholesterol, TG, and ApoB. PMID- 21291690 TI - Efficacy and tolerability of fixed-dose combination of simvastatin plus ezetimibe in patients with primary hypercholesterolemia: Results of a multicentric trial from India. AB - OBJECTIVE: To compare the efficacy and safety of fixed-dose combination (FDC) of simvastatin and ezetimibe vs simvastatin monotherapy in Indian patients with primary hypercholesterolemia. METHODS: This multicentric, double-blind, comparative, study conducted in India enrolled 230 patients with hypercholesterolemia (baseline low-density lipoprotein cholesterol [LDL-C] >120 mg/dL for patients on previous hypolipidemic drugs or >135 mg/dL for naive subjects) were randomly assigned to receive either simvastatin (10 mg/day) or simvastatin (10 mg) plus ezetimibe (10 mg) FDC for 12 weeks. The primary efficacy endpoint was the mean percentage change in LDL-C from baseline to 12 weeks of therapy for simvastatin monotherapy vs simvastatin plus ezetimibe FDC. Secondary efficacy endpoints were mean percentage of changes in total cholesterol (TC), triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C) from baseline to end of treatment, as well as proportion of patients achieving National Cholesterol Education Program Adult Treatment Panel III target LDL-C levels in each risk category. RESULTS: At the end of 12 weeks, the mean percentage reduction from baseline in LDL-C (-33.7%) was significantly greater with simvastatin and ezetimibe FDC compared to simvastatin alone (-26.28%, P < 0.05). Significantly greater percentage of patients (88%, P < 0.001) attained National Cholesterol Education Program Adult Treatment Panel III LDL-C target levels following ezetimibe/simvastatin treatment compared to simvastatin monotherapy (71%). Reductions in TG were significantly greater with ezetimibe/simvastatin than simvastatin (P < 0.001). Increases in HDL-C, and reduction in TC were similar between treatment groups. Safety and tolerability profiles were comparable for both treatments. CONCLUSION: Fixed-dose combination of simvastatin and ezetimibe provides a more effective means for reducing LDL cholesterol levels in Indian patients with hypercholesterolemia than simvastatin monotherapy without compromising the safety and tolerability profile. PMID- 21291691 TI - Assessment of lipoprotein profiles study (ALPS) and antioxidant activity in healthy subjects treated with AGI-1067. AB - BACKGROUND: AGI-1067 (succinobucol) is a phenolic derivative of probucol that inhibits the vascular oxidative-inflammatory cascade and is intended to have an improved clinical profile. OBJECTIVE: The Assessment of Lipoprotein Profiles (ALPS) study evaluated the effects of AGI-1067 on lipid, antioxidant, antiinflammatory and safety profiles in healthy subjects. METHODS: This was a double-blind, placebo-controlled, 12-week, multicenter trial. Eligible subjects, aged 18 to 65 years, had low-density lipoprotein cholesterol (LDL-C) <= 190 mg/dL, triglyceride (TG) <= 600 mg/dL and Framingham risk <10%. Subjects were randomized 1:1 to oral 300 mg AGI-1067 (n = 127) or matching placebo (n = 127) once daily. RESULTS: AGI-1067 and placebo treatment had small changes (mean) in: LDL-C (+2.98 vs -1.52 mg/dL, respectively; P = 0.057), apolipoprotein B (+1.48 vs -1.91 mg/dL; P = 0.267), high-density lipoprotein cholesterol (HDL-C) [-3.69 vs 0.29 mg/dL; P < 0.001], and apolipoprotein (Apo) A-I (-10.43 vs -6.14 mg/dL; P = 0.021). Subjects with baseline LDL-C > 130 mg/dL showed the largest decreases in HDL-C and ApoA-I, while subjects with LDL-C <=130 mg/dL had insignificant changes in both parameters. Changes in cholesteryl ester transfer protein mass were significantly correlated (P < 0.0001) with LDL-C changes, but not HDL-C. Paraoxonase activity increased with AGI-1067 vs little change in placebo (+1.78 vs +0.15 U/L, respectively; P = 0.077). HDL particles isolated from AGI-1067 treated subjects showed significant antioxidant potency vs HDL particles from placebo subjects (thiobarbituric acid reactive substances in a LDL oxidation assay decreased -25.88% vs +7.88, respectively; P = 0.011). CONCLUSION: The ALPS study demonstrated that AGI-1067 had minor effects on LDL and HDL cholesterol. More dramatic effects were observed for HDL-associated paraoxonase and thiobarbituric acid reactive substances activity, suggesting that the antiatherosclerotic properties of AGI-1067 may involve an HDL antioxidant mechanism consistent with inhibition of the oxidative-inflammatory cascade, rather than involving a lipid regulating pathway. PMID- 21291692 TI - Further reduction of low-density lipoprotein cholesterol and C-reactive protein with the addition of ezetimibe to maximum-dose rosuvastatin in patients with severe hypercholesterolemia. AB - BACKGROUND: Patients with severe hypercholesterolemia, including familial hypercholesterolemia, are considered at high risk for coronary artery disease and often prove difficult to treat to current low-density lipoprotein cholesterol (LDL-C) guidelines. METHODS: In this open-label, 12-week substudy within a larger trial, ezetimibe 10 mg was added to stable therapy with rosuvastatin 40 mg (+/- bile acid sequestrant/niacin) in 107 patients with severe hypercholesterolemia who had not achieved LDL-C goal of <100 mg/dL. RESULTS: Prior to the start of rosuvastatin treatment, on diet alone, mean LDL-C levels were 291 +/- 59 mg/dL and decreased to 141 +/- 30 mg/dL on rosuvastatin 40 mg daily at the substudy baseline prior to ezetimibe. After 12 weeks, the addition of ezetimibe produced an additional 15% +/-9% reduction in LDL-C (P < 0.001) compared to pre rosuvastatin levels and a mean LDL-C of 103 +/- 27 mg/dL, resulting in 59% of patients reaching their LDL-C goals. The combination reduced LDL-C by 65% +/- 9% from diet alone. Combination with ezetimibe also produced significant additional percent reductions in non-high-density lipoprotein (14%), apolipoprotein B (10%), and triglycerides (6%). Median C-reactive protein was reduced 54% (P < 0.001) by the combination compared with diet alone, a further incremental reduction of 13% (P < 0.001) with the addition of ezetimibe. The combination was well tolerated, with no patients developing myopathy or clinically significant elevations of creatine kinase or transaminases. CONCLUSIONS: The combination of rosuvastatin 40 mg and ezetimibe 10 mg offers the most effective LDL-C-lowering therapy yet reported, and is helpful in achieving lipid goals and reducing C-reactive protein levels in high-risk patients with severe hypercholesterolemia, including familial hypercholesterolemia. PMID- 21291693 TI - Comparison of short-term renal effects and efficacy of rosuvastatin 40 mg and simvastatin 80 mg, followed by assessment of long-term renal effects of rosuvastatin 40 mg, in patients with dyslipidemia. AB - BACKGROUND: An open-label, randomized, multinational, parallel-group trial compared the short-term (6-week) renal effects of rosuvastatin 40 mg and simvastatin 80 mg in patients with hypercholesterolemia. Most patients (93%) then entered an optional open-label extension (OLE) to assess long-term (up to 72 weeks) renal effects of rosuvastatin. METHODS: After dietary lead-in, 626 patients were randomized to rosuvastatin or simvastatin for 6 weeks, followed by an optional, single-arm OLE to assess longer-term effects of rosuvastatin on renal function, safety, and efficacy. RESULTS: The primary endpoint, a shift in urine dipstick protein from "none" or "trace" at baseline to "+" or greater in the first 4 weeks, was observed in 6.4% of patients receiving rosuvastatin and 1.0% of those receiving simvastatin. The incidence of shifts in urine dipstick protein at any time from none or trace to "++" or greater (proteinuria), was low (1.3%, rosuvastatin; 0.3%, simvastatin), transient and urine protein was predominantly of tubular or mixed origin. More patients achieved Third Adult Treatment Panel of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP ATP III) low-density lipoprotein cholesterol (LDL-C) goals with rosuvastatin vs simvastatin after 6 weeks (77.9% vs 60.4%). Results from the OLE (median rosuvastatin treatment = 47 weeks) were consistent with the randomized period. Mean serum creatinine levels remained stable, indicating no decline in renal function. CONCLUSION: A small proportion of patients treated with rosuvastatin 40 mg may experience a transient proteinuria, predominantly of tubular origin and not associated with declining renal function. Rosuvastatin modified lipid levels effectively, enabled more patients to attain LDL-C goals, and demonstrated a favorable benefit/risk profile. PMID- 21291694 TI - From the Editor-in-Chief. PMID- 21291695 TI - News from the National Lipid Association Lipid Luminations update. PMID- 21291696 TI - From the Editor-in-Chief. PMID- 21291697 TI - News from the national lipid association. PMID- 21291698 TI - Management of stable patients with coronary heart disease: Clinical implications of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial. AB - Early coronary revascularization has been shown to reduce major adverse cardiovascular events in patients with acute coronary syndromes. In patients with stable coronary heart disease (CHD), however, coronary revascularization does not reduce death or myocardial infarction compared to intensive medical therapy. The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial was the first to study whether coronary revascularization performed in addition to medical therapy, rather than as an alternative, would reduce death or myocardial infarction in patients with stable CHD. Between 1999 and 2004, 2287 patients were enrolled in 50 centers throughout Canada and the United States. After a median follow-up of 4.6 years, revascularization performed in addition to intensive medical therapy did not result in reduced mortality or myocardial infarction compared to medical therapy alone. At the end of follow-up, anginal control was similar in both groups, although patients receiving medical therapy only did require more antianginal medications, and one-third ultimately required revascularization. We review the strengths, limitations, and clinical relevance of the COURAGE trial in the context of the current literature on the benefits of medical management and coronary revascularization in patients with stable CHD. PMID- 21291699 TI - Cardiovascular disease in obesity: A review of related risk factors and risk reduction strategies. AB - Cardiovascular disease (CVD) is the number one cause of mortality in men and women. Currently, two thirds of US adults are overweight or obese. CVD and obesity are closely linked and together take a substantial toll on the health of individuals and the community. It is creating a growing burden on public health and financial difficulties in both personal and institutional funding of health care. A review of recent scientific literature reveals that modest weight loss of 5% to 10% ameliorates cardiometabolic risk factors and improves health outcomes. To date, successful weight-loss interventions have been elusive. The choice of weight-loss medications is limited, and the risks of surgical intervention demand that this option be reserved for those patients with extreme obesity. Research has elucidated an improved understanding of the mechanisms leading to obesity and disease. The potential role of hormones, such as leptin and adiponectin, in altering metabolism and vascular disease is better understood. The endocannabinoid system is now recognized as a potentially viable pathway to modulate appetite and energy, lipid, and glucose metabolism. PMID- 21291700 TI - Free oxygen radicals in whole blood correlate strongly with high-sensitivity C reactive protein. AB - BACKGROUND: Increased concentrations of reactive oxygen molecules are believed to be a driving force in inflammation. Although evident in tissue culture and animal models, it has been difficult to link reactive oxygen species (ROS) and inflammatory markers in humans. In patients recruited to represent a broad spectrum of risk factors, we investigated the relationship between the plasma concentration of oxygen radicals and high-sensitivity C-reactive protein (hs CRP), utilizing a new chemistry with an easily oxidized chromophore. METHODS: ROS and hs-CRP were measured in blood from 59 fasting subjects selected to have variable risk predicted by classical risk factors. ROS were determined using the free oxygen radical monitor, which is an indirect colorimetric assay for the concentration of hydroperoxides in whole blood. RESULTS: Using log transformation, the correlation between ROS and hs-CRP was r = 0.505 (P < 0.0001). This relationship between ROS and hs-CRP was comparable (r = 0.527, P = 0.001) in the subgroup not currently on statin therapy (n = 39). ROS were not correlated with Framingham risk, r = -0.027 (P = 0.84). CONCLUSION: ROS directly measured in human blood correlates strongly with hs-CRP. PMID- 21291701 TI - Small, dense low-density lipoprotein and C-reactive protein in obese subjects with and without other criteria for the metabolic syndrome. AB - BACKGROUND: Although obesity is an important cardiovascular risk factor, growing evidence shows that a substantial portion of obese subjects can be considered metabolically healthy but obese (MHO). However the extent to which obese subjects manifest small, dense low-density lipoprotein (LDL) particles without other characteristics of the metabolic syndrome (MS) remains unknown. OBJECTIVE: The purpose of this study was to determine the difference between MHO (only meeting the obesity criteria) and obese subjects meeting all the criteria for the MS with regard to LDL size and high-sensitivity C-reactive protein (hs-CRP), as a biomarker of inflammation. METHODS: Two hundred obese subjects (168 women, mean age 36.5 +/- 5 years [range, 20-60]; mean body mass index [BMI; calculated as kg/m(2)] 39 +/- 5 [range, 30-80.4]) were studied for LDL particles size and hs CRP levels. RESULTS: Of 200 enrolled obese subjects, 55 were defined MHO subjects meeting only obesity criteria. The other 145 met all five criteria and were defined as having MS. Although MHO and MS subjects had similar BMI, MHO subjects had a lower percentage of small LDL particles (8% vs 29%, P < 0.001), higher average LDL diameter (274 +/- 5 vs 270 +/- 7 A, P < 0.001), and lower hs-CRP levels (P < 0.05) than MS patients. CONCLUSION: The major finding of this study is that MHO subjects compared to equally obese subjects meeting the criteria of the MS have statistically significant differences in size of LDL and concentration of hs-CRP. However, the absolute differences are very small and of uncertain clinical significance. PMID- 21291702 TI - Efficacy of controlled-release niacin in treatment of metabolic syndrome: Correlation to surrogate markers of atherosclerosis, vascular reactivity, and inflammation. AB - BACKGROUND: The mechanisms that link metabolic syndrome to development of atherosclerosis are largely unknown. There is increasing evidence for the role of adipokines in this process. Niacin would appear to be a logical choice in combating the atherogenic dyslipidemia seen in metabolic syndrome, as it remains the most effective agent in raising high-density lipoprotein cholesterol, and also reduces triglycerides. We hypothesized that statin-intolerant patients with insulin resistance would respond to controlled-release niacin with a rise in plasma adiponectin levels. METHODS: Fifty patients with the metabolic syndrome (National Cholesterol Education Program/Adult Treatment Panel III criteria) were randomized to either once-daily controlled-release niacin (1000 mg/day) or placebo. Measurements at baseline and after 52 weeks of treatment were made of the carotid intimal media thickness, flow-mediated dilation of the brachial artery, and blood plasma adiponectin levels. These measures were compared to changes in lipoprotein concentrations in plasma. RESULTS: Changes in high-density lipoprotein cholesterol correlated significantly to changes in flow-mediated vasodilation and carotid artery intima-media thickness, and there was a trend toward correlation with plasma adiponectin levels. There was a significant difference in mean serum levels of adiponectin after the treatment period between placebo and niacin groups (16.3 +/- 1.7 and 17.7 +/- 1.9 mg/dL, respectively) (P = 0.022). CONCLUSIONS: Treatment with controlled-release niacin for 52 weeks results in sustained improvements in adiponectin levels compared to placebo in patients with metabolic syndrome. No adverse effects of niacin on glycemic control were found. PMID- 21291703 TI - Effects of niacin and Niaspan on HDL lipoprotein cellular SR-BI-mediated cholesterol efflux. AB - BACKGROUND: Niacin, the lipid-regulating agent with the longest therapeutic experience, has been demonstrated to both raise high-density lipoprotein cholesterol (HDL-C) levels and to diminish the risk of atherosclerosis and its vascular complications. OBJECTIVE: The present study was carried out to explore niacin's effect on scavenger receptor class B type I (SR-BI)-mediated cholesterol efflux, a component of reverse cholesterol transport, using an in vitro model system. METHODS: Thirty frozen samples from a large randomized, multicenter trial comparing crystalline niacin, extended-release niacin (Niaspan), and placebo were analyzed for SR-BI efflux. RESULTS: Both the extended-release and crystalline niacin demonstrated significant increases in HDL-C (approximately 50%) over baseline values compared to the placebo group (14%). This was associated with a significant increase in SR-BI efflux of 2.7% and 3.4% for extended-release niacin and niacin, respectively, compared to placebo (0.4%). Although, there was no relationship between HDL-C and SR-BI efflux at baseline or at the end of treatment, there was a linear relation between the changes in HDL-C and SR-BI efflux (r = 0.58, P < 0.002). CONCLUSION: This study suggests that niacin has a beneficial effect on SR-BI efflux that is related to the change in level of HDL C. PMID- 21291704 TI - Effects of adding extended-release niacin and colesevelam to statin therapy on lipid levels in subjects with atherosclerotic disease. AB - BACKGROUND: The use of combination therapies is needed to treat dyslipidemia in patients with both elevated low-density lipoprotein cholesterol (LDL-C) and low high-density lipoprotein cholesterol (HDL-C). We conducted a study to assess the efficacy and safety of combination therapy with statin plus extended-release (ER) niacin and colesevelam, aimed at lowering LDL-C and raising HDL-C, in subjects with atherosclerotic disease. METHODS: This 1-year study randomized 123 subjects with atherosclerotic disease to atorvastatin alone, double therapy with atorvastatin plus ER niacin, or triple therapy with atorvastatin, plus ER niacin and colesevelam. Target LDL-C was <=80 mg/dL for single and double therapy, and <=60 mg/dL for triple therapy. Target HDL-C was an increase of >=10 mg/dL for double and triple therapy. RESULTS: Single therapy, with mean atorvastatin dose 30 mg/day, had a 47% reduction in LDL-C (P < 0.001) from 148 +/- 29 mg/dL to 77 +/- 15 mg/dL. With the addition of ER niacin, the double therapy had a 25% increase in HDL-C, from 42 +/- 11 mg/dL to 53 +/- 16 mg/dL (P < 0.001). The triple therapy decreased LDL-C by 57%, from 157 +/- 29 mg/dL to 66 +/- 18 mg/dL (P < 0.001), and increased HDL-C by 29%, from 40 +/- 9 mg/dL to 50 +/- 14 mg/dL (P < 0.001). Double and triple therapy required a lower atorvastatin dose of 20 mg/day to reach the target LDL-C levels. On average, 75% and 67% of subjects reached the predefined LDL-C and HDL-C treatment targets. No related myopathy or hepatotoxicity required stopping the therapy. CONCLUSION: This study demonstrated that combination therapy with atorvastatin plus ER niacin and colesevelam can safely and effectively treat dyslipidemia in subjects with atherosclerotic disease. PMID- 21291705 TI - Plant sterols added to combination statin and colesevelam hydrochloride therapy failed to lower low-density lipoprotein cholesterol concentrations. AB - BACKGROUND: The purpose of this study was to evaluate the effects on LDL cholesterol (LDL-C) from addition of plant sterol treatment to patients with dyslipidemia already taking a statin and colesevelam hydrochloride (HCl). Current cholesterol treatment guidelines recommend use of plant stanols/sterols to help reach LDL-C goals in patients taking other lipid-lowering therapies. Previous data demonstrate LDL-C lowering by adding stanols/sterols to statins. However, data are conflicting regarding the benefit from combination stanols/sterols with bile acid sequestrants. METHODS: Fifty-five subjects on a stable dose of statin completed a 10-week, double-blind, randomized study of colesevelam HCl 3.75 g/day alone for 4 weeks, then 6 weeks of additional 2 g/day plant sterol-fortified orange juice (S-OJ) or placebo orange juice (P-OJ). Serum total cholesterol (TC), LDL-C, HDL-cholesterol (HDL-C), triglycerides (TG), apolipoprotein B (ApoB), and high-sensitivity C-reactive protein (hs-CRP) were measured at baseline, 4 weeks, and 10 weeks. RESULTS: Baseline LDL-C measurements (mean +/- SD) were similar between S-OJ and P-OJ groups (122 +/- 20 vs 126 +/- 24 mg/dL, respectively). Four weeks of colesevelam HCl in combination with a statin significantly reduced TC, LDL-C, and ApoB (9.6%, P < 0.001; 21.9%, P < 0.001; and 8.5%, P = 0.001, respectively), and significantly increased HDL-C (6.2%, P = 0.002) and TG (18.8%, P = 0.002). However, compared to P-OJ, 10 weeks of S-OJ produced no effect on any outcome parameter beyond that of colesevelam HCl. CONCLUSION: Plant S-OJ appears to be ineffective at further reducing LDL-C when added to statin and colesevelam HCl combination therapy in patients with dyslipidemia. PMID- 21291706 TI - A retrospective study of the lipid-lowering efficacy and safety of ezetimibe added to hydroxy methylglutaryl coenzyme A reductase therapy in HIV-infected patients with hyperlipidemia. AB - BACKGROUND: Abnormalities in lipid metabolism are a well-described consequence of human immunodeficiency virus (HIV) infection being treated with highly active antiretroviral therapies (HAART). OBJECTIVE: The purpose of this study is to evaluate the lipid-lowering efficacy and safety of ezetimibe added to existing hydroxy methylglutaryl coenzyme A reductase (statin) therapy in HIV-infected patients with hyperlipidemia. METHODS: This is a retrospective study utilizing a comprehensive electronic patient registry to identify all adult HIV-infected patients seen at the Dallas Veterans Affairs (VA) Medical Center during a 4-year period from October 1, 2002 through October 1, 2006. RESULTS: A total of 26 HIV infected patients initiated on ezetimibe 10 mg were identified, with 14 adult males meeting strict criteria for inclusion. Median age was 54 years (interquartile range [IQR], 45-59) with a median duration of HIV of 13 years, CD4 count of 513 cells/mm(3) (IQR, 289-736), and 9 of 14 patients had undetectable viral loads at baseline. Initiation of ezetimibe 10 mg resulted in a significant decrease in total cholesterol (TC) from baseline (-12.9%, P = 0.001); low-density lipoprotein cholesterol (LDL-C; -25.7%, P = 0.001); and non-high-density lipoprotein cholesterol (non-HDL-C; -23.9%, P = 0.001). There was also a nonsignificant decrease in triglycerides (15.8%, P = 0.43), and an increase in number of patients achieving National Cholesterol Education Program/Adult Treatment Panel III goal for LDL-C after initiation of ezetimibe (+20.9%, P = 0.125). These improvements occurred without adverse effects or changes in virologic and immunologic control. CONCLUSION: Addition of ezetimibe to existing statin therapy in HIV-infected VA patients treated with HAART significantly reduces TC, LDL-C, and non-HDL-C concentrations without apparent side effects or compromising of virologic control. PMID- 21291707 TI - From the Editor-in-Chief. PMID- 21291708 TI - News from the national lipid association. PMID- 21291709 TI - High-density lipoprotein, sphingosine 1-phosphate, and atherosclerosis. AB - Numerous epidemiologic and interventional studies have revealed an inverse relationship between plasma concentrations of high-density lipoprotein (HDL) and coronary risk. There are several well-documented HDL functions, which may account for the antiatherogenic effects of this lipoprotein. Recent studies document that HDL serves as a carrier for the bioactive lysosphingolipid sphingosine 1 phosphate (S1P), which determines its functional properties. Generally available databases (eg, PubMed) were used, as well as our own results. An increasing body of evidence indicates that S1P is a mediator of many of the atheroprotective effects of HDL, including the ability to promote vasodilation and angiogenesis and protection against ischemia/reperfusion injury. These latter effects are believed to involve S1P-mediated retardation or suppression of inflammatory processes, such as endothelial expression of adhesion molecules, production of proinflammatory chemokines and cytokines, generation of reactive oxygen species, and cardiomyocyte apoptosis after myocardial infarction. This review article summarizes the evidence that S1P is a component of HDL contributing to the antiatherogenic and cardioprotective potential attributed to this lipoprotein. PMID- 21291710 TI - Efficacy of simvastatin therapy in attainment of LDL-C and TG goal levels in patients with type 2 diabetic dyslipidemia. AB - BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) has been identified as the primary target of cholesterol-lowering therapy, with the LDL-C goal set at <=100 mg/dL for patients at high risk, such as those with diabetes. OBJECTIVE: To evaluate the efficacy of simvastatin (S) in achieving LDL-C levels <70 mg/dL in patients with type 2 diabetes mellitus (DM). METHODS: This was a post-hoc analysis of a multicenter, randomized, double-blind, three-way crossover, placebo (PL)-controlled study that evaluated S80 mg or S40 mg versus PL for increasing high-density lipoprotein cholesterol (HDL-C). Patients with type 2 DM (n = 151), LDL-C >100 mg/dL, HDL-C <40 mg/dL, and triglycerides (TG) >150 and <700 mg/dL were randomized to daily S80 mg, S40 mg, or PL for three 6-week periods. The percentage of patients reaching LDL-C <70 mg/dL and the percentage reaching TG <150 mg/dL after 6 weeks was assessed. RESULTS: After 6 weeks, 59% (82 of 140) of patients in the S80 mg group achieved LDL-C <70 mg/dL versus 43% (60 of 139) receiving S40 m, and 0% (0 fo 140) in the PL group (P < 0.001 for S80 mg and S40 mg vs PL, and S80 mg vs S40 mg). In patients with coronary heart disease (CHD) (n = 32), 63% (20 of 32) receiving S80 mg reached LDL-C <70 mg/dL, versus 50% (15 of 30) in the S40 mg and 0% (0 of 32) in the PL group (P <0.001 for S80 mg and S40 mg vs PL, and P = 0.063 for S80 mg vs S40 mg). For TG levels, 27% (35 of 132) of the S80 mg patients and 23% (30 of 130) of the S40 mg patients reached a goal of TG <150 mg/dL. The dual goal of LDL-C level <70 mg/dL and TG level <150 mg/dL was attained by 14.7% of patients in the S80 mg, 7.8% in the S40 mg, and 0% in the PL group. CONCLUSION: S40 mg or S80 mg daily allowed 43% to 59% of patients with type 2 DM at risk of CHD to reach the goal of lowering LDL-C levels to the National Cholesterol Education Program Adult Treatment Panel III optional target level of <70 mg/dL. Reaching TG goals may require additional therapeutic considerations. PMID- 21291711 TI - Lipoprotein and apolipoprotein ratios in the VYTAL trial of ezetimibe/simvastatin compared with atorvastatin in type 2 diabetes. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with a high risk for coronary heart disease (CHD). A variety of lipoprotein and apolipoprotein (Apo) ratios have been proposed that may reflect the balance of cholesterol delivery and removal at the arterial wall and provide an assessment of CHD risk that is supplemental to low-density lipoprotein cholesterol (LDL-C), the primary guide for cholesterol-lowering therapy in patients at risk. OBJECTIVE: To examine changes in lipoprotein and apolipoprotein ratios in the VYTAL trial of hypercholesterolemic patients with T2DM. METHODS: Changes in the ratios LDL C/high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC)/HDL-C, non HDL-C/HDL-C, and ApoB/ApoA-I were assessed in this randomized, double-blind, parallel-group study that enrolled T2DM patients with LDL-C >=100 mg/dL for 6 week treatments with either the usual daily starting doses of atorvastatin (ATORVA) 10 or 20 mg or ezetimibe/simvastatin (EZE/SIMVA) 10/20 mg, or the next highest doses (ATORVA 40 mg, EZE/SIMVA 10/40 mg). Changes in lipoprotein and apolipoprotein ratios, prespecified exploratory endpoints, were analyzed using analysis of variance. RESULTS: Efficacy results were based on 1198 patients with sufficient data among 1229 randomized patients. Baseline lipoproteins, apolipoproteins, and ratios were comparable among treatment groups. EZE/SIMVA produced significantly greater reductions compared with ATORVA in each lipoprotein or apolipoprotein ratio at each dose comparison (P < 0.001). For example, reductions from baseline in TC/HDL-C were ATORVA 10 mg, -30.2%; ATORVA 20 mg -34.9%; EZE/SIMVA 10/20 mg, -41.6%; ATORVA 40 mg, -37.9%; and EZE/SIMVA 10/40 mg, -43.5%. Tolerability of the two treatments was similar. CONCLUSION: For the doses assessed, EZE/SIMVA was more effective compared with ATORVA in lowering the lipoprotein and apolipoprotein ratios that might be considered secondary measures of CHD risk. PMID- 21291712 TI - Effect of ezetimibe/simvastatin vs atorvastatin on lowering levels of LDL-C and non-HDL-C, ApoB, and hs-CRP in patients with type 2 diabetes. AB - BACKGROUND: In addition to low-density lipoprotein cholesterol (LDL-C), non-high density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), and high sensitivity C-reactive protein (hs-CRP) are considered predictive for cardiovascular disease in type 2 diabetes mellitus (T2DM) patients. OBJECTIVE: To assess the proportion of T2DM patients with hypercholesterolemia who attained the optional target level of LDL-C (<70 mg/dL) and additionally non-HDL-C (<100 mg/dL), ApoB (<90 mg/dL), and hs-CRP (<2 mg/L), following treatment with ezetimibe/simvastatin (E/S) vs atorvastatin (A). METHODS: This post-hoc analysis of a multicenter, randomized, double-blind, 6-week parallel study assessed the proportion of T2DM patients who attained specified LDL-C levels and non-HDL-C, ApoB, and hs-CRP with usual, recommended starting doses of E/S (10/20 mg) vs A (10 or 20 mg) and next highest doses of E/S (10/40 mg) vs A (40 mg) by logistic regression. Baseline triglyceride and hs-CRP effects were also evaluated. RESULTS: Significantly higher percentages of patients treated with E/S compared to A achieved individual and concurrent target levels of LDL-C (<70 mg/dL), non HDL-C (<100 mg/dL), and ApoB (<90 mg/dL) at all dose comparisons (P < 0.05 to P < 0.001). Baseline triglyceride levels had no effect on reaching LDL-C levels. Attainment of non-HDL-C (<100 mg/dL), and ApoB (<90 mg/dL) was lower at triglycerides >=200 mg/dL than <200 mg/dL. Achievement of hs-CRP level (<2 mg/L) was comparable for both treatments. Significantly more patients attained both LDL C (<70 mg/dL) and hs-CRP (<2 mg/L) at all E/S doses compared to A (P < 0.05 to P < 0.001), regardless of baseline CRP levels. CONCLUSION: E/S provides a therapeutic option to T2DM patients for lowering not only LDL-C, but also non-HDL C, ApoB, and hs-CRP. These factors may help guide assessment and treatment of cardiovascular disease risk in these patients. PMID- 21291713 TI - Differential response of cholesterol and particle measures of atherogenic lipoproteins to LDL-lowering therapy: implications for clinical practice. AB - BACKGROUND: Low-density lipoprotein (LDL)-lowering with pharmacologic therapy has been repeatedly shown to substantially reduce risk of vascular disease. LDL cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (HDL-C) are the cholesterol indices used to measure the adequacy of LDL-lowering therapy, whereas apolipoprotein B (ApoB) is the most widely used index of atherogenic particle number. OBJECTIVE: This study examines whether LDL-lowering therapy reduces cholesterol indices and ApoB to the same extent. If they are not equally affected, they may not be equally informative about change in risk. METHODS: Data from 11 studies, which include 17,035 subjects, were analyzed. All the statins in common use were included, as well as all the doses at which they are commonly used. More limited data are presented on combination therapy with statins and ezetimibe. RESULTS: Reductions in LDL-C, non-HDL-C, and ApoB differed significantly, averaging 42.1%, 39.6%, and 33.1%, respectively (P < 0.001 ApoB versus LDL-C or non-HDL-C). Mean value for the measure in question was expressed as the percentile level from a distribution analysis of two reference populations (Framingham Offspring Study and National Health and Nutrition Examination Survey III). The lower the population percentile, the more effective the apparent response. For LDL-C, non-HDL-C, and ApoB, these were the 21st, the 29th, and the 55th percentile of the population, respectively. This value for ApoB was significantly different from both LDL-C and non-HDL-C (P < 0.001). Very similar results were obtained in eight studies of LDL-lowering in 889 subjects in which the responses of LDL-C and LDL particle number (LDL-P) assessed by nuclear magnetic resonance spectroscopy were compared. LDL-C was reduced to the 27th percentile of the population, whereas LDL-P was only reduced to the 51st percentile of the population (P < 0.001). CONCLUSIONS: Many patients who achieve LDL-C and non-HDL-C target levels will not have achieved correspondingly low population-equivalent ApoB or LDL-P targets. Reliance on LDL-C and non-HDL-C can create a treatment gap in which the opportunity to give maximal LDL-lowering therapy is lost. PMID- 21291714 TI - Serum paraoxonase activity, high-sensitivity C-reactive protein, and lipoprotein disturbances in end-stage renal disease patients on long-term hemodialysis. AB - BACKGROUND: Hemodialysis patients are at high risk for atherosclerotic events. Enhanced oxidant stress, dyslipidemia, and inflammation may have a major role in this risk. In this work, we assessed lipoprotein status, total homocysteine, high sensitivity C-reactive protein (hs-CRP), and paraoxonase activity in hemodialysis patients to determine the correlations among these parameters and to compare these values with those measured in normal control subjects. METHODS: We enrolled 109 end-stage renal disease patients on long-term hemodialysis and 100 age- and gender-matched healthy subjects. Total cholesterol, triglycerides, and high density lipoprotein cholesterol levels were evaluated using colorimetric methods. Low-density lipoprotein (LDL) cholesterol was calculated according to the Friedewald formula. Serum levels of hs-CRP, apolipoproteins (Apo) AI, B, E, and lipoprotein(a) were measured by nephelometry. Lipoprotein particle (Lp) A-I and LpA-I:A-II were determined by immunoelectrophoresis. Total homocysteine levels were evaluated by the fluorescence polarization immunoassay method. Paraoxonase activity was determined using the paraoxon-like substrate. RESULTS: Compared with controls, hemodialysis patients had more frequent atherogenic dyslipidemia, hyperhomocysteinemia, and elevated hs-CRP levels. These latter findings inversely correlate with ApoA-I and LpA-I:A-II and positively with ApoB, lipoprotein(a), and ApoB/ApoA-I ratio. Homocysteine levels correlated positively with age. Paraoxonase activity was decreased in hemodialysis patients, especially in elderly patients. This enzyme activity positively correlated with LpA-I:A-II, and inversely with hs-CRP, LDL-cholesterol, and ApoE levels. CONCLUSION: The present study demonstrated an abnormal lipoprotein profile associated with increased hs CRP and decreased paraoxonase activity in hemodialysis patients. Hence, inflammation, dyslipidemia, and increased oxidant stress linked to uremia may be contributors to increased cardiovascular risk in this population. PMID- 21291715 TI - Misperception among physicians and patients regarding the risks and benefits of statin treatment: the potential role of direct-to-consumer advertising. AB - BACKGROUND: Statins are commonly used to reduce the risk of heart attacks and strokes. Despite the benefit and limited risks in properly identified patients, clinicians are often challenged by patient acceptance and adherence to these medications. OBJECTIVES: To assess if patients and physicians may have unfounded safety concerns about hepatotoxicity from these medications, we surveyed physicians and patients. RESULTS: We found inconsistent liver function-monitoring practices as well as exaggerated fears of statin-induced hepatotoxicity. Patients who received risk information from their physician were more likely to accurately estimate hepatotoxic risk than patients receiving such information from other sources. CONCLUSIONS: We believe these misperceptions about the relative risk and benefits of statin therapy are propagated by direct-to-consumer advertising, which may emphasize potential adverse events relative to treatment benefits. These perceptions are likely to adversely affect statin adherence, and may be addressed by patient education. PMID- 21291716 TI - Images in cardiovascular medicine: xanthomas triggered by bile acid sequestrants. PMID- 21291717 TI - A case report of myopathy from consumption of red yeast rice. PMID- 21291718 TI - Interrupting bile-acid handling and lipid and glucose control: Effects of colesevelam on glucose levels. AB - The digestive tract plays a key role in lipid metabolism and in cardiovascular risk through the physiology of bile acids on lipid absorption, enterohepatic recycling of bile acids, and cholesterol oxidation in synthesis of bile acids. Recent evidence associates the activation of farnesoid X receptor by bile acids with alterations in high-density lipoprotein cholesterol, triglyceride metabolism, and glucose metabolism. Bile-acid sequestrants augment cholesterol excretion via enhanced conversion to bile acids to lower low-density lipoprotein cholesterol. Several recent studies have demonstrated a role for the bile-acid sequestrant colesevelam hydrochloride in improving glycemic control as well as lipid profiles in subjects with type 2 diabetes. This work reviews the mechanisms of action of colesevelam hydrochloride in interrupting bile acid reabsorption and in lipid transport and glucose control. PMID- 21291719 TI - Clinical commentary: Reaching new targets in monotherapy and combination therapy. AB - Cardiovascular disease remains the most common cause of death in the United States. There has, however, been a decline in the age-adjusted death rate for coronary heart disease. This decline may be due, in part, to more aggressive treatment guidelines for treating cardiovascular risk factors, such as hypertension, diabetes, and dyslipidemia. The 2004 update to the National Cholesterol Education Program guidelines have recommended lower low-density lipoprotein cholesterol goals in high-risk patients. Based on the new targets for low-density lipoprotein cholesterol, clinicians will need more efficacious lipid lowering therapies and improved options for combination therapy. Statin and statin-based combinations have been the mainstays of therapy during the last several years, and as statin utilization increases in the United States, more high-risk patients become exposed to potential statin intolerance. This commentary reviews statin-sparing combinations and use of cholesterol-absorption inhibitors. PMID- 21291720 TI - Dietary agents that target gastrointestinal and hepatic handling of bile acids and cholesterol. AB - Several food components have been demonstrated to exhibit cholesterol-lowering properties by interfering with cholesterol absorption and bile-acid trafficking. Such components include stearic acid, plant sterols, soluble fiber, and soy protein. Among saturated fatty acids, stearic acid is unique in its ability to reduce circulatory low-density lipoprotein cholesterol levels. This action is accompanied by an observed suppression in cholesterol absorption, an effect seen repeatedly in animal and human studies. Proposed mechanisms include micellar exclusion of cholesterol by this high melting point fatty acid, as well as the ability of stearate to alter the biliary ratios of primary to secondary bile acids, leading to a reduction in hydrophobicity index and lower overall solubility of sterols in micelles. Another dietary ingredient that interferes with absorption of sterols is soy protein, in which studies in animals and humans have identified that compared to casein, consumption of soy protein reduces intestinal absorption of cholesterol while enhancing fecal cholesterol excretion. Considerable investigation using free amino acid mixtures mirroring the composition of soy versus animal proteins has determined that co-existing agents other than soy's amino acid pattern are likely responsible for the inhibitory action of soy protein on sterol uptake. Recently, it has been shown that hydrolysates of soy protein appear to be effective in reducing sterol absorption; these are now being targeted as the possible factor responsible for the overall effect of this dietary ingredient. Plant sterols appear to impact absorption of sterols through several mechanisms, including competition with cholesterol for incorporation into micelles, co-crystallization with cholesterol to form insoluble crystals, interaction with digestive enzymes, and inhibition of cholesterol transporter proteins. Clinical trials attest to plant sterols lowering cholesterol absorption by 20% to 40%, an extent beyond which cholesterogenesis can compensate to restore normal circulatory cholesterol levels. As such, 2 g/day of plant sterols effectively lowers low-density lipoprotein cholesterol by 8% to 12%. Dietary soluble fiber represents another means of reducing intestinal cholesterol uptake, in part through enhanced bile acid clearance through the gut. Pectin, beta-glucans, fructans, and gums have been identified as agents that can work through the production of a viscous matrix that hinders movement of cholesterol and bile acids into micelles as well as the subsequent uptake of micelles into the enterocyte. Additional work on design of novel fibers that impede sterol absorption is warranted. In summary, a number of novel dietary factors exist that contribute to heart disease risk reduction via mechanisms that involve cholesterol absorption inhibition and/or biliary pathway perturbation. PMID- 21291721 TI - From the Editor-in-Chief. PMID- 21291722 TI - News from the national lipid association. PMID- 21291723 TI - Male hypogonadism: The unrecognized cardiovascular risk factor. AB - Normal levels of male sex hormones are essential to men's health. Many studies demonstrate that hypogonadal men are at higher risk for developing a host of metabolic derangements, including dyslipidemia, type 2 diabetes mellitus, obesity, and hypertension. We examined the most recent studies supporting this notion of hypogonadism as a cardiac risk factor by reviewing all relevant PubMed data. Most studies showed an increase in metabolic disorders and cardiac events in hypogonadal men compared to their eugonadal counterparts. Mechanisms explaining this increased risk include adverse cytokine profiles produced by excess adipose tissue, abnormal lipid metabolism by understimulated hormone sensitive lipase, and abnormal cellular respiration leading to insulin resistance. In contrast, some studies have not demonstrated such an increased cardiac risk. Conflicting data between studies is expected, given the complexity of testosterone and its metabolic effects. Additionally, the interaction of testosterone with the androgen receptor differs based on an individual genome. Hypogonadism will affect individual men differently because of this genomic variance. The literature points toward true hypogonadism as a major cardiac risk factor. Men at risk of being hypogonadal should be screened and brought back to eugonadism with hormone replacement. PMID- 21291724 TI - Comparison of the efficacy and safety of a combination tablet of niacin extended release and simvastatin with simvastatin 80 mg monotherapy: the SEACOAST II (high dose) study. AB - BACKGROUND: The number of patients with multiple lipid abnormalities is increasing. Lipid treatment guidelines are established for low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non HDL-C). The importance of treating HDL-C and triglycerides is gaining recognition. OBJECTIVE: To determine, in patients who had been treated previously with simvastatin 40 mg/day, the efficacy, safety, and tolerability of two regimens of a combination of proprietary niacin, extended-release core, coated with 40 mg/day simvastatin (NER/S), compared to 80 mg/day simvastatin monotherapy (S80). METHODS: High-risk patients (n = 343) with dyslipidemia were treated for 24 weeks with NER/S (1000/40 mg/day or 2000/40 mg/day) or S80. RESULTS: Median percentage change from baseline to week 24 in non-HDL-C in either NER/S group was noninferior to S80 (-11.3%, -17.1%, and -10.1%, respectively). Changes in LDL-C were comparable (-8.6%, -11.6%, and -12.7%, respectively). Doubling the dose of simvastatin (S80) did not alter HDL-C, triglycerides, or lipoprotein(a); however, both NER/S doses resulted in significant improvements in all three parameters (+21.9%, -31.8%, and -21.0%, respectively, for NER/S 2000/40 mg/day). The safety of NER/S was consistent with the safety profile of each individual component. Treatment with both doses of NER/S was well tolerated; 59% of patients experienced flushing, 78% of flushing was mild or moderate in intensity, 49% of those who flushed during dose titration did not flush during weeks 13 to 24, and only 4.6% of patients discontinued because of flushing. CONCLUSION: NER/S provides similar reductions in non-HDL-C and LDL-C compared to doubling the simvastatin dose to 80 mg; however, only NER/S resulted in improvements in HDL-C, triglycerides, and lipoprotein(a). PMID- 21291725 TI - Effect of ezetimibe/simvastatin versus atorvastatin or rosuvastatin on modifying lipid profiles in patients with diabetes, metabolic syndrome, or neither: Results of two subgroup analyses. AB - BACKGROUND: Patients with diabetes mellitus (DM) and metabolic syndrome (MS) are at increased risk of developing coronary heart disease. OBJECTIVE: To compare the effects of ezetimibe/simvastatin (E/S) combination therapy, atorvastatin, and rosuvastatin in patients with DM, MS without DM, or neither disease. METHODS: Subgroup analysis of data from two 6-week, randomized, double-blind trials comparing E/S 10/10, 10/20, 10/40, or 10/80 mg with either atorvastatin 10, 20, 40, or 80 mg (Study 1), or rosuvastatin 10, 20, or 40 mg (Study 2). Treatments were compared by pooling across all doses for effects on low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), non-HDL-C, apolipoprotein B (ApoB), LDL-C:HDL-C, TC:HDL-C, and LDL-C goal attainment. RESULTS: E/S provided greater improvements than atorvastatin or rosuvastatin in LDL-C, TC, HDL-C (vs atorvastatin only), non-HDL C, LDL-C:HDL-C, TC:HDL-C, and ApoB in all disease subgroups. There were no interactions of treatment by disease subgroup for these parameters, indicating a consistent treatment difference favoring E/S effect across the disease subgroups. A greater percentage of patients receiving E/S than atorvastatin or rosuvastatin attained their individual National Cholesterol Education Program Adult Treatment Panel III LDL-C goals, LDL-C <100 mg/dL, LDL-C <70 mg/dL, and non-HDL-C goals regardless of subgroup. All treatments were well-tolerated, with generally similar adverse experience rates. CONCLUSIONS: Overall, E/S generally provided greater efficacy than either atorvastatin or rosuvastatin that was consistent across the subgroups of patients with DM, MS, or neither, in agreement with the results from the full study cohorts. PMID- 21291726 TI - A pilot study in the efficacy and safety of gemfibrozil in a pediatric population. AB - BACKGROUND: Gemfibrozil reduces plasma triglycerides and raises high-density lipoprotein cholesterol (HDL-C) in adults and also reduces the incidence of cardiovascular endpoints in adults. Its efficacy in improving lipid abnormalities has not been evaluated in children. OBJECTIVE: Our purpose was to investigate whether gemfibrozil would lower triglycerides and raise HDL-C with minimal adverse effects in a pediatric population with metabolic syndrome. METHODS: We conducted a retrospective study of 47 pediatric patients with metabolic syndrome who started gemfibrozil treatment, 1200 mg/day because of failure or lack of interest in therapeutic lifestyle changes. Eligibility required patients to be younger than 21 years of age, and have pretreatment and on-treatment fasting lipid profiles. Data recorded included age at start of treatment, blood pressure, body mass index, waist circumference, percent body fat, total plasma cholesterol, HDL, low-density lipoprotein, triglycerides, alanine aminotransferase, and aspartate aminotransferase. Treatment duration was elapsed time between starting gemfibrozil and the last clinic visit. RESULTS: Average age of the study cohort was 14 years and mean duration on medication was 249 days. Those patients who had pretreatment and on-treatment plasma lipid data (33 of 47) were included in an analysis for efficacy. All 47 patients were monitored for safety. Mean triglycerides decreased by 57%: 426 (standard error of mean = 33.6) to 184 mg/dL (standard error of mean = 19) (P < 0.0001). Mean HDL increased by 20%: 35 to 42 mg/dL (P < 0.001). Body composition changes were insignificant, indicating that the lipid changes can be attributed to gemfibrozil. Two of forty-seven patients reported muscle pain from the drug, one of whom was considered to have had a possible adverse effect from the medication as indicated by muscle pain. CONCLUSION: Gemfibrozil significantly lowers triglycerides and raises HDL with reasonable safety in a pediatric population with metabolic syndrome. PMID- 21291727 TI - From the Editor-in-Chief. PMID- 21291728 TI - News from the national lipid association. PMID- 21291729 TI - Overview: Pediatric lipid disorders. PMID- 21291730 TI - Coronary heart disease risk factors and atherosclerosis in young people. AB - Atherosclerosis begins in childhood or adolescence and progresses during the young adult years to cause clinical coronary heart disease (CHD) in middle-aged and older individuals. This article reviews evidence regarding the association of the major established CHD risk factors with atherosclerosis in adolescents and young adults, with emphasis on the findings of the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study. Age, non-high-density lipoprotein cholesterol concentration, smoking, hypertension, obesity, and hyperglycemia are positively associated with atherosclerotic lesions, whereas female gender and high-density lipoprotein cholesterol concentration are negatively associated with lesions. The PDAY study developed a risk score that provides a weighted summary of the risk factor effects on advanced atherosclerosis. Although developed to predict advanced atherosclerotic lesions, the risk score is also associated with all stages of lesion severity, including the transition from normal tissue to the earliest anatomically detectable lesion. Application of the PDAY risk score to data from longitudinal studies of risk factors in young adults shows that early measurement of risk factors predicts atherosclerosis assessed noninvasively up to 15 years later, and that subsequent change in risk score during the 15-year interval also predicts atherosclerosis. These findings provide strong support for maintaining a low lifetime risk and for focusing on preventing atherosclerosis as the most effective way to prevent CHD. Risk-factor control beginning in the late teenage years will retard development of the earliest stage of atherosclerosis and its progression, and will reduce or delay occurrence of CHD. PMID- 21291731 TI - Lipid metabolism in children and adolescents: Impact on vascular biology. AB - Age remains one of the strongest risk factors for atherosclerotic disease, but the protection conferred by youth can be eroded by cardiovascular risk factors such as dyslipidemia. Elevated atherogenic lipoproteins and inadequate reverse cholesterol transport contribute to an inflammatory response in the vascular wall that promotes atheroma formation. The focus of this review is on the hepatic lipid triage that determines the balance of atherogenic and atheroprotective lipoproteins. Under the continuous influence of energy intake, level of insulin sensitivity, and circulating free fatty acids, the dynamic hepatic processing of lipoproteins is subject to global metabolic transcriptional regulation by the family of lipid-sensing peroxisome proliferator-activated receptors. The endogenous activation of gene networks under the control of these receptors may play an underappreciated role in maintaining vascular health in children by mediating energy metabolism, lipid storage, and transport, as well as innate immunity. Multiple independent lines of evidence suggest that the progressive dyslipidemia, insulin resistance, vascular dysfunction, and cardiovascular risk associated with age can be either delayed or accelerated as a function of lifestyle choices that either activate or repress these central transcriptional regulators. The implications for pediatric lipid metabolism and vascular biology are considerable. PMID- 21291732 TI - Elevated atherogenic lipoproteins in childhood: Risk, prevention, and treatment. AB - Elevated low-density lipoprotein cholesterol (LDL-C) level in childhood is an increasing problem, mainly due to a rising prevalence secondary to the childhood obesity epidemic and better recognition and screening. Vascular changes and impaired endothelial function associated with elevated LDL-C are apparent even in early childhood. Secondary adiposity-related cases are at higher risk due to the clustering of risk factors besides overweight, such as the atherogenic lipid triad, change in the atherogenic properties of the LDL-C particle itself, and the presence of insulin resistance. Prevention should focus on maintaining a healthy lifestyle, including a restricted fat and cholesterol diet, encouraging physical activity, and decreasing sedentary pursuits to maintain an appropriate weight in children. For children and adolescents found to have elevated LDL-C, management should focus on the pursuit of a healthy lifestyle mirroring that for prevention for at least 6 months. Additional dietary therapy, such as plant stanol and sterol esters, have also been shown to modestly reduce LDL-C levels. If the adoption of a healthy lifestyle is not sufficient to reduce LDL-C, lipid-lowering drugs should be considered in selected patients. Current drugs of choice are statins and potentially ezetimibe. Long-term treatment with statins has been shown to markedly reduce carotid intima-media thickness in children and adolescents, particularly when started early. Current evidence supports early and efficient treatment for affected children. PMID- 21291733 TI - Metabolic syndrome and dyslipidemia in youth. AB - Obesity is a well-known risk factor for metabolic syndrome. Although the cause or causes of metabolic syndrome are debated, insulin resistance, dyslipidemia, and hypertension are increasingly recognized in children and adolescents, especially those who are overweight or obese. Although adoption of a healthy lifestyle early in life offers the best long-term solution, many children and adolescents are currently at risk for future cardiovascular disease. Although long-term outcome data are lacking, the dyslipidemic triad commonly seen in youth with metabolic syndrome (elevated triglycerides, low high-density lipoprotein, and small dense low-density lipoprotein) is likely to significantly contribute to future vascular disease. Surrogate markers (carotid intima-media thickness and flow-mediated vasodilatation) for the precursors of cardiovascular disease are increased in obese youth, consistent with early vascular damage. In this work, we review the features of metabolic syndrome in children and adolescents, including age- and gender-specific norms for lipid values. Diagnostic criteria and modifications of screening guidelines unique to youth are discussed. Although recommendations for lifestyle modification are suggested for all, many youth at high risk of future cardiovascular risk may need more aggressive medical interventions to improve insulin sensitivity, achieve a less atherogenic lipid profile, and lower blood pressure. PMID- 21291734 TI - Societal aspects in the dietary management of childhood hyperlipidemia. AB - Pediatric hyperlipidemias increasingly require dietary management of overweight and obesity for resolution. Dietary management of inappropriate weight gain may be outside of normal pediatric expertise. This review used scientific statements of expert professional groups, federal program documentation, and selected original articles or opinions to survey dietary techniques and highlight continuing controversies and therapeutic successes. At present, complex societal and environmental factors underlie the current epidemic in pediatric overweight, precluding definitive statements of best practices. Thus, although first generation professional group recommendations are available, clinicians should expect recommendations to change. However, lack of standardized practices to assess the degree and quality of overweight (central versus peripheral adiposity) limit objective determination of therapeutic need and timely referral to nutrition professionals. Dietary management of insulin-resistant, overweight/obese children with dyslipidemias (metabolic syndrome) requires appropriate laboratory diagnostics to ensure that total fat and energy restrictions do not provoke or exacerbate hypertriglyceridemia or liver fat accumulation. Integrated treatment approaches that combine nutrition education, behavioral modification, and individualized diet instruction are showing success. Diet instructions that include practical translation of nutrition principles to daily eating habits are able to bring about substantial dietary change. The role of the school as a significant component of a child's lifestyle is described, as well as consideration of federally mandated feeding programs as a factor in designing effective dietary management strategies for those likely to be at high risk for overweight and dyslipidemias. The need for coordination among families, and health and school professionals to achieve success is emphasized. PMID- 21291735 TI - Exercise-Promoting healthy lifestyles in children and adolescents. AB - Regular physical activity is an important component of a healthy lifestyle in children and adolescents. However, despite the noted short- and long-term health benefits associated with physical activity, monitoring and surveillance studies show that a significant percentage of children and adolescents fail to meet the recommended guideline of 60 minutes or more of moderate-to-vigorous physical activity daily. This review examines key evidence from the public health and health promotion literature on promotion of health-enhancing physical activity in children and adolescents. We describe best practice in three key behavior settings-schools, homes, and health care settings. In school-based settings, it has been shown that physical education programs can be modified to increase the percentage of class time engaged in moderate-to-vigorous physical activity. In the home setting, there is evidence that teaching parents to establish and monitor physical activity goals and provide appropriate rewards for meeting these goals results in gains in physical activity and/or physical fitness. In health care settings, evidence from two studies suggests that physician-based counseling coupled with stage appropriate written materials can be effective among adolescent youth. PMID- 21291736 TI - Promoting healthy lifestyles: Behavior modification and motivational interviewing in the treatment of childhood obesity. AB - Childhood obesity has increased dramatically during the past two decades. The growing incidence of childhood obesity is alarming, given the significant short- and long-term health consequences associated with obesity and the strong tracking of obesity from childhood to adulthood. Lifestyle plays an important role in the development and maintenance of obesity. Behavior modification programs targeting eating, exercise, and diet behaviors continue to be the mainstay for treating obese children. Although family-based behavioral weight management programs have resulted in significant improvements in weight status, maintaining improvements in weight status continues to be a challenge, with many interventions resulting in considerable relapse. Motivational interviewing is one innovative approach, used alone or in conjunction with standard behavioral modification programs, which has been proposed to have the potential to enhance motivation for change and therefore improve long-term treatment outcomes for obese children. A broad literature search using two electronic databases, Medline and PsycINFO, to identify studies that used an intervention with a motivational interviewing component to modify diet and/or physical activity in the prevention or treatment of childhood obesity identified two studies that targeted weight as a primary outcome. The studies reviewed indicate that, although initial findings are encouraging, further research is needed to determine the effectiveness of motivational interviewing for prevention and treatment of childhood obesity. Concerted efforts are clearly needed to elucidate the mechanisms for maintenance of initial treatment gains, as well as the ultimate achievement of more ideal weight once formal treatment ceases. PMID- 21291737 TI - Pediatric dyslipidemias: Prescription medication efficacy and safety. AB - Pharmacologic treatment of patients with severe pediatric dyslipidemias remains problematic and is of significant concern for health care professionals treating these individuals. Issues include selection of appropriate treatment modalities, lack of pediatric indications for some therapies, duration of treatment, and possible adverse effects with early initiation of potentially life-long therapies. The objective of this review is to evaluate the safety and efficacy of the various prescription medications used to treat severe pediatric dyslipidemias, particularly heterozygous familial hypercholesterolemia. A PubMed search was used to identify published literature evaluating safety and efficacy of various pharmacologic interventions in severe pediatric dyslipidemias. In addition, product monographs for various branded and generic products identified in the published literature were reviewed for pediatrics-related information. Clinical trials literature, review articles, and national guidelines provide limited information indicating short-term safety and efficacy of 3-hydroxy-3 methylglutaryl coenzyme A reductase inhibitors, bile acid sequestrants, ezetimibe, fibrates, niacin formulations, and combinations of these agents in pediatric patients. However, no long-term data regarding safety and efficacy are currently available. No long-term risk-benefit data are available for pediatric use of agents used for severe pediatric dyslipidemias, mostly familial hypercholesterolemia. Extended-duration clinical trials and observational data are needed to assess the safety and efficacy of long-term treatment for these patients. PMID- 21291738 TI - From the Editor-in-Chief. PMID- 21291739 TI - News from the national lipid association. PMID- 21291740 TI - Clinical presentation, laboratory values, and coronary heart disease risk in marked high-density lipoprotein-deficiency states. AB - Our purpose is to provide a framework for diagnosing the inherited causes of marked high-density lipoprotein (HDL) deficiency (HDL cholesterol levels <10 mg/dL in the absence of severe hypertriglyceridemia or liver disease) and to provide information about coronary heart disease (CHD) risk for such cases. Published articles in the literature on severe HDL deficiencies were used as sources. If apolipoprotein (Apo) A-I is not present in plasma, then three forms of ApoA-I deficiency, all with premature CHD,and normal low-density lipoprotein (LDL) cholesterol levels have been described: ApoA-I/C-III/A-IV deficiency with fat malabsorption, ApoA-I/C-III deficiency with planar xanthomas, and ApoA-I deficiency with planar and tubero-eruptive xanthomas (pictured in this review for the first time). If ApoA-I is present in plasma at a concentration <10 mg/dL, with LDL cholesterol that is about 50% of normal and mild hypertriglyceridemia, a possible diagnosis is Tangier disease due to mutations at the adenosine triphosphate binding cassette protein A1 (ABCA1) gene locus. These patients may develop premature CHD and peripheral neuropathy, and have evidence of cholesteryl ester-laden macrophages in their liver, spleen, tonsils, and Schwann cells, as well as other tissues. The third form of severe HDL deficiency is characterized by plasma ApoA-I levels <40 mg/dL, moderate hypertriglyceridemia, and decreased LDL cholesterol, and the finding that most of the cholesterol in plasma is in the free rather than the esterified form, due to a deficiency in lecithin:cholesterol acyltransferase activity. These patients have marked corneal opacification and splenomegaly, and are at increased risk of developing renal failure, but have no clear evidence of premature CHD. Marked HDL deficiency has different etiologies and is generally associated with early CHD risk. PMID- 21291741 TI - Clinical and laboratory assessment of cardiovascular risk in children: Guidelines for screening, evaluation, and treatment. AB - The early lesions of atherosclerosis begin in childhood and are related to antecedent cardiovascular disease (CVD) risk factors. Environmental and genetic factors (eg, diet, obesity, exercise, and certain inherited dyslipidemias) influence progression of such lesions. Identification of youth at risk for atherosclerosis includes an integrated assessment of these predisposing factors. Treatment starts with a diet low in total and saturated fat and cholesterol, use of water-soluble fiber, plant stanols and plant sterols, weight control, and exercise. Drug therapy, for example, with inhibitors of hydroxymethylglutaryl-CoA reductase, bile acid sequestrants, and cholesterol absorption inhibitors, can be considered in those with a positive family history of premature CVD and low density lipoprotein cholesterol >160 mg/dL after dietary and hygienic measures. Candidates for drug therapy often include those with familial hypercholesterolemia, familial combined hyperlipidemia, the metabolic syndrome, polycystic ovarian syndrome, type 1 diabetes, and the nephrotic syndrome. Such dietary and drug therapy appears safe and efficacious. Early identification and treatment of youth with CVD risk factors and dyslipidemia are likely to retard the atherosclerotic process. Optimal detection and treatment of high-risk children either from the general population or from families with premature CVD will require a comprehensive universal screening and evaluation program. PMID- 21291742 TI - The importance of non-HDL cholesterol reporting in lipid management. AB - Plasma levels of lipids and lipoproteins are essential to the management of lipid disorders by generalists and by practitioners of the emerging specialty of clinical lipidology. The routine lipid panel consists of total cholesterol, low density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. Several additional lipid parameters are emerging as potentially valuable adjuncts to the standard panel, including measurements of apolipoproteins and LDL particle size and concentration, but most of these serve mainly as research tools at present. One major exception is non-HDL-C, which is readily available for routine clinical use. This review outlines some of the numerous research studies that clearly establish the clinical utility and even preeminence of non-HDL-C as a comprehensive measure of atherogenic lipoproteins. Non-HDL-C was highlighted as a key secondary goal of therapy several years ago in the National Cholesterol Education Program Adult Treatment Panel III national lipid treatment guidelines and recently was further emphasized as a major goal of therapy in the consensus guidelines for lipoprotein management in patients with cardiometabolic risk from the American Diabetes Association and the American College of Cardiology. Non-HDL-C is superior to LDL-C for the prediction of cardiovascular events and has many other compelling advantages over LDL-C and other traditional lipid parameters. Importantly, it can be calculated directly from values in routine lipid panels, at no added expense. It is our opinion that non-HDL-C should be reported on all routine lipid profiles and used regularly in the management of dyslipidemia for optimal prevention of atherosclerosis and cardiovascular disease. PMID- 21291743 TI - Plasma lipids in Nigerians with systemic arterial hypertension. AB - BACKGROUND: In a nationwide survey of Nigeria, residents of Kano were shown to have the highest prevalence of hypertension and the highest levels of plasma cholesterol. Because hypertension and high cholesterol together markedly increase the risk for cardiovascular disease, we examined lipid profiles among hypertensives and nonhypertensives in Kano. To determine the extent to which there were differences in lipid profiles based on therapy for blood pressure, we created three strata for comparison. METHODS: The study was conducted at Aminu Kano Teaching Hospital, Kano, Nigeria. Lipid levels were examined among randomly selected hypertensives on antihypertensive regimens (n = 70), treatment-naive hypertensives (n = 70), and normotensive individuals (n = 70) matched for age and gender. Overall mean age for hypertensives was 50.5 +/- 11.9 years, and 54.3% were female. For the control group, mean age was 49.3 +/- 12.9 years, and 55.7% were female. RESULTS: Mean total cholesterol of the hypertensives on therapy (group 1) was 5.69 +/- 1.19 mmol/L. Total cholesterol was significantly higher than levels in the treatment-naive hypertensives (group 2) (5.24 +/- 0.76 mmol/L; P = 0.01) and the controls (group 3) (4.91 +/- 0.72 mmol/L; P = 0.000). Significant differences were also evident between groups for low-density lipoprotein (LDL) cholesterol. For high-density lipoprotein (HDL) cholesterol, the difference between the hypertensives on therapy and the treatment-naive was not significant. Difference in this index between each hypertensive group and control was significant. The difference between groups for triglycerides followed the same pattern as HDL cholesterol. Increased total cholesterol (>6.5 mmol/L) was found to be 20%, 4.4%, and 1.4% in the hypertensive on therapy, treatment naive hypertensive, and control groups, respectively. CONCLUSION: High levels of total and LDL cholesterol were more prevalent in treated versus untreated hypertensives and normotensive individuals, suggesting co-occurrence of two important risk factors for cardiovascular disease that is not ameliorated by treatment for hypertension. PMID- 21291744 TI - Analysis of 6-month effect of orlistat administration, alone or in combination with fenofibrate, on triglyceride-rich lipoprotein metabolism in overweight and obese patients with metabolic syndrome. AB - BACKGROUND: Orlistat significantly reduced serum triglycerides (TG) in most clinical trials. Orlistat-induced TG reduction has not been studied to determine the factors contributing to TG alterations in clinical settings. OBJECTIVE: We examined the factors influencing TG reduction during orlistat administration, alone or in combination with fenofibrate, and we investigated the effects of these treatments on apolipoprotein C-II (ApoC-II) and C-III (ApoC-III) levels. METHODS: Patients with the metabolic syndrome were randomly allocated to receive orlistat 120 mg three times daily (n = 28, O group), micronized fenofibrate 200 mg/day (n = 28, F group), or both (n = 27, OF group) for 6 months. Plasma ApoC-II and ApoC-III were determined by an immunoturbidimetric assay. RESULTS: In the O group, we observed reductions of plasma ApoC-III (P < 0.05) and ApoC-II (P = NS) levels. Fenofibrate administration significantly reduced concentrations of ApoC II and ApoC-III, whereas the combination of orlistat and fenofibrate had an additive effect on these apolipoproteins. There were significant in-group reductions in serum TG levels in all treatment groups. Multivariate analysis showed that in O group's baseline TG levels were independently positively correlated, whereas the baseline ApoC-II levels were negatively correlated with TG-lowering. In the F group, baseline TG levels and ApoC-III reduction were significantly and independently correlated with TG reduction. OF group's baseline TG levels and ApoC-III reduction were independently positively correlated and baseline ApoC-II levels were negatively correlated with TG-lowering. CONCLUSIONS: Orlistat-mediated TG-lowering is independently associated with baseline TG and ApoC-II levels. When orlistat is combined with fenofibrate, ApoC-III reduction is another independent contributor to TG alterations. PMID- 21291745 TI - Flushing and the HDL-C response to extended-release niacin. AB - BACKGROUND: Several lines of evidence suggest that a linkage between niacin efficacy and flushing is plausible. OBJECTIVE: To examine the relationship between niacin-induced flushing and clinical endpoints among participants of the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2 study. METHODS: Seventy-seven subjects were randomized to extended-release niacin (1 g/day) and completed the 12-month endpoint assessment of ARBITER 2. The relationships between self-reported flushing and changes in high-density lipoprotein cholesterol (HDL-C) and change in carotid intima-media thickness (CIMT) at 12 months were evaluated. RESULTS: Flushing was reported by 53 subjects (68.8%) over 12 months. Mean increases in HDL-C at 12 months were significantly greater among subjects with flushing versus those without flushing (7.3 +/- 6.6 vs 4.0 +/- 6.9 mg/dL; P < 0.05). On multivariate analysis, HDL-C increase was significantly associated with self-reported flushing, controlling for age, gender, diabetes, baseline HDL-C and triglycerides, aspirin use, and medication adherence (P = 0.019). There was a nonsignificant trend for less progression of CIMT among subjects with flushing (0.011 +/- 0.012 vs 0.033 +/- 0.026 mm; P = 0.38). Medication adherence assessed by pill counts was high and was similar among those with (90%) and without (92%) flushing. CONCLUSION: In the ARBITER 2 trial, niacin-induced flushing was independently associated with a greater HDL-C response and with a directional trend for slowed CIMT progression. PMID- 21291746 TI - High levels of urinary F2-isoprostanes predict cardiovascular mortality in postmenopausal women. AB - BACKGROUND: F2-isoprostanes are prostaglandin-like compounds formed via arachidonic acid oxidation during oxidative stress. OBJECTIVE: To study the relation between urinary concentrations of 8-iso-prostaglandin F2alpha (8-iso PGF2alpha) and mortality due to cardiovascular disease (CVD) in a nested case cohort design. METHODS: Follow-up duration of this prospective study among postmenopausal women was 18 years. Cases included 141 women who died of coronary heart disease and 109 women who died of stroke, whereas controls were a random cohort sample of 142 women. The concentration of 8-iso PGF2alpha was determined with liquid chromatography/tandem mass spectrometry in urine samples collected at baseline. RESULTS: Smokers had 34.8% higher urinary 8-iso PGF2alpha concentrations than nonsmokers (P < 0.001). High levels of urinary 8-iso PGF2alpha were associated with increased incidence of fatal CVD. Women who were in the highest quartile of urinary 8-iso PGF2alpha levels had, independently of age, an odds ratio of 1.8 (95% confidence interval, 1.1-3.1, P < 0.05) for CVD mortality. Further adjustment by systolic blood pressure, history of CVD, diabetes, smoking, and body mass index did not attenuate this association. CONCLUSION: Women with high levels of urinary 8-iso PGF2alpha had an 80% increased risk of dying of coronary heart disease or stroke, supporting involvement of oxidative stress in the pathophysiology of cardiovascular disease. PMID- 21291747 TI - Point: Statins, plant sterol absorption, and increased coronary risk. PMID- 21291748 TI - Counterpoint: Sorting wheat from chaff. PMID- 21291750 TI - Closing comment. PMID- 21291749 TI - Comment from the editor. PMID- 21291751 TI - Rebuttal to counterpoint. PMID- 21291752 TI - Responses of authors to the arguments made in the point and counterpoint. PMID- 21291753 TI - From the Editor-in-Chief. PMID- 21291754 TI - News from the national lipid association. PMID- 21291755 TI - A Commentary on the implications of the ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) Trial: Should ezetimibe move to the "Back of the Line" as a therapy for dyslipidemia? PMID- 21291756 TI - Chronic kidney disease as a cardiovascular risk state and considerations for the use of statins. AB - Chronic kidney disease (CKD) creates one of the highest risk atherosclerotic states that can occur in human beings. The use of 3-hydroxy-3-methylglutaryl coenzyme reductase inhibitors (statins) has gained widespread acceptance in the general population for the purposes of lowering low-density lipoprotein cholesterol (LDL-C) and reducing the future risks of myocardial infarction, stroke, and cardiac death. In patients with CKD, the balance of benefits and risks of statins appears to be different than that in the general population. Reductions in LDL-C with statins may be associated with a reduced progression of CKD. Importantly, recent studies suggest statins are associated with a reduction in rates of acute kidney injury, mediated by ischemic insults and oxidative stress, after cardiac surgery and exposure to iodinated contrast. A reduction in cardiovascular events with LDL-C reduction in CKD and dialysis patients is yet to be proven. In addition, studies suggest that there are higher adverse drug effects with statins in CKD. This work will address the benefits and risks of this important treatment option for the growing population of patients with CKD, who have not undergone renal transplantation, and are at very high risk of cardiovascular events. PMID- 21291757 TI - Ezetimibe-related myopathy: A systematic review. AB - Ezetimibe is a synthetic 2-azetidinone that inhibits the absorption of sterols, including cholesterol, in the intestine. It is used as monotherapy or in combination with statins to reduce low-density lipoprotein cholesterol (LDL-C). Although extremely well-tolerated, there are reports of myopathy associated with ezetimibe. We performed a PubMed search through April 2008 to identify English language articles examining ezetimibe safety as monotherapy or in combination with other lipid-lowering agents. The incidence of musculoskeletal disorders in clinical trials using ezetimibe alone or in combination with statins is identical to placebo or the statin alone, respectively. We identified only six case reports of possible ezetimibe-associated myopathy. We concluded that ezetimibe neither produces nor exacerbates statin myopathy except, possibly, in rare cases. PMID- 21291758 TI - Optimal management of lipids in diabetes and metabolic syndrome. AB - Patients with diabetes or metabolic syndrome frequently have higher triglycerides, lower high-density lipoprotein (HDL) cholesterol, and more particles containing apolipoprotein B (ApoB); this combination contributes significantly to their cardiovascular risk. Optimal management of dyslipidemia and increased atherosclerotic risk requires a fundamental understanding of diabetic dyslipidemia, the clinical evidence for different interventional strategies, and the potential benefit of achieving therapeutic targets. For this review, we considered guidelines, recent reviews, and clinical trial results. The features of dyslipidemia in type 2 diabetes and the metabolic syndrome are linked metabolically and are related to central adiposity and insulin resistance. Levels of ApoB and HDL cholesterol are particularly important markers of risk. Guidelines broadly agree that low-density lipoprotein (LDL) cholesterol should be reduced below population average levels. Additional or secondary strategies in patients with diabetes or the metabolic syndrome are to decrease non-HDL cholesterol, ApoB and/or LDL particle concentration, to increase HDL cholesterol, and to reduce triglycerides. Lifestyle changes and statins are the bedrock of treatment, although second-line treatment using fibrates or niacin will likely benefit many patients with residual risk. Ezetimibe, too, has a favorable effect on lipid profile and inflammatory biomarkers of risk. Dyslipidemia in type 2 diabetes and metabolic syndrome has a distinct profile, suggesting the need for a tailored therapy that targets the key features of lowered HDL cholesterol and raised triglycerides, in addition to the primary antiatherogenic strategy of lowering ApoB-containing lipoproteins, such as LDL. With the prominent failure of some recent intervention trials, new therapeutic strategies-particularly safe and effective means to raise HDL-are needed to manage dyslipidemia in this high-risk population. PMID- 21291759 TI - Achieving optimal lipid values in patients with dyslipidemia is associated with reduced risk of cardiovascular events. AB - BACKGROUND: Cardiovascular (CV) event risk is significantly lower in patients with combined low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) at desired levels versus those without lower levels. However, this has not been investigated relative to specific patterns of baseline lipid abnormalities. OBJECTIVE: To evaluate the association between desired combined lipid value achievement and risk of CV events in patients with different baseline lipid profiles. METHODS: A retrospective managed care database analysis among treatment-naive adults with elevated CV event risk, >=12 months follow-up, and full lipid panel from January 1, 2001 to December 31, 2001 plus >=1 panel before a CV event or study end. Patients were stratified into three baseline cohorts: isolated high LDL-C (Cohort 1), high LDL-C + low HDL-C or high TG (Cohort 2), and high LDL-C, low HDL-C, and high TG (Cohort 3). CV event risk stratified by combined desired lipid value achievement was assessed in each cohort. RESULTS: Achievement of combined desired lipid values/median days to achievement was 29% in 385 days (Cohort 1), 11% in 413 days (Cohort 2), and 7% in 505 days (Cohort 3). Achievement of combined desired lipid values was associated with an adjusted 25%-46% lower CV event risk in Cohort 1 (hazards ratio, 0.75; 95% confidence interval 0.65-0.87), Cohort 2 (hazards ratio, 0.54; 95% confidence interval 0.43-0.67), and Cohort 3 (hazard ratio, 0.54; 95% confidence interval 0.37-0.78). CONCLUSION: Patients with combined desired lipid values had lower risk of CV events versus those without such values. The risk reduction was greatest among patients with multiple lipid abnormalities, suggesting a potential benefit of interventions targeting low HDL C and/or high TG in addition to high LDL-C. PMID- 21291760 TI - Increasing lipid adherence to goal. AB - BACKGROUND: In April 2004, the National Cholesterol Education Program Adult Treatment Panel III Guidelines for management of high cholesterol encouraged even lower levels of low-density lipoprotein (LDL) than previous guidelines for high and very high risk groups. Assessing patients' risk factors to determine LDL goals is the first step to help guide therapy. OBJECTIVE: To determine whether the use of the Mobile Lipid Clinic Personal Digital Assistant (PDA) Calculator during office visits will increase the number of patients achieving their LDL goal compared to using electronic medical records or conventional methods. METHODS: Four family medicine residency programs affiliated with the Northeastern Ohio Network participated with each site using a different method. The PDA site used the Mobile Lipid Clinic Calculator, the second site used electronic health records (EHRs), the control site used usual care methods, and the transition site moved from paper charts to EHRs during the study. In 2006, baseline chart reviews were conducted to randomly enroll 100 patients per site (aged 40-75 years) with LDL levels at least 10% above goal. In 2007, follow-up chart reviews were conducted on the same patients to determine reductions in LDL and the percent of patients that reached their LDL goals. RESULTS: The percentage reaching their LDL goal and option goal were as follows: PDA site 27% and 12%, EHR site 19% and 3%, control site 4% and 1%, transition site 32% and 12%. Cholesterol-lowering medication usage increased significantly from 38% at baseline to 47% at follow-up (chi(2) = 149.5, P <0.0001). CONCLUSIONS: Using a PDA tool can be just as effective as EHRs in getting patients to their LDL goal and is better than some conventional methods, suggesting the benefit of utilizing technology to improve patient care and health outcomes. PMID- 21291761 TI - Association between apolipoprotein E polymorphism, lipids, and coronary artery disease in Tunisian type 2 diabetes. AB - BACKGROUND: The relationship between apolipoprotein E (ApoE) polymorphism, fasting lipid parameters, and coronary artery disease (CAD) is controversial. METHODS: We studied this relationship, for the first time, in Tunisian type 2 diabetic patients. The studied population comprised 157 type 2 diabetic patients (145 of them were not on any lipid-lowering drugs). Fasting lipids were measured by enzymatic methods and ApoE genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: Our results showed that the alleles E2, E3, and E4 were found in 4%, 88%, and 8% of patients, respectively. In the total type 2 diabetic population, no association was found between ApoE polymorphism, lipid parameters, and CAD. However, the E4 allele was associated with elevated low-density lipoprotein cholesterol concentration and with CAD in type 2 diabetic men. CONCLUSION: The effect of ApoE polymorphism on CAD is gender-dependent in the Tunisian type 2 diabetic population. ApoE 4 allele may enhance atherogenesis indirectly by a strong effect on low-density lipoprotein cholesterol. PMID- 21291762 TI - Lipid therapy utilization rates in a managed-care mixed dyslipidemia population. AB - BACKGROUND: National clinical treatment guidelines recommend pharmacologic treatment in addition to therapeutic lifestyle modifications in patients with mixed dyslipidemia and multiple risk factors for coronary heart disease (CHD). OBJECTIVES: To evaluate real-world pharmacologic treatment of mixed dyslipidemia patients with cardiovascular disease (CVD) risk factors. METHODS: Commercial health plan members in a large, United States managed-care database with complete lipid panel results (ie, high-density lipoprotein cholesterol [HDL-C], low density lipoprotein cholesterol [LDL-C], total cholesterol [TC], triglycerides [TG]) between January 1, 2006 and December 31, 2006 were included. Mixed dyslipidemia was defined as any two nonoptimal lipid parameters (LDL-C, HDL-C, TG) according to National Cholesterol Education Program/Adult Treatment Panel III guidelines. Subjects were observed for 182 days pre-index to determine CVD risk factors (ie, male aged 45+ years, female 55+ years, CHD history, hypertension, diabetes mellitus). Lipid treatment status 6 months pre- and post-index dates was determined using pharmacy claims for any lipid monotherapy (statin, fibrate, niacin, "other"), or combination therapy (statin + fenofibrate; statin + niacin; statin + other). RESULTS: Lipid treatment increased post-index for all mixed dyslipidemia groups and by total number of risk factors. The increased LDL-C and low HDL-C group had the lowest treatment rates; the group with low HDL-C and elevated TG had the highest. In the latter group, when treated, primarily statin monotherapy (51%) was used post-index; only 26% received niacin or fibrate therapy targeting HDL-C or TG abnormalities. Across all mixed dyslipidemia patients, >30% with three to four CVD risk factors were not treated >=6 months post-index. CONCLUSIONS: In real-world clinical practice, pharmacologic treatment rates increased upon assessment of multiple lipid abnormalities and by total risk factors for CHD. However, mixed dyslipidemia remained undertreated with low rates of niacin and fibrate usage. PMID- 21291763 TI - Effects of a niacin receptor partial agonist, MK-0354, on plasma free fatty acids, lipids, and cutaneous flushing in humans. AB - BACKGROUND: Development of niacin-like agents that favorably affect lipids with an improved flushing profile would be beneficial. OBJECTIVE: To evaluate a niacin receptor partial agonist, MK-0354, in Phase I and II studies. METHODS: The pharmacokinetic/pharmacodynamic effects of single and multiple doses (7 days) of MK-0354 (300-4000 mg) were evaluated in two Phase I studies conducted in healthy men. A Phase II study assessed the effects of MK-0354 2.5 g once daily on lipids during 4 weeks in 66 dyslipidemic patients. RESULTS: MK-0354 single doses up to 4000 mg and multiple doses (7 days) up to 3600 mg produced robust dose-related reductions in free fatty acid (FFA) over 5 hours. Single doses of MK-0354 300 mg and extended release-niacin (Niaspan) 1 g produced comparable reductions in FFA. Suppression of FFA following 7 daily doses of MK-0354 was similar to that after a single dose. In the Phase II study, MK-0354 2.5 g produced little flushing but no clinically meaningful effects on lipids (placebo-adjusted percent change: high density lipoprotein cholesterol, 0.4%, 95% confidence interval -5.2 to 6.0; low density lipoprotein cholesterol, -9.8%, 95% confidence interval -16.8 to -2.7; triglyceride, -5.8%, 95% confidence interval -22.6 to 11.9). CONCLUSION: Treatment with MK-0354 for 7 days resulted in plasma FFA suppression with minimal cutaneous flushing. However, 4 weeks of treatment with MK-0354 failed to produce changes in high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, or triglycerides. PMID- 21291764 TI - Familial hypobetalipoproteinemia due to a novel early stop mutation. AB - BACKGROUND: Familial hypobetalipoproteinemia (FHBL) is a co-dominant disorder associated with low circulating levels of low-density lipoprotein (LDL) cholesterol and apolipoprotein B100 (ApoB). A proband was identified in whom the condition was due to an E110X mutation of APOB, creating a particularly early truncation of ApoB in the region of the molecule necessary for very-low-density lipoprotein (VLDL) assembly. The mutation was also associated with nonalcoholic fatty liver disease. OBJECTIVE: To assess the effect of the mutation on metabolism and the formation of VLDL and LDL subfractions. RESULTS: Both the proband and his son, who had the same mutation, had low LDL cholesterol and decreased ApoB, but an increased small-dense LDL level. Lipoprotein profiles were normal in the proband's sister and grandson, in whom the mutation was absent. In the proband. there was a profoundly diminished rate of production of VLDL-2. VLDL 1 production, however, was relatively preserved and, because of its decreased catabolism, its pool size was increased. Direct formation of intermediate-density lipoprotein (IDL) and LDL was undetectable. Intermediate-density lipoprotein catabolism was greatly increased and its conversion to LDL was increased. The LDL produced was entirely small-dense LDL. High-density lipoprotein cholesterol levels were low, perhaps also related to the relative increase in VLDL-1, which is an avid acceptor of cholesteryl ester. CONCLUSIONS: This novel mutation provides evidence to support the hypothesis that hepatic production of large VLDL 1 leads to the creation of small-dense LDL. PMID- 21291765 TI - Point: Lipoproteins are significant factors in Alzheimer's disease: Dementia is impacted by blood plasma lipoproteins. PMID- 21291766 TI - Counterpoint: Lipoproteins and dementia: Is there compelling evidence to treat Alzheimer's patients with statins? PMID- 21291767 TI - Rebuttal: Lipids and dementia. PMID- 21291768 TI - Closing comment. PMID- 21291769 TI - Acute elevation of triglycerides after initiation of fosamprinavir/ritonavir in an HIV-negative patient with baseline hypertriglyceridemia. PMID- 21291770 TI - Letter to the editor. PMID- 21291772 TI - News from the NLA. PMID- 21291771 TI - From the Editor-in-chief. PMID- 21291773 TI - Plasma lipid profile and lipid peroxidation in beta-thalassemic children. AB - BACKGROUND: Beta-thalassaemic patients who usually have a combination of; chronic hemolytic anemia, iron storage disease, myocarditis, and premature death especially due to heart failure may also have increased oxidation of lipids and abnormal lipoprotein concentrations. OBJECTIVE: To determine plasma lipids, triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and lipid peroxidation product malondialdehyde (MDA) in children with beta-thalassemia and unaffected control children. Relationships with age, gender, hemoglobin, serum iron, and serum ferritin were examined. Children with beta-thalassemia (28 males and 15 females, aged 4 to 18 years) and 31 age- and gender-matched healthy controls were studied. RESULTS: In children with beta-thalassemia, there was an increase in TG, MDA, and the MDA/LDL-C ratio (P = .000) and a decrease in TC, LDL-C, HDL-C, and the LDL-C/ TG ratio (P < .001) compared to unaffected controls. The LDL-C/HDL-C ratio was not different. The MDA/LDL-C ratio was correlated negatively with blood hemoglobin and TC (P < .05 for each), whereas the LDL-C/HDL-C ratio was correlated with age, weight, body mass index, and TC (P < .05, < .05, < .05, and < .01 respectively). CONCLUSION: Despite the derangement in plasma lipid profile in children with beta-thalassemia accompanied by excess lipid peroxidation, the lipoprotein concentrations do not suggest increased risk. The MDA/LDL-C ratio may prove to be a valuable marker for lipid peroxidation. PMID- 21291774 TI - Population variations in atherogenic dyslipidemia: A report from the HeartSCORE and IndiaSCORE Studies. AB - BACKGROUND: Asian Indians and blacks have a higher risk for cardiovascular disease (CVD) events compared to whites. Atherogenic dyslipidemia, comprised of small-dense low-density lipoprotein (LDL), low high-density lipoprotein (HDL) levels, and high triglyceride (TG) levels, constitutes an important risk factor for CVD often seen in the presence of obesity. The contribution of atherogenic dyslipidemia to CVD risk across diverse racial populations is not well established. OBJECTIVE: Our primary aim was to investigate the relationship between race and atherogenic dyslipidemia among whites, blacks, and Asian Indians. A secondary aim was to evaluate the association between obesity and atherogenic dyslipidemia across populations. METHODS: From community-based sampling, 720 whites and 373 blacks underwent evaluation of CVD risk factors, including fasting lipoproteins. An identical protocol was administered to 205 Asian Indians from Chennai, India. Lipid profiles, including those comprising atherogenic dyslipidemia, were compared among populations. RESULTS: The prevalence of small-dense LDL (pattern B) and of TG/HDL ratio >3 was greatest among Asian Indians and smallest among blacks. Compared to whites, the adjusted odds for Indians having a LDL pattern B was 2.06 (P < .001) and TG/HDL ratio >3 was 9.42 (P < .001). The adjusted odds of having LDL pattern B (odds ratio 0.39, P < 0.001) or TG/HDL ratio >3 (odds ratio 0.41, P < .001) was lower in blacks compared to whites. Among Indians, obesity had a weak association with atherogenic dyslipidemia, in contrast to the strong association among whites. CONCLUSIONS: Significant population variations in atherogenic dyslipidemia exist. This may be an important component to explain population differences in cardiovascular risk. PMID- 21291775 TI - Rosuvastatin reduces non-high-density lipoprotein cholesterol and lipoprotein remnants in patients with dysbetalipoproteinemia (Fredrickson type III hyperlipoproteinemia). AB - BACKGROUND: Dysbetalipoproteinemia is an uncommon genetic disorder characterized by accumulation of plasma remnant lipoproteins, severe mixed dyslipidemia, elevated apolipoprotein E levels, accelerated atherosclerosis, and premature cardiovascular disease. OBJECTIVE: To evaluate the efficacy and safety of rosuvastatin in patients with dysbetalipoproteinemia. METHODS: Following a 6-week washout, 32 patients with dysbetalipoproteinemia received rosuvastatin 10 mg, rosuvastatin 20 mg, and pravastatin 40 mg, each for 6 weeks in a randomized, double-blind, three-way crossover design. Patients subsequently entered an 18 week open-label phase in which the rosuvastatin dosage could be increased from 20 mg to a maximum of 40 mg at 6 weekly intervals to reach National Cholesterol Education Program goals for non-high-density lipoprotein cholesterol (non-HDL-C) and optimal triglyceride (TG). Fibrates (except gemfibrozil) could be added if patients were not at goal on rosuvastatin 40 mg. The primary efficacy variable was percent change from baseline in non-HDL-C during the double-blind phase. The prespecified efficacy criterion was for the 95% confidence interval (CI) of non HDL-C to lie entirely below -25% for any rosuvastatin dose. RESULTS: Following drug washout, median total cholesterol was 8.86 mmol/L, non-HDL-C 7.61 mmol/L, and TG 5.69 mmol/L. After 6-week treatment, median change in non-HDL-C was -48.2% (95% CI -56.7% to -45.6%) for rosuvastatin 10 mg, -56.4% (95% CI -61.4% to 48.5%) for rosuvastatin 20 mg, and -35.1% (95% CI -41.6% to -29.6%) for pravastatin 40 mg. Rosuvastatin increased HDL-C and apolipoprotein A-I and substantially reduced total, very low-, intermediate-, and low-density lipoprotein cholesterol and TG, and corresponding apolipoproteins. Efficacy was maintained in the open-label phase, with reduction in non-HDL-C of -61.5%, -62.8% and -65.8% at weeks 24, 30 and 36, respectively. All treatments were well tolerated. CONCLUSION: Rosuvastatin 10 and 20 mg favorably modify the dyslipidemia of patients with dysbetalipoproteinemia. PMID- 21291776 TI - Long-term safety and efficacy of fenofibric acid in combination with statin therapy for the treatment of patients with mixed dyslipidemia. AB - BACKGROUND: Co-administration of a fibrate and statin is an effective treatment option for patients with multiple lipid abnormalities, yet adequate long-term safety and efficacy data are lacking. OBJECTIVE: To evaluate the long-term safety and efficacy of fenofibric acid combined with statins in adults with mixed dyslipidemia. METHODS: Three large, 12-week, phase three, double-blind, randomized, controlled trials evaluated fenofibric acid 135 mg combined with a low- or moderate-dose statin compared to fenofibric acid or statin monotherapy, and a subsequent 52-week open-label extension study evaluated fenofibric acid 135 mg combined with moderate-dose statin (rosuvastatin 20 mg, simvastatin 40 mg, or atorvastatin 40 mg). This prespecified analysis integrated results from these studies to assess the long-term safety and efficacy of combination therapy. RESULTS: Across the controlled studies and the extension study, 2201 patients received at least one dose of fenofibric acid + statin for a median duration of 364 days. The most common adverse events were headache, upper respiratory tract infection, nasopharyngitis, and back pain, with the incidence of all adverse events being similar across all combination therapy treatment groups. Rhabdomyolysis or treatment-related death was not reported in any group. Combination therapy resulted in sustained improvements in multiple lipid parameters, including triglycerides, high-density lipoprotein cholesterol, low density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, total cholesterol, apolipoprotein B, and high-sensitivity C-reactive protein. CONCLUSION: Long-term fenofibric acid + statin combination therapy was generally well tolerated and resulted in comprehensive and sustained improvements in multiple lipid parameters in adults with mixed dyslipidemia. PMID- 21291777 TI - Ezetimibe/simvastatin compared with atorvastatin or rosuvastatin in lowering to specified levels both LDL-C and each of five other emerging risk factors for coronary heart disease: Non-HDL-cholesterol, TC/HDL-C, apolipoprotein B, apo B/apo-A-I, or C-reactive protein. AB - BACKGROUND: Recent evidence suggests that in addition to low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo-B), non-high-density lipoprotein cholesterol (non-HDL-C), some lipoprotein ratios, and C-reactive protein (CRP) are predictive of coronary heart disease (CHD) risk. This post-hoc analysis of two trials comparing single-tablet ezetimibe/simvastatin (EZE/SIMVA) to atorvastatin (ATORVA) or rosuvastatin (ROSUVA) evaluates the proportion of patients attaining LDL-C <70 mg/dL and specific levels of these emerging risk factors. METHODS: These were double-blind, 6-week, parallel group trials of hypercholesterolemic patients randomized to milligram equivalent doses of ATORVA versus EZE 10 mg/SIMVA, or to usual starting, next higher, and maximum doses of ROSUVA versus EZE/SIMVA. This analysis examined the percent of patients in prespecified dose comparisons and overall achievement of LDL-C <70 mg/dL and/or Apo-B <90 mg/dL, total cholesterol (TC)/HDL-C <4.0, or Apo-B/Apo-A-I <0.7 among all treated patients, non-HDL-C <100 mg/dL among patients with baseline triglycerides >=200 mg/dL, or CRP <2.0 mg/L among patients with baseline CRP >=2.0 mg/L. RESULTS: Within each trial, baseline characteristics were similar among groups. At all dose comparisons, significantly more patients receiving EZE/SIMVA reached LDL-C <70 mg/dL and achieved both LDL-C <70 mg/dL and either Apo-B <90 mg/dL, TC/HDL-C <4.0, or Apo-B/Apo-A-I <0.7 (EZE/SIMVA versus ATORVA) compared to ATORVA and ROSUVA. For most dose comparisons, significantly more patients receiving EZE/SIMVA attained both LDL-C <70 mg/dL and either non-HDL-C <100 mg/dL or CRP <2 mg/L compared to ATORVA or ROSUVA. CONCLUSION: The greater efficacy related to changes in blood lipids of EZE/SIMVA compared with both ATORVA and ROSUVA extends to changes in many emerging risk factors. Ultimate clinical implications of these findings still need to be defined. PMID- 21291778 TI - Combination thiazolidinedione and fibrate effect on high-density lipoprotein cholesterol (HDL-C) concentration in a Veterans Affairs patient population. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is a coronary heart disease (CHD) risk equivalent warranting aggressive management of dyslipidemia and tight glycemic control. Recent reports demonstrate a paradoxic decrease in high-density lipoprotein cholesterol (HDL-C) with thiazolidinedione (TZD) and fibrate combination therapy. OBJECTIVE: Evaluate change in HDL-C from start of combination therapy to 1 year and assess the proportion, characteristics, and regimens of patients who developed a >=20% decrease in HDL-C from baseline. METHODS: Patients with T2DM treated concurrently with a combination of TZD and fibrate were identified through retrospective query from a Veterans Affairs medical center database. HDL-C was recorded for 1 year after patients started combination therapy. Logistic regression analysis was performed to determine any predictors of HDL-C change. RESULTS: A total of 322 patients were included in the analysis. There was no significant differences in mean +/- standard deviation HDL C from baseline to end point (36.8 +/- 8.5 to 40.3 +/- 11.8 mg/dL; P = 0.097). There was a subset of patients identified (13%; n = 43) on combination therapy who experienced a >=20% reduction in HDL-C. Of these patients, a decrease in HDL C was more likely to occur with fenofibrate-based regimens (odds ratio 3.08, 95% confidence interval 1.22 to 7.75; P = 0.018). There was a trend toward more of these patients in this subset to have the combination of rosiglitazone and fenofibrate in their profiles (odds ratio 2.82, 95% confidence interval 0.98 to 8.0; P = 0.064). CONCLUSION: Our study demonstrated that a subset of patients with T2DM experienced a paradoxic decrease in HDL-C when taking a fibrate and TZD combination. PMID- 21291779 TI - Concomitant use of statins and CYP3A4 inhibitors in administrative claims and electronic medical records databases. AB - BACKGROUND: Patients may experience increased risk of adverse drug interactions when statins are administered concomitantly with cytochrome P450 3A4 (CYP3A4) inhibitors. OBJECTIVE: To determine patient numbers in routine clinical practice with concomitant exposure to CYP3A4-metabolized statins and CYP3A4 inhibitors and highlight potential risk for adverse drug interaction. METHODS: Exposure to prescription medications over 1 year (2005-2006) was evaluated from patient records: US PharMetrics Integrated Patient-Centric administrative claims database and the US General Electric Medical System (GEMS) database. Rates of concomitant prescribing of statins with CYP3A4 inhibitors (listed in United States of America product labels and all identified potential inhibitors) were examined in the cohort overall, in those aged >=65 years, and in those receiving higher doses of statins. RESULTS: Overall, 951,166 patient records were included (PharMetrics n = 650,825; GEMS, n = 300,341). Of these, 792,081 (83%) patients used a CYP3A4 metabolized statin as opposed to a non-CYP3A4-metabolized statin (17%). Findings from both databases were consistent. Overall, 25-30% of patients given a CYP3A4 metabolized statin were concomitantly exposed to a CYP3A4 inhibitor, including approximately 9% concomitantly exposed to a labeled inhibitor, findings consistent with those in patients aged >=65 years, and patients on higher doses of statins. CONCLUSIONS: Clinicians frequently co-prescribe CYP3A4-metabolized statins with CYP3A4 inhibitors. Physician education regarding the impact of these inhibitors on the metabolism of lovastatin, simvastatin, and atrovastatin is needed. Further studies are also needed to determine whether concomitant administration of a non-CYP3A4-metabolized statin (such as fluvastatin, pravastatin, or rosuvastatin) with a CYP3A4 inhibitor, may reduce adverse event rates in routine clinical practice. PMID- 21291780 TI - From the Editor-in-Chief. PMID- 21291781 TI - News from the national lipid association. PMID- 21291782 TI - Progress report: EMR-based cholesterol management. PMID- 21291783 TI - Not so choppy SEAS. PMID- 21291784 TI - Dyslipidemia in South Asians living in a western community. AB - An increased prevalence of coronary heart disease (CHD) has been well documented in the South Asian population living worldwide. The prevalence of certain traditional CHD risk factors, like diabetes mellitus and tobacco use, have been on the rise in this ethnic group and likely contribute to the increase in CHD prevalence. Still, a disproportionate excess of CHD exists, and this may be linked to novel CHD risk factors. We have reviewed the prevalence of CHD in South Asians and its association to both traditional and novel CHD risk factors. We present a literature review of traditional and novel CHD risk factors, and incorporate the results of a cross-sectional study investigating the prevalence of these factors in a South Asian population residing in the United States with no prior diagnosis of CHD. The total cholesterol (TC) (mean +/- standard deviation) was 193.72 +/- 33.76 mg/dL, high-density lipoprotein (HDL) was 42.20 +/- 12.11 mg/dL, and low-density lipoprotein (LDL) was 124.88 +/- 27.22 mg/dL. The mean triglyceride level was 166.60 mg/dL. The prevalence of elevated TC (>200 mg/dL) was 41.3% and elevated LDL (>130 mg/dL) 40.7%. There was a significant difference between men and women in the prevalence of reduced HDL (<40 mg/dL) (67.3% vs. 49.4%), elevated triglycerides (>130 mg/dL) (56.4 vs. 30.4%), and small-dense LDL particles (53.6% vs. 27.8%). Considerably higher prevalence of novel CHD risk factors has been noted in the South Asian population. The CHD risk may increase significantly when these novel factors co-exist with traditional CHD risk factors. PMID- 21291785 TI - Effects of moderate (MF) versus lower fat (LF) diets on lipids and lipoproteins: a meta-analysis of clinical trials in subjects with and without diabetes. AB - BACKGROUND: Dyslipidemia increases coronary heart disease (CHD) risk and often presents in diabetes, which amplifies risk of CHD. Lower fat (LF) diets increase triglyceride (TG) and decrease high-density lipoprotein cholesterol (HDL-C); moderate fat (MF) diets decrease TG and lower HDL-C less. OBJECTIVE: To quantify the magnitude of lipid and lipoprotein responses to MF versus LF cholesterol lowering weight maintenance diets in subjects with and without diabetes. METHODS: A meta-analysis of 30 controlled-feeding studies (n = 1213 subjects) was conducted to evaluate LF versus MF diets on lipids and lipoproteins in subjects with and without diabetes. RESULTS: In all subjects, MF and LF diets decreased low-density lipoprotein cholesterol (LDL-C) similarly. MF diets decreased HDL-C less versus LF diets. The estimated increase in HDL-C after MF diets versus LF diets was 2.28 mg/dL (95% confidence interval 1.66 to 2.90 mg/dL, P < .0001). MF diets decreased TG, whereas LF diets increased TG. The decrease in TG was -9.36 mg/dL (-12.16 to -6.08 mg/dL, P < .00001) for MF versus LF diets. In subjects with diabetes, there was a similar increase in HDL-C (2.28 mg/dL) versus subjects without diabetes; however, there was a greater reduction in TG (-24.79 mg/dL, P < .05) on the MF diet. Subjects with diabetes had greater reductions in the total cholesterol (TC) to HDL-C ratio (TC:HDL-C) (-0.62, P < .0001) and non-HDL-C ( 5.39 %, P < .06) after MF versus LF diets. CONCLUSIONS: Both men and women had greater estimated reductions (6.37% and 9.34%, respectively) in predicted CHD risk after MF diets compared to LF diets. Moreover, based on greater reductions in TG, the TC:HDL-C ratio and non-HDL-C in subjects with diabetes, the CHD risk reduction would be greater for a MF versus a LF weight maintenance, cholesterol lowering diet. PMID- 21291786 TI - Prescription omega-3 acid ethyl esters plus simvastatin 20 and 80 mg: effects in mixed dyslipidemia. AB - BACKGROUND: Prescription omega-3 acid ethyl esters (P-OM3) plus simvastatin 20 and 40 mg/day improves lipids in subjects with mixed dyslipidemia, but no previous studies have examined P-OM3 with the maximum prescribed dose of simvastatin (80 mg). OBJECTIVE: To assess the effects of P-OM3 + simvastatin 80 mg versus P-OM3 + simvastatin 20 mg or placebo + simvastatin 20 mg on non-high density lipoprotein cholesterol (non-HDL-C) and other lipid concentrations. METHODS: Subjects with mixed dyslipidemia who had completed a 12-week double blind crossover study of simvastatin 20 mg/day + either placebo or P-OM3 4 g/day were enrolled. An analysis (n = 14) was performed following the first six weeks of the extension, during which all subjects received open-label P-OM3 + open label simvastatin 80 mg/day. RESULTS: P-OM3 + simvastatin 80 mg resulted in significantly larger reductions from baseline (P < .05 for all) versus P-OM3 + simvastatin 20 mg and placebo + simvastatin 20 mg, respectively, for non-HDL-C ( 51.0%, -40.8%, -34.9%), low-density lipoprotein cholesterol (-48.0%, -35.5%, 38.0%), total cholesterol (TC) (-42.6%, -31.9%, -27.1%), the TC/HDL-C ratio ( 52.9%, -44.3%, -36.2%), and apolipoprotein B (-42.6%, -32.6%, -30.5%). P-OM3 + simvastatin (80- and 20-mg doses, respectively) resulted in significantly larger changes from baseline (P < .05 for all) versus placebo in very low-density lipoprotein cholesterol (-50.7%, -47.9%, -23.0%), triglycerides (TG; -58.6%, 54.7%, -32.0%), HDL-C (24.5%, 20.7%, 17.9%), and the TG/HDL-C ratio (-66.5%, 62.3%, -42.5%). CONCLUSION: These results suggest non-HDL-C, TG (both 50% to 60%), and HDL-C (~25%) concentrations can be markedly improved by a combination of P-OM3 (4 g/day) and simvastatin (80 mg/day) in subjects with mixed dyslipidemia. PMID- 21291787 TI - Fatty acid composition of HDL phospholipids and coronary artery disease. AB - BACKGROUND: The phospholipid fatty acid content of high-density lipoprotein (HDL) partially reflects that of the diet and has been reported to be associated with several important biological functions that might serve as risk markers for coronary heart disease. OBJECTIVE: To investigate whether fatty acid composition of HDL phospholipids correlates with angiographically documented coronary artery disease (CAD). METHODS: The population included 212 patients who underwent clinically indicated coronary angiography. The patients were classified with significantly diseased arteries (SDA) if one or more coronary arteries had a stenosis >50% and with minimally diseased arteries (MDA) if there was no significant stenosis (<40%) in any artery. The severity of CAD was expressed by the number of affected vessels. The fatty acid composition of HDL phospholipids was determined by gas liquid chromatography. Multivariate analyses were used to test the independence of associations between the presence and severity of CAD as outcome variables and fatty acid composition of HDL phospholipids. RESULTS: Patients with SDA showed significantly lower levels of linoleic acid (P = .041), eicosapentaenoic acid (EPA) (P = .027), and docosahexaenoic acid (DHA) (P = .026) than patients with MDA in univariate analyses. The association of linoleic acid (odds ratio [OR] .90, P < .05), EPA (OR, 0.41, P < .02), and DHA (OR, 0.48, P < .02) remained statistically significant in the multivariate analyses. The content of EPA (beta = -0.23, P < .01) and DHA (beta = -0.17, P < .05) remained inversely significantly associated with the severity of CAD. CONCLUSIONS: This study shows that polyunsaturated fatty acids, including EPA and DHA content of HDL particles, are independently associated with the presence and severity of angiographically documented CAD. PMID- 21291788 TI - Extended-release niacin reduces LDL particle number without changing total LDL cholesterol in patients with stable CAD. AB - BACKGROUND: The importance of the number of circulating low-density lipoprotein (LDL) cholesterol particles, in addition to total LDL level, has been increasingly recognized. The effects of extended-release niacin (ERN) on LDL particle numbers have not been studied. OBJECTIVE: To evaluate ERN's effects on LDL particle numbers. METHODS: Fifty-four patients with stable coronary artery disease (CAD) and well-controlled LDL levels were randomly assigned to 3 months of ERN (1 g/day) or placebo in addition to their baseline medications. Lipoprotein particle number was analyzed by proton nuclear magnetic resonance spectroscopy at baseline and after 3 months. RESULTS: Compared to baseline, the addition of ERN had no significant effect on total LDL cholesterol levels; however, ERN decreased the number of medium and small LDL particles (P < .005). After 3 months, ERN decreased the number of medium and small LDL particles compared to placebo-treated patients (P < .05). ERN raised HDL cholesterol levels by 2.7%, significantly increased the number of large HDL particles (P < .001), and decreased the number of small HDL particles (P = .027) compared to placebo. There were no significant changes in lipid values or particle numbers in the placebo-treated patients. In patients with stable coronary artery disease and well-controlled LDL cholesterol levels, ERN reduced the number of circulating particles of the more atherogenic subtypes of LDL, despite having no effect on total LDL cholesterol levels. ERN also favorably altered the number of HDL particles. CONCLUSION: ERN-induced alterations in lipoprotein particle numbers may contribute to its anti-atherosclerotic effects, and these effects may not be evident from the standard lipid profile. PMID- 21291789 TI - Prevalence of dyslipidemia in normoglycemic subjects with newly diagnosed high blood pressure in Abuja, Nigeria. AB - BACKGROUND: High blood pressure and dyslipidemia additively increases the risk of cardiovascular disease. There is a high prevalence of high blood pressure in Nigeria, but there are little data regarding the prevalence of dyslipidemia in subjects with high blood pressure. OBJECTIVE: In this observational prospective study, we examined the prevalence of dyslipidemia in newly diagnosed normoglycemic subjects with high blood pressure. METHODS: A total of 171 subjects presenting with high blood pressure for the first time in the cardiology and nephrology clinics at the University of Abuja Teaching Hospital were studied. Height, weight, and blood pressure were measured. Total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were determined in fasting plasma. The total cholesterol/HDL-C and non-HDL-C values were calculated. These measures were then classified according to the 2001 report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults. RESULTS: Of the 171 subjects studied, 84 (49%) were male and 87 (51%) were female. Low HDL C was present in 71 (45.8%), elevated LDL-C in 29 (17%), elevated total cholesterol in 19 (11.1%), and elevated triglyceride in 13 (7.6%), whereas eight (4.7%) of the study population had combined elevated total cholesterol and triglyceride. Female subjects had higher total cholesterol and lower HDL-C than male subjects, but these differences were not statistically significant. Obese subjects, compared to the nonobese, had significantly higher LDL-C and total cholesterol/HDL-C ratios in males and significantly higher triglyceride levels in females. CONCLUSIONS: Given the prevalence of dyslipidemia seen in this study, we suggest that fasting lipid measurements should be performed in all Nigerians with high blood pressure. These data suggest the need for health education and lifestyle modifications in hypertensive Nigerians to reduce both types of risk factors. PMID- 21291790 TI - Niemann-Pick disease type B with severe coronary artery disease and early recurrence after coronary artery bypass grafting. PMID- 21291791 TI - Letter to the editor. PMID- 21291792 TI - From the editor. PMID- 21291793 TI - News from the NLA. PMID- 21291794 TI - The use of niacin. PMID- 21291795 TI - Is HDL function as important as HDL quantity in the coronary artery disease risk assessment? AB - Over the past several decades, it has been clearly established that higher plasma concentrations of high-density lipoprotein (HDL) are related to lower risk of coronary artery disease (CAD). According to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines, the HDL level of <40 mg/dL is considered low and is one of the CAD risk predictors. However, in the last decade, several studies have indicated the importance of the quality of HDL as another potential measure for CAD risk assessment. The loss of normal biological function of HDL particles as a result of multifactorial actions of chronic inflammation and acute phase responses has suggested a new potential pathway in the pathophysiology of atherosclerosis. The concept of "dysfunctional HDL" or "proinflammatory HDL," which exhibits chameleon-like properties of converting a positive force protecting arteries to a negative one, enhancing atherogenesis is now under active investigation. Measurements of this dysfunctional quality of HDL in cell-based or cell-free assays by analyzing anti inflammatory functions may link these changes to in vivo assessments of vascular disease. This review provides details on functional and dysfunctional HDL and summarizes recent studies into dysfunctional HDL and its potential links to CAD. PMID- 21291796 TI - Postprandial lipemia as an early predictor of cardiovascular complications in childhood obesity. AB - Abstract. The growing trend of childhood overweight and obesity is a major health concern worldwide. Although obesity is a key risk factor for cardiovascular disease, the etiologic link between obesity and the progression of vascular disease remains unknown. Traditionally, lowering fasting blood cholesterol concentration has been the main interventional target for decreasing the risk of heart disease. However, there is increasing evidence that elevated concentrations of intestinally-derived chylomicron particles are associated with cardiovascular disease risk and that this is particularly evident in insulin-resistance and obesity in adulthood. In this review we comment on recent evidence suggesting that overweight children have fasting chylomicron concentrations equivalent to that found in adults diagnosed with cardiovascular disease. Further, we consider the hypothesis that fasting and postprandial chylomicron metabolism has a central role in the genesis of cardiovascular disease during childhood obesity. PMID- 21291797 TI - The role of lipoprotein-associated phospholipase A2 on cardiovascular disease risk assessment and plaque rupture: a clinical review. AB - During the last several last decades, reduction in lipids has been the main focus to decrease the risk of coronary heart disease (CHD). Several lines of evidence, however, have indicated that lipids account only for the <50% of variability in cardiovascular risk in the United States. Therefore, for better identification of people at high cardiovascular risk, a more effective and complete approach is required. Our understanding of atherosclerosis has shifted from a focal disease resulting in symptoms caused by severe stenosis to a systemic disease distinguished by plaque inflammation with a potential to rupture and thrombosis, turning a substenotic atherosclerotic lesion into a complete occlusive lesion. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is a novel inflammatory biomarker that can provide much needed information about plaque inflammation and plaque stability. Lp-PLA(2) is among the multiple biomarkers that have been associated with increased CHD risk. In this present work, we review the evidence from previous studies addressing the effect of different therapies on decreasing Lp-PLA(2) and the role of direct Lp-PLA(2) inhibitors. This work also briefly reviews the evidence of Lp-PLA(2) clinical utility as a potential marker of vascular inflammation and formation of rupture prone plaques. Additionally, we also discuss the implication of available evidence in context of current cardiovascular inflammatory biomarkers recommendations and the evidence from epidemiologic studies addressing the relationship of Lp-PLA(2) and risk of cardiovascular disease. PMID- 21291798 TI - Benefits of the MEDPED treatment support program for patients with familial hypercholesterolemia. AB - BACKGROUND: Patients with heterozygous familial hypercholesterolemia (FH) patients often have difficultly achieving National Cholesterol Education Program (NCEP) goals. Herein we present an evaluation of a centrally located, nationwide treatment support program that remotely attempted to educate and guide FH patients by monitoring their serum low-density lipoprotein (LDL) cholesterol levels and giving appropriate treatment recommendations through mail contact. All subjects were FH patients registered with the Make Early Diagnosis to Prevent Early Deaths (MEDPED) program. METHODS: In this descriptive evaluation, we compared self-reported lipid levels in 386 FH patients participating in our treatment support program with 295 non-participants who had responded to questionnaires. Participants were recruited into the treatment support program if they had not reached their LDL cholesterol goal after at least 1 year of follow up and were unable to receive specialized lipid care due to location. RESULTS: Participants who continued for a longer term in the treatment support program achieved greater total cholesterol reductions (14%) than the comparison group (7%, P=.004). Reductions in total and LDL cholesterol were highly correlated with more aggressive use of statin medications (P <.0001). CONCLUSIONS: These results demonstrate the potential benefits and limitations of a centralized program operating remotely to encourage appropriate treatment of severe hypercholesterolemia. PMID- 21291799 TI - Flushing and other dermatologic adverse events associated with extended-release niacin therapy. AB - BACKGROUND: Niacin lowers levels of atherogenic apolipoprotein-B-containing lipoproteins, including lipoprotein(a), and raises levels of atheroprotective high-density lipoproteins. However, cutaneous flushing has been a major impediment to the clinical use of niacin. OBJECTIVE: Extended-release niacin (niacin ER) is a once-daily prescription niacin formulated to limit flushing. An analysis of flushing events with niacin ER should facilitate its clinical use. METHODS: The analysis pools previously unpublished data on flushing and related side effects from four randomized, double-blind studies of niacin ER, and also reviews long-term data on flushing from a 96-week open label, uncontrolled study. RESULTS: Among 333 patients treated with niacin ER (once daily at bedtime) for 3 to 6 months, 83% reported at least one flushing episode, compared to 18% of patients treated with placebo or gemfibrozil. Approximately 50% had <=5 flushing events, and only 5% reported >20 flushing events. The majority (76%) of patients treated with niacin ER rated flushing events as mild to moderate in intensity; 6% of patients withdrew due to flushing. In an 8-week comparison of niacin ER once daily at bedtime with immediate-release niacin three times daily at equivalent total daily doses, the total number of flushing events was 76% lower in the niacin ER group. CONCLUSION: Niacin ER can help control flushing events while providing favorable effects on lipids and lipoproteins. The generalizability of this analysis may be limited by self-selection and motivation of research subjects, and further studies of flushing in the clinical practice setting are warranted. PMID- 21291800 TI - Efficacy and safety of combination therapy with niacin extended-release and simvastatin versus atorvastatin in patients with dyslipidemia: The SUPREME Study. AB - BACKGROUND: Aggressive treatment of low-density lipoprotein cholesterol (LDL-C) fails to prevent most cardiovascular (CV) events. Concurrent treatment of LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) should be considered in patients with dyslipidemia. OBJECTIVE: The efficacy and safety of a proprietary niacin extended-release and simvastatin (NER/S) combination were compared to atorvastatin monotherapy in a multicenter, Prospective, Randomized (3:2), Open-label, Blinded Endpoint (PROBE) study. METHODS: Following >=4 weeks without lipid-modifying therapies, 193 patients with dyslipidemia were treated with NER/S (n = 114; 1000/40 mg/day, weeks 1 to 4; 2000/40 mg/day weeks 5 to 12) or atorvastatin (n = 79; 40 mg/day, weeks 1 to 12). RESULTS: Compared to atorvastatin, NER/S had a larger beneficial effect on HDL-C (primary end point: 30.1 +/- 2.3% and 9.4 +/- 2.6%, respectively; P <.001), TG (P = .02), and lipoprotein(a) (Lp[a]; P <.001), and similar effects on LDL-C and non-HDL-C. Two thirds of patients treated with NER/S concurrently attained LDL-C (CV risk adjusted goals), HDL-C (>=40 mg/dL), and TG (<150 mg/dL) targets, compared to one third of patients treated with atorvastatin (P <.001). Flushing was the most common treatment-emergent adverse event (TEAE) (67.5% NER/S and 10.1% atorvastatin; P <.001). Seventy-five percent of flushing episodes were mild to moderate. More patients treated with NER/S discontinued due to TEAEs (21.1% and 3.8%; P <.001); the most common TEAE was flushing. CONCLUSION: Compared to atorvastatin, NER/S provided superior improvements in HDL-C, TG, and Lp(a) and comparable improvements in non-HDL-C and LDL-C. Treatment with NER/S should be considered for patients with dyslipidemia requiring comprehensive lipid control. PMID- 21291801 TI - Add-on therapy for hypercholesterolemia: a pilot comparison of two gastrointestinally-acting agents in statin-treated patients. AB - BACKGROUND: Both colesevelam hydrochloride (colesevelam) and ezetimibe monotherapy have been reported to lower low-density lipoprotein cholesterol (LDL C) approximately 15-17% in patients with hypercholesterolemia. When statin therapy is inadequate to reach desired LDL-C goals, the choice of add-on therapy, while multifactorial, must consider efficacy of additional LDL-C reduction. OBJECTIVE: To provide pilot study data in assessing the relative potential of ezetimibe or colesevelam to further reduce LDL-C in statin-treated patients. METHODS: Fourteen patients with hypercholesterolemia, who at baseline were on treatment with a stable regimen of low- to moderate-dose statin therapy, were randomized to receive colesevelam HCl 3.75 g/day or ezetimibe 10 mg/day as add-on therapy (AOT). At the end of 6 weeks, each patient was crossed over to the alternative AOT. RESULTS: LDL cholesterol fell an additional 21.0% on colesevelam (P < .001) and 28.3% on ezetimibe (P <.001) with a 7.3% difference between AOTs (P <.02). Non-high-density lipoprotein cholesterol (non-HDL-C) fell an additional 15.1% on colesevelam (P <.001) and 25.6% on ezetimibe (P <.001) with a 10.5% difference between AOTs (P <.001). The non-HDL-C/HDL-C ratio fell an additional 15.3% on colesevelam (P <.01) and 22.8% on ezetimibe (P <.001) with a 7.5% difference between AOTs (P <.02). Zero of 10 and six of 10 secondary prevention patients reached an LDL-C level of <70 mg/dl on colesevelam and ezetimibe respectively (P <.005). CONCLUSION: Colesevelam HCl and ezetimibe are both effective AOTs in patients on statin therapy. The superior further improvement in the lipid panel with ezetimibe compared to colesevelam was demonstrated in this placebo uncorrected crossover pilot study. PMID- 21291802 TI - Efficacy and safety of fenofibric acid in combination with a statin in patients with mixed dyslipidemia: Pooled analysis of three phase 3, 12-week randomized, controlled studies. AB - BACKGROUND: Patients with mixed dyslipidemia often require combination therapy to manage multiple lipid abnormalities. OBJECTIVE: To evaluate fenofibric acid in combination with a statin across three studies of patients with mixed dyslipidemia. METHODS: As prospectively planned, data were pooled from three randomized, double-blind, phase 3 studies of patients with low-density lipoprotein cholesterol (LDL-C) >=130mg/dL, triglycerides (TG) >=150mg/dL, and high-density lipoprotein cholesterol (HDL-C) <40mg/dL (men) or <50mg/dL (women). A total of 2715 patients were randomly assigned to 12-week treatment with fenofibric acid 135mg monotherapy; low-, moderate-, or high-dose statin (rosuvastatin, simvastatin, or atorvastatin, depending on study) monotherapy; or fenofibric acid + low- or moderate-dose statin. The primary efficacy comparisons were mean percent change in HDL-C and TG (combination therapy vs. statin) and LDL C (combination therapy vs. fenofibric acid). RESULTS: Fenofibric acid + low-dose statin increased HDL-C (18.1% vs. 7.4%) and reduced TG (-43.9% vs. -16.8%) versus low-dose statin monotherapy and reduced LDL-C (-33.1% vs. -5.1%) versus fenofibric acid monotherapy (P <.001 for all). Fenofibric acid + moderate-dose statin increased HDL-C (17.5% vs. 8.7%) and reduced TG (-42.0% vs. -23.7%) versus moderate-dose statin monotherapy and reduced LDL-C (-34.6% vs. -5.1%) versus fenofibric acid monotherapy (P <.001 for all). Combination therapy was generally well tolerated, and safety profiles were similar to monotherapies. No rhabdomyolysis was reported. CONCLUSION: In patients with mixed dyslipidemia, combination therapy simultaneously improved multiple lipid abnormalities more effectively than fenofibric acid or statin monotherapies. PMID- 21291803 TI - Ezetimibe, and the combination of ezetimibe/simvastatin, and risk of cancer: A post-marketing analysis. AB - BACKGROUND: In the recently reported Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial, the combination of ezetimibe/simvastatin (E/S) was associated with a significantly increased risk of cancer compared to placebo, causing widespread public concern. OBJECTIVE: We examined the rates of cancer adverse event reports filed with the US Food and Drug Administration (FDA) of patients on ezetimibe or E/S, and compared these to reports with other potent cholesterol-lowering drugs. METHODS: We tabulated all adverse event reports listing "cancer" or "malignancy" filed with the FDA (July 2004 to March 2008) of patients taking ezetimibe or E/S, and compared those to reports of patients taking simvastatin, atorvastatin, or rosuvastatin. We calculated rates for such reports per million prescriptions. A secondary analysis examined cancer reports as a proportion of all reported adverse events for each medication. RESULTS: Prescriptions for all drugs totaled 559 million (approximately 52 and 55 million prescriptions of ezetimibe and E/S, respectively), and cancer adverse event reports totaled 2334. There were 2.9 and 1.3 cancer-associated adverse event reports per million ezetimibe or E/S prescriptions, respectively, compared to a range of 3.1 to 5.1 per million prescriptions for the other drugs. Findings were similar when only reports listing the drug as "suspect" were considered. The proportions of reports listing cancer relative to all adverse event reports were 2.0% and 1.9% for ezetimibe and E/S, respectively, compared to a range of 1.3% to 3.9% for the other drugs. CONCLUSIONS: This large-scale post-marketing analysis of reported adverse events does not support that ezetimibe or E/S increase the risk of cancer. PMID- 21291804 TI - A patient with new-onset hypercholesterolemia. PMID- 21291805 TI - The first recorded heterozygote for familial hypercholesterolemia. PMID- 21291806 TI - Reply. PMID- 21291807 TI - Letter to the editor. PMID- 21291808 TI - From the Editor-in-Chief. PMID- 21291809 TI - News from the national lipid association. PMID- 21291810 TI - The effects of diets enriched in beta-glucans on blood lipoprotein concentrations. AB - Dietary beta-glucans lower the blood concentrations of cholesterol in animals and humans. Recent studies have uncovered mechanisms by which dietary beta-glucans may regulate cholesterol homeostasis. There is evidence that beta-glucans sequester bile acids in the intestine, reducing their reabsorption and return to the liver. Reducing hepatic bile acid concentrations activates the enzyme CYP7A1, which converts cholesterol into bile acids. This action leads to a reduction of hepatic cell cholesterol content, which up-regulates low-density lipoprotein (LDL) receptor synthesis and thereby accelerates the transportation of LDL cholesterol from the blood into hepatocytes. Reduced intracellular cholesterol also up-regulates the hepatic synthesis of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol synthesis. Statins inhibit 3 hydroxy-3-methylglutaryl coenzyme A reductase and could therefore provide an additive effect in suppressing hepatocyte cholesterol to that produced by enhancing its depletion with beta-glucans. Through this combination of agents, one would expect a greater clearance of LDL from the plasma with lower steady state levels of LDL-cholesterol. PMID- 21291811 TI - Lipid-altering effects of different formulations of hydroxypropylmethylcellulose. AB - BACKGROUND: Hydroxypropylmethylcellulose (HPMC), a viscous, soluble dietary fiber, has been shown to be efficacious for lowering total and low-density lipoprotein cholesterol (LDL-C) concentrations. The relative effects of various dosages and viscosities of HPMC have not been fully evaluated. OBJECTIVE: To examine the lipid-altering effects of several formulations of HPMC. METHODS: In this randomized, double-blind pilot study, 165 men and women with primary hypercholesterolemia consumed a control product (snack bar or drink mix) or an HPMC-containing test bar or drink for 4 weeks. HPMC-containing products delivered 3, 5, or 10g of HPMC of low, moderate, moderately high, or high viscosity (9 HPMC groups, each with ~15 subjects). RESULTS: Data from drink and bar groups were combined because there was no evidence of a vehicle effect. The resulting analysis included data from the control and 6 HPMC dose and viscosity combinations. All HPMC groups showed LDL-C reductions ranging from 6.1 to 13.3% (P < .05 vs. baseline for 6 of the 7 groups), compared with a nonsignificant reduction (1.9%) in the control group. Changes in total and non-high-density lipoprotein cholesterol paralleled those for LDL-C. Concentrations of high density lipoprotein cholesterol, triglycerides, apolipoprotein B, and high sensitivity C-reactive protein were not significantly altered. CONCLUSION: This pilot study provides preliminary evidence to support the efficacy of various formulations of HPMC for reducing cholesterol carried by atherogenic particles in men and women with primary hypercholesterolemia. Additional research will be required to more clearly define the roles of viscosity and dosage on the lipid altering effects of HPMC. PMID- 21291812 TI - Lipid-modifying efficacy of extended release niacin/laropiprant in Asian patients with primary hypercholesterolemia or mixed hyperlipidemia. AB - BACKGROUND: Niacin has proven lipid-modifying efficacy and cardiovascular benefit; however, it is underused because of skin flushing, a process mediated primarily by prostaglandin D(2) (PGD(2)). Laropiprant (LRPT), a PGD(2) receptor (DP1) antagonist that mitigates niacin-induced flushing, has been combined with extended-release niacin (ERN) into a fixed-dose tablet containing 1g of ERN and 20mg of LRPT (ERN/LRPT 1g). In a large-scale (n=~1600), multinational, 6-month study in dyslipidemic patients, ERN/LRPT 2g produced superior lipid-modifying efficacy vs placebo, whether administered alone or with concomitant statins. OBJECTIVE: This Phase III, randomized, double-blind study evaluated the lipid modifying efficacy of ERN/LRPT alone or added to ongoing statins in Asian patients with primary hypercholesterolemia or mixed hyperlipidemia. METHODS: After a 4-week placebo run-in, patients were randomized to ERN/LRPT 1g (n=322) or placebo (PBO; n=324). After 4 weeks, the dose was advanced to 2 tablets/d (ERN/LRPT 2g or PBO) for 8 additional weeks. End points included effects of ERN/LRPT 2g vs PBO on low-density lipoprotein cholesterol (LDL-C; primary), high density lipoprotein cholesterol (HDL-C), triglyceride (TG), and other lipids/lipoproteins. RESULTS: Relative to PBO, ERN/LRPT 2g produced significant (P < .001) changes in LDL-C (-14.7%), HDL-C (15.9%), TG (-23.4%), LDL-C:HDL-C ( 25.5%), non-HDL-C (-16.4%), apolipoprotein (Apo) B (-15.4%), and Apo A-I (5.3%) from baseline to week 12 in the total population. Similar results were observed in patients treated with ERN/LRPT alone or added to ongoing statin. CONCLUSION: ERN/LRPT 2g, administered alone or with a statin, produced significant improvements in multiple lipid/lipoprotein parameters in dyslipidemic Asian patients. PMID- 21291813 TI - Association between the FABP2 Ala54Thr, PPARalpha Leu162/Val, and PPARalpha intron7 polymorphisms and blood lipids ApoB and ApoCIII in hypertriglyceridemic subjects in Tehran. AB - BACKGROUND: The alanine to threonine substitution at codon 54 in the FABP2 gene and PPARalpha Val162 allele have been associated with hypertriglyceridemia. OBJECTIVE: We sought to determine the prevalence of the Ala54Thr polymorphism of fatty acid binding protein (FABP) 2 gene and the Leu162/Val in exon 5 and G/C in intron7 polymorphism of peroxisome proliferator-activated receptor alpha (PPARalpha) gene in hypertriglyceridemic patients and their associations with blood lipid concentrations. METHODS: A total of 170 hypertriglyceridemic subjects were enrolled and genotyped for Ala54Thr, Leu162Val, and intron 7 polymorphism by the use of a polymerase chain reaction-restriction fragment length polymorphism method. Fasting blood triglyceride, total cholesterol (TC), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, apolipoprotein (Apo)B, and ApoCIII also were determined. RESULTS: We found frequency of 81.2% for the Thr54 polymorphism among hypertriglyceridemic subjects. Positive associations were observed between this polymorphism and greater blood triglyceride, very low-density lipoprotein, and ApoCIII levels and lower blood high-density lipoprotein cholesterol concentration both in men and women. However, no association was found between the Thr54 polymorphism and TC, low density lipoprotein cholesterol, ApoB, and body mass index. Frequency of the Leu162Val polymorphism was 21.8%. The Leu162Val polymorphism was not associated with lipid and lipoprotein concentrations in hypertriglyceridemic subjects (both in men and women). The frequency of intron7 polymorphism was 55.3% in subjects studied and, except for body mass index and TC, no association was found between the intron7 allele and blood lipids ApoB, and ApoCIII. CONCLUSION: Frequency of the Thr54 polymorphism is high in hypertriglyceridemic subjects, and the presence of this allele may increase some blood lipid and lipoprotein concentrations. In addition, the frequency of intron7 polymorphism may be greater than Leu162Val in hypertriglyceridemic patients. PMID- 21291814 TI - Low-density lipoprotein cholesterol goal attainment in high-risk family medicine patients. AB - BACKGROUND: The Adult Treatment Panel III guideline recommends a low-density lipoprotein-cholesterol (LDL-C) goal of <100mg/dl for patients with coronary heart disease or risk equivalence (ie, other forms of atherosclerotic vascular disease [peripheral vascular disease, abdominal aortic aneurysm, cerebrovascular disease], diabetes). An optional LDL-C goal of <70mg/dl is recommended for patients considered "very high risk." This category is not well defined, and clinical interpretation of this category varies. METHODS: To define this category and to determine eligibility for an LDL-C goal of <70mg/dl, 5 definitions of "very high risk" were developed. Patients with coronary heart disease or risk equivalence within the University of Colorado Family Medicine system over the course of 2 years were identified using International Classification of Diseases, 9th Revision codes (n=445). Their medical records were evaluated retrospectively. Patients characterized as "very high risk" according to the 5 definitions were assessed for LDL-C <70mg/dl goal attainment. RESULTS: Twenty-seven patients did not have LDL-C measurements and were excluded. Using the 5 definitions, we discovered that prevalence as "very high risk" was 10.8% (atherosclerotic vascular disease [AVD] plus smoking), 19.1% (AVD plus diabetes), 21.5% (AVD plus metabolic syndrome plus uncontrolled hypertension or smoking), 47.1% (AVD plus metabolic syndrome), and 67.2% (All AVD), P < .0001. LDL-C <70mg/dl was attained in 26.7%, 46.3%, 31.1%, 39.1%, and 35.2%, respectively (P=.13). CONCLUSION: Classifying patients as "very high risk" is highly variable depending on individual definitions, but this does not appear to alter the rates of attaining an LDL-C goal of <70mg/dl. When the Adult Treatment Panel IV guidelines are developed and issued, simplicity and clarity will be important in assisting clinicians in defining patient risk and developing LDL-C goals. PMID- 21291815 TI - Severe hypertriglyceridemia is related to episodes of epididymitis. PMID- 21291816 TI - Hypervitaminosis A altering the lipid profile in a hypercholesterolemic patient. PMID- 21291817 TI - From the Editor-in-Chief. PMID- 21291818 TI - News from the NLA. PMID- 21291819 TI - Niacin and cholesterol: The history of a discovery. PMID- 21291820 TI - In defense of the metabolic syndrome. PMID- 21291821 TI - Appropriate use of noninvasive vascular measures in the prevention of arterial disease. PMID- 21291822 TI - Acute exercise and impaired glucose tolerance in obese humans. AB - BACKGROUND: Individuals with impaired glucose tolerance (IGT) have a greater risk of developing diabetes and cardiovascular disease compared with those with normal glycemic control. The aim of this study was to examine the effects of acute aerobic exercise on glycemia, regional arterial stiffness, and oxidative stress in obese subjects with IGT. DESIGN: Twelve obese subjects (7 men and 5 women; 48.0+/-9.4 years; body mass index 32.4+/-7.0kg/m(2)) with IGT participated in a 30-minute bout of walking at 65% of maximum predicted heart rate. Pulse wave velocity (PWV, for determination of arterial stiffness) and blood pressure were examined before and after exercise, whereas venous blood samples were drawn for the determination of glucose, blood lipids, and indices of oxidative stress and inflammation (lipid hydroperoxides; superoxide dismutase; high-sensitivity C reactive protein). RESULTS: After exercise PWV (9.1+/-1.2m/s vs. 8.6+/-1.0m/s), glucose (5.7+/-0.6 mmol.L(-1) vs. 5.4+/-0.6 mmol.L(-1)), and diastolic blood pressure (94+/-14mm Hg vs. 86+/-13mm Hg) decreased, respectively (P < .05). A correlation was observed between PWV and glucose (r=0.544, P < .05). There were no changes in lipid hydroperoxides, superoxide dismutase, high-sensitivity C reactive protein, or blood lipids (P > .05). CONCLUSIONS: These findings suggest that acute aerobic exercise can reduce regional arterial stiffness in obese subjects with IGT by possibly improving glucose metabolism, independent of changes in oxidative stress. PMID- 21291823 TI - Adiponectin, leptin, and lipid profile in type 1 diabetic children and adolescents. AB - BACKGROUND: Adipose tissue is known to produce and secrete a variety of bioactive substances known as adipocytokines. Adiponectin and leptin are considered to be among the most important adipocytokines: OBJECTIVES: We sought to explore the relationships between adipocytokines (adiponectin and leptin), plasma lipoprotein lipid, and diabetic control indices in type 1 diabetic subjects. SUBJECTS AND METHODS: In this study 63 clinically diagnosed type 1 diabetic subjects and 30 age- and sex-matched healthy control subjects were analyzed. Age, sex, diabetic duration, family history of diabetes, daily insulin dose, weight, height, body mass index, and systolic and diastolic blood pressure were recorded. Fasting blood glucose, glycated hemoglobin A(1c), total hemoglobin, plasma lipoprotein, lipid and plasma concentrations of adiponectin and leptin were measured in type 1 diabetic subjects and control subjects. RESULTS: In this study a significant increase in triglycerides and high-density lipoprotein cholesterol in plasma of type 1 diabetics was found as compared with normal control subjects. In type 1diabetic subjects, plasma adiponectin was significantly elevated, whereas leptin showed a significant decrease as compared to a normal control group. Leptin concentrations showed a positive correlation with body mass index and systolic blood pressure but a negative correlation with both fasting blood glucose and glycated hemoglobinA(1c). CONCLUSION: The results of this study suggest that blood leptin but not adiponectin concentrations have a significant correlation with indices of glycemic control. PMID- 21291824 TI - Effects of lifestyle counseling and combination lipid-modifying therapy on lipoprotein-associated phospholipase A2 mass concentration. AB - BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA(2)) is a novel inflammatory biomarker that is associated with increased cardiovascular disease risk independent of and additive to traditional risk factors. Lp-PLA(2) activity is correlated with the degree of inflammation in the atherosclerotic plaque. In human blood, approximately 80% of Lp-PLA(2) is associated with low-density lipoproteins (LDL). Thus, it is hypothesized that changes in Lp-PLA(2) should imitate the changes in the LDL cholesterol. OBJECTIVE: In this present study, we examined the efficacy of lifestyle intervention and combination lipid-lowering therapy on reducing the Lp-PLA(2) levels and determined the relationship between changes in LDL-C and Lp-PLA(2). METHODS: This retrospective chart review study includes two hundred forty eight patients (58% men and 42% women) who completed the life style intervention in combination with pharmacologic therapy for an average period of 10.5 months. Life style modification included diet and exercise counseling. Combination therapy included omega 3 fish oil (2000mg/d), extended release niacin (500-1000mg/d), ezetimibe (10mg/d), fenofibrate 160mg/d and colesevelam HCI (1850mg/d), as well as statins. The statins used were either simvastatin (20-40mg/d) or rosuvastatin (5-20mg/d). Sixty five percent (n=161) received low to medium doses of simvastatin, whereas 35% (n=87) received low to medium doses of rosuvastatin. RESULTS: The study revealed a 32.5% reduction in mean Lp-PLA(2) values (baseline 181.1+/-41.5 vs 122.1+/-28.1 ng/mL after treatment; P<.001). The change observed in LDL-C was 41%, (baseline 126.2+/-43 vs 73.9+/-37.7mg/dL after treatment), which also was significant (P < .001). However, a Pearson correlation test analysis revealed only a weak positive association between changes in Lp-PLA(2) and LDL-C (r(2)=0.052, P < .001). CONCLUSION: Lp-PLA(2) is reduced with the use of life style counseling and combination lipid lowering therapy. Results also revealed that changes in Lp PLA(2) may be partially explained by the changes in LDL-C. PMID- 21291825 TI - Regulation of human stearoyl-CoA desaturase by omega-3 and omega-6 fatty acids: Implications for the dietary management of elevated serum triglycerides. AB - BACKGROUND: Polyunsaturated fatty acids lower serum triglycerides by a mechanism that may involve the inhibition of stearoyl-CoA desaturase (SCD). OBJECTIVE: We sought to evaluate the effects of serum fatty acids on 1) the SCD index in a controlled clinical setting, and 2) SCD regulation in Hep G2 cells. METHODS: The SCD index was determined in 23 subjects randomly sequenced through 3 diets for 6 weeks in a crossover study. Diets were variably enriched with n-3 and n-6 polyunsaturated fatty acids; notably, monounsaturated fatty acids were held constant. Effects of linoleic acid (LA), alpha-linolenic acid (ALA), and eicosapentaenoic acid (EPA) on mRNA levels of SCD, fatty acid elongases 5 and 6 (Elovl5 and Elovl6), fatty acid synthase, carnitine palmitoyltransferase-1, and sterol response element binding protein-1c were investigated in Hep G2 cells after 24-hour incubations. RESULTS: The SCD indexes C18:1/18:0 and C16:1/C16:0 were significantly (P < .0001) correlated with serum TG with R(2) values of 0.71 and 0.58. The correlation was negatively associated with LA and positively associated with ALA. LA and EPA decreased SCD mRNA (EC(50) of 0.50 and 1.67MUM), whereas ALA did not. Likewise, LA and EPA decreased sterol response element binding protein-1c mRNA (EC(50) of 0.78 and 1.78MUM), but ALA did not. Similar results were observed for Elovl6. GW9662, a peroxisome proliferation activator receptor antagonist, did not obviate the effects of LA and EPA on SCD mRNA. CONCLUSIONS: Diets enriched in LA, ALA, and by metabolic inference EPA, can regulate SCD activity at the level of transcription, a nutritional intervention that may be useful in the management of increased levels of serum triglycerides in cardiometabolic disorders. PMID- 21291826 TI - Serum 25-hydroxyvitamin D is independently associated with high-density lipoprotein cholesterol and the metabolic syndrome in men and women. AB - BACKGROUND: Low vitamin D status has been associated with markers of cardiovascular disease risk. OBJECTIVE: This cross-sectional study assessed the relationships between serum 25-hydroxyvitamin D [25(OH)D] and selected markers for cardiovascular disease risk, including metabolic syndrome and its components, in adult men and women. METHODS: Fasting blood samples, anthropometric measurements, and blood pressure were assessed in 257 men and women. Dietary intake was assessed with food frequency and dietary supplement questionnaires. RESULTS: Total vitamin D intake and that from dietary supplements were significantly associated with increasing serum 25(OH)D tertile (both P < .001). Mean+/-SEM serum high-density lipoprotein cholesterol (HDL-C) increased in a graded fashion (P < .001) from the lowest (48.4+/-1.8mg/dL) to the highest (62.3+/-2.1mg/dL) 25(OH)D tertile. The relationship between 25(OH)D and HDL-C remained significant (P < .001) after adjustment for established determinants of the HDL-C, with each 10-ng/mL increase in 25(OH)D associated with a 4.2-mg/dL increase in HDL-C concentration. Serum triglycerides (P=.008), waist circumference (P < .001), and body mass index (P < .001) showed graded, inverse relationships with 25(OH)D tertile, and the prevalence of metabolic syndrome decreased significantly from the lowest to the highest 25(OH)D tertile (31%, 14%, and 10%, respectively, P for trend=.001). CONCLUSIONS: Lower serum 25(OH)D is associated with the metabolic syndrome and adverse values for some metabolic syndrome risk factors, particularly the HDL-C concentration. Research is warranted to assess whether increasing vitamin D intake will improve the metabolic cardiovascular risk factor profile. PMID- 21291827 TI - From the Editor-in-Chief. PMID- 21291828 TI - News from the NLA. PMID- 21291829 TI - Discussion on dietary fat. PMID- 21291830 TI - Medical management of patients before the incidence of a cardiovascular event. AB - OBJECTIVE: We sought to examine the diagnoses and medical management patterns of patients before the incidence of a cardiovascular (CV) event. METHODS: A retrospective study of claims data from a national managed care plan was conducted. Eligible patients had a myocardial infarction, stroke, or revascularization between January 1, 2004 and December 31, 2005, and at least 3 years of continuous enrollment before the CV event. Patients were stratified by whether or not they had a diagnosis of atherosclerosis in the 3 years before the CV event. Diagnostic testing, lipid monitoring, and statin treatment patterns were assessed during the 3-year period before the CV event. RESULTS: There were 16,543 patients with a CV event, and 65% had no previous diagnosis of atherosclerosis. For all patients, 58% were men, and mean age was 60 years. Angiography or cardiac imaging was performed in <3% of patients, and cardiac stress testing was performed in 13% of patients before the event. Only 19% of patients had >=1 lipid test in the 12 months and 32% in the 3 years before the event, and their 12-month mean low-density lipoprotein cholesterol was 113 mg/dL. Thirty-four percent of patients were on statin therapy within the 3 years before event. The patient subgroup diagnosed with atherosclerosis had significantly more patients with cardiac testing, lipid monitoring, and statin therapy compared with patients with no previous diagnosis of atherosclerosis. CONCLUSION: These results from an actual clinical practice dataset indicate opportunities for improved detection and management of underlying atherosclerotic heart disease to avoid future cardiovascular events. PMID- 21291831 TI - Effects of prescription omega-3-acid ethyl esters on lipoprotein particle concentrations, apolipoproteins AI and CIII, and lipoprotein-associated phospholipase A(2) mass in statin-treated subjects with hypertriglyceridemia. AB - BACKGROUND: Prescription omega-3-acid ethyl esters (P-OM3) often are used for hypertriglyceridemic patients receiving statin therapy who have residual increases in atherogenic lipoprotein lipid levels. To date, limited information has been published regarding the effects of omega-3 fatty acid consumption on lipoprotein particle concentrations. OBJECTIVE: We evaluated the effects of adding P-OM3 4g/d to an ongoing regimen of simvastatin 40mg/d on lipoprotein particles (P) in subjects with hypertriglyceridemia. METHODS: Data were analyzed from the multicenter, randomized, double-blind, placebo-controlled Combination of Prescription Omega-3s with Simvastatin (COMBOS) study. After an 8-week simvastatin lead-in, 254 subjects received P-OM3 (n=122) or placebo (n=132) for an additional 8 weeks. Nuclear magnetic resonance spectroscopy was used to assess lipoprotein concentrations and sizes. Remnant-like particle cholesterol, apolipoprotein (Apo) CIII, Apo AI, and lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) levels also were measured. RESULTS: Compared with placebo, P-OM3 reduced mean very-low-density lipoprotein (VLDL-P) size and increased low-density lipoprotein particle (LDL-P) size (P < .006 for both) without altering high density lipoprotein particle (HDL-P) size. P-OM3 did not significantly change total VLDL-P or LDL-P concentrations relative to placebo, but large VLDL-P and intermediate-density lipoprotein particle (IDL-P) concentrations were lowered (P < .01 for both), and the large LDL-P concentration was increased (P < .0001). HDL P concentration was reduced (P < .0001) as the result of a decrease in medium HDL P. Remnant-like particle cholesterol, Apo CIII, and Lp-PLA(2) concentrations were reduced compared with placebo (all P < .003). CONCLUSIONS: P-OM3 induces changes in sizes, concentrations, and compositions of lipoproteins that may have relevance for the atherothrombotic process. PMID- 21291832 TI - Efficacy and tolerability of multidrug therapy for hypertriglyceridemia. AB - BACKGROUND: Although there is clinical evidence for the safety and efficacy of single-drug therapy and some two-drug combinations for the treatment of hypertriglyceridemia, information is limited on the use of more than 2 drugs. OBJECTIVE: We evaluated the efficacy and safety of multidrug regimens (>=3 agents) in the management of hypertriglyceridemia. METHODS: The study included 40 individuals in an academic lipid referral clinic with mean follow-up of 1.98 years and an average use of 3.5 medications. RESULTS: During the study, mean body mass index decreased significantly (P=.0127), from 29.2kg/m(2) to 28.7kg/m(2), and mean hemoglobin A1C showed a trend towards decreasing (P=.06), from 7.9% to 7.2% in patients with diabetes (n=17). All lipid parameters decreased significantly: total cholesterol level decreased significantly from (mean+/-SD) 334.3+/-282.9mg/dL to 183.8+/-54.8mg/dL (P=.001, mean reduction of 45%), mean (+/ SD) triglyceride level decreased significantly from 1900.9+/-4576.8mg/dL to 300.7+/-372.2mg/dL (P=.02), median (range) triglyceride level decreased from 599 (242-28,550) mg/dL to 301 (40-1960) mg/dL (P < .001, mean reduction of 50%), and mean (+/- SD) non-high-density lipoprotein cholesterol decreased significantly from 189.9+/-131.6mg/dL to 138.4+/-49.1mg/dL (P=.014, mean reduction of 27%). There were no serious adverse effects (rhabdomyolysis or increased liver function tests >3 times upper limit of normal). CONCLUSION: In a 2-year follow-up of 40 individuals on multidrug therapy (average of 3.5 drugs) for severe hypertriglyceridemia, combination therapy was efficacious and well tolerated. PMID- 21291833 TI - High plasma high-density lipoprotein levels, very low cardiovascular risk profile, and subclinical carotid atherosclerosis in postmenopausal women. AB - BACKGROUND: Low plasma concentrations of high-density lipoprotein (HDL) are associated with increased risk of cardiovascular disease. However, recently several studies have questioned the protective role of high plasma HDL levels. OBJECTIVE: This study was designed to evaluate HDL functions in women with high plasma HDL cholesterol and very low risk profile with relation to subclinical carotid atherosclerosis (ATS). METHODS: Included were 158 middle-aged women with plasma HDL >60 mg/dL and Framingham risk score <7% who had B-mode ultrasound of the carotid arteries. Subclinical ATS was determined by the presence of plaques and/or intima-media thickness (IMT) >1.0 mm. RESULTS: ATS was observed in 51 women, with the majority (n=41) having carotid plaques, some with advanced morphology. In a multivariable model analysis, each, HDL or age, were independently associated with increased prevalence of ATS. Odds ratios for ATS were 3.1 and 2.5 greater for age>60 years and HDL >70 mg/dL, respectively. None of HDL functions determined by its antioxidative properties, reverse-cholesterol transport, or activities of HDL-associated enzyme were different between -ATS and +ATS. C-reactive protein was similar in both groups. CONCLUSION: Subclinical carotid ATS is present in one-third of middle-aged women independently of conventional risk factors. A greater ATS prevalence was associated with very high HDL values. We could not find association between ATS and HDL dysfunction. PMID- 21291834 TI - The identification of occult cardiovascular disease through the use of a novel biomarker: a case report. PMID- 21291835 TI - From the Editor-in-Chief. PMID- 21291836 TI - News from the NLA. PMID- 21291837 TI - Using exercise to reduce risk. PMID- 21291838 TI - Cholesterol, lipoproteins, and cognitive impairment. AB - This article discussed the central role of the deposition of amyloid beta in the pathogenesis of Alzheimer disease. (AD), and the animal data which supports the role of cholesterol on its deposition. The effect of mid-life cholesterol is discussed, and the presence of cardiovascular disease risk factors in the patients with evidence for AD and vascular disease. The role of statin therapy is mentioned, although concrete evidence in controlled prospective trials has not been published in a large trial. The value of hygienic approaches including exercise, diet and behavioral changes is mentioned. Currently there are no safe and effective drugs which have been proven to reduce the incidence or the progression of AD, although research in this important area is ongoing. PMID- 21291839 TI - Atherosclerosis in a managed care plan: hypercholesterolemia treatment patterns and low-density lipoprotein cholesterol monitoring. AB - BACKGROUND: Clinical guidelines have recommended a LDL-C goal of <100 mg/dL for high-risk individuals and lipid-modifying therapy for patients not reaching this goal. OBJECTIVE: This investigation assessed low-density lipoprotein cholesterol (LDL-C) levels and treatment patterns among patients diagnosed with atherosclerosis with or without a previous cardiovascular disease (CVD) event. METHODS: We conducted a retrospective study by using claims data from a national health plan that included patients with >= 1 medical claim for atherosclerosis (ICD-9 of 440.xx, 414.x, 437.0, 437.1, or 437.3) between January 2004 and March 2006. Use of lipid-modifying medications at the time of diagnosis and thereafter, patient demographics, comorbid conditions, baseline, and postdiagnosis LDL-C were assessed. RESULTS: There were 311,567 patients who had an atherosclerosis ICD-9 code, 46% of whom had a previous CVD event. Among patients with an atherosclerosis diagnosis and CVD event, lipid-modifying therapy was received by 50% before diagnosis and 57% after diagnosis, compared with 37% before and 48% after diagnosis for patients with an atherosclerosis diagnosis and no previous CVD event. Of the patients with baseline LDL-C (15%, n=46,923), 44% had an LDL-C <100mg/dL at diagnosis; of those with LDL-C >= 100mg/dL, only 54% received lipid modifying therapy and only 64% achieved an LDL-C <100mg/dL in the 12 succeeding months. Among patients with baseline and postdiagnosis LDL-C values (n=24,724), 55% had a baseline LDL-C >= 100mg/dL and 46% had a baseline non-HDL-C >= 130mg/dL. CONCLUSIONS: In conclusion, many patients in a managed care plan diagnosed with atherosclerosis with or without a previous CVD event present opportunities for better lipid management. Healthcare providers should evaluate more aggressive lipid management interventions for these patients for potential downstream cardiovascular benefits. PMID- 21291840 TI - Acquired severe hypercholesterolemia and hypoalphalipoproteinemia. PMID- 21291841 TI - The paradox of severe hypercholesterolemia and cachexia as a paraneoplastic manifestation of hepatocellular carcinoma. PMID- 21291842 TI - Juvenile idiopathic arthritis presenting with prolonged fever. AB - BACKGROUND/PURPOSE: Systemic-onset juvenile idiopathic arthritis (s-JIA) is a systemic disease often accompanied by a fever. We examined 16 patients with s-JIA and reported the clinical manifestations, laboratory data, treatments and outcomes. METHODS: From 1984 to 2007, 16 children (aged 1-16 years), who were diagnosed as having s-JIA, were admitted to the Mackay Memorial Hospital in Taiwan. We retrospectively reviewed their medical charts. RESULTS: There were nine boys and seven girls, with mean age of onset of 7.4+/-5.5 years. Fever (100%), typical rash (63%), and arthritis (75%) were the three most common symptoms. Lymphadenopathy (50%), hepatosplenomegaly (63%), pleural pulmonary manifestations (13%) and myalgia (25%) were also noted. One patient had Epstein Barr virus-associated hemophagocytic syndrome complications. Neutrophilic leukocytosis was a common feature. Other laboratory data showed elevated C reactive protein levels (25.1+/-50.3 mg/dL), and erythrocyte sedimentation rates (69+/-28 mm/hr) and abnormal liver enzymes. Marked hyperferritinemia (> 2,000 ng/mL) was noted in 57% (4/7) of the patients. The mean time from onset of symptoms to diagnosis was 9.2 weeks. Non-steroidal anti-inflammatory drugs, steroids, disease-modifying anti-rheumatic drugs and anti-tumor necrosis factor agents were used for treatment. Due to prolonged fever, 2.0+/-1.6 (maximum=5) different kinds of antibiotics were used before a diagnosis was made. Most cases had satisfactory therapeutic outcomes except one boy, who had permanent joint contracture. CONCLUSION: The clinical manifestations of s-JIA in Taiwan were often accompanied by a prolonged fever. This results in clinicians often suspecting bacterial infections and prescribing several kinds of antibiotics. In the case of prolonged fever, s-JIA should always be placed on the list of differential diagnoses. PMID- 21291843 TI - Primary human immunodeficiency virus infection presenting as elevated aminotransferases. AB - BACKGROUND/PURPOSE: Primary human immunodeficiency virus type 1 (HIV-1) infection is often under-diagnosed because of its nonspecific presentations. Elevated aminotransferase levels is one of its clinical manifestations, but is infrequently reported in the literature. The objective of this study was to investigate cases of elevated aminotransferases as a manifestation of primary HIV 1 infection. METHODS: A retrospective chart review from October 1990 to May 2009 of HIV-1 infected patients in a registered database at a tertiary hospital was conducted to identify patients diagnosed with primary HIV-1 infection. An elevated aminotransferase level was broadly defined as above-normal values of alanine or aspartate aminotransferases. Acute hepatitis markers were determined using stored serum samples. RESULTS: Twenty-three of the 827 (2.8%) patients were identified as having a primary HIV-1 infection. All were male, with a median age of 26 years (range, 19-77 years), and the majority were men who had sex with men (19/23, 82.6%). The most common clinical manifestations were fever (95.7%), elevated aminotransferases (65.2%), fatigue (47.8%), and pharyngitis (47.8%). The median CD4 lymphocyte count was 374/MUL (range, 109-674/MUL) and the median log HIV viral load was 5.0 (range, 4.3-5.9). For the 15 patients with abnormal liver function tests, the median aspartate aminotransferase level was 112 U/L (range, 62-969 U/L) and the median alanine aminotransferase level was 146 U/L (range, 42 1,110 U/L). CONCLUSION: Elevated aminotransferases may be an initial manifestation of primary HIV infection and is more common than expected. Primary HIV-1 infection should be one of the differential diagnoses considered in young men presenting with unexplained, new-onset liver function impairment. PMID- 21291844 TI - Antimicrobial susceptibility and multiplex PCR screening of AmpC genes from isolates of Enterobacter cloacae, Citrobacter freundii, and Serratia marcescens. AB - BACKGROUND/PURPOSE: The emergence of multiple drug resistance in Enterobacteriaceae is of particular concern. The aim of this study was to evaluate the antimicrobial susceptibility and screen for the ampC gene in three members of the Enterobacteriaceae family (Enterobacter cloacae, Citrobacter freundii, and Serratia marcescens) found at Taichung Veterans General Hospital during the past 5 years using multiplex polymerase chain reaction (PCR). METHODS: The susceptibility of thirty isolates from each of the three Enterobacteriaceae family members to five antimicrobial agents (ceftazidime, flomoxef, imipenem, moxifloxacin, and colistin) was assessed. The susceptibility was analyzed by disk diffusion, screening and confirmatory tests for extended-spectrum beta-lactamases (ESBL) and minimum inhibitory concentration tests according to the recommendations of the Clinical and Laboratory Standards Institute. The detection of ampC genes (3 families, including DHA, EBC and CIT) was performed by multiplex PCR. To detect the coexistence of ESBL genes, PCR was performed using five primer pairs: TEM, SHV, SHV-5, CTX-M-3, and CTX-M-14. RESULTS: Of the 90 isolates, 53 (58.9%) were positive in the screening test for ESBL. Resistance genes were detected in 12 (22.6%) of these isolates: ampC gene of DHA type in one E. cloacae isolate and EBC type in three E. cloacae isolates; ampC gene of CIT type in four C. freundii isolates; CTX-M-3-like in one C. freundii isolate and one S. marcescens isolate; TEM in three E. cloacae isolates, three C. freundii isolates and two S. marcescens isolates; SHV in one C. freundii isolate. CONCLUSION: Antibiotic phenotypes cannot accurately distinguish the resistance mechanisms caused by ampC or ESBL, and especially in ESBL-ampC combinations. However, PCR is a useful technique for the identification of the different types of resistance genes. PMID- 21291845 TI - Abdominal tuberculosis in children: a diagnostic challenge. AB - BACKGROUND/PURPOSE: Abdominal tuberculosis (TB) is a rare manifestation of childhood TB. Abdominal TB is characterized by long-lasting abdominal symptoms, which are usually confused with other conditions, and the diagnosis is usually delayed. METHODS: During a 5-year period, we identified 10 cases of abdominal TB in a tertiary care children's hospital. Data including demographic characteristics, presenting symptoms, history of Bacille Calmette-Guerin vaccination, lesion sites, laboratory data, image findings, diagnosis, tuberculin skin test, risk factors, treatment, and outcome were collected and analyzed. RESULTS: There were six female patients and four male patients, with a mean age of 14.7 years. One patient died due to the complication of disseminated TB with a pneumothorax. Household members with TB could be traced in six (60%) patients. The most common clinical presentations included fever (9/10), abdominal pain (8/10), and weight loss (8/9). The diagnosis of abdominal TB was suspected initially in only three patients; the others were not diagnosed until 7-36 days (mean=19 days) after hospitalization. The abnormal abdominal image findings, by either computed tomography or ultrasound, included lymphadenopathy (7/9), high density ascites (6/9), thickening of the omentum or peritoneum (6/9), inflammatory mass (3/9), bowel wall thickening (1/9), and liver abscess (1/9). The chest radiography was abnormal in nine patients. Mycobacterium tuberculosis was isolated from ascites in two out of four patients, gastric aspirates in three, sputum in three, and intra-abdominal tissue specimens in two. Laparotomy was performed in three patients, laparoscopy in one, and colonoscopy in one. CONCLUSION: In Taiwan, abdominal TB should be considered in patients with fever, abdominal pain, weight loss, and abnormal chest radiography. Characteristic computed tomography findings of abdominal TB and a history of exposure to TB contribute to the diagnosis. PMID- 21291846 TI - Impact of Extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae on the outcome of community-onset bacteremic urinary tract infections. AB - BACKGROUND/PURPOSE: The number of community-onset bacteremic urinary tract infections (UTIs) caused by Escherichia coli and Klebsiella pneumoniae is increasing. However, the impact of extended-spectrum beta-lactamase (ESBL) producing E. coli and K. pneumoniae (ESBL-EK) on bacteremic UTI outcomes is unknown. The aim of this study was to retrospectively analyze the impact of ESBL EK on community-onset bacteremic UTIs. METHODS: Of the 58 patients enrolled, 12 suffered from ESBL-EK-caused community-onset bacteremic UTIs. Patients were categorized into ESBL (n=12) and non-ESBL (n=46) groups. Diagnosis was based on findings of concurrent bacteremia and bacteriuria caused by the same pathogen on admission. RESULTS: The ESBL group had significantly more male patients (66.7%vs. 23.9%; p=0.005), indwelling urinary catheters (41.7%vs. 6.5%; p=0.002), patients admitted from other healthcare facilities (50.0%vs. 8.7%; p=0.001), and patients with higher Acute Physiology and Chronic Health Evaluation II scores (23.3+/-7.1 vs. 15.9+/-6.3; p=0.001) and intensive care unit admissions (41.7%vs. 4.4%; p=0.003) than the non-ESBL group. Multiple logistic regression analysis revealed that male gender (odds ratio=9.2; 95%, confidence interval=1.7-50.6) and healthcare facility residency (odds ratio=15.5; 95% confidence interval=2.4-98.9) were independent risk factors for ESBL-producer infections among bacteremic UTIs. Although the mortality rate of both groups was similar (8.3%vs. 4.4%; p=0.403), the ESBL group had longer hospital stays (16.3+/-9.3 days vs. 7.9+/-5.2 days; p=0.010) and higher antibiotic costs (615.1+/-423.5 USD vs. 252.8+/-269.2 USD, p=0.014). CONCLUSION: Male gender and healthcare facility residency are risk factors for ESBL-producer infections among patients with community-onset bacteremic UTIs. Patients with bacteremic UTIs caused by ESBL-EK also have prolonged hospital stays and higher antibiotic costs. Early detection of ESBLs and appropriate antibiotic coverage are likely to shorten hospital stays and reduce medical costs. PMID- 21291847 TI - The emerging life-threatening opportunistic fungal pathogen Kodamaea ohmeri: optimal treatment and literature review. AB - BACKGROUND/PURPOSE: The yeast Kodamaea ohmeri rarely causes life-threatening human infections. However, risk factors, laboratory diagnoses, and treatments for K. ohmeri infection have been limited, and the optimal therapy for K. ohmeri infection has not been identified. METHODS: Twenty cases of K. ohmeri infection have been reported in the English medical literature. We present two new cases of K. ohmeri fungemia. We investigated the nature and treatment of K. ohmeri infections using minimum inhibitory concentrations of antifungal agents and by comparing the two cases with those described in the literature. RESULTS: From March 1998 to December 2008, a total of 22 patients with K. ohmeri infections were studied. Hematological malignancies and diabetes were the most common co morbidities for K. ohmeri infections, with crude prevalence rates of 27.3% and 18.2%, respectively. The K. ohmeri isolates showed less susceptibility to fluconazole but greater susceptibility to amphotericin B [15/25 isolates (60%) vs. 25/25 isolates (100%), respectively]. Good outcomes (8/9 cases; 88.9%) were found following removal of indwelling catheters and implants. In addition, voriconazole and echinocandins, such as caspofungin and micafungin, also showed excellent minimum inhibitory concentrations against K. ohmeri. CONCLUSION: K. ohmeri should not be regarded as a contaminant of blood cultures. Favorable outcomes for this potentially life-threatening infection are promoted by the removal of indwelling catheters; furthermore, outcomes are associated with optimal antifungal regimens, especially voriconazole and echinocandins. PMID- 21291848 TI - Comparison of acute lobar nephronia and uncomplicated urinary tract infection in children. AB - BACKGROUND/PURPOSE: This aim of this study was to assess the clinical manifestations, the microorganisms involved and their antibiotic resistance in children hospitalized due to acute lobar nephronia (ALN) and non-ALN community acquired urinary tract infections (UTIs). METHODS: We retrospectively reviewed the records of 265 previously healthy children hospitalized due to a first episode of community-acquired febrile UTI between July 2004 and June 2007. Based on the results of renal ultrasonography and computed tomography, they were divided into ALN and non-ALN groups. Their demographic and clinical characteristics, distribution of microorganisms, and their antimicrobial resistance were analyzed. RESULTS: Of the total number of cases of children admitted with a first-episode community-acquired UTI, 19.2% (n=51) were diagnosed as ALN. Children with ALN were older (1.86 years vs. 0.81 years; p < 0.01), had longer periods of fever before admission (4.7 days vs. 1.4 days; p < 0.01), higher peak body temperatures (39.5 degrees C vs. 38.9 degrees C; p < 0.01), higher white cell counts (18.86 * 10(9)/L vs. 15.08 * 10(9)/L; p < 0.01) and higher C-reactive protein levels (9.0 mg/dL vs. 3.5 mg/dL; p < 0.01) compared with non-ALN children. Fever also persisted for longer after the start of antibiotic treatment in the ALN children (2.7 days vs. 1.4 days: p < 0.01) and they required longer hospital stays and incurred higher medical costs. The major pathogen found in ALN was E. coli (90%). The E. coli isolated from ALN children was more resistant to cotrimoxazole and ciprofloxacin than those from non-ALN children. CONCLUSION: ALN is not uncommon in children with a first-episode febrile UTI. They have a prolonged clinical course, higher inflammatory parameters, longer hospital stays and incur higher medical costs. E. coli is the major pathogen isolated from these children. PMID- 21291849 TI - Comparisons of clinical characters in patients with pneumococcal and Legionella pneumonia. AB - BACKGROUND/PURPOSE: The etiology of pneumonia is usually unknown, but the availability of urinary pneumococcal and Legionella antigen tests can improve the diagnostic yield. Our aim was to provide clinical clues to help clinicians perform the appropriate urinary antigen tests. METHODS: A retrospective study of patients admitted to the National Cheng Kung University Hospital between July 2006 and June 2008 was conducted. Patients aged over 18 years presenting with clinical symptoms and signs, radiological findings compatible with pneumonia, and a positive pneumococcal or Legionella pneumophila urinary antigen test, were included. Medical records were reviewed for data collection. RESULTS: Overall, 55 adults with pneumonia, including 42 with pneumococcal pneumonia (PP) and 13 with Legionella pneumonia (LP), were enrolled. On admission, patients with PP tended to be older (73.5 years vs. 59.1 years; p=0.001), had lower body weights (52.0 kg vs. 69.7 kg; p < 0.001), more frequent respiratory symptoms (59.5%vs. 0%; p < 0.001), and lower systolic (123.0 mmHg vs. 141.0 mmHg; p=0.004) and diastolic blood pressures (68.3 mmHg vs. 81.7 mmHg; p=0.008), compared with patients with LP. However, those with LP had higher body temperatures (39.0 degrees C vs. 37.5 degrees C; p < 0.001), a higher incidence of relative bradycardia (45.5%vs. 0%; p < 0.001), diarrhea (15.4%vs. 0%; p= 0.053), and lower platelet counts (178.5 * 10(3)/mm(3)vs. 233.7 * 10(3)/mm(3); p= 0.026). Radiological findings showed that the major abnormality, lobar consolidation, was indistinguishable between LP and PP. The percentage of patients requiring intensive care (35.7%vs. 38.5%) or ventilator support (31%vs. 23.1%) and in-hospital crude mortality rates (9.5%vs. 7.7%) was similar in both groups. CONCLUSION: Some clinical and laboratory characteristics may be regarded as important clues indicating the need for an appropriate urinary antigen test in patients with pneumonia. PMID- 21291850 TI - Semi-quantitative procalcitonin test for the diagnosis of bacterial infection: clinical use and experience in Japan. AB - BACKGROUND/PURPOSE: The efficacy of the rapid semi-quantitative procalcitonin (PCT) test for the diagnosis of bacterial infection was evaluated in patients with systemic inflammatory response syndrome. METHODS: A retrospective observational study was performed from June to December 2008 at the Chugoku Rosai General Hospital, Japan. This study analyzed consecutive patients (both outpatients and inpatients) who developed systemic inflammatory response syndrome and whose PCT test was measured semi-quantitatively within 24 hours of onset, or at the first hospital visit. Based on the clinical diagnosis, the patients were divided into two groups. Group I comprised patients with a bacterial infection, and group II comprised patients with a non-bacterial infection, or non-infectious disease. Receiver operating characteristic curves were used to evaluate the diagnostic value of the semi-quantitative PCT test kit, C-reactive protein levels and white blood cells counts for the detection of bacterial infections, and the areas under the resulting curves were compared. RESULTS: A total of 168 patients were included and divided into groups I (n=112) and II (n=56). Group I showed a significantly higher percentage of positive PCT tests (>= 0.5 ng/mL) than group II (67.8%vs. 19.6%, p < 0.001). PCT showed a sensitivity of 67.8% [95% confidence interval (CI)=58.4-76.4] and a specificity of 80.4% (95% CI=67.6-89.8). The areas under the resulting curves for PCT (0.764) were significantly larger than those seen for C-reactive protein (0.650, p=0.02) and white blood cells (0.618, p=0.006). CONCLUSION: The semi-quantitative PCT test is as useful for distinguishing bacterial infection from other inflammatory diseases in common clinical practice as the quantitative PCT. PMID- 21291851 TI - Helminthic infections in school children in Puducherry, South India. AB - BACKGROUND/PURPOSE: Intestinal parasites are widely prevalent in developing countries, probably due to poor sanitation and inadequate personal hygiene. It is estimated that as much as 60% of the world's population is infected with intestinal parasites, which may play a significant role in morbidity due to intestinal infections. This study was designed to estimate the prevalence of helminthic infections among school children in Puducherry, South India. METHODS: The prevalence of helminthic infections was studied in 1,172 children in public schools in Puducherry (Pondicherry), South India, between March and September 2006. The stools collected were concentrated using the formol-ether sedimentation technique, screened using conventional iodine and saline wet mounts, and examined by direct microscopy. RESULTS: The prevalence of helminthic infection was found to be 34.56% in school children; Ascaris lumbricoides constituted 43.21% of total infections; Ancylostoma duodenale (hookworm), 28.89%; Trichuris trichiura, 10.87%; Hymenolepis nana, 7.66%; Taenia spp., 7.41%; and Enterobius vermicularis, 1.98%. Co-infections were also common; dual infections accounted for 8.40% and multiple infections for 2.47%, respectively, of total infection. The stool samples found to be positive for hookworm ova were further processed for culture using the Harada-Mori culture technique. Sixty-five (55.56%) hookworm ova positive stools were found to be culture positive. CONCLUSION: The infection prevalent in school children in this area is Ascariasis. PMID- 21291852 TI - Clinical characteristics and risk factors for fatality in patients with bloodstream infections caused by glucose non-fermenting gram-negative Bacilli. AB - BACKGROUND/PURPOSE: Glucose non-fermenting Gram-negative bacilli (GNF-GNB) bloodstream infections (BSIs) are often hospital-acquired and are important causes of morbidity and mortality. Our objectives were to evaluate the epidemiology and clinical characteristics of GNF-GNB BSIs, and to identify risk factors for fatality. METHODS: We retrospectively reviewed cases of GNF-GNB BSIs in adult patient (>= 18 years of age) hospitalized between January and December 2005. RESULTS: A total 221 GNF-GNB bacteremic episodes (200 hospital-acquired and 21 community-acquired) in 215 patients (123 men and 92 women; mean age, 63.38+/ 16.10 years) were included in our study. Of these, 52.5% were elderly (age > 65). Malignancy (43.0%), diabetes mellitus (22.6%) and steroid use (22.6%) were the major underlying diseases/conditions. Central venous catheter (CVC) placement had been carried out in 57.5% of patients. The 28-day mortality was significantly higher in those patients with: liver cirrhosis, steroid use, pneumonia as the primary source of infection, intensive care unit-acquired infections, septic shock, and a high Pitt bacteremia score (>= 4 points). Liver cirrhosis [odds ratio (OR)=6.4; 95% confidence interval (CI)=1.7-23.9; p < 0.01)], hematologic malignancy (OR=3.9; 95% CI=1.1-14.1; p=0.04), pneumonia (OR=4.0; 95% CI=1.4 - 11.0; p< 0.01), septic shock (OR=13.0; 95% CI=4.6-36.6; p< 0.01), and intensive care unit-acquired infections (OR=2.9; 95% CI=1.1-8.0; p= 0.04) were all independent risk factors for fatality. CONCLUSION: Our data suggested that CVC placement and steroid use predispose to GNF-GNB bacteremia. Early removal of CVC and avoidance of steroids may minimize the chances of acquiring this infection, which is of particular importance for patients at high risk of mortality once they are infected with GNF-GNB. PMID- 21291853 TI - Clinical implications, risk factors and mortality following community-onset bacteremia caused by extended-spectrum beta-lactamase (ESBL) and non-ESBL producing Escherichia coli. AB - BACKGROUND/PURPOSE: Infections caused by extended-spectrum beta-lactamase (ESBL) producing bacteria have become a serious clinical concern worldwide. The occurrence of ESBLs in Taiwan has been well-documented and is reviewed in recent publications. However, studies comparing community-onset bacteremia caused by ESBL- and non-ESBL-producing Escherichia coli are limited. METHODS: We retrospectively reviewed the medical records of patients with E. coli bacteremia who visited the emergency department of Kaohsiung Chang Gung Memorial Hospital from January 2005 to December 2006. Clinical data were collected to compare the clinical features of patients with ESBL-producing E. coli with those of patients with non-ESBL-producers and to identify the risk factors associated with ESBL producing E. coli bacteremia. RESULTS: There were 404 episodes of community-onset E. coli bacteremia. The overall 30-day mortality rate was 11.4% (46/404) and the mortality rate of healthcare-associated infections was significantly higher than that of community-acquired infections [4/13 (30.8%) vs. 42/391 (10.7%); p= 0.049] Nonurinary focus was independently associated with an increased risk of fatality [47/178 (26.4%) vs. 4/226 (1.8%); p < 0.001]. The frequency of ESBL producers was 4.7% (19/404). Of these, four (21.1%) were associated with a long-term care facility. Significant risk factors associated with ESBL-producing E. coli bacteremia included recent antibiotic exposure (within 30 days) and urinary catheter placement. Although the trend was towards higher mortality in patients with ESBL-producing E. coli bacteremia, the difference did not reach statistical significance compared with the mortality of patients with non-ESBL E. coli bacteremia. CONCLUSION: Fewer than 5% of community-onset E. coli bacteremia episodes in Southern Taiwan were due to ESBL-producers. Prior antibiotic use within 30 days and urinary catheter placement were independently associated with ESBL-producing E. coli bacteremia. PMID- 21291854 TI - Cerebral infarction as the first presentation of tuberculosis in an infant: a case report. AB - The case of a child admitted to hospital with acute onset of hemiparesis and seizure is presented. Extensive evaluation of an acute ischemic event in the form of a brain infarct found on brain magnetic resonance imaging was inconclusive. Two months later, the patient was referred with severe hydrocephalus, which was managed with ventriculoperitoneal shunting in the presence of normal ventricular cerebrospinal fluid. The shunt was complicated by distal end infection. During the insertion of a second shunt, and after 3 months of antibiotic therapy, peritoneal thickening was found. Peritoneal biopsy showed evidence of a granulomatous reaction. This finding, along with positive polymerase chain reaction of the cerebrospinal fluid, confirmed tuberculosis. The patient recovered from most of his symptoms after antituberculous therapy, and a new ventriculoperitoneal shunt was inserted. This is a very peculiar presentation of tuberculosis that began with a cerebral infarction due to vasculopathy and hydrocephalus without any constitutional symptoms, and was later confirmed by peritoneal pathology. PMID- 21291855 TI - Primary Epstein-Barr virus infection associated with Kikuchi's disease and hemophagocytic lymphohistiocytosis: a case report and review of the literature. AB - An association between hemophagocytic lymphohistiocytosis (HLH) and Kikuchi's disease is rarely seen in children. Here, we present the case of a male adolescent (age 16 years and 3 months) who suffered from spiking fever for more than 1 week, and multiple nodules over the neck and bilateral axilla for 2 months. A skin rash also developed over all four limbs, abdomen and face. Laboratory data and skin biopsy gave results compatible with a diagnosis of Kikuchi's disease. Hemophagocytosis in the bone marrow, hyper-triglyceridemia, elevated ferritin, and splenomegaly were also found, fulfilling the criteria for HLH. A recent primary Epstein-Barr virus infection was also diagnosed by serology. The patient ran a relatively benign course. Intravenous immunoglobulins, steroids or etoposide-containing regimens were not used, and his recovery was uneventful. A review of the literature showed that up to February 2009, 11 additional cases of Kikuchi's disease presenting simultaneously with, or mimicking, HLH had been reported. Complete resolution within several weeks, with no recurrence, was seen in all but one patient (a pregnant woman). PMID- 21291856 TI - High-resolution Native-PAGE for membrane proteins capable of fluorescence detection and hydrodynamic state evaluation. AB - An improved native polyacrylamide gel electrophoresis (PAGE) method capable of evaluating the hydrodynamic states of membrane proteins and allowing in-gel fluorescence detection was established. In this method, bis(alkyl) sulfosuccinate is used to provide negative charges for detergent-solubilized membrane proteins to facilitate proper electrophoretic migration without disturbing their native hydrodynamic states. The method achieved high-resolution electrophoretic separation, in good agreement with the elution profiles obtained by size exclusion chromatography. The applicability of in-gel fluorescence detection for tagged green fluorescent protein (GFP) facilitates the analysis of samples without any purification. This method might serve as a general analytical technique for assessing the folding, oligomerization, and protein complex formation of membrane proteins. PMID- 21291857 TI - Interactions between GIPC-APPL and GIPC-TRP1 regulate melanosomal protein trafficking and melanogenesis in human melanocytes. AB - By virtue of the presence of multiple protein-protein interaction and signaling domains, PDZ proteins play important roles in assembling protein complexes that participate in diverse cell biological processes. GIPC is a versatile PDZ protein that binds a variety of target proteins in different cell types. In previous studies we showed that, in epidermal melanocytes, GIPC interacts with newly synthesized melanosomal protein TRP1 in the Golgi region and proposed that this interaction may facilitate intracellular trafficking of TRP1. However, since GIPC contains a single PDZ domain and no other known protein interaction motifs, it is not known how GIPC-TRP1 interaction affects melanosome biogenesis and/or melanin pigmentation. Here, we show that in human primary melanocytes GIPC interacts with AKT-binding protein APPL (adaptor protein containing pleckstrin homology, leucine zipper and phosphotyrosine binding domains), which readily co-precipitates with newly synthesized TRP1. Knockdown of either GIPC or APPL inhibits melanogenesis by decreasing tyrosinase protein levels and enzyme activity. In melanocytes, APPL exists in a complex with GIPC and phospho-AKT. Inhibition of AKT phosphorylation using a PI3-kinase inhibitor abolishes this interaction and results in retardation TRP1 in the Golgi. These data suggest that interactions between TRP1 GIPC and GIPC-APPL-AKT provide a potential link between melanogenesis and PI3 kinase signaling. PMID- 21291858 TI - The myosin phosphatase targeting protein (MYPT) family: a regulated mechanism for achieving substrate specificity of the catalytic subunit of protein phosphatase type 1delta. AB - The mammalian MYPT family consists of the products of five genes, denoted MYPT1, MYPT2, MBS85, MYPT3 and TIMAP, which function as targeting and regulatory subunits to confer substrate specificity and subcellular localization on the catalytic subunit of type 1delta protein serine/threonine phosphatase (PP1cdelta). Family members share several conserved domains, including an RVxF motif for PP1c binding and several ankyrin repeats that mediate protein-protein interactions. MYPT1, MYPT2 and MBS85 contain C-terminal leucine zipper domains involved in dimerization and protein-protein interaction, whereas MYPT3 and TIMAP are targeted to membranes via a C-terminal prenylation site. All family members are regulated by phosphorylation at multiple sites by various protein kinases; for example, Rho-associated kinase phosphorylates MYPT1, MYPT2 and MBS85, resulting in inhibition of phosphatase activity and Ca(2+) sensitization of smooth muscle contraction. A great deal is known about MYPT1, the myosin targeting subunit of myosin light chain phosphatase, in terms of its role in the regulation of smooth muscle contraction and, to a lesser extent, non-muscle motile processes. MYPT2 appears to be the key myosin targeting subunit of myosin light chain phosphatase in cardiac and skeletal muscles. MBS85 most closely resembles MYPT2, but little is known about its physiological function. Little is also known about the physiological role of MYPT3, although it is likely to target myosin light chain phosphatase to membranes and thereby achieve specificity for substrates involved in regulation of the actin cytoskeleton. MYPT3 is regulated by phosphorylation by cAMP-dependent protein kinase. TIMAP appears to target PP1cdelta to the plasma membrane of endothelial cells where it serves to dephosphorylate proteins involved in regulation of the actin cytoskeleton and thereby control endothelial barrier function. With such a wide range of regulatory targets, MYPT family members have been implicated in diverse pathological events, including hypertension, Parkinson's disease and cancer. PMID- 21291859 TI - The Pseudomonas aeruginosa membranes: a target for a new amphiphilic aminoglycoside derivative? AB - Aminoglycosides are among the most potent antimicrobials to eradicate Pseudomonas aeruginosa. However, the emergence of resistance has clearly led to a shortage of treatment options, especially for critically ill patients. In the search for new antibiotics, we have synthesized derivatives of the small aminoglycoside, neamine. The amphiphilic aminoglycoside 3',4',6-tri-2-naphtylmethylene neamine (3',4',6-tri-2NM neamine) has appeared to be active against sensitive and resistant P. aeruginosa strains as well as Staphylococcus aureus strains (Baussanne et al., 2010). To understand the molecular mechanism involved, we determined the ability of 3',4',6-tri-2NM neamine to alter the protein synthesis and to interact with the bacterial membranes of P. aeruginosa or models mimicking these membranes. Using atomic force microscopy, we observed a decrease of P. aeruginosa cell thickness. In models of bacterial lipid membranes, we showed a lipid membrane permeabilization in agreement with the deep insertion of 3',4',6 tri-2NM neamine within lipid bilayer as predicted by modeling. This new amphiphilic aminoglycoside bound to lipopolysaccharides and induced P. aeruginosa membrane depolarization. All these effects were compared to those obtained with neamine, the disubstituted neamine derivative (3',6-di-2NM neamine), conventional aminoglycosides (neomycin B and gentamicin) as well as to compounds acting on lipid bilayers like colistin and chlorhexidine. All together, the data showed that naphthylmethyl neamine derivatives target the membrane of P. aeruginosa. This should offer promising prospects in the search for new antibacterials against drug- or biocide-resistant strains. PMID- 21291860 TI - Integrin alphabeta1, alphavbeta, alpha6beta effectors p130Cas, Src and talin regulate carcinoma invasion and chemoresistance. AB - Ligand engagement by integrins induces receptor clustering and formation of complexes at the integrin cytoplasmic face that controls cell signaling and cytoskeletal dynamics critical for adhesion-dependent processes. This study searches for a subset of integrin effectors that coordinates both tumor cell invasion and resistance to the chemotherapeutic drug cisplatin in oral carcinomas. Candidate integrin effectors were identified in a proteomics screen of proteins recruited to clustered integrin alphabeta1, alpha(v)beta or alpha(6)beta receptors in oral carcinomas. Proteins with diverse functions including microtubule and actin binding proteins, and factors involved in trafficking, transcription and translation were identified in oral carcinoma integrin complexes. Knockdown of effectors in the oral carcinoma HN12 cells revealed that p130Cas, Dek, Src and talin were required for invasion through Matrigel. Disruption of talin or p130Cas by RNA interference increased resistance to cisplatin, whereas targeting Dek, Src or zyxin reduced HN12 resistance to cisplatin. Analysis of the spreading of HN12 cells on collagen I and laminin I revealed that a decrease in p130Cas or talin expression inhibited spreading on both matrices. Interestingly, a reduction in zyxin expression enhanced spreading on laminin I and inhibited spreading on collagen I. Reduction of Dek, Src, talin or zyxin expression reduced HN12 proliferation by 30%. Proliferation was not affected by a reduction in p130Cas expression. We conclude that p130Cas, Src and talin function in both oral carcinoma invasion and resistance to cisplatin. PMID- 21291861 TI - 14-3-3 eta inhibits chondrogenic differentiation of ATDC5 cell. AB - It was previously shown that 14-3-3 eta is overexpressed in the synovial fluid of patients with joint inflammation, which is often associated with growth failure. In this study, we investigated the role of 14-3-3 eta in chondrogenesis using ATDC5 cells. Upon treatment with TNF-alpha, cells overexpressed 14-3-3 eta with inhibition of chondrogenesis. Chondrogenesis was also inhibited by overexpression of 14-3-3 eta without TNF-alpha treatment, whereas silencing of 14-3-3 eta promoted chondrogenic differentiation. Further, G1 phase arrest was inhibited by overexpression of 14-3-3 eta. In summary, we suggest that 14-3-3 eta plays a regulatory role in chondrogenic differentiation. PMID- 21291862 TI - Axotomy induces axonogenesis in hippocampal neurons by a mechanism dependent on importin beta. AB - We characterize the previously unrecognized phenomenon of axotomy-induced axonogenesis in rat embryonic hippocampal neurons in vitro and elucidate the underlying mechanism. New neurites arose from cell bodies after axotomy and grew. These neurites were Tau-1-positive, and the injured axons showed negative immunoreactivity for Tau-1. Axonogenesis was delayed in these neurons by inhibiting the dynein-dynactin complex through the overexpression of p50. Importin beta, which was locally translated after axotomy, was associated with the dynein-importin alpha complex and was required for axonogenesis. Taken together, these results suggest that retrograde transport of injury-induced signals in injured axons play key roles in the axotomy-induced axonogenesis of hippocampal neurons. PMID- 21291863 TI - Microarray analysis of differentially regulated genes in human neuronal and epithelial cell lines upon exposure to type A botulinum neurotoxin. AB - Among the seven serotypes (A-G), type A botulinum neurotoxin (BoNT/A) is the most prevalent etiologic agent and the most potent serotype to cause foodborne botulism, characterized by flaccid muscle paralysis. Upon ingestion, BoNT/A crosses epithelial cell barriers to reach lymphatic and circulatory systems and blocks acetylcholine release at the pre-synaptic cholinergic nerve terminals of neuromuscular junctions (NMJs) resulting in paralysis. One of the unique features of BoNT/A intoxication is its neuroparalytic longevity due to its persistent catalytic activity. The persistent presence of the toxin inside the cell can induce host cell responses. To understand the pathophysiology and host response at the cellular level, gene expression changes upon exposure of human HT-29 colon carcinoma (epithelial) and SH-SY5Y neuroblastoma cell lines to BoNT/A complex were investigated using microarray analysis. In HT-29 cells, 167 genes were up regulated while 60 genes were down-regulated, whereas in SH-SY5Y cells about 223 genes were up-regulated and 18 genes were down-regulated. Modulation of genes and pathways involved in neuroinflammatory, ubiquitin-proteasome degradation, phosphatidylinositol, calcium signaling in SH-SY5Y cells, and genes relevant to focal adhesion, cell adhesion molecules, adherens and gap junction related pathways in HT-29 cells suggest a massive host response to BoNT/A. A clear differential response in epithelial and neuronal cells indicates that the genes affected may play a distinct role in BoNTs cellular mode of action, involving these two types of host cells. PMID- 21291864 TI - Inhibition of checkpoint kinase 1 sensitizes lung cancer brain metastases to radiotherapy. AB - The most important therapeutic tool in brain metastasis is radiation therapy. However, resistance to radiation is a possible cause of recurrence or treatment failure. Recently, signal pathways about DNA damage checkpoints after irradiation have been noticed. We investigated the radiosensitivity can be enhanced with treatment of Chk1 inhibitor, AZD7762 in lung cancer cell lines and xenograft models of lung cancer brain metastasis. Clonogenic survival assays showed enhancement of radiosensitivity with AZD7762 after irradiation of various doses. AZD7762 increased ATR/ATM-mediated Chk1 phosphorylation and stabilized Cdc25A, suppressed cyclin A expression in lung cancer cell lines. In xenograft models of lung cancer (PC14PE6) brain metastasis, AZD7762 significantly prolonged the median survival time in response to radiation. Depletion of Chk1 using shRNA also showed an enhancement of sensitivity to radiation in PC14PE6 cells. The results of this study support that Chk1 can be a good target for enhancement of radiosensitivity. PMID- 21291865 TI - Regulation of ethanol-sensitive EAAT2 expression through adenosine A1 receptor in astrocytes. AB - Adenosine-regulated glutamate signaling in astrocytes is implicated in many neurological and neuropsychiatric disorders. In this study, we examined whether adenosine A1 receptor regulates EAAT2 expression in astrocytes using pharmacological agents and siRNAs. We found that adenosine A1 receptor-specific antagonist DPCPX or PSB36 decreased EAAT2 expression in a dose-dependent manner. Consistently, knockdown of A1 receptor in astrocytes decreased EAAT2 mRNA expression while overexpression of A1 receptor upregulated EAAT2 expression and function. Since A1 receptor activation is mainly coupled to inhibitory G-proteins and inhibits the activity of adenylate cyclase, we investigated the effect of forskolin, which activates adenylate cyclase activity, on EAAT2 mRNA levels. Interestingly, we found that forskolin reduced EAAT2 expression in dose- and time dependent manners. In contrast, adenylate cyclase inhibitor SQ22536 increased EAAT2 expression in dose- and time-dependent manners. In addition, forskolin blocked ethanol-induced EAAT2 upregulation. Taken together, these results suggest that A1 receptor-mediated signaling regulates EAAT2 expression in astrocytes. PMID- 21291866 TI - Insulin increases glutamate transporter GLT1 in cultured astrocytes. AB - The astroglial cell-specific glutamate transporter subtype 2 (excitatory amino acid transporter 2, GLT1) plays an important role in excitotoxicity that develops after damage to the central nervous system (CNS) is incurred. Both the protein kinase C signaling pathway and the epidermal growth factor (EGF) pathway have been suggested to participate in the modulation of GLT1, but the modulatory mechanisms of GLT1 expression are not fully understood. In the present study, we aimed to evaluate the effects of insulin on GLT1 expression. We found that short term stimulation of insulin led to the upregulation of both total and surface expressions of GLT1. Akt phosphorylation increased after insulin treatment, and triciribine, the inhibitor of Akt phosphorylation, significantly inhibited the effects of insulin. We also found that the upregulation of GLT1 expression correlated with increased kappa B motif-binding phosphoprotein (KBBP) and GLT1 mRNA levels. Our results suggest that insulin may modulate the expression of astrocytic GLT1, which might play a role in reactive astrocytes after CNS injuries. PMID- 21291867 TI - Aurora inhibitor MLN8237 in combination with docetaxel enhances apoptosis and anti-tumor activity in mantle cell lymphoma. AB - Auroras (A and B) are oncogenic serine/threonine kinases that play key roles in the mitotic phase of the eukaryotic cell cycle. Analysis of the leukemia lymphoma molecular profiling project (LLMPP) database indicates Aurora over-expression correlates with poor prognosis. A tissue microarray (TMA) composed of 20 paired mantle cell lymphoma (MCL) patients demonstrated >75% of patients had high levels Aurora expression. Aurora A and B were also found elevated in 13 aggressive B-NHL cell lines. MLN8237, an Aurora inhibitor induced G2/M arrest with polyploidy and abrogated Aurora A and histone-H3 phosphorylation. MLN8237 inhibited aggressive B NHL cell proliferation at an IC(50) of 10-50 nM and induced apoptosis in a dose- and time-dependent manner. Low dose combinations of MLN8237+docetaxel enhanced apoptosis by ~3-4-fold in cell culture compared to single agents respectively. A mouse xenograft model of MCL demonstrated that MLN8237 (10 or 30 mg/kg) or docetaxel (10mg/kg) alone had modest anti-tumor activity. However, MLN8237 plus docetaxel demonstrated a statistically significant tumor growth inhibition and enhanced survival compared to single agent therapy. Together, our results suggest that MLN8237 plus docetaxel may represent a novel therapeutic strategy that could be evaluated in early phase trials in relapsed/refractory aggressive B-cell NHL. PMID- 21291868 TI - PPARgamma activation redirects macrophage cholesterol from fecal excretion to adipose tissue uptake in mice via SR-BI. AB - PPARgamma agonists, used in the treatment of Type 2 diabetes, can raise HDL cholesterol, therefore could potentially stimulate macrophage-to-feces reverse cholesterol transport (RCT). We aimed to test whether PPARgamma activation promotes macrophage RCT in vivo. Macrophage RCT was assessed in mice using cholesterol loaded/(3)H-cholesterol labeled macrophages. PPARgamma agonist GW7845 (20 mg/kg/day) did not change (3)H-tracer plasma appearance, but surprisingly decreased fecal (3)H-free sterol excretion by 43% (P<0.01) over 48h. Total free cholesterol efflux from macrophages to serum (collected from control and GW7845 groups) was not different, although ABCA1-mediated efflux was significantly higher with GW7845. To determine the effect of PPARgamma activation on HDL cholesterol uptake by different tissues, the metabolic fate of HDL labeled with (3)H-cholesteryl ether (CE) was also measured. We observed two-fold increase in HDL derived (3)H-CE uptake by adipose tissue (P<0.005) with concomitant 22% decrease in HDL derived (3)H-CE uptake by the liver (P<0.05) in GW7845 treated wild type mice. This was associated with a significant increase in SR-BI protein expression in adipose tissue, but not liver. The same experiment in SR-BI knockout mice, showed no difference in HDL derived (3)H-CE uptake by adipose tissue or liver. In conclusion, PPARgamma activation decreases the fecal excretion of macrophage derived cholesterol in mice. This is not due to inhibition of cholesterol efflux from macrophages, but rather involves redirection of effluxed cholesterol from liver towards adipose tissue uptake via SR-BI. This represents a novel mechanism for regulation of RCT and may extend the therapeutic implications of these ligands. PMID- 21291869 TI - Effect of its deaminated metabolite, 2',2'-difluorodeoxyuridine, on the transport and toxicity of gemcitabine in HeLa cells. AB - Gemcitabine is a pyrimidine analog effective against many solid tumors. Following intravenous administration, deaminases in the plasma rapidly convert the parent compound, gemcitabine, to its deaminated metabolite, 2',2'-difluorodeoxyuridine (dFdU), resulting in an elimination half-life for gemcitabine of 8min. The half life of dFdU, however, is upwards of 14h, yielding plasma concentrations that are frequently 10-20-fold higher than that of gemcitabine. The uptake of gemcitabine into tumor cells is facilitated by both concentrative (hCNT) and equilibrative (hENT) nucleoside transporters. Recently, it was observed that dFdU is a substrate for hCNT as well. The purpose of this study was to investigate the effects of dFdU on gemcitabine uptake and efflux via hENT1 and hENT2 in HeLa cells. Our results suggest that dFdU is a substrate for both hENT1 and hENT2 as well as a competitive inhibitor of gemcitabine transport at concentrations >100 fold lower than those typically achieved in plasma (IC(50)=0.45 and 1.2MUM for hENT1/2 and hENT2, respectively). However, inhibition of gemcitabine uptake is time-dependent, as dFdU limits gemcitabine uptake into HeLa cells by more than 80% during short (<20s) incubation periods but increases net gemcitabine retention as incubation length increases. While dFdU enhances the accumulation of gemcitabine by up to 1.5-fold following a 60 min incubation, dFdU did not enhance gemcitabine cytotoxicity. In conclusion, this is the first report of an interaction between dFdU and gemcitabine suggesting that the deaminated metabolite may play an important role in the disposition of gemcitabine in tumor cells. PMID- 21291870 TI - Opioid-like compound exerts anti-fibrotic activity via decreased hepatic stellate cell activation and inflammation. AB - Hepatic fibrosis is characterized by excess type I collagen deposition and exacerbated inflammatory response. Naltrexone, an opioid receptor antagonist used for treating alcohol abuse, attenuates hepatocellular injury in fibrotic animal models, which can be accompanied by deleterious side effects. Additionally, opioid neurotransmission is upregulated in patients with inflammatory liver disease. Several derivatives of Naltrexone, Nalmefene (Nal) and JKB-119, exert immunomodulatory activity; however, unlike Nal, JKB-119 does not show significant opioid receptor antagonism. To delineate the potential hepatoprotective effects of these compounds, we investigated if JKB-119 and Nal could modulate activation of hepatic stellate cells (HSCs), primary effector cells that secrete type I collagen and inflammatory mediators during liver injury. Our results demonstrated that Nal or JKB-119 treatment decreased smooth muscle alpha-actin, a marker of HSC activation, mRNA and protein expression. Despite decreased collagen mRNA expression, both compounds increased intracellular collagen protein expression; however, inhibition of collagen secretion was observed. To address a possible mechanism for suppressed collagen secretion or retention of intracellular collagen, endoplasmic (ER) protein expression and matrix metalloproteinase (MMP) activity were examined. While no change in ER protein expression (Grp78, PDI, Hsp47) was observed, MMP13 mRNA expression was dramatically increased. In an acute LPS inflammatory injury animal model, JKB-119 treatment decreased liver injury (ALT), plasma TNFalpha and PMN liver infiltration. Overall, these results suggest that JKB-119 can directly inhibit HSC activation attributed to anti inflammatory activity and may, therefore, attenuate inflammation associated with HSC activation and liver disease. PMID- 21291871 TI - The pyramidal neurons in the medial prefrontal cortex show decreased response to 5-hydroxytryptamine-3 receptor stimulation in a rodent model of Parkinson's disease. AB - In the present study, effect of SR 57227A, a selective 5-hydroxytryptamine-3 (5 HT(3)) receptor agonist, on the firing activity of pyramidal neurons in the medial prefrontal cortex (mPFC) was studied in normal rats and rats with 6 hydroxydopamine lesions of the substantia nigra pars compacta by using extracellular recording. Systemic administration of SR 57227A (40-640 MUg/kg, i.v.) decreased the mean firing rate of pyramidal neurons in normal and the lesioned rats. This inhibition was significant only at doses higher than 320 MUg/kg and 640 MUg/kg in normal and the lesioned rats, respectively, and was reversed by i.v. administration of 5-HT(3) receptor antagonist tropisetron or GABA(A) receptor antagonist bicuculline. Furthermore, local application of SR 57227A (0.01 MUg) in the mPFC inhibited the firing rate of pyramidal neurons in normal rats while having no effect on firing rate in the lesioned rats. The i.v. administration of bicuculline excited the pyramidal neurons in normal rats, and then local application of SR 57227A did not alter the mean firing rate of these neurons. However, these two drugs did not affect the activity of the pyramidal neurons in the lesioned rats. We conclude that activation of 5-HT(3) receptors inhibited pyramidal neurons in the mPFC of normal rats via GABAergic interneurons, and degeneration of the nigrostriatal pathway decreased response of the pyramidal neurons to SR 57227A, suggesting the dysfunction of 5-HT(3) receptors and/or down-regulation of the expression on GABAergic interneurons in the lesioned rats. PMID- 21291872 TI - Mammalian alcohol dehydrogenases--a comparative investigation at gene and protein levels. AB - Mammalian alcohol dehydrogenase (ADH) can be divided into six classes, ADH1-ADH6, according to primary structure and function, where the classes are further subdivided into isozymes and allelic forms. With the increasing amount of available genomic data a general pattern is possible to trace within the mammalian ADH gene and protein families. The transcriptional order for the ADH genes in all mammalian genomes is the same (ADH4-ADH1-ADH6-ADH5-ADH2-ADH3), but the cluster is found on different chromosomes in different species. However, in primates only ADH1-ADH5 are present, where the loss of ADH6 may have occurred simultaneously as the split into ADH1 isoforms. ADH3, also denoted glutathione dependent formaldehyde dehydrogenase and S-nitrosoglutathione reductase, is identified as the last gene in the ADH transcriptional order, but several pseudogenes for ADH3 have been traced at other chromosomes. The flanking genes outside the ADH genome are similar or identical for all species showing that a larger DNA region has been duplicated and further evolved. However, the only entirely completed ADH genomes are those from primates and rodents. The latest identified ADH forms, ADH5 (class V) and ADH6 (class VI), are truly different classes and both are very diverged in contrast to ADH3, which is the most conserved class of all ADHs. ADH5 and ADH6 have been identified at the gene and transcriptional levels only, and their functions are still an enigma. PMID- 21291873 TI - Quantitative assessment of sterol traffic in living cells by dual labeling with dehydroergosterol and BODIPY-cholesterol. AB - Cholesterol with BODIPY at carbon-24 of the side chain (BCh2) has recently been introduced as new cholesterol probe with superior fluorescence properties. We compare BCh2 with the intrinsically fluorescent dehydroergosterol (DHE), a well established marker for cholesterol, by introducing simultaneous imaging of both sterols in model membranes and living cells. BCh2 had a lower affinity than DHE for the biologically relevant liquid-ordered phase in model membranes. Still, DHE and BCh2 trafficked from the plasma membrane to the endocytic recycling compartment (ERC) of BHK cells with identical kinetics. This transport pathway was strongly reduced after energy depletion of cells or expression of the dominant-negative clathrin heavy chain. The partitioning into lipid droplets of BHK and HeLa cells was higher for BCh2 than for DHE. Within droplets, the photodegradation of BCh2 was enhanced and followed a stretched exponential decay, while the fluorescence lifetime of BCh2 was comparable in various cellular regions. Our results indicate that BCh2 is suitable for analyzing sterol uptake pathways and inter-organelle sterol flux in living cells. The BODIPY-moiety affects lipid phase preference of the sterol probe and causes some differential targeting of BCh2 and DHE in cells with high fat content. PMID- 21291874 TI - Plasma ceruloplasmin as a biomarker for obesity: a proteomic approach. AB - OBJECTIVES: This study aimed to investigate new biomarkers of obesity particularly in relation with inflammation-associated proteins using protein differential display techniques. DESIGN AND METHODS: Comparison of protein expression in plasma between non-obese (n=109, body mass index, BMI<25kg/m(2)) and obese (n=32, BMI>=25kg/m(2)) groups was carried out using two-dimensional gel electrophoresis (2-DE) analysis. ELISA was also performed for validation. RESULTS: Among six differentially expressed protein spots, ceruloplasmin (Cp) and fibrinogen were over-expressed in obese group. Plasma Cp levels were significantly higher in obese group than non-obese group (34.0 +/- 8.6 vs. 41.3 +/- 12.7mg/dL, p<0.001) and positively correlated with age (r=0.253, p<0.005), BMI (r=0.265, p<0.001) and hsCRP (r=0.385, p<0.001). In stepwise multiple linear regression analysis, plasma Cp along with hsCRP were found predictors for obesity (adjusted beta-coefficient=0.266, p<0.01). CONCLUSION: Elevated plasma Cp levels were significantly associated with obesity, which may be suggested to be a marker of obesity. PMID- 21291875 TI - Asymmetric dimethylarginine (ADMA) levels are increased in patients with fibromyalgia: correlation with tumor necrosis factor-alpha (TNF-alpha) and 8-iso prostaglandin F(2alpha) (8-iso-PGF(2alpha)). AB - OBJECTIVE: The aim of the study was to investigate serum levels of asymmetric dimethylarginine (ADMA), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and plasma levels of 8-iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)) in patients with fibromyalgia. DESIGN AND METHOD: Twenty-seven patients with fibromyalgia and twenty healthy controls were enrolled in this study. ADMA, TNF alpha, IL-6 and 8-iso-PGF(2alpha) levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Serum levels of ADMA and TNF-alpha and plasma levels 8-iso-PGF(2alpha) were significantly increased in patients with fibromyalgia compared to controls. However, no significant difference was observed in IL-6 levels between the two groups. ADMA concentrations were positively correlated with TNF-alpha and 8-iso-PGF(2alpha) levels in patients with fibromyalgia. CONCLUSION: This is the first study reporting that ADMA levels are significantly elevated in patients with fibromyalgia in association with increased 8-iso-PGF(2alpha) and TNF-alpha concentrations. Thereby, ADMA could be suggested as a reliable marker of endothelial dysfunction in patients with fibromyalgia. PMID- 21291876 TI - Reply to "pediatric reference intervals for immunoglobulin G and its subclasses with Siemens immunonephelometric assays". PMID- 21291877 TI - Quantitative indices of dynamics in concentrations of lipopolysaccharide-binding protein (LBP) as prognostic factors in severe sepsis/septic shock patients- comparison with CRP and procalcitonin. AB - OBJECTIVES: To devise and evaluate quantitative indices of dynamics in lipopolysaccharide-binding protein (LBP), CRP, and procalcitonin concentrations as prognostic markers in sepsis. DESIGN AND METHODS: Prospective observational cross-sectional study with 5-day follow-up. Simple (Delta(5-1)) and relative (chain indices-based) rates for LBP (ELISA), procalcitonin (immunoluminometry), and CRP were devised. RESULTS: Admission concentrations of all markers were higher in septic patients than controls. Not the admission levels but markers' time-courses differed between survivors (declining) and non-survivors (persistently high). Simple and relative rates were greater in survivors than non survivors. Their accuracies as outcome predictors were comparable, higher for LBP and CRP than PCT. At ~95% sensitivity, the highest specificity had LBP relative and simple rates. Except for sepsis severity scores, only LBP was independently associated with lethal outcome. CONCLUSIONS: For outcome prediction, the evaluation of dynamics of sepsis mediators, expressed by simple or relative rates, is a more suitable alternative to markers' peak values. PMID- 21291878 TI - The problems of proteinuria measurement in urine with presence of Bence Jones protein. AB - OBJECTIVES: Protein concentration measurement in the urine can be problematic in the presence of Bence Jones protein. We have carried out an external quality control assessment with the participation of 79 clinical biochemistry laboratories from the Czech Republic and Slovakia. DESIGN AND METHODS: The laboratories received a reference urine sample obtained from a patient with multiple myeloma and lambda free light chain proteinuria and were asked to type the paraprotein using immunofixation and to measure total urinary protein using their established method, most commonly turbidimetry, pyrogallol red assay, and biuret assay. RESULTS: There was a very wide inter-laboratory variability in the protein concentration readouts with up to three-fold difference in some cases. High-resolution two-dimensional electrophoresis and linear mass spectrometry showed that a high proportion of the urinary paraprotein was composed of lambda light chain fragments with molecular weight of 12kDa. CONCLUSIONS: Our results highlight the challenges of reliable and reproducible measurement of urinary protein concentration in the presence of Bence Jones protein. PMID- 21291879 TI - Impaired GFR is the most important determinant for FGF-23 increase in chronic kidney disease. AB - OBJECTIVES: It is unclear whether fibroblast growth factor-23 (FGF-23) increases in response to phosphate accumulation or to decrease clearance in chronic kidney disease (CKD) as is the case with other low molecular weight proteins such as cystatin C (CysC). DESIGN AND METHODS: This cross-sectional study measured serum FGF-23, CysC, and other serum markers of bone metabolism in 69 patients, aged 18 months-24 years, with various stages of CKD (eGFR=11-214mL/min). RESULTS: FGF-23 levels were significantly correlated with CysC and parathyroid hormone levels (PTH) on univariate non-linear regression analysis. In multivariate linear regression analysis, log (CysC) (beta=0.660, p<0.0001), log (PTH) (beta=0.038, p=0.37), and phosphate (beta=0.222, p=0.028) explained 69.1% of the variance of FGF-23. CONCLUSIONS: CysC had the largest unique contribution to FGF-23 variance in this model, supporting the hypothesis that renal clearance may be the most responsible factor for elevated FGF-23 levels in early stages of CKD. PMID- 21291880 TI - Cul4A is essential for spermatogenesis and male fertility. AB - The mammalian Cul4 genes, Cul4A and Cul4B, encode the scaffold components of the cullin-based E3 ubiquitin ligases. The two Cul4 genes are functionally redundant. Recent study indicated that mice expressing a truncated CUL4A that fails to interact with its functional partner ROC1 exhibit no developmental phenotype. We generated a Cul4A-/- strain lacking exons 4-8 that does not express any detectable truncated protein. In this strain, the male mice are infertile and exhibit severe deficiencies in spermatogenesis. The primary spermatocytes are deficient in progression through late prophase I, a time point when expression of the X-linked Cul4B gene is silenced due to meiotic sex chromosome inactivation. Testes of the Cul4A-/- mice exhibit extensive apoptosis. Interestingly, the pachytene spermatocytes exhibit persistent double stranded breaks, suggesting a deficiency in homologous recombination. Also, we find that CUL4A localizes to the double stranded breaks generated in pre-pachytene spermatocytes. The observations identify a novel function of CUL4A in meiotic recombination and demonstrate an essential role of CUL4A in spermatogenesis. PMID- 21291881 TI - Colonic submucosal 5-HT(3) receptor-mediated somatostatin-dependent secretoinhibitory pathway is suppressed in water-immersion restraint stressed rats. AB - We have demonstrated that the activation of 5-hydroxytryptamine (5-HT) receptor 3 in the submucosal plexus suppresses 5-HT-induced colonic ion secretion by increasing submucosal somatostatin release. A number of psychological and physical stresses have impacts on the intestinal mucosal functions, including secretion and the epithelial barrier. Whether the 5-HT(3) receptor-mediated somatostatin-dependent secretoinhibitory pathway in the rat distal colon is involved in the stress process is still unknown. The present study aims to investigate the effect of the water-immersion restraint stress on this inhibitory pathway and its underlying mechanisms. Mucosa/submucosa preparations from the rat distal colon were mounted in the Ussing chambers for the measurement of short circuit current (I(SC)). Real-time PCR and western blot were performed to study the expression of the 5-HT(3) receptor, 5-HT(4) receptor, and somatostatin receptor 2. Radioimmunoassay was used to measure somatostatin release. After 2h of water-immersion restraint stress, the membrane resistance (Rte) of rat mucosa/submucosa preparations was significantly decreased, but the baseline I(SC) and 5-HT-induced I(SC) responses were significantly increased. The protein expression of the submucosal 5-HT(3) receptors and mucosal somatostatin receptor 2 were down-regulated, and the 5-HT-induced somatostatin release from the mucosa/submucosa preparations was significantly reduced in the stress group. Taken together, these results suggest that the 5-HT(3) receptor-mediated somatostatin-dependent secretoinhibitory pathway is suppressed in the water immersion restraint stressed rats, which may contribute to the acute stress induced increase in colonic secretion. PMID- 21291882 TI - Intracerebroventricular administration of morphine confers remote cardioprotection--role of opioid receptors and calmodulin. AB - The current study aimed to delineate the mechanism of remote preconditioning by intracerebroventricular morphine (RMPC) against myocardial ischemia-reperfusion injury. Male Sprague-Dawley rats were given an intracerebroventricular morphine injection before myocardial ischemia and reperfusion injury. Ischemia-reperfusion injury was achieved by 30min of left coronary artery occlusion followed by 120min of reperfusion. The effects of remote preconditioning by intracerebroventricular morphine preconditioning were also determined upon selective blockade of the delta, kappa or MU-opioid receptors, or calmodulin (CaM). The infarct size, as a percentage of the area at risk, was determined by 2,3,5-triphenyltetrazolium staining. Remote preconditioning by intracerebroventricular morphine reduced infarct size in the ischemic/reperfused myocardium, and the effect was abolished by the selective blockade of any one of the three delta, kappa and MU opioid receptors or CaM. Furthermore, remote preconditioning by intracerebroventricular morphine increased the expression of CaM in the hippocampus and the plasma level of calcitonin gene-related peptide (CGRP). The results of the present study provide evidence that the cardioprotection of remote preconditioning by intracerebroventricular morphine involves not only all three types of opioid receptors in the central nervous system, but also CaM, which releases CGRP, one of the mediators of remote preconditioning. PMID- 21291883 TI - Modulation of benzodiazepine receptor, adrenoceptor and muscarinic receptor by diazepam in rat parotid gland. AB - This study investigated the influence of diazepam on the binding characteristics of adrenoceptor, muscarinic and benzodiazepine receptors in rat parotid gland membrane using a radioligand binding assay. At a concentration of >10(-6)M, diazepam competed with [(3)H]dihydroalprenolol for beta-adrenoceptor, but not [(3)H]prazosin for alpha-adrenoceptor or [(3)H]quinuclidinyl benzilate for muscarinic receptor. Continuous administration of diazepam at doses of 0.4mg/kg/day, i.p. for 7days in rat significantly decreased pilocarpine (4.0mg/kg, i.p.)-induced parotid salivary flow. Diazepam also produced a significant increase in the dissociation constant (Kd) value for [(3)H]dihydroalprenolol binding, but no change in the maximal binding capacity (Bmax) value, and a decrease in the Kd value for [(3)H]diazepam binding to benzodiazepine receptors, but no change in the Kd or Bmax values for [(3)H]prazosin or [(3)H]quinuclidinyl benzilate binding. These results suggest that continuous administration of diazepam modifies affinity for beta adrenoceptor and benzodiazepine receptor binding sites in parotid gland membrane and that changes in these binding sites may be closely related to diazepam induced suppression of salivary secretion. PMID- 21291884 TI - Human TopBP1 localization to the mitotic centrosome mediates mitotic progression. AB - TopBP1 contains repeats of the BRCA1 C-terminal (BRCT) domain and plays important roles in DNA damage response, DNA replication, and other cellular regulatory functions during the interphase. In prometaphase, metaphase, and anaphase, TopBP1 localizes to the mitotic centrosomes, which function as spindle-poles for the bipolar separation of sister chromatids. The localization of TopBP1 to the mitotic centrosomes is mediated by amino acid residues 1259 to 1420 in the TopBP1 C-terminal region (TbpCtr). GST and DsRed2 tags fused to TbpCtr were localized in the mitotic centrosomes, thereby suggesting that TbpCtr functions as a mitosis specific centrosome localization signal (CLS). Mutations of Ser 1273 and/or Lys 1317, which were predicted to interact with a putative phosphoprotein, inhibited CLS function. Ectopic expression of TbpCtr specifically eliminated endogenous TopBP1 from the mitotic centrosomes, whereas mutant TbpCtr derivatives, containing substitutions at Ser 1273 and/or Lys 1317, did not. The specific elimination of TopBP1 from the mitotic centrosomes prolonged the durations of prometaphase and metaphase and shortened the inter-kinetochore distances of metaphase sister chromatids while maintaining the spindle assembly checkpoint. These results suggest that the localization of TopBP1 to the mitotic centrosomes is necessary for proper mitotic progression. PMID- 21291885 TI - Chronic and acute stress responses in Senegalese sole (Solea senegalensis): the involvement of cortisol, CRH and CRH-BP. AB - The hypothalamus-pituitary-interrenal (HPI) axis is pivotal in the endocrine stress response of fish. Hypothalamic corticotropin-releasing hormone (CRH) initiates the endocrine stress response and stimulates the release of adrenocorticotropic hormone (ACTH) from the pituitary pars distalis, which in turn activates cortisol production and release by the interrenal cells of the head kidney. CRH activity depends on the levels of a specific CRH binding protein (CRH-BP). We have characterized the cDNAs coding for CRH and CRH-BP in Senegalese sole (Solea senegalensis) and investigated their mRNA expression in juveniles that were submitted to a protocol that involved exposure to a chronic stressor (viz. increased cultivation densities) followed by an acute stressor (viz. transfer to increased ambient salinity). Juveniles were cultivated at three densities (1.9, 4.7 and 9.8 kg/m(2)) for 33 days, and then exposed to an osmotic challenge that involved transfer from seawater (390/00 salinity, SW) to hypersaline seawater (550/00, HSW). The highest density imposed stress as indicated by elevated cortisol levels and CRH mRNA expression compared to fish stocked at low density. Fish kept at high density differentially responded to a posterior transfer to HSW; no cortisol or CRH response was seen, but osmoregulatory and metabolic parameters were affected. No differences in CRH-BP mRNA expression levels were found at different stocking densities; transfer to HSW enhanced expression in both low and high density stocked animals, suggesting that CRH-BP acts as a modulator of the acute stress response, not so of the chronic stress response. We conclude that stocking of Senegalese sole at high density is a stressful condition that may compromise the capacity to cope with subsequent stressors. PMID- 21291886 TI - Exogenous GDF9 but not Activin A, BMP15 or TGFbeta alters tight junction protein transcript abundance in zebrafish ovarian follicles. AB - The tight junction (TJ) complex plays an important role in regulating paracellular permeability and provides mechanical stability in vertebrate epithelia and endothelia. In zebrafish ovarian follicles, TJ complexes in the follicular envelope degenerate as the follicles develop towards maturation. In the current study, transcript abundance of claudins (cldn d, g, h, 1, and 12) and occludins (ocln, and ocln b) were assessed in mid-vitellogenic follicles in response to treatment with exogenous growth factors that are reported to be involved in zebrafish follicle development (i.e. Activin A, BMP15, GDF9 and TGFbeta). Exogenous GDF9 reduced the transcript abundance of cldn g, ocln and ocln b in mid-vitellogenic follicles, whereas Activin A, BMP15, and TGFbeta had no effect. Subsequent studies with GDF9 revealed that this factor did not alter TJ protein transcript abundance in pre-vitellogenic follicles but did increase the abundance of ocln b in fully grown (maturing) follicles. GDF9 was also seen to increase the abundance of StAR mRNA in all but primary stage follicles. These data suggest a role for GDF9 in the regulation of TJ integrity in zebrafish ovarian follicles, perhaps in the facilitation of ovulation, and support a previously postulated role for GDF9 in zebrafish ovarian follicle development. In addition, data also support the idea that endocrine factors play an important role in the regulation of TJ proteins during ovarian follicle development. PMID- 21291887 TI - Corticosterone, brood size, and hatch order in free-living Florida scrub-jay (Aphelocoma coerulescens) nestlings. AB - It is well known that variation in developmental conditions can have profound effects upon lifetime fitness. In altricial avian species, nestlings undergo a substantial portion of development in the nest after hatching, often in the presence of nest-mates. This can result in the formation of brood hierarchies based on age, size, and competitive ability. Measurement of baseline corticosterone (CORT) levels in developing birds may provide a means to assess whether individuals within a brood experience stress due to sibling competition or nutritional state. However, few studies have attempted to correlate corticosterone concentrations with brood hierarchies in free-living, developing birds. We investigated the degree to which corticosterone levels in nestling Florida scrub-jays (Aphelocoma coerulescens) were predicted by brood size, hatching order, and body mass. Nestling corticosterone levels were inversely correlated with body mass but did not differ among brood sizes. Within broods of two, second-hatched nestlings had lower CORT than first-hatched nestlings, although there was no effect of hatch order in broods of three or four nestlings. The results of this study suggest that conditions within the nest, particularly those associated with within-brood hierarchies, are manifested through differential body condition and nestling corticosterone secretion. The consequences of this variation in nestling corticosterone are unknown, but development of the adult phenotype, as well as life-long survival, may be impacted. PMID- 21291888 TI - Expression pattern of clock under acute phase-delay of the light/dark cycle in the chicken pineal model. AB - Shift workers have a higher risk of metabolic syndrome, a condition that also develops in mice carrying mutation in their circadian clock gene clock. To collect more data on the transcriptional changes of clock under phase-shifted light/dark LD conditions, we examined the 24h patterns of clock mRNA expression in vivo and in vitro in chickens exposed acutely to a reversed LD (DL) cycle. Under controlled LD conditions (lights on at 6:00, lights off at 20:00), clock mRNA expression peaked in vivo at 2:00 (Zeitgeber Time 20, ZT20) and in vitro at 22:00 (ZT16). Even higher mRNA contents were measured in the first cycle of in vivo DL conditions between 22:00 and 6:00 (lights at night), but in the second cycle by 2:00, lower mRNA contents were detected than the control peak values seen at this time point. Furthermore, no alterations were found in vitro in clock mRNA content during the first 12h of DL conditions (lights at night). The differences seen between the first and the second DL cycles in vivo and between the in vivo and in vitro data for the first DL cycle support the idea that neurohumoral signals perturbed by a phase-delayed light-dark cycle may also play a role in the in vivo rapid transcriptional resetting of the circadian clock in the chicken pineal model. PMID- 21291889 TI - Exercise training does not improve cardiac function in compensated or decompensated left ventricular hypertrophy induced by aortic stenosis. AB - There is ample evidence that regular exercise exerts beneficial effects on left ventricular (LV) hypertrophy, remodeling and dysfunction produced by ischemic heart disease or systemic hypertension. In contrast, the effects of exercise on pathological LV hypertrophy and dysfunction produced by LV outflow obstruction have not been studied to date. Consequently, we evaluated the effects of 8 weeks of voluntary wheel running in mice (which mitigates post-infarct LV dysfunction) on LV hypertrophy and dysfunction produced by mild (mTAC) and severe (sTAC) transverse aortic constriction. mTAC produced ~40% LV hypertrophy and increased myocardial expression of hypertrophy marker genes but did not affect LV function, SERCA2a protein levels, apoptosis or capillary density. Exercise had no effect on global LV hypertrophy and function in mTAC but increased interstitial collagen, and ANP expression. sTAC produced ~80% LV hypertrophy and further increased ANP expression and interstitial fibrosis and, in contrast with mTAC, also produced LV dilation, systolic as well as diastolic dysfunction, pulmonary congestion, apoptosis and capillary rarefaction and decreased SERCA2a and ryanodine receptor (RyR) protein levels. LV diastolic dysfunction was likely aggravated by elevated passive isometric force and Ca(2+)-sensitivity of myofilaments. Exercise training failed to mitigate the sTAC-induced LV hypertrophy and capillary rarefaction or the decreases in SERCA2a and RyR. Exercise attenuated the sTAC-induced increase in passive isometric force but did not affect myofilament Ca(2+)-sensitivity and tended to aggravate interstitial fibrosis. In conclusion, exercise had no effect on LV function in compensated and decompensated cardiac hypertrophy produced by LV outflow obstruction, suggesting that the effect of exercise on pathologic LV hypertrophy and dysfunction depends critically on the underlying cause. PMID- 21291890 TI - Cardiac myosin-binding protein C in hypertrophic cardiomyopathy: mechanisms and therapeutic opportunities. AB - Cardiac myosin-binding protein C (cMyBP-C) is a component of the thick filaments of the sarcomere. Understanding the structural and functional role of cMyBP-C in the heart is clinically relevant since cMyBP-C gene mutations are a widely recognized cause of hypertrophic cardiomyopathy (HCM), which affects 0.2% of the general population. Nonsense and frameshift mutations are common in cMyBP-C and their expressions are regulated by three quality control systems, the nonsense mediated mRNA decay, ubiquitin-proteasome system, and autophagy, which contribute to minimize the production of potential poison mutant proteins. This review discusses the structural and regulatory functions of cMyBP-C, the molecular mechanisms involved in cMyBP-C-related HCM, as well as potential causative therapies for HCM. PMID- 21291891 TI - RGS2 is a primary terminator of beta2-adrenergic receptor-mediated G(i) signaling. AB - Two major beta-adrenergic receptor (betaAR) subtypes, beta(1)AR and beta(2)AR, are expressed in mammalian heart with beta(1)AR coupling to G(s) and beta(2)AR dually coupling to G(s) and G(i) proteins. In many types of chronic heart failure, myocardial contractile response to both beta(1)AR and beta(2)AR stimulation is severely impaired. The dysfunction of betaAR signaling in failing hearts is largely attributable to an increase in G(i) signaling, because disruption of the G(i) signaling restores myocardial contractile response to beta(1)AR as well as beta(2)AR stimulation. However, the mechanism terminating the beta(2)AR-G(i) signaling remains elusive, while it has been shown activation of the G(i) signaling is dependent on agonist stimulation and subsequent PKA mediated phosphorylation of the receptor. Here we demonstrate that regulator of G protein signaling 2 (RGS2) is a primary terminator of the beta(2)AR-G(i) signaling. Specifically, prolonged absence of agonist stimulation for 24h impairs the beta(2)AR-G(i) signaling, resulting in enhanced beta(2)AR- but not beta(1)AR mediated contractile response in cultured adult mouse cardiomyocytes. Increased beta(2)AR contractile response is accompanied by a selective upregulation of RGS2 in the absence of alterations in other major cardiac RGS proteins (RGS3-5) or G(s), G(i) or betaAR subtypes. Administration of a betaAR agonist, isoproterenol (ISO, 1.0 nM), prevents RGS2 upregulation and restores the beta(2)AR-G(i) signaling in cultured cells. Furthermore, RGS2 ablation, similar to betaAR agonist stimulation, sustains the beta(2)AR-G(i) signaling in cultured cells, whereas adenoviral overexpression of RGS2 suppresses agonist-activated beta(2)AR G(i) signaling in cardiomyocytes and HEK293 cells. These findings not only define RGS2 as a novel negative regulator of the beta(2)AR-G(i) signaling but also provide a potential novel target for the treatment of chronic heart failure. PMID- 21291892 TI - A genome evolution-based framework for measures of originality for clades. AB - To evaluate the originality of a species for determining its conservation priority, most indices use the branching pattern and the branch length of a phylogenetic tree to represent the diversification pattern and the number of characters. One limitation of these indices is their lack of consideration of the dynamic process, such as character changes and distribution along lineages during evolution. In this study, we propose a robust framework incorporating the underlying dynamic processes under a framework of genome evolution to model character changes and distribution along different lineages in a given phylogenetic tree. Our framework provides a more transparent modeling, instead of the simple surrogates of branching pattern and branch length previously employed. Nonrandom extinction has been found to be clustered within old and species-poor clades, thus it is desirable to combine the evaluation of originality of clades, which will provide a more complete picture and a useful tool for setting global conservation priorities. Using a phylogenetic tree consisting of 70 species of New World terrestrial Carnivora, we demonstrate that the index derived from our framework can discern the difference in originality of clades. Moreover, we demonstrate that the originality of clades and species in a tree changes with different scenarios of dynamic processes, which were neglected by previous indices. We find that the originality of clades should be one of the criteria for setting global conservation priorities. PMID- 21291893 TI - Two optimal mutation rates in obligate pathogens subject to deleterious mutation. AB - Pathogen species with high mutation rates are likely to accumulate deleterious mutations that reduce their reproductive potential within the host. By altering the within-host growth rate of the pathogen, the deleterious mutation load has the potential to affect epidemiological properties such as prevalence, mean pathogen load, and the mean duration of infections. Here, I examine an epidemiological model that allows for multiple segregating mutations that affect within-host replication efficiency. The model demonstrates a complex range of outcomes depending on pathogen mutation rate, including two distinct, widely separated mutation rates associated with high pathogen prevalence. The low mutation rate prevalence peak is associated with small amounts of genetic diversity within the pathogen population, relatively stable prevalence and infection dynamics, and genetic variation partitioned between hosts. The high mutation rate peak is characterized by considerable genetic diversity both within and between hosts, relatively frequent invasions by more virulent types, and is qualitatively similar to an RNA virus quasispecies. The two prevalence peaks are separated by a valley where natural selection favors evolution toward the optimal within-host state, which is associated with high virulence and relatively rapid host mortality. Both chronic and acute infections are examined using stochastic forward simulations. PMID- 21291894 TI - A three-species model explaining cyclic dominance of Pacific salmon. AB - The four-year oscillations of the number of spawning sockeye salmon (Oncorhynchus nerka) that return to their native stream within the Fraser River basin in Canada are a striking example of population oscillations. The period of the oscillation corresponds to the dominant generation time of these fish. Various-not fully convincing-explanations for these oscillations have been proposed, including stochastic influences, depensatory fishing, or genetic effects. Here, we show that the oscillations can be explained as an attractor of the population dynamics, resulting from a strong resonance near a Neimark Sacker bifurcation. This explains not only the long-term persistence of these oscillations, but also reproduces correctly the empirical sequence of salmon abundance within one period of the oscillations. Furthermore, it explains the observation that these oscillations occur only in sockeye stocks originating from large oligotrophic lakes, and that they are usually not observed in salmon species that have a longer generation time. PMID- 21291895 TI - Maintenance affects the stability of a two-tiered microbial 'food chain'? AB - Microbial 'food chains' are fundamentally different from canonical food chains in the sense that the waste products of the organisms on one trophic level are consumed by organisms of the next trophic level rather than the organisms themselves. In the present paper we introduce a generalised model of a two-tiered microbial 'food chain' with feedback inhibition, after applying an appropriate dimensionless transformation, and investigate its stability analytically. We then parameterised the model with consensus values for syntrophic propionate degradation compiled by the IWA Task Group for Mathematical Modelling of Anaerobic Digestion Processes. Consumption of energy for all processes other than growth is called maintenance. In the absence of maintenance and decay the microbial 'food chain' is intrinsically stable, but when decay is included in the description this is not necessarily the case. We point out that this is in analogy to canonical food chains where introduction of maintenance in the description of a stable (equilibrium or limit cycle) predator-prey system generates chaos. PMID- 21291896 TI - Deficiency of calcium and magnesium induces apoptosis via scavenger receptor BI. AB - AIMS: Cells undergo apoptosis in stressed status such as in intracellular calcium overload or extracellular calcium/magnesium deficiency. The mechanisms of how deficiency of the divalent metal ions induces apoptosis remain to be defined. Scavenger receptor BI (SR-BI) is a high density lipoprotein (HDL) receptor. Recent studies demonstrated that SR-BI is a stress response molecule which induces apoptosis upon serum deprivation. In this study, we assessed our hypothesis that the deficiency of calcium/magnesium induces apoptosis via SR-BI apoptotic pathway. MAIN METHODS: We employed CHO cell lines expressing vector and SR-BI to test the effect of SR-BI on apoptosis induced by deficiency of calcium, magnesium and zinc in culture medium. The regain of different metal ions in deficient medium was also performed, respectively. Cell death was detected by morphological changes and quantified by LDH cytotoxicity assay. Apoptosis was also assessed by DNA ladder assay and DNA condensation assay. The SR-BIC323G mutant cells which lack the apoptotic activity of SR-BI were employed to verify the SR-BI-dependent effect on calcium/magnesium induced apoptosis. KEY FINDINGS: The deficiency of calcium/magnesium induced cell apoptosis in CHO-SR-BI cells, but not in CHO-vector cells. Moreover, no apoptotic cell death was observed in SR BIC323G mutant cells, indicating that the deficiency of divalent metal ions induces apoptosis in a SR-BI-dependent manner. Furthermore, the restoration of calcium or magnesium, but not zinc, protected CHO-SR-BI cells from apoptotic cell death, in a dose-dependent fashion. SIGNIFICANCE: These findings extend our understanding about how calcium and magnesium deficiency induces apoptosis. PMID- 21291897 TI - Decreased length of telomeric DNA sequences and increased numerical chromosome aberrations in human osteoarthritic chondrocytes. AB - Length of telomeric DNA sequences and numerical chromosome aberrations from uncultured human osteoarthritic (OA) articular chondrocytes were compared with those from peripheral blood leukocytes (PBL) from the same individual and from chondrocytes and PBL from control subjects. Cells were both obtained from 39 OA patients (age range: 43-80 years) and from 20 control subjects (age range: 39-94 years). Mean length of telomeric DNA sequences was determined using a quantitative real-time polymerase chain reaction (qPCR) assay and numerical chromosome aberrations were identified in interphase nuclei by Fluorescence In Situ Hybridization (FISH) using cocktails of specific DNA probes for chromosomes 7, 8 and for 18, X and Y. Chondrocytes revealed higher telomere size than PBL, both in control subjects and in OA patients, being 2 and 1.6 times higher respectively, thus revealing cell type specific differences. However, chondrocytes from OA patients showed significantly shorter telomere size than chondrocytes from control subjects (T/S ratio 1.64+/-0.41 vs. 1.99+/-0.54; mean+/ sd; p=0.008). Regarding the percentage of numerical chromosome aberrations, OA chondrocytes showed 1.7 times higher than chondrocytes from control subjects (19.80+/-3.31 vs.11.48+/-4.11; p<0.01) and 1.5 times average higher than that from PBL from the own OA patient (13.06+/-1.45; p<0.001). Moreover, PBL from OA patients also showed 1.4 times more anomalies than PBL from controls (13.06+/ 1.45 vs. 9.54+/-1.61; p<0.001). No significant differences were found between chondrocytes and PBL in control subjects. Chromosome loss was the more frequent aneuploidy, mainly monosomy 18. The decreased telomere size and increased chromosome instability in chondrocytes from OA affected joints may imply a local advanced senescence that could contribute to the pathogenesis or progression of the degenerative articular disease. Moreover, the increased chromosomal abnormalities in PBL from OA patients suggest a more general accelerated senescence phenotype that could promote the age-related degenerative joint pathology. PMID- 21291898 TI - Factors affecting germline mutations in a hypervariable microsatellite: a comparative analysis of six species of swallows (Aves: Hirundinidae). AB - Microsatellites mutate frequently by replication slippage. Empirical evidence shows that the probability of such slippage mutations may increase with the length of the repeat region as well as exposure to environmental mutagens, but the mutation rate can also differ between the male and female germline. It has been hypothesized that more intense sexual selection or sperm competition can also lead to elevated mutation rates, but the empirical evidence is inconclusive. Here, we analyzed the occurrence of germline slippage mutations in the hypervariable pentanucleotide microsatellite locus HrU10 across six species of swallow (Aves: Hirundinidae). These species exhibit marked differences in the length range of the microsatellite, as well as differences in the intensity of sperm competition. We found a strong effect of microsatellite length on the probability of mutation, but no residual effect of species or their level of sperm competition when the length effect was accounted for. Neither could we detect any difference in mutation rate between tree swallows (Tachycineta bicolor) breeding in Hamilton Harbour, Ontario, an industrial site with previous documentation of elevated mutation rates for minisatellite DNA, and a rural reference population. However, our cross-species analysis revealed two significant patterns of sex differences in HrU10 germline mutations: (1) mutations in longer alleles occurred typically in the male germline, those in shorter alleles in the female germline, and (2) male germline mutations were more often expansions than contractions, whereas no directional bias was evident in the female germline. These results indicate some fundamental differences in male and female gametogenesis affecting the probability of slippage mutations. Our study also reflects the value of a comparative, multi-species approach for locus specific mutation analyses, through which a wider range of influential factors can be assessed than in single-species studies. PMID- 21291899 TI - Progesterone signals through membrane progesterone receptors (mPRs) in MDA-MB-468 and mPR-transfected MDA-MB-231 breast cancer cells which lack full-length and N terminally truncated isoforms of the nuclear progesterone receptor. AB - The functional characteristics of membrane progesterone receptors (mPRs) have been investigated using recombinant mPR proteins over-expressed in MDA-MB-231 breast cancer cells. Although these cells do not express the full-length progesterone receptor (PR), it is not known whether they express N-terminally truncated PR isoforms which could possibly account for some progesterone receptor functions attributed to mPRs. In the present study, the presence of N-terminally truncated PR isoforms was investigated in untransfected and mPR-transfected MDA MB-231 cells, and in MDA-MB-468 breast cancer cells. PCR products were detected in PR-positive T47D Yb breast cancer cells using two sets of C-terminus PR primers, but not in untransfected and mPR-transfected MDA-MB-231 cells, nor in MDA-MB-468 cells. Western blot analysis using a C-terminal PR antibody, 2C11F1, showed the same distribution pattern for PR in these cell lines. Another C terminal PR antibody, C-19, detected immunoreactive bands in all the cell lines, but also recognized alpha-actinin, indicating that the antibody is not specific for PR. High affinity progesterone receptor binding was identified on plasma membranes of MDA-MB-468 cells which was significantly decreased after treatment with siRNAs for mPRalpha and mPRbeta. Plasma membranes of MDA-MB-468 cells showed very low binding affinity for the PR agonist, R5020, <=1% that of progesterone, which is characteristic of mPRs. Progesterone treatment caused G protein activation and decreased production of cAMP in MDA-MB-468 cells, which is also characteristic of mPRs. The results indicate that the progestin receptor functions in these cell lines are mediated through mPRs and do not involve any N terminally truncated PR isoforms. PMID- 21291900 TI - Photo-DHEA--a functional photoreactive dehydroepiandrosterone (DHEA) analog. AB - The steroid hormone dehydroepiandrosterone (DHEA) has beneficial effects on vascular function, survival of neurons, and fatty acid metabolism. However, a specific receptor for DHEA has not been identified to date. Here, we describe the synthesis of a photoreactive DHEA derivative (Photo-DHEA). In Photo-DHEA, typical characteristics of DHEA are conserved: (i) a "planar" tetracyclic ring system with a Delta(5) double bond, (ii) a 3beta-hydroxyl group, and (iii) a keto group at C17. In cell-based assays, Photo-DHEA showed the same properties as DHEA. We conclude that Photo-DHEA is suitable for radioiodination to yield a tool for the identification of the elusive DHEA receptor. PMID- 21291901 TI - Paraoxonase-1 genetic polymorphisms and susceptibility to DNA damage in workers occupationally exposed to organophosphate pesticides. AB - Human paraoxonase 1 (PON1) is a lipoprotein-associated enzyme involved in the detoxification of organophosphate pesticides (OPs) by hydrolyzing the bioactive oxons. Polymorphisms of the PON1 gene are responsible for variation in the expression and catalytic activity of PON1 enzyme. In the present study, we have determined (a) the prevalence of two common PON1 polymorphisms, (b) the activity of PON1 and acetylcholinesterase enzymes, and (c) the influence of PON1 genotypes and phenotypes variation on DNA damage in workers exposed to OPs. We examined 230 subjects including 115 workers exposed to OPs and an equal number of normal healthy controls. The results revealed that PON1 activity toward paraoxon (179.19+/-39.36 vs. 241.52+/-42.32nmol/min/ml in controls) and phenylacetate (112.74+/-17.37 vs. 134.28+/-25.49MUmol/min/ml in controls) was significantly lower in workers than in control subjects (p<0.001). No significant difference was observed in the distribution of genotypes and allelic frequencies of PON1(192)QR (Gln/Arg) and PON1(55)LM (Leu/Met) in workers and control subjects (p>0.05). The PON1 activity toward paraoxonase was found to be significantly higher in the R/R (Arg/Arg) genotypes than Q/R (Gln/Arg) and lowest in Q/Q (Gln/Gln) genotypes in both workers and control subjects (p<0.001). For PON1(55)LM (Leu/Met), PON1 activity toward paraoxonase was observed to be higher in individuals with L/L (Leu/Leu) genotypes and lowest in individuals with M/M (Met/Met) genotypes in both groups (p<0.001). No influence of PON1 genotypes and phenotypes was seen on the activity of acetylcholinesterase and arylesterase. The DNA damage was observed to be significantly higher in workers than in control subjects (p<0.05). Further, the individuals who showed least paraoxonase activity i.e., those with (Q/Q [Gln/Gln] and M/M [Met/Met]) genotypes showed significantly higher DNA damage compared to other isoforms in workers exposed to OPs (p<0.05). The results indicate that the individuals with PON1 Q/Q and M/M genotypes are more susceptible toward genotoxicity. In conclusion, the study suggests wide variation in enzyme activities and DNA damage due to polymorphisms in PON1 gene, which might have an important role in the identification of individual risk factors in workers occupationally exposed to OPs. PMID- 21291902 TI - Integrating mechanistic and polymorphism data to characterize human genetic susceptibility for environmental chemical risk assessment in the 21st century. AB - Response to environmental chemicals can vary widely among individuals and between population groups. In human health risk assessment, data on susceptibility can be utilized by deriving risk levels based on a study of a susceptible population and/or an uncertainty factor may be applied to account for the lack of information about susceptibility. Defining genetic susceptibility in response to environmental chemicals across human populations is an area of interest in the NAS' new paradigm of toxicity pathway-based risk assessment. Data from high throughput/high content (HT/HC), including -omics (e.g., genomics, transcriptomics, proteomics, metabolomics) technologies, have been integral to the identification and characterization of drug target and disease loci, and have been successfully utilized to inform the mechanism of action for numerous environmental chemicals. Large-scale population genotyping studies may help to characterize levels of variability across human populations at identified target loci implicated in response to environmental chemicals. By combining mechanistic data for a given environmental chemical with next generation sequencing data that provides human population variation information, one can begin to characterize differential susceptibility due to genetic variability to environmental chemicals within and across genetically heterogeneous human populations. The integration of such data sources will be informative to human health risk assessment. PMID- 21291903 TI - Acute stress response modified by modest inhibition of growth hormone axis: a potential machinery of the anti-aging effect of calorie restriction. AB - Calorie restriction (CR) may exert antiaging effects by inhibiting the growth hormone (GH)/IGF-1 axis. The present study investigated the effect of modest inhibition of GH signaling on stress response and compared it with the effect of CR. Heterozygous (tg/-) rats of a transgenic strain of male rats, whose GH signaling was inhibited by overexpression of the anti-sense GH gene, and wild type (WT) rats were used. Rats were fed ad libitum (AL) or 30% CR diets from 6 weeks of age. At 6 months of age, rats were killed between 0 and 8h after lipopolysaccharide (LPS) injection to evaluate the acute phase stress response. tg/- rats had less tissue injury, indicated by blood aspartate aminotransferase (AST) concentrations, than WT rats. Successive waves of incremental plasma TNF alpha, IL-6, and interferon (IFN)-gamma levels were also attenuated in tg/- rats. Activation of NF-kappaB, a redox-sensitive transcription factor, was slightly diminished in tg/- rats, whereas the AP-1 activity was increased. Similar trends were also observed in the CR groups as compared to the AL groups. The present results suggest an involvement of the GH/IGF-1 axis in the effect of CR for stress response, even if CR does not act solely through the GH axis. PMID- 21291904 TI - Transgenerational endocrine pancreatic adaptation in mice from maternal protein restriction in utero. AB - Exposure of pregnant mice to a low-protein diet (LP) impairs endocrine pancreas development in their offspring. There is evidence that this phenomenon may persist in subsequent generations. Here, we evaluated the effect of LP on glucose metabolism and pancreatic morphometry in the F3 offspring of mice at birth and weaning. LP pups in the first generation were smaller at birth, but catch-up growth; F2-LP offspring had higher body mass at birth, but there was no difference in the F3 generation. The pancreatic mass decreased in F1-LP through F3-LP at birth but increased in F2-LP at weaning. The islet volume density and diameter were smaller in all restricted groups at day 1 and 21, and F1-LP had the lowest islet number; at birth, beta cell mass was smaller in F1-LP through F3-LP and remained low throughout suckling. At day 1 and 21, pups were normoglycemic, but were hypoinsulinemic at weaning. Thus, protein restriction in mice during pregnancy produces morphologic changes in pancreatic islets, suggesting that glucose homeostasis is maintained by an increased sensitivity to insulin during the early stages of life in offspring over three consecutive generations. PMID- 21291905 TI - The association between school-based physical activity, including physical education, and academic performance: a systematic review of the literature. AB - OBJECTIVE: The purpose of this review is to synthesize the scientific literature that has examined the association between school-based physical activity (including physical education) and academic performance (including indicators of cognitive skills and attitudes, academic behaviors, and academic achievement). METHOD: Relevant research was identified through a search of nine electronic databases using both physical activity and academic-related search terms. Forty three articles (reporting a total of 50 unique studies) met the inclusion criteria and were read, abstracted, and coded for this synthesis. Findings of the 50 studies were then summarized. RESULTS: Across all the studies, there were a total of 251 associations between physical activity and academic performance, representing measures of academic achievement, academic behavior, and cognitive skills and attitudes. Slightly more than half (50.5%) of all associations examined were positive, 48% were not significant, and 1.5% were negative. Examination of the findings by each physical activity context provides insights regarding specific relationships. CONCLUSION: Results suggest physical activity is either positively related to academic performance or that there is not a demonstrated relationship between physical activity and academic performance. Results have important implications for both policy and schools. PMID- 21291906 TI - Neural correlates of pediatric obesity. AB - OBJECTIVE: Childhood obesity rates have increased over the last 40 years and have a detrimental impact on public health. While the causes of the obesity epidemic are complex, obesity ultimately arises from chronic imbalances between energy intake and expenditure. An emerging area of research in obesity has focused on the role of the brain in evaluating the rewarding properties of food and making decisions about what and how much to eat. METHOD: This article reviews recent scientific literature regarding the brain's role in pediatric food motivation and childhood obesity. RESULTS: The article will begin by reviewing some of the recent literature discussing challenges associated with neuroimaging in children and the relevant developmental brain changes that occur in childhood and adolescence. The article will then review studies regarding neural mechanisms of food motivation and the ability to delay gratification in children and how these responses differ in obese compared to healthy weight children. CONCLUSION: Increasing our understanding about how brain function and behavior may differ in children will inform future research, obesity prevention, and interventions targeting childhood obesity. PMID- 21291907 TI - Phosphate buffer effects on thermal stability and H2O2-resistance of horseradish peroxidase. AB - Horseradish peroxidase (HRP) has attracted intense research interest due to its potential applications in biotechnological fields. However, inadequate stability under prevalent conditions such as elevated temperatures and H(2)O(2) exposure, has limited its industrial application. In this study, stability of HRP was investigated in the presence of different buffer systems (potassium phosphate and Tris-HCl) and additives. It was shown that the concentration of phosphate buffer severely affects enzyme thermostability in a way that in diluted potassium phosphate buffer (10mM) half-life (from 13 to 35 min at 80 degrees C) and T(m) (from 73 to 77.5 degrees C) increased significantly. Among additives tested, trehalose had the most thermostabilizing effect. Exploring the role of glycosylation in stabilizing effect of phosphate buffer, non-glycosylated recombinant HRP was also examined for its thermal and H(2)O(2) stability in both diluted and concentrated phosphate buffers. The recombinant enzyme was more thermally stable in diluted buffer in accordance to glycosylated HRP; but interestingly recombinant HRP showed higher H(2)O(2) tolerance in concentrated buffer. PMID- 21291908 TI - Fabrication of chitosan/poly(caprolactone) nanofibrous scaffold for bone and skin tissue engineering. AB - Chitosan/poly(caprolactone) (CS/PCL) nanofibrous scaffold was prepared by a single step electrospinning technique. The presence of CS in CS/PCL scaffold aided a significant improvement in the hydrophilicity of the scaffold as confirmed by a decrease in contact angle, which thereby enhanced bioactivity and protein adsorption on the scaffold. The cyto-compatibility of the CS/PCL scaffold was examined using human osteoscarcoma cells (MG63) and found to be non toxic. Moreover, CS/PCL scaffold was found to support the attachment and proliferation of various cell lines such as mouse embryo fibroblasts (NIH3T3), murine aneuploid fibro sarcoma (L929), and MG63 cells. Cell attachment and proliferation was further confirmed by nuclear staining using 4',6-diamidino-2-phenylindole (DAPI). All these results indicate that CS/PCL nanofibrous scaffold would be an excellent system for bone and skin tissue engineering. PMID- 21291909 TI - Analyzing the dynamics of brain circuits with temperature: design and implementation of a miniature thermoelectric device. AB - Traditional lesion or inactivation methods are useful for determining if a given brain area is involved in the generation of a behavior, but not for determining if circuit dynamics in that area control the timing of the behavior. In contrast, localized mild cooling or heating of a brain area alters the speed of neuronal and circuit dynamics and can reveal the role of that area in the control of timing. It has been shown that miniaturized solid-state heat pumps based on the Peltier effect can be useful for analyzing brain dynamics in small freely behaving animals (Long and Fee, 2008). Here we present a theoretical analysis of these devices and a procedure for optimizing their design. We describe the construction and implementation of one device for cooling surface brain areas, such as cortex, and another device for cooling deep brain regions. We also present measurements of the magnitude and localization of the brain temperature changes produced by these two devices. PMID- 21291910 TI - Turbulence in globus pallidum neurons in patients with Parkinson's disease: exponential decay of the power spectrum. AB - Exponential decay of the power spectrum is typically observed in turbulent flow patterns, as evidenced both in experiments and in the Navier-Stokes equations describing fluid dynamics. In this study, we present evidence on the exponential decay of power spectra belonging to interspike interval time series, registered in pallidal neurons from patients with Parkinson's disease. Extracellular neuronal recordings were obtained during functional neurosurgery and processed off-line. Interspike interval power spectra were calculated for single unit recordings. All power spectra analyzed were similar, presenting rapid decay of power with frequency. Regression coefficient (adjusted R squared) for exponential function fit was very high, over 0.99 (p<0.001) in every case. We therefore suggest that the neurons studied here show turbulent-like behavior from a spectral point of view, and theorize that Navier-Stokes-like equations may be potentially useful tools to model spectral patterns of firing activity in neurons of this type. We propose to classify neural systems according to the general form of their power spectrum into two major groups of physical systems: systems with scale invariance and a power-law behavior of the power spectrum, and systems with critical scale and an exponential decay of the power spectrum. PMID- 21291911 TI - Quantifying chirp in sleep spindles. AB - Sleep spindles are considered as a marker of integrity for thalamo-cortical circuits. Recently, attention has been given to internal frequency variation in sleep spindles. In this study, a procedure based on matching pursuit with a Gabor chirplet dictionary was applied in order to measure chirp rate in atoms representing sleep spindles, also categorized into negative, positive or zero chirp types. The sample comprised 707 EEG segments containing visual sleep spindles, labeled TP, obtained from nine healthy male volunteers (aged 20-34, average 24.6 y). Control datasets were 333 non-REM (NREM) sleep background segments and 287 REM sleep intervals, each with 16s duration. Analyses were carried out on the C3-A2 EEG channel. In TP and NREM groups, the proportion of non-null chirp types was non-random and total chirp distribution was asymmetrical towards negative values, in contrast to REM. Median negative chirp rate in the TP and NREM groups was significantly lower than in REM (-0.4 Hz/s vs -0.3 Hz/s, P < 0.05). Negative chirp atoms outnumbered positives by 50% in TP, while in NREM and REM, they were, respectively, only 22% and 12% more prevalent. TP negative chirp atoms were significantly higher in amplitude compared to positive or zero types. Considering individual subjects, 88.9% had a TP negative/positive chirp ratio above 1 (mean +/- sd=1.64 +/- 0.65). We propose there is increasing evidence, corroborated by the present study, favoring systematic measurement of sleep spindle chirp rate or internal frequency variation. Preferential occurrence of negatively chirping spindles is consistent with the hypothesis of electrophysiological modulation of neocortical memory consolidation. PMID- 21291912 TI - Ex vivo identification of protein-protein interactions involving the dopamine transporter. AB - The dopamine (DA) transporter (DAT) is a key regulator of dopaminergic signaling as it mediates the reuptake of extrasynaptic DA and thereby terminates dopaminergic signaling. Emerging evidence indicates that DAT function is influenced through interactions with other proteins. The current report describes a method to identify such interactions following DAT immunoprecipitation from a rat striatal synaptosomal preparation. This subcellular fraction was selected since DAT function is often determined ex vivo by measuring DA uptake in this preparation and few reports investigating DAT-protein interactions have utilized this preparation. Following SDS-PAGE and colloidal Coomassie staining, selected protein bands from a DAT-immunoprecipitate were excised, digested with trypsin, extracted, and analyzed by liquid chromatography tandem mass spectrometry (LC/MS/MS). From the analysis of the tryptic peptides, several proteins were identified including DAT, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) beta, CaMKII delta, protein kinase C (PKC) beta, and PKC gamma. Co immunoprecipitation of PKC, CaMKII, and protein interacting with C kinase-1 with DAT was confirmed by Western blotting. Thus, the present study highlights a method to immunoprecipitate DAT and to identify co-immunoprecipitating proteins using LC/MS/MS and Western blotting. This method can be utilized to evaluate DAT protein-protein interactions but also to assess interactions involving other synaptic proteins. Ex vivo identification of protein-protein interactions will provide new insight into the function and regulation of a variety of synaptic, membrane-associated proteins, including DAT. PMID- 21291913 TI - MiR-101 regulates HSV-1 replication by targeting ATP5B. AB - MicroRNAs (miRNAs) are short non-coding RNAs that negatively modulate gene expression at the post-transcriptional level and are known to be involved in the cross-talk between the host and virus. Using a standard plaque assay and real time PCR method, we found that ectopic expression of miR-101 could significantly suppress herpes simplex virus-1 (HSV-1) replication, and that blocking endogenous miR-101 could increase viral progeny without affecting cell viability. Bioinformatics analysis indicates the 3' untranslated region (UTR) of mitochondrial ATP synthase subunit beta (ATP5B) has a putative binding site for miR-101. MiR-101 can directly bind to ATP5B 3'UTR and negatively regulate ATP5B expression. Using a RNA interference technique, knockdown of ATP5B significantly inhibited HSV-1 replication, indicating that ATP5B functions as a pro-viral factor. The ectopic expression of ATP5B lacking the 3'UTR could override the suppressive effect of miR-101 on HSV-1 replication. A concordant inverse correlation between miR-101 and ATP5B was observed in HSV-1-infected HeLa cells. Up-regulation of miR-101 expression may play a role in repressing productive HSV 1 replication by targeting ATP5B. Exploring the role of host-encoded miRNA in the regulation of viral infection would enable us to better understand the intricate networks of host-pathogen interactions. PMID- 21291914 TI - Hippocampus lesions induced deficits in social and spatial recognition in Octodon degus. AB - Previous studies of rodents reported that the hippocampus plays an important role in social behavior as well as spatial behavior. However, there are inconsistencies between reports of the effects of hippocampal lesions on social behavior. The present study sought to clarify the aspects of social behavior in which the hippocampus plays a role in the degu, Octodon degus, a social rodent. We examined the effects of hippocampal lesions on social behavior in the degu using familiar and novel partners. When placed in a familiar environment with a familiar partner after surgery, sham operation control (S.Cont) degus exhibited affinitive behavior longer compared with hippocampal lesioned (HPC) degus. In a novel environment, S.Cont degus exhibited longer aggressive behavior toward novel partners, and longer affinitive behavior with familiar partners compared with HPC degus. HPC degus did not show evidence of differentiation in social behavior, regardless of partner's novelty. The results of an anxiety test confirmed that these findings could not be attributed to changes in emotional state. We conducted an object-recognition test with the same subjects. HPC degus showed an impairment in spatial recognition but not object recognition. Taken together, these results suggest that the degu hippocampus plays an important role not only in spatial recognition but also social recognition. The changes in social behavior resulting from hippocampal lesions were interpreted as due to an impairment of social recognition rather than an impairment in novelty detection. PMID- 21291915 TI - Social stress reduces forebrain cell proliferation in rainbow trout (Oncorhynchus mykiss). AB - Compared to mammals, teleost fish have a very high rate of adult brain cell proliferation. Still little is known about how this process is regulated in comparative models, and what its functional implications are. We investigated the effect of stressful social interaction on brain cell proliferation in size matched rainbow trout pairs after the formation of stable social hierarchies. After 4 days of interaction, socially subordinate fish displayed common signs of chronic stress including reduced feeding behaviour, elevated plasma cortisol levels, and up-regulated brain stem 5-HT activity. The number of newborn cells in the telencephalon was quantified using immunohistochemistry for the exogenously administered S-phase marker BrdU. Subordinate fish had 40% fewer BrdU-positive telencephalic cells compared to isolated controls, while dominant individuals showed a non-significant tendency towards reduced cell proliferation. Cell proliferation in subordinate animals correlated negatively with aggression received immediately after hierarchy formation, indicating that the level of cell division suppression is related to the severity of the social stressor. These findings are comparable to findings in mammalian models of psychosocial stress, indicating that the suppressive effect of social stress on brain cell proliferation is conserved, and thus likely confers adaptive benefits throughout the vertebrate subphylum. PMID- 21291916 TI - Functional characterization of NADP-dependent isocitrate dehydrogenase isozymes from Trypanosoma cruzi. AB - Trypanosoma cruzi exhibits two putative isocitrate dehydrogenases (IDHs). Both idh genes were cloned and the recombinant enzymes expressed in Escherichia coli. Our results showed that T. cruzi IDHs are strictly dependent on NADP(+) and display apparent affinities towards isocitrate and the coenzyme in the low micromolar range. In T. cruzi, IDHs are cytosolic and mitochondrial enzymes, and there is no evidence for the typical Krebs cycle-related NAD-dependent IDH. Hence, like in Trypanosoma brucei, the Krebs cycle is not a canonical route in T. cruzi. However, the citrate produced in the mitochondrion could be isomerized into isocitrate in the cytosol and the mitochondrion by means of the putative aconitase, which would provide the substrate for both IDHs. The cytosolic IDH is significantly more abundant in amastigotes, cell-derived and metacyclic trypomastigotes than in epimastigotes. This observation fits in well with the expected oxidative burst this pathogen has to face when infecting the mammalian host. PMID- 21291917 TI - Small-scale in vitro culture and purification of Plasmodium berghei for transfection experiment. AB - The standard protocol for genetic modification of the rodent malaria parasite Plasmodium berghei requires infected blood from one or more laboratory mice, followed by large-scale in vitro parasite culture and purification of mature schizonts. Here, protocols are described for small-scale in vitro culture from 20 MUL of mouse tail blood and purification of mature P. berghei schizonts sufficient for a single transfection experiment. All procedures are performed in 1.5-mL microcentrifuge tubes. We confirmed that transgenic parasites could be obtained using schizonts prepared by this protocol. This small-scale protocol provides significant advantages, namely reduction of parasite sample, laboratory consumables and mice for transfection experiments. PMID- 21291918 TI - The Hus1 homologue of Leishmania major encodes a nuclear protein that participates in DNA damage response. AB - The protozoan parasite Leishmania presents a dynamic and plastic genome in which gene amplification and chromosome translocations are common phenomena. Such plasticity hints at the necessity of dependable genome maintenance pathways. Eukaryotic cells have evolved checkpoint control systems that recognize altered DNA structures and halt cell cycle progression allowing DNA repair to take place. In these cells, the PCNA-related heterotrimeric complex formed by the proteins Hus1, Rad9, and Rad1 is known to participate in the early steps of replicative stress sensing and signaling. Here we show that the Hus1 homolog of Leishmania major is a nuclear protein that improves the cell capability to cope with replicative stress. Overexpression of LmHus1 confers resistance to the genotoxic drugs hydroxyurea (HU) and methyl methanesulfonate (MMS) and resistance to HU correlates to reduced net DNA damage upon LmHus1 expression. PMID- 21291919 TI - High pain sensitivity is distinct from high susceptibility to non-painful sensory input at threshold level. AB - Individuals may differ considerably in their sensitivity towards various painful stimuli supporting the notion of a person as stoical or complaining about pain. Molecular and functional imaging research provides support that this may extend also to other sensory qualities. Whether a person can be characterized as possessing a generally high or low sensory acuity is unknown. This was therefore assessed with thresholds to painful and non-painful stimuli, with a focus on chemical stimuli that besides pain may evoke clearly non-painful sensations such as taste or smell. In 36 healthy men and 78 women (ages 18 to 52 years), pain thresholds to chemo-somatosensory (intranasal gaseous CO(2)) and electrical stimuli (cutaneous stimulation) were significantly correlated (rho(2)=0.2268, p<0.001). Two clusters separated persons with either high (n=72) or low (n=22) pain sensitivity. However, the correlation did not extend to non-painful stimuli of other sensory qualities, i.e., for the rose-like odor phenyl ethyl alcohol and gustatory thresholds for sour (citric acid) and salty (NaCl). Similarly, pain clusters showed no differences in thresholds to other stimuli. Moreover, no clustering was obtained for thresholds to both painful and non-painful stimuli together. Thus, individuals could not be characterized as highly sensitive (or insensitive) to all chemical stimuli no matter of evoking pain. This suggests that pain is primarily a singular sensory perception distinct from others such as olfaction or taste. PMID- 21291920 TI - Saccadic context indicates information processing within visual fixations: evidence from event-related potentials and eye-movements analysis of the distractor effect. AB - Attention, visual information processing, and oculomotor control are integrated functions of closely related brain mechanisms. Recently, it was shown that the processing of visual distractors appearing during a fixation is modulated by the amplitude of its preceding saccade (Pannasch & Velichkovsky, 2009). So far, this was demonstrated only at the behavioral level in terms of saccadic inhibition. The present study investigated distractor-related brain activity with cortical eye fixation-related potentials (EFRPs). Moreover, the following saccade was included as an additional classification criterion. Eye movements and EFRPs were recorded during free visual exploration of paintings. During some of the fixations, a visual distractor was shown as an annulus around the fixation position, 100 ms after the fixation onset. The saccadic context of a fixation was classified by its preceding and following saccade amplitudes with the cut-off criterion set to 4 degrees of visual angle. The prolongation of fixation duration induced by distractors was largest for fixations preceded and followed by short saccades. EFRP data revealed a difference in distractor-related P2 amplitude between the saccadic context conditions, following the same trend as in eye movements. Furthermore, influences of the following saccade amplitude on the latency of the saccadic inhibition and on the N1 amplitude were found. The EFRP results cannot be explained by the influence of saccades per se since this bias was removed by subtracting the baseline from the distractor EFRP. Rather, the data suggest that saccadic context indicates differences in how information is processed within single visual fixations. PMID- 21291921 TI - The melanocortin system is involved in regulating autonomic nerve activity through central pituitary adenylate cyclase-activating polypeptide. AB - Pituitary adenylate cyclase-activating polypeptide (PACAP) is a peptidergic neurotransmitter that is highly expressed in the nervous system. We have previously reported that a central injection of PACAP leads to changes in the autonomic nervous system tones including sympathetic excitation and parasympathetic inhibition. An anatomical study revealed that melanocortin and PACAP are colocalized in some hypothalamic nuclei. Here, we investigated the possible role of the melanocortin system in autonomic control by PACAP using SHU9119, an antagonist of the melanocortin receptors (MC3-R/MC4-R). Pretreatment with SHU-9119 did not affect the activating neural responses of adrenal, renal, and lumbar sympathetic nerves following a PACAP injection However, SHU9119 significantly eliminated the suppressing effect of a PACAP injection on gastric vagal nerve activity and excitation effects on liver and brown adipose tissue sympathetic nerve activities. These results suggest that the brain melanocortin system might play a key role in the control of thermogenic sympathetic outflows and digestive parasympathetic outflow by PACAP, but this system does not participate in the central effects of PACAP on cardiovascular function and neural activities of renal, adrenal, and lumbar sympathetic nerves. PMID- 21291922 TI - Internet-based atlas of the primate spinal cord. AB - In 2009, we reported an online brain atlas of the common marmoset (Callithrix jacchus) at http://marmoset-brain.org:2008. Here we report new digital images of the primate spinal cord sections added to the website. We prepared histological sections of every segment of the spinal cord of the common marmoset, rhesus monkey and Japanese monkey with various staining techniques. The sections were scanned with Carl Zeiss MIRAX SCAN at light microscopic resolution. Obtained digital data were processed and converted into multi-resolutionary images with Adobe Photoshop and Zoomify Design. These images of the primate spinal cords are now available on the web via the Internet. PMID- 21291923 TI - Brain imaging of mechanically induced muscle versus cutaneous pain. AB - This study aimed to investigate the differences in the brain responses between muscle versus skin pain, both of which were caused by tonic mechanical stimuli. Using local anesthesia (LA), we induced muscle pain without any accompanying cutaneous sensation. Subjects underwent functional magnetic resonance imaging while tonic pressure was applied to the right calf under the following four conditions: (1) non-painful pressure without LA (causing mechanoreceptive skin and muscle stimulation); (2) painful pressure without LA (causing nociceptive skin stimulation and mechanoreceptive skin and muscle stimulation); (3) non painful pressure with LA (causing mechanoreceptive muscle stimulation); (4) painful pressure with LA (causing nociceptive and mechanoreceptive muscle stimulation). Although there was no brain region specifically activated by nociceptive muscle stimuli, activation in the following regions was observed specifically during nociceptive muscle stimuli: anterior midcingulate cortex, anterior and posterior insular cortex, lentiform nucleus, thalamus, pre supplementary motor area, dorsolateral prefrontal cortex, and inferior parietal lobule. This indicates that there is no region specific for muscle pain but activation pattern or network specific for muscle pain. Furthermore, secondary somatosensory cortex (S2) was found to be responsive to cutaneous pain, not muscle pain, because S2 was specifically activated by nociceptive cutaneous stimuli. PMID- 21291925 TI - Vasomotor response induced by change of extracellular potassium and magnesium in cerebral penetrating arterioles. AB - We investigated the effects of changing the extracellular potassium as well as magnesium concentration ([K+]0 and [Mg2+]0) in cerebral penetrating arterioles. The internal diameter of isolated pressurized cerebral penetrating arterioles in rat was measured under the microscope in the low [K+]0, low [Mg2+]0 and high [Mg2+]0, respectively. Vascular responses induced by the low [K+]0 were observed in the absence and presence of several inhibitors. The low [K+]0 produced a biphasic response consisting of an initial transient constriction followed by dilation. The transient constriction was attenuated by Na+-K+-adenosine triphosphatase (ATPase) inhibitor in a concentration-dependent manner and L-type Ca2+ channel inhibitor but not by all K+ channel inhibitors. The low [Mg2+]0 significantly induced constriction, whereas the high [Mg2+]0 induced dilation. We analyzed that transient constriction in the low [K+]0 may be led by membrane depolarization induced by inactivity in Na+-K+-ATPase. The vasomotor responses of the changing of [K+]0 as well as [Mg2+]0 in a cerebral microcirculation may influence the pathological and therapeutic condition in cerebrovascular diseases, and may provide new therapeutic targets. PMID- 21291924 TI - Parallel high throughput neuronal toxicity assays demonstrate uncoupling between loss of mitochondrial membrane potential and neuronal damage in a model of HIV induced neurodegeneration. AB - Neurocognitive deficits seen in HIV-associated neurocognitive disorders (HANDs) are attributed to the release of soluble factors from CNS-resident, HIV-infected and/or activated macrophages and microglia. To study HIV-associated neurotoxicity, we used our in vitro model in which primary rat neuronal/glial cultures are treated with supernatants from cultured human monocyte-derived macrophages, infected with a CNS-isolated HIV-1 strain (HIV-MDM). We found that neuronal damage, detected as a loss of microtubule-associated protein-2 (MAP2), begins as early as 2h and is preceded by a loss of mitochondrial membrane potential (Deltapsi(m)). Interestingly, inhibitors of calpains, but not inhibitors of caspases, blocked MAP2 loss, however neither type of inhibitor prevented the loss of Deltapsi(m). To facilitate throughput for these studies, we refined a MAP2 cell-based-ELISA whose data closely compare with our standardized method of hand counting neurons. In addition, we developed a tetramethyl rhodamine methyl ester (TMRM)-based multi-well fluorescent plate assay for the evaluation of whole culture Deltapsi(m). Together, these findings indicate that calpain activation and loss of Deltapsi(m) may be parallel pathways to death in HIV-MDM-treated neurons and also demonstrate the validity of plate assays for assessing multiple experimental parameters as is useful for screening neurotherapeutics for neuronal damage and death. PMID- 21291926 TI - Aequorin-expressing yeast emits light under electric control. AB - In this study, we show the use of direct external electrical stimulation of a jellyfish luminescent calcium-activated protein, aequorin, expressed in a transgenic yeast strain. Yeast cultures were electrically stimulated through two electrodes coupled to a standard power generator. Even low (1.5 V) electric pulses triggered a rapid light peak and serial light pulses were obtained after electric pulses were applied periodically, suggesting that the system is re enacted after a short refraction time. These results open up a new scenario, in the very interphase between synthetic biology and cybernetics, in which complex cellular behavior might be subjected to electrical control. PMID- 21291927 TI - Chondrogenesis in injectable enzymatically crosslinked heparin/dextran hydrogels. AB - In this study, injectable hydrogels were prepared by horseradish peroxidase mediated co-crosslinking of dextran-tyramine (Dex-TA) and heparin-tyramine (Hep TA) conjugates and used as scaffolds for cartilage tissue engineering. The swelling and mechanical properties of these hydrogels can be easily controlled by the Dex-TA/Hep-TA weight ratio. When chondrocytes were incorporated in these gels, cell viability and proliferation were highest for gels with a 50/50 weight ratio of Dex-TA/Hep-TA. Moreover, these hydrogels induced an enhanced production of chondroitin sulfate and a more abundant presence of collagen as compared to Dex-TA hydrogels. The results indicate that injectable Dex-TA/Hep-TA hydrogels are promising scaffolds for cartilage regeneration. PMID- 21291928 TI - Body mass index moderates gaze orienting biases and pupil diameter to high and low calorie food images. AB - The primary goal of this study was to examine eye gaze behavior to different kinds of food images in individuals differing in BMI status. Eye-tracking methods were used to examine gaze and pupil responses while normal weight and overweight women freely viewed pairs of different food images: high calorie sweet foods, high calorie savory foods, and low calorie foods. Self-report measures of hunger, state and trait cravings, and restrained eating were also obtained. Results revealed orienting biases to low calorie foods and decreases in pupil diameter to high calorie sweet foods relative to low calorie foods in the overweight group. Groups did not differ in the average amount of time spent gazing at the different image types. Furthermore, increased state cravings were associated with larger pupil diameters to high calorie savory foods, especially in individuals with lower BMIs. In contrast, restrained eating scores were associated with a decreased orienting bias to high calorie sweet foods in the high BMI group. In conclusion, BMI status appears to influence gaze parameters that are less susceptible to cognitive control. Results suggest that overweight individuals, especially those who diet, have negative implicit attitudes toward high calorie foods, especially sweets. PMID- 21291929 TI - Mealtime family interactions in home environments of children with loss of control eating. AB - Experimental and self-report studies have shown that parents have a strong influence on their normal or overweight children's eating behavior, i.e. through parental feeding behavior or communication. Studies in children with loss of control (LOC) eating that have investigated this relationship are scarce, and ecologically valid observational studies are missing. This study examined family functioning at mealtimes in home environments in 43 families of a child with LOC eating and 31 families of a child without LOC eating; the children were 8-13 years old. Familial interactions, child eating behavior, and parental mealtime behavior were assessed using the Mealtime Family Interaction Coding System, observation of bite speed of the child, and self-report questionnaires. Less healthy patterns of communication (U=201.53, p<.01) and interpersonal involvement (U=207.54, p<.01) and more maladaptive overall family functioning (U=233.52, p<.05) were observed but not self-reported in families of a child with LOC eating compared to those without LOC eating. Children with LOC eating (M=4.73, SD=1.88) ate faster than controls (M=3.71, SD=1.19; p<.05), with highest bite speed in a group with high recurrent LOC eating (p<.01). The results indicate that maladaptive patterns of family functioning during family mealtimes are present in LOC eating in children and are associated with the child's eating behavior. Parent-child communication training should be tested as an intervention for children with LOC episodes. PMID- 21291930 TI - Confirmatory factor analysis of a questionnaire measuring control in parental feeding practices in mothers of Head Start children. AB - Parental control in child feeding has focused primarily on directive types of control, such as pressure to eat and food restriction. This study aimed to develop an instrument to assess other types of directive control and two additional aspects of parental child feeding, non-directive and food environmental control. Mothers of Head Start children (n=330) completed a 29-item instrument designed to assess these three feeding constructs and reported their children's food intakes. Researchers measured heights and weights of both mothers and children. Confirmatory factor analysis revealed that the model with three constructs did not provide an acceptable fit to the data, but an alternative model with seven sub-constructs did (Chi-square=330, df=228 p<.05, CFI=.942, RMSEA=.037). The latter model included 24 items loading onto one of the following seven factors: high control, high contingency, child-centered feeding, encouraging nutrient-dense foods, discouraging energy-dense foods, mealtime behaviors, and timing of meals. By allowing researchers to quantitatively measure feeding practices in parents with limited resources, this instrument may contribute to an improved understanding of how parental child feeding behaviors can influence children's food intakes and weight status. PMID- 21291931 TI - Time-dependent effects of leptin on food intake and locomotor activity in goldfish. AB - The present study investigates the possible circadian dependence of leptin effects on food intake, locomotor activity, glycemia and plasma cortisol levels in goldfish (Carassius auratus). Fish were maintained under 12L:12D photoperiod and subjected to two different feeding schedules, one group fed during photophase (10:00) and the other one during scotophase (22:00). Leptin or saline were intraperitoneally injected at two different times (10:00 or 22:00), coincident or not with the meal time. To eliminate the entraining effect of the light/dark cycle, goldfish maintained under 24h light (LL) were fed and leptin-injected at 10:00. A reduction in food intake and locomotor activity and an increase in glycemia were found in goldfish fed and leptin-injected at 10:00. No significant changes in circulating cortisol were observed. Those effects were not observed when leptin was administered during the scotophase, regardless the feeding schedule; neither in fish maintained under LL, suggesting that a day/night cycle would be necessary to observe the actions of leptin administered during the photophase. Changes in locomotor activity and glycemia were only observed in goldfish when leptin was injected at daytime, coincident with the feeding schedule, suggesting that these leptin actions could be dependent on the feeding time as zeitgeber. In view of these results it appears that the circadian dependence of leptin actions in goldfish can be determined by the combination of both zeitgebers, light/dark cycle and food. Our results point out the relevance of the administration time when investigating regulatory functions of hormones. PMID- 21291932 TI - Neuropeptides of human thymus in normal and pathological conditions. AB - Human thymus of healthy subjects and patients affected by thymoma-associated Myastenia Gravis were studied in order to visualize and compare the morphological distributive pattern of four neuropeptides: vasoactive intestinal peptide, substance P, neuropeptide Y, and neurotensin. Based on our observations, we formulated hypotheses on their relations in neuro-immunomodulation under physiological and pathophysiological conditions. Immuno-histochemical staining for neuropeptides was performed and morphological and morphometrical analyses were conducted on healthy and diseased thymus. In normal thymus, a specific distributive pattern was observed for the several neuropeptide-positive nerves in different thymus lobular zones. In particular substance P-positive fibers were observed in subcapsular zone, specifically located into parenchyma, where they represent the almost total amount of fibers; neurotensin-positive fibers were observed primarily located in parenchyma than perivascular site of several thymus lobular zones, and more abundant the cortico-medullary and medullary zones. Instead VIP- and NPY-positive fibers were widely distributed in perivascular and parenchymal sites of several thymus lobular zones. In thymoma, the distribution of neuropeptide-positive fibers was quantitatively reduced, while cells immunopositive to VIP and substance P were quantitatively increased and dispersed. Observation of the perivascular and parenchymal distribution of the analyzed neuropeptides suggests evidence that a regulatory function is performed by nerves and cells that secrete neuropeptide into the thymus. The alteration of neuropeptide patterns in thymoma suggests that these neurotransmitters play a role in autoimmune diseases such as Myastenia Gravis. PMID- 21291933 TI - Exercise training intensity/volume affects plasma and tissue adiponectin concentrations in the male rat. AB - The objective of the study was to determine the effects of exercise training intensity/volume on plasma total and high molecular weight (HMW) adiponectin and tissue total adiponectin concentrations. Thirty-two, eight week-old male Wistar rats (185 +/- 5g) were randomly assigned to one of four groups: high intensity (HI: 34 m/min ~%80-%85 VO(2)max), moderate intensity (MI: 28 m/min ~%70-%75 VO(2)max), low intensity (LI: 20 m/min ~ %50-%55 VO(2)max), and sedentary control (SED). Experimental groups completed a 12-week exercise program of treadmill running at 0 degrees slope, 1h/day, 5 days/week. Since frequency and duration of exercise were identical among training groups, the volume of training was highest in the HI group followed by the MI and LI groups. Compared with SED animals, fasting plasma total and HMW adiponectin and adipose tissue total adiponectin concentrations were significantly higher in the HI and MI groups, but total adiponectin concentrations in liver and soleus muscle were not significantly lower than the SED rats. There were significantly lower plasma total testosterone levels in the HI group vs. SED group. Plasma total and HMW adiponectin were negatively correlated with HOMA-IR and insulin whereas total adiponectin was inversely related to TNF-alpha and HMW adiponectin was negatively correlated with total testosterone. Thus, data suggest there is a dose effect for exercise training intensity and accompanying volume for the adaptation of adipose tissue and circulating total and HMW adiponectin concentrations, whereas the changes of adiponectin concentrations in skeletal muscle and liver tissue may depend on the body's energy balance in the recovery period. PMID- 21291934 TI - A natural peptide and its variants derived from the processing of infectious pancreatic necrosis virus (IPNV) displaying enhanced antimicrobial activity: a novel alternative for the control of bacterial diseases. AB - The larger segment of the infectious pancreatic necrosis virus (IPNV) codifies most of the structural and non-structural proteins of the virus in two overlapping open reading frames (ORFs). The longer of the two ORF is expressed as a polyprotein which generates a number of variable length peptides of unknown function during processing. Since an appealing hypothesis would be that these peptides are generated by the virus to act as antimicrobial agents that favor viral infectivity in their fish host, we decided to test this possibility by selecting a master peptide and using it to generate substitution variants that may enhance their antimicrobial potential. A 20-residue master peptide (p20) was selected from the well-described maturation process of the structural viral protein VP2; several variants were then designed and chemically synthesized, ranging in size from 16 to 20 residues. The synthesized peptides were tested for in vitro activity against several prototype bacterial pathogens using standardized laboratory procedures. Chemically synthesized p20 and all its variants displayed broad activity against the tested bacteria and none of them were toxic to eukaryotic cells at least 10* the concentration used against the bacteria. Interestingly, when p20 was tested against the very aggressive bacterial pathogen Piscirickettsia salmonis, a common co-infectant of IPNV in salmonid fish, the specific activity of the novel peptide was significantly higher than that displayed for bactericidal fish farm antibiotics such as oxolinic acid, flumequine and florfenicol, which are commonly used to control Piscirickettsiosis in the field. It is potentially significant that the approach presented in this report provides a novel alternative for generating new and ideally more efficient and friendly safeguards for bacterial prophylaxis. PMID- 21291935 TI - Dispersion of peptides in vegetable oil as a simple slow release formula for both injection and oral uptake in insects: a case study with [His7]-corazonin in an albino Locusta migratoria deficient in corazonin. AB - Upon realizing that for drug delivery in the body, lipidization is a technique used in the pharmaceutical industry, we took in consideration that corazonin melanizes the cuticle of albino Locusta migratoria only when injected in an emulsion in oil, not when applied in a watery solution. In this study, we investigate the possibility for oral uptake of corazonin dispersed in oil, and validated the activity by a melanization assay. Not only was it active, it also induced red cuticular coloration in some animals, and it was also unexpectedly lethal for nymphs, but not for adults. These results necessitate the revision of the potential of (some) peptides for insect control. Also, they suggest practical recommendations for the application of other peptides in physiological assays where oil could be used as a simple slow release formula. PMID- 21291936 TI - Effect of centrally administered apelin-13 on gastric emptying and gastrointestinal transit in mice. AB - Apelin, as the endogenous ligand for the APJ, regulates many biological functions, including blood pressure, neuroendocrine, drinking behavior, food intake and colonic motility. The present study was designed to investigate the effect of central apelin-13 on gastric emptying and gastrointestinal transit in mice. Intracerebroventricular (i.c.v.) injection of apelin-13 (3 and 10 MUg/mouse) decreased gastric emptying rate by 10.9% and 17.1%. This effect was significantly antagonized by the APJ receptor antagonist apelin-13(F13A) and the opioid receptor antagonist naloxone, respectively. However, intraperitoneal (i.p.) injection of apelin-13 (10-100 MUg/mouse) did not affect gastric emptying. Apelin-13 (0.3, 1 and 3 MUg/mouse, i.c.v.) inhibited gastrointestinal transit by 16.8%, 23.4% and 19.2%. Apelin-13(F13A) and naloxone could also reverse this antitransit effect induced by apelin-13. Taken together, these results suggest that i.c.v. injected apelin-13 inhibits gastric emptying and gastrointestinal transit and it seems that APJ receptor and opioid receptor might be involved in these processes. PMID- 21291937 TI - The role of C-terminal part of ghrelin in pharmacokinetic profile and biological activity in rats. AB - Ghrelin is an endogenous ligand for growth hormone secretagogue receptor 1a (GHS R1a), and consists of 28 amino acid residues with octanoyl modification at Ser(3). The previous studies have revealed that N-terminal part of ghrelin including modified Ser(3) is the active core for the activation of GHS-R1a. On the other hand, the role of C-terminal (8-28) region in ghrelin has not been clarified yet. In the present study, we prepared human ghrelin, C-terminal truncated ghrelin derivatives and anamorelin, a small molecular GHS compound which supposedly mimics the N-terminal active core, and examined GHS-R1a agonist activity in vitro, pharmacokinetic (PK) profile and growth hormone (GH) releasing activity in rats. All compounds demonstrated potent GHS-R1a agonist activities in vitro. Although the lack of C-terminal two amino acids did not modify PK profile and GH releasing activity, the deletion of C-terminal 8 and 20 amino acids affected them, and ghrelin(1-7)-Lys-NH(2) exhibited very short plasma half-life and low GH releasing activity in vivo. In rat plasma, ghrelin(1-7)-Lys-NH(2) was degraded more rapidly than ghrelin, suggesting that C-terminal part of ghrelin protected octanoylation of Ser(3) from plasma esterases. Subdiaphragmatic vagotomy significantly attenuated GH response to ghrelin but not to anamorelin. These results suggest that the C-terminal part of ghrelin has an important role in the biological activity in vivo. We also found that ghrelin stimulated GH release mainly via a vagal nerve pathway but anamorelin augmented GH release possibly by directly acting on brain in rats. PMID- 21291938 TI - Anti-Legionella activity of staphylococcal hemolytic peptides. AB - A collection of various Staphylococci was screened for their anti-Legionella activity. Nine of the tested strains were found to secrete anti-Legionella compounds. The culture supernatants of the strains, described in the literature to produce hemolytic peptides, were successfully submitted to a two step purification process. All the purified compounds, except one, corresponded to previously described hemolytic peptides and were not known for their anti Legionella activity. By comparison of the minimal inhibitory concentrations, minimal permeabilization concentrations, decrease in the number of cultivable bacteria, hemolytic activity and selectivity, the purified peptides could be separated in two groups. First group, with warnericin RK as a leader, corresponds to the more hemolytic and bactericidal peptides. The peptides of the second group, represented by the PSMalpha from Staphylococcus epidermidis, appeared bacteriostatic and poorly hemolytic. PMID- 21291939 TI - Antimicrobial decapeptide KSL-W attenuates Candida albicans virulence by modulating its effects on Toll-like receptor, human beta-defensin, and cytokine expression by engineered human oral mucosa. AB - We investigated the toxicity of synthetic antimicrobial decapeptide KSL-W on normal human gingival epithelial cell cultures, its effect on Candida albicans adhesion and growth, and the activation of epithelial cell innate immunity. Our results indicate that KSL-W had no toxic effect on cell adhesion or growth, suggesting its safe use with human cells. Pre-treating C. albicans with KSL-W attenuated the yeast's virulence as demonstrated by its reduced adhesion and growth on engineered human oral mucosa epithelium and the subsequent decreased expression of some innate defense molecules by targeted epithelial cells. Indeed, the expression of Toll-like receptors and human beta-defensins was reduced in tissues infected with KSL-W-treated Candida. Proinflammatory cytokine secretion (IL-1beta and IL-6) by the epithelial cells was also regulated by KSL-W in a manner similar to that of antifungal molecule amphotericin B. These findings therefore show that KSL-W is safe for use with human cells and is able to attenuate Candida virulence by modulating its effects on host innate immunity. This study proposes the potential application of KSL-W peptide as an alternative antifungal agent. PMID- 21291940 TI - Urotensin II inhibits the proliferation but not the differentiation of cardiac side population cells. AB - Urotensin II (UII) induces the development of cardiac remodeling and atherosclerosis by promoting hypertrophy of cardiomyocytes and mitogenesis of fibroblasts and vascular smooth muscle cells. But its effect on cardiac side population cells (CSPs), one of somatic stem cells, is unclear. The present study examined the influences of UII on the differentiation and proliferation of CSPs. CSPs were isolated from neonatal rat hearts by fluorescence-activated cell sorting (FACS) and cultured with or without the presence of UII (10(-8), 10(-7), 10(-6)mol/l). The expressions of alpha-cardiac myosin heavy chain (alpha-MHC), alpha-smooth muscle actin (SMA) and Von Willebrand factor (vWF) mRNAs and proteins were analyzed by reverse transcriptional PCR (RT-PCR) and immunofluorescence to evaluate the differentiation of CSPs into cardiomyocytes, smooth muscle cells and endothelial cells, respectively. The proliferation of CSPs was assessed by Luminescent Cell Viability Assay. The influence of UII on the proliferation of CSPs in vivo was also evaluated by FACS. Our results revealed that UII did inhibit the proliferation of CSPs through up-regulation of phosphorylated c-Jun N-terminal protein kinase (JNK), although it didn't affect the differentiation of cultured CSPs. Experiments in vivo also showed that UII reduced the number of CSPs in mice compared with control group. These data indicate that UII reduces the number of CSPs by inhibiting the proliferation of CSPs possibly through increase of JNK phosphorylation. PMID- 21291941 TI - A prospective study of glucose homeostasis in quetiapine-treated schizophrenic patients by using the intravenous glucose tolerance test. AB - Increasing attention has been paid recently to the potential diabetogenic effect of second-generation antipsychotics (SGAs). The objective of this prospective study was to evaluate the effects of quetiapine treatment on pancreatic beta-cell function in SGA-naive schizophrenic patients. Seventeen schizophrenic subjects completed an eight-week trial. The metabolic parameters were assessed at weeks 0, 2, 4, and 8. We measured glucose homeostasis with the intravenous glucose tolerance test. After the eight-week treatment, body weight and body mass index showed to be significantly increased compared to those at baseline. No significant changes were found in serum levels of fasting glucose, insulin, total cholesterol, and high-density lipoprotein. Insulin resistance and insulin secretion were significantly increased. Incidences of clinically significant weight gain and treatment-emergent metabolic syndrome were 11.8% and 11.8%, respectively. This study result confirms the association of quetiapine treatment and impairment of glucose homeostasis in schizophrenic patients. PMID- 21291942 TI - Targeting oxidative stress, mitochondrial dysfunction and neuroinflammatory signaling by selective cyclooxygenase (COX)-2 inhibitors mitigates MPTP-induced neurotoxicity in mice. AB - Several studies have pointed towards the role of oxidative stress, mitochondrial dysfunction and neuroinflammation in Parkinson's disease (PD). The present study was focused on the possible neuroprotective effect of selective cyclooxygenase (COX)-2-inhibitors: valdecoxib and NS-398 in 1-methyl-4-phenyl-1,2,3,6 tertahydropyridine (MPTP)-induced neurotoxicity in mice. MPTP administration in dose of 40 mg/kg, i.p (four injections of 10mg/kg, i.p. at an interval of 1h each) significantly induced the Parkinson-like symptoms in mice as indicated by change in locomotor activity, inability to correct posture (bar test), and oxidative stress (increased levels of lipid peroxidation, nitrite concentration, and depletion of antioxidant enzyme). MPTP administration significantly impaired mitochondrial complex-I activity and redox activity, upregulated the caspase-3 and NF-kappaB levels as compared to vehicle group. Treatment with valdecoxib (5 or 10 mg/kg, p.o.) or NS-398 (5 or 10mg/kg, p.o.) for 7 days significantly reversed behavioral, biochemical, mitochondrial complex alterations as well as attenuated the induction of proinflammatory mediators in MPTP-treated groups. The findings of the present study substantiate the neuroprotective role of selective COX-2 inhibitors in ameliorating MPTP-induced neurodegeneration in mice and suggest the possible therapeutic potential of these drugs in the management of PD. PMID- 21291943 TI - Topiramate augmentation in patients with resistant major depressive disorder: a double-blind placebo-controlled clinical trial. AB - BACKGROUND: Despite evolution of new antidepressant treatment, clinicians still encounter challenges in the treatment of depressed patients. Looking for new medications that can potentiate the effects of current antidepressants seems to be necessary. Our objective is to survey the efficacy of topiramate augmentation in resistant major depressive disorder (MDD). METHOD: This augmentation trial was designed as an 8-week randomized, placebo-controlled, double-blind study. Fifty three patients with DSM-IV diagnosis of MDD who had failed to respond to at least 8 weeks of treatment with an adequate dose of one of the SSRIs (fluoxetine, citalopram or serteraline) were included in the study. Patients were randomized to receive a flexible dose of topiramate (100-200 mg/day) or placebo beside their current antidepressant medication for a period of eight weeks. Outcome measures were Hamilton Depression Scale (HAM-D) and Clinical Global Impression (CGI). RESULTS: 42 patients completed the study and there were 6 and 5 dropouts in topiramate and placebo groups, respectively. The topiramate group demonstrated significant improvement over the study period based on mean HAM-D score at week 8 compared to baseline (P = .000, Z = 3.699). Those receiving topiramate demonstrated to have a mean decrease of 32.0% in HAM-D score, compared to only 5.5% for those receiving placebo. Depressed mood, suicidality, insomnia (early, middle and late), agitation and anxiety symptoms were significantly improved in the topiramate group. CONCLUSION: Our double-blind placebo-controlled study demonstrated that topiramate augmentation potentiate the efficacy of selective serotonin reuptake inhibitors (SSRIs) in treatment of resistant major depressive disorder. Of note is that our study is preliminary and larger double-blind studies are needed to confirm the results. PMID- 21291944 TI - Honeybee-collected pollen from five Portuguese Natural Parks: palynological origin, phenolic content, antioxidant properties and antimicrobial activity. AB - The aim of this study was to determine the palynological origin, phenolic content, antioxidant and antimicrobial properties of pollen from five Portuguese Natural-Parks [Parque Nacional Peneda Geres (PNPG); Parque Natural do Montesinho (PNM); Parque Natural do Alvao (PNA); Parque Natural da Serra da Estrela (PNSE) and Parque Natural do Douro Internacional (PNDI)]. Eight families were found in the mixture of bee pollen: Rosaceae, Cistaceae, Boraginaceae, Asteraceae, Fagaceae, Ericaeae, Myrtaceae and Fabaceae. The phenolic compounds content, determined by the Folin-Ciocalteu method, varied between 10.5 and 16.8 mg of gallic acid equivalents/g of extract (mg GAE/g) found in bee pollen from PNM and PNDI, respectively. The free radical scavenging measured showed the highest effective extract - PNM with EC(50) 2.16, followed by PND with 2.24 mg/mL. In the beta-carotene bleaching assay the same behaviour as in the DPPH method was verified. We also verified that the presence of pollen differentially affected the growth of bacteria Gram-positive, Gram-negative and yeasts under study, depending this on the microorganism and the pollen used. This is an important study since, as far we know, it is the first time that Portuguese bee pollen from Natural Parks was studied, and their characterization can increase their economic value. PMID- 21291945 TI - Ferulic acid protects against carbon tetrachloride-induced liver injury in mice. AB - Ferulic acid (FA), isolated from the root of Scrophularia buergeriana, is a phenolic compound possessing antioxidant, anticancer, and antiinflammatory activities. Here, we have investigated the hepatoprotective effect of FA against carbon tetrachloride (CCl(4))-induced acute liver injury. Mice were treated intraperitoneally with vehicle or FA (20, 40, and 80mg/kg) 1h before and 2h after CCl(4) (20MUl/kg) injection. The serum activities of aminotransferases and the hepatic level of malondialdehyde were significantly higher after CCl(4) treatment, while the concentration of reduced glutathione was lower. These changes were attenuated by FA. The serum level and mRNA expression of tumor necrosis factor-alpha significantly increased after CCl(4) treatment, and FA attenuated these increases. The levels of inducible nitric oxide synthase and cyclooxygenase-2 protein and mRNA expression after CCl(4) treatment were significantly higher and FA reduced these increases. CCl(4)-treated mice showed increased nuclear translocation of nuclear factor-kappaB (NF-kappaB), and decreased levels of inhibitors of NF-kappaB in cytosol. Also, CCl(4) significantly increased the level of phosphorylated JNK and p38 mitogen-activated protein (MAP) kinase, and nuclear translocation of activated c-Jun. FA significantly attenuated these changes. We also found that acute CCl(4) challenge induced TLR4, TLR2, and TLR9 protein and mRNA expression, and FA significantly inhibited TLR4 expression. These results suggest that FA protects from CCl(4) induced acute liver injury through reduction of oxidative damage and inflammatory signaling pathways. PMID- 21291946 TI - An in vitro study of vascular endothelial toxicity of CdTe quantum dots. AB - Quantum dots (QDs), as novel bioimaging and drug delivery agents, are generally introduced into vascular system by injection, and thus directly exposed to vascular endothelial cells (ECs). However, the adverse effects of QDs on ECs are poorly understood. In this study, employing human umbilical vein ECs (HUVECs), we investigated the potential vascular endothelial toxicity of mercaptosuccinic acid (MSA)-capped CdTe QDs in vitro. In the experiment, water-soluble and pH stable CdTe QDs were synthesized; and the cell viability assays showed that CdTe QDs (0.1-100MUg/mL) dose-dependently decreased the cell viability of HUVECs, indicating CdTe QDs induced significant endothelial toxicity. The flow cytometric and immunofluorescence results revealed that 10MUg/mL CdTe QDs elicited significant oxidative stress, mitochondrial network fragmentation as well as disruption of mitochondrial membrane potential (Deltapsi(m)); whereas ROS scavenger could protect HUVECs from QDs-induced mitochondrial dysfunction. Moreover, upon 24h exposure to 10MUg/mL CdTe QDs, the apoptotic HUVECs dramatically increased by 402.01%, accompanied with alternative expression of apoptosis proteins, which were upregulation of Bax, downregulation of Bcl-2, release of mitochondrial cytochrome c and cleavage of caspase-9/caspase-3. These results suggested that CdTe QDs could not only impair mitochondria but also exert endothelial toxicity through activation of mitochondrial death pathway and induction of endothelial apoptosis. Our results provide strong evidences of the direct toxic effects of QDs on human vascular ECs, and reveal that exposure to QDs is a significant risk for the development of cardiovascular diseases. These results also provide helpful guidance on the future safe use and manipulation of QDs to make them more suitable tools in nanomedicine. PMID- 21291947 TI - Dicofol degradation to p,p'-dichlorobenzophenone - a potential antiandrogen. AB - In the present investigation, the degradation of the acaricide dicofol (also known as kelthane) was investigated with special emphasis on generation of p,p' dichlorobenzophenone (DCBP) under alkaline conditions as well as induced by UV light. Dicofol was also incubated in the presence and absence of microsomal preparations to measure potential metabolic formation of DCBP. The results indicate that the degradation of dicofol to DCBP primarily proceeds as an abiotic process via hydroxide ion catalysed elimination of a trichloromethyl anion. The generated anion picks up a proton from the solvent to generate chloroform. Microsomal metabolism does not appear to play a major role in the degradation of dicofol. DCBP is structurally analogous to the antiandrogen p,p' dichlorodiphenylethene (DDE). We therefore investigated whether DCBP displays antiandrogenic properties. In an in vitro transactivation system utilising transiently transfected African green monkey kidney (COS-7) cells, DCBP showed potent antiandrogenic efficacy. This finding was confirmed by further studies in T47D human mammary carcinoma cells by measuring mRNA and protein expression of androgen dependent genes i.e. TRMP-2 (testosterone-repressed prostate message-2) mRNA and PSA (prostate-specific antigen) protein. PMID- 21291948 TI - Effects of light attenuation by fibre posts on polymerization of a dual-cured resin cement and microleakage of post-restored teeth. AB - OBJECTIVES: The influence of light transmitting ability of different fibre posts on the polymerization of a dual-cured resin cement, and the further microleakage of the post-restored endodontically treated teeth were examined. METHODS: An LED curing light was used as light source and the measurements of 470 nm irradiances were made at 1mm intervals along the posts (P-Lux, P-White, and P-Steel). The polymerization of a dual-cured resin cement surrounding the posts at five depths (0, 2, 5, 8, and 10mm) from the top was evaluated using micro-Raman spectra after 40s light-curing. Meanwhile, 36 human single-rooted endodontically treated teeth were randomly divided into three groups and restored with these posts and the cement according to the manufacturers' instructions. Microleakages of the post restored teeth were compared using an electrochemical measurement system on three consecutive days, and statistically analysed using nonparametric tests. RESULTS: Light transmission through fibre posts was exponentially reduced as the depth increased (p<0.05, R(2)>0.95), and the polymerization of the resin cement beyond the depth of 5mm significantly declined for all specimens (p<0.05). Fibre posts displayed higher value of light transmission, exhibited a higher polymerization rate of surrounding resin cement, and also demonstrated less microleakage; whilst P-Steel posts had the lowest polymerization rate and produced higher microleakage (p<0.017). CONCLUSIONS: The effective radiance along the post was diminished exponentially, which features the insufficient polymerization of a dual-cured resin cement surrounding the posts at apical region and might therefore influence the microleakage of post-restored teeth. PMID- 21291949 TI - Serotonin transporter gene (5-HTTLPR) polymorphisms are associated with emotional modulation of pain but not emotional modulation of spinal nociception. AB - The short allele of the serotonin transporter gene (5-HTTLPR) is associated with greater negative emotionality. Given that emotion modulates pain, short allele carriers (s-carriers) may also demonstrate altered pain modulation. The present study used a well-validated emotional picture-viewing paradigm to modulate pain and the nociceptive flexion reflex (NFR, a measure of spinal nociception) in 144 healthy genotyped participants. As expected, pain/NFR responses were largest during unpleasant pictures and smallest during pleasant pictures. However, relative to l/l-carriers, s-carriers demonstrated greater pain inhibition during pleasant pictures and greater pain facilitation during unpleasant pictures. Neither emotional modulation of NFR nor NFR threshold was associated with 5 HTTLPR polymorphisms. Results also indicated that men who were s-carriers had a higher pain threshold and tolerance than other participants. Taken together, our results indicate 5-HTTLPR polymorphisms may influence pain modulation at the supraspinal (not spinal) level; however, the influence on pain sensitivity may be sex-specific. PMID- 21291950 TI - Disinhibited behaviors in young children: relations with impulsivity and autonomic psychophysiology. AB - Cardiac activity has long been considered as a psychophysiological marker of adaptive psychological adjustment. Irregularities in autonomic nervous system activity have long been implicated in both externalizing and disinhibitory behaviors. The present study used a battery of assessments in children ages 4.5 5.5 years to examine the relation among disinhibitory measures. Additionally, cardiovascular activity and reactivity was examined. Mothers rated impulsivity and internalizing/externalizing behaviors. Reward-dominance and passive-avoidance response inhibition (i.e., via errors of commission) tasks were included. Results showed that behaviorally uninhibited children began with an attenuated sympathetic response (i.e., lengthened pre-ejection period) to an interview with a novel experimenter, while inhibited children began with a high level of sympathetic activity. Further, behavioral impulsivity was related to low sympathetic activity at rest. Consistent with theories of disinhibition, externalizing behaviors and measures of behavioral impulsivity were related to a reward-dominant response style. Findings are discussed with regard to motivational theories of behavior. PMID- 21291951 TI - High perceived stress in relation to life events is associated with blunted cardiac reactivity. AB - The current study examined whether the perception of life stress related to cardiovascular reactivity. Participants (n = 100) completed the Perceived Stress Scale, the Undergraduate Stress Questionnaire, and undertook a standard mental arithmetic stress task. Blood pressure and pulse rate were measured at baseline, during, and following stress task exposure. Reactivity was the difference between stress and baseline cardiovascular activity. A perceived stress difference score (PSDS) was calculated by subtracting the Undergraduate Stress Questionnaire scores from the Perceived Stress Scale scores. Two groups were created: high PSDS (n = 15; PSDS at least 1SD above the mean) and low PSDS (n = 15; PSDS at least 1SD below the mean). There was a significant difference between groups in pulse rate reactivity, F(1,28) = 8.73, p = .006, eta2 = .24. High PSDS scores were associated with significantly lower pulse rate reactions to stress. Those who perceived their lives as more stressful than their actual stress exposures justified would appear to be characterised by blunted cardiac reactivity. PMID- 21291952 TI - In vivo expansion of the megakaryocyte progenitor cell population in adult CD26 deficient mice. AB - OBJECTIVE: Megakaryopoiesis involves commitment of hematopoietic stem cells (HSC) toward the myeloid lineage in combination with the proliferation, maturation, and terminal differentiation of progenitors into megakaryocytes. The exact mechanism of megakaryocyte development from HSC is unknown, but growth factors such as thrombopoietin have been identified as critical. Additionally, it has been suggested that the chemokine CXCL12/stromal-cell derived factor-1alpha has a role in regulating megakaryopoiesis and thrombopoiesis. We recently reported the importance of the extracellular protease CD26 (dipeptidylpeptidase IV) in regulating HSC responses to CXCL12, as well as modulating HSC trafficking into and out of the bone marrow. However, the importance of CD26 for megakaryopoiesis has not been reported. We therefore compared megakaryocyte development between CD26-deficient (CD26(-/-)) mice and C57BL/6 control mice. MATERIALS AND METHODS: Adult CD26(-/-) mice and C57BL/6 control mice were evaluated using blood differentials, histological analysis, flow cytometric analysis, and progenitor colony assays. RESULTS: Bone marrow from CD26(-/-) mice has a significantly expanded megakaryocyte and megakaryocyte progenitor population compared to control C57BL/6 mice bone marrow. CONCLUSIONS: Our results indicate that endogenous CD26 normally suppresses megakaryopoiesis and that loss of CD26 activity results in expansion of the megakaryocyte progenitor population in vivo. This suggests the potential use of CD26 inhibitors to improve megakaryocyte progenitor function and/or reconstitution of the megakaryocyte cell population. PMID- 21291953 TI - Sublethal radiation injury uncovers a functional transition during erythroid maturation. AB - OBJECTIVE: Clastogenic injury of the erythroid lineage results in anemia, reticulocytopenia, and transient appearance of micronucleated reticulocytes. However, the micronucleated reticulocyte dose-response in murine models is only linear to 2 Gy total body irradiation and paradoxically decreases at higher exposures, suggesting complex radiation effects on erythroid intermediates. To better understand this phenomenon, we investigated the kinetics and apoptotic response of the erythron to sublethal radiation injury. MATERIALS AND METHODS: We analyzed the response to 1 and 4 Gy total body irradiation of erythroid progenitors and precursors using colony assays and imaging flow cytometry, respectively. We also investigated cell cycling and apoptotic gene expression of the steady-state erythron. RESULTS: After 1 Gy total body irradiation, erythroid progenitors and precursors were partially depleted. In contrast, essentially all bone marrow erythroid progenitors and precursors were lost within 2 days after 4 Gy irradiation. Imaging flow cytometry analysis revealed preferential loss of phenotypic erythroid colony-forming units and proerythroblasts immediately after sublethal irradiation. Furthermore, these populations underwent radiation-induced apoptosis, without changes in steady-state cellular proliferation, at much higher frequencies than later-stage erythroid precursors. Primary erythroid precursor maturation is associated with marked Bcl-xL upregulation and Bax and Bid downregulation. CONCLUSIONS: Micronucleated reticulocyte loss after higher sublethal radiation exposures results from rapid depletion of erythroid progenitors and precursors. This injury reveals that erythroid colony-forming units and proerythroblasts constitute a particularly proapoptotic compartment within the erythron. We conclude that the functional transition of primary proerythroblasts to later-stage erythroid precursors is characterized by a shift from a proapoptotic to an antiapoptotic phenotype. PMID- 21291954 TI - Increased numbers of tumor-lysing monocytes in cancer patients. AB - Lymphatic infiltration is a well known phenomenon in different tumors including endocrine malignancies. However, little is known about the role of antigen presenting cells and T cell activation in this context. The aim of our study was to investigate the quantity and function of CD14+/CD56+ monocytes in tumor patients including endocrine malignancies. First, these cells were characterized in peripheral blood of endocrine and non-endocrine cancer patients as well as in tumor tissue samples. Cancer patients had in mean 3.7 times more CD14+/CD56+ monocytes in the peripheral blood compared to healthy controls (p<=0.0001), while the highest frequencies were seen in patients with heavy tumor load. Importantly, these cells additionally expressed several NK cell markers. A proof of CD14+/CD56+ infiltrations into papillary thyroid carcinoma was shown by immunohistochemical analyses. Functional analyses revealed an apoptosis inducing capacity in vitro after IFN-alpha re-stimulation. Our data indicate the importance of tumor-lysing monocytes in antitumor immunity. PMID- 21291955 TI - LC, a novel estrone-rhein hybrid compound, concurrently stimulates osteoprotegerin and inhibits receptor activator of NF-kappaB ligand (RANKL) and interleukin-6 production by human osteoblastic cells. AB - Estrogen analogues are promising drugs for postmenopausal osteoporosis, but because of their possible side effects such as increased risk of cancer, estrogens which exert their estrogenic effects selectively on bone are desired. It has been shown that rhein inhibits osteoclast formation and bone resorption activity and has an antitumor role in several types of cancers. Having found that rhein had high affinity for the bone mineral, we synthesized estrone-rhein hybrid compounds and confirmed that one of these hybrid compounds, LC, exhibited a selective profile in the bone and prevented bone loss but had no effect on endometrium growth in ovariectomized rats. However, the mechanisms underlying its actions on human bone cells have not been well defined. Here we show that LC concurrently stimulates osteoprotegerin (OPG) and inhibits receptor activator of nuclear factor-kappaB ligand (RANKL) and Interleukin-6 (IL-6) production by human osteoblastic MG-63 cells containing two estrogen receptor (ER) isotypes. Treatment with the ER antagonist ICI 182,780 abrogates the above actions of LC on osteoblast-derived cells. Using small interfering double-stranded RNAs (siRNA) technology, we further demonstrate that the effects of LC on IL-6 production are mediated by both ERalpha and ERbeta but those on OPG and RANKL expression primarily by ERalpha. Furthermore, we also demonstrate that LC functions at least partially through activation of the classic estrogen response element (ERE) pathway as well as Ras/MEK/ERK and PI3K/Akt signaling. The effect of LC on bone is due to not only its estrogenic activity but also action of its rhein moiety. Also, this compound shows much weaker effect on breast epithelial cell growth than that of estrone. Therefore, using rhein for conjugating compounds is a promising method of effectively targeting estrogens to the bone. PMID- 21291956 TI - Progesterone maintains amniotic tight junctions during midpregnancy in mice. AB - The amniotic epithelium is in direct contact with the amniotic fluid and restricts fluid flux via the paracellular pathway by means of tight junctions (TJs). Several factors affect TJs to modulate the paracellular flux. Progesterone contributes to the antenatal formation and disappearance of TJs in uterine and mammary epithelial tissues. In this study, we investigated whether progesterone positively or negatively influences amniotic TJs. The administration of RU-486, a progesterone receptor (PR) antagonist, into pregnant mice adversely affects the localization and expression of claudin-3 and claudin-4 in the amniotic epithelium. RU-486 administration also increased the permeability of the amniotic membrane. In organ-cultured amniotic membranes, progesterone induced increases in claudin-3 and claudin-4 expression in a dose-dependent manner but did not influence their localization. PRs were also present in the amniotic epithelium during midpregnancy but they disappeared during late pregnancy. These results indicate that the progesterone/PR pathway maintains TJs in the amniotic epithelium during midpregnancy. PMID- 21291957 TI - Magnesium valproate in learning disabled children with interictal paroxysmal EEG patterns: Preliminary report. AB - Previous studies have investigated whether routine use of antiepileptic drugs is adequate to improve cognitive abilities in children who are learning disabled not otherwise specified (LD NOS) and who display interictal paroxysmal patterns in the electroencephalogram (EEG) but do not have epilepsy, and the findings of these studies have been controversial. In the current study, 112 LD children without epilepsy were assessed; however, only 18 met the strict inclusion/exclusion criteria in order to obtain a homogeneous sample. These children showed interictal paroxysmal patterns in the EEG, and a randomized, double-blind trial was carried out on them. The children were treated with either magnesium valproate (MgV; 20mg/kg/day) or a placebo for six months, and differences in WISC subtests, in a computerized reading skills battery (BTL) and EEG recordings were evaluated between groups before and after the treatment period. Performance IQ score and several items of the BTL (rhymes and ordering of words) improved in children who received MgV, whereas no changes were observed in the placebo group. No changes in the number of interictal paroxysmal patterns were observed in any group; however increased EEG currents at 10.92 and 12.87Hz (alpha band) in posterior regions and decreased currents in frequencies within the theta band (3.90, 4.29 and 5.07Hz) in frontal regions and at 4.68 and 5.46Hz in the parietal cortex were observed, suggesting an improvement in EEG maturation. PMID- 21291958 TI - Personality traits and the amplitude of spontaneous low-frequency oscillations during resting state. AB - Recently, neural substrates of the Big Five personality model were investigated using neuroimaging. We examined the relationships between the amplitude of spontaneous low-frequency oscillations (LFO) and the Big Five traits using resting-state functional magnetic resonance imaging (R-fMRI). Twenty-four healthy right-handed undergraduates (23.13+/-1.87 years, 9 males and 15 females) participated in 5-min R-fMRI and completed the NEO Five-Factor Inventory. We observed that Neuroticism correlated negatively with regional activity of the middle frontal gyrus and precuneus; Extraversion correlated positively with regional activity of the striatum, precuneus, and superior frontal gyrus; Openness correlated positively with the thalamus and amygdala, and negatively with the superior frontal gyrus; Conscientiousness correlated positively with regional activity of the middle frontal gyrus and correlated negatively with the cerebellum. Our results revealed the neural substrates of Extraversion, Neuroticism, Openness, and Conscientiousness in the amplitude of spontaneous LFO. PMID- 21291959 TI - The enhanced cortical activation induced by transcranial direct current stimulation during hand movements. AB - The aim of this study is to evaluate whether tDCS applied on the primary motor cortex (M1) in company with hand movements could enhance cortical activation, using functional MRI (fMRI). Twelve right-handed normal subjects were recruited. Real tDCS and sham tDCS with hand movements were applied during fMRI scanning. Subjects performed grasp-release hand movements at a metronome-guided frequency of 1Hz, while direct current with 1.0mA was delivered to the primary motor cortex. The averaged cortical map and the intensity index were compared between real tDCS with hand movements and sham tDCS with hand movements. Our result showed that cortical activation on the primary sensorimotor cortex was observed under both of two conditions; real tDCS with hand movements and sham tDCS with hand movements. Voxel count and peak intensity were 365.10+/-227.23 and 5.66+/ 1.97, respectively, in the left primary sensorimotor cortex during real tDCS with right hand movements; in contrast, those were 182.20+/-117.88 and 4.12+/-0.88, respectively, during sham tDCS with right hand movements. Significant differences in voxel count and peak intensity were observed between real tDCS and sham tDCS (p<0.05). We found that anodal tDCS application during motor task enhanced cortical activation on the underlying targeted motor cortex, compared with the same motor task without tDCS. Therefore, it seemed that tDCS induced more cortical activity and modulated brain function when concurrently applied with motor task. PMID- 21291961 TI - A novel aporphine alkaloid from Magnolia officinalis. AB - A novel aporphine alkaloid, magnofficine (1), has been isolated from the root barks of the Chinese medicinal plant Magnolia officinalis, along with seven known compounds. Elucidations of their structures were achieved by spectroscopic methods. Magnofficine is the first example of an adduct of aporphine alkaloid and 4-hydroxyphenethylamino bridged by a methylene. PMID- 21291960 TI - Viruses and asthma. AB - BACKGROUND: Viral respiratory infection has long been known to influence the occurrence of asthma exacerbations. Over the last 20years much effort has been put into clarifying the role that viral respiratory infections play in the eventual development of asthma. SCOPE OF REVIEW: In this review we give a general background of the role of viruses in the processes of asthma exacerbation and asthma induction. We review recent additions to the literature in the last 3years with particular focus on clinical and epidemiologic investigations of influenza, rhinovirus, bocavirus, respiratory syncytial virus, and metapneumovirus. MAJOR CONCLUSIONS: The development of asthma emerges from a complex interaction of genetic predisposition and environmental factors with viral infection likely playing a significant role in the effect of environment on asthma inception. This article is part of a Special Issue entitled: Biochemistry of Asthma. GENERAL SIGNIFICANCE: Further understanding of the role that viruses play in asthma exacerbation and inception will contribute to decreased asthma morbidity in the future. This article is part of a Special Issue entitled: Biochemistry of Asthma. PMID- 21291962 TI - Effects of chelerythrine, a specific inhibitor of cyclooxygenase-2, on acute inflammation in mice. AB - Chelerythrine (CHE), a quaternary benzo[c]phenanthridine alkaloid, which is an agent in traditional Chinese medicine exhibits a wide spectrum of pharmacological effects. In this study, we examined the anti-inflammatory activities and mechanism of CHE in vivo and in vitro, respectively. Further, in the analgesic test, CHE also showed pronounced inhibition of the acetic acid-induced writhing response. These results clearly suggested that CHE is a bioactive agent which has a significant anti-inflammatory action, which may be relevant to the inhibition of the release/production of exudates and prostaglandin E(2) mediated through cyclooxygenase-2 regulation. PMID- 21291963 TI - The role of context in risky choice. AB - Human choice behavior was assessed in a concurrent-chain schedule, where two equal initial links (IL) each led to a distinct terminal-link (TL). One TL was associated with a fixed ratio schedule of reinforcement, while the other was associated with a bi-valued mixed ratio schedule of reinforcement, whose arithmetic mean equaled the Fixed TL schedule. The fixed component (FR50; FR25; FR5) was arranged to be equal to the alternative mixed component in each condition (FR1/99; FR1/49; FR1/9), and choice behavior was measured by proportion of responses to each IL. In addition, the IL duration varied across conditions (VI 30s; VI 15s; FI 1s). Preference for the mixed option was observed with longer durations (e.g., when IL=VI 30s and TL=FR1/99). Participants were relatively indifferent in other conditions, though the results suggested a monotonic increase in preference as either durations or programmed efforts increased. It is concluded that both choice and the conditioned reinforcement value of the mixed option is contextually based, so that the value of a stimulus correlated with an immediate reward (i.e., FR 1) is enhanced the greater the temporal context in which the FR1 is embedded. PMID- 21291964 TI - Changes in the concentrations of creatinine, cystatin C and NGAL in patients with acute paraquat self-poisoning. AB - An increase in creatinine > 3 MUmol/L/h has been suggested to predict death in patients with paraquat self-poisoning and the value of other plasma biomarkers of acute kidney injury has not been assessed. The aim of this study was to validate the predictive value of serial creatinine concentrations and to study the utility of cystatin C and neutrophil gelatinase-associated lipocalin (NGAL) as predictors of outcome in patients with acute paraquat poisoning. The rate of change of creatinine (dCr/dt) and cystatin C (dCyC/dt) concentrations were compared between survivors and deaths. Receiver-operating characteristic (ROC) curves were constructed to determine the best threshold for predicting death. Paraquat was detected in 20 patients and 7 of these died between 18 h and 20 days post ingestion. The dCr/dt ROC curve had an area of 0.93 and the cut-off was > 4.3 MUmol/L/h (sensitivity 100%, specificity 85%, likelihood ratio 7). The dCyC/dt ROC curve had an area of 0.97 and the cutoff was > 0.009 mg/L/h (sensitivity 100%, specificity 91%, likelihood ratio 11). NGAL did not separate survivors from deaths. Death due to acute paraquat poisoning is associated with changes in creatinine and cystatin concentrations. Further validation of these measurements is needed before they can be adopted in guiding intensive treatments. PMID- 21291965 TI - Physiologically based toxicokinetic modelling as a tool to assess target organ toxicity in route-to-route extrapolation--the case of coumarin. AB - Coumarin (1,2-benzopyrone) is occurring in food, and is also used in cosmetics. In order to perform a risk assessment for both oral and dermal exposure, we applied a physiologically based approach to model kinetics in humans by simulating both routes of exposure. The concentration-time profile in liver revealed a higher peak concentration (C(max-hep)) for the oral when compared to the dermal route. The area under the concentration-time curve in the liver (AUC(hep)) was found the same for both routes if the same extent of absorption is assumed. Dose response information from published rat studies were used to identify the metric relevant for liver toxicity. Liver exposure levels resulting from doses and durations as outlined in the studies were simulated in a rat model. We obtained 31 data pairs of C(max-hep) and AUC(hep). Liver toxicity was observed at doses which resulted in simulated C(max-hep) values exceeding a certain liver concentration whereas we could not identify a clear cut off value of AUC(hep). Our findings support the notion that liver toxicity of coumarin in rats is related to C(max-hep) rather than to AUC(hep). If these findings can be transferred to the situation in humans, the result demonstrates that route specific differences in organ peak concentrations have to be considered when performing route-to-route extrapolation. PMID- 21291966 TI - Effects of non-dioxin-like polychlorinated biphenyl congeners (PCB 101, PCB 153 and PCB 180) alone or mixed on J774A.1 macrophage cell line: modification of apoptotic pathway. AB - Non-dioxin-like polychlorinated biphenyls (PCBs) are stable and lipophilic chemicals that persist in the environment and tend to bioaccumulate in the food chains. In the present study, we have investigated the effect of PCBs 101, 153, and 180 on macrophage J774A.1 by assessing cell viability and apoptotic cell death. We have combined morphological techniques and biochemical ones to establish the relevance of apoptosis in macrophage cell death induced by PCBs, alone or in combination. Treatment with the examined PCBs caused the loss of cell viability and accelerated apoptosis in a concentration-dependent manner. Moreover, a synergistic effect on cell death and apoptosis was evidenced for all PCBs at concentrations which were inactive alone. The apoptosis induced by PCBs involved the increase of caspase-3 activity. Also, Bcl-2 and Bax proteins were assessed to elucidate the apoptosis machinery induced in macrophage cultures by PCBs. Our results indicate that the increase in PCB-induced apoptosis correlates with a reduction in the expression of antiapoptotic Bcl-2 and an increase in the expression of proapoptotic Bax. Interestingly, concentrations of PCBs inactive by themselves induce apoptosis when PCBs are combined. In conclusion, our findings suggest that, although less toxic than dioxin like congeners, the examined non dioxin-like PCBs are equally dangerous as immunotoxic pollutants, also considering their presence as mixtures at higher levels than dioxin-like PCBs in biotic and abiotic matrices. PMID- 21291967 TI - Aristolochic acid I suppressed iNOS gene expression and NF-kappaB activation in stimulated macrophage cells. AB - Aristolochic acid I (AAI) is a phytotoxin that has been found in various herbal remedies and linked to the development of human carcinogenesis. To investigate the playing role of AAI in the function of macrophages, lipopolysaccharide (LPS) stimulated macrophage cells RAW264.7 were employed as a model to examine the effect of AAI on the expression of the inducible nitric oxide synthase (iNOS) gene. AAI reduced the expression of iNOS mRNA and protein, as well as the production of NO in LPS-stimulated macrophages. Treatment of transfected macrophages with AAI effectively suppressed the luciferase activities of the iNOS promoter which is activated by LPS. The results of promoter deletion and electrophoretic gel mobility shift assay (EMSA) indicated that the NF-kappaB binding site at nucleotides -86 to -76 was the major site that was most responsible for the inhibitory effect of AAI. Moreover, the presence of AAI substantially reduced the phosphorylation of the inhibitory kappaBalpha (IkappaBalpha) protein in LPS-stimulated cultures. AAI also down-regulated the LPS-induction of TNF-alpha, a NF-kappaB regulated gene. On the other hand, AAI did not modulate the luciferase activities of reporter construct that contained iNOS mRNA 3'-UTR. Taken together, the data herein suggest that in activated macrophages, AAI effectively down-regulated the expression of iNOS gene by interfering with the activation of NF-kappaB at the transcription level. The stability of iNOS mRNA was not the target of AAI inhibition. PMID- 21291968 TI - Comparison of humoral and cell-mediated immune responses to cationic PLGA microspheres containing recombinant hepatitis B antigen. AB - Presently available marketed alum adsorbed hepatitis B vaccine used for prophylactic immunization, can effectively elicit humoral immunity but is poor inducer of cell-mediated immunity (CMI). Besides, conventional alum-adjuvant vaccines require multiple injections to achieve long-lasting protective immune responses. Therefore, as a result of insufficient immunization, infections are still the leading killer among diseases. The present investigation was therefore, aimed at developing "single-shot" HBsAg adsorbed microspheres of poly (DL) lactide-co-glycolide (PLGA) (L/G 50:50 and 75:25) and their capability to stimulate the cell mediated immune response against hepatitis B surface antigen. These microspheres were characterized in vitro for their size, shape polydispersity index, percentage HBsAg adsorption efficiency and in vitro release profile. The immune-stimulating activities were also studied following subcutaneous injection of HBsAg adsorbed PLGA microspheres (single-dose on day 0) and compared with alum adsorbed vaccines (two-doses on 0 and 28 days) in Balb/c mice. Specific cell-mediated immune responses such as lymphocyte transformation assay (stimulation-index) including release of interferon-gamma (IFN-gamma), interleukin-2 (IL-2) and nitric-oxide were determined. Cellular responses in case of alum adsorb HBsAg vaccine was very low. These studies demonstrate the potential of cationic polymeric microspheres based vaccine in stimulating cell mediated immune response along with humoral response against hepatitis B. PMID- 21291969 TI - Electrospun diclofenac sodium loaded Eudragit(r) L 100-55 nanofibers for colon targeted drug delivery. AB - Eudragit(r) L 100-55 nanofibers loaded with diclofenac sodium (DS) were successfully prepared using an electrospinning process, and characterized for structural and pharmacodynamic properties. The influence of solvent and drug content on fiber formation and quality was also investigated. Fiber formation was successful using a solvent mixture 5:1 (v/v) ethanol:DMAc. XRD and DSC analysis of fibers confirm electron microscopic evidence that DS is evenly distributed in the nanofibers in an amorphous state. FTIR analysis indicates hydrogen bonding occurs between the drug and the polymer, which accounts for the molecular integration of the two components. In vitro dissolution tests verified that all the drug-loaded Eudragit(r) L 100-55 nanofibers had pH-dependent drug release profiles, with limited, less than 3%, release at pH 1.0, but a sustained and complete release at pH 6.8. This profile of properties indicates drug-loaded Eudragit(r) L 100-55 nanofibers have the potential to be developed as oral colon targeted drug delivery systems. PMID- 21291970 TI - Evaluating tamsulosin hydrochloride-released microparticles prepared using single step matrix coating. AB - The objective of the present study was to determine the optimum composition for sustained-release of tamsulosin hydrochloride from microparticles intended for orally disintegrating tablets. Microparticles were prepared from an aqueous ethylcellulose dispersion (Aquacoa(r)), and an aqueous copolymer based on ethyl acrylate and methyl methacrylate dispersion (Eudragit(r)) NE30D), with microcrystalline cellulose as core particles with a fluidized bed coating process. Prepared microparticles were about 200 MUm diameter and spherical. The microparticles were evaluated for in vitro drug release and in vivo absorption to assess bioequivalence in a commercial product, Harnal(r) pellets. The optimum ratio of Aquacoat(r) and Eudragit(r) NE30D in the matrix was 9:1. We observed similar drug release profiles in microparticles and Harnal(r) pellets. Higuchi model analysis of the in vitro drug release from microparticles was linear up to 80% release, typical of Fickian diffusion sustained-release profile. The in vivo absorption properties from microparticles were comparable to Harnal(r) pellets, and there was a linear relationship between in vitro drug release and in vivo drug release. In conclusion, this development produces microparticles in single step coating, that provided a sustained-release of tamsulosin hydrochloride comparable to Harnal(r) pellets. PMID- 21291971 TI - Preparation and characterization of baicalin-poly -vinylpyrrolidone coprecipitate. AB - Baicalin-polyvinylpyrrolidone (PVP) coprecipitate was prepared by the solvent method of solid dispersion technology to improve the dissolution rate of baicalin. The coprecipitate was characterized using differential scanning calorimetry (DSC), X-ray powder diffraction (XRD), infrared spectrometry (IR) and dissolution testing. Furthermore, AFM.IPC-208B high-resolution atomic force microscopy (AFM) was utilized to characterize the molecular morphology of baicalin within its carrier and the interaction between baicalin and its carrier. The results of DSC and XRD indicated that baicalin resided in PVP polymers in an amorphous or molecular phase, dissolution test results demonstrated that the dissolution rate of the coprecipitate was 21.4 times that of the active pharmaceutical ingredient (API). The results of IR indicated the possibility of the formation of intermolecular hydrogen bonds. The AFM.IPC-208B findings revealed that baicalin was dispersed in PVP polymers with a molecular size of 2 nm and either wrapped or surrounded by approximately 0.4 nm of a five-membered ring of PVP arranged along the carbon chain sequentially. An intermolecular hydrogen bond was formed between the 4-OH of the glucuronide of baicalin and the O of the carbonyl group from PVP in addition to the formation of intramolecular hydrogen bonds within baicalin. PMID- 21291972 TI - Gene transfer efficacies of serum-resistant amino acids-based cationic lipids: dependence on headgroup, lipoplex stability and cellular uptake. AB - Serum is a major obstacle to efficient cationic liposome-mediated gene transfection. In this paper, three alkaline amino acids based cationic lipids including lysinylated cholesterol (lipid 1), histidinylated cholesterol (lipid 2) and argininylated cholesterol (lipid 3) were used as non-viral gene vectors. The physicochemical properties such as size, Zeta potential, stability and cellular uptake of the lipoplexes formed from lipids 1-3 as well as the transfection efficacies with or without serum were investigated. The results demonstrated that lipid 1 and lipid 3 showed good properties in lipoplex stability and cellular uptake. Interestingly, lipid 3-based liposome showed serum-enhanced effect on the gene transfection. The transfection efficiency of lipid 1 and lipid 3 was remarkably higher than that of lipid 2. Moreover, they exhibited 10-20-fold more efficaciously than the control, 1,2-dioleoyloxy-3-(trimethylammonio)-propane (DOTAP) liposome in serum-containing media. The data suggested the strong effect of the type of the headgroup on gene transfection. The lysine/arginine derivative cationic lipids could be promising nonviral vectors for gene delivery in vivo. PMID- 21291973 TI - Influence of compression on water sorption, glass transition, and enthalpy relaxation behavior of freeze-dried amorphous sugar matrices. AB - An amorphous matrix comprised of sugar molecules are frequently used in the pharmaceutical industry. The compression of the amorphous sugar matrix improves the handling. Herein, the influence of compression on the water sorption of an amorphous sugar matrix was investigated. Amorphous sugar samples were prepared by freeze-drying, using several types of sugars, and compressed at 0-443 MPa. The compressed amorphous sugar samples as well as uncompressed samples were rehumidified at given RHs, and the equilibrium water content and glass transition temperature (T(g)) were then measured. Compression resulted in a decrease in the equilibrium water content of the matrix, the magnitude of which was more significant for smaller sized sugars. Diffusivity of water vapor in the sample was also decreased to one-hundredth by the compression. The T(g) value for a given RH remained unchanged, irrespective of the compression. Accordingly, the decrease in T(g) with increasing water content increased as the result of compression. The structural relaxation of the amorphous sugar matrices were also examined and found to be accelerated to the level of a non-porous amorphous sugar matrix as the result of the compression. The findings indicate that pores contained in freeze-dried sugar samples interfere with the propagation of structural relaxation. PMID- 21291974 TI - Cationic nanoemulsion as a delivery system for oligonucleotides targeting malarial topoisomerase II. AB - A promising strategy based on the antisense oligonucleotides against the Plasmodium falciparum topoisomerase II has been considered using cationic nanoemulsion as oligonucleotide delivery system. Phosphodiester and chemically modified phosphorothioate oligonucleotides bearing negative charges were adsorbed on positively charged emulsion composed of medium chain triglycerides, egg lecithin, 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), and water, at different +/- charge ratios (positive charges from cationic lipid/negative charges from oligonucleotide): +0.5/-, +2/-, +4/- and +6/-. The physicochemical properties of the complexes were determined, as well as their stability in culture medium. Their interaction with erythrocytes through hemolysis, binding experiments and confocal microscopy were also evaluated. Finally, the in vitro evaluation of parasite growth and reinfection capacity was performed. The overall results showed that antisense oligonucleotides against P. falciparum topoisomerase II gene can be efficiently adsorbed onto a cationic nanoemulsion forming complexes. Whereas unloaded nanoemulsion displayed an hemolytic effect due to the presence of the cationic lipid, this was not the case of loaded nanoemulsion at low +/- ratios. Oligonucleotide-loaded nanoemulsions were found to be located inside the infected erythrocytes, inhibiting efficiently parasite growth (until 80%) and causing a delay in P. falciparum life cycle. PMID- 21291975 TI - Improving solubility and chemical stability of natural compounds for medicinal use by incorporation into liposomes. AB - Natural bioactive compounds have been studied for a long time for their chemopreventive and therapeutic potential in several chronic inflammatory diseases, including cancer. However, their physicochemical properties generally result in poor chemical stability and lack of in vivo bioavailability. Very few human clinical trials have addressed absorption, distribution, metabolism, and excretion of these compounds in relation to efficacy. This limits the use of these valuable natural compounds in the clinic. In this study, we examined caffeic acid (derivatives), carvacrol (derivatives), thymol, pterostilbene (derivatives), and N-(3-oxo-dodecanoyl)-l-homoserine lactone. These are natural compounds with strong anti-inflammatory properties derived from plants and bacteria. However, these compounds have poor water solubility or are chemically unstable. To overcome these limitations we have prepared liposomal formulations. Our results show that lipophilic 3-oxo-C(12)-homoserine lactone and stilbene derivatives can be loaded into liposomal lipid bilayer with efficiencies of 50 70%. Thereby, the liposomes solubilize these compounds, allowing intravenous administration without use of solvents. When compounds could not be loaded into the lipid bilayer (carvacrol and thymol) or are rapidly extracted from the liposomes in the presence of serum albumin (3-oxo-C(12)-homoserine lactone and pterostilbene derivatives), derivatization of the compound into a water-soluble prodrug was shown to improve loading efficiency and encapsulation stability. The phosphate forms of carvacrol and pterostilbene were loaded into the aqueous interior of the liposomes and encapsulation was unaffected by the presence of serum albumin. Chemical instability of resveratrol was improved by liposome encapsulation, preventing inactivating cis-trans isomerization. For caffeic acid, liposomal encapsulation did not prevent oxidation into a variety of products. Still, by derivatization into a phenyl ester, the compound could be stably encapsulated without chemical degradation. Despite the instability of liposome association of 3-oxo-C(12)-homoserine lactone and resveratrol, intravenous administration of these compounds inhibited tumor growth for approximately 70% in a murine tumor model, showing that simple solubilization can have important therapeutic benefits. PMID- 21291976 TI - Organic-inorganic hybrid anion exchange hollow fiber membranes: a novel device for drug delivery. AB - The clinical use of nonsteroidal anti-inflammatory drugs (NSAIDs) (such as sodium salicylate (NaSA)) for the treatment of chronic arthritis is limited due to the adverse effects and patient non-compliance. In order to solve these problems, anion exchange hollow fiber membranes (AEHFMs) are proposed for the first time here as potential drug carriers. Brominated poly(2,6-dimethyl-1,4-phenylene oxide) (BPPO) is used as the starting membrane material. In-situ sol-gel process of gamma-methacryloxypropyl trimethoxysilane (gamma-MPS) in BPPO matrix is operated so as to enhance the membranes' thermal and dimensional stability. The performances of the membranes in controlled release of the drug (NaSA as the model drug) are improved accordingly. Loading and release experiments illustrate that the hybrid AEHFM can bind salicylate (SA-) at a high loading efficiency (28.4%), and the retention of the drug on the membrane matrix is significantly prolonged (drug released in 7 days under physiological condition: 51.9%, neglecting the drug bound by protein). Meanwhile, the membrane is biocompatible and can support the adherence, growth, and survival of human cells. Overall, the prepared AEHFM is a promising scaffolding material for drug delivery and tissue engineering. PMID- 21291977 TI - Novel chitosan-magnesium aluminum silicate nanocomposite film coatings for modified-release tablets. AB - Chitosan (CS), a positively charged polysaccharide, and magnesium aluminum silicate (MAS), a negatively charged clay with silicate layers, can electrostatically interact to form nanocomposite films. In this study, CS-MAS nanocomposite films were evaluated for use in tablet film coating. Effects of CS MAS ratio and coating level on water uptake and drug release from the coated tablets were investigated. Surface and film matrix morphology of the coated film and the effect of enzymes in the simulated gastro-intestinal fluid on drug release were also examined. The results demonstrated that the CS-MAS coated tablets had a rough surface and a layered matrix film, whereas a smooth surface and dense matrix film on the CS coated tablets was found. However, the CS-MAS coated tablets provided fewer film defects than the CS coated tablets. Nanocomposite formation between CS and MAS could retard swelling and erosion of CS in the composite films in acidic medium. The higher MAS ratio of the CS-MAS coated tablets gave lower water uptake and slower drug release when compared with the CS coated tablets. Moreover, the CS-MAS films on the tablets presented good stability towards enzymatic degradation in simulated intestinal fluid. The release of drug from the CS-MAS coated tablets could be modulated by varying CS MAS ratios and coating levels. Additionally, drug solubility also influenced drug release characteristics of the CS-MAS coated tablets. These findings suggest that the CS-MAS nanocomposites displays a strong potential for use in tablet film coating intended for modifying drug release from tablets. PMID- 21291978 TI - Introduction to Annual Reviews 2011. PMID- 21291979 TI - Tannin-rich fraction from Terminalia catappa inhibits quorum sensing (QS) in Chromobacterium violaceum and the QS-controlled biofilm maturation and LasA staphylolytic activity in Pseudomonas aeruginosa. AB - AIM OF THE STUDY: The study aimed to test the activity of Terminalia catappa L. against bacterial quorum sensing (QS) in order to provide a potential scientific basis for the traditional use of leaf extracts of this plant as an antiseptic. MATERIALS AND METHODS: The anti-QS activity of the methanolic leaf extract of Terminalia catappa was detected through the inhibition of the QS-controlled violacein pigment production in Chromobacterium violaceum. Fractions resulting from size-exclusion chromatography were assayed. The most active fraction was characterized through qualitative phytochemical detection methods. The effect of this fraction on known QS-controlled phenotypes in test strains was assessed. RESULTS: The fraction with the highest activity (labeled as TCF12) was characterized to be tannin-rich. It specifically inhibited QS-controlled violacein production in Chromobacterium violaceum with 50% reduction achieved at 62.5 MUg mL(-1) without significantly affecting growth up to about 962 MUg mL( 1). The assessment of its effects on LasA activity of Pseudomonas aeruginosa ATCC 10145 found that the production of this virulence determinant is reduced in a concentration dependent manner with about 50% reduction at 62.5 MUg mL(-1). Furthermore, it was found that TCF12 was able to inhibit the maturation of biofilms of Pseudomonas aeruginosa, a phenotype that has also been known to be QS regulated. CONCLUSION: Therefore, tannin-rich components of Terminalia catappa leaves are able to inhibit certain phenotypic expression of QS in the test strains used. PMID- 21291980 TI - In vitro growth stimulatory and in vivo wound healing studies on cycloartane-type saponins of Astragalus genus. AB - AIM OF THE STUDY: The present study was undertaken to evaluate the wound healing effects of the four chief saponins of Astragalus species [cycloastragenol (CA), astragaloside IV (AG), cyclocephaloside I (CCI) and cyclocanthoside E (CCE)]. MATERIAL AND METHODS: Effects of cell viability and proliferation of the isolated compounds were evaluated by the MTT assay on human keratinocyte. The wound healing activity was studied by using in vitro wound healing, proliferation and migration scratch assay. In order to see in vivo effectiveness of the compounds, an animal study with Sprague-Dawley male rats at the age of 12 weeks was carried out, and then the main histological outcomes were investigated to observe reepithelization, neovascularization, and presence of inflammatory cells, granulation tissue amount and maturation. RESULTS: All the compounds increased both fibroblast proliferation and migration, but the effects were much superior for CA at 1 ng/ml concentration. Among the compounds, based on the histological findings, 5% CA preparation was found to be the most remarkable in vivo wound healing agent showing greater cell density, more regularly organized dermis and more newly formed blood vessels. CONCLUSION: Results of this study indicate that the cycloartane-type saponins are the principal constituents responsible for wound healing activities of the roots of Astragalus species substantiating its use in traditional medicine. PMID- 21291981 TI - Ethnobotanical survey of medicinal plants commonly used by Kani tribals in Tirunelveli hills of Western Ghats, India. AB - ETHNOPHARMACOLOGICAL RELEVANCE: For thousands of years, medicinal plants have played an important role throughout the world in treating and preventing a variety of diseases. Kani tribal people in Tirunelveli hills still depend on medicinal plants and most of them have a general knowledge of medicinal plants which are used for first aid remedies, to treat cough, cold, fever, headache, poisonous bites and some simple ailments. AIM OF THE STUDY: The present study was initiated with an aim to identify traditional healers who are practicing herbal medicine among the Kani tribals in Tirunelveli hills of Western Ghats, India and quantitatively document their indigenous knowledge on the utilization of medicinal plants particularly most common ethnomedicinal plants. METHODS: Field study was carried out over a period of 4 years in Tirunelveli hills. The ethnomedicinal information was collected through interviews among the Kani traditional healers. The collected data were analyzed through use value (UV), informant consensus factor (F(ic)), fidelity level (FL) and relative importance (RI). RESULTS: A total of 90 species of plants distributed in 83 genera belonging to 52 families were identified as commonly used ethnomedicinal plants by the Kani traditional healers in Tirunelveli hills for the treatment of 65 types of ailments. These ailments were categorized into 15 ailment categories based on the body systems treated. Leaves were the most frequently used plant parts and most of the medicines were prepared in the form of paste and administered orally. F(ic) values of the present study indicated that there was a high agreement in the use of plants in the treatment of jaundice and diabetes among the users. Dermatological infections/diseases and gastro-intestinal disorders had highest use-reports and 29 species of plants had the highest fidelity level of 100%. The most important species according to their use value were Gymneme sylvestre (2.00), Melia azedarach, Murraya koenigii, Syzygium cumini and Terminalia chebula (1.83). CONCLUSION: As a result of the present study we can recommend the plants Alpinia galanga, Azadirachta indica, Calophyllum inophyllum, Gymnema sylvestre, Leucas aspera, M. azedarach, Mollugo nudicaulis, Ocimum tenuiflorum, S. cumini, T. chebula and Tribulus terrestris (with high UV and RI values), Bambusa arundinacea, Datura metel, Evolvulus nummularius, Opuntia dillenii and Physalis minima (newly reported claims with highest FL) for further ethnopharmacological studies for the discovery of potential new drugs. PMID- 21291982 TI - Acute and sub-chronic toxicity study of standardized extract of Fumaria indica in rodents. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Despite Fumaria indica (FI) widespread medicinal uses in the Indian traditional medicine, no systematic study of the potential toxicity of the plant has been described. AIM OF THE STUDY: To assess acute and sub-chronic toxicity of a 50% ethanolic extract of FI in mice and rats respectively. MATERIALS AND METHODS: In acute toxicity study, Swiss strain albino mice of either sex were administered orally FI doses of 1, 2.5 and 5 g/kg and observed for behavioural changes and mortality, if any. In sub-chronic toxicity study, Charles Foster albino rats of either sex were administered two doses of FI i.e., 100 and 400mg/kg, p.o. for 30 consecutive days. During 30 days of treatment, rats were observed for any change in body weight and daily food and water intake. After 30 days, rats were sacrificed for haematological, biochemical and histopathology study. Control animals were administered 0.3% carboxymethyl cellulose (CMC) suspension by oral route. RESULTS: There was no mortality or abnormal behaviour, observed in acute toxicity study in mice at all the three dose levels. In sub-chronic toxicity study, FI did not produce any significant change in body weight and daily food and water intake of rats when compared to vehicle treated rats. Further, haematological and biochemical parameters were also found normal. Histopathological study revealed normal architecture of kidney and liver of FI treated rats. CONCLUSIONS: FI extract, provisionally standardized on its fumarate contents, seems to fulfill a preclinical criterion necessary for its further development as a clinically useful adaptogen. PMID- 21291983 TI - Deciphering molecular mechanism underlying antileishmanial activity of Nyctanthes arbortristis, an Indian medicinal plant. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Nyctanthes arbortristis L. (Oleaceae) is widely used in the traditional medicine of India. The plant is shown to have antibacterial and antileishmanial activities. AIM OF THE STUDY: Evaluation of iridoid glucosides from the plant as inhibitor of trypanothione reductase (TryR), a validated drug target enzyme of the Leishmania parasite. The study contributes towards understanding mechanism of antileishmanial effect of the plant. MATERIALS AND METHODS: TryR of Leishmania parasite is expressed and purified. Iridoid glucosides are isolated from the plant and tested as inhibitor of TryR enzyme of the parasite. RESULTS: Inhibitory constant (K(i)) of various iridoid glucosides ranges from 3.24+/-0.05 MUM to 6.49+/-0.05 MUM. Thus, the molecular mechanism underlying antileishmanial activity of these compounds is mediated through inhibition of TryR. CONCLUSION: The current study also points out towards potential application of iridoid glucosides as novel drugs against the disease. PMID- 21291984 TI - Protective effect of Zhen-Wu-Tang (ZWT) through keeping DA stable and VMAT 2/DAT mRNA in balance in rats with striatal lesions induced by MPTP. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Zhen-Wu-Tang (ZWT), the modified formulation of a classical Chinese prescription from "Treaties on Febrile Disease", was clinically employed to treat Parkinson's disease. AIM OF THE STUDY: To investigate the neuroprotective effect of ZWT on intra-striatum injection of MPTP-induced Parkinson's disease in rats. MATERIALS AND METHODS: The effect of ZWT on the behavioral changes (open-field test, Ladder walking, spontaneous alternation in Y maze), the dopamine transmitter systems of substantia nigra, striatum and frontal cortex of rats by HPLC-ECD, mRNA expression of tyrosine hydroxylase (TH), dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT 2) of the above three brain regions was investigated. RESULTS: This study showed that ZWT not only ameliorated the behavior induced by the administration of MPTP in striatum, but also increased DA in the brain, prevented the decreasing of TH and balanced the ratio of VMAT 2/DAT in mRNA level. CONCLUSIONS: These results suggest that ZWT possesses neuroprotective and anti-parkinsonism properties. PMID- 21291985 TI - A comparative study of the antimicrobial and phytochemical properties between outdoor grown and micropropagated Tulbaghia violacea Harv. plants. AB - AIM OF THE STUDY: The study aimed to compare the antimicrobial and phytochemical properties of in vitro cultured and outdoor grown Tulbaghia violacea plants in the quest to validate the use of micropropagated plants as alternatives to outdoor grown plants in traditional medicine. Tulbaghia violacea is used extensively in South African traditional medicine for HIV/AIDS patients and in the treatment of gastrointestinal ailments, asthma, fever and tuberculosis. MATERIALS AND METHODS: Extracts of micropropagated and outdoor grown Tulbaghia violacea plants were evaluated for their antibacterial and antifungal activities against Bacillus subtilis, Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus and a fungus Candida albicans using microdilution methods. Saponins and phenolic compounds including condensed tannins, gallotannins and flavonoids were quantitatively determined using spectrophotometric methods. A qualitative test for saponins was also carried out. RESULTS: The petroleum ether (PE) extracts of micropropagated plants and dichloromethane (DCM) extracts of outdoor grown plants showed good antibacterial activity, each against two bacterial test strains. PE extracts of micropropagated plants showed the best antibacterial activity with a minimum inhibitory concentration (MIC) of 0.39 mg/ml against Bacillus subtilis. Good MIC (<1mg/ml) and minimum fungicidal concentration (MFC) values of 0.78 mg/ml were only obtained in DCM extracts of outdoor grown plants. MIC and MFC values for water and ethanol extracts of both micropropagated and outdoor grown plants were similar and in the range 3.125 12.5mg/ml. Total phenolics, gallotannins, flavonoids and saponins were significantly higher in micropropagated plants than in outdoor grown ones. In all cases, the amounts of phytochemical compounds in micropropagated plants were more than twice that of outdoor grown plants except for condensed tannins. CONCLUSION: The results form a good basis for the use of Tulbaghia violacea micropropagated plants as a complement to the outdoor grown plants in traditional medicine. PMID- 21291986 TI - Parallels between zootherapeutic practices in ethnoveterinary and human complementary medicine in northeastern Brazil. AB - AIM OF THE STUDY: The purpose of this study was to describe the local zootherapeutic practices in ethnoveterinay medicine of semi-arid of NE Brazil (Caatinga biome) and to contribute to future research about the validation of the effects and side effects of these animal products. In this sense, we sought to determine the connections between human and animal ethnopharmacology and their implications for ethnoveterinary medicine in northeastern Brazil. MATERIALS AND METHODS: In this study we analyze data gathered through fieldwork conducted in the semi-arid of Paraiba State, NE Brazil, where 123 people (98 men and 25 women) provided information on animal species used as medicine, body parts used to prepare the remedies and illnesses to which the remedies were prescribed. The information obtained through semi-structured interviews was complemented by free interviews and informal conversations. RESULTS: A total of 46 animal species (43 vertebrates and 3 invertebrates) were found to be used to treat 33 different ailments in livestocks and pets and 62 conditions in humans. Interviewees cited a wide range of materials derived from animal bodies (or their metabolic products) that are used as remedies in local EVM, nonetheless, fats (and/or suet) is the most frequently reported natural remedies. EVM practices have close relationships with human complementary and alternative medicine (CAM) and probably evolved based on traditional human medicine practices; as such, the division between EVM and CAM is not always obvious from the viewpoint of the local residents. Descriptions of diseases, symptoms or treatments were often associated with both humans and animals (especially livestock), and 24 animal species (52%) were prescribed to treat similar ailments in both humans and animals based on local knowledge about CAM. CONCLUSIONS: Our results suggest that traditional knowledge of animal-based medicines in ethnoveterinary practices co-evolved with traditional knowledge of human ethnomedicine. The examination of folk knowledge and animal health practices will give us a better understanding of human interactions with their local environment and aid in formulating appropriate strategies for the validation of traditional remedies and for natural resource conservation. PMID- 21291987 TI - The effect of the whole extract of common ivy (Hedera helix) leaves and selected active substances on the motoric activity of rat isolated stomach strips. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The long tradition of using the dry extract of Hedera helix (common ivy) leaves in traditional and contemporary alternative medicine caused that many biological and pharmacological studies have been aimed at evaluating the effects of ivy. Some of the results suggest that Hedera helix extract possesses bronchodilatatory and antispasmodic activity. On the other hand, the symptoms of ivy intoxication in human and animals, as well as adverse reactions observed during the therapy with ivy-based pharmaceuticals, indicate rather stimulant effect of the plant on smooth muscle. Thus, the aim of this study was to evaluate the effect of two main active substances extracted from the plant (alpha-hederin and hederacoside C) and the whole dry extract of Hedera helix on the gut motility. MATERIALS AND METHODS: The experiments were carried out on isolated stomach corpus and fundus strips. The tissues were isolated from rats. The experiments were performed in isotonic conditions. The results are expressed as the percent of the reaction caused by a reference contractile substance, acetylcholine. RESULTS AND CONCLUSIONS: The obtained results revealed that alpha-hederin applied in the concentration ranged from 25 to 320MUM significantly changed the spontaneous motoric activity of rat stomach smooth muscle. The observed reaction had always the same character, a contraction, and its force was concentration dependent. The second tested saponin, hederacoside C, did not alter the motility of rat isolated stomach corpus and fundus strips when administered in the concentration up to 100 MUM, however, if applied in the concentration of 350 MUM it induced a remarkable concentration of smooth muscle. Eventually, the whole extract of Hedera helix in a dose containing 60 MUM of hederacoside C produced a strong contraction which strength was comparable with the reaction generated by acetylcholine. According to the results, it is very likely that alpha-hederin, but not hederacoside C contributes to the contractile response of isolated stomach corpus and fundus strips to the application of Hedera helix leaves' extract. PMID- 21291988 TI - Cytotoxicity of some Cameroonian spices and selected medicinal plant extracts. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Several medicinal plants and spices are used traditionally to treat cancers in Cameroon. AIM: Methanol extracts from thirty four spices and plants, with related ethnobotanical use were investigated for their in vitro cytotoxicity on the human pancreatic cancer cell line MiaPaCa-2, leukemia CCRF-CEM cells and their multidrug resistant (MDR) subline CEM/ADR5000, and the normal human umbilical vein endothelial cells (HUVECs). In addition the anti-angiogenic properties of the most active extracts were investigated. MATERIAL AND METHODS: The MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3 carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay was used for cytotoxic studies and the CAM-assay (chicken-chorioallantoic-membrane-assay) for anti-angiogenesis test. RESULTS: The results of the cytotoxicity tests indicated that, when tested at 20 MUg/ml, extracts from Xylopia aethiopica, Echinops giganteus, Imperata cylindrica, Dorstenia psilirus and Piper capense were able to inhibit more that 50% the proliferation of the three tested cancer cells (MiaPaCa 2, CEM/ADR5000 CCRF-CEM). The lowest IC(50) values of 6.86 MUg/ml on MiaPaCa-2 and 3.91 MUg/ml on CCRF-CEM cells were obtained with X. aethiopica, while the corresponding value of 6.56 MUg/ml was obtained with P. capense on CEM/ADR5000 cells. Against leukemia cells, no cross-resistance was observed with I. cylindrica, P. capense and Zinziber officinalis. Extracts from D. psilirus and E. giganteus were able to inhibit angiogenesis by more than 50% in quail embryo. CONCLUSION: The overall results of the present study provide supportive data on the use of some Cameroonian plants for cancer treatment. PMID- 21291989 TI - Ethnobotanical authentication and identification of Khrog-sman (Lower Elevation Medicinal Plants) of Bhutan. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The Bhutanese form of g.so-ba-rig-pa medicine, which is a scholarly medical system, belongs to a larger system of medicinal corpus that spreads from Mongolia to India. It uses medicinal plants as a bulk ingredient but only 'Higher Elevation Medicinal Plants' have been botanically identified so far. Our study reports the botanical identification of 'Lower Elevation Medicinal Plants' and their ethnomedical uses. AIM OF THE STUDY: To botanically identify the 'Lower Elevation Medicinal Plants' used in Bhutanese traditional medicine. MATERIALS AND METHODS: A five stage process was conducted which consisted of: (1) a survey of specialized ancient ethnomedical literatures (Pharmacopoeias and formularies); (2) freely listing the 'Lower Elevation Medicinal Plants' reported in the ancient Bhutanese medical texts and translating their ethnomedical uses in equivalent terms of English; (3) making field visits, collecting herbarium specimens and photographs, and spot identification of plants; (4) double blind testing of Bhutanese traditional medicine practitioners for authentication and standardization of Bhutanese g.so-ba-rig-pa names; (5) organising workshops for open forum discussions on medicinal plants involving Traditional Physicians and other professional participants of the relevant areas. RESULTS: We identified the botanical names of 113 'Lower Elevation Medicinal Plants' belonging to 68 families and 104 genera. Out of 113 medicinal plant species identified, 92 species are currently used in Bhutan and the remaining 21 species were not used in the current formulation, but described in the Bhutanese traditional medical texts. The identification of these 21 species was achieved both ethnomedically and botanically for the first time. Out of the 28 plant species that are currently imported from India, we found for the first time, even to the knowledge of Traditional Physicians, that 16 of them are actually growing abundantly in Bhutan. Among the plant parts collected, seeds were the most prominent followed by fruits and then roots. CONCLUSIONS: Our study identified 113 'Lower Elevation Medicinal Plants' out of which 92 of them are used daily in formulating 102 multi-ingredient prescription medicines in Bhutan. PMID- 21291990 TI - Characterization of the anticancer properties of monoglycosidic cardenolides isolated from Nerium oleander and Streptocaulon tomentosum. AB - AIM OF THE STUDY: For identification of the active constituents we investigated the anticancer activity of cardenolides from Streptocaulon tomentosum Wight & Arn. (Asclepiadaceae) and from Nerium oleander L. (Apocynaceae) which are both used against cancer in the traditional medicine in their region of origin. MATERIAL, METHODS AND RESULTS: The antiproliferative activity of cardenolides isolated from roots of Streptocaulon tomentosum (IC(50)<1-15.3 MUM after 2 days in MCF7) and of cardenolide containing fractions from the cold aqueous extract of Nerium oleander leaves ("Breastin", mean IC(50) 0.85 MUg/ml in a panel of 36 human tumor cell lines), their influence on the cellular viability and on the cell cycle (block at the G2/M-phase or at the S-phase in tumor cells, respectively) were determined using different cell lines. The murine cell line L929 and normal non-tumor cells were not affected. Bioactivity guided fractionation of Breastin resulted in the isolation of the monoglycosidic cardenolides oleandrine, oleandrigeninsarmentoside, neritaloside, odoroside H, and odoroside A (IC(50)-values between 0.010 and 0.071 MUg/ml). CONCLUSIONS: The observed anticancer activities of extracts and isolated cardenolides are in agreement with the ethnomedicinal use of Streptocaulon tomentosum and Nerium oleander. The most active anticancer compounds from both species are monoglycosidic cardenolides possessing the 3beta,14beta-dihydroxy-5beta-card 20(22)-enolide structure with or without an acetoxy group at C-16. The results indicate that the cytotoxic effects are induced by the inhibition of the plasma membrane bound Na(+)/K(+)-ATPase. PMID- 21291991 TI - The in vivo and in vitro diabetic wound healing effects of a 2-herb formula and its mechanisms of action. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The herbs Radix Astragali (RA) and Radix Rehmanniae (RR) have long been used in traditional Chinese Medicine and serve as the principal herbs in treating diabetic foot ulcer. AIM OF STUDY: Diabetic complications, such as foot ulcer, impose major public health burdens worldwide. In our previous clinical studies, two Chinese medicine formulae F1 and F2 have achieved over 80% limb salvage. A simplified 2-herb formula (NF3) comprising of RA and RR in the ratio of 2:1 was used for further study. NF3 was examined for the ulcer healing effect in diabetic rats, and its potential mechanisms of action in fibroblast proliferation, angiogenesis and anti-inflammation in vitro. MATERIALS AND METHODS: A chemically induced diabetic foot ulcer rat model was used for studying the wound healing effect. In the in vitro mechanistic studies, human fibroblast cells (Hs27), human umbilical vein endothelial cells (HUVEC) and mouse macrophage cells (RAW264.7) were assessed for tissue regeneration, angiogenesis and anti-inflammatory activities, respectively. RESULTS: Our in vivo results demonstrated a significant reduction of wound area at day 8 in NF3 (0.98g/kg) group as compared to control (p<0.01). NF3 could significantly stimulate Hs27 proliferation in a dose dependent manner (p<0.05). Besides, NF3 could significantly increase the cell migration and tube formation (p<0.05-0.001) of HUVEC in the angiogenesis study. Furthermore, significant inhibition of nitric oxide production (p<0.01) was found in NF3-treated macrophage cells, suggesting its anti-inflammatory activity. CONCLUSIONS: Our study presents for the first time scientific evidence towards the efficacy of the two-herb formula NF3 in enhancing diabetic wound healing through the actions of tissue regeneration, angiogenesis and anti-inflammation. PMID- 21291992 TI - Acute and subchronic oral toxicity studies of Nelumbo nucifera stamens extract in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Since the use of Nelumbo nucifera stamens in herbal medicines as well as in cosmetic products are highly prevalent in Thailand and increasing worldwide, acute and subchronic toxicity studies to confirm the safe use of Nelumbo nucifera stamens are warranted. AIM OF THE STUDY: Acute and subchronic oral toxicity studies of Nelumbo nucifera stamens extract in rats were performed in the present study in order to evaluate its safety. MATERIALS AND METHODS: In acute toxicity study, Nelumbo nucifera stamens extract was administered by oral gavage to Sprague-Dawley rats (5 males and 5 females) at a dose of 5000 mg/kg. In subchronic toxicity study, the extract at doses of 50, 100, and 200mg/kg/day were given orally to groups of rats (6 rats/dose/sex) for 90 consecutive days. RESULTS: The extract at a dose of 5000 mg/kg produced no treatment-related signs of toxicity or mortality in any of the animals tested during 14 days of the study. In the repeated dose 90-day oral toxicity study, there was no significant difference in body weight between the control and all treatment groups with the exception of the body weight of the female group treated with 200mg/kg/day of the extract which was statistically significantly less than that of its control counterpart on day 90 but the percent weight changes of both groups were almost similar. Some statistically significant differences in hematological and biochemical parameters as well as in some internal organ weights of both male and female rats treated with the extract at the highest dose were observed. However, no abnormality of internal organs was observed in both gross and histopathological examinations. CONCLUSIONS: These results suggest that the oral lethal dose of Nelumbo nucifera stamens extract for male and female rats is in excess of 5000 mg/kg and the no-observed-adverse effect level (NOAEL) of the extract for both male and female rats is considered to be 200mg/kg/day. PMID- 21291993 TI - Bioactive phenolic compounds: production and extraction by solid-state fermentation. A review. AB - Interest in the development of bioprocesses for the production or extraction of bioactive compounds from natural sources has increased in recent years due to the potential applications of these compounds in food, chemical, and pharmaceutical industries. In this context, solid-state fermentation (SSF) has received great attention because this bioprocess has potential to successfully convert inexpensive agro-industrial residues, as well as plants, in a great variety of valuable compounds, including bioactive phenolic compounds. The aim of this review, after presenting general aspects about bioactive compounds and SSF systems, is to focus on the production and extraction of bioactive phenolic compounds from natural sources by SSF. The characteristics of SSF systems and variables that affect the product formation by this process, as well as the variety of substrates and microorganisms that can be used in SSF for the production of bioactive phenolic compounds are reviewed and discussed. PMID- 21291994 TI - Insular volume reduction in fragile X syndrome. AB - Fragile X syndrome (FraX) is the most common form of inherited mental deficit and is caused by mutations of the Fragile X Mental Retardation 1 (FMR1) gene on the X chromosome. While males and females with the full FMR1 mutation are affected differently because the disorder is X-linked, both suffer from varying degrees of cognitive impairment, attention deficits and social anxiety. The insula is a sensory integrative region that has been increasingly suggested as a critical area involved in anxiety manifestation. The current study was designed to examine possible changes in insular volume in FraX compared to age- and gender-matched typically developing healthy controls (HC) as well as age-, gender-, and intelligence-matched developmentally delayed controls (DD). An established native space, manual morphometry method was utilized to quantify total and regional insular volumes using structural magnetic resonance imaging. Total, anterior and posterior insular volumes were found to be reduced in FraX compared to both HC and DD. The current data add to a growing literature concerning brain abnormalities in FraX and suggests that significant volume reduction of the insula is a component of the FraX neuroanatomical phenotype. This finding also provides an intriguing potential neural correlate for hyperarousal and gaze aversion, which are prominent behavioral symptoms of FraX. PMID- 21291995 TI - Validation study of the Short Time Exposure (STE) test to assess the eye irritation potential of chemicals. AB - Short time exposure (STE) test is a cytotoxicity test in SIRC cells (rabbit corneal cell line) that assesses eye irritation potential following a 5-min chemical exposure. This validation study assessed transferability, intra- and inter-laboratory reproducibility, and predictive capacity of STE test in five laboratories (supported by Japanese Society for Alternatives to Animal Experiments). Sodium lauryl sulfate, calcium thioglycolate, and Tween 80 were evaluated, in triplicate, using 5%, 0.5%, and 0.05% concentrations in physiological saline, to confirm transferability. Good transferability was noted when similar mean relative viabilities and rank classifications were obtained in all five laboratories and were comparable to data from test method developing laboratory. Good intra- and inter-laboratory reproducibility was obtained with four assay controls (three solvents and one positive control), and four assay controls and 25 chemicals, respectively. STE irritation category based on relative viability of a 5% solution of 25 blinded test chemicals showed good correlation with Globally Harmonized System (GHS) categories (NI; I: Cat. 1 and 2). The STE prediction model, using relative viability of the 5% and 0.05% solutions, provided an irritation rank (1, 2, or 3) that had a good correlation (above 80%), or predictive capacity, with GHS irritation ranks in all laboratories. Based on these findings, the STE test is a promising alternative eye irritation test that could be easily standardized. PMID- 21291996 TI - Evidence for cellular injury in the midbrain of rats following chronic constriction injury of the sciatic nerve. AB - Complex behavioural disabilities, as well as pain, characterise neuropathic pain conditions for which clinical treatment is sought. In rats, chronic constriction injury (CCI) of the sciatic nerve evokes, allodynia and hyperalgesia as well as three distinct patterns of disability, characterised by changes in social and sleep-wake behaviours: (i) Pain & Disability; (ii) Pain & Transient Disability and (iii) Pain alone. Importantly, the degree of allodynia and hyperalgesia is identical for each of these groups. Social-interactions and sleep-wake behaviours are regulated by neural networks, which converge on the periaqueductal grey (PAG). Rats with Pain & Disability show astrocyte activation restricted to the lateral and ventrolateral PAG. Reactive astrocytes are a hallmark of cell death (apoptosis and necrosis). Quantitative real-time RT-PCR for the mRNAs encoding Bax, Bcl-2, heat shock protein 60 (HSP60), mitogen activated kinase kinase (MEK2) and iNOS was performed on the dorsal midbrains of individual, disability characterised rats, extending our earlier Gene-Chip data, showing a select up regulation of Bax and MEK2 mRNA, and a down-regulation of HSP60 mRNA, in Pain & Disability rats. The anatomical location of TUNEL and cleaved-caspase-3 immunoreactive profiles in the midbrain was also identified. Rats with Pain & Disability showed: (i) pro-apoptotic ratios of Bax:Bcl-2 mRNAs; (ii) decreased HSP60 mRNA; (iii) increased iNOS and MEK2 mRNAs; (iv) TUNEL-positive profiles in the lateral and ventrolateral PAG; and (v) caspase-3 immunoreactive neurons in the mesencephalic nucleus of the trigeminal nerve. Cell death in these specific midbrain regions may underlie the disabilities characterising this subgroup of nerve-injured rats. PMID- 21291997 TI - Development of the olfactory system in turbot (Psetta maxima L.). AB - We have examined the histogenesis of the olfactory system during turbot development using histological and immunohistochemical methods. Proliferating cell nuclear antigen (PCNA) immunohistochemistry was used to detect dividing cells, whereas calretinin (CR) immunohistochemistry was used to distinguish some neuronal components of the olfactory system. Around hatching, the olfactory placode of embryos transforms into an olfactory pit, which enlarges progressively during development. In metamorphic turbots, the right olfactory organ moves to the tip of the head. Each olfactory chamber opens to the external medium by two nostrils and accessory nasal sacs develop during metamorphosis. The order of birth of olfactory receptor cells in the sensory epithelium follows the pattern of most teleosts: ciliated cells differentiate prior to microvillous cells in turbot larvae, and crypt cells are generated during metamorphosis. Axons of olfactory sensory neurons reach the rostral forebrain by hatching, and calretinin immunoreactive (CR-ir) glomerular fields were apparent during the subsequent larval development. During metamorphosis olfactory bulbs become strongly distorted by head torsion and glomeruli acquire asymmetric organization. The spatio-temporal course of proliferation in the olfactory system reveals changes in the distribution of dividing cells in the sensory epithelium throughout the developmental period investigated. In the olfactory bulb, proliferative activity becomes restricted to the ventral periventricular zone in turbot larvae, as well as in metamorphic specimens. PMID- 21291998 TI - Potent and selective inhibition of angiotensin AT1 receptor signaling by RGS2: roles of its N-terminal domain. AB - Emerging evidence indicates that R4/B subfamily RGS (regulator of G protein signaling) proteins play roles in functional regulation in the cardiovascular system. In this study, we compared effects of three R4/B subfamily proteins, RGS2, RGS4 and RGS5 on angiotensin AT1 receptor signaling, and investigated roles of the N-terminus of RGS2. In HEK293T cells expressing AT1 receptor stably, intracellular Ca(2+) responses induced by angiotensin II were much more strongly attenuated by RGS2 than by RGS4 and RGS5. N-terminally deleted RGS2 proteins lost this potent inhibitory effect. Replacement of the N-terminal residues 1-71 of RGS2 with the corresponding residues (1-51) of RGS5 decreased significantly the inhibitory effect. On the other hand, replacement of the residues 1-51 of RGS5 with the residues 1-71 of RGS2 increased the inhibitory effect dramatically. Furthermore, we investigated functional contribution of N-terminal subdomains of RGS2, namely, an N-terminal region (residues 16-55) with an amphipathic alpha helix domain (the subdomain N1), a probable non-specific membrane-targeting subdomain, and another region (residues 56-71) between the alpha helix and the RGS box (the subdomain N2), a probable GPCR-recognizing subdomain. RGS2 chimera proteins with the residues 1-33 or 34-52 of RGS5 showed weak inhibitory activity, and either of RGS5 chimera proteins with residues 1-55 or 56-71 of RGS2 showed strong inhibitory effects on AT1 receptor signaling. The present study indicates the essential roles of both N-terminal subdomains for the potent inhibitory activity of RGS2 on AT1 receptor signaling. PMID- 21291999 TI - Atomistic simulation study of surfactant and polymer interactions on the surface of a fenofibrate crystal. AB - It is currently of great interest to the pharmaceutical industry to control the size and agglomeration of nano- and micro-particles for the enhancement of drug delivery. Typically, surfactants and polymers are used as additives to interact with and stabilize the growing crystal surface, thus controlling size and agglomeration; however, selection is traditionally done empirically or using heuristics. The objective of this study was to use molecular dynamic simulations to investigate and predict additive interactions, and thus, evaluate the stabilization potential of individual and multiple additives on the surface of the model drug fenofibrate. Non-ionic surfactant Tween 80, anionic surfactant sodium dodecyl sulfate (SDS), and polymers hydroxypropyl methylcellulose (HPMC) and Pullulan were evaluated individually on three distinct crystal surfaces [(001), (010), (100)], as well as in surfactant-polymer combinations. HPMC was determined to have the strongest interaction with the surfaces of the fenofibrate crystal, and therefore, was predicted to be the most effective individual additive. A mixture of HPMC with SDS was determined to be the most effective mixture of additives, and more effective than HPMC alone, indicating a synergistic effect. The predictions of mixed additives indicated a relative order of effectiveness as follows: HPMC-SDS>HPMC-Tween 80>Pullulan-Tween 80>Pullulan SDS. The simulations were subsequently validated by an anti-solvent crystallization of fenofibrate where it was found that HPMC individually, and a mixture of HPMC-SDS, produced the smallest and most stable crystals, as measured by laser diffraction; this, in combination with measurements of the crystal growth rate in the presence and absence of additives confirmed the results of the simulations. PMID- 21292000 TI - Brain specific delivery of pegylated indinavir submicron lipid emulsions. AB - The aim of this study was to develop stable parenteral pegylated indinavir submicron lipid emulsions (SLEs) for improving brain specific delivery. The O/W SLEs were prepared by homogenization and ultra sonication process. The sizes of oil globules varied from 241.5 to 296.4nm and zeta potential from -26.6 to 42.4mV. During in vitro drug release studies the cumulative amount of drug released within 12h from SLE-5, DSP2-3 and DPP5-3 was 71.8+/-0.76, 66.09+/-1.45 and 68.33+/-1.29, respectively. The total drug content and entrapment efficiencies were determined. The optimized formulations were stable for the effect of centrifugal stress, thermal stress, dilution stress and storage. In vivo pharmacokinetic and tissue distribution studies were performed in Swiss albino mice, the therapeutic availability (TA) of DSP2-3 was 3.59 times and 2.36 times in comparison to drug solution and SLE-5 respectively, where as DPP5-3 showed TA 2.8 and 1.84 times the drug solution and SLE-5, respectively. The brain to serum ratio of indinavir from DSP2-3 and DPP5-3 varied between 0.4 and 0.7 at all time points indicated the preferential accumulation of drug in brain. In conclusion, pegylated SLEs improved brain specific delivery of indinavir and will be useful in treating chronic HIV infection. PMID- 21292001 TI - Reduced chondrogenic matrix accumulation by 4-methylumbelliferone reveals the potential for selective targeting of UDP-glucose dehydrogenase. AB - 4-Methylumbelliferone (4-MU) is described as a selective inhibitor of hyaluronan (HA) production. It is thought that 4-MU depletes UDP-glucuronic acid (UDP-GlcUA) substrate for HA synthesis and also suppresses HA-synthase expression. The possibility that 4-MU exerts at least some of its actions via regulation of UDP glucose dehydrogenase (UGDH), a key enzyme required for both HA and sulphated glycosaminoglycan (sGAG) production, remains unexplored. We therefore examined the effects of 4-MU on basal and retroviral UGDH-driven HA and sGAG release in cells derived from chick articular cartilage and its influence upon UGDH protein and mRNA expression and HA and sGAG production. We found that 4-MU: i) suppressed UGDH mRNA and protein expression and chondrogenic matrix accumulation in chick limb bud micromass culture, ii) significantly reduced both HA and sGAG production and iii) more selectively reversed the potentiating effects of UGDH overexpression on the production of HA than sGAG. Understanding how GAG synthesis is controlled and the mechanism of 4-MU action may inform its future clinical success. PMID- 21292002 TI - Differential in vivo zymography: a method for observing matrix metalloproteinase activity in the zebrafish embryo. AB - Investigations into the molecular mechanisms of, and cellular signaling pathways modulating ECM remodeling are especially challenging due to the complex post translational regulation of the primary effectors of ECM catabolism - the matrix metalloproteinases (MMPs). Recently a variety of approaches to the detection of MMP activity have been developed, and the prospect of visualizing ECM remodeling activity in living tissues is now opening exciting avenues of research for matrix biologists. In particular the use of FRET-quenched MMP substrates, which generate a fluorescent signal upon hydrolysis, is becoming increasingly popular, especially because linkers with defined and/or restricted proteolytic sensitivity can be used to bind fluorophore-quencher pairs, making these probes useful in characterizing the activity of specific proteases. We have taken advantage of the transparency and amenability to reverse genetics of the zebrafish embryo, in combination with these fluorogenic MMP substrates, to develop a multiplex in vivo assay for MMP activity that we dub "differential in vivo zymography." PMID- 21292003 TI - Endothelin-1 and diabetic complications: focus on the vasculature. AB - Diabetes is not only an endocrine but also a vascular disease. Cardiovascular complications are the leading cause of morbidity and mortality associated with diabetes. Diabetes affects both large and small vessels and hence diabetic complications are broadly classified as microvascular (retinopathy, nephropathy and neuropathy) and macrovascular (heart disease, stroke and peripheral arterial disease) complications. Endothelial dysfunction, defined as an imbalance of endothelium-derived vasoconstrictor and vasodilator substances, is a common denominator in the pathogenesis and progression of both macro and microvascular complications. While the pathophysiology of diabetic complications is complex, endothelin-1 (ET-1), a potent vasoconstrictor with proliferative, profibrotic, and proinflammatory properties, may contribute to many facets of diabetic vascular disease. This review will focus on the effects of ET-1 on function and structure of microvessels (retina, skin and mesenteric arteries) and macrovessels (coronary and cerebral arteries) and also discuss the relative role(s) of endothelin A (ET(A)) and ET(B) receptors in mediating ET-1 actions. PMID- 21292004 TI - NCOA6 differentially regulates the expression of the CYP2C9 and CYP3A4 genes. AB - CYP2Cs and CYP3A4 sub families of enzymes of the Cytochrome P450 super family metabolize clinically prescribed therapeutics. Constitutive and induced expressions of these enzymes are under the control of HNF4alpha and rifampicin activated PXR. In the present study, we show a mechanism for ligand dependent synergistic cross talk between PXR and HNF4alpha. Two-hybrid screening identified NCOA6 as a HNF4alpha interacting protein. NCOA6 was also found to interact with PXR through the first LXXLL motif in GST pull down and mammalian two hybrid assays. NCOA6 enhances the synergistic activation of CYP2C9 and CYP3A4 promoter activity by PXR and HNF4alpha in the presence of rifampicin. However silencing NCOA6 abrogated the synergistic activation and induction of CYP2C9 by PXR HNF4alpha but not of CYP3A4. ChIP analysis revealed that NCOA6 could bridge HNF4alpha and PXR binding sites of the CYP2C9 promoter. Our results indicate that NCOA6 is responsible for the synergistic activation of CYP2C9 by HNF4alpha and PXR and NCOA6 differentially regulates CYP2C9 and CYP3A4 gene expression though both the genes are regulated by the same nuclear receptors. PMID- 21292005 TI - HIV fragment gag vaccine induces broader T cell response in mice. AB - Broad T-cell response is considered critical for HIV-1 vaccines to compensate viral diversity. Usually, a limited number of immunodominant epitopes are recognized in natural infections, as well as in vaccinations. Here, we seek to overcome immunofocusing of CD8 T Cell responses to HIV-1 CN54 gag DNA (delivered as a plasmid) in BalB/C mice by splitting it into fragments for reducing competition of recognition between dominant and sub-dominant epitopes. As expected, mice immunized with mixture of DNA fragments elicited significantly broader T cell responses than whole-length gag. We also further studied the effects when fragments and full-length DNA vaccines are combined for prime-boost vaccination. Interestingly, mice primed with full-length gag and boosted with DNA vaccine fragments induced similar T-cell response breadth as mice both primed and boosted by fragments DNA. In contrast, mice primed with DNA vaccine fragments and boosted with full-length gag failed to broaden T cell responses, once again, only the dominant epitopes were recognized. In summary, our study demonstrated that "fragmentation strategy" can indeed broaden T cell responses. This enhancement is more likely achieved in boosting stage. This study offers a promising way to design a vaccine with higher chance covering the highly diversified circulating strains. PMID- 21292006 TI - Detection of naturally occurring antibodies against Protein D of Haemophilus influenzae. PMID- 21292007 TI - Further evidence of antigenic drift and protective efficacy afforded by a recombinant HVT-H5 vaccine against challenge with two antigenically divergent Egyptian clade 2.2.1 HPAI H5N1 strains. AB - In this study, we have compared the protection afforded by a recombinant turkey herpesvirus vaccine expressing the H5 gene from a clade 2.2 H5N1 strain (rHVT-H5) and a Mexican-origin H5N2 inactivated vaccine, alone or in combination, against two antigenically divergent H5N1 Egyptian strains isolated in 2007 and 2008. Our results confirm the existence of a major antigenic drift among the Egyptian H5N1 strains such that, although protection against the "classical" 2007 HPAI H5N1 Egyptian strain could be obtained with both types of vaccines, only vaccination with the rHVT-H5 vaccine protected against challenge with the "variant" 2008 HPAI H5N1 Egyptian strain. PMID- 21292008 TI - No effect of 2008/09 seasonal influenza vaccination on the risk of pandemic H1N1 2009 influenza infection in England. AB - This study reports effectiveness of trivalent influenza vaccine (TIV) against confirmed pandemic influenza infection in England using a retrospective test negative case-control study. Cases and controls were frequency matched by age, swabbing-week and region. On univariable and multivariable analysis adjusted for underlying clinical risk factors, cases were no more or less likely than controls to be vaccinated with 2008-09 or 2007-08 season TIV. Adjusted vaccine effectiveness for the former was -6% (-43% to 22%). Vaccine effectiveness did not differ significantly by age-group or hospitalisation status. There was no evidence prior vaccination with TIV significantly altered subsequent risk of pandemic influenza H1N1 2009 infection. PMID- 21292009 TI - Indoleamine 2,3-dioxygenase is increased in hemodialysis patients and affects immune response to hepatitis B vaccination. AB - BACKGROUND: Acquired immunity is impaired in hemodialysis (HD) patients. Indoleamine 2,3-dioxygenase (IDO) is inducible by inflammation and through tryptophan depletion and generation of kynurenine pathway products suppresses adaptive immune response. In the present study plasma IDO levels were assessed in HD patients. Its effect on response to HBV vaccination program was evaluated. PATIENTS AND METHODS: Sixty-six HD patients and twenty-four healthy volunteers enrolled into the study. All the HD patients were initially vaccinated with four double doses of recombinant HBV vaccine. All doses were repeated in patients who had not responded after complete first vaccination series. Only one boost dose was being administered in patients with initial adequate antibody levels against the HBV surface antigen (anti-HBs>10I U/L) who then presented with reduced anti HBs levels. IDO, CRP, IL-6 and TNF-alpha were measured by means of ELISA. RESULTS: Compared to healthy volunteers, IDO levels were twice higher in HD patients. CRP, IL-6 and TNF-alpha were also much higher in HD patients. IDO levels were almost twice higher in HD patients with inadequate response to HBV vaccination, than in those with adequate immune response. CRP, IL-6 and TNF-alpha did not differ between the two patients' groups. IDO was negatively correlated with all markers of inflammation in HD patients. CONCLUSION: IDO is increased in HD patients. It is possible that after its initial upregulation due to chronic inflammation, IDO curtails its own provoking agent, i.e., inflammation. Increased IDO suppresses adaptive immunity in HD patients, as it is assessed by the response to HBV vaccination. PMID- 21292010 TI - Pertussis after end of a mass vaccination project--end of the "vaccination honey moon". AB - After 16 years of no vaccination against pertussis in Sweden, mass vaccination of infants and catch-up vaccination of children up to 10 years with a monocomponent pertussis toxoid vaccine was performed in the Greater Gothenburg area of Sweden between 1995 and 1999. At the end of the project in February 1999, 56% of all 10 year old children born in the Greater Gothenburg area had received 3 doses of the pertussis toxoid. No booster doses were given. This led to a temporary almost complete elimination of the disease. The aim of the present study was to follow the incidence of pertussis after end of the mass vaccination project (1999-2009) as it is reflected by laboratory verified cases (cultures and/or PCR) and pertussis hospitalizations. A reemergence of pertussis was seen from the end of 1999 with a peak in 2004 followed by a decrease when booster doses to both 6 and 10 year old children were introduced in 2005-2006. From July 1, 1999 through December 31, 2009 a total of 1973 cases were diagnosed with culture or PCR. The disease was prevalent in all age groups. The highest documented incidence was seen in infants younger than 12 months. 450 patients with verified pertussis had received 3 doses of the pertussis toxoid vaccine in the mass vaccination project and some other trials (comprising a total of 69,423 children). The mean time from the last dose to the laboratory verification of pertussis was 5 years in these 450 cases. There were 128 hospitalizations, 106 of which were in infants. In conclusion, pertussis is still not eliminated from the area. Booster doses are needed but the numbers and optimal timing are not known. PMID- 21292011 TI - NG2 cells are uniformly distributed and NG2 is not required for barrel formation in the somatosensory cortex. AB - The somatosensory barrel cortex in the rodent forms during the first postnatal week setting up a periphery related map with each whisker represented as a bundle of thalamocortical axons (TCAs) in layer IV. The centers of each barrel (hollows) contain the densely packed TCAs, while the areas between each barrel (septa) form a boundary between each barrel. NG2 chondroitin sulfate proteoglycan (CSPG) expressing cells (NG2 cells, polydendrocytes) make up a unique population of glial cells that receive synaptic like input and form close contacts with growing axons. In the present study we investigated the developmental distribution of NG2 cells in the barrel cortex to determine if they display preferential septa distribution similar to other extracellular and cell surface CSPGs. Immunohistochemistry for NG2 and platelet-derived growth factor receptor alpha (PDGFRalpha) in NG2DsRedBAC transgenic mice showed uniform distribution of NG2 cells and processes in barrel hollows and septa at postnatal (P) days 5, 6, 7, 8, 14, and 30. Changes in the barrel pattern formation caused by cauterization of one row of whiskers at P1 resulted in corresponding changes in extracellular and cell surface CSPG distribution at P7 but no detectable changes in NG2 cell bodies and processes. Furthermore, no abnormalities in barrel formation or reorganization were detected in NG2 knockout mice. These observations suggest that NG2 cells are unlikely to play an inhibitory boundary role on TCA growth and that NG2 expression is not necessary for normal barrel formation. PMID- 21292012 TI - High level soluble production of functional ribonuclease inhibitor in Escherichia coli by fusing it to soluble partners. AB - Ribonuclease inhibitor (RI) is a 50-kDa cytosolic scavenger of pancreatic-type ribonucleases which inhibits ribonucleolytic activity. Expression of recombinant RI is extremely difficult to reach high levels in soluble form in the cytoplasm of Escherichia coli. Here, we utilized five N-terminal fusion partners to improve the soluble expression of RI. Among these five fusion partners which have been screened, maltose-binding protein (MBP), N-utilization substance A (NusA) and translation initiation factor 2 domain I (IF2) have greatly improved the soluble expression level of recombinant murine RI under the drive of T7 promoter, while glutathione S-transferase (GST) and small ubiquitin modifying protein (SUMO) were much less efficient. All these RI-fusion proteins remained to be highly active in inhibiting RNase A activity. Furthermore, all fusion tags can be efficiently removed by enterokinase digestion to generate native RI which results the highest yield to date (>30mg of native RI per liter culture). And a convenient two-step immobilized metal affinity chromatography (IMAC) method has been implemented in our study, comparing with the traditional RNase A affinity chromatography method. PMID- 21292014 TI - Plant molecular phylogeography in China and adjacent regions: Tracing the genetic imprints of Quaternary climate and environmental change in the world's most diverse temperate flora. AB - The Sino-Japanese Floristic Region (SJFR) of East Asia harbors the most diverse of the world's temperate flora, and was the most important glacial refuge for its Tertiary representatives ('relics') throughout Quaternary ice-age cycles. A steadily increasing number of phylogeographic studies in the SJFR of mainland China and adjacent areas, including the Qinghai-Tibetan-Plateau (QTP) and Sino Himalayan region, have documented the population histories of temperate plant species in these regions. Here we review this current literature that challenges the oft-stated view of the SJFR as a glacial sanctuary for temperate plants, instead revealing profound effects of Quaternary changes in climate, topography, and/or sea level on the current genetic structure of such organisms. There are three recurrent phylogeographic scenarios identified by different case studies that broadly agree with longstanding biogeographic or palaeo-ecological hypotheses: (i) postglacial re-colonization of the QTP from (south-)eastern glacial refugia; (ii) population isolation and endemic species formation in Southwest China due to tectonic shifts and river course dynamics; and (iii) long term isolation and species survival in multiple localized refugia of (warm )temperate deciduous forest habitats in subtropical (Central/East/South) China. However, in four additional instances, phylogeographic findings seem to conflict with a priori predictions raised by palaeo-data, suggesting instead: (iv) glacial in situ survival of some hardy alpine herbs and forest trees on the QTP platform itself; (v) long-term refugial isolation of (warm-)temperate evergreen taxa in subtropical China; (vi) 'cryptic' glacial survival of (cool-)temperate deciduous forest trees in North China; and (vii) unexpectedly deep (Late Tertiary/early-to mid Pleistocene) allopatric-vicariant differentiation of disjunct lineages in the East China-Japan-Korea region due to past sea transgressions. We discuss these and other consequences of the main phylogeographic findings in light of palaeo environmental evidence, emphasize notable gaps in our knowledge, and outline future research prospects for disentangling the evolution and biogeographic history of the region's extremely diverse temperate flora. PMID- 21292013 TI - A nonparametric Riemannian framework for processing high angular resolution diffusion images and its applications to ODF-based morphometry. AB - High angular resolution diffusion imaging (HARDI) has become an important technique for imaging complex oriented structures in the brain and other anatomical tissues. This has motivated the recent development of several methods for computing the orientation probability density function (PDF) at each voxel. However, much less work has been done on developing techniques for filtering, interpolation, averaging and principal geodesic analysis of orientation PDF fields. In this paper, we present a Riemannian framework for performing such operations. The proposed framework does not require that the orientation PDFs be represented by any fixed parameterization, such as a mixture of von Mises-Fisher distributions or a spherical harmonic expansion. Instead, we use a nonparametric representation of the orientation PDF. We exploit the fact that under the square root re-parameterization, the space of orientation PDFs forms a Riemannian manifold: the positive orthant of the unit Hilbert sphere. We show that various orientation PDF processing operations, such as filtering, interpolation, averaging and principal geodesic analysis, may be posed as optimization problems on the Hilbert sphere, and can be solved using Riemannian gradient descent. We illustrate these concepts with numerous experiments on synthetic, phantom and real datasets. We show their application to studying left/right brain asymmetries. PMID- 21292015 TI - Molecular phylogenetic relationships and the coevolution of placentotrophy and superfetation in Poecilia (Poeciliidae: Cyprinodontiformes). AB - Members of Poeciliidae are used as model organisms for experimental studies on natural and sexual selection, and comparative studies of life-history evolution. The latter have demonstrated multiple origins of both superfetation and placentotrophy within Poeciliidae. Most recently, placentotrophy has been described in five species of Poecilia (Pamphorichthys), but only one of these (P.hasemani) shows evidence of superfetation. Here, we use a molecular phylogeny based on concatenated nuclear and mitochondrial gene sequences to test hypotheses of correlated evolution between superfetation and placentotrophy in Poecilia. Taxon sampling included all species in the subgenera Micropoecilia and Pamphorichthys for which the presence or absence of placentotrophy and superfetation have been determined, as well as representatives of all other Poecilia subgenera (Acanthophacelus, Limia, Mollienesia, Poecilia, Pseudolimia). Phylogenetic analyses were performed with maximum parsimony, maximum likelihood, and Bayesian methods; ancestral states for life-history characters were reconstructed with parsimony and SIMMAP; correlation analyses were performed with SIMMAP; and divergence times were estimated using a relaxed molecular clock. All subgenera in Poecilia were recovered as monophyletic. The basal split in Poecilia is between P. (Acanthophacelus)+P. (Micropoecilia) and the other five subgenera. In the latter clade, P. (Poecilia) is the sister-group to the remaining four subgenera. Within P. (Pamphorichthys), all analyses with the combined data set recovered P. (Pamphorichthys) araguaiensis as the sister taxon to P. (Pamphorichthys) hollandi, and P. (Pamphorichthys) scalpridens as the sister taxon to P. (Pamphorichthys) minor. P. (Pamphorichthys) hasemani was either the sister taxon to P. (Pamphorichthys) hollandi+P. (Pamphorichthys) minor (maximum likelihood, Bayesian) or the sister taxon to all other Pamphorichthys species (maximum parsimony). Ancestral state reconstructions suggest that placentotrophy and superfetation evolved on the same branch in P. (Micropoecilia), whereas placentotrophy evolved before superfetation in P. (Pamphorichthys). SIMMAP analyses indicate a statistically significant association between placentotrophy and superfetation. Within P. (Micropoecilia) both placentotrophy and superfetation evolved in <=4 million years. Within P. (Pamphorichthys), superfetation evolved in <=9 million years on the P. (Pamphorichthys) hasemani branch, and placentotrophy evolved in <=10 million years in the common ancestor of this subgenus. PMID- 21292016 TI - Hybrid genera in Liatrinae (Asteraceae: Eupatorieae). AB - Liatrinae is a small subtribe of Eupatorieae that occurs in North America with a center of generic-level diversity in the southeastern United States. Molecular phylogenetic data were sought to assess whether two monotypic genera, Garberia and Hartwrightia, are accurately placed in the subtribe, and to resolve questions of the generic-level classification of Carphephorus. Phylogenetic analyses of nuclear ITS/ETS and plastid DNA data indicated that Garberia is the basalmost diverging lineage, and that Hartwrightia is phylogenetically embedded in the subtribe. There was significant incongruence between the ITS/ETS and plastid DNA datasets in the placement of Hartwrightia and another monotypic genus, Litrisa, suggesting that both are of original hybrid origin. The results also showed that Carphephorus s.l. is not monophyletic, and even after removal of the two species of Trilisa, it is still paraphyletic to Liatris. The apparent hybrid origin of Hartwrightia, which is morphologically transgressive relative to its inferred parental lineages, suggests that reticulation between phylogenetically distinct lineages may be a recurrent problem for phylogenetic estimation in Asteraceae. PMID- 21292017 TI - An agarose spot chemotaxis assay for chemokine receptor antagonists. AB - INTRODUCTION: Chemokines are important players in directing the migration of cancer cells as part of the metastatic process. The aim of this study is to develop an easy-to-perform, reliable, and inexpensive assay for rapid analysis of anti-chemotactic activity of chemokine antagonists under a number of experimental conditions. METHODS: An agarose spot containing the chemokine chemoattractant is applied to a glass petri dish. Live cells in a media, both with and without a chemokine antagonist, are added to the dish and, following cell adhesion, the migration under the agarose spot is observed and analysed by microscopy. RESULTS: In the absence of CXCL12 in the agarose, no migration under the agarose spot is detected. In the presence of CXCL12, significant migration under the agarose spot is observed which can be retarded if a neutralising monoclonal antibody or a small molecule antagonist is added to the media. DISCUSSION: This experimental configuration is a reliable, inexpensive and easy-to-perform chemotaxis assay, which enables assessment of the activity of CXCR4 antagonists. PMID- 21292018 TI - Betulinic acid protects against cerebral ischemia-reperfusion injury in mice by reducing oxidative and nitrosative stress. AB - Increased production of reactive oxygen and nitrogen species following cerebral ischemia-reperfusion is a major cause for neuronal injury. In hypercholesterolemic apolipoprotein E knockout (ApoE-KO) mice, 2h of middle cerebral artery (MCA) occlusion followed by 22h of reperfusion led to an enhanced expression of NADPH oxidase subunits (NOX2, NOX4 and p22phox) and isoforms of nitric oxide synthase (neuronal nNOS and inducible iNOS) in the ischemic hemisphere compared with the non-ischemic contralateral hemisphere. This was associated with elevated levels of 3-nitrotyrosine, an indicator of peroxynitrite mediated oxidative protein modification. Pre-treatment with betulinic acid (50mg/kg/day for 7days via gavage) prior MCA occlusion prevented the ischemia reperfusion-induced upregulation of NOX2, nNOS and iNOS. In parallel, betulinic acid reduced the levels of 3-nitrotyrosine. In addition, treatment with betulinic acid enhanced the expression of endothelial eNOS in the non-ischemic hemispheres. Finally, betulinic acid reduced infarct volume and ameliorated the neurological deficit in this mouse stroke model. In conclusion, betulinic acid protects against cerebral ischemia-reperfusion injury in mice. This is likely to result from a reduction of oxidative stress (by downregulation of NOX2) and nitrosative stress (by reduction of nNOS and iNOS), and an enhancement of blood flow (by upregulation of eNOS). PMID- 21292019 TI - Chronic 'cough hypersensitivity syndrome': a more precise label for chronic cough. AB - Chronic cough remains a challenge to many clinicians because there is often no diagnostic link to causation, and because indirect antitussives are largely ineffective. Chronic cough can also be a predominant symptom associated with many chronic respiratory diseases such as COPD, asthma and pulmonary fibrosis. Chronic cough itself does impair the quality of life and is associated with psychological impairment. The symptoms associated with chronic cough include persistent tickling or irritating sensation in the chest or throat, hoarse voice, dysphonia or vocal cord dysfunction. Currently, the clinical diagnosis of cough is associated with chronic cough caused by airway eosinophilic conditions such as asthma, gastrooesophageal reflux disease or post-nasal drip (or upper airway syndrome), which implies cause and effect, or with chronic cough associated with other diseases such as COPD, cancer or heart failure, that does not necessarily imply cause and effect. A recently-recognised category is idiopathic cough, with no associated or causative diagnosis. We suggest that there is a better label needed for chronic cough, that includes the common association with a hypersensitive cough response to tussive stimuli such as capsaicin or citric acid. This would invoke a hypersensitive syndrome, and there are good reasons to use a new label that would encompass the problem of chronic cough: the chronic 'cough hypersensitivity syndrome'. This would focus the problem on the cough symptomatology and lead to greater focus on understanding the mechanisms of cough sensitisation, with the ultimate aim of obtaining more effective antitussives. PMID- 21292020 TI - Structural changes in the airways: cause or effect of chronic cough? AB - Patients with a chronic cough have asthma or "asthma-related" diagnoses such as cough variant asthma or non-asthmatic eosinophilic bronchitis usually responsive to inhaled corticosteroid therapy, or non-asthma-related diagnoses including "idiopathic" or "unexplained" cases. Both of these conditions involve airway inflammation. More recently, structural changes or remodeling of the lower airways, which have been considered characteristic of classic asthma with wheezing, have also been demonstrated in patients with chronic cough, irrespective of its cause. In this article, the presence, pathogenesis, and possible consequences of such structural changes in patients with chronic cough are reviewed. Although whether chronic cough leads to structural changes or structural changes is a cause of chronic cough is difficult to determine, the concomitance of both mechanisms may lead to a positive feedback mechanism or a vicious cycle of cough persistence. PMID- 21292021 TI - Probabilistic pathway construction. AB - Expression of novel synthesis pathways in host organisms amenable to genetic manipulations has emerged as an attractive metabolic engineering strategy to overproduce natural products, biofuels, biopolymers and other commercially useful metabolites. We present a pathway construction algorithm for identifying viable synthesis pathways compatible with balanced cell growth. Rather than exhaustive exploration, we investigate probabilistic selection of reactions to construct the pathways. Three different selection schemes are investigated for the selection of reactions: high metabolite connectivity, low connectivity and uniformly random. For all case studies, which involved a diverse set of target metabolites, the uniformly random selection scheme resulted in the highest average maximum yield. When compared to an exhaustive search enumerating all possible reaction routes, our probabilistic algorithm returned nearly identical distributions of yields, while requiring far less computing time (minutes vs. years). The pathways identified by our algorithm have previously been confirmed in the literature as viable, high-yield synthesis routes. Prospectively, our algorithm could facilitate the design of novel, non-native synthesis routes by efficiently exploring the diversity of biochemical transformations in nature. PMID- 21292022 TI - Hybrid antibiotics with the nikkomycin nucleoside and polyoxin peptidyl moieties. AB - Acting as competitive inhibitors of chitin synthase, nikkomycins and polyoxins are potent antibiotics against pathogenic fungi. Taking advantage of the structural similarities between these two peptidyl nucleoside antibiotics, genes required for the biosynthesis of the dipeptidyl moiety of polyoxin from Streptomyces cacaoi were introduced into a Streptomyces ansochromogenes mutant producing the nucleoside moiety of nikkomycin X. Two hybrid antibiotics were generated. One of them was identified as polyoxin N, and the other, a novel compound, was named polynik A. The hybrid antibiotics exhibited merits from both parents: they had better inhibitory activity against phytopathogenic fungi than polyoxin B, and were more stable under different pH and temperature conditions than nikkomycin X. This study demonstrates the use of the combinatorial biosynthetic approach to produce valuable and novel hybrid antibiotics with improved properties. PMID- 21292023 TI - The beta-catenin/Tcf4/survivin signaling maintains a less differentiated phenotype and high proliferative capacity of human corneal epithelial progenitor cells. AB - It is clear that the microenvironment or niche plays an important role in determining the fate of stem cells: being stem cells or differentiated. However, the intrinsic pathways controlling the fate of adult stem cells in different niches are largely unknown. This study was to explore the role of beta catenin/Tcf4/survivin signaling in determining the fate of human corneal epithelial stem cells in different media. We observed that the low calcium serum free media, especially CnT-20, promoted proliferative capacity, colony forming efficiency and stem cell-like phenotype of human corneal epithelial cells (HCECs) when compared with the cells cultured in a high calcium serum-containing medium SHEM. Three key factors in Wnt signaling, beta-catenin, Tcf4 and survivin, were found to be expressed higher by HCECs grown in CnT-20 than those cultured in SHEM, as evaluated by real-time PCR, Western blotting and immunostaining. Transfection of siRNA-Tcf4 at 10-50nM knocked down Tcf4, and also significantly suppressed its down stream molecule survivin at both mRNA and protein levels in HCECs. Furthermore, Tcf4 silencing significantly suppressed the proliferative capacity of HCECs, measured by WST-1 assay, compared with the control groups, untreated or transfected with non-coding sequence siRNA-fluorescein. These findings demonstrate that low calcium serum free media promote ex vivo expansion of corneal epithelial progenitor cells that retain a less differentiated phenotype and high proliferative capacity via beta-catenin/Tcf4/survivin signaling, a novel intrinsic pathway. This study may have high impact and clinic implication on the expansion of corneal epithelial stem cells in regenerative medicine, especially for ocular surface reconstruction. PMID- 21292024 TI - Scavenger receptors: Implications in atherothrombotic disorders. AB - Scavenger receptors are modified lipoprotein binding receptors, expressed on the surface of a variety of cells including endothelial, macrophages and platelets. The most extensively studied class B scavenger receptors comprise of CD36 and SR BI and have been found to bind to native and modified LDL. Interaction of modified LDL to CD36 accelerates foam cell formation, the key step in atherosclerotic plaque deposition. Recently scavenger receptors have also been implicated in thrombosis. Platelet CD36 serves as a sensor of oxidative stress and modulator of platelet reactivity under hyperlipidemic conditions thus, inducing prothrombotic signals. In contrast, targeting platelet SR-BI corresponds to reduce platelet hyperreactivity in hyperlipidemia suggesting that targeting these receptors could be a promising strategy for the treatment of atherothrombotic disorders. PMID- 21292025 TI - Trichinellosis, another helminthiasis affecting the central nervous system. PMID- 21292026 TI - Toxoplasma gondii infection and schizophrenia: a case control study in a low Toxoplasma seroprevalence Mexican population. AB - There are conflicting reports concerning the association of Toxoplasma gondii infection and schizophrenia in humans. Therefore, we determined such association in a Mexican population of Mestizo ethnicity. Through a case-control study design, 50 schizophrenic patients and 150 control subjects matched by gender, age, residence place, and ethnicity were examined with enzyme-linked immunoassays for the presence and levels of T. gondii IgG antibodies and for the presence of T. gondii IgM antibodies. Schizophrenic patients attended a public psychiatric hospital in Durango City, Mexico, and the control group consisted of individuals of the general population of the same city. Socio-demographic, clinical and behavioral characteristics from the study subjects were also obtained. Both the seroprevalence and the level of T.gondii IgG antibodies were higher in schizophrenic patients (10/50; 20%) than in control subjects (8/150; 5.3%) (OR=4.44; 95% CI: 1.49-13.37; P=0.003). The IgG T. gondii levels higher than 150 IU/ml were more frequently observed in patients than in controls (10% versus 2%, respectively; P=0.02). One (50%) of the two patients with recently diagnosed schizophrenia and none of the controls had T. gondii IgM antibodies (P=0.01). T. gondii seropositivity was significantly higher in patients with a history of cleaning cat excrement (P=0.005), and suffering from simple schizophrenia (ICD-10 classification: F20.6) (P=0.03) than patients without these characteristics. Toxoplasma seroprevalence was also significantly higher in patients with simple schizophrenia (F20.6) than in those with paranoid schizophrenia (F20.0) (P=0.02). This study provides elements to clarify the controversial information on the association of T. gondii infection and schizophrenia. PMID- 21292027 TI - The role of phosphatidylethanolamine methyltransferase in a mouse model of intrahepatic cholestasis. AB - Intrahepatic cholestasis eventually leads to liver failure. We report here a condition that decreases liver damage in intrahepatic cholestasis based on a mouse model that lacks multiple drug resistant protein 2 (ABCB4). We found that lack of phosphatidylethanolamine N-methyltransferase (PEMT) decreased liver damage in Abcb4(-/-) mice caused by exposure of the liver to excess bile acids. The protective effect was not related to hepatic ratio of phosphatidylcholine to phosphatidylethanolamine or the level of cholesterol. The decreased concentration of bile acids in liver was related to impaired re-absorption of bile acids in intestine and increased disposal of bile acids in feces in Abcb4(-/-)/Pemt(-/-) mice as compared to Abcb4(-/-) mice. PEMT deficiency affected intestinal Na(+) absorption resulting in an impaired Na(+) concentration gradient along the length of the small intestine and abnormal absorption of bile acids mediated by apical sodium-dependent bile acid transporter (ASBT). The findings of this study suggest that inhibition of PEMT and/or reduction of intestinal sodium concentration may be helpful in attenuating liver damage and prolonging hepatic function in intrahepatic cholestasis. PMID- 21292028 TI - Participation of mammary gland in long-chain polyunsaturated fatty acid synthesis during pregnancy and lactation in rats. AB - Metabolic adaptations are triggered in the maternal organism to synthesize milk with an adequate concentration of long-chain polyunsaturated fatty acids (LC PUFAs) required to the newborn. They may be a high uptake of dietary linoleic acid and its conversion to LC-PUFAs by desaturases of fatty acids (FADS) 1 and 2 in the mammary gland (MG). It is unknown if they also occur from onset of pregnancy. The aim of this study was to explore the participation of the MG as a mechanism involved in LC-PUFAs synthesis to support their demand during pregnancy and lactation in rats. The expression of desaturases in MG was significantly (P<0.05) higher (12.3-fold for FADS1 and 41.2-fold for FADS2) during the late pregnancy and throughout lactation (31.7-fold for FADS1 and 67.1-fold higher for FADS2) than in nonpregnant rats. SREBF-1c showed a similar pattern of increase during pregnancy but remained higher only during the early lactation (11.7-fold, P<0.005). Transcript of ELOVL6 and FASN increased throughout pregnancy and lactation, respectively. ELOVL5 mRNA increased in MG only during lactation (2.8 to 5.3-fold, P<0.005). Accordingly, a higher content of LC-PUFAs was found in lactating MG than in nonpregnant rats. Results suggest that MG participates from late pregnancy and throughout lactation by expressing desaturases and elongases as a mechanism involved in LC-PUFAs synthesis, probably by SREBF-1c. Because desaturases and ELOVL5 were expressed in cultured lactocytes and such expression was downregulated by linoleic and arachidonic acid, these cells may be a useful model for understanding the regulatory mechanisms for LC-PUFAs synthesis in MG. PMID- 21292029 TI - Modeling the acceptance of clinical information systems among hospital medical staff: an extended TAM model. AB - Recent empirical research has utilized the Technology Acceptance Model (TAM) to advance the understanding of doctors' and nurses' technology acceptance in the workplace. However, the majority of the reported studies are either qualitative in nature or use small convenience samples of medical staff. Additionally, in very few studies moderators are either used or assessed despite their importance in TAM based research. The present study focuses on the application of TAM in order to explain the intention to use clinical information systems, in a random sample of 604 medical staff (534 physicians) working in 14 hospitals in Greece. We introduce physicians' specialty as a moderator in TAM and test medical staff's information and communication technology (ICT) knowledge and ICT feature demands, as external variables. The results show that TAM predicts a substantial proportion of the intention to use clinical information systems. Findings make a contribution to the literature by replicating, explaining and advancing the TAM, whereas theory is benefited by the addition of external variables and medical specialty as a moderator. Recommendations for further research are discussed. PMID- 21292030 TI - Mining association language patterns using a distributional semantic model for negative life event classification. AB - PURPOSE: Negative life events, such as the death of a family member, an argument with a spouse or the loss of a job, play an important role in triggering depressive episodes. Therefore, it is worthwhile to develop psychiatric services that can automatically identify such events. This study describes the use of association language patterns, i.e., meaningful combinations of words (e.g., ), as features to classify sentences with negative life events into predefined categories (e.g., Family, Love, Work). METHODS: This study proposes a framework that combines a supervised data mining algorithm and an unsupervised distributional semantic model to discover association language patterns. The data mining algorithm, called association rule mining, was used to generate a set of seed patterns by incrementally associating frequently co-occurring words from a small corpus of sentences labeled with negative life events. The distributional semantic model was then used to discover more patterns similar to the seed patterns from a large, unlabeled web corpus. RESULTS: The experimental results showed that association language patterns were significant features for negative life event classification. Additionally, the unsupervised distributional semantic model was not only able to improve the level of performance but also to reduce the reliance of the classification process on the availability of a large, labeled corpus. PMID- 21292031 TI - Epidemiological network analysis in HIV-1 B infected patients diagnosed in Italy between 2000 and 2008. AB - This study, through a phylogenetic analysis, is aimed to identify potential epidemiological networks and sequence interrelationships between acute/early and chronic infections in both drug-naive and drug-experienced individuals within a local, well-defined setting and to investigate the population dynamics of transmitted resistance and the potential contribution of untreated patients to the spread of antiretroviral resistance. A total of 884 HIV-1 B subtype pol gene sequences from 306 drug-naive (40 recently and 266 chronically infected) and 578 drug-treated HIV-1 infected patients were collected through routine drug resistance testing between 2000 and 2008 in a single center (Division of Infectious Disease, Bergamo, Northern Italy). Bayesian phylogenetic tree was reconstructed and transmission clusters were recognized using a posterior probability as statistical support of each cluster. Differences among clustered and non-clustered drug-resistance mutations were assessed by Fisher's exact test. In our cohort we identified five clusters including >=6 sequences with the root posterior probability of 100%. Dated phylogenies reconstructed through Bayesian Markov chain Monte Carlo model was possible for only two main clade (>=10 sequences) originated between 1990 and 2002. Among the 306 drug-naive individuals, 12% carried a viral strain with at least 1 major mutation associated with transmitted drug resistance and 36% of these strains were involved in significant clusters. We report for the first time that many (34%) of HIV-1 subtype B transmission clusters identified in Italy were only composed by drug naive individuals and that the 14% of transmitted drug resistance was linked to transmission clusters composed only of newly diagnosed individuals. The phylogenetic analysis was performed on a large cohort of drug-naive recently/chronically infected individuals where drug-experienced patients represent almost all infected individuals in a restricted geographical area. Our findings highlight the role of newly diagnosed individuals, not yet exposed to antiretroviral drugs, in the transmission of drug-resistant HIV-1 strains, providing new insights for the planning and management of treatment programs in developing countries. PMID- 21292032 TI - Genetic variability of human metapneumovirus amongst an all ages population in Cambodia between 2007 and 2009. AB - First identified in 2001, human metapneumovirus (HMPV) is a novel pathogen and causative agent of acute respiratory tract infection. Re-infection with HMPV is common, and currently there is no available vaccine against HMPV infection. Two genotypes of HMPV have been identified, A and B, both of which can be divided further into at least two distinct sub-genotypes. Here we report the results of the first study to investigate the genetic variability of HMPV strains circulating within Cambodia. The overall incidence of HMPV infection amongst an all-ages population of patients hospitalised with ALRI in Cambodia during 3 consecutive years, between 2007 and 2009, was 1.7%. The incidence of HMPV infection was highest amongst children less than 5 years of age, with pneumonia or bronchopneumonia the most frequent clinical diagnoses across all age groups. The incidence of HMPV infection varied annually. As anticipated, genetic diversity was low amongst the conserved F gene sequences but very high amongst G gene sequences, some strains sharing as little as 56.3% and 34.2% homology at the nucleotide and amino acid levels, respectively. Simultaneous co-circulation of strains belonging to the HMPV sub-genotypes B1, B2 and lineage A2b, amongst patients recruited at 2 geographically distinct provincial hospitals, was detected. Sub-genotype B2 strains were responsible for the majority of the infections detected, and a significant (p=0.013) association between infection with lineage A2b strains and disease severity was observed. PMID- 21292033 TI - Sequence variability of HCV Core region: important predictors of HCV induced pathogenesis and viral production. AB - Hepatitis C virus (HCV), a RNA virus belonging to the family Flaviviridae, has been considered to be a significant risk factor in HCV induced liver diseases and development of hepatocellular carcinoma (HCC). Current combination treatment of pegylated interferon-alpha (PEG-IFN-alpha) and ribavirin has shown limited efficiency, poor tolerability and significant expense mainly depending upon the HCV genotype. HCV has been divided into six genotypes and 52 subtypes present all over the world. The genetic diversity is more than 30% in different genotypes and 20% in subtypes. It has been suggested that different genotypes do vary in their infectivity and pathogenicity due to the variations in amino acid sequence, thereby influencing the rate of disease progression, severity to cirrhosis and the risk of HCC. HCV Core protein has multifunctional activities in regulation of cells growth and host genes expression essential for infectivity including apoptosis, HCV associated steatosis, immune cell functions, cell transformation, signal transduction and transcriptional regulation. Recent studies have shown variable responses for IFN-ribavirin combination therapy, steatosis, insulin resistance and HCC due to amino acid substitutions in HCV Core region of different genotypes. In the present review, we emphasize on the pathogenicity cause by HCV Core and effect of amino acid sequence variation in disease progression and HCV life cycle. PMID- 21292034 TI - Analysing complete genome sequence of swine hepatitis E virus (HEV), strain CHN XJ-SW13 isolated from Xinjiang, China: putative host range, and disease severity determinants in HEV. AB - Hepatitis E is a worldwide public health problem, particular in areas where hygiene conditions are poor. Hepatitis E virus (HEV) has at least four genotypes: genotypes 1 and 2 exclusively infect human; while genotypes 3 and 4, are considered to be a zoonotic agent, infecting both humans and animals. This study was aimed at determining why genotype 3 and 4 HEV strains isolated from swine are able to cross species borders, whereas genotype1 and 2 strains isolated from humans are not. The full length genome of the swine HEV isolate CHN-XJ-SW13 was amplified as overlapping fragments using reverse-transcription-nested polymerase chain reaction (RT-nPCR) and rapid amplification of cDNA ends (RACE). The sequence of CHN-XJ-SW13 was compared with those of 90 HEV strains covering genotype 1-4 retrieved from GenBank. Possible regions of the viral genome, specifying the host range of HEV or associated with the severity of hepatitis E disease, were then screened for with the aid of the ALIGNX sequences alignment software package. The CHN-XJ-SW13 swine HEV isolate was determined to be a novel subtype of genotype 4, whose sequence provided several valuable clues for tracing the sources of human HEV infection. 25 specific nucleotide positions were identified to possibly being involved specifying the host range of HEV or determining the severity of hepatitis E disease. PMID- 21292035 TI - Granulocyte-colony stimulating factor attenuates mitochondrial dysfunction induced by oxidative stress in cardiac mitochondria. AB - During cardiac ischemia-reperfusion injury, reactive oxygen species (ROS) level is markedly increased, leading to oxidative stress and mitochondrial dysfunction. Although granulocyte-colony stimulating factor (G-CSF) is known to be cardioprotective, its effects on cardiac mitochondria during oxidative stress have never been investigated. In this study, we discovered that G-CSF completely prevented mitochondrial swelling and depolarization, and markedly reduced ROS production caused by H(2)O(2)-induced oxidative stress in isolated cardiac mitochondria. Its effects were similar to those treated with cyclosporine A and 4'-chlorodiazepam. These findings suggest that G-CSF could act directly on cardiac mitochondria to prevent mitochondrial dysfunction caused by oxidative stress. PMID- 21292036 TI - Induction of mitochondrial destabilization and necrotic cell death by apolar mitochondria-directed SOD mimetics. AB - In this paper, we present evidence, for the first time, that increasing the lipophilicity of mitochondria targeting SOD mimetics reverses their cytoprotective properties, destabilizing the mitochondrial membrane system and promoting cell death. A new mitochondria-directed apolar SOD mimetic, HO-3814, was found to provoke mitochondrial swelling and loss of mitochondrial membrane potential, and these effects were not inhibited by cyclosporine A. HO-3814 induced cell death was predominantly necrotic, caspase-independent, and not affected by mitochondrial permeability transition inhibitors or cyclophilin D suppression, inhibitors of mitogen-activated protein kinases or Akt, or various antioxidants. In contrast, Bcl-2 overexpression diminished the effects of HO 3814. PMID- 21292037 TI - A genome-wide shRNA screen for new OxPhos related genes. AB - The mitochondrial oxidative phosphorylation (OxPhos) system produces most of the ATP required by the cell. The structural proteins of the OxPhos holoenzymes are well known, but important aspects of their biogenesis and regulation remain to be uncovered and a significant fraction of mitochondrial proteins have yet to be identified. We have used a high throughput, genome-wide RNA interference (RNAi) approach to identify new OxPhos-related genes. We transduced a mouse fibroblast cell line with a lentiviral-based shRNA-library, and screened the cell population for growth impairment in galactose-based medium, which requires an intact OxPhos system. Candidate genes were ranked according to their co-expression with known genes encoding OxPhos mitochondria-located proteins. For the top ranking candidates the cellular process in which they are involved was evaluated. Our results show that the use of genome-wide RNAi together with screening for deficient growth in galactose medium is a suitable approach to identifying OxPhos related and cellular energy metabolism-related genes. Interestingly also ubiquitin-proteasome related genes were selected. PMID- 21292038 TI - Mitogenomic analysis of Chinese snub-nosed monkeys: Evidence of positive selection in NADH dehydrogenase genes in high-altitude adaptation. AB - Chinese snub-nosed monkeys belong to the genus Rhinopithecus and are limited in distribution to six isolated mountainous areas in the temperate regions of Central and Southwest China. Compared to the other members of the subfamily Colobinae (or leaf-eating monkeys), these endangered primates are unique in being adapted to a high altitude environment and display a remarkable ability to tolerate low temperatures and hypoxia. They thus offer an interesting organismal model of adaptation to extreme environmental stress. Mitochondria generate energy by oxidative phosphorylation (OXPHOS) and play important roles in oxygen usage and energy metabolism. We analyzed the mitochondrial genomes of two Chinese snub nosed monkey species and eight other colobines in the first attempt to understand the genetic basis of high altitude adaptation in non-human primates. We found significant evidence of positive selection in one Chinese snub-nosed monkey, Rhinopithecus roxellana, which is suggestive of adaptive change related to high altitude and cold weather stress. In addition, our study identified two potentially important adaptive amino acid residues (533 and 3307) in the NADH2 and NADH6 genes, respectively. Surprisingly, no evidence for positive selection was found in Rhinopithecus bieti (the other Chinese snub-nosed monkey analyzed). This finding is intriguing, especially considering that R. bieti inhabits a higher altitudinal distribution than R. roxellana. We hypothesize that a different adaptive genetic basis to high altitude survival exists in R. bieti from those seen in other mammals, and that positive selection and functionally associated mutations in this species may be detected in nuclear genes related to energy and oxygen metabolism. More information on the structure, function, and evolution of mitochondrial and nuclear genomes in Chinese snub-nosed monkeys is required to reveal the molecular mechanisms that underlie adaptations to high altitude survival in non-human primates. PMID- 21292039 TI - Mitochondrial DNA variations associated with recurrent pregnancy loss among Indian women. AB - Several genetic factors have been found to be associated with recurrent pregnancy loss (RPL). However, not many attempts have been made to associate the mitochondrial DNA (mtDNA) variations with RPL. Therefore, we have analyzed the complete mtDNA of 100 women with RPL and 12 aborted fetal tissues. Our analysis revealed a total of 681 variations, most of which were in NADH Dehydrogenase (ND) genes that encode mitochondrial enzyme Complex I. Presence of T4216C variation (ND1 gene) in 9% of the RPL women and several pathogenic, and novel mutations suggest the role of mtDNA variations in RPL. PMID- 21292040 TI - Impairment of mitochondrial tRNAIle processing by a novel mutation associated with chronic progressive external ophthalmoplegia. AB - We report a sporadic case of chronic progressive external ophthalmoplegia associated with ragged red fibers. The patient presented with enlarged mitochondria with deranged internal architecture and crystalline inclusions. Biochemical studies showed reduced activities of complex I, III and IV in skeletal muscle. Molecular genetic analysis of all mitochondrial tRNAs revealed a G to A transition at nt 4308; the G is a highly conserved nucleotide that participates in a GC base-pair in the T-stem of mammalian mitochondrial tRNA(Ile). The mutation was detected at a high level (approx. 50%) in muscle but not in blood. The mutation co-segregated with the phenotype, as the mutation was absent from blood and muscle in the patient's healthy mother. Functional characterization of the mutation revealed a six-fold reduced rate of tRNA(Ile) precursor 3' end maturation in vitro by tRNAse Z. Furthermore, the mutated tRNA(Ile) displays local structural differences from wild-type. These results suggest that structural perturbations reduce efficiency of tRNA(Ile) precursor 3' end processing and contribute to the molecular pathomechanism of this mutation. PMID- 21292041 TI - Revisiting the cholinergic hypothesis of behavioral and psychological symptoms in dementia of the Alzheimer's type. AB - Behavioral and psychological symptoms of dementia (BPSD) include agitation, aberrant motor behavior, anxiety, elation, irritability, depression, apathy, disinhibition, delusions, hallucinations, and sleep or appetite impairment. These symptoms have adverse consequences for patients and caregivers, such as greater impairment in activities of daily living, worsening quality of life and earlier institutionalization. While the etiology of BPSD has not been clearly delineated, studies assessing the benefits of acetylcholinesterase inhibitors on BPSD suggest that some of the neuropsychiatric symptoms of dementia such as agitation, apathy and psychosis may represent a specific central cholinergic deficiency syndrome. Biochemical and neuroimaging studies of BPSD in Alzheimer's patients support these pharmacological data. This review discusses the literature describing the association between cholinergic deficiency and manifestations of BPSD. PMID- 21292042 TI - Hormesis and epigenetics: is there a link? AB - Epigenetic regulation of gene expression is a key molecular mechanism linking environmental factors with the genome with consequences for health status throughout the life course. According to the modern view, epigenetic changes are far more likely than genetic changes to be directed, and many of these changes are manifestly adaptive. Recent experimental studies clearly indicate that environmental fluctuations can induce specific and predictable epigenetic-related molecular changes, and support the possibility of adaptive epigenetic phenomenon. The epigenetic adaptation processes implying alterations of gene expression to buffer the organism against environmental changes support adaptability to the expected life-course conditions. It appears likely that adaptive epigenetic rearrangements can occur not only during early developmental stages but also through the adulthood, and they can cause hormesis, a phenomenon in which adaptive responses to low doses of otherwise harmful conditions improve the functional ability of cells and organisms. In this review, several lines of evidence are presented that epigenetic mechanisms can be involved in hormesis like responses. PMID- 21292043 TI - The impact of hydrogen sulfide (H2S) on neurotransmitter release from the cat carotid body. AB - Do cat carotid bodies (CBs) increase their release of acetylcholine and ATP in response to H(2)S? Two CBs, incubated in a Krebs Ringer bicarbonate solution at 37 degrees C, exhibited a normal response to hypoxia-increased release of acetylcholine (ACh) and ATP. They were challenged with several concentrations of Na(2)S, an H(2)S donor. H(2)S, a new gasotransmitter, is reported to open K(ATP) channels. Under normoxic conditions the CBs reduced their release of ACh and ATP below control values. They responded identically to pinacidil, a well-known K(ATP) channel opener. CB glomus cells exhibited a positive immunohistochemical signal for cystathione-beta-synthetase, a H(2)S synthesizing enzyme, and for a subunit of the K(ATP) channel. The data suggest that Na(2)S may have opened the glomus cells' K(ATP) channels, hyperpolarizing the cells, thus reducing their tonic release of ACh and ATP. Since during hypoxia H(2)S levels rise, the glomus cells responding very actively to hypoxia may be protected from over-exertion by the H(2)S opening of the K(ATP) channels. PMID- 21292045 TI - Geriatric behavior therapy: the challenges of a changing environment. Introduction. PMID- 21292044 TI - Experimental protocols and preparations to study respiratory long term facilitation. AB - Respiratory long-term facilitation is a form of neuronal plasticity that is induced following exposure to intermittent hypoxia. Long-term facilitation is characterized by a progressive increase in respiratory motor output during normoxic periods that separate hypoxic episodes and by a sustained elevation in respiratory activity for up to 90min after exposure to intermittent hypoxia. This phenomenon is associated with increases in phrenic, hypoglossal or carotid sinus nerve inspiratory-modulated discharge. The examination of long-term facilitation has been steadily ongoing for approximately 3 decades. During this period of time a variety of animal models (e.g. cats, rats and humans), experimental preparations and intermittent hypoxia protocols have been used to study long-term facilitation. This review is designed to summarize the strengths and weaknesses of the models, preparations and protocols that have been used to study LTF over the past 30 years. The review is divided into two primary sections. Initially, the models and protocols used to study LTF in animals other than humans will be discussed, followed by a section specifically focused on human studies. Each section will begin with a discussion of various factors that must be considered when selecting an experimental preparation and intermittent hypoxia protocol to examine LTF. Model and protocol design recommendations will follow, with the goal of presenting a prevailing model and protocol that will ultimately ensure standardized comparisons across studies. PMID- 21292046 TI - Alive and well: the state of behavioral gerontology in 2011. AB - In this paper, the authors present a brief personal account of the senior author's 30 years of exploration in behavioral gerontology. The main thesis of the paper is that behavioral methods and interventions have found a home both in mainstream gerontology and at the National Institutes of Health (NIH). There are three sections: (a) a personal vignette discussing the problems inherent in using operant terminology in a nonoperant world; (b) a discussion, with examples from NIH sources, of the Institutes' views on behavior change; and (c) using Burgio and Burgio (1986) as a reference point, the authors show evidence of progress and vitality of behavioral gerontology in 2011. PMID- 21292047 TI - The role of behavior analysis in the rehabilitation of persons with dementia. AB - With the rapidly aging population, it is expected that increases in cases of dementia will double over the next 20 years. Currently, there is no cure for diseases such as Alzheimer's disease or frontotemporal dementia (FTD) that cause progressive dementia, and only a few pharmacological interventions that slow the progression of the decline exist. Given that there is no cure available, a rehabilitation approach that emphasizes maintaining existing abilities and removing excess disability (as opposed to emphasizing cure or recovery) for as long as possible is warranted. The current paper proposes that nonpharmacological rehabilitation efforts need to target 5 broad areas/targets: memory enhancement, altering social contingencies and communication styles, improving self-care skills, the arrangement of physical environments to maintain and improve functioning, and increasing physical fitness/physical activity. The purpose of this paper is to review specific behaviorally oriented interventions that target these 5 areas and show promise for inclusion in comprehensive rehabilitation efforts for individuals with dementia. PMID- 21292048 TI - Depressed nursing home residents' activity participation and affect as a function of staff engagement. AB - Behavioral interventions for depression target activity engagement and increased positive reinforcement, particularly from social interaction. Nursing homes provide limited opportunity for meaningful social engagement, and have a high prevalence of depression. Often residents obtain most of their social contacts from staff members. We present intra-individual correlations among positive staff engagement, resident affect, and resident activity participation from behavior stream observations of residents who were participants in an ongoing trial of an intervention for depression. Sixteen residents were observed 6 times weekly for 8 to 45 weeks, 5 minutes per observation. Positive staff engagement during the observations was significantly correlated with resident interest and pleasure. Positive staff engagement was related to resident participation in organized group activity; however, residents tended to be more engaged and show more pleasure when in informal group activities, especially those residents receiving the behavioral treatment. Positive staff engagement was not related to time in activities of daily living. Results have implications for understanding mechanisms and potential targets of interventions for depression. PMID- 21292049 TI - Acceptability of interventions for aggressive behavior in long-term care settings: comparing ratings and hierarchical selection. AB - Fifty-six active treatment team members in long-term nursing care facilities completed an online survey assessing treatment acceptability of modern behavioral, pharmacological, and sensory interventions. A traditional treatment acceptability rating scale was compared to treatment selections in a paired options format. Unlike earlier research, there were no significant differences in acceptability between the 3 interventions on the traditional rating scale. However, ratings and selections were significantly correlated for behavioral and pharmacological interventions. The clinical significance of such relations and the implications for the use of treatment ratings is discussed. PMID- 21292050 TI - Linking resident behavior to dementia care communication: effects of emotional tone. AB - Care for older adults with dementia is complicated by behaviors such as verbal and physical aggression and withdrawal that disrupt and increase the costs of providing care. These behaviors, referred to as resistiveness to care (RTC), have been linked to staff elderspeak communication, measured by behaviorally coded explicit behaviors. This study examined videotapes of nursing home (NH) residents with dementia interacting with staff during bathing to explore the relationships between implicit messages communicated by nursing staff and resident RTC behavior. Implicit messages in nursing staff communication were rated using the Emotional Tone Rating Scale by naive coders. Associations between implicit ratings of care, respect, and control were analyzed in relation to RTC scale scores. Highly controlling communication was significantly correlated with increased resident RTC (r=.49, p<.05). Associations between the care and respect dimensions of communication were not significantly correlated with RTC; however, trends in hypothesized directions were identified. The association between emotional tone and RTC found in this study suggests that it is an important factor in care. Understanding affective messages is a first step in modifying these implicit messages conveyed during staff-resident communication. Research is needed to confirm these findings and to identify and test interventions to teach staff to reduce controlling messages that will to reduce RTC and improve care. PMID- 21292051 TI - Command use and compliance in staff communication with elderly residents of long term care facilities. AB - Verbal communication between nursing assistants and individuals with dementia can be challenging, particularly during hands-on caregiving tasks. Although there are many aspects of verbal communication that can affect the quality of an interaction, one potentially important communication variable is the types of commands issued by nursing assistants when they need a resident to complete a task. The purpose of this study was to examine the kinds of commands used by nursing care staff when they interact with patients with dementia during activities of daily living. Commands were categorized according to their feasibility/specificity as well as form. An additional goal of this study was to measure compliance and noncompliance rates associated with the various categories of commands. Results indicate that alpha commands (clear, concise, and feasible) account for higher compliance and less noncompliance compared with beta commands (ambiguous, interrupted, and not feasible). In addition, commands that are stated directly, that clarify a previous command, and that are repeated exactly produce better compliance. It is concluded that training nursing staff to change the types of commands they provide during caregiving tasks may reduce distress experienced by both staff and residents. PMID- 21292052 TI - Commentary on the current status and the future of behavior therapy in long-term care settings. PMID- 21292053 TI - A positive aging framework for guiding geropsychology interventions. AB - This article characterizes the human aging process from the perspectives of normal, pathological, usual, successful, and positive aging. Positive aging is described based on four characteristics: the mobilizing of latent resources, psychological flexibility, an affirmative decision-making style, and the propensity to generate an optimistic response to stressors inherent in age related decline. A positive aging strategy framework is proposed, inclusive of recent developments in intervention research employing gratitude, forgiveness, and altruism to preserve subjective well-being. The role of positive aging strategies in conjunction with behavioral intervention approaches to promote well being in one's later years is recommended for addressing the complex needs of our graying population. PMID- 21292054 TI - Integration of the pleasant events and activity restriction models: development and validation of a "PEAR" model of negative outcomes in Alzheimer's caregivers. AB - This study examined an activity restriction/pleasurable activities mismatch model for psychosocial and health-related outcomes. A total of 108 spousal caregivers of patients with Alzheimer's Disease (AD) were assessed for their experience of social and recreational activities over the past month as well as their perception of how restricted they were for engaging in social and recreational activities. Participants were divided into three groups based on their reported activities and activity restriction: HPLR=High Pleasant Events+Low Activity Restriction (i.e., reference group; N=28); HPHR/LPLR=Either High Pleasant Events+High Activity Restriction or Low Pleasant Events+Low Activity Restriction (N=43); LPHR=Low Pleasant Events+High Activity Restriction (N=37). We hypothesized that participants reporting low pleasant events combined with high activity restriction (LPHR) would demonstrate greater disturbance relative to other two groups in multiple outcome domains, including: (a) greater mood disturbance, (b) greater use of negative coping factors, (c) reduced use of positive coping strategies, (d) reduced report of psychological resource factors (e.g., personal mastery, self-efficacy), and (e) increased report of subjective health difficulties (e.g., sleep disturbance). Results generally supported our hypotheses, suggesting that assessment of both constructs is important for best predicting quality of well-being in AD caregivers, and potentially for establishing maximal effect in behavior therapy for caregivers. PMID- 21292055 TI - Measuring the person-centeredness of caregivers working with nursing home residents with dementia. AB - There is increasing interest in promoting person-centered caregiving within gerontology. However, few observational instruments have been developed to measure person-centered caregiving behaviors. In the present study, two innovative coding instruments-the Person-Centered Behavior Inventory (PCBI) and the Global Behavior Scale (GBS)-were used to test the hypothesis that caregivers' person-centeredness would be negatively correlated with residents' resistiveness to care. The study hypothesis was based on the need-driven dementia-compromised theory of behavior. It was expected that person-centered caregiving would better meet residents' needs and be associated with less resistiveness to care. This hypothesis was tested by coding 70 videotaped interactions between 54 caregivers and 20 residents diagnosed with dementia. Resistiveness to care was measured by behaviorally coding residents' resistive behaviors based on the Resistiveness to Care scale. The study hypothesis was supported when the GBS was used to measure person-centeredness, but not when the PCBI was used. The findings provide preliminary support for the predictive and construct validity of the GBS and the PCBI. PMID- 21292056 TI - The effects of behavioral activation therapy with inpatient geriatric psychiatry patients. AB - This study examined the effects of Behavioral Activation (BA) treatment on depressive symptoms and quality of life among older adult patients in a geriatric psychiatry facility. There were 50 participants with mild to moderate cognitive impairment, each being 65 years of age or older. A 2 (between)*3 (time of measurement) design was used in this study comparing control (treatment-as-usual) and experimental (BA) conditions at pre-, mid-, and posttreatment. BA consisted of eight 30- to 60-minute sessions across 4 weeks. Intent-to-treat analyses indicated a significant Group*Time interaction on depressive symptoms, with this effect remaining when only completer data were included. Further analyses indicated that this effect was due to significant change early in treatment in both the full and completer samples. There was no evidence of a significant effect on the quality-of-life measure. Cognitive status was not related to change in depressive symptoms, suggesting that BA may be useful across a range of older adults. PMID- 21292057 TI - A DBT Skills training group for family caregivers of persons with dementia. AB - A Dialectical Behavior Therapy Skills training manual (DBT Skills) was adapted for use with caregivers of individuals with dementia. Implementation occurred in a community clinic with a heterogeneous caregiver group at risk for elder abuse. Sixteen caregivers completed the 9-week group. The results point to improved psychosocial adjustment, particularly increased problem-focused coping, enhanced emotional well-being, and less fatigue. Caregivers tended to utilize individual therapeutic services at a higher rate during the period of group attendance, indicative of appropriate help-seeking behavior in highly demanding situations. Six of the 16 caregivers repeated the training sequence in "booster" groups. Follow-up data from the booster groups suggest that high-risk caregivers may require continuing support to maintain treatment gains. In addition to demonstrating the feasibility of DBT Skills with caregivers, the results warrant a controlled outcome evaluation. PMID- 21292058 TI - Applying Skinner's analysis of verbal behavior to persons with dementia. AB - Skinner's 1957 analysis of verbal behavior has demonstrated a fair amount of utility to teach language to children with autism and other various disorders. However, the learning of language can be forgotten, as is the case for many elderly suffering from dementia or other degenerative diseases. It appears possible that Skinner's operants may facilitate not only acquisition of language but also the ability to recall items or objects that may have appeared to be "forgotten." The present study examined the utility of having a series of adults in long-term care emit tacts, echoics, or intraverbals upon presentation of various visual stimuli. Compared to a no-verbal response condition, it appears that the incorporation of Skinner's verbal operants can in fact improve recall for this population. Implications for the retraining of lost language are presented. PMID- 21292059 TI - Acceptance and Commitment Therapy for generalized anxiety disorder in older adults: a preliminary report. AB - Some evidence suggests that acceptance-based approaches such as Acceptance and Commitment Therapy (ACT) may be well-suited to geriatric generalized anxiety disorder (GAD). The primary goal of this project was to determine whether ACT was feasible for this population. Seven older primary-care patients with GAD received 12 individual sessions of ACT; another 9 were treated with cognitive-behavioral therapy. No patients dropped out of ACT, and worry and depression improved. Findings suggest that ACT may warrant a large-scale investigation with anxious older adults. PMID- 21292060 TI - Assessment and treatment of hoarding in an individual with dementia. AB - The authors used a reinforcer assessment to evaluate possible interventions for hoarding in an older individual with dementia. The most preferred condition from the assessment (sorting activity) was compared to a staff developed treatment involving item removal and redirection. Hoarding was reduced during both interventions with a greater reduction in the sorting condition. The behavioral reductions were maintained during schedule thinning of social interactions and follow-up. PMID- 21292061 TI - Understanding behavioral health in late life: why age matters. PMID- 21292062 TI - Segmental transposition of ileal muscle layers: a rare cause of myopathic pseudoobstruction in a newborn. AB - Gastrointestinal motility disorders are induced by various causes in neonates, some of which are not classified. Generally, these disorders can be classified as a neuropathy or myopathy, each of which can be subdivided into a primary or secondary type. We describe a neonate with a rare form of myopathy related to segmental transposition of the smooth muscle of the ileum and a brief review of the relevant literature. PMID- 21292063 TI - Acquired ileal atresia complicating an ileocolic intussusception in a 4-month-old infant. AB - We report a 4-month-old female infant who was apparently well before the onset of vomiting, abdominal distension, and the passage of red currant jelly stools. A clinical diagnosis of intussusception was made, and the infant was prepared for a laparotomy. Intraoperative findings were a gangrenous ileocolic intussusception with a proximal atretic ileal segment (similar to a type IIIa ileal atresia). An extended right hemicolectomy including the atretic ileal segment was done with an ileotransverse anastomosis to establish bowel continuity. The patient had a wound dehiscence on the fourth postoperative day that was repaired. She subsequently made satisfactory clinical recovery and was discharged on the 10th day. PMID- 21292064 TI - Laparoscopic excision of a retroperitoneal lymphatic malformation in a newborn. AB - Abdominal lymphatic malformations may be challenging to eradicate. Retroperitoneal lesions may more difficult to resect than mesenteric ones; however, the latter may predispose to intestinal volvulus, leading to calls for their prompt excision. Such lesions identified perinatally may pose particular challenges: in one case, respiratory failure caused by abdominal distension required emergency drainage followed by later laparoscopic excision; laparoscopy has also been used promptly to diagnose and resect neonatal mesenteric lymphatic malformations with their inherent volvulus risk. We illustrate that even if neonatal laparoscopy identifies a retroperitoneal rather than mesenteric lymphatic malformation, curative endosurgical excision remains feasible. PMID- 21292065 TI - Terlipressin as rescue therapy for refractory pulmonary hypertension in a neonate with a congenital diaphragmatic hernia. AB - We report the case of a 38-week gestational age neonate, with isolated congenital diaphragmatic hernia presenting with refractory persistent pulmonary hypertension, systemic hypotension, and hypoxemia, resistant to usual therapeutics. Arginine vasopressin is responsible for systemic vasoconstriction and decreases pulmonary hypertension. We theorized that terlipressin, its long acting analogue, could have the same properties. We used terlipressin as rescue therapy after parental and local ethics committee acceptance. After a bolus of terlipressin 20 MUg/kg and continuous infusion at a rate of 5 MUg/kg per hour, blood oxygen saturation improved from 75% to 98%, oxygen requirements fell from fraction of inspired oxygen 100% to 40%, and mean arterial pressure rose from 28 to 46 mm Hg, allowing a decrease of vasopressor infusion. Terlipressin may be useful in the management of neonates with congenital diaphragmatic hernia and refractory pulmonary hypertension. PMID- 21292066 TI - Laparoscopic repair of diaphragmatic Morgagni hernia in children: review of 3 cases. AB - This article retrospectively reviews the laparoscopic repair of Morgagni hernias in 3 children. The surgical procedure was performed by closing the defect using extracorporeal, interrupted, nonabsorbable sutures. Recovery was uneventful in all 3 patients. There were no recurrences and the chest radiograph stayed normal during the postoperative follow-up. PMID- 21292067 TI - Familial case of prenatally diagnosed intralobar and extralobar sequestrations with cystadenomatoid change. AB - Hybrid lesions are part of a spectrum of rare pulmonary diseases that are characterized as having elements of both congenital pulmonary airway malformation and bronchopulmonary sequestration. Fetal thoracic masses arise from alterations during lung development that are separated by timing of the inciting event and are often associated with an underlying degree of bronchial atresia. There are a handful of documented reports of sequestrations occurring in siblings, but no known reports of prenatally diagnosed lesions occurring in families. We present a case of 2 siblings diagnosed prenatally with fetal thoracic lesions who underwent postnatal resection revealing hybrid lesions on pathologic examination. Newer radiologic techniques have increased our ability to detect these masses prenatally, as well as follow them throughout pregnancy to determine their natural history. Ongoing laboratory investigation into the etiology of congenital lung lesions has brought forth more questions and suggested a familial component at a cellular level that has not yet been fully discovered. We reviewed the current literature of factors contributing to the development of congenital lung lesions and suggest that there is a familial link in certain patient populations where screening may be indicated. PMID- 21292068 TI - Diagnosis and laparoscopic treatment of ileoileal intussusception secondary to heterotopic pancreas in an infant: case report and review of the literature. AB - Small bowel intussusception in infancy owing to a pathologic lead point is a rare event requiring immediate surgical attention. We report a case of a 7-month-old patient presenting with ileoileal intussusception with isolated heterotopic pancreas as the lead point. We review the literature of small bowel intussusception focusing on diagnosis and treatment. In contrast to comparable previous reports of infants with heterotopic pancreas and intussusception, the diagnosis was based solely on ultrasound findings followed by operative management using a laparoscopically assisted surgical approach. PMID- 21292069 TI - Application of a fetal scalp electrode for continuous fetal heart rate monitoring during an ex utero intrapartum treatment. AB - Fetal monitoring is required to avoid hypoxic injury during ex utero intrapartum treatment (EXIT). We performed a tracheostomy under EXIT in a case of suspected airway obstruction caused by a cervical teratoma. The scalp electrode was applied for continuous fetal heart rate monitoring. This device enabled us to promptly deal with fetal bradycardia caused by cord compression. We describe here the usefulness of the fetal scalp electrode for fetal monitoring under EXIT. PMID- 21292070 TI - Embryogenesis of triple neural tube defects: sonic hedgehog--a key? AB - Neural tube closure is a complex spatio-temporal process. Multiple neural tube defects (NTDs) in a single patient are extremely rare. Only a few cases of multiple NTDs have been reported in the world literature, including less than 20 cases of double NTDs and 3 cases of triple NTDs. We report a fourth case of triple NTDs and review the literature regarding the embryogenesis. An effort is made to understand the theories of neural tube closure in light of recent advances in molecular biology and identification of the signaling pathways involved. PMID- 21292071 TI - Toxic epidermal necrolysis complicated by small bowel intussusception: a case report. AB - Intestinal involvement in toxic epidermal necrolysis (TEN) has been identified only rarely. We report a case of TEN complicated by small bowel intussusception. The patient was a previously healthy 8-year-old boy who presented with TEN and extensive lesions, including up to 40% of the body surface area as well as conjunctival, oropharyngeal, respiratory, and genital mucosa. Rapidly after the onset of a constant rate of enteral feeding, he developed bilious vomiting, diarrhea, and significant abdominal distension. Abdominal sonography showed a small bowel intussusception. At abdominal exploration, an ileoileal intussusception was observed with a viable but inflamed bowel wall. Manual reduction was performed. During the postoperative clinical course, the patient was managed with total parenteral nutrition and local care of the skin and mucous membranes. Enteral feeding was introduced on the sixth postoperative day, and the child left the hospital 15 days after his admission. The association of TEN and small bowel intussusception has not been previously reported in the literature. PMID- 21292072 TI - Videosurgery--the second generation. PMID- 21292073 TI - Indications and strategies for intestinal transplantation. AB - This lecture updates the pediatric surgeon on current indications, techniques, and results of intestinal transplantation in children with intestinal failure with reference to the Paris series. PMID- 21292074 TI - The Aberdeen Medico-Chirurgical Society 1789 to the present day: some leaders in medicine. AB - The Aberdeen Medico-Chirurgical Society was founded in 1789 based on a model of the Royal Medical Society of Edinburgh by Sir James McGrigor and 11 medical students. The objectives at that time, as at present, were to promote teaching, self education, the application of medical skills learned at the bedside, fellowship, and social intercourse. A number of examples of key leaders in the profession and members of the Medico-Chirurgical Society of Aberdeen are featured. These include Alexander Gordon (puerperal fever), Sir James McGrigor (founder of the British Army Medical Services), Sir Alexander Ogston (associated with Lister's theory of antisepsis in surgery and the discovery of the staphylococcus), Sir Patrick Manson (the father of tropical medicine), Prof JJR Macleod (Nobel Laureate and the discoverer of insulin), Prof Sir Matthew Hay (public health physician who offered the first description of typhus and its origins), and Sir Dugald Baird (the founder in the United Kingdom and Europe of modern-day maternity services). PMID- 21292075 TI - Management of gastroesophageal reflux associated with malrotation in children. AB - AIM: Children being investigated for gastroesophageal reflux (GOR) have a high incidence of malrotation. Current literature suggests these patients should be managed with a combined antireflux and Ladd's procedure. We review our experience, the largest series to date, of performing an elective Ladd's procedure as the first-line intervention. METHOD: Retrospective case note review of 20 children with significant symptoms of GOR and an incidental finding of malrotation. Children presenting immediately with bilious vomiting were excluded. All patients underwent a Ladd's procedure as their sole primary operative intervention. RESULTS: Median age at operation was 7 months (21 days-12 years). Fifteen patients (75%) had evidence of reflux on barium contrast study. All children were followed up for at least 6 months. Eighteen (90%) had resolution or significant improvement of their symptoms postsurgery. Only 3 have not managed to tolerate a full oral diet, all unrelated to GOR. None of our series required an antireflux procedure. CONCLUSION: In children with debilitating vomiting necessitating surgical management, a contrast study is imperative in the work up. The high incidence of GOR and the significant improvement after correction of malrotation show the relationship between delayed gastric emptying and GOR. We suggest that when an abnormally placed duodenojejunal flexure is found, a Ladd's procedure alone is sufficient and may obviate the need for a more invasive antireflux procedure. PMID- 21292076 TI - Prenatal diagnosis and outcome of fetal lung masses. AB - AIM: The purpose of this study is to evaluate the accuracy of prenatal diagnostic features, particularly congenital cystic adenomatoid malformation volume ratio (CVR), in predicting outcomes for fetuses with lung masses. METHODS: The records and imaging features of all fetuses referred to the Texas Children's Fetal Center with a fetal lung mass between July 2001 and May 2010 were reviewed retrospectively. Data collected included gestational age (GA) at diagnosis, fetal magnetic resonance imaging findings, CVR, mass size, nature of fetal treatment, surgical findings, pathology, and outcome. Data were analyzed for predicting development of hydrops or the need for fetal therapy using receiver operating characteristic curves. RESULTS: Of 82 fetuses (41 male) evaluated for a lung mass, 53 (65%) were left-sided (1 bilateral), and the mean (SD) GA at diagnosis was 21.5 (4.3) weeks. Seventy-three fetuses underwent fetal magnetic resonance imaging at a mean (SD) GA of 26.1 (4.6) weeks. Thirteen fetuses (16%) had fetal treatment. Four fetuses with hydrops underwent open fetal surgical resection, and 3 survived. Six fetuses with large lung masses and persistent mediastinal compression near term underwent ex-utero intrapartum therapy-to-resection procedures, and 3 fetuses with hydrops underwent serial thoracentesis. Congenital cystic adenomatoid malformation volume ratio correlated strongly with the development of hydrops and the need for fetal therapy with an area under the receiver operating characteristic curve of 0.96 (P < .0001) and 0.88 (P < .0001), respectively. Of 18 fetuses with a CVR greater than 2.0 compared with 2 (3%) of 60 with a CVR of 2.0 or less, 10 (56%) required fetal intervention (P < .0001). CONCLUSION: Congenital cystic adenomatoid malformation volume ratio correlates strongly with the development of fetal hydrops and the need for fetal intervention. A threshold value of 2.0 yields the most powerful statistical results. PMID- 21292077 TI - Intrahepatic duct dilatation in type 4 choledochal malformation: pressure related, postoperative resolution. AB - BACKGROUND: Type 4 choledochal malformations (CMs) may be defined as those with both intrahepatic and extrahepatic bile duct dilatation. The aims of this study were to investigate possible causes of intrahepatic duct (IHD) dilatation in CM and to define the effect of surgery over time. METHODS: This study was a single center retrospective review of a database of all children with CM undergoing surgery (excision of extrahepatic bile duct dilatation and hepaticojejunostomy) and identified as type 4 (on imaging and at surgery). Data included intraoperative choledochal pressure measurements and biliary amylase content and were expressed as median (interquartile range [IQR]). All comparisons used nonparametric statistical tests. P <=.05 was regarded as significant. RESULTS: Twenty children were identified as type 4 CM (age, 4.3 years; range, 2.7-10.4 years) with preoperative IHD dilatation (right duct: diameter [range], 8.5 [4.5 14] mm; left: 8 [4-14.5] mm). Median intraoperative choledochal pressure was 17 (8-27) mm Hg (normal, <5 mm Hg), and intraoperative bile amylase was 3647 (range, 500-58,000) IU/L (normal, <100 IU/L). Preoperative IHD diameter correlated with choledochal pressure (right: r(s)=0.46, P = .03; left: r(s)=0.34, P = .07) but not with biliary amylase (P = .28 and P = .39, respectively). At 1 year postsurgery, median (range) IHD diameter had decreased to 1 (1-2.5) mm for right duct (P = .0002) and 1.5 (1-3) mm for left duct (P = .0006) and remained stable for up to a 10-year follow-up. CONCLUSION: Our data suggest that IHD dilatation is related to sustained increased intrabiliary pressure rather than any intrinsic intrahepatic CM. Effective surgery invariably reduces measured IHD toward normal values. PMID- 21292078 TI - Button cholecystostomy for management of progressive familial intrahepatic cholestasis syndromes. AB - BACKGROUND/PURPOSE: Progressive familial intrahepatic cholestasis syndromes are characterized by impaired bile acid secretion resulting in pruritus, coagulopathy, diarrhea, and malnutrition leading to progressive liver failure and death in childhood. Partial internal or external biliary drainage can relieve symptoms and slow the progression of the disease. Objections to partial external biliary drainage include the need for a permanent biliary stoma with all the inherent complications of a stoma. We propose a novel approach to these diseases- placement of a "button" cholecystostomy tube. METHODS: Under general anesthesia and through a small right subcostal incision, a MIC-KEY button (Kimberly-Clark Worldwide, Inc, Draper, UT) is inserted into the mobilized fundus of the gallbladder and secured with 2 purse-string sutures. Time of drainage is adjusted to relieve pruritus. RESULTS: Three children with progressive familial intrahepatic cholestasis achieved adequate bile drainage via the cholecystostomy button to relieve pruritus for 1, 2, and 2 1/2 years postoperatively, with drainage periods of 12 to 14 hours per day. There were no episodes of cholangitis. Dislodged tubes can be replaced, or stones can be retrieved via the tract that is formed. Patient (parent) acceptance has been excellent. CONCLUSION: Button cholecystostomy is simple to perform, relieves pruritus with intermittent (nighttime) drainage, avoids complications of a permanent stoma, avoids an enteric anastomosis, and is accepted by parents. PMID- 21292079 TI - Management and classification of type II congenital portosystemic shunts. AB - BACKGROUND: Congenital portosystemic shunts (PSS) with preserved intrahepatic portal flow (type II) present with a range of clinical signs. The indications for and benefits of repair of PSS remain incompletely understood. A more comprehensive classification may also benefit comparative analyses from different institutions. METHODS: All children treated at our institution for type II congenital PSS from 1999 through 2009 were reviewed for presentation, treatment, and outcome. RESULTS: Ten children (7 boys) with type II PSS were identified at a median age of 5.5 years. Hyperammonemia with varying degrees of neurocognitive dysfunction occurred in 80%. The shunt arose from a branch of the portal vein (type IIa; n = 2), from the main portal vein (type IIb; n = 7), or from a splenic or mesenteric vein (type IIc; n = 1). Management included operative ligation (n = 6), endovascular occlusion (n = 3), or a combined approach (n = 1). Shunt occlusion was successful in all cases. Serum ammonia decreased from 130 +/- 115 MUmol/L preoperatively to 31 +/- 15 MUmol/L postoperatively (P = .03). Additional benefits included resolution of neurocognitive dysfunction (n = 3), liver nodules (n = 1), and vaginal bleeding (n = 1). CONCLUSION: Correction of type II PSS relieves a wide array of symptoms. Surgery is indicated for patients with clinically significant shunting. A refined classification system will permit future comparison of patients with similar physiology. PMID- 21292080 TI - Persistent ascites can be effectively treated by peritoneovenous shunts. AB - AIM: The aim the study was to review our experience and determine the effectiveness of peritoneovenous shunts in the management of persistent ascites. METHODS: A retrospective review of all patients who had a peritoneovenous shunt inserted for persistent ascites in our institution over 32 years (1977-2010) was performed. RESULTS: Thirty-one peritoneovenous shunts were inserted into 25 patients. Records from 22 were available. Median age was 34 months (range, 1 month-12 years), with median duration of ascites of 1.75 months (range, 3 weeks 2.5 years). Sixteen had previous abdominal surgery, whereas one had previous thoracic surgery. Other underlying pathologies included hepatitis (n = 2), lymphohistiocytosis, lymphatic hypoplasia, and carcinomatosis. One was regarded as idiopathic. Previous management consisted of paracentesis (n = 15), dietary modification (n = 11), diuretics (n = 9), and total parenteral nutrition (TPN) (n = 4). One underwent fetal drainage of ascites. No intraoperative complications occurred. Eight (36%) had postoperative complications, including shunt occlusion (n = 2), pulmonary edema (n = 2), infection (n = 2), and wound leakage (n = 1). One developed a varix following shunt removal. The ascites resolved after shunting in 20 (91%) of the 22 children. Four died from their underlying pathology. In children with malignancy, the shunt allowed prompt resumption in treatment schedule. CONCLUSION: This represents the largest series of children receiving peritoneovenous shunt for persistent ascites. It is a safe and effective treatment which should be considered early. PMID- 21292081 TI - Hedgehog signal inhibitor forskolin suppresses cell proliferation and tumor growth of human rhabdomyosarcoma xenograft. AB - BACKGROUND/PURPOSE: We have previously reported that the Hedgehog (Hh) signaling pathway is activated in pediatric malignancies. In this study, we examined the effect of the Hh signal inhibitor forskolin on the growth of rhabdomyosarcoma (RMS) in vivo and in vitro and thereby elucidated the possibility of considering Hh signaling pathway as a therapeutic target for RMS. METHODS: We evaluated the messenger RNA expressions of Hh signal mediators in 3 human RMS cell lines using reverse transcriptase-polymerase chain reaction method. The effect of forskolin on the tumor cell proliferation was investigated using WST-1 assay (Dojindo Co, Kumamoto, Japan). We inoculated 10(7) tumor cells into the back of nude mice to create RMS xenograft tumor models. Forskolin was subcutaneously administered in the region around the tumor, and the effect on the tumor growth was evaluated. RESULTS: The messenger RNA expression of glioma-associated oncogene homolog 1, the marker of Hh signaling activation, was expressed at various levels in RMS cell lines. The proliferation of RMS cells was inhibited in a dose-dependent fashion by forskolin. Similarly, in the xenograft model, tumor growth was also significantly reduced by forskolin treatment. CONCLUSIONS: Our findings suggest that the Hh signaling pathway plays an important role in the tumorigenesis of RMS and that this pathway can be considered to be a potential molecular target of new treatment strategies for RMS. PMID- 21292082 TI - The role of WT1 gene in neuroblastoma. AB - BACKGROUND/PURPOSE: The oncogenic properties of the Wilms' tumor gene (WT1) have recently been reported in various malignancies. However, the role of WT1 in pediatric tumors is unclear. To elucidate the role of WT1 in the development of neuroblastoma (NB), we examined the WT1 expression in NB and the effect of WT1 suppression on NB cell proliferation. METHODS: We examined the expression of the WT1 protein in 20 NBs and 5 ganglioneuromas (GNs) by performing immunohistochemical analysis. We determined WT1 messenger RNA expression in 22 NBs, 5 GNs, and 4 NB cell lines by real-time reverse transcription polymerase chain reaction. We studied the effects of WT1 suppression on cell proliferation using small interfering RNA against WT1. RESULTS: Expression of WT1 was higher in mature ganglionic cells, and in the immunohistochemical analysis, the WT1 positivity for GNs was significantly higher than that for NBs (P < .01). The level of WT1 messenger RNA expression did not correlate with histologic grade, clinical stage, and prognosis of the tumor. Knockdown of WT1 gene promoted the proliferation of NB69 cells (P < .01). CONCLUSIONS: The WT1 may govern cell differentiation and suppress cell proliferation in NB. The WT1 does not act as an oncogene, but it may participate in the maturation of NB. PMID- 21292083 TI - Resection of pulmonary metastases in pediatric patients with Ewing sarcoma improves survival. AB - BACKGROUND: Ewing sarcoma (ES) is the second most common bone tumor in children, and survival of those with metastatic ES has not improved. Previous studies have shown a survival benefit to whole lung irradiation in patients with pulmonary metastases and may be given either before, after, or instead of surgical pulmonary metastasectomy (PM). The contribution of surgery compared with irradiation in ES has not previously been studied. METHODS: A retrospective review of patients younger than 21 years (median age, 16 years) treated at a single institution (1990-2006) was performed. Kaplan-Meier survival curves were compared using log-rank test and a multivariate Cox proportional hazards model. P <= .05 was regarded as significant. RESULTS: Eighty patients with ES were identified. Of these, 31 (39%) had pulmonary metastases. Nine patients had incomplete details of their full treatment regimen, but the following groups could be defined from the remainder: resection alone (n = 5), radiation alone (n = 3), radiation and resection (n = 3), or chemotherapy alone (n = 11). There were 24 deaths overall, with a median overall survival (OS) of 2.7 (95% confidence interval [CI], 1.7-5.2) years. Patients who had PM had the best OS (80%), whereas those who underwent radiation to the lung without PM compared with chemotherapy only for pulmonary metastasis both had similar OS of 0% at 5 years (P = .002). Patients who had radiation followed by PM for lung metastasis had a 5-year OS of 65%. Patients with PM had a longer OS compared with those without lung resection (P < .0001). CONCLUSION: These data suggest a possible benefit for ES patients who undergo surgical resection of lung metastases. PMID- 21292084 TI - Complications following restorative proctocolectomy in children. AB - BACKGROUND: Adverse outcomes following restorative proctocolectomy (RPC) in adults have been attributed to steroid exposure and use of hand-sutured anastomoses. This study analyses complications in children undergoing RPC. METHODS: This study is a retrospective review of all children undergoing RPC in an English regional center over a 10-year period. The main outcome measure was defined as a complication within 30 days of surgery. Logistic regression analysis was used with possible explanatory variables (eg, steroid use, indication for surgery, weight and height z scores, hematologic indices, degree of blood loss, and use of laparoscopic surgery). RESULTS: Sixty (33 female) patients underwent RPC at a median age of 13.5 years. Of these, 16 had an operative complication and 17 had a late complication. Only severe acute colitis with inability to induce remission as an indication for surgery was significant in predicting operative complications (odds ratio, 6.8 [95% confidence interval, 1.2-37]; P = .03). CONCLUSIONS: Severe acute colitis resistant to medical therapy but not steroid use or hand-sutured anastomoses appears to be a risk factor for complication. This differs from the adult experience. PMID- 21292085 TI - Redo pull-through in Hirschsprung's [corrected] disease for obstructive symptoms due to residual aganglionosis and transition zone bowel. AB - BACKGROUND: Reoperations in Hirschsprung disease may be required for residual aganglionosis or transition-zone bowel found at the distal pull-through. We aimed to review the management of patients who had this complication and offer suggestions on how to avoid it. METHODS: Ninety-three patients with Hirschsprung disease were referred to our institution with recurrent problems after a pull through done elsewhere. All required reoperations with a variety of indications, and of these, 25 had residual aganglionosis/transition-zone histology. This was the only indication for redo in 16 children. RESULTS: Children (range, 2-17 years) presented 6 to 66 months after the initial pull-through. The predominant symptoms were enterocolitis (n = 9 [56%]), constipation (n = 7 [44%]), failure to thrive (n = 5 [31%]), and impaction (n = 4 [25%]). The rectal biopsy performed as part of their post pull-through work up showed hypertrophic nerves (n = 16), absent ganglion cells (n = 6), and normal ganglion cells (n = 10). The original frozen-section biopsy, determining the level of the pull-through, only sampled the seromuscular layer in 3 children, leading to misdiagnosis. Reoperations involved a transanal resection (n = 15) and a posterior sagittal approach (n = 1). In all cases, obstructive symptoms were resolved, and no patient has had recurrent enterocolitis. CONCLUSION: Patients' post pull-through with recurrent obstructive symptoms may have residual aganglionosis or transition-zone bowel. Reoperation can result in the resolution of these symptoms. A full-thickness biopsy at the time of the initial pull-through to include the mucosa and submucosa may increase the possibility of identifying hypertrophic nerves. PMID- 21292086 TI - Necrotizing enterocolitis: early conventional and fluorescein laparoscopic assessment. AB - AIM: The clinical and radiological diagnosis of necrotizing enterocolitis (NEC) can be difficult. When radiological evidence is present, severity and complications, such as perforation and full-thickness necrosis, often may not be obvious. This study aims to establish early signs of full-thickness necrosis or perforation by using standard and fluorescein laparoscopy before clinical deterioration of patients occurs. PATIENTS AND METHODS: Thirteen patients with preoperative presumed clinical and/or radiological diagnosis of NEC underwent laparoscopy. A 4.7-mm umbilical or left upper quadrant camera port was inserted by using the open method. The abdominal cavity was inspected for bowel ischemia, fibrin, adhesion formation, and presence of free intestinal contents. If necessary, one or two 3-mm working ports were inserted for manipulation of bowel. RESULTS: Median age of 13 patients was 17 (3-38) days. Their median weight was 1160 (910-2415) g. The first 5 infants had standard laparoscopy only, with the next 8 having fluorescein-aided assessment added to the laparoscopy. Standard laparoscopy identified perforation in 5 patients and gangrenous bowel in 2. One patient was found to have chyle ascites, and 1 patient had no abnormal findings on laparoscopy. Fluorescein identified gangrenous bowel in 3 additional patients. Laparotomy and necessary surgical intervention were performed in all 10 patients with positive laparoscopy findings. Eleven patients survived and were doing well at a median of 9 (range, 6-39) months of follow-up. CONCLUSION: Laparoscopy helps to improve assessment of patients with a diagnosis of NEC. It allows for early identification of perforation and necrosis. Where ischemia is suspected, fluorescein laparoscopy may have an added benefit in identifying necrotic segments. PMID- 21292087 TI - Intraperitoneal microdialysis in the postoperative surveillance after surgery for necrotizing enterocolitis: a preliminary report. AB - BACKGROUND/PURPOSE: The aim of the present pilot study was to evaluate the safety and clinical application of intraperitoneal microdialysis (MD) in preterm infants operated on for necrotizing enterocolitis (NEC). METHODS: Fourteen infants underwent MD. Two were excluded from analysis: 1 because of catheter malfunction and 1 because of fatal outcome immediately after surgery. The median MD time was 122 hours. Samples were collected every 4 hours, and the concentration of glucose, lactate, pyruvate, and glycerol was measured. RESULTS: Three infants were reoperated on: 2 because of recurrent NEC and 1 because of ileal stenosis. In the 2 cases with recurrent NEC, changes in MD variables were found. Another had a prolonged postoperative period owing to diffuse fecal peritonitis. The values of MD normalized along with the return of bowel function. In 8 infants, the postoperative course was uncomplicated. The results of peritoneal MD in patients with complications were significantly different from those with an uncomplicated course (lactate/pyruvate ratio and glucose concentration). CONCLUSION: Peritoneal MD is a safe procedure and an applicable method in surveillance of the metabolic and inflammatory changes in the peritoneal cavity after surgery for NEC. Larger series are needed to evaluate the clinical significance and use of this method. PMID- 21292088 TI - The effect of hepatocyte growth factor on gene transcription during intestinal adaptation. AB - PURPOSE: Previously, we investigated the physiologic effects of hepatocyte growth factor (HGF) on intestinal adaptation using a massive small bowel resection (MSBR) rat model. To correlate these altered physiologic changes with gene alterations, we used microarray technology at 7, 14, and 21 days after MSBR. METHODS: Forty-five adult female rats were divided into 3 groups and underwent 70% MSBR, MSBR + HGF (intravenous 150 MUg/kg per day), or sham operation (control). Five animals per group were killed at each time point. Ileal mucosa was harvested and RNA extracted. Rat Gene Chips and Expression Console software (Affymetrix, Santa Clara, CA) were used. Statistical analysis was done by analysis of variance using Partek Genomics Suite (Partek, Inc, St Louis, MO). Results were significant if fold change was more than 2 or less than -2, with P < .05. RESULTS: Compared with the control group, MSBR group had significant increases in up-regulated and down-regulated genes. The MSBR-HGF group had further increases in up-regulated and down-regulated genes compared with the MSBR group. At 7 days, 6 cellular hypertrophy families had 30 genes up-regulated, and HGF up-regulated an additional 14 genes. At 21 days, 5 hyperplasia gene families had 32 up-regulated genes. Hepatocyte growth factor up-regulated an additional 16 genes. CONCLUSIONS: Microarray analysis of intestinal adaptation identified an early emphasis on hypertrophy and later emphasis on hyperplasia. This is the first demonstration that the effect of HGF on intestinal adaptation is recruitment of more genes rather than an increase in the fold change of already up-regulated genes. PMID- 21292089 TI - Recent trends in the use of antibiotic prophylaxis in pediatric surgery. AB - AIMS: The use of surgical antibiotic prophylaxis (AP) in children is poorly characterized. The aims of this study were to examine (1) trends in the use of AP for commonly performed operations, (2) appropriateness in the context of available guidelines, and (3) adverse events potentially attributable to AP. METHODS: We conducted a 5-year retrospective analysis of 22 children's hospitals (January 2005-March 2009) for all patients younger than 18 years who underwent 1 of the 40 commonly performed general and urological procedures. Indications for AP were defined by published specialty-specific guidelines. Clostridium difficile infection and surrogate events for drug allergy (diphenhydramine and epinephrine administrations) were examined as potential antibiotic-associated adverse events. RESULTS: Procedures of 246,316 were identified, of which 25% met criteria for AP. Eighty-two percent of the children received antibiotics during procedures when AP was indicated (range, 60%-96% by hospital), and 40% of the patients received antibiotics when there was no indication (range, 10%-83%). The likelihood of receiving AP was significantly different between hospitals for all procedures examined (P < .0001 for each procedure). Adverse events were significantly more frequent in children receiving AP than in those who did not (odds ratio [95% confidence interval] C difficile: 18.8 [6.9-51.5], P < .0001; epinephrine: 1.8 [1.7-2.0], P < .0001; diphenhydramine: 6.0 [5.6-6.5], P < .0001). CONCLUSIONS: Significant variation exists in the use of AP in the pediatric surgical population. Many children do not receive AP when indicated, and an even greater proportion may receive antibiotics when there is no indication. These findings may have profound implications from a public health perspective when extrapolated to all children undergoing surgical procedures. PMID- 21292090 TI - Use of tissue expanders in the repair of complex abdominal wall defects. AB - BACKGROUND/PURPOSE: Closure of abdominal wall defects in children poses a challenge for pediatric surgeons. We describe a technique using tissue expanders placed either intraperitoneally or in the abdominal wall to aid in the reconstruction of a variety of complex abdominal wall defects. METHODS: The tissue expanders are inserted under general anesthesia. Initial expansion is done in the operating room with attention to peak airway pressure, urine output, and end-tidal carbon dioxide. The expanders are inflated in the outpatient setting via percutaneous access until the calculated inflation volume is achieved. They are then removed; and definitive closure is accomplished using a combination of native tissue flaps, abdominal component separation techniques, biomaterials, and synthetic material. RESULTS: Six children underwent tissue expansion for treatment of abdominal wall defects (omphalocele, n = 3), trauma (n = 1), and thoracopagus twins (n = 1 pair). One to 4 expanders were used per patient, with all having a successful reconstruction of their abdominal walls. Two to 3 operations were required to restore abdominal domain and consisted of expander insertion, removal with reconstruction, and possible revision of the reconstruction. CONCLUSIONS: Tissue expanders possess a broad range of applications for abdominal wall reconstruction and can be used in patients of all ages. PMID- 21292091 TI - The common fetal development of the mammary fat pad and gubernaculum. AB - BACKGROUND/AIMS: Recent work both from our laboratory and in marsupial models of testicular descent suggests a strong connection between the mammary line and gubernacular migration. This study investigated the relationship between the mammary fat pad (MFP) that underlies the mammary line and the developing gubernaculum by fluorescent immunohistochemistry. METHODS: Rats at E17 and E19 were fixed and processed for immunohistochemistry. Sagittal sections of male fetuses were stained with antibodies against androgen receptor (AR), prolyl-4 hydroxylase beta, Desmin, activated Notch-1, Jagged-1, and Ki-67. These were analyzed by fluorescent confocal microscopy. RESULTS: At E17 and E19, the MFP anlage forms a continuous distribution of fibroblasts passing immediately adjacent the gubernaculum to the future scrotum. Within this exists a distinct subpopulation of fibroblasts expressing AR distributed over the path of inguinoscrotal descent of the gubernaculum. Proliferation and Notch-1 signaling were similar throughout the MFP with differential Notch-1 signaling in the E19 gubernaculum. CONCLUSION: This investigation has identified the presence of a distinct AR-expressing subpopulation of MFP fibroblasts over the path of inguinoscrotal descent during the key androgenic programming window of this phase. This unique developmental pattern is consistent with a prime role for the MFP in testicular descent. PMID- 21292092 TI - The testicular regression syndrome--do remnants require routine excision? AB - AIM: Excision of testicular remnants is debatable in the scenario where hypoplastic vas and vessels can be seen entering a closed internal ring during laparoscopy for impalpable testes. We aimed to establish how frequently excised remnants have identifiable testicular tissue and, hence, malignant potential. METHODS: This study is a retrospective review of all excised testicular remnants in children with impalpable testis. Specimens that were excised for indications other than testicular regression syndrome were excluded. Pathology reports of excised specimens were reviewed, and the presence of multiple histologic features was noted. Histologic confirmation of testicular/paratesticular tissue required the presence of 1 or more of the following: seminiferous tubules, germ cells, Sertoli cells, Leydig cells, vas deferens, or epididymal structures. Malignancy potential was defined by the presence of germ cells or seminiferous tubules. All patients with seminiferous tubules were further examined by a single histopathologist. RESULTS: A total of 208 testicular remnants from 206 children were excised over the 11-year period (1999-2009). Histologic evidence confirmed excision of testicular/paratesticular tissue in 180 cases (87%). Seminiferous tubules were noted in 27 (15%), and germ cells were present in 19 (11%) cases. CONCLUSION: Viable germ cells were found in 11% of examined remnants, which, in our opinion, justifies their removal. PMID- 21292093 TI - The development and anatomy of the gubernaculum in Hoxa11 knockout mice. AB - BACKGROUND: The gubernaculum is central to testicular descent, with recent evidence suggesting that it elongates to the scrotum like a limb bud. Homeobox (Hox) genes involved in limb bud outgrowth are expressed within the gubernaculum. Mice with homozygous Hoxa11 gene deletions have bilateral cryptorchidism. This study investigated the precise anatomical effects of Hoxa11 mutation on the mouse gubernaculum. METHODS: The pelvises of postnatal mice (n = 46; days 1-10) with Hoxa11 knockout (n = 19), heterozygotes (n = 11), and wild-type (n = 16) mice were serially sectioned and stained with hematoxylin and eosin. Immunohistochemistry was performed for the presence of desmin. RESULTS: Hoxa11 mutant mice had intraabdominal cryptorchid testes and highly convoluted vas deferentia. The gubernacular bulbs were abnormal, with no "outgrowth" and persistence of the prenatal "swelling reaction." Desmin immunostaining revealed the lack of undifferentiated mesenchymal cells usually seen as a "swirl" within the bulb and decreased formation of cremaster muscle. CONCLUSIONS: Hoxa11 may be involved in forming the growth center seen as the "swirl" of mesenchyme within the gubernacular bulb, consistent with these cells being required for gubernacular elongation during testicular descent. Hoxa11 mutations may well contribute to failure of gubernacular migration in boys with cryptorchidism. PMID- 21292094 TI - Summary of the 57th British Association of Paediatric Surgeons congress in Aberdeen, July 22-24, 2010. AB - This is a summary of the 57th annual meeting of the British Association of Paediatric Surgeons held in Aberdeen, Scotland, 22nd to 24th of July, 2010. PMID- 21292095 TI - The simulation of an ex utero intrapartum procedure to extracorporeal membrane oxygenation. AB - We report a case of using simulation to aid in the performance of ex utero intrapartum treatment (EXIT) procedure to extracorporeal membrane oxygenation (ECMO). A primigravid with a fetus who was diagnosed with hypoplastic left heart syndrome was scheduled for an EXIT to ECMO procedure to be done by members of her obstetrical and neonatal teams. It would be the first time any of the members of the 2 teams would work together. Simulation was used to allow all involved parties to experience the procedure before the live operation. In addition, the simulation enabled the interdisciplinary teams to work with each other, identify possible complications, and further plan the coordination during the event. The EXIT to ECMO surgery was completed successfully. The use of low-fidelity, cost effective simulation during a surgical rehearsal can give a surgical team critical advantage when performing a rare and/or complex procedure. PMID- 21292096 TI - Surgical treatment of esophagogastric dysfunction forty years after reverse gastric tube esophagoplasty for congenital esophageal anomaly. AB - BACKGROUND: In 1968, Burrington first described use of the reverse gastric tube esophagoplasty for esophageal replacement in children with esophageal atresia or acquired stenosis. There are few documented cases of long-term follow-up of these patients. CASE REPORT: We describe a 41-year-old female who presented with progressive dysphagia 40 years after reverse gastric tube for a congenital esophageal stenosis as an infant. Repeated endoscopic dilations were unsuccessful in relieving her symptoms, and she subsequently underwent a modified Ivor-Lewis esophagogastrectomy with resection of the reverse gastric tube and reconstruction using her remaining gastric remnant. CONCLUSIONS: This report describes what we believe to be the longest recorded follow-up after reverse gastric tube esophagoplasty and highlights the potential for long-term complications after surgery for congenital anomalies. PMID- 21292097 TI - Hydrostatic rectosigmoid perforation: a rare personal watercraft injury. AB - Personal watercrafts (PWC), also known as jet skis, seadoos, and wave-runners have risen in popularity since their introduction in the 1970s. Hydrostatic rectal injury is a rare presentation of passengers thrown off a PWC. The perforation of the rectum is owing to the excessive hydrostatic force of water exerted through the anal canal. We present the first case of rectosigmoid perforation secondary to PWC hydrostatic injury in Canada. A 14-year-old female passenger presented to the pediatric trauma center with severe abdominal pain and blood per rectum following a fall off the back of a PWC at a local lake. Computed tomography of the abdomen and pelvis demonstrated a laceration in the anterolateral rectal wall at the rectosigmoid junction with associated free intra peritoneal air and profuse free fluid. At exploratory laparotomy, a full thickness perforation was identified at the rectosigmoid junction. The rectum was oversewn as a Hartman pouch, and a proximal end colostomy was performed to divert the fecal stream. Management of traumatic pediatric rectal injuries involves detailed perineal examination with proctoscopy, and if warranted, exploratory laparotomy. Despite the rare occurrence of hydrostatic rectal perforations in Canada, it is a serious and potentially devastating injury. In the United States, the National Transportation Safety Board recommends wet suit bottoms for all pediatric PWC operators and passengers. In Canada, similar recommendations have not been made. The use of PWC in Canada is less common than in the US. However, it is steadily increasing, especially on local lakes. Education regarding potential injuries and prevention is recommended. PMID- 21292098 TI - Ultrasound diagnosis of peroneal nerve variant in a child with compressive mononeuropathy. AB - We report on a 6-year-old child presenting with subacute foot drop. Neurophysiologic and radiologic studies revealed a peroneal nerve compression secondary to fibular exostosis. Before undergoing surgical removal of the exostosis, the patient underwent further neurophysiologic and ultrasonographic evaluation that showed the presence of an accessory peroneal nerve branch that caused gastrocnemius involvement. Findings at surgery confirmed the supposed anatomical variant. Both nerve components were carefully preserved during the operative procedure. The association of ultrasonographic and neurophysiologic studies was crucial in identifying the etiopathologic mechanism and anatomical picture and provided clinicians and surgeons with important information in planning the procedure. PMID- 21292099 TI - Sialolipoma of the submandibular gland in a child. AB - Sialolipoma is a new variant of salivary gland lipoma that was first proposed by Nagao et al (Histopathology 2001;38:30-36). Three cases of submandibular gland sialolipoma have been previously reported in the English literature, all of which were in adults. We report an unusual case of sialolipoma of the submandibular gland in a 3-year-old boy. This is the first reported case of submandibular gland sialolipoma in a child. PMID- 21292100 TI - Laparoscopic excision of a rudimentary uterine horn in a child. AB - Unicornuate uterus with a rudimentary horn is the rarest congenital anomaly of the female genital system. It can result in a variety of gynecologic and obstetric complications. This case report is an acute presentation of a cavitated, noncommunicating, rudimentary horn in a premenarcheal girl. Successful laparoscopic excision was performed. The full extent of the anomaly was diagnosed by a combination of operative findings and postoperative magnetic resonance imaging. PMID- 21292101 TI - Abdominal wall ectopic testis mimicking spigelian hernia. AB - We encountered a patient with a swelling in the left lateral infraumbilical region and a left undescended testis. The appearance of the swelling was suggestive of a spigelian hernia. At operation, the swelling was actually an abdominal ectopic testis with associated inguinal hernia. This unusual finding led us to report this occurrence and present a brief review of the relevant literature. PMID- 21292102 TI - The epigastric heteropagus conjoined twins. AB - Conjoined twins are rare and are classified as symmetrical or asymmetrical, in which a member, the host (autosite), is near normal and bears the parasite, which is incomplete, smaller, and fully dependent for growth on it. This form of conjoined twins is referred to as heteropagus and when attached to the epigastrium of the autosite is called epigastric heteropagus. Only 44 cases of epigastric heteropagus twins have been previously reported in the world literature. We hereby report the successful separation of a pair of heteropagus twins. PMID- 21292103 TI - Laparoendoscopic single site orchiopexy. AB - We report a laparoendoscopic single site orchiopexy in a 2-year-old boy with a right nonpalpable testis. Diagnostic laparoscopy using a 5-mm port revealed a right intraabdominal testis. The 5-mm port site was extended to accommodate the smallest commercially available triport, and orchiopexy was performed. The operative time was 55 minutes, and the estimated blood loss was minimal. There were no complications, and surgical and cosmetic results were excellent. Laparoendoscopic single site surgery is a feasible technique for orchiopexy of the nonpalpable testis. PMID- 21292104 TI - Laparoscopic localization and microlaparotomy for focal isolated perforation in necrotizing enterocolitis: an alternative approach to a challenging problem. AB - BACKGROUND: Necrotizing enterocolitis has a wide clinical spectrum of manifestation. We report a novel method of managing focal isolated perforation in necrotizing enterocolitis by using diagnostic laparoscopy to localize the site of perforation and by making a microincision over the perforation to perform exteriorization or limited resection and primary anastomosis. METHODS: We included low-birth weight infants presenting with sudden clinical deterioration and pneumoperitoneum. Patients with gross abdominal wall signs were excluded on the probability that they had extensive disease. Diagnostic laparoscopy was performed using a 3.5-mm trocar and 1.9-mm telescope. A 1-cm incision was made over the site of perforation, and local surgical debridement was performed. RESULTS: There were 3 extremely low-birth weight patients (580, 700, and 780 g) and 1 larger infant (1.6 kg). In all cases, an isolated perforation was detected. None had widespread disease. The 3 smaller infants had exteriorization and enterostomies. The larger patient had resection and primary anastomosis. All patients recovered uneventfully. CONCLUSION: Diagnostic laparoscopy can be safely performed in extremely low-birth weight infants. It allows precise identification of the site of perforation to perform a limited microlaparotomy at this site, significantly reducing the surgical trauma of extensive bowel handling. We report a novel method of managing this vexing problem. PMID- 21292105 TI - Fibrin glue, hemophilia, and circumcision in low-income countries. PMID- 21292106 TI - Effective surveillance of gastroschisis and omphalocele: separate International Classification of Diseases, Ninth Revision codes! PMID- 21292107 TI - Primary congenital glaucoma in the developing world. PMID- 21292108 TI - Outcomes of goniotomy for primary congenital glaucoma in East Africa. AB - OBJECTIVE: To evaluate the effectiveness of goniotomy to treat primary congenital glaucoma in an east African population. DESIGN: A retrospective series using case records. For patients who underwent goniotomies in both eyes, only the first was analyzed. PARTICIPANTS: Forty-seven children undergoing goniotomy (47/80 operated eyes analyzed). Thirty-six children (77%) were male. Mean age was 19 months (range 1-204 months, standard deviation [SD] = 35). INTERVENTION: First goniotomy was performed from the temporal side. Repeat surgery, if necessary, was performed via nasal side approach and 100% ethanol-soaked cotton-tipped swabs were used to clear the corneal epithelium when necessary for angle visualization. MAIN OUTCOME MEASURES: Postoperative intraocular pressure (IOP) <21 mmHg was considered success. Potential risk factors for failure were analyzed. Quantitative visual acuities were measured with Cardiff acuity cards and Lea tests in older children. RESULTS: A total of 36 of 47 children (77%) returned for follow-up. Mean follow up interval was 12 months (range, 1-62 months; SD = 15). A total of 28 of 47 children (60%) had >3 months of follow-up, and 11 children had >1 year of follow up. A total of 12 of 47 eyes (26%) required repeat goniotomy. Three of these required further trabeculectomy with mitomycin C, 1 of which required eventual enucleation after failure to control IOP, enlargement, and pain. A total of 11 of 28 children (39%) with >3 months follow-up required repeat surgery. A total of 24 of 28 children (86%) with follow-up intervals of at least 3 months achieved postoperative IOPs of <21 mmHg. Mean IOPs decreased (t = 6.1, P < 0.0005) from 23.4 mmHg (SD = 5.3 mmHg) to 14.4 mmHg (SD = 7.6 mmHg). Only 1 predictor of failure to achieve successful control of IOP was identified: female gender (relative risk = 5.3, 95% confidence interval, 1.1-26.3). Corneas were clear in 4 of 47 eyes (8.5%) preoperatively and 32 of 41 eyes (78%) postoperatively. Of 25 children with preoperative and postoperative acuities measured, 22 (88%) recorded improvement. CONCLUSIONS: Preliminary results of goniotomy in an African population with advanced disease and late presentation are reasonably encouraging. Overall results are comparable with historical drainage procedures, with the advantage of preserving conjunctiva. Further studies are justified. PMID- 21292109 TI - Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. AB - BACKGROUND: The American Academy of Ophthalmology recommendations for screening of chloroquine (CQ) and hydroxychloroquine (HCQ) retinopathy were published in 2002, but improved screening tools and new knowledge about the prevalence of toxicity have appeared in the ensuing years. No treatment exists as yet for this disorder, so it is imperative that patients and their physicians be aware of the best practices for minimizing toxic damage. RISK OF TOXICITY: New data have shown that the risk of toxicity increases sharply toward 1% after 5 to 7 years of use, or a cumulative dose of 1000 g, of HCQ. The risk increases further with continued use of the drug. DOSAGE: The prior recommendation emphasized dosing by weight. However, most patients are routinely given 400 mg of HCQ daily (or 250 mg CQ). This dose is now considered acceptable, except for individuals of short stature, for whom the dose should be determined on the basis of ideal body weight to avoid overdosage. SCREENING SCHEDULE: A baseline examination is advised for patients starting these drugs to serve as a reference point and to rule out maculopathy, which might be a contraindication to their use. Annual screening should begin after 5 years (or sooner if there are unusual risk factors). SCREENING TESTS: Newer objective tests, such as multifocal electroretinogram (mfERG), spectral domain optical coherence tomography (SD-OCT), and fundus autofluorescence (FAF), can be more sensitive than visual fields. It is now recommended that along with 10-2 automated fields, at least one of these procedures be used for routine screening where available. When fields are performed independently, even the most subtle 10-2 field changes should be taken seriously and are an indication for evaluation by objective testing. Because mfERG testing is an objective test that evaluates function, it may be used in place of visual fields. Amsler grid testing is no longer recommended. Fundus examinations are advised for documentation, but visible bull's-eye maculopathy is a late change, and the goal of screening is to recognize toxicity at an earlier stage. COUNSELING: Patients should be aware of the risk of toxicity and the rationale for screening (to detect early changes and minimize visual loss, not necessarily to prevent it). The drugs should be stopped if possible when toxicity is recognized or strongly suspected, but this is a decision to be made in conjunction with patients and their medical physicians. PMID- 21292110 TI - Conjunctival lymphoproliferative disorder. PMID- 21292111 TI - Paraneoplastic conjunctival cicatrization. PMID- 21292112 TI - First DLEK series: 10-year follow-up. PMID- 21292114 TI - LASIK infectious keratitis. PMID- 21292116 TI - Lens implant opacification. PMID- 21292117 TI - Cataract surgical skill assessment. PMID- 21292118 TI - Microplasmin before vitrectomy. PMID- 21292120 TI - Double fovea artifact. PMID- 21292122 TI - Abusive head trauma. PMID- 21292123 TI - Stroke caused by left ventricular myxoma. PMID- 21292124 TI - Clinical, molecular, and genomic changes in response to a left ventricular assist device. AB - The use of left ventricular assist devices in treating patients with end-stage heart failure has increased significantly in recent years, both as a bridge to transplantation and as destination therapy in those who are ineligible for cardiac transplantation. This increase is based largely on the results of several recently completed clinical trials with the new second-generation continuous-flow devices that showed significant improvements in survival, functional capacity, and quality of life. Additional information on the use of the first- and second generation left ventricular assist devices has come from a recently released report spanning the years 2006 to 2009, from the Interagency Registry for Mechanically Assisted Circulatory Support, a National Heart, Lung, and Blood Institute-sponsored collaboration between the U.S. Food and Drug Administration, the Centers for Medicare and Medicaid Services, and the scientific community. The authors review the latest clinical trials and data from the registry, with tight integration of the landmark molecular, cellular, and genomic research that accompanies the reverse remodeling of the human heart in response to a left ventricular assist device and functional recovery that has been reported in a subset of these patients. PMID- 21292125 TI - With the "universal definition," measurement of creatine kinase-myocardial band rather than troponin allows more accurate diagnosis of periprocedural necrosis and infarction after coronary intervention. AB - OBJECTIVES: We aimed to assess the differential implications of creatine kinase myocardial band (CK-MB) and troponin measurement with the universal definition of periprocedural injury after percutaneous coronary intervention. BACKGROUND: Differentiation between definitions of periprocedural necrosis and periprocedural infarction has practical, sociological, and research implications. Troponin is the recommended biomarker, but there has been debate about the recommended diagnostic thresholds. METHODS: Thirty-two patients undergoing multivessel percutaneous coronary intervention and late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) imaging in a prospective study had cardiac troponin I, CK-MB, and inflammatory markers (C-reactive protein, serum amyloid A, myeloperoxidase, tumor necrosis factor alpha) measured at baseline, 1 h, 6 h, 12 h, and 24 h after the procedure. Three "periprocedural injury" groups were defined with the universal definition: G1: no injury (biomarker <99th percentile); G2: periprocedural necrosis (1 to 3 * 99th percentile); G3: myocardial infarction (MI) type 4a (>3 * 99th percentile). Differences in inflammatory profiles were analyzed. RESULTS: With CK-MB there were 17, 10, and 5 patients in groups 1, 2, and 3, respectively. Patients with CK-MB-defined MI type 4a closely approximated patients with new CMR-LGE injury. Groups defined with CK MB showed progressively increasing percentage change in C-reactive protein and serum amyloid A, reflecting increasing inflammatory response (p < 0.05). Using cardiac troponin I resulted in 26 patients defined as MI type 4a, but only a small minority had evidence of abnormality on CMR-LGE, and only 3 patients were defined as necrosis. No differences in inflammatory response were evident when groups were defined with troponin. CONCLUSIONS: Measuring CK-MB is more clinically relevant for diagnosing MI type 4a, when applying the universal definition. Current troponin thresholds are oversensitive with the arbitrary limit of 3 * 99th percentile failing to discriminate between periprocedural necrosis and MI type 4a. (Myocardial Injury following Coronary Artery bypass Surgery versus Angioplasty: a randomised controlled trial using biochemical markers and cardiovascular magnetic resonance imaging; ISRCTN25699844). PMID- 21292126 TI - A nail in the coffin of troponin measurements after percutaneous coronary intervention. PMID- 21292127 TI - Long-term prevention of stroke: a modern comparison of current carotid stenting and carotid endarterectomy. AB - OBJECTIVES: This study sought to evaluate long-term outcomes of carotid stenting (CAS) versus carotid endarterectomy (CEA) based on physician-guided indications. BACKGROUND: The issue regarding long-term outcome of CAS versus CEA in patients with carotid stenosis is clinically relevant but remains unsettled. METHODS: Consecutive patients (71% men, mean age 71.3 years) treated by CEA (n = 1,118) or CAS (n = 1,084) after a training phase were reviewed. Selection of treatment was based on better-suitability characteristics (morphology and clinical). Data were adjusted with propensity score analysis and stratified by symptoms, age, and sex. RESULTS: Thirty-day stroke/death rates were similar: 2.8% in CAS and 2.0% in CEA (p = 0.27). The risk was higher in symptomatic (3.5%) versus asymptomatic (2.0%) patients (p = 0.04) but without significant difference between CAS and CEA groups. Five-year survival rates were 82.0% in CAS and 87.7% in CEA (p = 0.05). Kaplan-Meier estimates of the composite of any periprocedural stroke/death and ipsilateral stroke at 5 years after the procedure were similar in all patients (4.7% vs. 3.7%; p = 0.4) and the subgroups of symptomatic (8.7% vs. 4.9%; p = 0.7) and asymptomatic (2.5% vs. 3.3%; p = 0.2) patients in CEA versus CAS, respectively. Cox analysis, adjusted by propensity score, identified statin treatment (p = 0.016) and symptomatic disease (p = 0.003) associated with the composite end point. There were no sex- or age-related significant outcome differences. CONCLUSIONS: When physicians use their clinical judgment to select the appropriate technique for carotid revascularization CAS can offer efficacy and durability comparable to CEA with benefits persisting at 5 years. PMID- 21292128 TI - Mechanical rescue of the heart in shock. PMID- 21292129 TI - Clinical characteristics, management, and outcomes of patients diagnosed with acute pulmonary embolism in the emergency department: initial report of EMPEROR (Multicenter Emergency Medicine Pulmonary Embolism in the Real World Registry). AB - OBJECTIVES: In a large U.S. sample, this study measured the presentation features, testing, treatment strategies, and outcomes of patients diagnosed with pulmonary embolism (PE) in the emergency department (ED). BACKGROUND: No data have quantified the demographics, clinical features, management, and outcomes of outpatients diagnosed with PE in the ED in a large, multicenter U.S. study. METHODS: Patients of any hemodynamic status were enrolled from the ED after confirmed acute PE or with a high clinical suspicion prompting anticoagulation before imaging for PE. Exclusions were inability to provide informed consent (where required) or unavailability for follow-up. RESULTS: A total of 1,880 patients with confirmed acute PE were enrolled from 22 U.S. EDs. Diagnosis of PE was based upon positive results of computerized tomographic pulmonary angiogram in most cases (n = 1,654 [88%]). Patients represented both sexes equally, and racial and ethnic composition paralleled the overall U.S. ED population. Most (79%) patients with PE were employed, and one-third were older than age 65 years. The mortality rate directly attributed to PE was 20 in 1,880 (1%; 95% confidence interval [CI]: 0% to 1.6%). Mortality from hemorrhage was 0.2%, and the all-cause 30-day mortality rate was 5.4% (95% CI: 4.4% to 6.6%). Only 3 of 20 patients with major PE that ultimately proved fatal had systemic anticoagulation initiated before diagnostic confirmation, and another 3 of these 20 received a fibrinolytic agent. CONCLUSIONS: Patients diagnosed with acute PE in U.S. EDs have high functional status, and their mortality rate is low. These registry data suggest that appropriate initial medical management of ED patients with severe PE with anticoagulation is poorly standardized and indicate a need for research to determine the appropriate threshold for empiric treatment when PE is suspected before diagnostic confirmation. PMID- 21292130 TI - Women with peripheral arterial disease experience faster functional decline than men with peripheral arterial disease. AB - OBJECTIVES: We hypothesized that women with lower extremity peripheral arterial disease (PAD) would have greater mobility loss and faster functional decline than men with PAD. BACKGROUND: Whether rates of mobility loss or functional decline differ between men and women with PAD is currently unknown. METHODS: Three hundred eighty men and women with PAD completed the 6-min walk, were assessed for mobility disability, and underwent measures of 4-m walking velocity at baseline and annually for up to 4 years. Computed tomography-assessed calf muscle characteristics were measured biannually. Outcomes included becoming unable to walk for 6 min continuously among participants who walked continuously for 6 min at baseline. Mobility loss was defined as becoming unable to walk for a quarter mile or to walk up and down 1 flight of stairs without assistance among those without baseline mobility disability. Results were adjusted for age, race, body mass index, physical activity, the ankle brachial index, comorbidities, and other confounders. RESULTS: At 4 years of follow-up, women were more likely to become unable to walk for 6 min continuously (hazard ratio: 2.30, 95% confidence interval: 1.30 to 4.06, p = 0.004), more likely to develop mobility disability (hazard ratio: 1.79, 95% confidence interval: 1.30 to 3.03, p = 0.030), and had faster declines in walking velocity (p = 0.022) and the distance achieved in the 6-min walk (p = 0.041) compared with men. Sex differences in functional decline were attenuated after additional adjustment for baseline sex differences in calf muscle area. CONCLUSIONS: Women with PAD have faster functional decline and greater mobility loss than men with PAD. These sex differences may be attributable to smaller baseline calf muscle area among women with PAD. PMID- 21292131 TI - Use of intravenous gamma globulin and corticosteroids in the treatment of maternal autoantibody-mediated cardiomyopathy. AB - OBJECTIVES: This study sought to evaluate the outcome of maternal autoantibody mediated fetal cardiomyopathy/endocardial fibroelastosis following intravenous gamma globulin (IVIG) and corticosteroid therapy. BACKGROUND: We have previously shown that 85% of fetuses and infants with maternal autoantibody-mediated fetal cardiomyopathy/endocardial fibroelastosis suffer demise or need for transplant. In an attempt to improve this outcome, in 1998, we began to empirically treat affected patients with IVIG and corticosteroids. METHODS: We reviewed the clinical records and echocardiograms of 20 affected patients encountered in our institutions and treated with IVIG and corticosteroids from 1998 to 2009. RESULTS: All 20 were initially referred at a median gestational age of 23 weeks (range 18 to 38 weeks). Nineteen mothers were anti-Ro antibody positive, 8 anti La antibody positive, and 7 had clinical autoimmune disease. Endocardial fibroelastosis was seen in 16 and was not obvious in 4 others with reduced ventricular function, and 16 (80%) had reduced or borderline ventricular shortening fraction (<=30%) before or after birth. Eighteen had atrioventricular block at referral (16 in 3 degrees ). During pregnancy, maternal IVIG was given in 9 and dexamethasone in 17. After birth, 17 infants received IVIG (n = 14) and/or corticosteroids (n = 15). Twelve underwent pacemaker implantation. Four with hydrops at presentation died perinatally, despite initial improvement in function in 3. At a median follow-up of 2.9 years (1.1 to 9.8 years), 16 (80%) patients are currently alive with normal systolic ventricular function and 6 are not paced. CONCLUSIONS: Treatment of maternal autoantibody-mediated fetal cardiomyopathy/endocardial fibroelastosis with IVIG and corticosteroids potentially improves the outcome of affected fetuses. Further studies are needed to determine the optimal dose and timing of IVIG administration. PMID- 21292132 TI - Early versus late functional outcome after successful percutaneous pulmonary valve implantation: are the acute effects of altered right ventricular loading all we can expect? AB - OBJECTIVES: The purpose of this study was to assess the potential of late positive functional remodeling after percutaneous pulmonary valve implantation (PPVI) in right ventricular outflow tract dysfunction. BACKGROUND: PPVI has been shown to impact acutely on biventricular function and exercise performance, but the potential for further late functional remodeling remains unknown. METHODS: Sixty-five patients with sustained hemodynamic effects of PPVI at 1 year were included. Patients were divided into 2 subgroups based on pre-procedural predominant pulmonary stenosis (PS) (n = 35) or predominant pulmonary regurgitation (PR) (n = 30). Data from magnetic resonance imaging and cardiopulmonary exercise testing were compared at 3 time points: before PPVI, within 1 month (early) and at 12 months (late) after PPVI. RESULTS: There was a significant decrease in right ventricle end-diastolic volume early after PPVI in both subgroups of patients. Right ventricle ejection fraction improved early only in the PS group (51 +/- 11% vs. 58 +/- 11% and 51 +/- 12% vs. 50 +/- 11%, p < 0.001 for PS, p = 0.13 for PR). Late after intervention, there were no further changes in magnetic resonance parameters in either group (right ventricle ejection fraction, 58 +/- 11% in the PS group and 52 +/- 11% in the PR group, p = 1.00 and p = 0.13, respectively). In the PS group at cardiopulmonary exercise testing, there was a significant improvement in peak oxygen uptake early (24 +/- 8 ml/kg/min vs. 27 +/- 9 ml/kg/min, p = 0.008), with no further significant change late (27 +/- 9 ml/kg/min, p = 1.00). In the PR group, no significant changes in peak oxygen uptake from early to late could be demonstrated (25 +/- 8 ml/kg/min vs. 25 +/- 8 ml/kg/min vs. 26 +/- 9 ml/kg/min, p = 0.48). CONCLUSIONS: In patients with a sustained hemodynamic result 1 year after PPVI, a prolonged phase of maintained cardiac function is observed. However, there is no evidence for further positive functional remodeling beyond the acute effects of PPVI. PMID- 21292133 TI - Favorable changes in cardiac geometry and function following gastric bypass surgery: 2-year follow-up in the Utah obesity study. AB - OBJECTIVES: The objective of this study was to test the hypothesis that gastric bypass surgery (GBS) would favorably impact cardiac remodeling and function. BACKGROUND: GBS is increasingly used to treat severe obesity, but there are limited outcome data. METHODS: We prospectively studied 423 severely obese patients undergoing GBS and a reference group of severely obese subjects that did not have surgery (n = 733). RESULTS: At a 2-year follow up, GBS subjects had a large reduction in body mass index compared with the reference group (-15.4 +/- 7.2 kg/m(2) vs. -0.03 +/- 4.0 kg/m(2); p < 0.0001), as well as significant reductions in waist circumference, systolic blood pressure, heart rate, triglycerides, low-density lipoprotein cholesterol, and insulin resistance. High density lipoprotein cholesterol increased. The GBS group had reductions in left ventricular (LV) mass index and right ventricular (RV) cavity area. Left atrial volume did not change in GBS but increased in reference subjects. In conjunction with reduced chamber sizes, GBS subjects also had increased LV midwall fractional shortening and RV fractional area change. In multivariable analysis, age, change in body mass index, severity of nocturnal hypoxemia, E/E', and sex were independently associated with LV mass index, whereas surgical status, change in waist circumference, and change in insulin resistance were not. CONCLUSIONS: Marked weight loss in patients undergoing GBS was associated with reverse cardiac remodeling and improved LV and RV function. These data support the use of bariatric surgery to prevent cardiovascular complications in severe obesity. PMID- 21292134 TI - Load-reducing therapy prevents development of arrhythmogenic right ventricular cardiomyopathy in plakoglobin-deficient mice. AB - OBJECTIVES: We used a murine model of arrhythmogenic right ventricular cardiomyopathy (ARVC) to test whether reducing ventricular load prevents or slows development of this cardiomyopathy. BACKGROUND: At present, no therapy exists to slow progression of ARVC. Genetically conferred dysfunction of the mechanical cell-cell connections, often associated with reduced expression of plakoglobin, is thought to cause ARVC. METHODS: Littermate pairs of heterozygous plakoglobin deficient mice (plako(+/-)) and wild-type (WT) littermates underwent 7 weeks of endurance training (daily swimming). Mice were randomized to blinded load reducing therapy (furosemide and nitrates) or placebo. RESULTS: Therapy prevented training-induced right ventricular (RV) enlargement in plako(+/-) mice (RV volume: untreated plako(+/-) 136 +/- 5 MUl; treated plako(+/-) 78 +/- 5 MUl; WT 81 +/- 5 MUl; p < 0.01 for untreated vs. WT and untreated vs. treated; mean +/- SEM). In isolated, Langendorff-perfused hearts, ventricular tachycardias (VTs) were more often induced in untreated plako(+/-) hearts (15 of 25), than in treated plako(+/-) hearts (5 of 19) or in WT hearts (6 of 21, both p < 0.05). Epicardial mapping of the RV identified macro-re-entry as the mechanism of ventricular tachycardia. The RV longitudinal conduction velocity was reduced in untreated but not in treated plako(+/-) mice (p < 0.01 for untreated vs. WT and untreated vs. treated). Myocardial concentration of phosphorylated connexin43 was lower in plako(+/-) hearts with VTs compared with hearts without VTs and was reduced in untreated plako(+/-) compared with WT (both p < 0.05). Plako(+/-) hearts showed reduced myocardial plakoglobin concentration, whereas beta-catenin and N-cadherin concentration was not changed. CONCLUSIONS: Load-reducing therapy prevents training-induced development of ARVC in plako(+/-) mice. PMID- 21292135 TI - Use of mouse models to evaluate novel therapeutic approaches to treatment of arrhythmogenic right ventricular cardiomyopathy the future is now. PMID- 21292136 TI - Isolated innominate artery from the main pulmonary artery in DiGeorge syndrome. PMID- 21292137 TI - Upper limits of physiological cardiac adaptation in ultramarathon runners. PMID- 21292139 TI - Pharmacogenetic testing for warfarin dosing still awaits validation. PMID- 21292140 TI - Foreword: Radiculopathy. PMID- 21292142 TI - Natural history of radiculopathy. AB - Radicular pain is a frequent complaint of patients presenting to outpatient primary care and musculoskeletal clinics. Most cases of radiculopathy are self limiting, and symptoms resolve over the course of weeks to months. There is spontaneous resolution of disc herniations, and clinical improvement correlates with morphologic resolution. Knowledge of the natural history of radiculopathy is crucial for the health care provider to appropriately counsel and treat patients with this disorder. Although each patient should be managed individually, the favorable prognosis of radiculopathy based on the natural history supports a conservative approach for the initial weeks to months for most patients. PMID- 21292143 TI - Physical examination in radiculopathy. AB - History and physical examination is the cornerstone in the appropriate diagnosis and treatment of any patient. A comprehensive physical examination is necessary to aid in determining distributions of symptoms and to lead one to the site of pathology. The aim of this article is to aid the clinician in distinguishing radiculopathy from other causes of neck and low back pain. Physical examination of the patient with suspected radiculopathy needs to be thorough and complete to make the most accurate diagnosis. Thorough knowledge of the evidence-based literature is beneficial in maximizing patient care, particularly in the light of health care reform. PMID- 21292144 TI - Imaging in radiculopathy. AB - All patients presenting with signs and symptoms of lumbar radiculopathy must undergo a thorough history taking and physical examination. Often, however, the diagnosis remains unclear; it is accurate anatomically, but the underlying cause of the lesion is not confirmed, or the symptoms are so severe that more information on the anatomy is required. Therefore, the next step in the diagnostic process is imaging studies. This article discusses imaging modalities, including plain radiographs, magnetic resonance imaging, computed tomography (CT), CT myelogram, selective nerve root block, and bone scan. PMID- 21292145 TI - The electrodiagnostic evaluation of radiculopathy. AB - Electrodiagnostic studies play an important role in the evaluation of radiculopathy. This article reviews the use of standard nerve conduction studies, late responses, evoked potentials, and needle electrode examination in the work up of lumbosacral and cervical radiculopathy. PMID- 21292146 TI - Mechanical diagnosis and therapy for radiculopathy. AB - Despite its classic clinical presentation, and even when confirmed by compatible imaging findings of a herniated disc, the radiculopathy diagnosis provides only limited assistance for making decisions about treatment. The 2003 Medicare data revealed an eightfold variation in the rates of lumbar laminectomy and discectomy across geographic regions. In an effort to address this uncertainty in care, this article describes the management paradigm known as Mechanical Diagnosis and Therapy and its usefulness in decision-making for patients with lumbar radiculopathies, and reviews the relevant literature. PMID- 21292147 TI - The role of core stabilization in lumbosacral radiculopathy. AB - Lumbosacral radiculopathy is relatively common, and most cases resolve with appropriate conservative management. Along with pain control, the mainstay of treatment is a comprehensive rehabilitation program to correct for biomechanical factors that adversely affect spinal stability and predispose the patient to recurrent pain. Developing an appropriate treatment plan depends on thorough understanding of the structures providing core stability and the exercises to correct identifiable deficits. A comprehensive rehabilitation program includes postural training, muscle reactivation, correction of flexibility and strength deficits, and subsequent progression to functional exercises. This article reviews the current concepts regarding core stability and rehabilitation in lumbosacral radiculopathy. PMID- 21292148 TI - Spinal manipulation or mobilization for radiculopathy: a systematic review. AB - In this systematic review, we present a comprehensive and up-to-date systematic review of the literature as it relates to the efficacy and effectiveness of spinal manipulation or mobilization in the management of cervical, thoracic, and lumbar-related extremity pain. There is moderate quality evidence that spinal manipulation is effective for the treatment of acute lumbar radiculopathy. The quality of evidence for chronic lumbar spine-related extremity symptoms and cervical spine-related extremity symptoms of any duration is low or very low. At present, no evidence exists for the treatment of thoracic radiculopathy. Future high-quality studies should address these conditions. PMID- 21292149 TI - Pharmaceutical therapy for radiculopathy. AB - Pharmaceutical treatments for radiculopathy include opioid, antiinflammatory (steroidal and nonsteroidal), neuromodulating, topical, and adjuvant treatments. These medications act locally, peripherally, or centrally on the neural axis. This article reviews the history of medication use for radiculopathy and the available literature along with the breadth of current treatment and indications. PMID- 21292150 TI - The efficacy of lumbar epidural steroid injections: transforaminal, interlaminar, and caudal approaches. AB - Conservative management of low back pain includes the use of lumbar epidural steroid injections, which have become increasingly more popular in the last 20 years. The body of literature regarding the efficacy of these injections is vast, conflicting, and difficult to summarize. This article reviews the updated evidence for efficacy and the indications for these injections. PMID- 21292151 TI - Epidural steroid injections for cervical radiculopathy. AB - Epidural steroid injection (ESI) has been used to treat cervical radiculopathy for several decades. Generally, available studies demonstrate favorable results, although definitive evidence of efficacy is lacking. ESIs are not considered a first line treatment and are undertaken after non-interventional treatments have been adequately provided. In the cervical spine, where evidence of potential benefit is moderate and there is risk of major complication, non-interventional care is even more germane. This article reviews the available literature regarding risks and efficacy of ESIs for cervical radiculopathy, and aims to guide practitioners in treatment decisions for individual patients. PMID- 21292152 TI - Surgical treatment and outcomes of lumbar radiculopathy. AB - Lumbar disk herniation is a significant cause of lumbar radiculopathy and results in billions of dollars in health care expenditure. Herniated lumbar disks cause mechanical and chemical irritation of the nerve roots leading to complaints of sciatica. Surgeons have several surgical options when approaching herniated disks, including various microsurgical procedures. The 3 most prominent studies to date on surgical and nonsurgical management of herniated disks agree on the efficacy of surgery over medical management in the short term but have some discrepancies when looking at long-term results. Cauda equina syndrome is a variation of lumbar disk herniation in which patients experience a combination of saddle anesthesia, abnormal lower extremity reflexes, and neurogenic bowel or bladder symptoms. PMID- 21292153 TI - Surgical treatment and outcomes of cervical radiculopathy. AB - Cervical radiculopathy, when resistant to conservative treatment, can require surgical treatment. There are numerous surgical treatment options available, such as posterior cervical foraminotomy, anterior cervical foraminotomy, anterior cervical diskectomy and fusion, and cervical disk arthroplasty. This article describes the surgical techniques, reviews their respective indications, and examines their outcomes. PMID- 21292155 TI - Ultrasensitivity and positive feedback to promote sharp mitotic entry. AB - In this issue, Trunnell et al. (2011) show that in mitotic entry the positive feedback that drives the activation of cyclin-dependent kinase (Cdk) involves a very ultrasensitive step of phosphorylation of Cdc25C by Cdk, thus strongly contributing to the switch-like behavior of this essential cell-cycle transition. PMID- 21292156 TI - Sweet business: Spot42 RNA networks with CRP to modulate catabolite repression. AB - Spot42 is a paradigm for small RNAs that fine-tune carbon metabolism. In this issue of Molecular Cell, Beisel and Storz (2011) reveal that this conserved RNA acts through a multioutput feedforward loop to modulate the global dynamics of sugar consumption. PMID- 21292157 TI - Peptides in the ribosomal tunnel talk back. AB - In this issue of Molecular Cell, Ramu et al. demonstrate that nascent peptides located within the ribosomal tunnel can talk back to the peptidyl transferase center to induce translational stalling by restricting the species of aminoacyl tRNAs that can bind there. PMID- 21292158 TI - Single-molecule studies of RNA polymerase: one singular sensation, every little step it takes. AB - Transcription is the first of many biochemical steps that turn the genetic information found in DNA into the proteins responsible for driving cellular processes. In this review, we highlight certain advantages of single-molecule techniques in the study of prokaryotic and eukaryotic transcription, and the specific ways in which these techniques complement conventional, ensemble-based biochemistry. We focus on recent literature, highlighting examples where single molecule methods have provided fresh insights into mechanism. We also present recent technological advances and outline future directions in the field. PMID- 21292159 TI - Ultrasensitivity in the Regulation of Cdc25C by Cdk1. AB - Cdc25C is a critical component of the interlinked positive and double-negative feedback loops that constitute the bistable mitotic trigger. Computational studies have indicated that the trigger's bistability should be more robust if the individual legs of the loops exhibit ultrasensitive responses. Here, we show that in Xenopus extracts two measures of Cdc25C activation (hyperphosphorylation and Ser 287 dephosphorylation) are highly ultrasensitive functions of the Cdk1 activity; estimated Hill coefficients were 11 to 32. Some of Cdc25C's ultrasensitivity can be reconstituted in vitro with purified components, and the reconstituted ultrasensitivity depends upon multisite phosphorylation. The response functions determined here for Cdc25C and previously for Wee1A allow us to formulate a simple mathematical model of the transition between interphase and mitosis. The model shows how the continuously variable regulators of mitosis work collectively to generate a switch-like, hysteretic response. PMID- 21292160 TI - Viral-mediated noisy gene expression reveals biphasic E2f1 response to MYC. AB - Gene expression mediated by viral vectors is subject to cell-to-cell variability, which limits the accuracy of gene delivery. When coupled with single-cell measurements, however, such variability provides an efficient means to quantify signaling dynamics in mammalian cells. Here, we illustrate the utility of this approach by mapping the E2f1 response to MYC, serum stimulation, or both. Our results revealed an underappreciated mode of gene regulation: E2f1 expression first increased, then decreased as MYC input increased. This biphasic pattern was also reflected in other nodes of the network, including the miR-17-92 microRNA cluster and p19Arf. A mathematical model of the network successfully predicted modulation of the biphasic E2F response by serum and a CDK inhibitor. In addition to demonstrating how noise can be exploited to probe signaling dynamics, our results reveal how coordination of the MYC/RB/E2F pathway enables dynamic discrimination of aberrant and normal levels of growth stimulation. PMID- 21292161 TI - The base-pairing RNA spot 42 participates in a multioutput feedforward loop to help enact catabolite repression in Escherichia coli. AB - Bacteria selectively consume some carbon sources over others through a regulatory mechanism termed catabolite repression. Here, we show that the base-pairing RNA Spot 42 plays a broad role in catabolite repression in Escherichia coli by directly repressing genes involved in central and secondary metabolism, redox balancing, and the consumption of diverse nonpreferred carbon sources. Many of the genes repressed by Spot 42 are transcriptionally activated by the global regulator CRP. Since CRP represses Spot 42, these regulators participate in a specific regulatory circuit called a multioutput feedforward loop. We found that this loop can reduce leaky expression of target genes in the presence of glucose and can maintain repression of target genes under changing nutrient conditions. Our results suggest that base-pairing RNAs in feedforward loops can help shape the steady-state levels and dynamics of gene expression. PMID- 21292162 TI - p38 MAPK controls prothrombin expression by regulated RNA 3' end processing. AB - Thrombin is a key protease involved in blood coagulation, complement activation, inflammation, angiogenesis, and tumor invasion. Although induced in many (patho )physiological conditions, the underlying mechanisms controlling prothrombin expression remained enigmatic. We have now discovered that prothrombin expression is regulated by a posttranscriptional regulatory mechanism responding to stress and inflammation. This mechanism is triggered by external stimuli that activate p38 MAPK. In turn, p38 MAPK upmodulates canonical 3' end processing components and phosphorylates the RNA-binding proteins FBP2 and FBP3, which inhibit 3' end processing of mRNAs, such as prothrombin mRNA, that bear a defined upstream sequence element (USE) in their 3'UTRs. Upon phosphorylation, FBP2 and FBP3 dissociate from the USE, making it accessible to proteins that stimulate 3' end processing. We provide in vivo evidence suggesting the importance of this mechanism in inflammatory hypercoagulation and tumor invasion. Regulated 3' end processing thus emerges as a key mechanism of gene regulation with broad biological and medical implications. PMID- 21292163 TI - Structural basis for dimerization and activity of human PAPD1, a noncanonical poly(A) polymerase. AB - Poly(A) polymerases (PAPs) are found in most living organisms and have important roles in RNA function and metabolism. Here, we report the crystal structure of human PAPD1, a noncanonical PAP that can polyadenylate RNAs in the mitochondria (also known as mtPAP) and oligouridylate histone mRNAs (TUTase1). The overall structure of the palm and fingers domains is similar to that in the canonical PAPs. The active site is located at the interface between the two domains, with a large pocket that can accommodate the substrates. The structure reveals the presence of a previously unrecognized domain in the N-terminal region of PAPD1, with a backbone fold that is similar to that of RNP-type RNA binding domains. This domain (named the RL domain), together with a beta-arm insertion in the palm domain, contributes to dimerization of PAPD1. Surprisingly, our mutagenesis and biochemical studies show that dimerization is required for the catalytic activity of PAPD1. PMID- 21292164 TI - Nascent peptide in the ribosome exit tunnel affects functional properties of the A-site of the peptidyl transferase center. AB - The ability to monitor the nascent peptide structure and to respond functionally to specific nascent peptide sequences is a fundamental property of the ribosome. An extreme manifestation of such response is nascent peptide-dependent ribosome stalling, involved in the regulation of gene expression. The molecular mechanisms of programmed translation arrest are unclear. By analyzing ribosome stalling at the regulatory cistron of the antibiotic resistance gene ermA, we uncovered a carefully orchestrated cooperation between the ribosomal exit tunnel and the A site of the peptidyl transferase center (PTC) in halting translation. The presence of an inducing antibiotic and a specific nascent peptide in the exit tunnel abrogate the ability of the PTC to catalyze peptide bond formation with a particular subset of amino acids. The extent of the conferred A-site selectivity is modulated by the C-terminal segment of the nascent peptide, where the third from-last residue plays a critical role. PMID- 21292165 TI - The structural basis for tight control of PP2A methylation and function by LCMT 1. AB - Proper formation of protein phosphatase 2A (PP2A) holoenzymes is essential for the fitness of all eukaryotic cells. Carboxyl methylation of the PP2A catalytic subunit plays a critical role in regulating holoenzyme assembly; methylation is catalyzed by PP2A-specific methyltransferase LCMT-1, an enzyme required for cell survival. We determined crystal structures of human LCMT-1 in isolation and in complex with PP2A stabilized by a cofactor mimic. The structures show that the LCMT-1 active-site pocket recognizes the carboxyl terminus of PP2A, and, interestingly, the PP2A active site makes extensive contacts to LCMT-1. We demonstrated that activation of the PP2A active site stimulates methylation, suggesting a mechanism for efficient conversion of activated PP2A into substrate specific holoenzymes, thus minimizing unregulated phosphatase activity or formation of inactive holoenzymes. A dominant-negative LCMT-1 mutant attenuates the cell cycle without causing cell death, likely by inhibiting uncontrolled phosphatase activity. Our studies suggested mechanisms of LCMT-1 in tight control of PP2A function, important for the cell cycle and cell survival. PMID- 21292166 TI - SecA interacts with ribosomes in order to facilitate posttranslational translocation in bacteria. AB - In Escherichia coli, translocation of exported proteins across the cytoplasmic membrane is dependent on the motor protein SecA and typically begins only after synthesis of the substrate has already been completed (i.e., posttranslationally). Thus, it has generally been assumed that the translocation machinery also recognizes its protein substrates posttranslationally. Here we report a specific interaction between SecA and the ribosome at a site near the polypeptide exit channel. This interaction is mediated by conserved motifs in SecA and ribosomal protein L23, and partial disruption of this interaction in vivo by introducing mutations into the genes encoding SecA or L23 affects the efficiency of translocation by the posttranslational pathway. Based on these findings, we propose that SecA could interact with its nascent substrates during translation in order to efficiently channel them into the "posttranslational" translocation pathway. PMID- 21292167 TI - Linear ubiquitin assembly complex negatively regulates RIG-I- and TRIM25-mediated type I interferon induction. AB - Upon detection of viral RNA, retinoic acid-inducible gene I (RIG-I) undergoes TRIM25-mediated K63-linked ubiquitination, leading to type I interferon (IFN) production. In this study, we demonstrate that the linear ubiquitin assembly complex (LUBAC), comprised of two RING-IBR-RING (RBR)-containing E3 ligases, HOIL 1L and HOIP, independently targets TRIM25 and RIG-I to effectively suppress virus induced IFN production. RBR E3 ligase domains of HOIL-1L and HOIP bind and induce proteasomal degradation of TRIM25, whereas the NZF domain of HOIL-1L competes with TRIM25 for RIG-I binding. Consequently, both actions by the HOIL-1L/HOIP LUBAC potently inhibit RIG-I ubiquitination and antiviral activity, but in a mechanistically separate manner. Conversely, the genetic deletion or depletion of HOIL-1L and HOIP robustly enhances virus-induced type I IFN production. Taken together, the HOIL-1L/HOIP LUBAC specifically suppresses RIG-I ubiquitination and activation by inducing TRIM25 degradation and inhibiting TRIM25 interaction with RIG-I, resulting in the comprehensive suppression of the IFN-mediated antiviral signaling pathway. PMID- 21292168 TI - A randomized, placebo-controlled phase 3 trial (Study SB-767905/013) of alvimopan for opioid-induced bowel dysfunction in patients with non-cancer pain. AB - The balance between the pain relief provided by opioid analgesics and the side effects caused by such agents is of particular significance to patients who take opioids for the long-term relief of non-cancer pain. The spectrum of signs and symptoms affecting the gastrointestinal (GI) tract associated with opioid use is known as opioid-induced bowel dysfunction. Alvimopan is an orally administered, systemically available, peripherally acting mu-opioid receptor (PAM-OR) antagonist, approved in the US for the management of postoperative ileus in patients undergoing bowel resection (short-term, in-hospital use only). Alvimopan was under clinical development for long-term treatment of opioid-induced constipation (OIC) but this program has been discontinued. This double-blind, placebo-controlled trial, part of the former OIC development program, enrolled patients (N = 485) receiving opioids for non-cancer pain. Patients were randomized to receive alvimopan .5 mg once daily, alvimopan .5 mg twice daily, or placebo, for 12 weeks. The primary efficacy endpoint was the proportion of patients who experienced >= 3 spontaneous bowel movements (SBMs; bowel movements with no laxative use in the previous 24 hours) per week over the treatment period, and an average increase from baseline of >= 1 SBM per week. There were greater proportions of SBM responders in both alvimopan treatment groups (63% in both groups) compared with placebo (56%), although these differences were not statistically significant. Secondary efficacy analyses indicated that alvimopan was numerically superior to placebo in improving opioid-induced bowel dysfunction symptoms and patients' global assessment of opioid-induced bowel dysfunction, and reduced the requirement for rescue laxatives. Active treatment was well tolerated and alvimopan did not antagonize opioid analgesia. PERSPECTIVE: Although the primary endpoint was not met in this study, the magnitude of alvimopan-induced improvements versus baseline, together with previous study results, suggest that a PAM-OR antagonist has the potential to improve OIC. PMID- 21292169 TI - A randomized, placebo-controlled phase 3 trial (Study SB-767905/012) of alvimopan for opioid-induced bowel dysfunction in patients with non-cancer pain. AB - Gastrointestinal (GI) side effects are common with opioid medication, and constipation affects ~40% of patients. Such symptoms considerably impair patients' quality of life. Alvimopan is an orally administered, systemically available, peripherally acting mu-opioid receptor (PAM-OR) antagonist approved in the US for short-term, in-hospital management of postoperative ileus in patients undergoing bowel resection. This double-blind, placebo-controlled trial was conducted as part of a recently discontinued clinical program, in which alvimopan was being developed for opioid-induced constipation (OIC). Patients (N = 518) receiving opioids for non-cancer pain were randomized to receive alvimopan .5 mg once daily, alvimopan .5 mg twice daily, or placebo for 12 weeks. The primary efficacy endpoint was the proportion of patients experiencing >= 3 spontaneous bowel movements (SBMs; bowel movements with no laxative use in the previous 24 hours) per week over the treatment period and an average increase from baseline of >= 1 SBM per week. A significantly greater proportion of patients in the alvimopan .5 mg twice-daily group met the primary endpoint compared with placebo (72% versus 48%, P < .001). Treatment with alvimopan twice daily improved a number of other symptoms compared with placebo and reduced the requirement for rescue laxative use. The opioid-induced bowel dysfunction Symptoms Improvement Scale (SIS) responder rate was 40.4% in the alvimopan .5 mg twice daily group, versus 18.6% with placebo (P < .001). In general, alvimopan .5 mg once daily produced qualitatively similar but numerically smaller responses than twice-daily treatment. Active treatment did not increase the requirement for opioid medication or increase average pain intensity scores. Over the 12-week treatment period, alvimopan appeared to be well tolerated. PERSPECTIVE: These results demonstrate the potential for a PAM-OR antagonist to improve the symptoms of OIC without antagonizing opioid analgesia. PMID- 21292170 TI - Re: "an 'a la carte' academic radiology compensation plan: something for everyone". PMID- 21292171 TI - Re: "radiology practice in Kuwait: ambitions and obstacles". PMID- 21292174 TI - Re: "lexicon for uncertain times". PMID- 21292175 TI - Re: "managing incidental findings on abdominal CT: White Paper of the ACR Incidental Findings Committee". PMID- 21292177 TI - Transparency in leadership. PMID- 21292178 TI - The thrill of victory. PMID- 21292179 TI - Boston Med: the untold stories. PMID- 21292180 TI - Tips for incorporating quality improvement projects into a residency program curriculum. PMID- 21292181 TI - Unicorn ahead. PMID- 21292182 TI - ACR Appropriateness Criteria((r)) on suspected physical abuse-child. AB - The appropriate imaging for pediatric patients being evaluated for suspected physical abuse depends on the age of the child, the presence of neurologic signs and symptoms, evidence of thoracic or abdominopelvic injuries, and whether the injuries are discrepant with the clinical history. The clinical presentations reviewed consider these factors and provide evidence-based consensus recommendations by the ACR Appropriateness Criteria((r)) Expert Panel on Pediatric Imaging. PMID- 21292183 TI - Managing hospital-radiologist relationships: proceedings of the Tenth Annual ACR Forum. AB - The annual ACR Forum brings together a multidisciplinary group to discuss a topic of present and future importance to radiologists. The 2010 gathering was dedicated to radiologist-hospital relationships. This article summarizes the conversations and details the advice of attendees to the ACR as to what actions might best benefit radiologists and the specialty. PMID- 21292184 TI - Preventing another group from displacing your practice: perspectives from the 2010 AMCLC. AB - Most hospital-based radiology practices have enjoyed stable long-term relationships with the institutions they serve. Recently, however, an increasing number of hospitals have replaced established radiologists. In some cases, the incoming group provides only a small number of on-site radiologists and uses long distance teleradiology for the bulk of image interpretations. Such technology, along with changing market forces, places many practices at risk. A number of strategies to maintain and foster long-term service relationships were discussed by the ACR Council and are reviewed herein. PMID- 21292185 TI - Outsourcing to teleradiology companies: bad for radiology, bad for radiologists. AB - Outsourcing night and weekend call to teleradiology companies has become a common practice among private radiology groups. While this may lead to an easier lifestyle, the authors discuss the serious negative consequences for radiologists and the specialty as a whole. These include the likelihood of commoditization of the field, lowering of fees, displacement from hospital contracts and outpatient reading contracts, greater encroachment by other specialties, and lowering of quality. PMID- 21292186 TI - Charting a professional course: a review of mentorship in medicine. AB - Developing physicians require firm knowledge of the clinical science and technical procedures within their specialties, a knowledge base founded in residency and supplemented throughout training. However, the day-to-day practice of medicine demands the skillful balance of various leadership, administrative, educational, and research roles, and expertise that cannot be obtained from a textbook. This professional curriculum is increasingly being sought through mentorship, a relationship between a junior physician and an experienced advisor or mentor. The authors review the current literature for mentorship in medicine, including characteristics of successful mentors and their mentees, and the emerging role of formal institution-wide mentorship programs. PMID- 21292187 TI - A survey-based evaluation of the radiology residency interview process. AB - PURPOSE: The aim of this study was to assess the diagnostic radiology residency interview process and determine variability among programs in their approach to interviewing candidates. METHODS: A survey of the residency interview process was sent to diagnostic radiology program directors through an e-mail address list provided by the Association of Program Directors in Radiology. Questions addressed were (1) the number of applicants interviewed per residency position offered; (2) the number of interviews scheduled for each applicant on the interview day; (3) whether interviews were performed by staff members, residents, or both; and (4) whether interviewers were granted time away from clinical services to interview applicants. RESULTS: Two electronic mailings were sent to 313 individuals. Responses were received from 89 of 188 accredited diagnostic radiology residency programs (response rate, 47.3%). The average number of interviews per residency position was 12.6 (range, 3-28), with university-based programs interviewing significantly fewer candidates (mean, 11.5) than non university-based programs (mean, 15.3). The average number of individual interviews during the interview day was 3.9 (range, 1-8) per candidate at each program. Of responding programs, 69% of responding programs included residents in interviews, and 67% compensated their interviewing staff members with time off clinical service, with no statistical difference between large and small programs. CONCLUSION: There is a large amount of variability present in the residency interview process. Applicants to programs may have very different experiences while visiting programs. Further study of this variation may allow programs to optimize resource utilization while maintaining success in the match process. PMID- 21292188 TI - Using radiology to teach physiology. AB - BACKGROUND: Radiology is well poised to play an important role in the teaching of physiology, one of the core disciplines of medicine. Physiology is an absolutely foundational medical discipline that informs every diagnostic test and therapy physicians prescribe, and radiology teaches a deep understanding. METHODS: Radiologic case studies using pairs of radiologic cases, one illustrating normal physiology and the second illustrating pathophysiology, are presented. The presentation uses the 2 radiologic images (normal and pathophysiology) to focus on 4 broad physiologic principles that apply across all organ systems. These principles are (1) homeostasis, (2) biologic energy use, (3) structure-function relationships, and (4) communication. Two examples are given for each of the principles. RESULTS: Radiologic case studies teach the integrating principles. A demonstration of the first integrated principle, homeostasis, is given. For example, cerebral perfusion scintigraphy measures blood flow to the brain and can determine if flow is disrupted. Normal results will demonstrate the tracer in the arteries and veins during the flow phase and accumulation of the tracer within the brain during the delayed imaging. A second clinical example of homeostasis is erythropoiesis. Two radiologic examples of each principle (normal and pathologic) support the use of radiology to teach physiology. CONCLUSION: Radiologic case studies can illustrate physiologic principles in ways that can enhance students' grasp of both the physiology and its role in helping physicians take better care of patients. Working with actual images brings physiology to life; the learning is relevant and practical. PMID- 21292189 TI - Evidence requirements for innovative imaging devices: from concept to adoption. AB - Changes in the regulatory and reimbursement environment for advances in imaging in the United States are leading to increasing requirements for formal clinical evidence of efficacy, effectiveness, and safety. The authors describe 5 phases of an imaging product's lifecycle: design, regulatory clearance and approval, early adoption, reimbursement, and full adoption. Each phase has distinct needs for clinical evidence. With increasing costs of clinical evidence generation, the question of ownership of the responsibility to gather clinical evidence at each successive phase becomes important. Mismatch between the pace of advances in imaging technologies and the time required to do formal clinical trials to clear regulatory and reimbursement evidence requirements threatens patient access to the benefits of innovation such as reduction in exposure to radiation. Public and payer requirements for clinical evidence must also be evaluated for their impact on incremental design improvements, which have historically characterized advances in diagnostic imaging. PMID- 21292190 TI - New strategies for medical data mining, part 3: automated workflow analysis and optimization. AB - The practice of evidence-based medicine calls for the creation of "best practice" guidelines, leading to improved clinical outcomes. One of the primary factors limiting evidence-based medicine in radiology today is the relative paucity of standardized databases. The creation of standardized medical imaging databases offer the potential to enhance radiologist workflow and diagnostic accuracy through objective data-driven analytics, which can be categorized in accordance with specific variables relating to the individual examination, patient, provider, and technology being used. In addition to this "global" database analysis, "individual" radiologist workflow can be analyzed through the integration of electronic auditing tools into the PACS. The combination of these individual and global analyses can ultimately identify best practice patterns, which can be adapted to the individual attributes of end users and ultimately used in the creation of automated evidence-based medicine workflow templates. PMID- 21292191 TI - CMS incentive payments for meaningful use of health care IT for radiologists: will they fund the needed change? PMID- 21292192 TI - Early experience with electronic messaging tightly integrated within PACS. PMID- 21292193 TI - No protocol left behind: current clinical issues in CT protocols and dosimetry. PMID- 21292194 TI - John Evans. PMID- 21292195 TI - Ultrasonography in the evaluation of low-extremity deep vein thrombosis. PMID- 21292196 TI - Justifying the high prevalence of microalbuminuria for type 2 diabetic patients in Taiwan with conditional probability approach--a DEMAND II study. AB - BACKGROUND: To examine the prevalence of microalbuminuria (MAU) and chronic kidney disease as well as the correlation between MAU and renal and cardiovascular risks of Type 2 diabetes mellitus (T2DM) patients for public health policy making in Taiwan. METHODS: This was a multicenter, hospital-based, randomly selected, and cross-sectional study. T2DM patients aged 18-80 years without a known diagnosis of proteinuria were eligible. MAU was defined as urinary albumin-to-creatinine ratio (ACR) within 30-299 mg/g, and macroalbuminuria as that greater than or equal to 300 mg/g. Two positive out of three urinary screening results were required to make the diagnosis of MAU. The adjusted prevalence of MAU was calculated by conditional probability approach. RESULTS: 51.1% of the analyzed population (n=1,827) were women, with a mean (standard deviation) age of 59.16 years (11.19 years) and mean hemoglobin A1c (HbA1c) of 8.15% (1.83%). Median duration of DM history was 6 years (interquartile range, 3-11 years). The adjusted prevalence of MAU was 26.9%. Overall prevalence of chronic kidney disease Stage 3 or higher (estimated Glomerular filtration rate (eGFR) less than 60/mL/min/1.73 m2) was 13.8%. Only 4.7% of the T2DM patients had serum albumin test recorded and 68.7% with serum creatinine test recorded within the last 6 months. After adjustment for center and gender, the odds ratios for MAU or macroalbuminuria were 1.73 (95% CI, 1.27 2.36) for age greater than or equal to 60 years, 1.54 (1.13-2.10) for abnormal waist circumference, 1.10 (1.02-1.19) for every 1% increase in hemoglobin A1c, 1.91 (1.38-2.65) for higher systolic blood pressure, and 1.92 (1.19-3.07) for abnormal serum creatinine level. CONCLUSION: This study demonstrates the application of "conditional probability" method to justify the rationale of adopting two positive out of three urinary screening tests for the diagnosis of MAU. An adjusted prevalence rate of MAU as 26.9% is reported. These results may provide a basis for cost-benefit consideration in designing preventive and interventional policies in public health. Furthermore, the awareness and practice of early monitoring of MAU for DM patients should be strengthened. PMID- 21292197 TI - Kinetics and involvement of interleukin-17 in the outcome of peritonitis in nondiabetic patients undergoing peritoneal dialysis. AB - BACKGROUND: Peritonitis is the most serious complication of peritoneal dialysis (PD). We previously showed that high levels of interleukin (IL)-12 and IL-18 in PD effluents (PDE) during the early phase of peritonitis correlated with a predominant Type 1 immune response and a favorable outcome in PD-related peritonitis. To further clarify the longitudinal changes of peritoneal immunity during PD-related peritonitis, we examined the kinetic production of IL-17 in PDE during peritonitis. The correlation between the IL-17 expression pattern and peritonitis outcome was analyzed. METHODS: The levels of IL-17 were measured in PDE during various phases of peritonitis in 38 patients undergoing PD. The patients were divided into two groups, according to whether they had a rapid versus a delayed response to antibiotic treatment. RESULTS: The kinetic expression of IL-17, as measured by enzyme-linked immunosorbent assay, differed between the two groups. In the rapid response group, high level of IL-17 was detected in PDE initially and progressively decreased during treatment. In the delayed response group, IL-17 levels in PDE were persistently low throughout the whole course of treatment. In the early phase of peritonitis, the IL-17 levels in PDE were significantly higher in the rapid response group (p<0.05). CONCLUSION: These data suggested that local IL-17 production is part of a protective early immune response to PD-related peritonitis. High levels of IL-17 in PDE during the early phase of peritonitis correlated with a favorable outcome. Manipulation of IL-17 cytokine expression in patients with peritonitis may modulate peritoneal immune response and affect peritonitis outcome. PMID- 21292198 TI - The effects of Vaseline gauze strip, Merocel, and Nasopore on the formation of synechiae and excessive granulation tissue in the middle meatus and the incidence of major postoperative bleeding after endoscopic sinus surgery. AB - BACKGROUND: Endoscopic sinus surgery (ESS) has become the widely accepted procedure for the treatment of medically refractory chronic rhinosinusitis and nasal polyps. Nasal packing is usually placed after ESS to prevent synechia formation and postoperative bleeding and to support wound healing. The aim of this study was to evaluate the effects of three different nasal packing materials [Vaseline gauze strip, Merocel (Metronic Xomed, Jacksonville, FL, USA), and Nasopore (Polyganics, Rozenburglaan, Groningen, The Netherlands)] on the formation of synechiae and excessive granulation tissue in the middle meatus and incidence of major postoperative bleeding in patients who had undergone ESS. METHODS: A total of 626 patients (1,018 sides) who had undergone ESS were studied retrospectively. Each patient chose one of the three different nasal packing materials according to his or her own preference. The outcome variable was the formation of synechiae and excessive granulation tissue in the middle meatus, which was identified from the medical records of endoscopic evaluations performed 3-4 weeks and 10-12 weeks after surgery. Major postoperative bleeding within 2 weeks after the operation was also documented for analysis. Finally, multiple logistic regression models were used to confirm the results of this study. RESULTS: We did not observe significant intergroup differences in the effect on the formation of synechiae in the middle meatus. Nasopore packing showed a trend toward causing the formation of excessive granulation tissue during the early stages of wound healing (p=0.004). Patients who had received packing with Nasopore had a greater chance of undergoing readmission or additional packing because of major nasal bleeding within the first 2 weeks after the operation (p=0.03). Multivariable logistic regression models showed that Nasopore was a significant factor for the formation of excessive granulation tissue at 3-4 weeks after the operation (p=0.022) and for major postoperative nasal bleeding within the first 2 weeks after the operation (p=0.023). CONCLUSION: Among patients who had undergone ESS for rhinosinusitis with or without polyps, the incidence of synechiae and excessive granulation tissue in the middle meatus and major postoperative bleeding in the patients who received Vaseline gauze packing was equivalent to the incidence of these complications in the patients who received Merocel. Nasopore was not superior to the other two nonabsorbable packing materials. PMID- 21292199 TI - High-surgical-volume hospitals associated with better quality and lower cost of kidney transplantation in Taiwan. AB - BACKGROUND: Only a small proportion of patients with end-stage renal disease can receive kidney transplants because of insufficiency of kidney donors in Taiwan. Hospitals compete with each other for kidney transplant surgeries. This study examined the association between hospital surgical volume of kidney transplants and patients' outcomes and utilizations. METHODS: Claims data of all kidney transplants between 1996 and 2003 were retrieved from the National Health Insurance Research Database for analysis. Every kidney recipient was followed up for 3 years until the end of 2006. Hospitals were classified as high-surgical volume hospitals (HSVHs) if their total number of kidney transplants was 72 or more between 1996 and 2003; otherwise, they were grouped into the low-surgical volume hospitals (LSVHs). The differences in quality (infection rate, graft rejection rate, readmission rate, mortality, and survival rates of patients and transplanted grafts at 1, 2, and 3 years after surgery) and cost (length of stay, total transplant cost, and annual medical cost for 3 years) of kidney transplants were examined between the two groups. RESULTS: Totally, 1,060 kidney transplants were analyzed, 77% of which were conducted at 6 of 29 qualified hospitals. Compared with those performed at LSVHs, transplant surgeries at HSVHs were associated with lower bacteria (35.1% vs. 48.8%, p<0.001), fungus (0.2% vs. 1.3%, p=0.008), and cytomegalovirus (1.2% vs. 4.6%, p=0.003) infection; lower mortality (1.1% vs. 5.0%, p<0.001); and higher 1-, 2-, and 3-year survival rates for patients (96.3%, 94.1%, 93.5% vs. 91.2%, 87.1%, 85.4%, respectively, p<0.01) and for transplanted grafts (89.5%, 81.0%, 80.5% vs. 85.8%, 74.6%, 73.3%, respectively, p<0.015). The transplant cost was lower for HSVHs than for LSVHs (New Taiwan $221,977 vs. New Taiwan $257,992, p=0.018). CONCLUSION: Seventy-seven percent of kidney transplant surgeries were concentrated at six hospitals in Taiwan. There were significant differences in quality and cost between HSVHs and LSVHs. We suggest adopting volume-based strategies for nonurgent kidney transplants. PMID- 21292200 TI - The effect of cerebral monitoring on recovery after sevoflurane anesthesia in ambulatory setting in children: a comparison among bispectral index, A-line autoregressive index, and standard practice. AB - BACKGROUND: The bispectral index (BIS) and A-line autoregressive index (AAI) are electroencephalogram-derived monitoring indices of anesthesia. This study evaluated the efficacy of BIS- and AAI-guided sevoflurane anesthesia in children receiving ambulatory urologic surgeries. METHODS: One hundred sixty children (aged 3-12 years) undergoing ambulatory urologic surgery were randomized to receive sevoflurane anesthesia controlled either solely by clinical parameters (standard practice group), BIS-guided group within the BIS range of 40-60 (BIS group), or AAI-guided group within the AAI range of 15-30 (AAI group). The primary outcome was the recovery time, and the secondary outcome was the quality of recovery, including the incidence of emergency delirium measured by Pediatric Anesthesia Emergence Delirium score, incidence of postoperative nausea and vomiting, and parental satisfaction. RESULTS: Compared with the standard practice group, patients with BIS or AAI monitoring had shortened recovery time and consumed less sevoflurane. There were no significant differences in the incidences of emergence delirium, postoperative nausea and vomiting, or parental satisfaction among the three groups. CONCLUSION: BIS- and AAI- guided titration sevoflurane anesthesia could result in shortened recovery and reduced sevoflurane concentration and consumption without affecting the quality of recovery in children receiving ambulatory urologic surgery. The beneficial effects of AAI- and BIS-guided anesthesia in pediatric ambulatory surgeries are similar. PMID- 21292201 TI - Preserved motor-evoked potentials but without good motor recovery in a patient with decerebrate rigidity. AB - The corticospinal tract is not incriminated in decerebrate rigidity (DR). However, this has not yet been proven in humans. We applied transcranial magnetic stimulation (TMS) in a decerebrate patient to support the hypothesis. A patient suffering from pontine hemorrhage with the fourth ventricular extension was admitted unconscious and in a decerebrate posture. Five days later, she regained consciousness but remained in a decerebrate posture. Motor-evoked potentials (MEPs) to TMS were measured 1 week after she had regained consciousness, and this provoked muscle responses in her hands and feet bilaterally. During the follow up, the patient's muscle tone became persistently flaccid, although her strength increased to varying degrees in different body and limb muscles. She remained bedridden for 3 years after the stroke and could neither turn on the bed by herself nor perform skilled movements using her hands. The findings of TMS confirmed the animal studies in that the mechanism of decerebrate rigidity did not come through a damage of the corticospinal pathway. This also implies that a preserved corticospinal tract function cannot guarantee a good motor recovery in a stroke patient. PMID- 21292202 TI - Axillary artery thrombus and infective endocarditis in lupus. AB - Systemic lupus erythematosus is a chronic systemic autoimmune disease, often associated with severe infection. A female patient was referred for surgical treatment of infective endocarditis after being treated for systemic lupus erythematosus and lupus nephritis. She developed symptoms of left axillary artery occlusion before heart operation. Bulky fungal hyphae were noted on pathological examination of the surgically removed thrombi. The patient had an uncomplicated recovery after receiving high doses of antibiotics and subsequent mitral valve replacement. Either infective endocarditis or fungal thrombi may be secondary to systemic lupus erythematosus and impaired renal function. PMID- 21292203 TI - Imaging findings of primary urachal actinomycosis. AB - Primary actinomycosis in urachal remnant is documented rarely in the English literature. The disease is usually misdiagnosed as urachal carcinoma because of its infiltrating and enhancing natures. We illustrate a case of urachal actinomycosis with ultrasound, computed tomography, and magnetic resonance images. The clinical, radiological, and pathological findings are reviewed. Some imaging findings may help us to differentiate an inflammatory process from malignancy. PMID- 21292204 TI - Cytomegalovirus and herpes simplex virus as causes of bilateral anterior uveitis in an immunocompetent patient. AB - We report a case with two distinct clinical manifestations of bilateral anterior uveitis caused by two different members of the herpes virus group. A 72-year-old immunocompetent man, who had a documented history of two episodes of Posner Schlossman syndrome in the left eye, presented with multiple mutton-fat keratic precipitates and elevated intraocular pressure (IOP) in his right eye. Herpes simplex virus Type I DNA was detected by polymerase chain reaction in the aqueous humor of the right eye. One year later, the patient appeared with a few round and whitish keratic precipitates and elevated IOP in his left eye. Polymerase chain reaction analysis showed positive for cytomegalovirus in the aqueous humor of the left eye. During both episodes, the anterior uveitis subsided and IOP returned to normal after systemic and topical antiglaucomatous medication as well as topical steroid. PMID- 21292205 TI - Erythema Ab igne after footbath with Chinese herbal remedies. AB - Erythema ab igne (EAI) is a reticulated, telangiectatic, and hyperpigmented skin eruption resulting from chronic exposure to long-term moderate heat. The incidence has decreased substantially today because of the advent of modern central heating systems. Recently, we encountered a patient who developed EAI after 2 weeks of footbaths with Chinese herbal remedies, which she used to treat her acute ankle sprain. Alternative Chinese medicine, such as herbal footbath, is a prevalent medical practice to treat acute pains as well as many chronic musculoskeletal ailments among Chinese and Asian populations. It has also become increasingly popular in Western countries in the past decade. Herein, we would like to report an uncommon case of iatrogenic EAI caused by footbath and raise the attention of clinicians to such rare, potentially malignant-transforming, dermatosis. PMID- 21292206 TI - The countdown. PMID- 21292207 TI - A deficiency in knowledge of basic principles of laparoscopy among attendees of an advanced laparoscopic surgery course. AB - INTRODUCTION: Advanced laparoscopic courses serve as a comprehensive and popular Continuing Medical Education (CME) activity. Knowledge of basic laparoscopy is an assumed prerequisite for attendance at these courses. OBJECTIVE: To determine the baseline laparoscopic knowledge of attendees at an advanced laparoscopic surgical course. METHODS: A.17-question examination was designed using data from the basic laparoscopic quizzes on the Society of American Gastrointestinal Surgeons (SAGES) website (http://www.sages.org/education/quiz). The questions covered 4 realms of basic laparoscopy: access, pneumoperitoneum, camera navigation, and surgical instrumentation. The questionnaire was distributed to all attendees at an advanced laparoscopic course at the 2009 Canadian Surgical Forum organized by the Canadian Association of General Surgeons. RESULTS: Forty-three respondents completed the survey. Fifty-three percent (53%) of responders had been in practice for more than 10 years and 65% had over 5 years experience. Fifty-five percent (55%) [24/43] of respondents listed laparoscopic courses as the sole means of laparoscopic training. Sixty-one percent (61%) [28/43] were performing > 50 laparoscopic cases per year. The median score on the knowledge-based questions was 70.6% [12/17]. In terms of overall score, respondents with more than 5 years experience performed similarly to respondents with less than 5 years experience (73% correct answers). Interestingly, in a subgroup analysis, respondents performed well in camera skills and pneumoperitoneum-themed questions (84% correct answers) but performed poorly on questions pertaining to instrumentation or access (52% correct answers). CONCLUSION: Basic laparoscopic knowledge among the attendees of an advanced laparoscopic course is suboptimal. A review of basic principles of laparoscopy particularly pertaining to instrumentation and access should form part of these CME activities. PMID- 21292208 TI - A multi-institutional comparison of pediatric appendicitis outcomes between teaching and nonteaching hospitals. AB - OBJECTIVE: In this era of heightened emphasis on patient outcomes, it is important to document the effect of residents acting as the surgeon for a surgical procedure. This study compares the outcomes of appendicitis between teaching and nonteaching institutions. DESIGN: A retrospective review from 1998 to 2007 was performed. The study outcomes were postoperative morbidity and length of hospitalization (LOH). Data were analyzed using Wilcoxon rank-sum test and chi(2) analysis. SETTING: Two teaching institutions (each with its own General Surgery residency program) were compared with 10 nonteaching institutions. RESULTS: A total of 1472 patients were treated at the teaching institutions (mean age = 9.8 years, male = 63%), and 6431 patients were treated at the nonteaching institutions (mean age = 10.8 years, male = 62%). The perforated appendicitis rate was 37% at the teaching institutions and 30% at the nonteaching institutions (p < 0.0001). For nonperforated appendicitis, a higher rate of laparoscopic appendectomy was found at the nonteaching institutions versus the teaching institutions (39% vs 52%, p < 0.0001). Otherwise, no difference was noted in the rate of wound infection, postoperative abscess drainage, or readmissions between the institutions. The LOH was also similar. For perforated appendicitis, a lower wound infection (5.2% vs 8.2%, p = 0.03) and readmission (5.6% vs 9.7%, p = 0.004) rate was found at the teaching institutions. No differences were discovered in the incidence of postoperative abscess drainage or LOH between teaching versus nonteaching hospitals. Perforated appendicitis was managed nonoperatively more commonly at the teaching institutions (7.4% vs 12.8%, p = 0.0001). CONCLUSIONS: Postoperative morbidity was similar in children with nonperforated appendicitis and lower in children with perforated appendicitis at teaching institutions. LOH was similar between teaching and nonteaching institutions. Overall, the presence of surgical trainees had no adverse impact on the quality of care for children with appendicitis. PMID- 21292209 TI - Differences in public belief and reality in the care of operative patients in a teaching hospital. AB - OBJECTIVE: The accreditation Council for Graduate Medical Education (ACGME) restricts residents from working more than 80 hours per week averaged over a 4 week period. No such restriction exists, however, for attending surgeons. Little exploration has been done of the public's perception of the number of hours that surgeons work and how residents work with the staff surgeons at a teaching institution. METHODS: A survey was designed to study the public's belief on surgeon work hours and habits. The survey also asked their opinion on resident involvement. All patients and accompanying persons arriving through the Surgicare Center for elective procedures older than age 18 were surveyed. The overall survey responses were calculated, and the results then were stratified by sex, age, race, and education. RESULTS: Of the 1516 surveys distributed, 370 were completed and returned (24.4%). Of those responding, 91% believed that a work hour limit should be in place for surgeons, and 77% believed the limit should be 12 consecutive hours or less. Eighty-four percent of the population believed that limit should be in place on the hours/week that a surgeon works, and 68% believe that it should be 60 hours or less. Although 82% would reschedule if they knew their surgeon had less than 4 hours of sleep the night before their procedure, 79% trust their surgeon's judgment to cancel if he/she were too tired. Only 28% of those surveyed were aware whether a resident was involved in their care, and 14% were against resident involvement. Respondents also were asked if the attending surgeon deemed a resident capable, then what percent of the procedure should the resident be able to perform? Ninety-one percent of those surveyed believed that the attending should be present for the entire case, and 78% believed that they should not be able to schedule more than 1 procedure at any given time. CONCLUSIONS: These findings illustrate a difference between the public's beliefs in regard to the hours a surgeon should be permitted to work and the reality of a surgeon's work life. Although the public may not be aware of the surgeon's schedule at a given time, they do trust the surgeon would cancel if too fatigued. The majority surveyed were not aware of resident involvement, but they trusted the attending surgeon's judgment with deciding how much of the actual procedure he/she could perform. With work-hour restrictions and resident involvement continuing to evolve, keeping the public informed should be a priority. PMID- 21292210 TI - Impact of endovascular technique in vascular surgery training at a large university hospital in Brazil. AB - OBJECTIVES: The aim of this study was to determine the impact of endovascular surgery versus open vascular technique training in a Brazilian teaching service. DESIGN: Cross-sectional study. SETTING: Hospital das Clinicas-Faculty of Medicine University of Sao Paulo, a tertiary institutional hospital-Brazil. PARTICIPANTS: We reviewed 1,040 arterial operations performed during 2 distinct time periods: January 1995 to December 1996, and January 2006 to December 2007. Based on the disease treated, the procedures were classified into the following 5 groups: abdominal aortic aneurysms (AAA), aorto-iliac obstructive disease (AI), obstructive disease of the femoropopliteal-tibial segment (FP), carotid disease (C), and others (O). The operations were also divided into an endovascular surgery (ES) group and an open surgery (OS) group. We compared the number of open and endovascular procedures for each arterial disease group during both periods. RESULTS: During the 2006-2007 period, 654 patients were treated surgically, whereas over the 1995-1996 period, 386 arterial operations were performed. A significant increase in endovascular procedures (p < 0.001) was found from the 1995-1996 period to the 2006-2007 period (35 vs 351, respectively) in all groups, whereas open surgery showed a slight increase in the number of procedures in the AAA and O groups only. In the 1995-1996 period, OS was the primary surgical method for all groups, but in the 2006-2007 time frame, OS was performed more frequently than ES only in the AAA and O groups. Considering all vascular disease groups, OS was the technique used in 90.9% (351 of 386) of the operations during 1995-1996, whereas in 2006-2007, OS was performed in only 46.3% (303 of 654) of the procedures. CONCLUSIONS: The increase in the number of ES observed over the past decade has had little impact on OS procedures performed at our medical center, not bringing harm to open surgical training. PMID- 21292211 TI - Improving surgical resident's performance in the American Board of Surgery in Training Examination (ABSITE)--do review courses help? The program directors' perspective. AB - BACKGROUND: The implementation of the 80-hour week compounded by the need for the current trainee to be well versed technically with the newer developments in surgery has resulted in limited time for didactic education. Commercial American Board of Surgery in Training examination (ABSITE) review courses are flourishing and may seem to be filling the gap in didactic education. OBJECTIVE: This study ascertained the opinion of the general surgery program directors across the country on the role of the review courses in the ABSITE performance of a surgical resident. METHODS: A questionnaire was designed and sent out to all program directors using online survey. RESULTS: Sixty-five of 242 program directors completed the questionnaire. Fifty-seven percent belonged to university-based surgical residency programs. Seventy-two percent used ABSITE performance as a measure while evaluating the resident for promotion. Although 60% agreed that review courses help the performance of the residents, 80% did not have any institutional or regional review courses. Ninety percent allowed their residents to attend commercial review courses but 60% did not reimburse them. CONCLUSIONS: Program directors do feel that ABSITE by itself is important in evaluating the progression of surgical residents and has a correlation with the boards' pass percentile. Due to the limited hours available for didactics in current surgical residency, intensive review course over a 2- to 3-day period may help the surgical residents to perform better. In the current economy, review courses offered by a consortium of programs geared toward improving ABSITE performance and conducted by the surgical faculty may be of essence. PMID- 21292212 TI - Knot integrity as a function of suture expiration. AB - OBJECTIVE: To test the integrity of knots tied with expired suture and non expired suture, using 5 different suture materials. STUDY DESIGN: Knots were tied using expired and non-expired chromic catgut, polyglactin 910, polydioxanone, silk, or coated polyester. Expired sutures were a mean of 10.5 years past the date of expiration stamped on the packaging. Suture packaging was inspected for any flaws or humidity. There were 116 knots with expired suture and 109 non expired knots. All knots were tied by hand. Suture was soaked in 0.9% sodium chloride for 60 seconds and subsequently transferred to a tensiometer where the tails of the knots were cut to 3 mm length. We compared the tensile strength of knots using a tensiometer to pull the knots until the suture broke or untied. A minimum of 30 knots were needed in order to detect a statistically significant main effect for expired and non-expired sutures with 80% power and a 5% chance of type I error. RESULTS: A total of 225 knots were tied. Overall, we found no difference in mean tension between expired suture (77.5 +/- 31.7 N) and non expired suture at failure (81.9 +/- 30.2 N). All the sutures broke at the knot and none untied. Expired chromic and polydioxanone were significantly weaker than the non-expired suture of the same material (p = 0.002 and p = 0.001, respectively). There was no statistically significant difference in tensile strength between expired absorbable or permanent suture materials. Based on a univariate analysis of variance ([SCAP]ANOVA)[R] there was no difference in the tension at failure between expired and non-expired sutures with suture packet as a covariate. No suture untied when knotted with expired suture. CONCLUSIONS: Under laboratory conditions, expired chromic and polydioxanone sutures broke at lower tensile strength than non-expired sutures of the same material. PMID- 21292213 TI - Providing endoscopy for underserved patients benefits public health and resident education. AB - OBJECTIVE: To determine the clinical and educational value of a new model for providing endoscopy for medically indigent patients. HYPOTHESIS: A model can be developed at minimal cost to provide essential endoscopy services for underserved patients while providing resident education. DESIGN: In our community, there was limited access to endoscopy for indigent patients, and surgical resident endoscopy experience was inadequate. To address these problems, a new endoscopy program was developed. Procedures were performed during underused times in a hospital endoscopy clinic. Endoscopies were performed on patients referred from the public health clinics. All procedures were performed by senior surgical residents supervised by attending endoscopists. The data were collected over 30 months. Colonoscopies were performed for both diagnostic and screening purposes. INTERVENTIONS: In all, 205 colonoscopies, 65 upper endoscopies, and 14 combined endoscopies were performed. OUTCOME MEASURES: Positive findings on endoscopy were documented. The cost-effectiveness was calculated. RESULTS: Of 205 colonoscopies, 35% had positive findings. Sixty-six (32%) patients had polyps and 6 (3%) patients had carcinomas. Of 65 upper endoscopies, 34 (55%) patients had positive findings. Thirty (47%) patients had moderate to severe gastritis/esophagitis or ulcers, 2 (3%) patients had esophageal varices, 2 (5%) patients had carcinomas, 10 (15%) patients had positive H. pylori biopsies, and 2 (3%) patients had Barrett's esophagus. The program incurred minimal incremental costs, and large cost savings were realized in prevention and early detection of colon and gastric carcinomas. CONCLUSIONS: Our 30-month experience resulted in clinical benefits to patients at minimal incremental cost while reducing future medical costs by preventing and detecting disease. Surgical residents received essential training. PMID- 21292214 TI - Spirituality within the patient-surgeon relationship. AB - OBJECTIVE: To assess the attitudes of general and orthopaedic surgical outpatients regarding inquiry into their religious beliefs, spiritual practices, and personal faith. DESIGN: Prospective, voluntary, self-administered, and anonymously-completed questionnaire, regarding religious beliefs, spiritual practices, and personal faith, March-August, 2009. SETTING: General and orthopaedic surgical outpatient settings, Health Services Foundation, College of Medicine, University of South Alabama, a tertiary care academic medical center in Mobile, Alabama. PARTICIPANTS: All patients referred for evaluation and management of general and orthopaedic surgical conditions, pre- and postoperatively, were approached. METHODOLOGY: The questionnaire solicited data regarding patient: (1) demographics; (2) religious beliefs, spiritual practices, and personal faith; and (3) opinions regarding inquiry into those subjects by their surgeon. The latter opinions were stratified on a 5-point Likert scale ranging from "strongly disagree" to "strongly agree." Statistical analysis was conducted using software JMP((r)) 8 Statistical Discovery Software (S.A.S. Institute Inc., Cary, North Carolina) and a 5% probability level was used to determine significance of results. RESULTS: Eighty-three percent (83%) of respondents agreed or strongly agreed that surgeons should be aware of their patients' religiosity and spirituality; 63% concurred that surgeons should take a spiritual history; and 64% indicated that their trust in their surgeon would increase if they did so. Nevertheless, 17%, 37%, and 36% disagreed or strongly disagreed with those perspectives, respectively. CONCLUSIONS: By inference to the best explanation of the results, we would argue that religiosity and spirituality are inherent perspectives of patient-surgeon relationships. Consequently, those perspectives are germane to the therapeutic milieu. Therefore, discerning each patient's perspective in those regards is warranted in the context of an integrative and holistic patient-surgeon relationship, the intent of which is to restore a patient to health and well-being. PMID- 21292215 TI - Surgical training: the impact of changes in curriculum and experience. AB - INTRODUCTION: Craft specialties, such as surgery, rely on practice to acquire skill. Yet recent changes in training in the United Kingdom have decreased experience and altered the balance of curriculum content. Most recently, the European Working Time Directive has led to a reduction in working hours and expansion in the number of trainees. The impact that these changes have had on operative experience, patient management, communication, and teaching skills is unclear. This study aims to assess the effects of the changing curriculum and work patterns on the experience of trainees at senior house officer (SHO, equivalent to junior resident) level in general surgery. METHODS: A structured questionnaire was sent to general surgery trainees at the SHO (n = 52) and specialist registrar (SpR, n = 69) levels (equivalent to senior resident) in the Severn Deanery, United Kingdom. RESULTS: In all, 70% of both SHOs and SpRs responded. SpRs had spent a mean of 50 months (21 months in general surgery) at the SHO level, compared with 24 months (9 months in general surgery) for current SHOs. A total of 90% of SpRs could perform an open appendectomy unsupervised by the end of their SHO training, compared with 28% of current SHOs. In all, 63% of SpRs and 8% of SHOs could undertake inguinal hernia repair unsupervised at SHO level. In addition, 90% of SpRs and 84% of SHOs felt operative skills have declined, whereas communication and teaching skills were deemed the same or better. Of the respondents, 88% of SpRs and 76% of SHOs thought surgical training was getting worse. DISCUSSION: Trainees are spending less time in surgery at the SHO level, and this is reflected in reported operative ability. The introduction of communication and teaching skills into the curriculum has had a perceived benefit. The reduction in working hours must be offset by implementing measures to maximize limited training opportunities. The potential implications of these changes in training and experience on patient outcomes remain to be determined. PMID- 21292216 TI - Template for success: using a resident-designed sign-out template in the handover of patient care. AB - OBJECTIVE: Report our implementation of a standardized handover process in a general surgery residency program. DESIGN: The standardized handover process, sign-out template, method of implementation, and continuous quality improvement process were designed by general surgery residents with support of faculty and senior hospital administration using standard work principles and business models of the Virginia Mason Production System and the Toyota Production System. SETTING: Nonprofit, tertiary referral teaching hospital. PARTICIPANTS: General surgery residents, residency faculty, patient care providers, and hospital administration. RESULTS: After instruction in quality improvement initiatives, a team of general surgery residents designed a sign-out process using an electronic template and standard procedures. The initial implementation phase resulted in 73% compliance. Using resident-driven continuous quality improvement processes, real-time feedback enabled residents to modify and improve this process, eventually attaining 100% compliance and acceptance by residents. CONCLUSIONS: The creation of a standardized template and protocol for patient handovers might eliminate communication failures. Encouraging residents to participate in this process can establish the groundwork for successful implementation of a standardized handover process. Integrating a continuous quality-improvement process into such an initiative can promote active participation of busy general surgery residents and lead to successful implementation of standard procedures. PMID- 21292217 TI - "Reality surgery"--a research ethics perspective on the live broadcast of surgical procedures. AB - In recent years, the live broadcasting of medical and surgical procedures has gained worldwide popularity. While the practice has appropriately been met with concerns for patient safety and privacy, many physicians tout the merits of real time viewing as a form of investigation, accelerating the process leading to adoption or abolition of newer techniques or technologies. This view introduces a new series of ethical considerations that need to be addressed. As such, this article considers, from a research ethics perspective, the use of live surgical procedure broadcast for investigative purposes. PMID- 21292218 TI - Amyand hernia repaired with Bio-A: a case report and review. AB - A 53-year-old man with an Amyand hernia with indirect and direct components was repaired with a Bio-A (Gore, Newark, Delaware) plug and a patch made of Bio-A tissue reinforcement material. The repair of an Amyand hernia addresses the pathology of the appendix as well as the hernia. We report a case in which a plug and patch repair was undertaken using Bio-A implants in a clean-contaminated field with no signs of infection or recurrence in the follow-up period, and we review the literature regarding the diagnosis and repair of an Amyand hernia. PMID- 21292219 TI - How we select our residents--a survey of selection criteria in general surgery residents. AB - INTRODUCTION: The future of general surgery depends on the quality of the resident trainees, and successful resident selection is a factor that is important in the process of high-quality surgical education. METHODS: A 36 question survey regarding resident selection and the interview process was sent to surgical program directors, department chairs, and associate program directors across the United States and Canada. RESULTS: In all, 262 valid replies were received (65%), of which 83% were program directors. University hospital programs accounted for 49% of the completed surveys. The mean yearly applicant number per residency program was 571. Most programs indicated that they strictly adhere to their selection criteria (82%). The screening selection is made by the program director in 62%. Only 31% of programs show their selection criteria on their web page. United States Medical Licensing Examination (USMLE) Step 1 is the single most important factor in screening criteria (37%), followed by USLME Step 2 (24%). A total of 96% of all programs have female residents, 66% have non-Liaison Committee on Medical Education graduates, and 38% have Doctor of Osteopathy (DO) residents. Final selection is made by the program director in 49%. Although research experience is considered in selection criteria (80%), only 46% of programs offer research opportunities to their residents and only 13% require 1 year of research. On a Likert 5-point scale, the interview is by far the most important factor (4.69), followed by Step 1 score (4.21), and letters of recommendation (4.02). CONCLUSIONS: Even though all general surgery programs have a wide range of screening/selection criteria, USLME Step 1 is the single most important factor for preliminary screening, and the interview is the most important factor in determining the final selection. The final selection is relatively subjective and based on a combination of interview, USLME scores, research experience, and personal judgment. PMID- 21292220 TI - Northwestern Center for Advanced Surgical Education (N-CASE). PMID- 21292221 TI - The Goodman Simulation Center at Stanford. PMID- 21292222 TI - Methodist Institute for Technology, Innovation and Education. PMID- 21292223 TI - Penn Medicine Clinical Simulation Center. PMID- 21292224 TI - The Center of Excellence for Laparoscopic and Minimally Invasive Surgery at the University of Miami. PMID- 21292225 TI - Texas A&M/Scott & White Surgical Skills Program. PMID- 21292226 TI - ISIS: The Institute for Simulation and Interprofessional Studies at the University of Washington. PMID- 21292227 TI - Influence of head orientation on visually and memory-guided arm movements. AB - In the absence of visual supervision, tilting the head sideways gives rise to deviations in spatially defined arm movements. The purpose of this study was to determine whether these deviations are restricted to situations with impoverished visual information. Two experiments were conducted in which participants were positioned supine and reproduced with their unseen index finger a 2 dimensional figure either under visual supervision or from memory (eyes closed). In the former condition, the figure remained visible (using a mirror). In the latter condition, the figure was first observed and then reproduced from memory. Participants' head was either aligned with the trunk or tilted 30 degrees towards the left or right shoulder. In experiment 1, participants observed first the figure with the head straight and then reproduced it with the head either aligned or tilted sideways. In Experiment 2, participants observed the figure with the head in the position in which the figure was later reproduced. Results of Experiment 1 and 2 showed deviations of the motor reproduction in the direction opposite to the head in both the memory and visually-guided conditions. However, the deviations decreased significantly under visual supervision when the head was tilted left. In Experiment 1, the perceptual visual bias induced by head tilt was evaluated. Participants were required to align the figure parallel to their median trunk axis. Results revealed that the figure was perceived as parallel with the trunk when it was actually tilted in the direction of the head. Perceptual and motor responses did not correlate. Therefore, as long as visual feedback of the arm is prevented, an internal bias, likely originating from head/trunk representation, alters hand-motor production irrespectively of whether visual feedback of the figure is available or not. PMID- 21292228 TI - [Acquired epidermodysplasia verruciformis in a renal transplant recipient]. PMID- 21292229 TI - Association between maternal serum cytokine profiles at 7-10 weeks' gestation and birthweight in small for gestational age infants. AB - OBJECTIVE: The purpose of this study was to investigate whether birth of a small for-gestational-age (SGA) baby (birthweight, <10th percentile) is preceded by altered maternal serum cytokine profiles at early pregnancy, compared with control babies (birthweight, 30-80th percentile). STUDY DESIGN: A retrospective case-control study of maternal serum collected prospectively across 7-10 weeks of gestation from women attending their first prenatal visit (SGA, 57 cases; control subjects, 71 cases selected retrospectively). Serum concentrations of 27 cytokines were measured in each sample and analyzed by 2-way analysis of variance and nonparametric tests. Logistic regression was used for predictive modeling. RESULTS: Of 21 detectable cytokines/chemokines, 14 analytes varied significantly (P <= .030) among those women who were destined to deliver an SGA baby, when compared with control subjects. Of the cytokines that varied in association with SGA, interferon-gamma concentrations increased, and major proinflammatory (interleukin [IL]-2, -7, -12) and antiinflammatory (IL-1 receptor antagonist, -4, -10, -13) cytokine concentrations decreased. Eotaxin and macrophage inflammatory protein-1alpha were higher; monocyte chemoattractant protein-1 and IL-8 were lower. CONCLUSION: SGA births may be preceded by altered immune cytokine profiles at 7-10 weeks of gestation. PMID- 21292230 TI - Ultrasound measurement of fetal adrenal gland enlargement: an accurate predictor of preterm birth. AB - OBJECTIVE: The objective of the study was to test whether ultrasound-measured fetal adrenal gland volume (AGV) and fetal zone enlargement (FZE) predicts preterm birth (PTB) better than cervical length (CL). STUDY DESIGN: Three dimensional and 2-dimensional ultrasound were used prospectively to measure fetal AGV, FZE, and CL in women with preterm labor symptoms. We corrected AGV for fetal weight (cAGV). The ratio between whole gland depth (D) and central fetal zone depth (d) (d/D) was used to measure FZE. Ability of cAGV, d/D, and CL to predict PTB 7 days or less was compared. RESULTS: Twenty-seven of 74 women (36.5%) presenting between 21 and 34 weeks had PTB of 7 days or less. FZE greater than 49.5% was the single best predictor for PTB (sensitivity/specificity 100%/89%) compared with cAGV (81%/87%) and CL (56%/60%; P < .05). Prediction was independent of obstetrics history and tocolytic use. CONCLUSION: The 2 dimensional measurement of the adrenal gland FZE is highly effective performing superior to CL in identifying women at risk for PTB within 7 days. PMID- 21292231 TI - Of parachutes and patient care: a call to action. AB - Obstetric caregivers are plagued with lawsuits alleging negligence for suboptimal outcomes. Some of those claims are unjustified, but many have merit. We are obligated to create systems designed to minimize the potential for errors that harm our patients. A variety of safety initiatives have been shown to improve patient outcomes in several centers in the United States, but it has been difficult to document the expected association between those results and reduced liability premiums. Furthermore, some individuals and institutions have been reluctant to adopt safety tools such as electronic fetal monitoring certification for all staff working on their Labor and Delivery floor, protocols for managing common clinical scenarios, simulation drills for dealing with uncommon dangerous events, and pre-procedure checklists because of the paucity of evidence based data documenting the effectiveness of those approaches. It is time to move forward with these and other safety initiatives in a serious national attempt to eliminate all preventable adverse patient outcomes in our specialty. PMID- 21292232 TI - Use of vaginal mesh in the face of the recent FDA warnings and litigation. PMID- 21292234 TI - Body image perceptions in women with pelvic organ prolapse: a qualitative study. AB - OBJECTIVE: To describe perceptions of prolapse-specific body image in women with symptomatic prolapse. STUDY DESIGN: Women with symptomatic pelvic organ prolapse quantification stage >= II prolapse participated in semistructured focus groups or self-report questionnaire. Transcripts were independently reviewed and body image themes were identified and confirmed by consensus. RESULTS: Twenty-five women participated in focus groups and 27 in online questionnaires. Transcript analysis revealed 3 central themes and 25 body-image related subthemes. Women living with prolapse were more likely to feel self-conscious, isolated, "different," less feminine, and less attractive. Women often changed sexual intimacy practices because of embarrassment or discomfort, and many avoided intimacy all together. Prolapse greatly affected women's personal and professional activities causing some women to adjust routines or stop activities. Women reported loss of interest in activities, distraction while performing daily/work-related tasks, and embarrassment when asking for help with activities. CONCLUSION: Themes identified in this qualitative study demonstrate the profound effect of prolapse on a woman's body image. PMID- 21292235 TI - [Aneurysmal dilatation of pulmonary artery and its branches on mitral stenosis: a case report]. AB - Pulmonary arteries aneurysms are rare and the rarely described bilateral aneurysms. A 45-year-old patient carrier of mitral stenosis was admitted for dyspnoea class III of the NYHA, chest pain and a not infectious cough. The clinical examination found semiology of mitral stenosis, tricuspid incapacity and pulmonary arterial hypertension. The electrocardiogram showed atrial fibrillation and right ventricle hypertrophy. Chest X-ray found a cardiomegaly, an aspect of double outline of the inferior right bow, a prominent aspect of the left average bow reminding an aneurysm of the left pulmonary artery. The echocardiography Doppler found a pure tight mitral stenosis (mitral surface=0.6 cm(2)), a dilation of the trunk of the pulmonary artery (diameter=74 mm) and of its branches (diameter of the right pulmonary artery=28 mm, diameter of the left pulmonary artery=36 mm) seat of a spontaneous contrast. The left atrium and right cardiac cavities were also dilated. There was an important tricuspid incapacity with a major pulmonary hypertension (systolic pulmonary arterial=109 mmHg). The thoracic angioscan showed a pseudoaneurysm of the trunk of pulmonary artery and its branches to their distal parts. Under diuretic, anticoagulating and analgesic treatment the clinical signs improved however the spontaneous contrast persisted. The patient was rejected by the surgery for exceeded clinical board. She is at present followed in our service for 5 months. PMID- 21292236 TI - [Are patients undergoing coronary angiography well-informed? Prospective evaluation of the effectiveness of written information]. AB - INTRODUCTION: Prior information in the realization of an invasive intervention is crucial. Indeed, the patient has to know theoretically his disease, diagnostic and therapeutic means, but also the risks of the used technique. The habits of information vary many from one center to another, in spite of the proposition of an information leaflet written by the French Society of Cardiology. Our aim was to evaluate the effectiveness of written information for patients hospitalized for coronary arteriography. METHODS: Among patients hospitalized for realization of a programmed coronarography, a questionnaire was delivered before the information leaflet. The knowledge of the patients was so tested (27 items) before and after the reading of the information sheet (not limited time). The knowledge of the patients concerning coronarography indication, modalities, benefits, possible complications or still later possibilities was informed. RESULTS: Thirty-four patients were included: all knew hospitalization reason, 86% were men, middle-aged 65 (IC 95% 60-70). Thirty-four percent (15-54) had studied in higher education. Ninety-seven percent had had information before. Only 56% (38-74) were informed about the mode of anesthesia, 36% (19-53) duration, 69% (53 86) the injection of iodine, 44% the risk of allergy, 53% the risk of bruise, 15% of the cardiac risks, 21% the renal risks. Seventy-one percent knew the diagnostic benefits, 44% the possible coronary angioplasty, 17% the eventuality of a bypass surgery. The delivery of the information leaflet did not modify the knowledge on most of these items, in particular the modalities and the profits. The risks were known significantly better for the allergy (P=0.019), the bruise (P=0.018), the cardiac risks (0.001). CONCLUSIONS: The population benefiting from a coronarography considers to be enough informed. However, knowledge of the modalities, profits and risks is very low. The delivery of the consensual leaflet does not allow improving the situation, except as far as concerned the complications. Better information is so indispensable, not only to obtain a better support of the patient in the treatment, but also to prevent the forensic implications. The improvement of the information must be multifactorial, but usually used means could be not sufficient. PMID- 21292237 TI - Management of delayed gastric emptying after esophagectomy with endoscopic balloon dilatation of the pylorus. AB - BACKGROUND: This study seeks to evaluate the use of postoperative pyloric balloon dilatation for delayed gastric emptying after esophageal substitution with gastric conduit. METHODS: A total of 436 patients underwent esophagectomy with gastric conduit from 2002 to 2009. All approaches to esophagectomy were included except patients with alternative reconstruction or emergent esophagectomy. Gastric conduit diameter, anastomotic location, and mediastinal route were variable. Gastric outlet obstruction (GOO) was strictly defined to include patients with clinical and radiographic delayed gastric emptying requiring intervention. RESULTS: Gastric outlet obstruction was found in 22% (98 of 436) of patients who underwent esophagectomy. Pyloromytomy was performed on 52% (51 of 98) of these patients and employed in 41% (179 of 436) of patients in the entire cohort. GOO was present in 28% (51 of 179) of patients who underwent a pyloric drainage procedure compared with 18% (47 of 257) of patients with no pyloric intervention (p = 0.01). Endoscopic balloon dilatation of the pylorus was used to treat 39% (38 of 98) of patients with delayed gastric emptying yielding a 95% (36 of 98) success rate. Pyloric dilatations were performed with controlled radial expansion esophageal balloon dilators (range,10 to 20 mm). The remaining patients were treated conservatively with prokinetics, nasogastric drainage, or observation. Nasogastric drainage was employed for 7.4 +/- 4.4 days in patients with GOO and 6.8 +/- 4.0 days in asymptomatic patients (p = 0.15). Neoadjuvant chemoradiotherapy did not contribute to increased incidence of GOO. There was a significant difference in postoperative pneumonia (18.4% vs 10.6%, p = 0.05) and median length of hospital stay (12 +/- 16 vs 10 +/- 9 days, p < 0.0001) in patients with GOO versus normal emptying. CONCLUSIONS: Delayed gastric emptying after esophageal substitution with gastric conduit can be adequately treated with balloon dilatation of the pylorus despite an operative drainage procedure. PMID- 21292238 TI - Kaizen method for esophagectomy patients: improved quality control, outcomes, and decreased costs. AB - BACKGROUND: The majority of costs associated with esophagectomy are related to the initial 3 days of hospital stay requiring intensive care unit stays, ventilator support, and intraoperative time. Additional costs arise from hospital based services. The major cost increases are related to complications associated with the procedure. We attempted to define these costs and identify expense management by streamlining care through strict adherence to patient care maps, operative standardization, and rapid discharge planning to reduce variability. METHODS: Utilizing methods of Kaizen philosophy we evaluated all processes related to the entire experience of esophageal resection. This process has taken over 5 years to achieve, with quality and cost being tracked over this time period. Cost analysis included expenses related to intensive care unit, anesthesia, disposables, and hospital services. Quality improvement measures were related to intraoperative complications, in-hospital complications, and postoperative outcomes. The Institutional Review Board approved the use of anonymous data from standard clinical practice because no additional treatment was planned (observational study). RESULTS: Utilizing a continuous process improvement methodology, a 43% reduction in cost per case has been achieved with a significant increase in contribution margin for esophagectomy. The length of stay has been reduced from 14 days to 5. With intraoperative and postoperative standardization the leak rate has dropped from 12% to less than 3% to no leaks in our current Kaizen modification of care in our last 64 patients. CONCLUSIONS: Utilizing lean manufacturing techniques and continuous process evaluation we have attempted to eliminate variability, standardized the phases of care resulting in improved outcomes, decreased length of stay, and improved contribution margins. These Kaizen improvements require continuous interventions, strict adherence to care maps, and input from all levels for quality improvements. PMID- 21292239 TI - Tea polyphenols protect against irradiation-induced injury in submandibular glands' cells: a preliminary study. AB - AIM: To study the protective effect of tea polyphenols (TPs) on submandibular glands affected by radiation injury. METHODS: Sixty rats were randomly divided into radiation group (R-group, N = 30) and TP-pre-treated-radiation group (TPR group, N = 30). The rats were intragastrically administered with TP or normal sodium from 14 days before radiation, continuously daily, until the experiment. All the rats in both groups were irradiated with a single exposure dose of 15 Gy gamma rays that were delivered to the head and neck areas. Ten rats of each group were anatomised on the 3rd, 6th and 30th day after irradiation, respectively. The submandibular glands of the rats were removed for the study. The morphologic changes of the submandibular glands were observed by transmission electron microscopy (TEM). The terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP)-biotin nick-end labelling (TUNEL) method was used to detect apoptosis of the submandibular glands' cells. RESULTS: Electron microscope observation of the submandibular glands showed that the lesions of the TPR-group were mild. Change in apoptosis of the cells was not obvious compared with the R-group. The cell apotosis was typical after irradiation in the R-group. Apoptosis index that was detected in the cells of submandibular glands of the TPR group was statistically significantly decreased compared with the R-group (P < 0.01) on the 3rd, 6th and 30th day after irradiation. CONCLUSION: TP could protect submandibular glands from radiation injuries, and the protection mechanism may be realised by anti-apoptosis. PMID- 21292240 TI - Mineral distribution of artificial dentinal caries lesions after treatment with fluoride agents in combination with saliva substitutes. AB - OBJECTIVE: Some saliva substitutes have been shown to demineralize dentine in vitro. This effect is counteracted by the application of various fluorides. In contrast, remineralizing saliva substitutes might be supported by these treatments, depending on the dynamics during remineralization. The aim of this in vitro study was to evaluate the effects of fluoride mouthrinses or gels in combination with de-/remineralizing saliva substitutes on dentinal subsurface lesions. DESIGN: Demineralized bovine dentine specimens were stored either in mineral water [saturation with respect to octacalcium phosphate (S(OCP)): 0.7], Glandosane (G, S(OCP): 0.3) or in a modified saliva substitute Saliva natura (SN, S(OCP): 1.9) for five weeks (37 degrees C). Fluoride agents were applied twice daily for 10 min (n = 15/group): no treatment, Meridol mouthrinse, Elmex sensitive solution, ProSchmelz fluoride gel, Elmex gelee. After storage thin sections were prepared and mineral losses before and after storage were evaluated from microradiographs. RESULTS: Specimens stored in G alone showed significantly higher mineral loss compared to those stored in water, SN or G in combination with any additional treatment (p < 0.05). Storage in SN and treatment with ProSchmelz fluoride gel led to significantly higher remineralization compared to all other groups (p < 0.05) and resulted in distinct mineral gain within the lesion body. CONCLUSIONS: Under the in vitro conditions chosen, use of fluoride agents in combination with a demineralizing saliva substitute resulted in reduced mineral loss. Storage in modified Saliva natura in combination with the application of ProSchmelz fluoride gel induced the most pronounced remineralization also of deeper lesion areas. PMID- 21292241 TI - Clarifying boundaries of binge eating disorder and psychiatric comorbidity: a latent structure analysis. AB - Binge eating disorder (BED) presents with substantial psychiatric comorbidity. This latent structure analysis sought to delineate boundaries of BED given its comorbidity with affective and anxiety disorders. A population-based sample of 151 women with BED, 102 women with affective or anxiety disorders, and 259 women without psychiatric disorders was assessed with clinical interviews and self report-questionnaires. Taxometric analyses were conducted using DSM-IV criteria of BED and of affective and anxiety disorders. The results showed a taxonic structure of BED and of affective and anxiety disorders. Both taxa co-occurred at an above-chance level, but also presented independently with twice-as-large probabilities. Within the BED taxon, diagnostic co-occurrence indicated greater general psychopathology, lower social adaptation, and greater premorbid exposure to parental mood and substance disorder, but not greater eating disorder psychopathology. Eating disorder psychopathology discriminated individuals in the BED taxon from individuals in the affective and anxiety disorders taxon. Diagnostic criteria of BED were more indicative of the BED taxon than were criteria of affective and anxiety disorders. The results show that at the latent level, BED was co-occurring with, yet distinct from, affective and anxiety disorders and was not characterized by an underlying affective or anxiety disorder. PMID- 21292242 TI - Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. AB - BACKGROUND: Despite widely reported clinical and preclinical studies of rapid antidepressant actions of glutamate N-methyl-D-aspartate (NMDA) receptor antagonists, there has been very little work examining the effects of these drugs in stress models of depression that require chronic administration of antidepressants or the molecular mechanisms that could account for the rapid responses. METHODS: We used a rat 21-day chronic unpredictable stress (CUS) model to test the rapid actions of NMDA receptor antagonists on depressant-like behavior, neurochemistry, and spine density and synaptic function of prefrontal cortex neurons. RESULTS: The results demonstrate that acute treatment with the noncompetitive NMDA channel blocker ketamine or the selective NMDA receptor 2B antagonist Ro 25-6981 rapidly ameliorates CUS-induced anhedonic and anxiogenic behaviors. We also found that CUS exposure decreases the expression levels of synaptic proteins and spine number and the frequency/amplitude of synaptic currents (excitatory postsynaptic currents) in layer V pyramidal neurons in the prefrontal cortex and that these deficits are rapidly reversed by ketamine. Blockade of the mammalian target of rapamycin protein synthesis cascade abolishes both the behavioral and biochemical effects of ketamine. CONCLUSIONS: The results indicate that the structural and functional deficits resulting from long-term stress exposure, which could contribute to the pathophysiology of depression, are rapidly reversed by NMDA receptor antagonists in a mammalian target of rapamycin dependent manner. PMID- 21292243 TI - Effects of cue-exposure treatment on neural cue reactivity in alcohol dependence: a randomized trial. AB - BACKGROUND: In alcohol-dependent patients, alcohol-associated cues elicit brain activation in mesocorticolimbic networks involved in relapse mechanisms. Cue exposure based extinction training (CET) has been shown to be efficacious in the treatment of alcoholism; however, it has remained unexplored whether CET mediates its therapeutic effects via changes of activity in mesolimbic networks in response to alcohol cues. In this study, we assessed CET treatment effects on cue induced responses using functional magnetic resonance imaging (fMRI). METHODS: In a randomized controlled trial, abstinent alcohol-dependent patients were randomly assigned to a CET group (n = 15) or a control group (n = 15). All patients underwent an extended detoxification treatment comprising medically supervised detoxification, health education, and supportive therapy. The CET patients additionally received nine CET sessions over 3 weeks, exposing the patient to his/her preferred alcoholic beverage. Cue-induced fMRI activation to alcohol cues was measured at pretreatment and posttreatment. RESULTS: Compared with pretreatment, fMRI cue-reactivity reduction was greater in the CET relative to the control group, especially in the anterior cingulate gyrus and the insula, as well as limbic and frontal regions. Before treatment, increased cue-induced fMRI activation was found in limbic and reward-related brain regions and in visual areas. After treatment, the CET group showed less activation than the control group in the left ventral striatum. CONCLUSIONS: The study provides first evidence that an exposure-based psychotherapeutic intervention in the treatment of alcoholism impacts on brain areas relevant for addiction memory and attentional focus to alcohol-associated cues and affects mesocorticolimbic reward pathways suggested to be pathophysiologically involved in addiction. PMID- 21292244 TI - NMR structural study of fructans produced by Bacillus sp. 3B6, bacterium isolated in cloud water. AB - Bacillus sp. 3B6, bacterium isolated from cloud water, was incubated on sucrose for exopolysaccharide production. Dialysis of the obtained mixture (MWCO 500) afforded dialyzate (DIM) and retentate (RIM). Both were separated by size exclusion chromatography. RIM afforded eight fractions: levan exopolysaccharide (EPS), fructooligosaccharides (FOSs) of levan and inulin types with different degrees of polymerization (dp 2-7) and monosaccharides fructose:glucose=9:1. Levan was composed of two components with molecular mass ~3500 and ~100kDa in the ratio 2.3:1. Disaccharide fraction contained difructose anhydride DFA IV. 1 Kestose, 6-kestose, and neokestose were identified as trisaccharides in the ratio 2:1:3. Fractions with dp 4-7 were mixtures of FOSs of levan (2,6-betaFruf) and inulin (1,2-betaFruf) type. DIM separation afforded two dominant fractions: monosaccharides with fructose: glucose ratio 1:3; disaccharide fraction contained sucrose only. DIM trisaccharide fraction contained 1-kestose, 6-kestose, and neokestose in the ratio1.5:1:2, penta and hexasaccharide fractions contained FOSs of levan type (2,6-betaFruf) containing alpha-glucose. In the pentasaccharide fraction also the presence of a homopentasaccharide composed of 2,6-linked betaFruf units only was identified. Nystose, inulin (1,2-betaFruf) type, was identified as DIM tetrasaccharide. Identification of levan 2,6-betaFruf and inulin 1,2-betaFruf type oligosaccharides in the incubation medium suggests both levansucrase and inulosucrase enzymes activity in Bacillus sp. 3B6. PMID- 21292245 TI - Potentiometric and 31P NMR studies on inositol phosphates and their interaction with iron(III) ions. AB - Potentiometric, conductometric and 31P NMR titrations have been applied to study interactions between myo-inositol hexakisphosphate (phytic acid), (+/-)-myo inositol 1,2,3,5-tetrakisphosphate and (+/-)-myo-inositol 1,2,3-trisphosphate with iron(III) ions. Potentiometric and conductometric titrations of myo-inositol phosphates show that addition of iron increases acidity and consumption of hydroxide titrant. By increasing the Fe(III)/InsP(6) ratio (from 0.5 to 4) 3 mol of protons are released per 2 mol of iron(III). At first, phytates coordinate iron octahedrally between P2 and P1,3. The second coordination site represents P5 and neighbouring P4,6 phosphate groups. Complexation is accompanied with the deprotonation of P1,3 and P4,6 phosphate oxygens. At higher concentration of iron(III) intermolecular P-O-Fe-O-P bonds trigger formation of a polymeric network and precipitation of the amorphous Fe(III)-InsP(6) aggregates. (31)P NMR titration data complement the above results and display the largest chemical shift changes at pD values between 5 and 10 in agreement with strong interactions between iron and myo-inositol phosphates. The differences in T(1) relaxation times of phosphorous atoms have shown that phosphate groups at positions 1, 2 and 3 are complexated with iron(III). The interactions between iron(III) ions and inositol phosphates depend significantly on the metal to ligand ratio and an attempt to coordinate more than two irons per InsP(6) molecule results in an unstable heterogeneous system. PMID- 21292247 TI - [Microorganisms and cancer: scientific evidence and new hypotheses]. AB - Microorganism involvement in cancer has been known for over a century, and different types of parasites, bacteria and viruses have been associated with oncogenic processes. Among the bacteria, the first recognised was Helicobacter pylori which causes gastric cancer and might be related to extra-gastric cancer in humans. Helicobacter hepaticus has been associated with liver cancers using animal models. Other bacteria, such as Chlamydia psitacii, Borrelia burgdorferi and Streptococcus bovis, have been associated with ocular, skin and colorectal cancers, respectively. Also, a commensal bacterium in the human intestine, Bacteroides fragilis, has been linked, very recently, with colorectal cancer using animal models. PMID- 21292246 TI - Characterization of monocyte maturation/differentiation that facilitates their transmigration across the blood-brain barrier and infection by HIV: implications for NeuroAIDS. AB - The prevalence of human immunodeficiency virus 1 (HIV) associated neurocognitive disorders resulting from infection of the central nervous system (CNS) by HIV continues to increase despite the success of combination antiretroviral therapy. Although monocytes are known to transport HIV across the blood-brain barrier (BBB) into the CNS, there are few specific markers that identify monocyte subpopulations susceptible to HIV infection and/or capable of infiltrating the CNS. We cultured human peripheral blood monocytes and characterized the expression of the phenotypic markers CD14, CD16, CD11b, Mac387, CD163, CD44v6 and CD166 during monocyte/macrophage (Mo/Mac) maturation/differentiation. We determined that a CD14(+)CD16(+)CD11b(+)Mac387(+) Mo/Mac subpopulation preferentially transmigrates across our in vitro BBB model in response to CCL2. Genes associated with Mo/Mac subpopulations that transmigrate across the BBB and/or are infected by HIV were identified by cDNA microarray analyses. Our findings contribute to the understanding of monocyte maturation, infection and transmigration into the brain during the pathogenesis of NeuroAIDS. PMID- 21292248 TI - [Sutureless hepatic transection using a new radiofrequency assisted device. Theoretical model, experimental study and clinic trial]. AB - The ideal instrument for performing hepatic transection should combine safe and rapid haemostasis in a single tool. We present a new multidisciplinary investigation designed to develop a hepatic transection device assisted by radiofrequency (RF); the investigation included: a computerised theoretical model, and experimental study and a clinical trial of this device. The theoretic modelling was performed by computer, based on the Finite Elements Method (FEM), with the objective of studying the distribution of electrical energy and temperature in the tissue, and to assess the effect of the characteristics of the instrument. The experimental study, based on an in vivo porcine model, suggested that the new instrument would allow the transection velocity of the hepatic parenchyma to be increased with lower bleeding per transection area compared with other techniques extensively used in liver surgery. These data should enable the first phase of clinical trial to be conducted, with preliminary results that suggest that the new device is safe and effective. PMID- 21292249 TI - Money enhances memory consolidation--but only for boring material. AB - Money's ability to enhance memory has received increased attention in recent research. However, previous studies have not directly addressed the time dependent nature of monetary effects on memory, which are suggested to exist by research in cognitive neuroscience, and the possible detrimental effects of monetary rewards on learning interesting material, as indicated by studies in motivational psychology. By utilizing a trivia question paradigm, the current study incorporated these perspectives and examined the effect of monetary rewards on immediate and delayed memory performance for answers to uninteresting and interesting questions. Results showed that monetary rewards promote memory performance only after a delay. In addition, the memory enhancement effect of monetary rewards was only observed for uninteresting questions. These results are consistent with both the hippocampus-dependent memory consolidation model of reward learning and previous findings documenting the ineffectiveness of monetary rewards on tasks that have intrinsic value. PMID- 21292250 TI - Biomechanical simulation of anterior cruciate ligament strain for sports injury prevention. AB - The purpose of this study was to quantify in vivo anterior cruciate ligament (ACL) strain by computer simulation, which includes a marker-based biomechanical model and a skeletal geometry model. Kinematic data collected by a motion capture system was used as the input and ACL strain during the movement time period was the output. Case studies were conducted to simulate ACL strain during jump landing, running and sidestep cutting activities. The simulation results were analysed and compared with previous findings in literature. The results show that the simulation is a useful tool in understanding ACL injury mechanisms related to sports activities. PMID- 21292251 TI - Symmetrical hemispheric priming in spatial neglect: a hyperactive left-hemisphere phenomenon? AB - Hemispheric rivalry models of spatial neglect suggest that the left hemisphere becomes hyperactive following right-hemisphere lesions since the two hemispheres normally exert an inhibitory influence on each other via callosal connections. Using a masked hemifield priming paradigm, we investigated whether the putative change in hemispheric balance involves other, higher-order abstract representational systems in spatial neglect. Participants consisted of 12 neglect patients with right-hemisphere damage and three groups of control participants, i.e., 12 young healthy controls, 10 age-matched healthy controls and 10 right hemisphere patients without spatial neglect. In each trial, participants made semantic categorization about a centrally presented target word which was preceded by a masked prime flashed either to the left or right visual field. All three control groups exhibited strong left-hemisphere advantage in inhibitory syllabic priming, consistent with the known left-hemisphere dominance in lexical inhibition during reading. By contrast, neglect patients exhibited a symmetrical pattern of priming between the left and right visual fields. These results suggest that (1) the neglected hemifield can rapidly extract abstract information even from weak and normally non-perceptible visual stimuli, but that (2) the normal left hemispheric dominance in reading is absent in neglect patients probably because of the generalized hyperactivity of the left hemisphere. Our results demonstrate a covert behavioral change in spatial neglect which may reflect the altered inter-hemispheric balance in the bilateral word recognition system encompassing lexico-semantic memory. PMID- 21292252 TI - Does exposure to air pollution in urban parks have socioeconomic, racial or ethnic gradients? AB - Little is known about the levels of air pollution at public parks where regular exercise takes place or in park-adjacent neighborhoods where people have easy access to parks. In this study we investigated the ambient concentrations of criteria pollutants nitrogen dioxide (NO(2)), fine particulate (PM(2.5)) and ozone (O(3)) at public parks and in park-adjacent neighborhoods for metropolitan Los Angeles. Socioeconomic and racial-ethnic inequalities in exposure to the three criteria pollutants were also investigated using multiple linear regression models. In addition, differences in inhalation doses from breathing the three +criteria pollutants were investigated for the top and bottom quartile racial composition in the parks and neighborhoods. Our research showed that although public parks had on average the lowest pollutant concentrations of NO(2) and PM(2.5), they had relatively high O(3) concentrations. Park-adjacent neighborhoods, by contrast, had the highest NO(2) and PM(2.5) concentrations, but the lowest O(3) concentrations. Higher exposures to NO(2) and PM(2.5) were systematically identified for the lower socioeconomic position or higher minority population neighborhoods. For children and adolescents aged 6-15 engaging in high and moderate intensity activities in and around public parks, those from the top quartile of primarily Hispanic neighborhoods had much higher (63%) inhaled doses of NO(2) compared to the bottom quartile counterpart. PM(2.5) showed a similar but less pronounced pattern of inhalation doses. Evidence of socioeconomic and racial-ethnic gradients was found in air pollution exposure and inhalation doses in and around the urban parks in Los Angeles. This suggests that patterns of exposure inequality found in other environmental justice research are present in exposures in and around urban parks. PMID- 21292253 TI - Sperm chromatin condensation in infertile men with varicocele before and after surgical repair. AB - OBJECTIVE: To assess sperm chromatin integrity in infertile men with varicocele before and after surgical repair. DESIGN: Prospective. SETTING: Academic setting. PATIENT(S): Seventy-two infertile men with varicocele compared with 20 healthy fertile men. INTERVENTION(S): History taking, genital examination, semen analysis, sperm chromatin condensation assessment by aniline blue stain before and 3 months after varicocelectomy. MAIN OUTCOME MEASURE(S): Stained sperm heads (abnormal chromatin condensation) before and 3 months after varicocelectomy. RESULT(S): The mean percentage of aniline blue-stained sperm heads was significantly higher in infertile men with varicocele compared with fertile controls. The mean percentage of stained sperm heads was significantly decreased in infertile men with varicocele 3 months after surgery compared with the preoperative data. There was a significant negative correlation between percentage of stained sperm heads and normal morphology where nonsignificant correlation was elicited regarding sperm count and sperm motility. CONCLUSION(S): There is a significant increase of abnormal sperm chromatin condensation in infertile men with varicocele that is markedly improved after varicocelectomy. PMID- 21292254 TI - Finasteride-induced secondary infertility associated with sperm DNA damage. AB - OBJECTIVE: To report a case of low-dose finasteride-induced secondary infertility with associated elevated sperm DNA fragmentation index (DFI) and otherwise normal semen parameters. DESIGN: Case report. SETTING: University hospital. PATIENT(S): A 48-year-old man on low-dose finasteride and his 37-year-old wife with normal menses and normal gynecologic exam. INTERVENTION(S): Determination of sperm DFI and discontinuation of low-dose finasteride. MAIN OUTCOME MEASURE(S): Sperm DFI. RESULT(S): The sperm DFI done a year earlier was 30%. This value was unchanged when repeated 2 months later. The patient was advised to stop finasteride. Three months after discontinuing the finasteride, the DFI decreased to 21% and subsequent DFI after another 3 months improved to 16.5%. To date, there is still no documented full-term pregnancy or live birth. CONCLUSION(S): The significant reduction in DFI within 3 months of finasteride cessation and continued improvement suggests a causal link between finasteride and sperm DNA damage. We hypothesize that low-dose finasteride may exert a negative influence on sperm DNA integrity, resulting in increased pregnancy losses. We suggest that in infertile men using finasteride, sperm DFI should be measured in addition to semen parameters, and a trial of discontinuation of finasteride may be warranted. PMID- 21292255 TI - Random-start controlled ovarian hyperstimulation for emergency fertility preservation in letrozole cycles. AB - OBJECTIVE: To report an emergency approach of random-start controlled ovarian hyperstimulation (COH) in the late follicular or luteal phase of the menstrual cycle for embryo cryopreservation in patients with cancer. DESIGN: Case series. SETTING: Academic tertiary referral centers. PATIENT(S): Three patients with a diagnosis of breast cancer requiring emergency fertility preservation in the late follicular or luteal phase of the menstrual cycle. INTERVENTION(S): After baseline pelvic ultrasound and hormonal evaluation, random-start COH was commenced immediately on menstrual cycle days 11, 14, or 17 with use of letrozole 2.5 mg/d and recombinant FSH 150 to 300 IU/d. Gonadotropin-releasing hormone antagonist was administered to prevent ovulation in all cases. Ovulation was triggered with either 250 MUg of recombinant hCG or 10,000 IU of urinary hCG. MAIN OUTCOME MEASURE(S): Number of oocytes harvested, maturity and fertilization rates, number of embryos frozen. RESULT(S): Nine to 17 oocytes were harvested, resulting in the freezing of seven to 10 embryos with the mean maturity and fertilization rates of 58.8% to 77.7% and 69.2% to 87.5%, respectively. CONCLUSION(S): In an emergent setting, ovarian stimulation can be started at a random cycle date for the purpose of fertility preservation without compromising fertilization rates in letrozole cycles. PMID- 21292256 TI - Is there really no improvement in pregnancy rate with double intrauterine insemination in unexplained infertility? PMID- 21292258 TI - Cervical pregnancy. AB - OBJECTIVE: To present a case of successful management of a heavily bleeding cervical ectopic pregnancy with ultrasound-guided termination procedure of evacuation. DESIGN: Case report. SETTING: University hospital. PATIENT(S): A 34 year-old woman, secundigravida with one previous full-term natural childbirth and history of one spontaneous abortion, with a cervical pregnancy. INTERVENTION(S): Prophylactic suture ligation of the cervicovaginal branches of the uterine artery, with absorbable sutures at the 3 and 9 o'clock positions of the cervix. Evacuation, with dilatation and curettage, under transabdominal ultrasound guidance was performed. Control of hemorrhage by placing a running-lock absorbable suture around the entire edge of the cervix followed by cervical packing with iodoform gauze medicated with anticoagulant drugs. MAIN OUTCOME MEASURE(S): Recovery of the patient, successful conservative treatment of the cervical ectopic pregnancy, with preservation of the uterus. RESULT(S): The cervical ectopic pregnancy was successfully evacuated, and the reproductive capability of the patient was preserved. CONCLUSION(S): Ultrasound-guided evacuation with prophylactic closure of the cervical branches of the uterine artery and application of a running-lock suture around the cervix can be used in case of heavily bleeding cervical ectopic pregnancy. PMID- 21292259 TI - The role of gene defects underlying isolated hypogonadotropic hypogonadism in patients with constitutional delay of growth and puberty. AB - Variation in FGFR1, GNRHR, TAC3, and TACR3 was evaluated in 146 Finnish subjects with constitutional delay of growth and puberty. Although one male subject carried a previously undescribed heterozygous deletion (Phe309del) in GNRHR, which segregated with delayed puberty in his family, mutations in the coding regions of FGFR1, GNRHR, TAC3, and TACR3 are not likely to underlie common constitutional delay of growth and puberty. PMID- 21292260 TI - In vitro fertilization outcomes in patients experiencing a premature rise in luteinizing hormone during a gonadotropin-releasing hormone antagonist cycle. AB - Patients undergoing controlled ovarian hyperstimulation and pituitary suppression with a GnRH antagonist who experienced a transient premature rise in LH were compared with those who did not have an early surge. Those experiencing a premature LH surge had equivalent clinical and ongoing pregnancy rates per ET. PMID- 21292261 TI - Successful fertility management of a patient with factor V deficiency: planned transfusion of fresh frozen plasma under infertility treatment. AB - OBJECTIVE: To report the case of a patient with factor V deficiency who achieved pregnancy with the planned transfusion of fresh frozen plasma (FFP) while monitoring follicle development and ovulation induction using gonadotropin. DESIGN: Case report. SETTING: University hospital. PATIENT(S): A 28-year-old nulliparous female. INTERVENTION(S): Medical management including infertility treatment. MAIN OUTCOME MEASURE(S): Clinical follow-up. RESULT(S): A patient with factor V deficiency experienced repeated ovulation-related hemoperitoneum following the withdrawal of oral contraceptive pills. The monitoring of follicle development and ovulation induction using gonadotropin followed by FFP transfusion was useful to avoid hemoperitoneum. Pregnancy was achieved within a relatively short period using intrauterine insemination. CONCLUSION(S): Planned prophylactic FFP administration and intervention with infertility treatment might be useful to minimize the risk of ovulation-related hemoperitoneum in patients with factor V deficiency. PMID- 21292262 TI - Endoscopic radiofrequency ablation combined with endoscopic resection for early neoplasia in Barrett's esophagus longer than 10 cm. AB - BACKGROUND: Radiofrequency ablation (RFA) is safe and effective for eradicating Barrett's esophagus (BE) and BE-associated early neoplasia. Most RFA studies have limited the baseline length of BE (<10 cm), and therefore little is known about RFA for longer BE. OBJECTIVE: To assess the safety and efficacy of RFA with or without prior endoscopic resection (ER) for BE >= 10 cm containing neoplasia. DESIGN: Prospective trial. SETTING: Two tertiary-care centers. PATIENTS: This study involved consecutive patients with BE >= 10 cm with early neoplasia. INTERVENTION: Focal ER for visible abnormalities, followed by a maximum of 2 circumferential and 3 focal RFA procedures every 2 to 3 months until complete remission. MAIN OUTCOME MEASUREMENTS: Complete remission, defined as endoscopic resolution of BE and no intestinal metaplasia (CR-IM) or neoplasia (CR-neoplasia) in biopsy specimens. RESULTS: Of the 26 patients included, 18 underwent ER for visible abnormalities before RFA. The ER specimens showed early cancer in 11, high-grade intraepithelial neoplasia (HGIN) in 6, and low-grade intraepithelial neoplasia (LGIN) in 1. The worst residual histology, before RFA and after any ER, was HGIN in 16 patients and LGIN in 10 patients. CR-neoplasia and CR-IM were achieved in 83% (95% confidence interval [CI], 63%-95%) and 79% (95% CI, 58% 93%), respectively. None of the patients had fatal or severe complications and 15% (95% CI, 4%-35%) had moderate complications. During a mean (+/- standard deviation) follow-up of 29 (+/- 9.1) months, no neoplasia recurred. LIMITATIONS: Tertiary-care center, short follow-up. CONCLUSION: ER for visible abnormalities, followed by RFA of residual BE is a safe and effective treatment for BE >= 10 cm containing neoplasia, with a low chance of recurrence of neoplasia or BE during follow-up. PMID- 21292263 TI - Recursive fuzzy c-means clustering for recursive fuzzy identification of time varying processes. AB - In this paper we propose a new approach to on-line Takagi-Sugeno fuzzy model identification. It combines a recursive fuzzy c-means algorithm and recursive least squares. First the method is derived and than it is tested and compared on a benchmark problem of the Mackey-Glass time series with other established on line identification methods. We showed that the developed algorithm gives a comparable degree of accuracy to other algorithms. The proposed algorithm can be used in a number of fields, including adaptive nonlinear control, model predictive control, fault detection, diagnostics and robotics. An example of identification based on a real data of the waste-water treatment process is also presented. PMID- 21292264 TI - Genetic predisposition influences plasma lipids of participants on habitual diet, but not the response to reductions in dietary intake of saturated fatty acids. AB - OBJECTIVE: SNPs identified from genome-wide association studies associate with lipid risk markers of cardiovascular disease. This study investigated whether these SNPs altered the plasma lipid response to diet in the 'RISCK' study cohort. METHODS: Participants (n=490) from a dietary intervention to lower saturated fat by replacement with carbohydrate or monounsaturated fat, were genotyped for 39 lipid-associated SNPs. The association of each individual SNP, and of the SNPs combined (using genetic predisposition scores), with plasma lipid concentrations was assessed at baseline, and on change in response to 24 weeks on diets. RESULTS: The associations between SNPs and lipid concentrations were directionally consistent with previous findings. The genetic predisposition scores were associated with higher baseline concentrations of plasma total (P=0.02) and LDL (P=0.002) cholesterol, triglycerides (P=0.001) and apolipoprotein B (P=0.004), and with lower baseline concentrations of HDL cholesterol (P<0.001) and apolipoprotein A-I (P<0.001). None of the SNPs showed significant association with the reduction of plasma lipids in response to the dietary interventions and there was no evidence of diet-gene interactions. CONCLUSION: Results from this exploratory study have shown that increased genetic predisposition was associated with an unfavourable plasma lipid profile at baseline, but did not influence the improvement in lipid profiles by the low saturated-fat diets. PMID- 21292265 TI - Phytoestrogen alpha-zearalanol improves vascular function in ovariectomized hyperhomocysteinemic rats. AB - Previous studies have showed that phytoestrogen alpha-zearalanol (alpha-ZAL) could antagonize homocysteine (Hcy) induced endothelin-1 (ET-1) expression, oxidative stress and apoptosis in human umbilical vein endothelial cells in vitro, however, its effect on vascular function in vivo remains to be determined. This study was designed to investigate the effects of alpha-ZAL on vascular function in ovariectomized (OVX) hyperhomocysteinemia (HHcy) rats and explore the mechanisms involved primarily. HHcy rat model was induced by diets containing 2.5% methionine (Met) for 12 weeks. Forty adult female Wistar rats were assigned randomly into five groups: (1) Con; (2) Met; (3) OVX+Met; (4) OVX+Met+alpha-ZAL; (5) OVX+Met+17beta-E(2) (17beta-estradiol). Blood was collected to analyze plasma estradiol, Hcy and ET-1. Thoracic aortas were isolated to detect its response to phenylephrine (PE) and acetylcholine (ACh) or sodium nitroprusside (SNP). Aortas eNOS expression was determined by Western blot. Thoracic aortas histological characterization was analyzed by optical microscope and scanning electron microscope (SEM). Rat plasma Hcy was significantly elevated after fed with 2.5% methionine diets, and ovariectomy aggravated this elevation. Phytoestrogen alpha ZAL or 17beta-E(2) could attenuate this elevation. Plasma ET-1 levels increased significantly in ovariectomized HHcy rats, and supplement with alpha-ZAL or 17beta-E(2) could reverse these changes. In rats of OVX+Met group, PE elicited significantly greater contraction in a dose-dependent manner in endothelium intact thoracic aortas rings; ACh elicited significantly less percentage relaxation. These effects were significantly attenuated by supplement with alpha ZAL or 17beta-E(2). There was no significant difference between groups in relaxation induced by SNP whether endothelium intact or not. Thoracic aortas morphology study also showed severe endothelium injury in ovariectomized HHcy rats, both alpha-ZAL and 17beta-E(2) could attenuate this change. Aortas eNOS expression was decreased in ovariectomized HHcy rats, and supplement with alpha ZAL or 17beta-E(2) could reverse these changes. These findings demonstrated that alpha-ZAL could effectively alleviate the impairment of endothelial cells and improve vascular function in ovariectomized HHcy rats by decreasing plasma Hcy and antagonizing decreasing of aortas eNOS expression. This protective effect is somewhat similar with 17beta-E(2). PMID- 21292266 TI - Electronegative low-density lipoprotein: origin and impact on health and disease. AB - Oxidative modifications in lipoproteins (LP), especially in low-density lipoproteins (LDL), are associated with initiation and progression of atherosclerosis. The levels of a sub-fraction of LDL with oxidative characteristics, named electronegative LDL [LDL(-)], minimally oxidized LDL, and minus LDL, are known to be increased in subjects with familial hypercholesterolemia, hypertriglyceridemia, nonalcoholic steatohepatitis, diabetes mellitus, coronary artery disease, patients undergoing hemodialysis, and athletes after aerobic exercise. In addition to the oxidative profile, physical and biological characteristics of LDL(-) consist of nonenzymatic glycosylation, increased expression and activity of platelet-activating factor acetylhydrolase (PAF-AH) and phospholipase A(2) (PLA(2)), enriched NEFA content, hemoglobin and ApoB-100 cross-linking, and increase in ApoC-III and ApoE in LDL. Herein, we summarize the state of the art of the up-to-date body of knowledge on the possible origin and impact of LDL(-) in health and disease. Further, the potential perspectives of using LDL(-) as a biomarker in conditions under metabolic stress are also discussed. PMID- 21292267 TI - The effects of the periodontal ligament on mandibular stiffness: a study combining finite element analysis and geometric morphometrics. AB - It is generally accepted that the periodontal ligament (PDL) plays a crucial role in transferring occlusal forces from the teeth to the alveolar bone. Studies using finite element analysis (FEA) have helped to better understand this role and show that the stresses and strains in the alveolar bone are influenced by whether and how PDL is included in FE models. However, when the overall distribution of stresses and strains in crania and mandibles are of interest, PDL is often not included in FE models, although little is known about how this affects the results. Here we study the effect of representing PDL as a layer of solid material with isotropic homogeneous properties in an FE model of a human mandible using a novel application of geometric morphometrics. The results show that the modelling of the PDL affects the deformation and thus strain magnitudes not only of the alveolar bone around the biting tooth, but that the whole mandible deforms differently under load. As a result, the strain in the mandibular corpus is significantly increased when PDL is included, while the strain in the bone beneath the biting tooth is reduced. These results indicate the importance of the PDL in FE studies. Thus we recommend that the PDL should be included in FE models of the masticatory apparatus, with tests to assess the sensitivity of the results to changes in the Young's modulus of the PDL material. PMID- 21292268 TI - Multiple mitral leaflet contractile systems in the beating heart. AB - Mitral valve closure may be aided by contraction of anterior leaflet (AL) cardiac myocytes located in the annular third of the leaflet. This contraction, observed as a stiffening of the annular region of the AL during isovolumic contraction (IVC), is abolished by beta-blockade (betaB). Sub-threshold rapid pacing in the region of aorto-mitral continuity (STIM) also causes AL stiffening, although this increases the stiffness of the entire leaflet during both IVC and isovolumic relaxation (IVR). We investigated whether these contractile events share a common pathway or whether multiple AL contractile mechanisms may be present. Ten sheep had radiopaque-markers implanted: 13 silhouetting the LV, 16 on the mitral annulus, an array of 16 on the AL, and one on each papillary muscle tip. 4-D marker coordinates were obtained from biplane videofluoroscopy during control (C), betaB (esmolol) and during betaB+STIM. Circumferential and radial stiffness values for three AL regions (Annular, Belly, and free-Edge), were obtained from inverse finite element analysis of AL displacements in response to trans-leaflet pressure changes during IVC and IVR. betaB+STIM increased stiffness values in all regions at both IVC and IVR by 35 +/- 7% relative to betaB (p<0.001). Thus, even when AL myocyte contraction was blocked by betaB, STIM stiffened all regions of the AL during both IVC and IVR. This demonstrates the presence of at least two contractile systems in the AL; one being the AL annular cardiac muscle, involving a beta-dependent pathway, others via a beta-independent pathway, likely involving valvular interstitial cells and/or AL smooth muscle cells. PMID- 21292269 TI - Asymmetrical flow field-flow fractionation technique for separation and characterization of biopolymers and bioparticles. AB - Field-flow fractionation (FFF) is one of the most versatile separation techniques in the field of analytical separation sciences, capable of separating macromolecules in the range 103-1015 g mol-1 and/or particles with 1 nm-100 MUm in diameter. The most universal and most frequently used FFF technique, flow FFF, includes three types of techniques, namely symmetrical flow FFF, hollow fiber flow FFF, and asymmetrical flow FFF which is most established variant among them. This review provides a brief look at the theoretical background of analyte retention and separation efficiency in FFF, followed by a comprehensive overview of the current status of asymmetrical flow FFF with selected applications in the field of biopolymers and bioparticles. PMID- 21292270 TI - Triazolo-linked cinchona alkaloid carbamate anion exchange-type chiral stationary phases: Synthesis by click chemistry and evaluation. AB - Immobilization strategy based on Huisgen 1,3-dipolar cycloaddition (click chemistry) of 10,11-didehydrocinchona tert-butylcarbamates to azido-grafted silica gels has been evaluated for preparation of novel chiral stationary phases (CSP 1-3). The resultant 1,2,3-triazole-linked CSPs were tested under various mobile phase conditions (polar organic and reversed phase mode) with a representative set of structurally diverse racemic acids including N-protected aminoacids, aromatic and aryloxycarboxylic acids as well as binaphthol phosphate. The chiral recognition performance of the C3-triazole-linked CSPs was found to mirror largely that of the known C3-thioether-linked CSP in terms of elution order, enantioselectivity and retention behavior. In an effort to assess the non specific binding expressed as retention increment of these triazole-linked CSPs, the parent azidopropyl- and triazole-modified silica materials (thus not containing the chiral head ligand) were studied independently. Compared with the corresponding CSPs, the analyte retention on the azidopropyl control column was very low, and practically negligible on the corresponding triazole-modified reference column. Only minor losses in analyte retention behavior (<5%) were observed with triazole-linked CSPs after two month of continuous use with polar organic and reversed-phase-type mobile phases, highlighting the excellent stability of the 1,2,3-triazole linker. PMID- 21292271 TI - Determination of volatile organic compounds in recycled polyethylene terephthalate and high-density polyethylene by headspace solid phase microextraction gas chromatography mass spectrometry to evaluate the efficiency of recycling processes. AB - A method for the determination of volatile organic compounds (VOCs) in recycled polyethylene terephthalate and high-density polyethylene using headspace sampling by solid-phase microextraction and gas chromatography coupled to mass spectrometry detection is presented. This method was used to evaluate the efficiency of cleaning processes for VOC removal from recycled PET. In addition, the method was also employed to evaluate the level of VOC contamination in multilayer packaging material containing recycled HDPE material. The optimisation of the extraction procedure for volatile compounds was performed and the best extraction conditions were found using a 75 MUm carboxen-polydimethylsiloxane (CAR-PDMS) fibre for 20 min at 60 degrees C. The validation parameters for the established method were linear range, linearity, sensitivity, precision (repeatability), accuracy (recovery) and detection and quantification limits. The results indicated that the method could easily be used in quality control for the production of recycled PET and HDPE. PMID- 21292272 TI - Characterization of new R-naphthylethyl cyclofructan 6 chiral stationary phase and its comparison with R-naphthylethyl beta-cyclodextrin-based column. AB - Derivatized cyclofructans have been recently introduced as a new class of chiral selectors with great application potential. In this study, a R-naphthylethyl functionalized cyclofructan 6 based chiral stationary phase (RN CF6 CSP) was used for separation of substituted binaphthyl catalysts in the normal phase HPLC mode. Dominant interaction types that play a role in the separation mechanism were revealed by a linear free energy relationship (LFER) method. In order to evaluate the contribution of the substituent on the cyclofructan structure to retention, the R-naphthylethyl-functionalized beta-cyclodextrin (RN CD) CSP was chosen for comparison. Retention factors of 46 widely different solutes, with known solvation parameters, were determined on each of the columns under the same mobile phase compositions used for the enantiomeric separations. The LFER results showed that hydrogen bond acidity and polarity/polarizibility have the greatest impact on retention and enantioresolution on the RN CF6 CSP. The equal influence of the naphthylethyl substituent on the both CSPs was also confirmed while the effects of the basic cyclofructan versus cyclodextrin structures were different. The addition of trifluoroacetic acid to the hexane/propane-2-ol mobile phase was negligible on the RN CF6 CSP for the majority of atropoisomers except for one with ionizable functional groups. The RN CF6 column was shown to be more suitable for enantioseparation of the binaphthyl catalysts than the RN CD column. Higher retention offered by the latter CSP had no positive effect on the enantioresolution. PMID- 21292273 TI - The hydrophilic interaction like properties of some reversed phase high performance liquid chromatography columns in the analysis of basic compounds. AB - The hydrophilic interaction chromatography (HILIC) like properties of an ACE cyano (CN) HPLC column was studied for the separation of some basic compounds. Good separation of a test mix of basic compounds was obtained with a mobile phase consisting of acetonitrile/water (95:5) containing 3.25 mM ammonium acetate. The retention times of the basic compounds decreased with increased ionic strength or with increased water content in the mobile phase. When Trishydroxymethyl aminomethane (Tris) (pK(a) 8.0), which is a weaker amine than ammonia (pK(a) 9.3), was used as an additive in the mobile phase retention of the basic compounds was increased. The ACE CN column gave excellent peak shapes for all the basic compounds. The utility of the column for impurity profiling of two basic drugs was tested and some impurities in oxprenolol were characterised by interfacing with Fourier transform mass spectrometry. It was also observed that ACE butyl and ACE phenyl columns retained basic compounds when the columns were eluted with a mobile phase consisting of acetonitrile/water (95:5) containing 3.25 mM ammonium acetate. PMID- 21292274 TI - Fast cation-exchange separation of proteins in a plastic microcapillary disc. AB - A novel disposable adsorbent material for fast cation-exchange separation of proteins was developed based on plastic microcapillary films (MCFs). A MCF containing 19 parallel microcapillaries, each with a mean internal diameter of 142 MUm, was prepared using a melt extrusion process from an ethylene-vinyl alcohol copolymer (EVOH). The MCF was surface functionalized to produce a cation exchange adsorbent (herein referred as MCF-EVOH-SP). The dynamic binding capacity of the new MCF-EVOH-SP material was experimentally determined by frontal analysis using pure protein solutions in a standard liquid chromatography instrument for a range of superficial flow velocities, u(LS)=5.5-27.7 cm s-1. The mean dynamic binding capacity for hen-egg lysozyme was found to be approximately 100 MUg for a 5 m length film, giving a ligand binding density of 413 ng cm-2. The dynamic binding capacity did not vary significantly over the range of u(LS) tested. The application of this novel material to subtractive chromatography was demonstrated for anionic BSA and cationic lysozyme at pH 7.2. The chromatographic separation of two cationic proteins, lysozyme and cytochrome-c, was also performed with a view to applying this technology to the analysis or purification of proteins. Future applications might include separation based on anion exchange and other modes of adsorption. PMID- 21292275 TI - Monoliths for the purification of whey protein-dextran conjugates. AB - Proteins conjugated to neutral biopolymers are of keen interest to the food and pharmaceutical industries. Conjugated proteins are larger and more charge shielded than un-reacted proteins, making purification difficult using conventional beaded chromatographic supports because of slow mass transfer rates, weak binding, and viscous solutions. Past methods developed for pharmaceuticals are unsuitable for foods. In this work, a food-grade whey protein-dextran conjugate was purified from a feed solution also containing un-reacted protein and dextran using either a column packed with 800 mL of a beaded support that was specifically designed for purification of conjugated proteins or an 8 mL tube monolith. The monolith gave a similar dynamic binding capacity as the beaded support (4-6 g/L), at a 42-fold greater mass productivity, and 48-fold higher flow rate, albeit at somewhat lower conjugate purity. Performance of the monolith did not depend on flow rate. In conclusion, monoliths were found to be well suited for the purification of whey protein-dextran conjugates. PMID- 21292276 TI - Simultaneous determination of pesticides, biopesticides and mycotoxins in organic products applying a quick, easy, cheap, effective, rugged and safe extraction procedure and ultra-high performance liquid chromatography-tandem mass spectrometry. AB - A method for the simultaneous determination of pesticides, biopesticides and mycotoxins from organic products was developed. Extraction of more than 90 compounds was evaluated and performed by using a modified QuEChERS-based (acronym of Quick, Easy, Cheap, Effective, Rugged, and Safe) sample preparation procedure. The method was based on a single extraction with acidified acetonitrile, followed by partitioning with salts, avoiding any clean-up step prior the determination by ultra-high performance liquid chromatography/tandem quadrupole mass spectrometry (UHPLC-MS/MS). Validation studies were carried out in wheat, cucumber and red wine as representative matrixes. Recoveries of the spiked samples were in the range between 70 and 120% (with intra-day precision, expressed as relative standard deviation, lower than 20%) for most of the analysed compounds, except picloram and quinmerac. Inter-day precision, expressed as relative standard deviation, was lower than 24%. Limits of quantification were lower than 10MUg kg 1 and the developed method was successfully applied to the analysis of organic food products, detecting analytes belonging to the three types of compounds. PMID- 21292277 TI - Location of anti-TB drugs and microstructural changes in organized surfactant media using optical properties. AB - Microstructure elucidation is a critical step in the understanding of organized surfactant media such as microemulsions. In this work, a systematic approach for revelation of microstructure changes of Tween 80 microemulsion has been carried out using photophysical properties. Microemulsion structural changes have been monitored using pyrene and different solvatochromic probes for the presence of oil-rich, water-rich, and bicontinuous microstructures. The hydrophobic optical probe, Nile red (NR), has been used to report from the side of the oil-surfactant interface and to complement this, a hydrophilic optical probe tris(2,2' bipyridine)ruthenium(II) dichloride (RC) from the side of the water-surfactant interface. The results show the partitioning of probes into different microenvironments within the system. NR occupies the interface toward the apolar side and RC toward the polar. The analysis also indicates conspicuous dependence of the emission/absorbance behavior of optical probes on the water:surfactant molar ratio (omega). Quantitative estimates have been obtained for the polarities (ET(30)) of solubilization sites of the probes in different regions of microemulsions and are well correlated with a Stokes shift. Lastly, these probes of different solubilities have been used to locate the position of anti tuberculosis drugs, i.e., rifampicin (hydrophobic), pyrazinamide, and isoniazid (hydrophilic) of variable solubilities loaded in Tween 80 systems. PMID- 21292278 TI - Thermodynamic parameters and counterion binding to the micelle in binary anionic surfactant systems. AB - Competitive counterion binding of sodium and calcium to micelles, and mixed micellization have been investigated in the systems sodium dodecylsulfate (NaDS)/sodium decylsulfate (NaDeS) and NaDS/sodium 4-octylbenzenesulfonate (NaOBS) in order to accurately model the activity of the relevant species in solution. The critical micelle concentration (CMC) and equilibrium micelle compositions of mixtures of these anionic surfactants, which is necessary for determining fractional counterion binding measurements, is thermodynamically modeled by regular solution theory. The mixed micelle is ideal (the regular solution parameter beta(M)=0) for the NaDS/NaOBS system, while the mixed micelle for NaDS/NaDeS has beta(M)=-1.05 indicating a slight synergistic interaction. Counterion binding of sodium to the micelle is influenced by the calcium ion concentration, and vice versa. However, the total degree of counterion binding is essentially constant at approximately 0.65 charge negation at the micelle's surface. The counterion binding coefficients can be quantitatively modeled using a simple equilibrium model relating concentrations of bound and unbound counterions. PMID- 21292279 TI - Self-assembly of disk-like multiring ZnO-SnO2 colloidal nanoparticles. AB - ZnO-SnO(2) colloidal nanoparticles have been successfully synthesized by using the composite of ZnCl(2) and Sn(OC(4)H(9))(4) as inorganic precursor and dodecylbenzenesulfonic acid (DBSA) as an organic template. The assembled nanostructures of ZnO-SnO(2) products have been carefully investigated by powder X-ray diffraction (XRD) and transmission electron microscopy (TEM). It is found that ZnO-SnO(2) colloidal nanoparticles take a disk-like multiring nanostructure. This interesting structure is predominantly determined by the tenacity for ZnO SnO(2) mixtures to stabilize lamellae. A mechanism based on electrostatic interactions between the precursor and template has been proposed to illustrate the resulting nanoparticle structure. PMID- 21292280 TI - Patterns of levels of biological metals in CSF differ among neurodegenerative diseases. AB - We measured the levels of some biological metals: copper (Cu), iron (Fe), magnesium (Mg), manganese (Mn), and zinc (Zn) in the cerebrospinal fluid (CSF) in patients with neurodegenerative diseases (52 patients with amyotrophic lateral sclerosis (ALS)), 21 patients with Alzheimer's disease (AD), and 20 patients with Parkinson's disease (PD) by inductively coupled plasma mass spectrometry (ICP MS). The diagnoses were additionally supported by neuroimaging techniques for AD and PD. In ALS, the levels of Mg (p<0.01 significant difference), Fe, Cu (p<0.05), and Zn (p<0.10) in CSF were higher than those in controls. Some patients showed very high levels of Cu and Zn before the critical deterioration of the disease. In AD, the levels of Cu and Zn in CSF were significantly higher in patients with late-onset AD (p<0.01). In PD, we found significantly increased levels of especially Cu and Zn in particular (p<0.01) and Mn (p<0.05) in CSF. A multiple comparison test suggested that the increased level of Mg in ALS and that of Mn in PD were the pathognomonic features. These findings suggest that Cu and Zn in particular play important roles in the onset and/or progression of ALS, AD, and PD. Therefore, Cu-chelating agents and modulators of Cu and Zn such as metallothionein (MT) can be new candidates for the treatment of ALS, AD, and PD. PMID- 21292281 TI - Review of the etiologies of viral meningitis and encephalitis in a dengue endemic region. AB - OBJECTIVES: To evaluate the etiology of viral meningitis and encephalitis in adults and adolescents living in areas affected by dengue. METHODS: Over two years, adults and adolescents with diagnoses of viral encephalitis or meningitis were selected for study in Brazil. PCRs for dengue, enterovirus, HSV1 and 2 and cytomegalovirus were performed in CSF samples. Serum and CSF samples were tested for the presence of anti-dengue IgM antibodies. RESULTS: The etiologies of encephalitis and meningitis were determined in 70% of cases (30/47). Dengue was the leading cause of encephalitis (47%) with normal CSF cellularity in 75% of these patients. HSV1 was found in 17.6% of the cases, two of which had mild encephalitis. Enterovirus was the most common cause of meningitis (50%), followed by HSV1 (15%), cytomegalovirus and dengue (10%, each). CONCLUSIONS: We identified the viral agents causing encephalitis and meningitis in a higher proportion of cases than has been reported in other studies. Dengue was the most frequent cause of encephalitis, which surpassed HSV. In endemic areas, dengue should be investigated as an important cause of encephalitis. Normal CSF cellularity should not exclude dengue encephalitis. Enterovirus is known to be the leading cause of meningitis in children, but here we found it was also the main cause of the disease in adults. HSV1 should be investigated in patients with mild forms of encephalitis and meningitis. PMID- 21292283 TI - Diagnostic accuracy of dual-source multislice computed tomographic analysis for the preoperative detection of coronary artery anomalies in 100 patients with tetralogy of Fallot. AB - OBJECTIVES: A detailed preoperative evaluation of coronary anatomy is mandatory before surgical intervention for tetralogy of Fallot. In pediatric patients, the preoperative evaluation of coronary anatomy has relied classically on conventional angiographic analysis and, more recently, on echocardiographic analysis, which have well-known limitations and complications. Recent technological improvements allow the use of multislice computed tomographic analysis to evaluate coronary artery anatomy in very young children, even those with high heart rates. The purpose of this prospective study was to assess the accuracy of preoperative dual-source computed tomographic analysis in detecting coronary artery abnormalities by using surgical findings as the reference standard. METHODS: We prospectively evaluated 100 patients with tetralogy of Fallot before surgical intervention between November 2006 and September 2009 by using dual-source computed tomographic analysis with either retrospective, electrocardiographically gated, helical computed tomographic analysis or prospective, electrocardiographically triggered, sequential computed tomographic acquisition. The patients had a median age of 6.8 months (range, 1.2 months-6.8 years) and a median weight of 7.9 kg (range, 3-30 kg). RESULTS: Compared with surgical findings, dual-source computed tomographic analysis had 100% sensitivity and 100% specificity for detecting coronary artery abnormalities. Major coronary artery abnormalities were found in 7 (7%) patients. The radiation dose was low. CONCLUSIONS: Dual-source computed tomographic analysis is an accurate and noninvasive tool for delineating coronary artery anatomy before surgical intervention in children with tetralogy of Fallot. Dual-source computed tomographic analysis might deserve to be used routinely instead of angiographic analysis and in combination with echocardiographic analysis for the preoperative assessment of patients with tetralogy of Fallot. PMID- 21292284 TI - Assessment and repair of aortic valve cusp prolapse: implications for valve sparing procedures. AB - OBJECTIVES: Cusp prolapse causing aortic insufficiency is associated with unique echocardiographic, clinical, and surgical features. Recognition and appropriate surgical repair of this pathologic condition can not only treat affected patients but also improve results of aortic valve-sparing procedures, for which pre existing or induced cusp prolapse is an important cause of failure. METHODS: Of 428 patients undergoing aortic valve repair, 195 (46%) were treated for cusp prolapse, and 111 (57%) of those had trileaflet aortic valve and make up this cohort. Cusp disease was the sole mechanism for aortic insufficiency (isolated group) in 50 patients whereas aortic dilatation was contributory in 61 (associated group). In total, 144 cusps were repaired in 111 patients. Preoperative echocardiograms, intraoperative findings, and clinical and echocardiographic outcomes were reviewed. RESULTS: On preoperative echocardiography, presence of an eccentric aortic insufficiency jet, regardless of severity, had 92% sensitivity and 96% specificity for the detection of single cusp prolapse. A transverse fibrous band was characteristically identified on the prolapsing cusp (sensitivity 57%; specificity 92%), correctly localizing a prolapsing cusp in all cases. Freedom from aortic valve reoperation at 8 years was 100% in the isolated group and 93% +/- 5% in the associated group (p = 0.33). Freedom from recurrent aortic insufficiency (>2+) at 5 years was 90% +/- 5% in the isolated and 85% +/- 8% in the associated group (P = .54). The choice of surgical technique did not affect aortic insufficiency recurrence at follow-up (P = .6). CONCLUSIONS: Recognition and repair of isolated aortic cusp prolapse provides durable midterm outcome. An eccentric aortic insufficiency jet and a fibrous band can aid in the diagnosis and localization of cusp prolapse associated with ascending aortic disease and may help to improve results of aortic valve-sparing procedures. PMID- 21292285 TI - Bicuspid aortic valve surgery with proactive ascending aorta repair. AB - OBJECTIVES: Bicuspid aortic valves are associated with aortic catastrophes, particularly dissection. We examined whether proactive repair of associated dilatation would reduce risk of subsequent aortic dissection or reoperation and whether more aggressive resection is needed in patients undergoing bicuspid aortic valve surgery alone. METHODS: From January 1993 to June 2003, 1989 patients (of our total experience of 4316) underwent bicuspid aortic valve surgery. Long-term outcomes of 1810 were analyzed according to aortic size and whether bicuspid aortic valve surgery was performed alone or with aortic repair. RESULTS: In-hospital 30-day survival was similar (98.8% valve alone vs 98.9% with aortic repair), with no penalty incurred for concomitant aortic repair. Bicuspid aortic valve-alone patients had worse late survival (75% vs 85% at 10 years, P = .0001), but in the matched cohort survival was nearly identical (85% vs 86%; P = .7). With this strategy, freedom from late aortic events was high in both groups (99% valve alone vs 97% with aortic repair at 10 years; P[log-rank] = .06) and similar in the matched cohort (95% vs 97%; P = .2). Approximately 95% of patients undergoing valve-alone surgery had aortic diameters smaller than 4.6 cm or cross sectional area/height ratios less than 9.4 cm(2)/m; 80% undergoing valve surgery plus aortic repair had diameters larger than 4.1 cm or ratios greater than 7.3 cm(2)/m. Only 0.2% of events occurred at an aortic diameter size of less than 4.5 cm. CONCLUSIONS: Aortic size larger than 4.5 cm or aortic cross-sectional area/height ratio greater than 8 to 10 should be considered triggers for concurrent aortic repair, because there is no added risk, and late survival is better; however, more aggressive resection is unwarranted. PMID- 21292286 TI - Effect of cleavage enzyme, search algorithm and decoy database on mass spectrometric identification of wheat gluten proteins. AB - While tandem mass spectrometry (MS/MS) is routinely used to identify proteins from complex mixtures, certain types of proteins present unique challenges for MS/MS analyses. The major wheat gluten proteins, gliadins and glutenins, are particularly difficult to distinguish by MS/MS. Each of these groups contains many individual proteins with similar sequences that include repetitive motifs rich in proline and glutamine. These proteins have few cleavable tryptic sites, often resulting in only one or two tryptic peptides that may not provide sufficient information for identification. Additionally, there are less than 14,000 complete protein sequences from wheat in the current NCBInr release. In this paper, MS/MS methods were optimized for the identification of the wheat gluten proteins. Chymotrypsin and thermolysin as well as trypsin were used to digest the proteins and the collision energy was adjusted to improve fragmentation of chymotryptic and thermolytic peptides. Specialized databases were constructed that included protein sequences derived from contigs from several assemblies of wheat expressed sequence tags (ESTs), including contigs assembled from ESTs of the cultivar under study. Two different search algorithms were used to interrogate the database and the results were analyzed and displayed using a commercially available software package (Scaffold). We examined the effect of protein database content and size on the false discovery rate. We found that as database size increased above 30,000 sequences there was a decrease in the number of proteins identified. Also, the type of decoy database influenced the number of proteins identified. Using three enzymes, two search algorithms and a specialized database allowed us to greatly increase the number of detected peptides and distinguish proteins within each gluten protein group. PMID- 21292287 TI - Acylated flavonol glycosides from the forage legume, Onobrychis viciifolia (sainfoin). AB - Ten acylated flavonol glycosides were isolated from aqueous acetone extracts of the aerial parts of the forage legume, Onobrychis viciifolia, and their structures determined using spectroscopic methods. Among these were eight previously unreported examples which comprised either feruloylated or sinapoylated derivatives of 3-O-di- and 3-O-triglycosides of kaempferol (3,5,7,4' tetrahydroxyflavone) or quercetin (3,5,7,3',4'-pentahydroxyflavone). The diglycosides were acylated at the primary Glc residue of O-alpha-Rhap(1->6)-beta Glcp (rutinose), whereas the triglycosides were acylated at the terminal Rha residues of the branched trisaccharides, O-alpha-Rhap(1->2)[alpha-Rhap(1->6)] beta-Galp or O-alpha-Rhap(1->2)[alpha-Rhap(1->6)]-beta-Glcp. Identification of the primary 3-O-linked hexose residues as either Gal or Glc was carried out by negative ion electrospray and serial MS, and cryoprobe NMR spectroscopy. Analysis of UV and MS spectra of the acylated flavonol glycosides provided additional diagnostic features relevant to direct characterisation of these compounds in hyphenated analyses. Quantitative analysis of the acylated flavonol glycosides present in different aerial parts of sainfoin revealed that the highest concentrations were in mature leaflets. PMID- 21292288 TI - A sesquiterpenol extract potently suppresses inflammation in macrophages and mice skin and prevents chronic liver damage in mice through JNK-dependent HO-1 expression. AB - This study aimed to elucidate the anti-inflammatory and hepatoprotective bioactivities of a sesquiterpenol, (1S,6R)-2,7(14),10-bisabolatrien-1-ol-4-one (BSL), isolated from Cryptomeria japonica (Taxodiaceae) wood extract. BSL markedly suppressed TNF-alpha and IL-6 secretion, PGE(2) production, and mRNA expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX 2), in lipopolysaccharide (LPS)-stimulated mouse macrophages. BSL also potently inhibited the 12-O-tetradecanoylphorbol-13-acetate (TPA) induced protein levels of nitrotyrosine and COX-2 in mouse skin with dermatitis. Conversely, the stress protein heme oxygenase-1 (HO-1) was found upregulated in the same BSL-treated macrophages, probably through activation of the JNK-dependent pathway. LPS induced activation of NF-kappaB and mitogen-activated protein kinase signaling pathways, however, was not responsive to BSL treatment. A BSL-enriched extract (BSL-E; 10mg/kg) significantly prevented CCl(4)-induced chronic liver injury, lipid accumulation, and cell necrosis and inhibited aminotransferase activities and iNOS and COX-2 overexpression in mice liver tissues, an effect comparable with that of silymarin, a hepatoprotective drug. PMID- 21292289 TI - [Long-term follow-up of cemento-osseous dysplasia: a contralateral recurrence before radiotherapy]. AB - INTRODUCTION: Cemento-osseous dysplasia is a benign fibro-osseous lesion of the jaws. Its complications are very rare. OBSERVATION: A panoramic x-ray was made to complete the pre-radiotherapy oral assessment of a 71-year-old female patient presenting with lung adenocarcinoma. This revealed a periapical fibro-osseous lesion on tooth n degrees 46. She had presented with a similar lesion on tooth n degrees 36, 16 years before. This had been treated by extraction and alveolar curettage. No surgical treatment was suggested for this recurrence on tooth n degrees 46. DISCUSSION: The diagnosis of focal cemento-osseous dysplasia is usually made on radiological and clinical data. The risk for transition to a florid form is unknown. Exeresis surgery before radiotherapy is discussed. PMID- 21292290 TI - [The tongue flap in palatal defect reconstruction]. AB - INTRODUCTION: A palatal defect with bucconasal fistula often follows exeresis of palatal tumors. It cannot be directly sutured. Several techniques have been used to cure such defects: palatal obturator, free, or local flaps. TECHNICAL NOTE: The tongue pediculated flap is an easy, safe, and reliable surgical option to reconstruct palatal defects. The tongue flap is a double-layer muscular and mucosal flap that requires two surgeries. During the first, the flap is harvested on the tongue and partially sutured on the anterior portion of the palatal defect. During the second, the pedicle is freed from the tongue and sutured to the posterior portion of the palatal defect. Between these two surgeries the patient is fed through a nasogastric tube. DISCUSSION: The tongue flap is easy and reproducible. It can be recommended in mediopalatal defects after cancer palatal surgery. Its esthetical and functional results are excellent. It is an alternative to palatal obturator, which are not well tolerated in the long run. Similar but uneven results are obtained with free flaps. Free flaps do not require a second surgery but are more difficult to implement in developing countries. PMID- 21292291 TI - Epidemic of Plasmodium falciparum malaria in Central India, an area where chloroquine has been replaced by artemisinin-based combination therapy. AB - India contributes greatly to the global incidence of malaria. The factors influencing malaria in India are highly diverse and vary greatly from the epidemiological setting of any other country. Central India is the most vulnerable area to malaria in India. This study was carried out in three community health centres in Dindori District, Madhya Pradesh (Central India). Dindori District is mesoendemic for malaria, with both Plasmodium falciparum and P. vivax being present in all age groups. Anopheles culicifacies and A. fluviatilis are highly efficient vectors of malaria. In this study, an epidemic of malaria among indigenous ethnic group Baigas was investigated to determine the causes of the epidemic and the population involved in order to aid in disease containment. The existence of sporozoite-positive A. culicifacies and A. fluviatilis indicates either that spraying had not been done properly or the presence of insecticide resistance. A combination of factors propagated the epidemic. Evidence suggests that the non-availability of artemisinin-based combination therapy and rapid diagnostic tests along with an immunogenically vulnerable population each played an important role. As the global prevalence of malaria decreases owing to initiatives to control or eliminate the disease, more areas will become mesoendemic or hypoendemic for malaria. Detection and control of epidemics requires greater attention, and mechanisms to ensure the quality of interventions are essential. PMID- 21292292 TI - Dynamic modeling of thickness-mode piezoelectric transducer using the block diagram approach. AB - This paper aims to provide an alternative method to determine the characteristics of a piezoelectric transducer from measurement. A block diagram approach is proposed to analyze the dynamic characteristics of a thickness-mode piezoelectric transducer at its resonance frequency. Based on the feedback loop framework, the input-output relations of the electromechanical interaction of the transducer are described in terms of linear block diagram models. Furthermore, the closed-loop relations from external force to vibration velocity and electric current from generated voltage are easily found by Mason's rule to characterize the equivalent mechanical admittance and electrical impedance, respectively. An example of a Langevin transducer with 28.15kHz resonance frequency is illustrated for dynamics analysis. The frequency responses of the piezoelectric transducer, resulting from a force and current input, are respectively measured to identify the system parameters of the feedback model. The experimental results demonstrate the effectiveness of the proposed method. PMID- 21292293 TI - West Nile virus (WNV) genome RNAs with up to three adjacent mutations that disrupt long distance 5'-3' cyclization sequence basepairs are viable. AB - Mosquito-borne flavivirus genomes contain conserved 5' and 3' cyclization sequences (CYC) that facilitate long distance RNA-RNA interactions. In previous studies, flavivirus replicon RNA replication was completely inhibited by single or multiple mismatching CYC nt substitutions. In the present study, full-length WNV genomes with one, two or three mismatching CYC substitutions showed reduced replication efficiencies but were viable and generated revertants with increased replication efficiency. Several different three adjacent mismatching CYC substitution mutant RNAs were rescued by a second site mutation that created an additional basepair (nts 147-10913) on the internal genomic side of the 5'-3' CYC. The finding that full-length genomes with up to three mismatching CYC mutations are viable and can be rescued by a single nt spontaneous mutation indicates that more than three adjacent CYC basepair substitutions would be required to increase the safety of vaccine genomes by creating mismatches in inter-genomic recombinants. PMID- 21292295 TI - Residency choices by graduating medical students: why not pathology? AB - Pathology is an unpopular residency choice for medical students worldwide. In some countries, this has contributed to a crisis in pathologist human resources that has affected the quality of clinical laboratories. Several previous studies have used information from junior medical students and from residents to suggest ways of improving pathology recruitment. There are, however, no published studies of pathology residency choice that focus on the senior medical students who must be recruited. This study uses focus groups of senior medical students to explore both general and pathology-specific influences on residency choice. Several general influences are identified, including students' expectations for their future clinical practices, their own clinical rotation experiences, influences from other people including mentors, and their choice to reject certain fields. Several specific antipathology influences are also revealed, including negative stereotypes about pathologists, a perceived incompatibility of personality between most medical students (extroverted) and pathologists (introverted), and perceptions of pathologists as being in some ways nonmedical. The most important antipathology influence was that, from the students' perspective, pathology was utterly invisible in clinical practice. Most students did not consider and then reject a pathology residency: instead, pathology was completely ignored. Given the importance of clerkship electives in influencing medical student career choice, promoting clerkship experiences in pathology may improve recruitment. However, departments of pathology must first make pathology visible to students and teach them how pathologists contribute to clinical care. PMID- 21292294 TI - Complement and viral pathogenesis. AB - The complement system functions as an immune surveillance system that rapidly responds to infection. Activation of the complement system by specific recognition pathways triggers a protease cascade, generating cleavage products that function to eliminate pathogens, regulate inflammatory responses, and shape adaptive immune responses. However, when dysregulated, these powerful functions can become destructive and the complement system has been implicated as a pathogenic effector in numerous diseases, including infectious diseases. This review highlights recent discoveries that have identified critical roles for the complement system in the pathogenesis of viral infection. PMID- 21292296 TI - A comparative study of intraductal papillary neoplasia of the biliary tract and pancreas. AB - Intraductal papillary mucinous neoplasm of the pancreas is a rare but well established entity in contrast to intraductal papillary mucinous neoplasm of the biliary tract. The aim of this study was to compare the clinicopathologic features of intraductal papillary mucinous neoplasms of the biliary tract and of the pancreas. Twenty patients who underwent resection for intraductal papillary mucinous neoplasm of the biliary tract were compared with 29 cases resected for intraductal papillary mucinous neoplasm of the pancreas. Clinicopathologic characteristics and resection specimens of all patients were reassessed and immunohistochemically screened for expression of a distinct set of tumor markers. Median ages of patients with intraductal papillary mucinous neoplasms of the biliary tract and of the pancreas were 66 and 62 years, respectively (P < .05). Twelve patients with intraductal papillary mucinous neoplasm of the biliary tract (60%) had neoplasms with infiltrating carcinoma, compared with 6 patients with intraductal papillary mucinous neoplasm of the pancreas (21%, P < .05). Cytokeratin 7 and 20 expressions were equal in biliary and pancreatic intraductal papillary mucinous neoplasms. Cytokeratin 20 expression was mainly found in intestinal-type tumors. Gastric, pancreaticobiliary, and oncocytic subtypes were all observed in the intraductal papillary mucinous neoplasm of the biliary tract group. The distribution was significantly different from the intraductal papillary mucinous neoplasm of the pancreas group. The 3-year overall survival rate of malignant biliary and pancreatic intraductal papillary mucinous neoplasm was 63% and 65%, respectively (P = .798). Positive lymph nodes and a high expression of membranous mucin were associated with a significantly shorter overall survival in patients with malignant intraductal papillary mucinous neoplasm. Finally, p53 and Ki67 proliferation index were both associated with the carcinogenesis of intraductal papillary mucinous neoplasm, whereas DPC4 and CDX2 were not. Clinicopathologic features of intraductal papillary mucinous neoplasm of the biliary tract largely resemble those of intraductal papillary mucinous neoplasm of the pancreas, although intraductal papillary mucinous neoplasm of the biliary tract was associated with a higher malignancy rate at the time of surgical treatment. The level of membranous mucin expression and positive lymph nodes are significant prognosticators in patients with malignant intraductal papillary mucinous neoplasm. PMID- 21292297 TI - Intragraft vascular occlusive sickle crisis with early renal allograft loss in occult sickle cell trait. AB - Early renal allograft failure due to sickle cell trait is rare. We present clinical and pathologic findings in 2 cases of early renal allograft failure associated with renal vein thrombosis and extensive erythrocyte sickling. Hemoglobin AS was identified in retrospect. In case 1, a 41-year-old female recipient of a deceased donor renal transplant developed abdominal pain and acute allograft failure on day 16, necessitating immediate nephrectomy. In case 2, the transplanted kidney in a 58-year-old female recipient was noted to be mottled blue within minutes of reperfusion. At 24 hours, the patient was oliguric; and the graft was removed. Transplant nephrectomies had diffuse enlargement with diffuse, nonhemorrhagic, cortical, and medullary necrosis. Extensive sickle vascular occlusion was evident in renal vein branches; interlobar, interlobular, and arcuate veins; vasa recta; and peritubular capillaries. The renal arteries had sickle vascular occlusion in case 1. Glomeruli had only focal sickle vascular occlusion. The erythrocytes in sickle vascular occlusion had abundant cytoplasmic filaments by electron microscopy. Acute rejection was not identified in either case. Protein C and S levels, factor V Leiden, and lupus anticoagulant assays were within normal limits. Hemoglobin analysis revealed hemoglobin S of 21.8% and 25.6%, respectively. Renal allograft necrosis with intragraft sickle crisis, characterized by extensive vascular occlusive erythrocyte sickling and prominent renal vein thrombosis, was observed in 2 patients with sickle cell trait. Occult sickle cell trait may be a risk factor for early renal allograft loss. PMID- 21292299 TI - Insulin-like growth factor I receptor beta expression in hepatocellular carcinoma. AB - The insulinlike growth factor signaling axis (factors I and II and their receptor) has been implicated in hepatocarcinogenesis. Previous studies on insulinlike growth factor I receptor using resected hepatocellular carcinoma generated mixed results; however, the distribution and clinical significance of insulinlike growth factor I receptor beta expression in hepatocellular carcinoma in the setting of liver transplantation have not been evaluated. Immunohistochemical staining for insulinlike growth factor I receptor beta was performed in 72 liver explants from patients with hepatocellular carcinoma undergoing liver transplantation. Expression of insulinlike growth factor I receptor beta in hepatocytes was noted in 59.7% of tumors but only 6.9% of adjacent, nontumorous liver tissues (P < .001). Compared with subjects with tumors within Milan criteria, those who fell beyond had 3.1 times higher odds of having insulinlike growth factor I receptor beta-positive tumors (95% confidence interval, 1.003-9.8). Poorly differentiated hepatocellular carcinomas had 10.3 times higher odds of insulinlike growth factor I receptor beta positivity compared with well- or moderately differentiated tumors (95% confidence interval, 1.3-85.2). Subjects with nonalcoholic steatohepatitis were less likely to have insulinlike growth factor I receptor beta-positive tumors (P = .015). Finally, higher arteriolar insulinlike growth factor I receptor beta scores in the tumor and adjacent liver were significantly associated with insulinlike growth factor I receptor beta expression in tumor cells (P = .015 and .043 for intratumoral and adjacent arterioles, respectively) in a subset of 26 randomly chosen hepatocellular carcinoma. Our results suggest that synchronized up-regulation of the insulinlike growth factor I receptor axis in tumor cells and intratumoral and adjacent arterioles could represent a mechanism of hepatocarcinogenesis and progression as manifest by poor differentiation and tumors beyond Milan criteria. Targeted therapies against insulinlike growth factor receptors may be justifiable in the treatment of hepatocellular carcinoma. PMID- 21292298 TI - Expression of vitamin D receptor decreases during progression of pigmented skin lesions. AB - 1,25-dihydroxyvitamin D3 affects proliferation, differentiation, and apoptosis and protects DNA against oxidative damage with a net tumorostatic and anticarcinogenic effect. It acts through a specific nuclear receptor that is widely distributed through the body. Although a beneficial role of vitamin D in melanoma patients has been suggested, there is lack of information on the changes in the expression pattern of vitamin D receptor during progression of pigmented lesions. Using immunohistochemistry, we analyzed the expression of vitamin D receptor in 140 samples obtained form 82 patients, including 25 benign nevi, 70 primary cutaneous melanomas, 35 metastases, 5 re-excisions, and 5 normal skin biopsies. The strongest expression was observed in normal skin that significantly decreased in melanocytic proliferations with the following order of expression: normal skin > melanocytic nevi > melanomas = metastases. The vitamin D receptor expression in skin surrounding nevi and melanoma was also significantly reduced as compared to normal skin. Tumor-infiltrating and lymph node lymphocytes retained high levels of vitamin D receptor. There was negative correlation between tumor progression and vitamin D receptor expression with a remarkable decrease of the immunoreactivity in nuclei of melanoma cells at vertical versus radial growth phases and with metastatic melanomas showing the lowest cytoplasmic receptor staining. Furthermore, lack of the receptor expression in primary melanomas and metastases was related to shorter overall patients' survival. In addition, the receptor expression decreased in melanized melanoma cells in comparison to amelanotic or poorly pigmented cells. Therefore, we propose that reduction or absence of vitamin D receptor is linked to progression of melanocytic lesions, that its lack affects survival of melanoma patients, and that melanogenesis can attenuate receptor expression. In conclusion, changes in vitamin D receptor expression pattern can serve as important variables for diagnosis, predicting clinical outcome of the disease, and/or as a guidance for novel therapy of melanomas based on use of vitamin D or its derivatives. PMID- 21292300 TI - The immunohistochemical staining pattern of Gab2 correlates with distinct stages of chronic myeloid leukemia. AB - Grb2-associated binder 2 protein (Gab2) is a member of scaffold proteins, playing crucial roles in (receptor-) tyrosine kinase and cytokine signaling. Chronic myeloid leukemia cells with t(9;22)(q34;q11) express the Bcr/Abl fusion protein, which interacts with Grb2 and Gab2 signaling, thereby triggering hematopoietic cell proliferation. The aim of this study was to examine in detail the total and subcellular Gab2 protein expression in myeloid cells in bone marrow biopsies of patients with chronic myeloid leukemia in different disease stages. The study included 50 fixed bone marrow biopsies of controls (unaffected hematopoiesis, n = 11) and Bcr/Abl-positive chronic myeloid leukemia cases (n = 39) of different stages (chronic phase, n = 13; accelerated phase, n = 4; blast crisis, n = 11; complete remission, n = 11). Immunohistochemistry and quantitative evaluation of Gab2 staining in 600 myeloid cells/bone marrow biopsy were performed before statistical analyses. Immunohistochemistry revealed Gab2 expression in hematopoietic cells. Gab2-positive myeloid cells occurred significantly more frequent in chronic myeloid leukemia cases than in controls (P < .001) and appeared to markedly increase from chronic phase to accelerated phase to blast crisis. Importantly, within the distinct stages of chronic myeloid leukemia, a significant switch of Gab2-positive myeloid cells with cytoplasmic or nuclear/perinuclear Gab2 staining occurred: Nuclear/perinuclear Gab2-positive myeloid cells significantly increased from chronic phase to accelerated phase (P = .001) and from chronic phase to blast crisis (P < .001). Still, an overlap and, hence, a wider range of Gab2 staining patterns were seen between and within chronic myeloid leukemia stages, most likely reflecting a high plasticity of Grb2 associated binder 2 functions in the progression of chronic myeloid leukemia. In summary, the present study, for the first time, analyzed Grb2-associated binder 2 protein expression in bone marrow biopsies of patients with chronic myeloid leukemia in detail, demonstrating a novel and distinct Grb2-associated binder 2 staining pattern in normal and chronic myeloid leukemia bone marrow biopsies as well as in distinct chronic myeloid leukemia stages. Grb2-associated binder 2 immunohistochemistry may provide a valuable supplementary tool to routine histopathology and standard immunohistochemistry for classification and staging of (borderline) chronic myeloid leukemia bone marrow biopsies and hence improved therapeutic disease management. PMID- 21292301 TI - Pseudointraductal papillary mucinous neoplasia caused by microscopic periductal endocrine tumors of the pancreas: a report of 3 cases. AB - Intraductal papillary mucinous neoplasms constitute histologically distinctive pancreatic tumors characterized by cystically dilated pancreatic ducts lined by papillary epithelium, often with extensive mucin production. With increasing awareness of and vigilance for these tumors, there has been a surge in the incidence of intraductal papillary mucinous neoplasms in the last few decades. However, resections of presumed intraductal papillary mucinous neoplasms sometimes reveal other types of cystic lesions. Here we describe 3 cases of small, incidentally identified pancreatic endocrine tumors that focally compressed the main pancreatic duct and presented clinically, radiologically, and grossly as intraductal papillary mucinous neoplasm. The histology of the dilated ducts in all cases lacked convincing features of intraductal papillary mucinous neoplasm, prompting more careful examination of the specimens and eventual identification of small well-differentiated endocrine neoplasms. The constellation of findings represented by pancreatic endocrine neoplasm-associated duct stricture and dilatation can mimic intraductal papillary mucinous neoplasm clinically and pathologically. Awareness of this phenomenon can potentially avoid misdiagnosis of intraductal papillary mucinous neoplasm in such cases. PMID- 21292302 TI - Detection of myeloperoxidase in membranous nephropathy-like deposits in patients with anti-neutrophil cytoplasmic antibody-associated glomerulonephritis. AB - Anti-neutrophil cytoplasmic antibody-associated glomerulonephritis is usually classified as a pauci-immune type. However, it sometimes shows immune complex deposition of unknown origin. We examined the glomerular localization of myeloperoxidase by double immunofluorescence and immunoelectron microscopy in cases of anti-neutrophil cytoplasmic antibody-associated glomerulonephritis with membranous nephropathy-like immunoglobulin G deposition to investigate the immune complex antigens in these cases. Six (35%) of the biopsy samples from 17 cases with anti-neutrophil cytoplasmic antibody-associated glomerulonephritis showed granular deposition of immunoglobulin G along the glomerular capillary walls. Light microscopy revealed necrotizing crescentic glomerulonephritis with segmental thickening of the glomerular basement membrane. Electron microscopy showed electron-dense deposits in intramembranous and mesangial areas. However, the size and distribution of the deposits were irregular and segmental in the examined cases, unlike typical global and subepithelial lesions of membranous nephropathy. Double immunofluorescence using Alexa Fluor 594-labeled anti myeloperoxidase antibody and fluorescein isothiocyanate-labeled anti immunoglobulin G antibody, as well as immunoelectron microscopy using anti myeloperoxidase antibody labeled with 25-nm gold particles revealed partial colocalization of myeloperoxidase and immunoglobulin G within the glomerular basement membrane and mesangium. In some cases of anti-neutrophil cytoplasmic antibody-associated glomerulonephritis, myeloperoxidase may form immune complexes and develop membranous nephropathy-like lesions. PMID- 21292303 TI - Natural killer cell subsets and natural killer-like T-cell populations in benign and neoplastic B-cell proliferations vary based on clinicopathologic features. AB - Microenvironmental factors play a critical role in B-cell lymphomas. Most studies emphasize the role of lymphoma-infiltrating T-cells and macrophages, with few studies on natural killer cells. Natural killer cells include a less mature (CD56(bright)/CD16-) subset that is more common in lymph nodes and a more mature (CD56(dim)/CD16+) subset that is more numerous in peripheral blood. Therefore, the proportions of natural killer cells, natural killer subsets, and natural killer-like T-cells (CD3+, CD56+, and/or CD16/57+) were determined by flow cytometry in 150 cases of tissue-based B-cell non-Hodgkin lymphoma and 89 nonneoplastic tissue biopsies. Results were correlated with the clinicopathologic findings. A higher percentage of natural killer cells was found in nonneoplastic spleen versus other nonneoplastic tissue (P < .001), in splenic-based B-cell non Hodgkin lymphoma versus other B-cell non-Hodgkin lymphoma (P < .01), and in stage II to IV diffuse large B-cell lymphoma versus stage I diffuse large B-cell lymphoma (n = 19, P = .02). The more mature natural killer subset was increased in benign spleen (P < .001) and nonsplenic B-cell non-Hodgkin lymphoma (P < .01) versus nonsplenic, nonneoplastic tissue; in diffuse large B-cell lymphoma versus other B-cell non-Hodgkin lymphoma (P < .001); and in follicular lymphoma with an intermediate follicular lymphoma international prognostic index score (n = 17, P = .04). A higher proportion of natural killer-like T-cells was seen in diffuse large B-cell lymphoma versus other B-cell non-Hodgkin lymphoma (P = .001), whereas chronic lymphocytic leukemia/small lymphocytic lymphoma contained fewer natural killer-like T-cells (P < .001). The proportions of natural killer cells, natural killer subsets, and natural killer-like T-cells vary with tissue site, type of B-cell non-Hodgkin lymphoma, and clinical stage in diffuse large B-cell lymphoma and follicular lymphoma. A higher proportion of CD56(dim)/CD16/57+ natural killer cells is found in spleen, in more aggressive B-cell non-Hodgkin lymphoma, and in follicular lymphoma with an intermediate follicular lymphoma international prognostic index score. This may be of importance with increasing therapeutic use of immunomodulatory agents. PMID- 21292304 TI - Aberrant expression of the human epidermal growth factor receptor 2 oncogene is not a common feature in osteosarcoma. AB - Human epidermal growth factor receptor 2 expression in osteosarcoma and its relationship to prognosis have been the subject of several conflicting reports, most of them relying on immunohistochemical studies. Because the urgent need of prognostic markers and effective new treatment options for osteosarcoma patients, we evaluated the role of human epidermal growth factor receptor 2 in 2 well characterized sets of pretherapeutic osteosarcoma samples (46 paraffin-embedded and 46 fresh-frozen biopsy samples) using immunohistochemistry with 2 different antibodies [DAKO A0485 (Glostrup, Denmark) and Novocastra CB11 (Newcastle, UK)] as well as fluorescence in situ hybridization, real-time polymerase chain reaction, and SNP array analyses and correlated our findings with clinicopathological parameters. However, our study failed to detect unequivocal evidence of human epidermal growth factor receptor 2 gene amplification or overexpression of human epidermal growth factor receptor 2 messenger RNA or protein in any of the investigated tumors. Only in a small subset of samples, a moderate increase in messenger RNA levels (13.6%) or focal membranous immunoreactivity (8.7%; A0485) was detected but did not correlate with survival or response to chemotherapy. Cytoplasmic staining was identified more frequently (63%; CB11) but again did not show any association with clinicopathological parameters. In conclusion, our study does not support a role for human epidermal growth factor receptor 2 as a prognostic marker in osteosarcoma. PMID- 21292305 TI - Differential expression of cell-cycle regulatory proteins defines distinct classes of follicular lymphoma. AB - Follicular lymphoma, a relatively common neoplasm of mature B lymphocytes, generally pursues an indolent clinical course. The disease is biologically heterogeneous, however, and aggressive instances associated with short survival are relatively common. Because defects in the regulation of apoptotic cell death are fundamental in follicular lymphoma pathogenesis, we hypothesized that deregulated expression of components of the Rb signaling pathway may promote cell proliferation, thereby complementing antecedent antiapoptotic mutations and producing more aggressive disease. We determined the differential expression of key cell-cycle regulatory proteins in lymphoma cells by incorporating formalin fixed, paraffin-embedded samples from the initial, diagnostic biopsies from 127 cases of follicular lymphoma into tissue microarrays, histologic sections of which were stained by immunohistochemistry for p53, pRb, p16(INK4a), and cyclin D3. The results were ascertained by visual inspection and then correlated with histopathological and clinical parameters, including overall survival. Our findings show that increased abundance of p53 or p16(INK4a) is associated with reduced overall survival and conventional pathological markers of tumor aggressiveness including high histologic grade. Therefore, subjective quantification of cell-cycle regulatory proteins by immunohistochemistry can identify biologically and clinically distinct subsets of follicular lymphoma cases. PMID- 21292306 TI - Gluten-dependent enteropathy and atypical human leukocyte antigen alleles. AB - The risk for developing celiac disease is associated with the major histocompatibility complex class II human leukocyte antigen DQ2 and DQ8. We retrospectively reviewed the medical records of 127 consecutive cases of adult onset celiac disease evaluated at a single United States center to determine the distribution of the associated human leukocyte antigen DQA1 and DQB1 alleles. The median patient age of diagnosis was 41 (range, 16-81) years. Ninety-five adults underwent human leukocyte antigen DQ typing. Eighty patients were DQ2 positive, 24 were DQ8 positive, and 11 were DQ2 and DQ8 positive. Four patients carried the uncommon, low-risk haplotype DQ2.2 (DQA1*02 and DQB1*02) without DQA1*05. Two patients did not carry human leukocyte antigen DQ2 or DQ8. All of the patients with atypical human leukocyte antigen DQ responded to a gluten-free diet. Although the majority of patients carry the human leukocyte antigen DQ2 or DQ8, gluten-dependent enteropathy periodically presents in adults with low-risk alleles. PMID- 21292308 TI - High-grade neuroendocrine carcinomas of the lung highly express enhancer of zeste homolog 2, but carcinoids do not. AB - Enhancer of zeste homolog 2, the catalytic subunit of polycomb repressive complex 2, is a histone methyltransferase and plays an important role in cell proliferation and cell cycle regulation. It has been shown to be overexpressed in a number of malignant neoplasms. This study aimed to determine the expression pattern of enhancer of zeste homolog 2 in neuroendocrine tumors of the lung and the potential of enhancer of zeste homolog 2 to serve as a biomarker to segregate carcinoids from high-grade neuroendocrine carcinomas. Fifty-four cases, including 25 typical carcinoids, 7 atypical carcinoids, 9 large-cell neuroendocrine carcinomas, and 13 small-cell lung carcinomas, were immunohistochemically studied using a monoclonal antibody against enhancer of zeste homolog 2. All 13 small cell lung carcinomas demonstrated moderate to strong nuclear staining with 12 exhibiting more than 90% of tumor cells staining. All 9 large-cell neuroendocrine carcinomas were moderately to strongly positive for enhancer of zeste homolog 2, with 6 cases having staining in more than 80% of tumor cells. In contrast, all 25 typical carcinoids and 6 atypical carcinoids showed only rare scattered enhancer of zeste homolog 2-positive tumor cells, with 1 case of atypical carcinoid exhibiting moderate staining in 40% of tumor cells. A subsequent validation study of the 14 specimens of lung or mediastinal lymph node biopsy and fine-needle aspiration, including 6 small-cell lung carcinomas, 2 large-cell neuroendocrine carcinomas, 5 typical carcinoids, and 1 atypical carcinoid, was performed. Enhancer of zeste homolog 2 was diffusely and strongly positive in all small-cell lung carcinomas and large-cell neuroendocrine carcinomas, even with severe crush artifact, whereas it was only positive in rare tumor cells in carcinoids. These findings support the formulation that enhancer of zeste homolog 2 may play an important role in the regulation of biologic behavior of high-grade neuroendocrine carcinomas and as a diagnostically useful marker in distinguishing high-grade neuroendocrine carcinomas from carcinoids. PMID- 21292307 TI - Subcellular localization of p27 and prostate cancer recurrence: automated digital microscopy analysis of tissue microarrays. AB - Previous investigations have linked decreased nuclear expression of the cell cycle inhibitor p27 with poor outcome in prostate cancer. However, these reports are inconsistent regarding the magnitude of that association and its independence from other predictors. Moreover, cytoplasmic translocation of p27 has been proposed as a negative prognostic sign. Given the cost and accuracy limitations of manual scoring, particularly of tissue microarrays, we determined if laser based fluorescence microscopy could provide automated analysis of p27 in both nuclear and cytoplasmic locations and, thus, clarify its significance as a prognostic biomarker. We constructed tissue microarrays covering 202 recurrent cases (rising prostate-specific antigen) and 202 matched controls without recurrence. Quadruplicate tumor samples encompassed 5 slides and 1616 cancer histospots. Cases and controls matched on age, Gleason grade, stage, and hospital. We immunolabeled epithelial cytoplasm with Alexafluor 647, p27 with Alexafluor 488, and nuclei with 4c6-diamidino-2-phenylindole.2HCl. Slides were scanned on an iCys laser scanning cytometer (CompuCyte Corp, Cambridge, MA). Nuclear crowding required a stereological approach--random arrays of circles (phantoms) were layered on images and the content of each phantom was analyzed in scatter plots. Both nuclear and cytoplasmic p27 were significantly lower in cases versus controls (P = .014 and P = .004, respectively). Regression models controlling for matching variables plus prostate-specific antigen showed strong linear trends for increased risk of recurrence with lower p27 in both nucleus and cytoplasm (highest versus lowest quartile; odds ratio, 0.35; P = .006). Manual scoring identified an inverse association between p27 expression and tumor grade but no independent association with recurrence. In conclusion, we developed an automated method for subcellular scoring of p27 without the need to segment individual cells. Our method identified a strong relationship, independent of tumor grade, stage, and prostate-specific antigen, between p27 expression- regardless of subcellular location--and prostate cancer recurrence. This relationship was not observed with manual scoring. PMID- 21292309 TI - Analysis of glial cell line-derived neurotrophic factor-inducible zinc finger protein 1 expression in human diseased kidney. AB - The glial cell line-derived neurotrophic factor (GDNF)-RET signaling pathway plays an important role in kidney development. We have previously identified a novel zinc finger protein, glial cell line-derived neurotrophic factor-inducible zinc finger protein 1 (GZF1), whose expression was induced in the human neuroblastoma cell line TGW expressing RET by GDNF stimulation and was also detected in mouse metanephric kidney. In the present study, we examined the immunohistochemical expression of GZF1 in normal human kidney and various kidney diseases including chronic kidney disease, acute kidney injury, and cancers, and assessed the clinical significance of GZF1 expression. In the normal kidney, GZF1 was highly expressed only in the proximal tubular epithelial cells that were also positive for angiotensin-converting enzyme. We also evaluated GZF1 expression in various kidney diseases including membranous nephropathy, minimal change nephrotic syndrome with or without acute kidney injury, immunoglobulin A nephropathy, diabetic nephropathy, acute tubular necrosis, and antineutrophil cytoplasmic antibody-related glomerulonephritis. We found that decreased expression of GZF1 was associated with an increase in tubulointerstitial damage and serum creatinine levels. In addition, GZF1 expression was undetectable or very low in most cases of renal cell carcinomas and Wilms tumors. These findings suggest that GZF1 represents a new marker for renal proximal tubules and that there is an inverse correlation between the expression level of GZF1 and tubular function. PMID- 21292310 TI - Updating the carbon footprint of the Galician fishing activity (NW Spain). AB - Recent life cycle assessment studies have revealed the relevance of cooling agent leakage when assessing the greenhouse gas (GHG) emissions generated by fishing vessel operations. The goal of this communication is to update the carbon footprinting of the Galician fishing activity (NW Spain) by including the GHG emissions from cooling agent leakage. Results proved the relevant role played by refrigerants regarding their contribution to the carbon footprint of fishing activities. Thus, an overall increase of 13% was found when comparing the final global carbon footprint for the Galician fishing activity with previous calculations that did not include these emissions. Nevertheless, further efforts should be made in order to provide robust data in this respect. PMID- 21292311 TI - Mercury and selenium levels in 19 species of saltwater fish from New Jersey as a function of species, size, and season. AB - There are few data on risks to biota and humans from mercury levels in saltwater fish. This paper examines mercury and selenium levels in muscle of 19 species of fish caught by recreational fisherfolk off the New Jersey shore, as a function of species of fish, size, and season, and risk of mercury to consumers. Average mercury levels ranged from 0.01 ppm (wet weight) (Menhaden Brevoortia tyrannus) to 1.83 ppm (Mako Shark Isurus oxyrinchus). There were four categories of mercury levels: very high (only Mako), high (averaging 0.3-0.5 ppm, 3 species), medium (0.14-0.20 ppm, 10 species), and low (below 0.13 ppm, 5 species). Average selenium levels for the fish species ranged from 0.18 ppm to 0.58 ppm, and had lower variability than mercury (coefficient of variation=38.3 vs 69.1%), consistent with homeostatic regulation of this essential element. The correlation between mercury and selenium was significantly positive for five and negative for two species. Mercury levels showed significant positive correlations with fish size for ten species. Size was the best predictor of mercury levels. Selenium showed no consistent relationship to fish length. Over half of the fish species had some individual fish with mercury levels over 0.3 ppm, and a third had fish with levels over 0.5 ppm, levels that pose a human health risk for high end consumers. Conversely several fish species had no individuals above 0.5 ppm, and few above 0.3 ppm, suggesting that people who eat fish frequently, can reduce their risk from mercury by selecting which species (and which size) to consume. Overall, with the exception of shark, Bluefin Tuna (Thunnus thynnus), Bluefish (Pomatomus saltatrix) and Striped Bass (Morone saxatilis), the species sampled are generally medium to low in mercury concentration. Selenium:mercury molar ratios were generally above 1:1, except for the Mako shark. PMID- 21292312 TI - Lake restoration by hypolimnetic Ca(OH)2 treatment: impact on phosphorus sedimentation and release from sediment. AB - A whole-lake hypolimnetic Ca(OH)(2) addition, that induced calcium carbonate precipitation, combined with deep water aeration has been applied to eutrophic Lake Luzin, Germany during 1996-1998. In this study we investigated the dynamic of phosphorus and its binding forms in seston and sediment before and during the treatment. The sedimentation rates of phosphorus increased within three years of induced calcite precipitation. The phosphorus binding forms shifted to the calcite-bound phosphorus in the settling matter. The increase of calcite-bound P in the settling material did not coincide with the maximum induced CaCO(3) precipitation caused by the hypolimnetic addition of Ca(OH)(2). An impact of chemicals additions and pH on phosphorus binding forms in seston and surface sediments has been studied in laboratory experiments with sediment core incubations and slurry experiments. Laboratory studies showed that the lowest phosphorus flux from sediment was related to the experiment with pH=7 in overlaying water adjusted with Ca(OH)(2). The adjusting of pH with Ca(OH)(2) leads to a lower P flux of 2.3 mg Pm(-2)d(-1), while the highest P-flux is attributed to the experiment with the pH which was adjusted with NaOH. Phosphorus fraction which reflects phosphorus binding on carbonates in surface sediments increased within one year of treatment, enhancing the phosphorus retention capacity of sediments. PMID- 21292313 TI - Feasibility of same-day discharge after laparoscopic surgery in gynecologic oncology. AB - OBJECTIVE: The purpose of this study is to evaluate whether same-day discharge after laparoscopic gynecologic oncology surgery is feasible and determines factors associated with admission. METHODS: This retrospective cohort study included all patients consented for laparoscopy by two gynecologic oncologists at a tertiary care academic teaching hospital between January 2006 and June 2009. Procedures included those not typically discharged same-day, such as total laparoscopic simple or radical hysterectomies or radical trachelectomy +/- salpingo-oophorectomy +/- pelvic and para-aortic lymph node dissection +/- omentectomy. Those discharged same-day were compared to those admitted. Multivariate logistic regression analysis was done to determine factors associated with admission. RESULTS: Three hundred three patients were included. 6.9% were converted to laparotomy. One hundred forty-seven (48.5%) had same-day discharge (median stay 295minutes). Among outpatients, 7 (4.8%) were readmitted within three weeks of surgery. Three patients (2%) could have avoided the ER or hospital admission had they been originally admitted postoperatively. No patients with same-day discharge had a major acute postoperative complication. Factors associated with admission include age (OR 1.76 for age 70years vs 50years, p=0.001), surgeon (OR 6.91, p<0.0001), conversion to laparotomy (p<0.0001), radical hysterectomy (OR 3.43, p=0.002), length of surgery (OR 2.94 for 4hours vs 2hours, p<0.0001), and surgery start time after 1PM (OR 3.77, p=0.0001). CONCLUSION: Same-day discharge for laparoscopic gynecologic oncology surgery is feasible, with low morbidity and few readmissions within three weeks of surgery. Successful same-day discharge can increase by refining patient selection and operating room scheduling. PMID- 21292314 TI - Prevalence of lymph nodes in the parametrium of radical vaginal trachelectomy (RVT) specimen. AB - OBJECTIVE: In order to evaluate radicality in fertility preserving surgery in women with early invasive cervical cancer we analyzed the parametrium of specimens of patients treated by radical vaginal trachelectomy for the presence of lymph nodes. We tried to identify morphologic factors associated with the presence of parametrial lymph nodes. METHODS: We analyzed surgical specimens of 112 patients who underwent radical trachelectomy between June 2004 and April 2009 at the Department of Gynecologic Oncology at Charite Campus Benjamin Franklin and Campus Mitte. All parametrial tissue was step sectioned and a total of 1878H&E stained histological sections were analyzed. RESULTS: In 8 patients (7.1%) a total of 13 lymph nodes were detected. Five lymph nodes in four patients had been primarily detected by routine histological examination. In one of these patients (0.9%) a 2mm lymph node metastasis was found. Serial sectioning revealed additional seven lymph nodes in four patients. The thickness of parametrium correlated significantly with the presence of lymph nodes in the parametrium. CONCLUSION: The presence of small lymph nodes in the parametrium of specimens of radical trachelectomy is low. In patients with early-stage cervical cancer, the incidence of metastasis is less than 1%. Preoperative assessment of the volume of the parametrium may indicate which patients need parametrial resection. PMID- 21292316 TI - From GWAS to clinical utility in Parkinson's disease. PMID- 21292317 TI - Dissolving microneedles for transdermal drug administration prepared by stepwise controlled drawing of maltose. AB - Dissolving microneedles, three-dimensional polymer structures with microscale cross-sectional dimensions, have been introduced as a means of safe transdermal drug delivery. Most dissolving microneedles have been fabricated using a traditional micro-casting method that cures biopolymers within three-dimensional mold, nevertheless, repeated molding process may cause damage to encapsulated drugs, a critical hurdle for clinical application. Here, we describe the stepwise controlled drawing technique that can directly fabricate dissolving microneedle from maltose by precise controlling the drawing time and the viscosity of the maltose. Controlled drawing shaped the particular sharp-conical microneedles of 1200 MUm length with tip diameter of 60 MUm, and dissolved within 20 min in-vivo after inserting to the skin. This technique surpasses the limitations of micro casting for dissolving microneedle. Furthermore, transdermal delivery of impermeable hydrophilic molecules such as ascorbic acid-2-glucoside and niacinamide was confirmed as inhibition of cutaneous hypermelanosis. We anticipate that controlled drawing technique will be suitable to design dissolving microneedles for use in minimally invasive transcutaneous drug delivery to patients. PMID- 21292315 TI - Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies. AB - BACKGROUND: Genome-wide association studies (GWAS) for Parkinson's disease have linked two loci (MAPT and SNCA) to risk of Parkinson's disease. We aimed to identify novel risk loci for Parkinson's disease. METHODS: We did a meta-analysis of datasets from five Parkinson's disease GWAS from the USA and Europe to identify loci associated with Parkinson's disease (discovery phase). We then did replication analyses of significantly associated loci in an independent sample series. Estimates of population-attributable risk were calculated from estimates from the discovery and replication phases combined, and risk-profile estimates for loci identified in the discovery phase were calculated. FINDINGS: The discovery phase consisted of 5333 case and 12 019 control samples, with genotyped and imputed data at 7 689 524 SNPs. The replication phase consisted of 7053 case and 9007 control samples. We identified 11 loci that surpassed the threshold for genome-wide significance (p<5*10(-8)). Six were previously identified loci (MAPT, SNCA, HLA-DRB5, BST1, GAK and LRRK2) and five were newly identified loci (ACMSD, STK39, MCCC1/LAMP3, SYT11, and CCDC62/HIP1R). The combined population attributable risk was 60.3% (95% CI 43.7-69.3). In the risk-profile analysis, the odds ratio in the highest quintile of disease risk was 2.51 (95% CI 2.23-2.83) compared with 1.00 in the lowest quintile of disease risk. INTERPRETATION: These data provide an insight into the genetics of Parkinson's disease and the molecular cause of the disease and could provide future targets for therapies. FUNDING: Wellcome Trust, National Institute on Aging, and US Department of Defense. PMID- 21292318 TI - Reduction of oxidative stress by p-hydroxybenzyl alcohol-containing biodegradable polyoxalate nanoparticulate antioxidant. AB - The large production of reactive oxygen species (ROS) leads to the oxidative stress and the subsequent functional decline of organ systems. p-Hydroxybenzyl alcohol (HBA) is known to play a pivotal protective role against oxidative stress related diseases. We have developed biodegradable antioxidant copolyoxalate, in which HBA is chemically incorporated into its backbone for the treatment of oxidative stress-related diseases. HBA-incorporated copolyoxalate (HPOX) was designed to possess aromatic peroxalate ester linkages in its backbone and release HBA during its hydrolytic degradation. Peroxalate ester linkages in the backbone reacted with and scavenged hydrogen peroxide, leading the release of HBA in vitro. HBA released from HPOX exerted excellent antioxidant activity, such as inhibition of nitric oxide (NO) production by suppressing iNOS (inducible nitric oxide synthases) expression in lipopolysaccharide (LPS)-activated RAW 264.7 cells. HPOX nanoparticles delivered intranasally significantly reduced pulmonary inflammation and suppressed the iNOS expression. Given their excellent antioxidant and anti-inflammatory activities, we anticipate that HPOX nanoparticles are highly potent for the treatment of oxidative damage-related diseases, such as asthma. PMID- 21292319 TI - A review of the biological response to ionic dissolution products from bioactive glasses and glass-ceramics. AB - Several inorganic materials such as special compositions of silicate glasses, glass-ceramics and calcium phosphates have been shown to be bioactive and resorbable and to exhibit appropriate mechanical properties which make them suitable for bone tissue engineering applications. However, the exact mechanism of interaction between the ionic dissolution products of such inorganic materials and human cells are not fully understood, which has prompted considerable research work in the biomaterials community during the last decade. This review comprehensively covers literature reports which have investigated specifically the effect of dissolution products of silicate bioactive glasses and glass ceramics in relation to osteogenesis and angiogenesis. Particularly, recent advances made in fabricating dense biomaterials and scaffolds doped with trace elements (e.g. Zn, Sr, Mg, and Cu) and investigations on the effect of these elements on the scaffold biological performance are summarized and discussed in detail. Clearly, the biological response to artificial materials depends on many parameters such as chemical composition, topography, porosity and grain size. This review, however, focuses only on the ion release kinetics of the materials and the specific effect of the released ionic dissolution products on human cell behaviour, providing also a scope for future investigations and identifying specific research needs to advance the field. The biological performance of pure and doped silicate glasses, phosphate based glasses with novel specific compositions as well as several other silicate based compounds are discussed in detail. Cells investigated in the reviewed articles include human osteoblastic and osteoclastic cells as well as endothelial cells and stem cells. PMID- 21292320 TI - Osteoblast function on electrically conductive electrospun PLA/MWCNTs nanofibers. AB - The electrospinning process was utilized successfully to fabricate the random oriented and aligned electrically conductive nanofibers of biodegradable poly-DL lactide (PLA) in which multiwalled carbon nanotubes (MWCNTs) were embedded. The topographical features of the composite nanofibers were characterized by SEM. The dispersion and alignment of MWCNTs in nanofiber matrix were observed by TEM. The in vitro degradation was characterized in terms of the morphological change, the mass loss and the reduction of polymer molecular weight as well as the decrease of pH value of degradation media. In particular, these conductive nanofiber meshes offered a unique system to study the synergistic effect of topographic cues and electrical stimulation on osteoblasts outgrowth as a way of exploring their potential application in bone tissue engineering. The results of obsteoblasts assay unstimulated showed that the aligned nanofibers as topographic cues could enhance the extension and direct the outgrowth of obsteoblasts better than random fibers. In the presence of direct current (DC) of 100 MUA, the obsteoblasts on all samples grew along the electrical current direction. The cellular elongation and proliferation were mainly dependent on the electrical stimulation whereas the topographical features played a minor role in them. Therefore, electrical stimulation with an appropriate DC value imparted on conductive substrate had great potential in application of bone tissue engineering. PMID- 21292321 TI - Do double-stranded RNA receptors play a role in preeclampsia? AB - Dysregulation of the maternal immune system during pregnancy has been implicated in the development of preeclampsia (PE), however the pathogenetic signals and mechanisms have not been completely elucidated. Here we provide a hypothesis and evidence that dsRNA is a danger signal leading to maternal immune system activation and an "antiviral" immune response that manifests as PE. dsRNA released from necrotic cells and/or from viruses causes excessive activation of dsRNA receptors and PE-like symptoms in animals. Additionally, high expression levels of dsRNA receptors have been identified in human and animal placental tissue as well as trophoblast cells, and these receptors appear to be excessively activated in PE. These key components of the innate immune system that respond to invading pathogens and dead or necrotic tissue likely play a major role in the development of PE. PMID- 21292323 TI - Changes in the activity of the GPx-1 anti-oxidant selenoenzyme in mononuclear cells following imatinib treatment. AB - Imatinib inhibits the ABL tyrosine kinase and is effective for the treatment of chronic myeloid leukemia (CML). ABL activates GPx-1, an enzyme associated with protection against oxidative DNA damage and disease. Enzyme activity was assessed in sample pairs consisting of mononuclear cells obtained from patients before and after imatinib therapy. Control sample sets obtained from patients not receiving imatinib showed little change in GPx activity over a several month interval. Five of 7 sample sets obtained from imatinib-receiving patients showed changes in GPx activity greater than 30%. One sample decreased 42% while 4 others increased 33 208%. Patients with the largest increase in activity were female and had the lowest baseline levels of GPx activity. Changes in GPx activity may influence the clinical outcome of patients being treated for CML. PMID- 21292322 TI - Upregulation of growth signaling and nutrient transporters in cotyledons of early to mid-gestational nutrient restricted ewes. AB - Multiparous ewes received 100% (control, C, n = 13) or 50% (nutrient restricted, NR, n = 14) of NRC dietary requirements from d28-d78 of gestation. On d78, 5 C and 6 NR ewes were necropsied. The remaining 8 C and 8 NR ewes were fed to 100% of NRC from d78-d135 and necropsied. Maternal blood was collected at both necropsies and at weekly intervals for assay of glucose, insulin and leptin. Fetal blood was collected at d78 and d135 necropsies for assay of glucose and lipids. Cotyledonary (COT) tissue was evaluated for protein and mRNA expression [fatty acid transporter (FATP)1, FATP4, CD36, glucose transporter (GLUT)1 and GLUT3], mRNA expression only [placenta fatty acid binding protein (FABPpm) and lipoprotein lipase (LPL)], or expression of phosphorylated and total protein forms [AMP kinase (AMPK)alpha, acetyl-CoA carboxylase (ACC), extracellular signal regulated kinase (Erk)1/2, mammalian target of rapamycin (mTOR) and protein kinase B (Akt)]. On d78, but not d135, placental and fetal weights were reduced (P < 0.05) in NR vs. C ewes. Maternal circulating glucose, insulin and leptin levels were decreased in NR vs. C ewes on d78 (P < 0.05) but similar at d135. Fetal blood glucose and triglyceride levels were lower in NR vs. C ewes (P < 0.05) on d78, but similar on d135. On d78, GLUT1, FATP4, CD36 mRNA and protein expression levels, FABPpm mRNA level, and leptin protein level were all increased (P < 0.05) in COT of NR vs. C ewes. AMPK, ACC, and Erk1/2 activities were also increased (P < 0.05) in NR vs. C COT on d78. In contrast, only FATP4 was increased (P < 0.05) at both the mRNA and protein levels in COT of NR realimented vs. C ewes on d135. These data demonstrate placental adaptation to maternal NR through increasing nutrient transporter production and growth signaling activity. PMID- 21292324 TI - Inhibition of mouse TAP by immune evasion molecules encoded by non-murine herpesviruses. AB - Herpesviruses escape elimination by cytotoxic T lymphocytes through specific interference with the antigen-presenting function of MHC class I (MHC I) molecules. The transporter associated with antigen processing (TAP) forms a bottleneck in the MHC I antigen presentation pathway. The fact that multiple viruses, especially herpesviruses, encode molecules blocking TAP function is a case in point. The action of these viral immuno evasins is usually potent and very specific, making these proteins valuable tools for studying the cell biology of antigen presentation, including alternative antigen processing pathways. Yet, no dedicated TAP inhibitor has been described for any of the mouse herpesviruses. To permit the use of immuno evasins derived from non-mouse herpesviruses in mouse models, we assessed the cross-species activity of four TAP inhibitors and one tapasin inhibitor in the context of three different mouse haplotypes, H-2(b), H 2(d), and H-2(k). Two of the four TAP inhibitors, the bovine herpesvirus 1 encoded UL49.5 and the human cytomegalovirus (HCMV)-encoded US6 protein, potently inhibited mouse TAP. ICP47 and BNLF2a, encoded by herpes simplexvirus 1 and Epstein-Barr virus, respectively, failed to inhibit TAP in all mouse cells tested. Previous work, however, demonstrated that US6 did not cross the mouse species barrier. We now show that substitution of the cysteine residue at position 108 was responsible for this lack of activity. The HCMV-encoded tapasin inhibitor US3 efficiently downregulated H-2(d) molecules on 3T3 cells, but not in other cell lines tested. Finally, we show that synthetic peptides comprising the functional domain of US6 can be exploited as a versatile TAP inhibitor. In conclusion, a complete overview is presented of the applicability of herpesvirus encoded TAP and tapasin inhibitors in mouse cells of different genetic background. PMID- 21292325 TI - Amniotic membrane transplantation for restrictive strabismus. AB - PURPOSE: To report the use of amniotic membrane transplant in patients with restrictive strabismus. DESIGN: Retrospective, interventional case series. PARTICIPANTS: Patients with restrictive strabismus treated with amniotic membrane transplantation. METHODS: Chart review of 7 consecutive patients (8 eyes) who developed restrictive strabismus after periocular surgery and were treated with surgical removal of restrictive adhesions and placement of an amniotic membrane transplant. MAIN OUTCOME MEASURES: Intraoperative findings to explain the mechanism of restrictive strabismus, and clinical postoperative results, including ocular alignment, ductions and versions, symptom relief, and resolution of diplopia. RESULTS: Restrictive strabismus occurred after surgery for pterygium, retinal detachment, orbital floor fracture, dermoid cyst, and dermatochalasis. Restrictive strabismus was due to a combination of conjunctival contracture, fat adherence, or rectus muscle contracture. All patients developed postoperative scarring, with failed additional standard surgery to remove the adhesions, including 1 patient treated with mitomycin C for recurrent scarring after pterygium. Reoperation using amniotic membrane transplantation was associated with improvement of ocular motility in 6 of the 7 patients; 1 patient had recurrence of scarring with persistent diplopia. The remaining 6 of 7 patients had no significant recurrence of scarring, and motility remained stable during the follow-up period of 5 to 13 months. CONCLUSIONS: Amniotic membrane transplantation seems to help prevent recurrence of adhesions in patients with restrictive strabismus caused by conjunctival scarring, fat adherence syndrome, or rectus muscle contracture. Use of an amniotic membrane transplant should be considered as a treatment option for these difficult cases of restrictive strabismus. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 21292326 TI - Treatment of periocular infantile hemangiomas with propranolol: case series of 18 children. AB - PURPOSE: To study the efficacy of propranolol in the treatment of periocular infantile hemangiomas (IHs). DESIGN: Retrospective interventional case series. PARTICIPANTS: Eighteen children presenting periocular IH with occlusion of the pupil, anisometropic astigmatism, proliferating eyelid IH, or cosmetically disfiguring periocular IH. METHODS: All patients received treatment with propranolol started at 0.5 mg/kg/day with an incremental increase by 0.5 mg/kg/day every 4 days, up to a maximum of 2 to 3 mg/kg/day. Complete eye examinations and serial photographs were obtained before, during, and after treatment. Doppler ultrasound and magnetic resonance imaging performed pre- and post-treatment were compared when available. MAIN OUTCOME MEASURES: Evolution of the treated IH was evaluated with respect to astigmatism, amblyopia, and size of the lesion. RESULTS: The IH size decreased in 17 of 18 patients. We noted a greater reduction when treatment was administered during the proliferative phase of growth of IHs. At the conclusion of treatment, none of our patients had amblyopia. The mean value of amblyogenic astigmatism (n = 7) decreased from 2.71 diopters (D) pretreatment to 1.03 D post-treatment. On radiology, 8 patients had significant regression of the lesion size of their IH and 1 patient had a limited progression. Propranolol had to be temporarily discontinued in only 1 patient because of symptomatic hypotension. CONCLUSIONS: Propranolol seems to be an effective modality of treatment for periocular IH. It seems to be most efficacious when initiated in the proliferative phase of IH but may be beneficial even in the later stage. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 21292327 TI - Comparison of fibrin glue versus suture for conjunctival autografting in pterygium surgery: a meta-analysis. AB - PURPOSE: To evaluate the safety and clinical efficacy of fibrin glue in pterygium surgery with conjunctival autografting. DESIGN: The use of fibrin glue has been introduced in the treatment of pterygium. However, its role versus traditional suturing is still a matter of debate. We performed a meta-analysis to compare the safety and clinical efficacy of fibrin glue with suture for conjunctival autograft attachment in pterygium surgery. PARTICIPANTS: A total of 342 participants with 366 eyes in 7 studies were analyzed. METHODS: We searched Medline, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, and Google Scholar for relevant randomized controlled trials (RCTs). MAIN OUTCOME MEASURES: The methodological quality of all the included trials was assessed with the Jadad score. The meta-analysis was performed with the fixed-effects model for complication rate and recurrence rate, and random-effects model for operating time. RESULTS: Fibrin glue was associated with a significantly decreased operating time (weighted mean difference -17.61 minutes, 95% confidence interval [CI], -26.03 to -9.18, P<0.0001) and was more effective in reducing the recurrence rate (Peto odds ratio [OR] 0.33, 95% CI, 0.15-0.71, P = 0.004) compared with suture. There were no significant differences in the complication rate (Peto OR 1.82, 95% CI, 0.63-5.27, P = 0.27) between the 2 groups. CONCLUSIONS: Our meta-analysis supports the superiority of fibrin glue to suture in pterygium surgery with conjunctival autografting in that the use of fibrin glue can significantly reduce the recurrence rate without increasing the risk of complications. Ophthalmologists should consider the use of fibrin glue in pterygium surgery. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 21292328 TI - Evidence of abnormalities in mid-latency auditory evoked responses (MLAER) in cognitive subtypes of patients with schizophrenia. AB - Abnormalities in measures of mid-latency auditory evoked responses (MLAER) have frequently been reported in schizophrenia, while few studies have examined whether these measures could distinguish cognitive subtypes of schizophrenia. The aim of this study was to investigate whether patterns of performance on MLAER measures could differentiate a cognitive subtype of patients characterized by pervasive cognitive deficits (CD) from patients with only mild cognitive deficits (CS) and controls. An auditory paired-click conditioning test was administered to 55 schizophrenia patients (26 CD, 29 CS) and 49 healthy controls. Amplitudes, latencies and sensory gating indices of the P50, N100, and P200 MLAER were analysed. The results showed that CD patients exhibited smaller S1 amplitudes of N100 and P200 than controls, while CS patients were comparable to controls. Binary logistic regression identified the P200 S1 amplitude as a significant predictor of patients' membership in the CD subtype. However, none of the other MLAER measures could differentiate the two subtypes of schizophrenia. These findings suggest that the abnormal pathophysiologic mechanisms underlying the electrophysiological brain responses to auditory stimulation are associated with the pervasive cognitive deficits, which characterize the CD subtype of schizophrenia. This finding might provide additional electrophysiological endophenotypes for future genetic research of schizophrenia. PMID- 21292329 TI - Faster REM sleep EEG and worse restedness in older insomniacs with HLA DQB1*0602. AB - HLA DQB1*0602 is found in most individuals with hypocretin-deficient narcolepsy, a disorder characterized by a severe disruption of sleep and wake. Population studies indicate that DQB1*0602 may also be associated with normal phenotypic variation of rapid eye movement (REM) sleep. Disruption of REM sleep has been linked to specific symptoms of insomnia. We here examine the relationship of sleep and DQB1*0602 in older individuals (n=46) with primary insomnia, using objective (polysomnography, wrist actigraphy) and subjective (logs, scales) measures. DQB1*0602 positivity was similarly distributed in the older individuals with insomnia (24%) as in the general population (25%). Most sleep variables were statistically indistinguishable between DQB1*0602 positive and negative subjects except that those with the allele reported that they were significantly less well rested than those without it. When sleep efficiencies were lower than 70%, DQB1*0602 positive subjects reported being less well rested at the same sleep efficiency than those without the allele. Examination of EEG during REM sleep also revealed that DQB1*0602 positive subjects had EEG shifted towards faster frequencies compared with negative subjects. Thus, DQB1*0602 positivity is associated with both a shift in EEG power spectrum to faster frequencies during REM sleep and a diminution of restedness given the same sleep quantity. PMID- 21292330 TI - Experimental Staphylococcus aureus infection of the mammary gland induces region specific changes in innate immune gene expression. AB - Staphylococcus aureus is a prolific mastitis-causing bacterium that resides naturally in the environment of the dairy cow. The aim of this study was to profile immune gene expression in tissue from the alveolar, ductal, gland cistern and teat canal regions of the bovine mammary gland following intramammary infection with S. aureus. Quantitative real-time PCR (qPCR) was used to profile expression of innate immune genes including pattern recognition receptors (PRRs), cytokines, antimicrobial peptides (AMPs) and acute phase proteins (APPs). Consistent expression of Toll-like receptors (TLRs) 1-10 and NOD-like receptors (NODs) 1-2 was detected in all four tissue regions. Pro-inflammatory cytokines (IL6, IL17A and IL8) and anti-inflammatory cytokine (IL10) were induced in all 4 tissues. APP (SAA3 and HP) and AMP (DEFB4 and DEFB5) genes showed the greatest induction throughout the mammary gland in response to S. aureus, with particularly high expression in alveolar tissue (SAA3 and HP >133- and >80-fold respectively, P<0.05; DEFB4 and DEFB5 >9- and >27-fold respectively, P<0.05). Collectively, our data show both sentinel and effector immune functions throughout the mammary gland in response to S. aureus challenge. PMID- 21292331 TI - Immunological characterization of the equine airway epithelium and of a primary equine airway epithelial cell culture model. AB - Our understanding of innate immunity within the equine respiratory tract is limited despite growing evidence for its key role in both the immediate defense and the shaping of downstream adaptive immune responses to respiratory disease. As the first interface to undergo pathogen invasion, the respiratory epithelium is a key player in these early events and our goal was to examine the innate immune characteristics of equine respiratory epithelia and compare them to an in vitro equine respiratory epithelial cell model cultured at the air-fluid interface (AFI). Respiratory epithelial tissues, isolated epithelial cells, and four-week old cultured differentiated airway epithelial cells collected from five locations of the equine respiratory tract were examined for the expression of toll-like receptors (TLRs) and host defense peptides (HDPs) using conventional polymerase chain reaction (PCR). Cultured, differentiated, respiratory epithelial cells and freshly isolated respiratory epithelial cells were also examined for the expression of TLR3, TLR9 and major histocompatibility complex (MHC) class I and class II using fluorescence-activated cell sorting (FACS) analysis. In addition, cytokine and chemokine profiles from respiratory epithelial tissues, freshly isolated respiratory epithelial cells, and cultured, differentiated, epithelial cells from the upper respiratory tract were examined using real-time PCR. We found that respiratory epithelial tissues and isolated epithelial cells expressed TLRs 1-4 and 6-10 as well as HDPs, MxA, 2'5' OAS, beta-defensin-1, and lactoferrin. In contrast, epithelial cells cultured at the AFI expressed TLRs 1-4 and 6 and 7 as well as MxA, 2'5' OAS, beta-defensin-1, but had lost expression of TLRs 8-10 and lactoferrin. In addition, MHC-I and MHC-II surface expression decreased in epithelial cells cultured at the AFI compared to isolated epithelial cells whereas TLR3 and TLR9 were expressed at similar levels. Lastly, we found that equine respiratory epithelial cells express an array of pro-inflammatory, antiviral and regulatory cytokines and that after four weeks of in vitro growth conditions, equine respiratory epithelial cells cultured at the AFI retained expression of GM-CSF, IL-10, IL-8, TGF-beta, TNF-alpha, and IL-6. In summary, we describe the development of an in vitro equine respiratory epithelial cell culture model that is morphologically similar to the equine airway epithelium and retains several key immunological properties. In the future this model will be a used to study equine respiratory viral pathogenesis and cell-to-cell interactions. PMID- 21292332 TI - Comparison of steroid antibiotic pack and 10% ichthammol glycerine pack in relieving pain of acute otitis externa in children. AB - OBJECTIVE: This study was carried out with the objective of comparing clinical efficacy of 10% ichthammol glycerine (IG) pack with steroid-antibiotic pack for relieving pain in cases of acute otitis externa. MATERIALS AND METHODS: A prospective quasi-randomized clinical trial was completely carried out in 65 patients at Department of ENT and Head and Neck Surgery, TU Teaching Hospital, Kathmandu. Patients of less or equal to 12 years of age and both gender presenting in our outpatient department from October 2008 to December 2009 and diagnosed to have acute otitis externa was evaluated. Six patients were excluded from the study because of not meeting the inclusion criteria. Alternately IG and steroid antibiotic packing were done. For steroid antibiotic group, we use betnovate-N, a combination of betnovate sodium phosphate 0.1% and neomycin sulphate 0.5%. Before packing was carried out, pain was assessed using Wong Baker Scale. Statistical analysis was done using "Z" test of mean to compare average number of pain score and visits in two different groups. RESULTS: There were 33 patients in IG pack group and 32 patients in steroid antibiotic group. In less than 4 years, there were 30 children and in more than 4 years children, there were 35 children. There was male predominance in both the treatment groups and disease was most common in age group less than 4 years. There was statistical significant decrease in number of visits in steroid group in both children less than and more than 4 years. There was also significantly less pain in children with steroid antibiotic group. CONCLUSION: Use of steroid antibiotic pack in children presenting with acute otitis externa causes earlier relief of pain as well as significantly lesser number of visits. Thus, steroid antibiotic pack is better than 10% ichthammol glycerine packs in relieving pain in acute otitis externa in children. PMID- 21292333 TI - Anxiety of the mothers with referred baby during Universal Newborn Hearing Screening. AB - OBJECTIVE: To investigate the anxiety among mothers whom their babies have failed test results in the first stage of Universal Neonatal Hearing Screening Program. PATIENTS AND METHODS: A cross-sectional study was carried out on mothers whom their baby have positive test results in the first stage of Universal Neonatal Hearing Screening Program. Face to face interview was conducted to obtain data on sociodemographic profiles, knowledge about hearing loss and past medical history. Symptoms experienced by the mothers due to positive hearing test results and level of anxiety were measured by using the Malay translation Beck Anxiety Inventory questionnaire. These mothers were then given an appointment to come for the second screening six weeks after the first screening. The same questionnaire was given to them before the start of the second screening. SPSS version 11.5 was used for data entry and analysis. Wilcoxon signed Rank Test was used to compare the level of anxiety between the first and second screening. RESULTS: From a total of 78 mothers who were participated during the first screening, 50 of them have completed the study at the second screening (response rate=64%). Fifty-two percent of them knew about the hearing screening before hand. Ninety-six percent of the mothers became alert about their child response towards sounds after they knew that their child had failed the first hearing screening. During the first screening, 74% of the mothers felt mild anxiety which was decreased to 68% before the mothers undergone the second screening. Moderate anxiety was felt by 10% of the mothers during both the first and second screening. There were 8% of the mothers having severe anxiety during the first screening but have reduced to half (4%) before the mothers undergone the second screening. The anxiety level was significantly less before the second screening with the median score of 5 (IQR: 13.0) compared to after the first screening (8, IQR=14.25); p=0.001. CONCLUSIONS: There are considerable portion of the mothers of false-positive test result during Universal Neonatal Hearing Screening Program experienced unacceptable anxiety. This group of mothers needs to be identified and given a necessary help. PMID- 21292334 TI - Predicting heart failure mortality in frail seniors: comparing the NYHA functional classification with the Resident Assessment Instrument (RAI) 2.0. AB - BACKGROUND: Though the NYHA functional classification is recommended in clinical settings, concerns have been raised about its reliability particularly among older patients. The RAI 2.0 is a comprehensive assessment system specifically developed for frail seniors. We hypothesized that a prognostic model for heart failure (HF) developed from the RAI 2.0 would be superior to the NYHA classification. The purpose of this study was to determine whether a HF-specific prognostic model based on the RAI 2.0 is superior to the NYHA functional classification in predicting mortality in frail older HF patients. METHODS: Secondary analysis of data from a prospective cohort study of a HF education program for care providers in long-term care and retirement homes. Univariate analyses identified RAI 2.0 variables predicting death at 6 months. These and the NYHA classification were used to develop logistic models. RESULTS: Two RAI 2.0 models were derived. The first includes six items: "weight gain of 5% or more of total body weight over 30 days", "leaving 25% or more food uneaten", "unable to lie flat", "unstable cognitive, ADL, moods, or behavioural patterns", "change in cognitive function" and "needing help to walk in room"; the C statistic was 0.866. The second includes the CHESS health instability scale and the item "requiring help walking in room"; the C statistic was 0.838. The C statistic for the NYHA scale was 0.686. CONCLUSIONS: These results suggest that data from the RAI 2.0, an instrument for comprehensive assessment of frail seniors, can better predict mortality than the NYHA classification. PMID- 21292335 TI - Association between cardiovascular risk factors and the presence of coronary plaque in a zero or low coronary artery calcium score. PMID- 21292336 TI - Qualitative risk assessment in a data-scarce environment: a model to assess the impact of control measures on spread of African Swine Fever. AB - In the absence of data, qualitative risk assessment frameworks have proved useful to assess risks associated with animal health diseases. As part of a scientific opinion for the European Commission (EC) on African Swine Fever (ASF), a working group of the European Food Safety Authority (EFSA) assessed the risk of ASF remaining endemic in Trans Caucasus Countries (TCC) and the Russian Federation (RF) and the risk of ASF becoming endemic in the EU if disease were introduced. The aim was to develop a tool to evaluate how current control or preventive measures mitigate the risk of spread and giving decision makers the means to review how strengthening of surveillance and control measures would mitigate the risk of disease spread. Based on a generic model outlining disease introduction, spread and endemicity in a region, the impact of risk mitigation measures on spread of disease was assessed for specific risk questions. The resulting hierarchical models consisted of key steps containing several sub-steps. For each step of the risk pathways risk estimates were determined by the expert group based on existing data or through expert opinion elicitation. Risk estimates were combined using two different combination matrices, one to combine estimates of independent steps and one to combine conditional probabilities. The qualitative risk assessment indicated a moderate risk that ASF will remain endemic in current affected areas in the TCC and RF and a high risk of spread to currently unaffected areas. If introduced into the EU, ASF is likely to be controlled effectively in the production sector with high or limited biosecurity. In the free range production sector, however, there is a moderate risk of ASF becoming endemic due to wild boar contact, non-compliance with animal movement bans, and difficult access to all individual pigs upon implementation of control measures. This study demonstrated the advantages of a systematic framework to assist an expert panel to carry out a risk assessment as it helped experts to disassociate steps in the risk pathway and to overcome preconceived notions of final risk estimates. The approach presented here shows how a qualitative risk assessment framework can address animal diseases with complexity in their spread and control measures and how transparency of the resulting estimates was achieved. PMID- 21292338 TI - Incretin secretion is not restored by short-term strict glycaemic control in Korean hyperglycaemic patients with type 2 diabetes. AB - AIMS: To determine whether short-term strict glycaemic control could restore incretin secretion in type 2 diabetic patients. The factors associated with incretin levels were also investigated. METHODS: A meal tolerance test (MTT) was performed in eighteen poorly controlled (pDM) and fifteen well controlled (wDM) diabetic patients. Fourteen patients in the pDM group underwent follow-up MTT after strict glycaemic control. The secretions of intact glucagon-like peptide-1 (iGLP-1) and total glucose-dependent insulinotropic polypeptide (tGIP) during MTT were calculated by total and incremental area under the curve (TAUC and IAUC) values. RESULTS: Posttreatment HbA1c level was significantly improved in the pDM group (11.2+/-0.9 to 7.9+/-0.9%). However, the secretion of incretin hormones was not increased in the posttreatment pDM group (TAUCiGLP-1, 3612+/-587 to 2916+/ 405 pmol/L min; TAUCtGIP, 9417+/-1099 to 8338+/-903 pmol/L min). IAUCiGLP-1 was negatively correlated (r=-0.446, P=0.011) and independently associated (beta= 137.2, P=0.027) with insulin resistance assessed by homeostasis model assessment. CONCLUSIONS: Incretin secretion is not restored by short-term strict glycaemic control. Decreased incretin secretion seems to develop early in the course of type 2 diabetes with increasing insulin resistance, but not to be influenced by glycaemic status. PMID- 21292337 TI - MALDI imaging mass spectrometry of human tissue: method challenges and clinical perspectives. AB - The molecular complexity of biological tissue and the spatial and temporal variation in the biological processes involved in human disease requires new technologies and new approaches to provide insight into disease processes. Imaging mass spectrometry is an effective tool that provides molecular images of tissues in the molecular discovery process. The analysis of human tissue presents special challenges and limitations because the heterogeneity among human tissues and diseases is much greater than that observed in animal models, and discoveries made in animal tissues might not translate well to their human counterparts. In this article, we briefly review the challenges of imaging human tissue using mass spectrometry and suggest approaches to address these issues. PMID- 21292339 TI - Circulating osteocalcin is increased in early-stage diabetes. AB - We aimed to examine whether circulating levels of osteocalcin, bone formation marker secreted from osteoblast, are changed in glucose-intolerant subjects without taking glucose lowering agent, because bone metabolism is reportedly related to glucose metabolism in animal and human studies. According to 75 g oral glucose tolerance test (75 g-OGTT), all subjects (47.6 +/- 10.2 years of age; 45 men and 10 women) were divided into three categories: normal glucose tolerance (NGT, n = 39), prediabetes (PDM, n = 11) that included impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), and diabetes (T2DM, n = 5). Serum osteocalcin levels were increased in T2DM as compared to NGT. In all the participants, simple regression analysis model revealed positive correlation of osteocalcin with plasma glucose at 120 min, G(120), on 75 g-OGTT, negative with both creatinine and Ln(CRP), but not significantly with fasting plasma glucose. Osteocalcin and leptin were independent variables for G(120) (P = 0.026 and 0.035, respectively). In multinomial logistic analysis leptin (PDM vs. NGT: P = 0.02 Odds ratio (OR) of 1.05, 95% confidence intervals, 1.007-1.084) and osteocalcin (T2DM vs. NGT: P = 0.038, OR 10.8, 1.13-102.4) were independently associated. We conclude that circulating osteocalcin and leptin are related to glucose intolerant state. PMID- 21292340 TI - Key elements for successful intensive insulin pump therapy in individuals with type 1 diabetes. AB - OBJECTIVE: Clinical trials have demonstrated that in individuals with type 1 diabetes the use of CSII pump resulted in better glucose control. Advantages of pumps therapy include many features such as the bolus calculators (wizard). These features are optional and therefore it is important to determine whether their use is associated with better glucose control. Thus, the aim of this analysis was to assess which features and parameters of insulin pump use are associated with better glucose control. METHODS: Data regarding consecutive patients with type 1 diabetes treated with an insulin pump and attending a tertiary referral for intensive glucose control was included in this analysis. The relationship between glycemic indices and treatment parameters (number of insulin units, number of glucose readings, bolus calculator use etc.) was assessed. RESULTS: A statistically significant relationship was found between glycemic indices and wizard use. Thus, individuals that used the wizard function in 50% of their boluses had an A1C, mean blood glucose values that were 0.6% (p=0.008) and 25mg/dL (p=0.000) lower respectively. CONCLUSION: The use of the bolus calculator feature was associated with better glucose control. Larger prospective clinical trials are needed in order to further validate this finding. PMID- 21292341 TI - Prognostic significance of metabolic parameters measured by (18)F fluorodeoxyglucose positron emission tomography/computed tomography in patients with small cell lung cancer. AB - OBJECTIVE: The aim of this study was to evaluate the prognostic significance of some metabolic parameters measured by (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) in patients with small cell lung cancer (SCLC). METHODS: We retrospectively reviewed 98 patients with pathologically proven SCLC who underwent pre-treatment (18)F-FDG PET/CT. Metabolic tumor volume (MTV), integrated standardized uptake value (iSUV) and average SUV (SUV(mean)) of all malignant lesions, and maximum SUV (SUV(max)) of the primary tumor were measured by (18)F-FDG PET/CT. We determined the relationship between overall survival (OS) and progression free survival (PFS) and these PET metabolic parameters. RESULTS: The estimated median OS and PFS for the entire cohort were 16.7 months and 9.8 months. The patients with larger MTV had significantly shorter median OS (9.6 months vs 23.2 months, P<0.001) and PFS (6.9 months vs 15.5 months, P<0.001) than the patients with smaller MTV. On multivariate analysis, MTV, iSUV, tumor stage and LDH were the significantly prognostic factors with OS and PFS. SUV(max) did not show correlation with OS and PFS. In subgroup analysis, limited disease (LD) with larger MTV showed significantly shorter median OS and PFS than LD with smaller MTV. Extensive disease (ED) with larger MTV also had significantly shorter median OS and PFS than the same stage with smaller MTV. CONCLUSIONS: MTV and iSUV are important independent prognostic factors for survival in patients with SCLC. Either MTV or iSUV may identify subgroups of patients at higher risk of progression or death in both LD and ED SCLC. PMID- 21292342 TI - NAT2 polymorphism and lung cancer risk: a meta-analysis. AB - N-acetyltransferase 2 (NAT2) gene encodes a key enzyme involved in the metabolism of xenobiotics and whose polymorphisms have been related to individual susceptibility to several malignancies. Although many epidemiological studies have explored the association between NAT2 genetic polymorphism and lung cancer risk, the results remain controversial. In order to assess the overall relationship between NAT2 polymorphism and lung cancer risk, we performed a meta analysis including 3945 lung cancer cases and 6085 controls from 19 published studies which were selected from 29 articles identified by a search of PubMed up to 1st June 2010. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association. No significant association was found in overall analysis (OR=1.02, 95% CI=0.90-1.16, P=0.01 for heterogeneity) and in subgroup analyses by ethnicity, sex, histological type, smoking status and study design. In conclusion, this meta-analysis found little evidence of an association between the NAT2 polymorphism and the risk of lung cancer. PMID- 21292343 TI - Association of genetic polymorphisms of CXCL12/SDF1 gene and its receptor, CXCR4, to the susceptibility and prognosis of non-small cell lung cancer. AB - BACKGROUND: The aim of this study was to evaluate the relations of chemokine CXCL12, previously known as stromal cell-derived factor-1 (SDF1), and its receptor, CXCR4, gene variants on non-small cell lung cancer (NSCLC) risk and disease severity. METHODS: Through a case-control study design, genomic DNA samples of 247 NSCLC patients and 328 age and sex-matched controls were subjected to polymerase chain reaction-restriction fragment length polymorphism analysis. The validity of this technique was proven by direct sequencing of amplified products. Statistical analyses were conducted to explore the contribution of polymorphism of the CXCL12/SDF1 gene and CXCR4, in the susceptibility to and prognosis of NSCLC. RESULTS: Overall, the genotype frequencies of CXCL12/SDF1 gene and CXCR4, were significantly different between lung cancer patients and controls (p<0.0001), and also different between patients with lung cancers of various stages (p<0.0001). Logistic regression analysis revealed that higher odds ratios (ORs) for lung cancer were seen for individuals with CXCL12/SDF1 AA (an OR of 1.95, 95% CI 1.08-3.50, p=0.018), or CXCR4 TT (an OR of 4.71, 95% CI 1.99 11.2, p<0.0001), and for individuals with both CXCL12/SDF1 AA and CXCR4 TT genotypes (an OR of 12.4, 95% CI 1.56-98.3, p=0.002). The patients carrying a homologous AA genotype at CXCL12/SDF1, or a homologous TT genotype at CXCR4, had a tendency to advanced disease and toward poorer prognoses compared with other patients. CONCLUSION: A significant association between the polymorphisms of CXCL12/SDF1 and CXCR4, and the susceptibility to and prognosis of NSCLC was demonstrated. PMID- 21292344 TI - Regulation of T cell activation by TLR ligands. AB - Regulatory T cells (Treg) maintain peripheral tolerance and play a critical role in the control of the immune response in infection, tumor defense, organ transplantation and allergy. CD4(+)CD25(high) Treg suppress the proliferation and cytokine production of CD4(+)CD25(-) responder T cells. The suppression requires cell-cell-contact and/or production of inhibitory cytokines like IL-10 or TGF beta. The current knowledge about the regulation of Treg suppressive function is limited. Toll-like receptors (TLR) are widely expressed in the innate immune system. They recognize conserved microbial ligands such as lipopolysaccharide, bacterial lipopeptides or viral and bacterial RNA and DNA. TLR play an essential role in innate immune responses and in the initiation of adaptive immune responses. However, certain TLR are also expressed in T lymphocytes, and the respective ligands can directly modulate T cell function. TLR2, TLR3, TLR5 and TLR9 act as costimulatory receptors to enhance proliferation and/or cytokine production of T-cell receptor-stimulated T lymphocytes. In addition, TLR2, TLR5 and TLR8 modulate the suppressive activity of naturally occurring CD4(+)CD25(high) Treg. The direct responsiveness of T lymphocytes to TLR ligands offers new perspectives for the immunotherapeutic manipulation of T cell responses. In this article we will discuss the regulation of Treg and other T cell subsets by TLR ligands. PMID- 21292345 TI - Sunscreens: an overview and update. AB - Sunscreens are an important aspect of photoprotection. Their efficacy in reducing photocarcinogenesis and photoaging is widely documented. Although there are concerns regarding long-term sunscreen safety, the advantages of sunscreen use are far more compelling. In addition, novel technologies and ultraviolet filters are improving the aesthetics and efficacy of modern products. PMID- 21292346 TI - Dermatoscopy: alternative uses in daily clinical practice. AB - Dermatoscopy, also known as dermoscopy, epiluminescence microscopy, or surface microscopy, is a noninvasive technique allowing rapid and magnified (* 10) in vivo observation of the skin with the visualization of morphologic features often imperceptible to the naked eye. Videodermatoscopy (VD) represents the evolution of dermatoscopy and is performed with a video camera equipped with lenses providing higher magnification (* 10 to * 1000). Over the past few years, both dermatoscopy and VD have been demonstrated to be useful in a wide variety of cutaneous disorders, including ectoparasitic infestations, cutaneous/mucosal infections, hair and nail abnormalities, psoriasis, and other dermatologic as well as cosmetologic conditions. Depending on the skin disorder, both dermatoscopy and VD may be useful for differential diagnosis, prognostic evaluation, and monitoring response to treatment. Nowadays, it represents an important and relatively simple aid in daily clinical practice. PMID- 21292347 TI - Holistic approach to treatment of intractable central neuropathic itch. AB - Central neuropathic itch can be a lifelong debilitating condition and treatment challenge. We report a patient with a traumatic brain injury with severe intractable pruritus who failed extensive pharmacologic and nonpharmacologic treatment but responded to a holistic approach using healing touch. We discuss the complexity of this type of neuropathic itch and present a holistic approach as an adjunct to therapy in reducing itch intensity. This case presentation along with the literature discussed suggests a therapeutic strategy for the management of complicated central neuropathic itch. PMID- 21292348 TI - Clinical features of pyoderma gangrenosum and current diagnostic trends. AB - BACKGROUND: The diagnosis of pyoderma gangrenosum (PG) can be exceedingly difficult, and misdiagnosis can potentially yield serious consequences. Clinical criteria for establishing a reliable diagnosis have been previously proposed, but a consensus in their application has yet to be reached. OBJECTIVE: We sought to review recent trends in diagnosing PG and compare them with previously suggested diagnostic criteria. METHODS: Data for this article were obtained by searching the PubMed database using the key words "pyoderma gangrenosum." Our search was limited to adult case reports that appeared in the English-language literature and received a final diagnosis of PG. The full text of the latest published 30 case reports that fulfilled these search criteria was reviewed. The articles spanned the years 2008 and 2009. Clinical features that appeared in the case descriptions were summarized and compared with the diagnostic criteria for the disease that were previously proposed. RESULTS: Of the 30 case reports, 16 described ulcers involving one or both legs, whereas only one case had peristomal involvement. Although 8 cases were associated with inflammatory bowel disease, 11 of the 30 patients did not have a systemic comorbidity. Fifteen lesions were noted to manifest at sites of trauma, which ranged from surgical incision sites to prolonged seatbelt compression. Nine case reports mentioned an undermined border in their clinical description, whereas only 5 authors commented on pustules and 6 described a purulent discharge. Only two authors commented on cribriform scarring. LIMITATIONS: We only reviewed the latest published 30 case reports. Case series, which may have shown more typical cases, were excluded. CONCLUSION: Currently, there is an underemphasis of clinical features in the diagnosis of PG, which can potentially lead to overdiagnosis. Establishing firm clinical criteria for diagnosing PG will ensure that case reports describe the same disease. This has implications in optimizing treatment strategies and improving patient outcomes. PMID- 21292349 TI - Should healthcare workers be screened routinely for meticillin-resistant Staphylococcus aureus? A review of the evidence. AB - Meticillin-resistant Staphylococcus aureus (MRSA) is considered endemic in the UK National Health Service (NHS), and routine MRSA screening of hospital inpatients has recently been introduced in both Scotland and England. The UK National Screening Committee states that public pressure for widening the eligibility criteria of a proposed screening programme should be anticipated and any related decisions scientifically justifiable. A literature review was conducted to examine whether MRSA screening in Scotland should be expanded to include the routine screening of healthcare workers (HCWs). There are no published prevalence studies reporting the overall MRSA carriage rate in HCWs in NHS hospitals. Estimates of HCW carriage from the worldwide literature vary widely depending on the country, hospital specialty and setting (endemic, non-endemic or outbreak). Recent studies conducted in endemic hospital settings report non-outbreak carriage rates of 0-15%. The role of HCW carriage in the transmission of MRSA is not well understood. Persistent carriage could act as a reservoir for infection and HCWs have been implicated as the source in a number of published outbreak reports. There are no published controlled trials examining the impact of routine HCW screening as an intervention in the prevention and control of MRSA infections in the endemic hospital setting. Most of the evidence for HCW screening comes from outbreak reports where the outbreak was brought to an end following the introduction of staff screening as part of a suite of infection control measures. Further research is required before a recommendation could be made to introduce routine MRSA screening of HCWs in the NHS in Scotland. PMID- 21292350 TI - [Partial laparoscopic adrenalectomy in primary hyperaldosteronism]. AB - INTRODUCTION: primary hyperaldosteronism is one of the few potentially curable causes of secondary arterial hypertension. One of the most important variants is the adenoma of the adrenal cortex that produces aldosterona (Conn's Syndrome). The treatment of choice in this subgroup of patients was the removal of the lesion. An initial series of patients with aldosteronoma subjected to partial laparoscopic adrenalectomy is presented. MATERIALS AND METHOD: We examined the case selection and methods applied to hypertensive patients subjected to partial laparoscopic adrenalectomy between November 2001 and March 2004 due to primary hyperaldosteronism. They all presented an imaging study (CT scan) compatible with a tumour of the adrenal cortex and, in two patients the lesion was bilateral. One patient had a history of incidental adrenalectomy during and open colecistectomy performed some years previously. RESULTS: we operated on 16 patients, 13 of them women and 3 men, with a mean age of 55.4 years. We performed 18 laparoscopic adrenalectomies: 17 conservative operations and one total adrenalectomy of a 4.3 cm tumour in a patient with bilateral lesion. The mean duration of the operations was 70.9 minutes, with a mean bleeding rate of 30 ml. There were no complications or the need to resort to open surgery. Postoperative hospital stay was 2.8 days. In all the cases, the hypertension improved totally or partially. CONCLUSION: although small, the series confirmed that partial laparoscopic suprarenalectomy can be performed with good results and with the advantages of minimally invasive surgery. PMID- 21292351 TI - [Contribution to the history of urological pharmacotherapy]. AB - INTRODUCTION: The aim of this work is to present a historical review of urological pharmacotherapy. The containers used to preserve and store medicines are an important source of information in historical research. MATERIAL AND METHODS: I studied written sources such as treaties of Medical and Therapeutical Materials, as well as material sources available at the Pharmacy Museum of the Farmacia Monastica de la Real Cartuja de Valldemossa in Mallorca. I examined the old medicine containers and the labelling on ceramic recipients, glass jars and wooden boxes and other medicines found inside them. RESULTS: Different medicines, the most used over the centuries to treat diseases of the urinary system are described, including both simple (of plant, mineral or animal origin) and compound medicines: drumstick tree, agaricus, mechoacan, lupine, fennel, acacia gum, myrtle, Armenian bole, oleum scorpionum, hartshorn plantain, cantharides. I present evidence of knowledge available for each of these remedies in the main bibliographic sources, as well as proof that they were used in Valldemossa. CONCLUSIONS: The basis of general and urological pharmacotherapy was concentrated on nature. Medicines of plant origin were the most used. The therapeutic inventory that mankind has accumulated throughout history is the result of a lengthy process of combining practices and knowledge of different cultures and societies. PMID- 21292352 TI - [Tenofovir, an antiviral agent with low spermiostatic activity]. PMID- 21292353 TI - [Retrograde intrarenal surgery (RIRS). Technical complement for cases of acute lithiasis]. AB - INTRODUCTION: Washing the renal cavities using minipercutaneous surgery shaft is an ideal technical procedure for retrograde intrarenal surgery (RIRS) when lithiasic fragmentation is significant or if the anatomy of the renal cavities may obstruct the spontaneous elimination of fragments. MATERIALS AND METHODS: we performed 37 RIRS on 35 patients with renal lithiasis (14 men, 21 women) with a mean age of 56 (range 33-72) years, divided into two groups in accordance with the size of their kidney stones. Group A, 23 patients with lithiasis <1.5 cm; Group B, 12 cases with lithiasis >1.5 cm. 28 patients had a single kidney stone and 7 had multiple stones. APPROACH: Flexible uretrorenoscopy, 7.5 Fr (Flex X((r), Karl Storz) by means of a ureteral access sheath. Holmium laser lithotripsy (Calculase(r), Karl Storz) using 200 and 365 micrometer fibres. Fragment extraction with 1.7 Fr nitinol baskets (N-gage, Cook). In cases of significant fragmented stone burden, the renal cavities were washed with low pressure fluid irrigation using a ureteral access sheath, which was collected together with the stone fragments carried by the "mini-perc" sheath (Ultrax-x(r) 18Fr, Cook; Rusch, 14 Fr) placed under radiologic and endoscopic control at the level of the calyx-papilla selected for fragment drainage. RESULTS: the mean diameter for group A was 9.13 (range 5-13) mm and 20.25 (range 16-28) mm for group B. The overall mean operating time was 81 (range 30-160) min. Group A required 66.43+/-35.18 min. and group B 107.5+/-46.73 min. (p=0.006). The rate of absence of stones immediately after surgery was 83.2%, 93.1% at 3 months (95.6% for A and 83.3% for B; p=0.217). In no case was ureteral stenosis observed as a result of the use of ureteral access sheaths. In 7 group B patients (58.3%) with acute lithiasis and/or alteration in their pyelocaliceal anatomy, we performed active lavage of the renal cavities applying the aforementioned percutaneous technique. The mean post-surgery hospital stay was 2.1 (range 1-4) days. There were post-surgery complications (Clavien 1) in 7 patients (20%). Two patients required a second FURS. CONCLUSIONS: RIRS can be effective treatment for renal lithiasis >1.5 cm. Lavage of the renal cavities helps to eliminate stone fragments, reducing the possibility of retreatment. PMID- 21292354 TI - [Clinical-administrative databases: information that adds value to the investigation of re-admissions in the elderly population]. PMID- 21292355 TI - Use of aliphatic poly(amide urethane)s for the controlled release of 5 fluorouracil. AB - The controlled release of 5-fluorouracil (5FU) from aliphatic poly(amide urethane)s (PURs) was studied in vitro. Linear PUR conjugates were prepared by the reaction between oligo(E-caprolactone) (PCL), oligolactide (PLA), copolymers of E-caprolactone (CL) and rac-lactide (rac-LA), dihydroxy(polyethylene adipate) (OEDA) with 1,6-diisocyanatohexane (HDI). Release of 5FU from PURs was found to depend on the nature of oligoester units and consist of soft and hard segments. PMID- 21292356 TI - Discovery of torezolid as a novel 5-hydroxymethyl-oxazolidinone antibacterial agent. AB - A series of novel substituted pyridyl phenyl oxazolidinone analogues were synthesized and their structure-activity relationship (SAR) was investigated based on in vitro and in vivo antibacterial activities. The minimum inhibitory concentrations (MICs) of the synthesized compounds against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) ranged from 0.12 to 2.0 MUg/mL, and against Haemophilus influenzae (Hi) from 2.0 to 8.0 MUg/mL. Compared to linezolid, only four compounds (11, 12, 21 and 29) showed higher in vitro antibacterial activities and better in vivo protective effects in mice. To improve the aqueous solubility, various prodrugs of compound 11 (DA 7157), which exerted a potency that was enhanced by 2-8-fold compared to that of linezolid, were synthesized. Among the prodrugs, the phosphate compound 42 exhibited excellent aqueous solubility (>50mg/mL in DW) and good pharmacokinetic profiles, along with better in vivo efficacy than linezolid. This compound 42 is currently undergoing clinical trials with the brand name Torezolid. PMID- 21292357 TI - [Type 2 diabetes and universal health care for low-income groups: a case-control study]. AB - PURPOSE: In 2007 in France, type 2 diabetes involved 2.5 million people, and 4.5 million patients received free healthcare coverage under the universal healthcare coverage program (CMU) for low-income households. An optimal glycemic control and adequate diabetes monitoring can reduce the incidence of complications. The objective of this study was to compare the diabetes care of low-income patients (as defined by CMU coverage) with the rest of the population. METHODS: A retrospective case-control study (non-CMU and CMU) over a one-year period of glycemic control for both populations through private laboratory data (number and values of HbA1c) and of individuals monitoring through data from the regional health insurance public institute. RESULTS: Regarding glycemic control, 154 patients were included. The number of annual HbA1c tests was similar between CMU and non-CMU patients. The mean HbA1c value was higher for CMU patients (8.7% versus 8%; P<0.01). Regarding monitoring, 1254 patients were included. Over a one year period, the number of HbA1c tests, lipid profile tests, serum creatinine measures and cardiology consultations were similar across groups. However, CMU patients benefited from less microalbuminuria testing (P<0.001), ophthalmologic monitoring visits (P<0.01), endocrinology consultations (P<0.01), and from more general physician consultations (P<0.001). CONCLUSIONS: Receiving CMU health coverage was associated with a poorer glycemic control and lesser specialized monitoring than that was observed in control patients. Across the population, follow-up recommendations are far from being implemented satisfactorily. PMID- 21292358 TI - [Bone lesions]. PMID- 21292359 TI - [Clinical relevance of leukocyte differential in patients with marked leukocytosis in the emergency room]. AB - PURPOSE: We analyzed the characteristics of the leukocyte differential and the clinical outcome in patients admitted in an emergency department with marked leukocytosis greater than 20*10(9)G/L. METHODS: We studied a case series of consecutive patients admitted in an emergency department. The medical records were retrospectively reviewed after patient discharge. Three groups were defined: patients with infectious disorders (group I), noninfectious disorders (group II), and trauma (group III). Admission in intensive care unit (ICU), consciousness impairment or death defined the subgroup S of high severity. RESULTS: Groups I, II and III comprised, respectively, 150, 95 and 86 patients. The group I presented with higher temperature and neutrophilia (22,2+/-4.9 vs 20.9+/-4.0 and 21.1+/-3.9*10(9)G/L; P<0.001), and more profound eosinopenia (0.058+/-0.094 versus 0.098+/-0.170 and 0.092+/-0.104*10(9)G/L; P<0.001) and lymphopenia (1.16+/ 0.98 vs 1.53+/-1.04 and 1.73+/-1.10*10(9)G/L; P<0.001) than the two other groups. Both neutrophilia and lymphopenia were independent predictors of infection by multivariate analysis. Frequencies of admission in ICU were, respectively, 8.7%, 40% and 43% (P<0.001). Leukocyte and neutrophil counts were significantly higher and basophil count significantly lower in subgroup S. Overall, 13.6% of the patients died and were characterized by basopenia. CONCLUSION: Marked leukocytosis indicated severe illness. Lymphopenia, eosinopenia and temperature were significant predictors of infection. A more severe clinical course was correlated with higher neutrophilia and basopenia. PMID- 21292360 TI - Emotional intelligence: its relationship to stress, coping, well-being and professional performance in nursing students. AB - Emotional intelligence (EI) has been highlighted as an important theoretical and practical construct. It has the potential to enable individuals to cope better and experience less stress thus contributing to a healthy and stable workforce. The study aimed to explore the EI of nursing students (n=130, 52.0%) and its relationship to perceived stress, coping strategies, subjective well-being, perceived nursing competency and academic performance. Students were on the adult pathway of a nursing diploma or degree programme in one Higher Education Institution (HEI) in the United Kingdom (UK). A prospective correlational survey design was adopted. Three methods of data collection were used: i) A self-report questionnaire; ii) an audit of students' academic performance; and iii) mapping of EI teaching in the curricula. Emotional intelligence was positively related to well-being (p<0.05), problem-focused coping (p<0.05) and perceived nursing competency (p<0.05), and negatively related to perceived stress (p<0.05). The findings suggest that increased feelings of control and emotional competence assist nursing students to adopt active and effective coping strategies when dealing with stress, which in turn enhances their subjective well-being. This study highlights the potential value of facilitating the EI of students of nursing and other healthcare professions. PMID- 21292361 TI - Preliminary study of the effects of an educational workshop on therapeutic use of music and aesthetic experience with music in first-line nurses. AB - AIM: The purpose of this study was to assess the effects of an educational workshop on knowledge of and attitude toward therapeutic use of music and aesthetic experiences with music among first-line nurses. DESIGN: A one-group pre test/post-test design was used. METHODS: Forty-six first-line nurses, aged 21-56 years, were recruited from seven different hospitals. Questionnaires were used to assess the nurses' knowledge of and attitude toward therapeutic use of music and aesthetic experience with music before and after the workshop, and 3 months after the workshop. The workshop comprised three sessions; the nurses participated in 8h of instruction the first week and 4h, the second week covering analytical music appreciation, music staves comprehension, theory and practice of music therapy, and evidence-based music intervention. RESULTS: Educational workshop significantly improved knowledge of and attitudes toward therapeutic use of music and music aesthetic experiences (p<0.001). A sustained effect of the workshop was found at follow up 3-month after workshop. The mean change in scores for music aesthetic experiences between nurse with and without music backgrounds differed significantly (p=0.01). CONCLUSIONS: The workshop enhanced the knowledge of and attitude toward therapeutic use of music and aesthetic experiences with music among first-line nurses. PMID- 21292362 TI - Impact of nutritional status on the oral bioavailability of leucine administered to rats as part of a standard enteral diet. AB - BACKGROUND: To investigate the absorption and relative bioavailability of leucine administered orally as part of an enteral diet in well and malnourished animals. METHODS: Two groups - RN (regular nutrition) and PCR (protein-calorie restricted) - were fed with different diets for 23-25 days. Rats from each group were assigned randomly to one of three treatments (water, T-Diet Plus Standard((r)) (problem) or Isosource ST((r)) (reference)) administered in single (N = 76) or multiple (N = 39) doses. Blood samples were assayed for leucine content. Area under the curve (AUC) was calculated by non-compartmental analysis. Log transformed AUC(s) were statistically compared by analysis of variance, and 90% confidence intervals (CI 90%) of the ratio of the log-transformed AUC(s) between problem and reference diets, and between enteral diet and water were determined. RESULTS: The AUC (last) between the problem and reference diets was not statistically different. 90% CIs for single and multiple doses were 58.4-137.5% and 78-134.6% for RN and 76.7-172.2% and 72-167.2% for PCR, respectively. Leucine absorption was 12% higher among malnourished animals when multiple doses were administered, but the differences detected were not statistically different. CONCLUSIONS: In spite of the different composition of proteins in the enteral diets tested, the absorption of leucine, even though slightly higher in the malnourished state, is similar in both of them. PMID- 21292363 TI - Modeling short-term variability of semivolatile organic chemicals in air at a local scale: an integrated modeling approach. AB - Monitoring campaigns from different locations have recently shown how air concentrations of persistent semivolatile contaminants such as polychlorinated biphenyls (PCBs) often exhibit short-term (less than 24 h) variations. The observed patterns have been ascribed to different factors, such as temperature mediated air-surface exchange and variability of planetary boundary layer (PBL) height and dynamics. Here, we present a new modeling approach developed in order to investigate the short-term variability in air concentrations of organic pollutants at a local scale. A new dynamic multimedia box model is supplied by a meteorological preprocessor (AERMET) with hourly values of air compartment height and wind speed. The resulting model is tested against an existing dataset of PCB air concentrations measured in Zurich, Switzerland. Results show the importance of such modeling approach in elucidating the short- and long-term behavior of semivolatile contaminants in the air/soil system. PMID- 21292364 TI - Aporrectodea caliginosa, a suitable earthworm species for field based genotoxicity assessment? AB - There is a growing interest for the application of biomakers to field-collected earthworms. Therefore we have evaluated the usability of native populations of endogeic, widely distributed earthworm Aporrectodea caliginosa in the assessment of soil genotoxicity using the Comet assay. Validation of the Comet assay on earthworm coelomocytes has been established using commercially available Eisenia fetida exposed to copper, cadmium, and pentachlorophenol, along with A. caliginosa exposed to copper in a filter paper contact test. Neutral red retention time (NRRT) assay was conducted on copper exposed and field-collected earthworms. Significant DNA and lysosomal damage was measured using Comet and NRRT assays in native populations of A. caliginosa sampled from the polluted soils in the urban area in comparison to the earthworms from the reference site. The results of this study confirm the employment of A. caliginosa as a suitable species for the in situ soil toxicity and genotoxicity field surveys. PMID- 21292367 TI - Photoelastic analysis of stress distribution of surgically assisted rapid maxillary expansion with and without separation of the pterygomaxillary suture. AB - PURPOSE: The aim of this study was to evaluate in vitro the mechanical effect over teeth and bone structures of surgically assisted rapid maxillary expansion (SARME) in photoelastic analogs by observing stress produced during Hyrax-type and Haas-type appliances activation. MATERIALS AND METHODS: Two photoelastic analogs were fabricated by use of birefringent materials to simulate an adult skull that contained teeth, bone, and maxillary sinus. Hyrax-type and Haas-type appliances were applied to the anchor teeth and incrementally activated. SARME was simulated by subsequent cuts of the lateral maxillary wall and midpalatine suture and separation of the pterygomaxillary junction. After each osteotomy, the appliances were activated. Resulting stress patterns were recorded photographically in the field of a plane polariscope. RESULTS: Before any osteotomy, the activation of the appliances distributed stress through the anchoring teeth to the zygomaticomaxillary walls, concentrating at the zygomaticomaxillary and zygomaticofrontal sutures and at the midline of the maxilla. After midpalatal and maxillary wall osteotomies, a marked reduction of the stress at the zygomaticomaxillary walls was observed. With successive activations, the stresses increased in intensity at the molars, maxillary tuberosity, and pterygoid plates. After pterygomaxillary separation, the stress intensity at the molar area, maxillary tuberosity, and pterygoid plates decreased considerably. With successive activations, stress increased in intensity around the molars and maxillary tuberosity. There were no differences between stresses produced by the 2 appliances. CONCLUSIONS: In this biomechanical model, sectioning of all maxillary articulations, including separation of the pterygomaxillary junction, caused a decrease in stress over anchorage teeth. These data cannot be completely extrapolated to the clinical situation but indicate that electing to perform the SARME technique should be based on periodontal health and amount of expansion necessary for each case. PMID- 21292365 TI - Traffic exposure in a population with high prevalence type 2 diabetes--do medications influence concentrations of C-reactive protein? AB - Type 2 Diabetes (T2D) and particulate air pollution are associated with inflammatory dysregulation. We assessed the modifying effects of diabetes medications on the association of C-reactive protein (CRP), a marker of inflammation, and traffic exposure in adults with T2D (n = 379). CRP concentrations were significantly positively associated with residence <=100 m of a roadway, >100 m and <=200 m of a roadway and increased traffic density for individuals using insulin. For individuals using oral hypoglycemic medications (OHAs), CRP was significantly negatively associated with residence >100 m - <=200 m of a roadway and multiple roadway exposure in an interaction model. Among people with diabetes, individuals on insulin appear to be most vulnerable to the effects of traffic exposure. Disease severity among insulin users may promote the pro-inflammatory response to traffic exposure, though diabetes medications may also modify the response. Possible anti-inflammatory effects of OHAs with traffic exposure merit further evaluation. PMID- 21292366 TI - Lower urinary connective tissue growth factor levels and incident CKD stage 3 in the general population. AB - BACKGROUND: Connective tissue growth factor (CTGF) is involved in the development and progression of kidney diseases, including diabetic nephropathy and kidney fibrosis, but also may have a role in mesangial repair after injury. It is unknown whether, in the general population, urinary CTGF levels are associated with a decrease in estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73 m(2) (ie, development of chronic kidney disease [CKD] stage 3). STUDY DESIGN: Nested case-control. SETTING & PARTICIPANTS: 100 cases of incident CKD stage 3 and 100 age-and sex-matched controls in the Framingham Heart Study; 141 cases and 135 age-, sex-, and race-matched controls in the Atherosclerosis Risk in Communities (ARIC) Study. Controls had eGFR >=60 mL/min/1.73 m(2) at follow-up in both studies. PREDICTORS: Urinary CTGF concentrations. OUTCOMES: Incident CKD stage 3, defined as eGFR <60 mL/min/1.73 m(2). MEASUREMENTS: Stored urine samples from Framingham Heart Study and ARIC were measured for CTGF. Covariates were obtained from Framingham Heart Study and ARIC participant examinations. RESULTS: In the Framingham Heart Study, the median baseline urinary CTGF concentration was lower in cases (1.35 ng/mL) than controls (2.35 ng/mL; paired t test, P < 0.0001). The multivariable-adjusted OR for incident CKD stage 3 was 0.33 (95% CI, 0.17-0.64; P < 0.001) per 1-standard deviation in log urinary CTGF level after adjustment for CKD risk factors, baseline eGFR, and baseline log urinary albumin creatinine ratio, with similar results in participants without diabetes (n = 184). Results were not materially different when urinary CTGF level was indexed to urinary creatinine level (multivariable-adjusted OR, 0.34; 95% CI, 0.21-0.56; P < 0.001). A similar, but nonsignificant, trend of risk of incident CKD stage 3 with lower baseline urinary CTGF concentration was observed in an independent case-control study conducted in the ARIC Study, with the strongest results observed in participants free of diabetes. This inverse relationship was robust in meta-analysis of both the overall and diabetes-free groups. LIMITATIONS: Observational study; causality cannot be inferred. CONCLUSIONS: Lower urinary CTGF concentrations precede the onset of CKD stage 3 in the general population. Further work is required to fully characterize how CTGF level influences risk of CKD. PMID- 21292368 TI - Darkening of third molar roots: panoramic radiographic associations with inferior alveolar nerve exposure. AB - PURPOSE: The aim of the present study was to examine the association between the darkening of the root on the preoperative panoramic radiograph and intraoperative inferior alveolar nerve (IAN) exposure. PATIENTS AND METHODS: In the present study, 116 mandibular third molar surgical extraction cases with darkening of the third molar roots on the preoperative panoramic radiographs were selected for a case group, and 193 patients with one or more of the following "high-risk" signs, indicating a close spatial relationship between the root and dental canal, were selected for the control group: interruption of the white line, diversion of the canal, and/or narrowing of the canal. The correlation between the radiographic markers and IAN exposure was estimated using bivariate analysis. RESULTS: The IAN was visible in 47 (15.2%) of 309 intraoperative extractions. Darkening of the third molar roots was significantly associated with IAN exposure (P < .001). Those with both darkening and adjacent "high-risk" radiographic markers present simultaneously had a significantly greater risk of IAN exposure than those with darkening only (P < .001) or any other combination of multiple high-risk factors (P = .001). CONCLUSIONS: Significant differentiation between isolated darkening and darkening with both adjacent and high-risk signs seems to be essential in predicting IAN exposure. PMID- 21292369 TI - Novel treatment of atypical human papillomavirus-associated epithelial hyperplasia with cidofovir. AB - PURPOSE: We report a severe case of human papillomavirus-associated epithelial hyperplasia in a man infected with human immunodeficiency virus. These lesions were recalcitrant to treatment with surgical modalities and were eventually controlled with the daily application of a topical cidofovir gel. PATIENT AND METHODS: A single case is presented, along with a relevant review of the published data. RESULTS: Before the initiation of cidofovir treatment, the patient had approximately 80% of his gingiva and buccal mucosa engrossed by confluent papillomatous lesions. At 2 weeks after cidofovir treatment, the lesions had markedly regressed, and by 4 weeks, they were almost fully resolved. No untoward adverse reactions occurred. CONCLUSIONS: Cidofovir formulated as a gel can be safe and effective for the treatment of epithelial hyperplasia in those with human immunodeficiency virus infection. PMID- 21292370 TI - Management of central giant cell granuloma of mandible using intralesional corticosteroids: case report and review of literature. PMID- 21292371 TI - Comparison of heat generation during implant drilling using stainless steel and ceramic drills. AB - PURPOSE: The purpose of this study was to compare the heat generated from implant drilling using stainless steel and ceramic drills. MATERIALS AND METHODS: A total of 40 fresh bovine femoral cortical bone samples were used in this study. A constant drill load of 2.0 kg was applied throughout the drilling procedures via a drilling rig at a speed of 1,500 rpm. Two different implant drill types (stainless steel and ceramic) were evaluated. Heat was measured with type K thermocouple from 3 different depths. Data were subjected to the independent sample t test and Pearson correlation analysis. The alpha level was set a priori at 0.05. RESULTS: The mean maximum temperatures at the depths of 3 mm, 6 mm, and 9 mm with the stainless steel drill were 32.15 degrees C, 35.94 degrees C, and 37.05 degrees C, respectively, and those with the ceramic drill were 34.49 degrees C, 36.73 degrees C, and 36.52 degrees C, respectively. A statistically significant difference was found at the depth of 3 mm (P = .014) whereas there was no significant difference at the depths of 6 and 9 mm (P > .05) between stainless steel and ceramic drills. CONCLUSION: Within the limitations of the study, although more heat was generated in the superficial part of the drilling cavity with the ceramic drill, heat modifications seemed not to be correlated with the drill type, whether stainless steel or ceramic, in the deep aspect of the cavity. Further clinical studies are required to determine the effect of drill type on heat generation. PMID- 21292373 TI - Temporomandibular joint synovial chondromatosis with intracranial extension: a review and observations of patient observed for 4 years. PMID- 21292372 TI - Quality of life of patients with segmental mandibular resection and immediate reconstruction with plates. AB - PURPOSE: The surgical management of some head-and-neck pathology affects a patient's form and fundamental function and, eventually, the quality of the individual's daily life. Restoring mandibular continuity after resection will improve form, function, and eventually, quality of life (QOL). The aim of this study was to evaluate the effect of our limited restoration with immediate plate reconstruction after segmental mandibular resection on the QOL of patients. PATIENTS AND METHODS: A total of 13 patients were included in the study. They were treated for benign but aggressive mandibular pathology. Treatment included segmental mandibular resection with immediate plate reconstruction. A modified University of Washington QOL questionnaire was used to assess QOL. Data on clinico-dermographic variables were also collated. A total of 17 surgeries were undertaken, with 16 implants placed. RESULTS: Patients with smaller tumors seemed to have better QOL scores than those with larger tumors. The overall QOL scores for younger patients seemed better than those of older patients. Spontaneous regeneration of the mandible, occurring in our younger patients, was an added reason for this seemingly better QOL. CONCLUSIONS: Patients with segmental mandibulectomy and spontaneous mandibular regeneration tended to have a better QOL than those with no reconstruction and immediate plate reconstruction. PMID- 21292374 TI - Ki-67 from clinically and histologically "normal" distant mucosa as prognostic marker in early-stage (T1-T2N0) oral squamous cell carcinoma: a prospective study. AB - PURPOSE: The aggressive behavior and long-term prognosis of oral squamous cell carcinoma (OSCC) have recently been related to the mucosa surrounding the primary mass, consisting of genetically altered cells that might be responsible for cancer progression. Early-stage T1-T2N0 OSCCs have been associated with a good prognosis; however, a certain percentage of them can be complicated by locoregional metastases. The purpose of our study was to determine whether an abnormal proliferative status can be found in clinically and histologically "normal" mucosa situated in areas distant from the primary tumor. We also sought to determine whether this is associated with a poor prognosis in terms of local recurrence or lymph node metastasis. PATIENTS AND METHODS: The prospective study included 42 consecutive patients with T1N0M0 (n = 19) and T2N0M0 (n = 23) OSCC. Disease-free survival endpoints were defined as the duration between surgical resection and the diagnosis of recurrence, lymph node metastasis, or last follow up visit. Proliferative status in distant areas (opposite cheek) was evaluated by Ki-67 expression. RESULTS: The mean Ki-67 value (17.6% +/- 8.2%) in the distant mucosa was significantly greater (F = 13.87; P < .01) than that found in the controls (9.8 +/- 3.1). "Abnormally high" Ki-67 values were detected in 13 patients with OSCC (30%). Four patients developed locoregional recurrence during follow-up. Kaplan-Meier analysis showed that Ki-67 in the distant mucosa was a significant independent prognostic factor for disease-free survival. CONCLUSIONS: A certain percentage of patients surgically treated for early T1-T2 OSCC will have an abnormal proliferative status in areas very distant from the primary tumor that seems to be related to a poor prognosis. PMID- 21292375 TI - Surgical treatment of sagittal fracture of mandibular condyle using long-screw osteosynthesis. AB - PURPOSE: The retrospective study evaluated long-screw (bicortical screw) osteosynthesis used in the surgical treatment of sagittal fracture of the mandibular condyle and compared it with titanium plates and removal of the condylar fragment. PATIENTS AND METHODS: Ninety-five patients with sagittal fracture of the mandibular condyle received open surgical treatment from 1997 to 2008. Among these patients, the condylar fragments were fixed with long screws in 56 cases (group A), were fixed with titanium plates in 12 cases (group B), and were completely removed in 24 cases (group C). Follow-up was carried out clinically and radiologically. The clinical features included limitation of mandibular mobility, occlusion disturbance, lateral deviation on mouth opening, joint pain, clicking, facial asymmetry, and patient's subjective evaluation. The radiologic parameters consisted of degree of bony resorption, bony change, change of osteosynthesis material, and shortening of mandibular ramus height. RESULTS: Anatomic reduction and functional restoration were obtained and no severe complication was detected in group A. However, 3 of 14 patients had severe osteoarthrosis and 2 of 14 patients had ankylosis in group B. In group C 3 of 24 patients had mandibular retrusion, 4 of 24 patients had front teeth open bite, 4 of 24 patients had severe osteoarthrosis, and 1 of 24 patients had ankylosis. CONCLUSION: The long-screw fixation group had a more favorable prognosis than the titanium plate group and the group in which removal of the condylar fragment was performed. The long-screw fixation technique might be suitable for use in the surgical treatment of sagittal fractures of the mandibular condyle. PMID- 21292376 TI - Sequencing bimaxillary surgery: mandible first. PMID- 21292377 TI - Forty sandwich osteotomies in atrophic mandibles: a retrospective study. AB - PURPOSE: The aim of the present retrospective study was to assess the suitability of segmental mandibular sandwich osteotomy combined with an interpositional autograft to meet the dimensional requirements of preimplant bone augmentation in cases of a severely atrophic mandible. PATIENTS AND METHODS: A total of 27 consecutive patients (6 men and 21 women) were included in the present study. The amount of bone gain was calculated using digital volume tomography before surgery and 3 months after bone augmentation. RESULTS: The postoperative course was uneventful for 18 patients. Temporary sensory disturbances were observed in 6 patients, with complete recovery after 3 to 12 weeks. Dehiscence of soft tissue closure occurred in 3 patients. The mean vertical gain was 3.41 mm (range 0.3 to 12). The mean horizontal gain was 3.08 mm (range 0.2 to 8.5). A total of 88 implants were placed in 40 surgical sites at 12 weeks after bone reconstruction. CONCLUSION: Segmental mandibular sandwich osteotomy is a suitable augmentation procedure in the mandible for the atrophic alveolar ridge and provides adequate height and transversal bone augmentation. PMID- 21292378 TI - [Poland's syndrome in women: Therapeutic indications according to the grade. Apropos of 11 cases and review of the literature]. AB - INTRODUCTION: Correction of chest and breast abnormalities in Poland's syndrome differs among authors. The aim of this study is to discuss surgical protocols according to the grade of Poland's syndrome in women. PATIENTS AND METHODS: The authors present a series of 11 women with Poland's syndrome among which nine were operated. Several surgical techniques were used. Cosmetic results were analysed according to the treatment and grade. Median follow up is 9 years. RESULTS: In grade I, a round breast implant seems to be the best choice. In grade II, a latissimus dorsi flap combined with a breast implant gives better results than a breast implant alone. In grade III, breast and chest reconstruction are linked. The authors present a case of costal reconstruction followed by an expansion without a latissimus flap. CONCLUSION: Many authors recommend a latissimus flap combined with a breast implant in severe grades of Poland's syndrome. Using this flap is not always possible nor mandatory. According to soft tissue quality, expansion may be an alternative way or a temporary solution during growth. PMID- 21292379 TI - Pulmonary thromboembolism observed by endobronchial ultrasound (EBUS). PMID- 21292380 TI - Comparison of non-calibrated pulse-contour analysis with continuous thermodilution for cardiac output assessment in patients with induced hypothermia after cardiac arrest. AB - AIM: Induced mild hypothermia after cardiac arrest interferes with clinical assessment of the cardiovascular status of patients. In this situation, non invasive cardiac output measurement could be useful. Unfortunately, arterial pulse contour is altered by temperature, and the performance of devices using arterial blood pressure contour analysis to derive cardiac output may be insufficient. METHODS: Mild hypothermia (32-34 degrees C) was induced in eight patients after out-of-hospital cardiac arrest and successful resuscitation. Cardiac output (CO) was measured simultaneously by continuous thermodilution using a pulmonary artery catheter and a cardiac output monitor (Vigilance II, Edwards Lifesciences) and by pulse contour analysis using an arterial line and the Vigileo monitor (Edwards Lifesciences) during both normothermia (>36 degrees C) and hypothermia. Continuous CO from both monitors was compared (Bland-Altman) and concordance of changes measured in consecutive 8-min intervals was measured. RESULTS: Mean cardiac output was 3.9+/-1.2 l/min during hypothermia and 6.1+/-2.6 l/min during normothermia (p<0.001). During hypothermia (normothermia), bias was 0.23 (0.77)l/min, precision (1 SD) was 0.6 (0.72) l/min, and the limits of agreement were -1.06 to 1.51 (-0.64 to 2.18) l/min, corresponding to a percentage error of +/-34% (+/-24%). Concordance of directional CO changes >10% was 53.9% in hypothermia and 51.4% in normothermia. CONCLUSION: Induced hypothermia was not associated with increased bias or limits of agreement for the comparison of Vigileo and continuous thermodilution, but percentage error was high during normothermia and increased further during hypothermia. Less than 50% of clinically relevant CO changes during hypothermia were concordant. PMID- 21292381 TI - Epidemiology and patient outcome after medical emergency team calls triggered by atrial fibrillation. AB - INTRODUCTION: Atrial fibrillation (AF) in hospitalized patients may lead to activation of the medical emergency team (MET). We sought to assess the baseline characteristics and outcomes of the patients presenting AF as a cause of MET call activation. METHODS: Using a prospectively constructed MET database, we retrospectively reviewed all patients with AF as a trigger for MET activation between August 2005 and April 2010. Demographics, principal diagnostic and outcome of these patients were compared with those of a control group of patients matched for age, sex and ward of origin, randomly selected from the database. RESULTS: We studied 5431 MET calls of which 557 (10.3%), in 458 patients were triggered by AF. Mean age for AF patients was 74.8 years, 230 (50.2%) were female and 271 (59.1%) were in a surgical ward. 92 (20.1%) AF patients died in hospital compared with 131 (28.6%) in the control group. Among the 336 patients without limitations of medical therapy (LOMT), 46 (13.7%) died in hospital. In total, 46 (13.7%) patients were transferred to a higher level care ward while 290 (86.3%) remained on the ward. Only 2 (4.3%) of these patients died compared with 44 (15.2%) among those who remained in the general ward (p=0.03). CONCLUSIONS: In our hospital, AF triggers one tenth of MET activations and mortality associated with it is high even when issues of LOMT are excluded. The decreased mortality among patients admitted to a higher level ward suggests that some of these deaths may be avoidable. PMID- 21292382 TI - A popular song improves CPR compression rate and skill retention by schoolchildren: a manikin trial. PMID- 21292383 TI - Glycodelin in endometrial flushing fluid and endometrial biopsies from infertile and fertile women. AB - OBJECTIVE: To investigate in the natural cycle just before IVF, whether glycodelin levels in endometrial flushing fluid obtained days LH+1 and LH+7 can be used in predicting pregnancy in the following IVF cycle, and whether there are differences in women with tubal factor infertility compared to women with unexplained infertility and fertile controls. STUDY DESIGN: A prospective observational multicentre study of 21 fertile and 75 infertile women (25 showed abnormal tubes with no signs of hydrosalpinges, 18 had uni- or bi-lateral hydrosalpinges, 17 were salpingectomised because of hydrosalpinges, and 15 women had unexplained infertility). Endometrial flushing at days LH+1 and LH+7, endometrial biopsy, and blood sampling at day LH+7 were performed before down regulation for IVF. Glycodelin levels in endometrial flushing fluids (EFF), biopsies, and plasma samples were related to tubal pathology, endometrial dating and IVF outcome. Furthermore, total protein concentration was measured in EFF to investigate the influence of normal endometrial maturation on protein concentrations from days LH+1 and LH+7. RESULTS: At day LH+1, EFF glycodelin levels were higher in infertile women with abnormal tubes compared to fertile women, particularly in women conceiving after the following IVF. For women with unexplained infertility, a higher level at day LH+1 was present only in women not conceiving after the following IVF. ROC curve analysis showed that at day LH+1 EFF glycodelin levels had no predictive value for IVF outcome. At day LH+7, glycodelin levels in endometrial flushing fluids and biopsies depended on endometrial dating. CONCLUSIONS: At day LH+1, glycodelin concentration is increased in endometrial flushing fluid from infertile women with abnormal tubes compared to fertile controls without being a valuable predictor of subsequent pregnancy. At day LH+7 the glycodelin level depends on endometrial dating. PMID- 21292384 TI - Dexamethasone stimulates the expression of leptin and 11beta-HSD2 in primary human placental trophoblastic cells. AB - OBJECTIVES: Fetal glucocorticoid excess is thought to play an important role in early-life programming, promoting growth restriction and contributing to adult metabolic, cardiovascular and neuroendocrine disease. We hypothesized that dexamethasone incubation of primary trophoblastic cells from human healthy placentas at term might induce altered gene and protein expression of several endocrine placental regulators. STUDY DESIGN: Primary villous trophoblastic cells were incubated with 10 MUM dexamethasone for 6, 12, 24, 48 and 72 h. Non incubated trophoblastic cells served as vehicle control. Gene expression of leptin, 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) and insulin-like growth factor-binding protein-1 (IGFBP-1) was measured. Moreover, leptin, beta human chorionic gonadotropine (beta-hCG) and lactate dehydrogenase (LDH) release into the culture medium was determined. RESULTS: Leptin gene expression was significantly increased in dexamethasone-incubated trophoblastic cells after 24, 48 and 72 h. There was a significant increase in leptin concentration in the medium of the cell culture after 48 h. Gene expression of 11beta-HSD2 was significantly higher in dexamethasone-stimulated trophoblastic cells compared to vehicle controls after 72 h. The expression rate of IGFBP-1 mRNA was basal throughout the incubation period. The concentration of beta-HCG in the supernatant increased significantly after 72 h of dexamethasone incubation, while LDH concentrations remained stable. CONCLUSION: Our findings suggest that dexamethasone incubation stimulates leptin and 11beta-HSD2 gene expression in primary villous trophoblastic cells of healthy human placentas, while enhancing cytotrophoblast differentiation. PMID- 21292385 TI - Experimental design for the optimization of copper biosorption from aqueous solution by Aspergillus terreus. AB - An experimental design methodology was applied to study the effects of temperature, pH, biomass dose, and stirring speed on copper removal from aqueous solutions by Aspergillus terreus in a biosorption batch system. To identify the effects of the main factors and their interactions on copper removal efficiency and to optimize the process, a full 2(4) factorial design with central points was performed. Four factors were studied at two levels, including stirring speed (50 150 min(-1)), temperature (30-50 degrees C), pH (4-6) and biosorbent dose (0.01 0.175 g). The main factors observed were pH and biomass dose, along with the interactions between pH and biomass, and stirring speed. The optimal operational conditions were obtained using a response surface methodology. The adequacy of the proposed model at 99% confidence level was confirmed by its high adjusted linear coefficient of determination (R(Adj)(2)=0.9452). The best conditions for copper biosorption in the present study were: pH 6, biosorbent dose of 0.175 g, stirring speed of 50 min(-1) and temperature of 50 degrees C. Under these conditions, the maximum predicted copper removal efficiency was 68.52% (adsorption capacity of 15.24 mg/g). The difference between the experimental and predicted copper removal efficiency at the optimal conditions was 4.8%, which implies that the model represented very well the experimental data. PMID- 21292386 TI - The impact of prostate size, median lobe, and prior benign prostatic hyperplasia intervention on robot-assisted laparoscopic prostatectomy: technique and outcomes. AB - BACKGROUND: Large prostate size, median lobes, and prior benign prostatic hyperplasia (BPH) surgery may pose technical challenges during robot-assisted laparoscopic prostatectomy (RALP). OBJECTIVE: To describe technical modifications to overcome BPH sequelae and associated outcomes. DESIGN, SETTINGS, AND PARTICIPANTS: A retrospective study of prospective data on 951 RALP procedures performed from September 2005 to November 2010 was conducted. Outcomes were analyzed by prostate weight, prior BPH surgical intervention (n=59), and median lobes >1 cm (n=42). SURGICAL PROCEDURE: RALP. MEASUREMENTS: Estimated blood loss (EBL), blood transfusions, operative time, positive surgical margin (PSM), and urinary and sexual function were measured. RESULTS AND LIMITATIONS: In unadjusted analysis, men with larger prostates and median lobes experienced higher EBL (213.5 vs 176.5 ml; p<0.001 and 236.4 vs 193.3 ml; p=0.002), and larger prostates were associated with more transfusions (4 vs 1; p=0.037). Operative times were longer for men with larger prostates (164.2 vs 149.1 min; p=0.002), median lobes (185.8 vs 155.0 min; p=0.004), and prior BPH surgical interventions (170.2 vs 155.4 min; p=0.004). Men with prior BPH interventions experienced more prostate base PSM (5.1% vs 1.2%; p=0.018) but similar overall PSM. In adjusted analyses, the presence of median lobes increased both EBL (p=0.006) and operative times (p<0.001), while prior BPH interventions also prolonged operative times (p=0.014). However, prostate size did not affect EBL, PSM, or recovery of urinary or sexual function. CONCLUSIONS: Although BPH characteristics prolonged RALP procedure times and increased EBL, prostate size did not affect PSM or urinary and sexual function. PMID- 21292387 TI - A risk-stratified approach to prostate-specific antigen screening. PMID- 21292388 TI - Prospective evaluation of 11C-choline positron emission tomography/computed tomography and diffusion-weighted magnetic resonance imaging for the nodal staging of prostate cancer with a high risk of lymph node metastases. AB - BACKGROUND: Contrast-enhanced computed tomography (CT) and magnetic resonance (MR) imaging for lymph node (LN) staging of prostate cancer (PCa) are largely inadequate. OBJECTIVE: Our aim was to assess prospectively the sensitivity, specificity, and positive and negative predictive values for the LN staging by (11)C-choline positron emission tomography (PET)-CT and MR diffusion-weighted imaging (DWI) of the pelvis before retropubic radical prostatectomy (RRP) with extended pelvic LN dissection (PLND). DESIGN, SETTING, AND PARTICIPANTS: From February 2008 to August 2009, 36 patients with histologically proven PCa and no pelvic LN involvement on contrast-enhanced CT with a risk >= 10% but <= 35% at LN metastasis according to the Partin tables were enrolled in this study. INTERVENTION: Patients preoperatively underwent (11)C-choline PET-CT and DWI. Subsequently all patients underwent a wide RRP and an extended PLND. MEASUREMENTS: Sensitivity, specificity, and positive and negative predictive values (PPV and NPV) for LN status of (11)C-choline PET-CT and DWI were calculated with the final histopathology of the LNs as comparator. RESULTS AND LIMITATIONS: Seventeen patients (47%) had a pN1 stage, and 38 positive LNs were identified. On a LN region-based analysis, sensitivity, specificity, PPV, NPV, and the number of correctly recognised cases at (11)C-choline PET-CT were 9.4%, 99.7%, 75.0%, 91.0%, and 7.9%, respectively, and at DWI these numbers were 18.8%, 97.6%, 46.2%, 91.7%, and 15.8%, respectively. Twelve LN regions containing macrometastases, of which 2 had capsular penetration, were not detected by (11)C choline PET-CT; 11 LNs, of which 2 had capsular penetration, were not detected by DWI. This is a small study with 36 patients, but we intend to recruit more patients. CONCLUSIONS: From this prospective histopathology-based evaluation of (11)C-choline PET-CT and DWI for LN staging in high-risk PCa patients, it is concluded that these techniques cannot be recommended at present to detect occult LN metastases before initial treatment. PMID- 21292389 TI - Identification of venous variants in the pineal region with three-dimensional preoperative magnetic resonance imaging navigation in patients harbouring tumors in this area: significance for surgical approach to the lesion. AB - OBJECT: The purpose of this study was to identify the anatomy of pineal region venous complex using neuronavigation software when distorted by the presence of a space-occupying lesion and to describe the anatomical relationship between lesion and veins. Moreover we discuss its influence on the choice of the surgical strategy. METHODS: Of the 33 patients treated at our Institute for pineal region tumors between 2003 and 2008 we used the neuronavigation software to depict the venous system of the pineal region in 14 patients. We focused on depiction of the basal vein of Rosenthal (BV), the internal cerebral vein (ICV) and the vein of Galen: connection patterns between the veins and the type of anatomical distortion caused by the lesion were investigated and classified. RESULTS: Using the neuronavigation software for three-dimensional (3D) reconstruction of MRI images the ICV was clearly depicted in all patients on both sides (100%). Last segment of the BV was identified in 25 sides on a total of 28 (89.3%) and absent in 3 of the 28 sides (10.7%). Studying the distortion effect of the tumor on the galenic venous system, three directions of displacement were observed: craniocaudal, anteroposterior and lateral. Seven patients presented a cranial dislocation, 5 patients caudal dislocation and there was no craniocaudal shift in 2 patients. Considering the anteroposterior displacement: 3 subjects showed an anterior shift of the veins, 5 subjects posterior shift and no anterioposterior shift was present in 6 patients. Only 2 of the 14 patients presented lateral displacement of the veins. The principal approaches used in this series were: supracerebellar infratentorial and interhemispheric parieto-occipital. The craniocaudal displacement of the pineal veins seems to be the most important for the choice of the approach. CONCLUSION: The galenic venous system has a central role in the surgery pineal region tumors. Our study demonstrates that the architecture of the pineal veins and their anatomical relationship with the lesion can be depicted with great accuracy by using 3D neuronavigation software in order to facilitate surgical planning and intraoperative orientation. PMID- 21292390 TI - Clinical experiences with spontaneous intracranial hypotension: a proposal of a diagnostic approach and treatment. AB - OBJECTIVE: We analyzed our clinical experience with patients with intracranial hypotension and developed a strategic model for the diagnosis mainly using Radioisotope (RI) cisternography and treatment of spontaneous intracranial hypotension (SIH). METHODS AND MATERIALS: We retrospectively analyzed our clinical experiences with 30 cases of SIH from January 2000 through December 2006. All patients had confirmed by magnetic resonance image (MRI). RI cisternography or computed-tomography (CT) myelography was done for disclosing a cerebrospinal fluid leakage point. Initially patients were treated with medication. When patients complained of persistent headache, we performed epidural blood patch (EBP) administration. We performed subdural hematoma evacuation when it grew or worsened neurological status. RESULTS: Twenty-one women (70%) and 9 men (30%) were enrolled. The mean age was 40 years (range: 30 58 years). After initial diagnosis with MRI, RI cisternography and CT myelography were helpful in pinpointing the exact leakage site. Four patients were treated only with the medication and 24 patients were treated with the epidural blood patch (EBP). Half of them achieved dramatic relief of symptoms after the initial EBP. A blind EBP was performed in 15 patients. Six patients experienced recurrence of symptoms. Hematoma evacuation was performed in 8 patients. None of diagnostic tools or treatment methods showed distinct superiority in predicting a favorable clinical outcome. CONCLUSION: Clinicians should be systematic in their approach to plan a treatment regimen for patients with SIH. We suggest the use of a flow diagram when determining how to best approach and treat patients with SIH. PMID- 21292391 TI - Historical changes in polycyclic aromatic hydrocarbons (PAHs) input in Lake Baiyangdian related to regional socio-economic development. AB - The accumulation of polycyclic aromatic hydrocarbons (PAHs) over a period of almost 180 years was studied in a sediment core collected from Lake Baiyangdian in northern China. Total PAHs concentration varied from 97.2 to 2402 ng g(-1) dry weight. We found the highest total PAH concentration in 1940s and 1990s, and a decreasing trend from 1990 until present. The warfare and increasing economic activity had the largest impact on the PAH vertical distribution. The implemented measures for pollution control in catchment since 1990 might reduce point source input of PAH in some degree in recently. The historical record of PAHs is different from the developed countries and areas due to difference in socio economic development condition. PAHs in the core are dominantly pyrogenic in source, i.e., they are mainly from the incomplete combustion of wood and coal. PAHs from terrigenous organic matter input decreased obviously from the 1950s due to rainfall reduction during this period. PMID- 21292392 TI - Disinfection byproducts in Canadian provinces: associated cancer risks and medical expenses. AB - Chlorination for drinking water forms various disinfection byproducts (DBPs). Some DBPs are probably linked to human cancer (e.g., bladder, colorectal cancers) and other chronic and sub-chronic effects. This emphasizes the need to understand and characterize DBPs in drinking water and possible risks to human health. In this study, occurrences of DBPs throughout Canada were investigated. Trihalomethanes (THMs) were observed to be highest in Manitoba followed by Nova Scotia and Saskatchewan, while haloacetic acids were highest in Nova Scotia followed by Newfoundland and Labrador. Based on the characterization of DBPs, risk of cancer from exposure to THMs was predicted using ingestion, inhalation and dermal contact pathways of exposure. In Canada, approximately 700 cancer cases may be caused by exposure to THMs in drinking water. Medical expenses associated with these cancer incidents are estimated at some $140 million/year. Expense may be highest in Ontario (~$47 million/year) followed by Quebec (~$25 million/year) due to a greater population base. This paper suggests improvements in water treatment, source protection and disinfection processes, and caution in the use of alternative disinfectants to reduce DBPs. Finally, elements are provided to mitigate risks and reduce cost estimates in future studies. PMID- 21292393 TI - Cr (III) bioremoval capacities of indigenous and adapted bacterial strains from Palar river basin. AB - The effluents from tanning industries in and around Palar river basin are the major cause of Cr (III) pollution. Forty-five chromium (III) tolerant bacterial strains were isolated from the Palar river basin. Bacillus subtilis VITSCCr01 showed tolerance up to 1500 mg/l and its Cr (III) bioremoval capacity was 64%. Increasing the concentration of Cr (III) increased exopolysaccharide (EPS) production by the bacteria. FT-IR spectral studies confirmed the presence of polysaccharides in the Cr (III) treated bacteria. Adaptation of Bacillus subtilis VITSCCr01 with higher Cr (III) concentration improved the bioremoval capacity to 85%. SEM-EDX showed that the adapted bacteria accumulated high concentration of chromium. Bacillus subtilis VITSCCr01 could be used as a tool for in situ removal of Cr (III) especially in the tannery polluted environment. PMID- 21292395 TI - How perfect studies may be? Comment on Peng et al. A randomized placebo controlled trial of intradiscal methylene blue injection for the treatment of chronic discogenic low back pain. Pain 2010;149:124-9. PMID- 21292396 TI - Affective state and quality of life in mice. PMID- 21292394 TI - Orofacial pain. PMID- 21292397 TI - Role of psychological flexibility in parents of adolescents with chronic pain: development of a measure and preliminary correlation analyses. AB - Parent responses to the experiences of adolescents with chronic pain are deemed important. At the same time the best ways to conceptualize, measure, and intervene with these are unclear. The purpose of the present study was to develop a measure of parent responses based on the approach proposed in Acceptance and Commitment Therapy (ACT), an approach that focuses on psychological flexibility. A total of 183 adolescents attending a specialty treatment center for chronic pain, and adults attending with them, provided the data examined in this study. Standard measures of adolescent functioning and parent responses were obtained. In addition, the attending adults, who were mostly mothers, also completed a pool of items for an instrument called the Parent Psychological Flexibility Questionnaire (PPFQ). Preliminary analyses of these items showed an internal consistency of alpha=0.91. The total score for parent psychological flexibility was negatively correlated with protective and encouraging parent responses to pain, as predicted. It was also positively correlated with adolescent acceptance of pain and negatively correlated with measures of pain-related impact on their social, emotional, family, and developmental functioning. Additional analyses showed that the PPFQ yields significant unique information about adolescent functioning independent of age and gender and beyond that provided by another well-established measure of parent responses. There is increasing evidence for the effectiveness of ACT in the treatment of a range of behavior problems in adults and young people and in training for persons without identified "disorders." It seems potentially applicable for parent training in the context of adolescent chronic pain. PMID- 21292398 TI - Anomalous distribution in atom map of solute carbon in steel. AB - The distribution of carbon in atom probe tomography maps was investigated in various phases of steel. Carbon atoms in 3D atom maps of martensite and cementite phases showed an almost uniform distribution. On the other hand, carbon atoms in ferrite were consistently enriched along the zone line joining the (0 0 2) and the (2 2 2) poles, and in the depth direction of analysis, which was different from the actual distribution. The width and concentration of the enriched regions remained unchanged at a specimen temperature ranging from 90 to 30K. Moreover, the ratio of molecular carbon ions to total carbon ions decreased with decreasing temperature, but did not change between the enriched and diluted regions. Based on the results, the reason for the anomalous distribution of solute carbon atoms in atom maps is discussed. PMID- 21292399 TI - Characteristics of cross-sectional atom probe analysis on semiconductor structures. AB - The laser-assisted Atom Probe has been proposed as a metrology tool for next generation semiconductor technologies requiring sub-nm spatial resolution. In order to assess its potential for the analysis of three-dimensional semiconductor structures like FinFETs, we have studied the Atom Probes lateral resolution on a silicon, silicon-germanium multilayer structure. We find that the interactions of the laser with the semiconductor materials in the sample distort the sample surface. This results in transient errors of the measured dimensions of the structure. The deformation of the sample furthermore leads to a degradation of the lateral resolution. In the experiments presented in this paper, the Atom Probe reaches a lateral resolution of 1-1.8 nm/decade. In this paper we will discuss the reasons for the distortions of the tip and demonstrate that with the present state of data reconstruction severe quantification errors limit its applicability for the quantitative analysis of heterogeneous semiconductor structures. Our experiments show that reconstruction algorithms taking into account the time dependent nanostructure of the tip shape are required to arrive at accurate results. PMID- 21292400 TI - Low-threshold field emission from carbon nano-clusters. AB - Detonation carbon materials (DCM) composed of non-equilibrium nano-structures show the low-threshold field emission (LTFE). These materials have forward looking application especially due to high reproducibility of the LTFE-phenomenon on a surface of emitter, where the emitting centers are homogeneously distributed. In this paper we link the effect of LTFE to the nature of the corresponding wave functions based on the experiment results obtained for DCM by the field effect on electrolytes. As we had shown before DCM had been described by an ultra-relativistic dispersion function with extremely small effective mass of electrons and the size-quantization effect had been observed in DCM at even room temperature. Our results based on emission and electrolyte technics of the field-effect measurements in DCM along with modern observations of the field emission in strong electric fields allowed to propose a new resonance transmission model for LTFE-phenomenon, which is alternative to most widely discussed models based on the field-enhancing factors or barrier-lowering mechanisms. PMID- 21292401 TI - Can heartworm prevalence in dogs be used as provisional data for assessing the prevalence of the infection in cats? AB - Cats are considered a susceptible host for Dirofilaria immitis; however, increased host resistance is reflected by relatively low adult worm burdens in natural and experimental infections; the prolonged prepatent period (8 months); the low level and short duration of microfilaremia; and the short life span of adult worms (2-3 years). From April to September 2006, 212 cats and 608 dogs, all exposed for at least one transmission season, were screened for D. immitis infection in a multi-center study in the Po River Valley in northern Italy. Cats were initially evaluated by antibody testing; positive subjects were followed up by antigen testing and echocardiography (and necropsy if death occurred). The prevalence in dogs was 29% by a modified Knott test and antigen testing compared with a prevalence of 4.7% in cats by an antibody test; six of these infections (2.8%) were confirmed by the follow-up evaluations. This field study demonstrated that the prevalence of heartworm infection in cats in this area is within the expected limits of 9-18% of the prevalence in dogs. Antibody testing likely underestimates the real prevalence of D. immitis infection in cats. These results also emphasize the importance of preventive treatment in cats. PMID- 21292402 TI - Effects of latex from "Amapazeiro"Parahancornia amapa (Apocynaceae) on blowfly Chrysomya megacephala (Diptera: Calliphoridae) post-embryonic development. AB - Nowadays, insect control is usually carried out using chemical insecticides, but insect resistance and other negative side effects have prompted the search for alternatives. Biopesticides provide a positive alternative to synthetic pesticides because they have low impact on the environmental, low toxicity to humans and low costs among other advantages. This research was carried out to evaluate the activity of Parahancornia amapa (Huber) Ducke (Apocynaceae) lyophilized latex on the post embryonic development of Chrysomya megacephala (F.) (Diptera: Calliphoridae). Larvae treated with 1.0% latex showed a shorter post embryonic development period (larval, pupal and newly hatched larvae to adult); whereas larvae treated with 3.0% latex provoked a prolongation of these periods. Viability (53%) was also very low at the newly hatched larvae to adult period for larvae treated with 3.0% latex, indicating that latex from P. amapa at high concentrations could change C. megacephala post embryonic development. PMID- 21292403 TI - Evaluation of lung pathology in Dirofilaria immitis-experimentally infected dogs treated with doxycycline or a combination of doxycycline and ivermectin before administration of melarsomine dihydrochloride. AB - Adulticide therapy in heartworm (Dirofilaria immitis)-infected dogs can lead to thromboembolism, which can seriously compromise post-treatment health status. Lung pathology following adulticide therapy was evaluated in three groups of experimentally infected dogs. Group 1 was treated with doxycycline at 20 mg/kg per os once daily for 30 days post infection followed by an intramuscular injection of melarsomine dihydrochloride (2.5 mg/kg) at Week 12, followed 1 month later by two injections 24 h apart. Group 2 was treated as described for Group 1, with the addition of ivermectin at 6 mcg/kg given monthly per os for 24 weeks post-infection. Group 3 received melarsomine alone, as described above. All dogs were necropsied at Week 24 and lung pathology was evaluated. Lesion criteria included perivascular inflammation and endothelial proliferation. Lesions were scored by two independent pathologists who were blinded as to treatment. Results indicate that doxycycline treatment alone or combined with ivermectin had lower lesion scores than lungs from dogs who had received melarsomine alone. Dogs that received the combined doxycycline/ivermectin protocol and treated with adulticide showed less severe arterial lesions and the virtual absence of thrombi. PMID- 21292404 TI - Geographical information systems as a tool in the control of heartworm infections in dogs and cats. AB - Geospatial tools (e.g., geographical information systems, remote sensing, global positioning systems, and virtual globes) are very useful for the simultaneous visualization of health data with environmental data, which holds promise to understand environmental-health linkages and to generate new hypotheses to be tested in future research. Current epidemiological studies clearly show that the distribution patterns of vector-borne infections are changing; for example, in Europe, heartworm infection and subcutaneous dirofilariosis are spreading throughout areas that previously had little to no incidence of heartworm. In view of the changes of the distribution patterns of Dirofilaria immitis and Dirofilaria repens, geospatial tools are now more useful for mapping (including territorial sampling), monitoring, ecological analysis, risk assessment, forecasting (including the choose of the timing of treatment), early warning, and surveillance of both heartworm and subcutaneous dirofilariosis. All these issues have control of these infections as the ultimate goal. PMID- 21292405 TI - Dim light at night provokes depression-like behaviors and reduces CA1 dendritic spine density in female hamsters. AB - The prevalence of major depression has increased in recent decades; however, the underlying causes of this phenomenon remain unspecified. One environmental change that has coincided with elevated rates of depression is increased exposure to artificial light at night. Shift workers and others chronically exposed to light at night are at increased risk of mood disorders, suggesting that nighttime illumination may influence brain mechanisms mediating affect. We tested the hypothesis that exposure to dim light at night may impact affective responses and alter morphology of hippocampal neurons. Ovariectomized adult female Siberian hamsters (Phodopus sungorus) were housed for 8 weeks in either a light/dark cycle (LD) or a light/dim light cycle (DM), and then behavior was assayed. DM-hamsters displayed more depression-like responses in the forced swim and the sucrose anhedonia tests compared with LD-hamsters. Conversely, in the elevated plus maze DM-hamsters reduced anxiety-like behaviors. Brains from the same animals were processed using the Golgi-Cox method and hippocampal neurons within CA1, CA3, and the dentate gyrus were analyzed for morphological characteristics. In CA1, DM hamsters significantly reduced dendritic spine density on both apical and basilar dendrites, an effect which was not mediated by baseline cortisol, as concentrations were equivalent between groups. These results demonstrate dim light at night is sufficient to reduce synaptic spine connections to CA1. Importantly, the present results suggest that night-time low level illumination, comparable to levels that are pervasive in North America and Europe, may contribute to the increasing prevalence of mood disorders. PMID- 21292406 TI - Th17 response promotes angiotensin II-induced atherosclerosis. AB - Vascular wall chronic inflammation plays a critical role in the development and progression of cardiovascular diseases such as atherosclerosis and hypertension. Circulating and tissue angiotensin II can induce potent inflammatory responses in vascular cells and promotes atherosclerosis, whereas the underlying mechanisms remain uncertain. Several data indicated that the upregulation of Th17 response has been found in the local atherosclerotic lesions and circulating lymphocytes in atherosclerosis prone models and the onset of acute coronary syndrome. Evidence from animal models shown that angiotensin II not only induced the Th1 response, but also amplified Th17 response. In addition, angiotensin II-induced hypertension and vascular dysfunction were abolished by blocking Th17/IL-17 effects. Therefore, we hypothesized that Th17 response may play an important role in angiotensin II-induced atherosclerosis. PMID- 21292407 TI - Cerebral hydrodynamics are at a most a third order system. AB - The human body employs a sophisticated windkessel mechanism to dampen the arterial pulse entering the brain, thus ensuring the smooth flow of blood through the cerebral capillary bed. The energy from the arterial pulse is transferred to the cerebrospinal fluid (CSF), which pulses backwards and forwards across the foramen magnum. The dynamics associated with this system are complex and poorly understood. In an attempt to better understand the physiology, a number of researchers have constructed electrical analogue circuits to simulate the hydrodynamic behaviour of the brain. These generally consist of several low-pass filters. While such models have great potential, to date, they have met with only limited success. We suspect that this is in part due to a failure to identify the order of the model required to successfully capture the hydrodynamics of the brain. Here, we advance the hypothesis that the cerebral hydrodynamic system is at most a third order system, using evidence collected from the spectral eigen system of the arterial, venous and CSF flows. Using singular spectrum analysis we computed the singular vectors for the measured arterial, venous and CSF flows from an individual. This revealed that the first singular vector contributes 67% of the observed variance; the first plus the second singular vectors contribute 96% of the variance; and sum of the first three singular vectors contribute more than 99.5% of the observed variance. PMID- 21292408 TI - Centrifugal drip is an accessible source for protein indicators of pork ageing and water-holding capacity. AB - Achieving an improvement in water-holding capacity (WHC) of pork and a reduction in the incidence of pale, soft and exudative (PSE)- and dark, firm and dry (DFD) like meat is a major challenge for the swine industry. Using proteomics, we sought to identify proteins associated with WHC and to monitor postmortem protein degradation. Twenty longissimus samples were categorised into WHC phenotypes. The centrifugal drip was subjected to SDS-PAGE and mass-spectrometry. Forty-four proteins were identified in the centrifugal drip proteome. Changes occurred in volume of five bands across the ageing period, with most significant changes representing increases between day 3 and day 7. Seven proteins were identified in these bands, most with functions in glycolysis. One band significantly differed in abundance across WHC phenotypes. Peptide signatures of the heat shock protein family were identified in this band. PMID- 21292409 TI - Prevalence and characterization of Shiga toxin-producing Escherichia coli O157 and O26 in beef farms. AB - Rectal content grab samples were collected from 2436 beef cattle reared on 406 beef farms in Japan between November 2007 and March 2008. STEC strains O157 and O26 were isolated from 110 (27.1%) and 7 (1.7%) farms, respectively. Farms that tested positive for STEC O157 were located in 35 out of all 47 Japanese prefectures. This indicates that STEC O157 strains are widespread on beef farms nationwide. Of the 2436 tested beef cattle, 218 (8.9%) and 10 (0.4%) had STEC strains O157 and O26 in the rectal content, respectively. The most common Shiga toxin genes detected in the isolated STEC O157 strains were: stx(2c) alone (32.1%), stx(2)/stx(2c) (27.2%), and stx(1)/stx(2) (21.8%). Almost all of the STEC O157 and STEC O26 strains expressed Shiga toxins (Stx). Most of the STEC O157 and STEC O26 strains possessed eaeA and EHEC-hlyA. These results strongly suggest that STEC strains O157 and O26 from beef cattle would be pathogenic to humans. Therefore, it is important to reduce STEC strains O157 and O26 in beef cattle in order to prevent foodborne disease caused by STEC. The presence of dogs and/or cats on a farm was significantly (P=0.02) associated with the prevalence of STEC O157. More research is needed to clarify the role of dogs and cats. PMID- 21292410 TI - Equine herpesvirus 4: recent advances using BAC technology. AB - The equine herpesviruses are major infectious pathogens that threaten equine health. Equine herpesvirus 4 (EHV-4) is an important equine pathogen that causes respiratory tract disease, known as rhinopneumonitis, among horses worldwide. EHV 4 genome manipulation with subsequent understanding of the viral gene functions has always been difficult due to the limited number of susceptible cell lines and the absence of small-animal models of the infection. Efficient generation of mutants of EHV-4 would significantly contribute to the rapid and accurate characterization of the viral genes. This problem has been solved recently by the cloning of the genome of EHV-4 as a stable and infectious bacterial artificial chromosome (BAC) without any deletions of the viral genes. Very low copy BAC vectors are the mainstay of present genomic research because of the high stability of inserted clones and the possibility of mutating any gene target in a relatively short time. Manipulation of EHV-4 genome is now feasible using the power of BAC technology, and should aid greatly in assessing the role of viral genes in the virus-host interaction. PMID- 21292411 TI - Changes in follicular blood flow and nitric oxide levels in follicular fluid during follicular deviation in cows. AB - Two experiments were conducted to test the hypothesis that there are dynamic changes in follicular blood flow during follicular deviation and that nitric oxide (NO) in follicular fluid (FF) plays a role in regulation of follicular blood flow. In Experiment I, follicular blood flow of the two largest follicles was monitored by using Power Doppler ultrasonography during follicular deviation in sixteen follicular waves during eight estrous cycles in eight cows. Blood flow did not differ (P>0.05) between the dominant follicle (DF) and the largest subordinate follicle (SF) until the beginning of the deviation of the follicular size, but was higher (P<0.05) in DF than in the largest SF one and two days after the beginning of diameter deviation in ovulatory (n=5) and atretic (n=11) waves; respectively. In Experiment II, FF was aspirated from DF and the largest SF on the day of diameter deviation (DF, n=6; SF, n=6) and two days later (DF, n=12; SF, n=9). Nitric oxide did not differ (P>0.05) between DF and the largest SF on the day of diameter deviation but, one or two days after observed diameter deviation NO concentrations were lower (P<0.01) in DF compared to the largest SF. On the day of diameter deviation and two days later E2 levels in FF were higher (P<0.01) in DF than in the largest SF. P4 concentrations in FF were higher (P<0.05) in DF than in the largest SF on the day of diameter deviation, but did not (P>0.05) differ two days later. E2/P4 ratio in FF was the same (P>0.05) in DF and the largest SF on the day of diameter deviation, but was higher (P<0.01) in DF than in the largest SF one or two days later. In conclusion, area of follicular blood flow of DF and the largest SF increased in parallel with follicular size during follicular deviation. Furthermore, there were relationships between changes in follicular blood flow, NO concentrations and E2/P4 ratio in FF following the beginning of diameter deviation in cattle. PMID- 21292412 TI - Effects of sexual maturation and Salmonella infection on the expression of Toll like receptors in the chicken vagina. AB - Toll-like receptors (TLRs) are a critical component of the innate immune response in many vertebrates, including avian species. The recent findings of chicken TLRs (cTLRs) expression in ovarian follicles and in the chicken ovary in vivo, as well as the changes in their expression in response to lipopolysaccharide or Salmonella enteritidis (SE) infection, have broad implications for reproductive physiology and for the prevention of transmission of zoonotic diseases to humans through the consumption of contaminated poultry eggs. Because the main route of egg contamination is from infection of the oviduct and mainly from the vagina, the aim of this study was to investigate the expression of the ten cTLRs identified to date in the chicken oviduct in vivo, to determine whether sexual maturation affects their mRNA abundance and to investigate whether SE infection alters the expression of TLRs in the chicken vagina. RNA was extracted from the vagina of healthy prepubertal, sexually mature and aged birds, and from sexually mature and aged SE infected birds. RT-PCR analysis revealed that all types of cTLRs apart from TLR1-1 were expressed in the vagina of sexually mature birds. Quantitative real-time PCR analysis revealed that the mRNA abundance of TLR2-1, 2 2 and 4 differ with respect to sexual maturation in the chicken vagina. SE infection resulted in a significant induction of TLR5 and 15 in the vagina of sexually mature birds, and in a significant induction of TLR2-1, 4 and 15 in the vagina of aged birds, while a significant down-regulation was observed for TLR7 in the vagina of sexually mature birds. These findings suggest that a TLR mediated immune response mechanism exists in the chicken vagina, playing a crucial role in preventing microbial pathogens from being incorporated into newly forming eggs. PMID- 21292413 TI - Severe stress urinary incontinence: Objective analysis of risk factors. AB - OBJECTIVE: To assess differences between patients suffering from severe degree of stress urinary incontinence versus those with mild degree and to detect the risk factors of severity. MATERIALS AND METHODS: 118 patients suffered from pure SUI were enrolled in a prospective study. According to VLPP, patients were categorized into 2 groups: mild (VLPP>60) and severe (VLPP<60). Risk factors included age, parity, gravidity, menopausal status, co-morbidities and surgical history were investigated. RESULTS: 35 patients had severe SUI; their mean VLPP+/ SD was 47+/-8cm H2O, while in 83 patients with mild SUI, mean VLPP was 90+/-20cm H2O. No significant difference was detected between both groups concerning clinical parameters except for the presence of bronchial asthma in which the difference was approaching statistical significance (P=0.07). Patients with multiple deliveries have triple risk to develop severe SUI. Obese patients with BMI>30 and those with bronchial asthma are more prone to develop severe type (OR: 1.9, 95%CI: .07-5 and OR: 9.4, 95% CI: 0.7-25 respectively). CONCLUSIONS: Bronchial asthma, obesity and multiple parities might be associated with low VLPP. Severe SUI is a resultant of multi-factors rather than one risk factor. PMID- 21292414 TI - Still further remarks on: "Paternity analysis in special fatherless case without direct testing of alleged father" [Forensic Science International 146S (2004) S159-S161] and remarks on it [FSI 163 (2006) 158-160, FSI 172 (2007) e6-e8]. PMID- 21292415 TI - The clinical features of patients with the homozygous 235delC and the compound heterozygous Y136X/G45E of the GJB2 mutations (Connexin 26) in cochlear implant recipients. AB - OBJECTIVE: This study aimed to investigate the prevalence of GJB2 gene for the 235delC mutations, the clinical features and the outcomes of patients who had undergone cochlear implantation. METHODS: We have sequenced the coding region of GJB2 gene for 135 patients with sensorineural deaf from September 2000 to May 2009. Of the 135 patients, the patients with the homozygous 235delC and the compound-heterozygous Y136X/G45E were detected and were investigated clinically. RESULTS: The GJB2 gene for the 235delC mutations was found in 39 alleles of 270 alleles (14.4%), especially for the homozygous of 235delC was detected in 26 alleles (9.6%), the single heterozygous of 235delC was 1 allele (0.4%), the compound heterozygous of 235delC was found in 12 alleles (4.4%). Of 16 subjects (29 alleles) with the homozygous 235delC and the compound-heterozygous Y136X/G45E, 2 subjects (4 alleles) were found to have complications. All of the subjects were found to show severe hearing loss and some of them have indicated progressive hearing loss. However, they showed better performance regarding the thresholds after implantation. The subjects with complications, although, suggested poorer performance in the auditory speech performance. CONCLUSION: The findings of poorer outcomes might depend on complications and brain functions. In addition, considering the blood test parameters, an independent elevated LDH and ChE at diagnosis were found to be associated with hereditary enzyme's metabolic disease. Therefore, the value of LDH measurements in patients might be a helpful predictive parameter in hereditary diseases. PMID- 21292416 TI - Does high-resolution CT has diagnostic value in patients presenting with respiratory symptoms after hematopoietic stem cell transplantation? AB - BACKGROUND: Hematopoietic stem cell transplantation (SCT) can be complicated by a variety of live-threatening infectious and non-infectious pulmonary complications. The management of these complications is critically dependent on the most probable diagnosis, which is in part based on imaging work-up. METHODS: Systematic review of the literature related to the diagnostic value of high resolution computed tomography (HRCT) in patients who underwent SCT and developed respiratory symptoms. RESULTS: Literature review did not reveal systematic cohort studies that included patients with respiratory symptoms post-SCT who underwent HRCT and had a well-defined outcome. Most studies selected participants based on their final diagnosis instead of the indication for diagnostic testing in practice. Nevertheless, several papers clearly indicated a potential role for HRCT when complications after SCT occur. A variety of articles described the role of certain HRCT findings in the diagnosis of specific infectious complications, but less data were available for non-infectious complications. CONCLUSION: We believe more diagnostic studies are needed to determine the value of HRCT for a specific diagnosis in SCT-recipients who present with respiratory symptoms at the transplant clinic. Currently, radiologists should be cautious since HRCT interpretation in these patients is not unambiguous. PMID- 21292417 TI - Identification of Gram-positive anaerobic cocci by MALDI-TOF mass spectrometry. AB - Gram-positive anaerobic cocci (GPAC) are part of the commensal microbiota of humans and are a phylogenetically heterogeneous group of organisms. To evaluate the suitability of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) for the identification of GPAC, a database was constructed, using reference strains of commonly encountered GPAC and clinical isolates of which the sequence of the 16S rRNA gene was determined. Subsequently, the database was validated by identifying 107 clinical isolates of GPAC. Results were compared with the identifications obtained by 16S sequencing or fluorescent in situ hybridization (FISH). Strains belonging to the same species grouped together, in most cases, by MALDI-TOF MS analyses. Strains with sequence similarities less than 98% to their closest relatives, formed clusters distinct from recognized species in the MALDI-TOF MS dendrogram and, therefore could not be identified. These strains probably represent new species. Only three clinical isolates (2 strains of Finegoldia magna and 1 strain of Anaerococcus vaginalis) could not be identified. For all the other GPAC strains (96/107), reliable identifications were obtained. Therefore, we concluded that MALDI-TOF MS is an excellent tool for the identification of phylogenetically heterogeneous groups of micro-organisms such as GPAC. PMID- 21292418 TI - Beat-to-beat respiratory motion correction with near 100% efficiency: a quantitative assessment using high-resolution coronary artery imaging. AB - This study quantitatively assesses the effectiveness of retrospective beat-to beat respiratory motion correction (B2B-RMC) at near 100% efficiency using high resolution coronary artery imaging. Three-dimensional (3D) spiral images were obtained in a coronary respiratory motion phantom with B2B-RMC and navigator gating. In vivo, targeted 3D coronary imaging was performed in 10 healthy subjects using B2B-RMC spiral and navigator gated balanced steady-state free precession (nav-bSSFP) techniques. Vessel diameter and sharpness in proximal and mid arteries were used as a measure of respiratory motion compensation effectiveness and compared between techniques. Phantom acquisitions with B2B-RMC were sharper than those acquired with navigator gating (B2B-RMC vs. navigator gating: 1.01+/-0.02 mm(-1) vs. 0.86+/-0.08 mm(-1), P<.05). In vivo B2B-RMC respiratory efficiency was significantly and substantially higher (99.7%+/-0.5%) than nav-bSSFP (44.0%+/-8.9%, P<.0001). Proximal and mid vessel sharpnesses were similar (B2B-RMC vs. nav-bSSFP, proximal: 1.00+/-0.14 mm(-1) vs. 1.08+/-0.11 mm( 1), mid: 1.01+/-0.11 mm(-1) vs. 1.05+/-0.12 mm(-1); both P=not significant [ns]). Mid vessel diameters were not significantly different (2.85+/-0.39 mm vs. 2.80+/ 0.35 mm, P=ns), but proximal B2B-RMC diameters were slightly higher (2.85+/-0.38 mm vs. 2.70+/-0.34 mm, P<.05), possibly due to contrast differences. The respiratory efficiency of B2B-RMC is less variable and significantly higher than navigator gating. Phantom and in vivo vessel sharpness and diameter values suggest that respiratory motion compensation is equally effective. PMID- 21292419 TI - Quantitative assessment of mobile protein levels in human knee synovial fluid: feasibility of chemical exchange saturation transfer (proteinCEST) MRI of osteoarthritis. AB - PURPOSE: To establish the feasibility of chemical exchange saturation transfer (proteinCEST) MRI in the differentiation of osteoarthritis (OA) knee joints from non-OA joints by detecting mobile protein and peptide levels in synovial fluid by determining their relative distribution. MATERIALS AND METHODS: A total of 25 knees in 11 men and 12 women with knee injuries were imaged using whole knee joint proteinCEST MRI sequence at 3 T. The joint synovial fluid was segmented and the asymmetric magnetization transfer ratio at 3.5 ppm MTR(asym) (3.5 ppm) was calculated to assess protein content in the synovial fluid. The 85th percentile of synovial fluid MTR(asym) (3.5 ppm) distribution profile was compared using the independent Student's t test. The diagnostic performance of the 85th percentile of synovial fluid MTR(asym) (3.5 ppm) in differentiating OA and non-OA knee joints was evaluated. RESULTS: The 85th percentile of synovial fluid MTR(asym) (3.5 ppm) in knee joints with OA was 8.6%+/-3.4% and significantly higher than that in the knee joints without OA (6.3%+/-1.4%, P<.05). A knee joint with an 85th percentile of synovial fluid MTR(asym) (3.5 ppm) greater than 7.7% was considered to be an OA knee joint. With the threshold, the sensitivity, specificity and overall accuracy for differentiating knee joints with OA from the joints without OA were 54% (7/13), 92% (11/12) and 72% (18/25), respectively. CONCLUSION: proteinCEST MRI appears feasible as a quantitative methodology to determine mobile protein levels in synovial fluid and identify patterns characteristic for OA disease. PMID- 21292422 TI - Herbal syncope: ginger-provoked bradycardia. PMID- 21292420 TI - Application of machine learning methods to describe the effects of conjugated equine estrogens therapy on region-specific brain volumes. AB - Use of conjugated equine estrogens (CEE) has been linked to smaller regional brain volumes in women aged >=65 years; however, it is unknown whether this results in a broad-based characteristic pattern of effects. Structural magnetic resonance imaging was used to assess regional volumes of normal tissue and ischemic lesions among 513 women who had been enrolled in a randomized clinical trial of CEE therapy for an average of 6.6 years, beginning at ages 65-80 years. A multivariate pattern analysis, based on a machine learning technique that combined Random Forest and logistic regression with L(1) penalty, was applied to identify patterns among regional volumes associated with therapy and whether patterns discriminate between treatment groups. The multivariate pattern analysis detected smaller regional volumes of normal tissue within the limbic and temporal lobes among women that had been assigned to CEE therapy. Mean decrements ranged as high as 7% in the left entorhinal cortex and 5% in the left perirhinal cortex, which exceeded the effect sizes reported previously in frontal lobe and hippocampus. Overall accuracy of classification based on these patterns, however, was projected to be only 54.5%. Prescription of CEE therapy for an average of 6.6 years is associated with lower regional brain volumes, but it does not induce a characteristic spatial pattern of changes in brain volumes of sufficient magnitude to discriminate users and nonusers. PMID- 21292423 TI - A matter of faith. PMID- 21292424 TI - A standardized approach to qualitative content analysis of focus group discussions from different countries. AB - OBJECTIVE: To describe the methodological procedures of a multi-centre focus group research for obtaining content categories also suitable for categorical statistical analyses. METHODS: Inductive content analyses were performed on a subsample of 27 focus groups conducted in three different countries, the Netherlands (Utrecht), the UK (Liverpool) and Italy (Verona). The analyses of the subsample of focus group discussions were performed in five steps: (1) independent development of content categories in each of the participating centres, (2) obtaining consensus categories, (3) creation of a manual with coding rules and defining criteria for categories and subcategories, (4) assessment of inter-rater reliability to identify unreliable categories to be revised, and (5) repetition of inter-rater reliability assessment. RESULTS: The resulting coding system considers five areas: non verbal communication, process oriented expression, task oriented or problem focused expressions, affective or emotional expressions, and physician's personal characteristics. It contains 12 categories of acceptable inter-rater reliability and 41 subcategories. CONCLUSION: The coding procedures show how focus group data, obtained in an international multi centre study can be analysed in a systematic way combining scientific rigour with the richness of data obtainable from qualitative methodologies. PRACTICE IMPLICATION: The applied procedures may be helpful for multi-centre focus group research on other topics. PMID- 21292425 TI - Training peers to provide ongoing diabetes self-management support (DSMS): results from a pilot study. AB - OBJECTIVE: This study determined the feasibility of training adults with diabetes to lead diabetes self-management support (DSMS) interventions, examined whether participants can achieve the criteria required for successful graduation, and assessed perceived efficacy of and satisfaction with the peer leader training (PLT) program. METHODS: We recruited nine African-American adults with diabetes for a 46-h PLT pilot program conducted over 12 weeks. The program utilized multiple instructional methods, reviewed key diabetes education content areas, and provided communication, facilitation, and behavior change skills training. Participants were given three attempts to achieve the pre-established competency criteria for diabetes knowledge, empowerment-based facilitation, active listening, and self-efficacy. RESULTS: On the first attempt 75%, 75%, 63%, and 75% passed diabetes knowledge, empowerment-based facilitation, active listening, and self-efficacy, respectively. Those participants who did not pass on first attempt passed on the second attempt. Participants were highly satisfied with the program length, balance between content and skills development, and preparation for leading support activities. CONCLUSION: Findings suggest that it is feasible to train and graduate peer leaders with the necessary knowledge and skills to facilitate DSMS interventions. PRACTICAL IMPLICATIONS: With proper training, peer support may be a viable model for translating and sustaining DSMS interventions into community-based settings. PMID- 21292426 TI - Studying the social construction of cancer-related fatigue experience: the heuristic value of Ethnoscience. AB - OBJECTIVES: Patients' lived experience of illness and health is receiving increased attention in the medical field. Understanding patients' perspective and experiences is an undoubted asset for efficient health interventions and improved clinical concordance. Patients' experiences of care and cure, however, are influenced by the cultural setting in which these experiences take place. This implies that health interventions should be "ecological" and attuned to the specific sociocultural context of the patients. METHODS: Our research group is conducting a cross-cultural qualitative study aimed ad exploring how fatigue (a symptom very common in cancer) is perceived and manifested by patients in different countries (Canada, Thailand, England and Italy). In order to achieve this, the study was design according to the method of Ethnoscience, that appeared to us the best suited to explore the meanings that patients attribute to their state and the linguistic patterns they use to describe it. In this paper we will describe in details the process of Ethnoscience and will discuss the heuristic value of this research approach. RESULTS: Ethnoscience was an effective research strategy for exploring how beliefs and values shape symptoms and the behavioural manifestations of cancer related fatigue. CONCLUSIONS: This paper discusses the heuristic value of Ethnoscience and its applicability to the study of health relate topics, particularly those where issues of social construction are important. PRACTICAL IMPLICATIONS: Ethnoscience is a promising and innovative research approach, able to cast light on the way people experience and make sense of their illness. PMID- 21292427 TI - Effects of hyperinsulinemia on glucose and lipid transporter expression in insulin-sensitive horses. AB - Plasma insulin concentrations are elevated (hyperinsulinemia) in horses with obesity-associated insulin resistance. In other species, insulin resistance is partly due to reduced levels of insulin receptor and the insulin-sensitive glucose transporter, and, in vitro, chronic hyperinsulinemic conditions reduce the expression of these proteins. Consumption of grain-based concentrate feeds results in postprandial hyperinsulinemia in horses, and adaptation to these diets is associated with insulin resistance. As such, it is possible that the repeated, chronic postprandial hyperinsulinemia associated with these diets could contribute to the development of insulin resistance. The purpose of the current study was to investigate the influence of a 6-h insulin infusion that increased plasma insulin concentrations to >1,000 mIU/L, on the expression of insulin receptor and glucose and lipid transporters in skeletal muscle and adipose tissue of lean, insulin-sensitive horses. Insulin infusion decreased transcript abundance of the glucose transporter 4 (P<0.05), glucose transporter 1 (GLUT1; P<0.09), and the insulin receptor (P<0.001) in adipose tissue, while increasing transcript abundance of GLUT1 (P<0.09) and decreasing protein abundance of the insulin receptor (P<0.09) in skeletal muscle. The acute, 6 hyperinsulinemic conditions achieved in this experiment resulted in alterations to mechanisms of glucose transport that could promote insulin resistance via reduced insulin stimulated glucose disposal. Insulin infusion also reduced transcript abundance of the lipid transporters CD36 (P<0.001) and fatty acid transporter protein (FATP; P<0.05) in adipose tissue while increasing FATP (P<0.05) and lipoprotein lipase (P<0.01) in skeletal muscle. The reduction in adipose tissue lipid transporters could have been due to the decreased plasma lipid concentrations, whereas the increase in skeletal muscle may indicate that insulin stimulates lipid uptake into equine skeletal muscle. This report provides preliminary evidence that severe hyperinsulinemia alters glucose and lipid transporter expression that could promote an insulin-resistant state; these should be further investigated in horses consuming grain-based concentrates. PMID- 21292428 TI - Graft infection after endovascular abdominal aortic aneurysm repair. AB - INTRODUCTION: Although the natural history and management of infected open abdominal aortic aneurysm (AAA) repair is well described, only sporadic case reports have described the fate of patients with infected endografts placed in the abdominal aorta. The present study describes a tertiary referral center's experience with infected endovascular aneurysm repairs (EVARs). METHODS: The medical records of 1302 open and endovascular aortic procedures were queried from January 2000 to January 2010. The cases were reviewed for prior aortic procedures, prosthetic implants, and etiology of current open procedure. Demographics, operative details, and perioperative courses were documented. RESULTS: Nine patients (1 woman) with a mean age of 71 years had an EVAR that later required an open procedure for explantation and surgical revision for suspected infection. All grafts were explanted through a midline transperitoneal approach, with a mean time to explant of 33 months. The explanted endografts included 4 Zenith (Cook, Bloomington, Ind), 2 Ancure (Endovascular Technologies, Menlo Park, Calif), 2 Excluders (Gore, Flagstaff, Ariz), and 1 AneuRx (Medtronic, Minneapolis, Minn). Eight of the nine original EVARs were performed at other hospitals; 1 patient had EVAR and open explant at the University of Michigan. All patients had preoperative computed tomography scans, except one who was transferred in extremis with a gastrointestinal hemorrhage. Three patients also had a tagged leukocyte scan, and two had magnetic resonance imaging to further reinforce the suspicion of infection before explantation and bypass planning. Rifampin-soaked Hemashield (Boston Scientific) in situ grafts were used in four patients, with extra-anatomic (axillary-bifemoral) bypass used in the other five. The in situ group had no positive preoperative or postoperative cultures, with the exception of the unstable patient who died the day of surgery. For the other five patients, positive tissue cultures were found for Bacteroides, Escherichia coli, coagulase-negative Staphylococcus, Streptococcus, and Candida. Three patients were found to have aortic-enteric fistula, two of whom died before discharge from the hospital. The remaining seven survived to discharge. Average length of stay was 22 days, with a median follow-up of 11 months. CONCLUSION: This series of infected EVARs is the largest group of infected AAA endografts reported to date. Because EVAR of AAAs is presently the most common method of repair, development of endograft infection, while rare, can be managed with acceptable mortality rates. Patients presenting with aortic-enteric fistula after EVAR appear to have a more virulent course. PMID- 21292430 TI - Cryopreserved arterial homografts vs silver-coated Dacron grafts for abdominal aortic infections with intraoperative evidence of microorganisms. AB - OBJECTIVE: The gold standard for the treatment of abdominal aortic infections remains controversial. Cryopreserved arterial homografts and silver-coated Dacron grafts have both been advocated as reasonable grafts. Direct clinical or experimental comparisons between these two treatment options have not been published before. This study compared cryopreserved arterial homografts and silver-coated Dacron grafts for the treatment of abdominal aortic infections in a contaminated intraoperative field. METHODS: From January 2004 to December 2009, 56 patients underwent in situ arterial reconstruction for an abdominal aortic infection. Patients with negative intraoperative microbiologic specimens were excluded. We compared 22 of 36 patients (61%) receiving cryopreserved arterial homografts (group A) vs 11 of 20 (55%) receiving a silver-coated Dacron graft (group B). Primary outcomes were survival and limb salvage; secondary outcomes were graft patency and reinfection. Direct costs of therapy were also calculated. RESULTS: Thirty-day mortality was 14% in group A and 18% in group B (P >.99), and 2-year survival rates were 82% and 73%, respectively (P = .79). After 2 years, limb salvage was 96% and 100%, respectively (P = .50), whereas graft patency was 100% for both groups. Major complications were an aneurysmal degeneration in group A and graft reinfection in group B (n = 2). Median direct costs of therapy (in US $) were $41,697 (range, $28,347-$53,362) in group A and $15,531 (range, $11,310-$22,209) in group B (P = .02). CONCLUSIONS: Our results show comparable effectiveness between cryopreserved arterial homograft and silver-coated Dacron graft in the contaminated operative field with respect to early mortality and midterm survival. Graft-inherent complications, aneurysmal degeneration for homografts, and reinfection for silver graft, were also observed. The in situ arterial reconstruction with homografts is nearly three times more expensive than with silver graft. PMID- 21292431 TI - Comparison of indirect radiation dose estimates with directly measured radiation dose for patients and operators during complex endovascular procedures. AB - BACKGROUND: A great deal of attention has been directed at the necessity and potential for deleterious outcomes as a result of radiation exposure during diagnostic evaluations and interventional procedures. We embarked on this study in an attempt to accurately determine the amount of radiation exposure given to patients undergoing complex endovascular aortic repair. These measured doses were then correlated with radiation dose estimates provided by the imaging equipment manufacturers that are typically used for documentation and analysis of radiation induced risk. METHODS: Consecutive patients undergoing endovascular thoracoabdominal aneurysm (eTAAA) repair were prospectively studied with respect to radiation dose. Indirect parameters as cumulative air kerma (CAK), kerma area product (KAP), and fluoroscopy time (FT) were recorded concurrently with direct measurements of dose (peak skin dose [PSD]) and radiation exposure patterns using radiochromatic film placed in the back of the patient during the procedure. Simultaneously, operator exposure was determined using high-sensitivity electronic dosimeters. Correlation between the indirect and direct parameters was calculated. The observed radiation exposure pattern was reproduced in phantoms with over 200 dosimeters located in mock organs, and effective dose has been calculated in an in vitro study. Scatter plots were used to evaluate the relationship between continuous variables and Pearson coefficients. RESULTS: eTAAA repair was performed in 54 patients over 5 months, of which 47 had the repair limited to the thoracoabdominal segment. Clinical follow-up was complete in 98% of the patients. No patients had evidence of radiation-induced skin injury. CAK exceeded 15 Gy in 3 patients (the Joint Commission on Accreditation of Healthcare Organizations [JCAHO] threshold for sentinel events); however, the direct measurements were well below 15 Gy in all patients. PSD was measured by quantifying the exposure of the radiochromatic film. PSD correlated weakly with FT but better with CAK and KAP (r = 0.55, 0.80, and 0.76, respectively). The following formula provides the best estimate of actual PSD = 0.677 + 0.257 CAK. The average effective dose was 119.68 mSv (for type II or III eTAAA) and 76.46 mSv (type IV eTAAA). The operator effective dose averaged 0.17 mSv/case and correlated best with the KAP (r = 0.82, P < .0001). CONCLUSION: FT cannot be used to estimate PSD, and CAK and KAP represent poor surrogate markers for JCAHO defined sentinel events. Even when directly measured PSDs were used, there was a poor correlation with clinical event (no skin injuries with an average PSD >2 Gy). The effective radiation dose of an eTAAA is equivalent to two preoperative computed tomography scans. The maximal operator exposure is 50 mSv/year, thus, a single operator could perform up to 294 eTAAA procedures annually before reaching the recommended maximum operator dose. PMID- 21292432 TI - Infrainguinal bypass is associated with lower perioperative mortality than major amputation in high-risk surgical candidates. AB - BACKGROUND: Major amputation is often selected over infrainguinal bypass in patients with severe systemic comorbidities because it is assumed to have lower perioperative risks, yet this assumption is unproven and largely unexamined. METHODS: The 2005 to 2008 National Surgical Quality Improvement Project (NSQIP) database was used to identify all patients undergoing either infrainguinal bypass or major amputation using procedural codes. Patients with systemic or local infections were excluded. A subset of high-risk patients were then defined as American Society of Anesthesiologists (ASA) class 4 or 5, or ASA class 3 with renal failure, dyspnea at rest, ventilator dependence, recent congestive heart failure, or recent myocardial infarct. Propensity score matching was used to obtain two high-risk patient groups matched for preoperative characteristics. RESULTS: No significant differences in demographic, preoperative, or anesthetic variables were found between the matched, high-risk amputation or bypass groups (792 and 780 patients, respectively). Bypass was associated with a lower 30-day postoperative mortality than amputation (6.54% vs 9.97%; P = .0147). Amputation was associated with higher rates of pulmonary embolism (0.9% vs 0% for amputation vs bypass groups, respectively; P = .009) and urinary tract infection (5.2% vs 2.7%; P = .01), while bypass was associated with higher rates of return to the operating room (14.1% vs 27.6%; P < .001) and a trend toward higher postoperative transfusion requirements (0.9% vs 2.1%; P = .054). The postoperative time to discharge did not differ between the two groups. CONCLUSION: The decision to perform an infrainguinal bypass or amputation should depend on well-established predictors of graft patency and functional success rather than presumptions about different perioperative risks between the two procedures. PMID- 21292433 TI - Accuracy of sentinel lymph node biopsy in large and multifocal/multicentric breast carcinoma--a systematic review. AB - BACKGROUND: While sentinel lymph node biopsy (SLNB) is established in the management of small unifocal breast cancer its role in management of multifocal (MF), multicentric (MC) and larger tumors is still evolving. METHODS: Medline was searched; studies meeting pre-determined criteria were included. Data were extracted and entered into evidence tables. RESULTS: Twenty six studies met inclusion criteria and reported data on accuracy; no randomized trials were identified. For MF cancers (n = 314 cases), success rate for identification of an SLN was 86-94%, SLN positivity rate 42-59%, false negative rate (FNR) 0-33% and overall accuracy 78-100%. For MC (n = 294 cases): success rate 92-100%, SLN positivity rate 25-61%, FNR 4-8% and accuracy 96-100%. For 'multiple breast cancer' (studies combining MF/MC cases; n = 996 cases): success rate 92-100%, SLN positivity rate 12-63%, FNR 0-25%, and accuracy 82-100%. For larger tumors (n = 1912 cases): success rate 86-100%, SLN positivity rate 49-77%, FNR 3-18% and accuracy 85-98%. For MC/MF and larger cancers overall non-SLN positivity rates were up to 82%; axillary recurrence rates were low but seldom reported. CONCLUSION: There are no randomized trials evaluating the safety of SLNB in MF/MC and larger breast cancers. Based on limited evidence, success rate and FNR appear to be similar to those for small unifocal cancers, however node positivity rates are higher and rates of non-SLN positivity are very high. Awareness of these issues is essential when recommending SLNB based axillary management for these higher-risk tumors. PMID- 21292434 TI - Re-resection rates after breast-conserving surgery as a performance indicator: introduction of a case-mix model to allow comparison between Dutch hospitals. AB - AIM: Re-resection rate after breast-conserving surgery (BCS) has been introduced as an indicator of quality of surgical treatment in international literature. The present study aims to develop a case-mix model for re-resection rates and to evaluate its performance in comparing results between hospitals. METHODS: Electronic records of eligible patients diagnosed with in-situ and invasive breast cancer in 2006 and 2007 were derived from 16 hospitals in the Rotterdam Cancer Registry (RCR) (n = 961). A model was built in which prognostic factors for re-resections after BCS were identified and expected re-resection rate could be assessed for hospitals based on their case mix. To illustrate the opportunities of monitoring re-resections over time, after risk adjustment for patient profile, a VLAD chart was drawn for patients in one hospital. RESULTS: In general three out of every ten women had re-surgery; in about 50% this meant an additive mastectomy. Independent prognostic factors of re-resection after multivariate analysis were histological type, sublocalisation, tumour size, lymph node involvement and multifocal disease. After correction for case mix, one hospital was performing significantly less re-resections compared to the reference hospital. On the other hand, two were performing significantly more re resections than was expected based on their patient mix. CONCLUSIONS: Our population-based study confirms earlier reports that re-resection is frequently required after an initial breast-conserving operation. Case-mix models such as the one we constructed can be used to correct for variation between hospitals performances. VLAD charts are valuable tools to monitor quality of care within individual hospitals. PMID- 21292435 TI - Arthroscopic reconstruction of the ligamentum teres. AB - We describe a case of arthroscopic reconstruction of the ligamentum teres using a novel technique. This technique is both simple and reproducible. We believe it to be a useful addition to the procedures available to the arthroscopic hip surgeon. PMID- 21292436 TI - [A serious "acetaldehyde syndrome" compounded by dopamine]. AB - Disulfiram is commonly used in the treatment of alcohol dependence. It induces aversive symptoms after alcohol ingestion: the "acetaldehyde syndrome". Most often "acetaldehyde syndrome" is moderate but severe life-threatening symptoms may occur in specific circumstances. We report the case of a serious "acetaldehyde syndrome" with shock compounded by the initial administration of dopamine. Discussion clarifies the pathophysiology and develops the therapeutic management. PMID- 21292437 TI - Promoted cancer growth by stimulating cell proliferation and decreasing apoptosis using a lentivirus-based EphB2 RNAi in pancreatic carcinoma CFPAC-1 cells. AB - Several studies have reported the change of EphB2 in a variety of carcinomas and suggested a functional relation between EphB2 and tumor progression. However, its role in human pancreatic carcinoma has not been described. The aim of this study was to evaluate the significance of EphB2 in human pancreatic carcinoma CFPAC-1 cells. A lentivirus-based RNA interference (RNAi) vector was designed, synthesized and transfected into CFPAC-1 cells to inhibit EphB2 expression. WST-8 based Colorimetric Assay Cell Counting kit 8 (CCK-8) in vitro and xenograft transplantation model in nude mice was used to evaluate cell proliferation and growth respectively. Cell-cycle and apoptosis were analyzed by flow cytometry (FCM). RT-PCR and Western blot were used to assess mRNA expression and protein levels. EphB2 expression was significantly suppressed both in mRNA and protein levels using the lentivirus-based EphB2 RNAi in CFPAC-1 cells (P<0.01, P<0.01). Silencing EphB2 stimulated cell growth in vitro (P<0.05) and proliferation in vivo (P<0.01) versus Control RNAi. EphB2 RNAi significantly increased S phase cells from 18.15 to 27.18% (P<0.05), and significantly decreased G1 phase cells from 72.93 to 57.61% compared with Control RNAi (P<0.05). In addition, decreased apoptosis was observed in CFPAC-1 EphB2 RNAi cells compared with Control RNAi cells (P<0.01). The apoptosis rate was 1.63% and 7.44%, respectively. Silencing EphB2 increased CyclinD1, cyclindependent kinase 6 (CDK6) and Bcl-2 expression in both mRNA and protein levels compared with Control RNAi. A lentivirus-based EphB2 RNAi efficiently inhibited EphB2 gene and its protein expression. Silencing EphB2 stimulated pancreatic carcinoma growth by increasing cell proliferation through G1/S phase breakthrough, which relied on a CyclinD1/CDK6 cell-cycle regulated signal. Similarly, EphB2 inhibition also reduced CFPAC-1 cells apoptosis by up regulating Bcl-2 expression. Thus, at least in the context of pancreatic carcinoma CFPAC-1 cells, EphB2 plays a tumor suppressor role in cell proliferation and apoptosis. PMID- 21292438 TI - Restless legs syndrome secondary to sacral zona zoster. PMID- 21292439 TI - Combined modality treatment of adductor spasmodic dysphonia. AB - INTRODUCTION: The hallmark characteristic of adductor spasmodic dysphonia (ADSD) is irregular and uncontrollable spasms within the intrinsic laryngeal muscles, resulting in erratic disruption of normal voicing. METHODS: Using a random assignment and the inclusion of a behavioral sham to determine the effect of voice therapy after initial botulinum toxin type A (BTX-A) injections for ADSD, this study examined duration of injection benefit, perceived vocal quality of life from the Voice-Related Quality of Life (V-RQOL) scale, acoustic measures of vocal instability, and perceptual ratings of voice quality. Measures of these variables were collected before initial injection; 3, 7, and 12 weeks postinjection; and immediately before reinjection. Thirty-one individuals with ADSD participated in this study. One-third received no further intervention after BTX-A injection, one-third received a standard 5-week course of voice therapy after BTX-A injection, and one-third received a 5-week course of sham voice therapy after BTX-A injection. RESULTS AND CONCLUSIONS: Significant effects were observed on perceived quality of life and acoustic variables for all participants, over time. Participants who received voice therapy after BTX-A injection did not experience longer injection effect duration or significantly greater improvements in V-RQOL or acoustic variables than participants in BTX-A only or BTX-A plus sham therapy groups. Additionally, perceptual ratings of voice quality improved for all participants in response to BTX-A injection. For participants in this investigation, undertaking voice therapy did not appear to exert significant beneficial effects on the variables of interest. PMID- 21292440 TI - Multiple imputation was an efficient method for harmonizing the Mini-Mental State Examination with missing item-level data. AB - OBJECTIVE: The Mini-Mental State Examination (MMSE) is used to estimate current cognitive status and as a screen for possible dementia. Missing item-level data are commonly reported. Attention to missing data is particularly important. However, there are concerns that common procedures for dealing with missing data, for example, listwise deletion and mean item substitution, are inadequate. STUDY DESIGN AND SETTING: We used multiple imputation (MI) to estimate missing MMSE data in 17,303 participants who were drawn from the Dynamic Analyses to Optimize Aging project, a harmonization project of nine Australian longitudinal studies of aging. RESULTS: Our results indicated differences in mean MMSE scores between those participants with and without missing data, a pattern consistent over age and gender levels. MI inflated MMSE scores, but differences between those imputed and those without missing data still existed. A simulation model supported the efficacy of MI to estimate missing item level, although serious decrements in estimation occurred when 50% or more of item-level data were missing, particularly for the oldest participants. CONCLUSIONS: Our adaptation of MI to obtain a probable estimate for missing MMSE item level data provides a suitable method when the proportion of missing item-level data is not excessive. PMID- 21292441 TI - Electronic reminders did not improve postal questionnaire response rates or response times: a randomized controlled trial. AB - OBJECTIVE: We aim to evaluate the effectiveness of electronic reminders (ERs) to improve the response rates and time to response of postal questionnaires in a health research setting. STUDY DESIGN AND SETTING: This pragmatic randomized controlled trial (RCT) was nested within a multicenter RCT of yoga for lower back pain. Participants who provided an electronic mail address and/or mobile phone number were randomized to receive an ER or no reminder (controls) on the day they were due to receive a follow-up questionnaire. RESULTS: One hundred twenty-five participants (32 males and 93 females) mean age 46 (standard deviation: 11, range: 20-65) were randomized to ER (n=62) or controls (n=63). Overall 85.6% of participants returned postal questionnaires (87.1% ER group and 84.1% from controls). No significant differences were found between the two groups for response rate (difference between groups=3.0%, 95% confidence interval [CI]=-10, 16; P=0.64) or time to response after adjusting for age, gender, and treatment allocation (chi(2) ([3df])=7.10; P=0.07). CONCLUSION: In the present RCT, we found little evidence for the effectiveness of ERs to increase response rates or time to respond for the return of questionnaires in this study population group. PMID- 21292442 TI - Bayesian random effects for interrater and test-retest reliability with nested clinical observations. AB - OBJECTIVE: The assessment of inter- and intrarater reliability usually involves more than one level of nesting structures in the collected data, where repeated observations are made by multiple raters. Most approaches, however, are not designed to accommodate both inter- and intrarater reliability jointly, not to mention further difficulties arising when modeling with dichotomous responses. The multiple sources of dependence because of nesting structures and the existence of covariates can result in complexity in inference. STUDY DESIGN AND SETTING: We first establish the equivalence between correlation and kappa under common positive correlation models for multiple raters and then apply a Bayesian generalized linear mixed-effects model to interpret simultaneously both types of reproducibility through different annotations of similarity. In addition to marginal correlations, the correlated random effects among raters are adopted to infer similarity between raters, whereas the correlation for random time effects may contribute to test-retest reliability. RESULTS: This model accounts for individual covariates and random effects because of subjects, raters, and time, and it covers a wide variety of data structures and types. An application of endodontic radiographic examinations is illustrated. CONCLUSION: This Bayesian hierarchical correlation model offers a wide applicability, flexibility, and feasibility in modeling inter- and intrarater reliability together. PMID- 21292444 TI - Construction of the eight-item patient-reported outcomes measurement information system pediatric physical function scales: built using item response theory. AB - OBJECTIVE: To create self-report physical function (PF) measures for children using modern psychometric methods for item analysis as part of patient-reported outcomes measurement information system (PROMIS). STUDY DESIGN AND SETTING: PROMIS qualitative methodology was applied to develop two PF item pools that comprised 32 mobility and 38 upper extremity items. Items were computer administered to subjects aged 8-17 years. Scale dimensionality and sources of local dependence (LD) were evaluated with factor analysis. Items were analyzed for differential item functioning (DIF) between genders. Items with LD, DIF, or low discrimination were considered for removal. Computerized adaptive testing performance was simulated, and short forms were constructed. RESULTS: Three thousand forty-eight children (51.8% female, 40% nonwhite, and 22.7% chronically ill) participated. At least 754 respondents answered each item. Factor analytical results confirmed two dimensions of PF. Fifty-two of 70 items tested were retained. A 23-item mobility bank and a 29-item upper extremity bank resulted, and an eight-item short forms were created. The item banks have high information from the population mean to three standard deviations below. CONCLUSIONS: PROMIS pediatric PF item banks and eight-item short forms assess two dimensions, mobility, and upper extremity function and show good psychometric characteristics after large-scale testing. PMID- 21292445 TI - Deficit and nondeficit schizophrenia: boundaries in question. PMID- 21292446 TI - Arginine metabolism in soft tissue sarcoma. AB - BACKGROUND: L-Arginine (L-Arg) is a conditionally essential amino acid for humans, which is the substrate for both arginase (ARG) and the inducible form of nitric oxide synthase (iNOS) enzymes. Whether L-Arg metabolism has detrimental or beneficial influence on the tumor growth depends on local up regulation of the NOS or ARG pathways at the tumor site. OBJECTIVE: To evaluate the expression profile of ARG and iNOS in various histological subtypes of soft tissue sarcomas (STSs). METHODS: A series of 81 adult STSs were tested for ARG1, ARG2 and iNOS expression by immunohistochemical analysis. RESULTS: ARG1, ARG2 and iNOS expression was found in tumor cells of all cases of STSs except dermatofibrosarcoma protuberans (DFSP) in a cytoplasmic pattern. However, there was no significant correlation found between ARG, iNOS expression and histopathological parameters. Conversely, the majority of DFSP were devoid of ARG and iNOS expression, while only two cases showed focal and weak expression. CONCLUSIONS: Overexpression of L-Arg-metabolizing enzymes ARG and iNOS in tumor cells of all of the STS cases except DFSP may have a role in mediating the biological processes which characterize STSs. New knowledge of the regulation of arginine metabolism in tumor tissues is key to designing sound therapeutic means to effectively prevent tumorigenesis. Further studies are needed to clarify the absence of ARG and iNOS staining in DFSP. PMID- 21292447 TI - Radiation-induced mast cell mediators differentially modulate chemokine release from dermal fibroblasts. AB - BACKGROUND: Ionizing radiation has been demonstrated to result in degranulation of dermal mast cells. Chemokines are thought to play a crucial role in the early phase of the cutaneous radiation reaction. In human skin, mast cells are located in close proximity to dermal fibroblasts, which thus are a potential target for the action of mast cell mediators. OBJECTIVE: In this study, we evaluated the effects of mast cell-derived histamine, serotonin, tumour necrosis factor (TNF) alpha and tryptase on chemokine release from dermal fibroblasts. METHODS: Human mast cells (HMC-1) were investigated for histamine release and cytokine production after ionizing radiation using enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Receptor expression on human fetal foreskin fibroblasts (HFFF2) and human adult skin fibroblasts (HDFa) was examined by flow cytometry. Chemokine mRNA and protein expression were analyzed by gene array and ELISA, respectively. RESULTS: Ionizing radiation significantly increased histamine release and cytokine expression by HMC-1 cells. Receptors for histamine, serotonin, TNF-alpha and tryptase were detected both in HFFF2 and in HDFa cells. Dermal fibroblasts constitutively expressed distinct sets of chemokine mRNA. Mast cell mediators differentially affected the release of chemokines CCL8, CCL13, CXCL4 and CXCL6 by fibroblasts. CONCLUSIONS: Our data suggest that radiation-induced mast cell mediators have a tremendous impact on inflammatory cell recruitment into irradiated skin. We postulate the activation of mast cells to be an initial key event in the cutaneous radiation reaction, which might offer promising targets for treatment of both normal tissue side effects in radiation therapy and radiation injuries. PMID- 21292448 TI - Effect of topoisomerase inhibitors and DNA-binding drugs on the cell proliferation and ultrastructure of Trypanosoma cruzi. AB - Trypanosomatids present unusual organelles, such as the kinetoplast that contains the mitochondrial DNA arranged in catenated circles. The nucleus of these protozoa presents distinct domains during interphase as well as a closed mitosis. DNA topoisomerases modulate the topological state of DNA by regulating supercoiling of the double-stranded DNA during replication, transcription, recombination and repair. Because topoisomerases play essential roles in cellular processes, they constitute a potential target for antitumour and antimicrobial drugs. In this study, the effects of various topoisomerase inhibitors and DNA binding drugs were tested on the cellular proliferation and ultrastructure of the Trypanosoma cruzi epimastigote form Blastocrithidia culicis was used as a comparative model, which has a more relaxed kinetoplast DNA (kDNA) organization. The results showed that the eukaryotic topoisomerase I inhibitors camptothecin and rebeccamycin were the most effective compounds in the arrest of T. cruzi proliferation. Of the eukaryotic topoisomerase II inhibitors, mitoxantrone, but not merbarone, was effective against cell proliferation. The prokaryotic topoisomerase II inhibitors norfloxacin and enoxacin targeted the kinetoplast specifically, thus promoting ultrastructural kDNA rearrangement in B. culicis. Of the DNA-binding drugs, berenil caused remarkable kDNA disorganization. With the exception of camptothecin, there have been no previous evaluations of the compounds tested here on trypanosomatid ultrastructure. In conclusion, inhibitors of the same class may have different effects on trypanosomatid proliferation and ultrastructure. The results obtained in this work may help to reveal the mechanism of action of different topoisomerase inhibitors in trypanosomatids. PMID- 21292449 TI - Clinical implications of beta-lactam-aminoglycoside synergism: systematic review of randomised trials. AB - beta-Lactam-aminoglycoside combinations are commonly used despite lack of evidence of a clinical benefit. In this study, all randomised controlled trials (RCTs) assessing directly the clinical implications of synergism by comparing a beta-lactam with the same beta-lactam in combination with an aminoglycoside as empirical or definitive therapy for any type of infection and clinical scenario were compiled. A systematic search was undertaken to identify all trials regardless of language, date or publication status. The primary outcomes assessed were all-cause mortality and clinical failure regardless of antibiotic modifications. Risk of bias was evaluated and its effect was assessed through sensitivity analyses. Two reviewers applied inclusion criteria and extracted the data independently. A fixed-effect meta-analysis was performed. Fifty-two RCTs were identified assessing patients with febrile neutropenia, pneumonia, abdominal infections, bacteraemia, endocarditis or cystic fibrosis. Only five trials were double-blinded. All-cause mortality was similar with monotherapy versus combination therapy [risk ratio (RR)=0.96, 95% confidence interval (CI) 0.78 1.18, 28 trials, 3756 episodes]. Clinical failure regardless of antibiotic modifications was not significantly different (RR=0.88, 95% CI 0.74-1.05, 27 trials, 2500 episodes). Treatment failure including antibiotic addition/modification occurred more frequently with monotherapy (RR=1.20, 95% CI 1.12-1.28, 48 trials, 6643 episodes). There were no significant differences with regard to bacterial or fungal superinfections or development of antibiotic resistant strains. Combination therapy resulted in a significantly higher incidence of adverse events, mainly nephrotoxicity. Overall, no clinical benefit was found for the use of a beta-lactam with an aminoglycoside compared with a beta-lactam alone. Treatment with beta-lactams as monotherapy entailed more antibiotic regimen modifications in open trials. PMID- 21292450 TI - Baseline and prodromal characteristics of first- versus multiple-episode mania in a French cohort of bipolar patients. AB - OBJECTIVE: To identify some of the main features of bipolar disorder for both first-episode (FE) mania and the preceding prodromal phase, in order to increase earlier recognition. METHODS: One thousand and ninety manic patients (FE=81, multiple-episodes [ME]=1009) were assessed for clinical and temperamental characteristics. RESULTS: Compared to ME, FE patients reported more psychotic and less depressive symptoms but were comparable with respect to temperamental measures and comorbid anxiety. The following independent variables were associated with FE mania: a shorter delay before correct diagnosis, greater substance use, being not divorced, greater stressors before current mania, a prior diagnosis of an anxiety disorder, lower levels of depression during index manic episode, and more suicide attempts in the past year. CONCLUSION: In FE patients, the diagnosis of mania may be overlooked, as they present with more psychotic symptoms than ME patients. The prodromal phase is characterised by high levels of stress, suicide attempts, anxiety disorders and alcohol or substance abuse. Data suggest to consider these prodromes as harmful consequences of temperamental predispositions to bipolar disorder that may concur to precipitate mania onset. Their occurrence should therefore incite clinicians to screen for the presence of such predispositions, in order to identify patients at risk of FE mania. PMID- 21292451 TI - Initial evidence for the role of CACNA1C on subcortical brain morphology in patients with bipolar disorder. AB - BACKGROUND: The polymorphism rs1006737 within the CACNA1C gene is associated with increased risk for bipolar disorder (BD) and variations in brain morphology and function of subcortical regions. Here we sought to investigate the influence of CACNA1C polymorphism on key subcortical brain structures implicated in the pathophysiology of BD. METHODS: Structural magnetic resonance imaging scans were acquired from 41 euthymic patients with BD and 40 healthy controls, who were also genotyped for the CACNA1C rs1006737 polymorphism. The effect of diagnosis, genotype and their interaction was examined in predefined volumes of interest in the basal ganglia, hypothalamus and amygdala extracted using SPM5. RESULTS: Carriers of the CACNA1C rs1006737 risk allele showed increased grey matter density in the right amygdala and right hypothalamus irrespective of diagnosis. An interaction between genotype and diagnosis was observed in the left putamen which was smaller in BD patients carrying the risk allele than in healthy controls. CONCLUSIONS: The CACNA1C rs1006737 polymorphism influences anatomical variation within subcortical regions involved in emotional processing. PMID- 21292452 TI - Age at onset in bipolar disorder: Investigation of the role of TaqIA polymorphism of DRD2 gene in a Sardinian sample. AB - Bipolar disorder (BD) is a highly heterogeneous and heritable psychiatric illness. Age at onset has been shown to be a powerful tool for dissecting both the phenotypic and genetic complexity of BD. In this article, we present findings from an association study between the DRD2 TaqIA polymorphism and age at onset, showing that both alleles and genotypes at this locus associate with early onset BD. PMID- 21292453 TI - Intensive care in psychiatry. AB - Psychiatric intensive care is supposed to offer treatment and to hold patients with psychiatric illness, if they pose a threat to themselves or to others. Besides treating the underlying psychiatric diagnoses, it is also necessary to take care of severe somatic comorbidity, which is often impeded by patients' limited ability to cooperate. Treatment often requires the administration of sedative medication and occasionally the use of medical restraints. Involuntary commitment, involuntary treatment and the usage of physical restraints is regulated by national mental health laws. Medical professionals working in the field of psychiatric intensive care must have expert knowledge in the fields of psychopharmacology and intensive care medicine. Treatment concepts should be aimed to provide optimized care for psychiatric inpatients in a potentially life threatening phase of their illness. This article outlines current clinical practice at the psychiatric intensive care unit of the Medical University of Vienna (Austria). Furthermore, we present diagnoses, diagnostic procedures and specific treatments of a sample of 100 consecutive inpatients treated in the years 2008 and 2009 at this ward. PMID- 21292454 TI - Is psychoeducation for parents and teachers of children and adolescents with ADHD efficacious? A systematic literature review. AB - OBJECTIVE: To identify evidence from comparative studies on the effects of psychoeducation programs on clinical outcomes in children and adolescents with ADHD. METHOD: Articles published between January 1980 and July 2010 were searched through electronic databases and hand search. A qualitative systematic review of comparative studies of psychoeducation in ADHD was performed. Psychoeducation was considered if studies use a specific therapeutic program focusing on the didactically communication of information and provide patients and families with coping skills. RESULTS: Seven studies were identified (four randomized-controlled trials, three uncontrolled pre-post treatment designs). Studies differed on whether psychoeducation approaches were applied to parents of ADHD children (three studies), to ADHD children/adolescents and their families (three studies) or to their teachers (one study). Positive outcomes measured as improvement on a number of different variables, including patient's behavior, parent and child satisfaction, child's knowledge of ADHD, children's opinion of the use of medication and adherence to medical recommendations were found. CONCLUSIONS: Although available evidence is limited and some findings may be difficult to be interpreted, the positive role of psychoeducation and other educational interventions in children and adolescents with ADHD in regard to several outcome measures is supported by most of the literature referenced in this review. PMID- 21292455 TI - The course of depressive symptoms and prescribing patterns of antidepressants in schizophrenia in a one-year follow-up study. AB - BACKGROUND: Antidepressants are frequently prescribed in patients with psychotic disorders, but little is known about their effects in routine clinical practice. The objective was to investigate the prescribing patterns of antidepressants in relation to the course of depressive symptoms in patients with psychotic disorders. METHODS: A cohort of 214 Dutch patients with psychotic disorders received two assessments of somatic and psychiatric health, including a clinician rated screening for depressive symptoms, as part of annual routine outcome monitoring. RESULTS: Depressive symptoms were prevalent among 43% (93) of the patients. Antidepressants were prescribed for 40% (86) of the patients and the majority 83% (71) continued this therapy after one year. Multivariable analysis showed that patients with more severe psychopathology had a higher risk to develop depressive symptoms the following year (OR [95% CI]=0.953 [0.912-0.995]). For patients with depressive symptoms at baseline, polypharmacy was a potential risk factor to keep having depressive symptoms (OR [95% CI]=1.593 [1.123-2.261]). Antidepressant use was not an independent predictor in both analyses. CONCLUSIONS: Routine outcome monitoring in patients with psychotic disorders revealed a high prevalence of depressive symptoms. Antidepressants were frequently prescribed and continued in routine clinical practice. PMID- 21292456 TI - [Prospective study at 1 week of life of thyroid function in 97 consecutive pre term newborns under 32 weeks of gestation]. AB - Hypothyroxinemia of prematurity (HTOP) is associated with neurodevelopmental impairment in pre-term newborns born at less than 32 weeks of gestation (WG). HTOP is not clearly defined in the literature and there is no consensus on whether or not treatment of HTOP is beneficial. OBJECTIVE: To describe the epidemiologic characteristics of HTOP and to determine the population at risk of HTOP. POPULATION AND METHODS: Ninety-seven pre-term newborns under 32 WG were prospectively included in this study. FT4 and thyroid-stimulating hormone (TSH) serum levels were assessed between day of life 5 and 7. HTOP was defined as serum level of FT4 0.80 ng/dl or less and TSH less than 20 mUI/l. RESULTS: The HTOP incidence was 29% in pre-term newborns under 32 WG and 64% in pre-term newborns 28 WG or less. FT4 levels were correlated with gestational age (P<0.001). The incidence of hypotension (61% vs 33%; P<0.05), patent ductus arteriosus (50% vs 17%; P<0.05), dopamine treatment (39% vs 16%; P<0.05), and hydrocortisone treatment (25% vs 6%; p<0.05) was higher in the HTOP group. Similarly, severe intracerebral hemorrhage (14% vs 0%; P<0.01) and hypothermic events under 36 degrees C (1.8 +/- 1.7 vs 0.0 +/- 0.4; P<0.05) were higher in the HTOP group. CONCLUSION: Incidence of HTOP is high in pre-term newborns born at less than 28 WG. Morbidity during the first week of life is higher in cases of HTOP. Whether or not treatment of all pre-term with l-thyroxin is beneficial is unknown. However, treatment of the subgroup of pre-term newborns under 28 WG with HTOP should be considered. PMID- 21292457 TI - [Systemic congenital candidiasis, a rare condition in neonates: case report in a premature infant]. AB - Congenital cutaneous candidiasis presenting at birth is very uncommon and is due to intra-uterine infection. The systemic form has to be considered when cutaneous signs are associated with sepsis symptoms. CASE REPORT: A female infant was born by vaginal delivery at 35 weeks' gestation to a mother whose pregnancy had been complicated by urinary tract infection treated 3 days before delivery. The infant was admitted because of respiratory distress. Clinical features consisted of respiratory retraction signs associated with hepatomegaly and rash on the trunk. The white blood cell (WBC) count was 50 * 10(9)/L and C-reactive protein was negative. Maternofetal bacterial infection was suspected and intravenous antibiotics were prescribed. Over the next 6h, macules appeared on the trunk, back, and limbs, which changed after 24h into papulovesicular lesions over the trunk, back, limbs, palms, and scalp. Congenital candidiasis was suspected, confirmed by cultures from vesicle swabs and maternal vaginal discharge. The systemic form was considered because of respiratory distress requiring oxygen therapy for 4 days, hepatomegaly, elevated WBC count, and chest X-ray infiltrates. The infant was started on intravenous systemic antifungal therapy (fluconazole, 6 mg/day). Treatment was continued for 3 weeks. The rash resolved by desquamation after about 1 week and hepatomegaly disappeared. The infant remained well at follow-up. PMID- 21292458 TI - [Pulmonary stenosis and atresia with intact ventricular septum]. AB - Pulmonary atresia and critical pulmonary stenosis with intact ventricular septum includes a wide spectrum of cardiopathies with great morphological heterogeneity. The pulmonary valve may be completely atretic or may contain a puncture hole if stenosis is present. The obstruction may be membranous and/or muscular. All components of the right ventricle can be affected, even the coronary circulation with ventriculocoronary connections and stenosis or atresia of the pulmonary arteries. Prenatal diagnosis is made when the right ventricle is hypoplastic and hypertrophic. The pulmonary valve is thickened and the pulmonary artery is perfused retrogradely through the ductus arteriosus. Right ventriculocoronary connections may sometimes be seen with fetal echocardiography. Postnatal survival depends on the patency of the ductus arteriosus, requiring prostaglandin E1 infusion. When hypoplastic right ventricle and/or ventricle-dependent coronary circulation exists, biventricular circulation is not possible. In these cases, surgical treatment is palliative. In cases with well-developed right ventricle, transcatheter therapy is usually provided with perforation and balloon dilation of the pulmonary valve. In cases of muscular obstruction of the right ventricle outflow tract, surgery may be considered as first-line therapy. In case of prenatal diagnosis, the medical termination of pregnancy is possible when severe right ventricular hypoplasia exists, precluding biventricular circulation. Postnatally, the prognosis of the patients is highly variable, mainly related to the size of the right cavities and the presence of coronary anomalies. PMID- 21292459 TI - [Cerebellar injury in premature infants less than 30 weeks of gestation]. AB - Traditionally, the cerebellum has been regarded as a central component of the motor system. Recent studies suggest an important role played by the cerebellum in the development of cognitive and social functions. The objective of this study was to evaluate the incidence of cerebellar injury and to define the obstetrical, neonatal, and radiologic characteristics, as well as the functional outcomes in a population of very preterm infants. METHODS: This retrospective study included neonates born before 30 weeks of gestational age between March 2004 and July 2007. Infants underwent MRI studies at a term-adjusted age; for each preterm infant with cerebellar injury, we identified two infants for the control group with normal MRI, matched on the basis of gestational age. We collected pertinent demographic, prenatal, and acute postnatal data for all infants. Follow-up assessment was performed at 2 years, using the Brunet-Lezine scale. RESULTS: A total of 148 ex-preterm infants were studied. Cerebellar injury was present in 14 (9 %) cases and associated with supratentorial parenchymal injury in 90 %. Duration of ventilation was longer in children with cerebellar injury, compared to controls (19.5 days vs 16.5 days; P=0.03). The other neonatal criteria analyzed were comparable between the two groups. Global developmental, functional, and social-behavioral deficits were more common and profound in preterm infants with cerebellar injury, with no significant difference. CONCLUSION: This study confirms the high incidence of cerebellar injury in very preterm infants and the importance of a specific neurobehavioral follow-up. PMID- 21292460 TI - Cancer immunology. PMID- 21292461 TI - Control maintenance can be predicted by exhaled NO monitoring in asthmatic patients. AB - BACKGROUND: Fractional exhaled nitric oxide (F(E)NO) is a marker of airway inflammation in asthma. Monitoring of such inflammation is currently not included in asthma guidelines and remains controversial. The hypothesis underlying the present study was that, F(E)NO could help assessing asthma control and, therefore, improve its management, by predicting loss of control in asthmatics. METHODS: A total of 90 adult asthmatics were included in the study. Asthma control was evaluated according to ACQ. All patients underwent F(E)NO by chemiluminescent (EndoNO) and hand-held (MINO) devices, followed by lung function testing. RESULTS: MINO was accurate as compared to EndoNO. F(E)NO was significantly increased in uncontrolled as compared to controlled asthmatics using both devices. F(E)NO measurement was able to predict control maintenance in controlled asthmatics in the absence of any change in their treatment. Indeed, using cut-off values of 31 and 40 ppb, the negative predictive values were 95 and 97% for EndoNO and MINO, respectively. EndoNO and MINO were also able to assess asthma control, although to a lesser extent. CONCLUSIONS: These findings suggest that F(E)NO can predict the persistence of asthma control in controlled patients and may now be used in asthma management since it can accurately be measured by means of hand-held devices. PMID- 21292463 TI - Effect of marginal vitamin A deficiency during pregnancy on retinoic acid receptors and N-methyl-D-aspartate receptor expression in the offspring of rats. AB - This study examined whether pregnancy-related marginal vitamin A deficiency (MVAD) influences postnatal development of retinoic acid receptors (RARs) and N methyl-D-aspartate (NMDA) receptor subunit 1 (NR1) in hippocampus of rat pups. Sixteen female rats were randomized equally into control and MVAD groups. Dams and pups were fed with either a normal control diet or one deficient in vitamin A. Eight female pups in each group were killed at 1 day, 2 weeks, 4 weeks and 8 weeks after birth, respectively. Serum retinol levels were monitored. The messenger RNA (mRNA) and protein expressions and subcellular localization of RARalpha, RARbeta and NR1 in postnatal hippocampus were detected. At 1 day, 2 weeks and 8 weeks after birth, serum retinol levels in the MVAD group were significantly lower than those in the control group. Results of Morris water maze test at 7 weeks of age showed that spatial learning and memory in the MVAD group were affected. Vitamin A deficiency resulted in decreased mRNA levels of RARalpha, RARbeta and NR1 (P<.05). The protein level of RARalpha and NR1 in the MVAD group was lower than that of the control group (P<.05). There was no significant difference in RARbeta between the groups (P>.05). A mass of RARalpha and NR1 colocalized in hippocampal cell cytoplasm on postnatal day 1. Our data suggested that vitamin A deficiency in pregnancy may affect the postnatal expression of RARalpha and NR1, affecting learning and memory function in the hippocampus and synaptic plasticity of the calcium signaling pathway. PMID- 21292462 TI - Gene positioning and expression. AB - Within the nucleus, the genome is spatially organized. Individual chromosomes are non-randomly positioned with respect to each other and with respect to nuclear landmarks [1,2]. Furthermore, the position of individual genes can reflect their expression. Here we discuss two well-characterized examples of gene relocalization associated with transcriptional activation: 1) developmentally regulated genes that move from the nuclear periphery to transcription factories in the nucleoplasm upon induction and 2) genes that are targeted from the nucleoplasm to the nuclear periphery, through interactions with the nuclear pore complex (NPC), upon activation. Finally, we speculate as to the mechanistic and functional commonalities of these phenomena. PMID- 21292464 TI - Diosgenin stimulates osteogenic activity by increasing bone matrix protein synthesis and bone-specific transcription factor Runx2 in osteoblastic MC3T3-E1 cells. AB - Diosgenin, a steroid saponin extracted from the root of wild yam (Dioscorea villossa) is claimed to have osteogenic property. However, detailed studies providing evidence to this claim have not been fully undertaken. In this study, we investigated the effect of diosgenin on the osteogenesis of murine MC3T3-E1 osteoblastic cells. Cells were cultured with varying levels of diosgenin (0-10 MUM) within 25 days of bone formation period. Diosgenin was found to stimulate proliferation within the range of 0.01-5 MUM using MTT assay. The medium and cellular levels of Type 1 collagen and alkaline phosphatase (ALP), both of which are major bone matrix proteins, increased within the low range of diosgenin concentration (>0-3 MUM), and this pattern was further confirmed by collagen and ALP staining of the extracellular matrix (ECM). The cellular protein expression of ALP and collagen Type 1 was also increased at 0.1-1 MUM diosgenin treatment as analyzed by Western blot. Calcium deposition within the ECM also showed the same pattern as assessed by Alizarin Red S and Von Kossa staining. Bone-specific transcription factor runt-related transcription factor 2 (Runx2) and Runx2 regulated osteopontin protein expressions were induced at low concentration (0.1 1 MUM) and again decreased with high diosgenin concentrations. Based on our findings, our study suggests that diosgenin can enhance bone formation by stimulating the synthesis and secretion of Type 1 collagen and ALP and bone marker proteins Runx2 and osteopontin expression. The increased levels of these marker proteins, in turn, can increase the formation of calcium deposits within the ECM thereby increasing bone formation. PMID- 21292465 TI - gamma-Tocotrienol inhibits angiogenesis of human umbilical vein endothelial cell induced by cancer cell. AB - Antiangiogenic therapy mediated by food components is an established strategy for cancer chemoprevention. Growth factors play critical roles in tumor angiogenesis. A conditioned medium containing growth factors from human gastric adenocarcinoma SGC-7901 cell conditioned medium was used as an angiogenic stimulus in this study. The purpose of this study was to evaluate the inhibitory effect and possible mechanism of gamma-tocotrienol on tumor angiogenesis. The results showed that gamma-tocotrienol (10-40 MUmol/L) significantly suppressed proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVECs) induced by SGC-7901 cell conditioned medium in a dose-dependent manner. gamma Tocotrienol (800-1200 MUg/egg) also inhibited new blood vessel formation on the growing chick embryo chorioallantoic membrane in a dose-dependent manner. Moreover, the inhibitory effects of gamma-tocotrienol on HUVECs were correlated with inducing the apoptosis and arresting cell cycle at the G(0)/G(1) phase at a dose of 40 MUmol/L gamma-tocotrienol. In addition, gamma-tocotrienol inhibited angiogenesis in HUVECs by down-regulation of beta-catenin, cyclin D1, CD44, phospho-VEGFR-2 and MMP-9. The antiangiogenic effects of gamma-tocotrienol on HUVECs may be attributable to regulation of Wnt signaling by decreasing beta catenin expression. Thus, our results suggest that gamma-tocotrienol has a potential chemopreventive agent via antiangiogenesis. PMID- 21292466 TI - Green tea (-)-epigallocatechin-3-gallate inhibits HGF-induced progression in oral cavity cancer through suppression of HGF/c-Met. AB - Hepatocyte growth factor (HGF) and c-Met have recently attracted a great deal of attention as prognostic indicators of patient outcome, and they are important in the control of tumor growth and invasion. Epigallocatechin-3-gallate (EGCG) has been shown to modulate multiple signal pathways in a manner that controls the unwanted proliferation and invasion of cells, thereby imparting cancer chemopreventive and therapeutic effects. In this study, we investigated the effects of EGCG in inhibiting HGF-induced tumor growth and invasion of oral cancer in vitro and in vivo. We examined the effects of EGCG on HGF-induced cell proliferation, migration, invasion, induction of apoptosis and modulation of HGF/c-Met signaling pathway in the KB oral cancer cell line. We investigated the antitumor effect and inhibition of c-Met expression by EGCG in a syngeneic mouse model (C3H/HeJ mice, SCC VII/SF cell line). HGF promoted cell proliferation, migration, invasion and induction of MMP (matrix metalloproteinase)-2 and MMP-9 in KB cells. EGCG significantly inhibited HGF-induced phosphorylation of Met and cell growth, invasion and expression of MMP-2 and MMP-9. EGCG blocked HGF-induced phosphorylation of c-Met and that of the downstream kinases AKT and ERK, and inhibition of p-AKT and p-ERK by EGCG was associated with marked increases in the phosphorylation of p38, JNK, cleaved caspase-3 and poly-ADP-ribose polymerase. In C3H/HeJ syngeneic mice, as an in vivo model, tumor growth was suppressed and apoptosis was increased by EGCG. Our results suggest that EGCG may be a potential therapeutic agent to inhibit HGF-induced tumor growth and invasion in oral cancer. PMID- 21292467 TI - Encapsulation of selenium in chitosan nanoparticles improves selenium availability and protects cells from selenium-induced DNA damage response. AB - Selenium, an essential mineral, plays important roles in optimizing human health. Chitosan (CS) is an effective, naturally oriented material for synthesizing nanoparticles with preferable properties such as biocompatibility, biodegradation and resistance to certain enzymes. We have recently shown that cellular exposure to selenium compounds activates ataxia-telangiectasia mutated (ATM)-dependent DNA damage responses, a tumorigenesis barrier. To test whether nanoencapsulation of selenium modulates the cellular response to selenium compounds, the HCT 116 cancerous and the MRC-5 normal cells were treated with Na(2)SeO(3) and methylseleninic acid (MSeA) encapsulated in CS/polyphosphate nanoparticles. Analyses of cellular selenium levels demonstrate that (1) the nanoencapsulation enhances selenium levels in cells after exposure to Na(2)SeO(3) and MSeA (1-10 MUM); (2) cells retained more selenium when treated with Na(2)SeO(3) than with MSeA; (3) selenium levels are greater in HCT 116 than in MRC-5 cells after Na(2)SeO(3), but not MSeA, exposure. Survival analysis shows that CS encapsulation desensitizes HCT 116 and MRC-5 cells to Na(2)SeO(3) or MSeA exposure. Immunofluorescent analysis demonstrates that CS encapsulation attenuates the selenium-induced ATM phosphorylation on Ser-1981, and the extent is greater in HCT 116 than in MRC-5 cells. Our results reveal features of selenium nanoencapsulation in CS, including increased selenium retention in cells and decreased cellular sensitivity and DNA damage response to selenium exposure. PMID- 21292469 TI - The enhancement of the oral bioavailability of gamma-tocotrienol in mice by gamma cyclodextrin inclusion. AB - Cyclodextrin (CD) is widely used in the pharmaceutical and nutritional fields to form an inclusion complex with lipophilic compounds for the improvement of their aqueous solubility, stability and diffusibility under physiological conditions. In this study, we investigated the effect of the gamma-tocotrienol (gammaT3) inclusion complex with CD on its oral bioavailability. Five-week-old C57BL6 mice were fed a vitamin E-free diet for 28 days, followed by the oral administration of 2.79 mg of gammaT3-rich fraction (TRF) extracted from rice bran or the equivalent dose (14.5 mg) of a CD inclusion complex with TRF (TRF/CD). The levels of gammaT3 in sequentially collected plasma were determined by LC-MS/MS. The pharmacokinetic study revealed that the plasma concentrations of gammaT3 were increased and peaked at 6 or 3 h after the oral administration of TRF or TRF/CD, respectively (C(max) values of 7.9+/-3.3 or 11.4+/-4.5 MUM, respectively). The area under the curve of plasma gammaT3 concentration also showed a 1.4-fold increase in the group administered with TRF/CD compared with the TRF-only group. Furthermore, the mice that had received the TRF/CD tended to reduce the endotoxin shock induced by injection with lethal amounts of Escherichia coli lipopolysaccharide, compared with the mice that had received TRF alone. Taken together, our results suggest that the CD inclusion improved gammaT3 bioavailability, resulting in the enhancement of gammaT3 physiological activity, which would be a useful approach for the nutrition delivery system. PMID- 21292468 TI - Caveolae: a regulatory platform for nutritional modulation of inflammatory diseases. AB - Dietary intervention strategies have proven to be an effective means of decreasing several risk factors associated with the development of atherosclerosis. Endothelial cell dysfunction influences vascular inflammation and is involved in promoting the earliest stages of lesion formation. Caveolae are lipid raft microdomains abundant within the plasma membrane of endothelial cells and are responsible for modulating receptor-mediated signal transduction, thus influencing endothelial activation. Caveolae have been implicated in the regulation of enzymes associated with several key signaling pathways capable of determining intracellular redox status. Diet and plasma-derived nutrients may modulate an inflammatory outcome by interacting with and altering caveolae associated cellular signaling. For example, omega-3 fatty acids and several polyphenolics have been shown to improve endothelial cell function by decreasing the formation of ROS and increasing NO bioavailability, events associated with altered caveolae composition. Thus, nutritional modulation of caveolae-mediated signaling events may provide an opportunity to ameliorate inflammatory signaling pathways capable of promoting the formation of vascular diseases, including atherosclerosis. PMID- 21292470 TI - Probiotics as an emerging therapeutic strategy to treat NAFLD: focus on molecular and biochemical mechanisms. AB - Nonalcoholic fatty liver disease (NAFLD) is currently the most common liver disease worldwide, both in adults and in children. NAFLD is characterized by aberrant lipid storage in hepatocytes (hepatic steatosis) and inflammatory progression to nonalcoholic steatohepatitis. Evidences so far suggest that intrahepatic lipid accumulation does not always derive from obesity. Gut microbiota has been considered as a regulator of energy homeostasis and ectopic fat deposition, suggesting its implications in metabolic diseases. Probiotics are live microbial that alter the enteric microflora and have beneficial effects on human health. Although the molecular mechanisms of probiotics have not been completely elucidated yet, many of their effects have proved to be beneficial in NAFLD, including the modulation of the intestinal microbiota, an antibacterial substance production, an improved epithelial barrier function and a reduced intestinal inflammation. Given the close anatomical and functional correlation between the bowel and the liver, and the immunoregulatory effects elicited by probiotics, the aim of this review is to summarize today's knowledge about probiotics in NAFLD, focusing in particular on their molecular and biochemical mechanisms, as well as highlighting their efficacy as an emerging therapeutic strategy to treat this condition. PMID- 21292471 TI - Bidirectional signaling of mammary epithelium and stroma: implications for breast cancer--preventive actions of dietary factors. AB - The mammary gland is composed of two major cellular compartments: a highly dynamic epithelium that undergoes cycles of proliferation, differentiation and apoptosis in response to local and endocrine signals and the underlying stroma comprised of fibroblasts, endothelial cells and adipocytes, which collectively form the mammary fat pad. Breast cancer originates from subversions of normal growth regulatory pathways in mammary epithelial cells due to genetic mutations and epigenetic modifications in tumor suppressors, oncogenes and DNA repair genes. Diet is considered a highly modifiable determinant of breast cancer risk; thus, considerable efforts are focused on understanding how certain dietary factors may promote resistance of mammary epithelial cells to growth dysregulation. The recent indications that stromal cells contribute to the maintenance of the mammary epithelial 'niche' and the increasing appreciation for adipose tissue as an endocrine organ with a complex secretome have led to the novel paradigm that the mammary stromal compartment is itself a relevant target of bioactive dietary factors. In this review, we address the potential influence of dietary factors on mammary epithelial-stromal bidirectional signaling to provide mechanistic insights into how dietary factors may promote early mammary epithelial differentiation to decrease adult breast cancer risk. PMID- 21292472 TI - Evaluation of respiration in compost landfill biocovers intended for methane oxidation. AB - A low-cost alternative approach to reduce landfill gas (LFG) emissions is to integrate compost into the landfill cover design in order to establish a biocover that is optimized for biological oxidation of methane (CH(4)). A laboratory and field investigation was performed to quantify respiration in an experimental compost biocover in terms of oxygen (O(2)) consumption and carbon dioxide (CO(2)) production and emission rates. O(2) consumption and CO(2) production rates were measured in batch and column experiments containing compost sampled from a landfill biowindow at Fakse landfill in Denmark. Column gas concentration profiles were compared to field measurements. Column studies simulating compost respiration in the biowindow showed average CO(2) production and O(2) consumption rates of 107 +/- 14 gm(-2)d(-1) and 63 +/- 12 gm(-2)d(-1), respectively. Gas profiles from the columns showed elevated CO(2) concentrations throughout the compost layer, and CO(2) concentrations exceeded 20% at a depth of 40 cm below the surface of the biowindow. Overall, the results showed that respiration of compost material placed in biowindows might generate significant CO(2) emissions. In landfill compost covers, methanotrophs carrying out CH(4) oxidation will compete for O(2) with other aerobic microorganisms. If the compost is not mature, a significant portion of the O(2) diffusing into the compost layer will be consumed by non-methanotrophs, thereby limiting CH(4) oxidation. The results of this study however also suggest that the consumption of O(2) in the compost due to aerobic respiration might increase over time as a result of the accumulation of biomass in the compost after prolonged exposure to CH(4). PMID- 21292473 TI - Phenotypic spectrum of the tubulin-related disorders and functional implications of disease-causing mutations. AB - A spectrum of neurological disorders characterized by abnormal neuronal migration, differentiation, and axon guidance and maintenance have recently been attributed to missense and splice-site mutations in the genes that encode alpha tubulin and beta-tubulin isotypes TUBA1A, TUBA8, TUBB2B, and TUBB3, all of which putatively coassemble into neuronal microtubules. The resulting nervous system malformations can include different types of cortical malformations, defects in commissural fiber tracts, and degeneration of motor and sensory axons. Many clinical phenotypes and brain malformations are shared among the various mutations regardless of structural location and/or isotype, while others segregate with distinct amino acids or functional domains within tubulin. Collectively, these disorders provide novel paradigms for understanding the biological functions of microtubules and their core components in normal health and disease. PMID- 21292474 TI - The influence of synaptic activity on neuronal health. AB - According to the theory of neuronal health, neurons exist in a spectrum of states ranging from highly resilient to vulnerable. An unhealthy neuron may be rendered dysfunctional or non-viable by an insult that would ordinarily be non-toxic to a healthy neuron. Over the years it has become clear that a neuron's health is subject to dynamic regulation by electrical or synaptic activity. This review highlights recently identified activity dependent signalling events that boost neuronal health through the transcriptional control of pro-apoptotic and anti apoptotic genes, the enhancement of antioxidant defences, and the regulation of mitochondrial and neurotrophic factor availability. Furthermore, activity dependent signals have recently been shown to influence a variety of events specific to individual neurodegenerative diseases, which will also be highlighted. PMID- 21292476 TI - Immunotherapy for treating metastatic colorectal cancer. AB - BACKGROUND: Colorectal cancer remains one of the leading causes of death in the world. Surgery still remains the mainstay of treatment for primary and metastatic colorectal cancer. Immunotherapy used as an adjunct to surgery can play an important role in controlling the spread of tumour. METHODS: The online databases PubMed, Medline, Scirus and Medscape Oncology were used to identify articles of relevance. Keywords included; "Immunotherapy", "Cellular Immunotherapy", "Metastatic Colorectal Cancer", "Monoclonal Antibody" "Tumour Vaccines" and "Adoptive Cell Therapy". The databases search was from the period of June 1995 until May 2010 inclusive. RESULTS: Our understanding of tumour immunology has allowed the development of some successful therapies. Immunotherapy through the use of monoclonal antibodies is an effective adjunct to chemotherapy for metastatic colorectal cancer. Other modalities that are in the stages of development are cellular and conjugated vaccines. However, these vaccines are being experimented in advanced stages of colorectal tumours. CONCLUSION: Colorectal cancer vaccines are being developed for advanced stages of colorectal tumour. However, their use as an early adjunct could potentially limit the spread of tumour or even result in cure. Further trials are required to ensure the safety and efficacy of cellular vaccines against colorectal tumours to allow their use on patients early in their disease presentation. PMID- 21292475 TI - Structure-based systems biology for analyzing off-target binding. AB - Here off-target binding implies the binding of a small molecule of therapeutic interest to a protein target other than the primary target for which it was intended. Increasingly such off-targeting appears to be the norm rather than the exception, rational drug design notwithstanding, and can lead to detrimental side effects, or opportunities to reposition a therapeutic agent to treat a different condition. Not surprisingly, there is significant interest in determining a priori what off-targets exist on a proteome-wide scale. Beyond determining putative off-targets is the need to understand the impact of such binding on the complete biological system, with the ultimate goal of being able to predict the phenotypic outcome. While a very ambitious goal, some progress is being made. PMID- 21292477 TI - Experimental study of wood downdraft gasification for an improved producer gas quality through an innovative two-stage air and premixed air/gas supply approach. AB - This study conducted experiments on three different downdraft gasification approaches: single stage, conventional two-stage, and an innovative two-stage air and premixed air/gas supply approach. The innovative two-stage approach has two nozzle locations, one for air supply at combustion zone and the other located at the pyrolysis zone for supplying the premixed gas (air and producer gas). The producer gas is partially bypassed to mix with air and supplied to burn at the pyrolysis zone. The result shows that producer gas quality generated by the innovative two-stage approach improved as compared to conventional two-stage. The higher heating value (HHV) increased from 5.4 to 6.5 MJ/Nm(3). Tar content in producer gas reduced to less than 45 mg/Nm(3). With this approach, gas can be fed directly to an internal combustion engine. Furthermore, the gasification thermal efficiency also improved by approximately 14%. The approach gave double benefits on gas qualities and energy savings. PMID- 21292478 TI - The biosorption of heavy metals from aqueous solution by Spirogyra and Cladophora filamentous macroalgae. AB - The aim of this research was to develop a low cost adsorbent for wastewater treatment. The prime objective of this study was to search for suitable freshwater filamentous algae that have a high heavy metal ion removal capability. This study evaluated the biosorption capacity from aqueous solutions of the green algae species, Spirogyra and Cladophora, for lead (Pb(II)) and copper (Cu(II)). In comparing the analysis of the Langmuir and Freundlich isotherm models, the adsorption of Pb(II) and Cu(II) by these two types of biosorbents showed a better fit with the Langmuir isotherm model. In the adsorption of heavy metal ions by these two types of biosorbents, chemical and physical adsorption of particle surfaces was perhaps more significant than diffusion and adsorption between particles. Continuous adsorption-desorption experiments discovered that both types of biomass were excellent biosorbents with potential for further development. PMID- 21292479 TI - Use of evolutionary operation (EVOP) factorial design technique to develop a bioprocess using grease waste as a substrate for lipase production. AB - The aim of the present work was to develop a bioprocess using EVOP-factorial design technique employing grease waste as a substrate for the production of lipase. A newly isolated fungal strain of Penicillium chrysogenum was explored for the fermentation process. Solid-state fermentation (SSF) was carried out using grease waste and Czapek-dox medium, supplemented with wheat bran. The yield of lipase was 38 U/ml when SSF was carried out at 32 degrees C for 8 days and grease:wheat bran:Czapek-dox media in 1:1:2 (w/w/v). Different physicochemical parameters affecting the production of lipase were optimized through evolutionary operation (EVOP) factorial design technique and after optimization yield was enhanced up to 46 U/ml at 30 degrees C, pH 7.0 with 1:1:2 (w/w/v) grease waste:wheat bran:Czapek-dox media. Industrial grease waste has never been reported before for the production of industrially important lipase enzyme. PMID- 21292480 TI - Synthesis and evaluation of 2-phenyl-1,4-butanediamine-based CCR5 antagonists for the treatment of HIV-1. AB - We describe the synthesis and potency of a novel series of N-substituted 2-phenyl and 2-methyl-2-phenyl-1,4-diaminobutane- based CCR5 antagonists. Compounds 7a and 12f were found to be potent in anti-HIV assays and bioavailable in the low dose rat PK model. PMID- 21292481 TI - Synthesis of N-alkylated noeurostegines and evaluation of their potential as treatment for Gaucher's disease. AB - The potent and selective inhibitor of beta-glucosidases, noeurostegine, was evaluated as an inhibitor of glucocerebrosidase (GCase) to give an IC(50) value of 0.4 MUM, being 250- and 150-fold better than N-butyl and N-nonyl noeurostegine, respectively. The parent noeurostegine and its N-butyl and N-nonyl alkylated congeners were also tested as pharmacological chaperones against a N370S GCase mutant. Of these, only noeurostegine, was found to increase enzyme activity, which in potency was comparable to that previously reported for isofagomine. PMID- 21292482 TI - Structure and activity relationship of 2-(substituted benzoyl)-hydroxyindoles as novel CaMKII inhibitors. AB - A series of novel 2-substituted-5-hydroxyindoles were synthesized and evaluated for their inhibitory activity against CaMKII. Structure and activity relationship results indicated that potent inhibitory activity could be achieved by modification at the para-position of the phenyl ring of the high throughput screening hit compound 2. Among the prepared compounds, we identified 14 as a novel CaMKII inhibitor with an activity stronger than that of KN-93, a known CaMKII inhibitor. PMID- 21292483 TI - Identification of a new series of non-peptidic NK3 receptor antagonists. AB - The identification and structure-activity relationships of 2-aminomethyl-1-aryl cyclopropane carboxamides as novel NK(3) receptor antagonists are reported. The compound series was optimized to give analogues with low nanomolar binding to the NK(3) receptor and brain exposure, leading to activity in vivo in the senktide induced hypoactivity model in gerbils. PMID- 21292484 TI - Design and synthesis of AApeptides: a new class of peptide mimics. AB - A new family of peptide mimics termed 'AApeptides', which are oligomers of N acylated-N-aminoethyl amino acids, was proposed. The design and efficient synthesis of AApeptides are described. As proof-of-the-concept, we show that AApeptides can inhibit p53/MDM2 protein-protein interaction with significant activity (IC(50)=38 MUM) and specificity. Preliminary data also demonstrates that AApeptides are resistant to enzymatic hydrolysis. With the ease of synthesis and diversification, potent bioactivity, and resistance to proteolysis, the development of sequence-specific AApeptides may expand the potential biomedical applications of peptidomimetics. PMID- 21292485 TI - Immediate conservative breast surgery reconstruction with perforator flaps: new challenges in the era of partial mastectomy reconstruction? AB - INTRODUCTION: Although the use of local flaps in conservative breast surgery (CBS) reconstruction is a reliable technique, little information has been available regarding outcome following the use of perforator flaps. The purpose of this study is to analyze the feasibility, surgical planning and outcome following CBS reconstruction with intercostal artery perforator (ICAP) flap. PATIENTS/METHODS: Thirteen patients underwent CBS reconstructions with an ICAP flap. These flaps were raised from adjacent tissue located on the lateral and thoracic region and based on perforators originating from the costal and muscular segment of the intercostal vessels. The technique was indicated in patients with small/moderate volume breasts. RESULTS: Mean time of follow-up was 32 months. Flap complications were evaluated and information on patient satisfaction were collected. 61.5 percent had tumors located in the lower-outer quadrants and 69.2 percent had tumors measuring 2 cm or less (T1). Complications occurred in 3 patients (23%), including wound dehiscence in 2 patients and fat necrosis in one. All cases were treated by conservative approach with a good result. No flap loss or wound infection were reported. 90 percent were either satisfied or very satisfied with their result. CONCLUSION: The ICAP flap is a reliable technique for immediate CBS reconstruction. The technique is advantageous because it does not require the use of muscle transfer, with minimum donor site morbidity. Success depends on patient selection, coordinated planning with the oncological surgeon and careful intra-operative management. PMID- 21292486 TI - Simultaneous excision of ipsilateral nonpalpable multiple breast lesions using radioguided occult lesion localization. AB - The purpose of this study was to determine the feasibility and effectiveness of ROLL technique for the identification and excision of ipsilateral nonpalpable multiple breast lesions. Between August 2005 and August 2010, eight women, aged 40-61 years, with a radiographic evidence of two separate nonpalpable lesions within the same breast underwent ROLL, as we termed it, double-ROLL. Each lesion was localized with Tc-99m-labeled human serum albumin macroaggregate under ultrasonography or mamography control. A gamma probe was used to guide surgical excisions. There was no radiotracer overlapping or extravasation in any case. Out of the 16 resected specimens, histopathologic examination revealed benign findings in 13 lesions and malignancy in 3. There was no lesion involvement at the surgical margins, and no residuals were detected in any of the benign cases during follow-up. Double-ROLL technique is feasible and safe for the identification and excision of such multiple ipsilateral breast lesions. PMID- 21292487 TI - Development and validity of a new model for assessing pressure redistribution properties of support surfaces. AB - Pressure ulcers are a common problem, especially in older patients. In Japan, most institutionalized older people are malnourished and show extreme bony prominence (EBP). EBP is a significant factor in the development of pressure ulcers due to increased interface pressure concentrated at the skin surface over the EBP. The use of support surfaces is recommended for the prophylaxis of pressure ulcers. However, the present equivocal criteria for evaluating the pressure redistribution of support surfaces are inadequate. Since pressure redistribution is influenced by physique and posture, evaluations using human subjects are limited. For this reason, models that can substitute for humans are necessary. We developed a new EBP model based on the anthropometric measurements, including pelvic inclination, of 100 bedridden elderly people. A comparison between the pressure distribution charts of our model and bedridden elderly subjects demonstrated that maximum contact pressure values, buttock contact pressure values, and bone prominence rates corresponded closely. This indicates that the model provides a good approximation of the features of elderly people with EBP. We subsequently examined the validity of the model through quantitative assessment of pressure redistribution functions consisting of immersion, envelopment, and contact area change. The model was able to detect differences in the hardness of urethane foam, differences in the internal pressure of an air mattress, and sequential changes during the pressure switching mode. These results demonstrate the validity of our new buttock model in evaluating pressure redistribution for a variety of surfaces. PMID- 21292488 TI - A biomechanical comparison of the running gait of mature and young females. AB - BACKGROUND: Due to health and social advantages, the popularity of running among mature female runners is expanding steadily. However, the incidence of running injuries and associated conditions is vast among this group. This study aimed to quantify gait parameters of mature and younger female runners to assess whether certain running characteristics predispose to debilitating conditions. It was hypothesised that mature females would exhibit greater rearfoot eversion, knee internal rotation, knee external adductor moments and loading rate of ground reaction force when compared to younger runners. METHODS: Fifteen mature (40-60 years) and 15 young (18-24 years) females performed 10 running trials at 3.5 m s( 1) in the biomechanics laboratory. Both kinematic and ground reaction force data were collected. Signs of osteoarthritis and knee injuries were assessed using the Knee Osteoarthritis Observation Survey (KOOS) scale. FINDINGS: Mature females produced significantly higher peak rearfoot eversion, knee internal rotation, external adductor moment and loading rate of ground reaction force compared to the young participants (p<0.05). INTERPRETATIONS: Although all participants recorded "symptom free" on the KOOS scale, all variables of gait found higher among the mature group have previously been associated with development of overuse injuries and debilitating conditions, suggesting a possible predisposition towards these conditions among the mature group. PMID- 21292489 TI - Kinetic analysis of stair descent: Part 1. Forwards step-over-step descent. AB - This study examined lower extremity biomechanics during the initiation of stair descent from an upright, static posture. Seventeen healthy subjects (aged 23+/ 2.4 years) descended a five-step, steel-reinforced, wooden laboratory staircase (34 degrees decline). Ten trials of stair descent were separated into two blocks of five trials. Beginning from an upright posture, subjects descended the staircase at their preferred velocity (0.53+/-0.082 m/s) and continued the length of the laboratory walkway (~4 m). Joint mechanics were contrasted between gait cycles. Relative to the initiation cycle at the top of the staircase, the dissipative knee extensor (K3) and hip flexor (H2) moments and powers were independent of progression velocity and approximated steady-state (i.e., constant) values after the first cycle of the trail limb (Step 5 to Step 3). In contrast, a salient relationship was observed between progression velocity and ankle joint mechanics at initial-contact. The plantiflexor moment, power and work at initial-contact (A1) increased with centre of mass velocity. Our results demonstrate that while the knee extensor moment is the primary dissipater of mechanical energy in stair descent, the ankle plantiflexors are the primary dissipaters associated with increased progression velocity. In addition, the results show that steady-state stair descent may not be attained during the first gait cycle of the trail limb. These data shed light on locomotive strategies used in stair descent and can be applied in biomechanical models of human stair gait. Researchers and practitioners should take into consideration the influence of gait cycle and progression velocity when evaluating lower extremity function in stair descent. PMID- 21292490 TI - Predictive factors for early symptomatic recurrence in pilocytic astrocytoma: does angiogenesis have a role to play? AB - We studied predictive factors with respect to angiogenesis and proliferative indices for early symptomatic recurrences in patients with pilocytic astrocytoma (PA). One hundred and eighteen patients who underwent surgery for PA were divided into non-recurrent and early symptomatic recurrence groups to analyze clinicoradiological and immunohistopathological (n=33) parameters. Patients with non-recurrent tumors presented with symptoms for a mean duration of 10.2 +/- 9.1 months while those with recurrent tumors presented slightly earlier (6.9 +/- 4.5 months). Common tumor locations were the cerebellum (38.1%), optic chiasm (27.9%), supratentorial region (19.4%) and brainstem (9.3%). Recurrent tumors were mostly located in the cerebellum (44%) and brainstem (33%). Strong contrast enhancement was noted in 70 (59.3%) tumors, while 48 (40.7%) showed poor contrast. Resection was complete in 53% of patients while near total excision was achieved for the remaining patients. Cellularity and pleomorphism were similar in both groups. Extensive endothelial proliferation was observed in 18.1% of patients while the remainder showed a focal pattern. Diffuse vascular endothelial growth factor (VEGF) expression was observed in 36.3% of patients while 63.6% showed mild-to-moderate focal expression. Endothelial proliferation and VEGF expression were more pronounced in patients with non-recurrent tumors, but this was not statistically significant. MIB-I labeling indices were similar (1-5%) for both groups. Symptomatic recurrences were common in infratentorial PAs. Radiology, histopathology and proliferative indices did not offer any prognostic information. Angiogenesis markers such as endothelial proliferation and VEFG expression did not predict early symptomatic recurrence. Diffuse VEGF expression and endothelial proliferation were observed in tumors that showed strong contrast enhancement. PMID- 21292491 TI - Metal hypersensitivity in total knee arthroplasty: revision surgery using a ceramic femoral component - a case report. AB - We present a case involving the revision of a total knee arthroplasty with a metal femoral component using a ceramic implant due to metal hypersensitivity. A 58-year-old female patient underwent total knee arthroplasty (TKA) with a standard metal bicondylar knee system. She suffered from persistent pain and strong limitations in her range of motion (ROM) associated with flexion during the early postoperative period. Arthroscopic arthrolysis of the knee joint and intensive active and passive physical treatment, in combination with a cortisone regime, temporarily increased the ROM and reduced pain. No signs of low grade infection or other causes of implant failure were evident. Histology of synovial tissue revealed lymphoplasmacellular fibrinous tissue, consistent with a type IV allergic reaction. Allergometry (skin reaction) revealed type IV hypersensitivity against nickel-II-sulfate and palladium chloride. Revision surgery of the metal components was performed with a cemented ceramic femoral component (same bicondylar design) and a cemented titanium alloy tibial component. Postoperative evaluations were performed 10days, and 3 and 12months after the revision surgery. There was an increased ROM in flexion to 90 degrees at the 12month follow-up. No swelling or effusion was observed at all clinical examinations after the revision surgery. No pain at rest and moderate walking pain were evident. The presented case demonstrates that ceramic implants are a promising solution for patients suffering from hypersensitivity to metal ions in total knee arthroplasty. PMID- 21292492 TI - Modulation of the activity of histone acetyltransferases by long chain alkylidenemalonates (LoCAMs). AB - A novel class of KAT modulators (long chain alkylidenemalonates, LoCAMs) has been identified. Variations of the alkyl chain length can change the activity profile from inhibition of both KAT3A/KAT2B (as derivative 2a) to the peculiar profile of pentadecylidenemalonate 1b, the first activator/inhibitor of histone acetyltransferases. Together with the powerful apoptotic effect (particularly notable if considering that anacardic acid and other KAT inhibitors are not cell permeable) appoint them as valuable biological tools to understand the mechanisms of lysine acetyltransferases. PMID- 21292493 TI - Amino-benzosuberone: a novel warhead for selective inhibition of human aminopeptidase-N/CD13. AB - This paper describes the design and synthesis of compounds belonging to a novel class of highly selective mammalian CD13 inhibitors. Racemic homologues of 3 amino-2-tetralone 1 were synthesised and evaluated for their ability to selectively inhibit the membrane-bound, zinc-dependent aminopeptidase-N/CD13 (EC 3.4.11.2). Some of these novel non-peptidic compounds are potent, competitive inhibitors of the mammalian enzyme, with K(i) values in the low micromolar range in spite of their minimal size (MW <200 Da). Moreover, they show an interesting selectivity profile against representative members of the aminopeptidase family, that is leucine aminopeptidase (EC 3.4.11.1), Aeromonas proteolytica aminopeptidase (EC 3.4.11.10) and the aminopeptidase activity of leukotriene A4 hydrolase (EC 3.3.2.6). The amino-benzosuberone derivative 4 is the most promising compound in terms of potency, stability and selectivity. A hypothetical binding mode of 4 to the catalytic zinc and several conserved active site residues is proposed, based on the observed structure-activity relationships, structural insights from aminopeptidase-N homologues of known three-dimensional structure. PMID- 21292494 TI - Brassinin oxidase mediated transformation of the phytoalexin brassinin: structure of the elusive co-product, deuterium isotope effect and stereoselectivity. AB - Brassinin oxidase, a fungal detoxifying enzyme that mediates the conversion of the phytoalexin brassinin into indole-3-carboxaldehyde, is the first enzyme described to date that catalyzes the transformation of a dithiocarbamate group into an aldehyde equivalent. Brassinin is an essential phytoalexin due to its antifungal activity and its role as biosynthetic precursor of other phytoalexins produced in plants of the family Brassicaceae (common name crucifer). In this report, the isolation, structure determination and synthesis of the elusive co product of brassinin transformation by brassinin oxidase, S-methyl dithiocarbamate, the syntheses of dideuterated and (R) and (S) monodeuterated brassinins, kinetic analyses of isotope effects and chemical modifications of brassinin oxidase are described. The reaction of [1'-(2)H(2)]brassinin was found to be slowed by a kinetic isotope effect of 5.3 on the value of k(cat)/K(m). This result indicates that the hydride/hydrogen transfer step preceding brassinin transformation is rate determining in the overall reaction. In addition, the use of (R) and (S)-[1'-(2)H]brassinins as substrates indicated that the hydride/hydrogen transfer step is ca. 88% stereoselective for the pro-R hydrogen. A detailed chemical mechanism of the enzymatic transformation of brassinin is proposed. PMID- 21292495 TI - Synthesis and biological assay of 4-aryl-6-chloro-quinoline derivatives as novel non-nucleoside anti-HBV agents. AB - A series of 4-aryl-6-chloro-quinoline derivatives were synthesized and evaluated for their anti-hepatitis B virus (HBV) activities, namely the abilities to inhibit the secretion of HBV surface antigen (HBsAg), HBV e antigen (HBeAg), and replication of HBV DNA in HepG 2.2.15 cells. Most of the compounds exhibited moderate inhibitory activity against the secretion of HBsAg and HBeAg. Nine compounds (3, 5, 6, 7, 10, 14, 17, 20, 24) showed significant inhibition against HBV DNA replication with IC(50) values in the range of 4.4-9.8 MUM, which were comparative to that of positive control tenofovir. Of them, compounds 10, 17, and 20 had low cytotoxicities, resulting in high SI values, >551.2, >143.7, and >284.5, respectively. PMID- 21292496 TI - Aortic arch replacement with prophylactic aortic arch debranching during type A acute aortic dissection repair: initial experience with 23 patients. AB - OBJECTIVE: To improve the long-term results of acute type A dissection repair, we developed a technique that combines radical surgical resection, and, at the same time, creates a safe and long landing zone for subsequent endovascular procedure on the descending aorta. METHODS: Since November 2006, 23 patients (62 +/- 13 years) underwent aortic arch replacement concomitant with prophylactic debranching of the supra-aortic vessels, with a specially designed arch graft. The technique consists of replacing the ascending aorta and the aortic arch, and, at the same time, relocating the origin of the supra-aortic vessels just above the sinotubular junction creating a long and safe proximal landing zone for subsequent stent-graft deployment. Perfusion was antegrade through the ascending aorta during cooling and through the vascular prosthesis during rewarming. Distal arch anastomosis was performed under moderate hypothermic circulatory arrest for 25 +/- 7 min and antegrade selective cerebral perfusion (46 +/- 14 min). Cardiopulmonary bypass and aortic cross-clamp time were 138 +/- 46 and 63 +/- 22 min. RESULTS: Hospital mortality was 4.3% (1/23). Postoperative morbidity includes five acute renal failures and four lung failures. No major neurological complications were observed. At follow-up (22+/-10 months), survival was 100% and two patients required an endovascular thoracic aorta repair for aneurysmal enlargement. In both cases, the stent grafts were successfully released in the landing zone created at the time of primary repair. CONCLUSIONS: Our technique extends the suitability of endovascular therapies during type A acute dissection repair, creating a long and stable landing zone that allows safe performance of a second endovascular step if needed, both in the short- and long term. PMID- 21292497 TI - IL-6 plays an essential role in neutrophilia under inflammation. AB - In the present study, we explored the involvement of interleukin-6 (IL-6) in neutrophilia under inflammatory conditions. The neutrophil count in the peripheral blood was high in arthritic monkeys, and anti-IL-6 receptor antibody reduced neutrophil counts to normal levels. IL-6 injection into normal monkeys significantly increased neutrophil counts in the blood 3h after injection. The expression of cluster of differentiation (CD) 162 on circulating neutrophils was reduced by IL-6 injection. IL-6 treatment in vitro did not affect CD162 expression on neutrophils from human blood. In IL-6-treated monkeys, IL-8 and granulocyte-macrophage colony-stimulating factor (GM-CSF) levels in plasma were clearly elevated. IL-8 and GM-CSF treatment in vitro reduced cell-surface CD162 expression on human neutrophils, and moreover, increased soluble CD162 expression in the cell supernatant. The addition of IL-6 into human whole peripheral blood induced IL-8 production and reduced CD162 expression on neutrophils. Furthermore, IL-8 and GM-CSF augmented mRNA expression of a disintegrin and metalloprotease like domain 10 (ADAM10) in neutrophils. Knock-down of ADAM10 by siRNA in neutrophil-like HL-60 cells partially reversed the expression of CD162 reduced by GM-CSF and IL-8 on HL-60 cells. In conclusion, IL-6 induced neutrophilia and reduced CD162 expression on neutrophils in inflammation. PMID- 21292498 TI - Blockade of the Ras/MEK/ERK and Ras/PI3K/Akt pathways by statins reduces the expression of bFGF, HGF, and TGF-beta as angiogenic factors in mouse osteosarcoma. AB - The tumor microenvironment plays a critical role in modulating malignant behavior and can dramatically influence cancer treatment strategies. We investigated whether statins inhibit the expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), and transforming growth factor-beta (TGF-beta) mRNA in the mouse osteosarcoma cell line LM8. We found that statins significantly inhibited mRNA expressions of bFGF, HGF, and TGF-beta, and bFGF, HGF, and TGF-beta secretions at concentrations that did not have antiproliferative effects on LM8 cells, but had no effect on the mRNA expression and secretion of VEGF. The inhibition of bFGF, HGF, and TGF beta mRNA expression, and bFGF, HGF, TGF-beta secretions was reversed when geranylgeranyl pyrophosphate (GGPP), an intermediate in the mevalonate pathway, was used in combination with statins. Furthermore, statins reduced the membrane localization of K-Ras, phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2), and phosphorylated Akt. Our research indicates that statins inhibit GGPP biosynthesis in the mevalonate pathway, and then inhibit signal transduction in the Ras/ERK and Ras/Akt pathways, thereby inhibiting bFGF, HGF, TGF-beta expression in LM8 cells. These results suggest that statins are potentially useful as anti-angiogenic agents for the treatment of osteosarcoma. PMID- 21292499 TI - Commensal flora and the regulation of inflammatory and autoimmune responses. AB - The gut microbiota has recently been recognized for its role in immune regulation, and changes in gut microbiota may be the basis for an increased incidence of autoimmune diseases and asthma in developed countries. Beneficial microbes produce factors that are distributed systemically, and therefore can influence peripheral inflammatory responses. Such symbiosis factors are important for the control and resolution of inflammation and autoimmune diseases. Here we discuss immune regulation by recently identified symbiosis factors and how certain environmental factors favor their production and influence the composition of the gut microflora. PMID- 21292500 TI - Microbiotal influence on T cell subset development. AB - The mammalian alimentary tract harbors hundreds of bacterial species that constitute the indigenous microbial flora. The indigenous microbial flora has long been appreciated for its role in host immune system development. Recent reports suggest that components of the microbial flora differentially affect the proportion and number of functionally distinct subsets of T cells in the intestine. Substantial changes in the composition of the microbiota are associated with inflammatory bowel disease. This review will discuss the importance of individual species of microbial flora in the induction of T cell subsets, particularly Th17 cells and regulatory T (Treg) cells in the intestine. PMID- 21292501 TI - The type I interferon system in the development of lupus. AB - The type I interferon (IFN) system induces inhibition of viral replication, but can also activate the innate and adaptive immune system. An important role of the type I IFN system in autoimmune diseases, including lupus, is suggested by the observation that these disorders display a prominent over-expression of type I IFN regulated genes. The development of autoimmune diseases in some individuals treated with IFN-alpha directly supports a pivotal role for this cytokine in breaking tolerance and inducing autoimmune reactions. A genetic setup that promotes type I IFN production and/or response and the presence of endogenous inducers of IFN-alpha production have been described in patients with lupus. Several known environmental risk factors for development of lupus or disease flares may contribute to the ongoing type I IFN production. In the present review we will describe the possible role of the type I IFN system in the lupus disease process. The possible connection between the type I IFN system and some environmental and genetic risk factors for lupus is also discussed. PMID- 21292502 TI - Management of gut inflammation through the manipulation of intestinal dendritic cells and macrophages? AB - Inflammatory bowel diseases (IBDs) including Crohn's disease and ulcerative colitis represent a major challenge to clinicians and immunologists trying to understand why in certain individuals the peaceful coexistence of the commensal microflora and its host breaks down and results in chronic inflammation. Here we summarize the recent progress in our understanding of the organization of the intestinal mononuclear phagocytes with dendritic cells and macrophages of distinct phenotype, origin and function. Finally, we discuss potential strategies to translate the recent findings into the management of chronic inflammation in animal models of IBD. PMID- 21292503 TI - Endovascular management of acute infrarenal aortic thrombosis caused by heparin induced thrombocytopenia in a patient treated with low molecular weight heparin. PMID- 21292504 TI - Anesthetic implications of aneurysmal main pulmonary artery and left pulmonary artery and right pulmonary artery stenosis in a child undergoing main pulmonary artery and right pulmonary artery plasty and atrial septal defect closure. PMID- 21292505 TI - Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs. AB - Animal models for seizures and epilepsy have played a fundamental role in advancing our understanding of basic mechanisms underlying ictogenesis and epileptogenesis and have been instrumental in the discovery and preclinical development of novel antiepileptic drugs (AEDs). However, there is growing concern that the efficacy of drug treatment of epilepsy has not substantially improved with the introduction of new AEDs, which, at least in part, may be due to the fact that the same simple screening models, i.e., the maximal electroshock seizure (MES) and s.c. pentylenetetrazole (PTZ) seizure tests, have been used as gatekeepers in AED discovery for >6 decades. It has been argued that these old models may identify only drugs that share characteristics with existing drugs, and are unlikely to have an effect on refractory epilepsies. Indeed, accumulating evidence with several novel AEDs, including levetiracetan, has shown that the MES and PTZ models do not identify all potential AEDs but instead may fail to discover compounds that have great potential efficacy but work through mechanisms not tested by these models. Awareness of the limitations of acute seizure models comes at a critical crossroad. Clearly, preclinical strategies of AED discovery and development need a conceptual shift that is moving away from using models that identify therapies for the symptomatic treatment of epilepsy to those that may be useful for identifying therapies that are more effective in the refractory population and that may ultimately lead to an effective cure in susceptible individuals by interfering with the processes underlying epilepsy. To realize this goal, the molecular mechanisms of the next generation of therapies must necessarily evolve to include targets that contribute to epileptogenesis and pharmacoresistance in relevant epilepsy models. PMID- 21292506 TI - The mystery of electroencephalography in acute lymphoblastic leukemia. AB - The aim of the study was to evaluate changes in electroencephalogram (EEG) recordings during the course of acute lymphoblastic leukemia (ALL) in children. The study group consisted of 48 children with ALL who underwent a total of 72 EEGs at various stages of the disease. The medical files were reviewed for pertinent clinical data, and the EEGs were evaluated for changes in brain activity. Abnormal background activity was noted in 52.2% of the EEGs done at 1 10 days of therapy, in 43.5% of those done at 10-60 days, and only 4.3% of those done at later stages (p=0.037). These findings, together with earlier reports, suggest that early-stage ALL, even before treatment, may be associated with excessive slow EEG activity, which improves over time. The EEG changes, by themselves, are not an indication of central nervous system leukemia or a predictor of later seizures or other central nervous system involvement. PMID- 21292507 TI - Analysis of 2-[Fluorine-18]-Fluoro-2-deoxy-D-glucose uptake kinetics in PET studies of pulmonary inflammation. AB - Dynamic positron emission tomography (PET) imaging of the lung using the radiotracer 2-[fluorine-18]-fluoro-2-deoxy-D-glucose ((18)F-FDG) is an emerging method to assess noninvasively the metabolic activity of pulmonary inflammatory cells. Nevertheless, because of the distinct functional and structural characteristics of inflamed lung tissue standard methods of (18)F-FDG analysis can be substantially limited and there is no consensus about the best method for quantification of the (18)F-FDG signal for acute or chronic inflammatory lung diseases. This article gives an overview on recent advances in quantitative analysis of (18)F-FDG uptake kinetics in non-neoplastic inflamed lung tissue. PMID- 21292508 TI - HIFU as salvage first-line treatment for palpable, TRUS-evidenced, biopsy-proven locally recurrent prostate cancer after radical prostatectomy: a pilot study. AB - OBJECTIVE: To test high-intensity focused ultrasound (HIFU) as salvage first-line treatment for palpable, TRUS-evidenced, biopsy-proven locally recurrent prostate cancer (CaP) after radical prostatectomy (RP). MATERIALS AND METHODS: Nineteen patients with palpable, TRUS-evidenced, biopsy-proven local recurrence of CaP after RP, unwilling to undergo salvage radiotherapy (SRT), underwent HIFU as a single-session procedure. Pre-, intra-, and postoperative data including early and late complications, and oncologic outcomes (PSA nadir, biochemical recurrence (BCR)-free survival, and need of secondary adjuvant treatment) were prospectively evaluated. Success was defined as PSA nadir <=0.1 ng/ml obtained within 3 months from HIFU. In case of PSA nadir >0.1 ng/ml or PSA increase >=1 ng/ml above the PSA nadir, a biopsy of the treated lesion was performed, and if negative, maximum androgen blockade (MAB) was adopted. In case of positive biopsy, RT was performed. Failure was defined as use of secondary adjuvant treatment (MAB or RT). RESULTS: Median follow-up was 48 months. All cases were performed as overnight procedure. No case of urethrorectal fistula or anastomotic stricture was observed. Two cases of acute urinary retention were resolved with prolonged urethral catheterization. Four cases of stress urinary incontinence were observed; 2 (mild incontinence) were resolved after pelvic floor exercises within 6 months, while 2 cases of severe incontinence required surgical minimally invasive treatment;17/19 patients (89,5%) were classified as success. Two patients failed to show a PSA nadir <0.1 ng/ml. During follow-up, 8/17 patients (47%) were classified as failure, with consequent total rate of failures 10/19 (52.6%). A statistically significant difference was observed in pre-HIFU median PSA (2 vs. 5.45 ng/ml, respectively, P = 0.013) and Gleason score of the RP specimen (P = 0.01) between the success and failure group. CONCLUSIONS: Salvage first-line HIFU for palpable, TRUS-evidenced, biopsy-proven local recurrence of CaP is a feasible, minimally invasive day-case procedure, with an acceptable morbidity profile. It seems to have a good cancer control in the short- and mid term. Patients with lower pre-HIFU PSA level and favorable pathologic Gleason score presented better oncologic outcomes. A prospective randomized trial with an adequate recruitment and follow-up is necessary to confirm our preliminary oncologic results. PMID- 21292509 TI - Polymorphisms of glutathione S-transferase MU and theta, MDR1 and VEGF genes as risk factors of bladder cancer: a case-control study. AB - OBJECTIVE: The present study was aimed at examining the local distribution of GSTM1, GSTT1, MDR1, and VEGF gene polymorphisms as possible risk factors contributing to the development of bladder cancer among the population from Canary Islands, Spain. MATERIALS AND METHODS: The genotypes were determined by PCR-based methods in a hospital-based case-control study consisting of 119 cases and 110 controls. The socio-demographic and clinicopathologic data were collected, including the smoking habits of the population covered in the study. RESULTS: The observed allelic frequencies were (%): GSTM1-GSTT1, (positive) 54 and (null) 46 in cases, and 65 and 35, respectively, in controls (P = 0.144); MDR1 C3435T, (C) 57 and (T) 43 in cases, and 54 and 46, respectively, in controls (P = 0.633); VEGF A2578C, (A) 40 and (C) 60 in cases, and 51 and 49, respectively, in controls (P = 0.221). Among Canary Islands subjects, GSTT1-null genotype appeared as a significant risk factor for bladder cancer (odds ratio (OR) 2.0; 95% confidence interval (CI), 1.0-3.7; P = 0.041), in multivariate analysis adjusted by age and smoking habits. No statistical changes in genotype distribution of GSTM1, MDR1 C3435T, and VEGF A2578C gene polymorphisms were observed between cases and controls. The distribution of the initial clinical stage, clinical grade, or recurrence status was not significantly different among the polymorphic variants in the case group (P = NS). CONCLUSIONS: Subjects with the GSTT1-null genotype might be at an increased risk of bladder cancer in Canary Islands, Spain. However, extensive studies are required for accurate confirmation of these results. PMID- 21292510 TI - Prognostic influence of the third Gleason grade in prostatectomy specimens. AB - BACKGROUND: Gleason grading of prostatic specimens remains as one of the most powerful factors predicting prognosis in patients with prostate cancer. This grading system was created by Donald Gleason about 49 years ago and it takes into account the 2 most prevalent grades in the tumor sample, but it does not consider the presence of a third high grade pattern when it represents less than 5% of the whole radical prostatectomy specimen. OBJECTIVE: The objective of the present study is to determine whether the existence of a third pattern of growth in the radical prostatectomy samples correlates with a shorter recurrence free survival. MATERIAL AND METHODS: We have reviewed 85 consecutive specimens of radical prostatectomy from patients with clinical localized disease. Those who received previous hormonal or radiation therapy were excluded. We have determined the Gleason grade and also the presence of a third higher grade pattern, surgical margins status, capsular, vascular, and lymphatic invasion. We have analyzed whether the existence of this high grade third pattern areas influences prognosis. Recurrence was defined with PSA levels (biochemical recurrence). RESULTS: We have shown that the presence of a Gleason's grade 5 pattern of growth worsens prognosis in patients with tumors grade 7 (both 3 + 4 and 4 + 3), with a shorter time to recurrence. The latter group of patients behaves more like patients with Gleason 8 tumors. This worse prognosis should be taken into account for patient surveillance and future adjuvant therapies. We feel this information is relevant and should be reported in the pathology reports. PMID- 21292511 TI - Robot-assisted laparoscopic partial nephrectomy for tumors greater than 4 cm and high nephrometry score: feasibility, renal functional, and oncological outcomes with minimum 1 year follow-up. AB - OBJECTIVES: Minimally invasive robotic assistance is being increasingly utilized to treat larger complex renal masses. We report on the technical feasibility and renal functional and oncologic outcomes with minimum 1 year follow-up of robot assisted laparoscopic partial nephrectomy (RALPN) for tumors greater than 4 cm. MATERIALS AND METHODS: The urologic oncology database was queried to identify patients treated with RALPN for tumors greater than 4 cm and a minimum follow-up of 12 months. We identified 19 RALPN on 17 patients treated between June 2007 and July 2009. Two patients underwent staged bilateral RALPN. Demographic, operative, and pathologic data were collected. Renal function was assessed by serum creatinine levels, estimated glomerular filtration rate, and nuclear renal scans assessed at baseline, 3, and 12 months postoperatively. All tumors were assigned R.E.N.A.L. nephrometry scores (http://www.nephrometry.com). RESULTS: The median nephrometry score for the largest tumor from each kidney was 9 (range 6-11) while the median size was 5 cm (range 4.1-15). Three of 19 cases (16%) required intraoperative conversion to open partial nephrectomy. No renal units were lost. There were no statistically significant differences between preoperative and postoperative creatinine and eGFR. A statistically significant decline of ipsilateral renal scan function (49% vs. 46.5%, P = 0.006) was observed at 3 months and at 12 mo postoperatively (49% vs. 45.5%, P = 0.014). None of the patients had evidence of recurrence or metastatic disease at a median follow-up of 22 months (range 12-36). CONCLUSIONS: RALPN is feasible for renal tumors greater than 4 cm with moderate or high nephrometry scores. Although there was a modest decline in renal function of the operated unit, RALPN may afford the ability resect challenging tumors requiring complex renal reconstruction. The renal functional and oncologic outcomes are promising at a median follow-up of 22 months, but longer follow-up is required. PMID- 21292512 TI - Expression of pigment epithelium-derived factor and tumor necrosis factor-alpha is correlated in bladder tumor and is related to tumor angiogenesis. AB - OBJECTIVE: Angiogenesis is a pivotal process on which solid tumor growth is substantially dependent. Pigment epithelium-derived factor (PEDF) is the most potent natural anti-angiogenic factor, which has seldom been studied in bladder tumor, and whose functioning pathway remains unclear. We have thus investigated PEDF expression in relation to tumor necrosis factor-alpha (TNF-alpha) and microvessel density (MVD) with immunohistochemistry. METHODS: Antibodies of PEDF and TNF-alpha were examined by Western blotting before immunohistochemistry. Sixty-four urothelial tumor sections and 23 normal controls were stained and expression of PEDF, TNF-alpha, and MVD were studied. RESULTS: Decreased PEDF expression and increased TNF-alpha expression was noticed in tumorous tissue compared with healthy urothelium. Lower PEDF expression was related to higher tumor grade but stage. Increased TNF-alpha expression was noticed in recurrent, larger tumors as well as in tumors with progression in grade and stage. Expression of PEDF and TNF-alpha was correlated in bladder tumor. PEDF or TNF alpha was correlated with MVD negatively or positively, respectively, in cancerous tissue and tumorous grouping without correlation in papillary urothelial neoplasm of low malignant potential. CONCLUSION: Expressional change of PEDF and TNF-alpha is in relation to angiogenesis of bladder tumor, especially in bladder cancer development. PMID- 21292513 TI - Bone formation of block and particulated biphasic calcium phosphate lyophilized with Escherichia coli-derived recombinant human bone morphogenetic protein 2 in rat calvarial defects. AB - The objective of this study was to evaluate bone formation in rat calvarial defects after surgical implantation of block or particulated biphasic calcium phosphate (BCP) lyophilized with Escherichia coli-derived recombinant human bone morphogenetic protein 2 (ErhBMP-2). Critical-size calvarial osteotomy defects were created in 5 groups of Sprague-Dawley rats. Each group received one of the following: 1) sham surgery control; 2) biphasic calcium phosphate particles (CPP); 3) biphasic calcium phosphate block (CPB); 4) ErhBMP-2-coated CPP; or 5) ErhBMP-2-coated CPB. ErhBMP was coated on BCP by a stepwise lyophilizing protocol. The new bone formation was significantly greater in ErhBMP-2-treated groups compared with the untreated group. In particular, the ErhBMP-2/CPB group showed stability of augmented areas during the period of healing, due to relevant space-providing capacity. Thus, it can be concluded that CPP and CPB lyophilized with ErhBMP-2 enhance the formation of new bone, and CPB appears to be a suitable carrier for ErhBMP-2 in which a 3-dimensional structural integrity is an important consideration factor. PMID- 21292514 TI - Condylar resorption and functional outcome after unilateral sagittal split osteotomy. AB - OBJECTIVE: The objective of this study was to evaluate the radiological and functional results of unilateral sagittal split osteotomy (USSO) of the mandible. STUDY DESIGN: Between January 2001 and December 2008, 26 patients underwent USSO to correct laterognathia (isolated USSO in 3 patients and Le Fort I osteotomies in combination with USSO in 23 patients). Radiographs of 23 patients were evaluated for signs of condylar resorption or loss of ramus height; 16 patients were clinically examined and the movement of both condyles was measured with a nontouch device. RESULTS: Unilateral condylar resorption was observed in 1 patient and bilateral signs of resorption with loss of ramus height were observed in a further patient. Mouth opening and protrusion were significantly reduced after surgery (6.06 +/- 6.91 mm, P = .005/0.63 +/- 0.89 mm, P = .020). The selected surgical site, whether left or right, had no influence on laterotrusion or retrusion (P > .05), but patients operated on the right side showed higher values of protrusion on the left side than patients who were operated on the left (mean difference: 3.13 +/- 1.24 mm; P = .038). CONCLUSIONS: USSO appears to be a procedure that can be used in orthognathic surgery, if applied to a certain extent. In this study, there was no evidence of adverse results in terms of condylar resorption or functional outcome when compared with the results of regular bilateral sagittal split osteotomy (BSSO) reported in the literature. To our best knowledge this is the first study in the literature investigating the impact of USSO in orthognathic surgery. PMID- 21292515 TI - Prevalence of apical periodontitis relative to endodontic treatment in an adult Dutch population: a repeated cross-sectional study. AB - OBJECTIVE: We aimed to compare an Amsterdam subpopulation's current prevalence of root canal fillings and associated periapical radiolucencies with a similar patient sample from 1988. STUDY DESIGN: An Amsterdam subpopulation was evaluated for missing teeth, restorations, quality of endodontic treatment, and periapical radiolucency. RESULTS: A total of 178 radiographs were evaluated and 4594 teeth were examined. Of these, 324 (7%) exhibited widening of the apical periodontal ligament or periapical radiolucency and 224 (4.8%) had been endodontically treated. A total of 118 teeth (2.5%) had radiographic signs of apical periodontitis. Of these lesions, 54 (45.7%) were linked to endodontically treated teeth (24.1% of endodontically treated teeth). Inadequate root canal fillings were frequent (55.8%). Apical radiolucency was significantly higher in these teeth than in adequately root-filled teeth. CONCLUSION: Findings indicate that the periapical status in an Amsterdam subpopulation has not improved over almost 2 decades. PMID- 21292516 TI - Three-dimensional computerized tomographic angiography diagnosis and surgical treatment of macroglossia with huge venous malformation: a case report. PMID- 21292517 TI - Calcifications may be a frequent finding in mucoepidermoid carcinomas of the salivary glands: a clinicopathologic study. AB - Calcifications in mucoepidermoid carcinoma (MEC) of the salivary glands are considered to be exceptionally rare and are often associated with high-grade tumors. This study reviewed 30 cases of MECs to access the frequency of calcifications and the clinical profile of the patients and histopathologic aspects of the tumors. In total, 6 cases of calcifications (20%) were identified. Five patients were women and 1 was a man, patients' ages ranged from 22 to 69 years old, and calcifications were found in conventional and clear cell-type MECs. Areas of calcification showed positivity for periodic acid-Schiff and mucicarmine, supporting the hypothesis that they originate from the precipitation of mucous secretion. The presence of calcifications in MECs was independent of the histologic grade of the tumors and the histopathologic variants. Calcifications in salivary MECs may not be as rare as previously mentioned in the literature and may be not associated with high-grade tumors. PMID- 21292518 TI - Correction of zygoma and zygomatic arch protrusion in East Asian individuals. AB - OBJECTIVE: Prominent zygoma is commonly seen in the East Asian population with the clinical characteristics of anteriorly and/or laterally projected zygoma and zygomatic arch resulting in an increased midfacial width. The esthetic surgical modification of zygoma is one of the major aspects of facial-contouring surgery in certain parts of the world. This article aims to evaluate the effectiveness of various surgical methods for reducing the prominent zygoma so as to obtain a harmonious and natural facial contour. METHODS: Surgical approaches, such as zygomatic complex shaving, I-shaped osteotomy, L-shaped osteotomy, and C-shaped osteotomy were used according to the clinical characteristics of zygoma and zygomatic arch protrusion. The corrective effectiveness was then evaluated through cephalometric radiographs, 3D-CT, and pre- and postsurgical standard facial photographs. RESULTS: The zygoma and zygomatic arch protrusion was effectively corrected resulting in improved facial contours in all cases postoperatively. The postoperative period was uneventful except for the slight limitation in mouth opening, which recovered fully after mouth-opening exercises. Serious complications, such as facial nerve injury, were not witnessed in our study. CONCLUSIONS: Malar reduction is an effective and a safe method for the treatment of prominent zygoma. The selection of surgical procedure should be based on different presenting characteristics of zygoma and zygomatic arch protrusion. The correction of prominent zygoma should be designed well, performed precisely, and observed carefully to avoid severe complications so as to achieve a harmonious facial contour. PMID- 21292519 TI - Clinical management of masses arising from the accessory parotid gland. AB - OBJECTIVE: Accessory parotid lesions are clinically rare and its management remains poorly understood. The aim of this study was to analyze the clinical management of accessory parotid lesions. STUDY DESIGN: From April 1999 to November 2008, a retrospective analysis of 32 patients with accessory parotid lesions was performed. The preoperative examinations, surgical treatment, and prognosis were recorded and analyzed. RESULTS: Among the 32 patients, there were 8 men and 24 women with an overall average age of 45 years. These patients always presented without obvious symptoms, and the masses were moderate to hard in hardness without tenderness, mobile, and with clear boundary. The pathologic diagnoses were 24 benign and 8 malignant lesions. Surgery and surgery plus radiotherapy were performed in the patients with benign and malignant lesions, respectively, with good prognosis. CONCLUSIONS: Accessory parotid lesions are rare, and the clinical manifestation is always the same for benign tumors. Surgical resection and surgical resection plus radiotherapy are the primary choices of treatment for benign and malignant lesions, respectively. The prognosis is always good. PMID- 21292520 TI - "All that glitters is not gold": standards for cone-beam computerized tomographic imaging. PMID- 21292521 TI - Coxiella burnetii associated placental lesions and infection level in parturient cows. AB - Cotyledons (n=170) from dairy cattle were analysed for Coxiella burnetii by real time (rt) PCR targeting the IS1111a and icd genes. Positive cases (n=90) and a random selection of negative cases (n=20) were examined by histology, immunohistochemistry and, if infection level was high, by fluorescence in situ hybridisation. PCR results were compared to bulk tank milk (BTM) antibody levels. Placental infection was detected in cows from herds at all BTM antibody levels. However the likelihood of placental infection was generally higher in herds with intermediate or high BMT antibody levels than in herds with low antibody levels. Histological examination revealed a range of mostly mild cotyledonary changes; C. burnetii infection was only rarely associated with inflammation. This may explain why bovine Q fever is usually not clinically apparent. Nevertheless, infected cattle will shed C. burnetii at calving and this can occur even in herds without BTM antibodies. PMID- 21292522 TI - Tenovaginoscopic approach to the common digital flexor tendon sheath of adult cattle: technique, normal findings and preliminary results in four clinical cases. AB - The aim of this study was to describe the tenovaginoscopic approach to the bovine common digital flexor tendon sheath (CDFTS). A comparative anatomical, ultrasonographic and endoscopic study was undertaken using 26 healthy cadaver feet from adult dairy cows. Tenovaginoscopy was performed using a rigid, 30 degrees arthroscope (length 18 cm; outer diameter 4mm) enabling a direct view of the synovial cavity and the following structures: digital flexor tendons, digital annular ligaments, lateral and medial pouches, three mesotendons, the vinculum of the superficial digital flexor tendon, and a slot-shaped opening in the manicaflexoria of the hind feet. Additionally, four clinical cases of septic tenosynovitis treated with lavage under tenovaginoscopic control were examined. Tenovaginoscopy represents a feasible, minimally invasive method for the diagnosis and treatment of septic tenosynovitis of the CDFTS, which allows the degree of alterations of the normal structures to be evaluated. PMID- 21292523 TI - The fish (IMRT) needs a bicycle (MLC)? The bicycle factories seem flourishing; not so the goldfish-bowl factories. AB - In this brief letter the arguments of Sherouse in 2002, that the delivery of intensity-modulated radiation therapy (IMRT) does not necessarily require a multileaf collimator (MLC), are extended with specific reference to the possibility to use the jaws-only (JO) of an accelerator or some moving mask. With reference to the work in the last decade to develop JO IMRT the argument is made that it is not just the limitations of JO that are precluding its commercial development but also the commercial/business and reimbursement situations. A new moving-mask-IMRT technique that has high monitor-unit (MU) efficiency, but low MU per component, is illustrated. The letter is intended to stimulate debate and is not a criticism by the author of current MLC-based IMRT. PMID- 21292524 TI - [Prevalence of diarrhea in critical patients units in Spain: a multicenter study]. AB - INTRODUCTION: Diarrhea is a frequent complication in patients admitted to intensive care and nursing consumes a significant percentage of time for them. Although this is a common condition, the exact size of the problem is unknown. The main objective of this study has been to determine the prevalence of diarrhea in hospitalized patients in critical care units (CCU)in Spain. METHOD: An observational, cross-sectional, prospective and multicenter study including the month of April 2008 on patients in CCUs. Variables recorded were age, gender, diagnosis, severity (Apache II, Sofa), stool frequency and consistency, skin condition, pressure ulcer risk scale according to Norton, average time for hygiene, mortality, associated treatments, diet, mortality. Statistical analysis method: SPSS 14.00. RESULTS: Twenty-five critical care units, to which 2,114 patients were admitted, participated. 162 questionnaires corresponding to different diarrhea episodes of 141 patients were received. Mean prevalence was 6.4% (range 0.01%-30%). Age 59 +/- 14.6 years, 56.7% men. Principal medical diagnoses: Patients with respiratory condition 36 (25.5%), patients with sepsis and multi-organ failure 26 (18.4%) postoperatory patients with varied etiology 21 (14.9%), subarachnoid hemorrhage 15 (10.6%), heart patients 13 (9.2%), polytraumatized patients 12 (8.5%), severe pancreatitis 10 (7.1%), autoimmune diseases 7 (5%) and others (0.7%). Apache II: 12.54 +/- 9 (10). Admission Norton Scale: 9.38 +/- 4 percent. Days of stay 15.9 +/- 9.5, percentage of patients administered sedoanalgesia: 61.7% (we calculated the percentage of each medical treatment over the 162 episodes registered) (some patients received more than one medication simultaneously): morphine (25.5%), benzodiazepines (34.84%), propofol (33.3%), remifentanil (17%), inotropos (38.3%), antibiotics (93.2%), antifungals (41.3%), laxatives (21.6%), selective digestive decontamination (30.2%), enteral nutrition (67.3%), parenteral (24.1%), oral (24.7%). Average frequency of stools per day was 5.3. Consistency was liquid slurry in 59.3% and 40.7% of cases. 4.9% of patients had positive culture for Clostridium difficile. The skin condition was unchanged in 61.7% of cases, stage I lesions (17.9%), stage II lesion (13.6%), stage III lesion (3.7%) and stage IV (2.5%). Average time used for hygiene performed with the diarrhea was 2h 45. Average staff involved was 14 nurses, 14 auxiliaries and 9 guards. To control diarrhea, medication was used (9.9%), pot (1.2%), diapers and absorbent pads (98.1%), fecal collection device (10.5%) and rectal probes (9.3%). CONCLUSIONS: This study has allowed us to determine the prevalence of diarrhea in patients in critical care units. We were able to describe the characteristics of these patients and to establish the presence of skin lesions, the time spent by staff to handle this problem as well as materials used for management. PMID- 21292525 TI - Postoperative radiation therapy after hip replacement in high-risk patients for development of heterotopic bone formation. AB - PURPOSE: To report the results of postoperative radiation therapy in preventing the development of heterotopic bone formation after hip replacement surgery in high-risk patients. PATIENTS AND METHODS: Between 1991 and 2007, 44 patients were preventively treated with postoperative RT after total hip replacement. In total, 47 hips were treated. All patients were considered at high risk for developing heterotopic bone formation. Most patients (63.5%) were treated because of a history of severe osteoarthritis or ankylosing spondylitis. All patients were treated with shaped parallel-opposed fields with a single fraction of 7 Gy using 6 or 18 MV photons. Most patients (94%) received radiation therapy within 72 hours postoperative and in only three patients radiation therapy was delivered after 72 hours post-surgery (5-8 days). RESULTS: Minimum follow-up was 1 year. There were 18 females and 26 males. Median age was 63 years (range: 18-80). Treatments were well tolerated and no acute toxicity was seen post-radiation therapy. Only one of the 47 hips (2%) developed heterotopic bone formation. This patient received postoperative radiation therapy to both hips but only developed heterotopic bone formation in one of them. None of the three patients treated beyond 72 hours failed. To date no late toxicity has been observed. CONCLUSION: The use of postoperative radiation therapy was an effective and safe treatment in the prevention of heterotopic bone formation in a high-risk group of patients undergoing total hip replacement. PMID- 21292526 TI - [Assisted reproductive technique for an opiates dependant couple]. AB - The aim of our network "Motherhood and Addiction Alsace" is to take care of opiates addicted pregnant women in order to permit the birth of a healthy child, raised by stabilized parents both on drug use and psychosocial status. A couple, both on methadone treatment, with chronic hepatitis for the husband had access to an in vitro fertilization program thanks to the network care. The difficulties on the path to parenthood, the adequate use of painkillers, neonatal care and the use of a coordinated action of all health professionals are discussed. PMID- 21292527 TI - [Rudimentary horn pregnancy: an unusual cause of spontaneous hemoperitoneum during the second-trimester of pregnancy]. AB - Spontaneous hemoperitoneum during pregnancy is an unusual but serious event. We report a case of profuse spontaneous hemoperitoneum resulting from the rupture of a non-communicating rudimentary uterine horn at 26 weeks of gestation. An emergency laparotomy was performed and a 900 g birth weight safe infant was delivered. We performed a hemi-hysterectomy in the same time. Fetal and maternal outcomes resulted without complication. Causes of spontaneous hemoperitoneum are discussed. PMID- 21292528 TI - [Pre-eclampsia and facial paralysis]. AB - We describe here the case of a patient affected with pre-eclampsia and who had idiopathic facial palsy and HELLP syndrome during the puerperium. It developed favourably with a treatment associated with an antihypertensive medicine, corticoid therapy and ophtalmological care. There is an association between pre eclampsia and idiopathic facial palsy during pregnancy. This can be explained by identical physiopathological mechanisms. Facial palsy generally appears in the course of the third trimester of pregnancy or during the early puerperium. The prognosis is usually good and does not seem to be influenced by pregnancy. When idiopathic facial palsy appears during pregnancy, evidence of pre-eclampsia must be looked for. PMID- 21292529 TI - Facile stereoslective synthesis of spiro[indole-oxiranes] by combination of phase transfer catalyst and ultrasound irradiation and their bioassay. AB - An alternative and environmentally benign pathway for diastereoslective synthesis of fluorinated spiro[indole-3,2'-oxirane]-3'-benzoyl-2(1H)-ones (2a-g) is reported. The spiro[indole-3,2'-oxiranes] derivatives were obtained in 90-97% yield exclusively via the epoxidation of 3-aroylmethylene indole-2-ones with 30% aqueous hydrogen peroxide using cetyltrimethyl ammonium bromide as a phase transfer catalyst under ultrasound irradiation. The lead compounds have been tested for their antimicrobial activity and antioxidant properties. PMID- 21292530 TI - Benign hereditary chorea: an update. AB - Benign hereditary chorea (BHC, MIM 118700) is a rare autosomal dominant disorder manifesting with chorea in conjunction with hypothyroidism and respiratory problems, a triad also named "brain-lung-thyroid syndrome". BHC is characterized by childhood onset with minimal or no progression into adult life and normal cognitive function. The genetic basis of BHC has been partially resolved, when mutations in the TTF1 gene on chromosome 14q13 encoding the thyroid transcription factor-1 have been identified in a number of BHC patients, suggesting that aberration of TTF1 transcriptional function or haploinsufficiency is associated with this disorder. TTF1 (also known as TITF1, TEBP or NKX2-1), belonging to the NKX2 homeodomain transcription factor family, has been implicated in several important molecular pathways essential for brain, thyroid and lung morphogenesis. Clinical evaluation of TTF1 gene mutations carrier patients exposed the involvement of each of the triad's components characterized by heterogeneity between index cases and even within families. This review highlights the current updates on expanded clinical aspects of BHC, imaging and treatment experience, its genetic markers, proposed molecular mechanisms, animal models and link to cancer. PMID- 21292531 TI - Anxiety and self-perceived health status in Parkinson's disease. AB - Both anxiety and depression are associated with lower self-perceived health status (HS) in persons with Parkinson's disease (PD). Given the high co-morbidity with depression and other non-motor symptoms, it is unclear whether anxiety disorders, in general, versus specific anxiety subtypes have an independent effect on HS in PD. To examine this question, comprehensive assessments of motor and non-motor symptoms from 249 subjects with idiopathic PD followed in three community-based movement disorders neurology practices were analyzed. HS was measured using the 8-item PD Questionnaire (PDQ-8). Psychiatric diagnoses were established by consensus using a panel of six psychiatrists with expertise in geriatric psychiatry and movement disorders. Stepwise multiple regression analyses were used, with the PDQ-8 score as the dependent variable, to identify independent predictors of HS among motor, psychiatric, and other non-motor variables. Among the anxiety disorders, only anxiety associated with motor fluctuations was an independent predictor of HS after accounting for co-morbid depression and other clinical features. In addition, depressive disorders were also an independent predictor of lower HS. Prevention or treatment of state dependent anxiety may improve HS in persons with PD. PMID- 21292532 TI - Authors' reply to the comments of Miyamoto et al. regarding "Cardiac (123)I-MIBG accumulation in Parkinson's disease differs in association with REM sleep behavior disorder". PMID- 21292533 TI - Female-headed households contending with AIDS-related hardship in rural South Africa. AB - Mainstream research and the popular media often equate female-headship with household vulnerability, crisis, and disorganization. Epidemic levels of HIV/AIDS in some parts of sub-Saharan Africa compound this portrait of hopelessness. In South Africa, the impact of HIV/AIDS on households depends on race, class, and place. As female-headed households increase in number, we need to better understand how female-heads in poor rural areas contend with AIDS related challenges. We analyze qualitative interviews with 16 female heads and the members of their households in a rural community to examine the response to AIDS related illness, death, or caring for orphaned children. Our analysis examines female-heads' financial and social resources and how these resources buffer against hardship in households affected by AIDS. We find considerable heterogeneity among rural female-headed households and their access to resources to combat AIDS-related hardship. Our findings have important policy implications both in terms of identifying individual and household vulnerabilities as well as leveraging the potential for resilience for female-heads in rural South African communities. PMID- 21292534 TI - Geography of suicide in Taiwan: spatial patterning and socioeconomic correlates. AB - In industrialised Western nations suicide rates tend to be high in inner city areas and socially fragmented neighbourhoods. Few studies have investigated spatial variations in suicide in non-Western settings. We estimated smoothed standardised mortality ratios (1999-2007) for suicide for each of the 358 Taiwanese districts (median population aged 15+: 27,000) and investigated their associations with area characteristics using Bayesian hierarchical models. The geographic distribution of suicide was similar in men and women; young people showed the greatest spatial variation in rates. Rates were highest in East Taiwan, a mostly mountainous rural area. There was no evidence of above average rates in large cities. Spatial patterns of method-specific suicide rates varied markedly, with solids/liquids poisonings showing the greatest geographic variation and hangings the least. Factors most strongly associated with area suicide rates were median household income, population density and lone-parent households. Spatial patterning of suicide in Taiwan differed from that observed in Western nations. Suicide prevention strategies should take into account unique local patterns. PMID- 21292535 TI - Circadian rhythm of cortisol and neighborhood characteristics in a population based sample: the Multi-Ethnic Study of Atherosclerosis. AB - Although stress is often hypothesized to contribute to the effects of neighborhoods on health, very few studies have investigated associations of neighborhood characteristics with stress biomarkers. This study helps address the gap in the literature by examining whether neighborhood characteristics are associated with cortisol profiles. Analyses were based on data from the Multi Ethnic Study of Atherosclerosis Stress study, which collected multiple measures of salivary cortisol over three days on a population based sample of approximately 800 adults. Multilevel models with splines were used to examine associations of cortisol levels with neighborhood poverty, violence, disorder, and social cohesion. Neighborhood violence was significantly associated with lower cortisol values at wakeup and with a slower decline in cortisol over the earlier part of the day, after sociodemographic controls. Associations were weaker and less consistent for neighborhood poverty, social cohesion, and disorder. Results revealed suggestive, though limited, evidence linking neighborhood contexts to cortisol circadian rhythms. PMID- 21292536 TI - Neighbourhood deprivation and physical activity in UK older adults. AB - The benefits of regular physical activity for older adults are now well established but this group remain the least active sector of the population. In this paper, the association between levels of neighbourhood deprivation and physical activity was assessed. A sample of 125 males with a mean age of 77.5 (+/ 5.6) years, and 115 females with a mean age of age 78.6 (+/-8.6) underwent 7-day accelerometry, a physical performance battery, and completed a daily journeys log. Univariate associations between physical activity parameters and level of deprivation of neighbourhood were extinguished in regression models controlling for age, gender, and level of educational attainment. Age, gender, educational attainment, body mass index, physical function, and frequency of journeys from the home explained between 50% and 54% of variance in activity parameters. These results suggest the importance of strategies to help older adults maintain physical function, healthy weight, and remain active in their communities. PMID- 21292537 TI - Knowledge and use of craniovertebral instability testing by Australian physiotherapists. AB - Internationally, manual therapy has moved towards formalised guidelines for pre manipulative screening of the cervical spine. A controversial aspect to emerge from this involves craniovertebral instability (CVI) testing. This study examined current practice, knowledge and attitudes of Australian physiotherapists regarding pre-manipulative testing for CVI. Members of Musculoskeletal Physiotherapy Australia were surveyed by formally validated questionnaire. Sub group analysis was performed by post-graduate musculoskeletal qualification. The response rate was 37.8%. Respondents provided differing definitions of CVI; 46.5% describing loss of anatomical integrity and 24.9% a biomechanical problem. Over half indicated they rarely or never used stress tests for CVI screening. Of 42 published signs and symptoms associated with CVI, seven were identified by more than 50% of respondents. Of published disorders associated with CVI, four were considered worthy of testing by more than 30% of respondents. Support for inclusion of information on CVI in pre-manipulative guidelines was given by 87% of respondents. Recommendations for screening tests received less support, particularly among physiotherapists holding post-graduate musculoskeletal qualifications (p = 0.0002). These results indicate disagreement regarding the nature and presentation of CVI. Clinical testing is inconsistent, reflecting underlying confusion about CVI. Currently, there is not an appropriate level of knowledge or willingness to recommend guidelines for CVI screening. PMID- 21292538 TI - The intermediate effect in clinical case recall is present in musculoskeletal physiotherapy. AB - Previous research into medical expertise has shown that expert physicians perform significantly better than non-experts when providing a diagnosis for a clinical case. By contrast, when asked to recall the details of the case, individuals of intermediate level of expertise (typically, final-year students) obtain better results than novices and experienced physicians, a phenomenon called the "intermediate effect". However, this effect has not been documented outside of internal medicine and dentistry. The aim of this paper was to investigate the possibility that the intermediate effect in clinical case recall exists in musculoskeletal physiotherapy. 40 participants (sport science students, musculoskeletal physiotherapy students and expert musculoskeletal physiotherapists) were assigned to four groups based upon their experience in musculoskeletal physiotherapy (control group with no experience, novices, intermediates and experts). Participants were instructed to read a case study, provide a diagnosis, justify this diagnosis, and recall the case study. It was found that the quality of diagnosis and the number of high-level inferences increased with expertise. By contrast, recall performance followed an inverted U curve, with the best recall being obtained by intermediates. Thus, the intermediate effect is present in musculoskeletal physiotherapy, despite clear differences in the way medicine and musculoskeletal physiotherapy are taught. PMID- 21292539 TI - Representing multiple objects as an ensemble enhances visual cognition. AB - The visual system can only accurately represent a handful of objects at once. How do we cope with this severe capacity limitation? One possibility is to use selective attention to process only the most relevant incoming information. A complementary strategy is to represent sets of objects as a group or ensemble (e.g. represent the average size of items). Recent studies have established that the visual system computes accurate ensemble representations across a variety of feature domains and current research aims to determine how these representations are computed, why they are computed and where they are coded in the brain. Ensemble representations enhance visual cognition in many ways, making ensemble coding a crucial mechanism for coping with the limitations on visual processing. PMID- 21292540 TI - Iron-containing transcription factors and their roles as sensors. AB - Iron-binding transcription factors are widespread throughout the bacterial world and to date are known to bind several types of cofactors, such as Fe2+, heme, or iron-sulfur clusters. The known chemistry of these cofactors is exploited by transcription factors, including Fur, FNR, and NsrR, to sense molecules such as Fe2+, gases (e.g. oxygen and nitric oxide), or reactive oxygen species. New structural data and information generated by genome-wide analysis studies have provided additional details about the mechanism and function of iron-binding transcription factors that act as sensors. PMID- 21292541 TI - Surgery-triggered and non surgery-triggered Bisphosphonate-related Osteonecrosis of the Jaws (BRONJ): A retrospective analysis of 567 cases in an Italian multicenter study. AB - Invasive local procedures are often reported in clinical history of patients suffering from Bisphosphonates-Related Osteonecrosis of the Jaws (BRONJ) but over 40% of spontaneous forms have been also described in literature. We compared age, gender, underlying bone disorders, bisphosphonate therapy, clinical features and surgical outcome of 205 cases (36.2%) of BRONJ non surgery-triggered (group 1) with 362 (63.8%) cases of surgery-triggered forms (group 2). Differences between group 1 and 2 were analysed using Mann-Whitney U and chi(2) tests. Statistical analysis was performed using STATA 8. Zoledronate was the most used type of bisphosphonate (63.4% versus 69.0%) and the mandible was the most frequently involved site (63.9% versus 63.4%) in both groups. BRONJ in group 1 was more frequently multicentric (9.3% versus 5%, p<0.05), had a lower clinical stage (45.9% versus 13.8% in stage 1, p<0.01) and had a better outcome after surgical therapy (improvement in 74.1% versus 58.6%, p<0.05). The high prevalence of non surgery-triggered forms of BRONJ should be considered by oncologists, haematologists and general physicians who are advised to inform their patients regarding the importance of preventive dental protocols to control the possible causes of osteonecrosis not related to dental invasive procedures. PMID- 21292542 TI - MicroRNA let-7a represses chemoresistance and tumourigenicity in head and neck cancer via stem-like properties ablation. AB - Head and neck cancer (HNC) is a prevalent cancer worldwide. Let-7 has been shown to function as a tumour suppressor by regulating multiple oncogenic signalling pathways. However, the role of let-7 in head and neck cancer (HNC) and in HNC associated tumour initiating cells (TIC) remains unclear. In this study, we first demonstrated that let-7a expression was significantly decreased but that Nanog/Oct4 expression was increased in HNC tissues as compared to adjacent normal cells. Expression of let-7a in recurrent HNC tissue and in regional metastatic lymph nodes of HNC patients was also significantly decreased, but Nanog/Oct4 expression was increased as compared to the expression levels in the parental tumours. Consistently, the stemness genes were significantly up-regulated and let 7a was down-regulated in HNC-ALDH1(+) cells relative to HNC-ALDH1(-) cells. Furthermore, lentiviral-mediated let-7a overexpression could significantly inhibit the stemness signature and the chemoresistant abilities of HNC-ALDH1(+) cells. Most importantly, overexpression of let-7 or knockdown of Nanog in ALDH1(+) cells effectively blocked tumour metastasis and significantly prolonged survival time in ALDH1(+)-transplanted immunocompromised mice. Overall, restoration of let-7a in HNC and HNC-TIC may be a new approach for the therapeutic treatment of HNC in the future. These results show that let-7a negatively modulates the expression of stemness genes and plays a role as a tumour suppressor in HNC by eliminating the putative HNC-TIC population. PMID- 21292543 TI - Phase variation: how to create and coordinate population diversity. AB - Phase variation yields phenotypic heterogeneity in a clonal population as the result of one of a limited number of known molecular mechanisms. These include slipped strand mispairing, site-specific recombination and epigenetic regulation mediated by DNA methylation. Recently new regulatory variants utilizing these mechanisms have been identified, which is facilitating the identification of additional phase variation events solely from genome sequence analysis. Furthermore, it is becoming increasingly clear that in many cases phase variation control is integrated with regulatory networks and with cellular processes of a growing cell. This review focuses specifically on these recent advances in the understanding of the regulation of phase variation. PMID- 21292544 TI - Spectroscopy study on the noncovalent interactions in the binary and ternary systems of L-lysine, adenosine 5'-triphosphate and magnesium ions. AB - Intermolecular interactions of adenosine 5'-triphosphate (ATP) with Lysine (Lys) and Mg(2+) were studied in aqueous solution by (1)H and (31)P NMR spectra. In the metal-free system, the N-1 atom of the purine ring of ATP and carboxyl group of Lys are the interaction sites at low pH conditions. With increasing pH, the interaction efficiency between the phosphate group of ATP and the protonated ammonium group of Lys increased significantly, while that with carboxyl group in Lys decreased. In the Mg(2+)-Lys-ATP system, multi-interactions, such as coordination, cations (Mg(2+), NH(3)(+))-pi, hydrogen bonding, ion-pairing interactions and electrostatic interactions co-existed. In addition, the recognition of ATP by the amino acid cation (Lys) was significantly promoted by the addition of magnesium ion, which led to the coordination competition between Lys and ATP. PMID- 21292545 TI - Critical evaluation of a handheld Raman spectrometer with near infrared (785nm) excitation for field identification of minerals. AB - Handheld Raman spectrometers (Ahura First Defender XL, Inspector Raman DeltaNu) permit the recording of acceptable and good quality spectra of a large majority of minerals outdoors and on outcrops. Raman spectra of minerals in the current study were obtained using instruments equipped with 785 nm diode lasers. Repetitive measurements carried out under an identical instrumental setup confirmed the reliability of the tested Raman spectrometers. Raman bands are found at correct wavenumber positions within +/-3 cm(-1) compared to reference values in the literature. Taking into account several limitations such as the spatial resolution and problems with metallic and black and green minerals handheld Raman spectrometers equipped with 785 nm diode lasers can be applied successfully for the detection of minerals from the majority of classes of the mineralogical system. For the detection of biomarkers and biomolecules using Raman spectroscopy, e.g. for exobiological applications, the near infrared excitation can be considered as a preferred excitation. Areas of potential applications of the actual instruments include all kind of common geoscience work outdoors. Modified Raman systems can be proposed for studies of superficial or subsurface targets for Mars or Lunar investigations. PMID- 21292546 TI - Transforming healthcare with information technology in Japan: a review of policy, people, and progress. AB - PURPOSE: Healthcare reform as part of the economic recovery plan in Japan is placing emphasis on the use of healthcare information technology (HIT). This research mainly focuses on the HIT efforts in Japan with reference to the US for context. The purpose is to: (a) provide detail on governmental policy impacting promotion of HIT adoption to provide services to the people of Japan, (b) describe the outcomes of past and present policy impacting progress based on a case study of HIT use in the Kyoto Yamashina area, and (c) discuss issues for refinement of current policy. METHODS: The method is case study, and data collection techniques include: (a) interviews of people involved in policy making for HIT in Japan (Japanese healthcare professionals, government officials, and academics involved in HIT research in Japan) and use in the medical community of HIT in the Kyoto Yamashina area, (b) archived document analysis of reports regarding government policy for HIT policy and user assessment for HIT mainly in the case study site, and (c) the literature review about HIT progression and effectiveness assessments to explore and describe issues concerning the transformation with HIT in Japan. RESULTS: This study reveals the aspects of governmental policy that have been effective in promoting successful HIT initiatives as well as some that have been detriments in Japan to help solve pressing social issues regarding healthcare delivery. For example, Japan has stipulated some standardized protocols and formats for HIT but does not mandate exactly how to engage in inter-organizational or intra-organizational health information exchange. This provides some desired autonomy for healthcare organizations and or governments in medical communities and allows for more advanced organizations to leverage current resources while providing a basis for lesser equipped organizations to use in planning the initiative. The insights gained from the Kyoto Yamashina area initiative reflect the success of past governmental policy efforts and the current intent to promote HIT adoption. Insights from the case study as well as other social issues facing Japan warrant some refinement of policy. The refinement concerns: (a) the necessity for leadership and IT knowledge in the medical communities, (b) provider incentives, (c) legislation regarding accountability, security, privacy and confidentiality, (d) inclusion of stakeholders in solution development, and (e) creating sustainable business models. CONCLUSION: The research highlights the efforts of Japan for using HIT in healthcare reform. We present outcomes from a case study of the Kyoto Yamashina area medical community as proof of concept for past and present policy in Japan that are insightful for proliferation of successful projects in Japan and adoption of HIT in general. PMID- 21292547 TI - A case of a girl presenting with fever, cytopenia, liver dysfunction, hepatosplenomegaly, and hemophagocytosis in the bone marrow. PMID- 21292548 TI - Clinical evaluation of a fully automated CMV PCR assay. AB - BACKGROUND: There is a growing need for sensitive high-throughput cytomegalovirus (CMV) PCR tests due to the increasing number of immunocompromised patients requiring monitoring for active CMV infection. OBJECTIVES: To compare the fully automated COBAS((r)) AmpliPrep/COBAS((r)) TaqMan((r)) (CAP/CTM) CMV test (this test is currently under development and not commercially available) for EDTA plasma to the reference method COBAS((r)) AMPLICOR CMV MONITOR. STUDY DESIGN: A prospective feasibility study with parallel analysis of 433 EDTA-plasma samples from 277 patients on both systems was carried out after the analytical performance of the new system had been assessed. RESULTS: The new system has a wide linear range from 2.0 to 7.3 log(10) CMV-DNA copies/ml EDTA-plasma and a detection limit of 46 copies/ml with excellent accuracy and precision. When testing clinical samples, the CAP/CTM CMV test compared extremely well with the COBAS((r)) AMPLICOR CMV MONITOR (R(2)=0.93, p<0.001) with increased sensitivity and linear range. Discrepant samples all contained low titers of CMV-DNA. In two of the study patients, CMV-DNAemia was detected by the CAP/CTM CMV test up to eight weeks earlier than by COBAS((r)) AMPLICOR CMV MONITOR. CONCLUSION: An IVD/CE marked version of the CAP/CTM CMV test will enable laboratories to provide a sensitive, fully automated high-throughput CMV PCR. PMID- 21292549 TI - EEG and MEG in mesial temporal lobe epilepsy: where do the spikes really come from? AB - OBJECTIVE: There is persistent debate as to whether or not EEG and MEG recordings in patients with mesial temporal lobe epilepsy (MTLE) can detect mesial temporal interictal epileptiform discharges (spikes), and this issue is particularly relevant for source localization studies. With the aim of providing direct evidence pertinent to this debate we present detailed examples of the intracranial sources of spikes recorded with EEG and MEG in MTLE. METHODS: Spikes recorded in five different patients with MTLE during intracranial EEG (n=2), intraoperative electrocorticography (ECOG; n=1), combined scalp-intracranial EEG (n=2) and combined EEG-MEG (n=1) were analyzed and the intracranial sources of the spike foci were matched with their corresponding extracranial EEG and/or MEG fields. EEG and MEG dipole source localization was performed on six independent spike foci identified in one representative patient with bilateral MTLE. RESULTS: Spikes with an electrical field maximal at F7/8, F9/10>=T3/4 were generated in the anterolateral temporal neocortex. The absence of coincident spiking at mesial locations indicated that these were not propagated from or to the hippocampus. Spikes with an electrical field maximal at T3/4>=T9/10 were generated in the lateral temporal neocortex and likewise did not involve the hippocampus. Individual spikes generated in the mesiobasal temporal neocortex, including the fusiform gyrus, were difficult to detect with EEG (low amplitude diphasic waves most apparent after spike averaging at T3/4, T9/10>=T5/6, P9/10) and only slightly more identifiable with MEG. Spikes generated within and confined to the mesial temporal structures, as confirmed by intracranial recordings, could not be detected with EEG or MEG. Notably, such spikes could not be detected even at intracranial recording sites on the lateral surface of the temporal lobe. CONCLUSIONS: We present detailed evidence in a small case series showing that typical anterior temporal spikes recorded with EEG and MEG in MTLE arose from the anterolateral temporal neocortex and were neither propagated from nor to the hippocampus. Mid temporal EEG spikes were localized to the lateral temporal neocortex. Intracranially detected mesial temporal spikes were not detected with EEG or MEG. SIGNIFICANCE: The spikes recorded with EEG and MEG in MTLE are localized to neocortical foci, and not to the mesial temporal structures. Current noninvasive EEG and MEG source localization studies cannot accurately identify true mesial temporal spikes. PMID- 21292550 TI - Subcortical stimulation (mapping) of the corticospinal tract. PMID- 21292551 TI - Optimization of medium components and cultural variables for enhanced production of acidic high maltose-forming and Ca2+-independent alpha-amylase by Bacillus acidicola. AB - The production of acidic alpha-amylase by a novel acidophilic bacterium Bacillus acidicola TSAS1 was optimized in submerged fermentation using statistical approaches. The process parameters that significantly affected alpha-amylase production (starch, K(2)HPO(4), inoculum size and temperature) were identified by Plackett and Burman design. The optimum levels of the significant variables as determined using central composite design of response surface methodology are starch (2.75%), K(2)HPO(4) (0.01%), inoculum size [2% (v/v) containing 1.9*10(8) CFU ml(-1)], and temperature (33 degrees C). An overall 2.4 and 2.9-fold increase in enzyme production has been attained in batch and fed-batch fermentations in the laboratory fermentor, respectively. PMID- 21292552 TI - High risk of obstructive sleep apnea is a risk factor of death censored graft loss in kidney transplant recipients: an observational cohort study. AB - OBJECTIVES: Obstructive sleep apnea (OSA) is associated with increased risk of cardiovascular morbidity in the general population. The clinical significance of OSA among kidney transplant patients is unknown. Our aim was to investigate the association of "high risk of OSA" with death-censored graft loss and mortality in a large cohort of kidney transplant recipients. PATIENTS AND METHODS: Using the Berlin questionnaire 1067 prevalent kidney transplant recipients were assessed for risk of OSA. Socio-demographic variables, laboratory parameters and data about graft loss and mortality were obtained from the medical records. Multivariable-adjusted associations of OSA risk with graft loss and with all cause mortality was assessed in competing-risks regression models. RESULTS: Of the 823 patients who completed the Berlin questionnaire 28% had high risk of OSA (HRO) at baseline. Patients with HRO were older (52+/-11 vs. 47+/-13years, p<0.001), had a higher prevalence of diabetes (22 vs. 15%, p=0.018), worse baseline kidney function (estimated glomerular filtration rate: 46+/-18 vs. 51+/ 19ml/min/1.73m(2), p=0.001) and higher BMI (27+/-5 vs. 24+/-4kg/m(2), p<0.001). In multivariate models HRO was an independent predictor of graft loss among females after adjusting for age, comorbidity, hypertension, BMI, kidney function, duration of chronic kidney disease, other laboratory parameters and transplant related data (HR=3.05; CI: 1.24-7.51; p=0.015), while HRO did not predict graft survival among males. HRO at baseline was not independently associated with all cause mortality in the sample. CONCLUSION: High risk of OSA is an independent predictor of graft loss among female kidney transplant patients. PMID- 21292553 TI - A motivational school-based intervention for adolescent sleep problems. AB - OBJECTIVE: The current study aimed to develop and evaluate a motivational school based intervention for adolescent sleep problems. METHODS: The intervention was implemented in three co-educational secondary schools in Adelaide, South Australia. Two year-11 Psychology classes from each school participated, with one as the intervention class (N=53) and one as the control class (N=51). Students in the intervention classes attended four 50-min sleep education classes, held once per week. The lessons were modified from those of Moseley and Gradisar [23] to incorporate a motivational interviewing framework. Students completed an online questionnaire battery measuring school day and weekend sleep parameters, daytime sleepiness, and depression at pre- and post-program and follow-up, and completed motivation to change questionnaires during the program. RESULTS: Students in the intervention group significantly increased their knowledge about sleep relative to the control group (p=0.001). During the intervention, students' motivation to regularize their out-of-bed times improved (p=0.03), and there was a trend towards improved motivation to increase average total sleep time (p=0.11). But despite improvements in sleep and daytime functioning for adolescents in the program group (p<0.05), these changes were not significantly different from the control group (all p>0.05). CONCLUSIONS: School-based interventions are promising for educating adolescents about sleep. Future programs should translate increased motivation into long-term behavioral change. The identification of barriers and support to assist this change is recommended. PMID- 21292554 TI - Characterization of FarR as a highly specialized, growth phase-dependent transcriptional regulator in Neisseria meningitidis. AB - Transcriptional regulators play an important role for the survival of Neisseria meningitidis within its human host. We have recently shown that FarR acts as transcriptional repressor of the adhesin nadA in N. meningitidis. Here, we examined the FarR regulon by microarray analyses, qRT-PCR, and electrophoretic mobility shift assays, revealing that FarR is a highly specific repressor of nadA. We demonstrate by reporter gene fusion assays that alterations of the FarR binding site within the nadA promoter are sufficient to induce transcription of nadA. Furthermore, farR expression is growth phase-dependent. The highest transcription rate was observed in the late-exponential growth phase of meningococci. Upon contact with active components of the complement system in normal human serum, expression of farR is slightly downregulated. Concluding, we present FarR as an exquisitely specialized, growth phase-dependent, possibly complement-responsive transcriptional regulator in N. meningitidis. PMID- 21292555 TI - Nuocytes and beyond: new insights into helminth expulsion. AB - T helper 2 (Th2) responses, characterized by the expression of the type-2 cytokines interleukin (IL)-4, IL-5, IL-9 and IL-13, are essential for the control of parasitic helminth infections and also drive the pathogenesis of allergy and asthma. Such responses are initiated, maintained and regulated, in part, by an array of innate effector cells and cytokines. However, relatively little is known about how the initiation of type-2 immune responses occurs in vivo. The recent discovery, using helminth models, of several novel innate immune cells capable of shaping type-2 immune responses allows us to reflect on the progress made in this area. It also affords us the opportunity to highlight the diversity of immune responses that can be driven by innate cells responding rapidly to early cytokine cues. PMID- 21292556 TI - Mass-scale red cell genotyping of blood donors. AB - Blood centers are able to recruit and process large numbers of blood donations to meet the demand for antigen-matched blood. However, there are limitations with the use of hemagglutination that can be circumvented with blood group genotyping. Antisera do not exist for several clinically important blood group antigens and many methods have been developed (direct hemagglutination, indirect antiglobulin dependent, solid phase, or gel column). There is increasing interest to apply mass-scale red cell genotyping of blood donors to find rare (predicted) phenotypes, rare combinations of antigens and locus haplotypes, and to have access to information on the common clinically relevant blood group antigens. This review outlines technological advances, emerging algorithms, and the future of mass-scale red cell genotyping of blood donors. PMID- 21292557 TI - Peripheral blood galectin-1-expressing T and natural killer cells in normal pregnancy and preeclampsia. AB - The purpose of this study was to determine whether the proportion of galectin-1 expressing peripheral blood T and NK cells is altered in normal pregnancy and preeclampsia (PE). We also examined whether circulating levels of galectin-1 and anti-galectin-1 autoantibodies are affected in PE. Seventy preeclamptic patients, 75 healthy pregnant and 21 healthy non-pregnant women were involved in this study. Serum galectin-1 and anti-galectin-1 autoantibody levels were measured by ELISA. Intracellular galectin-1 expression of lymphocytes was determined with flow cytometry. Serum galectin-1 and anti-galectin-1 IgG levels did not differ significantly between the healthy pregnant and the PE group. In healthy pregnant women, significantly higher percentage of T and NK cells expressed gal-1 in their cytoplasma than in healthy non-pregnant women. However, the proportion of galectin-1-expressing peripheral blood T and NK cells was markedly decreased in PE compared to normal pregnancy, which might contribute to the activation of innate and acquired immune cells. PMID- 21292558 TI - Electroencephalographic and seizure manifestations of pyridoxal 5'-phosphate dependent epilepsy. AB - We describe the electroencephalographic and clinical seizure manifestations of pyridoxal 5'-phosphate-dependent epilepsy (PLP-DE) in two patients [diagnosis confirmed by low cerebrospinal fluid (CSF) PLP, complete resolution of previously intractable seizures with PLP supplementation, negative pyridoxine-dependent epilepsy CSF biomarkers, and/or positive disease causing pyridox(am)ine 5' phosphate oxidase gene mutation] along with a comprehensive review of the literature. One patient presented with neonatal tonic status epilepticus with subsequent generalized tonic-clonic seizures, and the second, with refractory complex partial seizures starting at 2 years of age. The pretreatment EEG revealed, interictally, burst suppression, multifocal independent sharp waves, and electrical status epilepticus in sleep. Ictally and interictally, it revealed runs of unilateral spike/slow waves. Previously reported features include burst suppression, myoclonus, tonic seizures, clonic seizures, and spasms. In the appropriate clinical scenario, the aforementioned features should raise the possibility of PLP-DE and appropriate treatment should be initiated. The first late-onset case (at 2 years) of PLP-DE is reported. PMID- 21292559 TI - Evaluation of knowledge of and attitudes toward epilepsy among the health science students of Manipal University. AB - This study was carried out to assess the knowledge, attitudes, and practices with respect to epilepsy among health science students of Manipal University. The study was conducted among first-year health science students of Kasturba Medical College on the Manipal and Mangalore campuses of Manipal University. All students willing to participate (n=587) were asked to answer a standardized questionnaire on epilepsy. Our study group included educated urban people from various ethnic backgrounds of various countries who chose health science as a career, which makes the study different from others. Even though most of the students had heard about epilepsy, very few knew about the underlying cause. Most of the students were ignorant about the drugs and ways to deal with epileptic seizures. Questions related to community and religion were deliberately avoided as some subjects found such questions offensive, which may have resulted in a difference in response as compared with previously published studies. It was observed that a large number of students were not aware of the nuances of epilepsy. However, we expect the knowledge, attitudes and awareness to improve considerably with time and increased exposure. These findings support a need to promote epilepsy awareness programs as a means of increasing public knowledge of epilepsy. PMID- 21292560 TI - Mozart K.448 acts as a potential add-on therapy in children with refractory epilepsy. AB - Mozart's Sonata for two pianos in D major, K.448 (Mozart K.448), has been shown to improve mental function, leading to what is known as the Mozart effect. Our previous work revealed that epileptiform discharges in children with epilepsy decreased during and immediately after listening to Mozart K.448. In this study, we evaluated the long-term effects of Mozart K.448 on children with refractory epilepsy. Eleven children with refractory epilepsy were enrolled. All of the patients were diagnosed as having had refractory epilepsy for more than 1 year (range =1 year to 6 years 4 months, mean =3 years 11 months) and had been receiving at least two antiepileptic drugs (AED). During the study period, they listened to Mozart K.448 once a day before bedtime for 6 months. Seizure frequencies were recorded 6 months before they started listening to this music and monthly during the study period. All of the patients remained on the same AEDs during the 6-month study period. Frequencies of seizures were compared before and after listening to Mozart K.448. Eight of eleven patients were seizure free (N=2) or had very good responses (N=6) after 6 months of listening to Mozart K.448. The remaining three (27.3%) showed minimal or no effect (effectiveness <50%; unmodified or worsened seizure frequency). The average seizure reduction was 53.6 +/- 62.0%. There were no significant differences in seizure reduction with IQ, etiology, or gender. We conclude that Mozart K.448 should be further studied as a potential add-on therapy in the treatment of children with refractory epilepsy. PMID- 21292561 TI - Preoperative grading scale to predict survival in patients undergoing resection of malignant primary osseous spinal neoplasms. AB - BACKGROUND CONTEXT: Large population-based studies of malignant primary osseous spinal neoplasms are lacking and are necessary to have sufficient statistical power to determine if various patient-related factors are in fact significant indicators of prognosis. PURPOSE: Using a 30-year US national cancer registry (Surveillance, Epidemiology, and End Results [SEER]), we introduce a preoperative grading scale that is associated with survival in patients undergoing surgical resection for malignant primary osseous spinal neoplasms. STUDY DESIGN: Large scale retrospective study. PATIENT SAMPLE: SEER registry. OUTCOME MEASURE: Survival. METHODS: The SEER registry (1973-2003) was queried to identify adult patients undergoing surgical resection of histologically confirmed primary spinal chordoma, chondrosarcoma, or osteosarcoma via International Classification of Disease for Oncology, Third Edition coding. Variables independently associated with survival were determined via Cox proportional hazards regression analysis for all tumor types. A grading scale comprising these independent survival predictors was then developed and applied to each histology-specific tumor cohort. RESULTS: Three hundred forty-two patients who underwent surgical resection of a malignant primary osseous spinal neoplasm (114 chordoma, 156 chondrosarcoma, and 72 osteosarcoma) were identified. Overall median survival after surgical resection was histology specific (osteosarcoma: 22 months; chordoma: 100 months; and chondrosarcoma: 160 months). Increasing age (years) and increasing tumor invasion (confined to periosteum; invasion through periosteum into adjacent tissues; and distal site metastasis) were the only variables independently associated with decreased survival (p<.05) for all tumor types. For spinal chordoma, sacrum/pelvic location (p<.05) and earlier year of surgery (p<.005) were also independently associated with decreased survival. Using variables of patient age, extent of local tumor invasion, and metastasis status in a five-point grading scale, increasing score (1-5) closely correlated (p<.001) with decreased survival for chordoma, chondrosarcoma, and osteosarcoma. CONCLUSIONS: In our analysis of a US population-based cancer registry (SEER), a grading scale consisting of age, metastasis status, and extent of local tumor invasion was associated with overall survival after surgical resection of chordoma, chondrosarcoma, and osteosarcoma of the spine. Although this analysis could not take into account specific chemotherapy regimens and variations in surgical technique, this grading scale may offer valuable prognostic data based on variables available to the surgeon and patient before surgery and may help guide level of aggressiveness in subsequent treatment strategies. PMID- 21292562 TI - Idiopathic scoliosis patients with curves more than 45 Cobb degrees refusing surgery can be effectively treated through bracing with curve improvements. AB - BACKGROUND CONTEXT: It is a broad consensus today that scoliosis curves cannot be improved through bracing, and the Scoliosis Research Society (SRS) methodological criteria for bracing have the avoidance of progression as their only objective. Consequently, in curves more than 45 degrees , fusion is considered as basically the only possible treatment. PURPOSE: The purpose of the study was to verify in a series of patients who utterly refused surgery if it was possible to achieve improvements of scoliosis of more than 45 degrees through a complete conservative treatment (bracing and exercises). STUDY DESIGN/SETTING: Retrospective cohort from a prospective database. PATIENT SAMPLE: Out of 1,148 idiopathic scoliosis (IS) patients at the end of treatment, the sample comprised 28 subjects older than 10 years, still growing, with at least one curve above 45 degrees , who had continually refused fusion. The group comprised 24 females and four males, including 14 in which previous brace treatments had failed; at the start of treatment, the age was 14.2+/-1.8 years and Cobb degrees in the curve were 49.4 degrees (range, 45 degrees -58 degrees ). Subgroups considered were gender, bone age, type of scoliosis, treatment used, and previous failed treatment. OUTCOME MEASURES: Self-report measurement: SRS-22; physiological measures: Cobb degrees, Bunnell angle of trunk rotation (ATR), aesthetic index (AI), and sagittal plumb line distances. METHODS: The methods comprised full-time treatment (23 or 24 hours per day) for 1 year with Risser cast, Lyon, or Sforzesco brace; weaning of 1 to 2 hours every 6 months; with strategies to maximize compliance through the Society on Scoliosis Orthopaedic and Rehabilitation Treatment (SOSORT) management criteria applied and specific scientific exercises approach to scoliosis exercises (SEAS) performed. RESULTS: Reported compliance in the 4.10+/-1.2 treatment years was 94%, with satisfaction regarding treatment and excellent results at the SRS-22. Two patients (7%) remained above 50 degrees Cobb but six patients (21%) finished between 30 degrees and 35 degrees Cobb and 12 patients (43%) finished between 36 degrees and 40 degrees Cobb. Improvements have been found in 71% of patients and a 5 degrees Cobb progression in one patient. Statistically, we found highly significant reductions of the main (-9.25 degrees ), average (-6.6 degrees ), thoracic (-7.8 degrees ), and lumbar (-15.9 degrees ) curves. Statistically significant improvements have been found for the AI and ATR, with a general decrease in plumb line distances. CONCLUSIONS: Bracing can be successfully used in patients who do not want to undergo operations for IS with curves ranging between 45 degrees and 60 degrees Cobb, given sufficient clinical expertise to apply good braces and achieve great compliance. Future studies could demonstrate the percentages at which this result can be achieved. PMID- 21292563 TI - An injectable method for noninvasive spine fusion. AB - BACKGROUND CONTEXT: Bone morphogenetic proteins (BMPs) induce bone formation but are difficult to localize, and subsequent diffusion from the site of interest and short half-life reduce the efficacy of the protein. Currently, spine fusion requires stripping, decortications of the transverse processes, and an autograft harvest procedure. Even in combination with BMPs, clinical spinal fusion has a high failure rate, presumably because of difficulties in localizing sufficient levels of BMP. PURPOSE: The goal was to achieve reliable spine fusion through a single injection of a cell-based gene therapy system without the need for any surgical intervention. STUDY DESIGN: Eighty-seven immunodeficient (n=44) and immune-competent (n=43) mice were injected along the paraspinous musculature to achieve rapid induction of heterotopic ossification (HO) and ultimately spinal arthrodesis. METHODS: Immunodeficient and immune-competent mice were injected with fibroblasts, transduced with an adenoviral vector to express BMP2, along the paraspinous musculature. Bone formation was evaluated via radiographs, microcomputed tomography, and biomechanical analysis. RESULTS: ew bridging bone between the vertebrae and the fusion to adjacent skeletal bone was obtained as early as 2 weeks. Reduction in spine flexion-extension also occurred as early as 2 weeks after injection of the gene therapy system, with greater than 90% fusion by 4 weeks in all animals regardless of their genetic background. CONCLUSIONS: Injection of our cell-based system into the paraspinous musculature induces spinal fusion that is dependent neither on the cell type nor on the immune status. These studies are the first to harness HO in an immune-competent model as a noninvasive injectable system for clinically relevant spinal fusion and may one day impact human spinal arthrodesis. PMID- 21292564 TI - Dercum's disease as a cause of weight loss failure after gastric bypass surgery. PMID- 21292565 TI - Alimentary limb mesenteric thrombosis after laparoscopic Roux-en-Y gastric bypass. PMID- 21292566 TI - Relations between carotid artery distensibility and heart rate variability The Cardiovascular Risk in Young Finns Study. AB - OBJECTIVE: Reduction in carotid artery wall elasticity may interfere with baroreceptor function that could lead to low vagal tone. We studied at the population level the relations between carotid-artery-distensibility (Cdist) and vagal modulation of heart rate. METHODS AND RESULTS: Cdist was assessed with ultrasonic measurements of changes in carotid artery diameter during cardiac cycle. Vagal tone was estimated with the heart rate variability (HRV) in 1872 healthy 24-39year-old subjects. Cdist was significantly related with all HRV components (always P<0.0001). After adjustments with sex, age and heart rate, we found statistically significant correlation between Cdist and the high-frequency component (HF, estimate of vagal-tone) of HRV (P<0.05). An inverse association between the number of cardiovascular risk-factors and vagal-tone was seen in subjects with less elastic arteries, but not in subjects with more elastic arteries (P for interaction=0.01). CONCLUSIONS: These data support the hypothesis that reduction in carotid artery wall elastic properties may lead to low vagal tone. Furthermore, carotid distensibility seemed to modify the relation between risk-factors and HRV. Increased cardiovascular risk associated with low vagal tone may partly be mediated via changes in carotid artery elastic properties. PMID- 21292567 TI - The RecRO pathway of DNA recombinational repair in Helicobacter pylori and its role in bacterial survival in the host. AB - Two pathways for DNA recombination, AddAB (RecBCD-like) and RecRO, were identified in Helicobacter pylori, a pathogenic bacterium that colonizes human stomachs resulting in a series of gastric diseases. In this study, we examined the physiological roles of H. pylori RecRO pathway in DNA recombinational repair. We characterized H. pylori single mutants in recR and in recO, genes in the putative gap repair recombination pathway, and an addA recO double mutant that is thus deficient in both pathways that initiate DNA recombinational repair. The recR or recO single mutants showed the same level of sensitivity to mitomycin C as the parent strain, suggesting that the RecRO pathway is not responsible for the repair of DNA double strand breaks. However, H. pylori recR and recO mutants are highly sensitive to oxidative stress and separately to acid stress, two major stress conditions that H. pylori encounters in its physiological niche. The complementation of the recR mutant restored the sensitivity to oxidative and acid stress to the wild type level. By measuring DNA transformation frequencies, the recR and recO single mutants were shown to have no effect on inter-genomic recombination, whereas the addA recO double mutant had a greatly (~12-fold) reduced transformation frequency. On the other hand, the RecRO pathway was shown to play a significant role in intra-genomic recombination with direct repeat sequences. Whereas the recA strain had a deletion frequency 35-fold lower than that of background level, inactivation of recR resulted in a 4-fold decrease in deletion frequency. In a mouse infection model, the three mutant strains displayed a greatly reduced ability to colonize the host stomachs. The geometric means of colonization number for the wild type, recR, recO, and addA recO strains were 6 x 105, 1.6 x 104, 1.4 x 104 and 4 x 103 CFU/g stomach, respectively. H. pylori RecRO-mediated DNA recombinational repair (intra-genomic recombination) is thus involved in repairing DNA damage induced by oxidative and acid stresses and plays an important role in bacterial survival and persistent colonization in the host. PMID- 21292568 TI - Simultaneous determination of sphingosine and sphingosine 1-phosphate in biological samples by liquid chromatography-tandem mass spectrometry. AB - D-erythro-sphingosine (Sph) and its phosphorylated product, d-erythro-sphingosine 1-phosphate (S1P) are sphingolipids mediating numerous cellular processes. Imbalance of Sph/S1P levels contributes to many diseases. Given the interconversion of these two opposing signaling molecules, it is essential to examine their levels simultaneously. In the present study, we developed a rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to simultaneously quantify the levels of Sph and S1P in biological samples using C17 Sph and C17-S1P as internal standards. With one step of methanol-induced protein precipitation, each sample was subjected to LC-MS/MS analysis using positive electrospray ionization under selected reaction monitoring mode. The running time was within 4 min with a simple mobile phase consisting of methanol-0.1% formic acid (95:5, v/v) at a flow rate of 0.2 mL/min. Standard curves were linear over ranges of 1-100 ng/mL for Sph and 0.1-10 ng/mL for S1P with correlation coefficient (r2) greater than 0.997. The lower limit of quantifications (LLOQs) were 1 ng/mL for Sph and 0.1 ng/mL for S1P. The intra-batch and inter-batch precision was less than 15% for all quality control samples. The recoveries of the method were found to be 76.36-89.84%. The method was applied to simultaneously determine the Sph and S1P levels in mouse kidney, human plasma, and HEK 293 cells treated with tumor necrosis factor-alpha (TNF-alpha) and N,N dimethylsphingosine (DMS). The S1P levels increased in cells treated with TNF alpha whereas decreased in cells treated with DMS. These results indicated that this new LC-MS/MS method was rapid, sensitive, specific and reliable to quantify Sph and S1P levels in biological samples simultaneously. PMID- 21292569 TI - Quantification of 22 plasma amino acids combining derivatization and ion-pair LC MS/MS. AB - Time efficient and comprehensive quantification of amino acids continues to be a challenge. We developed a sensitive and precise method for quantitative analysis of amino acids from very small plasma and serum volumes. Ion-pair chromatography of amino acid butyl esters proved to provide an optimal combination of selectivity, sensitivity and robustness. 10 MUL of plasma or serum are added to precipitation reagent containing stable isotope standards. After protein precipitation, the supernatants is dried and incubated with 3N butanolic HCl for improving chromatographic separation and ionization efficiency. Amino acid butyl esters are separated using ion-pair (heptafluorobutyric acid) reversed-phase chromatography coupled to triple quadrupole mass spectrometry. The established method enables quantitative analysis of 22 amino acids, all 20 proteinogenic amino acids, ornithine and citrulline. Cysteine is measured as cystine. The combination of precipitation, derivatization and chromatographic separation effectively avoids ion suppression and coelution. Simultaneous with quantification, analyte identity is verified in each sample using qualifier ions. The micro-method is very sensitive and accurate. The intra-assay precision for the analysis of plasma was 2.6-10.1%. Absolute accuracy as determined by comparison of external reference samples was 82-117.7%. Excellent linearity of detection response was demonstrated for all compounds in the range representative for clinical samples from infants and adults. Lower limits of quantification were in the range of 1 MUmol/L for all analytes. In conclusion, the method is ideally suited for cost-effective high-throughput analysis of large numbers of samples in clinical studies and metabolomics research. PMID- 21292570 TI - Fractionation and recovery of whey proteins by hydrophobic interaction chromatography. AB - A method for the recovery and fractionation of whey proteins from a whey protein concentrate (80%, w/w) by hydrophobic interaction chromatography is proposed. Standard proteins and WPC 80 dissolved in phosphate buffer with ammonium sulfate 1 M were loaded in a HiPrep Octyl Sepharose FF column coupled to a fast protein liquid chromatography (FPLC) system and eluted by decreasing the ionic strength of the buffer using a salt gradient. The results showed that the most hydrophobic protein from whey is alpha-lactalbumin and the less hydrophobic is lactoferrin. It was possible to recover 45.2% of beta-lactoglobulin using the HiPrep Octyl Sepharose FF column from the whey protein concentrate mixture with 99.6% purity on total protein basis. PMID- 21292571 TI - Development of a process for large-scale purification of C-phycocyanin from Synechocystis aquatilis using expanded bed adsorption chromatography. AB - In this paper a large and scaleable method for purification of C-phycocyanin (C PC) from the cyanobacteria Synechocystis aquatilis has been developed. Phycobiliproteins are extracted from the cells by osmotic shock and separated by passing the centrifuged cell suspension through an expanded bed adsorption chromatography (EBAC) column using Streamline-DEAE as adsorbent. The eluted C-PC rich solution is finally purified by packed-bed chromatography using DEAE cellulose. Optimal extraction is achieved using phosphate 0.05 M buffer pH 7.0 twice. The operation of EBAC is optimized on a small scale using a column of 15 mm internal diameter (I.D.). The optimal conditions are a sample load of 4.9 mg C PC/mL adsorbent, an expanded bed volume twice the settled bed volume and a sample viscosity of 1.020 mP. The EBAC process is then scaled up by increasing the column I.D. (15, 25, 40, 60 and 90 mm) and the success of the scale-up process is verified by determining the protein breakthrough capacity and product recovery. The yield of the EBAC step is in the range of 90-93% for every column diameter. To obtain pure C-PC, conventional ion-exchange chromatography with DEAE-cellulose is utilized and a yield of 74% is obtained. The overall yield of the process, comprising all steps, is 69%. The purification steps are monitored using SDS-PAGE and the purity of recovered C-PC is confirmed by absorption and emission spectroscopy and RP-HPLC. Results show that EBAC method is a scalable technology that allows large quantities of C-PC to be obtained without product loss, maintaining a high protein recovery while reducing both processing cost and time. PMID- 21292572 TI - The nature of DNA sequence preferences for nucleosome positioning. Comment on 'Cracking the chromatin code: precise rule of nucleosome positioning' by Trifonov. PMID- 21292573 TI - Through a glass, darkly: biology seen from mathematics: comment on "Toward a mathematical theory of living systems focusing on developmental biology and evolution: a review and perspectives" by N. Bellomo and B. Carbonaro. PMID- 21292574 TI - Predicting nucleosome-positioning signals: comment on "Cracking the chromatin code: precise rule of nucleosome positioning" by E.N. Trifonov. PMID- 21292575 TI - Preliminaries for a future mathematical formulation of Evolution Theory: comment on "Toward a mathematical theory of living systems focusing on developmental biology and evolution: a review and perspectives" by N. Bellomo and B. Carbonaro. PMID- 21292576 TI - Cost of gestational diabetes-related antenatal visits in health care based on the Finnish Medical Birth Register. AB - The aim was to evaluate frequency and costs of antenatal health care visits related to risk of gestational diabetes (GDM) using Birth Register. Costs among all GDM risk groups were 10-41% larger than non-risk groups. Primary health care is needed to reduce special health care costs related to GDM. PMID- 21292577 TI - Wire load-deflection characteristics relative to different types of brackets. AB - OBJECTIVE: To test the hypothesis that the dimension of the bracket, both in labial and in lingual orthodontics, is a relevant parameter to determine the forces acting on the teeth, and that some wires commonly used in labial orthodontics (0.016"-diameter SS, TMA and Nitinol) are not suitable for the first phase of lingual treatment. MATERIALS AND METHODS: An ideal dental cast was bonded with eight different brackets (Damon 3MX, Ovation, Time 2, Innovation and Smart Clip Clarity on the vestibular face; STB, Adenta Time and Innovation-L on the lingual). After photographic documentation, the interbracket distance was calculated for each type of bracket, using ImageJ software. The mean elasticity modulus of the tested wires was obtained from the review of the available literature. The theoretical wire load on every tooth was calculated mathematically at three different levels of deflection (0.5mm; 1.0mm and 1.5mm), on both the labial and lingual sides, for all types of bracket. RESULTS: The lingual arch in the anterior segment is always shorter than the vestibular arch. The different brackets, having different dimensions, have an influence on the interbracket distance, and, consequently, on the wire load. At large deflections, superelastic NiTi expresses light and continuous forces, which are significantly lower than the other examined alloys. CONCLUSION: The initial hypothesis was supported. Because of the reduced interbracket distance, the adoption of superelastic wires is required in lingual mechanics and with smaller diameter compared to labial mechanotherapy, in particular during the first phases of treatment. The use of a bracket with reduced mesiodistal dimensions can contribute to reduce the load on the teeth. PMID- 21292579 TI - X-chromosomal haplotype frequencies of four linkage groups using the Investigator Argus X-12 Kit. PMID- 21292580 TI - Insertion-/deletion polymorphisms close to the repeat region of STR loci can cause discordant genotypes with different STR kits. AB - It is well known that mutations in the primer binding site of STR loci can cause "null alleles". If a sample is typed with different sets of PCR primers (for example if different kits or kits of different manufacturers are used) discordant results might be observed, thus making the use of different STR kits for deviant genotypes necessary. Here we present another reason for using different kits: Insertion-/deletion polymorphism between the repeat region of the STR locus and the primer binding site can also cause genotypes that vary between different kits/primer sets. PMID- 21292581 TI - Cell free DNA as a component of forensic evidence recovered from touched surfaces. AB - In the course of a criminal investigation, DNA is often recovered from items that have been handled by an individual. Whilst there have been studies investigating the propensity of different individuals to deposit DNA, little is known about the factors involved in the transference of DNA through touch. This investigation seeks to clarify some of the underlying processes involved in DNA transfer, as to better understand the significance of so-called "touch DNA" evidence (tDNA). It was shown that an average yield of 11.5 ng of DNA could be recovered from 1 mL cell-free sweat samples leading to the hypothesis that cell-free nucleic acids (CNAs) of a suitable length for standard DNA profiling are transferred during handling/touching items. A method of standardization of tDNA deposition was developed to overcome the significant sample to sample variability in DNA levels characteristic of tDNA samples. The glass bead method allowed the creation of identical tDNA sample sets, thus permitting direct comparisons to be made in the efficiency of various extraction methods. Extraction methods designed to optimize CNA recovery from touched articles resulted in comparable yields in a general population study, however the methods resulted in a twofold increase in DNA yields from touched items touched by individuals with sweaty hands. These results suggest that the CNA component of touched surfaces should be included to maximize profiling success of tDNA. PMID- 21292582 TI - Spondylolisthesis on bilateral pedicle stress fracture in the lumbar spine: a case study. AB - We report the clinical case of a 54-year-old woman presenting radicular low back pain on the right side of L4 associated to spondylolisthesis on L4-L5, without any notion of trauma or spine surgery. Furthermore this patient is regularly seen for benign rheumatoid polyarthritis complicated by steroid-induced osteoporosis. A preventive treatment was implanted with good results on pain improvement and functional capacities. For pedicle fractures the literature review reports several different etiologies: spontaneous fractures, hereditary fractures or stress-related fractures. There was a discussion on the various treatments available and in this case of spondylolisthesis on pedicle fracture a conservative treatment was implemented similar to the one for isthmic spondylolisthesis. It yielded satisfying results. PMID- 21292583 TI - Human papillomavirus infection in women with and without cervical cancer in Tbilisi, Georgia. AB - BACKGROUND: No accurate estimates of cervical cancer incidence or mortality currently exist in Georgia. Nor are there any data on the population-based prevalence of high-risk (HR) human papillomavirus (HPV) infection, which, in the absence of good-quality screening, is known to correlate with cervical cancer incidence. METHODS: We obtained cervical cell specimens from 1309 women aged 18 59 years from the general population of Tbilisi, and also from 91 locally diagnosed invasive cervical cancers (ICC). DNA of 44 HPV types was tested for using a GP5+/6+-based PCR assay. RESULTS: In the general population (of whom 2% reported a previous Pap smear) HPV prevalence was 13.5% (95% CI: 11.6-15.9), being highest in women aged 25-34 years (18.7%) and falling to between 8.6% and 9.5% for all age groups above 34 years. HR HPV prevalence was 8.6% overall, being 6.8% and 38.9% among women with normal and abnormal cytology, respectively. HPV45 (1.6%) was the most common type in women with normal cytology, whereas HPV16 predominated among women with cervical abnormalities (including 7 of 10 histologically confirmed cervical intraepithelial neoplasia 2/3) and among ICC (57.6%). The next most common types in ICC in Georgia were HPV45 and 18 (13.2 and 11.0%, respectively). CONCLUSIONS: We report a relatively high burden of HPV infection in Tbilisi, Georgia. Improving cervical cancer prevention, through screening and/or HPV vaccination, is an important public health issue in Georgia, where 70% of ICC are theoretically preventable by HPV16/18 vaccines. PMID- 21292584 TI - Hidden malignant cells within leukocyte aggregates: seeds for invasive and metastatic cancer? AB - BACKGROUND: Our previous studies revealed that leukocyte infiltration into aged or injured myoepithelial cell layers is a key trigger for breast tumor invasion and metastasis. Our current study further assessed the possibility that leukocyte aggregates may harbor detached individual tumor cell or clusters of tumor cells. MATERIALS AND METHODS: Tissue sections from patients with pregnancy-associated breast cancer (PABC) and controls were subjected to morphological and immunohistochemical assessment with a panel of leukocyte and tumor cell related markers. RESULTS: A total of 63 leukocyte aggregates were detected in the 20 PABC cases studied. Of these, 55 (87%) were distributed within normal or hyperplastic lobules adjacent to invasive lesions. Over 70% of these leukocyte aggregates harbored detached individual tumor cell or cell clusters with malignant properties, including strong p53 positivity, elevated proliferation, reduced cell surface adhesion molecules, and cytological resemblance to adjacent invasive cancer cells. A significant number of these tumor cells or condensed chromosomes of mitotic tumor cells were observed to conjoin with the plasma membrane of leukocytes. Similar alterations were seen in leukocyte aggregates within the inter-lobular space and in non-PABC with a lower frequency. CONCLUSIONS: These findings suggest that leukocyte infiltration may trigger dissemination of tumor cells from their primary site, and that leukocyte aggregates may serve as a reservoir for disseminated tumor cells that may be physically dragged to distant sites by leukocytes during their migration. PMID- 21292585 TI - Vocal fold medialization: which are the available fillers in France in 2010? PMID- 21292586 TI - Optimal filter framework for automated, instantaneous detection of lesions in retinal images. AB - Automated detection of lesions in retinal images is a crucial step towards efficient early detection, or screening, of large at-risk populations. In particular, the detection of microaneurysms, usually the first sign of diabetic retinopathy (DR), and the detection of drusen, the hallmark of age-related macular degeneration (AMD), are of primary importance. In spite of substantial progress made, detection algorithms still produce 1) false positives-target lesions are mixed up with other normal or abnormal structures in the eye, and 2) false negatives-the large variability in the appearance of the lesions causes a subset of these target lesions to be missed. We propose a general framework for detecting and characterizing target lesions almost instantaneously. This framework relies on a feature space automatically derived from a set of reference image samples representing target lesions, including atypical target lesions, and those eye structures that are similar looking but are not target lesions. The reference image samples are obtained either from an expert- or a data-driven approach. Factor analysis is used to derive the filters generating this feature space from reference samples. Previously unseen image samples are then classified in this feature space. We tested this approach by training it to detect microaneurysms. On a set of images from 2739 patients including 67 with referable DR, DR detection area under the receiver-operating characteristic curve (AUC) was comparable (AUC=0.927) to our previously published red lesion detection algorithm (AUC=0.929). We also tested the approach on the detection of AMD, by training it to differentiate drusen from Stargardt's disease lesions, and achieved an AUC=0.850 on a set of 300 manually detected drusen and 300 manually detected flecks. The entire image processing sequence takes less than a second on a standard PC compared to minutes in our previous approach, allowing instantaneous detection. Free-response receiver-operating characteristic analysis showed the superiority of this approach over a framework where false positives and the atypical lesions are not explicitly modeled. A greater performance was achieved by the expert-driven approach for DR detection, where the designer had sound expert knowledge. However, for both problems, a comparable performance was obtained for both expert- and data-driven approaches. This indicates that annotation of a limited number of lesions suffices for building a detection system for any type of lesion in retinal images, if no expert-knowledge is available. We are studying whether the optimal filter framework also generalizes to the detection of any structure in other domains. PMID- 21292587 TI - The effect of anthropometric variations on acoustical flow estimation: proposing a novel approach for flow estimation without the need for individual calibration. AB - Tracheal sound average power is directly related to the breathing flow rate and recently it has attracted considerable attention for acoustical flow estimation. However, the flow-sound relationship is highly variable among people and it also changes for the same person at different flow rates. Hence, a robust model capable of estimating flow from tracheal sounds at different flow rates in a large group of individuals does not exist. In this paper, a model is proposed to estimate respiratory flow from tracheal sounds. The proposed model eliminates the dependence of the previous methods on calibrating the model for every individual and at different flow rates. To validate the model, it was applied to the respiratory sound and flow data of 93 healthy individuals. We investigated the statistical correlation between the model parameters and anthropometric features of the subjects. The results have shown that gender, height, and smoking are the most significant factors that affect the model parameters. Hence, we grouped nonsmoker subjects into four groups based on their gender and height. The average of model parameters in each group was defined as the group-calibrated model parameters. These models were applied to estimate flow from data of subjects within the same group and in the other groups. The results show that flow estimation error based on the group-calibrated model is less than 10%. The low estimation errors confirm the possibility of defining a general flow estimation model for subjects with similar anthropometric features with no need for calibrating the model parameters for every individual. This technique simplifies the acoustical flow estimation in general applications including sleep studies and patients' screening in health care facilities. PMID- 21292588 TI - Constructing accurate contact maps for hydroxyl-radical-cleavage-based high throughput RNA structure inference. AB - For rapid ribonucleic acid (RNA) tertiary structure prediction, innovative methods have been proposed that exploit hydroxyl radical cleavage agents in a high-throughput manner. In such techniques, it is critical to determine accurately which residue a specific cleavage agent interacts with, since this information directly reveals the residue-residue interaction points needed for structure inference. Due to lack of effective automated methods, the process of locating contact points has been mostly done manually, becoming a bottleneck of the whole procedure. To address this problem, we propose a novel computational method to determine residue-residue interaction points from 2-D electrophoresis profiles. This method combines the deconvolution method for signal detection and statistical learning techniques for filtering noise, thus boosting specificity and sensitivity in harmony. According to our experiments with over 2000 actual gel profiles, the proposed technique exhibited 56.44%-90.50% higher performance than traditional methods in terms of the accuracy of reproducing manual contact maps measured by the F-measure, a widely used evaluation metric. We expect that adopting the proposed technique will significantly accelerate RNA tertiary structure inference, allowing researchers to explore more structures in given time. PMID- 21292589 TI - Real-time brain oscillation detection and phase-locked stimulation using autoregressive spectral estimation and time-series forward prediction. AB - Neural oscillations are important features in a working central nervous system, facilitating efficient communication across large networks of neurons. They are implicated in a diverse range of processes such as synchronization and synaptic plasticity, and can be seen in a variety of cognitive processes. For example, hippocampal theta oscillations are thought to be a crucial component of memory encoding and retrieval. To better study the role of these oscillations in various cognitive processes, and to be able to build clinical applications around them, accurate and precise estimations of the instantaneous frequency and phase are required. Here, we present methodology based on autoregressive modeling to accomplish this in real time. This allows the targeting of stimulation to a specific phase of a detected oscillation. We first assess performance of the algorithm on two signals where the exact phase and frequency are known. Then, using intracranial EEG recorded from two patients performing a Sternberg memory task, we characterize our algorithm's phase-locking performance on physiologic theta oscillations: optimizing algorithm parameters on the first patient using a genetic algorithm, we carried out cross-validation procedures on subsequent trials and electrodes within the same patient, as well as on data recorded from the second patient. PMID- 21292590 TI - Device for quantification of bilirubin in cerebral spinal fluid. AB - In North America, an estimated 30,000 patients annually experience an aneurysmal subarachnoid hemorrhage (SAH). In approximately five percent of these patients, the hemorrhage is not visible on computerized tomography scans due to the inability to image blood at time intervals greater than 12 h post symptom onset. For these patients (many of which have experienced a sentinel hemorrhage that is a precursor to a more significant rupture), a method is needed for accurately analyzing cerebral spinal fluid (CSF) for evidence of SAH. Further, it is necessary to differentiate blood associated with the SAH from blood associated with the spinal tap procedure. This letter presents a point-of-care device that is capable of performing such an analysis. The stand-alone prototype device uses commercially available embedded system components to implement a point-of-care device that is capable of collecting and analyzing optical absorbance spectra. A mathematical model for the hemorrhagic CSF sample is then developed by using a partial-least-squares-regression-based regression methodology that is able to differentiate between SAH and blood associated with the spinal tap. This differentiation is achieved by quantifying bilirubin (associated with the breakdown of old blood) in the CSF. Initial testing on the prototype device suggests that the device is able to quantify bilirubin in the presence of hemoglobin over concentrations ranges that are clinically relevant to the patient population of interest. PMID- 21292591 TI - Representing cardiac bidomain bath-loading effects by an augmented monodomain approach: application to complex ventricular models. AB - Although the cardiac bidomain model has been widely used in the simulation of electrical activation, its relatively computationally expensive nature means that monodomain approaches are generally required for long-duration simulations (for example, investigations of arrhythmia mechanisms). However, the presence of a conducting bath surrounding the tissue is known to induce wavefront curvature (surface leading bulk), a phenomena absent in standard monodomain approaches. Here, we investigate the biophysical origin of the bidomain bath-loading induced wavefront curvature and present a novel augmented monodomain-equivalent bidomain approach faithfully replicating all aspects of bidomain wavefront morphology and conduction velocity, but with a fraction of the computational cost. Bath-loading effects are shown to be highly dependent upon specific conductivity parameters, but less dependent upon the thickness or conductivity of the surrounding bath, with even relatively thin surrounding fluid layers (~ 0.1 mm) producing significant wavefront curvature in bidomain simulations. We demonstrate that our augmented monodomain approach can be easily adapted for different conductivity sets and applied to anatomically complex models, thus facilitating fast and accurate simulation of cardiac wavefront dynamics during long-duration simulations, further aiding the faithful comparison of simulations with experiments. PMID- 21292592 TI - Fully-3D PET image reconstruction using scanner-independent, adaptive projection data and highly rotation-symmetric voxel assemblies. AB - For iterative, fully 3D positron emission tomography (PET) image reconstruction intrinsic symmetries can be used to significantly reduce the size of the system matrix. The precalculation and beneficial memory-resident storage of all nonzero system matrix elements is possible where sufficient compression exists. Thus, reconstruction times can be minimized independently of the used projector and more elaborate weighting schemes, e.g., volume-of-intersection (VOI), are applicable. A novel organization of scanner-independent, adaptive 3D projection data is presented which can be advantageously combined with highly rotation symmetric voxel assemblies. In this way, significant system matrix compression is achieved. Applications taking into account all physical lines-of-response (LORs) with individual VOI projectors are presented for the Siemens ECAT HR+ whole-body scanner and the Siemens BrainPET, the PET component of a novel hybrid-MR/PET imaging system. Measured and simulated data were reconstructed using the new method with ordered-subset-expectation-maximization (OSEM). Results are compared to those obtained by the sinogram-based OSEM reconstruction provided by the manufacturer. The higher computational effort due to the more accurate image space sampling provides significantly improved images in terms of resolution and noise. PMID- 21292593 TI - Accelerated dynamic MRI exploiting sparsity and low-rank structure: k-t SLR. AB - We introduce a novel algorithm to reconstruct dynamic magnetic resonance imaging (MRI) data from under-sampled k-t space data. In contrast to classical model based cine MRI schemes that rely on the sparsity or banded structure in Fourier space, we use the compact representation of the data in the Karhunen Louve transform (KLT) domain to exploit the correlations in the dataset. The use of the data-dependent KL transform makes our approach ideally suited to a range of dynamic imaging problems, even when the motion is not periodic. In comparison to current KLT-based methods that rely on a two-step approach to first estimate the basis functions and then use it for reconstruction, we pose the problem as a spectrally regularized matrix recovery problem. By simultaneously determining the temporal basis functions and its spatial weights from the entire measured data, the proposed scheme is capable of providing high quality reconstructions at a range of accelerations. In addition to using the compact representation in the KLT domain, we also exploit the sparsity of the data to further improve the recovery rate. Validations using numerical phantoms and in vivo cardiac perfusion MRI data demonstrate the significant improvement in performance offered by the proposed scheme over existing methods. PMID- 21292594 TI - FSIM: a feature similarity index for image quality assessment. AB - Image quality assessment (IQA) aims to use computational models to measure the image quality consistently with subjective evaluations. The well-known structural similarity index brings IQA from pixel- to structure-based stage. In this paper, a novel feature similarity (FSIM) index for full reference IQA is proposed based on the fact that human visual system (HVS) understands an image mainly according to its low-level features. Specifically, the phase congruency (PC), which is a dimensionless measure of the significance of a local structure, is used as the primary feature in FSIM. Considering that PC is contrast invariant while the contrast information does affect HVS' perception of image quality, the image gradient magnitude (GM) is employed as the secondary feature in FSIM. PC and GM play complementary roles in characterizing the image local quality. After obtaining the local quality map, we use PC again as a weighting function to derive a single quality score. Extensive experiments performed on six benchmark IQA databases demonstrate that FSIM can achieve much higher consistency with the subjective evaluations than state-of-the-art IQA metrics. PMID- 21292595 TI - Graph Laplace for occluded face completion and recognition. AB - This paper proposes a spectral-graph-based algorithm for face image repairing, which can improve the recognition performance on occluded faces. The face completion algorithm proposed in this paper includes three main procedures: 1) sparse representation for partially occluded face classification; 2) image-based data mining; and 3) graph Laplace (GL) for face image completion. The novel part of the proposed framework is GL, as named from graphical models and the Laplace equation, and can achieve a high-quality repairing of damaged or occluded faces. The relationship between the GL and the traditional Poisson equation is proven. We apply our face repairing algorithm to produce completed faces, and use face recognition to evaluate the performance of the algorithm. Experimental results verify the effectiveness of the GL method for occluded face completion. PMID- 21292596 TI - LCD motion blur: modeling, analysis, and algorithm. AB - Liquid crystal display (LCD) devices are well known for their slow responses due to the physical limitations of liquid crystals. Therefore, fast moving objects in a scene are often perceived as blurred. This effect is known as the LCD motion blur. In order to reduce LCD motion blur, an accurate LCD model and an efficient deblurring algorithm are needed. However, existing LCD motion blur models are insufficient to reflect the limitation of human-eye-tracking system. Also, the spatiotemporal equivalence in LCD motion blur models has not been proven directly in the discrete 2-D spatial domain, although it is widely used. There are three main contributions of this paper: modeling, analysis, and algorithm. First, a comprehensive LCD motion blur model is presented, in which human-eye-tracking limits are taken into consideration. Second, a complete analysis of spatiotemporal equivalence is provided and verified using real video sequences. Third, an LCD motion blur reduction algorithm is proposed. The proposed algorithm solves an l(1)-norm regularized least-squares minimization problem using a subgradient projection method. Numerical results show that the proposed algorithm gives higher peak SNR, lower temporal error, and lower spatial error than motion compensated inverse filtering and Lucy-Richardson deconvolution algorithm, which are two state-of-the-art LCD deblurring algorithms. PMID- 21292597 TI - Robust spatiotemporal matching of electronic slides to presentation videos. AB - We describe a robust and efficient method for automatically matching and time aligning electronic slides to videos of corresponding presentations. Matching electronic slides to videos provides new methods for indexing, searching, and browsing videos in distance-learning applications. However, robust automatic matching is challenging due to varied frame composition, slide distortion, camera movement, low-quality video capture, and arbitrary slides sequence. Our fully automatic approach combines image-based matching of slide to video frames with a temporal model for slide changes and camera events. To address these challenges, we begin by extracting scale-invariant feature-transformation (SIFT) keypoints from both slides and video frames, and matching them subject to a consistent projective transformation (homography) by using random sample consensus (RANSAC). We use the initial set of matches to construct a background model and a binary classifier for separating video frames showing slides from those without. We then introduce a new matching scheme for exploiting less distinctive SIFT keypoints that enables us to tackle more difficult images. Finally, we improve upon the matching based on visual information by using estimated matching probabilities as part of a hidden Markov model (HMM) that integrates temporal information and detected camera operations. Detailed quantitative experiments characterize each part of our approach and demonstrate an average accuracy of over 95% in 13 presentation videos. PMID- 21292598 TI - In vitro and in vivo evaluation of PEDOT microelectrodes for neural stimulation and recording. AB - Cortical neural prostheses require chronically implanted small-area microelectrode arrays that simultaneously record and stimulate neural activity. It is necessary to develop new materials with low interface impedance and large charge transfer capacity for this application and we explore the use of conducting polymer poly(3,4-ethylenedioxythiophene) (PEDOT) for the same. We subjected PEDOT coated electrodes to voltage cycling between -0.6 and 0.8 V, 24 h continuous biphasic stimulation at 3 mC/cm2 and accelerated aging for four weeks. Characterization was performed using cyclic voltammetry, electrochemical impedance spectroscopy, and voltage transient measurements. We found that PEDOT coated electrodes showed a charge injection limit 15 times higher than Platinum Iridium (PtIr) electrodes and electroplated Iridium Oxide (IrOx) electrodes when using constant current stimulation at zero voltage bias. In vivo chronic testing of microelectrode arrays implanted in rat cortex revealed that PEDOT coated electrodes show higher signal-to-noise recordings and superior charge injection compared to PtIr electrodes. PMID- 21292599 TI - Online myoelectric control of a dexterous hand prosthesis by transradial amputees. AB - A real-time pattern recognition algorithm based on k-nearest neighbors and lazy learning was used to classify, voluntary electromyography (EMG) signals and to simultaneously control movements of a dexterous artificial hand. EMG signals were superficially recorded by eight pairs of electrodes from the stumps of five transradial amputees and forearms of five able-bodied participants and used online to control a robot hand. Seven finger movements (not involving the wrist) were investigated in this study. The first objective was to understand whether and to which extent it is possible to control continuously and in real-time, the finger postures of a prosthetic hand, using superficial EMG, and a practical classifier, also taking advantage of the direct visual feedback of the moving hand. The second objective was to calculate statistical differences in the performance between participants and groups, thereby assessing the general applicability of the proposed method. The average accuracy of the classifier was 79% for amputees and 89% for able-bodied participants. Statistical analysis of the data revealed a difference in control accuracy based on the aetiology of amputation, type of prostheses regularly used and also between able-bodied participants and amputees. These results are encouraging for the development of noninvasive EMG interfaces for the control of dexterous prostheses. PMID- 21292600 TI - Low-level lead exposure and elevations in blood pressure during pregnancy. AB - BACKGROUND: Lead exposure is associated with elevated blood pressure during pregnancy; however, the magnitude of this relationship at low exposure levels is unclear. OBJECTIVES: Our goal was to determine the association between low-level lead exposure and blood pressure during late pregnancy. METHODS: We collected admission and maximum (based on systolic) blood pressures during labor and delivery among 285 women in Baltimore, Maryland. We measured umbilical cord blood lead using inductively coupled plasma mass spectrometry. Multivariable models were adjusted for age, race, median household income, parity, smoking during pregnancy, prepregnancy body mass index, and anemia. These models were used to calculate benchmark dose values. RESULTS: Geometric mean cord blood lead was 0.66 MUg/dL (95% confidence interval, 0.61-0.70). Comparing blood pressure measurements between those in the highest and those in the lowest quartile of lead exposure, we observed a 6.87-mmHg (1.51-12.21 mmHg) increase in admission systolic blood pressure and a 4.40-mmHg (0.21-8.59 mmHg) increase in admission diastolic blood pressure after adjustment for confounders. Corresponding values for maximum blood pressure increase were 7.72 (1.83-13.60) and 8.33 (1.14-15.53) mmHg. Benchmark dose lower limit values for a 1-SD increase in blood pressure were < 2 MUg/dL blood lead for all blood pressure end points. CONCLUSIONS: A significant association between low-level lead exposures and elevations in maternal blood pressure during labor and delivery can be observed at umbilical blood lead levels < 2 MUg/dL. PMID- 21292601 TI - Coronary stent fracture: how frequent it is? Does it matter? PMID- 21292602 TI - The impact of moderate aerobic physical training on left ventricular mass, exercise capacity and blood pressure response during treadmill testing in borderline and mildly hypertensive males. AB - INTRODUCTION: We sought to investigate the effect of moderate physical exercise on left ventricular mass, exercise tolerance and blood pressure response during treadmill testing, in middle-aged pre-hypertensive and mildly hypertensive men without any evidence of coronary heart disease. METHODS: Forty of 52 male borderline and mildly hypertensive subjects (mean age 53 +/- 7 years old) with a normal treadmill exercise test and echocardiographic evaluation were randomly assigned to an exercise rehabilitation programme. Patients in the exercise group participated in an aerobic exercise program for 16 weeks, three times per week, at 60 to 80 percent of the maximum heart rate achieved during the preceding exercise test. RESULTS: At baseline no statistically significant differences between the two groups were observed in METS, in left ventricular mass index, or in blood pressure measurements at rest and during treadmill testing. Sixteen weeks later the exercise group showed higher values of METS compared to the control group (p<0.001), while changes in METS from baseline to 16 weeks' follow up differed significantly between the two groups (p<0.001 for group-time interaction). Additionally, 16 weeks after randomisation, systolic/diastolic blood pressure and heart rate were significantly lower in the exercise group compared to the control group at all stages of stress testing. Finally, the left ventricular mass index decreased significantly in the exercise group (118.80 +/- 3.89 to 96.10 +/- 8.95 kg/m) during the 16 weeks of intervention. CONCLUSION: This study revealed the beneficial effect of regular exercise training on left ventricular mass index, exercise capacity and systolic/diastolic blood pressure levels in borderline hypertensive patients. PMID- 21292603 TI - Long-term results after drug-eluting stent implantation in diabetic patients according to diabetic treatment. AB - INTRODUCTION: In this prospective, single-center study we assessed the long-term results after drug-eluting stent implantation in non insulin-dependent diabetic patients compared to insulin-dependent patients. METHODS: A total of 610 consecutive diabetic patients (mean age 65 +/- 9 years) underwent percutaneous coronary intervention with drug-eluting stent implantation. They were classified into 2 groups according to their diabetic treatment: 1) non insulin-dependent patients (477); 2) insulin-dependent patients (133). The primary endpoint was the composite of death, non-fatal myocardial infarction, bypass surgery and target lesion revascularization. RESULTS: Clinical follow up for more than 12 months (median 29 months) was achieved in 597/610 patients (98%). The insulin-dependent group had more women (29% vs. 18%, p=0.003), as well as a higher incidence of multivessel disease (84% vs. 65%, p<0.0001) and ejection fraction <40% (16% vs. 9%, p=0.037) compared to the non insulin-dependent group. The in-hospital results were almost the same in both groups, except for the incidence of non-Q myocardial infarction and bleeding complications, which were more frequent in the insulin dependent group (9.8% vs. 4.8%, p=0.03, and 1.5% vs. 0%, p=0.047, respectively). During clinical follow up, no significant differences in the incidence of death or non-fatal myocardial infarction were observed, but target lesion revascularization and bypass surgery were more frequent in the insulin-dependent group (8.5% vs. 3.4%, p=0.01, and 4.7% vs. 1.3%, p=0.01, respectively). The event free survival was lower in the insulin-dependent group (hazard ratio: 0.52; 95% confidence interval, 0.31-0.85, p=0.01). CONCLUSION: The implantation of drug eluting stents in diabetics is associated with excellent in-hospital and long term results. However, the long-term effectiveness in insulin-dependent patients is lower, because of the greater risk of new revascularization. PMID- 21292604 TI - The relationship between the time interval difference of isovolumic relaxation (T[IVRT-IVRTa]) and serum levels of N-terminal pro-brain natriuretic peptide in patients with intermediate E/Ea ratio. AB - INTRODUCTION: The ratio of early diastolic transmitral velocity to early mitral annular diastolic velocity (E/Ea) can be used to group patients according to filling pressures. However this relationship has not been validated in the intermediate group (E/Ea = 8-15). The time difference between the onset of E and Ea also correlates with left ventricular (LV) filling pressures. The purpose of our study was to evaluate the correlation between the time interval difference of isovolumic relaxation (T[IVRT-IVRTa]) and N-terminal pro-brain natriuretic peptide (NTpro-BNP) in patients with an intermediate E/Ea ratio. METHODS: Echocardiography was performed simultaneously with NTpro-BNP measurement in 60 consecutive patients who had an intermediate E/Ea and were in sinus rhythm. Ea and the isovolumic relaxation time (IVRTa) at the septal and lateral sites of the mitral annulus were measured using pulsed tissue Doppler and the average was utilised. Pulsed Doppler was used to measure E and IVRT. E/Ea and IVRT-IVRTa (T[IVRT-IVRTa]) were calculated. RESULTS: We demonstrated significant correlations between T[IVRT-IVRTa] and NTpro-BNP (r = -0.72, p<0.001), maximal systolic velocity of the mitral annulus (Sa: r = -0.50, p < 0.001), pulmonary artery systolic pressure (r = 0.42, p = 0.002), IVRTa (r = -0.27, p = 0.03), LV ejection fraction (LVEF: r = -0.26, p = 0.04), IVRT (r = -0.24, p = 0.04). We were unable to demonstrate significant relationships between NTpro-BNP and E deceleration time, left atrial diameter/area/volume, Ea or E. By a multiple linear regression analysis, including T[IVRT-IVRTa], IVRT, IVRTa, E/Ea, LVEF, pulmonary artery systolic pressure and Sa as potential determinants, TIVRT-IVRTa (= -0.57, p < 0.001) was shown to be the best independent predictor of NTpro-BNP (r 2 = 0.68, p < 0.001). CONCLUSIONS: T[IVRT-IVRTa] correlates strongly with NTpro-BNP levels in patients with intermediate E/Ea, and could be used as a simple echocardiographic index, with reasonable accuracy. PMID- 21292605 TI - The role of inflammation in heart failure: new therapeutic approaches. PMID- 21292606 TI - Patient-prosthesis mismatch and strategies to prevent it during aortic valve replacement. PMID- 21292607 TI - New oral anticoagulants: should they replace heparins and warfarin? PMID- 21292608 TI - Sinus venosus defect: right heart catheterisation and computed tomographic scan. PMID- 21292609 TI - A penetrating heart injury resulting in ventricular septal defect. AB - Penetrating heart injuries can be lethal. Here we report a case of self-inflicted cardiac injury with glass fragments by a psychiatric patient. The patient presented with cardiogenic shock and was initially treated surgically for a large pneumothorax and cardiac tamponade. A few days later she presented with dyspnoea and hypotension. An echo-Doppler study was performed and an acquired post traumatic ventricular septal defect (VSD) with left-to-right shunt was diagnosed. The patient was transferred to theatre where the defect was successfully repaired. Post-traumatic VSD is a rare complication of penetrating heart injuries and has a tendency to present late. Follow up of such cases is recommended with repeat echocardiography. PMID- 21292610 TI - Incidental diagnosis of a large coronary fistula: angiographic and cardiac MRI findings. AB - Coronary artery fistulas are rare anomalies of the coronary arteries that may sometimes be totally asymptomatic and can be found incidentally during coronary arteriography later in adult life. We report the case of a 75-year-old man with such a fistula and describe our diagnostic approach. In addition, we review the literature on the etiology, epidemiology, the diagnostic modalities and treatment of coronary fistulas. PMID- 21292611 TI - Septal wire entrapment during recanalisation of a chronic total occlusion with the retrograde approach. AB - We report the case of an unsuccessful attempt at recanalisation of a chronic total occlusion via the retrograde approach, and describe a rare complication, guide wire entrapment in the donor artery and septal branch. Several conventional attempts to retrieve the guide wire were unsuccessful and led to wire fracture. A new approach, involving very deep guiding catheter intubation followed by a double guide wire rotary motion, was then used to retrieve the proximal end of the wire fragment and re-engage the uncoiled segment within the distal part of the donor artery. After assessment of the length of the remaining distal end of the wire segment with intravascular ultrasound, stent implantation crushed the wire filament to the vessel wall. PMID- 21292612 TI - Post mortem coronary angiographic visualization of a rare sinus node artery anatomical variant. AB - The incidence of sinoatrial artery variants and their significance have been repeatedly reported in the literature. Herein we describe a rare post mortem angiographic finding which concerns a unique and previously unreported case where the sinus node artery had an abnormal origin from the proximal conus artery. Although it was asymptomatic, any possible involvement with invasive or surgical procedures and its clinical consequences should be considered. PMID- 21292613 TI - Use of the frontrunner catheter to cross a chronic total occlusion of the left subclavian artery. AB - Crossing a subclavian artery chronic total occlusion may be challenging. We report the treatment of such an occlusion in a patient with a patent left internal mammary graft to the left anterior descending artery, who presented with progressive angina. Several attempts to cross the occlusion, both antegrade and retrograde, with various guidewires failed. The lesion was successfully crossed antegradely using the Frontrunner catheter and was successfully stented with resolution of the patient's angina. PMID- 21292614 TI - Lippi-induced cardiomyopathy. PMID- 21292615 TI - Cardiomyopathy centers in Greece. PMID- 21292616 TI - Are all drug-eluting stents the same? PMID- 21292621 TI - Parent mentor perspectives on providing social support to empower parents. AB - PURPOSE: To describe the experience of parent mentors providing a social support intervention to parents of children < 13 years old newly diagnosed with type 1 diabetes mellitus. METHODS: Qualitative descriptive interviews were conducted with 6 parent mentors (all mothers) who provided social support to 34 mothers and 19 fathers of children newly diagnosed with type 1 diabetes mellitus over a 12 month period. The mentors were trained to provide informational, affirmational, and emotional social support through home visits, phone calls, and/or e-mail. Qualitative content analysis was used to identify themes guided by the Ireys social support framework. FINDINGS: The parent mentors described support activities that could be categorized into the 3 types of support defined in the Ireys framework. The parent mentors provided informational support, such as tips for travel, school, parties and family get-togethers, camp resources, and how to advocate for the child. Affirmational support was provided by sharing stories and validating parents' feelings and experiences. Emotional support was provided by "being there" for the parents. No instances were described where parent mentors were pushed to give advice on medical management issues but were more so used for advice on growth and development, sleep, and healthy eating suggestions. Parent mentors also reported being empowered by the role by helping others. CONCLUSION: Careful selection of parent mentors is a strategy for providing social support to parents of children newly diagnosed with type 1 diabetes mellitus, especially in day-to-day management areas that the health care professionals have not experienced. PMID- 21292622 TI - Understanding self-monitoring of blood glucose among individuals with type 1 and type 2 diabetes: an information-motivation-behavioral skills analysis. AB - PURPOSE: To evaluate self-monitoring of blood glucose (SMBG) information deficits, motivational obstacles, and behavioral skills limitations in individuals with type 1 and type 2 diabetes, and to assess the relationship of these deficits with SMBG frequency. METHODS: Individuals with type 1 (n = 208; 103 male, 105 female) and type 2 (n = 218; 107 male, 111 female) diabetes participated in an online survey assessing SMBG information, motivation, behavioral skills, and behavior. RESULTS: A substantial proportion of participants scored as SMBG uninformed, unmotivated, and unskilled on specific assessment items. SMBG information, motivation, and behavioral skills deficits were significantly correlated with SMBG frequency, such that individuals with type 1 or type 2 diabetes, who were less informed, less motivated, and less behaviorally skilled, reported lower frequency of SMBG. CONCLUSION: Common and consequential SMBG information, motivation, and behavioral skills deficits were present, and patients with these gaps were less likely to test frequently. Clinical education focusing on relevant SMBG information, motivation to act, and behavioral skills for acting effectively may be a priority. PMID- 21292623 TI - The ABCs of diabetes: diabetes self-management education program for African Americans affects A1C, lipid-lowering agent prescriptions, and emergency department visits. AB - PURPOSE: The purpose of the study was to examine the feasibility and impact of a concise community-based program on diabetes self-management education (DSME), according to frequency of emergency department visits and knowledge of, prescriptions for, and control of A1C, blood pressure, and low-density lipoprotein (LDL) cholesterol. METHODS: A free community-based DSME program was placed in a public library. Adults with diabetes (N, 360) consented to participate in this prospective nonrandomized cohort study with preintervention postintervention design. The small-group interactive DSME (two 2.5-hour classes) focused on improving cardiovascular disease risk factors and facilitating communication with the primary care physician. RESULTS: An increase in knowledge of American Diabetes Association-recommended targets for A1C, blood pressure, and LDL cholesterol from baseline to postintervention was seen among participants. Significant clinical outcomes included reduction in self-reported emergency department visits and reduction in mean A1C. However, despite an increase in prescriptions written for lipid-lowering drugs, blood pressure and LDL cholesterol did not change. Participants who started on insulin were more likely to achieve or maintain A1C < 7% compared to those who either did not take or stopped taking insulin during the study. CONCLUSIONS: Offering DSME classes for African Americans at a public library was feasible and significantly affected 6 month clinical outcomes, including a reduction in A1C, an increased likelihood of attaining a target A1C of < 7% if insulin was started during the study period, and a two-thirds reduction in emergency department visits for uncontrolled diabetes. Observed results suggest that partnering with community-based organizations such as public libraries offers an accessible and well-received location for offering DSME programs. PMID- 21292624 TI - Re: Community-based diabetes education for Latinos. PMID- 21292625 TI - Drug burden index and beers criteria: impact on functional outcomes in older people living in self-care retirement villages. AB - The objectives of this study were to determine whether Drug Burden Index (DBI), a measure of individuals' exposure to anticholinergic and sedative drugs, and Beers criteria, an explicit measure of potentially inappropriate drug use, are associated with function in older adults living in low-level care facilities; and to compare DBI with Beers criteria as a predictor of function in older people. The study population consisted of 115 residents living in low-level care facilities in Sydney, Australia. Data on demographics, drugs, and comorbidities were collected. Outcomes included objective measures of physical function Short Performance Physical Battery (SPPB) and grip strength. In total, 50 (44%) participants were exposed to DBI drugs, 51 (44%) participants received at least 1 Beers criteria drug, and 30 (26%) were exposed to both. After adjusting for confounders, for every unit increase in DBI, the SPPB score decreased by 1.3 (P = .04). DBI was not associated with weaker grip strength. Beers criteria were not associated with any of the outcomes. In older adults living in self-care retirement villages, DBI was associated with impairments in physical functioning. Exposure to Beers criteria drugs was common; however, Beers criteria did not predict functional outcomes in this population of older adults. PMID- 21292626 TI - Family doctors' views of pharmaceutical sales representatives: assessment scale development. AB - BACKGROUND: The prescribing patterns depend on the physicians' attitudes and their subjective norms towards prescribing a particular drug, as well as on their personal experience with a particular drug. The physicians are affected by their interactions with pharmaceutical industry. OBJECTIVE: The objectives were to develop a scale for assessment of pharmaceutical sales representatives (PSRs) by the family doctors (FDs) and to determine factors for their evaluation. METHOD: Cross-sectional anonymous postal study. We included a random sample of 250 Slovenian FDs. Settings. Slovenian FDs' surgeries. MAIN OUTCOME MEASURE: The score of various items regarding FDs' assessment of PSRs on a 7-point Likert scale. RESULTS: We got 163 responses (65.2% response rate). The most important characteristic of PSRs, as rated by respondents on the scale from 1 to 7, was the fact that they did not mislead when presenting products' information. The second most important characteristic was the ability to provide objective information about the product. The first three most important characteristics, as rated by the respondents by themselves, were 'Shows good knowledge on the promoted subject', 'Provides objective product information' and 'Makes brief and exact visits'. Cronbach's alpha of the composite scale was 0.844. Factor analysis revealed three PSRs' factors: selling skills, communicating skills and sense of trustworthiness. CONCLUSION: FDs evaluate PSRs mainly by their managerial skills and trustworthiness. The scale proved to be a reliable tool for assessing PSRs by FDs. PMID- 21292627 TI - Asthma medication use in infancy: determinants related to prescription of drug therapy. AB - BACKGROUND: Little is known about factors that determine prescribing of asthma therapy in infancy. OBJECTIVE: To describe factors related to the initiation and refill of asthma therapy in infancy. METHODS: This study included 1202 infants who participated in a prospective birth cohort study: the 'Wheezing Illnesses Study Leidsche Rijn (WHISTLER)'. Outcomes, asthma therapy initiation and refill, were assessed using prescription data. Logistic regression analysis was used to study determinants of therapy initiation in two groups: total population and infants with a respiratory system symptom diagnosis. In addition, determinants of refilling prescriptions were studied in infants who started therapy in their first year of life. RESULTS: Fifteen per cent of all infants started asthma therapy in their first year of life. Respiratory symptoms were an important driver of both initiation and refill of prescriptions. In the total population, therapy initiation was associated with male gender [odds ratio (OR): 1.6, 95% confidence interval (CI): 1.1-2.6], day-care attendance (OR: 1.6, 95% CI: 1.0 2.5) and breastfeeding (OR: 0.6, 95% CI: 0.3-1.0). For infants with a respiratory system symptom diagnosis, day-care attendance was associated with an increased chance of therapy initiation (OR: 5.3, 95% CI: 1.8-16.2) and breastfeeding was associated with a lower chance of starting therapy (OR: 0.4, 95% CI: 0.1-1.1). Dutch children had a higher chance of refilling prescriptions in infancy (OR: 5.3, 95% CI: 1.1-26.8). CONCLUSIONS: Apart from other factors involved, the principal reason for initiation and refill of asthma therapy in infancy was the presence of respiratory symptoms. This appeared the only reason to prescribe medication and physicians are not distracted by other factors. PMID- 21292628 TI - Plastids, genomes, and the probability of gene transfer. PMID- 21292629 TI - Correlation between nuclear plastid DNA abundance and plastid number supports the limited transfer window hypothesis. AB - The abundance of nuclear plastid DNA-like sequences (NUPTs) in nuclear genomes can vary immensely; however, the forces responsible for this variation are poorly understood. "The limited transfer window hypothesis" predicts that species with only one plastid per cell will have fewer NUPTs than those with many plastids per cell, but a lack of genome sequence data from monoplastidic species has made this hypothesis difficult to test. Here, by analyzing newly available genome sequences from diverse mono- and polyplastidic taxa, we show that the hypothesis holds. On average, the polyplastidic species we studied had 80 times more NUPTs than those that were monoplastidic. Moreover, NUPT content was positively related to nuclear genome size, indicating that in addition to plastid number, NUPTs are influenced by the forces controlling the expansion and contraction of noncoding nuclear DNA. These findings are consistent with data on nuclear DNAs of mitochondrial origin (NUMTs), suggesting that similar processes govern the abundance of both NUPTs and NUMTs. PMID- 21292630 TI - Complete bacteriophage transfer in a bacterial endosymbiont (Wolbachia) determined by targeted genome capture. AB - Bacteriophage flux can cause the majority of genetic diversity in free-living bacteria. This tenet of bacterial genome evolution generally does not extend to obligate intracellular bacteria owing to their reduced contact with other microbes and a predominance of gene deletion over gene transfer. However, recent studies suggest intracellular coinfections in the same host can facilitate exchange of mobile elements between obligate intracellular bacteria-a means by which these bacteria can partially mitigate the reductive forces of the intracellular lifestyle. To test whether bacteriophages transfer as single genes or larger regions between coinfections, we sequenced the genome of the obligate intracellular Wolbachia strain wVitB from the parasitic wasp Nasonia vitripennis and compared it against the prophage sequences of the divergent wVitA coinfection. We applied, for the first time, a targeted sequence capture array to specifically trap the symbiont's DNA from a heterogeneous mixture of eukaryotic, bacterial, and viral DNA. The tiled array successfully captured the genome with 98.3% efficiency. Examination of the genome sequence revealed the largest transfer of bacteriophage and flanking genes (52.2 kb) to date between two obligate intracellular coinfections. The mobile element transfer occurred in the recent evolutionary past based on the 99.9% average nucleotide identity of the phage sequences between the two strains. In addition to discovering an evolutionary recent and large-scale horizontal phage transfer between coinfecting obligate intracellular bacteria, we demonstrate that "targeted genome capture" can enrich target DNA to alleviate the problem of isolating symbiotic microbes that are difficult to culture or purify from the conglomerate of organisms inside eukaryotes. PMID- 21292631 TI - Association between sex-biased gene expression and mutations with sex-specific phenotypic consequences in Drosophila. AB - Genome-wide mRNA transcription profiles reveal widespread molecular sexual dimorphism or "sex-biased" gene expression, yet the relationship between molecular and phenotypic sexual dimorphism remains unclear. A major unresolved question is whether sex-biased genes typically perform male- and female-specific functions (whether these genes have sex-biased phenotypic or fitness consequences) or have similar functional importance for both sexes. To elucidate the relationship between sex-biased transcription and sex-biased fitness consequences, we analyzed a large data set of lethal, visible, and sterile mutations that have been mapped to the Drosophila melanogaster genome. The data permitted us to classify genes according to their sex-specific mutational effects and to infer the relationship between sex-biased transcription level and sex specific fitness consequences. We find that mutations in female-biased genes are (on average) more deleterious to females than to males and that mutations in male biased genes tend to be more deleterious to males than to females. Nevertheless, mutations in most sex-biased genes have similar phenotypic consequences for both sexes, which suggests that sex-biased transcription is not necessarily associated with functional genetic differentiation between males and females. These results have interesting implications for the evolution of sexual dimorphism and sex specific adaptation. PMID- 21292632 TI - A strong case for personalized, targeted cancer prevention. AB - The study reported by Lee and colleagues in this issue of the journal (beginning on page 185) incorporated global genetic variation within a new assessment of the outcome of a previously reported phase-III trial of low-dose 13-cis-retinoic acid (13-cRA) for preventing second primary tumors (SPT) or the recurrence of head-and neck cancer. This analysis identified genotypes of common single-nucleotide polymorphisms (SNP) and cumulative effect and potential gene-gene interactions that were highly associated with increased placebo-arm risk (prognostic) and/or with reduced treatment-arm risk and longer event-free survival (predictive). For example, the wild-type rs3118570 SNP of the retinoid X receptor alpha gene (carried by 71% of the 13-cRA trial population) marked a 3.33-fold increased SPT/recurrence risk in the placebo arm and a 38% reduced risk in the treatment arm. Adding two other informative genotypes strengthened the treatment-arm risk reduction to 76%, although the genotype trio reflected only 13% of the trial population. This report extends the concept of personalized therapy to cancer prevention. PMID- 21292633 TI - Global assessment of genetic variation influencing response to retinoid chemoprevention in head and neck cancer patients. AB - Head and neck squamous cell carcinoma (HNSCC) patients are at an increased risk of developing a second primary tumor (SPT) or recurrence following curative treatment. 13-cis-retinoic acid (13-cRA) has been tested in chemoprevention clinical trials, but the results have been inconclusive. We genotyped 9,465 single nucleotide polymorphisms (SNP) in 450 patients from the Retinoid Head and Neck Second Primary Trial. SNPs were analyzed for associations with SPT/recurrence in patients receiving placebo to identify prognosis markers and further analyzed for effects of 13-cRA in patients with these prognostic loci. Thirteen loci identified a majority subgroup of patients at a high risk of SPT/recurrence and in whom 13-cRA was protective. Patients carrying the common genotype of rs3118570 in the retinoid X receptor (RXRA) were at a 3.33-fold increased risk (95% CI, 1.67-6.67) and represented more than 70% of the study population. This locus also identified individuals who received benefit from chemoprevention with a 38% reduced risk (95% CI, 0.43-0.90). Analyses of cumulative effect and potential gene-gene interactions also implicated CDC25C:rs6596428 and JAK2:rs1887427 as 2 other genetic loci with major roles in prognosis and 13-cRA response. Patients with all 3 common genotypes had a 76% reduction in SPT/recurrence (95% CI, 0.093-0.64) following 13-cRA chemoprevention. Carriers of these common genotypes constituted a substantial percentage of the study population, indicating that a pharmacogenetic approach could help select patients for 13-cRA chemoprevention. The lack of any alternatives for reducing risk in these patients highlights the need for future clinical trials to prospectively validate our findings. PMID- 21292634 TI - Characterization of the methylation patterns in human papillomavirus type 16 viral DNA in head and neck cancers. AB - Human papillomavirus (HPV) type 16 can integrate into the host genome, thereby rendering the viral coding genes susceptible to epigenetic modification. Using bisulfite genomic sequencing, we determined the methylation status of all 110 CpG sites within the viral epigenome in advanced stage III/IV HPV-16-associated head and neck cancers. We found that the viral genome was hypomethylated in the majority of head and neck cancers, in particular within the viral regulatory region, long control region (LCR), which controls transcription of the E6 and E7 oncogenes. The hypomethylation status of LCR correlated with detectable levels of E6 and E7 expression, which suggests that the tumors may still be dependent on these viral oncogenes to maintain the malignant phenotype. In addition to the methylation status of LCR, we report other potential factors which may influence intratumoral E6 and E7 expression including viral copy number and integration site. We were able to detect the viral epigenetic alterations in sampled body fluids, such as serum and saliva, which correlated with the changes observed in the primary tumors. Because viral epigenetic changes occur in the setting of viral integration into the human genome, the detection of methylated HPV genes in the serum and/or saliva may have diagnostic potential for early detection strategies of viral integration and assessment of risk for cancer development in high-risk individuals. Our findings also support continued targeting of the E6 and/or E7 antigens through various vaccine strategies against HPV-associated cancers. PMID- 21292635 TI - Gene expression profiling predicts the development of oral cancer. AB - Patients with oral premalignant lesion (OPL) have a high risk of developing oral cancer. Although certain risk factors, such as smoking status and histology, are known, our ability to predict oral cancer risk remains poor. The study objective was to determine the value of gene expression profiling in predicting oral cancer development. Gene expression profile was measured in 86 of 162 OPL patients who were enrolled in a clinical chemoprevention trial that used the incidence of oral cancer development as a prespecified endpoint. The median follow-up time was 6.08 years and 35 of the 86 patients developed oral cancer over the course. Gene expression profiles were associated with oral cancer-free survival and used to develop multivariate predictive models for oral cancer prediction. We developed a 29-transcript predictive model which showed marked improvement in terms of prediction accuracy (with 8% predicting error rate) over the models using previously known clinicopathologic risk factors. On the basis of the gene expression profile data, we also identified 2,182 transcripts significantly associated with oral cancer risk-associated genes (P value < 0.01; univariate Cox proportional hazards model). Functional pathway analysis revealed proteasome machinery, MYC, and ribosomal components as the top gene sets associated with oral cancer risk. In multiple independent data sets, the expression profiles of the genes can differentiate head and neck cancer from normal mucosa. Our results show that gene expression profiles may improve the prediction of oral cancer risk in OPL patients and the significant genes identified may serve as potential targets for oral cancer chemoprevention. PMID- 21292636 TI - The association of maternal factors with delayed implantation and the initial rise of urinary human chorionic gonadotrophin. AB - BACKGROUND Late implantation and the pattern of early rise in hCG have been associated with early pregnancy loss. We explored factors that might be predictive of these markers of poor embryonic health in spontaneously conceived pregnancies. METHODS Participants in the North Carolina Early Pregnancy Study collected daily first-morning urine specimens while attempting to conceive. Samples were assayed for estrogen and progesterone metabolites (to identify day of ovulation) and hCG (to detect conception). Data were available for 190 pregnancies, 48 of which ended in early loss (within 6 weeks of the last menstrual period). We used logistic regression to identify characteristics associated with late implantation (>=10 days post-ovulation). For pregnancies surviving at least 6 weeks (n= 142), we used linear mixed models to identify factors associated with variations in hCG rise in the first 7 days from detection. RESULTS Later implantation was associated with current maternal smoking [odds ratio (OR): 5.7; 95% confidence interval (CI): 1.1-30] and with oocytes that were likely to have been fertilized late in their post-ovulatory lifespan (OR: 5.1; CI: 1.9-16). Older women had a faster rise in hCG (P= 0.01), as did women who had relatively late menarche (P for trend = 0.02). Women exposed in utero to diethylstilbestrol showed an unusual pattern of slow initial hCG rise followed by a fast increase, a pattern significantly different from that of unexposed women (P= 0.002). CONCLUSIONS Although limited by small numbers and infrequent exposures, our analyses suggest that a woman's exposures both early in life and at the time of pregnancy may influence early development of the conceptus. PMID- 21292637 TI - Two cheers for clinical practice guidelines: the hopes and headaches of quality improvement in reproductive healthcare. PMID- 21292638 TI - PGD for a complex chromosomal rearrangement by array comparative genomic hybridization. AB - Patients carrying a chromosomal rearrangement (CR) have an increased risk for chromosomally unbalanced conceptions. Preimplantation genetic diagnosis (PGD) may avoid the transfer of embryos carrying unbalanced rearrangements, therefore increasing the chance of pregnancy. Only 7-12 loci can be screened by fluorescence in situ hybridization whereas microarray technology can detect genome-wide imbalances at the single cell level. We performed PGD for a CR carrier with karyotype 46,XY,ins(3;2)(p23;q23q14.2),t(6;14)(p12.2;q13) using array comparative genomic hybridization. Selection of embryos for transfer was only based on copy number status of the chromosomes involved in both rearrangements. In two ICSI-PGD cycles, nine and seven embryos were analysed by array, leaving three and one embryo(s) suitable for transfer, respectively. The sensitivity and specificity of single cell arrays was 100 and 88.8%, respectively. In both cycles a single embryo was transferred, resulting in pregnancy following the second cycle. The embryo giving rise to the pregnancy was normal/balanced for the insertion and translocation but carried a trisomy 8 and nullisomy 9 in one of the two biopsied blastomeres. After 7 weeks of pregnancy the couple miscarried. Genetic analysis following hystero-embryoscopy showed a diploid (90%)/tetraploid (10%) mosaic chorion, while the gestational sac was empty. No chromosome 8 aneuploidy was detected in the chorion, while 8% of the cells carried a monosomy for chromosome 9. In summary, we demonstrate the feasibility and determine the accuracy of single cell array technology to test against transmission of the unbalanced meiotic products that can derive from CRs. Our findings also demonstrate that the genomic constitution of extra-embryonic tissue cannot necessarily be predicted from the copy number status of a single blastomere. PMID- 21292639 TI - The post-operative decline in serum anti-Mullerian hormone correlates with the bilaterality and severity of endometriosis. AB - BACKGROUND To assess the impact of ovarian cystectomy for endometriomas on the ovarian reserve, we evaluated the pre- and post-operative levels of serum anti Mullerian hormone (AMH). We also analyzed the correlations between factors related to endometriosis and surgery for endometriomas and the serum AMH levels to investigate which factors affect ovarian reserve. METHODS Thirty-eight patients who were undergoing ovarian cystectomy for unilateral endometrioma (n = 20) and bilateral endometriomas (n = 18) participated. Preoperative and post operative serum samples were collected and assayed for AMH levels, and changes between the two samples were analyzed in association with parameters of endometriosis and surgery for endometriomas. RESULTS The mean AMH level was 3.9 ng/ml prior to surgery, and was reduced to 2.1 ng/ml at 1 month post-surgery. The rate of decline of the serum AMH level was significantly higher in the bilateral group than the unilateral group (62.8 +/- 29.6 versus 24.7 +/- 32.5%, P < 0.001). The rate of decline in the serum AMH levels showed a significant correlation to the revised American Society for Reproductive Medicine (rASRM) score (P = 0.003), but not age, cyst diameter, blood loss during the operation or the number of follicles removed in the specimens. CONCLUSIONS Our results suggest that the decrease in ovarian reserve should be taken into account in patients indicated for cystectomy for bilateral endometriomas or unilateral endometrioma with high rASRM scores. PMID- 21292640 TI - Aryl hydrocarbon receptor ligands of widely different toxic equivalency factors induce similar histone marks in target gene chromatin. AB - Posttranslational histone modifications are a critical regulatory mechanism of gene transcription. Previous studies from our laboratory have shown that contingent on binding to its cognate promoter motifs in the Cyp1a1 gene, activation of the aryl hydrocarbon receptor (AHR) by benzo[a]pyrene (BaP) treatment induces histone modifications in the Cyp1a1 promoter that are required for activation of gene transcription. Here, we have studied different AHR ligands, including polychlorinated biphenyls (PCBs) of different toxic equivalency factors (TEF), to determine whether changes in histone modifications are linked to different levels of Cyp1a1 expression or dependent on AHR-ligand affinity. We find that all ligands lead to the same pattern of histone modifications in a relationship that parallels the strength of their AHR-ligand affinity. Thus, whereas PCB126 (TEF 0.1), 3-methylcholanthrene, beta naphthoflavone, and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) initiate a pattern of histone marks similar to those induced by BaP, PCB77 (TEF 0.0001) causes a lower level of change in the same marks and requires a longer activation time than PCB126, BaP, or TCDD. In contrast, the non-dioxin-like PCB153 recruits AHR to the Cyp1a1 enhancer causing a displacement of enhancer-associated histone H3 but does not cause the other observed histone mark changes nor does it induce transcription. These results indicate that AHR recruitment to the promoter is not sufficient to induce the histone modifications needed to activate gene expression and show that there is a good correlation between the regulatory chromatin changes associated with ligand-induced AHR target gene transcription and the resultant toxicity of the ligand. PMID- 21292641 TI - Toluene effect on the olivocochlear reflex. AB - Animal studies have shown that toluene can cause hearing loss and can exacerbate the effects of noise by inhibiting the middle ear acoustic reflex. In this investigation, carried out in Long-Evans rats, the tensor tympani tendon was cutoff and the stapedius muscle was electrocoagulated in one or both middle ears. Rat hearing was evaluated by measuring cubic distortion otoacoustic emissions (2f1-f2; f1 = 8000 Hz; f2 = 9600 Hz; f1/f2 = 1.2) prior to, during, and after activation of the olivocochlear (OC) reflex. A band noise centered at 4 kHz was used as suppressor noise. It was delivered contralaterally to decrease 2f1-f2 amplitude. The strength of the inner ear acoustic reflex was tested by increasing contralateral noise intensity, and toluene injected into the carotid artery was used to study physiological efficacy. Results showed that the protective effect of the OC reflex is intensity dependent. In addition, the OC reflex was found to be less sensitive to toluene than the middle ear acoustic reflex. This may be because the efferent neurons involved in inner ear and middle ear reflexes are located differently. In conclusion, the synergistic effects on hearing of co exposure to noise and aromatic solvents are because of solvents depressing the central nuclei, which mainly drive the middle ear acoustic reflex. PMID- 21292643 TI - Changes in pre-diagnostic serum C-reactive protein concentrations and ovarian cancer risk: a longitudinal study. AB - BACKGROUND: Evidence suggests that inflammation may be associated with increased risk of ovarian cancer but there is paucity of studies investigating this association, especially using over-time changes in inflammatory biomarkers. MATERIALS AND METHODS: We conducted a prospective population-based case-control study nested within the Finnish Maternity Cohort (FMC). Within the FMC, 170 women with ovarian cancer who had donated serum samples to the cohort twice, >=1 year apart, before cancer diagnoses were identified. One control per case was matched for age, parity and sampling date. RESULTS: Comparing the highest with lowest tertiles, the odds ratio (OR) of ovarian cancer using the first set of serum samples (mean lag time to cancer diagnosis 9.0 years) was 1.62 [95% confidence interval (CI) 0.93-2.83]. However, analysis conducted using the second set of serum samples donated closer to cancer diagnosis (mean lag time 6.4 years) revealed a significantly increased risk of ovarian cancer comparing extreme tertiles of C-reactive protein (CRP) concentrations; OR 1.96 (95% CI 1.11-3.4). Over time, increases in individuals' CRP concentrations were also associated with increased risk; OR 1.90 (95% CI 1.12-3.23). CONCLUSION: The results suggest that inflammation may precede ovarian cancer since increasing CRP concentrations, both across tertiles and longitudinally at the individual level, were associated with increased risk. PMID- 21292642 TI - Reversal and prevention of arsenic-induced human bronchial epithelial cell malignant transformation by microRNA-200b. AB - Arsenic is a well-recognized human carcinogen, yet the mechanism by which it causes human cancer has not been elucidated. MicroRNAs (miRNAs) are a big family of small noncoding RNAs and negatively regulate the expression of a large number of protein-coding genes. We investigated the role of miRNAs in arsenic-induced human bronchial epithelial cell malignant transformation and tumor formation. We found that prolonged exposure of immortalized p53-knocked down human bronchial epithelial cells (p53(low)HBECs) to low levels of arsenite (NaAsO2, 2.5 MUM) caused malignant transformation that was accompanied by epithelial to mesenchymal transition (EMT) and reduction in the levels of miR-200 family members. Stably reexpressing miR-200b in arsenite-transformed cells (As-p53(low)HBECs) completely reversed their transformed phenotypes, as evidenced by inhibition of colony formation in soft agar and prevention of xenograft tumor formation in nude mice. Moreover, stably expressing miR-200b alone in parental nontransformed p53(low)HBECs was sufficient to completely prevent arsenite exposure from inducing EMT and malignant transformation. Further mechanistic studies showed that depletion of miR-200 in arsenite-transformed cells involved induction of the EMT-inducing transcription factors zinc-finger E-box-binding homeobox factor 1 (ZEB1) and ZEB2 and increased methylation of miR-200 promoters. Stably expressing ZEB1 alone in parental nontransformed p53(low)HBECs was sufficient to deplete miR 200, induce EMT and cause cell transformation, phenocopying the oncogenic effect of 16-week arsenite exposure. These findings establish for the first time a causal role for depletion of miR-200b expression in human cell malignant transformation and tumor formation resulting from arsenic exposure. PMID- 21292644 TI - Randomized comparison of pegfilgrastim day 4 versus day 2 for the prevention of chemotherapy-induced leukocytopenia. AB - BACKGROUND: To study the effects of deferring pegfilgrastim until day 4 on the reduction of chemotherapy-induced leukocytopenia. PATIENTS AND METHODS: Patients of age 61-80 years with aggressive lymphoma were randomly assigned to receive 6 mg pegfilgrastim on day 2 or 4 of a 2-week chemotherapy regimen (R-CHOP-14). RESULTS: Two hundred and ninety-two and 313 chemotherapy cycles were evaluable in 103 patients. Post-nadir pegfilgrastim serum levels were higher after day 4 than after day 2 application. This was associated with an attenuated leukocyte nadir after day 4 pegfilgrastim and there were fewer days with leukocytes <2 * 10(3)/mm(3) compared with day 2 pegfilgrastim. Grade 3 and 4 leukocytopenias (70% versus 43.3%; P < 0.001) and grade 4-only leukocytopenias (47% versus 20.5%; P < 0.001) were more frequent after day 2 pegfilgrastim. There were more chemotherapy cycles with grade 3 and 4 infections after day 2 than day 4 pegfilgrastim (9.4% versus 6.0%; P = 0.118). Interventional antibiotics were given more often after day 2 than after day 4 pegfilgrastim (30.7% versus 21.9% of cycles; P = 0.008). There were five deaths during leukocytopenia after day 2 and none after day 4 pegfilgrastim (P = 0.027). CONCLUSIONS: Administration of pegfilgrastim on day 4 was more effective in reducing severe leukocytopenias and resulted in fewer deaths during leukocytopenia. Pegfilgrastim should be given on day 4 to better exploit its myeloprotective potential. PMID- 21292645 TI - Is FISH floating or still swimming in the lung cancer ocean? PMID- 21292646 TI - Current trials of cytotoxic and targeted agents in breast cancer: the caveat of radiotherapy. PMID- 21292647 TI - Association of a novel functional promoter variant (rs2075533 C>T) in the apoptosis gene TNFSF8 with risk of lung cancer--a finding from Texas lung cancer genome-wide association study. AB - Published genome-wide association studies (GWASs) have identified few variants in the known biological pathways involved in lung cancer etiology. To mine the possibly hidden causal single nucleotide polymorphisms (SNPs), we explored all SNPs in the extrinsic apoptosis pathway from our published GWAS dataset for 1154 lung cancer cases and 1137 cancer-free controls. In an initial association analysis of 611 tagSNPs in 41 apoptosis-related genes, we identified only 10 tagSNPs associated with lung cancer risk with a P value<10(-2), including four tagSNPs in DAPK1 and three tagSNPs in TNFSF8. Unlike DAPK1 SNPs, TNFSF8 rs2181033 tagged other four predicted functional but untyped SNPs (rs776576, rs776577, rs31813148 and rs2075533) in the promoter region. Therefore, we further tested binding affinity of these four SNPs by performing the electrophoretic mobility shift assay. We found that only rs2075533T allele modified levels of nuclear proteins bound to DNA, leading to significantly decreased expression of luciferase reporter constructs by 5- to -10-fold in H1299, HeLa and HCT116 cell lines compared with the C allele. We also performed a replication study of the untyped rs2075533 in an independent Texas population but did not confirm the protective effect. We further performed a mini meta-analysis for SNPs of TNFSF8 obtained from other four published lung cancer GWASs with 12 214 cases and 47 721 controls, and we found that only rs3181366 (r2=0.69 with the untyped rs2075533) was associated to lung cancer risk (P=0.008). Our findings suggest a possible role of novel TNFSF8 variants in susceptibility to lung cancer. PMID- 21292648 TI - Successful treatment of catecholaminergic polymorphic ventricular tachycardia with flecainide: a case report and review of the current literature. AB - Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease that can cause sudden cardiac death due to ventricular fibrillation (VF). While pharmacological therapy with beta-blockers and/or Ca(2)(+) antagonists is often unreliable, a recent study has demonstrated that flecainide can effectively suppress arrhythmia in a murine model of CPVT as well as clinically in two human subjects suffering from CPVT. We here present the case of an 11-year-old boy suffering from CPVT-1 as well as a review of the current relevant literature. After resuscitation due to VF at age 9, an automated implantable cardioverter-defibrillator (ICD) was implanted in 2007. Under beta blocker therapy, repeated shocks were delivered due to either fast ventricular tachycardia (VT) or VF. This persisted under additional therapy with verapamil. Implantable cardioverter-defibrillator routine interrogations showed frequent non sustained VT with an average of 8.8 per day. Additionally, the patient suffered from impaired physical performance due to decreased chronotropic competence. In July 2009, flecainide was added to the beta-blocker/verapamil regimen, resulting in a plasma level of 0.20 mg/L. No ICD shock or sustained VT occurred until December 2010. Genetic testing revealed an RyR2 receptor mutation. The case demonstrates the challenge of diagnosis and management of CPVT. It furthermore supports recent experimental evidence that the class 1 antiarrhythmic drug flecainide can suppress CPVT. The presented case supports a novel strategy in treating CPVT with the class I antiarrhythmic agent flecainide. PMID- 21292649 TI - A case of difficult temporary pacing. AB - A 55-year-old lady came with recurrent syncope due to complete heart block. A temporary pacing lead could not be advanced via the inferior vena cava (IVC) to the right atrium. A venogram demonstrated that the IVC had no connection to the right atrium. The temporary lead could then be advanced through the azygos and superior caval vein to the right atrium and ventricle. The patient had no congenital heart disease or visceral heterotaxy. PMID- 21292654 TI - International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. AB - A Panel of International Experts was convened by the Infectious Diseases Society of America (IDSA) in collaboration with the European Society for Microbiology and Infectious Diseases (ESCMID) to update the 1999 Uncomplicated Urinary Tract Infection Guidelines by the IDSA. Co-sponsoring organizations include the American Congress of Obstetricians and Gynecologists, American Urological Association, Association of Medical Microbiology and Infectious Diseases-Canada, and the Society for Academic Emergency Medicine. The focus of this work is treatment of women with acute uncomplicated cystitis and pyelonephritis, diagnoses limited in these guidelines to premenopausal, non-pregnant women with no known urological abnormalities or co-morbidities. The issues of in vitro resistance prevalence and the ecological adverse effects of antimicrobial therapy (collateral damage) were considered as important factors in making optimal treatment choices and thus are reflected in the rankings of recommendations. PMID- 21292655 TI - Analysis of drug-resistant strains of Mycobacterium leprae in an endemic area of Vietnam. AB - BACKGROUND: Multidrug therapy has effectively reduced the number of leprosy cases in the world. However, the rate of reduction has decelerated over the years, giving early detection of Mycobacterium leprae and epidemiological study of relapse renewed relevance in attempts to eliminate the disease. METHODS: A molecular epidemiological survey for drug-resistant M. leprae was conducted in the central and highland regions of Vietnam. A total of 423 samples taken from patients, including 83 patients with new cases, 321 patients receiving treatment, and 19 patients with relapse, were studied for detection of M. leprae with mutations relating to drug resistance by sequencing the drug resistance determining region of the folP1, rpoB, and gyrA genes, which are responsible for dapsone, rifampicin, and ofloxacin resistance, respectively. RESULTS: Nineteen mutations were found in the folP1 gene samples, and no mutations relating to drug resistance were found in either the rpoB or gyrA genes. Samples from patients with relapse showed folP1 mutation rates as high as 57%, and the mutation rates in samples from new and recent cases were <10%. Patients with relapse who had histories of treatment with dapsone monotherapy showed high mutation rates (78%), compared with patients with relapse who had previously only received multidrug therapy (33%). CONCLUSIONS: Our study indicated high rates of dapsone resistance in patients with relapse, compared with patients with new and recent cases of leprosy. Moreover, it was observed that many of the patients with relapse who had dapsone-resistant mutations had histories of treatment with dapsone monotherapy. PMID- 21292656 TI - Severe refractory erythema nodosum leprosum successfully treated with the tumor necrosis factor inhibitor etanercept. AB - Erythema nodosum leprosum (ENL), or type II reaction, is a common complication of lepromatous leprosy that can cause significant patient debility. First-line therapy includes prednisone and thalidomide, with clofazimine reserved for patients who do not respond to first-line treatment. We present the case of a 33 year-old woman with ENL that failed to respond adequately to conventional therapy over a 6-year period. Because of the severe nature of her disease and the adverse effects of therapy that she experienced, a trial of etanercept was undertaken, which led to full resolution of her ENL. The rationale behind our choice of therapy and its future implications are discussed. PMID- 21292659 TI - Clinical and microbiologic outcomes in patients receiving treatment for Mycobacterium abscessus pulmonary disease. AB - BACKGROUND: Mycobacterium abscessus can produce a chronic pulmonary infection for which little is known regarding optimal treatment and long-term outcomes. METHODS: We performed a retrospective observational study (2001-2008) including all patients who met American Thoracic Society criteria for M. abscessus pulmonary disease. Our aim was the evaluation of clinical and microbiologic outcomes in patients treated with combined antibiotic and surgical therapy, compared with antibiotic therapy alone. RESULTS: A total of 107 patients were included in the analysis. Patients were predominantly female (83%) and never smokers (60%), with a mean age of 60 years. Fifty-nine (55%) of 107 patients had coexistent or previous history of Mycobacterium avium complex pulmonary infection. High-resolution chest CT showed bronchiectasis and nodular opacities in 98% of patients and cavities in 44%. Sixty-nine (46 medical, 23 surgical) patients were followed up for a mean duration of 34 months (standard deviation, 21.1 months, range, 2-82 months). Cough, sputum production, and fatigue remained stable, improved, or resolved in 80%, 69%, and 59% of patients, respectively. Twenty (29%) of 69 patients remained culture positive, 16 (23%) converted but experienced relapse, 33 (48%) converted to negative and did not experience relapse, and 17 (16%) died during the study period. There were significantly more surgical patients than medical patients whose culture converted and remained negative for at least 1 year (57% vs 28%; P = .022). CONCLUSIONS: Patients with M. abscessus pulmonary disease who are treated with multidrug antibiotic therapy and surgery or antibiotic therapy alone had similar clinical outcomes. However, surgical resection, in addition to antibiotics, may offer a prolonged microbiologic response. PMID- 21292660 TI - The talking Mycobacterium abscessus blues. PMID- 21292661 TI - Prospective identification of congenital cytomegalovirus infection in newborns using real-time polymerase chain reaction assays in dried blood spots. AB - BACKGROUND: Congenital cytomegalovirus (CMV) infection is a public health issue, and implementation of neonatal screening has been debated. Detection of CMV DNA by polymerase chain reaction (PCR) of dried blood spots (DBS) routinely collected for metabolic screening from all newborns has been proposed for congenital CMV infection screening. The goal of this study was to prospectively assess the performance of 2 CMV PCR assays of DBS for CMV neonatal screening in a selected population of neonates. METHODS: We studied prospective congenital CMV screening in a population of neonates either born with symptoms compatible with congenital CMV or born to mothers with a history of primary infection during pregnancy. For each neonate, 2 CMV PCR assays of DBS were blindly performed in parallel with a gold standard technique (ie, CMV PCR of a urine sample). RESULTS: Two hundred seventy-one neonates were studied, and CMV infection, defined by a positive urine sample in the first week of life, was confirmed in 64 (23.6%). Nineteen infected (29.7%) neonates were symptomatic, and 45 (70.3%) were asymptomatic. The ranges of sensitivity, specificity, positive predictive value, and negative predictive value for the 2 CMV PCR assays of DBS were 95.0%-100%; 98.1%-99.0%; 94.1%-96.9%, and 98.5%-100%, respectively. CONCLUSIONS: The sensitivity and specificity of both CMV PCR assays of DBS to identify congenital CMV were very high in this population of neonates with a high risk of sequelae. These new data should be considered in the ongoing debate on the appropriateness of the use of DBS as a sample to screen for congenital CMV infection. PMID- 21292662 TI - Dried blood spots and universal newborn screening for congenital cytomegalovirus infection. PMID- 21292663 TI - Endemic foodborne botulism among Alaska Native persons--Alaska, 1947-2007. AB - BACKGROUND: Foodborne botulism resulting from consumption of uncooked aquatic game foods has been an endemic hazard among Alaska Native populations for centuries. Our review was conducted to help target botulism prevention and response activities. METHODS: Records of Alaska botulism investigations for the period 1947-2007 were reviewed. We used the Centers for Disease Control and Prevention case definitions for foodborne botulism and linear regression to evaluate incidence trends and chi(2) or Fisher's Exact tests to evaluate categorical data. RESULTS: A total of 317 patients (61% of whom were female) and 159 outbreaks were reported. Overall mean annual incidence was 6.9 cases per 100,000 Alaska Native persons; mean incidence was lower in 2000 (5.7 cases per 100,000 Alaska Native persons) than in any period since 1965-1969 (0.8 cases per 100,000 Alaska Native persons). Age-specific incidence was highest (26.6 cases per 100,000 Alaska Native persons) among persons aged >=60 years. The overall case-fatality rate was 8.2%, and the case-fatality rate was <=4.0% since 1980. Misdiagnosis was associated with a higher case-fatality rate and delayed antitoxin administration. CONCLUSIONS: Foodborne botulism remains a public health problem in Alaska. Incidence might be decreasing, but it remains >800 times the overall US rate (0.0068 cases per 100,000 persons). Prevention messages should highlight the additional risk to female individuals and older persons. Early diagnosis is critical for timely access to antitoxin and supportive care. PMID- 21292664 TI - Botulism in the North: a disease without borders. PMID- 21292665 TI - Evaluation of clinical prediction rules for respiratory isolation of inpatients with suspected pulmonary tuberculosis. AB - BACKGROUND: In the framework of hospital infection control, various clinical prediction rules (CPRs) for respiratory isolation of patients with suspected pulmonary tuberculosis (PTB) have been developed. Our aim was to evaluate their performance in an emergency department setting with a high prevalence of PTB. METHODS: We searched the MEDLINE and OVID databases to identify CPRs to predict PTB. We used a previously collected database containing clinical, radiographical, and microbiological information on patients attending an emergency department with respiratory complaints, and we applied each CPR to every patient and compared the result with culture for Mycobacterium tuberculosis as the reference standard. We also simulated the proportion of isolated suspects and missed cases for PTB prevalences of 5% and 30%. RESULTS: We withheld 13 CPRs for evaluation. We had complete data on 345 patients. Most CPRs achieved a high sensitivity but very low specificity and very low positive predictive value. Mylotte's score, which includes results of sputum smear as a predictive finding, was the best performing CPR. It attained a sensitivity of 88.9% and a specificity of 63.9%. However, at a 30% PTB prevalence, 498 of 1000 individuals with suspected PTB would have to be isolated; 267 of these cases would be true PTB cases, and 33 cases would be missed. Two consecutive sputum smears had a sensitivity of 75.6% and a specificity of 99.7%. CONCLUSIONS: In a setting with a high prevalence of PTB, only 1 of the 13 assessed CPRs demonstrated high sensitivity combined with satisfactory specificity. Our results highlight the need for local validation of CPRs before their application. PMID- 21292666 TI - Plasmodium vivax recurrence following falciparum and mixed species malaria: risk factors and effect of antimalarial kinetics. AB - BACKGROUND: Plasmodium vivax malaria commonly follows treatment of falciparum malaria in regions of co-endemicity. This is an important cause of preventable morbidity. METHODS: We examined the factors contributing to the risk of recurrence of P. vivax infection after treatment of acute falciparum malaria in a series of clinical trials conducted on the Thai-Myanmar border from 1991 through 2005. RESULTS: Overall, 10,549 patients (4960 children aged <15 years and 5589 adults) were treated for falciparum malaria; of these patients, 9385 (89.0%) had Plasmodium falciparum monoinfection and 1164 (11.0%) had mixed P. falciparum/P. vivax infections according to microscopic examinations performed at screening. The cumulative proportion of patients with P. falciparum infection recurrence by day 63 was 21.5% (95% confidence interval [CI], 20.3%-22.8%), and the cumulative proportion with P. vivax infection recurrence was 31.5% (95% CI, 30.1%-33.0%). Significant risk factors for P. vivax infection recurrence were mixed infection at enrollment, male sex, younger age, lower hematocrit, higher asexual P. falciparum parasite density (P < .001 for all factors), and P. falciparum gametocytemia at enrollment (P = .001). By day 63, the cumulative risk of vivax malaria after P. falciparum monoinfection was 51.1% (95% CI, 46.1%-56.2%) after treatment with rapidly eliminated drugs (t(1/2) <1 day), 35.3% (95% CI, 31.8% 39.0%) after treatment with intermediate half-life drugs (t(1/2) 1-7 days), and 19.6% (95% CI, 18.1%-21.3%) after treatment with slowly eliminated drugs (t(1/2) > 7 days) (P < .001, by test for trend). Artemisinin-based combinations containing mefloquine or piperaquine, compared with the artemether-lumefantrine and artesunate-atovaquone-proguanil combinations, were associated with a 3.6-fold to 4.2-fold lower adjusted hazard ratio for P. vivax infection recurrence within 63 days after pure or mixed P. falciparum infections (P < .001, for comparisons with artesunate-mefloquine). CONCLUSIONS: On the Thai-Myanmar border, P. vivax is the most common cause of parasitological failure after treatment for falciparum malaria. Slowly eliminated antimalarials reduce the risk of early P. vivax infection recurrence. PMID- 21292667 TI - Radical cure: the case for anti-relapse therapy against all malarias. PMID- 21292668 TI - The potential role for protein-conjugate pneumococcal vaccine in adults: what is the supporting evidence? AB - Vaccination with protein-conjugate pneumococcal vaccine (PCV) provides children with extraordinary protection against pneumococcal disease, although the protective effect may be blunted by the emergence of replacement strains. Studies in adults have compared PCV with pneumococcal polysaccharide vaccine (PPV) using surrogate markers of protection, namely, serum anticapsular IgG antibody and opsonic activity. Results suggest that PCV is at least as effective as PPV for the strains covered, but a definitive and consistent advantage has not been demonstrated. Unfortunately, persons who are most in need of vaccine do not respond as well as otherwise healthy adults to either vaccine. Newer formulations of PCV will protect against the most prevalent of the current replacement strains, but replacement strains will create a moving target for PCVs. Unless an ongoing trial comparing 13-valent PCV with placebo (not to PPV) demonstrates a clearly better effect than that seen in the past with PPV, cost-effectiveness considerations are likely to prevent widespread use of PCV in adults. PMID- 21292669 TI - Fever and productive cough in a patient with AIDS. PMID- 21292670 TI - Conceptual model for reducing infections and antimicrobial resistance in skilled nursing facilities: focusing on residents with indwelling devices. AB - Infections in skilled nursing facilities (SNFs) are common and result in frequent hospital transfers, functional decline, and death. Colonization with multidrug resistant organisms (MDROs) - including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and multidrug-resistant gram-negative bacilli (R-GNB) - is also increasingly prevalent in SNFs. Antimicrobial resistance among common bacteria can adversely affect clinical outcomes and increase health care costs. Recognizing a need for action, legislators, policy-makers, and consumer groups are advocating for surveillance cultures to identify asymptomatic patients with MDROs, particularly MRSA in hospitals and SNFs. Implementing this policy for all SNF residents may be costly, impractical, and ineffective. Such a policy may result in a large increase in the number of SNF residents placed in isolation precautions with the potential for reduced attention by health care workers, isolation, and functional decline. Detection of colonization and subsequent attempts to eradicate selected MDROs can also lead to more strains with drug resistance. We propose an alternative strategy that uses a focused multicomponent bundle approach that targets residents at a higher risk of colonization and infection with MDROs, specifically those who have an indwelling device. If this strategy is effective, similar strategies can be studied and implemented for other high-risk groups. PMID- 21292671 TI - Restoration of T cell responses to toxoplasma gondii after successful combined antiretroviral therapy in patients with AIDS with previous toxoplasmic encephalitis. AB - BACKGROUND: It is unknown whether a Toxoplasma gondii-specific T cell response is restored after successful combined antiretroviral therapy (cART) in patients with AIDS and current or previous toxoplasmic encephalitis (TE). METHODS: We performed a multicenter cross-sectional study with 17 healthy T. gondii-positive human immunodeficiency virus (HIV)-1-uninfected individuals and 90 patients coinfected with HIV-1 and T. gondii distributed in 5 groups according to their CD4(+) T cell counts and T. gondii infection (with or without current or previous TE). We investigated the lymphocyte proliferative response (LPR) and interferon (IFN) gamma production in response to T. gondii soluble antigen extract (SATg) and as CD4(+) and CD8(+) T cell subsets. RESULTS: SATg-specific LPR and IFN-gamma production were not observed in many of the most immunosuppressed patients (CD4(+) T cell count, <200 cells/MUL, with or without current or previous TE). By contrast, these responses occurred in a considerable percentage (LPR, 43%; IFN gamma production, 80%) of patients receiving successful cART (CD4(+) T cell count, >200 cells/MUL) who presented with TE and had already stopped secondary TE prophylaxis. Similar results were found in immunocompetent asymptomatic patients who did not receive TE prophylaxis. The predictors of SATg-specific T cell responses and IFN-gamma production were a cART-mediated increase in CD4(+) T cell count and LPR to phytohemagglutinin and viral suppression and a decrease in the activated (CD38(+)) CD8(+) T cell count, respectively. CONCLUSIONS: cART restores T. gondii-specific CD4 T cell responses in most patients with AIDS who had previous TE. Our data support the safety of withdrawing TE prophylaxis when the CD4(+) T cell count returns to levels >200 cells/MUL. PMID- 21292672 TI - The evolution of coreceptor tropism in HIV-infected patients interrupting suppressive antiretroviral therapy. AB - CCR5 antagonists may provide a well-tolerated switch option for patients experiencing tolerability or toxicity of their antiretroviral regimen. We analyzed stored samples from patients undergoing planned treatment interruptions for reasons other than virological failure, in order to analyze tropism evolution during fully suppressive antiretroviral therapy (ART). Two of 37 patients showed evidence of switching. Tropism switching after suppressive ART was uncommon in this cohort. Pretreatment human immunodeficiency virus (HIV) RNA tropism testing may help guide the switch to CCR5 antagonists in patients with undetectable HIV RNA. PMID- 21292673 TI - Lack of health insurance coverage for oral vancomycin: it's time to tackle the elephant in the room. PMID- 21292674 TI - Coexistence of blaNDM-1 with the prevalent blaOXA23 and blaIMP in pan-drug resistant Acinetobacter baumannii isolates in China. PMID- 21292675 TI - Reproductive biology of Abolboda pulchella and A. poarchon (Xyridaceae: Poales). AB - BACKGROUND AND AIMS: Abolboda (Xyridaceae) belongs to the Poales, a predominantly wind-pollinated order whose phylogeny has been widely studied in recent years. The reproductive biology of Abolboda pulchella and A. poarchon was studied to determine the main pollination system of these species, providing the first experimental data on reproduction in the Xyridaceae. METHODS: A field study was conducted, including observations on the morphology and biology of the flowers, insect visits and pollinator behaviour. Experimental pollination treatments were performed to assess agamospermy, spontaneous self-pollination and self compatibility. Pollination success was determined by pollen tube growth, and reproductive success was assessed by fruit- and seed-set. KEY RESULTS: Abolboda pulchella and A. poarchon were pollinated by Apidae, Megachilidae and Halictidae bees. The floral resources were pollen and nectar that was produced by stylar appendages, an uncommon nectary type for monocotyledons. The species were self compatible, and pollen tube growth from self-pollen was similar to that of cross pollen. However, herkogamy prevented spontaneous selfing, rendering the plants dependent on the pollinator's activity. There was no production of seeds by agamospermy. CONCLUSIONS: Melittophily is the main pollination system of these two Abolboda species. Nectar production was first recorded here for Xyridaceae, and along with self-compatibility, herkogamy and bee pollination, is an informative characteristic that can be used in future phylogenetic analyses of the family as well as Poales. PMID- 21292676 TI - Performance of dryland and wetland plant species on extensive green roofs. AB - BACKGROUND AND AIMS: Green roofs are constructed ecosystems where plants perform valuable services, ameliorating the urban environment through roof temperature reductions and stormwater interception. Plant species differ in functional characteristics that alter ecosystem properties. Plant performance research on extensive green roofs has so far indicated that species adapted to dry conditions perform optimally. However, in moist, humid climates, species typical of wetter soils might have advantages over dryland species. In this study, survival, growth and the performance of thermal and stormwater capture functions of three pairs of dryland and wetland plant species were quantified using an extensive modular green roof system. METHODS: Seedlings of all six species were germinated in a greenhouse and planted into green roof modules with 6 cm of growing medium. There were 34 treatments consisting of each species in monoculture and all combinations of wet- and dryland species in a randomized block design. Performance measures were survival, vegetation cover and roof surface temperature recorded for each module over two growing seasons, water loss (an estimate of evapotranspiration) in 2007, and albedo and water capture in 2008. KEY RESULTS: Over two seasons, dryland plants performed better than wetland plants, and increasing the number of dryland species in mixtures tended to improve functioning, although there was no clear effect of species or habitat group diversity. All species had survival rates >75 % after the first winter; however, dryland species had much greater cover, an important indicator of green roof performance. Sibbaldiopsis tridentata was the top performing species in monoculture, and was included in the best treatments. CONCLUSIONS: Although dryland species outperformed wetland species, planting extensive green roofs with both groups decreased performance only slightly, while increasing diversity and possibly habitat value. This study provides further evidence that plant composition and diversity can influence green roof functions. PMID- 21292677 TI - Functional implications of the staminal lever mechanism in Salvia cyclostegia (Lamiaceae). AB - BACKGROUND AND AIMS: Flower morphology and inflorescence architecture affect pollinator foraging behaviour and thereby influence the process of pollination and the reproductive success of plants. This study explored possible ecological functions of the lever-like stamens and the floral design in Salvia cyclostegia. METHODS: Flower construction was experimentally manipulated by removing either the lower lever arms or the upper fertile thecae of the two stamens from a flower. The two types of manipulated individuals were intermixed with the control ones and randomly distributed in the population. KEY RESULTS: Removing the sterile lower lever arms significantly reduced handling time per flower of the main pollinator, Bombus personatus. Interestingly, this manipulation did not increase the number of flowers probed per plant visit, but instead reduced it, i.e. shortened the visit sequence of the bumble-bees. Both loss of staminal lever function by removing lower lever arms and exclusion of self pollen by removing upper fertile thecae significantly reduced seed set per flower and seed set per plant. Both the manipulations interacted significantly with inflorescence size for the effect on female reproductive output. CONCLUSIONS: Though the intact flowers demand a long handling time for pollinators, the reversible staminal lever is of advantage by promoting dispersal of pollen and thus the male function. The particular floral design in S. cyclostegia contributes to the floral constancy of B. personatus bumble-bees, with the lower lever arms acting as an optical cue for foraging cognition. PMID- 21292678 TI - The late stent malapposition develops also after paclitaxel balloon predilatation before bare-metal stent implantation: case description. PMID- 21292679 TI - Percutaneous aortic valve implantation in severe stenosis associated with anomalous origin of the circumflex coronary artery. PMID- 21292680 TI - Fibroblast activation protein is induced by inflammation and degrades type I collagen in thin-cap fibroatheromata. AB - AIMS: Collagen degradation in atherosclerotic plaques with thin fibrous caps renders them more prone to rupture. Fibroblast activation protein (FAP) plays a role in arthritis and tumour formation through its collagenase activity. However, the significance of FAP in thin-cap human fibroatheromata remains unknown. METHODS AND RESULTS: We detected enhanced FAP expression in type IV-V human aortic atheromata (n = 12), compared with type II-III lesions (n = 9; P < 0.01) and healthy aortae (n = 8; P < 0.01) by immunostaining and western blot analyses. Fibroblast activation protein was also increased in thin-cap (<65 um) vs. thick cap (>= 65 um) human coronary fibroatheromata (n = 12; P < 0.01). Fibroblast activation protein was expressed by human aortic smooth muscle cells (HASMC) as shown by colocalization on immunofluorescent aortic plaque stainings (n = 10; P < 0.01) and by flow cytometry in cell culture. Although macrophages did not express FAP, macrophage burden in human aortic plaques correlated with FAP expression (n = 12; R(2)= 0.763; P < 0.05). Enzyme-linked immunosorbent assays showed a time- and dose-dependent up-regulation of FAP in response to human tumour necrosis factor alpha (TNFalpha) in HASMC (n = 6; P < 0.01). Moreover, supernatants from peripheral blood-derived macrophages induced FAP expression in cultured HASMC (n = 6; P < 0.01), an effect abolished by blocking TNFalpha (n = 6; P < 0.01). Fibroblast activation protein associated with collagen-poor regions in human coronary fibrous caps and digested type I collagen and gelatin in vitro (n = 6; P < 0.01). Zymography revealed that FAP-mediated collagenase activity was neutralized by an antibody directed against the FAP catalytic domain both in HASMC (n = 6; P < 0.01) and in fibrous caps of atherosclerotic plaques (n = 10; P < 0.01). CONCLUSION: Fibroblast activation protein expression in HASMC is induced by macrophage-derived TNFalpha. Fibroblast activation protein associates with thin-cap human coronary fibroatheromata and contributes to type I collagen breakdown in fibrous caps. PMID- 21292681 TI - Recommendations for the use of natriuretic peptides in acute cardiac care: a position statement from the Study Group on Biomarkers in Cardiology of the ESC Working Group on Acute Cardiac Care. PMID- 21292682 TI - Left ventricular outflow tract pseudoaneurysm compromising blood flow through the left main coronary artery after mechanical aortic valve implantation. PMID- 21292683 TI - Evolutionary patterns of hepatitis B virus quasispecies under different selective pressures: correlation with antiviral efficacy. AB - OBJECTIVE: To investigate the evolution of hepatitis B virus (HBV) quasispecies (QS) within the reverse transcriptase (RT) region during the early stage of entecavir treatment and its impact on virological response, and to compare evolutionary patterns under different selective pressures. METHODS: 31 patients with chronic hepatitis B receiving entecavir (17 responders and 14 partial responders according to the HBV DNA levels at week 48) and 25 patients receiving lamivudine (14 responders and 11 non-responders) as controls were included. An average of 26 clones (2892 total from both groups) spanning the RT region per sample was sequenced. RESULTS: QS complexity and diversity, in addition to alanine aminotransferase and HBV DNA levels, were comparable between responders and partial responders at baseline. However, QS complexity in responders at week 4 was statistically lower than that in partial responders at the nucleotide level (0.6494 vs. 0.7723, p=0.039). Net changes in diversity as well as the viral nucleotide substitution rate of responders were higher than those of partial responders, and both correlated with virological responses at both week 48 and the final visit (mean: 28 months). A preliminary model of QS evolution variables predicted 16 of 17 responders and 13 of 14 partial responders in the entecavir group. Despite significant differences between responders to entecavir and responders to lamivudine at week 4, the characteristics of QS were quite similar between partial responders to entecavir and non-responders to lamivudine. CONCLUSIONS: The evolutionary patterns of HBV RT QS differ between responders and partial responders during the early stage of entecavir treatment. Characteristics of HBV QS evolution during the first 4 weeks contribute to the prediction of long term virological responses. The similar patterns of HBV RT QS in partial responders and non-responders receiving different nucleoside analogues may imply a novel mechanism of drug resistance, which warrants further investigation. PMID- 21292684 TI - Managing symptoms of irritable bowel syndrome in patients with inflammatory bowel disease. PMID- 21292685 TI - Amiodarone sensitizes human glioma cells but not astrocytes to TRAIL-induced apoptosis via CHOP-mediated DR5 upregulation. AB - Amiodarone is a widely used anti-arrhythmic drug that inhibits diverse ion channels, including the Na(+)/Ca(2+) exchanger (NCX), L-type Ca(2+) channels, and Na(+) channels. Here, we report that subtoxic doses of amiodarone and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) synergistically induced apoptosis of various glioma cells. Treatment of U251MG glioma cells with amiodarone increased intracellular Ca(2+) levels and enhanced the expression of the endoplasmic reticulum (ER) stress-inducible transcription factor C/EBP homologous protein (CHOP). This upregulation of CHOP was followed by marked upregulation of the TRAIL receptor, DR5. Suppression of DR5 expression by small interfering (si) RNAs almost completely blocked amiodarone/TRAIL-induced apoptosis in U251MG glioma cells, demonstrating that DR5 is critical to this cell death. siRNA-mediated CHOP suppression reduced amiodarone-induced DR5 upregulation and attenuated the cell death induced by amiodarone plus TRAIL. In addition, omitting Ca(2+) from the external medium using ethylene glycol tetraacetic acid markedly inhibited this cell death, reducing the protein levels of CHOP and DR5. These results suggest that amiodarone-induced influx of Ca(2+) plays an important role in sensitizing U251MG cells to TRAIL-mediated apoptosis through CHOP-mediated DR5 upregulation. Furthermore, subtoxic doses of bepridil and cibenzoline, two other anti-arrhythmic drugs with NCX-inhibitor activity, also sensitized glioma cells to TRAIL-mediated apoptosis, via the upregulation of both CHOP and DR5. Notably, amiodarone/TRAIL cotreatment did not induce cell death in astrocytes, nor did it affect the expression of CHOP or DR5 in these cells. These results collectively suggest that a combined regimen of amiodarone plus TRAIL may offer an effective therapeutic strategy for safely and selectively treating resistant gliomas. PMID- 21292686 TI - Hot spots in dynamic (18)FET-PET delineate malignant tumor parts within suspected WHO grade II gliomas. AB - Molecular imaging studies have recently found inter- and intratumoral heterogeneity in World Health Organization (WHO) grade II gliomas. A correlative analysis with tumor histology, however, is still lacking. For elucidation we conducted the current prospective study. Fifty-five adult patients with an MRI based suspicion of a WHO grade II glioma were included. [F-18]Fluoroethyltyrosine ((18)FET) uptake kinetic studies were combined with frame-based stereotactic localization techniques and used as a guide for stepwise (1-mm steps) histopathological evaluation throughout the tumor space. In tumors with heterogeneous PET findings, the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status and expression of mutated protein isocitrate dehydrogenase variant R132H (IDH1) were determined inside and outside of hot spot volumes. Metabolic imaging revealed 3 subgroups: the homogeneous WHO grade II glioma group (30 patients), the homogeneous malignant glioma group (10 patients), and the heterogeneous group exhibiting both low- and high-grade characteristics at different sites (15 patients). Stepwise evaluation of 373 biopsy samples indicated a strong correlation with analyses of uptake kinetics (p < 0.0001). A homogeneous pattern of uptake kinetics was linked to homogeneous histopathological findings, whereas a heterogeneous pattern was associated with histopathological heterogeneity; hot spots exhibiting malignant glioma characteristics covered 4-44% of the entire tumor volumes. Both MGMT and IDH1 status were identical at different tumor sites and not influenced by heterogeneity. Maps of (18)FET uptake kinetics strongly correlated with histopathology in suspected grade II gliomas. Anaplastic foci can be accurately identified, and this finding has implications for prognostic evaluation and treatment planning. PMID- 21292687 TI - A phase II study of gefitinib and irradiation in children with newly diagnosed brainstem gliomas: a report from the Pediatric Brain Tumor Consortium. AB - This phase II study was designed to assess the safety and efficacy of gefitinib given with and following radiation therapy in children newly diagnosed with a poor prognosis brainstem glioma. Eligible patients were those with a previously untreated nondisseminated diffuse intrinsic brainstem glioma. Histological confirmation was not required, provided patients had a characteristic clinical history and MRI findings. Treatment consisted of gefitinib, administered orally, 250 mg/m(2)/day, during standard external beam radiotherapy, continuing for up to 13 monthly courses in the absence of disease progression or unacceptable toxicity. Toxicities, particularly intratumoral hemorrhage, were monitored. Pharmacokinetics and investigational imaging studies were performed in consenting patients. Forty-three eligible patients were included in the study. Therapy was well tolerated; only 4 patients were withdrawn from the study for dose-limiting toxicity after receiving therapy for 6, 9, 17, and 24 weeks. The 12- and 24-month progression-free survival rates were 20.9 +/-5.6 % and 9.3 +/-4%, respectively. Overall survival rates were 56.4 +/-7.6% and 19.6 +/-5.9%, respectively, which appear nominally superior to other contemporaneous Pediatric Brain Tumor Consortium trials. Three patients remain progression-free survivors with >=36 months follow-up. The observation that a subset of children with this generally fatal tumor experienced long-term progression-free survival, coupled with recent observations regarding the molecular features of brainstem gliomas, raises the possibility that prospective molecular characterization may allow enrichment of treatment responders and improvement in outcome results in future studies of biologically targeted agents. PMID- 21292688 TI - Chromosome 17 alterations identify good-risk and poor-risk tumors independently of clinical factors in medulloblastoma. AB - Current risk stratification schemas for medulloblastoma, based on combinations of clinical variables and histotype, fail to accurately identify particularly good- and poor-risk tumors. Attempts have been made to improve discriminatory power by combining clinical variables with cytogenetic data. We report here a pooled analysis of all previous reports of chromosomal copy number related to survival data in medulloblastoma. We collated data from previous reports that explicitly quoted survival data and chromosomal copy number in medulloblastoma. We analyzed the relative prognostic significance of currently used clinical risk stratifiers and the chromosomal aberrations previously reported to correlate with survival. In the pooled dataset metastatic disease, incomplete tumor resection and severe anaplasia were associated with poor outcome, while young age at presentation was not prognostically significant. Of the chromosomal variables studied, isolated 17p loss and gain of 1q correlated with poor survival. Gain of 17q without associated loss of 17p showed a trend to improved outcome. The most commonly reported alteration, isodicentric chromosome 17, was not prognostically significant. Sequential multivariate models identified isolated 17p loss, isolated 17q gain, and 1q gain as independent prognostic factors. In a historical dataset, we have identified isolated 17p loss as a marker of poor outcome and 17q gain as a novel putative marker of good prognosis. Biological markers of poor risk and good-risk tumors will be critical in stratifying treatment in future trials. Our findings should be prospectively validated independently in future clinical studies. PMID- 21292689 TI - Self-collected anal swabs in men who have sex with men: minimal benefit of routine peri-anal examination. PMID- 21292690 TI - Flu and pneumococcal immunisations in HIV-infected children: methodological quality of current recommendations. AB - OBJECTIVE: To assess the quality of guidelines, consensus statements and systematic reviews on flu and pneumococcal immunisations in HIV-infected children. METHOD: The authors screened PubMed and Embase databases until the year 2009 for guidelines, consensus statements and systematic reviews on flu and pneumococcal immunisations in HIV-infected patients. The authors also explored relevant websites of agencies/institutions involved with HIV infection, immunisation or guidelines. The Appraisal of Guidelines for Research and Evaluation instrument and the checklists of the Scottish Intercollegiate Guidelines Network were used to evaluate the scientific quality of guidelines and systematic reviews. RESULTS: Eighteen articles were identified. Only one guideline was of good overall quality. Generally the weakest domains were 'Applicability' and 'Editorial Independence.' Although of poor methodological quality, the main recommendations on flu and pneumococcus vaccinations were similar. There were minor differences in the type of pneumococcal vaccines in relation to patient's age, namely based on the settings in which recommendations were produced. CONCLUSIONS: Although guidelines and systematic reviews on flu and pneumococcal vaccination in HIV-infected children came from authoritative institutions, their overall quality is poor, with the weakest fields being the methodological domains. PMID- 21292691 TI - Measuring the learning capacity of organisations: development and factor analysis of the Questionnaire for Learning Organizations. AB - AIMS: To investigate internal consistency and factor structure of a questionnaire measuring learning capacity based on Senge's theory of the five disciplines of a learning organisation: Personal Mastery, Mental Models, Shared Vision, Team Learning, and Systems Thinking. DESIGN: Cross-sectional study. SETTING: Substance abuse treatment centres (SATCs) in The Netherlands. PARTICIPANTS: A total of 293 SATC employees from outpatient and inpatient treatment departments, financial and human resources departments. MAIN OUTCOME MEASURES: Psychometric properties of the Questionnaire for Learning Organizations (QLO), including factor structure, internal consistency, and interscale correlations. FINDINGS: A five-factor model representing the five disciplines of Senge showed good fit. The scales for Personal Mastery, Shared Vision and Team Learning had good internal consistency, but the scales for Systems Thinking and Mental Models had low internal consistency. CONCLUSIONS: The proposed five-factor structure was confirmed in the QLO, which makes it a promising instrument to assess learning capacity in teams. The Systems Thinking and the Mental Models scales have to be revised. Future research should be aimed at testing criterion and discriminatory validity. PMID- 21292692 TI - Quality for home palliative care: an Italian metropolitan multicentre JCI certified model. AB - BACKGROUND: Assessing the quality of care and service delivery through the analysis of ad hoc indicators is a relevant process for quality monitoring and improvement with a view to providing patients, the community and administrators alike with appropriate elements of evaluation. This paper describes the key results of a certification process based on the Joint Commission International (JCI) criteria for the home hospitalisation model implemented by the palliative care units of seven Milan hospitals for terminally ill patients with cancer. METHODS: In 2006, the interhospital working team implemented a certification project based on the JCI Disease or Condition-Specific Care (DSCS) programme. Thirty standards subdivided into five functional areas with 150 measurable elements were the starting-point for periodic improvement plans within and across participating hospitals. Programme compliance was analysed in terms of annual performance improvement and consistency across the seven PCUs involved in achieving set goals. The JCI standards were applied on 3316 terminally ill patients with cancer treated at home from 2005 to 2009. RESULTS: As a result of the work carried out, the JCI survey conducted 3 years after project implementation demonstrated full compliance with the established standards, leading to the JCI certification award (for the first time in this clinical setting internationally). CONCLUSION: The work carried out with a view to certification has confirmed the possibility that facilities spread across different hospitals can actually share common processes and standardise the activities for the care of end-of-life patients with cancer at home as if they were one single service provider. PMID- 21292693 TI - From research to practice: factors affecting implementation of prospective targeted injury-detection systems. AB - AIM This paper describes key factors that shaped implementation of prospective targeted injury-detection systems (TIDS) for adverse drug events (ADEs) and nosocomial pressure ulcers (PrU). METHODS Using case-study methodology, the authors conducted semistructured interviews with implementation champions and TIDS users at five hospitals. Interviews focused on implementation experiences, assessment of TIDS' effectiveness and utility, and plans for sustainability. The authors used content analysis techniques to compare implementation experiences within and across organisations and triangulated data for explanation and confirmation of common themes. FINDINGS Participating hospitals were more successful in implementing the low-complexity PrU-TIDS, as compared with high complexity ADE-TIDS. This pattern reflected the greater complexity of ADE-TIDS, its higher costs and poorer alignment with existing workflows. Complexity affected the innovations' perceived usability, the time needed to learn and install the trigger systems, and their costs. Local factors affecting implementation and sustainability of both innovations included turnover affecting champions and other staff, shifting organisational priorities, changing information infrastructures, and institutional constraints on adapting existing IT to the electronic TIDS. CONCLUSIONS To facilitate implementation of complex healthcare innovations such as ADE-TIDS, staff in adopting organisations should give high priority to innovation implementation; allocate sufficient resources; effectively communicate with and involve local champions and users; and align innovations with workflows and information systems. In addition, they should monitor local factors, such as changes in organisational priorities and IT, availability of implementation staff and champions, and external regulations and constraints that may pose barriers to innovation implementation and sustainability. PMID- 21292694 TI - To lie or not to lie: resident physician attitudes about the use of deception in clinical practice. AB - BACKGROUND: Physicians face competing values of truth-telling and beneficence when deception may be employed in patient care. The purposes of this study were to assess resident physicians' attitudes towards lying, explore lie types and reported reasons for lying. METHOD: After obtaining institutional review board review (OSR# 58013) and receiving exempt status, posts written by Loma Linda University resident physicians in response to forum questions in required online courses were collected from 2002 to 2007. Responses were blinded and manually coded by two investigators using NVivo software. Qualitative and quantitative analyses of the data were performed with links to various attributes. A 95% binomial proportion CI was used to analyse the attribute data. RESULTS: The study found that the majority of residents (90.3%) would disclose the truth about medical errors. Similarly, many residents (55.7%) would disclose the truth regarding unanticipated events, especially if the error was serious enough to result in a malpractice suit (74.7%). However, many residents (40.9%) would not reveal a near miss event because they believe it has no impact on patient health. Some residents (47.3%) would deceive the insurance company for additional patient benefits. Of those willing to lie, only a small group (4.2%) gave self-serving reasons. CONCLUSIONS: This study demonstrates that the ethical issues related to deception that trouble attending physicians also exist at the resident physician level. Residents primarily lie for altruistic reasons and rarely for egoistic or self-serving purposes that may or may not result in harm to patients, insurance companies and/or physicians themselves. PMID- 21292695 TI - The ideal application of surveillance technology in residential care for people with dementia. AB - BACKGROUND: As our society is ageing, nursing homes are finding it increasingly difficult to deal with an expanding population of patients with dementia and a decreasing workforce. A potential answer to this problem might lie in the use of technology. However, the use and application of surveillance technology in dementia care has led to considerable ethical debate among healthcare professionals and ethicists, with no clear consensus to date. AIM: To explore how surveillance technology is viewed by care professionals and ethicists working in the field, by investigating the ideal application of surveillance technology in the residential care of people with dementia. METHODS: Use was made of the concept mapping method, a computer-assisted procedure consisting of five steps: brainstorming, prioritizing, clustering, processing by the computer and analysis. Various participants (ranging from ethicists to physicians and nurses) were invited on the basis of their professional background. RESULTS: The views generated are grouped into six categories ranging from the need for a right balance between freedom and security, to be beneficial and tailored to the resident, and clearly defined procedures to competent and caring personnel, active monitoring and clear normative guidance. The results are presented in the form of a graphic chart. CONCLUSIONS: There appears to be an inherent duality in the views on using surveillance technology which is rooted in the moral conflict between safety and freedom. Elaboration of this ethical issue has proved to be very difficult. PMID- 21292696 TI - The limits of empathy: problems in medical education and practice. AB - Empathy is commonly regarded as an essential attribute for doctors and there is a conviction that empathy must be taught to medical students. Yet it is not clear exactly what empathy is, from a philosophical or sociological point of view, or whether it can be taught. The meaning, role and relevance of empathy in medical education have tended to be unquestioningly assumed; there is a need to examine and contextualise these assumptions. This paper opens up that debate, arguing that 'empathy', as it is commonly understood, is neither necessary nor sufficient to guarantee good medical or ethical practice. PMID- 21292697 TI - Socially and temporally extended end-of-life decision-making process for dementia patients. AB - There are two contrasting views on the decision-making for life-sustaining treatment in advanced stages of dementia when the patient is deemed incompetent. One is to respect the patient's precedent autonomy by adhering to advance directives or using the substituted judgement standard. The other is to use the best-interests standard, particularly if the current judgement on what is best for the incapacitated patient contradicts the instructions from the patient's precedent autonomy. In this paper, I argue that the protracted clinical course of dementia over many years requires the extended perspective of a progressive decision-making process-extended in both social space and time. The ongoing debate between these two competing views has missed this perspective by focussing on an exclusive disjunction between the competent former self and the incompetent current self. Drawing on theories of situated cognition in cognitive science, I will show that the cognition of a demented patient can be viewed as extended and embodied by her supportive social environment. As the disease progresses, the content of the mind of a demented person becomes partially constituted by such external resources along with her diminishing intrinsic mind. With this understanding, medical decision-making for a demented patient can be construed as a temporally and socially extended practice. A collective decision-making body consisting of the patient, her family and surrogates, and the clinician, should make progressive decisions as a whole over years of the disease course. Finally, I will provide a practical example of how this proposal can be applied in clinical practice. PMID- 21292698 TI - Limitation of treatment at the end of life: an empirical-ethical analysis regarding the practices of physician members of the German Society for Palliative Medicine. AB - OBJECTIVES: To determine the frequencies and types of limitation of medical treatment performed by physician members of the German Society for Palliative Medicine and to analyse the findings with respect to clinical and ethical aspects of end-of-life practices. DESIGN: Cross-sectional postal survey. SETTING: Data collection via the secretary of the German Society for Palliative Medicine using the German language version of the EURELD survey instrument. SUBJECTS: All 1645 physician members of the German Society for Palliative Medicine. Main outcome measures Types and frequencies of limitation of treatment and possible determinants. RESULTS: 901 physicians participated in the study (response rate 55.8%). Participants reported limitation of treatment in 69.1% of cases. These decisions most often affected artificial nutrition (19%), chemotherapy (14%), antibiotics (11%) and medication other than antibiotics (11%). In the majority of eligible cases, physicians estimated the life-shortening effect of limitation of treatment to be <7 days. However, estimations differ depending on the medical measures in question. Bivariate statistical analysis indicated that withholding of treatment was performed significantly more frequently for patients aged >=65 years (p=0.019). In addition, there were significant associations between the incidence of limitation of treatment and the different diseases reported by respondents as the underlying cause of death. CONCLUSION: The findings of this study provide information on the current state of an ethically and clinically challenging aspect of clinical practice and can serve as a starting point for further interdisciplinary research on normative and empirical aspects of treatment decision-making at the end of life. PMID- 21292699 TI - Brain death revisited: it is not 'complete death' according to Islamic sources. AB - Concepts, such as death, life and spirit cannot be known in their quintessential nature, but can be defined in accordance with their effects. In fact, those who think within the mode of pragmatism and Cartesian logic have ignored the metaphysical aspects of these terms. According to Islam, the entity that moves the body is named the soul. And the aliment of the soul is air. Cessation of breathing means leaving of the soul from the body. Those who agree on the diagnosis of brain death may not able to agree unanimously on the rules that lay down such diagnosis. That is to say, there are a heap of suspicions regarding the diagnosis of brain death, and these suspicions are on the increase. In fact, Islamic jurisprudence does not put provisions, decisions on suspicious grounds. By virtue of these facts, it can be asserted that brain death is not absolute death according to Islamic sources; for in the patients diagnosed with brain death the soul still has not abandoned the body. Therefore, these patients suffer in every operation performed on them. PMID- 21292700 TI - Parental procreative obligation and the categorisation of disease: the case of cystic fibrosis. AB - The advent of prenatal genetic diagnosis has sparked debates among ethicists and philosophers regarding parental responsibility towards potential offspring. Some have attempted to place moral obligations on parents to not bring about children with certain diseases in order to prevent harm to such children. There has been no rigorous evaluation of cystic fibrosis in this context. This paper will demonstrate cystic fibrosis to have unique properties that make it difficult to categorize among other diseases with the goal of promulgating a reproductive rule. Once this is established, it will be demonstrated that procreative rules that appeal to future health are inadequate in the era of advancing genetic knowledge. Utilising a specification of Joel Feinberg's 'open future' concept outlined by Matteo Mameli, it will offer an analysis of parental obligation that does not constrain parents of potential children with cystic fibrosis with a moral obligation not to bring them about. PMID- 21292701 TI - Could some people be wronged by contracting swine flu? A case discussion on the links between the farm animal sector and human disease. AB - This paper uses the imaginary case of Gemma, presented initially at the International Swine Flu Conference (London, March 2010), to discuss whether a nurse who disagrees with most ways in which animals are farmed would be wronged if she contracted swine flu. It is argued that the farm animal sector has contributed to the emergence of H1N1 flu, and that the sector in general contributes significantly to the burden of human disease. The aim of this paper is to promote debate on the question as to whether a range of systems used by the farm animal sector survive moral scrutiny in light of these concerns. PMID- 21292702 TI - Performance factors of mobile rich media job aids for community health workers. AB - OBJECTIVE: To study and analyze the possible benefits on performance of community health workers using point-of-care clinical guidelines implemented as interactive rich media job aids on small-format mobile platforms. DESIGN: A crossover study with one intervention (rich media job aids) and one control (traditional job aids), two periods, with 50 community health workers, each subject solving a total 15 standardized cases per period per period (30 cases in total per subject). MEASUREMENTS: Error rate per case and task, protocol compliance. RESULTS: A total of 1394 cases were evaluated. Intervention reduces errors by an average of 33.15% (p = 0.001) and increases protocol compliance 30.18% (p < 0.001). Limitations Medical cases were presented on human patient simulators in a laboratory setting, not on real patients. CONCLUSION: These results indicate encouraging prospects for mHealth technologies in general, and the use of rich media clinical guidelines on cell phones in particular, for the improvement of community health worker performance in developing countries. PMID- 21292703 TI - Early cost and safety benefits of an inpatient electronic health record. AB - There is controversy over the impact of electronic health record (EHR) systems on cost of care and safety. The authors studied the effects of an inpatient EHR system with computerized provider order entry on selected measures of cost of care and safety. Laboratory tests per week per hospitalization decreased from 13.9 to 11.4 (18%; p < 0.001). Radiology examinations per hospitalization decreased from 2.06 to 1.93 (6.3%; p < 0.009). Monthly transcription costs declined from $74,596 to $18,938 (74.6%; p < 0.001). Reams of copy paper ordered per month decreased from 1668 to 1224 (26.6%; p < 0.001). Medication errors per 1000 hospital days decreased from 17.9 to 15.4 (14.0%; p < 0.030), while near misses per 1000 hospital days increased from 9.0 to 12.5 (38.9%; p < 0.037), and the percentage of medication events that were medication errors decreased from 66.5% to 55.2% (p < 0.007). In this manuscript, we demonstrate that the implementation of an inpatient EHR with computerized provider order entry can result in rapid improvement in measures of cost of care and safety. PMID- 21292704 TI - Explaining physicians' use of EMR systems and performance in the shakedown phase. AB - OBJECTIVE: This work seeks to complement and extend prior work by using a multidisciplinary approach to explain electronic medical records (EMR) system use and consequent performance (here, patient satisfaction) among physicians during early stages of the implementation of an EMR. DESIGN: This was a quantitative study, with data obtained from three distinct sources: individual-level and social-network data from employees; use data from EMR system logs; and patient satisfaction data from patients and/or authorized decision-makers. Responses were obtained from 151 physicians and 8440 patient satisfaction surveys over the course of a 1-year period at the shakedown phase of an EMR system implementation. RESULTS: Physicians who were better connected, both directly and indirectly, to their peers-that is, other physicians-for advice on their work, used the system less than those who were less connected. In addition to such social network ties, demographic characteristics (gender and age), three personality characteristics (openness to experience, agreeableness and extroversion) and a key technology perception (perceived usefulness) predicted EMR system use. CONCLUSIONS: For hospital administrators and other stakeholders, understanding the contributors to, and the relative importance of, various factors in explaining EMR system use, and its impact on patient satisfaction is of great importance. The factors identified in this work that influence a physician's use of EMR systems can be used to develop interventions and applications that can increase physician buy-in and use of EMR systems. PMID- 21292705 TI - The military health system's personal health record pilot with Microsoft HealthVault and Google Health. AB - OBJECTIVE: To design, build, implement, and evaluate a personal health record (PHR), tethered to the Military Health System, that leverages Microsoft(r) HealthVault and Google(r) Health infrastructure based on user preference. MATERIALS AND METHODS: A pilot project was conducted in 2008-2009 at Madigan Army Medical Center in Tacoma, Washington. Our PHR was architected to a flexible platform that incorporated standards-based models of Continuity of Document and Continuity of Care Record to map Department of Defense-sourced health data, via a secure Veterans Administration data broker, to Microsoft(r) HealthVault and Google(r) Health based on user preference. The project design and implementation were guided by provider and patient advisory panels with formal user evaluation. RESULTS: The pilot project included 250 beneficiary users. Approximately 73.2% of users were < 65 years of age, and 38.4% were female. Of the users, 169 (67.6%) selected Microsoft(r) HealthVault, and 81 (32.4%) selected Google(r) Health as their PHR of preference. Sample evaluation of users reflected 100% (n = 60) satisfied with convenience of record access and 91.7% (n = 55) satisfied with overall functionality of PHR. DISCUSSION: Key lessons learned related to data transfer decisions (push vs pull), purposeful delays in reporting sensitive information, understanding and mapping PHR use and clinical workflow, and decisions on information patients may choose to share with their provider. CONCLUSION: Currently PHRs are being viewed as empowering tools for patient activation. Design and implementation issues (eg, technical, organizational, information security) are substantial and must be thoughtfully approached. Adopting standards into design can enhance the national goal of portability and interoperability. PMID- 21292706 TI - Use of electronic clinical documentation: time spent and team interactions. AB - OBJECTIVE: To measure the time spent authoring and viewing documentation and to study patterns of usage in healthcare practice. DESIGN: Audit logs for an electronic health record were used to calculate rates, and social network analysis was applied to ascertain usage patterns. Subjects comprised all care providers at an urban academic medical center who authored or viewed electronic documentation. MEASUREMENT: Rate and time of authoring and viewing clinical documentation, and associations among users were measured. RESULTS: Users spent 20-103 min per day authoring notes and 7-56 min per day viewing notes, with physicians spending less than 90 min per day total. About 16% of attendings' notes, 8% of residents' notes, and 38% of nurses' notes went unread by other users, and, overall, 16% of notes were never read by anyone. Viewing of notes dropped quickly with the age of the note, but notes were read at a low but measurable rate, even after 2 years. Most healthcare teams (77%) included a nurse, an attending, and a resident, and those three users' groups were the first to write notes during an admission. Limitations The limitations were restriction to a single academic medical center and use of log files without direct observation. CONCLUSIONS: Care providers spend a significant amount of time viewing and authoring notes. Many notes are never read, and rates of usage vary significantly by author and viewer. While the rate of viewing a note drops quickly with its age, even after 2 years inpatient notes are still viewed. PMID- 21292707 TI - A curricula-based comparison of biomedical and health informatics programs in the USA. AB - OBJECTIVE: The field of Biomedical and Health Informatics (BMHI) continues to define itself, and there are many educational programs offering 'informatics' degrees with varied foci. The goal of this study was to develop a scheme for systematic comparison of programs across the entire BMHI spectrum and to identify commonalities among informatics curricula. DESIGN: Guided by several published competency sets, a grounded theory approach was used to develop a program/curricula categorization scheme based on the descriptions of 636 courses offered by 73 public health, nursing, health, medical, and bioinformatics programs in the USA. The scheme was then used to compare the programs in the aforementioned five informatics disciplines. RESULTS: The authors developed a Course-Based Informatics Program Categorization (CBIPC) scheme that can be used both to classify coursework for any BMHI educational program and to compare programs from the same or related disciplines. The application of CBIPC scheme to the analysis of public health, nursing, health, medical, and bioinformatics programs reveals distinct intradisciplinary curricular patterns and a common core of courses across the entire BMHI education domain. Limitations The study is based on descriptions of courses from the university's webpages. Thus, it is limited to sampling courses at one moment in time, and classification for the coding scheme is based primarily on course titles and course descriptions. CONCLUSION: The CBIPC scheme combines empirical data about educational curricula from diverse informatics programs and several published competency sets. It also provides a foundation for discussion of BMHI education as a whole and can help define subdisciplinary competencies. PMID- 21292708 TI - Opt-out HIV testing during antenatal care: experiences of pregnant women in rural Uganda. AB - Two years after the introduction of provider-initiated, opt-out HIV counselling and testing during antenatal care (ANC) in Uganda, HIV testing uptake is still low. This study was carried out to explore pregnant women's experiences of, and views on, the policies for opt-out, and couple HIV testing, and to understand how the policy implementation could be improved in order to increase access to prevention of mother-to-child-transmission (PMTCT) services. The study was conducted at three ANC health facilities at different levels of care in rural eastern Uganda. Data were collected through sit-in observations during ANC and 18 semi-structured interviews with pregnant women receiving ANC, and thereafter analysed using latent content analysis. Pregnant women who received ANC from facilities that provided HIV testing on-site perceived HIV testing as compulsory without actually fully realizing the benefits of HIV testing and PMTCT. No referral for HIV testing or information about testing was given at ANC facilities that lacked HIV testing on-site. A major challenge of couple HIV testing was that pregnant women were made responsible for recruiting their spouses for testing, a precarious dilemma for many women who tried to fulfil health workers' requests without having the power to do so. In order to increase uptake of PMTCT services, the pre-test counselling in groups that precedes the provider-initiated HIV testing should be adjusted to inform women about the benefits of PMTCT. Further, if testing is perceived as compulsory it could potentially deter some women from seeking ANC services. In order to increase HIV testing of male partners new strategies are needed, for example peer-sensitization and male clinics. Moreover, to achieve the desired outcomes of the PMTCT programme, monitoring and evaluation should be built into the programme. PMID- 21292709 TI - Nutrition agenda setting, policy formulation and implementation: lessons from the Mainstreaming Nutrition Initiative. AB - Undernutrition is the single largest contributor to the global burden of disease and can be addressed through a number of highly efficacious interventions. Undernutrition generally has not received commensurate attention in policy agendas at global and national levels, however, and implementing these efficacious interventions at a national scale has proven difficult. This paper reports on the findings from studies in Bangladesh, Bolivia, Guatemala, Peru and Vietnam which sought to identify the challenges in the policy process and ways to overcome them, notably with respect to commitment, agenda setting, policy formulation and implementation. Data were collected through participant observation, documents and interviews. Data collection, analysis and synthesis were guided by published conceptual frameworks for understanding malnutrition, commitment, agenda setting and implementation capacities. The experiences in these countries provide several insights for future efforts: (a) high-level political attention to nutrition can be generated in a number of ways, but the generation of political commitment and system commitment requires sustained efforts from policy entrepreneurs and champions; (b) mid-level actors from ministries and external partners had great difficulty translating political windows of opportunity for nutrition into concrete operational plans, due to capacity constraints, differing professional views of undernutrition and disagreements over interventions, ownership, roles and responsibilities; and (c) the pace and quality of implementation was severely constrained in most cases by weaknesses in human and organizational capacities from national to frontline levels. These findings deepen our understanding of the factors that can influence commitment, agenda setting, policy formulation and implementation. They also confirm and extend upon the growing recognition that the heavy investment to identify efficacious nutrition interventions is unlikely to reduce the burden of undernutrition unless or until these systemic capacity constraints are addressed, with an emphasis initially on strategic and management capacities. PMID- 21292710 TI - Telehealthcare for long term conditions. PMID- 21292711 TI - Effect of training traditional birth attendants on neonatal mortality (Lufwanyama Neonatal Survival Project): randomised controlled study. AB - OBJECTIVE: To determine whether training traditional birth attendants to manage several common perinatal conditions could reduce neonatal mortality in the setting of a resource poor country with limited access to healthcare. DESIGN: Prospective, cluster randomised and controlled effectiveness study. SETTING: Lufwanyama, an agrarian, poorly developed district located in the Copperbelt province, Zambia. All births carried out by study birth attendants occurred at mothers' homes, in rural village settings. PARTICIPANTS: 127 traditional birth attendants and mothers and their newborns (3559 infants delivered regardless of vital status) from Lufwanyama district. INTERVENTIONS: Using an unblinded design, birth attendants were cluster randomised to intervention or control groups. The intervention had two components: training in a modified version of the neonatal resuscitation protocol, and single dose amoxicillin coupled with facilitated referral of infants to a health centre. Control birth attendants continued their existing standard of care (basic obstetric skills and use of clean delivery kits). MAIN OUTCOME MEASURES: The primary outcome was the proportion of liveborn infants who died by day 28 after birth, with rate ratios statistically adjusted for clustering. Secondary outcomes were mortality at different time points; and comparison of causes of death based on verbal autopsy data. RESULTS: Among 3497 deliveries with reliable information, mortality at day 28 after birth was 45% lower among liveborn infants delivered by intervention birth attendants than control birth attendants (rate ratio 0.55, 95% confidence interval 0.33 to 0.90). The greatest reductions in mortality were in the first 24 hours after birth: 7.8 deaths per 1000 live births for infants delivered by intervention birth attendants compared with 19.9 per 1000 for infants delivered by control birth attendants (0.40, 0.19 to 0.83). Deaths due to birth asphyxia were reduced by 63% among infants delivered by intervention birth attendants (0.37, 0.17 to 0.81) and by 81% within the first two days after birth (0.19, 0.07 to 0.52). Stillbirths and deaths from serious infection occurred at similar rates in both groups. CONCLUSIONS: Training traditional birth attendants to manage common perinatal conditions significantly reduced neonatal mortality in a rural African setting. This approach has high potential to be applied to similar settings with dispersed rural populations. Trial registration Clinicaltrials.gov NCT00518856. PMID- 21292712 TI - Poor inpatient care for older people. PMID- 21292716 TI - Is quality of care improving in the UK? PMID- 21292717 TI - Enteroviruses and type 1 diabetes. PMID- 21292718 TI - Effectiveness of AS03 adjuvanted pandemic H1N1 vaccine: case-control evaluation based on sentinel surveillance system in Canada, autumn 2009. AB - OBJECTIVE: To assess the effectiveness of the pandemic influenza A/H1N1 vaccine used in Canada during autumn 2009. DESIGN: Test negative incident case-control study based on sentinel physician surveillance system. SETTING: Community based clinics contributing to sentinel networks in British Columbia, Alberta, Ontario, and Quebec, Canada. PARTICIPANTS: 552 patients who presented to a sentinel site within seven days of onset of influenza-like illness during the primary analysis period between 8 November and 5 December 2009; participants were mostly (>80%) children and adults under 50 years old. INTERVENTIONS: Monovalent AS03 adjuvanted pandemic influenza A/H1N1 vaccine as the predominant formulation (>95%) distributed in Canada. MAIN OUTCOME MEASURES: Vaccine effectiveness calculated as 1-(odds ratio for influenza in vaccinated (received pandemic H1N1 vaccine at least two weeks before onset of influenza-like illness) versus unvaccinated participants), with adjustment for age, comorbidity, province, timeliness of specimen collection, and week of illness onset. Sensitivity analyses explored the influence of varying analysis periods between 1 November and 31 December, receipt of trivalent seasonal influenza vaccine, and restriction to participants without comorbidity. RESULTS: During the primary analysis period, pandemic H1N1 was detected by reverse transcription polymerase chain reaction in 209/552 (38%) participants; rates were highest in children and young adults (40%) and lowest in people aged 65 or over (9%). Among the 209 cases, 35 (17%) reported comorbidity compared with 80/343 (23%) controls. Two (1%) cases had received pandemic H1N1 vaccine at least two weeks before the onset of illness, compared with 58/343 (17%) controls, all single dose. Adjusted vaccine effectiveness overall was 93% (95% confidence interval 69% to 98%). High estimates of vaccine protection generally at least 90%-were maintained across most sensitivity analyses. CONCLUSIONS: Although limited by a small number of vaccine failures, this study suggests that the monovalent AS03 adjuvanted vaccine used in Canada during autumn 2009 was highly effective in preventing medically attended, laboratory confirmed pandemic H1N1 illness, with reference in particular to a single dose in children and young adults. PMID- 21292719 TI - Large scale organisational intervention to improve patient safety in four UK hospitals: mixed method evaluation. AB - OBJECTIVES: To conduct an independent evaluation of the first phase of the Health Foundation's Safer Patients Initiative (SPI), and to identify the net additional effect of SPI and any differences in changes in participating and non participating NHS hospitals. DESIGN: Mixed method evaluation involving five substudies, before and after design. SETTING: NHS hospitals in the United Kingdom. PARTICIPANTS: Four hospitals (one in each country in the UK) participating in the first phase of the SPI (SPI1); 18 control hospitals. INTERVENTION: The SPI1 was a compound (multi-component) organisational intervention delivered over 18 months that focused on improving the reliability of specific frontline care processes in designated clinical specialties and promoting organisational and cultural change. RESULTS: Senior staff members were knowledgeable and enthusiastic about SPI1. There was a small (0.08 points on a 5 point scale) but significant (P < 0.01) effect in favour of the SPI1 hospitals in one of 11 dimensions of the staff questionnaire (organisational climate). Qualitative evidence showed only modest penetration of SPI1 at medical ward level. Although SPI1 was designed to engage staff from the bottom up, it did not usually feel like this to those working on the wards, and questions about legitimacy of some aspects of SPI1 were raised. Of the five components to identify patients at risk of deterioration--monitoring of vital signs (14 items); routine tests (three items); evidence based standards specific to certain diseases (three items); prescribing errors (multiple items from the British National Formulary); and medical history taking (11 items)--there was little net difference between control and SPI1 hospitals, except in relation to quality of monitoring of acute medical patients, which improved on average over time across all hospitals. Recording of respiratory rate increased to a greater degree in SPI1 than in control hospitals; in the second six hours after admission recording increased from 40% (93) to 69% (165) in control hospitals and from 37% (141) to 78% (296) in SPI1 hospitals (odds ratio for "difference in difference" 2.1, 99% confidence interval 1.0 to 4.3; P = 0.008). Use of a formal scoring system for patients with pneumonia also increased over time (from 2% (102) to 23% (111) in control hospitals and from 2% (170) to 9% (189) in SPI1 hospitals), which favoured controls and was not significant (0.3, 0.02 to 3.4; P = 0.173). There were no improvements in the proportion of prescription errors and no effects that could be attributed to SPI1 in non-targeted generic areas (such as enhanced safety culture). On some measures, the lack of effect could be because compliance was already high at baseline (such as use of steroids in over 85% of cases where indicated), but even when there was more room for improvement (such as in quality of medical history taking), there was no significant additional net effect of SPI1. There were no changes over time or between control and SPI1 hospitals in errors or rates of adverse events in patients in medical wards. Mortality increased from 11% (27) to 16% (39) among controls and decreased from 17% (63) to 13% (49) among SPI1 hospitals, but the risk adjusted difference was not significant (0.5, 0.2 to 1.4; P = 0.085). Poor care was a contributing factor in four of the 178 deaths identified by review of case notes. The survey of patients showed no significant differences apart from an increase in perception of cleanliness in favour of SPI1 hospitals. CONCLUSIONS: The introduction of SPI1 was associated with improvements in one of the types of clinical process studied (monitoring of vital signs) and one measure of staff perceptions of organisational climate. There was no additional effect of SPI1 on other targeted issues nor on other measures of generic organisational strengthening. PMID- 21292720 TI - Multiple component patient safety intervention in English hospitals: controlled evaluation of second phase. AB - OBJECTIVE: To independently evaluate the impact of the second phase of the Health Foundation's Safer Patients Initiative (SPI2) on a range of patient safety measures. Design A controlled before and after design. Five substudies: survey of staff attitudes; review of case notes from high risk (respiratory) patients in medical wards; review of case notes from surgical patients; indirect evaluation of hand hygiene by measuring hospital use of handwashing materials; measurement of outcomes (adverse events, mortality among high risk patients admitted to medical wards, patients' satisfaction, mortality in intensive care, rates of hospital acquired infection). Setting NHS hospitals in England. PARTICIPANTS: Nine hospitals participating in SPI2 and nine matched control hospitals. INTERVENTION: The SPI2 intervention was similar to the SPI1, with somewhat modified goals, a slightly longer intervention period, and a smaller budget per hospital. RESULTS: One of the scores (organisational climate) showed a significant (P = 0.009) difference in rate of change over time, which favoured the control hospitals, though the difference was only 0.07 points on a five point scale. Results of the explicit case note reviews of high risk medical patients showed that certain practices improved over time in both control and SPI2 hospitals (and none deteriorated), but there were no significant differences between control and SPI2 hospitals. Monitoring of vital signs improved across control and SPI2 sites. This temporal effect was significant for monitoring the respiratory rate at both the six hour (adjusted odds ratio 2.1, 99% confidence interval 1.0 to 4.3; P = 0.010) and 12 hour (2.4, 1.1 to 5.0; P = 0.002) periods after admission. There was no significant effect of SPI for any of the measures of vital signs. Use of a recommended system for scoring the severity of pneumonia improved from 1.9% (1/52) to 21.4% (12/56) of control and from 2.0% (1/50) to 41.7% (25/60) of SPI2 patients. This temporal change was significant (7.3, 1.4 to 37.7; P = 0.002), but the difference in difference was not significant (2.1, 0.4 to 11.1; P = 0.236). There were no notable or significant changes in the pattern of prescribing errors, either over time or between control and SPI2 hospitals. Two items of medical history taking (exercise tolerance and occupation) showed significant improvement over time, across both control and SPI2 hospitals, but no additional SPI2 effect. The holistic review showed no significant changes in error rates either over time or between control and SPI2 hospitals. The explicit case note review of perioperative care showed that adherence rates for two of the four perioperative standards targeted by SPI2 were already good at baseline, exceeding 94% for antibiotic prophylaxis and 98% for deep vein thrombosis prophylaxis. Intraoperative monitoring of temperature improved over time in both groups, but this was not significant (1.8, 0.4 to 7.6; P = 0.279), and there were no additional effects of SPI2. A dramatic rise in consumption of soap and alcohol hand rub was similar in control and SPI2 hospitals (P = 0.760 and P = 0.889, respectively), as was the corresponding decrease in rates of Clostridium difficile and meticillin resistant Staphylococcus aureus infection (P = 0.652 and P = 0.693, respectively). Mortality rates of medical patients included in the case note reviews in control hospitals increased from 17.3% (42/243) to 21.4% (24/112), while in SPI2 hospitals they fell from 10.3% (24/233) to 6.1% (7/114) (P = 0.043). Fewer than 8% of deaths were classed as avoidable; changes in proportions could not explain the divergence of overall death rates between control and SPI2 hospitals. There was no significant difference in the rate of change in mortality in intensive care. Patients' satisfaction improved in both control and SPI2 hospitals on all dimensions, but again there were no significant changes between the two groups of hospitals. CONCLUSIONS: Many aspects of care are already good or improving across the NHS in England, suggesting considerable improvements in quality across the board. These improvements are probably due to contemporaneous policy activities relating to patient safety, including those with features similar to the SPI, and the emergence of professional consensus on some clinical processes. This phenomenon might have attenuated the incremental effect of the SPI, making it difficult to detect. Alternatively, the full impact of the SPI might be observable only in the longer term. The conclusion of this study could have been different if concurrent controls had not been used. PMID- 21292721 TI - Enterovirus infection and type 1 diabetes mellitus: systematic review and meta analysis of observational molecular studies. AB - OBJECTIVE: To review the association between current enterovirus infection diagnosed with molecular testing and development of autoimmunity or type 1 diabetes. DESIGN: Systematic review and meta-analysis of observational studies, analysed with random effects models. DATA SOURCES: PubMed (until May 2010) and Embase (until May 2010), no language restrictions, studies in humans only; reference lists of identified articles; and contact with authors. Study eligibility criteria Cohort or case-control studies measuring enterovirus RNA or viral protein in blood, stool, or tissue of patients with pre-diabetes and diabetes, with adequate data to calculate an odds ratio and 95% confidence intervals. RESULTS: The 24 papers and two abstracts (all case-control studies) that met the eligibility criteria included 4448 participants. Study design varied greatly, with a high level of statistical heterogeneity. The two separate outcomes were diabetes related autoimmunity or type 1 diabetes. Meta-analysis showed a significant association between enterovirus infection and type 1 diabetes related autoimmunity (odds ratio 3.7, 95% confidence interval 2.1 to 6.8; heterogeneity chi(2)/df = 1.3) and clinical type 1 diabetes (9.8, 5.5 to 17.4; chi(2)/df = 3.2). CONCLUSIONS: There is a clinically significant association between enterovirus infection, detected with molecular methods, and autoimmunity/type 1 diabetes. Larger prospective studies would be needed to establish a clear temporal relation between enterovirus infection and the development of autoimmunity and type 1 diabetes. PMID- 21292723 TI - RE-AIM evaluation of the Alcohol and Pregnancy Project: educational resources to inform health professionals about prenatal alcohol exposure and fetal alcohol spectrum disorder. AB - The objective was to evaluate the Alcohol and Pregnancy Project that provided health professionals in Western Australia (WA) with educational resources to inform them about prevention of prenatal alcohol exposure and fetal alcohol spectrum disorder (FASD). The authors developed, produced, and distributed educational resources to 3,348 health professionals in WA. Six months later, they surveyed 1,483 of these health professionals. The authors used the RE-AIM framework (reach, effectiveness, adoption, implementation, and maintenance) to evaluate the project. The educational resources were effective in producing a 31% increase in the proportion of health professionals who routinely provided pregnant women with information about the consequences of drinking alcohol during pregnancy. One hundred percent of the settings adopted the project, it reached 96.3% of the target population, it was implemented as intended, and the resources were maintained (http://www.ichr.uwa.edu.au/alcoholandpregnancy). The educational resources for health professionals have potential to contribute to reducing prenatal alcohol exposure and FASD. PMID- 21292724 TI - Case study: An ethics case study of HIV prevention research on Facebook: the Just/Us study. AB - OBJECTIVE: To consider issues related to research with youth on social networking sites online. METHODS: Description of the data collection process from 1,588 participants in a randomized controlled trial testing the efficacy of HIV prevention education delivered on Facebook. Using respondent-driven sampling, staff-recruited participants are encouraged to recruit up to three friends to enroll in the study. RESULTS: Researchers should (a) consider whether an online social networking site is an appropriate place to implement a research study; (b) offer opportunities to review informed consent documents at multiple times and in multiple locations throughout the study; and (c) collect data outside the social networking site and store it behind secure firewalls to ensure it will not be accessible to any person on the social networking site. CONCLUSIONS: Online social networks are growing in popularity. Conducting research on social media sites requires deliberate attention to consent, confidentiality, and security. PMID- 21292725 TI - Nanostructured glass-ceramic coatings for orthopaedic applications. AB - Glass-ceramics have attracted much attention in the biomedical field, as they provide great possibilities to manipulate their properties by post-treatments, including strength, degradation rate and coefficient of thermal expansion. In this work, hardystonite (HT; Ca2ZnSi2O7) and sphene (SP; CaTiSiO5) glass-ceramic coatings with nanostructures were prepared by a plasma spray technique using conventional powders. The bonding strength and Vickers hardness for HT and SP coatings are higher than the reported values for plasma-sprayed hydroxyapatite coatings. Both types of coatings release bioactive calcium (Ca) and silicon (Si) ions into the surrounding environment. Mineralization test in cell-free culture medium showed that many mushroom-like Ca and phosphorus compounds formed on the HT coatings after 5 h, suggesting its high acellular mineralization ability. Primary human osteoblasts attach, spread and proliferate well on both types of coatings. Higher proliferation rate was observed on the HT coatings compared with the SP coatings and uncoated Ti-6Al-4V alloy, probably due to the zinc ions released from the HT coatings. Higher expression levels of Runx2, osteopontin and type I collagen were observed on both types of coatings compared with Ti-6Al-4V alloy, possibly due to the Ca and Si released from the coatings. Results of this study point to the potential use of HT and SP coatings for orthopaedic applications. PMID- 21292726 TI - IGF2, IGF binding protein 1, and matrix metalloproteinases 2 and 9 in implantation-stage endometrium following immunoneutralization of vascular endothelial growth factor in the rhesus monkey. AB - Blastocyst implantation in the rhesus monkey is inhibited by administration of antibody against vascular endothelial growth factor (VEGF) A during peri implantation period with no change in the circulatory concentrations of estradiol, progesterone, and VEGF. In this study, we have investigated the effect of administration of a MAB to VEGFA on days 5 and 10 after ovulation upon the mRNA expression, immunopositive protein expression, and immunohistological localization of IGF2, IGF binding protein 1 (IGFBP1) and matrix metalloproteinases (MMPs) 2 and 9 in the implantation-stage endometrium collected on day 13 after ovulation from fecund cycles of rhesus monkeys. The comparison between isotype-matched IgG (control; n=8)- and VEGF antibody (VEGF Mab; n=8) treated animals revealed higher (P<0.05) IGF2 in lacunar and villous syncytiotrophoblasts, trophoblast cell columns, migrating extravillous trophoblast cells, and endovascular trophoblast cells in control animals, but with no change in the various cell types of maternal endometrium between the two groups. No change in IGFBP1 expression in the endometrium was observed between the two groups. MMPs 2 and 9 were detected in syncytiotrophoblast in lacunae and villi, trophoblast cell columns, and extravillous trophoblast cells in control samples. MMP9 transcript expression in maternal endometrium and its immunopositivity in endometrial stroma and trophoblast cells were lower (P<0.05) with no change in MMP2 level in VEGF Mab-exposed samples compared with those in control samples. A functional network involving VEGF, IGF2, and MMP9 in early placental trophoblast cells and maternal endometrium appears to be important for normal placentation. PMID- 21292727 TI - Assessment of follicular development in cryopreserved primate ovarian tissue by xenografting: prepubertal tissues are less sensitive to the choice of cryoprotectant. AB - Improvements in cancer survival rates have renewed interest in the cryopreservation of ovarian tissue for fertility preservation. We used the marmoset as a non-human primate model to assess the effect of different cryoprotectives on follicular viability of prepubertal compared to adult ovarian tissue following xenografting. Cryopreservation was performed with dimethylsulfoxide (DMSO), 1,2-propanediol (PrOH), or ethylene glycol (EG) using a slow freezing protocol. Subsequently, nude mice received eight grafts per animal from the DMSO and the PrOH groups for a 4-week grafting period. Fresh, cryopreserved-thawed, and xenografted tissues were serially sectioned and evaluated for the number and morphology of follicles. In adult tissue, the percentage of morphologically normal primordial follicles significantly decreased from 41.2 +/- 4.5% (fresh) to 13.6 +/- 1.8 (DMSO), 9.5 +/- 1.7 (PrOH), or 6.8 +/- 1.0 (EG) following cryopreservation. After xenografting, the percentage of morphologically normal primordial (26.2 +/- 2.5%) and primary follicles (28.1 +/- 5.4%) in the DMSO group was significantly higher than that in the PrOH group (12.2 +/- 3 and 5.4 +/- 2.1% respectively). Proliferating cell nuclear antigen (PCNA) staining suggests the resumption of proliferative activity in all cellular compartments. In prepubertal tissues, primordial but not primary follicles display a similar sensitivity to cryopreservation, and no significant differences between DMSO and PrOH following xenografting were observed. In conclusion, DMSO shows a superior protective effect on follicular morphology compared with PrOH and EG in cryopreserved tissues. Xenografting has confirmed better efficacy of DMSO versus PrOH in adult but not in prepubertal tissues, probably owing to a greater capacity of younger animals to compensate for cryoinjury. PMID- 21292728 TI - Interference RNA-based silencing of endogenous SMAD4 in porcine granulosa cells resulted in decreased FSH-mediated granulosa cells proliferation and steroidogenesis. AB - FSH plays a critical role in granulosa cell (GC) proliferation and steroidogenesis through modulation by factors including bone morphogenetic proteins family, which belongs to transforming growth factor beta (TGFB) superfamily. TGFBs are the key factors in maintaining cell growth and differentiation in ovaries. However, the interaction of FSH and TGFB on the GCs' proliferation and steroidogenesis remains to be elucidated. In this study, we have investigated the role of SMAD4, a core molecule mediating the intracellular TGFB/SMAD signal transduction pathway, in FSH-mediated proliferation and steroidogenesis of porcine GCs. In this study, SMAD4 was knocked down using interference RNA in porcine GCs. Our results showed that SMAD4-siRNA causes specific inhibition of SMAD4 mRNA and protein expression after transfection. Knockdown of SMAD4 significantly inhibited FSH-induced porcine GC proliferation and estradiol production and changed the expression of cyclin D2, CDK2, CDK4, CYP19a1, and CYP11a1. Thus, these observations establish an important role of SMAD4 in the regulation of the response of porcine GCs to FSH. PMID- 21292729 TI - Deiodinases: the balance of thyroid hormone: local control of thyroid hormone action: role of type 2 deiodinase. AB - The thyroid gland predominantly secretes the pro-hormone thyroxine (T(4)) that is converted to the active hormone 3,5,3'-l-triiodothyronine (T(3)) in target cells. Conversion of T(4) to T(3) is catalyzed by the type 2 iodothyronine deiodinase enzyme (DIO2), and T(3) action in target tissues is determined by DIO2-regulated local availability of T(3) to its nuclear receptors, TRalpha and TRbeta. Studies of Dio2 knockout mice have revealed new and important roles for the enzyme during development and in adulthood in diverse tissues including the cochlea, skeleton, brown fat, pituitary, and hypothalamus. In this review, we discuss the molecular mechanisms by which DIO2 controls intracellular T(3) availability and action. PMID- 21292730 TI - Exposure to tetrachloroethylene in dry cleaning shops in the Nordic countries. AB - OBJECTIVES: Tetrachloroethylene is the dominant solvent used in dry cleaning worldwide and many workers are potentially exposed. We report here on results of 1296 measurements of tetrachloroethylene undertaken in Nordic dry cleaning shops 1947-2001. METHODS: We searched documents and files in the Nordic institutes of occupational health for air measurements of tetrachloroethylene. Repeated measurements from the same facility during a short time interval were registered only once using the time-weighted average. We registered also changes over time in occupational exposure limits (OELs) to tetrachloroethylene. RESULTS: Only scattered measurements were available from the early years, and the exposure level seemed fairly stable up until the mid 1970s. The median exposure level was 20 p.p.m. in 1976 and decreased to 3 p.p.m. in 2000. Exposure levels in the four Nordic countries followed similar trends. In the late 1960s, the OELs varied between the Nordic countries from 30 to 100 p.p.m. Sweden was first to lower the limit, but limits gradually converged over time. At present, Denmark, Finland, and Sweden use 10 p.p.m., while Norway uses 6 p.p.m. Over time, the average observed exposure level was lower than the OEL in all countries, but in Denmark and Sweden, up to one-third of measured exposures exceeded the OEL. Overall, the stationary measurements for maintenance work showed 36 p.p.m., while the personal measurements showed 7.5 p.p.m. for dry cleaners and 6.25 p.p.m. for shop assistants. CONCLUSION: The Nordic data illustrate that it is possible over time to control chemical exposures even in an industry consisting of many small and scattered work places. PMID- 21292731 TI - Total inward leakage of nanoparticles through filtering facepiece respirators. AB - Nanoparticle (<100 nm size) exposure in workplaces is a major concern because of the potential impact on human health. National Institute for Occupational Safety and Health (NIOSH)-approved particulate respirators are recommended for protection against nanoparticles based on their filtration efficiency at sealed conditions. Concerns have been raised on the lack of information for face seal leakage of nanoparticles, compromising respiratory protection in workplaces. To address this issue, filter penetration and total inward leakage (TIL) through artificial leaks were measured for NIOSH-approved N95 and P100 and European certified Conformit'e Europe'en-marked FFP2 and FFP3 filtering facepiece respirator models sealed to a breathing manikin kept inside a closed chamber. Monodisperse sucrose aerosols (8-80 nm size) generated by electrospray or polydisperse NaCl aerosols (20-1000 nm size) produced by atomization were passed into the chamber. Filter penetration and TIL were measured at 20, 30, and 40 l min(-1) breathing flow rates. The most penetrating particle size (MPPS) was ~50 nm and filter penetrations for 50 and 100 nm size particles were markedly higher than the penetrations for 8 and 400 nm size particles. Filter penetrations increased with increasing flow rates. With artificially introduced leaks, the TIL values for all size particles increased with increasing leak sizes. With relatively smaller size leaks, the TIL measured for 50 nm size particles was ~2 fold higher than the values for 8 and 400 nm size particles indicating that the TIL for the most penetrating particles was higher than for smaller and larger size particles. The data indicate that higher concentration of nanoparticles could occur inside the breathing zone of respirators in workplaces where nanoparticles in the MPPS range are present, when leakage is minimal compared to filter penetration. The TIL/penetration ratios obtained for 400 nm size particles were larger than the ratios obtained for 50 nm size particles at the three different flow rates and leak sizes indicating that face seal leakage, not filter penetration, contributing to the TIL for larger size particles. Further studies on face seal leakage of nanoparticles for respirator users in workplaces are needed to better understand the respiratory protection against nanoparticle exposure. PMID- 21292732 TI - Fabrication and evaluation of Bis-GMA/TEGDMA resin with various amounts of silane coated silica for orthodontic use. AB - The objective of this research was to fabricate a composite with an optimum filler level in a bisphenol-A-glycidyldimethacrylate (Bis-GMA) triethylene glycidal dimethacrylate (TEGDMA) resin for bonding of metallic orthodontic brackets to achieve the best handling characteristics with optimum bond strength and without compromising the mechanical properties of the adhesive. One-hundred and sixty extracted human premolars free of any detectable pathology or buccal surface alterations were collected and divided into four groups. In group 1 (control), the teeth were bonded with stainless steel brackets using Transbond XT. In groups 2, 3, and 4, the teeth were bonded with metal brackets using a Bis GMA/TEGDMA resin with 80, 60, and 20 per cent by weight silane-coated silica of a spherical shape with a mean size of 0.01 MUm. Shear bond strength (SBS) of the composites was determined and the adhesive remnant index (ARI) and enamel fracture post-debonding were assessed. According to one-way analysis of variance and Tukey's honestly significant difference (HSD) multiple comparison tests, the SBS of group 4 (10.54 MPa) was considerably less than that of groups 1 (26.1 MPa), 2 (25.5 MPa), and 3 (24.6 MPa). Chi-square analysis revealed that there was an insignificant difference in the incidence of enamel fracture between groups 1 and 2, while a significant difference was present between groups 1 and 2 and 3 and 4. An insignificant difference was also observed in the location of the adhesive failure between the four groups. While all the bonding adhesives tested can be safely used for bonding of brackets, 60 per cent filled Bis-GMA/TEGDMA was superior clinically due to its ease of handling and superior bond strength. PMID- 21292733 TI - Sensitivity and specificity of 2010 rheumatoid arthritis classification criteria. AB - OBJECTIVE: To validate the sensitivity and specificity of the 2010 RA classification criteria. METHODS: A total of 313 undiagnosed subjects, who first visited Keio University Hospital with joint symptoms, including arthralgia, joint swelling and morning stiffness, without any previous treatment except for NSAIDs, were included in the present study. A clinical diagnosis of RA was made by rheumatologists, and the gold standard diagnosis of RA was defined as an indication for instituting DMARDs for RA. RESULTS: Seventy-six subjects were diagnosed as gold standard RA. Among these, 8 did not have any swollen joints, 50 were classified as definite RA under the 2010 criteria and the other 18 as not having RA. Eighty-two subjects were eligible for the 2010 criteria, and the sensitivity and specificity under the 2010 criteria were 73.5 and 71.4%, respectively, compared with 47.1 and 92.9% under the 1987 criteria. But the sensitivity of the 2010 criteria decreased to 15.8% when both RF and anti-CCP were negative. According to the result of a receiver-operated characteristic (ROC) curve of the scoring system, if swollen joints and differential diagnosis are not accurately detected, it would be better to use a score of 5 as the cut off level to detect RA. CONCLUSION: The 2010 classification criteria have a high sensitivity and have been verified to be useful for distinguishing RA at an early stage. PMID- 21292734 TI - 28-Joint count disease activity score at 3 months after diagnosis of early rheumatoid arthritis is strongly associated with direct and indirect costs over the following 4 years: the Swedish TIRA project. AB - OBJECTIVE: To explore possible association between disease activity at 3-month follow-up after RA diagnosis and costs over the following 4 years. METHODS: Three hundred and twenty patients with early (<= 1 year) RA were assessed at regular intervals. Clinical and laboratory data were collected and patients reported health-care utilization and number of days lost from work. At 3-month follow-up, patients were divided into two groups according to disease activity, using DAS-28 with a cut-off level at 3.2. Direct and indirect costs and EuroQol-5D over the following 4 years were compared between the groups. Multivariate regression models were used to control for possible covariates. RESULTS: Three months after diagnosis, a DAS-28 level of >= 3.2 was associated with high direct and indirect costs over the following 4 years. Patients with DAS-28 >= 3.2 at 3-month follow up had more visits to physician, physiotherapist, occupational therapist and nurse, higher drug costs, more days in hospital and more extensive surgery compared with patients with 3-month DAS-28 < 3.2. Number of days lost from work due to sick leave and permanent work disability was also higher in this group. The effect of disease activity on health-related quality of life was highly significant. In regression models, DAS-28 at 3-month follow-up was significantly associated with costs over the following years. CONCLUSIONS: Three months after diagnosis, DAS-28 is an important prognostic marker regarding health-care utilization and costs. Achieving remission or low disease activity 3 months after diagnosis is likely to decrease morbidity, increase quality of life and save costs for the patient and for society over the following years. PMID- 21292735 TI - ANCA vasculitis: time for a change in treatment paradigm? Not yet. AB - The ANCA-associated vasculitides (AAVs) are conventionally treated with a strategy of remission induction followed by maintenance therapy using glucocorticoids combined with CYC during induction and AZA for maintenance. Recently, several randomized controlled trials have been published that question whether these drugs should remain those of choice. B-cell depletion using rituximab is at least as effective as CYC for remission induction in newly presenting patients, but long-term efficacy, safety and cost-effectiveness data are awaited, and thus rituximab should be reserved for patients at high risk of infertility. Rituximab seems to be effective at inducing remission in relapsing patients. Whether routine pre-emptive treatment with rituximab for remission maintenance is a better approach than waiting for relapse is unknown. MTX and LEF have similar efficacy to AZA, but are not significantly safer; while MMF is less effective. Thus, AZA remains the conventional maintenance drug of choice. PMID- 21292736 TI - Abnormal body composition phenotypes in Vietnamese women with early rheumatoid arthritis. AB - OBJECTIVES: To characterize body composition phenotypes using a dual-energy X-ray absorptiometry (DXA) method and to explore factors potentially contributing to alterations in body composition in Vietnamese women with early RA. METHODS: A total of 105 women with early RA (disease duration <= 3 years) and 105 age matched healthy women underwent physical examination, total and regional lean mass (LM) and fat mass (FM) with DXA. The 28-joint DAS (DAS-28) and disability using HAQ score, nutrition, physical activity and medications were recorded. RESULTS: Means of weight and BMI were similar in RA patients and controls, but means of total body and trunk FM in RA patients were higher: 19.1 vs 16.9 kg (P = 0.007) and 10.1 vs 8.1 kg (P = 0.01), respectively, and appendicular LM was lower: 12.9 vs 14.1 kg (P = 0.02). The proportion of unhealthy body composition phenotypes (sarcopenia, overfat and sarcopenic obesity) in RA patients was higher (P < 0.001) than in controls. DAS-28 score was positively correlated with total FM and fat distribution ratio, and HAQ score was inversely correlated with appendicular LM. These body composition changes were associated with RF seropositivity, HAQ and DAS-28 scores. CONCLUSIONS: Women with early RA had a significantly higher proportion of unhealthy body composition phenotypes, higher total and truncal FM and lower appendicular LM than controls. Disease activity and disability scores were associated with unhealthy body composition. These findings suggest that clinicians should encourage muscle strengthening and fat loss in RA patients to reduce their disability. PMID- 21292737 TI - Fertility in women with chronic inflammatory arthritides. AB - OBJECTIVE: To compare fertility rates in women with RA, other chronic arthritides (OCAs) and JIA with reference women from the general population. METHODS: Each woman from a Norwegian patient registry was matched by year of birth with 100 reference women randomly selected from the National Population Registry. Data linkage of patients and references with the Medical Birth Registry of Norway (MBRN) identified all offspring in patients and references until October 2007, and indirectly also nulliparous (childless) women. Groups were compared with Mann Whitney U-test for continuous variables and chi-squared tests for categorical variables. Poisson regression analysis was applied to calculate relative fertility rates in the diagnostic groups vs references. RESULTS: Among 631 patients 849 children were registered in MBRN. Of these, 289 children (34.0%) were born after time of diagnosis vs 44.3% in references. Altogether, 206 of 631 patients (32.6%) were nulliparous vs 26.4% in references (P < 0.001). Among RA patients, 28.4% (96 of 338) were nulliparous vs 24.5% in references (P = 0.09), 30.7% (67 of 218) in OCA patients vs 24.5% in references (P = 0.03) and 57.3% (43 of 75) in JIA patients vs 40.9% in references (P = 0.004). Adjusted relative fertility rates in RA, OCA and JIA after diagnosis were 0.88, 0.84 and 0.84, respectively, compared with references. CONCLUSION: A higher proportion of women with chronic inflammatory arthritides were nulliparous compared with references, and relative fertility rates were reduced in all patient groups. PMID- 21292739 TI - Comment on: steroid injection for hip osteoarthritis: efficacy under ultrasound guidance. PMID- 21292740 TI - Diagnosis of Churg-Strauss syndrome: eotaxin-3 makes it easier. PMID- 21292741 TI - Factors affecting early feeding performance in preterm infants below 32 weeks gestation. AB - OBJECTIVE: To identify the influence of various physiological and behavioral factors on feeding performance of preterm infants in the transition to full oral feeding. METHODS: We retrospectively reviewed data from a feeding assessment conducted on 24 preterm infants born at 25-31 weeks without severe brain complications. RESULTS: Prolonged oxygen use and low current weight are two adverse factors for feeding efficiency (volume of milk ingested orally per minute in the initial 5 min of feeding) and proficiency (percentage of prescribed volume ingested orally over the entire feeding). Young post-menstrual age, low baseline oxygen saturation and high feeding efficiency were risk factors for oxygen desaturation during the initial feeding. CONCLUSION: Proper feeding strategies are needed for preterm infants with those disadvantageous factors to improve their early feeding performance. PMID- 21292742 TI - Cardiovascular dysfunction in HIV-infected children in a sub-Saharan African country: comparative cross-sectional observational study. AB - OBJECTIVE: Cardiac dysfunction is rarely diagnosed in HIV-infected children in our setting and standard care does not include baseline and follow-up echocardiography. We aimed to determine the prevalence, pattern and predictors of HIV-related cardiac dysfunction. METHODS: Pre-diagnosed HIV-infected children aged 18 months to 12 years from a tertiary teaching hospital in Lagos, South-West Nigeria were enrolled in a comparative, observational cross-sectional study; matched with apparently healthy controls of the same age group, were recruited sequentially between May 2004 and 2007. Proportions of pre-defined cardiac abnormalities such as heart failure diagnosed by clinical examination and dilated cardiomyopathy and ventricular dysfunction by echocardiography were determined. RESULTS: Prevalence of cardiac abnormalities in HIV-infected children was 75.9%. Abnormalities included heart failure, dilated cardiomyopathy (33.7%), decreased LVSF of <= 25% in 33.7%, increased left ventricular mass (20.5%) and pericardial effusion (14.5%). CONCLUSION: Structural and functional abnormalities are prevalent in HIV-infected African children and therefore justify inclusion of routine echocardiography in their standard care. PMID- 21292743 TI - Participation of CheR and CheB in the chemosensory response of Campylobacter jejuni. AB - Campylobacter jejuni is a leading cause of bacterial gastroenteritis in humans and a commensal bacterium of the intestinal tracts of animals, especially poultry. Chemotaxis is an important determinant for chicken colonization of C. jejuni. Adaptation has a crucial role in the gradient-sensing mechanism that underlies chemotaxis. The genome sequence of C. jejuni reveals the presence of genes encoding putative adaptation proteins, CheB and CheR. In-frame deletions of cheB, cheR and cheBR were constructed and the chemosensory behaviour of the resultant mutants was examined on swarm plates. CheB and CheR proteins significantly influence chemotaxis but are not essential for this behaviour to occur. Increased mobility of two methyl-accepting chemotaxis proteins (MCPs), DocC and Tlp1, during SDS-PAGE was detected in the mutants lacking functional CheB in the presence of CheR, presumably resulting from stable methylation of receptors. In vitro studies using tissue culture revealed that deletion of cheR resulted in hyperadherent and hyperinvasive phenotypes, while deletion of cheB resulted in nonadherent, noninvasive phenotypes. Furthermore, the DeltacheBR mutant showed significantly reduced ability to colonize chick caeca. Our data suggest that modification of chemoreceptors by the CheBR system is involved in regulation of chemotaxis in C. jejuni although CheB is apparently not controlled by phosphorylation. PMID- 21292744 TI - Specific and promiscuous functions of multiple DnaJ proteins in Synechocystis sp. PCC 6803. AB - Cyanobacterial genomes typically encode multiple Hsp70 (DnaK) and Hsp40 (DnaJ) chaperones, and in the genome of the cyanobacterium Synechocystis PCC 6803, three DnaK proteins are encoded together with seven DnaJ proteins. While only two of the DnaJ proteins can complement the growth defect of an Escherichia coli DeltadnaJ strain, only disruption of the dnaJ gene sll0897 resulted in a growth defect at elevated temperatures. Based on the domain structure and the phenotype observed following disruption of the encoding gene, Sll0897 can be classified as a canonical heat-shock protein in Synechocystis. Furthermore, most dnaJ genes could be deleted individually, whereas disruption of the gene encoding the DnaJ Sll1933 failed, which suggests an essential, yet undefined, function for Sll1933. Since after deletion of the remaining dnaJ genes the phenotypes were not altered, the functions of these DnaJs either are not critical or are taken over by the remaining DnaJs. Nevertheless, only the two dnaJ genes sll0909 and sll1384 could be disrupted in combination, suggesting physiological functions for the two encoded proteins which either are not overlapping and/or can be fulfilled by the remaining DnaJs in the double-disruption strain. Taken together, the present analysis indicates specific and promiscuous functions for multiple DnaJ proteins in Synechocystis. PMID- 21292745 TI - Comparative analysis and mutation effects of fpp2-fpp1 tandem genes encoding proteolytic extracellular enzymes of Flavobacterium psychrophilum. AB - Flavobacterium psychrophilum is a very significant fish pathogen that secretes two biochemically characterized extracellular proteolytic enzymes, Fpp1 and Fpp2. The genes encoding these enzymes are organized as an fpp2-fpp1 tandem in the genome of strain F. psychrophilum THC02/90. Analysis of the corresponding encoded proteins showed that they belong to two different protease families. For gene function analysis, new genetic tools were developed in F. psychrophilum by constructing stable isogenic fpp1 and fpp2 mutants via single-crossover homologous recombination. RT-PCR analysis of wild-type and mutant strains suggested that both genes are transcribed as a single mRNA from the promoter located upstream of the fpp2 gene. Phenotypic characterization of the fpp2 mutant showed lack of caseinolytic activity and higher colony spreading compared with the wild-type strain. Both characteristics were recovered in the complemented strain. One objective of this work was to assess the contribution to virulence of these proteolytic enzymes. LD(50) experiments using the wild-type strain and mutants showed no significant differences in virulence in a rainbow trout challenge model, suggesting instead a possible nutritional role. The gene disruption procedure developed in this work, together with the knowledge of the complete genome sequence of F. psychrophilum, open new perspectives for the study of gene function in this bacterium. PMID- 21292746 TI - Cell invasion of poultry-associated Salmonella enterica serovar Enteritidis isolates is associated with pathogenicity, motility and proteins secreted by the type III secretion system. AB - Salmonella enterica serovar Enteritidis (S. Enteritidis) is a major cause of food borne gastroenteritis in humans worldwide. Poultry and poultry products are considered the major vehicles of transmission to humans. Using cell invasiveness as a surrogate marker for pathogenicity, we tested the invasiveness of 53 poultry associated isolates of S. Enteritidis in a well-differentiated intestinal epithelial cell model (Caco-2). The method allowed classification of the isolates into low (n = 7), medium (n = 18) and high (n = 30) invasiveness categories. Cell invasiveness of the isolates did not correlate with the presence of the virulence associated gene spvB or the ability of the isolates to form biofilms. Testing of representative isolates with high and low invasiveness in a mouse model revealed that the former were more invasive in vivo and caused more and earlier mortalities, whereas the latter were significantly less invasive in vivo, causing few or no mortalities. Further characterization of representative isolates with low and high invasiveness showed that most of the isolates with low invasiveness had impaired motility and impaired secretion of either flagella-associated proteins (FlgK, FljB and FlgL) or type III secretion system (TTSS)-secreted proteins (SipA and SipD) encoded on Salmonella pathogenicity island-1. In addition, isolates with low invasiveness had impaired ability to invade and/or survive within chicken macrophages. These data suggest that not all isolates of S. Enteritidis recovered from poultry may be equally pathogenic, and that the pathogenicity of S. Enteritidis isolates is associated, in part, with both motility and secretion of TTSS effector proteins. PMID- 21292747 TI - Role of sphingosine-1-phosphate (S1P) and S1P receptor 2 in the phagocytosis of Cryptococcus neoformans by alveolar macrophages. AB - The pathogenic fungus Cryptococcus neoformans is a major cause of morbidity and mortality in immunocompromised individuals. Infection of the human host occurs through inhalation of infectious propagules following environmental exposure. In the lung, C. neoformans can reside in the extracellular environment of the alveolar spaces or, upon phagocytosis, it can survive and grow intracellularly within alveolar macrophages (AMs). In previous studies, we found that sphingosine kinase 1 (SK1) influenced the intracellular residency of C. neoformans within AMs. Therefore, with this study we aimed to examine the role of the SK1 lipid product, sphingosine-1-phosphate (S1P), in the AMs-C. neoformans interaction. It was found that extracellular S1P enhances the phagocytosis of C. neoformans by AMs. Using both genetic and pharmacological approaches we further show that extracellular S1P exerts its effect on the phagocytosis of C. neoformans by AMs through S1P receptor 2 (S1P2). Interestingly, loss of S1P2 caused a dramatic decrease in the mRNA levels of Fcgamma receptors I (FcgammaRI), -II and -III. In conclusion, our data suggest that extracellular S1P increases antibody-mediated phagocytosis through S1P2 by regulating the expression of the phagocytic Fcgamma receptors. PMID- 21292748 TI - Parallel evolution and local differentiation in quinolone resistance in Pseudomonas aeruginosa. AB - The emergence and spread of antibiotic resistance in pathogens is a major impediment to the control of microbial disease. Here, we review mechanisms of quinolone resistance in Pseudomonas aeruginosa, an important nosocomial pathogen and a major cause of morbidity in cystic fibrosis (CF) patients. In this quantitative literature review, we find that mutations in DNA gyrase A, the primary target of quinolones in Gram-negative bacteria, are the most common resistance mutations identified in clinical samples of all origins, in keeping with previous observations. However, the identities of non-gyrase resistance mutations vary systematically between samples isolated from CF patients and those isolated from acute infections. CF-derived strains tend to harbour mutations in the efflux pump regulator nfxB, while non-CF strains tend to bear mutations in the efflux regulator mexR or in parC, which encodes one of two subunits of DNA topoisomerase IV. We suggest that differences in resistance mechanisms between CF and non-CF strains result either from local adaptation to different sites of infection or from differences in mutational processes between different environments. We further discuss the therapeutic implications of local differentiation in resistance mechanisms to a common antibiotic. PMID- 21292749 TI - Deletion of the mmpL4b gene in the Mycobacterium abscessus glycopeptidolipid biosynthetic pathway results in loss of surface colonization capability, but enhanced ability to replicate in human macrophages and stimulate their innate immune response. AB - Mycobacterium abscessus is considered to be the most virulent of the rapidly growing mycobacteria. Generation of bacterial gene knockout mutants has been a useful tool for studying factors that contribute to virulence of pathogenic bacteria. Until recently, the optimal genetic approach to generation of M. abscessus gene knockout mutants was not clear. Based on the recent identification of genetic recombineering as the preferred approach, a M. abscessus mutant was generated in which the gene mmpL4b, critical to glycopeptidolipid synthesis, was deleted. Compared to the previously well-characterized parental strain 390S, the mmpL4B deletion mutant had lost sliding motility and the ability to form biofilm, but acquired the ability to replicate in human macrophages and stimulate macrophage Toll-like receptor 2. This study demonstrates that deletion of a gene associated with expression of a cell-wall lipid can result in acquisition of an immunostimulatory, invasive bacterial phenotype and has important implications for the study of M. abscessus pathogenesis at the cellular level. PMID- 21292750 TI - Identification and characterization of the Streptomyces globisporus 1912 regulatory gene lndYR that affects sporulation and antibiotic production. AB - Here, we report the identification and functional characterization of the Streptomyces globisporus 1912 gene lndYR, which encodes a GntR-like regulator of the YtrA subfamily. Disruption of lndYR arrested sporulation and antibiotic production in S. globisporus. The results of in vivo and in vitro studies revealed that the ABC transporter genes lndW-lndW2 are targets of LndYR repressive action. In Streptomyces coelicolor M145, lndYR overexpression caused a significant increase in the amount of extracellular actinorhodin. We suggest that lndYR controls the transcription of transport system genes in response to an as yet-unidentified signal. Features that distinguish lndYR-based regulation from other known regulators are discussed. PMID- 21292751 TI - A novel role for SarX in Staphylococcus epidermidis biofilm regulation. AB - Biofilm production by staphylococci is an important virulence determinant mediated by the icaADBC-encoded polysaccharide intercellular adhesin (PIA) or by surface and extracellular proteins. Deletion of the Staphylococcus accessory regulator sarX significantly reduced biofilm-forming capacity in Staphylococcus epidermidis CSF41498, whereas multicopy sarX complemented the sarX mutant and increased wild-type biofilm production. In Staphylococcus aureus, SarX negatively regulates the accessory gene regulator (Agr) system, which in turn has strain specific effects on biofilm regulation. Here we found that purified S. epidermidis SarX protein bound specifically to the agr P3 promoter. However RT PCR analysis revealed that both mutation of sarX and multicopy sarX activated RNAIII transcription, making it difficult to correlate sarX-mediated biofilm regulation with altered agr activity. In contrast, RT-PCR and immunoblot analysis revealed that icaA transcription and PIA expression were decreased in the sarX mutant, whereas multicopy sarX increased ica and PIA expression. Furthermore, multicopy sarX did not promote biofilms in an icaC mutant. Finally, purified SarX protein bound specifically to the ica operon promoter. Taken together, these data reveal that the S. epidermidis SarX protein regulates the transcriptional activity of the agr and ica loci and controls the biofilm phenotype, primarily by regulating icaADBC transcription and PIA production. PMID- 21292752 TI - Factors associated with problematic vocalizations in nursing home residents with dementia. AB - PURPOSE OF THE STUDY: Problematic vocalizations (PVs) are the most frequent and persistent disruptive behaviors exhibited by nursing home residents with dementia. Understanding factors associated with these behaviors are important to prevent or reduce them. We used the Need-Driven Dementia-Compromised Behavior model to identify the characteristics of persons with dementia who are likely to display nonaggressive and aggressive PVs and the conditions under which these behaviors are likely to occur and persist. DESIGN AND METHODS: This multisite descriptive study included 138 residents of 17 nursing homes, and approximately half had a history of PVs. Background data were gathered through interviews, chart reviews, and administration of physical and neuropsychological assessments. Proximal data were obtained from observations and videotapes. RESULTS: When the 2 subscales of the Verbal Behavior Scale were used as the dependent variables, agreeableness and conscientiousness, positive affect, and discomfort were associated with nonaggressive vocalizations, and general health state (GHS), age, and negative and positive affect were associated with aggressive vocalizations. When the verbally agitated (nonaggressive) section of the Cohen-Mansfield Agitation Inventory was the dependent variable, the background factors of gender, agreeableness, GHS, and age remained predictors, as did the proximal factors of affect and discomfort. IMPLICATIONS: We identified 5 background factors and 3 proximal factors as risk factors for PVs in persons with dementia, with variation between nonaggressive or aggressive PVs. These data provide direction for caregiving for persons with dementia and design of interventions to prevent or reduce PVs. PMID- 21292753 TI - Theory and practice in participatory research: lessons from the Native Elder Care Study. AB - Models for community-based participatory research (CBPR) urge academic investigators to collaborate with communities to identify and pursue research questions, processes, and outcomes valuable to both partners. The tribal participatory research (TPR) conceptual model suggests modifications to CBPR to fit the special needs of American Indian communities. This paper draws upon authors' collaboration with one American Indian tribe to recommend theoretical revision and practical strategies for conducting gerontological research in tribal communities. We rated the TPR model as a strong, specialized adaptation of participatory research principles. Although the need for some TPR mechanisms may vary, our experience recommends incorporating dissemination as a central TPR mechanism. Researchers and communities can expect well-crafted collaborative projects to generate particular types of positive project outcomes for both partners, but should prepare for both predictable and unique challenges. PMID- 21292754 TI - The number of lymph node metastases as a prognostic factor in patients with N1 non-small cell lung cancer. AB - BACKGROUND: Lymph node (LN) status is an important component of staging; it provides valuable prognostic information and influences treatment decisions. However, the prognostic significance of the number of positive LNs in N1 non small cell lung cancer (NSCLC) remains unclear. In this study we evaluated whether a higher number of positive LNs results in worse survival among patients with N1 disease. METHODS: The Surveillance, Epidemiology, and End Results database was used to identify 3,399 patients who underwent resection for N1 NSCLC. Subjects were categorized into groups based on the number of positive nodes: one, two to three, four to eight, and more than eight positive LNs. The prognostic significance of the number of positive LNs in relation to survival was evaluated using the Kaplan-Meier method. Stratified and Cox regression analysis were used to evaluate the relationship between the number of positive LNs and survival after adjusting for potential confounders. RESULTS: Unadjusted survival analysis showed that a greater number of N1 LNs was associated with worse lung cancer-specific (P < .0001) and overall (P < .0001) survival. Mean lung cancer specific survival was 8.8, 8.2, 6.0, and 3.9 years for patients with one, two to three, four to eight, and more than eight positive LNs, respectively. Stratified and adjusted analysis also showed the number of N1 LNs was an independent predictor of survival after controlling for potential confounders. CONCLUSION: The number of positive LNs is an independent prognostic factor of survival in patients with N1 NSCLC. This information may be used to further stratify patients with respect to risk of recurrence in order to determine postoperative management. PMID- 21292755 TI - Code status orders and goals of care in the medical ICU. AB - BACKGROUND: Decisions about CPR in the medical ICU (MICU) are important. However, discussions about CPR (code status discussions) can be challenging and may be incomplete if they do not address goals of care. METHODS: We interviewed 100 patients, or their surrogates, and their physicians in an MICU. We queried the patients/surrogates on their knowledge of CPR, code status preferences, and goals of care; we queried MICU physicians about goals of care and treatment plans. Medical records were reviewed for clinical information and code status orders. RESULTS: Fifty patients/surrogates recalled discussing CPR preferences with a physician, and 51 recalled discussing goals of care. Eighty-three patients/surrogates preferred full code status, but only four could identify the three main components of in-hospital CPR (defibrillation, chest compressions, intubation). There were 16 discrepancies between code status preferences expressed during the interview and code status orders in the medical record. Respondents' average prediction of survival following in-hospital cardiac arrest with CPR was 71.8%, and the higher the prediction of survival, the greater the frequency of preference for full code status (P = .012). Of six possible goals of care, approximately five were affirmed by each patient/surrogate and physician, but 67.7% of patients/surrogates differed with their physicians about the most important goal of care. CONCLUSIONS: Patients in the MICU and their surrogates have inadequate knowledge about in-hospital CPR and its likelihood of success, patients' code status preferences may not always be reflected in code status orders, and assessments may differ between patients/surrogates and physicians about what goal of care is most important. PMID- 21292756 TI - The utility of cardiopulmonary exercise testing in difficult asthma. AB - BACKGROUND: Unexplained persistent breathlessness in patients with difficult asthma despite multiple treatments is a common clinical problem. Cardiopulmonary exercise testing (CPX) may help identify the mechanism causing these symptoms, allowing appropriate management. METHODS: This was a retrospective analysis of patients attending a specialist-provided service for difficult asthma who proceeded to CPX as part of our evaluation protocol. Patient demographics, lung function, and use of health care and rescue medication were compared with those in patients with refractory asthma. Medication use 6 months following CPX was compared with treatment during CPX. RESULTS: Of 302 sequential referrals, 39 patients underwent CPX. A single explanatory feature was identified in 30 patients and two features in nine patients: hyperventilation (n = 14), exercise induced bronchoconstriction (n = 8), submaximal test (n = 8), normal test (n = 8), ventilatory limitation (n = 7), deconditioning (n = 2), cardiac ischemia (n = 1). Compared with patients with refractory asthma, patients without "pulmonary limitation" on CPX were prescribed similar doses of inhaled corticosteroid (ICS) (median, 1,300 MUg [interquartile range (IQR), 800-2,000 MUg] vs 1,800 MUg [IQR, 1,000-2,000 MUg]) and rescue oral steroid courses in the previous year (median, 5 [1-6] vs 5 [1-6]). In this group 6 months post-CPX, ICS doses were reduced (median, 1,300 MUg [IQR, 800-2,000 MUg] to 800 MUg [IQR, 400-1,000 MUg]; P < .001) and additional medication treatment was withdrawn (n = 7). Patients with pulmonary limitation had unchanged ICS doses post CPX and additional therapies were introduced. CONCLUSIONS: In difficult asthma, CPX can confirm that persistent exertional breathlessness is due to asthma but can also identify other contributing factors. Patients with nonpulmonary limitation are prescribed inappropriately high doses of steroid therapy, and CPX can identify the primary mechanism of breathlessness, facilitating steroid reduction. PMID- 21292757 TI - Does home sleep testing impair continuous positive airway pressure adherence in patients with obstructive sleep apnea? AB - BACKGROUND: The increasing recognition of obstructive sleep apnea (OSA) and demand for polysomnography has created a need for home sleep testing (HST) using unattended diagnostic and titration studies. Although these studies increase access to care and reduce cost, the limited interaction with sleep laboratories may negatively affect positive airway pressure (PAP) adherence. We sought to determine the difference in PAP use between HST and traditional in-laboratory studies. METHODS: This observational cohort study included 210 patients with OSA classified into three equal groups. Following preestablished guidelines, group 1 underwent unattended, type III home diagnostic and unattended home auto adjustable PAP (APAP) titrations; group 2 underwent in-laboratory, type I diagnostic and continuous PAP titration studies; group 3 underwent type I diagnostic and APAP titration studies. Group 1 was primarily managed and educated in a primary care clinic, whereas groups 2 and 3 received extensive education in an academic sleep medicine center. Objective measures of PAP use during the first 4 to 6 weeks of therapy were compared between groups. RESULTS: Type of study and location of care did not affect PAP adherence. PAP was used for 70%, 73%, and 72% of nights in groups 1, 2, and 3, respectively (P = .94). Mean hours of nightly use (4.4 +/- 2.0 h, 4.7 +/- 1.5 h, and 4.6 +/- 1.5 h; P = .98) was also similar. Regular use was observed in 54%, 51%, and 50% of subjects (P = .84). Discontinuation rates were similar between groups. CONCLUSIONS: PAP usage did not differ between those undergoing HST vs in-laboratory studies. HST offers a more accessible and cost-effective alternative without compromising therapeutic adherence. PMID- 21292758 TI - The influence of race/ethnicity and socioeconomic status on end-of-life care in the ICU. AB - BACKGROUND: There is conflicting evidence about the influence of race/ethnicity on the use of intensive care at the end of life, and little is known about the influence of socioeconomic status. METHODS: We examined patients who died in the ICU in 15 hospitals. Race/ethnicity was assessed as white and nonwhite. Socioeconomic status included patient education, health insurance, and income by zip code. To explore differences in end-of-life care, we examined the use of (1) advance directives, (2) life-sustaining therapies, (3) symptom management, (4) communication, and (5) support services. RESULTS: Medical charts were abstracted for 3,138/3,400 patients of whom 2,479 (79%) were white and 659 (21%) were nonwhite (or Hispanic). In logistic regressions adjusted for patient demographics, socioeconomic factors, and site, nonwhite patients were less likely to have living wills (OR, 0.41; 95% CI, 0.32-0.54) and more likely to die with full support (OR, 1.59; 95% CI, 1.30-1.94). In documentation of family conferences, nonwhite patients were more likely to have documentation that prognosis was discussed (OR, 1.47; 95% CI, 1.21-1.77) and that physicians recommended withdrawal of life support (OR, 1.57; 95% CI, 1.11-2.21). Nonwhite patients also were more likely to have discord documented among family members or with clinicians (OR, 1.49; 95% CI, 1.04-2.15). Socioeconomic status did not modify these associations and was not a consistent predictor of end-of-life care. CONCLUSIONS: We found numerous racial/ethnic differences in end-of-life care in the ICU that were not influenced by socioeconomic status. These differences could be due to treatment preferences, disparities, or both. Improving ICU end-of-life care for all patients and families will require a better understanding of these issues. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00685893; URL: www.clinicaltrials.gov. PMID- 21292759 TI - Bone health, daily physical activity, and exercise tolerance in patients with cystic fibrosis. AB - BACKGROUND: Daily physical activity (PA) may be an excellent tool for the maintenance of bone health in patients with cystic fibrosis (CF). The aim of this study was to analyze the possible association between physical capacity and activity and bone mineral density (BMD) in young adults with CF. A secondary goal was to evaluate vertebral fractures in this population. METHODS: A cross sectional study was conducted in 50 patients with CF who were clinically stable and aged > 16 years but not lung transplant recipients. PA was quantified with a portable motion monitor (BodyMedia Fit Armband). Cardiopulmonary exercise and 6 min walk tests were used to assess exercise capacity. BMD was obtained from dual energy x-ray absorptiometry of the lumbar column, hip, and whole body. To analyze vertebral fractures and deformity, we performed the Genant and Cobb methods. RESULTS: Daily PA time at low (3-4.8 metabolic equivalent tasks [METs]) and moderate (4.8-7.2 METs) intensity, respectively, was correlated with Z score (BMD) of the lumbar column (r = 0.36, P < .01 and r = 0.59, P < .001), the neck of femur (r = 0.51, P < .001 and r = 0.72, P < .001), and the total hip (r = 0.54, P < .001 and r = 0.74, P < .001). PA, BMI, age, and sex were predictors of BMD. Vertebral fractures correlated with kyphosis (r = 0.42, P = .02), but not with BMD. Patients who were mildly and severely affected differed in vertebral fracture rate and kyphosis prevalence (P = .002 and P = .013, respectively). CONCLUSIONS: The most active patients with better exercise capacity had higher BMD. Those with more affected pulmonary function had a greater prevalence of vertebral fractures and dorsal kyphosis. PMID- 21292760 TI - Predictors of symptoms are different from predictors of severe exacerbations from asthma in children. AB - BACKGROUND: Asthma therapy is typically prescribed and titrated based on patient or parent self-report of symptoms. No longitudinal studies have assessed the relationship between symptoms and severe asthma exacerbations in children. The goal of our study was (1) to assess the association of asthma symptoms with severe asthma exacerbations and (2) to compare predictors of persistent asthma symptoms and predictors of severe asthma exacerbations. METHODS: The Childhood Asthma Management Program was a multicenter clinical trial of 1,041 children randomized to receive budesonide, nedocromil, or placebo (as-needed beta agonist). We conducted a post hoc analysis of diary cards that were completed by subjects on a daily basis to categorize subjects as having persistent vs intermittent symptoms. We defined a severe asthma exacerbation as an episode requiring >= 3 days use of oral corticosteroids, hospitalization, or ED visit due to asthma based on self-report at study visits every 4 months. RESULTS: While accounting for longitudinal measures, having persistent symptoms from asthma was significantly associated with having severe asthma exacerbations. Predictors of having persistent symptoms compared with intermittent symptoms included not being treated with inhaled corticosteroids, lower FEV(1)/FVC ratio, and a lower natural logarithm of provocative concentration of methacholine producing a 20% decline in FEV(1) (lnPC(20)). Predictors of having one or more severe asthma exacerbations included younger age, history of hospitalization or ED visit in the prior year, >= 3 days use of oral corticosteroids in the prior 3 months, lower FEV(1)/FVC ratio, lower lnPC(20), and higher logarithm to the base 10 eosinophil count; treatment with inhaled corticosteroids was predictive of having no severe asthma exacerbations. CONCLUSIONS: Patients with persistent symptoms from asthma were more likely to experience severe asthma exacerbations. Nevertheless, demographic and laboratory predictors of having persistent symptoms are different from predictors of severe asthma exacerbations. Although symptoms and exacerbations are closely related, their predictors are different. The current focus of the National Asthma Education and Prevention Program guidelines on the two separate domains of asthma control, impairment and risk, are supported by our analysis. PMID- 21292761 TI - Influence of oral and craniofacial dimensions on mandibular advancement splint treatment outcome in patients with obstructive sleep apnea. AB - BACKGROUND: Mandibular advancement splints (MASs) can effectively treat obstructive sleep apnea (OSA); however, no validated and reliable prediction method for treatment outcome currently exists. The efficacy of MAS may relate to anatomic factors, including craniofacial size and upper-airway soft-tissue volume and anatomic balance between them. We aimed to assess whether craniofacial and oral measurements are associated with MAS treatment outcome. METHODS: Dental impressions and lateral cephalometric radiographs were obtained from patients with OSA prior to commencing MAS treatment. Intertooth distances and palatal depths were measured on dental casts, and standard cephalometric analysis was performed with the addition of cross-sectional area (CSA) of the tongue and bony oral enclosure. Treatment outcome was determined by polysomnography. RESULTS: Of 53 patients, 25 were complete responders (posttreatment apnea-hypopnea index [AHI] < 5/h), 17 were partial responders (>= 50% AHI reduction), and 11 were nonresponders (< 50% AHI reduction). Cephalometric analyses did not reveal any significant differences between responders and nonresponders. Oral cavity measurements or CSA did not differ with treatment outcome; however, there was a trend toward a larger tongue CSA in complete vs partial and nonresponders (39.5 +/- 1.3 cm(2) vs 35.5 +/- 0.5 cm(2), P = .09). Tongue/oral enclosure CSA ratio, indicating a larger tongue for a given oral cavity size, was greater in complete responders (P = .012, n = 30). CONCLUSIONS: Oral dimensions do not appear to differ between patients who respond and those who do not respond to MAS treatment. However, the larger tongue for a given oral cavity size in responders suggests that MAS may help to correct anatomic imbalance. Further research to assess whether the ratio between tongue and bony oral enclosure size may be useful in selecting patients for MAS treatment is warranted. PMID- 21292762 TI - Modulating micro-opioid receptor phosphorylation switches agonist-dependent signaling as reflected in PKCepsilon activation and dendritic spine stability. AB - A new role of G protein-coupled receptor (GPCR) phosphorylation was demonstrated in the current studies by using the MU-opioid receptor (OPRM1) as a model. Morphine induces a low level of receptor phosphorylation and uses the PKCepsilon pathway to induce ERK phosphorylation and receptor desensitization, whereas etorphine, fentanyl, and [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) induce extensive receptor phosphorylation and use the beta-arrestin2 pathway. Blocking OPRM1 phosphorylation (by mutating Ser363, Thr370 and Ser375 to Ala) enabled etorphine, fentanyl, and DAMGO to use the PKCepsilon pathway. This was not due to the decreased recruitment of beta-arrestin2 to the receptor signaling complex, because these agonists were unable to use the PKCepsilon pathway when beta arrestin2 was absent. In addition, overexpressing G protein-coupled receptor kinase 2 (GRK2) decreased the ability of morphine to activate PKCepsilon, whereas overexpressing dominant-negative GRK2 enabled etorphine, fentanyl, and DAMGO to activate PKCepsilon. Furthermore, by overexpressing wild-type OPRM1 and a phosphorylation-deficient mutant in primary cultures of hippocampal neurons, we demonstrated that receptor phosphorylation contributes to the differential effects of agonists on dendritic spine stability. Phosphorylation blockage made etorphine, fentanyl, and DAMGO function as morphine in the primary cultures. Therefore, agonist-dependent phosphorylation of GPCR regulates the activation of the PKC pathway and the subsequent responses. PMID- 21292763 TI - The final conformation of the complete ectodomain of the HA2 subunit of influenza hemagglutinin can by itself drive low pH-dependent fusion. AB - One of the best characterized fusion proteins, the influenza virus hemagglutinin (HA), mediates fusion between the viral envelope and the endosomal membrane during viral entry into the cell. In the initial conformation of HA, its fusogenic subunit, the transmembrane protein HA2, is locked in a metastable conformation by the receptor-binding HA1 subunit of HA. Acidification in the endosome triggers HA2 refolding toward the final lowest energy conformation. Is the fusion process driven by this final conformation or, as often suggested, by the energy released by protein restructuring? Here we explored structural properties as well as the fusogenic activity of the full sized trimeric HA2(1 185) (here called HA2*) that presents the final conformation of the HA2 ectodomain. We found HA2* to mediate fusion between lipid bilayers and between biological membranes in a low pH-dependent manner. Two mutations known to inhibit HA-mediated fusion strongly inhibited the fusogenic activity of HA2*. At surface densities similar to those of HA in the influenza virus particle, HA2* formed small fusion pores but did not expand them. Our results confirm that the HA1 subunit responsible for receptor binding as well as the transmembrane and cytosolic domains of HA2 is not required for fusion pore opening and substantiate the hypothesis that the final form of HA2 is more important for fusion than the conformational change that generates this form. PMID- 21292764 TI - Down-regulation of Runx1 expression by TCR signal involves an autoregulatory mechanism and contributes to IL-2 production. AB - Runx1 transcription factor plays multiple roles in T cell development, differentiation, and function. However, the regulatory mechanisms and functional significance of high Runx1 protein expression in resting peripheral CD4+ T cells is not well understood. Here, we demonstrate that T-cell receptor (TCR) activation down-regulates distal Runx1 transcription, resulting in a significant reduction of Runx1 protein. Interestingly, this down-regulation of distal Runx1 transcription appears to be mediated through a negative auto-regulatory mechanism, whereby Runx1 protein binds to a Runx consensus site in the distal promoter. Through the use of Runx1-overexpressing cells from transgenic mice, we demonstrate that interference with TCR-mediated Runx1 down-regulation inhibits IL 2 production and proliferation in activated CD4+ T cells. In contrast, using Runx1-deficient cells prepared from targeted mice, we show that the absence of Runx1 in unstimulated CD4+ T cells results in IL-2 derepression. In summary, we propose that high levels of Runx1 in resting CD4+ T cells functions negatively in the regulation of IL-2 transcription, and that TCR activation-mediated down regulation of Runx1 involves negative auto-regulation of the distal Runx1 promoter and contributes to IL-2 production. PMID- 21292765 TI - P2X7 receptors trigger ATP exocytosis and modify secretory vesicle dynamics in neuroblastoma cells. AB - Previously, we reported that purinergic ionotropic P2X7 receptors negatively regulate neurite formation in Neuro-2a (N2a) mouse neuroblastoma cells through a Ca(2+)/calmodulin-dependent kinase II-related mechanism. In the present study we used this cell line to investigate a parallel though faster P2X7 receptor mediated signaling pathway, namely Ca(2+)-regulated exocytosis. Selective activation of P2X7 receptors evoked exocytosis as assayed by high resolution membrane capacitance measurements. Using dual-wavelength total internal reflection microscopy, we have observed both the increase in near-membrane Ca(2+) concentration and the exocytosis of fluorescently labeled vesicles in response to P2X7 receptor stimulation. Moreover, activation of P2X7 receptors also affects vesicle motion in the vertical and horizontal directions, thus, involving this receptor type in the control of early steps (docking and priming) of the secretory pathway. Immunocytochemical and RT-PCR experiments evidenced that N2a cells express the three neuronal SNAREs as well as vesicular nucleotide and monoamine (VMAT-1 and VMAT-2) transporters. Biochemical measurements indicated that ionomycin induced a significant release of ATP from N2a cells. Finally, P2X7 receptor stimulation and ionomycin increased the incidence of small transient inward currents, reminiscent of postsynaptic quantal events observed at synapses. Small transient inward currents were dependent on extracellular Ca(2+) and were abolished by Brilliant Blue G, suggesting they were mediated by P2X7 receptors. Altogether, these results suggest the existence of a positive feedback mechanism mediated by P2X7 receptor-stimulated exocytotic release of ATP that would act on P2X7 receptors on the same or neighbor cells to further stimulate its own release and negatively control N2a cell differentiation. PMID- 21292766 TI - The low resolution structure of ApoA1 in spherical high density lipoprotein revealed by small angle neutron scattering. AB - Spherical high density lipoprotein (sHDL), a key player in reverse cholesterol transport and the most abundant form of HDL, is associated with cardiovascular diseases. Small angle neutron scattering with contrast variation was used to determine the solution structure of protein and lipid components of reconstituted sHDL. Apolipoprotein A1, the major protein of sHDL, forms a hollow structure that cradles a central compact lipid core. Three apoA1 chains are arranged within the low resolution structure of the protein component as one of three possible global architectures: (i) a helical dimer with a hairpin (HdHp), (ii) three hairpins (3Hp), or (iii) an integrated trimer (iT) in which the three apoA1 monomers mutually associate over a portion of the sHDL surface. Cross-linking and mass spectrometry analyses help to discriminate among the three molecular models and are most consistent with the HdHp overall architecture of apoA1 within sHDL. PMID- 21292767 TI - Identification of essential lysines involved in substrate binding of vacuolar H+ pyrophosphatase. AB - H+-translocating pyrophosphatase (H+-PPase; EC 3.6.1.1) drives proton transport against an electrochemical potential gradient by hydrolyzing pyrophosphate (PPi) and is found in various endomembranes of higher plants, bacteria, and some protists. H+-PPase contains seven highly conserved lysines. We examined the functional roles of these lysines, which are, for the most part, found in the cytosolic regions of mung bean H+-PPase by site-directed mutagenesis. Construction of mutants that each had a cytosolic and highly conserved lysine substituted with an alanine resulted in dramatic drops in the PPi hydrolytic activity. The effects caused by ions on the activities of WT and mutant H+-PPases suggest that Lys-730 may be in close proximity to the Mg2+-binding site, and the great resistance of the K694A and K695A mutants to fluoride inhibition suggests that these lysines are present in the active site. The modifier fluorescein 5' isothiocyanate (FITC) labeled a lysine at the H+-PPase active site but did not inhibit the hydrolytic activities of K250A, K250N, K250T, and K250S, which suggested that Lys-250 is essential for substrate binding and may be involved in proton translocation. Analysis of tryptic digests indicated that Lys-711 and Lys 717 help maintain the conformation of the active site. Proteolytic evidence also demonstrated that Lys-250 is the primary target of trypsin and confirmed its crucial role in H+-PPase hydrolysis. PMID- 21292768 TI - Two distinct amyloid beta-protein (Abeta) assembly pathways leading to oligomers and fibrils identified by combined fluorescence correlation spectroscopy, morphology, and toxicity analyses. AB - Nonfibrillar assemblies of amyloid beta-protein (Abeta) are considered to play primary roles in Alzheimer disease (AD). Elucidating the assembly pathways of these specific aggregates is essential for understanding disease pathogenesis and developing knowledge-based therapies. However, these assemblies cannot be monitored in vivo, and there has been no reliable in vitro monitoring method at low protein concentration. We have developed a highly sensitive in vitro monitoring method using fluorescence correlation spectroscopy (FCS) combined with transmission electron microscopy (TEM) and toxicity assays. Using Abeta labeled at the N terminus or Lys(16), we uncovered two distinct assembly pathways. One leads to highly toxic 10-15-nm spherical Abeta assemblies, termed amylospheroids (ASPDs). The other leads to fibrils. The first step in ASPD formation is trimerization. ASPDs of ~330 kDa in mass form from these trimers after 5 h of slow rotation. Up to at least 24 h, ASPDs remain the dominant structures in assembly reactions. Neurotoxicity studies reveal that the most toxic ASPDs are ~128 kDa (~32-mers). In contrast, fibrillogenesis begins with dimer formation and then proceeds to formation of 15-40-nm spherical intermediates, from which fibrils originate after 15 h. Unlike ASPD formation, the Lys(16)-labeled peptide disturbed fibril formation because the Abeta(16-20) region is critical for this final step. These differences in the assembly pathways clearly indicated that ASPDs are not fibril precursors. The method we have developed should facilitate identifying Abeta assembly steps at which inhibition may be beneficial. PMID- 21292769 TI - Parkin ubiquitinates Drp1 for proteasome-dependent degradation: implication of dysregulated mitochondrial dynamics in Parkinson disease. AB - Mutations in Parkin, an E3 ubiquitin ligase that regulates protein turnover, represent one of the major causes of familial Parkinson disease, a neurodegenerative disorder characterized by the loss of dopaminergic neurons and impaired mitochondrial functions. The underlying mechanism by which pathogenic Parkin mutations induce mitochondrial abnormality is not fully understood. Here, we demonstrate that Parkin interacts with and subsequently ubiquitinates dynamin related protein 1 (Drp1), for promoting its proteasome-dependent degradation. Pathogenic mutation or knockdown of Parkin inhibits the ubiquitination and degradation of Drp1, leading to an increased level of Drp1 for mitochondrial fragmentation. These results identify Drp1 as a novel substrate of Parkin and suggest a potential mechanism linking abnormal Parkin expression to mitochondrial dysfunction in the pathogenesis of Parkinson disease. PMID- 21292770 TI - Escape from p21-mediated oncogene-induced senescence leads to cell dedifferentiation and dependence on anti-apoptotic Bcl-xL and MCL1 proteins. AB - Oncogene-induced senescence (OIS) is a tumor suppressor response that induces permanent cell cycle arrest in response to oncogenic signaling. Through the combined activation of the p53-p21 and p16-Rb suppressor pathways, OIS leads to the transcriptional repression of proliferative genes. Although this protective mechanism has been essentially described in primary cells, we surprisingly observed in this study that the OIS program is conserved in established colorectal cell lines. In response to the RAS oncogene and despite the inactivation of p53 and p16(INK4), HT29 cells enter senescence, up-regulate p21(WAF1), and induce senescence-associated heterochromatin foci formation. The same effect was observed in response to B-RAF(v600E) in LS174T cells. We also observed that p21(WAF1) prevents the expression of the CDC25A and PLK1 genes to induce cell cycle arrest. Using ChIP and luciferase experiments, we have observed that p21(WAF1) binds to the PLK1 promoter to induce its down-regulation during OIS induction. Following 4-5 weeks, several clones were able to resume proliferation and escape this tumor suppressor pathway. Tumor progression was associated with p21(WAF1) down-regulation and CDC25A and PLK1 reexpression. In addition, OIS and p21(WAF1) escape was associated with an increase in DNA damage, an induction of the epithelial-mesenchymal transition program, and an increase in the proportion of cells expressing the CD24(low)/CD44(high) phenotype. Results also indicate that malignant cells having escaped OIS rely on survival pathways induced by Bcl-xL/MCL1 signaling. In light of these observations, it appears that the transcriptional functions of p21(WAF1) are active during OIS and that the inactivation of this protein is associated with cell dedifferentiation and enhanced survival. PMID- 21292771 TI - Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. AB - Hastening posttransplantation immune reconstitution is a key challenge in human leukocyte antigen (HLA)-haploidentical hematopoietic stem-cell transplantation (HSCT). In experimental models of mismatched HSCT, T-regulatory cells (Tregs) when co-infused with conventional T cells (Tcons) favored posttransplantation immune reconstitution and prevented lethal graft-versus-host disease (GVHD). In the present study, we evaluated the impact of early infusion of Tregs, followed by Tcons, on GVHD prevention and immunologic reconstitution in 28 patients with high-risk hematologic malignancies who underwent HLA-haploidentical HSCT. We show for the first time in humans that adoptive transfer of Tregs prevented GVHD in the absence of any posttransplantation immunosuppression, promoted lymphoid reconstitution, improved immunity to opportunistic pathogens, and did not weaken the graft-versus-leukemia effect. This study provides evidence that Tregs are a conserved mechanism in humans. PMID- 21292772 TI - C5a-mediated neutrophil dysfunction is RhoA-dependent and predicts infection in critically ill patients. AB - Critically ill patients are at heightened risk for nosocomial infections. The anaphylatoxin C5a impairs phagocytosis by neutrophils. However, the mechanisms by which this occurs and the relevance for acquisition of nosocomial infection remain undetermined. We aimed to characterize mechanisms by which C5a inhibits phagocytosis in vitro and in critically ill patients, and to define the relationship between C5a-mediated dysfunction and acquisition of nosocomial infection. In healthy human neutrophils, C5a significantly inhibited RhoA activation, preventing actin polymerization and phagocytosis. RhoA inhibition was mediated by PI3Kdelta. The effects on RhoA, actin, and phagocytosis were fully reversed by GM-CSF. Parallel observations were made in neutrophils from critically ill patients, that is, impaired phagocytosis was associated with inhibition of RhoA and actin polymerization, and reversed by GM-CSF. Among a cohort of 60 critically ill patients, C5a-mediated neutrophil dysfunction (as determined by reduced CD88 expression) was a strong predictor for subsequent acquisition of nosocomial infection (relative risk, 5.8; 95% confidence interval, 1.5-22; P = .0007), and remained independent of time effects as assessed by survival analysis (hazard ratio, 5.0; 95% confidence interval, 1.3-8.3; P = .01). In conclusion, this study provides new insight into the mechanisms underlying immunocompromise in critical illness and suggests novel avenues for therapy and prevention of nosocomial infection. PMID- 21292773 TI - Inhibition of the Nef regulatory protein of HIV-1 by a single-domain antibody. AB - The Nef protein of HIV-1 is important for AIDS pathogenesis, but it is not targeted by current antiviral strategies. Here, we describe a single-domain antibody (sdAb) that binds to HIV-1 Nef with a high affinity (K(d) = 2 * 10(-9)M) and inhibited critical biologic activities of Nef both in vitro and in vivo. First, it interfered with the CD4 down-regulation activity of a broad panel of nef alleles through inhibition of the Nef effects on CD4 internalization from the cell surface. Second, it was able to interfere with the association of Nef with the cellular p21-activated kinase 2 as well as with the resulting inhibitory effect of Nef on actin remodeling. Third, it counteracted the Nef-dependent enhancement of virion infectivity and inhibited the positive effect of Nef on virus replication in peripheral blood mononuclear cells. Fourth, anti-Nef sdAb rescued Nef-mediated thymic CD4(+) T-cell maturation defects and peripheral CD4(+) T-cell activation in the CD4C/HIV-1(Nef) transgenic mouse model. Because all these Nef functions have been implicated in Nef effects on pathogenesis, this anti-Nef sdAb may represent an efficient tool to elucidate the molecular functions of Nef in the virus life cycle and could now help to develop new strategies for the control of AIDS. PMID- 21292774 TI - G-CSF improves murine G6PC3-deficient neutrophil function by modulating apoptosis and energy homeostasis. AB - G6PC3 (or glucose-6-phosphatase-beta) deficiency underlies a congenital neutropenia syndrome in which neutrophils exhibit enhanced endoplasmic reticulum (ER) stress, increased apoptosis, impaired energy homeostasis, and impaired functionality. Here we show that murine G6pc3(-/-) neutrophils undergoing ER stress activate protein kinase-like ER kinase and phosphatidylinositol 3,4,5 trisphosphate/Akt signaling pathways, and that neutrophil apoptosis is mediated in part by the intrinsic mitochondrial pathway. In G6PC3-deficient patients, granulocyte colony-stimulating factor (G-CSF) improves neutropenia, but its impact on neutrophil apoptosis and dysfunction is unknown. We now show that G-CSF delays neutrophil apoptosis in vitro by modulating apoptotic mediators. However, G6pc3(-/-) neutrophils in culture exhibit accelerated apoptosis compared with wild-type neutrophils both in the presence or absence of G-CSF. Limiting glucose (0.6mM) accelerates apoptosis but is more pronounced for wild-type neutrophils, leading to similar survival profiles for both neutrophil populations. In vivo G CSF therapy completely corrects neutropenia and normalizes levels of p-Akt, phosphatidylinositol 3,4,5-trisphosphate, and active caspase-3. Neutrophils from in vivo G-CSF-treated G6pc3(-/-) mice exhibit increased glucose uptake and elevated intracellular levels of G6P, lactate, and adenosine-5'-triphosphate, leading to improved functionality. Together, the results strongly suggest that G CSF improves G6pc3(-/-) neutrophil survival by modulating apoptotic mediators and rectifies function by enhancing energy homeostasis. PMID- 21292775 TI - Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. AB - It is essential that there be consistency in the conduct, analysis, and reporting of clinical trial results in myeloma. The goal of the International Myeloma Workshop Consensus Panel 1 was to develop a set of guidelines for the uniform reporting of clinical trial results in myeloma. This paper provides a summary of the current response criteria in myeloma, detailed definitions for patient populations, lines of therapy, and specific endpoints. We propose that future clinical trials in myeloma follow the guidelines for reporting results proposed in this manuscript. PMID- 21292776 TI - Deciphering the molecular and biologic processes that mediate histone deacetylase inhibitor-induced thrombocytopenia. AB - Histone deacetylase inhibitor (HDACI)-induced thrombocytopenia (TCP) is a major dose-limiting toxicity of this new class of drugs. Using preclinical models to study the molecular and biologic events that underpin this effect of HDACI, we found that C57BL/6 mice treated with both the HDAC1/2-selective HDACI romidepsin and the pan-HDACI panobinostat developed significant TCP. HDACI-induced TCP was not due to myelosuppression or reduced platelet lifespan, but to decreased platelet release from megakaryocytes. Cultured primary murine megakaryocytes showed reductions in proplatelet extensions after HDACI exposure and a dose dependent increase in the phosphorylation of myosin light chain 2 (MLC2). Phosphorylation of MLC to phospho-MLC (pMLC) and subsequent proplatelet formation in megakaryocytes is regulated by the Rho-GTPase proteins Rac1, CDC42, and RhoA. Primary mouse megakaryocytes and the human megakaryoblastic cell line Meg-01 showed reductions in Rac1, CDC42, and RhoA protein levels after treatment with HDACIs. We were able to overcome HDACI-induced TCP by administering the mouse specific thrombopoietin (TPO) mimetic AMP-4, which improved platelet numbers to levels similar to untreated controls. Our report provides the first detailed account of the molecular and biologic processes involved in HDACI-mediated TCP. Moreover, our preclinical studies provide evidence that dose-limiting TCP induced by HDACIs may be circumvented using a TPO mimetic. PMID- 21292777 TI - Consensus recommendations for risk stratification in multiple myeloma: report of the International Myeloma Workshop Consensus Panel 2. AB - A panel of members of the 2009 International Myeloma Workshop developed guidelines for risk stratification in multiple myeloma. The purpose of risk stratification is not to decide time of therapy but to prognosticate. There is general consensus that risk stratification is applicable to newly diagnosed patients; however, some genetic abnormalities characteristic of poor outcome at diagnosis may suggest poor outcome if only detected at the time of relapse. Thus, in good-risk patients, it is necessary to evaluate for high-risk features at relapse. Although detection of any cytogenetic abnormality is considered to suggest higher-risk disease, the specific abnormalities considered as poor risk are cytogenetically detected chromosomal 13 or 13q deletion, t(4;14) and del17p, and detection by fluorescence in situ hybridization of t(4;14), t(14;16), and del17p. Detection of 13q deletion by fluorescence in situ hybridization only, in absence of other abnormalities, is not considered a high-risk feature. High serum beta(2)-microglobulin level and International Staging System stages II and III, incorporating high beta(2)-microglobulin and low albumin, are considered to predict higher risk disease. There was a consensus that the high-risk features will change in the future, with introduction of other new agents or possibly new combinations. PMID- 21292778 TI - Consensus recommendations for standard investigative workup: report of the International Myeloma Workshop Consensus Panel 3. AB - A panel of members of the 2009 International Myeloma Workshop developed guidelines for standard investigative workup of patients with suspected multiple myeloma. Both serum and urine should be assessed for monoclonal protein. Measurement of monoclonal protein both by densitometer tracing and/by nephelometric quantitation is recommended, and immunofixation is required for confirmation. The serum-free light chain assay is recommended in all newly diagnosed patients with plasma cell dyscrasias. Bone marrow aspiration and/or biopsy along with demonstration of clonality of plasma cells are necessary. Serum beta(2)-microglobulin, albumin, and lactate dehydrogenase are necessary for prognostic purposes. Standard metaphase cytogenetics and fluorescent in situ hybridization for 17p, t(4;14), and t(14;16) are recommended. The skeletal survey remains the standard method for imaging screening, but magnetic resonance imaging frequently provides valuable diagnostic and prognostic information. Most of these tests are repeated during follow-up or at relapse. PMID- 21292780 TI - Lymphoma invisibility-vaccination-attack? AB - In this issue of Blood, Navarrete et al report that upfront immunization of follicular B-cell lymphoma patients with bacterially produced Fab fragments induces immune responses; however, the influence on patient outcome is not yet known. PMID- 21292779 TI - Ataxin-2 intermediate-length polyglutamine expansions in European ALS patients. AB - Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease primarily affecting motor neurons. We recently identified intermediate length polyglutamine (polyQ) expansions (27-33 Qs) in ataxin 2 as a genetic risk factor for sporadic ALS in North American ALS patients. To extend these findings, we assessed the ataxin 2 polyQ repeat length in 1294 European ALS patients and 679 matched healthy controls. We observed a significant association between polyQ expansions and ALS (>30 Qs; P= 6.2 * 10(-3)). Thus, intermediate-length ataxin 2 polyQ repeat expansions are associated with increased risk for ALS also in the European cohort. The specific polyQ length cutoff, however, appears to vary between different populations, with longer repeat lengths showing a clear association. Our findings support the hypothesis that ataxin 2 plays an important role in predisposing to ALS and that polyQ expansions in ataxin 2 are a significant risk factor for the disease. PMID- 21292781 TI - A sheep in wolf's clothing. AB - Most are familiar with the biblical warnings about false prophets presenting as the wolf in sheep's clothing, but in this issue of Blood, Mansoor and colleagues expose a sheep in wolf's clothing by shining a bright light on a newly described benign disease previously pretending to be a very bad malignancy, and doing so quite convincingly. PMID- 21292782 TI - CLL: a supplementary question? AB - In this issue of Blood, Shanafelt and colleagues provide the first evidence that vitamin D deficiency is a risk factor for disease progression in chronic lymphocytic leukemia (CLL). Their findings imply that dietary vitamin D supplementation could potentially modify the natural history of this incurable disease. PMID- 21292783 TI - How "immunomodulatory" are IMIDs? AB - In this issue of Blood, Hsu and colleagues report that the immunostimulatory effect of lenalidomide on natural killer (NK)-cell function is profoundly suppressed by concurrent dexamethasone (Dex) therapy in multiple myeloma (MM) patients. These results could have major implications for the design of clinical trials combining lenalidomide and immunotherapies with the intent to stimulate the anti-MM activity of the latter. PMID- 21292784 TI - When the negative is positive. AB - In this issue of Blood, Hosking and colleagues report the lack of correlation between genetic variants within the MHC and the risk of ALL. PMID- 21292785 TI - Talin's second act-ivation: retraction. AB - In this issue of Blood, Haling and colleagues demonstrate that in addition to talin-dependent integrin activation, talin is required for platelet fibrin clot retraction by physically linking integrins to the actin cytoskeleton. PMID- 21292786 TI - Activate Rac to rescue new vessels. AB - Vascular endothelial growth factor (VEGF) is a major driver of physiologic and pathologic vascularization, but VEGF therapies generally fail to sustainably revascularize ischemic tissues. In this issue of Blood, Hoang and coworkers demonstrate that Rac1 may be the missing ingredient for achieving this goal. PMID- 21292787 TI - Expression and mutation analysis of EGFR, c-KIT, and beta-catenin in pulmonary blastoma. AB - INTRODUCTION: Pulmonary blastoma (PB) is a rare malignant lung tumour with an immature mesenchymal and epithelial component resembling fetal lung. In order to define potential therapeutic targets in PB, the authors analysed the status and possible role of EGFR, HER2 and c-KIT in the pathogenesis of this tumour type, and the diagnostic value of beta-catenin mutation analysis in PB. METHODS: 5 PBs were analysed for EGFR, HER2, c-KIT, and beta-catenin expression, as well as for mutations in EGFR, c-KIT, k-ras and the beta-catenin gene (CTNNB1). RESULTS: EGFR expression was observed in all PBs. An EGFR mutation was found in one of the tumours. No overexpression of c-KIT or HER2 was seen. No mutations were found in k-ras or c-KIT. 3 of 5 PBs displayed CTNNB1 mutations. Nuclear translocation of beta-catenin was seen in 2 of these tumours. CONCLUSIONS: Detection of EGFR expression and mutation in PB suggest EGFR inhibition as a potential therapeutic option in the treatment of advanced PB. Moreover, the data confirm a crucial role of CTNNB1 mutations in the pathogenesis of PB, and indicate that CTNNB1 gene sequencing may be a useful in distinguishing PB from other types of lung cancer. PMID- 21292789 TI - Intravenous thrombolysis in acute ischaemic stroke: a systematic review and meta analysis to aid decision making in patients over 80 years of age. AB - Introduction Patients >= 80 years of age are increasingly receiving intravenous thrombolysis for acute ischaemic stroke (AIS) despite lack of firm evidence. This systematic review assesses the safety and efficacy of intravenous thrombolysis with alteplase in >= 80 versus < 80 year old patients with AIS. Methods The existing literature was systematically analysed for outcome measures of mortality, functional recovery by modified Rankin scale and symptomatic intracranial haemorrhage (SICH) at 3 months following intravenous thrombolysis with alteplase in <80 and >= 80 year old patients with AIS. Statistical tests were performed for heterogeneity and publication bias. A detailed sensitivity analysis was performed and Forest plot was constructed for each of the outcome measures. Results 13 studies were identified. The overall OR was 2.77 (95% CI 2.25 to 3.40) for death, 0.49 (95% CI 0.40 to 0.61) for achieving a favourable outcome and 1.31 (95% CI 0.93 to 1.84) for SICH in >= 80 year old patients compared with those < 80 years old. The total number of events contributing to the estimates of effect for each outcome was: death 199, favourable outcome 141 and SICH 49. Conclusion Patients >= 80 years of age appear to have a lower probability of gaining a favourable outcome and a higher mortality rate compared with patients < 80 years old; however, the rate of SICH was not significantly increased. This supports recruitment of patients aged >= 80 years into ongoing trials comparing thrombolysis with controls. For patients who refuse or cannot be randomised, it provides information on risks and benefits of using alteplase off licence. PMID- 21292788 TI - Involvement of vascular peroxidase 1 in angiotensin II-induced vascular smooth muscle cell proliferation. AB - AIMS: Vascular peroxidase 1 (VPO1) is a newly identified haem-containing peroxidase that catalyses the oxidation of a variety of substrates by hydrogen peroxide (H(2)O(2)). Considering the well-defined effects of H(2)O(2) on the vascular remodelling during hypertension, and that VPO1 can utilize H(2)O(2) generated from co-expressed NADPH oxidases to catalyse peroxidative reactions, the aims of this study were to determine the potential role of VPO1 in vascular remodelling during hypertension. METHODS AND RESULTS: The vascular morphology and the expression of VPO1 in arterial tissues of spontaneously hypertensive rats and Wistar-Kyoto rats were assessed. The VPO1 expression was significantly increased concomitantly with definite vascular remodelling assessed by evaluating the media thickness, lumen diameter, media thickness-to-lumen diameter ratio and mean nuclear area in artery media in spontaneously hypertensive rats. In addition, in cultured rat aortic smooth muscle cells we found that the angiotensin II-mediated cell proliferation was inhibited by knockdown of VPO1 using small hairpin RNA. Moreover, the NADPH oxidase inhibitor, apocynin, and the hydrogen peroxide scavenger, catalase, but not the ERK1/2 inhibitor, PD98059, attenuated angiotensin II-mediated up-regulation of VPO1 and generation of hypochlorous acid. CONCLUSION: VPO1 is a novel regulator of vascular smooth muscle cell proliferation via NADPH oxidase-H(2)O(2)-VPO1-hypochlorous acid-ERK1/2 pathways, which may contribute to vascular remodelling in hypertension. PMID- 21292790 TI - The effect of syncope on brain natriuretic peptide. AB - BACKGROUND: Brain natriuretic peptide (BNP) may be a good prognostic marker in syncope. The aim of this study was to establish whether there is any change in BNP in association with an acute presentation. METHODS: Patients aged >=60 years admitted following presentation to the emergency department (ED) with syncope were eligible for prospective enrolment. Serial BNP measurements were performed on admission and at intervals up to 4 weeks after presentation. RESULTS: Between 8 March 2010 and 14 April 2010, 31 patients were recruited and were suitable for analysis, including seven patients who returned to the ED at 4 weeks. Mean BNP rose from a baseline of 167.8 ng/ml to a peak of 303.2 ng/ml at 48 h and then returned to baseline at 4 weeks. BNP ratio reached 2.3 (more than twice admission level) at 18 h and peaked at 2.4 at 1 week before returning to baseline at 4 weeks. CONCLUSIONS: BNP seems to rise from baseline to a peak between 18 h and 1 week after an acute syncopal episode in many patients. The reasons for this are not clear. PMID- 21292791 TI - Case report: prehospital use of intranasal ketamine for paediatric burn injury. AB - In this study, the administration of an intravenous ketamine formulation to the nasal mucosa of a paediatric burn victim is described in the prehospital environment. Effective analgesia was achieved without the need for vascular or osseous access. Intranasal ketamine has been previously described for chronic pain and anaesthetic premedication. This case highlights its potential as an option for prehospital analgesia. PMID- 21292792 TI - Performance measurement in British Helicopter Emergency Medical Services and Australian Air Medical Services. AB - BACKGROUND: Performance outcome measures are an essential component of health service improvement. Whereas hospital critical care services have established performance measures, prehospital care services have less well-established outcome measures and this has been identified as a key issue for development. Individual studies examining long-term survival and functional outcome measures have previously been used to evaluate prehospital care delivery. There is no set of standardised patient outcome measures for Helicopter Emergency Medical Services (HEMS) in the UK or Air Medical Services (AMS) in Australia. The aim of this study is to document the patient outcome measures currently in use within British HEMS and Australian AMS. METHODS: This is an observational study analysing point prevalence of practice as of November 2009. A structured questionnaire was designed to assess the method of routine patient follow-up, and the timing and nature of applied patient outcome measures. RESULTS: Full responses were received from 17/21 (81%) British services and 6/7 (86%) Australian services. The overall response rate was 82%. CONCLUSIONS: HEMS in Britain and Australian aeromedical retrieval services do not have uniform patient outcome measures. Services tend not to follow-up patients beyond 24 h post transfer. Patient outcome data are rarely presented to an external organisation and there is no formal data comparison between surveyed services. Services are not satisfied that the data currently being collected reflects the quality of their service. PMID- 21292793 TI - Slow infusion metoclopramide does not affect the improvement rate of nausea while reducing akathisia and sedation incidence. AB - OBJECTIVE: To compare the effects of metoclopramide infusion in emergency department (ED) patients complaining of nausea to determine the changes in its therapeutic effect and prevention of side effects such as akathisia and sedation. METHODS: A prospective, randomised, double blind trial, from 1 March 2007 to 1 May 2008 in the ED of Pamukkale University Faculty of Medicine. Patients with moderate to severe nausea were randomised and divided into two groups: group 1 received 10 mg metoclopramide as a slow intravenous infusion over 15 min plus placebo (SIG); group 2 received 10 mg metoclopramide as an intravenous bolus infusion over 2 min plus placebo (BIG). The whole procedure was observed, and nausea scores, akathisia and vital changes were recorded. RESULTS: 140 patients suffering from moderate to severe nausea in the ED were included in the study. There was no significant difference between the groups in terms of mean nausea scores during follow-up (p=0.97). A significant difference in akathisia incidence was observed between the groups (18 (26.1%) in the BIG and 5 (7%) in the SIG) (p=0.002). There was also a significant difference in sedation incidence between the groups (19 (27.5%) in the BIG and 10 (14.5%) in the SIG) (p=0.05). CONCLUSION: Even though slowing the rate of infusion of metoclopramide does not affect the rate of improvement in nausea, it may be an effective strategy for reducing the incidence of akathisia and sedation in patients with nausea. PMID- 21292794 TI - MR imaging-based localized intra-arterial thrombolysis assisted by mechanical clot disruption for acute ischemic stroke due to middle cerebral artery occlusion. AB - BACKGROUND AND PURPOSE: LIT-MCD is used in our institution for acute stroke due to MCA occlusion, with the goal of reducing symptomatic intracranial hemorrhage by maintaining recanalization of the occluded vessels. The purpose of the study was to investigate the safety and efficacy of LIT-MCD and to identify factors associated with a poor outcome in patients undergoing this procedure. MATERIALS AND METHODS: LIT-MCD for MCA occlusion was performed in 90 of 1907 consecutive patients with acute stroke admitted to our institution. Radiographic data and clinical outcome were evaluated in the 90 patients, and factors predictive of a poor outcome (3-month mRS score, 3-6) were investigated by multivariate analysis. RESULTS: Recanalization was achieved in 73 of the 90 patients (81%); symptomatic intracranial hemorrhage occurred in 7 (8%); procedure-related complications, in 9 (10%); and a favorable clinical outcome (3-month mRS score, 0-2), in 48 (53%). A high baseline NIHSS score (>=20), a low preprocedural ASPECTS on MR imaging (<=7), proximal M1 occlusion (in the horizontal segment of the MCA at or proximal to the lenticulostriate arteries), and no recanalization were significant predictors of a poor clinical outcome. CONCLUSIONS: LIT-MCD is a safe and effective treatment for acute stroke due to MCA occlusion. However, further intervention is needed to improve the outcome of patients with proximal M1 occlusion. PMID- 21292795 TI - Suspicious neuroimaging pattern of thrombotic microangiopathy. AB - The TMAs are a group of microvascular occlusive disorders characterized by thrombocytopenia and intravascular hemolysis. Literature review reveals a spectrum of neuroimaging findings, including a single case report of multifocal hemorrhagic infarctions. We present a series of 12 patients with TMA demonstrating a similar pattern of multifocal cortical and subcortical hemorrhagic infarctions. PMID- 21292796 TI - Computer-assisted system for diagnosis of Alzheimer disease using data base- independent estimation and fluorodeoxyglucose- positron-emission tomography and 3D-stereotactic surface projection. AB - BACKGROUND AND PURPOSE: Recently, voxel-based statistical parametric images have been developed as additional diagnostic tools for AD. However these methods require the generation of a data base of healthy brain images. The purpose of this study was to produce and evaluate an automatic method using a data base independent estimation system for the diagnosis of mild AD. MATERIALS AND METHODS: We retrospectively selected 66 subjects, including 33 patients with early AD and 33 age-matched healthy volunteers. Individual brain metabolic images were obtained by using FDG-PET. These were transformed by using 3D-SSP. We then produced CADDIES, which compares the parietal and sensorimotor metabolic counts by using t tests. If parietal metabolism was significantly lower than the sensorimotor metabolism, the subject was automatically diagnosed as having AD. The FDG-PET images were also analyzed by using a previous automatic diagnosis system (CAAD) that is dependent on the construction of a "normal data base" of healthy brain images. Diagnostic performance was compared between the 2 methods. RESULTS: The CADDIES demonstrated a sensitivity of 88%, specificity of 79%, and accuracy of 85%, while the CAAD system demonstrated a sensitivity of 70%, specificity of 94%, and accuracy of 82%. The area under the ROC curve of CADDIES was 0.964. The areas under ROC curves of the CAAD method in the parietal and posterior cingulate gyri were 0.843 and 0.939, respectively. CONCLUSIONS: The CADDIES method demonstrated a diagnostic accuracy similar to that of the CAAD system. Our results indicate that this method can be applied to the detection of patients with early AD in routine clinical examinations, with the benefit of not requiring the generation of a normal data base. PMID- 21292797 TI - 3D turbo spin-echo sequence with motion-sensitized driven-equilibrium preparation for detection of brain metastases on 3T MR imaging. AB - BACKGROUND AND PURPOSE: MSDE preparation is a technique for black-blood imaging. Our purpose was to evaluate the usefulness of a 3D TSE sequence with MSDE preparation in detecting brain metastases by comparing it with conventional sequences. MATERIALS AND METHODS: Postcontrast images of 227 patients who were suspected of having brain metastasis were prospectively obtained by using 3 T1 weighted 3D sequences: a gradient-echo sequence (MPRAGE), TSE-noMSDE, and TSE MSDE. The number of visualized blood vessels and the lesion-to-normal CNR were compared among the 3 sequences. An observer test involving 9 radiologists was performed, and their diagnostic performance by using TSE-MSDE, MPRAGE, and combined TSE-MSDE and MPRAGE was compared by means of an FOM as an index of diagnostic performance derived by the JAFROC analysis, sensitivity, FP/case, and reading time. RESULTS: TSE-MSDE resulted in significantly better vessel suppression than the other 2 methods. TSE with and without MSDE resulted in significantly higher CNRs than MPRAGE. In the observer test, significantly higher sensitivity and FOM as well as significantly shorter reading time were achieved by TSE-MSDE compared with MPRAGE, but FP/case was significantly higher with TSE MSDE. Combined TSE-MSDE/MPRAGE resulted in significantly higher sensitivity and FOM and similar FP/case and reading time compared with MPRAGE alone. CONCLUSIONS: With blood vessel suppression and increased CNR, TSE-MSDE improves radiologists' performances in detecting brain metastases compared with MPRAGE, but it may increase FP results. Combined with MPRAGE, TSE-MSDE achieves high diagnostic performance while maintaining a low FP rate. PMID- 21292798 TI - Isolated fractures of the posterior maxillary sinus: CT appearance and proposed mechanism. AB - A heretofore unreported type of facial fracture is discussed. Twenty-two cases of posterior maxillary wall fracture are reviewed, of which 59% demonstrated concomitant mandibular fracture. The proposed mechanism for this injury is an impact from the ipsilateral mandibular coronoid process striking the posterior maxillary wall, with associated mandibular dislocation or fracture. As such, further investigation of the mandible may be warranted when this type of maxillary wall fracture is encountered to exclude concomitant injury. PMID- 21292799 TI - Identification of the nervus intermedius using 3T MR imaging. AB - BACKGROUND AND PURPOSE: Improved MR imaging at higher field strengths enables more detailed imaging of cranial nerves. The aim of this study was to assess the identifiability of the NI in the CPA and IAC by using high-resolution 3T MR imaging. MATERIALS AND METHODS: Twenty-seven healthy volunteers (13 men and 14 women; mean age, 33 years) underwent 3T MR imaging of the CPA. The section thicknesses of the CISS sequence was 0.4 mm (TR, 12.18 ms; TE, 6.09 ms) using a 12-channel head coil. Evaluation was performed by using MPR mode. Image quality and identifiability of the NI were rated independently by 2 observers according to predefined criteria on an ordinal scale. Interobserver agreement was assessed by kappa statistics. RESULTS: Fifty-four NIs were evaluated. Both observers were able to identify the NI in nearly 60% of cases. It was possible to indentify at least 1 NI in 70% of all volunteers in the CPA and/or IAC. Image quality ratings showed a substantial agreement (kappa = 0.65) and identifiability ratings an almost perfect (kappa = 0.83) agreement. CONCLUSIONS: Careful evaluation of all nervous and vascular structures in the CPA and IAC at high-resolution 3T MR imaging allows reliable depiction of the NI. PMID- 21292800 TI - How everybody wins when playing by the rules: the benefits of investigator initiated industry-sponsored clinical trials. PMID- 21292801 TI - Multiple sclerosis and chronic cerebrospinal venous insufficiency: the neuroimaging perspective. PMID- 21292802 TI - Redefining the Guillain-Barre spectrum in children: neuroimaging findings of cranial nerve involvement. AB - GBS and its MFS variant are acute polyneuropathies that are considered to represent a continuum rather than distinct entities, due to the overlap in their clinical features. Enhancement of the CE roots represents the neuroradiologic hallmark of GBS, while findings of neuroimaging studies in MFS are usually unremarkable. Our purpose was to evaluate the MR imaging findings of polyneuropathy in 17 children affected by GBS and its MFS variant. Fourteen of our 17 patients demonstrated CE enhancement, with predominant involvement of the anterior roots. Of 6 patients who underwent MR imaging of the brain, 5 had cranial nerve involvement. In children affected by GBS-MFS, involvement of the CE roots may be considered part of a more extensive autoimmune neuropathy, as demonstrated by enhancement of cranial nerves. Brain MR imaging should be considered in the routine evaluation in pediatric patients with GBS-MFS for the evaluation of the cranial nerves. PMID- 21292803 TI - Strengthening and optimal movements for painful shoulders (STOMPS) in chronic spinal cord injury: a randomized controlled trial. AB - BACKGROUND: Shoulder pain is a common problem after spinal cord injury (SCI), with negative effects on daily activities and quality of life (QOL). OBJECTIVE: The purpose of this study was to determine the effect of an exercise program and instruction to optimize performance of upper-extremity tasks on shoulder pain in people with paraplegia from SCI. METHODS: Design Eighty individuals with paraplegia from SCI and shoulder pain were randomly assigned to receive either an exercise/movement optimization intervention or an attention control intervention. The exercise/movement optimization intervention consisted of a 12-week home-based program of shoulder strengthening and stretching exercises, along with recommendations on how to optimize the movement technique of transfers, raises, and wheelchair propulsion. The attention control group viewed a 1-hour educational video. Outcome measures of shoulder pain, muscle strength (force generating capacity), activity, and QOL were assessed at baseline, immediately after intervention, and 4 weeks later. RESULTS: Shoulder pain, as measured with the Wheelchair User's Shoulder Pain Index, decreased to one third of baseline levels after the intervention in the exercise/movement optimization group, but remained unchanged in the attention control group. Shoulder torques, most 36-Item Short-Form Health Survey questionnaire (SF-36) subscale scores, and QOL scores also were improved in the exercise/movement optimization group, but not in the attention control group. Improvements were maintained at the 4-week follow-up assessment. Limitations Many of the outcome measures were self-reported, and the participant dropout rate was high in both groups. Additional studies are needed to determine whether the results of this study can be generalized to individuals with tetraplegia. CONCLUSIONS: This home-based intervention was effective in reducing long-standing shoulder pain in people with SCI. The reduction in pain was associated with improvements in muscle strength and health-related and overall QOL. PMID- 21292804 TI - Homology modelling and site-directed mutagenesis studies of the epoxide hydrolase from Phanerochaete chrysosporium. AB - Three-dimensional structural model of epoxide hydrolase (PchEHA) from Phanerochaete chrysosporium was constructed based on X-ray structure of Agrobacterium radiobacter AD1 sEH using SWISS-MODEL server. Conserved residues constituting the active site cavity were identified, of which the functional roles of 14 residues were determined by site-directed mutagenesis. In catalytic triad, Asp105 and His308 play a leading role in alkylation and hydrolysis steps, respectively. Distance between Asp105 and epoxide ring of substrate may determine the regiospecificity in the substrate docking model. Asp277 located at the entrance of substrate tunnel is concerned with catalysis but not essential. D307E had the highest activity and lower enantioselectivity among 14 mutants, suggesting Asp307 may be involved in choice of substrate configuration. Y159F and Y241F almost exhibited no activity, indicating that they are essential to bind substrate and facilitate opening of epoxide ring. Besides, His35-Gly36-Asn37 Pro38, Trp106 and Trp309 surrounding Asp105, may coordinate the integration of active site cavity and influence substrate binding. Especially, W106I reversed the enantioselectivity, perhaps due to more deteriorative impact on the preferred (R)-styrene oxide. Gly65 and Gly67 occurring at beta-turns and Gly36 are vital in holding protein conformation. Conclusively, single conserved residue around the active sites has an important impact on catalytic properties. PMID- 21292806 TI - Blood cigarettes: cigarette smuggling and war economies in central and eastern Africa. AB - OBJECTIVE: To analyse cigarette smuggling practices in central and eastern Africa. METHODS: Primary data were gathered during long-term qualitative field research in which about 400 interviews were conducted. Analysis of secondary sources included academic literature and reports from non-government organisations, multilateral organisations and the press. RESULTS: Our research suggests that the following factors play an important role in cigarette smuggling in eastern and central Africa: (1) government officials encounter difficulties monitoring the long and porous borders; (2) there is a general problem of corrupt government officials and particularly those who allow large-scale smugglers to operate; (3) criminal elements also play an important role in smuggling- cigarette smuggling has helped rebel groups to finance their activities, something illustrated through examples from the war economy in the eastern part of the Democratic Republic of Congo. CONCLUSIONS: Our research suggests that cigarette smuggling in this region is not primarily the result of different taxation levels in neighbouring states, but rather the outcome of weak state capacity, high levels of corruption and the activities of rebel groups. Under these conditions smuggling cigarettes becomes an attractive option as taxation is so easily avoided. This explains why in the low-income countries in this study there are high levels of smuggling in spite of low cigarette prices. Comprehensive supply control and enforcement legislation, and cooperation at national, regional and global level are needed to tackle fraudulent practices facilitated by corruption at state level, and to effectively punish interaction between cigarette traders and rebel groups. PMID- 21292805 TI - Stabilization of cGMP-dependent protein kinase G (PKG) expression in vascular smooth muscle cells: contribution of 3'UTR of its mRNA. AB - The type-I cGMP-dependent protein kinase (PKG-I) expression regulation is not yet completely understood. In this study, we examined the role of 3'-untranslated region (3'UTR)-PKG-I messenger RNA (mRNA) in the control of PKG-I expression in vascular smooth muscle cells (VSMCs). Using a 3'-rapid amplification of cDNA ends (RACE) for the amplification of complementary DNA (cDNA) ends, we generated and cloned a 1.2-kb-3'UTR mRNA PKG-I in pGL3 control vector downstream of the luciferase reporter gene. Serial deletions and functional studies revealed that among the deleted constructs, only the 1.2-kb-3'UTR PKG-I mRNA possesses the highest activity in transfected VSMC. Kinetic luciferase assays in the presence of actinomycin D showed that this construct stabilizes luciferase activity compared to the control vector. Sequence analysis of 3'UTR-PKG-I mRNA revealed the existence of four AU-rich regions (AU1 through AU4) in addition to a potential poly(A) site. Different riboprobes were generated either by 5'-end labelling of designed ribonucleotides, containing individual AU-rich regions or by in vitro transcription assay using cloned 1.2-kb cDNA as a template. RNA electrophoretic mobility shift assay (EMSA) and ultra-violet cross-linking (UV CL) assays showed that AU1, AU3, AU4 and 1.2-kb probes were able to retard cytosolic and nuclear proteins. Taken together, these data suggest that PKG-I expression is subjected to post-transcriptional regulation in VSMC through the 3'UTR of its mRNA. PMID- 21292807 TI - Counting 15 million more poor in India, thanks to tobacco. AB - OBJECTIVE: To quantify the impact of tobacco use and the related medical expenditure on poverty in India. METHODS: Tobacco expenditure and associated medical expenditure attributable to tobacco use were subtracted from the household monthly consumption expenditure in order to derive an appropriate measure of household disposable income. The 2004 National Sample Survey, a nationally representative survey of Indian households, was used to estimate the true level of poverty. RESULTS: Our estimates indicate that accounting for direct expenditure on tobacco would increase the rural and the urban poverty rates by 1.5% (affecting 11.8 million people) and 0.72% (affecting 2.3 million people), respectively. Similarly, the out-of-pocket costs of tobacco-attributable medical care result in 0.09% higher poverty rates in rural areas (affecting 0.7 million people) and in 0.07% higher poverty rates in urban locations (affecting 0.23 million people). CONCLUSIONS: Tobacco consumption impoverishes roughly 15 million people in India. Hence tobacco control measures would not only improve public health, but would also reduce poverty in India. PMID- 21292808 TI - The economic impact of Mexico City's smoke-free law. AB - OBJECTIVE: To evaluate the economic impact of Mexico City's 2008 smoke-free law- The Non-Smokers' Health Protection Law on restaurants, bars and nightclubs. MATERIAL AND METHODS: We used the Monthly Services Survey of businesses from January 2005 to April 2009--with revenues, employment and payments to employees as the principal outcomes. The results are estimated using a differences-in differences regression model with fixed effects. The states of Jalisco, Nuevo Leon and Mexico, where the law was not in effect, serve as a counterfactual comparison group. RESULTS: In restaurants, after accounting for observable factors and the fixed effects, there was a 24.8% increase in restaurants' revenue associated with the smoke-free law. This difference is not statistically significant but shows that, on average, restaurants did not suffer economically as a result of the law. Total wages increased by 28.2% and employment increased by 16.2%. In nightclubs, bars and taverns there was a decrease of 1.5% in revenues and an increase of 0.1% and 3.0%, respectively, in wages and employment. None of these effects are statistically significant in multivariate analysis. CONCLUSIONS: There is no statistically significant evidence that the Mexico City smoke-free law had a negative impact on restaurants' income, employees' wages and levels of employment. On the contrary, the results show a positive, though statistically non-significant, impact of the law on most of these outcomes. Mexico City's experience suggests that smoke-free laws in Mexico and elsewhere will not hurt economic productivity in the restaurant and bar industries. PMID- 21292809 TI - Weight loss and self-regulatory eating efficacy in older adults: the cooperative lifestyle intervention program. AB - OBJECTIVES: Using the weight efficacy lifestyle questionnaire (WEL), we examined whether a group-mediated intervention for weight loss among older, obese adults resulted in changes in self-regulatory self-efficacy for eating behavior and whether these changes mediated weight loss. METHODS: This was a randomized controlled design, and 288 older adults received 1 of 3 treatments for 6 months: physical activity only (PA), weight loss + physical activity (WL + PA), or a successful aging (SA) health education program. The WEL was administered prior to randomization and again at the 6-month follow-up visit. RESULTS: A significant treatment effect was observed for the WEL, F (2249) = 15.11, p < .0001, partial eta2 = .11, showing that improvement occurred only in the WL + PA group as compared with PA and SA. Changes in WEL scores partially mediated the effects of the WL + PA intervention on weight loss. DISCUSSION: These results illustrate that WL + PA can be effective in improving older adults' self-efficacy for the self-regulation of eating behavior and that these changes are prospectively related to the amount of weight loss. Further research is warranted on an expanded concept of self-efficacy as well as controlled experimental studies on eating behavior in older adults. PMID- 21292810 TI - Indicators of job strain at midlife and cognitive functioning in advanced old age. AB - OBJECTIVES: We used data from SWEOLD, a Swedish nationally representative study of individuals aged 77 years or older, to examine midlife indicators of job strain in relation to cognitive performance and impairment. METHODS: In all, 827 participants completed an abridged 11-point version of the Mini-Mental State Examination in-person in 1992 and/or 2002 and had self-reported and/or occupation based scores for job control and demands from data collected in 1968. Seventeen percent scored below the cutoff for cognitive impairment. RESULTS: Controlling for age, sex, education, self-rated health, and year of cognitive screening, low self-reported and occupation-based job control at midlife was associated with poorer cognitive performance later (ps < .001). For the occupation-based measure, low job control was also associated with greater likelihood of impairment, whereas having an active job (high job control/high job demands) was associated with better cognitive performance and lower likelihood of impairment (ps < .01). Childhood environment, midlife depressive symptoms, and social activity had limited influence, whereas the influence of both adulthood socioeconomic position and work complexity on these results was more pronounced. DISCUSSION: Job control at midlife, by itself and in combination with job demands, may influence cognitive functioning later above and beyond demographic variables and other occupational characteristics. PMID- 21292811 TI - CD73-deficient mice have increased antitumor immunity and are resistant to experimental metastasis. AB - CD73 is a cell-surface enzyme that suppresses immune responses by producing extracellular adenosine. In this study, we employed CD73 gene-targeted mice to investigate the role of host-derived CD73 on antitumor immunity and tumor cell metastasis. We found that CD73 ablation significantly suppressed the growth of ovalbumin-expressing MC38 colon cancer, EG7 lymphoma, AT-3 mammary tumors, and B16F10 melanoma. The protective effect of CD73 deficiency on primary tumors was dependent on CD8(+) T cells and associated with an increased frequency of antigen specific CD8(+) T cells in peripheral blood and tumors and increased antigen specific IFN-gamma production. Replicate studies in bone marrow chimeras established that both hematopoietic and nonhematopoietic expression of CD73 was important to promote tumor immune escape. Using adoptive reconstitution of T regulatory cell (Treg)-depleted DEREG (depletion of regulatory T cells) mice, we demonstrated that part of the protumorigenic effect of Tregs was dependent on their expression of CD73. CD73-deficient mice were also protected against pulmonary metastasis of B16F10 melanoma cells after intravenous injection. Unexpectedly, we found that the prometastatic effect of host-derived CD73 was dependent on CD73 expression on nonhematopoietic cells. CD73 expression on nonhematopoietic cells, most likely endothelial cells, was critical for promoting lung metastasis in a manner independent from immunosuppressive effects. Notably, in vivo blockade of CD73 with a selective inhibitor or anti-CD73 monoclonal antibody significantly reduced tumor growth and metastasis of CD73-negative tumors. Taken together, our findings indicate that CD73 may be targeted at multiple levels to induce anticancer effects including at the level of tumor cells, Tregs, and nonhematopoietic cells. PMID- 21292812 TI - Functional EGFR germline polymorphisms may confer risk for EGFR somatic mutations in non-small cell lung cancer, with a predominant effect on exon 19 microdeletions. AB - Somatic mutations in the EGFR tyrosine kinase domain play a critical role in the development and treatment of non-small cell lung cancer (NSCLC). Strong genetic influence on susceptibility to these mutations has been suggested. To identify the genetic factors conferring risk for the EGFR tyrosine kinase mutations in NSCLC, a case-control study was conducted in 141 Taiwanese NSCLC patients by focusing on three functional polymorphisms in the EGFR gene [-216G/T, intron 1 (CA)n, and R497K]. Allelic imbalance of the EGFR -216G/T polymorphism was also tested in the heterozygous patients and in the NCI-60 cancer cell lines to further verify its function. We found that the frequencies of the alleles -216T and CA-19 are significantly higher in the patients with any mutation (P = 0.032 and 0.01, respectively), in particular in those with exon 19 microdeletions (P = 0.006 and 0.033, respectively), but not in the patients with L858R mutation. The 216T allele is favored to be amplified in both tumor DNA of lung cancer patients and cancer cell lines. We conclude that the local haplotype structures across the EGFR gene may favor the development of cellular malignancies and thus significantly confer risk to the occurrence of EGFR mutations in NSCLC, particularly the exon 19 microdeletions. PMID- 21292813 TI - Endogenous cardiotonic steroids in chronic renal failure. AB - BACKGROUND: Previous reports demonstrated that digitalis-like cardiotonic steroids (CTS) contribute to the pathogenesis of end-stage renal disease. The goal of the present study was to define the nature of CTS in patients with chronic kidney disease (CKD) and in partially nephrectomized (PNx) rats. METHODS: In patients with CKD and in healthy controls, we determined plasma levels of marinobufagenin (MBG) and endogenous ouabain (EO) and erythrocyte Na/K-ATPase activity in the absence and in the presence of 3E9 anti-MBG monoclonal antibody (mAb) and Digibind. Levels of MBG and EO were also determined in sham-operated Sprague-Dawley rats and in rats following 4 weeks of PNx. RESULTS: In 25 patients with CKD plasma, MBG but not EO was increased (0.86 +/- 0.07 versus 0.28 +/- 0.02 nmol/L, P < 0.01) and erythrocyte Na/K-ATPase was inhibited (1.24 +/- 0.10 versus 2.80 +/- 0.09 MUmol Pi/mL/h, P < 0.01) as compared to that in 19 healthy subjects. Ex vivo, 3E9 mAb restored Na/K-ATPase in erythrocytes from patients with CKD but did not affect Na/K-ATPase from control subjects. Following chromatographic fractionation of uremic versus normal plasma, a competitive immunoassay based on anti-MBG mAb detected a 3-fold increase in the level of endogenous material having retention time similar to that seen with MBG. A similar pattern of CTS changes was observed in uremic rats. As compared to sham operated animals, PNx rats exhibited 3-fold elevated levels of MBG but not that of EO. CONCLUSIONS: In chronic renal failure, elevated levels of a bufadienolide CTS, MBG, contribute to Na/K-ATPase inhibition and may represent a potential target for therapy. PMID- 21292814 TI - Estimation of renal allograft half-life: fact or fiction? AB - INTRODUCTION: Renal allograft half-life time (t1/2) is the most straightforward representation of long-term graft survival. Since some statistical models overestimate this parameter, we compare different approaches to evaluate t1/2. PATIENTS AND METHODS: Patients with a 1-year functioning graft transplanted in Spain during 1990, 1994, 1998 and 2002 were included. Exponential, Weibull, gamma, lognormal and log-logistic models censoring the last year of follow-up were evaluated. The goodness of fit of these models was evaluated according to the Cox-Snell residuals and the Akaike's information criterion (AIC) was employed to compare these models. RESULTS: We included 4842 patients. Real t1/2 in 1990 was 14.2 years. Median t1/2 (95% confidence interval) in 1990 and 2002 was 15.8 (14.2-17.5) versus 52.6 (35.6-69.5) according to the exponential model (P < 0.001). No differences between 1990 and 2002 were observed when t1/2 was estimated with the other models. In 1990 and 2002, t1/2 was 14.0 (13.1-15.0) versus 18.0 (13.7-22.4) according to Weibull, 15.5 (13.9-17.1) versus 19.1 (15.6 22.6) according to gamma, 14.4 (13.3-15.6) versus 18.3 (14.2-22.3) according to the log-logistic and 15.2 (13.8-16.6) versus 18.8 (15.3-22.3) according to the lognormal models. The AIC confirmed that the exponential model had the lowest goodness of fit, while the other models yielded a similar result. CONCLUSIONS: The exponential model overestimates t1/2, especially in cohorts of patients with a short follow-up, while any of the other studied models allow a better estimation even in cohorts with short follow-up. PMID- 21292815 TI - Peripheral augmentation index and vascular inflammation in autosomal dominant polycystic kidney disease. AB - BACKGROUND: Cardiovascular disease is the leading cause of premature mortality in autosomal dominant polycystic kidney disease (ADPKD). We examined peripheral augmentation index (AIx) as a measure of systemic vascular function and circulating markers of vascular inflammation in patients with ADPKD. METHODS: Fifty-two ADPKD patients with hypertension and estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2), 50 ADPKD patients with hypertension and eGFR >= 60 mL/min/1.73 m(2), 42 normotensive ADPKD patients with eGFR >= 60 mL/min/1.73 m(2) and 51 normotensive healthy controls were enrolled in this study. AIx was measured from peripheral artery tone recordings using finger plethysmography. Serum levels of soluble intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule-1, P-selectin, E-selectin, soluble Fas (sFas) and Fas ligand (FasL) were measured as markers of vascular inflammation. RESULTS: AIx was higher in all three patient groups with ADPKD compared to healthy controls (P < 0.05). AIx was similar between the normotensive ADPKD patients with eGFR >= 60 mL/min/1.73 m(2) and hypertensive ADPKD patients with eGFR < 60 mL/min/1.73 m(2) (P > 0.05). ICAM, P-selectin, E-selectin and sFas were higher and FasL lower in all ADPKD groups compared to controls (P < 0.05). ICAM, P-selectin and E-selectin were similar between the normotensive ADPKD patients with eGFR >= 60 mL/min/1.73 m(2) and hypertensive ADPKD patients with eGFR < 60 mL/min/1.73 m(2) (P > 0.05). According to multiple regression analysis, predictors of AIx in ADPKD included age, height, heart rate and mean arterial pressure (P < 0.05). Vascular inflammatory markers were not predictors of AIx in ADPKD. CONCLUSIONS: Systemic vascular dysfunction, manifesting as an increase in AIx and vascular inflammation is evident in young normotensive ADPKD patients with preserved renal function. Vascular inflammation is not associated with elevated AIx in ADPKD. PMID- 21292816 TI - Inappropriate drug use and mortality in community-dwelling elderly with impaired kidney function--the Three-City population-based study. AB - BACKGROUND: Glomerular filtration rate (GFR) decline with age increases the risk of inappropriate dosing of drugs. We investigated the determinants and the mortality associated with the use of drugs that are contraindicated or require dose adjustment according to kidney function among the community-dwelling elderly. METHODS: The Three-City population-based study included 8701 participants >=65 years from 1999 to 2001. Exposure to the risk of inappropriate drug dosage was defined as reported use of either a contraindicated drug or one requiring dose adjustment according to the individual baseline glomerular filtration rate estimated (eGFR) with the Modification of Diet in Renal disease study equation. Six-year mortality was analysed using Cox models adjusted for several sociodemographic, biologic and clinical risk factors. RESULTS: The overall percentage of exposure to the risk of inappropriate drug use was 13.3% (contraindication, 0.8%): it was 52.5% (4.5%) in those with an eGFR of 30-59 and 96% (48%) in those <30 mL/min/1.73 m(2). Antihypertensive agents, fibrates and psycholeptics accounted for most of the drugs with dosing recommendations and antidiabetic agents and antihistamines for those contraindicated. Individuals at risk were more likely to be men, older, and under treatment for hypertension or hypercholesterolemia. Exposure to either risk was independently related to higher all-cause mortality (hazard ratio 1.4, 95% confidence interval 1.0-1.9) in participants with eGFR <60 mL/min/1.73 m(2). CONCLUSIONS: Contraindicated drug prescription was uncommon but >10% of the population took drugs requiring renal dosing adjustments. Regular monitoring of eGFR may prevent excess mortality associated with inappropriate drug prescription in the elderly. PMID- 21292817 TI - Serum phosphorus predicts incident chronic kidney disease and end-stage renal disease. AB - BACKGROUND: Elevations in serum phosphorus are associated with renal decline in animal models and progression of established chronic kidney disease (CKD) in human observational studies. We examined whether serum phosphorus levels increase the risk of incident CKD or end-stage renal disease (ESRD) in two population based prospective cohort studies. METHODS: Overall, 2269 participants free of CKD [estimated glomerular filtration rate (eGFR) <60 mL/min/1.73(2)] from the Framingham Heart Study (FHS; mean age 42 years; 53% women) and 13,372 participants from the Third National Health and Nutrition Examination Survey (NHANES III; mean age 44.3 years, 52% women) contributed to the present study. In the FHS, we evaluated the relationship between baseline phosphorus category (<2.5 mg/dL, 2.5-3.49 mg/dL, 3.5-3.99 mg/dL and >=4 mg/dL) and incident CKD (n = 267). In NHANES, we examined the relationship between phosphorus below and above 4 mg/dL in relation to incident ESRD (n = 65). RESULTS: FHS participants in the highest phosphorus category had an increased risk of CKD [odds ratio 2.14; 95% confidence interval (CI), 1.07-4.28; P = 0.03] in multivariable-adjusted models when compared to the referent group (2.5-3.49 mg/dL). Similarly, NHANES III participants with phosphorus levels >=4 mg/dL demonstrated an increased risk of incident ESRD compared to those <4 mg/dL (relative risk 1.90; 95% CI 1.03-3.53; P = 0.04). CONCLUSIONS: In prospective studies of the general population, serum phosphorus levels in the upper-normal range were associated with a doubling in the risk of developing incident CKD and ESRD. PMID- 21292818 TI - Heat-shock induction of tumor-derived danger signals mediates rapid monocyte differentiation into clinically effective dendritic cells. AB - PURPOSE: This study characterizes, biologically and clinically, a novel type of dendritic cells (DC) produced in the short term and called tumor antigen presenting cells (TAPCells). In particular, we identified factors present in a lysate derived from heat-shocked allogeneic melanoma cells (TRIMEL) that are associated with TAPCells' enhanced capability to induce CD8(+) T-cell responses in vitro and in vaccinated melanoma patients. EXPERIMENTAL DESIGN: First, extensive phenotypic and functional characterization of TAPCells was performed, followed by vaccination of 45 melanoma patients with four doses of TAPCells over a period of 2 months. Specific delayed-type hypersensitivity (DTH) reaction was analyzed posttreatment and correlated with overall survival rates. Furthermore, heat-shock (HS)-induced factors present in TRIMEL and their effects on DC activation were identified and studied. RESULTS: TRIMEL induced a committed, mature, DC-like phenotype in TAPCells and effectively activated melanoma-specific CD4(+) and CD8(+) T cells. Clinically, 64% of vaccinated patients showed positive DTH reaction against TRIMEL, and this was associated with improved overall survival. HS treatment of tumor cells increased calreticulin (CRT) plasma membrane translocation and induced the release of high-mobility group box 1 proteins (HMGB1). Both CRT and HMGB1 mobilization were associated with enhanced TAPCells' maturation and antigen (Ag) cross-presentation, respectively. DTH infiltration analysis revealed the presence of CD8(+)/CD45RO(+) T cells, thus confirming TAPCells' ability to cross-present Ags in vivo. CONCLUSIONS: Our results indicate that lysates derived from heat-shocked tumor cells are an optimal source of tumor-associated Ags, which are crucial for the generation of DCs with improved Ag cross-presentation capacity and clinically effective immunogenicity. PMID- 21292819 TI - Comparison of genomics and functional imaging from canine sarcomas treated with thermoradiotherapy predicts therapeutic response and identifies combination therapeutics. AB - PURPOSE: While hyperthermia is an effective adjuvant treatment to radiotherapy, we do not completely understand the nature of the response heterogeneity. EXPERIMENTAL DESIGN: We performed gene expression analysis of 22 spontaneous canine sarcomas before and after the first hyperthermia treatment administered as an adjuvant to radiotherapy. In parallel, diffusion-weighted MRI (DWI) was done prior to the treatment course and at the end of therapy. RESULTS: From the integrative analysis of gene expression and DWI, we identified significant correlation between tumor responses with genes involved in VEGF signaling, telomerase, DNA repair, and inflammation. The treatment-induced changes in gene expression identified 2 distinct tumor subtypes with significant differences in their gene expression and treatment response, as defined by changes in DWI. The 2 tumor subtypes could also be readily identified by pretreatment gene expression. The tumor subtypes, with stronger expression response and DWI increase, had higher levels of HSP70, POT1, and centrosomal proteins, and lower levels of CD31, vWF, and transferrin. Such differential gene expression between the 2 subtypes was used to interrogate connectivity map and identify linkages to an HSP90 inhibitor, geldanamycin. We further validated the ability of geldanamycin to enhance cell killing of human tumor cells with hyperthermia and radiotherapy in clonogenic assays. CONCLUSIONS: To our knowledge, this is one of the first successful attempts to link changes in gene expression and functional imaging to understand the response heterogeneity and identify compounds enhancing thermoradiotherapy. This study also demonstrates the value of canine tumors to provide information generalizable to human tumors. PMID- 21292820 TI - Bortezomib enhances the efficacy of fulvestrant by amplifying the aggregation of the estrogen receptor, which leads to a proapoptotic unfolded protein response. AB - PURPOSE: Fulvestrant is known to promote the degradation of the estrogen receptor (ER) in the nucleus. However, fulvestrant also promotes the aggregation of the newly synthesized ER in the cytoplasm. Accumulation of protein aggregates leads to cell death but this effect is limited as a result of their elimination by the proteasome. We tested whether combining fulvestrant with the proteasome inhibitor, bortezomib, could enhance the accumulation of ER aggregates and cause apoptotic cell death. EXPERIMENTAL DESIGN: The rate of aggregation of the ER was monitored in ER(+) breast cancer cells lines, T47D, ZR-75.1, BT474, MDA-MB-361, MCF-7, fulvestrant resistance MCF-7, and tamoxifen-resistant T47D-cyclin D1 cells. Activation of the unfolded protein response, apoptosis, and metabolic rate were also monitored in these cell lines following treatment with fulvestrant, bortezomib, or bortezomib in combination with fulvestrant. RESULTS: We found that bortezomib enhances the fulvestrant-mediated aggregation of the ER in the cytoplasm without blocking the degradation of the ER in the nucleus. Further, these aggregates activate a sustained unfolded protein response leading to apoptotic cell death. Further, we show that the combination induced tumor regression in a breast cancer mouse model of tamoxifen resistance. CONCLUSIONS: Adding bortezomib to fulvestrant enhances its efficacy by taking advantage of the unique ability of fulvestrant to promote cytoplasmic aggregates of the ER. As this effect of fulvestrant is independent of the transcriptional activity of the ER, these results suggest that this novel combination may be effective in breast cancers that are ER(+) but estrogen independent. PMID- 21292821 TI - Arsenic accumulation and speciation in rice are affected by root aeration and variation of genotypes. AB - Root aeration, arsenic (As) accumulation, and speciation in rice of 20 different genotypes with regular irrigation of water containing 0.4 mg As l(-1) were investigated. Different genotypes had different root anatomy demonstrated by entire root porosity (ranging from 12.43% to 33.21%), which was significantly correlated with radial oxygen loss (ROL) (R=0.64, P<0.01). Arsenic accumulation differed between genotypes, but there were no significant differences between Indica and Japonica subspecies, as well as paddy and upland rice. Total ROL from entire roots was correlated with metal tolerance (expressed as percentage mean of control straw biomass, R=0.69, P<0.01) among the 20 genotypes; total As concentration (R=-0.67, P<0.01) and inorganic As concentration (R=-0.47, P<0.05) in rice grains of different genotypes were negatively correlated with ROL. There were also significant genotype effects in percentage inorganic As (F=15.8, P<0.001) and percentage cacodylic acid (F=22.1, P<0.001), respectively. Root aeration of different genotypes and variation of genotypes on As accumulation and speciation would be useful for selecting genotypes to grow in areas contaminated by As. PMID- 21292822 TI - Singleminded-2s (Sim2s) promotes delayed involution of the mouse mammary gland through suppression of Stat3 and NFkappaB. AB - Postlactational involution of the mammary gland provides a unique model to study breast cancer susceptibility and metastasis. We have shown that the short isoform of Singleminded-2s (Sim2s), a basic helix loop helix/PAS transcription factor, plays a role in promoting lactogenic differentiation, as well as maintaining mammary epithelial differentiation and malignancy. Sim2s is dynamically expressed during mammary gland development, with expression peaking during lactation, and decreasing in early involution. To determine the role of SIM2S in involution, we used transgenic mice expressing SIM2S under the mouse mammary tumor virus-Sim2s promoter. Overexpression of Sim2s in the mouse mammary gland resulted in delayed involution, indicated by a lower proportion of cleaved caspase-3-positive cells and slower reestablishment of the mammary fat pad. Immunohistochemical and quantitative RNA analysis showed a decrease in apoptotic markers and inflammatory response genes, and an increase in antiapoptotic genes, which were accompanied by inhibition of signal transducer and activator of transcription 3 activity. Microarray analysis confirmed that genes in the signal transducer and activator of transcription 3 signaling pathway were repressed by SIM2S expression, along with nuclear factor-kappaB and other key pathways involved in mammary gland development. Multiparous mouse mammary tumor virus-Sim2s females displayed a more differentiated phenotype compared with wild-type controls, characterized by enhanced beta-casein expression and alveolar structures. Together, these results suggest a role for SIM2S in the normal involuting gland and identify potential downstream pathways regulated by SIM2S. PMID- 21292823 TI - Thyroid hormone receptor alpha and regulation of type 3 deiodinase. AB - Mice deficient in thyroid hormone receptor alpha (TRalpha) display hypersensitivity to thyroid hormone (TH), with normal serum TSH but diminished serum T(4). Our aim was to determine whether altered TH metabolism played a role in this hypersensitivity. TRalpha knockout (KO) mice have lower levels of rT(3), and lower rT(3)/T(4) ratios compared with wild-type (WT) mice. These alterations could be due to increased type 1 deiodinase (D1) or decreased type 3 deiodinase (D3). No differences in D1 mRNA expression and enzymatic activity were found between WT and TRalphaKO mice. We observed that T(3) treatment increased D3 mRNA in mouse embryonic fibroblasts obtained from WT or TRbetaKO mice, but not in those from TRalphaKO mice. T(3) stimulated the promoter activity of 1.5 kb 5' flanking region of the human (h) DIO3 promoter in GH3 cells after cotransfection with hTRalpha but not with hTRbeta. Moreover, treatment of GH3 cells with T(3) increased D3 mRNA after overexpression of TRalpha. The region necessary for the T(3)-TRalpha stimulation of the hD3 promoter (region -1200 to -1369) was identified by transfection studies in Neuro2A cells that stably overexpress either TRalpha or TRbeta. These results indicate that TRalpha mediates the up regulation of D3 by TH in vitro. TRalphaKO mice display impairment in the regulation of D3 by TH in both brain and pituitary and have reduced clearance rate of TH as a consequence of D3 deregulation. We conclude that the absence of TRalpha results in decreased clearance of TH by D3 and contributes to the TH hypersensitivity. PMID- 21292824 TI - C/EBPbeta mediates growth hormone-regulated expression of multiple target genes. AB - Regulation of c-Fos transcription by GH is mediated by CCAAT/enhancer binding protein beta (C/EBPbeta). This study examines the role of C/EBPbeta in mediating GH activation of other early response genes, including Cyr61, Btg2, Socs3, Zfp36, and Socs1. C/EBPbeta depletion using short hairpin RNA impaired responsiveness of these genes to GH, as seen for c-Fos. Rescue with wild-type C/EBPbeta led to GH dependent recruitment of the coactivator p300 to the c-Fos promoter. In contrast, rescue with C/EBPbeta mutated at the ERK phosphorylation site at T188 failed to induce GH-dependent recruitment of p300, indicating that ERK-mediated phosphorylation of C/EBPbeta at T188 is required for GH-induced recruitment of p300 to c-Fos. GH also induced the occupancy of phosphorylated C/EBPbeta and p300 on Cyr61, Btg2, and Socs3 at predicted C/EBP-cAMP response element-binding protein motifs in their promoters. Consistent with a role for ERKs in GH-induced expression of these genes, treatment with U0126 to block ERK phosphorylation inhibited their GH-induced expression. In contrast, GH-dependent expression of Zfp36 and Socs1 was not inhibited by U0126. Thus, induction of multiple early response genes by GH in 3T3-F442A cells is mediated by C/EBPbeta. A subset of these genes is regulated similarly to c-Fos, through a mechanism involving GH stimulated ERK 1/2 activation, phosphorylation of C/EBPbeta, and recruitment of p300. Overall, these studies suggest that C/EBPbeta, like the signal transducer and activator of transcription proteins, regulates multiple genes in response to GH. PMID- 21292825 TI - Altered AIB1 or AIB1Delta3 expression impacts ERalpha effects on mammary gland stromal and epithelial content. AB - Amplified in breast cancer 1 (AIB1) (also known as steroid receptor coactivator 3) is a nuclear receptor coactivator enhancing estrogen receptor (ER)alpha and progesterone receptor (PR)-dependent transcription in breast cancer. The splice variant AIB1Delta3 demonstrates increased ability to promote ERalpha and PR dependent transcription. Both are implicated in breast cancer risk and antihormone resistance. Conditional transgenic mice tested the in vivo impact of AIB1Delta3 overexpression compared with AIB1 on histological features of increased breast cancer risk and growth response to estrogen and progesterone in the mammary gland. Combining expression of either AIB1 or AIB1Delta3 with ERalpha overexpression, we investigated in vivo cooperativity. AIB1 and AIB1Delta3 overexpression equivalently increased the prevalence of hyperplastic alveolar nodules but not ductal hyperplasia or collagen content. When AIB1 or AIB1Delta3 overexpression was combined with ERalpha, both stromal collagen content and ductal hyperplasia prevalence were significantly increased and adenocarcinomas appeared. Overexpression of AIB1Delta3, especially combined with overexpressed ERalpha, led to an abnormal response to estrogen and progesterone with significant increases in stromal collagen content and development of a multilayered mammary epithelium. AIB1Delta3 overexpression was associated with a significant increase in PR expression and PR downstream signaling genes. AIB1 overexpression produced less marked growth abnormalities and no significant change in PR expression. In summary, AIB1Delta3 overexpression was more potent than AIB1 overexpression in increasing stromal collagen content, inducing abnormal mammary epithelial growth, altering PR expression levels, and mediating the response to estrogen and progesterone. Combining ERalpha overexpression with either AIB1 or AIB1Delta3 overexpression augmented abnormal growth responses in both epithelial and stromal compartments. PMID- 21292826 TI - GnRH induces the c-Fos gene via phosphorylation of SRF by the calcium/calmodulin kinase II pathway. AB - Despite extensive studies on GnRH regulation of the gonadotropin subunit genes, very little is known about mechanism of induction of intermediary immediate early genes, such as c-Fos, that are direct targets of GnRH signaling and that upon induction, activate transcription of gonadotropin genes. Although c-Fos is induced by a variety of stimuli in other cell types, in the gonadotropes, only GnRH induces c-Fos and through it FSHbeta. Thus, understanding the specificity of c-Fos induction by GnRH will provide insight into GnRH regulation of FSHbeta gene expression. GnRH induction of c-Fos in LbetaT2 cells requires the serum response factor (SRF)-binding site, but not the Ets/ELK1 site. This is in contrast to c Fos induction by growth factors in other cells, which activate c-Fos transcription via phosphorylation of ELK1 and require the ELK1-binding site. The SRF site alone is sufficient for induction by GnRH, whereas induction by 12 tetradecanoylphorbol-13-acetate (TPA) requires both the ELK1 and SRF sites. Although ELK1 site is not required, upon GnRH stimulation, ELK1 interacts with SRF and is recruited to the SRF site. GnRH phosphorylates ELK1 through ERK1/2 and p38 MAPK, which correlates with the signaling pathways necessary for c-Fos and FSHbeta induction. GnRH also causes phosphorylation of SRF through calmodulin dependent kinase II (CamKII), which leads to increased binding to its site. CamKII activation is sufficient for phosphorylation of SRF and for induction of the c-Fos gene through the SRF site. Thus, GnRH uses a combination of growth factor signaling and the CamKII pathway to induce c-Fos to regulate FSHbeta gene expression in gonadotrope cells. PMID- 21292827 TI - Research resource: Update and extension of a glycoprotein hormone receptors web application. AB - The SSFA-GPHR (Sequence-Structure-Function-Analysis of Glycoprotein Hormone Receptors) database provides a comprehensive set of mutation data for the glycoprotein hormone receptors (covering the lutropin, the FSH, and the TSH receptors). Moreover, it provides a platform for comparison and investigation of these homologous receptors and helps in understanding protein malfunctions associated with several diseases. Besides extending the data set (> 1100 mutations), the database has been completely redesigned and several novel features and analysis tools have been added to the web site. These tools allow the focused extraction of semiquantitative mutant data from the GPHR subtypes and different experimental approaches. Functional and structural data of the GPHRs are now linked interactively at the web interface, and new tools for data visualization (on three-dimensional protein structures) are provided. The interpretation of functional findings is supported by receptor morphings simulating intramolecular changes during the activation process, which thus help to trace the potential function of each amino acid and provide clues to the local structural environment, including potentially relocated spatial counterpart residues. Furthermore, double and triple mutations are newly included to allow the analysis of their functional effects related to their spatial interrelationship in structures or homology models. A new important feature is the search option and data visualization by interactive and user-defined snake plots. These new tools allow fast and easy searches for specific functional data and thereby give deeper insights in the mechanisms of hormone binding, signal transduction, and signaling regulation. The web application "Sequence-Structure Function-Analysis of GPHRs" is accessible on the internet at http://www.ssfa gphr.de/. PMID- 21292828 TI - TNF is necessary for castration-induced prostate regression, whereas TRAIL and FasL are dispensable. AB - TNF, a proinflammatory and immune-regulatory cytokine, is a potent apoptotic stimulus in vitro. However, there have been few examples of a physiologic role for TNF-induced apoptosis in vivo. Here, we describe a novel role for TNF in prostate epithelial cell apoptosis after androgen withdrawal. Employing high resolution serial magnetic resonance imaging to measure mouse prostate volume changes over time, we demonstrate that the extent of castration-induced prostate regression is significantly reduced in mice null for either the Tnf or Tnfr1 genes but not mice deficient for TNF-related apoptosis-inducing ligand or Fas signaling. Wild-type mice receiving soluble TNF (sTNF) receptor 2 (to bind TNF and block signaling) before castration exhibit an identical reduction of prostate regression. Together, these data indicate that uniquely among known extrinsic death signals, TNF is required for castration-induced prostate regression. Additionally, membrane-bound TNF protein and stromal cell specific TNF mRNA levels increase in rat prostate after castration. This is consistent with a paracrine role for TNF in prostate regression. When injected into the peritoneum of Tnf(-/-) mice at the time of castration, sTNF restores normal levels of prostate regression. However, wild-type mice receiving sTNF in the absence of castration do not exhibit prostate regression, indicating that TNF alone is not sufficient but acts in the context of additional castration-induced signals. These findings support a physiologic role for TNF in prostate regression after androgen withdrawal. Understanding this role may lead to novel therapies for prostate cancer. PMID- 21292829 TI - The IGF pathway regulates ERalpha through a S6K1-dependent mechanism in breast cancer cells. AB - The IGF pathway stimulates malignant behavior of breast cancer cells. Herein we identify the mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) axis as a critical component of IGF and estrogen receptor (ER)alpha cross talk. The insulin receptor substrate (IRS) adaptor molecules function downstream of IGF-I receptor and dictate a specific biological response, in which IRS-1 drives proliferation and IRS-2 is linked to motility. Although rapamycin-induced mTOR inhibition has been shown to block IGF-induced IRS degradation, we reveal differential effects on motility (up-regulation) and proliferation (down-regulation). Because a positive correlation between IRS-1 and ERalpha expression is thought to play a central role in the IGF growth response, we investigated the potential role of ERalpha as a downstream mTOR target. Small molecule inhibition and targeted knockdown of S6K1 blocked the IGF-induced ERalpha(S167) phosphorylation and did not influence ligand-dependent ERalpha(S118) phosphorylation. Inhibition of S6K1 kinase activity consequently ablated IGF-stimulated S6K1/ERalpha association, estrogen response element promoter binding and ERalpha target gene transcription. Moreover, site-specific ERalpha(S167) mutation reduced ERalpha target gene transcription and blocked IGF-induced colony formation. These findings support a novel link between the IGF pathway and ERalpha, in which the translation factor S6K1 affects transcription of ERalpha-regulated genes. PMID- 21292830 TI - Species-specific strategies underlying conserved functions of metabolic transcription factors. AB - The winged helix protein FOXA2 and the nuclear receptor peroxisome proliferator activated receptor-gamma (PPARgamma) are highly conserved, regionally expressed transcription factors (TFs) that regulate networks of genes controlling complex metabolic functions. Cistrome analysis for Foxa2 in mouse liver and PPARgamma in mouse adipocytes has previously produced consensus-binding sites that are nearly identical to those used by the corresponding TFs in human cells. We report here that, despite the conservation of the canonical binding motif, the great majority of binding regions for FOXA2 in human liver and for PPARgamma in human adipocytes are not in the orthologous locations corresponding to the mouse genome, and vice versa. Of note, TF binding can be absent in one species despite sequence conservation, including motifs that do support binding in the other species, demonstrating a major limitation of in silico binding site prediction. Whereas only approximately 10% of binding sites are conserved, gene-centric analysis reveals that about 50% of genes with nearby TF occupancy are shared across species for both hepatic FOXA2 and adipocyte PPARgamma. Remarkably, for both TFs, many of the shared genes function in tissue-specific metabolic pathways, whereas species-unique genes fail to show enrichment for these pathways. Nonetheless, the species-unique genes, like the shared genes, showed the expected transcriptional regulation by the TFs in loss-of-function experiments. Thus, species-specific strategies underlie the biological functions of metabolic TFs that are highly conserved across mammalian species. Analysis of factor binding in multiple species may be necessary to distinguish apparent species-unique noise and reveal functionally relevant information. PMID- 21292831 TI - Spatial non-homogeneity of the antagonistic surround in motion perception. AB - At high contrast, duration thresholds for motion direction discrimination deteriorate with increasing stimulus size. This counterintuitive result has been explained by the center-surround antagonism present in the neurons of visual area MT. Conversely, at very low contrast, direction discrimination improves with increasing size, a result that has been explained by spatial summation. In this investigation, we study the effects of stimulus shape and contrast on center surround antagonism. Using adaptive Bayesian staircases, we measured duration thresholds of 5 subjects for vertically oriented Gabor patches of 1 cycle/deg with two types of oval Gaussian windows, one vertically elongated (Sx = 0.35, Sy = 2.5 deg) and other horizontally elongated (Sx = 2.5, Sy = 0.35 deg) moving rightward or leftward at a speed of 2 deg/s. We found that at high contrast (92%) duration thresholds were lower for vertically than horizontally elongated windows. However, at low contrast (2.8%), we found that duration thresholds were lower for horizontally than vertically elongated windows. These asymmetric results mirror the spatial non-homogeneity of the antagonistic surround found in MT neurons and suggest that the underlying center-surround antagonism is stronger along the direction of motion. PMID- 21292832 TI - New remission criteria for RA: 'modern times' in rheumatology--not a silent film, rather a 3D movie. PMID- 21292833 TI - American College of Rheumatology/European League against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. AB - OBJECTIVE: Remission in rheumatoid arthritis (RA) is an increasingly attainable goal, but there is no widely used definition of remission that is stringent but achievable and could be applied uniformly as an outcome measure in clinical trials. This work was undertaken to develop such a definition. METHODS: A committee consisting of members of the American College of Rheumatology, the European League Against Rheumatism, and the Outcome Measures in Rheumatology Initiative met to guide the process and review prespecified analyses from RA clinical trials. The committee requested a stringent definition (little, if any, active disease) and decided to use core set measures including, as a minimum, joint counts and levels of an acute-phase reactant to define remission. Members were surveyed to select the level of each core set measure that would be consistent with remission. Candidate definitions of remission were tested, including those that constituted a number of individual measures of remission (Boolean approach) as well as definitions using disease activity indexes. To select a definition of remission, trial data were analysed to examine the added contribution of patient-reported outcomes and the ability of candidate measures to predict later good radiographic and functional outcomes. RESULTS: Survey results for the definition of remission suggested indexes at published thresholds and a count of core set measures, with each measure scored as 1 or less (eg, tender and swollen joint counts, C reactive protein (CRP) level, and global assessments on a 0-10 scale). Analyses suggested the need to include a patient reported measure. Examination of 2-year follow-up data suggested that many candidate definitions performed comparably in terms of predicting later good radiographic and functional outcomes, although 28-joint Disease Activity Score based measures of remission did not predict good radiographic outcomes as well as the other candidate definitions did. Given these and other considerations, we propose that a patient's RA can be defined as being in remission based on one of two definitions: (1) when scores on the tender joint count, swollen joint count, CRP (in mg/dl), and patient global assessment (0-10 scale) are all <=1, or (2) when the score on the Simplified Disease Activity Index is <=3.3. CONCLUSION: We propose two new definitions of remission, both of which can be uniformly applied and widely used in RA clinical trials. The authors recommend that one of these be selected as an outcome measure in each trial and that the results on both be reported for each trial. PMID- 21292834 TI - Eplerenone suppresses aldosterone/ salt-induced expression of NOX-4. AB - INTRODUCTION: Salt-induced hypertension in the Dahl rat is associated with increases in angiotensin II, aldosterone, free radical generation and endothelial dysfunction. However, little is known about the specific mechanism(s) associated with the end-organ damage effects of aldosterone. We hypothesised that eplerenone reduces kidney damage by blocking nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. METHODS: Dahl salt-sensitive rats fed either a low-salt (LS) or high-salt (HS) diet were treated with aldosterone in the presence of eplerenone or apocynin. Indirect blood pressure was measured prior to start of diet and weekly thereafter. Levels of plasma nitric oxide (NO) and urinary 8 isoprostane were measured following treatment. Protein levels of selected subunits of NADPH were assessed by western blot. RESULTS: Eplerenone and apocynin inhibited the rise in blood pressure induced by HS and/or aldosterone. This observation was accompanied with a parallel change in kidney protein levels of NADPH oxidase 4 (NOX-4) and p22phox. Aldosterone and high salt were associated with lower NO levels and greater renal oxidative stress. CONCLUSIONS: NADPH oxidase is associated with the vascular and renal remodelling observed in high dietary salt intake. Aldosterone-induced expression of NOX-4 plays a pivotal role in the end-organ damage effect of aldosterone, as eplerenone tended to reduce kidney damage and inhibit NOX expression. PMID- 21292835 TI - Contribution of arterial Windkessel in low-frequency cerebral hemodynamics during transient changes in blood pressure. AB - The Windkessel properties of the vasculature are known to play a significant role in buffering arterial pulsations, but their potential importance in dampening low frequency fluctuations in cerebral blood flow has not been clearly examined. In this study, we quantitatively assessed the contribution of arterial Windkessel (peripheral compliance and resistance) in the dynamic cerebral blood flow response to relatively large and acute changes in blood pressure. Middle cerebral artery flow velocity (MCA(V); transcranial Doppler) and arterial blood pressure were recorded from 14 healthy subjects. Low-pass-filtered pressure-flow responses (<0.15 Hz) during transient hypertension (intravenous phenylephrine) and hypotension (intravenous sodium nitroprusside) were fitted to a two-element Windkessel model. The Windkessel model was found to provide a superior goodness of fit to the MCA(V) responses during both hypertension and hypotension (R2 = 0.89 +/- 0.03 and 0.85 +/- 0.05, respectively), with a significant improvement in adjusted coefficients of determination (P < 0.005) compared with the single resistance model (R2 = 0.62 +/- 0.06 and 0.61 +/- 0.08, respectively). No differences were found between the two interventions in the Windkessel capacitive and resistive gains, suggesting similar vascular properties during pressure rise and fall episodes. The results highlight that low-frequency cerebral hemodynamic responses to transient hypertension and hypotension may include a significant contribution from the mechanical properties of vasculature and, thus, cannot solely be attributed to the active control of vascular tone by cerebral autoregulation. The arterial Windkessel should be regarded as an important element of dynamic cerebral blood flow modulation during large and acute blood pressure perturbation. PMID- 21292836 TI - Endogenous reactive oxygen species modulates voltage-gated sodium channels in dorsal root ganglia of rats. AB - We recently reported that reactive oxygen species (ROS) plays an excitatory role in modulation of the exercise pressor reflex (EPR) in normal rats. In this study, we further tested two independent hypotheses: 1) ROS interacts with EPR-related ionotropic receptors such as the purinergic receptors (P(2)) and transient receptor potential vanilloid 1 receptors (TRPV1) to indirectly modulate the EPR function; 2) ROS directly affects excitability of muscle afferents by modulating the voltage-gated sodium (Na(v)) channels. To test the first hypothesis, we performed animal experiments to investigate the effect of the SOD mimetic 4 hydroxy-2,2,6,6-tetramethyl piperidine 1-oxyl (Tempol) on the pressor response to hindlimb intra-arterial (IA) injection of either alpha,beta-methylene ATP (a P(2X) agonist) or capsaicin (a TRPV1 agonist) in decerebrate rats. To test the second hypothesis, we used the patch-clamp technique to determine the effect of ROS on Na(v) channels on the soma of muscle afferents. We also performed local microinjection of a sodium channel blocker, tetrodotoxin (TTX), into ipsilateral L4/L5 dorsal root ganglia (DRGs) to investigate whether the blockade of Na(v) channels by TTX affects the EPR function. We found that Tempol did not affect the pressor response to injection of either capsaicin or alpha,beta-methylene ATP but significantly decreased the Na(v) current in small and medium-sized 1,1' dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI)-labeled DRG neurons. A membrane-permeant superoxide dismutase, polyethylene glycol (PEG)-SOD, had an effect on the Na(v) current in these neurons similar to that of Tempol. Microinjection of TTX into L4/L5 DRGs dramatically attenuated the pressor response to static contraction induced by electrical stimulation of L4/L5 ventral roots. These data suggest that ROS modulates the EPR by affecting the activity of the Na(v) channels on muscle afferents. PMID- 21292837 TI - Antagonism of soluble guanylyl cyclase attenuates cutaneous vasodilation during whole body heat stress and local warming in humans. AB - We hypothesized that nitric oxide activation of soluble guanylyl cyclase (sGC) participates in cutaneous vasodilation during whole body heat stress and local skin warming. We examined the effects of the sGC inhibitor, 1H [1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), on reflex skin blood flow responses to whole body heat stress and on nonreflex responses to increased local skin temperature. Blood flow was monitored by laser-Doppler flowmetry, and blood pressure by Finapres to calculate cutaneous vascular conductance (CVC). Intradermal microdialysis was used to treat one site with 1 mM ODQ in 2% DMSO and Ringer, a second site with 2% DMSO in Ringer, and a third site received Ringer. In protocol 1, after a period of normothermia, whole body heat stress was induced. In protocol 2, local heating units warmed local skin temperature from 34 to 41 degrees C to cause local vasodilation. In protocol 1, in normothermia, CVC did not differ among sites [ODQ, 15 +/- 3% maximum CVC (CVC(max)); DMSO, 14 +/- 3% CVC(max); Ringer, 17 +/- 6% CVC(max); P > 0.05]. During heat stress, ODQ attenuated CVC increases (ODQ, 54 +/- 4% CVC(max); DMSO, 64 +/- 4% CVC(max); Ringer, 63 +/- 4% CVC(max); P < 0.05, ODQ vs. DMSO or Ringer). In protocol 2, at 34 degrees C local temperature, CVC did not differ among sites (ODQ, 17 +/- 2% CVC(max); DMSO, 18 +/- 4% CVC(max); Ringer, 18 +/- 3% CVC(max); P > 0.05). ODQ attenuated CVC increases at 41 degrees C local temperature (ODQ, 54 +/- 5% CVC(max); DMSO, 86 +/- 4% CVC(max); Ringer, 90 +/- 2% CVC(max); P < 0.05 ODQ vs. DMSO or Ringer). sGC participates in neurogenic active vasodilation during heat stress and in the local response to direct skin warming. PMID- 21292838 TI - Contribution of adenosine to compensatory dilation in hypoperfused contracting human muscles is independent of nitric oxide. AB - We previously demonstrated that nitric oxide (NO) contributes to compensatory vasodilation in the contracting human forearm subjected to acute hypoperfusion. We examined the potential role of an adenosine-NO interaction to this response in 17 male subjects (25 +/- 2 yr). In separate protocols subjects performed rhythmic forearm exercise (20% of maximum) while hypoperfusion was evoked by balloon inflation in the brachial artery above the elbow. Each trial included exercise before inflation, exercise with inflation, and exercise after deflation (3 min each). Forearm blood flow (FBF; ultrasound) and local [brachial artery catheter pressure (BAP)] and systemic [mean arterial pressure (MAP); Finometer] arterial pressure were measured. In protocol 1 (n = 10), exercise was repeated during nitric oxide synthase inhibition [N(G)-monomethyl-L-arginine (L-NMMA)] alone and during L-NMMA-aminophylline (adenosine receptor blockade) administration. In protocol 2, exercise was repeated during aminophylline alone and during aminophylline-L-NMMA. Forearm vascular conductance (FVC; ml.min(-1).100 mmHg(-1)) was calculated from blood flow (ml/min) and BAP (mmHg). Percent recovery in FVC during inflation was calculated as (steady-state inflation + exercise value - nadir)/[steady-state exercise (control) value - nadir]. In protocol 1, percent recovery in FVC was 108 +/- 8% during the control (no drug) trial. Percent recovery in FVC was attenuated with inhibition of NO formation alone (78 +/- 9%; P < 0.01 vs. control) and was attenuated further with combined inhibition of NO and adenosine (58 +/- 9%; P < 0.01 vs. L-NMMA). In protocol 2, percent recovery was reduced with adenosine receptor blockade (74 +/- 11% vs. 113 +/- 6%, P < 0.01) compared with control drug trials. Percent recovery in FVC was attenuated further with combined inhibition of adenosine and NO (48 +/- 11%; P < 0.05 vs. aminophylline). Our data indicate that adenosine contributes to compensatory vasodilation in an NO-independent manner during exercise with acute hypoperfusion. PMID- 21292839 TI - Biological aortic age derived from the arterial pressure waveform. AB - Indexes for arterial stiffness are, by their nature, influenced by the ambient blood pressure due to the curvilinear nature of arterial compliance. We developed a new concept of the "Modelflow aortic age," which is, theoretically, not influenced by the ambient blood pressure and provides an easily understood context (biological vs. chronological age) for measures of arterial stiffness. The purpose of the present study was to validate this pressure-independent index for aortic stiffness in humans. Twelve sedentary elderly (65-77 yr), 11 Masters athletes (65-73 yr), and 12 sedentary young individuals (20-42 yr) were studied. Modelflow aortic ages were comparable with chronological ages in both sedentary groups, indicating that healthy sedentary individuals have age-appropriate aortas. In contrast, Masters athletes showed younger Modelflow aortic ages than their chronological ages. The coefficient of variation of sedentary subjects was three times smaller with the Modelflow aortic age (21%) than with other indexes, such as static systemic arterial stiffness (61%), central pulse wave velocity (61%), or carotid beta-stiffness index (58%). The typical error was very small and two times smaller in the Modelflow aortic age (<7%) than in static systemic arterial stiffness (>13%) during cardiac unloading by lower body negative pressure. The Modelflow aortic age can more precisely and reliably estimate aortic stiffening with aging and modifiers, such as life-long exercise training compared with the pressure-dependent index of static systemic arterial stiffness, and provides a physiologically relevant and clinically compelling context for such measurements. PMID- 21292840 TI - Emergent behavior of regional heterogeneity in the lung and its effects on respiratory impedance. AB - The ability to maintain adequate gas exchange depends on the relatively homogeneous distribution of inhaled gas throughout the lung. Structural alterations associated with many respiratory diseases may significantly depress this function during tidal breathing. These alterations frequently occur in a heterogeneous manner due to complex, emergent interactions among the many constitutive elements of the airways and parenchyma, resulting in unique signature changes in the mechanical impedance spectrum of the lungs and total respiratory system as measured by forced oscillations techniques (FOT). When such impedance spectra are characterized by appropriate inverse models, one may obtain functional insight into derangements in global respiratory mechanics. In this review, we provide an overview of the impact of structural heterogeneity with respect to dynamic lung function. Recent studies linking functional impedance measurements to the structural heterogeneity observed in acute lung injury, asthma, and chronic obstructive pulmonary disease are highlighted, as well as current approaches for the modeling and interpretation of impedance. Finally, we discuss the potential diagnostic role of FOT in the context of therapeutic interventions. PMID- 21292841 TI - Bouncing to conclusions: clear evidence for the metabolic cost of generating muscular force. PMID- 21292842 TI - Multi-scale lung modeling. AB - Multi-scale modeling of biological systems has recently become fashionable due to the growing power of digital computers as well as to the growing realization that integrative systems behavior is as important to life as is the genome. While it is true that the behavior of a living organism must ultimately be traceable to all its components and their myriad interactions, attempting to codify this in its entirety in a model misses the insights gained from understanding how collections of system components at one level of scale conspire to produce qualitatively different behavior at higher levels. The essence of multi-scale modeling thus lies not in the inclusion of every conceivable biological detail, but rather in the judicious selection of emergent phenomena appropriate to the level of scale being modeled. These principles are exemplified in recent computational models of the lung. Airways responsiveness, for example, is an organ-level manifestation of events that begin at the molecular level within airway smooth muscle cells, yet it is not necessary to invoke all these molecular events to accurately describe the contraction dynamics of a cell, nor is it necessary to invoke all phenomena observable at the level of the cell to account for the changes in overall lung function that occur following methacholine challenge. Similarly, the regulation of pulmonary vascular tone has complex origins within the individual smooth muscle cells that line the blood vessels but, again, many of the fine details of cell behavior average out at the level of the organ to produce an effect on pulmonary vascular pressure that can be described in much simpler terms. The art of multi-scale lung modeling thus reduces not to being limitlessly inclusive, but rather to knowing what biological details to leave out. PMID- 21292843 TI - Can muscle size fully account for strength differences between children and adults? PMID- 21292844 TI - Oxygen-dependent quenching of phosphorescence used to characterize improved myocardial oxygenation resulting from vasculogenic cytokine therapy. AB - This study evaluates a therapy for infarct modulation and acute myocardial rescue and utilizes a novel technique to measure local myocardial oxygenation in vivo. Bone marrow-derived endothelial progenitor cells (EPCs) were targeted to the heart with peri-infarct intramyocardial injection of the potent EPC chemokine stromal cell-derived factor 1alpha (SDF). Myocardial oxygen pressure was assessed using a noninvasive, real-time optical technique for measuring oxygen pressures within microvasculature based on the oxygen-dependent quenching of the phosphorescence of Oxyphor G3. Myocardial infarction was induced in male Wistar rats (n = 15) through left anterior descending coronary artery ligation. At the time of infarction, animals were randomized into two groups: saline control (n = 8) and treatment with SDF (n = 7). After 48 h, the animals underwent repeat thoracotomy and 20 MUl of the phosphor Oxyphor G3 was injected into three areas (peri-infarct myocardium, myocardial scar, and remote left hindlimb muscle). Measurements of the oxygen distribution within the tissue were then made in vivo by applying the end of a light guide to the beating heart. Compared with controls, animals in the SDF group exhibited a significantly decreased percentage of hypoxic (defined as oxygen pressure <= 15.0 Torr) peri-infarct myocardium (9.7 +/- 6.7% vs. 21.8 +/- 11.9%, P = 0.017). The peak oxygen pressures in the peri infarct region of the animals in the SDF group were significantly higher than the saline controls (39.5 +/- 36.7 vs. 9.2 +/- 8.6 Torr, P = 0.02). This strategy for targeting EPCs to vulnerable peri-infarct myocardium via the potent chemokine SDF 1alpha significantly decreased the degree of hypoxia in peri-infarct myocardium as measured in vivo by phosphorescence quenching. This effect could potentially mitigate the vicious cycle of myocyte death, myocardial fibrosis, progressive ventricular dilatation, and eventual heart failure seen after acute myocardial infarction. PMID- 21292845 TI - The interdependent contributions of gravitational and structural features to perfusion distribution in a multiscale model of the pulmonary circulation. AB - Recent experimental and imaging studies suggest that the influence of gravity on the measured distribution of blood flow in the lung is largely through deformation of the parenchymal tissue. To study the contribution of hydrostatic effects to regional perfusion in the presence of tissue deformation, we have developed an anatomically structured computational model of the pulmonary circulation (arteries, capillaries, veins), coupled to a continuum model of tissue deformation, and including scale-appropriate fluid dynamics for blood flow in each vessel type. The model demonstrates that both structural and the multiple effects of gravity on the pulmonary circulation make a distinct contribution to the distribution of blood. It shows that postural differences in perfusion gradients can be explained by the combined effect of tissue deformation and extra acinar blood vessel resistance to flow in the dependent tissue. However, gravitational perfusion gradients persist when the effect of tissue deformation is eliminated, highlighting the importance of the hydrostatic effects of gravity on blood distribution in the pulmonary circulation. Coupling of large- and small scale models reveals variation in microcirculatory driving pressures within isogravitational planes due to extra-acinar vessel resistance. Variation in driving pressures is due to heterogeneous large-vessel resistance as a consequence of geometric asymmetry in the vascular trees and is amplified by the complex balance of pressures, distension, and flow at the microcirculatory level. PMID- 21292846 TI - Temporal complexity in clinical manifestations of lung disease. AB - In this review, we summarize results of recent research on the temporal variability of lung function, symptoms, and inflammatory biomarkers. Specifically, we demonstrate how fluctuation analysis borrowed from statistical physics can be used to gain insight into neurorespiratory control and complex chronic dynamic diseases such as asthma viewed as a system of interacting components (e.g., inflammatory, immunological, and mechanical). Fluctuation analysis tools are based on quantifying the distribution and the short- and long term temporal history of tidal breathing and lung function parameters to assess neurorespiratory control and monitor chronic disease. The latter includes the assessment of severity and disease control, the impact of treatment and environmental triggers, the temporal characterization of disease phenotypes, and the individual risk of exacerbation. While in many cases specific mechanistic insight into the fluctuations still awaits further research, appropriate analyses of the fluctuations already impact on clinical science and practice. PMID- 21292847 TI - Effect of calorie restriction on the free-living physical activity levels of nonobese humans: results of three randomized trials. AB - The objective of this study was to evaluate the influence of calorie restriction (CR) on free-living physical activity levels among humans. Data were from three CALERIE phase I site-specific protocols. Participants were nonobese (body mass index = 23.5-29.9 kg/m2 adults randomly assigned to 25% CR, low-calorie diet (LCD, 890 kcal/day supplement diet until 15% weight loss, then weight maintenance), or control at Pennington Biomedical Research Center (PBRC); 30% or 10% CR at Tufts University; and 20% CR or control at Washington University School of Medicine (WUSM). Activity was measured at months 0, 3, and 6 (PBRC) and at months 0, 3, 6, 9, and 12 (WUSM and Tufts). Total daily energy expenditure (TEE) by doubly labeled water and resting metabolic rate (RMR) were used to compute activity energy expenditure: AEE = TEE - RMR - 0.1 * TEE. Accelerometry and 7-day recall categorized activities by intensity. At Tufts, the 10% and 30% CR groups experienced significant decreases in AEE at months 6, 9, and 12. At month 6, a larger decrease in AEE was observed in the CR than the control group at WUSM. At months 3 and 6, larger decreases in AEE were observed in the CR and LCD groups than the control group at PBRC. Accelerometry and 7-day PAR did not consistently detect changes in activity categories. CR-associated changes in AEE were variable but, generally, reduced the energy deficit, which would reduce the expected rate of weight loss. Accelerometry and recall did not consistently explain reduced AEE, suggesting that increased muscle efficiency and/or decreased fidgeting accounted for decreased AEE. Inaccuracy of accelerometry and recall also likely negatively affected sensitivity. PMID- 21292848 TI - Prevention and control of phosphate retention/hyperphosphatemia in CKD-MBD: what is normal, when to start, and how to treat? AB - Phosphate retention and, later, hyperphosphatemia are key contributors to chronic kidney disease (CKD)-mineral and bone disorder (MBD). Phosphate homeostatic mechanisms maintain normal phosphorus levels until late-stage CKD, because of early increases in parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF 23). Increased serum phosphorus, and these other mineral abnormalities, individually and collectively contribute to bone disease, vascular calcification, and cardiovascular disease. Earlier phosphate control may, therefore, help reduce the early clinical consequences of CKD-MBD, and help control hyperphosphatemia and secondary hyperparathyroidism in late-stage CKD. Indeed, it is now widely accepted that achieving normal phosphorus levels is associated with distinct clinical benefits. This therapeutic goal is achievable in CKD stages 3 to 5 but more difficult in dialysis patients. Currently, phosphate control is only initiated when hyperphosphatemia occurs, but a potentially beneficial and simple approach may be to intervene earlier, for example, when tubular phosphate reabsorption is substantially diminished. Early CKD-MBD management includes dietary phosphate restriction, phosphate binder therapy, and vitamin D supplementation. Directly treating phosphorus may be the most beneficial approach because this can reduce serum phosphorus, PTH, and FGF-23. This involves dietary measures, but these are not always sufficient, and it can be more effective to also consider phosphate binder use. Vitamin D sterols can improve vitamin D deficiency and PTH levels but may worsen phosphate retention and increase FGF-23 levels, and thus, may also require concomitant phosphate binder therapy. This article discusses when and how to optimize phosphate control to provide the best clinical outcomes in CKD-MBD patients. PMID- 21292849 TI - Source matters: from phosphorus load to bioavailability. PMID- 21292850 TI - World Kidney Day 2011: protect your kidneys, save your heart. PMID- 21292851 TI - Fetal awareness and fetal pain: the emperor's new clothes. PMID- 21292852 TI - Detecting rare thrombophilia variants by high-resolution melting. PMID- 21292853 TI - Rifaximin disc diffusion test for in vitro susceptibility testing of Clostridium difficile. AB - Rifaximin is a rifampicin derivative, poorly absorbed by the gastro-intestinal tract. We studied the in vitro susceptibility to rifamixin of 1082 Clostridium difficile isolates; among these, 184 isolates from a strain collection were tested by an in-house rifaximin disc (40 ug) diffusion test, by an in-house rifaximin broth microdilution test, by rifampicin Etest and by rpoB gene sequencing. In the absence of respective CLSI or EUCAST MIC breakpoints for rifaximin and rifampicin against C. difficile we chose MIC >=32 ug ml(-1) as criterion for reduced in vitro susceptibility. To further validate the disc diffusion test 898 consecutive clinical isolates were analysed using the disc diffusion test, the Etest and rpoB gene sequence analysis for all resistant strains. Rifaximin broth microdilution tests of the 184 reference strains yielded rifaximin MICs ranging from 0.001 (n = 1) to >=1024 ug ml(-1) (n = 61); 62 isolates showed a reduced susceptibility (MIC >=32 ug ml(-1)). All of these 62 strains showed rpoB gene mutations producing amino acid substitutions; the rifampicin- and rifaximin-susceptible strains showed either a wild-type sequence or silent amino acid substitutions (19 strains). For 11 arbitrarily chosen isolates with rifaximin MICs of >1024 ug ml(-1), rifaximin end-point MICs were determined by broth dilution: 4096 ug ml(-1) (n = 2), 8192 ug ml(-1) (n = 6), 16,384 ug ml(-1) (n = 2) and 32,678 ug ml(-1) (n = 1). Rifampicin Etests on the 184 C. difficile reference strains yielded MICs ranging from <=0.002 (n = 117) to >=32 ug ml(-1) (n = 59). Using a 38 mm inhibition zone as breakpoint for reduced susceptibility the use of rifaximin disc diffusion yielded 59 results correlating with those obtained by use of rifaximin broth microdilution in 98.4 % of the 184 strains tested. Rifampicin Etests performed on the 898 clinical isolates revealed that 67 isolates had MICs of >=32 ug ml(-1). There were no discordant results observed among these isolates with reduced susceptibility using an MIC of >=32 ug ml(-1) as breakpoint for reduced rifampicin susceptibility and a <38 mm inhibition zone as breakpoint for reduced rifaximin susceptibility. The prevalence of reduced susceptibility was 7.5 % for all isolates tested. However, for PCR ribotype 027 the prevalence of reduced susceptibility was 26 %. Susceptibility testing in the microbiology laboratory therefore could have an impact on the care and outcome of patients with infection. Our results show that rifaximin--despite its water-insolubility--may be a suitable candidate for disc diffusion testing. PMID- 21292854 TI - Population structure and uropathogenic virulence-associated genes of faecal Escherichia coli from healthy young and elderly adults. AB - We investigated the population structures of faecal Escherichia coli in 30 healthy young adults (13 males and 17 females) aged between 20 and 45 years and 29 elderly adults (14 females and 15 males) aged between 65 and 77 years. In all, 1566 strains were typed with the PhPlate system and grouped into biochemical phenotypes (BPTs). Strains with shared BPTs were further typed using randomly amplified polymorphic DNA analysis. Forty-four per cent of the strains were shared between two or more age and gender groups. Elders had a significantly higher (P<0.001) number of BPTs (mean+/-standard error 3.3+/-0.27) than younger groups (1.82+/-0.27). Phylogenetic affiliation and virulence-associated genes (VAGs) of the strains showed that more than 80 % of the strains belonging to dominant types belonged to phylogroups B2 and D. Amongst dominant BPTs, phylogenetic group A was significantly associated with females (P<0.0001), and elders were more likely to carry group D (P<0.0124). Elderly males had a higher prevalence of VAGs than young males (P<0.0001) and young females (P<0.0005). We conclude that there is a lower prevalence of E. coli with uropathogenic properties in healthy young adults than in elders. PMID- 21292855 TI - Sequence type 38 Escherichia coli carrying bla(CTX-M-14). PMID- 21292856 TI - Detection and characterization of an ST97-SCCmec-V community-associated meticillin-resistant Staphylococcus aureus clone in a neonatal intensive care unit and special care baby unit. AB - A total of 29 meticillin-resistant Staphylococcus aureus (MRSA) isolates were obtained from 15 neonates and three healthcare workers (HCWs) in a neonatal intensive care unit (NICU) and special care baby unit (SCBU) and four patients in a medical ward of a Kuwait hospital between 10 and 30 April 2007. The isolates were characterized using antibiogram results, coagulase gene RFLP (coa-RFLP), PFGE, staphylococcal cassette chromosome mec (SCCmec) typing and multilocus sequence typing (MLST). All isolates were assessed for the carriage of Panton Valentine leukocidin (PVL) and arginine catabolic mobile element (ACME) genes. The isolates belonged to three SCCmec types, six coa-RFLP types, six pulsotypes and six sequence types. One isolate was positive for PVL. None were positive for ACME. All MRSA isolates from the 15 neonates were phenotypically and genetically different from the MRSA isolates obtained from HCWs and those from patients in other wards. They were resistant to gentamicin, kanamycin and fusidic acid, had identical coa-RFLP and PFGE patterns, carried the type V SCCmec element and belonged to MLST sequence type ST97. The results showed the transmission of a rare clone of community-associated MRSA belonging to ST97 with the SCCmec-V genotype among neonates in a NICU and SCBU. PMID- 21292857 TI - Analysis of risk factors for a high prevalence of extended-spectrum {beta} lactamase-producing Enterobacteriaceae in asymptomatic individuals in rural Thailand. AB - The prevalence of and risk factors associated with extended-spectrum beta lactamase (ESBL)-producing micro-organisms have not been well studied in healthy individuals. The aim of this study was to determine this in healthy individuals in Thailand. Stool samples and questionnaires obtained from 445 participants from three provinces in Thailand were analysed. The antimicrobial susceptibility of the isolates was assessed using phenotypic and genotypic methods. PCR analysis was performed to detect and group the bla(CTX-M) genes. The prevalence of CTX-M type ESBL-producing Enterobacteriaceae in the three provinces was as follows: 29.3 % in Nan (43/147), 29.9 % in Nakhon Si Thammarat (43/144) and 50.6 % in Kanchanaburi (78/154) (P<0.001). Of the 445 samples, 33 (7.4 %), 1 (0.2 %) and 127 (28.5 %) isolates belonged to the bla(CTX-M) gene groups I, III and IV, respectively. Escherichia coli was the predominant member of the Enterobacteriaceae producing CTX-M-type ESBLs (40/43, 39/43 and 70/78 isolates in Nan, Nakhon Si Thammarat and Kanchanaburi, respectively). No statistically significant association was observed between the presence of ESBL-producing bacteria and gender, age, education, food habits or antibiotic usage. However, the provinces that had the highest prevalence of ESBL-producing Enterobacteriaceae also had the highest prevalence of use and purchase of antibiotics without a prescription. Thus, this study revealed that faecal carriage of ESBL-producing Enterobacteriaceae is very high in asymptomatic individuals in Thailand, with some variations among the provinces. This high prevalence may be linked to antibiotic abuse. PMID- 21292858 TI - Alanine-scanning mutagenesis of selected residues in the N-terminal region alters the functionality of LuxO: lessons from a natural variant LuxOPL91. PMID- 21292859 TI - Phylogenetic relationships of Shiga toxin-producing Escherichia coli isolated from Peruvian children. AB - The aim of this study was to determine the prevalence, virulence factors (stx, eae, ehxA and astA) and phylogenetic relationships [PFGE and multilocus sequence typing (MLST)] of Shiga toxin-producing Escherichia coli (STEC) strains isolated from four previous cohort studies in 2212 Peruvian children aged <36 months. STEC prevalence was 0.4 % (14/3219) in diarrhoeal and 0.6 % (15/2695) in control samples. None of the infected children developed haemolytic uraemic syndrome (HUS) or other complications of STEC. stx1 was present in 83 % of strains, stx2 in 17 %, eae in 72 %, ehxA in 59 % and astA in 14 %. The most common serotype was O26 : H11 (14 %) and the most common seropathotype was B (45 %). The strains belonged mainly to phylogenetic group B1 (52 %). The distinct combinations of alleles across the seven MLST loci were used to define 13 sequence types among 19 STEC strains. PFGE typing of 20 STEC strains resulted in 19 pulsed-field patterns. Comparison of the patterns revealed 11 clusters (I-XI), each usually including strains belonging to different serotypes; one exception was cluster VI, which gathered exclusively seven strains of seropathotype B, clonal group enterohaemorrhagic E. coli (EHEC) 2 and phylogenetic group B1. In summary, STEC prevalence was low in Peruvian children with diarrhoea in the community setting. The strains were phylogenetically diverse and associated with mild infections. However, additional studies are needed in children with bloody diarrhoea and HUS. PMID- 21292860 TI - Diagnostic utility of boronic acid inhibition with different cephalosporins against Escherichia coli producing AmpC beta-lactamases. PMID- 21292861 TI - Categorical agreements and discrepancies of direct susceptibility tests in Acinetobacter from blood cultures. PMID- 21292862 TI - Bullous cellulitis in cirrhotic patients--a rare but life-threatening infection caused by non-O1, non-O139 Vibrio cholerae bacteraemia. PMID- 21292863 TI - The relationship between insulin resistance and incidence and progression of coronary artery calcification: the Multi-Ethnic Study of Atherosclerosis (MESA). AB - OBJECTIVE: We sought to determine whether insulin resistance predicts the incidence and progression of coronary artery calcification (CAC). RESEARCH DESIGN AND METHODS: We studied 5,464 participants not on hypoglycemic therapy from the Multi-Ethnic Study of Atherosclerosis (MESA). Each had baseline homeostasis model assessment of insulin resistance (HOMA-IR) and baseline and follow-up CAC scores. Incident CAC was defined as newly detectable CAC; progression was defined as advancing CAC volume score at follow-up. RESULTS: Median HOMA-IR was 1.2 (0.8 2.0). Across all ethnicities, there was a graded increase in CAC incidence and progression with increasing HOMA-IR. When compared with those in the 1st quartile, participants in the 2nd-4th quartiles had 1.2, 1.5, and 1.8 times greater risk of developing CAC. Median annualized CAC score progression was 8, 14, and 17 higher, respectively. However, HOMA-IR was not predictive after adjustment for metabolic syndrome components. CONCLUSIONS: HOMA-IR predicts CAC incidence and progression, but not independently of metabolic syndrome. PMID- 21292864 TI - A comparison of methods for the measurement of 8-isoPGF(2alpha): a marker of oxidative stress. AB - BACKGROUND: Oxidative stress describes the cellular damage caused by excess reactive oxygen species not adequately inactivated by antioxidants. Oxidative stress has been implicated in playing a role in many disorders. Lipid peroxidation end-products are employed as markers of oxidative stress, of which the isoprostane, 8-iso-PGF(2alpha), is widely used. 8-iso-PGF(2alpha) is measured in plasma or urine by gas chromatography-mass spectrometry (GC/MS), liquid chromatography-mass spectrometry (LC/MS), tandem-mass spectrometry or enzyme linked immunosorbent assay (ELISA). However, discrepancies between the specificity of these methods means correlation is poor. METHODS: A tandem-mass spectrometric (LC/MS/MS) method, using immunoaffinity purification, for urinary 8 iso-PGF(2alpha) was developed and compared with two commercial ELISAs (A--Cayman Chemicals, B--Oxford Biomedical Research) in urine samples (n = 156). RESULTS: An LC/MS/MS method coupled to immunoaffinity purification was developed with satisfactory performance and comparison to ELISAs A and B. Spearman rank correlation demonstrated significant correlation between all methods (P = <0.0001); however, r2 values ranged from 0.68 to 0.72. Bland-Altman plots revealed a proportional positive bias of ELISA B when compared with ELISA A and LC/MS/MS. Furthermore, the agreement between ELISA A and LC/MS/MS was poor. CONCLUSIONS: The poor agreement between methods for measurement of 8-iso PGF(2alpha) highlights differences in selectivity. 8-iso-PGF(2alpha) is an isoprostane, a family of isomeric end-products of arachidonic acid peroxidation, which are produced by peroxidation or enzymatically. This makes avoiding cross reactivity between 8-iso-PGF(2alpha) and related isomers challenging. When assessing oxidative stress studies, the selectivity of the methods used should be taken into account, particularly when comparing studies. PMID- 21292865 TI - The effect of survival bias on case-control genetic association studies of highly lethal diseases. AB - BACKGROUND: Survival bias is the phenomenon by which individuals are excluded from analysis of a trait because of mortality related to the expression of that trait. In genetic association studies, variants increasing risk for disease onset as well as risk of disease-related mortality (lethality) could be difficult to detect in genetic association case-control designs, possibly leading to underestimation of a variant's effect on disease risk. METHODS AND RESULTS: We modeled cohorts for 3 diseases of high lethality (intracerebral hemorrhage, ischemic stroke, and myocardial infarction) using existing longitudinal data. Based on these models, we simulated case-control genetic association studies for genetic risk factors of varying effect sizes, lethality, and minor allele frequencies. For each disease, erosion of detected effect size was larger for case-control studies of individuals of advanced age (age >75 years) and/or variants with very high event-associated lethality (genotype relative risk for event-related death >2.0). We found that survival bias results in no more than 20% effect size erosion for cohorts with mean age <75 years, even for variants that double lethality risk. Furthermore, we found that increasing effect size erosion was accompanied by depletion of minor allele frequencies in the case population, yielding a "signature" of the presence of survival bias. CONCLUSIONS: Our simulation provides formulas to allow estimation of effect size erosion given a variant's odds ratio of disease, odds ratio of lethality, and minor allele frequencies. These formulas will add precision to power calculation and replication efforts for case-control genetic studies. Our approach requires validation using prospective data. PMID- 21292866 TI - Detection of renal lesion enhancement with dual-energy multidetector CT. AB - PURPOSE: To determine whether dual-energy multidetector CT enables detection of renal lesion enhancement by using calculated nonenhanced images with spectral based extraction in a non-body weight-restricted patient population. MATERIALS AND METHODS: Between January 2008 and December 2009, 139 patients were enrolled in this prospective HIPAA-compliant, institutional review board-approved study. Written informed consent was obtained from all patients. After single-energy nonenhanced 120-kVp CT images were acquired, contrast material-enhanced dual energy multidetector CT images were acquired at 80 and 140 kVp. Calculated nonenhanced images were generated by using spectral-based iodine extraction. Lesion attenuation was measured on the acquired nonenhanced, calculated nonenhanced, and 140-kVp contrast-enhanced nephrographic images. Enhancement, defined as a 15-HU or greater increase in attenuation on the nephrographic images, was assessed by using the baseline attenuation on the acquired and calculated nonenhanced images. Acquired nonenhanced versus calculated nonenhanced image attenuation, as well as enhancement values, were compared by using paired Student t tests and Bland-Altman plots. RESULTS: Hypoattenuating (n = 66) and hyperattenuating (n = 28) cysts, angiomyolipomas (n = 18), and solid enhancing lesions (n = 27) were detected. Mean attenuation values for hypoattenuating cysts on the acquired and calculated nonenhanced CT images were 6.5 HU +/- 5.8 (standard deviation) and 8.1 HU +/- 3.1 (P = .13), respectively, with corresponding enhancement values of 1.1 HU +/- 5.2 and -0.5 HU +/- 6.2 (P = .12), respectively. Mean values for hyperattenuating cysts were 29.4 HU +/- 5.6 on acquired images and 31.7 HU +/- 5.1 on calculated images (P = .39) (corresponding enhancement, 4.7 HU +/- 3.3 and 2.3 HU +/- 4.1, respectively; P = .09). Mean values for fat-containing enhancing lesions were -90.6 HU +/- 24.7 on acquired images and -85.9 HU +/- 23.7 on calculated images (P = .57) (corresponding enhancement, 18.2 HU +/- 10.1 and 13.6 HU +/- 10.7, respectively; P = .19). Mean attenuation values for solid enhancing lesions were 26.0 HU +/- 15.0 on acquired images and 27.7 HU +/- 14.9 on calculated images (P = .45) (corresponding enhancement, 60.3 HU +/- 13.1 and 58.3 HU +/- 15.5, respectively; P = .38). CONCLUSION: Dual-energy CT acquisitions with spectral-based postprocessing enabled accurate detection of renal lesion enhancement across the attenuation spectrum of frequently encountered renal lesions in a non-body habitus-restricted patient population. PMID- 21292867 TI - Focal cystic pancreatic lesions: assessing variation in radiologists' management recommendations. AB - PURPOSE: To estimate the prevalence of focal cystic pancreatic lesions (FCPLs) among patients undergoing computed tomographic (CT) or magnetic resonance (MR) imaging at one institution and to examine any variation in radiologists' recommendation practice pattern with regards to FCPLs. MATERIALS AND METHODS: Institutional review board approval was obtained for this retrospective HIPPA compliant study. The requirement to obtain informed consent was waived. A cohort of patients with FCPLs was identified from radiology reports by using natural language processing. Patient-specific (ie, age, sex, symptoms, history of pancreatitis), radiologist-specific (ie, years of experience, area of expertise), and FCPL-specific (ie, size, location, septation, calcification, mural nodularity, pancreatic duct involvement, and presence of multiple cysts) variables were obtained. The outcome measure was whether a follow-up study was recommended. A logistic regression model was used to identify relative recommendation rates after controlling for key explanatory variables. RESULTS: Between January 1 and December 31, 2009, a total of 1067 FCPLs were identified in 765 patients. Prevalence rates ranged from 2.2% at CT to 15.9% at MR imaging. Radiologists recommended a follow-up imaging study in 23.7% of cases of a FCPL. A 2.8-fold difference in the rate of recommendation of further imaging existed across radiologists after controlling for explanatory variables such as lesion-, radiologist-, and patient-specific characteristics. A history of pancreatitis was associated with a nearly two-fold decrease in recommending further imaging. CONCLUSION: FCPLs are common, and nearly one-quarter of radiology reports recommend at least one follow-up imaging study. Significant variation exists in the rate of recommendation for further imaging studies by radiologists, even after controlling for key explanatory variables. PMID- 21292868 TI - Fracture risk score and absolute risk of fracture. AB - PURPOSE: To report the 5- and 10-year absolute risk of fracture associated with the previously reported fracture risk (FRISK) score. MATERIALS AND METHODS: All participants gave written, informed consent, and the Barwon Health Human Research Ethics Committee approved the study. An age-stratified population-based sample of women aged 60 years and older (n = 600) was recruited during 1994-1996. FRISK scores of 0-10 incorporating bone mineral density (BMD) at two sites (hip and spine), falls scores in the previous 12 months of 1-4, weight, and number of fractures as an adult were calculated. Fractures of the hip, spine, humerus, and wrist were ascertained during a median follow-up period of 9.6 years (interquartile range, 6.6-10.5). The cumulative probability of fracture at 5 and 10 years after baseline measurements was calculated by using actuarial methods. The utility of this model was compared with other FRISK algorithms, including the World Health Organization FRISK assessment tool FRAX designed for United Kingdom and that designed for the United States and the Garvan nomogram (Australia). RESULTS: This study supplies the 5- and 10-year absolute risk of fracture associated with all levels of the FRISK score. While there are modest differences in absolute risk of fracture seen for different numbers of prior fractures, the more marked differences occur across the different categories of falls scores and different categories of BMD. The receiver operating characteristic curves showed no significant difference in area under the curve for all four absolute risk of fracture algorithms. CONCLUSION: Absolute risk of fracture can be determined by using readily obtainable clinical information that may aid treatment decisions. PMID- 21292869 TI - Quantitative assessment of tumor blood flow in mice after treatment with different doses of an antiangiogenic agent with contrast-enhanced destruction replenishment US. AB - PURPOSE: To quantify tumor blood flow by using contrast material-enhanced destruction-replenishment ultrasonography (US) to evaluate tumor response to different doses of an agent for antiangiogenic treatment in hepatoma-bearing mice, with histologic measurements of microvascular density (MVD) as the reference standard. MATERIALS AND METHODS: Experiments were approved by the regional animal care committee. Mice bearing subcutaneous H22 hepatoma were treated with different doses of thalidomide, 100 mg/kg in group B and 200 mg/kg in group C. Group A (control group) was treated with 0.5% carboxylmethylcellulose. Treatment groups and the control group included 10 mice each. Contrast-enhanced US was used to evaluate the percentage of nonenhanced area, and contrast-enhanced destruction-replenishment US was used to evaluate tumor blood flow. Tumor blood flow was compared with measurements of MVD. Comparisons were made by using one-way analysis of variance and the post hoc least significant difference test for multiple comparisons. RESULTS: Contrast enhanced gray-scale US showed significant increases in the percentage of nonenhanced area in group C (mean, 10.56% +/- 7.25 [standard deviation]), as compared with groups A (mean, 2.40% +/- 3.12; P = .004) and B (mean, 3.75% +/- 5.55; P = .012). Contrast-enhanced destruction-replenishment US showed significant decreases of tumor blood flow in groups B and C, as compared with group A (P = .003 and P < .001, respectively), and the blood flow in group C was significantly lower than that of group B (P = .01). Immunohistochemical analysis revealed significant decreases of MVD in groups B and C, as compared with MVD in group A (P = .002 and P < .001, respectively); however, there was no significant difference in MVD between groups B and C (P = .21). CONCLUSION: Quantification of tumor blood flow by using contrast-enhanced destruction-replenishment US shows the potential to guide drug dosage during antiangiogenic therapy. PMID- 21292870 TI - Diet and gastrointestinal bypass-induced weight loss: the roles of ghrelin and peptide YY. AB - OBJECTIVE: Bariatric surgery causes durable weight loss. Gut hormones are implicated in obesity pathogenesis, dietary failure, and mediating gastrointestinal bypass (GIBP) surgery weight loss. In mice, we determined the effects of diet-induced obesity (DIO), subsequent dieting, and GIBP surgery on ghrelin, peptide YY (PYY), and glucagon-like peptide-1 (GLP-1). To evaluate PYY's role in mediating weight loss post-GIBP, we undertook GIBP surgery in PyyKO mice. RESEARCH DESIGN AND METHODS: Male C57BL/6 mice randomized to a high-fat diet or control diet were killed at 4-week intervals. DIO mice underwent switch to ad libitum low-fat diet (DIO-switch) or caloric restriction (CR) for 4 weeks before being killed. PyyKO mice and their DIO wild-type (WT) littermates underwent GIBP or sham surgery and were culled 10 days postoperatively. Fasting acyl-ghrelin, total PYY, active GLP-1 concentrations, stomach ghrelin expression, and colonic Pyy and glucagon expression were determined. Fasting and postprandial PYY and GLP 1 concentrations were assessed 30 days postsurgery in GIBP and sham pair-fed (sham.PF) groups. RESULTS: DIO progressively reduced circulating fasting acyl ghrelin, PYY, and GLP-1 levels. CR and DIO-switch caused weight loss but failed to restore circulating PYY to weight-appropriate levels. After GIBP, WT mice lost weight and exhibited increased circulating fasting PYY and colonic Pyy and glucagon expression. In contrast, the acute effects of GIBP on body weight were lost in PyyKO mice. Fasting PYY and postprandial PYY and GLP-1 levels were increased in GIBP mice compared with sham.PF mice. CONCLUSIONS: PYY plays a key role in mediating the early weight loss observed post-GIBP, whereas relative PYY deficiency during dieting may compromise weight-loss attempts. PMID- 21292871 TI - Plasmodium vivax vaccine research: insights from Colombian studies. PMID- 21292872 TI - Consistent safety and infectivity in sporozoite challenge model of Plasmodium vivax in malaria-naive human volunteers. AB - A safe and reproducible Plasmodium vivax infectious challenge method is required to evaluate the efficacy of malaria vaccine candidates. Seventeen healthy Duffy (+) and five Duffy (-) subjects were randomly allocated into three (A-C) groups and were exposed to the bites of 2-4 Anopheles albimanus mosquitoes infected with Plasmodium vivax derived from three donors. Duffy (-) subjects were included as controls for each group. Clinical manifestations of malaria and parasitemia were monitored beginning 7 days post-challenge. All Duffy (+) volunteers developed patent malaria infection within 16 days after challenge. Prepatent period determined by thick smear, was longer for Group A (median 14.5 d) than for Groups B and C (median 10 d/each). Infected volunteers recovered rapidly after treatment with no serious adverse events. The bite of as low as two P. vivax-infected mosquitoes provides safe and reliable infections in malaria-naive volunteers, suitable for assessing antimalarial and vaccine efficacy trials. PMID- 21292873 TI - Phase I safety and immunogenicity trial of Plasmodium vivax CS derived long synthetic peptides adjuvanted with montanide ISA 720 or montanide ISA 51. AB - We assessed the safety, tolerability, and immunogenicity of a mixture of three synthetic peptides derived from the Plasmodium vivax circumsporozoite protein formulated in Montanide ISA 720 or Montanide ISA 51. Forty healthy malaria-naive volunteers were allocated to five experimental groups (A-E): four groups (A-D) were immunized intramuscularly with 50 and 100 MUg/dose injections of a mixture of N, R, and C peptides formulated in the two different adjuvants at 0, 2, and 4 months and one group was administered placebo. Vaccines were immunogenic, safe, well tolerated, and no serious adverse events related to the vaccine occurred. Seroconversion occurred in > 90% of the vaccines and antibodies recognized the sporozoite protein on immunofluorescent antibody test. Vaccines in Montanide ISA 51 showed a higher sporozoite protein recognition and interferon production. Results encourage further testing of the vaccine protective efficacy. PMID- 21292874 TI - Preclinical vaccine study of Plasmodium vivax circumsporozoite protein derived synthetic polypeptides formulated in montanide ISA 720 and montanide ISA 51 adjuvants. AB - Plasmodium vivax circumsporozoite (CS) protein is a leading malaria vaccine candidate previously assessed in animals and humans. Here, combinations of three synthetic polypeptides corresponding to amino (N), central repeat (R), and carboxyl (C) regions of the CS protein formulated in Montanide ISA 720 or Montanide ISA 51 adjuvants were assessed for immunogenicity in rodents and primates. BALB/c mice and Aotus monkeys were divided into test and control groups and were immunized three times with doses of 50 and 100 MUg of vaccine or placebo. Antigen-specific antimalarial antibodies were determined by enzyme linked immunosorbent assay, immunofluorescent antibody test, and IFN-gamma responses by enzyme-linked immunosorbent spot (ELIspot). Both vaccine formulations were highly immunogenic in both species. Mice developed better antibody responses against C and R polypeptides, whereas the N polypeptide was more immunogenic in monkeys. Anti-peptide antibodies remained detectable for several months and recognized native proteins on sporozoites. Differences between Montanide ISA 720 and Montanide ISA 51 formulations were not significant. PMID- 21292875 TI - Plasmodium vivax sporozoite production in Anopheles albimanus mosquitoes for vaccine clinical trials. AB - Vaccine development for Plasmodium vivax malaria is underway. A model to assess the protective efficacy of vaccine candidates in humans is urgently needed. Given the lack of continuous P. vivax cultures, we developed a system to infect Anopheles albimanus mosquitoes using blood from P. vivax-infected patients and determined parameters for challenge of malaria-naive volunteers by mosquito bite. Absence of co-infections in parasitized blood was confirmed by tests consistent with blood bank screening. A total of 119 experiments were conducted using batches of 900-4,500 mosquitoes fed by an artificial membrane feeding method. Optimal conditions for mosquito probing and infection were determined. Presence of oocyst and sporozoites were assessed on Days 7-8 and 14-15, respectively, and conditions to choose batches of infected mosquitoes for sporozoite challenge were established. Procedures to infect volunteers took a 2-hour period including verification of inoculum dose. Anopheles albimanus mosquitoes represent a valuable resource for P. vivax sporozoite challenge of volunteers. PMID- 21292876 TI - Antibody-mediated and cellular immune responses induced in naive volunteers by vaccination with long synthetic peptides derived from the Plasmodium vivax circumsporozoite protein. AB - Plasmodium vivax circumsporozoite (CS) protein is a leading malaria vaccine candidate. We describe the characterization of specific immune responses induced in 21 malaria-naive volunteers vaccinated with long synthetic peptides derived from the CS protein formulated in Montanide ISA 720. Both antibody- and cell mediated immune responses were analyzed. Antibodies were predominantly of IgG1 and IgG3 isotypes, recognized parasite proteins on the immunofluorescent antibody test, and partially blocked sporozoite invasion of hepatoma cell lines in vitro. Peripheral blood mononuclear cells from most volunteers (94%) showed IFN-gamma production in vitro upon stimulation with both long signal peptide and short peptides containing CD8+ T-cell epitopes. The relatively limited sample size did not allow conclusions about HLA associations with the immune responses observed. In summary, the inherent safety and tolerability together with strong antibody responses, invasion blocking activity, and the IFN-gamma production induced by these vaccine candidates warrants further testing in a phase II clinical trial. PMID- 21292877 TI - Immune responses and protection of Aotus monkeys immunized with irradiated Plasmodium vivax sporozoites. AB - A non-human primate model for the induction of protective immunity against the pre-erythrocytic stages of Plasmodium vivax malaria using radiation-attenuated P. vivax sporozoites may help to characterize protective immune mechanisms and identify novel malaria vaccine candidates. Immune responses and protective efficacy induced by vaccination with irradiated P. vivax sporozoites were evaluated in malaria-naive Aotus monkeys. Three groups of six monkeys received two, five, or ten intravenous inoculations, respectively, of 100,000 irradiated P. vivax sporozoites; control groups received either 10 doses of uninfected salivary gland extract or no inoculations. Immunization resulted in the production low levels of antibodies that specifically recognized P. vivax sporozoites and the circumsporozoite protein. Additionally, immunization induced low levels of antigen-specific IFN-gamma responses. Intravenous challenge with viable sporozoites resulted in partial protection in a dose-dependent manner. These findings suggest that the Aotus monkey model may be able to play a role in preclinical development of P. vivax pre-erythrocytic stage vaccines. PMID- 21292878 TI - Antigenic diversity of the Plasmodium vivax circumsporozoite protein in parasite isolates of Western Colombia. AB - Circumsporozoite (CS) protein is a malaria antigen involved in sporozoite invasion of hepatocytes, and thus considered to have good vaccine potential. We evaluated the polymorphism of the Plasmodium vivax CS gene in 24 parasite isolates collected from malaria-endemic areas of Colombia. We sequenced 27 alleles, most of which (25/27) corresponded to the VK247 genotype and the remainder to the VK210 type. All VK247 alleles presented a mutation (Gly -> Asn) at position 28 in the N-terminal region, whereas the C-terminal presented three insertions: the ANKKAGDAG, which is common in all VK247 isolates; 12 alleles presented the insertion GAGGQAAGGNAANKKAGDAG; and 5 alleles presented the insertion GGNAGGNA. Both repeat regions were polymorphic in gene sequence and size. Sequences coding for B-, T-CD4(+), and T-CD8(+) cell epitopes were found to be conserved. This study confirms the high polymorphism of the repeat domain and the highly conserved nature of the flanking regions. PMID- 21292879 TI - Evaluation of the naturally acquired antibody immune response to the Pv200L N terminal fragment of Plasmodium vivax merozoite surface protein-1 in four areas of the Amazon Region of Brazil. AB - Frequency and levels of IgG antibodies to an N-terminal fragment of the Plasmodium vivax MSP-1 (Pv200L) protein, in individuals naturally exposed to malaria in four endemic areas of Brazil, were evaluated by enzyme-linked immunosorbent assay. Plasma samples of 261 P. vivax-infected individuals from communities of Macapa, Novo Repartimento, Porto Velho, and Placido de Castro in the Amazonian region with different malaria transmission intensities. A high mean number of studied individuals (89.3%) presented with antibodies to the Pv200L that correlated with the number of previous malaria infections; there were significant differences in the frequency of the responders (71.9-98.7) and in the antibody levels (1:200-1:51,200) among the four study areas. Results of this study provide evidence that Pv200L is a naturally immunogenic fragment of the PvMSP-1 and is associated with the degree of exposure to parasites. The fine specificity of antibodies to Pv200L is currently being assessed. PMID- 21292880 TI - Polymorphism of the Pv200L fragment of merozoite surface protein-1 of Plasmodium vivax in clinical isolates from the Pacific coast of Colombia. AB - Merozoite surface protein 1 (MSP-1) is a polymorphic malaria protein with functional domains involved in parasite erythrocyte interaction. Plasmodium vivax MSP-1 has a fragment (Pv200L) that has been identified as a potential subunit vaccine because it is highly immunogenic and induces partial protection against infectious parasite challenge in vaccinated monkeys. To determine the extent of genetic polymorphism and its effect on the translated protein, we sequenced the Pv200L coding region from isolates of 26 P. vivax-infected patients in a malaria endemic area of Colombia. The extent of nucleotide diversity (pi) in these isolates (0.061 +/- 0.004) was significantly lower (P <= 0.001) than that observed in Thai and Brazilian isolates; 0.083 +/- 0.006 and 0.090 +/- 0.006, respectively. We found two new alleles and several previously unidentified dimorphic substitutions and significant size polymorphism. The presence of highly conserved blocks in this fragment has important implications for the development of Pv200L as a subunit vaccine candidate. PMID- 21292881 TI - Characterization of Plasmodium vivax transmission-blocking activity in low to moderate malaria transmission settings of the Colombian Pacific coast. AB - Malaria infection induces antibodies capable of suppressing the infectivity of gametocytes and gametes, however, little is known about the duration of the antibody response, the parasite specificity, and the role of complement. We report the analyses of the transmission-blocking (TB) activity of sera collected from 105 Plasmodium vivax-infected and 44 non-infected individuals from a malaria endemic region of Colombia, using a membrane feeding assay in Anopheles albimanus mosquitoes. In infected donors we found that TB activity was antibody dose dependent (35%), lasted for 2-4 months after infection, and in 70% of the cases different P. vivax wild isolates displayed differential susceptibility to blocking antibodies. Additionally, in a number of assays TB was complement dependent. Twenty-seven percent of non-infected individuals presented TB activity that correlated with antibody titers. Studies here provide preliminary data on factors of great importance for further work on the development of TB vaccines. PMID- 21292882 TI - Subconjunctival loiasis. PMID- 21292883 TI - The effects of informational interventions on household water management, hygiene behaviors, stored drinking water quality, and hand contamination in peri-urban Tanzania. AB - Safe water storage and hand hygiene have been shown to reduce fecal contamination and improve health in experimental settings; however, triggering and sustaining such behaviors is challenging. This study investigates the extent to which personalized information about Escherichia coli contamination of stored water and hands influenced knowledge, reported behaviors, and subsequent contamination levels among 334 households with less than 5-year-old children in peri-urban Dar es Salaam, Tanzania. One-quarter of the study participants received information about strategies to reduce risk of water- and sanitation-related illness. Respondents in another three study cohorts received this same information, along with their household's water and/or hand-rinse test results. Findings from this study suggest that additional work is needed to elucidate the conditions under which such testing represents a cost-effective strategy to motivate improved household water management and hand hygiene. PMID- 21292884 TI - Drug resistance surveillance in resource-poor settings: current methods and considerations for TB, HIV, and malaria. AB - In resource-constrained environments, monitoring the occurrence of tuberculosis (TB), human immunodeficiency virus (HIV), or malaria resistant to the limited number of available drugs is essential for national treatment program success. Countries with limited resources and technical capacity rely on survey designs and methods that are simple and easily integrated into routine clinical activities to minimize the impact on overburdened clinics. This paper reviews the most commonly used methods for drug-resistance surveillance of TB, HIV, and malaria and discusses the strengths and limitations of these different strategies. PMID- 21292885 TI - Economic impact of dengue illness in the Americas. AB - The growing burden of dengue in endemic countries and outbreaks in previously unaffected countries stress the need to assess the economic impact of this disease. This paper synthesizes existing studies to calculate the economic burden of dengue illness in the Americas from a societal perspective. Major data sources include national case reporting data from 2000 to 2007, prospective cost of illness studies, and analyses quantifying underreporting in national routine surveillance systems. Dengue illness in the Americas was estimated to cost $2.1 billion per year on average (in 2010 US dollars), with a range of $1-4 billion in sensitivity analyses and substantial year to year variation. The results highlight the substantial economic burden from dengue in the Americas. The burden for dengue exceeds that from other viral illnesses, such as human papillomavirus (HPV) or rotavirus. Because this study does not include some components (e.g., vector control), it may still underestimate total economic consequences of dengue. PMID- 21292886 TI - Initial assessment of the acceptability of a Push-Pull Aedes aegypti control strategy in Iquitos, Peru and Kanchanaburi, Thailand. AB - As part of a larger research program evaluating chemical threshold levels for a Push-Pull intervention to reduce man-vector (Aedes aegypti) contact, this qualitative study explored local perceptions and strategies associated with mosquito control within dengue-endemic communities in Peru and Thailand. Focus groups were used to provide preliminary information that would identify possible public acceptance issues to the Push-Pull strategy in each site. Nine focus group discussions (total of 102 individuals) conducted between September 2008 and March 2009 examined several themes: 1) current mosquito control practices; 2) perceptions of spatial repellency and contact irritancy versus killing mosquitoes; and 3) initial perceptions toward mosquito host-seeking traps. Results indicate participants use household-level strategies for insect control that reveal familiarity with the concept of spatial repellent and contact irritant actions of chemicals and that placing traps in the peridomestic environment to remove repelled mosquitoes was acceptable. Preliminary evidence suggests a Push-Pull strategy should be well accepted in these locations. These results will be beneficial for developing future large scale push-pull interventions and are currently being used to guide insecticide application strategies in (entomological) proof-of-concept studies using experimental huts. PMID- 21292887 TI - Factors influencing dengue virus isolation by C6/36 cell culture and mosquito inoculation of nested PCR-positive clinical samples. AB - Dengue viral isolation is necessary for definitive diagnosis, pathogenesis and evolutionary research, vaccine candidates, and diagnostic materials. Using standardized techniques, we analyzed isolation rates of 1,544 randomly selected polymerase chain reaction (PCR)-positive samples, representing all four dengue serotypes, from patients with serologically confirmed dengue infections and evaluated whether clinical and laboratory results could be predictive of isolation using standard and mosquito isolation techniques. Viruses were isolated from 62.5% of the samples by direct application to C6/36 cells and increased to 79.4% when amplifying C6/36 negative samples by intrathorasic inoculation in Toxyrhynchites splendens mosquitoes. High viremia, measured by reverse transcriptase (RT)-PCR, was a strong predictor for viral isolation by either method. Isolation was most successful in samples collected early in the disease, had low antibody levels, temperatures greater than 38 degrees C, and had a final clinical diagnosis of dengue fever. Dengue serotypes also played a role in the success of viral isolation. PMID- 21292888 TI - Evaluation of the NS1 rapid test and the WHO dengue classification schemes for use as bedside diagnosis of acute dengue fever in adults. AB - Because healthcare facilities in many dengue endemic countries lack laboratory support, early dengue diagnosis must rely on either clinical recognition or a bedside diagnostic test. We evaluated the sensitivity and specificity of the 1997 and 2009 World Health Organization (WHO) dengue classification schemes and the NS1 strip test in acute sera from 154 virologically confirmed dengue patients and 200 patients with other febrile illnesses. Both WHO classification schemes had high sensitivity but lacked specificity. The NS1 strip test had high specificity, but its sensitivity was significantly lower in secondary compared with primary dengue infections. Differences in viral serotypes did not affect the performance of any of the three diagnostic approaches. Taken collectively, our findings indicate that the 1997 WHO dengue case definition can be used to exclude dengue, and the NS1 strip test can be used to confirm dengue infection, although the latter should be interpreted with caution in regions where secondary dengue infection is prevalent. PMID- 21292889 TI - Experience with extrarenal manifestations of hemorrhagic fever with renal syndrome in a tertiary care hospital in South Korea. AB - Reports on the clinical entity of hemorrhagic fever with renal syndrome (HFRS) have focused on acute renal failure. Data on the extrarenal manifestations are limited primarily to case reports. In this study, protean extrarenal manifestations involving the major organs occurred in one-third of patients with HFRS during various stages (i.e., febrile phase through diuretic phase). Pancreatobiliary manifestations and major bleeding occurred in 11% and 10% of patients, respectively. Cardiovascular and central nervous system manifestations developed during the febrile or oliguric phase, whereas pancreatobiliary manifestations and major bleeding were detected even in the diuretic phase. Thus, close monitoring of and additional knowledge about various extrarenal manifestations are needed. PMID- 21292890 TI - Regional differences in the association between land cover and West Nile virus disease incidence in humans in the United States. AB - West Nile virus (WNV) is generally considered to be an urban pathogen in the United States, but studies associating land cover and disease incidence, seroprevalence, or infection rate in humans, birds, domesticated and wild mammals, and mosquitoes report varying and sometimes contradictory results at an array of spatial extents. Human infection can provide insight about basic transmission activity; therefore, we analyzed data on the incidence of WNV disease in humans to obtain a comprehensive picture of how human disease and land cover type are associated across the United States. Human WNV disease incidence in Northeastern regions was positively associated with urban land covers, whereas incidence in the Western United States was positively associated with agricultural land covers. We suggest that these regional associations are explained by the geographic distributions of prominent WNV vectors: Culex pipiens complex (including Cx. pipiens and Cx. quinquefasciatus) in the Northeast and Cx. tarsalis in the Western United States. PMID- 21292891 TI - What is AIDS in the Amazon and the Guianas? Establishing the burden of disseminated histoplasmosis. AB - The pathogen ecology of Amazonian regions may lead to specific differences in the most frequent clinical presentations of acquired immunodeficiency syndrome (AIDS). A retrospective cohort study was thus conducted to describe the main AIDS defining events in French Guiana. Disseminated histoplasmosis was the most frequent opportunistic infection (15.4/1000 person years). PMID- 21292892 TI - Isolation and phylogenetic analysis of Batai virus, Germany. AB - A molecular survey including 16,057 mosquitoes captured in Southwest Germany during the summer of 2009 showed the presence of Batai virus (BATV) in Anopheles maculipennis sensu lato. Until this survey, there was no evidence for circulation of BATV in Germany. Analysis of partial S, M, and L segments showed that the sequences from all three segments were most closely related to BATV, indicating that the virus has not undergone reassortment. Phylogenetic analysis revealed a close relationship of the isolated BATV strain from Germany with strains from Slovakia, Ukraine, and Russia. PMID- 21292893 TI - A focus of dogs and Rickettsia massiliae-infected Rhipicephalus sanguineus in California. AB - A recurrent focus of Rhipicephalus sanguineus infestation was investigated in a suburban area of southern California after reports of suspected Rocky Mountain spotted fever in two dogs on the same property. Abundant quantities of Rh. sanguineus were collected on the property and repeatedly from each dog, and Rickettsia massiliae DNA was detected by polymerase chain reaction (PCR). Whole blood and serum samples from four dogs were tested by using PCR and microimmunofluorescent assay for antibodies against spotted fever group rickettsiae. Serum samples from all four dogs contained antibodies reactive with R. massiliae, R. rhipicephali, R. rickettsii, and 364D Rickettsia but no rickettsial DNA was detected by PCR of blood samples. Serum cross-absorption and Western blot assays implicated R. massiliae as the most likely spotted fever group rickettsiae responsible for seropositivity. To our knowledge, this is the first detection of R. massiliae in ticks in California. PMID- 21292894 TI - Phylogenetic analysis of the 56 kDa protein genes of Orientia tsutsugamushi in Southwest Area of Korea. AB - This study was conducted to determine which genotypes were present in southwestern Korea. Nested polymerase chain reaction (PCR) and DNA sequence analysis targeting the Orientia tsutsugamushi-specific 56-kDa protein gene was performed with samples of blood and eschar. Of the 69 PCR-positive samples, 61 clustered with the Boryong previously isolated in Korea. CUH 4-6 had sequence homology of 100% with Kato, and CUH 4-3 had homology of 99.8% with Kato and formed the Kato cluster. CUH 4-57, CUH 4-31, CUH 4-142, and CUH 4-324 formed a Kawasaki cluster. CUH 4-271 had sequence homology of 100% with Jecheon and formed a Karp cluster. CUH 4-117 had homology of 99.8% with Neimeng-65, and Gilliam cluster. The most common genotype of O. tsutsugamushi in the southwestern part of Korea is the Boryong genotype. We also identified O. tsutsugamushi of the Kato, Neimeng-65 and Kawasaki genotypes, which had not been identified before in Korea. PMID- 21292895 TI - Randomized controlled clinical trial to access efficacy and safety of miltefosine in the treatment of cutaneous leishmaniasis Caused by Leishmania (Viannia) guyanensis in Manaus, Brazil. AB - Miltefosine has been used in the treatment of several new world cutaneous leishmaniasis (CL) species with variable efficacy. Our study is the first evidence on its clinical efficacy in Leishmania (Viannia) guyanensis. In this phase II/III randomized clinical trial, 90 CL patients were randomly allocated (2:1) to oral miltefosine (2.5 mg/kg/day/28 days) (N = 60) or parenteral antimony (15-20 mg/Sb/kg/day/20 days) (N = 30) according to age groups: 2-12 y/o and 13-65 y/o. Patients were human immunodeficiency virus (HIV) noninfected parasitological proven CL without previous treatment. Definitive cure was accessed at 6 months follow-up visit. No severe adverse events occurred. Vomiting was the most frequent adverse event (48.3%) followed by nausea (8.6%) and diarrhea (6.7%). Cure rates were 71.4% (95% confidence interval [CI] = 57.8-82.7) and 53.6% (95% CI = 33.9-72.5) (P = 0.05) for miltefosine and antimonial, respectively. There were no differences in cure rates between age groups within the same treatment arms. Miltefosine was safe and relatively well tolerated and cure rate was higher than antimony. PMID- 21292896 TI - Antileishmania immunological tests for asymptomatic subjects living in a visceral leishmaniasis-endemic area in Brazil. AB - The objective of this study was to evaluate the behavior of different tests used for the diagnosis of visceral leishmaniasis (VL) in asymptomatic subjects living in an endemic area. No gold standard is available for the diagnosis of asymptomatic infection with Leishmania. In continuation of a previous study, 1,017 subjects living in a VL-endemic area were clinically reevaluated. Of these, 576 had at least one positive serological test in a first assessment. About 3 years after the first evaluation, none of the subjects had progressed to clinical VL. Among this group, 246 subjects were selected, and five serological tests (enzyme-linked immunosorbent assay p [ELISAp], ELISArK39, ELISArK26, indirect immunofluorescence test [IIFT] using L. amazonensis promastigote antigen, and an immunochromatographic test using rK39 antigen [TRALd]) and the Montenegro skin test (MST) were repeated. There was a significant increase in the number of subjects who tested positive in the MST, IIFT, ELISAp, and ELISArK39 in the second evaluation. For all tests, there were subjects who tested positive in the first evaluation and negative in the second evaluation. A positive result in the serological tests and MST in subjects from the endemic area studied did not indicate a risk of progression to VL and may only be temporary. PMID- 21292897 TI - Spontaneous postpartum clearance of Plasmodium falciparum parasitemia in pregnant women, Benin. AB - The question of malaria in the postpartum period is controversial. Malaria was investigated during a randomized trial of intermittent preventive treatment in pregnancy in Benin. Women infected at delivery were tested for parasitemia in the early postpartum period; they had not received treatment unless they were symptomatic. Among the 35 of 1,346 infected women, parasitologic follow-up results could not be interpreted in 15 because they were treated for symptoms, 18 cleared parasitemia spontaneously within five days postpartum, and 2 had a strong decrease in parasitemia before being treated. Because the placenta is the privileged site for sequestration of parasites, it facilitates their persistence during pregnancy, and its elimination may rapidly induce their clearance. PMID- 21292898 TI - Prevention of malaria during pregnancy: assessing the effect of the distribution of IPTp through the national policy in Benin. AB - The efficiency of malaria prevention during pregnancy was compared between three studies in Benin for malaria infection of the placenta (MIP) and low birth weight (LBW). The first was carried out when chloroquine prophylaxis was still recommended, the second was an intermittent preventive treatment in pregnancy (IPTp) clinical trial comparing sulfadoxine pyrimetamine (SP) versus mefloquine, and the third was an observational study after SP-IPTp national implementation. We showed an association between the use of IPTp and the reduction of LBW (10% with national IPTp and 8.7% in IPTp trial versus 15.7% in pre-trial study). The effect on MIP was better in the trial (2.9% versus 11.2% and 16.7% for national IPTp and pre-trial studies, respectively). In spite of a good overall compliance with the national IPTp (with 84% of women taking at least one dose of SP), there are still failures in adherence to the directly observed therapy (DOT) scheme and needs for better training of health staff. PMID- 21292899 TI - Genetic diversity of polymorphic vaccine candidate antigens (apical membrane antigen-1, merozoite surface protein-3, and erythrocyte binding antigen-175) in Plasmodium falciparum isolates from western and central Africa. AB - The malaria vaccine candidate antigens erythrocyte binding antigen 175 (EBA-175), merozoite surface protein 3 (MSP-3), and apical membrane antigen (AMA-1) from Plasmodium falciparum isolates from countries in central and west Africa were assessed for allelic diversity. Samples were collected on filter paper from 600 P. falciparum-infected symptomatic patients in Cameroon, Republic of Congo, Burkina Faso, Ghana, and Senegal and screened for class-specific amplification fragments. Genetic diversity, assessed by mean heterozygosity, was comparable among countries. We detected a clinical increase in eba 175 F-allele frequency from west to east across the study region. No statistical difference in msp-3 allele distribution between countries was observed. The ama-1 3D7 alleles were present at a lower frequency in central Africa than in West Africa. We also detected little to no genetic differentiation among sampling locations. This finding indicates that, at least at the level of resolution offered by restriction fragment length polymorphism analysis, these antigens showed remarkable genetic homogeneity throughout the region sampled, perhaps caused by balancing selection to maintain a diverse array of antigen haplotyes. PMID- 21292900 TI - Modeling the relationship between precipitation and malaria incidence in children from a holoendemic area in Ghana. AB - Climatic factors influence the incidence of vector-borne diseases such as malaria. They modify the abundance of mosquito populations, the length of the extrinsic parasite cycle in the mosquito, the malarial dynamics, and the emergence of epidemics in areas of low endemicity. The objective of this study was to investigate temporal associations between weekly malaria incidence in 1,993 children < 15 years of age and weekly rainfall. A time series analysis was conducted by using cross-correlation function and autoregressive modeling. The regression model showed that the level of rainfall predicted the malaria incidence after a time lag of 9 weeks (mean = 60 days) and after a time lag between one and two weeks. The analyses provide evidence that high-resolution precipitation data can directly predict malaria incidence in a highly endemic area. Such models might enable the development of early warning systems and support intervention measures. PMID- 21292901 TI - Genetic polymorphism of Plasmodium vivax msp1p, a paralog of merozoite surface protein 1, from worldwide isolates. AB - Plasmodium vivax msp1p, a paralog of the candidate vaccine antigen P. vivax merozoite surface protein 1, possesses a signal peptide at its N-terminus and two epidermal growth factor-like domains at its C-terminus with a glycosylphosphatidylinositol attachment site. The msp1p gene locus may have originated by a duplication of the msp1 gene locus in a common ancestor of the analyzed Plasmodium species and lost from P. yoelii, P. berghei, and P. falciparum during their evolutionary history. Full-length sequences of the msp1p gene were generally highly conserved; they had a few amino acid substitutions, one highly polymorphic E/Q-rich region, and a single-to-triple hepta-peptide repeat motif. Twenty-one distinguishable allelic types (A1-A21) of the E/Q-rich region were identified from worldwide isolates. Among them, four types were detected in isolates from South Korea. The length polymorphism of the E/Q-rich region might be useful as a genetic marker for population structure studies in malaria-endemic areas. PMID- 21292902 TI - Estimation of the Human Blood Index in malaria mosquito vectors in Equatorial Guinea after indoor antivector interventions. AB - We determined the Human Blood Index (HBI) of malaria mosquito vectors in Equatorial Guinea. We used a polymerase chain reaction (PCR)-based methodology to identify blood meal sources in engorged mosquitoes. We observed high HBI values, indicating that these vectors are highly anthropophilic despite intensive intradomicillary application of residual insecticides. Our results suggest that estimating the HBI can be a relatively simple and easy way to evaluate the efficacy of antimalaria interventions where an observed diversion to non-human hosts may successfully contribute to the interruption of malaria transmission. PMID- 21292903 TI - Burkholderia pseudomallei antibodies in individuals living in endemic regions in Northeastern Brazil. AB - A seroepidemiological investigation was conducted among the population of two municipalities in Northeastern Brazil. Immunoglobulin M (IgM) and IgG antibodies to Burkholderia pseudomallei were positive in 51.27% (161 in 317 samples) and 58.49% (186), respectively. IgM titers were higher in children than in adults. On the contrary, IgG increased progressively with age. We observed a significant association between agricultural occupation and raised IgM titers (P < 0.005) and IgG titers (P < 0.001), and between construction workers and raised IgG titers (P = 0.005). Antibody IgG avidities did not correlate with age. The highest titers of antibodies (1/800) showed the highest antibody avidity indexes (P < 0.01). Most of the serum samples recognized 45-kDa and 200-kDa bands by IgG1 and IgG2 subclasses. Our study showed a high seropositivity among individuals living in endemic regions of the state of Ceara, and highlights the need for further surveillance close to water courses such as dams and rivers in Northeastern Brazil. PMID- 21292904 TI - Shell vial cell culture as a tool for Streptobacillus moniliformis "resuscitation". AB - Streptobacillus moniliformis is a fastidious growing Gram-negative bacillus responsible of rat-bite fever. We describe here the first report of this disease in la Reunion and the first isolation using shell vial cell culture from a blood culture bottle with a bacterium suspected to be dead. PMID- 21292905 TI - Comparison of microscopy, culture, and conventional polymerase chain reaction for detection of blastocystis sp. in clinical stool samples. AB - We tested 513 stool samples from patients in Sydney, Australia for Blastocystis by using five diagnostic techniques: microscopy of a permanently stained smear using a modified iron-hematoxylin stain, two xenic culture systems (a modified Boeck and Drbohlav's medium and tryptone, yeast extract, glucose, methionine-9 medium), and two published conventional polymerase chain reaction methods specific for the small subunit ribosomal DNA. Ninety-eight (19%) samples were positive for Blastocystis in one or more of the diagnostic techniques. The PCR 2 method was the most sensitive at detecting Blastocystis with a sensitivity of 94%, and the least sensitive was microscopy of the permanent stain (48%). Subtype 3 was the most predominant subtype (present in 43% of samples assigned to this group). This study highlights the low sensitivity of microscopy when used as the sole diagnostic modality for detection of Blastocystis sp. PMID- 21292906 TI - Emergence of community-associated methicillin-resistant Staphylococcus aureus carriage in children in Cambodia. AB - We previously described the first reported isolation of methicillin-resistant Staphylococcus aureus (MRSA) (a case series of pediatric community-associated MRSA infections) in Cambodia. We define the rate of pediatric MRSA carriage in the same population and characterize the associated bacterial genotypes by using pulsed-field gel electrophoresis and multilocus sequence typing. A prospective cohort study of MRSA carriage conducted over one month at the Angkor Hospital for Children, Siem Reap, Cambodia, identified MRSA carriage in 87 (3.5%) of 2,485 children who came to the outpatient department, and 6 (4.1%) of 145 inpatients, including at least two with cases of nosocomial acquisition. Genotyping of all 93 MRSA isolates resolved 5 genotypes. Most (91%) isolates were assigned to sequence type 834. Only 28 (32%) of 87 MRSA carriers identified in the outpatient department had no history of recent healthcare contact. The study findings have important implications for healthcare in a setting where diagnostic microbiology and access to antimicrobial drugs with efficacy against MRSA are limited. PMID- 21292907 TI - Seroprevalence to Coxiella burnetii among residents of the Hunter New England region of New South Wales, Australia. AB - Exposure to Coxiella burnetii is a risk in the Hunter New England (HNE) region of New South Wales (NSW), Australia, based on yearly reported cases of Q fever. We assessed seroprevalence of phase II antibodies to C. burnetii by indirect immunofluorescence assay (IFA; screening at 1/50 dilution) of residents of 24 local government areas (LGA) of the HNE region of NSW. A total of 2,438 randomly selected sera sent to the Hunter Area Pathology Service for routine diagnostic purposes (not Q fever testing) during the period of 2006-2009 were tested. The overall seroprevalence in sample group was 7%. The proportion of males (59%) was higher than females (41%). In age distribution, the largest proportion (37%) of seropositives was in the > 60 years age group. Lower prevalence was observed in 0 9 years (1%) and 10-19 years (5%) age groups. The seroprevalence in different LGAs varied between 0.5% and 22%. It was highest in Guyra (22%), Gunnedah (21%), Tenterfield (18%), and Narrabri (16%), with Newcastle (0.5%), Port Stephens (2%), Lake Macquarie (3%), and Singleton (3%) being the lowest. In most of the LGAs, seroprevalence was between 6% and 12%. This report indicates a considerable exposure to C. burnetii of residents in rural areas of the HNE region and is consistent with the high notification rate for Q fever in this part of Australia. PMID- 21292908 TI - Human schistosomiasis is associated with endotoxemia and Toll-like receptor 2- and 4-bearing B cells. AB - Schistosomiasis is caused by parasitic trematodes. Individuals can accumulate hundreds of intravascular worms, which secrete a myriad of antigenic molecules into the bloodstream. Some of these molecules suppress immunity to microbial Toll like receptor (TLR) ligands, such as lipopolysaccharides, which may increase host susceptibility to coinfecting pathogens. We show that schistosomiasis is associated with extremely high levels of endotoxemia as well as high mobility group 1, an endogenous inflammatory TLR ligand, in the absence of other coinfected pathogens. Circulating B cells express surface TLR2 and TLR4, reflecting systemic exposure to microbial ligands. Bacterial translocation may occur with schistosomal egg movement from the vascular to the gut and other routes, such as the skin during infection. Our report suggests that immunosuppressive schistosome antigens may have evolved to curb inflammatory responses to the high antigenic burden of translocated bacteria products and endogenous TLR ligands that arise during parasite exposure and inflammation. PMID- 21292909 TI - Low doses of simvastatin therapy ameliorate cardiac inflammatory remodeling in Trypanosoma cruzi-infected dogs. AB - Chagas cardiomyopathy remodeling is based on the presence of Trypanosoma cruzi in heart tissue and on the complex inflammatory response leading to a myocardium fibrosis and alterations in conductive and functional heart parameters. This study aims to evaluate Simvastatin on the inflammatory response and heart functionality using dogs infected with Y strain of T. cruzi. Animals were treated daily with Simvastatin (20 mg) for 6 months and submitted to clinical and immunopathological evaluations. Simvastatin reduced heart expression and serum levels of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF alpha) but not interleukin-10 (IL-10), possibly favoring blood parasitism but reducing inflammation and fibrosis in the left ventricle and right atrium. Simvastatin also ameliorated ejection fraction, diastolic diameter, and mass index of the left ventricle 6 months after infection. This study suggests that more investigation should be performed on the use of statins as a prophylactic therapy against cardiac remodeling because of their effects on modifying immune response and benefiting functional parameters in dogs with T. cruzi-induced ventricular dysfunctions. PMID- 21292910 TI - High throughput multiplex PCR and probe-based detection with Luminex beads for seven intestinal parasites. AB - Polymerase chain reaction (PCR) assays for intestinal parasites are increasingly being used on fecal DNA samples for enhanced specificity and sensitivity of detection. Comparison of these tests against microscopy and copro-antigen detection has been favorable, and substitution of PCR-based assays for the ova and parasite stool examination is a foreseeable goal for the near future. One challenge is the diverse list of protozoan and helminth parasites. Several existing real-time PCR assays for the major intestinal parasites-Cryptosporidium spp., Giardia intestinalis, Entamoeba histolytica, Ancylostoma duodenale, Ascaris lumbricoides, Necator americanus, and Strongyloides stercoralis-were adapted into a high throughput protocol. The assay involves two multiplex PCR reactions, one with specific primers for the protozoa and one with specific primers for the helminths, after which PCR products are hybridized to beads linked to internal oligonucleotide probes and detected on a Luminex platform. When compared with the parent multiplex real-time PCR assays, this multiplex PCR-bead assay afforded between 83% and 100% sensitivity and specificity on a total of 319 clinical specimens. In conclusion, this multiplex PCR-bead protocol provides a sensitive diagnostic screen for a large panel of intestinal parasites. PMID- 21292911 TI - A pentaplex real-time polymerase chain reaction assay for detection of four species of soil-transmitted helminths. AB - Soil-transmitted helminth infections remain a major public health burden in low- and middle-income countries. The traditional diagnosis by microscopic examination of fecal samples is insensitive and time-consuming. In this study, a pentaplex real-time polymerase chain reaction (PCR) was evaluated for the simultaneous detection of Ancylostoma, Necator americanus, Ascaris lumbricoides, and Strongyloides stercoralis. The results were compared with those obtained by conventional parasitological diagnostic methods. Real-time PCR was positive in 48 of 77 samples (62.3%) and microscopic examination was positive in six samples (7.8%) only (P < 0.05). In conclusion, the real-time PCR assay described in this study provides a specific and sensitive diagnostic tool for the detection of these four helminth species in epidemiological studies and monitoring of treatment programs. PMID- 21292912 TI - Magnetic resonance imaging to assess blood-brain barrier damage in murine trypanosomiasis. AB - The ability of trypanosomes to invade the brain and induce an inflammatory reaction is well-recognized. This study uses magnetic resonance imaging (MRI) in conjunction with a murine model of central nervous system (CNS) stage trypanosomiasis to investigate this phenomenon at the level of the blood-brain barrier (BBB). Mice were scanned before and after administration of the contrast agent. Signal enhancement maps were generated, and the percentage signal change was calculated. The severity of the neuroinflammation was also assessed. Statistical analysis of the signal change data revealed a significantly (P = 0.028) higher signal enhancement in mice at 28 days post-infection (least squares mean = 26.709) compared with uninfected animals (6.298), indicating the presence of BBB impairment. Leukocytes were found in the meninges and perivascular space of some blood vessels in the infected mice. This study shows that the integrity of the BBB is compromised during CNS stage trypanosomiasis and that the impairment does not correlate with inflammatory cell infiltration. PMID- 21292913 TI - Evaluation of nitazoxanide for the treatment of disseminated cystic echinococcosis: report of five cases and literature review. AB - We aimed to evaluate the effectiveness of nitazoxanide in disseminated cystic echinococcosis (DCE) that failed to respond to surgical and antiparasitic therapy. We report on seven patients (five of them with bony involvement): two cases from the literature and five patients who were included in a compassionate trial of nitazoxanide therapy in our hospital. Median follow-up time until nitazoxanide therapy was 12 years and all patients had received prior medical treatment and extensive surgery. Nitazoxanide (500 mg/12 h) in combination with albendazole, with/without praziquantel, was administered for 3-24 months. Three patients improved: one with muscle involvement (clinico-radiological response), one with lung involvement (radiological response), and another with soft tissue and bony involvement (clinico-radiological response of soft tissue cysts). There was one discontinuation after 15 days of starting therapy. Nitazoxanide combination therapy could have a role in the treatment of DCE when there is no bony involvement. Long-term safety profile seems to be favorable. PMID- 21292914 TI - Response to Moore and others (2010) and Mehta (2010). PMID- 21292916 TI - Scaling up malaria control in Zambia: progress and impact 2005-2008. PMID- 21292918 TI - Cyclooxygenase-2 expression is related with localization, proliferation, and overall survival in canine melanocytic neoplasms. AB - A direct relationship has been firmly established between cyclooxygenase-2 (COX 2) expression and malignant behavior in human melanoma. This report examines the relationship between COX-2 expression and tumor location, mitotic and proliferative indices, degree of T CD3(+) lymphocyte infiltration, overall survival, and frequency of recurrence and metastasis of 57 melanocytic tumors (25 oral and 32 cutaneous). COX-2 was highly or moderately expressed in 88% of oral neoplasms (22 of 25), whereas for their cutaneous counterparts, COX-2 expression was low or insignificant in 75% of cases (24 of 32). High and moderate COX-2 expression levels were observed in 73% of melanocytic tumors with a mitotic index >= 3 per 10 high-power fields (26 of 36), whereas in 81% of tumors with a mitotic index < 3 (17 of 21), expression was mild or absent. There were 41 cases with known clinical outcomes; of those showing high, moderate, and mild COX-2 expression, 83.3% (10 of 12), 37.5% (3 of 8), and 25% (2 of 8) died, respectively, whereas 100% of animals showing no COX-2 expression (13 of 13) were still alive at the last follow-up. COX-2 expression was statistically correlated with tumor location, mitotic and percentage Ki-67 proliferative indices, and overall survival, frequency of neoplastic recurrence and metastasis. Regression analysis also showed disease-specific predictive value for COX-2 expression for subjects with melanocytic neoplasms. Additionally, only high COX-2 expression showed significant differences in overall survival, in comparison with moderate, mild, or absent expression. These results suggest that high COX-2 expression may be considered a prognostic biomarker and potentially as a target for therapeutic and preventive strategies in canine melanocytic neoplasms. PMID- 21292919 TI - Congenital IGF1 deficiency tends to confer protection against post-natal development of malignancies. AB - OBJECTIVE: To investigate whether congenital IGF1 deficiency confers protection against development of malignancies, by comparing the prevalence of malignancies in patients with congenital (secondary) deficiency of IGF1 with the prevalence of cancer in their family members. METHOD: Only patients with an ascertained diagnosis of either Laron syndrome (LS), congenital IGHD, congenital multiple pituitary hormone deficiency (cMPHD) including GH or GHRHR defect were included in this study. In addition to our own patients, we performed a worldwide survey and collected data on a total of 538 patients, 752 of their first-degree family members, of which 274 were siblings and 131 were further family members. RESULTS: We found that none of the 230 LS patients developed cancer and that only 1 out of 116 patients with congenital IGHD, also suffering from xeroderma pigmentosum, had a malignancy. Out of 79 patients with GHRHR defects and out of 113 patients with congenital MPHD, we found three patients with cancer in each group. Among the first-degree family members (most heterozygotes) of LS, IGHD and MPHD, we found 30 cases of cancer and 1 suspected. In addition, 31 malignancies were reported among 131 further relatives. CONCLUSIONS: Our findings bear heavily on the relationship between GH/IGF1 and cancer. Homozygous patients with congenital IGF1 deficiency and insensitivity to GH such as LS seem protected from future cancer development, even if treated by IGF1. Patients with congenital IGHD also seem protected. PMID- 21292920 TI - Linear growth and intellectual outcome in children with long-term idiopathic subclinical hypothyroidism. AB - OBJECTIVE: The treatment of children with subclinical hypothyroidism (SH) is controversial for TSH values between 4.5 and 10 mU/l. The aim of this cross sectional, controlled study was to evaluate growth and intellectual outcome in children with persistent SH who have never been treated with levothyroxine. DESIGN AND METHODS: Clinical and auxological parameters, thyroid function, and intellectual outcome were evaluated in 36 children with persistent SH at the age of 9.7+/-0.6 (range 4-18.0) years. Children had been followed longitudinally for 3.3+/-0.3 (range 2.0-9.3) years, from first diagnosis of SH until enrollment in the study. Thirty-six age- and sex-matched children were enrolled in the study as controls. RESULTS: At study entry, height (-0.8+/-0.2 SDS), bone age/chronological age (BA/CA ratio 0.92+/-0.6), and body mass index (BMI -0.1+/ 0.2 SDS) in SH children were normal. Despite long-term duration of SH, none of these parameters showed a worsening with respect to height (-0.7+/-0.2 SDS), BA/CA (0.97+/-0.03), and BMI (-0.1+/-0.2) at the time of first SH detection. None of the children showed overt signs or symptoms of hypothyroidism during the follow-up. Verbal (99.1+/-2.2), performance (100.4+/-1.9), and full-scale (99.7+/ 1.9) intelligence quotient (IQ) scores in SH children were normal and comparable to those of controls. No relationship was detected between IQ scores and the degree or duration of SH. CONCLUSIONS: Persistent SH in children is not associated with alterations in growth, bone maturation, BMI, and cognitive function or other complaints that could be ascribed to SH even after several years without therapeutic intervention. PMID- 21292921 TI - Hypofibrinogenemia in a patient with systemic lupus erythematosus: always a bad sign? Or not. PMID- 21292922 TI - Effectiveness of haloperidol, risperidone and olanzapine in the treatment of first-episode non-affective psychosis: results of a randomized, flexible-dose, open-label 1-year follow-up comparison. AB - The aim of this study was to investigate the long-term effectiveness and efficacy of haloperidol, risperidone and olanzapine in first-episode schizophrenia spectrum disorders. This was a prospective, randomized, open-label study. Data for the present investigation were obtained from a large epidemiological and 3 year longitudinal intervention programme of first-episode psychosis conducted at the University Hospital Marques de Valdecilla, Santander, Spain. One hundred and seventy-four patients were randomly assigned to haloperidol (N = 56), olanzapine (N = 55), or risperidone (N = 63) and followed up for 1 year. The primary effectiveness measure was all causes of treatment discontinuation. Effectiveness analyses were based on intend-to-treat populations. In addition, an analysis based on per protocol populations was conducted in the analysis for clinical efficacy. The treatment discontinuation rate for any cause was higher with haloperidol than with risperidone and olanzapine (chi(2) = 8.517; p = 0.014). The difference in discontinuation rate between risperidone and olanzapine was not significant (chi(2) = 0.063; p = 0.802). There were no significant advantages of any of the three treatments in reducing the severity of psychopathology. Risperidone and olanzapine demonstrated higher effectiveness relative to haloperidol, but the three antipsychotics were equally effective in reducing the severity of psychopathology. Specific clinical programmes and the use of second generation antipsychotics may enhance the effectiveness of antipsychotic treatments. PMID- 21292923 TI - Evidence-based guidelines for the pharmacological treatment of schizophrenia: recommendations from the British Association for Psychopharmacology. AB - These guidelines from the British Association for Psychopharmacology address the scope and targets of pharmacological treatment for schizophrenia. A consensus meeting, involving experts in schizophrenia and its treatment, reviewed key areas and considered the strength of evidence and clinical implications. The guidelines were drawn up after extensive feedback from the participants and interested parties, and cover the pharmacological management and treatment of schizophrenia across the various stages of the illness, including first-episode, relapse prevention, and illness that has proved refractory to standard treatment. The practice recommendations presented are based on the available evidence to date, and seek to clarify which interventions are of proven benefit. It is hoped that the recommendations will help to inform clinical decision making for practitioners, and perhaps also serve as a source of information for patients and carers. They are accompanied by a more detailed qualitative review of the available evidence. The strength of supporting evidence for each recommendation is rated. PMID- 21292924 TI - Sport for all seasons, a new philosophy. PMID- 21292925 TI - Developing healthcare systems to support exercise: exercise as the fifth vital sign. PMID- 21292926 TI - Impact of crisis resolution and home treatment teams on psychiatric admissions in England. AB - BACKGROUND: In 2000/01 crisis resolution and home treatment (CRHT) teams were introduced in England and have been associated in previous studies with reductions in in-patient admissions. AIMS: To examine whether the implementation of CRHT teams has been associated with reductions in admissions. METHOD: We used data from a previous national study for 229 primary care trusts (PCTs) between 1998/99 and 2003/04. We used a robust policy evaluation methodology to simultaneously examine temporal changes (PCTs before versus after the introduction of CRHT teams) and cross-sectional changes (PCTs with and without CRHT teams). RESULTS: Controlling for various confounding factors, using different control groups and estimation methods, we find no significant differences in admissions between PCTs with and without CRHT teams. CONCLUSIONS: Contrary to previous studies, we find no evidence that the CRHT policy per se has made any difference to admissions and suggest a need for more research on the policy as a whole. PMID- 21292927 TI - Unrecognised bipolar disorder in primary care patients with depression. AB - BACKGROUND: Bipolar disorder is complex and can be difficult to diagnose. It is often misdiagnosed as recurrent major depressive disorder. AIMS: We had three main aims. To estimate the proportion of primary care patients with a working diagnosis of unipolar depression who satisfy DSM-IV criteria for bipolar disorder. To test two screening instruments for bipolar disorder (the Hypomania Checklist (HCL-32) and Bipolar Spectrum Diagnostic Scale (BSDS)) within a primary care sample. To assess whether individuals with major depressive disorder with subthreshold manic symptoms differ from those individuals with major depressive disorder but with no or little history of manic symptoms in terms of clinical course, psychosocial functioning and quality of life. METHOD: Two-phase screening study in primary care. RESULTS: Three estimates of the prevalence of undiagnosed bipolar disorder were obtained: 21.6%, 9.6% and 3.3%. The HCL-32 and BSDS questionnaires had quite low positive predictive values (50.0 and 30.1% respectively). Participants with major depressive disorder and with a history of subthreshold manic symptoms differed from those participants with no or little history of manic symptoms on several clinical features and on measures of both psychosocial functioning and quality of life. CONCLUSIONS: Between 3.3 and 21.6% of primary care patients with unipolar depression may have an undiagnosed bipolar disorder. The HCL-32 and BSDS screening questionnaires may be more useful for detecting broader definitions of bipolar disorder than DSM-IV-defined bipolar disorder. Subdiagnostic features of bipolar disorder are relatively common in primary care patients with unipolar depression and are associated with a more morbid course of illness. Future classifications of recurrent depression should include dimensional measures of bipolar symptoms. PMID- 21292928 TI - Clozapine v. chlorpromazine in treatment-naive, first-episode schizophrenia: 9 year outcomes of a randomised clinical trial. AB - BACKGROUND: The differential effects of so-called 'first- and second generation' antipsychotic medications, when given in the first episode, on the long-term outcome of schizophrenia remain to be elucidated. AIMS: We compared the 9-year outcomes of individuals initially randomised to clozapine or chlorpromazine. METHOD: One-hundred and sixty individuals with treatment-naive, first episode schizophrenia or schizophreniform disorder in a mental health centre in Beijing, China were randomised to clozapine or chlorpromazine treatment for up to 2 years,followed by up to an additional 7 years of naturalistic treatment. The primary outcome was remission status for individuals in each group. RESULTS: Individuals in both groups spent essentially equal amounts of time in each clinical state over the follow-up time period(remission, 78%; intermediate, 8%; relapse, 14%). There were no significant differences on other measures of illness severity. The clozapine group was more likely than the chlorpromazine group to remain on the medication to which they were originally assigned (26% v. 10%, P = 0.01). There were no significant differences between the two groups on other secondary efficacy outcomes. CONCLUSIONS: These findings support the comparability in effectiveness between antipsychotic medications but with slightly greater tolerability of clozapine in the treatment of first-episode psychosis. PMID- 21292929 TI - Posterior fixation of the upper cervical spine: contemporary techniques. AB - Instrumentation in the upper cervical spine has changed considerably in the past two decades. Previous stand-alone wiring techniques have been made largely obsolete with the development of occipital segmental plating, transarticular screws, and C1 lateral mass screws, as well as a myriad of C2 fixation options, including pedicle, pars, and translaminar screws. Polyaxial screws and segmental fixation are more user-friendly than stand-alone wiring and provide a stronger construct. Awareness of the risks and benefits associated with the use of modern instrumentation and thorough familiarity with the anatomy of the upper cervical spine are essential to avoid complications and optimize outcomes. PMID- 21292930 TI - Success in orthopaedic training: resident selection and predictors of quality performance. AB - Multiple studies have attempted to determine which attributes are predictive of success during residency as well as the optimal method of selecting residents who possess these attributes. Factors that are consistently ranked as being important in the selection of candidates into orthopaedic residency programs include performance during orthopaedic rotation, United States Medical Licensing Examination (USMLE) Step 1 score, Alpha Omega Alpha Honor Medical Society membership, medical school class rank, interview performance, and letters of recommendation. No consensus exists regarding the best predictors of resident success, but trends do exist. High USMLE Step 1 scores have been shown to correlate with high Orthopaedic In-Training Examination scores and improved surgical skill ratings during residency, whereas higher numbers of medical school clinical honors grades have been correlated to higher overall resident performance, higher residency interpersonal skills grading, higher resident knowledge grading, and higher surgical skills evaluations. Successful resident performance can be measured by evaluating psychomotor abilities, cognitive skills, and affective domain. PMID- 21292931 TI - Reconstruction of soft-tissue injury associated with lower extremity fracture. AB - Soft-tissue loss associated with lower extremity fracture poses a substantial reconstructive challenge. Following stabilization of life-threatening conditions and bony disruptions, the reconstructive team must address the soft-tissue envelope of the limb. The wound is managed with debridement followed by coverage. Coverage options range from basic to complex and include delayed primary closure, healing by secondary intention, skin grafting, local flap coverage, and distant tissue transfer. The choice of soft-tissue coverage method is based on its ability to provide an environment conducive to fracture healing. Understanding the merits and disadvantages of each reconstructive option helps to avoid undertreatment or overtreatment. PMID- 21292932 TI - Lyme disease and the orthopaedic implications of lyme arthritis. AB - Lyme disease is the most common tick-borne disease in the United States and Europe. Increased awareness of the clinical manifestations of the disease is needed to improve detection and treatment. In the acute and late stages, Lyme disease may be difficult to distinguish from other disease processes. The epidemiology and pathophysiology of Lyme disease are directly related to the Borrelia burgdorferi spirochete and its effects on the integumentary, neurologic, cardiac, and musculoskeletal systems. Lyme arthritis is a common clinical manifestation of Lyme disease and should be considered in the evaluation of patients with monoarticular or pauciarticular joint complaints in a geographic area in which Lyme disease is endemic. Management of Lyme arthritis involves eradication of the spirochete with antibiotics. Generally, the prognosis is excellent. Arthroscopic synovectomy is reserved for refractory cases that do not respond to antibiotics. PMID- 21292933 TI - Enhancement of bone formation during distraction osteogenesis: pediatric applications. AB - Delayed bone healing during distraction osteogenesis negatively affects clinical outcome. In addition to autologous bone grafting, several mechanical, chemical, biologic, and external treatment modalities may be employed to promote bone growth during distraction osteogenesis in the pediatric patient. Mechanical approaches include compressive loading of the distraction regenerate, increased frequency of small increments of distraction, and compression-distraction. Intramedullary nailing and submuscular plating can reduce the time in external fixation; however, these techniques are associated with technical difficulties and complications. Exogenous application of low-intensity pulsed ultrasound or pulsed electromagnetic fields may shorten the duration of external fixation. Other promising modalities include diphosphonates, physician-directed use (off label use) of bone morphogenetic proteins, and local injection of bone marrow aspirate and platelet gel at the osteotomy site. Well-designed clinical studies are needed to establish safe and effective guidelines for various modalities to enhance new bone formation during distraction osteogenesis in children. PMID- 21292934 TI - Bone grafting in surgery about the foot and ankle: indications and techniques. AB - Bone grafting is a common procedure in foot and ankle surgery. Historically, autogenous bone graft has most often been harvested from the ipsilateral iliac crest. However, other sites offer similar volumes of cancellous bone and are associated with fewer complications. The ipsilateral proximal tibia, distal tibia, and calcaneus provide adequate amounts of bone graft material for most arthrodesis procedures about the foot and ankle. Emerging techniques have enabled the development of a seemingly unlimited supply of alternative bone graft materials with osteoconductive properties. The osteoprogenitor cells in bone marrow aspirates can be concentrated by use of selective retention systems. These aspirate-matrix composites may be combined with allograft preparations, resulting in a product that promotes osteoconduction, osteoinduction, and osteogenesis with limited morbidity. PMID- 21292935 TI - Total elbow arthroplasty. PMID- 21292936 TI - The formation and fragmentation of disks around primordial protostars. AB - The very first stars to form in the universe heralded an end to the cosmic dark ages and introduced new physical processes that shaped early cosmic evolution. Until now, it was thought that these stars lived short, solitary lives, with only one extremely massive star, or possibly a very wide binary system, forming in each dark-matter minihalo. Here we describe numerical simulations that show that these stars were, to the contrary, often members of tight multiple systems. Our results show that the disks that formed around the first young stars were unstable to gravitational fragmentation, possibly producing small binary and higher-order systems that had separations as small as the distance between Earth and the Sun. PMID- 21292937 TI - Vibrationally quantum-state-specific reaction dynamics of H atom abstraction by CN radical in solution. AB - Solvent collisions can often mask initial disposition of energy to the products of solution-phase chemical reactions. Here, we show with transient infrared absorption spectra obtained with picosecond time resolution that the nascent HCN products of reaction of CN radicals with cyclohexane in chlorinated organic solvents exhibit preferential excitation of one quantum of the C-H stretching mode and up to two quanta of the bending mode. On time scales of approximately 100 to 300 picoseconds, the HCN products undergo relaxation to the vibrational ground state by coupling to the solvent bath. Comparison with reactions of CN radicals with alkanes in the gas phase, known to produce HCN with greater C-H stretch and bending mode excitation (up to two and approximately six quanta, respectively), indicates partial damping of the nascent product vibrational motion by the solvent. The transient infrared spectra therefore probe solvent induced modifications to the reaction free energy surface and chemical dynamics. PMID- 21292938 TI - Cascading effects of bird functional extinction reduce pollination and plant density. AB - Reductions in bird numbers could hamper ecosystem services such as pollination, but experimental proof is lacking. We show that functional extinction of bird pollinators has reduced pollination, seed production, and plant density in the shrub Rhabdothamnus solandri (Gesneriaceae) on the North Island ("mainland") of New Zealand but not on three nearby island bird sanctuaries where birds remain abundant. Pollen limitation of fruit set is strong [pollen limitation index (PLI) = 0.69] and significant on the mainland but small (PLI = 0.15) and nonsignificant on islands. Seed production per flower on the mainland is reduced 84%. Mainland sites have similar adult densities, but 55% fewer juvenile plants per adult, than island sites. Seed addition experiments near adult R. solandri plants on the mainland found strong seed limitation 5 years after sowing for R. solandri but not for two other co-occurring woody species. This demonstrates a terrestrial trophic cascade. PMID- 21292940 TI - Suppression of collisional shifts in a strongly interacting lattice clock. AB - Optical lattice clocks with extremely stable frequency are possible when many atoms are interrogated simultaneously, but this precision may come at the cost of systematic inaccuracy resulting from atomic interactions. Density-dependent frequency shifts can occur even in a clock that uses fermionic atoms if they are subject to inhomogeneous optical excitation. However, sufficiently strong interactions can suppress collisional shifts in lattice sites containing more than one atom. We demonstrated the effectiveness of this approach with a strontium lattice clock by reducing both the collisional frequency shift and its uncertainty to the level of 10(-17). This result eliminates the compromise between precision and accuracy in a many-particle system; both will continue to improve as the number of particles increases. PMID- 21292939 TI - A sorting platform determines the order of protein secretion in bacterial type III systems. AB - Bacterial type III protein secretion systems deliver effector proteins into eukaryotic cells in order to modulate cellular processes. Central to the function of these protein-delivery machines is their ability to recognize and secrete substrates in a defined order. Here, we describe a mechanism by which a type III secretion system from the bacterial enteropathogen Salmonella enterica serovar Typhimurium can sort its substrates before secretion. This mechanism involves a cytoplasmic sorting platform that is sequentially loaded with the appropriate secreted proteins. The sequential loading of this platform, facilitated by customized chaperones, ensures the hierarchy in type III protein secretion. Given the presence of these machines in many important pathogens, these findings can serve as the bases for the development of novel antimicrobial strategies. PMID- 21292941 TI - Lessons from genomics. PMID- 21292945 TI - U.S. science policy. Can Obama strike a deal with House Republicans? PMID- 21292946 TI - Agricultural research. With reforms under way, international centers ask: where is the money? PMID- 21292947 TI - Agbiotech. USDA decides against new regulation of GM crops. PMID- 21292948 TI - U.S. energy policy. Obama shifts focus from emissions to 'clean' energy. PMID- 21292949 TI - Professional development. NIH report urges greater emphasis on training for all graduate students. PMID- 21292950 TI - Human genome 10th anniversary. Waiting for the revolution. PMID- 21292951 TI - Human genome 10th anniversary. Human genetics in the clinic, one click away. PMID- 21292952 TI - Human genome 10th anniversary. The Human Genome (patent) Project. PMID- 21292953 TI - Healthcare venture capital for Africa. PMID- 21292954 TI - Benefits of intertwining teaching and research. PMID- 21292956 TI - Ecology. Better science needed for restoration in the Gulf of Mexico. PMID- 21292957 TI - Genomics. A genome for the environment. PMID- 21292958 TI - Anthropology. Climate and human evolution. PMID- 21292959 TI - Psychology. Happy people live longer. PMID- 21292960 TI - Cell biology. A translational pause to localize. PMID- 21292961 TI - Physics. Exciton quenching and migration in single conjugated polymers. PMID- 21292962 TI - Genome-sequencing anniversary. The human genome at 10: successes and challenges. PMID- 21292963 TI - Genome-sequencing anniversary. Faces of the genome. PMID- 21292964 TI - Genome-sequencing anniversary. A celebration of the genome, part I. PMID- 21292965 TI - Genome-sequencing anniversary. Genomics and clinical relevance. PMID- 21292966 TI - Genome-sequencing anniversary. The golden age of human population genetics. PMID- 21292967 TI - Genome-sequencing anniversary. What defines us? PMID- 21292968 TI - Genome-sequencing anniversary. Bringing genomics and genetics back together. PMID- 21292969 TI - Genome-sequencing anniversary. Painting the genome for the public. PMID- 21292970 TI - A parsimonious model for gene regulation by miRNAs. AB - MicroRNAs (miRNAs) and small interfering RNAs (siRNAs) act with the Argonaute family of proteins to regulate target messenger RNAs (mRNAs) posttranscriptionally. SiRNAs typically induce endonucleolytic cleavage of mRNA with near-perfect complementarity. For targets with less complementarity, both translational repression and mRNA destabilization mechanisms have been implicated in miRNA-mediated gene repression, although the timing, coupling, and relative importance of these events have not been determined. Here, we review gene specific and global approaches that probe miRNA function and mechanism, looking for a unifying model. More systematic analyses of the molecular specificities of the core components coupled with analysis of the relative timing of the different events will ultimately shed light on the mechanism of miRNA-mediated repression. PMID- 21292971 TI - The 2010 Amazon drought. AB - In 2010, dry-season rainfall was low across Amazonia, with apparent similarities to the major 2005 drought. We analyzed a decade of satellite-derived rainfall data to compare both events. Standardized anomalies of dry-season rainfall showed that 57% of Amazonia had low rainfall in 2010 as compared with 37% in 2005 (<=-1 standard deviation from long-term mean). By using relationships between drying and forest biomass responses measured for 2005, we predict the impact of the 2010 drought as 2.2 * 10(15) grams of carbon [95% confidence intervals (CIs) are 1.2 and 3.4], largely longer-term committed emissions from drought-induced tree deaths, compared with 1.6 * 10(15) grams of carbon (CIs 0.8 and 2.6) for the 2005 event. PMID- 21292973 TI - Ultralong-range polaron-induced quenching of excitons in isolated conjugated polymers. AB - In conjugated polymers, radiative recombination of excitons (electron-hole pairs) competes with nonradiative thermal relaxation pathways. We visualized exciton quenching induced by hole polarons in single-polymer chains in a device geometry. The distance-scale for quenching was measured by means of a new subdiffraction, single-molecule technique--bias-modulated intensity centroid spectroscopy--which allowed the extraction of a mean centroid shift of 14 nanometers for highly ordered, single-polymer nanodomains. This shift requires energy transfer over distances an order of magnitude greater than previously reported for bulk conjugated polymers and far greater than predicted by the standard mechanism for exciton quenching, the unbiased diffusion of free excitons to quenching sites. Instead, multistep "energy funneling" to trapped, localized polarons is the probable mechanism for polaron-induced exciton quenching. PMID- 21292974 TI - Two-dimensional nanosheets produced by liquid exfoliation of layered materials. AB - If they could be easily exfoliated, layered materials would become a diverse source of two-dimensional crystals whose properties would be useful in applications ranging from electronics to energy storage. We show that layered compounds such as MoS(2), WS(2), MoSe(2), MoTe(2), TaSe(2), NbSe(2), NiTe(2), BN, and Bi(2)Te(3) can be efficiently dispersed in common solvents and can be deposited as individual flakes or formed into films. Electron microscopy strongly suggests that the material is exfoliated into individual layers. By blending this material with suspensions of other nanomaterials or polymer solutions, we can prepare hybrid dispersions or composites, which can be cast into films. We show that WS(2) and MoS(2) effectively reinforce polymers, whereas WS(2)/carbon nanotube hybrid films have high conductivity, leading to promising thermoelectric properties. PMID- 21292972 TI - The ecoresponsive genome of Daphnia pulex. AB - We describe the draft genome of the microcrustacean Daphnia pulex, which is only 200 megabases and contains at least 30,907 genes. The high gene count is a consequence of an elevated rate of gene duplication resulting in tandem gene clusters. More than a third of Daphnia's genes have no detectable homologs in any other available proteome, and the most amplified gene families are specific to the Daphnia lineage. The coexpansion of gene families interacting within metabolic pathways suggests that the maintenance of duplicated genes is not random, and the analysis of gene expression under different environmental conditions reveals that numerous paralogs acquire divergent expression patterns soon after duplication. Daphnia-specific genes, including many additional loci within sequenced regions that are otherwise devoid of annotations, are the most responsive genes to ecological challenges. PMID- 21292975 TI - Protein native-state stabilization by placing aromatic side chains in N glycosylated reverse turns. AB - N-glycosylation of eukaryotic proteins helps them fold and traverse the cellular secretory pathway and can increase their stability, although the molecular basis for stabilization is poorly understood. Glycosylation of proteins at naive sites (ones that normally are not glycosylated) could be useful for therapeutic and research applications but currently results in unpredictable changes to protein stability. We show that placing a phenylalanine residue two or three positions before a glycosylated asparagine in distinct reverse turns facilitates stabilizing interactions between the aromatic side chain and the first N acetylglucosamine of the glycan. Glycosylating this portable structural module, an enhanced aromatic sequon, in three different proteins stabilizes their native states by -0.7 to -2.0 kilocalories per mole and increases cellular glycosylation efficiency. PMID- 21292976 TI - Seasonal erosion and restoration of Mars' northern polar dunes. AB - Despite radically different environmental conditions, terrestrial and martian dunes bear a strong resemblance, indicating that the basic processes of saltation and grainfall (sand avalanching down the dune slipface) operate on both worlds. Here, we show that martian dunes are subject to an additional modification process not found on Earth: springtime sublimation of Mars' CO(2) seasonal polar caps. Numerous dunes in Mars' north polar region have experienced morphological changes within a Mars year, detected in images acquired by the High-Resolution Imaging Science Experiment on the Mars Reconnaissance Orbiter. Dunes show new alcoves, gullies, and dune apron extension. This is followed by remobilization of the fresh deposits by the wind, forming ripples and erasing gullies. The widespread nature of these rapid changes, and the pristine appearance of most dunes in the area, implicates active sand transport in the vast polar erg in Mars' current climate. PMID- 21292977 TI - Directed evolution of a protein container. AB - Confinement of enzymes in protein nanocompartments represents a potentially powerful strategy for controlling catalytic activity in cells. By using a simple electrostatically based tagging system for protein encapsulation, we successfully sequestered HIV protease, a toxic enzyme when produced cytoplasmically, within an engineered lumazine synthase capsid. The growth advantage resulting from protecting the Escherichia coli host from the protease enabled directed evolution of improved capsids. After four rounds of mutagenesis and selection, we obtained a variant with a 5- to 10-fold higher loading capacity than the starting capsid, which permitted efficient growth even at high intracellular concentrations of HIV protease. The superior properties of the evolved capsid can be ascribed to multiple mutations that increase the net negative charge on its luminal surface and thereby enhance engineered Coulombic interactions between host and guest. Such structures could be used for diverse biotechnological applications in living cells. PMID- 21292978 TI - A cryptic subgroup of Anopheles gambiae is highly susceptible to human malaria parasites. AB - Population subgroups of the African malaria vector Anopheles gambiae have not been comprehensively characterized owing to the lack of unbiased sampling methods. In the arid savanna zone of West Africa, where potential oviposition sites are scarce, widespread collection from larval pools in the peridomestic human habitat yielded a comprehensive genetic survey of local A. gambiae population subgroups, independent of adult resting behavior and ecological preference. A previously unknown subgroup of exophilic A. gambiae is sympatric with the known endophilic A. gambiae in this region. The exophilic subgroup is abundant, lacks differentiation into M and S molecular forms, and is highly susceptible to infection with wild Plasmodium falciparum. These findings might have implications for the epidemiology of malaria transmission and control. PMID- 21292979 TI - Action-potential modulation during axonal conduction. AB - Once initiated near the soma, an action potential (AP) is thought to propagate autoregeneratively and distribute uniformly over axonal arbors. We challenge this classic view by showing that APs are subject to waveform modulation while they travel down axons. Using fluorescent patch-clamp pipettes, we recorded APs from axon branches of hippocampal CA3 pyramidal neurons ex vivo. The waveforms of axonal APs increased in width in response to the local application of glutamate and an adenosine A(1) receptor antagonist to the axon shafts, but not to other unrelated axon branches. Uncaging of calcium in periaxonal astrocytes caused AP broadening through ionotropic glutamate receptor activation. The broadened APs triggered larger calcium elevations in presynaptic boutons and facilitated synaptic transmission to postsynaptic neurons. This local AP modification may enable axonal computation through the geometry of axon wiring. PMID- 21292980 TI - The pleiotropic mouse phenotype extra-toes spotting is caused by translation initiation factor Eif3c mutations and is associated with disrupted sonic hedgehog signaling. AB - Polydactyly is a common malformation and can be an isolated anomaly or part of a pleiotropic syndrome. The elucidation of the mutated genes that cause polydactyly provides insight into limb development pathways. The extra-toes spotting (Xs) mouse phenotype manifests anterior polydactyly, predominantly in the forelimbs, with ventral hypopigmenation. The mapping of Xs(J) to chromosome 7 was confirmed, and the interval was narrowed to 322 kb using intersubspecific crosses. Two mutations were identified in eukaryotic translation initiation factor 3 subunit C (Eif3c). An Eif3c c.907C>T mutation (p.Arg303X) was identified in Xs(J), and a c.1702_1758del mutation (p.Leu568_Leu586del) was identified in extra-toes spotting-like (Xsl), an allele of Xs(J). The effect of the Xs(J) mutation on the SHH/GLI3 pathway was analyzed by in situ hybridization analysis, and we show that Xs mouse embryos have ectopic Shh and Ptch1 expression in the anterior limb. In addition, anterior limb buds show aberrant Gli3 processing, consistent with perturbed SHH/GLI3 signaling. Based on the occurrence of Eif3c mutations in 2 Xs lines and haploinsufficiency of the Xs(J) allele, we conclude that the Xs phenotype is caused by a mutation in Eif3c, a component of the translation initiation complex, and that the phenotype is associated with aberrant SHH/GLI3 signaling. PMID- 21292981 TI - Asparagine endopeptidase is required for normal kidney physiology and homeostasis. AB - Although protein recapture and catabolism is known as a key function of kidney proximal tubular cells (PTCs), to date, no single protease has been shown to be required. Asparagine endopeptidase (AEP) is an unusually specific endosomal and lysosomal cysteine protease, expressed at high levels in the PTCs of the mammalian kidney. We report that mice lacking AEP accumulate a discrete set of proteins in their PTC endosomes and lysosomes, which indicates a defect in the normal catabolism of proteins captured from the filtrate. Moreover, the mice develop progressive kidney pathology, including hyperplasia of PTCs, interstitial fibrosis, development of glomerular cysts, and renal pelvis dilation. By 6 mo of age, the glomerular filtration rate in AEP-null mice dropped by almost a factor of 2, and the mice developed proteinuria. We also show that EGF receptor levels are significantly higher in AEP-null PTCs, which likely explains the hyperplasia, and we show that chemical inhibition of AEP activity suppresses down-regulation of the EGF receptor in vitro. Thus, AEP is required for normal protein catabolism by PTCs, and its loss induces proliferative and other abnormalities in the murine kidney, at least in part through defective regulation of the EGF receptor. PMID- 21292982 TI - Ribosome recycling depends on a mechanistic link between the FeS cluster domain and a conformational switch of the twin-ATPase ABCE1. AB - Despite some appealing similarities of protein synthesis across all phyla of life, the final phase of mRNA translation has yet to be captured. Here, we reveal the ancestral role and mechanistic principles of the newly identified twin-ATPase ABCE1 in ribosome recycling. We demonstrate that the unique iron-sulfur cluster domain and an ATP-dependent conformational switch of ABCE1 are essential both for ribosome binding and recycling. By direct (11) interaction, the peptide release factor aRF1 is shown to synergistically promote ABCE1 function in posttermination ribosome recycling. Upon ATP binding, ABCE1 undergoes a conformational switch from an open to a closed ATP-occluded state, which drives ribosome dissociation as well as the disengagement of aRF1. ATP hydrolysis is not required for a single round of ribosome splitting but for ABCE1 release from the 30S subunit to reenter a new cycle. These results provide a mechanistic understanding of final phases in mRNA translation. PMID- 21292983 TI - General purpose computer-assisted clustering and conceptualization. AB - We develop a computer-assisted method for the discovery of insightful conceptualizations, in the form of clusterings (i.e., partitions) of input objects. Each of the numerous fully automated methods of cluster analysis proposed in statistics, computer science, and biology optimize a different objective function. Almost all are well defined, but how to determine before the fact which one, if any, will partition a given set of objects in an "insightful" or "useful" way for a given user is unknown and difficult, if not logically impossible. We develop a metric space of partitions from all existing cluster analysis methods applied to a given dataset (along with millions of other solutions we add based on combinations of existing clusterings) and enable a user to explore and interact with it and quickly reveal or prompt useful or insightful conceptualizations. In addition, although it is uncommon to do so in unsupervised learning problems, we offer and implement evaluation designs that make our computer-assisted approach vulnerable to being proven suboptimal in specific data types. We demonstrate that our approach facilitates more efficient and insightful discovery of useful information than expert human coders or many existing fully automated methods. PMID- 21292985 TI - Microdissection of neural networks by conditional reporter expression from a Brainbow herpesvirus. AB - Transneuronal transport of neurotropic viruses is widely used to define the organization of neural circuitry in the mature and developing nervous system. However, interconnectivity within complex circuits limits the ability of viral tracing to define connections specifically linked to a subpopulation of neurons within a network. Here we demonstrate a unique viral tracing technology that highlights connections to defined populations of neurons within a larger labeled network. This technology was accomplished by constructing a replication-competent strain of pseudorabies virus (PRV-263) that changes the profile of fluorescent reporter expression in the presence of Cre recombinase (Cre). The viral genome carries a Brainbow cassette that expresses a default red reporter in infected cells. However, in the presence of Cre, the red reporter gene is excised from the genome and expression of yellow or cyan reporters is enabled. We used PRV-263 in combination with a unique lentivirus vector that produces Cre expression in catecholamine neurons. Projection-specific infection of central circuits containing these Cre-expressing catecholamine neurons with PRV-263 resulted in Cre-mediated recombination of the PRV-263 genome and conditional expression of cyan/yellow reporters. Replication and transneuronal transport of recombined virus produced conditional reporter expression in neurons synaptically linked to the Cre-expressing catecholamine neurons. This unique technology highlights connections specific to phenotypically defined neurons within larger networks infected by retrograde transneuronal transport of virus from a defined projection target. The availability of other technologies that restrict Cre expression to defined populations of neurons indicates that this approach can be widely applied across functionally defined systems. PMID- 21292986 TI - Real-time analysis of double-strand DNA break repair by homologous recombination. AB - The ability to induce synchronously a single site-specific double-strand break (DSB) in a budding yeast chromosome has made it possible to monitor the kinetics and genetic requirements of many molecular steps during DSB repair. Special attention has been paid to the switching of mating-type genes in Saccharomyces cerevisiae, a process initiated by the HO endonuclease by cleaving the MAT locus. A DSB in MATa is repaired by homologous recombination--specifically, by gene conversion--using a heterochromatic donor, HMLalpha. Repair results in the replacement of the a-specific sequences (Ya) by Yalpha and switching from MATa to MATalpha. We report that MAT switching requires the DNA replication factor Dpb11, although it does not require the Cdc7-Dbf4 kinase or the Mcm and Cdc45 helicase components. Using Southern blot, PCR, and ChIP analysis of samples collected every 10 min, we extend previous studies of this process to identify the times for the loading of Rad51 recombinase protein onto the DSB ends at MAT, the subsequent strand invasion by the Rad51 nucleoprotein filament into the donor sequences, the initiation of new DNA synthesis, and the removal of the nonhomologous Y sequences. In addition we report evidence for the transient displacement of well-positioned nucleosomes in the HML donor locus during strand invasion. PMID- 21292987 TI - Toll in the vessel wall--for better or worse? PMID- 21292988 TI - Elixir of life: In vino veritas. PMID- 21292989 TI - Antigen-stimulated CD4 T-cell expansion is inversely and log-linearly related to precursor number. AB - Antigen-driven expansion of specific CD4 T cells diminishes, on a per cell basis, as infused cell number increases. There is a linear relation between log precursor number and log factor of expansion (FE), with a slope of ~-0.5 over a range from 3 to 30,000 precursors. Cell number dependence of FE is observed at low precursor number, implying that the underlying process physiologically regulates antigen-driven T-cell expansion. FE of small numbers of transgenic precursors is not significantly affected by concomitant responses of large numbers of cells specific for different antigens. Increasing antigen amount or exogenous IL-2, IL-7, or IL-15 does not significantly affect FE, nor does FE depend on Fas, TNF-alpha receptor, cytotoxic T-lymphocyte antigen-4, IL-2, or IFN gamma. Small numbers of Foxp3-deficient T-cell receptor transgenic cells expand to a greater extent than do large numbers, implying that this effect is not mediated by regulatory T cells. Increasing dendritic cell number does result in larger FE, but the quantitative relation between FE and precursor number is not abrogated. Although not excluding competition for peptide/MHC complexes as an explanation, fall in FE with increasing precursor number could be explained by a negative feedback in which increasing numbers of responding cells in a cluster inhibit the expansion of cells of the same specificity within that cluster. PMID- 21292990 TI - Feedback regulation of proliferation vs. differentiation rates explains the dependence of CD4 T-cell expansion on precursor number. AB - The mechanisms regulating clonal expansion and contraction of T cells in response to immunization remain to be identified. A recent study established that there was a log-linear relation between CD4 T-cell precursor number (PN) and factor of expansion (FE), with a slope of ~-0.5 over a range of 3-30,000 precursors per mouse. The results suggested inhibition of precursor expansion either by competition for specific antigen-presenting cells or by the action of other antigen-specific cells in the same microenvironment as the most likely explanation. Several molecular mechanisms potentially accounting for such inhibition were examined and rejected. Here we adopt a previously proposed concept, "feedback-regulated balance of growth and differentiation," and show that it can explain the observed findings. We assume that the most differentiated effectors (or memory cells) limit the growth of less differentiated effectors, locally, by increasing the rate of differentiation of the latter cells in a dose dependent manner. Consequently, expansion is blocked and reversed after a delay that depends on initial PN, accounting for the dependence of the peak of the response on that number. We present a parsimonious mathematical model capable of reproducing immunization response kinetics. Model definition is achieved in part by requiring consistency with available BrdU-labeling and carboxyfluorescein diacetate succinimidyl ester (CFSE)-dilution data. The calibrated model correctly predicts FE as a function of PN. We conclude that feedback-regulated balance of growth and differentiation, although awaiting definite experimental characterization of the hypothetical cells and molecules involved in regulation, can explain the kinetics of CD4 T-cell responses to antigenic stimulation. PMID- 21292991 TI - Pulmonary vascular response patterns during exercise in left ventricular systolic dysfunction predict exercise capacity and outcomes. AB - BACKGROUND: Elevated resting pulmonary arterial pressure (PAP) in patients with left ventricular systolic dysfunction (LVSD) purports a poor prognosis. However, PAP response patterns to exercise in LVSD and their relationship to functional capacity and outcomes have not been characterized. METHODS AND RESULTS: Sixty consecutive patients with LVSD (age 60+/-12 years, left ventricular ejection fraction 0.31+/-0.07, mean+/-SD) and 19 controls underwent maximum incremental cardiopulmonary exercise testing with simultaneous hemodynamic monitoring. During low-level exercise (30 W), LVSD subjects, compared with controls, had greater augmentation in mean PAPs (15+/-1 versus 5+/-1 mm Hg), transpulmonary gradients (5+/-1 versus 1+/-1 mm Hg), and effective pulmonary artery elastance (0.05+/-0.02 versus -0.03+/-0.01 mm Hg/mL, P<0.0001 for all). A linear increment in PAP relative to work (0.28+/-0.12 mm Hg/W) was observed in 65% of LVSD patients, which exceeded that observed in controls (0.07+/-0.02 mm Hg/W, P<0.0001). Exercise capacity and survival was worse in patients with a PAP/watt slope above the median than in patients with a lower slope. In the remaining 35% of LVSD patients, exercise induced a steep initial increment in PAP (0.41+/-0.16 mm Hg/W) followed by a plateau. The plateau pattern, compared with a linear pattern, was associated with reduced peak Vo(2) (10.6+/-2.6 versus 13.1+/-4.0 mL . kg(-1) . min(-1), P=0.005), lower right ventricular stroke work index augmentation with exercise (5.7+/-3.8 versus 9.7+/-5.0 g/m(2), P=0.002), and increased mortality (hazard ratio 8.1, 95% CI 2.7 to 23.8, P<0.001). CONCLUSIONS: A steep increment in PAP during exercise and failure to augment PAP throughout exercise are associated with decreased exercise capacity and survival in patients with LVSD, and may therefore represent therapeutic targets. CLINICAL TRIAL INFORMATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00309790. PMID- 21292992 TI - Comparison of mass spectrometry and clinical assay measurements of circulating fragments of B-type natriuretic peptide in patients with chronic heart failure. AB - BACKGROUND: Multiple B-type natriuretic peptide (BNP) fragments circulate in patients with heart failure (HF) but the types and relative quantities, particularly in relation to bioactive BNP 1-32, remain poorly defined. The purpose of the study was to relate clinically available BNP values with quantitative information on the concentration of pre-secretion and post-processed fragments of BNP detected by mass spectrometry. METHODS AND RESULTS: Seventy Class I-IV patients were prospectively enrolled with blood drawn into tubes containing a preservative to protect against BNP degradation. Samples were analyzed by quantitative mass spectrometry (MS) immunoassay for intact BNP 1-32 and its fragments. Clinical BNP 1-2 was measured by standard clinical laboratory methods. ProBNP 1-108, corin, and clinically measured BNP levels were elevated, but MS BNP 1-32 levels were low and differed from clinical BNP (P=0.01). Intact MS BNP 1-32 correlated modestly with clinical BNP (r=0.46, P<0.001). MS BNP fragments 3-32, 4-32, and 5-32 demonstrated the best associations with clinical BNP; fragment 5-32 with a correlation coefficient of r=0.81 (P<0.001). CONCLUSIONS: ProBNP 1-108 is measured by clinical BNP assays and contributes to the cumulative results of the BNP assay. However, the observation that clinically measured BNP correlates best with MS degradation fragments and relatively poorly with MS BNP 1-32 suggests that a significant component of circulating clinical BNP is composed of such fragments that are known to demonstrate little biological activity. There appear to be multiple pathways involved in the dysregulation of proBNP in HF, and both the processing of proBNP and the downstream degradation to BNP 1-32 appear to be critical. PMID- 21292993 TI - Accumulation of CD4+ T cells in the colon of CsA-treated mice following myeloablative conditioning and bone marrow transplantation. AB - Syngeneic graft vs. host disease (SGVHD) was first described as a graft vs. host disease-like syndrome that developed in rats following syngeneic bone marrow transplantation (BMT) and cyclosporin A (CsA) treatment. SGVHD can be induced by reconstitution of lethally irradiated mice with syngeneic bone marrow cells followed by 21 days of treatment with the immunosuppressive agent CsA. Clinical symptoms of the disease appear 2-3 wk following cessation of CsA therapy, and disease-associated inflammation occurs primarily in the colon and liver. CD4(+) T cells have been shown to play an important role in the inflammatory response observed in the gut of SGVHD mice. Time-course studies revealed a significant increase in migration of CD4(+) T cells into the colon during CsA therapy, as well as significantly elevated mRNA levels of TNF-alpha, proinflammatory chemokines, and cell adhesion molecules in colonic tissue of CsA-treated animals compared with BMT controls, as early as day 14 post-BMT. Homing studies revealed a greater migration of labeled CD4(+) T cells into the gut of CsA-treated mice at day 21 post-BMT than control animals via CsA-induced upregulation of mucosal addressin cell adhesion molecule. This study demonstrates that, during the 21 days of immunosuppressive therapy, functional mechanisms are in place that result in increased homing of CD4(+) T effector cells to colons of CsA-treated mice. PMID- 21292994 TI - Iron loading and oxidative stress in the Atm-/- mouse liver. AB - Ataxia-Telangiectasia (A-T) is an autosomal recessive disorder resulting in a myriad of abnormalities, including progressive neurodegeneration and cancer predisposition. At the cellular level, A-T is a disease of chronic oxidative stress (OS) causing damage to proteins, lipids, and DNA. OS is contributed to by pro-oxidative transition metals such as iron that catalyze the conversion of weakly reactive oxygen species to highly reactive hydroxyl radicals. Iron associated OS has been linked to neurodegeneration in Alzheimer's and Parkinson's diseases and development of lymphoid tumors (which afflict ~30% of A-T patients). To investigate iron regulation in A-T, iron indexes, regulatory genes, and OS markers were studied in livers of wild-type and Ataxia telangiectasia mutated (Atm) null mice on control or high-iron diets. Atm(-/-) mice had increased serum iron, hepatic iron, and ferritin and significantly higher Hepcidin compared with wild-type mice. When challenged with the high-iron diet, Bmp6 and Hfe expression was significantly increased. Atm(-/-) mice had increased protein tyrosine nitration and significantly higher Heme Oxygenase (decycling) 1 levels that were substantially increased by a high-iron diet. Ferroportin gene expression was significantly increased; however, protein levels were unchanged. We demonstrate that Atm(-/-) mice have a propensity to accumulate iron that is associated with a significant increase in hepatic OS. The iron-induced increase in hepcidin peptide in turn suppresses ferroportin protein levels, thus nullifying the upregulation of mRNA expression in response to increased OS. Our results suggest that increased iron status may contribute to the chronic OS seen in A-T patients and development of disease pathology. PMID- 21292995 TI - Alterations of serum protein N-glycosylation in two mouse models of chronic liver disease are hepatocyte and not B cell driven. AB - N-glycosylation of immunoglobulin G (IgG) has an important impact on the modification of the total serum N-glycome in chronic liver patients. Our aim was to determine the role and magnitude of the alterations in which hepatocytes and B cells are involved in two mouse models of chronic liver disease. Common bile duct ligation (CBDL) and subcutaneous injections with CCl(4) were induced in B cell deficient and wild-type (WT) mice. IgG depletion was performed with beads covered with protein A/G and the depletions were evaluated by SDS-PAGE and Western blot analysis. N-glycan analysis was performed by improved DSA-FACE technology. Structural analysis of the mouse serum N-glycans was performed by exoglycosidase digests and MALDI-TOF mass spectrometry of permethylated glycans. The alterations seen in B cell-deficient mice closely resembled the alterations in WT mice, in both the CBDL and the CCl(4) models. N-glycan analysis of the IgG fraction in both mouse models revealed different changes compared with humans. Overall, the impact of IgG glycosylation on total serum glycosylation was marginal. Interestingly, the amount of fibrosis present in CBDL B cell-deficient mice was significantly increased compared with CBDL WT mice, whereas the opposite was true for the CCl(4) model as determined by Sirius red staining. However, this had no major effect on the alteration of N-glycosylation of serum proteins. Alterations of total serum N-glycome in mouse models of chronic liver disease are hepatocyte driven. Undergalactosylation of IgG is not present in mouse models of chronic liver disease. PMID- 21292996 TI - Sry-box (Sox) transcription factors in gastrointestinal physiology and disease. AB - The genetic mechanisms underlying tissue maintenance of the gastrointestinal tract are critical for the proper function of the digestive system under normal physiological stress. The identification of transcription factors and related signal transduction pathways that regulate stem cell maintenance and lineage allocation is attractive from a clinical standpoint in that it may provide targets for novel cell- or drug-based therapies. Sox [sex-determining region Y (Sry) box-containing] factors are a family of transcription factors that are emerging as potent regulators of stem cell maintenance and cell fate decisions in multiple organ systems and might provide valuable insight toward the understanding of these processes in endodermally derived tissues of the gastrointestinal tract. In this review, we focus on the known genetic functions of Sox factors and their roles in epithelial tissues of the esophagus, stomach, intestine, colon, pancreas, and liver. Additionally, we discuss pathological conditions in the gastrointestinal tract that are associated with a dysregulation of Sox factors. Further study of Sox factors and their role in gastrointestinal physiology and pathophysiology may lead to advances that facilitate control of tissue maintenance and development of advanced clinical therapies. PMID- 21292997 TI - Fibrosis is regulated by Th2 and Th17 responses and by dynamic interactions between fibroblasts and macrophages. AB - Dysregulated wound healing leads to fibrosis, whereby fibroblasts synthesize excess extracellular matrix and scarring impairs proper organ function. Although fibrotic diseases arise from diverse causes and display heterogeneous features, fibrosis commonly associates with chronic inflammation. Recent discoveries reinforce the idea that communication between fibroblasts, macrophages, and CD4 T cells integrates the processes of wound healing and host defense. Signals between macrophages and fibroblasts can exacerbate, suppress, or reverse fibrosis. Fibroblasts and macrophages are activated by T cells, but their activation also engages negative feedback loops that reduce fibrosis by restraining the immune response, particularly when the Th2 cytokine IL-13 contributes to pathology. Thus the interactions among fibroblasts, macrophages, and CD4 T cells likely play general and critical roles in initiating, perpetuating, and resolving fibrosis in both experimental and clinical conditions. PMID- 21292999 TI - Impact of CCR7 on the gastrointestinal field effect. AB - Standardized intestinal manipulation (IM) leads to local bowel wall inflammation subsequently spreading over the entire gastrointestinal tract. Previously, we demonstrated that this so-called gastrointestinal field effect (FE) is immune mediated. This study aimed to investigate the role of CCR7 in IM-induced FE. Since CCR7 is expressed on activated dendritic cells and T cells and is well known to control their migration, we hypothesized that lack of CCR7 reduces or abolishes FE. Small bowel muscularis and colonic muscularis from CCR7(-/-) and wild-type (WT) mice were obtained after IM of the jejunum or sham operation. FE was analyzed by measuring gastrointestinal transit time of orally given fluorescent dextran (geometric center), colonic transit time, infiltration of MPO positive cells, and circular smooth muscle contractility. Furthermore, mRNA levels of the inflammatory cytokine IL-6 were determined by RT-PCR. The number of dendritic cells and CD3+CD25+ T cells separately isolated from jejunum and colon was determined in mice after IM and sham operation. There was no significant difference in IL-6 mRNA upregulation in colonic muscularis between sham-operated WT and CCR7(-/-) mice after IM. Contractility of circular muscularis strips of the colon was significantly improved in CCR7(-/-) animals following IM and did not vary significantly from sham-operated animals. Additionally, inflammation of the colon determined by the number of MPO-positive cells and colonic transit time was significantly reduced in CCR7(-/-) mice. In contrast, jejunal contractility and jejunal inflammation of transgenic mice did not differ significantly from WT mice after IM. These data are supported by a significant increase of CD3+CD25+ T cells in the colonic muscularis of WT mice after IM, which could not be observed in CCR7(-/-) mice. These data demonstrate that CCR7 is required for FE and postoperative ileus. CCR7 indirectly affects FE by inhibiting migration of activated dendritic cells and of T cells from the jejunum to the colon. These findings support the critical role of the adaptive immune system in FE. PMID- 21292998 TI - TNF-alpha potentiates lysophosphatidic acid-induced COX-2 expression via PKD in human colonic myofibroblasts. AB - The myofibroblast (MFB) has recently been identified as an important mediator of tumor necrosis factor-alpha (TNF-alpha)-associated colitis and cancer, but the mechanism(s) involved remains incompletely understood. Here, we show that treatment of 18Co cells, a model of human colonic MFBs, with TNF-alpha and lysophosphatidic acid (LPA) induced striking synergistic cyclooxygenase-2 (COX-2) protein expression and production of PGE(2). This effect was prevented by the LPA(1) receptor antagonist Ki16425, the G(ialpha)-specific inhibitor pertussis toxin, and by the preferential protein kinase (PK) C inhibitors GF109203X and Go6983. As a known downstream target of LPA and PKC, we tested whether PKD, recently implicated in the regulation of COX-2 expression in MFB, was involved in this response. TNF-alpha, while having no detectable effect on the activation of PKD when added alone, augmented PKD activation stimulated by LPA, as measured by PKD autophosphorylation at Ser(910). LPA-induced PKD activation was also inhibited by Ki16425, pertussis toxin, GF109203X, and Go6983. Transfection of 18Co cells with short interfering RNA targeting PKD completely inhibited the synergistic increase in COX-2 protein, demonstrating a critical role of PKD in this response. Our results imply that cross talk between TNF-alpha and LPA results in the amplification of COX-2 protein expression via a conserved PKD dependent signaling pathway that appears to involve the LPA(1) receptor and the G protein G(ialpha). PKD plays a critical role in the expression of COX-2 in human colonic MFBs and may contribute to an inflammatory microenvironment that promotes tumor growth. PMID- 21293000 TI - Altered adrenal chromaffin cell function during experimental colitis. AB - The sympathetic nervous system regulates visceral function through the release of catecholamines and cotransmitters from postganglionic sympathetic neurons and adrenal chromaffin cells (ACCs). Previous studies have shown that norepinephrine secretion is decreased during experimental colitis due to the inhibition of voltage-gated Ca(2+) current (I(Ca)) in postganglionic sympathetic neurons. The present study examined whether colonic inflammation causes a similar impairment in depolarization-induced Ca(2+) influx in ACCs using the dextran sulfate sodium (DSS) model of acute colitis in mice. Alterations in ACC function during colitis were assessed using fura 2-acetoxymethyl ester Ca(2+) imaging techniques and perforated patch-clamp electrophysiology. In ACCs isolated from mice with DSS induced acute colitis, the high-K(+)-stimulated increase in intracellular Ca(2+) concentration ([Ca(2+)](i)) was significantly reduced to 74% of the response of ACCs from control mice. Acute colitis caused a 10-mV hyperpolarization of ACC resting membrane potential, without a significant effect on cellular excitability. Delayed-rectifier K(+) and voltage-gated Na(+) current densities were significantly enhanced in ACCs from mice with DSS-induced acute colitis, with peak current densities of 154 and 144% that of controls, respectively. Importantly, acute colitis significantly inhibited I(Ca) in ACCs between -25 and +20 mV. Peak I(Ca) density in ACCs from mice with DSS-induced acute colitis was 61% that of controls. High-K(+)-induced increases in [Ca(2+)](i) were also reduced in ACCs from mice with 2,4,6-trinitrobenzene sulfonic acid-induced acute colitis and DSS-induced chronic colitis to 68 and 78% of the control responses, respectively. Our results suggest that, during colitis, voltage-dependent Ca(2+) influx is impaired in ACCs. Given the importance of Ca(2+) signaling in exocytosis, these alterations may decrease systemic catecholamine levels, which could play an important role in inflammatory bowel disease. This is the first demonstration of aberrant ACC function during experimental colitis. PMID- 21293001 TI - Human resistin stimulates hepatic overproduction of atherogenic ApoB-containing lipoprotein particles by enhancing ApoB stability and impairing intracellular insulin signaling. AB - RATIONALE: Obese individuals are at high risk for developing atherosclerosis primarily attributable to elevated plasma concentrations of apolipoprotein (apo)B containing particles, including very-low-density lipoprotein (VLDL). Plasma levels of the adipose tissue adipokine resistin are increased in human obesity, and resistin expression is positively correlated with coronary atherosclerosis and VLDL levels. OBJECTIVE: We sought to determine for the first time whether resistin directly stimulates human hepatocyte production of apoB-containing particles and to elucidate the mechanisms responsible. METHODS AND RESULTS: Treatment of human hepatocytes with resistin at levels observed in human obesity stimulated apoB secretion up to 10-fold, because of increased microsomal triglyceride transfer protein (MTP) activity and decreased expression/phosphorylation of proteins in the insulin signaling pathways (insulin receptor substrate-2, Akt, and extracellular signal-regulated kinase). Resistin also increased hepatocyte lipid content by stimulating de novo lipogenesis via the SREBP1 and SREBP2 pathways. Furthermore, obese serum with elevated resistin levels induced greater hepatocyte stimulation of apoB secretion than lean human serum, an effect that was ameliorated by antibody immunoprecipitation removal of serum resistin. CONCLUSIONS: Resistin has a direct deleterious impact on human hepatic lipid and lipoprotein regulation. Resistin greatly increased hepatocyte VLDL apoB and lipid secretion because of MTP activation and induction of hepatocyte insulin resistance. Conversely, antibody removal of serum resistin ameliorated human serum stimulation of apoB secretion. Increased hepatic cellular lipids mediated by resistin reflects the fatty liver/steatosis observed with elevated resistin in humans. Thus, human resistin is a novel therapeutic target for mitigating common hepatic pathophysiological processes associated with human obesity, dyslipidemia and atherosclerosis. PMID- 21293002 TI - ATP production rate via creatine kinase or ATP synthase in vivo: a novel superfast magnetization saturation transfer method. AB - RATIONALE: 31P magnetization saturation transfer (MST) experiment is the most widely used method to study ATP metabolism kinetics. However, its lengthy data acquisition time greatly limits the wide biomedical applications in vivo, especially for studies requiring high spatial and temporal resolutions. OBJECTIVE: We aimed to develop a novel superfast MST method that can accurately quantify ATP production rate constants (k(f)) through creatine kinase (CK) or ATP synthase (ATPase) with 2 spectra. METHODS AND RESULTS: The T1(nom) (T1 nominal) method uses a correction factor to compensate the partially relaxed MST experiments, thus allowing measurement of enzyme kinetics with an arbitrary repetition time and flip angle, which consequently reduces the data acquisition time of a transmurally differentiated CK k(f) measurement by 91% as compared with the conventional method with spatial localization. The novel T1(nom) method is validated theoretically with numeric simulation, and further verified with in vivo swine hearts, as well as CK and ATPase activities in rat brain at 9.4 Tesla. Importantly, the in vivo data from swine hearts demonstrate, for the first time, that within an observation window of 30 minutes, the inhibition of CK activity by iodoacetamide does not limit left ventricular chamber contractile function. CONCLUSIONS: A novel MST method for superfast examination of enzyme kinetics in vivo has been developed and verified theoretically and experimentally. In the in vivo normal heart, redundant multiple supporting systems of myocardial ATP production, transportation, and utilization exist, such that inhibition of one mechanism does not impair the normal left ventricular contractile performance. PMID- 21293003 TI - Docking protein Gab1 is an essential component of postnatal angiogenesis after ischemia via HGF/c-met signaling. AB - RATIONALE: Grb2-associated binder (Gab) docking proteins, consisting of Gab1, Gab2, and Gab3, have crucial roles in growth factor-dependent signaling. Various proangiogenic growth factors regulate angiogenesis and endothelial function. However, the roles of Gab proteins in angiogenesis remain elusive. OBJECTIVE: To elucidate the role of Gab proteins in postnatal angiogenesis. METHODS AND RESULTS: Endothelium-specific Gab1 knockout (Gab1ECKO) mice were viable and showed no obvious defects in vascular development. Therefore, we analyzed a hindlimb ischemia (HLI) model of control, Gab1ECKO, or conventional Gab2 knockout (Gab2KO) mice. Intriguingly, impaired blood flow recovery and necrosis in the operated limb was observed in all of Gab1ECKO, but not in control or Gab2KO mice. Among several proangiogenic growth factors, hepatocyte growth factor (HGF) induced the most prominent tyrosine phosphorylation of Gab1 and subsequent complex formation of Gab1 with SHP2 (Src homology-2-containing protein tyrosine phosphatase 2) and phosphatidylinositol 3-kinase subunit p85 in human endothelial cells (ECs). Gab1-SHP2 complex was required for HGF-induced migration and proliferation of ECs via extracellular signal-regulated kinase (ERK)1/2 pathway and for HGF-induced stabilization of ECs via ERK5. In contrast, Gab1-p85 complex regulated activation of AKT and contributed partially to migration of ECs after HGF stimulation. Microarray analysis demonstrated that HGF upregulated angiogenesis-related genes such as KLF2 (Kruppel-like factor 2) and Egr1 (early growth response 1) via Gab1-SHP2 complex in human ECs. In Gab1ECKO mice, gene transfer of vascular endothelial growth factor, but not HGF, improved blood flow recovery and ameliorated limb necrosis after HLI. CONCLUSION: Gab1 is essential for postnatal angiogenesis after ischemia via HGF/c-Met signaling. PMID- 21293004 TI - Effect of the oxLDL binding protein Fc-CD68 on plaque extension and vulnerability in atherosclerosis. AB - RATIONALE: There is strong evidence that oxidative modification of low-density lipoprotein (oxLDL) plays a critical role in atherogenesis and that oxLDL may profoundly influence the mechanical stability of atherosclerotic plaques. OBJECTIVE: To block oxLDL, we designed, expressed, and tested Fc-CD68, a soluble oxLDL binding protein consisting of human Fc and the extracellular domain of the human oxLDL-binding receptor CD68. METHODS AND RESULTS: Fc-CD68 bound with high specific affinity to oxLDL and strongly bound and colocalized with oxLDL in plaques. To study the effects of repeated administrations of Fc-CD68 on the progression of atherosclerosis and plaque vulnerability, 12- and 16-week old cholesterol-fed ApoE(-/-) mice received either Fc-CD68 (n = 6) or Fc control protein (n = 6 to 8) thrice weekly for 4 weeks. Macroscopic and histological analysis of Sudan red lipid staining showed strong and significant reduction of plaque extension in the aorta and in the aortic root, respectively. Histological analysis of pentachrome- and Sirius-stained sections of the brachiocephalic arteries of 20 week-old ApoE(-/-) mice revealed that Fc-CD68 significantly reduced the occurrence of spontaneous ruptures of established plaques by ~20%, compared with Fc and drastically increased the collagen content of plaques. Furthermore, in immunostained sections of the brachiocephalic artery and the aortic root, Fc-CD68 reduced the infiltration of plaques with T lymphocytes, and macrophages by ~50% and 30%, respectively. CONCLUSIONS: The oxLDL binding protein Fc-CD68 attenuates atherosclerosis and strengthens the stability of atherosclerotic plaques. PMID- 21293005 TI - Restriction of big hearts by a small RNA. PMID- 21293006 TI - The transcription factor C/EBPbeta serves as a master regulator of physiologic cardiac hypertrophy. PMID- 21293007 TI - Developmental and regenerative biology of multipotent cardiovascular progenitor cells. AB - Our limited ability to improve the survival of patients with heart failure is attributable, in part, to the inability of the mammalian heart to meaningfully regenerate itself. The recent identification of distinct families of multipotent cardiovascular progenitor cells from endogenous, as well as exogenous, sources, such as embryonic and induced pluripotent stem cells, has raised much hope that therapeutic manipulation of these cells may lead to regression of many forms of cardiovascular disease. Although the exact source and cell type remains to be clarified, our greater understanding of the scientific underpinning behind developmental cardiovascular progenitor cell biology has helped to clarify the origin and properties of diverse cells with putative cardiogenic potential. In this review, we highlight recent advances in the understanding of cardiovascular progenitor cell biology from embryogenesis to adulthood and their implications for therapeutic cardiac regeneration. We believe that a detailed understanding of cardiogenesis will inform future applications of cardiovascular progenitor cells in heart failure therapy and regenerative medicine. PMID- 21293010 TI - Tissue factor pathway inhibitor: a new link among arterial stiffness, pulse pressure, and coagulation in postmenopausal women. AB - OBJECTIVE: To investigate in women older than 60 whether aortic stiffness or pulse pressure (PP) is associated with selected procoagulant or anticoagulant factors and to examine whether pulsatile stretch influences these factors in human vascular smooth muscle cells (VSMCs) in vitro. METHODS AND RESULTS: Aortic pulse wave velocity (PWV) and carotid PP were studied in 123 apparently healthy postmenopausal women. PWV, PP, von Willebrand factor, and free tissue factor pathway inhibitor (TFPI), but not mean arterial pressure, increased with age. Free TFPI and PWV were positively correlated, even after adjustment for age and PP and other confounding parameters. In vitro, 5% or 10% pulsatile stretch (at 1 Hz) enhanced TFPI synthesis and secretion by VSMCs in a time-independent manner (1 to 48 hours) without changes in protein level of smooth muscle myosin heavy chain. Application of 5% static stretch had no effect. CONCLUSIONS: In postmenopausal women, free TFPI increases as vascular wall function deteriorates and PP increases. These findings are supported by the increase in TFPI synthesized by VSMCs in response to cyclic stress in vitro. They suggest that VSMCs require pulsatility to interfere with the coagulation process and highlight the relevance of plasma free TFPI levels to cardiovascular diseases. PMID- 21293008 TI - Vascular smooth muscle progenitor cells: building and repairing blood vessels. AB - Molecular pathways that control the specification, migration, and number of available smooth muscle progenitor cells play key roles in determining blood vessel size and structure, capacity for tissue repair, and progression of age related disorders. Defects in these pathways produce malformations of developing blood vessels, depletion of smooth muscle progenitor cell pools for vessel wall maintenance and repair, and aberrant activation of alternative differentiation pathways in vascular disease. A better understanding of the molecular mechanisms that uniquely specify and maintain vascular smooth muscle cell precursors is essential if we are to use advances in stem and progenitor cell biology and somatic cell reprogramming for applications directed to the vessel wall. PMID- 21293011 TI - Tissue kallikrein inhibits retinal neovascularization via the cleavage of vascular endothelial growth factor-165. AB - OBJECTIVE: Tissue kallikrein, a widely used vasodilator for the treatment of hypertension and peripheral circulatory disorder, acts by releasing kinin, a potent vasodilator peptide. To identify the role of tissue kallikrein in retinal neovascularization, we investigated the antiangiogenic effect by using an in vitro and in vivo angiogenesis model. METHODS AND RESULTS: Tissue kallikrein in vitreous fluid was markedly elevated in proliferative diabetic retinopathy patients compared with that in control patients with macular hole and epiretinal membrane. Tissue kallikrein inhibited vascular endothelial growth factor-165 (VEGF165)-induced tube formation, proliferation, and migration in vitro angiogenesis model via suppression of the VEGF165-induced phosphorylation of VEGF receptor-2. Furthermore, tissue kallikrein cleavage of VEGF165 was on the C terminal side, which was analyzed by Western blotting and mass spectrometry. When administered subcutaneously, tissue kallikrein reduced the pathological vascular changes in retinal neovascularization induced in neonatal mice by returning the retina to normoxia after exposure to hyperoxia. CONCLUSIONS: These findings indicate that tissue kallikrein is partly involved in pathogenesis of proliferative diabetic retinopathy and may be a promising therapeutic agent that could cleave VEGF165 itself when administered by a peripheral route. PMID- 21293012 TI - NCX1 is a novel target gene for hypoxia-inducible factor-1 in ischemic brain preconditioning. AB - BACKGROUND AND PURPOSE: The sodium-calcium exchanger-1 (NCX1) represents a key mediator for maintaining [Na(+)](i) and [Ca(2+)](i) homeostasis. Although changes in NCX1 protein and transcript expression have been detected during stroke, its transcriptional regulation is still unknown. Thus far, however, there is evidence that hypoxia-inducible factor-1 (HIF-1) is a nuclear factor required for transcriptional activation of several genes implicated in stroke. The main objective of this study was to investigate whether NCX1 gene might be a novel target of HIF-1 in the brain. METHODS: Here we report that: (1) in neuronal cells, NCX1 increased expression after oxygen and glucose deprivation or cobalt induced HIF-1 activation was prevented by silencing HIF-1; (2) the brain NCX1 promoter cloned upstream of the firefly-luciferase gene contained 2 regions of HIF-1 target genes called hypoxia-responsive elements that are sensitive to oxygen and glucose deprivation or cobalt chloride; (3) HIF-1 specifically bound hypoxia-responsive elements on brain NCX1, as demonstrated by band-shift and chromatin immunoprecipitation assays; (4) HIF-1alpha silencing prevented NCX1 upregulation and neuroprotection induced by ischemic preconditioning; and (5) NCX1 silencing partially reverted the preconditioning-induced neuroprotection in rats. CONCLUSIONS: NCX1 gene is a novel HIF-1 target, and HIF-1 exerts its prosurvival role through NCX1 upregulation during brain preconditioning. PMID- 21293009 TI - Chromatin remodeling in cardiovascular development and physiology. AB - Chromatin regulation provides an important means for controlling cardiac gene expression under different physiological and pathological conditions. Processes that direct the development of normal embryonic hearts and pathology of stressed adult hearts may share general mechanisms that govern cardiac gene expression by chromatin-regulating factors. These common mechanisms may provide a framework for us to investigate the interactions among diverse chromatin remodelers/modifiers and various transcription factors in the fine regulation of gene expression, essential for all aspects of cardiovascular biology. Aberrant cardiac gene expression, triggered by a variety of pathological insults, can cause heart diseases in both animals and humans. The severity of cardiomyopathy and heart failure correlates strongly with abnormal cardiac gene expression. Therefore, controlling cardiac gene expression presents a promising approach to the treatment of human cardiomyopathy. This review focuses on the roles of ATP dependent chromatin-remodeling factors and chromatin-modifying enzymes in the control of gene expression during cardiovascular development and disease. PMID- 21293013 TI - Tissue plasminogen activator for stroke and concomitant influenza infection: is this a dangerous combination? PMID- 21293014 TI - Thrombolysis with intravenous tissue plasminogen activator predicts a favorable discharge disposition in patients with acute ischemic stroke. AB - BACKGROUND AND PURPOSE: Acute ischemic stroke patients who receive recombinant tissue plasminogen activator (rt-PA) within 3 hours of symptom onset are 30% more likely to have minimal to no disability at 3 months. During hospitalization, short-term disability is subjectively measured by discharge disposition, whether to home, inpatient rehabilitation, a skilled nursing facility, or subacute care. There are no studies assessing the role of recombinant tissue plasminogen activator use as a predictor of poststroke discharge disposition. METHODS: We conducted a retrospective analysis of all patients with ischemic stroke who presented within the original three hour window for intravenous thrombolysis, and who were admitted to the University of Texas Houston Medical School Stroke Service at Memorial Hermann Hospital - Texas Medical Center between January 2004 and October 2009. Baseline demographics and National Institute of Health Stroke Scale score were collected. Cerebrovascular disease risk factors were used for risk stratification in the multivariate regression. RESULTS: Out of 2225 patients with acute ischemic stroke, 1019 were discharged to home, 719 to inpatient rehabilitation, 371 to a skilled nursing facility and 116 to subacute care. Patients who received recombinant tissue plasminogen activator therapy were more likely to be discharged home compared to the other levels of care (P<0.0001; OR, 1.945; 95% CI, 1.538 to 2.459). Considering post-acute inpatient rehabilitation versus skilled nursing facility/subacute care and disposition at a skilled nursing facility versus subacute care, there were no differences in disposition between patients who received recombinant tissue plasminogen activator therapy. Inpatient Rehabilitation versus Skilled Nursing Facility or Subacute Care (P = 0.123); Skilled Nursing Facility versus Subacute Care (P = 0.605). CONCLUSIONS: Patients who receive intravenous recombinant tissue plasminogen activator as treatment for acute ischemic stroke are more likely to be discharged directly home after hospitalization. This study is limited by its retrospective nature and the undetermined role of psychosocial factors related to discharge. PMID- 21293015 TI - Effects of exercise on quality of life in stroke survivors: a meta-analysis. AB - BACKGROUND AND PURPOSE: One of the major consequences after stroke is the deterioration in health-related quality of life (HRQOL). Three previous systematic reviews indicated that exercise has limited to no effect in improving HRQOL in stroke survivors. The objective of this meta-analysis was to update the evidence on exercise and HRQOL in stroke survivors with additional new information on randomized controlled trials that have been published since these 3 previous reviews. METHODS: MEDLINE, Cumulated Index to Nursing and Allied Health Literature, EMBASE, and SportsDiscus databases were searched for randomized controlled trials reporting the effects of exercise on HRQOL in stroke survivors from 1950 to March 2010. The methodological quality of each study was appraised using the Physiotherapy Evidence Database scale. Standardized mean difference was used to compute effect size and subgroup analysis was conducted to test the consistency of results across the subgroups with different characteristics. RESULTS: A total of 1101 citations was identified and 9 studies met all criteria for a total sample of 426 stroke survivors. Eight studies were rated as good quality (ie, Physiotherapy Evidence Database scale >=5). This meta analysis provided evidence that exercise can have a small to medium effect on HRQOL outcomes (standardized mean difference, 0.32, P<0.01) at postintervention but not at follow-up after exercise was terminated (standardized mean difference, 0.17, P=0.12). No adverse events related to exercise were reported. CONCLUSIONS: The results provide moderate support for the use of exercise to improve HRQOL in stroke survivors. However, the challenge for researchers is identifying effective strategies for sustaining these effects postintervention. PMID- 21293016 TI - Letter by Tsuda regarding article "Endothelial activation in lacunar stroke subtypes". PMID- 21293017 TI - The hidden mismatch: an explanation for infarct growth without perfusion-weighted imaging/diffusion-weighted imaging mismatch in patients with acute ischemic stroke. AB - BACKGROUND AND PURPOSE: In ischemic stroke, MR perfusion-weighted imaging (PWI) and diffusion-weighted imaging (DWI) mismatch represents tissue at risk for infarction. Infarct growth should only take place in the presence of mismatch, although there have been reports of this occurring. We hypothesized that this observation may be attributable to the presence of undetected "hidden mismatch," which may become obvious when coregistration techniques are used. METHODS: MR PWI/DWI was performed within 48 hours of stroke onset and a final T2-weighted image at ~3 months. Volumetric-subtraction mismatch volume was defined as PWI minus DWI volume and infarct growth was defined as T2 minus DWI volume. Coregistration mismatch volume was PWI not overlapped by DWI. Mismatch salvage was the proportion of coregistered mismatch tissue that had not progressed to infarction. RESULTS: Thirty-four patients were studied with MR at a median of 4.9 hours (interquartile range, 2.9-21.1 hours). With the volumetric-subtraction technique, 5 patients (14.7%; 95% CI, 0.05%-0.31%) had infarct growth exceeding mismatch volume, 11 patients (32.0%) had no mismatch and, among these, 3 (27.3%) had infarct growth (median volume, 2.2 mL; interquartile range, 1.0-6.5 mL). All patients had mismatch volume identified by coregistration method that was greater than infarct growth volume. The proportion of this volume salvaged was 77.7% (interquartile range, 63.0%-98.9%). CONCLUSIONS: The illogical finding of infarct growth volume being greater than the presence of mismatch volume can be explained by the presence of "hidden mismatch," which may be detected by coregistration methods. PMID- 21293018 TI - Influenza virus infection aggravates stroke outcome. AB - BACKGROUND AND PURPOSE: Stroke is triggered by several risk factors, including influenza and other respiratory tract infections. However, it is unknown how and in which way influenza infection affects stroke outcome. METHODS: We infected mice intranasally with human influenza A (H1N1) virus and occluded the middle cerebral artery to induce ischemic strokes. Infarct volume and intracerebral hemorrhage were determined by histology. To evaluate the integrity of the blood brain barrier and inflammation, we measured various cytokines in vivo and in vitro and performed immunohistochemistry of leukocyte markers, collagen IV, immunoglobulins, and matrix metalloproteinase-9. RESULTS: Influenza virus infection increased infarct size. Whereas changes in cardiovascular parameters did not explain this effect, we found evidence for an inflammatory mechanism. In influenza virus infection, the respiratory tract released cytokines into the blood, such as RANTES that induced macrophage inflammatory protein-2 and other inflammatory mediators in the ischemic brain. In infected mice, there was an increased number of neutrophils expressing the matrix metalloproteinase-9 in the ischemic brain. This was accompanied by severe disruption of the blood-brain barrier and an increased rate of intracerebral hemorrhages after tissue plasminogen activator treatment. To investigate the role of cytokines, we blocked cytokine release by using GTS-21, a selective agonist of the alpha7 nicotinic acetylcholine receptor. GTS-21 ameliorated ischemic brain damage and improved survival. CONCLUSIONS: Influenza virus infection triggers a cytokine cascade that aggravates ischemic brain damage and increases the risk of intracerebral hemorrhage after tissue plasminogen activator treatment. Blockade of cytokine production by alpha7 nicotinic acetylcholine receptor agonists is a novel therapeutic option to treat stroke in a proinflammatory context. PMID- 21293019 TI - Letter by De Meyer et al regarding article "High von Willebrand factor levels increase the risk of stroke: the Rotterdam study". PMID- 21293020 TI - Decompressive hemicraniectomy in elderly patients with malignant hemispheric infarction: open questions remain beyond DESTINY. PMID- 21293021 TI - Letter by Pierot regarding article "Flow-diverter stent for the endovascular treatment of intracranial aneurysms: a prospective study in 29 patients with 34 aneurysms". PMID- 21293022 TI - Early decompressive hemicraniectomy in older patients with nondominant hemispheric infarction improves outcome. PMID- 21293023 TI - Diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the American Heart Association/American Stroke Association. AB - BACKGROUND: The purpose of this statement is to provide an overview of cerebral venous sinus thrombosis and to provide recommendations for its diagnosis, management, and treatment. The intended audience is physicians and other healthcare providers who are responsible for the diagnosis and management of patients with cerebral venous sinus thrombosis. METHODS AND RESULTS: Members of the panel were appointed by the American Heart Association Stroke Council's Scientific Statement Oversight Committee and represent different areas of expertise. The panel reviewed the relevant literature with an emphasis on reports published since 1966 and used the American Heart Association levels-of-evidence grading algorithm to rate the evidence and to make recommendations. After approval of the statement by the panel, it underwent peer review and approval by the American Heart Association Science Advisory and Coordinating Committee. CONCLUSIONS: Evidence-based recommendations are provided for the diagnosis, management, and prevention of recurrence of cerebral venous thrombosis. Recommendations on the evaluation and management of cerebral venous thrombosis during pregnancy and in the pediatric population are provided. Considerations for the management of clinical complications (seizures, hydrocephalus, intracranial hypertension, and neurological deterioration) are also summarized. An algorithm for diagnosis and management of patients with cerebral venous sinus thrombosis is described. PMID- 21293024 TI - Early predictive biomarkers for lesion after transient cerebral ischemia. AB - BACKGROUND AND PURPOSE: Despite the improving imaging techniques, it remains challenging to predict the outcome early after transient cerebral ischemia. The aim of this study was thus to identify early metabolic biomarkers for outcome prediction. METHODS: We modeled transient ischemic attacks and strokes in mice. Using high-field MR spectroscopy, we correlated early changes in the neurochemical profile of the ischemic striatum with histopathologic alterations at a later time point. RESULTS: A significant increase in glutamine was measured between 3 hours and 8 hours after all ischemic events followed by reperfusion independently of the outcome and can thus be considered as an indicator of recent transient ischemia. On the other hand, a reduction of the score obtained by summing the concentrations of N-acetyl aspartate, glutamate, and taurine was a good predictor of an irreversible lesion as early as 3 hours after ischemia. CONCLUSIONS: We identified biomarkers of reversible and irreversible ischemic damage, which can be used in an early predictive evaluation of stroke outcome. PMID- 21293025 TI - Intracortical infarcts in small vessel disease: a combined 7-T postmortem MRI and neuropathological case study in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy. AB - BACKGROUND AND PURPOSE: The purpose of this study was to report the detection of infarcts of the cerebral cortex in a patient with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) using high-resolution postmortem 7-T MRI in association with pathological examination. METHODS: Whole brain high-resolution MRI data were obtained postmortem at 7 T in a 53-year-old patient with CADASIL. These MRI data were used to guide the neuropathological examination of the cortex. RESULTS: Combined with neuropathology, MRI allowed the delineation of intracortical infarcts confirmed by histological examination in this case. These lesions were not visible on the last in vivo MRI obtained at 1.5 T and were difficult to detect on neuropathological examination only. CONCLUSIONS: Postmortem high-resolution MRI may help to detect intracortical infarcts in CADASIL and possibly in other small vessel diseases of the brain. PMID- 21293026 TI - Early decompressive hemicraniectomy in older patients with nondominant hemispheric infarction does not improve outcome. PMID- 21293027 TI - Assessment of human papillomavirus in lung tumor tissue. AB - BACKGROUND: Lung cancer kills more than 1 million people worldwide each year. Whereas several human papillomavirus (HPV)-associated cancers have been identified, the role of HPV in lung carcinogenesis remains controversial. METHODS: We selected 450 lung cancer patients from an Italian population-based case-control study, the Environment and Genetics in Lung Cancer Etiology. These patients were selected from those with an adequate number of unstained tissue sections and included all those who had never smoked and a random sample of the remaining patients. We used real-time polymerase chain reaction (PCR) to test specimens from these patients for HPV DNA, specifically for E6 gene sequences from HPV16 and E7 gene sequences from HPV18. We also tested a subset of 92 specimens from all never-smokers and a random selection of smokers for additional HPV types by a PCR-based test for at least 54 mucosal HPV genotypes. DNA was extracted from ethanol- or formalin-fixed paraffin-embedded tumor tissue under strict PCR clean conditions. The prevalence of HPV in tumor tissue was investigated. RESULTS: Specimens from 399 of 450 patients had adequate DNA for analysis. Most patients were current (220 patients or 48.9%) smokers, and 92 patients (20.4%) were women. When HPV16 and HPV18 type-specific primers were used, two specimens were positive for HPV16 at low copy number but were negative on additional type-specific HPV16 testing. Neither these specimens nor the others examined for a broad range of HPV types were positive for any HPV type. CONCLUSIONS: When DNA contamination was avoided and state-of-the-art highly sensitive HPV DNA detection assays were used, we found no evidence that HPV was associated with lung cancer in a representative Western population. Our results provide the strongest evidence to date to rule out a role for HPV in lung carcinogenesis in Western populations. PMID- 21293028 TI - Drosophila sperm motility in the reproductive tract. AB - Motile cilia and flagella exhibit many waveforms as outputs of dynein activation sequences on the highly conserved axoneme. Motility change of sperm in the reproductive tract is difficult to study and remains an important area of investigation. Sperm typically execute a sinusoidal waveform. Increased viscosity in the medium induces somewhat unusual arc-line and helical waveforms in some sperm. However, whether the latter two waveforms occur in vivo is not known. Using green fluorescence protein imaging, we show that Drosophila sperm in the uterus move in circular foci via arc-line waves, predominantly in a tail-leading orientation. From the uterus, a small fraction of the sperm enters the seminal receptacle (SR) in parallel formations. After sperm storage and coincident with fertilization of the egg, the sperm exit the SR via head-leading helical waves. Consistent with the observed bidirectional movements, the sperm show the ability to propagate both base-to-tip and tip-to-base flagellar waves. Numerous studies have shown that sperm motility is regulated by intraflagellar calcium concentrations; in particular, the Pkd2 calcium channel has been shown to affect sperm storage. Our analyses here suggest that Pkd2 is required for the sperm to adopt the correct waveform and movement orientation during SR entry. A working model for the sperm's SR entry movement is proposed. PMID- 21293029 TI - PTGS2-related PGE2 affects oocyte MAPK phosphorylation and meiosis progression in cattle: late effects on early embryonic development. AB - During the periovulatory period, the induction of prostaglandin G/H synthase-2 (PTGS2) expression in cumulus cells and associated prostaglandin E2 (PGE2) production are implicated in the terminal differentiation of the cumulus-oocyte complex. During the present study, the effects of the PTGS2/PGE2 pathway on the developmental competence of bovine oocytes were investigated using an in vitro model of maturation, fertilization, and early embryonic development. The specific inhibition of PTGS2 activity with NS-398 during in vitro maturation (IVM) significantly restricted mitogen-activated protein kinase (MAPK) activation in oocytes at the germinal vesicle breakdown stage and reduced both cumulus expansion and the maturation rate after 22 h of culture. In addition, significantly higher rates of abnormal meiotic spindle organization were observed after 26 h of culture. Periconceptional PTGS2 inhibition did not affect fertilization but significantly reduced the speed of embryo development. Embryo output rates were significantly decreased on Day 6 postfertilization but not on Day 7. However, total blastomere number was significantly lower in embryos obtained after PTGS2 inhibition. The addition of PGE2 to IVM and in vitro fertilization cultures containing NS-398 overrode oocyte maturation and early embryonic developmental defects. Protein and mRNA expression for the prostaglandin E receptor PTGER2 were found in oocytes, whereas the PTGER2, PTGER3, and PTGER4 subtypes were expressed in cumulus cells. This study is the first to report the involvement of PGE2 in oocyte MAPK activation during the maturation process. Taken together, these results indicate that PGE2-mediated interactions between somatic and germ cells during the periconceptional period promote both in vitro oocyte maturation and preimplantation embryonic development in cattle. PMID- 21293030 TI - The testis-enriched histone demethylase, KDM4D, regulates methylation of histone H3 lysine 9 during spermatogenesis in the mouse but is dispensable for fertility. AB - Epigenetic modifications, and methylation of histones in particular, dynamically change during spermatogenesis. Among various methylations of histone H3, methylation of histone H3 lysine 9 (H3K9) and its regulation are essential for spermatogenesis. Trimethytransferases as well as dimethyltransferase are required for meiotic progression. In addition, didemethylase of H3K9 is also critical for spermatogenesis through transcriptional regulation of spermatid-specific genes. However, the requirement for demethylation of trimethylated H3K9 (H3K9me3) during spermatogenesis remains to be elucidated. Here, we report the targeted disruption of KDM4D, a testis-enriched tridemethylase of H3K9. Kdm4d-null mice are viable and fertile and do not show any obvious phenotype. However, H3K9me3 accumulates significantly in Kdm4d-null round spermatids, and the distribution of methylated H3K9 in germ cells is dramatically changed. Nevertheless, the progression of spermatogenesis and the number of spermatozoa are normal, likely secondary to the earlier nuclear localization of another H3K9 tridemethylase, KDM4B, in Kdm4d-null elongating spermatids. These results suggest that demethylation of H3K9me3 in round spermatids is dispensable for spermatogenesis but that possible defects in Kdm4d-null elongating spermatids could be rescued by functional redundancy of the KDM4B demethylase. PMID- 21293031 TI - Receptor specificity and functional comparison of recombinant sea bass (Dicentrarchus labrax) gonadotropins (FSH and LH) produced in different host systems. AB - Different yields, biopotency, and in vivo pharmacokinetics are obtained for recombinant sea bass gonadoltropins depending on the production system and DNA construct, but they show specific activation of their corresponding receptors. Gonadotropins (GTHs) are glycoprotein hormones that play a major role in the regulation of gonadal functions. Recently, we succeeded in isolating the native sea bass Fsh from sea bass pituitaries, but to ensure the availability of bioactive GTHs and no cross-contamination with other related glycoproteins, recombinant sea bass GTHs were produced using two expression systems-insect and mammalian cells-and different constructs that yielded tethered or noncovalently bound dimers. Their production levels, binding specificity to their homologous cognate receptors, and bioactivity were investigated and compared. Both expression systems were successful in the generation of bioactive recombinant GTHs, but insect Sf9 cells yielded higher amounts of recombinant proteins than mammalian Chinese Hamster Ovary (CHO) stable clones. All recombinant GTHs activated their cognate receptors without cross-ligand binding and were able to stimulate sea bass gonadal steroidogenesis in vitro, although with different biopotencies. To assess their use for in vivo applications, their half-life in sea bass plasma was evaluated. Sf9-GTHs had a lower in vivo stability compared with CHO-GTHs due to their rapid clearance from the blood circulation. Cell dependent glycosylation could be contributing to the final in vivo stability and biopotency of these recombinant glycoproteins. In conclusion, both insect and mammalian expression systems produced bioactive sea bass recombinant gonadotropins, although with particular features useful for different proposes (e.g., antibody production or in vivo studies, respectively). PMID- 21293032 TI - The fused toes locus is essential for somatic-germ cell interactions that foster germ cell maturation in developing gonads in mice. AB - Ovarian development absolutely depends on communication between somatic and germ cell components. In contrast, it is not until after birth that interactions between somatic and germ cells play an important role in testicular maturation and spermatogenesis. Previously, we discovered that Irx3 expression was localized specifically to female gonads during embryonic development; therefore, we sought to determine the function of this genetic locus in developing gonads of both sexes. The fused toes (Ft) mutant mouse is missing 1.6 Mb of chromosome 8, which includes the entire IrxB cluster (Irx3, Irx5, Irx6), Ftm, Fts, and Fto genes. Homozygote Ft mutant embryos die around embryonic day 13.5 (E13.5); therefore, to assess later development, we harvested gonads at E11.5 and transplanted them into nude mouse hosts. Our results show defects in somatic and germ cell maturation in developing gonads of both sexes. Testis development was normal initially; however, by 3-wk posttransplantation, expression of Sertoli and peritubular myoid cell markers were decreased. In many cases, gonocytes failed to migrate to structurally impaired basement membranes of seminiferous cords. Developmental abnormalities of the ovary appeared earlier and were more severe. Over time, the Ft mutant ovary formed very few primordial or primary follicles, which contained oocytes that failed to grow and were surrounded by scarce granulosa cells that expressed low levels of FOXL2. By 3 wk after transplantation, it was difficult to identify ovarian tissue in Ft mutant ovary transplants. In summary, we conclude that the Ft locus contains genes essential for somatic-germ cell interactions, without which the germ cell niche fails to mature in both sexes. PMID- 21293033 TI - Changes of DNA methylation level and spatial arrangement of primordial germ cells in embryonic day 15 to embryonic day 28 pig embryos. AB - The mammalian germline is generally assumed to undergo extensive epigenetic reprogramming during embryonic development, including a nearly complete erasure of DNA methylation. This assumption does, however, to large degree rely on data from mouse, and despite a well-grounded picture the general nature of these data needs to be validated by investigations of other mammalian species. This study represents such a contribution in the examination of the germline in the domestic pig (Sus scrofa). Semiquantitative immunohistochemistry was used to investigate the level of DNA methylation in the POU5F1-positive primordial germ cells (PGCs) compared with neighboring somatic cells in porcine embryos at Embryonic Day 15 (E15), E17, E20, E21, and E28. We show that, in agreement with the mouse model, a significantly lower level of DNA methylation was observed in the early migrating PGCs. This level was decreasing until a stage coinciding with the entrance of the PGCs to the genital ridge. After this, the methylation level increased. Using whole-mount immunostaining, we determined the spatial arrangement of the porcine PGCs in the period between E15 and E28, allowing some comparison with the migration of the murine germline. The overall conclusion from the obtained data is that the DNA methylation changes in porcine PGCs, as well as the migration of these cells, parallels the picture reported for the mouse. PMID- 21293034 TI - Select nutrients in the ovine uterine lumen. IX. Differential effects of arginine, leucine, glutamine, and glucose on interferon tau, ornithine decarboxylase, and nitric oxide synthase in the ovine conceptus. AB - Nutrients are primary requirements for development of conceptuses (embryo and extraembryonic membranes), including protein synthesis. We have shown that arginine (Arg), leucine (Leu), and glucose stimulate protein synthesis through phosphorylation of MTOR signaling molecules, thereby increasing proliferation of ovine trophectoderm cells. This study determined whether Arg, Leu, glutamine (Gln), and glucose influence gene expression and protein synthesis in explant cultures of ovine conceptuses recovered from ewes on Day 16 of pregnancy. Conceptuses were deprived of select nutrients and then cultured with either Arg, Leu, Gln, or glucose for 18 h, after which they were analyzed for abundance of MTOR, RPS6K, RPS6, EIF4EBP1 (also known as 4EBP1), IFNT, NOS2, NOS3, GCH1, and ODC1 mRNAs and proteins. Levels of MTOR, RPS6K, RPS6, and EIF4EBP1 mRNAs were not affected by treatment with any of the select nutrients. Similarly, expression of IFNT, NOS2, NOS3, and ODC1 mRNAs were not different. Interestingly, GCH1 mRNA levels increased in response to Arg treatment. Importantly, Arg, Leu, Gln, and glucose increased the abundance of phosphorylated MTOR, RPS6K, RPS6, and EIF4EBP1 proteins as well as NOS and ODC1 proteins, but only Arg increased the abundance of IFNT protein. These findings indicate that Arg, Leu, Gln, and glucose stimulate translation of mRNAs to increase synthesis of proteins through phosphorylation and activation of components of the MTOR signaling pathway. Increases in abundance of IFNT protein (the pregnancy recognition signal), NOS2, NOS3 and GCH1 for conversion of Arg to nitric oxide, and ODC1 for synthesis of polyamines are all important for growth and development of the ovine conceptus during pregnancy. PMID- 21293035 TI - Mouse cumulus-oocyte complexes from in vitro-cultured preantral follicles suggest an anti-luteinizing role for the EGF cascade in the cumulus cells. AB - The mammalian ovulatory process is a fairly complex succession of events that leads to the release of a competent oocyte. The luteinizing hormone (LH) triggers the cascade of events, which starts with the production of secondary messengers in the follicular wall and ends with the release of a fertilizable oocyte. Most of these events can be reproduced using in vitro models, which offer a wide range of possibilities for study strategies. Although it is accepted that epidermal growth factor receptor (EGFR) activation is required for transmission of the LH initiated signal, we hypothesized that LH receptor activation might also play a role in oocyte meiotic resumption and cumulus cell response, because the current mouse preantral follicle in vitro model expresses functional LH receptor. To separate the LH-mediated response and the epidermal growth factor (EGF)-mediated response (following LH stimulus), in vitro-grown mouse ovarian follicles were stimulated for ovulation with a combination of human chorionic gonadotropin (hCG) plus galardin (inhibitor for the release of endogenous EGF-like factors) or hCG plus galardin plus EGF. Results suggest that the stimulation provided by LH (hCG) is insufficient to induce a maximum oocyte meiotic resumption and that EGFR activation is also required. Analysis of transcript levels of Egfr, Ereg, Cyp19a1, Hsd3b1, Adamts1, and Has2 in cumulus cells further indicate that the triggers for the EGFR cascade preserve the expression profile of the studied transcripts. Therefore, it is proposed that within this in vitro mouse model, EGF signaling during ovulation might protect the cumulus cells from the potential luteinizing effects of LH. PMID- 21293036 TI - Validation of an instrument to assess evidence-based practice knowledge, attitudes, access, and confidence in the dental environment. AB - This article reports the validation of an assessment instrument designed to measure the outcomes of training in evidence-based practice (EBP) in the context of dentistry. Four EBP dimensions are measured by this instrument: 1) understanding of EBP concepts, 2) attitudes about EBP, 3) evidence-accessing methods, and 4) confidence in critical appraisal. The instrument-the Knowledge, Attitudes, Access, and Confidence Evaluation (KACE)-has four scales, with a total of thirty-five items: EBP knowledge (ten items), EBP attitudes (ten), accessing evidence (nine), and confidence (six). Four elements of validity were assessed: consistency of items within the KACE scales (extent to which items within a scale measure the same dimension), discrimination (capacity to detect differences between individuals with different training or experience), responsiveness (capacity to detect the effects of education on trainees), and test-retest reliability. Internal consistency of scales was assessed by analyzing responses of second-year dental students, dental residents, and dental faculty members using Cronbach coefficient alpha, a statistical measure of reliability. Discriminative validity was assessed by comparing KACE scores for the three groups. Responsiveness was assessed by comparing pre- and post-training responses for dental students and residents. To measure test-retest reliability, the full KACE was completed twice by a class of freshman dental students seventeen days apart, and the knowledge scale was completed twice by sixteen faculty members fourteen days apart. Item-to-scale consistency ranged from 0.21 to 0.78 for knowledge, 0.57 to 0.83 for attitude, 0.70 to 0.84 for accessing evidence, and 0.87 to 0.94 for confidence. For discrimination, ANOVA and post hoc testing by the Tukey-Kramer method revealed significant score differences among students, residents, and faculty members consistent with education and experience levels. For responsiveness to training, dental students and residents demonstrated statistically significant changes, in desired directions, from pre- to post-test. For the student test-retest, Pearson correlations for KACE scales were as follows: knowledge 0.66, attitudes 0.66, accessing evidence 0.74, and confidence 0.76. For the knowledge scale test-retest by faculty members, the Pearson correlation was 0.79. The construct validity of the KACE is equivalent to that of instruments that assess similar EBP dimensions in medicine. Item consistency for the knowledge scale was more variable than for other KACE scales, a finding also reported for medically oriented EBP instruments. We conclude that the KACE has good discriminative validity, responsiveness to training effects, and test-retest reliability. PMID- 21293037 TI - Faculty development to improve teaching at a health sciences center: a needs assessment. AB - There has been increasing interest at health science centers in improving the education of health professionals by offering faculty development activities. In 2007-08, as part of an effort to expand education-related faculty development offerings on campus, the University of Tennessee Health Science Center surveyed faculty members in an effort to identify faculty development activities that would be of interest. Factor analysis of survey data indicated that faculty interests in the areas of teaching and learning can be grouped into six dimensions: development of educational goals and objectives, the use of innovative teaching techniques, clinical teaching, improving traditional teaching skills, addressing teaching challenges, and facilitating participation. There were significant differences in the level of interest in education-related faculty development activities by academic rank and by the college of appointment. Full professors expressed somewhat less interest in faculty development activities than faculty members of lower ranks. Faculty members in the Colleges of Medicine and Dentistry expressed somewhat greater interest in faculty development to improve traditional teaching skills. The policy implications of the survey results are discussed, including the need for faculty development activities that target the needs of specific faculty groups. PMID- 21293038 TI - A model for overview of student learning: a matrix of educational outcomes versus methodologies. AB - A concise overview of an institution's aspirations for its students becomes increasingly elusive because dental education has evolving emphases on priorities like critical thinking and adapting to new technology. The purpose of this article is to offer a learner-oriented matrix that gives a focus for discussion and an overview of an institution's educational outcomes. On one axis of the matrix, common educational outcomes are listed: knowledge, technical skills, critical thinking, ethical and professional values, patient and practice management, and social responsibility awareness. On the other axis, methodologies are listed: definition, cultivation strategies, measures (summative/formative, objective/subjective), institutional coordination, and competency determination. By completing the matrix, an overview of the process by which students reach these outcomes emerges. Each institution would likely complete the matrix differently and, ideally, with active discussion. While the matrix can first be used to establish "Where are we now?" for an institution, it can also be a starting point for more extensive matrices and further discussion. Vertical and horizontal analyses of the matrix provide a unique lens for viewing the institution's learning environment. PMID- 21293039 TI - Effectively teaching self-assessment: preparing the dental hygiene student to provide quality care. AB - Literature on self-assessment presents substantial evidence regarding the impact of self-assessment on dental practitioners and quality of care. Related dental hygiene research documents a need to enhance self-assessment curricula; however, no published curriculum module exists to effectively teach self-assessment. The purpose of this study was to explore the impact of a self-assessment educational module for dental hygiene curricula designed using adult learning principles. This module was implemented with thirty-three dental hygiene students in their junior year using a one-group, pretest-posttest design. Results analyzed using matched pairs Wilcoxon signed-rank test indicated the self-assessment module was effective (p<0.01 corresponding to a Bonferroni FWER of 0.20) in improving some aspects of the students' perceptions and voluntary clinical application of self assessment. No statistically significant relationship was found between the students' perceptions and their application of self-assessment using Pearson's correlation. The quality of self-assessment comments on the students' daily clinical evaluation forms was also enhanced after module implementation (p<0.05). This change in quality after module implementation was demonstrated by a quantitative analysis using a self-designed rubric and a qualitative thematic analysis of student comments to identify predominant themes. Students also were surveyed to determine which module components were most effective. Findings indicate a self-assessment educational module enhanced these dental hygiene students' self-assessment perceptions and skills. PMID- 21293040 TI - Evaluation of social interaction, task management, and trust among dental hygiene students in a collaborative learning environment. AB - The purpose of this study was to evaluate the impact of collaborative learning on the development of social interaction, task management, and trust in dental hygiene students. These three traits were assessed with the Teamwork Assessment Scale in two different learning environments (traditional lecture/lab and collaborative learning environment). A convenience sample of fifty-six entry level dental hygiene students taking an introductory/preclinic course at two metropolitan area dental hygiene programs provided comparable experimental and control groups. Factor scores were computed for the three traits, and comparisons were conducted using the Ryan-Einot-Gabriel-Welsh multiple comparison procedure among specific cell comparisons generated from a two-factor repeated measures ANOVA. The results indicate that the collaborative learning environment influenced dental hygiene students positively regarding the traits of social interaction, task management, and trust. However, comparing dental hygiene students to undergraduate students overall indicates that dental hygiene students already possess somewhat higher levels of these traits. Future studies on active learning strategies should examine factors such as student achievement and explore other possible active learning methodologies. PMID- 21293046 TI - Eukaryotic pyruvate formate lyase and its activating enzyme were acquired laterally from a Firmicute. AB - Most of the major groups of eukaryotes have microbial representatives that thrive in low oxygen conditions. Those that have been studied in detail generate ATP via pathways involving anaerobically functioning enzymes of pyruvate catabolism that are typically absent in aerobic eukaryotes and whose origins remain controversial. These enzymes include pyruvate:ferredoxin oxidoreductase, pyruvate:NADP(+) oxidoreductase, and pyruvate formate lyase (Pfl). Pfl catalyzes the nonoxidative generation of formate and acetyl-Coenzyme A (CoA) from pyruvate and CoA and is activated by Pfl activating enzyme (Pfla). Within eukaryotes, this extremely oxygen-sensitive pathway was first described in the hydrogenosomes of anaerobic chytrid fungi and has more recently been characterized in the mitochondria and chloroplasts of the chlorophyte alga Chlamydomonas reinhardtii. To clarify the origins of this pathway, we have comprehensively searched for homologs of Pfl and Pfla in publicly available large-scale eukaryotic genomic and cDNA sequencing data, including our own from the anaerobic amoebozoan Mastigamoeba balamuthi. Surprisingly, we find that these enzymes are widely distributed and are present in diverse facultative or obligate anaerobic eukaryotic representatives of the archaeplastidan, metazoan, amoebozoan, and haptophyte lineages. Using maximum likelihood and Bayesian phylogenetic methods, we show that the eukaryotic Pfl and Pfla sequences each form monophyletic groups that are most closely related to homologs in firmicute gram-positive bacteria. Topology tests exclude both alpha-proteobacterial and cyanobacterial affinities for these genes suggesting that neither originated from the endosymbiotic ancestors of mitochondria or chloroplasts. Furthermore, the topologies of the eukaryote portion of the Pfl and Pfla trees significantly differ from well accepted eukaryote relationships. Collectively, these results indicate that the Pfl pathway was first acquired by lateral gene transfer into a eukaryotic lineage most probably from a firmicute bacterial lineage and that it has since been spread across diverse eukaryotic groups by more recent eukaryote-to-eukaryote transfer events. PMID- 21293047 TI - Glyburide is anti-inflammatory and associated with reduced mortality in melioidosis. AB - BACKGROUND: Patients with diabetes mellitus are more prone to bacterial sepsis, but there are conflicting data on whether outcomes are worse in diabetics after presentation with sepsis. Glyburide is an oral hypoglycemic agent used to treat diabetes mellitus. This K(ATP)-channel blocker and broad-spectrum ATP-binding cassette (ABC) transporter inhibitor has broad-ranging effects on the immune system, including inhibition of inflammasome assembly and would be predicted to influence the host response to infection. METHODS: We studied a cohort of 1160 patients with gram-negative sepsis caused by a single pathogen (Burkholderia pseudomallei), 410 (35%) of whom were known to have diabetes. We subsequently studied prospectively diabetics with B. pseudomallei infection (n = 20) to compare the gene expression profile of peripheral whole blood leukocytes in patients who were taking glyburide against those not taking any sulfonylurea. RESULTS: Survival was greater in diabetics than in nondiabetics (38% vs 45%, respectively, P = .04), but the survival benefit was confined to the patient group taking glyburide (adjusted odds ratio .47, 95% confidence interval .28-.74, P = .005). We identified differential expression of 63 immune-related genes (P = .001) in patients taking glyburide, the sum effect of which we predict to be antiinflammatory in the glyburide group. CONCLUSIONS: We present observational evidence for a glyburide-associated benefit during human melioidosis and correlate this with an anti-inflammatory effect of glyburide on the immune system. PMID- 21293049 TI - Shape-shifting and tumor suppression by PLZF. PMID- 21293050 TI - Bortezomib: killing two birds with one stone in gastrointestinal stromal tumors. PMID- 21293051 TI - Phase 2 clinical trial of 5-azacitidine, valproic acid, and all-trans retinoic acid in patients with high-risk acute myeloid leukemia or myelodysplastic syndrome. AB - In this Phase 2 study, we evaluated the efficacy of combination of 5-azacitidine (AZA), valproic acid (VPA), and all-trans retinoic acid (ATRA) in patients with high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Treatment consisted of six cycles of AZA and VPA for 7 days, followed by ATRA for 21 days. Sixty-five patients were enrolled (median age, 72 years; 55 AML including 13 relapsed/refractory patients, 10 MDS; 30 unfavorable karyotypes). Best responses included 14 CR and 3 PR (26%), 75% of the responders and 36% of the non-responders achieving an erythroid response. Median overall survival (OS) was 12.4 months. Untreated patients had a longer OS than relapsed/refractory patients. In patients who fulfilled the 6 planned cycles, OS did not appear to depend on CR/PR achievement, suggesting that stable disease while on-treatment would be a surrogate for survival with this approach. During therapy, early platelet response and demethylation of the FZD9, ALOX12, HPN, and CALCA genes were associated with clinical response. Finally, there was no evidence for the restoration of an ATRA-induced differentiation during therapy. Epigenetic modulation deserves prospective comparisons to conventional care in patients with high-risk AML, at least in those presenting previously untreated disease and low blast count. PMID- 21293052 TI - The tumor suppressor p53 connects ribosome biogenesis to cell cycle control: a double-edged sword. AB - Since its first description more than 30 years ago p53 has become a paradigm for a protein with versatile functions. P53 sensitizes a large variety of genetic alterations and has been entitled the guardian of the genome. Stabilization of p53 upon DNA damage is accompanied by a complex pattern of modifications, which ascertain the cellular response either in the direction of a reversible or irreversible cell cycle arrest or programmed cell death. More recently it became evident that p53 also responds to non-genotoxic cell stress, in particular if ribosome biogenesis is affected. PMID- 21293053 TI - ID4: a new player in the cancer arena. AB - Id proteins (Id-1 to 4) are dominant negative regulators of basic helix-loop helix transcription factors. They play a key role during development, preventing cell differentiation while inducing cell proliferation. They are poorly expressed in adult life but can be reactivated in tumorigenesis. Several evidences indicate that Id proteins are associated with loss of differentiation, unrestricted proliferation and neoangiogenesis in diverse human cancers. Recently, we identified Id4 as a transcriptional target of the protein complex mutant p53/E2F1/p300 in breast cancer. Id4 protein binds, stabilizes and enhances the translation of mRNAs encoding proangiogenic cytokines, such as IL8 and GRO-alpha, increasing the angiogenic potential of cancer cells. We present here an overview of the current experimental data that links Id4 to cancer. We provide evidence also of the induction of Id4 following anticancer treatments in mutant p53- carrying cells. Indeed, mutant p53 is recruited to a specific region of the Id4 promoter upon DNA damage. Our findings indicate that Id4, besides its proangiogenic role, might also participate in the chemoresistance associated to mutant p53 proteins exerting gain of function activities. PMID- 21293054 TI - Minocycline-released hydroxyapatite-gelatin nanocomposite and its cytocompatibility in vitro. AB - The incorporation of antibacterial agents into biomaterials is extremely desirable for repairing bone defects. Minocycline, a semi-synthetic tetracycline antibiotic, is active against aerobic, anaerobic, Gram-positive and Gram-negative bacteria, and can enhance bone formation, decrease connective tissue breakdown and diminish bone resorption. In this study, a novel minocycline-releasing biomaterial was synthesized using a biomimetic method. A measured amount of an acidic hydroxyapatite and minocycline solution was respectively added to a gelatin solution and kept at 40 degrees C and pH 7-8 for 2 h. The mixture was aged overnight, lyophilized and a hydroxyapatite-gelatin-minocycline composite was obtained. The composite was co-cultured with rat bone marrow stromal cells (BMSCs) in vitro. Our results show that nanohydroxyapatite was distributed evenly in the fibrils of the gelatin. Minocycline was incorporated into the composite and could be released from the composite particles slowly over 2 weeks in vitro. The composite promoted BMSC adhesion, proliferation and differentiation in vitro. The approach described here may provide a basis for the preparation of an antibacterial biomaterial for bone regeneration. PMID- 21293055 TI - In vitro and in vivo evaluation of SLA titanium surfaces with further alkali or hydrogen peroxide and heat treatment. AB - The present study aimed to evaluate the bioactivity of titanium surfaces sandblasted with large-grit corundum and acid etched (SLA) plus further alkali or hydrogen peroxide and heat treatment for dental implant application. Pure titanium disks were mechanically polished as control surface (Ti-control) and then sandblasted with large-grit corundum and acid etched (SLA). Further chemical modifications were conducted using alkali and heat treatment (ASLA) and hydrogen peroxide and heat treatment (HSLA) alternatively. The surface properties were characterized by scanning electron microscopy (SEM), x-ray photoelectron spectroscopy (XPS), and contact angle and roughness measurements. Further evaluation of surface bioactivity was conducted by MC3T3-E1 cell attachment, proliferation, morphology, alkaline phosphatase (ALP) activity and calcium deposition on the sample surfaces. After insertion in the beagle's mandibula for a specific period, cylindrical implant samples underwent micro-CT examination and then histological examination. It was found that ASLA and HSLA surfaces significantly increased the surface wettability and MC3T3-E1 cell attachment percentage, ALP activity and the quality of calcium deposition in comparison with simple SLA and Ti-control surfaces. Animal studies showed good osseointegration of ASLA and HSLA surfaces with host bone. In conclusion, ASLA and HSLA surfaces enhanced the bioactivity of the traditional SLA surface by integrating the advantages of surface topography, composition and wettability. PMID- 21293056 TI - A poly(epsilon-caprolactone) device for sustained release of an anti-glaucoma drug. AB - Implantable dorzolamide-loaded discs were prepared by blending poly(epsilon caprolactone), PCL, with poly(ethylene oxide)-b-poly(propylene oxide)-b poly(ethylene oxide), Lu. By blending, crystallinity, water uptake and mass loss were modified relative to the pure polymers. Burst was diminished by coating the discs with a PCL shell. All samples presented burst release except PCL-coated samples that showed controlled release during 18 days. For PCL-coated samples, barrier control of diffusion coupled with partition control from the core slowed down the release, while for 50/50 Lu/PCL-coated samples, the enhancement in the porosity of the core diminished partition control of drug release. Nonlinear regression analysis suggested that a degradation model fully describes the release curve considering a triphasic release mechanism: the instantaneous diffusion (burst), diffusion and polymer degradation stages. The MTT test indicated that the materials are not cytotoxic for corneal endothelial cells. A good in vitro-in vivo correlation was obtained, with similar amounts of drug released in vitro and in vivo. The discs decreased intraocular pressure (IOP) in normotensive rabbit eyes by 13.0% during 10 days for PCL-coated and by 13.0% during 4 days for 50/50 Lu/PCL-coated samples. The percentages of IOP decrease are similar to those obtained by dorzolamide eyedrop instillation (11.0%). PMID- 21293057 TI - Deficiency of liver sinusoidal scavenger receptors stabilin-1 and -2 in mice causes glomerulofibrotic nephropathy via impaired hepatic clearance of noxious blood factors. AB - Tissue homeostasis and remodeling are processes that involve high turnover of biological macromolecules. Many of the waste molecules that are by-products or degradation intermediates of biological macromolecule turnover enter the circulation and are subsequently cleared by liver sinusoidal endothelial cells (LSEC). Besides the mannose receptor, stabilin-1 and stabilin-2 are the major scavenger receptors expressed by LSEC. To more clearly elucidate the functions of stabilin-1 and -2, we have generated mice lacking stabilin-1, stabilin-2, or both stabilin-1 and -2 (Stab1-/- Stab2-/- mice). Mice lacking either stabilin-1 or stabilin-2 were phenotypically normal; however, Stab1-/- Stab2-/- mice exhibited premature mortality and developed severe glomerular fibrosis, while the liver showed only mild perisinusoidal fibrosis without dysfunction. Upon kidney transplantation into WT mice, progression of glomerular fibrosis was halted, indicating the presence of profibrotic factors in the circulation of Stab1-/- Stab2-/- mice. While plasma levels of known profibrotic cytokines were unaltered, clearance of the TGF-beta family member growth differentiation factor 15 (GDF-15) was markedly impaired in Stab1-/- Stab2-/- mice but not in either Stab1-/- or Stab2-/- mice, indicating that it is a common ligand of both stabilin-1 and stabilin-2. These data lead us to conclude that stabilin-1 and -2 together guarantee proper hepatic clearance of potentially noxious agents in the blood and maintain tissue homeostasis not only in the liver but also distant organs. PMID- 21293059 TI - Detection of human tumor cells by amplicon fusion site polymerase chain reaction (AFS-PCR). AB - Reliable diagnostic strategies for individuals with cancer demand practical methods for highly sensitive and specific detection of tumor cells. Amplification of genomic regions that include putative oncogenes is common in tumor cells of various types. Genomic array platforms offer the opportunity to identify and precisely map amplified genomic regions (ampGRs). The stable existence of these tumor cell-specific genomic aberrations during and after therapy, in theory, make ampGRs optimal targets for cancer diagnostics. In this study, we mapped ampGRs around the proto-oncogene MYCN of human neuroblastomas using a high-resolution tiling array (HR-TA). Based on the HR-TA data, we were able to precisely describe the telomeric and centromeric borders of the ampGRs and deduce virtual fusion sites of the joined ampGRs (amplicon fusion sites [AFSs]). These AFSs served as blueprints for the subsequent design of AFS bridging PCR assays (AFS-PCRs). Strikingly, these assays were absolutely tumor cell specific and capable of detecting 1 tumor cell in 1 * 10(6) to 8 * 10(6) control cells. We successfully proved the in vivo practicability of AFS-PCR by detecting and quantifying the specific AFS DNA of human MYCN-amplified neuroblastomas in the patients' corresponding peripheral blood and bone marrow samples. Thus, we believe AFS-PCR could become a powerful and nevertheless feasible personalized diagnostic tool applicable to a large number of cancer patients, including children with MYCN amplified neuroblastomas. PMID- 21293058 TI - A microRNA-dependent program controls p53-independent survival and chemosensitivity in human and murine squamous cell carcinoma. AB - The p53 tumor suppressor, a central mediator of chemosensitivity in normal cells, is functionally inactivated in many human cancers. Therefore, a central challenge in human cancer therapy is the identification of pathways that control tumor cell survival and chemosensitivity in the absence of functional p53. The p53-related transcription factors p63 and p73 exhibit distinct functions-p73 mediates chemosensitivity while p63 promotes proliferation and cell survival-and are both overexpressed in squamous cell carcinomas (SCCs). However, how p63 and p73 interact functionally and govern the balance between prosurvival and proapoptotic programs in SCC remains elusive. Here, we identify a microRNA-dependent mechanism of p63/p73 crosstalk that regulates p53-independent survival of both human and murine SCC. We first discovered that a subset of p63-regulated microRNAs target p73 for inhibition. One of these, miR-193a-5p, expression of which was repressed by p63, was activated by proapoptotic p73 isoforms in both normal cells and tumor cells in vivo. Chemotherapy caused p63/p73-dependent induction of this microRNA, thereby limiting chemosensitivity due to microRNA-mediated feedback inhibition of p73. Importantly, inhibiting miR-193a interrupted this feedback and thereby suppressed tumor cell viability and induced dramatic chemosensitivity both in vitro and in vivo. Thus, we have identified a direct, microRNA-dependent regulatory circuit mediating inducible chemoresistance, whose inhibition may provide a new therapeutic opportunity in p53-deficient tumors. PMID- 21293060 TI - Gene therapy by allele selection in a mouse model of beta-thalassemia. AB - To be of therapeutic use, autologous stem cells derived from patients with inherited genetic disorders require genetic modification via gene repair or insertion. Here, we present proof of principle that, for diseases associated with dominant alleles (gain-of-function or haploinsufficient loss-of-function), disease allele-free ES cells can be derived from afflicted individuals without genome manipulation. This approach capitalizes on the derivation of uniparental cells, such as parthenogenetic (PG) ES cell lines from disease allele-free gametes. Diploid mammalian uniparental embryos with only maternally (oocyte-) or paternally (sperm-)derived genomes fail early in development due to the nonequivalence of parental genomes caused by genomic imprinting. However, these uniparental embryos develop to the blastocyst stage, allowing the derivation of ES cell lines. Using a mouse model for dominant beta-thalassemia, we developed disease allele-free PG ES cell lines from the oocytes of affected animals. Phenotype correction was obtained in donor-genotype recipients after transplantation of in vitro hematopoietic ES cell derivatives. This genetic correction strategy without gene targeting is potentially applicable to any dominant disease. It could also be the sole approach for larger or more complex mutations that cannot be corrected by homologous recombination. PMID- 21293061 TI - alpha3(V) collagen is critical for glucose homeostasis in mice due to effects in pancreatic islets and peripheral tissues. AB - Collagen V, broadly expressed as alpha1(V)2 alpha2(V) heterotrimers that regulate collagen fibril geometry and strength, also occurs in some tissues, such as white adipose tissue (WAT), pancreatic islets, and skeletal muscle, as the poorly characterized alpha1(V) alpha2(V) alpha3(V) heterotrimer. Here, we investigate the role of alpha3(V) collagen chains by generating mice with a null allele of the alpha3(V) gene Col5a3 (Col5a3-/- mice). Female Col5a3-/- mice had reduced dermal fat and were resistant to high-fat diet-induced weight gain. Male and female mutant mice were glucose intolerant, insulin-resistant, and hyperglycemic, and these metabolic defects worsened with age. Col5a3-/- mice demonstrated decreased numbers of pancreatic islets, which were more susceptible to streptozotocin-induced apoptosis, and islets isolated from mutant mice displayed blunted glucose-stimulated insulin secretion. Moreover, Col5a3-/- WAT and skeletal muscle were defective in glucose uptake and mobilization of intracellular GLUT4 glucose transporter to the plasma membrane in response to insulin. Our results underscore the emerging view of the importance of ECM to the microenvironments that inform proper development/functioning of specialized cells, such as adipocytes, beta cells, and skeletal muscle. PMID- 21293062 TI - Generation of hyaline cartilaginous tissue from mouse adult dermal fibroblast culture by defined factors. AB - Repair of cartilage injury with hyaline cartilage continues to be a challenging clinical problem. Because of the limited number of chondrocytes in vivo, coupled with in vitro de-differentiation of chondrocytes into fibrochondrocytes, which secrete type I collagen and have an altered matrix architecture and mechanical function, there is a need for a novel cell source that produces hyaline cartilage. The generation of induced pluripotent stem (iPS) cells has provided a tool for reprogramming dermal fibroblasts to an undifferentiated state by ectopic expression of reprogramming factors. Here, we show that retroviral expression of two reprogramming factors (c-Myc and Klf4) and one chondrogenic factor (SOX9) induces polygonal chondrogenic cells directly from adult dermal fibroblast cultures. Induced cells expressed marker genes for chondrocytes but not fibroblasts, i.e., the promoters of type I collagen genes were extensively methylated. Although some induced cell lines formed tumors when subcutaneously injected into nude mice, other induced cell lines generated stable homogenous hyaline cartilage-like tissue. Further, the doxycycline-inducible induction system demonstrated that induced cells are able to respond to chondrogenic medium by expressing endogenous Sox9 and maintain chondrogenic potential after substantial reduction of transgene expression. Thus, this approach could lead to the preparation of hyaline cartilage directly from skin, without generating iPS cells. PMID- 21293063 TI - Practical use of the HOAC II for clinical decision making and subsequent therapeutic interventions in an elite athlete with low back pain. AB - STUDY DESIGN: Resident's case problem. BACKGROUND: This case report describes the diagnostic process, based on the Hypothesis-Oriented Algorithm for Clinicians II (HOAC II), and subsequent interventions in an elite athlete with subacute low back pain. It also demonstrates the clinical application of the HOAC II and shows how disablement terms, as used in the World Health Organization's International Classification of Functioning, Disability and Health model, can be integrated into patient management in a manner that we believe enhances clinical practice. It also demonstrates the practical use of validated questionnaires and how these can be used to gather necessary information for the algorithm. DIAGNOSIS: A structured, evidence-based assessment led to a multifaceted, activity limitation based diagnosis of being unable to (1) remain in a deep squat position during speed skating, (2) accelerate in turns while speed skating, and (3) rise from a slouched position without pain. We believed that these dysfunctions were due to local limited lumbar segmental mobility, concurrent with an inability to properly and functionally stabilize the lumbopelvic area. DISCUSSION: The HOAC II requires the therapist to develop an evidence-based strategy for the examination that is based on initial hypotheses developed from the medical history and other data obtained prior to the examination. The examination was tailored to identify and quantify activity limitations and participation restrictions that we believed could help to explain why this patient had his health problem. The case demonstrates how all elements of the HOAC II can be used for what we consider to be relatively common types of patients. We believe that by applying the HOAC II on an individual-patient basis, therapists will be ideally positioned to apply evidence to patient care and to defend their interventions to colleagues and third-party payers. LEVEL OF EVIDENCE: Differential diagnosis, level 4. PMID- 21293064 TI - Adrenal hemangioma in a 19-year-old female. AB - Adrenal masses are being detected with increasing frequency due to the widespread use of computed tomography, magnetic resonance imaging and even ultrasonography for the evaluation of diseases with abdominal involvement. It is estimated that adrenal masses are an accidental finding in 1% to 5% of all abdominal CT scans performed. Adrenal hemangiomas are rare and nonfunctioning benign tumors and their differential diagnosis preoperatively is rather challenging. Adrenal hemangiomas are most usually cavernous, unilateral lesions of the adrenal glands; bilateral involvement has been reported twice, which appears between the ages 50 and 70 years, with a 2:1 female-to-male ratio. Approximately 60 surgical cases have been reported in the literature. In general, this tumor is large, and all cases reported were treated with open surgery or retroperitoneoscopic procedure. We report a case of a 19-year-old female patient with adrenal hemangioma that was removed by laparoscopic adrenalectomy. PMID- 21293065 TI - Unusual anatomic location of a primary intracranial yolk sac tumor. AB - A nongerminomatous germ cell tumor occurring in the brain parenchyma is extremely rare. A 2-year-old boy presented with symptoms of abnormal movements in the hand and mouth. MRI scanning revealed a lesion occupying the left temporoparietal region. Craniotomy was performed and the tumor was removed by en bloc resection. Histological examination revealed that the tumor was arranged in a reticular pattern, and Schiller-Duval bodies were evident at the center of the tumor. Immunohistochemical study showed that the tumor cells were positive for alpha fetoprotein and vimentin, but negative for glial fibrillary acidic protein. The histological diagnosis was pure yolk sac tumor. PMID- 21293066 TI - Cold agglutinin disease in fibrolamellar hepatocellular carcinoma: a rare association with a rare cancer variant. AB - Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia. Although it can occur secondary to lymphoproliferative disorders and autoimmune or infectious diseases, CAD is rarely reported as secondary to solid tumors. We report a case of a woman aged 18 years diagnosed with a well-differentiated hepatocellular carcinoma of the fibrolamellar subtype, who was shown to have CAD also. Her general condition, including CAD, improved after targeted therapy with sorafenib for the hepatocellular carcinoma and only conservative measures for the CAD that consisted of avoidance of cold. In summary, although it is an extremely rare association and less common than lymphoproliferative disorders, CAD can be associated with solid tumors. PMID- 21293067 TI - Human immunodeficiency virus type 2 in two Saudi families. AB - Human immunodeficiency virus type 2 (HIV-2), the second retrovirus that causes the acquired immune deficiency syndrome (AIDS) in humans, is limited in its distribution to West Africa. We report cases in two Saudi families with HIV-2 infection and AIDS, resulting in death of the index cases-the husbands, while the wives and a daughter were maintained on antiretroviral therapy. When HIV viral loads were undetectable in initial assays, further testing confirmed the presence of HIV-2. In the first family, the 30-year-old wife was found to be HIV-positive after the diagnosis in her 30-year-old husband, who later died with AIDS. In the second family, HIV-2 infection was diagnosed in the 50-year-old wife and 18-year old daughter of a man who had died of AIDS at the age of 48 years. Recognizing HIV-2 infection is essential for appropriate workup, assessment, therapy and care of the pregnant woman. PMID- 21293068 TI - Oral hamartomas with von Recklinghausen disease. AB - Neurofibromatosis is a genetically-inherited disorder of the nervous system that primarily affects the development and growth of neural (nerve) cell tissues and also causes cafe-au-lait spots on the skin, dysplastic abnormalities of the skin, nervous system, bones, endocrine organs and blood vessels. The two major classifications are NF-1, a generalized form, is the commonest and affects peripheral nerve tissues and NF-2, a rare central form, affects the central nervous system. An unusual finding of oral hamartomas may occur as part of NF-1 and here we presented one such rare case of oral hamartomas in a patient with Von Recklinghausen's disease. PMID- 21293069 TI - Attributable fractions of risk factors for cardiovascular diseases. AB - BACKGROUND: Cardiovascular disease (CVD) is a leading cause of death in Japan. To reduce the threat of CVD, it is important to identify its major risk factors. The population attributable fraction (PAF) is calculated from the prevalence and relative risk of risk factors and can be used to estimate the burden of these factors with respect to CVD. We analyzed the findings from several prospective studies to determine the PAFs of CVD. METHODS: PAF was calculated as pd * (multiadjusted relative risk - 1)/multiadjusted relative risk, where pd is the proportion of patients exposed to that risk factor category, according to data from the Ohsaki Cohort Study, EPOCH-JAPAN, NIPPON DATA80, Miyagi Cohort Study, CARDIA Study, and ARIC Study. RESULTS: Nonoptimal blood pressure explained 47% and 26% of CVD mortality in middle-aged and elderly Japanese, respectively. Cigarette smoking explained 34% of all-cause mortality in middle-aged men. The combination of hypertension and cigarette smoking explained 57% and 44% of CVD mortality in younger men and women, respectively. Furthermore, the presence of at least 1 nonoptimal risk factor explained most CVD deaths and all-cause deaths. CONCLUSIONS: Established CVD risk factors, especially high blood pressure and cigarette smoking, explained a large proportion of CVD mortality and all-cause mortality. Prevention, early detection, and treatment of these conventional risk factors are required to reduce mortality risk. PMID- 21293070 TI - Vitamin E-deficiency did not exacerbate partial skin reactions in mice locally irradiated with X-rays. AB - We previously showed that free radicals and oxidative stress are involved in radiation-induced skin reactions. Since vitamin E (VE) is a particularly important lipophilic antioxidant, VE-deficient mice were used to examine its effects on radiation-induced skin damage. The VE content of the skin was reduced to one fourth of levels of normal mice. Neither the time of onset nor the extent of the reactions quantified with a scoring system differed between normal and VE deficient mice after local X-irradiation (50 Gy). Similarly, there was no difference in the levels of the ascorbyl radical between the groups, although they were higher in irradiated skin than non-irradiated skin. X-irradiation increased the amount of Bax protein in the skin of normal mice both in the latent and acute inflammatory stages, time- and dose-dependently. The increase was associated with an increase in cytochrome c in the cytosolic fraction, indicating that apoptosis was also promoted by the irradiation. The increase in Bax protein correlated well with the thickness of the skin. Although a deficiency in VE should lower resistance to free radicals in the mitochondrial membrane and thus enhance radiation-induced Bax expression and apoptosis, it actually attenuated the increase in Bax protein caused by irradiation. PMID- 21293071 TI - Gene silencing of Tead3 abrogates radiation-induced adaptive response in cultured mouse limb bud cells. AB - There is a crucial need to better understand the effects of low-doses of ionizing radiation in fetal models. Radiation-induced adaptive response (AR) was described in mouse embryos pre-exposed in utero to low-doses of X-rays, which exhibited lower apoptotic levels in the limb bud. We previously described AR-specific gene modulations in the mouse embryo. In this study, we evaluated the role of three candidate genes in the apoptotic AR in a micromass culture of limb bud cells: Csf1, Cacna1a and Tead3. Gene silencing of these three genes abrogated AR. Knowing that TEAD3 protein levels are significantly higher in adapted cells and that YAP/TAZ/TEAD are involved in the control of cell proliferation and apoptosis, we suggest that modulation of Tead3 could play a role in the induction of AR in our model, seen as a reduction of radiation-induced apoptosis and a stimulation of proliferation and differentiation in limb bud cells. PMID- 21293072 TI - Intracavitary combined with CT-guided interstitial brachytherapy for locally advanced uterine cervical cancer: introduction of the technique and a case presentation. AB - We report a new technique of brachytherapy consisting of intracavitary combined with computed tomography (CT)-guided interstitial brachytherapy for locally advanced cervical cancer. A Fletcher-Suit applicator and trocar point needles were used for performing high-dose rate brachytherapy under in-room CT guidance. First, a tandem and ovoids were implanted into the patient's vagina and uterus by conventional brachytherapy method. Based on clinical examination and MRI/CT imaging, operating radiation oncologists decided the positions of insertion in the tumor and the depth of the needles from the upper surface of the ovoid. Insertion of the needle applicator was performed from the vaginal vault inside the ovoid within the tumor under CT guidance. In treatment planning, dwell positions and time adaptations within the tandem and ovoids were performed first for optimization based on the Manchester system, and then stepwise addition of dwell positions within the needle was continued. Finally, dwell positions and dwell weights were manually modified until dose-volume constraints were optimally matched. In our pilot case, the dose of D90 to high-risk clinical target volume was improved from 3.5 Gy to 6.1 Gy by using our hybrid method on the dose-volume histogram. D1cc of the rectum, bladder and sigmoid colon by our hybrid method was 4.8 Gy, 6.4 Gy and 3.5 Gy, respectively. This method consists of advanced image guided brachytherapy that can be performed safely and accurately. This approach has the potential of increasing target coverage, treated volume, and total dose without increasing the dose to organs at risk. PMID- 21293073 TI - Fractionated stereotactic radiation therapy for orbital optic nerve sheath meningioma - a single institution experience and a short review of the literature. AB - Optic nerve sheath meningioma (ONSM) is a rare orbital tumor that generally induces a slow progressive visual loss in affected patients. Radiotherapy (RT) has currently become the first choice to treat ONSM. In this study our experience in ONSM treatment with fractionated stereotactic radiotherapy (FSRT) is reported. Five patients with diagnosis of orbital ONSM were treated between April 2007 and December 2009 at the Radiation Oncology department of our institution. All patients underwent history and physical, and ophthalmic examinations. Orbital MRI was performed before and 6 weeks after treatment; thereafter every 6 months for the first 2 years. By previous stereotactic localization of the target, RT was delivered with 28 daily fraction of 1.8 Gy by multiple non coplanar arcs dynamically conformed by a micro multileaf-collimator. At diagnosis, in all 5 patients, visual acuity limitations of different degrees were found, while exophthalmos was present in 2, diplopy in 2, orbital pain in 1, and proptosis in 1. In all patients pre-treatment MRI showed an orbital mass involving the optic nerve. After radiotherapy, previous symptoms improved in all patients. However, after RT the MRI consistently showed a stationary status compared to the MRI before RT. At a median follow up of 26 months (range 9-37) all patients had a subjective and/or objective better visual performance than before RT without any evidence of disease progression. No late side effects were recorded. Accordingly to the current literature, our experience confirms the efficacy and the safety of FSRT in patients with orbital ONSM. PMID- 21293074 TI - Intrafractional respiratory motion for charged particle lung therapy with immobilization assessed by four-dimensional computed tomography. AB - The aim of this study was to quantify the magnitude of intrafractional lung tumor motion under free-breathing conditions with an immobilization device using four dimensional computed tomography (4DCT). 4DCT data sets were acquired for 17 patients with lung tumors receiving carbon ion beam therapy. A single respiratory cycle was subdivided into 10 phases, and intrafractional tumor motion was calculated by identifying the gross tumor volume (GTV) center of mass (COM) in two scenarios; respiratory-ungated and -gated treatments, which were based on a whole respiratory cycle and a 30% duty cycle around peak exhalation, respectively. For the respiratory-ungated case, the mean (+/- standard deviation) GTV-COM displacements from the peak exhalation position over the 17 patients were 0.6 (+/- 0.8) / 0.9 (+/- 1.2) mm, 2.0 (+/- 1.4) / 0.4 (+/- 0.7) mm, and 0.2 (+/- 0.5) / 7.8 (+/- 6.9) mm in left/right, anterior/posterior and superior/inferior directions, respectively, while these were reduced for the respiratory-gated case to 0.3 (+/- 0.4) / 0.4 (+/- 0.6) mm (left/right), 0.8 (+/- 0.7) / 0.3 (+/- 0.5) mm (anterior/posterior), and 0.1 (+/- 0.2) / 2.8 (+/- 2.9) mm (superior/inferior). Quantitative analysis of tumor motion with immobilization is valuable not only for particle beam therapy but also for photon beam therapy. PMID- 21293075 TI - The 1st YRBAJ Seminar: Techniques and knowledge to probe biological cellular responses occurring in a hypoxic microenvironment. PMID- 21293076 TI - Cone beam computed tomography data acquisition during VMAT delivery with subsequent respiratory phase sorting based on projection image cross-correlation. PMID- 21293077 TI - Prevalence of Dirofilaria immitis infection in living raccoon dogs assessed by hematological examination. AB - The prevalence of Dirofilaria immitis in free-ranging raccoon dogs (Nyctereutes procyonoides viverrinus) was examined in the southeast region of Kanagawa Prefecture, Japan, using a rapid immunomigration (RIM) test kit. Between April 2007 and March 2010, we examined 108 raccoon dogs rescued and housed by the Kanazawa Zoological Garden. D. immitis infection was found in 8 (7.4%) raccoon dogs. This is the first report to reveal the prevalence of D. immitis infection in living raccoon dogs. The prevalence of the infection was lower than previously reported values obtained on postmortem examination. One reason might be that the present study included young raccoon dogs infected with immature worms. Significant high-risk areas of D. immitis infection in the raccoon dogs were not observed. PMID- 21293078 TI - Effects of fibroblasts derived from the olfactory bulb and nasal olfactory mucosa on proliferation of olfactory ensheathing cells harvested from the olfactory bulb. AB - Olfactory ensheathing cells (OECs) have been reported to promote axonal regeneration when transplanted to rodent spinal cord injury models. OECs are available from the olfactory bulb (OB) and olfactory mucosa (OM). Although harvesting OECs from the OM is less traumatic, OECs originating from the OM are less proliferative than those from the OB (OB-OECs). One possible reason for this difference is coexisting fibroblasts. Here, we examined the effect of coculturing either fibroblasts from the OB (OB-Fibs) or fibroblasts from the OM (OM-Fibs) on the proliferation of OB-OECs. Proliferation of OB-OECs was significantly higher in 5:5 coculture with OB-Fibs and in 7:3 and 5:5 cocultures with OM-Fibs than without fibroblasts. These results indicated that coculture with both OB-Fibs and OM-Fibs promoted the proliferation of OB-OECs. PMID- 21293079 TI - Screening tests for renal impairment in patients with type 2 diabetes: the what, when, and how. AB - The global course of obesity and diabetes presents an alarming forecast for the near future. As the prevalence rates continue to increase and the afflicted population grows younger in age, the associated complications of diabetes will come to pose a greater strain on patients, society, and national health care systems. In recent years, a number of studies have demonstrated the clinical benefits of strict diabetes control in the prevention of debilitating complications, including retinal, renal, and cardiovascular disease. These data highlight the need to maximize our efforts in diabetes prevention and early disease management. Renal dysfunction is a surrogate marker of diabetic microvascular disease, and thus early recognition of renal impairment in patients with diabetes provides an opportunity to modify treatment strategy and improve long-term disease outcomes. This review will summarize methods of assessing renal function and the most recent guidelines for the early screening and diagnosis of diabetic kidney disease. PMID- 21293080 TI - Advantages of extended-release metformin in patients with type 2 diabetes mellitus. AB - Metformin is a first-line pharmacological treatment for patients with type 2 diabetes mellitus because of its favorable overall profile, including its glucose lowering ability, weight-neutral effects, and low risk of hypoglycemia; however, gastrointestinal (GI) intolerance may limit use in some patients. Extended release metformin improves GI tolerability, allows once-daily dosing, and is currently available in multiple branded and generic formulations; however, it is more expensive than immediate-release metformin. Maximum plasma metformin concentrations are reached more slowly with the extended-release formulation compared with conventional immediate-release metformin, although both provide similar exposure at a given total daily dose. Extended-release metformin is as effective as immediate-release metformin in patients newly started on metformin and those switched from the immediate-release formulation, with similar weight neutral effects. Tolerability is generally comparable, although patients switched from the immediate-release formulation--even those switched due to GI intolerance -are often better able to tolerate the extended-release formulation. Based on studies of extended-release formulations in other disease states, metformin extended-release formulation has the potential to improve patient adherence with a simpler dosing regimen and increased tolerability. Increased adherence may result in greater glycemic control, and in turn, improve outcomes and lower health care usage and costs. Extended-release metformin provides an appropriate option for patients with type 2 diabetes mellitus who require several medications to achieve glycemic control or manage comorbid conditions, and for those who have GI intolerance with the immediate-release formulation. PMID- 21293081 TI - Bariatric surgery in patients with type 2 diabetes: a viable option. AB - The prevalence of obesity is increasing and is co-epidemic with type 2 diabetes mellitus (T2DM). Treatment of obesity has been less than adequate, particularly when managing morbidly obese patients. Research on T2DM has shown a number of new pharmacologic therapies along with the rapid employment of bariatric surgery. Improvement of T2DM, including its remission, after bariatric surgery has been recognized for more than a decade. However, not all procedures are the same. Restrictive procedures, malabsorptive procedures, or a combination of both procedures have their own categorical risks and benefits. Which procedure to choose has to do with many patient selection factors, notwithstanding insurance coverage. Based on operative and postoperative mortality data, laparoscopically assisted gastric bypass (LAGB) has been shown to be the safest bariatric surgery procedure. However, the Roux-en-Y gastric bypass procedure is one of the most widely used for obese patients with T2DM. The mechanisms involved in weight loss and improved blood glucose control appear to involve increased insulin sensitivity, decreased lipotoxicity/inflammation, and changes in gut hormones/incretins. The safety of bariatric procedures has improved; complication rates are low and mortality is < 1% for all procedures. As a result of the dramatic, positive impact of bariatric procedures on T2DM in obese patients, physicians should be cautious during patient selection to avoid performing the procedure on patients who are overzealous about reported outcomes, but who are not candidates for the procedure. Other data gaps still exist regarding diabetes surgery, which must be filled using data from well-designed, well-implemented randomized controlled clinical trials. In the future, it will be prudent to compare surgical interventions with other rigorous medical interventions in more robust studies. A combination of surgical, medical, and behavioral interventions should be considered for treating obese patients with T2DM. PMID- 21293082 TI - The pharmacological treatment and management of obesity. AB - Obesity is a pandemic with many complications that increase the societal disease burden and cost of health care, and decrease longevity and quality of life. Currently, 1 in 3 adults in the United States is obese. Physicians must therefore regularly confront obesity and its consequent diseases, and develop strategies for effective treatment and management. This article summarizes current lifestyle modifications, pharmacological treatment, and surgical options for the management of obesity and discusses the benefits, limitations, and risks of each. As insights are gained into the pathophysiology of a gut-brain neurochemical feedback axis governing satiety and feeding behavior, targets for new pharmacotherapies are being developed. In particular, gut hormone analogs are an attractive antiobesity therapy because they appear to lack the adverse effects historically associated with central nervous system-acting agents. PMID- 21293083 TI - Differential regulations of lipid profiles between Japanese responders and nonresponders treated with pioglitazone. AB - The aim of this study was to evaluate the effects of pioglitazone on lipid profiles in relation to glycemic control. Eighty-one treatment-naive patients with type 2 diabetes mellitus received pioglitazone monotherapy. Subjects who had >= 1% reduction in hemoglobin A(1c) (HbA(1c)) levels were defined as responders (n = 47) and those with < 1% reduction as nonresponders (n = 34). At 3 months, the HbA(1c) levels and several lipid parameters were compared with baseline values. Because it is known that the response to some antihyperglycemic agents is proportional to baseline HbA(1c) levels, the changes (Delta) in these parameters were compared for 2 groups based on their DeltaHbA(1c)/baseline HbA(1c) ratio. The lowest tertile was called super-responders (n = 25) and highest tertile was called extreme nonresponders (n = 24). At baseline, HbA(1c) levels and body mass index (BMI) were significantly higher in responders; no significant differences were observed in total cholesterol (TC), triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), LDL C/HDL-C ratio, or non-HDL-C between the 2 groups. At 3 months, significant decreases in TGs and increases in HDL-C were observed in both groups. In contrast, TC, non-HDL-C, and LDL-C/HDL-C ratio significantly decreased in responders. Low-density lipoprotein cholesterol had a tendency to decrease in responders. However, these parameters were nonsignificantly increased in nonresponders. Body mass index significantly increased in responders, while it slightly increased in nonresponders. Analysis of covariance revealed that significant intergroup differences existed with TC, LDL-C, non-HDL-C, and LDL C/HDL-C ratio, while no such differences were observed with TGs, HDL-C, and BMI. Very similar results were obtained with super-responders and extreme nonresponders. These results suggest that approximately 40% of the treatment naive Japanese subjects with type 2 diabetes mellitus were nonresponders to pioglitazone, and differential regulations of lipid parameters exist between responders and nonresponders treated with pioglitazone. Bad cholesterols (eg, TC, LDL-C, and non-HDL-C) were reduced only in responders. Irrespective of its efficacy on glycemic control, pioglitazone can significantly downregulate TGs and upregulate HDL-C levels. PMID- 21293084 TI - Focus on incretin-based therapies: targeting the core defects of type 2 diabetes. AB - Glucose homeostasis is regulated by a complex interaction of hormones, principally including insulin, glucagon, amylin, and the incretins. Glucagon, cortisol, catecholamines, and growth hormone serve as the classic glucose counterregulatory hormones. The incretins are hormones released by enteroendocrine cells in the intestine in response to a meal. Classically, type 2 diabetes mellitus (T2DM) has been considered to be a triad of insulin resistance, increased hepatic gluconeogenesis, and progressive beta-cell exhaustion/failure. However, disordered enteroendocrine physiology, specifically the reduced activity of glucagon-like peptide-1 (GLP-1), is also a principal pathophysiologic abnormality of the disease. Glucagon-like peptide-1 receptor agonists that have been studied include exenatide and liraglutide, which have been approved by the US Food and Drug Administration for use in patients with T2DM. Sitagliptin and saxagliptin, both approved for use in the United States, modulate incretin physiology by inhibiting degradation of GLP-1 by the enzyme dipeptidyl peptidase 4 (DPP-4). Modulators of incretin physiology have been shown to improve glycemic control with a low risk for hypoglycemia and beneficially affect beta-cell function. Unlike the DPP-4 inhibitors, GLP-1 receptor agonist therapy also produces weight loss, an important consideration given the close association among T2DM, overweight/obesity, and cardiovascular disease. The GLP-1 receptor agonists have also demonstrated beneficial effects on cardiovascular risk factors other than hyperglycemia and excess body weight, such as lipid concentrations and blood pressure. This article describes incretin physiology and studies of pharmacologic therapy designed to address the blunted incretin response in patients with T2DM. Information was obtained by a search of the PubMed and MEDLINE databases for articles published from January 1, 1995 to June 1, 2009. PMID- 21293085 TI - Levels of acculturation and effect on glycemic control in Mexicans and Mexican Americans with type 2 diabetes. AB - BACKGROUND: Acculturation of Mexican Americans toward the predominant American culture has been shown to influence health outcomes. Little is known about the role of acculturation in diabetes control. OBJECTIVE: To measure the association between acculturation and diabetes control in Mexicans and Mexican Americans with type 2 diabetes mellitus (T2DM). DESIGN: Cross-sectional survey and chart review. SETTING: Ambulatory family medicine clinics. PATIENTS: Sixty-six Mexican and Mexican American adults with T2DM for >= 1 year. INSTRUMENT AND OUTCOMES: A survey tool was developed that included the General Acculturation Index developed by Balcazar et al to measure acculturation. Basic demographics, psychosocial factors, patient satisfaction, and patients' most recent hemoglobin A(1c) (HbA(1c)) levels were also obtained. RESULTS: There was no significant correlation between acculturation score and HbA(1c) levels. On binary logistic regression, HbA(1c) levels were associated with patient satisfaction in having their questions answered (odds ratio [OR], 0.44; P < 0.05), interference of diabetes with daily life (OR, 1.4; P < 0.05), male gender (OR, 3.93; P < 0.01), and number of diabetes complications (OR, 1.81; P < 0.05). In the multivariate linear regression model, age (beta, -0.348; P < 0.05) and frequency of physician visits (beta, -0.403; P < 0.05) were the only variables significantly associated with glycemic control. Variables included in the model that were not associated with glycemic control include family history of diabetes and confidence in diabetes treatment efficacy. CONCLUSIONS: Acculturation was not associated with glycemic control in this population. Family physicians should not assume that acculturation difficulties explain poor glycemic control in their Mexican American patients with T2DM. PMID- 21293086 TI - Pharmacokinetics, drug metabolism, and safety of prasugrel and clopidogrel. AB - Thienopyridines are platelet adenosine diphosphate receptor antagonists used in the treatment and prevention of thrombotic events in patients with acute coronary syndrome. The pharmacokinetic profile of the thienopyridine clopidogrel has resulted in highly variable pharmacokinetics and efficacy responses. The purpose of this review is to provide a brief overview of the pharmacokinetics of prasugrel and clopidogrel and discuss factors that would influence the metabolism of those drugs. Clinical studies have shown that the coadministration of prasugrel with other drugs is less likely to result in clinically relevant pharmacokinetic drug interactions compared with clopidogrel. The lack of effect of variant genotypes on the efficacy of prasugrel suggests that more patients will receive adequate platelet inhibition after administration of prasugrel. The efficient generation of the active metabolite of prasugrel results in greater and more rapid inhibition of P2Y(12) receptor-mediated platelet aggregation. PMID- 21293087 TI - A randomized, double-blind, forced-titration study to compare olmesartan medoxomil versus losartan potassium in patients with stage 1 and 2 hypertension. AB - OBJECTIVE: To evaluate the comparative efficacy and safety of once-daily olmesartan medoxomil (OM) and losartan potassium (LOS) in patients with hypertension. METHODS: This was a multicenter, prospective, randomized, double blind, active-comparator, forced-titration study. After a 3-week placebo run-in, 941 patients were randomized in an 8:1:9 ratio to once-daily treatment with OM (20 mg for 4 weeks, then OM 40 mg for 4 weeks [n = 420]), placebo plus OM (placebo for 2 weeks, then OM 20 mg for 2 weeks and OM 40 mg for 4 weeks [n = 52]), or LOS (50 mg for 4 weeks, then LOS 100 mg for 4 weeks [n = 469]). A subset of 246 patients underwent ambulatory blood pressure (BP) monitoring. The primary endpoint was mean change from baseline in trough seated cuff diastolic BP (SeDBP) at week 8. Secondary endpoints were mean changes from baseline in trough SeDBP at week 4 and seated systolic BP (SeSBP) at weeks 4 and 8. Tertiary endpoints included change from baseline in mean 24-hour ambulatory BP at weeks 4 and 8 and percentage of patients achieving seated cuff BP (SeBP) goal of < 140/90 mm Hg and mean 24-hour ambulatory BP target of < 130/80 mm Hg at weeks 4 and 8. RESULTS: At week 8, least-squares (LS) mean (+/- standard error) SeDBP reductions from baseline were 9.7 +/- 0.5 and 7.1 +/- 0.5 mm Hg (treatment difference: -2.5 +/- 0.6 mm Hg; P < 0.0001) and LS mean SeSBP reductions were 13.6 +/- 0.7 and 9.7 +/- 0.7 mm Hg (treatment difference: -3.9 +/- 1.0 mm Hg; P = 0.0001) for OM versus LOS, respectively. A significantly greater proportion of patients receiving OM reached SeBP goal of < 140/90 mm Hg at week 8. There was a similar incidence of adverse events with OM and LOS. CONCLUSION: Treatment with low- and high-dose OM achieved superior SeBP reductions compared with low- and high-dose LOS, resulting in significantly more patients achieving SeBP goal, with similar tolerability. PMID- 21293088 TI - Long-term blood pressure control: what can we do? AB - There are unique problems associated with the long-term control of blood pressure (BP) in patients with hypertension. Many of these problems warrant specific discussion for the primary care physician. Up to one-third of high-risk patients are estimated to have uncontrolled hypertension. Although long-term control is essential to avoid complications of cardiovascular disease, such as myocardial infarction, stroke, heart failure, and kidney disease, it can become troublesome because of challenges with patient compliance and adherence to medication regimens. This may be due to low tolerability profiles, complicated regimens, or prohibitive costs. Trials have shown that a combination approach may reduce side effects with complementary therapies such as a calcium channel blocker (CCB)/angiotensin receptor blocker (ARB) combination. Combination therapy can be used in any patient group not responsive to monotherapy, or who remain 20 mm Hg higher than their BP goal. This method may achieve the goal of reaching target BP sooner as a first-line approach and, in a fixed-dose combination, may be a more economic choice as well as a simpler regimen for the patient. Together with supportive measures, CCB/ARB combinations are a compelling alternative for the long-term treatment of hypertension. PMID- 21293089 TI - Efficacy and tolerability of solifenacin in patients aged >= 65 years with overactive bladder: post-hoc analysis of 2 open-label studies. AB - BACKGROUND: Antimuscarinics have proven efficacy as first-line therapy in overactive bladder (OAB); however, data on their use in older adults are needed. OBJECTIVE: To assess the efficacy and tolerability of solifenacin in patients aged >= 65 years, we conducted post-hoc analyses of data from VESIcare(r) Open Label Trial (VOLT) and VESIcare(r) Efficacy and Research Study US (VERSUS). METHODS: In both of these 12-week, open-label, flexible-dosing studies involving 2645 patients with OAB for >= 3 months, patients received 5 mg solifenacin daily for 4 weeks, with an option to increase to 10 mg at week 4 (both studies) and week 8 (VOLT). VERSUS patients had received tolterodine extended release 4 mg for >= 4 weeks without sufficient subjective improvement in urgency (mean >= 3 urgency episodes/24 h). Baseline values 14 days after tolterodine washout were used for comparison with VOLT. Common study endpoints were the Patient Perception of Bladder Condition (PPBC) scale and the Overactive Bladder Questionnaire (OAB q). VOLT used a horizontal visual analog scale (VAS), and diary-recorded symptom data were captured in VERSUS. RESULTS: In the full analysis sets (FAS), 40% of VOLT and 44% of VERSUS patients were aged >= 65 years. After 12 weeks of solifenacin, older patients experienced decreases in OAB symptoms, and improvements from baseline on the PPBC, OAB-q, and VAS. In total, 59% of older VOLT and 62% of older VERSUS patients reported >= 1 treatment-emergent adverse event (AE); the AEs were mostly anticholinergic and of mild-to-moderate severity. Results were consistent with younger patients and the FAS. CONCLUSIONS: In this large group of older patients, flexibly dosed solifenacin was associated with reductions in diary-documented OAB symptoms (VERSUS). In both studies, solifenacin was associated with improvements in measures assessing patients' perception of their bladder problems, symptom bother, and aspects of health related quality of life. Adverse event rates in older patients were comparable to those in younger patients and the FAS. PMID- 21293090 TI - Active surveillance of renal cortical neoplasms: a contemporary review. AB - INTRODUCTION: Over the past 2 decades, there has been a significant increase in the number of incidentally found small renal cortical neoplasms (RCNs). As more RCNs are being discovered in the elderly and infirmed patient populations, there has been a growing interest in the role of active surveillance (AS). Active surveillance is recommended for high surgical-risk patients and those with a reduced life expectancy. It is also an option for patients wishing to avoid surgery. We review the current literature on AS and highlight the natural history of disease, the important factors to evaluate during AS, and the contemporary role of biopsy. METHODS AND MATERIALS: The MEDLINE database was searched using PubMed. Search terms included active surveillance, renal mass, natural history, and renal mass histology. From 1966 to present, 17 AS series were identified, all of which have been included in this summary. A summary was performed by compiling all available data and performing a weighted mean where applicable. RESULTS: Initial tumor size does not correlate with growth rate or malignancy. The mean growth rate in large published series is low (0.28-0.34 cm/year). Tumors with high growth rates usually represent malignant lesions and typically undergo delayed intervention. Progression to metatatic disease is a low-probability event for tumors on AS (1.4%); however, this is still a risk that patients must be willing to accept. Larger tumors (cT1b and cT2) also demonstrate relatively low growth (0.57 cm/year); however, these tumors should be monitored carefully. Tumors followed for > 5 years demonstrate a low growth rate (0.15 cm/year), will not likely require intervention, and have a low chance of progression to metastatic disease. CONCLUSION: For highly selected patients with RCN, AS is a reasonable treatment option. Age, surgical risk, comorbidities, and patient opinion must all factor into the final decision when considering a patient for AS. PMID- 21293091 TI - C-reactive protein and high-sensitivity C-reactive protein: an update for clinicians. AB - The measurement of C-reactive protein (CRP) using both standard and high sensitivity CRP (hs-CRP) assays is becoming common in clinical practice. This article addresses the causes of CRP elevation and the use of different CRP assays in internal medicine, including cardiology, gastroenterology, rheumatology, infectious diseases, and oncology. We focus on the recent medical literature on the use of hs-CRP in cardiovascular disease risk stratification and management, including updated screening guidelines on the use of hs-CRP, such as those issued in 2009 by the Canadian Cardiovascular Society. We also discuss the Reynolds Risk Score, which incorporates hs-CRP and family history with more standard cardiovascular risk factors (eg, tobacco use, hypertension, and dyslipidemia) and frequently leads to improved recategorization of cardiovascular disease risk levels. As the recently completed Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial indicated that statin therapy decreases the vascular events among persons with elevated hs-CRP by half, even when cholesterol levels are low, the inclusion of information on hs-CRP values with other cardiovascular risk factors may assist physicians in medical decision making for patients. PMID- 21293092 TI - Human seminal plasma hypersensitivity: an under-recognized women's health issue. AB - Human seminal plasma (HSP) hypersensitivity is defined as a spectrum of systemic and/or localized symptoms after exposure to specific protein components in seminal plasma. The major antigen is believed to be prostate-specific antigen, but other proteins are likely involved in this heterogenous disorder. There are no known risk factors for developing seminal plasma hypersensitivity, although women who develop systemic symptoms are more frequently atopic. Of interest, for both systemic and localized forms, symptoms can manifest after first time intercourse in up to 50% of cases. Diagnosis requires a careful history. The gold standard for diagnosing HSP is that symptoms are completely abated with the use of a condom prophylactic. Although women with HSP hypersensitivity often have difficulty conceiving due to their inability to have unprotected sexual intercourse, infertility has not been demonstrated to be related to HSP hypersensitivity. Patients with HSP hypersensitivity often elicit positive skin prick testing and/or serum-specific immunoglobulin E to whole seminal fluid or fractionated seminal plasma proteins. Treatment involves either avoidance with the use of condoms, an intravaginal graded challenge using dilutions of whole seminal fluid, or subcutaneous desensitization to relevant fractionated seminal plasma proteins obtained from the woman's sexual partner. In most cases, treatment using >= 1 of the above approaches has been very successful. PMID- 21293093 TI - Management of mild-to-moderate osteoarthritis: a study of the primary care perspective. AB - OBJECTIVES: Examine the knowledge, attitudes, and practice patterns of primary care clinicians regarding the management of mild-to-moderate osteoarthritis (OA). DESIGN: Case vignette-based survey. METHODS: A survey was distributed to 251 physicians, physician assistants (PAs), and nurse practitioners (NPs) in the primary care setting. The survey assessed practice patterns in the management of patients with mild-to-moderate OA, as well as attitudes toward guidelines and future educational topics that may be of benefit to the clinician. RESULTS: We found that primary care clinicians are most likely to treat mild-to-moderate OA with an oral nonsteroidal anti-inflammatory drug regimen. Patients with initial or recurrent OA were "very likely" to be recommended to a physical therapy maintenance program. Two-thirds of respondents claimed to be unfamiliar with Osteoarthritis Research Society International guidelines for OA management. CONCLUSION: This study reflects the need for further education for primary care physicians, NPs, and PAs on the management of OA. PMID- 21293094 TI - Switching among antipsychotics in everyday clinical practice: focus on ziprasidone. AB - OBJECTIVES: This article addresses points to consider when switching patients to the second-generation antipsychotic (SGA), ziprasidone, in everyday clinical practice: 1) the pharmacologic properties of the pre-switch antipsychotic and of ziprasidone; 2) switch and dosing strategies to ensure maintenance or attainment of efficacy; 3) recognition and management of possible rebound effects of the pre switch medication discontinuation; 4) recognition and management of potential side effects of ziprasidone; and 5) education and support for patients/caregivers concerning correct ziprasidone administration. METHODS: A Medline search (up to July 7, 2010) identified studies in which adult patients with schizophrenia were switched to ziprasidone from another antipsychotic. In addition, based on their extensive clinical experience, an expert faculty of European psychiatrists provided advice on identifying patients who may be appropriate candidates for switching to ziprasidone, and on establishing optimal strategies for switching to ziprasidone in everyday clinical practice. RESULTS: Data from 10 studies, in which 1395 patients were switched to ziprasidone, showed that switching from first-generation antipsychotics (FGAs) or SGAs generally resulted in maintenance or improvement of efficacy across all studied symptom domains, improvements in tolerability, and acute and long-term benefits regarding cardiometabolic parameters, including body weight. Maintenance of efficacy is most likely to be achieved using a plateau cross-titration strategy, with a rapid uptitration of ziprasidone to a dose range of 60 to 80 mg administered twice daily with food. Temporary coadministration of benzodiazepines, anticholinergics, or beta-blockers should be considered for the management of potential rebound effects. CONCLUSION: Optimal switching of patients with schizophrenia from FGAs or SGAs to ziprasidone requires careful attention to differences in the pharmacological profiles of the pre-switch medication and of ziprasidone, which may impact efficacy and tolerability. Good communication between the clinician and patient/caregiver about the goals of switching, the importance of adherence to the chosen switch strategy, and the correct administration of ziprasidone are essential. PMID- 21293095 TI - Practical guidelines for evaluating lead exposure in children with mental health conditions: molecular effects and clinical implications. AB - Children in the United States are exhibiting extremely high levels of attentional and learning disabilities. Although lead has been eliminated from many industrial products, children continue to come into contact with it, such as in toys and cosmetics. Lead exposure occurs most commonly in poor, urban populations, and can exacerbate psychiatric disorders associated with stress. We present 1) an overview of lead exposure; 2) a detailed summary of current research on the molecular synergy of toxicity caused by lead and stress; 3) a review of human studies that appear to correlate with these molecular findings, including understanding nutrition, environmental enrichment, and caregiving as risk modifiers; and 4) a systematic approach for mental health practitioners in managing children presenting with multiple symptoms and risk factors for mental health conditions. In this article, we review some of the clinical and scientific challenges that relate to the assessment and treatment of children presenting for mental health care who may have potential lead exposure. PMID- 21293096 TI - Bile acids promote HCV replication through the EGFR/ERK pathway in replicon harboring cells. AB - OBJECTIVES: Bile acids promoted the replication of hepatitis C virus (HCV) and compromised the anti-HCV effects of interferon-alpha (IFN-alpha) in replicon harboring cells. To explore a potential mechanism for the observation, we studied the effects of bile acids on the epidermal growth factor receptor (EGFR) and the extracellular signal-regulated kinase (ERK) pathway in association with HCV replication in genotype 1a or 1b replicon-harboring cells. METHODS: Replicon harboring cells were treated with various bile acids, IFN-alpha and small molecule inhibitors either individually or combined together. The effects of these treatments were measured using cell cycle analysis, qRT-PCR, and Western blot analysis. RESULTS: Bile acids induced the activation of EGFR/ERK pathway and extended S-phase of cells, which was correlated with the increased levels of viral replication. The inhibitors of EGFR (AG1478) or ERK (U0126) significantly mitigated the bile acid-mediated promotion of HCV replication. When AG1478 or U0126 were added to the treatment of bile acids and IFN-alpha, they were able to restore the anti-HCV effects of IFN-alpha. CONCLUSION: Our data suggest that the addition of an EGFR or ERK inhibitor to the current IFN-alpha-based regimen may improve overall treatment efficacy by blocking the bile acid-mediated promotion of HCV replication. PMID- 21293097 TI - Statins reduce dengue virus production via decreased virion assembly. AB - BACKGROUND: Most of the effects of statins can be explained by pleiotropic effects independent of their lowering of serum cholesterol; in some cases, these effects have been shown to be a result of the role of statins in the prenylation of cellular proteins, some of which are involved in the life cycle of animal viruses. This study evaluated the potential antiviral activity of lovastatin (LOV) against dengue virus (DENV) infection of epithelial and endothelial cells (VERO cells, epithelial cells derived from African green monkey kidney, and HMEC 1 cells, human dermal microvascular endothelial cells). METHODS: To evaluate its potential antiviral effects, LOV was used before, during and after inoculation of cell cultures with DENV. RESULTS: Before and after viral inoculation, LOV caused a reduction in virus yield (80% for HMECs and 25% for VERO cells). However, with LOV treatment after inoculation induced a marked increase (2- to 9-fold) in viral positive RNA while the amount of viral protein increased only by 13-23%. A moderate reduction (1 log unit) in viral titer occurred concurrent with the increase in DENV genomic RNA and protein within the cells. CONCLUSIONS: According to our results, LOV appears to have a greater effect on viral assembly than on replication, resulting in the cellular presence of viral genomic RNA and proteins that fail to take the normal assembly pathway. PMID- 21293098 TI - Polymorphisms of hepatitis C virus non-structural protein 5A and core protein and clinical outcome of pegylated-interferon/ribavirin combination therapy. AB - OBJECTIVE: Hepatitis C virus (HCV genome) polymorphisms are thought to influence the outcome of pegylated-interferon/ribavirin (PEG-IFN/RBV) therapy. This study aimed to examine non-structural protein 5A (NS5A) polymorphisms, e.g. IFN/RBV resistance-determining region (IRRDR) and IFN sensitivity-determining region (ISDR), and core protein polymorphism as predictive therapeutic markers. METHODS: Pretreatment sequences of NS5A and core regions were analyzed in 68 HCV-1b infected patients treated with PEG-IFN/RBV. RESULTS: Of 24 patients infected withHCV having an IRRDR with 6 or more mutations (IRRDR>=6), 18 (75%) patients achieved sustained virological response (SVR), whereas only 11 (25%) of 44 patients infected with HCV having IRRDR<=5 did. IRRDR>=6 was significantly associated with SVR (p < 0.0001). On the other hand, ISDR>=2 was significantly associated with relapse (either before [breakthrough] or after end-of-treatment response [ETR[-]relapse]) (p < 0.05) and a point mutation of the core protein from Arg to Gln at position 70 (Gln(70)) was significantly associated with null response (p < 0.05). Multivariate analysis identified IRRDR>=6 as the only viral genetic factor that independently predicted SVR. CONCLUSION: NS5A (IRRDR and ISDR) and core protein polymorphisms are associated with the outcome of PEG IFN/RBV therapy for chronic hepatitis C. In particular, IRRDR>=6 is a useful marker for prediction of SVR. PMID- 21293099 TI - Evolutionary characterization of human H1N1 influenza virus hemagglutinin genes isolated from 1947 to 2009 in China. AB - OBJECTIVE: Our aim was to reveal the molecular characteristics of human H1N1 influenza virus hemagglutinin (HA) genes from 1947 to 2009 in China. METHODS: 129 HA gene sequences were downloaded from NCBI's GenBank and analyzed by DNASTAR software. Additionally, the three-dimensional structure of HA protein was predicted by the SWISS-MODEL service. RESULTS: First, 2009 Chinese HA genes were 99% identical to those of Mexican and American ones; their key sites remained highly conserved. Second, 50 Chinese strains from 1947 to 2009 clustered by the year of isolation, and 2009 strains had only 70% identity to 1947-2008 ones. Third, over the past 60 years, 3 receptor-binding (RB) sites and 2 of the 8 glycosylation sites (amino acids 279 and 290) underwent considerable changes while the cleavage sites remained stable. Fourth, the human HA sequences differed completely from swine and avian isolates. Finally, the mutation of cleavage sites can change the three-dimensional structures, but single mutations cannot. CONCLUSIONS: Thus, in the past 60 years, Chinese H1N1 influenza HA genes kept stable with high affinity and low pathogenicity to human except changes in 2 glycosylation and 3 RB sites which were associated with the pandemic strength, range and host specificity of viruses. PMID- 21293100 TI - Acute hepatic failure-derived bone marrow mesenchymal stem cells express hepatic progenitor cell genes. AB - Hepatic progenitor cell (HPC) transplantation is a promising alternative to liver transplantation for patients with end-stage liver disease. However, the precise origin of HPCs is unclear. This study aimed to determine whether bone marrow mesenchymal stem cells (BMSCs) isolated from rats in acute hepatic failure (AHF) possess hepatic potential and/or characteristics. BMSCs were isolated from normal rats as well as rats in which AHF was induced by D-galactosamine. HPCs and primary hepatocytes were isolated from normal rats for comparison. The Affymetrix GeneChip Rat Genome 230 2.0 Array was used to perform transcriptome profiling of the AHF-derived BMSCs and HPCs. The results showed that AHF-derived BMSCs had a gene expression profile significantly different from that of control BMSCs. More than 87.7% of the genes/probe sets that were upregulated more than 2-fold in AHF derived BMSCs were expressed by HPCs, including 12 genes involved in liver development, early hepatocyte differentiation and hepatocyte metabolism. Confirmatory quantitative RT-PCR analysis yielded similar results. In addition, 940 probe sets/genes were expressed in both AHF-derived BMSCs and HPCs but were absent in control cells. Compared to the control cells, AHF-derived BMSCs shared more commonly expressed genes with HPCs. AHF-derived BMSCs have a hepatic transcriptional profile and express many of the same genes expressed by HPCs, strongly suggesting that BMSCs may be a resource for hepatocyte regeneration, and further confirming their potential as a strong source of hepatocyte regeneration during severe hepatic damage. PMID- 21293101 TI - Coupling of alpha1-adrenoceptors to ERK1/2 in the human prostate. AB - INTRODUCTION: alpha1-Adrenoceptors are considered critical for the regulation of prostatic smooth muscle tone. However, previous studies suggested further alpha1 adrenoceptor functions besides contraction. Here, we investigated whether alpha1 adrenoceptors in the human prostate may activate extracellular signal-regulated kinases (ERK1/2). METHODS: Prostate tissues from patients undergoing radical prostatectomy were stimulated in vitro. Activation of ERK1/2 was assessed by Western blot analysis. Expression of ERK1/2 was studied by immunohistochemistry. The effect of ERK1/2 inhibition by U0126 on phenylephrine-induced contraction was studied in organ-bath experiments. RESULTS: Stimulation of human prostate tissue with noradrenaline (30 MUM) or phenylephrine (10 MUM) resulted in ERK activation. This was reflected by increased levels of phosphorylated ERK1/2. Expression of ERK1/2 in the prostate was observed in smooth muscle cells. Incubation of prostate tissue with U0126 (30 MUM) resulted in ERK1/2 inhibition. Dose-dependent phenylephrine-induced contraction of prostate tissue was not modulated by U0126. CONCLUSIONS: alpha1-Adrenoceptors in the human prostate are coupled to ERK1/2. This may partially explain previous observations suggesting a role of alpha1 adrenoceptors in the regulation of prostate growth. PMID- 21293102 TI - Immunosuppressant prograf(r) (tacrolimus) induces histopathological disorders in the peritubular tissue of rat testes. AB - Treatment with tacrolimus (FK-506) has been shown to induce a significant decrease in the number of spermatocytes, spermatids, and Sertoli cells. Regarding the importance of the peritubular tissue for the maintenance of Sertoli cells, the integrity of the cellular and extracellular components of the peritubular tissue was evaluated in adult rats that were treated with 1 mg/kg/day of FK-506 for 30 and 60 days. Testicular sections were used for a quantitative analysis of the peritubular cells (PCs) and were submitted to the PAS method. Paraffin sections were submitted to the TUNEL method and to immunohistochemistry for the detection of caspase-3. Several testicular fragments were analyzed under a transmission electron microscope (TEM). A weak PAS reaction was noted in the peritubular tissue of the tacrolimus-treated animals. Next to the damaged peritubular tissue, the Sertoli cell nuclei were absent or dislocated from the basement membrane. In the treated animals, the number of PCs decreased significantly compared to the control animals, and these cells showed apoptotic features, were TUNEL positive, and were caspase-3 immunolabeled. Using the TEM, apoptosis was confirmed in myoid cells; moreover, the thickness and undulation of the basal laminae and an enlargement of the collagen I layer adjacent to the myoid cells was observed. Long-term treatment with the immunosuppressor induced peritubular myoid cell death by apoptosis and disarrangement of the peritubular extracellular layers. Future studies are necessary to confirm whether the structural alterations in the seminiferous epithelium are related to the effect of FK-506 on peritubular tissue. PMID- 21293103 TI - Adapted T cell interferon-gamma release assay for the diagnosis of pleural tuberculosis. AB - BACKGROUND: Better and more rapid tests are needed for the diagnosis of tuberculous pleural effusion (TPE), given the known limitations of conventional diagnostic tests. OBJECTIVES: To estimate diagnostic accuracy of the QuantiFERON TB Gold In-Tube (QFT-GIT) test (and its components) using data-derived cutoffs in pleural fluid. METHODS: The QFT-GIT test was performed on whole blood and pleural fluid from 43 patients with TPE and 29 control subjects (non-TPE). To achieve the objective, QFT-GIT test, estimating likelihood ratios and receiver operating curve analysis were performed. RESULTS: The sensitivity and specificity using the QFT-GIT for the diagnosis of TPE were 48.8% and 79.3%, respectively, in pleural fluid. The best cutoff points for tuberculosis (TB) antigen, nil and TB antigen minus nil results were estimated at 0.70, 0.90 and 0.30 IU/ml, respectively. Area under the curve of TB antigen IFN-gamma response was 0.86 (CI: 0.76-0.93), nil tube was 0.80 (CI: 0.69-0.89) and TB antigen minus nil tube was 0.82 (CI: 0.72 0.90). When the best cutoff scores of the nil tubes were set at this value, the results of a likelihood ratio of a positive and a negative test were 9.44 (7.4 12.0) and 0.37 (0.09-1.5), respectively. The percentages of indeterminate results in pleural fluid among the TPE cases were 42% (most of them caused by high nil IFN-gamma values) using the QFT-GIT test. CONCLUSION: QFT-GIT test or its components have poor accuracy in the diagnosis of TPE, largely because of a high number of indeterminate results due to high background IFN-gamma production in the TPE. PMID- 21293104 TI - Occurrence of cleft-palate and alteration of Tgf-beta(3) expression and the mechanisms leading to palatal fusion in mice following dietary folic-acid deficiency. AB - Folic acid (FA) is essential for numerous bodily functions. Its decrease during pregnancy has been associated with an increased risk of congenital malformations in the progeny. The relationship between FA deficiency and the appearance of cleft palate (CP) is controversial, and little information exists on a possible effect of FA on palate development. We investigated the effect of a 2-8 weeks' induced FA deficiency in female mice on the development of CP in their progeny as well as the mechanisms leading to palatal fusion, i.e. cell proliferation, cell death, and palatal-shelf adhesion and fusion. We showed that an 8 weeks' maternal FA deficiency caused complete CP in the fetuses although a 2 weeks' maternal FA deficiency was enough to alter all the mechanisms analyzed. Since transforming growth factor-beta(3) (TGF-beta(3)) is crucial for palatal fusion and since most of the mechanisms impaired by FA deficiency were also observed in the palates of Tgf-beta(3)null mutant mice, we investigated the presence of TGF-beta(3) mRNA, its protein and phospho-SMAD2 in FA-deficient (FAD) mouse palates. Our results evidenced a large reduction in Tgf-beta(3) expression in palates of embryos of dams fed an FAD diet for 8 weeks; Tgf-beta(3) expression was less reduced in palates of embryos of dams fed an FAD diet for 2 weeks. Addition of TGF-beta(3) to palatal-shelf cultures of embryos of dams fed an FAD diet for 2 weeks normalized all the altered mechanisms. Thus, an insufficient folate status may be a risk factor for the development of CP in mice, and exogenous TGF-beta(3) compensates this deficit in vitro. PMID- 21293105 TI - Maternal serum adiponectin at 11-13 weeks of gestation in pregnancies delivering small for gestation neonates. AB - OBJECTIVE: To investigate whether maternal serum levels of adiponectin in the first trimester are altered in pregnancies that subsequently deliver small for gestational age (SGA) neonates. METHODS: Maternal serum adiponectin and pregnancy associated plasma protein A (PAPP-A) were measured at 11-13 weeks' gestation in 50 singleton normotensive pregnancies that delivered SGA neonates and 300 non-SGA controls. The median adiponectin and PAPP-A levels in the SGA and non-SGA groups, expressed as multiple of the unaffected median (MoM), were compared. RESULTS: The distribution of serum adiponectin was made gaussian by square root (sqrt) transformation. Regression analysis in the non-SGA group demonstrated that for sqrt adiponectin a significant independent contribution was provided by maternal age, weight, smoking status, African and South-Asian racial origin. Each value in the SGA and non-SGA group was then converted into a multiple of the non-SGA median (MoM) after adjustment for maternal characteristics. In the SGA group, compared to the non-SGA controls, median maternal serum PAPP-A was decreased (0.79, interquartile range [IQR] 0.54-1.06 MoM vs. 1.00, IQR 0.71-1.39 MoM) but adiponectin MoM was not significantly different (0.89, IQR 0.65-1.31 MoM vs. 1.02, IQR 0.70-1.29 MoM). CONCLUSION: Maternal serum adiponectin is not a useful biochemical marker for early prediction of SGA. PMID- 21293106 TI - Zoledronic acid treatment in children with osteogenesis imperfecta. AB - BACKGROUND: Intravenous disodium pamidronate has become an established treatment in osteogenesis imperfecta (OI). Another bisphosphonate, zoledronic acid, has been indicated for the treatment of adult osteoporosis. We studied its efficacy and safety in children with mild OI. METHODS: Patients were treated for 1.0-3.2 years with 0.05 mg/kg zoledronic acid intravenously every 6 months as part of their clinical care. They were carefully followed for clinical and biochemical parameters, side effects, bone mineral densities (BMD) and compression fractures. RESULTS: The study included 17 patients (age 1.5-16.8 years) with type I OI. They had sustained altogether 73 fractures; 9 had compression fractures. During the treatment, 6 patients suffered in total 10 new long-bone fractures. The median lumbar spine areal BMD z-score increased from -2.0 to -0.7 during 2 years of treatment. The infusions were associated with a transient decrease in serum calcium and phosphate and a significant increase in serum PTH. Two patients developed symptomatic hypocalcemia. Bone turnover markers decreased during the treatment. CONCLUSIONS: Intravenous zoledronic acid is an effective mode of treatment in children with OI. The treatment response is comparable to pamidronate but the infusion protocol is more convenient. Further studies are needed to establish optimal dosing and long-term safety. PMID- 21293107 TI - Calcipotriol plus betamethasone dipropionate gel compared with tacalcitol ointment and the gel vehicle alone in patients with psoriasis vulgaris: a randomized, controlled clinical trial. AB - OBJECTIVE: To establish the efficacy and safety of once daily treatment of Daivobet(r)/Dovobet(r) gel in patients with psoriasis vulgaris, relative to tacalcitol ointment and the gel vehicle alone. METHODS: 458 patients with at least moderately severe disease were randomized in 3 treatment arms for an 8-week period. Treatment was investigator blinded, and treatment success was defined as patients with an Investigator's Global Assessment of 'clear' or 'almost clear' at week 8. RESULTS: The proportion of patients who were 'clear or almost clear' was significantly higher in the 2-compound gel group (39.9%) compared with 17.9% in the tacalcitol group and 5.5% in the gel vehicle group: p < 0.001 in both comparisons. The proportion of patients with at least 1 adverse drug reaction was significantly lower in the 2-compound gel group compared to the other 2 treatment groups. CONCLUSIONS: Once-a-day treatment with the 2-compound Daivobet/Dovobet gel is a safe and efficacious therapeutic regimen for individuals with psoriasis on the body. PMID- 21293108 TI - Plasma tissue factor levels and salivary tissue factor activities of periodontitis patients with and without cardiovascular disease. AB - The association between periodontal and cardiovascular disease has received considerable attention. Studies have demonstrated a higher incidence of atherosclerotic complications in patients with periodontal disease. Tissue factor (TF) has been known as a key initiator of the coagulation cascade, and the TF pathway is the primary physiological mechanism of initiation of blood coagulation. Recently, it has been shown that the circulating pool of TF in blood is associated with increased blood thrombogenicity in patients with coronary artery disease (CAD). Various tissues and saliva have been known to have TF activity. Consequently, the aim of this study was to investigate plasma TF levels and TF activity of saliva in periodontitis patients with and without diagnosed CAD. Twenty-six patients with a diagnosis of CAD and 26 systemically healthy patients were examined in the dental clinic, and the Community Periodontal Index Treatment Needs (CPITN) scores were recorded. Plasma TF levels were determined using commercially available ELISA kit. Salivary TF activities were determined according to Quick's one-stage method. Plasma TF levels were significantly increased in patients with CAD when compared with the control group. There was no difference in salivary TF activities between the 2 groups, but there was a strong and negative correlation between salivary TF activities and CPITN indexes in both groups. In order to determine the possible role of TF activity as a salivary marker in CAD and periodontitis and to fully understand the negative correlation between salivary TF activities and CPITN, TF activity of gingival crevicular fluid that may also affect saliva can be evaluated. PMID- 21293109 TI - Expression of DcR3 and its effects in kaposi's sarcoma-associated herpesvirus infected human endothelial cells. AB - OBJECTIVE: Kaposi's sarcoma-associated herpesvirus (KSHV) is classified as a gamma-herpesvirus and it causes Kaposi's sarcoma in patients infected with the human immunodeficiency virus (HIV). Decoy receptor 3 (DcR3) is known as a decoy receptor for Fas ligand, LIGHT and TL1A and it can neutralize the biological effect of TL1A by inhibiting the TL1A-DR3 interaction in human endothelial cells. The present study examined the expression of DcR3 in human endothelial cells and its effect during the early stages of KSHV infection. METHODS: The expression of DcR3 was assessed using real-time RT-PCR and ELISA in human umbilical cord vein endothelial cells (HUVECs) infected with KSHV. Cell proliferation and apoptosis of KSHV-infected HUVECs were assessed after treatment of infected cells with an anti-DcR3 antibody or recombinant human TL1A. RESULTS: DcR3 expression was induced during the early phase of KSHV infection. Inhibition of DcR3 with anti DcR3 antibodies or recombinant human TL1A-induced apoptosis in KSHV-infected HUVECs. CONCLUSION: The expression of DcR3 plays an important role in the prevention of apoptosis in HUVECs during the early phases of KSHV infection, thus ensuring the successful establishment and maintenance of the viral infection. PMID- 21293110 TI - Characterization of hepatitis B virus molecular genotypes in Chongqing and quantitative serological markers in patients during natural phases of chronic hepatitis B infection. AB - BACKGROUND/AIMS: The present study was launched to systematically characterize the molecular genotypes and quantitative serological biomarkers during the natural course of chronic hepatitis B (CHB) infection in a patient population from Chongqing, China. METHODS: A total of 140 patients were enrolled and grouped according to the natural phases of HBV infection: HBeAg (+) immune tolerance, immune clearance, HBeAg (-) low replicative and reactivation phase. Nested PCR was used for HBV molecular genotyping and chemiluminescent microparticle immunoassay for quantitative serological detection. RESULTS: Subgenotypes B2 and C2 were found to be most prevalent with genotype B patients showing more potent viral activity. HBsAg level was found to be significantly correlated with HBV DNA, HBeAg, age, ALT and AST levels during some phases of CHB. CONCLUSION: These results indicated that molecular genotyping and quantitative serological detection might be helpful for earlier prediction of the long-term disease outcomes. PMID- 21293111 TI - Prenatal findings in congenital leukemia: a case report. AB - We here describe a case of congenital leukemia that ended in intrauterine fetal demise at 30 weeks of gestation. Acute enlargement of the fetal trunk, elevated pulsatility index of the umbilical artery with concomitant decline of pulsatility index of the middle cerebral artery, pleural effusion, and polyhydramnios preceded the fetal death. Diagnosis of congenital myeloid leukemia was suggested by microscopic examination of the placental tissue, revealing immature myeloid precursors filling the lumina of fetal vessels in the umbilical cord and chorionic villi. Extensive vascular involvement of the placenta by leukemic cells was considered to be a primary cause of the fetal death. PMID- 21293112 TI - The comparison of two experimental rat varicocele models and their effect on sperm quality. AB - OBJECTIVE: To develop a modified rat varicocele model. METHODS: 300 male Sprague Dawley rats were selected. In 82 rats (classic group, CG), this was achieved by dissecting the left renal vein and ligating it using a 0.8-mm metal clip and 3-0 silk suture proximal to the inferior vena cava, followed by removal of the bar. In 118 rats (modified group, MG), in addition to the partial ligation of the left renal vein, the communicating branch was fully ligated. In 100 rats (sham operation group, SG), the left renal vein and communicating branches were dissected, but not ligated. The seminal fluid was aspirated and the diameters of the left spermatic veins were analyzed. Three months later, the examination was performed again. RESULTS: The diameters were 0.16 +/- 0.1 mm and 1.88 +/- 0.1 mm before and after operation, respectively, in the CG (p < 0.01), and 0.15 +/- 0.05 mm and 2.0 +/- 0.1 mm in the MG (p < 0.01). Postsurgical diameters in the CG and MG were 1.88 +/- 0.1 mm and 2.0 +/- 0.1 mm (p > 0.5), and 0.16 +/- 0.1 mm and 0.16 +/- 0.11 mm in the SG (p > 0.5). Semen parameters in the CG had significant differences before and after the operation (p < 0.01), were significantly lower in the MG (p < 0.01), and had no significant differences in the SG (p > 0.5). CONCLUSION: Simple partial ligation of the renal vein combined with ligation of the communicating branch leads to acceptable models for varicocele. PMID- 21293113 TI - Aneuploidy in the human cleavage stage embryo. AB - The cleavage stage embryo (days 1-3) stands out due to the high level of chromosomal anomalies, especially mosaicism that arises prior to global embryonic genome activation. Molecular cytogenetic studies show that an average of 60% of in vitro derived embryos have at least one aneuploid cell by the time they are 3 days old. However, comprehensive studies of the chromosome content of individual cells have revealed that 25% of these embryos have no aneuploid cells, a fact that sits well with the knowledge that at most 1 in 5 have the capacity to implant. The evidence is that extensive mosaicism, affecting several chromosomes, interferes with development to a greater extent than does uniform aneuploidy. Follow-up studies on embryos after pre-implantation genetic aneuploidy screening indicate that the frequency of meiotic errors varies according to the referral reason, with the highest frequency being recorded for the recurrent miscarriage category and the lowest in the repeated implantation failure group where younger women have a good response to ovarian stimulation. The exceptionally high incidence of pre- and post-zygotic chromosomal anomalies seen in early human embryos is thus the product of several mechanisms. Firstly, the error-prone cell cycle during the embryonic cleavage stage and secondly, parental susceptibility to meiotic and mitotic chromosomal instability together with their general genetic background. PMID- 21293114 TI - Methylation status of imprinted genes and repetitive elements in sperm DNA from infertile males. AB - Stochastic, environmentally and/or genetically induced disturbances in the genome wide epigenetic reprogramming processes during male germ-cell development may contribute to male infertility. To test this hypothesis, we have studied the methylation levels of 2 paternally (H19 and GTL2) and 5 maternally methylated (LIT1, MEST, NESPAS, PEG3, and SNRPN) imprinted genes, as well as of ALU and LINE1 repetitive elements in 141 sperm samples, which were used for assisted reproductive technologies (ART), including 106 couples with strictly male-factor or combined male and female infertility and 28 couples with strictly female factor infertility. Aberrant methylation imprints showed a significant association with abnormal semen parameters, but did not seem to influence ART outcome. Repeat methylation also differed significantly between sperm samples from infertile and presumably fertile males. However, in contrast to imprinted genes, ALU methylation had a significant impact on pregnancy and live-birth rate in couples with male-factor or combined infertility. ALU methylation was significantly higher in sperm samples leading to pregnancy and live-birth than in those that did not. Sperm samples leading to abortions showed significantly lower ALU methylation levels than those leading to the birth of a baby. PMID- 21293115 TI - Beta-cell dysfunction and insulin resistance after subarachnoid haemorrhage. AB - BACKGROUND: Hyperglycaemia is a common finding and an independent risk factor for increased morbidity and mortality in aneurysmal subarachnoid haemorrhage (SAH). Although in these patients hyperglycaemia is commonly ascribed to insulin resistance, there is little understanding of underlying mechanisms. AIMS: To prospectively study temporal disturbances of glucose metabolism after aneurysmal SAH in patients without known abnormalities of glucose metabolism and to explore possible correlations with markers of stress. METHODS: In consecutive aneurysmal SAH patients not subjected to insulin therapy, in-hospital and follow-up oral glucose tolerance tests (OGTTs) and assessments of insulin resistance, pancreatic beta-cell function, free fatty acids (FFA) and cortisol were performed and compared with reference values. RESULTS: We included 13 patients. In the first 2 weeks of admission, median fasting glucose and FFA levels were elevated while insulin levels were not. OGTTs were indicative of glucose intolerance in all patients at days 3 and 7, while on follow-up 1 patient had glucose intolerance and all patients had normal fasting glucose levels. Pancreatic beta-cell function was impaired throughout the first week and insulin resistance from day 4 to 10. Levels of cortisol correlated with higher fasting glucose and increased FFA. FFA in turn correlated with pancreatic beta-cell dysfunction. CONCLUSIONS: Aneurysmal SAH patients have transient abnormalities of glucose metabolism. During the first week, it appears to result predominantly from transient pancreatic beta-cell dysfunction, in combination with insulin resistance. PMID- 21293116 TI - Assessment of body composition in peritoneal dialysis patients using bioelectrical impedance and dual-energy x-ray absorptiometry. AB - INTRODUCTION: Protein energy wasting is closely related to increased morbidity and mortality in peritoneal dialysis (PD) patients. Simple reliable and easily available methods of determining nutritional status and recognition of short-term changes in body composition are therefore important for clinical practice. METHODS: We compared whole-body and segmental composition using multifrequency bioelectrical impedance analysis (MF-BIA) and dual-energy X-ray absorptiometry (DEXA) in 104 stable PD patients. RESULTS: Assessment of whole-body composition showed that lean body mass (LBM) was highly correlated with good method agreement using DEXA as the reference test (r = 0.95, p < 0.0001; bias -0.88 kg, 95% CI 1.53 to 0.23 kg). Similarly, high correlation and good method agreement were found for fat mass (r = 0.93, p < 0.0001; bias 0.69 kg, 95% CI 0.03-1.36 kg). Segmental analysis of LBM revealed strong correlations between LBM for trunk, left and right arms and legs (r = 0.90, 0.84, 0.86, 0.89 and 0.90, respectively, p < 0.0001). Bone mineral content derived by MF-BIA overestimated that measured by DEXA (bias 0.740 kg, 95% CI 0.66-0.82 kg). CONCLUSION: MF-BIA may potentially be a useful tool for determining nutritional status in PD patients and serial estimations may help recognize short-term changes in body composition. PMID- 21293117 TI - Racial and ethnic differences in mortality of hemodialysis patients: role of dietary and nutritional status and inflammation. AB - BACKGROUND: Racial/ethnic disparities prevail among hemodialysis patients. We hypothesized that significant differences exist between Black and non-Hispanic and Hispanic White hemodialysis patients in nutritional status, dietary intake and inflammation, and that they account for racial survival disparities. METHODS: In a 6-year (2001-2007) cohort of 799 hemodialysis patients, we compared diet and surrogates of nutritional-inflammatory status and their mortality predictabilities between 279 Blacks and 520 Whites using matched and regression analyses and Cox with cubic splines. RESULTS: In age-, gender- and diabetes matched analyses, Blacks had higher lean body mass and serum prealbumin, creatinine and homocysteine levels than Whites. In case-mix-adjusted analyses, dietary intakes in Blacks versus Whites were higher in energy (+293 +/- 119 cal/day) and fat (+18 +/- 5 g/day), but lower in fiber (-2.9 +/- 1.3 g/day) than Whites. In both races, higher serum albumin, prealbumin and creatinine were associated with greater survival, whereas CRP and IL-6, but not TNF-alpha, were associated with increased mortality. The highest (vs. lowest) quartile of IL-6 was associated with a 2.4-fold (95% CI: 1.3-3.8) and 4.1-fold (2.2-7.2) higher death risk in Blacks and Whites, respectively. CONCLUSIONS: Significant racial disparities exist in dietary, nutritional and inflammatory measures, which may contribute to hemodialysis outcome disparities. Testing race-specific dietary and/or anti-inflammatory interventions is indicated. PMID- 21293118 TI - Effects of an N-type calcium antagonist on angiotensin II-renin feedback. AB - BACKGROUND: Interrupting the renin-angiotensin system (RAS) with an angiotensin II receptor blocker (ARB) has been found to induce RAS overactivation. In this study, we investigated the effect of 2 calcium channel blockers (CCBs), cilnidipine (L-/N-type CCB) and amlodipine (L-type CCB), on the RAS activation induced by an ARB in a strain of spontaneously hypertensive rats (SHR/Izm, 10 weeks of age). METHODS: Rats intravenously catheterized for blood collection were randomly divided into groups that were administered the vehicle, the ARB valsartan or valsartan combined with one of the 2 CCBs. Their blood and kidneys were collected 270 min after administration. RESULTS: Valsartan increased the plasma angiotensin II (Ang II) level in a dose-dependent manner. Cilnidipine suppressed the increase in plasma renin activity and plasma Ang II levels induced by valsartan, but amlodipine did not. Combined administration of cilnidipine, but not amlodipine, and valsartan significantly reduced the noradrenaline content in the renal cortex. CONCLUSIONS: The results of this study suggest that the suppressive effect of cilnidipine on the valsartan-induced increase in RAS activity can be partly explained by its sympatholytic action mediated by N-type calcium channel blockade, and that combined administration of cilnidipine and valsartan might provide a synergistic therapeutic effect. PMID- 21293119 TI - The impact of strict volume control strategy on patient survival and technique failure in peritoneal dialysis patients. AB - Strict volume control strategy provides better cardiac functions and control of hypertension in dialysis patients. We investigated the effect of this strategy on mortality and technique failure in peritoneal dialysis patients over a 10-year period. 243 patients were enrolled. Strict volume control by dietary salt restriction and ultrafiltration was applied. Mean systolic and diastolic blood pressures decreased from 138.4 +/- 29.9 and 86.3 +/- 16.8 to 114.9 +/- 32.3 and 74.7 +/- 18.3 mm Hg, respectively. Overall and cardiovascular mortality rates were 48.4 and 29.6 per 1,000 patient-years, respectively. In multivariate analysis, age, diabetes and baseline serum albumin level were independent predictors of overall mortality, and age, diabetes and baseline serum calcium of cardiovascular mortality. Residual diuresis and peritoneal equilibration test values were not related to mortality. Strict volume control leads to lower mortality than comparable series in the literature. Technique survival is better during the first 3 years, but not after 5 years. PMID- 21293120 TI - Application of speckle-tracking echocardiography in detecting coronary artery disease in patients with maintenance hemodialysis. AB - BACKGROUND: Satisfactory and noninvasive diagnostic tools for coronary artery disease (CAD) are not available in hemodialysis patients. We aimed to elucidate a reliable tool to diagnose CAD in these patients. METHODS: 102 hemodialysis patients received 2D speckle-tracking echocardiography with left ventricular (LV) strain analysis and blood tests for cardiac troponin T, high-sensitive C-reactive protein, interleukin (IL)-6, and IL-18. RESULTS: The levels of biomarkers did not differ between patients with and without CAD. The factors associated with CAD were decreased circumferential strain, decreased global longitudinal strain, and the number of LV segments with decreased longitudinal strain. Logistic regression analyses showed that the number of LV segments with decreased longitudinal strain, over 6 segments, was strongly associated with CAD in hemodialysis patients (OR 12.08, 95% CI 3.724-39.209). CONCLUSIONS: The noninvasive modality of speckle-tracking echocardiography with strain analysis is efficient and objective for identifying CAD in hemodialysis patients. PMID- 21293121 TI - Second-line combination chemotherapy with vinorelbine and capecitabine in patients with advanced breast cancer previously treated with anthracyclines and/or taxanes. AB - OBJECTIVE: This phase II study was designed to evaluate the effects of vinorelbine (VRL) and capecitabine (CAP) as second-line combination chemotherapy in patients with advanced breast cancer (ABC) previously treated with anthracyclines and/or taxanes. METHODS: Treatment consisted of VRL 25 mg/m(2) administered on days 1 and 8 of a 21-day treatment cycle, along with oral CAP 825 mg/m(2) twice daily for 14 days, followed by 7 days of rest. RESULTS: 50 patients were enrolled and 48/50 (96.0%) patients were assessable for response. The median time to progression (TTP) and overall survival (OS) of the patients were 5.0 (95% confidence interval, CI, 2.1-7.9 months) and 12.0 months (95% CI, 8.0-16.0 months), respectively. The objective response rate was 26.0% (95% CI, 13.8-38.2%) with 1 confirmed complete response and 12 partial responses. The most frequent hematological adverse event was neutropenia of grade 3 and 4 in 5 (10.4%) and 2 patients (4.2%), respectively. Grade 3 stomatitis, asthenia, and diarrhea were observed in 1 (2.1%), 2 (4.2%) and 3 (6.3%) patients, respectively. CONCLUSION: The combination of VRL and CAP is feasible as second-line chemotherapy in patients with ABC previously treated with anthracyclines and/or taxanes, with efficacy being comparable to other available combination regimens. PMID- 21293122 TI - In situ fluoride response of caries lesions with different mineral distributions at baseline. AB - The present in situ study investigated the fluoride response of caries lesions with similar mineral loss but two distinct mineral distributions (low- and high 'R', calculated as the ratio of mineral loss to lesion depth). Sixteen subjects wore eight gauze-covered enamel specimens with preformed lesions placed buccally on their mandibular partial dentures for periods up to 4 weeks. The participants brushed twice daily for 1 min with an 1,100 ppm F (as NaF) dentifrice. After 3 and 4 weeks, specimens were retrieved and analyzed microradiographically (TMR) and by quantitative light fluorescence (QLF). TMR results revealed that low- and high-R lesions showed opposite behaviors - low-R lesions further demineralized, whereas high-R lesions exhibited some remineralization. In comparison, lesion depth increased in low-R, but remained unchanged in high-R lesions; R decreased in both, but more in high-R lesions; mineral density at the lesion surface remained unchanged in low-R, but increased in high-R lesions. Differences in mineral loss between lesion types increased further between 3 and 4 weeks. QLF did not mirror TMR results as low-R lesions were found to remineralize, whereas high-R lesions remained unchanged. It is likely that low-R lesions differ from high-R lesions chemically and microstructurally; therefore rendering low-R lesion more susceptible to further dissolution. During lesion formation, low-R in contrast to high-R lesions may not lose all of the solubility-determining impurities such as magnesium and carbonate, which can reprecipitate again in different mineral phases within the lesion. In conclusion, mineral distribution at baseline directly impacts in situ lesion response to fluoride. PMID- 21293123 TI - High white matter lesion load is associated with hippocampal atrophy in mild cognitive impairment. AB - BACKGROUND: Mild cognitive impairment (MCI) is a heterogeneous condition suggested as a prodromal state of Alzheimer's disease (AD) and subcortical vascular dementia (SVD). Recent findings suggest that white matter lesions (WML) may be associated with hippocampal atrophy. The objective of the study was to examine hippocampal and WML volumes in MCI patients and to examine if WML were linked to hippocampal atrophy. METHODS: The Gothenburg MCI study is a clinically based longitudinal study with biennial clinical assessments. The participants (n = 166) consist of 92 patients with stable MCI, 30 patients with converting MCI, and 44 healthy controls. WML volumes was measured manually using MRIcron. Automated segmentation of hippocampal and total white matter volumes was performed using FreeSurfer. RESULTS: The patients converting from MCI to dementia had reduced hippocampal volume. Stable MCI patients had fewer WML and converting MCI patients had more WML compared to controls. Hippocampal volume was only correlated to WML volume (rho = 0.57; p < 0.01) in the quartile (n = 42) with the most WML. CONCLUSIONS: Hippocampal atrophy is present in both AD and SVD. Hippocampal volume was associated with WML volume only in the high WML quartile, suggesting that the WML volume must reach a threshold before hippocampal atrophy is seen. PMID- 21293125 TI - Left thoracoabdominal approach in surgical treatment of adenocarcinoma of the esophagogastric junction in the Northern Henan Province of China. AB - BACKGROUND: The left thoracoabdominal (LTA) approach is the conventional way to treat adenocarcinoma of the esophagogastric junction (EGJ). The study was to review the outcome of the LTA approach with adenocarcinoma of the EGJ in a single institution in China. METHODS: 135 consecutive adenocarcinomas of EGJ patients who underwent surgical treatment were retrospectively analyzed; data gathered included basic information on the tumor, surgical approach, postoperative complications and survival rate. RESULTS: LTA esophagogastrectomy was performed in all patients. No patients received allogeneic blood transfusion during the operation. Among the resective procedures, proximal gastrectomy was performed in 122 cases. The mean operation time was 150 min (90-240). R(0) resection was obtained in 120 patients (88.9%). Two patients developed respiratory failure 2 days after surgery. Contrast swallow revealed a leak at the anastomosis in 2 patients. One early anastomotic stricture was observed radiologically, and pneumonia was observed in 3 patients. The number of patients with spontaneous pneumothorax and wound infections were 3 and 5, respectively. The percentage was zero in-hospital deaths. The overall survival rates at 1 year and 2 years were 89.2 and 69%, respectively. The median survival was 27.1 months. CONCLUSION: LTA esophagogastrectomy has a major role in the management of adenocarcinoma of the EGJ, at least in the northern Henan Province of China. PMID- 21293126 TI - Splenectomy in chronic hepatic disorders: portal vein thrombosis and improvement of liver function. AB - BACKGROUND: Splenectomy is gaining increasing importance for cirrhotic patients with hypersplenism. However, its safety and efficacy for patients with chronic liver disease remain unclear. METHODS: We retrospectively examined the medical records of 38 consecutive cirrhotic patients who underwent splenectomy or simultaneous hepatectomy and splenectomy for hepatocellular carcinoma. RESULTS: White blood cell and platelet counts significantly increased 3 months after splenectomy. Serum levels of total bilirubin and prothrombin time significantly improved 1 year after splenectomy. Interferon therapy was administered to 25 patients after splenectomy. A sustained viral response was achieved in 8 patients (42%). The total incidence of portal or splenic vein thrombosis (PSVT) detected by postoperative dynamic computed tomography was 13/38 (34.2%). Multivariate analysis revealed preoperative spleen volume (SV) to be the sole independent predictor of postoperative PSVT. Receiver-operator characteristic curve analysis showed that a cut-off SV of 450 ml corresponded to a sensitivity of 85% and a specificity of 56%. CONCLUSIONS: Splenectomy improved the liver function and facilitated effective interferon therapy in cirrhotic patients with hypersplenism, although preoperative SV was frequently associated with postoperative PSVT. PMID- 21293127 TI - Benefits of a well-structured diagnostic process in colon cancer. AB - INTRODUCTION: Preoperative work-up in colorectal cancer is comprehensive and can be time consuming. In our institution, the preoperative track for colorectal patients was reorganized in order to reduce the therapeutic delay and the number of outpatient clinic visits. We assessed the impact upon the patient outcomes. METHODS: All consecutive patients with colon cancer who entered the reorganized preoperative track between January 2008 and December 2009 (n = 87) were retrospectively compared with a consecutively diagnosed traditionally evaluated patient group diagnosed between January 2005 and December 2006 (n = 108). Time between diagnostic procedures and surgery as well as needed number of preoperative outpatient department visits were calculated. All rectal malignancies, patients who received preoperative chemotherapy and/or radiotherapy and patients who underwent emergency procedures were excluded from analysis. RESULTS: Time between colonoscopy and surgery was reduced from [median (25-75%)] 44 (34-54) to 27 (21-34) days, p < 0.001. The number of outpatient department visits declined from 6 (5-7) to 3 (3-4), p < 0.001. Time between first diagnostic test and colonoscopy was reduced from 44 (11-68) to 9 days (0-30), p < 0.001. Time between first diagnostic test and operation was reduced from 85.5 (56-120.5) to 42 days (28-62), p < 0.001. Before the reorganizations, 7% of colonoscopies were ordered by GPs and went up afterwards to 60%. CONCLUSION: Reorganization of traditional logistic routes for patients diagnosed with colon cancer reduces therapeutic delay and improves care. Moreover, the surgeon, gastroenterologist and oncologist can focus on the oncologic patient and his/her family instead of having to perform administrative tasks. PMID- 21293128 TI - Laparoscopic colorectal surgery in patients with prior abdominal surgery. AB - PURPOSE: We retrospectively investigated the impact of prior abdominal surgery on the outcome of laparoscopic colorectal surgery. PATIENTS: Among 607 colorectal cancer patients who underwent laparoscopic surgery, 192 patients had previously undergone abdominal surgery (S group) and 415 had not (non-S group). RESULTS: The percentage of female patients was higher in the S group than in the non-S group. The incidence of conversion to open surgery was higher in the S group (5.2%, 10/192) than in the non-S group (2.6%, 11/415), but the difference was not significant (p = 0.108). Although the mean operating time and estimated blood loss were similar in the two groups, right and transverse colectomy after prior gastrectomy and ipsilateral colectomy after prior colectomy took longer and were associated with greater blood loss. The morbidity rates of the two groups were similar (S group: 15.6%, 30/192; non-S group: 14.5%, 60/415). There were 5 intraoperative small-bowel injuries or postoperative small-bowel perforations in the S group, especially in the patients with prior gastrointestinal-tract surgery. CONCLUSION: Our findings suggest that there is no reason to avoid laparoscopic procedures in most patients with prior abdominal surgery despite a higher conversion rate, but caution is warranted in patients who have undergone major gastrointestinal-tract surgery. PMID- 21293129 TI - Cervical or thoracic anastomosis after esophagectomy for cancer: a systematic review and meta-analysis. AB - BACKGROUND: Cervical anastomosis and thoracic anastomosis are used for gastric tube reconstruction after esophagectomy for cancer. This systematic review was conducted in order to identify randomized trials that compare cervical with thoracic anastomosis. METHODS: A literature search for randomized trials was performed in the following databases: Medline, Embase and the Cochrane Library. RESULTS: A total of 4 trials were included. All studies had a small sample size and were of moderate quality. One trial was excluded from the meta-analysis. The following outcomes were significantly associated with a cervical anastomosis: recurrent laryngeal nerve trauma (OR: 7.14; 95% CI: 1.75-29.14; p = 0.006) and anastomotic leakage (OR: 3.43; 95% CI: 1.09-10.78; p = 0.03). None of the following outcomes were associated with the location of the anastomosis: pulmonary complications (OR: 0.86; 95% CI: 0.13-5.59; p = 0.87), perioperative mortality (OR: 1.24; 95% CI: 0.35-4.41; p = 0.74), benign stricture formation (OR: 0.79; 95% CI: 0.17-3.87; p = 0.79) or tumor recurrence (OR: 2.01; 95% CI: 0.68-5.91; p = 0.21). CONCLUSION: Cervical anastomosis could be associated with a higher leak rate and recurrent nerve trauma. However, the currently available randomized evidence is limited. Further randomized trials are needed to provide sufficient evidence for the preferred location of the anastomosis after esophagectomy. PMID- 21293130 TI - Accuracy of multislice liver CT and MRI for preoperative assessment of colorectal liver metastases after neoadjuvant chemotherapy. AB - INTRODUCTION: To determine the best imaging modality for preoperative detection, characterization and measurement of colorectal liver metastases (CRLM) after neoadjuvant chemotherapy (NAC). METHODS: A total of 79 lesions in 15 patients with CRLM were included. Following NAC, all patients received multislice liver CT (MSCT) and magnetic resonance imaging (MRI) that were scored by two observers for lesion number, type, diameter (mm) and segmental location. Intraoperative findings, histopathology and follow-up imaging were used as reference standard for surgically treated patients; non-surgical candidates underwent follow-up imaging. RESULTS: Lesion detection rate was similar for MSCT and MRI (76 and 80%, respectively, p = 0.648). Lesion characterization was significantly superior (p = 0.021) at MRI (89%, kappa 0.747, p = 0.001) compared to MSCT (77%, kappa 0.235, p = 0.005). Interobserver variability for diameter measurement was not significant at MRI (p = 0.909 [95% CI -1.245 to 1.395]), but significant at MSCT (p = 0.028 [95% CI -3.349 to -2.007]). Differences in diameter measurement were independent of observer (p = 0.131), and no statistical effect from imaging modality on diameter measurement was observed (p = 0.095). CONCLUSION: MRI is superior to MSCT in preoperative characterization and measurement of CRLM after NAC. Lesion detection rates for both modalities are comparable. PMID- 21293131 TI - Laparoscopic resection of Bismuth type I and II hilar cholangiocarcinoma: an audit of 14 cases from two institutions. AB - OBJECTIVE: To evaluate the feasibility and safety of laparoscopic resection of Bismuth type I and II hilar cholangiocarcinoma. BACKGROUND: Laparoscopic resection of hilar cholangiocarcinoma is uncommon. METHOD: Fourteen cases of Bismuth type I and II hilar cholangiocarcinoma were selected for laparoscopic resection. Eight cases involved local resection and 6 cases included partial hepatectomy. RESULTS: The mean operating time and blood loss were 305 min and 386 ml, respectively. The R0 resection rate was 100 and 60% in patients with type I and II lesions, respectively. The mean postoperative hospital stay was 9 days and 19 days in patients with type I and II tumor, respectively. In-hospital mortality and morbidity were 0 and 35.7% (5 of 14 patients), respectively. Bile leakage occurred in 1 of 7 (14.3%) and 3 of 5 (60%) patients with type I and II tumors, respectively. Port-site metastases were found in 2 cases of type II tumor. The survival rate during a 20-month follow-up period was 85.7% (12 of 14 patients). CONCLUSION: Laparoscopic resection is a potential alternative to open surgery for appropriately selected patients with Bismuth type I hilar cholangiocarcinoma. Due to the lower R0 resection and more complications, the value of laparoscopic resection for patients with type II tumors needs further evaluation. PMID- 21293132 TI - A thick pancreas is a risk factor for pancreatic fistula after a distal pancreatectomy: selection of the closure technique according to the thickness. AB - BACKGROUND/AIMS: Hand-sewn closures or stapler closures of the pancreatic remnant after a distal pancreatectomy have commonly been employed; however, the choice of technique in each patient depending on their clinical characteristics has not been discussed. METHODS: Forty-eight patients who underwent a distal pancreatectomy at Osaka University Hospital between January 2007 and October 2009 were enrolled. A hand-sewn closure was planned during the 1st period (before June 2008, 26 consecutive patients), whereas a stapler closure was planned for the 2nd period (after June 2008, 22 consecutive patients). The incidence of pancreatic fistula and the patients' characteristics were retrospectively investigated. RESULTS: Seven patients (27%) developed a fistula in the hand-sewn group, while 5 (23%) developed a fistula in the stapler group (p = n.s.). Using logistic regression analysis for all patients, younger age and the thickness of the pancreatic remnant were identified as independent risk factors for pancreatic fistula. In the stapler group, 50% of patients with a thick pancreas developed a pancreatic fistula, while no patients with a thin pancreas developed one. CONCLUSION: Thick pancreas is one of the risk factors for pancreatic fistula after a distal pancreatectomy; however, a stapler closure seems to be suitable at least for thin pancreas. PMID- 21293133 TI - Experiences in central pancreatectomy. AB - BACKGROUND: Non-cancerous pancreatic lesions have been increasing, and function preserving pancreatectomy may be an adequate approach to them. Recent advanced experience of major pancreatectomy has stimulated interest in central pancreatectomy (CP). MATERIALS AND METHODS: Nineteen patients who underwent CP for benign and borderline malignant lesions of the pancreas from January 1990 to December 2007 were retrospectively reviewed. We also summarized recent literature reporting more than 10 cases of CP. RESULT: Nine patients (47.4%) experienced postoperative complications. Pancreatic leak was noted in 7 patients (36.8%). Two patients (10.5%) required reoperation due to intractable pancreatic leak and postoperative bleeding. No mortality was noted. During the follow-up period (median 35 months, range 3-182 months), only 1 patient (5.3%) developed new-onset diabetes after successful CP. In a comparative study, similar perioperative morbidity was noted between CP and extended distal pancreatectomy with splenectomy (extended DP-S); however, the operation time and postoperative hospital stay were significantly longer in the CP group and the incidence of new onset diabetes was much lower in the CP group as compared with the DP-S group (p < 0.05). CONCLUSION: CP can be carefully selected as an appropriate surgical option for benign and borderline malignant lesions limited to the pancreatic neck area. PMID- 21293134 TI - Preoperative localisation and surgical management of insulinoma: single centre experience. AB - BACKGROUND: The majority of insulinomas are benign, small and intrapancreatic. Preoperative localisation is important to plan the surgical management. METHODS: We retrospectively analysed our data on the preoperative imaging, type of surgery and histopathological features of the operated patients with an insulinoma from January 1993 to March 2010. Univariate and multivariate analyses were performed to detect the predictive factors for survival following surgery. RESULTS: Forty patients were operated on for insulinoma, of which 33 were benign and 7 were malignant. The sensitivity of preoperative computed tomogram scan, magnetic resonance imaging and endoscopic ultrasound, for localising the lesions was 62, 82 and 94%, respectively. Enucleation was performed in 21 (52.5%) patients, and remaining had pancreatic resection. Hepatic resection was performed in 2 and liver transplantation in 1 patient. Morbidity and perioperative mortality was 17 (42.5%) and 1 (2.7%), respectively. The overall 5- and 10-year survival was 89 and 86.5%, respectively. The presence of metastases was found to be an independent predictor of poor survival on multivariate analysis. CONCLUSION: Preoperative computed tomogram/magnetic resonance imaging and endoscopic ultrasound are sensitive in localizing the majority of insulinomas. Surgery offers a good long-term survival, even in patients with malignant insulinoma. PMID- 21293135 TI - Initial experience in laparoscopic single-port appendectomy: a pilot study. AB - BACKGROUND: We describe our initial experience performing a single-port (SP) advanced laparoscopic appendectomy in comparison to the conventional port (CP) technique, which uses three ports. METHODS: Between June and September 2009, 40 consecutive patients with acute appendicitis underwent laparoscopic appendectomy at Vivantes Klinikum Am Urban, Berlin, Germany. Twenty patients were operated on using the SP technique (SP group), and the data were compared to a control group of 20 patients operated on using the CP technique (CP group) during the same time period. RESULTS: SP surgery was successfully performed on all patients without conversion to CP laparoscopic appendectomy or an open procedure. The mean age was 27.7 +/- 8.3 years in the SP group and 31.7 +/- 9.3 in the CP group (p = 0.32). Gender (p = 0.352), status of the American Society of Anesthesiologists (p = 0.765) and body mass index (p = 0.971) did not differ significantly between the two groups. The mean operating time was 48.0 +/- 13.2 min in the SP group versus 49.0 +/- 19.9 min in the CP group (p = 0.694). No patient in the SP group developed surgical complications. No patient in either group developed an incisional hernia or wound infection during the mean follow-up of 98.17 +/- 38.56 days. CONCLUSION: Transumbilical SP appendectomy via a tri-port system with a single incision is a feasible and safe new approach for routine appendectomy. It is easy to perform and good training for more advanced SP surgery. PMID- 21293136 TI - Nissen versus Dor fundoplication for treatment of gastroesophageal reflux disease: a blinded randomized clinical trial. AB - INTRODUCTION: Fundoplication techniques for treatment of gastroesophageal reflux are discussed concerning impairments and success. This randomized trial was conducted to compare Nissen's wrap and the anterior partial technique (Dor) concerning patients' quality of life (QoL) and functional data after a mid-term follow-up. METHODS: In a 24-month period, 64 patients were equally randomized into group A (Nissen's fundoplication) and group B (180 degrees anterior partial fundoplication). After a mean follow-up of 18 months, all patients were examined and interviewed using standardized QoL questionnaires (Gastrointestinal Quality of Life Index), Visick score, 24-hour pH-metry and esophageal manometry. Data of 57 patients (group A: 27, group B: 30) could be analyzed. RESULTS: After partial fundoplication, 9 patients (30%) stated the operative results were worse than perfect. Only 2 patients (7%) evaluated the outcome after Nissen's fundoplication as unsuccessful (p = 0.04). However, postoperative Gastrointestinal Quality of Life Index showed no differences between groups (p = 0.5). Additionally, functional data were not different (DeMeester 10 vs. 12, p = 0.17, and lower esophageal sphincter pressure 13 vs. 12 mm Hg, p = 0.5). CONCLUSION: The anterior partial fundoplication technique did not lead to disadvantages in postoperative QoL, physiological function and reflux control when compared to Nissen's approach in a mid-term follow-up. PMID- 21293137 TI - Genome-wide meta-analysis of joint tests for genetic and gene-environment interaction effects. AB - BACKGROUND: There is growing interest in the study of gene-environment interactions in the context of genome-wide association studies (GWASs). These studies will likely require meta-analytic approaches to have sufficient power. METHODS: We describe an approach for meta-analysis of a joint test for genetic main effects and gene-environment interaction effects. Using simulation studies based on a meta-analysis of five studies (total n = 10,161), we compare the power of this test to the meta-analysis of marginal test of genetic association and the meta-analysis of standard 1 d.f. interaction tests across a broad range of genetic main effects and gene-environment interaction effects. RESULTS: We show that the joint meta-analysis is valid and can be more powerful than classical meta-analytic approaches, with a potential gain of power over 50% compared to the marginal test. The standard interaction test had less than 1% power in almost all the situations we considered. We also show that regardless of the test used, sample sizes far exceeding those of a typical individual GWAS will be needed to reliably detect genes with subtle gene-environment interaction patterns. CONCLUSION: The joint meta-analysis is an attractive approach to discover markers which may have been missed by initial GWASs focusing on marginal marker-trait associations. PMID- 21293138 TI - Genome-wide linkage screen for systolic blood pressure in the Veterans Administration Genetic Epidemiology Study (VAGES) of Mexican-Americans and confirmation of a major susceptibility locus on chromosome 6q14.1. AB - OBJECTIVE: Hypertension or high blood pressure is a strong correlate of diseases such as obesity and type 2 diabetes. We conducted a genome-wide linkage screen to identify susceptibility genes influencing systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Mexican-Americans from the Veterans Administration Genetic Epidemiology Study (VAGES). METHODS: Using data from 1,089 individuals distributed across 266 families, we performed a multipoint linkage analysis to localize susceptibility loci for SBP and DBP by applying two models. In model 1, we added a sensible constant to the observed BP values in treated subjects [Tobin et al.; Stat Med 2005;24:2911-2935] to account for antihypertensive use (i.e. 15 and 10 mm Hg to SBP and DBP values, respectively). In model 2, we fixed values of 140 mm Hg for SBP and 90 mm Hg for DBP, if the treated values were less than the standard referenced treatment thresholds of 140/ 90 mm Hg for hypertensive status. However, if the observed treated BP values were found to be above these standard treatment thresholds, the actual observed treated BP values were retained in order not to reduce them by substitution of the treatment threshold values. RESULTS: The multipoint linkage analysis revealed strong linkage signals for SBP compared with DBP. The strongest evidence for linkage of SBP (model 1, LOD = 5.0; model 2, LOD = 3.6) was found on chromosome 6q14.1 near the marker D6S1031 (89 cM) in both models. In addition, some evidence for SBP linkage occurred on chromosomes 1q, 4p, and 16p. Most importantly, our major SBP linkage finding on chromosome 6q near marker D6S1031 was independently confirmed in a Caucasian population (LOD = 3.3). In summary, our study found evidence for a major locus on chromosome 6q influencing SBP levels in Mexican Americans. PMID- 21293139 TI - They tell me I'm allergic to ragweed. PMID- 21293140 TI - Profilins: mimickers of allergy or relevant allergens? AB - Profilins are ubiquitous proteins, present in all eukaryotic cells and identified as allergens in pollen, latex and plant foods. The highly conserved structure justifies the cross-reactive nature of IgE antibodies against plant profilins and their designation as pan-allergens. Primary sensitization to profilin seems to arise from pollen sensitization with later development of cross-reactive IgE antibodies against plant food (and possibly latex) profilins. The role of profilin in inducing allergic symptoms needs to be evaluated and raises important issues in allergy diagnosis due to cross-reactivity. IgE cross-reactivity among profilins is associated with multiple pollen sensitization and with various pollen-food syndromes. In respiratory allergy, sensitization to pollen to which the patient has virtually no environmental exposure has been identified as a manifestation of profilin sensitization. As a food allergen, profilin usually elicits mild reactions, such as oral allergy syndrome, is not modified by processing and is especially important in allergy to some fruits, such as melon, watermelon, banana, tomato, citrus fruit and persimmon. Purified natural and recombinant profilins for in vitro and in vivo allergy tests are helpful in the diagnostic work-up. Herein we review the current state of knowledge about the allergen profilin and its implications in the diagnosis and treatment of allergic diseases. We conclude that, although its role in triggering allergic symptoms is still controversial, profilin is undoubtedly a relevant allergen. As a pan allergen, profilin is associated with multiple pollen sensitization and pollen food-latex syndromes that the allergist has to be aware of in order to accomplish an accurate diagnosis and successful treatment of allergic diseases. PMID- 21293141 TI - The roles of B cells and their interactions with fibroblast-like synoviocytes in the pathogenesis of rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder that may affect many tissues and organs but principally attacks synovial joints. The pathogenesis of RA is complex and encompasses many cell types, including T cells, B cells and fibroblast-like synoviocytes (FLSs); each is believed to play a significant role in the process of RA. Interactions between T cells and B cells and between T cells and FLSs have been studied in depth. However, it has been showed that B cells also play a critical role in rheumatoid synovitis. Therefore, cell-cell contact between B cells and FLSs may be significant in the pathophysiology of RA. This review focuses on recent advances in the research of the interaction between B cells and FLSs. Considering this interaction may provide directions for innovations in RA therapy. PMID- 21293142 TI - Effect of imatinib on airway smooth muscle thickening in a murine model of chronic asthma. AB - BACKGROUND: Asthma is characterized by airway hyperresponsiveness (AHR), inflammation and remodeling. The tyrosine kinase inhibitor imatinib mesylate was developed to inhibit BCR-ABL kinase activity; however, it also has potent inhibitory activity against the c-Kit and platelet-derived growth factor receptors. The present study aimed to determine whether imatinib suppresses airway smooth muscle (ASM) remodeling and whether its effect is associated with growth factors such as transforming growth factor (TGF)-beta1 and stem cell factor (SCF). METHODS: We developed a mouse model of airway remodeling, which includes smooth muscle thickening, in which ovalbumin (OVA)-sensitized mice were repeatedly exposed to intranasal OVA administration twice a week for 3 months. Mice were treated with imatinib during the OVA challenge. RESULTS: Mice chronically exposed to OVA developed sustained eosinophilic airway inflammation and AHR compared with control mice. In addition, the mice chronically exposed to OVA developed features of airway remodeling, including thickening of the peribronchial smooth muscle layer. Administration of imatinib significantly inhibited the development of AHR, eosinophilic inflammation and, importantly, ASM remodeling in mice chronically exposed to OVA. Imatinib treatment significantly reduced the levels of interleukin-4, -5 and -13. In addition, TGF-beta1 and SCF were significantly reduced in the imatinib-treated animals. CONCLUSIONS: These results suggest that imatinib administration can prevent not only airway inflammation, but also airway remodeling associated with chronic allergen challenge. Imatinib may provide a clinically attractive therapy for chronic severe asthma. PMID- 21293143 TI - Subcutaneous immunotherapy with a depigmented polymerized birch pollen extract--a new therapeutic option for patients with atopic dermatitis. AB - BACKGROUND: Birch pollen is an important outdoor allergen able to aggravate symptoms in atopic dermatitis (AD). Specific immunotherapy (SIT), an established procedure for allergic airway diseases, might also represent an attractive therapeutic option for the causal treatment of allergen-triggered cutaneous symptoms in these patients. Studies with house dust mite SIT have already shown beneficial effects in AD patients, whereas the safety and efficacy of SIT with birch pollen extract in AD patients have not been studied so far. The aim of this study was to evaluate for the first time the safety and efficacy of SIT with a depigmented polymerized birch pollen extract in AD patients. METHODS: Fifty-five adult patients with moderate-to-severe AD and clinically relevant sensitization to birch pollen received SIT for 12 weeks. SIT was continued during birch pollen season. The assessment of safety, the total SCORAD value, and the Dermatology Life Quality Index (DLQI) were evaluated. RESULTS: The median total SCORAD value was reduced by 34% (p < 0.001) during the course of treatment and the mean DLQI improved by 49% (p < 0.001) despite strong simultaneous birch pollen exposure. Eight patients (14.5%) developed systemic reactions and 19 patients (34.5%) developed local reactions which were of mild intensity in most cases. No patient discontinued the study prematurely due to adverse drug reactions. Coseasonal treatment was well tolerated. CONCLUSION: SIT with a depigmented polymerized birch pollen extract leads to significant improvement of the SCORAD value and the DLQI in patients suffering from moderate-to-severe AD sensitized to birch pollen. PMID- 21293144 TI - Basophil responsiveness and clinical picture of acetylsalicylic acid intolerance. AB - BACKGROUND: Exposure to acetylsalicylic acid (ASA) may exacerbate respiratory or skin diseases or induce anaphylactoid reactions in apparently healthy individuals. We wanted to evaluate specific responsiveness of basophils to ASA in correlation with the clinical picture. METHODS: We performed a prospective single blind study of 59 subjects involved in clinical evaluation and/or ASA provocation testing. Whole blood basophils were stained with anti-CD63/CD123/HLA-DR mAbs after stimulation with 0.25 or 1 mg/ml ASA. RESULTS: We found that 40 subjects were ASA tolerant and 19 were ASA intolerant. Both groups had comparable manifestations of asthma and/or rhinitis (13 in the tolerant and 9 in the intolerant group). Intolerant subjects showed significantly higher basophil responsiveness to ASA in comparison to tolerant subjects, which was concentration dependent in both groups. The ratio between responses at 1 mg/ml of ASA and at baseline (activation index) was analyzed according to the clinical picture. We demonstrate that the activation index was higher only in the intolerant subjects with anaphylactoid reactions, but not in a subgroup of subjects with asthma/rhinitis. The ROC calculations show that the optimal threshold activation index was more than 2.18. The sensitivity was 80% and the specificity was 83% in the subgroup with anaphylactoid reactions. In the asthma/rhinitis subgroup, the sensitivity was 78% and the specificity was 50%. CONCLUSIONS: Our study demonstrates that there is a significantly higher in vitro basophil response to ASA in intolerant as compared to tolerant subjects. ROC analyses suggest that this measurement might only have a diagnostic value in subjects without asthma and/or rhinitis. PMID- 21293145 TI - Differences and similarities between allergic and nonallergic rhinitis in a large sample of adult patients with rhinitis symptoms. AB - BACKGROUND: Allergic rhinitis (AR) and nonallergic rhinitis (NAR) may present with different clinical and laboratory characteristics. METHODS: A total of 1,511 consecutive patients, aged 18-81 years, diagnosed with rhinitis, 56% females and 44% males, underwent complete allergic evaluation including skin prick test, blood eosinophil counts, nasal eosinophil counts, peak nasal inspiratory flow (PNIF) measurement and evaluation of nasal symptoms using a visual analog scale (VAS). RESULTS: A total of 1,107 patients (73%)had AR, whereas 404 (27%) had NAR. Patients with NAR were older and predominantly female. A higher nasal eosinophils count was associated with AR and a lack of clinical response to antihistamines. AR patients had more sneezing and nasal pruritus, whereas NAR was characterized mainly by nasal obstruction and rhinorrhea. AR patients had more severe symptoms and recurrent conjunctivitis, whereas NAR patients had slightly more frequent episodes of recurring headaches as well as olfactory dysfunction. PNIF, blood eosinophil counts and VAS of nasal symptoms were higher in patients with AR. In a final logistic regression model, 10 variables were statistically different between AR and NAR: age [OR 0.97 (95% CI 0.96-0.98)], sneezing [OR 4.09 (95% CI 2.78-6.00)], nasal pruritus [OR 3.84 (95% CI 2.60-5.67)], mild symptoms [OR 0.21 (95% CI 0.09-0.49)], intermittent/severe nasal symptoms [OR 3.66 (95% CI 2.06 6.50)], VAS [OR 1.06 (95% CI 1.04-1.08)], clinical response to antihistamines [OR 22.59 (95% CI 13.79-37.00)], conjunctivitis [OR 4.49 (95% CI 2.86-7.05)], PNIF [OR 1.01 (95% CI 1.00-1.01)] and nasal eosinophil counts [OR 1.14 (95% CI 1.10 1.18)]. Receiver operating characteristic analysis showed high predictive accuracy for a model including these variables independently of the diagnosis of AR/NAR (cutoff <0.74). CONCLUSIONS: We showed that the several clinical and laboratory parameters reported above may help to reinforce or exclude the diagnosis of AR obtained with skin prick test. PMID- 21293146 TI - Full-course drug challenge test in the diagnosis of delayed allergic reactions to penicillin. AB - BACKGROUND: Drug challenge test (DCT) has long been the most sensitive test in the allergological work-up when investigating for penicillin allergy. OBJECTIVE: To improve sensitivity of the diagnostic work-up in diagnosing penicillin allergics with histories of allergic reactions on day 2 or later in the course of penicillin treatment. METHODS: A full-course DCT was added to the current protocol if specific IgE, skin tests and DCT were all negative in patients who had a nonimmediate reaction to penicillin treatment. Sixteen patients with a history of an immediate reaction to penicillin treatment underwent testing with negative outcomes. RESULTS: Fifty percent of patients undergoing full-course DCT experienced a cutaneous adverse drug reaction. None of the controls reacted (p = 0.001). The mean time of reaction was 6 days. Penicillin V accounted for most reactions. Urticaria was the most frequent clinical reaction observed. CONCLUSIONS: Full-course DCT offers an improvement of sensitivity and predictive values of the diagnostic work-up of allergic reactions to penicillin occurring on day 2 of penicillin treatment or later. PMID- 21293147 TI - Effects of prenatal and perinatal exposure to fine air pollutants and maternal fish consumption on the occurrence of infantile eczema. AB - BACKGROUND: As there is a scarcity of evidence on potential hazards and preventive factors for infantile eczema operating in the prenatal period, the main goal of this study was to assess the role of prenatal exposure to fine particulate matter and environmental tobacco smoke (ETS) in the occurrence of infant eczema jointly with the possible modulating effect of maternal fish consumption. METHODS: The study sample consisted of 469 women enrolled during pregnancy, who gave birth to term babies (>36 weeks of gestation). Among all pregnant women recruited, personal measurements of fine particulate matter (PM2.5) were performed over 48 h in the second trimester of pregnancy. After delivery, every 3 months in the first year of the newborn's life, a detailed, standardized, face-to-face interview was administered to each mother, in the process of which a trained interviewer recorded any history of infantile eczema and data on potential environmental hazards. The estimated risk of eczema related to higher prenatal exposure to fine particulate matter (PM2.5 > 53.0 MUg/m3) and postnatal ETS as well as the protective effect of maternal fish intake were adjusted for potential confounders in a multivariable logistic regression model. RESULTS: While the separate effects of higher prenatal PM2.5 and postnatal ETS exposure were not statistically significant, their joint effect appeared to have a significant influence on the occurrence of infantile eczema [odds ratio 2.39, 95% confidence interval (CI) 1.10-5.18]. With maternal fish intake of more than 205 g/week, the risk of eczema decreased by 43% (odds ratio 0.57, 95% CI 0.35 0.93). The incidence rate ratio (IRR) for eczema symptoms, estimated from the Poisson regression model, was increased with both higher exposure to prenatal PM2.5 and postnatal ETS (IRR 1.55, 95% CI 0.99-2.44) and in children of atopic mothers (IRR 1.35, 95% CI 1.04-1.75) but was lower in girls (IRR 0.78, 95% CI 0.61-1.00). The observed preventive effect of fish consumption on the frequency of eczema symptoms was consistent with the results of the logistic analysis (IRR 0.72, 95% CI 0.52-0.99). CONCLUSIONS: The findings indicate that higher prenatal exposure to fine particulate matter combined with postnatal exposure to ETS may increase the risk of infant eczema, while maternal fish intake during pregnancy may reduce the risk of infantile eczema. PMID- 21293148 TI - Release of mast cell tryptase into saliva: a tool to diagnose food allergy by a mucosal challenge test? AB - BACKGROUND: Our aim was to examine whether measurement of the saliva mast cell tryptase (MCT) concentrations before and after a mucosal challenge test with the offending food would be helpful in diagnosing food allergy. METHODS: We performed a retrospective analysis of 44 food challenge tests performed in 38 patients between 2006 and 2009. Patients with a suspected history of food allergy chewed the food until they developed symptoms or until the amount of time known from the patients' history to usually be required for the provocation of symptoms had passed. In 5 patients, saliva samples for the measurement of MCT were collected at minutes 0, 1, 4, 8, 11, and 16 after the first onset of symptoms. The remainder of the patients only had samples taken before chewing and 4 min after the end of the test period. RESULTS: During repeated measurements, MCT peaked about 4 min after the onset of symptoms (p = 0.028). During 33 of the 44 tests (75.0%), we observed oral symptoms during testing; after 25 of the 33 (75.8%) tests evoking symptoms, the saliva MCT concentration increased. The MCT increase was negative in all other tests where no oral symptoms could be provoked. CONCLUSIONS: The measurement of saliva MCT 4 min after the onset of symptoms may be helpful to diagnose food allergy. Because of numerous confounding variables, however, a negative saliva MCT increase does not exclude food allergy. PMID- 21293149 TI - A prospective, clinical study on asymptomatic sensitisation and development of allergic rhinitis: high negative predictive value of allergological testing. AB - BACKGROUND: Asymptomatic aeroallergen sensitisation affects approximately 10% of Western adolescents and is an established risk factor for the development of respiratory allergy. The reported incidence is 2-20% annually. Previous studies are based on out-seasonal symptom recollection or selected populations, conferring bias towards higher incidence rates. OBJECTIVE: The aim was to determine the incidence of onset of symptoms among clinically well-characterised asymptomatic, sensitised subjects compared with controls, and to evaluate the predictive values of common allergological tests. METHODS: We performed a prospective, clinical, non-interventional, 2-year follow-up study on subjects (identified by population screening) with seasonal allergic birch or grass pollen rhinitis (n = 52), asymptomatic sensitisation to grass or birch (AS, n = 52) or non-atopic, healthy control subjects (n = 39). Experimental allergen susceptibility was assessed at inclusion and at follow-up by skin prick test, conjunctival challenge, intradermal late-phase reaction and measurement of specific IgE. Participants completed in-seasonal symptom and medication diaries during 2 subsequent seasons. RESULTS: We observed an annual incidence rate of 5% for the onset of symptoms in the AS group (healthy control group 0%). At baseline, the AS group displayed intermediate experimental allergen susceptibility. Subjects developing symptoms had higher levels of specific IgE and larger late-phase reaction than those persistently asymptomatic. However, the positive predictive values were low (14-27%) in contrast to the negative predictive values (95-100%). CONCLUSION: In a well-characterised young population, asymptomatic aeroallergen sensitisation conferred a low risk for onset of symptoms during the 2-year follow-up. Persistent asymptomatic phenotype could be accurately predicted by negative results from simple allergological testing. PMID- 21293150 TI - Hypersensitivity reactions to contrast media: prevalence, risk factors and the role of skin tests in diagnosis--a cross-sectional survey. AB - BACKGROUND: Hypersensitivity to contrast media (CMs) may be common and serious. AIM: To evaluate the prevalence of CM hypersensitivity, risk factors associated with it and the role of skin testing in its diagnosis. METHODS: A structured questionnaire was administered to patients who underwent computed tomography during a 1-year period. Skin tests with CMs, including skin prick tests (SPTs), intradermal tests (IDTs) and patch tests (PTs), were conducted on CM reactors (n = 24). Volunteers who tolerated CM exposure or had never been exposed to any CMs served as controls (n = 37). RESULTS: A total of 1,131 patients (630 females and 501 males; mean age 55 +/- 14.2 years) were enrolled in the study. The prevalence of historical and current CM reactors was 33/1,131 (2.92%) and 8/1,105 (0.72%), respectively. The skin was the most affected site, with mild to moderate reactions. Female gender, a history of doctor-diagnosed asthma, drug allergy, food allergy and psychiatric diseases were significant risk factors. The sensitivities of SPTs and early readings of IDTs in the diagnosis of immediate reactions were 0 and 20%, respectively, and the specificities were 94.6 and 91.4%, respectively. For early readings of IDTs, the positive predictive value (PPV) and negative predictive value (NPV) were 40 and 80%, respectively. For nonimmediate reactions, the sensitivities of delayed readings of IDTs and PTs were 14.3 and 25%, respectively; specificity was 100% for both tests. The PPV was 100% for both of these tests, and the NPVs were 85.4 and 82.4%, respectively. CONCLUSIONS: Our findings are comparable with the incidence, profile and risk factors associated with CM hypersensitivity reported previously. Skin testing with CMs has a high specificity, but its role in diagnosis is limited due to low sensitivity. PMID- 21293151 TI - Classification and response criteria in mast cell disorders: time to revise? PMID- 21293152 TI - Is insulin resistance a risk factor for the progression of chronic kidney disease? AB - BACKGROUND: The aim of this research was to establish whether there is a link between insulin resistance (IR) and glomerular filtration rate (GFR), and assess whether insulin-resistant subjects experience a more rapid deterioration in GFR. METHODS: We enrolled 73 non-diabetic chronic kidney disease (CKD) stage 2-4 patients. All blood samples were taken after 10 h of overnight fasting. Fasting blood glucose (FBG), creatinine, uric acid, albumin, cholesterol, triglyceride, insulin, HbA1c, high-sensitivity C-reactive protein (hs-CRP) and intact parathyroid hormone (iPTH) levels as well as proteinuria were analyzed. Patients were followed up for a mean of 30 (24-35) months and renal and metabolic parameters were compared in conjunction with a homeostasis model assessment of IR (HOMA-IR) between the entry and the end of the study period. CKD progression was assessed by recording renal endpoints, which included end-stage renal disease, requiring renal replacement therapy, or overall mortality. RESULTS: The study patients were divided into group 1 (n = 36), without IR, and group 2 (n = 37), with IR. Group 2 patients had a higher FBG (p = 0.003) and insulin level (p = 0.001) compared to group 1. The baseline and end of study systolic (p = 0.007) and diastolic (p = 0.001) blood pressures were decreased in group 1. In group 2, FBG (p = 0.008), HbA1c (p = 0.009), systolic (p = 0.024) and diastolic (p = 0.001) blood pressures and CRP (p = 0.047) were decreased. In group 2, 8 patients reached renal endpoints while in group 1, 9 patients reached study endpoints. HOMA-IR was not significantly higher among 17 patients who reached the renal endpoint than among the 56 who did not. At baseline, those patients who reached the renal endpoint showed lower GFR (p = 0.001), higher iPTH (p = 0.004) and hs CRP (p = 0.002) levels. CONCLUSION: There was no significant difference in GFR at the end of the study between patients who had or did not have IR. Furthermore, HOMA-IR was not significantly different in patients with or without renal endpoints. PMID- 21293153 TI - Matching, an appealing method to avoid confounding? AB - Matching is a technique used to avoid confounding in a study design. In a cohort study this is done by ensuring an equal distribution among exposed and unexposed of the variables believed to be confounding. In a matched case-control study, a case, affected by the disease, is matched with one or more individuals not affected by the disease, the controls. Because in a matched case-control study case and control group become too similar not only in the distribution of the confounder but also in the distribution of the exposure, one finds a lower effect estimate (odds ratio closer to 1). A matched case-control study requires statistical analysis to correct for this phenomenon. Nonetheless, a matched case control study is suitable for confounders that are difficult to measure. PMID- 21293154 TI - Sample size calculations. AB - The sample size is the number of patients or other experimental units that need to be included in a study to answer the research question. Pre-study calculation of the sample size is important; if a sample size is too small, one will not be able to detect an effect, while a sample that is too large may be a waste of time and money. Methods to calculate the sample size are explained in statistical textbooks, but because there are many different formulas available, it can be difficult for investigators to decide which method to use. Moreover, these calculations are prone to errors, because small changes in the selected parameters can lead to large differences in the sample size. This paper explains the basic principles of sample size calculations and demonstrates how to perform such a calculation for a simple study design. PMID- 21293155 TI - Albumin:creatinine ratio--a flawed measure? The merits of estimated albuminuria reporting. AB - Current guidelines illogically recommend that a different approach is taken to the correction for creatinine generation rate when estimating glomerular filtration rate (GFR) and when interpreting urine albumin:creatinine ratio (ACR). Age, gender and race are routinely used to adjust for predicted muscle mass in GFR estimation, even though estimated GFR is expressed per unit body surface area. Conversely, ACR is at most adjusted with the use of gender-specific classification thresholds. This difference is surprising since the proportional effect of muscle mass on serum and urine creatinine is identical. Failure to adjust for creatinine generation rate compromises ACR, potentially adversely affecting management decisions and mislabelling individuals as having/not having CKD. A greater ACR is also a marker of low muscle mass, which has confounding prognostic effects. Determination of the optimal method to adjust ACR for estimated muscle mass should improve its performance. Routine reporting of the resulting 'estimated albumin excretion rate', as for routine eGFR reporting, would remove the need for gender-specific thresholds. PMID- 21293156 TI - Proteinuria in type 2 diabetic patients with renal impairment: the changing face of diabetic nephropathy. AB - Type 2 diabetic nephropathy (type 2 DN) patients traditionally develop significant proteinuria prior to the development of renal impairment. However, this clinical paradigm, based on observations prior to the widespread usage of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB), has recently been questioned. 2,303 patients enrolled in the Sulodexide Overt Nephropathy Study (OVERT) were analyzed. Prior therapy with ACEi and/or ARB at the time of screening was recorded in 951 patients. 22% of patients had significant renal impairment with a PCR at screening of <500 mg/g. Therapy with ACEi and/or ARB at the time of screening was recorded in 94%, where prior medication data was available. In patients with type 2 DN and advanced renal impairment, levels of proteinuria below that which traditionally defines overt diabetic nephropathy, are found in more than one fifth of patients. We suggest that the high prevalence of ACEi and ARB usage in patients with type 2 DN may be effecting the traditional clinical paradigm of type 2 DN. PMID- 21293157 TI - Serum levels of BAFF and APRIL in myeloperoxidase anti-neutrophil cytoplasmic autoantibody-associated renal vasculitis: association with disease activity. AB - BACKGROUND: A proliferation-inducing ligand (APRIL) and the B cell activation factor belonging to the tumor necrosis factor family (BAFF) have proven to be key factors in the selection and survival of B cells, and a higher concentration of BAFF has been shown to contribute to autoreactive B cell survival and elevated autoantibody production. Here, serum BAFF and APRIL levels were investigated to analyze their association with disease activity in myeloperoxidase anti neutrophil cytoplasmic autoantibody (MPO-ANCA)-associated renal vasculitis. METHODS: APRIL and BAFF levels in serum obtained from 37 patients with MPO-ANCA associated vasculitis were measured by ELISA. Samples were taken from active vasculitis patients, inactive vasculitis patients and inactive vasculitis patients with infectious complications. RESULTS: Although there was no difference in serum APRIL among the active vasculitis, inactive vasculitis and infectious complication patients, serum BAFF was higher in active vasculitis patients than in inactive vasculitis, infectious complication and control patients (for all, p < 0.001). There was no significant correlation between serum APRIL and ANCA titers, but there was a significant correlation between serum BAFF and ANCA titers (r = 0.465, p < 0.001). CONCLUSION: Excessive BAFF production in MPO-ANCA associated vasculitis may be one of the factors for autoimmune B cell tolerance, resulting in MPO-ANCA production. PMID- 21293158 TI - Treatment of HIV-associated nephropathies. AB - In patients with HIV, the use of highly active antiretroviral therapy has improved life expectancy. At the same time, this increase in life expectancy has been associated with a higher frequency of chronic kidney disease due to factors other than HIV infection. Besides HIV-associated nephropathy, a number of different types of immune complex and non-immune complex-mediated processes have been identified on kidney biopsies, including vascular disease (nephrosclerosis), diabetes, and drug-related renal injury. In this setting, renal biopsy needs to be considered in order to obtain the correct diagnosis in individual patients with HIV and kidney impairment. Many issues regarding the optimal treatment of the different pathological processes affecting the kidneys of these patients have remained unresolved. Further research is needed in order to optimize treatment and renal outcomes in patients with HIV and kidney disease. PMID- 21293159 TI - The significance of the external limiting membrane in the recovery of photoreceptor layer after successful macular hole closure: a study by spectral domain optical coherence tomography. AB - PURPOSE: To evaluate the external limiting membrane (ELM) by spectral domain optical coherence tomography (SDOCT) and its correlation with the inner segment/outer segment (IS/OS) line in patients with successful macular hole surgery. PROCEDURES: Forty-five eyes were divided into 3 groups according to the interval between surgery and first examination. In the first group the interval was between 6 and 12 months, in group 2 it was >12 months and <= 24 months, and in group 3 it was >24 months. The IS/OS and ELM of participants' eyes were postoperatively assessed using SDOCT in 2008 and 12 months later. RESULTS: A statistically significant association between the integrity of the ELM and the IS/OS junction line was observed in postoperative examinations in all 3 groups. Eyes with a complete IS/OS junction line had an intact ELM. Between the first and the second examinations, a significant improvement in best-corrected visual acuity (BCVA) was noted only in group 1. A positive statistical association was also observed in group 1 between restoration of the IS/OS junction line and improvement in BCVA over follow-up. CONCLUSIONS: The restoration of the IS/OS junction line is directly related to the integrity of the ELM. PMID- 21293160 TI - Diabetic macular edema - prognostic factors. PMID- 21293161 TI - Progress in the development of vision prostheses. AB - Degenerative retinal diseases like retinitis pigmentosa and age-related macular degeneration are among the most common causes of blindness worldwide. Electronic visual prostheses represent a potential therapeutic option of increasing importance in otherwise incurably impaired patients. Based on extensive animal experiments, several devices are now being tested in clinical trials. According to the placement of the electrodes, possible stimulation sites are located subretinally, epiretinally, along the optic nerve or cortically. Anatomical, physiological and pathophysiological aspects must be considered in development and clinical application. To provide an appropriate retinal substitute, the optimal integration and adaptation of the prosthesis into the highly complex system of the visual pathway is important. This article aims to summarize the relevant studies and provides an overview of the current status of developments and challenges that still need to be mastered. PMID- 21293162 TI - Impact of panretinal photocoagulation on optic nerve head parameters. AB - BACKGROUND: To investigate the impact of panretinal photocoagulation (PRP) on quantitative optic nerve head (ONH) assessment in patients with diabetic retinopathy. METHODS: Eighty eyes of 80 diabetic patients who did not undergo PRP and 45 eyes of 45 subjects with diabetes who underwent PRP were enrolled in the prospective, cross-sectional study. Participants were evaluated by confocal scanning laser ophthalmoscopy (CSLO). The global values of ONH parameters were compared among the groups. RESULTS: The eyes that had been treated with PRP had a significantly greater rim area (1.84 +/- 0.45 vs. 1.68 +/- 0.30 mm(2)), smaller cup/disc area ratio (0.14 +/- 0.12 vs. 0.19 +/- 0.12), smaller linear cup/disc ratio (0.34 +/- 0.17 vs. 0.42 +/- 0.14) and shallower cup depth (0.15 +/- 0.09 vs. 0.18 +/- 0.07 mm) than controls (p = 0.021, p = 0.019, p = 0.007, p = 0.04, respectively). On the other hand, PRP-treated eyes were found to have a significantly thinner mean peripapillary retinal nerve fibre layer compared with the eyes in the control group (0.21 +/- 0.08 vs. 0.25 +/- 0.09 mm; p = 0.029). CONCLUSIONS: These results suggest that the ONH morphology in eyes treated with PRP may be altered to mask glaucomatous cupping due to PRP itself. Therefore caution must be taken to interpret the CSLO parameters obtained from eyes that have been treated with PRP. PMID- 21293163 TI - A pilot study on the combination treatment of reduced-fluence photodynamic therapy, intravitreal ranibizumab, intravitreal dexamethasone and oral minocycline for neovascular age-related macular degeneration. AB - AIM: To assess the safety and efficacy of the combined treatment of reduced fluence verteporfin photodynamic therapy (PDT), intravitreal ranibizumab, intravitreal dexamethasone and oral minocycline for choroidal neovascularisa- tion (CNV) secondary to age-related macular degeneration (AMD). METHODS: Nineteen patients with subfoveal CNV secondary to AMD were recruited into the trial. All study eyes (n = 19) received a single cycle of reduced-fluence (25 mJ/cm(2)) PDT with verteporfin followed by an intravitreal injection of ranibizumab 0.3 mg/0.05 ml and dexamethasone 200 MUg at baseline. Oral minocycline 100 mg daily was started the following day and continued for 3 months. Patients were followed up monthly for 12 months. Repeat intravitreal ranibizumab was given if best corrected visual acuity (BCVA) deteriorated by >5 letters on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart or central retinal thickness (CRT) on ocular coherence tomography increased >100 MUm. RESULTS: Eighteen patients completed the 12-month study. Stable vision (loss of <=15 ETDRS letters) was maintained in 89% eyes (16/18). The mean change in BCVA was -5.0 +/- 10.5 ETDRS letters. The mean number of ranibizumab injections was 3.4 (range 2-6). The mean reduction in the CRT was 66.3 MUm (+/-75). CONCLUSION: This open-label clinical trial has demonstrated the safety in terms of adverse effects and maintenance of stable vision of combination treatment with verteporfin, ranibizumab, dexamethasone and minocycline in exudative AMD. However, the outcomes with reduced-fluence PDT combination therapy does not differ significantly with outcomes of clinical trials on combination treatment with standard dose PDT and intravitreal ranibizumab in neovascular AMD. PMID- 21293164 TI - A technique of distal to proximal revision of peripheral neurostimulator leads: technical note. AB - BACKGROUND: Peripheral nerve stimulation for chronic pain states is a safe and efficacious technique, being used with increasing frequency. The incidence of hardware-related complications requiring revision remains high. OBJECTIVES: The authors describe a technique of distal to proximal neurostimulator lead revision, which does not require the changing of generators or extension leads, and thus presumably will minimize further device-related complications. METHODS: The authors present a case series of 3 patients where the distal to proximal neurostimulator lead revision technique was utilized. RESULTS: The technique was well tolerated in each instance and all patients reported >50% pain reduction at long-term follow-up. CONCLUSIONS: The distal to proximal neurostimulator lead revision technique quickly and safely adjusts lead position, including both lead depth and lead tip location, without a need for replacement of components or revision of the entire system. PMID- 21293165 TI - Skewering the subthalamic nucleus via a parietal approach. AB - BACKGROUND/AIMS: A frontal burr hole around the level of the coronal suture is the conventional entry point when performing subthalamic nucleus (STN) deep brain stimulation (DBS). However, alternative approaches may sometimes be necessary. METHODS: We present a report of delayed hardware erosion through the scalp in the left frontal region after successful bilateral STN DBS for Parkinson's disease. The left STN was retargeted via a parietal entry point. RESULTS: Significant improvement in UPDRS motor score (59%) was obtained with bilateral stimulation 6 months after re-operation. The literature was examined for similar approaches and the rationale, risks and benefits of non-frontal entry points in functional neurosurgery were explored. CONCLUSION: Together with a brief review of STN anatomy, this report demonstrates that the parietal approach to the STN remains a viable option in addition to the more traditional frontal access. PMID- 21293166 TI - Incidence and management of venous air embolisms during awake deep brain stimulation surgery in a large clinical series. AB - BACKGROUND/AIMS: Venous air embolism (VAE) is a potential complication during neurosurgical procedures, particularly in the sitting position. The diagnosis and management of VAE in patients undergoing awake deep brain stimulation (DBS) lead implantation in the sitting position are underreported. METHODS: We performed a retrospective chart review of 467 consecutive DBS surgeries at the University of California, San Francisco. Data was collected for patient demographics, diagnosis, intraoperative events, and postoperative course. RESULTS: Six cases of clinically diagnosed VAE were found, amounting to a total incidence of 1.3% per procedure. We did not observe a statistical association with patient age, diagnosis, or DBS target. The most common symptoms of intraoperative VAE were coughing, oxygen desaturation, and hypotension. In all cases, VAE was treated by copious irrigation of the surgical field and lowering the patient's head. In 4 cases, DBS implantation was abandoned because of ongoing symptoms of VAE. The respiratory outcome in all patients was good after several days of close observation. CONCLUSION: The incidence of VAE during DBS procedures is small, but prompt recognition and management of VAE are critical to avoid further associated complications. PMID- 21293167 TI - Motor cortex stimulation for trigeminal neuropathic or deafferentation pain: an institutional case series experience. AB - BACKGROUND: Trigeminal neuropathy is a rare, devastating condition that can be intractable and resistant to treatment. When medical treatment fails, invasive options are limited. Motor cortex stimulation (MCS) is a relatively recent technique introduced to treat central neuropathic pain. The use of MCS to treat trigeminal neuropathic or deafferentation pain is not widespread and clinical data in the medical literature that demonstrate efficacy are limited. METHOD: We retrospectively reviewed patients with trigeminal neuropathic or trigeminal deafferentation pain who were treated at the Oregon Health & Science University between 2001 and 2008 by 1 neurosurgeon using MCS. RESULTS: Eight of 11 patients (3 male, 8 female) underwent successful permanent implantation of an MCS system. All 8 patients reported initial satisfactory pain control. Three failed to experience continued pain control (6 months of follow-up). Five continued to experience long-term pain control (mean follow-up, 33 months). Average programming sessions were 2.2/year (all 8 patients) and 1.55/year (5 patients who sustained long-term pain control). Patients with anesthesia dolorosa or trigeminal deafferentation pain who had previously undergone ablative trigeminal procedures responded poorly to MCS. We encountered no perioperative complications. CONCLUSION: MCS is a safe and potentially effective therapy in certain patients with trigeminal neuropathy. PMID- 21293168 TI - Long-term surgical and hardware-related complications of deep brain stimulation. AB - OBJECTIVE: To evaluate the incidence of surgical and hardware-associated complications of deep brain stimulation (DBS) for a range of movement disorders. METHODS: The study design is a retrospective analysis and review of surgical and hardware complications of DBS performed by a single surgeon from 1999 to 2009. A total of 153 cases of DBS (298 electrodes) for various movement disorders and a minimum follow-up of 1 year have been included. Two patients could not be implanted. A further 54 patients who underwent change of the implantable pulse generator (IPG) have been included for analysis of hardware-related complications. RESULTS: The mean follow-up was 64 +/- 36.15 (range = 12-129) months for the DBS group. Twenty-four (15.6%) patients developed complications. Confusion occurred in 3.9%, vasovagal attack in 1.9%, lead migration/misplaced lead in 2.5%, erosion and infection in 4.5% and IPG malfunction occurred in 1.4% of the patients. When calculated with respect to the number of electrodes and IPG replacements, the complication rate was lower (11.9%). Three patients had their system explanted, two of them being patients with dystonia who had inadvertently damaged their operative site. CONCLUSION: DBS surgery is a relatively safe surgery, with most of the complications being minor, without long-term morbidity. The complication rate in elderly (age >=65 years) is comparable to that in younger patients. However, confusion is more frequent in this age group, and patients and relatives can be prepared to accept this as a transient morbidity. PMID- 21293169 TI - Surgical treatment for late complications following gamma knife surgery for arteriovenous malformations. AB - BACKGROUND: To establish the surgical indications and strategy for late complications following gamma knife surgery (GKS) for arteriovenous malformations (AVMs). METHODS: Ten male and 7 female patients aged 17-52 years (mean 28.0 years) were retrospectively identified among 686 patients who underwent GKS for AVM at our hospital. Ten patients showed cyst formation (group A), 2 patients had expanding hematoma (group B), and 5 patients had both cyst and expanding hematoma (group C). RESULTS: The mean nidus volume was 10.1 ml (range 0.1-36 ml), and the mean prescription dose at the nidus margin was 19.9 Gy (range 18-28 Gy). Complete obliteration of the nidus was obtained in 12 patients, partial obliteration in 4, and no change in 1. Cyst formation (group A) was asymptomatic in 5 patients, and symptomatic in 5 patients, manifesting as headache, hemianopia, aphasia, and motor weakness. Expanding hematoma (groups B and C) was associated with surrounding brain edema and was symptomatic in all 7 patients. Cyst opening in 1 patient and placement of an Ommaya reservoir in 2 patients were necessary in group A. Both patients in group B underwent craniotomy. Four of the 5 patients in group C required craniotomy. Another patient in group C was lost to follow-up and the final outcome was unknown. CONCLUSIONS: Cyst formation is one of the late complications of GKS for AVM. Some cysts show spontaneous regression but others gradually increase in size and become symptomatic, although relatively large asymptomatic cysts are also known. Predicting the future course of a cyst is difficult. Surgery such as placement of an Ommaya reservoir should be considered for symptomatic cases. Expanding hematoma always increases in size and becomes symptomatic, so removal by craniotomy is necessary. Surrounding brain edema decreases rapidly after surgery and neurological symptoms quickly resolve. PMID- 21293170 TI - Why monitor the recurrent laryngeal nerve in thyroid surgery? PMID- 21293173 TI - Type 1 diabetes mellitus and Rett syndrome: is there a link? PMID- 21293172 TI - Consensus statement on diagnosis and clinical management of Klinefelter syndrome. AB - Nearly 70 years after its description, Klinefelter syndrome (KS) remains a largely undiagnosed condition. As its clinical presentation may be subtle, many of those affected may be unaware or diagnosed only during evaluation for hypogonadism and/or infertility. In February 2010 an interdisciplinary panel of specialists met in Abano Terme (Padua, Italy) in a workshop on "Klinefelter Syndrome: diagnosis and clinical management". The main aim of this meeting was to discuss several aspects related to the epidemiology, pathogenesis, and evaluation of KS and to develop a consensus defining its early diagnosis and treatment. In the present consensus we have highlighted the features that may prompt the physicians to look after patients with KS both for the syndrome and correlated diseases. We have provided evidences that, during the different phases of life, there might be some advantages in establishing the diagnosis and starting proper follow-up and treatment. The workshop was carried out under the auspices of the Italian Society of andrology and Sexual Medicine (SIAMS). PMID- 21293171 TI - Current and potential roles of ghrelin in clinical practice. AB - Ghrelin is a novel GH-releasing peptide, which has been identified as an endogenous ligand for GH-secretagogue receptor. Ghrelin is mainly secreted by the stomach and plays a critical role in a variety of physiological processes including endocrine, metabolic, cardiovascular, immunological, and other actions. Ghrelin stimulates food intake via hypothalamic neurons and causes a positive energy balance and body weight gain by decreasing fat utilization and promoting adiposity. Given the multiple effects of ghrelin, its potential clinical applications have been evaluated in various conditions. Preliminary trials have shown that it may prove valuable in the management of disease-induced cachexia. Ghrelin may improve the wasting syndrome through GH-dependent or GH-independent effects. Moreover, ghrelin may play a role in the management of disorders of gut motility and obesity. Finally, other potential clinical applications of ghrelin include the treatment of patients with diabetes mellitus, infections, rheumatological diseases or GH deficiency and the diagnosis of this hormonal disorder. PMID- 21293174 TI - Adult onset hypoparathyroidism in a patient with psychiatric illness: a 71 years delayed diagnosis of DiGeorge syndrome. PMID- 21293175 TI - Endocrinology and art. A dwarf and some fried eggs. 'Velazquez dying behind the window on the left side out of which a spoon projects,' Salvador Dali--1982. (Dali Museum, Figueres, Spain). PMID- 21293176 TI - Molecular mechanisms of resistance to the EGFR monoclonal antibody cetuximab. AB - The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase belonging to the HER family of receptor tyrosine kinases. Receptor activation upon ligand binding leads to down stream activation of the PI3K/AKT, RAS/RAF/MEK/ERK and PLCgamma/PKC pathways that influence cell proliferation, survival and the metastatic potential of tumor cells. Increased activation by gene amplification, protein overexpression or mutations of the EGFR has been identified as an etiological factor in a number of human epithelial cancers (e.g., NSCLC, CRC, glioblastoma and breast cancer). Therefore, targeting the EGFR has been intensely pursued as a cancer treatment strategy over the last two decades. To date, five EGFR inhibitors, including three small molecule tyrosine kinase inhibitors (TKIs) and two monoclonal antibodies have gained FDA approval for use in oncology. Both approaches to targeting the EGFR have shown clinical promise and the anti-EGFR antibody cetuximab is used to treat HNSCC and CRC. Despite clinical gains arising from use of cetuximab, both intrinsic resistance and the development of acquired resistance are now well recognized. In this review we focus on the biology of the EGFR, the role of EGFR in human cancer, the development of antibody-based anti-EGFR therapies and a summary of their clinical successes. Further, we provide an in depth discussion of described molecular mechanisms of resistance to cetuximab and potential strategies to circumvent this resistance. PMID- 21293177 TI - Plasma exchange therapy for thrombotic microangiopathies. AB - Thrombotic microangiopathies (TMAs) are syndromes associated with thrombocytopenia and multiple organ failure. Plasma exchange is a proven therapy for primary TMA such as thrombotic thrombocytopenic purpura (TTP). There is growing evidence that plasma exchange therapy might also facilitate resolution of organ dysfunction and improve outcomes for secondary TMAs such as disseminated intravascular coagulation (DIC) and systemic inflammation-induced TTP. In this review, we survey the current available evidence and practice of plasma exchange therapy for TMAs. PMID- 21293178 TI - Systems biology of the autophagy-lysosomal pathway. AB - The mechanisms of the control and activity of the autophagy-lysosomal protein degradation machinery are emerging as an important theme for neurodevelopment and neurodegeneration. However, the underlying regulatory and functional networks of known genes controlling autophagy and lysosomal function and their role in disease are relatively unexplored. We performed a systems biology-based integrative computational analysis to study the interactions between molecular components and to develop models for regulation and function of genes involved in autophagy and lysosomal function. Specifically, we analyzed transcriptional and microRNA-based post-transcriptional regulation of these genes and performed functional enrichment analyses to understand their involvement in nervous system related diseases and phenotypes. Transcriptional regulatory network analysis showed that binding sites for transcription factors, SREBP1, USF, AP-1 and NFE2, are common among autophagy and lysosomal genes. MicroRNA enrichment analysis revealed miR-130, 98, 124, 204 and 142 as the putative post-transcriptional regulators of the autophagy-lysosomal pathway genes. Pathway enrichment analyses revealed that the mTOR and insulin signaling pathways are important in the regulation of genes involved in autophagy. In addition, we found that glycosaminoglycan and glycosphingolipid pathways also make a major contribution to lysosomal gene regulation. The analysis confirmed the known contribution of the autophagy-lysosomal genes to Alzheimer and Parkinson diseases and also revealed potential involvement in tuberous sclerosis, neuronal ceroidlipofuscinoses, sepsis and lung, liver and prostatic neoplasms. To further probe the impact of autophagy-lysosomal gene deficits on neurologically-linked phenotypes, we also mined the mouse knockout phenotype data for the autophagylysosomal genes and found them to be highly predictive of nervous system dysfunction. Overall this study demonstrates the utility of systems biology-based approaches for understanding the autophagy-lysosomal pathways and gaining additional insights into the potential impact of defects in these complex biological processes. PMID- 21293179 TI - RepA-WH1 prionoid: a synthetic amyloid proteinopathy in a minimalist host. AB - The intricate complexity, at the molecular and cellular levels, of the processes leading to the development of amyloid proteinopathies is somehow counterbalanced by their common, universal structural basis. The later has fueled the quest for suitable model systems to study protein amyloidosis under quasi-physiological conditions in vitro and in simpler organisms in vivo. Yeast prions have provided several of such model systems, yielding invaluable insights on amyloid structure, dynamics and transmission. However, yeast prions, unlike mammalian PrP, do not elicit any proteinopathy. We have recently reported that engineering RepA-WH1, a bacterial DNA-toggled protein conformational switch (dWH1 -> mWH1) sharing some analogies with nucleic acid-promoted PrPC -> PrPSc replication, enables control on protein amyloidogenesis in vitro. Furthermore, RepA-WH1 gives way to a non infectious, vertically-transmissible (from mother to daughter cells) amyloid proteinopathy in Escherichia coli. RepA-WH1 amyloid aggregates efficiently promote aging in bacteria, which exhibit a drastic lengthening in generation time, a limited number of division cycles and reduced fitness. The RepA-WH1 prionoid opens a direct means to untangle the general pathway(s) for protein amyloidosis in a host with reduced genome and proteome. PMID- 21293180 TI - Molecular characterization of the cervical and systemic B-cell repertoire: Unique, yet overlapping, immune compartments of an HIV-1 resistant individual. AB - The cervical mucosa of women who are highly exposed to HIV-1, yet remain persistently seronegative (HEPS), presents a unique opportunity to study the dynamics of an immune compartment potentially capable of preventing HIV-1 infection. Herein, we provide a detailed characterization of the immunoglobulin repertoire of cervical and systemic B cells from one such HEPS individual from Nairobi, Kenya. Analysis was done on 512 VH sequences that were RT-PCR amplified from B cells in a paired sample from the cervix and peripheral blood. The VH3 and DH repertoire of class switched cervical B cells differs significantly from that of systemic B cells indicating that the cervical environment affects local B cell populations and hence VH gene expression. Six networks of clonally related, heavily mutated B cells were identified that spanned the systemic and cervical B cell compartments. Analysis of somatic mutations suggests this is likely the result of systemic, class switched B cells homing to the cervical mucosa. Multiple networks of somatically mutated V-gene sequences, unique to the cervical mucosa, were also identified. This supports the notion that site specific responses occur and have unique regulation of tolerance and recruitment into local memory or blast B cell compartments. We conclude that while the nature of the cervical environment shapes the local B cell repertoire, the infusion of post germinal center B cells to the human cervix is a common occurrence, and represents a means by which systemic immunization could provide the local antibodies necessary to prevent HIV-1 at the site of initial contact. PMID- 21293181 TI - MiRNA-mediated regulation of cell signaling and homeostasis in the early mouse embryo. AB - At the time of implantation the mouse embryo is composed of three tissues the epiblast, trophectoderm and primitive endoderm. As development progresses the epiblast goes on to form the foetus whilst the trophectoderm and primitive endoderm give rise to extra-embryonic structures with important roles in embryo patterning and nutrition. Dramatic changes in gene expression occur during early embryo development and these require regulation at different levels. miRNAs are small non coding RNAs that have emerged over the last decade as important post transcriptional repressors of gene expression. The roles played by miRNAs during early mammalian development are only starting to be elucidated. In order to gain insight into the function of miRNAs in the different lineages of the early mouse embryo we have analysed in depth the phenotype of embryos and extra-embryonic stem cells mutant for the miRNA maturation protein Dicer. This study revealed that miRNAs are involved in regulating cell signaling and homeostasis in the early embryo. Specifically, we identified a role for miRNAs in regulating the Erk signaling pathway in the extra-embryonic endoderm, cell cycle progression in extra-embryonic tissues and apoptosis in the epiblast. PMID- 21293183 TI - Role for Geminin in sustaining the activity of hematopoietic stem cells. PMID- 21293182 TI - Transcription-induced DNA toxicity at trinucleotide repeats: double bubble is trouble. AB - Trinucleotide repeats (TNR) are a blessing and a curse. In coding regions, where they are enriched, short repeats offer the potential for continuous, rapid length variation with linked incremental changes in the activity of the encoded protein, a valuable source of variation for evolution. But at the upper end of these benign and beneficial lengths, trinucleotide repeats become very unstable, with a dangerous bias toward continual expansion, which can lead to neurological diseases in humans. The mechanisms of expansion are varied and the links to disease are complex. Where they have been delineated, however, they have often revealed unexpected, fundamental aspects of the underlying cell biology. Nowhere is this more apparent than in recent studies, which indicate that expanded CAG repeats can form toxic sites in the genome, which can, upon interaction with normal components of DNA metabolism, trigger cell death. Here we discuss the phenomenon of TNR-induced DNA toxicity, with special emphasis on the role of transcription. Transcription-induced DNA toxicity may have profound biological consequences, with particular relevance to repeat-associated neurodegenerative diseases. PMID- 21293184 TI - Cse4 gets a kiss-of-death from Psh1. PMID- 21293185 TI - Inositol pyrophosphates in cell death and life. PMID- 21293186 TI - Myc orchestrates a regulatory network required for the establishment and maintenance of pluripotency. AB - Pluripotent stem cells (PSCs) are maintained by a complex regulatory network orchestrated by transcription factors, epigenetic modifiers and non-coding RNAs. Central to this regulatory network is the Myc family of transcription factors. Defining roles for Myc in PSCs has been problematic but recently, a number of reports have provided insight into this question. An emerging picture now places Myc as a key regulator of the cell cycle, genomic maintenance and general metabolic activity in PSCs through its ability to directly regulate large numbers of target genes and more indirectly through control of microRNAs. One of Myc's main roles is to repress the activity of genes required for differentiation such as the endoderm master regulator, GATA6. The general mechanism by which Myc activates target genes is well understood but a remaining major challenge is to understand how it represses gene activity. Here we discuss potential mechanisms for how Myc establishes and maintains the pluripotent state and incorporate proteomics data that supports a model where Myc acts as part of a regulatory network with epigenetic modifiers. PMID- 21293187 TI - "Licensed to kill": tyrosine dephosphorylation and Bak activation. AB - The genomes of multi-cellular organisms are under constant assault from a host of environmental agents. The efficient elimination of cells harbouring damage is essential to avoid the accumulation of deleterious changes that may promote tumorigenesis. Consequently, a complex and elaborate series of damage responses have evolved to either ensure that correct repair of the DNA has been carried out, or alternatively, to initiate programmes that result in the ablation of the damaged cell. Apoptosis is recognized as both a fast an efficient way of disposing of damaged or unwanted cells before they accumulate changes that may result in the acquisition of neoplastic autonomy. The mitochondrial apoptotic pathway relies upon two effector proteins of the Bcl2 family, Bax and Bak, that when activated form pores in the outer mitochondrial membrane that release cytochrome c and other apoptogenic factors. We have recently shown that the initiation of Bak activation is controlled by dephosphorylation. In particular, we found that a specific tyrosine dephosphorylation was required for Bak activation to proceed, and that tyrosine phosphatases may serve to integrate apoptotic signals that culminate in Bak dephosphorylation. Here, we discuss these findings and present additional data underlining the importance of dephosphorylation in the Bak activation process, and how the modulation of Bak phosphorylation status may be modified to enhance cell killing. PMID- 21293188 TI - Post-translational control of Myc function during differentiation. AB - Myc proteins are deeply involved in multiple biological processes including cell proliferation, growth, metabolism, apoptosis, differentiation, and tumorigenesis. Paradoxically, Myc proteins have been found to be capable of both inhibiting and facilitating differentiation depending on the biological context. Recently we identified a new mode of Myc regulation in differentiating muscle cells in which c-Myc protein is proteolytically cleaved by calcium-dependent calpains in the cytoplasm. This cleavage serves two purposes. First, it inactivates the transcriptional function of Myc by removing its C-terminus, a region responsible for the interaction of Myc with Max and DNA. Second, it alters cytoskeletal architecture and accelerates muscle differentiation through the activity of the remaining N-terminal cleavage product (termed Myc-nick). Here we discuss the roles and regulation of full-length Myc and Myc-nick in terminal differentiation and propose a model in which calpain-mediated cleavage of Myc operates as a functional switch. PMID- 21293189 TI - Cell migration regulates the kinetics of cytokinesis. AB - Cytokinesis is the final stage of cell division in which the daughter cells separate. Although a growing body of evidence suggests that cell migration induced traction forces may be required to provide physical assistance for daughter cells to dissociate during abscission, the role of cell migration in cytokinesis has not been directly elucidated. Recently, we have demonstrated that Crk and paxillin, which are pivotal components of the cell migration machinery, localize to the midbody and are essential for the abscission. These findings provided an important link between the cell migration and cytokinesis machineries and prompted us to dissect the role of cell migration in cytokinesis. We show that cell migration controls the kinetics of cleavage furrowing, midbody extension and abscission and coordinates proper subcellular redistribution of Crk and syntaxin-2 to the midbody after ingression. PMID- 21293190 TI - While p73 is essential, p63 is completely dispensable for the development of the central nervous system. AB - The ancient p53 paralogs p63 and p73 regulate specific tissue formation, cell survival and cell death via their TA and DeltaN isoforms. Targeted disruption of the p73 locus leads to severe defects in the development of the central nervous system (CNS), and p73 has recently been shown to be an essential regulator of neural stem cell maintenance and differentiation in both embryonal and adult neurogenesis. In contrast, global p63-/- mice lack skin and limbs. Moreover, p63 is detectable in embryonic cortex. It has previously been proposed to also play critical pro-death and pro-survival roles in neural precursors of the developing sympathetic and central nervous system, respectively, based on experimental overexpression and siRNA-mediated knockdown of p63. Here we perform an extensive analysis of the developing central nervous system in global p63-/- mice and their wildtype littermates. Brain and spinal cord of embryos and newborn mice were assessed in vivo for neuroanatomy, histology, apoptosis, proliferation, stemness and differentiation, and in vitro for self-renewal and maturation in neurosphere assays. None of these analyses revealed a detectable phenotype in p63-/- mice. Hence, despite the profound impact of p63 on the development of stratified epithelia and limbs, p63 is completely dispensable for proper development of the central nervous system. Thus, despite their strong homology, the non-overlapping tissue specificity of p63 and p73 functions appears more pronounced than previously anticipated. PMID- 21293191 TI - Dynamic and selective DNA-binding activity of Smc5, a core component of the Smc5 Smc6 complex. AB - Members of the structural maintenance of chromosome (SMC) family of proteins are essential regulators of genomic stability. In particular, the conserved Smc5-6 complex is required for efficient DNA repair, checkpoint signaling, and DNA replication in all eukaryotes. Despite these important functions, the actual nature of the DNA substrates recognized by the Smc5-6 complex in chromosomes is currently unknown. Furthermore, how the core SMC components of the Smc5-6 complex use their ATPase-driven mechanochemical activities to act on chromosomes is not understood. Here, we address these issues by purifying and defining the DNA binding activity of Smc5. We show that Smc5 binds strongly and specifically to single-stranded DNA (ssDNA). Remarkably, this DNA-binding activity is independent of Smc6 and is observed with the monomeric form of Smc5. We further show that Smc5 ATPase activity is essential for its functions in vivo and that ATP regulates the association of Smc5 with its substrates in vitro. Finally, we demonstrate that Smc5 is able to bind efficiently to oligonucleotides consistent in size with ssDNA intermediates produced during DNA replication and repair. Collectively, our data on the DNA-binding activities of Smc5 provide a compelling molecular basis for the role of the Smc5-6 complex in the DNA damage response. PMID- 21293192 TI - Protective roles of SIRT1 in atherosclerosis. AB - SIRT1 is a NAD (+) -dependent class III histone deacetylase (HDAC) that mediates the effects of caloric restriction on lifespan and metabolic pathways in various organisms. It deacetylates both histone and non-histone proteins, and targets proteins with diverse cellular and tissue functions. In the vasculature of rodent models SIRT1 mediates vasodilatation via eNOS-derived nitric oxide (NO) and scavenging reactive oxygen species (ROS). Recent studies demonstrated further protective roles of SIRT1 in vascular biology and atherosclerosis. In endothelial cells and macrophages SIRT1 has anti-inflammatory functions by downregulating the expression of various pro-inflammatory cytokines by interfering with the NF-kB signaling pathway. Deacetylation of RelA/p65-NF-kB by SIRT1 in macrophages also suppresses the expression of Lox-1, a scavenger receptor for oxidized low-density lipoproteins (oxLDL), thereby preventing macrophage foam cell formation. Moreover, SIRT1 has been shown to regulate the activity of Liver X-receptor (LXR), thereby promoting ABCA1-driven reverse cholesterol transport in plaque macrophages. Finally, SIRT1 suppresses the expression of endothelial tissue factor (coagulation factor III) and hence exerts anti-thrombotic properties. These findings indicate atheroprotective effects of SIRT1 in atherogenesis and highlight the need for translational research from bench-to-bedside. Indeed, SIRT1 activators are available for experimental research and undergo clinical testing. Taken together, these studies suggest SIRT1 activation as a promising therapeutic approach in atherosclerosis. Further studies are necessary to better understand the exact role of SIRT1 in the protagonist cells orchestrating atherogenesis and to identify the specificity, target effects and putative off target effects of these promising SIRT1 activators. PMID- 21293193 TI - Candidate pathways linking inducible nitric oxide synthase to a basal-like transcription pattern and tumor progression in human breast cancer. AB - Inducible nitric oxide synthase (NOS2) is an inflammation responsive enzyme (EC 1.14.13.39) that is induced during acute and chronic inflammation and tissue injury as part of the host defense and wound healing process. NOS2 up-regulation leads to increased nitric oxide (NO) production, the means by which this enzyme can initiate NO-dependent signal transduction, influence the redox state of cells and induce modifications of proteins, lipids, and DNA. Aberrant expression of NOS2 has been observed in many types of human tumors. In breast cancer, increased NOS2 is associated with markers of poor outcome and decreased survival. Growth factor and cytokine signaling, tissue remodeling, NF-kB activation, and hypoxia are candidate mechanisms that induce NOS2 in tumor epithelial and tumor infiltrating cells. NOS2 induction will trigger the release of variable amounts of NO into the tumor microenvironment and can activate oncogenic pathways, including the Akt, epidermal growth factor receptor and c-Myc signaling pathways, and stimulate tumor microvascularization. Constitutively increased NO levels may also select for mutant p53 cells to overcome the tumor suppressor function of NO activated wild-type p53. More recent findings suggest that NO induces stem cell like tumor characteristics in breast cancer. In this review, we will discuss the effects of NO in tumor biology and disease progression with an emphasis on breast cancer, and will examine the mechanisms that link increased NO to a basal-like transcription pattern in human breast tumors and poor disease outcome. PMID- 21293194 TI - Pretransplant donor-specific antibodies detected by single-antigen bead flow cytometry are associated with inferior kidney transplant outcomes. AB - BACKGROUND: The clinical significance of pretransplant donor-specific antibodies (pre-Tx DSAs) detected by single-antigen bead flow cytometry (SAB-FC) remains unclear. METHODS: To investigate the impact that pre-Tx DSAs detected by SAB-FC have on early clinical outcomes, we tested pre-Tx sera from all consecutive deceased-donor kidney transplants performed between January 2005 and July 2006 (n=237). RESULTS: In the study population of which 66% had a high-immunologic risk, mean fluorescence intensity (MFI) more than or equal to 100 for class I and more than or equal to 200 for class II were the lowest DSA thresholds associated with inferior antibody-mediated rejection-free graft survival (75% vs. 90%, P=0.004 and 76% vs. 87%, P=0.017, respectively). The hazard ratio for antibody mediated rejection increased linearly with higher class II DSA from MFI 100 to 800 (1.7[0.8-3.2], P=0.1 for MFI >=100 vs. 4.7[2.4-8.8], P<0.001 for MFI >= 800). Differences in graft function were only evident in patients with class II MFI more than or equal to 500 (estimated glomerular filtration rate: 47.6 vs. 54.3, P=0.02 and proteinuria: 0.6 +/- 0.6 vs. 0.4 +/- 0.3, P=0.03). A difference in death-censored graft survival was detected in patients with class II MFI more than or equal to 1000 (75% vs. 91.9%, P=0.055). CONCLUSION: High-pre-Tx DSAs detected by SAB-FC are associated with incrementally poor graft outcomes in deceased-donor kidney transplant with high-immunologic risk. PMID- 21293200 TI - Diabetes mellitus, HIV infection, and vitamin D: time to act or time to think? PMID- 21293199 TI - First-line antiretroviral therapy after single-dose nevirapine exposure in South Africa: a cost-effectiveness analysis of the OCTANE trial. AB - BACKGROUND: The OCTANE trial reports superior outcomes of lopinavir/ritonavir vs. nevirapine-based antiretroviral therapy (ART) among women previously exposed to single-dose nevirapine to prevent mother-to-child HIV transmission. However, lopinavir/ritonavir is 12 times costlier than nevirapine. METHODS: We used a computer model, with OCTANE and local data, to simulate HIV-infected, single-dose nevirapine-exposed women in South Africa. Outcomes of three alternative ART sequences were projected: no ART (for comparison), first-line nevirapine, and first-line lopinavir/ritonavir. OCTANE data included mean age (31 years) and CD4 cell count (135/MUl); median time since single-dose nevirapine (17 months); and 24-week viral suppression efficacy for first-line ART (nevirapine: 85%, lopinavir/ritonavir: 97%). Outcomes included life expectancy, per-person costs (2008 US$), and incremental cost-effectiveness ratios. RESULTS: With no ART, projected life expectancy was 1.6 years and per-person cost was $2980. First-line nevirapine increased life expectancy (15.2 years) and cost ($13 990; cost effectiveness ratio: $810/year of life saved versus no ART). First-line lopinavir/ritonavir further increased life expectancy to 16.3 years and cost to $15 630 (cost-effectiveness ratio: $1520/year of life saved versus first-line nevirapine). First-line lopinavir/ritonavir cost-effectiveness was sensitive to prevalence of nevirapine-resistant virus at ART initiation, time from single-dose nevirapine exposure to ART initiation (6-12, 12-24, or >24 months), second-line ART efficacies, and outcomes after 24 weeks on ART. CONCLUSIONS: First-line lopinavir/ritonavir-based ART is very cost-effective in single-dose nevirapine exposed, South African women similar to OCTANE participants. Lopinavir/ritonavir should be initiated in women with known nevirapine resistance or single-dose nevirapine exposure less than 12 months prior, or in whom such information is unknown. PMID- 21293201 TI - Drug interactions between voriconazole, darunavir/ritonavir and etravirine in an HIV-infected patient with Aspergillus pneumonia. PMID- 21293202 TI - Detecting HIV-1 superinfection by pol gene population sequencing among untreated HIV-1-infected men who experience sudden rises in plasma HIV-1 RNA load. PMID- 21293203 TI - Preregistration of epidemiology protocols: a commentary in support. PMID- 21293204 TI - Biological interaction: time to drop the term? PMID- 21293205 TI - In defense of "biological interaction". PMID- 21293206 TI - Advancing industrial livestock production: health effects research and sustainability. PMID- 21293207 TI - Name of the bias and sex of the angels. PMID- 21293208 TI - Blood lead levels, ALAD gene polymorphisms, and mortality. AB - BACKGROUND: Previous analyses from the National Health and Nutrition Examination Survey (NHANES III) have found that elevated blood lead levels may be associated with cardiovascular mortality, cancer mortality, and all-cause mortality. The 5 aminolevulinic acid dehydratase (ALAD) G177C genetic polymorphism (rs 1800435) affects lead toxicokinetics and may alter the adverse effects of lead exposure. We examined whether the ALAD G177C single nucleotide polymorphism (SNP) affects the relationship between lead and mortality. METHODS: We analyzed a subset of 3349 genotyped NHANES III participants at least 40 years of age. Using Cox proportional hazards regression, we estimated the relative risk of all-cause, cardiovascular disease, and cancer mortality by ALAD genotype, and by blood lead levels (<5 MUg/dL vs. >=5 MUg/dL). We also tested whether the ALAD genotype modified the relationship between blood lead level and mortality. RESULTS: The adjusted overall relative risk for participants with the variant ALAD genotype was decreased for all-cause mortality (hazards ratio = 0.68; [95% confidence interval = 0.50-0.93]) compared with persons having the common GG genotype. There was some suggestion that higher lead levels were associated with cancer mortality (1.48 [0.92-2.38]). We observed no convincing interaction effect between ALAD genotype and blood lead level on mortality risk. CONCLUSION: The ALAD genotype may be associated with decreased mortality from all causes and from cancer. This association does not seem to be affected by lead exposure. PMID- 21293209 TI - Increasing study participation. PMID- 21293210 TI - Sample-size formula for case-cohort studies. PMID- 21293211 TI - Maternal epilepsy and cognitive/psychiatric status of sons. PMID- 21293212 TI - Sensitivity analysis when data are missing not-at-random. PMID- 21293213 TI - Aircraft noise and myocardial infarction mortality. PMID- 21293215 TI - Response to Plon et al.--Genetic testing and cancer risk management recommendations by physicians for at-risk relatives. PMID- 21293217 TI - Rectal perforation secondary to rape and fisting in a female adolescent. AB - We present the case of a 16-year-old girl who was sexually assaulted with transanal forearm penetration resulting in rectal perforation. She required a sigmoid colostomy that was later reversed. The patient's history and physical examination was complicated by multiple factors: she was intoxicated at the time of presentation as well as during the assault; her presentation fluctuated over time, she was obese, and she carried a psychiatric diagnosis. This case report documents a rare injury caused by sexual assault in the adolescent population and also serves as a platform to discuss the evaluation and management of pediatric victims of sexual assault. We support a collaborative model of care including qualified sexual assault pediatricians, sexual assault nurse (or forensic) examiners, medical specialists, and the criminal justice system. The importance of developing updated sexual assault protocols, ensuring their implementation, and maintaining continuous quality assurance cannot be overemphasized. PMID- 21293218 TI - Alice in Wonderland syndrome in H1N1 influenza: case report. AB - The different aspects of the global H1N1 influenza and its complications are currently of great interest. Neurological complications of the disease and its frequency are still unknown. We report a case of an 11-year-old girl who developed Alice in Wonderland syndrome associated with H1N1 influenza. This unique clinical syndrome was previously described in other diseases. The clinician's awareness of the existence of this syndrome in H1N1 influenza might save the child from undergoing extensive diagnostic procedures. PMID- 21293219 TI - Cryptorchid testicular torsion. AB - Torsion of the testicle is a well-recognized urological emergency. Torsion of the cryptorchid testicle, however, is described in the urology literature, but not well recognized in the emergency department. We discuss a case of a torsed cryptorchid testicle and review the pathophysiology, imaging modalities, and prognosis. PMID- 21293220 TI - Alkalosis-induced respiratory depression from infantile hypertrophic pyloric stenosis. AB - We report an infant with apnea due to infantile hypertrophic pyloric stenosis. The distinct mechanism of compensatory respiratory depression of severe metabolic acidosis is implicated. PMID- 21293221 TI - A case of lower extremity venous thrombosis in the pediatric emergency department: associations with May-Thurner syndrome and isotretinoin use. AB - Unilateral calf swelling and pain is not a common complaint in the pediatric emergency department. We present a case of a 17-year-old adolescent boy with no past medical history who presented with left leg swelling and pain while taking prednisone and isotretinoin. He was found to have an extensive occlusive thrombus throughout the deep venous system in his left leg. He was later diagnosed with May-Thurner syndrome, an anatomic variant in which the right iliac artery compresses the left iliac vein. We review the differential diagnosis, diagnostic workup, and initial ED management of deep venous thrombosis and provide a brief discussion of May-Thurner syndrome and the association of isotretinoin and vascular thrombi. PMID- 21293222 TI - Prolonged QT syndrome and sedation: a case report and a review of the literature. AB - Prolonged QT syndrome is the most common genetic arrhythmia syndrome, and the majority of patients are undiagnosed. The syndrome is characterized by abnormally long ventricular repolarization (QT interval) on electrocardiogram, which may manifest as syncopal episodes, arrhythmias, or sudden death. Arrhythmias may be precipitated by stress or medications. There are few randomized controlled trials examining the safety of typical sedation medications in the patient with prolonged long-QT syndrome. This case describes the management of sedation in a patient with prolonged long-QT syndrome and then reviews the current literature regarding commonly utilized sedation medications. PMID- 21293223 TI - Cataracts as the initial manifestation of type 1 diabetes mellitus. AB - A 13-year-old girl presented with the gradual onset of bilateral visual changes. She was initially diagnosed with idiopathic cataracts, but a medical evaluation revealed new-onset type 1 diabetes mellitus with ketosis. The patient was hospitalized and started on a regimen of insulin before discharge and eventual surgical correction of her cataracts. Cataracts are an uncommon initial manifestation of new-onset type 1 diabetes, occasionally in the absence of other more classic symptoms of diabetes. Pediatric patients presenting with bilateral cataracts should be evaluated for a underlying etiology of their cataracts before being referred for surgical correction. PMID- 21293224 TI - Seizure and altered mental status in a 12-year-old child with Shigella sonnei gastroenteritis. AB - We report a case of Shigella-associated altered mental status and seizure in a 12 year-old boy. Although seizure is a known complication of shigellosis, it is quite unusual in patients older than 9 years. This case illustrates the importance of considering the diagnosis of shigellosis in any pediatric patient with altered mental status or seizure in the context of gastrointestinal symptoms such as diarrhea. PMID- 21293225 TI - False elevation of carboxyhemoglobin: case report. AB - BACKGROUND: Carbon monoxide toxicity in infants and children, like adults, produce nonspecific symptoms with normal vital signs necessitating the serum measurement of carboxyhemoglobin (COHb). In infants, the COHb may be falsely elevated. OBJECTIVES: Our goal was to report a case of suspected carbon monoxide toxicity in an infant and the likely cause of the falsely elevated serum COHb. CASE: A previously healthy 3-month-old girl presented to the pediatric emergency department (ED) with smoke inhalation from a defective furnace. She was asymptomatic. On examination, she was alert, with Glasgow Coma Scale of 15 and normal vital signs. Cardiorespiratory and neurological examinations were completely normal. Because of concern regarding carbon monoxide poisoning, she was treated with normobaric oxygen therapy. Initial and subsequent serum COHb levels were persistently elevated, despite treatment and the infant appearing clinically well. As such, she had a prolonged stay in the ED. Further investigations found that fetal hemoglobin interferes with the spectrophotometric method used to analyze serum COHb levels. CONCLUSIONS: Carboxyhemoglobin serum level, in infants, may be falsely elevated due to the fetal hemoglobin interfering with standard methods of analysis. Knowledge of the false elevation using standard spectrophotometric methods of COHb in clinically well-appearing infants can decrease unnecessary oxygen therapy and monitoring time in the ED. PMID- 21293226 TI - Tick-borne illnesses: a CME update. AB - North American tick-borne illnesses are a group of important emerging diseases whose incidence has been increasing for the past decade. Emergency physicians may be the first contact for patients with symptoms of tick-borne illness, thus it is important that these diseases remain on a physicians' differential diagnosis when presented with an appropriate clinical presentation. This CME activity provides an overview of the most common tick-borne illnesses in North America and will help physicians evaluate their clinical presentation, order appropriate diagnostic tests, develop pediatric treatment recommendations, and prepare to include tick-borne illnesses in the differential diagnosis of pediatric patients presenting with multisystem disease. PMID- 21293228 TI - Causes of eye burns in children. AB - OBJECTIVE: Eye burns can cause significant ocular morbidity and miss early detection if unsuspected. The objective was to ascertain the reported causes of burns to the eyes in children. METHODS: Published literature on eye burns in children was searched from 1950 to July 2008 in MEDLINE and from 1982 to July 2008 in CINAHL (Cumulative Index to Nursing and Allied Health Literature) to identify all reported cases. RESULTS: Forty-two articles from MEDLINE, 5 from CINAHL database, and 6 from the reference lists were included in the analysis. Eye burns in children were caused by thermal, electrical, microwaved food and drinks, and solar hazards. Chemical agents included household cleaning agents, industrial chemicals, certain medications, agricultural chemicals, and some miscellaneous agents. Biological agents reported were millipedes, snake venom, vesicatory insects, and Manchineel tree sap. CONCLUSIONS: This article shows that children experience eye burns due to many preventable causes. Public education strategies should be implemented to prevent eye burns in children. PMID- 21293229 TI - ECGs in the ED. PMID- 21293230 TI - Pediatric emergency medicine: legal briefs. PMID- 21293232 TI - Epidemiology of sports injury in pediatric athletes. AB - In the United States, youth interest in sports participation has increased steadily over the past 2 decades. Although such trends are encouraging to the medical community, especially given the concurrent obesity epidemic among American youth, this increase in sports participation is accompanied by an increase in rates of sports injury in the pediatric population. Appropriate diagnosis and treatment of these injuries by primary care and orthopedic providers rests heavily on a fundamental understanding of the epidemiology of such pathologies. PMID- 21293233 TI - Back pain in the young athlete. AB - Back pain in the young athlete is a common finding. There are many different problems that can cause back pain in active children. It is important for the treating physician to obtain a thorough history and physical examination to help in establishing the underlying cause for the discomfort. Appropriate imaging can be determined by these findings and further help to define the pathology. Depending upon the specific pathology, appropriate treatment may help the patient to safely return to the activities that they enjoy. PMID- 21293234 TI - Upper extremity injuries in the adolescent athlete. AB - There has been a significant increase in youth sports participation and athletic activities over the past 3 decades. With the increase in participation, there has been a commensurate rise in the number of sports-related injuries. A majority of these injuries are due to overuse as athletes frequently compete in multiple sports with year round competition and training. As higher demands are placed on these young athletes, the likelihood of injury during and individual's playing career continues to increase. This review will focus on both overuse and traumatic injuries of the upper extremity in the adolescent athlete. A significant emphasis will be placed on the evaluation and management of soft tissue and bony injuries in the overhead throwing athlete. The review will conclude with a discussion on common wrist and hand injuries seen in this population. PMID- 21293235 TI - Anterior knee pain in the young athlete: diagnosis and treatment. AB - The underlying etiology of anterior knee pain has been extensively studied. Despite many possible causes, often times the diagnosis is elusive. The most common causes in the young athlete are osteosynchondroses, patellar peritendinitis and tendinosis, synovial impingement, malalignment, and patellar instability. Less common causes are osteochondritis dissecans and tumors. It is always important to rule out underlying hip pathology and infections. When a diagnosis cannot be established, the patient is usually labeled as having idiopathic anterior knee pain. A careful history and physical examination can point to the correct diagnosis in the majority of cases. For most of these conditions, treatment is typically nonoperative with surgery reserved for refractory pain for an established diagnosis. PMID- 21293236 TI - Anterior cruciate ligament injuries in the young athlete: evaluation and treatment. AB - Injuries to the pediatric and adolescent athlete are becoming more common as increasing numbers of this patient population are participating in year-round sporting activities. As these figures continue to rise, there have been an escalating number of patients with both traumatic and nontraumatic, sports related knee injuries presenting to orthopedic surgeons for evaluation. Anterior cruciate ligament injuries in these patients, specifically in the skeletally immature, represent a complex problem. Treatment of these patients requires a thorough understanding of anatomy and physiology of the pediatric patient, the natural history of this injury, and knowledge of the potential complications of surgical intervention. This review will address these topics and will describe the presentation, diagnosis, and most commonly used surgical techniques currently being used with these patients. Future directions and advances in care of these injuries will also be discussed. PMID- 21293237 TI - The potential for primary repair of the ACL. AB - The objective of this work is to assess the feasibility of successfully repairing the torn anterior cruciate ligament (ACL). Two major motivators for developing a new treatment for ACL injuries are the recently reported high rates of osteoarthritis, after conventional ACL reconstruction, and the problem of how to safely treat skeletally immature patients. A key factor in developing such a technique was the identification of the main inhibitor of intrinsic ACL healing the lack of clot formation between the 2 torn ends of the ligament. A bioactive and biocompatible scaffold, which could be placed in the wound site to enhance cellular proliferation and biosynthesis, was developed. This biomaterial has shown promising functional outcomes in several large animal models of primary repair of partial and complete ACL transection over 4 to 14 weeks, suggesting potential for a successful, future clinical application. PMID- 21293238 TI - Meniscus tears in children. AB - Increased athletic participation by the skeletally immature athlete and a heightened suspicion by physicians have contributed to an increase in the incidence of meniscal injuries in children and adolescents. In young patient, meniscal injury could have long-term consequences, so an understanding of recognition and treatment is essential. We review the anatomy and development of the menisci, review classification and diagnosis of meniscal tears, discuss management options and outcomes of treatment, and focus on discoid lateral meniscus and meniscal cysts. PMID- 21293239 TI - Juvenile osteochondritis dissecans. AB - Juvenile osteochondritis dissecans (JOCD) has been a recognized entity for more than 100 years. Despite our long recognition of OCD, the natural history and most effective therapies are poorly understood. Although conclusive evidence of an exact cause is lacking, there is widespread agreement that JOCD is related to repetitive trauma. Patients with JOCD present with vague pain and occasionally, mechanical symptoms. The diagnosis of JOCD can be confirmed on plain radiographs. Magnetic resonance imaging has emerged as the study of choice to evaluate the stability of the lesion and integrity of the overlying articular cartilage. Treatment decisions are based on the stability of the lesion. Stable JOCD lesions should be treated initially with activity modification and possibly, immobilization. Unstable lesions and stable lesions not responding to an initial course of nonoperative therapy should be surgically treated. Surgical treatment is based on the radiographic and arthroscopic characteristics of the lesion. Multiple techniques from simple arthroscopic drilling and fixation to salvage techniques for cartilage restoration are discussed. PMID- 21293240 TI - Injuries about the hip in the adolescent athlete. AB - Athletic injuries in or around the hip in the adolescent athlete encompass possible causes such as a single, traumatic event to those of repetitive microtrauma. The injuries may involve the bone or the soft tissues, with former involving the epiphysis, apophysis, metaphysis, or diaphysis, whereas the latter includes muscles and tendons. With the improvements in surgical technique and instrumentation for hip arthroscopy and the development of magnetic resonance arthrography, clinicians have been able to diagnose and treat labral tears, hip instability, snapping hip, loose bodies, chondral injuries, and femoroacetabular impingement. The clinician needs to consider acquired conditions that may have coincidentally become apparent as a result of the adolescent's participation in an organized sports program. These include slipped capital femoral epiphysis, Legg-Calve-Perthes disease, and pathologic lesions and fractures. This study reviews the more common acute and chronic overuse injuries in or around the hip in the adolescent athlete and discusses hip injury prevention in this active patient population. PMID- 21293241 TI - Pediatric exercise: truth and/or consequences. AB - Pediatric exercise recommendations are becoming increasingly more important. The recommendation for physical activity in children and adolescents is 60 min/d of moderate to vigorous physical activity. The United States Department of Health and Human Services recommends that vigorous physical activity be included a minimum of 3 d/wk. In addition, strength training, for both the muscle and bone should be included 3 d/wk. As the incidence of childhood obesity increases and the implications towards chronic disease, musculoskeletal issues, and self-esteem issues continue to rise, it is clear that many children do not meet these guidelines. Despite the childhood obesity epidemic, an estimated 38 million children and adolescents participate in organized sports. Both active and inactive children need to be educated on the benefits of exercise, exercise safety, and appropriate exercise recommendations specific to this specialized population. PMID- 21293242 TI - Phase II clinical study on stent therapy for unresectable malignant colorectal obstruction (JIVROSG-0206). AB - PURPOSE: A phase II study of stent therapy for unresectable malignant colorectal obstruction was conducted to ascertain the clinical efficacy, safety, and procedural feasibility. METHODS: Inclusion criteria comprised unresectable obstruction of the rectum or sigmoid colon; no other apparent stenosis; performance status by Eastern Cooperative Oncology Group <=3; and maintained major organ function. The treatment protocol was to place an uncovered metal stent through the anus in an obstructive portion under x-ray fluoroscopic guidance. The patients were followed for 4 weeks after therapy, and the degree of improvement in subjective symptoms lasting >=2 weeks was assessed as effective when the patient was decompressed with stent, or ineffective when not decompressed. Rate of clinical efficacy was defined as the proportion of effective cases. RESULTS: The participants of the study comprised 33 patients (13 men and 20 women; mean age, 60 y). Rate of procedure completion was 97.0% (32/33). Treatment was effective in 27 patients, ineffective in 4, and unassessable in 1, yielding a clinical efficacy rate of 81.8% (27/33). Death owing to underlying disease (n=3), stent removal owing to anal pain (n=1), and occlusion at another location (n=1) were noted. No recurrences were seen among clinically effective cases. Adverse reactions included grades 2 to 3 diarrhea (n=12), pain (n=5), bleeding (n=1), and dysuria (n=1), but no grade 4 adverse reactions or treatment-related deaths were identified. CONCLUSIONS: Stent therapy for unresectable malignant colorectal obstruction is effective, safe, and feasible. PMID- 21293243 TI - Randomized phase II study of carboplatin-paclitaxel or gemcitabine-vinorelbine in patients with advanced nonsmall cell lung cancer and a performance status of 2: West Japan Thoracic Oncology Group 0004. AB - OBJECTIVES: The aim of the present study was to evaluate the efficacy and safety of carboplatin plus paclitaxel versus gemcitabine plus vinorelbine in patients with advanced nonsmall cell lung cancer (NSCLC) and an Eastern Cooperative Oncology Group performance status (PS) of 2. METHODS: Chemotherapy-naive patients with NSCLC of stage IIIB or IV and a PS of 2 were eligible. The patients received 3-week cycles of carboplatin (area under the curve of 6) plus paclitaxel (200 mg/m(2)) on day 1 (CP) or gemcitabine (1000 mg/m(2)) plus vinorelbine (25 mg/m(2)) on days 1 and 8 (GV). The primary end point was 1-year survival rate for selection of the better treatment arm for further study. RESULTS: Of the 89 patients enrolled, 84 were assessable (41 in the CP arm, 43 in the GV arm). The overall response rate, median survival time, and 1-year survival rate were 29.3%, 5.9 months, and 22.0%, respectively, for the CP arm and 20.9%, 6.0 months, and 27.9% for the GV arm. Common toxicities of grade 3 or 4 included neutropenia (67.5% for the CP arm vs. 65.1% for the GV arm), febrile neutropenia (20% vs. 14%), and infection (25.0% vs. 23.2%). The frequency of nausea of grade 3 was greater for the CP arm (17.5% vs. 2.3%), whereas that of anemia of grade 3 or 4 (30.2% vs. 12.5%) or treatment-related death (7.0% vs. 2.4%) was greater for the GV arm. CONCLUSIONS: The 1-year survival rate did not exceed 30% for either doublet chemotherapy. Furthermore, each treatment was associated with a substantial degree of toxicity. PMID- 21293244 TI - Weekly paclitaxel and carboplatin induction chemotherapy followed by concurrent chemoradiotherapy in locally advanced squamous cell carcinoma of the head and neck. AB - OBJECTIVE: To perform a phase II trial evaluating dose dense induction chemotherapy for locally advanced head and neck cancer. PATIENTS AND METHODS: Thirty-five patients received 6 weekly doses of carboplatin (area under the curve=2) and paclitaxel (135 mg/m) followed by concurrent weekly paclitaxel (40 mg/m) and carboplatin (area under the curve=1) and daily radiation (66-72 Gy). RESULTS: There was 1 induction death from neutropenic sepsis and 1 sudden death during chemoradiotherapy. The overall response rate with induction was 79%. With >40 months of follow-up, the 36-month overall survival was 67% and squamous cell carcinoma of the head and neck survival 84%. Patients undergoing biopsy of the primary tumor site after the therapies had 17/18 (94%) pathologic complete response rate. The locoregional relapse rate was 40% (24 mo 28%) and distant relapse rate was 8% with only 1 distant site. CONCLUSIONS: Therapy was active but patients must be carefully selected and monitored. Compared with the historical controls, dose dense and intense induction chemotherapy decreased distant failure rate without compromising the locoregional control. PMID- 21293245 TI - Cost-effectiveness analysis of a randomized study comparing radiosurgery with radiosurgery and whole brain radiation therapy in patients with 1 to 3 brain metastases. AB - BACKGROUND: In this study, we compare 2 treatment options and determine cost effectiveness and cost-utility. METHODS: We carried out a decision analysis populated with data from patients with brain metastasis in a concurrent trial randomized to either stereotactic radiosurgery (SRS) and observation or SRS and whole brain radiation therapy. Outcomes included actual life years saved (LYS), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER). Costs used were from the healthcare perspective and utilities were captured through a time-trade-off method, using 10-year, 5-year, and 1-year time horizons. One-way sensitivity analyses were carried out to determine robustness of the decision analysis model. RESULTS: Compared with SRS and whole brain radiation therapy, SRS and observation not only had a higher average cost ($74,000 vs $119,000, respectively) but also a higher average effectiveness (0.60 LYS vs 1.64 LYS, respectively) with an ICER of $44,231/LYS or $41,783/QALY (with utilities captured using a 10-year horizon). Slightly higher ICER estimates were achieved with utilities captured using the other time horizons ($43,280/QALY and $44,064/QALY, respectively). Sensitivity analysis showed that the following variables had the highest impact on the ICER: probability of no recurrence in recursive-partitioning analysis class 2 after SRS and observation; probability of being alive after SRS and observation in recursive-partitioning analysis class 2 and being treated for recurrence. CONCLUSIONS: Compared with other interventions in the $50,000 to $100,000/QALY cost-effectiveness range, the application of SRS and observation, with subsequent neurosurgical management of recurrences, is shown to be a reasonable treatment modality for brain metastases. PMID- 21293246 TI - Outcomes in transplant patients undergoing brachytherapy for prostate cancer. AB - OBJECTIVES: To determine the failure rate of brachytherapy as definitive treatment for localized prostate cancer in transplant and otherwise immunosuppressed patients compared with patients not undergoing immunosuppressive therapy. METHODS: A retrospective study of 314 patients treated with brachytherapy for prostate cancer between July 1995 and March 2007, 7 of whom were previously transplanted and currently on immunosuppression (4 heart transplants, 3 renal transplants), and 10 of whom were on immunosuppression for other medical conditions. Outcomes were defined by both American Society for Radiation Oncology (ASTRO) and Phoenix definitions of biochemical failure. RESULTS: The mean patient age at implant was 67.3+/-7.3 years; mean follow-up was 7.5+/-2.8 years, with a minimum follow-up of 3 years. In the nonimmunosuppressed group, a 15.8% failure rate by the ASTRO definition and 13.6% rate by the Phoenix definition were observed. When excluding patients with previous external beam radiation and/or neoadjuvant hormone therapy, a 13.6% failure rate by the ASTRO definition and 11.4% rate by the Phoenix definition were observed. Within the transplanted patient subset, failure rates by both ASTRO and Phoenix definitions were 14.3%. For all immunosuppressed patients, failure rates were 11.8% by both definitions. While performing a Fisher exact test, there was no statistical difference in failure rates between all groups by either definition of failure. CONCLUSIONS: Immunosuppressed prostate cancer patients treated by brachytherapy seem to enjoy similar cancer control rates as the similarly treated nonimmunosuppressed population. It is recognized, however, that a much larger cohort of immunosuppressed patients would need to be studied to demonstrate statistical equivalence. PMID- 21293247 TI - Health behaviors among cancer survivors receiving screening mammography. AB - OBJECTIVES: The purpose of this study was to evaluate the prevalence of cancer related behavioral risk factors among female cancer survivors, relative to women without a previous diagnosis of cancer. METHODS: In a large cohort of 19,948 women presenting for screening mammography, questionnaires on health behaviors were administered. RESULTS: A total of 18,510 had detailed history on health behaviors and previous cancer history. Overall 2713 (14.7%) reported a previous cancer history. We found statistically significant results indicating that cancer survivors were less likely than those with no cancer history to: report their overall health as "excellent" (13.6% vs. 21.5%), to engage in moderate or strenuous exercise (56.5% vs. 63.3%), and to use complementary and alternative medicine (57.4% vs. 60.2%). Conversely, cancer survivors were more likely to be current smokers (6.3% vs. 5.5%), rate their overall health as "poor" (15.8% vs. 9.1%), and to report more weight gain over time. Among cancer survivors, differences also emerged by the type of primary cancer. For example, cervical cancer survivors (n = 370) were most likely to report being current smokers (15.7%) and regular alcohol users (71.7%) compared with other survivors. Ovarian (n = 185) and uterine (n = 262) cancer survivors most frequently reported being obese (41% and 34.4%, respectively). Cervical cancer survivors reported the largest weight gain (4.9 lbs at 5 y and 13.4 lbs at 10 y). CONCLUSIONS: These results suggest opportunities for tailored behavioral health risk factor interventions for specific populations of cancer survivors. PMID- 21293248 TI - Carvedilol therapy after cocaine-induced myocardial infarction in patients with asthma. AB - INTRODUCTION: Cocaine-induced myocardial infarction (MI) is well documented. Current literature recommends avoiding beta-blockers in the acute care setting, but after discharge from the hospital, benefits of beta-blocker use may outweigh risks in patients with recent MI resulting from cocaine use. Cardioselective beta blocker therapy has been demonstrated to be beneficial in post-MI patients with nonsevere asthma. This review article is to compare the risks and benefits of using carvedilol in patients with asthma who have had cocaine-induced MI. METHODS: The authors searched the English literature from 1984 to July 2010 via PubMed, EMBASE and SCOPUS using the following search terms: "cocaine-induced myocardial infarction AND treatment," "cocaine AND carvedilol," "beta blockers AND asthma," and "carvedilol AND asthma." All studies and case reports related to carvedilol use associated with bronchospasm in patients with asthma and carvedilol use after cocaine-induced MI were included. RESULTS: Carvedilol has theoretical advantages in patients who use cocaine, but there are no controlled studies confirming the superior efficacy of this agent. Reports of carvedilol use in patients with asthma are rare, but findings include increased asthma symptoms and hospitalization in some patients. Fatal asthma has also been reported because of this noncardioselective beta-blocker. CONCLUSIONS: Based on a lack of evidence supporting the theoretical advantages but documented risks associated with its use in patients with asthma, carvedilol should be avoided in asthma patients who have a history of cocaine-induced MI. Cardioselective beta-blockers should be used in post-MI patients with nonsevere asthma. PMID- 21293249 TI - Efficacy and safety of mizoribine combined with losartan in the treatment of IgA nephropathy: a multicenter, randomized, controlled study. AB - INTRODUCTION: Few have tried to prove the effectiveness of mizoribine combined with losartan for adult IgA nephropathy patients in a randomized controlled trial. METHODS: A multicenter, randomized, controlled, 12-month study was performed to evaluated the efficacy and safety of mizoribine combined with losartan for adult IgA nephropathy. Ninety-nine patients with primary IgA nephropathy from 8 clinical institutions were randomly assigned to the losartan group (n = 30), the mizoribine group (n = 35) or the combination (losartan+mizoribine) group (n = 34). The primary outcome was 24-hour urinary protein excretion (24 hours-UP). RESULTS: There were no significant differences in baseline data among the 3 groups. In all 3 groups, 24 hours-UP after 3, 6, 9 and 12 months of treatment were significantly lower than the baseline level. The reduction in 24 hours-UP in the losartan group was observed early and reached maximum after 6 months of treatment. Twenty-four hours-UP in the mizoribine group and combination group continuously decreased during the study. Comparisons among the 3 groups showed that the losartan group was superior to the mizoribine group after 3 months of treatment, but that after 12 months of treatment, both the combination group and the mizoribine group were superior to the losartan group in the reduction of 24 hours-UP. There were no significant differences among the 3 groups in serum creatinine. No serious adverse events occurred in any of the 3 groups. CONCLUSIONS: The treatment of adult IgA nephropathy with mizoribine alone, losartan alone or a combination of the 2 reduced 24 hours-UP. Mizoribine and losartan, when used in combination, complement each other's activities. PMID- 21293250 TI - Opioid facilitation of rewarding electrical brain stimulation is suppressed in rats with neuropathic pain. AB - INTRODUCTION: Opioids are powerful analgesics, but are also common drugs of abuse. Few studies have examined how neuropathic pain alters the pharmacology of opioids in modulating limbic pathways that underlie abuse liability. METHODS: Rats with or without spinal nerve ligation (SNL) were implanted with electrodes into the left ventral tegmental area and trained to lever press for electrical stimulation. The effects of morphine, heroin, and cocaine on facilitating electrical stimulation of the ventral tegmental area and mechanical allodynia were assessed in SNL and control subjects. RESULTS: Responding for electrical stimulation of the ventral tegmental area was similar in control and SNL rats. The frequency at which rats emitted 50% of maximal responding was 98.2 +/- 5.1 (mean +/- SEM) and 93.7 +/- 2.8 Hz in control and SNL rats, respectively. Morphine reduced the frequency at which rats emitted 50% of maximal responding in control (maximal shift of 14.8 +/- 3.1 Hz), but not SNL (2.3 +/- 2.2 Hz) rats. Heroin was less potent in SNL rats, whereas cocaine produced similar shifts in control (42.3 +/- 2.0 Hz) and SNL (37.5 +/- 4.2 Hz) rats. CONCLUSIONS: Nerve injury suppressed potentiation of electrical stimulation of the ventral tegmental area by opioids, suggesting that the positive reinforcing effects are diminished by chronic pain. Given concerns regarding prescription opioid abuse, developing strategies that assess both analgesia and abuse liability within the context of chronic pain may aid in determining which opioids are most suitable for treating chronic pain when abuse is a concern. PMID- 21293251 TI - Comparison of the neuroapoptotic properties of equipotent anesthetic concentrations of desflurane, isoflurane, or sevoflurane in neonatal mice. AB - BACKGROUND: Volatile anesthetics facilitate surgical procedures and imaging studies in millions of children every year. Neuronal cell death after prolonged exposure to isoflurane in developing animals has raised serious concerns regarding its safe use in children. Although sevoflurane and desflurane are becoming more popular for pediatric anesthesia, their cytotoxic effects have not been compared with those of isoflurane. Accordingly, using newborn mice, the current study established the respective potencies of desflurane, isoflurane, and sevoflurane and then compared equipotent doses of these anesthetics regarding their effects on cortical neuroapoptosis. METHODS: Minimum alveolar concentrations were determined in littermates (aged 7-8 days, n = 42) using tail clamp stimulation in a bracketing study design. By using equipotent doses of approximately 0.6 minimum alveolar concentration, another group of littermates was randomly assigned to receive desflurane, isoflurane, or sevoflurane or to fast in room air for 6 h. After exposure, animals (n = 47) were euthanized, neocortical apoptotic neuronal cell death was quantified, and caspase 3 activity was compared between the four groups. RESULTS: The minimum alveolar concentration was determined to be 12.2% for desflurane, 2.7% for isoflurane, and 5.4% for sevoflurane. After a 6-h exposure to approximately 0.6 minimum alveolar concentration of desflurane, isoflurane, or sevoflurane, neuronal cell death and apoptotic activity were significantly increased, irrespective of the specific anesthetic used. CONCLUSIONS: In neonatal mice, equipotent doses of the three commonly used inhaled anesthetics demonstrated similar neurotoxic profiles, suggesting that developmental neurotoxicity is a common feature of all three drugs and cannot be avoided by switching to newer agents. PMID- 21293252 TI - Bispectral index monitoring, duration of bispectral index below 45, patient risk factors, and intermediate-term mortality after noncardiac surgery in the B Unaware Trial. AB - BACKGROUND: Postoperative mortality has been associated with cumulative anesthetic duration below an arbitrary processed electroencephalographic threshold (bispectral index [BIS] <45). This substudy of the B-Unaware Trial tested whether cumulative duration of BIS values lower than 45, cumulative anesthetic dose, comorbidities, or intraoperative events were independently associated with postoperative mortality. METHODS: The authors studied 1,473 patients (mean +/- SD age, 57.9 +/- 14.4 yr; 749 men) who underwent noncardiac surgery at Barnes-Jewish Hospital in St. Louis, Missouri. Multivariable Cox regression analysis was used to determine whether perioperative factors were independently associated with all-cause mortality. RESULTS: A total of 358 patients (24.3%) died during a follow-up of 3.2 +/- 1.1 yr. There were statistically significant associations among various perioperative risk factors, including malignancy and intermediate-term mortality. BIS-monitored patients did not have lower mortality than unmonitored patients (24.9 vs. 23.7%; difference = 1.2%, 95% CI, -3.3 to 5.6%). Cumulative duration of BIS values less than 45 was not associated with mortality (multivariable hazard ratio, 1.03; 95% CI, 0.93 1.14). Increasing mean and cumulative end-tidal anesthetic concentrations were not associated with mortality. The multivariable Cox regression model showed a good discriminative ability (c-index = 0.795). CONCLUSIONS: This study found no evidence that either cumulative BIS values below a threshold of 40 or 45 or cumulative inhalational anesthetic dose is injurious to patients. These results do not support the hypothesis that limiting depth of anesthesia either by titration to a specific BIS threshold or by limiting end-tidal volatile agent concentrations will decrease postoperative mortality. PMID- 21293253 TI - Differential effects of isoflurane on high-frequency and low-frequency gamma oscillations in the cerebral cortex and hippocampus in freely moving rats. AB - BACKGROUND: Cortical gamma oscillations are thought to play a role in conscious cognitive functions. Suppression of 40-Hz gamma activity was implicated in the loss of consciousness during general anesthesia. However, several experimental studies found that gamma oscillations were preserved in anesthesia. The authors investigated the concentration-dependent effect of isoflurane on spontaneous gamma oscillations in two frequency bands and three distinct brain regions in the rat. METHODS: Adult Sprague-Dawley rats were chronically implanted with epidural and coaxial depth electrodes to record cortical field potentials in frontal cortex, visual cortex, and hippocampus in waking and at steady-state isoflurane concentrations of 0.4, 0.8, and 1.2%. The gamma power was calculated for the frequency bands 30-50 and 70-140 Hz. Temporal variation and interregional synchrony of gamma activity were analyzed using wavelet transform. Loss of consciousness was indexed by the loss of righting reflex. RESULTS: Rats lost their righting reflex at 0.8 +/- 0.1% isoflurane. High-frequency gamma power was decreased by isoflurane in a concentration-dependent manner (P < 0.001, 50% decrease at 0.8% isoflurane) in all brain regions. Low-frequency gamma power was unaffected by isoflurane. The duration and interregional synchrony of high frequency gamma bursts was also reduced (P l < 0.001, 40% decrease at 0.8% isoflurane). CONCLUSIONS: Distinction between high- and low-frequency gamma bands is important when evaluating the effect of general anesthetics on brain electrical activity. Spontaneous 40-Hz gamma power does not indicate the state of consciousness. The attenuation and interregional desynchronization of high frequency gamma oscillations appear to correlate with the loss of consciousness. PMID- 21293254 TI - Spinal macrophage migration inhibitory factor is a major contributor to rodent neuropathic pain-like hypersensitivity. AB - BACKGROUND: Neuropathic pain-like hypersensitivity evoked by peripheral nerve injury is a salient clinical feature of pathologic pain; however, the underlying mechanisms of this condition remain largely unknown. Previous work has confirmed that spinal macrophage migration inhibitory factor (MIF) contributes to the pathogenesis of formalin-induced inflammatory hyperalgesia, but the role for MIF in neuropathic pain is still not well defined. METHODS: After approval by the Ethical Committee of Animal Use and Care, the sciatic chronic constriction nerve injury-induced rodent model of neuropathic pain was built. The mechanical threshold with von Frey hairs and thermal latency with hot plate were measured, and the expression of spinal MIF, CD74, and downstream extracellular signal regulated kinase 1/2 signaling cascade was detected. Finally, MIF gene mutation and exogenous recombinant MIF were used for further clarification. RESULTS: Intrathecal MIF tautomerase inhibitor reversed sciatic chronic constriction nerve injury-induced pain behaviors. The expression of MIF and CD74 up-regulated in a time-dependent manner in the ipsilateral spinal cord dorsal horn. These changes were associated with the activation of extracellular signal-regulated kinase 1/2 signaling by MIF/CD74 interaction, which subsequently led to up-regulation of interleukin-8 and N-methyl-D-aspartic acid receptor expression and additional production of prostaglandin E(2). Further, MIF gene mutation and exogenous recombinant MIF could desensitize and mimic sciatic chronic constriction nerve injury-evoked pain responses and cellular changes, respectively. CONCLUSIONS: MIF associated extracellular signal-regulated kinase 1/2-N-methyl-D-aspartic acid receptor or prostaglandin E(2) cascade accounts for the changes in peripheral nerve injury-induced nociceptive responses. PMID- 21293256 TI - Diagnostic value of automated Her2 evaluation in breast cancer: a study on 272 equivocal (score 2+) Her2 immunoreactive cases using an FDA approved system. AB - Goal of this study was to asses the performance of Aperio computer-assisted analysis for HER2 immunohistochemical measurement in 292 equivocally (score2+) HercepTest immunoreactive breast cancer cases, evaluated by an experienced pathologist and analyzed with fluorescent in situ hybridization (FISH). The automatic Aperio categorization and the percentage of immunoreactive cells as evaluated by the computer and by the pathologist were recorded. Computer-assisted analysis classified 7 (2.4%) cases as negative (0), 136 (46.6%) as faintly positive (1+), 134 (40.5%) as moderately positive (2+), and 15 (5.1%) as strongly positive (3+). Correlative component analysis (CCA) classification is associated with Her2 amplification (P<0.0001). Compared with the human evaluation, automated CCA classification would save 157 (58%) FISH analyses, while not identifying 15 amplified cases (6% false-negative rate). The mean computer percentage value (CPV) is 18.44% standard deviation +/-19.00 (range, 0.01 to 76.10). CPV and the pathologist percentage value are significantly associated and correlated (P<0.001) and have similar sensitivity and specificity in identifying Her2 FISH amplified cases. CPV has a very low interobserver variation. The difference in CPV in amplified and nonamplified subgroups is statistically significant (P<0.001). Receiver operating characteristic analysis indicates that CPV is good at separating FISH nonamplified from amplified cases (P<0.001). The optimal cut off value maximizing both sensitivity and specificity is 17.6% (sensitivity=73.3%, specificity=71.6%). Using a different cut-off value (2% of positive cells) we would have missed only 3 amplified cases (1% false-negative rate) while not submitting to FISH 52 cases (18% of the whole series). This false negative rate is well below the expected false-negative rate usually observed in score 1 cases, supporting the use of CCA with a modified cut-off value in routine diagnostics for equivocally stained HER2 cases. PMID- 21293255 TI - Involvement of the lateral amygdala in the antiallodynic and reinforcing effects of heroin in rats after peripheral nerve injury. AB - BACKGROUND: Neuropathic pain alters opioid self-administration in rats. The brain regions altered in the presence of neuropathic pain mediating these differences have not been identified, but likely involve ascending pain pathways interacting with the limbic system. The amygdala is a brain region that integrates noxious stimulation with limbic activity. METHODS: MU-Opioid receptors were blocked in the amygdala using the irreversible antagonist, beta-funaltrexamine, and the antiallodynic and reinforcing effects of heroin were determined in spinal nerve ligated rats. In addition, the effect of beta-funaltrexamine was determined on heroin self-administration in sham-operated rats. RESULTS: beta-Funaltrexamine decreased functional activity of MU-opioid receptors by 60 +/- 5% (mean +/- SD). Irreversible inhibition of MU-opioid receptors in the amygdala significantly attenuated the ability of doses of heroin up to 100 MUg/kg to reverse hypersensitivity after spinal nerve ligation. Heroin intake by self administration in spinal nerve-ligated rats was increased from 5.0 +/- 0.3 to 9.9 +/- 2.1 infusions/h after administration of 2.5 nmol of beta-funaltrexamine in the lateral amygdala, while having no effect in sham-operated animals (5.8 +/- 1.6 before, 6.7 +/- 0.9 after). The antiallodynic effects of 60 MUg/kg heroin were decreased up to 4 days, but self-administration was affected for up to 14 days. CONCLUSIONS: MU-Opioid receptors in the lateral amygdala partially meditate heroin's antiallodynic effects and self-administration after peripheral nerve injury. The lack of effect of beta-funaltrexamine on heroin self-administration in sham-operated subjects suggests that opioids maintain self-administration through a distinct mechanism in the presence of pain. PMID- 21293257 TI - Protein microarray-based comparison of HER2, estrogen receptor, and progesterone receptor status in core biopsies and surgical specimens from FFPE breast cancer tissues. AB - Currently, core biopsies are routinely used for diagnosis of breast cancer and they are often the only sample for providing prognostic and predictive markers before treatment. However, biopsies may not accurately reflect protein expression profiles from the whole tumor. In the last few years, reverse phase protein arrays (RPPA) have become a very promising tool for biomarker profiling allowing quick, precise, and simultaneous analysis of many components of a protein network. After extraction of full-length proteins from formalin-fixed and paraffin-embedded (FFPE) tissues, we compared human epidermal growth factor receptor 2 (HER2), estrogen receptor (ERalpha), and progesterone receptor (PGR) expression levels in a series of 35 FFPE breast cancer surgical specimens and their corresponding core biopsies using RPPA. We found a high concordance between protein expression in core biopsies and surgical specimens with concordance and kappa-values of 91.4% and kappa=0.677 for HER2; 80% and kappa=0.587 for ERalpha; and 82.8% and kappa=0.656 for PGR. In this study, we could show that HER2, ERalpha, and PGR expression can be assessed reliably on core biopsies of FFPE breast cancer tissues using RRPA. These results might facilitate the implementation of RPPA technology in routine clinical settings. PMID- 21293258 TI - Primary peritoneal clear cell adenocarcinoma associated with endometriosis. PMID- 21293259 TI - Comparative analysis of detecting monocytic cells and their aberrancy. AB - BACKGROUND AND STUDY PURPOSE: Detection of monocytic cells (MCs) and their aberrancy is important in the diagnoses of monocytic leukemias [chronic myelomonocytic leukemia (CMML), acute MML (AMML), and acute monocytic/monoblastic leukemia (AMoL)]. MCs may be identified by cytomorphology (CM), enzyme cytochemical staining with nonspecific esterases, flow cytometric analysis (FCA), and immunohistochemical analysis (IHCA); their aberrancy, by FCA or IHCA. As aberrant antigen expression on MCs is not detected by CM or enzyme cytochemical staining and as there may be instances of "dry tap" or a fresh bone marrow aspirate is not available for further analysis, the primary and specific purpose of this study is to globally compare the detection of MCs and their aberrancy by the 2 methods of FCA and IHCA. PROCEDURES: Forty bone marrow (aspirate, clot, and biopsy) samples (7 CMMLs; 33 AMMLs and AMoLs) are evaluated by CM, FCA (complete immunophenotypic panel), and retrospective IHCA (CD2, CD3, CD14, CD33, CD56, CD68, CD123, and CD163). RESULTS: Forty-five percent showed a higher percentage of MCs by FCA than by CM. In addition, CD14, CD2, and CD56 detections on MCs showed greater sensitivity by FCA than by IHCA. By IHCA, CD14 showed the highest specificity for MCs (CD163, less specificity; CD68 and CD33, low specificity). CD123 did not correlate with CD14 or CD163, stained a subset of AMMLs/AMoLs, and stained no CMMLs. By comparing IHCA in clot versus biopsy sections, CD56 showed highest correlation (93%), followed by CD14 (85%) and CD33 (70%). CD68, CD163, and CD123 showed greater reactivities in clots (48%, 44%, and 35%, respectively), likely because of decalcification. CONCLUSIONS: FCA is most sensitive in detecting MCs and their aberrancy. By IHCA, CD14 is most specific. CD123 inconsistently marks AMMLs/AMoLs. Further evaluation of CD123 may determine the usefulness of CD123 in AML subtyping and possible prognostic implications and targeted therapy. PMID- 21293260 TI - Mutational analysis (c.402C>G) of the FOXL2 gene and immunohistochemical expression of the FOXL2 protein in testicular adult type granulosa cell tumors and incompletely differentiated sex cord stromal tumors. AB - BACKGROUND: Recently a somatic point mutation in the FOXL2 gene has been characterized in ovarian adult type of granulosa cell tumor (ATGCT) (94.6%), thecomas (12.5%), but not in juvenile type of ovarian granulosa cell tumor, other ovarian sex cord tumors and ovarian surface epithelial neoplasms. Whether this mutation is present in testicular ATGCT or incompletely differentiated sex cord stromal tumor (ISCST) is not known. DESIGN: Four ATGCTs, 4 ISCST were immunohistochemically investigated with anti-FOXL2 and 3 ovarian ATGCTs were used as positive control. RESULTS: Weak-to-moderate immunoreactivity was found in all tested testicular and ovarian tumors. PCR and direct sequencing were used for detection of c.402C>G of the FOXL2 gene. No mutation was found in any of the testicular ATGCTs or ISCSTs whereas all ovarian tumors showed the c.402C>G point mutation of the FOXL2 gene. CONCLUSIONS: On the basis of this small series of these rare testicular neoplasms, it seems that the c.402C>G mutation of the FOXL2 gene frequently found in adult type of ovarian GCT does not play any significant role in the development of ATGCT and ISCST. PMID- 21293261 TI - Intracranial pressure: why we monitor it, how to monitor it, what to do with the number and what's the future? AB - PURPOSE OF REVIEW: The review touches upon the current physiopathological concepts relating to the field of intracranial pressure (ICP) monitoring and offers an up-to-date overview of the ICP monitoring technologies and of the signal-analysis techniques relevant to clinical practice. RECENT FINDINGS: Improved ICP probes, antibiotic-impregnated ventricular catheters and multimodality, computerized systems allow ICP monitoring and individualized optimization of brain physiology. Noninvasive technologies for ICP and cerebral perfusion pressure assessment are being tested in the clinical arena. Computerized morphological analysis of the ICP pulse-waveform can provide an indicator of global cerebral perfusion. SUMMARY: Current recommendations for the management of traumatic brain injury indicate ICP monitoring in patients who remain comatose after resuscitation if the admission computed tomography scan reveals intracranial abnormalities such as haematomas, contusions and cerebral oedema. The most reliable methods of ICP monitoring are ventricular catheters and intraparenchymal systems. A growing number of these devices are being safely placed by neurointensivists. The consensus is to treat ICP exceeding the 20 mmHg threshold, and to target cerebral perfusion pressure between 50 and 70 mmHg. Recent evidence suggests that such thresholds should be optimized based on multimodality monitoring and individual brain physiology. Noninvasive ICP estimation using transcranial Doppler can have a role as a screening tool in patients with low to intermediate risk of developing intracranial hypertension. However, the technology remains insufficiently accurate and too cumbersome for continuous ICP monitoring. PMID- 21293262 TI - Fluid resuscitation in multiple trauma patients. AB - PURPOSE OF REVIEW: Fluid resuscitation in trauma patients with hemorrhagic shock is controversially discussed in the literature. The coincidence of brain injury complicates management of these patients. This article summarizes the current knowledge on nonblood component fluid resuscitation and choice of fluids in patients with multiple trauma. RECENT FINDINGS: Whereas current evidence suggests the efficacy of fluid therapy in hemorrhagic shock without active bleeding, experimental and clinical data demonstrate that aggressive volume challenge may be futile or even deleterious in the setting of uncontrolled hemorrhage. Large amounts of isotonic crystalloids may be associated with hypothermia, acidosis and inflammation. In patients with traumatic brain injury hypertonic solutions may positively influence inflammation and intracranial pressure without affecting neurologic outcome or mortality. SUMMARY: To date no large-scale clinical studies exist to either support or refute the use of nonblood component fluid resuscitation of hemorrhagic shock in trauma patients. The optimal choice of fluid remains to be determined, but existing evidence suggests avoiding crystalloids in favor of hypertonic solutions. The role of modern, iso-oncotic colloids in the treatment of hemorrhagic shock has not yet been sufficiently defined. In patients with concomitant brain injury, arterial hypotension must be avoided and infusion of hypotonic solutions is obsolete, whereas administration of hypertonic solutions may exert beneficial effects beyond hemodynamic stabilization. PMID- 21293263 TI - Oesophageal Doppler monitoring: should it be routine for high-risk surgical patients? AB - PURPOSE OF REVIEW: To determine whether sufficient evidence exists to justify routine use of oesophageal Doppler monitoring to guide perioperative haemodynamic management in high-risk surgery. RECENT FINDINGS: Systematic reviews of the literature have been performed independently by the National Health Service Centre for Evidence-based Purchasing in the UK, and the US Agency for Healthcare Related Quality. A before-after evaluation was also recently performed in three hospitals by the National Health Service Technology Adoption Centre. Although multicentre prospective randomized controlled trials are lacking, the evidence base for both outcome-benefit and cost-benefit is considered strong enough by the National Institute for Health and Clinical Excellence in the UK for them to recommend use of this technology in high-risk surgical patients. Whether these findings also apply to other monitoring technologies requires formal validation. SUMMARY: Better patient outcomes can be achieved by perioperative haemodynamic optimization using oesophageal Doppler monitoring and should be considered for routine use in most types of high-risk surgery. PMID- 21293264 TI - Immunotherapy after trauma: timing is essential. AB - PURPOSE OF REVIEW: To address and summarize some key issues and recent insights into the use of immunomodulating interventions to prevent and treat inflammatory complications in trauma patients. RECENT FINDINGS: Immunomodulatory therapies are aimed at altering the systemic inflammatory response after trauma to prevent and treat the inflammatory complications a patient can develop after sustaining injuries. This inflammatory response induced by injury is a complex and dynamic process with multiple humoral and cellular cascades involved, which leads to large heterogeneity in clinical outcome. Effective solutions are, therefore, expected to influence all involved facets. Over the years, a large body of evidence has accumulated testing over a hundred of monoclonal antibodies, antiendotoxins and antioxidants. However recently, intervention studies testing such agents in a clinical setting have become sparse. The majority of the promising experimental therapeutic approaches for inflammatory complications that target the inflammatory response did not lead to changes in clinical practice. SUMMARY: More insight is needed in the pathology of systemic inflammation after trauma for selection of patients, optimal timing and therapy to address the mechanism underlying inflammatory complications. PMID- 21293265 TI - Diaphragmatic dysfunction in mechanical ventilation. AB - PURPOSE OF REVIEW: It has become clear from experimental data that prolonged mechanical ventilation can induce diaphragm dysfunction, also known as ventilator induced diaphragm dysfunction. In this article we will discuss most recent understanding on ventilator-induced diaphragm dysfunction and data on diaphragm dysfunction in patients. RECENT FINDINGS: Over the last year several studies confirmed the existence of diaphragm dysfunction in patients. Known atrophy pathways are activated in patients undergoing prolonged conventional ventilation resulting in muscle proteolysis and a decrease in myofiber content. The loss of diaphragm force is time-dependent, but current data do not distinguish between the role played by other factors involved in diaphragm dysfunction. SUMMARY: Diaphragm dysfunction occurs in patients, especially when ventilated with controlled modes of ventilation that minimize diaphragm activity. Time on the ventilator seems to be one of the biggest risk factors resulting in difficulties in weaning patients and prolonging time on the ventilator. Future trials should investigate whether improved patient-ventilator synchrony can reduce ventilator induced diaphragm dysfunction and decrease weaning failure. PMID- 21293266 TI - Intracranial monitoring in traumatic brain injury. AB - PURPOSE OF REVIEW: This review focuses on the role of various intracranial monitoring technologies in the diagnosis and therapy of traumatic brain injury injury. RECENT FINDINGS: There exist many controversial points as to the utility of different intracranial monitoring with regard to improvement of outcomes from severe traumatic brain injury. Most recent studies are confirming that the use of multiple modalities in the neurological ICU setting may offer promising results. SUMMARY: Increased adherence to guideline-based and protocol-driven neurointensive care utilizing multimodality in monitoring technology for patients with severe traumatic brain injury is likely to give clinicians increased insight into the elusive mechanisms underlying the complex pathophysiology of this disease process and may further improve outcomes in this patient population. PMID- 21293267 TI - Knowing when to stop: futility in the ICU. AB - PURPOSE OF REVIEW: Decisions to withdraw or withhold potentially life-sustaining treatment are common in intensive care and precede the majority of deaths. When families resist or oppose doctors' suggestions that it is time to stop treatment, it is often unclear what should be done. This review will summarize recent literature around futility judgements in intensive care emphasising ethical and practical questions. RECENT FINDINGS: There has been a shift in the language of futility. Patients' families often do not believe medical assessments that further treatment would be unsuccessful. Attempts to determine through data collection which patients have a low or zero chance of survival have been largely unsuccessful, and are hampered by varying definitions of futility. A due-process model for adjudicating futility disputes has been developed, and may provide a better solution to futility disputes than previous futility statutes. SUMMARY: Specific criteria for unilateral withdrawal of treatment have proved hard to define or defend. However, it is ethical for doctors to decline to provide treatment that is medically inappropriate or futile. Understanding the justification for a futility judgement may be relevant to deciding the most appropriate way to resolve futility disputes. PMID- 21293269 TI - Epilepsy and neurodevelopmental disorders of language. AB - PURPOSE OF REVIEW: Neurodevelopmental disorders of language are increasingly appreciated as part of the phenotype of childhood-onset epilepsy. Here I review studies of the prevalence and prognosis of language impairment in new-onset childhood epilepsy and provide an update of new genetic discoveries that shed light on molecular pathways common to epilepsy and language impairment. RECENT FINDINGS: Three recent papers describe the cognitive and language phenotype of children with new-onset epilepsy and their discrepancy with controls over a 2-3 year period of follow-up. A new study examines the question of pleiotropic effects acting on both electro-encephalographic (EEG) abnormalities and speech sound disorder in rolandic epilepsy families - another study questions the rationale for EEG recording in patients with specific language impairment (SLI) - whereas two studies examine the effect of anti-epileptic drug treatment on speech and language. Two MRI studies indicate the neural basis for language impairment in epilepsy. Three new copy number variant hotspots are reported linking epilepsy and speech or language impairment; and the links between two known genes for developmental verbal dyspraxia, FOXP2 and SRPX2, begin to be elucidated. SUMMARY: Comprehensive neuropsychological and speech pathology assessment need to be factored into the initial evaluation and continued monitoring of children with new-onset epilepsy. EEG recording remains of unknown utility in children with SLI or speech sound disorder (SSD) who do not have epilepsy. Some anti-epileptic drugs may worsen SSD. As the molecular pathways for speech continue to be elucidated, future genetic imaging studies will show how genetic variants map onto to altered structural and connectivity patterns, which could be used as biomarkers for interventions. PMID- 21293268 TI - The neurology of autism spectrum disorders. AB - PURPOSE OF REVIEW: Neurological comorbidities in autism spectrum disorders (ASDs) are not only common, but they are also associated with more clinical severity. This review highlights the most recent literature on three of autism's most prevalent neurological comorbidities: motor impairment, sleep disorders and epilepsy. RECENT FINDINGS: Motor impairment in ASDs manifests as both delays and deficits, with delays found in gross and fine motor domains and deficits found in praxis, coordination and gait, all of which affect other cognitive and behavioral domains. Sleep disorders, especially insomnia, occur in up to 83% of children with ASDs and recent studies have begun to explore the underlying biochemical and behavioral basis of the impairment, which has bolstered treatment studies. Epilepsy is reported in up to one third of children with ASDs, and new studies have focused on identifying the genetic causes of this association. SUMMARY: Better characterization of the phenotype, developmental trajectory and underlying pathophysiology of these neurological comorbidities will enable us to define neurological endophenotypes within the autism spectrum. Future studies must investigate the emergence of these comorbidities prospectively in order to determine whether they lie on the causal pathway to ASDs or whether they reflect epiphenomena of the disorder. As epilepsy and sleep disorders can be treated and may contribute significantly to behavioral and cognitive abnormalities in ASDs, their identification is of high clinical relevance. PMID- 21293270 TI - Epilepsy, antiepileptic drugs and suicidality. AB - PURPOSE OF REVIEW: The risk of suicide is thought be increased in epilepsy. Antiepileptic drugs (AEDs) remain the primary treatment. An FDA alert in 2008 raised concerns that AEDs may increase the risk of suicidal thoughts and behaviour. The risk profile for suicide in epilepsy is examined in the context of recent reports investigating the risk of suicide and the reported association between AEDs and risk of suicide. RECENT FINDINGS: Following a diagnosis of epilepsy the risk of completed suicide is increased (standardized mortality ratio 2-3.5); although the causes remain poorly understood, co-morbid depression and the first 6 months after epilepsy surgery seem to be particular risk factors. The evidence for AEDs increasing risk for suicide remains mixed and is based on retrospective data. SUMMARY: The identification of risk factors such as mood or anxiety disorders in patients with epilepsy should not delay AED treatment as the risks associated with seizures far outweigh the current research evidence for increased AED-related suicide risk. A pragmatic approach to clinical assessment and management is suggested. Prospective AED trials should include validated scales to systematically identify neuropsychiatric complications of AEDs. PMID- 21293271 TI - Causes of learning disability and epilepsy: a review. AB - PURPOSE OF REVIEW: Although the association between learning disability and epilepsy is well known, until relatively recently specific processes underlying this association were relatively poorly understood. However, scientific advances in molecular biology are starting to guide researchers towards descriptions of genetic and pathophysiological processes that may explain why syndromes of epilepsy and learning disability often co-exist. RECENT FINDINGS: This article will focus largely on three areas of advancing knowledge: insights gained from wider use of genome-wide array comparative genomic hybridization (aCGH), specific insights gained from detailed study of Rett syndrome and the role of abnormalities of astrocytic function in predisposing to both epilepsy and learning disability. SUMMARY: The enormous complexity of the biological underpinnings of the co-occurrence of epilepsy and learning disability are becoming apparent. In the future it is likely that research into therapeutic approaches will include, amongst other approaches, investigations of gene structure and expression, the role of astrocytes and the stability of dendritic spines. PMID- 21293272 TI - Update on child maltreatment: toward refining the evidence base. AB - PURPOSE OF REVIEW: This review is designed to aid general pediatricians as they assess cases of possible child maltreatment. The authors have selected salient articles that inform the daily practice of any professional involved in assessing child abuse. RECENT FINDINGS: The incidence of child abuse continues to decline in the United States, although a large number of children still suffer from abuse and neglect, and many are subject to more than one type of maltreatment. Clinicians are encouraged to be vigilant about the subtle indicators of physical abuse, with many authors adding to our understanding about how children present after inflicted abdominal or skeletal trauma. Clinicians are also cautioned to watch for signs of Munchausen syndrome by proxy, which may be elusive and difficult to discern. SUMMARY: The field of child abuse pediatrics is still young, with the first board certification in 2009. The volume of research in the field is exploding and there is a greater level of awareness and data collection occurring throughout the world. Pediatric clinicians are encouraged to play a role in preventing abuse and neglect, as well as addressing intimate partner violence, and to maintain vigilance about child maltreatment and its subtle clinical presentations. PMID- 21293273 TI - Bisphenol A and children's health. AB - PURPOSE OF REVIEW: Bisphenol A (BPA) is a widely used chemical that has been shown to adversely affect health outcomes in experimental animal studies, particularly following fetal or early life exposure. Despite widespread human exposure in the United States and developed countries, there are limited epidemiological studies on the association of BPA with adverse health outcomes. This review briefly summarizes the epidemiological literature with special emphasis on childhood health outcomes. RECENT FINDINGS: Several studies report correlations between urinary BPA and serum sex steroid hormone concentrations in adults. Two studies report weak associations between urinary BPA concentrations and delayed onset of breast development in girls. One study found a relationship between prenatal BPA exposure and increased hyperactivity and aggression in 2 year-old female children. SUMMARY: Additional large prospective cohort studies are needed to confirm and validate findings from animal studies. Even in the absence of epidemiological studies, concern over adverse effects of BPA is warranted given the unique vulnerability of the developing fetus and child. Healthcare providers are encouraged to practice primary prevention and counsel patients to reduce BPA exposures. PMID- 21293274 TI - Accidental and iatrogenic causes of acute kidney injury. AB - PURPOSE OF REVIEW: Ingestions and iatrogenic administration of drugs are all too common causes of acute kidney injury. This review will discuss these preventable causes of acute kidney injury. RECENT FINDINGS: Recent studies have examined the pathophysiology of acute kidney injury by several commonly used drugs. These studies have shown that drugs and toxins can cause acute kidney injury by altering renal hemodynamics, direct tubular injury or causing renal tubular obstruction. SUMMARY: Knowledge of the drugs that cause acute kidney injury and how this injury is manifested can lead to improved diagnosis and treatment with the ultimate goal of prevention. PMID- 21293275 TI - Risk and uncertainty: shifting decision making for aneuploidy screening to the first trimester of pregnancy. AB - PURPOSE: The clinical introduction of first trimester aneuploidy screening uniquely challenges the informed consent process for both patients and providers. This study investigated key aspects of the decision-making process for this new form of prenatal genetic screening. METHODS: Qualitative data were collected by nine focus groups that comprised women of different reproductive histories (N = 46 participants). Discussions explored themes regarding patient decision making for first trimester aneuploidy screening. Sessions were audio recorded, transcribed, coded, and analyzed to identify themes. RESULTS: Multiple levels of uncertainty characterize the decision-making process for first trimester aneuploidy screening. Baseline levels of uncertainty existed for participants in the context of an early pregnancy and the debate about the benefit of fetal genetic testing in general. Additional sources of uncertainty during the decision making process were generated from weighing the advantages and disadvantages of initiating screening in the first trimester as opposed to waiting until the second. Questions of the quality and quantity of information and the perceived benefit of earlier access to fetal information were leading themes. Barriers to access prenatal care in early pregnancy presented participants with additional concerns about the ability to make informed decisions about prenatal genetic testing. CONCLUSIONS: The option of the first trimester aneuploidy screening test in early pregnancy generates decision-making uncertainty that can interfere with the informed consent process. Mechanisms must be developed to facilitate informed decision making for this new form of prenatal genetic screening. PMID- 21293276 TI - Early-onset seizures due to mosaic exonic deletions of CDKL5 in a male and two females. AB - PURPOSE: Mutations in the CDKL5 gene have been associated with an X-linked dominant early infantile epileptic encephalopathy-2. The clinical presentation is usually of severe encephalopathy with refractory seizures and Rett syndrome (RTT) like phenotype. We attempted to assess the role of mosaic intragenic copy number variation in CDKL5. METHODS: We have used comparative genomic hybridization with a custom-designed clinical oligonucleotide array targeting exons of selected disease and candidate genes, including CDKL5. RESULTS: We have identified mosaic exonic deletions of CDKL5 in one male and two females with developmental delay and medically intractable seizures. These three mosaic changes represent 60% of all deletions detected in 12,000 patients analyzed by array comparative genomic hybridization and involving the exonic portion of CDKL5. CONCLUSION: We report the first case of an exonic deletion of CDKL5 in a male and emphasize the importance of underappreciated mosaic exonic copy number variation in patients with early-onset seizures and RTT-like features of both genders. PMID- 21293278 TI - Phyllodes tumor with malignant stromal morphology of the vulva: a case report and review of the literature. AB - We present a hitherto unreported case of vulvar phyllodes tumor which displayed morphologically malignant stroma including rhabdomyosarcomatous cellular elements. Clinically, the 61-year-old patient is free of recurrence 1 year after wide local excision. PMID- 21293279 TI - Two cases of adenosquamous carcinoma of the cervix with extensive in situ and invasive endometrial extension. AB - Adenosquamous carcinoma of the cervix is rare. It is defined as having both glandular and squamous cell differentiation, each component malignant and clearly seen on haematoxylin and eosin-stained slides alone. We report two cases of adenosquamous carcinoma of the uterine cervix, both of which showed in situ and invasive components and both of which showed cephalad extension to involve the endometrium with invasive squamous and adenocarcinomatous components. The mechanisms for cephalad endomyometrial extension is discussed, as are the potential implications for management and staging. PMID- 21293280 TI - Patterns of parametrial involvement in radical hysterectomy specimens of cervical cancer patients. AB - A tumor in the parametria, either continuous with or separate from the primary malignancy, is an unfavorable prognostic factor in cervical cancer. The incidence of a parametrial tumor localized in blood or lymph vessels, or in tissue, and the relationship of these involvement patterns with pathologic characteristics and prognosis were investigated. Seventy-nine of 763 surgically treated cervical cancer patients (10%) had a tumor in the parametria in hysterectomy specimens. The available patient material was reviewed to discriminate between continuous and discontinuous parametrial tumor growth. The involvement pattern for discontinuous growth was specified on the basis of immunohistochemical staining with different specific markers. Fifty percent of the parametrial tumor involvement found postoperatively was caused by continuous extension of the primary process into the parametria. In the other 50%, the parametrial tumor was separate from the primary process. In this discontinuous group, we found a frequent presence of tumor in the lymph nodes and/or lymph vessels (together 79%) and even a rare appearance of tumor in the blood vessels (14%). A tumor was further found in unspecified vessels in 2 patients (5%), and as isolated foci in 6 patients (14%). Fourteen patients (33%) had more than 1 involvement pattern. Positive pelvic lymph nodes were more frequent in the discontinuous group. The involvement pattern was no independent predictor of overall survival. Parametrial blood vessel involvement was related to the development of distant metastases. The majority (79%) of parametrial involvement in the discontinuous group is caused by lymphatic metastases. Parametrial blood vessel involvement might be an independent predictor for the development of distant metastasis. PMID- 21293281 TI - Prevalence of human papillomavirus infection and associated risk factors in young women in Brazil, Canada, and the United States: a multicenter cross-sectional study. AB - To determine the prevalence of cervical human papillomavirus (HPV) infection and risk factors in young women from Brazil, Canada, and the USA. Cross-sectional study in 3204 healthy women, aged 15 to 25 years. Cervical samples were collected for cytology and for HPV DNA detection (SPF 10-LiPA 25 system). Serum samples were collected for the measurement of HPV-16 and HPV-18 antibodies by enzyme linked immunosorbent assay. Risk factors were obtained through a questionnaire. Overall, 26.6% of women had DNA detected for at least 1 HPV type. The prevalence for oncogenic HPV types was 21.7% (25% in Brazil, 16.9% in Canada, and 19.1% in the USA). HPV-16 was the most prevalent oncogenic type (5.2%). The next most common oncogenic HPV types were 51 (3.3%), 52 (3.3%), 31 (2.9%), 66 (2.3%), and 39 (2.0%). Multiple oncogenic types were detected in one-third of the infections. The prevalence of HPV-16 and/or HPV-18 infections detected by DNA and/or enzyme linked immunosorbent assay was 24.8%. The majority of women (85%) had a normal cervical cytology. Sexual behavior was the main determinant for HPV-16/18 infections and squamous intraepithelial lesions. The prevalence of HPV oncogenic infections was high and linked to sexual behavior. Strategies to reduce the burden of oncogenic HPV infection, such as prophylactic vaccination programs, are likely to impact the burden of disease due to cervical precancer and cancer. PMID- 21293282 TI - Ovarian involvement of epithelioid trophoblastic tumor: a case report. AB - Epithelioid trophoblastic tumor (ETT) is an uncommon type of gestational trophoblastic neoplasia originating from the chorionic-type intermediate trophoblast. To our knowledge, ovarian involvement of ETT with initial presentation as an ovarian tumor has not been reported. A 32-year-old woman presented with a 9-cm left ovarian mass. No clinical evidence of uterine involvement was identified at diagnosis or follow-up. The patient had a previous history of hydatidiform mole treated with suctional curettage 5 years before. Ovarian involvement of ETT can be challenging to pathologists and may be potentially confused with ovarian epithelial carcinoma, particularly of clear cell differentiation. PMID- 21293283 TI - Multicystic mesothelioma caused by endometriosis: 2 case reports and review of the literature. AB - Multicystic mesothelioma was described as a benign neoplasm in most reports. But, whether it is neoplastic or reactive is still controversial. Although multicystic mesothelioma is often accompanied by endometriosis, histologic findings of the lesion with endometriosis have not been well documented. In this report, 2 cases of multicystic mesothelioma with endometriosis were studied histologically. The first lesion consisted of multiple cysts having thin walls lined with single layered cuboidal mesothelia, and in the cystic walls, small foci of endometriosis were found. The second lesion was next to the endometriotic cysts in the pelvic space. These histologic findings suggest that endometriosis greatly contributes to the origin of the lesions. In addition, from the review of the literature, cystic mesothelioma was divided into 2 categories, that is, neoplastic or non neoplastic lesions. Differentiation of both disorders might be possible by the following: size of the lesion, macroscopic and microscopic solid proliferation, features of adenomatoid tumor, and common mesothelioma-like histology. In conclusion, multicystic mesothelioma accompanied by endometriosis is thought to be a secondary non-neoplastic lesion induced by adhesion or inflammation rather than a neoplasm. PMID- 21293284 TI - Malignant melanoma arising in an ovarian carcinosarcoma: case report and review of the literature. AB - A case of ovarian malignant mixed mullerian tumor (MMMT) with melanocytic differentiation is described. A 74-year-old woman presented with left lower quadrant pain. Pathologic examination of the left ovary revealed a MMMT, composed predominantly of serous carcinoma (90%) with a minor sarcoma component containing focal chondroid differentiation. There was also a single focus of malignant melanoma. Immunohistochemical studies showed that the latter was positive for S 100, HMB-45, and pan-melanoma cocktail, and was negative for synaptophysin and neuron-specific enolase. To the best of our knowledge, this is the first case of MMMT with melanocytic differentiation described in the ovary. PMID- 21293285 TI - Relationship between endometriosis, endometrioid adenocarcinoma, gliomatosis peritonei, and carcinoid tumor in a patient with recurrent ovarian teratoma. AB - Gliomatosis peritonei (GP) describes the implantation of mature neuroglial tissue in the peritoneum and is usually associated with mature ovarian teratoma but is also found in cases of immature teratoma. We report the case of a patient with recurrent mature ovarian teratoma, GP, endometriosis (with malignant transformation), and carcinoid tumor, found at the time of hysterectomy for a primary endometrial adenocarcinoma. This unusual combination of tumor types has not been reported earlier. Metaplasia of the totipotential subcoelomic or submesothelial stem cells is a recognized pathway for the development of endometriosis. Evidence from molecular genetic studies suggests that a similar process of stem cell differentiation may explain at least some cases of GP. The coexistence (and colocalization) of endometriosis, GP, and carcinoid tumor in this case raises the possibility that peritoneal stem cells may occasionally show an even wider spectrum of aberrant differentiation. This has relevance for the assessment and management of patients with synchronous gynecologic tumors or presumed metastatic disease. PMID- 21293286 TI - Clinical significance of astrocyte elevated gene-1 expression in human epithelial ovarian carcinoma. AB - Astrocyte elevated gene-1 (AEG-1) plays an important role in tumor progression including transformation, evasion of apoptosis, invasion, metastasis, and chemoresistance. However, the expression of AEG-1 in ovarian carcinoma and its significance are still unclear. The aim of this study was to examine the expression of AEG-1 in ovarian carcinoma. Immunohistochemistry was performed to determine the expression of AEG-1 in 81 ovarian carcinoma specimens. The correlation of AEG-1 expression with clinicopathological parameters was assessed using chi2 analysis. Patient survival was analyzed using the Kaplan-Meier and log rank tests. Cox regression was used for the multivariate analysis of prognostic factors. High expression of AEG-1 was detected in 66.67% of the ovarian carcinomas and was significantly associated with the International Federation of Gynecology and Obstetrics stage, histological grade, presence of residual tumor after primary surgery, and tumor recurrence. Patients with high AEG-1 expression had significantly poorer overall survival and disease-free survival (both P<0.001) when compared with patients with low expression of AEG-1. The multivariate Cox analysis showed that AEG-1 was an independent factor for both overall survival and disease-free survival (both P<0.001). These results showed that high AEG-1 expression was associated with progression and prognosis of ovarian carcinoma. PMID- 21293287 TI - Expression of poly (adenosine diphosphate-ribose) polymerase and p53 in epithelial ovarian cancer and their role in prognosis and disease outcome. AB - PARP, poly (adenosine diphosphate-ribose) polymerase, is a damage-sensing protein, which is essential for the repair of DNA single-strand breaks. PARP and p53 function synergistically in repairing DNA damage and suppressing chromosomal rearrangements. The aim of this study was to determine the expression of PARP and p53 in epithelial ovarian cancer (EOC) and to correlate their expression with clinicopathologic characteristics. PARP and p53 were evaluated using immunohistochemistry applied on a tissue microarray of 189 EOC and their expressions were correlated to clinicopathologic variables, including the age of diagnosis, stage, grade, histologic type, optimal debulking, progression-free survival, and overall survival (OS). PARP and p53 expressions were shown in 61% and 54% of cases, respectively. PARP-positive tumors are more likely to have higher grade (P=0.03) and complete response to initial first-line chemotherapy (P=0.009). Patients with positive p53 staining are more likely to be at the advanced stage disease (P=0.004). Finally, there were no significant associations between PARP and p53 expression and no differences in progression-free survival and OS for PARP or p53 expressions. The overexpression of PARP and p53 in high grade, and advanced stage tumors indicated that these 2 markers might serve as an indicator of aggressive disease behavior. Additional studies are warranted to evaluate the role of PARP and PARP inhibitors in the setting of adjuvant chemotherapy. PMID- 21293288 TI - Validation of the histologic grading for ovarian clear cell adenocarcinoma: a retrospective multi-institutional study by the Japan Clear Cell Carcinoma Study Group. AB - Pathologic slides from 150 patients with clear cell adenocarcinoma from the collaborating institutions were reviewed independently by 2 pathologists, and each tumor was graded histologically using the Shimizu-Silverberg and International Federation of Gynecology and Obstetrics (FIGO) grading systems. For the Shimizu-Silverberg grading system, 3 parameters-architectural pattern, nuclear pleomorphism, and mitotic activity-were assessed and scored as 1 to 3. When the summed scores of these parameters were 3 to 5, 6 to 7, and 8 to 9, grades 1, 2, and 3 were assigned, respectively. The FIGO grade was based on the ratio of glandular/papillary growth versus solid growth: grade 1, less than 5% solid tumor; grade 2, 5% to 50% solid tumor; grade 3, greater than 50% solid tumor. Interobserver agreement levels for assignment of both gradings were fair (kappa=0.32 and 0.24, respectively). After consensus had been acquired, 82 (55%), 56 (37%), and 12 (8%) tumors were classified as grades 1, 2, and 3 by the Shimizu Silverberg grading system, and 88 (59%), 38 (25%), and 24 (16%) were classified as grades 1, 2, and 3 by the FIGO grading system, respectively. Survival analyses indicated that patients with grade 3 tumors, as defined by both the grading systems, tended to have a poor outcome, but any differences between them were not statistically significant. Multivariate analysis showed that only the presence of residual tumor after initial surgery was an independent prognostic factor for overall survival. These results suggest that the 2 tested grading systems have limited value for the prognostication of patients with clear cell adenocarcinoma, and that a more effective grading system for this tumor may be required. PMID- 21293289 TI - The morphologic spectrum of uterine PEC-cell associated tumors in a patient with tuberous sclerosis. AB - Perivascular epithelioid cell (PEC) neoplasms are an unusual group of mesenchymal tumors thought to arise from the PEC, which characteristically expresses melanocytic markers with common coexpression of muscle markers. They show a wide morphologic spectrum and have been described in multiple anatomical locations, including the uterus. We report a 59-year-old woman with tuberous sclerosis, initially diagnosed with a uterine malignant mixed mullerian tumor, in whom the hysterectomy specimen also showed 3 other incidental tumors: a subserosal angiomyolipoma consisting of blood vessels of varying caliber, mature adipose tissue, and nests of spindle cells arranged in a perivascular location, a sclerosing PEComa consisting of small nests of clear epithelioid cells present in a background of marked sclerosis centered in the lower uterine segment/endocervix, and diffuse lymphangiomyomatosis involving the endocervix, lower uterine segment, and uterine corpus. This case provides further evidence of a common precursor cell of origin for these lesions. PMID- 21293290 TI - Evolution of a trophoblastic tumor from an endometrioid carcinoma--a morphological and molecular analysis. AB - We report the clinicopathological and molecular characteristics of a rare uterine endometrioid carcinoma with a nongestational trophoblastic neoplastic component that was composed of both choriocarcinoma and epithelioid trophoblastic tumor. Molecular genetic analysis showed a clonal evolution from endometrioid carcinoma to trophoblastic tumor. The findings from this case have both diagnostic and biological implications that may inspire future studies on the pathogenic mechanisms by which cancer stem cells assume aberrant differentiation programs and the molecular switch(es) that initiates trophoblastic differentiation in adult tumor tissues. PMID- 21293291 TI - Hydatidiform moles: ancillary techniques to refine diagnosis. AB - Distinction of hydatidiform moles from nonmolar specimens and subclassification of hydatidiform moles as complete hydatidiform mole (CHM), partial hydatidiform mole (PHM), or early CHM are important for both clinical practice and investigational studies. The risk of persistent gestational trophoblastic disease and hence, clinical management, differs for CHMs, PHMs, and nonmolar specimens. However, diagnosis based solely on morphology suffers from poor interobserver reproducibility and remains problematic even for experienced gynecologic pathologists. The unique genetic features of CHMs (androgenetic diploidy), PHMs (diandric triploidy), and nonmolar specimens (biparental diploidy) allow for certain molecular techniques, including immunohistochemical analysis of p57 expression (a paternally imprinted maternally expressed gene) and molecular genotyping, to refine the diagnosis of hydatidiform moles. Although p57 immunostaining alone can identify CHMs, which lack p57 expression because of the lack of maternal DNA, this analysis cannot distinguish PHMs from nonmolar specimens as both express p57 because of the presence of maternal DNA. Short tandem repeat genotyping, which can determine the parental source of polymorphic alleles, can distinguish among all of these entities by discerning androgenetic diploidy, diandric triploidy, and biparental diploidy to rigorously diagnose CHMs, PHMs, and nonmolar specimens, respectively. An algorithmic approach using these techniques to refine morphologic diagnosis has been developed for routine practice. This review discusses current issues in the diagnosis of hydatidiform moles, including the limitations of morphologic diagnosis, the need for refined diagnosis to assure accurate ascertainment of risk of persistent gestational trophoblastic disease associated with the different subtypes of hydatidiform moles, the use of ancillary immunohistochemical and molecular techniques for providing such refined diagnosis, and problems that can be encountered with these techniques. PMID- 21293292 TI - Antiplatelet agents do not impact the hospital course in patients with gastrointestinal bleeding. AB - BACKGROUND: Use of antiplatelet agents (APAs) have been shown to increase the risk of gastrointestinal (GI) bleeding despite their cardiovascular benefits. AIM: To understand the impact of APAs, we assessed the outcomes in patients admitted with acute GI bleeding to our hospital. We hypothesized there is no difference among GI bleeders admitted to the hospital while bleeding on or off APAs. METHODS: In an observational prospective cohort study, 104 sequential patients admitted with a diagnosis of GI bleeding were followed. Patients were classified as either on APA or not. RESULTS: Thirty of 104 (29%) patients were on long-term aspirin and/or clopidogrel on admission and 5 were taking nonaspirin nonsteroidal anti-inflammatory drugs, total of 35 (34%). There was no difference between patients using APA and those not using APA with regard to admission hemoglobin, age, presentation, source of bleed, total number of units transfused, intensive care unit admission rates, and overall length of stay. There was, however, a significant difference in the presence of hemodynamic compromise on initial presentation, with a higher proportion of APA users being orthostatic (51.4% vs 26% in nonusers, with P=0.02, by Fisher exact test). Clopidogrel was safely restarted in high-risk patients with significant cardiac history. CONCLUSIONS: This study demonstrated that APA use did not significantly alter the course or outcome in GI bleeders admitted to our institution during their hospital stay. PMID- 21293293 TI - Diagnosis of depression in former injection drug users with chronic hepatitis C. AB - GOALS: This study seeks to define the performance characteristics of 2 common depression screening tests and how psychiatric diagnoses affect adherence to treatment. BACKGROUND: Hepatitis C virus is common in former injection drug users (IDU). Many former IDUs have depression, which may complicate treatment, and are often denied therapy. STUDY: Ninety patients with chronic hepatitis C virus and reported IDU were recruited from a Hepatology Clinic in Seattle. Subjects completed the Beck Depression Inventory (BDI) and Patient Health Questionnaire-9 (PHQ-9) before antiviral therapy. A psychiatrist administered the Mini International Neuropsychiatric Interview as the "gold standard." Adherence was measured by self-report of missed doses. RESULTS: The BDI and PHQ-9 were highly correlated (r=0.75). Using a BDI score of >=20 and a PHQ-9 score of >=10, 39% and 52%, respectively, were misclassified as being depressed, as compared with the Mini International Neuropsychiatric Interview. Maximal sensitivity (85.7%) and specificity (82.6%) was achieved using a BDI score cutoff of 31, with an area under the curve of 0.82. For the PHQ-9, a cutoff of 14 yielded the best sensitivity (85.7%) and specificity (73.9%) with an area under the curve of 0.84. Adherence to at least 80% of medications was achieved by the majority. CONCLUSIONS: Subjects reported good adherence and outcomes despite a high level of psychiatric comorbidity. The BDI and PHQ-9 were highly correlated but both tended to overdiagnose depression. A high score on BDI or PHQ-9 should not be the sole basis for withholding treatment. These patients should be evaluated by a psychiatrist to make an informed decision. PMID- 21293294 TI - Racial disparities in community identification of autism spectrum disorders over time; Metropolitan Atlanta, Georgia, 2000-2006. AB - OBJECTIVE: Past research indicates that non-Hispanic black (NHB) children are less likely than non-Hispanic white (NHW) children to have an autism spectrum disorder (ASD) diagnosis, even if they seem to meet criteria for the disorder. This study examined differences in community identification of ASDs between NHB and NHW children identified by a population-based surveillance system. METHODS: Participants were identified as an ASD surveillance case by the Metropolitan Atlanta Developmental Disabilities Surveillance Program in surveillance years 2000, 2002, 2004, and 2006. Health and education records were abstracted and reviewed to determine ASD surveillance case status; community identification was defined by a documented ASD diagnosis, special education eligibility, and behaviors noted in records. Children were placed in 1 of 5 mutually exclusive categories on the basis of ASD specificity. RESULTS: Total ASD prevalence was higher for NHW than NHB children, but NHB children were more likely than NHW children to have autistic disorder and autism eligibility at a public school documented in records. NHB children were less likely than NHW children to have pervasive developmental disorder-not otherwise specified and Asperger's disorder documented in records, even after controlling for socioeconomic status. NHB children were more likely than NHW children to have co-occurring intellectual disability. CONCLUSION: NHB children were less likely than NHW children to have been identified with less severe ASDs, which might have prevented or delayed intervention services that would have catered to their needs. This study illustrates the need for continued professional education, particularly concerning milder ASDs in minority groups. PMID- 21293295 TI - Neuronal-astrocyte metabolic interactions: understanding the transition into abnormal astrocytoma metabolism. AB - Brain function depends on complex metabolic interactions among only a few different cell types, with astrocytes providing critical support for neurons. Astrocyte functions include buffering the extracellular space, providing substrates to neurons, interchanging glutamate and glutamine for synaptic transmission with neurons, and facilitating access to blood vessels. Whereas neurons possess highly oxidative metabolism and easily succumb to ischemia, astrocytes rely more on glycolytic metabolism and hence are less susceptible tolack of oxygen. Astrocytoma cells seem to retain basic metabolic mechanisms of astrocytes; for example, they show a high glycolytic rate, lactate extrusion, ability to flourish under hypoxia, and opportunistic use of mechanisms to enhance cell division and maintain growth. Differences in metabolism between neurons and astrocytes may also extend to astrocytoma cells, providing therapeutic opportunities against astrocytomas, including sensitivity to acetate, a high rate of glycolysis and lactate extrusion, glutamate uptake transporters, differential sensitivities of monocarboxylate transporters, presence of glycogen, high interlinking with gap junctions, use of nicotinamide adenine dinucleotide phosphate for lipid synthesis, using different isoforms of synthetic enzymes (e.g. isocitrate dehydrogenase, pyruvate carboxylase, pyruvate kinase, lactate dehydrogenase), and different glucose uptake mechanisms. These unique metabolic susceptibilities may augment conventional therapeutic attacks based on cell division differences and surface receptors alone. PMID- 21293296 TI - Neutrophil depletion reduces blood-brain barrier breakdown, axon injury, and inflammation after intracerebral hemorrhage. AB - Neutrophils are thought to contribute to damage after intracerebral hemorrhage (ICH), but there is little direct evidence for this. We depleted circulating blood neutrophils with an anti-polymorphonuclear leukocyte antibody (anti-PMN) before inducing ICH in the rat striatum. Neutrophil infiltration, which was mainly at the edge of the hematoma, was decreased by more than 60% by anti-PMN mediated depletion. We then analyzed neutrophil contributions to BBB breakdown, white matter damage (axons and myelin), and glial and inflammatory responses, both spatially and temporally. Neutrophil depletion reduced BBB leakiness in the peri-hematoma region. Matrix metalloprotease 9, which is thought to contribute to BBB breakdown, was restricted to neutrophils after ICH and was thus reduced by neutrophil depletion. Early perihematomal axonal injury seen at 1 and 3 days after ICH was decreased by depleting neutrophils, and at later times (7 and 14 days), the astrocytic and microglia/macrophage responses were reduced in the perihematoma region and the surrounding striatum. Detailed spatial analysis showed that neutrophil depletion reduced infiltration of activated microglia/macrophages in the peri-hematoma white matter tracts and decreased myelin fragmentation and axon damage. These results show that, in experimental ICH, neutrophils produce matrix metalloprotease9and contribute to blood vessel disruption, BBB breakdown, axon damage, and astrocytic and microglial/macrophage responses that evolve after ICH. PMID- 21293297 TI - Hypoxia-induced cellular and vascular changes in the nucleus tractus solitarius and ventrolateral medulla. AB - Major changes in arterial pressure, autonomic, and respiratory activity occur in response to hypoxia. We analyzed structural damage and increased vascular permeability in the ventrolateral medulla and nucleus tractus solitarius, which control autonomic, respiratory, and cardiovascular functions in adult Wistar rats subjected to 2 hours of hypoxia (7% oxygen + 93% nitrogen) for up to 14 days after hypoxicexposure. Brainstem tissue levels of vascular endothelial growth factor (VEGF), nitric oxide (NO), and glutamate were significantly increased over control levels after hypoxic injury. By electron microscopy, swollen neurons and dendrites, degenerating axons, disrupted myelin sheaths, and swollen astrocyte processes were observed in the nucleus tractus solitarius and ventrolateral medulla. Leakage of intravenously administered horseradish peroxidase was observed through vascular walls in hypoxic rats. These results suggest that increased VEGF and NO production in hypoxia resulted in increased vascular permeability, which, along with increased levels of glutamate, may have induced structural alterations of the neurons, dendrites, and axons. Administration of the antioxidant neurohormone melatonin (10mg/kg) before and after the hypoxia reduced VEGF, NO, and glutamate levels and improved ultrastructural abnormalities induced by hypoxia exposure, suggesting that it may have a therapeutic potential in reducing hypoxia-associated brainstem damage. PMID- 21293298 TI - Comprehensive neuropathologic analysis of genetic prion disease associated with the E196K mutation in PRNP reveals phenotypic heterogeneity. AB - The genetic forms of human transmissible spongiform encephalopathies (TSEs) are linked to mutations in the gene encoding the prion protein (PRNP) and account for 10% to 15% of human TSE cases. Some are distinct with respect to clinical signs, disease onset/duration, and diagnostic findings, whereas others closely resemble sporadic Creutzfeldt-Jakob disease (sCJD). We report a comprehensive analysis of 4 patients carrying the rare E196K (GAG->AAG) mutation who presented with clinical features of CJD. To date, information on this PRNP mutation is limited to clinical and genetic data. Consequently, the E196K mutation could not be unequivocally assigned to human prion disease. We report histopathologic and biochemical findings in addition to clinical observations, thus providing a more comprehensive analysis of this presumably genetic prion disease. Our data indicate that (i) the E196K mutation is causally linked to human prion disease, (ii) there is a complex phenotypic spectrum of this mutation that includes nonspecific symptoms at onset and features typical of sCJD during disease progression, and (iii) the corresponding histologic picture comprises both cases with atypical neuropathology and cases that closely resemble subtypes of sCJD corresponding to the classification of Parchi et al, with subtle modifications in hippocampal regions CA1-4. PMID- 21293299 TI - Mild traumatic brain injury results in extensive neuronal degeneration in the cerebral cortex. AB - Mild traumatic brain injury (mTBI) leads to long-term cognitive and emotional difficulties and behavioral disturbances, but the diagnosis and treatment of mTBI have historically been hampered by a lack of evidence-based correlates of these clinical manifestations. Unlike moderate and severe TBI, mTBI does not show significant tissue lesions or cavities in the cortex. Moreover, neuroimaging by magnetic resonance imaging or computed tomography is usually negative, suggesting that the damage is beyond the resolution of current structure-based scanning technologies. Therefore, we investigated the morphologies of spared neurons in the mouse cortex after mTBI in a controlled cortical impact injury model. Our results indicate that, although mTBI caused only a mild extent of cell death, it led to extensive dendrite degeneration and synapse reduction in the cortex in this model. This study sheds light on the neuropathologic consequences of mTBI in humans and suggests that neurodegeneration may be a novel target for developing diagnostic methods and therapeutic approaches for mTBI. PMID- 21293300 TI - Loss of chromosome 1p/19q in oligodendroglial tumors: refinement of chromosomal critical regions and evaluation of internexin immunostaining as a surrogate marker. AB - Loss of chromosome 1p/19q in oligodendrogliomas represents a powerful predictor of good prognosis. Expression of internexin (INA), a neuronal specific intermediate filament protein, has recently been proposed as a surrogate marker for 1p/19q deletion based on the high degree of correlation between both parameters in oligodendrogliomas. The aim of this study was to assess further the diagnostic utility of INA expression in a set of genetically well-characterized oligodendrogliomas. On the basis of a conservative approach for copy number determination, using both comparative genomic hybridization and fluorescent in situ hybridization, INA expression as a surrogate marker for 1p/19q loss had both reduced specificity (80%) and sensitivity (79%) compared with respective values of 86% and 96% reported in the previous report. The histologic interpretation and diagnostic value of INA expression in oligodendrogliomas should therefore be assessed with greater caution when compared with 1p/19q DNA copy number analysis. In addition, DNA copy number aberrations of chromosomes 10, 16, and 17 were detected exclusively in 1p/19q codeleted samples, suggesting that other regions of the genome may contribute to the 1p/19q-deleted tumor phenotype inthese samples. PMID- 21293301 TI - Results from the US industry-wide phosgene surveillance: the Diller Registry. AB - OBJECTIVE: In 2004, The American Chemistry Council Phosgene Panel established a phosgene exposure registry among US phosgene producers with the primary purpose of monitoring health outcome information for workers with acute exposure. METHODS: We examine symptoms among 338 workers with phosgene exposure. The phosgene exposures averaged 8.3 ppm-minutes ranging up to 159 ppm-minutes with most exposures below 10 ppm-minutes. RESULTS: We found that the level of phosgene exposure in ppm-minutes was related to workers reporting mostly irritation symptoms of the nose, throat and eyes within 48 hours of exposure. However, we found no relationship between phosgene exposure and the presence of symptoms 30 days after exposure. CONCLUSIONS: These findings lend credence to the theory that prolonged respiratory effects do not occur with doses less than 150 ppm-minutes. PMID- 21293302 TI - Prevalence of beryllium sensitization among Department of Defense conventional munitions workers at low risk for exposure. AB - OBJECTIVE: To estimate the prevalence of beryllium sensitization among former and current Department of Defense workers from a conventional munitions facility. METHODS: Participants were screened by using Beryllium Lymphocyte Proliferation Test. Those sensitized were offered clinical evaluation for chronic beryllium disease. RESULTS: Eight (1.5%) of 524 screened workers were found sensitized to beryllium. Although the confidence interval was wide, the results suggested a possibly higher risk of sensitization among workers exposed to beryllium by occasional resurfacing of copper-2% beryllium alloy tools compared with workers with the lowest potential exposure (odds ratio = 2.6; 95% confidence interval, 0.23-29.9). CONCLUSIONS: The findings from this study suggest that Department of Defense workers with low overall exposure to beryllium had a low prevalence of beryllium sensitization. Sensitization rates might be higher where higher beryllium exposures presumably occurred, although this study lacked sufficient power to confirm this. PMID- 21293303 TI - Nanotechnology and health. AB - There has been a considerable scientific, governmental, and public interest in potential adverse health effects associated with exposure to engineered or synthesized nanomaterials. Although such effects have not been reported in humans, there is accumulating evidence from animal studies that exposure to some nanomaterials may be harmful. There is sparse knowledge as to the likelihood, frequency, and intensity of exposures experienced by those working around engineered nanoparticles. Similarly, there is little knowledge regarding the potential existence, type, and dose dependence of adverse health effects, which might result from workplace exposures to engineered nanoparticles. This uncertainty, reflecting a relative lack of research, makes it difficult at present (and probably for the near future) to fully rely upon firm scientific evidence for the development of rational, preventive, and screening measures to protect against such potential effects. Recognizing this predicament, the American College of Occupational and Environmental Medicine (ACOEM) has developed this guidance document for occupational medicine physicians and their colleagues. The purpose of the document is to offer current prudent preventive recommendations on the topics of exposure monitoring, exposure controls, and medical surveillance. This document will not attempt to review the rapidly evolving animal toxicology literature in detail, as any review would be quickly outdated, but general areas of concern will be discussed. PMID- 21293304 TI - Minimal effect of acute caffeine ingestion on intense resistance training performance. AB - The primary aim of the study was to determine the efficacy of acute caffeine intake to enhance intense resistance training performance. Fourteen resistance trained men (age and body mass = 23.1 +/- 1.1 years and 83.4 +/- 13.2 kg, respectively) who regularly consumed caffeine ingested caffeine (6 mg . kg(-1)) or placebo 1 hour before completion of 4 sets of barbell bench press, leg press, bilateral row, and barbell shoulder press to fatigue at 70-80% 1-repetition maximum. Two minutes of rest was allotted between sets. Saliva samples were obtained to assess caffeine concentration. The number of repetitions completed per set and total weight lifted were recorded as indices of performance. Two-way analysis of variance with repeated measures was used to examine differences in performance across treatment and sets. Compared to placebo, there was a small but significant effect (p < 0.05) of acute caffeine intake on repetitions completed for the leg press but not for upper-body exercise (p > 0.05). Total weight lifted across sets was similar (p > 0.05) with caffeine (22,409.5 +/- 3,773.2 kg) vs. placebo (21,185.7 +/- 4,655.4 kg), yet there were 9 'responders' to caffeine, represented by a meaningful increase in total weight lifted with caffeine vs. placebo. Any ergogenic effect of caffeine on performance of fatiguing, total-body resistance training appears to be of limited practical significance. Additional research is merited to elucidate interindividual differences in caffeine-mediated improvements in performance. PMID- 21293305 TI - The acute effects of manipulating volume and load of back squats on countermovement vertical jump performance. AB - The acute effects of manipulating the volume and load of back squats on subsequent countermovement vertical jump performance were investigated in the present study. Eleven National Collegiate Athletic Association division II female volleyball players performed 10 countermovement vertical jumps (CMJs) on a force platform 2 minutes after the last squat repetition of a high-load (HL) or high volume (HV) squat protocol. Two minutes of rest was provided between each CMJ. The HL protocol culminated in the subjects having to perform 3 repetitions with a load equivalent to 90% 1 repetition maximum (1RM) back squat, whereas 12 repetitions with a load equivalent to 37% 1RM were performed in the HV protocol. During an initial familiarization session, knee angles were recorded during a series of CMJs, and these angles were used to control the depth of descent during all subsequent back squats. Jump height (JH) and vertical stiffness (VStiff) were calculated during each of the 10 CMJ, and the change in these variables after the 2 squat protocols was assessed using an analysis of variance model with repeated measures on 2 factors (Protocol [2-levels]; Time [2-levels]). There was no significant difference in JH after the HL and HV protocols (p > 0.05). A significant Protocol * Time interaction for VStiff resulted from the increase after the HL protocol being greater than that after the HV protocol (p = 0.03). The knee angles before the HL and HV protocols were significantly greater than those measured during the initial familiarization session (p = 0.001). Although neither squat protocol provided any benefit in improving JH, the heavy squat protocol produced greater increases in VStiff during the CMJ. Because of the increased VStiff caused by the HL protocol, volleyball coaches may consider using such protocols with their players to improve performance in jumps performed from a run such as the spike and on-court agility. PMID- 21293306 TI - Repeated sprint training improves intermittent peak running speed in team-sport athletes. AB - The aim of this study was to compare the effect of 2 repeated sprint training interventions on an intermittent peak running speed (IPRS) test designed for Australian Rules football. The test required participants to perform 10 * 10-m maximal efforts on an 80-m course every 25 seconds, for each of which the mean peak speed (kilometers per hour) was recorded to determine IPRS. The training interventions were performed twice weekly for 4 weeks immediately before regular football training. In the constant volume intervention (CVol), sprint repetition number remained at 10 (n = 9), and in the linear increase in volume (LIVol) intervention, repetition number increased linearly each week by 2 repetitions (n = 12). Intermittent peak running speed, 300-m shuttle test performance, and peak running speed were assessed before and upon completion of training. All measures were compared to a control group (CON; n = 8) in which players completed regular football training exclusively. Intermittent peak running speed performance in CVol and LIVol improved significantly (p < 0.01) by 5.2 and 3.8%, respectively, with no change in IPRS for CON. There were no differences in IPRS changes between CVol and LIVol. Additionally, peak running speed improved significantly (p < 0.01) by 5.1% for CVol, whereas 300-m shuttle performance improved significantly (p < 0.01) by 2.6% for LIVol only. Intermittent peak running speed, 300-m shuttle performance and peak running speed were improved after 4 weeks of training; however, progressively increasing sprint repetition number had no greater advantage on IPRS adaptation. Additionally, exclusive regular football training over a 4-week period is unlikely to improve IPRS, peak running speed, or 300-m shuttle performance. PMID- 21293307 TI - The effect of graduated compression stockings on running performance. AB - The aim of this study was to examine the effects of wearing different grades of graduated compression stockings (GCS) on 10-km running performance. After an initial familiarization run, 9 male and 3 female competitive runners (VO2max 68.7 +/- 5.8 ml.kg-1.min-1) completed 4 10-km time trials on an outdoor 400-m track wearing either control (0 mm Hg; Con), low (12-15 mm Hg; Low), medium (18-21 mm Hg; Med), or high (23-32 mm Hg; Hi) GCS in a randomized counterbalanced order. Leg power was assessed pre and postrun via countermovement jump using a jump mat. Blood-lactate concentration was assessed pre and postrun, whereas heart rate was monitored continuously during exercise. Perceptual scales were used to assess the comfort, tightness, and any pain associated with wearing GCS. There were no significant differences in performance time between trials (p = 0.99). The change in pre to postexercise jump performance was lower in Low and Med than in Con (p < 0.05). Mean heart rate (p = 0.99) and blood lactate (p = 1.00) were not different between trials. Participants rated Con and Low as more comfortable than Med and Hi (p < 0.01), Med and Hi were rated as tighter than Low (p < 0.01), all GCS were rated as tighter than Con (p < 0.01), and Hi was associated with the most pain (p < 0.01). In conclusion, GCS worn by competitive runners during 10-km time trials did not affect performance time; however Low and Med GCS resulted in greater maintenance of leg power after endurance exercise. Athletes rated low-grade GCS as most comfortable garments to wear during exercise. PMID- 21293308 TI - Time to exhaustion and time spent at a high percentage of VO2max in severe intensity domain in children and adults. AB - The aim of the study was to compare time spent at a high percentage of VO2max (>90% of VO2max) (ts90%), time to achieve 90% of VO2max (ta90%), and time to exhaustion (TTE) for exercise in the severe intensity domain in children and adults. Fifteen prepubertal boys (10.3 +/- 0.9 years) and 15 men (23.5 +/- 3.6 years) performed a maximal graded exercise to determine VO2max, maximal aerobic power (MAP) and power at ventilatory threshold (PVTh). Then, they performed 4 constant load exercises in a random order at PVTh plus 50 and 75% of the difference between MAP and PVTh (PDelta50 and PDelta75) and 100 and 110% of MAP (P100 and P110). VO2max was continuously monitored. The P110 test was used to determine maximal accumulated oxygen deficit (MAOD). No significant difference was found in ta90% between children and adults. ts90% and TTE were not significantly different between children and adults for the exercises at PDelta50 and PDelta75. However, ts90% and TTE during P100 (p < 0.05 and p < 0.01, respectively) and P110 (p < 0.001) exercises were significantly shorter in children. Children had a significantly lower MAOD than adults (34.3 +/- 9.4 ml . kg vs. 53.6 +/- 11.1 ml . kg). A positive relationship (p < 0.05) was obtained between MAOD and TTE values during the P100 test in children. This study showed that only for intensities at, or higher than MAP, lower ts90% in children was linked to a reduced TTE, compared to adults. Shorter TTE in children can partly be explained by a lower anaerobic capacity (MAOD). These results give precious information about exercise intensity ranges that could be used in children's training sessions. Moreover, they highlight the implication of both aerobic and anaerobic processes in endurance performances in both populations. PMID- 21293309 TI - Impact of atomoxetine on subjective attention and memory difficulties in perimenopausal and postmenopausal women. AB - OBJECTIVE: Perimenopausal and postmenopausal women frequently report midlife onset of impairments of attention, organization, and short-term memory. We sought to determine whether these cognitive symptoms in healthy women in the menopause transition without a history of attention-deficit/hyperactivity disorder (ADHD) would respond to treatment with atomoxetine (ATX), a medication demonstrated to be effective in reducing similar cognitive impairments in adults with ADHD. METHODS: Sixteen healthy women with complaints of midlife-onset subjective difficulties in memory and concentration/attention and without a history of ADHD or other psychiatric disorders were enrolled in a double-blind, placebo controlled crossover study of ATX 80 mg/day. Treatment arms were 6 weeks long, separated by a 4-week washout. The Brown Attention Deficit Disorder Scale (BADDS) was used to systematically elicit self-report of perceived cognitive difficulties in executive function. Participants also underwent neuropsychological testing, behavioral assessments, and vital signs monitoring. RESULTS: Mean baseline BADDS scores were 37.9 for all 16 participants and 42.3 for the 12 who completed both arms of the study. Total BADDS scores decreased significantly from baseline during ATX treatment but not placebo treatment. ATX treatment was superior to placebo in reducing the BADDS working memory cluster score, whereas there was a trend for ATX superiority for the BADDS attention/concentration cluster score. ATX did not differ from placebo with respect to effects on neuropsychological tests, behavioral assessments, or cardiac vital signs. CONCLUSIONS: Perimenopausal and postmenopausal women presenting with midlife-onset subjective cognitive difficulties may experience significant subjective improvement in memory and attention/concentration with ATX treatment. PMID- 21293311 TI - Epigenetic impacts on neurodevelopment: pathophysiological mechanisms and genetic modes of action. AB - Disruptions of genes that are involved in epigenetic functions are known to be causative for several mental retardation/intellectual disability (MR/ID) syndromes. Recent work has highlighted genes with epigenetic functions as being implicated in autism spectrum disorders (ASDs) and schizophrenia (SCZ). The gene environment interaction is an important factor of pathogenicity for these complex disorders. Epigenetic modifications offer a mechanism by which we can explain how the environment interacts with, and is able to dynamically regulate, the genome. This review aims to provide an overview of the role of epigenetic deregulation in the etiopathology for neurodevelopment disease. PMID- 21293310 TI - Neuronal nitric oxide synthase inhibition improves diastolic function and reduces oxidative stress in ovariectomized mRen2.Lewis rats. AB - OBJECTIVE: The loss of estrogen in mRen2.Lewis rats leads to an exacerbation of diastolic dysfunction. Because specific neuronal nitric oxide synthase (nNOS) inhibition reverses renal damage in the same model, we assessed the effects of inhibiting neuronal nitric oxide on diastolic function, left ventricular remodeling, and the components of the cardiac nitric oxide system in ovariectomized (OVX) and sham-operated mRen2.Lewis rats treated with N5-(1-imino 3-butenyl)-L-ornithine (L-VNIO; 0.5 mg/kg per day for 28 d) or vehicle (saline). METHODS: Female mRen2.Lewis rats underwent either bilateral oophorectomy (OVX; n = 15) or sham operation (or surgical procedure) (sham; n = 19) at 4 weeks of age. Beginning at 11 weeks of age, the rats were randomized to receive either L-VNIO or vehicle. RESULTS: The surgical loss of ovarian hormones, particularly estrogen, led to exacerbated hypertension, impaired myocardial relaxation, diminished diastolic compliance, increased perivascular fibrosis, and increased relative wall thickness. The cardiac tetrahydrobiopterin-to-dihydrobiopterin levels were lower among OVX rats compared with sham-operated rats, and this altered cardiac biopterin profile was associated with enhanced myocardial superoxide production and decreased nitric oxide release. L-VNIO decreased myocardial reactive oxygen species production, increased nitrite concentrations, attenuated cardiac remodeling, and improved diastolic function. CONCLUSIONS: Impaired relaxation, diastolic stiffness, and cardiac remodeling were found among OVX mRen2.Lewis rats. A possible mechanism for this unfavorable cardiac phenotype may have resulted from a deficiency in available tetrahydrobiopterin and subsequent increase in nNOS-derived superoxide and reduction in nitric oxide synthase metabolites within the heart. Selective nNOS inhibition with L-VNIO attenuated cardiac superoxide production and limited remodeling, leading to improved diastolic function in OVX mRen2.Lewis rats. PMID- 21293312 TI - Retinal fluorescein and indocyanine green angiography and spectral-domain optical coherence tomography findings in acute retinal pigment epitheliitis. AB - PURPOSE: To determine the specific location of the initial lesion in acute retinal pigment epitheliitis. METHODS: Four patients diagnosed with acute retinal pigment epitheliitis were studied. Fundus photographs, fluorescein angiography and indocyanine green angiography, and spectral-domain optical coherence tomography findings were reviewed. RESULTS: Four healthy young patients presented with acute onset of unilateral decreased vision. Ophthalmoscopy showed macular pigment mottling with surrounding yellow hypopigmented areas at the level of the retinal pigment epithelium (RPE). Fluorescein angiography revealed transmission hyperfluorescence. Early-phase and midphase indocyanine green angiography images showed a patchy macular hyperfluorescence. At late phase of indocyanine green angiography, a hyperfluorescent halo with a cockadelike appearance of the macular area was observed. Spectral-domain optical coherence tomography showed a disruption of the photoreceptors' inner segment and outer segment interface associated with a wider disruption of the RPE inner band. These disrupted lines were replaced by a dome-shaped highly reflective lesion involving the RPE inner layer, the photoreceptors' inner segment and outer segment layers, and, in two cases, the outer nuclear layer. With time, indocyanine green angiography showed resolution of the observed lesions. Spectral-domain optical coherence tomography showed restored and continuous inner segment and outer segment layers and RPE inner band. CONCLUSION: Spectral-domain optical coherence tomography findings suggest that the initial lesion in acute retinal pigment epitheliitis is located at the junction between the photoreceptor outer segments and the apical side of the RPE cells. Indocyanine green angiography and spectral-domain optical coherence tomography show that the RPE appears to be more widely involved than the neurosensory retina. PMID- 21293313 TI - Intravitreal injection of autologous bone marrow-derived mononuclear cells for hereditary retinal dystrophy: a phase I trial. AB - PURPOSE: To evaluate the short-term (10 months) safety of a single intravitreal injection of autologous bone marrow-derived mononuclear cells in patients with retinitis pigmentosa or cone-rod dystrophy. METHODS: A prospective, Phase I, nonrandomized, open-label study including 3 patients with retinitis pigmentosa and 2 patients with cone-rod dystrophy and an Early Treatment Diabetic Retinopathy Study best-corrected visual acuity of 20/200 or worse. Evaluations including best-corrected visual acuity, full-field electroretinography, kinetic visual field (Goldman), fluorescein and indocyanine green angiography, and optical coherence tomography were performed at baseline and 1, 7, 13, 18, 22, and 40 weeks after intravitreal injection of 10 * 10(6) autologous bone marrow derived mononuclear cells (0.1 mL) into 1 study eye of each patient. RESULTS: No adverse event associated with the injection was observed. A 1-line improvement in best-corrected visual acuity was measured in 4 patients 1 week after injection and was maintained throughout follow-up. Three patients showed undetectable electroretinography responses at all study visits, while 1 patient demonstrated residual responses for dark-adapted standard flash stimulus (a wave amplitude approximately 35 MUV), which remained recordable throughout follow-up, and 1 patient showed a small response (a wave amplitude approximately 20 MUV) recordable only at Weeks 7, 13, 22, and 40. Visual fields showed no reduction (with a Goldman Standard V5e stimulus) for any patient at any visit. No other changes were observed on optical coherence tomography or fluorescein and indocyanine green angiograms. CONCLUSION: Intravitreal injection of autologous bone marrow-derived mononuclear cells in eyes with advanced retinitis pigmentosa or cone-rod dystrophy was associated with no detectable structural or functional toxicity over a period of 10 months. Further studies are required to investigate the role, if any, of autologous bone marrow-derived mononuclear cell therapy in the management of retinal dystrophies. PMID- 21293314 TI - Comparative study of 50 early- or late-onset retinal detachments after open or closed globe injury. AB - PURPOSE: To compare initial findings and final prognosis of retinal detachments (RDs) secondary to open or closed ocular injuries. METHODS: This prospective study comprised 50 consecutive patients with open (n = 25, with initial successful repair) or closed (n = 25) globe injuries during a 3-year period (2004 2007), with follow-up of at least 6 months (10.1 +/- 5.8 months). The most common surgical procedure (76%) was pars plana vitrectomy. RESULTS: Clinical findings were similar in both groups for RD location and extent, frequency of macular involvement, number and nature of tears, and grade of proliferative vitreoretinopathy. Retinal detachment secondary to open/closed globe injury differed significantly, with longer time to onset after trauma, lower frequency in children, and higher rate of aphakia. Final anatomical and functional prognosis and rate of RD recurrence (25%) were similar in both groups. Good final visual prognosis (>=20/40) was significantly associated with initial visual acuity >20/200 and macula-on RD. Definitive redetachments (n = 3) were related to history of posttrauma endophthalmitis, posterior intraocular foreign body, or severe proliferative vitreoretinopathy. CONCLUSION: Final prognosis was similar in eyes with RD secondary to open and closed globe injuries. The surgical technique depended mainly on lens status, type of retinal tear (dialysis and giant retinal tear), and the presence of preoperative proliferative vitreoretinopathy. Final prognosis (visual acuity >=20/40) was associated with initial visual acuity >20/200 and macula-on status. PMID- 21293315 TI - Macular thickness changes after phacoemulsification in previously vitrectomized eyes for diabetic macular edema. AB - PURPOSE: To report visual results and anatomical outcome after uncomplicated phacoemulsification in eyes that previously underwent pars plana vitrectomy for diabetic macular edema. METHODS: This retrospective noncomparative study included 22 eyes of 19 diabetic patients who underwent uncomplicated cataract surgery with phacoemulsification and intraocular lens implantation after pars plana vitrectomy with internal limiting membrane removal for diabetic macular edema. Main outcome measures included visual acuity and foveal thickness (FT) changes as assessed by optical coherence tomography. Wilcoxon test was used for statistical analysis. RESULTS: Mean follow-up time was 11.9 +/- 8.75 months. Mean FT increased by 20.5 +/- 67.6 MUm (8.4%), with a mean preoperative FT of 237 +/- 69 MUm compared with a mean postoperative FT of 257.6 +/- 89.8 MUm (P = 0.236). Foveal thickness increased by at least 20% in 6 eyes (27.3%), remained within 20% in 14 eyes (63.6%), and decreased by 20% in 2 eyes (9.1%). Visual acuity improved by >=2 lines in 16 eyes (72.7%) and remained stable in 6 eyes (27.3%). Visual acuity was 20/40 or better in 11 eyes (50%). CONCLUSION: Moderate but insignificant increase in FT was observed after phacoemulsification in eyes that previously underwent pars plana vitrectomy for diabetic macular edema. Prospective studies with a large number of patients are warranted for a more reliable conclusion. PMID- 21293316 TI - Prevalence of age-related macular degeneration in rural central India: the Central India Eye and Medical Study. AB - PURPOSE: To evaluate the prevalence of age-related macular degeneration (AMD) in the adult population of rural central India. METHODS: The population-based Central India Eye and Medical Study was conducted in rural central India and included 4,711 subjects (aged >=30 years). Age-related macular degeneration was defined by the international classification of the Wisconsin age-related maculopathy grading system. RESULTS: Fundus photographs were available for 4,542 subjects (96.4%). In subjects aged >=40, >=50, and >=60 years, prevalence of early AMD was 6.1 +/- 0.4% (95% confidence interval [CI]: 5.3-6.9%), 8.2 +/- 0.6% (95% CI: 7.0-9.4%), and 8.3 +/- 0.8% (95% CI: 6.8-9.9%), respectively, and that of late AMD was 0.2 +/- 0.8% (95% CI: 0.1-0.4%), 0.2 +/- 0.1% (95% CI: 0.1-0.4%), and 0.6 +/- 0.2% (95% CI: 0.2-1.0%), respectively. The prevalence of early AMD increased from 1.3 +/- 0.3% per subject in the 30-year-old to 40-year-old group, to 3.6 +/- 0.5% in the 41-year-old to 50-year-old group, to 7.9 +/- 0.9% in the 51-year-old to 60-year-old group, to 10.0 +/- 1.1% in the 61-year-old to 70-year old group, to 8.3 +/- 0.2% in the 71-year-old to 80-year-old group, and to 8.0 +/ 5.5% in the >=81-year-old group. Age-related macular degeneration was causative for visual impairment (best-corrected visual acuity in the better eye: <20/60 and >=20/400) in 3 of 342 subjects (0.9%) and for blindness (visual acuity <20/400) in 0 of 17 subjects. CONCLUSION: After age adjustment, AMD was found less frequently in the adult population of rural central India than in European populations. Accordingly, visual impairment because of AMD was relatively uncommon in rural central India. PMID- 21293317 TI - Oxygen therapy for diabetic macular ischemia: a pilot study. AB - PURPOSE: To evaluate the structural and functional effects of systemic oxygen therapy in patients with diabetic macular ischemia. METHODS: This interventional case series was performed on 20 eyes from 13 consecutive diabetic patients with macular ischemia. For each patient, baseline optical coherence tomography and electroretinography were obtained before and after administration of 100% oxygen by face mask at a flow rate of 10 L/minute for 1 hour. Central macular thickness and b-wave amplitude were measured before and after oxygen therapy. RESULTS: The patients included 9 women and 4 men with mean (SD) age of 63.38 (7.34) years. Central macular thickness decreased from 358.55 +/- 96.27 MUm before to 326.55 +/ 84.11 MUm after the oxygen therapy (P < 0.001). A reduction of >10% was observed in 55% of the eyes. In dark-adapted combined response electroretinography, the amplitude of b-wave increased from 227.76 +/- 105.66 MUV before to 264.35 +/- 128.48 MUV after the oxygen therapy (P < 0.001), representing a 16% increase. More than a 10% increase in b-wave amplitude occurred in 60% of the eyes. CONCLUSION: Oxygen therapy seems to have beneficial effects on the structural and functional changes of the retina in patients with diabetic macular ischemia. It may decrease central macular thickness and improve electrophysiologic function of the retina. PMID- 21293318 TI - Twisting maneuver for sutureless vitrectomy trocar insertion to reduce intraoperative intraocular pressure rise. AB - PURPOSE: To investigate real-time intraocular pressure (IOP) during a new surgical technique-the "twisting maneuver"-when inserting a sutureless vitrectomy system trocar in porcine eyes. METHODS: An interventional prospective study of 2 trocar insertion methods-direct insertion and gently twisting insertion-in a 25 gauge vitrectomy system (Alcon, Fort Worth, TX). These methods were used to create a scleral wound using a trocar blade and trocar cannula in freshly enucleated porcine eyes. The IOP changes induced by the procedures were recorded with a pressure transducer connected to the posterior chamber by direct cannulation. RESULTS: Fourteen porcine eyes were studied in each group. During insertion, the mean of highest IOP rise (peak IOP rise) was 63.9 +/- 25.5 mmHg in the direct insertion group compared with 30.3 +/- 16.9 mmHg in the twisting insertion group (P = 0.001). During insertion, the mean of average IOP rise in the direct insertion group was 39.9 +/- 16.5 mmHg compared with 21.5 +/- 8.9 mmHg in the twisting insertion group (P = 0.002). The total time needed to complete the procedure in the twisting insertion group was significantly longer than that in the direct insertion group (43.3 +/- 21.8 vs. 14.9 +/- 8.1 seconds, P = 0.0003). CONCLUSION: A simple modification of surgical technique, namely, using a gently twisting insertion maneuver during trocar insertion, could significantly reduce the IOP elevation to allow a safer sutureless vitrectomy. PMID- 21293319 TI - Prospective study of intravitreal triamcinolone acetonide versus bevacizumab for macular edema secondary to central retinal vein occlusion. AB - PURPOSE: To compare the efficacy and safety of intravitreal triamcinolone acetonide (IVT) versus intravitreal bevacizumab (IVB) for the treatment of macular edema (ME) secondary to central retinal vein occlusion. METHODS: Prospective, consecutive, clinical interventional study. A total of 31 consecutive patients (32 eyes) with ME associated with central retinal vein occlusion were randomized to 2 groups. Sixteen eyes were treated with intravitreal injection of 4 mg/0.1 mL preservative-free triamcinolone acetonide; 16 eyes received IVB 1.25 mg/0.05 mL. Patients were given additional injections if they had ME as determined by optical coherence tomography 3 months after the first treatment or visual acuity loss of at least 2 lines in a Snellen chart. Best-corrected visual acuity, slit-lamp biomicroscopy, intraocular pressure, fundus fluorescein angiography, optical coherence tomography, the number of required injections, and adverse events were recorded during the 9-month follow up period. RESULTS: Best-corrected visual acuity was significantly improved at 2 weeks and 1, 3, 6, and 9 months after injection in both the IVT and IVB groups, but no statistical difference was found between the 2 treatment groups during the 9-month follow-up period. The mean central macular thickness decreased at 1, 3, 6, and 9 months after injection within each treatment group, and no statistical difference was found between the 2 treatment groups at any time during the follow up period (P > 0.05). Patients who received IVT treatment appeared to have quicker visual recovery and improved central macular thickness at Week 2 compared with those who received IVB treatment. Five of 16 eyes in the IVT group and 12 of 16 eyes in the IVB group required a repeated injection because of recurrent ME or unresolved intraretinal or subretinal fluid. The mean number of treatment was 1.31 +/- 0.48 in the IVT group, as compared with 2.38 +/- 1.04 in the IVB group. Significant intraocular pressure increase was found only in the IVT group, and six patients received topical intraocular pressure lowering medication, and one patient required trabeculectomy. Premacular membranes were developed in 2 patients in the IVT group. CONCLUSION: This is a prospective interventional study evaluating the efficacy and safety outcomes of IVT and IVB treatment for ME secondary to central retinal vein occlusion. Both IVT and IVB treatments can effectively improve best-corrected visual acuity and reduce central macular thickness in patients with ME secondary to central retinal vein occlusion without systemic side effects; no statistical differences were found in either best corrected visual acuity or mean central macular thickness measurement between the two treatment groups. Both the effect of triamcinolone acetonide and that of bevacizumab were not permanent, and less injections were performed in the IVT group. However, triamcinolone acetonide causes more adverse events than bevacizumab. PMID- 21293320 TI - Infrared scanning laser ophthalmoscope imaging of the macula and its correlation with functional loss and structural changes in patients with stargardt disease. AB - PURPOSE: To correlate the degree of functional loss with structural changes in patients with Stargardt disease. METHODS: Eighteen eyes of 10 patients with Stargardt disease were studied. Scanning laser ophthalmoscope infrared images were compared with corresponding spectral-domain optical coherence tomography scans. Additionally, scanning laser ophthalmoscope microperimetry was performed, and results were superimposed on scanning laser ophthalmoscope infrared images and in selected cases on fundus autofluorescence images. RESULTS: Seventeen of 18 eyes showed a distinct hyporeflective foveal and/or perifoveal area with distinct borders on scanning laser ophthalmoscope infrared images, which was less evident on funduscopy and incompletely depicted in fundus autofluorescence images. This hyporeflective zone corresponded to areas of significantly elevated psychophysical thresholds on microperimetry testing, in addition to thinning of the retinal pigment epithelium and disorganization or loss of the photoreceptor cell inner segment-outer segment junction and external-limiting membrane on spectral-domain optical coherence tomography. CONCLUSION: Scanning laser ophthalmoscope infrared fundus images are useful for depicting retinal structural changes in patients with Stargardt disease. A spectral-domain optical coherence tomography/scanning laser ophthalmoscope microperimetry device allows for a direct correlation of structural abnormalities with functional defects that will likely be applicable for the determination of retinal areas for potential improvement of retinal function in these patients during future clinical trials and for the monitoring of the diseases' natural history. PMID- 21293321 TI - Immunosuppression withdrawal after liver transplantation: what are the next steps? AB - Achieving operational tolerance after liver transplantation remains a challenge for clinicians and scientists. Prospective immunosuppression withdrawal trials coupled with biomarker development and histologic assessment will be critical to the increasing applicability of drug-free transplantation from a sporadic event to a safely achieved, predictable state for increasing numbers of patients. PMID- 21293322 TI - Maintenance of IKKbeta activity is necessary to protect lung grafts from acute injury. AB - BACKGROUND: Signaling pathways that target I-kappaB kinase beta (IKKbeta) activation stimulate the expression of nuclear factor (NF)-kappaB-dependent genes and are thus believed to primarily promote inflammation and injury in solid organ grafts. METHODS: We examined the role of IKKbeta in a mouse model of lung transplantation-mediated ischemia-reperfusion injury using NF-kappaB essential modulator (NEMO)-binding domain (NBD) peptide to pharmacologically inhibit IKK activation. As myeloid cells are primarily responsible for the production of acute inflammatory mediators after lung transplantation, we also investigated the effects of myeloid cell-specific IKKbeta gene deletion on acute lung graft injury by transplanting mutant mice. RESULTS: When NBD was administered at a dose that partially inhibits IKKbeta activation, we observed attenuated lung graft injury and blunted expression of intragraft proinflammatory mediators. Surprisingly, when the dose of NBD was increased to a level that ablates intragraft IKKbeta activation, graft inflammation, and injury were significantly worse compared with recipients treated with control peptide. Similar to lung recipients with pharmacologically ablated IKKbeta activity, donor-recipient transplant combinations with a myeloid cell-specific IKKbeta gene deletion had marked intragraft inflammation and poor lung function. CONCLUSIONS: Our data show maintenance of IKKbeta activity is critical for promoting graft homeostasis with important implications for targeting NF-kappaB-dependent signaling pathways for treating acute lung injury. PMID- 21293323 TI - Disparities in diagnoses of HIV infection between blacks/African Americans and other racial/ethnic populations--37 states, 2005-2008. AB - Blacks/African Americans have been affected disproportionately by human immunodeficiency virus (HIV) infection since early in the epidemic. Despite representing a smaller proportion (13.6%) of the U.S. population, blacks/African Americans accounted for half of the HIV diagnoses in adolescents and adults in 37 states during 2005-2008. Data from the National HIV Surveillance System were used to estimate numbers, percentages, and rates of HIV diagnoses in blacks/African Americans during 2005-2008. Those data were reported to CDC through June 2009 from 37 states with mature (in operation since at least January 2005) HIV surveillance systems. This report describes the results of those analyses, which indicated that during 2005-2008, blacks/African Americans were diagnosed with HIV infection more frequently than any other racial/ethnic population. During 2008, black/African American males and females were diagnosed with HIV infection at eight and 19 times the rates for white males and females and two and four times the rates for Hispanic/Latino males and females, respectively. In addition, the number of HIV diagnoses made each year among black/African American males increased during 2005-2008. The reduction of HIV-related health disparities has been identified as one of the three goals in the National HIV/AIDS Strategy. Reducing HIV risk behaviors and increasing access to testing and referral to health care can help eliminate disparities between blacks/African Americans and other racial/ethnic populations in the rates at which HIV infection is diagnosed. PMID- 21293324 TI - Increase in newly diagnosed HIV infections among young black men who have sex with men--Milwaukee County, Wisconsin, 1999-2008. AB - During 2001-2006, new human immunodeficiency virus (HIV) diagnoses among black men aged 13-24 years who have sex with men (MSM) in 33 states increased by 93%. The Wisconsin Division of Public Health (WDPH) recently reported to CDC a 144% increase during 2000-2008 in HIV diagnoses among black MSM aged 15-29 years in Milwaukee County. In October 2009, the City of Milwaukee Health Department (MHD), WDPH, and CDC investigated whether the increase in HIV infections among young black MSM in Milwaukee represented increased HIV transmission or simply better identification of prevalent infections. This report describes the results of that investigation, which indicated that a new "social networks" HIV testing strategy and the recent expansion of better targeted HIV testing efforts accounted for few diagnoses among young black MSM and occurred after HIV diagnoses increased, respectively. Therefore, although some diagnoses were made because of intensified testing, an increase in HIV transmission likely occurred. Moreover, an increase in syphilis diagnoses among young black MSM in Milwaukee preceded the increase in HIV diagnoses, which suggests that changes in risk behavior or sexual networks might explain the increase. These findings highlight the need for new or improved interventions promoting prevention education, early HIV detection, and entry to care for young HIV-infected and at-risk black MSM in Milwaukee. PMID- 21293325 TI - Vital signs: prevalence, treatment, and control of hypertension--United States, 1999-2002 and 2005-2008. AB - BACKGROUND: Hypertension is a modifiable risk factor for cardiovascular disease. It affects one in three adults in the United States and contributes to one out of every seven deaths and nearly half of all cardiovascular disease-related deaths in the United States. METHODS: CDC analyzed data from the National Health and Nutrition Examination Survey (NHANES) on the prevalence, treatment, and control of hypertension among U.S. adults aged >=18 years. Hypertension was defined as an average blood pressure >=140/90 mmHg or the current use of blood pressure lowering medication. Control of hypertension was reported as an average treated systolic/diastolic blood pressure <140/90 mmHg. Multivariate analysis was performed to assess changes in prevalence of hypertension, use of pharmacologic treatment, and control of blood pressure between the 1999-2002 and 2005-2008 survey cycles. RESULTS: During 2005-2008, approximately 68 million (31%) U.S. adults aged >=18 years had hypertension, and this prevalence has shown no improvement in the past decade. Of these adults, 48 million (70%) were receiving pharmacologic treatment and 31 million (46%) had their condition controlled. Although 86% of adults with uncontrolled blood pressure had medical insurance, the prevalence of blood pressure control among adults with hypertension was especially low among participants who did not have a usual source of medical care (12%), received medical care less than twice in the previous year (21%), or did not have health insurance (29%). Control prevalence also was low among young adults (31%) and Mexican Americans (37%). Although the prevalence of hypertension did not change from 1999-2002 to 2005-2008, significant increases were observed in the prevalence of treatment and control. CONCLUSIONS: Hypertension affects millions of persons in the United States, and less than half of those with hypertension have their condition controlled. Prevalence of treatment and control are even lower among persons who do not have a usual source of medical care, those who are not receiving regular medical care, and those who do not have health insurance. IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: To improve blood pressure control in the United States, a comprehensive approach is needed that involves policy and system changes to improve health-care access, quality of preventive care, and patient adherence to treatment. Nearly 90% of persons with uncontrolled hypertension have health insurance, indicating a need for health care system improvements. Health-care system improvements, including use of electronic health records with registry and clinical decision support functions, could facilitate better treatment and follow-up management, and improve patient physician interaction. Allied health professionals (e.g., nurses, dietitians, health educators and pharmacists) could help increase patient adherence to medications. Patient adoption of healthy behaviors could improve their blood pressure control. Reducing dietary intake of salt would greatly support prevention and control of hypertension; a 32% decrease in average daily consumption, from 3,400 mg to 2,300 mg, could reduce hypertension by as many as 11 million cases. Further reductions in sodium intake to 1,500 mg/day could reduce hypertension by 16.4 million cases. PMID- 21293326 TI - Vital signs: prevalence, treatment, and control of high levels of low-density lipoprotein cholesterol--United States, 1999-2002 and 2005-200. AB - BACKGROUND: High levels of low-density lipoprotein cholesterol (LDL-C), a major risk factor for coronary heart disease (CHD), can be treated effectively. METHODS: CDC analyzed data from 1999-2002 and 2005-2008 to examine the prevalence, treatment, and control of high LDL-C among U.S. adults aged >=20 years. Values were determined from blood specimens obtained from persons participating in the National Health and Nutrition Examination Survey (NHANES), a nationally representative cross-sectional, stratified, multistage probability sample survey of the U.S. civilian, noninstitutionalized population. The National Cholesterol Education Program Adult Treatment Panel-III guidelines set LDL-C goal levels of <100 mg/dL, <130 mg/dL, and <160 mg/dL for persons with high, intermediate, and low risk for developing CHD during the next 10 years, respectively. A person with high LDL-C was defined as either a person whose LDL-C levels were above the LDL-C goal levels or a person who reported currently taking cholesterol-lowering medication. Control of high LDL-C was defined as having a treated LDL-C value below the goal levels. RESULTS: Based on data from the 2005 2008 NHANES, an estimated 71 million (33.5%) U.S. adults aged >=20 years had high LDL-C, but only 34 million (48.1%) were treated and 23 million (33.2%) had their LDL-C controlled. Among persons with uncontrolled LDL-C, 82.8% reported having some form of health insurance. The proportion of adults with high LDL-C who were treated increased from 28.4% to 48.1% between the 1999-2002 and 2005-2008 study periods. Among adults with high LDL-C, the prevalence of LDL-C control increased from 14.6% to 33.2% between the periods. The prevalence of LDL-C control was lowest among persons who reported receiving medical care less than twice in the previous year (11.7%), being uninsured (13.5%), being Mexican American (20.3%), or having income below the poverty level (21.9%). CONCLUSIONS: The prevalence of control of high LDL-C in the United States, although improving, remains low, especially among low-income adults and those with limited access to health care. Strengthening the use of preventive services through improvement in health-care access and quality of care is expected to help achieve better control of high LDL C in the United States. IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: To improve LDL-C control levels, a comprehensive approach that involves improved clinical care, as well as improved health-care access, sustainability, and affordability, is needed. A standardized system of patient care incorporating electronic health records, registries, and automated reminders for practitioners, focusing on achieving regular patient follow-up, has the potential to improve control of high LDL-C. Lower out-of-pocket costs and simplification of the drug regimen, as well as involvement of nurses, dietitians, health educators, pharmacists and other allied health-care professionals in direct patient care also could be used to improve patient adherence to prescribed regimens. PMID- 21293328 TI - Earth 2.0. PMID- 21293327 TI - General recommendations on immunization --- recommendations of the Advisory Committee on Immunization Practices (ACIP). AB - This report is a revision of the General Recommendations on Immunization and updates the 2006 statement by the Advisory Committee on Immunization Practices (ACIP) (CDC. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2006;55[No. RR-15]). The report also includes revised content from previous ACIP recommendations on the following topics: adult vaccination (CDC. Update on adult immunization recommendations of the immunization practices Advisory Committee [ACIP]. MMWR 1991;40[No. RR-12]); the assessment and feedback strategy to increase vaccination rates (CDC. Recommendations of the Advisory Committee on Immunization Practices: programmatic strategies to increase vaccination rates-assessment and feedback of provider-based vaccination coverage information. MMWR 1996;45:219-20); linkage of vaccination services and those of the Supplemental Nutrition Program for Women, Infants, and Children (WIC program) (CDC. Recommendations of the Advisory Committee on Immunization Practices: programmatic strategies to increase vaccination coverage by age 2 years-linkage of vaccination and WIC services. MMWR 1996;45:217-8); adolescent immunization (CDC. Immunization of adolescents: recommendations of the Advisory Committee on Immunization Practices, the American Academy of Pediatrics, the American Academy of Family Physicians, and the American Medical Association. MMWR 1996;45[No. RR-13]); and combination vaccines (CDC. Combination vaccines for childhood immunization: recommendations of the Advisory Committee on Immunization Practices [ACIP], the American Academy of Pediatrics [AAP], and the American Academy of Family Physicians [AAFP]. MMWR 1999;48[No. RR-5]). Notable revisions to the 2006 recommendations include 1) revisions to the tables of contraindications and precautions to vaccination, as well as a separate table of conditions that are commonly misperceived as contraindications and precautions; 2) reordering of the report content, with vaccine risk-benefit screening, managing adverse reactions, reporting of adverse events, and the vaccine injury compensation program presented immediately after the discussion of contraindications and precautions; 3) stricter criteria for selecting an appropriate storage unit for vaccines; 4) additional guidance for maintaining the cold chain in the event of unavoidable temperature deviations; and 5) updated revisions for vaccination of patients who have received a hematopoietic cell transplant. The most recent ACIP recommendations for each specific vaccine should be consulted for comprehensive details. This report, ACIP recommendations for each vaccine, and additional information about vaccinations are available from CDC at http://www.cdc.gov/vaccines. PMID- 21293329 TI - Preserve the past. PMID- 21293330 TI - Tough on truth. PMID- 21293331 TI - Listen to the lessons of The King's Speech. PMID- 21293343 TI - Flaw in induced-stem-cell model. PMID- 21293344 TI - Antenna decision makes waves. PMID- 21293345 TI - China sets 2020 vision for science. PMID- 21293346 TI - EU advisers urge funding reform. PMID- 21293347 TI - Swindon, we have a problem. PMID- 21293348 TI - Social science lines up its biggest challenges. PMID- 21293349 TI - Astronomy: Beyond the stars. PMID- 21293350 TI - Astronomy: Exoplanets on the cheap. PMID- 21293351 TI - Tighten regulations on deep-sea mining. PMID- 21293357 TI - Research type can affect citation rate. PMID- 21293358 TI - Self-plagiarism in music and science. PMID- 21293359 TI - Think bigger for conservation. PMID- 21293360 TI - Controversy over GM maize in Peru. PMID- 21293361 TI - Negative results need airing too. PMID- 21293362 TI - Eugene Goldwasser (1922-2010). PMID- 21293363 TI - Drug discovery: A question of library design. PMID- 21293364 TI - Plant biology: Defence at dawn. PMID- 21293365 TI - Astrophysics: Big black hole found in tiny galaxy. PMID- 21293366 TI - Molecular biology: DNA fragility put into context. PMID- 21293367 TI - Theoretical ecology: Waltz of the weevil. PMID- 21293369 TI - Global change: Methane and monsoons. PMID- 21293370 TI - Archaeology: Trailblazers across Arabia. PMID- 21293371 TI - A closely packed system of low-mass, low-density planets transiting Kepler-11. AB - When an extrasolar planet passes in front of (transits) its star, its radius can be measured from the decrease in starlight and its orbital period from the time between transits. Multiple planets transiting the same star reveal much more: period ratios determine stability and dynamics, mutual gravitational interactions reflect planet masses and orbital shapes, and the fraction of transiting planets observed as multiples has implications for the planarity of planetary systems. But few stars have more than one known transiting planet, and none has more than three. Here we report Kepler spacecraft observations of a single Sun-like star, which we call Kepler-11, that reveal six transiting planets, five with orbital periods between 10 and 47 days and a sixth planet with a longer period. The five inner planets are among the smallest for which mass and size have both been measured, and these measurements imply substantial envelopes of light gases. The degree of coplanarity and proximity of the planetary orbits imply energy dissipation near the end of planet formation. PMID- 21293373 TI - Femtosecond X-ray protein nanocrystallography. AB - X-ray crystallography provides the vast majority of macromolecular structures, but the success of the method relies on growing crystals of sufficient size. In conventional measurements, the necessary increase in X-ray dose to record data from crystals that are too small leads to extensive damage before a diffraction signal can be recorded. It is particularly challenging to obtain large, well diffracting crystals of membrane proteins, for which fewer than 300 unique structures have been determined despite their importance in all living cells. Here we present a method for structure determination where single-crystal X-ray diffraction 'snapshots' are collected from a fully hydrated stream of nanocrystals using femtosecond pulses from a hard-X-ray free-electron laser, the Linac Coherent Light Source. We prove this concept with nanocrystals of photosystem I, one of the largest membrane protein complexes. More than 3,000,000 diffraction patterns were collected in this study, and a three-dimensional data set was assembled from individual photosystem I nanocrystals (~200 nm to 2 MUm in size). We mitigate the problem of radiation damage in crystallography by using pulses briefer than the timescale of most damage processes. This offers a new approach to structure determination of macromolecules that do not yield crystals of sufficient size for studies using conventional radiation sources or are particularly sensitive to radiation damage. PMID- 21293374 TI - Single mimivirus particles intercepted and imaged with an X-ray laser. AB - X-ray lasers offer new capabilities in understanding the structure of biological systems, complex materials and matter under extreme conditions. Very short and extremely bright, coherent X-ray pulses can be used to outrun key damage processes and obtain a single diffraction pattern from a large macromolecule, a virus or a cell before the sample explodes and turns into plasma. The continuous diffraction pattern of non-crystalline objects permits oversampling and direct phase retrieval. Here we show that high-quality diffraction data can be obtained with a single X-ray pulse from a non-crystalline biological sample, a single mimivirus particle, which was injected into the pulsed beam of a hard-X-ray free electron laser, the Linac Coherent Light Source. Calculations indicate that the energy deposited into the virus by the pulse heated the particle to over 100,000 K after the pulse had left the sample. The reconstructed exit wavefront (image) yielded 32-nm full-period resolution in a single exposure and showed no measurable damage. The reconstruction indicates inhomogeneous arrangement of dense material inside the virion. We expect that significantly higher resolutions will be achieved in such experiments with shorter and brighter photon pulses focused to a smaller area. The resolution in such experiments can be further extended for samples available in multiple identical copies. PMID- 21293375 TI - Late Holocene methane rise caused by orbitally controlled increase in tropical sources. AB - Considerable debate surrounds the source of the apparently 'anomalous' increase of atmospheric methane concentrations since the mid-Holocene (5,000 years ago) compared to previous interglacial periods as recorded in polar ice core records. Proposed mechanisms for the rise in methane concentrations relate either to methane emissions from anthropogenic early rice cultivation or an increase in natural wetland emissions from tropical or boreal sources. Here we show that our climate and wetland simulations of the global methane cycle over the last glacial cycle (the past 130,000 years) recreate the ice core record and capture the late Holocene increase in methane concentrations. Our analyses indicate that the late Holocene increase results from natural changes in the Earth's orbital configuration, with enhanced emissions in the Southern Hemisphere tropics linked to precession-induced modification of seasonal precipitation. Critically, our simulations capture the declining trend in methane concentrations at the end of the last interglacial period (115,000-130,000 years ago) that was used to diagnose the Holocene methane rise as unique. The difference between the two time periods results from differences in the size and rate of regional insolation changes and the lack of glacial inception in the Holocene. Our findings also suggest that no early agricultural sources are required to account for the increase in methane concentrations in the 5,000 years before the industrial era. PMID- 21293376 TI - Alternative stable states explain unpredictable biological control of Salvinia molesta in Kakadu. AB - Suppression of the invasive plant Salvinia molesta by the salvinia weevil is an iconic example of successful biological control. However, in the billabongs (oxbow lakes) of Kakadu National Park, Australia, control is fitful and incomplete. By fitting a process-based nonlinear model to thirteen-year data sets from four billabongs, here we show that incomplete control can be explained by alternative stable states--one state in which salvinia is suppressed and the other in which salvinia escapes weevil control. The shifts between states are associated with annual flooding events. In some years, high water flow reduces weevil populations, allowing the shift from a controlled to an uncontrolled state; in other years, benign conditions for weevils promote the return shift to the controlled state. In most described ecological examples, transitions between alternative stable states are relatively rare, facilitated by slow-moving environmental changes, such as accumulated nutrient loading or climate change. The billabongs of Kakadu give a different manifestation of alternative stable states that generate complex and seemingly unpredictable dynamics. Because shifts between alternative stable states are stochastic, they present a potential management strategy to maximize effective biological control: when the domain of attraction to the state of salvinia control is approached, augmentation of the weevil population or reduction of the salvinia biomass may allow the lower state to trap the system. PMID- 21293377 TI - A thymus candidate in lampreys. AB - Immunologists and evolutionary biologists have been debating the nature of the immune system of jawless vertebrates--lampreys and hagfish--since the nineteenth century. In the past 50 years, these fish were shown to have antibody-like responses and the capacity to reject allografts but were found to lack the immunoglobulin-based adaptive immune system of jawed vertebrates. Recent work has shown that lampreys have lymphocytes that instead express somatically diversified antigen receptors that contain leucine-rich-repeats, termed variable lymphocyte receptors (VLRs), and that the type of VLR expressed is specific to the lymphocyte lineage: T-like lymphocytes express type A VLR (VLRA) genes, and B like lymphocytes express VLRB genes. These clonally diverse anticipatory antigen receptors are assembled from incomplete genomic fragments by gene conversion, which is thought to be initiated by either of two genes encoding cytosine deaminase, cytosine deaminase 1 (CDA1) in T-like cells and CDA2 in B-like cells. It is unknown whether jawless fish, like jawed vertebrates, have dedicated primary lymphoid organs, such as the thymus, where the development and selection of lymphocytes takes place. Here we identify discrete thymus-like lympho epithelial structures, termed thymoids, in the tips of the gill filaments and the neighbouring secondary lamellae (both within the gill basket) of lamprey larvae. Only in the thymoids was expression of the orthologue of the gene encoding forkhead box N1 (FOXN1), a marker of the thymopoietic microenvironment in jawed vertebrates, accompanied by expression of CDA1 and VLRA. This expression pattern was unaffected by immunization of lampreys or by stimulation with a T-cell mitogen. Non-functional VLRA gene assemblies were found frequently in the thymoids but not elsewhere, further implicating the thymoid as the site of development of T-like cells in lampreys. These findings suggest that the similarities underlying the dual nature of the adaptive immune systems in the two sister groups of vertebrates extend to primary lymphoid organs. PMID- 21293372 TI - Mapping copy number variation by population-scale genome sequencing. AB - Genomic structural variants (SVs) are abundant in humans, differing from other forms of variation in extent, origin and functional impact. Despite progress in SV characterization, the nucleotide resolution architecture of most SVs remains unknown. We constructed a map of unbalanced SVs (that is, copy number variants) based on whole genome DNA sequencing data from 185 human genomes, integrating evidence from complementary SV discovery approaches with extensive experimental validations. Our map encompassed 22,025 deletions and 6,000 additional SVs, including insertions and tandem duplications. Most SVs (53%) were mapped to nucleotide resolution, which facilitated analysing their origin and functional impact. We examined numerous whole and partial gene deletions with a genotyping approach and observed a depletion of gene disruptions amongst high frequency deletions. Furthermore, we observed differences in the size spectra of SVs originating from distinct formation mechanisms, and constructed a map of SV hotspots formed by common mechanisms. Our analytical framework and SV map serves as a resource for sequencing-based association studies. PMID- 21293378 TI - Timing of plant immune responses by a central circadian regulator. AB - The principal immune mechanism against biotrophic pathogens in plants is the resistance (R)-gene-mediated defence. It was proposed to share components with the broad-spectrum basal defence machinery. However, the underlying molecular mechanism is largely unknown. Here we report the identification of novel genes involved in R-gene-mediated resistance against downy mildew in Arabidopsis and their regulatory control by the circadian regulator, CIRCADIAN CLOCK-ASSOCIATED 1 (CCA1). Numerical clustering based on phenotypes of these gene mutants revealed that programmed cell death (PCD) is the major contributor to resistance. Mutants compromised in the R-gene-mediated PCD were also defective in basal resistance, establishing an interconnection between these two distinct defence mechanisms. Surprisingly, we found that these new defence genes are under circadian control by CCA1, allowing plants to 'anticipate' infection at dawn when the pathogen normally disperses the spores and time immune responses according to the perception of different pathogenic signals upon infection. Temporal control of the defence genes by CCA1 differentiates their involvement in basal and R-gene mediated defence. Our study has revealed a key functional link between the circadian clock and plant immunity. PMID- 21293381 TI - Transcutaneous bilirubin levels in an outpatient and office population. AB - OBJECTIVE: The use of transcutaneous bilirubin (TcB) measurements has been studied extensively in the newborn population, but there have been few studies in outpatient populations and none from the offices of practicing pediatricians. STUDY DESIGN: We performed TcB measurements on a mixed-race population of 120 jaundiced infants, >= 35 weeks of gestation, in two hospital-based outpatient clinics, a regional public health nurse follow-up program and two pediatric office practices. Three individual TcB readings were obtained from the mid sternum, and the average and maximum values were recorded. RESULT: There was good correlation between the TcB and total serum bilirubin (TSB) measurements (r=0.78, P=0.0). 59% of TSB's were >=15 mg dl(-1) and, although the number of false negative readings increased when the TSB values exceeded 15 mg dl(-1), it was nevertheless possible to use TcB measurements to accurately predict the risk of TSB levels >= 15 mg dl(-1). CONCLUSION: In outpatient settings, a TcB measurement with the JM-103 provides a reliable screening method for the identification of hyperbilirubinemia even when the TSB level exceeds 15 mg dl(-1). Using the maximum of three independent measurements reduces the number of false negatives, but increases the number of false positives. The use of TcB measurements in an outpatient practice should be a valuable tool for the practitioner. PMID- 21293379 TI - MMSET regulates histone H4K20 methylation and 53BP1 accumulation at DNA damage sites. AB - p53-binding protein 1 (53BP1) is known to be an important mediator of the DNA damage response, with dimethylation of histone H4 lysine 20 (H4K20me2) critical to the recruitment of 53BP1 to double-strand breaks (DSBs). However, it is not clear how 53BP1 is specifically targeted to the sites of DNA damage, as the overall level of H4K20me2 does not seem to increase following DNA damage. It has been proposed that DNA breaks may cause exposure of methylated H4K20 previously buried within the chromosome; however, experimental evidence for such a model is lacking. Here we found that H4K20 methylation actually increases locally upon the induction of DSBs and that methylation of H4K20 at DSBs is mediated by the histone methyltransferase MMSET (also known as NSD2 or WHSC1) in mammals. Downregulation of MMSET significantly decreases H4K20 methylation at DSBs and the subsequent accumulation of 53BP1. Furthermore, we found that the recruitment of MMSET to DSBs requires the gammaH2AX-MDC1 pathway; specifically, the interaction between the MDC1 BRCT domain and phosphorylated Ser 102 of MMSET. Thus, we propose that a pathway involving gammaH2AX-MDC1-MMSET regulates the induction of H4K20 methylation on histones around DSBs, which, in turn, facilitates 53BP1 recruitment. PMID- 21293382 TI - FBXO11, a regulator of the TGFbeta pathway, is associated with severe otitis media in Western Australian children. AB - Otitis media (OM) is a common childhood disease characterised by middle ear inflammation following infection. Susceptibility to recurrent acute OM (rAOM) and chronic OM with effusion (COME) is highly heritable. Two murine mutants, Junbo and Jeff, spontaneously develop severe OM with similar phenotypes to human disease. Fine-mapping of these mutants identified two genes (Evi1 and Fbxo11) that interact with the transforming growth factor beta (TGFbeta) signalling pathway. We investigated these genes, as well as four Sma- and Mad-related (SMAD) genes of the TGFbeta pathway, as candidate rAOM/COME susceptibility genes in two predominantly Caucasian populations. Single-nucleotide polymorphisms (SNPs) within FBXO11 (family-based association testing Z-Score=2.61; P(best)=0.009) were associated with severe OM in family-based analysis of 434 families (561 affected individuals) from the Western Australian Family Study of OM. The FBXO11 association was replicated by directed analysis of Illumina 660W-Quad Beadchip data available for 253 cases and 866 controls (OR=1.55 (95% CI 1.28-1.89); P(best)=6.9 * 10(-6)) available within the Western Australian Pregnancy Cohort (Raine) Study. Combined primary and replication results show P(combined)=2.98 * 10(-6). Neither cohort showed an association with EVI1 variants. Family-based associations at SMAD2 (P=0.038) and SMAD4 (P=0.048) were not replicated. Together, these data provide strong evidence for FBXO11 as a susceptibility gene for severe OM. PMID- 21293383 TI - HLA-DPB1-COL11A2 and three additional xMHC loci are independently associated with RA in a UK cohort. AB - The aim of this study was to investigate the complex association pattern of the extended major histocompatibility complex (xMHC) region with rheumatoid arthritis (RA) susceptibility to identify effects independent of HLA-DRB1. A total of 1804 RA cases and 1474 controls were included. High-resolution HLA-DRB1 typing was performed. Subjects were genotyped for 1546 single-nucleotide polymorphisms (SNPs) using Affymetrix GeneChip 500 K (Santa Clara, CA, USA) as part of the Wellcome Trust Case Control Consortium Study. Statistical analysis was carried out using PLINK. To avoid confounding by RA-associated HLA-DRB1 alleles, we analyzed xMHC SNPs using a data set with pairwise matching of cases and controls on DRB1 genotypes. A total of 594 case-control pairs with identical DRB1 genotypes were identified. After this adjustment, 104 SNPs remained significantly associated with RA (P<0.05), suggesting that additional RA loci independent of HLA-DRB1 can be found in the xMHC region. Of these, four loci showed the strongest associations with RA (P<0.005): ZNF391, the olfactory receptor (OR) gene cluster, C6orf26-RDBP and HLA-DPB1-COL11A2. An additional locus mapping to the BTN (butyrophilin) cluster showed independent association with RA in anti cyclic citrullinated peptide-positive patients exclusively. We have validated the previously described independent association of the HLA-DPB1-COL11A2 locus with RA. In addition, association with three novel independent RA loci in the xMHC region (ZNF391, OR2H1 and C6orf26-RDBP) has been detected. PMID- 21293384 TI - Severe combined immunodeficiency in Frisian Water Dogs caused by a RAG1 mutation. AB - Mortality of pups at 8-12 weeks of age was frequently observed in Frisian Water Dogs. Blood parameters and clinical signs of newborns from three litters were monitored. Three pups from two litters showed strongly reduced levels of immunoglobulins and lymphocytes. These dogs were euthanized after first display of disease. Concurrent clinical and pathological features were consistent with a diagnosis of severe combined immunodeficiency (SCID). Defective V(D)J recombination is one of the causes of SCID in humans and animals. Eight genes involved in V(D)J recombination were investigated by segregation analysis of closely located microsatellite markers and by DNA sequence analysis. A nonsense mutation in the gene coding for V(D)J recombination factor RAG1 was identified in DNA from the cases at a position similar to that of nonsense mutations found in human SCID. It was concluded that SCID due to a mutation of RAG1 led to the high mortality. PMID- 21293385 TI - Predictors of large and small artery elasticity in healthy subjects from 9 to 89 years old. AB - BACKGROUND: We identified demographic variables, cardiovascular risk factors, and ambulatory activity measures that predict large and small artery elasticity in apparently healthy subjects between 9 and 89 years of age. METHODS: A total of 480 subjects were assessed on large artery elasticity index (LAEI), small artery elasticity index (SAEI), demographic measures, cardiovascular risk factors, and daily ambulation during 7 consecutive days. All possible regression and Mallow's C(p) were used to select multivariate models for prediction of LAEI and SAEI. RESULTS: In subjects 20 years of age and younger, LAEI model (R(2) = 0.25, P < 0.001) included age, average ambulatory cadence, and obesity. SAEI model (R(2) = 0.39, P < 0.001) contained body mass index (BMI), maximum daily ambulatory cadence for 30 continuous min, age, and total ambulatory strides. In subjects between 21 and 50 years, LAEI model (R(2) = 0.41, P < 0.001) included systolic blood pressure (SBP), gender, race, and diastolic blood pressure (DBP). SAEI model (R(2) = 0.42, P < 0.001) contained gender, BMI, DBP, race, dyslipidemia, and SBP. In subjects older than 50 years, LAEI model (R(2) = 0.54, P < 0.001) included SBP, gender, age, and BMI. SAEI model (R(2) = 0.45, P < 0.001) contained gender, age, BMI, DBP, current smoking, and SBP. CONCLUSIONS: Daily ambulatory activity, particularly cadence of 30 continuous min of ambulation, is positively associated with arterial elasticity in children and adolescents. In contrast, the predominant factors related to the decline in arterial elasticity in adults are blood pressure and age. PMID- 21293386 TI - Aliskiren vs. angiotensin receptor blockers in hypertension: meta-analysis of randomized controlled trials. AB - BACKGROUND: Aliskiren, a newly discovered renin inhibitor, blocks the renin angiotensin system (RAS) from the top of the enzyme cascade and therefore, might provide comparable or even superior clinical efficacy of blood pressure (BP) control than angiotensin receptor blockers (ARBs). With this meta-analysis, we aimed to compare the efficacy and tolerability of aliskiren and ARBs in the treatment of hypertension in the short-term treatment period. METHODS: Reports of randomized controlled trials (RCTs) comparing aliskiren and ARBs in patients with hypertension were selected by a search of the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE. The main outcome measures were reduction in diastolic BP (DBP) and systolic BP (SBP) and rates of therapeutic response and BP control. We also compared the tolerability of aliskiren and ARBs. Revman v5.0 was used to obtain the pooled estimates. RESULTS: We analyzed data from 10 reports of trials involving 3,732 participants. DBP and SBP reduction did not differ between aliskiren and ARBs (weighted mean difference (WMD), -0.18; 95% confidence interval (CI), -1.07 to 0.71, and WMD, 0.15; 95% CI, -1.38 to 1.69, respectively). Aliskiren and ARB treatment did not differ in rates of BP control or therapeutic response. Moreover, aliskiren and ARB treatment led to a similar number of adverse events, severe adverse events, and withdrawal due to adverse events. CONCLUSION: Aliskiren is as effective as ARBs (losartan, valsartan, and irbesartan) in controlling BP and does not differ from ARBs in risk of adverse events. PMID- 21293387 TI - Blood pressure awareness in Austria: lessons from a 30 years horizon. AB - BACKGROUND: Blood pressure (BP) awareness is a main focus of public health efforts. In Austria, an increase of knowledge and perception regarding hypertension was seen after a nationwide educational campaign in 1978, but subsequent surveys documented only short-term impact. We report results of the latest survey in 2009 in comparison to 1978 and 1998. METHODS: Balanced for Austrian demographic characteristics 1,005 men and women older than 15 years of age were randomly selected for face-to-face interviews about BP awareness, risk factors, and hazards of hypertension and treatment options including life-style interventions. RESULTS: Overall, 15% identified themselves as hypertensive, which is similar to results from 1978 (14%) but significantly higher than 1998 (12%; P < 0.01). The proportion of hypertensives not undertaking any measure (i.e., pharmacotherapy or life-style changes) significantly decreased since 1998 (5% vs. 10%; P < 0.0001). Thirty-three percent recalled to have measured their BP within the last 3 months, which is comparable to 1998 (34%) but lower than in 1978 (49%) after the nationwide educational BP campaign (P < 0.0001). Alarmingly, an unchanged proportion of 8% reported no BP measurement ever (1978 and 1998: 8%, respectively). Sixty-one percent believed they would be able to clearly identify symptoms of hypertension, while only 19% knew that hypertension might not be noticeable. Heart attack and stroke were considered the most common sequelae of hypertension. CONCLUSION: Despite a high understanding of the risks of hypertension among the Austrian population, a widespread misconception regarding BP symptoms and infrequent personal checks are worrisome and might also be valid in other Western countries. PMID- 21293388 TI - Taurine prevents hypertension and increases exercise capacity in rats with fructose-induced hypertension. AB - BACKGROUND: Fructose-induced hypertension was used to test the hypothesis that taurine supplementation and/or exercise can prevent hypertension and increase exercise capacity. METHODS: Five groups of 15 Sprague-Dawley rats were allocated and designated as control, high fructose-fed (fructose), high fructose-fed plus exercise (FE), high fructose-fed plus 2% taurine supplement (FT) and high fructose-fed plus 2% taurine supplement and exercise (FET) groups. Noninvasive systolic blood pressure (SBP) was recorded weekly and invasive arterial blood pressure (ABP) was recorded at the end of the 4-week trial. Three consecutive swimming tests were performed in the selected rats from each group and the plasma biomarkers were measured in the remaining rats. RESULTS: Noninvasive SBP differed significantly (P < 0.001) from week 3, both noninvasive and invasive ABP increased significantly (P < 0.001), and exercise capacity significantly decreased (P < 0.001) in the fructose group compared with the control group. The individual effects of swimming and taurine supplementation were incapable of preventing the development of hypertension and SBP significantly (P < 0.001) increased in the FE and FT groups; exercise capacity in those groups remained similar to control. The combined effects of exercise and taurine alleviated hypertension and significantly increased exercise capacity in the FET group. Insulin resistance increased significantly and plasma nitric oxide (NO) decreased significantly in the F, FE, and FT groups. Both parameters remained similar to control values in the FET group with an increasing antioxidant activity. CONCLUSION: Taurine supplementation in combination with exercise prevents hypertension and increases exercise capacity by possibly antioxidation and maintaining NO concentrations. PMID- 21293389 TI - High tail-cuff blood pressure in mice 1 week after shipping: the need for longer acclimation. AB - BACKGROUND: For vendor-derived mice, an acclimation period of 1 week is usually recommended before blood pressure measurements are started. However, we observed hypertension in wild-type vendor-derived mice 1 week after shipping. METHODS: The index group (n = 12, BALB/c, age 3 months, weight 26-28 g) was shipped overnight (by truck, duration 13 h). Tail-cuff systolic blood pressures (SBPs) of the index group were compared to two control groups (n = 6/group), one acclimated for 3 weeks after shipping, and one derived from an in-house colony. RESULTS: One week after shipping, SBP in the index group was 141 +/- 3 mm Hg. Because this was much higher than reported previously for this strain, acclimation was prolonged. Six weeks after shipping, SBP had fallen to 124 +/- 3 mm Hg (P < 0.005). During this time, heart rate also fell from 721 +/- 15 to 665 +/- 13 bpm (P < 0.01). SBP in the two control groups was also lower than in the index group 1 week after shipping, including the group acclimated for 3 weeks (129 +/- 3 vs. 141 +/- 3 mm Hg, P < 0.05) and the in-house mice (124 +/- 3 vs. 141 +/- 3 mm Hg, P < 0.005). CONCLUSIONS: Vendor-derived mice are hypertensive 1 week after shipping, become normotensive after 3 weeks, but do not return to levels of in-house mice until after 6 weeks. Acclimation periods of at least 3 weeks are required when measuring blood pressure in mice. PMID- 21293390 TI - Temporary treatment with AT1 receptor blocker, valsartan, from early stage of hypertension prevented vascular remodeling. AB - BACKGROUND: The present study examined the inhibitory action of temporary treatment with an angiotensin type 1 (AT(1)) receptor blocker (ARB) on vascular remodeling using hypertensive mice with overexpression of the human renin (hRN) and angiotensinogen (hANG) genes. METHODS: hRN/hANG transgenic mice (hRN/hANG-Tg) were treated with an ARB, valsartan, from 4 weeks of age. In some mice, valsartan treatment was stopped at 8 weeks of age (temporary treatment). Inflammatory vascular injury was induced by polyethylene-cuff placement around the femoral artery at the age of 10 weeks. RESULTS: Compared with wild-type (WT) mice, hRN/hANG-Tg showed higher blood pressure (BP) and enhancement of oxidative stress and medial thickening even before cuff placement. Inflammatory vascular remodeling and oxidative stress after cuff placement were further enhanced in hRN/hANG-Tg. Temporary treatment with valsartan continuously lowered BP even after cessation of administration, and inhibited these changes. In contrast, administration of hydralazine lowered BP to a similar level to that with valsartan, but did not inhibit medial thickening and inflammatory vascular remodeling. In contrast to the valsartan treatment, BP immediately increased to the untreated level after cessation of hydralazine. CONCLUSIONS: These results indicate that temporary ARB treatment leads to prolonged effect of BP lowering and prevents vascular remodeling in hypertensive mice induced by activation of the human renin-angiotensin system. The inhibitory action of valsartan is not due to the BP lowering but is at least in part due to a decrease in oxidative stress and inflammation. PMID- 21293445 TI - Molecular hydrogen improves obesity and diabetes by inducing hepatic FGF21 and stimulating energy metabolism in db/db mice. AB - Recent extensive studies have revealed that molecular hydrogen (H(2)) has great potential for improving oxidative stress-related diseases by inhaling H(2) gas, injecting saline with dissolved H(2), or drinking water with dissolved H(2) (H(2) water); however, little is known about the dynamic movement of H(2) in a body. First, we show that hepatic glycogen accumulates H(2) after oral administration of H(2)-water, explaining why consumption of even a small amount of H(2) over a short span time efficiently improves various disease models. This finding was supported by an in vitro experiment in which glycogen solution maintained H(2). Next, we examined the benefit of ad libitum drinking H(2)-water to type 2 diabetes using db/db obesity model mice lacking the functional leptin receptor. Drinking H(2)-water reduced hepatic oxidative stress, and significantly alleviated fatty liver in db/db mice as well as high fat-diet-induced fatty liver in wild-type mice. Long-term drinking H(2)-water significantly controlled fat and body weights, despite no increase in consumption of diet and water. Moreover, drinking H(2)-water decreased levels of plasma glucose, insulin, and triglyceride, the effect of which on hyperglycemia was similar to diet restriction. To examine how drinking H(2)-water improves obesity and metabolic parameters at the molecular level, we examined gene-expression profiles, and found enhanced expression of a hepatic hormone, fibroblast growth factor 21 (FGF21), which functions to enhance fatty acid and glucose expenditure. Indeed, H(2) stimulated energy metabolism as measured by oxygen consumption. The present results suggest the potential benefit of H(2) in improving obesity, diabetes, and metabolic syndrome. PMID- 21293446 TI - Randomized controlled trial to improve adiposity, inflammation, and insulin resistance in obese African-American and Latino youth. AB - The purpose of this study was to examine ethnic differences in the metabolic responses to a 16-week intervention designed to improve insulin sensitivity (SI), adiposity, and inflammation in obese African-American and Latino adolescents. A total of 100 participants (African Americans: n = 48, Latino: n = 52; age: 15.4 +/- 1.1 years, BMI percentile: 97.3 +/- 3.3) were randomly assigned to interventions: control (C; n = 30), nutrition (N; n = 39, 1*/week focused on decreasing sugar and increasing fiber intake), or nutrition + strength training (N+ST; n = 31, 2*/week). The following were measured at pre- and postintervention: strength, dietary intake, body composition (dual-energy X-ray absorptiometry/magnetic resonance imaging) and glucose/insulin indexes (oral glucose tolerance test (OGTT)/intravenous glucose tolerance test (IVGTT)) and inflammatory markers. Overall, N compared to C and N+ST reported significant improvements in SI (+16.5% vs. -32.3% vs. -6.9% respectively, P < 0.01) and disposition index (DI: +15.5% vs. -14.2% vs. -13.7% respectively, P < 0.01). N+ST compared to C and N reported significant reductions in hepatic fat fraction (HFF: -27.3% vs. -4.3% vs. 0% respectively, P < 0.01). Compared to N, N+ST reported reductions in plasminogen activator inhibitor-1 (PAI-1) (-38.3% vs. +1.0%, P < 0.01) and resistin (-18.7% vs. +11.3%, P = 0.02). There were no intervention effects for all other measures of adiposity or inflammation. Significant intervention by ethnicity interactions were found for African Americans in the N group who reported increases in total fat mass, 2-h glucose and glucose incremental areas under the curve (IAUC) compared to Latinos (P's < 0.05). These interventions yielded differential effects with N reporting favorable improvements in SI and DI and N+ST reporting marked reductions in HFF and inflammation. Both ethnic groups had significant improvements in metabolic health; however some improvements were not seen in African Americans. PMID- 21293447 TI - Circulating omentin as a novel biomarker of endothelial dysfunction. AB - Omentin is a novel soluble lectin expressed mainly in the stromal-vascular cells from visceral adipose tissue with vasodilator effect in isolated blood vessels. To gain insight in the relationship between obesity and cardiovascular risk factors, we aimed to explore the interaction among circulating omentin, metabolic parameters, and endothelial function. Circulating omentin (enzyme-linked immunosorbent assay) was studied in 248 white men (148 with normal glucose tolerance (NGT) and 100 with impaired glucose tolerance (IGT)). Insulin sensitivity was measured using the frequently sampled intravenous glucose tolerance test. Vascular reactivity was measured by high-resolution ultrasound of the brachial artery. Circulating omentin concentration was significantly increased in lean compared with overweight and obese subjects (53.7 +/- 16.9 vs. 45.2 +/- 16.8 and vs. 40.1 +/- 15.5 ng/ml, P < 0.0001). Circulating omentin concentration correlated with age, BMI, waist-to-hip ratio (WHR), percentage of fat mass, systolic and diastolic blood pressure, endothelium-dependent and independent vasodilation (EDV and EIV), C-reactive protein, and interleukin-6 (IL 6). In IGT subjects, circulating omentin concentration also correlated with insulin sensitivity, although this association did not remain significant after controlling for BMI. In a multiple linear regression analysis, circulating omentin concentration (P = 0.01), systolic blood pressure (P = 0.04), and BMI (P = 0.04) contributed independently to EDV after controlling for age and C-reactive protein in IGT subjects. In NGT subjects, only circulating omentin concentration (P = 0.01) was significantly associated with EDV. In conclusion, circulating omentin concentration could be a useful marker of endothelial function. PMID- 21293448 TI - Cardiorespiratory fitness, different measures of adiposity, and total cancer mortality in women. AB - The objective was to examine associations among cardiorespiratory fitness (CRF), adiposity, and cancer mortality in women. Healthy women (N = 14,256) without cancer history completed a baseline health examination 1970-2005. Measures included BMI, percent body fat (%Fat), and CRF quantified as duration of a maximal treadmill test. CRF was classified as low (quintile 1), moderate (Q2-3), and high fit (Q4-5) by age. Standard BMI cutpoints were used, while participants were classified by %Fat quintiles. Cancer mortality rates were calculated following age, exam year, and smoking adjustment. During a mean follow-up period of 15.2 +/- 9.4 years, 250 cancer deaths occurred. Adjusted mortality rates across BMI groups were 4.6, 5.7, and 8.8 (P trend 0.08); %Fat 3.0, 4.9, 2.9, 3.8, and 6.9 (P trend 0.17); and CRF 7.9, 5.5, and 2.9 (P trend 0.003). When grouped into categories of fit and unfit (upper 80% and lower 20% of CRF distribution), and using BMI as the adiposity exposure, cancer mortality rates of unfit-obese women were significantly higher than fit-normal weight women (9.8 vs. 4.1 deaths/10,000 woman-years; P = 0.02), while fit-overweight and fit-obese women had no greater risk of mortality than fit-normal weight women. Using %Fat as the adiposity exposure, unfit-obese women tended to have higher cancer mortality than fit-normal weight women (7.0 vs. 3.3 deaths/10,000 woman-years, P = 0.10). Higher levels of CRF are associated with lower cancer mortality risk in women and attenuate the risk of cancer mortality in overweight women. Using adiposity measures to estimate cancer mortality risk in women can be potentially misleading unless CRF is considered. PMID- 21293449 TI - Influence of BMI on level of circulating progenitor cells. AB - Obesity complicates a number of diseases through mechanisms that are poorly defined. Mobilization and recruitment of progenitor cells to pathological sites is an important factor in disease progression. Here, we analyzed the influence of obesity on the systemic circulation of CD34(+) cell populations and correlated frequencies of cells displaying previously established cell marker signatures with the BMI. Comparative analysis of peripheral blood mononuclear cells (PBMC) from 12 nonobese (BMI <30 kg/m(2)) and 14 obese (BMI >30 kg/m(2)) disease-free donors by flow cytometry revealed that obesity is associated with a fivefold increased frequency of circulating progenitor cells (CPC), a population consisting of hematopoietic and endothelial precursors. Our data also indicate that obesity is associated with increased frequency of circulating mesenchymal stromal progenitor cells (MSC). In contrast, the frequencies of mature endothelial cells (EC) and CD34-bright leukocytes are unaffected by obesity. Combined, our results indicate that obesity promotes mobilization of progenitor cells, which may have clinical relevance. PMID- 21293450 TI - Glycemic variability in abdominally obese men with normal glucose tolerance as assessed by continuous glucose monitoring system. AB - The purpose of this study was to observe both the glycemic variability in abdominally obese men with normal glucose tolerance (NGT) and the relationship between glycemic variability and early atherosclerosis. This case-control study included 23 abdominally obese men (waist circumference (WC) >=90 cm) and 23 nonabdominally obese men (WC <90 cm) with NGT who were between 20 and 50 years of age. All subjects were of the Han ethnicity. The cases and controls were age matched. A continuous glucose monitoring system (CGMS) was used in this study. With the CGMS, the standard deviation of blood glucose (SDBG) and the mean amplitude of glucose excursion (MAGE) were calculated to estimate glycemic variability. The carotid intima-media thickness (CIMT) was used as a surrogate marker of early atherosclerosis. Mean blood glucose (MBG) (6.13 +/- 0.94 vs. 5.55 +/- 0.87 mmol/l), SDBG (0.89 +/- 0.34 vs. 0.64 +/- 0.24 mmol/l), MAGE (2.05 +/- 0.83 vs. 1.57 +/- 0.52 mmol/l), and CIMT (0.73 +/- 0.12 vs. 0.67 +/- 0.05 mm) were significantly higher in the abdominally obese men than in the nonabdominally obese men (P < 0.05). WC positively correlated with MBG (r = 0.302, P = 0.041), SDBG (r = 0.362, P = 0.013), MAGE (r = 0.302, P = 0.041), and CIMT (r = 0.487, P = 0.001). CIMT did not correlate with MBG (r = 0.206, P = 0.169), SDBG (r = 0.114, P = 0.450), and MAGE (r = 0.085, P = 0.574). After multivariate analysis, WC was still significantly associated with MBG (beta = 0.025, P = 0.041), SDBG (beta = 0.010, P = 0.013), MAGE (beta = 0.019, P = 0.042), and CIMT (beta = 0.008, P = 0.022). This study demonstrates that glycemic variability is increased in abdominally obese men with NGT. A relationship between glycemic variability and atherosclerosis was not observed in this study and requires further investigation. PMID- 21293451 TI - Efficacy and safety of CP-945,598, a selective cannabinoid CB1 receptor antagonist, on weight loss and maintenance. AB - Three double-blind, placebo-controlled, three-parallel-group, multicenter phase 3 trials were conducted to assess the efficacy and safety of CP-945,598 for weight loss and weight-loss maintenance. Two trials were designed to be 2 years in duration (in obese and overweight patients) and one as a 1-year study (in obese and overweight patients with type 2 diabetes). However, the 2-year trials and the CP-945,598 development program were terminated before completion due to changing regulatory perspectives of CB1 receptor-related drugs. In total, 1,253 and 2,536 participants in the two 2-year multinational and North American studies were randomized to 10-mg CP-945,598 (n = 360; 718); 20-mg CP-945,598 (n = 534, 1,084) and placebo (n = 359, 734), respectively; and 975 participants were randomized to 10-mg CP-945,598 (n = 318); 20-mg CP-945,598 (n = 320); and placebo (n = 337) in the 1-year multinational diabetes trial. Baseline demographics were similar between treatment groups within each trial. One year of treatment with CP-945,598 resulted in a dose-related mean percentage reduction from baseline body-weight in all trials. A significant proportion of all participants also achieved 5% and 10% weight loss after 1 year. In participants with mainly well-controlled type 2 diabetes, the combination of lifestyle and CP-945,598 induced substantial improvements in glycemic control. The most frequent adverse events (AEs) for CP 945,598 were: diarrhea, nausea, nasopharyngitis, and headache. Self-reported experiences of anxiety and suicidal thoughts were higher with CP-945,598 than placebo, as were the incidence of depression and depressed mood. However, the reported increases in psychiatric symptoms were not consistently dose dependent. PMID- 21293452 TI - Obesity, overweight, and their life course trajectories in veterans and non veterans. AB - Veterans comprise a large and growing segment of the US population. Results from national telephone surveys suggest higher prevalence of overweight among Veterans compared with demographically similar non-Veterans, based on self-reported height and weight. Using 1999-2008 data from the National Health and Nutrition Examination Survey (NHANES), we compared 3,768 Veterans and 21,974 non-Veterans on: (i) several measures of adiposity based on direct anthropometry; (ii) life course of self-reported BMI; and (iii) behaviors related to weight loss or maintenance. Whether Veterans were more likely than demographically similar non Veterans to be obese or overweight depended on the adiposity measure employed. On BMI, Veterans were about equally likely to be obese (30+ kg/m(2)), but more likely to be overweight (25-29.9 kg/m(2)) by both self-report and by direct measurement (significantly so only by self-report). On waist-stature ratio, a roughly similar pattern was observed. On waist circumference, Veterans tended to have larger values than demographically similar non-Veterans, with more Veterans in the largest two categories. But on dual-photon X-ray absorptiometry, Veterans were less likely to have 35+% body fat than non-Veterans of similar age, gender, and race/ethnicity. Life-course trends in self-reported BMI suggested a possible burst of weight gain after military discharge. These results suggest that Veterans may, on average, have less excess body fat than non-Veterans--a pattern not revealed by standard anthropometric measures. PMID- 21293453 TI - Basic statistical analysis in genetic case-control studies. AB - This protocol describes how to perform basic statistical analysis in a population based genetic association case-control study. The steps described involve the (i) appropriate selection of measures of association and relevance of disease models; (ii) appropriate selection of tests of association; (iii) visualization and interpretation of results; (iv) consideration of appropriate methods to control for multiple testing; and (v) replication strategies. Assuming no previous experience with software such as PLINK, R or Haploview, we describe how to use these popular tools for handling single-nucleotide polymorphism data in order to carry out tests of association and visualize and interpret results. This protocol assumes that data quality assessment and control has been performed, as described in a previous protocol, so that samples and markers deemed to have the potential to introduce bias to the study have been identified and removed. Study design, marker selection and quality control of case-control studies have also been discussed in earlier protocols. The protocol should take ~1 h to complete. PMID- 21293454 TI - Creating localized DNA double-strand breaks with microirradiation. AB - We describe a protocol for creating localized DNA double-strand breaks (DSBs) with minimal requirements that can be applied in cell biology and molecular biology. This protocol is based on the combination of 5-bromo-2'-deoxyuridine (BrdU) labeling and ultraviolet C (UVC) irradiation through porous membranes. Cells are labeled with 10 MUM BrdU for 48-72 h, washed with Ca(2+)- and Mg(2+) free PBS(-), covered by polycarbonate membranes with micropores and exposed to UVC light. With this protocol, localized DSBs are created within subnuclear areas, irrespective of the cell cycle phase. Recruitment of proteins involved in DNA repair, DNA damage response, chromatin remodeling and histone modifications can be visualized without any specialized equipment. The quality is the same as that obtained by laser microirradiation or by any other focal irradiation. DSBs become visible within 30 min of UVC irradiation. PMID- 21293455 TI - Rapid isolation of single malaria parasite-infected red blood cells by cell sorting. AB - Malaria research often requires isolation of individually infected red blood cells (RBCs) or of a homogenous parasite population derived from a single parasite (clone). Traditionally, isolation of individual, parasitized RBCs or parasite cloning is achieved by limiting dilution or micromanipulation. This protocol describes a method for more efficient cloning of the malaria parasite; the method uses a cell sorter to rapidly isolate Plasmodium falciparum-infected RBCs singly. By gating the parameters of forward-angle light scatter and side angle light scatter in a cell sorter, singly infected RBCs can be isolated and automatically deposited into a 96-well culture plate within 1 min. Including a Percoll purification step; the entire procedure to seed a 96-well plate with singly infected RBCs can take <40 min. This highly efficient single-cell sorting protocol should be useful for cloning of both laboratory parasite populations from genetic manipulation experiments and clinical samples. PMID- 21293456 TI - Use of stable isotope labeling by amino acids in cell culture as a spike-in standard in quantitative proteomics. AB - Mass spectrometry (MS)-based proteomics is increasingly applied in a quantitative format, often based on labeling of samples with stable isotopes that are introduced chemically or metabolically. In the stable isotope labeling by amino acids in cell culture (SILAC) method, two cell populations are cultured in the presence of heavy or light amino acids (typically lysine and/or arginine), one of them is subjected to a perturbation, and then both are combined and processed together. In this study, we describe a different approach--the use of SILAC as an internal or 'spike-in' standard--wherein SILAC is only used to produce heavy labeled reference proteins or proteomes. These are added to the proteomes under investigation after cell lysis and before protein digestion. The actual experiment is therefore completely decoupled from the labeling procedure. Spike in SILAC is very economical, robust and in principle applicable to all cell- or tissue-based proteomic analyses. Applications range from absolute quantification of single proteins to the quantification of whole proteomes. Spike-in SILAC is especially advantageous when analyzing the proteomes of whole tissues or organisms. The protocol describes the quantitative analysis of a tissue sample relative to super-SILAC spike-in, a mixture of five SILAC-labeled cell lines that accurately represents the tissue. It includes the selection and preparation of the spike-in SILAC standard, the sample preparation procedure, and analysis and evaluation of the results. PMID- 21293457 TI - Application of isothermal titration calorimetry and column chromatography for identification of biomolecular targets. AB - This protocol describes a method for identifying unknown target proteins from a mixture of biomolecules for a given drug or a lead compound. This method is based on a combination of chromatography and isothermal titration calorimetry (ITC) where ITC is used as a tracking tool. The first step involves the use of ITC to confirm the binding of ligand to a component in the biomolecular mixture. Subsequently, the biomolecular mixture is fractionated by chromatography, and the binding of the ligand with individual fractions (or subfractions) is verified by ITC. The iteration of chromatographic purification on the fractions combined with ITC results in identifying the target protein. This method is useful when the target protein or ligand is unknown and/or not amenable to labeling, chemical modification or immobilization. This protocol has been successfully used by our team and by others to identify both low-abundance and highly abundant target proteins present in biomolecular mixtures. With this protocol, it takes approximately 3-5 d to identify the target protein from a mixture. PMID- 21293458 TI - cDNA library generation from ribonucleoprotein particles. AB - Most, if not all, known noncoding RNAs (ncRNAs) are associated with RNA binding proteins, thus forming ribonucleoprotein particles or RNPs. Here we describe a protocol for the generation of a specialized cDNA library from RNPs, thereby increasing the proportion of functional ncRNA species in the library. To that end, cellular extracts are fractionated on 10-30% glycerol gradients. Subsequently, RNP-derived ncRNAs are isolated and 3'-tailed by cytidine triphosphate and poly(A) polymerase; this is followed by 5' adapter ligation by T4 RNA ligase. Reverse transcription of ncRNAs into cDNAs is carried out with an oligo-d(G) anchor primer. The generated cDNA libraries are subsequently submitted to high-throughput sequencing. This RNP selection procedure increases the probability of the presence of biologically relevant ncRNA species in the library compared with libraries generation methods that use size-selected, protein-devoid ncRNAs. The protocol enables the generation of deep-sequencing-compatible cDNA libraries that code for functional ncRNAs within 1 week. PMID- 21293459 TI - Absolute quantification of protein and post-translational modification abundance with stable isotope-labeled synthetic peptides. AB - In the analysis of biological systems, it is of interest to identify the components of the system and to monitor their changes in abundance under different conditions. The AQUA (for 'absolute quantification') method allows sensitive and specific targeted quantification of protein and post-translational modifications in complex protein mixtures using stable isotope-labeled peptides as internal standards. Each AQUA experiment is composed of two stages: method development and application to a biological scenario. In the method development stage, peptides from the protein of interest are chosen and then synthesized with stable isotopes such as (13)C, (2)H or (15)N. The abundance of these internal standards and their endogenous counterparts can be measured by mass spectrometry with selected reaction monitoring or selected ion monitoring methods. Once an AQUA method is established, it can be rapidly applied to a wide range of biological samples, from tissue culture cells to human plasma and tissue. After AQUA peptide synthesis, the development, optimization and application of AQUA analyses to a specific biological problem can be achieved in ~1 week. Here we demonstrate the usefulness of this method by monitoring both Polo-like kinase 1 (Plk1) protein abundance in multiple lung cancer cell lines and the extent of Plk1 activation loop phosphorylation (pThr-210) during release from S phase. PMID- 21293460 TI - Assaying stem cell mechanobiology on microfabricated elastomeric substrates with geometrically modulated rigidity. AB - We describe the use of a microfabricated cell culture substrate, consisting of a uniform array of closely spaced, vertical, elastomeric microposts, to study the effects of substrate rigidity on cell function. Elastomeric micropost substrates are micromolded from silicon masters comprised of microposts of different heights to yield substrates of different rigidities. The tips of the elastomeric microposts are functionalized with extracellular matrix through microcontact printing to promote cell adhesion. These substrates, therefore, present the same topographical cues to adherent cells while varying substrate rigidity only through manipulation of micropost height. This protocol describes how to fabricate the silicon micropost array masters (~2 weeks to complete) and elastomeric substrates (3 d), as well as how to perform cell culture experiments (1-14 d), immunofluorescence imaging (2 d), traction force analysis (2 d) and stem cell differentiation assays (1 d) on these substrates in order to examine the effect of substrate rigidity on stem cell morphology, traction force generation, focal adhesion organization and differentiation. PMID- 21293461 TI - Generation of subtype-specific neurons from postnatal astroglia of the mouse cerebral cortex. AB - Instructing glial cells to generate neurons may prove to be a strategy to replace neurons that have degenerated. Here, we describe a robust protocol for the efficient in vitro conversion of postnatal astroglia from the mouse cerebral cortex into functional, synapse-forming neurons. This protocol involves two steps: (i) expansion of astroglial cells (7 d) and (ii) astroglia-to-neuron conversion induced by persistent and strong retroviral expression of Neurog2 (encoding neurogenin-2) or Mash1 (also referred to as achaete-scute complex homolog 1 or Ascl1) and/or distal-less homeobox 2 (Dlx2) for generation of glutamatergic or GABAergic neurons, respectively (7-21 d for different degrees of maturity). Our protocol of astroglia-to-neuron conversion by a single neurogenic transcription factor provides a stringent experimental system to study the specification of a selective neuronal subtype, thus offering an alternative to the use of embryonic or neural stem cells. Moreover, it can be a useful model for studies of lineage conversion from non-neuronal cells, with potential for brain regenerative medicine. PMID- 21293462 TI - High-throughput imaging of adult fluorescent zebrafish with an LED fluorescence macroscope. AB - Zebrafish are a useful vertebrate model for the study of development, behavior, disease and cancer. A major advantage of zebrafish is that large numbers of animals can be economically used for experimentation; however, high-throughput methods for imaging live adult zebrafish had not been developed. Here, we describe protocols for building a light-emitting diode (LED) fluorescence macroscope and for using it to simultaneously image up to 30 adult animals that transgenically express a fluorescent protein, are transplanted with fluorescently labeled tumor cells or are tagged with fluorescent elastomers. These protocols show that the LED fluorescence macroscope is capable of distinguishing five fluorescent proteins and can image unanesthetized swimming adult zebrafish in multiple fluorescent channels simultaneously. The macroscope can be built and used for imaging within 1 day, whereas creating fluorescently labeled adult zebrafish requires 1 hour to several months, depending on the method chosen. The LED fluorescence macroscope provides a low-cost, high-throughput method to rapidly screen adult fluorescent zebrafish and it will be useful for imaging transgenic animals, screening for tumor engraftment, and tagging individual fish for long-term analysis. PMID- 21293463 TI - Circular polymerase extension cloning for high-throughput cloning of complex and combinatorial DNA libraries. AB - High-throughput genomics, proteomics and synthetic biology studies require ever more efficient and economical strategies to clone complex DNA libraries or variants of biological modules. In this paper, we provide a protocol for a sequence-independent approach for cloning complex individual or combinatorial DNA libraries, and routine or high-throughput cloning of single or multiple DNA fragments. The strategy, called circular polymerase extension cloning (CPEC), is based on polymerase overlap extension and is therefore free of restriction digestion, ligation or single-stranded homologous recombination. CPEC is highly efficient, accurate and user friendly. Once the inserts and the linear vector have been prepared, the CPEC reaction can be completed in 10 min to 3 h, depending on the complexity of the gene libraries. PMID- 21293464 TI - A functionally characterized test set of human induced pluripotent stem cells. AB - Human induced pluripotent stem cells (iPSCs) present exciting opportunities for studying development and for in vitro disease modeling. However, reported variability in the behavior of iPSCs has called their utility into question. We established a test set of 16 iPSC lines from seven individuals of varying age, sex and health status, and extensively characterized the lines with respect to pluripotency and the ability to terminally differentiate. Under standardized procedures in two independent laboratories, 13 of the iPSC lines gave rise to functional motor neurons with a range of efficiencies similar to that of human embryonic stem cells (ESCs). Although three iPSC lines were resistant to neural differentiation, early neuralization rescued their performance. Therefore, all 16 iPSC lines passed a stringent test of differentiation capacity despite variations in karyotype and in the expression of early pluripotency markers and transgenes. This iPSC and ESC test set is a robust resource for those interested in the basic biology of stem cells and their applications. PMID- 21293465 TI - Ubiquitination/deubiquitination and acetylation/deacetylation: making DNMT1 stability more coordinated. PMID- 21293466 TI - Active ingredients in Chinese medicines promoting blood circulation as Na+/K+ ATPase inhibitors. AB - The positive inotropic effect of cardiac glycosides lies in their reversible inhibition on the membrane-bound Na(+)/K(+)-ATPase in human myocardium. Steroid like compounds containing a core structure similar to cardiac glycosides are found in many Chinese medicines conventionally used for promoting blood circulation. Some of them are demonstrated to be Na(+)/K(+)-ATPase inhibitors and thus putatively responsible for their therapeutic effects via the same molecular mechanism as cardiac glycosides. On the other hand, magnesium lithospermate B of danshen is also proposed to exert its cardiac therapeutic effect by effectively inhibiting Na(+)/K(+)-ATPase. Theoretical modeling suggests that the number of hydrogen bonds and the strength of hydrophobic interaction between the effective ingredients of various medicines and residues around the binding pocket of Na(+)/K(+)-ATPase are crucial for the inhibitory potency of these active ingredients. Ginsenosides, the active ingredients in ginseng and sanqi, substantially inhibit Na(+)/K(+)-ATPase when sugar moieties are attached only to the C-3 position of their steroid-like structure, equivalent to the sugar position in cardiac glycosides. Their inhibitory potency is abolished, however, when sugar moieties are linked to C-6 or C-20 position of the steroid nucleus; presumably, these sugar attachments lead to steric hindrance for the entrance of ginsenosides into the binding pocket of Na(+)/K(+)-ATPase. Neuroprotective effects of cardiac glycosides, several steroid-like compounds, and magnesium lithospermate B against ischemic stroke have been accordingly observed in a cortical brain slice-based assay model, and cumulative data support that effective inhibitors of Na(+)/K(+)-ATPase in the brain could be potential drugs for the treatment of ischemic stroke. PMID- 21293467 TI - Enhanced NMDA receptor NR1 phosphorylation and neuronal activity in the arcuate nucleus of hypothalamus following peripheral inflammation. AB - AbstractAim:To investigate the role of glutamate and N-methyl-D-aspartate (NMDA) receptors in central sensitization following peripheral inflammation in the arcuate nucleus (ARC) of the mediobasal hypothalamus. METHODS: Mediobasal hypothalamic slices were prepared from rats undergoing peripheral inflammation, which was induced by a unilateral injection of complete Freund's adjuvant (CFA) into hind paw. Neuronal activation levels in the ARC were monitored by recording extracellular unit discharges. The NMDA receptor NR1 subunit (NR1) was measured using Western blot analysis. RESULTS: Enhanced NR1 phosphorylation was observed in the ARC of CFA-inflamed rats. Compared with the control rats, the firing rate of spontaneous discharges in ARC neurons of inflamed rats was significantly higher, and it was significantly reduced both by an NMDA receptor antagonist (MK 801, 300 MUmol/L) and by a non-NMDA receptor antagonist (CNQX, 30 MUmol/L). Application of exogenous glutamate (200 MUmol/L) or NMDA (25 MUmol/L) resulted in increased neuronal discharges for ARC neurons, which was enhanced to a greater extent in inflamed rats than in control rats. CONCLUSION: Glutamate receptor activation in the hypothalamic ARC plays a crucial role in central sensitization associated with peripheral inflammation. PMID- 21293468 TI - Kynurenic acid attenuates multiorgan dysfunction in rats after heatstroke. AB - AIM: To assess whether systemic delivery of kynurenic acid improves the outcomes of heatstroke in rats. METHODS: Anesthetized rats were divided into 2 major groups and given vehicle solution (isotonic saline 0.3 mL/kg rat weight) or kynurenic acid (30-100 mg in 0.3 mL saline/kg) 4 h before the start of thermal experiments. They were exposed to an ambient temperature of 43 degrees C for 68 min to induce heatstroke. Another group of rats were exposed to room temperature (26 degrees C) and used as normothermic controls. Their core temperatures, mean arterial pressures, serum levels of systemic inflammatory response molecules, hypothalamic values of apoptotic cells and neuronal damage scores, and spleen, liver, kidney and lung values of apoptotic cells were determined. RESULTS: The survival time values during heatstroke for vehicle-treated rats were decreased from the control values of 475-485 min to new values of 83-95 min. Treatment with KYNA (30-100 mg/kg, iv) 4 h before the start of heat stress significantly and dose-dependently decreased the survival time to new values of 152-356 min (P<0.05). Vehicle-treated heatstroke rats displayed hypotension, hypothalamic neuronal degeneration and apoptosis, increased serum levels of tumor necrosis factor-alpha (TNF-alpha), intercellular adhesion molecule-1 (ICAM-1), and interleukin-10 (IL-10), and spleen, liver, kidney, and lung apoptosis. KYNA preconditioning protected against hypotension but not hyperthermia and attenuated hypothalamic neuronal degeneration and apoptosis during heatstroke. KYNA preconditioning attenuated spleen, kidney, liver, and lung apoptosis and up regulated serum IL-10 levels but down-regulated serum TNF-alpha and ICAM-1 levels during heatstroke. CONCLUSION: Our results suggest that systemic delivery of kynurenic acid may attenuate multiorgan dysfunction in rats after heatstroke. PMID- 21293469 TI - Alteration of synaptic plasticity in rat dorsal striatum induced by chronic ethanol intake and withdrawal via ERK pathway. AB - AIM: The dorsal striatum has been proposed to contribute to the formation of drug seeking behaviors, leading to excessive and compulsive drug usage, such as addiction. The current study aimed to investigate the involvement of extracellular signal-regulated kinase (ERK) pathway in the modification of striatal synaptic plasticity. METHODS: Ethanol was administered to rats in drinking water at concentration of 6% (v/v) for 30 days. Rats were sacrificed on day 10, 20, or 30 during ethanol intake or on withdrawal day 1, 3, or 7 following 30-d ethanol intake. The striata were removed either for electrophysiological recording or for protein immuno-blot analysis. Extracellular recording technique was used to record population spikes (PS) induced by high-frequency stimulation (HFS) in the dorsolateral striatum (DLS). RESULTS: Corticostriatal long-term depression (LTD) was determined to be dependent upon ERK signaling. Chronic ethanol intake (CEI) attenuated ERK phosphorylation and LTD induction, whereas withdrawal for one day (W1D) potentiated ERK phosphorylation and LTD induction. These results showed that the impact of chronic ethanol intake and withdrawal on corticostriatal synaptic plasticity was associated with ethanol's effect on ERK phosphorylation. In particular, pharmacological inhibition of ERK hyper phosphorylation by U0126 prevented LTD induction in the DLS and attenuated ethanol withdrawal syndrome as well. CONCLUSION: In rat DLS, chronic ethanol intake and withdrawal altered LTD induction via ERK signaling pathway. Ethanol withdrawal syndrome is mediated, at least partly, by ERK hyper-phosphorylation in the DLS. PMID- 21293470 TI - Novel neuroprotectant chiral 3-n-butylphthalide inhibits tandem-pore-domain potassium channel TREK-1. AB - AIM: To study the effects of 3-n-butylphthalide (NBP) on the TREK-1 channel expressed in Chinese hamster ovary (CHO) cells. METHODS: Whole-cell patch-clamp recording was used to record TREK-1 channel currents. The effects of varying doses of l-NBP on TREK-1 currents were also observed. Current-clamp recordings were performed to measure the resting membrane potential in TREK-1-transfected CHO (TREK-1/CHO) and wild-type CHO (Wt/CHO) cells. RESULTS: l-NBP (0.01-10 MUmol/L) showed concentration-dependent inhibition on TREK-1 currents (IC(50)=0.06+/-0.03 MUmol/L), with a maximum current reduction of 70% at a concentration of 10 MUmol/L. l-NBP showed a more potent inhibition on TREK-1 current than d-NBP or dl-NBP. This effect was partially reversed upon washout and was not voltage-dependent. l-NBP 10 MUmol/L elevated the membrane potential in TREK-1/CHO cells from -55.3 mV to -42.9 mV. However, it had no effect on the membrane potential of Wt/CHO cells. CONCLUSION: 1-NBP potently inhibited TREK-1 current and elevated the membrane potential, which may contribute to its neuroprotective activity. PMID- 21293471 TI - High glucose stimulates TNFalpha and MCP-1 expression in rat microglia via ROS and NF-kappaB pathways. AB - AIM: To investigate whether high glucose stimulates the expression of inflammatory cytokines and the possible mechanisms involved. METHODS: ELISA and real-time PCR were used to determine the expression of the inflammatory factors, and a chemiluminescence assay was used to measure the production of reactive oxygen species (ROS). RESULTS: Compared to low glucose (10 mmol/L), treatment with high glucose (35 mmol/L) increased the secretion of tumor necrosis factor (TNF)alpha and monocyte chemotactic protein-1 (MCP-1), but not interleukin (IL) 1beta and IL-6, in a time-dependent manner in primary cultured rat microglia. The mRNA expression of TNFalpha and MCP-1 also increased in response to high glucose. This upregulation was specific to high glucose because it was not observed in the osmotic control. High-glucose treatment stimulated the formation of ROS. Furthermore, treatment with the ROS scavenger NAC significantly reduced the high glucose-induced TNFalpha and MCP-1 secretion. In addition, the nuclear factor kappa B (NF-kappaB) inhibitors MG132 and PDTC completely blocked the high glucose induced TNFalpha and MCP-1 secretion. CONCLUSION: We found that high glucose induces TNFalpha and MCP-1 secretion as well as mRNA expression in rat microglia in vitro, and this effect is mediated by the ROS and NF-kappaB pathways. PMID- 21293472 TI - Role of vascular K(ATP) channels in blood pressure variability after sinoaortic denervation in rats. AB - AIM: To investigate the role of ATP-sensitive potassium (K(ATP)) channels on blood pressure variability (BPV) in sinoaortic denervated (SAD) rats. METHODS: SAD was performed on male Sprague-Dawley rats 4 weeks before the study. mRNA expression of Kir6.1, Kir6.2 and SUR2 in aorta and mesenteric artery was determined using real-time quantitative polymerase chain reaction, and confirmed at the protein level using Western blotting and laser confocal immunofluorescence assays. Concentration-response curves of isolated aortic and mesenteric arterial rings to adenosine and pinacidil were established. Effects of K(ATP) channel openers and blocker on BPV were examined in conscious SAD rats. RESULTS: Aortic SUR2 expression was significantly greater, while Kir6.1 was lower, in SAD rats than in sham-operated controls. In contrast, in the mesenteric artery both SUR2 and Kir6.1 expression were markedly lower in SAD rats than controls. For both arteries, Kir6.2 expression was indistinguishable between sham-operated and SAD rats. These findings were confirmed at the protein level. Responses of the aorta to both adenosine and pinacidil were enhanced after SAD, while the mesenteric response to adenosine was attenuated. Pinacidil, diazoxide, nicorandil, and glibenclamide significantly decreased BPV. CONCLUSION: These findings indicate that expression of vascular K(ATP) channels is altered by chronic SAD. These alterations influence vascular reactivity, and may play a role in the increased BPV in chronic SAD rats. PMID- 21293473 TI - N-benzyl-5-phenyl-1H-pyrazole-3-carboxamide promotes vascular endothelial cell angiogenesis and migration in the absence of serum and FGF-2. AB - AIM: To investigate the effect of N-benzyl-5-phenyl-1H-pyrazole-3-carboxamide (BPC) on angiogenesis in human umbilical vein endothelial cells (HUVECs). METHODS: Capillary-like tube formation on matrigel and cell migration analyses were performed in the absence of serum and fibroblast growth factor (FGF-2). Reactive oxygen species (ROS) were measured using a fluorescent probe, 2', 7'- dichlorodihydrofluorescein (DCHF). The nitric oxide (NO) production of HUVECs was examined using a NO detection kit. Morphological observation under a phase contrast microscope, a viability assay using 3-[4, 5-dimethylthiazol-2-yl]-2, 5 diphenyl-tetrazolium (MTT) and a lactate dehydrogenase (LDH) activity analysis by a detection kit were performed to evaluate the toxicity of BPC on HUVECs in the presence of serum and FGF-2. The level of hypoxia-inducible factor 1alpha (HIF 1alpha) and the release of vascular endothelial growth factor (VEGF) were measured by Western blot and ELISA, respectively. RESULTS: In the absence of serum and FGF-2, cells treated with BPC (5-20 MUmol/L) rapidly aligned with one another and formed tube-like structures within 12 h. In the presence of serum and FGF-2, cells treated with BPC for 24, 48 and 72 h had no changes in morphology, viability or LDH release compared with the control group. Cell migration in the BPC-treated group was significantly increased compared with the control group. During this process, NO production and ROS level were elevated dramatically, and the levels of HIF-1alpha and VEGF were increased dependent on the generation of ROS. CONCLUSION: BPC most effectively promoted angiogenesis and migration in HUVECs in the absence of FGF-2 and serum. PMID- 21293474 TI - Isoproterenol-induced FKBP12.6/12 downregulation is modulated by ETA and ETB receptors and reversed by argirhein, a derivative of rhein. AB - AIM: To investigate which endothelin receptors mediated isoproterenol (ISO) induced downregulation of FKBP12.6/12 in cardiomyocytes and study whether argirhein, a novel compound containing rhein and L-arginine that has anti inflammatory activity, could reverse the downregulation of FKBP12.6/12 induced by ISO. METHODS: Neonatal rat cardiomyocytes were incubated with ISO to downregulate FKBP12.6/12. Then the cells were treated with a selective ET(A) blocker (PD156707) and a ET(B) blocker (IRL1038), a dual ET(A)/ET(B) antagonist (CPU0213), and argirhein, respectively. FKBP12.6/12 expression was assayed by RT PCR, Western blot, and immunocytochemistry. RESULTS: The expression of FKBP12.6 mRNA was reduced by 37.7% (P<0.01) and 28.9% (P<0.05) relative to the control by ISO 1 and 0.1 MUmol/L, respectively, but no response to ISO 0.01 MUmol/L was observed in vitro. FKBP12.6/12 protein expression was reduced by 47.2% (P<0.01) and 37.8% (P<0.05) by ISO 1 and 0.1 MUmol/L, respectively. This decrease was reversed significantly by PD156707, or IRL1038, and CPU0213. CPU0213 was more potent than either PD156707 or IRL-1038. Argirhein 10 MUmol/L blunted the downregulation of FKBP12.6/12 by ISO, as demonstrated by the rising mRNA and protein levels and by the fluorescent density of the ISO-incubated cardiomyocytes. CONCLUSION: In cardiomyocytes, the ISO induced downregulation of FKBP12.6/12 is modulated by both ET(A) and ET(B). A new compound, argirein, reversed the down-regulation of FKBP12.6/12 expression in myocardial cells stimulated with ISO. PMID- 21293475 TI - 17beta-Estradiol inhibition of PPARgamma-induced adipogenesis and adipocyte specific gene expression. AB - AIM: To investigate the molecular interaction of peroxisome proliferator activated receptor gamma (PPARgamma) with 17beta-estradiol (E) in the regulation of adipogenesis. METHODS: Female ovariectomized (OVX) mice and differentiated 3T3 L1 adipocytes were treated with combinations of the PPARgamma agonist troglitazone or E, and the variables and determinants of adipogenesis were measured using in vivo and in vitro approaches. RESULTS: Troglitazone (250 mg.kg( 1).d(-1) for 13 weeks) decreased the size of adipocytes without the change in white adipose tissue (WAT) mass and increased the expression of adipocyte specific genes, such as PPARgamma, adipocyte fatty acid binding protein, and lipoprotein lipase, compared with OVX control mice. E (0.05 mg/pellet, sc implanted) significantly reduced WAT mass, adipocyte size, and adipose marker gene expression. When mice were concomitantly treated with troglitazone and E, E blunted the effects of troglitazone on WAT mass, adipocyte size, and adipose PPARgamma target gene expression. Consistent with the in vivo data, E (10 MUmol/L) treatment inhibited lipid accumulation and the expression of adipocyte specific genes caused by troglitazone (10 MUmol/L) in 3T3-L1 cells. E (10 MUmol/L) also decreased troglitazone-induced PPARgamma reporter activity through both estrogen receptor (ER) alpha and ERbeta. Mechanistic studies indicated that E (0.1 MUmol/L) decreased the DNA binding of PPARgamma induced by troglitazone (1 MUmol/L) and inhibited the recruitment of the PPARgamma coactivator CREB-binding protein. CONCLUSION: These results suggest that in vivo and in vitro treatment of E interferes with the actions of PPARgamma on adipogenesis by down-regulating adipogenesis-related genes, which are mediated through the inhibition of PPARgamma coactivator recruitment. In addition, it is likely that the activities of PPARgamma activators may be enhanced in estrogen-deficient states. PMID- 21293476 TI - The effect of the fibrinolytic enzyme FIIa from Agkistrodon acutus venom on acute pulmonary thromboembolism. AB - AIM: To evaluate the effects of the fibrinolytic enzyme FII(a) from Agkistrodon acutus venom on acute pulmonary thromboembolism (APT) in animal models. METHODS: Both rabbit and dog APT models were used. For the rabbit APT model, the thrombi weight before and after administration was measured. Central venous pressure (CVP) and mean arterial pressure (MAP) were measured before and 15, 30, 60, and 120 min after the injection of the blood clot. Partial thromboplastin time (APTT), prothrombin time (PT), platelet count, and fibrinogen concentration were measured using auto analyzers. Plasminogen activity was measured based on chromogenic substrates. In the dog APT model, pulmonary blood flow was recorded using pulmonary angiography. RESULTS: Intravenous administration of FIIa (0.1-5.0 mg/kg) improved the APT-induced hemodynamic derangements and reduced thrombi weight. The angiography evidence also showed that the pulmonary emboli had almost disappeared after FII(a) infusion. FII(a) (0.1, 0.5, or 1.0 mg/kg) did not impair the coagulation pathways, although very high doses of FII(a) (5.0 mg/kg) could stimulate the production of plasminogen and result in impairment of the pathways. CONCLUSION: FII(a) could effectively protect against APT via degradation of thrombi with less activation of plasminogen, and may provide a novel fibrinolytic enzyme for targeting the main pathological processes of the disease. PMID- 21293477 TI - Over-expression of aldehyde dehydrogenase-2 protects against H2O2-induced oxidative damage and apoptosis in peripheral blood mononuclear cells. AB - AIM: To construct an eukaryotic expression vector containing the aldehyde dehydrogenase-2 (ALDH2) gene, and determine whether transfection with the ALDH2 gene can provide protection against hydrogen peroxide-induced oxidative damage, as well as attenuate apoptosis or cell death in human peripheral blood mononuclear cells (PBMCs). METHODS: The ALDH2 gene was cloned from human hepatocytes by RT-PCR. The eukaryotic expression vector containing the gene was constructed and then transfected into PBMCs via liposomes. RT-PCR, indirect immunofluorescence assay, and Western blot were used to evaluate the expression of the transgene in target cells. MTT assay and flow cytometry were used to detect the effects of ALDH2 on PBMCs damaged by hydrogen peroxide (H2O2). The level of intracellular reactive oxygen species (ROS) was determined by fluorescence spectrophotometry. RESULTS: The eukaryotic expression vector pcDNA3.1/myc-His-ALDH2 was successfully constructed and transfected into PBMCs. RT-PCR results showed higher mRNA expression of ALDH2 in the gene-transfected group than in the two control groups (empty vector-transfected group and negative control). Indirect immunofluorescence assay and Western blot indicated distinct higher protein expression of ALDH2 in the gene-transfected group. The cell survival rate against H2O2-induced oxidative damage was higher in the ALDH2 gene transfected group. Moreover, apoptosis rates in gene-transfected PBMCs incubated with 50 and 75 MUmol/L H2O2 decreased by 7% and 6%, respectively. The generation of intracellular ROS was also markedly downregulated. CONCLUSION: ALDH2 gene transfection can protect PBMCs against H2O2-induced damage and attenuate apoptosis, accompanied with a downregulation of intracellular ROS. ALDH2 functions as a protector against oxidative stress. PMID- 21293478 TI - Over-expression of Gadd45a enhances radiotherapy efficacy in human Tca8113 cell line. AB - AIM: To investigate the effect of the growth arrest- and DNA damage-inducible Gadd45a gene on the radiosensitivity of human tongue squamous cell carcinoma cell line to ionizing radiation (IR). METHODS: Short interfering ribonucleic acid (si RNA) targeting Gadd45a or an irrelevant mRNA (nonsense si-RNA) was chemically synthesized. The constructed si-RNAs were transfected into Tca8113 cells and Gadd45a expression was determined using quantitative real-time PCR and Western blot. After 24-h exposure to IR at a dose rate of 4 Gy/min, apoptosis of Tca8113 cells was detected using flow cytometry, and radiosensitivity was measured using MTT assays. RESULTS: IR apparently increased the expression of Gadd45a at mRNA and protein levels in Tca8113 cells. The effect was efficiently inhibited by transfection with Gadd45a si-RNA (P<0.01). Furthermore, silencing Gadd45a gene significantly increased cell viability and decreased the percentage of apoptotic cells during irradiation, which indicated that IR-induced Gadd45a over-expression could increase the radiosensitivity of Tca8113 cells. CONCLUSION: These results indicated that targeting Gadd45a may have important therapeutic implications in sensitizing Tca8113 cells to IR. PMID- 21293479 TI - Genome-wide analysis of microRNA and mRNA expression signatures in hydroxycamptothecin-resistant gastric cancer cells. AB - AIM: To investigate the involvement of microRNAs (miRNAs) in intrinsic drug resistance to hydroxycamptothecin (HCPT) of six gastric cancer cell lines (BGC 823, SGC-7901, MGC-803, HGC-27, NCI-N87, and AGS). METHODS: A sulforhodamine B (SRB) assay was used to analyze the sensitivity to HCPT of six gastric cancer cell lines. The miRNA and mRNA expression signatures in HCPT-resistant cell lines were then identified using DNA microarrays. Gene ontology and pathway analysis was conducted using GenMAPP2. A combined analysis was used to explore the relationship between the miRNAs and mRNAs. RESULTS: The sensitivity to HCPT was significantly different among the six cell lines. In the HCPT-resistant gastric cancer cells, the levels of 25 miRNAs were deregulated, including miR-196a, miR 200 family, miR-338, miR-126, miR-31, miR-98, let-7g, and miR-7. Their target genes were related to cancer development, progression and chemosensitivity. Moreover, 307 genes were differentially expressed in HCPT-resistant cell lines, including apoptosis-related genes (BAX, TIAL1), cell division-related genes (MCM2), cell adhesion- or migration-related genes (TIMP2, VSNL1) and checkpoint genes (RAD1). The combined analysis revealed 78 relation pairs between the miRNAs and mRNAs. CONCLUSION: Hierarchical clustering showed that the miRNA and mRNA signatures in our results were informative for discriminating cell lines with different sensitivities to HCPT. However, there was slightly lower correlation between the expression patterns of the miRNA and those of the predicted target transcripts. PMID- 21293481 TI - Ethics, healthcare and spinal cord injury: research, practice and finance. PMID- 21293480 TI - GC-TOF/MS-based metabolomic profiling of estrogen deficiency-induced obesity in ovariectomized rats. AB - AIM: To explore the alteration of endogenous metabolites and identify potential biomarkers using metabolomic profiling with gas chromatography coupled a time-of flight mass analyzer (GC/TOF-MS) in a rat model of estrogen-deficiency-induced obesity. METHODS: Twelve female Sprague-Dawley rats six month of age were either sham-operated or ovariectomized (OVX). Rat blood was collected, and serum was analyzed for biomarkers using standard colorimetric methods with commercial assay kits and a metabolomic approach with GC/TOF-MS. The data were analyzed using multivariate statistical techniques. RESULTS: A high body weight and body mass index inversely correlated with serum estradiol (E2) in the OVX rats compared to the sham rats. Estrogen deficiency also significantly increased serum total cholesterol, triglycerides, and low-density lipoprotein cholesterol. Utilizing GC/TOF-MS-based metabolomic analysis and the partial least-squares discriminant analysis, the OVX samples were discriminated from the shams. Elevated levels of cholesterol, glycerol, glucose, arachidonic acid, glutamic acid, glycine, and cystine and reduced alanine levels were observed. Serum glucose metabolism, energy metabolism, lipid metabolism, and amino acid metabolism were involved in estrogen-deficiency-induced obesity in OVX rats. CONCLUSION: The series of potential biomarkers identified in the present study provided fingerprints of rat metabolomic changes during obesity and an overview of multiple metabolic pathways during the progression of obesity involving glucose metabolism, lipid metabolism, and amino acid metabolism. PMID- 21293483 TI - Nanomechanics: Terahertz radiation gets shaken up. PMID- 21293484 TI - Surface properties: Immune attack on nanoparticles. PMID- 21293485 TI - Gold nanoparticles: Grown in a crystal. PMID- 21293486 TI - Scanning probe microscopy: Taking a closer look at conductivity. PMID- 21293487 TI - Sorafenib induces cell death in chronic lymphocytic leukemia by translational downregulation of Mcl-1. AB - Chronic lymphocytic leukemia (CLL) has a high prevalence in western countries and remains incurable to date. Here, we provide evidence that the multikinase inhibitor sorafenib induces apoptosis in primary CLL cells. This strong pro apoptotic effect is not restricted to any subgroup of patients, based on Binet stage and the expression of ZAP70 or CD38. Mechanistically, sorafenib-induced cell death is preceded by a rapid downregulation of Mcl-1 through the inhibition of protein translation. Subsequently, the cell intrinsic apoptotic pathway is activated, indicated by destabilization of the mitochondrial membrane potential and activation of caspase-3 and -9. In contrast to sorafenib, the monoclonal vascular epidermal growth factor (VEGF)-antibody bevacizumab failed to induce apoptosis in CLL cells, suggesting that sorafenib induces cell death irrespectively of VEGF signalling. Notably, although sorafenib inhibits phosphorylation of the Scr-kinase Lck, knock-down of Lck did not induce apoptosis in CLL cells. Of note, the pro-apoptotic effect of sorafenib is not restricted to cell-cycle arrested cells, but is also maintained in proliferating CLL cells. In addition, we provide evidence that sorafenib can overcome drug resistance in CLL cells protected by microenvironmental signals from stromal cells. Conclusively, sorafenib is highly active in CLL and may compose a new therapeutic option for patients who relapse after immunochemotherapy. PMID- 21293488 TI - Optimizing the use of lenalidomide in relapsed or refractory multiple myeloma: consensus statement. AB - An expert panel convened to reach a consensus regarding the optimal use of lenalidomide in combination with dexamethasone (Len/Dex) in patients with relapsed or refractory multiple myeloma (RRMM). On the basis of the available evidence, the panel agreed that Len/Dex is a valid and effective treatment option for most patients with RRMM. As with other therapies, using Len/Dex at first relapse is more effective regarding response rate and durability than using it after multiple salvage therapies. Len/Dex may be beneficial regardless of patient age, disease stage and renal function, although the starting dose of lenalidomide should be adjusted for renal impairment and cytopenias. Long-term treatment until there is evidence of disease progression may be recommended at the best-tolerated doses of both lenalidomide and dexamethasone. Recommendations regarding the prevention and management of adverse events, particularly venous thromboembolism and myelosuppression, were provided on the basis of the available evidence and practical experience of panel members. Ongoing trials will provide more insight into the effects of continuous lenalidomide-based therapy in myeloma. PMID- 21293489 TI - 5'-azacitidine in myelodysplastic syndromes with inversion of chromosome 3. PMID- 21293490 TI - Mediator is a transducer of amyloid-precursor-protein-dependent nuclear signalling. AB - Regulated intramembrane proteolysis of the amyloid precursor-protein (APP) produces both a characterstic amyloid-beta peptide that contributes to neuritic plaque formation and neurodegeneration in Alzheimer disease and a small APP intracellular domain (AICD) that transcriptionally activates genes implicated in Alzheimer disease pathology. Although the biochemical events leading to amyloidogenic APP processing at the cell membrane have been described in detail, comparably little is known about the mechanistic basis of AICD-dependent gene regulation in the nucleus. In this study, we show that the AICD activates transcription by targeting MED12, an RNA polymerase II transcriptional Mediator subunit that is implicated in human cognitive development. The AICD binds to MED12/Mediator in vitro and in vivo. Disruption of the AICD/MED12 interaction inhibits AICD transactivation potential and expression of AICD target genes. Mediator, in a MED12-dependent manner, occupies only AICD-bound promoter DNA, indicating that the AICD recruits Mediator to activate transcription. These results identify the MED12 interface in Mediator as a crucial transducer of AICD transactivation and a potential therapeutic target in Alzheimer disease. PMID- 21293491 TI - Control of AIF-mediated cell death by antagonistic functions of CHIP ubiquitin E3 ligase and USP2 deubiquitinating enzyme. AB - Apoptosis inducing factor (AIF) is a mitochondrial oxidoreductase that scavenges reactive oxygen species under normal conditions. Under certain stresses, such as exposure to N-methyl-N'-nitro-N'-nitrosoguanidine (MNNG), AIF is truncated and released from the mitochondria and translocated into the nucleus, where the truncated AIF (tAIF) induces caspase-independent cell death. However, it is unknown how cells decide to kill themselves or operate ways to survive when they encounter stresses that induce the release of tAIF. Here, we demonstrated that USP2 and CHIP contribute to the control of tAIF stability. USP2 deubiquitinated and stabilized tAIF, thus promoting AIF-mediated cell death. In contrast, CHIP ubiquitinated and destabilized tAIF, thus preventing the cell death. Consistently, CHIP-deficient cells showed an increased sensitivity to MNNG. On the other hand, knockdown of USP2 attenuated MNNG-induced cell death. Moreover, exposure to MNNG caused a dramatic decrease in CHIP level, but not that of USP2, concurrent with cell shrinkage and chromatin condensation. These findings indicate that CHIP and USP2 show antagonistic functions in the control of AIF mediated cell death, and implicate the role of the enzymes as a switch for cells to live or die under stresses that cause tAIF release. PMID- 21293492 TI - Dying for a cause: NETosis, mechanisms behind an antimicrobial cell death modality. AB - Neutrophil extracellular traps (NETs) are chromatin structures loaded with antimicrobial molecules. They can trap and kill various bacterial, fungal and protozoal pathogens, and their release is one of the first lines of defense against pathogens. In vivo, NETs are released during a form of pathogen-induced cell death, which was recently named NETosis. Ex vivo, both dead and viable neutrophils can be stimulated to release NETs composed of either nuclear or mitochondrial chromatin, respectively. In certain pathological conditions, NETs are associated with severe tissue damage or certain auto-immune diseases. This review describes the recent progress made in the identification of the mechanisms involved in NETosis and discusses its interplay with autophagy and apoptosis. PMID- 21293493 TI - Thirty-five year review of a mercury monitoring service for Scottish dental practices. AB - AIMS AND OBJECTIVES: To review a long-standing mercury monitoring service offered to staff in dental practices in Scotland. METHODS: During the first 20 years of the service, dentists and their staff were contacted by letter and invited to participate. Respondents were asked to collect samples of head hair, pubic hair, fingernail and toenail for analysis of mercury. After 1995, head hair samples were collected initially and further samples were only measured if head hair mercury was elevated. RESULTS: At the start of this scheme many staff, including administrative staff, had systemic exposure to mercury (defined as increased mercury in all four samples). Incidents of exposure have decreased over the 35 years and are now very rare. Male staff were found to have higher mercury concentrations than female staff and dentists tended to have higher concentrations than other staff. Staff working in dental practices more than five years old had small but discernable increases in head hair mercury concentration. In recent years the use of reusable capsules such as Dentomats has been associated with a slight but statistically significant increase in head hair mercury concentrations when compared to the use of encapsulated amalgam systems. Staff wearing open-toed footwear had significantly higher toenail mercury concentrations compared to those who wore shoes. CONCLUSIONS: Exposure of staff to mercury in Scottish dental practices is currently now very low. This is probably as a result of increased awareness to the toxicity of mercury and improved methods of preparing amalgam. It may be possible to reduce exposure further, although probably only slightly, by upgrading practices and using encapsulated mercury amalgam. PMID- 21293494 TI - Job satisfaction among dually qualified dental hygienist-therapists in UK primary care: a structural model. AB - OBJECTIVE: To investigate job satisfaction among hygienist-therapists. Increasing numbers of hygienist-therapists work in UK primary dental care teams. Earlier studies suggest a clinical remit/clinical activity mismatch, without investigating any link with job satisfaction. METHODS: A UK-wide survey of dental hygienist-therapists using a random sample of the General Dental Council Register of Dental Care Professionals. Factors associated with job satisfaction (measured by the Warr-Cook-Wall ten-dimension scale) were entered into a series of multiple regression analyses to build up a path model. RESULTS: Analysis was undertaken on 183 respondents (response rate: 60%). Mean score for overall satisfaction was 5.36 (SD 1.28) out of a range of 1-7. Multiple regression analysis confirmed the following direct predictors of overall job satisfaction: satisfaction with colleagues, remuneration, variety of work; rating of hygiene work as rewarding; and not being self-employed (R(2) = 0.69). Satisfaction with variety of work was the strongest predictor, itself strongly predicted by the extent the clinical remit was undertaken. Dentists' recognition of their remit, quality of clinical work and qualifications had a strong indirect effect on overall job satisfaction. CONCLUSIONS: The study suggests both greater use of the therapy skills these individuals possess, and better recognition of their remit, qualifications and quality of work by their dentist colleague, may be linked to higher job satisfaction. The implications for the policy of greater team working in dental primary care are discussed. PMID- 21293495 TI - Outer retinal abnormalities associated with inner retinal pathology in nonglaucomatous and glaucomatous optic neuropathies. AB - Inner and outer retinal morphology were quantified in vivo for 6 nonglaucomatous and 10 glaucomatous optic neuropathy patients. Custom, ultrahigh-resolution imaging modalities were used to evaluate segmented retinal layer thickness in 3D volumes (Fourier-domain optical coherence tomography), cone photoreceptor density (adaptive optics fundus camera), and the length of inner and outer segments of cone photoreceptors (adaptive optics-optical coherence tomography). Quantitative comparisons were made with age-matched controls, or by comparing affected and nonaffected retinal areas defined by changes in visual fields. The integrity of outer retinal layers on optical coherence tomography B-scans and density of cone photoreceptors were correlated with visual field sensitivity at corresponding retinal locations following reductions in inner retinal thickness. The photoreceptor outer segments were shorter and exhibited greater variability in retinal areas associated with visual field losses compared with normal or less affected areas of the same patient's visual field. These results demonstrate that nonglaucomatous and glaucomatous optic neuropathies are associated with outer retinal changes following long-term inner retinal pathology. PMID- 21293496 TI - Presumed tuberculous uveitis: diagnosis, management, and outcome. AB - PURPOSE: To assess the effectiveness of anti-tuberculous treatment in patients with chronic uveitis and either active systemic or latent tuberculosis (TB) in a non-endemic community. METHODS: Retrospective study of patients with chronic uveitis, non-ocular evidence of latent or active TB and no other identified cause of uveitis who underwent a 6-month course of standard anti-tuberculous chemotherapy. Response to treatment was assessed at 6 and 12 months after initiation of treatment. RESULTS: A total of 27 patients were included of whom 59% were female. In all, 19 were Asian, 4 Caucasian, and 4 Black. More than half of patients had a history of contact with another person treated for TB. Inflammation resolved after chemotherapy in 70.3% of patients, 18.5% had a change in the nature of their inflammation and 11.1% had no benefit. CONCLUSIONS: There were no uveitis features characteristic of TB uveitis and a wide range of manifestations was seen ranging from non-granulomatous anterior uveitis to occlusive retinal vasculitis. TB is not endemic in the United Kingdom, therefore consideration of ethnicity, immigration, and history of TB contact remain important to direct investigations. In a patient with uveitis and latent TB, a full 6-month course of anti-tuberculous chemotherapy is recommended although it may not be curative of the uveitis. PMID- 21293497 TI - Expression of tumor necrosis factor-alpha and interleukin-6 in corneal cells after excimer laser ablation in Wistar rats. PMID- 21293498 TI - Comparison of retinal thickness values and segmentation performance of different OCT devices in acute branch retinal vein occlusion. AB - PURPOSE: To compare retinal thickness (RT) measurement and segmentation performance of time domain (TD, Stratus) and spectral domain (SD) optical coherence tomography (OCT) devices (Cirrus, Spectralis) for imaging macular oedema (ME) secondary to branch retinal vein occlusion (BRVO). METHODS: In this study, 20 eyes of 20 consecutive patients with acute BRVO were included. A total of 18 unaffected fellow eyes served as control group. RT measurement was analysed in the five inner fields of the early-treatment diabetic retinopathy grid, and proportional segmentation errors were evaluated. RESULTS: Central millimetre thickness (CMT) showed a mean difference of -64, -74, and -18 MUm (P < 0.001) in the control group and -31 MUm (P=0.107), -92 MUm (P<0.001), and -105 MUm (P=0.016) in the BRVO group, between Stratus and Cirrus, between Stratus and Spectralis, and between Cirrus and Spectralis, respectively. Mean RT showed the highest variability between different devices in the area most intensively affected by BRVO-related ME. In eyes with BRVO, 14.6% of Spectralis, 20% of Stratus, and 36.6% of Cirrus scans demonstrated moderate and severe segmentation errors. CONCLUSION: RT measurement in eyes with BRVO, by TD and SD OCT, is compromised by a significant rate of segmentation errors. Deviations are most pronounced in the areas most severely affected by ME. PMID- 21293499 TI - Force requirements in topical medicine use--the squeezability factor. AB - INTRODUCTION: Patient compliance is essential to ensure efficacious treatment. The ease of topical drop delivery is of paramount importance. At least 50% of patients report difficulty in self-administration of topical ocular medicine. The two most frequently reported causes of difficulty include aiming the bottle and squeezing the bottle. PURPOSE: The aims of this study were to identify (I) the force required to deliver a single drop from a bottle (the squeezability factor), (II) are some bottle designs easier to use than others? (III) Do compliance aids reduce the finger strength required to deliver an eye drop? METHOD: We measured the force required to deliver a single drop from a variety of commonly used ophthalmic preparations. Force was slowly applied at the midpoint along the bottle until a drop fell from the tip. Compliance aids were also tested with this technique. RESULTS: We report a wide variation in the force requirements needed to use topical medicines. Three of the four compliance aids tested increased force requirements but may have had other beneficial effects by altering the grip on the medicine bottle. CONCLUSION: This study highlights the large variability in force required to deliver a single drop using the ophthalmic preparations and compliance aids tested. We feel our results will be of interest and relevant to prescribing physicians and manufactures alike. PMID- 21293502 TI - Clostridium difficile infection in 2010: advances in pathogenesis, diagnosis and management of CDI. AB - Clostridium difficile infection (CDI) publications have advanced in 2010 at a pace paralleling the increased frequency and severity of clinical infection. Both toxins A and B are essential virulence factors, pcr diagnostic testing is rapid, sensitive and specific, and recurrent CDI can be prevented using monoclonal antibodies to toxins A and B. PMID- 21293503 TI - Hepatitis in 2010: the dawn of a new era in HCV therapy. AB - Although several antiviral treatments for HBV infection have recently reached the market, no direct acting antiviral drugs to treat infection with HCV have been licensed in the 20 years since its identification. Excitingly, recent publications herald several small revolutions in antiviral treatment of HCV that have considerable relevance for prospective HCV therapies. PMID- 21293504 TI - Pancreatic cancer in 2010: new insights for early intervention and detection. AB - Pancreatic cancer is usually detected at an advanced stage and responds poorly to treatment. In 2010 new insights were gained into understanding the complex biology of pancreatic cancer. Importantly, these insights offer novel opportunities for early diagnosis and treatment of this disease. PMID- 21293505 TI - GERD in 2010: diagnosis, novel mechanisms of disease and promising agents. AB - The results of various studies from 2010 have underlined the importance of the careful diagnostic assessment of GERD. Recent studies have also provided further evidence of the complex pathogenesis of GERD, and promising agents targeting the underlying factors in the pathogenesis of this condition are in the pipeline, especially for treatment-refractory GERD. PMID- 21293506 TI - IBD in 2010: optimizing treatment and minimizing adverse events. AB - The management of IBD remains a challenge, with the main issue being to combine therapeutic efficiency with minimal side effects and optimal quality of life. Efforts towards achieving this objective continued in 2010-we discuss some of the most relevant publications and their potential impact on daily practice in the future. PMID- 21293507 TI - IBS in 2010: advances in pathophysiology, diagnosis and treatment. AB - IBS is a chronic, fluctuating disorder that continues to be the subject of considerable research. 2010 saw some key advances across all aspects of IBS, including further advances in our understanding of the pathophysiology, diagnosis and treatment of this condition. PMID- 21293508 TI - Optimal therapy for Helicobacter pylori infections. AB - Although Helicobacter pylori infection is both a common and a serious bacterial infection, antimicrobial therapies have rarely been optimized, are prescribed empirically, and provide inferior results compared with antimicrobial therapies for other common infectious diseases. The effectiveness of many of the frequently recommended H. pylori infection treatment regimens has been increasingly compromised by antimicrobial resistance. Regional data on the susceptibility of strains of H. pylori to available antimicrobials are sorely needed. Noninvasive molecular methods are possible to assess clarithromycin susceptibility in isolates obtained from stool specimens. As a general rule, clinicians should prescribe therapeutic regimens that have a >=90% or, preferably, >=95% eradication rate locally. If no available regimen can achieve a >=90% eradication rate, clinicians should use the most effective regimen(s) available locally. Eradication of infection should always be confirmed after treatment in order to provide feedback regarding local effectiveness and an early warning of increasing resistance. In most regions of the world, four-drug treatment regimens, including a PPI plus three antimicrobials (clarithromycin, metronidazole/tinidazole and amoxicillin), or a PPI plus a bismuth plus tetracycline and metronidazole provide the best results. Standard triple therapy (a PPI, amoxicillin and clarithromycin) should now be avoided owing to increasing resistance to this treatment. PMID- 21293509 TI - Stem cells and their implications for colorectal cancer. AB - The colonic crypt is home to several multipotent stem cells. These stem cells reside in a niche at the base of the crypt, which controls their behavior and maintains the stem cell's homeostasis through a variety of signaling pathways and interactions. Several attempts have been made to define markers that can identify colonic stem cells, the most useful of which is Lgr5, a Wnt target gene. Although the crypt base contains several stem cells, each colonic crypt comprises a single clone of cells. Investigators have attempted to reconcile these apparently contradictory observations by conducting research into stem cell division. The propagation of stem-cell-acquired mutations through a crypt results in a monocryptal adenoma that, through crypt fission, develops into a microadenoma. Some early adenomas become polyclonal through an as yet unknown mechanism. The discovery of subpopulations of cancer cells that can initiate tumors when implanted into mice has renewed interest in the existence of cancer stem cells, especially with regard to their implications for the use of chemotherapy. Various potential markers of cancer stem cells have been investigated, particularly CD133, but the cancer stem cell theory still has some limitations. PMID- 21293510 TI - Advancements in the analysis of esophageal pH monitoring in GERD. AB - Ambulatory 24 h esophageal pH monitoring enables quantification of esophageal acid exposure and assessment of the temporal relationship between symptoms and acid reflux events. Analysis of pH monitoring is currently divided into upright and recumbent periods based on the patient's body position. However, in this Review, we demonstrate that physiologic studies have shown that sleep, and not recumbency, has a greater impact on gastroesophageal reflux during night-time. The physiologic studies are further supported by clinical trials demonstrating that gastroesophageal reflux characteristics during the recumbent-awake period are similar to those in the upright rather than the recumbent-asleep period. The introduction of the integrated pH monitoring and actigraphy data analysis program offers better separation of the recumbent-awake and recumbent-asleep periods. The physiologic studies and clinical trials, as well as the availability of a better tool to measure pH during sleep, support a paradigm shift in the analysis of pH monitoring data from body position (upright or recumbent) to state of consciousness (awake or asleep). PMID- 21293512 TI - Photon diffusion in a homogeneous medium bounded externally or internally by an infinitely long circular cylindrical applicator. II. Quantitative examinations of the steady-state theory. AB - This is Part II of the work that examines photon diffusion in a homogenous medium enclosed by a concave circular cylindrical applicator or enclosing a convex circular cylindrical applicator. Part I of this work [J. Opt. Soc. Am. A 27, 648 (2010)] analytically examined the steady-state photon diffusion between a source and a detector for two specific cases: (1) the detector is placed only azimuthally with respect to the source, and (2) the detector is placed only longitudinally with respect to the source, in the infinitely long concave and convex applicator geometries. For the first case, it was predicted that the decay rate of photon fluence would become smaller in the concave geometry and greater in the convex geometry than that in the semi-infinite geometry for the same source-detector distance. For the second case, it was projected that the decay rate of photon fluence would be greater in the concave geometry and smaller in the convex geometry than that in the semi-infinite geometry for the same source detector distance. This Part II of the work quantitatively examines these predictions from Part I through several approaches, including (a) the finite element method, (b) the Monte Carlo simulation, and (c) experimental measurement. Despite that the quantitative examinations have to be conducted for finite cylinder applicators with large length-to-radius ratio to approximate the infinite-length condition modeled in Part I, the results obtained by these quantitative methods for two concave and three convex applicator dimensions validated the qualitative trend predicted by Part I and verified the quantitative accuracy of the analytic treatment of Part I in the diffusion regime of the measurement, at a given set of absorption and reduced scattering coefficients of the medium. PMID- 21293513 TI - Narrow-beam propagation in a two-dimensional scattering medium. AB - The problem of narrow-beam propagation in a medium with highly anisotropic scattering is considered within radiative transfer theory. A novel solution of the radiative transfer equation within small-angle approximation, accounting for the path length spread, is presented. A new stable numerical algorithm for the simulation of a narrow beam is developed and applied to a narrow beam in a two dimensional scattering medium. A truly three-dimensional version of the proposed approach is formulated. PMID- 21293511 TI - NF-kappaB in the liver--linking injury, fibrosis and hepatocellular carcinoma. AB - Hepatic cirrhosis and hepatocellular carcinoma (HCC) are the most common causes of death in patients with chronic liver disease. Chronic liver injury of virtually any etiology triggers inflammatory and wound-healing responses that in the long run promote the development of hepatic fibrosis and HCC. Here, we review the role of the transcription factor nuclear factor-kappaB (NF-kappaB), a master regulator of inflammation and cell death, in the development of hepatocellular injury, liver fibrosis and HCC, with a particular focus on the role of NF-kappaB in different cellular compartments of the liver. We propose that NF-kappaB acts as a central link between hepatic injury, fibrosis and HCC, and that it may represent a target for the prevention or treatment of liver fibrosis and HCC. However, NF-kappaB acts as a two-edged sword and inhibition of NF-kappaB may not only exert beneficial effects but also negatively impact hepatocyte viability, especially when NF-kappaB inhibition is pronounced. Finding appropriate targets or identifying drugs that either exert only a moderate effect on NF-kappaB activity or that can be specifically delivered to nonparenchymal cells will be essential to avoid the increase in liver injury associated with complete NF kappaB blockade in hepatocytes. PMID- 21293514 TI - Eigenfunctions and self-imaging phenomena of the two-dimensional nonseparable linear canonical transform. AB - The two-dimensional (2D) nonseparable linear canonical transform (NSLCT) is a generalization of the fractional Fourier transform (FRFT) and the LCT. It is useful in signal analysis and optics. The eigenfunctions of both the FRFT and the LCT have been derived. In this paper, we extend the previous work and derive the eigenfunctions of the 2D NSLCT. Although the 2D NSLCT is very complicated and has 16 parameters, with the proposed methods, we can successfully find the eigenfunctions of the 2D NSLCT in all cases. Since many optical systems can be represented by the 2D NSLCT, our results are useful for analyzing the self imaging phenomena of optical systems. PMID- 21293515 TI - Image field distribution model of wavefront aberration and models of distortion and field curvature. AB - The distribution model of wavefront aberrations, which takes on a significant role in the designs and alignments of imaging optical systems without vignetting, is newly presented. This model decomposes the complicated distributions into the characteristic components, which clarifies the alignment criteria. For the actual alignments, only small displacements (decentering, tilt, and surface distance) of rotationally symmetric surfaces in the system are assumed. Then, the model, which regards the aberration distributions of the system as the sum of the contributions of each surface, is extended for the system with surface displacements. As a result of the derivation, it is concluded that the aberration distributions in the rotationally nonsymmetric systems can be expressed as the sum of several folds of rotationally symmetric components. In addition, it is presented that, based on this model, suitable distribution models, even of the arbitrary higher order, can be constructed for any aberration coefficients in various optical systems. PMID- 21293516 TI - Two-dimensional point spread matrix of layered metal-dielectric imaging elements. AB - We describe the change of the spatial distribution of the state of polarization occurring during two-dimensional (2D) imaging through a multilayer and in particular through a layered metallic flat lens. Linear or circular polarization of incident light is not preserved due to the difference in the amplitude transfer functions for the TM and TE polarizations. In effect, the transfer function and the point spread function (PSF) that characterize 2D imaging through a multilayer both have a matrix form, and cross-polarization coupling is observed for spatially modulated beams with a linear or circular incident polarization. The PSF in a matrix form is used to characterize the resolution of the superlens for different polarization states. We demonstrate how the 2D PSF may be used to design a simple diffractive nanoelement consisting of two radial slits. The structure assures the separation of nondiffracting radial beams originating from two slits in the mask and exhibits an interesting property of a backward power flow in between the two rings. PMID- 21293517 TI - Analysis of electromagnetic scattering by uniaxial anisotropic bispheres. AB - Based on the generalized multiparticle Mie theory and the Fourier transformation approach, electromagnetic (EM) scattering of two interacting homogeneous uniaxial anisotropic spheres with parallel primary optical axes is investigated. By introducing the Fourier transformation, the EM fields in the uniaxial anisotropic spheres are expanded in terms of the spherical vector wave functions. The interactive scattering coefficients and the expansion coefficients of the internal fields are derived through the continuous boundary conditions on which the interaction of the bispheres is considered. Some selected calculations on the effects of the size parameter, the uniaxial anisotropic absorbing dielectric, and the sphere separation distance are described. The backward radar cross section of two uniaxial anisotropic spheres with a complex permittivity tensor changing with the sphere separation distance is numerically studied. The authors are hopeful that the work in this paper will help provide an effective calibration for further research on the scattering characteristic of an aggregate of anisotropic spheres or other shaped anisotropic particles. PMID- 21293518 TI - Radiative flux from a multiple-point bioluminescent or chemiluminescent source within a cylindrical reactor incident on a planar-circular coaxial detector. I. Arbitrary radiation field. AB - In a quantitative description of bioluminescence (BL) and chemiluminescence (CL) phenomena, it is indispensable to know the total fluxes of radiation emitted by the sources studied. Such knowledge is necessary for determining the quantum yields of the examined BL and CL reactions, for comparing the data measured by different optical radiometers (luminometers), and for expressing the power of the emitted radiation in absolute units, i.e., in watts or as a number of photons per specified time period. This paper presents an integral formula for calculating radiative fluxes incident on a planar-circular detector from a volume multiple point BL or CL source partially or completely filling an open coaxial cylindrical reactor. The formula represents the solution to the basic radiometric equation applied to the point emitters embedded within a homogeneous substrate separated from the detector by a different optical homogeneous isotropic medium. All calculations were performed for a nontransparent cylindrical reactor when the surface reflections were neglected and when optical radiation was incident on the detector through an open end of the cylindrical reactor. No additional restrictions were made with respect to the spatial distribution of the point emitters and angular distribution of the emitted radiations, so that the formula is applicable for arbitrarily distributed and arbitrarily radiating point emitters composing a BL or CL source. PMID- 21293519 TI - Variational estimation of inhomogeneous specular reflectance and illumination from a single view. AB - Estimating the illumination and the reflectance properties of an object surface from a few images is an important but challenging problem. The problem becomes even more challenging if we wish to deal with real-world objects that naturally have spatially inhomogeneous reflectance. In this paper, we derive a novel method for estimating the spatially varying specular reflectance properties of a surface of known geometry as well as the illumination distribution of a scene from a specular-only image, for instance, recovered from two images captured with a polarizer to separate reflection components. Unlike previous work, we do not assume the illumination to be a single point light source. We model specular reflection with a spherical statistical distribution and encode its spatial variation with a radial basis function (RBF) network of their parameter values, which allows us to formulate the simultaneous estimation of spatially varying specular reflectance and illumination as a constrained optimization based on the I-divergence measure. To solve it, we derive a variational algorithm based on the expectation maximization principle. At the same time, we estimate optimal encoding of the specular reflectance properties by learning the number, centers, and widths of the RBF hidden units. We demonstrate the effectiveness of the method on images of synthetic and real-world objects. PMID- 21293520 TI - Radiative flux from a multiple-point bioluminescent or chemiluminescent source within a cylindrical reactor incident on a planar-circular coaxial detector. II. Rotationally symmetric radiation. AB - In the previous paper [J. Opt. Soc. Am. A 28, 126 (2011)], an analytical formula was presented for calculating radiative fluxes from arbitrarily distributed and arbitrarily radiating multiple-point emitters of bioluminescent or chemiluminescent sources within cylindrical reactors, when the radiation from these point emitters propagates through two homogeneous isotropic media and reaches a planar-circular coaxial detector. This formula was based on two assumptions. The first is that radiation passes across a planar boundary interface between the two media. The second is that the surface reflections on the lateral surface and on the reactor base opposite the detector may be neglected. In this paper, the formula obtained previously was simplified for the case of uniformly distributed point emitters of bioluminescent or chemiluminescent sources emitting an identical rotationally symmetric radiation. The simplified formula is suitable for optimizing and calibrating the analyzed reactor-detector system, which is most commonly used to study the bioluminescence emitted by small biological objects and the chemiluminescence from chemical reactions. Representative data were calculated, illustrated graphically, and tabulated. PMID- 21293521 TI - Estimating the usefulness of distorted natural images using an image contour degradation measure. AB - Quality estimators aspire to quantify the perceptual resemblance, but not the usefulness, of a distorted image when compared to a reference natural image. However, humans can successfully accomplish tasks (e.g., object identification) using visibly distorted images that are not necessarily of high quality. A suite of novel subjective experiments reveals that quality does not accurately predict utility (i.e., usefulness). Thus, even accurate quality estimators cannot accurately estimate utility. In the absence of utility estimators, leading quality estimators are assessed as both quality and utility estimators and dismantled to understand those image characteristics that distinguish utility from quality. A newly proposed utility estimator demonstrates that a measure of contour degradation is sufficient to accurately estimate utility and is argued to be compatible with shape-based theories of object perception. PMID- 21293522 TI - Propagation of aberrations through phase-induced amplitude apodization coronagraph. AB - The specification of polishing requirements for the optics in coronagraphs dedicated to exoplanet detection requires careful and accurate optical modeling. Numerical representations of propagated aberrations through the system as well as simulations of the broadband wavefront compensation system using multiple DMs are critical when one devises an error budget for such a class of instruments. In this communication, we introduce an analytical tool that serves this purpose for phase-induced amplitude apodization (PIAA) coronagraphs. We first start by deriving the analytical form of the propagation of a harmonic ripple through a PIAA unit. Using this result, we derive the chromaticity of the field at any plane in the optical train of a telescope equipped with such a coronagraph. Finally, we study the chromatic response of a two-sequential-DM wavefront actuator correcting such a corrugated field and thus quantify the requirements on the manufacturing of PIAA mirrors. PMID- 21293523 TI - Dimensionality of color space in natural images. AB - The color histogram (or color cloud) of a digital image displays the colors present in an image regardless of their spatial location and can be visualized in (R,G,B) coordinates. Therefore, it contains essential information about the structure of colors in natural scenes. The analysis and visual exploration of this structure is difficult. The color cloud being thick, its more dense points are hidden in the clutter. Thus, it is impossible to properly visualize the cloud density. This paper proposes a visualization method that also enables one to validate a general model for color clouds. It argues first by physical arguments that the color cloud must be essentially a two-dimensional (2D) manifold. A color cloud-filtering algorithm is proposed to reveal this 2D structure. A quantitative analysis shows that the reconstructed 2D manifold is strikingly close to the color cloud and only marginally depends on the filtering parameter. Thanks to this algorithm, it is finally possible to visualize the color cloud density as a gray-level function defined on the 2D manifold. PMID- 21293524 TI - Self-similar focusing with generalized devil's lenses. AB - We introduce the generalized devil's lenses (GDLs) as a new family of diffractive kinoform lenses whose structure is based on the generalized Cantor set. The focusing properties of different members of this family are analyzed. It is shown that under plane wave illumination the GDLs give a single main focus surrounded by many subsidiary foci. It is shown that the total number of subsidiary foci is higher than the number of foci corresponding to conventional devil's lenses; however, the self-similar behavior of the axial irradiance is preserved to some extent. PMID- 21293525 TI - Clustering-driven residue filter for profile measurement system. AB - The profile measurement system is widely used in industrial quality control, and phase unwrapping (PU) is a key technique. An algorithm-driven PU is often used to reduce the impact of noise-induced residues to retrieve the most reliable solution. However, measuring speed is lowered due to the searching of optimal integration paths or correcting of phase gradients. From the viewpoint of the rapidity of the system, this paper characterizes the noise-induced residues, and it proposes a clustering-driven residue filter based on a set of directional windows. The proposed procedure makes the wrapped phases included in the filtering window have more similar values, and it groups the correct and noisy phases into individual clusters along the local fringe direction adaptively. It is effective for the tightly packed fringes, and it converts the algorithm-driven PU to the residue-filtering-driven one. This improves the operating speed of the 3D reconstruction significantly. The tests performed on simulated and real projected fringes confirm the validity of our approach. PMID- 21293526 TI - Utilization efficiency of spherical metal nanoparticles that increase light absorption in absorbing media. AB - This paper proposes a novel approach for estimating the utilization efficiency of metal particles to increase light energy absorption by a medium with a nonzero imaginary part of a medium refractive index. This method is implemented for spherical Ag and Au nanoparticles embedded in muscle tissue. Numerical calculations for spheres in absorbing media show that the utilization efficiency of metal particles increases with the decreasing absorbability of the medium. PMID- 21293527 TI - Angle-multiplexed holographic data storage with minimum cross talk noise. AB - The cross talk noise-to-signal ratio (NSR) of an angle-multiplexed holographic data storage system is studied, and we propose a method to determine the optimized multiplexing spacing with which the cross talk noise can be less than the conventional method. In our method, the optimization location at the image plane can be chosen arbitrarily, so the multiplexing of asymmetrical image patterns can be optimized. In particular, we investigate the 90 degrees scheme and the transmission scheme angle multiplexing. For the 90 degrees scheme, a holographic medium with a higher refractive index is recommended for cross talk limited multiplexing. For the transmission scheme, a holographic medium with a lower refractive index is recommended for angular range-limited multiplexing. In addition, for the transmission scheme, a larger angle between the object arm and the reference arm results in less cross talk noise, whereas the highest storage density is achieved at a 45 degrees angle. PMID- 21293528 TI - Derivation of plasmonic resonances in the Fourier modal method with adaptive spatial resolution and matched coordinates. AB - A very stable approach for finding optical resonances is to solve an eigenvalue equation that evolves from the linearization of the inverse scattering matrix. In this paper, we show how to use this approach in the Fourier modal method so that advanced coordinate transformation methods such as adaptive spatial resolution and matched coordinates can be included. Furthermore, we present a way that accelerates the computation of the inverse scattering matrix tremendously and allows the derivation of the resonant field distribution inside the structure efficiently. PMID- 21293529 TI - Wavelength decorrelation of speckle in propagation through a thick diffuser. AB - We present a careful theoretical analysis for the wavelength decorrelation of speckle intensity that occurs when plane-polarized laser illumination is propagated through an optical system consisting of a thick diffuser in cascade with the space-invariant 4F imaging system and a CCD monitoring configuration. Based on Maxwell's equations for propagation into the right half-space, our formulation for a scalar component of the electric field is accurate well inside of the Fresnel zone and in the nonparaxial regime as well. The diffuser is described as an artificial dielectric consisting of tiny dielectric spheres embedded in a host medium and randomly spaced. We model the thick diffusers using a thin multilayer decomposition, and we write computer software describing the output speckle pattern amplitude which results from the propagation of an input plane wave. This model provides a good description for opal milk glass (OMG), and we illustrate the usefulness of this software by two applications. First, for a series of OMG diffusers of varying thickness, we present curves for the wavelength decorrelation of speckle that are found to be in good agreement with earlier experiments by George et al.[Appl. Phys. 7, 157 (1975)]. Also, these results are used to compute internal parameters of these diffusers. Second, using these values, we present some first-order statistics of the intensity for this diffuser series and show that they are in accord with the published literature. PMID- 21293530 TI - Physical optics theory for the diffraction of waves by impedance surfaces. AB - The solution of the scattering problem of waves by a half-screen with equal face impedances, which was introduced by Malyughinetz, is transformed into a physical optics integral by using the inverse edge point method. The obtained integral is applied to the diffraction problem of plane waves by an impedance truncated circular cylinder and the scattered waves are derived asymptotically. The results are examined numerically. PMID- 21293531 TI - Fitting-determined formulation of effective medium approximation for 3D trench structures in model-based infrared reflectrometry. AB - The success of the model-based infrared reflectrometry (MBIR) technique relies heavily on accurate modeling and fast calculation of the infrared metrology process, which continues to be a challenge, especially for three-dimensional (3D) trench structures. In this paper, we present a simplified formulation for effective medium approximation (EMA), determined by a fitting-based method for the modeling of 3D trench structures. Intensive investigations have been performed with an emphasis on the generality of the fitting-determined (FD)-EMA formulation in terms of trench depth, trench pitch, and incidence angle so that its application is not limited to a particular configuration. Simulations conducted on a taper trench structure have further verified the proposed FD-EMA and demonstrated that the MBIR metrology with the FD-EMA-based model achieves an accuracy one order higher than that of the conventional zeroth-order EMA-based model. PMID- 21293532 TI - Trapping and releasing light by mechanical implementation in metamaterial waveguides. AB - We show that light trapping and releasing can be switched by a mechanic tuning effect in metamaterial waveguides. The transition mechanism between the trapping and releasing states relies on the synergetic effect of the local Bragg reflection and cavity resonance in the waveguides. As a proof-of-concept demonstration, a heterostructured metamaterial waveguide comprised of dielectric claddings and a tapered metamaterial core formed by arrays of metal slats is analytically and numerically investigated. The spatial separation of the trapped light with various frequencies and the transition between the trapping and releasing states can be predicted by a "rainbow equation." The proposed light trapping and releasing scheme based on the mechanical implementation of waveguide geometrical parameters can be exploited to develop opto-mechanical devices for slow light technology. PMID- 21293533 TI - Refractive-index distributions generating as light rays a given family of curves lying on a surface. AB - In the framework of geometrical optics, we consider the inverse problem consisting in obtaining refractive-index distributions n=n(u,v) of a two dimensional transparent inhomogeneous isotropic medium from a known family f(u,v)=c of monochromatic light rays, lying on a given regular surface. Using some basic concepts of differential geometry, we establish a first-order linear partial differential equation relating the assigned family of light rays with all possible refractive-index profiles compatible with this family. In particular, we study the refractive-index distribution producing, as light rays, a given family of geodesic lines on some remarkable surfaces. We give appropriate examples to explain the theory. PMID- 21293534 TI - Reflection, refraction, and the Legendre transform. AB - We construct in dimension two a mirror that reflects collimated rays into a set of directions that amplify the image and an optical lens so that collimated rays are refracted into a set of directions with a prescribed magnification factor. The profiles of these optical surfaces are given by explicit formulas involving the Legendre transformation. PMID- 21293538 TI - Lapatinib in breast cancer - the predictive significance of HER1 (EGFR), HER2, PTEN and PIK3CA genes and lapatinib plasma level assessment. AB - BACKGROUND: Breast cancer treatment trends are currently based on tailored therapies using tumor and patient biomarkers. Lapatinib is the first dual inhibitor of HER1 (EGFR, ErbB1) and HER2 (ErbB2, Neu) tyrosine kinases to be used in clinical practice. However, only HER2 is currently used for therapy indications and new predictors for the treatment with lapatinib are sought. METHODS AND RESULTS: This minireview focuses on lapatinib and its role in breast cancer treatment. Preclinical and clinical studies as well as pharmacological characteristics are briefly reviewed while the focus is on efficacy assessment including predictive factors for therapy outcome. CONCLUSION: Lapatinib (Tykerb/Tyverb) was Food and Drug Administration (FDA) approved in 2007 for use in combination with capecitabine for the treatment of HER2-positive advanced or metastatic breast cancer in patients who had received previous treatment (including anthracycline, taxane and trastuzumab containing regimens) and in 2010 for use in combination with letrozole for postmenopausal women with hormonal receptor positive and HER2- positive metastatic breast cancer. In contrast to trastuzumab (Herceptin), lapatinib is orally administered and it targets both HER2 and HER1 receptors. As a synthetic and oral tyrosine kinase inhibitor (TKI), it is convenient, cheaper and easier to produce than monoclonal antibodies. The recommended dosage is not dependent on body weight either. Lapatinib plasma level measurement could be an approach to tailored therapy for further optimizing the dose and prolonging this efficient therapy. New lapatinib response predictors are being evaluated. At this time, only HER2 amplification/overexpression is used to choose lapatinib therapy candidates. Further studies on concurrent HER1 fluorescent in situ hybridization (FISH)/immunohistochemistry (IHC) assessment and/or microarray analyses may produce new data on the predictive role of the HER1 (EGFR) gene/protein. PTEN loss and PIK3CA gene mutations are other markers that may predict lapatinib poor response. PMID- 21293539 TI - Genetic methods for detection of antibiotic resistance: focus on extended spectrum beta-lactamases. AB - BACKGROUND: In 1928, the first antibiotic, penicillin, was discovered. That was the beginning of a great era in the development and prescription of antibiotics. However, the introduction of these antimicrobial agents into clinical practice was accompanied by the problem of antibiotic resistance. Currently, bacterial resistance to antibiotics poses a major problem in both hospital and community settings throughout the world. METHODS AND RESULTS: This review provides examples of modern genetic methods and their practical application in the field of extended-spectrum beta-lactamase detection. Since extended-spectrum beta lactamases are the main mechanism of Gram-negative bacterial resistance to oxyimino-cephalosporins, rapid and accurate detection is requested in common clinical practice. CONCLUSIONS: Currently, the detection of extended-spectrum beta-lactamases is primarily based on the determination of bacterial phenotypes rather than genotypes. This is because therapeutic decisions are based on assessing the susceptibility rather than presence of resistance genes. One of the main disadvantages of genetic methods is high costs, including those of laboratory equipment. On the other hand, if these modern methods are introduced into diagnostics, they often help in rapid and accurate detection of certain microorganisms or their resistance and pathogenic determinants. PMID- 21293540 TI - Calcineurin inhibitor-induced renal allograft nephrotoxicity. AB - BACKGROUND: The introduction of the calcineurin inhibitors (CI) cyclosporine and tacrolimus into immunosuppressive protocols initiated a new era in organ transplantation with excellent short-term graft survival. Nevertheless, the chronic nephrotoxicity of these drugs represents a significant adverse factor limiting their long-term use. Patients treated with a CI can be at risk for developing renal failure and this problem is especially pronounced in patients after renal transplantation. METHODS AND RESULTS: In a review paper we summarize the clinical aspects, histological manifestations and pitfalls of diagnostics of acute and chronic CI nephrotoxicity in patients after kidney transplantation. We look in detail at the disputed relationship between blood concentrations of cyclosporine and tacrolimus and histological manifestation of toxicity and summarize data showing that for toxic effects, local renal exposure to CI and their metabolites can play a more significant role than systemic exposure. We also include recent views on the pathophysiologic and molecular mechanisms underlying these changes; factors influencing local susceptibility to CI nephrotoxicity are discussed, including variability of expression and activity of P-glycoprotein and cytochrome P450. Last but not least we summarize our own experience with clinically manifest and subclinical forms of nephrotoxicity and their impact on the progression of chronic graft changes. CONCLUSIONS: Owing to their unique effects, CI remain the cornerstone of most immunosuppressive protocols for renal transplantation. Together with optimization of local kidney exposure to CI and their metabolites, efforts to reduce systemic levels as much as possible are the most important preventive measure for reducing toxic renal graft damage. PMID- 21293541 TI - Psychological aspects and psychotherapy of inflammatory bowel diseases and irritable bowel syndrome in children. AB - BACKGROUND: Despite holistic approach to psychosomatic medicine, gastroenterological disorders (GI) tend to be categorized broadly into "functional" and "organic". Major GI illnesses are Inflammatory bowel diseases (IBD) include ulcerative colitis and Crohn's disease. Both are chronic, with remissions and relapses over the years while irritable bowel syndrome (IBS) is a common, often disabling functional gastrointestinal disorder. METHODS: A literature review was performed using the National Library of Medicine PubMed database, including all resources within the period 1991-2008, additional references were found through bibliography reviews of relevant articles. RESULTS: Psychological problems: Higher scores of neuroticism, depression, inhibition, and emotional instability, are typical for many patients with chronic diseases and nonspecific for chronic gastroenterological disorders. Patients with chronic gastrointestinal disorders have impaired health-related quality. Psychological treatments: There have been few adequate psychological treatment trials in IBD. These achieved lower demands for health care rather than a reduction of anxiety or depression. Psychotherapy with chronic gastrointestinal disorders could lead to improve the course of the disease, changing psychological factors such as depression and dysfunctional coping and improving the patient's quality of life. CONCLUSIONS: There seem to be "risk patients" in whom psychosocial components have a bigger influence on the course of disease than in other patients; and those would probably benefit from psychotherapeutic treatment. Psychological treatments help patients manage the psychological distress which worsens bowel symptoms and quality of life. PMID- 21293542 TI - High glucose increases susceptibility to oxidative-stress-induced apoptosis and DNA damage in K-562 cells. AB - AIM: The study was carried out to evaluate the effect of several substrates on oxidative stress induced apoptosis and in K-562 cells. METHODS: Glucose at 5, 11 and 30 mM concentrations was tested, as well as 5 mM glutamine and 5 mM fructose. The cells were exposed to tert-butylhydroperoxide (tBH) and apoptotic cells were evaluated by flow cytometry with FITC-Annexin V and propidium iodide. The effect of glucose concentration on DNA damage was evaluated using hydrogen peroxide and electrophoretic "DNA comets" assay at 5 mM and 30 mM glucose concentrations. RESULTS: The exposure of cells to tBH resulted in increased number of apoptotic cells, and this effect was prevented by administration of an antioxidant - N Acetyl cysteine. Rising concentrations of glucose added to the toxic effect of tBH; we also observed some toxic effect of fructose and no effect of glutamine. We found higher susceptibility to hydrogen peroxide induced DNA damage with 30 mM glucose concentration. CONCLUSION: Hyperglycemia increases the cell's susceptibility to oxidative stress and it also amplifies oxidative DNA damage. Glutamine - when used as a sole energetic substrate - showed no protective effect against oxidative stress. PMID- 21293543 TI - Identification of CD133+/nestin+ putative cancer stem cells in non-small cell lung cancer. AB - AIMS: No effective treatment for lung cancer exists currently. One reason for this, is the development of drug resistance, assumed to be associated with cancer stem cell (CSCs) emergence within the tumour. This pilot study aimed to identify CSCs in 121 non-small cell lung cancer (NSCLC) patient samples via detection of the expression of stem cell markers - CD133 and nestin. MATERIAL AND METHODS: Archived paraffin blocks of 121 patient samples were prepared as Tissue Microarrays (TMA). Indirect immunohistochemical staining was used to determine the level of expression of CD133 and nestin. Double immunofluorescence staining was used to investigate the co-expression of these two markers. To determine the correlation between expression of nestin and CD133 with the length of asymptomatic period and overall patient survival we used the Kaplan-Meyer analysis. RESULTS: CD133 expression was detected in 22 (19%), nestin in the epithelium in 74 (66%) and vasculature in 78 (70%) of patients. Co-expression of these two markers was found in 21 (17%) patients in less than 1% of positive cells without impact on disease free or overall survival. CONCLUSIONS: We identified CD133(+)/nestin(+) cells as novel potential markers of lung cancer CSCs. PMID- 21293544 TI - Influence of allergy on the immunomodulatory and clinical effects of long-term low-dose macrolide treatment of nasal polyposis. AB - AIMS: Cytokine levels in nasal secretions reflect the inflammatory status of the nasal and paranasal sinus mucosa and the development of mucosal disease. The results of previous investigations suggest that macrolide antibiotics can be effective in treatment of chronic rhinosinusitis and nasal polyposis. The aim of this prospective study was to compare the immunomodulatory and clinical effects of long-term low-dose macrolide treatment of nonatopic and atopic patients with nasal polyposis. METHODS: Forty (n = 40) patients with nasal polyposis, 22 allergic and 18 nonallergic were administered clarithromycin (CAM) 500 mg/day single oral dose for eight weeks. We measured the levels of proinflammatory Th1 cytokines TNF-alpha and IL-1beta, Th2 cytokines IL-4, IL-5 and IL-6, and chemokine IL-8 in the nasal fluid samples, before and after treatment, using flow cytometric method. We also scored each of the 40 patients before and after therapy according to nasal symptom score and endoscopic score. RESULTS: Following treatment, we found significantly reduced levels of IL-8 (p<0.01) and TNF-alpha (p<0.01) in nasal secretions in nonallergic patients. In subjects with nasal polyposis and allergy, we found decreased levels of IL-8 (p<0.01), IL-6 (p<0.05) and IL-1beta (p<0.01). Macrolide therapy decreased the size of polyps in 45.45% of nonatopic and in 50% of atopic patients. After macrolide treatment, we found 67.83% patients in nonallergic group and 55.55% patients in allergic group with improved nasal symptoms. CONCLUSIONS: Long-term low-dose treatment with CAM was effective in the management of nasal polyposis. Our results showed that macrolide treatment of nasal polyposis have different immunomodulatory and similar clinical effects in allergic and nonallergic patients. PMID- 21293545 TI - Management of two cases of desquamative gingivitis with clobetasol and Calendula officinalis gel. AB - BACKGROUND: The purpose of this paper is to describe two cases of desquamative gingivitis (DG) that were treated with a topic gel containing clobetasol propionate and Calendula officinalis L in an acetate tray over two years. METHODS: Two patients with a diagnosis of lichen planus presenting as DG who had undergone previous treatments for this condition with no significant results, were treated by a handling gel containing clobetasol, nystatin, Calendula officinalis L and pectin in custom trays. RESULTS: Both patients had remission of symptoms while using the trays and after they stopped the treatment, the symptomatic outbreaks were delayed and presented as less severe symptoms in the two years follow-up. The treatment is aimed primarily at reducing the length and severity of symptomatic outbreaks desquamative gingivitis. CONCLUSION: This handling gel using a tray may be an efficacious treatment of desquamative gingivitis. PMID- 21293546 TI - Mallampati test as a predictor of laryngoscopic view. AB - AIM: To determine the accuracy of the modified Mallampati test for predicting difficult tracheal intubation. DESIGN: A cross-sectional, clinical, observational, non-blinded study. A quality analysis of anesthetic care. SETTING: Operating theatres and department of anesthesiology in a university hospital. MATERIAL AND METHODS: Following the local ethics committee approval and patients' informed consent to anesthesia, all adult patients (> 18 yrs) presenting for any type of non-emergency surgical procedures under general anesthesia requiring endotracheal intubation were enrolled. Prior to anesthesia, Samsoon and Young's modification of the Mallampati test (modified Mallampati test) was performed. Following induction, the anesthesiologist described the laryngoscopic view using the Cormack-Lehane scale. Classes 3 or 4 of the modified Mallampati test were considered a predictor of difficult intubation. Grades 3 or 4 of the Cormack Lehane classification of the laryngoscopic view were defined as impaired glottic exposure. The sensitivity, specificity, positive and negative predictive value, relative risk, likelihood ratio and accuracy of the modified Mallampati test were calculated on 2x2 contingency tables. RESULTS: Of the total 1,518 patients enrolled, 48 had difficult intubation (3.2%). We failed to detect as many as 35.4% patients in whom glottis exposure during direct laryngoscopy was inadequate (sensitivity 0.646). Compared to the original article by Mallampati, we found lower specificity (0.824 vs. 0.995), lower positive predictive value (0.107 vs. 0.933), higher negative predictive value (0.986 vs. 0.928), lower likelihood ratio (3.68 vs. 91.0) and accuracy (0.819 vs. 0.929). CONCLUSION: When used as a single examination, the modified Mallampati test is of limited value in predicting difficult intubation. PMID- 21293547 TI - Biomechanical testing of spinal segment fixed by thoracolumbar spine locking plate on the swine lumbar spine. AB - BACKGROUND: The aim of the experiment was to compare the mechanical properties of intact spinal segment with impaired intervertebral disc and impaired intervertebral disc fixed by TSLP (Thoracolumbar Spine Locking Plate). METHODS AND RESULTS: Spinal specimens were taken from domestic swine. A total of 8 test mechanical states (intact, impaired and fixed) were modeled and the mechanical properties, expressed by the value of moment of couple necessary to twist the specimen at tensile force F = 200 N and the value of moments necessary for extension straining, were determined. The study was based on in vitro biomechanical testing of the TSLP plate used to stabilize the front thoracolumbar column of spinal segments taken from a pig. The plate was used for monosegmental fixation. The disc was cut by scalpel to simulate the Type A injury to front spinal column. In each state (intact, impaired or fixed), specimens were subjected to a tension load of prescribed force and, then, twisted by a given angle. Subsequently, extension load of intact, impaired and impaired & fixed segment was measured. Statistical evaluation verified the hypothesis of the different behavior of intact, impaired and fixed specimens - both for tension & torsion load and extension load. The analyses did not indicate different mechanical behavior of intact and fixed specimens. In other words, monosegmental fixation of both impaired and intact specimens by TSLP Synthes implant will lead to similar mechanical behavior of these specimens. Further, we found that intact and fixed specimens show non-symmetric behavior at positive and negative twisting angles. This was not observed for impaired specimens. CONCLUSION: Several stabilization systems were developed to stabilize the front thoracolumbar spinal column. Surgery of the anterior column of injured spine should restore the correct position of the spine, ensure decompression of vertebral canal when neural structures are compressed, and stabilize the spine to allow immediate loading and mobilization of the patient. The aim of this study was to compare mechanical properties of intact spinal segment, impaired spinal segment and impaired spinal segment stabilized by TSLP Synthes implant. The problems were solved by experimental modeling using a testing machine that simulated loads for several mechanical states of the spinal segment. Favorable mechanical properties of TSLP Synthes fixator were demonstrated. The experimental results will be used for subsequent computational modeling of the spinal segment in all experimentally solved states. PMID- 21293550 TI - Public relations and the private doctor. PMID- 21293548 TI - Augmentation of antidepressants with bright light therapy in patients with comorbid depression and borderline personality disorder. AB - BACKGROUND: Borderline personality disorder (BPD) is typically characterized by instability and impaired behaviour, affectivity, interpersonal relations and lifestyle. The most common condition comorbid with BPD is a depressive episode. Depression is associated with severe disturbance of the circadian rhythms. This is apparent in depressive patients with BPD. Both sleep and diurnal rhythms are disturbed and the symptoms fluctuate. Bright light may be an effective in treatment of seasonal affective disorder, circadian sleep disorder and jet lag. It also improves sleep-wake patterns and behavioural disorders in hospitalized patients with Alzheimer's disease. Several studies have suggested antidepressant effects of phototherapy in non-seasonal depressive episodes. The treatment of comorbid depressive disorder and borderline personality disorder (BPD) is usually reported to be less successful than the treatment of patients without personality disorder. Studies describing the use of bright light in depressed patients with comorbid BPD have not been published so far. METHOD: The aim of this open study was to assess the effectiveness of a 6-week combined therapy with the application of bright light (10,000 lux, 6:30 to 7:30 a.m. for 6 weeks) added to SSRIs in drug-resistant depressed patients with comorbid BPD who did not respond with improvement to 6-week administration of antidepressants. The study comprised 13 female patients who met the ICD-10 diagnostic criteria for research and the DSM IV-TR diagnostic criteria for major depression. The participants were regularly evaluated using the CGI, HAMD and MADRS scales and the BDI and BDI self-report inventories. RESULTS: According to all the assessment instruments, the application of bright white light leads to a significant improvement. However, the results must be interpreted with caution due to the open nature of the study. PMID- 21293551 TI - [Not Available]. PMID- 21293553 TI - ASA and acetaminophen.. PMID- 21293552 TI - [Not Available]. PMID- 21293554 TI - Babysitters needed.. PMID- 21293555 TI - Abortion.. PMID- 21293556 TI - Medical diary. PMID- 21293557 TI - When is a Head Injury Concussion? AB - The patient with concussion is one who, with or without brief unconsciousness, has recovered to nearly normal in a limited time. Just which patients are apt to do this is a process of exclusion. This article is a mixture of what to look for, what to do and what findings rule out simple concussion. While repeated observation of level of consciousness, airway control and careful assessment of vital signs usually rule out serious injury, we must be on our toes to avoid serious mistakes. PMID- 21293558 TI - The mouth: a window on systemic disease. AB - The oral cavity often presents signs and symptoms of systemic disease-frequently the earliest and perhaps the only signs and symptoms. This article presents a brief description of oral signs and symptoms of some hematologic, metabolic, dermatologic, connective tissue and nutritional diseases, together with a discussion of clinical diagnostic problems. Diagnosis of systemic disease may be facilitated by awareness of the oral presentation of systemic disease. PMID- 21293559 TI - Prophylaxis of migraine. AB - The treatment and prevention of migraine, which affects five to ten percent of the population, depends on recognizing its protean manifestations. Different types-including classic, common, complicated, basilar artery and others-may at times simulate disorders such as epilepsy and transient ischemic attacks. Migraine submerged in a sea of muscle contraction or tension headaches may escape detection and thus treatment. A knowledge of provoking factors may alleviate the need for medication at times. Adequate and appropriate application of drug therapy in a logical sequence can provide considerable success in taming this disorder. Failure to recognize this disorder condemns patients to years of periodic misery. PMID- 21293560 TI - Writing That's Worth Reading: A Practical Guide for Writers of Medical Articles Part 5: Reading Proofs or, Did I Really Write That? PMID- 21293561 TI - How to write a curriculum vitae. PMID- 21293562 TI - A safe doctor-or a good doctor? AB - Both the role and the training of today's primary care physicians have changed, in response to new knowledge, changing patterns of illness, and changes in society. The need now is for physicians with not only physical skills, but also attitudes and communicative abilities. Licensing bodies have been concerned only with safe standards, not optimal standards. This article recommends that licensure be awarded following achievement of certain described educational objectives, not safety alone. PMID- 21293563 TI - Rural medicine: implications for the future. PMID- 21293564 TI - [Not Available]. PMID- 21293565 TI - [Not Available]. PMID- 21293566 TI - Occupational health.. PMID- 21293567 TI - Histoplasmosis.. PMID- 21293568 TI - Metformin monitoring.. PMID- 21293569 TI - Nitrous oxide/oxygen analgesia.. PMID- 21293570 TI - Acid fast bacilli. PMID- 21293572 TI - Comparison of younger and older adolescent females attending birth control clinics. AB - Sexual and contraceptive attitudes and practices were assessed for 486 single females aged 13-20, attending ten birth control centres in Ontario. At last intercourse, 28% were not using any contraception and only 33% reported they had used contraceptives all of the time. Younger adolescents were less likely than older ones to have used effective methods of contraception or to have used contraceptive methods effectively. Younger adolescents expressed greater embarrassment about obtaining oral contraceptives, particularly from the family physician, and were more likely to perceive oral contraceptives as being difficult to obtain. PMID- 21293573 TI - Current status of Beta blocker therapy. AB - Beta-adrenergic blocking agents are an increasingly important class of drugs to the family physician. Diseases such as ischemic heart disease, hypertension and hyperthyroidism have responded dramatically to beta-blocking therapy. This article summarizes some of the current knowledge on the beta-receptor, the indications for beta-receptor blocking therapy, and the properties of the five beta-blocking agents currently available to Canadian physicians. PMID- 21293574 TI - [Not Available]. PMID- 21293575 TI - Patterns of benzodiazepine usage in a family medicine centre. AB - In a one year survey of the use of diazepam, chlordiazepoxide and flurazepam at a university family medicine centre, the per capita prescribing of the three drugs rose with the age of the patients. Diazepam was used approximately four times as frequently as chlordiazepoxide and for four times as many problems, even though it has similar pharmacological properties and a half-life nearly three times that of chlordiazepoxide. The over 65 age group received 36% of prescriptions for diazepam for more than six months, compared to three percent in the under 65 age group. Use of lower doses of shorter acting benzodiazepines in the over 65 age group, for a shorter duration, seems to be more rational than patterns determined in the study. A follow up study to measure the impact of the findings on the physicians' prescribing patterns is planned. PMID- 21293576 TI - Drug compliance and the psychiatric patient. AB - Non-compliance is one of the commonest causes of therapeutic failure in both medicine and psychiatry. With psychiatric patients the factors contributing to non-compliance are related to: illness variables (schizophrenia, mania, paranoia, chronicity), patient variables (inappropriate health beliefs, need to rebel against authority, a wish to remain sick, defective memory), medication variables (inefficient and ineffective regimens, side effects) and patient-therapist variables (degree of supervision, trust and information).Treatment must consist of constant vigilance, health teaching-both verbal and written-enlisting the help of family and community to provide supervision, simplification of drug regimens, frequent examination and vigorous treatment of side effects, and improving the patient-therapist interaction. PMID- 21293577 TI - Cervical intraepithelial neoplasia: new developments in diagnosis and treatment. AB - Cervical dysplasia appears to be a precursor of frank invasive cancer; the same epidemiological factors probably apply in cervical intraepithelial neoplasia. This article describes the tissue at risk and how it can be evaluated, treated and followed up using the colposcope. PMID- 21293579 TI - Family medicine in the 1980s. PMID- 21293578 TI - Smoking cessation experience in sweden. AB - Studies of post-infarct patients and healthy controls in Sweden show that likelihood of stopping smoking is greater in better informed patients, in those who suffer a sudden bout of serious disease, and those who stop smoking completely, rather than cutting down. PMID- 21293580 TI - Writing That's Worth Reading: A Practical Guide for Writers of Medical Articles Part 3: Submission, or, Don't Give Up on What You Give In. PMID- 21293581 TI - Drug induced confusion in the elderly: a report of two cases. AB - Two case histories are presented to illustrate the advent of cerebral dysfunction in elderly people treated with drugs not usually associated with these side effects at the levels prescribed. A brief review of the side effects of these agents is covered. Some suggestion about the need for caution in the use of any medication are made as well as the need to consider toxic effects of medications as an etiological factor in confusion in the aged. PMID- 21293582 TI - "Unfit to work?". PMID- 21293583 TI - [Not Available]. PMID- 21293584 TI - Hall's medicare review.. PMID- 21293585 TI - French in CFP.. PMID- 21293586 TI - Mandrax.. PMID- 21293587 TI - Hall's medicare review.. PMID- 21293588 TI - Hall's medicare review.. PMID- 21293589 TI - Hall's medicare review.. PMID- 21293590 TI - Hall's medicare review.. PMID- 21293591 TI - Hall's medicare review.. PMID- 21293592 TI - Pap smear.. PMID- 21293593 TI - Nature of family practice. PMID- 21293594 TI - The role of the family physician in hospital part 2: use of hospital privileges. AB - A questionnaire on the hospital involvement of family doctors was completed by the active staff members of the Department of Family Medicine at St. Joseph's Hospital, Hamilton, in April, 1977. This paper is the second of four; the first dealt with the study's conception, design and methodology.This paper deals with the reasons why family doctors attend hospital, what they do there, how much time they spend there, and the use of hospital privileges, both attending and procedural. A discussion of the study's implications for general understanding of the family doctor's role, and necessary education for this role, concludes this section.Subsequent sections will give more detailed results of the family doctor's involvement in obstetrics and lastly the attitudes of family doctors toward their hospital environment. PMID- 21293595 TI - Pulmonary histoplasmosis: a review of 50 cases. AB - Histoplasmosis is a systemic fungal infection caused by Histoplasma capsulatum. Infection, identified by skin testing, has been found in more than 50 countries. In Canada the disease is endemic in the St. Lawrence River Valley. Fifty patients with positive reaction to histoplasmin skin tests were reviewed at the Provincial Chest Clinic in Windsor, Ontario. All were asymptomatic; 27 had a history of present or previous involvement in farming or poultry rearing. PMID- 21293596 TI - The family physician in occupational health. AB - Canada's shortage of occupational health physicians is probably best met by family physicians working part-time in industry. The objectives of an occupational health service are stated and the separate components of occupational health practice presented. The skills of the family physician are appropriate to many of these component parts but new skills will also be needed. Some ethical concerns in occupational health practice are discussed. PMID- 21293597 TI - Degenerative arthritis of the lumbar spine in laborers. AB - Low back injuries due to lifting are becoming the single most common cause of industrial disabling injuries and lost work days. Degenerative arthritis of the lumbar spine is a progressive condition afflicting workers in heavy industry at least ten years earlier than average blue collar workers. Of 82 workers who sustained a lifting lumbosacral strain, 23.4% were disabled for one year or more and 81% of patients over 50 years of age were disabled for one year or even permanently. The best therapy is prevention; this can be achieved through a concerted effort by the medical profession, industries and government agencies to help workers move from one category of work to another. PMID- 21293598 TI - Family physicians and geriatrics: practice experience, age and attitudes. AB - A study of 180 family physicians and residents was conducted to identify their experience and attitudes towards the elderly. Older physicians had more patients over 65 than younger physicians. Geriatric patients were found dissatisfying by more residents than family physicians. The most frequently mentioned problems in treating the aged were: communication, inadequate medical education, insufficient time. Residents perceived a need for a geriatrician more often than did family physicians. The data do not support the theory that physician pessimism is related to age or experience. Improved educational experience at all levels of training should prevent therapeutic pessimism. PMID- 21293599 TI - Counselling and the family physician. AB - The effective family doctor is a caring counsellor. The counsellor must have an interest in this type of treatment, a knowledge of behavior in growth and development, self awareness, a proper approach, a plan of management, and above all, a caring attitude.The counselling process consists of active listening, awareness of emotions, search for insight, discussion of possible options and a formulation of understanding of the problems, the goals, and the contract. As the counsellor facilitates the patient's laying out of the problem and possible options, direction often becomes evident. PMID- 21293600 TI - Pointers towards early detection of alcoholism. AB - In a study of 100 male and 100 female urban Canadian alcoholics, the alcoholism had previously gone undiagnosed in 17 of the men and 31 of the women. Physicians appear to expect the typical alcoholic to be a male social derelict, thus missing the diagnosis in patients from upper socioeconomic groups, particularly women. Diagnostic pointers are given in the hope that this very common problem may be detected more readily by physicians. PMID- 21293601 TI - The role of the family physician in providing psychiatric care in the general hospital. AB - The College of Family Physicians of Canada defines a family physician as one who is trained to provide primary, continuing comprehensive medical care to any or all members of the family, using the available ancillary and consulting services to ensure exemplary medical care. Implicit in this statement is access to hospital beds to allow the continuing care process to extend throughout a hospital stay. Unfortunately, not all family physicians have ready access to psychiatric beds, nor are they adequately remunerated for their work in hospitals.This study compares attitudes of Saskatoon family physicians in 1979 to the provision of inpatient psychiatric care by the family physician, to the same study performed in 1962. More family physicians in 1979 showed interest in treating their own patients for any mental illness. PMID- 21293602 TI - Attitudes to infant circumcision. AB - Routine circumcision in Manitoba has decreased from 56% to 50%. To determine adult patients' attitudes towards circumcision, the authors interviewed a random sample of patients presenting at a family practice unit. Of 242 respondents, 78% favored circumcision, primarily because of cleanliness, family precedent and improved sexual function. They suggest better education of patients to dispel misconceptions. PMID- 21293603 TI - Emergency-evacuation! PMID- 21293604 TI - Never say die. AB - This article describes the events following the accidental strangulation of a child. The accident itself was pure misadventure which could not have been prevented by foresight or prudence, its immediate consequences were catastrophic and life-threatening and yet the eventual outcome was good.An important part of the story relates to the transfer of this gravely ill child by ambulance to a university centre. Some of the difficulties encountered can serve as an example to family physicians who may be involved in the management of such problems. PMID- 21293605 TI - Practice opportunities for family medicine graduates. AB - This paper documents the career choices of a graduating class of family medicine residents at Queen's University. In the first post-graduation year, residents were evenly divided between those who undertook a third year of training and those who began practice. For those who began practice, a profile of their first year of experience demonstrates the excellent variety of opportunities awaiting family medicine graduates. PMID- 21293607 TI - [Not Available]. PMID- 21293606 TI - Physical fitness: who needs it? PMID- 21293608 TI - Medical identification card.. PMID- 21293610 TI - Decongestant effect on blood pressure.. PMID- 21293609 TI - Value of controls.. PMID- 21293611 TI - Fort Franklin Shigella outbreak.. PMID- 21293612 TI - Ovoquinol.. PMID- 21293613 TI - Darvon. PMID- 21293614 TI - The Role Of The Family Physician In Hospital Part 4: FPs' Attitudes Towards Their Hospital Role. AB - This fourth and final part of the report of a survey carried out at St. Joseph's Hospital, Hamilton, Ontario, examines the results from that portion of the questionnaire relating to attitudes of the family physicians surveyed. It was found that family doctors have strong ties to the hospital and see an association between the quality of community and hospital care and the maintenance of these hospital ties. Problems in clarifying and consolidating their role in hospital are identified and discussed, together with some implications concerning training programs in family medicine. PMID- 21293615 TI - A study of referrals from a family practice unit. AB - In a study of all referrals originating from an urban family practice unit, a referral rate of 7.5% was found-somewhat higher than that seen in most other studies.In general, through all categories studied, no significant differences were found among three groups of physicians (first and second year residents, staff physicians) with the exception of referrals to allergy. Dermatology and allergy were most commonly referred to. This differed from other practices studied. Not surprisingly, 71.2% of the reasons given for referring a patient included help with diagnosis and/or therapy.In most cases the consultants and referring physicians were pleased with each other's general behavior. However, the referring physicians were seen as deficient in supplying pertinent details of their patients' history, physical and lab data. In almost one third of cases the referring physicians felt that they had learned nothing from the referral.The residents and staff physicians acted very similarly in almost all aspects of the referral process, reflecting positive and negative referral habits. PMID- 21293616 TI - A guide to the prevention of running injuries. AB - In North America, estimates of recreational runners have grown from two million in 1970 to 30 million in 1979. In Canada increased interest in running has been sparked by Participaction. Habituation to running is attributed to a sense of wellbeing and increased energy levels, as well as the possibility of reducing the threat of cardiovascular disease. Musculoskeletal injury is common to runners and can be prevented by carefully planned training programs, proper selection of training surface, regular stretching and strength drills, the use of protective footwear and balancing of vulnerable biomechanical alignments with functional orthotics in shoes. PMID- 21293617 TI - Exercise guidelines for physicians. AB - Fitness may be the latest fad or it may be a positive step towards refocusing on healthy lifestyles. Many individuals, before they jump into new activity, want reassurances from their physicians that they are in sound enough health to do so. The physician can rule out major risk factors, recommend further fitness assessment, and give general guidelines for a well rounded program and safe activity within the limits of the individual's health status. This paper discusses some guidelines that may be followed. PMID- 21293618 TI - A critique: coronary disease and exercise stress tests. AB - The exercise stress test is evaluated in terms of epidemiological criteria including validity, reliability, safety, rapidity, cost, yield, and acceptability. Rigid criteria for the diagnosis of abnormality allow a high specificity and sensitivity. It is one of the safer medical examinations, and can be completed in three to nine minutes. Costs can also be brought to an appropriate level for mass use, but such screening is hampered by a low yield of true positive tests and an unacceptably high proportion of false positive results. The procedure will become much more cost-effective if restricted to high risk individuals, and has demonstrated value in the management of the "post coronary" patient. PMID- 21293619 TI - Treatment of alcoholism in family practice. AB - Treatment goals and treatment methods for alcoholism are discussed with particular emphasis on the role of the family physician in the management of this extremely common problem. The office treatment of alcoholism of moderate severity is discussed, starting with the treatment of alcohol withdrawal, followed by making a treatment contract with the patient in order to help him remain sober, and to fit the patient to the optimal treatment methods on an individual basis. Office treatment methods are then discussed in detail with reference to medication, psychotherapy, and the effective utilization of community services, including Alcoholics Anonymous. The treatment of alcoholism can be a rewarding experience, if sometimes a frustrating one. Assuming each alcoholic affects the lives of at least four others around him, the successful treatment of an alcoholic provides a considerable service to the community. PMID- 21293620 TI - Guidelines for the rape examination. AB - The rape victim presents with legal and psychological problems as well as medical ones. In order to respond to all her needs, the physician must be aware of the legal questions to be answered in the record, the patient's psychological needs in this high stress situation, and the medical problems likely to be encountered. PMID- 21293621 TI - Writing That's Worth Reading: A Practical Guide for Writers of Medical Articles Part 2: Style, or How to Out-Funk Wagnall. PMID- 21293622 TI - Exercise induced acute renal failure in an athlete. AB - After a strenuous indoor competition, a 24 year old male 400 meter runner experienced severe back pain followed by three days of nausea and vomiting. This led to hospital admission with oliguria, serum creatinine of 12.6 mg%, and BUN of 72 mg%. Peritoneal dialysis was given for 96 hours and was discontinued when the diuretic phase developed. Myoglobinuria was suspected, but all tests for it were negative. Mechanisms of acute tubular necrosis are reviewed, noting predisposing factors-dehydration, acidosis, and hypoxia-which were present in this clinical case. Ischemia due to markedly reduced renal blood flow secondary to mass sympathetic discharge, dehydration and metabolic acidosis could cause sufficient tissue damage to trigger acute renal failure in the presence of myoglobinemia. Active fluid replacement in athletic training and competition is stressed as a preventive feature. PMID- 21293623 TI - Family practice residency training in the community: a report on four years' experience. AB - The Department of Family Medicine at the University of Western Ontario has been training family practice residents in community based group practices for four years. The methods used to select and evaluate the residents and their practice experience are outlined in this article. Despite difficulties which arose as a result of geographical distance, the experience was felt to be worthwhile by those who participated. The program has been approved by the Department of Family Medicine for expansion and continuation. PMID- 21293624 TI - The conserver society: prospects for a healthier future. AB - We live in an era of great change, and it is inevitable that the family physician will be caught up in this process. Many alternative futures are open to us; of these, the conserver society is perhaps the most attractive. Having briefly examined some of the major alternative futures for our society, and for medicine within that society, this paper defines the conserver society and describes some of its major health implications. The family physician needs to support and encourage the development of such a society for the sake of health, and should be prepared to accept new roles in community development. PMID- 21293625 TI - [Not Available]. PMID- 21293626 TI - [Not Available]. PMID- 21293627 TI - Syphilis.. PMID- 21293628 TI - Entonox.. PMID- 21293629 TI - Blood pressure testing in children. PMID- 21293630 TI - French in CFP.. PMID- 21293631 TI - The role of the family physician in hospital part 3: obstetrics. AB - This is the third paper in a series of four on the part played by the family physician in a general hospital.Of 88 family physicians on active staff at St.Joseph's Hospital in Hamilton, 56 did deliveries. Most of those practicing obstetrics did most of their own deliveries. As the procedures became more difficult, fewer doctors performed them. Most of the members were involved with routine prenatal care, and some with high risk prenatal care. The resons for not doing obstetrics varied, but obstetrics till seem to be a very important part of the family physician's activity within the hospital. PMID- 21293632 TI - An evaluation of early hospital discharge to home care services. AB - Of 3628 patients admitted to a program of early hospital discharge to home care services in 1977, only 116 required readmission to acute hospital or other facility. A further 13 died at home. Readmission to acute hospital or other facility was due to continuation of disease, complications, new disease, incorrect discharge planning or inability of the family to cope. Only one case could be attributed to insufficient nursing skill or insufficient equipment. The program is considered to be highly successful. PMID- 21293633 TI - Travellers from the tropics-a practical approach to common problems. AB - Increased immigration and travel abroad by Canadians have increased the need for family physicians to know more about tropical and parasitic diseases. This paper provides the practitioner with a practical approach to the following problems seen in travellers from the tropics: eosinophilia, fever, diarrhea, and the passage of worms in the stool.In addition, a discussion of the principles governing the treatment of parasitic infections is included. PMID- 21293634 TI - Rarer infectious diseases. AB - An infectious disease can be considered rare simply because the physician seldom thinks of that diagnosis. This paper describes the clinical features of chancroid, brain abscess, chlamydial pneumonia in infancy, mucocutaneous lymph node system, bronchopulmonary aspergillosis, and Lyme arthritis, in an attempt to widen the physician's diagnostic consideration. PMID- 21293635 TI - Le voyageur tropical et l'omnipraticien. PMID- 21293636 TI - Health problems of vietnamese refugees. AB - With Vietnamese immigrants currently arriving in Canada at the rate of 100 per day, physicians will be receiving an increasing number of them into their practice. The prevalence rates of helminthiasis, enterobacterial infections, tuberculosis, viral hepatitis B and leprosy are significantly higher among Southeast Asians, while the rates of protozoal infections are similar to that of the North American population. More than 90% of Southeast Asians have lactose intolerance. The incidences of reactive depression, psychosomatic complaints and adjustment reactions are also quite frequent among the refugees. A protocol is suggested for initial medical screening. PMID- 21293637 TI - Alopecia: a practical approach to diagnosis and management. AB - Hair loss may not be as serious as cancer or heart disease, but when patients lose one of their most treasured possessions, the psychological trauma can be extremely severe. Although the pathogenesis of alopecia may seem complicated, if one understands the basic physiology and the normal hair growth cycle and learns how to perform a methodical examination and investigation, one can easily diagnose and treat most cases of alopecia seen in family practice. PMID- 21293638 TI - The spouses of your heart attack patients: ways of helping with their emotional response. AB - The family physician must be prepared to deal with the emotional responses of the spouses of heart attack patients. The family physician has much useful prior knowledge of the family and can positively affect the patient's rehabilitation by involving the spouse. Marital partners' overprotectiveness or emotional inhibition can be prevented by the family physician's interventions. Spouses should be actively involved in the rehabilitation program from the outset. The physician should listen for the spouses' feelings and explore their perceptions of the illness. They should be involved through followup. PMID- 21293639 TI - Writing That's Worth Reading: A Practical Guide For Writers Of Medical Articles Part One: How to Love Librarians and Become Immortal. AB - Family practice is an expanding field which is beginning to produce its own literature. In order to make the job of writing an article easier, the author needs a method of organizing material and a checklist of things to remember when submitting the article for publication. This series of articles will cover the process of writing from rough notes to finished product, and will conclude with a description of the review process-what happens to an article after submission. PMID- 21293640 TI - As it happened: recurrent cerebral dysfunction. AB - In his constant effort to keep up to date the family physician has several options; one of them is to learn by experience. This case demonstrates one example of having to learn about a particular disease entity through encountering it in practice. PMID- 21293642 TI - Unions and 'opted-in' physicians. PMID- 21293641 TI - Postgraduate Training In Family Medicine At McMaster University And In West Scotland. AB - The experience of residents in family medicine at McMaster University is compared with that of vocational trainees in the West of Scotland, by means of a time-log diary used for two weeks towards the end of their fulltime attachment in family practice. Trainees in the West of Scotland see far more patients, but have much less supervision than their counterparts at McMaster. The findings are discussed in the context of postgraduate training for family medicine in Canada and the United Kingdom. PMID- 21293643 TI - Ethics in medicine. PMID- 21293645 TI - [Not Available]. PMID- 21293644 TI - [Not Available]. PMID- 21293646 TI - Tonsillopharyngitis. PMID- 21293647 TI - Loaded shopping bag syndrome.. PMID- 21293648 TI - National differences.. PMID- 21293649 TI - Illness episodes and service delivery in the hudson bay and james bay region. AB - In examining patterns of illness episode and service delivery in two native populations, a high frequency of respiratory tract infections and a poor obstetrical history with loss of children were found, particularly among the Inuit patients. The work of nurse practitioners, supported by specialist physicians, appeared to be effective in managing patients in isolated communities. PMID- 21293650 TI - The impaired physician: some coping mechanisms. AB - Doctoring is a stressful way of life. Both normal and neurotic needs can increase the complexity of the family physician's life. Certain vulnerable doctors seek easement in tranquilizers, sedatives or alcohol, and can become addicted. Impairment may be episodic or steady, leading to deterioration in personality and abilityUsually such individuals should, after withdrawing from the addicting substance, leave family practice.To cope with stress, the doctor should organize his work, his appetites for goods and money, his relationships with patients, peers and family. If he finds himself in serious personality difficulties, he should seek professional help. PMID- 21293651 TI - Suicide in doctors and wives of doctors. AB - This paper re-examines the widespread belief that doctors have a proneness for suicide greater than the general population. The Standardized Mortality Ratio for male physicians is 335 and for single women doctors 257. Doctors' wives have an even greater risk: their SMR is 458. These rates for doctors are higher than for most other professional groups (except pharmacists) and the rate for doctors' wives far exceeds that for wives of other professionals. The intrinsic causes of the physician's high occupational mortality include his knowledge of toxicology and ready access to lethal drugs, so that impulsive suicide is more often successful. Professional stress and overwork, particularly the unrelenting responsibility for decisions upon which the lives of others may depend, have been inculpated. These stresses interact with the decline in the doctors' self-respect and with a personality that is prestige-oriented and independent. Some physicians turn in their frustration to alcohol/and or drugs, accelerating the process of deterioration. The high suicide rate in doctors' wives appears to be the result of unrequited needs for caring and dependency which the doctors' career demands and personality deny them. PMID- 21293652 TI - The conspiracy of silence. AB - The issue of the impaired physician is compounded by not only mass denial of the problem, but also a 'conspiracy of silence' among many groups associated with the physician. The conspirators-including the physician himself, his family, community, professional colleagues and nurses as well as hospital boards and administration-are unable to reconcile deteriorating performance due to alcohol or drugs with an otherwise gifted professional who should know the dangers of substance abuse. They may also fear the effects of labels such as 'alcoholism', 'drug abuse' and 'psychiatric illness', and they may not know how to handle the problem.A Saskatchewan Medical Association committee was formed in 1976 to penetrate the shroud of silence by identifying and rehabilitating impaired physicians.However, the committee's experience since that time has been largely frustrating because its function has been viewed as more punitive than therapeutic. PMID- 21293653 TI - Alcohol and drug addicted physicians: the scope of the problem. AB - Alcoholism and drug addiction are occupational hazards in the practice of medicine. Reports from Canada, the U.S. and U.K. show a higher incidence of these problems in physicians than in the general population. This article reviews some characteristics of addicted doctors, including their backgrounds and reasons for starting the habit. The need for treatment to start as soon as the problem is discovered is emphasized. The prognosis for both alcoholism and drug addiction is good if the conditions are diagnosed early and treated vigorously. PMID- 21293654 TI - Physician survival: should the doctor come first? AB - Difficult patients are common in family practice and take a toll of physicians which is out of proportion to the frequency or duration of their visits. Recognizing that the problem is in the physician-patient relationship is the first step in physician survival.This article reviews the roles physicians adopt with patients-"doctor as God", "patient in command" and "on the level". It points out strategies and tactics to use with the problem patient and suggests that putting the physician's wellbeing first results in better patient care. PMID- 21293655 TI - The impaired physician and you. AB - This article deals with the question "What should you do when you suspect that a colleague's ability to practice medicine has become impaired?" The scope of the problem is now known, and the medical profession's response has been to organize provincial committees to help the impaired doctor. Several patterns suggesting impairment are summarized in this article. An affirmative response is needed; suggestions as to how one may respond are outlined. PMID- 21293656 TI - Women's Use of Psychotropic Medication: A Community Survey. AB - As a result of growing evidence of the increased consumption of psychotropic medication among women, a community development project was undertaken by an interagency group. In the spring and summer of 1977, a door-to-door survey was conducted to determine the extent of psychotropic drug use among women 18 years and older in the Borough of Etobicoke, Toronto. Findings revealed that approximately 15% of the women had used such medication in the previous 48 hours and approximately 24% had indicated use at any given time for common ailments such as anxiety and sleeplessness. The use of this type of medication was also found to be related to the women's age, marital status, employment status and health rating. Physicians in the community, social agencies and women's groups are now being urged to recognize the popularity of psychotropes as the panacea for many stressful situations and to give greater consideration to nonchemical solutions to these situations. PMID- 21293657 TI - Writing That's Worth Reading: A Practical Guide for Writers of Medical Articles Part 4: The Review Process or, What Do They Know Anyhow? PMID- 21293659 TI - The family physician and the care of the terminally ill. PMID- 21293658 TI - Anemia, growth failure and hypothyroidism. AB - A 12-year-old Caucasian female presented to her family physician with an old complaint of anemia and a new complaint of failure to grow. The anemia, first observed four years previously, had been diagnosed as iron deficiency, but had never satisfactorily responded to adequate iron therapy. Investigation of the failure to grow resulted in a diagnosis of hypothyroidism with related normochromic normocytic anemia.This case serves to review the rather complicated relationship between hypothyroidism and the three types of anemia. The case report also reminds family physicians of several diagnostic principles: the importance of knowing stages in the evolution of disease; the importance of time and repeated contact with patients; the importance of diagnostic pathways and investigation of symptoms, and after diagnosis is established, the importance of ongoing monitoring of the patient. PMID- 21293661 TI - La certification en medecine familiale/medecine d'urgence. PMID- 21293660 TI - [Not Available]. PMID- 21293662 TI - Investigating anemia.. PMID- 21293663 TI - Running and the runs. PMID- 21293664 TI - Impact of computerization on a small office. AB - Can a computer be viable even in a one doctor office? This article documents one family physician's attempt to answer this question, showing how he investigated the possibilities, what he achieved and what the problems and possibilities were. PMID- 21293665 TI - Taxation of small business corporations. AB - On December 6 1979, new legislation substantially changed the taxation of business income from Canadian-controlled private corporations. The new rules will be of particular interest to corporations providing personal, financial or management services, and to professionals contemplating the use of such corporations. PMID- 21293667 TI - [Not Available]. PMID- 21293666 TI - Opting Out Isn't Easy, Even With a Computer. AB - When a 13 member clinic group decided to opt out of medicare and set up a computerized billing system, they discovered many unforeseen problems. Cost of renting the program was one factor, unpaid accounts were another. The group eventually ended up opting back in to the medicare program. This article describes the experience and what the group learned from it. PMID- 21293669 TI - Writing That's Worth Reading: A Practical Guide For Writers of Medical Articles Part 6: Life After Publication-The Reprint Process. PMID- 21293668 TI - Chronic lead poisoning from industrial exposure: a review. AB - Lead poisoning from chronic industrial exposure is not uncommon. Early diagnosis is important in avoiding irreversible effects.A good occupational history is key to alerting the unsuspecting physician to the correct diagnosis. Blood lead levels are useful but ridden with shortcomings. Specific tests to assess functional impairment, such as urinary aminolevulinic acid (ALA) and coproporphyrins should be included in the diagnostic work-up.Lead poisoning is a preventable disease well worth the consideration of the family practitioner. (Can Fam Physician 1980; 26:1056-1062). PMID- 21293670 TI - Basic library list for family medical centres, 1980. PMID- 21293671 TI - Medical education in a rural health centre. AB - A health centre located in an isolated community on the northeast coast of Newfoundland has taken medical students since 1965. Currently students in their first year, in their clinical clerkship, and in the second year of the family practice residency, visit the centre. Responses from students at all levels have been very positive. To assess if this rotation had an effect on their subsequent choice of practice, questionnaires were sent to the former students three to nine years after their clerkship rotation. Almost all of the students subsequently went into family practice and there was a tendency for them to select small towns. A rotation of this type has real benefits for the supervising physicians and the rural community. It is helping to correct the maldistribution of physicians by specialty and location of practice. It is still viewed by the former students as a very valuable learning experience. PMID- 21293672 TI - The meaning of holistic medicine. PMID- 21293673 TI - [Not Available]. PMID- 21293674 TI - A means of skirting 'galloping crotch rot'. PMID- 21293675 TI - Breast self-examination.. PMID- 21293676 TI - Developmental screening, well baby care in Saskatchewan family practice. AB - A total of 246 Saskatchewan primary care physicians were contacted to identify those in family practice and doing well baby care; 65 urban and 44 rural physicians were surveyed.The urban physicians had similar practice patterns, attitudes and approaches to developmental surveillance, except that Regina physicians saw more patients daily (p<0.005) and 25/29 routinely referred suspected children versus eight of 36 in Saskatoon.All physicians, rural and urban, relied on their "clinical impressions" to detect a developmentally delayed child. No one regularly used a formal developmental screening test. They cited time, cost and questionable value as major barriers. No one identified a regional child's rehabilitation centre as an assessment or management resource.Family physicians, regardless of practice location, should tailor their practices to insure early detection and appropriate referral of the developmentally delayed child, thereby minimizing disability and maximizing the child's potential. PMID- 21293677 TI - Early detection of colorectal cancer: second feasibility study. AB - The second study undertaken to test the feasibility of wide-scale controlled trial of Hemoccult(r) as a useful means of early detection of colorectal cancer is described. Of eight physicians recruited for this study, five completed it; 260 patients were enrolled, and randomized to obtain 152 in the study group and 108 in the control group. Of patients in the study group, 71% complied with the protocol. A third feasibility study will have to be mounted to reassess physician compliance and also to reassess the predicted rate of patient enrollment to the study. PMID- 21293678 TI - Gastroenteritis in children: new concepts and old affirmations. AB - Gastroenteritis is a common pediatric problem in primary care practice. Some etiological agents are viruses. Maintaining an adequate fluid intake is important: in mild cases a five percent oral dextrose solution can usually prevent the development of significant dehydration. In patients with significant fluid loss, an intravenous infusion of hypotonic, dextrose-containing solution should be instituted before recognizable clinical signs of dehydration develop. PMID- 21293679 TI - Children's Perceptions of Health and Disease. AB - One aspect of preventive medicine is public education. Though primary care physicians educate their patients individually, their involvement in the school system has been limited.A study of children's attitudes toward health was undertaken to define a basis upon which a preventive education program could build. It was found that children are curious about the functioning of their bodies, aware of the importance of exercise and nutrition, and adamantly opposed to smoking. An effective education program should combine factual teaching with the "selling" of a healthy lifestyle to reinforce pre-existing interests and attitudes. PMID- 21293680 TI - How many well baby visits? A randomized trial in progress. AB - The objective of this study in progress is to determine whether decreasing the number of well-baby visits during the first two years of life from the currently allowable ten visits to five, can be done with efficacious and safe results. Five hundred babies under the care of their family physicians were randomly assigned to an experimental group receiving five well-baby visits in the first two years of life or to a control group receiving ten visits. This article presents the results pertaining to the collection of the cohort. PMID- 21293681 TI - Management and prophylaxis of seizures in children. AB - The National Child Development Study, U.K., provides a perspective of the types of seizures that might be anticipated in a representative childhood population. Management is considered under the broad headings of general and specific considerations. A classification enables a physician to perform a rapid triage of a child experiencing a seizure. Specific management considerations are outlined for status epilepticus, febrile seizures, and recurrent afebrile seizures, particularly of absence and temporal lobe type. Prophylaxis of post traumatic seizures, and the importance of recognizing the group of childhood disorders mimicking seizures, are also discussed. PMID- 21293682 TI - Infant feeding 1980. AB - Recent reports from the Canadian Pediatric Society's Nutrition Committee(1-5) have re-examined issues concerning the feeding of infants, and recommendations have been presented.In an article reviewing a similar report by the Nutrition Committee of the American Academy of Pediatrics, Woodruff(6) refers to the art of infant feeding and the science of infant nutrition-the former being the practical application of the latter.The distinction is important. While the science of infant nutrition is obviously a complex area of expertise appropriate to pediatricians, factors affecting the art of infant feeding-the interplay between the needs of the infant and the community's current social and cultural beliefs and practices, between the recommendations of professional groups and food manufacturers' products and advertising-fall very definitely within the purview of the family physician.These two papers examine some of the current Canadian recommendations, their rationale and the practical problems they pose from a family practice viewpoint. PMID- 21293683 TI - Treatment of acute excited psychosis with intramuscular haloperidol. AB - Haloperidol (Haldol) is useful in the management of acutely psychotic patients who present with excited behavior which threatens their safety and the safety of others. The use of haloperidol allows rapid control of psychotic behavior with minimal risk of hypotension and avoidance of the excessive sedation associated with other antipsychotics. This article summarizes the rationale, indications, goals and treatment techniques of rapid treatment with intramuscular haloperidol. Major side effects and their management are discussed. PMID- 21293684 TI - The trip home. AB - Some of the medical problems noted in one group of Vietnamese refugees prior to leaving the Kai Tak North Medical Centre in Hong Kong during February and March 1980 for resettlement in Canada are described in this article. Some insight is given into the illnesses and attitudes present in the refugees before (and therefore to some extent after) that long plane ride to a new life in Canada. PMID- 21293685 TI - Significance of X-ray Findings in Patients with Respiratory Allergy. AB - Sinus roentgenography has been thought to be the most sensitive method of detecting sinus infection; however, the significance of abnormal X-rays is uncertain. To determine the usefulness of X-rays in the clinical diagnosis and care of patients with sinus infection, 20 consecutive patients at the St. Joseph's Health Centre allergy clinic were evaluated. Sinus X-ray findings were of clinical assistance in only six cases. Close cooperation between the radiologist and clinician is urged to ensure adequate interpretation of X-ray changes, which can be considered diagnostic if they are compatible with clinical findings.However, clinical findings do not always direct attention to the primary sinus infection. Adequate information is available on the single Water's view for patients with sinus symptoms; other projections in a full radiologic investigation offer no useful information. PMID- 21293686 TI - Child care-who cares? AB - Child health care is best carried out by health professionals who are motivated to do so. The nature of the physician's training, the method of financial remuneration, and the changing health needs of Canadian children have all had a strong influence on the pattern of practice of family physicians and pediatricians. Changes are needed in all three areas to meet current and future needs. The National Child Health Goals suggested by the American Academy of Pediatrics should be considered as objectives for Canadian physicians and allied health professionals. A collaborative effort between parents, educators, social agencies and medical practitioners-including pediatricians and family physicians will help achieve these goals in the 1980s. PMID- 21293687 TI - What Effect is Marital Breakdown Having on Family Medicine? PMID- 21293688 TI - Suicide. PMID- 21293689 TI - [Not Available]. PMID- 21293690 TI - Concussion.. PMID- 21293691 TI - The consultation and communication.. PMID- 21293693 TI - Marital breakdown.. PMID- 21293692 TI - Anemia.. PMID- 21293694 TI - Public health. PMID- 21293695 TI - Marital breakdown.. PMID- 21293696 TI - Marital breakdown.. PMID- 21293697 TI - A comparison of oxytetracycline and trimethoprim/sulfamethoxasole in treating non gonococcal urethritis. AB - This double blind study compares the use of oxytetracycline to trimethoprim/sulfamethoxasole in the treatment on non-gonococcal urethritis. Designed to meet the reality of treating a clinical rather than a microbiological entity, the study involved 102 students with clinical evidence of NGU. Both drugs were found equally effective in treatment. PMID- 21293698 TI - Motor Vehicle Accidents: The Family Practitioner's Role in Their Management. AB - The modern epidemic of motor vehicle accidents claims more lives, creates more morbidity and causes more property damage every successive year. Prevention is a responsibility of every family practitioner as he prescribes and counsels in his office. He has a limited role at an accident scene, but here he supports the patient and may assist personnel of ambulance, police or fire services. In the receiving hospital emergency room the priorities of emergency care, investigations and the indications for transfer of the patient to another facility are discussed. If the victim dies, the relatives' mourning is helped by organ donation and the initiative of the family practitioner in these circumstances may help many people. PMID- 21293700 TI - Pulmonary edema. AB - The physician who deals with pulmonary edema from a pathophysiologic basis will seldom make a diagnostic or therapeutic error. Recent additions to preload and afterload therapy have greatly helped in the emergency and ambulatory treatment of pulmonary edema due to left heart failure. Careful follow-up and patient self monitoring are the most effective means of reducing hospitalization of chronic heart failure patients. PMID- 21293699 TI - Septic shock. AB - Septic shock is a dynamic syndrome of inadequate tissue perfusion caused by invasion of the blood by micro-organisms. Gram-negative rod bacteremia accounts for about two-thirds of patients with this syndrome. The fully developed syndrome of high fever, chills, cold, moist extremities, hypotension and oliguria is easy to recognize. However, the initial features of the syndrome may be quite non specific and subtle, particularly in elderly patients. Treatment is aimed at eliminating the infection, improving tissue perfusion, supporting ventilation and managing specific complications. PMID- 21293701 TI - The Doctor's Bag. AB - The effectiveness of a family physician in providing domiciliary and emergency care is closely related to the contents of his medical bag. The structure of the bag determines good organization of the contents. A wide range of diagnostic and therapeutic items can be handled through fitting containers into the bag's compartments. The effect of the Canadian winter on injectables must be considered. The writer's own bag is unpacked and reviewed in detail. PMID- 21293702 TI - Cardiac crises and the family physician robert. AB - Family physicians involved in pre-hospital emergency cardiac care need training in basic cardiac life support (BCLS) and advanced cardiac life support (ACLS). They should also become involved in mobilizing community resources to provide necessary equipment and training for the public in CPR. The article outlines the procedure to be followed in cardiac arrest, the contents of a critical care bag, and the administration of various drugs. PMID- 21293703 TI - Experiences with psychiatric referrals. AB - The nature of referral attrition can be studied by looking at the period between the referring physician's decision to seek psychiatric help for his patient and the patient's contact with the psychiatrist. Examples of breakdowns in the process are given, in comparison with results of outcome studies of patient orientation for psychotherapy. Bridging interviews would be beneficial, because they would help the patient align his/her expectations with the realities of the psychiatric interview. The educational and remoralizing functions of the referring physician are exemplified. The importance of the power position of the family physician to influence the course of the referral process and even the early stages of psychiatric treatment are kept in the foreground. Furthermore, the cost effectiveness of mental health care delivery, an important issue today, would improve if the referral process were more effectual. PMID- 21293704 TI - On the diagnosis and management of functional diseases. AB - The diagnosis and management of functional disease poses special problems for the family physician. This paper focuses on specific approaches and strategies that may be incorporated into the clinical style of any physician. Meticulous clinical method, careful planning and patient education are seen as the foundation for management of these disorders. PMID- 21293705 TI - Preventing chronic obstructive pulmonary disease: a multidisciplinary approach. AB - Chemoprophylaxis, combined with prolonged treatment of bronchospasm, in patients with incipient or minimal obstructive chest disease has shown promising results in 30 patients. Physicians should include in their regular examination some means of early detection for chronic obstructive pulmonary diseases and in suitable cases institute chemoprophylaxis during the winter, as well as preventive vaccinations. In addition, longterm treatment of bronchial problems should be continued. This combined approach will help prevent recurrent infections which accelerate the progress of chronic obstructive chest disease. PMID- 21293706 TI - Searching the medical literature. AB - The major medical library services and resources of most use to family physicians are outlined. Medical Subject Headings (MeSH) is the key to successful use of Index Medicus, Medline and the card catalogue. The new Family Medicine Literature Index (FAMLI) provides access to family medicine journals not indexed by Index Medicus. Other indexing and abstracting services helpful to family physicians are discussed. PMID- 21293707 TI - What was his name? A historical quiz. AB - In this paper, the reader is given a number of clues as to the identity of a country doctor who made unique contributions to medicine and science which still affect our daily practice and living. The paper also hints at our current responsibility to provide some foundation to the presently termed specialty of family practice. PMID- 21293708 TI - Screening indochinese refugee patients: result of 192 cases. AB - Between October and December 1979, 192 refugee patients received medical screening for hepatitis, intestinal parasites and tuberculosis at the Mount Sinai Hospital, Toronto. Of the 192 patients, 83 were found to harbor intestinal parasitic ova and cysts; 143 were tested for tuberculosis, of whom 50 were found to be positive; 192 were checked for hepatitis, of whom 21 had asymptomatic hepatitis B antigenemia. PMID- 21293709 TI - Exercised induced bronchospasm secondary to repeated nasal trauma. AB - Those engaged in heavy exercise may present with unusual or confusing symptoms. This case history documents the pre- and postoperative course of a 33 year old former wrestler who experienced respiratory difficulty and excessive mucous production after 10-15 minutes of heavy exercise. PMID- 21293710 TI - The purple bag syndrome. AB - This is an account of an unusual case of purple discoloration of plastic disposable urethral catheters and urine collecting bags. The likely causes are discussed with reference to the analogous situation of purple diapers in children. In this instance it appears that the phenomenon may have been due to the presence of indigo in the urine as a degradation product of tryptophan in the bowel lumen. PMID- 21293711 TI - The role of family and emergency medicine in undergraduate medical education. AB - Clinical clerks electing emergency and family medicine rotations during the 1977 and 1978 academic years at the University of Calgary Faculty of Medicine evaluated their clerkships on the opportunities provided to learn new useful medical knowledge, learn new clinical skills and practice them. All rotations were perceived as providing excellent opportunities to learn medical knowledge. However, nearly 20% of students felt that four of the teaching hospital ward based specialty and subspecialty rotations failed to provide them with a satisfactory opportunity to learn new clinical skills and even a greater number were lacking practice opportunities. On the other hand, emergency and family medicine were generally rated very favorably in providing these opportunities. PMID- 21293712 TI - The family physician: teacher or technocrat? AB - With all the technological advances in medicine, something is still missing doctors' responsiveness to patients' total health needs. Studies have shown that patients react more to the way in which they are treated than to the treatment itself. Physicians are often blinded by technology to the true root of a patient's problem. Their training needs more emphasis on individual and family dynamics, rather than on disease. PMID- 21293714 TI - Balance billing.. PMID- 21293713 TI - [Not Available]. PMID- 21293715 TI - Psychiatry references in a core library.. PMID- 21293716 TI - Maternal deaths.. PMID- 21293717 TI - Famli.. PMID- 21293718 TI - Computerization. PMID- 21293719 TI - Use of the cu-7 device in a family planning clinic. AB - The experience of 707 women undergoing a first insertion of the Cu-7(r) at the Family Planning Clinic, Edmundston, has been assessed.The majority (67.3%) of patients were parous, and 77.2% were 20-29 years of age. Insertion of the Cu-7 was considered easy in both nulliparous and parous patients.Two years of use have been completed by 136 women (7,917 woman months of use). Relevant life-table discontinuation rates for the first two years of use, respectively, were: involuntary pregnancy 1.50%, 1.39%; expulsion 6.60%, 1.11%; removal of the Cu-7 for some medical reason 19.83%, 14.85%.Removals for pain among nulliparous women were significantly more frequent than among parous patients (p<.001). PMID- 21293720 TI - Structuring a family assessment interview. AB - The Problem Centred Systems Therapy of the Family and the McMaster Model of Family Functioning on which it is based have been used by family physicians and a variety of health professionals. This paper outlines aspects of the models that are useful in structuring a family assessment, plus some of the benefits gained through using such a family oriented approach. PMID- 21293721 TI - Difficulties in the middle years of marriage: the role of the family physician. AB - Many more couples are splitting up after relatively long periods of marriage. The family physician can help them see whether this response is to breakdown of the marriage or to the inevitable stresses of middle life. A stepwise approach to such an evaluation need take only four to six sessions, covering trust, refocussing, validation, encouragement, clarification and feedback. PMID- 21293722 TI - Postpartum mental syndromes. AB - Recent evidence suggests that parturition is a precipitating factor against a background of an inherited or acquired host constitution predisposing to emotional disorder. Postpartum mental illness is a spectrum of syndromes ranging from the fairly benign transient "blues" to more severe affective, organic or schizophreniform psychoses. Neuroendocrine factors may be the underlying etiologic agent. Treatment may involve support and reassurance, formal psychotherapy or psychotropic and somatic therapies. PMID- 21293723 TI - The lost infant: impact on the family. AB - Stillbirth, sudden infant death syndrome, death of a premature infant or death of an infant through disease give rise grieving processes with many features in common. Feelings, particularly between the parents, and between parents and surviving children, must be dealt with if the grief reaction is to achieve a normal resolution. The family physician can be extremely helpful in bringing these issues to light. PMID- 21293724 TI - The runaway child: psychopathology or normal quest for independence? AB - The treatment of runaway children or teenagers has a particular role for the family physician in managing this increasingly common "symptom". It may be an indication on one hand of healthy, independent striving and on the other hand the final desperate act of a child in an intolerable family situation. Many such situations revolve around adapting to a "new" family constellation, especially new stepfathers or boyfriends of the mothers. PMID- 21293725 TI - Failure to thrive: an approach to management. AB - The family physician is often confronted with the problem of failure to thrive. The possible causes are numerous and diverse, so there is a tendency to attack the problem with a battery of expensive and sometimes unnecessary investigations, which serve only to upset the patient and contribute to the rising costs of health care. The use of a simple organized approach allows common diagnoses to be made with a minimum of costly investigations. In more complicated cases the use of this plan allows the family physician to pursue the investigation further, narrowing down the diagnostic possibilities before a consultation is required. PMID- 21293726 TI - Reproductive counselling. AB - In 1977 a reproductive clinic was started in the Department of Obstetrics, University of British Columbia. This is an account of the 191 couples who attended, with problems related to recurrent abortion, perinatal loss, an abnormality in a live child, family history of an anomaly or exposure of the embryo or fetus to a possible teratogen during early pregnancy. During the counselling session, the possible causes of the pregnancy loss were discussed. The risk of a recurrence of the event was assessed. Ultrasound monitoring and amniocentesis were offered in a subsequent pregnancy where appropriate. We found that following the reproductive counselling session couples developed a much more realistic attitude towards the subsequent pregnancy and their anxiety was considerably lessened. PMID- 21293727 TI - Self evaluation program. PMID- 21293728 TI - Postgraduate training: time to reassess. AB - A survey of current medical literature suggests the Canadian family physician is facing a difficult and uncertain future, especially by his inability to gain economic parity with the specialists and to have his certification recognized as an academic achievement, not just a mere category of membership. Also, there is the ever increasing encroachment upon traditional general practice roles by paramedical health professionals and medical specialists.The source of many of these contentious issues-threatening not only today's family practitioners but also the future of family medicine in Canada-can be found in the training of family practitioners in Canada. PMID- 21293729 TI - Systematic comparison of crystal and NMR protein structures deposited in the protein data bank. AB - Nearly all the macromolecular three-dimensional structures deposited in Protein Data Bank were determined by either crystallographic (X-ray) or Nuclear Magnetic Resonance (NMR) spectroscopic methods. This paper reports a systematic comparison of the crystallographic and NMR results deposited in the files of the Protein Data Bank, in order to find out to which extent these information can be aggregated in bioinformatics. A non-redundant data set containing 109 NMR - X-ray structure pairs of nearly identical proteins was derived from the Protein Data Bank. A series of comparisons were performed by focusing the attention towards both global features and local details. It was observed that: (1) the RMDS values between NMR and crystal structures range from about 1.5 A to about 2.5 A; (2) the correlation between conformational deviations and residue type reveals that hydrophobic amino acids are more similar in crystal and NMR structures than hydrophilic amino acids; (3) the correlation between solvent accessibility of the residues and their conformational variability in solid state and in solution is relatively modest (correlation coefficient = 0.462); (4) beta strands on average match better between NMR and crystal structures than helices and loops; (5) conformational differences between loops are independent of crystal packing interactions in the solid state; (6) very seldom, side chains buried in the protein interior are observed to adopt different orientations in the solid state and in solution. PMID- 21293730 TI - Long-term use of intravitreal bevacizumab (avastin) for the treatment of von hippel-lindau associated retinal hemangioblastomas. AB - Retinal hemangioblastomas are the most common manifestation of Von Hippel-Lindau (VHL) disease [1-3]. While peripheral retinal hemangioblastomas may be treated by thermal laser treatment or cryotherapy, optic nerve and macular lesions are more difficult to treat [4, 5]. Based on the theoretical benefit of administering anti VEGF treatment, intra-vitreally administered bevacizumab (Avastin, a general pan VEGF inhibitor) is attractive [6, 7]. Several short-term case series using ranibizumab (Lucentis, mAb fragment of bevacizumab with stronger affinity for VEGF-A) have shown it has promising but minimal success on most VHL-related hemangioblastomas [8, 9]. A comprehensive study by Wong et al. examined 5 patients over a period up to 61 weeks (47 +/- 14 weeks) while Michels et al. examined one patient over a period of 4 months. Due to the short-term nature of these studies, we attempted long-term bevacizumab treatment over 60 months in a monocular subject with progressive visual loss due to a VHL associated macular and optic nerve hemangioblastoma. Over the treatment regimen of 15 injections, visual acuity improved 25 letters, OCT thickness improved from 646 um to 424 um, and structural lesions stabilized while exudates and edema resolved. PMID- 21293731 TI - Transcutaneous Blepharoptosis Surgery: Simultaneous Advancement of the Levator Aponeurosis and Muller's Muscle (Levator Resection). AB - Transcutaneous blepharoptosis surgery with simultaneous advancement of the levator aponeurosis and Muller's muscle (levator resection) is a popular surgery which is considered effective for all types of blepharoptosis except for the myogenic type. Repair of ptosis cases with good levator function yields excellent results. A good outcome can be also obtained in cases with poor levator function, however, in such cases; a large degree of levator advancement may be required, which may result in postoperative dry eyes, unnatural eyelid curvature and astigmatism. These cases are therefore better treated with sling surgery. With the right patient selection, the levator resection technique is an effective method for ptosis repair. PMID- 21293733 TI - Oculoplastic. PMID- 21293732 TI - Aqueous humor dynamics: a review. AB - Glaucoma is a family of optic neuropathies which cause irreversible but potentially preventable vision loss. Vision loss in most forms of glaucoma is related to elevated IOP with subsequent injury to the optic nerve. Secretion of aqueous humor and regulation of its outflow are physiologically important processes for maintaining IOP in the normal range. Thus, understanding the complex mechanisms that regulate aqueous humor circulation is essential for management of glaucoma. The two main structures related to aqueous humor dynamics are the ciliary body and the trabecular meshwork (TM). Three mechanisms are involved in aqueous humor formation: diffusion, ultrafiltration and active secretion. Active secretion is the major contributor to aqueous humor formation. The aqueous humor flow in humans follows a circadian rhythm, being higher in the morning than at night. The aqueous humor leaves the eye by passive flow via two pathways - the trabecular meshwork and the uveoscleral pathway. In humans, 75% of the resistance to aqueous humor outflow is localized within the TM with the juxtacanalicular portion of the TM being the main site of outflow resistance. Glycosaminoglycan deposition in the TM extracellular matrix (ECM) has been suggested to be responsible for increased outflow resistance at this specific site whereas others have suggested deposition of proteins, such as cochlin, obstruct the aqueous humor outflow through the TM. The uveoscleral outflow pathway is relatively independent of the intraocular pressure and the proportion of aqueous humor exiting the eye via the uveoscleral pathway decreases with age. PMID- 21293734 TI - Phenotypic variability in a French family with a novel mutation in the BEST1 gene causing multifocal best vitelliform macular dystrophy. AB - AIMS: To describe genetic and clinical findings in a French family affected by best vitelliform macular dystrophy (BVMD). METHODS: We screened eight at-risk members of a family, including a BVMD-affected proband, by direct sequencing of 11 bestrophin-1 (BEST1) exons. Individuals underwent ophthalmic examination and autofluorescent fundus imaging, indocyanine green angiography, electro-oculogram (EOG), electroretinogram (ERG), multifocal ERG, optical coherence tomography (OCT), and where possible, spectral domain OCT. RESULTS: The sequence analysis of the BEST1 gene revealed one previously unknown mutation, c.15C>A (p.Y5X), in two family members and one recently described mutation, c.430A>G (p.S144G), in five family members. Fundus examination and electrophysiological responses provided no evidence of the disease in the patient carrying only the p.Y5X mutation. Three patients with the p.S144G mutation did not show any preclinical sign of BVMD except altered EOGs. Two individuals of the family exhibited a particularly severe phenotype of multifocal BVMD-one individual carrying the p.S144G mutation heterozygously and one individual harboring both BEST1 mutations (p.S144G inherited from his mother and p.Y5X from his father). Both of these family members had multifocal vitelliform autofluorescent lesions combined with abnormal EOG, and the spectral domain OCT displayed a serous retinal detachment. In addition, ERGs demonstrated widespread retinal degeneration and multifocal ERGs showed a reduction in the central retina function, which could be correlated with the decreased visual acuity and visual field scotomas. CONCLUSIONS: A thorough clinical evaluation found no pathological phenotype in the patient carrying the isolated p.Y5X mutation. The patients carrying the p.S144G variation in the protein exhibited considerable intrafamilial phenotypic variability. Two young affected patients in this family exhibited an early onset, severe, multifocal BVMD with a diffuse distribution of autofluorescent deposits throughout the retina and rapid evolution toward the loss of central vision. The other genetically affected relatives had only abnormal EOGs and displayed no or extremely slow electrophysiological evolution. PMID- 21293735 TI - Alteration of growth factors and neuronal death in diabetic retinopathy: what we have learned so far. AB - PURPOSE: Diabetic retinopathy (DR) is a leading cause of blindness in American adults. Over the years, DR has been perceived as a vascular disease characterized by vascular permeability, macular edema, and neovascularization that can lead to blindness. Relatively new research on neurodegeneration is expanding our views of the pathogenesis of DR. Evidence has begun to point to the fact that even before vascular complications begin to manifest, neuronal cell death and dysfunction have already begun. Based on the literature and our own studies, we address whether neuronal death is associated with loss of neurotrophic support due to less production of a given growth factor or due to impairment of its signaling events regardless of the level of the growth factor itself. METHODS: In this article we aimed to review the literature that looks at the neuronal side of DR and whether retinal neurons are adversely affected due to the lack of neurotrophic levels or activity. In particular, we examine the research looking at insulin, insulin-like growth factor, vascular endothelial growth factor, pigment epithelium-derived growth factor, brain-derived neurotrophic factor, and nerve growth factor. RESULTS: Research shows that insulin has neurotrophic properties and that the loss of its pro-survival pathways may have a role in diabetic retinopathy. There is also evidence to suggest that exogenously administered insulin may have a role in the treatment of DR. Insulin-like growth factor has been shown to have a role in retinal neurogenesis and there is early evidence that it may also have neuroprotective effects. While there is evidence of neuroprotective effects of vascular endothelial growth factor, paradoxically, there is also an increased amount of apoptotic activity in retinal neurons despite an increased level of VEGF in the diabetic eye. Further research is necessary to elucidate the exact mechanisms involved. Pigment epithelium derived growth factor has retinal neuroprotective effects and shows evidence that it may be an avenue for future therapeutic use in DR. Brain-derived growth factor has been shown to have neuroprotective effects in the retina and there is also some evidence in diabetic rats that it may have some therapeutic potential in treating DR. Nerve growth factor has also been shown to have neuroprotective effects and research has begun to elucidate some of the pathways and mechanisms through which these effects occur. CONCLUSIONS: Research has shown that there is some degree of neuronal death involved in DR. It is also evident that there are many growth factors involved in this process. Some of these growth factors have shown some potential as future therapeutic targets in DR. These findings should encourage further investigation into the mechanism of these growth factors, their potential for therapy, and the possibility of a new horizon in the clinical care of DR. PMID- 21293736 TI - Comparison of camel tear proteins between summer and winter. AB - PURPOSE: Proteins in the tear fluid have positive effects on maintaining the integrity and stabilization of the tear film, which is affected by several environmental factors. The aim of this study is to investigate seasonal variation of protein patterns in camel tears collected during the summer and winter season. METHODS: Tears from both eyes of 50 clinically normal camels (Camelus dromedarius) were collected in the summer (June-July) and in the winter (December January) respectively. Pooled tear protein samples from two seasons were separated by SDS-PAGE and two-dimensional electrophoresis (2-DE). Protein spots of differential expression in two season gels were excised and subjected to in gel digestion and identification by matrix assisted laser desorption/ionization time of flight/time of flight-mass spectrum (MALDI-TOF/TOF-MS) analysis. Two differentially expressed proteins, lactoferrin (LF) and vitelline membrane outer layer protein 1 homolog (VMO1 homolog), were validated by western blotting. RESULTS: Thirteen well resolved bands were detected in SDS-PAGE gels of both summer and winter camel tears. By band densitometry, significantly higher intensities of band 6, 7, 11, and lower intensity of band 13 were observed in the summer group compared to the winter group. In 2-DE profiles of camel tears, four protein spots were found expressed differentially in two seasons. Further protein identification by MALDI-TOF/TOF-MS and confirmation by western blotting indicated that there was a significant decrease in LF (p=0.002) and an increase in VMO1 homolog (p=0.042) in tears in the summer compared to the winter. CONCLUSIONS: The seasonal variation of camel tear fluids has been found in the composition of proteins, including LF and VMO1 homolog. This result will expand our knowledge of physiologic characteristics of tear fluids and establish a foundation for the mechanistic studies and clinical practices on ocular surface disorders. PMID- 21293737 TI - Exploiting Statistical Methodologies and Controlled Vocabularies for Prioritized Functional Analysis of Genomic Experiments: the StRAnGER Web Application. AB - StRAnGER is a web application for the automated statistical analysis of annotated gene profiling experiments, exploiting controlled biological vocabularies, like the Gene Ontology or the KEGG pathways terms. Starting from annotated lists of differentially expressed genes and gene enrichment scores, regarding the terms of each vocabulary, StRAnGER repartitions and reorders the initial distribution of terms to define a new distribution of elements. Each element pools terms holding the same enrichment score. The new distribution thus derived, is reordered in a decreasing order to the right, according to the observation score of the elements, while elements with the same score, are sorted again in a decreasing order of their enrichment scores. By applying bootstrapping techniques, a corrected measure of the statistical significance of these elements is derived, which enables the selection of terms mapped to these elements, unambiguously associated with respective significant gene sets. The selected terms are immunized against the bias infiltrating statistical enrichment analyses, producing technically very high statistical scores, due to the finite nature of the data population. Besides their high statistical score, another selection criterion for the terms is the number of their members, something that incurs a biological prioritization in line with a Systems Biology context. The output derived, represents a detailed ranked list of significant terms, which constitute a starting point for further functional analysis. PMID- 21293738 TI - From control to elimination: the research agenda for measles. PMID- 21293740 TI - The golden fountain--is urine the miracle drug no one told you about? PMID- 21293739 TI - Microbial evaluation and public health implications of urine as alternative therapy in clinical pediatric cases: health implication of urine therapy. AB - BACKGROUND: Cultural means of pediatric treatment during ill health is a mainstay in Africa, and though urine has been known to contain enteric pathogens, urine therapy is still culturally applicable in some health conditions and also advocated as alternative therapy. The study therefore, is to evaluate the microbial contents and safety of urine. METHODS: Urinary bacteria from cows and healthy children aged 5-11 years were identified by conventional phenotypic methods and antimicrobial susceptibility testing was performed using modified agar disc and well-diffusion methods. RESULTS: A total of 116 bacterial isolates (n = 77 children; n = 39 cows) were identified as Bacillus (10.4%; 5.1%)), Staphylococcus (2.6%; 2.6%), Citrobacter (3.9%; 12.8%), Escherichia coli (36.4%; 23.1%), Klebsiella (7.8%; 12.8%), Proteus (18.2%; 23.1%), Pseudomonas (9.1%; 2.6%), Salmonella (3.9%; 5.1%) and Shigella (7.8%; 12.8%) spp. Antibiotic resistance rates of the Gram-positive bacteria were high (50.0100%), except in Bacillus strains against chloramphenicol, gentamicin and tetracycline (14.3%), while higher resistance rates were recorded among the Gram-negative bacteria except in Citrobacter (0.0%) and Proteus (8.5%) spp. against gentamicin and tetracycline respectively. The Gram-negative bacteria from ito malu (cow urine) were more resistant bacteria except in Citrobacter (20.0%) and Shigella spp. (0.0%) against tetracycline and Proteus spp. (11.1%), (22.2%) against amoxicillin and tetracycline respectively. Multiple antibiotic resistance (MAR) rates recorded in children urinal bacterial species were 37.5-100% (Gram-positive) and 12.5-100% (Gram-negative), while MAR among the cow urinal bacteria was 12.5-75.0% (Gram-positive) and 25.0-100% (Gram-negative). Similar higher resistance rates were also recorded among the Gram-negative bacterial species from urine specimens against the pediatric antibiotic suspensions. CONCLUSION: The study reported presence of multiple antibiotic-resistant indicator bacteria in human urine and ito malu used as alternative remedy in pediatric health conditions like febrile convulsion. PMID- 21293741 TI - [Ileal duplication revealed by a perforation in adults ]. PMID- 21293742 TI - Regular vitamin C supplementation during pregnancy reduces hospitalization: outcomes of a Ugandan rural cohort study. AB - BACKGROUND: Vitamin C or ascorbic acid is a hydro-soluble lactone (synthesized from glucose) essential to human body and available from diet. Despite its broad availability in fruits and vegetables, in many developing countries the incidence of clinical symptoms due to the vitamin deficiency is still very high. Also, pregnant women in the developing countries are frequently hospitalized for several preventable reasons such as anemia in pregnancy, mostly iron-deficient anemia (IDA) and the upper/lower respiratory tract infections (RTI). The aim of the study was to investigate, in a Ugandan rural pregnant women cohort, the preventive effects of vitamin C supplementation on hospital admission. METHODS: 384 pregnant women met the inclusion criteria and were randomly assigned to receive either 400 mg of vitamin C daily (187) or not (197) in addition to their standard antenatal vitamins until delivery. The primary outcome measure of this study was to assess the prevention of hospitalization during pregnancy in the group of women supplemented with vitamin C compared to the controls. Fisher's exact test was employed in this assessment. RESULTS: 42.2% women in the vitamin C group and 27.9% in the control group were not hospitalized during pregnancy; this difference was found statistically significant. CONCLUSION: The results of this study suggest including vitamin C in the guidelines of multivitamin prevention for pregnant women, especially in developing countries where seasonal availability of fruits and vegetables could result in adverse clinical outcomes. PMID- 21293743 TI - The burden experienced by family caregivers of patients with epilepsy attending the government psychiatric hospital, Kaduna, Nigeria. AB - BACKGROUND: Caring for patients with chronic medical and psychiatric disorders is associated with significant burden. However little is known about the burden experience by caregivers of patients with epilepsy in Nigeria. The objective of this study, therefore, was to assess the level and correlates of burden among caregivers of patients with epilepsy. METHODS: It was a cross-sectional study carried out among 231 eligible caregivers of patients with epilepsy attending the psychiatric clinic of government psychiatric hospital in Kaduna, Northern Nigeria. Sociodemographic/clinical characteristics of patients and socio demographic characteristics of caregivers were recorded, and the Zarit Burden Interview administered to caregivers to assess their experience of burden. RESULTS: The mean age of the caregivers was 43.6 +/- 9.5 years, 52.4% lived outside Kaduna and the mean seizure-free period for the patients was 26.4 +/- 36.5 weeks. One hundred and twenty (51.9%) caregivers had high burden. High burden was significantly associated with patients aged less than 20 years, patient's unemployment, long duration of epilepsy, short seizure-free period, family history of epilepsy and living outside Kaduna (p value<0.05). CONCLUSION: Caregivers of patients with epilepsy experience significant burden while caring for their relatives and this is mainly associated with patient's factors and location of residence. Therefore efforts should be made control seizure and make health care available and affordable to all citizens irrespective of where they live. PMID- 21293744 TI - Polyradiculoneuritis revealing an acute monoblastic leukemia 5. AB - Acute polyradiculoneuritis has been frequently reported in association with malignant disorders, especially those of the lymphoid system. To date, there have been no reported cases of acute monoblastic leukemia associated with this polyradiculopathy. The authors tell us about a very rare case of leukemia presenting as acute monoblastic leukemia 5 (AML5) in a 28 years old patient from Morocco. PMID- 21293745 TI - Specialty preferences among medical students in a Kenyan university. AB - BACKGROUND: Specialty distribution in Kenya continues to exhibit gender disparities despite the increasing number of female medical students graduating each year. This study aimed at assessing specialty preferences and factors influencing these choices among male and female medical students in Kenya. METHODS: Four hundred and fifty medical students, from first to fifth year of study at the University of Nairobi, were each issued a self-administered questionnaire designed to assess their specialty preferences and factors influencing these choices. The specialty preferences were compared with the actual distribution of specialists in Kenya. Data collected were analyzed using Statistical Package for Social Sciences. RESULTS: Three hundred and eighty five (85.6%) questionnaires were completed. Surgery had the highest preference rate followed by pediatrics, internal medicine and obstetrics and gynecology. Significantly more males preferred surgery than females who mainly selected pediatrics (p<0.001). There was an increased likelihood of female students choosing controllable lifestyle specialties. These preferences mirrored the actual distribution of specialists in Kenya. Male students significantly considered prestige in a specialty (p=0.006), while their female counterparts mostly considered ease of raising a family and gender distribution in the specialty (p<0.001). CONCLUSION: Gender-based similarities and differences exist in factors influencing specialty preferences among Kenyan medical students. These factors may explain the observed specialist doctor distribution in the country. PMID- 21293746 TI - [Pheochromocytoma and pregnancy - Perioperative and obstetrical management: report of one case and review of literature ]. PMID- 21293747 TI - Diffuse pulmonary hemorrhage as presenting syndrome of HIV disease. AB - Pulmonary hemorrhage is infrequently encountered in pediatrics. It can occur in isolation or in association with an underlying condition. We report a case of diffuse pulmonary hemorrhage as a presenting syndrome of HIV disease. PMID- 21293748 TI - [Hydatid cysts of the spleen: conservative or radical surgery? ]. PMID- 21293749 TI - Sero-prevalence of HIV infection among tuberculosis patients in a rural tuberculosis referral clinic in northern Nigeria. AB - Co-infection with Human Immunodeficiency virus (HIV) and Mycobacterium tuberculosis the causative agent of Tuberculosis (TB), has been referred to as the "cursed duet" as a result of the attendant morbidity and mortality due to their synergistic actions. This study was carried out to determine the prevalence of HIV infection among Tuberculosis (TB) confirmed patients on admission at a TB referral centre. The association of HIV prevalence with gender and age as risk factors was also determined. Blood samples were collected by venipuncture from 257 TB patients and their HIV status determined. Viral antibody detection was carried out using ELISA kits which detected both HIV-1 and HIV-2 and confirmed by Western blot. Of the 257 patients screened, 44.20% (106) were HIV positive. The prevalence of co-infection was higher among the female (44.82%) than the male (38.30%) patients and highest among those aged 21-40 years old (45.30%). Co infection was found to be statistically highly associated with gender and age (p<0.05). A very high prevalence of HIV infection was reported in this study among patients that were on admission on the grounds that they had only TB. It is therefore important to screen for HIV among all TB patients. PMID- 21293750 TI - Dislocation of temporo-mandibular joint - an uncommon circumstance of occurrence: vaginal delivery. AB - Dislocation of temporo-mandibular joint (TMJ) is an infrequent disease but still spectacular. This disease consists of a permanent, to some extent complete disruption of the temporo-mandibular joint. These dislocations often occur in a context of yawning, and less frequently after a burst of laughing or relatively mild facial trauma (slap, punch on the chin). We report a case of TMJ occurring in an uncommon circumstance: vaginal delivery. A woman aged 24-years with no special past medical history; primipara was admitted in the Department of Maternity of the University Hospital Hassan II of Fez for an imminent delivery of a twin pregnancy. Ten minutes after admission, the patient delivered vaginally with episiotomy. She gave birth to twins weighing 2800 g and 2400 g. During labour, and due to efforts of crying, the patient developed a sudden and immediate loss of function of the temporo-mandibular joint, with difficulty of speaking, the mouth permanently opened and with the chin lowered and thrown forward. The examination found an empty glenoid fossa of the temporo-mandibular joint in both sides. The diagnosis of dislocation of the TMJ was established. A CT scan of facial bones was done, objectifying a bilateral dislocation of TMJ. The reduction of this dislocation was performed in the operating room under sedation. PMID- 21293751 TI - [Iatrogenic ileal perforation: complication of exceptional mechanical hemodialysis catheter placement at the femoral site ]. PMID- 21293752 TI - [Appendix abscess: analysis of 19 cases treated at University Hospital of Yaounde and practical deductions ]. PMID- 21293753 TI - Human trafficking in the emergency department. AB - Human trafficking continues to persist, affecting up to 200 million people worldwide. As clinicians in emergency departments commonly encounter victims of intimate partner violence, some of these encounters will be with trafficking victims. These encounters provide a rare opportunity for healthcare providers to intervene and help. This case report of a human trafficking patient from a teaching hospital illustrates the complexity in identifying these victims. Clinicians can better identify potential trafficking cases by increasing their awareness of this phenomenon, using qualified interpreters, isolating potential victims by providing privacy and using simple clear reassuring statements ensuring security. A multidisciplinary approach can then be mobilized to help these patients. PMID- 21293754 TI - Miliary tuberculosis coinfection with human immunodeficiency virus. PMID- 21293755 TI - Chronic or recurrent pain in the emergency department: national telephone survey of patient experience. AB - OBJECTIVE: Persons with chronic or recurrent pain frequently visit the emergency department (ED), yet little research examines this experience. We conducted this national survey to assess patients' ED experiences. METHODS: We developed and conducted a ten-minute telephone survey using random digit dial methodology. We included adults with chronic or recurrent pain reporting an ED visit within two years. RESULTS: We interviewed 500 adults. Sixty percent were female, their median age was 54, two-thirds were under a physician's care, and 14% were uninsured. They reported an average of 4.2 ED visits within the past two years. Almost one-half reported "complete" or "a great deal" of pain relief during the ED visit, while 78% endorsed as "somewhat or definitely true" that "the ED staff understood how to treat my pain." Although over three-fourths of patients felt that receiving additional information on pain management or referrals to specialists was "extremely" or "very" important, only one-half reported receiving such referrals or information. A significant minority (11%) reported that the "ED staff made me feel like I was just seeking drugs." The majority (76%) were "somewhat" to "completely satisfied" with their treatment while 24% were "neutral" to "completely dissatisfied". In multivariate models, age, recurrent pain, waiting time, imaging, receiving analgesics and pain relief predicted patient satisfaction. CONCLUSION: Although those with chronic or recurrent pain report relatively high satisfaction with the ED, our findings suggests that specific areas, such as unmet needs for information and specialty referral, might be targeted to improve care. PMID- 21293756 TI - Evaluation of emergency medicine community educational program. AB - Out-of-hospital emergencies occur frequently, and laypersons are often the first to respond to these events. As an outreach to our local communities, we developed "Basic Emergency Interventions Everyone Should Know," a three-hour program addressing cardiopulmonary resuscitation and automated external defibrillator use, heart attack and stroke recognition and intervention, choking and bleeding interventions and infant and child safety. Each session lasted 45 minutes and was facilitated by volunteers from the emergency department staff. A self administered 13-item questionnaire was completed by each participant before and after the program. A total of 183 participants completed the training and questionnaires. Average score pre-training was nine while the average score post training was 12 out of a possible 13 (P< .0001). At the conclusion of the program 97% of participants felt the training was very valuable and 100% would recommend the program to other members of their community. PMID- 21293757 TI - Prevalence, health and demographics of emergency department patients with diabetes. AB - OBJECTIVE: To determine the prevalence of diabetes in Southern California emergency department (ED) patients and describe the self-reported general health, demographic and social characteristics of these patients with diabetes. METHODS: Between April 2008 and August 2008, non-critical patients at two Southern California EDs completed a 57-question survey about their chronic medical conditions, general health, social and demographic characteristics. RESULTS: 11.3% of the 1,303 patients surveyed had diabetes. Patients with diabetes were similar to ED patients without diabetes with respect to gender, ethnicity and race. However, patients with diabetes were older (51 vs. 41), less likely to have a high school education (64.0% vs. 84.7%), less likely to speak English (44.9% vs. 55.4%), and less likely to be uninsured (33.3% vs. 49.5%). Additionally, patients with diabetes had markedly lower self-reported physical health scores (37.1 vs. 45.8) and mental component score and mental health scores (42.0 vs. 47.4) compared with ED patients without diabetes. CONCLUSION: In this study of two Southern California EDs, 11.3% of surveyed patients had diabetes. These patients were often poorly educated, possessed limited English language skills and poor physical health. ED personnel and diabetes educators should be mindful of these findings when designing interventions for ED patients with diabetes. PMID- 21293758 TI - Nonreciprocal and reciprocal dating violence and injury occurrence among urban youth. PMID- 21293759 TI - In reply. PMID- 21293760 TI - GlideScope Videolaryngoscopy in the Simulated Difficult Airway: Bougie vs Standard Stylet. AB - OBJECTIVE: GlideScope((r)) videolaryngoscopy (GVL) has been shown to improve visualization of the glottis compared to direct laryngoscopy (DL). However, due to the angle of approach to the glottis, intubation can still be challenging. We hypothesized that novice GVL users would be able to intubate faster and easier using an airway introducer (frequently known as a bougie) than with a standard intubating stylet. METHODS: Intubations were performed on a human airway simulator with settings for easy and difficult airways. Participants were emergency medicine (EM) residents or faculty (n=21) who were novice GVL users. Participants were intubated a total of eight times (four GVL, four DL) using either a bougie or an intubating stylet. We recorded time to intubate (TTI) and difficulty rating using a visual analog scale (VAS) and non-parametric statistical methods for analysis. We reported medians with interquartile range (IQR). RESULTS: The median TTI with difficult airway settings and the bougie-GVL was 76 seconds (IQR 50, 102) versus 64 seconds (IQR 50.5, 125), p=0.76 for the stylet-GVL combination. The median VAS difficulty score, on difficult airway settings, for the bougie-GVL was 5 cm (IQR 3.3, 8.0) versus 6.2 cm (IQR 5.0, 7.5) with the stylet-GVL, p=0.53. CONCLUSION: Among novices using GVL for simulated difficult airway management, there was no benefit, in terms of speed or ease of intubation, by using the bougie over the standard stylet. PMID- 21293761 TI - Adherence to dose of succinylcholine and etomidate in the emergency department. PMID- 21293762 TI - Randomized controlled trial of prophylactic antibiotics for dog bites with refined cost model. AB - OBJECTIVE: The aim of this study was to determine the rate of infection at which it is cost-effective to treat dog bite wounds with antibiotics. METHODS: Our study was composed of two parts. First we performed a randomized, double-blind controlled trial (RCT) to compare the infection rates of dog bite wounds in patients given amoxicillin-clavulanic acid versus placebo. Subjects were immunocompetent patients presenting to the emergency department (ED) with dog bite wounds less than 12 hours old without suspected neurovascular, tendon, joint or bone injury, and who had structured follow-up after two weeks. Second, we developed a cost model with sensitivity analysis to determine thresholds for treatment. RESULTS: In the RCT, primary outcomes were obtained in 94 patients with dog bites. The overall wound infection rate at two weeks was 2% [95% CI 0 to 7%]. Two of 46 patients (4%) receiving no antibiotics developed infections, while none of the 48 patients (0%) receiving prophylactic antibiotics developed an infection (absolute reduction 4% [95% CI -1.0 to 4.5%]). Using a sensitivity analysis across a rate of infections from 0-10%, our cost model determined that prophylactic antibiotics were cost effective if the risk of wound infection was greater than 5% and antibiotics could decrease that risk by greater than 3%. CONCLUSION: Our wound infection rate was lower than older studies and more in line with current estimates. Assuming that prophylactic antibiotics could provide an absolute risk reduction (ARR) of 3%, it would not be cost effective to treat wounds with an infection rate of less than 3% and unlikely that the ARR would be achievable unless the baseline rate was greater than 5%, suggesting that only wounds with greater than 5% risk of infection should be treated. Future work should focus on identifying wounds at high-risk of infection that would benefit from antibiotic prophylaxis. PMID- 21293763 TI - Competitive Wrestling-related Injuries in School Aged Athletes in U.S. Emergency Departments. AB - OBJECTIVE: To describe the characteristics of wrestling injuries occurring in male athletes aged 7-17 treated in United States (U.S.) emergency departments (ED) from 2000-2006, and to compare injury patterns between younger & older youth wrestlers. METHODS: A stratified probability sample of U.S. hospitals providing emergency services in the National Electronic Injury Surveillance System was used for 2000-2006. ED visits for injuries sustained in organized wrestling were analyzed for male patients ages 7-17 years old (subdivided into 7-11 years old [youth group] and 12-17 years old [scholastic group]). RESULTS: During the study period, there were an estimated 167,606 ED visits for wrestling injuries in 7-17 years old U.S. males, with 152,710 (91.1%) occurring in the older (12-17 years old) group. The annual injury incidence was 6.49 injuries/1,000 wrestlers in the youth group and 29.57 injuries/1,000 wrestlers in the scholastic group. The distribution of diagnoses was similar in both age groups, with sprain/strain as the most common diagnosis, followed by fracture and contusion/abrasion. Distributions of injury by location were significantly different between groups (p=0.02), although both groups exhibited approximately 75% of all injuries from the waist up. Overexertion and struck by/against were the most common precipitating and direct mechanisms in both groups, respectively. Over 97% of all injured wrestlers were treated and released. CONCLUSION: The types of injury in youth (7-11 years old) wrestlers are similar to those of scholastic (12-17 years old) wrestlers, although the distribution of body parts injured differs between the age groups. The majority of injuries occurs above the waist and may be a target for prevention strategies. PMID- 21293764 TI - Leukocytosis as prognostic indicator of major injury. AB - OBJECTIVE: To test the diagnostic use of the triage white blood cell (WBC) count in differentiating major from minor injuries. METHODS: We conducted a retrospective study of a prospectively collected database of trauma patients 13 years of age or older at a Level I trauma center from January 2005 through December 2008. We excluded all patients with obvious life-threatening injuries requiring immediate surgery, isolated head trauma, transferred from another institution or dead on arrival. We recorded age, sex, injury mechanism, vital signs, WBC, base deficit (BD), lactate (LAC) and calculated injury severity scores (ISS). Major injury was defined as either a change in hematocrit >10 points or blood transfused within 24 hours, or ISS >15. RESULTS: 805 patients were included in the study with an average age of 38.6 years (Range 13-95 yrs) years. 75.3% of patients were male, 45.6% had blunt and 34.4% had penetrating trauma. For vital signs, blood pressure was not significantly different between major and minor injury patients. Major compared to minor injury patients had a statistically but not clinically significant higher heart rate. Major injury patients had significantly (p < 0.0001) higher WBC count (10.53 K/MUl, 95% CI: 9.7-11.3) compared to patients with minor injuries (8.92 K/MUl, 95% CI: 8.7-9.2), but both were in the normal range. Patients with major compared to minor injury had significantly (p < 0.0001) higher BD (-3.1 versus -0.027 mmol/L) and higher LAC (3.9 versus 2.48 mmol/L). Areas under the curve for WBC count (0.60, 95% CI: 0.54-0.66) are similar to BD (0.69, 95% CI: 0.63-0.74) and LAC (0.66, 95% CI: 0.60-0.71). CONCLUSION: WBC count is not a useful addition as a diagnostic indicator of major trauma in our study population. PMID- 21293765 TI - Improving diagnostic accuracy of anaphylaxis in the acute care setting. AB - The identification and appropriate management of those at highest risk for life threatening anaphylaxis remains a clinical enigma. The most widely used criteria for such patients were developed in a symposium convened by National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network. In this paper we review the current literature on the diagnosis of acute allergic reactions as well as atypical presentations that clinicians should recognize. Review of case series reveals significant variability in definition and approach to this common and potentially life-threatening condition. Series on fatal cases of anaphylaxis indicate that mucocutaneous signs and symptoms occur less frequently than in milder cases. Of biomarkers studied to aid in the work-up of possible anaphylaxis, drawing blood during the initial six hours of an acute reaction for analysis of serum tryptase has been recommended in atypical cases. This can provide valuable information when a definitive diagnosis cannot be made by history and physical exam. PMID- 21293766 TI - Spectacular retroperitoneal impalement. PMID- 21293767 TI - Potentially low cost solution to extend use of early generation computed tomography. AB - In preparing a case report on Brown-Sequard syndrome for publication, we made the incidental finding that the inexpensive, commercially available three-dimensional (3D) rendering software we were using could produce high quality 3D spinal cord reconstructions from any series of two-dimensional (2D) computed tomography (CT) images. This finding raises the possibility that spinal cord imaging capabilities can be expanded where bundled 2D multi-planar reformats and 3D reconstruction software for CT are not available and in situations where magnetic resonance imaging (MRI) is either not available or appropriate (e.g. metallic implants). Given the worldwide burden of trauma and considering the limited availability of MRI and advanced generation CT scanners, we propose an alternative, potentially useful approach to imaging spinal cord that might be useful in areas where technical capabilities and support are limited. PMID- 21293768 TI - Targeted Needs Assessment of Off-service Residents in Emergency Medicine. AB - PURPOSE: The purpose of this study is to evaluate the needs of internal medicine residents rotating through the emergency department (ED). METHODS: A survey was distributed to 100 internal medicine residents (post-graduate years 2 and 3) from two different residency programs before the start of their emergency medicine (EM) rotation. Residents ranked the level of importance and the level of preparedness for 23 different EM topics, using a Likert-type scale ranging from 1 (least important/least prepared) to 4 (most important/most prepared). We calculated delta values (Delta) from the difference between importance and preparedness and undertook significance testing of this difference. RESULTS: A total of 71 out of 100 surveys were completed properly and returned. Internal medicine residents felt most ill-prepared in the areas of orthopedics, environmental emergencies, otolaryngology, airway management, and ophthalmology. The largest perceived gaps between importance and preparedness lay within the areas of airway management (Delta=1.30), ophthalmology (Delta=1.10), environmental emergencies (Delta=0.96), and orthopedics (Delta=0.96). CONCLUSION: Our data suggest that internal medicine residents are inadequately prepared for EM topics that they feel are important to their education, specifically airway management, ophthalmology, environmental emergencies and orthopedics. It is quite possible that other specialty residents are also poorly prepared for similar core EM topics. These data will hopefully guide future curricular change for off service residents in the ED. PMID- 21293769 TI - Emergency Medicine Residency Applicants' Perceptions about Being Contacted after Interview Day. AB - OBJECTIVE: We sought to characterize the experiences and preferences of applicants to emergency medicine (EM) residency programs about being contacted by programs after their interview day but before the rank list submission deadline. METHODS: This cross-sectional study surveyed all applicants to an academic EM residency during the 2006-2007 interview cycle. Participation was anonymous and voluntary. We used a Web-based survey software program to administer the survey in February 2007, after rank lists were submitted. Two additional invitations to participate were sent over the next month. The instrument contained multiple choice and free-text items. This study was submitted to our Institutional Review Board and was exempt from formal review. RESULTS: 240/706 (34%) of applicants completed the survey. 89% (214/240) of respondents reported being contacted by a residency program after their interview but before rank lists were due. Of those contacted, 91% report being contacted by e-mail; 67% by mail; and 55% by phone. 51% of subjects reported that being contacted changed the order of their rank list in at least one case. A majority of contacted applicants felt "happy" (58%) or "excited" (56%) about being contacted, but significant numbers reported feeling "put on the spot" (21%) or "uncomfortable" (17%).A majority felt that it is appropriate for programs to contact applicants after interview day but before the rank lists are submitted, but 39% of contacted subjects responded that contact by phone is either "always inappropriate" or "usually inappropriate." Regarding perceptions regarding the rules of the match, 80% (165/206) of respondents felt it was appropriate to tell programs where they would be ranked, and 41% (85/206) felt it was appropriate for programs to notify applicants of their place on the program's rank list. CONCLUSION: Most EM residency applicants report being contacted by programs after the interview day but before rank lists are submitted. Although applicants feel this practice is appropriate in general, over a third of subjects feel that contact by phone is inappropriate. These findings suggest that residency programs can expect a majority of their applicants to be contacted after an interview at another program, and shed light on how applicants perceive this practice. PMID- 21293770 TI - Quality improvement practices in academic emergency medicine: perspectives from the chairs. AB - OBJECTIVE: To assess academic emergency medicine (EM) chairs' perceptions of quality improvement (QI) training programs. METHODS: A voluntary anonymous 20 item survey was distributed to a sample of academic chairs of EM through the Association of Academic Chairs of Emergency Medicine. Data was collected to assess the percentage of academic emergency physicians who had received QI training, the type of training they received, their perception of the impact of this training on behavior, practice and outcomes, and any perceived barriers to implementing QI programs in the emergency department. RESULTS: The response rate to the survey was 69% (N = 59). 59.3% of respondents report that their hospital has a formal QI program for physicians. Chairs received training in a variety of QI programs. The type of QI program used by respondents was perceived as having no impact on goals achieved by QI (chi(2) = 12.382; p = 0.260), but there was a statistically significant (chi(2) = 14.383; p = 0.006) relationship between whether or not goals were achieved and academic EM chairs' perceptions about return on investment for QI training. Only 22% of chairs responded that they have already made changes as a result of the QI training. 78.8% of EM chairs responded that quality programs could have a significant positive impact on their practice and the healthcare industry. Chairs perceived that QI programs had the most potential value in the areas of understanding and reducing medical errors and improving patient flow and throughput. Other areas of potential value of QI include improving specific clinical indicators and standardizing physician care. CONCLUSION: Academic EM chairs perceived that QI programs were an effective way to drive needed improvements. The results suggest that there is a high level of interest in QI but a low level of adoption of training and implementation. PMID- 21293771 TI - Evaluating Emergency Medicine Faculty at End-of-Shift. AB - INTRODUCTION: Faculty often evaluate learners in the emergency department (ED) at the end of each shift. In contrast, learners usually evaluate faculty only at the end of a rotation. In December 2007 Southern Illinois University School of Medicine changed its evaluation process, requiring ED trainees to complete end-of shift evaluations of faculty. OBJECTIVE: Determine the feasibility and acceptance of end-of-shift evaluations for emergency medicine faculty. METHODS: We conducted this one-year observational study at two hospitals with 120,000 combined annual ED visits. Trainees (residents and students) anonymously completed seven-item shift evaluations and placed them in a locked box. Trainees and faculty completed a survey about the new process. RESULTS: During the study, trainees were assigned 699 shifts, and 633 end-of-shift evaluations were collected for a completion rate of 91%. The median number of ratings per faculty was 31, and the median number of comments was 11 for each faculty. The survey was completed by 16/22 (73%) faculty and 41/69 (59%) trainees. A majority of faculty (86%) and trainees (76%) felt comfortable being evaluated at end-of-shift. No trainees felt it was a time burden. CONCLUSION: Evaluating faculty following an ED shift is feasible. End-of shift faculty evaluations are accepted by trainees and faculty. PMID- 21293772 TI - Adaptation of EPEC-EM Curriculum in a Residency with Asynchronous Learning. AB - OBJECTIVE: The Education in Palliative and End-of-life Care for Emergency Medicine Project (EPECTM-EM) is a comprehensive curriculum in palliative and end of-life care for emergency providers. We assessed the adaptation of this course to an EM residency program using synchronous and asynchronous learning. METHODS: Curriculum adaptation followed Kern's standardized six-step curriculum design process. Post-graduate year (PGY) 1-4 residents were taught all EPECTM-EM cognitive domains, divided as seven synchronous and seven asynchronous modules. All synchronous modules featured large group didactic lectures and review of EPECTM-EM course materials. Asynchronous modules use only EPECTM-EM electronic course media for resident self-study. Targeted evaluation for EPECTM-EM knowledge objectives was conducted by a prospective case-control crossover study, with synchronous learning serving as the quasi-control, using validated exam tools. We compared de-identified test scores for effectiveness of learning method, using aggregate group performance means for each learning strategy. RESULTS: Of 45 eligible residents 55% participated in a pre-test for local needs analysis, and 78% completed a post-test to measure teaching method effect. Post-test scores improved across all EPECTM-EM domains, with a mean improvement for synchronous modules of +28% (SD=9) and a mean improvement for asynchronous modules of +30% (SD=18). The aggregate mean difference between learning methods was 1.9% (95% CI 15.3, +19.0). Mean test scores of the residents who completed the post-test were: synchronous modules 77% (SD=12); asynchronous modules 83% (SD=13); all modules 80% (SD=12). CONCLUSION: EPECTM-EM adapted materials can improve resident knowledge of palliative medicine domains, as assessed through validated testing of course objectives. Synchronous and asynchronous learning methods appear to result in similar knowledge transfer, feasibly allowing some course content to be effectively delivered outside of large group lectures. PMID- 21293773 TI - Standardized Patients to Teach Medical Students about Intimate Partner Violence. AB - OBJECTIVE: To use 360-degree evaluations within an Observed Structured Clinical Examination (OSCE) to assess medical student comfort level and communication skills with intimate partner violence (IPV) patients. METHODS: We assessed a cohort of fourth year medical students' performance using an IPV standardized patient (SP) encounter in an OSCE. Blinded pre- and post-tests determined the students' knowledge and comfort level with core IPV assessment. Students, SPs and investigators completed a 360-degree evaluation that focused on each student's communication and competency skills. We computed frequencies, means and correlations. RESULTS: Forty-one students participated in the SP exercise during three separate evaluation periods. Results noted insignificant increase in students' comfort level pre-test (2.7) and post-test (2.9). Although 88% of students screened for IPV and 98% asked about the injury, only 39% asked about verbal abuse, 17% asked if the patient had a safety plan, and 13% communicated to the patient that IPV is illegal. Using Likert scoring on the competency and overall evaluation (1, very poor and 5, very good), the mean score for each evaluator was 4.1 (competency) and 3.7 (overall). The correlations between trainee comfort level and the specific competencies of patient care, communication skill and professionalism were positive and significant (p<0.05). CONCLUSION: Students felt somewhat comfortable caring for patients with IPV. OSCEs with SPs can be used to assess student competencies in caring for patients with IPV. PMID- 21293774 TI - Multiple organ transplantation after suicide by acetaminophen and gunshot wound. AB - Emergency physicians (EP) and medical toxicologists are integral in identifying and treating patients with overdoses. Transplant centers are expanding acceptance criteria to consider those with poison-related deaths. We present a case of a simultaneous gunshot wound to the head and an acetaminophen overdose. This case highlights the importance of EPs and medical toxicologists in recognizing the medical complexity of suicides, optimizing treatment, and timing of organ procurement. Early antidote administration and aggressive supportive care allowed the patient to be evaluated as a potential donor. EPs and medical toxicologists have integral roles in overdose patients as organ donors. PMID- 21293775 TI - Seizure as initial manifestation of aortic dissection type a. AB - BACKGROUND: Seizure as the initial manifestation of aortic dissection is rare. CASE REPORT: An 88-year-old female experienced a first generalized tonic clonic seizure, which was terminated with midazolam. Acute cerebral magnetic resonance imaging and angiography were non-informative. After awaking she complained about cramping pain in the right upper extremity, which was accompanied by involuntary flexion movements of the right upper extremity. Blood pressure was initially normal. Blood gases revealed metabolic acidosis and blood chemical investigations a markedly increased D-dimer. Consecutively blood pressure declined and transthoracic echocardiography showed pericardial effusion. A computed tomography scan of the thorax revealed an aortic dissection type A. The patient died 16 hours after admission after cardiothoracic surgeons had refused surgical treatment. CONCLUSION: This case shows that a generalized tonic-clonic seizure may be the initial manifestation of an aortic dissection type A in the absence of thoracic chest pain and that brachyalgia may not develop earlier than with progression of the dissection. PMID- 21293776 TI - Iatrogenic claudication from a vascular closure device after cardiac catheterization. AB - We report a case of iatrogenic claudication as a result of a misplaced percutaneous arterial closure device (PACD) used to obtain hemostasis after cardiac catheterization. The patient presented one week after his procedure with complaints suggestive of right lower extremity claudication. Computed tomographic angiography demonstrated a near total occlusion of the right common femoral artery from a PACD implemented during the cardiac catheterization. The use of PACD's to obtain rapid hemostasis is estimated to occur in half of all cardiac catheterizations. Ischemic complications as a result of these devices must be considered when evaluating post procedural patients with extremity complaints. PMID- 21293777 TI - Dolor de pecho. PMID- 21293778 TI - Sciatic artery aneurysm. PMID- 21293779 TI - Emphysematous pyelonephritis and pneumo-vena cava. PMID- 21293780 TI - Torus mandibularis. PMID- 21293781 TI - Cardiomyopathy following latrodectus envenomation. AB - Latrodectus envenomations are common throughout the United States and the world. While many envenomations can result in catecholamine release with resultant hypertension and tachycardia, myocarditis is very rare. We describe a case of a 22-year-old male who sustained a Latrodectus envenomation complicated by cardiomyopathy. PMID- 21293782 TI - Cholinergic crisis after rodenticide poisoning. AB - Rodenticides have historically been common agents in attempted suicides. As most rodenticides in the United States (U.S.) are superwarfarins, these ingestions are generally managed conservatively with close monitoring for coagulopathy, and if necessary, correction of any resulting coagulopathy. However, alternate forms of rodenticides are imported illegally into the U.S. and may be ingested either accidentally or in suicide attempts. We present an unusual case of poisoning by the illegally imported rodenticide, "Tres Pasitos." The main ingredient of this rat poison is aldicarb, a potent carbamate pesticide that causes fulminant cholinergic crisis. This case is relevant and timely because carbamates and organophosphates are still used as insecticides and emergency physicians (EP) working in rural areas may have to evaluate and manage patients with these poisonings. As international travel and immigration have increased, so has the possibility of encountering patients who have ingested toxic substances from other countries. In addition, there has been increased concern about the possibility of acts of terrorism using chemical substances that cause cholinergic toxidromes.1,2 EPs must be able to recognize and manage these poisonings. This report describes the mechanism of action, clinical manifestations, laboratory evaluation and management of this type of poisoning. The pertinent medical literature on poisoning with aldicarb and similar substances is reviewed. PMID- 21293783 TI - Penetrating atherosclerotic aortic ulcer. PMID- 21293784 TI - Expressive aphasia and carotid dissection. AB - Ultrasound images of a patient presenting to the emergency department with expressive aphasia who was found to have carotid dissection. The first image is a standard two dimensional image that depicts the internal carotid with a visible flap within the lumen. The second image is a color Doppler image showing turbulent flow within the true lumen and visible flow within the false lumen. The case and the patient's outcome are summarized along with some teaching points about carotid dissection. Also, there is some background and research on using ultrasound to help identify dissection. PMID- 21293785 TI - Intrapericardial diaphragmatic hernia. PMID- 21293786 TI - Computational Study on the Conformations of Mitragynine and Mitragynaline. AB - A conformational search on mitragynine and mitragynaline, natural products isolated from the leaves of Mitragyna speciosa, was performed using the MMFF94s force field and the quantum mechanical B3LYP method. The main difference for the mitragynine conformers is caused by the position of the lone pair of the nitrogen shared by rings 3 and 4. Specifically, the lone pair can be syn or anti to the exocylic ethyl group on ring 4. Syn was found to be lower in energy than anti, because of less steric hindrance between the ethyl and the methylene group adjacent to the N in ring 3. The geometrical parameters for the lowest energy conformer of mitragynine are in excellent agreement with the published X-ray crystal structure's geometry. Because it has one more double bond, mitragynaline has less conformational freedom than mitragynine. The main possible conformational choice in mitragynaline is for orientational flexibility of a C-C single bond in ring 3. The finding of two low energy conformers of mitragynaline differing in ring 3 conformation matches reported X-ray crystal structural data. PMID- 21293787 TI - A "Self-Pinning" Adhesive Based on Responsive Surface Wrinkles. AB - Surface wrinkles are interesting since they form spontaneously into well-defined patterns. The mechanism of formation is well-studied and is associated with the development of a critical compressive stress that induces the elastic instability. In this work, we demonstrate surface wrinkles that dynamically change in response to a stimulus can improve interfacial adhesion with a hydrogel surface through the dynamic evolution of the wrinkle morphology. We observe that this control is related to the local pinning of the crack separation pathway facilitated by the surface wrinkles during debonding, which is dependent on the contact time with the hydrogel. PMID- 21293788 TI - A memory-based model of Hick's law. AB - We propose and evaluate a memory-based model of Hick's law, the approximately linear increase in choice reaction time with the logarithm of set size (the number of stimulus-response alternatives). According to the model, Hick's law reflects a combination of associative interference during retrieval from declarative memory and occasional savings for stimulus-response repetitions due to non-retrieval. Fits to existing data sets show that the model accounts for the basic set-size effect, changes in the set-size effect with practice, and stimulus response repetition effects that challenge the information-theoretic view of Hick's law. We derive the model's prediction of an interaction between set size, stimulus fan (the number of responses associated with a particular stimulus), and stimulus-response transition, which is subsequently tested and confirmed in two experiments. Collectively, the results support the core structure of the model and its explanation of Hick's law in terms of basic memory effects. PMID- 21293789 TI - Photosensitizer-doped conjugated polymer nanoparticles with high cross-sections for one- and two-photon excitation. AB - We report a novel nanoparticle that is promising for photodynamic therapy applications, which consists of a pi-conjugated polymer doped with a singlet oxygen photosensitizer. The nanoparticles exhibit highly efficient collection of excitation light due to the large excitation cross-section of the polymer. A quantum efficiency of singlet oxygen production of 0.5 was determined. Extraordinarily large two-photon excitation cross-sections were determined, indicating promise for near infrared multiphoton photodynamic therapy. Gel electrophoresis of DNA after near-UV irradiation in the presence of nanoparticles indicated both purine base and backbone DNA damage. PMID- 21293790 TI - A simple and rapid approach for measurement of dissociation constants of DNA aptamers against proteins and small molecules via automated microchip electrophoresis. AB - Automated microchip electrophoresis was used as a simple and rapid method to measure effective dissociation constants (K(d,eff)) of aptamers against both large and small molecule targets. Human thrombin, immunoglobulin E (IgE), and adenosine triphosphate (ATP) were selected as model analytes to validate the method, with four ligands including two DNA aptamers for thrombin (two distinct epitopes), an IgE aptamer, and an ATP aptamer. The approach is based on a microchip version of a DNA mobility shift assay. Non-denaturing microchip gel electrophoresis separations of DNA could resolve and quantify unbound from target bound aptamers when using large molecules as targets. To extend the technique to small molecule targets such as ATP, an aptamer/competitor strategy was used, in which a DNA competitor complementary to the aptamer could be displaced by ATP and electrophoretically resolved. Using an automated microchip electrophoresis platform, parallel separations of 11 titration samples were completed in ~0.5 h. Analytical performance comparisons show that our approach provides significant advantages in minimized reagent consumption (typically tens of pmol of aptamer and target), reduced analysis time, and minimized user interaction when compared to previously reported methods for aptamer K(d) measurement. Moreover, the flexibility and ease of K(d,eff) measurement for aptamers against large and small targets make this a unique and valuable approach that should find widespread use. Finally, the feasibility of using this method during aptamer selection processes (e.g. SELEX) was shown by accurate bulk K(d,eff) measurement of a known thrombin aptamer (THRaptA) spiked into a random-sequence DNA pool at as low as 5.0% (molar %) of the total pool; only ~825 fmol of total binding sequences were needed for an 11-point titration curve. PMID- 21293791 TI - A highly ordered titania nanotube array as a supercapacitor electrode. AB - We report the synthesis of self-organized titania nanotubes and nanocrystalline titania powders employing an alternative and novel approach. Integrating these nanostructures in a binder-free working electrode improved the capacitance up to 911 MUF cm(-2), which is around one to two orders of magnitude higher than the conventional electric double layer capacitors. PMID- 21293792 TI - Insights into scanning probe high-field chemistry of diphenylgermane. AB - Experiments and simulations are used to elucidate a new class of chemical reactions occurring near the tip-sample interface during high field chemistry of diphenylgermane. Current data during writing and bias dependent growth rate are analyzed, supplemented with data from ionization mass spectrometry, and compared with the simulation results. PMID- 21293793 TI - Millimeter-sized flat crystalline sheet architectures of fullerene assemblies with anisotropic photoconductivity. AB - The coassembly of C(60) derivatives through arene-perfluoroarene interactions has been used for the first time to develop millimeter-sized flat crystalline sheets. Time-resolved microwave conductivity (TRMC) measurements exhibited anisotropic features with over double the charge carrier mobility in the direction parallel to the plane of the crystal than perpendicular to the plane. This study demonstrates a strategy to obtain large-sized 2-dimensional architectures of C(60) with anisotropic optoelectronic functions. PMID- 21293794 TI - Altering the spin state of transition metal centers in metal-organic frameworks by molecular hydrogen adsorption: a first-principles study. AB - Our first-principles calculation shows that molecular hydrogen (H(2)) adsorption at an exposed Fe(II) site in metal-organic frameworks could induce a spin flip in the Fe(II) center resulting in a spin-state transition from a triplet high-spin (HS) to a singlet low-spin (LS) state. The Kubas-type Fe-H(2) interaction, where H(2) coordinates onto the Fe(II) center as a sigma-ligand, is found commensurate in strength with the exchange interaction of Fe 3d electrons, which is responsible for the occurrence of the spin-state transition in this system. The H(2) binding energies are 0.08 and 0.35 eV per H(2) at the HS and LS states, respectively. This effect is expected to find applications in spin-control in molecular magnets, hydrogen sensing and storage. PMID- 21293795 TI - Formation and coordination modes of the C4E4 moiety (E = COOMe) bound to two palladium(II) moieties. AB - The transmetallation of the palladacyclopentadiene complex Pd{C(COOMe)C(COOMe)C(COOMe)C(COOMe)}(bipy) with the dicationic Pd(II) complex [Pd(bipy)(CH(3)CN)(2)][BF(4)](2) afforded a terminally sigma-palladated diene complex [Pd(2){MU-eta(1):eta(1) C(COOMe)C(COOMe)C(COOMe)C(COOMe)}(bipy)(2)(CH(3)CN)(2)][BF(4)](2). It was revealed by X-ray crystallographic analysis that replacement of the acetonitrile ligands in a terminally sigma-palladated diene complex with PPh(3) ligands resulted in the conformation change of the sigma-palladated diene moiety from skewed s-cis to planar s-trans. Treatment of a bis-triphenylphosphine dipalladium complex [Pd(2)(PPh(3))(2)(CH(3)CN)(4)][PF(6)](2) with dimethoxyacetylene dicarboxylate (DMAD) (1 equiv.) in acetonitrile resulted in the insertion of DMAD to the Pd-Pd bond to afford [Pd(2){MU-eta(1):eta(1) C(COOMe)C(COOMe)}(PPh(3))(2)(CH(3)CN)(4)][PF(6)](2). Addition of the second DMAD gave the ylide-type complex [Pd(2){MU-eta(2):eta(3) C(COOMe)C(COOMe)C(COOMe)C(COOMe)(PPh(3))}(PPh(3))(2)(CH(3)CN)(3)][PF(6)](2) of which the structure was determined by X-ray crystallographic analysis. PMID- 21293796 TI - Synthesis, characterization and ethylene oligomerization behavior of 2 benzoimidazol-8-ethoxyquinolylnickel dihalides. AB - A series of 2-benzoimidazol-8-ethoxyquinolines (L1-L6) and the nickel dihalides thereof (C1-C12) were synthesized and characterized by elemental analysis and infrared spectroscopy. The molecular structures of representative complexes were determined by single crystal X-ray diffraction which revealed a distorted pyramidal geometry at nickel. All complexes, when activated with Et(2)AlCl, showed high activities towards ethylene oligomerization and enhanced thermodynamic stability. PMID- 21293797 TI - Electrosynthesis of Rh2(dpf)4(R) where dpf = N,N'-diphenylformamidinate anion and R = CH3, C2H5, C3H7, C4H9 or C5H11. AB - The electrosynthesis of Rh(2)(dpf)(4)(R) where dpf is the N,N' diphenylformamidinate anion and R = CH(3), C(2)H(5), C(3)H(7), C(4)H(9) or C(5)H(11) was carried out in THF containing 0.2 M tetra-n-butylammonium perchlorate (TBAP) and one of several alkyl iodides represented as RI. The initial step in the reaction involved a one-electron reduction of the Rh(2)(4+) unit in Rh(2)(dpf)(4) to its Rh(2)(3+) form followed by a homogeneous reaction involving electrogenerated [Rh(2)(dpf)(4)](-) and the alkyl iodide in solution to give Rh(2)(dpf)(4)(R). The homogeneously generated Rh(2)(5+) product was then immediately reduced by a second electron at the potential where [Rh(2)(dpf)(4)(R)](-) is generated, giving [Rh(2)(dpf)(4)(R)](-) which contains a Rh(2)(4+) center as a final product of an electrochemical ECE mechanism. The electrosynthesized [Rh(2)(dpf)(4)(CH(3))](-) derivative could be reoxidized to Rh(2)(dpf)(4)(CH(3)) on the reverse potential sweep and both forms of the CH(3) bonded derivative were in situ characterized by cyclic voltammetry combined with UV-visible and/or ESR spectroscopy. The reversible Rh(2)(4+/3+) process of Rh(2)(dpf)(4) is located at E(1/2) = -1.11 V in THF, 0.2 M TBAP while the electrogenerated Rh(2)(dpf)(4)(R) products are substantially easier to reduce, with E(p) values for the Rh(2)(5+/4+) couples ranging from -0.50 to -0.54 V vs. SCE depending upon the specific R group. PMID- 21293798 TI - Tuning the [L2Rh...H3B.NR3]+ interaction using phosphine bite angle. Demonstration by the catalytic formation of polyaminoboranes. AB - Efficient catalysts for the dehydrocoupling or dehydropolymerisation of H(3)B.NMe(x)H((3-x)) (x = 1, 2) have been developed by variation of the P-Rh-P angle in {Rh(Ph(2)P(CH(2))(n)PPh(2))}(+) fragments (n = 2-5). PMID- 21293799 TI - Surface-enhanced ATR-IR spectroscopy with interface-grown plasmonic gold-island films near the percolation threshold. AB - Flat nano-island films prepared by wet-chemical deposition were investigated with attenuated total reflection infrared (ATR-IR) spectroscopy and scanning electron microscopy (SEM) in order to analyze the correlation between film morphology and optical properties. Here we choose Au as representative coinage metal (Au, Ag, Cu) that shows strong structure-dependent surface-enhanced infrared absorption (SEIRA). Infrared spectra of octadecanethiol monolayers on films of different stages of morphologic development show effects that are characteristic for SEIRA, such as enhanced vibrational signals, Fano-type line shape, and adsorbate induced baseline shifts. Their extent was found to be strongly dependent on the structural details and the strongest enhancement occurs at the percolation threshold of the two-dimensional island system. Also films beyond percolation show significant enhancement due to residual nanoholes that are acting as hotspots. PMID- 21293800 TI - Visualisation of electrochemical processes at optically transparent carbon nanotube ultramicroelectrodes (OT-CNT-UMEs). AB - Optically transparent ultramicroelectrodes (OT-UMEs) comprising carbon nanotube (CNT) networks on quartz, are introduced and used to monitor quantitatively the interfacial concentration of tris(2,2'-bipyridine)ruthenium(II) during cyclic voltammetry. The OT-CNT-UMEs combine the attractive properties of small-scale electrodes, e.g., high diffusion rates and good signal-to-noise, with the ability to probe electrochemical processes optically, from the rear of the electrode. This enables optical measurements of the solution, close to the electrode surface, without significant interference from absorption or scattering processes. PMID- 21293801 TI - A microfabricated deformability-based flow cytometer with application to malaria. AB - Malaria resulting from Plasmodium falciparum infection is a major cause of human suffering and mortality. Red blood cell (RBC) deformability plays a major role in the pathogenesis of malaria. Here we introduce an automated microfabricated "deformability cytometer" that measures dynamic mechanical responses of 10(3) to 10(4) individual RBCs in a cell population. Fluorescence measurements of each RBC are simultaneously acquired, resulting in a population-based correlation between biochemical properties, such as cell surface markers, and dynamic mechanical deformability. This device is especially applicable to heterogeneous cell populations. We demonstrate its ability to mechanically characterize a small number of P. falciparum-infected (ring stage) RBCs in a large population of uninfected RBCs. Furthermore, we are able to infer quantitative mechanical properties of individual RBCs from the observed dynamic behavior through a dissipative particle dynamics (DPD) model. These methods collectively provide a systematic approach to characterize the biomechanical properties of cells in a high-throughput manner. PMID- 21293802 TI - Development of a fluorescent method for detecting the onset of coagulation in human plasma on microstructured lateral flow platforms. AB - Microfluidic devices and microsystems have been used to develop blood coagulation monitoring devices for point of care diagnostic use. However, many of them suffer from inherent variability and imprecision, partly due to the fact that they only detect changes in bulk clotting properties and do not reflect the microscopic nature of blood coagulation. This work demonstrates microstructured lateral flow platforms used in combination with fluorescently labelled fibrinogen to detect microscopic clot formation. Plasma samples applied to platforms modified with coagulation activation reagents and fluorescent fibrinogen produced changes in fluorescence intensity due to incorporation of the fluorophore into the forming microclots. It was found that the change in the distribution of the fluorescence within the sample over time was an excellent predictor of the onset of coagulation, which could be used to determine the clotting time. The impact of various assay parameters was optimised and the assay was shown to be capable of measuring the effect of heparin concentration on blood clotting time from 0 to 1.5 U mL(-1). PMID- 21293803 TI - Simultaneous control of spectroscopic and electrochemical properties in functionalised electrochemiluminescent tris(2,2'-bipyridine)ruthenium(II) complexes. AB - Using a combination of electrochemical, spectroscopic and computational techniques, we have explored the fundamental properties of a series of ruthenium diimine complexes designed for coupling with other molecules or surfaces for electrochemiluminescence (ECL) sensing applications. With appropriate choice of ligand functionality, it is possible to manipulate emission wavelengths while keeping the redox ability of the complex relatively constant. DFT calculations show that in the case of electron withdrawing substituents such as ester or amide, the excited state is located on the substituted bipyridine ligand whereas in the case of alkyl functionality it is localised on a bipyridine. The factors that dictate annihilation ECL efficiency are interrelated. For example, the same factors that determine DeltaG for the annihilation reaction (i.e. the relative energies of the HOMO and LUMO) have a corresponding effect on the energy of the excited state product. As a result, most of the complexes populate the excited state with an efficiency (Phi(ex)) of close to 80% despite the relatively wide range of emission maxima. The quantum yield of emission (Phi(p)) and the possibility of competing side reactions are found to be the main determinants of ECL intensity. PMID- 21293804 TI - A facile approach for morphosynthesis of Pd nanoelectrocatalysts. AB - A facile approach has been developed for synthesis of highly-structured, anisotropic Pd nanostructures. The dendritic Pd nanostructures show superior performance toward oxidation of formic acid and methanol for fuel cell application. PMID- 21293805 TI - Thienyl directed polyaromatic C-C bond fusions: S-doped hexabenzocoronenes. AB - With a view to combining the desirable electronic and photochemical properties of hexabenzocoronene (HBC) and the C-C bond forming capabilities of thiophenes, 1-(3 thienyl)-2,3,4,5,6-penta(4-tert-butyl-phenyl)benzene (1) was oxidised using FeCl(3). The resulting products, superaromatic thiophene (2) and its 5,5'-dimer (3), are S-HBC systems and provide a new pair of spectral comparators. PMID- 21293806 TI - An incommensurate thiourea inclusion compound. AB - X-Ray diffraction studies reveal that the tunnel inclusion compound formed between 1-tert-butyl-4-iodobenzene and thiourea has an incommensurate relationship between the periodicities of the host and guest substructures along the tunnel axis, representing the first reported case of an incommensurate thiourea inclusion compound. PMID- 21293807 TI - The first study on enhanced photoresponsivity of ZnO-TiO2 nanocomposite thin films by anodic polarization. AB - The physical and photoelectrochemical properties of the anodized ZnO-TiO(2) thin films were investigated in this study. Impedance spectroscopy revealed a decrease in charge transfer resistance and Tafel plots determined enhancement of about 200 times in the exchange current (i(0)) after anodization at high positive potential. It was found from XPS analysis that after applying the potential of 5 V to the ZnO-TiO(2) photoelectrode, the lattice oxygen (O(2-)) in the thin film is oxidized to molecular oxygen and then, cations such as Zn(2+) can be solved in the basic electrolyte and passed to the solution. Moreover, according to AFM analysis it was observed that the surface of the samples has been grooved by applying anodic voltage resulting in an increase of effective surface of the film. A mechanism for describing the significant enhancement in the photoresponse of the anodized layer is proposed. PMID- 21293808 TI - Metallacrowns of Ni(II) with alpha-aminohydroxamic acids in aqueous solution: beyond a 12-MC-4, an unexpected (vacant?) 15-MC-5. AB - Growing attention has been devoted in the recent years to a class of metallamacrocycles known as metallacrowns (MCs). They are structural analogues of crown ethers where the methylene bridges have been substituted by coordinative bonds formed by a transition metal ion ("ring" metal) and a nitrogen atom. The cavity of the metallacrown can accommodate an additional metal ion ("core" metal) either identical or different from the ring metal, thus forming a homo- or hetero metallic MC. The most studied ring metal ion is certainly Cu(2+) and the aminohydroxamic acids have proved to be very suitable ligands to form MCs. The behavioural analogies between Cu(2+) and Ni(2+) in forming complexes, along with recent literature data in the solid state, prompted us to investigate the possible MC formation between Ni(2+) and both (S)-alpha-alaninehydroxamic acid and (S)-valinehydroxamic acid, in aqueous solution. Two metallacrowns, a 12-MC-4 and an unexpected 15-MC-5 have been detected by potentiometry and confirmed by ESI-MS results. Their structures are discussed on the basis of potentiometric, calorimetric, spectroscopic data and DFT calculations. The existence of a vacant 15-MC-5 species in solution can be put forward for the first time, making the present metal/ligand systems very interesting for their potential applications in cation recognition and separation. Finally, the crystal structure of the binary complex K[NiL(2)H(-1)].5/3 H(2)O of (S)-alpha-alaninehydroxamic acid (LH) is also reported. PMID- 21293809 TI - Synthesis, functionalization and bioimaging applications of highly fluorescent carbon nanoparticles. AB - Highly fluorescent crystalline carbon nanoparticles (CNPs) have been synthesized by one step microwave irradiation of sucrose with phosphoric acid at 100 W for 3 min 40 s. This method is very simple, rapid and economical and hence can be used for large scale applications. The average particle sizes are 3 to 10 nm and they emit bright green fluorescence under the irradiation of UV-light. Therefore, the particles can be used as a unique material for bioimaging as well as drug delivery. To further increase the fluorescence property of the synthetic carbon nanoparticles we simply functionalized them by using different organic dyes, such as fluorescein, rhodamine B and alpha-naphthylamine; the maximum fluorescence intensity was observed for the particles functionalized with fluorescein. It is very interesting to note that all of those compounds show maximum fluorescence intensity at 225 nm excitation wavelength and for any excitation wavelength the peak positions are exactly same the position as that of CNPs itself, which is completely different from the individual precursors (dyes). All of the above compounds, including CNPs, have also been successfully introduced into the erythrocyte enriched fraction of healthy human blood cells with minimum cytotoxicity. PMID- 21293810 TI - Fluorescent neuroactive probes based on stilbazolium dyes. AB - A set of spectrally diverse stilbazolium dyes was identified in an uptake assay using cultured brainstem and cerebellum cells isolated from e19 chicks. Pretreatment of cells with indatraline, a monoamine reuptake inhibitor, allowed identification of dyes that may interact with monoamine transporters. Two structurally related, yet spectrally segregated, probes, (E)-1-methyl-4-[2-(2 naphthalenyl)ethenyl]-pyridinium iodide (NEP+, 3A) and (E)-4-[2-(6-hydroxy-2 naphthalenyl)ethenyl]-1-methyl-pyridinium iodide (HNEP+, 4A), were selected and further investigated using HEK-293 cells selectively expressing dopamine, norepinephrine or serotonin transporters. HNEP+ was selectively accumulated via catecholamine transporters, with the norepinephrine transporter (NET) giving the highest response; NEP+ was not transported, though possible binding was observed. The alternate modes of interaction enable the use of NEP+ and HNEP+ to image distinct cell populations in live brain tissue explants. The preference for HNEP+ accumulation via NET was confirmed by imaging uptake in the absence and presence of desipramine, a norepinephrine reuptake inhibitor. PMID- 21293811 TI - STM studies of single molecules: molecular orbital aspects. AB - As a fundamental and frequently referred concept in modern chemistry, the molecular orbital plays a vital role in the science of single molecules, which has become an active field in recent years. For the study of single molecules, scanning tunneling microscopy (STM) has been proven to be a powerful scientific technique. Utilizing specific distribution of the molecular orbitals at spatial, energy, and spin scales, STM can explore many properties of single molecule systems, such as geometrical configuration, electronic structure, magnetic polarization, and so on. Various interactions between the substrate and adsorbed molecules are also understood in terms of the molecular orbitals. Molecular engineering methods, such as mode-selective chemistry based on the molecular orbitals, and resonance tunneling between the molecular orbitals of the molecular sample and STM tip, have stimulated new advances of single molecule science. PMID- 21293812 TI - Synthesis, structural diversity and fluorescent characterisation of a series of d10 metal-organic frameworks (MOFs): reaction conditions, secondary ligand and metal effects. AB - Along with our recent investigation on the flexible ligand of H(2)ADA (1,3 adamantanediacetic acid), a series of Zn(II) and Cd(II) metal-organic frameworks, namely, [Zn(3)(ADA)(3)(H(2)O)(2)](n).5nH(2)O (1), [Zn(ADA)(4,4'-bipy)(0.5)](n) (2), [Zn(2)(ADA)(2)(bpa)](n) (3), [Zn(2)(ADA)(2)(bpa)](n) (4), [Zn(2)(ADA)(2)(bpp)](n) (5), [Cd(HADA)(2)((4,4'-bipy)](n) (6), [Cd(3)(ADA)(3)(bpa)(2)(CH(3)OH)(H(2)O)](n) (7), and [Cd(2)(ADA)(2)(bpp)(2)](n).7nH(2)O (8) have been synthesized and structurally characterized (where 4,4'-bipy = 4,4'-dipyridine, bpa = 1,2-bis(4-pyridyl)ethane and bpp = 1,3-bis(4-pyridyl)propane). Due to various coordination modes and conformations of the flexible dicarboxylate ligand and the different pyridyl containing coligands, these complexes exhibit structural and dimensional diversity. Complex 1 exhibits a three-dimensional (3D) framework containing one dimensional (1D) Zn(II)-O-C-O-Zn(II) clusters. Complex 2 exhibits a 2D structure constructed by 1D double chains based on [Zn(2)ADA(2)] units and a 4,4'-bipy pillar. Complexes 3 and 4 possess isomorphic 2D layer structures, resulting from the different coordination modes of carboxylate group of ADA ligands. Complex 5 features a 2D 4(4) layer in which ADA ligands and Zn(II) atoms construct a 1D looped chain and the chains are further connected by bpp ligands. Complex 6 is composed of 1D zig-zag chains that are entangled through hydrogen-bonding interactions to generate a 2D network. Complex 7 is a rare (3,5)-connected network. Complex 8 possesses a 3D microporous framework with lots of water molecules encapsulated in the channels. The structural diversity of the complexes perhaps mainly results from using diverse secondary ligands and different metal centre ions, and means the assistant ligand and metal centre play important roles in the design and synthesis of target metal-organic frameworks. This finding revealed that ADA could be used as an effective bridging ligand to construct MOFs and change coordination modes and conformational geometries in these complexes. The thermogravimetric analyses, X-ray powder diffraction and solid-state luminescent properties of the complexes have also been investigated. PMID- 21293813 TI - (NH4)6[Mn3B6P9O36(OH)3].4H2O: a new open-framework manganese borophosphate synthesized by using boric acid flux method. AB - A new three-dimensional (3-D) open-framework manganese borophosphate, (NH(4))(6)[Mn(3)B(6)P(9)O(36)(OH)(3)].4H(2)O (denoted as MnBPO-CJ31), has been synthesized by using boric acid flux method. Its anionic framework structure is constructed by the connection of MnO(6) octahedra and BO(4), PO(4) and PO(3)(OH) tetrahedra. It contains 12-ring channels along the [001] direction with a pore diameter of 7.1 A. It is the first borophosphate featuring a 3-D anionic partial structure with a B/P ratio of 2/3 and an unprecedented fifteen mer tetrahedral fundamental building unit (FBU) [B(6)P(9)O(36)(OH)(3)] exists in this compound. NH(4)(+) ions locate in the void space to balance the negative charge of the inorganic framework. The compound is further characterized by powder XRD, ICP, CHN, TGA and IR analyses. Magnetic study reveals that MnBPO-CJ31 shows interesting canted antiferromagnetic behaviour at low temperature. PMID- 21293814 TI - The multicomponent reaction of imidazo[1,5-a]pyridine carbenes with phthalaldehydes and dimethyl acetylenedicarboxylate: a facile construction of benzo[d]furo[3,2-b]azepines. AB - A study on the multicomponent reaction comprising both N-heterocyclic carbenes and substituted phthalaldehydes is reported. The imidazo[1,5-a]pyridine carbenes, namely imidazo[1,5-a]pyridine-3-ylidenes, reacted with phthalaldehydes and DMAD under very mild conditions to produce novel fused tricyclic benzo[d]furo[3,2 b]azepine derivatives. The resulting fused heterocyclic compounds are fluorescent and they give an emission around 500 nm with quantum yields (Phi(F)) being up to 0.81. This study provides not only a unique approach to fused azepine derivatives that are not easily accessible by other methods, but also opens a new avenue to complicated molecular skeletons. The fluorescence properties of long emission wavelength and high fluorescence quantum yields of some products predict their potential applications as optical sensors. PMID- 21293815 TI - Anion exchange induced tunable catalysis properties of an uncommon butterfly-like tetranuclear copper(II) cluster and magnetic characterization. AB - An uncommon butterfly-like tetranuclear copper(ii) cluster with the formula {[Cu(4)(MU(3)-OH)(2)(MU(4)-Cl)(H(2)O)(2)(L)(2)].Cl(H(2)O)(7)}(n) (1) (H(2)L = 1,2 bis[3-(1,2,4-triazolyl)-4-amino-5-carboxylmethylthio]ethane) has been synthesized. Compound 1 exhibits interesting anion exchange characteristics, in which both guest and coordinated Cl(-) can be replaced by I(-) or NO(3)(-) in water. Furthermore, a high catalytic selectivity to produce poly(phenylene ether) by the oxidative coupling of 2,6-dimethylphenol in water is found to be 74% for 1 and 87% for the anion-exchanged product 1-MI(x), respectively. Additionally, the antiferromagnetic interaction among Cu ions for compound 1 is also found. PMID- 21293816 TI - Nitrogen fixation to cyanide at a molybdenum center. AB - Facile methoxymethylation of N(2)-derived nitride NMo(N[(t)Bu]Ar)(3) provided the imido cation [MeOCH(2)NMo(N[(t)Bu]Ar)(3)](+) as its triflate salt in 88% yield. Treatment of the latter with LiN(SiMe(3))(2) provided blue methoxyketimide complex MeO(H)CNMo(N[(t)Bu]Ar)(3) in 95% yield. Conversion of the latter to the terminal cyanide complex NCMo(N[(t)Bu]Ar)(3), which was the subject of a single crystal X-ray diffraction study, was accomplished in 51% yield upon treatment with a combination of SnCl(2) and Me(2)NSiMe(3). PMID- 21293817 TI - Influences on the rotated structure of diiron dithiolate complexes: electronic asymmetry vs. secondary coordination sphere interaction. AB - In the pursuit of a "rotated" structure, and exploration of the influence of the aza nitrogen lone pair, the Fe(I)Fe(I) model complexes wherein two Fe(CO)(3 x)P(x) moieties are significantly twisted from the ideal configuration (torsion angle >30 degrees ) are reported. [Fe(2)(MU S(CH(2))(2)N(i)Pr(X)(CH(2))(2)S)(CO)(4)(kappa(2)-dppe)](2)(2+) (X = H, 4; Me, 5) prepared from protonation and methylation, respectively, of [Fe(2)(MU S(CH(2))(2)N(i)Pr(CH(2))(2)S)(CO)(4)(kappa(2)-dppe)](2), 1, possess Phi angles of 34.1 and 35.4 degrees (av.), respectively. Such dramatic twist is attributed to asymmetric substitution within the Fe(2) unit in which a dppe ligand is coordinated to one Fe site in the kappa(2)-mode. In the presence of the N...C(CO(ap)) interaction, the torsion angle is decreased to 10.8 degrees , suggesting availability of lone pairs of the aza nitrogen sites within 1 is in control of the twist. Backbones of the bridging diphosphine ligands also affect distortion. For a shorter ligand, the more compact structure of [Fe(2)(MU S(CH(2))(2)N(i)Pr(CH(2))(2)S)(MU-dppm)(CO)(4)](2), 7, is formed. Dppm in a bridging manner allows achievement of the nearly eclipsed configuration. In contrast, dppe in [Fe(2)(MU-S(CH(2))(2)N(i)Pr(CH(2))(2)S)(MU-dppe)(CO)(4)](2), 6, could twist the Fe(CO)(3-x)L(x) fragment to adopt the least strained structure. In addition, the NC(CO(ap)) interaction would direct the twist towards a specific direction for the closer contact. In return, the shorter N...C(CO(ap)) distance of 3.721(7) A and larger Phi angle of 26.5 degrees are obtained in 6. For comparison, 3.987(7) A and 3.9 degrees of the corresponding parameters are observed in 7. Conversion of (MU-dppe)[Fe(2)(MU S(CH(2))(2)N(i)Pr(CH(2))(2)S)(CO)(5)](2), 2, to complex 1 via an associative mechanism is studied. PMID- 21293818 TI - Access to multinuclear salen complexes using olefin metathesis. AB - The use of olefin metathesis as a construction tool for multimetallic salen-based structures is described. The approach involves mono- and diallyl-functionalized metallosalen complexes that can be directly coupled by metathesis leading to dimetallic species or mixtures of linear and cyclic oligomers. The metathesis of bis-allyl Ni(salen) complexes has been studied in detail. At high concentration it is possible to selectively obtain di-Ni species rather than heavier oligomers while under dilute conditions cyclic rather than linear oligomers are preferentially obtained. A mono-allyl Zn(salphen) complex was efficiently coupled using metathesis to give the di-Zn(salphen) product, which was subsequently transmetalated with a variety of metals to yield dimetallic salens of potential catalytic interest. Finally, a tetranuclear Zn(4) macrocycle was also prepared using buildings blocks obtained by metathesis from commercially available precursors. The methods described herein allow for the facile construction of multi-centered Schiff base complexes of catalytic or supramolecular interest. PMID- 21293819 TI - Effects of lanthanide metal size and amino ligand denticity on the solvothermal systems Ln/Sn/Se/en and Ln/Sn/Se/dien (Ln = lanthanide). AB - Two systems, Ln/Sn/Se/en and Ln/Sn/Se/dien, were investigated under solvothermal conditions, and novel lanthanide selenidostannates [{Ce(en)(4)}(2)(MU Se(2))]Sn(2)Se(6) (1a), [{Ln(en)(3)}(2)(MU-OH)(2)]Sn(2)Se(6) (Ln = Pr(1b), Nd(1c), Gd(1d); en = ethylenediamine), [{Ln(dien)(2)}(4)(MU(4)-Sn(2)Se(9))(MU Sn(2)Se(6))](infinity) (Ln = Ce(2a), Nd(2b)), and [Hdien][Gd(dien)(2)(MU SnSe(4))] (2c) (dien = diethylenetriamine) were prepared and characterized. Two structural types of lanthanide selenidostannates were obtained across the lanthanide series in both systems. In the Ln/Sn/Se/en system, two types of binuclear lanthanide complex cations [Ce(2)(en)(8)(MU-Se(2))](4+) and [{Ln(en)(3)}(2)(MU-OH)(2)](4+) (Ln = Pr, Nd, Gd) were formed depending on the Ln(3+) ions. The complex cations are compensated by the [Sn(2)Se(6)](4-) anions. In the Ln/Sn/Se/dien system, coordination polymer [{Ln(dien)(2)}(4)(MU(4) Sn(2)Se(9))(MU-Sn(2)Se(6))](infinity) and ionic complex [Hdien][Gd(dien)(2)(MU SnSe(4))] are obtained along the lanthanide series, among which the MU(4) Sn(2)Se(9), MU-Sn(2)Se(6) and MU-SnSe(4) ligands to the Ln(3+) ions were observed. The formation of title complexes shows the effects of lanthanide metal size and amino ligand denticity on the lanthanide selenidostannates. Complexes 1a 2c exhibit semiconducting properties with band gaps between 2.08 and 2.48 eV. PMID- 21293820 TI - SO2-binding properties of cationic eta6,eta1-NCN-pincer arene ruthenium platinum complexes: spectroscopic and theoretical studies. AB - The SO(2)-binding properties of a series of eta(6),eta(1)-NCN-pincer ruthenium platinum complexes (NCN = 2,6-bis[(dimethylamino)methyl]phenyl anion) have been studied by both UV-visible spectroscopy and theoretical calculations. When an electron-withdrawing [Ru(C(5)R(5))](+) fragment (R = H or Me) is eta(6) coordinated to the phenyl ring of the NCN-pincer platinum fragment (cf. [2](+) and [3](+), see Scheme 1), the characteristic orange coloration (pointing to eta(1)- SO(2) binding to Pt) of a solution of the parent NCN-pincer platinum complex 1 in dichloromethane upon SO(2)-bubbling is not observed. However, when the ruthenium center is eta(6)-coordinated to a phenyl substituent linked in para position to the carbon-to-platinum bond, i.e. complex [4](+), the SO(2)-binding property of the NCN-platinum center seems to be retained, as bubbling SO(2) into a solution of the latter complex produces the characteristic orange color. We performed theoretical calculations at the MP2 level of approximation and TD-DFT studies, which enabled us to interpret the absence of color change in the case of [2](+) as an absence of coordination of SO(2) to platinum. We analyze this absence or weaker SO(2)-coordination in dichloromethane to be a consequence of the relative electron-poorness of the platinum center in the respective eta(6) ruthenium coordinated NCN-pincer platinum complexes, that leads to a lower binding energy and an elongated calculated Pt-S bond distance. We also discuss the effects of electrostatic interactions in these cationic systems, which also seems to play a destabilizing role for complex [2(SO(2))](+). PMID- 21293821 TI - A series of new phases in the alkali metal-Nb(V)/Ta(V)-Se(IV)/Te(IV)-O systems. AB - Six new phases in the alkali metal-Nb(V)/Ta(V)-Se(IV)/Te(IV)-O systems have been prepared by solid-state reactions at high-temperatures. Their structures were determined by single-crystal X-ray diffraction studies. AM(3)O(6)(QO(3))(2) (A = K, Rb, M = Nb, Ta, Q = Te; A = K, M = Nb, Q = Se) are isomorphous and their structures feature a 3D network with 1D 4- and 6-MRs tunnels along the a-axis which is composed of 2D layers of corner-sharing MO(6) octahedra bridged by QO(3) groups. The alkali metal ions are located at the above 1D tunnels of 6-MRs. The structure of Cs(3)Nb(9)O(18)(TeO(3))(2)(TeO(4))(2) features a thick Nb-Te-O layer built of corner-sharing NbO(6) octahedra, TeO(3) and TeO(4) groups. The 2D layer of the NbO(6) octahedra with 1D tunnels of 6-MRs along the c-axis are formed by 1D chains of NbO(6) chains along the c-axis and linear Nb(4)O(21) tetramers by corner-sharing. The TeO(3) and TeO(4) groups are grafted on both sides of the niobium-oxide layer via Nb-O-Te or/and Te-O-Te bridges. The caesium(i) ions are located at the above 1D tunnels of 6-MRs. TGA, UV-vis and infrared spectral measurements as well as electronic structure calculations have also been performed. PMID- 21293822 TI - Nanostructures on surfaces of the metalorganic compound {Fe2(CO)6[u-S2C6H2(OH)2]} and its potential as catalyst precursor for the synthesis of carbon nanotubes. AB - The compound {Fe(2)(CO)(6)[u-S(2)C(6)H(2)(OH)(2)]} is organized by H-bond interactions on graphite and SiO(2) surfaces as micron-length nanofibres. Thermal degradation of these fibres adsorbed on SiO(2) leads to a very homogeneous surface filled with Fe(2)O(3) nanoparticles (ca. 2.5 nm diameter) suitable to produce few-walled carbon nanotubes laying on a clean surface. PMID- 21293823 TI - Urea derivatives enhance the photocatalytic activity of dye-modified titanium dioxide. AB - Trace amounts of urea derivatives enhance the rate of nitrobenzene N3-sensitized TiO(2) photoreduction by catalyzing the proton transfer. The usually required addition of transition metal co-catalysts becomes dispensable for this visible light photocatalysis, facilitating its application in organic synthesis. PMID- 21293824 TI - Assay for molecular transport across gap junction channels in one-dimensional cell arrays. AB - Transport across gap junction channels (GJCs) between neighboring cells is critical to synchronizing cell's electrical and metabolic activities and maintaining cell homeostasis. Here we present a non-invasive microfluidic method to measure molecular diffusion across GJCs in multiple 1D cell arrays in real time. Using the chip, selective loading of a membrane permeant fluorescence dye (carboxyfluorescein) in Normal Rat Kidney (NRK) cells shows that the dye was able to diffuse through three cells along single cell chains in ~35 minutes. Application of 100 uM 2-aminoethoxydiphenyl borate (2-APB) reversibly inhibits connexin-43 gap junctions in NRK cells; 0.8 mM 1-heptanol inhibits the diffusion partially. The method offers rapid exchange of reagents, enabling sequential screening of multiple gap junction specific drugs with only one preparation of cells. It is capable of measuring gap junction mediated diffusion between single cells. PMID- 21293825 TI - Programmed trapping of individual bacteria using micrometre-size sieves. AB - Monitoring the real-time behavior of spatial arrays of single living bacteria cells is only achieved with much experimental difficulty due to the small size and mobility of the cells. To address this problem, we have designed and constructed a simple microfluidic device capable of trapping single bacteria cells in spatially well-defined locations without the use of chemical surface treatments. The device exploits hydrodynamics to slow down and trap cells flowing near a narrow aperture. We have modeled this system numerically by approximating the motion of Escherichia coli cells as rigid 3-D ellipsoids. The numerical predictions for the speed and efficiency of trapping were tested by fabricating the devices and imaging GFP expressing E. coli at a high spatio-temporal resolution. We find that our numerical simulations agree well with the actual cell flow for varying trap geometries. The trapped cells are optically accessible, and combined with our ability to predict their spatial location we demonstrate the ease of this method for monitoring multiple single cells over a time course. The simplicity of the design, inexpensive materials and straightforward fabrication make it an accessible tool for any systems biology laboratory. PMID- 21293826 TI - Ring-shaped neuronal networks: a platform to study persistent activity. AB - Persistent activity in the brain is involved in working memory and motor planning. The ability of the brain to hold information 'online' long after an initiating stimulus is a hallmark of brain areas such as the prefrontal cortex. Recurrent network loops such as the thalamocortical loop and reciprocal loops in the cortex are potential substrates that can support such activity. However, native brain circuitry makes it difficult to study mechanisms underlying such persistent activity. Here we propose a platform to study synaptic mechanisms of such persistent activity by constraining neuronal networks to a recurrent loop like geometry. Using a polymer stamping technique, adhesive proteins are transferred onto glass substrates in a precise ring shape. Primary rat hippocampal cultures were capable of forming ring-shaped networks containing 40 60 neurons. Calcium imaging of these networks show evoked persistent activity in an all-or-none manner. Blocking inhibition with bicuculline methaiodide (BMI) leads to an increase in the duration of persistent activity. These persistent phases were abolished by blockade of asynchronous neurotransmitter release by ethylene glycol tetraacetic acid (EGTA-AM). PMID- 21293827 TI - Heating and separation using nanomagnet-functionalized metal-organic frameworks. AB - A magnetic functionalization of microcrystalline MOF particles was realized using magnetic iron oxide particles. Such magnetic MOFs can be separated using a static magnetic field after use in catalytic processes and heated by an external alternating magnetic field to trigger desorption of encaged drug molecules. PMID- 21293828 TI - Photoreactivity of crystals of a rhodium dithionite complex with ethyltetramethylcyclopentadienyl ligands: crystal surface morphology changes and degradation. AB - A photoreactive rhodium dithionite complex [(RhCp(Et))(2)(MU-CH(2))(2)(MU O(2)SSO(2))] (1(Et)) with Cp(Et) (eta(5)-C(5)Me(4)Et) ligands was newly synthesized. Upon short-time irradiation with low intensity light, two kinds of stepwise surface morphology changes of the crystal 1(Et) were observed. Prolonged irradiation with high intensity light caused cracking and breaking down of the crystal. PMID- 21293829 TI - Wirelessly powered microfluidic dielectrophoresis devices using printable RF circuits. AB - We report the first microfluidic device integrated with a printed RF circuit so the device can be wirelessly powered by a commercially available RFID reader. For conventional dielectrophoresis devices, electrical wires are needed to connect the electric components on the microchip to external equipment such as power supplies, amplifiers, function generators, etc. Such a procedure is unfamiliar to most clinicians and pathologists who are used to working with a microscope for examination of samples on microscope slides. The wirelessly powered device reported here eliminates the entire need for wire attachments and external instruments so the operators can use the device in essentially the same manner as they do with microscope slides. The integrated circuit can be fabricated on a flexible plastic substrate at very low cost using a roll-to-roll printing method. Electrical power at 13.56 MHz transmitted by a radio-frequency identification (RFID) reader is inductively coupled to the printed RFIC and converted into 10 V DC (direct current) output, which provides sufficient power to drive a microfluidic device to manipulate biological particles such as beads and proteins via the DC dielectrophoresis (DC-DEP) effect. To our best knowledge, this is the first wirelessly powered microfluidic dielectrophoresis device. Although the work is preliminary, the device concept, the architecture, and the core technology are expected to stimulate many efforts in the future and transform the technology to a wide range of clinical and point-of-care applications. PMID- 21293830 TI - Integrated DNA purification, PCR, sample cleanup, and capillary electrophoresis microchip for forensic human identification. AB - A fully integrated microdevice and process for forensic short tandem repeat (STR) analysis has been developed that includes sequence-specific DNA template purification, polymerase chain reaction (PCR), post-PCR cleanup and inline injection, and capillary electrophoresis (CE). Fragmented genomic DNA is hybridized with biotin-labeled capture oligos and pumped through a fluidized bed of magnetically immobilized streptavidin-coated beads in microchannels where the target DNA is bound to the beads. The bead-DNA conjugates are then transferred into a 250 nL PCR reactor for autosomal STR amplification using one biotin and one fluorescence-labeled primer. The resulting biotin-labeled PCR products are electrophoretically injected through a streptavidin-modified capture gel where they are captured to form a concentrated and purified injection plug. The thermally released sample plug is injected into a 14 cm long CE column for fragment separation and detection. The DNA template capture efficiency provided by the on-chip sequence-specific template purification is determined to be 5.4% using K562 standard DNA. This system can produce full 9-plex STR profiles from 2.5 ng input standard DNA and obtain STR profiles from oral swabs in about 3 hours. This fully integrated microsystem with sample-in-answer-out capability is a significant advance in the development of rapid, sensitive, and reliable micro total analysis systems for on-site human identification. PMID- 21293831 TI - Magnetic CoPt nanoparticles as MRI contrast agent for transplanted neural stem cells detection. AB - Neural stem cells (NSCs) exhibit features that make them suitable candidates for stem cell replacement therapy and spinal cord reconstruction. Magnetic resonance imaging (MRI) offers the potential to track cells in vivo using innovative approaches to cell labeling and image acquisition. In this study, experiments were carried out to optimize the loading condition of magnetic CoPt hollow nanoparticles (CoPt NPs) into neural stem cells and to define appropriate MRI parameters. Both cell viability and multipotency analysis showed that CoPt NPs at a concentration of 16 ug ml(-1) reduced T2 relaxation times in labeled rat NSCs, producing greater contrast on spin echo acquisitions at 4.7 T, yet did not affect cell viability and in vitro differentiation potential compared to controls. After optimizing nanoparticle loading concentrations and labeled cell numbers for MRI detection, CoPt-loaded NSCs were transplanted into organotypic spinal cord slices. The results showed that MRI could efficiently detect low numbers of CoPt labeled NSCs with the enhanced image contrast. Our study demonstrated that MRI of grafted NSCs labeled with CoPt NPs is a useful tool to evaluate organotypic spinal cord slice models and has potential applications in other biological systems. PMID- 21293832 TI - Epidemiological profile and strategies for diagnosing SIDS in a developing country. AB - OBJECTIVE: To describe the epidemiological profile, risk factors and best strategies for diagnosing sudden infant death syndrome (SIDS) in a developing country. METHODS: Population-based, case-control study with children born between January 1st, 2001, and December 31st, 2003, in Porto Alegre, southern Brazil, who were allocated into three groups: SIDS cases (33), explained death controls (192), and living controls (192). Children in the latter two groups were age- and sex-paired with SIDS cases. Families in which an infant had died at home within the first year of life were identified, and the information available on death certificates and autopsy reports was compared to confirm the diagnosis of SIDS. Explained death controls consisted of infants who had died at city hospitals, and living controls were selected in the same neighborhood as SIDS cases. All parents were interviewed to obtain information on children's health and sleep habits. Multivariate analysis was performed to identify risk factors in the study population. RESULTS: The incidence of SIDS in the population assessed was 0.55/1,000 live births. The analysis revealed the following risk factors: ethnicity (characterized by self-reported black skin color), prematurity, low birth weight, adolescent mother, smoking during pregnancy, and family income of less than one minimum wage. Ninety-four percent of SIDS cases were misdiagnosed in the death certificate. CONCLUSIONS: Although SIDS was misdiagnosed in official death certificates, the epidemiological profile is similar to the literature, as well as risk factors, which could be reduced with preventive campaigns. Investigating SIDS in developing countries requires special strategies to avoid misdiagnosis. PMID- 21293833 TI - Cutaneous side-effects of EGFR inhibitors and their management. AB - Epidermal growth factor receptor (EGFR) inhibitors are an increasingly important treatment option for metastasized cancer in patients. In addition to the pivotal role of EGFR in the development and progression of malignant tumors, EGFR is also important for proliferation and differentiation of the human epidermis and hair follicles. As a consequence, cutaneous side-effects are frequently observed during cancer therapy with EGFR inhibitors. During the first few weeks of treatment, acneiform eruptions are the earliest common side-effect. Xerosis and fissures are complications appearing in later treatment phases. Paronychia and alterations in hair growth are less common and generally seen after a longer period of treatment. We present an overview of the various cutaneous side-effects associated with EGFR inhibition and discuss their respective therapeutic options. PMID- 21293834 TI - Current effective topical therapies in the management of psoriasis. AB - Topical therapy forms the cornerstone of treatment in the management of psoriasis. It plays a significant role as monotherapy in mild to moderate psoriasis, and it is used predominantly as adjunctive therapy in moderate to severe forms of the disease. Over the past decade, the topical treatment of psoriasis has evolved from the age-old applications, such as coal tar, to the more cosmetically acceptable and efficacious options containing topical corticosteroids, vitamin D analogues, and combined agents. With the advent of topical therapies in tailored vehicles and sophisticated delivery modes, the outlook for effectively managing psoriasis with topical approaches appears promising. To ensure therapeutic success, patient education about the disease, treatment options, proper administration, and adverse effects is essential, which will alleviate the common problem of poor patient adherence and promote more optimal clinical outcomes. PMID- 21293835 TI - Magnetic resonance imaging of the spine in a patient with decompression sickness. PMID- 21293836 TI - Excessive contrast medium leakage in hyperperfusion syndrome. PMID- 21293837 TI - New approach for treatment of vertebral metastases using intensity-modulated radiotherapy. AB - PURPOSE: To perform aggressive radiotherapy for vertebral metastases. Using very steep dose gradients from intensity-modulated radiotherapy (IMRT), a protocol based on the concept of partial volume dose to the spinal cord was evaluated. PATIENTS AND METHODS: 50 patients with vertebral metastases were treated using IMRT. In previously unirradiated cases, where a prescribed dose of 80 Gy (BED10) was delivered, the constraint to the spinal cord should be less than 100 Gy (BED2). For previously irradiated cases, on the other hand, the dose is the same as in the previously unirradiated case; however, constraints for the spinal cord are a cumulative BED2 of less than 150 Gy, BED2 of less than 100 Gy in each instance, and a treatment gap of more than 6 months. There were 6 patients considered for a partial volume dose to the spinal cord. They all received higher BED2, ranging from 51-157 Gy of D1cc. RESULTS: Among the 24 patients who survived longer than 1 year, there was 1 case of transient radiation myelitis. There were no other cases of spinal cord sequelae. CONCLUSION: Based on the present results, we recommend a BED2 of 100 Gy or less at D1cc as a constraint for the spinal cord in previously unirradiated cases, and a cumulative BED2 of 150 Gy or less at D1cc in previously irradiated cases, when the interval was not shorter than 6 months and the BED2 for each session was 100 Gy or less. The prescribed BED10 of 80 Gy could be safely delivered to the vertebral lesions. PMID- 21293838 TI - [Perioperative anesthesia management of extended partial liver resection. Pathophysiology of hepatic diseases and functional signs of hepatic failure]. AB - The importance of partial liver resection as a therapeutic option to cure hepatic tumors has increased over the last decades. This has been influenced on the one hand by advances in surgical and anesthetic management resulting in a reduced mortality after surgery and on the other hand by an increased incidence of hepatocellular carcinoma. Nowadays, partial resection of the liver is performed safely and as a routine operation in specialized centers. This article describes the pathophysiological changes secondary to liver failure and assesses the perioperative management of patients undergoing partial or extended liver resection. It looks in detail at the preoperative assessment, the intraoperative anesthetic management including fluid management and techniques to reduce blood loss as well as postoperative analgesia and intensive care therapy. PMID- 21293839 TI - Genetic diversity of cultivated flax (Linum usitatissimum L.) germplasm assessed by retrotransposon-based markers. AB - Retrotransposon segments were characterized and inter-retrotransposon amplified polymorphism (IRAP) markers developed for cultivated flax (Linum usitatissimum L.) and the Linum genus. Over 75 distinct long terminal repeat retrotransposon segments were cloned, the first set for Linum, and specific primers designed for them. IRAP was then used to evaluate genetic diversity among 708 accessions of cultivated flax comprising 143 landraces, 387 varieties, and 178 breeding lines. These included both traditional and modern, oil (86), fiber (351), and combined use (271) accessions, originating from 36 countries, and 10 wild Linum species. The set of 10 most polymorphic primers yielded 141 reproducible informative data points per accession, with 52% polymorphism and a 0.34 Shannon diversity index. The maximal genetic diversity was detected among wild Linum species (100% IRAP polymorphism and 0.57 Jaccard similarity), while diversity within cultivated germplasm decreased from landraces (58%, 0.63) to breeding lines (48%, 0.85) and cultivars (50%, 0.81). Application of Bayesian methods for clustering resulted in the robust identification of 20 clusters of accessions, which were unstratified according to origin or user type. This indicates an overlap in genetic diversity despite disruptive selection for fiber versus oil types. Nevertheless, eight clusters contained high proportions (70-100%) of commercial cultivars, whereas two clusters were rich (60%) in landraces. These findings provide a basis for better flax germplasm management, core collection establishment, and exploration of diversity in breeding, as well as for exploration of the role of retrotransposons in flax genome dynamics. PMID- 21293840 TI - Downy mildew (Pl ( 8 ) and Pl ( 14 )) and rust (R ( Adv )) resistance genes reside in close proximity to tandemly duplicated clusters of non-TIR-like NBS-LRR encoding genes on sunflower chromosomes 1 and 13. AB - Nucleotide binding site-leucine rich repeat (NBS-LRR) proteins are encoded by a ubiquitous gene family in sunflower and frequently harbor disease resistance genes. We investigated NBS-LRR-encoding resistance gene candidates (RGCs) flanking the downy mildew resistance genes Pl ( 8 ) and Pl ( 14 ) and the rust resistance gene R ( Adv ), which map on the NBS-LRR clusters of linkage groups 1 and 13 in sunflower genome. We shotgun sequenced bacterial artificial chromosome (BAC) clones proximal to Pl ( 8 ), Pl ( 14 ) , and R ( Adv ) and identified seven novel non-Toll/interleukin-1 receptor (TIR)-like NBS-LRR RGCs, which clustered with previously identified RGCs of linkage group 13 but were phylogenetically distant from the TIR- and non-TIR-NBS-LRR-encoding superfamilies of sunflower. Six of the seven predicted RGCs have intact open reading frames and reside in genomic segments with abundant transposable elements. The genomic localization and sequence similarity of the novel non-TIR-like predicted RGCs suggests that they originated from tandem duplications. RGCs in the proximity of Pl ( 8 ) and R ( Adv ) were likely introgressed from silverleaf sunflower genome, where the RGC cluster of linkage group 13 is duplicated in two independent chromosomes that have different architecture and level of recombination from the respective common sunflower chromosomes. PMID- 21293841 TI - The mental health system in Lombardy, Italy: access to services and patterns of care. AB - PURPOSE: The psychiatric reform in Italy devolved to the regions the responsibility of implementing community psychiatric care. The aim of this paper is to evaluate the mental health system in Lombardy by assessing changes in accessibility and patterns of care occurred between 1999 and 2009. METHODS: Data on mental health services were collected through the regional mental health information system and analyzed in terms of treated prevalence, treated incidence, continuity of care and packages of care. RESULTS: Both treated incidence and treated prevalence in Lombardy increased between 1999 and 2009. There was an increasing access to psychiatric services of people with a better social integration. Incidence of schizophrenic and personality disorders decreased and that of affective and neurotic disorders increased dramatically, while increase in prevalence concerned all diagnostic groups. The percentage of patients in continuous care remained stable and was generally low. The majority of cases, even those with schizophrenia, are cared for on outpatient basis. The percentage of patients receiving integrated multiprofessional care declined. Rates of admission to inpatient services remained low and within the inpatient sector a shift from hospital towards residential care emerged, with decreasing hospital utilization and an increase in size of patient population entering community residences. Treatment gap is still a problem in schizophrenic disorders. CONCLUSIONS: The Lombardy mental health system is strongly based on community care. However, it is reaching a turning point and it needs to be improved in some key areas: the shifting balance towards the care of common mental disorders, in the absence of resource allocations targeted to severely mentally ill, may hinder the system ability to deal with more disabled people. A focus on early intervention and an improvement of continuity of care for people with severe mental disorder, by strengthening community teams, is a priority. PMID- 21293842 TI - Adolescent emotional and behavioural outcomes of nonparental preschool childcare. AB - PURPOSE: This study aimed to identify whether nonparental preschool childcare was associated with adolescent mental health outcomes as measured by the strengths and difficulties questionnaire (SDQ). METHOD: This study was a secondary analysis of data from the Croydon Assessment of Learning Study. From a general population sample of 2,726 adolescents tested for cognitive ability, additional data were collected from a stratified sub-sample of 197 subjects. A semi-structured interview asked parents about preschool childcare and early development concerns. Parent and teacher SDQ and IQ data were collected. Complete data were available from 167 subjects. Using nonparental preschool childcare as the 'treatment' effect and parental childcare as the 'control', propensity score matching analyses were used to analyse the effect of nonparental childcare on adolescent SDQ outcomes. RESULTS: Nonparental childcare was reported by 49% of the sample and was not significantly associated with conduct, emotional, peer or prosocial SDQ subscales, but was found to have a significant average treatment effect on symptoms of attention/hyperactivity, on average raising the symptom subscale score by 1.8 (95% confidence interval 0.12-3.65). The propensity score analysis ensures the results could not be explained by the available measures that influenced receiving nonparental care. Increased time spent in nonparental childcare was associated with greater attention/hyperactivity symptoms. CONCLUSIONS: Nonparental preschool care showed little association with generalized psychopathology but may be associated with hyperactivity and inattention problems. Replication of these findings in prospective studies is required. PMID- 21293843 TI - Prevalence of autism spectrum disorders and influence of country of measurement and ethnicity. AB - BACKGROUND: The prevalence of autism spectrum disorders (ASD) is generally somewhat lower in countries outside of North America and Europe. While there are culture-specific patterns of social cognitive processing, the influence of such patterns upon ASD prevalence has yet to be fully explored. METHODS: A comprehensive literature search for original articles reporting ASD prevalence was undertaken. Data across studies were compared with a particular focus on variables of geographic residence and ethnicity. RESULTS: ASD prevalence varies across countries in a manner that appears to suggest that the greatest influence is due to methodological variables. The nature of a potential influence of culture-specific patterns of cognitive processing upon prevalence remains unknown. The available little data concerning the association between ethnicity and prevalence are limited to studies within the United States (US) showing differences in children of Hispanic descent relative to Whites, a finding for which a definitive explanation is lacking. CONCLUSIONS: Available evidence suggests that methodological factors are largely responsible for differences in ASD prevalence across studies. The much discussed increase in prevalence in ASD has been observed worldwide, suggesting that the refinement of diagnostic methodology and/or broadening diagnostic concept is not limited to Western countries. Within individual countries, only in the US has the influence of ethnicity upon ASD prevalence been examined in depth. In the US, children of Hispanic descent have the lowest prevalence of ASD, while Whites tend to have the highest prevalence of ASD. Hypothesized etiological factors for such prevalence differences include methodological factors, socioeconomic variables, and bias. PMID- 21293844 TI - Prevalence, symptom patterns and comorbidity of anxiety and depressive disorders in primary care in Qatar. AB - AIM: The aim of this study was to assess the prevalence of anxiety and depressive disorders in a Qatari population who attend the primary health care settings and examine their symptom patterns and comorbidity. DESIGN: This is a prospective cross-sectional study conducted during the period from July 2009 to December 2009. SETTING: Primary Health Care Center and the Supreme Council of Health in the State of Qatar. SUBJECTS: A total of 2,080 Qatari subjects aged 18-65 years were approached and 1,660 (79.8%) patients participated in this study. METHODS: The study was based on a face-to-face interview with a designed diagnostic screening questionnaire, which consisted of 14 items for anxiety and depression disorders. Socio-demographic characteristics, comorbidity factors, and medical history of patients were collected. The Hospital Anxiety and Depression Rating Scale (HADS), which consisted of seven items for anxiety (HADS-A) and seven for depression (HADS-D), was used. The items are scored on a 4-point scale from zero (not present) to 3 (considerable). The HADS-A had an optimal cut-off >= 8 (sensitivity 0.87 and specificity 0.78), and the HADS-D had an optimal cut-off >= 8 (sensitivity 0.82 and specificity 0.86). The HADS scales generally used the cut off score >= 8 to identify respondents with the possible presence of anxiety or depression. RESULTS: Of the studied Qatari subjects, 46.2% were males and 53.8% were females. The mean HADS-A anxiety symptom scores were 4.1 +/- 3.6 for males and 4.9 +/- 3.7 for females (p = 0.048) and with a prevalence of 18.7% among males and 24.6% among females (p = 0.017). The mean HADS-D depressive symptom scores were 8.0 +/- 6.3 for males and 10.8 +/- 7.5 for females (p = 0.041) and with a prevalence of 26.6% among males and 30.1% among females (p = 0.219). Qatari women were at higher risk for depression (53.1 vs. 46.9%) and anxiety disorder (56.7 vs. 43.3%) as compared to men. More than half of the sufferers with anxiety (56.7%) and depression (53.1%) were Qatari women with a higher frequency in the age group 18-34 years. There were significant differences between men and women with depression in terms of age group (p = 0.004), marital status (p = 0.04), occupation (p < 0.001), and household income (p = 0.002). Nervousness was the most common symptom in subjects with anxiety disorders (68.4%), whereas sleep difficulty was the most common symptom in subjects with depressive disorder (59.4%). Diabetes mellitus (23.4 vs. 19.2%), hypertension (25.7 vs. 25.0%), headache and migraine (21.6 vs. 25.4%), and low back pain (22.2 vs. 28.6%) were the frequent comorbidity conditions in both anxiety and depressive disorders, respectively, in the studied subjects. CONCLUSION: The findings of this study revealed that depression was more prevalent in the Qatari population than anxiety disorders. Women were likelier than men to have depression and anxiety disorders. The high-risk groups of depression and anxiety disorders were female gender, being married, middle aged, and highly educated. PMID- 21293845 TI - The relationship between socioeconomic position and depression among a US nationally representative sample of African Americans. AB - PURPOSE: Findings from previous studies have not revealed significant, inverse relationships between socioeconomic position (SEP) and depression among African Americans. This study examined the relationship between multiple indicators of SEP and Major Depressive Episode (MDE) among African Americans. METHODS: Data were drawn from the National Survey of American Life main interview and re interview. MDE, at both 12 month and lifetime intervals, was assessed using the World Mental Health version of the Composite International Diagnostic Interview. Logistic regression models were adjusted for demographics. RESULTS: For 12-month MDE, household income and unemployment predicted greater odds of MDE among African American men, while there was an inverse relationship between education and 12-month MDE. Only unemployment was significantly associated with lifetime MDE among African American men. For African American women, a significant inverse relationship between household income and 12-month MDE was observed. CONCLUSIONS: Findings garnered from this study indicate that it is important to consider multiple measures of SEP in the prediction of depression among African Americans, and that the pattern of association between SEP and depression varies according to sex. Considering the paucity of studies that have explored the relationship between SEP and depression, additional research is needed to more firmly establish the relationship between SEP and depression. It is also important to consider stressors that may affect the relationship between SEP and depression among African Americans. PMID- 21293846 TI - Emotional support, negative interaction and major depressive disorder among African Americans and Caribbean Blacks: findings from the National Survey of American Life. AB - OBJECTIVES: Few studies have examined the association between social support, negative interaction, and major depressive disorder among representative samples of racial and ethnic minority groups. This study investigates the relationship between emotional support and negative interaction with family members on lifetime major depressive disorder among African Americans and Caribbean Blacks. METHOD: Cross-sectional epidemiologic data from the National Survey of American Life and multivariable logistic regression analyses were used to predict lifetime history of major depressive disorder and to examine the effect of perceived emotional support and negative interaction on major depressive disorder among 3,570 African Americans and 1,621 Caribbean Blacks aged 18 and older. RESULTS: Multivariate analyses found that perceived emotional support was associated with lower odds of MDD for African Americans and Caribbean Blacks. Negative interaction with family was associated with greater odds of MDD for African Americans and Caribbean Blacks. Emotional support moderated the impact of negative interaction on MDD for Caribbean Blacks, but not for African Americans. DISCUSSION: This is the first study to investigate the relationships between emotional support, negative interaction with family members and depressive disorder among African Americans and Caribbean Blacks. Negative interaction was a risk factor for depression and emotional support was a protective factor. PMID- 21293847 TI - Income-related inequalities in common mental disorders among ethnic minorities in England. AB - PURPOSE: The relative prevalence of common mental health problems among different ethnic groups in Britain is one of the least researched topics in health variations research. We calculate and compare income-related inequalities in common mental disorders among ethnic groups in Britain. METHOD: Data from a nationally representative survey of ethnic minorities (the EMPIRIC survey) were used to calculate concentration index values to indicate the extent of income related inequalities within and across ethnic groups. RESULTS: Looking at income related inequalities in common mental disorders within each of the ethnic groups, it was found that the burden of these disorders were greater for the lower income groups among the Irish, White and African Caribbean communities. Within-group inequality was less clearly defined for each of the three Asian communities: Indian, Bangladeshi and Pakistani. However, when the data were pooled and individuals were assigned income ranks in the pooled set (not within their own ethnic group), the relative position of those in lower income groups among the different groups was striking. The poor among the Bangladeshi, Pakistani and the African Caribbean groups clearly suffered both from low income and a greater burden of mental health morbidity than the other three groups. The effect of lower income is thus worse for the mental health of populations if they are African Caribbean, Pakistani or Bangladeshi than if they are White, Irish or Indian. CONCLUSION: Inequality in mental health morbidity between and within ethnic groups is at least partly linked to income, and thus to employment and education. Tackling disadvantage and discrimination in these areas could help to tackle the challenge of mental ill-health. PMID- 21293848 TI - Remodelling of human hamstring autografts after anterior cruciate ligament reconstruction. AB - PURPOSE: Histological analysis of the remodelling process of human hamstring tendon (HT) grafts after standardized anterior cruciate ligament reconstruction (ACLR) with an accelerated rehabilitation protocol. METHODS: Sixty-seven patients underwent retrieval of mid-substance biopsies after clinically successful hamstring autograft ACLR. Samples were allocated to one of three groups depending on the time point of retrieval: group 1 (6-12 months; n = 15), group 2 (13-24 months; n = 16) and group 3 (>24 months; n = 11). Biopsies from native HT (n = 17) and ACL (n = 8) served as controls. Cellular density, vascular density and myofibroblast density and collagen fibril alignment were analysed by haematoxylin eosin, Masson-Goldner-Trichrom and immunohistochemical staining protocols. RESULTS: Compared with native HT (330.4/mm2), total cell number was increased in groups 1-3 (Group 1 = 482.0/mm2 (P = 0.036); group 2 = 850.9/mm2 (P = 0.005); and group 3 = 595.6/mm2 (P = 0.043). There were no significant differences between the groups for vessel density. Myofibroblast density was higher in group 2 (199.6/mm2) compared with native HT (1.9/mm2, P = 0.014). Collagen orientation was irregular up to 12 months. Thereafter, collagen orientation became more regular, adapting to, but not fully restoring, the appearance of the intact ACL. For the first 12 months, cells were predominantly ovoid. Ensuing cell morphology changed to spindle shaped in group 2 and predominantly narrow long cells over 24 months. CONCLUSION: Human hamstring grafts showed typical stages of graft remodelling, which was not complete up to 2 years after ACLR. The remodelling process in humans was prolonged compared with the results obtained in several animal studies. LEVEL OF EVIDENCE: Case-control study, Level III. PMID- 21293849 TI - Is all risk bad? Young adult cigarette smokers fail to take adaptive risk in a laboratory decision-making test. AB - RATIONALE: Cigarette smoking has been linked to real-world risky behavior, but this association has been based largely on retrospective self-reports. Limitations of self-report data can be avoided by using laboratory, performance based measures, such as the Balloon Analogue Risk Task (BART; Lejuez et al., J Exp Psychol Appl 8:75-84, 2002). Initial studies have suggested that smokers display greater risk-taking on this task than nonsmokers, but these studies did not account for drug abuse and psychiatric comorbidities, which are commonplace among smokers. OBJECTIVES: We sought to examine the performance of smokers and nonsmokers on the BART after excluding drug abuse and psychiatric comorbidities. METHODS: We conducted a study of late adolescent/young adult (age 18 to 21) smokers (n = 26) and nonsmokers (n = 38) performing the BART and excluded individuals with positive drug or alcohol toxicology screens, substance abuse or dependence diagnoses, and/or current psychiatric conditions. RESULTS: Contrary to previous findings, smokers did not display greater risk-taking on the BART than nonsmokers. In fact, when performance was examined trial-by-trial, the nonsmokers displayed progressively greater pumping relative to smokers over time (p < .001), earning them a nonsignificantly greater amount of money than the smokers. Controlling for smoking status, additional analyses revealed that pumping on the BART was positively associated with years of education, nonverbal IQ, and employment. CONCLUSIONS: The results suggest that in young adults, smoking may be associated with a failure to take risks in situations where risk-taking is adaptive. PMID- 21293850 TI - The functional significance of velocity storage and its dependence on gravity. AB - Research in the vestibular field has revealed the existence of a central process, called 'velocity storage', that is activated by both visual and vestibular rotation cues and is modified by gravity, but whose functional relevance during natural motion has often been questioned. In this review, we explore spatial orientation in the context of a Bayesian model of vestibular information processing. In this framework, deficiencies/ambiguities in the peripheral vestibular sensors are compensated for by central processing to more accurately estimate rotation velocity, orientation relative to gravity, and inertial motion. First, an inverse model of semicircular canal dynamics is used to reconstruct rotation velocity by integrating canal signals over time. However, its low frequency bandwidth is limited to avoid accumulation of noise in the integrator. A second internal model uses this reconstructed rotation velocity to compute an internal estimate of tilt and inertial acceleration. The bandwidth of this second internal model is also restricted at low frequencies to avoid noise accumulation and drift of the tilt/translation estimator over time. As a result, low-frequency translation can be erroneously misinterpreted as tilt. The time constants of these two integrators (internal models) can be conceptualized as two Bayesian priors of zero rotation velocity and zero linear acceleration, respectively. The model replicates empirical observations like 'velocity storage' and 'frequency segregation' and explains spatial orientation (e.g., 'somatogravic') illusions. Importantly, the functional significance of this network, including velocity storage, is found during short-lasting, natural head movements, rather than at low frequencies with which it has been traditionally studied. PMID- 21293851 TI - Is inefficient multisensory processing associated with falls in older people? AB - Although falling is a significant problem for older persons, little is understood about its underlying causes. Spatial cognition and balance maintenance rely on the efficient integration of information across the main senses. We investigated general multisensory efficiency in older persons with a history of falls compared to age- and sensory acuity-matched controls and younger adults using a sound induced flash illusion. Older fallers were as susceptible to the illusion as age matched, non-fallers or younger adults at a short delay of 70 ms between the auditory and visual stimuli. Both older adult groups were more susceptible to the illusion at longer SOAs than younger adults. However, with increasing delays between the visual and auditory stimuli, older fallers did not show a decline in the frequency at which the illusion was experienced even with delays of up to 270 ms. We argue that this relatively higher susceptibility to the illusion reflects inefficient audio-visual processing in the central nervous system and has important implications for the diagnosis and rehabilitation of falling in older persons. PMID- 21293852 TI - Three novel mutations in the PHEX gene in Chinese subjects with hypophosphatemic rickets extends genotypic variability. AB - Mutations in the phosphate-regulating endopeptidase homolog, X-linked, gene (PHEX), which encodes a zinc-dependent endopeptidase that is involved in bone mineralization and renal phosphate reabsorption, cause the most common form of hypophosphatemic rickets, X-linked hypophosphatemic rickets (XLH). The distribution of PHEX mutations is extensive, but few mutations have been identified in Chinese with XLH. We extracted genomic DNA and total RNA from leukocytes obtained from nine unrelated Chinese subjects (three males and six females, age range 11-36 years) who were living in Taiwan. The PHEX gene was amplified from DNA by PCR, and the amplicons were directly sequenced. Expression studies were performed by reverse-transcription PCR of leukocyte RNA. Serum levels of FGF23 were significantly greater in the patients than in normal subjects (mean 69.4 +/- 18.8 vs. 27.2 +/- 8.4 pg/mL, P < 0.005), and eight of the nine patients had elevated levels of FGF23. Germline mutations in the PHEX gene were identified in five of 9 patients, including novel c.1843 delA, donor splice site mutations c.663+2delT and c.1899+2T>A, and two previously reported missense mutations, p.C733Y and p.G579R. These data extend the spectrum of mutations in the PHEX gene in Han Chinese and confirm variability for XLH in Taiwan. PMID- 21293853 TI - Epigenetic regulation of E2F-1-dependent Bnip3 transcription and cell death by nuclear factor-kappaB and histone deacetylase-1. AB - A delicate balance exists between cell growth and cell death. In the context of the adult myocardium, inappropriate or inordinate cell loss through an apoptotic process may profoundly influence cardiac structure, function, or both given the limited and meager ability of the heart for repair after injury. Earlier work by the authors' laboratory identified a close relation between cell cycle factor E2F 1 and hypoxia-inducible factor Bnip3 as the key regulator of apoptosis and autophagy in ventricular myocytes. Epigenetic changes by histone-modifying proteins, namely, histone deacetylases (HDACs) influence cell survival by altering the activity of histone core proteins, transcription factors, or both. This report highlights the intricate nature between the cellular factors E2F-1 and nuclear factor-kappaB (NF-kappaB) and the epigenetic regulation of Bnip3 gene transcription by HDAC1 for cell survival of ventricular myocytes. PMID- 21293854 TI - Engineered human cardiac tissue. AB - The human heart is the first organ to develop during embryogenesis and is arguably the most essential organ for life. However, after birth, the heart has very little capacity to repair malformations such as congenital heart defects or to regenerate after an injury such as myocardial infarction. Cardiac tissue engineering addresses the need for a therapeutic biologic implant to restore cardiac structure and muscle mass. This review highlights current research in cardiac tissue engineering that uses human cardiomyocytes derived from embryonic stem cells. Other human cell sources are discussed because future human therapies will benefit from novel techniques using human-induced pluripotent stem cells and cardiomyocytes derived from direct reprogramming of somatic cells. Furthermore, this review examines the main approaches to creating engineered cardiac tissue with synthetic scaffolds, natural scaffolds, or no exogenous scaffold (i.e., "scaffold free"). The choice of scaffold and cells ultimately depends on the goals of the therapy, so the review considers how congenital heart defects define the design parameters for cardiac tissue engineering needed for surgical repair in pediatric cardiac patients. PMID- 21293855 TI - Ileal pouch and related complications: spectrum of imaging findings with emphasis on MRI. AB - Proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the established surgical therapy for familial adenomatous polyposis (FAP) and refractory ulcerative colitis (UC). Despite general patient satisfaction with preserved fecal continence, this procedure is associated with a significant long-term morbidity approaching 70% after 10 years, and with a non-negligible rate of pouch failure leading to removal and permanent ileostomy. Following a concise description of the surgical technique, the normal imaging appearance of the ileal "pouch" reservoir at pelvic CT and MRI is explained. Since awareness of their imaging appearances is needed for a correct diagnosis, we discuss and illustrate common and unusual pouch-related complications, including pouchitis and irritable pouch disease; anastomotic leakages and pelvic abscess collections; fistulas involving the ano-perianal region, urinary bladder, vagina, perineal skin, and subcutaneous planes; anal stenosis and small-bowel obstruction. In our experience, pelvic contrast-enhanced MRI has proven invaluable for the diagnostic assessment of patients with suspected pouch-related complications, allowing differentiation of uncomplicated pouchitis from pelvic sepsis, the latter requiring aggressive therapy and possible even in patients with normal endoscopic findings. PMID- 21293856 TI - Tumour exosomes inhibit binding of tumour-reactive antibodies to tumour cells and reduce ADCC. AB - In order to grow within an immunocompetent host, tumour cells have evolved various strategies to cope with the host's immune system. These strategies include the downregulation of surface molecules and the secretion of immunosuppressive factors like IL-10 and PGE2 that impair the maturation of immune effector cells, among other mechanisms. Recently, tumour exosomes (TEX) have also been implicated in tumour-induced immune suppression as it has been shown that TEX can induce apoptosis in T lymphocytes. In this study, we extend our knowledge about immunosuppressive features of these microvesicles in that we show that TEX efficiently bind and sequester tumour-reactive antibodies and dramatically reduce their binding to tumour cells. Moreover, we demonstrate that this antibody sequestration reduces the antibody-dependent cytotoxicity by immune effector cells, which is among the most important anti-tumour reactions of the immune system and a significant activity of therapeutic antibodies. Taken together, these data point to the fact that tumour-derived exosomes interfere with the tumour-specific function of immune cells and constitute an additional mechanism how tumours escape from immune surveillance. PMID- 21293857 TI - Adherence inhibition of Cronobacter sakazakii to intestinal epithelial cells by prebiotic oligosaccharides. AB - Cronobacter sakazakii is an opportunistic pathogen that has been implicated in meningitis, NEC, and sepsis in neonates. Colonization and subsequent infection and invasion of C. sakazakii require that the organism adheres to host cell surfaces. Agents that inhibit or block attachment of the pathogen to epithelial cells could be useful in reducing infections. The goal of this research was to assess the ability of prebiotic galactooligosaccharides (GOS) and polydextrose (PDX) to inhibit adherence of C. sakazakii 4603 to a HEp-2 human cell line. Adherence experiments were performed in the presence or absence of prebiotics using HEp-2 cells grown to confluency on glass coverslips. Prebiotics and bacteria were added and incubated for 3 h. Coverslips were washed, and adherence was determined by cultural and microscopic methods. When measured microscopically or by cultural methods, significant reductions in adherence (56 and 71%, respectively) of C. sakazakii were observed in the presence of GOS (16 mg/ml). Adherence inhibition also occurred (48%) when a GOS-PDX blend (8 mg/ml each) was tested, although PDX by itself had less effect. Similar results were also observed for Caco-2 cells and also for another strain of C. sakazakii (29004). These results suggest that GOS and PDX, alone and in combination, may have an anti-adhesive effect on C. sakazakii and directly inhibit the adherence to gastrointestinal epithelial cells. PMID- 21293858 TI - Global existence for semilinear reaction-diffusion systems on evolving domains. AB - We present global existence results for solutions of reaction-diffusion systems on evolving domains. Global existence results for a class of reaction-diffusion systems on fixed domains are extended to the same systems posed on spatially linear isotropically evolving domains. The results hold without any assumptions on the sign of the growth rate. The analysis is valid for many systems that commonly arise in the theory of pattern formation. We present numerical results illustrating our theoretical findings. PMID- 21293859 TI - Power Doppler ultrasonography is useful for assessing disease activity and predicting joint destruction in rheumatoid arthritis patients receiving tocilizumab--preliminary data. AB - To evaluate the responsiveness of power Doppler ultrasonography (PDUS) in comparison with conventional measures of disease activity and structural damage in rheumatoid arthritis (RA) patients receiving tocilizumab (TCZ). Seven RA patients with active arthritis were enrolled in the study and prospectively monitored for 12 months. They were treated with TCZ (8 mg/kg) every 4 weeks as monotherapy or in combination with disease-modifying antirheumatic drugs (DMARDs). Clinical, laboratory, and ultrasound examinations were conducted at baseline, 1, 3, 6, 9, and 12 months. Power Doppler (PD) signals were graded from 0 to 3 in 24 joints, and total PD score was calculated as the sum of scores of individual joints. One-year radiographic progression of the hands was estimated by using Genant-modified Sharp scoring. The averages of the clinical parameters rapidly improved, and all patients achieved good response within 6 months based on standard 28-joint Disease Activity Score (DAS28). Although the average total PD score declined in parallel with clinical improvement, radiography of the hands showed progression of destruction in the joints where PD signals remained, even among clinical responders. DeltaSharp score correlated with the time-integrated value (TIV) of total PD scores (Deltatotal Sharp score: r = 0.77, P = 0.04; Deltaerosion: r = 0.78, P = 0.04; Deltajoint-space narrowing (JSN): r = 0.75, P = 0.05), but not with TIVs of clinical parameters including DAS28. PDUS can independently evaluate disease activity in RA patients receiving TCZ and is superior to DAS28, especially in predicting joint destruction. PMID- 21293860 TI - Tissue culture-induced flower-color changes in Saintpaulia caused by excision of the transposon inserted in the flavonoid 3', 5' hydroxylase (F3'5'H) promoter. AB - The variegated Saintpaulia cultivar Thamires (Saintpaulia sp.), which has pink petals with blue splotches, is generally maintained by leaf cuttings. In contrast, tissue culture-derived progeny of the cultivar showed not only a high percentage of mutants with solid-blue petals but also other solid-color variants, which have not been observed from leaf cuttings. Solid-color phenotypes were inherited stably by their progeny from tissue culture. Petals from each solid color variant were analyzed by high-performance liquid chromatography and shown to contain different proportions of three main anthocyanin derivatives: malvidin, peonidin, and pelargonidin. Analysis of flavonoid 3', 5'-hydroxylase (F3'5'H) sequences showed no differences in the coding region among the variants and variegated individuals. However, a transposon belonging to the hAT superfamily was found in the promoter region of variegated individuals, and the presence of transposon-related insertions or deletions correlated with the observed flower color phenotypes. Solid-blue flower mutants contained 8-base pair (bp) insertions (transposon excision footprints), while solid-pink mutants had 58- to 70-bp insertions, and purple- and deep-purple mutants had 21- and 24-bp deletions, respectively. Real-time reverse transcription polymerase chain reaction (RT-PCR) analysis showed that F3'5'H expression levels correlated with insertions and deletions (indels) caused by hAT excision, resulting in flower-color differences. Our results showed that tissue culture of Saintpaulia 'Thamires' elicits transposon excision, which in turn alters F3'5'H expression levels and flower colors. PMID- 21293861 TI - Genome-wide analysis of the SET DOMAIN GROUP family in grapevine. AB - The SET DOMAIN GROUP (SDG) proteins represent an evolutionarily-conserved family of epigenetic regulators present in eukaryotes and are putative candidates for the catalysis of lysine methylation in histones. Plant genomes analyses of this family have been performed in arabidopsis, maize, and rice and functional studies have shown that SDG genes are involved in the control of plant development. In this work, we describe the identification and structural characterization of SDG genes in the Vitis vinifera genome. This analysis revealed the presence of 33 putative SDG genes that can be grouped into different classes, as it has been previously described for plants. In addition to the SET domain, the proteins identified possessed other domains in the different classes. As part of our study regarding the growth and development of grapevine, we selected eight genes and their expression levels were analyzed in representative vegetative and reproductive organs of this species. The selected genes showed different patterns of expression during inflorescence and fruit development, suggesting that they participate in these processes. Furthermore, we showed that the expression of selected SDGs changes during viral infection, using as a model Grapevine Leafroll Associated Virus 3-infected symptomatic grapevine leaves and fruits. Our results suggest that developmental changes caused by this virus could be the result of alterations in SDG expression. PMID- 21293862 TI - Haploid and doubled haploid plants from developing male and female gametes of Gentiana triflora. AB - Protocols were developed for the generation of haploid or doubled haploid plants from developing microspores and ovules of Gentiana triflora. Plant regeneration was achieved using flower buds harvested at the mid to late uninucleate stages of microspore development and then treated at 4 degrees C for 48 h prior to culture. Anthers and ovaries were cultured on modified Nitsch and Nitsch medium supplemented with a combination of naphthoxyacetic acid and benzylaminopurine. The explants either regenerated new plantlets directly or produced callus that regenerated into plantlets upon transfer to basal media supplemented with benzylaminopurine. Among seven genotypes of different ploidy levels used, 0-32.6% of cultured ovary pieces and 0-18.4% of cultured anthers regenerated plants, with all the genotypes responding either through ovary or anther culture. Flow cytometry confirmed that 98% of regenerated plants were either diploid or haploid. Diploid regenerants were shown to be gamete-derived by observing parental band loss using RAPD markers. Haploid plants were propagated on a proliferation medium and then treated with oryzalin for 4 weeks before transfer back to proliferation medium. Most of the resulting plants were diploids. Over 150 independently derived diploidised haploid plants have been deflasked. The protocol has been successfully used to regenerate plants from developing gametes of seven different diploid, triploid and tetraploid G. triflora genotypes. PMID- 21293863 TI - Development of disease-resistant marker-free tomato by R/RS site-specific recombination. AB - The selection marker genes, imparting antibiotic or herbicide resistance, in the final transgenics have been criticized by the public and considered a hindrance in their commercialization. Multi-auto-transformation (MAT) vector system has been one of the strategies to produce marker-free transgenic plants without using selective chemicals and plant growth regulators (PGRs). In the study reported here, isopentenyltransferase (ipt) gene was used as a selection marker and wasabi defensin (WD) gene, isolated from Wasabia japonica as a target gene. WD was cloned from the binary vector, pEKH-WD to an ipt-type MAT vector, pMAT21 by gateway cloning and transferred to Agrobacterium tumefaciens strain EHA105. Infected cotyledons of tomato cv. Reiyo were cultured on PGR- and antibiotic-free MS medium. Adventitious shoots were developed by the explants infected with the pMAT21/wasabi defensin. The same PGR- and antibiotic-free MS medium was used in subcultures of the adventitious shoot lines (ASLs) to produce ipt and normal shoots. Approximately, 6 months after infection morphologically normal shoots were produced. Molecular analyses of the developed shoots confirmed the integration of gene of interest (WD) and excision of the selection marker (ipt). Expression of WD was confirmed by Northern blot and Western blot analyses. The marker-free transgenic plants exhibited enhanced resistance against Botrytis cinerea (gray mold), Alternaria solani (early blight), Fusarium oxysporum (Fusarium wilt) and Erysiphe lycopersici (powdery mildew). PMID- 21293864 TI - Contribution of the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI to Dynamic MRI in the detection of hypovascular small (<= 2 cm) HCC in cirrhosis. AB - OBJECTIVE: To prospectively assess the additional value of the hepatobiliary (HB) phase of Gd-EOB-DTPA-MRI in identifying and characterising small (<= 2 cm) hepatocellular carcinomas (HCCs) undetermined in dynamic phases alone because of their atypical features, according to the AASLD criteria. METHODS: 127 cirrhotic patients were evaluated with Gd-EOB-DTPA-MRI in two sets: unenhanced and dynamic phases; unenhanced, dynamic and HB phases. Sixty-two out of 215 nodules (29%) were atypical in 42 patients (33%). RESULTS: 62 atypical nodules were reported at histology: high-grade dysplastic nodules (HGDN)/early HCC (n = 20), low-grade DN (LGDN) (n = 21), regenerative nodules (n = 17) and nodular regenerative hyperplasia (n = 4). The sensitivity, specificity, accuracy, positive and negative predictive value (PPV, NPV) were increased by the addition of the HB phase: 88.4-99.4%, 88-95%, 88-98.5%, 97-99%, and 65-97.5%, respectively. Twenty atypical nodules were malignant (32%), 19 of which were characterised only during the HB phase. CONCLUSIONS: The HB phase is 11% more sensitive in the classification of HGDN/early HCC than dynamic MRI, with an added value of 32.5% in the NPV. The high incidence (33%) of atypical nodules and their frequent malignancy (32%) suggest the widespread employment of Gd-EOB-DTPA-MRI in the follow-up of small nodules (<= 2 cm) in cirrhosis. PMID- 21293865 TI - [Healthcare system and aspects of healthcare economics: sector ophthalmology- part 3: inpatient treatment]. AB - With annual costs of nearly 60 billion EUR, hospitals account for a large portion of the total costs of the German statutory health insurance, which stand at 178 billion EUR. The introduction of diagnosis-related groups (DRGs) was intended to reduce the demands on the healthcare system and promote a more economic approach in the system. This article presents the current DRGs since the discontinuation of care payments and explains how profits can be made applying the DRG system. Important issues such as base rate, cost weight, case mix or case mix index are discussed. The key figures for hospitals in terms of budget calculation are presented. Average inpatient stays were shortened following the introduction of DRGs in Germany. The relevance of surcharges and deductions in the case of non observance of prescribed patient stays is discussed. PMID- 21293866 TI - Seasonal variation of hypertrophic pyloric stenosis: a population-based study. AB - INTRODUCTION: Seasonal variation in the incidence of hypertrophic pyloric stenosis (HPS) has been long debated. The goal of this study was to determine if seasonal variation exists in the incidence of pyloric stenosis. METHODS: A population-based cohort consisted of all infants in the province of Ontario, Canada with HPS from 1993 to 2000. The incidence of HPS per season was adjusted by birth rate and expressed as number of pyloromyotomies per 100,000 infants less than 12 months of age. One-way analysis of variance was used to compare HPS incidence between seasons. Further time series and spectral analysis were performed to examine for seasonal variation. RESULTS: There were 1,777 infants included in the population-based cohort. June was the month with the highest rate of HPS. The highest rate of pyloromyotomy occurred in the summer 14.92 and the lowest in the winter 10.73, this difference was statistically significant (p = 0.01). Spectral analysis showed that June was the month with the highest rate and February had the lowest rates p = 0.0014. CONCLUSION: Hypertrophic pyloric stenosis more commonly presents in the summer. Seasonal variation suggests a possible etiological role for environmental factors. PMID- 21293867 TI - Physical and psychological outcome in long-term survivors of childhood malignant solid tumor in Japan. AB - PURPOSE: Few studies have assessed physical and psychological status in long-term survivors of childhood solid tumors in Japan. For children with such diseases diagnosed and treated in our hospital, our purpose was to clarify the physical and psychological status of long-term survivors and their parents. METHODS: Subjects were 56 patients who were diagnosed at our institution as having a childhood malignant solid tumor between 1982 and 2005 and had been alive for at least 5 years after treatment. Surveys were sent and returned by mail. RESULTS: Of the 56 patients surveyed, 32 responded. The current health condition and psychosocial status of survivors were evaluated as good by their parents. However, psychological tests revealed psychosocial problems in 28.1% of the children. Severe posttraumatic stress associated with the child's disease and its treatment was present in 15.6% of the parents. CONCLUSION: Physical status of long-term survivors of childhood malignant solid tumors was good in general. However, psychological tests revealed psychosocial problems in some of the children and posttraumatic stress in the parents. Considering the diversity of both the diseases and their clinical course, a qualitative study is warranted for further analysis. PMID- 21293868 TI - Nerve biopsy: requirements for diagnosis and clinical value. AB - In many instances, nerve biopsy is not necessary in the diagnostic work-up of a peripheral neuropathy. However, histological examination of a tissue sample is still mandatory to show specific lesions in various conditions involving peripheral nerves. As there are fewer laboratories that examine human nerve samples, practitioners including neurologists and general pathologists may not be completely aware of the technical issues and data that are provided by nerve biopsy. Nerve biopsy is considered an invasive diagnostic method, although, its complications are by far less disabling than most of the disorders that lead to its indications. Nevertheless, the decision to perform a nerve biopsy has to be made on a case-by-case basis, and its results must be discussed between the pathologist and the clinician who is in charge of the patient's care. In this paper, we review the minimal technical requirements for proper peripheral nerve tissue analysis. Moreover, we provide data on the usefulness of nerve biopsy in various situations including abnormal deposits, cell infiltrates, link between peripheral neuropathy and monoclonal gammopathy, and numerous hereditary disorders. PMID- 21293869 TI - Influence of endothelial nitric oxide synthase polymorphisms in psoriasis risk. AB - Nitric oxide (NO) is a potent regulator of keratinocyte growth and differentiation that has been implicated in the pathogenesis of psoriasis (Ps). The NOS3 -786 T/C (SNP id rs2070744; http://www.ensembl.org ), intron 4 variable number tandem repeat (VNTR), and Glu298Asp (SNP id rs1799983) polymorphisms, have been associated with differences in NO plasma concentrations and with the risk of hypertension (HT) and ischemic cardiac disease. The aim of this study was to determine whether the above-mentioned NOS3 variants contributed to the risk of Ps, and were associated with the risk for HT and CAD in these patients. A total of 368 patients with chronic plaque Ps and 400 healthy controls were genotyped for the NOS3 -786 T/C, intron 4 VNTR, and Glu298Asp polymorphisms. Carriers of the -786 C allele were significantly more frequent among the patients (p < 0.001). Carriers of the 4-repeats allele (45 + 44 genotypes) were also more frequent a (p < 0.001). No significant difference was found for the Glu298Asp polymorphism. None of the NOS3 variants was associated with Ht and CAD in our population. In conclusion, NOS3 gene polymorphism would be risk factors for developing Ps. PMID- 21293870 TI - Lower genital tract metastases at time of first diagnosis of mammary invasive lobular carcinoma. AB - INTRODUCTION: Although breast cancer is a major health problem worldwide, metastatic disease to the lower genital tract remains to be a rare event. CASE REPORT: A 64-year old woman was admitted to our hospital due to newly diagnosed ascites and peripheral edema. A computer tomography had shown peritoneal carcinosis but no clear evidence of an intraabdominal mass. CA 12-5 levels were elevated. Physical examination of the breast did not show any abnormal findings, except for the fact that the patient was post bilateral breast augmentation in 1999. The peritoneal carcinosis was thought to originate from the ovaries or the endometrium and therefore the patient underwent a laparotomy with hysterectomy, bilateral salpingoovariectomy and omentectomy. Histological findings revealed a low differentiated adenocarcinoma, most likely originating from primary breast cancer. A bilateral mammography was suspicious of a tumour in the left breast which was confirmed in a second surgery. Histology showed a moderately differentiated invasive-lobular breast cancer. CONCLUSION: To our knowledge, this is the first report about metastasis to the lower genital tract on initial presentation of an invasive-lobular carcinoma. In the differential diagnosis of peritoneal carcinosis, metastases of an invasive-lobular carcinoma should be considered. PMID- 21293871 TI - Cognitive profile and MRI findings in limb-girdle muscular dystrophy 2I. AB - Limb-girdle muscular dystrophy 2I (LGMD2I) is a neuromuscular disorder with a heterogeneous phenotype. It is caused by mutations in the Fukutin Related Protein (FKRP) gene, which is ubiquitously expressed in human tissues. FKRP functions in CNS are largely unknown. To investigate possible cognitive impairment in LGMD2I and to describe brain MRI features. Ten LGMD2I patients (four males and six females, mean age 44 years, age range 19-69 years) were assessed with an extensive neuropsychological battery, psychopathological tests and neuromuscular specific quality-of-life questionnaire. Adults were compared with ten matched healthy controls. All patients underwent complete neurological examination, and nine underwent brain MRI scanning. Patients showed a fairly specific cognitive profile with mild impairment in executive functions and visuo-spatial planning without substantial impairment in global and logic IQ. MRI findings were heterogeneous: four patients showed non-specific white matter abnormalities; two patients showed moderate ventriculomegaly; three patients showed mild enlargement of subarachnoid spaces, without a specific pattern. Cerebellar atrophy was marked in one patient. Abnormal glycosylation of alpha-dystroglycan in LGMD2I may interfere with brain development and cognitive performances involving the frontal and posterior parietal regions, but does not result in specific brain MRI abnormalities. PMID- 21293872 TI - Cancer and multiple sclerosis in the era of disease-modifying treatments. AB - Prior to the era of disease-modifying therapies (DMT), multiple sclerosis (MS) was linked to reduced rates of cancer. Early use of immunosuppressors (IS) in MS justifies the follow-up of patients to evaluate a possible increase in the incidence of cancer in these patients. We performed a descriptive study of MS patients with a documented oncological event. Among the 22,563 MS patients in the EDMUS databases, patients with a history of cancer were identified, and cancer risk in a multiple sclerosis cohort (CARIMS) was evaluated. Four groups were defined: (A) MS patients without cancer receiving DMT or not, (B) MS patients with cancer but without any history of DMT, (C) MS patients with cancer who received an immunomodulator (IM), and/or (D) MS patients treated with an IS. A total of 9,269 patients (44.1%) had a history of DMT (52% IM; 18% IS; 30% both); 253 patients with MS and cancer were identified, 182 had a history of DMT. The mean duration of DMT was longer for group D (A: 3.6 years vs. D: 4.9 years; P < 0.01). There was no increased risk of cancer among patients treated exclusively with IM. IS treatment (P = 0.043) and the duration of exposure (P < 0.001) significantly increased the risk of cancer, especially skin cancer, as observed in other autoimmune diseases. This result could influence the attitude of the medical profession with respect to the benefit to risk ratio when proposing DMT to MS patients. PMID- 21293873 TI - Multiple strokes in a young patient associated with an unruptured sinus of Valsalva aneurysm. PMID- 21293874 TI - Sleepwalking in Parkinson's disease: a questionnaire-based survey. AB - Sleepwalking (SW) corresponds to a complex sleep-associated behavior that includes locomotion, mental confusion, and amnesia. SW is present in about 10% of children and 2-3% of adults. In a retrospective series of 165 patients with Parkinson's disease (PD), we found adult-onset ("de novo") SW "de novo" in six (4%) of them. The aim of this study was to assess prospectively and systematically the frequency and characteristics of SW in PD patients. A questionnaire including items on sleep quality, sleep disorders, and specifically also SW and REM sleep behavior disorder (RBD), PD characteristics and severity, was sent to the members of the national PD patients organization in Switzerland. In the study, 36/417 patients (9%) reported SW, of which 22 (5%) had adult-onset SW. Patients with SW had significantly longer disease duration (p = 0.035), they reported more often hallucinations (p = 0.004) and nightmares (p = 0.003), and they had higher scores, suggestive for RBD in a validated questionnaire (p = 0.001). Patients with SW were also sleepier (trend to a higher Epworth Sleepiness Scale score, p = 0.055). Our data suggest that SW in PD patients is (1) more common than in the general population, and (2) is associated with RBD, nightmares, and hallucinations. Further studies including polysomnographic recordings are needed to confirm the results of this questionnaire-based analysis, to understand the relationship between SW and other nighttime wandering behaviors in PD, and to clarify the underlying mechanisms. PMID- 21293875 TI - Occupational exposure levels to benzene in Italy: findings from a national database. AB - PURPOSE: Benzene is classified as human carcinogen and the association with lymphohaematopoietic cancer has been observed in many occupational epidemiological studies. The aim of this study is to summarize data about occupational exposure levels to benzene in Italy. METHODS: Airborne concentrations of benzene were selected from the Italian database on occupational exposure to carcinogens in the period 1996-2007. Descriptive statistics were calculated for exposure-related variables. The number of workers potentially exposed was estimated for the industrial sectors better characterized in the database. An analysis through linear mixed model was performed to determine factors affecting the exposure level. RESULTS: The total number of benzene exposure measurements was 15,776, with an overall arithmetic mean of 0.09 ppm and a geometric mean of 0.02 ppm. Economic sectors with a higher number of measurements (N) were the manufacturing of chemicals (N = 10,480) and the petrochemical industry (N = 2,652). The number of workers potentially exposed in the selected sectors was 37,137, and the most predictive independent variables of the exposure level were measurement year and job category. CONCLUSIONS: Occupational benzene exposure is still widespread in many different industries, and proactive measures are needed to reduce its impact on the workers' health. The potential of occupational exposure databases as a source of data for exposure assessment is confirmed. PMID- 21293876 TI - Water relations of climbing ivy in a temperate forest. AB - Ivy (Hedera helix) is the most important liana in temperate European forests. We studied water relations of adult ivy in a natural, 35 m tall mixed deciduous forest in Switzerland using a construction crane to access the canopy. Predawn leaf water potential at the top of climbing ivy ranged from -0.4 to -0.6 MPa, daily minima ranged from -1.3 to -1.7 MPa. Leaf water potentials as well as relative sap flow were held surprisingly constant throughout different weather conditions, suggesting a tendency to isohydric behaviour. Maximum stomatal conductance was 200 mmol m-2 s-1. The use of a potometer experiment allowed us to measure absolute transpiration rates integrated over a whole plant of 0.23 mmol m 2 s-1. Nightly sap flow of ivy during warm, dry nights accounted for up to 20% of the seasonal maximum. Maximum sap flow rates were reached at ca. 0.5 kPa vpd. On the other hand, the host trees showed a less conservative stomatal regulation, maximum sap flow rates were reached at vpd values of ca. 1 kPa. Sap flow rates of ivy decreased by ca. 20% in spring after bud break of trees, suggesting that ivy profits strongly from warm sunny days in early spring before budbreak of the host trees and from mild winter days. This species may benefit from rising winter temperatures in Europe and thus become a stronger competitor against its host trees. PMID- 21293877 TI - The receptor architecture of the pigeons' nidopallium caudolaterale: an avian analogue to the mammalian prefrontal cortex. AB - The avian nidopallium caudolaterale is a multimodal area in the caudal telencephalon that is apparently not homologous to the mammalian prefrontal cortex but serves comparable functions. Here we analyzed binding-site densities of glutamatergic AMPA, NMDA and kainate receptors, GABAergic GABA(A), muscarinic M(1), M(2) and nicotinic (nACh) receptors, noradrenergic alpha(1) and alpha(2), serotonergic 5-HT(1A) and dopaminergic D(1)-like receptors using quantitative in vitro receptor autoradiography. We compared the receptor architecture of the pigeons' nidopallial structures, in particular the NCL, with cortical areas Fr2 and Cg1 in rats and prefrontal area BA10 in humans. Our results confirmed that the relative ratios of multiple receptor densities across different nidopallial structures (their "receptor fingerprints") were very similar in shape; however, the absolute binding densities (the "size" of the fingerprints) differed significantly. This finding enables a delineation of the avian NCL from surrounding structures and a further parcellation into a medial and a lateral part as revealed by differences in densities of nACh, M(2), kainate, and 5-HT(1A) receptors. Comparisons of the NCL with the rat and human frontal structures showed differences in the receptor distribution, particularly of the glutamate receptors, but also revealed highly conserved features like the identical densities of GABA(A), M(2), nACh and D(1)-like receptors. Assuming a convergent evolution of avian and mammalian prefrontal areas, our results support the hypothesis that specific neurochemical traits provide the molecular background for higher order processes such as executive functions. The differences in glutamate receptor distributions may reflect species-specific adaptations. PMID- 21293878 TI - Genetic contribution of the leukotriene pathway to coronary artery disease. AB - We evaluated the genetic contribution of the leukotriene (LT) pathway to risk of coronary artery disease (CAD) in 4,512 Caucasian and African American subjects ascertained through elective cardiac evaluation. Of the three previously associated variants, the shorter "3" and "4" alleles of a promoter repeat polymorphism in ALOX5 increased risk of CAD in African Americans (OR = 1.4, 95% CI 1.0-1.9; p = 0.04), whereas a haplotype of LTA4H (HapK) was associated with CAD in Caucasians (OR = 1.2, 95% CI 1.01-1.4; p = 0.03). In Caucasians, first stage analysis of 254 haplotype-tagging SNPs in 15 LT pathway genes with follow up of 19 variants in stage 2 revealed an LTA4H SNP (rs2540477) that increased risk of CAD (OR = 1.2, 95% CI 1.1-1.5; p = 0.003) and a PLA2G4A SNP (rs12746200) that decreased risk of CAD (OR = 0.7, 95% CI 0.6-0.9; p = 0.0007). The PLA2G4A rs12746200 variant also decreased risk of experiencing a major adverse cardiac event (MACE = myocardial infarction, stroke, or death) over 3 years of follow-up (HR = 0.7, 95% CI 0.5-0.9; p = 0.01), consistent with its cardioprotective effect. Functional experiments demonstrated that stimulated monocytes from carriers of LTA4H variants HapK or rs2540477 had 50% (p = 0.002) and 33% (p = 0.03) higher LTB(4) production, respectively, compared to non-carriers. These ex vivo results are consistent with LTB(4) being the direct product of the reaction catalyzed by LTA4H and its role in promoting monocyte chemotaxis to sites of inflammation, including the artery wall of atherosclerotic lesions. Taken together, this study provides additional evidence that functional genetic variation of the LT pathway can mediate atherogenic processes and the risk of CAD in humans. PMID- 21293879 TI - A dynamic model for genome-wide association studies. AB - Although genome-wide association studies (GWAS) are widely used to identify the genetic and environmental etiology of a trait, several key issues related to their statistical power and biological relevance have remained unexplored. Here, we describe a novel statistical approach, called functional GWAS or fGWAS, to analyze the genetic control of traits by integrating biological principles of trait formation into the GWAS framework through mathematical and statistical bridges. fGWAS can address many fundamental questions, such as the patterns of genetic control over development, the duration of genetic effects, as well as what causes developmental trajectories to change or stop changing. In statistics, fGWAS displays increased power for gene detection by capitalizing on cumulative phenotypic variation in a longitudinal trait over time and increased robustness for manipulating sparse longitudinal data. PMID- 21293880 TI - Production and activities of chitinases and hydrophobins from Lecanicillium lecanii. AB - The production of chitinases and hydrophobins from Lecanicillium lecanii was influenced by the cultivation method and type of carbon source. Crude enzyme obtained from solid-substrate culture presented activities of exochitinases (32 and 51 kDa), endochitinases (26 kDa), beta-N-acetylhexosaminidases (61, 80, 96 and 111 kDa). Additionally, submerged cultures produced exochitinases (32 and 45 kDa), endochitinases (10 and 26 kDa) and beta-N-acetylhexosaminidases (61, 96 and 111 kDa). beta-N-acetylhexosaminidases activity determined in solid-substrate culture with added chitin was ca. threefold (7.58 +/- 0.57 U mg(-1)) higher than submerged culture (2.73 + 0.57 U mg(-1)). Similarly, hydrophobins displayed higher activities in solid-substrate culture (627.3 +/- 2 MUg protein mL(-1)) than the submerged one (57.4 +/- 4.7 MUg protein mL(-1)). Molecular weight of hydrophobins produced in solid-substrate culture was 7.6 kDa and they displayed surface activity on Teflon. PMID- 21293881 TI - Calibration of a complex activated sludge model for the full-scale wastewater treatment plant. AB - In this study, the results of the calibration of the complex activated sludge model implemented in BioWin software for the full-scale wastewater treatment plant are presented. Within the calibration of the model, sensitivity analysis of its parameters and the fractions of carbonaceous substrate were performed. In the steady-state and dynamic calibrations, a successful agreement between the measured and simulated values of the output variables was achieved. Sensitivity analysis revealed that upon the calculations of normalized sensitivity coefficient (S(i,j)) 17 (steady-state) or 19 (dynamic conditions) kinetic and stoichiometric parameters are sensitive. Most of them are associated with growth and decay of ordinary heterotrophic organisms and phosphorus accumulating organisms. The rankings of ten most sensitive parameters established on the basis of the calculations of the mean square sensitivity measure (delta(msqr)j) indicate that irrespective of the fact, whether the steady-state or dynamic calibration was performed, there is an agreement in the sensitivity of parameters. PMID- 21293882 TI - Endoscopic stenting versus surgical colostomy for the management of malignant colonic obstruction: comparison of hospital costs and clinical outcomes. AB - BACKGROUND: Although stent placement is increasingly performed, colostomy still is considered the gold standard for emergent relief of malignant colonic obstruction (MCO). This study aimed to compare hospital costs and clinical outcomes between patients undergoing colostomy and those undergoing stenting for the management of MCO. METHODS: A retrospective claims analysis of the Medicare Provider Analysis and Review (MedPAR) data set was conducted to identify inpatient hospitalizations for colostomy or stent placement for the treatment of colon cancer (2007-2008). The outcomes evaluated using MedPAR compared the total length of hospital stay (LOS) and the costs associated with both techniques. Because MedPAR is a claims data set that does not provide outcomes at a patient level, a single-institution retrospective case-control study was conducted in which each stent placement patient was matched with two colostomy patients during the same period. Outcome measures (institutional data) were used to compare rates of treatment success, postprocedure LOS, and reinterventions between the two cohorts. RESULTS: The MedPAR data evaluated 778 stent placements and 5,868 colostomy hospitalizations. There were no differences in gender, age distribution, or comorbidity between the two groups. Compared with colostomy, the median LOS (8 vs. 12 days; p<0.0001) and the median cost ($15,071 vs. $24,695; p<0.001) per claim were significantly less for stent placement. Stent placement was more commonly performed at urban versus rural hospitals (84% vs. 16%; p<0.0001), teaching versus nonteaching hospitals (56% vs. 44%; p=0.0058) and larger versus smaller institutions (mean bed capacity, 331 vs. 227; p<0.0001). The institution data included 12 patients who underwent stent placement and 24 who underwent colostomy. Although both methods were technically successful, the median postprocedure LOS (2.17 vs. 10.58 days; p=0.0004) and the rate of readmissions for complications (0% vs. 25%; p=0.01) were significantly lower for stent placement. CONCLUSION: Although the technical and clinical outcomes for colostomy and stent placement appear comparable, stent placement is less costly and associated with shorter LOS and fewer complications. Dissemination of stent placement beyond large teaching hospitals located in urban areas as a treatment for MCO is important given its implications for patient care and resource use. PMID- 21293883 TI - Reconceptualising relocation for specialist treatment: insights from New Zealand. AB - PURPOSE: To date, the research on relocation has been conducted in countries such as Australia where there are vast distances that need to be travelled by regional, rural and remote patients to access specialist metropolitan treatment. This research considers the issue of relocation for specialist treatment in a New Zealand context. METHODS: The exploration of the experience of relocation from the consumers' perspective was conducted through an iterative, qualitative research methodology using open-ended interviews conducted by speaker-phone at the time and location of each participant's choice. RESULTS: The three factors that underpin the phenomenon of 'travel-based' accommodation in New Zealand are the strong desire to return home, the small geographical distances that make this possible for many and the strong determination to endure hardship associated with travel when distances are long. CONCLUSIONS: Any understanding of relocation for specialist treatment needs to be informed by two concepts: 'travel-based' relocation and 'accommodation-based' relocation. RELEVANCE OF MANUSCRIPT TO INFORM RESEARCH, POLICIES AND/OR PROGRAMS: The focus needs to be on providing supportive travel arrangements where possible. In New Zealand, as elsewhere, cancer supportive care organisations are increasingly providing volunteers to assist with travel. Such practical volunteer assistance is important, as is financial support through government subsidies to cover the cost of such travel. The insights from the study affirm the importance of health professionals who are supportive and creative in their efforts to assist people to return home. Supportive clinical care such as addressing issues in relation to nausea and pain management for those travelling must also be considered. PMID- 21293884 TI - Cancer-related symptom clusters for symptom management in outpatients after commencing adjuvant chemotherapy, at 6 months, and 12 months. AB - GOALS OF WORK: The aim of this secondary data analysis was to investigate symptom clusters over time for symptom management of a patient group after commencing adjuvant chemotherapy. MATERIALS AND METHODS: A prospective longitudinal study of 219 cancer outpatients conducted within 1 month of commencing chemotherapy (T1), 6 months (T2), and 12 months (T3) later. Patients' distress levels were assessed for 42 physical symptoms on a clinician-modified Rotterdam Symptom Checklist. Symptom clusters were identified in exploratory factor analyses at each time. Symptom inclusion in clusters was determined from structure coefficients. Symptoms could be associated with multiple clusters. Stability over time was determined from symptom cluster composition and the proportion of symptoms in the initial symptom clusters replicated at later times. MAIN RESULTS: Fatigue and daytime sleepiness were the most prevalent distressing symptoms over time. The median number of concurrent distressing symptoms approximated 7, over time. Five consistent clusters were identified at T1, T2, and T3. An additional two clusters were identified at 12 months, possibly due to less variation in distress levels. Weakness and fatigue were each associated with two, four, and five symptom clusters at T1, T2, and T3, respectively, potentially suggesting different causal mechanisms. CONCLUSION: Stability is a necessary attribute of symptom clusters, but definitional clarification is required. We propose that a core set of concurrent symptoms identifies each symptom cluster, signifying a common cause. Additional related symptoms may be included over time. Further longitudinal investigation is required to identify symptom clusters and the underlying causes. PMID- 21293885 TI - Preoxygenation with 20o head-up tilt provides longer duration of non-hypoxic apnea than conventional preoxygenation in non-obese healthy adults. AB - PURPOSE: Failed airway is the anesthesiologist's nightmare. Although conventional preoxygenation can provide time, atelectasis occurs in the dependent areas of the lungs immediately after anesthetic induction. Therefore, alternatives such as positive end-expiratory pressure (PEEP) and head-up tilt during preoxygenation have been explored. We compared the conventional preoxygenation technique (group C) with 20o head-up tilt (group H) and 5 cmH(2)O PEEP (group P) in non-obese individuals for non-hypoxic apnea duration. METHODS: A total of 45 patients were enrolled (15 in each group). After 5 min of preoxygenation, intubation was performed after induction of anesthesia with thiopentone and succinylcholine. After confirming the tracheal intubation by esophageal detector device and capnogram, all patients were administered vecuronium to maintain neuromuscular blockade and midazolam to prevent awareness. Post-induction, patients in all groups were left apneic in supine position with the tracheal tube exposed to atmosphere till the SpO(2) dropped to 93% or 10 min of safe apnea was achieved. RESULTS: The demographic data were comparable. Non-hypoxic apnea duration was higher with group H (452 +/- 71 s) compared to group C (364 +/- 83 s, P = 0.030). Group P did not show significant increase in the duration of non-hypoxic apnea (413 +/- 86 s). There were no adverse outcomes or events. CONCLUSIONS: Preoxygenation is clinically and statistically more efficacious and by inference more efficient in the 20o head-up position than with conventional technique in non-obese healthy adults. Although application of 5 cmH(2)O PEEP provides longer duration of non-hypoxic apnea compared to conventional technique, it is not statistically significant. PMID- 21293886 TI - Use of rocuronium-sugammadex, an alternative to succinylcholine, as a muscle relaxant during electroconvulsive therapy. AB - We compared the recovery time from neuromuscular blockade induced by rocuronium combined with sugammadex versus succinylcholine during electroconvulsive therapy (ECT). Anesthesia was induced using propofol, followed by succinylcholine (1 mg/kg) or rocuronium (0.6 mg/kg). Immediately after the seizure stopped, 16 mg/kg sugammadex was infused. Neuromuscular monitoring was performed and continued until recovery of the train-of-four ratio to 0.9. We compared the recovery time of T1 to 10 and 90% between groups. Patients were also assessed for clinical signs, such as time to first spontaneous breath from the administration of muscle relaxant and eye opening to verbal commands. Although recovery time of T1 to 10 and 90% in the rocuronium-sugammadex group was shorter than in the succinylcholine group, the difference was not statistically significant. Further, the seizure duration with succinylcholine (33 +/- 8 s) was shorter than that with rocuronium-sugammadex (39 +/- 4 s). In conclusion, this study demonstrates the potential benefit of use of rocuronium-sugammadex as an alternative to succinylcholine for muscle relaxation during ECT. PMID- 21293887 TI - IL-6 induction of TLR-4 gene expression via STAT3 has an effect on insulin resistance in human skeletal muscle. AB - We investigated the cytokines and mechanisms involved in the induction of insulin resistance in human skeletal muscle. Ten subjects with impaired glucose tolerance (IGT) and 10 control subjects were recruited. We performed biopsies on the vastus lateralis muscle and used immunoblotting to determine levels of inflammatory cytokines, Toll-like receptor (TLR) gene expression, and insulin signaling. We also used a human myotube culture system to examine the mechanisms underlying TLR 4 gene expression. To identify inflammatory cytokines associated with insulin resistance, we measured the levels of IL-6, TNF-alpha, TLR-2, and TLR-4 in skeletal muscle from non-obese patients with IGT and control subjects. Levels of IL-6, TNF-alpha, and TLR-4, but not TLR-2, were significantly increased in the IGT group. Insulin resistance decreased significantly in HSMMs following long term IL-6 treatment. TLR-4 gene expression was significantly increased in human skeletal muscle myoblasts (HSMMs) treated with IL-6. To determine the main signaling pathway for IL-6-induced TLR-4 gene expression, we examined several signaling factors associated with IL-6 signaling pathways. We found that the active form of "signal transducer and activator of transcription 3" (STAT3) was increased. "Stattic" (a STAT3 inhibitor) markedly inhibited TLR-4 gene expression. IL-6 induction of TLR-4 gene expression via STAT3 is one of the main mechanisms underlying insulin resistance in human skeletal muscle. PMID- 21293888 TI - Chiral, fully extended helical peptides. AB - The synthesis of the N-protected (blocked) homo-peptide esters from the chiral C(alpha)-ethyl, C(alpha)-n-pentylglycine was performed in solution to the hexapeptide level. The conformational propensity exhibited by these oligomers in chloroform solution and in the crystal state was assessed by use of FTIR absorption, NMR, and X-ray diffraction. The results indicated that fully extended helical structures (2.0(5)-helices) are overwhelmingly adopted irrespective of the peptide main-chain length. This oligomeric series is of great interest as it is characterized by the longest C ( i )(alpha) ,..., C ( i+1 )(alpha) (per residue) separation achievable in the class of chiral, rigid, helical peptide spacers based on alpha-amino acids. PMID- 21293889 TI - Application of amino acid amides as chiral auxiliaries in difluoro dinitro benzene and cyanuric chloride moieties for high-performance liquid chromatographic enantioseparation of selenomethionine and its mixture with methionine and cysteine. AB - L-Ala-NH(2), L-Val-NH(2), L-Leu-NH(2), and D-Phg-NH(2) were used as chiral auxiliaries to synthesize four chiral derivatizing reagents (CDRs) of each of the three categories, viz., difluoro dinitro benzene (DFDNB) based chiral variants, and cyanuric chloride (CC) based monochloro-s-triazine reagents (MCTs) and dichloro-s-triazine reagents (DCTs). DFDNB based chiral variants were synthesized by substituting one of the fluorine atoms of DFDNB with respective amino acid amides. The MCTs and DCTs were synthesized by substituting chlorine atom with aforesaid amino acid amide moieties in 6-methoxy dichloro-s-triazine and in CC, respectively. In total, 12 CDRs were characterized and used for microwave assisted synthesis (45 s at 80% of 800 W using DFDNB-based chiral variants, 80 s at 90% of 800 W power using MCTs, and 50 s at 80% of 800 W power using DCTs) of diastereomers of (A) SeMet, and (B) mixture of (1) SeMet and Met, and (2) SeMet, Met, and Cys. The diastereomers were enantioseparated by reversed-phase high performance liquid chromatography using gradient elution with mobile phases containing aq. TFA (0.1%)--MeCN in different compositions. The method was validated for accuracy, precision, and limit of detection. PMID- 21293890 TI - Acute regulation of IGF-I by alterations in post-exercise macronutrients. AB - This investigation sought to examine the contributions of exercise and nutrient replenishment on in vivo regulation of the insulin-like growth factor-I (IGF-I) axis components. Eight college-aged males completed three high-intensity interval training (HIIT) protocols followed by three post-exercise nutritional protocols: (1) placebo (EX); (2) carbohydrate only (CHO); and (3) essential amino acid/carbohydrate (EAA/CHO). Samples were analyzed for growth hormone (GH), free IGF-I, IGFBP-1, IGFBP-2, insulin, hematocrit, hemoglobin, serum leucine, matrix metalloproteinase-9 (MMP-9) proteolytic activity, and presence of IGFBP-3 protease activity. No evidence for IGFBP-3 proteolysis was observed. Significant increases in [free IGF-I] and [leucine] were observed in the EAA/CHO group only. Significant differences were noted in [IGFBP-1] and [IGFBP-2] across conditions. Significant increases in [GH] and MMP-9 activity were observed in all groups. These results indicate that post-exercise macronutrient ratio is a determinant of [free IGF-I], [IGFBP-1 and -2] and may play a role in modulating the IGF-I axis in vivo. PMID- 21293891 TI - Somatostatin is involved in anorexia in mice fed a valine-deficient diet. AB - The ingestion of a valine (Val)-deficient diet results in a significant reduction of food intake and body weight within 24 h, and this phenomenon continues throughout the period over which such a diet is supplied. Both microarray and real-time PCR analyses revealed that the expression of somatostatin mRNA was increased in the hypothalamus in anorectic mice that received a Val-deficient diet. On the other hand, when somatostatin was administered intracerebroventricularly to intact animals that were fed a control diet, their 24-h food intake decreased significantly. In addition, Val-deficient but not pair fed mice or those fasted for 24 h showed a less than 0.5-fold decrease in the hypothalamic mRNA expression levels of Crym, Foxg1, Itpka and two unknown EST clone genes and a more than twofold increase in those of Slc6a3, Bdh1, Ptgr2 and one unknown EST clone gene. These results suggest that hypothalamic somatostatin and genes responsive to Val deficiency may be involved in the central mechanism of anorexia induced by a Val-deficient diet. PMID- 21293892 TI - A 5-year epidemiological study on the prevalence rate of idiopathic scoliosis in Tokyo: school screening of more than 250,000 children. AB - BACKGROUND: School screening for scoliosis is a powerful tool that can be used to identify children who may have scoliosis. There have been no reports on the recent prevalence of idiopathic scoliosis in Japan since 1988. METHODS: A 5-year epidemiologic study was performed to determined the prevalence of idiopathic scoliosis, the curve magnitude, the distribution of this magnitude, and the sex ratio in school children. Between 2003 and 2007, a total of 255,875 children aged 11-14 years were screened. RESULTS: A total of 3,424 children were found to be positive as a result of Moire topography. With radiographic examination, 2,225 (65.0%) children with a Cobb angle of 10 degrees or more were detected. The overall prevalence rate in schoolchildren 11-14 years of age with Cobb angles of 10 degrees or more was 0.87%. The prevalence rate in girls increased from 0.78% at the age of 11-12 years to 2.51% at the age of 13-14 years. For boys, the prevalence rates were 0.04% at the age of 11-12 years and 0.25% at the age of 13 14 years. The overall ratio of girls to boys with scoliosis was 11:1. The ratio of girls to boys was 17:1 at the age of 11-12 years and 10:1 at the age of 13-14 years. CONCLUSIONS: The majority of the curves fell in the range of 10 degrees 19 degrees . There was a slight increase in the prevalence rates of children with a curve of high magnitude (>=20 degrees ) as compared to the prevalence rate in 1988. We suggest that school screening for scoliosis is effective for early detection; however, it is first necessary to review and optimize the target groups. PMID- 21293893 TI - Sustained-release rhBMP-2 increased bone mass and bone strength in an ovine model of postmenopausal osteoporosis. AB - OBJECTIVE: The purpose of this study was to analyze the local treatment effects of rhBMP-2 combined with fibrin sealant (FS) on bone mineral density, microarchitectural and mechanical properties in osteoporotic ovine spine. MATERIALS AND METHODS: Postmenopausal osteoporosis was induced in eight sheep through ovariectomy (OVX) and a low-calcium diet for a period of 12 months. According to the Latin square design, L3-L6 vertebrae were randomly assigned to four treatment groups: A (rhBMP-2/FS), B (rhBMP-2), C (FS) and D (blank control). All materials were injected into the assigned vertebra transpedicularly. All animals were euthanized 3 months after treatment. Bone mineral density (BMD), microarchitectural and mechanical properties were assessed. ANOVA analysis of variance was used to determine effects of rhBMP-2/FS (alpha = 0.05). RESULTS: The BMD in group A (rhBMP-2/FS) was 18.8, 30.4 and 27.9% higher than that in group B, C and D, respectively. Analysis of bone structure by micro-CT revealed higher trabecular bone volume (BV/TV), trabecular thickness (Tb.Th) and trabecular number (Tb.N) in the rhBMP-2/FS group (P < 0.01). In addition, vertebrae treated with rhBMP-2/FS exhibited higher yield stress, ultimate stress, energy absorption and bone modulus compared to the control groups. CONCLUSIONS: Local administration of rhBMP-2/FS showed a positive trend in improving BMD, microarchitectural parameters and mechanical strength of osteoporotic vertebra. Slow release of rhBMP-2 using FS appeared to be an effective method of protein delivery. The local treatment of osteoporosis in the spine can increase bone strength and reduce fracture risk quickly. PMID- 21293894 TI - Enhancing the antibacterial activity of biomimetic HA coatings by incorporation of norvancomycin. AB - BACKGROUND: Bacterial infections associated with the use of biomaterials remain a great challenge for orthopedic surgery. The main purpose of the work discussed in this paper was to improve the antibacterial activity of a biomimetic calcium phosphate (CP) coating widely used in orthopedic biomaterials by incorporation of norvancomycin in the biomimetic process. METHODS: CP coating and CP coating containing norvancomycin were produced on a titanium alloy (Ti6Al4V) surface by a biomimetic process. The morphology, surface crystal structure, and concentrations of elements in the coatings were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), and energy-dispersive X-ray spectroscopy (EDX), respectively. The amount of norvancomycin and its release were investigated by UV visible spectroscopy. MTT was used to investigate cell behavior. The morphology of adhered bacteria was observed by SEM. Antibacterial activity was expressed as inhibition zone by using Staphylococcus aureus (ATCC 25923) as model bacteria. RESULTS: Results from SEM, EDX, and XRD revealed formation of a hydroxyapatite (HA) coating. The amount of antibiotic in the CP coating increased with increasing concentration of norvancomycin in the coating solution, followed by a plateau when the concentration of norvancomycin in the coating solution reached 600 mg/l. Approximately 2.16 MUg norvancomycin per mg coating was co-precipitated with the CP layer onto titanium alloy discs when 600 mg/l norvancomycin coating solution was applied. The norvancomycin had a fast release profile followed by slow release. The MTT test of osteoblast cell cultures suggested that coatings containing norvancomycin did not cause any cytotoxicity compared with the CP coating and control titanium plate. The antibacterial activity test showed that the norvancomycin released from the coatings inhibited the growth of Staphylococcus aureus; more bacteria were found on the CP coating than on the norvancomycin-loaded coating. CONCLUSIONS: A norvancomycin-loaded HA-like coating was successfully obtained on titanium surfaces. The norvancomycin incorporated had no negative effects on osteoblast cell behavior. The released norvancomycin results in excellent antibacterial activity of Ca-P coatings. Therefore, incorporation of norvancomycin can enhance antibacterial activity and the norvancomycin-loaded CP coating can be used to inhibit post-surgical infections in orthopaedics. PMID- 21293895 TI - Factors associated with radiographic osteoarthritis of the knee among community dwelling Japanese women: the Hizen-Oshima Study. AB - BACKGROUND: Osteoarthritis (OA) of the knee is the most common form of arthritis and is a major contributor to functional impairment and reduced independence in older adults. In Japan, knee OA is a frequent cause of pain and disability, but few epidemiological studies have examined the demographic or lifestyle factors that influence OA of the knee. We examine the risk factors for OA of the knee among Japanese community-dwelling women aged 40-89 years (mean age 64.2, SD 9.6 years). METHODS: Anteroposterior weight-bearing knee radiographs were graded according to the criteria described by Kellgren-Lawrence (K/L). We defined knee OA as a K/L grade of 2 or higher (using a 0-4 scale) based on the plain radiographs. History of knee injury, type of occupation, and daily intake of antioxidant nutrients including vitamin C and carotene were obtained from questionnaires. RESULTS: Among the 582 subjects, 195 women (33.5%) suffered from knee OA. Logistic regression analysis showed that older age [odds ratio (OR) 1.8, 95% confidence interval (95% CI) 1.6-2.1 per 5-year increase], higher body mass index (OR 2.2, 95% CI 1.7-3.0 per 5-unit increase) and previous knee injury (OR 3.1, 95% CI 1.7-5.6) were associated with knee OA. The occupation of farming and intake of antioxidant nutrients were not associated with knee OA. CONCLUSION: Older age, obesity and previous knee injury represent independent risk factors for knee OA among Japanese women. PMID- 21293896 TI - Prospective study on the efficacies of fondaparinux and enoxaparin in preventing venous thromboembolism after hip fracture surgery. AB - BACKGROUND: Venous thromboembolism (VTE) is a common complication in hip fracture surgery (HFS). Fondaparinux (FPX) and enoxaparin (ENO) have been reported to decrease the incidence of VTE after HFS. The purpose of this study was to determine the efficacies of FPX and ENO and the superior agent for preventing VTE after HFS by performing a prospective study in a Japanese population. METHODS: Eighty-four Japanese patients who underwent HFS were assigned to either FPX (received FPX 1.5 or 2.5 mg/day for 14 days), ENO (received ENO 2000 IU once or twice/day for 14 days), or untreated control (CTRL) groups in order of surgery. All patients underwent ultrasonography of the lower extremities 7 days after HFS to evaluate the extent of deep-vein thrombosis. Incidence of VTE, D-dimer values measured at admission and 7 and 14 days after HFS, and the side effects of FPX and ENO were compared. RESULTS: The incidence of VTE and the D-dimer values on days 7 and 14 in the FPX group were significantly lower than the corresponding levels in the CTRL group (P < 0.05). The D-dimer values on day 7 in the ENO group were significantly lower than those in the CTRL group, whereas the incidence of VTE was not significantly different. Side effects were observed in 3 cases: major bleeding occurred in 2 patients who received FPX, whereas minor bleeding occurred in 1 patient who received ENO. CONCLUSIONS: We concluded that FPX was the superior agent for preventing VTE after HFS. However, patients receiving FPX should be monitored for bleeding. PMID- 21293897 TI - Occult hernias detected by laparoscopic totally extra-peritoneal inguinal hernia repair: a prospective study. AB - BACKGROUND: One distinct advantage of laparoscopic inguinal hernia repair is the opportunity for clear visualization of the direct, indirect, femoral, obturator and other groin spaces. The aim of this study was to examine/assess the potential of the laparoscopic totally extraperitoneal (TEP) inguinal hernia repair method in detecting unexpected additional hernias. METHODS: Patients who underwent an elective inguinal hernia repair, in the department of abdominal surgery at the institute of laparoscopic surgery (ILS, Bordeaux, France) between September 2003 and July 2005 were enrolled prospectively in the study. The patients' demographic data, operative, postoperative course and outpatient follow-up were studied. RESULTS: A total of 337 laparoscopic inguinal hernia repairs were performed in 263 patients. Of these, 189 patients had unilateral hernia (109 right and 80 left) and 74 patients had bilateral hernias. Indirect hernias were the most common, followed by direct and then femoral hernias. There were 218 male patients and 45 female patients with a mean age of 60 +/- 15 years. There were 44 unexpected hernias: 6 spegilian hernias, 19 obturator hernias and another 19 femoral hernias. Two patients were converted to transabdominal preperitoneal (TAPP) due to surgical difficulties. There were no major intraoperative complications in all patients except for three cases of bleeding arising from the inferior epigastric artery. Only one patient had postoperative bleeding and was re-operated on several hours after the hernia repair. No recurrence occurred in the present series. CONCLUSIONS: The laparoscopic inguinal hernia repair approach allows viewing of the entire myopectineal orifice, facilitating repair of any unexpected hernias and thereby reducing the chance of recurrence. PMID- 21293898 TI - Comparison of LEP and QST and their contribution to standard sensory diagnostic assessment of spinal lesions: a pilot study. AB - This study evaluates the additional use of laser-evoked potentials (LEP) and quantitative sensory testing (QST) in the sensory assessment of spinal lesions. Four consecutive patients with spinal lesions verified by MRI and clinical evidence for mild spinothalamic tract involvement were included. The electrophysiological workup [somatosensory evoked potentials (SEP) and LEP] was compared to QST. Electrophysiology and QST were reassessed after about 6 months. LEP detected impaired spinothalamic tract function in 7/8 examinations. QST pointed to spinothalamic tract lesions by loss of thermal function (3/8); most frequent positive sensory signs (3/8) were paradoxical heat sensations. LEP and QST results were concordant in 6/8 examinations. SEPs were abnormal in 2/8 examinations. Congruent results between SEP and both LEP and QST were obtained in 3/8 examinations. LEP detected more deficits than any single QST parameter or their combination but additional QST allows the detection of positive sensory signs. The diagnostic gain of SEP was limited. PMID- 21293899 TI - Burden of rotavirus infections in Liguria, Northern Italy: hospitalisations and potential savings by vaccination. AB - We evaluated the rates of gastroenteritis admissions to the emergency department and of rotavirus-related hospitalisations in children <=5 years of age in 2006 at an Italian paediatric hospital. We calculated the number of rotavirus cases avoidable through the universal vaccination of children. Epidemiological data were extracted from the Data Elaboration Centre. To calculate the hospitalisation rate due to rotavirus, the virus was sought in the faeces of children hospitalised for acute gastroenteritis by means of rapid immunochromatographic assay. Emergency department admissions due to gastroenteritis numbered 2,396 (11.58% of the total admissions). Of these, 276 children (11.52%) were examined and then sent home, 1,286 (53.67%) were kept in short observation and 776 (32.38%) were hospitalised. In 27.83% of hospitalised cases, the rotavirus test proved positive. The rotavirus hospitalisation rate was 55 per 10,000 children <=5 years of age in Genoa in 2006. In 85.6% of hospitalised patients with community-acquired rotavirus infection, the disease was severe. The number of avoidable cases confirmed that the vaccination of children <=1 year of age could reduce the burden of rotavirus infection, especially with regard to hospitalisation (45 per 10,000 children <=5 years of age) and admissions to short observation (85 per 10,000), generating benefits for the Italian healthcare system. PMID- 21293900 TI - Efficacy of serology driven "test and treat strategy" for eradication of H. pylori in patients with rheumatic disease in the Netherlands. AB - The treatment of choice of H. pylori infections is a 7-day triple-therapy with a proton pump inhibitor (PPI) plus amoxicillin and either clarithromycin or metronidazole, depending on local antibiotic resistance rates. The data on efficacy of eradication therapy in a group of rheumatology patients on long-term NSAID therapy are reported here. This study was part of a nationwide, multicenter RCT that took place in 2000-2002 in the Netherlands. Patients who tested positive for H. pylori IgG antibodies were included and randomly assigned to either eradication PPI-triple therapy or placebo. After completion, follow-up at 3 months was done by endoscopy and biopsies were sent for culture and histology. In the eradication group 13% (20/152, 95% CI 9-20%) and in the placebo group 79% (123/155, 95% CI 72-85%) of the patients were H. pylori positive by histology or culture. H. pylori was successfully eradicated in 91% of the patients who were fully compliant to therapy, compared to 50% of those who were not (difference of 41%; 95% CI 18-63%). Resistance percentages found in isolates of the placebo group were: 4% to clarithromycin, 19% to metronidazole, 1% to amoxicillin and 2% to tetracycline. PMID- 21293901 TI - Unilateral visual loss due to ischaemic injury in the right calcarine region: a functional magnetic resonance imaging and diffusion tension imaging follow-up study. AB - To study the functional recovery of a patient with cerebrovascular injury using combined functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI). A 24-year-old woman with left hemianopsia underwent fMRI and DTI in a 1.5-tesla machine both in the acute phase and 1 month after an ischaemic stroke involving the right calcarine cortex. Acute-phase fMRI demonstrated that peripheral left visual field stimulation did not activate the right primary visual cortex, whereas stimulation 1 month later activated the visual cortex bilaterally. Analysis of acute-phase DTI data disclosed that a reduction of fractional anisotropy in the right optic radiation had almost resolved after 1 month. Fibre direction was normal at either time point. fMRI and DTI can demonstrate functional damage and recovery in patients with neuro ophthalmological lesions. PMID- 21293902 TI - Cloning and characterisation of a novel 2,4-dichlorophenol hydroxylase from a metagenomic library derived from polychlorinated biphenyl-contaminated soil. AB - A novel 2,4-dichlorophenol hydroxylase (TfdB, EC 1.14.13.20) gene, designated as tfdB-JLU, was identified from a metagenome constructed from polychlorinated biphenyl-contaminated soil by functional screening and heterologously expressed in Escherichia coli. The deduced amino acid sequence of tfdB-JLU exhibited less than 48% homology with other known TfdBs. The enzyme exhibited a wider substrate spectrum than the previously reported TfdBs and higher relative activity towards ortho-substituted dichlorophenols, 2-chlorophenol, and 3-chlorophenol than towards 2,4-dichlorophenol, the preferred substrate of other known TfdBs. The enzyme had a K ( m ) of 5 MUM for 2,4-dichlorophenol and 6 MUM for NADPH. The optimal temperature and pH of the enzyme were 25 degrees C and 7.5, respectively. Activity of the purified TfdB-JLU was slightly enhanced by Ca(2+), Mn(2+), Co(2+), and Fe(2+), and completely inhibited by Cu(2+), Hg(2+), and Zn(2+). This study is the first report to identify a novel TfdB from a metagenome. PMID- 21293903 TI - Heavy oils produced by Aureobasidium pullulans. AB - From a survey of more than 50 diverse strains of Aureobasidium pullulans, 21 produced extracellular heavy oils. Most oil producers fell into phylogenetic clades 8, 9, and 11. Oil colors ranged from bright yellow to malachite. More than half of the strains produced oil that was fluorescent. In medium containing 5% (w/v) sucrose, oil yields ranged from 0.5 to 6 g oil/l. Strain CU 43 reached stationary growth phase at day 4 while oil yields were maximal at day 6. CU 43 produced bright yellow, highly fluorescent oil that also was visible as intracellular droplets under fluorescent microscopy. Oil was surface active, suggesting that it functions as a biosurfactant. Oil from two strains (CU 43 and NRRL Y-12974) differentially inhibited mammalian cancer cell lines. MALDI-TOF MS spectra suggested that A. pullulans strains produce a family of related oil structures. PMID- 21293904 TI - Synthesis of GDP-mannose using coupling fermentation of recombinant Escherichia coli. AB - Glucokinase (glk), phosphomannomutase (manB), and mannose-1-phosphate guanylytransferase (manC) are needed for the biosynthesis of GDP-mannose. A recombinant E. coli strain over-expressing these three genes was constructed to produce guanosine 5'-diphosphate (GDP)-mannose, the donor of GDP-fucose, an essential substrate for synthesis of fucosyloligosaccharides. In addition, the glk, manB, and manC genes were individually cloned into the expression vector pET 22b (+) to construct three recombinant E. coli strains pET-glk, pET-manB and pET manC, respectively. Fermentation of the recombinant strain BL21/pET-glk-manB-manC had a conversion rate of 23% from mannose to GDP-mannose under IPTG induction, while coupling fermentation of the three recombinant strains BL21/pET-glk, BL21/pET-manB, BL21/pET-manC resulted in a conversion rate of 33% under the same induction conditions. PMID- 21293905 TI - Ectopic expression of a poplar APETALA3-like gene in tobacco causes early flowering and fast growth. AB - A MADS-box gene, designated PtAP3, was isolated from a floral bud cDNA library derived from Populus tomentosa. Analysis by multiple alignments of both nucleotide and amino acid sequences, together with phylogenetic analysis, revealed that PtAP3 is an ortholog of Arabidopsis AP3. Analysis of RNA extracts from vegetative and reproductive tissues of P. tomentosa by RT-PCR indicated that PtAP3 is expressed in roots, stems, leaves and vegetative and floral buds. Notably, the expression of PtAP3 fluctuated during floral bud development between September and February with differences between male and female buds. In the former, a gradual down-regulation during this period, interrupted by a slight up regulation in December, was followed by a sharper up-regulation on February. In developing female floral buds, expression was stable from September to November, sharply up-regulated in December, and then gradually down-regulated until February. The functional role of PtAP3 was investigated in transgenic tobacco plants. Of 25 transformants, nine displayed an earlier flowering phenotype compared with the wild type plants. Furthermore, transgenic tobacco had faster growth and more leaves than untransformed controls. The traits proved to be heritable between the T0 and T1 generations. Our results demonstrate a regulatory role of the PtAP3 gene during plant flowering and growth and suggest that the gene may be an interesting target for genetic modification to induce early flowering in plants. PMID- 21293906 TI - Evidence for evolutionary constraints in Drosophila metal biology. AB - Mutations in single Drosophila melanogaster genes can alter total body metal accumulation. We therefore asked whether evolutionary constraints maintain biologically abundant metal ions (iron, copper, manganese and zinc) to similar concentrations in different species of Drosophilidae, or whether metal homeostasis is a highly adaptable trait as shown previously for triglyceride and glycogen storage. To avoid dietary influences, only species able to grow and reproduce on a standard laboratory medium were selected for analysis. Flame atomic absorption spectrometry was used to determine metal content in 5-days-old adult flies. Overall, the data suggest that the metallome of the nine species tested is well conserved. Meaningful average values for the Drosophilidae family are presented. Few statistically significant differences were noted for copper, manganese and zinc between species. In contrast, Drosophila erecta and Drosophila virilis showed a 50% increase above average and a 30% decrease below average in iron concentrations, respectively. The changes in total body iron content correlated with altered iron storage in intestinal ferritin stores of these species. Hence, the variability in iron content could be accounted for by a corresponding adaptation in iron storage regulation. We suggest that the relative expression of the multitude of metalloenzymes and other metal-binding proteins remains overall similar between species and likely determines relative metal abundances in the organism. The availability of a complete and annotated genome sequence of different Drosophila species presents opportunities to study the evolution of metal homeostasis in closely related organisms that have evolved separately for millions or dozens of million years. PMID- 21293907 TI - Metabolomic profiles delineate potential roles for gadolinium chloride in the proliferation or inhibition of Hela cells. AB - Lanthanides (Lns) compounds have been reported to possess contrary effects on cell activity, i.e., promoting cell cycle progression and cell growth by lower concentration treatment, but suppressing cell proliferation and inducing cell apoptosis at higher dosing. However, the cellular processes during the intervention and the possible underlying mechanisms are still not well clarified. Using a combination of high-throughput liquid chromatography (LC) with mass spectrometry (MS), we have investigated the metabolomic profiles of Hela cells following gadolinium chloride (GdCl(3)) treatment in time- and concentration- dependent manners. A total of 48 metabolites released by Hela cells are identified to be differentially expressed (P < 0.05) in different states. Metabolic pathways analyses reveal that the differential metabolites are mainly characterized by increased lipid and amino acid metabolisms and by decreased lipid, amino acid, and carbohydrate metabolisms for cells treated with GdCl(3) at lower and higher concentrations, respectively. Notably, in the higher level GdCl(3) case, the down-expressions of metabolites are predominantly in the glycolytic and the redox pathways. The above results, obtained by using a metabolomic strategy for the first time, disclose that different cell signaling pathways are activated by GdCl(3) treatment with different concentrations, leading to inhibitory or promotional effect on Hela cells. PMID- 21293908 TI - Functional analysis and expression profiling of HcrVf1 and HcrVf2 for development of scab resistant cisgenic and intragenic apples. AB - Apple scab resistance genes, HcrVf1 and HcrVf2, were isolated including their native promoter, coding and terminator sequences. Two fragment lengths (short and long) of the native gene promoters and the strong apple rubisco gene promoter (P(MdRbc)) were used for both HcrVf genes to test their effect on expression and phenotype. The scab susceptible cultivar 'Gala' was used for plant transformations and after selection of transformants, they were micrografted onto apple seedling rootstocks for scab disease tests. Apple transformants were also tested for HcrVf expression by quantitative RT-PCR (qRT-PCR). For HcrVf1 the long native promoter gave significantly higher expression that the short one; in case of HcrVf2 the difference between the two was not significant. The apple rubisco gene promoter proved to give the highest expression of both HcrVf1 and HcrVf2. The top four expanding leaves were used initially for inoculation with monoconidial isolate EU-B05 which belongs to race 1 of V. inaequalis. Later six other V. inaequalis isolates were used to study the resistance spectra of the individual HcrVf genes. The scab disease assays showed that HcrVf1 did not give resistance against any of the isolates tested regardless of the expression level. The HcrVf2 gene appeared to be the only functional gene for resistance against Vf avirulent isolates of V. inaequalis. HcrVf2 did not provide any resistance to Vf virulent strains, even not in case of overexpression. In conclusion, transformants carrying the apple-derived HcrVf2 gene in a cisgenic as well as in an intragenic configuration were able to reach scab resistance levels comparable to the Vf resistant control cultivar obtained by classical breeding, cv. 'Santana'. PMID- 21293909 TI - Arabidopsis SAP5 functions as a positive regulator of stress responses and exhibits E3 ubiquitin ligase activity. AB - AtSAP5, one of approximately 14 members of the Stress Associated Protein gene family in Arabidopsis, was identified by its expression in response to salinity, osmotic, drought and cold stress. AtSAP5 shows strong homology to OSISAP1, an A20/AN1-type zinc finger protein implicated in stress tolerance in rice. To evaluate the function of AtSAP5 in the regulation of abiotic stress responses, transgenic Arabidopsis plants that over-express AtSAP5 (35S::AtSAP5) were characterized, along with wild-type and T-DNA knock-down plants. Plants that over express AtSAP5 showed increased tolerance to environmental challenges including salt stress, osmotic stress and water deficit. Comparison of gene expression patterns between 35S::AtSAP5 transgenic plants and wild-type plants under normal conditions and water deficit stress indicated that over-expression of AtSAP5 correlates with up-regulation of drought stress responsive gene expression. Analysis of transgenic plants that express GFP-AtSAP5 showed that it is localized primarily in nuclei of root cells and recombinant AtSAP5 has E3 ubiquitin ligase activity in vitro. These results indicate that AtSAP5 has E3 ligase activity and acts as a positive regulator of stress responses in Arabidopsis. PMID- 21293911 TI - Ag-doped 45S5 Bioglass(r)-based bone scaffolds by molten salt ion exchange: processing and characterisation. AB - There is increasing interest in developing scaffolds with therapeutic and antibacterial potential for bone tissue engineering. Silver is a proven antibacterial agent which bacteria such as MRSA have little or no defense against. Using an ion exchange method, silver ions have been introduced into 45S5 Bioglass((r)) based scaffolds that were fabricated using the foam replication technique. This technique allows the introduction of Ag(+) ions onto the surface of the scaffold without compromising the scaffold bioactivity and other physical properties such as porosity. Controlling the amount of Ag(+) ions introduced onto the surface of the scaffold was achieved by tailoring the ion exchange parameters to fabricate samples with repeatable and predictable Ag(+) ion release behavior. In vitro studies in simulated body fluid were carried out to ensure that the scaffolds maintained their bioactivity after the introduction of Ag(+) ions. It was also shown that the addition of low concentrations (2000:1 w/w) of silver ions supported the attachment and viability of human periodontal ligament stromal cells on the 3D scaffolds. This work has thus confirmed ion exchange as an effective technique to introduce Ag(+) ions into 45S5 Bioglass((r)) scaffolds without compromising the basic properties of 45S5 Bioglass((r)) which are required for applications in bone tissue engineering. PMID- 21293912 TI - Calcium ions and a secreted peroxidase in Euphorbia characias latex are made for each other. AB - This minireview deals of a protein, a class III secreted peroxidase, present as unique isoform in the latex of the perennial Mediterranean shrub Euphorbia characias. The paper reports on the molecular properties, on the structures (primary, secondary and tertiary), and on the catalytic mechanism of this enzyme. Here is also reported the extraordinary effect of calcium ions on the structure and on the enzyme activity of Euphorbia peroxidase. These ions can either enhance the catalytic efficiency of the enzyme toward some substrates or can regulate the ability of the enzyme to execute different metabolic pathways toward the same substrate. This review will give a valuable reference to the peroxidase fans and the general readers will find many thorough suggestions for future researches giving birth to new studies and important discoveries. PMID- 21293913 TI - Stability and change in positive development during young adulthood. AB - Calls have been made for a greater focus on successful development and how positive functioning can be conceptualized in theory and empirical research. Drawing on a large Australian community sample (N = 890; 61.7% female), this article examines the structure and stability of positive development at two time points during young adulthood. Previously, we developed and empirically tested a model of positive development at 19-20 years comprised of five first-order constructs (civic action and engagement, trust and tolerance of others, trust in authorities and organisations, social competence, and life satisfaction) and a second-order positive development construct. In the current study, we replicated this model at 23-24 years and found that it was again a good fit for the data, and was equally applicable for young men and women. Hence, positive development can be conceptualized according to five important dimensions at both ages. While variable-oriented tests suggested continuity in levels of positive development, person-oriented analyses revealed four distinct patterns of positive development over time-two reflecting stability (stable high [34.5%] and stable very low [11.6%]) and two characterized by change (low/average increasing [30.4%] and average decreasing [23.5%]). There were significant differences in the gender composition of these groups, with young women overrepresented in the more favourable groups. Thus, despite mean level stability, positive development is characterized by change for many young people, suggesting the importance of identifying factors that support young people's capacity for positive functioning over this transitional period. The current findings contribute to our understanding of the nature and course of positive development over this important period. PMID- 21293914 TI - Social anxiety and aggression in early adolescents: examining the moderating roles of empathic concern and perspective taking. AB - Guided by a social information processing perspective, this study examined the unique and interactive contributions of social anxiety and two distinct components of empathy, empathic concern and perspective taking, to subsequent relational and overt aggression in early adolescents. Participants were 485 10- to 14-year old middle school students (54% female; 78% European-American) involved in two waves of a study with one year between each wave. Hierarchical regression analyses showed that higher levels of empathic concern were directly associated with decreases in subsequent relational and overt aggression one year later and buffered the impact of social anxiety on subsequent relational aggression. Although perspective taking did not moderate the impact of social anxiety on either form of aggression, it was a unique predictor of increased relational aggression one year later. Findings call for future research to assess both components of empathy separately as they relate to relational and overt aggression. PMID- 21293915 TI - Acculturation, gender, depression, and cigarette smoking among U.S. Hispanic youth: the mediating role of perceived discrimination. AB - Hispanic youth are at risk for experiencing depressive symptoms and smoking cigarettes, and risk for depressive symptoms and cigarette use increase as Hispanic youth acculturate to U.S. culture. The mechanism by which acculturation leads to symptoms of depression and cigarette smoking is not well understood. The present study examined whether perceived discrimination explained the associations of acculturation with depressive symptoms and cigarette smoking among 1,124 Hispanic youth (54% female). Youth in Southern California completed surveys in 9th-11th grade. Separate analyses by gender showed that perceived discrimination explained the relationship between acculturation and depressive symptoms for girls only. There was also evidence that discrimination explained the relationship between acculturation and cigarette smoking among girls, but the effect was only marginally significant. Acculturation was associated with depressive symptoms and smoking among girls only. Perceived discrimination predicted depressive symptoms in both genders, and discrimination was positively associated with cigarette smoking for girls but not boys. These results support the notion that, although Hispanic boys and girls experience acculturation and discrimination, their mental health and smoking behaviors are differentially affected by these experiences. Moreover, the results indicate that acculturation, gender, and discrimination are important factors to consider when addressing Hispanic youth's mental health and substance use behaviors. PMID- 21293916 TI - The role of masturbation in healthy sexual development: perceptions of young adults. AB - Despite efforts to identify masturbation as a strategy to improve sexual health, promote relational intimacy, and reduce unwanted pregnancy, STIs, and HIV transmission, masturbation as a context for healthy sexual development has been met with silence or trepidation in the scientific and educational communities. Relegated to the realm of commercial media, rather than rational discourse in families, schools, and the general public, young people receive mixed messages about this non-reproductive sexual behavior. In order to explore how young adults have learned about masturbation and currently perceive masturbation, we conducted a grounded theory study of 72 college students (56 females; 16 males) enrolled in a human sexuality class. Findings revealed that a young adult's perceptions of and feelings toward masturbation were the result of a developmental process that included: (1) learning about the act of masturbation and how to do it, (2) learning and internalizing the social contradiction of stigma and taboo surrounding this pleasurable act, and (3) coming to terms with this tension between stigma and pleasure. Although nearly all participants learned about masturbation through the media and peers (not parents or teachers), gender was salient in coming to terms with the contradiction of stigma and pleasure. Most of the women reported either still struggling with the contradiction or accepting it as normal. Most of the men recognized the beneficial aspects for healthy sexual development that result from masturbation. Both male and female participants identified differential sexual scripts as contributing to the double standard. PMID- 21293917 TI - Natural mentoring processes deter externalizing problems among rural African American emerging adults: a prospective analysis. AB - A 3-wave model linking natural mentoring relationships to externalizing behavior was tested with 345 rural African American emerging adults in their final year of high school. Structural equation models were executed linking multi-informant reports of mentor-emerging adult relationship quality with youths' externalizing behavior 18 months later. Consistent with our primary hypotheses, emerging adults whose relationships with their natural mentors were characterized by instrumental and emotional support and affectively positive interactions reported lower levels of anger, rule-breaking behavior, and aggression. These effects emerged independent of the influences of family support and youth gender. Two intrapersonal processes, a future orientation and self-regulation, emerged as mediators of the influence of natural mentoring relationships. The influence of natural mentors was most pronounced for emerging adults experiencing high levels of life stress. PMID- 21293918 TI - Elevated S100B and neuron specific enolase levels in patients with migraine without aura: evidence for neurodegeneration? AB - Although migraine has mainly been considered as a benign disease, there is cumulative evidence of silent changes in the brain, brainstem, or cerebellum and subtle subclinical cerebellar dysfunction. In this study, in order to investigate a possible neuronal and/or glial damage at the cellular level in migraine, we measured and compared serum levels of S100B which is a protein marker of glial damage or activation, and neuron specific enolase (NSE) which is a marker of neuronal damage, in migraine patients and control subjects. Serum levels of S100B and NSE were measured in blood samples from 41 patients with migraine-without aura taken during a migraine attack (ictal) and in the attack-free period between migraine attacks (interictal) and 35 age- and sex-matched controls. Patients with migraine-without aura had significantly higher ictal serum levels of S100B and NSE (P < 0.05, for both) than control subjects; whereas in the interictal phase, there was a significant increment only in S100B levels (P < 0.05) compared to controls. On the other hand, serum levels of S100B and NSE in ictal and interictal blood samples did not differ significantly. The findings of increased ictal serum S100B and NSE levels together with increased interictal levels of S100B suggested that migraine might be associated with glial and/or neuronal damage in the brain and a prolonged disruption of blood-brain barrier. Increased interictal serum levels of S100B might point out to an insidious and slow damaging process in migraine patients. PMID- 21293919 TI - Psychopathology in African unaccompanied refugee minors in Austria. AB - We assessed the prevalence of a range of psychopathology among African unaccompanied refugee minors (URMs) in Austria. Additionally, the predictive value of war exposure on PTSD symptoms was examined. Forty-one URMs were assessed with the Mini-International Neuropsychiatric Interview for children and adolescents, the Youth Self-Report, the UCLA PTSD Reaction Index and Facts About You. As expected, 56% of youth had at least one diagnosis by structured clinical interview. The most common diagnoses were adjustment disorder, PTSD and dysthymia. War affliction marginally predicted (p = 0.065) PTSD controlling for age and gender. URMs had high levels of psychopathology compared to norms. Their PTSD rates were somewhat lower than found in previous studies. We discuss methodological and substantive reasons for this finding. Future studies need to examine URMs across the entire diagnostic spectrum and employ multi-method designs to yield valid results. The psychopathology in URMs has clinical and forensic implications. PMID- 21293920 TI - Neoadjuvant chemotherapy for breast cancer: a surgeon's checklist. PMID- 21293921 TI - Effects on survival of menstrual cycle phase of adjuvant surgical oophorectomy in premenopausal women with breast cancer. AB - Adjuvant surgical oophorectomy is an effective and remarkably cost effective treatment for premenopausal women with hormone receptor positive operable breast cancer. Previously published secondary analyses indicated a survival benefit for patients whose surgery was performed in the luteal phase of the menstrual cycle as opposed to the follicular. This study utilizes additional follow-up and more fully examines this hypothesis and the general implications of long-term follow up on trial design. Beginning in 1993 we recruited women to a multicenter randomized clinical trial of adjuvant surgical oophorectomy and tamoxifen for 5 years. We recorded the reported day 1 of the patients' last menstrual cycle on the day of their adjuvant surgery. We conducted secondary analyses of the association of history-estimated luteal or follicular phase oophorectomy surgery with disease-free and overall survival. In multivariable Cox analyses, disease free survival (DFS) exhibited a positive trend and overall survival (OS) showed a significant improvement in patients whose surgery was estimated to have occurred in the luteal phase of the menstrual cycle compared to the follicular (HR for DFS: 0.66, 95% CI: 0.37-1.16; HR for OS: 0.49, 95% CI: 0.27-0.88). From the hazard function plots, it appears that the luteal phase surgery effect on DFS diminishes after 6 years of follow-up. In conclusion, adjuvant surgical oophorectomy during the luteal phase of the menstrual cycle resulted in a reduced hazard of recurrence as compared to oophorectomy in the follicular phase during the first 5.5 years of follow-up. The practical and biological implications of these findings deserve rigorous evaluation in clinical trials. PMID- 21293922 TI - Functional polymorphisms in CD166/ALCAM gene associated with increased risk for breast cancer in a Chinese population. AB - Activated Leukocyte Cell Adhesion Molecules (ALCAM, also called CD166, MEMD) are cell surface immunoglobulins that are considered to be prognostic markers for breast cancer. CD166/ALCAM has gained increasing attention because of its significant association with tumor progression and the metastatic spread of breast cancer. Two polymorphisms have been identified in the CD166/ALCAM gene: 5'UTR C/T (rs6437585) and 3'UTR A/G (rs11559013). We analyzed the genotypes of 1033 individuals with breast cancer, and 1116 controls; odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression. The effects and functions of polymorphisms were examined using luciferase gene expression assays and real-time PCR analyses. Our data demonstrated that individuals with the rs6437585 CT + TT genotype had an OR of 1.38 (95% CI, 1.11-1.72) for developing breast cancer, compared to those with the CC genotype. The T allele increased the risk of breast cancer in a dose-dependent manner (P (trend) < 0.001). However, there were no significant differences found between cases and controls at the rs11559013 A/G site. Additional experiments that we performed, which focused on reporter gene expression driven by CD166/ALCAM promoters, demonstrated that the presence of an rs6437585 T allele led to greater transcriptional activity than the rs6437585 C allele. This was consistent with the increased cancer risk that we observed in our case-control analysis. PMID- 21293923 TI - The relationships between problem characteristics, achievement-related behaviors, and academic achievement in problem-based learning. AB - This study investigated the influence of five problem characteristics on students' achievement-related classroom behaviors and academic achievement. Data from 5,949 polytechnic students in PBL curricula across 170 courses were analyzed by means of path analysis. The five problem characteristics were: (1) problem clarity, (2) problem familiarity, (3) the extent to which the problem stimulated group discussion, (4) self-study, and (5) identification of learning goals. The results showed that problem clarity led to more group discussion, identification of learning goals, and self-study than problem familiarity. On the other hand, problem familiarity had a stronger and direct impact on academic achievement. PMID- 21293924 TI - Dietary supplementation with tBHQ, an Nrf2 stabilizer molecule, confers neuroprotection against apoptosis in amyloid beta-injected rat. AB - Nuclear factor erythroid 2-related factor 2 (Nrf2) coordinates the up-regulation of cytoprotective genes via the antioxidant response element (ARE). There is significant evidence that oxidative stress is a critical event in the pathogenesis of AD. Considering the protective role of Nrf2 against oxidative injury, we studied to determine whether in vivo toxicity of amyloid beta (Abeta) can be attenuated by tBHQ, an Nrf2 stabilizer, Using an Abeta injection model. We demonstrated that pre-activation of endogenous Nrf2 by tBHQ attenuated Abeta induced caspase-3 expression. tBHQ enhanced GSH, decreased MDA level, and inhibited NF-kappaB. This investigation provides the first documentation of tBHQ's neuroprotective effect through decrease of Abeta accumulation in rat brain. Our results show the involvement of Hsp-70 in this protective effect. In summary tBHQ treatment for 1 week prior to Abeta injection protected against the oxidative damage, apoptosis and Abeta accumulation in rats. PMID- 21293925 TI - Hydrocortisone enhances the function of the blood-nerve barrier through the up regulation of claudin-5. AB - In autoimmune disorders of the peripheral nervous system (PNS), including Guillain-Barre syndrome and chronic inflammatory demyelinating polyradiculoneuropathy, breakdown of the blood-nerve barrier (BNB) has been considered to be a key step in the disease process. Although glucocorticoids (GCs) have been shown to effectively restore the blood-brain barrier (BBB) in some inflammatory central nervous system diseases such as multiple sclerosis, their action against the BNB has not yet been examined. To elucidate the role of GCs on the BNB, we established a novel human immortalized endothelial cell lines derived from the BNB. The established cell line termed "DH-BNBs" expresses two important tight junction proteins, claudin-5 and occludin. Using DH-BNBs, we analyzed how GCs affect BNB function. We herein report that GCs up-regulate the expression of claudin-5 and increase the barrier properties of the BNB. This is the first report which indicates how GCs affect the blood-nerve barrier. PMID- 21293926 TI - Phylogenetic groups, virulence genes and quinolone resistance of integron-bearing Escherichia coli strains isolated from a wastewater treatment plant. AB - We investigated phylogenetic affiliation, occurrence of virulence genes and quinolone resistance in 109 integron-containing strains of Escherichia coli isolated from a wastewater treatment plant. Selection for integron-bearing strains caused a shift toward phylogroup D, which was most numerous, followed by A, B1 and B2. Phylogroups D and B2, both of which are reported to include virulent extraintestinal pathotypes, made up 50.5% of all isolates and were present in every stage of wastewater treatment, including final effluent. Diarrheagenic pathotypes made up 21% of the strains. The average virulence factor genes score was low (1.40) and the range was from 0 to 5. Quinolone and fluoroquinolone resistance was observed in 56.0% and 50.4% of the strains, respectively; however, it was not associated with virulence factor score. Although the average virulence factor score was low, 17.4% of strains had three and more virulence genes. They were isolated mostly from raw sewage, but 30% of them were cultured from final effluent. Release of multiresistant integron bearing E. coli strains with virulence traits into the environment may create potential threat and be of public health concern. PMID- 21293927 TI - Gastric cancer: a well-behaved Helicobacter pylori-related disease? PMID- 21293928 TI - Implications of antisocial parents. AB - Antisocial behavior is a socially maladaptive and harmful trait to possess. This can be especially injurious for a child who is raised by a parent with this personality structure. The pathology of antisocial behavior implies traits such as deceitfulness, irresponsibility, unreliability, and an incapability to feel guilt, remorse, or even love. This is damaging to a child's emotional, cognitive, and social development. Parents with this personality makeup can leave a child traumatized, empty, and incapable of forming meaningful personal relationships. Both genetic and environmental factors influence the development of antisocial behavior. Moreover, the child with a genetic predisposition to antisocial behavior who is raised with a parental style that triggers the genetic liability is at high risk for developing the same personality structure. Antisocial individuals are impulsive, irritable, and often have no concerns over their purported responsibilities. As a parent, this can lead to erratic discipline, neglectful parenting, and can undermine effective care giving. This paper will focus on the implications of parents with antisocial behavior and the impact that this behavior has on attachment as well as on the development of antisocial traits in children. PMID- 21293929 TI - An evaluation of risk factors in pregnant women with Candida vaginitis and the diagnostic value of simultaneous vaginal and rectal sampling. AB - In this study, we investigated the epidemiological characteristics of VVC among pregnant women. We conducted a prospective survey among 372 pregnant women to investigate the prevalence, clinical forms, etiological agents, and predisposing factors of VVC. In addition, we determined the relationship between vaginal and rectal flora by simultaneously obtaining one high vaginal swab and one rectal swab from each patient using sterile cotton-tipped swabs. Furthermore, we compared the recovery and identification performances of chromID Candida agar to Sabouraud dextrose agar with gentamicin and chloramphenicol. Clinically and mycologically confirmed cases of VVC were detected in 139 (37.4%) and vaginal colonization described in 42 (11.3%) of 372 pregnant women. Rectal cultures were also positive in 98 of the 139 (70.5%) VVC cases. Candida albicans and C. glabrata were identified in vaginal samples in 58.0 versus 19.0% and from rectal samples in 49.0 versus 13.5%, respectively. Increases in gestational week and gravidae were identified to be statistically significant in patients with acute VVC (AVVC) and symptomatic recurrent VVC (RVVC), and asymptomatic RVVC (P = 0.04 and P = 0.03, respectively). In the laboratory diagnosis of VVC, specifically tailored chromogenic media are reliable tools for both the recovery and rapid identification of common Candida spp., particularly C. albicans, as well as for the detection of polyfungal populations in vaginal samples (P > 0.05). In addition, rectal colonization is a common finding in cases of AVVC and symptomatic-RVVC cases and corresponds well with the presence of the same yeast species in the vagina. PMID- 21293930 TI - Compared to what? A joint evaluation method for assessing quality of life. AB - PURPOSE: This study tests whether a joint evaluation method for assessing quality of life can stabilize ratings by providing contextual information, thereby helping participants calibrate responses on a rating scale. We also use the method to test for scale recalibration between patients and non-patients. METHOD: In an Internet survey, participants (N = 1,865) rated a target health condition, either diabetes or obesity, on a 100-point rating scale. Participants either rated several other items on the same rating scale first (joint evaluation), or rated the target condition first (single evaluation). We compared target condition ratings for joint versus single evaluation, as well as the rank position of that item among the other items. We also compared ratings and rankings for patients versus non-patients. RESULTS: The method effectively picked up distinct patterns of scale usage, with evidence of scale recalibration for obesity ratings, but not for diabetes ratings. The stabilizing effects of the method were mixed. For both diabetes and obesity, the joint evaluation task helped stabilize the rank position of the target condition, but not the rating. CONCLUSIONS: Results do not conclusively support joint evaluation as a method for reducing noise in rating scale usage, but do support its use for detecting scale recalibration between patients and non-patients. PMID- 21293931 TI - Maternal, paternal, and family health-related quality of life in the context of pediatric inflammatory bowel disease. AB - PURPOSE: The primary aim of this study was to examine the associations of disease activity and adolescent adjustment with parent and family health-related quality of life (HRQoL) among families of youths with inflammatory bowel disease (IBD). A secondary aim was to compare maternal and paternal perceptions of parent and family functioning. METHODS: Ninety-five primarily Caucasian families (92 mothers and 43 fathers) of youths with IBD ranging in age from 11 to 18 participated. Most adolescents were diagnosed with Crohn's disease and had been diagnosed with IBD for several years at the time of the study. Parents completed the PedsQL Family Impact Module, while youths completed the Pediatric Symptoms Checklist. Disease activity ratings were obtained from medical records. RESULTS: Multiple regression analyses suggested that disease activity was consistently associated with all father-reported outcomes and explained twice as much of the variance in father-reported parent and family HRQoL outcomes compared to mother-reported outcomes. In contrast, youth adjustment was consistently associated with all maternal outcomes but only one paternal outcome, and explained nearly twice as much variance in maternal-reported outcomes compared to paternal-reported outcomes. No significant differences between maternal and paternal reports of parent or family HRQoL were identified using independent samples t tests. CONCLUSIONS: Although mothers and fathers report similar individual and family HRQoL, the strength of associations between disease and youth adjustment factors with these outcomes differs somewhat by parent gender. Findings underscore the importance of examining maternal and paternal functioning separately and incorporating routine family assessment into the course of treatment. PMID- 21293932 TI - Health status and QOL instruments used in childhood cancer research: deciphering conceptual content using World Health Organization definitions. AB - PURPOSE: The impact of cancer on children can be assessed through various concepts including mental and physical health status and most significantly quality of life (QOL). It has been difficult to compare data collected through these instruments due to a lack of continuity or understanding of overlaps and gaps between them. To delineate the content of the most commonly used instruments in childhood cancer on an item-by-item basis, this study used standardized methods to link health information to the International Classification of Functioning, Disability, and Health (ICF) as well as World Health Organization (WHO) standard definitions of health and quality of life. METHOD: MEDLINE, CINAHL, EMBASE, PsycINFO, Cancerlit, and Sociological Abstracts were searched from the inception of each database to June 15th, 2009 for health status and quality of life instruments. The six most common cancer-specific and generic instruments employed in primary research in childhood cancer were analyzed on an item-by-item basis by two content assessors specializing in ICF linking and WHO definitions of health and QOL, using a standardized iterative technique developed at the ICF Research Branch. RESULTS: We report the extent to which health status and QOL are represented in each instrument. Most measures emphasize a majority health status perspective according to WHO definitions of health. The generic instruments stress activities and participation domains over body functions or environment factors according to the ICF while cancer-specific instruments vary in their emphasis. Initial phase of coding agreement between assessors was in the substantial range (0.6-0.8 using Cohen's kappa). CONCLUSION: A comprehensive and systematic content analysis of the most commonly employed health status and QOL instruments was conducted for this review. Two criteria were described as follows: the perspectives of the instruments (i.e., health vs. QOL) and the health content (according to ICF components). No single instrument demonstrated an ideal balance of content characteristics according to these criteria, and thus, each must be considered carefully relative to one's particular research or clinical evaluative purpose. PMID- 21293933 TI - Macroscopic serosal classification predicts peritoneal recurrence for patients with gastric cancer underwent potentially curative surgery. AB - BACKGROUND: Previous studies revealed serosal invasion as one of the most important predictors of peritoneal micrometastasis. However, even for cancers with serosal invasion, the macroscopic serosal appearance is highly heterogeneous. The aim of the present study was to propose a macroscopic serosal classification (MSC) and to investigate the validity of this classification as a predictor of peritoneal recurrence. MATERIALS AND METHODS: Clinicopathologic features including MSC of 1528 patients with pT3/pT4a stage gastric cancers who underwent potentially radical surgery were retrospectively reviewed. MSC was classified as reactive type, nodular type, tendonoid type, and color-diffused type according to the macroscopic serosal appearance. RESULTS: There were significant differences in tumor size, location, Bormann type, Lauren grade, lymphatic and/or blood vessels invasion (LBVI), width of serosa changes, depth of invasion, number of nodes metastasis, lymph node metastasis ratio, pN stage, and peritoneal cytology between patients with different types of serosa. Multivariate analysis revealed MSC, as well as depth of invasion, Lauren grade, and pN stage, significantly predicted the presence of peritoneal-free cancer cells. Both MSC and peritoneal cytology significantly correlated with patient survival. However, only MSC significantly predicted peritoneal recurrence on multivariate analysis, but peritoneal cytology did not, indicating MSC was more sensitive than cytologic examination. Further investigation suggested MSC and pN stage were also independent predictors of peritoneal recurrence for patients with negative peritoneal cytology. CONCLUSIONS: The MSC sensitively predicts the presence of peritoneal micrometastasis for pT3/pT4a-stage gastric cancer patients who underwent potentially radical surgery. Consequently, it might be considered a good indicator to guide perioperative adjuvant therapy for patients with high risk of peritoneal recurrence. PMID- 21293934 TI - Association of C-reactive protein gene polymorphisms and colorectal cancer. AB - BACKGROUND: An elevated plasma level of C-reactive protein (CRP) is a risk for, and prognostic factor of, colorectal cancer (CRC). In other reports of CRP concerning cardiovascular disease, CRP level correlated with its gene polymorphisms. We hypothesized that CRP polymorphisms associate risk and prognosis of CRC. METHODS: This study enrolled 421 patients with CRC and 218 healthy control subjects. After preliminary studies, we selected four single nucleotide polymorphisms (SNPs) in the CRP gene: +2147A > G (rs1205), +942G > C (rs1800947), -717A > G (rs2794521), and -757T > C (rs3093059). At first, analyzing distributions of four SNPs between CRC case and non-CRC control groups was performed. Subsequently, the impacts of these SNPs with other prognostic factors of disease-free interval (DFI) and cancer-specific survival (CSS) were analyzed using uni- and multivariate Cox regression analyses. RESULTS: The case and control groups differed in the frequency of -757T > C (P = 0.002). The CRC case group had a higher percentage of the TT genotype (odds, 1.75). Regarding prognoses, multivariate analyses revealed that four factors, including stage (I, II, III), gross tumor type (polypoid, ulcerative, infiltrative), location (right, left, rectum), and -757T > C SNP (odds, 1.29; P = 0.048), correlated with DFI; two factors, including stage and +2147A > G SNP (odds, 0.71; P = 0.03), correlated with CSS. CONCLUSIONS: The -757T > C SNP is a risk for and prognostic factor of DFI; the +2147A > G SNP is a prognostic factor of CSS. CRP polymorphisms associate the risk and survival of CRC. PMID- 21293935 TI - Toxic metal contamination in Artemisia annua L. herbal preparations from different commercial sources in China. AB - Toxic metal contamination was investigated in Artemisia annua L. herbal preparations from different commercial sources in China. Measurable amounts of copper (Cu), lead (Pb), arsenic (As), mercury (Hg), cadmium (Cd), chromium (Cr), manganese (Mn), nickel (Ni) and aluminium (Al) were detected in commercial dried Artemisia annua L., Massa Medicata Fermentata (Shenqu), Semen Sojae Praeparatum, medicated leaven (Jianqu) and an oral dose of Zhongganling-pian by inductively coupled plasma optical emission spectrometry (ICP-OES) and atomic fluorescence spectrometry (AFS). A total of 69 samples were collected from different sources in the Chinese market. Toxic metals contents in the investigated samples were found at different levels. Results showed that 94.20, 100, 97.10, 91.30 and 94.20% of the products fully complied with the quality requirement for traditional medicines in China pertaining to Cu, Pb, As, Hg and Cd, respectively. Although toxic metal concentrations measured in this study do not pose a serious health risk, they do affect the quality of herbal preparations. Moreover, on the basis of the results obtained in the present work, it is concluded that the present techniques are suitable for the routine determination of toxic metals concentration in various pharmaceutical dosage forms. PMID- 21293936 TI - Inhibition of proliferation by agricultural plant extracts in seven human adult T cell leukaemia (ATL)-related cell lines. AB - Adult T-cell leukaemia (ATL) is caused by human T-cell leukaemia virus type I (HTLV-I) infection and is resistant to conventional chemotherapy. We evaluated the inhibitory effects of agricultural plants on the proliferation of seven ATL related human leukaemia cells, using three ATL cell lines (ED, Su9T01 and S1T), two human T-cell lines transformed by HTLV-I infection (HUT-102 and MT-2) and two HTLV-I-negative human T-cell acute lymphoblastic leukaemia cell lines (Jurkat and MOLT-4). A total of 52 samples of 80% ethanol extracts obtained from 30 types of agricultural plants were examined. On the basis of IC(50) values, we selected samples with greater activity than genistein, which was used as a positive control. The highest inhibitory effect was observed with extracts from leaves of Vaccinium virgatum Aiton (blueberry) on four cell lines (ED, Su9T01, HUT-102 and Jurkat); seeds of Momordica charantia L. (bitter gourd) exhibited the second highest activity. The bitter gourd seeds suppressed the proliferation of three cell lines (Su9T01, HUT-102 and Jurkat). The extracts from edible parts of Ipomea batatas LAM. (sweet potato), edible parts of Colocasia esculenta (L.) Schott (taro), skin of taro and seeds of Prunus mume Sieb. et Zucc. (mume) showed markedly greater inhibitory effects on Su9T01 than genistein. These findings suggest that ATL-preventative bioactive compounds may exist in these agricultural plants, which are considered to be functional foods. PMID- 21293937 TI - Congruence between urban adolescent and caregiver responses to questions about the adolescent's asthma. AB - In clinical and research settings, it is increasingly acknowledged that adolescents may be better positioned than their caregivers to provide information in regard to their own health status, including information related to asthma. Very little is known, however, about the congruence between adolescent and caregiver responses to questions about asthma beyond reports of symptoms. We analyzed data for 215 urban, primarily African-American adolescent-caregiver pairs. Adolescents and caregiver reports concerning the adolescent's asthma related medical history were moderately correlated and not found to differ at the aggregate level. Correlations between adolescent and caregiver reports of the adolescent's asthma symptoms and functional status were weak, although these differences deteriorated at the aggregate level. Adolescent-caregiver reports of symptoms and functioning were more likely to be in agreement if the adolescent was older, if school personnel were unaware of the child's asthma, and if the adolescent's asthma was classified as mild intermittent. For questions concerning the frequency of hospitalizations, emergency department visits, and physician visits, moderate correlations between adolescent and caregiver responses were noted, although with some differences at the aggregate level. Findings suggest that, when adolescents and their caregivers are asked about the adolescent's asthma in clinical and research settings, the extent to which the two perspectives are likely to agree depends on the type of information sought. Clinicians and researchers may obtain more accurate information if questions about symptoms and functional status are directed toward adolescents. PMID- 21293938 TI - A three-generational study of risk factors for childhood externalizing behavior among African Americans and Puerto Ricans. AB - This is the first prospective study to examine the precursors of child externalizing behavior across three generations of African Americans and Puerto Ricans. Participants comprised a community cohort of male and female African Americans and Puerto Ricans (N = 366, X- age = 29.4 years), who are part of an ongoing study of drug use and problem behaviors, and who had a child. Data were collected at four time waves, spanning the participants' adolescence to adulthood. Questionnaires were initially self-administered in schools in East Harlem, NY, USA (time 1). Subsequently, structured interviews were conducted by trained interviewers (times 2 and 3), and self-administered via mail (time 4). The independent variables consisted of the participants' prospective reports of their (a) relationships with their parents during adolescence, (b) depressive mood and drug use (adolescence to adulthood), (c) relationship with their oldest child between the ages of 6-13, and (d) perceptions of neighborhood crime and deterioration (in adulthood). The dependent variable was externalizing behavior in the participant's oldest child (X- age = 9.6 years; SD = 2.0). Structural equation modeling showed that the parent-child relationship during participants' adolescence was linked with the participants' depressive mood and drug use which, in turn, were associated with the participants' relationship with their own child, as well as with neighborhood crime and deterioration when participants were adults. The participants' depressive mood, and relationship with their own child, as well as neighborhood crime and deterioration, each had a direct pathway to externalizing behavior in the participant's child. Findings suggest that intervention programs and public policy should address parental attributes, neighborhood factors, and, especially, parenting skills, to reduce risk factors for the intergenerational transmission of externalizing behavior. PMID- 21293939 TI - High-intensity focused ultrasound (HIFU) in patients with solid malignancies: evaluation of feasibility, local tumour response and clinical results. AB - PURPOSE: The purpose of this study was to evaluate the safety and efficacy of ultrasound-guided high-intensity focused ultrasound (USgHIFU) for ablation of solid tumours without damaging the surrounding structures. MATERIALS AND METHODS: A specific written informed consent was obtained from every patient before treatment. From September 2008 to April 2009, 22 patients with 29 lesions were treated: nine patients with liver and/or soft-tissue metastases from colorectal carcinoma (CRC), six with pancreatic solid lesions, three with liver and/or bone metastases from breast cancer, one with osteosarcoma, one with muscle metastasis from lung cancer, one with iliac metastasis from multiple myeloma and one with abdominal liposarcoma. The mean diameter of tumours was 4.2 cm. All patients were evaluated 1 day, 1 month and 3 months after HIFU treatment by multidetector computed tomography (MDCT), positron-emission tomography (PET)-CT and clinical evaluation. The treatment time and adverse events were recorded. RESULTS: All patients had one treatment. Average treatment and sonication times were, respectively, 162.7 and 37.4 min. PET-CT or/and MDCT showed complete response in 11/13 liver metastases; all bone, soft-tissue and pancreatic lesions were palliated in symptoms, with complete response to PET-CT, MDCT or magnetic resonance imaging (MRI); the liposarcoma was almost completely ablated at MRI. Local oedema was observed in three patients. No other side effects were observed. All patients were discharged 1-3 days after treatment. CONCLUSIONS: According to our preliminary experience in a small number of patients, we conclude that HIFU ablation is a safe and feasible technique for locoregional treatment and is effective in pain control. PMID- 21293940 TI - Fetal magnetic resonance imaging: indications, study protocols and safety. AB - The aim of this paper is to outline the real indications for fetal magnetic resonance imaging (FMRI) based on the current clinical and scientific evidence and to determine where it fits into prenatal diagnostic protocols. We also consider the most commonly used FMRI diagnostic protocols and take stock of the safety aspects of this examination. This paper is the result of the work of the Fetal Magnetic Resonance (FMR) Study Group of the Italian Society of Medical Radiology (SIRM) in cooperation with the Study Group of the Italian Society of Ultrasound in Obstetrics and Gynaecology (SIEOG). It has been reviewed and approved by the Italian Association of Neuroradiology (AINR). As FMRI is undergoing continuous development, and its indications and role are also likely to change over time, the Fetal Magnetic Resonance Study Group is in agreement with the other scientific bodies involved in the drafting of this document to propose subsequent modifications to it when new clinical and scientific evidence suggest the need. PMID- 21293941 TI - The ultrasonographic correlates of carpal tunnel syndrome in patients with normal electrodiagnostic tests. AB - PURPOSE: The diagnosis of carpal tunnel syndrome (CTS) is established by electrodiagnostic testing (EDT). Nonetheless, in a portion of patients complaining of the typical signs and symptoms of CTS, the EDT is negative, and yet no paraclinical tool has been acknowledged for confirming the diagnosis. The aim of this study was to investigate the value of ultrasound imaging in diagnosing clinically suspicious patients with normal EDT findings. MATERIALS AND METHODS: Thirty-four patients, with clinical evidence of CTS but without abnormal findings on electromyography, and 41 healthy controls were enrolled. Ultrasonography was performed in all participants, and cross-sectional area (CSA), hypoechogenicity and hypervascularity of the median nerve were evaluated. Multivariate logistic regression analysis was used to formulate a prediction model for CTS. RESULTS: CSA of the median nerve in the wrist and wrist-to-forearm ratio were significantly higher in patients compared with controls. Patients had significantly higher hypoechogenicity [odds ratio (OR) 4.317; 95% confidence interval (CI) 1.23-15.11) and hypervascularity (OR 5.004,; 95% CI 1.02-21.15) in the median nerve. Clinical evidence of CTS was predicted using a model comprising three ultrasonographic determinant factors, including hypoechogenicity, hypervascularity and wrist CSA of the median nerve. The probability of clinical evidence of CTS in a person with one, two, or three ultrasonographic signs of CTS was estimated to be 35%, 70%, and 90%, respectively. CONCLUSIONS: Ultrasound imaging is a useful technique in diagnosing CTS patients when EDT results are not confirmatory and the patient is suspected of having neuropathy. PMID- 21293942 TI - MR-guided vacuum-assisted breast biopsy in the management of incidental enhancing lesions detected by breast MR imaging. AB - PURPOSE: The objective of this study was to determine the clinical value and accuracy of magnetic resonance (MR)-guided vacuum-assisted breast biopsy (VAB). MATERIALS AND METHODS: We retrospectively analysed 106 incidental breast lesions detected on MR imaging in 98 patients. Patients with nonpalpable suspicious lesions that were only MR visible were referred for MR-VAB performed with a 10 gauge needle. All patients with a VAB diagnosis of infiltrating carcinoma, carcinoma in situ or atypical epithelial hyperplasia were referred for surgery. Histopathology of the surgical specimen was considered the reference standard. RESULTS: MR-guided VAB was attempted in 29/106 lesions (27%); in 2/29 patients, the procedure could not be performed owing to failure to visualise the lesion. Lesions with clearly malignant features and borderline lesions (atypical ductal hyperplasias) were identified in 12 cases (44%) and benign entities in 15 (56%). Seven of 12 (58%) malignant lesions were <10 mm. Among the 27 successful MR-VAB procedures, VAB yielded one false-negative diagnosis (4%) and underestimation (4%). MR-guided VAB sensitivity and specificity were 92% and 100%, respectively, with a positive predictive value of 100% and a negative predictive value of 93%. CONCLUSIONS: The results of this study indicate that MR-guided VAB offers good accuracy in characterising nonpalpable breast lesions visible on MR imaging alone. Small lesion size (<1 cm) did not prove to be a limitation for the success of the procedure. PMID- 21293943 TI - Incidental enhancing lesions found on preoperative breast MRI: management and role of second-look ultrasound. AB - PURPOSE: This study prospectively assessed second-look ultrasound (US) for the evaluation of incidental enhancing lesions identified on preoperative breast magnetic resonance imaging (MRI). MATERIALS AND METHODS: Between 2004 and 2007, 182 patients with malignant breast lesions detected on US and/or X-ray mammography and confirmed by cytology/histology underwent preoperative breast contrast-enhanced (CE)-MRI. Patients with incidental lesions on breast MRI underwent second-look high-resolution US directed at the site of the incidental finding. Diagnosis of incidental lesions was based on biopsy or 24-month follow up. RESULTS: Breast MRI detected 55 additional lesions in 46/182 (25.2%) patients. Forty-two of 55 (76.3%) lesions were detected on second-look US in 38/46 (82.6%) patients. Malignancy was confirmed for 24/42 (57.1%) correlate lesions compared with 7/13 (53.8%) noncorrelate lesions. Second-look US depicted 8/9 (88.8%) Breast Imaging Reporting and Data System (BI-RADS) 5, 16/22 (72.7%) BI-RADS 4 and 18/24 (75%) BI-RADS 3 lesions. Sensitivity, specificity, accuracy and positive and negative predictive values for lesion detection/diagnosis was 100%, 88.9%, 94.6%, 90.3% and 100% for MRI and 64.3%, 70.4%, 67.3%, 69.2% and 65.5% for second-look US. Improved performance for US was obtained when masslike lesions only were considered. CONCLUSIONS: Second-look US is a confirmatory method for incidental findings on breast MRI, particularly for mass-like lesions. PMID- 21293944 TI - Role of diffusion-weighted imaging in the differential diagnosis of benign and malignant lesions of the chest-mediastinum. AB - PURPOSE: We retrospectively evaluated the role of diffusion-weighted imaging (DWI) with fat and background signal suppression in the differential diagnosis of benign and malignant lesions of the chest-mediastinum by calculating the mean apparent diffusion coefficient (ADC) values. MATERIALS AND METHODS: Thirty-four patients with lung nodules/mediastinal masses underwent magnetic resonance (MR) imaging of the chest with conventional and DWI sequences. All patients had been previously studied with computed tomography (CT). After magnetic resonance (MR) imaging the patients underwent transthoracic CT-guided biopsy or mediastinoscopy. After the histopathological diagnosis had been obtained, the lesions were retrospectively divided into five groups: adenocarcinomas (n=16), squamous cell carcinomas (n=12), chronic pneumonias (n=2), malignant mediastinal tumours (n=2) and typical carcinoids (n=2). We compared ADC values in the different lesion groups using the Mann-Whitney U test. RESULTS: There were statistically significant differences (p<0.05) between ADC values of benign and malignant lesions. Using an ADC value of 1.25*10-3 mm2/s as a threshold, we were able to differentiate malignant from benign lesions with 91% diagnostic accuracy, 90% sensitivity, 100% specificity, 100% positive predictive value and 57% negative predictive value. CONCLUSIONS: Short-tau inversion-recovery echo-planar imaging (STIR-EPI) sequences applied to the chest-mediastinum provided potentially useful images for the differential diagnosis of benign and malignant lesions. PMID- 21293945 TI - Evaluation with 64-slice CT of the prevalence of coronary artery variants and congenital anomalies: a retrospective study of 3,236 patients. AB - PURPOSE: This study retrospectively evaluated the prevalence of anatomical coronary artery variants and congenital anomalies in 3,236 patients imaged with 64-slice computed tomography (CT). MATERIALS AND METHODS: Over a period of 4 years, 3,236 patients underwent CT coronary angiography performed with the standard protocol. We assessed coronary artery dominance, presence of the intermediate branch, presence and number of diagonal and marginal branches and coronary anomalies subdivided into anomalies of origin and course, intrinsic anomalies and termination anomalies. RESULTS: Coronary dominance was right-sided in 88.1% of patients; the intermediate branch was present in 21.3%, the number of diagonal and marginal branches was one to two in >90%, and the number of coronary anomalies was 224 (89 of origin and course, 129 intrinsic anomalies and six termination anomalies). CONCLUSIONS: Sixty-four-slice CT coronary angiography provides accurate three-dimensional evaluation of the coronary artery tree with correct visualisation of any coronary anomalies, a relatively common finding that had a prevalence of 5.7% in our study population. PMID- 21293946 TI - Branched chain fatty acid content of United States retail cow's milk and implications for dietary intake. AB - Branched chain fatty acids (BCFA) have recently been shown to be a major component of the normal human newborn gastrointestinal tract and have long been known to be a component of human milk. Ruminant food products are major sources of fat in the American diet, but there are no studies of milkfat BCFA content in retail milk. We report here the profile and concentrations of BCFA in a representative sampling of retail milk in the 48 contiguous United States (US), and their estimated intake in the American diet. Conventionally produced whole fluid milk samples were obtained from 56 processing plants across the contiguous 48 states. Retail milk samples contain exclusively iso- and anteiso-BCFA with 14 18 carbons. BCFA were 2.05 +/- 0.14%, w/w of milkfat fatty acids (mean +/- SD), and anteiso-BCFA comprised more than half this total. Based on these data and USDA food availability data, the average per capita BCFA intake of Americans is estimated to be about 220 mg/d from dairy; if current dietary recommendations were followed, BCFA intake would be about 400 mg/d. Adding intake from beef consumption, these estimates rise to approximately 400 and 575 mg/d, respectively. These results indicate that BCFA intake is a substantial fraction of daily fat intake, in amounts exceeding those of many bioactive fatty acids. PMID- 21293947 TI - A rapid access diagnostic clinic for prostate cancer: the experience after one year. AB - BACKGROUND: The National Cancer Control Programme is developing standards for access to diagnostics and treatment of prostate cancer. The Rapid Access Prostate Cancer (RAPC) clinic in St. James's Hospital commenced in May 2009 allowing general practitioners (GPs) more streamlined access for patients. AIMS: To demonstrate that RAPC clinics allow GPs direct access to a designated cancer centre improving the prostate cancer referral process. This ultimately should reduce referral delays. METHODS: A prospective analysis of all patients referred to the RAPC clinic in St. James's Hospital over a 12-month period beginning from May 2009. RESULTS: Over the 12-month period 215 patients were referred to the RAPC clinic. The median age was 63 years (range 45-78). The median waiting time between referral and review at the RAPC clinic was 13 days (range 1-37). The median PSA was 7.7 MUg/L (range 2.6-150). In total 199 TRUS biopsies were performed, of which 46% were positive for prostate cancer. We found that 70% of all patients had a PSA <= 10 MUg/L and of these 32% were positive for prostate cancer. For the remaining 30% of patients who had a PSA > 10 MUg/L, we found 63% were positive for prostate cancer. Regarding patients diagnosed with prostate cancer 56% have been referred for radiotherapy, 13% for surgery, 13% for hormonal treatment, 10% for active surveillance and 8% watchful waiting. CONCLUSION: RAPC clinics allow GPs easier access to specialist urological opinion for patients suspected of having prostate cancer. PMID- 21293948 TI - Disease-modifying drugs in multiple sclerosis: a review of expenditure in Ireland. AB - INTRODUCTION: The prevalence of multiple sclerosis (MS) in Ireland is well over the European and global averages and the costs associated with managing this disease are placing a heavy economic burden on the Irish healthcare system. This paper investigates how current therapies used to treat MS are impacting on the total cost of MS as well as the potential impact of oral therapies in the MS marketplace. METHODS: Sales and expenditure data on MS disease-modifying drugs were reviewed as were market reports on forthcoming therapies in the MS pipeline. Clinical trial results for both current and prospective compounds were also reviewed to analyse how safety and efficacy data are influencing drug availability and expenditure. RESULTS: The high cost of disease-modifying drugs is substantially increasing the total cost of MS in Ireland. Newer therapies are likely to contribute to this trend. Safety concerns continue to be a barrier to advancement of the most promising compounds in the MS pipeline. CONCLUSION: Structures and/or treatment algorithms may be needed to help manage the growing cost of treating MS in Ireland to ensure all patients have access to safe, efficacious treatments. PMID- 21293949 TI - Fabp3 inhibits proliferation and promotes apoptosis of embryonic myocardial cells. AB - Fatty acid binding protein 3 (FABP3) is a member of a family of binding proteins. The protein is mainly expressed in cardiac and skeletal muscle cells, and it has been linked to fatty acid metabolism, trafficking, and signaling. Using suppression subtractive hybridization, we previously found that FABP3 is highly regulated in ventricular septal defect (VSD) patients and may play a significant role in the development of human VSD. We therefore aimed to identify the biological characteristics of the FABP3 gene in embryonic myocardial cells. On the basis of RT-PCR and western blotting analyses, we demonstrated that the expression levels of FABP3 mRNA and protein were up-regulated initially and then gradually decreased with P19 cell differentiation. MTT assays and cell cycle analysis showed that FABP3 inhibits P19 cell proliferation, and data from annexin V-FITC assays revealed that FABP3 can promote apoptosis of P19 cells. Further data from quantitative real-time RT-PCR revealed lower expression levels of cardiac muscle-specific molecular markers (cTnT, alpha-MHC, GATA4, and MEF2c) in FABP3-overexpressing cell lines than in the control cells during differentiation. Our results demonstrate that FABP3 may be involved in the differentiation of cardiac myocytes. PMID- 21293950 TI - Modeling invasive species spread in Lake Champlain via evolutionary computations. AB - We use a reaction diffusion equation, together with a genetic algorithm approach for model selection to develop a general modeling framework for biological invasions. The diffusion component of the reaction diffusion model is generalized to include dispersal and advection. The reaction component is generalized to include both linear and non-linear density dependence, and Allee effect. A combination of the reaction diffusion and genetic algorithm is able to evolve the most parsimonious model for invasive species spread. Zebra mussel data obtained from Lake Champlain, which demarcates the states of New York and Vermont, is used to test the appropriateness of the model. We estimate the minimum wave spread rate of Zebra mussels to be 22.5 km/year. In particular, the evolved models predict an average northward advection rate of 60.6 km/year (SD +/- 1.9), which compares very well with the rate calculated from the known hydrologic residence time of 60 km/year. A combination of a reaction diffusion model and a genetic algorithm is, therefore, able to adequately describe some of the hydrodynamic features of Lake Champlain and the spread of a typical invasive species--Zebra mussels within the lake. PMID- 21293951 TI - Modelling survival and allele complementation in the evolution of genomes with polymorphic loci. AB - We have simulated the evolution of sexually reproducing populations composed of individuals represented by diploid genomes. A series of eight bits formed an allele occupying one of 128 loci of one haploid genome (chromosome). The environment required a specific activity of each locus, this being the sum of the activities of both alleles located at the corresponding loci on two chromosomes. This activity is represented by the number of bits set to zero. In a constant environment the best fitted individuals were homozygous with alleles' activities corresponding to half of the environment requirement for a locus (in diploid genome two alleles at corresponding loci produced a proper activity). Changing the environment under a relatively low recombination rate promotes generation of more polymorphic alleles. In the heterozygous loci, alleles of different activities complement each other fulfilling the environment requirements. Nevertheless, the genetic pool of populations evolves in the direction of a very restricted number of complementing haplotypes and a fast changing environment kills the population. If simulations start with all loci heterozygous, they stay heterozygous for a long time. PMID- 21293952 TI - Erythroblastic islands, terminal erythroid differentiation and reticulocyte maturation. AB - This review summarizes our current understanding of the role of erythroblastic islands in erythropoiesis, membrane assembly during terminal erythroid differentiation and cellular and membrane reorganization during reticulocyte maturation. PMID- 21293953 TI - Clinical value of assessing the response to imatinib monitored by interphase FISH and RQ-PCR for BCR-ABL in peripheral blood for long-term survival of chronic phase CML patients: results of the Niigata CML-multi-institutional co-operative clinical study. AB - This retrospective analysis investigated the prognostic value of monitoring the response to imatinib using peripheral blood (PB) samples and the impact of the response on outcome in 133 patients with chronic myeloid leukemia (CML). We divided the response into 3 categories according to the results of neutrophil (N) FISH and BCR-ABL transcript levels in PB; more than a 3-log reduction [major molecular response (MMR)], between a 2-log and 3-log reduction or negative with N FISH [complete cytogenetic response equivalent (CCyRe)], N-FISH positive or less than a 2-log reduction (non-CCyRe). The median follow-up was 5.46 years. At 5 years, the overall survival (OS) rate and progression-free survival (PFS) rate were 94.4 and 92.0%, respectively. The estimated rate of the CCyRe and MMR were 81.7 and 67.1%, respectively. 106 patients achieving the CCyRe had significantly better OS and PFS than 27 patients without achieving the CCyRe. Patients with MMR had significantly better survival free from death, progression, imatinib withdrawal and a loss of the CCyRe, than patients whose response level remained in the CCyRe without achieving MMR until 18 months. Our observation suggests that the response level of the CCyRe on PB serve as a prognostic indicator, and achieving MMR provides stable long-term survival. PMID- 21293954 TI - A case of Klinefelter syndrome with aplastic anemia. AB - In this manuscript, we report the first patient who suffered from Klinefelter syndrome with aplastic anemia and hyperprolactinemia. PMID- 21293955 TI - Potential protection of green tea polyphenols against 1800 MHz electromagnetic radiation-induced injury on rat cortical neurons. AB - Radiofrequency electromagnetic fields (EMF) are harmful to public health, but the certain anti-irradiation mechanism is not clear yet. The present study was performed to investigate the possible protective effects of green tea polyphenols against electromagnetic radiation-induced injury in the cultured rat cortical neurons. In this study, green tea polyphenols were used in the cultured cortical neurons exposed to 1800 MHz EMFs by the mobile phone. We found that the mobile phone irradiation for 24 h induced marked neuronal cell death in the MTT (3-(4,5 dimethylthiazole-2-yl)-2,5-diphenyl-tetrazolium bromide) and TUNEL (TdT mediated biotin-dUTP nicked-end labeling) assay, and protective effects of green tea polyphenols on the injured cortical neurons were demonstrated by testing the content of Bcl-2 Assaciated X protein (Bax) in the immunoprecipitation assay and Western blot assay. In our study results, the mobile phone irradiation-induced increases in the content of active Bax were inhibited significantly by green tea polyphenols, while the contents of total Bax had no marked changes after the treatment of green tea polyphenols. Our results suggested a neuroprotective effect of green tea polyphenols against the mobile phone irradiation-induced injury on the cultured rat cortical neurons. PMID- 21293956 TI - [Entomological investigations conducted around ten cases of yellow fever in 2009 in the Denguele sanitary region, Cote-d'Ivoire]. AB - In November 2009, ten suspicious cases of yellow fever, including six deaths, were notified in the region of Denguele, in the northwest of Cote-d'Ivoire. In order to evaluate the extent of yellow fever virus circulation and the risk for local people, a mission of entomological investigation was carried out by the Ministry of Health and Public Hygiene of Cote-d'Ivoire. Entomological investigations were conducted in the villages of confirmed cases (Banakoro and Tron-Touba) and the centers of consultation and hospitalization of cases during illness. Breteau index and recipient index were quasi nil. Aedes aegypti was absent among the captured mosquitoes. On the other hand, Aedes luteocephalus and Aedes opok were present at Banakoro and Tron-Touba with respective average biting rates of 0.8 and 0.6 bite/man/twilight. This situation of epidemic in the northwest of Cote-d'Ivoire could be explained by the deterioration of Denguele region's health system which is a consequence of the war started in the country in 2002 and which has lowered the immunity of the population. PMID- 21293959 TI - Formation of arenicin-1 microdomains in bilayers and their specific lipid interaction revealed by Z-scan FCS. AB - Z-scan fluorescence correlation spectroscopy (FCS) is employed to characterize the interaction between arenicin-1 and supported lipid bilayers (SLBs) of different compositions. Lipid analogue C8-BODIPY 500/510C5-HPC and ATTO 465 labelled arenicin-1 are used to detect changes in lipid and peptide diffusion upon addition of unlabelled arenicin-1 to SLBs. Arenicin-1 decreases lipid mobility in negatively charged SLBs. According to diffusion law analysis, microdomains of significantly lower lipid mobility are formed. The analysis of peptide FCS data confirms the presence of microdomains for anionic SLBs. No indications of microdomain formation are detected in SLBs composed purely of zwitterionic lipids. Additionally, our FCS results imply that arenicin-1 exists in the form of oligomers and/or aggregates when interacting with membranes of both compositions. PMID- 21293961 TI - Setting the bar for laparoscopic resection of sporadic insulinoma. AB - BACKGROUND: Laparoscopic insulinoma resection (LIR) for sporadic disease is increasingly supported as a feasible and safe operation in small series of patients. To determine whether LIR is an acceptable alternative to the open operation, it is necessary to compare LIR to historical controls. The purpose of this study was to identify the skills and technology needed for LIR and establish outcome standards. METHODS: A database of patients with benign sporadic insulinoma who underwent an open procedure at the Mayo Clinic was reviewed for demographics, imaging, operative/pathology reports, and outcomes. Outcomes were compared to a world-wide meta-analysis of patients who had undergone LIR reported in the English literature between 1996 and 2009. RESULTS: Two hundred fifteen patients underwent a primary open operation for benign sporadic insulinoma. Solitary tumors were found in 97%. Meta-analysis identified 232 patients who underwent LIR. The open and LIR groups underwent comparable operations that included enucleations (64 vs. 68%) and distal pancreatectomies (28 vs. 35%) (p = 0.06). The mean estimated blood loss, operating time, and length of stay were comparable between the open and LIR groups (p = NS). Pancreatic fistula occurred more often in the LIR group (24 vs. 11%, p < 0.05). A curative operation was performed in 98% of control patients and in 99% of the LIR group (p = NS). CONCLUSIONS: Multiple insulinomas are rare and a focused resection guided by imaging may be performed. LIR is associated with an increased incidence of pancreatic fistula. Success of LIR will depend on accurate multimodality preoperative imaging, skilled use of lap-US to replace palpation for localization, and safe methods to dissect the tumor adjacent to the pancreatic duct. PMID- 21293962 TI - Expanding laparoscopic cholecystectomy to rural Mongolia. AB - BACKGROUND: Although laparoscopic cholecystectomy was first introduced in Mongolia in 1994, the benefits of the laparoscopic approach have been largely unavailable to the majority of the population. The burden of gallbladder disease in Mongolia is significant. Despite the barriers to expanding laparoscopic surgery in Mongolia (lack of physical resources and adequate training opportunities, a difficult political situation, and an austere environment), the Health Sciences University of Mongolia (HSUM) began looking for ways to further the development of laparoscopy for the entire country, including the rural areas where half the population resides. METHODS: Combined didactic and practical training courses lasting 2 weeks were developed collaboratively by a private nongovernmental organization and HSUM. The courses were taught at tertiary care centers in the capital city (Ulaanbaatar) and in a smaller, rural city (Erdenet), the regional northern referral center. Demographic data, preoperative diagnosis, ultrasound and operative findings, operative times, length of hospital stay, and intraoperative and postoperative complication rates were compared from 2007-2008 from hospitals in Ulaanbaatar and Erdenet. RESULTS: A total of 36 surgeons participated in the training classes, and a total of 410 laparoscopic cholecystectomies were performed. Ultrasound was used as a diagnostic tool in all cases. There was no significant difference in intraoperative or postoperative complications between hospitals in the capital, where the procedures were performed by skilled laparoscopic surgeons, and in Erdenet, where the training courses first introduced laparoscopic cholecystectomy. Neither were there differences in complication rates between cases during the teaching and nonteaching periods. CONCLUSIONS: Laparoscopic cholecystectomy can be expanded safely to the regional diagnostic referral centers in rural Mongolia through short-term training courses as a method to markedly improve access and outcomes for the 50% of the country previously denied the benefits of minimally invasive surgery. PMID- 21293963 TI - Education and training in evidence-based urology. AB - OBJECTIVES: Urologists believe evidence-based clinical practice improves patient care. Competence in critical appraisal skills is necessary to successfully implement evidence-based practice. However, practicing urologists, urology program training directors, and residents have identified the need for urology specific resources to promote competence in evidence-based practice. The objective of this review is to identify urology-specific educational resources for critical appraisal skills. METHODS: The PubMed((r)) database was searched using the terms "evidence-based urology", "training" and "medical education." Results were limited to systematic reviews. Reference lists for manuscripts were manually searched to identify additional relevant publications. Additional educational resources and training opportunities were identified via direct communication with authors. RESULTS: New urology-specific educational resources are being developed to support evidence-based clinical practice. Resources exist in the medical literature, including the User's Guide to the Urological Literature series and the Evidence-Based Urology in Practice series. Electronic resources include the Evidence Based Reviews in Urology program sponsored by the American Urological Association. Finally, workshops exist for live training to develop expertise in teaching EBM skills to others. CONCLUSION: Educational support for the nascent evidence-based clinical practice movement in urology is growing. Journals provide the majority of urology-specific educational material for evidence-based medicine training. Additional online and live training opportunities should be developed to encourage competence and leadership in evidence-based urology. PMID- 21293964 TI - Subjective visual vertical in erect/supine subjects and under microgravity: effects of lower body negative pressure. AB - Perception of the subjective visual vertical (SVV) is mainly based on the contributions from the visual, vestibular, and proprioceptive systems, and participates to the process of spatial orientation in relation to the surrounding environment and to the gravito-inertial force. The SVV can be significantly influenced by the presence of a displaced visual field, as in the case of the rod and frame test (RFT). A series of studies showed the effects of haematic mass shifts to and from the lower limbs on SVV, due to visceral mechanoreceptors (VM) located at the level of the kidneys and of the thorax. These sensors may be artificially activated with a lower body negative pressure (LBNP) device. In this study, the role of visual and VM cues to orientation perception have been evaluated using the RFT and the LBNP devices under a microgravity environment. A preliminary investigation was conducted in a sample of military pilots to develop a RFT protocol to be used in microgravity environments. This protocol was adopted to evaluate the contribution of VM to the SVV in a cosmonaut before, during and after a 10 day space flight, with and without concurrent activation of LBNP. The same test sequence, including LBNP exposure, was repeated a few months later on Earth on the same subject. As expected, the influence of the frame on rod positioning was statistically significant in all test conditions. During the in flight experimental step, a substantial lack of significant changes compared to the pre-flight condition was observed. Moreover, substantially no effects due to LBNP were observed. A mild rod displacement from the body axis was detected under microgravity compared to the pre-flight recording. Such a finding was in part reduced during LBNP. The same findings were observed during the post-flight repetition of the experiment. Our results showed an absence in this subject of significant effects on the RFT due to microgravity. In conclusion, no effects from his VM on the RFT and minor changes in the SVV could be detected. PMID- 21293965 TI - Temporal variability within disturbance events regulates their effects on natural communities. AB - Disturbances are processes inherently variable in time and space. This variability comprises a key determinant of ecosystem responses to disturbance. Temporal patterns can, however, vary significantly both among and within individual disturbance events. While recent research has demonstrated an importance of the former, studies on the effects of variability within perturbations have consistently confounded temporal variability with other disturbance attributes (e.g. overall intensity or duration). We established a field experiment to test explicitly the hypothesis that the temporal pattern within perturbations can drive ecosystem responses independently of other disturbance traits. We examined the effects of two disturbance regimes comprising sediment pulses of contrasting temporal pattern (constant and temporally variable intensities) on the benthic invertebrate assemblage of a headwater stream. The overall intensity, duration, timing and frequency of the perturbations were, however, identical. Invertebrates drifting during the temporally variable pulses were more abundant and differed in taxonomic and trophic structure than those exposed to constant perturbations. Moreover, whereas temporal patterns of disturbance events had no immediate effect on benthic invertebrate assemblages in situ, assemblages exposed to the constant perturbations took longer to recover from sediment disturbances than those exposed to temporally variable perturbations. Our results demonstrate that variability in the temporal pattern of intensity within individual perturbations can regulate, independently of other disturbance attributes, the extent and type of ecosystem responses to, and recovery from, disturbances. Effective environmental management and policy therefore necessitate the explicit quantification of temporal patterns of intensity both within and among perturbations. PMID- 21293966 TI - Transmission of classical scrapie to wild-type mice: the influence of the ovine PrP sequence on lesion profiles. AB - Susceptibility of sheep to classical scrapie is determined by polymorphisms in the coding region of the prion protein gene (PRNP), mainly at codons 136, 154 and 171. It has recently been shown that lesion profiles from classical field scrapie isolates that transmitted to RIII mice can be classified into different groups. There was also strong, but not absolute, association between the different groups and codon 136. Here, we examine the hypothesis that additional polymorphisms in the open reading frame sequence of the ovine PRNP may account for the different groups of lesion profiles observed following transmission to mice. PMID- 21293967 TI - A single amino acid substitution in the 126-kDa protein of pepper mild mottle virus controls replication and systemic movement into upper non-inoculated leaves of bell pepper plants. AB - Previously, we generated attenuated variants of pepper mild mottle virus by replacing residue 649 in the 126-kDa replicase protein with various amino acids. Here, we examined the biological properties of the 16 variants that caused either mild mosaic or no mosaic. All but one (A649N) of the mild-mosaic-inducing strains replicated at higher levels in pepper plants and systemically moved at higher rates into the upper non-inoculated leaves than the no-mosaic strains. C1421, previously selected for practical use, not only caused mild symptoms but also had an especially high replication rate in pepper plants and spread more efficiently into the upper non-inoculated leaves. PMID- 21293968 TI - Mediterranean and central-eastern European countries host viruses of two different clades of plum pox virus strain M. AB - The genetic diversity of plum pox virus strain M (PPV-M) was assessed by analyzing 28 isolates collected in 8 European countries. Two genomic fragments spanning the (Cter)P3-6K1-(Nter)CI coding region as well as the full coat protein coding region were sequenced directly from PCR products. Phylogenetic analysis showed that the geographical origin of the collected isolates was clearly associated with two different PPV-M clades. Moreover, the pattern of substitutions in the CP gene shed light on the evolutionary relationships between PPV-M and the recombinant strains PPV-Rec and PPV-T. PMID- 21293969 TI - Disseminated Kaposi sarcoma in newly diagnosed HIV. PMID- 21293970 TI - Association of CRP and IL-6 with lung function in a middle-aged population initially free from self-reported respiratory problems: the Whitehall II study. AB - To assess whether two inflammatory markers, C-reactive protein (CRP) and interleukin-6 (IL-6), and change in their concentrations over 12 years, are associated with lung function (FVC and FEV(1)) 12 years after baseline. Data are from over 1,500 participants free from self-reported respiratory problems in a large-scale prospective cohort study of white-collar male and female civil servants. CRP and IL-6 measured at baseline (1991-1993) and follow-up (2002-2004) and FVC and FEV(1), measured at follow-up. Results adjusted for sociodemographic and anthropometric characteristics, health behaviours, biological factors, chronic conditions and medications, and corrected for short-term variability in CRP and IL-6 concentrations. Higher baseline levels of CRP and IL-6 were strongly associated with lower FVC and FEV(1), independent of potential confounders. A 10% increase serum CRP from baseline to follow-up was associated with lower values of FVC and FEV(1) at follow-up, 4.7 and 3.0 ml, respectively. The corresponding values for a 10% increase in IL-6 were 12.6 ml for FVC and 7.3 ml for FEV(1). Systemic low-grade inflammation is associated with only slightly poorer pulmonary function in a population free from self-reported respiratory problems 12 years earlier. These data provide evidence linking inflammation to adverse outcomes beyond cardiovascular disease. Interventions targeting inflammation may prevent lung function impairment. PMID- 21293972 TI - Conditioning and sampling issues of EMG signals in motion recognition of multifunctional myoelectric prostheses. AB - Historically, the investigations of electromyography (EMG) pattern recognition based classification of intentional movements for control of multifunctional prostheses have adopted the filter cut-off frequency and sampling rate that are commonly used in EMG research fields. In practical implementation of a multifunctional prosthesis control, it is desired to have a higher high-pass cut off frequency to reduce more motion artifacts and to use a lower sampling rate to save the data processing time and memory of the prosthesis controller. However, it remains unclear whether a high high-pass cut-off frequency and a low-sampling rate still preserve sufficient neural control information for accurate classification of movements. In this study, we investigated the effects of high pass cut-off frequency and sampling rate on accuracy in identifying 11 classes of arm and hand movements in both able-bodied subjects and arm amputees. Compared to a 5-Hz high-pass cut-off frequency, excluding the EMG components below 60 Hz decreased the average accuracy of 0.1% in classifying the 11 movements across able-bodied subjects and increased the average accuracy of 0.1 and 0.4% among the transradial (TR) and shoulder disarticulation (SD) amputees, respectively. Using a 500 Hz instead of a 1-kHz sampling rate, the average classification accuracy only dropped about 2.0% in arm amputees. The combination of sampling rate and high-pass cut-off frequency of 500 and 60 Hz only resulted in about 2.3% decrease in average accuracy for TR amputees and 0.4% decrease for SD amputees in comparison to the generally used values of 1 kHz and 5 Hz. These results suggest that the combination of sampling rate of 500 Hz and high-pass cut-off frequency of 60 Hz should be an optimal selection in EMG recordings for recognition of different arm movements without sacrificing too much of classification accuracy which can also remove most of motion artifacts and power-line interferences for improving the performance of myoelectric prosthesis control. PMID- 21293971 TI - Conflicting effects of nitric oxide and oxidative stress in chronic heart failure: potential therapeutic strategies. AB - Chronic heart failure (CHF) is characterized by decreased nitric oxide (NO) bioavailability. In addition, the beneficial NO turns to be deleterious when it reacts with superoxide anion, leading to peroxynitrite formation. Numerous experimental and clinical studies have reported increased production of reactive oxygen species (superoxide, hydrogen peroxide, hydroxyl radical) both in animals and patients with CHF. Moreover, there are indicative data suggesting mechanisms associated with endothelial dysfunction in states of CHF, mainly attributed to decreased NO bioavailability and enhanced inactivation of the latter. Thus, such molecules appear to be potential targets in patients with CHF. These patients are strong candidates to receive a variety of therapeutic agents, some of which have known antioxidant effects. Classic treatment with statins or angiotensin converting enzyme inhibitors has been found to be beneficial in restoring NO and improving myocardial function and structure. Other agents such as sildenafil and b-blockers along with novel agents such as NO synthase transcription enhancers have been proved to be also beneficial, but their use for such a purpose is still controversial. Approaches using more-effective antioxidants or targeting myocardial oxidant-producing enzymes and oxidative or nitrosative stress might be promising strategies in the future. PMID- 21293973 TI - X-ray velocimetry and haemodynamic forces within a stenosed femoral model at physiological flow rates. AB - High resolution in vivo velocity measurements within the cardiovascular system are essential for accurate calculation of vessel wall shear stress, a highly influential factor for the progression of arterial disease. Unfortunately, currently available techniques for in vivo imaging are unable to provide the temporal resolution required for velocity measurement at physiological flow rates. Advances in technology and improvements in imaging systems are allowing a relatively new technique, X-ray velocimetry, to become a viable tool for such measurements. This study investigates the haemodynamics of pulsatile blood flow in an optically opaque in vitro model at physiological flow rates using X-ray velocimetry. The in vitro model, an asymmetric stenosis, is designed as a 3:1 femoral artery with the diameter and flow rate replicating vasculature of a mouse. Velocity measurements are obtained over multiple cycles of the periodic flow at high temporal and spatial resolution (1 ms and 29 MUm, respectively) allowing accurate measurement of the velocity gradients and calculation of the wall shear stress. This study clearly illustrates the capability of in vitro X ray velocimetry, suggesting it as a possible measurement technique for future in vivo vascular wall shear stress measurement. PMID- 21293974 TI - A spin-drying technique for lyopreservation of mammalian cells. AB - Stabilization of cellular material in the presence of glass-forming sugars at ambient temperatures is a viable approach that has many potential advantages over current cryogenic strategies. Experimental evidence indicates the possibility to preserve biomolecules in glassy matrices of low-molecular mobility using "glass forming" sugars like trehalose at ambient temperatures. However, when cells are desiccated in trehalose solution using passive drying techniques, a glassy skin is formed at the liquid/vapor interface of the sample. This glassy skin prevents desiccation of the sample beyond a certain level of dryness and induces non uniformities in the final water content. Cells trapped underneath this glassy skin may degrade due to a relatively high molecular mobility in the sample. This undesirable result underscores the need for development of a uniform, fast drying technique. In the present study, we report a new technique based on the principles of "spin drying" that can effectively address these problems. Forced convective evaporation of water along with the loss of solution due to centrifugal force leads to rapid vitrification of a thin layer of trehalose containing medium that remains on top of cells attached to the spinning glass substrate. The glassy layer produced has a consistent thickness and a small "surface-area-to-volume" ratio that minimizes any non-homogeneity. Thus, the chance of entrapping cells in a high-mobility environment decreases substantially. We compared numerical predictions to experimental observations of the drying time of 0.2-0.6 M trehalose solutions at a variety of spinning speeds ranging from 1000 to 4000 rpm. The model developed here predicts the formation of sugar films with thicknesses of 200-1000 nm, which was in good agreement with experimental results. Preliminary data suggest that after spin drying cells to about 0.159 +/- 0.09 gH2O/gdw (n = 11, +/-SE), more than 95% of cells were able to preserve their membrane integrity. Membrane integrity after spin drying is therefore considerably higher than what is achieved by conventional drying methods; where about 90% of cells lose membrane integrity at 0.4 gH2O/gdw (Acker et al. Cell Preserv. Technol. 1(2):129-140, 2002; Elliott et al. Biopreserv. Biobank. 6(4):253-260, 2009). PMID- 21293975 TI - Child care in outpatient substance abuse treatment facilities for women: findings from the 2008 National Survey of substance Abuse Treatment Services. AB - Mothers with substance use disorders who lack access to child care are often unable to enter or remain in substance abuse treatment. This study examined the availability of child care in outpatient substance abuse treatment facilities and whether or not certain facility characteristics were associated with the availability of child care. Using data from the 2008 National Survey of Substance Abuse Treatment Services, 6.5% of outpatient substance abuse treatment facilities that served women provided child care. The results of multivariate logistic regression found that child care was more common among facilities that were located in metropolitan areas, were operated by non-profit or government agencies, received public funding, or provided free services or other ancillary services including case management, domestic violence counseling, and transportation assistance. Facilities that served only women had more than three times higher odds of providing child care compared with mixed-gender facilities. Further research is needed to identify strategies for expanding child care in outpatient substance abuse treatment facilities. PMID- 21293976 TI - Depression and the onset of chronic illness in older adults: a 12-year prospective study. AB - The relationship between depression and development of chronic illness among older adults is not well understood. This study uses data from the Health and Retirement Study to evaluate the relationship between depression at baseline and new onset of chronic illnesses including cancer, heart problems, arthritis, and diabetes. Analysis controlling for demographics (age, gender, race, education), health risk indicators (BMI and smoking), functional limitations (gross motor index, health limitations for work), and income show that working-age older people (ages 50-62) with depression at baseline are at significantly higher risk to develop diabetes, heart problems, and arthritis during the 12-year follow-up. No significant association was found between depression and cancer. Prevention efforts aimed at chronic illnesses among the elderly should recognize the mind body interaction and focus on preventing or alleviating depression. PMID- 21293977 TI - Sympathetic neural mechanisms in human blood pressure regulation. AB - Sympathetic neural function is essential to human blood pressure regulation, and overactivity of sympathetic nerves may have an important role in the development of hypertension and related cardiovascular disorders. Importantly, there is extensive interindividual variability in sympathetic vasoconstrictor nerve activity, even among healthy, young, normotensive people. Therefore, the relevance of each person's level of sympathetic nerve activity for his or her blood pressure must be evaluated in the context of other factors contributing to the overall level of blood pressure, including cardiac output and vascular adrenergic responsiveness. We include evidence showing that the balance of factors contributing to normal blood pressure in young people is influenced by sex. Hypertension itself can be multifactorial, but it is often associated with elevated sympathetic nerve activity, which can be reversed by some pharmacologic antihypertensive treatments. Although much work remains to be done in this area, an appropriate recognition of the complexity of integrated physiological regulation and of the importance of interindividual variability will be key factors in moving forward to even better understanding and treatment. PMID- 21293978 TI - Pacemakers and magnetic resonance imaging: Current status and survey in Switzerland. AB - Electromagnetic fields arising from magnetic resonance imaging (MRI) can cause various clinically relevant functional disturbances in patients with cardiac pacemakers. Consequently, an implanted pacemaker is generally considered a contraindication for an MRI scan. With approximately 60 million MRI scans performed worldwide per year, MRI may be indicated for an estimated majority of pacemaker patients during the lifetime of their pacemakers. The availability of MR conditional pacemakers with CE labelling is of particular advantage since they allow the safe use of pacemakers in MRI. In this article the current state of knowledge on pacemakers and MR imaging is discussed. We present the results of a survey conducted among Swiss radiologists to assess current practice in patients with pacemakers. PMID- 21293979 TI - Cyclosporine C0- versus C2-monitoring over three years in maintenance heart transplantation. AB - INTRODUCTION: There is an ongoing discussion as to whether monitoring of cyclosporine (CsA)-based immunosuppression with plasma levels two hours after medication intake (C2) offers clinical benefit over the measurement of CsA trough levels (C0) in patients after heart transplantation (HTx). In particular, data from long-term maintenance patients are not available. METHODS: C0 monitoring was performed during 19 months in 65 stable maintenance patients after HTx. During the following 19 months all patients were switched to C2 monitoring. During both periods biopsy proven acute rejections (BPAR), daily CsA dose, plasma creatinine, estimated creatinine clearance and blood pressure values for both periods were analysed. RESULTS: Data from 65 patients (9.2 +/- 3.9 years post HTx) were included. No differences were observed for BPAR >=2 between C0 (13 pts; 20%) and C2 (12 pts; 18.4%). C2 was associated with lower daily CsA doses (C0 208.7 mg/d vs. C2 182.3 mg/d, p <0.0001) while dose reduction over time was not different during both periods (C0 -13.3 mg/d vs. C2 -22.5 mg/d, p = 0.259). No difference was observed for blood pressure and creatinine clearance. CONCLUSION: In long term maintenance patients C2 monitoring was not associated with immediate beneficial effects on number of rejections, blood pressure levels, and renal parameters. However, patients received lower daily CsA doses. PMID- 21293980 TI - Variation in incidence of orthopaedic surgery between populations with basic or basic plus supplementary health insurance in Switzerland. AB - QUESTIONS UNDER STUDY: The aim of the study was to analyse the effects of supplementary health insurance on the incidence of hospitalisations for musculoskeletal conditions in Switzerland. METHODS: Cross sectional and small area analyses of surgical interventions for major musculoskeletal disorders in Switzerland were conducted. The regional distributions of populations with basic and basic plus supplementary insurance were estimated using census data for the period of 2002-2005. Effects of insurance class on the incidence of orthopaedic interventions were calculated with logistic regression using the complete discharge dataset of hospitalisations for orthopaedic conditions performed in the years 2002 to 2005. RESULTS: The data show significant differences in the age- and gender-adjusted incidence of surgery between populations with compulsory basic health insurance and those with basic plus supplementary cover. CONCLUSIONS: The study provides evidence that health insurance status accounts for variation in surgery for musculoskeletal problems in Switzerland. There are indications that supplementary health insurance - as a proxy for higher socioeconomic status - is related to lower need for surgery. There are signs that resources for spinal surgery and arthroscopy are diverted to the private sector at the expense of social health insurance. The results are only partially consistent with the hypothesis that volume of services increases with comprehensiveness of coverage. PMID- 21293981 TI - Burden of abdominal obesity in cardiac rehabilitation patients: Results from the Swiss CaRe study. AB - BACKGROUND: The burden of abdominal obesity (AO) and its association with other cardiovascular risk factors is not known in coronary artery disease (CAD) patients attending cardiac rehabilitation (CR). The aim of this study was, therefore, to investigate the prevalence of AO and differences in cardiovascular risk factors between AO and non-AO patients. METHODS: 415 consecutive male CAD patients (mean age 58 +/- 11 years) attending a three-month outpatient CR programme were assessed. Differences in cardiovascular risk profile, including blood lipids, psychosocial and socioeconomic status and exercise capacity, were compared in relation to AO and checked for obesity measured by body-mass index (BMI) in a multivariate analysis. RESULTS: Mean waist circumference was 102 +/- 11 cm. Patients of lower educational level had a higher prevalence of AO (p = 0.021) than patients with a higher educational level. AO was significantly associated with diabetes (p = 0.003) and hypertension (p <0.001). In AO patients, HDL-C levels were lower (p <0.001) and triglyceride levels higher (p = 0.006) than in non-AO patients. There was no difference in exercise capacity between AO and non-AO patients, but AO patients had a higher resting heart rate (p = 0.021). CONCLUSION: AO is highly prevalent in CAD patients attending CR. AO is, independently of BMI, associated with metabolic lipid disorders and autonomic cardiovascular dysregulation, suggesting an increased cardiovascular risk. AO patients therefore need particular attention during CR and follow-up care. PMID- 21293982 TI - Do not attempt resuscitation: the importance of consensual decisions. AB - AIMS: To describe the involvement and input of physicians and nurses in cardiopulmonary resuscitation (CPR / do not attempt resuscitation (DNAR) decisions; to analyse decision patterns; and understand the practical implications. DESIGN: A Qualitative Grounded Theory study using one-time open ended interviews with 40 volunteer physicians and 52 nurses drawn from acute care wards with mixes of heterogeneous cases in seven different hospitals in German speaking Switzerland. RESULTS: Establishing DNAR orders in the best interests of patients was described as a challenging task requiring the leadership of senior physicians and nurses. Implicit decisions in favour of CPR predominated at the beginning of hospitalisation; depending on the context, they were relieved/superseded by explicit DNAR decisions. Explicit decisions were the result of hierarchical medical expertise, of multilateral interdisciplinary expertise, of patient autonomy and/or of negotiated patient autonomy. Each type of decision, implicit or explicit, potentially represented a team consensus. Non consensual decisions were prone to precipitate personal or team conflicts, and, occasionally, led to non-compliance. CONCLUSION: Establishing DNAR orders is a demanding task. Reaching a consensus is of crucial importance in guaranteeing teamwork and good patient care. Communication and negotiation skills, professional and personal life experience and empathy for patients and colleagues are pivotal. Therefore, leadership by experienced senior physicians and nurses is needed and great efforts should be made with regard to multidisciplinary education. PMID- 21293983 TI - Socio-demographic factors associated with loss to follow-up of HIV-infected women attending a private sector PMTCT program in Maharashtra, India. AB - Currently, 40% of HIV-infected women enrolled in national prevention of mother-to child transmission (PMTCT) program in India are loss to follow-up (LTF) before they can receive single dose Nevirapine. To date no study from India has examined the reasons for inadequate utilization of PMTCT services. This study sought to examine the socio-demographic factors associated with LTF of HIV-infected women enrolled during 2002-2008 in a large-scale private sector PMTCT program in Maharashtra, India. Data on HIV-infected women who were enrolled during pregnancy (N=734) and who reported live birth (N=770) were used to analyze factors associated with LTF before delivery and after delivery, respectively. Univariate and multivariate analyses were conducted to estimate the associations between being LTF and socio-demographic factors using generalized linear models. Eighty (10.9%) women were LTF before delivery and 151 (19.6%) women were LTF after delivery. Women with less than graduate level education (RR = 6.32), from a poor family (RR = 1.61), who were registered after 20 weeks of pregnancy (RR = 2.02) and whose partners were HIV non-infected or with unknown HIV status (RR = 2.69) were more likely to be LTF before delivery. Similarly, the significant factors for LTF after delivery were less than graduate level education (RR = 1.82), poor family (RR = 1.42), and registration after 20 weeks of pregnancy (RR = 1.75). This study highlights the need for innovative and effective counseling techniques for less educated women, economic empowerment of women, better strategies to increase uptake of partner's HIV testing, and early registration of women in the program for preventing LTF in PMTCT programs. This need for innovative counseling techniques is even greater for PMTCT programs in the public health sector as the women accessing care in the public sector are likely to be less educated and economically more deprived. PMID- 21293984 TI - The consequences of post-election violence on antiretroviral HIV therapy in Kenya. AB - Over 1000 individuals were killed and 600,000 were displaced during post-election violence (PEV) in Kenya in 2008. Antiretroviral therapy (ART) depends on continuous access to medications which may have been interrupted due to PEV. In a mixed-methods retrospective review, treatment interruption of ART during PEV was measured among 2534 HIV-positive adults attending the Coptic Hope Center for Infectious Diseases in Nairobi, Kenya. Clients experiencing treatment interruption were compared between the PEV period (30 December 2007 to 28 February 2008) and the same time period one year earlier. Treatment interruption was defined as visiting the pharmacy >=48 hours after antiretrovirals were calculated to have been completed. Despite clinical services remaining open throughout the PEV period, more clients (16.1%) experienced treatment interruption than during the comparison period (10.2%). Mean daily pharmacy visits were significantly lower (87 vs. 104; p < 0.006) and more variable (p = 0.03) during PEV. Among clients present at both periods (n = 1605), the odds of treatment interruption were 71% higher during PEV (95% confidence interval [CI], 34-118%). In multivariate analysis, men (odds ratio [OR], 1.37; 95% CI, 1.07 1.76) and clients traveling >=3 hours to clinic (OR, 1.86; 95% CI, 1.28-2.71) were significantly more likely to experience treatment interruption. Clients affected by PEV were interviewed about factors associated with treatment interruption using semi-structured methods. Clients described fear, lack of transportation, and violence as contributing to treatment interruption. Widespread violence associated with the 2007 election in Kenya revealed the dependence of HIV patients on a stable civil society and infrastructure to access medications. Without the ability to maintain consistent HIV therapy, some patients face rapid treatment failure. HIV programs should have appropriate contingency plans wherever political instability may occur. Peace may be one of the most effective and most important public health interventions in Africa. PMID- 21293985 TI - Knowledge of free voluntary HIV testing centres and willingness to do a test among migrants in Cayenne, French Guiana. AB - In Cayenne, French Guiana, 80% of HIV-positive patients followed at the hospital are migrants. Behavioural information is crucial for optimising HIV testing for this vulnerable group. Predictors of ignorance of the existence of free voluntary counselling and testing (VCT) centre and willingness to get tested were investigated in 2006 among 398 migrants from Haiti, Guyana, Suriname and Brazil using a structured questionnaire. Only 27% of migrants knew simultaneously about the existence of free VCT, its localisation and its operating hours. Factors associated with ignorance of the existence of free VCT centre were birthplace in Haiti, being in French Guiana for less than three years, not thinking one's birth country as strongly affected by HIV and not thinking to be personally at risk for HIV. Factors independently associated with willingness to get tested were thinking to be at risk for HIV, birthplace in Brazil and Haiti, having a high integration level and fear of suffering if HIV test was positive. In order to improve testing among migrants, the accessibility of testing facilities and the knowledge of their whereabouts and operating hours must be improved to promote the desired behaviour among the majority of migrants which is often willing to do the test. PMID- 21293987 TI - Challenges in PMTCT antiretroviral adherence in northern KwaZulu-Natal, South Africa. AB - BACKGROUND: Women living with HIV in sub-Saharan Africa face significant challenges in accessing HIV care and adhering to antiretroviral therapy. Most reports have focused on issues relating to long-term adherence such as those surrounding stigma and disclosure, hunger, cultural factors, lack of accurate health information, lack of social support, medication side effects and overcrowded health systems. Information related to the challenges facing pregnant women when taking antiretrovirals for prophylactic purposes is limited. The "Kesho Bora Study" is a multicentre prevention of mother-to-child transmission (PMTCT) trial in sub-Saharan Africa evaluating the PMTCT efficacy of triple therapy until cessation of breast feeding compared to short course zidovudine monotherapy in a predominantly breast feeding population. Following unexplained discrepancies during objective adherence assessments, a sub-study was conducted at one site to examine the underlying adherence issues. METHODS: The counselling and clinical notes of all 100 enrolled Zulu women were examined. Extracted information was supplemented by unstructured, free-ranging interviews conducted by trained adherence counsellors on 43 consecutive women attending the trial clinic over a two-week period. Adherence was defined as good (>95% adherence), or poor (<95% adherence). RESULTS: Reasons provided for sub-optimal adherence included therapy misconceptions/misunderstandings, antiretroviral use by relatives, domestic violence, poverty and issues relating to disclosure and stigma. About 61% (57/94) of antenatal women had good adherence with their PMTCT prophylaxis, with no significant difference shown between those taking the long and short course. CONCLUSION: Antenatal women in northern rural KwaZulu-Natal face significant challenges in taking antiretroviral PMTCT prophylaxis. PMID- 21293986 TI - Association of ongoing drug and alcohol use with non-adherence to antiretroviral therapy and higher risk of AIDS and death: results from ACTG 362. AB - Drug and alcohol use have been associated with a worse prognosis in short-term and cross-sectional analyses of HIV-infected populations, but longitudinal effects on adherence to antiretroviral therapy (ART) and clinical outcomes in advanced AIDS are less well characterized. We assessed self-reported drug and alcohol use in AIDS patients, and examined their association with non-adherence and death or disease progression in a multicenter observational study. We defined non-adherence as reporting missed ART doses in the 48 hours before study visits. The association between drug use and ART non-adherence was evaluated using repeated measures generalized estimating equation (GEE) models. The association between drug and alcohol use and time to new AIDS diagnosis or death was evaluated via Cox regression models, controlling for covariates including ART adherence. Of 643 participants enrolled between 1997 and 1999 and followed through 2007, at entry 39% reported ever using cocaine, 24% amphetamines, and 10% heroin. Ongoing drug use during study follow-up was reported by 9% using cocaine, 4% amphetamines, and 1% heroin. Hard drug (cocaine, amphetamines, or heroin) users had 2.1 times higher odds (p=0.001) of ART non-adherence in GEE models and 2.5 times higher risk (p=0.04) of AIDS progression or death in Cox models. Use of hard drugs was attenuated as a risk factor for AIDS progression or death after controlling for non-adherence during follow-up (HR = 2.11, p=0.08), but was still suggestive of a possible adherence-independent mechanism of harm. This study highlights the need to continuously screen and treat patients for drug use as a part of ongoing HIV care. PMID- 21293988 TI - Treatment switching in South Indian patients on HAART: what are the predictors and consequences? AB - Early identification and management of treatment failure on highly active antiretroviral therapy (HAART) is crucial in maintaining a sustained response to therapy in HIV infection. However, HIV viral load (VL) and resistance testing, and second-line HAART regimens, are unaffordable to many patients in India, leaving them with limited treatment options. Predictors and reasons for antiretroviral switching, therefore, are likely to differ in settings of varying resources. A one-year, observational study of patients receiving antiretroviral therapy was conducted in a private, non-profit hospital in Bangalore. This paper examines the predictors and consequences of antiretroviral treatment switching in this setting and explores reasons for switching in a subset of patients. Data on demographics, drug regimens, adherence, and physical and psychosocial outcomes were collected quarterly. Tests of VL and CD4 cell counts were performed every six months. One-third of the patients switched therapy during the study period. Baseline predictors of switching included lower CD4 cell counts and more physical symptoms. Contrary to studies in other settings, a high VL did not predict treatment switching, and only a minority of those experiencing drug failure were switched to second-line regimens. Both groups (switchers and non-switchers) improved significantly over time with respect to CD4 counts and psychological well-being, and showed a reduction in physical and depressive symptoms. Any differences between the groups were no longer significant at the end of the study, once we controlled for baseline levels. Clinical, policy, and research implications of these findings are discussed within the context of resource limited settings. PMID- 21293989 TI - Non-enrollment for free community HIV care: findings from a population-based study in Rakai, Uganda. AB - Improved understanding of HIV-related health-seeking behavior at a population level is important in informing the design of more effective HIV prevention and care strategies. We assessed the frequency and determinants of failure to seek free HIV care in Rakai, Uganda. HIV-positive participants in a community cohort who accepted VCT were referred for free HIV care (cotrimoxazole prophylaxis, CD4 monitoring, treatment of opportunistic infections, and, when indicated, antiretroviral therapy). We estimated proportion and adjusted Prevalence Risk Ratios (adj. PRR) of non-enrollment into care six months after receipt of VCT using log-binomial regression. About 1145 HIV-positive participants in the Rakai Community Cohort Study accepted VCT and were referred for care. However, 31.5% (361/1145) did not enroll into HIV care six months after referral. Non-enrollment was significantly higher among men (38%) compared to women (29%, p=0.005). Other factors associated with non-enrollment included: younger age (15-24 years, adj. PRR = 2.22; 95% CI: 1.64, 3.00), living alone (adj. PRR = 2.22; 95% CI: 1.57, 3.15); or in households with 1-2 co-residents (adj. PRR = 1.63; 95% CI: 1.31, 2.03) compared to three or more co-residents, or a CD4 count >250 cells/ul (adj. PRR = 1.81; 95% CI: 1.38, 2.46). Median (IQR) CD4 count was lower among enrolled 388 cells/ul (IQR: 211,589) compared to those not enrolled 509 cells/ul (IQR: 321,754). About one-third of HIV-positive persons failed to utilize community based free services. Non-use of services was greatest among men, the young, persons with higher CD4 counts and the more socially isolated, suggesting a need for targeted strategies to enhance service uptake. PMID- 21293990 TI - Sexual risk behaviors among HIV-infected South Indian couples in the HAART era: implications for reproductive health and HIV care delivery. AB - The current study examines sexual behaviors among HIV-infected Indians in primary care, where access to highly active antiretroviral therapy (HAART) has recently increased. Between January and April 2008, we assessed the sexual behaviors of 247 HIV-infected South Indians in care. Multivariable logistic regression models were used to determine predictors of being in a HIV-seroconcordant primary relationship, being sexually active, and reporting unprotected sex. Over three fourths (80%) of participants were HAART-experienced. Among the 58% of participants who were currently in a seroconcordant relationship, one-third were serodiscordant when enrolling into care. Approximately two-thirds (63.2%) of participants were sexually active; 9.0% reported unprotected sex. In the multivariable analyses, participants who were in a seroconcordant primary relationship were more likely to have children, use alcohol, report unprotected sex, and have been enrolled in care for >12 months. Sexually active participants were more likely to be on HAART, have a prior tuberculosis diagnosis, test Herpes simplex type 2 antibody seropositive, and have low general health perceptions. Participants who reported unprotected sex were more likely to be in a seroconcordant relationship, be childless, want to have a child, and use alcohol. We did not document an association between HAART and unprotected sex. Among HIV infected Indians in primary care, predictors of unprotected sex included alcohol use and desire for children. Prevention interventions for Indian couples should integrate reproductive health and alcohol use counseling at entry into care. PMID- 21293991 TI - Measuring perceived stigma in female sex workers in Chennai, India. AB - Although sex work is highly stigmatized throughout the world, a limited body of research has examined stigma among female sex workers (FSWs). We developed a Sex Worker Stigma (SWS) Index to measure perceived stigma among 150 FSWs in Chennai, India. These women were at a median age of 35 years and reported, on average, having engaged in sex work for nine out of the previous 12 months. The two-factor structure of the index was verified in both exploratory and confirmatory factor analyses with acceptable goodness of fit. The final 10-item index comprises of two domains of perceived stigma from the community and perceived stigma from one's family. Cronbach's alpha coefficients were 0.87 and 0.88 for each domain, respectively. In regression analysis, we found that income from jobs other than sex work was correlated with decreased levels of perceived stigma from both the community (beta = - 0.16; 95% CI: -0.30 and -0.02) and the family (beta = - 0.24; 95% CI: -0.40 and -0.07); prior experience of accessing health care system increased perceived stigma from the community while heavier financial responsibility for the family was associated with lower perceived stigma from women's family. With the proposed SWS Index, we have a valid and reliable metric to document and track levels of perceived stigma among FSWs to assess the impact of stigma reduction interventions. PMID- 21293992 TI - Factors associated with non-adherence to antiretroviral therapy in the SUN study. AB - BACKGROUND: Adherence of 95% or greater to highly active combination antiretroviral therapy is generally considered necessary to achieve optimal virologic suppression in HIV-infected patients. Understanding factors associated with poor adherence is essential to improve patient compliance, maximize virologic suppression, and reduce morbidity and mortality. METHODS: We evaluated baseline data from 528 patients taking antiretrovirals, enrolled from March 2004 to June 2006, in a multicenter, longitudinal, prospective cohort study (the SUN study). Using multiple logistic regression, we examined independent risk factors for non-adherence, defined as reporting having missed one or more antiretroviral doses in the past three days on the baseline questionnaire. RESULTS: Of 528 participants (22% female, 28% black, median age 41 years, and median CD4 cell count 486 cells/mm(3)), 85 (16%) were non-adherent. In the final parsimonious multivariate model, factors independently associated with non-adherence included black race (adjusted odds ratio (aOR): 2.08, 95% confidence interval (CI): 1.20 3.60 vs. white race), being unemployed and looking for work (aOR: 2.03, 95% CI: 1.14-3.61 vs. all other employment categories), having been diagnosed with HIV >=5 years ago (aOR: 1.95, 95% CI: 1.18-3.24 vs. being HIV-diagnosed <5 years ago), drinking three or more drinks per day (aOR: 1.73, 95% CI: 1.02-2.91 vs. drinking <3 drinks per day), and having not engaged in any aerobic exercise in the last 30 days (aOR: 2.13, 95% CI: 1.25-3.57). CONCLUSION: Although the above factors may not be causally related to non-adherence, they might serve as proxies for identifying HIV-infected patients at greatest risk for non-adherence who may benefit from additional adherence support. PMID- 21293993 TI - Psychosocial and behavioral correlates of anxiety symptoms in a sample of HIV positive, methamphetamine-using men who have sex with men. AB - Studies show high rates of psychiatric symptoms among methamphetamine users; however, little information exists regarding methamphetamine use and anxiety. This study investigated psychosocial and behavioral correlates of anxiety symptoms in a sample of 245 HIV-positive men having sex with men (MSM) who were enrolled in a sexual risk-reduction intervention. In a multiple regression analysis, anxiety symptoms were associated with homelessness, recent experience of HIV symptoms, injection drug use, lifetime sexual abuse, engaging in risky sexual behaviors, and seeking out partners at risky sexual venues when "high" on methamphetamine. These findings can be used to inform and refine sexual risk reduction interventions and substance-use treatment programs for HIV-positive methamphetamine-using MSM. PMID- 21293994 TI - Knowledge base and caretaker-child communication about HIV in peri-urban schoolchildren of Lusaka, Zambia. AB - Peri-urban communities, which face health risks of both urban and rural environments, have grown extensively with recent global urbanization. These communities' combination of multiple HIV risk factors with the lack of a formalized sexual education system sets the stage for high-risk behavior in peri urban youth. We conducted a cross-sectional survey of children (ages 5-17, N=331) and accompanying caretakers in peri-urban Lusaka, Zambia, using both closed- and open-ended questions to investigate HIV knowledge and communication. We found that while 67% of children had heard of HIV, only 26% and 23% could accurately name a major mode of transmission and prevention, respectively. In a multivariate model, increasing age was the only significant demographic correlate of a child's ability to offer accurate responses to either question. Though HIV/AIDS knowledge levels were high in the eldest (14-17-year old) age group, in the 10-13-year-old age group accurate modes of transmission and prevention were provided by only 41% and 33% of study participants, respectively. Sharp instruments, particularly razor blades, were mentioned nearly as frequently as sexual intercourse with respect to both transmission and prevention, a response trend that predominated in the youngest age group but persisted into the oldest. Seventy percent of caretakers had not spoken with their child about HIV. A history of caretaker child communication about HIV was associated with an increased likelihood of a child offering an accurate mode of transmission (OR 2.70, 95% confidence interval (CI) 1.41-5.18, p=0.0029) or prevention (OR 3.43, 95% CI 1.78-6.60, p=0.0002), in multivariate analyses. Our results demonstrate a lack of knowledge and dialog about HIV in the pre-adolescent subset of high-risk peri-urban youth, and uncover undue emphasis on razor blades as a major mode of disease transmission. PMID- 21293995 TI - Injection risk behaviors among rural drug users: implications for HIV prevention. AB - OBJECTIVE: The purpose of this study was to examine injection drug use (IDU) among a cohort of felony probationers from rural Appalachian Kentucky. METHODS: An interviewer-administered questionnaire given to 800 rural felony probationers ascertained data regarding demographics, drug use, criminal behavior, psychological distress, and HIV-risk behaviors. RESULTS: The sample was primarily white (95.1%) and male (66.5%) and the median age was 32.3 years (interquartile range: 25.2, 40.5). There were no cases of HIV in the sample. Of the 800 rural probationers, 179 (22.4%) reported lifetime IDU. Receptive syringe sharing (RSS) and distributive syringe sharing (DSS) were reported by 34.5% and 97.1% of the IDUs, respectively. Independent correlates of risky injection behaviors included cocaine injection (adjusted odds ratio (AOR): 14.9, 95% confidence interval (CI): 8.0, 27.7) and prescription opioid injection (AOR: 14.7, 95% CI: 7.7, 28.1). DISCUSSION: Although HIV was not prevalent, data suggest that the rural felony probationers in this sample were engaging in risky injection practices that could facilitate transmission of HIV. This is especially problematic since those involved in the criminal justice system may be more likely to be exposed to HIV. Therefore, prevention aimed at reducing HIV-risk behaviors among rural, criminally involved individuals is warranted. PMID- 21293996 TI - Adverse life events proximal to adult suicide: a synthesis of findings from psychological autopsy studies. AB - The objective of this review was to summarize and interpret data about adverse life events proximal to adult suicide from major psychological autopsy studies. A PubMed search was conducted. Nearly all suicides have experienced at least 1 (usually more) adverse life event within 1 year of death (concentrated in last few months). Controlled studies have revealed specific life events, notably interpersonal conflict, as risk factors for suicide with some evidence of a dose response effect. Some of the risk is independent of mental disorder. The suicidogenic impact of adverse life events, especially interpersonal conflict, necessitates specific objectives in suicide prevention strategies. Cultural influences on relative contributions of adversity and mental disorder to suicide warrant further research. Limitations of psychological autopsy studies suggest the need for complementary research into life events prior to serious suicide attempts. PMID- 21293997 TI - Long-term suicide risk in forensic psychiatric patients. AB - The objectives of this study was to describe the rate of suicide and other causes of death in first admissions to a (medium) secure forensic psychiatric facility. All 595 patients were followed up for a maximum of 20 years. Death certificates were obtained and Standardized Mortality Ratios (SMRs) were calculated. At the June 2003 census, 57 patients (9.6%) had died of whom 18 (3.0%) had committed suicide; if deaths categorized as open verdicts are included the number rises to 26 (4.4%). The SMR for death by suicide was higher for a Mental Health Act classification of Mental Illness (SMR = 3,553) compared to Psychopathic Disorder (SMR = 1,892). The risks of mortality in this population are high from any cause, particularly from suicide. PMID- 21293998 TI - Variability in the definition and reporting of adverse events in suicide prevention trials: an examination of the issues and a proposed solution. AB - Adverse events (AEs) and serious adverse events (SAEs) are important outcomes of any intervention study yet are under-researched. Vague and variable definitions and substantial underreporting make comparisons of risk between studies difficult and evaluation of the safety of a particular intervention almost impossible. These realities may deter researchers from studying at-risk populations. Suicidal behavior is an adverse event in any study, and potentially a very serious one. Thus the issues of reporting and definition are particularly salient for researchers who work with populations at risk for suicidal behavior, especially when the suicidal behavior is the outcome of interest. We conducted a qualitative study with experienced suicide researchers and intervention experts to delineate the issues related to reporting serious adverse events faced by investigators conducting trials in suicide prevention. Participants from multiple sites were interviewed by phone, interviews transcribed and coded for definition and reporting issues and suggested solutions. A narrative synthesis was prepared and validated by all participants. Participants highlighted the difficulties in defining AEs and SAEs and stressed the importance and complexity of ensuring the AE was related to the study and reported properly, and were in agreement about the consequences of AEs to both institutions and individuals. Participants identified the need for the development of clear and consistent AE definitions and reporting requirements. Clear and consistently applied definitions of adverse and serious adverse events and reporting requirements would enhance the comparability of intervention studies in suicidal populations. PMID- 21293999 TI - Comparison of the Composite International Diagnostic interview (CIDI-Auto) with clinical diagnosis in a suicidal population. AB - The objective was to examine agreement between routine clinician diagnoses of DSM IV Anxiety, Depressive, Substance-Use disorders with diagnoses generated by CIDI Auto Version 2.1, administered by trained interviewers. Subjects were 329 deliberate self poisoning patients at a tertiary referral center in Australia. Tests of agreement were: percentage agreement, sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios, and Cohen's kappa coefficients, for 1 month and 12 month CIDI diagnoses. Agreement was poor (kappa <0.40) for Anxiety, Depressive and Substance-Use disorders. Since diagnosis largely determines subsequent treatment, these findings did not support the use of the less expensive CIDI-Auto procedure to replace clinical diagnosis by experienced clinicians for this group of patients exhibiting suicidal behavior. PMID- 21294000 TI - Non-suicidal and suicidal self-injurious behavior among Flemish adolescents: A web-survey. AB - The present study investigated the prevalence of non-suicidal self-injury (NSSI) and suicidal self-injury (SSI) in a sample of 1,417 Flemish adolescents aged 12 to 18, as well as psychosocial differences between adolescents engaging in NSSI and adolescents engaging in SSI. Participants completed an anonymous online survey inquiring about NSSI and SSI functions, sociodemographic correlates, help seeking behaviors, and stressful life events. Lifetime prevalence of NSSI was 13.71% and SSI was 3.93%. No gender or age differences appeared between adolescents engaging in NSSI or SSI; however, differences in educational level were observed. Significant differences in functions of the behavior and number of stressful life events were noted between groups. Finally, the likelihood of receiving professional help differed between adolescents engaging in NSSI and adolescents engaging in SSI. Implications of the findings for assessment and treating NSSI and SSI are discussed. PMID- 21294001 TI - Declining rates of suicidal behavior among general practice patients in Belgium: results from sentinel surveillance between 1993 and 2008. AB - The aim of this study was (1) to estimate the incidence of suicidal behavior, i.e., suicide and suicide attempts, among Belgian general practice patients in 2007-2008 and to estimate trends since previous surveillance periods, i.e., 1991 1993 and 2000-2001; and (2) to investigate characteristics of actors, acts, and first care delivery. Data were collected by the national network of sentinel general practitioners, recording all suicidal behavior they were confronted with in their daily practice in the three periods. In 2007-2008 incidence rates of both suicide and suicide attempts had declined compared to the previous periods while the use of violent versus non-violent suicidal methods remained unchanged. GP involvement in first care after suicidal behavior declined over time from 71% to 39% in the largest part of the population, i.e., younger and adult persons. The last surveillance of suicidal behavior by the Belgian sentinel network of GPs most likely resulted in an underestimation, probably as a result of a declining role of GPs in delivery of first care to patients following suicidal behavior. PMID- 21294002 TI - The prevalence of nonsuicidal self-injury and different subgroups of self injurers in Chinese adolescents. AB - Previous studies revealed a high prevalence of nonsuicidal self-injury (NSSI) in western adolescents and suggested the existence of multiple self-injurer subgroups. This study examined the prevalence of NSSI among Hong Kong Chinese adolescents and compared different subgroups of self-injurers on several psychological correlates of NSSI related to borderline personality disorder. A total of 6,374 secondary school students (67.6% girls) completed self-report questionnaires. Multivariate analyses of variance and follow-up logistic regression analyses were used to compare differences between subgroups of self injurers. Overall, 15% of adolescents reported engaging in NSSI. Gender differences varied regarding different self-injury methods. Repetitive self injurers had more emotional and impulse-control problems than episodic ones. Severe NSSI adolescents were also more impulsive than mild NSSI adolescents. The frequency and severity of NSSI acted as two important dimensions in distinguishing between self-injurers. Clinical implications of these results are discussed. PMID- 21294003 TI - Psychometric properties of the suicidal history self-rating screening scale. AB - The aim of this study was to develop a reliable self-report instrument (the Suicide History Self-Rating Screening Scale: SHSS) to identify individuals with a higher propensity for suicide in the near term. One hundred and twenty nine consecutive inpatients with mental illness completed the SHSS (a 16-item measure assessing death thoughts, suicidal ideation and behavior in the last 12 months and lifetime except in the last 12 months), the Mini International Neuropsychiatric Interview, the Beck Hopelessness Scale, and the Gotland Male Depression Scale. SHSS scores had high correlations with commonly used measures in the field of suicide risk assessment. The ROC curves indicated that the SHSS performed well in classifying cases based on their current suicide status (suicide attempt in the last 24-48 hours). The SHSS is a valid and reliable instrument for assessing suicide risk. PMID- 21294004 TI - Performance on the test of memory malingering (TOMM) among a large clinic referred pediatric sample. AB - Growing concerns with suboptimal effort in pediatric populations have led clinicians to investigate the utility of symptom validity tests (SVT) among children and adolescents. Performance on the Test of Memory Malingering (TOMM) was analyzed among a clinical sample of individuals ranging in age from 5 through 16 years. The 101 patients were referred for a variety of learning, developmental, psychiatric, and neurological concerns. All children were administered the TOMM as part of a clinical neuropsychological evaluation. Within the sample, 4 patients did not meet the adult cutoff criteria for passing the TOMM. Three of the 4 patients also demonstrated suboptimal effort on another SVT. Results revealed statistically significant correlations between TOMM performance and age, intelligence, and memory. Despite these correlations, 97 out of the 101 performed at or above the adult cutoff score. The findings suggest that children perform similarly to adults on the TOMM and that the TOMM is appropriate for use with pediatric clinical populations as young as 5 years. PMID- 21294005 TI - HEMETbeta: improvement of hepatocyte metabolism mathematical model. AB - This article describes hepatocyte metabolism mathematical model (HEMETbeta), which is an improved version of HEMET, an effective and versatile virtual cell model based on hepatic cell metabolism. HEMET is based on a set of non-linear differential equations, implemented in Simulink(r), which describes the biochemical reactions and energetic cell state, and completely mimics the principal metabolic pathways in hepatic cells. The cell energy function and modular structure are the core of this model. HEMETbeta as HEMET model describes hepatic cellular metabolism in standard conditions (cell culture in a plastic multi-well placed in an incubator at 37 degrees C with 5% of CO2) and with excess substrates concentration. The main improvements in HEMETbeta are the introductions of Michaelis-Menten models for reversible reactions and enzymatic inhibition. In addition, we eliminated hard non-linearities and modelled cell proliferation and every single aminoacid degradation pathway. All these innovations, combined with a user-friendly aspect, allow researchers to create new cell types and validate new experimental protocols just varying 'peripheral' pathways or model inputs. PMID- 21294006 TI - Pattern classification of kinematic and kinetic running data to distinguish gender, shod/barefoot and injury groups with feature ranking. AB - The identification of differences between groups is often important in biomechanics. This paper presents group classification tasks using kinetic and kinematic data from a prospective running injury study. Groups composed of gender, of shod/barefoot running and of runners who developed patellofemoral pain syndrome (PFPS) during the study, and asymptotic runners were classified. The features computed from the biomechanical data were deliberately chosen to be generic. Therefore, they were suited for different biomechanical measurements and classification tasks without adaptation to the input signals. Feature ranking was applied to reveal the relevance of each feature to the classification task. Data from 80 runners were analysed for gender and shod/barefoot classification, while 12 runners were investigated in the injury classification task. Gender groups could be differentiated with 84.7%, shod/barefoot running with 98.3%, and PFPS with 100% classification rate. For the latter group, one single variable could be identified that alone allowed discrimination. PMID- 21294007 TI - IMU-based ambulatory walking speed estimation in constrained treadmill and overground walking. AB - This study evaluated the performance of a walking speed estimation system based on using an inertial measurement unit (IMU), a combination of accelerometers and gyroscopes. The walking speed estimation algorithm segments the walking sequence into individual stride cycles (two steps) based on the inverted pendulum-like behaviour of the stance leg during walking and it integrates the angular velocity and linear accelerations of the shank to determine the displacement of each stride. The evaluation was performed in both treadmill and overground walking experiments with various constraints on walking speed, step length and step frequency to provide a relatively comprehensive assessment of the system. Promising results were obtained in providing accurate and consistent walking speed/step length estimation in different walking conditions. An overall percentage root mean squared error (%RMSE) of 4.2 and 4.0% was achieved in treadmill and overground walking experiments, respectively. With an increasing interest in understanding human walking biomechanics, the IMU-based ambulatory system could provide a useful walking speed/step length measurement/control tool for constrained walking studies. PMID- 21294008 TI - Active muscle response using feedback control of a finite element human arm model. AB - Mathematical human body models (HBMs) are important research tools that are used to study the human response in car crash situations. Development of automotive safety systems requires the implementation of active muscle response in HBM, as novel safety systems also interact with vehicle occupants in the pre-crash phase. In this study, active muscle response was implemented using feedback control of a nonlinear muscle model in the right upper extremity of a finite element (FE) HBM. Hill-type line muscle elements were added, and the active and passive properties were assessed. Volunteer tests with low impact loading resulting in elbow flexion motions were performed. Simulations of posture maintenance in a gravity field and the volunteer tests were successfully conducted. It was concluded that feedback control of a nonlinear musculoskeletal model can be used to obtain posture maintenance and human-like reflexive responses in an FE HBM. PMID- 21294009 TI - What could they have been thinking? How sociotechnical system design influences cognition: a case study of the Stockwell shooting. AB - Understanding why an individual acted in a certain way is of fundamental importance to the human factors community, especially when the choice of action results in an undesirable outcome. This challenge is typically tackled by applying retrospective interview techniques to generate models of what happened, recording deviations from a 'correct procedure'. While such approaches may have great utility in tightly constrained procedural environments, they are less applicable in complex sociotechnical systems that require individuals to modify procedures in real time to respond to a changing environment. For complex sociotechnical systems, a formative approach is required that maps the information available to the individual and considers its impact on performance and action. A context-specific, activity-independent, constraint-based model forms the basis of this approach. To illustrate, an example of the Stockwell shooting is used, where an innocent man, mistaken for a suicide bomber, was shot dead. Transferable findings are then presented. STATEMENT OF RELEVANCE: This paper presents a new approach that can be applied proactively to consider how sociotechnical system design, and the information available to an individual, can affect their performance. The approach is proposed to be complementary to the existing tools in the mental models phase of the cognitive work analysis framework. PMID- 21294010 TI - Description of dynamic shared knowledge: an exploratory study during a competitive team sports interaction. AB - This exploratory case study describes the sharedness of knowledge within a basketball team (nine players) and how it changes during an official match. To determine how knowledge is mobilised in an actual game situation, the data were collected and processed following course-of-action theory (Theureau 2003). The results were used to characterise the contents of the shared knowledge (i.e. regarding teammate characteristics, team functioning, opponent characteristics, opposing team functioning and game conditions) and to identify the characteristic types of change: (a) the reinforcement of a previous element of shared knowledge; (b) the invalidation of an element of shared knowledge; (c) fragmentation of an element of shared knowledge; (d) the creation of a new element of shared knowledge. The discussion deals with the diverse types of change in shared knowledge and the heterogeneous and dynamic nature of common ground within the team. STATEMENT OF RELEVANCE: The present case study focused on how the cognitions of individual members of a team coordinate to produce a team performance (e.g. surgical teams in hospitals, military teams) and how the shared knowledge changes during team activity. Traditional methods to increase knowledge sharedness can be enhanced by making use of 'opportunities for coordination' to optimise team adaptiveness. PMID- 21294011 TI - Effects of white noise on Callsign Acquisition Test and Modified Rhyme Test scores. AB - The Callsign Acquisition Test (CAT) is a speech intelligibility test developed by the US Army Research Laboratory. The test has been used to evaluate speech transmission through various communication systems but has not been yet sufficiently standardised and validated. The aim of this study was to compare CAT and Modified Rhyme Test (MRT) performance in the presence of white noise across a range of signal-to-noise ratios (SNRs). A group of 16 normal-hearing listeners participated in the study. The speech items were presented at 65 dB(A) in the background of white noise at SNRs of -18, -15, -12, -9 and -6 dB. The results showed a strong positive association (75.14%) between the two tests, but significant differences between the CAT and MRT absolute scores in the range of investigated SNRs. Based on the data, a function to predict CAT scores based on existing MRT scores and vice versa was formulated. STATEMENT OF RELEVANCE: This work compares performance data of a common speech intelligibility test (MRT) with a new test (CAT) in the presence of white noise. The results here can be used as a part of the standardisation procedures and provide insights to the predictive capabilities of the CAT to quantify speech intelligibility communication in high noise military environments. PMID- 21294012 TI - Slow eye movement as a possible predictor of reaction delays to auditory warning alarms in a drowsy state. AB - In recently developed intelligent vehicles, warning alarms are often used to prompt avoidance behaviours from drivers facing imminent hazardous situations. However, when critical reaction delays to auditory stimulation are anticipated, the alarm should be activated earlier to compensate for such delays. It was found that reaction times to an auditory stimulus significantly increased in the presence of slow eye movement (SEM), which is known to occur frequently during the wake-sleep transition. The reaction delay could not be attributed to temporal effects such as fatigue and was invariant regardless of response effectors (finger or foot). Moreover, it was found that applied pedal force decreased immediately after an auditory stimulus interrupted SEM. Consequently, it was concluded that SEM can be a good predictor of reaction delays to auditory warning alarms when drivers are in a drowsy state. STATEMENT OF RELEVANCE: The present study demonstrated that simple auditory reaction time significantly increased when SEM emerged. In the design of vehicle safety systems using warning alarms to prompt avoidance behaviours from drivers, such reaction delays during SEM must be taken into account. PMID- 21294013 TI - The effect of work pace on workload, motor variability and fatigue during simulated light assembly work. AB - This study investigated the effect of work pace on workload, motor variability and fatigue during light assembly work. Upper extremity kinematics and electromyography (EMG) were obtained on a cycle-to-cycle basis for eight participants during two conditions, corresponding to "normal" and "high" work pace according to a predetermined time system for engineering. Indicators of fatigue, pain sensitivity and performance were recorded before, during and after the task. The level and variability of muscle activity did not differ according to work pace, and manifestations of muscle fatigue or changed pain sensitivity were not observed. In the high work pace, however, participants moved more efficiently, they showed more variability in wrist speed and acceleration, but they also made more errors. These results suggest that an increased work pace, within the range addressed here, will not have any substantial adverse effects on acute motor performance and fatigue in light, cyclic assembly work. STATEMENT OF RELEVANCE: In the manufacturing industry, work pace is a key issue in production system design and hence of interest to ergonomists as well as engineers. In this laboratory study, increasing the work pace did not show adverse effects in terms of biomechanical exposures and muscle fatigue, but it did lead to more errors. For the industrial engineer, this observation suggests that an increase in work pace might diminish production quality, even without any noticeable fatigue being experienced by the operators. PMID- 21294014 TI - Ergonomics in bed design: the effect of spinal alignment on sleep parameters. AB - This study combines concepts of bed design and sleep registrations to investigate how quality of spine support affects the manifestation of sleep in healthy subjects. Altogether, 17 normal sleepers (nine males, eight females; age 24.3+/ 7.1 years) participated in an anthropometric screening, prior to the actual sleep experiments, during which personalised sleep system settings were determined according to individual body measures. Sleep systems (i.e. mattress and supporting structure) with an adjustable stiffness distribution were used. Subjects spent three nights of 8 h in bed in the sleep laboratory in a counterbalanced order (adaptation, personalised support and sagging support). During these nights, polysomnography was performed. Subjective sleep data were gathered by means of questionnaires. Results show that individual posture preferences are a determinant factor in the extent that subjects experience a negative effect while sleeping on a sagging sleep system. STATEMENT OF RELEVANCE: This study investigated how spine support affects sleep in healthy subjects, finding that the relationship between bedding and sleep quality is affected by individual anthropometry and sleep posture. In particular, results indicate that a sagging sleep system negatively affects sleep quality for people sleeping in a prone or lateral posture. PMID- 21294015 TI - Changes in mechanical load and extensor muscle activity in the cervico-thoracic spine induced by sitting posture modification. AB - The influence of whole body sitting posture on cervico-thoracic posture, mechanical load and extensor muscle activity was examined in 23 asymptomatic adults. Cervical and upper thoracic extensor muscle activity measured in guided slouched and lumbo-pelvic neutral postures was normalised to that measured in a self-selected habitual posture. Head and neck posture and gravitational load moment measurements were obtained in each posture. Sagittal head translation, upper cervical extension and load moment were significantly greater in the slouched posture (p < 0.001). Contrasting patterns of cervical and thoracic extensor activity were observed in the slouched and neutral postures, with cervical extensor activity 40% higher in the slouched posture (p < 0.0001). Thoracic extensor activity was significantly higher in the lumbo-pelvic neutral posture than the habitual posture (p = 0.002). The significant changes in extensor muscle activity with postural modification appear to be induced by the associated change in mechanical load moment of the head. STATEMENT OF RELEVANCE: More neutral sitting postures reduce the demand on the cervical extensor muscles and modify the relative contribution of cervical and thoracic extensors to the control of head and neck posture. Postures that promote these patterns of muscular activity may reduce cervical spine loading and the development of posture-related neck pain. PMID- 21294016 TI - Carrying a rifle with both hands affects upper body transverse plane kinematics and pelvis-trunk coordination. AB - The purpose of this study was to assess how carrying a rifle in both hands affects upper body motion and coordination during locomotion. In total, 11 male soldiers walked (1.34 m/s) and ran (2.46 m/s) with a weapon (M4 condition) and without a weapon (NW condition) while kinematic pelvis and trunk data were collected. Two-way ANOVA was used to compare segmental ranges of motion (ROM), pelvis-trunk coordination (continuous relative phase) and coordination variability between gait mode and weapon combinations. Carrying a weapon decreased sagittal plane trunk ROM at both speeds and increased trunk rotation during running. Mean (+/-SD) transverse plane coordination was more in-phase while carrying a weapon (M4 = 83 degrees +/-31, NW = 60 degrees +/-36, p = 0.027) and transverse plane coordination variability decreased (M4 = 23 degrees +/-3.6, NW = 15 degrees +/-4.4, p = 0.043). Coordination differences between M4 and NW were similar to differences reported in the literature between individuals with and without back pain. Long-term injury implications due to decreased coordination variability are discussed. STATEMENT OF RELEVANCE: Knowledge of the effects of rifle carriage on pelvis-trunk coordination may provide insight into short-term protective strategies and long-term injury mechanisms. These should be considered in occupations requiring individuals to carry torso loads in combination with holding an object in both hands that restricts arm swing. PMID- 21294017 TI - The influence of training on decision times and errors associated with classifying trunk postures using video-based posture assessment methods. AB - The purpose of this study was to examine the influence of training on the decision times and errors associated with video-based trunk posture classifications. Altogether, 30 amateur and 30 knowledge-based participants completed a three-phase study (pre-training, training, post-training) that required them to classify static trunk postures in images on a computer screen into a posture category that represented the angle of the trunk depicted. Trunk postures were presented in both flexion/extension and lateral bend views and at several distances from the boundaries of the posture categories. Both decision time and errors decreased as distance from the boundaries increased. On average, amateur analysts experienced a larger decrease in decision time per posture classification than knowledge-based analysts (amateur: 0.79 s, knowledge-based: 0.60 s; p <0.05) suggesting that training can have beneficial effects on classification performance. The implications are that the analysis time associated with video-based posture assessment methods can be reduced with appropriate training, making this type of approach feasible for larger-scale field studies. Statement of Relevance:Understanding the role that training can play in reducing errors associated with the use of video-based posture assessment methods may result in more efficient use of these tools by ergonomic practitioners. Reducing decision time and misclassification errors will provide a more efficient, accurate and representative assessment of injury risk. PMID- 21294018 TI - University students' notebook computer use: lessons learned using e-diaries to report musculoskeletal discomfort. AB - The objective of this pilot study was to identify if notebook accessories (ergonomic chair, desktop monitor and notebook riser) combined with a wireless keyboard, mouse and participatory ergonomics training would have the greatest impact on reducing self-reported upper extremity musculoskeletal discomfort in university students. In addition to pre-post computing and health surveys, the Ecological Momentary Assessment was used to capture change in discomfort over time using a personal digital assistant (PDA) as the e-diary. The PDA was programmed with a survey containing 45 questions. Four groups of university students were randomised to either intervention (three external computer accessories) or to control. Participants reported less discomfort with the ergonomic chair and notebook riser based on the pre-post survey data and the e diary/PDA ANOVA analysis. However, the PDA data, adjusted for the effect of hours per day of computer use, showed no benefit of the chair and limited benefit from the riser. Statement of Relevance:University students' use of notebook computers has increased. This study found evidence of a positive effect of an adjustable chair or notebook riser when combined with ergonomic training on reducing discomfort. Daily notebook computer use of 4 h was confirmed as a risk factor. Without some form of ergonomic intervention, these students are likely to enter the workforce with poor computing habits, which places them on the road to future injuries as technology continues to play a dominant role in their lives. PMID- 21294020 TI - Expanding the walls of the health care encounter: support and outcomes for patients online. AB - This paper assesses the relationship between patient-health care provider (HCP) interaction and health behaviors. In total, 109 Native American patients diagnosed with diabetes mellitus were enrolled in a Web-based diabetes monitoring system. The system tracks patient-HCP interaction, and in total 924 personal messages were exchanged. These 924 messages contained 6,411 message units that were content analyzed using a nine-category scheme. Patient blood glucose monitoring was found to be related to the frequency of phatic communication, informational social support, and tangible social support messages, as well as messages containing references to personal contact. Finally, person-centered messages proved to be the single best predictor of patient involvement with the telemedicine system (as measured by the number of times the patient logged into the system). PMID- 21294021 TI - A functional magnetic resonance imaging investigation of episodic memory after traumatic brain injury. AB - Traumatic brain injury often negatively impacts episodic memory; however, studies of the neural substrates of this impairment have been limited. In this study, both encoding and recognition of visually presented stimuli were examined with functional magnetic resonance imaging. Twelve adults with chronic complicated mild, moderate, and severe injuries were compared with a matched group of 12 controls. Behavioral task performance did not differentiate the groups. During neuroimaging, however, the group of individuals with traumatic brain injury exhibited increased activation, as well as increased bilaterality and dispersion as compared to controls. Findings are discussed in terms of increased resource recruitment. PMID- 21294022 TI - What does cancer treatment look like in consumer cancer magazines? An exploratory analysis of photographic content in consumer cancer magazines. AB - In an exploratory analysis of several highly circulated consumer cancer magazines, the authors evaluated congruency between visual images of cancer patients and target audience risk profile. The authors assessed 413 images of cancer patients/potential patients for demographic variables such as age, gender, and ethnicity/race. They compared this profile with actual risk statistics. The images in the magazines are considerably younger, more female, and more White than what is indicated by U.S. cancer risk statistics. The authors also assessed images for visual signs of cancer testing/diagnosis and treatment. Few individuals show obvious signs of cancer treatment (e.g., head scarves, skin/nail abnormalities, thin body types). Most images feature healthier looking people, some actively engaged in construction work, bicycling, and yoga. In contrast, a scan of the editorial content showed that nearly two thirds of the articles focus on treatment issues. To explicate the implications of this imagery-text discontinuity on readers' attention and cognitive processing, the authors used constructs from information processing and social identity theories. On the basis of these models/theories, the authors provide recommendations for consumer cancer magazines, suggesting that the imagery be adjusted to reflect cancer diagnosis realities for enhanced message attention and comprehension. PMID- 21294023 TI - Suburban queer: reading Grease. AB - This article examines how nontraditional representations of gender can complicate received social norms, and it examines, in particular, how pre-adolescent suburban youth reconfigure social codes within popular film in order to identify positive queer aesthetics. While several studies have documented the function of classic and mainstream film in the tradition of queer reading, there has been comparatively less analysis devoted to the ways that filmic representations themselves might contribute to theoretical debates regarding sexual identity. As a case in point, this essay analyzes the 1978 musical Grease in order to suggest ways that critics might navigate between strict social constructionist and essentialist theories of sexual identity in order to identify avenues for queer identification within non-queer contexts. PMID- 21294024 TI - Trend analysis of medical publications about LGBT persons: 1950-2007. AB - Although there are currently at least 6 million lesbian, gay, bisexual, and transgender (LGBT) persons in the United States, there are no prior studies analyzing how this group is represented in the medical literature. An examination of published LGBT topics over a 57-year period was performed using OvidSP. A total of 21,728 publications was analyzed for topic using information from the title, keywords, subject headings, and abstracts. Several trends became apparent. The largest proportion of LGBT publications (31.78%) was devoted to HIV/AIDS and other sexually transmitted infections (STIs), yet there was an overall lack of emphasis on general health topics or common causes of mortality. Further analysis showed that if publications on HIV/AIDS or STIs addressed sexual orientation, they were more likely to be about LGBT persons than heterosexuals. Overall, the volume and range of medical publications on LGBT persons may not be reflective of the health care needs of this population. PMID- 21294025 TI - Identifying the needs of LGBTQ immigrants and refugees in Southern Arizona. AB - This article reports on the results of a needs assessment conducted for lesbian, gay, bisexual, transgender, and queer (LGBTQ) immigrants, asylees, refugees, and their allies in Southern Arizona, and it is the first study of its kind in the United States. Utilizing interview data collected with migrants, allies, and service providers in Tucson, Arizona, this article presents findings on the quality of service provision provided to this very underserved community pertaining to health care, housing, and legal services. The assessment shows that no services are provided specifically for LGBTQ migrants, and most LGBTQ migrants turn to family and friends when they have needs. The most significant result of this study pertains to the lack of cultural competence and an overall deficiency in terms of cultural awareness when it comes to the specific needs of LGBTQ migrants. PMID- 21294026 TI - Whose crazy investment in sex? AB - By probing the processes of exclusion of transsexuals from the political sphere, this article offers contributions to social and political theory through an examination of the processes of exclusion from the category "human." This article considers how the erasure of investment in their own embodied sex constructs a platform from which to blame others for sex/gender variance, as well as to justify that blaming. Bringing together Giorgio Agamben, Georges Bataille, Judith Butler, and Nikolas Rose with transphobia, medicalization in psychiatry, law, and ethopolitics, this article questions whose investment in sexed embodiment counts and why that investment might be seen as "crazy." PMID- 21294027 TI - Judgments toward male and transgendered victims in a depicted stranger rape. AB - There has been an increasing amount of research interest into perceptions of male rape in recent years. However, no research has assessed how people react when a transgendered person is raped. The aim of this study was to investigate the effects of transgendered status and sexuality on victim blame and perceived severity in a depicted rape scenario. The sexuality of the victim was manipulated to include a heterosexual, homosexual, cross-dresser, female-to-male transsexual, and male-to-female transsexual. It was predicted that the heterosexual victims would be judged the most positively and that heterosexual male participants would make the most anti-victim judgments. One hundred thirty-three lesbian, gay male, and heterosexual members of the general population read a scenario depicting a rape and then completed a questionnaire measuring victim blame and perceived severity of the assault. Results conformed to the predictions. Results are discussed in relation to traditional gender roles and homophobia. PMID- 21294028 TI - Core American values and the structure of antigay prejudice. AB - This work presents a new scale to measure conflicting attitudes toward sexual minorities. This scale parallels existing measures of conflicting racial attitudes (anti-Black and pro-Black attitudes; Katz & Hass, 1988). After constructing and validating measures of antigay and progay attitudes, we tested relationships among core American values with racial and sexual minority attitudes. We examined relations among the Protestant Work Ethic (PWE), Traditional Family Ideology (TFI), and egalitarian values with attitudes toward racial outgroups and sexual minorities. The results revealed that both PWE values and egalitarian values predicted anti-Black attitudes. By contrast, endorsement of egalitarian values, but not PWE values, predicted pro-Black attitudes. Results also revealed a similar but distinct pattern among values and heterosexuals' attitudes toward sexual minorities. TFI, but not egalitarian value endorsement, predicted antigay attitudes, whereas both TFI and egalitarian value endorsement predicted progay attitudes. The implications of these findings are discussed. PMID- 21294029 TI - Application and testing the reliability and validity of a modified version of Herek's attitudes toward lesbians and gay men scale in China. AB - The present study was the first attempt to test the reliability and validity of Herek's Attitudes Toward Lesbians and Gay Men Scale (ATLG; Herek, 1988) in the Chinese population. Participants (n = 2,391 for the field trials and n = 200 for test-retest reliability) were asked to complete the translated, slightly modified version of the ATLG. The resulting ATLG has a two-dimensional factor structure as well as good validity and reliability in the Chinese culture. ATLG scores followed distinct patterns according sex and level of education that were consistent with previous studies in other populations. The significance of these findings in Chinese culture is discussed. PMID- 21294030 TI - Using hegemonic masculinity to explain gay male attraction to muscular and athletic men. AB - This article reviews relevant research on male homosexual attraction. Utilizing masculinity as its theoretical frame, the authors use childhood experiences with both fathers and peers, the gay community's inculcation of heteronormative ideologies, and the gay media's adherence to masculine prototypes, to provide causal explanations for the appeal of muscular, lean, and athletic physiques. While the authors acknowledge that not all individuals within the gay community look toward muscularity and athleticism as the primary components of attractiveness, it nonetheless remains important to examine the theoretical perspectives that may explain the appeal of this specific aesthetic. PMID- 21294032 TI - Intensities of exercise during match-play in FA Premier League referees and players. AB - The aim of the present study was to examine the relationship between intensities of exercise during match-play of elite-standard soccer referees with those of the players from the same match. Match analysis data were collected (Prozone(r) Leeds, UK) for 18 elite-standard soccer referees (age 26-49 years) on FA Premier League matches during the 2008/09 English FA Premier League season (236 observations). Running categories for referees and players were as follows: total distance covered (m); high-speed running distance (speed >19.8 km . h(-1)); and sprinting distance (speed >25.2 km . h(-1)). Analysis of the distance-time regression coefficients revealed no differences between the referees' and players' within-match rates of change for total distance covered (-0.594 +/- 0.394 vs. -0.713 +/- 0.269 m . min(-1); P = 0.104), high-speed running (-0.039 +/ 0.077 vs. -0.059 +/- 0.030 m . min(-1); P = 0.199), and sprinting (-0.003 +/- 0.039 vs. -0.021 +/- 0.017 m . min(-1); P = 0.114). In addition, there were no differences between across-season rates of change for total distance (-26.756 +/- 40.434 vs. -20.031 +/- 25.502 m per match day; P = 0.439) and sprinting (-9.662 +/- 7.564 vs. -8.589 +/- 4.351 m per match day; P = 0.542). These results show that elite-standard soccer referees' intensities of exercise during match-play are interrelated with those of the players and thus demonstrate that referees are able to keep pace with the players during FA Premier League matches. PMID- 21294033 TI - The Hit & Turn Tennis Test: an acoustically controlled endurance test for tennis players. AB - This study was conducted to validate and evaluate the "Hit & Turn Tennis Test", an acoustically progressive on-court endurance test for tennis players. Ninety eight competitive tennis players (53 males, 45 females) of different age groups participated in the study. For validation, the adult male players completed three Hit & Turn tests, one on a clay court and two on a carpet surface, a tennis specific ball machine test and an incremental treadmill run in a randomized order. A stronger correlation between maximal performance (r = 0.81, P < 0.01) and maximal oxygen uptake (r = 0.96, P < 0.01) was observed between the Hit & Turn test and the ball machine test, than between the Hit & Turn test and the treadmill test. For test-retest, we found a significant correlation between maximal performance on the same (r = 0.83, P < 0.01) and on different surfaces (r = 0.74, P < 0.01). During test evaluation, maximal performance was higher in males than in females (P < 0.01) and increased by consecutive age group in boys (P < 0.01) but not in girls (P = 0.97). In conclusion, Hit & Turn maximum test performance can be recommended as a valid and reliable indicator for tennis specific endurance. PMID- 21294034 TI - The effect of critical speed and exercise intensity on stroke phase duration and bilateral asymmetry in 200-m front crawl swimming. AB - The main aim of this study was to determine the absolute temporal relationship between the power and recovery phases of the stroke cycle in front crawl swimming in response to progressive changes in exercise intensity that occurred before and after critical speed. A second objective was to determine whether intensity related changes in the power/recovery phase relationship affects the bilateral symmetry of the stroke. Stroke parameters were recorded for each 25-m length during a progressive 200-m interval training set, in which eight (2 males, 6 females) national-level swimmers swam at intensities below, above, and at critical speed. The results demonstrated that substantial increases in stroke rate (P < 0.01) occurred at critical speed, and that these increases were related to a greater decrease in the duration of the power phase than the recovery phase (P < 0.01). The results also show that the degree of bilateral asymmetry was greater for the power phase than the recovery phase, and was inversely related to intensity in both phases of the stroke cycle. The findings of this study suggest that critical speed-related increases in stroke rate are an indirect consequence of increased force production in the power phase of the stroke, and that bilateral asymmetry is both intensity- and stroke-phase dependent. PMID- 21294035 TI - Dual-task effect on postural control in high-level competitive dancers. AB - We investigated balance in 33 competitive dancers (17 females, 16 males) and 22 controls (17 females, 5 males) (age 16-27 years) on a force plate in two conditions: single task (quiet stance) and dual task (with a concurrent mental task). Balance was evaluated using centre-of-pressure shift (sway) variability, mean speed, frequency, and sample entropy. The effect of the dual task in the medio-lateral plane was comparable in both groups, decreasing sway variability (P < 0.05) and increasing mean speed (P < 0.001), frequency, and sample entropy (P < 0.001), showing that the participants effectively increased the level of automaticity. In the antero-posterior plane, the dual task also increased sway frequency and sample entropy (P < 0.01) in dancers without affecting their standing performance. In contrast, postural control in non-dancers was vulnerable to reduced cognitive investment, which adversely interfered with baseline performance. There were very high correlations between sway sample entropy and frequency in each group, plane, and task (r = 0.92-0.98, P < 0.001), indicating that both parameters may measure the same characteristic of postural control and that higher sway frequency may play an important role in protecting stability in dual tasking. The postural control of dancers and non-dancers appears to be similar, although dancing seems to facilitate the increased level of automatic control in the antero-posterior plane. PMID- 21294036 TI - Examining the mechanisms of overgeneral autobiographical memory: capture and rumination, and impaired executive control. AB - Overgeneral autobiographical memory (OGM) is an important cognitive phenomenon in depression, but questions remain regarding the underlying mechanisms. The CaR-FA X model (Williams et al., 2007) proposes three mechanisms that may contribute to OGM, but little work has examined the possible additive and/or interactive effects among them. We examined two mechanisms of CaR-FA-X: capture and rumination, and impaired executive control. We analysed data from undergraduates (N=109) scoring high or low on rumination who were presented with cues of high and low self-relevance on the Autobiographical Memory Test (AMT). Executive control was operationalised as performance on both the Stroop Colour-Word Task and the Controlled Oral Word Association Test (COWAT). Hierarchical generalised linear modelling was used to predict whether participants would generate a specific memory on a trial of the AMT. Higher COWAT scores, lower rumination, and greater cue self-relevance predicted a higher probability of a specific memory. There was also a rumination*cue self-relevance interaction: Higher (vs lower) rumination was associated with a lower probability of a specific memory primarily for low self-relevant cues. We found no evidence of interactions between these mechanisms. Findings are interpreted with respect to current autobiographical memory models. Future directions for OGM mechanism research are discussed. PMID- 21294037 TI - Mood-congruent true and false memory: effects of depression. AB - The Deese/Roediger-McDermott paradigm was used to investigate the effect of depression on true and false recognition. In this experiment true and false recognition was examined across positive, neutral, negative, and depression relevant lists for individuals with and without a diagnosis of major depressive disorder. Results showed that participants with major depressive disorder falsely recognised significantly more depression-relevant words than non-depressed controls. These findings also parallel recent research using recall instead of recognition and show that there are clear mood congruence effects for depression on false memory performance. PMID- 21294038 TI - Mechanisms underlying skilled anticipation and recognition in a dynamic and temporally constrained domain. AB - We examined the mechanisms underlying skilled anticipation and recognition in a dynamic, interactive, and temporally constrained domain. Skilled and less-skilled participants viewed dynamic film stimuli, anticipated event outcome, and provided immediate retrospective verbal reports. Previously viewed and novel sequences were then presented in film or point-light display format. Participants made recognition judgements and again gave retrospective verbal reports on their thought processes. Skilled participants demonstrated superior anticipation accuracy and were more sensitive in distinguishing previously seen from novel stimuli than less-skilled participants. Skilled participants utilised more complex memory representations than less-skilled individuals, as indicated by references in their retrospective reports to more evaluation and prediction statements. The representations activated during anticipation were more complex than those for recognition judgements in both groups. Findings are discussed with reference to long-term working memory theory. PMID- 21294039 TI - Ironic effects of drawing attention to story errors. AB - Readers learn errors embedded in fictional stories and use them to answer later general knowledge questions (Marsh, Meade, & Roediger, 2003). Suggestibility is robust and occurs even when story errors contradict well-known facts. The current study evaluated whether suggestibility is linked to participants' inability to judge story content as correct versus incorrect. Specifically, participants read stories containing correct and misleading information about the world; some information was familiar (making error discovery possible), while some was more obscure. To improve participants' monitoring ability, we highlighted (in red font) a subset of story phrases requiring evaluation; readers no longer needed to find factual information. Rather, they simply needed to evaluate its correctness. Readers were more likely to answer questions with story errors if they were highlighted in red font, even if they contradicted well-known facts. Although highlighting to-be-evaluated information freed cognitive resources for monitoring, an ironic effect occurred: Drawing attention to specific errors increased rather than decreased later suggestibility. Failure to monitor for errors, not failure to identify the information requiring evaluation, leads to suggestibility. PMID- 21294040 TI - In vitro antioxidant activities of the methanol extract and its different solvent fractions obtained from the fruit pericarp of Terminalia bellerica. AB - Terminalia bellerica has been used as a traditional medicine in a variety of ailments including anaemia, asthma, cancer, inflammation, rheumatism and hypertension. In this study, the free radical scavenging and antioxidant activities of methanol extract (ME) and its different solvent fractions (namely hexane (HE), ethyl acetate (EA), butanol (BL) and water (WA)) of the T. bellerica fruit pericarp were evaluated and compared with standard antioxidant compounds like gallic acid (GA), catechin and ascorbic acid. Among the different fractions tested, the EA fraction exhibited higher antioxidant and radical scavenging activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH), superoxide and hydroxyl radicals than the other fractions, which may be attributed to its higher phenolic and flavonoid content, since a linear relation was observed between the phenolic content and the antioxidant parameters. The HPTLC analysis of the EA fraction revealed that it mainly contains GA and ferulic acid (FA) as major phenolics, and the higher antioxidant activities of EA fraction may be due to the presence of these compounds. PMID- 21294041 TI - Effect of probiotication on antioxidant and antibacterial activities of pomegranate juices from sour and sweet cultivars. AB - There is an increasing interest in using pomegranate juice as a natural antioxidant rather than synthetic compounds. In this study, the antioxidant capacities of probioticated and nonprobioticated aril juices of sweet (SWV) and sour (SV) pomegranate cultivars were determined by two different methods: ferric reducing antioxidant power (FRAP) and 1,1-diphenyl 2-picrylhydrazyl assay. Total counts of Lactobacillus casei GG increased by about 3 log in SWV and 2 log in SV juices after incubation for 48 h. Probiotication improved the antioxidant activity of SWV juice from 74.4% to 91.82%, and SV juice from 82.64% to 97.8%. Based on the FRAP value, the reducing power of the probioticated pomegranate juices was also much stronger than the nonprobioticated juices. The FRAP values for SWV and SV probioticated juices were 97.34 and 120.7 mmol L(-1), respectively, which were notably higher than 85.87 and 93.4 mmol L(-1) for SWV and SV nonprobioticated juices. Both fermentated and nonfermentated juices exhibited a potent and wide-spectrum antibacterial effect, with the highest activity against Pseudomonas aeruginosa. SV juice showed wider zones of growth inhibition. The results of this study verify for the first time that probiotication of SWV and SV pomegranate juices can add to their beneficial antioxidant activities. PMID- 21294042 TI - In vitro antiperoxidative, free radical scavenging and xanthine oxidase inhibitory potentials of ethyl acetate fraction of Saraca ashoka flowers. AB - Saraca ashoka is a widely used medicinal herb claimed to cure many diseases. This study investigated the antiperoxidative, free radical scavenging and xanthine oxidase (XO) inhibitory potential of the ethyl acetate fraction of S. ashoka flowers (SAF) and compared it with standard compounds like gallic acid, ascorbic acid, butylated hydroxyl toluene and allopurinol. The ethyl acetate fraction of SAF exhibited free radical scavenging activity against the 1,1-diphenyl-2 picrylhydrazyl radical and superoxide radical, along with hydroxyl radical scavenging activity. Lipid peroxidation inhibitory potential of SAF was studied using a linoleic acid emulsion system, which shows significant antioxidant potential. SAF also demonstrated significant XO (key enzyme linked to inflammation) inhibitory activity, which revealed its therapeutic potential as an antioxidant and XO inhibitor. HPLC profiling of the ethyl acetate fraction of SAF revealed that it contains ellagic acid as a major compound and thus the beneficial effects of this fraction may be due to the presence of this compound. PMID- 21294043 TI - In vitro cytotoxic and antiviral activities of Ficus carica latex extracts. AB - The latex of fig fruit (Ficus carica) is used in traditional medicine for the treatment of skin infections such as warts and also diseases of possible viral origin. Five extracts (methanolic, hexanic, ethyl acetate, hexane-ethyl acetate (v/v) and chloroformic) of this species were investigated in vitro for their antiviral potential activity against herpes simplex type 1 (HSV-1), echovirus type 11 (ECV-11) and adenovirus (ADV). To evaluate the capacity of the extracts to inhibit the replication of viruses, the following assays were performed: adsorption and penetration, intracellular inhibition and virucidal activity. Observation of cytopathic effects was used to determine the antiviral action. The hexanic and hexane-ethyl acetate (v/v) extracts inhibited multiplication of viruses by tested techniques at concentrations of 78 ug mL(-1). These two extracts were possible candidates as herbal medicines for herpes virus, echovirus and adenovirus infectious diseases. All extracts had no cytotoxic effect on Vero cells at all tested concentrations. PMID- 21294044 TI - Purification and identification of carvacrol from the root of Stellera chamaejasme and research on its insecticidal activity. AB - The root powder of Stellera chamaejasme was extracted with petroleum ether. The crude extract obtained was chromatographed repeatedly with silica gel columns. One pure natural product was obtained, which was identified as 5-isopropyl-2 methylphenol (carvacrol), separated for the first time from the root of S. chamaejasme. The results of a laboratory bioassay showed that it had good insecticidal activity against Aphis craccivora and Leucania separata. Its median lethal concentrations (LC(50)) (24 h after treatment) were 16.8 and 12.7 mg L( 1), respectively. This is the first report of the insecticidal activity of carvacrol against A. craccivora and L. separata. PMID- 21294045 TI - Line quadrisection errors in patients with hemispatial neglect. AB - Patients with left unilateral neglect misbisect lines toward the right. To discriminate between contralesional unawareness and ipsilesional hyperattention hypotheses for this ipsilesional bias, we performed the line quadrisection test on 18 patients with and 25 without neglect, and 24 normal controls. Overall the patients with neglect were unbiased when performing the left quadrisection task, but erred rightward on the right quadrisection task. These results suggest that the ipsilesional bisection errors produced by patients with neglect are primarily influenced by ipsilesional hyperattention rather than contralesional unawareness. However, further analyses showed heterogeneity of performance in left quadrisection, which can be explained by multiple factors that include the top down attention to left space associated with left quadrisection, the orienting to the salience of the line's left end, and distorted mental representation, in addition to ipsilesional hyperattention. PMID- 21294047 TI - Everyday action planning in schizophrenia. AB - Planning of everyday tasks was examined in 48 inpatients with schizophrenia and 26 healthy controls. Participants were administered the Naturalistic Action Test, which requires completion of three everyday tasks (e.g., make toast and coffee). Planning variables, including planning behaviours (e.g., gathering items before engaging in a subtask) and planning time (e.g., period between task instructions and first action) were coded to evaluate forward thinking in these tasks. Results showed that planning variables were reliably coded. Controls demonstrated more planning behaviours than participants with schizophrenia; however, this difference was accounted for by education. People with schizophrenia spent significantly less time planning when planning time was analysed as a proportion of the total time on tasks. Planning variables were related to the ability to accomplish everyday task steps and to perform everyday task steps accurately. Together these findings suggest that rehabilitation strategies that emphasise both planning time and planning behaviours may facilitate everyday functioning in people with schizophrenia. PMID- 21294049 TI - Rehabilitation of everyday memory deficits in paediatric brain injury: self instruction and diary training. AB - Memory problems that interfere with everyday living are frequently reported in children who have sustained acquired brain injury (ABI), but their nature and rehabilitation is under-researched. This study aimed to (1) determine neuropsychological correlates of everyday memory deficits in children with ABI, and (2) investigate the effectiveness of a newly developed programme for their rehabilitation. We assessed everyday memory, verbal memory, attention and behaviour in 15 children with ABI. The children attended the everyday memory rehabilitation programme: six weekly sessions that involved diary training, self instruction training and case examples. At the onset we found that everyday memory problems were related to impaired attention and behavioural difficulties. On completion of the programme there was a significant increase in children's abilities to perform daily routines that demanded recall of information and events. In addition, children used diaries more frequently. Moreover, significant secondary gains were found in attention and mood (anxiety and depression). In conclusion, the results provided preliminary evidence that our six week programme could be effective in reducing everyday memory difficulties and improving psychological well-being in children with ABI. PMID- 21294050 TI - The flavonoid quercetin modulates the hallmark capabilities of hamster buccal pouch tumors. AB - Epidemiological studies have consistently demonstrated the protective effects of dietary phytochemicals against cancer risk. Quercetin, a ubiquitous dietary flavonoid, has attracted considerable attention owing to its potent antioxidant and antiproliferative activities. The present study was designed to investigate the chemopreventive as well as the therapeutic ability of quercetin to modulate the key hallmark capabilities of 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinomas. We analyzed the expression of markers associated with cell proliferation and survival (PCNA, p21, p53, cyclin D1, GST P), apoptosis (Fas, Fas-L, Bcl-2 family proteins, cytochrome-C, Apaf-1, caspases, PARP, survivin, cFLIP, API1), invasion (MMPs, TIMP-2, RECK), angiogenesis (PlGF, VEGF, VEGF receptors, HIF-1alpha), as well as the epigenetic markers (HDAC-1, DNMT1) by immunohistochemical, Western blot, and RT-PCR analyses. Simultaneous administration of quercetin to DMBA-painted hamsters reduced tumor incidence and tumor burden, while posttreatment of quercetin resulted in a significant tumor growth delay. In addition, quercetin administration induced cell cycle arrest and apoptosis and blocked invasion and angiogenesis. We found a positive correlation between the inhibition of HDAC-1 and DNMT1 by quercetin and its anticancer properties. A dietary phytochemical such as quercetin that modulates a plethora of molecules offers promise as an ideal candidate for multitargeted cancer prevention and therapy. PMID- 21294051 TI - Accurate determination of energy needs in children and adolescents with cancer. AB - Studies on children with cancer have suggested that energy expenditure may indeed be greater than predicted for healthy children. Nutritional assessment is important for intervention and for the prevention of complications associated with malnutrition. The present study aimed to describe the nutritional status, energy expenditure, and substrate utilization of children and adolescents with cancer compared to healthy children matched for age, sex, and body mass index. Subjects were evaluated by anthropometry, food intake pattern, and body composition analysis. Energy expenditure and substrate oxidation were measured by indirect calorimetry. Indirect calorimetry data, energy, and macronutrient intake, anthropometry, and body composition parameters showed no significant differences between groups. There was no evidence of increased energy expenditure or of a change in substrate utilization in children with cancer compared to the healthy group. The data regarding usual food consumption showed no significant differences between groups. PMID- 21294052 TI - The effect of leucine restriction on Akt/mTOR signaling in breast cancer cell lines in vitro and in vivo. AB - The mammalian target of rapamycin (mTOR) is a central controller of cell growth and is currently being investigated as a potential target in breast cancer therapy. The essential amino acid leucine has been proposed to regulate mTOR signaling. The objective of this study was to determine whether leucine restriction would inhibit mTOR signaling in breast cancer cells. Leucine restriction did not decrease mTOR signaling in any of the 8 breast cancer cell lines tested. In addition, in vivo administration of a leucine-free diet for up to 4 days did not result in a decrease in phosphorylation of mTOR target proteins in breast cancer xenografts. Further, in 3 different cell lines, an increase in Akt phosphorylation was observed after leucine restriction. This was observed without a decrease in S6K phosphorylation, suggesting a mechanism different from the feedback loop activation of Akt observed with rapamycin treatment. We conclude that leucine restriction is not sufficient to inhibit mTOR signaling in most breast cancer cell lines but is associated with activation of survival molecule Akt, making leucine deprivation an undesirable approach for breast cancer therapy. PMID- 21294053 TI - Targeting cell signaling and apoptotic pathways by dietary agents: role in the prevention and treatment of cancer. AB - Cancer is one of the leading causes of death in the United States and around the world. Most modern drug-targeted therapies, besides being enormously expensive, are associated with serious side effects and morbidity. Still, the search continues for an ideal treatment that has minimal side effects and is cost effective. Indeed, the design and development of chemopreventive agents that act on specific and/or multiple molecular and cellular targets is gaining support as a rational approach to prevent and treat cancer. We present evidence on numerous dietary agents identified from fruits and vegetables that act on multiple signal transduction and apoptotic cascades in various tumor cells and animal models. Some of the most interesting and well documented are turmeric (curcumin), resveratrol, silymarin, EGCG, and genistein. This review will provide an insight on the cellular and molecular mechanism(s) by which dietary agents modulate multiple signaling and apoptotic pathways in tumor cells and elucidate the role of these agents in both prevention and treatment of cancer. PMID- 21294054 TI - Ethnic and religious differentials in Bulgarian mortality, 1993-98. AB - We investigated ethnic/religious mortality differentials in Bulgaria during the 1990s. The analyses employed a unique longitudinal data-set covering the entire population of Bulgaria from the census of 1992 until 1998. The mortality of Roma is very high compared to all other ethnic/religious groups. The excess applies to nearly every cause of death examined and is not entirely explained by the adverse location of Roma on social and economic variables. For young men, Muslim mortality is substantially lower than that of non-Muslims when socio-economic differences are controlled. An analysis of causes of death suggests that lower consumption of alcohol may contribute to this 'Muslim paradox'. For older Turkish women, a significant mortality disadvantage remains after controls are imposed. Suicide mortality is lower for Muslims than for Christian groups of the same ethnicity. Consistent with deteriorating economic conditions over the study period, mortality was rising, particularly for women. PMID- 21294055 TI - The problems of eligibility and endogenous confounders when assessing the mortality impact of a nationwide disease-prevention programme: the case of insecticide-treated nets in Togo. AB - Evaluation of the mortality impact of nationwide disease-prevention efforts is complicated by potential endogeneity: programme recipients may have unobserved characteristics that simultaneously make them both more likely to become recipients and more likely to survive as a result of other health practices. This population-based study assesses the mortality impact of a nationwide programme that distributed insecticide-treated nets (ITNs) to mothers of children aged 9-59 months in Togo. By comparing mortality rates before and after the programme according to households' eligibility status, we demonstrate that a one-time programme that restricts eligibility to households with a surviving child excludes some households with a high risk of child mortality. We then apply simultaneous estimation models to untangle the mortality impact of ITNs from the effects of unobserved confounders and show that among eligible households, living in a household with ITNs significantly reduces mortality for children aged 20-59 months, even after controlling for endogeneity. PMID- 21294061 TI - [Recommendations for invasive home mechanical ventilation]. AB - Due to chronic respiratory failure, a proportion of patients require long-term home ventilation therapy. The treating doctors, nurses and therapists, as well as employees of the health insurance provider, all require specialized knowledge in order to establish and monitor home ventilation. The following document represents a consensus formed by the participating specialist societies, the health insurers and their medical advisory services. The recommendations for accomplishing home mechanical ventilation are based on the "S2 Guidelines for Non Invasive and Invasive Mechanical Ventilation for Treatment of Chronic Respiratory Failure", and provide advice about the necessary qualifications of medical and nursing practitioners working in specialised ventilation centres or in the home setting. Management of transfer, which comprises the medical, technical and organisational requirements for releasing the patient from hospital care, is of paramount importance. In outpatient care, the requirements for the recruitment of resources, monitoring of procedures, adjustment of ventilation, and frequency of check-ups are each addressed. The recommendations are supplemented by appendices which include patient transfer forms, checklists for the supply of basic resources for home ventilation, as well as a template for the letter of discharge from hospital. PMID- 21294062 TI - [In memoriam Privatdozent Dr. rer. nat. Wolfgang Marek]. PMID- 21294063 TI - Oxygen-enhanced MRI of the lungs: intraindividual comparison between 1.5 and 3 tesla. AB - PURPOSE: To assess the feasibility of oxygen-enhanced MRI of the lung at 3 Tesla and to compare signal characteristics with 1.5 Tesla. MATERIALS AND METHODS: 13 volunteers underwent oxygen-enhanced lung MRI at 1.5 and 3 T with a T 1-weighted single-slice non-selective inversion-recovery single-shot half-Fourier fast-spin echo sequence with simultaneous respiratory and cardiac triggering in coronal orientation. 40 measurements were acquired during room air breathing and subsequently during oxygen breathing (15 L/min, close-fitting face-mask). The signal-to-noise ratio (SNR) of the lung tissue was determined with a difference image method. The image quality of all acquisitions was visually assessed. The mean values of the oxygen-induced relative signal enhancement and its regional coefficient of variation were calculated and the signal enhancement was displayed as color-coded parameter maps. Oxygen-enhancement maps were visually assessed with respect to the distribution and heterogeneity of the oxygen-related signal enhancement at both field strengths. RESULTS: The mean relative signal enhancement due to oxygen breathing was 13 % (+/- 5.6 %) at 1.5 T and of 9.0 % (+/- 8.0 %) at 3 T. The regional coefficient of variation was significantly higher at 3 T. Visual and quantitative assessment of the enhancement maps showed considerably less homogeneous distribution of the signal enhancement at 3 T. The SNR was not significantly different but showed a trend to slightly higher values (increase of about 10 %) at 3 T. CONCLUSION: Oxygen-enhanced pulmonary MRI is feasible at 3 Tesla. However, signal enhancement is currently more heterogeneous and slightly lower at 3 T. PMID- 21294064 TI - [Intraosseous hemangioma]. PMID- 21294065 TI - Severe respiratory distress syndrome unresponsive to intensive care treatment- diagnostic and therapeutic considerations. AB - Respiratory Distress Syndrome (RDS) is a common complication in preterm neonates. If RDS is not responding to conventional treatment modalities (surfactant therapy, ventilatory support, etc.), an underlying pathology (pulmonary lymphangiectasia, capillary alveolar dysplasia, alpha-1 antitrypsin deficiency, etc.) other then prematurity should be taken into consideration.Here, we report on a preterm neonate with the unusual simultaneous occurrence of pulmonary and systemic lymphangiectasia and homozygous alpha-1 antitrypsin deficiency who developed severe RDS that was refractory to conventional treatment. The diagnostic and therapeutic approach in this patient is presented. PMID- 21294066 TI - Chorioretinitis in a 7-year-old African girl, probably related to JSSc resolving to methotrexate therapy. AB - Juvenile systemic sclerosis (JSSc) is a rare but severe multi-system connective tissue disease of unknown etiology. It is one of the most difficult to treat rheumatic diseases in childhood and characterized by thickening and fibrosis of the skin and associated with fibrosis of internal organs. Eye involvement has rarely been reported. In a 7-year-old African girl, who presented with chorioretinitis and subsequently developed JSSc we discuss the possible association of chorioretinitis with JSSc and the putative implications of scleroderma vascular disease in the development of this complication and review the existing literature. PMID- 21294067 TI - Assessment of left ventricular global and regional longitudinal peak systolic strain, strain rate and velocity with feature tracking in healthy fetuses. AB - PURPOSE: The aim of this study was to evaluate the correlation of feature tracking-derived measurements of the left ventricular myocardium in healthy fetuses with gestational age. MATERIALS AND METHODS: The global and segmental longitudinal peak systolic strain, strain rate and velocity values of the left ventricular myocardium for each gestational age were assessed by a novel feature tracking technique in 150 healthy fetuses (gestational age range 13 - 39 weeks of gestation). The interobserver and intraobserver variability was analyzed. RESULTS: The global longitudinal peak systolic velocity exhibited a segmental base to apex gradient (p < 0.001). From 13 to 39 weeks of gestation, the global and segmental longitudinal peak systolic velocities increased significantly throughout gestation (p < 0.001), while the global longitudinal peak systolic strain remained constant (p = 0.34) and the strain rate exhibited only a tendency to decrease (p = 0.045). The interobserver and intraobserver variability of the global LV peak systolic strain, strain rate and velocity was acceptable. The standard deviations of measurement error between the two observers were 2.5 %, 0.7 s (-1) and 0.5 cm/sec, respectively. CONCLUSION: The global myocardial peak systolic velocities of the left ventricle increase with gestational age, while the global myocardial peak systolic strain and strain rate remained nearly constant throughout gestation. This novel angle-independent, noninvasive technique offers a new objective approach to quantify global and segmental fetal myocardial performance throughout gestation. PMID- 21294068 TI - The absence of the vomer in the first and early second trimester of pregnancy - a new marker of trisomy 21 and trisomy 13. AB - PURPOSE: The aim of this study was to measure the two frontomaxillo-facial (FMF) angles: the FMF-vomer (FMF-v) and the FMF-palate (FMF-p), and to visualize the vomer in the 1(st) and early 2(nd) trimester, in order to ascertain whether they can be used as markers for trisomy 21 and trisomy 13. MATERIALS AND METHODS: A 2D ultrasound scan was performed in the 340 normal and 12 abnormal pregnancies, using the linear, convex and endovaginal probes. RESULTS: We visualized the FMF angles within 1 to 5 minutes in 253 (72 %) of cases by using the linear probe. FMF-v angle was significantly smaller that the FMF-p angle (79.8 degrees vs. 89.7 degrees , 71.5 degrees vs. 84.5 degrees for the two trimesters, respectively), and that the value of both angles decreased in the second trimester. There was not one single case of trisomy in which vomer could be identified in the 1 (st) and early 2 (nd) trimester. The FMF-p angle failed to present difference between normal cases and the ones with trisomy (89.5 degrees ). There was not one single case of trisomy (21 or 13) in which vomer or FMF-v could be identified in the first or early second trimester. The diagnostic accuracy of vomer as a marker for trisomy was 0.985. CONCLUSION: If the vomer cannot be visualized in the 1 (st) and early 2 (nd) trimester, it is important to check the karyotype, and it is not necessary to measure the FMF-p angle. The high resolution probe (L 12 - 5 Mhz) enables easier assessment of the vomer. PMID- 21294069 TI - Is a routine ultrasound in the third trimester justified? Additional fetal anomalies diagnosed after two previous unremarkable ultrasound examinations. AB - PURPOSE: The detection of fetal structural abnormalities is a routine part of antenatal care. Ultrasound examination policies vary among European countries. An additional ultrasound for fetal structural anomalies in the 3 rd trimester seems important for many reasons. Some abnormalities develop or first become apparent later in pregnancy. The aim of the study was to analyze the rate of previously undetected structural abnormalities in the 3 rd trimester. MATERIALS AND METHODS: 8074 fetuses were examined in this prospective study between 1998 and 2008. All received an examination at 11 - 14 weeks and 79 % (6378 / 8074) of these fetuses also received an ultrasound at 20 - 24 weeks. If both of the examinations did not detect structural abnormalities, the fetuses were included in the study group and received an ultrasound at 28 - 32 weeks (n = 5044). New structural abnormalities in the 3 rd trimester were analyzed. The outcome was available in 96 % of the cases. RESULTS: The overall incidence of fetal malformations was 3.6 % (n = 289), of which 40 % (116 / 289) were diagnosed at 11 - 14 weeks. The following 2nd trimester scan revealed 102 (35 %) new fetal malformations. An additional 44 (15 %) structural abnormalities were found in the 3 rd trimester. These were mainly abnormalities of the urogenital system (n = 18). There were also anomalies of the cardiovascular system (n = 9), the gastrointestinal system (n = 6) and the central nervous system (n = 4). One of the cases had a previously undiagnosed abnormal karyotype. CONCLUSION: The ultrasound examination in the 3 rd trimester is of additional benefit and can detect previously unknown structural abnormalities. These findings are relevant for perinatal management and postnatal follow-up. PMID- 21294070 TI - Video sequence compared to conventional freeze image documentation: a way to improve the sonographic assessment of breast lesions? AB - PURPOSE: To compare video sequence and conventional freeze image documentation of breast ultrasound findings with respect to lesion assessment and the diagnostic power of established ultrasound characteristics. MATERIALS AND METHODS: Digitally stored freeze images and corresponding video sequences of 50 breast lesions were randomly arranged and interpreted by eight investigators with breast ultrasound training and experience. Established ultrasound criteria were documented on a standardized classification form for every lesion. The investigators were blinded to the clinical and radiological findings, patient characteristics including age, and lesion histology. Statistical analysis compared both groups and correlated the results with the lesion histology. A receiver operating characteristics (ROC) analysis was performed to evaluate the diagnostic performance of ultrasound criteria in lesions documented by video sequences compared to freeze images. RESULTS: Breast lesions were assessed almost identically in video sequences and freeze images. Only the features echogenic halo, orientation, and margin varied among both groups. The dynamic features compressibility and mobility were highly statistically significant correlated with the lesion histology in the video sequence interpretation (p < 0.0001). ROC analysis revealed almost identical diagnostic accuracy in both groups (area under the curve 0.719 for video sequences and 0.762 for freeze images). CONCLUSION: Video sequences are an appropriate tool to document lesions in breast ultrasound. In contrast to our hypothesis, however, this tool did not improve the diagnostic power of established ultrasound characteristics compared to freeze image documentation. PMID- 21294071 TI - Contrast-enhanced ultrasound of the injured spleen after embolization--comparison with computed tomography. AB - PURPOSE: The aim of this study was to compare the diagnostic performance of contrast-enhanced ultrasound (CEUS) to computed tomography (CT) in trauma patients after splenic embolization. MATERIALS AND METHODS: 22 patients (17 male and 5 female) with a mean age of 32 (15 - 57 years) were studied with ultrasound (US), CEUS and CT in 23 early follow-up examinations 5 days (range: 0 - 12 days) after intervention and 17 late follow-up examinations 69 days (range: 52 - 189 days) after intervention. Perisplenic fluid, hematoma, laceration, infarction, scars and injury grade were evaluated. US and CEUS readings were performed independently by two radiologist, blinded to the CT results. RESULTS: The sensitivity and specificity for CEUS at early follow-up were 85 % and 70 % for perisplenic fluid, 80 % and 94 % for subcapsular hematomas, 83 % and 73 % or lacerations and 75 % and 87 % for infarctions, respectively. The sensitivity and specificity at late follow-up were 60 % and 100 % for subcapsular hematomas, 91 % and 67 % for intrasplenic hematomas, 100 % and 93 % for lacerations and 89 % and 100 % for scars, respectively. The overall sensitivity and specificity for all lesions were 87 % and 88 % at early follow-up (n = 138) and 85 % and 95 % at late follow-up (n = 102), respectively. Compared to CT, CEUS underestimated the injury grade in 2 / 40 cases and overestimated the injury grade in 3/40 cases. CONCLUSION: CEUS is a useful tool for the detection of post-traumatic lesions. It is comparable to CT in follow-up after splenic embolization and may replace CT in follow-up studies. PMID- 21294072 TI - [Echocardiographic tissue Doppler imaging analysis of the systolic and early diastolic velocities of the mitral annulus motion in hypertrophic cardiomyopathy and in top-level athletes]. AB - BACKGROUND AND OBJECTIVE: Echocardiographic Tissue Doppler Imaging (TDI) has been proposed for the differentiation of pathological left ventricular hypertrophy (e. g. hypertrophic cardiomyopathy, HCM) and physiologic left ventricular hypertrophy (athlete's heart). The aim of this study was the TDI analysis of the systolic (S') and early diastolic (E') velocities in patients (pts.) with non-obstructive hypertrophic cardiomyopathy (HCM) and in top-level athletes in consideration of the previously published cut-off values (S' < 9 cm/s, E' < 9 cm/s). PATIENTS AND METHODS: Pulsed-wave TDI of the systolic and early-diastolic velocities was performed at the lateral and septal mitral annulus in the four-chamber view in 17 HCM pts (12 men; mean age 44 +/- 16 years) and 80 consecutive athletes (80 men; mean age 26 +/- 5 years). RESULTS: Pts with HCM showed significantly decreased systolic velocities of the septal (S' septal: 5.1 +/- 1.2 cm/s versus 9.5 +/- 1.5 cm/s, p < 0.001) and lateral mitral annulus (S' lateral: 6.4 +/- 2.0 cm/s vs. 10.5 +/- 2.1 cm/s, p < 0.001). The early diastolic velocity of the mitral annulus E' was significantly decreased in HCM, too (E' septal: 5.9 +/- 2.2 cm/s vs. 13.1 +/- 2.9 cm/s, p < 0.001; E' lateral: 8.2 +/- 3.0 cm/s vs. 16.5 +/- 3.4 cm/s, p < 0.001). CONCLUSION: Tissue Doppler Imaging of the systolic and early diastolic velocity of the mitral annulus might be helpful as a promising additional method for the echocardiographic differentiation between pathological and physiologic left ventricular hypertrophy. PMID- 21294073 TI - Metabolites of the ellagitannin geraniin and their antioxidant activities. AB - Different types of ellagitannins are reported to have various biological activities, such as antioxidant, antiviral, and antitumor activities. However, there are few definitive studies on the absorption and metabolism of ellagitannins. This review compares the absorption and metabolism of ellagitannins, and the antioxidant properties of their metabolites in rats, with those of intact ellagitannins by means of IN VITRO and IN VIVO assays. We isolated 7 urinary and intestinal microbial metabolites in rats after the ingestion of geraniin, which is a typical ellagitannin isolated from GERANIUM THUNBERGII, an antidiarrheic remedy in Japan. The structures of these metabolites were determined to be dibenzopyran derivatives ( 1- 7), using NMR and mass spectroscopic data. Four major metabolites ( 1- 4) prepared by chemical synthesis were evaluated for their antioxidant activities by using 2,2-diphenyl-1 picrylhydrazyl radical scavenging and oxygen radical absorbance capacity (ORAC) methods. The metabolites exhibited more potent antioxidant activities in the ORAC assay than intact ellagitannins, such as geraniin and corilagin. Furthermore, plasma ORAC scores increased with increases in the plasma concentration of the metabolites after the oral administration of geraniin to rats. These findings suggest that these metabolites may contribute to the health benefits of ellagitannins as antioxidants in the body. PMID- 21294074 TI - Involvement of mitochondrial permeability transition pore opening in 7-xylosyl-10 deacetylpaclitaxel-induced apoptosis. AB - 7-Xylosyl-10-deacetylpaclitaxel is a natural hydrophilic paclitaxel derivative. It has long been used in Chinese clinics to treat cancer. In order to further explore the underlying intracellular target of 7-xylosyl-10-deacetylpaclitaxel towards the PC-3 cell line, the ultra-structural morphology of mitochondria, the intracellular Ca (2+), the intracellular ATP, the intracellular hydrogen peroxide and pro-apoptotic Bax and Bcl-2 protein expression were measured. Additionally, the changes of mitochondrial morphology and membrane potential ( DeltaPsim) were analyzed by atomic force microscopy (AFM) and flow cytometry, respectively. Our results suggest that the intracellular target of 7-xylosyl-10-deacetylpaclitaxel may be the mitochondrial permeability transition pore (mPTP). To further evaluate this hypothesis, we assessed the effect of a specific mPTP inhibitor (cyclosporine A) on the toxic action of 7-xylosyl-10-deacetylpaclitaxel. The 7 xylosyl-10-deacetylpaclitaxel-induced decrease in mitochondrial inner transmembrane potential (DeltaPsim) was abolished by the addition of cyclosporine A (CsA) in PC-3 cells, indicating that 7-xylosyl-10-deacetylpaclitaxel may target mPTP. Furthermore, treatment with 7-xylosyl-10-deacetylpaclitaxel increased ROS levels in PC-3 cells. This effect was counteracted by 10 uM cyclosporine A. These data indicate that oxidative damage is involved in mPTP. PMID- 21294075 TI - Protective effects of isorhynchophylline on cardiac arrhythmias in rats and guinea pigs. AB - As one important constituent extracted from a traditional Chinese medicine, Uncaria Rhynchophylla Miq Jacks, isorhynchophylline has been used to treat hypertension, epilepsy, headache, and other illnesses. Whether isorhynchophylline protects hearts against cardiac arrhythmias is still incompletely investigated. This study was therefore aimed to examine the preventive effects of isorhynchophylline on heart arrhythmias in guinea pigs and rats and then explore their electrophysiological mechanisms. In vivo, ouabain and calcium chloride were used to establish experimental arrhythmic models in guinea pigs and rats. In vitro, the whole-cell patch-lamp technique was used to study the effect of isorhynchophylline on action potential duration and calcium channels in acutely isolated guinea pig and rat cardiomyocytes. The dose of ouabain required to induce cardiac arrhythmias was much larger in guinea pigs administered with isorhynchophylline. Additionally, the onset time of cardiac arrhythmias induced by calcium chloride was prolonged, and the duration was shortened in rats pretreated with isorhynchophylline. The further study showed that isorhynchophylline could significantly decrease action potential duration and inhibit calcium currents in isolated guinea pig and rat cardiomyocytes in a dose dependent manner. In summary, isorhynchophylline played a remarkably preventive role in cardiac arrhythmias through the inhibition of calcium currents in rats and guinea pigs. PMID- 21294076 TI - Antiproliferative constituents of the roots of Conyza canadensis. AB - Bioassay-guided fractionation of the N-hexane and CHCl3 phases of the methanol extract of the roots of Conyza canadensis (L.) Cronquist led to the isolation of two new dihydropyranones named conyzapyranone A (1) and B (2), and the known 4 Z,8 Z-matricaria- gamma-lactone (3), 4 E,8 Z-matricaria- gamma-lactone (4), 9,12,13-trihydroxy-10(E)-octadecenoic acid (5), epifriedelanol (6), friedeline (7), taraxerol (8), simiarenol (9), spinasterol (10), stigmasterol, beta sitosterol, and apigenin. The structures were determined by means of ESIMS and 1D and 2D NMR spectroscopy, including 1H-1H COSY, NOESY, HSQC, and HMBC experiments. The isolated compounds were evaluated for their antiproliferative activities and were demonstrated to exert considerable cell growth-inhibitory activity against human cervix adenocarcinoma (HeLa), skin carcinoma (A431), and breast adenocarcinoma (MCF-7) cells. Some of the active components, including 2, 4, and 10, proved to be substantially more potent against these cell lines than against noncancerous human foetal fibroblasts (MRC-5) and can therefore be considered selective antiproliferative natural products. PMID- 21294077 TI - Hydroxyframoside B, a secoiridoid of Fraxinus rhynchophylla, inhibits adipocyte differentiation in 3T3-L1 cells. AB - Fraxinus rhynchophylla showed significant inhibitory activity on adipocyte differentiation in the 3T3-L1 preadipocyte cell line as assessed by measuring fat accumulation using Oil Red O staining. Further fractionation led to the isolation of two secoiridoids, oleuropein and hydroxyframoside B. Hydroxyframoside B significantly reduced fat accumulation and triglyceride content in differentiated 3T3-L1 cells without affecting cell viability, whereas oleuropein showed little effect. Further studies with interval treatment demonstrated that hydroxyframoside B exerted inhibitory activity on adipocyte differentiation when treated within 2 days (days 0-2) after differentiation induction. In addition, hydroxyframoside B significantly blocked the induction of adipogenic transcription factors such as C/EBP alpha, C/EBP beta, and PPAR gamma. Taken together, these results suggest that hydroxyframoside B inhibited early/middle stage of adipogenic differentiation, in part, via inhibition of C/EBP alpha, C/EBP beta, and PPAR gamma-dependent pathways. PMID- 21294078 TI - [Lung function testing in children before and after an age-adapted SCUBA dive in a swimming pool]. AB - BACKGROUND: The number of children that SCUBA dive is increasing. Airway narrowing while SCUBA diving can cause dangerous complications like pulmonary barotrauma and arterial gas embolism. Statistics show that children are at an increased risk. Since data are scarce, the goal of this study was to gain new knowledge about acute lung function changes in children while SCUBA diving. MATERIAL AND METHODS: 41 children aged 8 - 14 years underwent lung function testing (spirometry and residual volume measurement) before and after a single age-adapted SCUBA dive in a swimming pool. RESULTS: A significant reduction of the dynamic expiratory lung function parameters FEV (1) (p < 0.01), FEV (1)/VC (p < 0.05), MEF 75 % (p < 0.05), MEF 50 % (p < 0.01) und MEF 25 % (p < 0.05) was measured. No statistically significant change of the residual volume was found. A decrease of FEV (1) > 10 % (12 % - 21 %) was found in 5 children (12.2 %). CONCLUSION: The majority of the children (87.8 %) did not show any relevant lung function changes. Five children had a considerable reduction of FEV (1). Signs indicate the importance of bronchial hyperreactivity (BHR) as a key factor. Children with asthma or BHR should not SCUBA dive. A detailed medical examination is recommended (including an unspecific bronchial provocation test) before starting to dive. PMID- 21294079 TI - [Prevention of occupational airway diseases: interdisciplinary guideline of the German Society for Occupational and Environmental Medicine]. PMID- 21294080 TI - [The burden of acute gastrointestinal illness in Hesse--a telephone survey]. AB - INTRODUCTION: Mandatory notifications of laboratory diagnosed cases of acute gastroenteritis are essential for public health surveillance of food-borne diseases; however, reported cases represent a subset of infection in the community. We aimed to determine the magnitude and distribution of self-reported, acute gastrointestinal illness in Hesse, Germany, and to describe factors associated with seeking medical care. METHODS: We conducted a retrospective, cross-sectional telephone survey in 4 551 randomly selected households from September 2004 to August 2006. We used a standardised questionnaire to collect data on the interview partner and all children <= 15 years living in the household. The case definition was 3 or more loose stools or any vomiting in 24 h, during the 4 weeks preceding the interview, but excluding those with non infectious causes. Frequency data were weighted to the Hessian population. RESULTS: Among the contacted households, 81% participated. 137 of the 2 100 children <= 15 years met the case definition, yielding an adjusted annual incidence rate of 0.86 (95% CI 0.72-1.03) episodes per person-year. 167 of the 4 551 study participants >= 16 years met the case definition, yielding an adjusted annual incidence rate of 0.46 (95% CI 0.37-0.51) episodes per person-year. This extrapolates to 807 000 (95% CI 672 000-962 000) cases of acute gastroenteritis in Hesse each year for children <= 15 years of age and 2 225 000 (95% CI 1 880 000-2 625 000) cases in individuals >= 16 years. On multivariate analysis, among individuals aged <= 15 years with an acute gastroenteritis, factors associated with seeking medical care included age, vomiting >= 3 times in 24 h, fever, and duration of illness. Among cases >= 16 years, duration of illness was associated with seeking medical care. Of those seeking medical care, 15% provided a stool sample. CONCLUSION: Acute gastrointestinal illness appears to pose a significant burden in the Hessian population. Cases of acute gastrointestinal illness ascertained through laboratory-based public health surveillance likely differ systematically from unreported cases. Further research into the pathogen-specific burden is needed to better target intervention strategies. PMID- 21294081 TI - [Health-related quality of life after surgical haemorrhoid treatment - results, methods and problems]. AB - In patients suffering from haemorrhoidal disease a hyperplasia of the corpus cavernosum recti is accompanied by various symptoms such as anal bleeding and minor continence disorders as well as itching, soiling and burning. According to the morphological findings, haemorrhoids are staged from grade I up to IV. Therapy strategies are adjusted to this staging. Early stages are treated by conservative measures, such as regulation of defaecation, sclerosis and rubber band ligations. Advanced stages require operative methods, such as segmental excision and stapled haemorrhoidopexy. Since patients demand a greater regard to the subjective experience of their disease and its treatment, quality of life evaluation has become an important issue in medical care. Therefore health related quality of life is increasingly becoming a relevant primary or secondary end point of clinical studies. Since up to 4 % of the general adult population in industrial nations is annually diagnosed to suffer from haemorrhoidal disease, in Germany per annum 3.5 Mio patients seek medical advice due to this condition and 40 000-50 000 surgical procedures are performed. Nevertheless only very few studies have been carried out to investigate the influence of this widespread disease on the quality of life of those patients. Additionally cost-effectiveness analyses measuring quality-adjusted life years are becoming more and more decisive in health politics. The present article discusses the definitions of health-related as well as disease-related quality of life. Different psychometric tests applied to evaluate the quality of life are summarised, quality criteria are outlined and limitations discussed. Several studies were analysed in regard to the quality of life in patients with haemorrhoidal disease and the specific influence of different operative techniques was reviewed. PMID- 21294082 TI - [Surgery in medical ambulatory care centres: trends and developments]. PMID- 21294083 TI - [Surgical treatment of extravasation injuries]. AB - OBJECTIVE: Extravasations account for most iatrogenic injuries. The aim of the study was to analyse the results of surgery in patients with extravasations and to draw conclusions for future treatment. MATERIALS AND METHODS: 24 patients with soft-tissue defects after extravasations were treated between 1999 and 2009 in our hospital. The cases were analysed retrospectively. We looked at the drugs causing tissue necrosis and the localisation in relation to the number of interventions and reconstruction complexity. RESULTS: In 83 % (n = 20) of cases tissue necrosis was caused by chemotherapeutic agents, in 8 % (n = 2) by contrast mediums and in 4 % (n = 1) by antibiotics and insulin. 70 % of the cases involved the upper extremity, in 30 % the thoracic wall was affected. 38 % of the extravasations occurred over venous access ports. In mean 2 +/- 1.5 interventions were necessary for defect coverage. Two patients died as a direct result of the extravasations, one due to sepsis originating from an infected necrosis area and one due to right-heart failure with prior pulmonary damage. CONCLUSION: Most extravasations can be treated without surgery. In cases of toxic extravasations or pressure-caused ischaemia rapid surgical intervention is necessary to prevent the necrosis progressing to deeper tissue layers. PMID- 21294084 TI - Effects of the hippocampal deep brain stimulation on cortical epileptic discharges in penicillin - induced epilepsy model in rats. AB - AIM: Experimental and clinical studies have revealed that hippocampal DBS can control epileptic activity, but the mechanism of action is obscure and optimal stimulation parameters are not clearly defined. The aim was to evaluate the effects of high frequency hippocampal stimulation on cortical epileptic activity in penicillin-induced epilepsy model. MATERIAL AND METHODS: Twenty-five Sprague Dawley rats were implanted DBS electrodes. In group-1 (n=10) hippocampal DBS was off and in the group-2 (n=10) hippocampal DBS was on (185 Hz, 0.5V, 1V, 2V, and 5V for 60 sec) following penicillin G injection intracortically. In the control group hippocampal DBS was on following 8 MUl saline injection intracortically. EEG recordings were obtained before and 15 minutes following penicillin-G injection, and at 10th minutes following each stimulus for analysis in terms of frequency, amplitude, and power spectrum. RESULTS: High frequency hippocampal DBS suppressed the acute penicillin-induced cortical epileptic activity independent from stimulus intensity. In the control group, hippocampal stimulation alone lead only to diffuse slowing of cerebral bioelectrical activity at 5V stimulation. CONCLUSION: Our results revealed that continuous high frequency stimulation of the hippocampus suppressed acute cortical epileptic activity effectively without causing secondary epileptic discharges. These results are important in terms of defining the optimal parameters of hippocampal DBS in patients with epilepsy. PMID- 21294085 TI - Meta-analyses of intracerebral hematoma treatment. AB - AIM: The aim of this study is to define the position of surgery preference in the treatment choice for spontaneous intracerebral hematoma (ICH) and to compare the efficacy of surgery with the medical treatment based on data from 18 previously reported randomized prospective studies on this topic. MATERIAL AND METHODS: Literature databases and articles were searched from 1960 to 2010. Eighteen randomized studies on this topic were evaluated. RESULTS: Among these 18 studies, 7 (38.9%) were multicenter and 11 (61.1%) were single center. Totally 204 centers were involved. 1769 patients were treated surgically and 3200 medically. Craniotomy was the most preferred method (n = 14; 77.8%). Follow-up time was mostly 6 months. In general, the effect of surgical versus medical treatment on outcome (mortality/morbidity) after a supratentorial spontaneous ICH do not differ significantly. In individual analysis, the mortality was found to be significantly lower in the operated group than the nonoperated group in only two studies (Kurtsoy's and Miller's studies). Meta-analysis of subgroup analysis revealed surgical treatment results were significantly better for hematoma volume > 40 ml, early surgery (before 24 hours), and Glasgow Coma Scale (GCS)>= 6. CONCLUSION: Surgical treatment results were found to be superior to medical treatment in cases with hematoma volume > 40 ml, and GCS >= 6. The studies are not adequate to analyze the best type of surgery. PMID- 21294086 TI - The management in the C2-C3 disc herniations: a clinical study. AB - AIM: Cervical disc herniation at C2-C3 level is an uncommon condition. In this paper, the management C2-C3 disc herniation and long-term follow-up data of 5 cases is reported. MATERIAL AND METHODS: 1100 patients who have been operated in our department for cervical disc herniation between 2000 and 2009 were studied retrospectively. A total of 5 patients were found to have been operated for C2-C3 herniation in that period . The preferred procedure was anterior cervical discectomy with fusion via retropharyngeal approach. RESULTS: The incidence of C2 C3 disc herniations was 0.45%. The mean patient age was 63 years (41- 82 years). Upper extremity paresis was the predominant neurological sign. Magnetic resonance images (MRI) revealed central, large and hard disc herniations in 4 cases and accompanying cord signal changes in 4 cases. Successful anterior decompresion was performed in 5 patients. Correct fusion was achieved in 4 patients, and one patient died of an operation unrelated cause early in the follow-up period. CONCLUSION: C2-C3 disc herniation is rare but may result with severe myelopathy. This kind of herniations tend to be central and large. The present study demonstrates that diagnosis and adequate anterior decompression in C2-C3 disc herniations may provide an excellent outcome. PMID- 21294087 TI - Benign cerebellar pilocytic astrocytomas in children. AB - AIM: Cerebellar astrocytomas are benign tumors of the central nervous system. They represent 10% of all pediatric intracranial brain tumors and 30% of all pediatric posterior fossa tumors especially in the first two decades of life. MATERIAL AND METHODS: We reviewed the medical records of patients; age at the time of surgery, pre- and post operative magnetic resonance imaging (MRI), localisation of the tumor, hydrocephalus, surgical approach, pre- and post operative neurological status, post operative adjuvant therapy and outcome were documented. RESULTS: The male to female ratio was 20/11. Age at the time of evaluation ranged from 3 to 23 years. Age at the time of surgery ranged from 1 to 18 years. Follow-up duration after surgery was 1-12 years. 55% of these tumors were located at the cerebellar vermis and 45% were at the cerebellar hemispheres. Complete surgical resection was done in 74% of these patients. 5 patients had a second operation because of residual tumor. Ventriculoperitoneal shunt insertion was performed in 3 of 31 patients because of symptomatic hydrocephalus and 1 patient had an endoscopic third ventriculostomy pre-operatively. 90% of these patients had no neurological sequelae at follow-up evaluation. CONCLUSION: Cerebellar astrocytomas are benign tumors where total resection is possible in the majority of cases with an excellent outcome. PMID- 21294088 TI - Immunohistochemical expression of cycloxygenase-2 in astrocytoma: correlation with angiogenesis, tumor progression and survival. AB - AIM: Cyclooxygenase-2 (Cox-2) appears to play a role in the regulation of progression, invasiveness and angiogenesis of various neoplasms. Experimental studies have indicated that COX-2 regulate angiogenesis by modulating vascular endothelial growth factor (VEGF) production. The aim of this study was to evaluate the immunohistochemical expression of COX-2 in astrocytoma, in relation to VEGF expression, microvessel density (MVD), clinicopathologic factors and patient survival. MATERIAL AND METHODS: 26 paraffin blocks of astrocytoma, with representative tissues and sufficient follow-up data, were evaluated immunohistochemically for protein marker expression. RESULTS: COX-2 expression was detected in 21 (80.7%) of 26 astrocytomas with an increased expression in grade IV (100%) as compared to grades II (63.6%) and III (83.3%) (p < 0.001), (r=0.64). A positive correlation was observed between the immunoreactive scores of COX-2, VEGF (p < 0.001), (r=0.61) and MVD (p < 0.001), (r=0.72). Also COX-2 expression was significantly associated with poor survival (p < 0.001), (r=0.58), but did not show significant difference among patient age, sex and tumor location. CONCLUSION: COX-2 is up-regulated in the majority of high-grade astrocytomas and may contribute to astrocytic tumorigenesis by promoting new vessel formation. Moreover, increased COX-2 expression is a significant negative predictor of survival. COX-2 inhibitors may represent an important therapeutic target. PMID- 21294089 TI - Occipital emissary foramina in human skulls: an anatomical investigation with reference to surgical anatomy of emissary veins. AB - AIM: The objectives were to find the incidence and topography of the occipital emissary foramina in skulls of South Indian Region. MATERIAL AND METHODS: In the present study, 78 dried adult human skulls were examined. They were analyzed for the gross incidence and position of the occipital emissary foramen. The observations were made in the squamous part of the occipital bone from the posterior margin of the foramen magnum to the external occipital protuberance. RESULTS: From our observations, the occipital emissary foramen was present in 11 (14.1%) skulls. Left sided foramen was observed in 5 cases (6.4%), right-sided foramen in 4 (5.1%) and the median foramen was seen in 2 (2.6%) of the cases. CONCLUSION: The occipital emissary vein is present in a small percentage (14.1%) of cases. It was also demonstrated that its location is variable as to left, right or midline. Its location was closer to the foramen magnum than to the external occipital protuberance in all the specimens. The morphology of this subject is important to the neurosurgeons and plastic surgeons. The knowledge is of importance in suboccipital craniotomies as this foramen transmits the occipital emissary vein and will keep awareness among the surgeons to avoid the excessive bleeding. PMID- 21294090 TI - Primary CNS lymphoma in immunocompetent: a review of literature and our experience from Kashmir. AB - AIM: To study the clinicopathological aspects of primary CNS lymphoma in immunocompetent patients. MATERIAL AND METHODS: Sixteen patients with primary CNS lymphoma were analyzed for their clinico-pathological characteristics and followed-up for the treatment and subsequent management in Neurosurgery, and Medical and Radiation Oncology. RESULTS: The fronto-parietal region was the commonest location of CNS lymphoma; four cases of cerebellar lymphoma were seen. Our patients were relatively young with a mean age of 48 years and an age range of 35-60 years. Females outnumbered males with a ratio of 2.7:1. The commonest presentation was focal neurological-deficits and features of raised intracranial pressure. All the patients histologically had diffuse large B-cell lymphoma. Radiologically, most presented as disc-enhancing lesions. Two patients had multiple lesions. Most of the patients (10) died within a mean of 4.4 months (range 2 weeks-16 months). CONCLUSION: Primary CNS lymphoma is seen in immunocompetent patients as well. Relapse is common after treatment and the overall prognosis is unfavorable. PMID- 21294091 TI - Long-term outcomes of percutaneous retrogasserian glycerol rhizotomy in 3370 patients with trigeminal neuralgia. AB - AIM: To assess the long-term outcomes of percutaneous retrogasserian glycerol rhizotomy (PRGR) in patients with medically unresponsive idiopathic trigeminal neuralgia. MATERIAL AND METHODS: A total of 3370 patients undergoing PRGR between 1983 and 2003 in our hospital were followed up for 13.1 years (range 3-23 years), and the outcomes were investigated. RESULTS: Of the 3370 patients, 99.58% had complete initial pain relief. A total of 2750 patients were followed up when 112 died of unrelated causes and 508 were lost to follow up. Of the 2750 patients, 962 (35%) had pain recurrence at various intervals: 0.3% in 1 year; 21% in 1 to 5 years; 7% in 5 to 10 years; 4% in 10 to 15 years and 3% in 15 to 23 years. The major complication was facial numbness, among which hypesthesia outweighed hypalgesia. Most patients recovered within half a year, although 109 patients (3.96%) developed permanent mild hypesthesia. There was no anesthesia dolorosa or surgery related mortality in this series. CONCLUSION: PRGR is a minimally invasive and simple procedure yielding a favorable outcome for trigeminal neuralgia. The major complications of this procedure are reversible within various time intervals. It may serve as a first-line surgical modality for patients unresponsive to pharmacotherapy. PMID- 21294092 TI - Clipping of large and giant aneurysms of anterior circulation. AB - AIM: Surgical outcome for giant intracranial aneurysms (GIA) is suboptimal. Reasons for higher complication rates in large and GIA surgery are the occlusion of perforators or parent arteries during aneurysm clipping, or prolonged temporary occlusion of main arteries. In this article, results of clipping of large and GIAs of anterior circulation are presented. MATERIAL AND METHODS: Ten patients with large or GIAs in the anterior circulation were treated by clipping (10/19, 52%). The most common location was the middle cerebral artery (MCA, 5/10), followed by the anterior cerebral artery (ACA, 3/10), and internal carotid artery (ICA, 2/10). Five aneurysms were large (17-20 mm), five were giant (27-53 mm). RESULTS: Uneventful aneurysm clipping was performed in eight, and cure was obtained in nine patients. Mortality and morbidity figures were 10% (1/10), and 0% (0/10), respectively. Mean follow up time is 2.8 years (range 1-10 years). CONCLUSION: Clipping is still the most common surgical method of dealing with these lesions. Clipping of all large and giant aneurysms of anterior circulation was achieved in our patients with 10% mortality and 0% morbidity rates. These rates are similar to figures reported in previous series. Clipping of large and giant aneurysms is still the best definitive treatment, and is applicable in majority of the patients. PMID- 21294093 TI - Outcomes of intrathecal baclofen (ITB) therapy in spacticity. AB - AIM: Spasticity is associated with various neurological conditions. Intrathecal baclofen (ITB) is one of the popular treatments for severe spasticity. In this paper we present our experience in treating 30 patients with both spinal and supraspinal spasticity with chronic infusion of Baclofen to evaluate the long term efficacy of this treatment on spasticity, disability and pain, and to evaluate the side effects of intrathecal Baclofen. MATERIAL AND METHODS: The medical records of 30 patients who underwent baclofen pump placement from 2000 to 2010 under Department of Neurosurgery at the University of Akdeniz at Antalya/Turkey, were reviewed. All study subjects had diffuse chronic, severe, and generalized spasticity (Ashworth score >= 3), and had shown inadequate response to various oral antispastic drugs including baclofen. All patients were evaluated by means of the Ashworth score, spasm frequency, Barthel index, Rankin scales and VAS. RESULTS: Spasticity and spasm frequency and pain scores were clinically and statistically decreased in all patients. CONCLUSION: ITB therapy increases the quality of lifestyle and functional independence by reducing not only cerebral but also spinal related spasticity in appropriately selected cases. PMID- 21294094 TI - Cerebro-spinal fluid shunt revisions, importance of the symptoms and shunt structure. AB - AIM: CSF shunt failure is still a frequent problem in children. This prospective study was designed for focusing symptoms and reasons of shunt failure. We also especially focused on the mechanical reasons of shunt failure. MATERIAL AND METHODS: We focused on the causes of shunt failures, and the symptoms and signs in patients who were operated for shunt malfunction between January 1, 2001 and December 31, 2005 in the neurosurgery department. All examination and operative data were collected prospectively. Evaluation of these data was with the chi square and Fisher exact tests. RESULTS: After the evaluation of data on 111 patients and 153 revision procedures, the major symptoms in this group were vomiting (62.16%), somnolence (59.45%) and headache (48.64%). In the majority of the shunt revisions (115 operations, 75.2% of the all 153 procedures), one or more mechanical problems of the shunt systems were identified in surgery. CONCLUSION: Shunt failures in children sometimes appear with very unusual symptoms. Also, probable structural problems of the shunt systems seem very important for shunt failure according to patient characteristics and etiology of the hydrocephalus. A systematic approach including CT, shunt series and abdominal ultrasound is needed to rule out shunt malfunction. PMID- 21294095 TI - Spontaneous pyogenic spinal epidural abscess. AB - AIM: Spontaneous pyogenic spinal epidural abscess (SEA) is a rare condition but might be devastating and fatal. Traditional treatment is surgical decompression and antibiotics. A retrospective study was designed to assess the eff ect of clinical findings and treatment methods on the outcome. MATERIAL AND METHODS: 14 patients were reviewed (10 male, 4 female, mean age 59.14). Six dorsal, seven ventral and one dorsal with ventral SEA were observed. SEA found in thoracal (5), lumbar (4), cervical (3) regions. One patient showed both cervical and thoracal and one patient showed cervical, thoracal and lumbar involvement. All patients received minimum 3 weeks of I.V., followed by minimum 3 weeks of oral antibiotics. All patients complained of spinal pain. Ten patients presented with fever. Neurological deficit was observed in 9 cases. RESULTS: A total of 22 interventions was performed. Instrumentation was applied in 5 cases. Full recovery was achieved in 7 patients, significant improvement was observed in 5 patients. The neurological findings did not change in one patient. One mortality and one morbidity were observed. CONCLUSION: Spontaneous SEA is a rare disease but might result in catastrophic neurological deficits and fatal even with prompt treatment. Therefore, one should always keep SEA in mind if a patient presents with fever, vague and spinal pain. PMID- 21294096 TI - Multiple aneurysms associated with agenesis of internal carotid artery. AB - Agenesis of internal carotid artery (ICA) is a rare anomaly. The contralateral dominant artery has a high incidence of aneurysms. A 50-year-old male patient had aneurysmal subarachnoid hemorrhage due to rupture of a paraclinoid aneurysm. He also had an anterior communicating artery (Acom) aneurysm and the contralateral ICA was absent. To the best of the authors knowledge, the combination of agenesis of unilateral internal carotid artery with the unique association of a paraclinoid and an Acom aneurysm has not been previously reported. A meticulous assessment of the collateral blood circulation prior to surgery is mandatory in these cases for avoiding postoperative ischemic injury. PMID- 21294097 TI - Transfacial approach, pedicled rhinotomy for a clival chordoma: a technical report. AB - Clival chordomas are frequently midline structures. Due to their critical location, invasive nature and aggressive recurrences, skull base chordomas are difficult to manage surgically. We present a case operated on with the pedicled transnasal and transfacial approach. The case presented with neurological deficits as cranial nerve palsy and findings of brainstem compression. The lesion was removed without any neurological deficit. Her deficits related to brainstem compression regressed after surgery. In our case, a large exposure was achieved through a lateral nasal incision in order to excise the tumor totally with acceptable cosmetic results, and a successful outcome was observed during the postoperative follow-up period with the surgical procedure applied. PMID- 21294098 TI - Spontaneus resolution of a traumatic vertebral artery pseudoaneurysm. AB - Injuries of the vertebral artery are rare and are usually seen after penetrating or blunt cervical trauma. Vertebral artery injuries (VAI) have been reported in 0.5% of blunt trauma cases. These injuries can lead to hemorrhage, thrombosis, arteriovenous fistula or traumatic pseudoaneurysm in the early or late period. They must be treated carefully due to their increased risk of morbidity and mortality. In this case report, we present a case of asymptomatic traumatic vertebral artery pseudoaneurysm(TVAP) seen after cervical spinal trauma with C5 C6 listhesis developing afterwards, treated with anterior-posterior stabilization and fusion. Spontaneous resolution of the pseudoaneurysm is demonstrated by vertebral arter angiogrphy. PMID- 21294099 TI - Intracerebral hematoma following lumboperitoneal shunt insertion: a rare case report. AB - Lumboperitoneal shunting is widely used for the surgical management of pseudotumor cerebri and other pathologies such as communicating hydrocephalus. Although it is a safe method, it could be associated with complications including subarachnoid hemorrhage, subdural and rarely intracerebral hematoma. A 44-year old female applied to our clinic with complaints of severe headache, retroorbital pain and blurred vision. Lumbar puncture demonstrated cerebrospinal fluid opening pressure of cmH2O. A non-programmable lumboperitoneal shunt with two distal slit valves was inserted due to pseudotumor cerebri. She deteriorated shortly after surgery. Immediate cranial computed tomography scan revealed a right parietal intracerebral hematoma. Development of intracerebral hematoma following lumboperitoneal shunt is a rare complication. We discuss this rare event accompanied by the literature. PMID- 21294100 TI - Congenital hypoplasia of the posterior arch of the atlas: case report and extensive review of the literature. AB - Congenital hypoplasia of the posterior arch of the atlas (C1), a developmental failure of chondrogenesis, is a rare anomaly and may range from partial clefts to total agenesis of the posterior arch. Ossification of the posterior arch usually occurs between the 3rd and 5th years of life. The incidence of posterior arch anomalies of the atlas is between 0.69% and 2.95%. For the evaluation of the patient, cervical lateral plain radiography, 2D or 3D reconstructed CT and MRI are very useful and important tools in initial diagnosis. Surgery is the treatment of choice in symptomatic compression. Excision of the posterior arch is performed. during surgery. After the surgery, patients may be followed up for instability and treated as necessary. A patient, admitted to the emergency department with head and neck trauma after a traffic accident is presented in this article. C1 hypoplasia was determined after detailed imagining studies and the radiology department consulted. When upper cervical anomalies are found in a young patient, the patient should be evaluated in detail with advanced radiological studies to avoid misinterpretation as fractures, luxation, osteolysis or instability. Consulting a radiologist could help making an accurate diagnosis and deciding on current therapeutic interventions. PMID- 21294101 TI - Ossifying fibroma of the lumbar spine: case report. AB - Ossifying fibroma of the vertebra is a very rare condition. We report a 16-year old boy with ossifying fibroma of the third lumbar vertebra. Neurological and laboratory examinations demonstrated normal findings. Low-back pain, in the absence of radicular pain, was the presenting symptom. Plain radiography and computerized tomography scanning revealed an osteolytic lesion. The tumor in the third lumbar vertebra was curetted and filled with bone allograft. The histopathological diagnosis was consistent with ossifying fibroma. There was no postoperative complication. The case is the second to be reported. The clinical and radiological aspects of this rare tumor are discussed with the pertinent literature. PMID- 21294102 TI - Traumatic intraventricular hemorrhage with a good prognosis. AB - We report a 10-year-old girl with an isolated traumatic intraventricular hemorrhage following a traffic accident, who had a good prognosis. Her neurological examination upon arrival was normal and she had no complaint other than headache and vomiting. Computed tomography on admission showed a hemorrhage in the lateral and fourth ventricles. She had a Glasgow Coma Score of 15, and she was thus given only antiepileptic drugs for prophylaxis and followed. Computed tomography that was repeated 5 days after admission showed no blood and all ventricles were of normal size. There was no vascular pathology on magnetic resonance imaging and magnetic resonance angiography. The patient remains well 5 months after her accident. Intraventricular hemorrhage does not always have a poor prognosis. PMID- 21294103 TI - Tumoral calcinosis and epidural lipomatosis of the lumbar spine. AB - Lumbar spinal tumoral calcinosis and spinal epidural lipomatosis are rare conditions. We present a 70-year-old female patient with serology negative spondyloarthropathy who developed paresis due to tumoral calcinosis in the left facet joint between L5 and S1 levels and spinal epidural lipomatosis at L5 and S1 levels. Surgery was performed to excise the lesions en bloc. Neural decompression was provided. Neurological symptoms improved after surgery. Here, we report the first serology negative spondyloarthropathy case that had concomitant development of tumoral calcinosis and spinal epidural lipomatosis. PMID- 21294104 TI - CT findings of a thoracic vertebral hemangioma presenting with acute neurological symptoms. AB - Vertebral body hemangiomas are benign lesions and account for 4% of all spinal tumors. The most common histological type is cavernous hemangioma. These tumors generally locate in the vertebral body as a solitary lesion. Multiple lesions are seen in approximately 25-30% of vertebral hemangiomas. Mostly they are asymptomatic and incidentally found with radiological studies. Symptomatic vertebral hemangiomas are rare and represent < 1% of all hemangiomas; however, if untreated, they may cause local or radicular pain and neurological deficits ranging from myeloradiculopathy to paralysis. In this case we aim to present preoperative and postoperative Computed Tomography findings of a cavernous hemangioma that caused sudden motor deficit and was localised to the thoracic vertebra corpus and posterior elements. PMID- 21294105 TI - Metamizole is not as safe as we think or assume. PMID- 21294107 TI - To improve outcomes we must define and measure them: toward defining remission in rheumatoid arthritis. PMID- 21294106 TI - American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. AB - OBJECTIVE: Remission in rheumatoid arthritis (RA) is an increasingly attainable goal, but there is no widely used definition of remission that is stringent but achievable and could be applied uniformly as an outcome measure in clinical trials. This work was undertaken to develop such a definition. METHODS: A committee consisting of members of the American College of Rheumatology, the European League Against Rheumatism, and the Outcome Measures in Rheumatology Initiative met to guide the process and review prespecified analyses from RA clinical trials. The committee requested a stringent definition (little, if any, active disease) and decided to use core set measures including, as a minimum, joint counts and levels of an acute-phase reactant to define remission. Members were surveyed to select the level of each core set measure that would be consistent with remission. Candidate definitions of remission were tested, including those that constituted a number of individual measures of remission (Boolean approach) as well as definitions using disease activity indexes. To select a definition of remission, trial data were analyzed to examine the added contribution of patient-reported outcomes and the ability of candidate measures to predict later good radiographic and functional outcomes. RESULTS: Survey results for the definition of remission suggested indexes at published thresholds and a count of core set measures, with each measure scored as 1 or less (e.g., tender and swollen joint counts, C-reactive protein [CRP] level, and global assessments on a 0-10 scale). Analyses suggested the need to include a patient reported measure. Examination of 2-year followup data suggested that many candidate definitions performed comparably in terms of predicting later good radiographic and functional outcomes, although 28-joint Disease Activity Score based measures of remission did not predict good radiographic outcomes as well as the other candidate definitions did. Given these and other considerations, we propose that a patient's RA can be defined as being in remission based on one of two definitions: (a) when scores on the tender joint count, swollen joint count, CRP (in mg/dl), and patient global assessment (0-10 scale) are all <= 1, or (b) when the score on the Simplified Disease Activity Index is <= 3.3. CONCLUSION: We propose two new definitions of remission, both of which can be uniformly applied and widely used in RA clinical trials. We recommend that one of these be selected as an outcome measure in each trial and that the results on both be reported for each trial. PMID- 21294108 TI - Force spectroscopy of chromatin fibers: extracting energetics and structural information from Monte Carlo simulations. AB - The folding of the nucleosome chain into a chromatin fiber is a central factor for controlling the DNA access of protein factors involved in transcription, DNA replication and repair. Force spectroscopy experiments with chromatin fibers are ideally suited to dissect the interactions that drive this process, and to probe the underlying fiber conformation. However, the interpretation of the experimental data is fraught with difficulties due to the complex interplay of the nucleosome geometry and the different energy terms involved. Here, we apply a Monte Carlo simulation approach to derive virtual chromatin fiber force spectroscopy curves. In the simulations, the effect of the nucleosome geometry, repeat length, nucleosome-nucleosome interaction potential, and the unwrapping of the DNA from the histone protein core on the shape of the force-extension curves was investigated. These simulations provide a framework for the evaluation of experimental data sets. We demonstrate how the relative contributions of DNA bending and twisting, nucleosome unstacking and unwrapping the nucleosomal DNA from the histone octamer can be dissected for a given fiber geometry. PMID- 21294109 TI - The unique plant RhoGAPs are dimeric and contain a CRIB motif required for affinity and specificity towards cognate small G proteins. AB - Plant Rho proteins (ROPs) are inactivated by specific GTPase activating proteins, called RopGAPs. Many of these comprise the exclusive combination of a classic, catalytic Arg-containing RhoGAP domain, and a Cdc42/ Rac interactive binding (CRIB) motif which in animal and fungi has been identified in effectors for Cdc42 and Rac1, but never in any GAP protein. Both elements are required for an efficient RopGAP activity. Here, we analyzed the effect of the CRIB motif on the complex formation and the binding reaction with plant and human Rho proteins by using kinetic and equilibrium methods. We show that RopGAP2 from Arabidopsis thaliana dimerizes via its GAP domain and forms a 2:2 complex with ROP. The CRIB effector motif mediates high affinity and specificity in binding. The catalytic Arg in the context of the CRIB motif is inhibitory for binding. The unusually slow association and dissociation reactions suggest a major conformational change whereby the CRIB motif functions as a lid for binding and/or release of ROP. We propose a two-site interaction model where ROP binds to the CRIB motif as described for the human CRIB effectors and to the catalytic GAP domain as described for animal RhoGAPs. PMID- 21294110 TI - Impact of ligand density on the optimization of ion-exchange membrane chromatography for viral vector purification. AB - The effect of ligand density on anion-exchange membrane chromatography (AEXmc) for the purification of recombinant baculoviruses (rBVs), potential viral vectors in clinical applications, is studied by surface plasmon resonance on customized AEX surfaces and gradient elution experiments on Sartobind D membrane prototypes with different diethylamine ligand densities, complemented by dynamic light scattering analysis for estimation of the hydrodynamic particle size of the various biologics. A chromatographic-column model based on the steric mass action model of ion exchange is employed to analyze the gradient-elution AEXmc experiments, extrapolate the results to other operating conditions, and provide directions for process improvement. Although counterintuitively, the experimental evidence provided in this study shows that the lowering of ligand density is beneficial for rBV purification by AEXmc in bind-and-elute-mode, because it decreases the residual concentrations of host cell protein, dsDNA, and non infective rBVs in the eluted product cut, and increases the overall yield by roughly 20% over current standard values. Overall, we present a case study on how rational design can streamline downstream process development. PMID- 21294111 TI - Relevance of lymph node metastasis along the superior mesenteric vein in gastric cancer. AB - BACKGROUND: The purpose of this study was to evaluate the prognostic value of lymph node metastasis along the superior mesenteric vein (station 14v) to determine the need for 14v dissection in gastric cancer surgery. METHODS: A total of 1104 patients with gastric cancer who underwent gastrectomy including 14v dissection were enrolled. Patients were categorized into two groups: those with and those without 14v lymph node involvement by metastasis. RESULTS: Of the total study population, 73 patients (6.6 per cent) had 14v-positive gastric cancer. These patients were more likely to have advanced tumour (T), node (N) and distant metastatic (M) status, and histologically undifferentiated gastric cancers. The 3 and 5-year survival rates of patients with 14v-positive disease were 24 and 9 per cent respectively. Survival in this group was similar to that of patients who had gastric cancer with distant metastasis (M1). Multivariable analysis demonstrated that 14v status was a significant prognostic factor for gastric cancer (hazard ratio 2.13; P < 0.001). After histologically complete (R0) resection, the overall survival of 14v-positive patients with any stage of cancer was significantly worse than that for 14v-negative patients with stage IV cancer (P = 0.006). CONCLUSION: 14v status is an independent prognostic factor for gastric cancer, with 14v-positive gastric cancer having a poor prognosis, similar to that of M1 disease. The exclusion of 14v in regional lymph node dissection should be considered. PMID- 21294112 TI - New data on BRCA mutations and prophylactic surgeries. PMID- 21294114 TI - Experts weigh in on BRCA1/2 mutations and prophylactic surgeries. PMID- 21294115 TI - Predictors of doctoral student success in professional psychology: characteristics of students, programs, and universities. AB - In the face of the rising number of doctoral recipients in professional psychology, many have voiced concerns about the quality of nontraditional training programs. Past research suggests that, on a variety of outcomes, graduates from clinical PhD programs outperform graduates from clinical PsyD and, to a lesser extent, counseling PhD programs. We examine an aggregate archival dataset to determine whether student or university characteristics account for the differences in outcomes among programs. The data show meaningful differences in the outcomes of clinical PhD, PsyD, and counseling PhD programs. Furthermore, graduates from research-intensive universities perform better on the psychology licensure exam and are more likely to become American Board of Professional Psychology diplomates. The available data support the notion that the ability to conduct research is an essential component of graduate education. In this light, PsyD programs represent a unique opportunity to train students in the types of evaluation and outcomes assessments used by practicing psychologists. We discuss implications for graduate-level training in professional psychology. PMID- 21294116 TI - The effectiveness of a trauma focused spiritually integrated intervention for veterans exposed to trauma. AB - Building Spiritual Strength (BSS) is an 8-session, spiritually integrated group intervention designed to address religious strain and enhance religious meaning making for military trauma survivors. It is based upon empirical research on the relationship between spirituality and adjustment to trauma. To assess the intervention's effectiveness, veterans with histories of trauma who volunteered for the study were randomly assigned to a BSS group (n = 26) or a wait-list control group (n = 28). BSS participants showed statistically significant reductions in PTSD symptoms based on self-report measures as compared with those in a wait-list control condition. Further research on spiritually integrated interventions for trauma survivors is warranted. PMID- 21294117 TI - A short version of the Kentucky Inventory of Mindfulness Skills. AB - The Kentucky Inventory of Mindfulness Skills (KIMS; Baer, Smith, & Allen, 2004) is a 39-item self-report measure for the assessment of four different mindfulness factors. This study aimed at developing a short version of the German adaptation of the KIMS (KIMS-Short). Confirmatory factor analyses were carried out with two samples (N = 469 and N = 602) to develop subscales with fewer items and to confirm the factor structure of the KIMS-Short. Furthermore, the relations between the KIMS-Short subscales and other scales were evaluated. The KIMS-Short with its 20 items enable researchers to replicate the basic factor structure of four separate mindfulness skills. However, the analyses for the "observing" subscale revealed two different but strongly correlated factors depending on whether the observed stimuli were internal or external phenomena. PMID- 21294118 TI - The Journal of Pathology's approach to publication ethics and misconduct. AB - This Editorial highlights recent changes at The Journal of Pathology intended to improve our ability to detect, and we hope deter, instances of ethical misconduct among submissions made to the Journal, such as cases of guest authorship and plagiarism. We also discuss our experience to date and describe our policies for dealing with such cases. These changes are all encapsulated in our full online Author Guidelines. PMID- 21294119 TI - Genetic changes in tumour microenvironments. AB - Numerous in vitro and in vivo studies have established that carcinoma-associated fibroblasts differ phenotypically from fibroblasts associated with normal tissue but the mechanisms underlying these differences are unclear. Since carcinoma associated fibroblasts can be propagated in vitro for extended periods and still maintain their cancer-promoting phenotype, some investigators have proposed that they might have acquired somatic genetic alterations analogous to those observed in malignant epithelium. Early molecular genetic studies appeared to validate this hypothesis by demonstrating remarkably high frequencies of clonal somatic genetic alterations in carcinoma-associated fibroblasts, including loss of heterozygosity, gene amplification, and point mutations in tumour suppressor genes such as TP53 and PTEN. The initial excitement of these paradigm-changing studies overshadowed concerns that there may have been a more mundane explanation for these observations. In addition to the fact that the data would necessarily invoke an unlikely scenario of the simultaneous generation of two symbiotic malignancies, subsequent molecular genetic studies found no evidence of frequent genomic aberrations. One striking common trait of those studies reporting frequent clonal somatic alterations in carcinoma-associated fibroblasts is the use of tissues and techniques which are well known to be highly prone to generating artefacts such as limiting and poor quality DNA followed by highly multiplexed PCR-based analyses. It is now clear that clonal somatic mutations are not the biological basis of the cancer-promoting attributes of carcinoma associated fibroblasts. PMID- 21294120 TI - Fibroblast gene expression profile reflects the stage of tumour progression in oral squamous cell carcinoma. AB - Oral cancer is a highly aggressive malignancy with poor prognosis. This study examined the behaviour of fibroblast strains from normal oral mucosa, dysplastic epithelial tissue, and genetically stable (minimal copy number alterations-CNA; minimal loss of heterozygosity-LOH; wild-type p53; wild-type p16INK4A) and unstable (extensive CNA and LOH; inactivation of p53 and p16INK4A) oral squamous cell carcinoma (OSCC). Fibroblasts from genetically unstable OSCC relative to the other fibroblast subtypes grew more slowly and stimulated the invasion of a non tumourigenic keratinocyte cell line into fibroblast-rich collagen gels. To understand these findings, genome-wide transcriptional profiles were generated using the GeneChip((r)) cDNA whole transcript microarray platform. Principal component analysis showed that the fibroblasts could be distinguished according to the stage of tumour development. Tumour progression was associated with down regulation of cell cycle- and cytokinesis-related genes and up-regulation of genes encoding transmembrane proteins including cell adhesion molecules. Gene expression was validated in independent fibroblast strains using qRT-PCR. Gene connectivity and interactome-transcriptome associations were determined using a systems biology approach to interrogate the gene expression data. Clusters of gene signatures were identified that characterized genetically unstable and stable OSCCs relative to each other and to fibroblasts from normal oral mucosa. The expression of highly connected genes associated with unstable OSCCs, including those that encode alpha-SMA and the integrin alpha6, correlated with poor patient prognosis in an independent dataset of head and neck cancer. The results of this study demonstrate that fibroblasts from unstable OSCCs represent a phenotypically distinguishable subset that plays a major role in oral cancer biology. PMID- 21294121 TI - Stromal features are predictive of disease mortality in oral cancer patients. AB - Worldwide, approximately 405 000 cases of oral cancer (OSCC) are diagnosed each year, with a rising incidence in many countries. Despite advances in surgery and radiotherapy, which remain the standard treatment options, the mortality rate has remained largely unchanged for decades, with a 5-year survival rate of around 50%. OSCC is a heterogeneous disease, staged currently using the TNM classification, supplemented with pathological information from the primary tumour and loco-regional lymph nodes. Although patients with advanced disease show reduced survival, there is no single pathological or molecular feature that identifies aggressive, early-stage tumours. We retrospectively analysed 282 OSCC patients for disease mortality, related to clinical, pathological, and molecular features based on our previous functional studies [EGFR, alphavbeta6 integrin, smooth muscle actin (SMA), p53, p16, EP4]. We found that the strongest independent risk factor of early OSCC death was a feature of stroma rather than tumour cells. After adjusting for all factors, high stromal SMA expression, indicating myofibroblast transdifferentiation, produced the highest hazard ratio (3.06, 95% CI 1.65-5.66) and likelihood ratio (3.6; detection rate: false positive rate) of any feature examined, and was strongly associated with mortality, regardless of disease stage. Functional assays showed that OSCC cells can modulate myofibroblast transdifferentiation through alphavbeta6-dependent TGF beta1 activation and that myofibroblasts promote OSCC invasion. Finally, we developed a prognostic model using Cox regression with backward elimination; only SMA expression, metastasis, cohesion, and age were significant. This model was independently validated on a patient subset (detection rate 70%; false positive rate 20%; ROC analysis 77%, p < 0.001). Our study highlights the limited prognostic value of TNM staging and suggests that an SMA-positive, myofibroblastic stroma is the strongest predictor of OSCC mortality. Whether used independently or as part of a prognostic model, SMA identifies a significant group of patients with aggressive tumours, regardless of disease stage. PMID- 21294122 TI - MicroRNA-200c attenuates tumour growth and metastasis of presumptive head and neck squamous cell carcinoma stem cells. AB - MicroRNA-200c (miR200c) is emerging as an important regulator of tumourigenicity and cancer metastasis with a strong capacity for inducing epithelial-mesenchymal transitions. However, the role of miR200c in head and neck squamous cell carcinoma (HNSCC) and HNSCC-associated cancer stem cells (HNSCC-CSCs) is unknown. In this study, the expression of miR200c in the regional metastatic lymph node of HNSCC tissues was significantly decreased, but BMI1 expression was increased as compared to parental tumours. Importantly, site-directed mutagenesis with a luciferase reporter assay showed that miR200c targeted the 3' UTR of BMI1 in HNSCC cells. Isolated HNSCC-derived ALDH1(+) /CD44(+) cells displayed CSC-like tumour initiating and radio-resistant properties. The expression levels of miR200c were significantly down-regulated while BMI1 was increased in HNSCC ALDH1(+) /CD44(+) compared to the other subsets of HNSCC cells. Furthermore, increased miR200c expression or knockdown of BMI1 could significantly inhibit the malignant CSC-like properties of ALDH1(+) /CD44(+) cells. miR200c over-expression further down-regulated the expressions of ZEB1, Snail and N-cadherin, but up regulated E-cadherin expression in ALDH1(+) /CD44(+) cells. Finally, a xenotransplantion study confirmed that over-expression of miR200c or BMI1 knockdown effectively inhibited the lung metastatic ability and prolonged the survival rate of ALDH1(+) /CD44(+) -transplanted mice. In summary, miR200c negatively modulates the expression of BMI1 but also significantly inhibits the metastatic capability of epithelial-mesenchymal transitions in malignant HNSCC by reducing the expression of BMI1/ZEB1. Restoration of miR200c in HNSCC and CSCs may be a promising therapeutic approach. PMID- 21294123 TI - Activated oncogenic pathways and therapeutic targets in extranodal nasal-type NK/T cell lymphoma revealed by gene expression profiling. AB - We performed comprehensive genome-wide gene expression profiling (GEP) of extranodal nasal-type natural killer/T-cell lymphoma (NKTL) using formalin-fixed, paraffin-embedded tissue (n = 9) and NK cell lines (n = 5) in comparison with normal NK cells, with the objective of understanding the oncogenic pathways involved in the pathogenesis of NKTL and to identify potential therapeutic targets. Pathway and network analysis of genes differentially expressed between NKTL and normal NK cells revealed significant enrichment for cell cycle-related genes and pathways, such as PLK1, CDK1, and Aurora-A. Furthermore, our results demonstrated a pro-proliferative and anti-apoptotic phenotype in NKTL characterized by activation of Myc and nuclear factor kappa B (NF-kappaB), and deregulation of p53. In corroboration with GEP findings, a significant percentage of NKTLs (n = 33) overexpressed c-Myc (45.4%), p53 (87.9%), and NF-kappaB p50 (67.7%) on immunohistochemistry using a tissue microarray containing 33 NKTL samples. Notably, overexpression of survivin was observed in 97% of cases. Based on our findings, we propose a model of NKTL pathogenesis where deregulation of p53 together with activation of Myc and NF-kappaB, possibly driven by EBV LMP-1, results in the cumulative up-regulation of survivin. Down-regulation of survivin with Terameprocol (EM-1421, a survivin inhibitor) results in reduced cell viability and increased apoptosis in tumour cells, suggesting that targeting survivin may be a potential novel therapeutic strategy in NKTL. PMID- 21294124 TI - Effect of fixation on brain and lymphoreticular vCJD prions and bioassay of key positive specimens from a retrospective vCJD prevalence study. AB - Anonymous screening of lymphoreticular tissues removed during routine surgery has been applied to estimate the UK population prevalence of asymptomatic vCJD prion infection. The retrospective study of Hilton et al (J Pathol 2004; 203: 733-739) found accumulation of abnormal prion protein in three formalin-fixed appendix specimens. This led to an estimated UK prevalence of vCJD infection of ~1 in 4000, which remains the key evidence supporting current risk reduction measures to reduce iatrogenic transmission of vCJD prions in the UK. Confirmatory testing of these positives has been hampered by the inability to perform immunoblotting of formalin-fixed tissue. Animal transmission studies offer the potential for 'gold standard' confirmatory testing but are limited by both transmission barrier effects and known effects of fixation on scrapie prion titre in experimental models. Here we report the effects of fixation on brain and lymphoreticular human vCJD prions and comparative bioassay of two of the three prevalence study formalin-fixed, paraffin-embedded (FFPE) appendix specimens using transgenic mice expressing human prion protein (PrP). While transgenic mice expressing human PrP 129M readily reported vCJD prion infection after inoculation with frozen vCJD brain or appendix, and also FFPE vCJD brain, no infectivity was detected in FFPE vCJD spleen. No prion transmission was observed from either of the FFPE appendix specimens. The absence of detectable infectivity in fixed, known positive vCJD lymphoreticular tissue precludes interpreting negative transmissions from vCJD prevalence study appendix specimens. In this context, the Hilton et al study should continue to inform risk assessment pending the outcome of larger-scale studies on discarded surgical tissues and autopsy samples. PMID- 21294125 TI - The expression of CXCR4, CXCL12 and CXCR7 in malignant pleural mesothelioma. AB - The chemokine CXCL12 and its receptors, CXCR4 and CXCR7, are involved in tumour progression, metastasis, and survival. We investigated the expression of CXCR4, CXCL12, and CXCR7 in malignant pleural mesothelioma to determine if they are possible biomarkers and potential therapeutic targets. Forty-one mesothelioma tumour tissues, ten normal human pleural tissues, and two mesothelioma cell lines were stained with anti-CXCR4, anti-CXCL12, anti-CXCR7, and anti-p-Akt antibodies. RT-PCR was performed to determine the expression of CXCR4, CXCL12, and CXCR7 in six human mesothelioma cell lines (H28, 211H, H2052, ms-1, H290, and H513) and one human normal mesothelial cell line, LP9. These seven cell lines were also stained with anti-CXCR7. We found that CXCR4 and CXCL12 were expressed in 97.6% and 78.0% mesothelioma tissue samples, concurrently with strong expression of p Akt (R(2) = 0.739 and 0.620, respectively). In addition, CXCR7 expression was weaker than CXCR4 expression in mesothelioma tissues. Furthermore, RT-PCR showed that CXCR4 and CXCL12 were overexpressed in 5/6 mesothelioma cell lines (211H, H2052, ms-1, H290, and H513), whereas CXCR7 was overexpressed in only 2/6 (H513 and H2052). Moreover, we found that the CXCR4 antagonist AMD3100 inhibited the growth of all five mesothelioma cell lines that overexpress CXCR4 and CXCL12. Our results suggest that the Akt-mTOR pathway is involved during the interruption of the CXCL12/CXCR4 axis in these five mesothelioma cell lines. In conclusion, CXCR4 and CXCL12 are highly expressed in most mesothelioma cell lines and tumour tissues, suggesting that CXCR4 and CXCL12 may be used as biomarkers for patients with mesothelioma. The CXCL12-CXCR4 interaction may be a potential therapeutic target for mesothelioma. PMID- 21294126 TI - Cartilage ultrastructure in proteoglycan-deficient zebrafish mutants brings to light new candidate genes for human skeletal disorders. AB - Proteoglycans are molecules consisting of protein cores onto which sugar chains, i.e., glycosaminoglycans (GAGs) such as heparan or chondroitin sulphates, are attached. Proteoglycans are produced by nearly all cells, and once secreted they become a major component of the extracellular matrix. Cartilage is particularly rich in proteoglycans, and changes in the structure and composition of GAGs have been found in osteochondromas and osteoarthritis. The zebrafish (Danio rerio) exhibits fast development, a growth plate-like organization of its craniofacial skeleton and an availability of various mutants, making it a powerful model for the study of human skeletal disorders with unknown aetiology. We analysed skeletons from five zebrafish lines with known mutations in genes involved in proteoglycan synthesis: dackel (dak/ext2), lacking heparan sulphate; hi307 (beta3gat3), deficient for most GAGs; pinscher (pic/slc35b2), presenting defective sulphation of GAGs and other molecules; hi954 (uxs1), lacking Notch and most GAGs due to impaired protein xylosylation; and knypek (kny/gpc4), missing the protein core of the Glypican-4 proteoglycan. Here we show that each mutant displays different phenotypes related to: (a) cartilage morphology; (b) composition of the extracellular matrix; (c) ultrastructure of the extracellular matrix; and (d) the intracellular ultrastructure of chondrocytes, proving that sulphated GAGs orchestrate the cartilage intra- and extracellular ultrastructures. The mild phenotype of the hi307 mutant suggests that proteoglycans consisting of a protein core and a short sugar linker might suffice for proper chondrocyte stacking. Finally, knypek supports the involvement of Glypican-4 in the craniofacial phenotype of Simpson-Golabi-Behmel syndrome and suggests GPC4 as a modulator of the overgrowth phenotype that is associated with this syndrome and is primarily caused by a mutation in GPC3. Moreover, we speculate on the potential involvement of SLC35B2, beta3GAT3 and UXS1 in skeletal dysplasias. This work promotes the use of zebrafish as a model of human skeletal development and associated pathologies. PMID- 21294127 TI - Amplification and overexpression of vinculin are associated with increased tumour cell proliferation and progression in advanced prostate cancer. AB - Androgen withdrawal is the standard treatment for advanced prostate cancer. Although this therapy is initially effective, nearly all prostate cancers become refractory to it. Approximately 15% of these castration-resistant prostate cancers harbour a genomic amplification at 10q22. The aim of this study was to explore the structure of the 10q22 amplicon and to determine the major driving genes. Application of high-resolution array-CGH using the 244k Agilent microarrays to cell lines with 10q22 amplification allowed us to narrow down the common amplified region to a region of 5.8 megabases. We silenced each of the genes of this region by an RNAi screen in the prostate cancer cell lines PC-3 and 22Rv1. We selected genes with a significant growth reduction in the 10q22 amplified cell line PC-3, but not in the non-amplified 22Rv1 cells, as putative target genes of this amplicon. Immunohistochemical analysis of the protein expression of these candidate genes on a tissue microarray enriched for 10q22 amplified prostate cancers revealed vinculin as the most promising target of this amplicon. We found a strong association between vinculin gene amplification and overexpression (p < 0.001). Further analysis of 443 specimens from across all stages of prostate cancer progression showed that vinculin expression was highest in castration-resistant prostate cancers, but negative or very low in benign prostatic hyperplasia (p < 0.0001). Additionally, high tumour cell proliferation measured by Ki67 expression was significantly associated with high vinculin expression in prostate cancer (p < 0.0001). Our data suggest that vinculin is a major driving gene of the 10q22 amplification in prostate cancer and that vinculin overexpression might contribute to prostate cancer progression by enhancing tumour cell proliferation. PMID- 21294128 TI - Chronic chorioamnionitis displays distinct alterations of the amniotic fluid proteome. AB - Acute chorioamnionitis of infectious origin and chronic chorioamnionitis of immunological origin are two major placental lesions of spontaneous preterm birth with elevated amniotic fluid interleukin-6 and CXCL10 concentrations, respectively. The changes in the amniotic fluid proteome associated with intra amniotic infection and acute chorioamnionitis are well defined, yet alterations unique to chronic chorioamnionitis remain to be elucidated. This study was conducted to determine those amniotic fluid proteins changing specifically in the presence of chronic chorioamnionitis. Amniotic fluid obtained from acute chorioamnionitis, chronic chorioamnionitis and gestational age-matched controls were analysed by two-dimensional (2D) difference in gel electrophoresis and MALDI TOF analyses. The type of histological inflammation was used to define each condition in preterm labour cases (n = 125) and term not in labour cases (n = 22), and the amniotic fluid concentrations of interleukin-6, CXCL8, CXCL10 and prostaglandin F(2alpha) were also measured by specific immunoassays. Among preterm labour cases, 31 differentially expressed proteins were identified in chronic chorioamnionitis cases as compared to both acute chorioamnionitis and control cases. Importantly, glycodelin-A, which maintains maternal tolerance against an allogeneic fetus, was decreased in chronic chorioamnionitis, while haptoglobin was increased. We report the amniotic fluid proteome of chronic chorioamnionitis for the first time, and the findings herein strongly suggest that there is a pathophysiological association between the changes of immunomodulatory proteins in the amniotic fluid and chronic chorioamnionitis, a histological manifestation of maternal anti-fetal allograft rejection. PMID- 21294129 TI - Identification of amino acid residues responsible for the release of free drug from an antibody-drug conjugate utilizing lysine-succinimidyl ester chemistry. AB - Unexpected release of free drug was observed during the stability testing of an antibody-drug conjugate (ADC). The ADC was designed to use lysine-succinimidyl ester chemistry to conjugate small molecule cytotoxic drugs to the antibody. To elucidate the mechanism of the release of free drug, a succinimidyl ester analog, 7-hydroxy-4-methyl-3-coumarinylacetic acid N-succinimidyl ester, and a series of peptides were used to probe the potential side reaction of succinimidyl ester with other amino acid residues. Cysteine and tyrosine residues were found to be reactive to succinimidyl ester, and the bonds formed through these reactions were found to be labile. Combining the fluorescent property of the succinimidyl ester analog and mass spectroscopy analysis, specific cysteine and tyrosine residues of the antibody were found to be reactive to succinimidyl ester and the bonds formed through this reaction were susceptible to hydrolysis. PMID- 21294130 TI - Assessment of net charge and protein-protein interactions of different monoclonal antibodies. AB - The purpose of this work was to compare biophysical properties of different monoclonal antibodies (mAbs). mAbs' theoretical isoelectric point (IEP) and theoretical net charge were compared with experimentally assessed values. IEP was determined by isoelectric focusing capillary electrophoresis, determination of zero electrophoretic mobility, or the minimum mutual diffusion coefficient during pH titration. Net charge was determined using electrophoretic mobility and self diffusion coefficient. It was found that antibodies differ substantially in their biophysical properties, that is, in IEP, net charge, and zeta potential. Also, the importance of these properties was studied with respect to protein-protein interactions. This was achieved by assessing the second virial coefficient (A(2)) determined by static light scattering (SLS) and dynamic light scattering (DLS). It was found that at low ionic strength formulation conditions [20 mM histidine (His)/His-HCl buffer, pH 6.0] proteins' charge is the main driver for overall repulsive protein interactions. At high ionic strength conditions (20 mM His/His HCl buffer, pH 6.0, + 150 mM NaCl), where counterions are shielding ionic interactions, proteins' repulsive forces were weakened, but to a different extent. Furthermore, a DLS method was developed allowing fast and easy assessment of A(2) by minimum need of material. PMID- 21294131 TI - Can lymphatic drainage of head and neck melanoma be predicted? AB - BACKGROUND: The lymphatic drainage patterns of the head and neck (H&N) is complex. Therefore, identification of the sentinel lymph node (SLN) for H&N melanoma can be challenging. METHODS: Retrospective review of a prospectively collected melanoma database, from February 1997 through October 2008, identified 137 patients with H&N melanoma. All underwent pre-operative lymphoscintigraphy, and after 2007, patients underwent single photon emission computed tomography combined with computed tomography (SPECT/CT). RESULTS: The mean number of SLNs per patient was 2.6. An SLN was successfully identified in 97% of patients, and in 9%, the SLN was positive for metastatic disease. The majority of patients (88%) drained to a unilateral level. Bilateral drainage occurred in 10%, with only two patients draining outside of the neck. The majority of patients (58%) had an SLN in level IIa (jugulodigastric lymph nodes). The regional recurrence rate was 4%, which all occurred prior to the use of SPECT/CT. DISCUSSION: Utilization of SPECT/CT and knowledge of common lymphatic drainage patterns in neck lymph node levels can assist the surgeon in properly locating and excising the SLN with minimal morbidity, limiting unnecessary dissections, as well as reducing false negative results. PMID- 21294132 TI - Carcinoid tumors of the appendix: a population-based study. AB - BACKGROUND: Carcinoid tumors of the appendix are rare, and as such there are few data guiding their optimal treatment. METHODS: The analysis included all patients with malignant, typical carcinoid tumor of the appendix for whom complete data were available in the Surveillance, Epidemiology, and End Results database between 1988 and 2003. Clinicopathologic factors predicting lymph node (LN) involvement and survival were determined. RESULTS: LN metastases were present in 44 of 89 patients (49%), including 4 of 27 patients (15%) with tumors <= 1.0 cm, 16 of 34 patients (47%) with tumors > 1.0 cm but <= 2.0 cm, and 24 of 28 patients (86%) with tumors >2.0 cm. Increasing tumor size predicted LN involvement, whereas age, gender, and depth of tumor invasion did not. Excluding patients with distant metastasis (DM), the 10-year overall survival rates of patients with positive LNs and tumor sizes <=1.0 cm, >1.0 cm but <=2.0 cm, and >2.0 cm were 100%, 92%, and 91%, respectively. CONCLUSIONS: Right hemicolectomy should be considered for patients with appendiceal carcinoid tumors >1.0 cm in size given their high incidence of LN metastases and limited data concerning the natural history of unresected LN metastases. Wiley-Liss, Inc. PMID- 21294133 TI - An analytical approach to the effect of finite-sized end reservoirs on electroosmotic transport through narrow confinements. AB - The presence of end reservoirs often alters the electrical potential distributions inside narrow fluidic confinements of electrokinetically actuated miniaturized devices to a significant extent. This paper examines the influence of finite size effect of the end reservoirs on the concerned potential distribution analytically, using the Schwarz-Christoffel conformal mapping. The effective electric field directly acting across the channel is accordingly represented by a calibration curve, which sums up the role of the key geometric parameters (reservoir-to-channel height and length ratios) on the potential distribution. The analytical model is further augmented to assess the flow characteristics through the channel. The results indicate that the alterations in the flow characteristics due to alterations in the effective electric field on account of the finite size effects of the end reservoirs can turn out to be significantly more prominent than the corresponding alterations due to the axial pressure gradients induced by the sudden contraction and expansion effects associated with the end reservoirs. The derived results can be further utilized to facilitate the practical design of miniaturized fluidic devices, using conveniently tractable analytical tools. PMID- 21294134 TI - 3-D ultrasound of the fetal ear and fetal autosomal trisomies: a pilot study of a new screening protocol. AB - OBJECTIVE: We hypothesize that the rotation of the ear in fetuses with common autosomal trisomies will be markedly different from euploid fetuses and amenable to detection by 3-D ultrasound in the render mode. METHODS: Study participants (10 weeks 4 days through 19 weeks 0 days) underwent a 3-D rendering of the fetal face and ear along with other biometric measurements prior to invasive testing. RESULTS: Of the 348 patients who underwent chorionic villi sampling (CVS) (n = 208) or amniocentesis (n = 140), 18 were diagnosed with trisomy 21, 4 with trisomy 18, and 1 with trisomy 13. Mean gestational age was 12 weeks 6 days (range: 10 weeks 6 days to 19 weeks 0 days). Ear angles were obtained in all cases; the time to obtain this angle ranged from 5 to 25 min. Thirty-two fetuses were found to have an abnormal ear angle with 23 of the 32 characterized by one of the aforementioned trisomies. CONCLUSIONS: These findings support the potential of this technique to provide valuable information in the identification of an increased-risk population. Prospective studies are needed to confirm the value of this screening modality as well as to assess its facility and ability to be incorporated into routine obstetrical practice. PMID- 21294135 TI - New and/or improved aspects of fetal surgery. AB - Open fetal surgery through a wide hysterotomy is no longer a real option for prenatal intervention, but a minimally invasive approach has emerged as treatment for a small number of indications. Endoscopic ablation of placental vessels is the preferred treatment for severe twin-to-twin transfusion syndrome and it may be the only chance to salvage the most severe forms of congenital diaphragmatic hernia. Several other indications are currently under review and may become justified in the future, provided that diagnostic accuracy and patient selection become more accurate. Before invasive fetal intervention becomes widely accepted, however, we need to better define outcome. It is no longer acceptable to express results in terms of survival at birth. Survival at discharge and long-term morbidity must be considered as well. PMID- 21294136 TI - Parents' perspectives on the unforeseen finding of a fetal sex chromosomal aneuploidy. AB - OBJECTIVE: To investigate the parental perspectives of being confronted with an unforeseen fetal sex chromosomal aneuploidy (SCA), in light of the fact that this accidental finding is avoidable by rapid aneuploidy detection (RAD). METHODS: Exploratory qualitative interview study. We conducted 16 semi-structured interviews with parents who decided to continue pregnancy after the unforeseen finding of a fetal SCA. RESULTS: The communication of the unforeseen finding of SCA; the informed decision-making process concerning the pregnancy follow-up and the child and its future were the extracted themes. Parents were not prepared to accidental findings in routine prenatal diagnostics. All started an unguided search on the Internet. It is not at all clear whether parents have preference for an RAD test with X and Y probes Parents were satisfied with the post-test professional information they received to make an informed decision, whereas after birth questions still remained to be answered. CONCLUSION: Parents' perspectives may serve as major contributors to research on the question whether or not the X and Y probes should be standard included for purposes of RAD. The fact that RAD has the possibility to avoid accidental findings of SCAs, brings up the question whether any benefits outweigh the potential harms. PMID- 21294137 TI - The stability of free-beta human chorionic gonadotrophin and pregnancy-associated plasma protein-A in first trimester dried blood spots. AB - OBJECTIVES: To determine the stability of first trimester free-beta human chorionic gonadotrophin (free-beta hCG) and pregnancy-associated plasma protein-A (PAPP-A) in dried blood spots (DBSs) under typical storage conditions. METHODS: First trimester maternal blood was spotted onto filter paper and left to dry. DBSs were analysed for PAPP-A and free-beta hCG using an AutoDELFIA dual assay at t = 0. Cards were stored at one of - 20 degrees C, refrigerator temperature, room temperature or 30 degrees C and reanalysed at set future time points. RESULTS: Free-beta hCG was stable (<10% change in concentration) under all temperatures tested for at least 35 days. PAPP-A was stable at - 20 degrees C and refrigerator temperature for at least 35 days. However, PAPP-A levels decreased by 10% at 4.1 days at room temperature and at 3.9 days at 30 degrees C. Longer-term storage at - 20 degrees C and refrigerator temperature showed that both PAPP-A and free-beta hCG levels were significantly decreased by 107 and 244 days. CONCLUSIONS: Free-beta hCG stability is greatly improved in DBS compared to serum storage; however PAPP-A stability is decreased in the DBS medium. Despite this DBS, screening may not necessitate such strict storage and transportation rules compared to serum screening programmes. PMID- 21294138 TI - Impact of random and systematic recall errors and selection bias in case--control studies on mobile phone use and brain tumors in adolescents (CEFALO study). AB - Whether the use of mobile phones is a risk factor for brain tumors in adolescents is currently being studied. Case--control studies investigating this possible relationship are prone to recall error and selection bias. We assessed the potential impact of random and systematic recall error and selection bias on odds ratios (ORs) by performing simulations based on real data from an ongoing case- control study of mobile phones and brain tumor risk in children and adolescents (CEFALO study). Simulations were conducted for two mobile phone exposure categories: regular and heavy use. Our choice of levels of recall error was guided by a validation study that compared objective network operator data with the self-reported amount of mobile phone use in CEFALO. In our validation study, cases overestimated their number of calls by 9% on average and controls by 34%. Cases also overestimated their duration of calls by 52% on average and controls by 163%. The participation rates in CEFALO were 83% for cases and 71% for controls. In a variety of scenarios, the combined impact of recall error and selection bias on the estimated ORs was complex. These simulations are useful for the interpretation of previous case-control studies on brain tumor and mobile phone use in adults as well as for the interpretation of future studies on adolescents. PMID- 21294139 TI - A simple RP-HPLC method for the simultaneous determination of curcumin and its prodrug, curcumin didecanoate, in rat plasma and the application to pharmacokinetic study. AB - A high-performance liquid chromatographic (HPLC) method has been developed for the simultaneous determination of curcumin and its prodrug, curcumin didecanoate (CurDD), in rat plasma. The analytes were extracted by ethyl acetate following the addition of sodium dodecyl sulfate, and separated on a reverse-phase C(18) column using a gradient mobile phase system of acetonitrile-tetrahydrofuran-water containing 0.1% formic acid. Detection by UV absorption at 425 nm gave a lower limit of quantitation (LLOQ) of 5 and 10 ng/mL for curcumin and CurDD in 50 MUL of plasma, respectively. Intra- and inter-day precisions of quality control samples except those at LLOQ were within 15% for curcumin and CurDD, respectively, and the accuracies for both compounds were between 93.9 and 108%. The method was successfully applied to determine plasma concentration-time curves of curcumin and CurDD in rats following intravenous (i.v.) administration of curcumin or CurDD at doses of 1 mg/kg (calculated as curcumin). The results suggested that i.v. dosed CurDD provided sustained plasma levels of curcumin. PMID- 21294140 TI - Development and validation of stable-isotope dilution liquid chromatography tandem mass spectrometric method for determination of salivary progesterone. AB - A method for the quantification of progesterone (PROG) in human saliva using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI MS/MS) has been developed and validated. The saliva was deproteinized with acetonitrile, purified using a StrataTM-X cartridge, and subjected to LC-ESI MS/MS. Quantification was based on selected reaction monitoring, and deuterated PROG was used as the internal standard. This method allowed the reproducible (intra- and inter-assay relative standard deviations, <2.2%) and accurate (analytical recovery, 96.6-99.7%) quantification of the salivary PROG using a 400 MUL sample, and the limit of quantification was 12.5 pg/mL. The developed method enabled detection of the variation in the salivary PROG concentrations of healthy volunteers during the menstrual cycle and measurement of the salivary concentrations of pregnant women. The method is expected to be an alternative to the blood PROG monitoring in clinical examinations, because saliva collection is easy, non-invasive and repeatable. PMID- 21294141 TI - Simultaneous determination of sibutramine and its active metabolites in human plasma by LC-MS/MS and its application to a pharmacokinetic study. AB - A simple and sensitive liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) technique was developed and validated for the determination of sibutramine and its N-desmethyl metabolites (M1 and M2) in human plasma. After extraction with methyl t-butyl ether, chromatographic separation of analytes in human plasma was performed using a reverse-phase Luna C18 column with a mobile phase of acetonitrile-10 mm ammonium formate buffer (50:50, v/v) and quantified by ESI-MS/MS detection in positive ion mode. The flow rate of the mobile phase was 200 MUL/min and the retention times of sibutramine, M1, M2 and internal standard (chlorpheniramine) were 1.5, 1.4, 1.3 and 0.9 min, respectively. The calibration curves were linear over the range 0.05-20 ng/mL, for sibutramine, M1 and M2. The lower limit of quantification was 0.05 ng/mL using 500 MUL of human plasma. The mean accuracy and the precision in the intra- and inter-day validation for sibutramine, M1 and M2 were acceptable. This LC MS/MS method showed improved sensitivity and a short run time for the quantification of sibutramine and its two active metabolites in plasma. The validated method was successfully applied to a pharmacokinetic study in human. PMID- 21294142 TI - Application of ultra-performance columns in high-performance liquid chromatography for determination of albendazole and its metabolites in turkeys. AB - Methods for determination of albendazole (ALB), albendazole sulfoxide (SOX) and albendazole sulfone (SON) in turkey blood plasma, using high-performance liquid chromatography (HPLC) with fluorescence detection, were developed. Moreover, comparison of HPLC columns with ultra-performance liquid chromatography (UPLC) columns was performed. Albendazol was administered orally in 5-week-old birds (n = 18) at a dose of 25 mg/kg b.w. Accuracy and precision of the developed method were satisfactory and stability studies showed acceptable variation (below 15%) in ALB, SOX and SON concentrations when the samples were stored at -75 degrees C for 15 days. UPLC((r)) columns gave higher peaks from typical HPLC columns retaining high quality of analysis. Pharmacokinetic analysis indicated quick elimination of ALB from turkey blood plasma. The mean residence time of SON was at least two times longer than that of SOX and four times longer than that of ALB. The elimination half-lives for ALB, SOX and SON were 0.7 +/- 0.27, 5.37 +/- 6.03, 9.17 +/- 5.12 h, respectively. The obtained results indicate that the described method allows for precise determination of albendazole and its metabolites in turkey plasma. Moreover, using UPLC columns in HPLC apparatus results in higher sensitivity as compared with the classical HPLC columns. PMID- 21294143 TI - Tenofovir improves the outcome in patients with spontaneous reactivation of hepatitis B presenting as acute-on-chronic liver failure. AB - Spontaneous reactivation of chronic hepatitis B (CHB) is an important cause of acute-on-chronic liver failure (ACLF). Antiviral drugs may help reduce the high morbidity and mortality in such patients, especially in places where liver transplant is not available. The aim was to evaluate the efficacy of tenofovir and to determine the predictors of mortality in patients with spontaneous reactivation of CHB with ACLF. Consecutive patients of ACLF due to spontaneous reactivation of CHB were randomized to receive either tenofovir or placebo. The primary endpoint was survival at 3 months. Of the 90 patients with ACLF of different etiologies, 27 (26%) were due to reactivation of CHB and were enrolled. The median baseline hepatitis B virus (HBV) DNA level was 9 * 10(5) IU/mL. Fourteen patients received tenofovir and 13 placebo. At 3 months the probability of survival was higher in the tenofovir than the placebo group (8/14 [57%] versus 2/13 [15%], respectively; P = 0.03). The cause of death in the 15 patients was progressive liver failure leading to multiorgan failure. Liver transplantation could not be offered due to its nonavailability. In the surviving patients, there was a significant improvement in the Child-Turcotte Pugh (CTP) and model for endstage liver disease (MELD) scores and significant decline in the HBV DNA levels in the tenofovir group, whereas these parameters did not change significantly in the placebo group. More than 2 log reduction in HBV DNA levels at 2 weeks was found to be an independent predictor of survival. CONCLUSION: Tenofovir significantly reduces HBV-DNA levels, improves CTP and MELD scores, and reduces mortality in patients with severe spontaneous reactivation of CHB presenting as ACLF. Reduction in HBV-DNA levels at 2 weeks should be a desirable goal and is a good predictor of survival. PMID- 21294144 TI - Hepatitis C virus receptors claudin-1 and occludin after liver transplantation and influence on early viral kinetics. AB - Liver transplantation (LT) is a unique model to study hepatitis C virus (HCV) entry into hepatocytes. Recent in vitro studies suggest significant changes in the expression of the HCV receptors claudin-1 and occludin after HCV infection. Our aims were: (1) to characterize claudin-1 and occludin expression in grafts from LT recipients and (2) to explore their potential influence on early HCV kinetics and their changes after HCV infection. We included 42 HCV-infected LT recipients and 19 uninfected controls. Claudin-1 and occludin were detected in paraffin-embedded liver biopsies obtained during reperfusion and 3 and 12 months after LT. HCV receptors were characterized by confocal immunofluorescence microscopy; quantification and colocalization studies were performed with dedicated software. Claudin-1 and occludin expression were restricted to the apical pole of hepatocytes. There was a significant correlation between the amount of scavenger receptor B1 at the time of reperfusion and the HCV-RNA decay during the first 24 hours following LT (r = 0.55, P = 0.007). Similarly, there was a significant correlation between the levels of claudin and occludin and the slope of HCV-RNA increase during the first week after LT (r = 0.63, P = 0.005). Occludin and claudin-1 levels increased significantly 12 months after LT (P = 0.03 and P = 0.007, respectively). The expression pattern of both proteins, however, remained unchanged, colocalizing strongly (60%-94%) at the apical membrane of hepatocytes. CONCLUSIONS: HCV receptor levels at the time of LT seem to modulate early HCV kinetics. Hepatitis C recurrence after LT was associated with increased levels of claudin-1 and occludin in the hepatocyte cell membrane, although it did not alter their localization within the tight junctions. PMID- 21294145 TI - Treatment of hepatic encephalopathy with rifaximin: more to think about. PMID- 21294146 TI - Septum transversum-derived mesothelium gives rise to hepatic stellate cells and perivascular mesenchymal cells in developing mouse liver. AB - The septum transversum mesenchyme (STM) signals to induce hepatogenesis from the foregut endoderm. Hepatic stellate cells (HSCs) are sinusoidal pericytes assumed to originate from the STM and participate in mesenchymal-epithelial interaction in embryonic and adult livers. However, the developmental origin of HSCs remains elusive due to the lack of markers for STM and HSCs. We previously identified submesothelial cells (SubMCs) beneath mesothelial cells (MCs) as a potential precursor for HSCs in developing livers. In the present study, we reveal that both STM in embryonic day (E) 9.5 and MC/SubMCs in E12.5 share the expression of activated leukocyte cell adhesion molecule (Alcam), desmin, and Wilms tumor 1 homolog (Wt1). A cell lineage analysis using MesP1(Cre) /Rosa26lacZ(flox) mice identifies the mesodermal origin of the STM, HSCs, and perivascular mesenchymal cells (PMCs). A conditional cell lineage analysis using the Wt1(CreERT2) mice demonstrates that Wt1(+) STM gives rise to MCs, SubMCs, HSCs, and PMCs during liver development. Furthermore, we find that Wt1(+) MC/SubMCs migrate inward from the liver surface to generate HSCs and PMCs including portal fibroblasts, smooth muscle cells, and fibroblasts around the central veins. On the other hand, the Wt1(+) STM and MC/SubMCs do not contribute to sinusoidal endothelial cells, Kupffer cells, and hepatoblasts. CONCLUSION: our results demonstrate that HSCs and PMCs are derived from MC/SubMCs, which are traced back to mesodermal STM during liver development. PMID- 21294147 TI - Quantifying bias in a health survey: modeling total survey error in the national immunization survey. AB - Random-digit-dial telephone surveys are experiencing both declining response rates and increasing under-coverage due to the prevalence of households that substitute a wireless telephone for their residential landline telephone. These changes increase the potential for bias in survey estimates and heighten the need for survey researchers to evaluate the sources and magnitudes of potential bias. We apply a Monte Carlo simulation-based approach to assess bias in the NIS, a land-line telephone survey of 19-35 month-old children used to obtain national vaccination coverage estimates. We develop a model describing the survey stages at which component nonsampling error may be introduced due to nonresponse and under-coverage. We use that model and components of error estimated in special studies to quantify the extent to which noncoverage and nonresponse may bias the vaccination coverage estimates obtained from the NIS and present a distribution of the total survey error. Results indicated that the total error followed a normal distribution with mean of 1.72 per cent(95 per cent CI: 1.71, 1.74 per cent) and final adjusted survey weights corrected for this error. Although small, the largest contributor to error in terms of magnitude was nonresponse of immunization providers. The total error was most sensitive to declines in coverage due to cell phone only households. These results indicate that, while response rates and coverage may be declining, total survey error is quite small. Since response rates have historically been used to proxy for total survey error, the finding that these rates do not accurately reflect bias is important for evaluation of survey data. Published in 2011 by John Wiley & Sons, Ltd. PMID- 21294148 TI - Bayesian hierarchical modeling for a non-randomized, longitudinal fall prevention trial with spatially correlated observations. AB - Because randomization of participants is often not feasible in community-based health interventions, non-randomized designs are commonly employed. Non randomized designs may have experimental units that are spatial in nature, such as zip codes that are characterized by aggregate statistics from sources like the U.S. census and the Centers for Medicare and Medicaid Services. A perennial concern with non-randomized designs is that even after careful balancing of influential covariates, bias may arise from unmeasured factors. In addition to facilitating the analysis of interventional designs based on spatial units, Bayesian hierarchical modeling can quantify unmeasured variability with spatially correlated residual terms. Graphical analysis of these spatial residuals demonstrates whether variability from unmeasured covariates is likely to bias the estimates of interventional effect. The Connecticut Collaboration for Fall Prevention is the first large-scale longitudinal trial of a community-wide healthcare intervention designed to prevent injurious falls in older adults. Over a two-year evaluation phase, this trial demonstrated a rate of fall-related utilization at hospitals and emergency departments by persons 70 years and older in the intervention area that was 11 per cent less than that of the usual care area, and a 9 per cent lower rate of utilization from serious injuries. We describe the Bayesian hierarchical analysis of this non-randomized intervention with emphasis on its spatial and longitudinal characteristics. We also compare several models, using posterior predictive simulations and maps of spatial residuals. PMID- 21294149 TI - Ion spectrometric detection technologies for ultra-traces of explosives: a review. AB - In recent years, explosive materials have been widely employed for various military applications and civilian conflicts; their use for hostile purposes has increased considerably. The detection of different kind of explosive agents has become crucially important for protection of human lives, infrastructures, and properties. Moreover, both the environmental aspects such as the risk of soil and water contamination and health risks related to the release of explosive particles need to be taken into account. For these reasons, there is a growing need to develop analyzing methods which are faster and more sensitive for detecting explosives. The detection techniques of the explosive materials should ideally serve fast real-time analysis in high accuracy and resolution from a minimal quantity of explosive without involving complicated sample preparation. The performance of the in-field analysis of extremely hazardous material has to be user-friendly and safe for operators. The two closely related ion spectrometric methods used in explosive analyses include mass spectrometry (MS) and ion mobility spectrometry (IMS). The four requirements-speed, selectivity, sensitivity, and sampling-are fulfilled with both of these methods. PMID- 21294150 TI - Tandem mass spectrometry strategies for phosphoproteome analysis. AB - Protein phosphorylation is involved in nearly all essential biochemical pathways and the deregulation of phosphorylation events has been associated with the onset of numerous diseases. A multitude of tandem mass spectrometry (MS/MS) and multistage MS/MS (i.e., MS(n) ) strategies have been developed in recent years and have been applied toward comprehensive phosphoproteomic analysis, based on the interrogation of proteolytically derived phosphopeptides. However, the utility of each of these MS/MS and MS(n) approaches for phosphopeptide identification and characterization, including phosphorylation site localization, is critically dependant on the properties of the precursor ion (e.g., polarity and charge state), the specific ion activation method that is employed, and the underlying gas-phase ion chemistries, mechanisms and other factors that influence the gas-phase fragmentation behavior of phosphopeptide ions. This review therefore provides an overview of recent studies aimed at developing an improved understanding of these issues, and highlights the advantages and limitations of both established (e.g., CID) and newly maturing (e.g., ECD, ETD, photodissociation, etc.) yet complementary, ion activation techniques. This understanding is expected to facilitate the continued refinement of existing MS/MS strategies, and the development of novel MS/MS techniques for phosphopeptide analysis, with great promise in providing new insights into the role of protein phosphorylation on normal biological function, and in the onset and progression of disease. (c) 2011 Wiley Periodicals, Inc., Mass Spec Rev 30:600-625, 2011. PMID- 21294151 TI - Fragmentation of toxicologically relevant drugs in positive-ion liquid chromatography-tandem mass spectrometry. AB - The identification of drugs and related compounds by LC-MS-MS is an important analytical challenge in several application areas, including clinical and forensic toxicology, doping control analysis, and environmental analysis. Although target-compound based analytical strategies are most frequently applied, at some point the information content of the MS-MS spectra becomes relevant. In this article, the positive-ion MS-MS spectra of a wide variety of drugs and related substances are discussed. Starting point was an MS-MS mass spectral library of toxicologically relevant compounds, available on the internet. The positive-ion MS-MS spectra of ~570 compounds were interpreted by chemical and therapeutic class, thus involving a wide variety of drug compound classes, such benzodiazepines, beta-blockers, angiotensin-converting enzyme inhibitors, phenothiazines, dihydropyridine calcium channel blockers, diuretics, local anesthetics, vasodilators, as well as various subclasses of anti-diabetic, antidepressant, analgesic, and antihistaminic drugs. In addition, the scientific literature was searched for available MS-MS data of these compound classes and the interpretation thereof. The results of this elaborate study are presented in this article. For each individual compound class, the emphasis is on class specific fragmentation, as discussing fragmentation of all individual compounds would take far too much space. The recognition of class-specific fragmentation may be quite informative in determining the compound class of a specific unknown, which may further help in the identification. In addition, knowledge on (class specific) fragmentation may further help in the optimization of the selectivity in targeted analytical approaches of compounds of one particular class. PMID- 21294152 TI - Performance of reclassification statistics in comparing risk prediction models. AB - Concerns have been raised about the use of traditional measures of model fit in evaluating risk prediction models for clinical use, and reclassification tables have been suggested as an alternative means of assessing the clinical utility of a model. Several measures based on the table have been proposed, including the reclassification calibration (RC) statistic, the net reclassification improvement (NRI), and the integrated discrimination improvement (IDI), but the performance of these in practical settings has not been fully examined. We used simulations to estimate the type I error and power for these statistics in a number of scenarios, as well as the impact of the number and type of categories, when adding a new marker to an established or reference model. The type I error was found to be reasonable in most settings, and power was highest for the IDI, which was similar to the test of association. The relative power of the RC statistic, a test of calibration, and the NRI, a test of discrimination, varied depending on the model assumptions. These tools provide unique but complementary information. PMID- 21294153 TI - CD34+ collection efficiency as a function of blood volumes processed in pediatric autologous peripheral blood stem cell collection. AB - PURPOSE: To characterize the relationship between CD34(+) collection efficiency and blood volumes processed in pediatric patients undergoing autologous peripheral blood stem cell (PBSC) collection. METHODS: Retrospective 8-year (2001 2009) study of pediatric patients (n = 79) with neuroblastoma and central nervous system (CNS) tumors undergoing first day of autologous PBSC harvest using MNC program on the COBE Spectra (Caridian BCT, Lakewood, CO) was performed. Patients undergoing 0 to 2.9 BV (standard volume), 3 to 6 BV (large volume), and greater than 6 BV (ultra large volume) harvests were evaluated for CD34(+) collection efficiency, diagnosis (neuroblastoma vs. nonneuroblastoma), disease type (primary vs. relapse), mobilization regimen, granulocyte colony stimulating factor (GCSF) dose, and apheresis complications. RESULTS: CD34(+) collection efficiencies (CE) for neuroblastoma patients were 67%, 50%, and 53% for standard (n = 14), large (n = 9), and ultra large (n = 5) volume harvests, respectively. Similarly, patients with nonneuroblastoma diagnoses had CD34(+) CE of 63%, 55%, and 65% for low (n = 19), large (n = 27), and ultra large (n = 5) volume harvests, respectively. Weight, granulocyte colony stimulating factor (G-CSF) stimulation, type of mobilization, and apheresis complications (normalized by run time) were similar between the standard, large, and ultra large volume groups in patients with either neuroblastoma or nonneuroblastoma diagnoses. CONCLUSIONS: CD34(+) collection efficiency in pediatric autologous PBSC collection on the first day of harvest does not decrease with higher numbers of blood volumes processed in patients with either neuroblastoma or nonneuroblastoma primary disease. These results indirectly indicate bone marrow CD34(+) cell mobilization occurs with longer apheresis procedures in pediatric patients. PMID- 21294154 TI - Three-dimensional MR-encephalography: fast volumetric brain imaging using rosette trajectories. AB - MR-Encephalography (MREG) is a technique that allows real time observation of functional changes in the brain that appears within 100 msec. The high sampling rate is achieved at the cost of some spatial resolution. The article describes a novel imaging method for fast three-dimensional-MR-encephalography whole brain coverage based on rosette trajectories and the use of multiple small receiver coils. The technique allows the observation of changes in brain physiology at very high temporal resolution. A highly undersampled three-dimensional rosette trajectory is chosen, to perform single shot acquisition of k-space data within 23 msec. By using a 32-channel head coil array and regularized nonuniform Fourier transformation reconstruction, the spatial resolution is sufficient to detect even subtle centers of activation (e.g. human MT+). The method was applied to visual block design paradigms and compared with echo planar imaging-based functional MRI. As a proof-of-principle of the method's ability to detect local differences in the hemodynamic response functions, the analyzed MR encephalography data revealed a spatially dependent delay of the arrival of the blood oxygenation level dependent response within the visual cortex. PMID- 21294155 TI - The man who could not walk backward: an unusual presentation of neuroferritinopathy. PMID- 21294156 TI - Identification of biochemical and putative biological role of a xenolog from Escherichia coli using structural analysis. AB - YagE is a 33 kDa prophage protein encoded by CP4-6 prophage element in Escherichia coli K12 genome. Here, we report the structures of YagE complexes with pyruvate (PDB Id 3N2X) and KDGal (2-keto-3-deoxy galactonate) (PDB Id 3NEV) at 2.2A resolution. Pyruvate depletion assay in presence of glyceraldehyde shows that YagE catalyses the aldol condensation of pyruvate and glyceraldehyde. Our results indicate that the biochemical function of YagE is that of a 2-keto-3 deoxy gluconate (KDG) aldolase. Interestingly, E. coli K12 genome lacks an intrinsic KDG aldolase. Moreover, the over-expression of YagE increases cell viability in the presence of certain bactericidal antibiotics, indicating a putative biological role of YagE as a prophage encoded virulence factor enabling the survival of bacteria in the presence of certain antibiotics. The analysis implies a possible mechanism of antibiotic resistance conferred by the over expression of prophage encoded YagE to E. coli. PMID- 21294157 TI - Specificity and cooperativity at beta-lactamase position 104 in TEM-1/BLIP and SHV-1/BLIP interactions. AB - Establishing a quantitative understanding of the determinants of affinity in protein-protein interactions remains challenging. For example, TEM-1/beta lactamase inhibitor protein (BLIP) and SHV-1/BLIP are homologous beta lactamase/beta-lactamase inhibitor protein complexes with disparate K(d) values (3 nM and 2 MUM, respectively), and a single substitution, D104E in SHV-1, results in a 1000-fold enhancement in binding affinity. In TEM-1, E104 participates in a salt bridge with BLIP K74, whereas the corresponding SHV-1 D104 does not in the wild type SHV-1/BLIP co-structure. Here, we present a 1.6 A crystal structure of the SHV-1 D104E/BLIP complex that demonstrates that this point mutation restores this salt bridge. Additionally, mutation of a neighboring residue, BLIP E73M, results in salt bridge formation between SHV-1 D104 and BLIP K74 and a 400-fold increase in binding affinity. To understand how this salt bridge contributes to complex affinity, the cooperativity between the E/K or D/K salt bridge pair and a neighboring hot spot residue (BLIP F142) was investigated using double mutant cycle analyses in the background of the E73M mutation. We find that BLIP F142 cooperatively stabilizes both interactions, illustrating how a single mutation at a hot spot position can drive large perturbations in interface stability and specificity through a cooperative interaction network. PMID- 21294158 TI - A distinct subset of glioma cell lines with stem cell-like properties reflects the transcriptional phenotype of glioblastomas and overexpresses CXCR4 as therapeutic target. AB - Glioblastomas contain stem-like cells that can be maintained in vitro using specific serum-free conditions. We investigated whether glioblastoma stem-like (GS) cell lines preserve the expression phenotype of human glioblastomas more closely than conventional glioma cell lines. Expression profiling revealed that a distinct subset of GS lines, which displayed a full stem-like phenotype (GSf), mirrored the expression signature of glioblastomas more closely than either other GS lines or cell lines grown in serum. GSf lines are highly tumorigenic and invasive in vivo, express CD133, grow spherically in vitro, are multipotent and display a Proneural gene expression signature, thus recapitulating key functional and transcriptional aspects of human glioblastomas. In contrast, GS lines with a restricted stem-like phenotype exhibited expression signatures more similar to conventional cell lines than to original patient tumors, suggesting that the transcriptional resemblance between GS lines and tumors is associated with different degrees of "stemness". Among markers overexpressed in patient tumors and GSf lines, we identified CXCR4 as a potential therapeutic target. GSf lines contained a minor population of CXCR4(hi) cells, a subfraction of which coexpressed CD133 and was expandable by hypoxia, whereas conventional cell lines contained only CXCR4(lo) cells. Convection-enhanced local treatment with AMD3100, a specific CXCR4 antagonist, inhibited the highly invasive growth of GS xenografts in vivo and cell migration in vitro. We thus demonstrate the utility of GSf lines in testing therapeutic agents and validate CXCR4 as a target to block the growth of invasive tumor-initiating glioma stem cells in vivo. PMID- 21294159 TI - Expression and detrimental role of hematopoietic prostaglandin D synthase in spinal cord contusion injury. AB - Prostaglandin D(2) (PGD(2) ) is a potent inflammatory mediator, which is implicated in both the initiation and resolution of inflammation in peripheral non-neural tissues. Its role in the central nervous system has not been fully elucidated. Spinal cord injury (SCI) is associated with an acute inflammatory response, which contributes to secondary tissue damage that worsens functional loss. We show here, with the use of hematopoietic prostaglandin D synthase (HPGDS) deficient mice and a HPGDS selective inhibitor (HQL-79), that PGD(2) plays a detrimental role after SCI. We also show that HPGDS is expressed in macrophages in the injured mouse spinal cord and contributes to the increase in PGD(2) in the contused spinal cord. HPGDS(-/-) mice also show reduced secondary tissue damage and reduced expression of the proinflammatory chemokine CXCL10 as well as an increase in IL-6 and TGFbeta-1 expression in the injured spinal cord. This was accompanied by a reduction in the expression of the microglia/macrophage activation marker Mac-2 and an increase in the antioxidant metallothionein III. Importantly, HPGDS deficient mice exhibit significantly better locomotor recovery after spinal cord contusion injury than wild-type (Wt) mice. In addition, systemically administered HPGDS inhibitor (HQL-79) also enhanced locomotor recovery after SCI in Wt mice. These data suggest that PGD(2) generated via HPGDS has detrimental effects after SCI and that blocking the activity of this enzyme can be beneficial. PMID- 21294160 TI - Inducible gene expression in GFAP+ progenitor cells of the SGZ and the dorsal wall of the SVZ-A novel tool to manipulate and trace adult neurogenesis. AB - In the adult mammalian brain, neurogenesis originates from astrocyte-like stem cells. We generated a transgenic mouse line in which the tetracycline dependent transactivator (tTA) is expressed under the control of the murine GFAP promoter. In this mouse line, inducible gene expression targets virtually all GFAP expressing stem-like cells in the dentate gyrus and a subset of GFAP-expressing progenitors located primarily in the dorsal wall/dorsolateral corner of the subventricular zone. Outside the neurogenic zones, astrocytes are infrequently targeted. We introduce a panel of transgenic mice which allow both inducible expression of candidate genes under control of the murine GFAP promoter and, at the same time, lineage tracing of all cells descendant from the original GFAP positive cell. This new mouse line represents a versatile tool for functional analysis of neurogenesis and lineage tracing. PMID- 21294161 TI - Isocitrate dehydrogenase mutations: a challenge to traditional views on the genesis and malignant progression of gliomas. AB - Isocitrate dehydrogenases (IDHs) convert isocitrate to alpha-ketoglutarate by oxidative decarboxylation and are thereby involved in multiple metabolic processes. Mutations in the genes encoding IDH1 and IDH2 were first reported in human gliomas in 2008 and later on also identified in a minority of patients with acute myeloid leukemia. The mutations universally affect codons 132 in IDH1 and 172 in IDH2 and result in decreased enzymatic activity. The oncogenic pathway triggered by IDH mutations may involve the activation of hypoxia-inducible factor pathway as well as the acquisition of a novel (gain of enzymatic) function consuming NADPH and generating alpha-hydroxyglutarate. Most intriguingly, IDH mutations are observed in ~70-80% of grade II/III gliomas and the majority of secondary glioblastomas, but only 10% of primary glioblastomas, suggesting a different cellular origin of the gliomas, which had previously been viewed as a multistep process of malignant progression. Understanding the oncogenic pathway mediated by mutant IDH might result in the development of novel, tailored pharmacological therapies for human glioma patients. PMID- 21294162 TI - An Alzheimer's disease-relevant presenilin-1 mutation augments amyloid-beta induced oligodendrocyte dysfunction. AB - White matter pathology has been documented in the brains of familial Alzheimer's disease (FAD)-afflicted individuals during presymptomatic and preclinical stages of AD. How these defects in myelination integrity arise and what roles they may play in AD pathophysiology have yet to be fully elucidated. We previously demonstrated that triple-transgenic AD (3xTg-AD) mice, which harbor the human amyloid precursor Swedish mutation, presenilin-1 M146V (PS1(M146V) ) knock-in mutation, and tau(P301L) mutation, exhibit myelin abnormalities analogous to FAD patients and that Abeta(1-42) contributes to these white matter deficits. Herein, we demonstrate that the PS1(M146V) mutation predisposes mouse oligodendrocyte precursor (mOP) cells to Abeta(1-42) -induced alterations in cell differentiation in vitro. Furthermore, PS1(M146V) expression compromised mOP cell function and MBP protein distribution, a process that is further aggravated with exposure to Abeta(1-42) . We found that the myelination defect and MBP subcellular mislocalization triggered by PS1(M146V) and Abeta(1-42) can be effectively prevented by treatment with the GSK-3beta inhibitor, TWS119, thereby implicating GSK-3beta kinase activity in this pathogenic cascade. Overall, this work provides further mechanistic insights into PS1(M146V) and Abeta(1-42) -driven oligodendrocyte dysfunction andmyelin damage during early presymptomatic stages of AD, and provides a new target in oligodendrocytes for developing therapies designed to avert AD-related white matter pathology. PMID- 21294163 TI - FOXO3a inhibits TNF-alpha- and IL-1beta-induced astrocyte proliferation:Implication for reactive astrogliosis. AB - Reactive astrogliosis is one of the pathological hallmarks of neurodegenerative diseases. Inflammatory cytokines, such as TNF-alpha and IL-1beta, have been shown to mediate the reactive astrogliosis in neurodegenerative diseases; however, the molecular mechanism remains unclear. In this study, we investigated the role of transcription factor FOXO3a on astrocyte proliferation, one primary aspect of severe reactive astrogliosis. Our results confirmed that TNF-alpha and IL-1beta increased astrocyte proliferation, as determined by Ki67 and BrdU immunostaining. Furthermore, we found that cytokine-mediated astrocyte proliferation was accompanied by an increase of the phosphorylation and reduced nuclear expression of FOXO3a. Intracranial injection of TNF-alpha and IL-1beta induced astrocyte proliferation and hypertrophy, which was associated with reduced nuclear expression of Foxo3a in astrocytes. To determine the function of FOXO3a in astrocyte proliferation, wild type FOXO3a was overexpressed with adenovirus, which subsequently upregulated p27Kip1 and Gadd45alpha, and significantly inhibited cytokine-induced astrocyte proliferation. In contrast, overexpression of dominant negative FOXO3a decreased p27Kip1, upregulated cyclin D1 and promoted astrocyte proliferation. Along the same line, astrocytes isolated from Foxo3a null mice have higher proliferative potential. In response to intracranial injection of cytokines, Foxo3a-null mice manifested severe astrogliosis in vivo. In conclusion, FOXO3a is important in restraining astrocyte proliferation during proinflammatory cytokine stimulation and loss of function of FOXO3a may be responsible for the proliferation of astrocytes in the severe form of reactive astrogliosis. Understanding the key regulatory role of FOXO3a in reactive astrogliosis may provide a novel therapeutic target during neuroinflammation. PMID- 21294164 TI - The ultrastructure of perisynaptic glia in the nucleus tractus solitarii of the adult rat: Comparison between single synapses and multisynaptic arrangements. AB - Astrocytes are now considered as essential partners of neurons. In particular, they play important roles in glutamatergic transmission, including transmitter inactivation by uptake. Here, we investigated the organization of astroglia in the Nucleus Tractus Solitarii (NTS), a sensory nucleus located in the caudal medulla. Special attention was given to perisynaptic astroglial processes. Investigations were performed at the light and electron microscope levels, using immunodetection of glial glutamate transporters, stereological methods, and serial reconstruction. In the NTS, the main glutamate transporter expressed by astrocytes was GLT1. The volume fraction of astrocyte processes and the density of astrocyte membranes reached 15% and 2.8 MUm(2) MUm(-3) , respectively. In spite of the relative abundance of astrocyte processes, we found that NTS glutamatergic synapses were not entirely surrounded by glia. Measurements were performed on 43 reconstructed asymmetric junctions which were either single synapses (n = 22) or synapses involved in multisynaptic arrangements (n = 21). Single synapses had 58% of their perimeter contacted by astrocyte processes on average. In multisynaptic arrangement, glial coverage was restricted to the outer part of synaptic diameters and amounted to 50% of this outer part on average. Incomplete glial coverage of NTS synapses may allow glutamate to diffuse out of the synaptic cleft and to activate extrasynaptic receptors as well as receptors from neighboring synapses. Especially, in multisynaptic arrangements, the lack of intervening glia may favor functional coupling between individual contacts. PMID- 21294165 TI - Signaling pathways of ATP-induced PGE2 release in spinal cord astrocytes are EGFR transactivation-dependent. AB - Traumatic spinal cord injury is characterized by an immediate, irreversible loss of tissue at the lesion site, as well as a secondary expansion of tissue damage over time. Although secondary injury should, in principle, be preventable, no effective treatment options currently exist for patients with acute spinal cord injury (SCI). Excessive release of ATP by the traumatized tissue, triggers the rapid release of arachidonic acid (AA) and prostaglandin E2 (PGE2), and has beenimplicated in acute and chronic neuropathic pain and inflammation. But the intracellular pathways between ATP and PGE2 remain largely unknown. We have explored the signaling events involved in this synthesis by primarily culturing spinal cord astrocytes: (1) we determined significant PGE2 production increased by ATP is mainly via Subtype 1 of P2 purinoceptors (P2Y1) but not P2Y2; (2) we found that ATP strongly increased the level of intracellular Ca(2+) via P2Y1 receptor; (3) we indicated that ATP stimulates the definitely release of AA and PGE2 which involved the transactivation of epidermal growth factor (EGF) receptor, the phosphorylation of extracellular-regulated protein kinases 1 and 2 (ERK(1/2) ) and the activation of cytosolic phospholipase A(2) (cPLA(2) ); (4) we examined ATP could increase the phosphorylation of Akt via P2Y1 receptor which also depend on the transactivation of EGFR, but the activation of Akt has no effect on the downstream of cPLA(2) phosphorylation. ATP induced by SCI could mobilize the release of AA and PGE2. And inhibition of PGE2 release reduces behavioral signs of pain after SCI and peripheral nerve injury. PMID- 21294166 TI - Effectiveness of virtual reality exposure therapy for active duty soldiers in a military mental health clinic. AB - Exposure therapy is an evidence-based treatment for posttraumatic stress disorder (PTSD), but research evaluating its effectiveness with active duty service members is limited. This report examines the effectiveness of virtual reality exposure therapy (VRE) for active duty soldiers (N = 24) seeking treatment following a deployment to Iraq or Afghanistan. Relative to their pretreatment self-reported symptoms on the PTSD Checklist, Military Version (M = 60.92; SD = 11.03), patients reported a significant reduction at posttreatment (M = 47.08; SD = 12.70; p < .001). Sixty-two percent of patients (n = 15) reported a reliable change of 11 points or more. This study supports the effectiveness of exposure therapy for active duty soldiers and extends previous research on VRE to this population. PMID- 21294167 TI - Deployment to a combat zone and other risk factors for mental health-related disability discharge from the U.S. Army: 1994-2007. AB - Combat exposure is associated with subsequent mental health symptoms, but progression to mental health disability is unclear. Army soldiers discharged with mental health disability (n = 4,457) were compared to two matched control groups: other disability discharge (n = 8,974) and routine discharge (n = 9,128). In multivariate logistic models, odds of mental health disability discharge versus other disability and routine discharge were significantly higher for soldiers deployed to combat zones; odds ratios increased with deployment time. Prior mental health hospitalization decreased these odds, though they remained significantly elevated. Mental health hospitalization with successful treatment may facilitate better coping during deployment. The frequency of disability after mental health hospitalization suggests remaining gaps in deployment-related mental health assessment and treatment. PMID- 21294168 TI - Magnetic materials and devices for the 21st century: stronger, lighter, and more energy efficient. AB - A new energy paradigm, consisting of greater reliance on renewable energy sources and increased concern for energy efficiency in the total energy lifecycle, has accelerated research into energy-related technologies. Due to their ubiquity, magnetic materials play an important role in improving the efficiency and performance of devices in electric power generation, conditioning, conversion, transportation, and other energy-use sectors of the economy. This review focuses on the state-of-the-art hard and soft magnets and magnetocaloric materials, with an emphasis on their optimization for energy applications. Specifically, the impact of hard magnets on electric motor and transportation technologies, of soft magnetic materials on electricity generation and conversion technologies, and of magnetocaloric materials for refrigeration technologies, are discussed. The synthesis, characterization, and property evaluation of the materials, with an emphasis on structure-property relationships, are discussed in the context of their respective markets, as well as their potential impact on energy efficiency. Finally, considering future bottlenecks in raw materials, options for the recycling of rare-earth intermetallics for hard magnets will be discussed. PMID- 21294169 TI - Recent progress in multiferroic magnetoelectric composites: from bulk to thin films. AB - Multiferroic magnetoelectric composite systems such as ferromagnetic ferroelectric heterostructures have recently attracted an ever-increasing interest and provoked a great number of research activities, driven by profound physics from coupling between ferroelectric and magnetic orders, as well as potential applications in novel multifunctional devices, such as sensors, transducers, memories, and spintronics. In this Review, we try to summarize what remarkable progress in multiferroic magnetoelectric composite systems has been achieved in most recent few years, with emphasis on thin films; and to describe unsolved issues and new device applications which can be controlled both electrically and magnetically. PMID- 21294172 TI - Enantioselective organocatalytic synthesis of fluorinated molecules. AB - The enantioselective synthesis of fluorinated molecules has drawn much attention within the chemical community due to its unique stereoelectronic properties. The main aim of this review is to cover the most important organocatalytic enantioselective methodologies to obtain them. The review is divided into three parts: first, the direct introduction of a fluorine atom studied in the early 2000s. Second, the later use of Michael reactions to introduce fluorine containing synthons. Finally, the simultaneously-developed trifluoromethylation reactions, giving the catalysts, mechanisms and reagents that have been used. PMID- 21294173 TI - Designing metal-free catalysts by mimicking transition-metal pincer templates. PMID- 21294174 TI - Synthesis and self-assembly of oligo(p-phenylenevinylene) peptide conjugates in water. PMID- 21294175 TI - Modulation of DNA-modified gold-nanoparticle stability in salt with concatemeric single-stranded DNAs for colorimetric bioassay development. PMID- 21294176 TI - Turn-on fluorescence sensing of cyanide ions in aqueous solution at parts-per billion concentrations. PMID- 21294177 TI - Cobalt imidazolate framework as precursor for oxygen reduction reaction electrocatalysts. PMID- 21294178 TI - A family of chiral metal-organic frameworks. AB - Chiral metal-organic frameworks with a three-dimensional network structure and wide-open pores (>30 A) were obtained by using chiral trifunctional linkers and multinuclear zinc clusters. The linkers, H(3) ChirBTB-n, consist of a 4,4',4'' benzene-1,3,5-triyltribenzoate (BTB) backbone decorated with chiral oxazolidinone substituents. The size and polarity of these substituents determines the network topology formed under solvothermal synthesis conditions. The resulting chiral MOFs adsorb even large molecules from solution. Moreover, they are highly active Lewis acid catalysts in the Mukaiyama aldol reaction. Due to their chiral functionalization, they show significant levels of enantioselectivity, thereby proving the validity of the modular design concept employed. PMID- 21294179 TI - Heteroatom-substituted secondary phosphine oxides (HASPOs) as decomposition products and preligands in rhodium-catalysed hydroformylation. AB - O,O'-3,3'-Di-tert-butyl-5,5'-dimethoxy-1,1'-biphenyl-2,2'-diyl phosphonate (1) is the hydrolysis product of several mono- and bis-phosphites used as ligands in industrial hydroformylation and other catalytic reactions. As a result of a tautomeric equilibrium, this pentavalent heteroatom-substituted phosphine oxide (HASPO) can rearrange to the corresponding trivalent phosphorus compound. The latter is able to react with typical rhodium-containing precursors frequently used for the generation of catalysts. The resulting species were characterised by NMR spectroscopy and X-ray structure analysis. Proof is given that a rhodium complex of 1 forms an active hydroformylation catalyst. Moreover, 1 can add to aldehydes, which are generated as products in the hydroformylation. Thus a broad range of subsequent reactions can be associated with the degradation of the original phosphite ligands, which has a strong influence on the overall outcome of the hydroformylation reaction. PMID- 21294180 TI - Syntheses, structures, and reactivities of homometallic rare-earth-metal multimethyl methylidene and oxo complexes. AB - Unsolvated, trinuclear, homometallic, rare-earth-metal multimethyl methylidene complexes [{(NCN)Ln(MU(2)-CH(3))}(3)(MU(3)-CH(3))(MU(3)-CH(2))] (NCN = L = [PhC{NC(6)H(4)(iPr-2,6)(2)}(2)](-); Ln = Sc (2a), Lu (2b)) have been synthesized by treatment of [(L)Ln{CH(2)C(6)H(4)N(CH(3))(2)-o}(2)] (Ln = Sc (1a), Lu (1b)) with two equivalents of AlMe(3) in toluene at ambient temperature in good yields. Treatment of 1 with three equivalents of AlMe(3) gives the heterometallic trinuclear complexes [(L)Ln(AlMe(4))(2)] (Ln = Sc (3a), Lu (3b)) in good yields. Interestingly, 2 can also be generated by recrystallization of 3 in THF/toluene, thereby indicating that the THF molecule can also induce C-H bond activation of 2. Reaction of 2 with one equivalent of ketones affords the trinuclear homometallic oxo-trimethyl complexes [{(L)Ln(MU(2) -CH(3))}(3) (MU(3) CH(3))(MU(3)-O)] (Ln = Sc(4a), Lu(4b)) in high yields. Complex 4b reacts with one equivalent of cyclohexanone to give the methyl abstraction product [{(L)Lu(MU(2) CH(3) )}(3) (MU(3) -OC(6)H(9))(MU(3)-O)] (5b), whereas reaction of 4b with acetophenone forms the insertion product [{(L)Lu(MU(2)-CH(3))}(3){MU(3) OCPh(CH(3))(2)}(MU(3)-O)] (6b). Complex 4a is inert to ketone under the same conditions. All these new complexes have been characterized by elemental analysis, NMR spectroscopy, and confirmed by X-ray diffraction determination. PMID- 21294181 TI - Selectivity among two lectins: probing the effect of topology, multivalency and flexibility of "clicked" multivalent glycoclusters. AB - The design of multivalent glycoconjugates has been developed over the past decades to obtain high-affinity ligands for lectin receptors. While multivalency frequently increases the affinity of a ligand for its lectin through the so called "glycoside cluster effect", the binding profiles towards different lectins have been much less investigated. We have designed a series of multivalent galactosylated glycoconjugates and studied their binding properties towards two lectins, from plant and bacterial origins, to determine their potential selectivity. The synthesis was achieved through copper(I)-catalysed azide-alkyne cycloaddition (CuAAC) under microwave activation between propargylated multivalent scaffolds and an azido-functionalised carbohydrate derivative. The interactions of two galactose-binding lectins from Pseudomonas aeruginosa (PA-IL) and Erythrina cristagalli (ECA) with the synthesized glycoclusters were studied by hemagglutination inhibition assays (HIA), surface plasmon resonance (SPR) and isothermal titration microcalorimetry (ITC). The results obtained illustrate the influence of the scaffold's geometry on the affinity towards the lectin and also on the relative potency in comparison with a monovalent galactoside reference probe. PMID- 21294182 TI - Two successive reactions on a DNA template: a strategy for improving background fluorescence and specificity in nucleic acid detection. AB - We report a new strategy for template-mediated fluorogenic chemistry that results in enhanced performance for the fluorescence detection of nucleic acids. In this approach, two successive templated reactions are required to induce a fluorescence signal, rather than only one. These novel fluorescein-labeled oligonucleotide probes, termed 2-STAR (STAR = Staudinger-triggered alpha azidoether release) probes, contain two quencher groups tethered by separate reductively cleavable linkers. When a 2-STAR quenched probe successively binds adjacent to two mono-triphenylphosphine-(TPP)-DNAs or one dual-TPP-DNA, the two quenchers are released, resulting in a fluorescence signal. Because of the requirement for two consecutive reactions, 2-STAR probes display an unprecedented level of sequence specificity for template-mediated probe designs. At the same time, background emission generated by off-template reactions or incomplete quenching is among the lowest of any fluorogenic reactive probes for the detection of DNA or RNA. PMID- 21294183 TI - A versatile tripodal host with cylindrical conformation: solvatomorphism, inclusion behavior, and separation of guests. AB - Tripodal host 2,4,6-tris(1-phenyl-1H-tetrazolylsulfanylmethyl)mesitylene (TPTM) has been synthesized through a facile procedure. As expected, it adopts an all syn cylindrical configuration, thereby delimiting an inner cavity. To explore the solvatomorphism and inclusion behavior of TPTM, a series of organic and inorganic species were employed as guests to afford 17 inclusion compounds (1, 2, 3 a-3 f, 4 a-4 i) that can be classified into four distinct forms (forms I-IV), under similar conditions. These compounds were characterized by single-crystal and powder X-ray diffraction, and (1)H NMR studies. In compound 1 with form I, one foot of a TPTM molecule inserts into the cavity of an opposite TPTM molecule to form a dimeric "hand-shake" motif with one acetonitrile molecule occupying the void. Compound 2 with form II contains three types of capsule-shaped dimers, each of which holds a CH(2)Cl(2) molecule as the guest. In compounds 3 a-3 f with form III, each pair of TPTM molecules interdigitates to form a capsule-shaped dimeric unit accommodating a guest molecule in the endo-cavity. In compounds 4 a-4 i with form IV, each TPTM molecule makes contact with three nearby TPTM molecules in a "self-including" manner to generate a graphite-like organic layer, and through further superposition to form open hexagonal channels. From the experimental and theoretical results, the intrinsic properties of guest molecules, such as size, shape, and self-interaction, can be regarded as the main factors leading to these solvatomorphism phenomena and the subtle inclusion behavior of TPTM. Thermogravimetric analyses show that the encapsulated guest molecules in these compounds can be evacuated at relatively high temperatures, and this demonstrates the outstanding inclusion capability of TPTM. In addition, for compound 4 a with benzene molecules in the channels, reversible exchange of toluene and separation of xylene isomers on single crystals have been observed. PMID- 21294184 TI - Factors that control zeolite L crystal size. AB - Time-series hydrothermal syntheses from two organic-cation-free gels with different compositions were employed to study the factors that control the final size of zeolite L crystals. The first gel had a starting K/Al ratio of 10, whereas in the second one it was three times lower. The relatively simple chemical composition of the starting gels and the combination of complementary characterization methods allowed us to track down the different stages of transformation of the initial amorphous gels into zeolite crystals and the factors that control the nucleation and growth processes. The role of the starting mixture components in the formation of the primary amorphous particles was explored. It was found that the profoundly different reaction kinetics in the two systems are caused by the difference in diffusion rates, which in turn are controlled by the extent of the polymerization reactions at room temperature during mixing of the starting components prior to hydrothermal treatment. As a consequence, nucleation is fast and ubiquitous in the first system with higher water content and K/Al ratio, whereas it is slow and sporadic in the second system with lower water content and K/Al ratio. Ultimately, these differences in the kinetics lead to the formation of two distinctly different patterns of crystal-size distribution, with a large number of small nanocrystals in the first sample and fewer large crystals in the second sample. The new findings put zeolite crystal growth on a rational basis that would enable the control of zeolite crystal size in similar organic-template-free systems. PMID- 21294185 TI - Au nanowire-on-film SERRS sensor for ultrasensitive Hg2+ detection. AB - We report an ultrasensitive and selective single nanowire-on-film (SNOF) surface enhanced resonance Raman scattering (SERRS) sensor for Hg(2+) detection based on structure-switching double stranded DNAs (dsDNAs). Binding of Hg(2+) induces conformational changes of the dsDNAs and let a Raman reporter get close to the SNOF structure, thereby turning on SERRS signal. The well-defined SNOF structure provides a detection limit of 100 pM with improved accuracy in Hg(2+) detection. This sensor is stable over a considerable amount of time and reusable after simple treatment. Since this SNOF sensor is composed of a single Au NW on a film, development of a multiplex sensor would be possible by employing NWs modified by multiple kinds of aptamers. PMID- 21294186 TI - Anthraquinone-sensitized photooxidation of 5-methylcytosine in DNA leading to piperidine-induced efficient strand cleavage. AB - One-electron photooxidations of 5-methyl-2'-deoxycytidine (d(m)C) and 5 trideuteriomethyl-2'-deoxycytidine ([D(3)]d(m)C) by sensitization with anthraquinone (AQ) derivatives were investigated. Photoirradiation of an aerated aqueous solution containing d(m)C and anthraquinone 2-sulfonate (AQS) afforded 5 formyl-2'-deoxycytidine (d(f)C) and 5-hydroxymethyl-2'-deoxycytidine (d(hm)C) in good yield through an initial one-electron oxidation process. The deuterium isotope effect on the AQS-sensitized photooxidation of d(m)C suggests that the rate-determining step in the photosensitized oxidation of d(m)C involves internal transfer of the C5-hydrogen atom of a d(m)C-tetroxide intermediate to produce d(f)C and d(hm)C. In the case of a 5-methylcytosine ((m)C)-containing duplex DNA with an AQ chromophore that is incorporated into the backbone of the DNA strand so as to be immobilized at a specific position, (m)C underwent efficient direct one-electron oxidation by the photoexcited AQ, which resulted in an exclusive DNA strand cleavage at the target (m)C site upon hot piperidine treatment. In accordance with the suppression of the strand cleavage at 5-trideuterio methylcytosine observed in a similar AQ photosensitization, it is suggested that deprotonation at the C5-methyl group of an intermediate (m)C radical cation may occur as a key elementary reaction in the photooxidative strand cleavage at the (m)C site. Incorporation of an AQ sensitizer into the interior of a strand of the duplex enhanced the one-electron photooxidation of (m)C, presumably because of an increased intersystem crossing efficiency that may lead to efficient piperidine induced strand cleavage at an (m)C site in a DNA duplex. PMID- 21294187 TI - Self-assembly approach toward chiral bimetallic catalysts: bis-urea functionalized (salen)cobalt complexes for the hydrolytic kinetic resolution of epoxides. AB - A series of novel bis-urea-functionalized (salen)Co complexes has been developed. The complexes were designed to form self-assembled structures in solution through intermolecular urea-urea hydrogen-bonding interactions. These bis-urea (salen)Co catalysts resulted in rate acceleration (up to 13 times) in the hydrolytic kinetic resolution (HKR) of rac-epichlorohydrin in THF by facilitating cooperative activation, compared to the monomeric catalyst. In addition, one of the bis-urea (salen)Co(III) catalyst efficiently resolves various terminal epoxides even under solvent-free conditions by requiring much shorter reaction time at low catalyst loading (0.03-0.05 mol %). A series of kinetic/mechanistic studies demonstrated that the self-association of two (salen)Co units through urea-urea hydrogen bonds was responsible for the observed rate acceleration. The self-assembly study with the bis-urea (salen)Co by FTIR spectroscopy and with the corresponding (salen)Ni complex by (1)H NMR spectroscopy showed that intermolecular hydrogen-bonding interactions exist between the bis-urea scaffolds in THF. This result demonstrates that self-assembly approach by using non covalent interactions can be an alternative and useful strategy toward the efficient HKR catalysis. PMID- 21294188 TI - Photochromic and reductive electrochemical switching of a dithiazolylethene with large redox modulation. AB - A new dipyridylthiazolylethene (1a) and its dicationic analogue (2a), with two N methylated pyridyl rings, have been synthesized and structurally characterized. Due to the N-methylation of the pyridyl rings, 2 a displays not only very different photochromic properties, but also undergoes a reductive ring-closing reaction to generate its closed-ring isomer 2b. Careful electrochemical studies coupled with EPR spectroscopy show that this reductive ring-closing reaction takes place when 2a is two-electron reduced. DFT calculations suggest that such a ground-state electrocyclization is driven by a very large stabilization of the reduced closed-ring isomer 2b relative to the reduced open-ring isomer 2a. In addition, 2b exhibits two successive and reversible one-electron reductions at half-wave potentials of 0.04 and -0.14 V versus SCE and a redox modulation as large as 1 V is achieved when passing from 2a to 2b. PMID- 21294189 TI - Mechanism of the dehydrogenative silylation of alcohols catalyzed by cationic gold complexes: an experimental and theoretical study. AB - The catalytic activity both of cationic [(XDPP)Au][X] (XDPP = bis-2,5 diphenylphosphole xantphos X = BF(4)) and of the isolated gold hydride complex [(XDPP)(2)Au(2)H][OTf] in the dehydrogenative silylation process is presented. A parallel theoretical study using density functional theory revealed a mechanism involving the counter anion as a co-catalyst, which was experimentally confirmed by testing various counterions (X = OTf, NTf(2), PF(6)). Finally, a "Au(2)H(+)" species was determined as the intermediate during the catalytic cycle, which correlates well with the experimental findings on the first example of catalytic activity of an isolated "Au-H" complex. PMID- 21294190 TI - N-heterocyclic carbene-catalyzed Michael additions of 1,3-dicarbonyl compounds. AB - A study of the organocatalytic activity of N-heterocyclic carbenes (NHCs) in the Michael addition of 1,3-dicarbonyl compounds has allowed us to identify 1,3 bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr) as an excellent catalyst for this transformation (up to 99 % yield with a 2.5 mol % catalyst loading), and the reaction was found to be of broad scope. Two early applications of this unprecedented catalytic activity of NHCs are described, that is, the domino carbocyclization reactions of simple cyclic 1,3-dicarbonyl and malonic acid derivatives, which allow stereoselective access to bridged bicyclic compounds, and the stereoselective synthesis of cyclohexanols (or cyclohexene). Early mechanistic investigations are also reported. PMID- 21294191 TI - An electrochemical and optical anion chemosensor based on tripodal tris(ferrocenylurea). AB - A neutral tripodal tris(ferrocenylurea) anion receptor has been designed that can electrochemically and optically recognize sulfate and phosphate anions. The binding of the tetrahedral anion induced distinct cathodic shifts of the ferrocene/ferrocenium redox couple in chloroform, whereas the UV/Vis spectrum of the receptor showed an increase in the d-d transition band upon addition of sulfate ions. Furthermore, the anion complexes (TBA)2 . [SO4 ?L] . H2O (1) and TBA[F?L] (2; TBA = tetrabutylammonium ion) were isolated. Crystal structural analyses showed that the receptor in the two 1:1 (host/guest) complexes encapsulated sulfate or fluoride ions in the tripodal cavity through multiple hydrogen bonds. (1)H NMR spectroscopic and ESI mass-spectrometric analysis revealed strong sulfate and fluoride binding in solution. PMID- 21294193 TI - Mechanistic insight into stereoselective carbolithiation. AB - This article addresses the mechanistic features of asymmetric carbolithiation of beta-methylstyrenes. While often the presence of functional groups is required to obtain high enantioselectivities in carbolithiation reactions, simple beta methylstyrene also gives high selectivities in (-)-sparteine-mediated addition of alkyl lithium compounds. Computational studies on the carbolithiation of beta methylstyrene with (-)-sparteine show that the observed selectivities are the result of repulsion effects in the diastereomeric transition states between the ( )-sparteine?alkyl lithium adduct and the beta-methylstyrene, upon approximation of the two reactants. In contrast, for the ortho-amino beta-methylstyrene (E) benzyl(2-propenylphenyl)amine (4) X-ray structure analyses of intermediate lithium amides indicate a carbolithiation mechanism in which one side of the double bond is shielded by the amide moiety, leaving only one side free for approach of the chiral alkyl lithium adduct. PMID- 21294194 TI - gamma- and delta-lactams through palladium-catalyzed intramolecular allylic alkylation: enantioselective synthesis, NMR Investigation, and DFT rationalization. AB - The Pd-catalyzed intramolecular allylic alkylation of unsaturated amides to give gamma- and delta-lactams has been studied in the presence of chiral ligands. Ligand (R)-3,5-tBu-MeOBIPHEP (MeOBIPHEP = 6,6'-dimethoxybiphenyl-2,2 diyl)bis(diphenylphosphine)) afforded the best results and allowed the cyclization reactions to take place in up to 94:6 enantiomeric ratio. A model Pd allyl complex has been prepared and studied through NMR spectroscopic analysis, which provided insight into the processes responsible for the observed enantiomeric ratios. DFT studies were used to characterize the diastereomeric reaction pathways. The calculated energy differences were in good agreement with the experimentally observed enantiomeric ratios. PMID- 21294195 TI - Fluoride-cleavable, fluorescently labelled reversible terminators: synthesis and use in primer extension. AB - Fluorescent 2'-deoxynucleotides containing a protecting group at the 3'-O position are reversible terminators that enable array-based DNA sequencing-by synthesis (SBS) approaches. Herein, we describe the synthesis and full characterisation of four reversible terminators bearing a 3'-blocking moiety and a linker-dye system that is removable under the same fluoride-based treatment. Each nucleotide analogue has a different fluorophore attached to the base through a fluoride-cleavable linker and a 2-cyanoethyl moiety as the 3'-blocking group, which can be removed by using a fluoride treatment as well. Furthermore, we identified a DNA polymerase, namely, RevertAid M-MuLV reverse transcriptase, which can incorporate the four modified reversible terminators. The synthesised nucleotides and the optimised DNA polymerase were used on CodeLink slides spotted with hairpin oligonucleotides to demonstrate their potential in a cyclic reversible terminating approach. PMID- 21294196 TI - Influence of the counterion on the synthesis of ZnO mesocrystals under solvothermal conditions. AB - Polymers and coordinating solvents have been shown to serve as templating agents to assist the precipitation of ZnO nanoparticles and address their morphology. In this work we show for the first time that a difference in the coordination strength between the polymer (poly-N-vinylpyrrolidone (PVP)) and the two Zn(II) precursor salts (nitrate and acetate) is able to promote or suppress the formation of mesocrystalline structures and even more importantly to tune their three-dimensional organization. On the basis of FTIR and (13)C NMR spectroscopic studies, we propose that not only the polymer (PVP) but also the solvent (DMF) play a key role as directing agents. PMID- 21294197 TI - Well-defined air-stable palladium HASPO complexes for efficient Kumada-Corriu cross-couplings of (hetero)aryl or alkenyl tosylates. AB - Palladium complexes of representative heteroatom-substituted secondary phosphine oxide (HASPO) preligands were synthesized and fully characterized, including X ray crystal structure analysis. Importantly, these well-defined complexes served as highly efficient catalysts for Kumada-Corriu cross-coupling reactions of aryl, alkenyl, and even heteroaryl tosylates. Particularly, an air-stable catalyst derived from inexpensive PinP(O)H displayed a remarkably high catalytic efficacy, which resulted in cross-couplings at low catalyst loadings under exceedingly mild reaction conditions with ample scope. PMID- 21294198 TI - Synthesis and isomerization studies of cyclotrisazobiphenyl. AB - We report an efficient synthesis of cyclotris[(E)-3'-(biphenyl-3-yldiazenyl)] compounds (CTBs). An unsubstituted CTB molecule is accessible in four steps in 10% yield overall, whereas a hexa(methoxymethyl ether) CTB analogue was prepared in nine steps (26% yield). The final macrocyclization step was accomplished in up to 80% yield by using a metal-template effect. Furthermore, the photochromic properties were investigated, and all four isomers were detected and characterized by NMR spectroscopy. A strong influence from the solvent and the irradiation wavelength on the switching process was observed. Irradiation in pyridine yielded the highest amount of the all-Z isomer in the photostationary state. For a full conversion to the all-E isomer, the reaction has to be heated to 45 degrees C. The isomerization to the all-E isomer is slow at room temperature, with a half-life time of the all-Z isomer of more than nine days in dimethyl sulfoxide (DMSO). Conditions were established to access each possible isomer as the major component in the photostationary state. PMID- 21294199 TI - A fully conjugated TTF-pi-TCAQ system: synthesis, structure, and electronic properties. AB - The synthesis of the first fully conjugated tetrathiafulvalene-tetracyano-p quinodimethane ((TTF)-TCNQ)-type system has been carried out by means of a Julia Kocienski olefination reaction. In particular, a tetracyanoanthraquinodimethane (TCAQ) formyl derivative and two new sulfonylmethyl-exTTFs (exTTF = 2-[9-(1,3 dithiol-2-ylidene)anthracen-10(9H)-ylidene]-1,3-dithiole)--prepared as new building blocks--were linked. A variety of experimental conditions reveal that the use of sodium hexamethyldisilazane (NaHMDS) as base in THF afforded the E olefins with excellent stereoselectivity. Theoretical calculations at the B3LYP/6 31G** level point to highly distorted exTTF and TCAQ that form an almost planar stilbene unit between them. Although calculations predicted appreciable electronic communication between the donor and the acceptor, cyclic voltammetric studies did not substantiate this effect. It was only in photophysical assays that the electronic communication emerged in the form of a charge-transfer (CT) absorption and emission. Once photoexcited (i.e., the locally excited state or excited charge-transfer state), an ultrafast, subpicosecond charge separation leads to a radical ion pair state in which the spectroscopic features of the radical cation of exTTF as well as the radical anion of TCAQ are discernable. The radical ion pair is metastable and undergoes a fast ((1.0+/-0.2) ps) charge recombination to reconstitute the electronic ground state. Such ultrafast charge separation and recombination processes come as a consequence of the very short vinyl linkage between the two electroactive units. PMID- 21294200 TI - In vitro repair of a biomineral with a mesocrystal structure. PMID- 21294201 TI - Cyclic peptides with a diversely substituted guanidine bridge: solid-phase synthesis and structural analysis. PMID- 21294202 TI - Gold(I)-catalyzed, highly diastereoselective, tandem heterocyclizations/[3+2] cycloadditions: synthesis of highly substituted cyclopenta[c]furans. PMID- 21294203 TI - A double-blind, placebo-controlled investigation of the effects of Passiflora incarnata (passionflower) herbal tea on subjective sleep quality. AB - Passiflora incarnata is a traditional herbal sedative, anxiolytic and a popular sleep aid used for the treatment of sleep disturbance. Several controlled experiments have demonstrated enhanced sleep in laboratory animals, but clinical trials in humans are lacking. The aim of the present study was to investigate the efficacy of Passiflora incarnata herbal tea on human sleep, as measured using sleep diaries validated by polysomnography (PSG). This study featured a double blind, placebo-controlled, repeated-measures design with a counterbalanced order of treatments (passionflower vs placebo tea), separated by a 1 week 'washout' period. Forty-one participants (18-35 years) were exposed to each treatment for a week, whereby they consumed a cup of the tea and filled out a sleep diary for 7 days, and completed Spielberger's state-trait anxiety inventory on the seventh morning. Ten participants also underwent overnight PSG on the last night of each treatment period. Of six sleep-diary measures analysed, sleep quality showed a significantly better rating for passionflower compared with placebo (t(40) = 2.70, p < 0.01). These initial findings suggest that the consumption of a low dose of Passiflora incarnata, in the form of tea, yields short-term subjective sleep benefits for healthy adults with mild fluctuations in sleep quality. PMID- 21294204 TI - Chemical ionization by [NO]+ and subsequent collision-induced dissociation for the selective on-line detection of monoterpenes and linalool. AB - Existing on-line Chemical Ionization Mass Spectrometry (CIMS) techniques for quantification of atmospheric trace gases, such as Biogenic Volatile Organic Compounds (BVOCs), suffer from difficulty in discriminating between isomeric (and more generally isobaric) compounds. Selective detection of these compounds, however, is important because they can affect atmospheric chemistry in different ways, depending on their chemical structure. In this work, Flowing Afterglow Tandem Mass Spectrometry (FATMS) was used to investigate the feasibility of the selective detection of a series of monoterpenes, an oxygenated monoterpene (linalool) and a sesquiterpene (beta-caryophyllene). Ions at m/z 137 from [H(3)O](+) chemical ionization of alpha-pinene, linalool and beta-caryophyllene have been subjected to Collision-Induced Dissociation (CID) with Ar in the collision cell of a tandem mass spectrometer at center-of-mass energies ranging between 0 and 8 eV. Similar fragmentation patterns were obtained, demonstrating that this method is not suited for the selective detection of these compounds. However, CID of the ions at m/z 136 produced via [NO](+) chemical ionization of a series of monoterpenes has revealed promising results. Some tracer-product ions for individual compounds or groups of compounds were found, which can be considered as a step forward towards selective on-line monitoring of BVOCs with CIMS techniques. PMID- 21294205 TI - Dysregulation of Claudin family genes in colorectal cancer in a Chinese population. AB - Claudins play an important role in tumor metastasis and in invasiveness of colorectal cancer (CRC). We have evaluated the relationship between CRC and expression of the claudin genes in Chinese patients with CRC. We measured CLDN1 and CLDN7 mRNA using quantitative PCR, and protein levels with immunohistochemistry in cancer tissues and adjacent normal tissue. Cancer tissues had significantly higher levels of CLDN1, and significantly lower levels of CLDN3, CLDN4, and CLDN7 than did normal tissue. CLDN3, CLDN4, and CLDN7 expression levels were higher in CRC of the protruded type than in CRC of the infiltrative type. Expression of CLDN7 correlated with lymph node metastasis. Stage N0 cancer tissues had higher levels of CLDN7 than did stages N1 and N2, suggesting that CLDN7 expression was closely related to the extent of lymph node metastasis. CLDN1 protein was upregulated, but CLDN7 protein was downregulated in cancer tissues when compared with expression in adjacent normal tissues. In conclusion, CLDN3, CLDN4, and CLDN7 were significantly downregulated, whereas CLDN1 was significantly upregulated in CRC. The altered expression of claudin genes may play a role in the initiation and development of CRC. PMID- 21294206 TI - 7-T (1) H MRS with adiabatic refocusing at short TE using radiofrequency focusing with a dual-channel volume transmit coil. AB - In vivo MRS of the human brain at ultrahigh field allows for the identification of a large number of metabolites at higher spatial resolutions than currently possible in clinical practice. However, the in vivo localization of single-voxel spectroscopy has been shown to be challenging at ultrahigh field because of the low bandwidth of refocusing radiofrequency (RF) pulses. Thus far, the proposed methods for localized MRS at 7 T suffer from long TE, inherent signal loss and/or a large chemical shift displacement artifact that causes a spatial displacement between resonances, and results in a decreased efficiency in editing sequences. In this work, we show that, by driving a standard volume coil with two RF amplifiers, focusing the B 1+ field in a certain location and using high bandwidth adiabatic refocusing pulses, a semi-LASER (semi-localized by adiabatic selective refocusing) localization is feasible at short TE in the human brain with full signal acquisition and a low chemical shift displacement artifact at 7 T. PMID- 21294207 TI - Background suppression in arterial spin labeling MRI with a separate neck labeling coil. AB - In arterial spin labeling (ASL) MRI to measure cerebral blood flow (CBF), pair wise subtraction of temporally adjacent non-labeled and labeled images often can not completely cancel the background static tissue signal because of temporally fluctuating physiological noise. While background suppression (BS) by inversion nulling improves CBF temporal stability, imperfect pulses compromise CBF contrast. Conventional BS techniques may not be applicable in small animals because the arterial transit time is short. This study presents a novel approach of BS to overcome these drawbacks using a separate 'neck' radiofrequency coil for ASL and a 'brain' radiofrequency coil for BS with the inversion pulse placed before spin labeling. The use of a separate 'neck' coil for ASL should also improve ASL contrast. This approach is referred to as the inversion-recovery BS with the two-coil continuous ASL (IR-cASL) technique. The temporal and spatial contrast-to-noise characteristics of basal CBF and CBF-based fMRI of hypercapnia and forepaw stimulation in rats at 7 Tesla were analyzed. IR-cASL yielded two times better temporal stability and 2.0-2.3 times higher functional contrast-to noise ratios for hypercapnia and forepaw stimulation compared with cASL without BS in the same animals. The Bloch equations were modified to provide accurate CBF quantification at different levels of BS and for multislice acquisition where different slices have different degree of BS and residual degree of labeling. Improved basal CBF and CBF-based fMRI sensitivity should lead to more accurate CBF quantification and should prove useful for imaging low CBF conditions such as in white matter and stroke. PMID- 21294208 TI - X-chromosomal genetic diversity and linkage disequilibrium patterns in Amerindians and non-Amerindian populations. AB - OBJECTIVES: We report X-chromosomal linkage disequilibrium (LD) patterns in Amerindian (Kogi, Wayuu, and Zenu) and admixed Latin American (Central Valley of Costa Rica and Southern Brazilian Gaucho) populations. METHODS: Short tandem repeats (STRs) widespread along the X-chromosome were investigated in 132 and 124 chromosomes sampled from the Amerindian tribes and the admixed Latin American populations, respectively. Diversity indexes (gene diversity and average numbers of alleles per locus) were estimated for each population and the level of LD was inferred with an exact test. RESULTS: The Amerindian populations presented lower genetic diversity and a higher proportion of loci in LD than the admixed ones. Two haplotype blocks were identified in the X-chromosome, both restricted to the Amerindians. The first involved DXS8051 and DXS7108 in Xp22.22 and Xp22.3, while the second found only among the Kogi, included eight loci in a region between Xp11.4 and Xq21.1. CONCLUSIONS: In accordance to previous work done with other populations, human isolates, such as Amerindian tribes, seem to be an optimal choice for the implementation of association studies due to the wide extent of LD which can be found in their gene pool. On the other hand, the low proportion of loci in LD found in both admixed populations studied here could be explained by events related to their history and similarities between the allele frequencies in the parental stocks. PMID- 21294210 TI - AXIN2 germline mutations are rare in familial melanoma. PMID- 21294211 TI - Intracellular neutralisation of adenovirus by antibody. PMID- 21294212 TI - Evidence and controversies on the role of XMRV in prostate cancer and chronic fatigue syndrome. AB - The recent discovery of xenotropic murine leukaemia virus-related virus (XMRV) in prostate cancer tissues and in the blood of individuals suffering from chronic fatigue syndrome has attracted considerable interest. However, the relevance and significance of XMRV to human disease remain unclear, since the association has not been confirmed in other studies. XMRV is the first gammaretrovirus to be found in humans. XMRV and murine leukaemia viruses share similar structures and genomic organisation. Human restriction factors such as APOBEC3 or tetherin inhibit XMRV replication. Although XMRV induces low rates of transformation in cell culture, it might be able to induce cancer by low-frequency insertional activation of oncogenes or through the generation of highly active transforming viruses. A preference for regulatory regions of transcriptional active genes has been observed after a genomic-wide analysis of XMRV integration sites. Genes related to carcinogenesis and androgen signalling have been identified in the vicinity of integration sites. The XMRV genome contains a glucocorticoid responsive element, and androgens could modulate viral replication in the prostate. Evidence supporting the involvement of XMRV in chronic fatigue syndrome is still very weak, and needs further confirmation and validation. Currently approved anti-retroviral drugs such as zidovudine, tenofovir and raltegravir are efficient inhibitors of XMRV replication in vitro. These drugs might be useful to treat XMRV infection in humans. The identification of XMRV has potentially serious health implications for the implementation of novel techniques including gene therapy or xenotransplantation, while raising concerns on the need for screening donated blood to prevent transmission through transfusion. PMID- 21294213 TI - Efficient cell culture systems for hepatitis E virus strains in feces and circulating blood. AB - Attempts have been made to propagate hepatitis E virus (HEV) in primary hepatocyte culture and various other cultured cells. However, the replication ability of HEV recovered from culture media remains extremely low. Recently, efficient culture systems have been established in PLC/PRF/5 (hepatocellular carcinoma) and A549 (lung cancer) cell lines for HEV strains of genotypes 3 and 4 in our laboratory. They originated in fecal extracts from patients containing HEV RNA in extremely high-titers (10(7) copies/ml), and named the JE03-1760F (genotype 3) and HE-JF5/15F (genotype 4) strains, respectively. HEV RNA in culture supernatants reached 10(8) copies/ml in titer, and were transmitted successively through many passages. An infectious HEV cDNA clone (pJE03-1760F/wt) was constructed that has replication activity comparable to that of the wild-type JE03-1760F in feces. The ORF3 protein is indispensable for shedding HEV particles from cells in the reverse genetics system. HEV recovered from culture media, as well as circulating HEV, possess ORF3 proteins on the surface and are covered with cellular membranes, and therefore, ORF2 epitopes are buried in these particles. In contrast, HEV excreted into feces are naked nucleocapsids without a lipid layer or surface expression of the ORF3 protein. HEV in sera of patients with acute hepatitis E can infect and replicate in PLC/PRF/5 and A549 cells, with efficiency comparable to the circulating HEV RNA levels. High-efficiency cell culture systems for infectious viruses, thus developed, are expected to open up a new era and resolve many mysteries in the epidemiology, molecular biology, and treatment of HEV. PMID- 21294214 TI - Kobuviruses - a comprehensive review. AB - Kobuviruses are members of the large and growing family Picornaviridae. Until now, two official, Aichi virus and Bovine kobuvirus, and one candidate kobuvirus species, 'porcine kobuvirus', have been identified in human, cattle and swine, respectively. In addition, kobu-like viruses were detected very recently in the bat. Aichi virus could be one of the causative agents of gastroenteritis in humans, and kobuviruses probably also cause diarrhoea in cattle and swine. Although Aichi virus has been detected relatively infrequently (0-3%) in human diarrhoea, high seroprevalence, up to 80-95% at the age of 30-40, was found indicating the general nature of infection in different human populations. In the previous years, much new information has accumulated relating to kobuviruses and their host species. This review summarises the current knowledge on kobuviruses including taxonomy, biology and viral characteristics, and covers all aspects of infection including epidemiology, clinical picture, host species diversity, laboratory diagnosis and it gives a summary about possible future perspectives. PMID- 21294215 TI - Multiple levels of PKR inhibition during HIV-1 replication. AB - Recent therapeutic approaches against HIV-1 include IFN in combination therapy for patients with coinfections or as an alternative strategy against the virus. These treatment options require a better understanding of the weak efficacy of the IFN-stimulated genes, such as the protein kinase RNA-activated (PKR), which results in viral progression. Activated PKR has a strong antiviral activity on HIV-1 expression and production in cell culture. However, PKR is not activated upon HIV-1 infection when the virus reaches high levels of replication, due to viral and cellular controls. PKR is activated by low levels of the HIV-1 trans activation response (TAR) RNA element, but is inhibited by high levels of this double-stranded RNA. The viral Tat protein also counteracts PKR activation by several mechanisms. In addition, HIV-1 replicates only in cells that have a high level of the TAR RNA binding protein (TRBP), a strong inhibitor of PKR activation. Furthermore, increased levels of adenosine deaminase acting on RNA (ADAR1) are observed when HIV-1 replicates at high levels and the protein binds to PKR and inhibits its activation. Finally, the PKR activator (PACT) also binds to PKR during HIV-1 replication with no subsequent kinase activation. The combination of all the inhibiting pathways that prevent PKR phosphorylation contributes to a high HIV-1 production in permissive cells. Enhancing PKR activation by counteracting its inhibitory partners could establish an increased innate immune antiviral pathway against HIV-1 and could enhance the efficacy of the IFN treatment. PMID- 21294217 TI - Characterization of acetaminophen overdose-related emergency department visits and hospitalizations in the United States. AB - PURPOSE: To estimate the number of acetaminophen overdose-related emergency department (ED) visits and hospitalizations in the United States, characterize these by intentionality, age, and gender, and compare the strengths and limitations of the utilized databases. METHODS: We used data from the National Hospital Ambulatory Medical Care Survey (NHAMCS) and the National Electronic Injury Surveillance System (NEISS) to estimate the number of relevant ED visits in the United States between 2000 and 2007, and the National Hospital Discharge Survey (NHDS) to estimate the number of relevant hospitalizations in the United States between 1991 and 2006. National estimates and their standard errors were calculated using information provided in each database. We used the standard United States population in 2000 to calculate age-adjusted rates. RESULTS: We estimate an annual average of 44,348 (NHAMCS, 2000-2007) or 78,414 (NEISS, 2006 2007) acetaminophen overdose-related ED visits and 33,520 (NHDS, 2000-2006) hospitalizations. For 2000-2006 we calculated an age-adjusted rate of 13.9 acetaminophen overdose-related hospitalizations per 100,000 US population, with the highest rate (15.7) occurring from 2005 to 2006. Between 1991 and 2006, there was no decrease noted in hospitalizations for intentional or unintentional overdoses. The majority of overdoses reported in NEISS (69.8%) and NHDS (74.2%) were classified as intentional (suicides or suicidal gestures), whereas in NHAMCS, intentionality was evenly distributed. CONCLUSIONS: Our results suggest that acetaminophen overdose, both intentional and unintentional, remains a significant public health concern. With an understanding of their methodological characteristics and limitations, these national databases can be useful tools to characterize acetaminophen overdose-related ED visits and hospitalizations. PMID- 21294218 TI - Self-report of current and prior antiretroviral drug use in comparison to the medical record among HIV-infected patients receiving primary HIV care. AB - OBJECTIVE: Patient antiretroviral (ARV) therapy knowledge is essential for regimen adherence, successful therapeutic response, and minimization of resistance evolution. Moreover, a complete and accurate patient ARV history is needed to construct efficacious and tolerable future regimens. In this study we assessed the ability of HIV-infected patients receiving care in a university infectious diseases clinic to accurately recall current and past ARVs. METHODS: A convenience sample (n = 205) of UNC HIV Clinical Cohort participants (n = 1840) completed a comprehensive in-person interview. Patients were asked about current and ever ARV use and were provided proprietary and generic ARV names and photographs. Self-reported sensitivity for current and ever ARV use (proportion that correctly identified all recorded ARVs), was calculated using the medical record as the gold standard. RESULTS: One hundred and eighty-five patients had received ARVs at some point after enrollment in the cohort study (ever users). For current ARV use (n = 138), self-reported sensitivity was 63% (95% CI: 54-71). For ever use (n = 185), sensitivity was 18% (95% CI: 13-24). CONCLUSION: Self reported cumulative ARV use is not accurate. Since HIV-infected patients are prescribed a number of medications over their treatment course, it is necessary to develop new medication reconciliation techniques that are not dependent on patient memory or knowledge in order to improve patient outcomes. PMID- 21294219 TI - Demand, selection and patient outcomes in German acute care hospitals. AB - This paper examines the effects of variation in unexpected demand on patient outcomes in acute care German hospitals. Naturally, an unexpected surge in demand may negatively affect the quality of care and thus patient outcomes, such as in hospital mortality. We estimate models explaining patient outcomes depending on demand, unobservable patient selection and seasonal factors, as well as patient specific risk factors and unobservable hospital and department fixed-effects. The main message of this analysis is that hospitals are well prepared to deal with this unexpected volatility in demand, as by and large it does not negatively affect patient outcomes. Hospitals seem to deal with high unexpected workload by steering the patients' length of stay relating to their severity of illness. Elective patients are discharged earlier, while discharges of high-risk emergency patients are postponed. PMID- 21294220 TI - What is driving the black-white difference in low birthweight in the US? AB - This is a first effort to quantify the contribution of different factors in explaining racial difference in low birthweight rate (LBW). Mother's health, child characteristics, prenatal care, socioeconomic status (SES), and the socioeconomic and healthcare environment of mother's community are important inputs into the birthweight production function, and a vast literature has delved into obtaining causal estimates of their effect on infant health. What is unknown is how much of the racial gap in LBW is explained by all these inputs together. We apply a nonlinear extension of the Oaxaca-Blinder method proposed by Fairlie to decompose this gap into the portion explained by differences in observed characteristics and the portion that remains unexplained. Data are obtained from several sources in order to capture as many observables as possible, although the primary data source is the Natality Detail Files. Results show that of the 6.8 percentage point racial gap in LBW, only 0.9-1.9 points are explained by white black differences in endowments across those measures, and of those endowments, most of the gap in LBW is explained by the differences in SES. The unexplained difference is attributed to racial differences in the returns to or the marginal product of investments in infant health. PMID- 21294221 TI - Information giving and receiving in hematological malignancy consultations. AB - PURPOSE: Little is known about communication with patients suffering from hematologic malignancies, many of whom are seen by subspecialists in consultation at tertiary-care centers. These subspecialized consultations might provide the best examples of optimal physician-patient communication behaviors, given that these consultations tend to be lengthy, to occur between individuals who have not met before and may have no intention of an ongoing relationship, and which have a goal of providing treatment recommendations. The aim of this paper is to describe and quantify the content of the subspecialty consultation in regards to exchanging information and identify patient and provider characteristics associated with discussion elements. METHODS: Audio-recorded consultations between 236 patients and 40 hematologists were coded for recommended communication practices. Multilevel models for dichotomous outcomes were created to test associations between patient, physician and consultation characteristics and key discussion elements. RESULTS: Discussions about the purpose of the visit and patient's knowledge about their disease were common. Other elements such as patient's preference for his/her role in decision-making, preferences for information, or understanding of presented information were less common. Treatment recommendations were provided in 97% of the consultations and unambiguous presentations of prognosis occurred in 81% of the consultations. Unambiguous presentations of prognosis were associated with non-White patient race, lower educational status, greater number of questions asked, and specific physician provider. CONCLUSION: Although some communication behaviors occur in most consultations, others are much less common and could help tailor the amount and type of information discussed. Approximately half of the patients are told unambiguous prognostic estimates for mortality or cure. PMID- 21294222 TI - The perils of a vanishing cohort: a study of social comparisons by women with advanced ovarian cancer. AB - OBJECTIVE: To examine the role social comparisons play in the experience of ovarian cancer patients and to consider the implications this may have for provision of supportive care services for ovarian cancer patients. METHODS: We conducted a longitudinal qualitative study of women with advanced ovarian cancer in Sydney, Australia. Semi-structured interviews were conducted with women with advanced ovarian cancer over a period of 2.5 years. Social comparisons made by 13 study participants in 33 interviews were extracted and analysed using coding categories based on social comparison theory. RESULTS: Participants favoured downward contrasts and lateral comparisons and avoided downward identifications, upward contrasts and upward identifications. Participants expressed a preference for avoiding contact with ovarian cancer patients, for the company of 'normal' others, for normalising information and information that facilitated upward identifications. CONCLUSIONS: We suggest that social comparisons made by women with ovarian cancer are influenced by specific clinical factors associated with their diagnosis-in particular, their status as a member of a 'vanishing cohort' and argue for further research examining the specific comparison needs and preferences of patients with advanced disease and types of cancer with poor prognoses. PRACTICE IMPLICATIONS: These findings raise questions about uniform approaches to the provision of cancer care and suggest that further research may be required to ensure that interventions are appropriately tailored to the supportive care needs of patients with different types and stages of disease. PMID- 21294224 TI - Desirability function combining metabolic stability and functionality of peptides. AB - The evaluation of peptides as potential therapeutic or diagnostic agents requires the consideration of several criteria that are targeted around two axes: functionality and metabolic stability. Most often, a compromise has to be made between these mutually opposing characteristics. In this study, Derringer's desirability function, a multi-criteria decision-making method, was applied to determine the best peptide for opioid studies in a single figure-of-merit. The penetration of the blood-brain barrier (BBB) determines the biological functionality of neuropeptides in the brain target tissue, and consists of an influx and an efflux component. The metabolic stability in the two concerned tissues, i.e. plasma and brain, are taken into consideration as well. The overall selection of the peptide drug candidate having the highest BBB-drugability is difficult due to these conflicting responses as well as the different scalings of the four biological parameters under consideration. The highest desirability, representing the best BBB-drugability, was observed for dermorphin. This peptide is thus the most promising drug candidate from the set of eight opioid peptides that were investigated. The least desirable candidate, with the worst BBB influx and/or metabolic stability, was found to be CTAP. Validation of the desirability function by in vivo medical imaging showed that dermorphin and DAMGO penetrate the BBB, whereas EM-1 and TAPP did not. These results are thus consistent with those obtained with the desirability evaluation. To conclude, the multi-criteria decision method was proven to be useful in biomedical research, where a selection of the best candidate based on opposing characteristics is often required. PMID- 21294223 TI - Alterations of excitation-contraction coupling and excitation coupled Ca(2+) entry in human myotubes carrying CAV3 mutations linked to rippling muscle. AB - Rippling muscle disease is caused by mutations in the gene encoding caveolin-3 (CAV3), the muscle-specific isoform of the scaffolding protein caveolin, a protein involved in the formation of caveolae. In healthy muscle, caveolin-3 is responsible for the formation of caveolae, which are highly organized sarcolemmal clusters influencing early muscle differentiation, signalling and Ca(2+) homeostasis. In the present study we examined Ca(2+) homeostasis and excitation contraction (E-C) coupling in cultured myotubes derived from two patients with Rippling muscle disease with severe reduction in caveolin-3 expression; one patient harboured the heterozygous c.84C>A mutation while the other patient harbored a homozygous splice-site mutation (c.102+ 2T>C) affecting the splice donor site of intron 1 of the CAV3 gene. Our results show that cells from control and rippling muscle disease patients had similar resting [Ca(2+) ](i) and 4 chloro-m-cresol-induced Ca(2+) release but reduced KCl-induced Ca(2+) influx. Detailed analysis of the voltage-dependence of Ca(2+) transients revealed a significant shift of Ca(2+) release activation to higher depolarization levels in CAV3 mutated cells. High resolution immunofluorescence analysis by Total Internal Fluorescence microscopy supports the hypothesis that loss of caveolin-3 leads to microscopic disarrays in the colocalization of the voltage-sensing dihydropyridine receptor and the ryanodine receptor, thereby reducing the efficiency of excitation-contraction coupling. PMID- 21294225 TI - DPP-IV-resistant, long-acting oxyntomodulin derivatives. AB - Obesity is one of the major risk factors for type 2 diabetes, and the development of agents, that can simultaneously achieve glucose control and weight loss, is being actively pursued. Therapies based on peptide mimetics of the gut hormone glucagon-like peptide 1 (GLP-1) are rapidly gaining favor, due to their ability to increase insulin secretion in a strictly glucose-dependent manner, with little or no risk of hypoglycemia, and to their additional benefit of causing a modest, but durable weight loss. Oxyntomodulin (OXM), a 37-amino acid peptide hormone of the glucagon (GCG) family with dual agonistic activity on both the GLP-1 (GLP1R) and the GCG (GCGR) receptors, has been shown to reduce food intake and body weight in humans, with a lower incidence of treatment-associated nausea than GLP 1 mimetics. As for other peptide hormones, its clinical application is limited by the short circulatory half-life, a major component of which is cleavage by the enzyme dipeptidyl peptidase IV (DPP-IV). SAR studies on OXM, described herein, led to the identification of molecules resistant to DPP-IV degradation, with increased potency as compared to the natural hormone. Analogs derivatized with a cholesterol moiety display increased duration of action in vivo. Moreover, we identified a single substitution which can change the OXM pharmacological profile from a dual GLP1R/GCGR agonist to a selective GLP1R agonist. The latter finding enabled studies, described in detail in a separate study (Pocai A, Carrington PE, Adams JR, Wright M, Eiermann G, Zhu L, Du X, Petrov A, Lassman ME, Jiang G, Liu F, Miller C, Tota LM, Zhou G, Zhang X, Sountis MM, Santoprete A, Capito E, Chicchi GG, Thornberry N, Bianchi E, Pessi A, Marsh DJ, SinhaRoy R. Glucagon-like peptide 1/glucagon receptor dual agonism reverses obesity in mice. Diabetes 2009; 58: 2258-2266), which highlight the potential of GLP1R/GCGR dual agonists as a potentially superior class of therapeutics over the pure GLP1R agonists currently in clinical use. PMID- 21294226 TI - Analogues of trypsin inhibitor SFTI-1 modified in the conserved P1' position by synthetic or non-proteinogenic amino acids retain their inhibitory activity. AB - A series of linear and monocyclic (with a disulfide bridge only) analogues of trypsin inhibitor SFTI-1 modified in the P1 and/or P1' positions were synthesized by the solid-phase method. In the substrate specificity P1 position, Phe or N benzylglycine (Nphe) were introduced, whereas the conserved Ser6 in Bownam-Birk (BBI) inhibitors was replaced by Hse (L-homoserine), Nhse [N-(2 hydroxyethyl)glycine], Sar, and Ala. Kinetic studies of interaction of the analogues with bovine alpha-chymotrypsin have shown that in monocyclic (but not linear) analogues, Hse and Nhse are tolerated to afford potent inhibitors. This is the first evidence that the absolutely conserved Ser present in the inhibitor's P1' position can be successfully replaced by a synthetic derivative. PMID- 21294227 TI - Neuroglobin-prion protein interaction: what's the function? AB - Neuroglobin and cellular prion protein (PrP(C) ) are expressed in the nervous system and co-localized in the retinal ganglion cell layer. Both proteins do not have an unambiguously assigned function, and it was recently reported that PrP(C) aggregates rapidly in the presence of neuroglobin, whereas it does not aggregate in the presence of myoglobin, another globin with different tissue specificity. Electrostatic complementarity between the unstructured PrP(C) N-terminus and neuroglobin has been proposed to mediate this specific interaction. To verifythis hypothesis experimentally, we have used a combined approach of automated docking and molecular dynamics (MD) studies carried out on short stretches of prion protein (PrP) N-terminus to identify the minimal electrostatically interacting aminoacidic sequences with neuroglobin. Subsequently, we have performed the synthesis of these peptides by solid phase methods, and we tested their interaction with neuroglobin by surface plasmon resonance (SPR). Preliminary results confirm unequivocally the specific interaction between synthetic PrP peptides and neuroglobin suggesting a crucial role of PrP(C) positively charged regions in thisprotein-protein association. PMID- 21294228 TI - Examination of the active secondary structure of the peptide 101.10, an allosteric modulator of the interleukin-1 receptor, by positional scanning using beta-amino gamma-lactams. AB - The relationship between the conformation and biological activity of the peptide allosteric modulator of the interleukin-1 receptor 101.10 (D-Arg-D-Tyr-D-Thr-D Val-D-Glu-D-Leu-D-Ala-NH2) has been studied using (R)- and (S)-Bgl residues. Twelve Bgl peptides were synthesized using (R)- and (S)-cyclic sulfamidate reagents derived from L- and D-aspartic acid in an optimized Fmoc-compatible protocol for efficient lactam installment onto the supported peptide resin. Examination of these (R)- and (S)-Bgl 101.10 analogs for their potential to inhibit IL-1beta-induced thymocyte cell proliferation using a novel fluorescence assay revealed that certain analogs exhibited retained and improved potency relative to the parent peptide 101.10. In light of previous reports that Bgl residues may stabilize type II'beta-turn-like conformations in peptides, CD spectroscopy was performed on selected compounds to identify secondary structure necessary for peptide biological activity. Results indicate that the presence of a fold about the central residues of the parent peptide may be important for activity. PMID- 21294229 TI - Cyclic neoglycodecapeptides: how to increase their inhibitory activity and selectivity on lectin/toxin binding to a glycoprotein and cells. AB - Protein (lectin/toxin)-glycan interaction can be clinically harmful so that the design of inhibitors has become an aim. Cyclic decapeptides are suited as rigid carriers for carbohydrate derivatives. We herein document the bioactivity of sugar headgroups covalently attached to this carrier for the cases of five proteins, i.e. a potent biohazardous plant agglutinin, a leguminous model lectin and three adhesion/growth-regulatory human lectins. They represent the different types of topological organization within the galectin family. The relative inhibitory activities of glycoclusters with the three ligands (galactose, lactose and the disaccharide of the Thomsen-Friedenreich antigen) reflected the affinity of free carbohydrates, hereby excluding an impairment of binding activity by chemical derivatization and conjugation. Headgroup tailoring is thus one route to optimize activity and selectivity of cyclopeptide-based glycoclusters. The increase of ligand density from tetra- to hexadecavalency added a second route. The plant toxin and tandem-repeat-type galectin-4 were especially sensitive to this parameter change. Strategically combining solid-phase assays for screening with analysis of lectin binding to cells in different systems revealed efficient inhibition by distinct glycoclusters, thereby protecting cells from lectin association. Cyclic neoglycodecapeptides thus warrant further study as lectin directed pharmaceuticals. PMID- 21294230 TI - The thin line between cell-penetrating and antimicrobial peptides: the case of Pep-1 and Pep-1-K. AB - Cell-penetrating peptides (CPPs) are cationic oligopeptides able to translocate across biological membranes without perturbing them, while antimicrobial peptides (AMPs) kill bacteria mainly by disrupting their membranes. The two peptide classes share several characteristics (charge, amphipathicity, helicity, and length), and therefore the molecular properties discriminating between the two different bioactivities are not clear. Pep-1-K (KKTWWKTWWTKWSQPKKKRKV) is a new AMP derived from the widely studied CPP Pep-1 (KETWWETWWTEWSQPKKKRKV), or 'Chariot', known for its ability to carry large cargoes across biological membranes. Pep-1-K was obtained from Pep-1 by substituting the three Glu residues with Lys, to increase its cationic character. Previous studies showed that these modifications endow Pep-1-K with a potent antimicrobial activity, with MICs in the low micromolar range. Here, we characterized the interaction of Pep-1 and Pep 1-K with model membranes to understand the reason for the antimicrobial activity of Pep-1-K. The data show that this peptide causes vesicle aggregation, perturbs membrane order, and induces the leakage of ions, but not of larger solutes, while these effects were not observed for Pep-1. These differences are likely due, at least in part, to the higher affinity of Pep-1-K toward anionic bilayers, which mimick the composition of bacterial membranes. PMID- 21294231 TI - Immunomodulatory efficacy of nisin--a bacterial lantibiotic peptide. AB - Nisin is a peptide bacteriocin, grouped under the category of lantibiotics. It is naturally produced by Lactococcus lactis to eliminate other competing gram positive bacteria from its vicinity. Moreover under certain conditions it is reported to be effective against a broad range of gram-negative bacteria as well. Thus, it has been widely used as a safe food preservative especially in the dairy industry. Because of its wide-scale consumption, its effect on eukaryotic cells should be of great concern. Here we examine the immunomodulatory efficacy of nisin in vitro. MTT-based cytotoxicity assay demonstrated nisin's cytotoxicity on human T-cell lymphoma Jurkat cells, Molt-4 cells and freshly cultured human lymphocytes at over 200 uM concentration (IC(50) 225 uM). The cell death mechanism induced by nisin in all these lymphocyte types was independent of oligonucleosomal DNA fragmentation, as analyzed by agarose gel electrophoresis and comet assay. Additionally, scanning electron microscope and fluorescence microscopy demonstrated the ability of nisin to activate human PMNs in vitro. Nisin-activated neutrophils extruded intact nuclear chromatin to form NETs, well known for neutralization of virulence factors and extermination of bacterial pathogens. Nisin's presence also elevated neutrophil intracellular superoxide levels, normally produced by activated NADPH oxidase and prerequisite to NET formation. These nisin-induced responses in cellular representatives of two separate branches of human immune system-adaptive and innate-although leading to cell death, did not include DNA fragmentation. From these findings, we propose that nisin might trigger similar AICD mechanisms in lymphocytes and neutrophils, different from conventional apoptosis which involves DNA fragmentation. PMID- 21294232 TI - Early difficulties of Chinese preschoolers at familial risk for dyslexia: deficits in oral language, phonological processing skills, and print-related skills. AB - The present study examined some early performance difficulties of Chinese preschoolers at familial risk for dyslexia. Seventy-six high-risk (40 good and 36 poor readers) and 25 low-risk Chinese children were tested on oral language, reading-related cognitive skills (e.g. phonological processing skills, rapid naming, and morphological awareness), and Chinese word reading and spelling over a 3-year period. The parents were also given a behaviour checklist for identifying child at-risk behaviours. Results showed that the High Risk (Poor Reading) group performed significantly worse than the Low Risk and the High Risk (Good Reading) group on most of the measures and domains. More children in the High Risk (Poor Reading) group displayed at-risk behaviours than in the other two groups. These results suggest that Chinese at-risk children with early difficulties in reading and spelling do show a wide range of language-, phonology , and print-related deficits, similar to their alphabetic counterparts. An understanding of these early difficulties may help prevent dyslexia from developing in at-risk children. PMID- 21294233 TI - Oxidizing directing groups enable efficient and innovative C-H activation reactions. PMID- 21294236 TI - Peptide hormones regulating appetite--focus on neuroimaging studies in humans. AB - In recent years, knowledge about hormonal feedback from the gastrointestinal tract and adipose tissue has increased tremendously. Peptide hormones modulating hunger have been intensively studied, mostly in animals but increasingly also in humans. The first therapeutic agents, such as GLP-1 analogues, are in successful clinical use for T2D and may beneficially affect hunger and reduce weight. Data from in vitro studies and animals provide detailed insight into regulatory mechanisms leading to peptide secretion and receptor bindings, as well as to the distribution of receptors involved in different parts of the body. With neuroimaging techniques human brain structures have been identified that play a role in hunger, satiety and eating behaviour. These include the primary gustatory (insular) and olfactory (pyriform) cortex and regions with a highly permeable blood-brain barrier (hypothalamus, brain stem), which facilitates humoral input via gut peptides and leptin. In addition, cerebral networks involved in higher cognitive functions, especially those relevant to reward, pleasure and also addiction (ventral and dorsal striatum, amygdala, orbitofrontal cortex (OFC), prefrontal cortex (PFC)) were shown to be involved. First indications of direct influences of peptide hormones on these networks have become available from neuroimaging studies administrating synthetic PYY, ghrelin and leptin. Insulin also appears to play an important role as a central satiety hormone, and evidence indicating the possibility of central insulin resistance in obesity is available. PMID- 21294237 TI - Gut-brain signalling: how lipids can trigger the gut. AB - The gut plays a unique role in the metabolic defence against energy excess and glucose imbalance. Nutrients, such as lipids, enter the small intestine and activate sensing mechanisms to maintain energy and glucose homeostasis. It is clear that a lipid-induced gut-brain axis exists and that cholecystokinin and a neuronal network are involved, yet the underlying mechanisms in gut lipid sensing that regulate homeostasis remain largely unknown. In parallel, studies underscore the importance of enzymes involved in lipid metabolism within the brain, such as adenosine monophosphate -activated protein kinase, to maintain homeostasis. In this review, we will first examine what is known regarding the mechanisms involved in this lipid-induced gut-brain neuronal axis that regulate food intake and hepatic glucose production. We will also discuss how enzymes that govern brain lipid metabolism could potentially reveal how lipids trigger the gut, and that both the gut and brain may share common biochemical pathways to sense lipids. PMID- 21294238 TI - Amino acid-induced gene expression profiling in clonal beta-cell line INS-1E cells. AB - BACKGROUND: There is abundant evidence that glucotoxicity and lipotoxicity contribute to impaired beta-cell function in type 2 diabetes. Interestingly, amino acid (AA) derangement is also a characteristic part of the diabetic state. The acute effects of AA on pancreatic beta-cell function have been widely explored; however, to our knowledge, the chronic effects of AA, e.g. proline (Pro), homocysteine (Hcy), and leucine (Leu), on pancreatic beta-cell function and integrity have not yet been studied. We aimed to investigate global alterations in beta-cell gene expression after long-term exposure of clonal INS 1E cells to elevated level of specific AA in vitro. METHODS: Global gene expression profiling was performed to characterize genes differently modified by Pro, Hcy, and Leu, respectively, in INS-1E cells. RESULTS: Gene expression profiling revealed significant changes in INS-1E cell mRNAs involved in the control of several aspects of beta-cell function, e.g. epigenetic regulation of gene expression, metabolism, innate and adaptive immune responses, cellular signalling, protein synthesis, apoptosis, and cellular stress response. After 72 h, INS-1E cells were differentially regulated (>=1.5- or <= -1.5-fold) by Pro (295 transcripts), Hcy (301 transcripts), and Leu (701 transcripts). It appears that Hcy effects changes opposite to those induced by Leu and/or Pro. CONCLUSIONS: AA appears to participate in and to influence many physiological processes including those involved in cholesterol metabolism, immune responses, and oxidative phosphorylation. Whether such events promote the beta-cell dysfunction and the beta-cell failure in diabetes remains to be elucidated. Our data strongly indicate that AA elevation may take part in the progressive development of type 2 diabetes. PMID- 21294239 TI - Association of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A) gene polymorphisms and type 2 diabetes mellitus: a meta analysis. AB - BACKGROUND: The association between peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A) polymorphisms and type 2 diabetes mellitus (T2DM) has been investigated in several studies, but these studies yielded contradictory results. We conducted a meta-analysis to assess the association between three polymorphisms (Gly482Ser, Thr394Thr and Thr612Met) in PPARGC1A and T2DM. METHODS: A literature-based search was conducted to collect data. The additive model was chosen to investigate the association between the three polymorphisms and T2DM. The random effects model was used if there was heterogeneity between studies. In addition, subgroup meta-analyses were made according to the ethnic groups. RESULTS: Twenty-three studies were enrolled in this meta-analysis (7539 cases and 9562 controls for Gly482Ser, 1818 cases and 2376 controls for Thr394Thr, 2042 cases and 1289 controls for Thr612Met). In the combined analysis of all eligible studies, a significant association was found between Gly482Ser, Thr394Thr and T2DM with pooled odds ratios 1.19 [95% confidence interval (CI) 1.05-1.34] and 1.33 (95% CI 1.04-1.70), respectively, but great heterogeneity was found between studies. In the subgroup meta-analyses, we found that Gly482Ser and Thr394Thr polymorphisms were associated with the risk of T2DM, and the pooled odds ratios were 1.66 (95% CI 1.28-2.15) and 1.72 (95% CI 1.45-2.03), respectively, in the Indian population; no significant evidence was found in the Caucasian and East Asian populations. CONCLUSIONS: This meta analysis indicated that Gly482Ser and Thr394Thr polymorphisms of PPARGC1A gene were significantly associated with the risk of T2DM, especially in the Indian population. No relationship was found between the Thr612Met and risk of T2DM. PMID- 21294240 TI - The decrement in circulating endothelial progenitor cells (EPCs) in type 2 diabetes is independent of the severity of the hypoadiponectemia. AB - BACKGROUND: Type 2 diabetes mellitus (DM) is associated with a decreased level of circulating endothelial progenitor cells (EPCs) and adiponectin. Experimental studies suggest a potential link between hypoadiponectinaemia and the depletion of the EPC level. This study investigated the relationships between adiponectin level and EPC in patients with type 2 DM. METHODS: A total of 95 type 2 DM patients (58.5 +/- 8.8 years, 42 men) and 95 age- and sex-matched healthy controls were recruited. Circulating EPC levels were determined by flow cytometry using CD133(+), CD34(+), CD133(+) /KDR(+) and CD34(+) /KDR(+) as surface markers. Plasma adiponectin levels were measured by enzyme-linked immunosorbent assay. EPC function was studied by in vitro tube formation and migration assay. RESULTS: The levels of CD133(+) (p < 0.001) and CD133(+) /KDR(+) (p < 0.001) EPCs were independently associated with the presence of type 2 DM. The levels of CD34(+) (p = 0.004) and CD34(+) /KDR(+) (p = 0.013) EPCs were independently associated with haemoglobin A(1c). Nevertheless, there was no relationship between the number of EPCs and adiponectin level. Tube formation assay showed impaired pro-angiogenic function of EPC in DM patients compared with controls (p = 0.007). Interestingly, adiponectin supplementation (5 ug/mL) increased tube formation by 17.6% in EPCs from DM patients (p = 0.002). It also significantly enhanced cell migration by 35.9% in EPCs from DM patients (p = 0.01). CONCLUSIONS: We detected no relationship between the reduction in the level of EPC and in the level of total adiponectin in blood from patients with type 2 diabetes. EPC from patients with diabetes were stimulated when exposed to adiponectin in the test tube, findings that warrant further study. PMID- 21294241 TI - Accelerated cognitive decline in patients with type 2 diabetes: MRI correlates and risk factors. AB - BACKGROUND: Type 2 diabetes mellitus is associated with an increased risk of cognitive decline and dementia. We examined brain imaging correlates and vascular and metabolic risk factors of accelerated cognitive decline in patients with type 2 diabetes. METHODS: Cognitive functioning and brain volume as well as metabolic and vascular risk factors were assessed twice in 68 patients with no dementia with type 2 diabetes with a 4-year interval. Thirty-eight control participants served as a reference group. Volumetric measurements of the total brain, lateral ventricles and white-matter hyperintensities were performed on 1.5T magnetic resonance imaging scans. A regression-based index score was calculated on the basis of the reference group to assess changes in cognitive performance over time, adjusted for age, sex and estimated intelligence quotient. Brain volumes were compared between patients with and without accelerated cognitive decline. Logistic regression analyses were used to identify baseline risk factors for accelerated cognitive decline within the diabetes group. RESULTS: Accelerated cognitive decline was found in 17 (25%) patients with type 2 diabetes and was associated with a greater increase in ventricular volume [mean difference (95% confidence interval): 0.23% (0.08-0.38); p = 0.003] and white-matter hyperintensities volume [0.16% (0.05-0.27); p = 0.006] over the 4-year period. There were no specific vascular or metabolic risk factors associated with accelerated cognitive decline. CONCLUSIONS: Accelerated cognitive decline in patients with type 2 diabetes was associated with progressive changes on brain magnetic resonance imaging, comprising both vascular damage and global atrophy. Exploration of vascular and metabolic risk factors revealed no specific determinants of accelerated cognitive decline. PMID- 21294242 TI - Vitamin D status in paediatric patients with cancer. AB - BACKGROUND: Children with malignant disease are at increased risk of bone disorders and cardiovascular disease. Vitamin D status may influence this risk and so we assessed vitamin D levels in children with malignant disease undergoing active treatment or surveillance post-therapy. PROCEDURE: This was an outpatient based cross-sectional study of 61 children with a history of malignancy (median age 11.1 years; range 1.5-24.4 years) and 60 control subjects (median age 8.4 years; range 0.2-18.0 years) attending hospital for the management of non malignant disorders. Serum vitamin D (25-OH-D), parathormone levels and bone biochemistry were determined. Vitamin D status and its relationship to age, sex, ethnicity, time of sampling and presence of malignant disease was determined. RESULTS: Vitamin D status was suboptimal in 62% of cases (25-OH-D < 50 nmol/L [20 ng/ml]). Vitamin D deficiency (25-OH-D < 25 nmol/L [10 ng/ml]) was more common in children with malignant disease than controls (21.3% vs. 3.3%; P = 0.013). Month of sampling (P < 0.001), ethnicity (P < 0.001), older age (P = 0.011), and history of malignancy (P = 0.012) were associated with a poorer vitamin D status. CONCLUSIONS: Vitamin D levels [25-OH-D] are lower in survivors of childhood cancer in comparison to control children with the majority either insufficient or deficient. Assessment and adequate replacement of vitamin D status may be of particular value in this group of children. PMID- 21294243 TI - AML1/RUNX1 gene point mutations in childhood myeloid malignancies. AB - BACKGROUND: Currently, it is widely accepted that one of the crucial players in adult leukemic transformation is the RUNX1 gene. However, there is little data available regarding whether mutations in this gene also contribute to pediatric leukemia, especially in childhood myeloid malignancies. Therefore we made a decision to screen patients with pediatric myeloid neoplasias for the presence of RUNX1 mutations in their samples. PROCEDURES: Patients (n = 238) with diagnoses of de novo acute myeloid leukemia (AML) (n = 198), de novo myelodisplastic syndrome (MDS) (n = 16), therapy-related AML (n = 9), juvenile myelomonocytic leukemia (JMML) (n = 15) were included in this study. All patients were Belarusians between the ages of 0 and 18 years. RESULTS: The frequency of RUNX1 point mutations in the total group of patients with de novo AML was 3% and de novo MDS was 15%. Cooperation of point mutations in the RUNX1 and NRAS genes, and the cytogenetic abnormality, -7/7q-, was demonstrated in children with therapy related AML. RUNX1 point mutations predominate in those de novo AML and MDS patients with a normal karyotype in leukemic cells. Frequency of RUNX1 point mutations was about 4% in a group of children with de novo AML aged 0-14 years diagnosed during the period of 1998-2009. CONCLUSION: During the course of this investigation, valuable data were obtained concerning RUNX1 gene mutation frequencies in different clinical, morphological, and cytogenetic groups of patients with myeloid malignancies, and its cooperation with other molecular aberrations. PMID- 21294244 TI - Predictors of independent living status in adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. AB - BACKGROUND: Adult survivors of childhood cancer and their siblings are compared on one of the most salient developmental milestones of adulthood, the ability to live independently. PROCEDURE: Adult survivors of childhood cancers (n = 6,047) and siblings (n = 2,326), all 25 years of age and older, completed a long-term follow-up questionnaire that assessed adaptive, neurocognitive, and psychological functioning, as well as demographic and health status. Multivariable logistic regression analyses and structural equation modeling (SEM) were used to identify predictors of independent living. RESULTS: Compared to siblings (n = 206, 8.7%), survivors (n = 1063; 17.7%) were more than twice as likely to live dependently (OR 2.07; 95% confidence interval [CI] 1.77-2.42). Survivors diagnosed with CNS tumors (OR 0.13, 95% CI 0.10-0.18) or leukemia (OR 0.29, 95% CI 0.23-0.27) were significantly less likely to live independently compared to those diagnosed with Hodgkin lymphoma. Other risk factors for reduced independent living included cranial radiation (<= 24 Gy OR 0.76, 95% CI 0.62-0.93; >24 Gy OR 0.31, 95% CI 0.24-0.41), use of neuroleptic, anticonvulsant, or psychostimulant medication (OR 0.32, 95% CI 0.24-0.43), attention and processing speed problems (OR 0.58, 95% CI 0.47-0.71), poor physical functioning (OR 0.49, 95% CI 0.38-0.63), depression (OR 0.68, 95% CI 0.53-0.88), and racial/ethnic minority status (OR 0.39, 95% CI 0.30 0.51). SEM demonstrated that neurocognitive functioning had both direct effects on independent living status, and indirect effects through use of neurologically directed medication, depression, and poor mental health. CONCLUSION: Adult survivors of childhood cancer who experience neurocognitive, psychological, or physical late effects are less likely to live independently as adults. PMID- 21294245 TI - Platelet disorders in children: A diagnostic approach. AB - The investigation of children with suspected inherited platelet disorders is challenging. The causes of mucocutaneous bleeding are many, and specialized testing for platelet disorders can be difficult to access or interpret. An algorithm developed for the investigation of suspected platelet disorders provides a sequential approach to evaluating both platelet function abnormalities and thrombocytopenia. Investigation begins with a clinical evaluation and laboratory testing that is generally available, including platelet counting, peripheral blood cell morphology, and aggregometry. Based on results of initial investigations, the algorithm recommends specialized testing for specific diagnoses, including flow cytometry, immunofluorescence microscopy, electron microscopy, and mutational analysis. PMID- 21294246 TI - Fludarabine, cyclophosphamide, doxorubicin (FCD), and rituximab: a remission induction therapy for aggressive pediatric post-transplant lymphoproliferative disease (PTLD). AB - Management of aggressive, usually late-occurring, post-transplant lymphoproliferative disorders (PTLDs), a life-threatening complication after solid organ transplants, remains controversial. Four children affected by aggressive CD20+ PTLDs received a chemo-immunotherapy regimen for remission induction based on fludarabine, cyclophosphamide, doxorubicin, and rituximab, associated with a rapid discontinuation of immunosuppression (IS). Subsequent consolidation chemotherapy consisted of Berlin-Frankfurt-Munster-modified blocks. All patients achieved a complete remission, which persisted for 25, 68+, 80+, and 103+ months after diagnosis. Therapy was well tolerated. No patients developed allograft rejection during PTLD treatment. Our experience suggests that this chemo-immunotherapeutic approach may be an effective treatment strategy while allowing for a concomitant discontinuation of IS. PMID- 21294247 TI - ADHD in Dutch adults: heritability and linkage study. AB - Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental phenotype that persists into adulthood. This study investigated the heritability of inattentive and hyperactive symptoms and of total ADHD symptomatology load (ADHD index) in adults and performed linkage scans for these dimensions. Data on sibling pairs and their family members from the Netherlands Twin Register with genotype and phenotype data for inattention, hyperactivity and ADHD index (~750 sib-pairs) were analyzed. Phenotypes were assessed with the short self-report form of the Conners' Adult ADHD Rating Scales (CAARS). Heritabilities were estimated in SOLAR under polygenic models. Genome-wide linkage scans were performed using variance components (VC) in MERLIN and MINX and model-based linkage analysis was carried out in MENDEL with empirical evaluation of the results via simulations. Heritability estimates for inattention, hyperactivity and ADHD index were 35%, 23%, and 31%, respectively. Chromosomes 18q21.31 18q21.32 (VC LOD = 4.58, p(emp) = 0.0026) and 2p25.1 (LOD = 3.58, p(emp) = 0.0372) provided significant evidence for linkage for inattention and the ADHD index, respectively. The QTL on chromosome 2p25.1 also showed suggestive linkage for hyperactivity. Two additional suggestive QTLs for hyperactivity and the ADHD index shared the same location on chromosome 3p24.3-3p24.1. Finally, a suggestive QTL on 8p23.3-8p23.2 for hyperactivity was also found. Heritability of inattention, hyperactivity and total ADHD symptoms is lower in adults than in children. Chromosomes 18q and 2p are likely to harbor genes that influence several aspects of adult ADHD. PMID- 21294248 TI - Familial transmission of schizophrenia in Palau: A 20-year genetic epidemiological study in three generations. AB - Our genetic epidemiological studies of schizophrenia and other psychotic disorders (SCZ) in the isolated population of Palau have been ongoing for 20 years. Results from the first decade showed that Palau has an elevated prevalence of SCZ and that cases cluster in extended multigenerational pedigrees interconnected via complex genetic relationships after centuries of endogamous, but not consanguineous, marriages. The aim of our second decade of research, which extended data collection into a third generation of young, high-risk (HR) Palauans, was to identify significant predictors of intergenerational transmission of illness. Our findings revealed that degree of familial loading and gender effects on reproductive fitness are important modifiers of risk for transmission of SCZ. Among 45 distinct multiplex families, we identified 10 high density (HD) Palauan families, each with 7-29 SCZ cases, which contain half of Palau's 260 SCZ cases and 80% of the 113 SCZ cases with one or more affected first-degree relatives, indicating that familial loading is a major risk factor for SCZ in Palau. Cases that belong to multiply affected sibships are more common than cases with an affected parent. Furthermore, only 6/38 multiply affected sibships have an affected parent, strong evidence that many unaffected parents are obligate carriers of susceptibility genes. Although reproductive fitness is dramatically reduced in affected males, the 30% minority who do become fathers are twice as likely as affected mothers to transmit SCZ to an offspring. As they evolve, these HD families can help to elucidate the genetic mechanisms that predict intergenerational transmission of SCZ. PMID- 21294249 TI - Variation in NGFB is associated with primary affective disorders in women. AB - Affective disorders (AFDs) are highly comorbid with substance dependence (SD) and both are genetically influenced. However, the specific etiology of the comorbidity is not well understood. We genotyped an array of 1,350 single nucleotide polymorphisms (SNPs) in or near 130 genes in 868 European-Americans (EAs), including 182 individuals with primary AFDs (PAFDs), 214 with SD comorbid with AFD (CAFD), and 472 screened controls. NGFB, which encodes nerve growth factor beta and was represented in the array by 15 SNPs, showed the strongest evidence of association, but only among women with PAFDs. Six of the SNPs showed nominally significant association with PAFDs in women (P's = 0.0007-0.01); three (rs2856813, rs4332358, and rs10776799) were empirically significant based on 1,000,000 permutations (P's = 0.008-0.015). Seven haplotypes were significantly associated with PAFDs in women (P's = 0.0014-0.01), of which six were significant based on empirical permutation analysis (minimal P = 0.0045). Four diplotypes were significantly associated with PAFDs in women (global P's = 0.001-0.01). The specific diplotype GG-TC, reconstructed from rs2856813 and rs6678788, showed the strongest evidence of association with PAFDs in women (OR = 4.07, P = 4.2E-05). No SNPs or haplotypes were associated with PAFDs in men or with CAFDs in either sex. We conclude that variation in NGFB is a risk factor for PAFDs in women, but not for CAFD. PMID- 21294250 TI - In vitro bioaccessibility and gut biotransformation of polyphenols present in the water-insoluble cocoa fraction. AB - SCOPE: Cocoa, especially the water-insoluble cocoa fraction (WICF), is a rich source of polyphenols. In this study, sequential in vitro digestion of the WICF with gastrointestinal enzymes as well as its bacterial fermentation in a human colonic model system were carried out to investigate bioaccessibility and biotransformation of WICF polyphenols, respectively. METHODS AND RESULTS: The yield of each enzymatic digestion step and the total antioxidant capacity (TAC) were measured and solubilized phenols were characterized by MS/MS. Fermentation of WICF and the effect on the gut microbiota, SCFA production and metabolism of polyphenols was analyzed. In vitro digestion solubilized 38.6% of WICF with pronase and Viscozyme L treatments releasing 51% of the total phenols from the insoluble material. This release of phenols does not determine a reduction in the total antioxidant capacity of the digestion-resistant material. In the colonic model WICF significantly increased of bifidobacteria and lactobacilli as well as butyrate production. Flavanols were converted into phenolic acids by the microbiota following a concentration gradient resulting in high concentrations of 3-hydroxyphenylpropionic acid (3-HPP) in the last gut compartment. CONCLUSION: Data showed that WICF may exert antioxidant action through the gastrointestinal tract despite its polyphenols being still bound to macromolecules and having prebiotic activity. PMID- 21294251 TI - Distinctive effects of plant protein sources on renal disease progression and associated cardiac hypertrophy in experimental kidney disease. AB - SCOPE: Dietary soy protein reduces renal disease progression in a number of renal diseases, suggesting that plant compared with animal proteins may be renoprotective. The inclusion of other plant protein sources could enhance compliance of intervention diets, but the effects of other plant protein sources are not known. METHODS AND RESULTS: Weanling Han:SPRD-cy rats with experimental polycystic kidney disease were given hemp-, pea- and soy protein-based diets compared with the standard AIN 93G diet with casein as the protein source. Kidneys from diseased rats given diets which contained soy or hemp protein compared with casein-based diets were less enlarged, had lower fluid content, smaller cyst volumes, less fibrosis, lower chemokine receptor 2 (CCR2) levels and normalized serum creatinine levels. Soy and hemp protein diets also normalized heart size, which was enlarged in diseased compared with normal rats consuming casein. Kidneys from diseased rats given pea protein compared with casein were more enlarged and had higher fluid content and cyst volumes, despite growing better and having lower serum creatinine and renal chemokine receptor 2 levels, and similar levels of renal fibrosis. CONCLUSION: Not all plant proteins are equally protective in experimental kidney disease and associated cardiac hypertrophy. PMID- 21294253 TI - Nanofiber membranes with controllable microwells and structural cues and their use in forming cell microarrays and neuronal networks. PMID- 21294254 TI - Self-assembly of a fullerene poly(3-hexylthiophene) dyad. PMID- 21294255 TI - Characteristics and properties of carboxylated cellulose nanocrystals prepared from a novel one-step procedure. PMID- 21294256 TI - Visualizing low-level point mutations: enzyme-like selectivity offered by nanoparticle probes. PMID- 21294257 TI - Photoinduced hydrogen-generating nanogel systems. PMID- 21294258 TI - Label-free indirect immunoassay using an avidin-induced surface-enhanced Raman scattering substrate. PMID- 21294259 TI - Fast fabrication of large-area, nanostructured arrays from polymers or carbon nanotubes by wet-processing. PMID- 21294260 TI - Generalized synthesis of mesoporous shells on zeolite crystals. PMID- 21294262 TI - Advanced optical imaging reveals the dependence of particle geometry on interactions between CdSe quantum dots and immune cells. AB - The biocompatibility and possible toxicological consequences of engineered nanomaterials, including quantum dots (QDs) due to their unique suitability for biomedical applications, remain intense areas of interest. We utilized advanced imaging approaches to characterize the interactions of CdSe QDs of various sizes and shapes with live immune cells. Particle diffusion and partitioning within the plasma membrane, cellular uptake kinetics, and sorting of particles into lysosomes were all independantly characterized. Using high-speed total internal reflectance fluorescence (TIRF) microscopy, we show that QDs with an average aspect ratio of 2.0 (i.e., rod-shaped) diffuse nearly an order of magnitude slower in the plasma membrane than more spherical particles with aspect ratios of 1.2 and 1.6, respectively. Moreover, more rod-shaped QDs were shown to be internalized into the cell 2-3 fold more slowly. Hyperspectral confocal fluorescence microscopy demonstrates that QDs tend to partition within the cell membrane into regions containing a single particle type. Furthermore, data examining QD sorting mechanisms indicate that endocytosis and lysosomal sorting increases with particle size. Together, these observations suggest that both size and aspect ratio of a nanoparticle are important characteristics that significantly impact interactions with the plasma membrane, uptake into the cell, and localization within intracellular vesicles. Thus, rather than simply characterizing nanoparticle uptake into cells, we show that utilization of advanced imaging approaches permits a more nuanced and complete examination of the multiple aspects of cell-nanoparticle interactions that can ultimately aid understanding possible mechanisms of toxicity, resulting in safer nanomaterial designs. PMID- 21294263 TI - Rigid dimers formed through strong interdigitated H-bonds yield compact 1D supramolecular helical polymers. AB - Hierarchical self-assembly of small abiotic molecular modules interacting through noncovalent forces is increasingly being used to generate functional structures and materials for electronic, catalytic, and biomedical applications. The greatest control over the geometry in H-bond supramolecular architectures, especially in H-bonded supramolecular polymers, can be achieved by using conformationally rigid molecular modules undergoing self-assembly through strong H-bonds. Their binding strength depends on the multiplicity of the H-bonds, the nature of donor/acceptor pairs and their secondary attractive/repulsive interactions. Here a functionalized molecular module is described, which is capable of self-associating through self-complementary H-bonding patterns comprising four strong and two medium-strength H-bonds to form dimers. The self association of these phenylpyrimidine-based dimers through directional H-bonding between two lateral pyridin-2(1H)-one units of neighboring molecules allows the formation of highly compact 1D supramolecular polymers by self-assembly on graphite. A concentration-dependent study by scanning tunneling microscopy at the solid-liquid interface, corroborated by dispersion-corrected density functional studies, reveals the controlled generation of either linear supramolecular 2D arrays, or long helical supramolecular polymers with a high shape persistence. PMID- 21294264 TI - Synthesis and characterization of ratiometric ion-sensitive polyelectrolyte capsules. AB - Micrometer-sized polyelectrolyte capsules are synthesized, which have ion sensitive fluorophores embedded in their cavities. As the membranes of the capsules are permeable to ions, the fluorescence of the capsules changed with the ion concentration. In particular, capsules sensitive to protons, sodium, potassium, and chloride ions are fabricated and their fluorescence response analyzed. In order to allow for ratiometric measurements, additional fluorophores whose emission do not depend on the ion concentration and which emit a different wavelength are co-embedded in the capsule cavities. PMID- 21294265 TI - Effective gene silencing by multilayered siRNA-coated gold nanoparticles. AB - Small interfering RNA (siRNA) has been widely proposed to treat various diseases by silencing genes, but its delivery remains a challenge. A well controlled assembly approach is applied to prepare a protease-assisted nanodelivery system. Protease-degradable poly-L-lysine (PLL) and siRNA are fabricated onto gold nanoparticles (AuNPs), by alternating the charged polyelectrolytes. In this study, up to 4 layers of PLL and 3 layers of siRNA (sR3P) are coated. Due to the slow degradation of PLL, the incorporated siRNA is released gradually and shows extended gene-silencing effects. Importantly, the inhibition effect in cells is found to correlate with the number of siRNA layers. PMID- 21294266 TI - Tailoring plasmonic nanostructures for optimal SERS sensing of small molecules and large microorganisms. AB - Local electric fields can be tuned dramatically by varying the diameter of quasi 3D gold plasmonic nanostructure arrays, as indicated by 3D finite-difference time domain calculations. Utilizing quasi-3D arrays that exhibit a maximum electric field intensity (i.e., a "hot" spot) either at the bottom (gold nanodisks) or on the top (gold film patterned with nanoholes), the optimal surface-enhanced Raman scattering (SERS) sensitivity for the detection of small molecules or large microorganisms can be achieved. The precisely fabricated and optimized SERS active quasi-3D nanostructure arrays make it possible to quantitatively and reproducibly detect chemical and biological species using SERS, leading to a new sensing platform with molecular specificity based on SERS for many important applications. PMID- 21294267 TI - Interplay between size and crystal structure of molybdenum dioxide nanoparticles- synthesis, growth mechanism, and electrochemical performance. AB - A detailed study is presented on the formation of MoO(2) nanoparticles from the dissolution of the precursor to the final rodlike product, with a focus on the exploration of the inorganic reaction occurring ahead of the nucleation step, and interplay between size and crystal structure of MoO(2). In situ X-ray absorption spectroscopy experiments show that the crystallization and the growth process of MoO(2) nanorods is initiated by rapid reduction of the MoO(2) Cl(2) precursor in benzyl alcohol and acetophenone. This reaction triggers the nucleation of 2 nm MoO(2) particles with spherical shape and hexagonal crystal structure. The transformation from spheres into rods emerges as a complex process driven by oriented attachment. High-resolution transmission electron microscopy and X-ray diffraction results provide evidence that the 2 nm particles first aggregate into 5-20 nm-large oriented assemblies. The increase in particle size induces the phase transition from hexagonal to the less symmetrical monoclinic crystal structure, and finally the transformation into rods. Is it shown that electrodes for lithium-ion batteries based on MoO(2) nanorods have a long-term cycling life. The specific discharge capacity even after 200 cycles at a discharge rate of 1 C is about 300 Ah kg(-1) . PMID- 21294268 TI - Receptor-mediated interactions between colloidal gold nanoparticles and human umbilical vein endothelial cells. AB - A new strategy to manipulate cell operations is demonstrated, based on membrane receptor-specific interactions between colloidal peptide-capped gold nanoparticles and human umbilical vein endothelial cells. It is shown that colloidal gold nanoparticles of similar charge and size but capped with different peptide sequences can deliberately trigger specific cell functions related to the important biological process of blood vessel growth known as angiogenesis. Specific binding of the peptide-capped particles to two endothelial-expressed receptors (VEGFR-1, NRP-1), which control angiogenesis, is achieved. The cellular fate of the functional nanoparticles is imaged and the influence of the different peptide-coated nanoparticles on the gene expression profile of hypoxia-related and angiogenic genes is monitored. The findings open up new avenues towards the deliberate biological control of cellular functions using strategically designed nanoparticles. PMID- 21294269 TI - Ultrasensitive detection of low-abundance surface-marker protein using isothermal rolling circle amplification in a microfluidic nanoliter platform. AB - With advances in immunology and cancer biology, there is an unmet need for increasingly sensitive systems to monitor the expression of specific cell markers for the development of new diagnostic and therapeutic tools. To address this challenge, a highly sensitive labeling method that translates antigen-antibody recognition processes into DNA detection events that can be greatly amplified via isothermal rolling circle amplification (RCA) is applied. By merging the single molecule detection power of RCA reactions with microfluidic technology, it is demonstrated that the identification of specific protein markers can be achieved on tumor-cell surfaces in miniaturized nanoliter reaction droplets. Furthermore, this combined approach of signal amplification in a microfluidic format could extend the utility of existing methods by reducing sample and reagent consumption and enhancing the sensitivities and specificities for various applications, including early diagnosis of cancer. PMID- 21294270 TI - Two-photon-sensitive and sugar-targeted nanocarriers from degradable and dendritic amphiphiles. AB - Increasing efforts are being put into the light-sensitive polymeric micelles that hold great potential for drug/gene/small interfering RNA delivery. However, these polymeric micelles lack highly efficient tumor-targeting properties and near infrared light sensitivity, and often exhibit an uncontrollable drug-release profile. To address these problems, a new strategy is introduced that combines sugar-triggered targeting (active targeting) and two-photon sensitivity to afford a degradable and dendritic micellar nanocarrier, in which the desired sugar residues and light-responsive groups can be modularly conjugated and/or altered. A clinical anticancer drug, doxorubicin, can be released in a controlled manner by changing the light irradiation time, which is induced by the gradual disruption of micelles in aqueous solution. The glucose- and lactose-coated micelles further demonstrate specific binding with the lectins Concanavalin A and Ricinus communis agglutinin, respectively, which makes them useful as targeted drug-delivery vesicles. PMID- 21294271 TI - Ordered mesoporous alpha-Fe2O3 (hematite) thin-film electrodes for application in high rate rechargeable lithium batteries. AB - Herein is reported the synthesis of ordered mesoporous alpha-Fe(2)O(3) thin films produced through coassembly strategies using a poly(ethylene-co-butylene)-block poly(ethylene oxide) diblock copolymer as the structure-directing agent and hydrated ferric nitrate as the molecular precursor. The sol-gel derived alpha Fe(2)O(3) materials are highly crystalline after removal of the organic template and the nanoscale porosity can be retained up to annealing temperatures of 600 degrees C. While this paper focuses on the characterization of these materials using various state-of-the-art techniques, including grazing-incidence small angle X-ray scattering, time-of-flight secondary ion mass spectrometry, X-ray photoelectron spectroscopy, and UV-vis and Raman spectroscopy, the electrochemical properties are also examined and it is demonstrated that mesoporous alpha-Fe(2)O(3) thin-film electrodes not only exhibit enhanced lithium ion storage capabilities compared to bulk materials but also show excellent cycling stabilities by suppressing the irreversible phase transformations that are observed in microcrystalline alpha-Fe(2)O(3). PMID- 21294272 TI - A nanochannel/nanoparticle-based filtering and sensing platform for direct detection of a cancer biomarker in blood. AB - A rapid nanochannel-based immunoassay capable of the filtering and subsequent detection of proteins in whole blood without any sample preparation is described. This is accomplished by using a nanoporous/nanochannel membrane modified with antibodies, the conductivity of which toward a redox indicator is tuned by primary and secondary immunoreactions with proteins and gold nanoparticles. This interesting nanopore blockage by gold nanoparticles is enhanced by silver deposition that further decreases the diffusion of the signaling indicator through the nanochannel. The efficiency of the nanochannels to act as immunoreaction platforms including the use of nanoparticles is also monitored by microscopic techniques. Successful detection of immunoglobulins including a cancer biomarker is achieved in buffer as well as in whole blood. This system constitutes an efficient immunoassay capable of detecting up to 52 U mL(-1) of CA15-3. The developed nanochannel/nanoparticle-based device can be used for several other proteins and extended also to DNA detection with interest not only for diagnostics but also environmental monitoring, food analysis, safety, and security applications. PMID- 21294273 TI - HMGB1-carbenoxolone interactions: dynamics insights from combined nuclear magnetic resonance and molecular dynamics. AB - The interplay of protein dynamics and molecular recognition is of fundamental importance in biological processes. Atomic-resolution insights into these phenomena may provide new opportunities for drug discovery. Herein, we have combined NMR relaxation experiments and residual dipolar coupling (RDC) measurements with molecular dynamics (MD) simulations to study the effects of the anti-inflammatory drug carbenoxolone (CBNX) on the conformational properties and on the internal dynamics of a subdomain (box A) of high-mobility group B protein (HMGB1). (15) N relaxation data show that CBNX binding enhances the fast pico- to nanosecond motions of a loop and partially removes the internal motional anisotropy of the first two helices of box A. Dipolar wave analysis of amide RDC data shows that ligand binding induces helical distortions. In parallel, increased mobility of the loop upon ligand binding is highlighted by the essential dynamics analysis (EDA) of MD simulations. Moreover, simulations detect two possible orientations for CBNX, which induces two possible conformations of helix H3, one being similar to the free form and the second one causing a partial helical distortion. Finally, we introduce a new approach for the analysis of the internal coordination of protein residues that is consistent with experimental data and allows us to pinpoint which substructures of box A are dynamically affected by CBNX. The observations reported here may be useful for understanding the role of protein dynamics in binding at atomic resolution. PMID- 21294274 TI - Postchemistry of inorganic-organic hybrid particles in aqueous solution: metal cation exchange. PMID- 21294275 TI - Osteogenic differentiation of two distinct subpopulations of human adipose derived stem cells: an in vitro and in vivo study. AB - The first stem cells considered for the reconstruction of bone were bone marrow mesenchymal stem cells (BMSCs). Subsequently, cells with similar marker expression panel and differentiation potential were found in new sources of cells, such as adipose tissue. This source of stem cells has a promising future in tissue-engineering applications, considering the abundance of this tissue in the human body, the easy harvesting and the high number of stem cells that are available from such a small amount of tissue. The isolation of the adipose stem cells is generally performed by means of enzymatic digestion of the tissues, followed by a natural selection of the stem cells based on their capacity to adhere to the culture flasks, leading to a quite heterogeneous population. This constitutes a major drawback for the use of these cells, since the heterogeneity of the cell culture obtained can compromise their proliferation and differentiation potential. In the present study we have analysed the in vitro and in vivo behaviour of two selected subpopulations with high osteogenic potential. For this purpose, ASCs(CD29+) and ASCs (STRO-1+)subpopulations were isolated and in vitro cultured onto a biodegradable polymeric scaffold, using osteogenic medium, before implantation in a nude mice model. The biodegradable polymeric scaffold used is a fibre-mesh structure based on a blend of starch and polycaprolatone (SPCL) that has been successfully used in several bone tissue engineering studies. The implanted ASCs-scaffold constructs promoted the formation of new bone tissue in nude mice. However, the results obtained show differences in the behaviour of the two ASCs subpopulations under study, particularly regarding their potential to differentiate into the osteogenic lineage, and allowed the indentification of ASCs (STRO-1+) as the best subpopulation for bone tissue-engineering applications. PMID- 21294276 TI - A LC-MS analysis of acamprosate from human plasma: pharmacokinetic application. AB - A rapid and highly sensitive method for the determination of acamprosate (ACM), in human plasma using ESI-LC-MS/MS (electrospray ionization liquid chromatography tandem mass spectrometry) in negative ionization polarity in multiple reactions monitoring (MRM) mode was developed and validated. The procedure involves a simple protein precipitation step. Chromatographic separation was carried out on a Hypersil BDS C(18) column (150 mm * 4.6 mm, 5 um) with an isocratic mobile phase and a total run time of 2.5 min. The standard calibration curves were linear within the range of 7.04-702.20 ng/mL for ACM (r >= 0.990). This study briefly describes the role of ion source design on matrix effects. ACM shows matrix effects in z-spray ionization source design, whereas it has no matrix effects in orthogonal spray ion source design. This method was successfully applied to a pharmacokinetic study after oral administration of acamprosate 333 mg tablet in Indian healthy male volunteers. PMID- 21294278 TI - [Surgical tactic in patients with high risk of occurrence of the intestinal anastomoses sutures insufficiency]. AB - The prognosis criteria for development of the intestinal anastomoses sutures insufficiency were elaborated, basing on analysis of the risk factors occurrence. Surgical tactic of treatment of the patients was substantiated, depending on the risk grade presence. In presence of high or moderate risk of the sutures insufficiency occurrence the methods of the deferred intestinal anastomoses formation were elaborated, excluding necessity of multistage intraabdominal operative interventions performance. Introduction of curative-diagnostic approach proposed promotes lowering of postoperative complications rate and lethality. PMID- 21294277 TI - Quantitative analysis of Pac1/LIS1-mediated dynein targeting: Implications for regulation of dynein activity in budding yeast. AB - LIS1 is a critical regulator of dynein function during mitosis and organelle transport. Here, we investigated how Pac1, the budding yeast LIS1 homologue, regulates dynein targeting and activity during nuclear migration. We show that Pac1 and Dyn1 (dynein heavy chain) are dependent upon each other and upon Bik1 (budding yeast CLIP-170 homologue) for plus end localization, whereas Bik1 is independent of either. Dyn1, Pac1 and Bik1 interact in vivo at the plus ends, where an excess amount of Bik1 recruits approximately equal amounts of Pac1 and Dyn1. Overexpression of Pac1 enhanced plus end targeting of Dyn1 and vice versa, while affinity-purification of Dyn1 revealed that it exists in a complex with Pac1 in the absence of Bik1, leading us to conclude that the Pac1-Dyn1 complex preassembles in the cytoplasm prior to loading onto Bik1-decorated plus ends. Strikingly, we found that Pac1-overexpression augments cortical dynein activity through a mechanism distinct from loss of She1, a negative regulator of dynein dynactin association. While Pac1-overexpression enhances the frequency of cortical targeting for dynein and dynactin, the stoichiometry of these complexes remains relatively unchanged at the plus ends compared to that in wild-type cells (~3 dynein to 1 dynactin). Loss of She1, however, enhances dynein-dynactin association at the plus ends and the cell cortex, resulting in an apparent 1:1 stoichiometry. Our results reveal differential regulation of cortical dynein activity by She1 and Pac1, and provide a potentially new regulatory step in the off-loading model for dynein function. PMID- 21294279 TI - [Application of early videothoracoscopic pulmonary decortication in the treatment of an acute pleural empyema and suppurated clotted hemothorax]. AB - There was presented the experience of performance of videothoracoscopic pulmonary decortications in 22 patients, suffering suppurated clotted hemothorax, and in 188--an acute pleural empyema. In 97.3% patients the cessation of purulent process and pulmonary volume restoration were achieved. Residual cavities with the pulmonary nonairtightness signs were revealed in 3 (1.4%) patients, the empyema recurrence--in 1 (0.5%), suppuration of the wound, made by thoracic port- in 1 (0.5%), all the patients are alive. PMID- 21294280 TI - [Peculiarities of using some methods to assess hand and finger functions in clinical practice]. AB - DASH questionnaire constitutes one of universal instrument, which are applied for estimation of the upper extremity function. Its disadvantages are massiveness, subjectivity, necessity of translation on Ukrainian language and adaptation to local conditions, what constitute a hard task. Comparative estimation of DASH questionnaires, short--DASH, Purdue pegboard test, Jebson-Taylor and Hand Tool Dexterity Test application was conducted. The analysis of correlation of the application results suggestion performed, concerning the methods of examination of the lower extremity and the hand function, trusts the possibility of wide application of Purdue pegboard test and Hand Tool Dexterity Test especially. Today the Erchard questionnaire, which is simple and need not to be translated, may serve as an alternative to DASH questionnaire. PMID- 21294281 TI - [The treatment of infectious complications after endoprosthesis of the joints in patients with oncological diseases of joints and bones]. AB - Infectious complications after endoprosthesis of the main joints, performed for tumors of the bones, are registered in 9.5% of observations. These complications occur more frequently in patients, to whom the conduction of supportive antitumoral therapy is indicated. Algorhythm, including the staged performance of conservative and surgical interventions, was elaborated for treatment of such complications. Conservative measures had included active draining of the wound, systemic and local antibacterial therapy, and while applying the surgical treatment--using of spacers and other methods of reconstruction (dystractional and bone-plasty one). Application of such algorhythm have permitted to achieve successful treatment of infectious complication, preserving functioning extremity in 66.7% of cases. PMID- 21294282 TI - [Hemorrhage in Dieulafoy disease as an example of an acute gastro-intestinal bleeding of uncertain etiology]. PMID- 21294284 TI - Diathermy or surgical scalpel for abdominal skin incisions: what is the impact on clinical practice? PMID- 21294285 TI - Diagnostic accuracy and receiver-operating characteristics curve analysis in surgical research and decision making. AB - In surgical research, the ability to correctly classify one type of condition or specific outcome from another is of great importance for variables influencing clinical decision making. Receiver-operating characteristic (ROC) curve analysis is a useful tool in assessing the diagnostic accuracy of any variable with a continuous spectrum of results. In order to rule a disease state in or out with a given test, the test results are usually binary, with arbitrarily chosen cut-offs for defining disease versus health, or for grading of disease severity. In the postgenomic era, the translation from bench-to-bedside of biomarkers in various tissues and body fluids requires appropriate tools for analysis. In contrast to predetermining a cut-off value to define disease, the advantages of applying ROC analysis include the ability to test diagnostic accuracy across the entire range of variable scores and test outcomes. In addition, ROC analysis can easily examine visual and statistical comparisons across tests or scores. ROC is also favored because it is thought to be independent from the prevalence of the condition under investigation. ROC analysis is used in various surgical settings and across disciplines, including cancer research, biomarker assessment, imaging evaluation, and assessment of risk scores.With appropriate use, ROC curves may help identify the most appropriate cutoff value for clinical and surgical decision making and avoid confounding effects seen with subjective ratings. ROC curve results should always be put in perspective, because a good classifier does not guarantee the expected clinical outcome. In this review, we discuss the fundamental roles, suggested presentation, potential biases, and interpretation of ROC analysis in surgical research. PMID- 21294286 TI - Laparoscopic colorectal surgery is associated with a higher intraoperative complication rate than open surgery. AB - OBJECTIVES: Laparoscopic colorectal resection is equivalent to open resection in a number of important areas. However, recent data have raised concern that intraoperative complications may be increased.We conducted a meta-analysis comparing intraoperative complication rates of laparoscopic and equivalent open colorectal resection. DATA SOURCES: Cochrane Central Register of Controlled Trials, MEDLINE, and Embase databases were searched, as were relevant scientific meeting abstracts and reference lists of included articles. REVIEW METHODS: Randomized controlled trials (RCTs) evaluating laparoscopic versus open surgery for any colorectal indication were included. Exclusion criteria were: trials assessing hand-assisted resection, and trials that excluded conversions to open surgery. There were no restrictions on language. Data were entered on an intention-to-treat basis in prospectively designed tables with complications categorized per event as: total complications, haemorrhage, bowel injury, and solid organ injury. Corresponding authors were contacted if information was missing. The Cochrane Collaboration tool was used for assessing risk of bias, the PETO odds ratio method was used for meta-analysis. RESULTS: Complete intraoperative complication data were obtained for 10 out of 30 included RCTs. Four thousand and fifty-five patients were analyzed; 2159 in the Laparoscopic Group and 1896 in the Open Group. There was a higher total intraoperative complication rate (OR 1.37, P = 0.010) and a higher rate of bowel injury in the Laparoscopic Group (OR 1.88, P = 0.020). There was no difference in the rate of intraoperative haemorrhage or solid organ injury. CONCLUSION: Laparoscopic colorectal resection is associated with a significantly higher intraoperative complication rate than equivalent open surgery. PMID- 21294287 TI - The time has come for a SYNTAX-like trial for transcatheter aortic valve implantation. PMID- 21294288 TI - Health-related quality of life in survivors with breast cancer 1 year after diagnosis compared with the general population: a prospective cohort study. AB - OBJECTIVE: To compare the health-related quality of life (HRQOL) of disease-free breast cancer survivors at the time of diagnosis and 1 year later with that of the general population (GP) and to examine the predictors of HRQOL change. BACKGROUND: Although studies that examine the changes HRQOL in breast cancer survivors with cohort design is increasing, few studies compared the HRQOL of breast cancer survivors from baseline (immediately after diagnosis) with that of the GP. METHODS: We administered European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and Quality of Life Questionnaire BR23 HRQOL immediately after diagnosis to evaluate a population-based cohort of 286 women with breast cancer. We compared HRQOL scores of subjects internally and with reference data from the GP externally. RESULTS: We found no significant change in HRQOL internally except for diarrhea. In the external comparison, however, breast cancer survivors reported poorer HRQOL scores than the GP at baseline and a year later; clinically meaningful detriments were found for emotional and social functioning and for the symptoms of fatigue and insomnia, financial difficulties, and most of the breast cancer-specific domains (P < 0.01 for all). Multiple linear regression analysis revealed that menopausal status and the sociodemographic characteristics of education level, employment status, and physical activity at baseline and increased symptom problems were significantly associated with functioning changes. CONCLUSION: Immediately after the diagnosis of breast cancer, patients reported a lower HRQOL than the GP, and they continued to do so a year later. Increased levels of fatigue, pain, and insomnia were the main symptoms responsible. PMID- 21294289 TI - Liver transplantation for advanced hepatocellular carcinoma using poor tumor differentiation on biopsy as an exclusion criterion. AB - BACKGROUND: Liberal acceptance criteria are used when offering liver transplantation (LTx) for treatment of hepatocellular carcinoma (HCC) at our center. This provides a unique opportunity to assess outcomes in a large North American series of patients with advanced tumors. OBJECTIVE: We hypothesized that acceptable survival rates can be achieved with LTx for any size or number of HCC provided that (a) imaging studies ruled out vascular invasion; (b) the HCC was confined to the liver; and (c) the HCC was not poorly differentiated on biopsy. METHODS: Survival, based on pretransplant imaging staging, was compared between 189 Milan Criteria (M) and 105 beyond Milan Criteria (M+) HCC patients who received an LTx between 1996 and 2008. RESULTS: Imaging understaged 30% of the M group and over staged 23% of the M+ group. There was no difference in the 5-year overall survival in the M (72%) and M+ (70%) groups or 5-year disease-free survival in the M (70%) and M+ (66%) groups. The introduction of a protocol for a biopsy to exclude patients with poorly differentiated tumors and use of aggressive bridging therapy improved overall survival in the M+ group (P = 0.034). Serum alpha-fetoprotein more than 400 at LTx was associated with poorer disease-free survival (hazard ratio: 2.3; P = 0.031). CONCLUSIONS: Cross sectional imaging did not reliably stage patients with HCC for LTx. A protocol using a biopsy to exclude poorly differentiated tumors and aggressive bridging therapy achieved excellent survival rates with LTx for otherwise incurable advanced HCC, irrespective of tumor size and number. PMID- 21294290 TI - Diffuse pachymeningeal enhancement. PMID- 21294292 TI - MCR 2009. Abstracts of the 4th International Conference on Multi-Component Reactions and Related Chemistry, Ekaterinburg, Russia. PMID- 21294291 TI - Epidermal panfolliculoma: A report of 2 cases. AB - There are a variety of known lesions displaying differentiation toward various portions of the hair follicle. However, there is no established term given to an intraepidermal entity showing differentiation toward both upper and lower portions of the follicle. We report 2 cases of a histologically distinct variant of panfolliculoma that, unlike the traditionally described panfolliculoma, is located intraepidermally. The lesions were taken from the medial thigh of an 81 year-old man and the lateral thigh of a 61-year-old woman, clinically suspected to be an inflamed seborrheic keratosis and a squamous cell carcinoma, respectively. Each case appeared as a demarcated plaque-like lesion with mild epidermal hyperplasia and prominent differentiation toward the upper and lower segments of the hair follicle. The specific histologic features included focal differentiation toward the infundibulum and isthmus (infundibular cystic structures and pilar epithelium), inner root sheath (trichohyalin granules), the matrix/hair shaft (matrical cells, ghost cells and refractile keratinization), and follicular germ/papilla (papillary mesenchymal bodies). This varied histology is similar to that of the previously described panfolliculoma, differing in that it emanates largely from the epidermis rather than being predominantly dermally located. We propose the term "epidermal panfolliculoma" for these lesions. PMID- 21294293 TI - Severe headache, dysarthria and ataxia in a 62-year-old man. PMID- 21294294 TI - Practical suggestions for implementing caries control and recall protocols for children and young adults. PMID- 21294295 TI - MDA a 'godsend'. PMID- 21294296 TI - Disagrees with health care commentary. PMID- 21294297 TI - Many radiographs clinically unacceptable. PMID- 21294298 TI - Causes of suicide in middle-aged men in prefectures in Japan during the recent spike in suicides. PMID- 21294299 TI - The process of reversible phosphorylation: the work of Edmond H. Fischer. PMID- 21294300 TI - The outcome of patients referred to a transcatheter aortic valve implantation multidisciplinary team. PMID- 21294301 TI - Movement disorder in a patient with stroke. PMID- 21294302 TI - [Angiotensin II antagonists and cancer: a storm that can do good ]. PMID- 21294303 TI - [Practice guidelines of the European Society of Hypertension for home blood pressure measurement]. AB - Self-measurement of blood pressure at home is increasingly used in the diagnostic and therapeutic approach of hypertension. This technique allows multiple measurements of blood pressure away from the clinical setting, making it possible to improve the evaluation of cardiovascular risk. Recently new guidelines on the use of self-measured blood pressure have been made available by the European Society of Hypertension, as summarized in the present paper. PMID- 21294304 TI - [Guidelines on hypertension management]. AB - The purpose of this review was to consider the Reappraisal of European guidelines on hypertension management published in 2009 in the light of 2005 French national guidelines and of recently published large randomized trials. We analyzed successively the recommendations dealing with assessment of global cardiovascular risk, hypertension treatment and blood pressure goals; we focused on patients at high cardiovascular risk: diabetic patients and patients with coronary disease and elderly population. PMID- 21294305 TI - [Managing hypertension: the uncertainty of definitions and targets]. AB - In clinical practice, physicians are confronted with a multitude of definitions and treatment goals for arterial hypertension, depending of the diagnostic method used (e.g. office, home and ambulatory blood pressure measurement) and the underlying disease. The historical background and evidence of these different blood pressure thresholds are discussed in this article, as well as some recent treatment guidelines. Besides, the debate of the "J curve", namely the possible risks associated with an excessive blood pressure reduction, is discussed. PMID- 21294306 TI - [Nutrition and hypertension: more than table salt]. AB - The role of dietary sodium intake in the development, and its impact on the treatment, of hypertension are well recognized. However, many other nutritional compounds have been shown, or are believed, to influence blood pressure. Some compounds, such as caffeine and fructose, may raise arterial blood pressure, whereas others might lower arterial blood pressure, for example garlic, dark chocolate, fibers and potassium. In this article, we review several alimentary compounds and their (hypothesized) mechanisms of action, as well as the available evidence supporting a role of these compounds in the "non pharmacological" treatment and prevention of hypertension. PMID- 21294307 TI - [Resistant hypertension]. AB - Resistant hypertension (rHTN) is a frequent problem with a high impact on cardiovascular risk. The preferred diagnostic approach is to systematically evaluate risk factors for rHTN and the presence of secondary hypertension. The follow-up of several key elements will often allow an improvement of blood pressure. Four therapeutic classes or even more are often used in these patients. Adding an aldosterone antagonist is often beneficial. Monitoring of patient compliance by electronic medication event monitoring systems can be helpful. Several new therapeutic approaches are currently in development: antagonists of the endothelin receptor and two interventional methods, carotid sinus stimulators and catheter-based renal sympathetic denervation therapy, have shown some promise. PMID- 21294308 TI - [Peyronie's disease-often a disabling disease for sexually active men]. AB - Peyronie's disease is an acquired penile condition characterized by fibrous plaques between the tunica albuginea and the subtunical tissue of the corpora cavernosa. Plaques are considered responsible for the main symptoms: penile pain and deviation. Even though several risk factors and associations with other diseases are known its exact aetiology remains unclear. Most commonly discussed hypotheses are micro traumata, inflammatory and/or ischemic processes. Currently different treatment forms exist raging form systemic or local medical treatment, to physical applications and surgery. All treatment forms are symptom based and evidence based treatment remains difficult to establish. Because conservative treatment is of limited success in many patients especially with severe deviations surgery becomes necessary. PMID- 21294309 TI - [Dog bites in Switzerland]. PMID- 21294310 TI - [Spousal abuse: the physician's responsibility]. PMID- 21294311 TI - [Alzheimer's: between hope and despair]. PMID- 21294312 TI - [Learning to drink in order to lose weight]. PMID- 21294313 TI - [Death of the Web and providing care networks ]. PMID- 21294314 TI - [Oral treatment, some points to consider]. PMID- 21294315 TI - [Oseltamivir suspensions]. PMID- 21294316 TI - [How to improve the continuity of pharmacotherapy at hospital admission and discharge]. AB - The continuity of pharmacotherapy is of vital importance when patients move from one health care setting to another. Unfortunately, this continuity is not always guaranteed. The aim of this study is to propose solutions to enhance the continuity of pharmacotherapy at hospital admission and discharge. The study consists of a systematic review of the international literature and an analysis of seamless care initiatives in seven selected countries; a summary of Belgian data on problems as well as solutions with regard to continuity of care; a quantification of the extent of medication changes as a result of a hospital stay in Belgium; and a qualitative analysis of the perception of Belgian health care professionals (HCPs) on approaches to improve seamless care. The literature review yielded 15 papers of sufficient quality. However, this review did not generate definitive conclusions on the clinical impact and the cost-effectiveness of interventions aiming to enhance the continuity of pharmacotherapy. The most important initiatives that have been put in practice in foreign countries include the development and implementation of guidelines for HCPs; national information campaigns; education of HCPs; and the development of information technologies as to share patient and prescription data between settings of care. For Belgium, 66 seamless care initiatives were identified. The high number and variety of projects show the interest for this topic as well as the involvement of various HCPs from diverse settings in the development of solutions. Based on this research, and the solutions discussed in the focus groups, the following elements are proposed to enhance the continuity of pharmacotherapy: a national guideline governing the continuity of pharmacotherapy; a national campaign to sensitize HCPs and patients in this area; the availability of a comprehensive and up to date medication list for each patient; and electronic healthcare infrastructure that facilitates sharing of information. PMID- 21294317 TI - [Medication review in the elderly by the community pharmacist: a pilot study]. PMID- 21294318 TI - [How to improve the collaboration between GP and community pharmacist? A survey in Antwerpen and Limburg]. PMID- 21294319 TI - [Prucalopride - oral (Resolor)]. PMID- 21294320 TI - [Pelargonium sidoides - oral (Kaloban).]. PMID- 21294321 TI - [Diagnosis and therapy for patients with essential thrombocythemia. Guidelines of Croatian Cooperative Group for hematologic disorders--KROHEM]. AB - Essential thrombocythemia (ET) is a clonal myeloproliferative neoplasm. Croatian Cooperative Group for hematologic disorders, KROHEM proposes the diagnostic and treatment guidelines for ET. Diagnosis of ET is based on the criteria and classification of World Health Organization (WHO). The level of treatment recommendation is based on the UpToDate (web based medical community database) criteria. For ET diagnosis it is mandatory to show sustained increased number of platelets with typical histomorphological changes of megakaryopoiesis in bone marrow. Secondary thrombocytosis and other chronic myeloproliferative neoplasms have to be excluded. Therapy is based on risk factors for ET. The risk factors are number of platelets, patient's age, and the risk levels for thrombosis and bleeding. Patients with low risk (age < 60 years and platelets < 1000 x 10(9)/L) arw not candidates for therapy. In younger group of patients with platelets between 1000 and 1500 x 10(9)/L or more than 1500 x 10(9)/L treatment with anagrelide or hydroxyurea is recommended respectively. In high risk patients hydroxyurea is the first line treatment. Anagrelide is indicated in these patients in the absence of treatment response. Alpha-interferon is recommended for pregnant women with ET and high platelet counts. PMID- 21294322 TI - [Guidelines for prevention, control and treatment of infections caused by methicillin-resistant Staphylococcus aureus (MRSA): changes and updates of chapter 7.0: treatment of patients with MRSA infection]. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is an important pathogen throughout the world, and as well in Croatia. Therefore it was decided to develop guidelines with the aim to reduce the number of patients infected/colonized with MRSA in healthcare facilities and in nursing homes in Croatia, consequently reducing MRSA-related morbidity and mortality. An interdisciplinary team of experts developed these guidelines using existing international guidelines from different countries, and literature reviews about prevention, control, treatment and laboratory diagnosis of MRSA infections. Grades of evidence for specific recommendations were determined using CDC/HICPAC grading system. Categorization is based on existing data, theoretical basis, applicability and economic impact. After a broad discussion in different professional societies, Guidelines were accepted. In the meantime, several new possibilities appeared in the treatment of patients with MRSA infections in Croatia, so the Chapter 7.0 Treatment of patients with MRSA infections is changed and updated according to the new treatment possibilities. The rest of the Guidelines was not changed. PMID- 21294323 TI - [The suicide analysis in Bjelovarsko-Bilogorska County in 1988-2005 period]. AB - Every forty seconds a person commits suicide according to the WHO, each year nearly one million people, mostly men in their sixties, but in recent years suicides of young men (aged 15 to 29 years) have increased. The last twenty years in Croatia, the annual number of suicides has been between 871 and 1142. We analyzed the number of suicides, rate, methods, scene and time of committing, gender, age and profession of committers, as well as interdependence of scene, methods and vocation, upon the pattern of 804 cases of suicides committed from 1988 to 2005 in Bjelovarsko-Bilogorska County. Our district is characterized by high suicide rate (31/100000). People who perform suicide are predominantly older and men more frequently then women. To add emphasis, there were 2.49% suicides committed by adolescents in overall sample. The most frequent method of performing suicide was by hanging, most suicides were commmitted at the start of the working week, also in morning hours and more in spring and summer months. Methods of committing suicide are correlated with access of means and scene of committting (indirectly with profession). Motives alter depending on committers' age, the most frequent motive being illness. PMID- 21294324 TI - [Combined penetrating wounds of the heart, abdomen and trunk--case report]. AB - This is an overview of a forty-year-old male with combined penetrating knife inflicted stab wounds to the left chest, heart, abdomen and trunk. Presented are clinical manifestations, course of first aid and overall surgical help given to the injured with multiple stab wounds. Efficiency of rapid diagnostics and surgical approach to penetrating stab wound of the heart is pointed out. Postoperative course and definitive outcome of treatment are presented. PMID- 21294325 TI - [Radioiodine versus surgery in the treatment of Graves' hyperthyroidism]. AB - The most common etiologic cause of thyrotoxicosis in children and adults is autoimmune Graves' (Basedow's) disease. Antithyroid medications, surgery and radioactive iodine have been used in the treatment of Graves' hyperthyroidism for more than six decades. The use of antithyroid drugs is the most common therapeutic approach. However, long-term remission with antithyroid drugs can be expected in 20-50% of adults and 20-30% of children. The methods for definitive treatment of Graves' hyperthyroidism are iodine-131 (radioiodine) and surgery. Both treatment modalities have benefits and risks and the decision is made according to the age, patient preference and the presence of other co morbidities, individual characteristics of patients and the availability of certain treatment modality. Radioiodine is simple, safe, effective and economic procedure for definitive treatment of Graves' hyperthyroidism. It is administered ambulatory and can be given to the patient in thyrotoxicosis. Due to many benefits, radioiodine is preferred in most of the adult patients with Graves' hyperthyroidism while only small proportion of patients is sent to surgery. Radioiodine is especially the treatment of choice in elderly patients and patients with heart disease. In these patients radioiodine is indicated immediately after reaching euthyroidism with antithyroid drugs. Surgery is mainly indicated in younger patients, in the case of patient preference or in special indications. Clear indications for surgical treatment of Graves' hyperthyroidism are: suspected or confirmed malignancy, coexisting pathology that demands surgical treatment, pregnancy and breastfeeding, large goiter (> 80 grams) or goiter with symptoms and signs of compression, severe toxic side effects of antithyroid medications, requirement for immediate control of disease, age younger than 5 years and active ophtalmopathy. The risk of surgical treatment is negatively correlated with the surgeon's experience and nowadays, total or near total thyroidectomy is preferred surgical approach. End point of both treatment modalities is usually hypothyroidism that should not be considered as the consequence of treatment. Moreover, due to thyroid hormones replacement therapy equilibrium can be easily achieved. PMID- 21294326 TI - [The role of perforin mediated cell cytotoxicity in psoriasis]. AB - Psoriasis is a common chronic inflammatory skin disease characterized by hyperproliferation and incomplete differentiation of epidermal keratinocytes as well as by inflammatory infiltrate of T-lymphocytes in dermis and epidermis. Psoriasis is nowadays also recognized as a T cell mediated disease resulting from aberrant activation of both innate and adaptive immunity. The main effector cells in mediating psoriatic phenotype are helper CD4+ T cells and cytotoxic CD8+ T cells. Both, CD4+ and CD8+ T cells, mediate apoptosis via the release of cell granules, perforin and granzymes or by binding of ligands to their death receptors on target cells. The role of cell cytotoxicity mechanisms, particularly those mediated by perforin, in psoriasis is as yet unclear. Perforin is a pore forming molecule, located within the cytoplasm of cytotoxic T cells and natural killer cells, which enables entry of granzymes and other apoptotic molecules into the target cell in order to mediate programmed cell death. The importance of perforin-mediated cytotoxicity has been demonstrated in several autoimmune diseases and in some inflammatory skin diseases. Recent studies claimed its role in the immunopathogenesis of psoriasis as well. Accumulation of perforin-positive cells in psoriatic epidermis close to damaged keratinocytes suggests that T lymphocytes induce damage to keratinocytes by releasing cytolytic molecules. On the other hand, apoptotic keratinocytes might trigger an injury response program causing regenerative hyperplasia of epidermal keratinocytes, a hallmark of psoriasis. Progress in understanding of effector part of cell cytotoxicity in psoriatic plaque might in future enable more specific treatment of psoriatic patients by blocking selectively each of proposed cytolytic mechanisms and molecules as potential new therapeutic targets. PMID- 21294327 TI - [Treatment of alopecia areata: modern principles and perspectives]. AB - Alopecia areata (AA) is a frequent disease with nonscarring hair loss on the scalp and/or body. Hair follicle in alopecia areata is not irreversibly destroyed, so potential for hair regrowth remains. Considering unknown etiopathogenesis, treatment of AA is symptomatic and directed toward halting disease activity. Lymphocytic inflammatory infiltrate around hair follicle, increased levels of autoantibodies, cytokine abnormalities and increased prevalence of autoimmune comorbidities, support the hypothesis of AA as an organ specific autoimmune disorder. Therefore, investigations are directed toward new immunomodulatory or immunosuppressive drugs with induction effect on hair growth. New biologic drugs and their influence on hair growth as well as genetic therapy for alopecia areata are currently under investigation. Contemporary principles in therapy of alopecia areata and treatments available will be discussed in this article. PMID- 21294328 TI - [Do we correctly manage adult asthma patients in family medicine?]. AB - Although prevalence of asthma has increased particularly among children, asthma is still underdiagnosed and undertreated or inappropriately treated disease. Most of the health care for patients with asthma is provided by family physicians in primary health care. Nowadays recommendations (GINA 2006) are based on assessing asthma control levels, the cornerstone of therapy for persistent asthma of all degrees of severity, both in adults and children, are inhaled corticosteroids (ICS) as monotherapy, while long-acting beta2-agonists (LABA), leukotriene modifiers (LTRA) or theophylline are add-on therapy if the control of disease is not successfully achieved. Fixed combination (ICS + LABA) could be used only for moderate to severe persistent asthma and in cases when satisfactory control is not achieved using ICS alone. Unjustified trend towards initial fixed combination prescribing has become more and more popular, but with potential of overuse. PMID- 21294329 TI - [Baptism out of necessity--a medico-historiografic view]. AB - Baptism of necessity of life-threatened newborns was proclaimed by church law and related midwifery regulations from the second half of the 16th century. Midwives were for centuries the only lay persons attending the pregnant woman, parturient woman and newborn, so they were obliged to baptize newborns with life-threatening conditions, which were rather common and associated with high mortality in those times. Medical historiography has demonstrated this obligation of midwives in the town of Bjelovar and its surroundings, where parish registers of births, marriages and deaths contain data on numerous newborns baptized out of necessity. PMID- 21294330 TI - [100000 lives can be saved per year in Europe--the new ERC guidelines on resuscitation 2010]. PMID- 21294331 TI - [Krypton--new, deadly Internet drug. Since October 2009 have nine young persons died in Sweden]. PMID- 21294333 TI - [The understanding that "chlamydia is a risk of chlamydia" is strengthened. The risk of "repeat infection" surveyed in a prospective, cohort study]. PMID- 21294334 TI - [Calcitonin gene-related peptide and migraine. Increases understanding of physiopathology can lead to new drug therapy]. PMID- 21294335 TI - [Neuromyelitis optica--important differential diagnosis to MS. Early treatment initiation crucial for the prognosis]. PMID- 21294336 TI - [Time to introduce audit of transfusion treatment. Local transfusion committees should be established in Sweden]. PMID- 21294337 TI - [Is there an ethical difference between euthanasia and sedation therapy?]. PMID- 21294338 TI - [Productivity in health care: physicians are prisoners in a bureuacratic system]. PMID- 21294339 TI - [Both betamethasone and dexamethasone should be accessible in acute pediatrics]. PMID- 21294340 TI - [Routine treatment of abdominal aortic aneurysm: surely, results from randomized studies should be applied, but...]. PMID- 21294341 TI - [The discussion about Multiferon should go on]. PMID- 21294342 TI - [Outcome of a web-based opinion survey: physicians demand better sick-listing routines]. PMID- 21294343 TI - [Starvation--the constant follower of human beings]. PMID- 21294344 TI - [Physician--for whom and why? can you beam away a notification?]. PMID- 21294345 TI - [Impossible computer systems in health care. Should SYSteam Cross be crushed?]. PMID- 21294346 TI - [Increased morbidity among Finland-born in Swedes put demands on health care. The cause of Finland is our cause]. PMID- 21294347 TI - [Finns living in Sweden have poorer health than native Swedes. But their psychological well-being is the same]. PMID- 21294348 TI - [Dietary advice in health care--a way lined with pros and cons]. PMID- 21294349 TI - [Tuberculosis in Somalia with consequences in Sweden]. PMID- 21294350 TI - [HbA1c--new standardization introduced in Sweden. The new unit is mmol/mol]. PMID- 21294351 TI - [Indwelling pleural catheters give symptom relief in malignant pleuritis]. PMID- 21294352 TI - [Pre-eclampsia]. PMID- 21294353 TI - [Time limit for palliative sedation is needed]. PMID- 21294354 TI - [Life style guidelines contrary to evidence based practice]. PMID- 21294355 TI - [Guidelines on disease preventive methods are important for health care]. PMID- 21294356 TI - [Medical Product Agency about Multiferon: positive benefit-risk relation]. PMID- 21294357 TI - [New internship requires changed point of view: from journeyman education to formal education]. PMID- 21294358 TI - [Accreditation of internship education--future instrument for development?]. PMID- 21294359 TI - [A reply about palliative care: it's all about the patient]. PMID- 21294360 TI - [Christmas in darkness: the physician and the priest Kurt Reuber in Stalingrad 1942]. PMID- 21294361 TI - [Exam callus]. PMID- 21294362 TI - [Evaluating the effectiveness of drugs. "The full potential of a therapy is often only clear after a number of years" (interview by Helmut Laschet)]. PMID- 21294363 TI - [Veiled symptoms, challenging therapy. Are you prepared for an emergency in the very elderly?]. PMID- 21294364 TI - [Do not cough with the hand! Elbow is better]. PMID- 21294365 TI - [Every year 200,000 new Alzheimer cases. Are you aware of the initial symptoms?]. PMID- 21294366 TI - [Naturopathy consultation. Obesity]. PMID- 21294367 TI - [Multidrug therapy and driving impairment]. PMID- 21294368 TI - [Shoulder dislocation: diagnosis and treatment]. PMID- 21294369 TI - [Conservative treatment for adolescent idiopathic scoliosis]. PMID- 21294370 TI - [Enuresis]. PMID- 21294371 TI - ["Rheumatic pain". Joint is painfully swollen overnight]. PMID- 21294372 TI - [2010 German Pain Congress. Backache - new data, specific muscle etiology and targeted therapy]. PMID- 21294373 TI - [IEffects of magnesium on the cardiovascular system]. PMID- 21294374 TI - [Also considering extraskeletal effects. ]. PMID- 21294375 TI - Foreign bodies; or, how did Darwin invent the symptom? AB - Beginning with a discussion of the sources in Darwin's writing for Freud's theory of the hysterical symptom, this essay proceeds to a symptomatic reading of Darwin himself. With reference to "The Origin of Species," "The Descent of Man," and "The Expression of the Emotions," this essay shows that Darwin's theories of involuntary expressive behavior and of aesthetic preference in sexual selection are linked by their role in his understanding of racial difference and also by their reliance on the idea that learned habits can be inherited as instincts, a view often identified with Lamarck. They are thus at once theories of the foreign body and theories that appear as foreigners within the body of Darwin's work. PMID- 21294376 TI - Form and deformity: the trouble with Victorian pockets. AB - This essay explores the Victorian debate about the place of pockets in men's and women's clothing. By studying the representation of men as naturally pocketed creatures and the general denial of useful pockets to middle-class women, the essay demonstrates the tenacious cultural logic by which men's and women's pockets were imagined to correspond to sexual differences and to index access, or lack thereof, to public mobility and financial agency. Interconnected readings of visual art, essays, and novels show how the common sense about gendered pockets was utilized and promulgated in Victorian narratives. The question of who gets pockets is thus positioned as part of the history of gendered bodies in public space. PMID- 21294377 TI - Activation of peroxisome-proliferator-receptor alpha and gamma mediates remote ischemic preconditioning against myocardial infarction. PMID- 21294378 TI - The sequence of pbp2b from penicillin-resistant Streptococcus pneumoniae in Thailand. AB - OBJECTIVE: Penicillin resistance in Streptococcus pneumoniae isolates results from altered penicillin-binding proteins (PBPs), especially PBP2, which has a reduced affinity to penicillin. This study evaluated drug resistance and the gene sequence of the conserved motif pbp2b of penicillin-resistant isolates in Thailand. MATERIAL AND METHOD: Penicillin-resistant pneumococci with minimum inhibitory concentrations (MIC) for penicillin > or = microg/ ml and penicillin susceptible strains were identified from clinical specimens. The pbp2b genes were amplified by polymerase chain reaction (PCR), and the purified PCR product was cloned into E. coli. The recombinant plasmid clones containing pbp2b were sequenced and evaluated for mutations corresponding to penicillin and cefotaxime resistance. RESULTS: Penicillin-susceptible S. pneumoniae isolates were susceptible to 12 other antibiotics tested (range 95-100%) while penicillin nonsusceptible isolates were resistant to most antibiotics except amoxicillin/clavulanate and levofloxacin. Sequence analysis of pbp2b showed a substitution of A for T451 next to the region of the SSN triad in all six resistant isolates tested and mutations clustered around the KTG triad in two isolates. Using the ClustalW alignment program, Thai isolates differed from those of European countries, but were more similar to those from Japan than Korea. CONCLUSION: Penicillin or cefotaxime resistance in S. pneumoniae in Thailand was due to affinity reduction of PBP2b, similar to changes found in other Asian isolates. PMID- 21294379 TI - A description of antimicrobial susceptibility of Streptococcus pneumoniae-Siriraj Hospital, Thailand: 2008. AB - Streptococcus pneumoniae was isolated from 170 patient specimens at Siriraj Hospital during January-December 2008. Patients were 66% male and ranged in age from 3 months to 94 years (mean +/- SD = 38.2 +/- 31.7). The largest proportion (29.4%) of isolates were from patients older than 60 years, followed by patients aged 2-5 years (20%) and from patients less than 2 years (12.4%). Monthly isolation was highest in December (22 isolates in December compared to the average of 13 isolates of the other months). Antimicrobial susceptibility for eight drugs was determined by the disk diffusion method. Overall, susceptibility was generally high to chloramphenicol (71.8%), linezolid (100%), ofloxacin (93.5%) and vancomycin (100%), but less susceptible to erythromycin (35.3%), penicillin (31.1%), tetracycline (28.8%) and trimethoprim/ sulfamethoxazole (24.1%). Among the 105 (62%) isolates resistant to three or more drugs, the most common resistance pattern was erythromycin-penicillin-tetracycline trimethoprim/sulfamethoxazole, accounting for 39% of such isolates, followed by chloramphenicol-erythromycin-penicillin-tetracycline- trimethoprim/sulfamethoxazole (29.5%). The minimal inhibitory concentrations (MIC) of penicillin and cefotaxime were determined by broth microdilution. By 2008 CLSI criteria, 92% and 90% of 51 sterile site isolates were penicillin and cefotaxime susceptible, including one of two meningitis cases. In contrast, of 26 non-sterile site isolates, only 26.9% and 76.9% were susceptible to penicillin and cefotaxime, respectively. The MICs of penicillin were higher for isolates from non-sterile sites than for those from sterile sites. PMID- 21294380 TI - Invasive pneumococcal disease in Phramongkutklao Hospital 2004-2008: clinical data, serotype distribution and antimicrobial resistance patterns. AB - OBJECTIVE: To describe the clinical course, serotype distribution and antimicrobial resistance patterns of invasive pneumococcal disease (IPD) cases in a public hospital. MATERIAL AND METHOD: Retrospective review of IPD cases occurring from January 2004 through December 2008 was performed. Antibiotic susceptibility testing and serotyping were performed for available isolates. RESULTS: Fifty one IPD cases occurred during the study period, of which 47 had medical records available for review. The majority of cases occurred among children under 5 years of age (23.4%) and adults over 60 years of age (36.1%). Underlying diseases were identified in 72.3% of patients. Fifty-three percent of cases were associated with pneumonia, while 17% had meningitis, and 15% had isolated bacteremia. Serotype could be determined for 15 (31.9%) isolates, and 6B was most common. Based on current antibiotic susceptibility breakpoints for meningitis, 4 of the 7 available isolates from meningitis cases were penicillin resistant and one had reduced susceptibility to cefotaxime. Among non-meningitis isolates, 96.7% were penicillin susceptible and 3.3% had intermediate susceptibility to penicillin. Overall case fatality proportion was 19%. CONCLUSION: At this tertiary care hospital in Bangkok, IPD has disproportionately affected young children and the elderly. High rates of penicillin resistance among meningitis cases, the most severe form of IPD, underscore the need of appropriate treatment strategies and vaccine usage. PMID- 21294381 TI - Invasive pneumococcal infection in neonates: 3 case reports. AB - Streptococcus pneumoniae is a rarely recognized cause of neonatal sepsis. We report invasive pneumococcal infection in three neonates. The infections were abrupt, severe, and rapidly progressive in two neonates with fatal outcome despite antibiotic therapy. There was no identifiable risk factor. Maternal colonization should be further studied. PMID- 21294382 TI - Cerebrospinal fluid lymphocytosis in an infant with acute Streptococcus pnuemoniae meningitis: a case report. AB - A 10 month-old female infant presented with one day of high fever with drowsiness and seizures. Physical examination showed meningeal irritation and mild cyanosis. The cerebrospinal fluid (CSF) profile revealed opening pressure of 27 cmH2O, closing pressure of 17 cmH2O, red blood cells 310 cells/microL, white blood cells 100 cells/microL of which 90 percents were lymphocytes, protein 391 mg/dl, sugar 0 mg/dL and blood sugar 74 mg/dl. Numerous gram positive diplococci were found on CSF Gram-stained smear. Bacterial meningitis was diagnosed and cefotaxime 300 mg/kg/day plus vancomycin 60 mg/kg/ day were given empirically. The patient developed hypotension, poor tissue perfusion, dyspnea and disseminated intravascular coagulopathy (DIC). She expired 10 hours after hospitalization. The CSF and blood culture grew out Streptococcus pneumoniae serotype 6B with the minimal inhibitory concentration (MIC) of 0.5 and 1.5 microg/mL for penicillin and cefotaxime respectively. Atypical characteristics of CSF in bacterial meningitis may cause delay in empirical antimicrobial therapy. Gram-stained smear of CSF is helpful for rapid diagnosis and proper management. PMID- 21294383 TI - Implication of pneumococcal conjugate vaccines to public health: Thailand perspective. AB - The pneumococcal conjugate vaccines (PCVs) have demonstrated good safety profile and efficacy against invasive pneumococcal diseases (IPD) caused by the serotypes included in the vaccines. The PCV also benefit to the unvaccinated children and adults from herd immunity. With the widespread use of the vaccine, emerging of non vaccine serotypes has been documented. The IPD burden in Thailand was found to be lower than that found in the western countries but the data in high risk population has been lacking. The PCV has been available in Thailand since 2006 as an optional vaccine, out of National Vaccine Program, with the uptake of less than 5% in children under 5 years of age. The serotypes distribution in Thailand has not changed significantly. In the year 2000-2005, compared with year 2006 2009, the most common serotypes in children < 5 years have been similar; comprising of 6B, 23F, 14, and 19F, however 19A has become more prevalence (6.2%) in the years 2006-2009. With the new breakpoint of penicillin susceptibility for non-meningeal strains, most penumococcal isolates in Thailand were susceptible to penicillin. To project the benefit for widespread use of PCV in Thailand the cost benefit analyses including the different types of PCV, the various dosing schedule, the benefit from herd immunity and the disadvantage of serotype replacement are needed. PMID- 21294384 TI - Pneumococcal infections in high-risk and immunocompromised hosts. AB - Streptococcus pneumoniae is an important cause of morbidity and mortality worldwide, it is responsible for invasive pneumococcal disease (IPD) (e.g. meningitis, bacteremic pneumonia and bacteremia) and non-IPD (e.g. pneumonia, acute otitis media, and sinusitis). IPD is preceded by nasopharyngeal colonization with high incidence of disease among young children, the elderly, persons with underlying medical conditions and immunocompromised hosts. The term "immunocompromised host" is generally applied to a variety of patients with various immune defects. The factors that contribute to the development of IPD include host immunity (specific and innate), genetic and environment. Specific defects in host responses to pneumococcal infections may due to very young age, deficiencies in levels of antibodies and complement factors, and splenic dysfunction. The combinations of these defects contribute to the increased rates of IPD. The immunocompromising and other conditions that predispose to pneumococcal disease were described. PMID- 21294385 TI - The real effectiveness of ultrasound guidance in subclavian venous access. AB - AIM: The technique of ultrasound-guided subclavian cannulation was evaluated in our experience assessing the real effectiveness of such procedure. METHODS: We have evaluated 297 subclavian cannulation, performed for the placement of central venous catheter both with landmark method (176 patients) and ultrasound guided technique (121 patients) to assess the real effectiveness of the ultrasound guided technique to reduce the mechanical complication of the subclavian vein puncture. RESULTS: A total of 23 mechanical complications were identified. Of these, 8 were pneumothorax and 15 arterial puncture. Such cases were identified from the pool of patients who had undergone subclavian venous cannulation with landmark method. However these complications occurred only in difficult venous access and teaching procedure performed with landmark method. DISCUSSION: An ultrasound-guided recent technique for the placement of central venous access should be adopted since such technique seems to reduce the incidence of failure and mechanical complications. However it is worth notice that the clinical effect of using ultrasound guidance technique seems to be more significant when the internal jugular vein rather than the subclavian vein is cannulated. CONCLUSION: Our experience demonstrate that, both in no difficult cases and in no teaching procedures, central venous catheterization using landmark technique seems to be acceptable on both clinical and medico-legal grounds. However the ultrasound guided technique is necessarily required to achieve the reduction of complications in difficult venous access. PMID- 21294386 TI - Clinicopathologic factors predicting involvement of nonsentinel axillary lymphnodes in breast cancer patients: is axillary dissection always indicated? AB - AIM: The aim of this study was to determine factors that predict non-sentinel axillary lymph nodes (NSLNs) metastases in breast cancer patients with positive sentinel node biopsy (SLNB). MATERIAL OF STUDY: We reviewed the records of a consecutive series of 176 breast cancer patients who underwent SLNB at our institution. From the database we analysed those cases with one or more positive sentinel lymph nodes (SLNs) in order to determine factors predicting NSLN metastases. RESULTS: From a series of 176 consecutive patients, we evaluated 41 cases (23.3%) with positive SLNB. Subsequent completion axillary lymph node dissection (CALND) revealed NSLN metastases in 15 cases (36.6%). The significant variables predictive of NSLN involvement were the presence of macrometastases with extranodal extension (p = 0.048), the presence of more than one positive SLN (p = 0.08) and a ratio between positive SLN and SLNs globally dissected higher than 0.5 (p = 0.05). DISCUSSION: CALND is the gold standard for patients with positive SLNB, but results, in almost 40-70% of cases, in no additional positive nodes and its therapeutic benefit remains controversial. Clinicopathologic factors predictive of NSLN metastases may be useful in identifying a subset of patients with lower risk of further axillary involvement. CONCLUSIONS: In patients with early breast carcinoma and a positive SLNB, the size of SLN metastases, the presence of extranodal extension, more than one positive SLN and a nodal ratio higher than 0.5 are the factors that significantly increase the frequency of additional axillary positive lymph nodes. PMID- 21294387 TI - Postoperative hematomas after thyroid surgery. Incidence and risk factors in our experience. AB - AIM: The aim of our study was to evaluate the incidence and timing of postoperative bleeding and to identify the potential aetiological factors of cervical hematomas complicating thyroid surgery. MATERIAL: Between September 2002 and December 2009, 2559 patients were operated on in Department of Surgery, University Hospital of Cagliari. 2257 total thyroidectomies, 191 total thyroidectomies associated to lymphadenectomy, 83 total thyroidectomies associated to parathyroidectomy, 24 thyroid lobectomies and 4 lobectomies associated to parathyroidectomy were performed. RESULTS: 35 Patients (1.36%) developed a postoperative hematoma, 32 of whom (1.25%) needed a surgical revision. Male sex seemed to have a greater risk: 13 men (2.79% of all males) vs. 19 women (0.90% of all female cases) had to undergo haemostasis revision (p = 0.00204). 16 of 32 patients (50%) who underwent surgical revision had hypertension; incidence of hematoma was 2.09% in patients with hypertension and 0.89% in patients without it (p = 0.02112). DISCUSSION: It is generally difficult to predict which patients are at risk for the development of a hematoma after thyroid surgery. The most intense postoperative monitoring is necessary during the first six hours but hematomas occurring after are not rare. CONCLUSIONS: Postoperative hematoma remains a rare but potentially life-threatening complication. Early recognition with immediate intervention is the key to the management of this complication. Because of the possibly long interval between the initial operation and the hematoma development, ambulatory and one-day thyroid surgery is not advisable. PMID- 21294388 TI - Meta-analysis of fibrin glue versus surgery for treatment of fistula-in-ano. AB - AIM: To evaluate the convenience in terms of recurrence and fecal incontinence rates of fibrin glue versus surgical treatment in the management of fistula-in ano. MATERIALS AND METHODS: Randomized controlled trials (RCTs) and non randomized studies (CCTs) comparing conventional surgical treatment versus fibrin glue treatment in patients with perianal fistulae were identified using a predefined search strategy. The post treatment anal incontinence rate and the fistula recurrence rates between the two operations were compared by using the methods provided by the Cochrane Handbook for Systematic Reviews of Interventions. The lack of homogeneity of results between the different studies did not allow to analyze other secondary outcomes. Patients with cryptoglandular and Crohn's anal fistula were enrolled in the analysis. The employed fibrin glue came from commercial kits: Beriplast (Aventis Behring, Sussex, United Kingdom) and Tisseal or Tissucol (Baxter, Inc, Mississauga, Ontario). Surgical conventional treatment consisted of fistulotomy, placement of a cutting or loose latex seton and advancement mucosal flap closure. All patients were followed up at 6 and 12 weeks, the longest follow up was 6 months. RESULTS: Two RCTs (106 patients) and 1 non randomized studies (232 patients) were identified. The recurrence rate is higher, although still not statistically significant, in those patients who underwent fibrin glue injection (44/81) versus conventional surgical treatment (108/230), (OR: 0.44; 95 %CI: 0.12-1.68; P = 0.23). Furthermore in the analysis of the subgroup of RCTs alone there were not significant differences with the previous results of RCTs with CCT analysis (OR: 0.33; 95 %CI: 0.03-3.66; P = 0.37). In the same way the analysis of the subgroup of RCTs with complex anal fistulae were not statistically significant and similar to the previous results regarding all type of fistulas (OR: 0.86; 95 %CI: 0.01-72.36; P = 0.95). The analysis of post-operative anal incontinence showed no difference between the group who underwent fibrin glue injection (9/230) and the conventional surgical treatment group (10/81), (OR: 1.00; 95 %CI: 0.43-2.34; P = 1.00). A very low heterogeneity in the analysis was detected (Chi-square = 0.04 - P = 0%). CONCLUSION: Our statistical analysis does not show any significant statistical difference between fibrin glue treatment versus conventional surgical treatment for all perianal fistulae in terms of recurrence (P = 0.23) and anal incontinence (P = 1.00). PMID- 21294389 TI - Simultaneous medullary carcinoma and differentiated thyroid cancer. Case report. AB - BACKGROUND: Medullary thyroid cancer (MTC) is an uncommon and aggressive tumour representing only 5-10% of all thyroid malignancies. MTC arises from parafollicular thyroid cells (C-cells) producing calcitonin hormone. Differentiated thyroid cancer (DTC) is the most frequent thyroid tumour (papillary or follicular), representing 80% of all thyroid cancer. DTC derives from follicular thyroid cells, that come from the central thyroid sketch. The association between medullary and papillary thyroid cancer is rare. Several cases have been reported of mixed carcinomas. CASE REPORT: We report two cases of associated medullary and papillary carcinomas in two different foci in patients with respectively Graves' disease and multinodular goiter. A young woman affected by Grave's disease and multinodular goiter under pharmacological treatment with antithyroidal drugs underwent total thyroidectomy. The histopathological examination revealed the presence of a medullary carcinoma of the middle third of right lobe (1.1 cm) with an adjacent papillary microcarcinoma (0.5 cm). A 72 years-old woman, affected by euthyroid multinodular goiter, underwent total thyroidectomy. The pathological findings were two microcarcinomas, medullary (0.44 cm) in the left lobe and papillary (0.22 cm) in the right lobe. CONCLUSION: We can speculate that this coexistence is inferred, not having shown a specific cause that justifies the association between the two types of tumour and the high prevalence of papillary carcinoma. PMID- 21294390 TI - Pitfalls in adrenal surgery. Report of two cases. AB - Pitfalls in diagnosis and treatment of adrenal diseases are frequent and not properly reported in literature. Among more than 51 adrenalectomies for incidentaloma performed during a l0 years period, we present 2 cases of diagnostic errors that a very formative opportunity in the approach to adrenal diseases. A precise and careful preoperative diagnosis is of utmost importance in the management of adrenal disease to avoid therapeutic pitfalls. PMID- 21294391 TI - The supero-medial dermal-glandular pedicle mastoplasty with Wise pattern: an easy technique with a shorten learning curve. is it the gold standard for severe gigantomastia? AB - The Authors present their experience using the supero-medial dermal-glandular pedicle technique with a "Wise pattern" for severe gigantomastia, which they found easy to perform and to explain when teaching and they recommend its use especially for junior who are at the beginning of their experience with breast reduction. Although the preferred technique in our practice is the vertical scar mammaplasty with the superomedial pedicle according to Hall-Findlay, we believe the extension of the "Wise pattern" is necessary for severe gigantomastia (> 1200 g). From January 2005 to April 2008 50 breast reductions were carried out by the Authors using the supero-medial pedicle technique with a Wise pattern skin resection. The mean age was 40 years (range 20 to 65), mean body mass index was 28 (range 25 to 32) and mean weight of breast tissue removed was 1450 g per side (range 1120 to 2200). A maximum follow-up of 3 years was carried out. The complications were minor and self-limiting. The revision rate was very low (2%) compared to the other techniques. The supero-medial pedicle technique is a safe and reliable procedure in patients with severe gigantomastia and its versatility allows to be performed on all types of breasts regardless of size or degree of ptosis. PMID- 21294392 TI - The preterm child in dentistry. Behavioural aspects and oral health. AB - BACKGROUND: Advancements in medical care have enabled more children born preterm to survive and develop as healthy individuals alongside their full-term peers. However, a higher frequency of medical health problems, cognitive and behavioural disturbances, including problems in school, has been reported. There is limited knowledge about how this affects preterm children (PT) in dentistry, and few studies have evaluated behavioural problems related to dental treatments and oral health in PT as compared with full-term control children (C). AIMS: The overall objective was to investigate behavioural problems related to dental treatments and the oral health in PT born between 23 and 32 weeks of gestation as compared with full-term C. Specific aims were to analyze behaviour management problems (BMP), dental fear and anxiety (DFA), prevalence of Molar-Incisor Hypomineralization (MIH), oral hygiene, gingival health, and dental caries in PT and full-term C. MATERIALS AND METHODS: The study group comprised all children born between 23 and 32 weeks of gestation in the catchment area of the University hospitals of Lund and Malmo in southern Sweden. The subjects in Papers I-III were PT and matched full-term C, followed from preschool years to adolescence. In Paper IV, a new group of children, living in the city of Malmo was identified, the subjects being 10-to-12-year old PT and matched full-term C. Information about dental treatment, oral health and oral health related factors were obtained from dental records, interviews, questionnaires and clinical examinations. RESULTS OF THE FOUR PAPERS: Paper I: BMP and dental caries was studied in 187 PT and 187 C, based on notes in dental records at 3 and 6 years of age, and during the preschool period (3-6 years). At age 3, but not at age 6, the prevalence of BMPat dental examinations were more common in PT than in C. At various kinds of dental treatments during the preschool period, PT presented more frequently with BMP. No differences were found regarding dental caries. Paper II: Parents of 153 PT and 153 C were interviewed on two occasions, two years apar (preschool period and early school years) regarding experience of their child's dental care, oral health behaviour and medical health. BMPwere reported more common in PT than in C during preschool period but not during the early school years. PT also reported more medical health problems than C. Paper III: AT 12-14 years of age, 109 PT and 108 C toop art in a questionnaire study, including, the Children's Fear Survey Schedule--Dental Subscale (CFSS-DS) to measure the level of DFA, oral health behaviour and medical health. Few PT and C reported DFA. PT reported more daily use of dental floss and use of extra fluorid supplements than C. Further, PT reported more medical health problems than C. Paper IV: Eighty-two PT and 82 full term C, aged 10 to 12 years, were clinicaly examined regarding the prevalence and severity of MIH as well as their levels of oral hygiene and gingival health. In addition, BMP and dental caries were recorded. MIH was more common in PT than in C. Low gestational age and low birth weight increased the risk of MIH. PT had more plaque and gingival inflammation and presented more BMP than C. No difference in caries prevalence was found. CONCLUSIONS AND IMPLICATIONS: In 3-to 10-year old PT and matched full-term C, and based on dental records and parental reports, it was concluded that BMP were more common in PT than in C during the preschool period. The difference decreased with increasing age and during the early school years there were no differences between the groups. However, at clinical examination at the age of 10-12 years, PT presented with BMP more frequently than C. During adolescence, based on the youngsters' own viewpoints, few PT and C reported DFA. The clinical examination at 10-12 years of age showed that PT had a higher prevaleance of Molar-Incisor Hypomineralization (MIH) than C, and low gestational age and low birth weight increased the risk of MIH. At this age, PT also had less favorable oral hygiene and gingival status than C. Problems with toothbrushing were more commonly reported in PT than in C during the preschool period. During adolescence, PT reported more daily use of dental floss and extra fluoride supplements than C. Regarding caries prevalence, there were no differences between the group in either the primary or in the permanent dentition. In contrast, PT had more medical health problems, persisting from preschool period in adolescence than C. The results in this thesis indicate more behavioural problems related to dental treatment and more oral health problems in PT than in C. Therefore, PT require special attention from the dental services, with treatment planning and prevention strategies from an early age. Collaboration between medical and dental health care professionals is advocated in order to ensure good oral health in PT. PMID- 21294393 TI - The healing effects of a topical phytogenic ointment on insect bite hypersensitivity lesions in horses. AB - Insect bite hypersensitivity (IBH) is the most common cause of pruritus in horses and is a serious welfare issue for affected animals. In this study, the effect of a topical phytogenic ointment on the healing of cutaneous lesions was investigated in a double-blind trial involving 26 horses with I B H. The number of lesions and their total surface area were recorded on days 0, 7, and 21 in horses treated for 3 weeks with either verum or placebo ointment. After unblinding of treatment assignment, the horses that had been treated with the placebo ointment received the verum preparation for an additional 3 weeks and the number of lesions and their total surface area were again recorded. This part of the study was not blinded. The number of lesions and the total surface area decreased in both treatment groups (no significant difference). Owners also scored the degree of discomfort suffered by their horses as a result of IBH lesions, and at the end of the 3-week period this score was significantly lower in the verum than in the placebo group (P = 0.04). When placebo-treated horses subsequently received the verum ointment, their wound severity score also decreased significantly (P < 0.01). Daily application of an ointment (verum or placebo) does not cure IBH, but use of the phytogenic ointment led to a decrease in the owner-assessed discomfort suffered by horses. PMID- 21294394 TI - Contact allergy in eczema patients in Thammasat University Hospital. AB - Many patients with eczematous dermatitis need continued care in case of a recurrent or persistent skin condition and potential adverse effect of medications. Allergic contact dermatitis should be considered in the differential diagnosis of eczematous dermatitis especially in a patient whose dermatitis is persistent despite appropriate therapies. Patch testing is an essential investigation in patients with persistent eczematous eruption when contact allergy cannot be ruled out. The purpose of this study was to determine the frequency of contact allergy in patients with eczematous dermatitis in Thammasat University Hospital, Prathumthani, Thailand from June 1, 2008 to June 30, 2009 and to identify a possible relationship between sex, age, occupational differences and type of eczema that is associated with positive patch test reactions. A total of 157 patients were patch tested with 23 standard allergens. One or more positive responses were noted in 70 patients (44.6%). The most common allergen was nickel sulfate (26.8%), followed by cobalt chloride (7.6%), p phenylenediamine (7.0%), fragrance mix (7.0%). Patients who were initially diagnosed with allergic contact dermatitis had significant correlation with positive patch test results to nickel sulfate, cobalt chloride and phenylenediamine (p = 0.00, p = 0.03, p = 0.02, respectively). Patients who were initially diagnosed with endogenous eczema had significant correlation with positive patch test results to colophony (p = 0.04). Contact allergy to fragrance mix was significantly more frequent in patients who had personal history of atopy (p = 0.04). There was no significant correlation between the frequency of contact allergy and sex, age, location of lesion and patient's occupation. In conclusion, this study demonstrated the prevalence in contact allergy in eczema patients in Thammasat University Hospital and compared the results with other region from Thailand. Further study involving many hospitals in various areas in Thailand is needed to provide more insight into contact allergy in Thailand. PMID- 21294395 TI - The change of umbilical cord components in intrauterine growth restriction comparative with normal growth fetuses by using sonographic measurement. AB - OBJECTIVE: To determine the diameter changes of umbilical cord components in intrauterine growth restriction (IUGR) fetuses comparative with normal growth fetuses by using the ultrasonogram. MATERIAL AND METHOD: A cross sectional study was performed with 140 singleton pregnant women who was attended at Maternal Fetal Medicine unit, Thammasat University Hospital between June, 2007 to May, 2009. The fetuses were between the gestational ages of 24 to 37 weeks at the time of data collection. Seventy pregnant women with IUGR fetuses and 70 pregnant women with normal growth (Appropriate for Gestational Age, AGA) fetuses were included. The sonogram of the umbilical cord, umbilical artery and umbilical vein diameter and circumference were obtained at the free loop of cord. Fetal weights were estimated by calculation in all cases. IUGR was defined as a fetus having an estimated fetal weight below the 10th percentile for the gestational age at time of the sonographic measurements. RESULTS: The mean age of the patients were 27.03 and 31.86 years in IUGR group and AGA group, respectively. The mean birth weight of the fetuses was 2153.60 +/- 386.13 gm and 3118.16 +/- 353.28 gm in IUGR fetuses and AGA fetuses, respectively. The result demonstrated the expected progressive increase of the umbilical cord circumference and diameter as a function of gestational age in AGA fetuses. These changes were not observed in the umbilical cord of IUGR fetuses. It was a contradictory finding that the measurement values from umbilical artery and umbilical vein IUGR fetuses were neither consistent nor correlated with fetal age. CONCLUSION: The ultrasonogram of the umbilical cord component demonstrated the increasing of umbilical cord circumference and diameter along with an increasing of gestational age in the AGA fetuses. These findings might be useful for further studies, such as early screening or prediction of adverse pregnancy outcome for high risk women. PMID- 21294396 TI - Evaluation of related factors and the outcome in cardiac arrest resuscitation at Thammasat Emergency Department. AB - OBJECTIVE: In the present study, we aimed to define the factors contributing to patient survival after treatment by cardiopulmonary resuscitation (CPR) following cardiac arrest. MATERIAL AND METHOD: Retrospective analysis was performed on cardiac arrest patients (n=138) who had CPR in the emergency department (ED) at Thammasat University hospital from 2007-2009. Logistic regression was used to analyze factors that related to the sustained return of spontaneous circulation (ROSC) for 20 minutes, survival until discharge, and survival up to 1 month post discharge. RESULTS: The sustained ROSC was 22.5%, survival to discharge 5.6%, and survival from discharge to 1 month 3.6%. Significant factors related to sustained ROSC was the location of cardiac arrest, the cause of arrest, shockable rhythm with defibrillation, the time until chest compression, and CPR duration. The factor influencing survival to discharge was chest compression performed within 15 minutes after cardiac arrest (p = 0.048). No factor however could be attributed to survivability up to 1 month following discharge. CONCLUSION: Our findings attribute six factors associated to ROSC including the location of arrest, the cause of cardiac arrest, initial cardiac rhythm, shockable rhythm with defibrillation, the time until chest compression and CPR duration. Statistically, resuscitation performed within 15 minutes of cardiac arrest increases the survivability of patients until discharge. However no factors could be related to the percentage of patients surviving up to 1 month post discharge. PMID- 21294397 TI - Acute poison exposure in the emergency department: a 2-year study in a university hospital. AB - BACKGROUND: Pattern of acute poison exposure varies in the different areas. The information will be useful for prevention. OBJECTIVE: To evaluate pattern, severity and clinical outcome of acute poison exposure in the Emergency Department of a University Hospital in Thailand. MATERIAL AND METHOD: Medical records of all acute poison exposure cases, presented the Emergency Department of Thammasat University Hospital between October 1, 2006 and September 30, 2008 were reviewed retrospectively. Demographic characteristics, exposure time, agents, route and cause of exposure, clinical course and outcome were analyzed. RESULTS: Of the total 76,805 Emergency Department visits, 1112 cases were related to acute poison exposures, which were accounted for 1.4%. Sixty-five percents were female. Patients whom their ages ranging from 21 to 40 years old showed the highest rate of acute poison exposures. Intentional and unintentional exposures accounted for 52.7% and 44.9%, respectively. Intentional exposure was the major cause of exposure in the age group of 11-40 years, while unintentional exposure was the major cause of exposure in children. Pharmaceutical products (38.1%) were the most common category of substances involved in acute poison exposure followed by bites and stings (31.7%) and household products (17.6%). The substances most frequently involved were acetaminophen (17.7%) and toilet cleaning agents (12.3%). Fifty-six (5%) cases developed severe clinical course and three (0.27%) patients died. Pesticide and toilet cleaning agents were responsible for all these fatalities. CONCLUSION: Acetaminophen and toilet cleaning agents were commonly involved in acute poison exposure. Pesticide and toilet cleaning agents caused severe morbidity and mortality. Unintentional exposure was the major cause of exposure in children. Public education regarding the danger of these agents and prevention of the poison exposure in children should be emphasized. PMID- 21294398 TI - Toxicity evaluation of sappan wood extract in rats. AB - BACKGROUND: The heartwood of Caesalpinia sappan L. or sappan wood has long been used in folk medicines to treat tuberculosis, diarrhea, dysentery, skin infections and anemia. OBJECTIVE: To study the acute and subacute toxicities of sappan wood extract in rats. MATERIAL AND METHOD: For studying acute toxicity, a single oral dose of 5000 mg/kg of sappan wood was administered to rats. Subacute toxicity was studied by the daily oral administration of the extract at the doses of 250, 500 and 1000 mg/kg body weight for consecutive 30 days. RESULTS: The extract of sappan wood (5000 mg/kg) showed no toxicity in terms of general behavior change, mortality, or change in gross appearance of internal organs. Subacute toxicity study showed no abnormalities in treatment groups as compared to the controls. Body and organ weights, hematological, blood chemical, necropsy, and histopathological parameter of all groups were similar. CONCLUSION: Sappan wood extract did not produce any acute or subacute toxicity in both female and male rats. PMID- 21294399 TI - Antibacterial and antifungal activities from Siamese crocodile blood. AB - OBJECTIVE: To evaluate the in vitro antimicrobial activity of the Siamese crocodile blood against bacteria and fungi. MATERIAL AND METHOD: Thirty Siamese crocodile blood samples including freeze dried whole blood (FDWB), fresh serum (FS), and freeze dried serum (FDS) were evaluated for antimicrobial susceptibility and MIC values against ATCC-registered strains of nine bacterial species and two fungal species and one fungus isolated from a clinical specimen, by using the standard broth microdilution method and a modified resazurin microtiter plate assay. RESULTS: The result showed that FS (80 mg/ml) and FDS (100 mg/ml) inhibited Gram negative bacteria including Enterobacter aerogenes ATCC 13048, Escherichia coli ATCC 25922, Klebsiella pneumoniae ATCC 27736, Salmonella typhimurium ATCC 13311 and Pseudomonas aeruginosa ATCC 27853 with the susceptibility rate at 23.30%, 10.00%, 40.00%, 70.00%, and 86.67%, respectively for FS, and 30.00%, 10.00%, 43.33%, 76.67% and 90.00%, respectively for FDS. The MIC and MBC were in the range of 12.50-100.00 mg/ml and 25.00-100.00 mg/m1 respectively. FS and FDS also inhibited Cryptococcus neoformans 250309 and Aspergillus niger with the susceptibility rate at 90.00% and 80.00%, respectively for FS and 100.00% and 83.33%, respectively for FDS. The MIC was in the range of 25.00-100.00 mg/ml. However, FS and FDS did not inhibit Gram positive bacteria and did not kill fungi. FDWB (100 mg/ml) could neither inhibit bacteria nor fungi. CONCLUSION: FS and FDS from Siamese crocodile exhibited potential antibacterial and antifungal activities. PMID- 21294400 TI - The combination of body mass index and age as a new index for identifying osteoporosis in Thai postmenopausal women. AB - OBJECTIVE: The purpose of this study was to evaluate the application of the combination of bone mass index (BMI) and age as a new screening tool to identify osteoporosis in Thai postmenopausal women. DESIGN: Diagnostic study. MATERIAL AND METHOD: Bone mineral density (BMD) data of Thai postmenopausal women, age 40-80 years old who attended the outpatient clinic, Thammasat University Hospital, Thailand, between January 2004 and December 2008 were enrolled. The participants with history of metabolic bone disease or use of drugs associated with secondary osteoporosis and/or history of treatment for osteoporosis were excluded. Each had BMD records of lumbar spine, femoral neck and intertrochanter. The data were completely collected in all 372 women. A diagnosis of osteoporosis made according to WHO criteria. RESULTS: The prevalence of osteoporosis at lumbar spine, femoral neck and intertrochanter were 8.1%, 20.2% and 15.3% respectively. The combination of BMI and age as the index to detect osteoporosis had a sensitivity at 76.67%, 76% and 77.19%, respectively. The OSTA index at the standard cut-point of -1 had a sensitivity at 80%, 70.67% and 70.17%, respectively. Raising the cut-point to < or =0 would had a sensitivity at 90%, 85.33% and 78.95%, respectively. CONCLUSION: The application of the combination of BMI and age as a screening tool is another option to identify osteoporosis in Thai postmenopausal women. Change the cut-point of < or =0, OSTA index could improve the detection of osteoporosis at a very high level of the sensitivity. PMID- 21294401 TI - Determination of phenolic compounds, flavonoids, and antioxidant activities in water extracts of Thai red and white rice cultivars. AB - BACKGROUND: Free radical-induced oxidative stress damages cellular components leading to many human diseases. Plant-derived antioxidant compounds have become a profitable alternative to prevent oxidative stress in cells. OBJECTIVE: To determine and compare total phenolic and flavonoid contents as well as antioxidant activity using both chemical and cell assays in the water extracts of brown rice and rice bran from two Thai rice cultivars: Sangyod, a red pigmented rice typically grown in Southern Thailand and Dawk Mali 105, a commercial white colored rice. MATERIAL AND METHOD: All the rice water extracts were analyzed for their total phenolic and flavonoid contents using the colorimetric assays, as well as for their antioxidant activity through two chemical assays: DPPH radical scavenging and inhibition of lipid peroxidation assays, as well as through cell based assays: scavenging capacity of intracellular ROS in HL60 cells using the fluorescent DCF and the NBT reduction. RESULTS: The two chemical assays detected free radical scavenging and free radical chain breaking activities in all the rice extracts with EC50 values ranging from 26 to 357 microg/ml. Moreover, the cell-based assays detected ROS scavenging activities of these extracts with EC50 values in the range of 0.6-5 mg/ml. All these assays indicated that the water extracts of Sangyod exerted significantly higher antioxidant activity than those of Dawk Mali 105, which exhibited only moderate to low activity. Furthermore, high levels of antioxidant activity of the water extracts of Sangyod were closely correlated to their flavonoid and phenolic contents, which were approximately 2.5 and 3 times higher, respectively, than those of Dawk Mali 105. CONCLUSION: These findings suggest that water extracts from colored brown rice or colored rice bran can be promising sources of potential natural antioxidants. PMID- 21294402 TI - Formaldehyde exposure of medical students and instructors and clinical symptoms during gross anatomy laboratory in Thammasat University. AB - To study formaldehyde concentrations in the breathing zone and symptoms induced by gaseous formaldehyde exposure of medical students and instructors during gross anatomy laboratory at faculty of Medicine, Thammasat university. Formaldehyde concentrations in the indoor air and breathing zone of medical students were measured during the cadaver dissection. Formaldehyde concentrations in the indoor air and in the breathing zone were ranged from 0.401 to 0.581 ppm (mean 0.491 +/- 0.090) and from 0.472 to 0.848 ppm (mean 0.660 +/- 0.188) respectively. The mean of formaldehyde concentrations in the breathing zone of medical students and instructors was significantly higher than the mean of formaldehyde concentration in indoor air (p < 0.05). The most symptoms were general fatigue (82.7-87.8%), burning eyes (66.2-85.0%) and burning nose (62.5-81.1%). There was no statistically significant difference in burning eye symptom between contact lenses users and no contact lenses users (p > 0.05). Even though formaldehyde concentrations were relatively low, medical students, instructors and cadaver related workers should wear personal protective devices to reduce the effect of gaseous formaldehyde exposure during gross anatomy laboratory or contact cadaver. PMID- 21294403 TI - Hypertension in Thai children: a report from a hospital in suburban area. AB - Hypertension in children is the major risk for cardiovascular disease in adult. Limited data are available for hypertension in children in Southeast Asia. To determine the cause, treatment, and long-term outcome of hypertension in Thai Children, the authors retrospectively studied 62 patients (age <15 years) diagnosed with hypertension at Thammasat University hospital, from December 01, 2004 through November 30, 2009. The mean age was 9.2 +/- 4.2 years; median follow up 8 months. Fifty five (88.7%) patients had secondary hypertension. Patients presented with stage 2 hypertension (67.7%), and hypertensive emergency (9.7%). Renal parenchymal disease caused 67.3% of secondary hypertension. End organ damage included left ventricular hypertrophy (11.3%) and hypertensive retinopathy (6.4%). Hypertensive emergency was caused mostly by acute poststreptococcal glmoerulnephritis (APSGN, 66.7%). Intravenous diuretic coupled with oral antihypertensive drugs gave uncontrolled blood pressure in APSGN with hypertensive emergency. Seventy percents of patients with essential hypertension had obesity. Majority of the patients had controlled hypertension without medication. Acute poststreptococcal glomerulonephritis remained the common cause of transient hypertension and hypertensive emergency in Thai children. The high incidence of obesity among essential hypertension in children demonstrated in the present study should alert Thai pediatrician to measure blood pressure in every obese child. Treatment of childhood hypertension was associated with good long term outcome. PMID- 21294404 TI - Lipid lowering efficacy between morning and evening simvastatin treatment: a randomized double-blind study. AB - OBJECTIVES: To compare lipid-lowering efficacy and high sensitive C-reactive protein (hsCRP) level between morning and evening simvastatin administration in hyperlipidemia subjects. MATERIAL AND METHOD: A randomized double blind controlled trial was conducted in 52 dyslipidemia subjects. A group of twenty five subjects received 10 mg simvastatin in the morning and placebo in the evening. The other group of twenty seven subjects received vice versa. Serum lipid profiles were evaluated every 4 weeks for the total course of 12 weeks. High sensitive CRP was measured at the beginning and the end of the study. RESULTS: Baseline LDL levels were similar in both groups (p = 0.95). The evening simvastatin group had significantly less low density lipoprotein level (LDL) than the morning group at 4 weeks (112 +/- 26.1 mg/dl vs. 136.3 +/- 32 mg/dl, p = 0.001) and 8 weeks after treatment (109.7 +/- 28 mg/dl vs. 129.5 +/- 27 mg/dl, p = 0.006). Difference in LDL after 12th week between two groups was not significant (p = 0.23). Triglyceride and HDL level were not different in both groups. Only evening simvastatin administration could significantly decrease hsCRP (p = 0.03). CONCLUSION: Simvastatin should be taken in the evening. Although lipid profiles were not statistically different in morning and nighttime simvastatin, the inflammatory marker (hsCRP level) is significantly reduced as a result of evening simvastatin administration. PMID- 21294405 TI - Do health care providers have a lower prevalence of abnormal pap smears than the general public? AB - BACKGROUND: Most Thai people believe that health care providers have a lower risk of any disease than their patients. This belief may lull Thai health care providers into accepting the false belief that they are at a lower risk of having the precancerous conditions that lead to cervical cancer. OBJECTIVE: This study compares the prevalence of abnormal Pap smears from health care providers (HC) and non health care providers (NHC) by using the standard liquid-based Pap smear processing at Thammasat University Hospital's pathology department, Thailand. MATERIAL AND METHOD: Both health care providers (HC) and non health care providers (NHC) were patients at the outpatient clinic, Thammasat University Hospital. They were screened for cervical cancer by using liquid-based Pap smear (LBP). Cytological diagnoses and specimen adequacy were classified using the Bethesda system 2001. All subjects who had abnormal cytology more than atypical squamous cells or atypical glandular cells were counseled to have performed a colposcopic directed biopsy for confirmation of pathology. STUDY DESIGN: A total of 250 liquid-base Pap smears were processed and evaluated at the Gynecology clinic, Thammasat University Hospital from April 2008 to May 2008. RESULTS: The groups of HC and NHC consisted of 122 and 128 women, respectively. In general, both the HC and NHC groups were similar in their age, religion, income and education level distributions. The range of ages was between 16 and 75 years, with the mean age equal to 40.2 +/- 10.5 years. Prevalence of abnormal Pap smears was 9.8% in HC and 9.4% in NHC (p-value = 0.90). HC showed atypical change (ASC, AGC), low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL) at 0.8%, 1.6% and 7.4%, respectively. NHC had an incidence of atypical change, LSIL and HSIL at 0.8%, 0.8% and 7.8%. HC had an equal incidence of abnormal Pap smears prevalence to NHC. Further, the percentage of HC and NHC groups with histological confirmed cervical intraepithelial neoplasia (CIN) 1 were not significantly different (4.92% vs. 6.25%, p-value = 0.70), likewise CIN 2/3 (1.64% vs. 1.56%, p-value = 1.00). According to our study the rate of abnormal Pap smears observed in both health care providers and clients was essentially the same. CONCLUSIONS: The prevalence of abnormal Pap smears in health care providers was statistically equivalent to that in their clients. PMID- 21294406 TI - In vitro and in vivo antiplasmodial activity and cytotoxicity of water extracts of Phyllanthus emblica, Terminalia chebula, and Terminalia bellerica. AB - OBJECTIVE: To evaluate the in vitro and in vivo antiplasmodial activity and the cytotoxicity of Phyllanthus emblica Linn, Terminalia chebula Retz, and Terminalia bellerica (Gaertn) Roxb extracts. MATERIAL AND METHOD: Standard phytochemical screening tests were used to detect metabolites in the plant extract. The water extracts of medicinal plants were tested for their antiplasmodial activity in vitro by assessing their ability to inhibit the uptake of [3H] hypoxanthine into the Plasmodium falciparum K1 multidrug-resistant strain. Cytotoxicity of all extracts was determined on Vero cell line. The in vivo antiplasmodial activity in Plasmodium berghei infected mice was evaluated by the standard 4-day suppressive test. RESULTS: Phytochemical screening of the water extracts of three plants revealed the presence of flavonoids, hydrolysable tannins, saponin and terpenes. All plant extracts showed antimalarial activity (IC50 values ranging from 14.33 +/- 0.25-15.41 +/- 0.61 microg/ml). The water extract of Terminalia bellerica (Gaertn) Roxb had the highest in vitro antiplasmodial activity followed by Phyllanthus emblica Linn. and Terminalia chebula Retz. The cytotoxic activity was exhibited by all plant extracts on Vero cells with IC50 values of 157.86 to 238.70 mg/ml. All of the plant extracts showed selectivity with the selectivity index (SI) ranged from 11 to 17. A standard 4-day suppressive test on P. berghei infected mice was used to evaluate the in vivo antiplasmodial activity of the extracts at 250 mg/kg/day. The results revealed that in vivo antiplasmodial activity with good suppression activity ranged from 53.40% to 69.46%. CONCLUSION: All of the plant extracts exhibited interesting in vitro and in vivo antiplasmodial activity with good selectivity. PMID- 21294407 TI - Second trimester uterine artery Doppler screening in prediction of adverse pregnancy outcome in high risk women. AB - OBJECTIVE: To assess the value of uterine artery colour Doppler waveform analysis in the prediction of adverse pregnancy outcome such as preeclampsia, fetal growth restriction in high risk pregnancy women. MATERIAL AND METHOD: Uterine artery Doppler screening was performed as part of mid trimester screening between 20 and 24 weeks gestation in high risk pregnancy women at Matermal Fetal Medicine unit, Thammasat University Hospital between June 1, 2008 and May 31, 2009. A pulsatility index (PI) was calculated from each uterine artery and the presence or absence of a notch was determined. A PI of > 1.58 or the presence of any diastolic notch were defined as abnormal. The main outcome measures were pre eclampsia and small for gestational aged baby (birth weight < 10th centile). RESULTS: Doppler examination of the uterine arteries were performed in 330 singleton pregnancies. Twenty-seven (8.18%) women developed pre-eclampsia, 16 (4.84%) women had SGA babies. The sensitivity ofPI > 1.58 and diastolic notch for preeclampsia, SGA were 59.25% and 56.25%, respectively.The specificity of PI >1.58 and diastolic notch for these outcomes were 66.67% and 65.60% respectively. CONCLUSION: In high-risk women, mid trimester uterine artery Doppler waveform analysis can not use as screening method in women at higher risk for the development of severe adverse outcome such as pre-eclampsia and SGA babies. However women with normal uterine artery Doppler results are unlikely to develop pre-eclampsia, fetal growth restriction (FGR) and therefore do not necessarily need repeated Doppler ultrasound follow-up. PMID- 21294408 TI - Health risk assessment of workers exposed to metals from an aluminium production plant. AB - OBJECTIVE: Foundry is an industry involved various kinds of metals and chemicals. Workers who work in foundry industry are at risk of exposure to these metals and chemicals. Objective of this study was to conduct quantitative health risk assessment for workers who exposed to metals from an aluminium production industry. MATERIAL AND METHOD: The U.S. National Academy of Sciences' four steps of health risk assessment were used to conduct quantitative health risk assessment in this study. RESULTS: This study showed that there were 6 types of metals involved in the aluminium foundry in this study. These metals could cause various health effects but not cancers. Workers were mostly exposed to these metals by inhalation. Calculated reference dose (RfD) for inhalation of aluminium used in this assessment was 0.000015 mg/kg/day. Calculated RID for inhalation of manganese used in this assessment was 0.000002 mg/kg/day. Calculated RfD for inhalation of copper used in this assessment was 0.000028 mg/kg/day. Calculated RID for inhalation of zinc used in this assessment was 0.000083 mg/ kg/day. Calculated RID for inhalation of magnesium used in this assessment was 0.949833 mg/kg/day. Calculated RID for inhalation of iron used in this assessment was 10.6219 mg/kg/day. Maximum daily doses (MDDs) for workers who exposed to metals measured in this foundry were 0, 0, 0.000463, 0.0000927, 0.000162 and 0 mg/kg/day for manganese, zinc, aluminium, iron, magnesium and copper, respectively. Finally, risk characterization for workers exposed to metals in this aluminium foundry showed that workers in this foundry had 31 times higher risk of developing diseases from aluminium than persons who were not exposed to aluminium. These workers had the same risk of developing diseases from other metals and chemicals as persons who were not exposed to those metals and chemicals. CONCLUSION: Workers who exposed to aluminium in this aluminium production plant had 31 times risk of developing non-carcinogenic effects from aluminium compared with normal persons. Therefore, appropriate preventive measures should be applied to protect workers. PMID- 21294409 TI - Prevalence and risk factors of low back pain among the university staff. AB - BACKGROUND: Low back pain (LBP) is one of the most common musculoskeletal disorders in the population especially in working population. Many intrinsic and extrinsic factors have been evaluated for associated factor for LBP Epidemiological researches have been provided information on the prevalence and risk factors of LBP in the workers. Little information has related individual and work-related factors to the prevalence of LBP among the university staff in Thailand. AIM: The author aims to investigate the prevalence of LBP and explore risk factors of LBP among university staff in the government sector. MATERIAL AND METHOD: The self-administered questionnaires were distributed to 1183 university staff on the list by official messenger. Data were collected over three months between October and December 2008. The questionnaire included low back pain information, demographic data, work-related characteristics, and habitual physical activity level. Data were analyzed using Chi-square and multivariate logistic regression techniques. The 6-month prevalence and associated risk factors were presented. RESULTS: Eight hundred and three staff returned the questionnaires (response rate of 67.9%). The past 6-month prevalence of self reported LBP was 22.3% (95% CI: 19.4-25.2). The result of multivariate analysis showed that habitual physical activity level were found to be independent factors associated with the LBP (p-value = 0.048 by LRT) after adjusted for gender nutritional level and work activity in a day. The physical activity as athletic level appeared to be the protective effect when compared to sedentary level (adjusted OR 0.43, 95% CI: 0.20-0.94). CONCLUSION: Based on the results of the study, the physical activity as athletic level appears to be associated with the 6-month prevalence of LBP Consequently, it is important that prevention programs take into account this risk factor in order to reduce the frequency of low back injuries in university staff and improve their work efficiency. PMID- 21294410 TI - General anesthesia with thoracic paravertebral block for modified radical mastectomy. AB - OBJECTIVE: To evaluate the effect of single-injection paravertebral block (PVB) combined with general anesthesia on 24-hour postoperative morphine requirement in patients undergoing modified radical mastectomy (MRM). MATERIAL AND METHOD: 20 patients were randomly assigned into 2 groups. Patients in the control group were given only general anesthesia. Patients in the PVB group received 0.3 ml/kg of 0.5% plain bupivacaine at T4 paravertebral space followed by general anesthesia. Both groups received intravenous morphine patient-controlled analgesia (PCA) device postoperatively. All patients were evaluated at 1 and 24 hours for pain, nausea and vomiting. Twenty-four hour morphine consumption, antiemetics requirement, and overall satisfaction were recorded. RESULTS: Patients with PVB had lower incidence and severity of postoperative pain, nausea and vomiting and other serious complications. No patients were unsatisfied with anesthetic techniques. CONCLUSION: PVB can reduce postoperative opioid requirement, pain, and severity of nausea and vomiting in MRM. PMID- 21294411 TI - A modified technique to simplify TLH with new developed uterine manipulator; Anurach uterine manipulator (AUM). AB - OBJECTIVE: Total Laparoscopic hysterectomy (TLH) has became more commonly procedures for gynaecological surgery, but high incidence of complications and the technical challenges are still problematic among less-experienced surgeons. To accomplish these difficulties, we developed the new uterine manipulator; Anurach uterine manipulator (AUM) to simplify TLH with the modified technique. Our objective was to evaluate the feasibility of the new uterine manipulator; AUM, with the modified total laparoscopic hysterectomy in an initial cohort of patients. MATERIAL AND METHOD: From October 2007 though September 2008, one hundred cases of hysterectomy were done by modified technique of TLH using A UM. After installation of AUM, a modified technique of TLH was started by posterior colpotomy, then extended to anterior colpotomy. The operation was performed using bipolar and harmonic scapel for coagulation and cutting the vascular pedicles and ligaments. The entire procedure was done laparoscopically and the uterus was removed vaginally. The vaginal cuff was closed by continuous suture, double layers with PDS material. RESULTS: Most common indication was symptomatic leiomyoma, the uterine size was 64-620 grams. Mean operation time was 98 +/- 27.1 minutes. Estimated blood loss was 188 +/- 87.5 ml. There were no bowel or ureteric injuries, except 2 cases of bladder injury which had been repaired laparoscopically. CONCLUSION: The modified technique using AUM could be the option to simplify TLH, in reducing the complications and having more favorable operative outcomes. PMID- 21294412 TI - Role of preoperative vascular ultrasonography in hemodialysis vascular access operation. AB - OBJECTIVE: Preoperative vascular mapping increase rate of successful hemodialysis vascular access operation. Several studies recommend using this procedure routinely. But some studies recommend using this procedure in selected patients. So this study aims to determine the impacts of preoperative vascular mapping in unfavorable-examined patients. MATERIAL AND METHOD: 55 patients were studied retrospectively from August 2006 to October 2009. Before April 2008, the operative plans were based on physical examination (group 1). After April 2008, the surgeon did preoperative vascular mapping prior to the operation in unfavorable-examined patients (group 2). The results were compared. RESULTS: There were high maturation rates in favorable-examined patients. In unfavorable examined patients, preoperative vascular mapping can identified nonpalpable favorable vein which successful maturation of 18.75%. Complementary duplex scan decrease rate of unsuccessful operation significantly (p = 0.037) but does not increase maturation rate. CONCLUSION: Careful physical examination is important part before operation. Preoperative vascular mapping has benefit only in patients with unfavorable-examined patients. It finds some nonpalpable favorable vein and decrease unsuccessful exploration. PMID- 21294413 TI - Isolation, characterization and neural differentiation potential of amnion derived mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) derived from amnion are considered to be adult stem cells that can be easily obtained in large quantities by a less invasive method in comparison to bone marrow-derived MSCs (BM-MSCs). However; the biological properties and the differentiation capacity of amnion-derived MSCs (AM-MSCs) are still poorly characterized. The objectives of this study were to isolate, characterize and explore the potential of AM-MSCs in differentiating toward neural lineage in comparison to those of BM-MSCs. To isolate AM-MSCs, amnion was digested with trypsin-EDTA and cultured in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% fetal bovine serum. The expression profiles of several MSC markers were examined by flow cytometry. AM-MSCs from passage 3-5 were used for adipogenic, osteogenic and neural differentiation assays by culturing in appropriate induction media. The expression of several neural marker genes, including MAP-2, GFAP and beta-tubulin III in AM-MSCs was determined by quantitative real time-PCR. The expression of neural-specific markers, MAP-2 and beta-tubulin III, was subsequently confirmed by immunocytochemistry using confocal laser microscope. The results demonstrated that AM-MSCs could be easily expanded to 18-20 passages while maintaining the undifferentiated state and exhibiting MSC markers (CD73, CD90, and CD105) but do not express the hematopoietic markers (CD34 and CD45). Similar to BM-MSCs, AM-MSCs were able to differentiate to several mesodermal-lineages including adipocytes and osteoblasts. Moreover; these cells could be induced to differentiate to neuron like cells as characterized by cell morphology and the expression of several neural markers including MAP-2, GFAP and beta-tubulin III. The present study demonstrated that AM-MSCs can be easily obtained and expanded in culture. These cells also have transdifferentiation capacity as evidenced by their neural differentiation potential. According to the results, amnion can be used as an alternative source of MSCs for stem cell therapy in neurodegenerative diseases. PMID- 21294414 TI - Cytotoxic saponin against lung cancer cells from Dioscorea birmanica Prain & Burkill. AB - OBJECTIVE: To investigate the cytotoxic activity against lung cancer cells of Dioscorea birmanica Prain & Burkill extract and its compounds. MATERIAL AND METHOD: Cytotoxic activity was tested against two types of lung cancer cell line (A549 and CORL-23), one type of normal lung cell (MRC-5) by sulforhodamine B assay. Bioassay guide fractionation was used for isolating cytotoxic compounds. The structure elucidation of active ingredients was proven by spectrophotometry technique. RESULTS: The results found that the ethanolic extract of Dioscorea birmanica Prain & Burkill (DBE) showed high cytotoxic activity against lung cancer cells; A 549 and COR-L23 (IC50 = 7.45 +/- 0.31, 8.71 +/- 0.29 microg/ml, respectively) but no cytotoxic activity against normal cancer cells MRC-5 (IC50 = 94.76 +/- 1.25 micro/ml). Six fractions from DBE were isolated by vaccuum liquid chromatography with ordering polarity of solvent and were coded as DB1-DB6, respectively. The fraction DB5 showed high cytotoxic against A 549 and COR-L23 (IC50 = 6.14 +/- 0.08 and 16.44 +/- 1.23 microg/ml, respectively) but less toxic to normal cell. Diosgenin-3-O-alpha-L-rhamnosyl (1-->2)-beta-D-glucopyranoside or Prosapogenin A of dioscin (DBS1) was isolated from DB5 fraction and had highest cytotoxic activity against those two types of lung cancer cells (IC50 = 1.81 +/- 0.03, 1.84 +/- 0.05 microg/ml), respectively) but less cytotoxic against normal lung cells MRC-5 (IC50 = 37.09 +/- 0.67 microg/ml). CONCLUSION: The steroid saponin from Dioscorea birmanica showed cytotoxic activity against human lung cancer cells but less toxic against normal lung cells. PMID- 21294415 TI - Determination of cytotoxic compounds of Thai traditional medicine called Benjakul using HPLC. AB - Benjakul is a Thai traditional medicine preparation, used for balanced health. From selective interviews of folk doctors in southern Thailand, it was used as the adaptogen drug for cancer patients. In our previous study, the ethanolic extract of Benjakul preparation exhibited high cytotoxic activity against lung cancer cell lines (COR-L23). Piperine has been identified as the main compound in the extract. In addition, plumbagin was found as the most cytotoxic compound. In this study, a reversed-phase high performance liquid chromatography (HPLC) method for quality control such as chemical fingerprint, quantification and stability of the ethanolic extract of Benjakul preparation was developed. The reversed-phase HPLC was performed with a gradient mobile phase composed of water and acetronitrile, and peaks were detected at 256 nm. Based on validation results, this analytical method is precise, accurate and stable for quantitative determination of piperine and plumbagin which are cytotoxic compounds isolated from the ethanolic extract of Benjakul preparation. This method could be suitable for analysis of Benjakul extract. PMID- 21294416 TI - Morinda citrifolia Linn. for prevention of postoperative nausea and vomiting. AB - OBJECTIVE: To be a preliminary, prospective, randomized double blinded, placebo controlled trial to evaluate the efficacy of Morinda citrifolia Linn or noni for the prevention of postoperative nausea and vomiting (PONV) in patients considered high risk for PONV after various types of surgery. MATERIAL AND METHOD: The plant extract was prepared by boiling of dried noni fruit (maturity stage 3-4) then evaporated under standard procedure and processed into capsules. The doses were 150 mg, 300 mg and 600 mg which are equivalent to 5, 10 and 20 g of dried noni fruit, respectively. One hundred patients of ASA physical status I or II, aged 18 65 years, and considered at risk for PONV, were randomized to receive 150, 300, 600 mg of noni extract or a placebo orally 1 hours before surgery. Standard general anesthetic technique and postoperative analgesia were employed. RESULTS: Significantly fewer patients who had received the 600 mg noni extract experienced nausea during the first 6 hours compared to the placebo group (48% for the 600 mg noni group and 80% for the placebo group, p-value = 0.04). The incidence of PONV in other time periods was not statistically different for all three noni doses compared to the placebo group. No side effects were reported in all groups. CONCLUSION: Morinda citrifolia Linn. has an antiemetic property and prophylactic noni extract at 600 mg (equivalent to 20g of dried noni fruit or scopoletin 8.712 microg) effectively reduces the incidence of early postoperative nausea (0-6 hours). PMID- 21294417 TI - Percutaneous coronary intervention in Thammasat University Hospital: the first three-year experience. AB - OBJECTIVE: To study the results of percutaneous coronary intervention (PCI) and in-hospital outcomes in cardiac catheterization laboratory, Thammasat University Hospital since May, 2006 until April, 2009. MATERIAL AND METHOD: This is the prospective, single-center study. The consecutive patients who underwent PCI in Thammasat University Hospital since May 2006 to April 2009 were recruited in the study. Clinical data, angiographic data, and in-hospital outcomes were analyzed and demonstrated. RESULTS: Six hundred and seventeen patients undergoing 755 PCI procedures were enrolled in the study. 62.70% were male and 37.30% were female. Mean age was 65.45 +/- 11.21 years (range 33-97 years) and 20.10% were more than 75 years old. The indications for PCI were non-ST segment-elevation acute coronary syndrome (NSTEACS) (41.72%), chronic stable angina (25.32%), acute ST segment elevation myocardial infarction (STEMI) (8.87%), staged PCI (15.76%). The other indications were heart failure, cardiomyopathy, post-cardiac arrest and etc. The procedure was single vessel PCI in 73.25% and multivessel PCI in 26.75% (double vessels PCI 24.64% and triple vessels PCI 2.11%). According to lesion locations, 45.21% were left anterior descending (LAD) artery lesions, 30.09% were right coronary artery (RCA) lesions, 23.28% were left circumflex (LCX) artery lesions, 1.19% were left main (LM) lesions and 0.24% were graft lesions. The overall angiographic success rate was 95.57%. During hospital stay the major adverse events developed as death in 0.93%, periprocedural myocardial infarction in 3.17%, emergency coronary artery bypass graft in 0.53%, and stroke in 0.26%. CONCLUSION: During the first three years of PCI experience in Thammasat University Hospital, the overall success rate was high with low in-hospital adverse outcomes. PMID- 21294418 TI - Liposome-containing Hibiscus sabdariffa calyx extract formulations with increased antioxidant activity, improved dermal penetration and reduced dermal toxicity. AB - Hibiscus sabdariffa Linn, or Roselle, is a medicinal plant used extensively in traditional Thai medicine since ancient times. The extracts of Roselle calyces possess antioxidant activity and have potential for development as active ingredients in cosmetic products. However the limitations of using Roselle extracts in cosmetics are its low skin permeation and dermal irritation. Liposome technology is an obvious approach that might overcome these problems. Liposome formulations of standardized Roselle extracts were developed with various lipid components. The formulation showing the highest entrapment efficiency was selected for stability, skin permeation and dermal irritability studies. The liposome formulation with the highest entrapment efficiency (83%) and smalolest particle size (332 mm) was formulated with phosphatidylcholine from soybean (SPC): Tween 80: deoxycholic acid (DA); 84:16:2.5 weight ratio, total lipid of 200 g/mL and 10% w/v Roselle extract in final liposomal preparation. This liposome formulation was found to be stable after storage at 4 degrees C, protected from light, for 2 months. The in vitro skin permeation studies, using freshly excised pig skin and modified Franz-diffusion cells, showed that the liposome formulation was able to considerably increased the rate of permeation of active compounds in Roselle extracts compared to the Roselle extract solution. The in vivo dermal irritability testing on rabbit skin showed that the liposome formulation dramatically decreased skin irritability compared to the unformulated extract. These results showed that the liposomes containing Roselle extracts had good stability, high entrapment efficacy, increased skin permeation and low skin irritation. PMID- 21294419 TI - Antioxidant and nitric oxide inhibition activities of Thai medicinal plants. AB - Nineteen Thai medicinal plants used in Thai traditional medicine preparation to treat colds, asthma and fever were studied for their antioxidant and NO inhibitory activities. Three extracts were obtained from each plant. First extract obtained by macerating the plant part in 95% ethanol (Et) residue was boiled in water, where water extract (EW) was obtained. The third extract (HW) was obtained by boiling each plant in water similar to that of Thai traditional medicine practice. These extracts were tested for their antioxidant activity using DPPH assay, and anti-inflammatory activity by determination of inhibitory activity on lipopolysaccharide (LPS) induced nitric oxide (NO) production in RAW 264.7 cell lines using Griess reagent. Results indicated that Et, EW and HW of Syzygium aromaticum showed the highest antioxidant activity (EC50 = 6.56, 4.73 and 5.30 microg/ml, respectively). Et of Atractylodes lancea exhibited the most potent inhibitory activity on lipopolysaccharide (LPS) induced nitric oxide (NO) production in RAW 264.7 cells, with IC50 value of 9.70 microg/ml, followed by Et of Angelica sinensis and Cuminum cyminum (IC50 = 12.52 and 13.56 microg/ml, respectively) but water extract (EW, HW) of all plants were apparently inactive. These results of anti-inflammatory activity of these plants correspond with the traditional use for fever; cold, allergic-related diseases and inflammatory related diseases. PMID- 21294420 TI - Primary muscle diseases in Thammasat University Hospital: muscle biopsy study of 12 cases. AB - We reviewed retrospectively 12 muscle biopsies of patients who were clinically diagnosed with a primary muscle diseases from the clinical data base of Thammasat University Hospital from January 2005 to January 2007. Most patients were male and had median age of 30.5 years (range 14 to 56). The most common clinical presentation was proximal muscle weakness. Nine of eleven patients had elevated CK concentrations ranging from 338 to 1023 IU/L. Clinicopathological correlation revealed specific diagnoses in nine patients. Suspected cases of mitochondrial neurogastrointestinal encephalopathy (MNGIE), myofibrillar myopathy (MFM) and distal myopathy with rimmed vacuoles (DMRV) were confirmed by molecular genetic studies examining thymidine phosphorylase, GNE, ZASP myotilin, desmin, abeta crystalline and filamin C genes. Specific histopathological findings on muscle biopsy help to select cases for advance molecular testing. PMID- 21294421 TI - The fractional excretion of urea in the differential diagnosis of prerenal failure and acute tubular necrosis in neonates. AB - BACKGROUND: Acute renal failure (ARF) in a newborn is a common problem. Fractional excretion of sodium (FENa) has been used to distinguish between the two main causes of ARF, prerenal failure and acute tubular necrosis (ATN). However, the clinical usefulness of FENa could be limited by furosemide diuretic that are commonly prescribed inARF patients. In contrast, urea is not reabsorbed significantly in the distal nephron, thus the fractional excretion of urea (FE UN) should not be affected by furosemide. OBJECTIVE: To test the hypothesis that FE UN is not effected by furosemide and useful in differentiating between prerenal failure and ATN. MATERIAL AND METHOD: Neonates admitted to the Department of Pediatrics, Thammasat University Hospital from August 2007-May 2009 were studies prospectively for ARF which is defined as urine output < 0.5 ml/kg/hr after the 1st day and serum creatinine > 1.5 mg/dl with normal maternal renal function. FENa and FEUN were performed on the initial time of diagnosis and were repeated on two consecutive days. RESULTS: Neonates with ARF were classified as prerenal failure (n=38) and ATN (n=5). The prerenal failure neonates were divided into two groups: those prerenal failure without furosemide (n=27), those prerenal failure with furosemide (n=11). The FENa at the initial time of diagnosis and the two consecutive days in prerenal failure neonates (0.33 +/- 0.57, 10.1 +/- 2.73, 0.8 +/- 1.32%, respectively) were lower than ATN neonates (4.74 +/- 6.12, 5.05 +/- 4.03, 3.98 +/- 2.47%, respectively) significantly. Both FENa and FE UN were no statistical difference between the two prerenal failure groups and ATN neonates. CONCLUSION: A FE Na in prerenal failure is significantly lower than ATN. A FE UN has no benefit in distinguishing between prerenal failure and ATN. Furosemide has no effect on both FENa and FE UN. PMID- 21294422 TI - A retrospective review of necrotizing fasciitis in Thammasat University Hospital. AB - OBJECTIVE: Necrotizing fasciitis is a rapidly progressive soft tissue infection. Clinicalfeatures and microbial knowledge will help reduce mortality and morbidity from delayed diagnosis and treatment. MATERIAL AND METHOD: From January 2004 to December 2009, records of 222 necrotizing fasciitis patients were reviewed for the study. The following data were collected and recorded: age, sex, location of lesion, inciting event, clinical manifestation, culture and sensitivity and procedures. RESULTS: The male-to-female ratio was 1.4:1 with 56.3 years mean age. The most of the occupations were elderly who stay at home and laborers. The highest incidence rate was during the raining seasons. The most common infection site was at the lower extremity with unknown inciting event. A common underlying disease was diabetes. The major complains presented was skin lesion, fever with chill, conscious change, gastrointestinal symptom. Examination revealed erythematous and swelling skin lesion (100%), fever (50.9)%, hypotension blood pressure (32.4%). Positive wound culture isolation was 55.9% and in blood culture was 48%. Dominant gram negative bacteria (71.98%) were in wound culture but gram positive bacteria (51.28%) were dominant in blood culture. Polymicrobial isolates in wound culture was 48% and in blood culture was 6%. The average 2.5 procedures were debridement (33.8%), skin graft coverage (59.9%), amputation (15.4%). Mortality rate was 5.9% that 46.2% were diabetes. CONCLUSION: Gram negative organisms were predominant wound isolates whereas gram positive organisms were predominant blood isolates. With high polymicrobial isolation, clinical manifestation can be described as necrotizing fasciitis type I. The elderly and diabetic patients were at risk. Early diagnosis is important in patients with fever, toxicity and erythematous swelling skin findings. The hallmarks of treatment are prompt surgical opening and debridement to get rid of the source of infection and broad-spectrum antibiotics treatment administered. PMID- 21294423 TI - Accuracy of visual inspection with acetic acid (VIA) for cervical cancer screening: a systematic review. AB - OBJECTIVE: To systematically review the performance characteristics of VIA in cervical cancer screening. MATERIAL AND METHOD: The Ovid (Medline) electronic database from January, 1996 to Febuary, 2007 was searched, using the following key search words of (1) MESH term "Uterine Cervical Neoplasms" with subheading "diagnosis", (2) Keywords "sensitivity" or "specificity" and (3) Keyword "visual inspection with acetic acid" Total of 11 studies were relevant and eligible for the review. Histology or combination of Colposcopy and histology were used as gold standard. Abnormal colposcopy must have histological confirmation by material obtained by colposcopic directed biopsy, loop excision, or endocervical curettage. Histologic threshold for positive outcome from screening tests was CIN2 (Cervical Intraepithelial Neoplasia 2) or higher (or equivalent categories by other classifications). A meta-analysis, yielding a quantitative summary measure was implemented with the random effect model. RESULTS: Using random effect method, the pooled estimates of sensitivity, specificity, positive predictive value and negative predictive value of VIA-VIAM were 71.8%, 79.4%, 16.7% and 99.0% respectively. When comparing with conventional cytology, VIA have favorably characteristics especially sensitivity and negative predictive value. CONCLUSION: VIA may be incorporated in cervical cancer screening programme in low resource setting country because of high negative predictive value of the test is sufficiently high to assure screening for negative and CIN I women. PMID- 21294424 TI - Cost-effectiveness analysis of home rehabilitation programs for Thai stroke patients. AB - BACKGROUND: The individual home rehabilitation program for ischemic stroke patients was conducted in a Thai healthcare setting. The program demonstrated that it was statistically significantly more effective than the conventional method. However for policy makers to adopt this program, the question of cost effectiveness must be answered. OBJECTIVE: To compare the costs and effects of a home rehabilitation program versus conventional hospital care for ischemic stroke patients in Thailand. MATERIAL AND METHOD: Cost-effectiveness analysis was conducted alongside a clinical trial. An open-label randomized control trial was conducted to explore the efficacy of a home rehabilitation program for acute stroke care for three months after hospital discharge. The Barthel Index and Modified Rankin Scale were used to evaluate the outcome measures. Success was defined as improvement by at least one level of the outcome scales. An incremental cost-effectiveness ratio, including sensitivity analysis, was presented. RESULTS: Fifty-eight patients were included in the study. Patients were randomly assigned to the study and control groups (28 and 30, respectively). The cost and number of successful cases in the study group were higher than those of the control group. The incremental cost-effectiveness ratio (ICER) was lowest- 13,644 Thai Baht (THB)--regarding the Modified Rankin Scale measurement. For patients achieving mild disability and no disability based on the Barthel Index, the ICERs were 14,212 THB and 24,364 THB, respectively. Sensitivity analyses regarding variations in number of patients and cost of home visits demonstrated more cost-effectiveness than the base case. CONCLUSION: Providing a home rehabilitation program with higher cost resulted in a greater number of patients avoiding disability than via conventional hospital care. The hospital had to pay approximately 24,000 THB for each additional disability-avoided patient when switching from conventional hospital care to a home rehabilitation program. This was assumed to be cost-effective when compared to per capita gross domestic product. PMID- 21294425 TI - Approximate iatrogenic blood loss in medical intensive care patients and the causes of anemia. AB - BACKGROUND: Anemia is the most common hematologic problem worldwide especially in developing world. There are many causes of anemia in ICU patient such as gastrointestinal bleeding, anemia of chronic inflammation, trauma or surgery. Patient who were admitted in the ICU need to have a lot of blood tests related to their illness and for further treatment, however that can cause decrease of hematocrit or anemia. OBJECTIVE: To identify the estimate volume of blood drawn from medical ICU patients and find out whether the volume of blood drawn effects the Hemoglobin/Hematocrit (Hb/Hct) or anemia and to identify the cause of anemia in ICU patient. MATERIAL AND METHOD: This is an observation prospective cohort study collecting the volume of blood drawn from patients who were admitted to ICU Thammasat university hospital during 1st October 2007 through 31st March 2008. RESULTS: This study found the mean volume of blood samples drawn from ICU patients is 77.8 ml. Sixty-eight percents of patients had a decrease Hb/Hct level during admission and around sixteen percent had anemia during admission. There is no statistically significant between the volume of blood drawn and the decrease of Hb/Hct. CONCLUSION: Decrease of Hb/Hct or anemia are common in ICU patient. This study showed that iatrogenic blood loss for laboratory investigation is one of the cause of anemia. We concluded that physician should order phlebotomy for necessary investigation for the most effective of diagnosis and treatment, but the less complication. PMID- 21294426 TI - Cytotoxic effect and its mechanism of dioscorealide B from Dioscorea membranacea against breast cancer cells. AB - BACKGROUND: Dioscorealide B is an active compound from the rhizome of Dioscorea membranacea Pierre which locally known as "Hua-Khao-Yen". This medicinal plant has long been used in the anticancer prescription of Thai traditional medicine. OBJECTIVE: To examine the cytotoxic effect and mechanism of Dioscorealide B in human breast carcinoma cells. MATERIAL AND METHOD: Dioscorealide B was isolated from the rhizome of Hua KhaoYen (Dioscorea membranacea).The cytotoxicity of Dioscorealide B was evaluated in two human breast cancer cell lines, MCF-7 and MDA-MB 468 by Sulphorhodamine B (SRB) assay. RT-PCR and Caspase-Glo assay were used to further elucidate its cytotoxic mechanism. RESULTS: Dioscorealide B showed cytotoxic effect on MCF-7 (IC50 = 2.76 microM) and MDA-MB 468 (IC50 = 9.93 microM). The mRNA level for p53, p21 and Bax were increased while Bcl-2 was decreased after the treatment. MCF-7 treated with Dioscorealide B showed the induction of apoptosis via the activation of caspase-9 and -7. CONCLUSION: The results suggested that the mechanisms of Dioscorealide B might be involved in p53 and the intrinsic apoptotic pathway. PMID- 21294427 TI - Pediatric systemic lupus erythematosus in Thammasat University Hospital. AB - Systemic lupus erythematosus (SLE) is a common autoimmune disease in children. Current standard therapies carry high adverse effects. Refractory SLE to conventional therapies is not uncommon. Rituximab, anti-CD20 monoclonal antibody, has been used as an adjunctive therapy in children with refractory SLE with limited reports. This study described pediatric SLE patients in a single center, Thailand. To determine the clinical manifestations, treatments, and outcome of SLE patients, the authors retrospectively studied 19 patients (age <15 years) diagnosed with SLE at Thammasat University hospital, from January 01, 2002 through March 31, 2010. The mean age was 12.9 +/- 1.6 years; mean follow-up 3.3 +/- 2.6 years. Seventeen (89.5%) patients were female. Clinical manifestations were hematological (89.5%), dermatologic (73.7%), and renal involvement (68.4%). SLE was diagnosed 1 year after systemic onset juvenile rheumatoid arthiris in one patient. Lupus nephritis (LN) class II was observed in 30.8%, class III (15.4%), and class IV (53.8%) of patients with LN. Overall, mean SLEDAI score at presentation was 14.9 +/- 2.2 and significantly decreased to 6.8 +/- 1.6 (p < 0.0001) at 1 month after treatment. Complete remission at 1 year demonstrated in 11 (68.7%) patients. Infection was the most common complication followed by ophthalmological complications. All patients survived during follow-up period. Rituximab induced remission of SLE after refractory diffuse alveolar hemorrhage in one patient, and rapidly progressive glomerulonephirits leading to end stage renal failure in one patient. Clinical outcome of pediatric SLE was favorable in the present study. Complications from corticosteroid and anti-inflammatory therapy were high. Rituximab may be a good adjunctive therapy for refractory SLE in children. Large controlled trials to establish safety profile and optimal regimen of rituximab in childhood SLE are required. PMID- 21294428 TI - NK/T cell lymphoma, nasal type with sinonasal mass and palatal ulcer: a clinical case report and review of treatment. AB - Extranodal Nasal NK/T cell lymphoma, relatively uncommon type of non-Hodgkin's lymphoma, is highly aggressive disease with poor outcomes. Early stage disease may response to radiotherapy alone. However the treatments are usually chemotherapy and radiotherapy combination and late stage disease may not response to any available therapy. We reported a 45-year-old woman with extranodal nasal type NK/T cell lymphoma. The patient presented with chronic nasal stuffiness and mucous bloody discharge. The nasal mass is extensively involved periorbital and sinonasal soft tissue. Due to the extensively involved of tumor, combination chemotherapy was used to induce response. This patient was involved by complicated infection and palatal ulcer with likely perforation. The salvage chemotherapy was given and the treatment of NK/T cell lymphoma from other reports and literatures were reviewed. PMID- 21294429 TI - A fluctuation of serum osmolality inducing osmotic demyelination syndrome. AB - Osmotic demyelination syndrome (ODS) is an uncommon acute demyelinating process which involves the central nervous system. Rapid correction of chronic hyponatremia with increasing serum osmolality is the most common cause of ODS. We report the first case of an infant with moderate dehydration and initially normal serum Na who developed ODS associated with a fluctuation of serum osmolality. We present the lowest decreasing rate of serum Na level ever reported causing ODS. The fluctuation of serum osmolality in this case expands the list of precipitating causes of ODS in children. The case also highlights the appropriate intravenous fluid for initial rehydration in infant. PMID- 21294430 TI - Result of esophageal reconstruction using supercharged interposition colon in corrosive and Boehave's injury: Thammasat University Hospital experience. AB - Seven esophageal reconstructions with interposition colon in severe suicide corrosive ingestion and Boehave's injury at Thammasat University Hospital were presented. Vascular enhancement (as called "supercharge") were done. Only one patient had micro-leakage at pharyngeal anastomosis with healed by conservative treatment and no late anastomotic stricture. The operation need more time and general surgeon skill but better comparison outcome. CONCLUSION: Using supercharged interposition colon in adult esophageal reconstruction in corrosive and Boehave's injury was benefit in lower the incidence of anastomotic leakage and late anastomotic stricture. Just a longer operative time and vascular anatomizes skill were need. PMID- 21294431 TI - Meralgia paresthetica-like syndrome may be caused by transient lumbar nerve root injury without definite compression: a case report. AB - Meralgia paresthetica is a well-known sensory syndrome describing paresthesia and/or anesthesia in the anterolateral aspect of the thigh that is supplied by the lateral femoral cutaneous nerve. Compression of the nerve usually occurs at the point where it passes between the anterior superior iliac spine and the inguinal ligament. Proximal lesions such as lumbar radiculopathy, lumbar disc herniation, and spinal stenosis have been reported to cause meralgia paresthetica like syndrome. These proximal lesions directly injure L2 and L3 spinal nerve roots and cause a constant compression of the nerve roots. The presented paper introduces a hypothesis that this syndrome can be caused by transient injury to the L2 and L3 nerve roots by the upper adjacent disc bulge without definite compression. This hypothesis is supported by lumbar spine magnetic resonance imaging of a patient presenting with a meralgia paresthetica-like symptom during bending forward and twisting of the body, showing no L2/L3 herniated disc but mildly posterior bulging of T12/L1 disc. This hypothesis emphasizes an importance of appropriate postures in patients with meralgia paresthetica-like symptoms in order to prevent long-term morbidity. PMID- 21294432 TI - Targeted therapy: novel agents against cancer. AB - Nowadays, malignancies still are crucial problems of healthcare system in many aspects including efficacy of therapeutic modalities, quality of patients' life and cost of treatment. The understanding of genetic alterations and intracellular pathways are very helpful to define the pathologic abnormalities specific to each cancer Consequently, there have been recently discovered agents which destroy the cancer cells with higher specificity than previously used agents. "Targeted therapy" is established to call this group of drugs because its mechanism of action selectively targets on tumor-specific abnormal cellular processes. These aimed extracellular or intracellular mechanisms are mainly divided into 3 groups; (1) activating natural immune system directly against tumor cells, (2) inhibiting cellular proliferation, (3) inducing tumor anti-angiogenesis. The targeted drugs are currently studied to establish the appropriate regimens for cancers with or without concurrent chemotherapy. It is important to understand and keep updated in these novel agents for better clinical outcome of cancer patients. PMID- 21294433 TI - Multipurpose external fixator for intraarticular fracture of distal radius. AB - Fracture of distal radius is one of a complicated injury which can be difficult in reduction and maintaining its alignment and may result in malunion and shortening following a variety of fixation. Since Anderson's and O'neil described the use of sustain traction by extraskeletal device anchored to the radius and the first metacarpal of the hand. Vidal et al [1979] demonstrated that the ligamentotaxis could be used to reduce the fracture around the wrist, ankle, hip and knee. The external fixation frame can maintain radial length and inclination by the pullout force from the radial styloid. External fixation is useful for management of complex intraarticular fracture of distal radius. There are few types of commercially available fixator. It is important to use one that allow versatility and follow biomechanic principles of ligamentotaxis, which can be used to reduce the severe comminution and the most difficult fracture by distraction and stabilization effectively. The ideal characteristic of the external fixation are: Telescoping connecting frame fixed externally compose of two joints which can be easily adjust in any direction, two pins clamp connected to the external connecting rod. Our TU Multipurpose external fixator can be designed as a multiplana, can be used as a bridge or non bridge fixation, and can be adjusted to any direction which require for the treatment of distal radius fracture. It is differed to other commercially available devices. PMID- 21294434 TI - Tissue engineering of skin and soft tissue augmentation, medical view. AB - Tissue engineering is one application of the regenerative medicine, which aims to promote replace, repair or regeneration of tissue or organ due to congenital abnormalities, disease, trauma, or aging. This field applies the principles of physical sciences, engineering, medicine and the life sciences. To integrate knowledge of stem cell biology, tissue scaffold biocompatibility and degradation, bioreactor on cell growth and differentiation may overcome some limitation of autologous tissue grafting, allogenic tissue rejection. Tissue engineering is really a new hope for future medicine. PMID- 21294435 TI - Health care reform and Connecticut's non-profit hospitals. AB - The recent federal Health Care Reform Act signed into law by President Obama is expected to lead to greater patient volumes at non-profit hospitals in Connecticut (and throughout the country). The financial implications for these hospitals depend on how the costs per patient are expected to change in response to the anticipated higher patient volumes. Using a regression analysis of costs with annual data on 30 Connecticut hospitals over the period 2006 to 2008, we find that there are considerable differences between outpatient and inpatient unit cost structures at these hospitals. Based on the results of our analysis, and assuming health care reform leads to an overall increase in the number of outpatients, we would expect Connecticut hospitals to experience lower costs per outpatient treated (economies of scale). On the other hand, an influx of additional inpatients would be expected to raise unit costs (diseconomies of scale). After controlling for other cost determinants, we find that the marginal cost of an inpatient is about $8,000 while the marginal cost of an outpatient is about $44. This disparity may provide an explanation for our finding that the effect of additional patient volumes overall (combining inpatient and outpatient) is an increase in hospitals' unit costs. PMID- 21294436 TI - Understanding the health care business model: the financial analysts' point of view. AB - This study focuses on how financial analysts understand the strategy of a health care company and which elements, from such a strategy perspective, they perceive as constituting the cornerstone of a health care company's business model. The empirical part of this study is based on semi-structured interviews with analysts following a large health care company listed on the Copenhagen Stock Exchange. The authors analyse how the financial analysts view strategy and value creation within the framework of a business model. Further, the authors analyze whether the characteristics emerging from a comprehensive literature review are reflected in the financial analysts' perceptions of which information is decision-relevant and important to communicate to the financial markets. Among the conclusions of the study is the importance of distinguishing between the health care companies' business model and the model by which the payment of revenues are allocated between end users and reimbursing organizations. PMID- 21294437 TI - Security market reaction to FDA fast track designations. AB - Pharmaceutical firms can apply for the Food and Drug Administration to 'fast track' research and de velopment on new drugs, accelerating clinical trials and expediting regulatory review required prior to marketing to consumers. We investigate security market reaction to more than 100 fast track designations from 1998 to 2004. Fast track designation appears to enhance investor recognition of firm value. Specifically, fast track designation coincides with abnormal trading volume and excess daily stock returns for sponsoring firms. Institutional ownership and analyst attention also increase. Market response is more pronounced for firms that are smaller, do not yet market products, and have low institutional ownership. PMID- 21294438 TI - Health care providers under pressure: making the most of challenging times. AB - Whether the slowing economic recovery, tight credit markets, increasing costs, or the uncertainty surrounding health care reform, the health care industry faces some sizeable challenges. These factors have put considerable strain on the industry's traditional financing options that the industry has relied on in the past--bonds, banks, finance companies, private equity, venture capital, real estate investment trusts, private philanthropy, and grants. At the same time, providers are dealing with rising costs, lower reimbursement rates, shrinking demand for elective procedures, higher levels of charitable care and bad debt, and increased scrutiny of tax-exempt hospitals. Providers face these challenges against a back ground of uncertainty created by health care reform. PMID- 21294439 TI - Inpatient cancer treatment: an analysis of financial and nonfinancial performance measures by hospital-ownership type. AB - This study uses longitudinal data of inpatient treatment from the Agency for Healthcare Research and Quality's (AHRQ's) Healthcare Cost and Utilization Project (HCUP) to examine the differences in historical trends and build future projections of charges, costs, and lengths of stay (LOS) for inpatient treatment of four of the most prevalent cancer types: breast, colon, lung, and prostate. We stratify our data by hospital ownership type and for the aforementioned four major cancer types. We use the Kruskal Wallis (nonparametric ANOVA) Test and time series models to analyze variance and build projections, respectively, for mean charges per discharge, mean costs per discharge, mean LOS per discharge, mean charges per day, and mean costs per day. We find that significant differences exist in both the mean charges per discharge and mean charges per day for breast, colon, lung, and prostate cancers and in the mean LOS per discharge for breast cancer. Additionally, we find that both mean charges and mean costs are forecast to continue increasing while mean LOS are forecast to continue decreasing over the forecast period 2008 to 2012. The methodologies we employ may be used by individual hospital systems, and by health care policy-makers, for various financial planning purposes. Future studies could examine additional financial and nonfinancial variables for these and other cancer types, test for geographic disparities, or focus on procedural-level hospital measures. PMID- 21294440 TI - Hospital revenue cycle management and payer mix: do Medicare and Medicaid undermine hospitals' ability to generate and collect patient care revenue? AB - The continuing efforts of government payers to contain hospital costs have raised concerns among hospital managers that serving publicly insured patients may undermine their ability to manage the revenue cycle successfully. This study uses financial information from two sources-Medicare cost reports for all US hospitals for 2002 to 2007 and audited financial statements for all bond-issuing, not-for profit hospitals for 2000 to 2006 to examine the relationship between hospitals' shares of Medicare and Medicaid patients and the amount of patient care revenue they generate as well as the speed with which they collect their revenue. Hospital-level fixed effects regression analysis finds that hospitals with higher Medicare and Medicaid payer mix collect somewhat higher average patient care revenues than hospitals with more privately insured and self-pay patients. Hospitals with more Medicare patients also collect on this revenue faster; serving more Medicaid patients is not associated with the speed of patient revenue collection. For hospital managers, these findings may represent good news. They suggest that, despite increases in the number of publicly insured patients served, managers have frequently been able to generate adequate amounts of patient revenue and collect it in a timely fashion. PMID- 21294441 TI - Greek and Chinese horse medicine: deja vu all over again. PMID- 21294442 TI - "Ein Liebhaber des Mysterii, und ein grosser Verwandter desselben." Toward the Life of Balthasar Walther: Kabbalist, Alchemist and Wandering Paracelsian Physician. AB - Despite the attention recently paid to Jakob Bohme's life and works, the Gorlitz theosopher's most famous disciple, Balthasar Walther (1558-c.1630), remains something of a historical puzzle. Utilizing several recently rediscovered print and manuscript sources located by the author, the present article seeks to provide the first detailed biographical study of Walther, highlighting his significance to sixteenth and seventeenth century history in a myriad of contexts. Far from being merely a follower of Bohme, Walther emerges as significant in his own right as a physician, Paracelsian, Kabbalist, Weigelian, religious heretic, and distributor of magical manuscripts, whose personal networks extended across Europe and beyond. In addition to providing a biography, this article seeks to discover new avenues of enquiry in which information concerning Walther's life and thought might be uncovered and contextualized. This investigation simultaneously throws light upon Walther himself, as well as Jakob Bohme's often neglected intellectual and social Umwelt. It also points to new and entirely unexamined sources for Bohme's thought. PMID- 21294443 TI - Diagnostic and prognostic value of serum nitric oxide, tumor necrosis factor alpha, basic fibroblast growth factor and copper as angiogenic markers in premenopausal breast cancer patients: a case-control study. AB - Many studies demonstrate that increased microvessel density (MVD) surrounding primary tumour is associated with decreased overall survival in patients with breast cancer. This study compares the diagnostic and prognostic values of the angiogenic serum factors nitric oxide (NO), tumour necrosis factor-alpha (TNFalpha), basic fibroblast growth factor (bFGF) and copper with those of serum CA15-3 as the standard tumour marker in breast cancer patients. Microvessel density was estimated in CD31-immunostained sections from breast cancer patients. Before surgery, NO, TNFalpha, bFGF, copper and CA 15-3 were measured in serum samples from 30 premenopausal breast cancer patients in comparison with 15 healthy controls. The diagnostic values of the assayed parameters were compared using receiver operating characteristic (ROC) curve analysis. Univariate survival analysis of patients was assessed using the Kaplan-Meier method. Breast cancer tissues showed higher MVD than did normal breast tissues adjacent to the tumour (P = 0.008). Before surgery, tumour MVD correlated significantly with serum NO, TNFalpha, bFGF and copper (r = 0.458, P = .011; r = 0.379, P = .039; r = 0.513, P = .004 and r = 0.613, P = 0.000, respectively). Serum NO, TNFalpha, bFGF, copper and CA 15-3 levels in patients were significantly elevated compared with controls (P = 0.011, P = 0.004, P = 0.039, P = 0.000 and P = 0.001, respectively). Kaplan Meier analysis revealed that patients with elevated serum TNFalpha, CA 15-3 and copper (P = 0.035, P = 0.040, P = 0.0339, respectively) had an overall survival significantly shorter than those who had lower levels of these parameters. These data suggest that serum TNFalpha, CA 15-3 and copper are useful predictive markers for overall survival in premenopausal breast cancer patients. PMID- 21294444 TI - Automatic skin tumour border detection for digital dermoscopy using a new digital image analysis scheme. AB - Malignant melanoma and basal cell carcinoma are common skin tumours. For skin lesion classification it is necessary to determine and calculate different attributes such as exact location, size, shape and appearance. It has been noted that illumination, dermoscopic gel and features such as blood vessels, hair and skin lines can affect border detection. Thus, there is a need for approaches that minimise the effect of such features. This study aims to detect multiple borders from dermoscopy with increased sensitivity and specificity for the detection of early melanoma and other pigment lesions. An automated border detection method based on minimising geodesic active contour energy and incorporating homomorphic, median and anisotropic diffusion (AD) filtering, as well as top-hat watershed transformation is used. Extensive experiments on various skin lesions were conducted on real dermoscopic images and proved to enhance accurate border detection and improve the segmentation result by reducing the error rate from 12.42% to 7.23%. The results have validated the integrated enhancement of numerous lesion border detections with the noise removal algorithm which may contribute to skin cancer classification. PMID- 21294445 TI - Complexed and total PSA in patients with benign prostatic hyperplasia and prostate cancer. AB - This study compares the diagnostic utility of complexed prostate-specific antigen (cPSA), total PSA (tPSA) and their ratios with free PSA (fPSA) for benign prostatic hyperplasia (BPH) and prostate cancer. This is though to be the first study to evaluate cPSA in the ethnic population of Saudi Arabia. Serum samples were collected from 54 patients (aged over 50) and assayed for tPSA, cPSA and fPSA. Thirty-five patients were histologically and clinically proven to have BPH and 19 patients were proven to have cancer. Sensitivity, specificity and ROC curves were calculated. With a cPSA cut-off of 4 ng/mL the sensitivity was 79%, the specificity was 34%, and the positive and negative predictive values (PPV and NPV) were 39% and 75%, respectively. At the same cut-off for tPSA, the sensitivity was 84%, the specificity was 29%, and the PPV and NPV were 39 and 77%, respectively. The sensitivity for both tests was lower at a cut-off of 20 ng/mL but the specificity increased to 77% for cPSA and 69% for tPSA. The areas under the receiver operating characteristic (ROC) curves were found to be 0.608 for tPSA and 0.559 for cPSA (P = 0.69). The incidence of prostate cancer in the Saudi population may be lower than that in Western populations. The data presented show little advantage in using cPSA over tPSA for discriminating BPH and prostate cancer in the population studied. PMID- 21294446 TI - Breast cancer invasion is mediated by beta-N-acetylglucosaminidase (beta-NAG) and associated with a dysregulation in the secretory pathway of cancer cells. AB - The extracellular matrix is enriched with carbohydrate polymers that mask the protein backbone. This study aims to test the hypothesis that for successful cancer cell invasion the cells must secrete glycosidases to reveal the protein backbone, and then the action of proteases provides the physical space needed for cancer cell movement. Thus, the activity of intracellular and secreted beta-N acetylglucosaminidase (beta-NAG) was assayed in luminal breast epithelial cells (HB4a) and breast cancer cells (BT474, ZR75-1, MDA-MB-435, MCF7). An increase in the V(max) of beta-NAG was observed in MDA-MB-435 and MCF7 cells. Exoglycosidases are normally located in the lysosomes and function at an acidic pH, but in the cancer cells there was significant enzyme activity at neutral pH. A change in lysosome location and number was observed in the cancer cells, consistent with alterations in the secretory pathway. Finally, applying a cocktail of protease inhibitors resulted in a 20% reduction in invasion of MDA-MB-435 cells through Matrigel after 24 h, and when the cells were treated with protease and beta-NAG inhibitors then cellular invasion was reduced by > 60%. The results suggest combination therapies that inhibit proteases and glycosidases might be a rational way forward for the design of drugs aimed at arresting cellular invasion. PMID- 21294447 TI - Antibiotic susceptibility patterns of Helicobacter pylori and triple therapy in a high-prevalence area. AB - This study aims to determine primary Helicobacter pylori resistance and its effect on eradication of the organism. Ninety-two patients with dyspeptic symptoms were enrolled. H. pylori was cultured and antibiotic sensitivity was determined by the Epsilometer test (Etest) for clarithromycin (CLR), amoxicillin (AMX) and metronidazole (MTR). 23S ribosomal RNA (rRNA) point mutations associated with clarithromycin resistance were also detected. Patients were treated with omeprazole (40 mg daily), CLR (500 mg) and AMX (1g twice a day) for 14 days. A 14C-urea breath test (14C-UBT) was repeated four weeks after completion of treatment to confirm eradication. Triple therapy failure was seen in 30 (33%) patients. The resistance rates were: CLR 33% (30/92), MTR 48% (44/92) and AMX 2% (2/92). Clarithromycin resistance (CLR-R) was present in the 16-39 age group in 21 (47%) (P = 0.007) compared to nine (19%) in the 40-79 age group. CLR resistance was seen in 30 H. pylori isolates, 20 (67%) from patients with non ulcer dyspepsia (NUD), six (20%) with gastric ulcer (GU) and four (13%) with duodenal ulcer (DU). Triple therapy failure was associated with CLR-R in 28 (93%) (P < 0.001). CLR-R mutations were present in 30 (33%) and were associated with treatment failure in 27 (90%; P < 0.001). They were present in 20 (44%) isolates obtained from patients in the 16-39 age group (P = 0.018). Treatment failure was associated with A2142G mutation in 20 (67%; P < 0.001), A2143G mutation in 12 (40%; P < 0.001) and A2142C mutation in five (17%; P = 0.003). In conclusion, triple therapy failure was associated with CLR-R. Metronidazole resistance exceeded that of CLR, hence it cannot be substituted for CLR in a triple therapy. PMID- 21294448 TI - Analysis of common MEFV mutations in Egyptian patients with familial Mediterranean fever: molecular characterisation of the disease. AB - Familial Mediterranean fever (FMF) is a hereditary inflammatory disorder transmitted as an autosomal recessive trait. It predominantly affects people living in, or originating from, areas around the Mediterranean and was difficult to diagnose until mutations in the MEFV gene were identified. This study aims to analyse the five most common MEFV mutations in Egyptian patients diagnosed clinically as FME Thirty-eight unrelated patients were tested for the presence of the MEFV gene mutations V726A, M694V, M694I, M680I and E148Q, using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and the amplification refractory mutation system (ARMS). Twenty-three patients (60.5%) had one or more mutations, whereas no mutation was found in the remaining 15 patients (39.5%). The most common mutation was M694I (42.5%), followed by V726A (22.5%), M680I (17.5%) and E148Q (17.5%). The M694V mutation was not detected. The profile of MEFV gene mutations in this study suggests that the origin of FMF in Egypt is heterogeneous, a finding in concordance with that for other Arab populations; however, some differences were observed as M694V, the most common mutation reported in Arabs, was not detected in this study. PMID- 21294449 TI - Molecular and comparative analyses of the full-length cytolethal distending toxin (cdt) gene operon and its adjacent genetic loci from urease-positive thermophilic Campylobacter (UPTC) organisms. AB - Molecular and comparative analyses of the full-length cytolethal distending toxin (cdt) gene operon and its adjacent genetic loci (2.7-9.4 kilo base pairs in length) are carried out with 12 urease-positive thermophilic Campylobacter (UPTC) isolates using several polymerase chain reaction (PCR) primer pairs. Three putative open reading frames (ORFs) for cdtA, cdtB and cdtC, two putative promoters and a hypothetically intrinsic rho-independent transcription terminator were identified in all the operons of the 12 UPTC isolates examined. Although the number of amino acid residues slightly varied for the putative cdtA and cdtC ORFs, those for the cdtB were similar among all the UPTC isolates, as well as the six urease-negative (UN) C. lari examined previously. Regarding the cdt genes in UPTC CF89-12, each ORF commenced with an ATG start codon and terminated with a TAG stop codon for cdtA and cdtB and a TAA for cdtC. Start and stop codons of the three ORFs for the other 11 UPTC isolates were identical to those from the UPTC CF89-12 isolate except for the TTG start codon for cdtC in the two isolates (NCTC12892 and 12893) and the TGA stop codon for cdtA in five isolates (A1, A2, A3, 89049 and 92251). Two putative promoter structures, consisting of sequences at the -35-like (TTAATA) and -10-like (TATTAA) regions, as well as the start codon (ATG), were identified for the transcriptional promoter, immediately upstream of the cdtA gene in all the 12 isolates, Although the genetic heterogeneity of the cdtB gene locus occurred in all 28 C. lari isolates (n = 16 UN C. lari; n = 12 UPTC) examined, all nine amino acid-specific DNase residues were completely conserved in all their cdtB genes. Variable gene insertions with heterogeneous order and combinations occurred between cdtC and lpxB genes in the all UPTC organisms examined. PMID- 21294450 TI - Acute effects of hyperglycaemia on asymmetric dimethylarginine (ADMA), adiponectin and inflammatory markers (IL-6, hs-CRP) in overweight and obese women with metabolic syndrome. PMID- 21294451 TI - Potential risk of patient misclassification using a point-of-care testing kit for urine drugs of abuse. PMID- 21294452 TI - No evidence for JAK2 V617F mutation in colorectal cancer. PMID- 21294453 TI - Maternal human papillomavirus (HPV) infection and its possible relationship with neonatal prematurity. PMID- 21294454 TI - Digging into dignity. PMID- 21294455 TI - Academic honesty. PMID- 21294456 TI - Fruitful nursing practice. PMID- 21294457 TI - (Re)searching for hidden treasure. PMID- 21294458 TI - Ethics and empathy (Part one). PMID- 21294459 TI - The place of dignity in everyday ethics. AB - Although ethics is often thought of in terms of "life-and-death" matters, many everyday situations involve ethics. Human dignity, a more recent way of expressing the belief that humans are made in the image of God (Genesis 1:26), captures the controversial notion that all humans are uniquely valuable and ought to be esteemed highly. Nurses have great opportunity to promote or demote dignity. A Christian holistic approach to ethics, exemplified by the narrative of the Good Samaritan (Luke 10:25-37), acknowledges the difficulty of always being ethical and integrates feeling, thinking, acting, and spirituality. PMID- 21294460 TI - Holding on to hope. AB - A nurse practitioner persists in caring for a patient with overwhelming problems. With God's help and against all odds, the patient's life eventually changes. PMID- 21294461 TI - Living out our values: the legacy of Christian academic nursing leadership. AB - Retired academic nursing leaders possess a rich legacy of knowledge. Using a grounded theory approach, knowledge possessed by 14 retired Christian Chairperson/Deans was explored. Two themes representing commitment to living out Christian values; and fortitude, understanding, and spiritual guidance emerged from written responses to open-ended survey questions. PMID- 21294462 TI - Faith community/parish nursing: what's in a name? AB - In the Christian faith tradition, using "Parish Nurse" to describe the form of nursing based in a Christian congregation is both historic and descriptive of the type of nursing specialty practice and ministry that reaches within the Church and out into the wider community. Reflecting on the work of Granger Westberg, the Scope and Standards of Practice for this specialty, and examining the etiology of the word "parish," the authors argue that retaining the language "Parish Nurse"promotes a broader understanding of the purpose of this specialty practice, not only as inreach or outreach on behalf of a church or health system, but as a focused and integrated "parish" ministry. PMID- 21294463 TI - Emotional competence makes a difference (for staff and patients)! AB - Emotional competence refers to the ability to appropriately manage and express one's emotions. It is especially critical in nursing practice as it impacts patient care, work relationships, and the healthcare environment, and can be a vital skill to model and teach patients. Characteristics of emotional competence include self-awareness, mood management, self-motivation, empathy, and managing relationships. PMID- 21294464 TI - Developing endurance. AB - Nurses frequently encounter trying experiences; trials, and tribulations in everyday practice. James 1:2-5 offers guidance to Christian nurses, who can draw on their faith and select Christ-like verbal responses and actions in times of stress. PMID- 21294465 TI - Feeling shame: Insights on intimate partner violence. AB - Intimate partner violence (IPV) is a serious health issue; however, many healthcare providers do not routinely ask about IPV or administer screening. Due to the high incidence of this problem, providers must be aware of risk factors, screening methods, and appropriate interventions, and screen all female patients for abuse. PMID- 21294466 TI - Living positively as HIV positive. AB - A nursing student records a brief biography of a Zambian nurse and certified midwife living with HIV/AIDS while shadowing the nurse during an undergraduate cross-cultural course in Macha, Zambia in January 2009. The nurse strives to live positively, educating, encouraging, and empowering others. PMID- 21294467 TI - Handling student excuses. PMID- 21294468 TI - How can I give spiritual care to patients in ICU? PMID- 21294469 TI - A healing balm. PMID- 21294470 TI - Myth busting: does real-world experience lead to better drug choices? AB - In the era of evidence-based medicine, clinical guidelines, andpersonalized medicine, one would think that convincing clinical trial data would influence clinical practice if disseminated in an appropriate manner. However, it has been estimated that only 50% of current medical practice is evidence-based, clearly demonstrating a compelling need to collect and analyze additional data to better inform practice. Current data are usually gathered from a variety of sources, including clinical trials, observational studies, and meta-analyses. Yet according to Jeff Forringer, CEO of IntrinsiQ, data from oncology practices provide real-world outcomes that give better insight into the efficacy of cancer therapeutics. PMID- 21294471 TI - Ipilimumab: a promising immunotherapy for melanoma. AB - Antibody-based targeting of the immune suppressor molecule cytotoxic T-lymphocyte antigen 4 (CTLA-4) with ipilimumab has been studied in metastatic melanoma in a number of clinical trials, including a recent phase III trial. This marks the first randomized clinical trial reporting an overall survival benefit using immune modulation in metastatic melanoma. Along with its therapeutic benefits, ipilimumab presents unique challenges to clinicians; these are related to the monitoring of treatment response and the management of drug-related toxicities. This drug is currently being investigated in various cancers, and its indications are likely to be expanded. PMID- 21294472 TI - Improving the therapeutic benefits of ipilimumab. PMID- 21294473 TI - Ipilimumab for advanced melanoma: let's not throw caution to the winds. PMID- 21294474 TI - CTLA-4-blocking immunotherapy with ipilimumab for advanced melanoma. PMID- 21294475 TI - A renaissance in the medical treatment of advanced prostate cancer. AB - Prostate cancer will be diagnosed in one of six men during their lifetimes, and a small portion of these will progress after primary and salvage therapies. For many years, there were few treatment options for these patients after routine hormonal maneuvers, and standard of care since the early 2000s has consisted primarily of docetaxel, which improved survival over the previous first-line therapy mitoxantrone. In recent years, however, new therapies have begun to emerge to treat this devastating form of prostate cancer. This review examines the mechanisms behind these therapeutics and the key trials seeking to validate their clinical use. PMID- 21294476 TI - Castration-refractory prostate cancer: new therapies, new questions. PMID- 21294477 TI - Is this a true renaissance for the treatment of prostate cancer? PMID- 21294478 TI - Recurrent pancreatic adenocarcinoma after pancreatic resection. AB - The patient is a 57-year old Caucasian female who presented with right upper quadrant pain and obstructive jaundice and was diagnosed with resectable pancreatic cancer. She underwent pancreaticoduodenectomy (PD) after preoperative biliary stenting. She subsequently presented to the clinic, where it was noticed that she had an elevated CA 19-9. CT C/A/P revealed multiple new liver lesions. PMID- 21294479 TI - The war on pancreatic cancer: are we gaining ground? PMID- 21294480 TI - Pancreatic adenocarcinoma: new approaches to a challenging malignancy. PMID- 21294481 TI - Will we be able to care for cancer patients in the future? AB - The number of cancer patients and cancer survivors continues to increase rapidly amid predictions of a shortfall in physicians to care for them. In addition, newer cancer therapies have become increasingly complex and resource-intensive, compounding the impending workforce shortage. Simultaneously, the growing understanding of the biologic heterogeneity of cancer and the development of pharmacogenomics have opened up the possibility of personalized approaches to cancer diagnosis and treatment. Such personalization has been promulgated as a means of decreasing the cost of drug development, improving the efficacy of treatments, and reducing treatment toxicity. Although there have been notable successes, the fulfillment of these promises has been inconsistent. Providing care for future cancer patients will require the development of innovative delivery models. Moreover, new approaches to clinical research design, to the assessment of therapeutic value, and to the approval of and reimbursement for diagnostics and treatments are needed. PMID- 21294482 TI - Where expert opinion meets public resistance. PMID- 21294483 TI - Caring for cancer patients in the future: a perfect storm on the horizon? PMID- 21294484 TI - Lycium (Lycium barbarum). AB - The berries of Lycium barbarum, a perennial plant native to Asia and southeastern Europe, have been used for centuries in traditional Chinese medicine to treat poor vision, anemia, inflammation, and cough. They are also consumed as food and used in soup recipes. Lycium has gained immense popularity in the United States over the past decade because of its antioxidant properties. It is available in health food stores and is marketed via the Internet in juice form, typically blended with the juices of other berries and fruits. A wide range of health benefits, including cancer prevention and treatment, have been claimed for lycium. PMID- 21294485 TI - ECG of the month. Chest pain one week after childbirth. Posterior fascicular tachycardia. PMID- 21294486 TI - Clinical case of the month. Heterotopic pancreas. PMID- 21294487 TI - Radiology case of the month. Left shoulder pain following trauma. Osteopoikilosis. PMID- 21294488 TI - Common sense in prescribing pain medications for the Louisiana physician. AB - Louisiana physicians often face difficult predicaments in treating patients with chronic pain complaints. On the one hand, there is a greater appreciation for the debilitating impact of chronic pain on quality of life and better recognition that chronic pain is a disease in its own right deserving treatment. On the other hand, we regularly learn of arrests of physicians for prescribing these medications and read reports of exploding pain medication abuse. This article dispenses common sense advice for the Louisiana physician in approaching chronic pain issues such as defining your treatment population, obtaining independent corroborating records, prescribing extended-release pain medications when possible, considering adjunctive treatments to reduce total opiate use, collaborating with colleagues regularly, utilizing treatment agreements, employing sensible verification methods of proper medication use, opening the doctor-patient relationship to include concerned family or friends, using psycho social indicators of good functioning, and reappraising the success of treatment at appropriate intervals. By employing these common-sense approaches Louisiana physicians can approach pain management prescribing with more assurance and confidence. PMID- 21294489 TI - Factors associated with hospital length of stay among HIV-infected adults in Louisiana. AB - This retrospective study aimed to evaluate the effect of predisposing (demographic), enabling (organizational), and illness (health status) factors on human immunodeficiency virus (HIV)/acquired immunodeficiency virus (AIDS)-related hospital length of stay (LOS). Inpatient hospital visit record data from 1998 through 2003 was abstracted from the Louisiana Hospital Inpatient Discharge Database. We hypothesized that enabling, not predisposing or illness factors, influenced hospital LOS among HIV-infected persons in Louisiana. Analyses were performed for the six-year period and then repeated for each year of admission. Aggregate multivariable analysis revealed that the LOS for rural residents was more than one-third longer than for urban residents (p = 0.025). This effect was consistent for each year of analysis, although it failed to reach statistical significance after adjusting for other covariates. Subjects' gender and age categories were found to be insignificant predictors for the LOS, controlling for other covariates in model. Other significant independent predictors of LOS in the aggregate time series model were number of comorbid conditions, number of inpatient medical procedures, presence of an AIDS defining illness, and source and type of admission; although effects of only the first two predictors were significant at each year of analysis (all p-values < .05). This study shows that neither gender nor age of HIV patients is a significant predictor of HIV-related LOS. However, the number of comorbid conditions and inpatient medical procedures are significant. PMID- 21294490 TI - Plasmacytoma in the thyroid. AB - OBJECTIVE: The paper presents a case of plasmacytoma unexpectedly found in a goiter. PATIENT MATERIAL AND METHODS: The patient presented with compressive symptoms, including dyspnea and dysphagia and had no documented prior history of multiple myeloma. Physical examination revealed thyromegaly with no specific nodule. Computerized tomographic (CT) scan of the neck and chest showed diffuse homogenous enlargement of both the thyroid lobes extending into the mediastinum. Total thyroidectomy was done because of the compressive symptoms. RESULTS: Pathology revealed evidence of fibrosis surrounding small nodules of residual follicles with massive infiltration by plasma cells. The pathologic diagnosis was plasmacytoma. CONCLUSION: Plasmacytoma should be added to the list of causes of diffuse thyromegaly. PMID- 21294491 TI - Squamous cell carcinoma of the palate presenting as Lemierre syndrome. PMID- 21294492 TI - A 63-year-old man with recurrent pulmonary infections: a case of Swyer-James Macleod syndrome. AB - Swyer-James Macleod syndrome is a rare disorder that leads to recurrent respiratory infections. The fibrosis and obstruction of the terminal and respiratory bronchioles, likely caused by respiratory infections in early childhood, prevents normal development of the alveolar bud. Organisms that have been associated with this syndrome include adenovirus, measles, bordetella pertussis, mycobacterium spp, influenza A and mycoplasma. The syndrome is an acquired cause of unilateral emphysema. The diagnosis of the syndrome can be made in infancy or early childhood, but in asymptomatic individuals can be delayed until adulthood and rarely in the elderly. Chest radiographs and computed tomographic (CT) scan can confirm the diagnosis and exclude other possibilities. A case of Swyer- James Macleod syndrome diagnosed at age 63 in a patient with recurrent respiratory infections and a history of childhood pertussis is presented. PMID- 21294493 TI - Louisiana death certificate accuracy: a concern for the public's health. AB - INTRODUCTION: The accuracy of death certificates is essential for public health prevention and research in the State of Louisiana. This article analyzes the accuracy of cause of death stated on Louisiana death certificates. METHODS: Discharge diagnoses from 2007 Louisiana Hospital Inpatient Discharge Diagnosis (LAHIDD) data were compared with the diagnoses in the cause of death section in the corresponding death certificates. RESULTS: Of the immediate causes of death, only 40.5% were considered an exact match and 17.4% did not have any type of match in the LAHIDD discharge diagnoses. For the preceding causes of death 54.0% of death certificates had no exact matches. There were only 55 (8.8%) of death certificates with no missing diagnosis. CONCLUSION: There are significant inconsistencies between the discharge diagnosis upon death and cause of death. This raises concern for public health and education is needed for physicians to improve accuracy of death certificates. PMID- 21294494 TI - Specialist services in line for cuts. PMID- 21294495 TI - Opportunities in heart surgery networks. PMID- 21294496 TI - Advocacy is a complex concept. PMID- 21294497 TI - Managing stress in a palliative care team. AB - This article describes a strategy to reduce the high levels of stress experienced by community nurses in a children's palliative care team. The development, use and effectiveness of a problem-solving team intervention are illustrated by direct quotations from the nurses themselves. PMID- 21294498 TI - Unplanned hospital admission: supporting children, young people and their families. AB - This article discusses issues relating to unplanned hospital admission which can be particularly distressing for children, families and carers. Good initial assessment can establish appropriate support from children's nurses throughout the hospital stay. Ongoing mutual understanding and clear explanations are essential, and prompt, effective pain management reduces stress. The article highlights that family-centred care, with as much family or carer involvement as possible, leads to the best outcomes. PMID- 21294499 TI - Students' experiences of managing type 1 diabetes. AB - AIM: To explore the experiences of young people managing their type 1 diabetes at college or university. METHOD: A convenience sample of 23 students, aged 17-19 years, with type 1 diabetes participated in semi-structured telephone interviews. FINDINGS: Thematic data analysis identified four main themes: balancing diabetes and further education; adverse diabetes management strategies at college or university; reduced quality of life with regard to participation in social events; and problematic transition from paediatric to adult diabetes clinics. CONCLUSION: Young people often face difficulties in their diabetes self management at college or university because of psychosocial issues, and may experience barriers when changing from paediatric to adult diabetes clinics. PMID- 21294500 TI - An epidemiological study of Henoch-Schonlein purpura. AB - AIM: To describe the incidence of hospital admission among children in the Scottish population for Henoch-Schonlein purpura (HSP). METHOD: The annual, quarterly and monthly incidences of HSP were derived from routinely collected data for Scotland from 1995 to 2007. RESULTS: Annual incidences of childhood cases of HSP in Scotland ranged from 20.3 to 26.7 per 100,000 of the child population over 1995-2007. Quarterly rates were highest in winter and lowest in summer. Monthly rates were highest in the months between December and March and consistently low in July and August. CONCLUSION: The annual incidence of childhood HSP in Scotland appears high compared with rates reported in other countries, and the results demonstrate a seasonal pattern. Health professionals should be aware of the symptoms, and of the best treatments and care available. Further research is needed to gain a better understanding of this disease, as the aetiology remains unknown and there are no clear evidence-based treatments or interventions. PMID- 21294501 TI - Antimicrobial resistance of Acinetobacter baumannii: six years of National Antimicrobial Resistance Surveillance Thailand (NARST) surveillance. AB - OBJECTIVE: To determine the prevalence, clinical epidemiology, and antimicrobial susceptibilities of Acinetobacter baumannii in Thailand from 2000 to 2005. MATERIAL AND METHOD: Twenty-eight hospitals participated in the National Antimicrobial Resistance Surveillance Thailand program. All data were reviewed and analyzed for the prevalence, clinical epidemiology, and antimicrobial susceptibilities of the clinical isolates of A. baumannii from 2000 to 2005. RESULTS: The number of clinical isolates of Acinetobacter spp. increased from 8,699 isolates in 2000 to 14,071 isolates in 2005. The most common species, identified by biochemical and growth characteristics, was A. baumannii. More than 50% of all isolates were from the respiratory tract specimens. The percentage of resistance has been increasing, particularly multi-drug-resistant (MDR) or carbapenem-resistant phenotypes. Of carbapenem-resistant strains, the prevalence was 2.1% and 46.7% in 2000 and 2005, respectively. Most carbapenem-resistant strains were also MDR. The prevalence of MDR strains was highest in the Central region and Bangkok. Cefoperazone/sulbactam was the antimicrobial against largest proportion Acinetobacter spp., although the prevalence of resistance to this agent is on the upward trend. CONCLUSION: A standardized technique to identify the organisms to the species level should be determined to be used in the surveillance system. Because the prevalence of Acinetobacter spp. resistant to multiple classes of antimicrobials including carbapenems and cefoperazone/sulbactam are increasing, there is an urgent need for a more active surveillance system, more stringent infection control efforts, and powerful antimicrobial stewardship programs in all healthcare sectors to minimize the further spread of this MDR strain. PMID- 21294502 TI - Long-term study of Escherichia coli and Klebsiella pneumoniae isolates producing extended-spectrum beta-lactamases. AB - OBJECTIVE: To evaluate the prevalence and susceptibility pattern of Escherichia coli and Klebsiella pneumoniae isolates producing extended-spectrum beta lactamases (ESBLs) in Thailand from 2000 to 2005. MATERIAL AND METHOD: Data on the WHONET, from 28 hospitals participated in the National Antimicrobial Resistance Surveillance, Thailand surveillance program, were reviewed and analyzed for the prevalence and susceptibility pattern. RESULTS: During the five year surveillance from 2000 to 2005, the prevalence of ESBL-producing E. coli detected by ceftazidime screening test was 17%, 21.3%, 23.2%, 20.4%, 23.1%, and 25.0%; as well as detected by cefotaxime screening test was 20.8%, 65.9%, 69.3%, 69.3%, 68.3%, and 33.8%, respectively. The prevalence of ESBL-producing K. pneumoniae detected by ceftazidime screening test was 30.9%, 34.7%, 32.5%, 34.4%, 372%, and 39.2%; as well as detected by cefotaxime screening test 38.4%, 39.3%, 40.1%, 41.0%, 42.8%, and 40.4%, respectively. CONCLUSION: From 2000 to 2005, the prevalence of ESBL-producing organisms in Thailand was high. ESBL-producing E. coli was most commonly isolated from sputum, followed by blood and urine specimens. ESBL-producing K. pneumoniae had not been increasingly isolated from sputum, blood and urine. PMID- 21294503 TI - Antimicrobial resistance surveillance of Vibrio cholerae in Thailand from 2000 to 2004. AB - OBJECTIVE: To study the trends of antimicrobial resistance pattern of Vibrio cholerae in Thailand between 2000 and 2004. MATERIAL AND METHOD: All isolates of Vibrio cholerae from 28 hospitals across Thailand between 2000 and 2004 were tested for their susceptibility to ampicillin, chloramphenicol, norfloxacin, tetracycline and trimethoprim/sulfamethoxazole by the disk diffusion method (Kirby Bauer). The relevant data were collected and analyzed by the WHONET software program supported by the World Health Organization (WHO). RESULTS: V. cholerae O1, serotype Inaba was much more common than serotype Ogawa. The most frequent type of clinical specimens that V. cholerae isolated was the stool. There was no trend of increasing resistance of all V. cholerae both O1 and non O1. Over all average rates of tetracycline resistance of V. cholerae O1, Inaba and Ogawa were 0.9% and 16.3% respectively and trimethoprim/sulfamethoxazole resistance were 0.4% and 60.5% respectively. The strains were not resistant to norfloxacin. CONCLUSION: In Thailand, V. cholerae O1 were still susceptible to tetracycline and norfloxacin which were the most frequently antimicrobial used for the treatment of cholera. The trend of increasing resistance during the study period was not detected. PMID- 21294504 TI - An overview of antimicrobial susceptibility patterns of gram-positive bacteria from National Antimicrobial Resistance Surveillance Thailand (NARST) program from 2000 to 2005. AB - In this overview, the authors summarize the antimicrobial susceptibility patterns of important Gram-positive bacteria from the National Antimicrobial Resistance Surveillance Thailand (NARST) program between 2000 and 2005 as well as the clinical implications. This collaborative network program was funded by the World Health Organization, and involved 33 hospitals throughout Thailand. There are rising trends of drug-resistant S. pneumoniae (DRSP), ampicillin-resistant enterococci, but a constant occurrence of methicillin-resistant S. aureus (MRSA) was noted during this period. The rates of penicillin and erythromycin resistances of S. pneumoniae were constantly high, ranging from 42.5% to 47.7% and 24.6% to 31.1%, respectively, whereas the rates of cefotaxime resistance were quite low, ranging from 2.1% to 8.4%. The rates of multidrug-resistant (MDR) S. pneumoniae ranged from 14.8% to 34.3%. Of all S. aureus isolates, MRSA comprised 24% to 27%, and vancomycin resistance rates of these MRSA isolates ranged from 0.1% to 0.8%. The antimicrobial resistance rates of methicillin-susceptible S. aureus isolates were very low. The rates of ampicillin and high-level gentamicin resistances of E. faecium from 2000 to 2005 have been significantly increasing from 52% to 84.1%, and from 46.9% to 75%, respectively, but vancomycin resistance was stable at the rates between 0.4% and 1.9%. In conclusions, antimicrobial resistance rates of important Gram-positive bacteria have been increasing in Thailand. All local, national, and international surveillance data will help to set the strategic plan for control and treatment of these resistant organisms. Appropriate and accurate microbiological procedures regarding the collection and transportation of clinical specimens as well as the identification of these emerging resistant organisms are urgently needed, in collaboration with other concerned sectors. PMID- 21294505 TI - Nonfunctionalized polydimethyl siloxane superhydrophobic surfaces based on hydrophobic-hydrophilic interactions. AB - Superhydrophobic surfaces based on polydimethyl siloxane (PDMS) were fabricated using a 50:50 PDMS-poly(ethylene glycol) (PEG) blend. PDMS was mixed with PEG, and incomplete phase separation yielded a hierarchic structure. The phase separated mixture was annealed at a temperature close to the crystallization temperature of the PEG. The PEG crystals were formed isothermally at the PDMS/PEG interface, leading to an engineered surface with PDMS spherulites. The resulting roughness of the surface was studied by scanning electron microscopy (SEM) and atomic force microscopy (AFM). The PDMS spherulites, a few micrometers in diameter observed from SEM images, were found to have an undulated (rippled) surface with nanometer-sized features. The combination of micrometer- and nanometer-sized surface features created a fractal surface and increased the water contact angle (WCA) of PDMS more than 60 degrees , resulting in a superhydrophobic PDMS surface with WCA of >160 degrees . The active surface layer for the superhydrophobicity was approximately 100 MUm thick, illustrating that the material had bulk superhydrophobicity compared to conventional fluorocarbon or fluorinated coated rough surfaces. Theoretical analysis of the fractal surface indicates that the constructed surface has a fractal dimension of 2.5, which corresponds to the Apollonian sphere packing. PMID- 21294506 TI - Highly selective hydrogenation of phenol and derivatives over a Pd@carbon nitride catalyst in aqueous media. AB - Cyclohexanone is an important intermediate in the manufacture of polyamides in chemical industry, but direct selective hydrogenation of phenol to cyclohexanone under mild conditions is a challenge. We report here a catalyst made of Pd nanoparticles supported on a mesoporous graphitic carbon nitride, Pd@mpg C(3)N(4), which was shown to be highly active and promoted the selective formation of cyclohexanone under atmospheric pressure of hydrogen in aqueous media without additives. Conversion of 99% and a selectivity higher than 99% were achieved within 2 h at 65 degrees C. The reaction can be accelerated at higher temperature, but even at room temperature, 99% conversion and 96% selectivity could still be obtained. The generality of the Pd@mpg-C(3)N(4) catalyst for this reaction was demonstrated by selective hydrogenation of other hydroxylated aromatic compounds with similar performance. PMID- 21294507 TI - Combinatorially inducible RNA interference triggered by chemically modified oligonucleotides. AB - Chemically inducible RNA interference (RNAi) enables temporal and/or spatial control of virtually any gene, making it useful for study of gene functions, discovery of potential drug targets, and gene therapy applications. Here we describe a new inducible RNAi platform in which orthogonal chemically modified oligonucleotides are used to trigger silencing of two genes in a combinatorial manner. We developed a modular RNA architecture consisting of an oligonucleotide sensor stem-loop and an RNAi effector domain that is designed to undergo a structural shift upon addition of an oligonucleotide inducer. The induced structural change allows the RNA to be processed by the RNAi machinery, ultimately resulting in gene silencing of the target encoded by the RNAi effector module. Combinatorial regulation of multiple genes should accelerate studies of complex gene-gene interactions and screening of new drug targets. PMID- 21294508 TI - X-ray photoelectron spectroscopy for wheat powders: measurement of surface chemical composition. AB - The functional properties of wheat powders depend largely on the surface characteristics of their particles. X-ray photoelectron spectroscopy (XPS) has been considered to investigate the surface composition of wheat powders. The objective of the present study is to evaluate the ability of XPS to discriminate wheat components and to calculate the surface composition of wheat powders. First, XPS surveys for the main wheat isolated components (starch, proteins, arabinoxylans, and lipids) were determined. XPS results demonstrate that it is able to distinguish wheat proteins, polysaccharides, and lipids, but it is not able to distinguish starch and arabinoxylan because of their similarity in chemical structure. The XPS analyses of simple reconstituted wheat flours based on two components (starch and protein) or three components (by adding arabinoxylan) demonstrated the ability of XPS to measure the surface composition of the wheat flours. The surface composition of native wheat flour demonstrated an overrepresentation of protein (54%) and lipids (44%) and an underrepresentation of starch (2%) compared to the bulk composition. Results are discussed with regard to difficulties in discriminating arabinoxylans and starch components. PMID- 21294509 TI - Identification of the Solanum nigrum extract component involved in controlling cabbage black leaf spot disease. AB - In this study, we discovered that an ethanol (EtOH) extract of Solanum nigrum inhibited spore germination of Alternaria brassicicola, the causative agent of cabbage black leaf spot disease. At a concentration of 500 mg/L, this ethanol extract also caused the germ tubes to become completely swollen. Detached cabbage leaves were then used to evaluate the effects of the extract in controlling the disease. It was observed that the extract-induced swelling of A. brassicicola germ-tube spores did not cause the symptoms of black spot disease on cabbage leaves. Furthermore, an n-butanol fraction of the EtOH extract exhibited strong antifungal activity; at a concentration of 25 mg/L, a derived subfraction (Bu-11 13) showed complete inhibition of spore germination. A white powder was collected from fraction Bu-11-13, and its minimum inhibitory concentration was determined to be 8 mg/L. Using NMR and LC-MS/MS analysis, this white powder compound was identified as degalactotigonin. PMID- 21294510 TI - Extracts of Maqui ( Aristotelia chilensis ) and Murta ( Ugni molinae Turcz.): sources of antioxidant compounds and alpha-Glucosidase/alpha-Amylase inhibitors. AB - The objective of this work was to evaluate the antioxidant and antihemolytic activities of crude, aqueous, and organic-aqueous extracts of maqui ( Aristotelia chilensis ) and murta ( Ugni molinae Turcz.), together with their inhibiting effect on enzymes involved in the metabolism of carbohydrates. Radical scavenging activity, inhibition of linoleic acid oxidation in a micellar system, antihemolytic activity, and inhibition of alpha-amylases and alpha-glucosidases were analyzed. Crude extracts of maqui leaves and fruits were found to be important sources of polyphenolic compounds, showing 69.0 +/- 0.9 and 45.7 +/- 1.1 mg GAE/g dm, respectively. Polyphenols from maqui leaves were active as antioxidants and antihemolytic compounds (p < 0.05), showing a noncompetitive inhibiting effect on alpha-glucosidase. Flavan-3-ol polymers and glycosylated flavonols, such as quercetin glucoside and kaempferol glucoside, were tentatively identified in extracts. This preliminary observation provides the basis for further examination of the suitability of polyphenol-enriched extracts from maqui and murta as nutritional or medicinal supplements with potential human health benefits. PMID- 21294511 TI - Poly(perfluoroalkylation) of metallic nitride fullerenes reveals addition-pattern guidelines: synthesis and characterization of a family of Sc3N@C80(CF3)n (n = 2 16) and their radical anions. AB - A family of highly stable (poly)perfluoroalkylated metallic nitride cluster fullerenes was prepared in high-temperature reactions and characterized by spectroscopic (MS, (19)F NMR, UV-vis/NIR, ESR), structural and electrochemical methods. For two new compounds, Sc(3)N@C(80)(CF(3))(10) and Sc(3)N@C(80)(CF(3))(12,) single crystal X-ray structures are determined. Addition pattern guidelines for endohedral fullerene derivatives with bulky functional groups are formulated as a result of experimental ((19)F NMR spectroscopy and single crystal X-ray diffraction) studies and exhaustive quantum chemical calculations of the structures of Sc(3)N@C(80)(CF(3))(n) (n = 2-16). Electrochemical studies revealed that Sc(3)N@C(80)(CF(3))(n) derivatives are easier to reduce than Sc(3)N@C(80), the shift of E(1/2) potentials ranging from +0.11 V (n = 2) to +0.42 V (n = 10). Stable radical anions of Sc(3)N@C(80)(CF(3))(n) were generated in solution and characterized by ESR spectroscopy, revealing their (45)Sc hyperfine structure. Facile further functionalizations via cycloadditions or radical additions were achieved for trifluoromethylated Sc(3)N@C(80) making them attractive versatile platforms for the design of molecular and supramolecular materials of fundamental and practical importance. PMID- 21294512 TI - Vanadate inhibition of fungal PhyA and bacterial AppA2 histidine acid phosphatases. AB - The fungal PhyA protein, which was first identified as an acid optimum phosphomonoesterase (EC 3.1.3.8), could also serve as a vanadate haloperoxidase (EC 1.11.1.10) provided the acid phosphatase activity is shut down by vanadate. To understand how vanadate inhibits both phytate and pNPP degrading activities of fungal PhyA phytase and bacterial AppA2 phytase, kinetic experiments were performed in the presence and absence of orthovanadate and metavanadate under various acidic pHs. Orthovanadate was found to be a potent inhibitor at pH 2.5 to 3.0. A 50% activity of fungal phytase was inhibited at 0.56 MUM by orthovanadate. However, metavanadate preferentially inhibited the bacterial AppA2 phytase (50% inhibition at 8 MUM) over the fungal phytase (50% inhibition at 40 MUM). While in bacterial phytase the K(m) was not affected by ortho- or metavanadate, the V(max) was reduced. In fungal phytase, both the K(m) and V(max) was lowered. The vanadate exists as an anion at pH 3.0 and possibly binds to the active center of phytases that has a cluster of positively charged Arg, Lys, and His residues below the enzymes' isoelectric point (pI). The active site fold of haloperoxidase was shown to be very similar to fungal phytase. The vanadate anions binding to cationic residues in the active site at acidic pH thus serve as a molecular switch to turn off phytase activity while turning on the haloperoxidase activity. The fungal PhyA phytase's active site housing two distinct reactive centers, one for phosphomonoesterase and the other for haloperoxidase, is a unique example of how one protein could catalyze two dissimilar reactions controlled by vanadate. PMID- 21294513 TI - Development and applications of fluorogenic probes for mercury(II) based on vinyl ether oxymercuration. AB - Mercury is a major threat to the environment and to human health. It is highly desirable to develop a user-friendly kit for on-site mercury detection. Such a method must be able to detect mercury below the threshold levels for drinking water, 1-2 ppb. We developed a fluorescence method based on the oxymercuration of vinyl ethers to detect mercury in dental and environmental samples. Chloride ions interfered with the oxymercuration reaction, but the addition of AgNO(3) solved this problem. Fine electronic and structural tuning led to the development of a more responsive probe that was less sensitive to chloride ion interference. This second-generation probe could detect 1 ppb mercury ions in water. PMID- 21294514 TI - Enhanced reliability of avian influenza virus (AIV) and Newcastle disease virus (NDV) identification using matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS). AB - In-solution enzymatic and nonenzymatic digestion methods have been successfully implemented in matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS)-based virus identification, extending to typing/subtyping of deadly influenza viruses. However, these methods are inefficient in obtaining more precise information on surface proteins of myxovirus particles, not only the hemagglutinin and neuraminidase of influenza virus but also the hemagglutinin neuraminidase of Newcastle disease virus (NDV). Imbalances in viral protein composition cause ion suppression of tryptic fragments from low-abundant target proteins (surface proteins), adversely affecting reproducibility of mass spectra. Additionally, the coexistence of tryptic peptides from several proteins requires sophisticated statistical solutions for precise result interpretations. To circumvent these, we apply detergent-based (gel-free) partitioning of whole viruses into soluble surface proteins and insoluble virus materials, using differential centrifugation. MALDI-TOF or MALDI-TOF/TOF MS was applied to analyze tryptic peptides from separated viral proteins. In this study, we achieved type/subtype of avian influenza virus (AIV) within 5 h, based on 4 major proteins, by significantly reducing ion suppression and signal overlap from various protein sources. Hence, our approach can both yield dependable results and allow Web-based search engines to be directly employed, obviating the need for additional statistical strategy. Additionally, we demonstrate the utility of the method using NDV. PMID- 21294515 TI - On-chip drop-to-drop liquid microextraction coupled with real-time concentration monitoring technique. AB - This paper demonstrates a novel drop-to-drop liquid-liquid micro-extraction (DTD LLME) device, which is based on an electrowetting on dielectric (EWOD) digital microfluidic chip. Droplets of two immiscible liquids, one of which is an ionic liquid, are formed in nanoliter volumes, driven along electrodes, merged and mixed for extraction, and finally separated upon the completion of the extraction process. All the steps are carried out on a microfluidic chip using combined electrowetting and dielectrophoretic forces, which act on the droplet upon the application of electric potential. Specially, the phase separation of two immiscible nanoliter-scale liquid drops was achieved for the first time on an EWOD digital microfluidic chip. To study the on-chip extraction kinetics, an image-based concentration measurement technique with suitable color parameters was studied and compared with the typical UV absorption based technique. Finally, the effect of applied ac voltage frequency on the extraction kinetics was studied. The observations on DTD-LLME, particularly phase separation, are discussed. The image-based method was found to be applicable for precise concentration measurements with the right choice of the color parameter. Results from experiments on finding the frequency dependence on extraction kinetics demonstrate that the application of higher frequencies can be a factor in accelerating the extraction on the proposed microextraction device. PMID- 21294516 TI - Glassy nature of water in an ultraconfining disordered material: the case of calcium-silicate-hydrate. AB - We present the structural and dynamic nature of water ultraconfined in the quasi two-dimensional nanopores of the highly disordered calcium-silicate-hydrate (C-S H), the major binding phase in cement. Our approach is based on classical molecular simulations. We demonstrate that the C-S-H nanopore space is hydrophilic, particularly because of the nonbridging oxygen atoms on the disordered silicate chains which serve as hydrogen-bond acceptor sites, directionally orienting the hydrogen atoms of the interfacial water molecules toward the calcium-silicate layers. The water in this interlayer space adopts a unique multirange structure: a distorted tetrahedral coordination at short range up to 2.7 A, a disordered structure similar to that of dense fluids and supercooled phases at intermediate range up to 4.2 A, and persisting spatial correlations through dipole-dipole interactions up to 10 A. A three-stage dynamics governs the mean square displacement (MSD) of water molecules, with a clear cage stage characteristic of the dynamics in supercooled liquids and glasses, consistent with its intermediate-range structure identified here. At the intermediate time scales corresponding to the beta-relaxation of glassy materials, coincident with the cage stage in MSD, the non-Gaussian parameter indicates a significant heterogeneity in the translational dynamics. This dynamic heterogeneity is induced primarily because of the heterogeneity in the distribution of hydrogen bond strengths. The strongly attractive interactions of water molecules with the calcium silicate walls serve to constrain their motion. Our findings have important implications on describing the cohesion and mechanical behavior of cement from its setting to its aging. PMID- 21294517 TI - Polyimide aerogels cross-linked through amine functionalized polyoligomeric silsesquioxane. AB - We report the first synthesis of polyimide aerogels cross-linked through a polyhedral oligomeric silsesquioxane, octa(aminophenyl)silsesquioxane (OAPS). Gels formed from polyamic acid solutions of 3,3',4,4'-biphenyltetracarboxylic dianhydride (BPDA), bisaniline-p-xylidene (BAX) and OAPS were chemically imidized and dried using supercritical CO(2) extraction to give aerogels having density around 0.1 g/cm(3). The aerogels are greater than 90 % porous, have high surface areas (230 to 280 m(2)/g) and low thermal conductivity (14 mW/m-K at room temperature). Notably, the polyimide aerogels cross-linked with OAPS have higher modulus than polymer reinforced silica aerogels of similar density and can be fabricated as both monoliths and thin films. Thin films of the aerogel are flexible and foldable making them an ideal insulation for space suits, and inflatable structures for habitats or decelerators for planetary re-entry, as well as more down to earth applications. PMID- 21294518 TI - Investigating the arenyl-diene double [3 + 2] photocycloaddition reaction. AB - The double [3 + 2] photocycloaddition reaction involving arenyl-dienes has been used to assemble seven separate [5.5.5.5] fenestrane structures that include ether and aza variants. The primary photolysis step was a meta photocycloaddition reaction, while a secondary photocycloaddition step formed the fenestrane structure. Investigations involving the insertion of an additional methylene group into the basic arenyl-diene skeleton failed to afford the desired [5.5.5.6] fenestrane structure. The presence of an oxime moiety in the aromatic photosubstrate allowed the primary photolysis step to take place; however, an attempted secondary photocycloaddition reaction involving the oxime did not provide the intended polyheterocyclic fenestrane. An alternative strategy to form various "criss-cross" double meta photocycloadducts was investigated and led to the discovery of a Paterno-Buchi cycloaddition reaction between acetone and an angular meta photocycloadduct. Other novel thermally and photochemically mediated skeletal rearrangement reactions were also recorded. PMID- 21294519 TI - Chiral epoxides via borane reduction of 2-haloketones catalyzed by spiroborate ester: application to the synthesis of optically pure 1,2-hydroxy ethers and 1,2 azido alcohols. AB - An enantioselective borane-mediated reduction of a variety of 2-haloketones with 10% spiroaminoborate ester 1 as catalyst is described. By a simple basic workup of 2-halohydrins, optically active epoxides are obtained in high yield and with excellent enantiopurity (up to 99% ee). Ring-opening of oxiranes with phenoxides or sodium azide is investigated under different reaction conditions affording nonracemic 1,2-hydroxy ethers and 1,2-azido alcohols with excellent enantioselectivity (99% ee) and in good to high chemical yield. PMID- 21294520 TI - Addition of a thallium vertex to empty and centered nine-atom deltahedral zintl ions of germanium and tin. AB - Nickel atoms were inserted into nine-atom deltahedral Zintl ions of E(9)(4-) (E = Ge, Sn) via reactions with Ni(cod)(2) (cod = cyclooctadiene), and [Ni@Sn(9)](3-) was structurally characterized. Both the empty and the Ni-centered clusters react with TlCp (Cp = cyclopentadienyl anion) and add a thallium vertex to form the deltahedral ten-atom closo-species [E(9)Tl](3-) and [Ni@E(9)Tl](3-), respectively. The structures of [Ge(9)Tl](3-) and [Ni@Sn(9)Tl](3-) showed that, as expected, the geometry of the ten-atom clusters is that of a bicapped square antiprism where the Tl-atom occupies one of the two capping vertices. This illustrates that centering a nine-atom cluster with a nickel atom does not change its reactivity toward TlCp. All compounds were characterized by electrospray mass spectrometry. PMID- 21294521 TI - Optically active mixed (phthalocyaninato)(porphyrinato) rare earth triple-decker complexes. Synthesis, spectroscopy, and effective chiral information transfer. AB - With the view to creating novel sandwich-type tetrapyrrole rare earth complexes toward potential applications in material science and chiral catalysis, two new optically active mixed (phthalocyaninato)(porphyrinato) rare earth triple-decker complexes with both (R)- and (S)-enantiomers [M(2)(Pc)(2)(TCBP)] {TCBP = Meso tetrakis [3,4-(11,12:13,14-di(1',2'-naphtho)-1,4,7,10,15,18-hexaoxacycloeicosa 2,11,13-triene)-phenyl] porphyrinate; M = Eu (1), Y (2)} have been designed and prepared by treating optically active metal free porphyrin (R)-/(S)-H(2)TCBP with M(Pc)(2) in the presence of corresponding M(acac)(3).nH(2)O (acac = acetylacetonate) in refluxing 1,2,4-trichlorobenzene (TCB). These novel mixed ring rare earth triple-decker compounds were characterized by a wide range of spectroscopic methods including MS, (1)H NMR, IR, electronic absorption, and magnetic circular-dichroism (MCD) spectroscopic measurements in addition to elemental analysis. Perfect mirror image relationship was observed in the Soret and Q absorption regions in the circular-dichroism (CD) spectra of the (R)- and (S)-enantiomers, indicating the optically active nature of these two mixed (phthalocyaninato)(porphyrinato) rare earth triple-decker complexes. This result reveals the effective chiral information transfer from the peripheral chiral binaphthyl units to the porphyrin and phthalocyanine chromophores in the triple decker molecule because of the intense pi-pi interaction between porphyrin and phthalocyanine rings. In addition, their electrochemical properties have also been investigated by cyclic voltammetry (CV). PMID- 21294522 TI - High, size-dependent quality factor in an array of graphene mechanical resonators. AB - Graphene's unparalleled strength, stiffness, and low mass per unit area make it an ideal material for nanomechanical resonators, but its relatively low quality factor is an important drawback that has been difficult to overcome. Here, we use a simple procedure to fabricate circular mechanical resonators of various diameters from graphene grown by chemical vapor deposition. In addition to highly reproducible resonance frequencies and mode shapes, we observe a striking improvement of the membrane quality factor with increasing size. At room temperature, we observe quality factors as high as 2400 +/- 300 for a resonator 22.5 MUm in diameter, about an order of magnitude greater than previously observed quality factors for monolayer graphene. Measurements of quality factor as a function of modal frequency reveal little dependence of Q on frequency. These measurements shed light on the mechanisms behind dissipation in monolayer graphene resonators and demonstrate that the quality factor of graphene resonators relative to their thickness is among the highest of any mechanical resonator demonstrated to date. PMID- 21294523 TI - Two stage magnetic ordering and spin idle behavior of the coordination polymer Co3(OH)2(C4O4)2.3H2O determined using neutron diffraction. AB - We report the magnetic structure of two of the magnetically ordered phases of Co(3)(OH)(2)(C(4)O(4))(2).3H(2)O, a coordination polymer that consists of a triangular framework decorated with anisotropic Co(II) ions. The combination of neutron diffraction experiments and magnetic susceptibility data allows us to identify one phase as displaying spin idle behavior, where only a fraction of the moments order at intermediate temperatures, while at the lowest temperatures the system orders fully. This novel magnetic behavior is discussed within the framework of a simple Hamiltonian and representational analysis and rationalizes this multiphase behavior by considering the combination of frustration and anisotropy. PMID- 21294524 TI - Breakdown of atomic-sized metallic contacts measured on nanosecond scale. AB - We report on a study of atomic-sized metallic contacts on a time scale of nanoseconds using a combined DC and AC circuit. The approach leads to a time resolution 3-4 orders of magnitude faster than the measurements carried out to date, making it possible to observe fast transient conductance-switching events associated with the breakdown, re-formation, and atomic scale structural rearrangements of the contact. The study bridges the wide gap in the time scales between the molecular dynamic simulations and real world experiments, and the method may be applied to study nano- and subnanosecond processes in other nanoscale devices, such as molecular junctions. PMID- 21294525 TI - Structural model for dry-drawing of sheets and yarns from carbon nanotube forests. AB - A structural model is developed for describing the solid-state transformation of a vertically oriented carbon multiwall nanotube (MWNT) forest to a horizontally oriented MWNT sheet or yarn. The key element of our model is a network of individual carbon nanotubes or small bundles interconnecting the array of main large-diameter MWNT bundles of the forest. The dry-draw self-assembly mechanism for MWNT sheet formation involves two principal processes that reconfigure the interconnection network: (1) unzipping by preferentially peeling off interconnections between the bundles in the forest and (2) self-strengthening of these interconnections by densification at the top and bottom of the forest during draw-induced reorientation of the bundles. It is shown that interconnection density is a key parameter that determines the ability of a MWNT forest to be dry-drawable into sheets and yarns. This model describes the principal mechanism of solid-state draw (confirmed by dynamic in situ scanning electron microscopy), the range of forest structural parameters that enable sheet draw, and observed dependencies of sheet properties on the parent MWNT forest structure. PMID- 21294526 TI - Interaction of mesoporous silica nanoparticles with human red blood cell membranes: size and surface effects. AB - The interactions of mesoporous silica nanoparticles (MSNs) of different particle sizes and surface properties with human red blood cell (RBC) membranes were investigated by membrane filtration, flow cytometry, and various microscopic techniques. Small MCM-41-type MSNs (~100 nm) were found to adsorb to the surface of RBCs without disturbing the membrane or morphology. In contrast, adsorption of large SBA-15-type MSNs (~600 nm) to RBCs induced a strong local membrane deformation leading to spiculation of RBCs, internalization of the particles, and eventual hemolysis. In addition, the relationship between the degree of MSN surface functionalization and the degree of its interaction with RBC, as well as the effect of RBC-MSN interaction on cellular deformability, were investigated. The results presented here provide a better understanding of the mechanisms of RBC-MSN interaction and the hemolytic activity of MSNs and will assist in the rational design of hemocompatible MSNs for intravenous drug delivery and in vivo imaging. PMID- 21294527 TI - Three-component strategy toward 5-membered heterocycles from isocyanide dibromides. AB - A three-component strategy starting from isocyanides allows a straightforward synthesis of five-membered ring heterocycles. New cascades were developed involving the addition of a nitrogenated nucleophile-an azide or a tetrazole-on isocyanide dibromides, an electrocyclization, and a Suzuki coupling, which afford new accesses to tetrazole and triazole scaffolds. PMID- 21294528 TI - Investigation of the stereochemistry of intermolecular conjugate additions of nucleophiles to acyclic nitrosoalkenes. AB - Michael-type conjugate additions of gamma-chiral aldehyde-derived acyclic nitrosoalkenes have been explored using a series of carbon and hetero nucleophiles. In all cases examined, these reactions are stereoselective, leading exclusively to the anti products. PMID- 21294529 TI - Enantioselective hydrocyanation of aldehydes catalyzed by [Li{Ru(phgly)2(binap)}]X (X = Cl, Br). AB - Novel bimetallic complexes [Li{Ru[(S)-phgly](2)[(S)-binap]}]X (X = Cl, Br) are readily synthesized by mixing Ru[(S)-phgly](2)[(S)-binap] and LiX. A single crystal X-ray analysis reveals the structure. These bimetallic complexes efficiently catalyze asymmetric hydrocyanation of aldehydes with a substrate-to catalyst molar ratio of 500-2000 at -78 to -60 degrees C. A range of aromatic, heteroaromatic, and alpha,beta-unsaturated aldehydes as well as a tert-alkyl aldehyde is converted to the cyanohydrins in high enantiomeric excess (up to 99%). PMID- 21294530 TI - Cross-coupling of mesylated phenol derivatives with potassium ammonio- and amidomethyltrifluoroborates. AB - A large array of aryl and heteroaryl mesylates have been successfully employed as electrophiles in a Csp(2)-Csp(3) Suzuki-Miyaura cross-coupling with potassium ammonio- and amidomethyltrifluoroborates to afford the corresponding products in high yields. PMID- 21294531 TI - Fluorescence and electroluminescence quenching evidence of interfacial charge transfer in poly (3-hexylthiophene): graphene oxide bulk heterojunction photovoltaic devices. AB - We present electrochemical studies of graphene oxide (GO) nanosheets and demonstrate the fluorescence and electrogenerated chemiluminescence quenching capability of GO nanosheets that are transferred into chloroform from aqueous solution utilizing a novel, surfactant-assisted method. Electrochemical studies indicate that GO can be reduced upon charge injection. Fluorescence quenching of the conjugate polymer poly (3-hexylthiophene) (P3HT) in both solution and solid films is demonstrated to show that GO can be used as an electron acceptor in a bulk heterojunction organic photovoltaic (OPV) device. OPV devices were then fabricated with an ITO/PEDOT:PSS/P3HT-GO/Al structure. Devices containing GO exhibited an increase in short-circuit current (I(sc)) and conductivity but a decrease in open circuit potential (V(oc)). These results display the potential for nonorganically functionalized GO to be used as an acceptor material in future OPV devices. The results also indicate that GO can increase the conductivity of the nanocomposite film so that charge recombination is an issue in such a device. The increased conductivity and fluorescence quenching are also supported by electrogenerated chemiluminescence (ECL) of P3HT/GO composite films. PMID- 21294532 TI - POCl3 chlorination of 4-quinazolones. AB - The reaction of quinazolones with POCl(3) to form the corresponding chloroquinazolines occurs in two distinct stages, which can be separated through appropriate temperature control. An initial phosphorylation reaction occurs readily under basic conditions (R(3)N, aq pK(a) > 9) at t < 25 degrees C to give a variety of phosphorylated intermediates. Pseudodimer formation, arising from reaction between phosphorylated intermediates and unreacted quinazolone, is completely suppressed at these temperatures, provided the system remains basic throughout the POCl(3)addition. Clean turnover of phosphorylated quinazolones to the corresponding chloroquinazoline is then achieved by heating to 70-90 degrees C. (N)- and (O)-phosphorylated intermediates, involving multiple substitution at phosphorus, have been identified and their reactions monitored using a combination of (1)H, (31)P, and (19)F NMR. Kinetic analysis of the reaction profiles suggest that the various intermediates react with both Cl(-) and Cl(2)P(O)O(-), but product formation arises exclusively from reaction of (O) phosphorylated intermediates with Cl(-). (O)- and (N)-phosphorylated intermediates equilibrate rapidly on the time scale of the reaction. A minimum of 1 molar equiv of POCl(3) is required for efficient conversion of the intermediates to product. PMID- 21294533 TI - Fluoride-induced cyclization of pentacenequinone to higher quinones. AB - Novel pentacenequinone derivatives 3, 7, and 10 have been synthesized via Suzuki Miyaura coupling. Derivatives 3 and 7 having OTBS groups undergo irreversible fluoride-induced cyclization to substituted higher quinones in the presence of TBAF in dry THF using one-pot, two-step strategies in moderate yields. These functionalized higher quinone derivatives are freely soluble in THF and DMSO and can be used as precursors for the synthesis of higher acene derivatives. PMID- 21294534 TI - Characterization and liquid chromatography-MS/MS based quantification of hydroxylated fullerenes. AB - Highly water-soluble hydroxylated fullerene derivatives are being investigated for a wide range of commercial products as well as for potential cytotoxicity. However, no analytical methods are currently available for their quantification at sub-ppm concentrations in environmental matrixes. Here, we report on the development and comparison of liquid chromatography-ultraviolet/visible spectroscopy (LC-UV/vis) and liquid chromatography-mass spectrometry (LC-MS) based detection and quantification methods for commercial fullerols. We achieved good separation efficiency using an amide-type hydrophilic interaction liquid chromatography (HILIC) column (plate number >2000) under isocratic conditions with 90% acetonitrile as the mobile phase. The method detection limits (MDLs) ranged from 42.8 ng/mL (UV detection) to 0.19 pg/mL (using MS with multiple reaction monitoring, MRM). Other MS measurement modes achieved MDLs of 125 pg/mL (single quad scan, Q1) and 1.5 pg/mL (multiple ion monitoring, MI). Each detection method exhibited a good linear response over several orders of magnitude. Moreover, we tested the robustness of these methods in the presence of Suvanee River fulvic acids (SRFA) as an example of organic matter commonly found in environmental water samples. While SRFA significantly interfered with UV- and Q1-based quantifications, the interference was relatively low using MI or MRM (relative error in presence of SRFA: 8.6% and 2.5%, respectively). This first report of a robust MS-based quantification method for modified fullerenes dissolved in water suggests the feasibility of implementing MS techniques more broadly for identification and quantification of fullerols and other water soluble fullerene derivatives in environmental samples. PMID- 21294535 TI - Luminescence-based spectroelectrochemical sensor for [Tc(dmpe)3]2+/+ (dmpe = 1,2 bis(dimethylphosphino)ethane) within a charge-selective polymer film. AB - A spectroelectrochemical sensor consisting of an indium tin oxide (ITO) optically transparent electrode (OTE) coated with a thin film of partially sulfonated polystyrene-blockpoly(ethylene-ran-butylene)-block-polystyrene (SSEBS) was developed for [Tc(dmpe)(3)](+) (dmpe = 1,2-bis(dimethylphosphino)ethane). [Tc(dmpe)(3)](+) was preconcentrated by ion-exchange into the SSEBS film after a 20 min exposure to aqueous [Tc(dmpe)(3)](+) solution, resulting in a 14-fold increase in cathodic peak current compared to a bare OTE. Colorless [Tc(dmpe)(3)](+) was reversibly oxidized to colored [Tc(dmpe)(3)](2+) by cyclic voltammetry. Detection of [Tc(dmpe)(3)](2+) was accomplished through emission spectroscopy by electrochemically oxidizing the complex from nonemissive [Tc(dmpe)(3)](+) to emissive [Tc(dmpe)(3)](2+). The working principle of the sensor consisted of electrochemically cycling between nonemissive [Tc(dmpe)(3)](+) and emissive [Tc(dmpe)(3)](2+) and monitoring the modulated emission (lambda(exc) = 532 nm; lambda(em) = 660 nm). The sensor gave a linear response over the concentration range of 0.16-340.0 MUM of [Tc(dmpe)(3)](2+/+) in aqueous phase with a detection limit of 24 nM. PMID- 21294536 TI - Spectrochemical series and the dependence of Racah and 10 Dq parameters on the metal-ligand distance: microscopic origin. AB - The origin of the spectrochemical series and the different dependence of crystal field splitting (10Dq) and Racah parameters on the metal-ligand distance, R, is explored through ab initio calculations on Cr(3+)-doped K2NaScF6, Cs2NaYCl6, Cs2NaYBr6, and Cs2NaYI6 lattices. For this purpose both periodic and cluster calculations have been performed. An analysis of ab initio results proves that 10Dq values mostly come from the small admixture of deep nLs ligand orbitals present in the antibonding eg(~ x(2)-y(2),3z(2)-r(2)) level and not from the dominant covalency with valence nLp ligand orbitals, which is actually responsible for the reduction of Racah parameters. This study thus reveals the microscopic origin of the stronger dependence upon R of 10Dq when compared to that observed for Racah parameters, thus explaining why electronic transitions which are 10Dq-independent give rise to sharp optical bands. As a salient feature, while the covalency with nLp levels increases significantly on passing from CrF6(3-) to CrI6(3-), the nLs admixture in eg is found to be practically unmodified. This fact helps to understand the progressive decrease of 10Dq through the series of CrF6(3-), CrCl6(3-), CrBr6(3-), and CrI6(3-) complexes embedded in the corresponding host lattices when compared at the corresponding equilibrium distance at zero pressure. The growing importance of the nLs admixture is well-depicted using deformation density diagrams on passing from the ground state (4)A2(t2g(3)) to the (4)T2(t2g(2)eg) excited state depicted at several R values. PMID- 21294537 TI - Low-frequency spectra of metallocenium ionic liquids studied by terahertz time domain spectroscopy. AB - Terahertz (THz) time-domain spectroscopic measurements have been done on five novel metallocenium ionic liquids based on the electro-optic sampling method. The study covered the spectral range from 10 to 85 cm(-1). The complex dielectric spectra were broad and dispersive in nature, and the imaginary part of the dielectric constant consisting of part of the dielectric constant was simulated with different combinations of model functions to unravel the intermolecular dynamics. We compared our results with the previous results on the other ionic liquid. It was revealed that the librational motion of the cations as well as the interion vibration between the cations and the anions are responsible for observed dynamics in THz region. No intramolecular vibrational mode has been found in the low-frequency region. PMID- 21294538 TI - Theoretical study of specific solvent effects on the optical and magnetic properties of copper(II) acetylacetonate. AB - Specific and basicity solvent effects on the visible near-infrared electronic transitions and the electron paramagnetic resonance (EPR) parameters of the copper(II) acetylacetonate complex, Cu(acac)2, have been investigated at the density functional theory level. The computed absorption transitions as well as the EPR parameters show a strong dependence on the direct coordination environment around the Cu(II) complex. High solvatocromic shifts are observed for 3d-3d transitions, with the highest effect observed for the dz(2)->dxy transition, which is red-shifted by 6000 cm(-1) and 9000 cm(-1) in water and pyridine solvent models, respectively. Compared to the electronic g-tensors, the hyperfine coupling constants of the Cu(acac)2 complex show a more pronounced dependence on the effect of base strength of solvent. Overall, the present methodology satisfactorily models the solvent effect on the optical and magnetic properties of the Cu(acac)2 complex, and theory and experiment agree sufficiently well to warrant the use of the computed optical and EPR parameters to elucidate the coordination environment of the Cu(II) systems in basic solutions. PMID- 21294539 TI - Introducing RGD peptides on PHBV films through PEG-containing cross-linkers to improve the biocompatibility. AB - Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), a biodegradable polyester, has been a good candidate of biomaterial employed in tissue engineering. However, the PHBV film is hydrophobic and has no recognition sites for cell attachment. In this study, PHBV films are activated by ammonia plasma treatment to produce amino groups on the surface, followed by sequential reactions with a heterobifunctional cross-linker containing a segment of poly(ethylene glycol) (PEG) and further with RGD-containing peptides. XPS analyses of modified surfaces after each reaction step reveal that the RGD-containing peptides have been covalently grafted onto PHBV films. The result of cell viability assay indicates that the RGD-modified PHBV films exhibit a distinctly improved cellular compatibility. Moreover, according to the results of serum adsorption tests by optical waveguide lightmode spectroscopy (OWLS) and fibrinogen adsorption tests by enzyme-linked immunosorbent assay (ELISA) on unmodified and modified PHBV surfaces, the introduced PEG chains can significantly decrease the nonspecific adsorption of proteins from serum and fibrinogen from plasma, thus decreasing the risk of thrombus formation and improving the blood compatibility of implanted materials. PMID- 21294540 TI - One-color reversible control of photochromic reactions in a diarylethene derivative: three-photon cyclization and two-photon cycloreversion by a near infrared femtosecond laser pulse at 1.28 MUm. AB - One-color control of colorization/decolorization reactions of diarylethene molecules was attained by using nonresonant high-order multiphoton absorption processes with a near-infrared (NIR) femtosecond laser pulse at 1.28 MUm with 35 fs full width at half-maximum (fwhm). The intensity of a rather weak laser pulse (<1 nJ/pulse) can induce the simultaneous three-photon absorption leading to the colorization, while much weaker intensity induces two-photon absorption resulting in the decolorization. The spatial patterning concomitant with higher-order multiphoton absorption processes was also demonstrated. PMID- 21294541 TI - Size-dependent Pb sorption to nanohematite in the presence and absence of a microbial siderophore. AB - This study focused on the effects of particle size (40, 8.6, and 3.6 nm) and the presence of the microbial ligand desferrioxamine B (DFOB) on Pb(II) sorption to hematite, based on sorption edge experiments (i.e., sorption as a function of pH). Effects of hematite nanoparticle size on sorption edges, when plotted either as sorption density or as % Pb uptake, depended on whether the experiments were normalized to account for differences in specific surface area within the reaction vessels or postnormalized after the fact. Accounting for specific surface area within reaction vessels is needed to maintain comparable ratios of sorbate to sorbent surface sites. When normalized for BET specific surface area (A(s,BET)) within the reaction vessels, the Pb(II) sorption edge shifted ~0.5 pH units to the left for <10 nm hematite particles, but maximum sorption density (at pH >= 6) was unaffected by particle size. DFOB had little or no effect on Pb(II) sorption to <10 nm particles, but DFOB decreased Pb(II) sorption to the 40 nm particles at pH >= 6 by ~20%. Hematite (nano)particle size thus exerts subtle effects on Pb(II) sorption, but the effects may be more pronounced in the presence of a metal complexing agent. PMID- 21294542 TI - Single-conformation ultraviolet and infrared spectra of jet-cooled monolignols: p coumaryl alcohol, coniferyl alcohol, and sinapyl alcohol. AB - Single-conformation spectroscopy of the three lignin monomers (hereafter "monolignols") p-coumaryl alcohol (pCoumA), coniferyl alcohol (ConA), and sinapyl alcohol (SinA) has been carried out on the isolated molecules cooled in a supersonic expansion. Laser-induced fluorescence excitation, dispersed fluorescence, resonant two-photon ionization, UV-UV hole-burning, and resonant ion-dip infrared spectroscopy were carried out as needed to obtain firm assignments for the observed conformers of the three molecules. In each case, two conformers were observed, differing in the relative orientations of the vinyl and OH substituents para to one another on the phenyl ring. In pCoumA, the two conformers have S(0)-S(1) origins nearly identical in size, split from one another by only 7 cm(-1), in close analogy with previous results of Morgan et al. on p-vinylphenol ( Chem. Phys. 2008 , 347 , 340 ). ConA, with its methoxy group ortho to the OH group, also has two low-energy conformers forming a syn/anti pair, in this case with the OH group locked into an orientation in which it forms an intramolecular H-bond with the adjacent methoxy group. The electronic frequency shift between the two conformers is dramatically increased to 805 cm( 1), with the dominant conformer of ConA (with S(0)-S(1) origin at 32 640 cm(-1)) about 5 times the intensity of its minor counterpart (with S(0)-S(1) origin at 33 444 cm(-1)). The presence of an OH...OCH(3) intramolecular H-bond is established by the shift of the OH stretch fundamental of the OH group to 3599 cm(-1), as it is in o-methoxyphenol ( Fujimaki et al. J. Chem. Phys. 1999 , 110 , 4238 ). Analogous single-conformation UV and IR spectra of o-methoxy-p-vinylphenol show a close similarity to ConA and provide a basis for a firm assignment of the red shifted (blue-shifted) conformer of both molecules to the syn (anti) conformer. The two observed conformers of SinA, with its two methoxy group straddling the OH group, have S(0)-S(1) origins split by 239 cm(-1) (33 055 and 33 294 cm(-1)), a value between those in pCoumA and ConA. A combination of experimental data and calculations on the three monolignols and simpler derivatives is used to establish that the conformational preferences of the monolignols reflect the preferences of each of the ring substituents separately, enhanced by the presence of the intramolecular OH...OCH(3) H-bond. Taken as a whole, the presence of multiple flexible substituents locks in certain preferred orientations of the groups relative to one another, even in the apparently flexible allyl alcohol side chain (-CH?CH-CH(2)OH), where the OH group orients itself so that the hydrogen is pointed back over the vinyl pi cloud in order to minimize interactions between the oxygen lone pairs and the pi electrons. PMID- 21294543 TI - Deep penetration of a PDT drug into tumors by noncovalent drug-gold nanoparticle conjugates. AB - Efficient drug delivery to tumors is of ever-increasing importance. Single-visit diagnosis and treatment sessions are the goal of future theranostics. In this work, a noncovalent PDT cancer drug-gold nanoparticle (Au NP) conjugate system performed a rapid drug release and deep penetration of the drug into tumors within hours. The drug delivery mechanism of the PDT drug through Au NPs into tumors by passive accumulation was investigated via fluorescence imaging, elemental analysis, and histological staining. The pharmacokinetics of the conjugates over a 7-day test period showed rapid drug excretion, as monitored via the fluorescence of the drug in urine. Moreover, the biodistribution of Au NPs in this study period indicated clearance of the NPs from the mice. This study suggests that noncovalent delivery via Au NPs provides an attractive approach for cancer drugs to penetrate deep into the center of tumors. PMID- 21294544 TI - G-quadruplex-binding benzo[a]phenoxazines down-regulate c-KIT expression in human gastric carcinoma cells. AB - There is considerable interest in the structure and function of G-quadruplex nucleic acid secondary structures, their cellular functions, and their potential as therapeutic targets. G-Quadruplex sequence motifs are prevalent in gene promoter regions and it has been hypothesized that G-quadruplex structure formation is associated with the transcriptional status of the downstream gene. Using a functional cell-based assay, we have identified two novel G-quadruplex ligands that reduce the transcription of a luciferase reporter driven from the G quadruplex-containing c-KIT promoter. We have further shown that endogenous c-KIT expression in a human gastric carcinoma cell line is also reduced on treatment with these molecules. Biophysical analysis using surface plasmon resonance has shown that these molecules preferentially bind with high affinity to one of the two G-quadruplex sequences in the c-KIT promoter over double-stranded DNA. This work highlights the utility of cell-based reporter assays to identify new G quadruplex binding molecules that modulate transcription and identifies benzo[a]phenoxazine derivatives as potential antitumor agents. PMID- 21294545 TI - Lead levels in Eurasian otters decline with time and reveal interactions between sources, prevailing weather, and stream chemistry. AB - The uptake of contaminants by biota varies spatially and temporally due to a complex range of interacting environmental variables, but such complexities are typically disregarded in studies of temporal change. Here, we use linear modeling to explore spatial and temporal variation in bone Pb levels measured in samples taken from 329 Eurasian otters (Lutra lutra) found dead in southwest England. Between 1992 and 2004 Pb levels in otters fell by 73%, following UK legislative control of Pb emissions implemented since the mid 1980s. Spatial variation in bone Pb was positively correlated with modeled Pb emissions and stream sediment Pb, which interacted negatively with wind-speed and sediment Ca, respectively. Opportunistic collection of samples from wildlife mortalities provided a valuable opportunity for monitoring environmental contamination, interpretation of which was aided by spatially explicit analysis of environmental variables. PMID- 21294546 TI - Solid-state electron transport across azurin: from a temperature-independent to a temperature-activated mechanism. AB - The temperature dependence of current-voltage values of electron transport through proteins integrated into a solid-state junction has been investigated. These measurements were performed from 80 up to 400 K [above the denaturation temperature of azurin (Az)] using Si/Az/Au junctions that we have described previously. The current across the ~3.5 nm thick Az junction was temperature independent over the complete range. In marked contrast, for both Zn-substituted and apo-Az (i.e., Cu-depleted Az), thermally activated behavior was observed. These striking temperature-dependence differences are ascribed to the pivotal function of the Cu ion as a redox center in the solid-state electron transport process. Thus, while Cu enabled temperature-independent electron transport, upon its removal the polypeptide was capable only of supporting thermally activated transport. PMID- 21294547 TI - Water-dispersible superparamagnetic microspheres adorned with two types of surface chains. AB - Water-dispersible superparamagnetic polymer/gamma-Fe(2)O(3) composite microspheres adorned with two types of surface polymer chains are prepared and characterized. To prepare these spheres, we first synthesize uniform gamma Fe(2)O(3) nanoparticles that are covered by poly(2-cinnamoyloxyethyl methacrylate)-block-poly(acrylic acid) (PCEMA-b-PAA). These nanoparticles are then mixed with a PCEMA homopolymer in CHCl(3) to form an oil phase. The oil phase is dispersed into water under vigorous stirring with the help of two diblock copolymer surfactants, PGMA-b-PCEMA and PSGMA-b-PCEMA. Here PGMA and PSGMA denote poly(glyceryl monomethacrylate) and succinated PGMA, respectively. Solid microspheres with cores composed of PCEMA and PCEMA-b-PAA-covered gamma Fe(2)O(3) nanoparticles are obtained after CHCl(3) evaporation and PCEMA photo cross-linking. Under certain conditions, the coronal PGMA and PSGMA chains become segregated, thus producing surface bumps, ridges, and valleys. The PSGMA chains preferentially cover the protruding regions. The PSGMA carboxyl groups are used to immobilize bovine serum albumin (BSA). The immobilized BSA retains its activity and binds with anti-BSA. These spheres should be useful in immunoassays. PMID- 21294548 TI - Lyme disease enolpyruvyl-UDP-GlcNAc synthase: fosfomycin-resistant MurA from Borrelia burgdorferi, a fosfomycin-sensitive mutant, and the catalytic role of the active site Asp. AB - MurAs (enolpyruvyl-UDP-GlcNAc synthases) from pathogenic bacteria such as Borrelia burgdorferi (Lyme disease) and tuberculosis are fosfomycin resistant because an Asp-for-Cys substitution prevents them from being alkylated by this epoxide antibiotic. Previous attempts to characterize naturally Asp-containing MurAs have resulted in no protein or no activity. We have expressed and characterized His-tagged Lyme disease MurA (Bb_MurA(H6)). The protein was most soluble at high salt concentrations but maximally active around physiological ionic strength. The steady-state kinetic parameters at pH 7 were k(cat) = 1.07 +/ 0.03 s(-1), K(M,PEP) = 89 +/- 12 MUM, and K(M,UDP-GlcNAc) = 45 +/- 7 MUM. Mutating the active site Asp to Cys, D116C, caused a 21-fold decrease in k(cat) and rendered the enzyme fosfomycin sensitive. The pH profile of k(cat) was bell shaped and centered around pH 5.3 for Bb_MurA(H6), with pK(a1) = 3.8 +/- 0.2 and pK(a2) = 7.4 +/- 0.2. There was little change in pK(a1) with the D116C mutant, 3.5 +/- 0.3, but pK(a2) shifted to >11. This demonstrated that the pK(a2) of 7.4 was due to D116, almost 3 pH units above an unperturbed carboxylate, and that it must be protonated for activity. This supports D116's proposed role as a general acid/base catalyst. As fosfomycin does not react with simple thiols, nor most protein thiols, the reactivity of D116C with fosfomycin, combined with the strongly perturbed pK(a2) for D116, strongly implies an unusual active site environment and a chemical role in catalysis for Asp/Cys. There is also good evidence for C115 having a role in product release. Both roles may be operative for both Asp- and Cys-containing MurAs. PMID- 21294550 TI - Preparation of Pickering emulsions and colloidosomes with relatively narrow size distributions by stirred cell membrane emulsification. AB - Stirred cell membrane emulsification has been used to prepare Pickering emulsions and covalently cross-linked colloidosomes using poly(glycerol monomethacrylate) stabilized polystyrene particles as the sole emulsifier. Pickering emulsions of 44-269 MUm in size can be prepared with coefficients of variation as low as 25%, by varying the emulsification parameters. The cell membranes consisted of 5 MUm pores with a pore-to-pore spacing of 200 MUm. Significantly more uniform emulsions are produced when these open pores are restricted to a narrow ring around the membrane surface. Increasing the oil flux rate through this annular ring membrane increases both the size and polydispersity of the resulting emulsion droplets. There was no evidence for a "push off" force contributing to droplet detachment over the oil flux range investigated. Increasing the paddle stirrer speed from 500 to 1500 rpm reduces the average droplet diameter from 269 to 51 MUm while simultaneously decreasing the coefficient of variation from 47% to 25%. Any further increase in surface shear led to droplet breakup within the dispersion cell and resulted in a significantly more polydisperse emulsion. The Pickering emulsions reported here have much narrower droplet size distributions than those prepared in control experiments by conventional homogenization (25% vs 74% coefficients of variation). Finally, low polydispersity colloidosomes can be conveniently prepared by the addition of an oil soluble polymeric cross-linker to the dispersed phase to react with the stabilizer chains. PMID- 21294549 TI - Identification of in vitro autophosphorylation sites and effects of phosphorylation on the Arabidopsis CRINKLY4 (ACR4) receptor-like kinase intracellular domain: insights into conformation, oligomerization, and activity. AB - Arabidopsis CRINKLY4 (ACR4) is a receptor-like kinase (RLK) that consists of an extracellular domain and an intracellular domain (ICD) with serine/threonine kinase activity. While genetic and cell biology experiments have demonstrated that ACR4 is important in cell fate specification and overall development of the plant, little is known about the biochemical properties of the kinase domain and the mechanisms that underlie the overall function of the receptor. To complement in planta studies of the function of ACR4, we have expressed the ICD in Escherichia coli as a soluble C-terminal fusion to the N-utilization substance A (NusA) protein, purified the recombinant protein, and characterized the enzymatic and conformational properties. The protein autophosphorylates via an intramolecular mechanism, prefers Mn(2+) over Mg(2+) as the divalent cation, and displays typical Michaelis-Menten kinetics with respect to ATP with an apparent K(m) of 6.67 +/- 2.07 MUM and a V(max) of 1.83 +/- 0.18 nmol min(-1) mg(-1). Autophosphorylation is accompanied by a conformational change as demonstrated by circular dichroism, fluorescence spectroscopy, and limited proteolysis with trypsin. Analysis by nanoliquid chromatography and mass spectrometry revealed 16 confirmed sites of phosphorylation at Ser and Thr residues. Sedimentation velocity and gel filtration experiments indicate that the ICD has a propensity to oligomerize and that this property is lost upon autophosphorylation. PMID- 21294551 TI - Identification, in vitro activity and mode of action of phosphoinositide dependent-1 kinase inhibitors as antifungal molecules. AB - Although protein kinases have recently emerged as important drug targets, the anti-infective potential of protein kinase inhibitors has not been developed extensively. We identified the mammalian PDK1 inhibitor KP-372-1 as a potent antifungal molecule with activity against yeast and fungal biofilms using a screening strategy for protein kinase inhibitors that block the cell wall stress response in yeast. Genetic and biochemical studies indicate that KP-372-1 inhibits fungal PDK1 orthologs (Pkh kinases) as part of its mode of action and support a role for Pkh kinases in eisosome assembly. Two other structurally distinct molecules that inhibit PDK1, OSU-03012 and UCN-01, also have antifungal activity. Taken together, these data indicate that fungal PDK1 orthologs are promising targets for new antifungal drug development. PMID- 21294552 TI - Monodisperse nonionic isoprenoid-type hexahydrofarnesyl ethylene oxide surfactants: high throughput lyotropic liquid crystalline phase determination. AB - The neat and lyotropic phase behavior of eight new ethylene oxide amphiphiles (EO = 1-8) with a hexahydrofarnesyl chain (3,7,11-trimethyldodecyl) and narrow polydispersity (>98.5% purity) is reported. Below five EO units the behavior of the neat surfactants show only a glass transition, Tg ~ -90 degrees C. Above four EO units, crystallization (Tcrys) and crystal-isotropic liquid (Tm) transitions are also observed that increase with degree of ethoxylation of the surfactant headgroup. The lyotropic liquid crystalline phase behavior spans a complex spectrum of surfactant-water interfacial curvatures. Specifically, inverse phases are present below ambient temperatures for EO < 4, with HFarn(EO)2 exhibiting an inverse hexagonal (H(II)) phase stable to dilution. The phase diagram of HFarn(EO)3 displays both the gyroid (Ia3d) and double diamond (Pn3m) inverse bicontinuous cubic phases, with the latter being thermodynamically stable in excess water within the physiological regime. There is a strong preference for planar bilayer structures at intermediate headgroup ethoxylation, with the crossover to normal phases occurring at HFarn(EO)(7-8) which exhibits normal hexagonal (H(I)) and cubic (Q(I)) phases at ambient temperatures. The toxicity of colloidal dispersions of these EO amphiphiles was assayed against normal breast epithelial (HMEpiC) and breast cancer (MCF7) cell lines. The IC50 of the EO amphiphiles was similar in both cell lines with moderate toxicity ranging from ca. <5 to 140 MUM in an in vitro cell viability assay. Observations are qualitatively rationalized in terms of the molecular geometry of the surfactant. The physicochemical behavior of the HFarnesyl ethylene oxide amphiphiles is compared to other ethylene oxide surfactants. PMID- 21294553 TI - Packing and sorting colloids at the contact line of a drying drop. AB - In this article, we study the drying kinetics of a sessile droplet containing latex particles. We find that a depletion film is left at the edge of the drops, whose width is controlled by two geometric parameters, the contact angle and the diameter of the particles. We show that this effect can be used to sort colloidal mixtures because nanometric colloids always segregate at the edge of the drop, whereas micrometric colloids are blocked further away from the edge. We also provide a simple method to measure the velocity of a micrometric latex as it flows toward the contact line. We find that the particles strongly accelerate at the end of the drying process. Using Deegan's prediction for the rate of evaporation in the vicinity of the contact line, we quantitatively explain this phenomenon by the fact that the contact angle vanishes at the end of the drying process, therefore inducing a strong increase in the flux of water and particles close to the edge. The decrease in the contact angle also controls the width of the ringlike deposit. PMID- 21294554 TI - Hydrogen peroxide sensing with horseradish peroxidase-modified polymer single conical nanochannels. AB - Inspired from the funtioning and responsiveness of biological ion channels, researchers attempt to develop biosensing systems based on polymer and solid state nanochannels. The applicability of these nanochannels for detection/sensing of any foreign analyte in the surrounding environment depends critically on the surface characteristics of the inner walls. Attaching recognition sites to the channel walls leads to the preparation of sensors targeted at a specific molecule. There are many nanochannel platforms for the detection of DNA and proteins, but only a few are capable of detecting small molecules. Here, we describe a nanochannel platform for the detection of hydrogen peroxide, H(2)O(2), which is not only a toxic waste product in the cellular systems but also a key player in the redox signaling pathways. The sensor is based on single conical nanochannels fabricated in an ion tracked polymer membrane. The inner walls of the channel are decorated with horseradish peroxidase (HRP) enzyme using carbodiimide coupling chemistry. The success of the HRP immobilization on the channel surface is confirmed by measuring the pH-dependent current-voltage (I-V) curves of the system. The reported HRP-nanochannel system detects nanomolar concentrations of H(2)O(2) with 2,2'-azino-bis(3-ethylbenzothiazoline-6 sulfonate) (ABTS) as the substrate. The immobilized HRP enzyme is thus capable of inducing redox reactions in a subfemtoliter volume of single nanochannels. We demonstrate that functioning of the designed biosensor is reversible and can be used multiple times to detect H(2)O(2) at various concentrations. PMID- 21294555 TI - Amorphous characteristics of an ultrathin cellulose film. AB - Swelling behavior and rearrangements of an amorphous ultrathin cellulose film (20 nm thickness) exposed to water and subsequently dried were investigated with grazing incidence X-ray diffraction, neutron reflectivity, atomic force microscopy, and surface energy calculations obtained from contact angle measurements. The film swelled excessively in water, doubling its thickness, but shrunk back to the original thickness upon water removal. Crystallinity (or amorphousness) and morphology remained relatively unchanged after the wetting/drying cycle, but surface free energy increased considerably (ca. 15%) due to an increase in its polar component, that is, the hydrophilicity of the film, indicating that rearrangements occurred during the film's exposure to water. Furthermore, stability of the films in aqueous NaOH solution was investigated with quartz crystal microbalance with dissipation monitoring. The films were stable at 0.0001 M NaOH but already 0.001 M NaOH partially dissolved the film. The surprising susceptibility to dissolve in dilute NaOH was hypothetically attributed to the lack of hierarchical morphology in the amorphous film. PMID- 21294556 TI - Effects of solvency and interfacial nanobubbles on surface forces and bubble attachment at solid surfaces. AB - The forces between a carbon sphere and highly ordered pyrolytic graphite (HOPG) surface were measured in ethanol aqueous solutions. A long-range attractive interaction was observed in ethanol aqueous solutions with less than 60% ethanol on a volume basis. The magnitude and the range of the attractive interaction decreased with an increase in ethanol concentration in solution. An air bubble was found to attach to the HOPG surface in solutions with an ethanol concentration less than 20 vol %. The presence of nanobubbles at the HOPG surface, made possible through a surface washing process and confirmed through in situ imaging, extended the range of both the long-range attraction and the bubble attachment regime to ethanol concentrations 60-80 vol %. The shear yield stress of suspensions of carbon black in ethanol-aqueous solutions was used as an indicator of the presence of a net attractive interaction between particles. The yield stress was observed to increase rapidly for ethanol concentrations less than 60 vol %. Contact angle analysis for ethanol-aqueous solutions in air showed that an angle of greater than 40 degrees was required to induce a long-range attraction. Modeling indicated that the range and form of the interaction was consistent with a capillary cavitation force. The data clearly shows that surface nanobubbles are not critical to the development of a long-range attractive force, bubble pickup on surfaces, or enhanced suspension rheology, but that their presence greatly aids these processes. PMID- 21294557 TI - Facile synthesis of (E)-alkenyl aldehydes from allyl arenes or alkenes via Pd(II) catalyzed direct oxygenation of allylic C-H bond. AB - Palladium-catalyzed oxygenation of allyl arenes or alkenes has been developed to produce (E)-alkenyl aldehydes with high yields. Allylic C-H bond cleavages occur under the mild conditions during this process. Mechanistic studies show that oxygen source is water. PMID- 21294559 TI - Label-free Raman mapping of surface distribution of protein a and IgG biomolecules. AB - We have demonstrated a nanoengineered substrate composed of micropatterned silver nanoparticles to be used for the label-free mapping of adsorbed biomolecules. We utilized surface-enhanced Raman scattering (SERS) phenomenon to monitor the known bioanalytes, protein A and human immunoglobulin G (IgG). The SERS substrate was composed of a poly(alylamine hydrochloride) (PAH)/poly(styrenesulfonate) (PSS) layer-by-layer (LbL) nanocoating micropatterned with silver nanoparticles confined to microscopic stripes. Selective adsorption of biomacromolecules is facilitated by the amine-terminated LbL nanocoating, which prevents the surface adsorption of positively charged protein A across the surface except on the patterned regions containing negatively charged silver nanoparticles. Furthermore, adsorption of IgG on predetermined regions is facilitated by the selective binding of the Fc region of IgG to protein A. This label-free SERS approach provides accurate, selective, and fast detection of protein A and IgG solutions with a nanomolar concentration, down to below 1 nM for IgG in solution. This method could also be utilized for the facile detection of proteins in field conditions as well as in clinical, forensic, industrial, and environmental laboratories. PMID- 21294558 TI - Differentiating between fluorescence-quenching metal ions with polyfluorophore sensors built on a DNA backbone. AB - A common problem in detecting metal ions with fluorescentchemosensors is the emission-suppressing effects of fluorescence-quenching metal ions. This quenching tendency makes it difficult to design sensors with turn-on signal, and differentiate between several metal ions that may yield a strong quenching response. To address these challenges, we investigate a new sensor design strategy, incorporating fluorophores and metal ligands as DNA base replacements in DNA-like oligomers, for generating a broader range of responses for quenching metal ions. The modular molecular design enabled rapid synthesis and discovery of sensors from libraries on PEG-polystyrene beads. Using this approach, water soluble sensors 1-5 were identified as strong responders to a set of eight typically quenching metal ions (Co(2+), Ni(2+), Cu(2+), Hg(2+), Pb(2+), Ag(+), Cr(3+), and Fe(3+)). They were synthesized and characterized for sensing responses in solution. Cross-screening with the full set of metal ions showed that they have a wide variety of responses, including emission enhancements and red- and blue-shifts. The diversity of sensor responses allows as few as two sensors (1 and 2) to be used together to successfully differentiate these eight metals. As a test, a set of unknown metal ion solutions in blind studies were also successfully identified based on the response pattern of the sensors. The modular nature of the sensor design strategy suggests a broadly applicable approach to finding sensors for differentiating many different cations by pattern based recognition, simply by varying the sequence and composition of ligands and fluorophores on a DNA synthesizer. PMID- 21294560 TI - Nonspecific adsorption of charged quantum dots on supported zwitterionic lipid bilayers: real-time monitoring by quartz crystal microbalance with dissipation. AB - Understanding how the composition and environmental conditions of membranes influence their interactions with guest species is central to cell biology and biomedicine. We herein study the nonspecific adsorption of charged quantum dots (QDs) onto a supported zwitterionic lipid bilayer by using quartz crystal microbalance with dissipation (QCM-D). It is demonstrated that (1) the adsorption of charged QDs is charge-dependent in a way similar to but much stronger than that of the capping molecules by reason of size effect; (2) the adsorption behavior of charged QDs is dominated by electrostatic interaction, which can be well described by an "adsorption window"; (3) the "adsorption window" can be broadened by exploiting the bridge role of Ca(2+) ions; and (4) by introducing a cationic lipid into the zwitterionic lipid bilayer, one can achieve preferential adsorption of anionic QDs but suppression of the cationic QD adsorption. Our QCM D data also indicates that these different adsorption traits effect different changes in the dissipation of supported lipid bilayers (SLBs) after adsorption of the charged QDs. The different adsorption propensities of cationic and anionic QDs on SLBs have reinforced the picture of electrostatic interactions. We believe that these findings provide important information on QD-lipid membrane interactions, which will help to develop new drug molecules and efficient drug delivery systems, and to predict and unravel their potential toxicities if any. PMID- 21294561 TI - Nanoparticles by decomposition of long chain iron carboxylates: from spheres to stars and cubes. AB - In this paper, we report the influence of reaction conditions and the chain length on the nanoparticle (NP) size and morphology for thermal decomposition of long-chain iron carboxylates such as Fe(III) oleate, palmitate, and myristate. In the majority of cases, spherical NPs are obtained; however, nonspherical morphologies were observed in some "extreme" conditions. For example, iron oxide nanostars are formed in eicosane at the Fe oleate/oleic acid ratio of 0.49 g/mL: the highest oleic acid content when NPs still form. The cubic NPs with flat facets are obtained by decomposition of iron palmitate at the lowest palmitic acid fractions, but the most monodisperse cubes are formed at the Fe palmitate/palmitic acid ratio of 1.19 g/mL. Elliptical NPs are formed from Fe myristate with the most well-defined structure. Easy transformation of these NPs from wustite to maghemite without aggregation and loss of solubility makes them excellent candidates for biomedical applications after proper functionalization described in our preceding papers. PMID- 21294562 TI - Direct observation and quantitative characterization of singlet oxygen in aqueous solution upon UVA excitation of 6-thioguanines. AB - The incorporation of 6-thioguanine (6-TG) into DNA increases the risk of (1)O(2) initiated skin cancer. We herein provide the first report on quantitative characterization of the photoactivity of 6-thioguanines including 6-TG and 6 thioguanosine. Time-resolved singlet oxygen luminescence was observed directly for the first time after UVA irradiation of 6-thioguanines in both CHCN(3) and aqueous solutions. Their photosensitization was characterized by the quantum yield of singlet oxygen production, showing a dramatic decrease over time from the initial 0.49-0.58 to zero. Experiments performed on both 6-TG and 6 thioguanosine did not show any significant difference in the quantum yield of singlet oxygen production, indicating that there was no potential participation of 7H- and 9H-tautomers. Our findings provide a primary basis for a better understanding of molecular events of thiopurine drugs in biological systems. PMID- 21294563 TI - Synthesis of amides via palladium-catalyzed amidation of aryl halides. AB - A new and efficient method for the synthesis of amides via palladium-catalyzed C C coupling of aryl halides with isocyanides is reported, by which a series of amides were formed from readily available starting materials under mild conditions. This transformation could extend its use to the synthesis of natural products and significant pharmaceuticals. PMID- 21294564 TI - Atomic view of calcium-induced clustering of phosphatidylserine in mixed lipid bilayers. AB - Membranes play key regulatory roles in biological processes, with bilayer composition exerting marked effects on binding affinities and catalytic activities of a number of membrane-associated proteins. In particular, proteins involved in diverse processes such as vesicle fusion, intracellular signaling cascades, and blood coagulation interact specifically with anionic lipids such as phosphatidylserine (PS) in the presence of Ca(2+) ions. While Ca(2+) is suspected to induce PS clustering in mixed phospholipid bilayers, the detailed structural effects of this ion on anionic lipids are not established. In this study, combining magic angle spinning (MAS) solid-state NMR (SSNMR) measurements of isotopically labeled serine headgroups in mixed lipid bilayers with molecular dynamics (MD) simulations of PS lipid bilayers in the presence of different counterions, we provide site-resolved insights into the effects of Ca(2+) on the structure and dynamics of lipid bilayers. Ca(2+)-induced conformational changes of PS in mixed bilayers are observed in both liposomes and Nanodiscs, a nanoscale membrane mimetic of bilayer patches. Site-resolved multidimensional correlation SSNMR spectra of bilayers containing (13)C,(15)N-labeled PS demonstrate that Ca(2+) ions promote two major PS headgroup conformations, which are well resolved in two-dimensional (13)C-(13)C, (15)N-(13)C, and (31)P-(13)C spectra. The results of MD simulations performed on PS lipid bilayers in the presence or absence of Ca(2+) provide an atomic view of the conformational effects underlying the observed spectra. PMID- 21294565 TI - SPME-GC-MS versus Selected Ion Flow Tube Mass Spectrometry (SIFT-MS) analyses for the study of volatile compound generation and oxidation status during dry fermented sausage processing. AB - The use of selected ion flow tube mass spectrometry (SIFT-MS) and gas chromatography-mass spectrometry together with solid phase microextraction (GC-MS SPME) has been compared in the analysis of volatile compounds during dry fermented sausage processing. Thus, the headspace (HS) of samples of dry fermented sausages with different fat contents was analyzed during their manufacture using both techniques, and significant and positive correlations were found between SIFT-MS and SPME-GC-MS measurements for the compounds pentanal, hexanal, 2-heptenal, octanal, 2-nonenal, 2-butanone, 2-pentanone, ethanol, acetic acid, and hexanoic acid. The oxidative status of fermented sausages during processing was also evaluated, and a significant correlation was obtained between the HS concentration of lipid autoxidation volatile compounds measured by SIFT-MS and SPME-GC-MS and the level of thiobarbituric acid reactive substances (TBARS) in the sausage. The hexanal measured by SIFT-MS resulted in a higher correlation coefficient (r = 0.936) than that obtained using SPME-GC-MS (r = 0.927). SIFT-MS is shown to be a fast, real time analytical technique for monitoring changes in the profile of volatile compounds in dry fermented sausages during processing and a useful tool to evaluate the oxidative status of meat products. PMID- 21294566 TI - Stable iron isotope fractionation between aqueous Fe(II) and hydrous ferric oxide. AB - Despite the ubiquity of poorly crystalline ferric hydrous oxides (HFO, or ferrihydrite) in natural environments, stable Fe isotopic fractionation between HFO and other Fe phases remains unclear. In particular, it has been difficult to determine equilibrium Fe isotope fractionation between aqueous Fe(II) and HFO due to fast transformation of the latter to more stable minerals. Here we used HFO stabilized by the presence of dissolved silica (2.14 mM), or a Si-HFO coprecipitate, to determine an equilibrium Fe(II)-HFO fractionation factor using a three-isotope method. Iron isotope exchange between Fe(II) and HFO was rapid and near complete with the Si-HFO coprecipitate, and rapid but incomplete for HFO in the presence of dissolved silica, the latter case likely reflecting blockage of oxide surface sites by sorbed silica. Equilibrium Fe(II)-HFO (56)Fe/(54)Fe fractionation factors of -3.17 +/- 0.08 (2sigma)0/00 and -2.58 +/- 0.14 (2sigma)0/00 were obtained for HFO plus silica and the Si-HFO coprecipitate, respectively. Structural similarity between ferrihydrite and hematite, as suggested by spectroscopic studies, combined with the minor isotopic effect of dissolved silica, imply that the true equilibrium Fe(II)-HFO (56)Fe/(54)Fe fractionation factor in the absence of silica may be ~-3.20/00. These results provide a critical interpretive context for inferring the stable isotope effects of Fe redox cycling in nature. PMID- 21294567 TI - SO2 adsorption on carbon-supported Pt electrocatalysts. AB - Adsorption of SO2 on a Pt/C catalyst typically used in proton exchange- membrane fuel cells (PEMFCs) has been investigated by temperature programmed desorption (TPD). SO2 concentrations in N2 were varied from 5 ppm to 1% (vol) and adsorption isotherms were determined at 25, 50, and 80 degrees C. Oxygen assisted (O assisted) desorption experiments (i.e., successive TPD experiments following exposure to room temperature O2 after the first TPD event) produced an additional SO2 peak at a temperature higher than the initial SO2 peak. These two types of SO2 adsorption were identified as weakly adsorbed SO2 species desorbed between 140 and 200 degrees C, depending on concentration, and a strongly adsorbed, dissociated species. For the strongly adsorbed, dissociative species, (18)O2 isotope introduction during O-assisted desorption yielded ratios of 50%, 36%, and 14% for SO2 masses of 64, 66, and 68, respectively. The activation energy and kinetic constant of desorption are reported for weakly adsorbed SO2 at 1% and 20 ppm SO2 using the Polanyi-Wigner equation. PMID- 21294568 TI - Toward "strong" green nanocomposites: polyvinyl alcohol reinforced with extremely oriented cellulose whiskers. AB - To exploit the maximum potential of cellulose whiskers (CWs), we report here for the first time the successful fabrication of nanocomposites reinforced with highly oriented CWs in a polymer matrix. The nanocomposites were prepared using polyvinyl alcohol (PVA) and a colloidal suspension of cotton-derived CWs. The macroscopically homogeneous PVA-CW suspensions were extruded into cold methanol to form gel fibers followed by a hot drawing. Compared to the neat PVA fiber, the as-spun fiber containing a small amount of CWs (5 wt % of solid PVA) showed higher drawability, leading to an extremely high orientation of CWs with the matrix PVA. The stress-transfer mechanism, a prime determining factor for high mechanical properties of nanocomposites, was studied by X-ray diffraction. The stress on the incorporated CWs was monitored by applying an in situ nondestructive load to the composite fibers. The applied stress to the whole sample was found to be effectively transferred to the CWs inside the composites, suggesting strong interfacial bonding between the filler and the matrix. Effective stress transfer to the oriented whiskers resulted in outstanding enhancement in mechanical properties of the nanocomposites. PMID- 21294569 TI - Potent agonists of the protease activated receptor 2 (PAR2). AB - Novel peptidomimetic pharmacophores to PAR(2) were designed based on the known activating peptide SLIGRL-NH(2). A set of 15 analogues was evaluated with a model cell line (16HBE14o-) that highly expresses PAR(2). Cells exposed to the PAR(2) activating peptide with N-terminal 2-furoyl modification (2-furoyl-LIGRLO-NH(2)) initiated increases in intracellular calcium concentration ([Ca(2+)](i) EC(50) = 0.84 MUM) and in vitro physiological responses as measured by the xCELLigence real time cell analyzer (RTCA EC(50) = 138 nM). We discovered two selective PAR(2) agonists with comparable potency: compound 1 (2-aminothiazol-4-yl; Ca(2+) EC(50) = 1.77 MUM, RTCA EC(50) = 142 nM) and compound 2 (6-aminonicotinyl; Ca(2+) EC(50) = 2.60 MUM, RTCA EC(50) = 311 nM). Unlike the previously described agonist, these novel agonists are devoid of the metabolically unstable 2-furoyl modification and thus provide potential advantages for PAR(2) peptide design for in vitro and in vivo studies. The novel compounds described herein also serve as a starting point for structure-activity relationship (SAR) design and are, for the first time, evaluated via a unique high throughput in vitro physiological assay. Together these will lead to discovery of more potent agonists and antagonists of PAR(2). PMID- 21294570 TI - Effect of chitosan chain architecture on gene delivery: comparison of self branched and linear chitosans. AB - Chitosan possesses many characteristics of an ideal gene delivery system. However, the transfection efficiency of conventional chitosans is generally found to be low. In this study, we investigated the self-branching of chitosans as a strategy to improve its gene transfer properties without compromising its safety profile. Self-branched (SB) and self-branched trisaccharide-substituted (SBTCO) chitosans with molecular weights of 11-71 kDa were synthesized, characterized, and compared with their linear counterparts with respect to transfection efficiency, cellular uptake, formulation stability, and cytotoxicity. Our studies show that in contrast with unmodified linear chitosans that were unable to transfect HeLa cells, self-branched chitosans mediated high transfection efficiencies. The most efficient chitosan, SBTCO30, yielded gene expression levels two and five times higher than those of Lipofectamine and Exgen, respectively, and was nontoxic to cells. Nanoparticles formed with SBTCO chitosans exhibited a higher colloidal stability of formulation, efficient internalization without excessive cell surface binding, and low cytotoxicity. PMID- 21294571 TI - Conjugation effects of various linkers on Gd(III) MRI contrast agents with dendrimers: optimizing the hydroxypyridinonate (HOPO) ligands with nontoxic, degradable esteramide (EA) dendrimers for high relaxivity. AB - One essential requirement for more sensitive gadolinium-based MRI contrast agents is to slow the molecular tumbling of the gadolinium(III) ion, which increases the gadolinium's relaxivity (i.e., its ability to speed up the NMR relaxation of nearby water molecules). One route to this is through conjugation to high molecular-weight polymers such as dendrimers. In this work, amine-functionalized TREN-bis(1,2-HOPO)-TAM-ethylamine and TREN-bis(1-Me-3,2-HOPO)-TAM-ethylamine ligands have been synthesized and attached to biocompatible 40 kDa esteramide (EA)- and poly-l-lysine (PLL)-based dendrimers capable of binding up to eight gadolinium complexes. These conjugates have T(1) relaxivities of up to 38.14 +/- 0.02 mM(-1) s(-1) per gadolinium at 37 degrees C, corresponding to relaxivities of up to 228 mM(-1) s(-1) per dendrimer molecule. This relaxivity expressed on a "per Gd" basis is several times that of the small-molecule complexes and an order of magnitude higher than that of current commercial agents. Because of their high performance and low toxicity, these macromolecules may constitute an attractive complement to currently available gadolinium(III)-based contrast agents. PMID- 21294572 TI - Role of galloylation and polymerization in cytoprotective effects of polyphenolic fractions against hydrogen peroxide insult. AB - Byproducts and wastes generated by agricultural, food, and forestry industries contain large amounts of polyphenols, which can be potentially used as sources of natural or semisynthetic antioxidants. This study examined and compared the protection against peroxidative damage induced in erythrocytes and 3T3 cell line of polyphenolic fractions from white grape pomace, pine bark, and witch hazel bark. The work pays special attention to the different degrees of polymerization and galloylation of the extracts to contribute to the understanding of their mechanisms of action. Fractions demonstrated different protections against erythrocyte lipid peroxidation, hemolysis, and 3T3 cytotoxicity caused by H(2)O(2). Galloylation is claimed to be related to antioxidant protective capacity, and it is also responsible for the pro-oxidant effect observed at high doses. The results show that not only the percentage of galloylation but also the degree of polymerization are important modulators of their antioxidant capacity. In this sense, it is crucial that novel polyphenolic fractions were prepared attending a value of 3 for the mean degree of polymerization and did not exceed a 30% of galloylation to reach the highest antioxidant capacity with the lowest cytotoxic effects. For this reason, the grape extracts appear to be the best strategy to fight against hydrogen peroxide cell damage. PMID- 21294573 TI - Semi-metallic single-component crystal of soluble La@C82 derivative with high electron mobility. AB - We prepared an organic conductor crystal having extremely high electron mobility, in which the adamantylidene (Ad) derivative of La@C(82) (an endohedral metallofullerene known as a n-type semiconductor) is aligned in an orderly fashion. The single-component crystal exhibits high electron mobility of MU > 10 cm(2) V(-1) s(-1) along the c axis under normal temperatures and pressures in the atmosphere, as shown by flash-photolysis time-resolved microwave conductivity (TRMC) measurements, which are the highest of reported organic conductors measured by TRMC. According to density functional calculations, the single crystal of La@C(82)Ad is semi-metallic, with a small band gap of 0.005 eV. PMID- 21294574 TI - Methyl and pentyl chloride in a microhydrated environment and at the liquid water vapor interface: a theoretical study. AB - The solvation properties of methyl and pentyl chloride were studied in a microhydrated environment with up to 10 explicit water molecules and at the liquid water-vapor interface. Geometry optimizations were performed in the former case using the density functional based tight binding (DFTB), DFTB-D, and Moller Plesset perturbation theory (MP2) levels of theory. The microhydrated alkyl chloride complexes were characterized in terms of hydrogen bonding and energetic stability. The DFTB and DFTB-D results were verified by comparison with those obtained by MP2. Good agreement between the MP2 and DFTB-D results is found. Complexes where the alkyl chloride molecule is attached to an edge of the water cluster are found to be most stable. Pronounced stability is also observed for cubic arrangements of the alkyl chloride-water complexes. Molecular dynamics simulations based on the DFTB and DFTB-D methods were used to study the adsorption process of the alkyl chloride molecules to a water surface. The dynamics simulations show that the methyl chloride molecule is located at the water surface preferentially with the methyl group oriented toward the water surface, while for pentyl chloride, owing to the longer nonpolar hydrocarbon chain, a parallel alignment at the water surface is found with the hydrocarbon chain pointing slightly to the gas phase. Despite some quantitative differences, the present work provides confirmation of the somewhat surprising preferential orientation of the methyl chloride molecule at the water-vapor interface predicted in a recent study using molecular dynamics simulations based on an empirical force field (Harper et al., J. Phys. Chem. A 2009, 113, 2015-2024). The observed difference in preferred alignment at the aqueous surface between the methyl chloride and the longer-chain alkyl chloride is likely to have consequences for the chemistry of alkyl halides adsorbed on the surface of aqueous and ice particles in the atmosphere. PMID- 21294575 TI - Atomic force microscopy characterization of room-temperature adlayers of small organic molecules through graphene templating. AB - We report on the use of graphene templating to investigate the room-temperature structure and dynamics of weakly bound adlayers at the interfaces between solids and vapors of small organic molecules. Monolayer graphene sheets are employed to preserve and template molecularly thin adlayers of tetrahydrofuran (THF) and cyclohexane on atomically flat mica substrates, thus permitting a structural characterization of the adlayers under ambient conditions through atomic force microscopy. We found the first two adlayers of both molecules adsorb in a layer by-layer fashion, and atomically flat two-dimensional islands are observed for both the first and the second adlayers. THF adlayers form initially as rounded islands but, over a period of weeks, evolve into faceted islands, suggesting that the adlayers possess both liquid and solid properties at room temperature. Cyclohexane adlayers form crystal-like faceted islands and are immobile under the graphene template. The heights of the second adlayers of THF and cyclohexane are measured to be 0.44 +/- 0.02 and 0.50 +/- 0.02 nm, respectively, in good agreement with the layer thicknesses in the monoclinic crystal structure of THF and the Phase I "plastic crystal" structure of cyclohexane. The first adlayers appear slightly thinner for both molecules, indicative of interactions of the molecules with the mica substrate. PMID- 21294576 TI - Isolation and confirmation of the proposed cleistanthol biogentic link from Croton insularis. AB - The proposed cleistanthol biosynthetic intermediate en route to spruceanol, and other related family members, was isolated for the first time from Croton insularis, confirming the Jacobs-Reynolds hypothesis. Anticancer evaluation of the new isolates and their aerial oxidation products is also reported. PMID- 21294577 TI - Facile syntheses of novel benzo-1,3-dioxolo-, benzothiazolo-, pyrido-, and quinolino-fused 5H-benzo[d]-pyrazolo[5,1-b][1,3]-oxazines and 1H-pyrazoles. AB - A number of novel benzo-1,3-dioxolo-, benzothiazolo-, pyrido-, and quinolino fused 5H-benzo[d]pyrazolo[5,1-b][1,3]-oxazines and 1H-pyrazoles were synthesized utilizing an easy and effective N,N-bond forming heterocyclization reaction. In so doing, the substrate scope of this heterocyclization reaction, which starts with o-nitroheterocyclic aldehydes, was expanded to provide several unique heterocyclic compounds for biological screening. This work further demonstrates the versatility of this simple, base-mediated, one-pot heterocyclization method in the construction of novel heterocycles. PMID- 21294578 TI - Synthesis of fluorescent probes based on the pyochelin siderophore scaffold. AB - Pyochelin is a siderophore common to several pathogenic bacterial strains. Two conjugates, 1 and 2, between the NBD (4-nitro-benzo[1,2,5]oxadiazole) fluorophore and an N3''-functionalized pyochelin were synthesized. These fluorescent probes unexpectedly increased their fluorescence in an aqueous medium in the presence of iron(III) and were transported into bacterial cells. PMID- 21294579 TI - Synthesis and crystal structure of a layered silicate HUS-1 with a halved sodalite-cage topology. AB - A new layered silicate, HUS-1, was synthesized by hydrothermal synthesis using decomposed FAU- and *BEA-type zeolites as nanosized silica parts. Structural analyses by X-ray powder diffractometry and solid-state magic-angle-spinning (MAS) NMR spectroscopy revealed that HUS-1 has a layered structure containing a silicate layer per unit cell along a stacking direction. Its framework topology is similar to that of SOD-type zeolites and consists of a halved sodalite cage, which includes four- and six-membered Si rings. Structure refinement by the Rietveld method showed that tetramethylammonium (TMA) ions used as a structure directing agent (SDA) were incorporated into the interlayer. The four methyl groups of the TMA molecule were located orderly in a hemispherical cage in the silicate layer, which suggests restraint of molecular motion. The interlayer distance is estimated at about 0.15 nm, which is unusually short in comparison with that in other layered silicates (e.g., beta-HLS or RUB-15) with similar framework topologies. The presence of hydrogen bonding between adjacent terminal O atoms was clearly revealed by the (1)H MAS NMR spectroscopy and by electron density distribution obtained by the maximum entropy method. PMID- 21294580 TI - Viruses in pharmaceutical research: swiss army knives for the prevention and treatment of disease. PMID- 21294581 TI - Comparison of three thermostable beta-glucosidases for application in the hydrolysis of soybean isoflavone glycosides. AB - A novel thermostable beta-glucosidase (Te-BglA) from Thermoanaerobacter ethanolicus JW200 was cloned, characterized and compared for its activity against isoflavone glycosides with two beta-glucosidases (Tm-BglA, Tm-BglB) from Thermotoga maritima. Te-BglA exhibited maximum hydrolytic activity toward pNP beta-d-glucopyranoside (pNPG) at 80 degrees C and pH 7.0, was stable for a pH range of 4.6-7.8 and at 65 degrees C for 3 h, and had the lowest K(m) for the natural glycoside salicin and the highest relative substrate specificity (k(cat)/K(m))((salicin))/(k(cat)/K(m))((pNPG)) among the three enzymes. It converted isoflavone glycosides, including malonyl glycosides, in soybean flour to their aglycons more efficiently than Tm-BglA and Tm-BglB. After 3 h of incubation at 65 degrees C, Te-BglA produced complete hydrolysis of four isoflavone glycosides (namely, daidzin, genistin and their malonylated forms), exhibiting higher productivity of genistein and daidzein than the other two beta glucosidases. Our results suggest that Te-BglA is preferable to Tm-BglA and Tm BglB, but all three enzymes have great potential applications in converting isoflavone glycosides into their aglycons. PMID- 21294582 TI - Alpha7 helix plays an important role in the conformational stability of PTP1B. AB - The C-terminus of Protein Tyrosine Phosphatase 1B (PTP1B) includes an alpha-helix alpha7), which forms an allosteric binding site 20 a away from the active site. This helix is specific to PTP1B and its truncation decreases the catalytic activity significantly. Here, molecular dynamics (MD) simulations in the presence and absence of alpha7 were performed to investigate the role played by alpha7. The highly mobile alpha7 was found to maintain its contacts with loop 11 (L11)alpha3 helix throughout the simulations. The interactions of Tyr152 on L11, Tyr176, Thr177 on the catalytically important WPD loop and Ser190 on alpha3 are important for the conformational stability and the concerted motions of the regions surrounding the WPD loop. In the absence of alpha7, L11 and WPD loop move away from their crystal structure conformations, resulting in the loss of the interactions in this region, and a decrease in the residue displacement correlations in the vicinity of WPD loop. Therefore, we suggest that one of the functionally important roles of alpha7 may be to limit the L11 and alpha3 motions, and, facilitate the WPD loop motions. Truncation of alpha7 in PTP1B is found to affect distant regions as well, such as the substrate recognition site and the phosphate binding-loop (P-loop), changing the conformations of these regions significantly. Our results show that the PTP1B specific alpha7 is important for the conformation and dynamics of the WPD loop, and also may play a role in ligand binding. PMID- 21294583 TI - In search of allosteric modulators of a7-nAChR by solvent density guided virtual screening. AB - Nicotinic acetylcholine receptors (nAChR) are pentameric ligand gated ion channels whose activity can be modulated by endogenous neurotransmitters as well as by synthetic ligands that bind the same or distinct sites from the natural ligand. The subtype of alpha7 nAChR has been considered as a potenial therapeutic target for Alzheimer's disease, schizophrenia and other neurological and psychiatric disorders. Here we have developed a homology model of alpha7 nAChR based on two high resolution crystal structures with Brookhaven Protein Data Bank (PDB) codes 2QC1 and 2WN9 for threading on one monomer and then for building a pentamer, respectively. A number of small molecule binding sites are identified using Pocket Finder (J. An, M. Tortov, and R. Abagyan, Molecular & Cellular Proteomics, 4.6, 752-761 (2005)) of Internal Coordinate Mechanics (ICM). Remarkably, these computer-identified sites match perfectly with ordered solvent densities found in the high-resolution crystal structure of alpha1 nAChR, suggesting that the surface cavities in the alpha7 nAChR model are likely binding sites of small molecules. A high throughput virtual screening by flexible ligand docking of 5008 small molecule compounds was performed at three potential allosteric modulator (AM) binding sites of alpha7 nAChR using Molsoft ICM software (R. Abagyan, M. Tortov and D. Kuznetsov, J Comput Chem 15, 488-506, (1994)). Some experimentally verified allosteric modulators of alpha7 like CCMI comp-6, LY 7082101, 5-HI, TQS, PNU-120596, genistein, and NS-1738 ranked among top 100 compounds, while the rest of the compounds in the list could guide further search for new allosteric modulators. PMID- 21294584 TI - Thermal stability and unfolding pathways of Sso7d and its mutant F31A: insight from molecular dynamics simulation. AB - The thermo-stability and unfolding behaviors of a small hyperthermophilic protein Sso7d as well as its single-point mutation F31A are studied by molecular dynamics simulation at temperatures of 300 K, 371 K and 500 K. Simulations at 300 K show that the F31A mutant displays a much larger flexibility than the wild type, which implies that the mutation obviously decreases the protein's stability. In the simulations at 371 K, although larger fluctuations were observed, both of these two maintain their stable conformations. High temperature simulations at 500 K suggest that the unfolding of these two proteins evolves along different pathways. For the wild-type protein, the C-terminal alpha-helix is melted at the early unfolding stage, whereas it is destroyed much later in the unfolding process of the F31A mutant. The results also show that the mutant unfolds much faster than its parent protein. The deeply buried aromatic cluster in the F31A mutant dissociates quickly relative to the wild-type protein at high temperature. Besides, it is found that the triple-stranded antiparallel beta-sheet in the wild type protein plays an important role in maintaining the stability of the entire structure. PMID- 21294585 TI - Two models of Smad4 and Hoxa9 complex are proposed: structural and interactional perspective. AB - Transforming growth factor-beta superfamily growth factors (TGF-beta) regulate a diverse range of cellular functions, including proliferation, differentiation, extracellular matrix secretion and cell adhesion. TGF-beta is also one of the most abundant of the known growth factors. Osteopontin (OPN), the major non collagenous bone matrix protein is a secreted, arginine-glycine-aspertate containing phosphorylated glycoprotein. Analysis of the OPN promoter sequence reveals both Hoxc8 and Hoxa9 (mouse homeotic gene) recognize and utilize the same consensus TAAT motif in the binding sequence to mediate the repression. Hoxa9 functions as a strong transcriptional repressor, similar to Hoxc-8 (X. Shi, X. Yang, D. Chen, Z. Chang, and X. Cao, J Biol Chem 274, 13711-13717, 1999). The DNA binding protein Hoxa9 interacts with Smad4 (X. Shi, S. Bai, L. Li and X, and Cao X, J Biol Chem 276, 850-855, 2001), but not with Smad3 (which binds to OPN promoter), and the interaction between Smad4 and Hoxa9 results in the transcriptional activation of OPN in response to TGF- stimulation. In this paper we have proposed two possible model structures of Hoxa9 and Smad4 complex. These have been modeled based on homology modeling and a new method has been used to model the flexible loop part. Manual docking has been used to achieve the final model involving the Hoxa9 -Smad4 complex which tallies with the experimental results. We have mutated some selective important residues and looked at their effect in terms of interaction energy in complex formation in both the models. PMID- 21294586 TI - The possible structural models for polyglutamine aggregation: a molecular dynamics simulations study. AB - Huntington's disease is a neurodegenerative disorder caused by a polyglutamine (polyQ) expansion near the N-terminus of huntingtin. Previous studies have suggested that polyQ aggregation occurs only when the number of glutamine (Q) residues is more than 36-40, the disease threshold. However, the structural characteristics of polyQ nucleation in the very early stage of aggregation still remain elusive. In this study, we designed 18 simulation trials to determine the possible structural models for polyQ nucleation and aggregation with various shapes and sizes of initial beta-helical structures, such as left-handed circular, right-handed rectangular, and left- and right-handed triangular. Our results show that the stability of these models significantly increases with increasing the number of rungs, while it is rather insensitive to the number of Qs in each rung. In particular, the 3-rung beta-helical models are stable when they adopt the left-handed triangular and right-handed rectangular conformations due to the fact that they preserve high beta-turn and beta-sheet contents, respectively, during the simulation courses. Thus, we suggested that these two stable beta-helical structures with at least 3 rungs might serve as the possible nucleation seeds for polyQ depending on how the structural elements of beta-turn and beta-sheet are sampled and preserved during the very early stage of aggregation. PMID- 21294587 TI - Insight into the enzyme-inhibitor interactions of the first experimentally determined human aromatase. AB - Aromatase is an important pharmacological target in the anti-cancer therapy as the intratumoral aromatase is the source of local estrogen production in breast cancer tissues. Suppression of estrogen biosynthesis by aromatase inhibition represents an effective approach for the treatment of hormone-sensitive breast cancer. Because of the membrane-bound character and heme-binding instability, no crystal structure of aromatase was reported for a long time, until recently when crystal structure of human placental aromatase cytochrome P450 in complex with androstenedione was deposited in PDB. The present study is towards understanding the structural and functional characteristics of aromatase to address unsolved mysteries about this enzyme and elucidate the exact mode of binding of aromatase inhibitors. We have performed molecular docking simulation with twelve different inhibitors (ligands), which includes four FDA approved drugs; two flavonoids; three herbal compounds and three compounds having biphenyl motif with known IC(50) values into the active site of the human aromatase enzyme. All ligands showed favorable interactions and most of them seemed to interact to hydrophobic amino acids Ile133, Phe134, Phe221, Trp224, Ala306, Val370, Val373, Met374 and Leu477 and hydrophilic Arg115 and neutral Thr310 residues. The elucidation of the actual structure-function relationship of aromatase and the exact binding mode described in this study will be of significant interest as its inhibitors have shown great promise in fighting breast cancer. PMID- 21294588 TI - Screening from the world's largest TCM database against H1N1 virus. AB - The swine influenza virus (H1N1) 2009 pandemic highlights the importance of having effective anti-viral strategies. Recently, oseltamivir (Tamiflu) resistant influenza viruses are identified; which further emphasizes the urgency in developing new antiviral agents. In influenza virus replication cycle, viral surface glycoprotein, hemagglutinin, is responsible for viral entry into host cells. Hence, a potentially effective antiviral strategy is to inhibit viral entry mechanism. To develop novel antiviral agent that inhibits viral entry, we analyzed 20,000 traditional Chinese medicine (TCM) ingredients in hemagglutinin subtype H1 sialic acid binding site found on H1N1 virus. We then performed molecular dynamics simulations to investigate receptor-ligand interaction of the candidates obtained from docking. Here, we report three TCM derivatives that have high binding affinities to H1 sialic acid binding site residues based on structure-based calculations. The top three derivatives, xylopine_2, rosmaricine_14 and rosmaricine_15, all have an amine group that interact with Glu83 and a pyridinium group that interact with Asp103. Molecular dynamics simulations show that these derivatives form strong hydrogen bonding with Glu83 but interact transiently with Asp103. We therefore suggest that an enhanced hemagglutinin inhibitor, based on our scaffold, should be designed to bind both Glu83 and Asp103 with high affinity. PMID- 21294589 TI - Using computer-aided drug design and medicinal chemistry strategies in the fight against diabetes. AB - The aim of this work is to present a simple, practical and efficient protocol for drug design, in particular Diabetes, which includes selection of the illness, good choice of a target as well as a bioactive ligand and then usage of various computer aided drug design and medicinal chemistry tools to design novel potential drug candidates in different diseases. We have selected the validated target dipeptidyl peptidase IV (DPP-IV), whose inhibition contributes to reduce glucose levels in type 2 diabetes patients. The most active inhibitor with complex X-ray structure reported was initially extracted from the BindingDB database. By using molecular modification strategies widely used in medicinal chemistry, besides current state-of-the-art tools in drug design (including flexible docking, virtual screening, molecular interaction fields, molecular dynamics, ADME and toxicity predictions), we have proposed 4 novel potential DPP IV inhibitors with drug properties for Diabetes control, which have been supported and validated by all the computational tools used herewith. PMID- 21294590 TI - Predicting sumoylation site by feature selection method. AB - The small ubiquitin-like modifier (SUMO) proteins are a kind of proteins that can be attached to a series of proteins. The sumoylation of protein is an important posttranslational modification. Thus, the prediction of the sumoylation site of a given protein is significant. Here we employed a combined method to perform this task. We predicted the sumoylation site of a protein by a two-staged procedure. At the first stage, whether a protein would be sumoylated was predicted; whereas at the second stage, the sumoylation sites of the protein were predicted if it was determined to be modified by SUMO at the first stage. At the first stage, we encoded a protein with protein families (PFAM) and trained the predictor with nearest network algorithm (NNA); at the second stage, we encoded nonapeptides (peptides that contain nine residues) of the protein containing the lysine residues, with Amino Acid Index, and trained the predictor with NNA. The predictor was tested by the k-fold cross-validation method. The highest accuracy of the second-staged predictor was 99.55% when 12 features were incorporated in the predictor. The corresponding Matthews Correlation Coefficient was 0.7952. These results indicate that the method is a promising tool to predict the sumoylation site of a protein. At last, the features used in the predictor are discussed. The software is available at request. PMID- 21294591 TI - Study on interaction of DNA from calf thymus with 1,10 phenanthrolinehexyldithiocarbamatopalladium(II) nitrate as potential antitumor agent. AB - A novel palladium(II) complex has been synthesized with hexyldithiocarbamate (Hex dtc) and 1,10-phenanthroline (phen) by the reaction of [Pd(phen)(H(2)O)(2)](NO(3))(2) with sodium salt of hexyldithiocarbamate and a complex of type [Pd(Hex-dtc) (phen)]NO(3) has been obtained. The complex has been characterized by elemental analysis, molar conductance, (1)H NMR, IR and electronic spectroscopic studies. The dithiocarbamate ligand acts in bidentate fashion. This water-soluble complex was screened against chronic myelogenous leukemia cell line, K562, for cytotoxic effects and showed significant antitumor activity much lower than that of cisplatin. The interaction of this complex with calf thymus DNA (ctDNA) was extensively investigated by a variety of spectroscopic techniques. Absorbance titration experiments imply the interaction of 4 Pd(II) complex molecules per 1000 nucleotides on DNA with positive cooperativity in the binding process and the complex denature the DNA at very low concentration (~14.3 uM). Fluorescence titration spectra and fluorescence Scatchard plots suggest that the Pd(II) complex intercalate in DNA. The gel chromatograms obtained from Sephadex G-25 column experiments showed that the binding of metal complex with DNA is so strong that it does not readily break. Furthermore, some thermodynamic and binding parameters found in the process of UV Visible studies are described. They may provide specificity of the compound with ctDNA. PMID- 21294592 TI - Improvements of the hierarchical approach for predicting RNA tertiary structure. AB - Computational prediction of RNA tertiary structures is a significant challenge, especially for longer RNA and pseudoknots. At present it is still difficult to do this by pure all-atom molecular dynamics simulation. One of possible approaches is through hierarchical steps: from sequence to secondary structure and then to tertiary structure. Here we present improvements of two key steps of this approach, the manual adjustment of atom clashes and bond stretches and molecular dynamics refinement. We provide an energy function to find the locations of atom clashes and bond stretches and to guide their manual adjustment and a new scheme of molecular dynamics refinement using a tested combination of solvent model and the ff98 Amber force field suitable for RNA. We predicted with higher accuracy the tertiary structures of nine typical RNA molecules of lengths from 12 to 52, including hairpins, duplex helices and pseudoknots. PMID- 21294593 TI - Novel hybrid encodes both continuous and split tRNA genes? AB - tRNAs are mostly transcribed from un-fragmented genes, but occasionally also from split genes, with separated 5' and 3' halves. A reanalysis of the existing data on Staphylothermus marinus and Staphylothermus hellenicus hints of a novel hybrid gene that encodes both an un-fragmented and a 5'-split-half together in one. The corresponding 3' complement-gene is located elsewhere on the genome. As un fragmented, the hybrid gene transcribes to tRNA(lys)(TTT). But as 5'-half, it trans-splices with its 3'-complement-half to tRNA(lys)(CTT), the tRNA missed so far. This hybrid of the split and the un-fragmented in one suggests a deeper synergy between the two, and hints of co-evolution. Furthermore, in a subtle contrast to the widely held idea of conservation of 3'-half, it is precisely the 3'-half that varies in these two tRNAs; the 5'-half remains conserved. PMID- 21294594 TI - An efficient binomial model-based measure for sequence comparison and its application. AB - Sequence comparison is one of the major tasks in bioinformatics, which could serve as evidence of structural and functional conservation, as well as of evolutionary relations. There are several similarity/dissimilarity measures for sequence comparison, but challenges remains. This paper presented a binomial model-based measure to analyze biological sequences. With help of a random indicator, the occurrence of a word at any position of sequence can be regarded as a random Bernoulli variable, and the distribution of a sum of the word occurrence is well known to be a binomial one. By using a recursive formula, we computed the binomial probability of the word count and proposed a binomial model based measure based on the relative entropy. The proposed measure was tested by extensive experiments including classification of HEV genotypes and phylogenetic analysis, and further compared with alignment-based and alignment-free measures. The results demonstrate that the proposed measure based on binomial model is more efficient. PMID- 21294596 TI - Development of 41Ca-based pharmacokinetic model for the study of bone remodelling in humans. AB - BACKGROUND AND OBJECTIVE: Initial studies show that 41Ca may be employed as a useful diagnostic bioassay for monitoring metabolic bone disease and its treatment management. The 41Ca-based pharmacokinetic model is developed to assess its feasibility in monitoring bone disease and clinical responsiveness to therapeutic regimens. METHODS: A four-compartment calcium kinetic model is developed to interpret the results of clinically measured 41Ca tracer kinetics for oral and intravenous dose. This model is extended to simulate changes in bone turnover due to osteoporosis by using Gompertzian function with and without cellular accommodation. The rate constants obtained by fitting to the experimental data on drug intervention are used to simulate the impact of strategic treatment intervention. RESULTS: The present model fits well with the available experimental data on 41Ca tracer kinetics. In the simulated osteoporotic model, the negative bone balance (i.e. bone loss) reflected by 41Ca/Ca urine ratio is used to demonstrate slow/fast increase over time compared to the normal state. The cellular accommodation impact is reflected by a recovery from perturbed balance. The model's predictive ability on the impact of therapeutic intervention is verified using published experimental data. The effect of bisphosphonate intervention results in positive bone balance (i.e. bone gain). CONCLUSION: The four-compartment 41Ca tracer kinetic model can be flexibly used in the interpretation of results obtained from ongoing clinical studies. PMID- 21294595 TI - Pharmacokinetic optimization of antiretroviral therapy in children and adolescents. AB - There are over 2.1 million HIV-infected children worldwide, who are increasingly exposed to antiretroviral therapy. Given the enormous physiological changes associated with maturation, the role of individualized therapy and optimal dosing in children and adolescents is likely different than in adults. This review summarizes the pharmacodynamics, pharmacokinetics and pharmacogenomics of antiretroviral therapy in children and adolescents, and it discusses the roles of these in the optimization of therapy through the practice of therapeutic drug monitoring/management. Within the pharmacodynamics section are tables and discussion about what is known of the relationships between drug concentrations, inhibitory quotients and effects - both desired and toxic. The pharmacokinetics section summarizes all reported antiretroviral pharmacokinetic data in children, divided into data from population and non-population analytic approaches. Measures of interindividual pharmacokinetic variability are reported. Sampling strategies for the measurement and the interpretation of plasma antiretroviral drug concentrations are suggested, as well as dosing with degrees of renal or hepatic failure. Relevant pharmacogenomic polymorphisms are summarized, and the role for pharmacogenomics testing is discussed. Incorporation of dose adjustment on the basis of measured serum drug concentrations is reviewed, including all such paediatric experience reported in the literature. Discussion of the influences of malnutrition and herbal remedies is also included. Finally, consideration is given to future work in this field. PMID- 21294597 TI - Population pharmacokinetic evaluation with external validation and Bayesian estimator of voriconazole in liver transplant recipients. AB - OBJECTIVES: The objectives of this study were to evaluate the pharmacokinetics of voriconazole in liver transplant patients, probe covariate effects on voriconazole pharmacokinetics, externally validate the model and explore limited sampling strategies (LSSs) using Bayesian approaches. METHODS: Full pharmacokinetic profiles were collected within one oral dosing interval from 13 liver transplant patients. Nonlinear mixed-effects pharmacokinetic models were developed using NONMEM software. The final model was internally evaluated using bootstrapping and visual predictive check (VPC), and externally validated by predicting additional samples from different patients that were not used for model building. Maximum a posteriori Bayesian estimators were developed to predict the area under the plasma concentration-time curve (AUC) using the validated final model as the a priori model, actual dosing record and covariate values as the input, and a few concentrations (limited sampling) as feedback information (LSS). Mean prediction error (MPE) and mean absolute prediction error (MAPE) were calculated for external validation and LSS. RESULTS: A one compartment model with an absorption lag time (t(lag)) adequately described the data. Population estimates of total clearance after oral administration (CL/F) and volume of distribution after oral administration (V(d)/F) were 7.92 L/h and 248 L, respectively. Values of CL/F, V(d)/F and t(lag) decreased with post operative time and converged to stable levels in about 7 post-operative days. CL/F significantly decreased with increased international normalized ratio. Co administration of pantoprazole, race and alanine aminotransferase were also significantly associated with pharmacokinetic parameters but ultimately excluded in the final model. VPC showed that most of the data fell within the 90% prediction interval and were symmetrically distributed around the median. Additional 52 samples from 19 patients were collected for external validation. MPE was 0.206 MUg/mL (not significantly different from zero) and MAPE was 0.99 MUg/mL. Compared with trough levels, LSS using two samples or one sample at a different time provided better MPE, MAPE and correlation (R2) between the observed and LSS-predicted AUC. CONCLUSIONS: The population model that was developed showed significant association of voriconazole pharmacokinetics with post-operative time and liver function, and was able to predict an independent external dataset. Our observations suggested a need for intravenous administration of voriconazole in the immediate post-operative period before an oral dose can be administrated. LSS using one sample appeared to be sufficient for reasonable AUC estimation. PMID- 21294598 TI - Intra- and interindividual variabilities in the pharmacokinetics of fentanyl buccal soluble film in healthy subjects: a cross-study analysis. AB - BACKGROUND AND OBJECTIVE: Breakthrough pain describes transient exacerbations of pain that occur in cancer patients with adequately controlled background pain. Transmucosal fentanyl administration produces rapid-onset and short-duration analgesia that is effective for treating patients with breakthrough pain. Although a significant amount of research has been devoted to the study of speed of analgesia onset of transmucosal fentanyl products, few data exist on their variability in absorption, particularly within the same individual, despite the importance of this characteristic to the dose-to-dose reliability of their analgesic effect. This cross-study analysis aimed to evaluate the intra- and interindividual pharmacokinetic differences of fentanyl administered via fentanyl buccal soluble film in healthy subjects. METHODS: Data were evaluated from 24 subjects in two pharmacokinetic studies of fentanyl administered via fentanyl buccal soluble film (Breakyl(r)/OnsolisTM; BEMA(r) [BioErodible MucoAdhesive] technology). In one study, 12 healthy subjects received 600 MUg doses of fentanyl as single film on two separate occasions; in the second study, 12 different healthy subjects received 800 MUg doses of fentanyl on two separate occasions, one as a single 800 MUg film and the other as four 200 MUg films. RESULTS: The analysis showed a minimal intraindividual variability and a relatively higher interindividual variability in pharmacokinetic parameters (i.e. maximum plasma concentration, area under the plasma concentration-time curve from time zero to infinity). The coefficient of variation for intraindividual exposure to fentanyl variability was 7-10%, and for interindividual variability was 23-39%. CONCLUSION: The minimal intraindividual variability in fentanyl absorption from the buccal soluble film demonstrates a predictable dose-to-dose exposure, which is a very desirable attribute for a medicine that is intended to treat breakthrough cancer pain, suggesting that this product would be expected to produce consistent effects in clinical practice. The greater interindividual variability highlights the need for individual titration of this product (as occurs with similar transmucosal fentanyl products), and for the availability of an adequately wide dose range. PMID- 21294599 TI - Thiazolidinediones and risk of heart failure in patients with or at high risk of type 2 diabetes mellitus: a meta-analysis and meta-regression analysis of placebo controlled randomized clinical trials. AB - BACKGROUND: Recent meta-analyses of randomized clinical trials (RCTs) demonstrated a higher risk of heart failure (HF) with the use of thiazolidinediones (TZDs). However, this effect may have been diluted by including active controls. Also, it is uncertain whether the risk of HF is similar with rosiglitazone and pioglitazone. OBJECTIVES: This study quantified the risks of HF with the use of TZDs in patients with or at high risk of developing type 2 diabetes mellitus (DM), and evaluated differential effects by type of TZD. Secondarily, we evaluated risks of peripheral edema. METHODS: We performed a systematic review and meta-analysis of placebo-controlled RCTs evaluating the effect of rosiglitazone or pioglitazone on investigator-reported HF and edema. Articles published before 31 December 2009 were searched in MEDLINE, The Web of Science, and Scopus, and the data were extracted by three investigators. RCTs with >=100 patients and >=3 months of follow-up were included. We quantified the effect of TZDs as odds ratios (ORs) by using the Mantel-Haenzel and alternative models. We further evaluated the risk of serious/severe HF, and the effect of several trial characteristics on HF risk by subgroup analysis and meta-regression analysis. RESULTS: 29 trials (n = 20 254) were evaluated. TZDs were significantly associated with HF (TZD 360/6807 [5.3%] vs placebo 234/6328 [3.7%], OR 1.59; 95% CI 1.34, 1.89; p < 0.00001). The risk of HF was higher with rosiglitazone than with pioglitazone (2.73 [95% CI 1.46, 5.10] vs 1.51 [1.26, 1.81]; p = 0.06). TZDs were associated with a similar risk of serious/severe HF (OR 1.47; 95% CI 1.16, 1.87; p = 0.002). Use of TZDs was also associated with edema (OR 2.04; 95% CI 1.85, 2.26; p < 0.00001). HF and edema risks were consistent using Peto and random effects models. Risks of HF were significantly high for the subgroups of trials including patients with or at high risk for type 2 DM, and for the subgroup of trials with >=12 months of follow-up. Meta-regression analysis showed that trials with lower overall baseline risk had higher HF risks. CONCLUSION: In placebo-controlled trials of adult patients with or at high risk for type 2 DM, TZD therapy is significantly and consistently associated with a higher risk of HF. The risk of serious/severe HF is also increased with the use of TZDs. HF risks are similar to those of meta-analyses combining active- and placebo-controlled trials. The benefit/risk profile of TZDs should be considered when treating diabetic patients with or without prior HF. PMID- 21294600 TI - Attitudes of GPs towards Older Adults Psychology Services in the Scottish Highlands. AB - INTRODUCTION: The mental health of older adults is of increasing concern in an aging population and GPs are frequently the gatekeepers to specialist mental health services. Psychotherapy, social interventions and bibliotherapy all have an evidence-base for treating depression and anxiety in the elderly, as does pharmacological treatment. However, the referral rate from GPs for an Older Adults Clinical Psychology service in the Scottish Highlands in the months prior to the study had been very low and the reasons for this were not clear. General practitioners may have felt that depression and anxiety are 'understandable' in older adults and are therefore unsuitable for treatment, or they may have felt that psycho-pharmacotherapy treatments are more effective than the psychotherapy treatment options. Alternatively, local issues associated with the remote location of many NHS Highland GP practices and patients may have prevented them referring. Therefore, the current study aimed to elicit the therapeutic preferences of Highland GPs, the perceived availability of these options and an estimate of the prevalence of older adults in the area suffering from mild or moderate mental health problems. METHOD: Questionnaires including brief quantitative and qualitative questions were sent to all 284 GPs in the area with 119 (46%) were completed and returned. RESULTS: Responses from GPs suggested that many patients with depression or anxiety may not be referred. The GPs indicated that social therapeutic options are seen to be as effective as pharmacological options and more effective than other psychological and bibliotherapy options. However, GPs indicated that they were substantially more likely to prescribe pharmacological options than other forms of therapy. The GPs suggested that lower waiting times and a more localised service would increase the likelihood of a referral being made. CONCLUSIONS: The current study suggests that low awareness of psychological service provision among GPs may have resulted in fewer referrals, rather than low confidence in psychotherapies for this population. The GPs' preference for social interventions may reflect the particular risk of isolation of the elderly in remote communities and may be worthy of consideration when developing services in these areas. PMID- 21294601 TI - Effectiveness of varenicline as an aid to smoking cessation: results of an inter European observational study. AB - BACKGROUND: Varenicline tartrate, a selective partial agonist of the alpha4beta2 nicotinic receptor, has been shown to be an effective smoking cessation aid with an acceptable safety profile in a number of randomized, controlled trials. The aim of the CHOICES (Champix Observational Investigation in the Cessation of Smoking) study was to investigate the effectiveness and safety of varenicline in real-world clinical practice. METHODS: The CHOICES study was a 12-week, prospective, observational, non-comparative study of varenicline conducted in four European countries (Belgium, Greece, Hungary, and Slovenia) between November 21, 2007 and August 3, 2009. Participants were prescribed varenicline according to the recommendations on the European Summary of Product Characteristics (SmPC). Smoking abstinence rates in the 7 days between week 11 and 12 were determined based on verbal reporting using a nicotine use inventory. The safety profile of varenicline was also assessed. RESULTS: Of 566 participants enrolled in this study, 551 received varenicline and were evaluated for effectiveness and safety. At baseline, the overall study population had a mean age of 45.5 years; a mean history of smoking of 27.0 years; and a mean score on the Fagerstrom Test of Nicotine Dependence (FTND) of 6.1. Overall, 64.6% (95% CI 60.1, 68.3) of participants successfully quit smoking by the end of the treatment phase at week 12. The most frequent treatment-emergent (all causality) adverse events were nausea (8.9%), insomnia (2.9%), and sleep disorder (2.2%) of mostly mild or moderate intensity. Discontinuations from the study due to treatment-related adverse events occurred in 3.4% of participants. LIMITATIONS: Abstinence rates were not validated by carbon monoxide measurements, as this is not a practice uniformly used in European countries. CONCLUSIONS: The CHOICES study shows that in a real-world clinical practice setting outside a clinical trial environment, varenicline is an effective smoking cessation aid with an acceptable safety profile. PMID- 21294602 TI - Antifibrinolytic therapy with tranexamic acid in pregnancy and postpartum. AB - OBJECTIVE: The aim of this study is critically to review the available evidence regarding the use, efficacy and safety of tranexamic acid in the management of hemorrhage during pregnancy and for prevention and treatment of postpartum hemorrhage. RESEARCH DESIGN AND METHODS: We performed a systematic search of electronic literature (PubMed, Embase, CINAHL, Scopus, Cochrane, DARE) to review all studies looking at the use of tranexamic acid during pregnancy and puerperium. We did a meta-analysis on three randomized controlled trials that evaluated reduction in blood loss in women undergoing cesarean sections with the use of tranexamic acid. RESULTS: An electronic search yielded 34 articles, the studies dating from 1976 to 2010, five randomized controlled trials, seven observational studies, and twenty-two case reports. Meta-analysis showed that the estimate of the combined effect of tranexamic acid compared with placebo was a difference of 32.5 ml reduction in blood loss (95% CI -4.1-69.13; p = 0.08). Tranexamic acid was also used successfully to prevent and treat bleeding in observation studies and case reports. Pulmonary embolism was reported in two cases; however, the possible involvement of tranexamic acid in these thrombotic episodes could neither be confirmed nor excluded. CONCLUSIONS: The clinical studies suggest that tranexamic acid reduces the amount of blood loss after delivery during cesarean sections and vaginal deliveries, and reduces the requirement for blood transfusion. Tranexamic acid seems to be safe and effective in the prevention and management of bleeding during pregnancy. Further investigation and larger clinical trials with better design and methodological quality are required to confirm these findings. PMID- 21294603 TI - Stabilization of liposomes during drying. AB - INTRODUCTION: During the past 40 years, liposomes have been investigated intensively as drug carriers for anticancer drugs and as the adjuvant components of vaccines, for example. In this context, the development of dry formulations of liposomes is important to ensure a more stable drug product and to avoid the use of the 'cold chain' during distribution. AREAS COVERED: This review provides an overview of the technologies commonly used for the drying of liposomal formulations and the significance of formulation and processing parameters for the drying process. In addition, a review is provided of the protective mechanisms proposed to be responsible for stabilization during processing and in the dry state, with special emphasis on the techniques used for the characterization of the mechanisms. Parameters are discussed that critically influence the liposomal stability during drying and the underlying stabilization mechanisms, including the water replacement theory, vitrification and kosmotropic effects. EXPERT OPINION: Drying of liposomal formulations has contributed to the development of more stable products because liposomes can be dehydrated in the presence of appropriate stabilizing excipients, without affecting the size or the drug encapsulation efficiency. The key to the successful design and preparation of optimal liposomal dry powder formulations is an understanding of the significance of the drying process parameters, and the mechanisms responsible for the stabilization of liposomes during drying and in the dry state. PMID- 21294604 TI - Gene silencing by the Polycomb group proteins and associations with cancer. AB - Cancer not only is associated with inherited genetic sequences but also results from epigenetic changes. Thus, understanding the mechanisms underlying epigenetic modifications is important for cancer prevention, diagnosis, and therapy. There is much evidence showing that some Polycomb group (PcG) proteins are abnormally expressed in certain tumors. This review addresses biological functions and biochemical behaviors of the Polycomb repression complex proteins, including their enzymatic activities. Additionally, the potential mechanisms of PcG gene silencing by PcG and its link to cancers are summarized that will shed light on this novel area of study in cancer. PMID- 21294605 TI - Patients' experiences with lifestyle counselling in general practice: a qualitative study. AB - OBJECTIVE. (1) To elucidate the relevance of Habermas's theory as a practical deliberation procedure in lifestyle counselling in general practice, using a patient perspective. (2) To search for topics which patients consider of significance in such consultations. DESIGN. Qualitative observation and interview study. SETTING. General practice. Subjects. A total of 12 patients were interviewed after lifestyle consultations with their GPs. MAIN OUTCOME MEASURES. How the patients perceived the counselling, how it affected them, and what they wanted from their GP in follow-up consultations. RESULTS. The GP should be a source of medical knowledge and a caretaker, but also actively discuss contextual reasons for lifestyle choices, and be a reflective partner exploring values and norms. The patients wanted their GP to acknowledge emotions and to direct the dialogue towards common ground where advice was adjusted to the concrete life situation. A good, personal doctor-patient relationship created motivation and obligation to change, and allowed counselling to be interpreted as care. CONCLUSION. The findings underscore the necessity of a patient-centred approach in lifestyle counselling and support the relevance of Habermas's theory as practical guidance for deliberation. IMPLICATIONS. The findings suggest that GPs should trust the long-term effects of investing in a good relationship and personalized care in lifestyle consultations. The study should incite the GP to act as an encouraging informer, an explorer of everyday life and reasons for behaviour, a reflective partner, and a caretaker, adjusting medical advice to patients' identity, context, and values. PMID- 21294606 TI - Morphological responses of Legionella pneumophila biofilm to nanoparticle exposure. AB - Legionella pneumophila is a pathogenic bacterium that forms biofilms in natural and anthropogenic habitats. This feature not only facilitates colonization but also limits the effectiveness of biocides. L. pneumophila was exposed to three sizes of citrate-capped gold nanospheres in both planktonic and biofilm stages. TEM micrographs indicated that gold nanoparticles (AuNPs) adsorbed to the bacterial cell surface, were absorbed into the cells, aggregated within the cells, and integrated into the extrapolymeric matrix of the biofilm. Both 4 and 18 nm, but not 50 nm AuNPs caused an alteration of biofilm morphology. Treatment with 20 nm polystyrene spheres did not induce these changes suggesting that the response was a result of the gold and not just the presence of the nanosphere. The morphological changes observed in the biofilm suggest that aquatic ecosystems may be affected by nanoparticle exposure. This may compromise ecosystem functions such as nutrient cycling facilitated by natural biofilms. PMID- 21294607 TI - "Sequential" boron neutron capture therapy (BNCT): a novel approach to BNCT for the treatment of oral cancer in the hamster cheek pouch model. AB - In the present study the therapeutic effect and potential toxicity of the novel "Sequential" boron neutron capture therapy (Seq-BNCT) for the treatment of oral cancer was evaluated in the hamster cheek pouch model at the RA-3 Nuclear Reactor. Two groups of animals were treated with "Sequential" BNCT, i.e., BNCT mediated by boronophenylalanine (BPA) followed by BNCT mediated by sodium decahydrodecaborate (GB-10) either 24 h (Seq-24h-BNCT) or 48 h (Seq-48h-BNCT) later. In an additional group of animals, BPA and GB-10 were administered concomitantly [(BPA + GB-10)-BNCT]. The single-application BNCT was to the same total physical tumor dose as the "Sequential" BNCT treatments. At 28 days post treatment, Seq-24h-BNCT and Seq-48h-BNCT induced, respectively, overall tumor responses of 95 +/- 2% and 91 +/- 3%, with no statistically significant differences between protocols. Overall response for the single treatment with (BPA + GB-10)-BNCT was 75 +/- 5%, significantly lower than for Seq-BNCT. Both Seq BNCT protocols and (BPA + GB-10)-BNCT induced reversible mucositis in the dose limiting precancerous tissue around treated tumors, reaching Grade 3/4 mucositis in 47 +/- 12% and 60 +/- 22% of the animals, respectively. No normal tissue toxicity was associated with tumor response for any of the protocols. "Sequential" BNCT enhanced tumor response without an increase in mucositis in dose-limiting precancerous tissue. PMID- 21294608 TI - Effect of solar particle event radiation on gastrointestinal tract bacterial translocation and immune activation. AB - Space flight conditions within the protection of Earth's gravitational field have been shown to alter immune responses, which could lead to potentially detrimental pathology. An additional risk of extended space travel outside the Earth's gravitational field is the effect of solar particle event (SPE) radiation exposure on the immune system. Organisms that could lead to infection include endogenous, latent viruses, colonizing pathogenics, and commensals, as well as exogenous microbes present in the spacecraft or other astronauts. In this report, the effect of SPE-like radiation on containment of commensal bacteria and the innate immune response induced by its breakdown was investigated at the radiation energies, doses and dose rates expected during an extravehicular excursion outside the Earth's gravitational field. A transient increase in serum lipopolysaccharide was observed 1 day after irradiation and was accompanied by an increase in acute-phase reactants and circulating proinflammatory cytokines, indicating immune activation. Baseline levels were reestablished by 5 days postirradiation. These findings suggest that astronauts exposed to SPE radiation could have impaired containment of colonizing bacteria and associated immune activation. PMID- 21294609 TI - The social interaction of return to work explored from co-workers experiences. AB - PURPOSE: The objective was to explore the role and contribution of co-workers in the return-to-work process. The social interaction of co-workers in the return-to work process are analysed within the framework of the Swedish national and local employer organisational return-to-work policies. METHODS: An exploratory qualitative method was used, consisting of open-ended interviews with 33 workplace actors across seven work units. Organisational return-to-work policies were collected from the three public sector employers. RESULTS: The key findings that emerged during analysis showed that some co-workers have a more work-task oriented approach towards the return-to-work process, whilst others had a more social relational approach. In both situations, the social relations worked hand in hand with job tasks (how task were allocated, and how returning workers were supported by others) and could make or break the return-to-work process. CONCLUSION: A suggestion for improvement of return-to-work models and policies is the need to take into account the social relations amongst workplace actors, especially involving co-workers when planning for return-to-work interventions. Otherwise the proper attention to work arrangements, social communication and the role of co-workers in the return-to-work process might not be seen. PMID- 21294610 TI - Heterotopic ossification after cervical total disc replacement: determination by CT and effects on clinical outcomes. AB - OBJECT: Heterotopic ossification (HO) after cervical total disc replacement (TDR) has been reported to impede artificial disc motion. In all previously reported cases of HO, assessment was based on plain radiographs. The authors hypothesized that CT scan is a more sensitive and accurate detector. The aims of this study were to assess the actual incidence of HO and its effect on outcome in a cohort of patients undergoing cervical TDR with the Bryan disc and to compare HO detection by means of plain radiographs and CT. METHODS: The authors retrospectively assessed data from medical records, radiological studies, and clinical evaluations of patients who underwent 1- or 2-level cervical TDR with the Bryan disc and were followed up for more than 12 months. The presence and grading of HO according to the McAfee classification were assessed by CT scan, and these findings were compared with findings on plain radiographs. Thirty-six patients (mean age 46.61 +/- 7.24 years; range 29-60 years; 21 men and 15 women) who underwent Bryan TDR at 52 levels were included in the study. The mean duration of CT follow-up was 19.03 +/- 4.64 months; the mean duration of clinical follow-up was 26.78 +/- 7.20 months. RESULTS: On the basis of CT, HO was identified in 18 (50%) of 36 patients and 25 (48.1%) of 52 levels treated. Grade 1 HO was present in 9 of the levels treated (17.3%), Grade 2 in 13 levels (25.0%), Grade 3 in 2 levels (3.8%), and Grade 4 in 1 level (1.9%). Nineteen (76%) of the 25 affected levels were in patients who had undergone 2-level TDR. There was no significant association with patient sex or disc pathology. There was a tendency for HO development among older patients, but this finding was not statistically significant (mean age 48.8 +/- 6.8 in patients with HO vs 44.4 +/- 7.2 in those without HO, p = 0.065). Although HO was found in 25 levels, 96.2% of the treated levels (50 of 52) had segmental range of motion on dynamic (flexion and extension) radiographs. The concordance between HO grading by CT and radiography was high, with an intraclass correlation coefficient of 0.822 (lower limit of 95% CI: 0.710, p < 0.001). Patients who had HO had the same clinical success rate as those who did not (94.4% vs 94.4%, p = 1.00). The visual analog scale scores for neck and arm pain were significantly improved in both the HO and the non-HO group. CONCLUSIONS: The rate of HO detected by CT scan in this cohort of patients undergoing cervical TDR with a Bryan disc was 48.1% per level treated and 50% per patient with minimal limitation of segmental motion (96.2% of levels remained mobile), but plain radiograph is an acceptable detection tool. Two-level surgery has a higher risk of HO, although development of HO does not affect clinical outcome. PMID- 21294611 TI - Posterior ring apophysis separation combined with lumbar disc herniation in adults: a 10-year experience in the surgical management of 87 cases. AB - OBJECT: The association of posterior ring apophysis separation (PRAS) with lumbar disc herniation (LDH) is uncommon and represents a true subgroup of disc herniation mainly seen in the adolescent population. The objective of this study was to describe a decade of experience in the care of adult patients with PRAS with LDH, giving particular attention to its diagnosis, surgical treatment, and outcome. METHODS: This retrospective study focuses on a case series of adult patients with PRAS associated with LDH who underwent surgery for lumbar disc disease in the author's neurosurgical department between 1999 and 2008. Posterior ring apophysis separation was diagnosed in 87 (5.35%) of 1625 patients surgically treated for LDH; these patients made up the PRAS group. During a 6-month period in 2005, LDH without PRAS was diagnosed in 89 consecutive patients at the same facility; these patients constituted the control group. Presenting symptoms, physical examination findings, and preoperative imaging results were obtained from medical records. Immediate operative results were assessed, as were complications, long-term outcome, and the need for repeat surgery. RESULTS: This study is the first to document the distinguishing features between adult patients with and those without PRAS. The difference in average age was statistically significant (p < 0.001) between the study group (36.22 years) and the control group (44.30 years), as was the incidence of male patients (86.20% vs 71.91%, p = 0.020), incidence of military patients (74.71% vs 57.30%, p = 0.015), average duration of symptoms (16.13 vs 8.4 months, p = 0.016), and incidence of reactive scoliosis (19.54% vs 4.49%, p = 0.002). The most common anatomical location of disc herniation in the PRAS group was L5-S1 (51.72%) versus L4-L5 (53.93%) in the control group (p = 0.017). In terms of previous injury, motor deficits, back and/or leg pain, lateral or central location of LDH, mean anteroposterior diameter of disc herniation, hard or soft discs, and surgical complications, there was no statistical difference between the 2 patient groups. Similarly, there was no difference in recurrence rates and clinical outcomes between the patients with or without PRAS. CONCLUSIONS: Posterior ring apophysis separation with LDH is probably more common in adults than is generally recognized. It must be suspected when young male patients with persistent sciatic scoliosis and no history of injury show signs of calcified LDH. Computed tomography scanning with sagittal reconstructions is the procedure of choice for diagnosing. The L5-S1 intervertebral disc level is most commonly affected, especially the superior endplate of S-1. This condition needs more extensive surgical exposure and resection to relieve the nerve impingement. The occurrence of an apophyseal lesion was not associated with recurrent disc herniation or a fair outcome. PMID- 21294612 TI - Ankylosing spondylitis of the craniovertebral junction: a single surgeon's experience. AB - OBJECT: The objective of this study was to describe a single surgeon's experience managing craniovertebral junction (CVJ) disease due to ankylosing spondylitis. METHODS: The authors undertook a retrospective review of the records of patients with CVJ disease due to ankylosing spondylitis who were evaluated and treated by the senior author. Charts were reviewed for symptoms and signs at presentation, radiography results, treatment, and outcome. In addition, some of the patients had pathology reports available for review. RESULTS: Eight patients with CVJ disease due to ankylosing spondylitis were identified who were evaluated by the senior author in the years 1990-2008. The most common presenting symptoms were neck pain (37.5%), cranial neuropathy (37.5%), and sensory disturbance (62.5%). On examination, the most common findings were limited cervical range of motion (37.5%), weakness (50%), and myelopathy (75%). Radiographic evaluation revealed atlantoaxial subluxation, retroodontoid pannus formation, basilar invagination, and bone erosion. Surgery was offered to all of the patients, 7 of whom underwent operations. In most cases, the treatment was transoral-transpalatopharyngeal decompression followed by occipitocervical fusion. One patient with a reducible lesion underwent dorsal fusion alone. Neurological outcomes were favorable overall. CONCLUSIONS: The incidence of CVJ disease in patients with ankylosing spondylitis varies among reports. These cases are rare in most neurosurgery clinics. It is important to recognize that patients with ankylosing spondylitis are at risk for CVJ disease, similar to patients with rheumatoid arthritis. Principles common to the management of other CVJ pathologies apply to these patients as well. PMID- 21294613 TI - Giant ganglionic cyst of the hip as a rare cause of sciatica. AB - Although ganglionic cysts located at the hip joint are described infrequently, those found in this region are usually small, deep-seated, and asymptomatic. Occasionally, however, a large ganglionic cyst of the hip area is observed that becomes symptomatic following compression of adjacent neurovascular bundles. In this report, the authors describe a 51-year-old man with symptoms of sciatica caused by a giant ganglionic cyst of the posterior hip joint. Because of its intermuscular location, the cyst was not palpable, and was probably misdiagnosed previously as a herniated disc of the lumbar spine. After resection of the cyst, the patient's symptoms resolved completely. This case highlights the importance of a detailed clinical examination for patients with multiple degenerative joint diseases. PMID- 21294614 TI - Spinal ependymomas in neurofibromatosis Type 2: a retrospective analysis of 55 patients. AB - OBJECT: The aim of this paper was to define the clinical characteristics of spinal ependymomas associated with neurofibromatosis Type 2 (NF2). METHODS: The authors retrospectively reviewed the clinical records of patients with NF2 who had imaging findings consistent with ependymomas and were seen at Massachusetts General Hospital between 1994 and 2007. Clinical characteristics of these patients were obtained from hospital records, imaging studies, surgical reports, and pathology reports. Mutational analysis of the NF2 gene was performed in 37 of 44 unrelated patients. RESULTS: Fifty-five patients met inclusion criteria for the study. The median age at diagnosis of NF2 was 21 years; the median time after diagnosis until identification of ependymomas was 5 years. Multiple ependymomas were present in 58% of patients. The most common site of involvement was the cervical cord or cervicomedullary junction (86% of imaging studies), followed by the thoracic and lumbar cords (62% and 8%, respectively). The majority of patients had no symptoms related to their tumors (42 patients [76%]). After a median follow-up of 50 months, surgery was performed in 11 patients (20%) for symptomatic progression (indications for surgery). Mutational analysis of the NF2 gene detected alterations in 28 (76%) of 37 unrelated patients, with nonsense and frameshift mutations accounting for 64% of detected mutations. The high rate of truncating mutations may help explain the high tumor burden in these patients. CONCLUSIONS: Neurofibromatosis Type 2-related ependymomas exhibit an indolent growth pattern with tumor progression limited to a minority of patients. The authors believe that surveillance is reasonable for asymptomatic ependymomas, including those with cystic areas that expand the cord. For symptomatic tumors, resection may be warranted depending on age, overall clinical status, and ease of resectability. PMID- 21294615 TI - Correlation of higher preoperative American Society of Anesthesiology grade and increased morbidity and mortality rates in patients undergoing spine surgery. AB - OBJECT: Patients with varied medical comorbidities often present with spinal pathology for which operative intervention is potentially indicated, but few studies have examined risk stratification in determining morbidity and mortality rates associated with the operative treatment of spinal disorders. This study provides an analysis of morbidity and mortality data associated with 22,857 cases reported in the multicenter, multisurgeon Scoliosis Research Society Morbidity and Mortality database stratified by American Society of Anesthesiologists (ASA) physical status classification, a commonly used system to describe preoperative physical status and to predict operative morbidity. METHODS: The Scoliosis Research Society Morbidity and Mortality database was queried for the year 2007, the year in which ASA data were collected. Inclusion criterion was a reported ASA grade. Cases were categorized by operation type and disease process. Details on the surgical approach and type of instrumentation were recorded. Major perioperative complications and deaths were evaluated. Two large subgroups- patients with adult degenerative lumbar disease and patients with major deformity -were also analyzed separately. Statistical analyses were performed with the chi square test. RESULTS: The population studied comprised 22,857 patients. Spinal disease included degenerative disease (9409 cases), scoliosis (6782 cases), spondylolisthesis (2144 cases), trauma (1314 cases), kyphosis (831 cases), and other (2377 cases). The overall complication rate was 8.4%. Complication rates for ASA Grades 1 through 5 were 5.4%, 9.0%, 14.4%, 20.3%, and 50.0%, respectively (p = 0.001). In patients undergoing surgery for degenerative lumbar diseases and major adult deformity, similarly increasing rates of morbidity were found in higher-grade patients. The mortality rate was also higher in higher-grade patients. The incidence of major complications, including wound infections, hematomas, respiratory problems, and thromboembolic events, was also greater in patients with higher ASA grades. CONCLUSIONS: Patients with higher ASA grades undergoing spinal surgery had significantly higher rates of morbidity than those with lower ASA grades. Given the common application of the ASA system to surgical patients, this grade may prove helpful for surgical decision making and preoperative counseling with regard to risks of morbidity and mortality. PMID- 21294616 TI - Chiari malformation Type I. PMID- 21294617 TI - Brain injury after intracerebral hemorrhage in spontaneously hypertensive rats. AB - OBJECT: Hypertension is the main cause of spontaneous intracerebral hemorrhages (ICHs), but the effects of hypertension on ICH-induced brain injury have not been well studied. In this study, the authors examined ICH-induced brain injury in spontaneously hypertensive rats (SHRs). METHODS: This 2-part study was performed in 12-week-old male SHRs and Wistar Kyoto (WKY) rats. First, the rats received an intracaudate injection of 0.3 U collagenase, and hematoma sizes were determined at 24 hours. Second, rats were injected with 100 MUl autologous whole blood into the right basal ganglia. Brain edema, neuronal death, ferritin expression, microglia activation, and neurological deficits were examined. RESULTS: Hematoma sizes were the same in SHR and WKY rats 24 hours after collagenase injection. The SHRs had greater neuronal death and neurological deficits after blood injection. Intracerebral hemorrhage also resulted in higher brain ferritin levels and stronger activation of microglia in SHRs. However, perihematomal brain edema was the same in the SHRs and WKY rats. CONCLUSIONS: Moderate chronic hypertension resulted in more severe ICH-induced neuronal death and neurological deficits, but did not exaggerate hematoma enlargement and perihematomal brain edema in the rat ICH models. PMID- 21294618 TI - Max Brodel: his art, legacy, and contributions to neurosurgery through medical illustration. AB - Max Brodel is considered the father of modern medical illustration. This report reviews his contributions to neurosurgery as a medical illustrator. Max Brodel, a young artist from Leipzig, Germany, was hired at Johns Hopkins Hospital in 1894, where he illustrated an operative textbook of gynecology for Howard A. Kelly. Although Brodel did not have any formal medical training, he quickly acquired knowledge of anatomy, pathology, physiology, and surgery. Brodel's extraordinary illustrations were characterized by an aerial perspective that conveyed the surgeon's operative viewpoint and precise surgical anatomy. He masterfully incorporated tissue realism with cross-sectional anatomy to accentuate concepts while maintaining topographical accuracy. Brodel's reputation spread quickly and resulted in collaborations with prominent surgeons, such as Cushing, Halsted, and Dandy. Cushing, who also possessed artistic talent, became a pupil of Brodel and remained a very close friend. In 1911, Brodel was appointed the director of the Department of Art as Applied to Medicine at Johns Hopkins, the first academic department of its kind in the world. For the next several decades, he trained generations of renowned medical illustrators. Just as Osler, Halsted, and Cushing passed their skills and knowledge to future leaders of medicine and surgery, Brodel did the same for the field of medical illustration. The advancement of neurosurgical education has been greatly facilitated by Max Brodel's artistic contributions. His unique ability to synthesize art and medicine resulted in timeless illustrations that remain indispensable to surgeons. The art produced by his legacy of illustrators continues to flourish in neurosurgical literature today. PMID- 21294619 TI - Posterior fossa volume increase after surgery for Chiari malformation Type I: a quantitative assessment using magnetic resonance imaging and correlations with the treatment response. AB - OBJECT: The aim of this paper was to measure the posterior fossa (PF) volume increase resulting from a given-sized occipital craniectomy in Chiari malformation Type I surgery and to analyze its correlations with the PF size and the treatment response, with the perspective of tailoring the amount of bone removal to the patient-specific PF dimensions. METHODS: Between January 2005 and June 2006, 11 adult patients with symptomatic Chiari malformation Type I underwent a standardized PF decompression. A prospective evaluation with clinical examination, functional grading, and MR imaging measurement protocols was performed pre- and postoperatively. A method is reported for the measurement of PF volume (PFV) after surgery. The degree of PFV increase was compared with the preoperative size of the PF and with the clinical outcome. RESULTS: All 11 patients improved postoperatively, with complete and partial recovery in 4 and 7 patients, respectively. No postoperative complication occurred after a mean follow-up period of 45 months. The mean relative increase in PFV accounted for 10% (range 1.5%-19.7%) of the initial PFV; the increase was greater in cases in which the PF was small (r = -0.52, p = 0.09) and the basiocciput was short (r = 0.37, p = 0.2). A statistically significant positive correlation was found between the degree of PFV increase and the treatment response (p = 0.014); complete recovery was observed with a PFV increase of 15% and partial recovery with an increase of 7%. CONCLUSIONS: The treatment response is significantly influenced by the degree of PFV increase, which is dependent on the size of the PF and the extent of the craniectomy, suggesting that the optimal patient specific PFV increase could be predicted on the basis of preoperative MR imaging and enhancing the perspective that the craniectomy size could be tailored to the individual PFV. PMID- 21294620 TI - Evaluation of a bispecific biological drug designed to simultaneously target glioblastoma and its neovasculature in the brain. AB - OBJECT: The authors of this study aimed to genetically design a bispecific targeted toxin that would simultaneously target overexpressed markers on glioma as well as the tumor vasculature, to mutate certain amino acids to reduce the immunogenicity of this new drug, and to determine whether the drug was able to effectively reduce aggressive human brain tumors in a rat xenograft model via a novel hollow fiber (HF) catheter delivery system. METHODS: A new bispecific ligand-directed toxin (BLT) was created in which 2 human cytokines-epidermal growth factor ([EGF], targeting overexpressed EGF receptor) and amino acid terminal fragment ([ATF], targeting urokinase plasminogen activator receptor) were cloned onto the same single-chain molecule with truncated Pseudomonas exotoxin with a terminal lysyl-aspartyl-glutamyl-leucine (KDEL) sequence. Site specific mutagenesis was used to mutate amino acids in 7 key epitopic toxin regions that dictate the B cell generation of neutralizing antitoxin antibodies to deimmunize the drug, now called "EGFATFKDEL 7mut." Bioassays were used to determine whether mutation reduced the drug's potency, and enzyme-linked immunosorbent assay studies were performed to determine whether antitoxin antibodies were decreased. Aggressive brain tumors were intracranially established in nude rats by using human U87 glioma genetically marked with a firefly luciferase reporter gene (U87-luc), and the rats were stereotactically treated with 2 intracranial injections of deimmunized EGFATFKDEL via convection enhanced delivery (CED). Drug was administered through a novel HF catheter to reduce drug backflow upon delivery. RESULTS: In vitro, EGFATFKDEL 7mut selectively killed the human glioblastoma cell line U87-luc as well as cultured human endothelial cells in the form of the human umbilical vein endothelial cells. Deimmunization did not reduce drug activity. In vivo, when rats with brain tumors were intracranially treated with drug via CED and a novel HF catheter to reduce backflow, there were significant tumor reductions in 2 experiments (p < 0.01). Some rats survived with a tumor-free status until 130 days post-tumor inoculation. An irrelevant BLT control did not protect establishing specificity. The maximal tolerated dose of EGFATFKDEL 7mut was established at 2 MUg/injection or 8.0 MUg/kg, and data indicated that this dose was nontoxic. Antitoxin antibodies were reduced by at least 90%. CONCLUSIONS: First, data indicated that the BLT framework is effective for simultaneously targeting glioma and its neovasculature. Second, in the rodent CED studies, newly developed HF catheters that limit backflow are effective for drug delivery. Third, by mutating critical amino acids, the authors reduced the threat of the interference of neutralizing antibodies that are generated against the drug. The authors' experiments addressed some of the most urgent limitations in the targeted toxin field. PMID- 21294621 TI - Selective ophthalmic artery infusion of chemotherapy for advanced intraocular retinoblastoma: initial experience with 17 tumors. AB - OBJECT: Retinoblastoma is the most common ocular neoplasm in children. Left untreated it spreads to the brain via the optic nerve. Traditional therapy is enucleation, and while this procedure is still the most common treatment worldwide, modern eye-preserving therapies can often spare the globe. However, patients with retinoblastoma often present in advanced stages of the disease when these globe-preserving strategies are often insufficient to prevent enucleation. In these challenging cases, direct infusion of chemotherapy into the ophthalmic artery has been attempted to achieve tumor control. The authors' aim in this study was to report on their initial experience with and clinical results for this approach. METHODS: The authors prospectively collected data on all cases of retinoblastoma treated with selective intraophthalmic melphalan at Bascom Palmer Eye Institute. All cases were classified as International Intraocular Retinoblastoma Classification (IIRC) Group D or Reese-Ellsworth Group Vb, had not responded to aggressive multimodal therapy consisting of chemotherapy and focal consolidating laser therapy, and were pending enucleation. Using digital subtraction angiography, a microcatheter was navigated under roadmap guidance into the ophthalmic artery, and melphalan was infused over 40 minutes. Early in the series, patients were treated with 3 or 5 mg of melphalan, but after low response rates occurred all eyes were treated with 7.5 mg of melphalan. All patients were examined with funduscopy while under anesthesia 3 weeks after treatment and every 3 months thereafter. Patients with persistent disease were retreated with repeat infusions of melphalan. RESULTS: Twenty-six procedures were performed to treat 17 tumors in 15 patients. Successful cannulation of the ophthalmic artery was achieved in all cases. The follow-up ranged from 3 to 12 months, with a mean of 8.6 months. Overall, 76% of the tumors responded to therapy and these cases were spared enucleation. The average number of treatments was 1.5 per tumor. Of the responders, 54% responded to a single dose of melphalan. Treatment with the higher dose of 7.5 mg up front was associated with a lower enucleation rate (0% vs 36%) as compared with the lower starting dose. Delayed vitreous hemorrhage occurred after 4 (15%) of 26 treatments, and these cases were treated with enucleation. CONCLUSIONS: In this challenging group of advanced retinoblastomas refractory to aggressive multimodal therapy, virtually 100% of eyes are generally enucleated. In contrast, the authors' protocol of infusing melphalan directly into the ophthalmic artery led to a dramatic decrease in the enucleation rate to 23.5%. While it is now the treatment of choice for refractory retinoblastoma at their center, its role in less advanced disease remains to be elucidated. PMID- 21294622 TI - The collagenic architecture of human dura mater. AB - OBJECT: Human dura mater is the most external meningeal sheet surrounding the CNS. It provides an efficient protection to intracranial structures and represents the most important site for CSF turnover. Its intrinsic architecture is made up of fibrous tissue including collagenic and elastic fibers that guarantee the maintenance of its biophysical features. The recent technical advances in the repair of dural defects have allowed for the creation of many synthetic and biological grafts. However, no detailed studies on the 3D microscopic disposition of collagenic fibers in dura mater are available. The authors report on the collagenic 3D architecture of normal dura mater highlighting the orientation, disposition in 3 dimensions, and shape of the collagen fibers with respect to the observed layer. METHODS: Thirty-two dura mater specimens were collected during cranial decompressive surgical procedures, fixed in 2.5% Karnovsky solution, and digested in 1 N NaOH solution. After a routine procedure, the specimens were observed using a scanning electron microscope. RESULTS: The authors distinguished the following 5 layers in the fibrous dura mater of varying thicknesses, orientation, and structures: bone surface, external median, vascular, internal median, and arachnoid layers. CONCLUSIONS: The description of the ultrastructural 3D organization of the different layers of dura mater will give us more information for the creation of synthetic grafts that are as similar as possible to normal dura mater. This description will be also related to the study of the neoplastic invasion. PMID- 21294623 TI - Effect of manufacturing method on the in vitro drug release and adhesive performance of drug-in-adhesive films containing binary mixtures of ibuprofen with poloxamer 188. AB - Drug-in-adhesive acrylic films, containing binary mixtures of ibuprofen:poloxamer 188 in 30:70, 40:60, 50:50, and 60:40 ratios, were prepared by incorporation either as physical mixture (PM), molten mixture (MM), or solid dispersion (SD). Dissolution testing showed that films prepared by MM had higher drug release compared to films prepared by PM, SD, and films containing ibuprofen alone. The MM 50:50 ratio showed the highest drug release (p < 0.05). Examination of the films by differential scanning calorimetry showed melting endotherms from the binary crystalline mixture but not from ibuprofen crystals regardless of the preparation method. Rheological measurements showed that MM films had lower elastic moduli compared to the neat adhesive, due to the plasticizing effect of the dissolved binary mixture. Fourier transfer infrared analysis confirmed the absence of ibuprofen crystal dimers in all films. It was therefore concluded that the MM method provided better mixing of the components providing crystal-free supersaturated films of high thermodynamic activity. PMID- 21294624 TI - The evolutionary genetics of emerging plant RNA viruses. AB - Over the years, agriculture across the world has been compromised by a succession of devastating epidemics caused by new viruses that spilled over from reservoir species or by new variants of classic viruses that acquired new virulence factors or changed their epidemiological patterns. Viral emergence is usually associated with ecological change or with agronomical practices bringing together reservoirs and crop species. The complete picture is, however, much more complex, and results from an evolutionary process in which the main players are ecological factors, viruses' genetic plasticity, and host factors required for virus replication, all mixed with a good measure of stochasticity. The present review puts emergence of plant RNA viruses into the framework of evolutionary genetics, stressing that viral emergence begins with a stochastic process that involves the transmission of a preexisting viral strain into a new host species, followed by adaptation to the new host. PMID- 21294625 TI - In vitro and in vivo pharmacokinetic characterizations of AMG 900, an orally bioavailable small molecule inhibitor of aurora kinases. AB - AMG 900 is a small molecule being developed as an orally administered, highly potent, and selective pan-aurora kinase inhibitor. The aim of the investigations was to characterize in vitro and in vivo pharmacokinetic (PK) properties of AMG 900 in preclinical species. AMG 900 was rapidly metabolized in liver microsomes and highly bound to plasma proteins in the species tested. It was a weak Pgp substrate with good passive permeability. AMG 900 exhibited a low-to-moderate clearance and a small volume of distribution. Its terminal elimination half-life ranged from 0.6 to 2.4 h. AMG 900 was well-absorbed in fasted animals with an oral bioavailability of 31% to 107%. Food intake had an effect on rate (rats) or extent (dogs) of AMG 900 oral absorption. The clearance and volume of distribution at steady state in humans were predicted to be 27.3 mL/h/kg and 93.9 mL/kg, respectively. AMG 900 exhibited acceptable PK properties in preclinical species and was predicted to have low clearance in humans. AMG 900 is currently in Phase I clinical testing as a treatment for solid tumours. Preliminary human PK results appear to be consistent with the predictions. PMID- 21294626 TI - In vitro metabolism of magnolin and characterization of cytochrome P450 enzymes responsible for its metabolism in human liver microsomes. AB - Magnolin is a major bioactive component found in Shin-i, the dried flower buds of Magnolia fargesii; it has anti-inflammatory and anti-histaminic activities. Incubation of magnolin in human liver microsomes with an nicotinamide adenine dinucleotide phosphate-generating system resulted in the formation of five metabolites, namely, O-desmethyl magnolin (M1 and M2), didesmethylmagnolin (M3), and hydroxymagnolin (M4 and M5). In this study, we characterized the human liver cytochrome P450 (CYP) enzymes responsible for the biotransformation of three major metabolites--M1, M2, and M4--of magnolin. CYP2C8, CYP2C9, CYP2C19, and CYP3A4 were identified as the major enzymes responsible for the formation of the two O-desmethyl magnolins (M1 and M2), on the basis of a combination of correlation analysis and experiments, including immunoinhibition of magnolin in human liver microsomes and metabolism of magnolin by human cDNA-expressed CYP enzymes. CYP2C8 played a predominant role in the formation of hydroxymagnolin (M4). These results suggest that the pharmacokinetics of magnolin may not be affected by CYP2C8, CYP2C9, CYP2C19, and CYP3A4 responsible for the metabolism of magnolin or by the co-administration of appropriate CYP2C8, CYP2C9, CYP2C19, and CYP3A4 inhibitors or inducers due to the involvement of multiple CYP enzymes in the metabolism of magnolin. PMID- 21294627 TI - An open, interoperable, and scalable prehospital information technology network architecture. AB - Some of the most intractable challenges in prehospital medicine include response time optimization, inefficiencies at the emergency medical services (EMS) emergency department (ED) interface, and the ability to correlate field interventions with patient outcomes. Information technology (IT) can address these and other concerns by ensuring that system and patient information is received when and where it is needed, is fully integrated with prior and subsequent patient information, and is securely archived. Some EMS agencies have begun adopting information technologies, such as wireless transmission of 12-lead electrocardiograms, but few agencies have developed a comprehensive plan for management of their prehospital information and integration with other electronic medical records. This perspective article highlights the challenges and limitations of integrating IT elements without a strategic plan, and proposes an open, interoperable, and scalable prehospital information technology (PHIT) architecture. The two core components of this PHIT architecture are 1) routers with broadband network connectivity to share data between ambulance devices and EMS system information services and 2) an electronic patient care report to organize and archive all electronic prehospital data. To successfully implement this comprehensive PHIT architecture, data and technology requirements must be based on best available evidence, and the system must adhere to health data standards as well as privacy and security regulations. Recent federal legislation prioritizing health information technology may position federal agencies to help design and fund PHIT architectures. PMID- 21294628 TI - Effectiveness of prehospital morphine, fentanyl, and methoxyflurane in pediatric patients. AB - OBJECTIVES: To compare the effectiveness of intravenous morphine, intranasal (IN) fentanyl, and inhaled methoxyflurane for managing moderate to severe pain in pediatric patients in the out-of-hospital setting. METHODS: We conducted a retrospective comparative study of 3,312 pediatric patients aged between 5 and 15 years who had moderate to severe pain (pain score >= 5) and who received intravenous morphine, IN fentanyl, or inhaled methoxyflurane, either alone or in combination, between January 1, 2004, and November 30, 2006. Multivariate logistic regression was used to analyze data extracted from a clinical database containing routinely entered information from patient health care records. The primary outcome measure was effective analgesia, defined as a reduction in pain severity of >= 30% of initial pain score using an 11-point verbal numeric rating scale. RESULTS: Effective analgesia was achieved in 82.5% of cases overall. All analgesic agents were effective in the majority of patients (87.5%, 89.5%, and 78.3% for morphine, fentanyl, and methoxyflurane, respectively). There was evidence that methoxyflurane was less effective than both morphine (odds ratio [OR] 0.52; 95% confidence interval [CI] 0.36-0.74) and fentanyl (OR 0.43; 95% CI 0.29-0.62; p < 0.0001). There was no clinical or statistical evidence of difference in the effectiveness of fentanyl and morphine in this population (OR 1.22; 95% CI 0.74-2.01). There was no evidence that combination analgesia was better than either fentanyl or morphine alone. CONCLUSION: Intranasal fentanyl and intravenous morphine are equally effective analgesic agents in pediatric patients with moderate to severe acute pain in the out-of-hospital setting. Methoxyflurane is less effective in comparison with both morphine and fentanyl, but is an effective analgesic in the majority of children. PMID- 21294629 TI - Prehospital emergency removal of football helmets using two techniques. AB - OBJECTIVE: To compare the Eject Helmet Removal (EHR) System with manual football helmet removal. METHODS: This quasiexperimental counterbalanced study was conducted in a controlled laboratory setting. Thirty certified athletic trainers (17 men and 13 women; mean +/- standard deviation age: 33.03 +/- 10.02 years; height: 174.53 +/- 12.04 cm; mass: 85.19 +/- 19.84 kg) participated after providing informed consent. Participants removed a Riddell Revolution IQ football helmet from a healthy model two times each under two conditions: manual helmet removal (MHR) and removal with the EHR system. A six-camera, three-dimensional motion capture system was used to record range of motion (ROM) of the head. A digital stopwatch was used to time trials and to record a split time associated with EHR system bladder insertion. A modified Borg CR10 scale was used to measure the rating of perceived exertion (RPE). Mean values were created for each variable. Three pairwise t-tests with Bonferroni-corrected alpha levels tested for differences between time for removal, split time, and RPE. A 2 x 3 (condition x plane) totally within-subjects repeated-measures design analysis of variance (ANOVA) tested for differences in head ROM between the sagittal, frontal, and transverse planes. Analyses were performed using SPSS (version 18.0) (alpha = 0.05). RESULTS: There was no statistically significant difference in perceived difficulty between EHR (RPE = 2.73) and MHR (RPE = 2.55) (t(29) = 0.76; p = 0.45; d = 0.20). Manual helmet removal was, on average, 28.95 seconds faster than EHR (t(29) = 11.44; p < 0.001). Head ROM was greater during EHR compared with MHR in the sagittal (t(29) = 4.57; p < 0.001), frontal (t(29) = 5.90; p < 0.001), and transverse (t(29) = 8.34; p < 0.001) planes. Head ROM was also greater during the helmet-removal portion of EHR in the frontal (t(29) = 4.44; p < 0.001) and transverse (t(29) = 5.99; p < 0.001) planes, compared with MHR. Regardless of technique, sagittal-plane head ROM was greater than frontal- and transverse-plane movements (F(2,58) = 241.47; p < 0.001). CONCLUSIONS: Removing a helmet manually is faster and creates slightly less motion than removing a helmet using the Eject system. Both techniques were equally easy to use. Future research should analyze the performance of the Eject system in other styles of football helmets and in helmets used in other sports such as lacrosse, motorsports, and ice hockey. PMID- 21294630 TI - Study of placing a second intravenous line in trauma. AB - OBJECTIVE: We evaluated the benefit of emergency medical services providers' placing a second intravenous (IV) line in the prehospital trauma setting. Our hypothesis was that the placement of a second IV catheter in trauma does not result in an improvement in heart rate, blood pressure, rehospitalizaton rate, or 30-day mortality. METHODS: A retrospective chart review of 320 trauma patients in a one-year period was conducted at our level I trauma center. All trauma patients who had vascular access obtained prehospitally were included. RESULTS: Patients with two IV lines received an average of 348.4 mL more fluid (95% confidence interval [CI]: 235.6, 461.1; p < 0.0001). No change in heart rate, pulse oximetry, Glasgow Coma Scale score, systolic blood pressure, rehospitalization rate, or 30-day mortality was noted. These effects persisted for patients who were initially tachycardic (heart rate 3.92 bpm; 95% CI ?3.01, 10.82; p = 0.27) or hypotensive (blood pressure 22.00 mmHg; 95% CI ?4.17, 48.16; p = 0.10). CONCLUSIONS: Redundant prehospital IV lines provided no noticeable benefit in physiologic support for trauma patients. When controlling for confounding variables, no significant outcome difference was noted, even in the hypotensive patients. The traditional approach for establishment of a secondary IV line in prehospital trauma patients should not be followed in a dogmatic fashion. PMID- 21294631 TI - A comparison of cooling techniques in firefighters after a live burn evolution. AB - OBJECTIVE: We compared the use of two active cooling devices with passive cooling in a moderate-temperature (~ 22 degrees C) environment on heart rate (HR) and core temperature (T(c)) recovery when applied to firefighters following 20 minutes of fire suppression. METHODS: Firefighters (23 men, two women) performed 20 minutes of fire suppression at a live-fire evolution. Immediately following the evolution, the subjects removed their thermal protective clothing and were randomized to receive forearm immersion (FI), ice water perfused cooling vest (CV), or passive (P) cooling in an air-conditioned medical trailer for 30 minutes. Heart rate and deep gastric temperature were monitored every 5 minutes during recovery. RESULTS: A single 20-minute bout of fire suppression resulted in near-maximal mean +/- standard deviation HR (175 +/- 13 b min(-1), P; 172 +/- 20 b.min(-1), FI; 177 +/- 12 b.min(-1), CV) when compared with baseline (p < 0.001), a rapid and substantial rise in T(c) (38.2 degrees +/- 0.7 degrees , P; 38.3 degrees +/- 0.4 degrees , FI; 38.3 degrees +/- 0.3 degrees , CV) compared with baseline (p < 0.001), and body mass lost from sweating of nearly 1 kilogram. Cooling rates ( degrees C.min) differed (p = 0.036) by device, with FI (0.05 +/- 0.04) providing higher rates than P (0.03 +/- 0.02) or CV (0.03 +/- 0.04), although differences over 30 minutes were small and recovery of body temperature was incomplete in all groups. CONCLUSIONS: During 30 minutes of recovery following a 20-minute bout of fire suppression in a training academy setting, there is a slightly higher cooling rate for FI and no apparent benefit to CV when compared with P cooling in a moderate temperature environment. PMID- 21294632 TI - Isolation of live label-retaining cells and cells undergoing asymmetric cell division via nonrandom chromosomal cosegregation from human cancers. AB - The ability to retain DNA labels over time is a property proposed to be associated with adult stem cells. Recently, label retaining cells (LRC) were indentified in cancer. LRC were suggested to be the result of either slow-cycling or asymmetric-cell-division with nonrandom-chromosomal-cosegregation (ACD-NRCC). ACD-NRCC is proposed to segregate the older template DNA strands into daughter stem cells and newly synthesized DNA into daughter cells destined for differentiation. The existence of cells undergoing ACD-NRCC and the stem-like nature of LRC remain controversial. Currently, to detect LRC and ACD-NRCC, cells need to undergo fixation. Therefore, testing the stem-cell nature and other functional traits of LRC and cells undergoing ACD-NRCC has been limited. Here, we show a method for labeling DNA with single and dual-color nucleotides in live human liver cancer cells avoiding the need for fixation. We describe a novel methodology for both the isolation of live LRC and cells undergoing ACD-NRCC via fluorescence-activated cell sorting with confocal microscopy validation. This has the potential to be a powerful adjunct to stem-cell and cancer research. PMID- 21294633 TI - Logistics and safety of extracorporeal membrane oxygenation in medical retrieval. AB - OBJECTIVE: This article reviews the logistics and safety of extracorporeal membrane oxygenation (ECMO) medical retrieval in New South Wales, Australia. METHODS: We describe the logistics involved in ECMO road and rotary-wing retrieval by a multidisciplinary team during the H1N1 influenza epidemic in winter 2009 (i.e., June 1 to August 31, 2009). Basic patient demographics and key retrieval time lines were analyzed. RESULTS: There were 17 patients retrieved on ECMO, with their ages ranging from 22 to 55 years. The median weight was 110 kg. Four critical events were recorded during retrieval, with no adverse outcomes. The retrieval distance varied from 20.8 to 430 km. There were delays in times from retrieval booking to both retrieval tasking and retrieval team departure in 88% of retrievals. The most common reasons cited were "patient not ready" 23.5% (4/17); "vehicle not available," 23.5% (4/17); and "complex retrieval," 41.2% (7/17). The median time (hours:minutes) from booking with the medical retrieval unit (MRU) to tasking was 4:35 (interquartile range [IQR] 3:27-6:15). The median time lag from tasking to departure was 1:00 (IQR 00:10-2:20). The median stabilization time was 1:30 (IQR 1:20-1:55). The median retrieval duration was 7:35 (IQR 5:50-10:15). CONCLUSION: The process of development of ECMO retrieval was enabled by the preexistence of a high-volume experienced medical retrieval service. Although ECMO retrieval is not a new concept, we describe an entire process for ECMO retrieval that we believe will benefit other retrieval service providers. The increased workload of ECMO retrieval during the swine flu pandemic has led to refinement in the system and process for the future. PMID- 21294634 TI - Lamellar spacing in cuboid hydroxyapatite scaffolds regulates bone formation by human bone marrow stromal cells. AB - BACKGROUND: A major goal in bone engineering is the creation of large volume constructs (scaffolds and stem cells) that bear load. The scaffolds must satisfy two competing requirements--they need be sufficiently porous to allow nutrient flow to maintain cell viability, yet sufficiently dense to bear load. We studied the effect of scaffold macroporosity on bone formation and scaffold strength, for bone formed by human bone marrow stromal cells. METHODS: Rigid cubical hydroxyapatite/tricalcium phosphate scaffolds were produced by robo-casting. The ceramic line thickness was held constant, but the distance between adjacent lines was either 50, 100, 200, 500, or 1000 MUm. Cultured human bone marrow stromal cells were combined with the scaffolds in vitro; transplants were placed into the subcutis of immunodeficient mice. Transplants were harvested 9, 18, 23, 38, or 50 weeks later. Bone formation and scaffold strength were analyzed using histology and compression testing. RESULTS: Sixty transplants were evaluated. Cortical bone increased with transplant age, and was greatest among 500 MUm transplants. In contrast, maximum transplant strength was greatest among 200 MUm transplants. CONCLUSIONS: Lamellar spacing within scaffolds regulates the extent of bone formation; 500 MUm yields the most new bone, whereas 200 MUm yields the strongest transplants. PMID- 21294635 TI - Internet-based intervention for the treatment of online addiction for college students in China: a pilot study of the Healthy Online Self-helping Center. AB - Internet addiction among college students has become a serious problem in China. This pilot study involved the development of an online expert system named Healthy Online Self-helping Center (HOSC) as an intervention tool to help those who wish to reduce online usage. The study also explored the effectiveness of HOSC for college students' Internet addiction behavior. Participants (N = 65) were recruited from a university in Beijing, and were randomly assigned to one of four conditions: using HOSC within a laboratory environment, using HOSC within a natural environment, using a noninteractive program, and a control group. All the participants were asked to answer questionnaires at the baseline and at the 1 month follow-up. The questionnaires included the participants' online hours per week, the legitimate ratio of Internet usage, online satisfaction, and the Young's Diagnostic Questionnaire. The results revealed that HOSC under both natural and laboratory environments could effectively reduce the participants' online hours per week as well as their Young's Diagnostic Questionnaire score, and improve online satisfaction at a 1-month follow-up. Participants using a noninteractive program also had similar results. The article concludes with a discussion of the limitations of the study, as well as the implications of the findings and future research directions. PMID- 21294636 TI - Development and utilization of activated STAT3 detection assays for screening a library of secreted proteins. AB - Interleukin-6 (IL-6) family of cytokines are multifunctional proteins that play an important role in host defenses, acute phase reactions, immune responses, hematopoiesis, and tumorigenesis. The cytokines are produced by various lymphoid and nonlymphoid cells and mediate their biological activity through initial low affinity binding to cell surface receptors, which are specific for their respective ligands. Ligand-specific receptor binding results in the receptor heterodimerization with ubiquitously expressed signal-transducing transmembrane component gp130 followed by activation of the gp130-associated Janus kinase, which, in turn, phosphorylates signal transducer and activator of transcription 3 (STAT3). Phosphorylated STAT3 (pSTAT3) dimerizes and translocates to the nucleus, where it activates gene transcription. Activation of STAT3 is essential to IL-6 family-associated physiological effects. Therefore, the ability to assess STAT3 phosphorylation is important for drug discovery efforts targeting IL-6 family cytokines. Various reagents and technologies are available to detect the effect of IL-6 type cytokines in treated cells. The present study describes the development of two pSTAT3 detection assays: the high-throughput screening assay based on Meso-Scale Discovery technology, which utilizes electrochemoluminescent signal measurements for the detection of pSTAT3 in treated cell extracts, and the secondary characterization assay based on fluorescent imaging analysis, which monitors pSTAT3 nuclear translocation in cells after activation. We have successfully utilized these assays to screen a small library of secreted proteins and identified inducers of STAT3 phosphorylation. The results obtained in this study demonstrate that both assays are robust, reliable, and amenable to high throughput screening applications. PMID- 21294637 TI - La protein can simultaneously bind to both 3'- and 5'-noncoding regions of Japanese encephalitis virus genome. AB - Japanese encephalitis virus (JEV) genome is a single-stranded, positive-sense RNA with noncoding regions (NCRs) of 95 and 585 bases at its 5' and 3' ends, respectively. These may interact with viral or host proteins important for viral replication. We have previously shown that La protein binds the 3'-stem-loop (SL) structure of JEV 3'-NCR. Using electrophoretic mobility shift and ultraviolet crosslinking assays, we now show that La protein binds both 3'-SL and 5'-NCR of JEV. La protein binding to 5'-NCR RNA was stable under high salt condition (300 mM KCl) and the affinity of RNA protein interaction was high; the dissociation constant (K(d)) for La binding with 5'-NCR RNA was 8.8 nM, indicating the physiological relevance of the interaction. RNA toe-printing assays showed that La protein interacted with nucleotides located in the top loop of the predicted structure of 5'-NCR RNA. Using competitive binding studies and 5'-3' coprecipitation assay, we have demonstrated that La protein could simultaneously bind both JEV 3'- and 5'-NCRs. This may help circularize the viral genome for its efficient transcription and translation. PMID- 21294638 TI - Damage escape and repair in dried Chroococcidiopsis spp. from hot and cold deserts exposed to simulated space and martian conditions. AB - The cyanobacterium Chroococcidiopsis, overlain by 3 mm of Antarctic sandstone, was exposed as dried multilayers to simulated space and martian conditions. Ground-based experiments were conducted in the context of Lichens and Fungi Experiments (EXPOSE-E mission, European Space Agency), which were performed to evaluate, after 1.5 years on the International Space Station, the survival of cyanobacteria (Chroococcidiopsis), lichens, and fungi colonized on Antarctic rock. The survival potential and the role played by protection and repair mechanisms in the response of dried Chroococcidiopsis cells to ground-based experiments were both investigated. Different methods were employed, including evaluation of the colony-forming ability, single-cell analysis of subcellular integrities based on membrane integrity molecular and redox probes, evaluation of the photosynthetic pigment autofluorescence, and assessment of the genomic DNA integrity with a PCR-based assay. Desiccation survivors of strain CCMEE 123 (coastal desert, Chile) were better suited than CCMEE 134 (Beacon Valley, Antarctica) to withstand cellular damage imposed by simulated space and martian conditions. Exposed dried cells of strain CCMEE 123 formed colonies, maintained subcellular integrities, and, depending on the exposure conditions, also escaped DNA damage or repaired the induced damage upon rewetting. PMID- 21294639 TI - SOLID3: a multiplex antibody microarray-based optical sensor instrument for in situ life detection in planetary exploration. AB - The search for unequivocal signs of life on other planetary bodies is one of the major challenges for astrobiology. The failure to detect organic molecules on the surface of Mars by measuring volatile compounds after sample heating, together with the new knowledge of martian soil chemistry, has prompted the astrobiological community to develop new methods and technologies. Based on protein microarray technology, we have designed and built a series of instruments called SOLID (for "Signs Of LIfe Detector") for automatic in situ detection and identification of substances or analytes from liquid and solid samples (soil, sediments, or powder). Here, we present the SOLID3 instrument, which is able to perform both sandwich and competitive immunoassays and consists of two separate functional units: a Sample Preparation Unit (SPU) for 10 different extractions by ultrasonication and a Sample Analysis Unit (SAU) for fluorescent immunoassays. The SAU consists of five different flow cells, with an antibody microarray in each one (2000 spots). It is also equipped with an exclusive optical package and a charge-coupled device (CCD) for fluorescent detection. We demonstrated the performance of SOLID3 in the detection of a broad range of molecular-sized compounds, which range from peptides and proteins to whole cells and spores, with sensitivities at 1-2 ppb (ng mL-1) for biomolecules and 104 to 103 spores per milliliter. We report its application in the detection of acidophilic microorganisms in the Rio Tinto Mars analogue and report the absence of substantial negative effects on the immunoassay in the presence of 50 mM perchlorate (20 times higher than that found at the Phoenix landing site). Our SOLID instrument concept is an excellent option with which to detect biomolecules because it avoids the high-temperature treatments that may destroy organic matter in the presence of martian oxidants. PMID- 21294640 TI - Role of NQO1 609C>T and NQO2-3423G>A polymorphisms in susceptibility to gastric cancer in Kashmir valley. AB - NADPH: quinone oxidoreductase 1 (NQO1) and dihydronicotinamide riboside: quinone oxidoreductase 2 (NQO2) are cytosolic enzymes that catalyze reductive activation of carcinogens from cigarette smoke, such as nitrosamines and heterocyclic amines. These enzymes also protect cells against oxidative damage from reactive oxygen species. The present study investigated the associations of genetic variants of NQO1 609C>T and NQO2 -3423G>A polymorphisms with susceptibility to gastric cancer (GC) as well as their interactions with known risk factors in Kashmir valley. A case control study was performed in 303 subjects (108 GC and 195 healthy controls). All subjects were genotyped using polymerase chain reaction-restriction fragment length polymorphism method. Data were statistically analyzed by chi-square test and logistic regression model. The NQO1 609C>T TT genotype and T allele were significantly associated with increased risk for GC, whereas NQO2 -3423G>A polymorphism did not show any association with GC. Also, NQO1 609C>T TT genotype showed significant association with gastric adenocarcinoma. The interaction of NQO1/NQO2 genotypes with high consumption of salted tea, a known risk factor, did not further modulate the risk of GC. In conclusion, NQO1 609C>T polymorphism shows association with GC risk in Kashmir valley. PMID- 21294641 TI - Acid sphingomyelinase contributes to evodiamine-induced apoptosis in human gastric cancer SGC-7901 cells. AB - Evodiamine-induced apoptosis has been shown to have anticancer activity by eradication of some carcinoma cell lines. This study was designed to evaluate the effects of evodiamine on the viability of human gastric cancer SGC-7901 cells and to define the cell death pathway. Flow cytometry detection showed that 1.5 MUM evodiamine significantly induced SGC-7901 cell apoptosis in a time-dependent manner. This apoptosis was partially inhibited by the pancaspase inhibitor carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoro-methylketone, which suggests that evodiamine-induced apoptosis in SGC-7901 cells is partially caspase independent. Further, the total content of sphingomyelin was decreased and expression of acid sphingomyelinase (aSMase) and neutral SMase genes in the SGC 7901cells was upregulated. Protein expression of aSMase, which was exposed to evodiamine, was shown to be increased by western blot analysis and could have been responsible for inducing caspase-independent apoptosis. Our results indicate that evodiamine stimulates upregulation of aSMase expression and hydrolysis of sphingomyelin into ceramide, which might be one of the mechanisms by which apoptosis occurs in SGC-7901 cells. PMID- 21294642 TI - Classification of modern and old Rio Tinto sedimentary deposits through the biomolecular record using a life marker biochip: implications for detecting life on Mars. AB - The particular mineralogy formed in the acidic conditions of the Rio Tinto has proven to be a first-order analogue for the acid-sulfate aqueous environments of Mars. Therefore, studies about the formation and preservation of biosignatures in the Rio Tinto will provide insights into equivalent processes on Mars. We characterized the biomolecular patterns recorded in samples of modern and old fluvial sediments along a segment of the river by means of an antibody microarray containing more than 200 antibodies (LDCHIP200, for Life Detector Chip) against whole microorganisms, universal biomolecules, or environmental extracts. Samples containing 0.3-0.5 g of solid material were automatically analyzed in situ by the Signs Of LIfe Detector instrument (SOLID2), and the results were corroborated by extensive analysis in the laboratory. Positive antigen-antibody reactions indicated the presence of microbial strains or high-molecular-weight biopolymers that originated from them. The LDCHIP200 results were quantified and subjected to a multivariate analysis for immunoprofiling. We associated similar immunopatterns, and biomolecular markers, to samples with similar sedimentary age. Phyllosilicate-rich samples from modern fluvial sediments gave strong positive reactions with antibodies against bacteria of the genus Acidithiobacillus and against biochemical extracts from Rio Tinto sediments and biofilms. These samples contained high amounts of sugars (mostly polysaccharides) with monosaccharides like glucose, rhamnose, fucose, and so on. By contrast, the older deposits, which are a mix of clastic sands and evaporites, showed only a few positives with LDCHIP200, consistent with lower protein and sugar content. We conclude that LDCHIP200 results can establish a correlation between microenvironments, diagenetic stages, and age with the biomarker profile associated with a sample. Our results would help in the search for putative martian biomarkers in acidic deposits with similar diagenetic maturity. Our LDCHIP200 and SOLID-like instruments may be excellent tools for the search for molecular biomarkers on Mars or other planets. PMID- 21294643 TI - One-week therapy with oral albendazole in hookworm-related cutaneous larva migrans: a retrospective study on 78 patients. AB - We evaluated retrospectively the efficacy and tolerability of oral albendazole (400 mg/day for 1 week) in 78 patients with hookworm-related cutaneous larva migrans characterized by multiple and/or extensive lesions. The diagnosis was based on history and the clinical picture. Neither topical or systemic drugs nor physical treatments were used. All patients were followed-up for at least 3 months after the therapy. All patients were cured at the end of the therapy. The disappearance of pruritus was reported after 2-3 days and skin lesions after 5-7 days of therapy. One patient reported nausea and abdominal pain; another patient reported worsening of pruritus: in both cases it was not necessary to stop the therapy. No recurrences were observed during follow-up. One week of therapy with 400 mg/day oral albendazole is very effective (cure rate: 100%) in patients with cutaneous larva migrans characterized by multiple and/or extensive lesions. This therapeutical regimen is not accompanied by the appearance of new and/or more severe side effects. PMID- 21294644 TI - Prospective self-controlled trial of the efficacy and tolerability of a herbal syrup for young children with eczema. AB - OBJECTIVES: Traditional Chinese medicine (TCM) is popular as an alternative medicine in children with atopic dermatitis (AD). A concoction of five herbs in a capsular preparation has been confirmed to be efficacious in improving the quality of life and sparing topical corticosteroid usage. We evaluated the clinical efficacy and tolerability of the same concoction in syrup form. METHODS: This was a prospective self-controlled trial set in the pediatric dermatology clinic of a teaching hospital. Children aged 4-7 years with moderate-to-severe AD received 20 ml of TCM syrup daily. Clinical parameters and laboratory markers were measured before and at 2 weeks, 7 weeks and 12 weeks of treatment, and at 4 weeks after completion. Disease severity was evaluated by the SCORing Atopic Dermatitis (SCORAD) index and quality of life by the Children's Dermatology Life Quality Index (CDLQI). Blood was obtained for a complete blood count, total IgE, eosinophil count, and biochemical studies prior to and after 3 months of TCM usage. RESULTS: Twenty-two patients participated in the study. There were significant improvements in the objective SCORAD, pruritus and CDLQI scores 4 weeks after study completion. There was no change in sleep score or amount of topical steroid consumption. No biochemical evidence of any adverse drug reaction was observed during the study period. The TCM syrup was generally palatable and well tolerated by the children. Adverse effects were generally mild but two patients with rash withdrew during the study. CONCLUSION: The palatability means that further evaluations and dosage studies of the concoction will be possible in young children. PMID- 21294645 TI - Thyrotropin receptor and membrane interactions in FRTL-5 thyroid cell strain in microgravity. AB - The aim of this work was to analyze the possible alteration of thyrotropin (TSH) receptors in microgravity, which could explain the absence of thyroid cell proliferation in the space environment. Several forms of the TSH receptor are localized on the plasma membrane associated with caveolae and lipid rafts. The TSH regulates the fluidity of the cell membrane and the presence of its receptors in microdomains that are rich in sphingomyelin and cholesterol. TSH also stimulates cyclic adenosine monophosphate (cAMP) accumulation and cell proliferation. Reported here are the results of an experiment in which the FRTL-5 thyroid cell line was exposed to microgravity during the Texus-44 mission (launched February 7, 2008, from Kiruna, Sweden). When the parabolic flight brought the sounding rocket to an altitude of 264 km, the culture media were injected with or without TSH in the different samples, and weightlessness prevailed on board for 6 minutes and 19 seconds. Control experiments were performed, in parallel, in an onboard 1g centrifuge and on the ground in Kiruna laboratory. Cell morphology and function were analyzed. Results show that in microgravity conditions the cells do not respond to TSH treatment and present an irregular shape with condensed chromatin, a modification of the cell membrane with shedding of the TSH receptor in the culture medium, and an increase of sphingomyelin-synthase and Bax proteins. It is possible that real microgravity induces a rearrangement of specific sections of the cell membrane, which act as platforms for molecular receptors, thus influencing thyroid cell function in astronauts during space missions. PMID- 21294646 TI - Ataxia telangiectasia and Rad3-related overexpressing cancer cells induce prolonged G2 arrest and develop resistance to ionizing radiation. AB - We investigated whether ataxia telangiectasia and rad3-related (ATR) kinases regulate prolongation of ionizing radiation (IR) induced-G2 arrest and radioresistance in ataxia telangiectasia mutated-intact cancer cells. ATR overexpressing cancer cells showed prolonged-G2 arrest after IR exposure and were significantly resistant to DNA damaging stresses. The phosphorylation of p-Ser15 p53, p-Ser345-Chk1, and p-Tyr15-Cdk1 phosphorylation was increased until 36 h after IR exposure in ATR-overexpressing cells, whereas p-Ser10-histone H3 decreased. ATR-overexpressing cells also showed rapid attenuation of increased gamma-H2AX foci after IR exposure compared with control cells. In contrast, ATR knockdown cells had limited clearance of gamma-H2AX foci after IR exposure. In conclusion, ATR overexpression seems to primarily induce prolonged G2 arrest after IR exposure, which increases IR resistance by enhancing DNA damage repair. These results may provide useful clues for understanding the function of ATR in controlling IR-induced G2 arrest and radiation response. PMID- 21294647 TI - Computed tomography and outcome in moderate and severe traumatic brain injury: hematoma volume and midline shift revisited. AB - Intracranial lesion volume and midline shift are powerful outcome predictors in moderate and severe traumatic brain injury (TBI), and therefore they are used in TBI and computed tomography (CT) classification schemes, like the Traumatic Coma Data Bank (TCDB) classification. In this study we aimed to explore the prognostic value of lesion volume and midline shift in moderate and severe TBI as measured from acute cranial CT scans. Also, we wanted to determine interrater reliability for the evaluation of these CT abnormalities. We included all consecutive moderate and severe TBI patients admitted to our hospital who were aged >=16 years, over an 8-year period, as part of the prospective Radboud University Brain Injury Cohort Study. Six months post-trauma we assessed outcomes using the Glasgow Outcome Scale-Extended (GOS-E). We analyzed 605 patients and found an association of both lesion volume and midline shift with outcome; increases were associated with a higher frequency of patients with an unfavorable outcome or death. A cut-off value, such as that used in the TCDB CT classification (lesion volume 25 mL and midline shift 5 mm), was not found. The average interrater difference in volume measurement was 6.8 mL, and it was 0.2 mm for the determination of degree of shift. Using lesion volume and midline shift as continuous variables in prognostic models might be preferable over the use of threshold values, although an association of these variables with outcome in relation to other CT abnormalities was not tested. The data provided here will be useful for stratification of patients enrolled in clinical trials of neuroprotective therapies. PMID- 21294648 TI - Early life infection alters adult BALB/c hippocampal gene expression in a sex specific manner. AB - During the perinatal period, the developing brain is sensitive to environmental events. Deleterious programing resulting from infection, dietary restriction, or psychological stress has been observed and affects adult immune and endocrine systems as well as behavior. In this study, we determined whether neonatal infection permanently alters immune and glucocorticoid receptor signaling pathways in the adult hippocampus. A Chlamydia muridarum respiratory infection was induced in male and female mice at birth. Mice were allowed to recover and microarray analysis was conducted on RNA from adult hippocampal tissue. In males, neonatal infection induced an up-regulation of genes associated with cellular development, nervous system development and function, such as cyclin-dependent kinase inhibitor 1A. After neonatal infection, adult females exhibited a T-helper 2 immune bias with genes such as major histocompatibility complex, class II, DQ beta 1 up-regulated. Expression of prolactin, vasopressin, hypocretin, corticotrophin-releasing hormone-binding protein, and oxytocin were confirmed by quantitative real-time polymerase chain reaction. This study shows that neonatal infection differentially alters the gene expression profiles of both female and male mice along immune and neuroendocrine pathways. PMID- 21294650 TI - Amyloid Beta induces oxidative stress-mediated blood-brain barrier changes in capillary amyloid angiopathy. AB - Cerebral amyloid angiopathy (CAA) is frequently observed in Alzheimer's disease (AD) and is characterized by deposition of amyloid beta (Abeta) in leptomeningeal and cortical brain vasculature. In 40% of AD cases, Abeta mainly accumulates in cortical capillaries, a phenomenon referred to as capillary CAA (capCAA). The aim of this study was to investigate blood-brain barrier (BBB) alterations in CAA affected capillaries with the emphasis on tight junction (TJ) changes. First, capCAA brain tissue was analyzed for the distribution of TJs. Here, we show for the first time a dramatic loss of occludin, claudin-5, and ZO-1 in Abeta-laden capillaries surrounded by NADPH oxidase-2 (NOX-2)-positive activated microglia. Importantly, we observed abundant vascular expression of the Abeta transporter receptor for advanced glycation endproducts (RAGE). To unravel the underlying mechanism, a human brain endothelial cell line was stimulated with Abeta1-42 to analyze the effects of Abeta. We observed a dose-dependent cytotoxicity and increased ROS generation, which interestingly was reversed by administration of exogenous antioxidants, NOX-2 inhibitors, and by blocking RAGE. Taken together, our data evidently show that Abeta is toxic to brain endothelial cells via binding to RAGE and induction of ROS production, which ultimately leads to disruption of TJs and loss of BBB integrity. PMID- 21294651 TI - Directed stem cell differentiation by fluid mechanical forces. AB - Stem cell research has opened new and exciting possibilities in the biological and biomedical sciences, and holds great promise of impacting many areas of medicine. However, despite the rapid advancements of the last decade, the precise and efficient differentiation of stem cells into distinct cell types and tissues still remains a major challenge for the field. In an effort to reproduce biologically relevant differentiation niches, or to direct stem cell differentiation into specific cellular fates, many investigators have explored the effect of biomechanical stimulation on pluripotent cells. This review focuses on a particular type of biomechanical force, namely fluid shear stress, and our current knowledge on its ability to direct differentiation and modulate function of embryonic and somatic stem cells. PMID- 21294652 TI - High-mobility group box 1 release and redox regulation accompany regeneration and remodeling of skeletal muscle. AB - High-mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) molecules, favors tissue regeneration via recruitment and activation of leukocytes and stem cells. Here we demonstrate, in a model of acute sterile muscle injury, that regeneration is accompanied by active reactive oxygen species (ROS) production counterbalanced and overcome by the generation of antioxidant moieties. Mitochondria are initially responsible for ROS formation. However, they undergo rapid disruption with almost complete disappearance. Twenty-four hours after injury, we observed a strong induction of MURF1 and atrogin-1 ubiquitin ligases, key signals in activation of the proteasome system and induction of muscle atrophy. At later time points, ROS generation is maintained by nonmitochondrial sources. The antioxidant response occurs in both regenerating fibers and leukocytes that express high levels of free thiols and antioxidant enzymes, such as superoxide dismutase 1 (SOD1) and thioredoxin. HMGB1, a protein thiol, weakly expressed in healthy muscles, increases during regeneration in parallel with the antioxidant response in both fibers and leukocytes. A reduced environment may be important to maintain HMGB1 bioactivity. Indeed, oxidation abrogates both muscle stem cell migration in response to HMGB1 and their ability to differentiate into myofibers in vitro. We propose that the early antioxidant response in regenerating muscle limits HMGB1 oxidation, thus allowing successful muscle regeneration. PMID- 21294653 TI - Antibody-mediated rejection in kidney transplantation: an update. AB - INTRODUCTION: Acute antibody-mediated rejection (AMR) in renal-transplant recipients is generally less responsive to conventional antirejection therapy and has a worse prognosis than acute cellular rejection. AREAS COVERED: This review provides a broad understanding of the pathogenesis of AMR, recent advances in its therapy, and future directions. Conventional therapeutic approaches to AMR have minimal impact on mature plasma cells, the major source of antibody production. Emerging therapies include bortezomib, a proteasome inhibitor, and eculizumab, an anti-C5 antibody. In several reports, bortezomib therapy resulted in prompt reversal of rejection, decreased titers of donor-specific antibodies (DSA), and improved renal allograft function. Eculizumab also reversed AMR and prevented its development in patients with high post-transplantation DSA levels. EXPERT OPINION: Despite the small sample size and lack of controls, these studies are encouraging, and although larger studies and long-term follow-up are needed, bortezomib and eculizumab may play a major future role in AMR therapy. PMID- 21294649 TI - Lipid raft redox signaling: molecular mechanisms in health and disease. AB - Lipid rafts, the sphingolipid and cholesterol-enriched membrane microdomains, are able to form different membrane macrodomains or platforms upon stimulations, including redox signaling platforms, which serve as a critical signaling mechanism to mediate or regulate cellular activities or functions. In particular, this raft platform formation provides an important driving force for the assembling of NADPH oxidase subunits and the recruitment of other related receptors, effectors, and regulatory components, resulting, in turn, in the activation of NADPH oxidase and downstream redox regulation of cell functions. This comprehensive review attempts to summarize all basic and advanced information about the formation, regulation, and functions of lipid raft redox signaling platforms as well as their physiological and pathophysiological relevance. Several molecular mechanisms involving the formation of lipid raft redox signaling platforms and the related therapeutic strategies targeting them are discussed. It is hoped that all information and thoughts included in this review could provide more comprehensive insights into the understanding of lipid raft redox signaling, in particular, of their molecular mechanisms, spatial temporal regulations, and physiological, pathophysiological relevances to human health and diseases. PMID- 21294654 TI - Epithelial barriers in intestinal inflammation. AB - The gastrointestinal epithelium transports solutes and water between lumen and blood and at the same time forms a barrier between these compartments. This highly selective and regulated barrier permits ions, water, and nutrients to be absorbed, but normally restricts the passage of harmful molecules, bacteria, viruses and other pathogens. During inflammation, the intestinal barrier can be disrupted, indicated by a decrease in transcellular electrical resistance and an increase in paracellular permeability for tracers of different size. Such inflammatory processes are accompanied by increased oxidative stress, which in turn can impair the epithelial barrier. In this review, we discuss the role of inflammatory oxidative stress on barrier function with special attention on the epithelial tight junctions. Diseases discussed causing barrier changes include the inflammatory bowel diseases Crohn's disease, ulcerative colitis, and microscopic colitis, the autoimmune disorder celiac disease, and gastrointestinal infections. In addition, the main cytokines responsible for these effects and their role during oxidative stress and intestinal inflammation will be discussed, as well as therapeutic approaches and their mode of action. PMID- 21294655 TI - Alterations to the blood-retinal barrier in diabetes: cytokines and reactive oxygen species. AB - Diabetic retinopathy (DR) is a leading cause of blindness in Western society. Since the prevalence of diabetes continues to increase dramatically, the impact of DR will only worsen unless new therapeutic options are developed. Recent data demonstrate that oxidative stress contributes to the pathology of DR and inhibition of oxidative stress reduces retinal vascular permeability. However, direct mechanisms by which oxidative stress alters the blood-retinal barrier (BRB) and increases vascular permeability remain to be elucidated. A large body of evidence demonstrates a clear role for altered expression of cytokines and growth factors in DR, resulting in increased vascular permeability, and the molecular mechanisms for these processes are beginning to emerge. The pathology of DR is likely a result of metabolic dysregulation contributing to both oxidative stress and cytokine production. This review will examine the evidence for oxidative stress, growth factors, and other cytokines in tight junction regulation and vascular permeability in DR. PMID- 21294656 TI - The glucocorticoid contribution to obesity. AB - Obesity is fast becoming the scourge of our time. It is one of the biggest causes of death and disease in the industrialized world, and affects as many as 32% of adults and 17% of children in the USA, considered one of the world's fattest nations. It can also cost countries billions of dollars per annum in direct and indirect care, latest estimates putting the USA bill for obesity-related costs at $147 billion in 2008. It is becoming clear that the pathophysiology of obesity is vastly more complicated than the simple equation of energy in minus energy out. A combination of genetics, sex, perinatal environment and life-style factors can influence diet and energy metabolism. In this regard, psychological stress can have significant long-term impact upon the propensity to gain and maintain weight. In this review, we will discuss the ability of psychological stress and ultimately glucocorticoids (GCs) to alter appetite regulation and metabolism. We will specifically focus on (i) GC regulation of appetite and adiposity, (ii) the apparent sexual dimorphism in stress effects on obesity and (iii) the ability of early life stress to programme obesity in the long term. PMID- 21294657 TI - ZO proteins and redox-dependent processes. AB - SIGNIFICANCE: ZO-1, ZO-2, and ZO-3 are scaffold proteins of the tight junction (TJ) that belong to the MAGUK protein family characterized for exhibiting PDZ, SH3, and GuK domains. ZO proteins are present only in multicellular organisms, being the placozoa the first to have them. ZO proteins associate among themselves and with other integral and adaptor proteins of the TJ, of the ZA and of gap junctions, as with numerous signaling proteins and the actin cytoskeleton. ZO proteins are also present at the nucleus of proliferating cells. RECENT ADVANCES: Oxidative stress disassembles the TJs of endothelial and epithelial cells. CRITICAL ISSUES: Oxidative stress alters ZO proteins expression and localization, in conditions like hypoxia, bacterial and viral infections, vitamin deficiencies, age-related diseases, diabetes and inflammation, alcohol and tobacco consumption. FUTURE DIRECTIONS: Molecules present in the signaling pathways triggered by oxidative stress can be targets for therapeutic intervention. PMID- 21294658 TI - Oxidative stress and blood-brain barrier dysfunction under particular consideration of matrix metalloproteinases. AB - A cell's "redox" (oxidation and reduction) state is determined by the sum of all redox processes yielding reactive oxygen species (ROS), reactive nitrogen species (RNS), and other reactive intermediates. Low amounts of ROS/RNS are generated by different mechanisms in every cell and are important regulatory mediators in many signaling processes (redox signaling). When the physiological balance between the generation and elimination of ROS/RNS is disrupted, oxidative/nitrosative stress with persistent oxidative damage of the organism occurs. Oxidative stress has been suggested to act as initiator and/or mediator of many human diseases. The cerebral vasculature is particularly susceptible to oxidative stress, which is critical since cerebral endothelial cells play a major role in the creation and maintenance of the blood-brain barrier (BBB). This article will only contain a focused introduction on the biochemical background of redox signaling, since this has been reported already in a series of excellent recent reviews. The goal of this work is to increase the understanding of basic mechanisms underlying ROS/RNS induced BBB disruption, with a focus on the role of matrix metalloproteinases, which, after all, appear to be a key mediator in the initiation and progression of BBB damage elicited by oxidative stress. PMID- 21294659 TI - Long-lasting effects of inescapable-predator stress on brain tryptophan metabolism and the behavior of juvenile mice. AB - The kynurenine (KYN) pathway, which is initiated by indoleamine 2,3-dioxygenase, is the main tryptophan (TRP) metabolic pathway. It shares TRP with the serotonin (5-HT) pathway. We investigated the influence of inescapable-predator (rat) stress on behavior and brain TRP metabolism in mice. Male ICR mice (4W) were exposed to 20-min inescapable-predator stress. Behavior on an elevated plus-maze, and TRP, KYN, and 5-HT levels in the prefrontal cortex, hippocampus, amygdala, and dorsal raphe nuclei were measured 1 and 4 weeks after stress exposure. Predator stress increased the number of open-arm entries (NOA) 4 weeks after stress exposure without altering the number of closed-arm entries (NCA). Thus, the open/closed-arm entry ratio (NOA/NCA) increased after stress exposure. Predator stress increased KYN levels in the prefrontal cortex (until 4 weeks after stress exposure) and dorsal raphe nuclei (for 1 week after stress exposure), decreased 5-HT levels in all brain regions (until 4 weeks after stress exposure). Thus, predator stress increased the KYN/5-HT ratio in all regions, in particular in the prefrontal cortex and hippocampus until 4 weeks after stress exposure. Predator stress shifted the balance between the KYN and 5-HT pathways to the KYN pathway, and induced behavioral disinhibition. PMID- 21294660 TI - Mars sedimentary geology: key concepts and outstanding questions. PMID- 21294661 TI - Dexamethasone-induced hepatic lipogenesis is insulin dependent in chickens (Gallus gallus domesticus). AB - Hepatic lipogenesis-induced de novo by glucocorticoids (GCs) is associated with the development of obesity and diabetes mellitus. The interaction of GCs and insulin in the regulation of hepatic lipogenesis remains unclear. The effect of exogenous GC administration on hepatic lipogenesis and fat deposition was studied in broiler chickens (Gallus gallus domesticus), and the role of insulin in the effect of GCs on hepatic lipogenesis was evaluated. Dexamethasone (DEX, 2 mg/kg body mass (BM)) administration for 3-d resulted in BM loss and increased liver and cervical adipose tissue mass compared to control and pair-fed counterparts. DEX treatment significantly (P < 0.05) increased plasma level of insulin in either the fed or fasting state, whereas plasma glucose level was only increased in the fed state. In fasted chickens, DEX treatment significantly (P < 0.01) upregulated the hepatic mRNA levels of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). In the fed state, the mRNA levels of ACC and FAS were not significantly influenced by DEX treatment, nor was FAS activity. In cultured primary hepatocytes, combined DEX and insulin significantly upregulated the transcription of the genes for FAS (1.34-fold) and malic enzyme (1.72-fold). By contrast, the expression of sterol response element-binding protein-1 (SREBP-1) was significantly upregulated by insulin (1.67-fold) regardless of DEX. In abdominal adipose tissue, DEX treatment had no significant (P>0.05) effect on the activities and transcription of FAS. The expressions of lipoprotein lipase and peroxisome proliferator-activated receptor-gamma were not significantly (P>0.05) affected by DEX treatment in either the fasting or fed state. The results indicate that DEX increased hepatic de novo lipogenesis via the increased activity and expression of lipogenic enzymes. Insulin-activated gene expression for SREBP-1 is suggested to be involved in stress-augmented hepatic lipogenesis. PMID- 21294662 TI - Stress conditioning in mice: alterations in immunity and tumor growth. AB - The neuroendocrine and autonomic nervous systems are known regulators of brain immune interaction. However, the functional significance of this interaction under stress is not fully understood. We investigated the effect of a stress paradigm by applying electric foot shock followed by three reminders, on behavior, immune parameters, and lymphoma tumor growth. Male C3H mice were divided into two groups: Group 1-exposed to electric foot shock followed by three reminders, and Group 2-untreated (controls). Sets of mice underwent the elevated plus maze, staircase, and hot plate tests. After foot shock, natural killer (NK) cell activity, and lymphocyte proliferation were measured. In addition, sets of mice were either vaccinated twice with B-cell lymphoma 38C-13 immunoglobulin for determination of anti-idiotype (Id) antibodies in sera, or inoculated with tumor cells and monitored for tumor development and survival time. Mice exposed to electric foot shock followed by the three reminders had higher NK cell activity, levels of anti-Id antibodies, and a higher proliferation rate of splenocytes in response to mitogens, than the control mice. The exposed mice also showed attenuated tumor growth. Thus, the stress paradigm inhibited tumor development and lead to some immune changes that were not accompanied by behavioral changes. PMID- 21294663 TI - Th9: a new player in asthma pathogenesis? AB - CD4(+) T helper (Th) cells act as important regulators of the mammalian adaptive immune response. CD4(+) Th cells were originally characterized as either Th1 or Th2 types, based on the cytokines they produce. Over the past two decades, however, we have attained a much more detailed understanding of CD4(+) T-cell differentiation, functions, and gene expression profiles, which led to the identification of additional types, such as the Th17 and induced regulatory T cells. Recently, researchers have characterized yet another novel and distinct population that exists among these immune-modulatory cells. The 'Th9' cells were first identified as a Th2 subpopulation that produced exceptionally large quantities of the Th2-specific cytokine interleukin 9. However, experimental analysis revealed that Th9 cells had divergent regulatory capabilities and were critically involved in different immune processes. In particular, we now know that Th9 acts as a major contributor to the onset and progression of allergies, especially asthma. Here, we will review the heterogeneity and biology of CD4(+) Th cells and summarize the characteristics known to date of interleukin 9 and Th9 cells to build a framework for better understanding of their roles in disease processes, especially in allergy-induced asthma. PMID- 21294664 TI - Endovascular therapy of acute ischemic stroke. AB - INTRODUCTION: Intravenous fibrinolysis is the only proven treatment for acute ischemic stroke (AIS), but a limited therapeutic time window and risk of systemic hemorrhagic limit its real-world effectiveness. Minimally invasive endovascular therapies may provide opportunities to expand the AIS treatment window and enhance clinical outcomes. AREAS COVERED: Current and future endovascular techniques that aim to address the hemodynamic, neuroanatomic and neurovascular complexities of acute cerebral ischemia are discussed. Scales for measuring relevant angiographic and clinical end points are also covered. Procedural timing and optimal patient selection using various imaging modalities are mentioned. Previous and ongoing clinical trials in AIS are discussed as well as emerging approaches. EXPERT OPINION: Endovascular therapy has opened up new horizons for treatment of AIS. It offers multiple new and promising therapeutic approaches that are not limited to one specific device or method, but could conceivably be additive and also individualized based upon each patient's characteristics. PMID- 21294665 TI - The next phase in our search for life: an expert discussion. PMID- 21294666 TI - The complexity of care in amyotrophic lateral sclerosis. PMID- 21294667 TI - Psychological health in patients with ALS is maintained as physical function declines. AB - Although quality of life (QoL) in patients with ALS has been shown to be independent of physical function and to be maintained over time, the status of psychological health over the disease course has not been studied using an ALS specific instrument. It is also uncertain how three common interventions - antidepressants, percutaneous endoscopic gastrostomy (PEG), and non-invasive ventilatory support (NIPPV) - influence psychological health. We performed a retrospective review of the Negative Emotion subscale (NES) score, a measure of psychological health within the ALS-Specific QoL Instrument. Analysis of 72 patients over three months, and of a subset of 48 over six months, showed stability of psychological health despite a decline in the ALS Functional Rating Scale-Revised to 88.4% of baseline at three months and 82.6% at six months. NES did not change after antidepressants, PEG, or NIPPV, although there was a suggestion of improvement with antidepressants in a subgroup. In conclusion, as with overall QoL, psychological health of ALS patients as measured with an ALS specific instrument does not decline as physical function is lost. Supports found in a multidisciplinary ALS clinic may influence expectations, facilitate response shift, and stabilize psychological health while masking the independent effects of specific interventions. PMID- 21294668 TI - Series: The research agenda for general practice/family medicine and primary health care in Europe. Part 6: reaction on commentaries - how to continue with the Research Agenda? AB - The Research Agenda should be used as a key reference point to which new research should relate its usefulness and added value. Primary care evolves towards more interdisciplinary care, and research should focus more on the core competency of person-centred team care. There is an urgent need to develop clear definitions and appropriate research instruments for this domain. It will be a particular challenge to study comprehensive approaches in primary-care patients with multi morbidity. The Research Agenda and the commentaries on it show future directions for primary care research. There are challenges related to a changing society, the shared responsibility and guidance of research by professionals and citizens (patients), and the need to fully integrate research as part of primary healthcare provision. There will be a need for a prioritization of spearheads to guide primary care research for the next decade: translational research, research on equity and health differences, on chronic disease and health systems research. This can not be realized without the development and maintenance of a solid research infrastructure: easily maintained and accessed observational databases, helpful information technology, strategies and techniques for patient involvement, advanced research training possibilities, and the development and validation of appropriate research instruments and outcome measures to capture the different challenges. Worldwide, primary care not only is a priority for health care policy, but it needs to become a research priority as well. PMID- 21294669 TI - Comparison of three different immunoassay methods for the evaluation of intact parathyroid hormone levels in hemodialysis patients. AB - BACKGROUND: Intact parathyroid hormone (iPTH) assays react with the non-(1-84) molecular form of PTH. This form behaves as a carboxy-terminal fragment and accumulates during renal failure. We wanted to examine the variation of iPTH levels between the more commonly used different immunoassay methods in hemodialysis patients. METHODS: Our study was designed to compare three commercial second-generation immunoassays based on electrochemiluminescent immunoassay (ECLIA), enzyme immunoassay (EIA) and immunoradiometric assay (IRMA) for intact PTH. The serum samples from 88 patients were collected and the iPTH concentrations measured. RESULTS: The median iPTH (IRMA) concentration (99 pg/mL) was lower than both median iPTH (ECLIA) concentration (290.5 pg/ml; p < 0.001) and iPTH (EIA) concentration (369 pg/mL; p < 0.001). The Bland-Altman graphs, which are plots of the percentage differences between the two methods against their mean, suggested that the IRMA methods are not in agreement with the other methods. CONCLUSION: It would be useful to reduce the variability among the methods with the use of a more standardized calibrator and of the same specific antibodies that only recognize the active PTH molecule. PMID- 21294670 TI - Aripiprazole for the treatment of irritability associated with autism. AB - INTRODUCTION: Irritability (including tantrums, aggression and moodiness) is often associated with autistic disorder. Children with autism are frequently prescribed atypical antipsychotic medications for these behaviors. Although multiple agents have been found to be effective, the safety and tolerability of each antipsychotic may be the determining factor in its selection. AREAS COVERED: The pharmacokinetics, pharmacodynamics, safety and efficacy data on aripiprazole for the treatment of irritability associated with autism are discussed. Knowledge of the mechanism of action, advantages and disadvantages relative to other atypical antipsychotics, and an appreciation of the efficacy of aripiprazole when used to treat irritability in autism is also explored in this paper. EXPERT OPINION: Aripiprazole may have a more favorable side-effect profile than another commonly prescribed medication, risperidone, because of its unique mechanism of action. It seems to be effective in treating irritability associated with autism, but more research is needed. PMID- 21294671 TI - Effect of curcumin and irradiation in PE/CA-PJ15 oral squamous cell carcinoma. AB - OBJECTIVE: An in vitro study was made to evaluate the effect of curcumin and irradiation upon oral squamous cell carcinoma. MATERIALS AND METHOD: Curcumin was administered at doses of 3, 3.75, 4.50 and 5.25 MUM in PE/CA-PJ15 oral squamous cell carcinoma cultures irradiated with different doses (1, 2.5 and 5 Gy), followed by evaluation of the effects upon cell viability after 24, 48 and 72 h, based on the MTT colorimetric test. RESULTS: The application of curcumin to the PECA/PJ15 tumor cells during 24, 48 and 72 h of incubation without irradiation exerted an inhibitor effect upon cell viability. The curcumin concentration at which the inhibition of cell viability proved maximum was 5.25 MUM, with statistically significant differences for 24 h (p = 0.002), 48 h (p < 0.001) and 72 h of incubation (p < 0.001). In contrast, the combination of curcumin and irradiation exerted a synergic effect-the greatest effects in relation to cell viability being recorded with a curcumin concentration of 3.75 MUM and 5 Gy of irradiation, in the studied cell line. CONCLUSIONS: Curcumin increases cytotoxic activity in the PE/CA PJ15 cell line, while the combination of curcumin and irradiation exerts a synergic effect. PMID- 21294672 TI - Dental fear and alexithymia among adults in Finland. AB - population sample, controlling for age, gender, education and marital status as well as depressive and anxiety disorders. An additional aim was to evaluate whether gender modified this association. MATERIAL AND METHODS. The two-stage stratified cluster sample (n = 8028) represented the Finnish population aged 30 years and older. Participants (n = 5241) answered the question 'How afraid are you of visiting a dentist?' They also filled out the 20-Item Toronto Alexithymia Scale (TAS-20), which included three sub-scales, i.e. difficulties in identifying feelings (DIF), difficulties in describing feelings (DDF) and externally oriented thinking (EOT). Anxiety and depressive disorders were assessed with a standardized structured psychiatric interview according to DSM-IV criteria. To evaluate the association between dental fear and alexithymia, multiple logistic regression analyses were performed, adjusting simultaneously for the effects of possible confounding variables. RESULTS. Gender modified the association between dental fear and alexithymia. Among women, those reporting higher scores for TAS 20, DIF and EOT sub-scale scores were more likely to have high dental fear than were those reporting lower scores. Among men no such association was observed. Those participants who reported high DDF sub-scale scores were more likely to have high dental fear than were those reporting lower scores. CONCLUSIONS. Alexithymics are more likely to have high dental fear than non-alexithymics are. The findings support the suggestion that some people with dental fear may have internal personality vulnerability to anxiety disorders. PMID- 21294673 TI - Hormone replacement therapy and some risk factors for breast cancer among Slovenian postmenopausal women. AB - OBJECTIVE: The aim of the study was to examine the influence of the use of hormone replacement therapy (HRT) and of some generally recognized risk factors on breast cancer risk among Slovenian postmenopausal women. METHODS: Eligible women diagnosed with breast cancer and a control group of women of the same age and ethnicity were invited to participate in the case-control study via a personal letter and asked to complete a written questionnaire. Adjusted odds ratios and 95% confidence intervals were estimated using multivariate logistic regression analysis. RESULTS: A total of 784 cases and 709 controls aged 50-69 years were enrolled. HRT use was inversely associated with breast cancer risk. The effect was most pronounced with the use of estrogen-only replacement therapy (odds ratio (OR) 0.51, 95% confidence interval (CI) 0.30-0.87). Longer duration of HRT use did not result in a significant change in risk (1 to <5 years of HRT use: OR 0.44, 95% CI 0.26-0.73; >= 5 years of HRT use: OR 0.51, 95% CI 0.30 0.87). Obesity (25 <= body mass index <30 kg/m(2): OR 1.34, 95% CI 1.04-1.73; body mass index >= 30 kg/m(2): OR 1.89, 95% CI 1.36-2.63), smoking >= 10 cigarettes per day (OR 1.70, 95% CI 1.20-2.43), and any first-degree relative with breast or ovarian cancer (OR 1.52, 95% CI 1.11-2.08) were positively associated with breast cancer risk. CONCLUSIONS: Our analysis revealed some differences from the previously published literature, which might reflect underlying demographic changes. Comprehensive medical care in HRT users without pre-existing breast abnormalities probably reduces the incidence of new breast cancer cases in Slovenia. PMID- 21294674 TI - A preliminary study comparing attitudes toward hospice referral between African American and white American primary care physicians. AB - End-of-life (EOL) decision making is an integral component of high-quality health care. Factors influencing individual primary care physicians (PCPs) can affect their perspectives and referral preferences for EOL care. Numerous barriers have been cited, including patient and family readiness, physicians' comfort with discussing death, and the pursuit of a cure. This study explores another barrier by examining physician ethnicity and comparing the attitudes toward hospice referral between African American and white American primary care providers (PCPs). Training PCPs to efficiently transition from a curative model of care to a palliative model of care has the potential to increase the level of appropriate EOL care, increase hospice referral, and enhance patient and provider satisfaction; it is also fiscally prudent. This preliminary study aims to compare attitudes toward hospice referral and physicians' personal experiences with hospice between African American and white American PCPs. METHODS: The survey tool was developed by PCPs at the Mayo Clinic Florida after a full literature review and consultation with hospice physicians, oncology specialists, and primary care colleagues from the residency programs at Mayo Minnesota and Mayo Arizona, with input from the Mayo Survey Office, and distributed to all physicians and residents in the departments of Family Medicine at via Mayo's intranet; Mayo's Midwest Regional Practices (245 physicians) received the survey via standard mail. The survey consisted of 17 questions regarding attitudes toward hospice referral and the one question regarding physicians' personal experience with hospice. The final sample size consisted of 167 white American physicians and 46 African American physicians. Responses were compared using a Wilcoxon rank sum test. P values <= 0.05 were considered statistically significant. All statistical analyses were performed using the SAS software package (SAS Institute, Cary, North Carolina). RESULTS: The distributions of physician age, specialty, board certification, and years practicing medicine were similar between African American and white American physicians, while male gender was more common in white American physicians than African American physicians. Statistically significant differences in attitudes toward hospice between African American and white American physicians were observed for five of the 17 survey questions. There was a dramatic difference in the distribution of patient race between African American and white American physicians, raising the possibility that any differences between white American and African American physicians could be attributed to patient race, rather than physician race. Due to survey limits, larger studies involving more African American physicians are needed to address this topic. CONCLUSION: The results of our preliminary study suggest that certain attitudes toward hospice referral may differ between African American and white American PCPs. If validated, further insight into this issue could lead to educational programs for PCPs that correct misperceptions. PMID- 21294675 TI - Pioneers of astrobiology. J. William Schopf. PMID- 21294676 TI - Helicobacter pylori-induced tyrosine phosphorylation of IKKbeta contributes to NF kappaB activation. AB - Helicobacter pylori, the etiological agent of several human gastric diseases, induces the transcription factor nuclear factor-kappaB (NF-kappaB) in colonized epithelial cells leading to the release of proinflammatory mediators. Activation of NF-kappaB involves the IkappaB kinase (IKK)-complex composed of two catalytic subunits, IKKalpha and IKKbeta, and a regulatory scaffold protein, IKKgamma. IKKbeta was shown to be essential for NF-kappaB activation in response to a variety of stimuli including H. pylori. In addition to the phosphorylation of serine residues, tyrosine phosphorylation could be crucial for IKKbeta activation. Here we provide evidence that IKKbeta phosphorylation is induced in lipid rafts (DRM fractions) of H. pylori-infected cells, but not TNFalpha stimulated cells. Furthermore, H. pylori transiently induces binding of IKKbeta to c-Src kinase. Inhibition of c-Src by specific inhibitors as well as knockdown of c-Src by small interfering RNA reduced phosphorylation of IkappaBalpha as well as of p65. Thus, tyrosine-phosphorylated IKKbeta contributes at least in part to NF-kappaB activation in response to H. pylori infection. PMID- 21294677 TI - Allele-selective inhibition of ataxin-3 (ATX3) expression by antisense oligomers and duplex RNAs. AB - Spinocerebellar ataxia-3 (also known as Machado-Joseph disease) is an incurable neurodegenerative disorder caused by expression of a mutant variant of ataxin-3 (ATX3) protein. Inhibiting expression of ATX3 would provide a therapeutic strategy, but indiscriminant inhibition of both wild-type and mutant ATX3 might lead to undesirable side effects. An ideal silencing agent would block expression of mutant ATX3 while leaving expression of wild-type ATX3 intact. We have previously observed that peptide nucleic acid (PNA) conjugates targeting the expanded CAG repeat within ATX3 mRNA block expression of both alleles. We have now identified additional PNAs capable of inhibiting ATX3 expression that vary in length and in the nature of the conjugated cation chain. We can also achieve potent and selective inhibition using duplex RNAs containing one or more mismatches relative to the CAG repeat. Anti-CAG antisense bridged nucleic acid oligonucleotides that lack a cationic domain are potent inhibitors but are not allele-selective. Allele-selective inhibitors of ATX3 expression provide insights into the mechanism of selectivity and promising lead compounds for further development and in vivo investigation. PMID- 21294678 TI - Regulatory RNAs in cyanobacteria: developmental decisions, stress responses and a plethora of chromosomally encoded cis-antisense RNAs. AB - Cyanobacteria are the only prokaryotes which directly convert solar energy into biomass using oxygenic photosynthesis. Therefore, these bacteria are of interest for the production of biofuels, biotechnology and are of tremendous relevance for primary carbon fixation in many ecosystems. Mechanisms controlling gene expression cannot be understood entirely without information on the numbers and functions of regulatory RNAs. In cyanobacteria, non-coding RNAs have been characterized from simple unicellular species such as Prochlorococcus up to complex species such as Anabaena. Several of these RNAs function in the control of stress responses, photosynthesis, outer cell membrane protein biosynthesis and the differentiation of cells. PMID- 21294679 TI - Organelle stress-induced activating transcription factor-3 downregulates low density lipoprotein receptor expression in Sk-Hep1 human liver cells. AB - The low-density lipoprotein receptor (LDLR) plays a central role in cholesterol homeostasis. Here, we provide evidence that an increase in endoplasmic reticulum (ER) stress response or a disturbance of mitochondrial function inhibits LDLR expression in human liver Sk-Hep1 cells. Both organelle stresses triggered activation of activating transcription factor-3 (ATF3), which subsequently reduced LDLR expression. Serial deletion studies revealed that the LDLR promoter region within -234 bp was involved in the repression of LDLR by ATF3. In addition, we identified the region between -8 and -3 of LDLR promoter region as a putative binding site for ATF3 by using deletion construct lacking 6 bp nucleotide corresponding to this region. Transfection of ATF3-specific siRNA rescued LDLR expression under organelle stress, indicating that ATF3 was mainly responsible for the repression of LDLR by these stressors. Additionally, chromatin immunoprecipitation revealed that ATF3 directly binds to the LDLR promoter in a stress-dependent manner. The unique sterol-independent LDLR repression by organelle stress via ATF3 demonstrated here could be involved in obesity-related hypercholesterolemia, which can lead to insulin resistance and type 2 diabetes. PMID- 21294680 TI - Identification of plasma haptoglobin forms which loosely bind hemoglobin. AB - Haptoglobin (Hpt) is known to capture circulating free hemoglobin (Hb) and bind apolipoprotein (Apo) A-I or E. Here, we report that Hb can be tightly bound by most of Hpt molecules (TB-Hpt, 80%), whereas loosely bound by a minor part of them (LB-Hpt, 20%). LB-Hpt amount was significantly increased (over 60%) in patients with acute coronary syndrome. LB-Hpt bound ApoA-I and ApoE less efficiently than TB-Hpt (8- and 4-fold less, respectively) and did not affect their activity of stimulating the enzyme lecithin-cholesterol acyltransferase. LB Hpt and TB-Hpt displayed comparable levels of nitrotyrosine residues, but differences in glycan chains. Changes in LB-Hpt level might be associated with changes in Hpt functions. PMID- 21294681 TI - Clustered regularly interspaced short palindromic repeats (CRISPRs): the hallmark of an ingenious antiviral defense mechanism in prokaryotes. AB - Many prokaryotes contain the recently discovered defense system against mobile genetic elements. This defense system contains a unique type of repetitive DNA stretches, termed Clustered Regularly Interspaced Short Palindromic Repeats (CRISPRs). CRISPRs consist of identical repeated DNA sequences (repeats), interspaced by highly variable sequences referred to as spacers. The spacers originate from either phages or plasmids and comprise the prokaryotes' 'immunological memory'. CRISPR-associated (cas) genes encode conserved proteins that together with CRISPRs make-up the CRISPR/Cas system, responsible for defending the prokaryotic cell against invaders. CRISPR-mediated resistance has been proposed to involve three stages: (i) CRISPR-Adaptation, the invader DNA is encountered by the CRISPR/Cas machinery and an invader-derived short DNA fragment is incorporated in the CRISPR array. (ii) CRISPR-Expression, the CRISPR array is transcribed and the transcript is processed by Cas proteins. (iii) CRISPR Interference, the invaders' nucleic acid is recognized by complementarity to the crRNA and neutralized. An application of the CRISPR/Cas system is the immunization of industry-relevant prokaryotes (or eukaryotes) against mobile genetic invasion. In addition, the high variability of the CRISPR spacer content can be exploited for phylogenetic and evolutionary studies. Despite impressive progress during the last couple of years, the elucidation of several fundamental details will be a major challenge in future research. PMID- 21294682 TI - RNA-dependent RNA polymerases in RNA silencing. AB - RNA-dependent RNA polymerases (RdRPs) synthesize double-stranded RNAs that are processed into small RNAs and mediate gene silencing. Viral RdRPs and cellular RdRPs show little structural homology to each other. Cellular RdRPs play key roles in RNA silencing by producing complementary strands for target RNAs via Dicer-dependent and -independent mechanisms. Although the existence of a functional mammalian homolog of RdRP has long been predicted, traditional approaches to identify such enzymes were unsuccessful. Recently, human telomerase reverse transcriptase, a polymerase closely related to viral RdRPs, has been shown to function as an RdRP and contributes to RNA silencing in vivo. These findings suggest that endogenous small interfering RNAs are produced by several mechanisms in eukaryotes. PMID- 21294684 TI - Oh what a year 2010 was! Impact on telemedicine and e-health. PMID- 21294685 TI - STORC helps deliver healthy babies: the telemedicine program that serves rural women with high-risk pregnancies. PMID- 21294686 TI - What is the point of the point-of-care? A case study of user resistance to an e health system. AB - The purpose of this article is to explore the response of nurses to a point-of care e-health system that was implemented in a large private hospital in South Africa, to determine why the nursing staff rejected the implementation of the system. The study examines user responses with reference to a model designed to account for the use and adoption of mobile handheld devices, having adapted the model for an e-health context. In addition to the input features of technological characteristics and individual differences identified in the model, the added features of nursing culture and group differences were found to be influential factors in fuelling the nurses' resistance to the point-of-care system. Nurses perceived a lack of cultural fit between the system and their work. Their commitment to their nursing culture meant that they were not prepared to adapt their processes to integrate the system into their work. The study shows that the model is useful for understanding adoption in an organizational context and also that the additional elements of nursing culture and group differences are important in an e-health context. PMID- 21294688 TI - Non-mosaic Klinefelter syndrome and successful testicular sperm extraction intracytoplasmic sperm injection procedure: case report. AB - INTRODUCTION: Klinefelter syndrome is the commonest chromosomal cause of non obstructive azoospermia. Despite reports that these men can have children using assisted reproduction techniques, it is not common practice in the Egypt to offer sperm retrieval to these men. DESIGN: Case report. SETTING: Private IVF center (EIFC-IVF) and a university hospital. PATIENT: A 24-year-old woman and a 29-year old man with non-mosaic Klinefelter syndrome. INTERVENTION: Testicular sperm extraction followed by intracytoplasmic sperm injection and embryo transfer (TESE ICSI). RESULTS: Fifteen immotile sperms were found, five oocytes were injected, and three embryos were transferred. Now the pregnancy is progressing beyond 20 weeks. CONCLUSION: Spermatozoa from a patient with non-mosaic Klinefelter syndrome retrieved through TESE can lead to pregnancy. PMID- 21294689 TI - Independent predictors of cardiovascular risk in polycystic ovarian syndrome. AB - We aimed to determine the independent predictors of cardiovascular risk in polycystic ovarian syndrome (PCOS). Ninety-one PCOS and 51 control patients were enrolled to our prospective cross sectional case-control study. In early follicular phase hormonal and lipid profile, fasting insulin and CRP (hs-CRP) levels and glucose levels on fasting and 2 h after the 75 g glucose intake were determined. Insulin resistance (IR) was evaluated with homeostasis model assessment and free testosterone was determined with free androgen index. PCOS was found to be associated with dyslipidemia, hyperandrogenism, IR and sub clinical inflammation. The prevalence of overweight-obesity (41.8% vs. 25.5%, p = 0.038), IR (42.9% vs. 23.5%, p = 0.035) and glucose intolerance (15.38% vs. 1.96%, p = 0.043) were significantly higher in PCOS compared to control group. Independent predictors of the risk of elevated hs-CRP level were PCOS status (OR = 5, 95% CI: 1.55-16.14, p = 0.007) and high BMI (OR = 4.2, 95% CI: 1.2-14.2, p = 0.022) and high BMI (OR = 1.2, 95% CI: 1.05-1.4, p = 0.007) and of TC/HDL ratio was high BMI (OR = 1.21, 95% CI: 1.05-1.4, p = 0.009) and increasing age (OR = 1.11, 95% CI: 1.01-1.2, p = 0.04). The presence of PCOS, independent from obesity and IR, is the strongest predictor of elevated hs-CRP level. Obesity and advanced age further increases the cardiovascular risk in PCOS. PMID- 21294690 TI - Induction of adaptive response: pre-exposure of mice to 900 MHz radiofrequency fields reduces hematopoietic damage caused by subsequent exposure to ionising radiation. AB - PURPOSE: To investigate whether an adaptive response can be induced in mice which were pre-exposed to 900 MHz radiofrequency fields. MATERIALS AND METHODS: Adult male Kunming mice were exposed to 900 MHz radiofrequency fields (RF) at power intensities of 12, 120 and 1200 MUW/cm(2) for 1 h/day for 14 days and then subjected to whole body gamma-irradiation. The results were compared with those in unexposed control animals and those exposed to gamma-irradiation alone (without pre-exposure to RF). The extent of survival and hematopoietic tissue damage (assessed in the form of nucleated colony forming cells in the bone marrow and colony forming cells in the spleen of lethally irradiated 'recipient' mice) as well as the expression of cell cycle-related genes were investigated. RESULTS: The results indicated a significant increase in survival time, reduction in the hematopoietic tissue damage in RF pre-exposed mice which were gamma-irradiated (as compared with those exposed to gamma-radiation alone). This was accompanied by significantly increased expression of cell cycle-related genes, namely, cyclin D1, cyclin-E, cyclin-DK4 and cyclin-DK2 in hematopoietic cells. CONCLUSIONS: Pre exposure of mice to 900 MHz radiofrequency fields has resulted in a significant reduction in hematopoietic damage caused by subsequent exposure to ionising radiation. This phenomenon appears to be similar to that of the 'adaptive response' which is well documented in scientific literature. PMID- 21294691 TI - Reactive oxygen species-induced release of signalling factors in irradiated cells triggers membrane signalling and calcium influx in bystander cells. AB - PURPOSE: The aim of this study was to elucidate the sequence of very early bystander signalling events and to determine the role of the different signalling molecules in both the production of the bystander signal and the response to this signal. MATERIALS AND METHODS: Human keratinocytes (HaCaT cell line) were irradiated (0.005, 0.05 and 0.5 Gy) using a cobalt 60 teletherapy unit, the medium was harvested one hour post irradiation and transferred to recipient HaCaT cells. Membrane permeability and levels of calcium, reactive oxygen species and nitric oxide were measured in the recipient cells immediately after the addition of irradiated cell conditioned medium (ICCM). Inhibitors of reactive oxygen species (ROS), nitric oxide (NO), calcium and membrane signalling were used in both donor and recipient cells to investigate if bystander effects could be blocked. RESULTS: It was found that membrane signalling followed by calcium influx was the first response in the recipient cells to addition of ICCM. ROS, NO and calcium were all found to be important signalling molecules involved in bystander responses, while ROS and calcium were found to be involved in the production of the bystander signal. CONCLUSIONS: The data suggest that calcium and/or ROS induce irradiated cells to release long-lived signalling factors which can trigger membrane signalling and an influx of calcium further inducing ROS in unirradiated cells. PMID- 21294693 TI - Glyoxalase I and aldose reductase gene polymorphisms and susceptibility to carotid atherosclerosis in type 2 diabetes. AB - AIMS: To investigate the association of polymorphisms of glyoxalase I (GLO1) A419C, GLO1 C-7T, and aldose reductase C-106T with type 2 diabetes and diabetic carotid atherosclerosis in a Chinese Han population. METHODS: The study population included 362 patients with type 2 diabetes and 301 nondiabetic control subjects. Genetic analyses were performed using either the Taqman polymerase chain reaction or direct sequencing. All patients with diabetes underwent carotid ultrasonography to assess the intima-media thickness and the presence of atherosclerotic plaques. RESULTS: There were no differences between the genotype frequencies of GLO1 A419C, GLO1 C-7T, and aldose reductase C-106T polymorphisms, in the control and diabetic groups. The value of mean carotid intima-media thickness and the prevalence of carotid atherosclerotic plaques were significantly increased in patients with type 2 diabetes with the GLO1-7CC genotype compared with those with the -7CT and TT genotypes (permutation p=0.003 and 0.031, respectively). Multiple regression analysis showed that the GLO1-7CC genotype was an independent determinant of carotid intima-media thickness (beta=0.12, p=0.014), but not an independent risk factor for carotid atherosclerotic plaques (odds ratio [OR]=1.74, 95% CI 0.89-3.42, p=0.10) in patients with type 2 diabetes. CONCLUSIONS: The GLO1 C-7T polymorphism is associated with carotid atherosclerosis in Chinese patients with type 2 diabetes. PMID- 21294694 TI - Sustained virologic response decreases serum markers of angiogenesis, inflammation, and fibrosis in HIV/HCV-coinfected patients on hepatitis C virus therapy. PMID- 21294695 TI - Treatment of osteoporosis and reduction in risk of invasive breast cancer in postmenopausal women with raloxifene. AB - INTRODUCTION: Raloxifene, a non-steroidal selective estrogen receptor modulator (SERM), offers a new dimension for the treatment and prevention of osteoporosis and risk reduction of invasive breast cancer in postmenopausal populations at high risk. Both osteoporosis and breast cancer are important public health issues for postmenopausal women. It is well known that estrogen and estrogen receptors play an important role in the pathogenesis of both diseases. Initially, hormone replacement therapy (HRT) was used for the purpose of preventing and treating postmenopausal osteoporosis. However, HRT significantly contributed to an increase in breast cancer risk. The SERM, raloxifene, is used for the prevention and for the treatment of postmenopausal osteoporosis and reducing the risk of invasive breast cancer in postmenopausal women. AREAS COVERED: This article reviews the emerging evidence of the efficacy of raloxifene in postmenopausal women, summarizes the results and places in perspective their therapeutic uses for women having either a high risk of osteoporosis or breast cancer. Emerging clinical evidence suggests bisphosphonates, currently used as drugs for the treatment of osteoporosis, may also reduce breast cancer risk. The status of other SERMs and bisphosphonates are included for completeness. A Medline search of raloxifene, osteoporosis, breast cancer and SERMs was used to derive a database of 355 references. EXPERT OPINION: Readers will understand the value of raloxifene to prevent osteoporosis and breast cancer in postmenopausal women. Although most women do not require pharmacotherapy for menopausal symptoms, many are severely affected by osteoporosis or breast cancer at and beyond menopause and, for such women, pharmacologic intervention is important if they are to retain an acceptable quality of life. It is reasonable to use raloxifene or bisphosphonate as an appropriate drug that targets symptom-free postmenopausal women for treatment and prevention of osteoporosis but raloxifene is proven to reduce the incidence of invasive breast cancer. PMID- 21294696 TI - A miniaturized homogenous assay of mitochondrial membrane potential. AB - Mitochondrial dysfunction is increasingly associated with disease states. These organelles, responsible for adenosine triphosphate production, have been targeted for improved function in such diseases as Parkinson's, Alzheimer's, type 2 diabetes, and sarcopenia. In addition, the importance of determining if a clinical drug candidate adversely effects mitochondria function, which could lead to overt toxicity, has been recognized. Hence, assays that measure mitochondria activity have become essential in early stage drug development. Limitations of current assays that measure mitochondria membrane potential have prohibited the high-throughput performance necessary to screen current chemical space. Here, we describe a homogeneous assay to measure mitochondria membrane potential that can utilize either adherent or suspension cell types. The assay has been miniaturized to 1,536-well plate format, and was used to perform a fully automated robotic high-throughput screen of a small molecule chemical library. PMID- 21294697 TI - Radiographic Evaluation of Narrow Diameter Implants after 5 years of clinical function: a Retrospective Study. AB - Abstract The use of regular sized dental implants is generally recommended to ensure adequate bone to implant contact. However when the width of the edentulous crest is insufficient for the placement of a regular sized implant, the use of a narrow diameter implant (NDI) should be considered to prevent the use of invasive reconstruction techniques such as grafting procedures. The aim of the present study was to evaluate the survival and marginal bone levels of NDIs five years after prosthetic loading. One hundred and fifty-nine NDIs belonging to four brands (Straumann, Astra Tech, Biolok, Xive) in 71 patients were evaluated. Clinical and radiographic evaluations using digital panoramic radiography were carried out. Two implants failed and no progressive bone loss or periapical lesions were detected in the remaining 157 implants which brings an overall success rate of 98.74%. The mean marginal bone loss (MBL) was found as 1 mm on mesial and 0.98 mm on distal side of the implants. No statistically significant relationship was detected between patient age, gender, implant location, implant length, type of the prosthesis and MBL (P > 0.05). Among the 4 brands used, the MBL around Biolok implants were detected as the highest; but significantly higher than the MBL around only the Astra Tech implants (P < 0.05). The results of the present study indicated that NDIs can be a good solution for specific clinical situations where regular sized implants are not suitable. PMID- 21294698 TI - Lipid modification in the elderly using the combination of a statin and a cholesterol absorption inhibitor. AB - While the optimal lipid-lowering treatment to reduce cardiovascular disease (CVD) risk in elderly patients has not been definitively established, evidence so far indicates that reducing low-density lipoprotein cholesterol (LDL-C) should be a primary goal, as with other patient groups. The VYTELD (VYTorin in the ELDerly) study--a multicenter, 12-week, randomized, double-blind trial--evaluated the efficacy and safety of combination therapy comprised of ezetimibe plus simvastatin (eze/simva) versus atorvastatin in 1289 hypercholesterolemic patients aged ? 65 years. For all prespecified comparisons, patients randomized to eze/simva were found to have significantly greater percentage decreases in LDL-C and were significantly more likely to achieve LDL-C target levels compared with those on atorvastatin monotherapy (p < 0.05 to < 0.001). Also, the proportions of subjects reaching secondary biochemical targets were similarly greater with eze/simva than with atorvastatin monotherapy for all prespecified comparisons (p < 0.01 to < 0.001). Finally, there were no differences in tolerability between the treatments. The authors concluded that in patients aged >= 65 years, the eze/simva combination provided significantly greater improvements in key lipid variables, with a larger proportion of subjects reaching target LDL-C compared with atorvastatin monotherapy. Despite these promising short-term results, the longer-term safety and efficacy of combination treatment across diverse populations requires further evaluation. PMID- 21294699 TI - Paediatric hospital admissions for rotavirus gastroenteritis and infectious gastroenteritis of all causes in England: an analysis of correlation with deprivation. AB - OBJECTIVES: Infectious intestinal diseases cause substantial morbidity and economic loss in the UK. Rotavirus gastroenteritis (RVGE), a form of gastroenteritis, is the primary cause of severe diarrhoea in children. The primary objective of this study was to examine whether hospitalisation for gastroenteritis, and particularly RVGE, is linked to social deprivation. METHODS: A retrospective study relating to hospital admissions in England with rotavirus, gastroenteritis, or type 1 diabetes mellitus (T1DM) was conducted in children aged under 5 years between 1st April 2009 and 31st March 2010 using the CHKS database. Admissions with selected diagnoses were extracted based on ICD-10 coding. Deprivation data were obtained from the Index of Multiple Deprivation (IMD) 2007 for England. RESULTS: A total of 20,571 unique hospital admissions were made by children, in England, with RVGE (n = 1334; 6.5%) together with a diagnosis of infectious gastroenteritis of all causes (n = 19,237; 93.5%), giving an overall hospital admission rate, for those aged under 5 years, of 65.7 per 10,000 population. With 'rank of average score' and the 'rank of average rank' as measures of deprivation, the rate of hospital admissions with gastroenteritis of all causes decreased by 0.346 and 0.287 per 10,000 (p < 0.001) respectively for every unit increase in deprivation rank (decreasing deprivation), though this trend was not observed in patients admitted with RVGE specifically. CONCLUSIONS: Hospital admissions with gastroenteritis of all causes increased as deprivation increased. The implementation of a rotavirus vaccination programme would help to reduce the burden of RVGE and gastroenteritis of all causes, and in the context of gastroenteritis, some elements of health and social inequality may be vaccine preventable. LIMITATIONS: It is possible that the study is limited by the accuracy and completeness of deprivation indices, and coding within CHKS; the existence of the 'ecological fallacy' must also be considered. PMID- 21294700 TI - Treatment patterns among physician specialties in the management of fibromyalgia: results of a cross-sectional study in the United States. AB - BACKGROUND: Fibromyalgia (FM) is characterized by persistent and widespread pain and often associated with other symptoms and comorbidities. Thus, FM patients seek care from multiple physician specialties. This study compared prescribing patterns, patient-reported outcomes (PROs), healthcare resource use (HRU), and direct costs related to FM in routine clinical practice across physician specialties. METHODS: This cross-sectional, observational study recruited 203 FM subjects from 20 community-based physician offices (eight primary care, six rheumatology, three neurology, three psychiatry). Subjects completed questions about pain, other symptoms, quality of life, productivity, treatment effectiveness and satisfaction, and out-of-pocket expenses related to FM; site staff recorded subjects' treatment and HRU based on medical chart review. Results were compared across specialties. Statistical significance was evaluated at the 0.05 level. Annual direct costs associated with FM were calculated in 2009 US dollars. RESULTS: Subject demographic and clinical characteristics were not significantly different across physician specialties, except psychiatry subjects had the highest mean number of co-morbid conditions; p < 0.001. PROs were similar across physician specialties except fatigue; neurology subjects reported the highest levels. There were no significant differences in subject-reported outcomes of medication effectiveness (p = 0.782) and medication satisfaction (p = 0.338) for FM. Psychiatry subjects had more FM-related physician visits compared to other specialties (p = 0.013) and a higher proportion received diagnostic tests related to FM (p = 0.013). The mean (SD) number of FM prescription medications prescribed per subject was highest in the primary care and lowest in the neurology group; p = 0.024. The proportion of hypnotic (p = 0.001), muscle relaxant (p = 0.005), anxiolytic (p = 0.005), anti-epileptic (p = 0.007), and other medications (p = 0.044) prescribed for FM were significantly different across specialties. Overall direct medical costs did not differ significantly (p = 0.284) across specialties. CONCLUSIONS: Patient characteristics were similar across specialties, except with regards to comorbidity burden. This study noted significant differences among physician specialties in HRU and treatment patterns among medications, diagnostics, and outpatient visits. Consistent with other studies, this study did not identify a dominant strategy for FM management across physician specialties as overall per patient medical costs and subject-reported treatment satisfaction were similar. Future research to better characterize differences among physician specialties in FM management, as well as the reasons for these differences, would be useful. PMID- 21294701 TI - Development of a chronic cervical cord compression model in rat: changes in the neurological behaviors and radiological and pathological findings. AB - Cervical myelopathy is caused by chronic segmental compression of the spinal cord because of degenerative changes of the spine. However, the exact mechanisms of chronic cervical cord compression are not fully understood. The purpose of this study was to validate a new animal model of chronic cervical cord compression capable of reproducing the clinical course without laminectomy in rats. A polyethylene line attached to a plastic plate was fastened with three turns around the vertebral body of C4 in 1-month-old rats. After surgery, the polyethylene line grows deeper into the dorsal wall of the spinal canal along with the growth of the spinal canal and vertebral body, producing a gradual compression of the spinal cord. The results show that this cervical canal stenosis (CCS) model in rats caused motor deficits and sensory disturbances 9 months after initiating CCS; however, no clinical manifestations took place until 6 months. The intramedullary high-intensity area on T2-weighted images was observed in 70% of the CCS model rats at 12 months after initiating CCS. In histological sections, the spinal cord was compressed along the entire circumference at 12 months after initiating CCS. The number of ventral neurons was decreased, and the white matter showed wallerian degeneration. This model might reproduce characteristic features of clinical chronic cervical cord compression, including progressive motor and sensory disturbances after a latency period and insidious neuronal loss, and represents chronic compression of the cervical spinal cord in humans. PMID- 21294702 TI - Pharmacotherapy and prevention of vascular dementia. AB - Vascular dementia (VAD), the second most common form of dementia after Alzheimer's disease (AD) is characterized by a cognitive deficit of cerebrovascular origin. As for AD, the main proposed treatment is based on cholinesterase inhibitors. However, randomized clinical trials (RCTs) with cholinesterase inhibitors in VAD reported modest - though sometimes statistically significant - clinical efficacy. Non-cholinergic drugs with diverse rationales and mechanisms of action have also been tested in a few RCTs for VAD; the outcomes measured are variable and the evidence of efficacy is weak. The limitations of pharmacological treatment for VAD have prompted a different strategy, i.e. primary prevention aimed at reducing vascular risk factors. Several epidemiological studies reported associations of hypertension, type 2 diabetes, obesity, and inflammation with VAD and in some cases, AD. These all coincide with those of stroke, which in turn is an established factor for cognitive decline and VAD. Here too, only a few RCTs have looked at prevention of these factors, except hypertension. Some pharmacological classes are particularly promising from the clinical and experimental viewpoints: Ca2+ channel blockers and drugs affecting the renin-angiotensin system may act independently of the effects on blood pressure. Despite some conflicting results and the need for further work, the control of risk factors might prevent cognitive decline and VAD in the elderly. The benefit of tackling vascular factors is probably larger when also considering the prevention of stroke. The objective of this review is to analyze the pharmacological treatment and prevention of VAD and their outcome. The literature on Pubmed from 1980 to 2009 was examined. PMID- 21294703 TI - Complement-initiated neuroinflammation and its role in early stage Alzheimer's disease. Commentary. PMID- 21294704 TI - Synthesis and screening of substituted thiosemicarbazone derivatives: an approach towards novel anticonvulsant search. AB - A series of thiosemicarbazones of halogen substituted benzaldehydes, benzophenone and acetophenone were synthesized using an appropriate synthetic route and characterized by thin layer chromatography and spectral analysis. The anticonvulsant activity of synthesized compounds was established in three seizures models which includes maximal electroshock (MES), subcutaneous pentylene tetrazole (scPTZ) induced seizures and minimal neurotoxicity test. Five compounds out of 21 exhibited protection in MES test while only one compound showed protection in scPTZ screen. Two compounds were found to be active in minimal clonic seizure (6Hz) model. Compound PS6 i.e. 2-(3-bromobenzylidene)-N-(4 chlorophenyl) hydrazinecarbothioamide emerged as the most active compound with MES ED50 of more than 50mg/kg and pI greater than 12, which is found to be better than the prototype drug, Phenytoin. The compound has shown neuroprotection in kainic acid model with IC50 value of 40.97 uM. It has also shown mild activation effect on CYP 269 and CYP 2C9 enzymes, indicating the usefulness of thiosemicarbazones as anticonvulsants. PMID- 21294705 TI - Properties and potency of small molecule agents for treatment of Mycobacterium tuberculosis infections of the central nervous system. AB - Tuberculous meningitis is caused by Mycobacterium tuberculosis, which is the bacteria that causes tuberculosis. This bacteria spreads to the brain from another site within the body. If untreated, tuberculous meningitis can be life threatening. Substantial brain damage can result from infection which results in mental impairment, motor paralysis, seizures, and abnormal behavior. This study presents the analysis of the effectiveness of 13 novel tuberculostatic agents, along with isoniazid (a first-line drug utilized for treatment of Mycobacterium tuberculosis). All 13 agents retain a diverse character of molecular structure effectuating a range of molecular properties such as in polar surface area, Log P, and formula weight. Properties such as polar surface area, formula weight, and Log P were determined for these agents as well as values of BB (Cbrain/Cblood), and Log BB. Values of BB varied from 0.0681 to 1.16. Only three of the novel drug structures showed one violation of the Rule of 5, while the remaining showed zero violations (an outcome favoring bioavailability). Values of polar surface area ranged from 55.121 Angstroms(2) to 110.24 Angstroms(2), and Log P from -3.52 to 4.965. This group of novel tuberculostatic agents reveals examples of three homologous series of tuberculostatic drugs which purposes the likelihood of as many as 20 effective tuberculostatic drugs. Determination of MIC60 disclosed eight novel structures matching the effectiveness of isoniazid, while two showed superior ability to deter Mycobacterium tuberculosis proliferation. These novel drug designs are shown to have substantial potential for the beneficial treatment of patients having infections of Mycobacterium tuberculosis within the central nervous system. PMID- 21294706 TI - Catatonia: a narrative review. AB - Catatonic syndromes involve a complex mixture of motor, behavioral, and systemic manifestations that are derived from unclear mechanisms. What is clear is that neurotransmitters, such as dopamine (DA), gamma-aminobutyric acid (GABA), and glutamate (GLU), are of major importance in the pathogenesis of catatonia and Neuroleptic Malignant Syndrome (NMS) and that serotonin (5-hydroxytryptamine [5 HT]) is crucial to the development of Serotonin Syndrome (SS). As medications with potent effects on modulation of monoamines proliferate, the diagnosis and management of these complex disorders become even more important. Without question, these syndromes have signs, symptoms and treatments that overlap, thus, considering the symptomatological load and the associated clinical burden (including potentially life-threatening conditions), the need for a better knowledge of the hypothesized biological mechanisms and pharmacological management is imperative. Although the search for a unique, conclusive approach to the management of catatonia is futile, stating the heterogeneity of the clinical pictures and the wide range of effective treatment choices (including non-pharmacological interventions), clinicians should not disregard an accurate, critical therapeutic approach to such a relevant, yet often disregarded, topic. The aim of this narrative review is to provide both clinicians and pharmacologists with a narrative, panoramic review on catatonia and associated clinical pictures, focusing on its general pharmacological management. PMID- 21294707 TI - Antioxidants in the treatment of diabetes. AB - Diabetes is a chronic metabolic disorder that continues to present as a major health problem worldwide. It is characterized by absolute or relative deficiencies in insulin secretion and/or insulin action and is associated with chronic hyperglycemia and disturbances of carbohydrate, lipid, and protein metabolism. Many studies suggest a central role for oxidative stress in the pathogenesis of this multi-faceted metabolic disorder. This has prompted investigations in the use of antioxidants as a complementary therapeutic approach. In this review we briefly summarize oxidative mechanisms implicated in diabetic complications and then focus on the findings resulting from human clinical trials where antioxidants were studied as an adjuvant to standard diabetes treatment during the last ten years. A literature search using PubMed (last ten years) was performed using the following terms: vitamin E, vitamin C, coenzyme Q10, alpha lipoic acid, L-carnitine, ruboxistaurin or LY 333531 and diabetes. This search was limited to human clinical trials. We concluded there is not any established benefit for antioxidants use in the management of diabetic complications. Therefore, routine vitamin or mineral supplementation is not generally recommended. PMID- 21294708 TI - Management of type 2 diabetes: more evidence is required to address the clinical and contextual facets. AB - Evidence based medicine has changed the manner in which medicine is practiced and learned. Epidemiological studies, meta-analyses and systematic reviews have been used to create algorithms for the treatment of hyperglycemia in patients with type 2 diabetes. Recently, several randomized controlled trials (i.e. ACCORD, ADVANCE, VADT) have generated new and valuable information regarding the benefits and risks of achieving optimal glucose control. As a result, guidelines and algorithms have been updated. However, many aspects remain controversial. In this article, the clinical implications of the existing guidelines are critically analyzed. The limitations of the current guidelines include the lack of applicability to relevant diabetic subgroups, the exclusion of important factors that modify the therapeutic response to glucose-lowering agents and the limited recognition of the importance of the socioeconomic situation on treatment efficacy. Many subgroups of patients have not been included in the studies used to generate recommendations. There is insufficient evidence to support the use of current treatment recommendations in patients with early onset type 2 diabetes, patients with advanced microvascular complications, and the elderly with or without chronic complications. The characteristics of the candidates for conservative or intensive treatment are poorly defined. Interventions are recommended without considering clinical variables (i.e. obesity, time since diagnosis or prolonged exposure to hyperglycemia) that may modify treatment efficacy and the occurrence of side effects. Finally, no consideration is given to the socioeconomic context of the population in which the guidelines are to be applied. In summary, this manuscript highlights the key areas which require further work. If these issues are adequately addressed, the guidelines for the management of type 2 diabetes will be relevant and applicable to all diabetic groups. PMID- 21294709 TI - Omacetaxine as an anticancer therapeutic: what is old is new again. AB - Omacetaxine mepesuccinate was originally identified more than 35 years ago and initial studies in chronic myeloid leukemia (CML) showed promising activity. It has also been studied in other hematologic and solid tumors as both a single agent and in combination with other treatments. However, the introduction of imatinib and related tyrosine kinase inhibitors (TKIs) abated the clinical development of omacetaxine as a treatment for CML. The advent of resistance to imatinib and other TKIs in CML patients (often due to the presence of an ABL mutation at position 315) has led to a revived clinical interest in omacetaxine in CML patients who failed TKIs. Here we review omacetaxine's mechanism of action (MOA) as a protein translation inhibitor, how its MOA may translate into activity in treatment of cancers, its potential to eradicate leukemia initiating cells and other cancer stem cells and the potential significance of this activity in clinical practice. PMID- 21294710 TI - Recent developments in anti-cancer agents targeting PI3K, Akt and mTORC1/2. AB - Inappropriate PI3K signaling is one of the most frequent occurrences in human cancer and is critical for tumor progression. A variety of genetic mutations and amplifications have been described affecting key components of this pathway, with implications not only for tumorigenesis but also for resistance to targeted agents. Emerging preclinical research has significantly advanced our understanding of the PI3K pathway and its complex downstream signalling, interactions and crosstalk. This knowledge, combined with the limited clinical antitumor activity of mTOR complex 1 inhibitors, has led to the development of rationally designed drugs targeting key elements of this pathway, such as pure PI3K inhibitors (both pan-PI3K and isoform-specific), dual PI3K/ mTOR inhibitors, Akt inhibitors, and mTOR complexes 1 and 2 catalytic site inhibitors. This review will focus primarily on an analysis of newly developed inhibitors of this pathway that have entered clinical trials, and recently registered patents in this field. PMID- 21294711 TI - Circulating levels of non-phosphorylated undercarboxylated matrix Gla protein are associated with disease severity in patients with chronic heart failure. AB - We recently demonstrated that circulating MGP [matrix Gla (gamma-carboxylated glutamate) protein] levels were associated with left ventricular dysfunction and increased mortality in patients with symptomatic aortic stenosis. We hypothesized that patients with chronic HF (heart failure) would have dysregulated MGP levels. We examined plasma dp-cMGP (non-phosphorylated carboxylated MGP) and dp-ucMGP (non-phosphorylated undercarboxylated MGP) in 179 patients with chronic HF and matched healthy controls as well as the relationship between MGP and cardiac dysfunction as assessed by echocardiographic measurements, inflammation [CRP (C reactive protein)] and neurohormonal activation [NT-proBNP (N-terminal proB-type natriuretic peptide)] and the prognostic value of MGP levels in relation to mortality in these patients. We found markedly enhanced plasma dp-cMGP and, in particular, of dp-ucMGP in chronic HF with increasing levels with disease severity. Elevated MGP species were associated with ischaemic aetiology, increased CRP and NT-proBNP levels, as well as systolic and diastolic dysfunction. Finally, dp-ucMGP was associated with long-term heart transplant free survival (n=48) in univariate, but not in multivariate, analysis. However, plasma dp-ucMGP was markedly higher in patients who died because of progression of HF (n=12) and gave prognostic information also in multivariate analysis. In conclusion, a dysregulated MGP system could be involved in left ventricular dysfunction in patients with chronic HF. PMID- 21294712 TI - Substrate specificity of haloalkane dehalogenases. AB - An enzyme's substrate specificity is one of its most important characteristics. The quantitative comparison of broad-specificity enzymes requires the selection of a homogenous set of substrates for experimental testing, determination of substrate-specificity data and analysis using multivariate statistics. We describe a systematic analysis of the substrate specificities of nine wild-type and four engineered haloalkane dehalogenases. The enzymes were characterized experimentally using a set of 30 substrates selected using statistical experimental design from a set of nearly 200 halogenated compounds. Analysis of the activity data showed that the most universally useful substrates in the assessment of haloalkane dehalogenase activity are 1-bromobutane, 1-iodopropane, 1-iodobutane, 1,2-dibromoethane and 4-bromobutanenitrile. Functional relationships among the enzymes were explored using principal component analysis. Analysis of the untransformed specific activity data revealed that the overall activity of wild-type haloalkane dehalogenases decreases in the following order: LinB~DbjA>DhlA~DhaA~DbeA~DmbA>DatA~DmbC~DrbA. After transforming the data, we were able to classify haloalkane dehalogenases into four SSGs (substrate specificity groups). These functional groups are clearly distinct from the evolutionary subfamilies, suggesting that phylogenetic analysis cannot be used to predict the substrate specificity of individual haloalkane dehalogenases. Structural and functional comparisons of wild-type and mutant enzymes revealed that the architecture of the active site and the main access tunnel significantly influences the substrate specificity of these enzymes, but is not its only determinant. The identification of other structural determinants of the substrate specificity remains a challenge for further research on haloalkane dehalogenases. PMID- 21294713 TI - The C2 domain of Tollip, a Toll-like receptor signalling regulator, exhibits broad preference for phosphoinositides. AB - TLRs (Toll-like receptors) provide a mechanism for host defence immune responses. Activated TLRs lead to the recruitment of adaptor proteins to their cytosolic tails, which in turn promote the activation of IRAKs (interleukin-1 receptor associated kinases). IRAKs act upon their transcription factor targets to influence the expression of genes involved in the immune response. Tollip (Toll interacting protein) modulates IRAK function in the TLR signalling pathway. Tollip is multimodular, with a conserved C2 domain of unknown function. We found that the Tollip C2 domain preferentially interacts with phosphoinositides, most notably with PtdIns3P (phosphatidylinositol 3-phosphate) and PtdIns(4,5)P2 (phosphatidylinositol 4,5-bisphosphate), in a Ca2+-independent manner. However, NMR analysis demonstrates that the Tollip C2 domain binds Ca2+, which may be required to target the membrane interface. NMR and lipid-protein overlay analyses suggest that PtdIns3P and PtdIns(4,5)P2 share interacting residues in the protein. Kinetic studies reveal that the C2 domain reversibly binds PtdIns3P and PtdIns(4,5)P2, with affinity values in the low micromolar range. Mutational analysis identifies key PtdIns3P- and PtdIns(4,5)P2-binding conserved basic residues in the protein. Our findings suggest that basic residues of the C2 domain mediate membrane targeting of Tollip by interaction with phosphoinositides, which contribute to the observed partition of the protein in different subcellular compartments. PMID- 21294714 TI - The 7-year course of depression and anxiety in the general population. AB - OBJECTIVE: Insight into the long-term course of depression and anxiety. METHOD: Data were derived from Netherlands Mental Health Survey and Incidence Study/Netherlands Study of Depression and Anxiety, epidemiologic surveys in the adult population in the Netherlands. Three hundred and three respondents with depressive and/or anxiety Composite International Diagnostic Interview (CIDI) disorder were interviewed, examining the 7-year course of depression (n = 141), anxiety (n = 102) and the comorbid state (n = 60) and possible prognostic factors. Outcomes were CIDI diagnostic status after 7 years and percentage of time during 7 years with depressive and/or anxiety symptoms, retrospectively assessed by the Life Chart Interview (LCI). RESULTS: After 7 years, 60.7% of the subjects were free from a 12-month CIDI depression or anxiety diagnosis. The odds were higher for subjects with anxiety and comorbidity compared to subjects with depression. Low physical functioning and high neuroticism predicted the presence of a diagnosis after 7 years. During 7-year follow-up, 37.3% of the subjects were free from depressive and anxiety symptoms according to the LCI, 51.8% had symptoms <50% of the time, and 10.9%>=50% of the time. (Comorbid) anxiety resulted in a poorer course. High neuroticism and childhood adversity predicted more follow-up time with symptoms. CONCLUSION: Course trajectories were more favorable than expected, although comorbidity resulted in poorer course. Neuroticism, physical functioning, and childhood adversity predicted an unfavorable course. PMID- 21294715 TI - Noninvasive genomic detection of melanoma. AB - BACKGROUND: Early detection and treatment of melanoma is important for optimal clinical outcome, leading to biopsy of pigmented lesions deemed suspicious for the disease. The vast majority of such lesions are benign. Thus, a more objective and accurate means for detection of melanoma is needed to identify lesions for excision. OBJECTIVES: To provide proof-of-principle that epidermal genetic information retrieval (EGIRTM; DermTech International, La Jolla, CA, U.S.A.), a method that noninvasively samples cells from stratum corneum by means of adhesive tape stripping, can be used to discern melanomas from naevi. METHODS: Skin overlying pigmented lesions clinically suspicious for melanoma was harvested using EGIR. RNA isolated from the tapes was amplified and gene expression profiled. All lesions were removed for histopathological evaluation. RESULTS: Supervised analysis of the microarray data identified 312 genes differentially expressed between melanomas, naevi and normal skin specimens (P<0.001, false discovery rate q<0.05). Surprisingly, many of these genes are known to have a role in melanocyte development and physiology, melanoma, cancer, and cell growth control. Subsequent class prediction modelling of a training dataset, consisting of 37 melanomas and 37 naevi, discovered a 17-gene classifier that discriminates these skin lesions. Upon testing with an independent dataset, this classifier discerned in situ and invasive melanomas from naevi with 100% sensitivity and 88% specificity, with an area under the curve for the receiver operating characteristic of 0.955. CONCLUSIONS: These results demonstrate that EGIR harvested specimens can be used to detect melanoma accurately by means of a 17 gene genomic biomarker. PMID- 21294716 TI - Down syndrome patients are less likely to develop some (but not all) malignant solid tumours. PMID- 21294718 TI - PRRX1 is mutated in a fetus with agnathia-otocephaly. PMID- 21294719 TI - Intragenic deletion in DYRK1A leads to mental retardation and primary microcephaly. PMID- 21294720 TI - Cellular localization and functional significance of CYP3A4 in the human epileptic brain. AB - PURPOSE: Compelling evidence supports the presence of P450 enzymes (CYPs) in the central nervous system (CNS). However, little information is available on the localization and function of CYPs in the drug-resistant epileptic brain. We have evaluated the pattern of expression of the specific enzyme CYP3A4 and studied its co-localization with MDR1. We also determined whether an association exists between CYP3A4 expression and cell survival. METHODS: Brain specimens were obtained from eight patients undergoing resection to relieve drug-resistant seizures or to remove a cavernous angioma. Each specimen was partitioned for either immunostaining or primary culture of human endothelial cells and astrocytes. Immunostaining was performed using anti-CYP3A4, MDR1, GFAP, or NeuN antibodies. High performance liquid chromatography-ultraviolet (HPLC-UV) analysis was used to quantify carbamazepine (CBZ) metabolism by these cells. CYP3A4 expression was correlated to DAPI) condensation, a marker of cell viability. Human embryonic kidney (HEK) cells were transfected with 4',6-diamidino-2 phenylindole (CYP3A4 to further evaluate the link between CYP3A4 levels, CBZ metabolism, and cell viability. KEY FINDINGS: CYP3A4 was expressed by blood-brain barrier (BBB) endothelial cells and by the majority of neurons (75 +/- 10%). Fluorescent immunostaining showed coexpression of CYP3A4 and MDR1 in endothelial cells and neurons. CYP3A4 expression inversely correlated with DAPI nuclear condensation. CYP3A4 overexpression in HEK cells conferred resistance to cytotoxic levels of carbamazepine. CYP3A4 levels positively correlated with the amount of CBZ metabolized. SIGNIFICANCE: CYP3A4 brain expression is not only associated with drug metabolism but may also represent a cytoprotective mechanism. Coexpression of CYP3A4 and MDR1 may be involved in cell survival in the diseased brain. PMID- 21294722 TI - Retinal cells suppress intraocular inflammation (uveitis) through production of interleukin-27 and interleukin-10. AB - Neuronal or photoreceptor deficit observed in uveitis and multiple sclerosis derives in part from inability to control inflammatory responses in neuroretina or brain. Recently, IL-27 was found to play a role in suppressing experimental autoimmune uveitis and experimental autoimmune encephalomyelitis, two animal models that share essential pathological features of human uveitis and multiple sclerosis, respectively. However, the mechanism by which interleukin-27 (IL-27) inhibits central nervous system (CNS) inflammation is not clear. In this study we have investigated mechanisms that mitigate or curtail intraocular inflammation (uveitis) and examined whether inhibitory effects of IL-27 are mediated locally by neuroretinal cells or by regulatory T cells. We show here that microglia cells in the neuroretina constitutively secrete IL-27 and its expression is up regulated during uveitis. We further show that photoreceptors constitutively express IL-27 receptor and respond to IL-27 signalling by producing anti inflammatory molecules, IL-10 and suppressor of cytokine signalling 1 (SOCS1) through signal transducer and activator of transcription 1 (STAT1) -dependent mechanisms. Moreover, STAT1-deficient mice produced reduced amounts of IL-27, IL 10 and SOCS1 and developed more severe uveitis. Surprisingly, IL-10-producing regulatory T cells had marginal roles in suppressing uveitis. These results suggest that suppression of intraocular inflammation might be mediated through endogenous production of IL-27 and IL-10 by retinal cells, whereas SOCS proteins induced by IL-27 during uveitis may function to protect the neuroretinal cells from the toxic effects of pro-inflammatory cytokines. Targeted delivery of IL-27 into immune privileged tissues of the CNS may therefore be beneficial in the treatment of CNS inflammatory diseases, such as uveitis and multiple sclerosis. PMID- 21294723 TI - Identification of MHC class II restricted T-cell-mediated reactivity against MHC class I binding Mycobacterium tuberculosis peptides. AB - Major histocompatibility complex (MHC) class I restricted cytotoxic T lymphocytes (CTL) are known to play an important role in the control of Mycobacterium tuberculosis infection so identification of CTL epitopes from M. tuberculosis is of importance for the development of effective peptide-based vaccines. In the present work, bioinformatics technology was employed to predict binding motifs of 9mer peptides derived from M. tuberculosis for the 12 HLA-I supertypes. Subsequently, the predicted peptides were synthesized and assayed for binding to HLA-I molecules in a biochemically based system. The antigenicity of a total of 157 peptides with measured affinity for HLA-I molecules of K(D) <= 500 nM were evaluated using peripheral blood T cells from strongly purified protein derivative reactive healthy donors. Of the 157 peptides, eight peptides (5%) were found to induce T-cell responses. As judged from blocking with HLA class I and II subtype antibodies in the ELISPOT assay culture, none of the eight antigenic peptides induced HLA class I restricted CD8(+) T-cell responses. Instead all responses were blocked by pan-HLA class II and anti-HLA-DR antibodies. In addition, CD4(+) T-cell depletion before the 10 days of expansion, resulted in total loss of reactivity in the ELISPOT culture for most peptide specificities. FACS analyses with intracellular interferon-gamma staining of T cells expanded in the presence of M. tuberculosis peptides confirmed that the responsive cells were indeed CD4(+). In conclusion, T-cell immunity against HLA-I binding 9mer M. tuberculosis-derived peptides might in many cases turn out to be mediated by CD4(+) T cells and restricted by HLA-II molecules. The use of 9mer peptides recognized by both CD8(+) and CD4(+) T cells might be of importance for the development of future M. tuberculosis peptide-based vaccines. PMID- 21294724 TI - Response of ecosystems to realistic extinction sequences. AB - Recent research suggests that effects of species loss on the structure and functioning of ecosystems will critically depend on the order with which species go extinct. However, there are few studies of the response of natural ecosystems to realistic extinction sequences. Using an extinction scenario based on the International Union for Conservation of Nature (IUCN) Red List, de Visser et al. sequentially deleted species from a topological model of the Serengeti food web. Under this scenario, large-bodied species like top predators and mega-herbivores go extinct first. The resulting changes in the trophic structure of the food web might affect the robustness of the ecosystem to future disturbances. PMID- 21294725 TI - Editorial: putting the 'clinical' in clinical neuroscience. PMID- 21294726 TI - Commentary: a contribution to evidence-informed education policy--reflections on Strong, Torgerson, Torgerson, and Hulme (2011). PMID- 21294727 TI - Commentary: are callous unemotional traits all in the eyes? Examining eye contact in youth with conduct problems and callous unemotional traits-reflections on Dadds et al. (2011). PMID- 21294729 TI - Youth suicide trends in Finland, 1969-2008. AB - BACKGROUND: There are only a few recent studies on secular trends in child and adolescent suicides. We examine here trends in rates and methods of suicide among young people in Finland, where suicide rates at these ages are among the highest in the world. METHODS: The data, obtained from Statistics Finland, consisted of all suicides (n = 901) committed by persons under 18 years of age over the period 1969-2008. Gender-specific trends were analysed separately for the years 1969 1989 and 1990-2008 using 3-year moving averages. Trends in methods of suicide were examined from 1975 to 2008 in five-year periods. RESULTS: The male-to-female ratio in youth suicides was 3.6:1. The male rates increased in 1969-1989, while the rates among females were inconsistent. After 1990, the rates decreased for males but turned to an increase among females. Shooting was the most common suicide method among males throughout the period, while hanging exceeded poisoning as the most common method among females after 1990. All violent suicides decreased for males and increased for females in 1990-2008. CONCLUSIONS: The increase in violent, i.e., more lethal, suicide methods among young females is alarming, as females are known to have higher rates of attempted suicide than males. Alcohol consumption, rates and treatment of depression and violent behaviour among adolescents are discussed as approaches towards explaining this phenomenon. PMID- 21294730 TI - Childhood behavior problems and health at midlife: 35-year follow-up of a Scottish birth cohort. AB - BACKGROUND: Childhood behavior problems are associated with premature mortality. To identify plausible pathways that may account for this association, we explored the extent to which childhood behavior problems relate to health behaviors and health outcomes at midlife. METHODS: The Aberdeen Children of the 1950s (ACONF) study comprises 12,500 children from the Aberdeen area, Scotland, UK. Childhood behavior problems were assessed by teacher ratings at children's age of 6-12 years. Between 2001 and 2003, surviving study members, then aged 46-51 years, were mailed a questionnaire containing enquiries about physician-diagnosed conditions (long-term disease, diabetes, high blood pressure), general health, well-being, weight, smoking, and alcohol intake. A total of 7,183 responded. RESULTS: Two dimensions of externalizing (conduct problems and hyperactivity) and one of internalizing (emotional problems) behaviors were associated with adult health. Childhood conduct problems were related to an increased risk of long-term disease (odds ratio per one standard deviation increase; 95% confidence interval: 1.15; 1.02-1.29 for men; 1.26; 1.08-1.47 for women), obesity (1.16; 1.01-1.33 in men; 1.38; 1.14-1.68 in women), cigarette smoking (1.20; 1.07-1.34 in men; 1.17; 1.01-1.35 in women), and lower well-being. Childhood hyperactivity was associated with earlier initiation of smoking in men and women; smoking more cigarettes in women; and binge-drinking, as well as a higher frequency of hangovers in men. Internalizing behavior was related to a reduced the risk of ever smoking (.87; .80-.95 in men; .92; .85-.99 in women) and to healthier drinking patterns. In women but not men, internalizing problems also predicted a later age of smoking onset. Adjusting for socio-economic status of origin, childhood intelligence, education and age had negligible effects on these results. CONCLUSIONS: Childhood behavior problems were associated with a series of adult health-related habits that may partially account for the link between early problem behaviors and premature mortality. PMID- 21294732 TI - Rib metastases from a non-tonsillar squamous cell carcinoma in a dog. AB - Metastatic spread to the ribs in a 15-year-old, male, neutered, Irish setter is reported occurring secondary to an oral squamous cell carcinoma (SCC). The dog presented with a history of a rapidly growing SCC of the right upper incisive region, which was confirmed by histopathology as a SCC. Thoracic radiographs showed bony lesions associated with the body of the right third rib, and the fifth and seventh costal cartilages. A rostral partial maxillectomy was performed as palliative treatment for the oral mass and a core biopsy of the lesion on the third rib was performed. The rib lesion was identified histopathologically as a metastatic SCC. A review of the literature of oropharyngeal SCC and the metastatic potential of non-tonsillar SCC is presented, in particular metastatic bone disease. This case report suggests possible implications of metastatic bone disease for treatment and prognosis for future cases of non-tonsillar SCC. PMID- 21294731 TI - ATP and glutamate released via astroglial connexin 43 hemichannels mediate neuronal death through activation of pannexin 1 hemichannels. AB - Inflammation contributes to neurodegeneration in post-ischemic brain, diabetes, and Alzheimer's disease. Participants in this inflammatory response include activation of microglia and astrocytes. We studied the role of microglia treated with amyloid-beta peptide (Abeta) on hemichannel activity of astrocytes subjected to hypoxia in high glucose. Reoxygenation after 3 h hypoxia in high glucose induced transient astroglial permeabilization via Cx43 hemichannels and reduction in intercellular communication via Cx43 cell-cell channels. Both responses were greater and longer lasting in astrocytes previously exposed for 24 h to conditioned medium from Abeta-treated microglia (CM-Abeta). The effects of CM Abeta were mimicked by TNF-alpha and IL-1beta and were abrogated by neutralizing TNF-alpha with soluble receptor and IL-1beta with a receptor antagonist. Astrocytes under basal conditions protected neurons against hypoxia, but exposure to CM-Abeta made them toxic to neurons subjected to a sub-lethal hypoxia/reoxygenation episode, revealing the additive nature of the insults. Astrocytes exposed to CM-Abeta induced permeabilization of cortical neurons through activation of neuronal pannexin 1 (Panx1) hemichannels by ATP and glutamate released through astroglial Cx43 hemichannels. In agreement, inhibition of NMDA or P2X receptors only partially reduced the activation of neuronal Panx1 hemichannels and neuronal mortality, but simultaneous inhibition of both receptors completely prevented the neurotoxic response. Therefore, we suggest that responses to ATP and glutamate converge in activation of neuronal Panx1 hemichannels. Thus, we propose that blocking hemichannels expressed by astrocytes and/or neurons in the inflamed nervous system could represent a novel and alternative strategy to reduce neuronal loss in various pathological states including Alzheimer's disease, diabetes and ischemia. PMID- 21294733 TI - Arthroscopic partial patellectomy in a dog. AB - A six-year-old, female, neutered, whippet was presented for evaluation of a severe, sudden-onset right pelvic limb lameness. The extensor mechanism of the right stifle was intact and there was periarticular swelling in the right stifle. Radiography showed a fracture of the distal pole of the patella. The distal fragment was approximately 25% of the patellar length and the fracture was deemed non-reconstructable. Fracture fragment removal was performed arthroscopically, which led to an excellent clinical outcome. The owner considered the dog to be exercising normally at the seven-month postoperative examination. To the authors' knowledge this report documents the first arthroscopically performed partial patellectomy in veterinary surgery. PMID- 21294734 TI - Postoperative haemorrhage associated with active suction drains in two dogs. AB - This article describes two dogs in which an active suction drain was placed to manage dead space at the surgical site and acute haemorrhage and hypovolaemia occurred postoperatively. In both instances, fluid resuscitation and temporary discontinuation of drainage resulted in resolution of clinical signs. Although the underlying cause of haemorrhage was not definitively identified, the use of low-pressure drainage systems and avoidance of interference with local blood vessels should be considered. This is a previously undocumented complication of active suction drain use in veterinary patients. PMID- 21294735 TI - Sensitivity of leaf size and shape to climate: global patterns and paleoclimatic applications. AB - * Paleobotanists have long used models based on leaf size and shape to reconstruct paleoclimate. However, most models incorporate a single variable or use traits that are not physiologically or functionally linked to climate, limiting their predictive power. Further, they often underestimate paleotemperature relative to other proxies. * Here we quantify leaf-climate correlations from 92 globally distributed, climatically diverse sites, and explore potential confounding factors. Multiple linear regression models for mean annual temperature (MAT) and mean annual precipitation (MAP) are developed and applied to nine well-studied fossil floras. * We find that leaves in cold climates typically have larger, more numerous teeth, and are more highly dissected. Leaf habit (deciduous vs evergreen), local water availability, and phylogenetic history all affect these relationships. Leaves in wet climates are larger and have fewer, smaller teeth. Our multivariate MAT and MAP models offer moderate improvements in precision over univariate approaches (+/- 4.0 vs 4.8 degrees C for MAT) and strong improvements in accuracy. For example, our provisional MAT estimates for most North American fossil floras are considerably warmer and in better agreement with independent paleoclimate evidence. * Our study demonstrates that the inclusion of additional leaf traits that are functionally linked to climate improves paleoclimate reconstructions. This work also illustrates the need for better understanding of the impact of phylogeny and leaf habit on leaf-climate relationships. PMID- 21294736 TI - Cellular pH measurements in Emiliania huxleyi reveal pronounced membrane proton permeability. AB - * To understand the influence of changing surface ocean pH and carbonate chemistry on the coccolithophore Emiliania huxleyi, it is necessary to characterize mechanisms involved in pH homeostasis and ion transport. * Here, we measured effects of changes in seawater carbonate chemistry on the fluorescence emission ratio of BCECF (2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein) as a measure of intracellular pH (pH(i)). Out of equilibrium solutions were used to differentiate between membrane permeation pathways for H(+), CO(2) and HCO(3)( ). * Changes in fluorescence ratio were calibrated in single cells, resulting in a ratio change of 0.78 per pH(i) unit. pH(i) acutely followed the pH of seawater (pH(e)) in a linear fashion between pH(e) values of 6.5 and 9 with a slope of 0.44 per pH(e) unit. pH(i) was nearly insensitive to changes in seawater CO(2) at constant pH(e) and HCO(3)(-). An increase in extracellular HCO(3)(-) resulted in a slight intracellular acidification. In the presence of DIDS (4,4' diisothiocyanatostilbene-2,2'-disulfonic acid), a broad-spectrum inhibitor of anion exchangers, E. huxleyi acidified irreversibly. DIDS slightly reduced the effect of pH(e) on pH(i). * The data for the first time show the occurrence of a proton permeation pathway in E. huxleyi plasma membrane. pH(i) homeostasis involves a DIDS-sensitive mechanism. PMID- 21294737 TI - Rapid changes in delta13C of ecosystem-respired CO2 after sunset are consistent with transient 13C enrichment of leaf respired CO2. AB - The CO2 respired by darkened, light-adapted, leaves is enriched in 13C during the first minutes, and this effect may be related to rapid changes in leaf respiratory biochemistry upon darkening. We hypothesized that this effect would be evident at the ecosystem scale. High temporal resolution measurements of the carbon isotope composition of ecosystem respiration were made over 28 diel periods in an abandoned temperate pasture, and were compared with leaf-level measurements at differing levels of pre-illumination. At the leaf level, CO2 respired by darkened leaves that had been preadapted to high light was strongly enriched in 13C, but such a 13C-enrichment rapidly declined over 60-100 min. The 13C-enrichment was less pronounced when leaves were preadapted to low light. These leaf-level responses were mirrored at the ecosystem scale; after sunset following clear, sunny days respired CO2 was first 13C enriched, but the 13C enrichment rapidly declined over 60-100 min. Further, this response was less pronounced following cloudy days. We conclude that the dynamics of leaf respiratory isotopic signal caused variations in ecosystem-scale 12CO2/13) CO2 exchange. Such rapid isotope kinetics should be considered when applying 13C based techniques to elucidate ecosystem carbon cycling. PMID- 21294738 TI - Distinct seasonal assemblages of arbuscular mycorrhizal fungi revealed by massively parallel pyrosequencing. AB - * Understanding the dynamics of rhizosphere microbial communities is essential for predicting future ecosystem function, yet most research focuses on either spatial or temporal processes, ignoring combined spatio-temporal effects. * Using pyrosequencing, we examined the spatio-temporal dynamics of a functionally important community of rhizosphere microbes, the arbuscular mycorrhizal (AM) fungi. We sampled AM fungi from plant roots growing in a temperate grassland in a spatially explicit manner throughout a year. * Ordination analysis of the AM fungal assemblages revealed significant temporal changes in composition and structure. Alpha and beta diversity tended to be negatively correlated with the climate variables temperature and sunshine hours. Higher alpha diversity during colder periods probably reflects more even competitive interactions among AM fungal species under limited carbon availability, a conclusion supported by analysis of beta diversity which highlights how resource limitation may change localized spatial dynamics. * Results reveal distinct AM fungal assemblages in winter and summer at this grassland site. A seasonally changing supply of host plant carbon, reflecting changes in temperature and sunshine hours, may be the driving force in regulating the temporal dynamics of AM fungal communities. Climate change effects on seasonal temperatures may therefore substantially alter future AM fungal community dynamics and ecosystem functioning. PMID- 21294739 TI - Units of nature or processes across scales? The ecosystem concept at age 75. AB - The ecosystem has served as a central organizational concept in ecology for nearly a half century and continues to evolve. As a level in the biotic hierarchy, ecosystems are often viewed as ecological communities integrated with their abiotic environments. This has always been imperfect because of a mismatch of scales between communities and ecosystem processes as they are made operational for field study. Complexity theory has long been forecasted to provide a renewed foundation for ecosystem theory but has been slow to do so. Partly this has arisen from a difficulty in translating theoretical tenets into operational terms for testing in field studies. Ecosystem science has become an important applied science for studying global change and human environmental impacts. Vigorous and important directions in the study of ecosystems today include a growing focus on human-dominated landscapes and development of the concept of ecosystem services for human resource supply and well-being. Today, terrestrial ecosystems are viewed less as well-defined entities or as a level in the biotic hierarchy. Instead, ecosystem processes are being increasingly viewed as the elements in a hierarchy. These occur alongside landscape processes and socioeconomic processes, which combine to form coupled social-ecological systems across a range of scales. PMID- 21294740 TI - Mitochondrial response to controlled nutrition in health and disease. AB - Mitochondria exert crucial physiological functions that create complex links among nutrition, health, and disease. While mitochondrial dysfunction with subsequent impairment of oxidative phosphorylation (OXPHOS) is the hallmark of the rare inherited OXPHOS diseases, OXPHOS dysfunction also plays a central role in the pathophysiology of common conditions such as type 2 diabetes and various neurodegenerative disorders. Dietary interventions, especially calorie restriction, have been shown to improve the course of these diseases and to extend the lifespan. Few data are available on the impact of nutraceuticals (macronutrients, vitamins, and cofactors) on primary inherited OXPHOS diseases. This review presents recent knowledge about the impact of nutritional modulation on mitochondria and lifespan regulation and about the development of potential treatments for mitochondrial dysfunction diseases. PMID- 21294741 TI - Early postnatal nutrition and programming of the preterm neonate. AB - Early postnatal nutrition is a vital determinant of adult health; this is particularly true for the infant born prematurely and cared for in a hospital setting such as the neonatal intensive care unit. Human and animal studies support the contribution of postnatal dietary composition and the rate of extrauterine growth to long-term metabolic outcomes. One mechanism by which postnatal nutrition affects long-term outcome is via developmental programming. Programming, or the modulation of gene expression to impart a short-term advantage accompanied by a long-term cost, may be achieved by epigenetic modifications to chromatin. This review summarizes the details of postnatal nutritional content and rate of growth on the development of metabolic disease. The role of epigenetics in developmental programming of the preterm infant is also discussed, with an emphasis on animal models of dietary manipulation and directions in which the field must move in order to formulate effective feeding strategies for the preterm infant. PMID- 21294742 TI - School feeding programs in developing countries: impacts on children's health and educational outcomes. AB - School feeding programs (SFPs) are intended to alleviate short-term hunger, improve nutrition and cognition of children, and transfer income to families. The present review explores the impact of SFPs on nutritional, health, and educational outcomes of school-aged children in developing countries. Peer reviewed journal articles and reviews published in the past 20 years were identified and screened for inclusion. Analysis of the articles revealed relatively consistent positive effects of school feeding in its different modalities on energy intake, micronutrient status, school enrollment, and attendance of the children participating in SFPs compared to non-participants. However, the positive impact of school feeding on growth, cognition, and academic achievement of school-aged children receiving SFPs compared to non-school-fed children was less conclusive. This review identifies research gaps and challenges that need to be addressed in the design and implementation of SFPs and calls for theory-based impact evaluations to strengthen the scientific evidence behind designing, funding, and implementing SFPs. PMID- 21294743 TI - Fermentation potential of the gut microbiome: implications for energy homeostasis and weight management. AB - Energy homeostasis is regulated by twin factors, energy intake and energy expenditure. Obesity arises when these two factors are out of balance. Recently, the microflora residing in the human gut has been found to be one of the influential factors disturbing energy balance. Recent interest in this field has led to use of the term "gut microbiome" to describe the genomes of trillions of microbes residing in the gut. Metagenomic studies have shown that the human gut microbiome facilitates fermentation of indigestible carbohydrates to short-chain fatty acids that provide excess energy to the body, thus contributing to the obese phenotype. Alteration in the ratio of Bacteroidetes and Firmicutes drives a change in fermentation patterns that could explain weight gain. Therefore, changes in the gut microbiome (induced by antibiotics or dietary supplements) may be helpful in curbing the obesity pandemic. This review provides information on the expansive role the gut microbiome is believed to play in obesity and other related metabolic disorders. PMID- 21294744 TI - Celiac disease, gluten-free diet, and oats. AB - Oats in a gluten-free diet increase the diet's nutritional value, but their use remains controversial. Contamination with prolamins of other cereals is frequent, and some clinical and experimental studies support the view that a subgroup of celiac patients may be intolerant to pure oats. Thus, this issue is more complex than previously suggested. In order to produce oats that are safe for all celiac patients, the following topics should be addressed: selection of oat cultivars with low avenin content, research on such recombinant varieties of oats, development of assay methods to detect avenins in oat products, guidelines for the agricultural processing of oats and the manufacture of oat products, as well as guidelines for following up with celiac patients who consume oats. PMID- 21294745 TI - The devil is in the details. PMID- 21294748 TI - Solvent dependence of the photophysical properties of 2-chlorothioxanthone, the principal photoproduct of chlorprothixene. AB - 2-chlorothioxanthone (CTX) is used as photoinitiator for the reticulation of synthetic resins and for the preparation of pharmaceuticals. It was previously determined that CTX is the primary photoproduct of z-chlorprothixene (CPTX) when irradiated at 313 nm and is formed in an autocatalyzed reaction through an energy transfer mechanism (Pinero et al. [2009] Photochem. Photobiol., 85, 895-900). In this work, the photophysical properties of CTX were measured in acetonitrile/water solutions to determine if their magnitude can affect the side effects of CPTX. The results show that CTX has higher absorption coefficients in the visible region (400-420 nm) and higher triplet quantum yields than its parent compound. Similar to TX, both properties strongly depend on the solvent polarity/hydroxylicity. The quantum yield of the triplet intermediate is very close to the value of the phenothiazine triplets. The phenothiazines are the most phototoxic antidepressants. Therefore, given the appropriate microenvironment, the photosensitization side effects of CPTX can be intensified on the production of CTX. PMID- 21294749 TI - Inhibitory activity of Pseudomonas sp. on Flavobacterium psychrophilum, in vitro. AB - A Pseudomonas sp. isolate MSB1 efficiently inhibited the growth of Flavobacterium psychrophilum of different serotypes on agar medium. A significant difference in the inhibition was observed between isolates of the less virulent Fp(T) serotype compared to the Fd and Th serotypes. In broth coculture experiments, a low number of cells of MSB1 inhibited and outcompeted the F. psychrophilum cells. Also cell free culture supernatant of MSB1 clearly repressed the growth of F. psychrophilum. A chromoazurol S assay suggested that MSB1 produced efficient siderophores, which most probably were responsible for the iron deficiency in the supernatant. The limited growth of F. psychrophilum in the supernatant was found to be partly because of the lack of available iron, but the results also indicated that some other mechanisms were probably involved in the observed inhibition. A potential use of MSB1 as a probiotic in rainbow trout aquaculture, especially in early life stages of the fish, is suggested, but future in vivo experiments needs to be carried out to verify this suggestion. This study also indicates a low iron acquisition efficiency of F. psychrophilum, compared to other examined bacterial fish pathogens. PMID- 21294750 TI - Rapid identification of Streptococcus iniae by specific PCR assay utilizing genetic markers in ITS rDNA. AB - The 16S-23S intergenic spacers (ITS) of ribosomal DNA from ten independent isolates of Streptococcus iniae and one reference strain ATCC29178 were sequenced, aligned and used to design a polymerase chain reaction (PCR) primer set for rapid and specific detection and identification of S. iniae. This primer set amplified a 377-bp DNA fragment specifically from S. iniae, but not from other common bacterial pathogens of fish or from non-fish pathogens. The PCR conditions were optimized to allow detection of the organism from agar, broth culture or infected fish tissue. The sensitivity of the PCR assay was established by the detection of DNA as low as 0.02 ng or as few as 10 CFU bacterial cells. The establishment of the specific PCR assay provides a useful tool for the identification and diagnosis of fish infection with S. iniae. PMID- 21294751 TI - A comparative study of marine salmonid alphavirus subtypes 1-6 using an experimental cohabitation challenge model. AB - A comparative challenge study of six marine isolates representing subtypes 1-6 of salmonid alphavirus (salmon pancreas disease virus, Genus Alphavirus, Family Togaviridae) was conducted in Atlantic salmon in a fresh water cohabitation trial. Histopathological lesions typical of pancreas disease were observed with all subtypes, and virus was re-isolated from serum of cohabitant fish in each case. Using a virus neutralization (VN) test neutralizing salmonid alphavirus (SAV) subtype 1 strain F93-125, VN antibodies were detected in all challenge groups, consistent with serological cross-reactivity between these subtypes. Using real-time RT-PCR, SAV RNA was detected in heart tissue from 2 to 3 weeks post-challenge (wpc) in all cohabitant groups excluding controls. The results obtained suggested differences in the dynamics of infection between strains of SAV and potentially between subtypes. Results for SAV subtypes 1 and 3 suggested essentially synchronous infection of cohabitant fish. These two study groups also had the highest virus load in heart tissue as measured by quantitative RT-PCR and also had the most extensive histopathological changes. In contrast, results for SAV subtypes 2 and 6 strains were consistent with asynchronous infection in the cohabitant fish and were characterized by slow spread, low virus loads and mild histopathological changes. The SAV subtype 4 and 5 strains occupied an intermediate position in this regard. Despite the use of concentration procedures, it was not possible to detect SAV RNA in water samples from selected study tanks. However, testing of faeces from the SAV subtypes 1, 3 and 6 challenge groups found positive signals in each beginning at 1-3 wpc and remaining detectable for a further 2-3 weeks. Parallel testing of mucus samples found these became positive at 2-3 wpc and remained positive for a further 1-3 weeks. These results demonstrate for the first time that shedding and transmission of virus may occur by both these routes and suggest that dispersal in these matrices should be included in any disease transmission models. PMID- 21294752 TI - If it matters for the group then it matters to me: collective action outcomes for seasoned activists. AB - The present article reports a longitudinal study of the psychological antecedents for, and outcomes of, collective action for a community sample of activists. At Time 1, activist identification influenced intentions to engage in collective action behaviours protesting the Iraq war, both directly and indirectly via perceptions of the efficacy of these behaviours for achieving group goals, as well as perceptions of individual-level benefits. At Time 2, identification was associated with differences in the dimensions on which the movement's success was evaluated. In the context of the movement's failure to achieve its stated objectives of troop withdrawal, those with strong activist identity placed less importance on influencing government decision making. The implications are discussed in terms of models of collective action and social identity, focusing on a dynamic model that relates identification with a group to evaluations of instrumentality at a group and individual level; and to beliefs about strategic responses to achieve group goals. PMID- 21294753 TI - Moderate prenatal alcohol exposure and serotonin genotype interact to alter CNS serotonin function in rhesus monkey offspring. AB - BACKGROUND: Moderate prenatal alcohol exposure can contribute to neurodevelopmental impairments and disrupt several neurotransmitter systems. We examined the timing of moderate level alcohol exposure, serotonin transporter gene polymorphic region variation (rh5-HTTLPR), and levels of primary serotonin and dopamine (DA) metabolites in cerebrospinal fluid (CSF) in rhesus monkeys. METHODS: Thirty-two 30-month old rhesus monkeys (Macaca mulatta) from 4 groups of females were assessed: (i) early alcohol-exposed group (n = 9), in which mothers voluntarily consumed 0.6 g/kg/d alcohol solution on gestational days 0 to 50; (ii) middle-to-late gestation alcohol-exposed group (n = 6), mothers consumed 0.6 g/kg/d alcohol solution on gestational days 50 to 135; (iii) a continuous exposure group (n = 8), mothers consumed 0.6 g/kg/d alcohol solution on gestational days 0 to 135; and (iv) controls (n = 9), mothers consumed an isocaloric control solution on gestational days 0 to 50, 50 to 135, or 0 to 135. Serotonin transporter promoter region allelic variants (homozygous s/s or heterozygous s/l vs. homozygous l/l) were determined. We examined CSF concentrations of the 5-HT and DA metabolites, 5-hydroxyindoleacetic acid (5 HIAA) and homovanillic acid (HVA), respectively, at baseline and 50 hours after separation from cage-mates, when the monkeys were 30 months old. RESULTS: Early- and middle-to-late gestation-alcohol exposed monkeys carrying the short allele had lower concentrations of 5-HIAA in CSF relative to other groups. Concentrations of 5-HIAA in CSF were lower for s allele carriers and increased from baseline relative to pre-separation values, whereas 5-HIAA levels in l/l allele carriers were not affected by separation. Monkeys carrying the short allele had lower basal concentrations of HVA in CSF compared with monkeys homozygous for the long allele. CONCLUSION: Carrying the s allele of the 5-HT transporter increased the probability of reduced 5-HIAA in early- and middle-to late gestation alcohol-exposed monkeys and reduced HVA at baseline. These findings that prenatal alcohol exposure altered central 5-HT activity in genetically sensitive monkeys raise questions about whether abnormal serotonin biological pathways could underlie some of the psychiatric disorders reported in fetal alcohol spectrum disorder. PMID- 21294754 TI - The change of plasma ghrelin and leptin levels by the development of type 2 diabetes mellitus in patients with alcohol dependence. AB - BACKGROUND: There have been lots of studies about the relationship between chronic use of alcohol and the development of type 2 diabetes mellitus (T2DM). Chronic use of alcohol can be affected by the altered level of ghrelin and leptin which regulate food-seeking behavior having similar mechanism of controlling alcohol-craving behavior. Those peptides are known to be correlated with T2DM. Ghrelin and leptin also have been regarded as possible regulators of glucose metabolism and insulin function. Hence, there is the possibility that ghrelin and leptin can be related with deteriorated pathophysiology of T2DM in alcoholic patients. METHODS: Patients with alcohol dependence diagnosed by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) underwent an 75 g oral glucose-tolerance test (OGTT), to classify them to normal glucose tolerance (NGT, n = 52), pre-diabetes including impaired glucose tolerance (IGT), impaired fasting glucose level (IFG) and combination of IGT and IFG (Pre-DM, n = 26) and T2DM (n = 24) groups. Fasting plasma ghrelin and leptin levels were compared among groups. RESULTS: There was no difference of ghrelin concentration among the groups but the leptin concentration was significantly different between NGT and T2DM group (p < 0.05). Increased leptin levels were significantly correlated with body mass index (BMI), insulin level, and insulin resistance. CONCLUSIONS: Chronic alcohol drinking might produce leptin resistance which makes leptin significantly correlated with fasting insulin concentration and insulin resistance. Therefore, we suppose that increased level of leptin by chronic alcohol use could be one of the main mechanisms that develop insulin resistance in alcoholic patients. PMID- 21294755 TI - Leptin and acetaldehyde synergistically promotes alphaSMA expression in hepatic stellate cells by an interleukin 6-dependent mechanism. AB - BACKGROUND: The mechanisms whereby patients with obesity/overweight are more susceptible to alcohol-associated liver fibrosis are unclear. Leptin, a peptide hormone secreted by white adipose tissue is increased in association with overweight/obesity and is recognized as mediator of liver fibrosis. We sought to assess whether leptin contributes to alcoholic liver fibrosis by in vitro studies in hepatic stellate cells (HSC). METHODS: Rat HSCs in second or third passage were utilised. Leptin, Acetaldehyde or combination with leptin and acetaldehyde were incubated for specific periods in cultured HSCs. Profibrogenic gene and protein expression were determined and associated-signalling pathways were assessed. Interleukin 6 (IL-6) antibody neutralization was used to evaluate the role of IL-6. RESULTS: Leptin did not promote acetaldehyde-induced gene expression of collagen I, transforming growth factor beta1 (TGFbeta1) and tissue inhibitor of metalloproteinase 1 (TIMP1) in vitro. However, combined treatment of leptin with acetaldehyde synergistically enhanced the protein expression of smooth muscle actin (alphaSMA), an activation marker of HSCs, and of Interleukin 6 (IL-6). The combination of leptin and acetaldehyde also augmented MAPK/p38 and MAPK/ERK1/2 phosphoprotein expression. IL-6 neutralization down-regulated protein expression of pp38, pERK1/2 and alphaSMA, while exogenous rat recombinant IL-6 administration up-regulated alphaSMA. Similarly, MAPK/p38 and MAPK/ERK1/2 inhibition attenuated alphaSMA expression. H(2)O(2) induction by acetaldehyde was not potentiated by co-treatment with leptin nor did IL-6 neutralization reduce acetaldehyde-induced H(2)O(2) production. CONCLUSIONS: We conclude that leptin potentiates acetaldehyde-induced HSC activation and alphaSMA expression by an IL 6-dependent mechanism. PMID- 21294756 TI - The MU opioid receptor is not involved in ethanol-stimulated dopamine release in the ventral striatum of C57BL/6J mice. AB - BACKGROUND: The mu opioid receptor (MOR) has previously been found to regulate ethanol-stimulated dopamine release under some, but not all, conditions. A difference in ethanol-evoked dopamine release between male and female mixed background C57BL/6J-129SvEv mice led to questions about its ubiquitous role in these effects of ethanol. Using congenic C57BL/6J MOR knockout (KO) mice and C57BL/6J mice pretreated with an irreversible MOR antagonist, we investigated the function of this receptor in ethanol-stimulated dopamine release. METHODS: Microdialysis was used to monitor dopamine release and ethanol clearance in MOR /-, +/+, and +/- . male and female mice after intraperitoneal (i.p.) injections of 1.0, 2.0, and 3.0 g/kg ethanol (or saline). We also measured the increase in dopamine release after 5 mg/kg morphine (i.p.) in male and female MOR+/+ and -/- mice. In a separate experiment, male C57BL/6J mice were pretreated with either the irreversible MOR antagonist beta funaltrexamine (BFNA) or vehicle, and dopamine levels were monitored after administration of 2 g/kg ethanol or 5 mg/kg morphine. RESULTS: Although ethanol-stimulated dopamine release at all the 3 doses of alcohol tested, there were no differences between MOR+/+, -/-, and +/- mice in these effects. Female mice had a more prolonged effect compared to males at the 1 g/kg dose. Administration of 2 g/kg ethanol also caused a similar increase in dopamine levels in both saline-pretreated and BFNA-pretreated mice. Five mg/kg morphine caused a significant increase in dopamine levels in MOR+/+ mice but not in MOR-/- mice and in saline-pretreated mice but not in BFNA pretreated mice. Intraperitoneal saline injections had a significant, albeit small and transient, effect on dopamine release when given in a volume equivalent to the ethanol doses, but not in a volume equivalent to the 5 mg/kg morphine dose. Ethanol pharmacokinetics were similar in all genotypes and both sexes at each dose and in both pretreatment groups. CONCLUSIONS: MOR is not involved in ethanol-stimulated dopamine release in the ventral striatum of C57BL/6J mice. PMID- 21294757 TI - Effects of acetaldehyde on hepatocyte glycerol uptake and cell size: implication of aquaporin 9. AB - BACKGROUND: The effects of ethanol and acetaldehyde on uptake of glycerol and on cell size of hepatocytes and a role Aquaporin 9 (AQP9), a glycerol transport channel, were evaluated. METHODS: The studies were done in primary rat and mouse hepatocytes. The uptake of [(14) C] glycerol was determined with hepatocytes in suspension. For determination of cell size, rat hepatocytes on coated dishes were incubated with a lipophilic fluorochrome that is incorporated into the cell membrane and examined by confocal microscopy. A three-dimensional z scan of the cell was performed, and the middle slice of the z scan was used for area measurements. RESULTS: Acute exposure to acetaldehyde, but not to ethanol, causes a rapid increase in the uptake of glycerol and an increase in hepatocyte size, which was inhibited by HgCl(2) , an inhibitor of aquaporins. This was not observed in hepatocytes from AQP9 knockout mice, nor observed by direct application of acetaldehyde to AQP9 expressed in Xenopus Laevis oocytes. Prolonged 24-hour exposure to either acetaldehyde or ethanol did not result in an increase in glycerol uptake by rat hepatocytes. Acetaldehyde decreased AQP9 mRNA and AQP9 protein, while ethanol decreased AQP9 mRNA but not AQP9 protein. Ethanol, but not acetaldehyde, increased the activities of glycerol kinase and phosphoenolpyruvate carboxykinase. CONCLUSIONS: The acute effects of acetaldehyde, while mediated by AQP9, are probably influenced by binding of acetaldehyde to hepatocyte membranes and changes in cell permeability. The effects of ethanol in enhancing glucose kinase, and phosphoenolpyruvate carboxykinase leading to increased formation of glycerol-3-phosphate most likely contribute to alcoholic fatty liver. PMID- 21294758 TI - Evaluation of commercial essential oil samples on the growth of postharvest pathogen Monilinia fructicola (G. Winter) Honey. AB - AIM: To assess the effect of several commercial essential oils samples Australian lemon myrtle (Backhousia citriodora), cinnamon bark (Cinnamomum zeylanicum), oregano (Origanum vulgare), thyme oil (Thymus vulgaris), clove bud (Eugenia caryophyllata), valerian (Valeriana officinalis) and Australian tea tree oil (Melaleuca alternifolia) on mycelium growth and spore germination of Monilinia fructicola. The effectiveness of lemon myrtle essential oil as a fumigant for the control of brown rot in nectarines was evaluated. METHODS AND RESULTS: Monilinia fructicola exhibited a different level of sensitivity to each tested essential oil with results suggesting that the essential oils provide excellent control of the pathogen with respect to mycelium growth and spore germination at very low concentrations, whereas for others higher concentrations are needed to reduce significant fungal growth. In vivo application of lemon myrtle essential oil effectively reduced the incidence of M. fructicola on noninoculated fruit. Fumigation of nectarines following inoculation did not reduce the incidence of brown rot in comparison with the inoculated control treatment. No evidence of phytotoxicity on the fruit was recorded. CONCLUSIONS: Lemon myrtle essential oil exhibited the strongest antifungal activity against M. fructicola, in vitro and to a lesser extent, under in vivo conditions. SIGNIFICANCE AND IMPACT OF THE STUDY: The results demonstrate that lemon myrtle essential oil, in particular, has potential as an antifungal agent to control M. fructicola. PMID- 21294759 TI - Variations in life tables of geographically isolated strains of the mosquito Culex quinquefasciatus. AB - Variations in the life tables and other biological attributes of four strains of Culex quinquefasciatus Say (Diptera: Culicidae) from geographically isolated regions of India that had been reared to the fifth generation in the laboratory were assessed under a standardized rearing regime under constant laboratory conditions. Two strains from arid habitats [Jodhpur (JD) and Bikaner (BKN)], one from a semi-arid inland habitat [Bathinda (BTH)], one from a semi-arid coastal habitat [Jamnagar (JMN)] and a standard laboratory strain (LAB) were compared. Horizontal life-table parameters were measured for each strain. Egg mortality ranged from 4.4% (JD and BTH) to 19.5% (BKN). The lowest rate of adult emergence and highest female : male ratio were found in BKN, and the highest rate of adult emergence and lowest female : male ratio were recorded in BTH. The egg-hatching period was longest in BTH and shortest in LAB. The duration from oviposition to adult emergence was longest in JD and shortest in LAB. Females lived longer than males in all strains. The net reproductive rates (R(0) ) of all field-derived strains (122.9-162.2) differed significantly between strains and were significantly greater than that of LAB (107.6). Similarly, both the intrinsic rate of increase (r(m) ) and finite rate of increase (lambda) were found to be lower in LAB than in the field strains, but the mean generation time (T) and doubling time (DT) were longest in LAB. For several life-table attributes, JD and BTH clustered together and were more similar to JMN than to BKN and LAB. The results indicate that BTH, BKN and JD can be characterized as r-strategists, more so than JMN. Overall fecundity increased with age. Differences in annual temperature ranges and mean annual rainfall between locations were positively correlated (r = 0.46-0.97) with egg production, female life expectancy, R(0) , r(m) , lambda and T. The results suggest that strains of Cx. quinquefasciatus from different geographical areas with contrasting habitats vary in their survival and reproductive strategies accordingly. PMID- 21294760 TI - Socio-demographic differences in adherence to evidence-based drug therapy after hospital discharge from acute myocardial infarction: a population-based cohort study in Rome, Italy. AB - WHAT IS KNOWN AND OBJECTIVE: Adherence to evidence-based drug therapy after acute myocardial infarction has increased over the last decades, but is still unsatisfactory. Our objectives are to set out to analyse patterns of evidence based drug therapy after acute myocardial infarction (AMI), and evaluating socio demographic differences. METHODS: A cohort of 3920 AMI patients discharged from hospital in Rome (2006-2007) was selected. Drugs claimed during the 12 months after discharge were retrieved. Drug utilization was defined as density of use (boxes claimed/individual follow-up; chronic use = 6+ boxes/365 days) and therapeutic coverage, calculated through Defined Daily Doses (chronic use: >=80% of individual follow-up). Patterns of use of single drugs and their combination were described. The association between poly-therapy and gender, age and socio economic position (small-area composite index based on census data) was analysed through logistic regression, accounting for potential confounders. RESULTS AND DISCUSSION: Most patients used single drugs: 90.5% platelet aggregation inhibitors (antiplatelets), 60.0%beta-blockers, 78.1% agents acting on the renin angiotensin system (ACEIs/ARBs), 77.8% HMG CoA reductase inhibitors (statins). Percentages of patients with >=80% of therapeutic coverage were 81.9% for antiplatelets, 17.8% for beta-blockers, 64.4% for ACEIs/ARBs and 76.1% for statins. The multivariate analysis showed gender and age differences in adherence to poly-therapy (females: OR = 0.84; 95% CI 0.72-0.99; 71-80 years age-group: OR = 0.82; 95% CI 0.68-0.99). No differences were observed with respect to socio economic position. WHAT IS NEW AND CONCLUSION: The availability of information systems offers the opportunity to monitor the quality of care and identify weaknesses in public health-care systems. Our results identify specific factors contributing to non-adherence and hence define areas for more targeted health care interventions. Our results suggest that efforts to improve adherence should focus on women and older patients. PMID- 21294761 TI - Patterns and forces of occlusal contacts during lateral excursions recorded by the T-Scan II system in young Chinese adults with normal occlusions. AB - The objective was to characterise the patterns and forces of occlusal contacts during lateral mandibular excursions in a young Chinese adult population. Angle Class I normal occlusions in 85 dental students aged 20-29 were evaluated using the T-Scan II occlusal imaging and analysis system. The frequency of occlusal contacts was recorded for right and left lateral excursions at the position of lateral disclusion, at the canine-to-canine position and at the lateral maximal position. At the canine-to-canine position, the occlusal contact patterns were classified, and the relative forces were compared by multiple regression analysis, with alpha = 0.05. At the position of lateral disclusion, a high percentage of canine contacts (58.5%) and individual posterior tooth contacts on the working side was observed. At the canine-to-canine position, the canines on the working side contacted most frequently (68.9%), and the occlusal contact patterns could be classified into six groups. At the lateral maximal position, incisors (39.0%) and canines (32.3%) contacted most frequently. At the canine-to canine position, subjects with occlusal contacts only on canines or on first premolars on the working side had the lowest relative occlusal forces (P < 0.001). Canine protection and group function do not identify all descriptors for lateral occlusal contact patterns in the natural dentition. Six occlusal contact patterns were found at the lateral canine-to-canine position. PMID- 21294762 TI - Development of temporomandibular disorder symptoms: a 3-year cohort study of university students. AB - The aims of this study were to examine the incidence of temporomandibular disorders (TMDs) over a 3-year period and to evaluate the risk of self-reported TMDs among university students in Japan. The study population comprised 2374 university students examined at the start of their undergraduate course and 492 students re-examined after 3 years using questionnaires on symptoms of TMD and experiences of jaw injury, stress, orthodontic treatment and parafunctional habits. Cumulative incidence (%) and relative risks were calculated overall. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to determine the degree of risks of these variables for symptoms of TMDs using logistic regression. Results of logistic regression analysis showed that male subjects with experience of jaw injury had a 3.54 (CI=1.45-8.68, P<0.01)-fold higher risk of temporomandibular joint (TMJ) pain than that for those who did not. Female subjects who reported experiencing stress and bruxism had 10.56 (CI=1.28-87.54, P<0.05)- and 5.00 (CI=1.21-20.71, P<0.05)-fold higher risks of TMJ sound, respectively, than the risk for female subjects who had not experienced stress or bruxism. The results indicated that experiences of jaw injury, stress and bruxism were significantly associated with increased risks of development of TMJ disorders in a 3-year cohort. PMID- 21294763 TI - Oropharyngeal airway dimensions after treatment with functional appliances in class II retrognathic children. AB - Class II skeletal malocclusion and respiratory disorders owing to the obstruction of the upper airway at early growth stages have been correlated. The retro/micrognathism can be treated with functional appliances. However, the effects of an early functional orthopedic treatment on the airway dimensions have not been evaluated before the growth peak. Therefore, the objective of this study was to evaluate the changes in the airway dimensions of class II retrognathic children who received treatment with either Klammt or Bionator on a pre-pubertal stage. The sample consisted of 50 lateral cephalograms of class II retrognathic patients in a pre-puberal stage, before and after the use of a Klammt or Bionator II treatment for 1 year. The data were evaluated by Student's t-test or Mann Whitney test, and significance was set at 5% (P < 0.05). When the measurements before and after treatment were compared, a statistically significant increase in the airway dimensions was found at the space where the adenoid tissue was located. The only airway dimensions that increased after treatment with functional appliances were the ones located at the nasopharynx. The adenoid tissue is still in the peak of growing at the ages of the subjects included in this study. However, the measurements along the nasopharynx increased when compared with the initial ones. Still, similar retrospective and prospective studies are needed at older stages. PMID- 21294764 TI - Implant-supported prosthesis following Branemark protocol on electromyography of masticatory muscles. AB - This research evaluated the effects of Branemark protocol on electromyography of the masseter and temporal muscles. The patients were divided into two groups: Group I: patients who wore an implant-supported prosthesis in the mandibular arch following Branemark protocol, and maxillary removable complete dentures; Group II: dentate individuals (control). Electromyography was carried out at rest, right (RL) and left (LL) laterality, protrusion and maximum voluntary contraction (MVC). Data were compared by t-test. At rest, a higher electromyographic (EMG) activity was observed in Group I, and the values were significant in the right masseter and left temporal muscles. In RL, there were statistically significant differences for right masseter (P < 0.01), left masseter and temporal muscles and for the left temporal muscle in LL (P < 0.05). In protrusion, Group I presented a higher EMG activity, and there was a statistically significant difference for the right masseter muscle (RM) (P < 0.05). In MVC, the EMG values were higher in Group II (control), but significant just for the right temporal muscle (P < 0.05). In conclusion, individuals with mandibular fixed dentures supported according to the Branemark protocol and maxillary removable complete dentures showed a higher activity of masticatory muscles during the mandibular postural clinical conditions examined; however, in the MVC, Group I presented lower values when compared to dentate group. Despite presenting different EMG values in all of the clinical conditions, both groups showed similar EMG patterns of muscle activation which demonstrates that the proposed treatment can be considered as a good option for oral rehabilitation. PMID- 21294765 TI - Maternal endothelial dysfunction and its association with abnormal fetal growth in diabetic pregnancy. AB - AIMS: Some authors consider the vascular endothelium to be a target organ in diabetes. However, there have only been a few studies of the function of the maternal endothelium during pregnancy in women with diabetes. We analysed the relationship between maternal vascular endothelial dysfunction and fetal growth in such pregnancies. METHODS: Markers of endothelial dysfunction (serum concentration of sE-selectin and sVCAM-1) were measured at admission (baseline) and before delivery in 97 women with pregestational diabetes and a singleton pregnancy,. After delivery, the group with pregestational diabetes was divided retrospectively according to neonatal birthweight into three groups-appropriate, small and large for gestational age- and the maternal variables were analysed in relation to birthweight. RESULTS: The baseline concentration of sE-selectin was significantly higher in the large-for-gestational-age group vs. the small-for gestational-age group (median: 53.1 vs. 39.0 ng/ml, P<0.05). The concentration of sVCAM-1 at baseline was significantly higher in the small-for-gestational-age vs. the appropriate- and large-for-gestational-age groups (median: 846.2 vs. 576.8 and 524.1 ng/ml, respectively; P<0.01 and P<0.001, respectively). The concentration of sE-selectin at baseline and gestational changes in the concentration of sVCAM-1 were related to birthweight. The baseline concentrations of sE-selectin and sVCAM-1 and the gestational change in sVCAM-1 concentration were predictive factors for large for gestational age (cut-off values: 45.0, 644.6 and 38.4 ng/ml; sensitivity: 67.7, 89.3 and 34.4%; specificity: 65.5, 39.7 and 85.5%, respectively). CONCLUSIONS: Our study showed a relationship between maternal endothelial dysfunction and fetal growth disturbances during pregnancy in women with diabetes that was not associated with maternal metabolic control. Higher levels of maternal sE-selectin in early pregnancy were associated with increased risk of the large-for-gestational-age condition. High levels of maternal sVCAM-1 in early pregnancy were characteristic of gestation complicated by the small-for-gestational-age condition. Further studies in larger groups are warranted to determine whether markers of maternal endothelial dysfunction are of use in the prediction of abnormal birthweight (large or small for gestational age) in pregnant women with diabetes. PMID- 21294766 TI - A first national prevalence estimate of diagnosed and undiagnosed diabetes in France in 18- to 74-year-old individuals: the French Nutrition and Health Survey 2006/2007. AB - AIMS: To estimate the nationwide prevalence of diagnosed and undiagnosed diabetes and pre-diabetes in adults residing in France. METHODS: A probability sample of a non-institutionalized civilian population residing throughout the whole of continental France was recruited from February 2006 to March 2007 for the French Nutrition and Health Survey. All individuals aged between 18 and 74 years who agreed to participate in the survey were included; thus there were 3115 participants, 2102 of whom were undergoing biochemical assessments. The prevalence of diagnosed diabetes was estimated using self-reported diabetes history and the prevalence of undiagnosed diabetes was estimated using fasting plasma glucose >= 7.0 mmol/l or HbA(1c) >= 6.5% (>= 48 mmol/mol). RESULTS: The prevalence of diagnosed diabetes was 4.6%, 95% CI 3.6-5.7. The prevalence of undiagnosed diabetes according to standard fasting plasma glucose criteria was 1% (95% CI 0.6-1.7) and contributed to less than 20% of all cases of diabetes. This proportion decreased with age from 30% in 30- to 54-year-olds to 12% in 55- to 74 year-olds. Based on HbA(1c) criteria, the prevalence of undiagnosed diabetes was 0.8% (95% CI 0.4-1.6). CONCLUSIONS: The prevalence of diagnosed diabetes in adults in France is comparable with recent estimates from Northern Europe. The percentage of total diabetes that is undiagnosed is low in France, which may be explained by a widely practised strategy of opportunist screening. During the past years, improvements in diabetes care and increased awareness may have contributed towards decreasing the prevalence of undiagnosed diabetes more widely in Europe, and studies should further monitor such improvements. PMID- 21294767 TI - Exclusion of patients from quality measurement of diabetes care in the UK pay-for performance programme. AB - BACKGROUND: We examined associations between patient and practice characteristics and exclusions from quality indicators for diabetes during the first 3 years of the Quality and Outcomes Framework, a major pay-for-performance scheme in the UK. METHODS: Three cross-sectional analyses, conducted using data from the electronic medical records of all patients with diabetes registered in 23 general practices in Brent, North West London between 2004/2005 and 2006/2007. Patterns of exclusions were examined for three intermediate outcome indicators. RESULTS: Excluded patients were less likely to achieve treatment targets for HbA(1c) (2004/2005, 2006/2007), blood pressure (2005/2006, 2006/2007) and cholesterol (2005/2006). Black and South Asian patients were more likely to be excluded from the HbA(1c) indicator than White patients [adjusted odds ratio = 1.64 (1.17-2.29) in 2005/2006]. Patients diagnosed with diabetes duration of > 10 years [adjusted odds ratio = 2.01 (1.65-2.45) for HbA(1c) in 2006-2007] and those with co morbidities (adjusted odds ratio, >= 3 co-morbidities compared with no co morbidity for HbA(1c) adjusted odds ratio = 1.90 (1.24-2.90) in 2004/2005] were more likely to be excluded. Larger practices excluded more patients from the HbA(1c) indicator [adjusted odds ratio, practice >= 7000 compared with < 3000, 3.52 (2.35-5.27) in 2005-2006]. More deprived practices consistently excluded more patients from all indicators, whilst in 2007 older patients were excluded to a larger degree [adjusted odds ratio = 2.52 (1.21-5.28) >= 75 compared with 18-44 for blood pressure control]. CONCLUSIONS: Patients excluded from pay-for performance programmes may be less likely to achieve treatment goals and disproportionately come from disadvantaged groups. Permitting physicians to exclude patients from pay-for-performance programmes may worsen health disparities. PMID- 21294768 TI - Asymmetric dimethylarginine in young people with Type 1 diabetes: a paradoxical association with HbA(1c). AB - AIMS: Asymmetric dimethylarginine (ADMA) is an independent risk factor for cardiovascular disease and its concentrations are increased in several diseases, including diabetes. However, there is limited information on this plasma marker in young people, particularly in those with Type 1 diabetes. The aim of the present study was therefore to perform a longitudinal evaluation of plasma ADMA and of its determinants in young people with childhood-onset Type 1 diabetes. METHODS: For measurement of ADMA using mass spectrometry, 1018 longitudinal stored blood samples were available from 330 young people with Type 1 diabetes followed in the Oxford Regional Prospective Study. Additional data concerning annual assessments of HbA(1c) , height, weight, insulin dose and three early morning urine samples for measurement of the albumin/creatinine ratio were available. RESULTS: ADMA levels were significantly higher in males than in females (mean +/- SD: 0.477 +/- 0.090 vs. 0.460 +/- 0.089 MUmol/l, P=0.002) and declined with chronological age (estimate +/- SE: -0.0106 +/- 0.0008, P<0.001). A significant inverse association was detected between ADMA and HbA(1c) (estimate +/- SE:-0.0113 +/- 0.001, P<0.001). ADMA levels were lower in subjects developing microalbuminuria (mean +/- SD: 0.455 +/- 0.093 vs. 0.476 +/- 0.087 MUmol/l, P=0.001) than in subjects with normoalbuminuria, but this difference disappeared after adjusting for HbA(1c) . CONCLUSIONS: In this longitudinal study, ADMA concentrations decreased with age and were significantly higher in males and lower in subjects developing microalbuminuria. These associations were largely explained by a paradoxical negative association between HbA(1c) and ADMA. We suggest that chronic hyperglycaemia might down-regulate mechanisms implicated in ADMA production or stimulate its metabolism confounding short-term associations with complications risk. PMID- 21294769 TI - Impact of a chronic care model based on patient empowerment on the management of Type 2 diabetes: effects of the SINERGIA programme. AB - AIMS: Several chronic care models for diabetes have been implemented in Italy, although conclusive data on their effectiveness are lacking. In the Cusano Milanino diabetes clinic, patients with Type 2 diabetes with a stable disease/therapy (i.e. a steady level of HbA(1c) without need for therapy changes) are included in the SINERGIA programme: diabetologists, nurses and dietitians empower patients and telemedicine resources are utilized efficiently. METHODS: Clinical outcomes measured in the year before and after the initiation of SINERGIA were compared. A generalized hierarchical linear regression model for repeated measures was used. RESULTS: Altogether, 1004 patients were included; baseline characteristics were (mean +/- sd): age 66.6 +/- 6.2 years, 54.1% male, diabetes duration 10.8 +/- 7.7 years, BMI 29.5 +/- 4.8 kg/m(2) , HbA(1c) 6.9 +/- 0.9% (52 +/- 14 mmol/mol); 72.9% of patients were treated with anti-hypertensive drugs; 32.7% were treated with lipid-lowering drugs. After a median follow-up of 12 months (range 6-24 months), the proportion of patients with HbA(1c) <= 7.0% (<= 53 mmol/mol) increased from 32.7 to 45.8% (P<0.0001), while those with HbA(1c) >=9% (>=75 mmol/mol) decreased from 10.5 to 4.3% (P<0.0001). Patients with LDL cholesterol <100 mg/dl (<2.59 mmol/l) increased from 40 to 47% (P <0.0001), while those with LDL cholesterol >=130 mg/dl (>=3.36 mmol/l) decreased from 26.6 to 19.7%; blood pressure levels were slightly improved. The mean number of face-to-face encounters decreased from (median and range) 2.8 (2.3-3.4) to 2.3 (1.9-2.7) (P<0.0001) visits per patient/year. CONCLUSIONS: The SINERGIA model is effective in improving metabolic control and major cardiovascular risk factors, while allowing diabetologists to dedicate more time to patients with more acute disease. PMID- 21294770 TI - Sensor-augmented pump therapy lowers HbA(1c) in suboptimally controlled Type 1 diabetes; a randomized controlled trial. AB - AIMS: To investigate the efficacy of sensor-augmented pump therapy vs. multiple daily injection therapy in patients with suboptimally controlled Type 1 diabetes. METHODS: In this investigator-initiated multi-centre trial (the Eurythmics Trial) in eight outpatient centres in Europe, we randomized 83 patients with Type 1 diabetes (40 women) currently treated with multiple daily injections, age 18-65 years and HbA(1c) >= 8.2% (>= 66 mmol/mol) to 26 weeks of treatment with either a sensor-augmented insulin pump (n = 44) (Paradigm((r)) REAL-Time) or continued with multiple daily injections (n = 39). Change in HbA(1c) between baseline and 26 weeks, sensor-derived endpoints and patient-reported outcomes were assessed. RESULTS: The trial was completed by 43/44 (98%) patients in the sensor-augmented insulin pump group and 35/39 (90%) patients in the multiple daily injections group. Mean HbA(1c) at baseline and at 26 weeks changed from 8.46% (SD 0.95) (69 mmol/mol) to 7.23% (SD 0.65) (56 mmol/mol) in the sensor-augmented insulin pump group and from 8.59% (SD 0.82) (70 mmol/mol) to 8.46% (SD 1.04) (69 mmol/mol) in the multiple daily injections group. Mean difference in change in HbA(1c) after 26 weeks was -1.21% (95% confidence interval -1.52 to -0.90, P < 0.001) in favour of the sensor-augmented insulin pump group. This was achieved without an increase in percentage of time spent in hypoglycaemia: between-group difference 0.0% (95% confidence interval -1.6 to 1.7, P = 0.96). There were four episodes of severe hypoglycaemia in the sensor-augmented insulin pump group and one episode in the multiple daily injections group (P = 0.21). Problem Areas in Diabetes and Diabetes Treatment Satisfaction Questionnaire scores improved in the sensor augmented insulin pump group. CONCLUSIONS: Sensor augmented pump therapy effectively lowers HbA(1c) in patients with Type 1 diabetes suboptimally controlled with multiple daily injections. PMID- 21294771 TI - An FTO variant is associated with Type 2 diabetes in South Asian populations after accounting for body mass index and waist circumference. AB - AIMS: A common variant, rs9939609, in the FTO (fat mass and obesity) gene is associated with adiposity in Europeans, explaining its relationship with diabetes. However, data are inconsistent in South Asians. Our aim was to investigate the association of the FTO rs9939609 variant with obesity, obesity related traits and Type 2 diabetes in South Asian individuals, and to use meta analyses to attempt to clarify to what extent BMI influences the association of FTO variants with diabetes in South Asians. METHODS: We analysed rs9939609 in two studies of Pakistani individuals: 1666 adults aged >=40 years from the Karachi population-based Control of Blood Pressure and Risk Attenuation (COBRA) study and 2745 individuals of Punjabi ancestry who were part of a Type 2 diabetes case control study (UK Asian Diabetes Study/Diabetes Genetics in Pakistan; UKADS/DGP). The main outcomes were BMI, waist circumference and diabetes. Regression analyses were performed to determine associations between FTO alleles and outcomes. Summary estimates were combined in a meta-analysis of 8091 South Asian individuals (3919 patients with Type 2 diabetes and 4172 control subjects), including those from two previous studies. RESULTS: In the 4411 Pakistani individuals from this study, the age-, sex- and diabetes-adjusted association of FTO variant rs9939609 with BMI was 0.45 (95%CI 0.24-0.67) kg/m(2) per A-allele (P=3.0 * 10(-5) ) and with waist circumference was 0.88 (95% CI 0.36-1.41) cm per A-allele (P=0.001). The A-allele (30% frequency) was also significantly associated with Type 2 diabetes [per A-allele odds ratio (95%CI) 1.18 (1.07 1.30); P=0.0009]. A meta-analysis of four South Asian studies with 8091 subjects showed that the FTO A-allele predisposes to Type 2 diabetes [1.22 (95%CI 1.14 1.31); P=1.07 * 10(-8) ] even after adjusting for BMI [1.18 (95%CI 1.10-1.27); P=1.02 * 10(-5) ] or waist circumference [1.18 (95%CI 1.10-1.27); P=3.97 * 10(-5) ]. CONCLUSIONS: The strong association between FTO genotype and BMI and waist circumference in South Asians is similar to that observed in Europeans. In contrast, the strong association of FTO genotype with diabetes is only partly accounted for by BMI. PMID- 21294773 TI - Development and evaluation of a standardized registry for diabetes in pregnancy using data from the Northern, North West and East Anglia regional audits. AB - OBJECTIVES: To develop and evaluate a standardized data set for measuring pregnancy outcomes in women with Type 1 and Type 2 diabetes and to compare recent outcomes with those of the 2002-2003 Confidential Enquiry into Maternal and Child Health. METHODS: Existing regional, national and international data sets were compared for content, consistency and validity to develop a standardized data set for diabetes in pregnancy of 46 key clinical items. The data set was tested retrospectively using data from 2007-2008 pregnancies included in three regional audits (Northern, North West and East Anglia). Obstetric and neonatal outcomes of pregnancies resulting in a stillbirth or live birth were compared with those from the same regions during 2002-2003. RESULTS: Details of 1381 pregnancies, 812 (58.9%) in women with Type 1 diabetes and 556 (40.3%) in women with Type 2 diabetes, were available to test the proposed standardized data set. Of the 46 data items proposed, only 16 (34.8%), predominantly the delivery and neonatal items, achieved >= 85% completeness. Ethnic group data were available for 746 (54.0%) pregnancies and BMI for 627 (46.5%) pregnancies. Glycaemic control data were most complete-available for 1217 pregnancies (88.1%), during the first trimester. Only 239 women (19.9%) had adequate pregnancy preparation, defined as pre-conception folic acid and first trimester HbA(1c) <= 7% (<= 53 mmol/mol). Serious adverse outcome rates (major malformation and perinatal mortality) were 55/1000 and had not improved since 2002-2003. CONCLUSIONS: A standardized data set for diabetes in pregnancy may improve consistency of data collection and allow for more meaningful evaluation of pregnancy outcomes in women with pregestational diabetes. PMID- 21294774 TI - Helicobacter pylori in the oral cavity and gastric mucosa: a meta-analysis. AB - BACKGROUND: Helicobacter pylori have been found in the oral cavity and stomach. This study is to establish whether there might be any associations between isolates of H. pylori in the oral cavity and those in the stomach by meta analysis. METHODS: Studies reporting raw data on the prevalence of H. pylori infection in the oral cavity in gastric H. pylori-positive and H. pylori-negative patients, in patients with gastroesophageal diseases, and in healthy individuals and studies reporting data on the eradication rate in the oral cavity or stomach, published in the English language, were identified through MEDLINE and EMBASE up to May 2010. RESULTS: The prevalence of H. pylori infection in the oral cavity in gastric H. pylori-positive patients was significantly higher (45.0%) than that in gastric H. pylori-negative patients (23.9%). The pooled odds ration (OR) was 3.61 and the 95% CI was 1.91-6.82 (P < 0.0001). Different diagnostic methods produced different pooled ORs with PCR the highest (OR = 5.11, 95% CI: 2.08-12.54, P = 0.0004) and rapid urease test (RUT) the lowest (OR = 2.00, 95% CI: 0.80-5.00, P = 0.14). The 44.8% (91/203) prevalence of H. pylori infection in the oral cavity in patients with clinical and/or histological gastroesophageal diseases was significantly higher than the 13.2% (21/159) in patients with non-ulcerous dyspepsia or healthy controls (OR = 5.15, 95% CI: 2.97-8.92, P < 0.00001). The eradication efficiency in stomach is 85.8% (187/218), while in oral cavity it is only 5.7% (9/158). The OR is 55.59, P < 0.00001. CONCLUSIONS: There is a close relation between the infection of H. pylori in the oral cavity and stomach. H. pylori in the oral cavity are more difficult to be eradicated than in the stomach. It may be a source of reinfection. PMID- 21294772 TI - Blood glucose control and quality of health care in non-insulin-treated patients with Type 2 diabetes in Spain: a retrospective and cross-sectional observational study. AB - AIMS: To assess blood glucose control and quality of health care provided to non insulin-treated patients with Type 2 diabetes mellitus in routine clinical practice in Spain. METHODS: In this observational, retrospective, cross-sectional study, patients were grouped as either having good or suboptimal blood glucose control according to International Diabetes Federation or American Diabetes Association HbA(1c) goals. Clinical and socio-demographic data and compliance with the main standard level of care recommendations of the International Diabetes Federation were recorded during a routine visit. Correlates of glucose control were analysed by logistic regression. RESULTS: Many patients were grouped as having suboptimal control under International Diabetes Federation (61.9%) or American Diabetes Association (45.0%) criteria. The mean number of accomplished International Diabetes Federation recommendations (7.3 out of 11) was higher for endocrinologists (than for internists or primary care physicians), and significantly more patients under their care were in the good glucose control group (than with primary care physicians). More recommendations were associated with blood glucose control using International Diabetes Federation than American Diabetes Association criteria, demanding higher quality of health care for achieving stricter goals. Some recommendations were poorly observed, particularly those concerning patients' education on diabetes, the prompt prescription of effective treatments and monitoring of complications. Diabetes complications were associated with being in the suboptimal control group. Patients' education on diabetes and HbA(1c) monitoring were associated with being in the good control group. CONCLUSIONS: These results demonstrate the need for improvement in the management of patients with non-insulin-treated Type 2 diabetes in actual clinical practice in Spain. Such improvement would entail a stricter adherence to International Diabetes Federation recommendations. PMID- 21294775 TI - Dietary docosahexaenoic acid in combination with arachidonic acid ameliorates allergen-induced dermatitis in mice. AB - OBJECTIVE: In this study, we investigated the impact of dietary docosahexaenoic (DHA) and arachidonic acid (AA) on development and severity of allergen-induced dermatitis. STUDY DESIGN: In sensitized mice, skin inflammation was induced by ovalbumin. Mice received either a diet containing 0.015% DHA, 0.029% AA or the combination of both. The severity of dermatitis was evaluated by using a clinical skin score (CSS), followed by immunohistologic and cytokine analysis. To unravel potential mechanisms, interleukin (IL)-4 or tumor necrosis factor alpha stimulated keratinocytes from the cell line Kera-308 was cultured with different DHA/AA compositions and analyzed regarding proliferation and cytokine production. RESULTS: Dietary DHA/AA significantly improved the severity of allergen-induced dermatitis as the CSS was reduced by 36 +/- 23% (p=0.005). Furthermore, reduced epidermal KI67 expression, increased number of forkhead box P3(+) cells, and elevated IL-10 expression were determined in skin lesions of dietary-treated mice. Correspondingly, in vitro DHA/AA-treated keratinocytes exhibited increased IL-10 expression and produced less thymic stromal lymphopoietin. CONCLUSION: Dietary DHA/AA supplementation leads to a significant amelioration of allergen induced dermatitis. This was accompanied with the presence of increased regulatory T cells and IL-10 expression in lesional skin. Moreover, we identify keratinocytes, which play a crucial role in the regulation of skin inflammation, as important targets of DHA/AA supplementation. Future studies are needed to clarify whether DHA/AA acts directly or whether its biologic active metabolites are responsible for these findings. This may unravel novel therapeutical compounds for allergen-induced dermatitis. PMID- 21294776 TI - Oral contraceptive pill use before pregnancy and respiratory outcomes in early childhood. AB - BACKGROUND: Oral contraceptive pills (OCPs) are often used soon before, and sometimes during, pregnancy. A few studies have suggested that OCP use before pregnancy may increase risks for childhood respiratory outcomes, but data are inconclusive. No studies have analyzed the two types of OCPs, estrogen-progestin combined pills and progestin-only pills, separately. METHODS: In the Norwegian Mother and Child Cohort Study (MoBa), we prospectively examined associations of OCP use before pregnancy, by type, with lower respiratory tract infections in 60,225 children followed to 6 months old, lower respiratory tract infections and wheezing in 42,520 children followed to 18 months old, and asthma in 24,472 children followed to 36 months old. We used logistic regression to estimate odds ratios (ORs) and their 95% confidence intervals (CIs) crudely and with adjustment for a wide range of potential confounders. RESULT: Combined pills were used much more commonly than progestin-only pills. Taking combined pills before pregnancy was not associated with lower respiratory tract infections, wheezing, or asthma. Progestin-only pill use in the year before pregnancy had a slight positive association with wheezing at 6-8 months old [adjusted OR (95% CI) = 1.19 (1.05 1.34)]. CONCLUSION: Our finding that combined pill use before pregnancy was not related to respiratory outcomes should provide reassurance to the vast majority of mothers using OCPs before becoming pregnant. The small association with progestin-only pill use and early respiratory outcomes may reflect uncontrolled confounding or other bias. Nonetheless, it does suggest that these two types of pills should be examined separately in future analyses of respiratory and other childhood outcomes. PMID- 21294777 TI - Balancing efficacy and safety in the management of atopic dermatitis: the role of methylprednisolone aceponate. AB - Although emollients can be sufficient to manage mild atopic dermatitis (AD), acute flares resulting in moderate-to-severe symptoms require treatment with anti inflammatory agents, such as topical corticosteroids (TCs) and topical calcineurin inhibitors (TCIs). This review examines the role of a member of the newest class of TCs, the fourth-generation compound methylprednisolone aceponate (MPA) in AD management, with reference to the chemical structure, pharmacokinetics, efficacy in AD, safety assessed in preclinical and clinical trials and dosing considerations. MPA has an optimized efficacy/safety profile with minimal local or systemic adverse effects. In addition, it offers the opportunity for once-daily dosing, which provides benefits in terms of patient compliance with treatment. PMID- 21294778 TI - Serum measurement of interleukin-31 (IL-31) in paediatric atopic dermatitis: elevated levels correlate with severity scoring. AB - BACKGROUND: Interleukin-31 (IL-31) is a novel T-helper-lymphocyte-derived cytokine that plays an important role in human T-cell-mediated skin diseases. When overexpressed in transgenic mice, IL-31 induces severe pruritus resembling eczema in humans. Serum IL-31 was previously found overexpressed in adults with atopic dermatitis (AD). The novelty of this study is the use of a pediatric patient group as well as comparison of IL-31 levels during flare and quiescence. OBJECTIVE: This case-controlled longitudinal study was designed to determine the levels of IL-31 in serum of AD children and its associations in relation to disease activity and severity. METHODS: Sera were obtained from 50 AD children and 40 healthy volunteers. IL-31 levels were measured using a sandwich ELISA. All AD patients were followed up and re-sampled for serum IL-31 after clinical remission. Serum IL-31 levels were correlated with AD disease activity and severity variables. RESULTS: Serum IL-31 levels were significantly higher whether during AD flare [median, 1600; mean (SD)=1457.8+/-770.4 pg/mL] or quiescence (1040; 958.7+/-419.5 pg/mL), than those in controls (220; 197.3+/-91.9 pg/mL). Serum IL-31 levels were significantly higher in the high disease severity group compared with the moderate or low severity group. Moreover, serum IL-31 levels correlated positively with the calculated severity scores (LSS, SSS and SCORAD index). CONCLUSION: The results of this study confirm the importance of IL-31 in AD pathophysiology. Serum IL-31 level is an objective reliable marker of AD severity in children. It may represent a novel target for antipruritic drug development. PMID- 21294779 TI - Efficacy, safety and tolerability of green tea catechins in the treatment of external anogenital warts: a systematic review and meta-analysis. AB - BACKGROUND: External anogenital warts (EGWs) are non-malignant skin tumours caused by human papillomavirus. They are one of the fastest growing sexually transmitted diseases. Current treatments are unsatisfactory. Green tea sinecatechin Polyphenon E ointment is a botanical extract from green tea leaves exhibiting anti-oxidant, anti-viral and anti-tumour properties. OBJECTIVE: The aim of this study was to integrate valid information and provide basis for rational decision making regarding efficacy and safety of green tea extracts in the treatment of EGWs. METHODS: A systematic search in electronic databases was conducted using specific key terms. Main search was performed independently by two reviewers. The accumulated relevant literature was subsequently systematically reviewed and a meta-analysis was conducted. RESULTS: Three randomized, double-blind, placebo-controlled studies evaluating efficacy and safety of Polyphenon E 15% and 10% in the treatment of warts were included in the systematic review and meta-analysis. A total of 660 men and 587 women were enrolled. Regarding primary outcome, both Polyphenon E 15% and 10% demonstrated significantly higher likelihood of complete clearance of baseline and baseline and new warts compared with controls. No significant heterogeneity was detected. Recurrence rates were very low. Commonest local skin sign was erythema and local skin symptom was itching. CONCLUSIONS: Efficacy of Polyphenon 15% and 10%, at least for the primary endpoint, is clearly indicated. Polyphenon E treatment exhibits very low recurrence rates and appears to have a rather favourable safety and tolerability profile. Recommendations for future studies should include evaluation of the efficacy of green tea catechins in the treatment of internal anogenital warts and direct comparison with its principal comparator, imiquimod. PMID- 21294780 TI - Efficacy and safety of subcutaneous human HBV-immunoglobulin (Zutectra) in liver transplantation: an open, prospective, single-arm phase III study. AB - Hepatitis B re-infection prophylaxis is crucial for graft and recipient survival for transplanted patients and is administered routinely after liver transplantation for hepatitis B. Aim of the current study was the investigation of efficacy, safety and feasibility of home-treatment of a novel human hepatitis B immunoglobulin BT088 (Zutectra) after weekly subcutaneous application in liver transplanted patients. A total of 23 patients (5 female, 18 male, median age 51 years) were enrolled and switched from monthly IV to weekly SC hepatitis B immunoglobulin administration. During a period of 18 weeks (optional 24 weeks) anti-HBs levels, signs of re-infection, adverse events and feasibility of self administration were studied. After 8 weeks of training patients showing good compliance and stable antibody titres were allowed to start self-administration at home. All patients maintained a safety level of >100 U/l anti-HBs. No failure was noted, no re-infection occurred. A total of 10 treatment-emergent events were assessed as related to study drug application (injection-site haematoma, headache, abdominal pain, fatigue and haematuria). High numbers of self administration (287 vs. 122 by staff) demonstrated general feasibility of SC administration. Weekly subcutaneous administration of BT088 (Zutectra - registered trade mark in the EU) is effective, safe and presents an easy-to-apply treatment option for combined hepatitis B virus re-infection prophylaxis in liver transplant patients (Eudra CT Number: 2005-003737-40). PMID- 21294782 TI - Have the efforts to prevent aspirin-related Reye's syndrome fuelled an increase in asthma? PMID- 21294783 TI - Proteomics of exhaled breath condensate: a realistic approach in children with asthma? PMID- 21294784 TI - The problem of cross-reactivity in the diagnosis of fungal allergy. PMID- 21294785 TI - Pharmacogenetics of beta2 adrenergic receptor gene polymorphisms, long-acting beta-agonists and asthma. AB - Adrenergic beta2 receptor (ADRbeta2) agonists are widely used in asthma. Approximately 10% of patients have severe, poorly controlled disease despite extensive use of ADRbeta2 agonists. Variations in responses to ADRbeta2 agonists can, in part, be attributed to genetic variation, with 49 different polymorphisms having been identified for the ADRbeta2 gene. Although clear associations exist between ADRbeta2 gene polymorphisms, such as +46G>A, and patient response, the importance of these polymorphisms remains controversial. Patient selection, the number of polymorphisms analysed, differences in the type/dose of ADRbeta2 agonist, use of inhaled corticosteroids and population sizes have all varied. Most studies were limited to mild or moderate asthmatics using ADRbeta2 agonists sparingly. It is difficult to extrapolate from these studies to individual patients who have severe asthma, use a variety of ADRbeta2 agonists and do so frequently. The extent to which ADRbeta2 gene polymorphisms are relevant to asthma management needs further review, both clinically and at the molecular level. In vitro studies have helped to define the functional changes induced by specific ADRbeta2 gene polymorphisms, including 3'-untranslated region poly-C repeat. The resulting ADRbeta2 gene haplotypes (rather than genotypes), the interactions among ADRbeta2 gene haplotypes and variations in the chemistry of different agonists deserve more detailed assessment. Responses to ADRbeta2 agonists depend on effective downstream signalling following ADRbeta2 activation and also on receptor regulation. Studies on other regulators of ADRbeta2 receptor signalling and trafficking may be equally important in understanding the functional role of ADRbeta2 gene polymorphisms. The role of ADRbeta2 gene polymorphisms in the pathogenesis and management of severe asthma cannot be clearly defined until more specific and targeted research studies are performed. PMID- 21294787 TI - Long-term, maintenance MMF monotherapy improves the fibrosis progression in liver transplant recipients with recurrent hepatitis C. AB - Hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (LT) is universal. We designed a retrospective case-control study to evaluate the effect of mycophenolate mofetil (MMF) monotherapy in patients with recurrent hepatitis C. Fifteen patients with histologically proven hepatitis C recurrence after LT were switched from calcineurin inhibitors (CNIs) to MMF monotherapy because of impairment of kidney function and/or metabolic side effects, and treated for 48 months (MMF group). Fifteen well-matched LT recipients who continued to receive CNIs therapy over the same period served as control group. Demographics, clinical data, time after LT, and baseline liver biopsies were similar in the two groups. There was no worsening of hepatic fibrosis during the study in the MMF group [2.6 +/- 1.5 (baseline) Ishak Units vs. 2.7 +/- 1.8 (after 48 months of MMF treatment), P = 0.6]. In contrast, a significant increase in the fibrosis score [2 +/- 1.1 (baseline) vs. 3.2 +/- 1.7 (after 48 months of CNI treatment), P = 0.0002] was observed in the control group. The yearly fibrosis progression rate was of 0.05 +/- 0.44 in the MMF group and 0.33 +/- 0.24 in the CNI group (P = 0.04). MMF monotherapy is associated with a favourable effect on hepatic fibrosis progression in HCV liver transplant recipients. PMID- 21294788 TI - Costimulatory blockade with mTor inhibition abrogates effector T-cell responses allowing regulatory T-cell survival in renal transplantation. AB - The advent of novel immunosuppressive strategies in renal transplantation, with immunomodulatory properties, might facilitate long-term allograft survival. T cell depletion, costimulation-blockade and mTor inhibition have been shown to favour anti-donor hyporesponsiveness. Recently, the combination of rATG, belatacept (Bela) and sirolimus (SRL) has been used in kidney transplantation, showing very low incidence of acute rejection and excellent 12-month graft and patient survival. Herein, we have analysed the 1-year evolution of memory/effector and regulatory T cells and assessed the donor-specific T-cell alloimmune response in a group of these patients and compared with others treated with a calcineurin-inhibitor(CNI)-based (rATG/tacrolimus/MMF), and two other Bela based regimens (rATG/Bela/MMF and basiliximab/Bela/MMF/steroids). During the first year after transplantation, patients receiving rATG/Bela/SRL had significantly higher percentage of Tregs upon the memory T-cell compartment and showed a potent anti-donor suppressive activity. In an in vitro naive and memory/effector T-cell co-culture, the combination of costimulation-blockade and SRL could abrogate both antigen-specific T-cell responses as efficiently as using a CNI drug. The combination of T-cell depletion, costimulation-blockade and mTor inhibition seems to be able to allow Treg survival and inhibit donor-specific alloreactive effector immune responses after kidney transplantation in humans. PMID- 21294789 TI - The negative impact of female donor/male recipient combination in allogeneic hematopoietic stem cell transplantation depends on disease risk. AB - Optimal donor selection is one of the key factors to enhance the success rate of allogeneic hematopoietic stem cell transplantation (HSCT). The effect of sex mismatch, especially the effect of Y chromosome mismatch in graft-versus-host disease (GVHD) direction (female donors to male recipients: denoted as FtoM mismatch) on overall survival (OS) has been controversial and not examined out of the patient population in Western countries. We retrospectively analyzed 225 cases of allogeneic HSCT and showed that FtoM mismatch confers a highly significant impact on OS (P < 0.005) in Japanese population. We demonstrated that this effect depends on the disease risk; for standard risk cases, this effect was significantly associated with poor outcome (for OS, P = 0.021), while for high risk cases, it had no effect on the results (for OS, P = 0.26). We further showed that FtoM mismatch was associated with nonrelapse mortality (P = 0.019) and most of them were GVHD-related in standard risk cases. In conclusion, FtoM mismatch has a significant impact on transplant outcome, especially in standard risk cases. PMID- 21294790 TI - Uncontrolled organ donation following prehospital cardiac arrest: a potential solution to the shortage of organ donors in the United Kingdom? AB - Uncontrolled donation after cardiac death (DCD) could increase the donor pool in the UK. Air ambulance (AA) teams may be well placed to recruit these donors. They cover large geographical areas, have short transfer times and tasked predominantly to life-threatening cases. The potential to recruit from this pool of donors was reviewed. Seventy-five month activity of an AA unit was analysed identifying patients who entered prehospital cardiac arrest (PHCA). Patients over 70 years of age were excluded as were those whose cardiac arrest was unwitnessed. A minimum potential donor pool was estimated based upon patients dying of medical causes. Rates of bystander resuscitation, mechanism of death and patient demographic data were observed. During 10,022 missions 534 patients entered PHCA. A total of 106 patients met inclusion criteria. There were 12 paediatric cases; 39 cases of 17-50 year olds and 55 cases of 50-70 year olds. Medical and traumatic causes of death accounted for 60 and 46 cases respectively. Bystander resuscitation efforts were provided in 47% of cases. A regional AA could contribute to a national uncontrolled DCD programme. Given that there are 31 AA's in England and Wales, we estimate that there could be a minimum of 300 additional potential donors annually. PMID- 21294791 TI - Efficacy of live zoster vaccine in preventing zoster and postherpetic neuralgia. AB - Declining cell-mediated immunity to varicella zoster virus (VZV) in elderly individuals results in virus reactivation manifest by zoster (shingles) and postherpetic neuralgia (PHN). To prevent virus reactivation, a new VZV vaccine (Zostavax; Merck) that boosts cell-mediated immunity to VZV was developed. The 3 year Shingles Prevention Study showed that Zostavax significantly reduced burden of disease because of zoster and PHN. Despite its cost-effectiveness for adults aged 65-75 years, as determined in the United States, Canada and UK, <2% of immunocompetent adults over age 60 years in the United States were immunized in 2007. This was because of a combination of lack of patient awareness of the vaccine, physicians' uncertainty about the duration of protection and different cost-sharing plans for immunization. Nevertheless, zoster vaccine is safe, effective and highly recommended for immunization of immunocompetent individuals over age 60 years with no history of recent zoster. PMID- 21294792 TI - Expression and clinical significance of glucose transporter 1 mRNA in bronchial brushing liquid-based cytology specimens from patients with and without lung cancer. AB - OBJECTIVE: The aim of this study was to evaluate the diagnostic utility of glucose transporter 1 (GLUT1) mRNA expression in bronchial brushing specimens from patients with lung cancer. METHODS: GLUT1 mRNA levels were detected by reverse transcription-polymerase chain reaction (RT-PCR) in SurePath(TM) liquid based cytology bronchial brushing specimens from patients with lung cancer (n=76) and benign lung disease (n=154). RESULTS: Compared with patients with benign disease and compared with cytology, GLUT1 mRNA was found significantly more frequently in patients with all carcinomas, squamous cell carcinomas, adenocarcinomas and small cell carcinomas, as well as central, peripheral and diffuse carcinomas (P<0.01). Minor differences were noted in GLUT1 mRNA and cytology results between histological types and tumour location but were not statistically significant. The diagnostic performance of RT-PCR analysis of GLUT1 mRNA was significantly higher than cytology in terms of sensitivity (97.4 +/- 3.6% versus 65.8 +/- 10.7) and negative predictive value (98.6 +/- 1.9%, versus 85.6 +/- 5.1%) but specificity (90.9 +/- 4.5%) and positive predictive value (84.1 +/- 7.6%) were lower than cytology (100%). CONCLUSIONS: Using liquid-based cytology, RT-PCR can be performed on bronchial brushing specimens to detect GLUT1 mRNA expression, and may be a useful adjunct to cytology diagnosis. It was more sensitive than cytology but its lower specificity should be taken into account. PMID- 21294793 TI - Enhanced apoptotic and reduced protective response in chondrocytes following endoplasmic reticulum stress in osteoarthritic cartilage. AB - Endoplasmic reticulum (ER) stress has been shown to participate in many disease pathologies. Although recent reports have demonstrated that ER stress in chondrocytes is present in human osteoarthritis (OA), its role in the pathology of cartilage degeneration, such as chondrocyte apoptosis, remains unclear. In the present study, we investigated the expression of phosphorylated PERK (pPERK), ubiquitin (Ub), GRP78, CHOP, phosphorylated JNK (pJNK) and cleaved caspase-3 (C CASP3) and the mRNA splicing of XBP1 (XBP1 splicing) in human OA cartilage by immunohistochemistry and RT-PCR. Additionally, human chondrocytes were treated with several concentrations of tunicamycin, an ER stress inducer, to assess the impact of ER stress on the mRNA expression of CHOP, XBP1 splicing and apoptosis, as determined by real-time PCR, RT-PCR and ELISA analyses respectively. In human OA cartilage, the number of chondrocytes expressing pPERK, Ub, CHOP and pJNK positively correlated with cartilage degeneration and the number of C-CASP3 positive chondrocytes. XBP1 splicing and GRP78 expression in severe OA containing the greatest number of C-CASP3-positive chondrocytes were similar to the levels in mild OA, however, XBP1 splicing was higher in moderate OA than in mild and severe OA. Tunicamycin dose dependently increased CHOP expression and apoptosis of cultured chondrocytes. Although tunicamycin upregulated XBP1 splicing in cultured chondrocytes, its impact on XBP1 splicing was weakened at higher concentrations. In conclusion, the present results indicate that ER stress may contribute to chondrocyte apoptosis along with OA progression, which was closely associated with an enhanced apoptotic response and a reduced protective response by the cells. PMID- 21294794 TI - KMS1 and KMS2, two plant endoplasmic reticulum proteins involved in the early secretory pathway. AB - We have identified two endoplasmic reticulum (ER)-associated Arabidopsis proteins, KMS1 and KMS2, which are conserved among most species. Fluorescent protein fusions of KMS1 localised to the ER in plant cells, and over-expression induced the formation of a membrane structure, identified as ER whorls by electron microscopy. Hydrophobicity analysis suggested that KMS1 and KMS2 are integral membrane proteins bearing six transmembrane domains. Membrane protein topology was assessed by a redox-based topology assay (ReTA) with redox-sensitive GFP and confirmed by a protease protection assay. A major loop domain between transmembrane domains 2 and 3, plus the N- and C-termini were found on the cytosolic side of the ER. A C-terminal di(tri)-lysine motif is involved in retrieval of KMS1 and deletion led to a reduction of the GFP-KMS1 signal in the ER. Over-expression of KMS1/KMS2 truncations perturbed ER and Golgi morphology and similar effects were also seen when KMS1/KMS2 were knocked-down by RNA interference. Microscopy and biochemical experiments suggested that expression of KMS1/KMS2 truncations inhibited ER to Golgi protein transport. PMID- 21294795 TI - Dynamics of Arabidopsis SUN proteins during mitosis and their involvement in nuclear shaping. AB - The nuclear envelope (NE) is a highly active structure with a specific set of nuclear envelope proteins acting in diverse cellular events. SUN proteins are conserved NE proteins among eukaryotes. Although they form nucleocytoplasmic linkage complexes in metazoan cells, their functions in the plant kingdom are unknown. To understand the function of plant SUN proteins, in this study we first investigated the dynamics of Arabidopsis SUN proteins during mitosis in Arabidopsis roots and cultured cells. For this purpose, we performed dual and triple visualization of these proteins, microtubules, chromosomes, and endoplasmic reticulum (ER) in cultured cells, and observed their dynamics during mitosis using a high-speed spinning disk confocal microscope. The localizations of SUN proteins changed dynamically during mitosis, tightly coupled with NE dynamics. Moreover, NE re-formation marked with SUN proteins is temporally and spatially coordinated with plant-specific microtubule structures such as phragmoplasts. Finally, the analysis with gene knockdowns of AtSUN1 and AtSUN2 indicated that they are necessary for the maintenance and/or formation of polarized nuclear shape in root hairs. These results suggest that Arabidopsis SUN proteins function in the maintenance or formation of nuclear shape as components of the nucleocytoskeletal complex. PMID- 21294796 TI - A recombineering-based gene tagging system for Arabidopsis. AB - One of the most information-rich aspects of gene functional studies is characterization of gene expression profiles at cellular resolution, and subcellular localization of the corresponding proteins. These studies require visualization of the endogenous gene products using specific antibodies, or, more commonly, generation of whole-gene translational fusions with a reporter gene such as a fluorescent protein. To facilitate the generation of such translational fusions and to ensure that all cis-regulatory sequences are included, we have used a bacterial homologous recombination system (recombineering) to insert fluorescent protein tags into genes of interest harbored by transformation competent bacterial artificial chromosomes (TACs). This approach has several advantages compared to other classical strategies. First, the researcher does not have to guess what the regulatory sequences of a gene are, as tens of thousands of base pairs flanking the gene of interest can be included in the construct. Second, because the genes of interest are not amplified by PCR, there are practically no limits to the size of a gene that can be tagged. Third, there are no restrictions on the location in which the fluorescent protein can be inserted, as the position is determined by sequence homology with the recombination primers. Finally, all of the required strains and TAC clones are publically available, and the experimental procedures described here are simple and robust. Thus, we suggest that recombineering-based gene tagging should be the gold standard for gene expression studies in Arabidopsis. PMID- 21294797 TI - A randomised controlled study of the effects of music on sleep quality in older people. AB - AIM: To determine the effect of music on sleep quality in older people. BACKGROUND: Sleep disturbance is common in older people and its impacts on older adults along with its conventional treatment merit our attention as our population ages. Conventional pharmacological method might result dependence and impairment in psychomotor and cognitive function. Listening to music, which is a non-pharmacological method, might promote relaxation, induce distraction responses and promote sleep quality. DESIGN: A randomised controlled study. METHODS: The study was conducted from December 2006-January 2007. Forty-two older people (21 using music and 21 controls) completed the study in Hong Kong. Physiological (blood pressure and heart rate) and sleep quality variables were collected once a week for one month. RESULTS: For all vital signs' results, no significant differences were found between both music and control groups within the four weeks. In the music group, there was statistically significant reduction in sleep scores at week 4. In control group, there was no statistically significant improvement of sleep scores in the four weeks. However, no significant difference was found between groups over the four weeks. CONCLUSION: Whilst there were no statistical differences between groups, there was some indication that music yielder higher improvement on sleep scores, which are worthier of further investigation in larger trials. RELEVANCE TO CLINICAL PRACTICE: The implication of this study is that music listening can help nurses build therapeutic relationships with older people. Nurses are recommended to use music as part of their holistic caring for older people. PMID- 21294798 TI - The relationships between uncertainty and its antecedents in Korean patients with atrial fibrillation. AB - OBJECTIVES: The aim of the study was to examine the relationships between uncertainty and its antecedents, including education, social support and symptom frequency in Korean patients with atrial fibrillation. BACKGROUND: The antecedents of uncertainty were theoretically identified from Mishel's theory of uncertainty in illness. There is a need to examine empirically whether theoretically driven antecedents of uncertainty work in a way that the theory proposed. DESIGN: Descriptive correlational and cross-sectional survey design. METHODS: Subjects were interviewed using structured study questionnaires. The data collected were statistically analysed by descriptive statistics and hierarchical regression analysis to determine the effects of antecedents on uncertainty. RESULTS: A convenience sample of 109 subjects recruited from three academic medical centres in South Korea. The overall model significantly explained 20.1% of the variance in uncertainty. Among antecedents of uncertainty, social support was significantly associated with less uncertainty (beta = -0.26), while the education was not associated with uncertainty. Persons with greater social supports perceived less uncertainty, and individuals with greater symptom frequency reported greater uncertainty (beta = 0.21). CONCLUSIONS: In Korean patients with atrial fibrillation, it was demonstrated that uncertainty in atrial fibrillation patients was predicted by social support and symptom frequency. Thus, the nursing strategies that reduce uncertainty which results in undesirable outcomes are required through maximising the social support patients perceived and minimising the symptom frequency. Therefore, these findings are relevant to clinical nurses who take care of patients with atrial fibrillation in terms of decreasing uncertainty that might result in patients' psychological distress. Relevance to clinical practice. The findings from this study may be beneficial for clinical nurses to understand and assess the psychosocial and emotional needs of patients with atrial fibrillation. PMID- 21294799 TI - Reticulate evolution of the Daphnia pulex complex as revealed by nuclear markers. AB - The study of species complexes is of particular interest to understand how evolutionary young species maintain genomic integrity. The Daphnia pulex complex has been intensively studied as it includes species that dominate freshwater environments in the Northern hemisphere and as it is the sole North American complex that shows transitions to obligate parthenogenesis. Past studies using mitochondrial markers have revealed the presence of 10 distinct lineages in the complex. This study is the first to examine genetic relationships among seven species of the complex at nuclear markers (nine microsatellite loci and one protein-coding gene). Clones belonging to the seven species of the Daphnia pulex complex were characterized at the mitochondrial NADH dehydrogenase (ND5) gene and at the Lactate dehydrogenase (LDH) locus. K-means, principal coordinate analyses and phylogenetic network analyses on the microsatellite data all separated European D. pulicaria, D. tenebrosa, North American D. pulex, D. pulicaria and their hybrids into distinct clusters. The hybrid cluster was composed of diploid and polyploid hybrids with D. pulex mitochondria and some clones with D. pulicaria mitochondria. By contrast, the phylogeny of the D. pulex complex using Rab4 was not well resolved but still showed clusters consisting mostly of D. pulex alleles and others of D. pulicaria alleles. Incomplete lineage sorting and hybridization may obscure genetic relationships at this locus. This study shows that hybridization and introgression have played an important role in the evolution of this complex. PMID- 21294800 TI - Effects of long work hours and poor sleep characteristics on workplace injury among full-time male employees of small- and medium-scale businesses. AB - The aim of this study was to investigate the effects of long work hours and poor sleep characteristics on workplace injury. A total of 1891 male employees, aged 18-79 years (mean 45 years), in 296 small- and medium-scale businesses in a suburb of Tokyo were surveyed by means of a self-administered questionnaire during August-December 2002. Work hours and sleep characteristics, including daily sleep hours, subjective sleep sufficiency, sleep quality and easiness to wake up in the morning, were evaluated. Information on workplace injury in the past 1-year period was self-reported. The risk of workplace injury associated with work hours and poor sleep was estimated using multivariate logistic regression with odds ratio (ORs) and 95% confidence intervals as measures of associations. Compared with those working 6-8 h day(-1) with good sleep characteristics, positive interactive effects for workplace injury were found between long work hours (>8-10 h day(-1) or >10 h day(-1) ) and short sleep duration (<6 h) [adjusted OR (aOR), 1.27-1.54], subjective insufficient sleep (aOR, 1.94-1.99), sleep poorly at night (aOR, 2.23-2.49) and difficulty waking up in the morning (aOR, 1.56-1.59). Long work hours (aOR, 1.31-1.48), subjective insufficient sleep (aOR, 1.49) and sleeping poorly at night (aOR, 1.72) were also independently associated with workplace injury. This study suggests that long work hours coupled with poor sleep characteristics are synergistically associated with increased risk of workplace injury. Greater attention should be paid to manage/treat poor sleep and reduce excessive work hours to improve safety at the workplace. PMID- 21294801 TI - A message from the editor. The role of the mucosal immunity in the male and female reproductive tract during HIV infection. PMID- 21294802 TI - Mucosal immunity in the male and female reproductive tract and prevention of HIV transmission. PMID- 21294803 TI - The forgotten epidemic: AIDS in the 21st century. PMID- 21294804 TI - From laboratory bench to living room: one woman's perspective on life with HIV. PMID- 21294806 TI - Compliance with the commission on cancer quality of breast cancer care measures: self-evaluation advised. AB - To provide evaluations of cancer care quality, the Commission on Cancer and the National Quality Forum (NQF) established three breast cancer treatment quality measures. Programs that submit data to the National Cancer Data Base (NCDB) can receive feedback on their compliance with these quality measures, and perform comparisons with other member institutions. Data received by a county hospital from the NCDB revealed poor compliance. The purpose of this study was to evaluate the accuracy of submitted data, identify contributing factors and initiate processes to improve. Reported 2004 NCDB quality measure compliance was 26% for radiation, 61.4% for chemotherapy, and 21.3% for hormonal therapy. Retrospective treatment review was performed. Data collected included: patient demographics, pathology, final surgical intervention, adjuvant treatment, and quality measure compliance. Sources included two electronic records, an electronic results depository, two paper charts, a pharmacy data base, and a "shadow chart." Applicability of and compliance with these quality measures was noted. Of 540 records reviewed, 132 met final study criteria. Actual compliance differed significantly from NCDB rates and were found to be 97% for radiation, 98% for chemotherapy, and 88% for hormonal therapy. Process analysis revealed the need for tumor registry staff to evaluate all sources of data. A significant problem was neo-adjuvant chemotherapy and the requirement to submit NCDB data within 6 months of initial diagnosis. Processes and education initiated for tumor registry staff, medical records personnel, physicians, and other care providers resulted in significantly improved 2007 compliance of data submitted to the NCDB. Prior to public reporting, institutions should perform NQF quality measure compliance assessments, confirm accuracy, and initiate educational processes/imperatives. PMID- 21294805 TI - Innate immunity in the human female reproductive tract: endocrine regulation of endogenous antimicrobial protection against HIV and other sexually transmitted infections. AB - Mucosal surfaces of the female reproductive tract (FRT) contain a spectrum of antimicrobials that provide the first line of defense against viruses, bacteria, and fungi that enter the lower FRT. Once thought to be a sterile compartment, the upper FRT is periodically exposed to pathogens throughout the menstrual cycle. More recently, secretions from the upper FRT have been shown to contribute to downstream protection in the lower FRT. In this review, we examine the antimicrobials in FRT secretions made by immune cells and epithelial cells in the upper and lower FRT that contribute to innate protection. Because each site is hormonally regulated to maintain fertility, this review focuses on the contributions of hormone balance during the menstrual cycle to innate immune protection. As presented in this review, studies from our laboratory and others demonstrate that sex hormones regulate antimicrobials produced by innate immune cells throughout the FRT. The goal of this review is to examine the spectrum of antimicrobials in the FRT and the ways in which they are regulated to provide protection against pathogens that compromise reproductive health and threaten the lives of women. PMID- 21294807 TI - The efficacy of preoperative vascular mapping by MDCTA in selecting flap in abdominal flap breast reconstruction. AB - Current methods of breast reconstruction using abdominal tissue include the transverse abdominal myocutaneous (TRAM) flap, deep inferior epigastric arterial perforator (DIEP) flap, superficial inferior epigastric arterial (SIEA) flap, and some other composite flaps. Because of the variant vascular anatomy in abdominal region, it is hard to choose an appropriate flap for a specific patient without accurate preoperative vascular mapping. This study was drawn to address the efficacy of preoperative vascular mapping by multidetector-row computed tomographic angiography (MDCTA) in selecting flap in abdominal flap breast reconstruction. A total of 34 breast reconstructions using abdominal flap from December 2006 to July 2009 were included. In all the patients included, MDCTA was performed preoperatively. Three indexes were obtained including choice of flaps, operation time, and flap complication rate. Then, these data were compared with the former data stored in the databank of our hospital from January 2004 to December 2006, before MDCTA was introduced in our center. Among the 34 patients, the flap selection was: SIEA flaps 11.8%, DIEP flaps 61.8%, TRAM flaps 11.8%, and bilateral flaps 14.7%. The correlate indexes from the data bank were as follows: SIEA flap 0; DIEP flaps 51.7%; TRAM flaps 32.8%; bilateral flaps 15.5%. p < 0.05 occurred between the comparison of SIEA, DIEP, and TRAM flap choice in the two groups. The operation time in the study group was as follows: SIEA flap (4.02 +/- 0.46) hours, DIEP flap (6.23 +/- 1.42) hours, TRAM flap (4.72 +/- 1.53) hours, Bilateral flap (7.86 +/- 1.16) hours; while the former correlate data were: DIEP (9.67 +/- 1.74) hours, TRAM flap (6.64 +/- 1.83) hours, bilateral flap (11.83 +/- 1.35) (all the three comparison p < 0.05). The total flap complication rate was about 5.9% in the test group; while in the databank, it was 12.1% (p < 0.05). With the accurate mapping of vascular territory in abdomen by MDCTA, we could easily select a suitable abdominal flap for breast reconstruction, and we can also simplify the procedure to save operation time and make the process more safely. PMID- 21294808 TI - Patient satisfaction with nurse-led follow-up for breast cancer: a questionnaire study. PMID- 21294809 TI - Cancer risk management decisions of women with BRCA1 or BRCA2 variants of uncertain significance. PMID- 21294810 TI - Responsibility for long-term care of breast cancer survivors. PMID- 21294811 TI - Use of argon beam for operative hemostasis of a bleeding, locally advanced breast tumor before neo-adjuvant chemotherapy. PMID- 21294812 TI - The protean manifestations of granular cell tumor of the breast. PMID- 21294813 TI - Cytological diagnosis of mammary hydatidosis. PMID- 21294814 TI - Bullous pemphigoid following adjuvant radiotherapy for breast cancer. PMID- 21294815 TI - Surgical experience with rFVIIa (NovoSeven) in congenital haemophilia A and B patients with inhibitors to factors VIII or IX. AB - Patients with congenital haemophilia with inhibitors are at risk of peri operative bleeding complications, since replacement of the missing coagulation factor is ineffective, presenting a therapeutic challenge in elective or emergency surgery. Therefore, the management of peri-operative bleeding requires the use of bypassing agents, such as recombinant activated FVII (rFVIIa, NovoSeven((r)) ). This article presents an updated evaluation of the safety and effectiveness of rFVIIa in the treatment of peri-operative bleeding in this patient population. Surgical and other medical procedures managed with rFVIIa from two randomized clinical trials, the Hemophilia Research Society/Hemophilia and Thrombosis Research Society (HRS/HTRS) registry databases and the medical literature were analysed. There were 395 rFVIIa-treated procedures (261 surgical, 89 dental and 45 other medical procedures) reported for 263 congenital haemophilia patients with inhibitors. In trials, initial rFVIIa dosing was 35-90 mcg kg(-1) bolus injection or 50 mcg kg(-1) h(-1) continuous infusion. Dosing in the registries and literature was more variable. Recombinant FVIIa effectiveness was comparable across data sources, with an overall rate of 84% (333/395). The incidence of thrombotic events was very low (0.4% of patients and 0.025% of procedures). Prior to the US approval of rFVIIa in 1999, surgical procedures in congenital haemophilia patients with inhibitors were often considered too risky. Recombinant FVIIa has consistently demonstrated effectiveness in treatment of bleeding in these patients during such procedures. Thrombotic events were rare. This analysis confirms the value of corroborating clinical trial results with post-marketing surveillance registries to assess small patient populations with clinically challenging management decisions. PMID- 21294816 TI - Analysis of ciliary beat frequency and ovum transport ability in the mouse oviduct. AB - The oviduct is important in reproduction where fertilization occurs, and the fertilized eggs are conveyed to the uterus. Multi-ciliated cells of the oviductal epithelium and muscle contractions are believed to generate this unidirectional flow. Although there are many studies in human oviducts, there are few reports on mouse oviductal ciliary movements where we can dissect underlying genetic programs. To study ciliary movements in the mouse oviduct, we exposed the ovary side of the oviduct (infundibulum) longitudinally and recorded the ciliary beatings in a hanging drop preparation. We calculated the ciliary beat frequency (CBF) by automated image analysis and found that the average CBF was 10.9 +/- 3.3 and 8.5 +/- 2.5 Hz (+/-standard deviation) during the diestrus and estrus stages, respectively. Mapping of the CBF to multiple locations in the epithelium showed that the cilia beat regularly at a local level, but have a range of frequencies within the entire plane. We also observed ova with cumulus cells were transported to the uterus side by the opened oviduct at the diestrus and estrus stages. These results suggest that the ciliated cells of the infundibulum can generate unidirectional flows and are able to deliver ova by their ciliary activities despite their discordance in beating periodicity. PMID- 21294817 TI - DT40 knock-out and knock-in studies determine the regions necessary and sufficient for transcription and epigenetic conversion of the chicken Ig-beta gene. AB - The chicken Ig-beta locus is organized by three cell-type-specific genes and two ubiquitously expressed genes. B-cell-specific DNase I hypersensitive sites (DHS) in that locus, including three present inside the flanking gene, were grouped into six regions and deleted. The deletions decreased Ig-beta mRNA content to <0.1% of that of normal DT40 cells and converted epigenetic parameters such as histone modifications, CG methylation and DNase I hypersensitivity into inactive states. Knocked-in DHS regions into knock-out cells reactivated both transcription of the Ig-beta gene and epigenetic parameters. Thus, the collaboration of the scattered regulatory regions was essential and sufficient not only for B-cell-specific transcription of the Ig-beta gene, but also for the conversion of epigenetic parameters. On the basis of the knock-in studies, we determined the regions involved in the conversion and maintenance of the epigenetic parameters. These scattered regulatory regions were limited in vicinity such as in an intron of the gene, in the intergenic regions and in the introns of a flanking gene. PMID- 21294818 TI - Positional cloning of silkworm white egg 2 (w-2) locus shows functional conservation and diversification of ABC transporters for pigmentation in insects. AB - The white, scarlet and brown genes of Drosophila melanogaster encode three half type ATP-binding cassette (ABC) transporters. In Drosophila, precursors of ommochromes and pteridines are transported by White/Scarlet and White/Brown heterodimers, respectively. The white egg 2 (w-2) mutant of the silkworm, Bombyx mori, has white eggs and eyes because of lack of ommochrome granules in the serosa and eyes. Here, we report that the silkworm w-2 locus encodes an ortholog of Drosophila scarlet. Our results indicate that Bombyx Scarlet forms a heterodimer with Bombyx White to transport ommochrome precursors, suggesting that formation of a White/Scarlet heterodimer and its involvement in the transport of ommochrome precursors are evolutionarily ancient and widely conserved traits in insects. Contrary to dipteran insects, white and scarlet were juxtaposed in a head-to-tail orientation in the silkworm genome, suggesting that the origin of white and scarlet was a tandem duplication of their ancestral transporter gene. In Bombyx, White is also essential for the transport of uric acid in larval epidermis. However, our results suggest that a Bombyx White/Scarlet heterodimer is not involved in this process. Our results emphasize the functional conservation and diversification of half-type ABC transporter families in insects, which may contribute to their extremely diverse color patterns. PMID- 21294819 TI - Enhanced solid-state citric acid bio-production using apple pomace waste through surface response methodology. AB - AIMS: To evaluate the potential of apple pomace (AP) supplemented with rice husk for hyper citric acid production through solid-state fermentation by Aspergillus niger NRRL-567. Optimization of two key parameters, such as moisture content and inducer (ethanol and methanol) concentration was carried out by response surface methodology. METHODS AND RESULTS: In this study, the effect of two crucial process parameters for solid-state citric acid fermentation by A. niger using AP waste supplemented with rice husk were thoroughly investigated in Erlenmeyer flasks through response surface methodology. Moisture and methanol had significant positive effect on citric acid production by A. niger grown on AP (P < 0.05). Higher values of citric acid on AP by A. niger (342.41gkg(-1) and 248.42gkg(-1) dry substrate) were obtained with 75% (v/w) moisture along with two inducers [3% (v/w) methanol and 3% (v/w) ethanol] with fermentation efficiency of 93.90% and 66.42%, respectively depending upon the total carbon utilized after 144h of incubation period. With the same optimized parameters, conventional tray fermentation was conducted. The citric acid concentration of 187.96gkg(-1) dry substrate with 3% (v/w) ethanol and 303.34gkg(-1) dry substrate with 3% (v/w) methanol were achieved representing fermentation efficiency of 50.80% and 82.89% in tray fermentation depending upon carbon utilization after 120h of incubation period. CONCLUSIONS: Apple pomace proved to be the promising substrate for the hyper production of citric acid through solid-state tray fermentation, which is an economical technique and does not require any sophisticated instrumentation. SIGNIFICANCE AND IMPACT OF THE STUDY: The study established that the utilization of agro-industrial wastes have positive repercussions on the economy and will help to meet the increasing demands of citric acid and moreover will help to alleviate the environmental problems resulting from the disposal of agro industrial wastes. PMID- 21294820 TI - Immunostimulatory activities of specific bacterial secondary metabolite of Anoxybacillus flavithermus strain SX-4 on carp, Cyprinus carpio. AB - AIMS: To determine the capacity of secondary metabolite of strain SX-4, to enhance the nonspecific immunity and survival of carp (Cyprinus carpio), and to identify the constituents that are responsible. METHODS AND RESULTS: A thermophilic strain SX-4 that is able to produce immunostimulatory metabolite was isolated from sludge sample of hot spring and identified by comparison with 16S rRNA sequences (99% of homology) as Anoxybacillus flavithermus. Bioactivity guided fractionation of methanol extract from its cell-free culture, one bacterial peptide with the capacity of improving the nonspecific immune responses and disease resistance (relative per cent survival = 66.67%) was obtained and the compound was characterized as cyclo-(L-Pro-Gly) by IR, ESI-MS, (1) H NMR and (13) C NMR spectroscopic analyses. After intraperitoneal administration of this peptide, selected innate immune parameters including phagocytic activity, superoxide anion production, serum lysozyme activity and serum SOD activity, along with immune-related genes expression (i.e. interleukin-1beta and inducible nitric oxide synthase), in the blood were found to be significantly increased. CONCLUSIONS: The bacterial peptide cyclo-(L-Pro-Gly) significantly enhances nonspecific immunity and survival of carp. SIGNIFICANCE AND IMPACT OF THE STUDY: There is a possibility of using cyclo-(L-Pro-Gly) as a better natural immunostimulant, which could have a promising role in aquaculture to prevent diseases and disease outbreaks. PMID- 21294821 TI - Flash infrared radiation disinfection of fibrous filters contaminated with bioaerosols. AB - AIMS: To investigate the effectiveness of infrared (IR) radiation heating in disinfecting air filters loaded with bioaerosols. METHODS AND RESULTS: An irradiation device was constructed considering the unique characteristics of IR and the physical dimensions and radiative properties of air filters. Filters loaded with test bioaerosols were irradiated with the device and flash heated to an ultra-high temperature (UHT). A maximum of 3.77-, 4.38- and 5.32-log inactivation of B. subtilis spores, E. coli, and MS2 virus respectively was achieved within 5 s of irradiation. Inactivation efficiency could be increased by using a higher IR power. Microscopic analysis showed no visible damage from the heat treatment that would affect filtration efficiency. CONCLUSIONS: Because the disinfection was a dry heat process, a temperature greater than 200 degrees C was found necessary to successfully inactivate the test micro-organisms. The results demonstrate that IR is able to quickly disinfect filters given sufficient incident power. Compared to existing filter disinfection technologies, it offers a faster and more effective solution. SIGNIFICANCE AND IMPACT OF THE STUDY: It has been shown that IR heating is a feasible option for filter disinfection; possibly reducing fomite transmission of collected micro-organisms and preventing bioaerosol reaerosolization. PMID- 21294822 TI - Influence of carbohydrates on the isolation of lactic acid bacteria. AB - AIMS: To determine the influence of carbohydrates on enrichment isolation of lactic acid bacteria from different niches. METHODS AND RESULTS: Lactic acid bacteria in three traditional fermented products in southern Africa (amasi, mahewu and tshwala) and in three fresh samples (two flowers and a fruit) were enrichment cultured in media supplemented with 13 different carbohydrates. Diversity of lactic acid bacteria was determined by PCR-denaturing-gradient gel electrophoresis. Carbohydrates used in enrichment media had a big impact on the isolation of lactic acid bacteria from fermented products. Depending on the carbohydrates tested, the number of species detected ranged from one to four in amasi, one to five in mahewu and one to three in tshwala. Fructose and mannitol selected for relatively higher numbers of lactic acid bacteria in fermented products. Specific relationships between substrates and lactic acid bacteria have been noted. On the other hand, small influences were found among carbohydrates tested in flowers and fruit. CONCLUSION: Carbohydrates have a big impact on the isolation of a variety of lactic acid bacteria in fermented food. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study that reports the influence of carbohydrates on the enrichment of lactic acid bacteria. PMID- 21294823 TI - Molecular analysis of autochthonous microbiota along the digestive tract of juvenile grouper Epinephelus coioides following probiotic Bacillus pumilus administration. AB - AIMS: To evaluate the diversity of dominant autochthonous microbiota along the digestive tract of juvenile Epinephelus coioides following the dietary administration of probiotic Bacillus pumilus for 60 days. METHODS AND RESULTS: Polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) with subsequently sequencing analysis was used to assess the gut microbiota. Generally similar DGGE patterns were observed in the foregut, midgut and hindgut of E. coioides, while the similarity dendrogram clearly revealed three different clusters depending on the three compartments of the GI tract. Dietary administration of B. pumilus stimulated its colonization in each compartment of the digestive tract. Samples collected from the probiotic group and the control group showed similar DGGE patterns, and no significant difference in the total number of bands and the Shannon index were detected between the probiotic group and the control group, suggested that B. pumilus exert no significant effect on the gut microbiota. However, various potentially beneficial bacteria, such as uncultured Bacillus sp. clone QJNY94-like, Nitratireductor sp. YCSC5-like, Methylobacterium hispanicum-like and Microbacterium sp. YACS1-like bacteria were stimulated by probiotic B. pumilus, while the potential harmful Staphylococcus saprophyticus-like bacterium was depressed. CONCLUSIONS: Autochthonous gut microbiota of E. coioides was modulated to some degree, not significant, by probiotic B. pumilus, various potentially beneficial bacteria were selectively stimulated, while one potential harmful species was depressed. SIGNIFICANCE AND IMPACT OF THE STUDY: This work represents the first report that dietary administration of probiotic B. pumilus modulated the gut microbiota of E. coioides. These findings broaden our understanding of probiotic effects at the gut level, which is helpful in understanding the mechanisms that underpin host benefits. PMID- 21294824 TI - Platelet binding and activity of a factor VIIa variant with enhanced tissue factor independent activity. AB - BACKGROUND AND OBJECTIVES: Platelet binding and activity play important roles in the efficacy of factor VIIa (FVIIa) as a bypassing agent for hemophilia treatment. An analog of FVIIa with increased tissue factor (TF)-independent activity, NN1731, has been produced by introducing three amino acid changes in the protease domain. NN1731 has a conformation similar to TF-bound FVIIa, even in the absence of TF. This results in much greater intrinsic proteolytic activity, but similar activity in the presence of TF. OBJECTIVES: We hypothesized that these changes would not alter binding to platelets or phospholipid, a characteristic thought to be localized to the Gla domain. The goal of the current work was to compare platelet binding and activity of NN1731 and wild-type FVIIa. METHODS/RESULTS: FVIIa and NN1731 bound identically to phospholipid vesicles as assessed by both activity assays and electrophoretic quasielastic light scattering techniques. However, NN1731 bound to a greater number of sites on activated platelets than FVIIa, as assessed by flow cytometry. Removal of the Gla domain abolished binding of both FVIIa and NN1731. Inhibition of the active site did not reduce NN1731 binding to the level of FVIIa. When corrected for the amount of protein bound, NN1731 had greater activity than FVIIa on platelet surfaces. CONCLUSIONS: While the Gla domain is essential for FVIIa binding to platelets, changes in the protease domain in NN1731 enhanced platelet binding as well as proteolytic activity. Features in addition to lipid composition appear to contribute to binding of rFVIIa and, especially, NN1731 to platelets. PMID- 21294825 TI - Recombinant ADAMTS13 normalizes von Willebrand factor-cleaving activity in plasma of acquired TTP patients by overriding inhibitory antibodies. AB - BACKGROUND: Severe deficiency of the von Willebrand factor (VWF)-cleaving protease ADAMTS13 as observed in acquired thrombotic thrombocytopenic purpura (TTP) is caused by inhibitory and non-inhibitory autoantibodies directed against the protease. Current treatment with plasma exchange is considered to remove circulating antibodies and to concurrently replenish the deficient enzyme. OBJECTIVES: To explore the use of recombinant ADAMTS13 (rADAMTS13) as a potential therapeutic agent in acquired TTP, we investigated its efficacy in normalizing VWF-cleaving activity in the presence of ADAMTS13 inhibitors. METHODS: Thirty-six plasma samples from TTP patients were adjusted to predefined inhibitor titers, and recovery of ADAMTS13 activity was analyzed following supplementation with rADAMTS13. RESULTS: We showed a linear relation between the inhibitor titer measured and effective rADAMTS13 concentration necessary for reconstitution of VWF-cleaving activity in the presence of neutralizing autoantibodies. CONCLUSIONS: Our results support the further investigation of the potential therapeutic applicability of rADAMTS13 as an adjunctive therapy in acquired TTP. PMID- 21294826 TI - Autopsy-proven untreated previous pulmonary thromboembolism: frequency and distribution in the pulmonary artery and correlation with patients' clinical characteristics. AB - BACKGROUND: This study aimed to evaluate untreated, previous pulmonary thromboembolism (PE) in patients with acute fatal PE. PATIENTS AND METHODS: We studied 64 patients diagnosed as having died from acute PE by medico-legal autopsy. Previous PE was histologically confirmed on the basis of organized thrombi (OT). The distributions of OT were analyzed in five different sizes of pulmonary artery branches in each of 18 pulmonary segmental arteries (90 in total). The frequency of OT in each patient was evaluated by determining the percentage of examined sections containing OT. RESULTS: OT were confirmed in 59 of 64 (92%) patients. The mean frequency of OT per patient was 27% of the 90 branches. Among the segmental arteries, the right posterior basal lobe showed the highest frequency of OT; among the five artery branches examined, the subsegmental branch showed the highest frequency of OT. OT were not detected in arterioles. Patients with recent trauma or surgery and inpatients showed significantly lower frequencies of OT than those without these risk factors. The 26 patients with prolonged pre-existing symptoms lasting more than a day showed a higher frequency of OT than the 12 patients who suffered for less than a day and the 26 without pre-existing symptoms. CONCLUSIONS: Most patients with acute fatal PE have a subclinical history of recurrent PE. The frequency of their untreated PE is suspected to correlate with specific risk factors for venous thromboembolism and their clinical course. PMID- 21294827 TI - High levels of glucose at time of diagnosing venous thrombosis: a case-control study. PMID- 21294828 TI - Systematic review: implications for scholars. PMID- 21294829 TI - International nursing: Culture in context, Part II. PMID- 21294830 TI - Learning from Kenyan nurses. PMID- 21294831 TI - What do you tell parents when their child is sick with the common cold? AB - PURPOSE: To review research supporting the Food and Drug Administration's recommendation to relabel over-the-counter cough and cold medications (OTC CCMs), warning against use in young children. CONCLUSIONS: Research has shown that the majority of OTC CCMs and antihistamines have little to no effect when used to treat the common cold and have a risky safety profile. Despite these findings, parents continue to use OTC CCMs for treatment of their children's colds. PRACTICE IMPLICATIONS: Educating parents on the lack of scientific evidence supporting the use of OTC CCMs and the potential for harm is important in altering parental perception and decreasing the purchase of OTC CCMs. PMID- 21294832 TI - Piloting the use of teen mentors to promote a healthy diet and physical activity among children in Appalachia. AB - PURPOSE: This study tested a mentoring model that paired trained teens with younger children in an after-school setting to deliver a curriculum aimed at promoting healthier patterns of dietary intake and physical activity. DESIGN AND METHODS: Using a pretest-posttest design, group comparisons were made. Descriptive, independent, and paired t-test analyses with Bonferroni corrections were conducted in a sample of 72 children. RESULTS: Group differences were noted with the intention to eat healthfully. Mentored children demonstrated greater improvement in knowledge, attitudes, efficacy, perceived support, and body mass index (BMI). PRACTICE IMPLICATIONS: Teen mentors can effectively impact children's intention to improve health behaviors, which is foundational to normalizing BMI. PMID- 21294833 TI - The use of nonpharmacological methods for children's postoperative pain relief: Singapore nurses' perspectives. AB - PURPOSE: The purpose of this study was to examine nurses' use of nonpharmacological methods for school-age children's postoperative pain relief. DESIGN AND METHODS: A survey was conducted in 2008 with a convenience sample of 134 registered nurses from 7 pediatric wards in Singapore. RESULTS: Nurses who were younger, had less education, lower designation, less working experience, and no children of their own used nonpharmacological methods less frequently. PRACTICE IMPLICATIONS: Nurses need training and education on nonpharmacological pain relief methods, particularly on methods that have been shown to be effective in prior research but that were less often used by nurses in this study: massage, thermal regulation, imagery, and positive reinforcement. PMID- 21294834 TI - A comparison of family adversity and family dysfunction in families of children with attention deficit hyperactivity disorder (ADHD) and families of children without ADHD. AB - PURPOSE: This study examined the presence of family adversity and family dysfunction in 32 families who had children diagnosed with attention deficit hyperactivity disorder (ADHD) compared with 23 families with similar sociodemographic characteristics whose children did not have ADHD. DESIGN AND METHODS: A descriptive comparative design was used to investigate family adversity and family dysfunction. RESULTS: Families of children with ADHD had significantly higher levels of family dysfunction than families whose children did not have ADHD. PRACTICE IMPLICATIONS: Earlier identification and intervention with families of children who have ADHD may result in healthier family and child outcomes. PMID- 21294835 TI - Human growth hormone treatment: synthesis of literature on product delivery systems and administration practices. AB - PURPOSE: To synthesize current literature on recombinant human growth hormone (rhGH) use and to identify areas of research that have received little to no attention in light of administration practice and patient perception/behavior. DESIGN AND METHODS: Relevant articles for a systematic review were identified through PubMed. RESULTS: A total of 43 articles were identified: 9 (15.9%) studies on product administration practices and 34 (84.1%) on patient behavior patterns. Patients primarily preferred simple, convenient, and easy-to-use delivery devices. However, literature addressing the effect of convenient product administration practices on treatment outcomes using real-world patient/caregiver data is lacking. PRACTICE IMPLICATIONS: Better understanding of real-world product administration practices will help nurses identify areas of improvement in patient education and training. PMID- 21294836 TI - The systematic review of literature: synthesizing evidence for practice. AB - PURPOSE: With current emphasis on evidence-based practice, nurses are searching for answers to questions generated at the bedside. One method to identify and evaluate the existing evidence is to conduct or read a systematic review of the literature. The purpose of this paper is to describe the process of conducting a systematic review of literature. CONCLUSION: Defining attributes, rationale for, and steps in conducting systematic reviews are presented. Examples from published reviews on pediatric nursing are included. PRACTICE IMPLICATIONS: Pediatric nurses may consult professionally prepared systematic reviews, such as The Cochrane Collection, or conduct their own reviews with the help of electronic search engines. PMID- 21294837 TI - The effects of the gulf oil spill on children. PMID- 21294838 TI - Modeling relationships in clinical research using path analysis Part II: evaluating the model. PMID- 21294839 TI - The heart beads program. AB - From July 2008 through June 2009, 760 infants and children with cardiac conditions were admitted to a pediatric hospital in Australia with approximately 360 cardiac surgical procedures performed.This was the first experience in hospital for many of these children, with diagnoses signaling the beginning of a long and arduous journey. These children undergo multiple treatments and procedures,as well as multiple admissions for further surgeries. Procedures in any regard can cause stress and anxiety, especially in children who often have limited understanding and so little control over what happens to them (Lau, 2002).A heart center for children exists at the hospital with the aim of providing a consistent experience for children with cardiac conditions as they move through the different hospital environments, from preadmission clinic to operating theaters to the pediatric intensive care unit (PICU), and then on to the cardiac ward. The Heart Beads Program was developed within a context of person-centered care to enrich the experience of children with cardiac conditions by providing them with distinctive beads specific to each procedure, treatment, or event in recognition of their experiences and endurance (McCormack et al., 2008). This column focuses on the process of starting the program and on preliminary responses from staff, children, and families. PMID- 21294841 TI - A point mutation in the pentatricopeptide repeat motif of the AtECB2 protein causes delayed chloroplast development. AB - AtECB2 encodes a pentatricopeptide repeat (PPR) protein that regulates the editing of the plastid genes accD and ndhF. The ecb2-1 knockout shows an albino phenotype and is seedling lethal. In this study, we isolated an allelic mutant of the AtECB2 gene, ecb2-2, which showed delayed greening phenotype but could complete their life cycle. In this mutant, the Thr(500) is converted to Ile(500) in the 13(th) PPR motif of the AtECB2 protein. Transmission electron microscopy demonstrated that chloroplast development was delayed in both the cotyledons and leaves of the mutant. An investigation of the chloroplast gene expression profile indicated that PEP (plastid-encoded RNA polymerase) activity in ecb2-2 cotyledons was not obviously affected, whereas it was severely impaired in ecb2-1. This result suggests that the PEP activities cause the different phenotypes of the ecb2-1 and ecb2-2 mutants. The editing efficiency of the three editing sites of accD (C794 and C1568) and ndhF (C290) in the mutant was dynamically altered, which was in agreement with the phenotype. This result indicates that the editing efficiency of accD and ndhF in the ecb2-2 mutant is associated with a delayed greening phenotype. As ecb2-2 can survive and set seeds, this mutant can be used for further investigation of RNA editing and chloroplast development in arabidopsis. PMID- 21294842 TI - Genetic analysis and fine mapping of a novel semidominant dwarfing gene LB4D in rice. AB - A dwarf mutant, designated LB4D, was obtained among the progeny of backcrosses to a wild rice introgression line. Genetic analysis of LB4D indicated that the dwarf phenotype was controlled by a single semidominant dwarfing gene, which was named LB4D. The mutants were categorized as dn-type dwarf mutants according to the pattern of internode reduction. In addition, gibberellin (GA) response tests showed that LB4D plants were neither deficient nor insensitive to GA. This study found that tiller formation by LB4D plants was decreased by 40% compared with the wild type, in contrast to other dominant dwarf mutants that have been identified, indicating that a different dwarfing mechanism might be involved in the LB4D dominant mutant. The reduction of plant height in F(1) plants ranged from 27.9% to 38.1% in different genetic backgrounds, showing that LB4D exerted a stronger dominant dwarfing effect. Using large F(2) and F(3) populations derived from a cross between heterozygous LB4D and the japonica cultivar Nipponbare, the LB4D gene was localized to a 46 kb region between the markers Indel 4 and Indel G on the short arm of chromosome 11, and four predicted genes were identified as candidates in the target region. PMID- 21294843 TI - Starch-binding domains in the CBM45 family--low-affinity domains from glucan, water dikinase and alpha-amylase involved in plastidial starch metabolism. AB - Starch-binding domains are noncatalytic carbohydrate-binding modules that mediate binding to granular starch. The starch-binding domains from the carbohydrate binding module family 45 (CBM45, http://www.cazy.org) are found as N-terminal tandem repeats in a small number of enzymes, primarily from photosynthesizing organisms. Isolated domains from representatives of each of the two classes of enzyme carrying CBM45-type domains, the Solanum tuberosumalpha-glucan, water dikinase and the Arabidopsis thaliana plastidial alpha-amylase 3, were expressed as recombinant proteins and characterized. Differential scanning calorimetry was used to verify the conformational integrity of an isolated CBM45 domain, revealing a surprisingly high thermal stability (T(m) of 84.8 degrees C). The functionality of CBM45 was demonstrated in planta by yellow/green fluorescent protein fusions and transient expression in tobacco leaves. Affinities for starch and soluble cyclodextrin starch mimics were measured by adsorption assays, surface plasmon resonance and isothermal titration calorimetry analyses. The data indicate that CBM45 binds with an affinity of about two orders of magnitude lower than the classical starch-binding domains from extracellular microbial amylolytic enzymes. This suggests that low-affinity starch-binding domains are a recurring feature in plastidial starch metabolism, and supports the hypothesis that reversible binding, effectuated through low-affinity interaction with starch granules, facilitates dynamic regulation of enzyme activities and, hence, of starch metabolism. PMID- 21294844 TI - Active site residue involvement in monoamine or diamine oxidation catalysed by pea seedling amine oxidase. AB - The structures of copper amine oxidases from various sources show good similarity, suggesting similar catalytic mechanisms for all members of this enzyme family. However, the optimal substrates for each member differ, depending on the source of the enzyme and its location. The structural factors underlying substrate selectivity still remain to be discovered. With this in view, we examined the kinetic behaviour of pea seedling amine oxidase with cadaverine and hexylamine, the first bearing two, and the second only one, positively charged amino group. The dependence of K(m) and catalytic constant (k(c)) values on pH, ionic strength and temperature indicates that binding of the monoamine is driven by hydrophobic interactions. Instead, binding of the diamine is strongly facilitated by electrostatic factors, controlled by polar side-chains and two titratable residues present in the active site. The position of the docked substrate is also essential for the participation of titratable amino acid residues in the following catalytic steps. A new mechanistic model explaining the substrate-dependent kinetics of the reaction is discussed. PMID- 21294845 TI - Calix[4]arene methylenebisphosphonic acids as inhibitors of fibrin polymerization. AB - Calix[4]arenes bearing two or four methylenebisphosphonic acid groups at the macrocyclic upper rim have been studied with respect to their effects on fibrin polymerization. The most potent inhibitor proved to be calix[4]arene tetrakis methylene-bis-phosphonic acid (C-192), in which case the maximum rate of fibrin polymerization in the fibrinogen + thrombin reaction decreased by 50% at concentrations of 0.52 * 10(-6) M (IC(50)). At this concentration, the molar ratio of the compound to fibrinogen was 1.7 : 1. For the case of desAABB fibrin polymerization, the IC(50) was 1.26 * 10(-6) M at a molar ratio of C-192 to fibrin monomer of 4 : 1. Dipropoxycalix[4]arene bis-methylene-bis-phosphonic acid (C-98) inhibited fibrin desAABB polymerization with an IC(50) = 1.31 * 10(-4) M. We hypothesized that C-192 blocks fibrin formation by combining with polymerization site 'A' (Aalpha17-19), which ordinarily initiates protofibril formation in a 'knob-hole' manner. This suggestion was confirmed by an HPLC assay, which showed a host-guest inclusion complex of C-192 with the synthetic peptide Gly-Pro-Arg-Pro, an analogue of site 'A'. Further confirmation that the inhibitor was acting at the initial step of the reaction was obtained by electron microscopy, with no evidence of protofibril formation being evident. Calixarene C 192 also doubled both the prothrombin time and the activated partial thromboplastin time in normal human blood plasma at concentrations of 7.13 * 10( 5) M and 1.10 * 10(-5) M, respectively. These experiments demonstrate that C-192 is a specific inhibitor of fibrin polymerization and blood coagulation and can be used for the design of a new class of antithrombotic agents. PMID- 21294846 TI - Discovery of small peptide antagonists of PED/PEA15-D4alpha interaction from simplified combinatorial libraries. AB - Most biological processes involve permanent and temporary interactions between different proteins: protein complexes often play key roles in human diseases and, as a consequence, molecules that prevent protein-protein interactions can be potential new therapeutic agents to treat diseases. Here, we describe a simplified approach by which small synthetic peptide libraries were screened to identify the inhibitors of the complex between phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes15 (PED/PEA15) and D4alpha, a functional domain of the phospholipase D1, that is involved in the molecular mechanisms of insulin resistance occurring in type 2 diabetes. By using an enzyme linked immunosorbent assay (ELISA)-based screening, performed on a fully automated platform, we analyzed two simplified peptide libraries in a positional scanning format. This screening led to the identification of small peptides able to inhibit PED/PEA15-D4alpha interaction. The selection of inhibitors was carried out employing combined competitive and direct experiments, through ELISA and surface plasmon resonance techniques, providing peptides with IC(50) values in the micromolar range. Our results showed that the protein complex PED/PEA15 D4alpha is susceptible to peptides having H-donor groups and aromatic rings on specific positions. These small sequences can be considered as promising scaffolds that could be converted into higher-affinity inhibitor compounds. PMID- 21294847 TI - Binding site analysis of CCR2 through in silico methodologies: docking, CoMFA, and CoMSIA. AB - Chemokine receptor (CCR2) is a G protein-coupled receptor that contains seven transmembrane domains. CCR2 is targeted for diseases like arthritis, multiple sclerosis, vascular disease, obesity and type 2 diabetes. Herein, we report on a binding site analysis of CCR2 through docking and three-dimensional quantitative structure-activity relationship (3D-QSAR). The docking study was performed with modeled receptor (CCR2) using beta2-andrenergic receptor structure as a template. Comparative molecular field analysis (CoMFA)- and comparative molecular similarity indices analysis (CoMSIA)-based 3D-QSAR models were developed using two different schemes: ligand-based (CoMFA; q2 =0.820, r2 =0.966, r2(pred) = 0.854 and CoMSIA; q2 =0.762, r2 =0.846, r2(pred) = 0.684) and receptor-guided (CoMFA; q2 =0.753, r2 =0.962, r2(pred) =0.786, CoMSIA; q2 =0.750, r2 =0.800, r2(pred)=0.797) methods. 3D-QSAR analysis revealed the contribution of electrostatic and hydrogen bond donor parameters to the inhibitory activity. Contour maps suggested that bulky substitutions on the para position of R1 substituted phenyl ring, electronegative and donor substitutions on meta (5') and ortho (2') position of R2 substituted phenyl ring were favorable for activity. The results correlate well with previous results and newly report additional residues that may be crucial in CCR2 antagonism. PMID- 21294848 TI - Transferred NOESY NMR studies of biotin mimetic peptide (FSHPQNT) bound to streptavidin: a structural model for studies of peptide-protein interactions. AB - Protein-protein interactions control signaling, specific adhesion, and many other biological functions. The three-dimensional structures of the interfaces and bound ligand can be approached with transferred nuclear Overhauser effect spectroscopy NMR, which can be applied to much larger proteins than conventional NMR and requires less concentrated protein. However, it is not clear how accurately the structures of protein-bound peptides can be determined by transferred nuclear Overhauser effect spectroscopy. We studied the structure of a biotin mimetic peptide (FSHPQNT) bound to streptavidin, because the X-ray structure of the complex is available to 1.74 A resolution, and we found that conditions could be adjusted so that the off-rates were fast enough for transferred nuclear Overhauser effect spectroscopy NMR. The off-rate was determined with (19)F NMR, using a para-fluoro-phenylalanine analog of the peptide. A new criterion for a lower limit on kinetic off-rate was found, which allowed accurate structure determination at a slower off-rate. Non-specific binding of the peptide to streptavidin was not significant, because biotin blocked the peptide transferred nuclear Overhauser effect spectroscopy. Protein mediation for the long-range peptide transferred nuclear Overhauser effect spectroscopy cross-peaks was corrected by a transferred nuclear Overhauser effect spectroscopy/ROESY averaging procedure. The protein-bound structure of the peptide was determined by transferred nuclear Overhauser effect spectroscopy constrained and simulated annealing. The structure deduced from the NMR was close to the X-ray structure. PMID- 21294849 TI - Synthesis and studies on three-compartment flavone-containing combi-molecules designed to target EGFR, DNA, and MEK. AB - In order to induce a tandem targeting of EGFR, DNA, and MEK, we built complex combi-molecules containing an EGFR targeting quinazoline and an aminoethyltriazene moiety linking the entire molecule to PD98059. Two complex molecules were synthesized: one with a short aminoethyl spacer, AL232, and the other AL414 with a longer aminoethylaminoethyl spacer. AL414 was a more potent inhibitor of EGFR tyrosine kinase than AL232. Both combi-molecules blocked EGFR phosphorylation in whole cells and downregulated extracellular signaling regulated kinases (ERK1,2). However, only AL414 was capable of inducing DNA damage. Thus, it was taken in vivo for metabolic analysis. The results showed that 3 h after injection, AL414 was hydrolyzed to an EGFR inhibitor FD105, which was further acetylated to FD105Ac, a more potent inhibitor of EGFR. The detected flavone derivative was PD98059 linked to the hydroxyalkyl moiety resulting from the decomposition of the alkyldiazonium species. Independent synthesis of the latter metabolite and further in vitro analysis showed that it was deprived of antiproliferative activity. The results in toto suggest that while AL414 is a three-compartment combi-molecule, only the EGFR and DNA targeting species can be released and the cleavage to the intact MEK inhibitor PD98059 was mitigated by the stability of the carbamate. PMID- 21294850 TI - Increased diversity of libraries from libraries: chemoinformatic analysis of bis diazacyclic libraries. AB - Combinatorial libraries continue to play a key role in drug discovery. To increase structural diversity, several experimental methods have been developed. However, limited efforts have been performed so far to quantify the diversity of the broadly used diversity-oriented synthetic libraries. Herein, we report a comprehensive characterization of 15 bis-diazacyclic combinatorial libraries obtained through libraries from libraries, which is a diversity-oriented synthetic approach. Using MACCS keys, radial and different pharmacophoric fingerprints as well as six molecular properties, it was demonstrated the increased structural and property diversity of the libraries from libraries over the individual libraries. Comparison of the libraries to existing drugs, NCI diversity, and the Molecular Libraries Small Molecule Repository revealed the structural uniqueness of the combinatorial libraries (mean similarity <0.5 for any fingerprint representation). In particular, bis-cyclic thiourea libraries were the most structurally dissimilar to drugs retaining drug-like character in property space. This study represents the first comprehensive quantification of the diversity of libraries from libraries providing a solid quantitative approach to compare and contrast the diversity of diversity-oriented synthetic libraries with existing drugs or any other compound collection. PMID- 21294851 TI - Applying molecular dynamics simulations to identify rarely sampled ligand-bound conformational states of undecaprenyl pyrophosphate synthase, an antibacterial target. AB - Undecaprenyl pyrophosphate synthase is a cis-prenyltransferase enzyme, which is required for cell wall biosynthesis in bacteria. Undecaprenyl pyrophosphate synthase is an attractive target for antimicrobial therapy. We performed long molecular dynamics simulations and docking studies on undecaprenyl pyrophosphate synthase to investigate its dynamic behavior and the influence of protein flexibility on the design of undecaprenyl pyrophosphate synthase inhibitors. We also describe the first X-ray crystallographic structure of Escherichia coli apo undecaprenyl pyrophosphate synthase. The molecular dynamics simulations indicate that undecaprenyl pyrophosphate synthase is a highly flexible protein, with mobile binding pockets in the active site. By carrying out docking studies with experimentally validated undecaprenyl pyrophosphate synthase inhibitors using high- and low-populated conformational states extracted from the molecular dynamics simulations, we show that structurally dissimilar compounds can bind preferentially to different and rarely sampled conformational states. By performing structural analyses on the newly obtained apo-undecaprenyl pyrophosphate synthase and other crystal structures previously published, we show that the changes observed during the molecular dynamics simulation are very similar to those seen in the crystal structures obtained in the presence or absence of ligands. We believe that this is the first time that a rare 'expanded pocket' state, key to drug design and verified by crystallography, has been extracted from a molecular dynamics simulation. PMID- 21294852 TI - Acute normobaric hyperoxia transiently attenuates plasma erythropoietin concentration in healthy males: evidence against the 'normobaric oxygen paradox' theory. AB - AIM: The purpose of the present study was to evaluate the 'normobaric oxygen paradox' theory by investigating the effect of a 2-h normobaric O(2) exposure on the concentration of plasma erythropoietin (EPO). METHODS: Ten healthy males were studied twice in a single-blinded counterbalanced crossover study protocol. On one occasion they breathed air (NOR) and on the other 100% normobaric O(2) (HYPER). Blood samples were collected Pre, Mid and Post exposure; and thereafter, 3, 5, 8, 24, 32, 48, 72 and 96 h, and 1 and 2 weeks after the exposure to determine EPO concentration. RESULTS: The concentration of plasma erythropoietin increased markedly 8 and 32 h after the NOR exposure (approx. 58% and approx. 52%, respectively, P <= 0.05) as a consequence of its natural diurnal variation. Conversely, the O(2) breathing was followed by approx. 36% decrement of EPO 3 h after the exposure (P <= 0.05). Moreover, EPO concentration was significantly lower in HYPER than in the NOR condition 3, 5 and 8 h after the breathing intervention (P <= 0.05). CONCLUSION: In contrast to the 'normobaric oxygen paradox' theory, the present results indicate that a short period of normobaric O(2) breathing does not increase the EPO concentration in aerobically fit healthy males. Increased O(2) tension suppresses the EPO concentration 3 and 5 h after the exposure; thereafter EPO seems to change in a manner consistent with natural diurnal variation. PMID- 21294853 TI - Compartment syndrome in the optic nerve: a new hypothesis in the pathogenesis of glaucoma. PMID- 21294854 TI - Treatment of proliferative diabetic retinopathy with anti-VEGF agents. AB - Proliferative diabetic retinopathy (PDR) is the most common cause of severe visual loss in people with diabetes. Although panretinal photocoagulation (PRP) remains the gold standard of care to date, several combinations of new treatment modalities have emerged. These approaches can be used to increase the extent of treatment, expedite the effect of laser treatment and provide alternate measures when laser delivery is difficult or impossible, especially in patients with vitreous haemorrhage. Currently, most of the research in this field is focussed on inhibitors of vascular endothelial growth factor (VEGF), referred to herein as anti-VEGF agents. Although limited by their short-lived effects and a lack of established protocols, anti-VEGF agents are widely available, especially for the treatment of aggressive PDR. This review analyses published studies using anti VEGF agents alone or as an adjunct to other therapies in the treatment of PDR. PMID- 21294855 TI - Experimental infection of common warthogs (Phacochoerus africanus) and bushpigs (Potamochoerus larvatus) with classical swine fever virus. I: Susceptibility and transmission. AB - An incursion of classical swine fever virus (CSFV) into the domestic pig population in South Africa, identified in 2005, raised the concern that infection might spread to wildlife species and be maintained in these hosts. This study sought to determine whether two wildlife Suidae species present in South Africa, the bushpig (Potamochoerus larvatus) and the common warthog (Phacochoerus africanus), could support productive CSFV infection. Both species could be infected with CSFV and transmitted infection to in-contact animals of the same species. Viral antigen and RNA genome were detected in blood/serum and animals that survived initial infection seroconverted approximately 10-14 days post inoculation. Viral RNA remained detectable in nasal and saliva secretions for prolonged periods until monitoring ended at 42-44 days after initial challenge. These data suggest that both Suidae species could serve to spread circulating CSFV within wild populations, with implications for disease control. PMID- 21294856 TI - Eriobotrya japonica hydrophilic extract modulates cytokines in normal tissues, in the tumor of Meth-A-fibrosarcoma bearing mice, and enhances their survival time. AB - BACKGROUND: Cytokines play a key role in the immune response to developing tumors, and therefore modulating their levels and actions provides innovative strategies for enhancing the activity of antigen presenting cells and polarizing towards T helper 1 type response within tumor microenvironment. One of these approaches could be the employment of plant extracts that have cytokine immunomodulation capabilities. Previously, we have shown that the Eriobotrya japonica hydrophilic extract (EJHE) induces proinflammatory cytokines in vitro and in vivo. METHODS: The present study explored the in vivo immunomodulatory effect on interferon-gamma (IFN-gamma), interleukin-17 (IL-17), and transforming growth factor-beta 1 (TGF-beta1) evoked by two water-extracts prepared from EJ leaves in the tissues of normal and Meth-A-fibrosarcoma bearing mice. RESULTS: Intraperitoneal (i.p.) administration of 10 MUg of EJHE and EJHE-water residue (WR), prepared from butanol extraction, increased significantly IFN-gamma production in the spleen (p < 0.01) and lung (p < 0.03) tissues at 6-48 hours and suppressed significantly TGF-beta1 production levels (p < 0.001) in the spleen for as long as 48 hours. The latter responses, however, were not seen in Meth-A fibrosarcoma-bearing mice. On the contrary, triple i.p. injections, 24 hours apart; of 10 MUg EJHE increased significantly IFN-gamma production in the spleen (p < 0.02) while only EJHE-WR increased significantly IFN-gamma, TGF-beta1 and IL 17 (p < 0.03 - 0.005) production within the tumor microenvironment of Meth-A fibrosarcoma. In addition, the present work revealed a significant prolongation of survival time (median survival time 72 days vs. 27 days of control, p < 0.007) of mice inoculated i.p. with Meth-A cells followed by three times/week for eight weeks of i.p. administration of EJHE-WR. The latter prolonged survival effect was not seen with EJHE. CONCLUSIONS: The therapeutic value of EJHE-WR as an anticancer agent merits further investigation of understanding the effect of immunomodulators' constituents on the cellular components of the tissue microenvironment. This can lead to the development of improved strategies for cancer treatment and thus opening up a new frontier for future studies. PMID- 21294857 TI - Use of dietary supplements in Olympic athletes is decreasing: a follow-up study between 2002 and 2009. AB - BACKGROUND: The aim of this study was to assess the frequency of use of dietary supplements (DS) among large sample of elite Finnish athletes and to describe possible changes in dietary supplement use between the years 2002 and 2009. METHODS: A prospective follow-up study was conducted on Olympic athletes. The first survey was conducted on Olympic athletes in 2002 (N = 446) and the follow up study was conducted between May 2008 and June 2009 (N = 372). RESULTS: In 2002, a total of 81% of the athletes used dietary supplements (a mean of 3.37 +/- 3.06 DS per user) and in 2009, a total of 73% of the athletes (a mean of 2.60 +/- 2.69 per DS user) used them. After adjusting for age-, sex- and sport type, the OR (95% confidence interval, CI) for use of any dietary supplement was significantly less in 2009 as compared with 2002 results (OR, 0.62; 95% CI, 0.43 0.90). Decrease in DS use was observed in all supplement subgroups (vitamins, minerals, nutritional supplements). Athletes in speed and power events and endurance events reported use of any dietary supplement significantly more often than team sport athletes both in 2002 and 2009. In year 2009, the frequency of all dietary supplement use increased when athlete's age increased and the increase was significant in older age groups: of the athletes under 21 years 63%, 21-24 years 83% and over 24 years 90% consumed nutritional supplements. CONCLUSIONS: Based in our study, there seems to be a lowering trend of dietary supplement use among elite Finnish athletes although differences between sport subgroups and age groups are considerable. PMID- 21294858 TI - A methodological review of resilience measurement scales. AB - BACKGROUND: The evaluation of interventions and policies designed to promote resilience, and research to understand the determinants and associations, require reliable and valid measures to ensure data quality. This paper systematically reviews the psychometric rigour of resilience measurement scales developed for use in general and clinical populations. METHODS: Eight electronic abstract databases and the internet were searched and reference lists of all identified papers were hand searched. The focus was to identify peer reviewed journal articles where resilience was a key focus and/or is assessed. Two authors independently extracted data and performed a quality assessment of the scale psychometric properties. RESULTS: Nineteen resilience measures were reviewed; four of these were refinements of the original measure. All the measures had some missing information regarding the psychometric properties. Overall, the Connor Davidson Resilience Scale, the Resilience Scale for Adults and the Brief Resilience Scale received the best psychometric ratings. The conceptual and theoretical adequacy of a number of the scales was questionable. CONCLUSION: We found no current 'gold standard' amongst 15 measures of resilience. A number of the scales are in the early stages of development, and all require further validation work. Given increasing interest in resilience from major international funders, key policy makers and practice, researchers are urged to report relevant validation statistics when using the measures. PMID- 21294859 TI - Independent component and pathway-based analysis of miRNA-regulated gene expression in a model of type 1 diabetes. AB - BACKGROUND: Several approaches have been developed for miRNA target prediction, including methods that incorporate expression profiling. However the methods are still in need of improvements due to a high false discovery rate. So far, none of the methods have used independent component analysis (ICA). Here, we developed a novel target prediction method based on ICA that incorporates both seed matching and expression profiling of miRNA and mRNA expressions. The method was applied on a cellular model of type 1 diabetes. RESULTS: Microarray profiling identified eight miRNAs (miR-124/128/192/194/204/375/672/708) with differential expression. Applying ICA on the mRNA profiling data revealed five significant independent components (ICs) correlating to the experimental conditions. The five ICs also captured the miRNA expressions by explaining > 97% of their variance. By using ICA, seven of the eight miRNAs showed significant enrichment of sequence predicted targets, compared to only four miRNAs when using simple negative correlation. The ICs were enriched for miRNA targets that function in diabetes relevant pathways e.g. type 1 and type 2 diabetes and maturity onset diabetes of the young (MODY). CONCLUSIONS: In this study, ICA was applied as an attempt to separate the various factors that influence the mRNA expression in order to identify miRNA targets. The results suggest that ICA is better at identifying miRNA targets than negative correlation. Additionally, combining ICA and pathway analysis constitutes a means for prioritizing between the predicted miRNA targets. Applying the method on a model of type 1 diabetes resulted in identification of eight miRNAs that appear to affect pathways of relevance to disease mechanisms in diabetes. PMID- 21294860 TI - An ontology-based nurse call management system (oNCS) with probabilistic priority assessment. AB - BACKGROUND: The current, place-oriented nurse call systems are very static. A patient can only make calls with a button which is fixed to a wall of a room. Moreover, the system does not take into account various factors specific to a situation. In the future, there will be an evolution to a mobile button for each patient so that they can walk around freely and still make calls. The system would become person-oriented and the available context information should be taken into account to assign the correct nurse to a call.The aim of this research is (1) the design of a software platform that supports the transition to mobile and wireless nurse call buttons in hospitals and residential care and (2) the design of a sophisticated nurse call algorithm. This algorithm dynamically adapts to the situation at hand by taking the profile information of staff members and patients into account. Additionally, the priority of a call probabilistically depends on the risk factors, assigned to a patient. METHODS: The ontology-based Nurse Call System (oNCS) was developed as an extension of a Context-Aware Service Platform. An ontology is used to manage the profile information. Rules implement the novel nurse call algorithm that takes all this information into account. Probabilistic reasoning algorithms are designed to determine the priority of a call based on the risk factors of the patient. RESULTS: The oNCS system is evaluated through a prototype implementation and simulations, based on a detailed dataset obtained from Ghent University Hospital. The arrival times of nurses at the location of a call, the workload distribution of calls amongst nurses and the assignment of priorities to calls are compared for the oNCS system and the current, place-oriented nurse call system. Additionally, the performance of the system is discussed. CONCLUSIONS: The execution time of the nurse call algorithm is on average 50.333 ms. Moreover, the oNCS system significantly improves the assignment of nurses to calls. Calls generally have a nurse present faster and the workload-distribution amongst the nurses improves. PMID- 21294861 TI - The MC1R gene in the guppy (Poecilia reticulata): Genotypic and phenotypic polymorphisms. AB - BACKGROUND: The guppy (Poecilia reticulata) is an important model organism for studying sexual selection; male guppies have complex and conspicuous pigmentation, and female guppies exhibit preferences for males with specific color spots. Understanding the genetic basis underlying pigmentation variation in the guppy is important for exploring the factors causing the maintenance of color polymorphism in wild populations. FINDINGS: We focused on the melanic black pigmentation of guppies, and examined genetic variations in the melanocortin 1 receptor (MC1R) gene because variation in this gene is known to contribute to polymorphism of melanin pigmentation in several animal species. The complete coding sequence of the guppy MC1R gene was determined, and two different MC1R alleles (963 and 969 bp) were found in wild populations. Ornamental strain guppies with a 963-bp MC1R tended to show less black pigmentation than those with a 969-bp MC1R, although the association between MC1R genotype and black pigmentation disappeared in the F2 offspring. CONCLUSIONS: The guppy MC1R gene showed variation in the five wild Trinidadian populations we examined, and these populations also differed in terms of allele frequencies. We identified a significant association between black pigmentation and MC1R genotype in fish obtained from aquarium shops. However, the results from F2 families suggest that there are other genes that modify the effects of the MC1R gene. PMID- 21294862 TI - Protective and risk factors in amateur equestrians and description of injury patterns: A retrospective data analysis and a case - control survey. AB - BACKGROUND: In Switzerland there are about 150,000 equestrians. Horse related injuries, including head and spinal injuries, are frequently treated at our level I trauma centre. OBJECTIVES: To analyse injury patterns, protective factors, and risk factors related to horse riding, and to define groups of safer riders and those at greater risk METHODS: We present a retrospective and a case-control survey at conducted a tertiary trauma centre in Bern, Switzerland.Injured equestrians from July 2000 - June 2006 were retrospectively classified by injury pattern and neurological symptoms. Injured equestrians from July-December 2008 were prospectively collected using a questionnaire with 17 variables. The same questionnaire was applied in non-injured controls. Multiple logistic regression was performed, and combined risk factors were calculated using inference trees. RESULTS: RETROSPECTIVE SURVEY: A total of 528 injuries occured in 365 patients. The injury pattern revealed as follows: extremities (32%: upper 17%, lower 15%), head (24%), spine (14%), thorax (9%), face (9%), pelvis (7%) and abdomen (2%). Two injuries were fatal. One case resulted in quadriplegia, one in paraplegia. CASE-CONTROL SURVEY: 61 patients and 102 controls (patients: 72% female, 28% male; controls: 63% female, 37% male) were included. Falls were most frequent (65%), followed by horse kicks (19%) and horse bites (2%). Variables statistically significant for the controls were: Older age (p = 0.015), male gender (p = 0.04) and holding a diploma in horse riding (p = 0.004). Inference trees revealed typical groups less and more likely to suffer injury. CONCLUSIONS: Experience with riding and having passed a diploma in horse riding seem to be protective factors. Educational levels and injury risk should be graded within an educational level-injury risk index. PMID- 21294863 TI - Selective loss of Purkinje cells in a patient with anti-gliadin-antibody-positive autoimmune cerebellar ataxia. AB - The patient was an 84-year-old woman who had the onset of truncal ataxia at age 77 and a history of Basedow's disease. Her ataxic gait gradually deteriorated. She could not walk without support at age 81 and she was admitted to our hospital at age 83. Gaze-evoked nystagmus and dysarthria were observed. Mild ataxia was observed in all limbs. Her deep tendon reflex and sense of position were normal. IgA anti-gliadin antibody, IgG anti-gliadin antibody, anti-SS-A/Ro antibody, anti SS-B/La antibody and anti-TPO antibody were positive. A conventional brain MRI did not show obvious cerebellar atrophy. However, MRI voxel based morphometry (VBM) and SPECT-eZIS revealed cortical cerebellar atrophy and reduced cerebellar blood flow. IVIg treatment was performed and was moderately effective. After her death at age 85, the patient was autopsied. Neuropathological findings were as follows: selective loss of Purkinje cells; no apparent degenerative change in the efferent pathways, such as the dentate nuclei or vestibular nuclei; no prominent inflammatory reaction. From these findings, we diagnosed this case as autoimmune cerebellar atrophy associated with gluten ataxia. All 3 autopsies previously reported on gluten ataxia have noted infiltration of inflammatory cells in the cerebellum.In this case, we postulated that the infiltration of inflammatory cells was not found because the patient's condition was based on humoral immunity. The clinical conditions of gluten ataxia have not yet been properly elucidated, but are expected to be revealed as the number of autopsied cases increases. PMID- 21294864 TI - Dual role of interleukin-17 in pannus growth and osteoclastogenesis in rheumatoid arthritis. AB - INTRODUCTION: In a murine model, interleukin (IL)-17 plays a critical role in the pathogenesis of arthritis. There are controversies, however, regarding whether IL 17 is a proinflammatory mediator in rheumatoid arthritis (RA). We previously established an ex vivo cellular model using synovial tissue (ST)-derived inflammatory cells, which reproduced pannus-like tissue growth and osteoclastic activity in vitro. Using this model, we investigated the effects of IL-17 on pannus growth and osteoclastogenesis in RA. METHODS: Inflammatory cells that infiltrated synovial tissue from patients with RA were collected without enzyme digestion and designated as ST-derived inflammatory cells. ST-derived inflammatory cells were cultured in the presence or absence of IL-17 or indomethacin, and the morphologic changes were observed for 4 weeks. Cytokines produced in the culture supernatants were measured by using enzyme-linked immunosorbent assay kits. Osteoclastic activity was assessed by the development of resorption pits in calcium phosphate-coated slides. RESULTS: Exogenous addition of IL-17 dramatically enhanced the spontaneous production of IL-6 and prostaglandin E2 (PGE2) by the ST-derived inflammatory cells, while it had no effect on the production of tumor necrosis factor (TNF)-alpha and macrophage colony-stimulating factor (M-CSF). Furthermore, IL-17 did not affect the spontaneous development of pannus-like tissue growth and osteoclastic activity by the ST-derived inflammatory cells. On the other hand, IL-17 enhanced pannus-like tissue growth, the production of TNF-alpha and M-CSF and the development of osteoclastic activity in the presence of indomethacin, an inhibitor of endogenous prostanoid production, while exogenous addition of PGE1 suppressed their activities. CONCLUSIONS: The present study suggests that IL-17 induces negative feedback regulation through the induction of PGE2, while it stimulates proinflammatory pathways such as inflammatory cytokine production, pannus growth and osteoclastogenesis in RA. PMID- 21294865 TI - Diacylglycerol regulates acute hypoxic pulmonary vasoconstriction via TRPC6. AB - BACKGROUND: Hypoxic pulmonary vasoconstriction (HPV) is an essential mechanism of the lung that matches blood perfusion to alveolar ventilation to optimize gas exchange. Recently we have demonstrated that acute but not sustained HPV is critically dependent on the classical transient receptor potential 6 (TRPC6) channel. However, the mechanism of TRPC6 activation during acute HPV remains elusive. We hypothesize that a diacylglycerol (DAG)-dependent activation of TRPC6 regulates acute HPV. METHODS: We investigated the effect of the DAG analog 1 oleoyl-2-acetyl-sn-glycerol (OAG) on normoxic vascular tone in isolated perfused and ventilated mouse lungs from TRPC6-deficient and wild-type mice. Moreover, the effects of OAG, the DAG kinase inhibitor R59949 and the phospholipase C inhibitor U73122 on the strength of HPV were investigated compared to those on non-hypoxia induced vasoconstriction elicited by the thromboxane mimeticum U46619. RESULTS: OAG increased normoxic vascular tone in lungs from wild-type mice, but not in lungs from TRPC6-deficient mice. Under conditions of repetitive hypoxic ventilation, OAG as well as R59949 dose-dependently attenuated the strength of acute HPV whereas U46619-induced vasoconstrictions were not reduced. Like OAG, R59949 mimicked HPV, since it induced a dose-dependent vasoconstriction during normoxic ventilation. In contrast, U73122, a blocker of DAG synthesis, inhibited acute HPV whereas U73343, the inactive form of U73122, had no effect on HPV. CONCLUSION: These findings support the conclusion that the TRPC6-dependency of acute HPV is induced via DAG. PMID- 21294866 TI - Detrimental effect of cardiopulmonary bypass (CPB) on malignant disease. AB - Patients with coronary artery disease associated with malignancy are a difficult group of patients to treat. The ideal approach to manage them is still controversial. Both problems can be manage by either a combined or staged operation. The use of CPB during revascularization of the myocardium among patients with malignant disease, may have an effect on dissimination of malignant cells. This was observed among two of our patients. We believe that the use of off-pump technique to revascularize the myocardium is a safe approach and can be performed either in combined or staged surgery to resect malignant disease. PMID- 21294867 TI - Early changes in inflammatory and pro-thrombotic biomarkers in patients initiating antiretroviral therapy with abacavir or tenofovir. AB - BACKGROUND: Abacavir has been associated with an increased risk of acute myocardial infarction, but the pathogenic mechanisms remain unknown. We evaluated longitudinal changes in pro-atherosclerotic biomarkers in patients initiating abacavir or tenofovir. METHODS: Consecutive patients initiating antiretroviral therapy (ART) with abacavir/lamivudine or tenofovir/emtricitabine were included. Plasma levels of high sensitivity C reactive protein (hsCRP), interleukin-6 (IL 6), intercellular adhesion molecule-1, vascular cell adhesion molecule-1 (sVCAM 1) and plasminogen activator inhibitor-1 (PAI-1) were measured at baseline and at different time points throughout 48 weeks. Comparisons were adjusted for age, sex, ART status at inclusion, viral load, lipodystrophy, Framingham score and hepatitis C virus co-infection status. RESULTS: 50 patients were analyzed, 28 initiating abacavir and 22 tenofovir. The endothelial biomarker sVCAM-1 declined significantly in both treatment groups. hsCRP tended to increase soon after starting therapy with abacavir, a trend that was not seen in those initiating tenofovir. IL-6 significantly increased only at week 24 from baseline in patients on abacavir (+225%, p < 0.01) although the differences were not significant between groups. The procoagulant biomarker PAI-1 plasma levels increased from baseline at week 12 (+57%; p = 0.017), week 24 (+72%; p = 0.008), and week 48 (+149%; p < 0.001) in patients on tenofovir, but differences between groups were not statistically significant. CONCLUSION: Changes in biomarkers of inflammation, coagulation, and endothelial function are not different in viremic patients starting ART with abacavir/lamivudine or tenofovir/emtricitabine. These changes occur in the early phases of treatment and include anti- and pro-atherosclerotic effects with both drugs. PMID- 21294868 TI - Severe male infertility after failed ICSI treatment--a phenomenological study of men's experiences. AB - BACKGROUND: Male-factor infertility underlies approximately 30% of infertility in couples seeking treatment; of which 10% is due to azoospermia. The development of assisted reproductive technology (ART), enabling the use of epididymal or testicular sperm for fertilization of the partner's oocytes, has made biological fatherhood possible for men with obstructive azoospermia. There is limited knowledge of men's experience of their own infertility. The aim of this study was to describe men's experiences of obstructive azoospermia infertility. METHODS: Eight men with obstructive azoospermia, who had terminated Swedish public health system ART treatment two years previously without subsequent childbirth, were interviewed using a descriptive phenomenological method. RESULTS: The essence of the phenomenon is expressed with a metaphor: climbing a mountain step by step with the aim of reaching the top, i.e. having a child and thus a family with a child. Four constituents are included (1) inadequacy followed by a feeling of redress (2) marginalisation, (3) chivalry (4) extension of life and starting a family as driving forces. CONCLUSIONS: Knowledge of men's experiences of their own infertility is important as a supporting measure to increase the quality of care of infertile couples. By adopting this facet of gender perspective in fertility treatment guidelines, care can hopefully be optimized. PMID- 21294870 TI - Evaluation of four novel genetic variants affecting hemoglobin A1c levels in a population-based type 2 diabetes cohort (the HUNT2 study). AB - BACKGROUND: Chronic hyperglycemia confers increased risk for long-term diabetes associated complications and repeated hemoglobin A1c (HbA1c) measures are a widely used marker for glycemic control in diabetes treatment and follow-up. A recent genome-wide association study revealed four genetic loci, which were associated with HbA1c levels in adults with type 1 diabetes. We aimed to evaluate the effect of these loci on glycemic control in type 2 diabetes. METHODS: We genotyped 1,486 subjects with type 2 diabetes from a Norwegian population-based cohort (HUNT2) for single-nucleotide polymorphisms (SNPs) located near the BNC2, SORCS1, GSC and WDR72 loci. Through regression models, we examined their effects on HbA1c and non-fasting glucose levels individually and in a combined genetic score model. RESULTS: No significant associations with HbA1c or glucose levels were found for the SORCS1, BNC2, GSC or WDR72 variants (all P-values > 0.05). Although the observed effects were non-significant and of much smaller magnitude than previously reported in type 1 diabetes, the SORCS1 risk variant showed a direction consistent with increased HbA1c and glucose levels, with an observed effect of 0.11% (P = 0.13) and 0.13 mmol/l (P = 0.43) increase per risk allele for HbA1c and glucose, respectively. In contrast, the WDR72 risk variant showed a borderline association with reduced HbA1c levels (beta = -0.21, P = 0.06), and direction consistent with decreased glucose levels (beta = -0.29, P = 0.29). The allele count model gave no evidence for a relationship between increasing number of risk alleles and increasing HbA1c levels (beta = 0.04, P = 0.38). CONCLUSIONS: The four recently reported SNPs affecting glycemic control in type 1 diabetes had no apparent effect on HbA1c in type 2 diabetes individually or by using a combined genetic score model. However, for the SORCS1 SNP, our findings do not rule out a possible relationship with HbA1c levels. Hence, further studies in other populations are needed to elucidate whether these novel sequence variants, especially rs1358030 near the SORCS1 locus, affect glycemic control in type 2 diabetes. PMID- 21294869 TI - The effects of the HEALTHY study intervention on middle school student dietary intakes. AB - BACKGROUND: The HEALTHY study was designed to respond to the alarming trends in increasing rates of overweight, obesity, and type 2 diabetes mellitus in youth. The objective of this analysis was to examine the effects of the HEALTHY study on student self-reported dietary intakes (energy, macronutrients and grams consumed of selected food groups). METHODS: HEALTHY was a cluster-randomized study in 42 public middle schools. Students, n=3908, self-reported dietary intake using the Block Kids Questionnaire. General linear mixed models were used to analyze differences in dietary intake at the end of the study between intervention and control schools. RESULTS: The reported average daily fruit consumption was 10% higher at the end of the study in the intervention schools than in the control schools (138 g or approximately 2 servings versus 122 g, respectively, p=0.0016). The reported water intake was approximately 2 fluid ounces higher in the intervention schools than in the control (483 g versus 429 g respectively; p=0.008). There were no significant differences between intervention and control for mean intakes of energy, macronutrients, fiber, grains, vegetables, legumes, sweets, sweetened beverages, and higher- or lower-fat milk consumption. CONCLUSION: The HEALTHY study, a five-semester middle school-based intervention program that integrated multiple components in nutrition, physical education, behavior change, and social marketing-based communications, resulted in significant changes to student's reported fruit and water intake. Subsequent interventions need to go beyond the school environment to change diet behaviors that may affect weight status of children. PMID- 21294871 TI - Prevalence and progression of visual impairment in patients newly diagnosed with clinical type 2 diabetes: a 6-year follow up study. AB - BACKGROUND: Many diabetic patients fear visual loss as the worst consequence of diabetes. In most studies the main eye pathology is assigned as the cause of visual impairment. This study analysed a broad range of possible ocular and non ocular predictors of visual impairment prospectively in patients newly diagnosed with clinical type 2 diabetes. METHODS: Data were from a population-based cohort of 1,241 persons newly diagnosed with clinical, often symptomatic type 2 diabetes aged >= 40 years. After 6 years, 807 patients were followed up. Standard eye examinations were done by practising ophthalmologists. RESULTS: At diabetes diagnosis median age was 65.5 years. Over 6 years, the prevalence of blindness (visual acuity of best seeing eye <= 0.1) rose from 0.9% (11/1,241) to 2.4% (19/807) and the prevalence of moderate visual impairment (> 0.1; < 0.5) rose from 5.4% (67/1,241) to 6.7% (54/807). The incidence (95% confidence interval) of blindness was 40.2 (25.3-63.8) per 10,000 patient-years. Baseline predictors of level of visual acuity (age, age-related macular degeneration (AMD), cataract, living alone, low self-rated health, and sedentary life-style) and speed of continued visual loss (age, AMD, diabetic retinopathy (DR), cataract, living alone, and high fasting triglycerides) were identified. CONCLUSIONS: In a comprehensive assessment of predictors of visual impairment, even in a health care system allowing self-referral to free eye examinations, treatable eye pathologies such as DR and cataract emerge together with age as the most notable predictors of continued visual loss after diabetes diagnosis. Our results underline the importance of eliminating barriers to efficient eye care by increasing patients' and primary care practitioners' awareness of the necessity of regular eye examinations and timely surgical treatment. PMID- 21294872 TI - The elicitation of a systemic resistance by Pseudomonas putida BTP1 in tomato involves the stimulation of two lipoxygenase isoforms. AB - BACKGROUND: Some non-pathogenic rhizobacteria called Plant Growth Promoting Rhizobacteria (PGPR) possess the capacity to induce in plant defense mechanisms effective against pathogens. Precedent studies showed the ability of Pseudomonas putida BTP1 to induce PGPR-mediated resistance, termed ISR (Induced Systemic Resistance), in different plant species. Despite extensive works, molecular defense mechanisms involved in ISR are less well understood that in the case of pathogen induced systemic acquired resistance. RESULTS: We analyzed the activities of phenylalanine ammonia-lyase (PAL) and lipoxygenase (LOX), key enzymes of the phenylpropanoid and oxylipin pathways respectively, in tomato treated or not with P. putida BTP1. The bacterial treatment did not stimulate PAL activity and linoleate-consuming LOX activities. Linolenate-consuming LOX activity, on the contrary, was significantly stimulated in P. putida BTP1 inoculated plants before and two days after infection by B. cinerea. This stimulation is due to the increase of transcription level of two isoforms of LOX: TomLoxD and TomLoxF, a newly identified LOX gene. We showed that recombinant TomLOXF preferentially consumes linolenic acid and produces 13-derivative of fatty acids. After challenging with B. cinerea, the increase of transcription of these two LOX genes and higher linolenic acid-consuming LOX activity were associated with a more rapid accumulation of free 13-hydroperoxy-octadecatrienoic and 13-hydroxy-octadecatrienoic acids, two antifungal oxylipins, in bacterized plants. CONCLUSION: In addition to the discovery of a new LOX gene in tomato, this work is the first to show differential induction of LOX isozymes and a more rapid accumulation of 13-hydroperoxy-octadecatrienoic and 13-hydroxy octadecatrienoic acids in rhizobacteria mediated-induced systemic resistance. PMID- 21294873 TI - Urban-rural inequities in knowledge, attitudes and practices regarding tuberculosis in two districts of Pakistan's Punjab province. AB - OBJECTIVE: The aim of this study was to explore inequities in knowledge, attitudes and practices regarding tuberculosis (TB) among the urban and rural populations. DESIGN: A cross-sectional study was conducted in two districts of Pakistan's Punjab province. The 1080 subjects aged 20 years and above, including 432 urban and 648 rural respondents, were randomly selected using multistage cluster sampling and interviewed after taking verbal informed consent. Logistic regression was used to calculate the crude odds ratio (OR) with 95% confidence interval (CI) for the urban area. The differences in knowledge, attitudes, practices and information sources between the urban and rural respondents were highlighted using Pearson chi-square test and Fisher's exact test. RESULTS: The study revealed poor knowledge regarding TB. The deficit was greater in the rural areas in all aspects. The knowledge regarding symptoms (OR 2.03, 95% CI 1.59 2.61), transmission (OR 1.93, 95% CI 1.44-2.59), prevention (OR 2.24, 95% CI 1.70 2.96), duration of standard treatment (OR 1.88, 95% 1.41-2.49) and DOTS (OR 1.84, 95% CI 1.43-2.38) was significantly higher in the urban areas (all P < 0.001). Although a majority of the subjects (urban 83.8%, rural 81.2%) were aware of the correct treatment for TB, less than half (urban 48.1%, rural 49.2%) were aware of the availability of the diagnostic facility and treatment free of cost. The practice of seeking treatment at a health facility (P = 0.030; OR 2.01, 95% CI 1.06-3.82), as soon as they realized that they had TB symptoms (P < 0.001; OR 1.72, 95% CI 1.26-2.35), was significantly higher in the urban areas. People in the urban areas were more likely to feel ashamed and embarrassed being a TB patient (P < 0.001; OR 2.03, 95% CI 1.50-2.76); however, they seem to be supportive in case their family member suffered from TB (P = 0.005; OR 1.53, 95% CI 1.13-2.06). Nearly half of the respondents, irrespective of the area of residence, believed that the community rejects the TB patient (urban 49.8%, rural 46.4%). Television (urban 80.1%, rural 68.1%) and health workers (urban 30.6%, rural 41.4%) were the main sources for people to acquire the TB related information. CONCLUSION: Respondents' knowledge regarding TB was deficient in all aspects, particularly in the rural areas. Intended health seeking behavior was better in the urban areas. Television and health workers were the main sources for TB related information in both the urban as well as the rural areas. Therefore, the area of residence should be considered in tailoring communication strategies and designing future interventions for TB prevention and control. PMID- 21294874 TI - Diagnostic implications of soluble triggering receptor expressed on myeloid cells 1 in patients with acute respiratory distress syndrome and abdominal diseases: a preliminary observational study. AB - INTRODUCTION: Patients admitted to the intensive care unit (ICU) because of acute or decompensated chronic abdominal disease and acute respiratory failure need to have the potential infection diagnosed as well as its site (pulmonary or abdominal). For this purpose, we measured soluble triggering receptor expression on myeloid cells-1 (sTREM-1) in alveolar and peritoneal fluid. METHODS: Consecutive patients (n = 21) with acute or decompensated chronic abdominal disease and acute respiratory failure were included. sTREM was measured in alveolar (A-sTREM) and peritoneal (P-sTREM) fluids. RESULTS: An infection was diagnosed in all patients. Nine patients had a lung infection (without abdominal infection), 5 had an abdominal infection (without lung infection) and seven had both infections. A-sTREM was higher in the patients with pneumonia compared to those without pneumonia (1963 ng/ml (1010-3129) vs. 862 ng/ml (333-1011); P 0.019). Patients with abdominal infection had an increase in the P-sTREM compared to patients without abdominal infection (1941 ng/ml (1088-3370) vs. 305 ng/ml (288-459); P < 0.001). A cut-off point of 900 pg/ml of A-sTREM-1 had a sensitivity of 81% and a specificity of 80% (NPV 57%; PPV 93%, AUC 0.775) for the diagnosis of pneumonia. In abdominal infections, a cut-off point for P-sTREM of 900 pg/ml had the best results (sensitivity 92%; specificity 100%; NPV 90%, PPV 100%, AUC = 0.903). CONCLUSIONS: sTREM-1 measured in alveolar and peritoneal fluids is useful in assessing pulmonary and peritoneal infection in critical state patients-A-sTREM having the capacity to discriminate between a pulmonary and an extra-pulmonary infection in the context of acute respiratory failure. PMID- 21294875 TI - The use of some nanoemulsions based on aqueous propolis and lycopene extract in the skin's protective mechanisms against UVA radiation. AB - BACKGROUND: The use of natural products based on aqueous extract of propolis and lycopene in the skin's protective mechanisms against UVA radiation was evaluated by means of experimental acute inflammation on rat paw edema. The aim of the present study was to evaluate the harmlessness of propolis - lycopene system through evaluation of skin level changes and anti-inflammatory action. The regenerative and protective effect of the aqueous propolis and lycopene extract is based on its richness in biologically active substances such as: tocopherols, flavonoids, amino acids, polyunsaturated fatty acids, the chlorophyll pigment, all substances with strong antioxidant activity, that modify the oxidative stress, mainly by reducing the prooxidant processes and enhancing the antioxidant ones. These substances participate in the synthesis of prostaglandins and phospholipids components of cell membrane thus enhancing skin protection mechanisms. RESULTS: The experimental systems offered a sustained release of the drug, in vitro, for aim eight hours. The prepared formulations aim did not reveal a deteriorating effect on tissues. They proved a better therapeutic efficiency Compared to standard suspension, they provided a better therapeutic efficiency coupled with extended time interval of tested parameters (24 hours). Preliminary examination of tissues showed that the experimental formulations did not irritate. Local application of propolis and lycopene aqueous extract nanoemulsion has a high potential both regarding its efficiency (the analgesic effect) and therapeutic safety. CONCLUSIONS: This study demonstrates that propolis and lycopene extract nanoemulsions, preparations contains active substances, can confer better therapeutic effects than those of the conventional formulations, based on local control-release of dozed form, for a longer period of time, which probably improve its efficiency and skin acceptance, meaning a better compliance. The information obtained in the present study suggests that administration of propolis and lycopene aqueous extract nanoemulsion is safe. The preparation can be useful for further preclinical studies lycopene embedded in aqueous propolis extract to be used in pharmaceuticals (targeted medical therapy). PMID- 21294876 TI - Chain of care for patients who have attempted suicide: a follow-up study from Baerum, Norway. AB - BACKGROUND: Individuals who have attempted suicide are at increased risk of subsequent suicidal behavior. Since 1983, a community-based suicide prevention team has been operating in the municipality of Baerum, Norway. This study aimed to test the effectiveness of the team's interventions in preventing repeated suicide attempts and suicide deaths, as part of a chain of care model for all general hospital treated suicide attempters. METHODS: Data has been collected consecutively since 1984 and a follow-up was conducted on all individuals admitted to the general hospital after a suicide attempt. The risk of repeated suicide attempt and suicide were comparatively examined in subjects who received assistance from the suicide prevention team in addition to treatment as usual versus those who received treatment as usual only. Logistic regression and Cox regression were used to analyze the data. RESULTS: Between January 1984 and December 2007, 1,616 subjects were registered as having attempted suicide; 197 of them (12%) made another attempt within 12 months. Compared to subjects who did not receive assistance from the suicide prevention team, individuals involved in the prevention program did not have a significantly different risk of repeated attempt within 6 months (adjusted OR = 1.08; 95% CI = 0.66-1.74), 12 months (adjusted OR = 0.86; 95% CI = 0.57-1.30), or 5 years (adjusted RR = 0.90; 95% CI = 0.67-1.22) after their first recorded attempt. There was also no difference in risk of suicide (adjusted RR = 0.85; 95% CI = 0.46-1.57). Previous suicide attempts, marital status, and employment status were significantly associated with a repeated suicide attempt within 6 and 12 months (p < 0.05). Alcohol misuse, employment status, and previous suicide attempts were significantly associated with a repeated attempt within 5 years (p < 0.05) while marital status became non-significant (p > 0.05). With each year of age, the risk of suicide increased by 3% (p < 0.05). CONCLUSIONS: The present study did not find any differences in the risk of fatal and non-fatal suicidal behavior between subjects who received treatment as usual combined with community assistance versus subjects who received only treatment as usual. However, assistance from the community team was mainly offered to attempters who were not receiving sufficient support from treatment as usual and was accepted by 50-60% of those deemed eligible. Thus, obtaining similar outcomes for individuals, all of whom were clinically judged to have different needs, could in itself be considered a desirable result. PMID- 21294877 TI - Evidence for regulatory diversity and auto-regulation at the TAC1 locus in sensory neurones. AB - The neuropeptide substance-P (SP) is expressed from the TAC1 gene in sensory neurones where it acts as a key modulator of neurogenic inflammation. The promoter of TAC1 (TAC1prom) plays a central role in the regulation of the TAC1 gene but requires the presence of a second regulatory element; ECR2, to support TAC1 expression in sensory neurones and to respond appropriately to signalling pathways such as MAPkinases and noxious induction by capsaicin. We examined whether the effect of capsaicin on ECR2-TAC1prom activity in larger diameter neurones was cell autonomous or non- cell autonomous. We demonstrate that TRPV1 is not expressed in all the same cells as SP following capsaicin induction suggesting the presence of a non-cell autonomous mechanism for TAC1 up-regulation following capsaicin induction. In addition, we demonstrate that induction of SP and ECR1-TAC1prom activity in these larger diameter neurones can be induced by potassium depolarisation suggesting that, in addition to capsaicin induction, transgene activity may be modulated by voltage gated calcium channels. Furthermore, we show that NK1 is expressed in all SP- expressing cells after capsaicin induction and that an agonist of NK1 can activate both SP and the transgene in larger diameter neurones. These observations suggest the presence of an autocrine loop that controls the expression of the TAC1 promoter in sensory neurones. In contrast, induction of the TAC1 promoter by LPS was not dependent on ECR2 and did not occur in large diameter neurones. These studies demonstrate the diversity of mechanisms modulating the activity of the TAC1 promoter and provide novel directions for the development of new anti-inflammatory therapies. PMID- 21294878 TI - Clinical value of SPECT/CT for evaluation of patients with painful knees after total knee arthroplasty--a new dimension of diagnostics? AB - BACKGROUND: The purpose of our study was to evaluate the clinical value of hybrid SPECT/CT for the assessment of patients with painful total knee arthroplasty (TKA). METHODS: Twenty-three painful knees in patients following primary TKA were assessed using Tc-99m-HDP-SPECT/CT. Rotational, sagittal and coronal position of the TKA was assessed on 3D-CT reconstructions. The level of the SPECT-tracer uptake (0-10) and its anatomical distribution was mapped using a validated localization scheme. Univariate analysis (Wilcoxon-Mann-Whitney, Spearmean's-rho test, p < 0.05) was performed to identify any correlations between component position, tracer uptake and diagnosis. RESULTS: SPECT/CT imaging changed the suspected diagnosis and the proposed treatment in 19/23 (83%) knees. Progression of patellofemoral OA (n = 11), loosening of the tibial (n = 3) and loosening of the femoral component (n = 2) were identified as the leading causes of pain after TKA.Patients with externally rotated tibial trays showed higher tracer uptake in the medial patellar facet (p = 0.049) and in the femur (p = 0.051). Patients with knee pain due to patellofemoral OA showed significantly higher tracer uptake in the patella than others (p < 0.001). CONCLUSIONS: SPECT/CT was very helpful in establishing the diagnosis and guiding subsequent management in patients with painful knees after TKA, particularly in patients with patellofemoral problems and malpositioned or loose TKA. PMID- 21294879 TI - Towards classifying species in systems biology papers using text mining. AB - BACKGROUND: In recent years high throughput methods have led to a massive expansion in the free text literature on molecular biology. Automated text mining has developed as an application technology for formalizing this wealth of published results into structured database entries. However, database curation as a task is still largely done by hand, and although there have been many studies on automated approaches, problems remain in how to classify documents into top level categories based on the type of organism being investigated. Here we present a comparative analysis of state of the art supervised models that are used to classify both abstracts and full text articles for three model organisms. RESULTS: Ablation experiments were conducted on a large gold standard corpus of 10,000 abstracts and full papers containing data on three model organisms (fly, mouse and yeast). Among the eight learner models tested, the best model achieved an F-score of 97.1% for fly, 88.6% for mouse and 85.5% for yeast using a variety of features that included gene name, organism frequency, MeSH headings and term species associations. We noted that term-species associations were particularly effective in improving classification performance. The benefit of using full text articles over abstracts was consistently observed across all three organisms. CONCLUSIONS: By comparing various learner algorithms and features we presented an optimized system that automatically detects the major focus organism in full text articles for fly, mouse and yeast. We believe the method will be extensible to other organism types. PMID- 21294880 TI - Effect of chemokine receptor CXCR4 on hypoxia-induced pulmonary hypertension and vascular remodeling in rats. AB - BACKGROUND: CXCR4 is the receptor for chemokine CXCL12 and reportedly plays an important role in systemic vascular repair and remodeling, but the role of CXCR4 in development of pulmonary hypertension and vascular remodeling has not been fully understood. METHODS: In this study we investigated the role of CXCR4 in the development of pulmonary hypertension and vascular remodeling by using a CXCR4 inhibitor AMD3100 and by electroporation of CXCR4 shRNA into bone marrow cells and then transplantation of the bone marrow cells into rats. RESULTS: We found that the CXCR4 inhibitor significantly decreased chronic hypoxia-induced pulmonary hypertension and vascular remodeling in rats and, most importantly, we found that the rats that were transplanted with the bone marrow cells electroporated with CXCR4 shRNA had significantly lower mean pulmonary pressure (mPAP), ratio of right ventricular weight to left ventricular plus septal weight (RV/(LV+S)) and wall thickness of pulmonary artery induced by chronic hypoxia as compared with control rats. CONCLUSIONS: The hypothesis that CXCR4 is critical in hypoxic pulmonary hypertension in rats has been demonstrated. The present study not only has shown an inhibitory effect caused by systemic inhibition of CXCR4 activity on pulmonary hypertension, but more importantly also has revealed that specific inhibition of the CXCR4 in bone marrow cells can reduce pulmonary hypertension and vascular remodeling via decreasing bone marrow derived cell recruitment to the lung in hypoxia. This study suggests a novel therapeutic approach for pulmonary hypertension by inhibiting bone marrow derived cell recruitment. PMID- 21294881 TI - International Conference on Advances in Radiation Oncology (ICARO): outcomes of an IAEA meeting. AB - The IAEA held the International Conference on Advances in Radiation Oncology (ICARO) in Vienna on 27-29 April 2009. The Conference dealt with the issues and requirements posed by the transition from conventional radiotherapy to advanced modern technologies, including staffing, training, treatment planning and delivery, quality assurance (QA) and the optimal use of available resources. The current role of advanced technologies (defined as 3-dimensional and/or image guided treatment with photons or particles) in current clinical practice and future scenarios were discussed.ICARO was organized by the IAEA at the request of the Member States and co-sponsored and supported by other international organizations to assess advances in technologies in radiation oncology in the face of economic challenges that most countries confront. Participants submitted research contributions, which were reviewed by a scientific committee and presented via 46 lectures and 103 posters. There were 327 participants from 70 Member States as well as participants from industry and government. The ICARO meeting provided an independent forum for the interaction of participants from developed and developing countries on current and developing issues related to radiation oncology. PMID- 21294882 TI - Supporting work practices through telehealth: impact on nurses in peripheral regions. AB - BACKGROUND: In Canada, workforce shortages in the health care sector constrain the ability of the health care system to meet the needs of its population and of its health care professionals. This issue is of particular importance in peripheral regions of Quebec, where significant inequalities in workforce distribution between regions has lead to acute nursing shortages and increased workloads. Information and communication technologies (ICTs) are innovative solutions that can be used to develop strategies to optimise the use of available resources and to design new nursing work practices. However, current knowledge is still limited about the real impact of ICTs on nursing recruitment and retention. Our aim is to better understand how work practice reorganization, supported by ICTs, and particularly by telehealth, may influence professional, educational, and organizational factors relating to Quebec nurses, notably those working in peripheral regions. METHODS/DESIGN: First, we will conduct a descriptive study on the issue of nursing recruitment. Stratified sampling will be used to select approximately twenty innovative projects relating to the reorganization of work practices based upon ICTs. Semi-structured interviews with key informants will determine professional, educational, and organizational recruitment factors. The results will be used to create a questionnaire which, using a convenience sampling method, will be mailed to 600 third year students and recent graduates of two Quebec university nursing faculties. Descriptive, correlation, and hierarchical regression analyses will be performed to identify factors influencing nursing graduates' intentions to practice in peripheral regions. Secondly, we will conduct five case studies pertaining to the issue of nursing retention. Five ICT projects in semi-urban, rural, and isolated regions have been identified. Qualitative data will be collected through field observation and approximately fifty semi-structured interviews with key stakeholders. DISCUSSION: Data from both parts of this research project will be jointly analysed using triangulation of researchers, theoretical approaches, methods, and results. Continuous exchanges with decision makers and periodic knowledge transfer activities are planned to facilitate the dissemination and utilization of research results in policies regarding the nursing recruitment and retention. PMID- 21294883 TI - Primary malignant mixed mullerian tumor of the peritoneum a case report with review of the literature. AB - Malignant mixed Mullerian tumor is a rare malignancy of the genital tract and extremely uncommon in extragenital sites. This report describes a case of malignant mixed Mullerian tumor arising in the lower peritoneum of a 72-year-old female patient. The patient presented with ascites, lower abdominal mass and pleural effusion. The serum level of CA125 was elevated. At operation a diffuse carcinosis associated with tumor mass measuring 20 * 15 * 10 cm in the vesicouterine and Duglas' pouch were found. The uterus and the adnexa were unremarkable. Histopathology revealed a typical malignant mixed Mullerian tumor, heterologous type. The epithelial component was positive for cytokeratin 7 and vimentin whereas the mesenchymal component was positive for Vimentin, S100 and focally for CK7. The histogenesis of this tumor arising from the peritoneum is still speculative. Based on the previous reports and the immunohistochemical analysis of our case, we believe that this is a monoclonal tumor with carcinoma being the "precursor" element. Nevertheless, further molecular and genetic evidence is needed to support such a conclusion. PMID- 21294884 TI - Influence of climate and river level on the incidence of malaria in Cacao, French Guiana. AB - BACKGROUND: The epidemiological profiles of vector-borne diseases, such as malaria, are strongly associated with environmental conditions. An understanding of the effect of the climate on the occurrence of malaria may provide indirect insight into the anopheles mosquito vectors endemic to a particular region. The association between meteorological and hydrographical factors and the occurrence of malaria was studied in a village in French Guiana during an epidemic caused essentially by Plasmodium vivax. METHODS: A cohort of confirmed cases of P. vivax malaria occurring between 2002 and 2007 was studied to search for an association between the number of new infection episodes occurring each month, mean, maximum and minimum monthly temperatures, cumulative rainfall for the month and the mean monthly height of the river bordering the village, with the aid of time series. Cross-correlation analysis revealed that these meteorological factors had large effects on the number of episodes, over a study period of 12 months. RESULTS: Climatic factors supporting the continuance of the epidemic were identified in the short-term (low minimum temperatures during the month), medium-term (low maximum temperatures two months before) and long-term (low maximum temperatures nine months before and high lowest level of the river 12 months before). Cross correlation analysis showed that the effects of these factors were greatest at the beginning of the short rainy season. CONCLUSION: The association between the river level and the number of malaria attacks provides clues to better understand the environment of malaria transmission and the ecological characteristics of the vectors in the region. PMID- 21294885 TI - Vaccination with human anti-trastuzumab anti-idiotype scFv reverses HER2 immunological tolerance and induces tumor immunity in MMTV.f.huHER2(Fo5) mice. AB - INTRODUCTION: Novel adjuvant therapies are needed to prevent metastatic relapses in HER2-expressing breast cancer. Here, we tested whether trastuzumab-selected single-chain Fv (scFv) could be used to develop an anti-idiotype-based vaccine to inhibit growth of HER2-positive tumor cells in vitro and in vivo through induction of long-lasting HER-specific immunity. METHODS: BALB/c mice were immunized with anti-trastuzumab anti-idiotype (anti-Id) scFv (scFv40 and scFv69), which mimic human HER2. Their sera were assessed for the presence of HER2 specific Ab1' antibodies and for their ability to reduce viability of SK-OV-3 cells, a HER2-positive cancer cell line, in nude mice. MMTV.f.huHER2(Fo5) transgenic mice were immunized with scFv40 and scFv69 and, then, growth inhibition of spontaneous HER2-positive mammary tumors, humoral response, antibody isotype as well as splenocyte secretion of IL2 and IFN-gamma were evaluated. RESULTS: Adoptively-transferred sera from BALB/c mice immunized with scFv40 and scFv69 contain anti-HER2 Ab1' antibodies that can efficiently inhibit growth of SK-OV-3 cell tumors in nude mice. Similarly, prophylactic vaccination with anti-Id scFv69 fully protects virgin or primiparous FVB-MMTV.f.huHER2(Fo5) females from developing spontaneous mammary tumors. Moreover, such vaccination elicits an anti-HER2 Ab1' immune response together with a scFv69-specific Th1 response with IL2 and IFN-gamma cytokine secretion. CONCLUSIONS: Anti-trastuzumab anti-Id scFv69, used as a therapeutic or prophylactic vaccine, protects mice from developing HER2-positive mammary tumors by inducing both anti-HER2 Ab1' antibody production and an anti-HER2 Th2-dependent immune response. These results suggest that scFv69 could be used as an anti-Id-based vaccine for adjuvant therapy of patients with HER2-positive tumors to reverse immunological tolerance to HER2. PMID- 21294886 TI - Correlation of the ratio of metastatic to non-metastatic cancer cases with the degree of socioeconomic deprivation among Texas counties. AB - BACKGROUND: Previous studies have demonstrated that cancer registrations and hospital discharge rate are closely correlated with census data-based socioeconomic deprivation indices. We hypothesized that communities with higher degrees of socioeconomic deprivation tend to have a higher ratio of metastatic to non-metastatic cancer cases (lung, breast, prostate, female genital system, colorectal cancers or all types of cancers combined). In this study, we investigate the potential link between this ratio and the Wellbeing Index (WI) among Texas counties. RESULTS: Cancer data in 2000 were provided by the Texas Cancer Registry, while data on the ten socioeconomic variables among the 254 Texas counties in 2000 for building the WI were obtained from U.S. Census Bureau. The ten socioeconomic status variables were subjected to the principal component analysis, and the first principal component scores were grouped into deciles for the WI (1 to 10) and the 254 Texas counties were classified into 10 corresponding groups. Weighted linear regression analyses and a Cochran-Armitage trend test were performed to determine the relationship between the ratio of age-adjusted metastatic to non-metastatic cancer incidence cases and WI. The ratios of metastatic to non-metastatic cases of female genital system cancer (r2 = 0.84, p = 0.0002), all-type cancers (r2= 0.73, p = 0.0017) and lung cancer (r2= 0.54, p = 0.0156) at diagnosis were positively correlated with WI. CONCLUSIONS: The ratios of metastatic to non-metastatic cases of all-type, female genital system and lung cancers at diagnosis were statistically correlated with socioeconomic deprivation. Potential mediators for the correlation warrant further investigation in order to reduce health disparities associated with socioeconomic inequality. PMID- 21294887 TI - Effects of Methylphenidate on performance of a practical pistol shooting task: a quantitative electroencephalography (qEEG) study. AB - BACKGROUND: The present study examined absolute alpha power using quantitative electroencephalogram (qEEG) in bilateral temporal and parietal cortices in novice soldiers under the influence of methylphenidate (MPH) during the preparatory aiming period in a practical pistol-shooting task. We anticipated higher bi hemispheric cortical activation in the preparatory period relative to pre-shot baseline in the methylphenidate group when compared with the control group because methylphenidate has been shown to enhance task-related cognitive functions. METHODS: Twenty healthy, novice soldiers were equally distributed in control (CG; n = 10) and MPH groups 10 mg (MG; n = 10) using a randomized, double blind design. Subjects performed a pistol-shooting task while electroencephalographic activity was acquired. RESULTS: We found main effects for group and practice blocks on behavioral measures, and interactions between group and phases on electroencephalographic measures for the electrodes T3, T4, P3 and P4. Regarding the behavioral measures, the MPH group demonstrated significantly poorer in shooting performance when compared with the control and, in addition, significant increases in the scores over practice blocks were found on both groups. In addition, regarding the electroencephalographic data, we observed a significant increase in alpha power over practice blocks, but alpha power was significantly lower for the MPH group when compared with the placebo group. Moreover, we observed a significant decrease in alpha power in electrodes T4 and P4 during PTM. CONCLUSION: Although we found no correlation between behavioral and EEG data, our findings show that MPH did not prevent the learning of the task in healthy subjects. However, during the practice blocks (PBs) it also did not favor the performance when compared with control group performance. It seems that the CNS effects of MPH demanded an initial readjustment period of integrated operations relative to the sensorimotor system. In other words, MPH seems to provoke a period of initial instability due to a possible modulation in neural activity, which can be explained by lower levels of alpha power (i.e., higher cortical activity). However, after the end of the PB1 a new stabilization was established in neural circuits, due to repetition of the task, resulting higher cortical activity during the task. In conclusion, MPH group performance was not initially superior to that of the control group, but eventually exceeded it, albeit without achieving statistical significance. PMID- 21294889 TI - Changes in joint coupling and variability during walking following tibialis posterior muscle fatigue. AB - BACKGROUND: The tibialis posterior muscle is believed to play a key role in controlling foot mechanics during the stance phase of gait. However, an experiment involving localised tibialis posterior muscle fatigue, and analysis of discrete rearfoot and forefoot kinematic variables, indicated that reduced force output of the tibialis posterior muscle did not alter rearfoot and forefoot motion during gait. Thus, to better understand how muscle fatigue affects foot kinematics and injury potential, the purpose of this study was to reanalyze the data and investigate shank, rearfoot and forefoot joint coupling and coupling variability during walking. METHODS: Twenty-nine participants underwent an exercise fatigue protocol aimed at reducing the force output of tibialis posterior. An eight camera motion analysis system was used to evaluate 3 D shank and foot joint coupling and coupling variability during treadmill walking both pre- and post-fatigue. RESULTS: The fatigue protocol was successful in reducing the maximal isometric force by over 30% and a concomitant increase in coupling motion of the shank in the transverse plane and forefoot in the sagittal and transverse planes relative to frontal plane motion of the rearfoot. In addition, an increase in joint coupling variability was measured between the shank and rearfoot and between the rearfoot and forefoot during the fatigue condition. CONCLUSIONS: The reduced function of the tibialis posterior muscle following fatigue resulted in a disruption in typical shank and foot joint coupling patterns and an increased variability in joint coupling. These results could help explain tibialis posterior injury aetiology. PMID- 21294891 TI - Treatment adherence with the easypodTM growth hormone electronic auto-injector and patient acceptance: survey results from 824 children and their parents. AB - BACKGROUND: Accurately monitoring adherence to treatment with recombinant human growth hormone (r-hGH) enables appropriate intervention in cases of poor adherence. The electronic r-hGH auto-injector, easypodTM, automatically records the patient's adherence to treatment. This study evaluated adherence to treatment of children who started using the auto-injector and assessed opinions about the device. METHODS: A multicentre, multinational, observational 3-month survey in which children received r-hGH as part of their normal care. Physicians reviewed the recorded dose history and children (with or without parental assistance) completed a questionnaire-based survey. Children missing <=2 injections per month (92% of injections given) were considered adherent to treatment. Adherence was compared between GH treatment-naive and treatment-experienced children. RESULTS: Of 834 recruited participants, 824 were evaluated. The median (range) age was 11 (1-18) years. From the recorded dose history, 87.5% of children were adherent to treatment over the 3-month period. Recorded adherence was higher in treatment naive (89.7%, n = 445/496) than in treatment-experienced children (81.7%, n = 152/186) [Fisher's exact test FI(X) = 7.577; p = 0.0062]. According to self reported data, 90.2% (607/673) of children were adherent over 3 months; 51.5% (421/817) missed >=1 injection over this period (mainly due to forgetfulness). Concordance between reported and recorded adherence was 84.3%, with a trend towards self-reported adherence being higher than recorded adherence. Most children liked the auto-injector: over 80% gave the top two responses from five options for ease of use (720/779), speed (684/805) and comfort (716/804). Although 38.5% (300/780) of children reported pain on injection, over half of children (210/363) considered the pain to be less or much less than expected. Given the choice, 91.8% (732/797) of children/parents would continue using the device. CONCLUSIONS: easypodTM provides an accurate method of monitoring adherence to treatment with r-hGH. In children who received treatment with r-hGH using easypodTM, short-term adherence is good, and significantly higher in treatment-naive children compared with experienced children. Children/parents rate the device highly. The high level of acceptability of the device is reflected by a desire to continue using it by over 90% of the children in the survey. PMID- 21294892 TI - A polymorphism in the interleukin-4 receptor affects the ability of interleukin-4 to regulate Th17 cells: a possible immunoregulatory mechanism for genetic control of the severity of rheumatoid arthritis. AB - INTRODUCTION: Rheumatoid arthritis (RA) is now suspected to be driven by pathogenic Th17 cells that secrete interleukin (IL)-17 and can be regulated by IL 4. A single-nucleotide polymorphism (SNP), I50V, in the coding region of the human IL-4 receptor (IL-4R) is associated with rapid development of erosive disease in RA. The present study was undertaken to determine whether this SNP renders the IL-4R less able to transduce signals that regulate IL-17 production. METHODS: Peripheral blood mononuclear cells were activated under Th17-stimulating conditions in the presence or absence of IL-4, and IL-17 production was measured by both enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Serum IL-17 was also measured by ELISA. Paired comparisons were performed using the two tailed t-test. IL-4 receptor gene alleles were determined by polymerase chain reaction. RESULTS: In healthy individuals, IL-4 significantly inhibited IL-17 production by cells from subjects with the I/I genotype (P = 0.0079) and the I/V genotype (P = 0.013), but not the V/V genotype (P > 0.05). In a cross-sectional sample of patients with established RA, the magnitude of the in vitro effect of IL-4 was lower and was not associated with a specific IL-4R allele. Serum IL-17 levels were higher in RA patients than in healthy individuals, as was the percentage of CD4+ cells that produced IL-17. CONCLUSIONS: These results indicate that an inherited polymorphism of the IL-4R controls the ability of the human immune system to regulate the magnitude of IL-17 production. However, in established RA, this pattern may be altered, possibly due to secondary effects of both RA itself as well as immunomodulatory medications. Ineffective control of Th17 immune responses is a potential mechanism to explain why IL-4R is an important severity gene in RA, but this issue will require careful study of a cohort of new-onset RA patients. PMID- 21294893 TI - Inhibition of RhoA GTPase and the subsequent activation of PTP1B protects cultured hippocampal neurons against amyloid beta toxicity. AB - BACKGROUND: Amyloid beta (Abeta) is the main agent responsible for the advent and progression of Alzheimer's disease. This peptide can at least partially antagonize nerve growth factor (NGF) signalling in neurons, which may be responsible for some of the effects produced by Abeta. Accordingly, better understanding the NGF signalling pathway may provide clues as to how to protect neurons from the toxic effects of Abeta. RESULTS: We show here that Abeta activates the RhoA GTPase by binding to p75NTR, thereby preventing the NGF induced activation of protein tyrosine phosphatase 1B (PTP1B) that is required for neuron survival. We also show that the inactivation of RhoA GTPase and the activation of PTP1B protect cultured hippocampal neurons against the noxious effects of Abeta. Indeed, either pharmacological inhibition of RhoA with C3 ADP ribosyl transferase or the transfection of cultured neurons with a dominant negative form of RhoA protects cultured hippocampal neurons from the effects of Abeta. In addition, over-expression of PTP1B also prevents the deleterious effects of Abeta on cultured hippocampal neurons. CONCLUSION: Our findings indicate that potentiating the activity of NGF at the level of RhoA inactivation and PTP1B activation may represent a new means to combat the noxious effects of Abeta in Alzheimer's disease. PMID- 21294894 TI - Effect of liver growth factor on both testicular regeneration and recovery of spermatogenesis in busulfan-treated mice. AB - BACKGROUND: Some adult stem cells persist in adult tissue; however, we do not know how to stimulate stem cells in adults to heal injuries. Liver growth factor (LGF) is a biliprotein with hepatic mitogen activity. Its concentration increases markedly in the presence of any type of liver injury, and it shows in vivo therapeutic biological activity at extrahepatic sites. METHODS: We have analyzed the effect of LGF on the replenishment of germinal cells in the testes of mice injected with busulfan, a common cancer drug that also specifically affects germ line stem cells and spermatogonia. We determined the testicular and epididymal weight, spermatozoal concentration in the epididymis and sperm motility, and performed a histological analysis. RESULTS: Intraperitoneal administration of LGF was able to partially restore spermatogenesis, as well as sperm production and motility, in mice sterilized with busulfan. LGF treatment in busulfan-treated animals that have suffered a disruption of spermatogenesis can accelerate the reactivation of this process in most of the tubules, as shown in the histological analysis. CONCLUSIONS: Our results suggest a potential use of LGF in the mobilization of testicular stem cells and in the restoration of spermatogenesis after busulfan-induced damage to the testicular germinal epithelium. PMID- 21294895 TI - Olive oil effectively mitigates ovariectomy-induced osteoporosis in rats. AB - BACKGROUND: Osteoporosis, a reduction in bone mineral density, represents the most common metabolic bone disease. Postmenopausal women are particularly susceptible to osteoporosis when their production of estrogen declines. For these women, fracture is a leading cause of morbidity and mortality. This study was conducted to evaluate the protective effects of olive oil supplementation against osteoporosis in ovariectomized (OVX) rats. METHODS: We studied adult female Wistar rats aged 12-14 months, divided into three groups: sham-operated control (SHAM), ovariectomized (OVX), and ovariectomized rats supplemented with extravirgin olive oil (Olive-OVX) orally for 12 weeks; 4 weeks before ovariectomy and 8 weeks after. At the end of the experiment, blood samples were collected. Plasma levels of calcium, phosphorus, alkaline phosphatase (ALP), malondialdehyde (MDA), and nitrates were assayed. Specimens from both the tibia and the liver were processed for light microscopic examination. Histomorphometric analysis of the tibia was also performed. RESULTS: The OVX-rats showed a significant decrease in plasma calcium levels, and a significant increase in plasma ALP, MDA, and nitrates levels. These changes were attenuated by olive oil supplementation in the Olive-OVX rats. Light microscopic examination of the tibia of the OVX rats revealed a significant decrease in the cortical bone thickness (CBT) and the trabecular bone thickness (TBT). In addition, there was a significant increase in the osteoclast number denoting bone resorption. In the Olive-OVX rats these parameters were markedly improved as compared to the OVX group. Examination of the liver specimens revealed mononuclear cellular infiltration in the portal areas in the OVX-rats which was not detected in the Olive-OVX rats. CONCLUSIONS: Olive oil effectively mitigated ovariectomy-induced osteoporosis in rats, and is a promising candidate for the treatment of postmenopausal osteoporosis. PMID- 21294896 TI - Extravasation of radiographic contrast material and compartment syndrome in the hand: a case report. AB - Radiocontrast agents are a type of medical contrast material used to improve the visibility of internal bodily structures in X-ray based imaging techniques such as computed tomography (CT) or radiography. Radiocontrast agents are typically iodine or barium compounds.Extravasation of contrast is a possible complication of imaging studies performed with contrasts. Most extravasations cause minimal swelling or erythema, however, skin necrosis, ulceration and compartment syndrome may occur with extravasation of large volumes of contrast. A case report is presented in which significant extravasation of contrast was caused while injecting the contrast intravenously into the back of the hand of a 50 year old patient during computed tomography. The patient was undergoing chemotherapy. The patient developed a compartment syndrome and a fasciotomy was required. Treatment options are outlined and emphasis is made on prevention of this iatrogenic complication.Some of the preventive measures to avoid these complications include use of non-ionic contrast (low osmolarity), careful choice of the site of intravenous administration, and close monitoring of the patient during injection of contrast to minimize or prevent extravasation injuries. Clear information to patients and prompt recognition of the complication can allow for other non surgical treatment options than the one required in this case. PMID- 21294897 TI - Respective implications of glutamate decarboxylase antibodies in stiff person syndrome and cerebellar ataxia. AB - BACKGROUND: To investigate whether Stiff-person syndrome (SPS) and cerebellar ataxia (CA) are associated with distinct GAD65-Ab epitope specificities and neuronal effects. METHODS: Purified GAD65-Ab from neurological patients and monoclonal GAD65-Ab with distinct epitope specificities (b78 and b96.11) were administered in vivo to rat cerebellum. Effects of intra-cerebellar administration of GAD65-Ab were determined using neurophysiological and neurochemical methods. RESULTS: Intra-cerebellar administration of GAD65-Ab from a SPS patient (Ab SPS) impaired the NMDA-mediated turnover of glutamate, but had no effect on NMDA-mediated turnover of glycerol. By contrast, GAD65-Ab from a patient with cerebellar ataxia (Ab CA) markedly decreased the NMDA-mediated turnover of glycerol. Both GAD65-Ab increased the excitability of the spinal cord, as assessed by the F wave/M wave ratios. The administration of BFA, an inhibitor of the recycling of vesicles, followed by high-frequency stimulation of the cerebellum, severely impaired the cerebello-cortical inhibition only when Ab CA was used. Moreover, administration of transcranial direct current stimulation (tDCS) of the motor cortex revealed a strong disinhibition of the motor cortex with Ab CA. Monoclonal antibodies b78 and b96.11 showed distinct effects, with greater effects of b78 in terms of increase of glutamate concentrations, impairment of the adaptation of the motor cortex to repetitive peripheral stimulation, disinhibition of the motor cortex following tDCS, and increase of the F/M ratios. Ab SPS shared antibody characteristics with b78, both in epitope recognition and ability to inhibit enzyme activity, while Ab CA had no effect on GAD65 enzyme activity. CONCLUSIONS: These results suggest that, in vivo, neurological impairments caused by GAD65-Ab could vary according to epitope specificities. These results could explain the different neurological syndromes observed in patients with GAD65-Ab. PMID- 21294898 TI - Modulation of small leucine-rich proteoglycans (SLRPs) expression in the mouse uterus by estradiol and progesterone. AB - BACKGROUND: We have previously demonstrated that four members of the family of small leucine-rich-proteoglycans (SLRPs) of the extracellular matrix (ECM), named decorin, biglycan, lumican and fibromodulin, are deeply remodeled in mouse uterine tissues along the estrous cycle and early pregnancy. It is known that the combined action of estrogen (E2) and progesterone (P4) orchestrates the estrous cycle and prepares the endometrium for pregnancy, modulating synthesis, deposition and degradation of various molecules. Indeed, we showed that versican, another proteoglycan of the ECM, is under hormonal control in the uterine tissues. METHODS: E2 and/or medroxiprogesterone acetate (MPA) were used to demonstrate, by real time PCR and immunoperoxidase staining, respectively, their effects on mRNA expression and protein deposition of these SLRPs, in the uterine tissues. RESULTS: Decorin and lumican were constitutively expressed and deposited in the ECM in the absence of the ovarian hormones, whereas deposition of biglycan and fibromodulin were abolished from the uterine ECM in the non-treated group. Interestingly, ovariectomy promoted an increase in decorin, lumican and fibromodulin mRNA levels, while biglycan mRNA conspicuously decreased. Hormone replacement with E2 and/or MPA differentially modulates their expression and deposition. CONCLUSIONS: The patterns of expression of these SLRPs in the uterine tissues were found to be hormone-dependent and uterine compartment-related. These results reinforce the existence of subpopulations of endometrial fibroblasts, localized into distinct functional uterine compartments, resembling the organization into basal and functional layers of the human endometrium. PMID- 21294899 TI - Plasma peptidome profiling of acute hepatitis E patients by MALDI-TOF/TOF. AB - BACKGROUND: Hepatitis E is endemic to resource-poor regions, where it manifests as sporadic cases and large waterborne outbreaks. The disease severity ranges from acute self-limited hepatitis with low mortality to fulminant hepatic failure with high mortality. It is believed that the host response plays an important role in determining the progression and outcome of this disease. We profiled the plasma peptidome from hepatitis E patients to discover suitable biomarkers and understand disease pathogenesis. RESULTS: The peptidome (< 10 kDa) fraction of plasma was enriched and analyzed by mass spectrometry. A comparative analysis of the peptide pattern of hepatitis E patients versus healthy controls was performed using ClinPro Tools. We generated a peptide profile that could be used for selective identification of hepatitis E cases. We have identified five potential biomarker peaks with m/z values of 9288.6, 7763.6, 4961.5, 1060.572 and 2365.139 that can be used to reliably differentiate between hepatitis E patients and controls with areas under the receiver operating characteristic curve (AUROC) values of 1.00, 0.954, 0.989, 0.960 and 0.829 respectively. A number of proteins involved in innate immunity were identified to be differentially present in the plasma of patients compared to healthy controls. CONCLUSIONS: Besides the utility of this approach for biomarker discovery, identification of changes in endogenous peptides in hepatitis E patient plasma has increased our understanding of disease pathogenesis. We have identified peptides in plasma that can reliably distinguish hepatitis E patients from healthy controls. Results from this and an earlier proteomics study are discussed. PMID- 21294900 TI - A genome-wide association study of serum uric acid in African Americans. AB - BACKGROUND: Uric acid is the primary byproduct of purine metabolism. Hyperuricemia is associated with body mass index (BMI), sex, and multiple complex diseases including gout, hypertension (HTN), renal disease, and type 2 diabetes (T2D). Multiple genome-wide association studies (GWAS) in individuals of European ancestry (EA) have reported associations between serum uric acid levels (SUAL) and specific genomic loci. The purposes of this study were: 1) to replicate major signals reported in EA populations; and 2) to use the weak LD pattern in African ancestry population to better localize (fine-map) reported loci and 3) to explore the identification of novel findings cognizant of the moderate sample size. METHODS: African American (AA) participants (n = 1,017) from the Howard University Family Study were included in this study. Genotyping was performed using the Affymetrix(r) Genome-wide Human SNP Array 6.0. Imputation was performed using MACH and the HapMap reference panels for CEU and YRI. A total of 2,400,542 single nucleotide polymorphisms (SNPs) were assessed for association with serum uric acid under the additive genetic model with adjustment for age, sex, BMI, glomerular filtration rate, HTN, T2D, and the top two principal components identified in the assessment of admixture and population stratification. RESULTS: Four variants in the gene SLC2A9 achieved genome-wide significance for association with SUAL (p-values ranging from 8.88 * 10(-9) to 1.38 * 10(-9)). Fine-mapping of the SLC2A9 signals identified a 263 kb interval of linkage disequilibrium in the HapMap CEU sample. This interval was reduced to 37 kb in our AA and the HapMap YRI samples. CONCLUSIONS: The most strongly associated locus for SUAL in EA populations was also the most strongly associated locus in this AA sample. This finding provides evidence for the role of SLC2A9 in uric acid metabolism across human populations. Additionally, our findings demonstrate the utility of following-up EA populations GWAS signals in African-ancestry populations with weaker linkage disequilibrium. PMID- 21294901 TI - Early blood glucose profile and neurodevelopmental outcome at two years in neonatal hypoxic-ischaemic encephalopathy. AB - BACKGROUND: To examine the blood glucose profile and the relationship between blood glucose levels and neurodevelopmental outcome in term infants with hypoxic ischaemic encephalopathy. METHODS: Blood glucose values within 72 hours of birth were collected from 52 term infants with hypoxic-ischaemic encephalopathy. Hypoglycaemia [< 46.8 mg/dL (2.6 mmol/L)] and hyperglycaemia [> 150 mg/dL (8.3 mmol/L)] were correlated to neurodevelopmental outcome at 24 months of age. RESULTS: Four fifths of the 468 blood samples were in the normoglycaemic range (392/468:83.8%). Of the remaining 76 samples, 51.3% were in the hypoglycaemic range and (48.7%) were hyperglycaemic. A quarter of the hypoglycaemic samples (28.2%:11/39) and a third of the hyperglycaemic samples (32.4%:12/37) were recorded within the first 30 minutes of life. Mean (SD) blood glucose values did not differ between infants with normal and abnormal outcomes [4.89(2.28) mmol/L and 5.02(2.35) mmol/L, p value = 0.15] respectively. In term infants with hypoxic ischaemic encephalopathy, early hypoglycaemia (between 0-6 hours of life) was associated with adverse outcome at 24 months of age [OR = 5.8, CI = 1.04-32)]. On multivariate analysis to adjust for grade of HIE this association was not statistically significant. Late hypoglycaemia (6-72 hours of life) was not associated with abnormal outcome [OR = 0.22, CI (0.04-1.14)]. The occurrence of hyperglycaemia was not associated with adverse outcome. CONCLUSION: During the first 72 hours of life, blood glucose profile in infants with hypoxic-ischaemic encephalopathy varies widely despite a management protocol. Early hypoglycaemia (0-6 hours of life) was associated with severe HIE, and thereby; adverse outcome. PMID- 21294902 TI - Dermatofibrosarcoma protuberans with fibrosarcomatous transformation of the head and neck. AB - Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous neoplasm associated with a high cure rate. We present a case of aggressive DFSP with fibrosarcomatous areas in the head and neck. A 28-year-old Mediterranean female presented with a 45-day history of rapidly growing cutaneous lesion of the face. Surgical biopsy confirmed the diagnosis of DFSP. Subsequently, the patient underwent wide local surgical resection, followed by reconstruction. Histopathology report revealed fibrosarcomatous transformation and the patient underwent adjuvant radiotherapy. The patient continues to be disease free at the 35-month follow-up.Although DFSP behave as non-aggressive malignancy, surgery with complete removal of the affected area is the intervention of choice. Moreover, adjuvant treatment and follow-up of the patient is essential in order to prevent recurrence. PMID- 21294903 TI - Establishing a relationship between prolactin and altered fatty acid beta oxidation via carnitine palmitoyl transferase 1 in breast cancer cells. AB - BACKGROUND: Mammary carcinomas have been associated with a high-fat diet, and the rate of breast cancer in overweight post-menopausal women is up to 50% higher than in their normal-weight counterparts. Epidemiological studies suggest that prolactin (PRL) plays a role in the progression of breast cancer. The current study examined breast cancer as a metabolic disease in the context of altered fatty acid catabolism by examining the effect of PRL on carnitine palmitoyl transferase 1 (CPT1), an enzyme that shuttles long-chain fatty acids into the mitochondrial matrix for beta-oxidation. The effect of PRL on the adenosine 5' monophosphate-activated protein kinase (AMPK) energy sensing pathway was also investigated. METHODS: MCF-7 and MDA-MB-231 breast cancer cells and 184B5 normal breast epithelial cells treated with 100 ng/ml of PRL for 24 hr were used as in vitro models. Real-time PCR was employed to quantify changes in mRNA levels and Western blotting was carried out to evaluate changes at the protein level. A non radioactive CPT1 enzyme activity assay was established and siRNA transfections were performed to transiently knock down specific targets in the AMPK pathway. RESULTS: PRL stimulation increased the expression of CPT1A (liver isoform) at the mRNA and protein levels in both breast cancer cell lines, but not in 184B5 cells. In response to PRL, a 20% increase in CPT1 enzyme activity was observed in MDA-MB 231 cells. PRL treatment resulted in increased phosphorylation of the alpha catalytic subunit of AMPK at Thr172, as well as phosphorylation of acetyl-CoA carboxylase (ACC) at Ser79. A siRNA against liver kinase B1 (LKB1) reversed these effects in breast cancer cells. PRL partially restored CPT1 activity in breast cancer cells in which CPT1A, LKB1, or AMPKalpha-1 were knocked down. CONCLUSIONS: PRL enhances fatty acid beta-oxidation by stimulating CPT1 expression and/or activity in MCF-7 and MDA-MB-231 breast cancer cells. These PRL-mediated effects are partially dependent on the LKB1-AMPK pathway, although the regulation of CPT1 is also likely to be influenced by other mechanisms. Ultimately, increased CPT1 enzyme activity may contribute to fueling the high energy demands of cancer cells. Targeting metabolic pathways that are governed by PRL, which has already been implicated in the progression of breast cancer, may be of therapeutic benefit. PMID- 21294904 TI - The pandemic (H1N1) 2009 influenza virus is resistant to mannose-binding lectin. AB - BACKGROUND: Mannose-binding lectin (MBL) is an important component of innate immunity because it promotes bacterial clearance and neutralization of human influenza A viruses. Since a majority of humans have no neutralizing antibody against the pandemic (H1N1) 2009 influenza (pandemic 2009) virus, innate immunity may be crucial and MBL susceptibility may therefore influence viral pathogenesis. RESULTS: We examined MBL susceptibility of influenza A viruses and observed that the pandemic 2009 virus was resistant to MBL, whereas all seasonal influenza A viruses tested were susceptible. The mortality of mice infected with a seasonal H1N1 influenza virus was evidently enhanced on transient blockage of MBL activity by simultaneous inoculation of mannan, whereas mannan inoculation had no effect on mice infected with a pandemic 2009 virus. This indicates that MBL protects mice against infection with the seasonal virus but not against that with the pandemic 2009 virus. CONCLUSIONS: These results indicate that the pandemic 2009 virus is not susceptible to MBL, an important component of innate immunity. PMID- 21294905 TI - Stuttered swallowing: electric stimulation of the right insula interferes with water swallowing. A case report. AB - BACKGROUND: Various functional resonance imaging, magnetoencephalographic and lesion studies suggest the involvement of the insular cortex in the control of swallowing. However, the exact location of insular activation during swallowing and its functional significance remain unclear. CASE PRESENTATION: Invasive electroencephalographic monitoring was performed in a 24-year-old man with medically intractable stereotyped nocturnal hypermotor seizures due to a ganglioglioma. During stimulation of the right inferior posterior insular cortex with depth electrodes the patient spontaneously reported a perception of a "stutter in swallowing". Stimulation of the inferior posterior insular cortex at highest intensity (4 mA) was also associated with irregular and delayed swallows. Swallowing was not impaired during stimulation of the superior posterior insular cortex, regardless of stimulation intensity. CONCLUSIONS: These results indicate that the right inferior posterior insular cortex is involved in the neural circuitry underlying the control of swallowing. PMID- 21294906 TI - Identification of alternatively spliced Dab1 and Fyn isoforms in pig. AB - BACKGROUND: Disabled-1 (Dab1) is an adaptor protein that is essential for the intracellular transduction of Reelin signaling, which regulates the migration and differentiation of postmitotic neurons during brain development in vertebrates. Dab1 function depends on its tyrosine phosphorylation by Src family kinases, especially Fyn. RESULTS: We have isolated alternatively spliced forms of porcine Dab1 from brain (sDab1) and liver (sDab1-Li) and Fyn from brain (sFyn-B) and spleen (sFyn-T). Radiation hybrid mapping localized porcine Dab1 (sDab1) and Fyn (sFyn) to chromosomes 6q31-35 and 1p13, respectively. Real-time quantitative RT PCR (qRT-PCR) demonstrated that different isoforms of Dab1 and Fyn have tissue specific expression patterns, and sDab1 and sFyn-B display similar temporal expression characteristics in the developing porcine cerebral cortex and cerebellum. Both sDab1 isoforms function as nucleocytoplasmic shuttling proteins. It was further shown that sFyn phosphorylates sDab1 at tyrosyl residues (Tyr) 185, 198/200 and 232, whereas sDab1-Li was phosphorylated at Tyr 185 and Tyr 197 (corresponding to Y232 in sDab1) in vitro. CONCLUSIONS: Alternative splicing generates natural sDab1-Li that only carries Y185 and Y197 (corresponding to Y232 in sDab1) sites, which can be phosphorylated by Fyn in vitro. sDab1-Li is an isoform that is highly expressed in peripheral organs. Both isoforms are suggested to be nucleocytoplasmic shuttling proteins. Our results imply that the short splice form sDab1-Li might regulate cellular responses to different cell signals by acting as a dominant negative form against the full length sDab1 variant and that both isoforms might serve different signaling functions in different tissues. PMID- 21294907 TI - Role of taurine on acid secretion in the rat stomach. AB - BACKGROUND: Taurine has chemical structure similar to an inhibitory neurotransmitter, gamma-aminobutyric acid (GABA). Previous studies on GABA in the stomach suggest GABAergic neuron is involved in acid secretion, but the effects of taurine are poor understood. METHODS: The effects of taurine on acid secretion, signal transduction, and localization of taurinergic neurons were determined in the rat stomach using everted whole stomach, RIA kit and immunohistochemical methods. RESULTS: We used antibodies against taurine synthesizing enzyme, cysteine sulfuric acid decarboxylase (CSAD), and taurine. CSAD- and taurine-positive cells were found in the muscle and mucosal layers. Distributions of CSAD- and taurine-positive cells in both mucosal and muscle layers were heterogeneous in the stomach. Taurine at 10-9~10-4 M induced acid secretion, and the maximum secretion was at 10-5 M, 1.6-fold higher than the spontaneous secretion. Taurine-induced acid secretion was completely inhibited by bicuculline and atropine but not by cimetidine, proglumide, or strychnine. Atropine and tetrodotoxin (TTX) completely inhibited the acid secretion induced by low concentrations of taurine and partially inhibited induced by high concentrations. Verapamil, a calcium blocker agent, inhibited acid output elicited by taurine. We assumed all Ca2+ channels involved in the response to these secretagogues were equally affected by verapamil. Intracellular cAMP (adenosine 3', 5'-monophosphate) in the stomach significantly increased with taurine treatment in a dose-dependent manner. High correlation (r=0.859, p < 0.001) of taurine concentrations with cAMP was observed. CONCLUSIONS: Our results demonstrated for the first time in taurine-induced acid secretion due to increase intracellular calcium may act through the A type of GABA receptors, which are mainly located on cholinergic neurons though cAMP pathway and partially on nonneuronal cells in the rat stomach. PMID- 21294908 TI - Comparison of the VersaTREK blood culture system against the Bactec9240 system in patients with suspected bloodstream infections. AB - BACKGROUND: To evaluate the VersaTREK (TREK Diagnostic Systems, Cleveland, Ohio) blood culture system against the Bactec9240 (BD Microbiology, Cockeysville, MD), for the recovery of bloodstream pathogens. METHODS: Venous blood from patients with suspected bacterial sepsis was evenly distributed into bottles of each system. Positive signals were recorded and bottles processed onto standard media for organism recovery. False positive signals were regarded if no organisms were seen on Gram stain and no growth was observed. RESULTS: 177 bottles were available for analysis; the Bactec9240 system yielded 43 positive, 134 negative results and no false positive signals. The VersaTREK system had 58 positive signals with 14 being false positives. CONCLUSIONS: In our setting with high background burden of immuno-compromised patients, the VersaTREK system compared favourably with the Bactec9240 in recovering blood stream aerobic and facultative anaerobic pathogens from patients with suspected bacterial sepsis. A concern is the high false positivity rate. Due to its versatility to accommodate small and large workloads as well as using smaller volumes of blood, this system may establish itself as a useful alternative for the recovery of bloodstream pathogens. PMID- 21294909 TI - Not just another genome. AB - Sequence analysis of the Daphnia pulex genome holds some surprises that could not have been anticipated from what was learned so far from other arthropod genomes. It establishes Daphnia as an eco-genetical model organism par excellence. PMID- 21294910 TI - Sensory and motor neuronopathy in a patient with the A382P TDP-43 mutation. AB - Patients with TARDBP mutations have so far been classified as ALS, sometimes with frontal lobe dysfunction. A 66-year-old patient progressively developed a severe sensory disorder, followed by a motor disorder, which evolved over nine years. Symptoms started in the left hand and slowly involved the four limbs. Investigations were consistent with a mixed sensory and motor neuronopathy. A heterozygous change from an alanine to a proline at amino acid 382 was identified in exon 6 of the TARDPB gene (p.A382P). This case expands the phenotypic spectrum associated with mutations in the TARDBP gene and shows that sensory neurons can be severely damaged early in the course of the disease, following a propagating process, with an orderly progression from a focal starting point. A combination of severe sensory and motor neuronopathy is rarely encountered in clinical practice. The possibility of an A382P TDP-43 mutation should be considered in patients with such an association. PMID- 21294911 TI - Disability in activities of daily living, depression, and quality of life among older medical ICU survivors: a prospective cohort study. AB - BACKGROUND: Accurate measurement of quality of life in older ICU survivors is difficult but critical for understanding the long-term impact of our treatments. Activities of daily living (ADLs) are important components of functional status and more easily measured than quality of life (QOL). We sought to determine the cross-sectional associations between disability in ADLs and QOL as measured by version one of the Short Form 12-item Health Survey (SF-12) at both one month and one year post-ICU discharge. METHODS: Data was prospectively collected on 309 patients over age 60 admitted to the Yale-New Haven Hospital Medical ICU between 2002 and 2004. Among survivors an assessment of ADL's and QOL was performed at one month and one-year post-ICU discharge. The SF-12 was scored using the version one norm based scoring with 1990 population norms. Multivariable regression was used to adjust the association between ADLs and QOL for important covariates. RESULTS: Our analysis of SF-12 data from 110 patients at one month post-ICU discharge showed that depression and ADL disability were associated with decreased QOL. Our model accounted for 17% of variability in SF12 physical scores (PCS) and 20% of variability in SF12 mental scores (MCS). The mean PCS of 37 was significantly lower than the population mean whereas the mean MCS score of 51 was similar to the population mean. At one year mean PCS scores improved and ADL disability was no longer significantly associated with QOL. Mortality was 17% (53 patients) at ICU discharge, 26% (79 patients) at hospital discharge, 33% (105 patients) at one month post ICU admission, and was 45% (138 patients) at one year post ICU discharge. CONCLUSIONS: In our population of older ICU survivors, disability in ADLs was associated with reduced QOL as measured by the SF-12 at one month but not at one year. Although better markers of QOL in ICU survivors are needed, ADLs are a readily observable outcome. In the meantime, clinicians must try to offer realistic estimates of prognosis based on available data and resources are needed to assist ICU survivors with impaired ADLs who wish to maintain their independence. More aggressive diagnosis and treatment of depression in this population should also be explored as an intervention to improve quality of life. PMID- 21294912 TI - Modeling the evolution of a classic genetic switch. AB - BACKGROUND: The regulatory network underlying the yeast galactose-use pathway has emerged as a model system for the study of regulatory network evolution. Evidence has recently been provided for adaptive evolution in this network following a whole genome duplication event. An ancestral gene encoding a bi-functional galactokinase and co-inducer protein molecule has become subfunctionalized as paralogous genes (GAL1 and GAL3) in Saccharomyces cerevisiae, with most fitness gains being attributable to changes in cis-regulatory elements. However, the quantitative functional implications of the evolutionary changes in this regulatory network remain unexplored. RESULTS: We develop a modeling framework to examine the evolution of the GAL regulatory network. This enables us to translate molecular changes in the regulatory network to changes in quantitative network function. We computationally reconstruct an inferred ancestral version of the network and trace the evolutionary paths in the lineage leading to S. cerevisiae. We explore the evolutionary landscape of possible regulatory networks and find that the operation of intermediate networks leading to S. cerevisiae differs substantially depending on the order in which evolutionary changes accumulate; in particular, we systematically explore evolutionary paths and find that some network features cannot be optimized simultaneously. CONCLUSIONS: We find that a computational modeling approach can be used to analyze the evolution of a well studied regulatory network. Our results are consistent with several experimental studies of the evolutionary of the GAL regulatory network, including increased fitness in Saccharomyces due to duplication and adaptive regulatory divergence. The conceptual and computational tools that we have developed may be applicable in further studies of regulatory network evolution. PMID- 21294913 TI - Adjuvant radiation therapy in metastatic lymph nodes from melanoma. AB - PURPOSE: To analyze the outcome after adjuvant radiation therapy with standard fractionation regimen in metastatic lymph nodes (LN) from cutaneous melanoma. PATIENTS AND METHODS: 86 successive patients (57 men) were treated for locally advanced melanoma in our institution. 60 patients (69%) underwent LN dissection followed by radiation therapy (RT), while 26 patients (31%) had no radiotherapy. RESULTS: The median number of resected LN was 12 (1 to 36) with 2 metastases (1 to 28). Median survival after the first relapse was 31.8 months. Extracapsular extension was a significant prognostic factor for regional control (p = 0.019). Median total dose was 50 Gy (30 to 70 Gy). A standard fractionation regimen was used (2 Gy/fraction). Median number of fractions was 25 (10 to 44 fractions). Patients were treated with five fractions/week. Patients with extracapsular extension treated with surgery followed by RT (total dose >=50 Gy) had a better regional control than patients treated by surgery followed by RT with a total dose <50 Gy (80% vs. 35% at 5-year follow-up; p = 0.004). CONCLUSION: Adjuvant radiotherapy was able to increase regional control in targeted sub-population (LN with extracapsular extension). PMID- 21294915 TI - Clinical significance of preoperative serum interleukin-6 and C-reactive protein level in breast cancer patients. AB - BACKGROUND: Breast cancer is a disease that continues to plague females during their entire lifetime. IL-6 and CRP are found to be elevated in various inflammatory and malignant diseases and their levels are found to correlate with the extent of the disease. The primary objective of this study was to determine the preoperative serum levels of IL-6 and CRP in breast carcinoma, and to correlate them with the staging of the disease and the prognosis. METHODS: 59 female patients admitted for breast cancer were identified for the study and were subjected to thorough evaluation. Serum levels of IL-6 were assessed via Enzyme Linked Immuno-Sorbent Assay (ELISA), and CRP was measured via immunoturbidimetry. Histological findings included tumour size, lymph node (LN) metastasis, and tumour staging. Relevant investigations were made to find out the presence of distant metastasis. Statistical analysis of the data was then processed. RESULTS: Increases in cancer invasion and staging are generally associated with increases in preoperative serum IL-6 levels. IL-6 and CRP levels correlated with LN metastasis (P < 0.001, P < 0.001) and TNM stage (P < 0.001, P < 0.001). Tumour invasion and the presence of distant metastasis is associated with higher IL-6 levels (P = 0.001, P = 0.009). When we established the cutoff value for IL-6 level (20.55 pg/dl) by ROC curve, we noted a significant difference in overall survival (OS; P = 0.008). However, CRP evidenced no significance with regard to patient's OS levels. Serum IL-6 levels were correlated positively with CRP levels (r2 = 0.579, P < 0.01) CONCLUSION: Serum levels of IL-6 correlates well with the extent of tumor invasion, LN metastasis, distant metastasis and TNM staging thus enveloping all aspects of breast cancer. PMID- 21294916 TI - Protecting HIV information in countries scaling up HIV services: a baseline study. AB - BACKGROUND: Individual-level data are needed to optimize clinical care and monitor and evaluate HIV services. Confidentiality and security of such data must be safeguarded to avoid stigmatization and discrimination of people living with HIV. We set out to assess the extent that countries scaling up HIV services have developed and implemented guidelines to protect the confidentiality and security of HIV information. METHODS: Questionnaires were sent to UNAIDS field staff in 98 middle- and lower-income countries, some reportedly with guidelines (G-countries) and others intending to develop them (NG-countries). Responses were scored, aggregated and weighted to produce standard scores for six categories: information governance, country policies, data collection, data storage, data transfer and data access. Responses were analyzed using regression analyses for associations with national HIV prevalence, gross national income per capita, OECD income, receiving US PEPFAR funding, and being a G- or NG-country. Differences between G- and NG-countries were investigated using non-parametric methods. RESULTS: Higher information governance scores were observed for G-countries compared with NG-countries; no differences were observed between country policies or data collection categories. However, for data storage, data transfer and data access, G-countries had lower scores compared with NG-countries. No significant associations were observed between country score and HIV prevalence, per capita gross national income, OECD economic category, and whether countries had received PEPFAR funding. CONCLUSIONS: Few countries, including G-countries, had developed comprehensive guidelines on protecting the confidentiality and security of HIV information. Countries must develop their own guidelines, using established frameworks to guide their efforts, and may require assistance in adapting, adopting and implementing them. PMID- 21294914 TI - Relationship between self-reported dietary intake and physical activity levels among adolescents: the HELENA study. AB - BACKGROUND: Evidence suggests possible synergetic effects of multiple lifestyle behaviors on health risks like obesity and other health outcomes. Therefore it is important to investigate associations between dietary and physical activity behavior, the two most important lifestyle behaviors influencing our energy balance and body composition. The objective of the present study is to describe the relationship between energy, nutrient and food intake and the physical activity level among a large group of European adolescents. METHODS: The study comprised a total of 2176 adolescents (46.2% male) from ten European cities participating in the HELENA (Healthy Lifestyle in Europe by Nutrition in Adolescence) study. Dietary intake and physical activity were assessed using validated 24-h dietary recalls and self-reported questionnaires respectively. Analyses of covariance (ANCOVA) were used to compare the energy and nutrient intake and the food consumption between groups of adolescents with different physical activity levels (1st to 3rd tertile). RESULTS: In both sexes no differences were found in energy intake between the levels of physical activity. The most active males showed a higher intake of polysaccharides, protein, water and vitamin C and a lower intake of saccharides compared to less active males. Females with the highest physical activity level consumed more polysaccharides compared to their least active peers. Male and female adolescents with the highest physical activity levels, consumed more fruit and milk products and less cheese compared to the least active adolescents. The most active males showed higher intakes of vegetables and meat, fish, eggs, meat substitutes and vegetarian products compared to the least active ones. The least active males reported the highest consumption of grain products and potatoes. Within the female group, significantly lower intakes of bread and cereal products and spreads were found for those reporting to spend most time in moderate to vigorous physical activity. The consumption of foods from the remaining food groups, did not differ between the physical activity levels in both sexes. CONCLUSION: It can be concluded that dietary habits diverge between adolescents with different self reported physical activity levels. For some food groups a difference in intake could be found, which were reflected in differences in some nutrient intakes. It can also be concluded that physically active adolescents are not always inclined to eat healthier diets than their less active peers. PMID- 21294917 TI - Carbon ion therapy for ameloblastic carcinoma. AB - Ameloblastic carcinomas are rare odontogenic tumors. Treatment usually consists of surgical resection and sometimes adjuvant radiation. We report the case of a 71 year-old male patient undergoing carbon ion therapy for extensive local relapse of ameloblastic carcinoma. Treatment outcome was favourable with a complete remission at 6 weeks post completion of radiotherapy while RT-treatment itself was tolerated well with only mild side effects. High dose radiation hence is a potential alternative for patients unfit or unwilling to undergo extensive surgery or in cases when only a subtotal resection is planned or the resection is mutilating. PMID- 21294918 TI - Relative survival: a useful tool to assess generalisability in longitudinal studies of health in older persons. AB - BACKGROUND: Generalisability of longitudinal studies is threatened by issues such as choice of sampling frame, representativeness of the initial sample, and attrition. To determine representativeness, cohorts are often compared with the population of interest at baseline on demographic and health characteristics. This study illustrates the use of relative survival as a tool for assessing generalisability of results from a cohort of older people among whom death is a potential threat to generalisability. METHODS: The authors used data from the 1921-26 cohort (n = 12,416, aged 70-75 in 1996) of the Australian Longitudinal Study on Women's Health (ALSWH). Vital status was determined by linkage to the National Death Index, and expected deaths were derived using Australian life tables. Relative survival was estimated using observed survival in the cohort divided by expected survival among women of the same age and State or Territory. RESULTS: Overall, the ALSWH women showed relative survival 9.5% above the general population. Within States and Territories, the relative survival advantage varied from 6% to 23%. The interval-specific relative survival remained relatively constant over the 12 years (1996-2008) under review, indicating that the survival advantage of the cohort has not diminished over time. CONCLUSION: This study demonstrates that relative survival can be a useful measure of generalisability in a longitudinal study of the health of the general population, particularly when participants are older. PMID- 21294919 TI - Factors affecting commencement and cessation of betel quid chewing behaviour in Malaysian adults. AB - BACKGROUND: Betel quid chewing is a common habit widely practiced in Southern Asian populations. However, variations are seen in the content of a betel quid across the different countries. Factors associated with commencement and cessation of this habit has been numerously studied. Unfortunately, data on Malaysian population is non-existent. This study aims to determine the factors associated with the inception and also cessation of betel quid chewing behaviour among Malaysian adults. METHOD: This study is part of a nationwide survey on oral mucosal lesions carried out among 11,697 adults in all fourteen states in Malaysia. The questionnaire included sociodemographic information and details on betel quid chewing habit such as duration, type and frequency. The Kaplan-Meier estimates were calculated and plotted to compare the rates for the commencement and cessation of betel quid chewing behaviour. Cox proportional hazard regression models were used to calculate the hazard rate ratios for factors related to commencement or cessation of this habit. RESULTS: Of the total subjects, 8.2% were found to be betel quid chewers. This habit was more prevalent among females and, in terms of ethnicity, among the Indians and the Indigenous people of Sabah and Sarawak. Cessation of this habit was more commonly seen among males and the Chinese. Females were found to be significantly more likely to start (p < 0.0001) and less likely to stop the quid chewing habit. Females, those over 40 years old, Indians and a history of smoking was found to significantly increase the likelihood of developing a quid chewing habit (p < 0.0001). However, those who had stopped smoking were found to be significantly more likely to promote stopping the habit (p = 0.0064). Cessation was also more likely to be seen among those who chewed less than 5 quids per day (p < 0.05) and less likely to be seen among those who included areca nut and tobacco in their quid (p < 0.0001). CONCLUSION: Factors that influence the development and cessation of this behaviour are gender, age, ethnicity, and also history of smoking habit while frequency and type of quid chewed are important factors for cessation of this habit. PMID- 21294920 TI - Development and applicability of Hospital Survey on Patient Safety Culture (HSOPS) in Japan. AB - BACKGROUND: Patient safety culture at healthcare organizations plays an important role in guaranteeing, improving and promoting overall patient safety. Although several conceptual frameworks have been proposed in the past, no standard measurement tool has yet been developed for Japan. METHODS: In order to examine possibilities to introduce the Hospital Survey on Patient Safety Culture (HSOPS) in Japan, the authors of this study translated the HSOPS into Japanese, and evaluated its factor structure, internal consistency, and construct validity. Healthcare workers (n = 6,395) from 13 acute care general hospitals in Japan participated in this survey. RESULTS: Confirmatory factor analysis indicated that the Japanese HSOPS' 12-factor model was selected as the most pertinent, and showed a sufficiently high standard partial regression coefficient. The internal reliability of the subscale scores was 0.46-0.88. The construct validity of each safety culture sub-dimension was confirmed by polychoric correlation, and by an ordered probit analysis. CONCLUSIONS: The results of the present study indicate that the factor structures of the Japanese and the American HSOPS are almost identical, and that the Japanese HSOPS has acceptable levels of internal reliability and construct validity. This shows that the HSOPS can be introduced in Japan. PMID- 21294921 TI - Health status and lifestyle factors as predictors of depression in middle-aged and elderly Japanese adults: a seven-year follow-up of the Komo-Ise cohort study. AB - BACKGROUND: Depression is a common mental disorder. Several studies suggest that lifestyle and health status are associated with depression. However, only a few large-scale longitudinal studies have been conducted on this topic. METHODS: The subjects were middle-aged and elderly Japanese adults between the ages of 40 and 69 years. A total of 9,650 respondents completed questionnaires for the baseline survey and participated in the second wave of the survey, which was conducted 7 years later. We excluded those who complained of depressive symptoms in the baseline survey and analyzed data for the remaining 9,201 individuals. In the second-wave survey, the DSM-12D was used to determine depression. We examined the risks associated with health status and lifestyle factors in the baseline survey using a logistic regression model. RESULTS: An age-adjusted analysis showed an increased risk of depression in those who had poor perceived health and chronic diseases in both sexes. In men, those who were physically inactive also had an increased risk of depression. In women, the analysis also showed an increased risk of depression those with a BMI of 25 or more, in those sleeping 9 hours a day or more and who were current smokers. A multivariate analysis showed that increased risks of depression still existed in men who had chronic diseases and who were physically inactive, and in women who had poor perceived health and who had a BMI of 25 or more. CONCLUSIONS: These results suggest that lifestyle and health status are risk factors for depression. Having a chronic disease and physical inactivity were distinctive risk factors for depression in men. On the other hand, poor perceived health and a BMI of 25 or more were distinctive risk factors for depression in women. Preventive measures for depression must therefore take gender into account. PMID- 21294922 TI - Oriental schistosomiasis with neurological complications: case report. AB - We describe a case of cerebral schistosomiasis, caused by Asian (oriental) Schistosoma japonicum trematode blood flukes, in a young Chinese patient and its management. We also provide a brief update for physicians on the clinical features, diagnosis and treatment of schistosomiasis, with particular emphasis on neuroschistosomiasis, the most severe clinical outcome associated with this parasitic infection. PMID- 21294923 TI - Relationships between post operative pain management and short term functional mobility in total knee arthroplasty patients with a femoral nerve catheter: a preliminary study. AB - BACKGROUND: Effective pain management following total knee arthroplasty (TKA) is fundamental in achieving positive rehabilitation outcomes. The purpose of our study was to investigate post operative pain management in relation to short term functional mobility in an intervention group receiving concomitant use of an IV narcotic PCA and a continuous infusion of local anaesthetic via a femoral nerve catheter (CFNC), compared to a group receiving narcotic PCA alone. This was a preliminary study conducted to establish an appropriate design for a larger investigative study. METHODS: A prospective design was used to measure the effect of a CFNC on post operative pain management and functional mobility prior to hospital discharge. The amount of fentanyl used, pain and nausea scores, timed up and go (TUG) tests and active range of knee movement (AROM) were used to compare a CFNC and supplemental narcotic patient controlled analgesia (PCA) group (n = 27) with a PCA only group (n = 25). RESULTS: The CFNC group used significantly less fentanyl than the PCA only group (p < .001) but there was no significant difference in TUG times between the two groups. There was however a significantly lower AROM reported for both extension (p < .04) and flexion (p < .006,) in the FNC group. Women had significantly slower TUG times (p < .005,) and there were moderate to strong positive correlations between post operative TUG times and the preoperative TUG time (r(s) = .505 p < .001), the time since oral analgesia (r(s) = .529 p < .014), and pain scores (r(s) = .328, p = .034) CONCLUSIONS: In this small preliminary study improved TUG performance at Day 4 post op was not influenced by the use of a CFNC but was positively correlated with male gender, preoperative performance, time elapsed since last oral analgesia and pain score. However AROM was decreased in the CFNC group suggesting further research on the relationship between CFNCs, local anaesthetic concentration and quadriceps strength should be incorporated in the follow up study's design. PMID- 21294924 TI - A new computational method to split large biochemical networks into coherent subnets. AB - BACKGROUND: Compared to more general networks, biochemical networks have some special features: while generally sparse, there are a small number of highly connected metabolite nodes; and metabolite nodes can also be divided into two classes: internal nodes with associated mass balance constraints and external ones without. Based on these features, reclassifying selected internal nodes (separators) to external ones can be used to divide a large complex metabolic network into simpler subnetworks. Selection of separators based on node connectivity is commonly used but affords little detailed control and tends to produce excessive fragmentation.The method proposed here (Netsplitter) allows the user to control separator selection. It combines local connection degree partitioning with global connectivity derived from random walks on the network, to produce a more even distribution of subnetwork sizes. Partitioning is performed progressively and the interactive visual matrix presentation used allows the user considerable control over the process, while incorporating special strategies to maintain the network integrity and minimise the information loss due to partitioning. RESULTS: Partitioning of a genome scale network of 1348 metabolites and 1468 reactions for Arabidopsis thaliana encapsulates 66% of the network into 10 medium sized subnets. Applied to the flavonoid subnetwork extracted in this way, it is shown that Netsplitter separates this naturally into four subnets with recognisable functionality, namely synthesis of lignin precursors, flavonoids, coumarin and benzenoids. A quantitative quality measure called efficacy is constructed and shows that the new method gives improved partitioning for several metabolic networks, including bacterial, plant and mammal species. CONCLUSIONS: For the examples studied the Netsplitter method is a considerable improvement on the performance of connection degree partitioning, giving a better balance of subnet sizes with the removal of fewer mass balance constraints. In addition, the user can interactively control which metabolite nodes are selected for cutting and when to stop further partitioning as the desired granularity has been reached. Finally, the blocking transformation at the heart of the procedure provides a powerful visual display of network structure that may be useful for its exploration independent of whether partitioning is required. PMID- 21294925 TI - Exercise-induced left bundle branch block and subsequent mechanical left ventricular dyssynchrony--resolved with pharmacological therapy. AB - A 53-year-old man with depressed ejection fraction (EF) of 35% and QRS width of 88 ms at rest was admitted to our institution with a complaint of exertional chest discomfort and dyspnea. During treadmill exercise, left bundle-branch block (LBBB) with a QRS width of 152 ms occurred at a heart rate of 100 bpm. During LBBB, the patient showed significant mechanical dyssynchrony as evidenced by a two-dimensional speckle tracking radial strain of 260 ms (>= 130 ms), defined as the time difference between anterior-septum and posterior wall. Five-month after carvedilol and candesartan administration, EF had improved to 49% and LBBB did not occur until a heart rate of 126 bpm was attained during treadmill exercise. It appears that pharmacological therapy may be useful for patients with heart failure and exercise-induced LBBB. PMID- 21294926 TI - Enhancive effects of Lewis y antigen on CD44-mediated adhesion and spreading of human ovarian cancer cell line RMG-I. AB - BACKGROUND: This study aimed to investigate the molecular structural relationship between cell adhesive molecule CD44 and Lewis y antigen, and determine the effects of Lewis y antigen on CD44-mediated adhesion and spreading of ovarian cancer cell line RMG-I and the Lewis y antigen-overexpressed cell line RMG-I-H. METHODS: The expression of CD44 in RMG-I and RMG-I-H cells before and after treatment of Lewis y monoclonal antibody was detected by immunocytochemistry; the expression of Lewis y antigen and CD44 was detected by Western Blot. The structural relationship between Lewis y antigen and CD44 was determined by immunoprecipitation and confocal laser scanning microscopy. The adhesion and spreading of RMG-I and RMG-I-H cells on hyaluronic acid (HA) were observed. The expression of CD44 mRNA in RMG-I and RMG-I-H cells was detected by real-time RT PCR. RESULTS: Immunocytochemistry revealed that the expression of CD44 was significantly higher in RMG-I-H cells than in RMG-I cells (P < 0.01), and its expression in both cell lines was significantly decreased after treatment of Lewis y monoclonal antibody (both P < 0.01). Western Blot confirmed that the content of CD44 in RMG-I-H cells was 1.46 times of that in RMG-I cells. The co location of Lewis y antigen and CD44 was confirmed by co-immunoprecipitation. The co-expression of CD44 and Lewis y antigen in RMG-I-H cells was 2.24 times of that in RMG-I cells. The adhesion and spreading of RMG-I-H cells on HA were significantly enhanced as compared to those of RMG-I cells (P < 0.01), and this enhancement was inhibited by Lewis y monoclonal antibody (P < 0.01). The mRNA level of CD44 in both cell lines was similar (P > 0.05). CONCLUSION: Lewis y antigen strengthens CD44-mediated adhesion and spreading of ovarian cancer cells. PMID- 21294927 TI - Social and cultural dimensions of hygiene in Cambodian health care facilities. AB - BACKGROUND: The frequency of bloodborne pathogen healthcare-associated infections is thought to be high in developing Southeast Asian countries. The underlying social-cultural logics contributing to the risks of transmission are rarely studied. This report provides some insights on the social and cultural factors that shape hygiene practices in Cambodian health care settings. METHODS: We conducted qualitative surveys in various public and private health facilities in Phnom Penh, the capital city and in provinces. We observed and interviewed 319 participants, health care workers and patients, regarding hygiene practices and social relationships amongst the health care staff and with patients. We also examined the local perceptions of hygiene, their impact on the relationships between the health care staff and patients, and perceptions of transmission risks. Data collection stem from face to face semi-structured and open-ended interviews and focus group discussions with various health care staffs (i.e. cleaners, nurses, midwives and medical doctors) and with patients who attended the study health facilities. RESULTS: Overall responses and observations indicated that hygiene practices were burdened by the lack of adequate materials and equipment. In addition, many other factors were identified to influence and distort hygiene practices which include (1) informal and formal social rapports in hospitals, (2) major infection control roles played by the cleaners in absence of professional acknowledgment. Moreover, hygiene practices are commonly seen as an unessential matter to be devoted to low-ranking staff. CONCLUSION: Our anthropological findings illustrate the importance of comprehensive understanding of hygiene practices; they need to be considered when designing interventions to improve infection control practices in a Cambodian medical setting. PMID- 21294928 TI - Flying with a 'death sentence' on board: electrophoretic detection of braconid parasitoid larvae in migrating winged grain aphids, Sitobion avenae (F.). AB - Polyacrylamide gel electrophoresis of enzymes (carboxylesterases) was used for the first time to monitor rates of parasitism in airborne alate (winged) grain aphid, Sitobion avenae (F.) population samples collected by suction trapping in Hertfordshire, UK. Using previously described electrophoretic 'keys', the species of hymenopterous parasitoids present in individual aphids were identified and found to be Aphidius ervi (Haliday) and/or Aphidius rhopalosiphi (De Stephani Perez) (Braconidae). Entomophthoralean fungal infection was also detected using this approach. Aphidiid wasp parasitism was detected from early June to mid August and fungal infection from late June to late July. The results are discussed in relation to parasitoid population structure and dynamics, especially (i) the fact that winged aphids passively transport the early stages of their braconid parasitoids and fungal pathogens, potentially to newly-founded colonies, which may directly impact on the dual aphid-parasitoid populations genetics; and (ii) the approach used to collect and assay parasitised and fungal infected aphids involving both suction trapping and electrophoretic testing may have potential in assessing the level and efficacy of these biological control agents in integrated pest management (IPM) schemes to combat cereal aphid outbreaks. PMID- 21294929 TI - Comparative effects of glucose and xylose on blood pressure, gastric emptying and incretin hormones in healthy older subjects. AB - Postprandial hypotension is an important disorder for which current management is suboptimal. In healthy older subjects, oral and small-intestinal glucose administration decreases blood pressure (BP), and the magnitude of the reduction is dependent on the rate of glucose entry into the small intestine and, possibly, the release of glucagon-like peptide-1 (GLP-1). There is little information about the effects of other carbohydrates, particularly those poorly absorbed, on BP. The aim of the present study was to compare the effects of drinks containing xylose, glucose or water alone on BP, gastric emptying (GE), incretin hormone secretion, glycaemia and insulinaemia in healthy older subjects. A total of eight healthy older subjects (aged 65-75 years) had simultaneous measurements of BP (DINAMAP), GE (three-dimensional ultrasound), blood glucose, serum insulin, GLP-1 and glucose-dependent insulinotropic peptide (GIP), on three separate occasions, in a double-blind, randomised order. On each day, subjects consumed a 300 ml drink of water, glucose (50 g) or d-xylose (50 g). Glucose (P = 0.02), but not xylose (P = 0.63), was associated with a fall in BP. There was no difference in the GE of glucose and xylose (P = 0.47); both emptied slower than water (P < 0.001). Xylose had minimal effects on blood glucose, serum insulin or serum GIP, but was more potent than glucose in stimulating GLP-1 (P = 0.002). In conclusion, in healthy older subjects, xylose empties from the stomach at the same rate as glucose, but has no effect on BP, possibly because it is a potent stimulus for GLP-1 release. Xylose may be considered as an alternative sweetener to glucose in the management of postprandial hypotension. PMID- 21294930 TI - Cor triatriatum dexter masquerading as Ebstein's anomaly. AB - We report the case of a child with cor triatriatum dexter masquerading as Ebstein's anomaly on transthoracic echocardiography. This was attributed to a floppy membrane arising from the right atrium, protruding into the tricuspid valve and pushing the leaflets downwards, giving an impression of Ebstein's anomaly. The importance of recognising this pitfall will prevent misdiagnosis of Ebstein's anomaly. PMID- 21294931 TI - The effect of high-dose vitamin A supplementation at birth on measles incidence during the first 12 months of life in boys and girls: an unplanned study within a randomised trial. AB - Vitamin A treatment reduces mortality during acute measles infection, and vitamin A supplementation (VAS) to children above 6 months of age may reduce the incidence of measles infection. The effect of VAS at birth on measles incidence is unknown. In a randomised placebo-controlled trial in Guinea-Bissau, normal birth-weight newborns were randomised to 50 000 IU (15 mg) VAS or placebo. During the trial, a measles epidemic occurred. We linked data from the trial with data from the measles infection surveillance and studied the effect of VAS on the measles incidence before 12 months of age in both sexes. A total of 165 measles cases were identified among the 4183 children followed from 28 d of age. Up to 6 months of age, the incidence rate ratio of measles for VAS compared with placebo was 0.54 (95 % CI 0.25, 1.15) among boys and 1.57 (95 % CI 0.80, 3.08) among girls (test of interaction, P = 0.04). The corresponding figures at 12 months were 0.67 (95 % CI 0.43, 1.05) and 1.17 (95 % CI 0.76, 1.79) (test of interaction, P = 0.08). VAS compared with placebo tended to be associated with less measles hospitalisation or death during the first 6 months of life in boys (P = 0.06), but not in girls. VAS at birth may affect the susceptibility to measles infection during the first 6 months of life in a sex-differential manner. PMID- 21294932 TI - Double venous drainage in scimitar syndrome. Ideal anatomy for percutaneous complete cure. AB - Congenital venolobular or scimitar syndrome is a rare congenital cardiopulmonary anomaly consisting in a partial anomalous pulmonary venous drainage, lung hypoplasia, and anomalous systemic arterial supply to the lung. It can associate with other congenital disorders which will confer the clinical presentation and prognosis of these patients. In most of the cases, the therapeutic approach is partial, as anatomy allows only aberrant arterial embolisation. We present a 6 year-old girl with recurrent pulmonary infections, diagnosed as scimitar syndrome with double collector drainage to the inferior caval vein and left atrium, undergoing interventional catheterisation for complete correction of her disorder. The anomalous systemic artery supply was embolised and the anomalous venous drainage was occluded. The patient was asymptomatic during follow-up, which supports the interventional catheterisation approach as a valid therapeutic option in cases of scimitar syndrome with double venous drainage. PMID- 21294933 TI - Red wine prevents the postprandial increase in plasma cholesterol oxidation products: a pilot study. AB - Moderate wine consumption has been shown to lower cardiovascular risk. One of the mechanisms could involve the control of postprandial hyperlipaemia, a well defined risk factor for atherosclerosis, reasonably by reducing the absorption of lipid oxidised species from the meal. The objective of the present study was to investigate whether wine consumption with the meal is able to reduce the postprandial increase in plasma lipid hydroperoxides and cholesterol oxidation products, in human subjects. In two different study sessions, twelve healthy volunteers consumed the same test meal rich in oxidised and oxidisable lipids (a double cheeseburger), with 300 ml of water (control) or with 300 ml of red wine (wine). The postprandial plasma concentration of cholesterol oxidation products was measured by GC-MS. The control meal induced a significant increase in the plasma concentration of lipid hydroperoxides and of two cholesterol oxidation products, 7-beta-hydroxycholesterol and 7-ketocholesterol. The postprandial increase in lipid hydroperoxides and cholesterol oxidation products was fully prevented by wine when consumed with the meal. In conclusion, the present study provides evidence that consumption of wine with the meal could prevent the postprandial increase in plasma cholesterol oxidation products. PMID- 21294934 TI - The ethanolamide metabolite of DHA, docosahexaenoylethanolamine, shows immunomodulating effects in mouse peritoneal and RAW264.7 macrophages: evidence for a new link between fish oil and inflammation. AB - Several mechanisms have been proposed for the positive health effects associated with dietary consumption of long-chain n-3 PUFA (n-3 LC-PUFA) including DHA (22 : 6n-3) and EPA (20 : 5n-3). After dietary intake, LC-PUFA are incorporated into membranes and can be converted to their corresponding N-acylethanolamines (NAE). However, little is known on the biological role of these metabolites. In the present study, we tested a series of unsaturated NAE on the lipopolysaccharide (LPS)-induced NO production in RAW264.7 macrophages. Among the compounds tested, docosahexaenoylethanolamine (DHEA), the ethanolamide of DHA, was found to be the most potent inhibitor, inducing a dose-dependent inhibition of NO release. Immune modulating properties of DHEA were further studied in the same cell line, demonstrating that DHEA significantly suppressed the production of monocyte chemotactic protein-1 (MCP-1), a cytokine playing a pivotal role in chronic inflammation. In LPS-stimulated mouse peritoneal macrophages, DHEA also reduced MCP-1 and NO production. Furthermore, inhibition was also found to take place at a transcriptional level, as gene expression of MCP-1 and inducible NO synthase was inhibited by DHEA. To summarise, in the present study, we showed that DHEA, a DHA-derived NAE metabolite, modulates inflammation by reducing MCP-1 and NO production and expression. These results provide new leads in molecular mechanisms by which DHA can modulate inflammatory processes. PMID- 21294935 TI - Effects of green tea catechins on the pro-inflammatory response after haemorrhage/resuscitation in rats. AB - Plant polyphenols, i.e. green tea extract (GTE), possess high antioxidative and anti-inflammatory capacity, thus being protective in various models of acute inflammation. However, their anti-inflammatory effect and a feasible mechanism in haemorrhage/resuscitation (H/R)-induced liver injury remain unknown. We investigated the effects of GTE and the role of NF-kappaB in the pathogenesis of liver injury induced by H/R, and their effects on intercellular adhesion molecule 1 (ICAM-1) expression and neutrophil infiltration. Female Lewis rats were fed a standard chow diet (control, ctrl) or a diet containing 0.1 % polyphenolic GTE for five consecutive days before H/R. Rats were haemorrhaged to a mean arterial pressure of 30 (sem 2) mmHg for 60 min and resuscitated. Control groups (sham_ctrl and sham_GTE) underwent surgical procedures without H/R. At 2 h after resuscitation, tissues were harvested. Serum alanine aminotransferase (ALT) and IL-6 were measured. Hepatic necrosis, ICAM-1 expression and polymorphonuclear leucocyte (PMNL) infiltration were assessed. Hepatic expression of IkappaBalpha (phospho) was measured. H/R induced strong liver damage with increased necrosis and serum ALT levels. Compared with both sham groups, inflammatory markers (serum IL-6 and hepatic PMNL infiltration) were elevated after H/R (P < 0.05). Also, H/R increased IkappaBalpha phosphorylation. GTE administration markedly (P < 0.05) decreased serum ALT and IL-6 levels, hepatic necrosis as well as PMNL infiltration and the expression of ICAM-1 and phosphorylated IkappaBalpha compared with H/R. In conclusion, we observed that NF-kappaB activation plays an important role in the pathogenesis of liver injury after H/R through the up regulation of hepatic ICAM-1 expression and subsequent PMNL infiltration. GTE pre treatment prevents liver damage in this model of acute inflammation through a NF kappaB-dependent mechanism. PMID- 21294936 TI - Helminth parasites of eastern box turtles (Terrapene carolina carolina) from southern Indiana, USA. AB - Very little is known about parasitic diseases of eastern box turtles (Terrapene carolina carolina). The objective of this study was to examine the parasitic fauna of eastern box turtles collected from southern Indiana, USA. Turtles (n = 40) were salvaged mostly as road kills from southern Indiana between May and October 2009. Seven species of helminths in total were found parasitizing the gastrointestinal tract, including two digenean trematodes (Brachycoelium salamandrae and Telorchis robustus) and five nematodes (Oswaldocruzia pipiens, Cosmocercoides dukae, Falcaustra affinis, F. chelydrae and Serpinema trispinosus). We report prevalence, abundance and mean intensity of infection for all helminths. Helminths were not found in any other organs examined (heart, gonads, liver, heart, kidney and urinary bladder) and no ectoparasites were found. Overall, mean intensity of infections was low (1-14 parasites/host), suggesting that these parasites are unlikely to be associated with negative health impacts. This constitutes the first study of this kind for Indiana. PMID- 21294937 TI - Spanish Revised Memory and Behavior Problems Checklist Scale (SpRMBPC): trans cultural adaptation and validation of the RMBPC questionnaire. AB - BACKGROUND: The use of standardized scales is critical for monitoring the interventions within and between different populations, but the current Spanish tools are dispersed in several scales. A simple tool for simultaneously and exhaustively evaluating patient's symptoms and caregiver's distress in Spanish speaking groups is needed. METHODS: RMBPC was translated into Spanish by cross cultural adaptation. Comprehensibility and easiness of SpRMBPC were evaluated with 92 patient-caregiver dyads. Reliability, stability and scale structure were evaluated by Cronbach's alpha, test-retest and factor analysis respectively. Concurrent and discriminant validity were assessed by correlation with validated tools for measuring stage of dementia; memory, disruptive behaviors and depression symptoms of the patients; and anxiety, depression and burden of the caregivers (CDR, MMSE, NPIq, NPI disruption, NPI depression, HADS-A; HADS-D and Zarit Burden Interview respectively). RESULTS: Almost all caregivers completed the questionnaire (97% completeness; 7.5% missing data). Both the frequency of Patient's Symptoms and Caregiver Reaction scores and subscores displayed high stability and reliability. All of these scores correlated positively with their respective validated tools as predicted, except with MMSE. The patients' subscores for Disruptive Behaviors and Memory Impairment displayed their highest correlation with the disruptive symptoms and level of dementia validated tools. CONCLUSIONS: SpRMBPC is a validated tool for assessing the dementia stage and the psychiatric morbidity of patients and caregivers. The Frequency Disruption and Memory subscales assess specifically patient's disruptive symptoms and dementia stages. These tools can be applied to analyze the burden of the patient's disease and the caregiver's distress in Spanish-speaking populations. PMID- 21294938 TI - Insulin-like growth factor-1 and delirium in critically ill mechanically ventilated patients: a preliminary investigation. AB - BACKGROUND: Delirium occurs frequently in the intensive care unit (ICU), but its pathophysiology is still unclear. Low levels of insulin-like growth factor 1 (IGF 1), a hormone with neuroprotective properties, have been associated with delirium in some non-ICU studies, but this relationship has not been examined in the ICU. We sought to test the hypothesis that low IGF-1 concentrations are associated with delirium during critical illness. METHODS: Mechanically ventilated medical ICU patients were prospectively enrolled, and blood was collected after enrollment for measurement of IGF-1 using radioimmunometric assay. Delirium and coma were identified daily using the Confusion Assessment Method for the ICU and the Richmond Agitation-Sedation Scale, respectively. The association between IGF 1 and delirium was evaluated with logistic regression. In addition, the association between IGF-1 and duration of normal mental state, measured as days alive without delirium or coma, was assessed using multiple linear regression. RESULTS: Among 110 patients, the median age was 65 years (IQR, 52-75) and APACHE II was 27 (IQR, 22 -32). IGF-1 levels were not a risk factor for delirium on the day after IGF-1 measurement (p = 0.97), at which time 65% of the assessable patients were delirious. No significant association was found between IGF-1 levels and duration of normal mental state (p = 0.23). CONCLUSIONS: This pilot study, the first to investigate IGF-1 and delirium in critically ill patients, found no association between IGF-1 and delirium. Future studies including serial measurements of IGF-1 and IGF-1 binding proteins are needed to determine whether this hormone has a role in delirium during critical illness. PMID- 21294939 TI - A qualitative investigation of adherence to nutritional therapy in malnourished adult AIDS patients in Kenya. AB - OBJECTIVE: To understand factors affecting the compliance of malnourished, HIV positive adults with a nutritional protocol using ready-to-use therapeutic food (RUTF; Plumpy'nut(r)). DESIGN: Qualitative study using key informant interviews, focus group discussions and direct observations. SETTING: Ministry of Health HIV/programme supported by Medecins Sans Frontiers (MSF) in Nyanza Province, Kenya. SUBJECTS: Adult patients (n 46) currently or previously affected by HIV associated wasting and receiving anti-retroviral therapy, their caregivers (n 2) and MoH/MSF medical employees (n 8). RESULTS: Thirty-four out of forty-six patients were receiving RUTF (8360 kJ/d) at the time of the study and nineteen of them were wasted (BMI < 17 kg/m2). Six of the thirteen wasted out-patients came to the clinic without a caregiver and were unable to carry their monthly provision (12 kg) of RUTF home because of physical frailty. Despite the patients' enthusiasm about their weight gain and rapid resumption of labour activities, the taste of the product, diet monotony and clinical conditions associated with HIV made it impossible for half of them to consume the daily prescription. Sharing the RUTF with other household members and mixing with other foods were common. Staff training did not include therapeutic dietetic counselling. CONCLUSIONS: The level of reported compliance with the prescribed dose of RUTF was low. An improved approach to treating malnourished HIV-positive adults in limited resource contexts is needed and must consider strategies to support patients without a caregiver, development of therapeutic foods more suited to adult taste, specific dietetic training for health staff and the provision of liquid therapeutic foods for severely ill patients. PMID- 21294940 TI - Improvement of behavioural and manic-like symptoms secondary to herpes simplex virus encephalitis with mood stabilizers: a case report. PMID- 21294941 TI - Adjunctive benzodiazepine treatment of hospitalized schizophrenia patients in Asia from 2001 to 2008. AB - Benzodiazepines are commonly prescribed to patients with schizophrenia in many countries, but as little is known about such treatment in Asia, we evaluated their adjunctive use for 6761 in-patients diagnosed with schizophrenia in nine Asian countries using a cross-sectional study design in 2001, 2004 and 2008. Multivariate logistic regression and multivariate linear regression analyses were performed to assess predictors of benzodiazepine use and dose, respectively. Overall, 54% of the patients received adjunctive benzodiazepines at an average daily dose equivalent to 30.3 mg diazepam, with minor changes over the years sampled. Benzodiazepine use was highest in Taiwan and Japan, lowest in Thailand and China, and was associated with fewer years ill, presence of delusions (OR 1.24), hallucinations (OR 1.22), disorganized speech (OR 1.17), social or occupational dysfunction (OR 1.16), and use of mood stabilizers (OR 3.15), antiparkinsonian (OR 1.79) or antidepressant drugs (OR 1.33), and lower doses of antipsychotics (all p=0.016 to <0.001). Benzodiazepine doses were highest in Taiwan and China, lowest in Korea and Singapore; higher doses were associated with being young, male, physically aggressive, receiving mood stabilizers, and having electroconvulsive treatment (all p=0.019 to <0.001). Benzodiazepine use was associated with neurological and systemic adverse effects. In conclusion, benzodiazepine use was common in Asian patients with schizophrenia. Predictors of benzodiazepine use and dose differed in this population. Critical clinical guidelines should be developed specifically for Asian countries to address sound practices in regard to use of benzodiazepines for psychotic disorders. PMID- 21294942 TI - Stability of prepulse inhibition and habituation of the startle reflex in schizophrenia: a 6-year follow-up study of initially antipsychotic-naive, first episode schizophrenia patients. AB - Deficits in information processing appear to be core features in the pathogenesis of schizophrenia. Prepulse inhibition (PPI) and habituation of the startle reflex are operational measures of early information processing. Impaired PPI in schizophrenia has been replicated in many studies and is regarded as an endophenotype for schizophrenia. However, reports on the stability of PPI over a longer period of time are lacking, both for patients with schizophrenia and for healthy subjects. The current study examined 25 initially drug-naive, first episode schizophrenia patients and 23 healthy matched controls. Three PPI measures [stimulus onset asynchrony (SOA) 30, 60, 120 ms] and habituation were assessed at baseline, and again after 6 yr. Sixteen patients and 17 healthy controls completed the study, and 13 patients and 17 healthy controls were included in the final analysis. The schizophrenia patients had PPI deficits compared to controls at baseline. After 6 yr, no significant group differences were found. PPI had increased significantly in the patients and had decreased significantly in controls. In addition, patients showed significantly less habituation than controls while habituation did not change in patients or controls. The present results show that PPI in drug-naive, first-episode schizophrenia patients can improve significantly over time. As PPI increased in patients over the same period that it decreased in controls, it is likely that the increase was caused by disease-related factors such as disease process, clinical state, or medication. PMID- 21294943 TI - Autologous serum improves yield and metabolic capacity of monocyte-derived hepatocyte-like cells: possible implication for cell transplantation. AB - Hepatocyte-transplantation is a therapeutic approach for diverse acute and chronic liver diseases. As availability of primary cells is limited, there is an increasing demand for hepatocyte-like cells (e.g., neohepatocytes generated from peripheral blood monocytes). The aim of this study was to evaluate the effects of six different human AB sera, fetal calf serum, or autologous serum on production of neohepatocytes. The yield and quality of neohepatocytes varied considerably depending on the different sera. Using autologous sera for the whole production process we constantly generated the highest amount of cells with the highest metabolic activity for phase I (e.g., CYP1A1/2, CYP3A4) and phase II enzymes (e.g., glutathione-S-transferase). Moreover, similar effects were seen examining glucose and urea metabolism. Especially, glucose-6-phosphatase and PAS staining showed distinct serum-dependent differences. The role of macrophage activation was investigated by measuring the secretion of TNF-alpha, TGF-beta, and RANKL, MMP activity, as well as mRNA levels of different interleukins in programmable cells of monocytic origin (PCMO). Our data clearly demonstrate that the use of autologous serum reduced initial macrophage activation in PCMOs and subsequently improved both yield and function of differentiated neohepatocytes. The autologous approach presented here might also be useful in other stem cell preparation processes where cell activation during generation shall be kept to a minimum. PMID- 21294944 TI - Emerging tropical diseases in Australia. Part 5. Hendra virus. AB - Hendra virus (HeV) was first isolated in 1994, from a disease outbreak involving at least 21 horses and two humans in the Brisbane suburb of Hendra, Australia. The affected horses and humans all developed a severe but unidentified respiratory disease that resulted in the deaths of one of the human cases and the deaths or putting down of 14 of the horses. The virus, isolated by culture from a horse and the kidney of the fatal human case, was initially characterised as a new member of the genus Morbillivirus in the family Paramyxoviridae. Comparative sequence analysis of part of the matrix protein gene of the virus and the discovery that the virus had an exceptionally large genome subsequently led to HeV being assigned to a new genus, Henipavirus, along with Nipah virus (a newly emergent virus in pigs). The regular outbreaks of HeV-related disease that have occurred in Australia since 1994 have all been characterised by acute respiratory and neurological manifestations, with high levels of morbidity and mortality in the affected horses and humans. The modes of transmission of HeV remain largely unknown. Although fruit bats have been identified as natural hosts of the virus, direct bat-horse, bat-human or human-human transmission has not been reported. Human infection can occur via exposure to infectious urine, saliva or nasopharyngeal fluid from horses. The treatment options and efficacy are very limited and no vaccine exists. Reports on the outbreaks of HeV in Australia are collated in this review and the available data on the biology, transmission and detection of the pathogen are summarized and discussed. PMID- 21294945 TI - Contribution of Anopheles funestus, An. gambiae and An. nili (Diptera: Culicidae) to the perennial malaria transmission in the southern and western forest areas of Cote d'Ivoire. AB - The involvement of members of the Anopheles gambiae complex Giles and An. funestus Giles and An. nili Theobald groups in the transmission of Plasmodium falciparum was recently investigated in the villages of Gbatta and Kpehiri, which lie, respectively, in forest areas in the west and south of Cote d'Ivoire. Adult female mosquitoes were collected, using human landing catches, inside and outside dwellings. After identification and dissection, the heads and thoraces of all the anopheline mosquitoes were tested, in an ELISA, for circumsporozoite protein (CSP). All the female anopheline mosquitoes collected and identified to species using PCR were found to be An. gambiae s.s., An. nili s.s. or An. funestus s.s., with An. gambiae s.s. and An. funestus s.s. predominant in Gbatta but An. nili s.s. the most common species in Kpehiri. In Gbatta, 3.1% of the female An. gambiae collected, 5.0% of the female An. funestus and 1.8% of the female An. nili were found CSP-positive. The corresponding values in Kpehiri were even higher, at 5.9%, 6.2% and 2.4%, respectively. The estimated entomological inoculation rates (EIR) were very high: 302 infected bites (139 from An. gambiae, 146 from An. funestus and 17 from An. nili)/person-year in Gbatta and 484 infected bites (204 from An. gambiae, 70 from An. funestus and 210 from An. nili)/person-year in Kpehiri. In Gbatta, An. gambiae s.s. was responsible for most of the rainy-season transmission while An. funestus became the main malaria vector in the dry seasons. In Kpehiri, however, An. nili appeared to be the main vector throughout the year, with An. gambiae of secondary importance and An. funestus only becoming a significant vector during the rainy season. Although, in both study sites, intense transmission was therefore occurring and the same three species of anopheline mosquito were present, the relative importance of each mosquito species in the epidemiology of the human malaria at each site differed markedly. PMID- 21294946 TI - Gastro-intestinal Chagas disease in migrants to Spain: prevalence and methods for early diagnosis. AB - Each year in Spain, the number of Latin American immigrants who present with chronic Trypanosoma cruzi infection increases. Although gastro-intestinal abnormalities are not as common as cardiomyopathy in such infection, they can still lead to an impaired quality of life. In a recent study based in Madrid, the frequencies of gastro-intestinal involvement in a cohort of Latin American immigrants infected with T. cruzi, and the role of early diagnostic techniques in the detection of such involvement, were explored. Between January 2003 and April 2009, all Latin Americans who attended the Tropical Medicine Unit of the Hospital Universitario Ramon y Cajal were tested for T. cruzi infection, in IFAT and ELISA. Each subject found both IFAT- and ELISA-positive was considered to be infected (chronically) and checked for symptoms indicative of Chagas disease. Each infected subject giving informed consent was investigated further, using an electrocardiogram, an echocardiogram and oesophageal manometry. Between January 2003 and June 2008, every infected subject who consented was also explored using a barium swallow and barium enema. After July 2008, however, only subjects showing oesophageal and/or colonic symptoms were investigated in this manner. Of the 248 patients found infected with T. cruzi, 118 underwent oesophageal manometry, 75 a barium enema and 48 a barium swallow. Thirteen (11%) showed evidence of oesophageal involvement (incomplete relaxation of the lower oesophageal sphincter; three cases) or bowel involvement (five cases of dolichosigma, three of dolichocolon and two of megacolon). Only six of these 13 had any gastro-intestinal symptoms (all six were suffering from constipation). None of the barium swallows revealed any pathology. It appears that oesophageal manometry can reveal mild abnormalities not detected by barium swallow, even in asymptomatic patients, while barium enemas are useful in the detection of colonic involvement. PMID- 21294947 TI - The Indian and Nepalese programmes of indoor residual spraying for the elimination of visceral leishmaniasis: performance and effectiveness. AB - Although, when applied under controlled conditions in India and Nepal, indoor residual spraying (IRS) has been found to reduce sandfly densities significantly, it is not known if IRS will be as effective when applied generally in these countries, via the national programmes for the elimination of visceral leishmaniasis. The potential benefits and limitations of national IRS programmes for the control of sandflies were therefore evaluated in the districts of Vaishali (in the Indian state of Bihar), Sarlahi (in Nepal) and Sunsari (also in Nepal). The use of technical guidelines, levels of knowledge and skills related to spraying operations, insecticide bio-availability on the sprayed surfaces, concentrations of the insecticide on the walls of sprayed houses, insecticide resistance, and the effectiveness of spraying, in terms of reducing sandfly densities within sprayed houses (compared with those found in unsprayed sentinel houses or control villages) were all explored. It was observed that IRS programme managers, at district and subdistrict levels in India and Nepal, used the relevant technical guidelines and were familiar with the procedures for IRS operation. The performance of the spraying activities, however, showed important deficiencies. The results of bio-assays and the chemical analysis of samples from sprayed walls indicated substandard spraying and suboptimal concentrations of insecticide on sprayed surfaces. This was particularly obvious at one of the Nepali study sites (Sunsari district), where no significant vector reduction was achieved. Sandfly resistance to the insecticide used in India (DDT) was widespread but the potential vectors in Nepal remained very susceptible towards a pyrethroid similar to the one used there. The overall short-term effectiveness of IRS was found to be satisfactory in two of the three study sites (in terms of reduction in the densities of the sandfly vectors). Unfortunately, the medium term evaluation, conducted 5 months after spraying, was probably made invalid by flooding or lime plastering in the study areas. Preparation for, and the monitoring of, the IRS operations against sandfly populations in India and Nepal need to be improved. PMID- 21294948 TI - Hospitalization of Cuban children for giardiasis: a retrospective study in a paediatric hospital in Havana. AB - The medical records of the 185 children who, in 2007, were admitted to the Academic Paediatric Hospital 'Centro Habana', in the Cuban capital of Havana, because of giardiasis were analysed retrospectively. A standardized form was used to collect data on the socio-demographic characteristics, clinical features, laboratory diagnosis, treatment and length of stay of each child. Information on the 15 children who had incomplete medical records was excluded from the data analysis. Of the remaining 170 children, 85 (50.0%) were aged 1-4 years, 97 (57.1%) were male, and 106 (62.4%), 92 (54.1%) and 69 (40.6%) had presented with diarrhoea, vomiting, and/or abdominal pain, respectively. Most (91.2%) of the cases had been diagnosed by the microscopical examination of a duodenal aspirate, and the drugs that had been most used frequently were quinacrine and tinidazole, which had been given to 72 (42.4%) and 62 (36.5%) of the cases, respectively. The mean length of hospital stay was 4.9 days. Such information on the clinical characteristics of giardiasis among children living in an endemic area may be valuable to paediatricians and public-health officials who wish to screen for the disease. PMID- 21294949 TI - Risk factors for Giardia infection among hospitalized children in Cuba. AB - The risk factors associated with Giardia infection, in children hospitalized in Havana, Cuba, were recently explored. Children aged >=5 years were more likely to be positive for Giardia infection than the younger children, with an odds ratio (OR) of 3.41 [95% confidence interval (CI) = 1.36-9.69]. The risk factors found to be associated with Giardia infection in univariate analyses were rural residence (OR = 3.01; CI = 1.23-7.35), belonging to a household that did not receive water from an aqueduct (OR = 3.27; CI = 1.21-8.91), drinking unboiled water (OR = 3.64; CI = 2.14-6.26), nail biting (OR = 3.47; CI = 1.97-6.08), eating unwashed vegetables raw (OR = 4.84; CI = 2.33-10.14), and a personal (OR = 3.23; CI = 1.58-6.59) or family history (OR = 3.96; CI = 1.53-10.47) of previous parasitic infection. In multivariate analyses, however, only two (modifiable) risk factors were found to be independently and significantly associated with Giardia infection: nail biting and eating unwashed vegetables raw. It therefore seems that, at least at the individual level, giardiasis-prevention activities in Havana should be focussed on health education to improve personal hygiene and food-related practices. If appropriately managed, the surveillance of drinking water and foodstuffs, for Giardia and other parasites, might also help to reduce the hospitalization of Cuban children. PMID- 21294950 TI - Treatment of angiostrongyliasis using a combination of albendazole and dexamethasone: the results of a retrospective and comparative study. AB - As the information available on the treatment of angiostrongyliasis with a combination of albendazole and dexamethasone is limited, the efficacy of such therapy was assessed using data collected during the 2006 outbreak of angiostrongyliasis in Beijing. In a retrospective and controlled study, 35 patients treated with albendazole-dexamethasone (given 20 mg albendazole/kg and 3 mg dexamethasone daily for 7 days) were compared with 34 controls who were treated only symptomatically (with acetaminophen or other drugs). Compared with the controls, the patients given the combination were less likely to have headaches after 7 days (P = 0.038), tended to have headaches that cleared quicker (P = 0.010), and received fewer doses of acetaminophen (P = 0.036). Since no serious adverse effects were observed, a 1-week treatment with a combination of albendazole and dexamethasone appears both safe and beneficial in the treatment of angiostrongyliasis. PMID- 21294951 TI - The role of fruit bats in the transmission of pathogenic leptospires in Australia. AB - Although antileptospiral antibodies and leptospiral DNA have been detected in Australian fruit bats, the role of such bats as infectious hosts for the leptospires found in rodents and humans remains unconfirmed. A cohort-design, replicated survey was recently conducted in Far North Queensland, Australia, to determine if the abundance and leptospiral status of rodents were affected by association with colonies of fruit bats (Pteropus conspicillatus spp.) via rodent contact with potentially infectious fruit-bat urine. In each of four study areas, a 'colony site' that included a fruit-bat colony and the land within 1500 m of the colony was compared with a 'control site' that held no fruit-bat colonies and was >2000 m from the nearest edge of the colony site. Rodents were surveyed, for a total of 2400 trap-nights, over six sampling sessions between September 2007 and September 2008. A low abundance of rodents but a high carriage of leptospires in the rodents present were found to be associated with proximity to a fruit-bat colony. For example, means of 0.4 and 2.3 fawn-footed melomys (Melomys cervinipes) were collected/100 trap-nights at sites with and without fruit-bat colonies, respectively (P<0.001), but the corresponding prevalences of leptospiral carriage were 100% and 3.6% (P<0.001). Such trends were consistent across all of the sampling sessions but not across all of the sampling sites. Leptospires were not isolated from fruit bats by culture, and the role of such bats in the transmission of leptospires to rodents cannot be confirmed. The data collected do, however, indicate the existence of a potential pathway for transmission of leptospires from fruit bats to rodents, via rodent contact with infectious fruit-bat urine. Fruit bats may possibly be involved in the ecology of leptospires (including emergent serovars), as disseminators of pathogens to rodent populations. Stringent quantitative risk analysis of the present and similar data, to explore their implications in terms of disease prevalence and wildlife population dynamics, is recommended. PMID- 21294952 TI - Pulmonary embolism in echinococcosis: two case reports and literature review. PMID- 21294953 TI - Pressure sores and myiasis: flesh flies (Diptera: Sarcophagidae) complicating a decubitus ulcer. PMID- 21294954 TI - Bone marrow contributes simultaneously to different neural types in the central nervous system through different mechanisms of plasticity. AB - Many studies have reported the contribution of bone marrow-derived cells (BMDC) to the CNS, raising the possibility of using them as a new source to repair damaged brain tissue or restore neuronal function. This process has mainly been investigated in the cerebellum, in which a degenerative microenvironment has been suggested to be responsible for its modulation. The present study further analyzes the contribution of BMDC to different neural types in other adult brain areas, under both physiological and neurodegenerative conditions, together with the mechanisms of plasticity involved. We grafted genetically marked green fluorescent protein/Cre bone marrow in irradiated recipients: a) the PCD (Purkinje Cell Degeneration) mutant mice, suffering a degeneration of specific neuronal populations at different ages, and b) their corresponding healthy controls. These mice carried the conditional lacZ reporter gene to allow the identification of cell fusion events. Our results demonstrate that BMDC mainly generate microglial cells, although to a lesser extent a clear formation of neuronal types also exists. This neuronal recruitment was not increased by the neurodegenerative processes occurring in PCD mice, where BMDC did not contribute to rescuing the degenerated neuronal populations either. However, an increase in the number of bone marrow-derived microglia was found along the life span in both experimental groups. Six weeks after transplantation more bone marrow-derived microglial cells were observed in the olfactory bulb of the PCD mice compared to the control animals, where the degeneration of mitral cells was in process. In contrast, this difference was not observed in the cerebellum, where Purkinje cell degeneration had been completed. These findings demonstrated that the degree of neurodegenerative environment can foster the recruitment of neural elements derived from bone marrow, but also provide the first evidence that BMDC can contribute simultaneously to different encephalic areas through different mechanisms of plasticity: cell fusion for Purkinje cells and differentiation for olfactory bulb interneurons. PMID- 21294955 TI - Autologous lung-derived mesenchymal stem cell transplantation in experimental emphysema. AB - Autologous lung-derived mesenchymal stem cells (LMSCs) were transplanted endoscopically into sheep with experimental emphysema to assess their capacity to regenerate functional tissue. LMSC lines were derived from transbronchial biopsies, cloned at passage 2, expanded in culture, and labeled. A delivery scaffold containing 1% fibrinogen, 20 MUg/ml of fibronectin, and 20 MUg/ml of poly-L-lysine was used to promote cell attachment and spreading. Treatment animals received scaffold containing 5-10 * 10(6) cells/site; control animals received scaffold alone. Phenotypic markers, differentiation capacity, extracellular matrix protein expression, and paracrine function of LMSCs were characterized in vitro. Responses to LMSC transplantation in vivo were assessed in terms of clinical toxicity, lung physiology, change in tissue mass (measured by CT scanning) and perfusion (measured by scintigraphy scanning), and tissue histology. At 4-week follow-up, transplants were well tolerated and associated with increased tissue mass and lung perfusion compared to control treatment. Histology confirmed cell retention, increased cellularity, and increased extracellular matrix content following LMSC treatment. Labeled cells were distributed in the alveolar septum and peribronchiolar interstitium. Some label was also present within phagocytes, indicating that a fraction of autologous LMSCs do not survive transplantation. These results suggest that endobronchial delivery of autologous LMSCs has potential therapeutic utility for regenerating functional lung in emphysema. PMID- 21294956 TI - Clinical-scale cultures of cord blood CD34(+) cells to amplify committed progenitors and maintain stem cell activity. AB - We developed a clinical-scale cord blood (CB) cell ex vivo procedure to enable an extensive expansion of committed progenitors--colony-forming cells (CFCs) without impairing very primitive hematopoietic stem cells (HSCs). CD34(++) cells, selected from previously cryopreserved and thawed CB units, were cultured in two steps (diluted 1:4 after 6 days) in the presence of stem cell factor (SCF), fms related tyrosine kinase 3 ligand (Flt-3L), megakaryocyte growth and development factor (MGDF) (100 ng/ml each), granulocyte-colony stimulating factor (G-CSF) (10 ng/ml) in HP01 serum-free medium. HSC activity was evaluated in a serial transplantation assay, by detection of human cells (CD45, CD33, CD19 and CFC of human origin) in bone marrow (BM) of primary and secondary recipient NOD/SCID mice 6-8 weeks after transplantation. A wide amplification of total cells (~350 fold), CD34(+) cells (~100-fold), and CFC (~130-fold) without impairing the HSC activity was obtained. The activity of a particular HSC subpopulation (SRC(CFC)) was even enhanced.Thus, an extensive ex vivo expansion of CFCs is feasible without impairing the activity of HSCs. This result was enabled by associating antioxidant power of medium with an appropriate cytokine cocktail (i.e., mimicking physiologic effects of a weak oxygenation in hematopoietic environment). PMID- 21294957 TI - Novel culture technique involving an histone deacetylase inhibitor reduces the marginal islet mass to correct streptozotocin-induced diabetes. AB - Islet transplantation is limited by the difficulties in isolating the pancreatic islets from the cadaveric donor and maintaining them in culture. To increase islet viability and function after isolation, here we present a novel culture technique involving an histone deacetylase inhibitor (HDACi) to rejuvenate the isolated islets. Pancreatic islets were isolated from Sprague-Dawley (SD) rats and one group (FIs; freshly isolated islets) was used after overnight culture and the other group (RIs; rejuvenated islet) was subjected to rejuvenation culture procedure, which is composed of three discrete steps including degranulation, chromatin remodeling, and regranulation. FIs and RIs were compared with regard to intracellular insulin content, glucose-stimulated insulin secretion (GSIS) capacity, gene expression profile, viability and apoptosis rate under oxidative stresses, and the engraftment efficacy in the xenogeneic islet transplantation models. RIs have been shown to have 1.9 +/- 0.28- and 1.7 +/- 0.31-fold greater intracellular insulin content and GSIS capacity, respectively, than FIs. HDACi increased overall histone acetylation levels, with inducing increased expression of many genes including insulin 1, insulin 2, GLUT2, and Ogg1. This enhanced islet capacity resulted in more resistance against oxidative stresses and increase of the engraftment efficacy shown by reduction of twofold marginal mass of islets in xenogeneic transplantation model. In conclusion, a novel rejuvenating culture technique using HDACi as chromatin remodeling agents improved the function and viability of the freshly isolated islets, contributing to the reduction of islet mass for the control of hyperglycemia in islet transplantation. PMID- 21294958 TI - Enhanced survival of dopaminergic neuronal transplants in hemiparkinsonian rats by the p53 inactivator PFT-alpha. AB - A key limiting factor impacting the success of cell transplantation for Parkinson's disease is the survival of the grafted cells, which are often short lived. The focus of this study was to examine a novel strategy to optimize the survival of exogenous fetal ventromesencephalic (VM) grafts by treatment with the p53 inhibitor, pifithrin-alpha (PFT-alpha), to improve the biological outcome of parkinsonian animals. Adult male Sprague-Dawley rats were given 6 hydroxydopamine into the left medial forebrain bundle to induce a hemiparkinsonian state. At 7 weeks after lesioning, animals were grafted with fetal VM or cortical tissue into the lesioned striatum and, thereafter, received daily PFT-alpha or vehicle injections for 5 days. Apomorphine-induced rotational behavior was examined at 2, 6, 9, and 12 weeks after grafting. Analysis of TUNEL or tyrosine hydroxylase (TH) immunostaining was undertaken at 5 days or 4 months after grafting. The transplantation of fetal VM tissue into the lesioned striatum reduced rotational behavior. A further reduction in rotation was apparent in animals receiving PFT-alpha and VM transplants. By contrast, no significant reduction in rotation was evident in animals receiving cortical grafts or cortical grafts + PFT-alpha. PFT-alpha treatment reduced TUNEL labeling and increased TH(+) cell and fiber density in the VM transplants. In conclusion, our data indicate that early postgrafting treatment with PFT-alpha enhances the survival of dopamine cell transplants and augments behavioral recovery in parkinsonian animals. PMID- 21294959 TI - Pdx1- and Ngn3-Cre-mediated PLAG1 expression in the pancreas leads to endocrine hormone imbalances that affect glucose metabolism. AB - Pleomorphic adenoma gene-like 1 (PLAGL1) has been linked to transient neonatal diabetes mellitus. Here, we investigated the role of the related pleomorphic adenoma gene 1 (PLAG1) in glucose homeostasis. PLAG1 transgenic mice in which expression of the PLAG1 transgene can be targeted to different organs by Cre mediated modulation were crossed with Pdx1-Cre or Ngn3-Cre mice, resulting in double transgenic P1-Pdx1Cre or P1-Ngn3Cre mice, respectively. P1-Pdx1Cre and P1 Ngn3Cre mice developed hyperplasia of pancreatic islets due to increased beta- and delta- but not alpha-cell proliferation. In young P1-Pdx1Cre mice (less than 15 weeks) there was a balanced increase in the pancreatic content of insulin and somatostatin, which was associated with normoglycemia. In older P1-Pdx1Cre mice the pancreatic somatostatin content far exceeded that of insulin, leading to the progressive development of severe hypoglycemia beyond 30 weeks. In contrast, in older P1-Ngn3Cre mice the relative increase of the pancreatic insulin content exceeded that of somatostatin and these mice remained normoglycemic. In conclusion, forced expression of PLAG1 under the control of the Pdx1 or Ngn3 promoter in murine pancreas induces different degrees of endocrine hormone imbalances within the pancreas, which is associated with hypoglycemia in P1 Pdx1Cre mice but not P1-Ngn3Cre mice. These results suggest that once stem cell derived islet transplantations become possible, the appropriate balance between different hormone-producing cells will need to be preserved to prevent deregulated glucose metabolism. PMID- 21294960 TI - The effect of two- and three-dimensional cell culture on the chondrogenic potential of human adipose-derived mesenchymal stem cells after subcutaneous transplantation with an injectable hydrogel. AB - Articular cartilage is an avascular tissue composed of chondrocytes, a unique cell type responsible for abundant matrix synthesis and maintenance. When damaged, it never heals spontaneously under physiological circumstances. Therefore, the delivery of mesenchymal stem cells using hydrogel has been considered for cartilage repair. This study aims at investigating the influence of in vitro chondrogenic differentiation of human adipose tissue-derived stem cells (hATSCs) on in vivo cartilage formation when associated with a cellulose based self-setting hydrogel (Si-HPMC). hATSCs were characterized for their proliferation, surface marker expression, and multipotency. The in vitro chondrogenic potential of hATSCs cultured within Si-HPMC in control or chondrogenic medium was evaluated by measuring COL2A1, ACAN, SOX9, and COMP expression by real-time PCR. Alcian blue and type II collagen staining were also performed. To determine whether in vitro chondrogenically differentiated hATSCs may give rise to cartilage in vivo, cells differentiated as a monolayer or in pellets were finally associated with Si-HPMC and implanted subcutaneously into nude mice. Cartilage formation was assessed histologically by alcian blue and type II collagen staining. Our data demonstrate that hATSCs exhibited proliferation and self-renewal. hATSCs also expressed typical stem cell surface markers and were able to differentiate towards the adipogenic, osteogenic, and chondrogenic lineages. Real-time PCR and histological analysis indicated that Si HPMC enabled chondrogenic differentiation of hATSCs in inductive medium, as demonstrated by increased expression of chondrogenic markers. In addition, histological analysis of implants showed that chondrogenically differentiated hATSCs (monolayers or pellets) have the ability to form cartilaginous tissue, as indicated by the presence of sulphated glycosaminoglycans and type II collagen. This study therefore suggests that an in vitro induction of hATSCs in 2D was sufficient to obtain cartilaginous tissue formation in vivo. Si-HPMC associated with autologous hATSCs could thus be a significant tool for regenerative medicine in the context of cartilage damage. PMID- 21294961 TI - A novel and simplified method of culture of human blood-derived early endothelial progenitor cells for the treatment of ischemic vascular disease. AB - Endothelial progenitor cells (EPCs) consist of two different subpopulations named early (eEPCs) and late EPCs (lEPCs) that are derived from CD14(+) and CD14(-) circulating cells, respectively. These cells are regularly cultured over fibronectin-coated surfaces in endothelial basal medium (EBM)-2 supplemented with insulin-like growth factor (IGF-1), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and fibroblast growth factor (FGF). We have developed a new and simplified method for culturing human EPCs obtained from peripheral blood and tested their ability to preserve cardiac function following infarction. We first demonstrated that eEPCs derived from human peripheral blood mononuclear cells (PBMCs) and cultured in EBM-2 medium supplemented with autologous serum (10%) over fibronectin-coated surfaces (10 MUg/ml) in the presence of IGF-1 (50 ng/ml) only, have a secretome similar to eEPCs cultured under regular conditions with IGF-1, VEGF, EGF, and FGF. Our data also indicate that IGF-1 modulates PBMC secretome in a dose-dependent manner. In another series of experiments, we showed that PBMCs cultured in suspension in bags (S-PBMCs) in basal medium supplemented with fibronectin and IGF-1 secrete significant amounts of stem cell factor (SCF, 31.3 +/- 3.1 pg/ml)), hepatocyte growth factor (HGF, 438.6 +/- 41.4 pg/ml), soluble tumor necrosis factor receptor 1 (sTNFR1, 127.1 +/ 9.9 pg/ml), VEGF (139.3 +/- 9.6 pg/ml), and IGF-1 (147.2 +/- 46.1 pg/ml) but very low levels of TNF-alpha (13.4 +/- 2.5 pg/ml). S-PBMCs injected intravenously into NOD SCID mice migrated to the injured myocardium, reduced cardiac fibrosis, enhanced angiogenesis, and preserved cardiac function after myocardial infarction (MI) in a manner similar to eEPCs cultured under standard conditions. In conclusion, we show in this study a refined and optimized method for culturing eEPCs. Our data indicate that S-PBMCs are composed of several cell populations including eEPCs and that they secrete high amounts of antiapoptotic, anti inflammatory, and proangiogenic factors capable of preserving cardiac function following MI. PMID- 21294962 TI - Improvement of rat islet viability during transplantation: validation of pharmacological approach to induce VEGF overexpression. AB - Delayed and insufficient revascularization during islet transplantation deprives islets of oxygen and nutrients, resulting in graft failure. Vascular endothelial growth factor (VEGF) could play a critical role in islet revascularization. We aimed to develop pharmacological strategies for VEGF overexpression in pancreatic islets using the iron chelator deferoxamine (DFO), thus avoiding obstacles or safety risks associated with gene therapy. Rat pancreatic islets were infected in vivo using an adenovirus (ADE) encoding human VEGF gene (4.10(8) pfu/pancreas) or were incubated in the presence of DFO (10 MUmol/L). In vitro viability, functionality, and the secretion of VEGF were evaluated in islets 1 and 3 days after treatment. Infected islets or islets incubated with DFO were transplanted into the liver of syngenic diabetic rats and the graft efficiency was estimated in vivo by measuring body weight, glycemia, C-peptide secretion, and animal survival over a period of 2 months. DFO induced transient VEGF overexpression over 3 days, whereas infection with ADE resulted in prolonged VEGF overexpression lasting 14 days; however, this was toxic and decreased islet viability and functionality. The in vivo study showed a decrease in rat deaths after the transplantation of islets treated with DFO or ADE compared with the sham and control group. ADE treatment improved body weight and C-peptide levels. Gene therapy and DFO improved metabolic control in diabetic rats after transplantation, but this effect was limited in the presence of DFO. The pharmacological approach is an interesting strategy for improving graft efficiency during transplantation, but this approach needs to be improved with drugs that are more specific. PMID- 21294963 TI - Alternatively expressed genes identified in the CD4+ T cells of allograft rejection mice. AB - Allograft rejection is a leading cause for the failure of allotransplantation. CD4(+) T cells play critical roles in this process. The identification of genes that alternatively expressed in CD4(+) T cells during allograft rejection will provide critical information for studying the mechanism of allograft rejection, finding specific gene markers for monitoring, predicting allograft rejection, and opening new ways to regulate and prevent allograft rejection. Here, we established allograft and isograft transplantation models by adoptively transferring wild-type BALB/c mouse CD4(+) T cells into severe combined immunodeficient (SCID) mice with a C57BL/6 or BALB/c mouse skin graft. Using the whole transcriptome sequencing-based serial analysis of gene expression (SAGE) technology, we identified 97 increasingly and 88 decreasingly expressed genes that may play important roles in allograft rejection and tolerance. Functional classification of these genes shows that apoptosis, transcription regulation, cell growth and maintenance, and signal transduction are among the frequently changed functional groups. This study provides a genome-wide view for the candidate genes of CD4(+) T cells related to allotransplantation, and this report is a good resource for further microarray studies and for identifying the specific markers that are associated with clinical organ transplantations. PMID- 21294964 TI - Effect of dimethyl sulfoxide (DMSO) on cryopreservation of porcine mesenchymal stem cells (pMSCs). AB - Dimethyl sulfoxide (DMSO), a commonly used cryoprotectant in cryopreservation procedures, is detrimental to viability of cells. In this view point, a comparative study was carried out to evaluate the effect of DMSO on porcine mesenchymal stem cells (pMSCs). We compared the viability, colony forming unit fibroblast (CFU-F) assay, expression of Bak and Bcl2 genes, Bcl2 protein antigen, and CD90 in pMSCs cryopreserved with 5%, 10%, and 20% DMSO. pMSCs isolated from bone marrow were characterized by alkaline phosphatase activity and the expression of transcription factors, such as Oct 3/4, Nanog, and Sox2. The cells were then cryopreserved by cooling at a rate of -1 degrees C/min in a programmable freezer and stored in liquid nitrogen. The results of survival of pMSCs cryopreserved at 5% DMSO were comparable to control group (fresh pMSCs). The survival and the number of colonies formed in cryopreserved pMSCs were inversely proportional to the concentration of DMSO. The number of colonies formed in pMSCs cryopreserved with all concentrations of DMSO was significantly (p < 0.05) lower than the control group. An increased tendency for Bak and Bcl2 gene expression was noticed in cryopreserved pMSCs at 3 h postthawing compared to control group. There was a close resemblance in higher level of expression of CD90 between control and cryopreserved pMSCs. Because there was no considerable difference in the results of pMSCs cryopreserved at 5% and 10% DMSO, this study strongly suggests the use of 5% DMSO in cryopreservation of pMSCs as an alternative to conventional 10% DMSO. PMID- 21294965 TI - Synthesis of O-oleoyl-chitosan and its sorption properties for lipoproteins. AB - In this study a lipotropic chitosan derivative, O-oleoyl-chitosan (OOCs), was obtained through the attachment of oleoyl groups to hydroxyl groups at C-6 of chitosan. The degree of substitution of OOCs was approx. 14-15%. OOCs had good solubility in organic solvents. Lipoprotein sorption tests in vitro and circular dichroism spectroscopy were applied to investigate the interaction between lipoproteins and OOCs. Observations indicated that the lipotropic OOCs, especially with lower viscosity-average molecular weight, could improve both LDL binding capacity and selectivity in human plasma. Circular dichroism analysis showed that the secondary structure of LDL was markedly changed by OOCs, for the alpha-helical content of the LDL was increased when interacted with OOCs. OOCs were proven to be effective for selective removal of LDL in plasma. PMID- 21294966 TI - Caprine (goat) collagen: a potential biomaterial for skin tissue engineering. AB - Collagens presently used in tissue engineering are primarily of bovine or porcine origin. However, a risk of a spongiform encephalopathy epidemic has limited the use of collagen from these sources. Keeping the aforementioned perspective in mind, we explored the possibility of using domestic goat available in the subcontinent as a potential source of collagen for tissue-engineering application. This article delineates the isolation, physico-chemical characterization, biocompatibility study and wound healing application of acid soluble caprine (goat) tendon collagen (GTC). Physico-chemical characterization of 1% acetic acid extracted GTC was done by SDS-PAGE, amino-acid composition analysis, FT-IR and CD spectroscopy. Results revealed that GTC was comprised of type-I collagen. Biocompatibility study showed that GTC augmented cell adhesion, cell cycle progression and proliferation. Immuno-cytochemical analysis in conjugation with traction force microscopy further confirmed a superior focal adhesion complex mediated cell-substrate interaction in GTC. Finally, in vivo study in mice model revealed that GTC has low immunogenicity and it augments healing process significantly. Throughout the study, calf skin collagen (CSC) was used as standard for comparative evaluation. In conclusion, it can be said that GTC may find its application as biomaterial in skin tissue engineering. PMID- 21294967 TI - Time controlled release of arabinofuranosylcytosine (Ara-C) from agarose hydrogels using layer-by-layer assembly: an in vitro study. AB - Experimentally induced axonal regeneration is compromised by glial scar formation arising from leptomeningeal fibroblasts cells in and around the hydrogel scaffold implanted for nerve repair. Strategies are needed to prevent such fibroblastic reactive cell layer formation for enhanced axonal regeneration. Here, we implement the technique of layer-by-layer assembled degradable, hydrogen bonded multilayers on agarose hydrogels to incorporate an anti-mitotic drug (1-beta-D arabinofuranosylcytosine (Ara-C)) within the agarose hydrogels. We show controlled release of Ara-C under physiological conditions over a period of days. The concentrations of Ara-C released from agarose at the different time points were sufficient to inhibit fibroblast growth in vitro, while not adversely affecting the viability of the neuronal cells. PMID- 21294968 TI - Investigation on injectable, thermally and physically gelable poly(ethylene glycol)/poly(octadecanedioic anhydride) amphiphilic triblock co-polymer nanoparticles. AB - A family of injectable, biodegradable and thermosensitive co-polymer nanoparticle (NP) hydrogels based on mPEG-b-POA-b-mPEG, which was synthesized from mono methoxy poly(ethylene glycol) (mPEG) and poly(octadecanedioic anhydride) (POA), was investigated in this paper. It was found that the aqueous dispersions of these NPs underwent a reversible gel-sol transition upon temperature change. By using paclitaxel and Bovine serum albumin (BSA) as model drugs, we noticed that the in vitro releases of both in situ gel-forming formulations were sustained and no initial burst releases were observed for 7 days. In vitro cytotoxicity tests via MTT assay indicate that mPEG-b-POA-b-mPEG NPs are non-toxic to normal mouse lung fibroblast cells (L929). The in vivo hydrogel formation and in vivo biocompatibility of co-polymer NP hydrogel were also investigated and the results further validate the biocompatible nature of co-polymer NP hydrogel. In conclusion, our mPEG-b-POA-b-mPEG NP hydrogel is able to control the release of incorporated drug for longer duration. PMID- 21294969 TI - Controlled drug release through a plasma polymerized tetramethylcyclo tetrasiloxane coating barrier. AB - A plasma polymerized tetramethylcyclo-tetrasiloxane (TMCTS) coating was deposited onto a metallic biomaterial, 316 stainless steel, to control the release rate of drugs, including daunomycin, rapamycin and NPC-15199 (N-(9-fluorenylmethoxy carbonyl)-leucine), from the substrate surface. The plasma-state polymerized TMCTS thin film was deposited in a vacuum plasma reactor operated at a radio frequency of 13.56 MHz, and was highly adhesive to the stainless steel, providing a smooth and hard coating layer for drugs coated on the substrate. To investigate the influence of plasma coating thickness on the drug diffusion profile, coatings were deposited at various time lengths from 20 s to 6 min, depending on the type of drug. Atomic force spectroscopy (AFM) was utilized to characterize coating thickness. Drug elution was measured using a spectrophotometer or high performance liquid chromatography (HPLC) system. The experimental results indicate that plasma polymerized TMCTS can be used as an over-coating to control drug elution at the desired release rate. The drug-release rate was also found to be dependent on the molecular weight of the drug with plasma coating barrier on top of it. The in vitro cytotoxicity test result suggested that the TMCTS plasma coatings did not produce a cytotoxic response to mammalian cells. The non cytotoxicity of TMCTS coating plus its high thrombo-resistance and biocompatibility are very beneficial to drug-eluting devices that contact blood. PMID- 21294970 TI - Regenerated silk fibroin nanofibrous matrices treated with 75% ethanol vapor for tissue-engineering applications. AB - As an excellent biocompatible and biodegradable protein polymer, silk fibroin (SF) has found wide applications, particularly serving as therapeutic agent for tissue-engineering applications, on which both post-spin treatment and sterilization processing are crucial to drug-loaded matrices. To find a safe, effective and appropriate post-spin treatment and sterilization approach for drug loaded biomaterial matrices is one of the major problems in the field of tissue engineering at present. In this work, a simple, safe and effective approach skillfully integrating post-spin treatment with sterilization processing was developed to drug-loaded SF nanofibrous matrices. Electrospun SF nanofibrous matrices from its aqueous solution were post-treated with 75% ethanol vapor. (13)C-NMR and WAXD analysis demonstrated that such post-spin treatment rendered the structure of SF nanofibrous matrices transform from the silk I form to the silk II form. Furthermore, biological assays suggested that as-treated SF nanofibrous matrices significantly promoted the development of murine connective tissue fibroblasts. Skillfully integrated with novel sterilization processing, 75% ethanol vapor treatment could be a potential approach to designing and fabricating diverse drug-loaded SF nanofibrous matrices serving as therapeutic agents for tissue-engineering applications in that it can effectively protect the drug from losing compared with traditional post-spin treatment and sterilization processing. PMID- 21294971 TI - An ectopic study of apatite-coated silk fibroin scaffolds seeded with AdBMP-2 modified canine bMSCs. AB - The present study was undertaken to evaluate ectopic new bone formation effects of apatite-coated silk fibroin scaffolds (mSS) seeded with adenovirus-mediated bone morphogenic protein-2 gene (AdBMP-2) transduced canine bone marrow stromal cells (bMSCs) in nude mice. In this study, bMSCs derived from canine were cultured and transduced with AdBMP-2 adenovirus-mediated enhanced green fluorescent protein gene (AdEGFP) in vitro. Osteogenic differentiation of bMSCs was determined by alkaline phosphatase (ALP) activity analysis, and the transcript levels for BMP-2, osteopontin (OPN), osteocalcin (OCN) and bone sialoprotein (BSP) genes via real-time quantitative PCR (RT-qPCR) analysis. The ectopic bone formation effects of mSS seeded with AdBMP-2-modified bMSCs were evaluated through histological and histomorphological analysis 4, 8 and 12 weeks post-operation in nude mice. ALP activity was statistically increased in the AdBMP-2 group, when compared with control groups. The mRNA expression of BMP-2, OPN, OCN and BSP was also statistically up-regulated 6 and 9 days after AdBMP-2 transduction. Significantly higher bone volume was achieved in AdBMP-2-transduced bMSCs/mSS constructs than that of AdEGFP-transduced bMSCs/mSS or bMSCs/mSS groups at 4, 8 and 12 weeks (P < 0.01). These results demonstrated that mSS seeded with AdBMP-2-transduced canine bMSCs can promote ectopic new bone formation and maturation in nude mice, suggesting the potential of this silk scaffold-based tissue-engineered bone for further bone regeneration studies in canine models. PMID- 21294972 TI - Correlation analysis of two serum-specific immunoglobulin E test systems and skin prick test in allergic rhinitis patients from northeast China. AB - BACKGROUND: Skin-prick testing (SPT) is the most common screening method for allergy evaluation. The detection of serum-specific immunoglobulin E (sIgE) is also commonly used. The sensitivity and specificity of these testing methods may vary due to type of causative allergen and type of allergic manifestation. The purpose of this study was to evaluate the correlation between two methods of measuring sIgE (AllergyScreen [Mediwiss Analytic GmbH, Moers, Germany] and ImmunoCAP [Pharmacia, Uppsala, Sweden]) and SPT for the diagnosis of allergic rhinitis (AR). METHODS: All 216 patients who were referred to the allergist for suspected AR from June to October 2009 had SPT and the two serological tests. One hundred fifty-eight patients had a positive clinical history and a related positive SPT. The SPT was used as reference standard, and we selected three allergens (Dermatophagoides pteronyssinus, mugwort, and ragweed), which were common in fall in northeast China, to analyze the correlation of the two serum tests and SPT. RESULTS: Compared with the SPT, the diagnostic indexes (accuracy, sensitivity and specificity) of the AllergyScreen system and the ImmunoCAP system were 0.819 versus 0.810, 0.780 versus 0.872, and 0.862 versus 0.741, respectively. The accuracy was similar between the two systems (p > 0.05). The ImmunoCAP system method had a higher sensitivity (p < 0.01). The AllergyScreen system had a higher specificity (p < 0.01). CONCLUSION: These data support that the AllergyScreen system and ImmunoCAP system can identify potentially significant allergens in the diagnosis of AR in patients from northeastern China. PMID- 21294973 TI - Endoscopic surgery for acquired choanal atresia after radiotherapy for nasopharyngeal carcinoma. AB - BACKGROUND: This study was designed to investigate the role of endoscopic surgery for acquired choanal atresia after radiotherapy for nasopharyngeal carcinoma. METHODS: Twenty-two patients with bilateral or unilateral acquired choanal atresia received transnasal endoscopic surgery with the aid of a powered microdebrider to open atresia choana and received endoscopic sinus surgery simultaneously if they had sinusitis. Merocel epistaxis packing was used to pack the nasal airway for 3 days postoperatively. All of the patients underwent endoscopy regularly for follow-up. RESULTS: Sixteen patients with acquired bilateral choanal atresia and 6 with unilateral choanal atresia were included in this study. The median age was 46 years old (range, 33-65 years). Twenty-one patients had sinusitis. Sixteen patients with bilateral choanal atresia and 4 patients with unilateral atresia had bilateral sinusitis. One patient with unilateral atresia had ipsilateral sinusitis. The mean follow-up period was 35 months (range, 12-72 months) after surgery. Twenty patients were symptom-free after a single operation; nasal obstruction, rhinorrhea, and xerostomia improved significantly for these patients. Two patients had unilateral restenosis that required revision surgery, and both were subsequently free from further restenosis. No complications occurred. CONCLUSION: Acquired posterior choanal atresia after radiotherapy can be successfully treated with transnasal endoscopic resection assisted by a powered instrument without stenting. PMID- 21294974 TI - Transdifferentiation of Clara cell 10-kDa protein secreting cells in experimental allergic rhinitis. AB - BACKGROUND: The reasons for the down-regulated Clara cell 10-kDa protein (CC10) expression in allergic rhinitis (AR) are unclear and the airway remodeling in AR has received little attention. This study explores epithelium remodeling and the change of CC10 secreting cells in AR by using a murine model. METHODS: AR murine models were established by ovalbumin sensitization and challenge. In some mice, dexamethasone was given before each challenge. Histological changes of nasal mucosa were examined by means of hematoxylin and eosin and periodic acid-Schiff staining. CC10 and trefoil factor family (TFF) 1 expression were evaluated by immunohistochemistry. RESULTS: In AR mice, both in turbinate and in septal mucosa, total cell number and the number of basal cells did not change; however, the number of dome-shaped cells decreased and the number of ciliated and goblet cells increased in turbinate mucosa, and the number of ciliated cells decreased and the number of goblet cells increased in septal mucosa. In turbinate mucosa, the number of CC10(+) cells (mainly dome-shaped cells) decreased whereas the number of TFF1(+) cells (mainly ciliated cells) increased. In septal mucosa, the number of CC10(+) and TFF1(+) cells (mainly ciliated cells) decreased simultaneously. Intermediate phenotypic goblet cells could express CC10 and TFF1. CC10 and TFF1 could be localized in the same cells. Dexamethasone reversed the changes of epithelium significantly. CONCLUSION: Allergen exposure leads to a possible transdifferentiation of CC10 secreting cells into TFF1 secreting cells and/or goblet cells in upper airways. Nasal turbinate and septal epithelium display different patterns of transdifferentiation. PMID- 21294976 TI - Community health workers for diabetes: can they help deliver improved care? PMID- 21294977 TI - Physician-community health worker partnering to support diabetes self-management in primary care. AB - BACKGROUND: The role of community health workers (CHWs) has expanded from outreach and education to working within a clinical team in a primary care setting. AIM: To improve self-management among patients with type 2 diabetes incorporating CHWs as members of a clinical team. METHODS: A cohort of 114 patients with type 2 diabetes enrolled in 2007 participated in a teambased self management intervention with followup in 2008. The study assessed whether significant changes occurred in clinical, patient satisfaction and activation measures after the intervention compared with baseline. The programme was located at St Luke's Health Care Center in San Francisco, California, in an ethnically diverse neighbourhood serving predominantly low-income Latino patients. Clinical outcomes measured included glycosylated haemoglobin (HbA1c), low-density lipoprotein (LDL), blood pressure and total cholesterol. A Patient Activation Measure (PAM) assessed self-management. Both provider and patient experiences with the programme were also assessed using a patient telephone satisfaction survey and provider focus group. RESULTS: The majority of patients were Latino Spanish speaking women on public insurance. Thirty-one patients participated in a telephone satisfaction survey. Six providers participated in a focus group to assess satisfaction with care. HealthFirst had a positive impact, improving HbA1c among high-risk patients with type 2 diabetes (HbA1c>= 9.0) and maintaining glycaemic control among patients with controlled glycaemic level at baseline (HbA1c<7.0). In addition, LDL, total cholesterol and self-management outcomes significantly improved. Ninety-seven percent of patients were satisfied with the CHWs' support. Overall, providers' comfort level in referring patients to CHWs was very high. CONCLUSIONS: Physician-CHW partnership had a positive impact on patients' self-management skills and clinical outcomes. Patients and physicians also had higher satisfaction with overall care. With appropriate training, CHWs can collaborate as team members with primary care providers and with non-medical providers to improve the quality of care. PMID- 21294978 TI - Influences on patient satisfaction survey results: is there a need for a rethink? AB - BACKGROUND: Patient experience is a key principle of the NHS and is increasingly linked to payment of providers. AIM: To establish if any correlation exists between patient satisfaction scores (as measured in the MORI survey) and practice list size or deprivation score. METHOD: This was a retrospective correlation review using data for general practices in Derbyshire County Primary Care Trust extracted from existing publicly available sources. Correlation between satisfaction score and both deprivation index and practice list size was examined. RESULTS: Data from all 96 practices were reviewed. Overall satisfaction showed a statistically significant negative correlation with deprivation (r= 0.28, P=0.006). Neither question pertaining to QOF payment showed a correlation with deprivation, however, there was a statistically significant negative correlation with list size (Q5a r=-0.52, P <0.01. Q7 r=-0.43, P <0.01). Questions regarding satisfaction with the doctor showed weak but statistically significant negative correlations with deprivation, (r varying from -0.21 to -0.39, P <0.05). Satisfaction with nurses showed positive correlations with deprivation, with satisfaction increasing in line with deprivation (r varying from 0.24 to 0.36, P <0.05). Regarding list size, for nurse care the reverse was seen, with increased list size being linked to decreased satisfaction (r varying from -0.21 to -0.45, P <0.05). CONCLUSION: Although variables showed weak correlations, there were correlations between list size and deprivation in the results of the patient experience questionnaire. Linking this to payment has implications for primary care contracting. PMID- 21294979 TI - Improving primary care quality now and into the next decade. PMID- 21294980 TI - Effect of a residential retreat promoting lifestyle modifications on health related quality of life in people with multiple sclerosis. AB - AIM: To evaluate the effect of a residential retreat on promoting lifestyle modification for the health-related quality of life (HRQOL) of people with multiple sclerosis (MS). METHODS: A longitudinal cohort study of adults with self reported MS who voluntarily attended a five-day residential retreat in rural Victoria, Australia. Participants were asked to complete the MSQOL-54 questionnaire just prior to the retreat, and at one year and 2.5 years post retreat. RESULTS: Of 188 participants 109 (58%) completed the questionnaire. The cohort showed a significant improvement in HRQOL at one year and 2.5 year follow up. After one year, overall quality of life (QOL) domain had increased from 73.4 to 81.7 (P<0.001), physical health composite from 66.2 to 76.4 (P=0.001) and mental health composite from 73.7 to 83.6 (P<0.001) in the subset of 76 with data at both time points. After 2.5 years, overall QOL had increased from 68.4 to 71.7 (P=0.03), physical health 59.7 to 70.0 (P=0.01), and mental health 66.9 to 76.6 (P<0.01) in the subset of 44 with data at both time points. CONCLUSIONS: HRQOL usually deteriorates over time in people with MS. Attendance at a residential retreat promoting lifestyle modification appears to have a significant short medium term positive effect on QOL for people with MS. General practitioners caring for people with MS should consider the potential benefits of this approach in overall management. PMID- 21294981 TI - A study of general practitioners' knowledge of ionizing radiation from diagnostic imaging examinations. AB - BACKGROUND: General practitioners (GPs) often decide to refer patients for medical imaging with ionizing radiation and are therefore responsible for assessing the benefits of the procedure against the possible risks. OBJECTIVE: To assess the level of general practitioners' knowledge concerning radiation doses for patients undergoing common radiological investigations and the associated risks of these radiation doses. METHOD: I used a self-administered postal questionnaire survey sent to all 200 GPs working in municipal general practices in Bergen to investigate their knowledge about radiation doses and the risks associated with ionizing radiation. RESULTS: The response rate was 47%. Most GPs showed poor knowledge of radiation doses and associated risks. Male GPs had greater knowledge compared with female GPs (P=0.049). GPs with training in radiation safety had significantly greater knowledge compared with those with no radiation safety training (P=0.005). CONCLUSION: Overall, GPs' knowledge of radiation doses and the risks associated with ionizing radiation was reported to be poor. PMID- 21294982 TI - An international perspective on the basis for payment for performance. AB - This discussion paper reflects on the pay-for-performance system in UK general practice - the Quality and Outcomes Framework (QOF) - from an international viewpoint. The QOF intends to bring the best scientific evidence to bear on primary care practice. However, the QOF and patient-centred medicine are often at odds. Inadequacies and commercial bias in the creation of evidence make the scientific basis of the QOF questionable. The framework for the QOF does not align well with the scope of primary care, making its basis as a tool for quality measurement questionable. The extent of impact of the QOF on health outcomes and on equity of health outcomes needs examination. Attention to resolution of patients' problems is an important aim of quality improvement activities. Alternative modes of improving patient care may be better than the QOF. PMID- 21294983 TI - Improving access to health care: is the investment in walk-in centres paying off? PMID- 21294984 TI - Web alert: resources to support commissioning - Part 1. PMID- 21294989 TI - Accuracy of bacterial DNA testing for central venous catheter-associated bloodstream infection in children with cancer. AB - BACKGROUND: Central venous catheters (CVCs) are widely used for children with cancer and are a major risk factor for bloodstream infection. Early and specific diagnosis of CVC-associated bloodstream infection allows early targeted treatment, reducing the risk of CVC removal and avoiding the operative risks and trauma of reinsertion, but peripheral vein sampling, as used in adults, improves specificity but is not usually acceptable in children. OBJECTIVE: To improve the detection and treatment of CVC-associated bloodstream infection in children (aged 0-18 years) with cancer admitted with fever. METHODS: There were four main studies: (1) evaluation of the diagnostic accuracy of a quantitative molecular method for the detection of bacterial deoxyribonucleic acid (DNA), based solely on blood samples drawn through the CVC; (2) analysis of the prognostic risk of CVC removal and duration of intravenous (i.v.) antibiotic treatment days in relation to presenting clinical features, blood culture results and bacterial DNA test results; (3) systematic reviews of treatment options for CVC-associated infection and a questionnaire survey of current practice in paediatric oncology centres; (4) evaluation of the clinical effectiveness of different test-treatment strategies to reduce i.v. antibiotic treatment days and unnecessary CVC removals. RESULTS: (1) The bacterial DNA test detected two-thirds [95% confidence interval (CI) 44% to 83%] of children classified with probable CVC-associated infection - specificity was 88% (95% CI 84% to 92%). Although high bacterial DNA concentrations were associated with subsequent CVC removal and long duration of i.v. antibiotic treatment, the test did not improve the prediction of these outcomes over and above clinical signs of CVC-associated infection combined with blood culture results. (2) High DNA load was predictive of CVC removal and i.v. treatment duration, before blood culture results became available at 48 hours after sampling. (3) There was limited evidence that antibiotic lock treatment reduces the risk of recurrent CVC-associated infection or CVC removal (pooled relative risk 0.7, 95% CI 0.47 to 1.05), but prophylactic use of antimicrobial locks halved the risk of bloodstream infection (pooled incidence rate ratio 0.43, 95% CI 0.36 to 0.51). Contrary to this, the national survey of paediatric oncology centres found that locks are being used for treatment rather than prevention and that problems related to the formulation of lock solutions currently impede a shift to their prophylactic use in children. (4) Most i.v. treatment days would be saved by early stopping of treatment for children at low risk of infection. LIMITATIONS: The accuracy study was limited primarily by the lack of an adequate reference standard, and the main limitation of the series of systematic reviews was the poor quality of included studies and lack of randomised controlled trials of CVC removal or antimicrobial locks for treatment of infection. CONCLUSIONS: There is strong evidence to support the use of antimicrobial locks for prevention of CVC-associated infection; however, few of these studies involved children with cancer. The analysis does not support routine bacterial DNA testing on admission to detect CVC-associated infection, but repeated testing (as a marker of microbial load) should be evaluated in high risk groups. Further research should determine the effectiveness of antibiotic locks for treating CVC-associated infection. TRIAL REGISTRATION: Current Controlled Trials ISRCTN68138140. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 15, No. 7. See the HTA programme website for further project information. PMID- 21294990 TI - Antidepressant use in the absence of common mental disorders in the general population. AB - OBJECTIVE: To examine the prevalence of antidepressant use in the absence of lifetime mental disorders and to examine sociodemographic correlates, indicators of need (hospitalization, suicidal behavior, perceived need, subthreshold disorders, disability, traumatic events), and antidepressant characteristics of such use. METHOD: Data came from the Collaborative Psychiatric Epidemiologic Surveys (N = 20,013), a nationally representative cross-sectional sample of community-dwelling adults in the United States. Sociodemographic correlates and indicators of need were examined as predictors of past-year use of antidepressants in the absence of a lifetime DSM-IV diagnosis as assessed by the World Mental Health Composite Diagnostic Interview. The surveys were conducted between 2001 and 2003. RESULTS: Among individuals who took an antidepressant in the past year (n = 1,441), 396 (26.3%) did not meet criteria for any lifetime diagnosis assessed. Respondents taking antidepressants in the absence of a lifetime diagnosis tended to be older, white, and female. All indicators of need except past-year suicidal behavior were significant predictors (adjusted odds ratios ranging from 2.12 to 14.22, P < .001), with 89% of individuals taking antidepressants in the absence of a lifetime diagnosis endorsing at least 1 indicator of need. Individuals taking antidepressants in the absence of a DSM-IV disorder were more likely to have been prescribed these medications by family physicians or other doctors compared to psychiatrists. CONCLUSIONS: These results suggest that antidepressant use among individuals without psychiatric diagnoses is common in the United States and is typically motivated by other indicators of need. These findings have important implications for the delivery of medical and psychiatric care and psychiatric nosology. PMID- 21294991 TI - Self-harm subscale of the Schedule for Nonadaptive and Adaptive Personality (SNAP): predicting suicide attempts over 8 years of follow-up. AB - OBJECTIVE: We examined the predictive power of the self-harm subscale of the Schedule for Nonadaptive and Adaptive Personality (SNAP) to identify suicide attempters in the Collaborative Longitudinal Study of Personality Disorders (CLPS). METHOD: The SNAP, a self-report personality inventory, was administered to 733 CLPS participants at baseline, of whom 701 (96%) had at least 6 months of follow-up data. Cox proportional hazards regression analyses were performed to examine the SNAP-self-harm subscale (SNAP-SH) in predicting the 129 suicide attempters over 8 years of follow-up. Possible moderators of prediction were examined, including borderline personality disorder, major depressive disorder (MDD), and substance use disorder. We also compared baseline administration of the SNAP-SH to subsequent administrations more proximal to the suicide attempt, and to a higher-order SNAP-negative temperament (SNAP-NT) subscale. Receiver operating characteristic analyses were conducted using suicide attempts (n = 58) over the first year of follow-up to provide reference points for sensitivity and specificity. RESULTS: The SNAP-SH demonstrated good predictive power for suicide attempts (hazard ratio = 1.28, P < .001) and appeared relatively consistent across borderline personality disorder, MDD, and substance use disorder diagnoses. Using more proximal scores did not increase predictive power. The SNAP SH compared favorably to the predictive power of the higher-order SNAP-NT. Receiver operating characteristic analyses indicate several cutoff scores on the SNAP-SH that yield moderate to high sensitivity and specificity for predicting suicide attempts over the first year of follow-up. CONCLUSIONS: The SNAP-SH may be a useful screening instrument for risk of suicide attempts in nonpsychotic psychiatric patients. PMID- 21294992 TI - Quality of reporting of randomized controlled trials of pharmacologic treatment of bipolar disorders: a systematic review. AB - OBJECTIVE: This study aimed to assess (1) the quality of reporting of randomized controlled trials of pharmacologic treatment of bipolar disorder, (2) the potential improvement in quality of reporting over time, and (3) differences in quality of reporting between journals that endorse or do not endorse the Uniform Requirements for Manuscripts Submitted to Biomedical Journals developed by the International Committee of Medical Journal Editors. DATA SOURCES: A systematic literature search was done to identify all randomized controlled trials published between 2000 and 2008 relevant to the pharmacologic treatment of bipolar disorder. The search strategy of the published National Institute for Health and Clinical Excellence guideline for management of bipolar disorders was used and adapted. All included and excluded clinical trials mentioned in the guideline and published from 2000 onward were reviewed for eligibility. For an update search from July 2004 through December 2008, an adapted search strategy was used in MEDLINE, EMBASE, PsycINFO, CINAHL, Ovid, and Cochrane Central Register of Controlled Trials. Titles and abstracts were scanned for relevance, and full texts were ordered in case of uncertainty to maximize sensitivity. Reference lists of retrieved systematic reviews were checked. STUDY SELECTION: All full texts were checked for eligibility. Only relevant randomized controlled trials published between 2000 and 2008 were included. Abstracts, randomized controlled trials published before 2000, nonrandomized clinical studies, pooled analyses, editorials, reviews, case reports, observational studies, and unpublished reports were excluded. DATA EXTRACTION: A checklist based on the Consolidated Standards of Reporting Trials (CONSORT) statement was used to assess quality of reporting of all included studies. RESULTS: A total of 105 randomized controlled trials were included in the analysis. Of the 72 applicable checklist items, 42% were generally reported adequately and 25% inadequately. Reporting was especially poor for randomization procedures, with, for example, 16% of studies defining generation of random allocation sequence and 15% defining method of allocation concealment. Inadequate randomization increases the potential for bias to influence the final results. Authors of clinical guidelines or health technology assessments are forced to exclude or downgrade trials with inadequate reporting on randomization. Also, information with essential clinical relevance was generally reported inadequately, such as the effect size (in 18% of studies) and the number needed to treat (in 8% of studies). Both effect measures are more important for clinicians than individual point estimates that have been reported adequately. No consistent trend could be shown for improvement in quality of reporting over time or for reporting of essential methodological items differently in journals that endorse the Uniform Requirements for Manuscripts (URM). The reporting of information on clinical relevance and generalizability of results, however, showed a consistent trend toward better reporting in journals endorsing the URM, with significant differences for the reporting of secondary outcomes (100% vs 89.9%; P = .03) and adverse events (93.2% vs 73.8%; P = .011) and interpretation of results with regard to totality of data (30.2% vs 11.5%; P = .029). CONCLUSIONS: Our findings suggest that, while some trial-related information is well reported, a good part of the reporting quality of randomized controlled trials in bipolar disorder falls well below the required and also practically feasible level for many aspects essential for adequate interpretation of methodological quality and clinical relevance. Authors should be further encouraged to follow the CONSORT criteria. PMID- 21294993 TI - Increased olanzapine discontinuation and health care resource utilization following a Medicaid policy change. AB - OBJECTIVE: To assess the short-term impact of Florida Medicaid's policy change on olanzapine discontinuation and health care resource utilization among olanzapine treated patients with schizophrenia or bipolar diagnoses. The announced policy change, effective on July 11, 2005, but rescinded on September 9, 2005, reclassified olanzapine as nonpreferred and gave physicians 60 days to change antipsychotics for current users. METHOD: Prescription patterns, health care resource utilization, and Medicaid payments were compared between patients using olanzapine on July 11, 2005, and matched prior-year controls. For reference, parallel analyses were conducted in New Jersey Medicaid, where access to olanzapine remained constant. The effect of Florida's policy change was also estimated among policy-sensitive olanzapine users by treating year (2004 vs 2005) as an instrumental variable. RESULTS: Matched Florida cohorts (N = 4,255) showed increases from 2004 to 2005 in 6-month rates of switching from olanzapine (+326%), hospitalization (+19.8%), and emergency room visits (+19.7%) (all P values < .001). Concurrently in the matched New Jersey cohorts (N = 2,680), there were no significant changes in these outcomes from 2004 to 2005. Among matched Florida policy-sensitive olanzapine users, an additional 9.3% experienced hospitalization in 2005 versus 2004 (P < .001), and increased payments for medical services and other antipsychotics largely offset decreased payments for olanzapine. CONCLUSIONS: The announced reclassification of olanzapine to nonpreferred status substantially disrupted the continuity of olanzapine therapy for many Florida Medicaid recipients diagnosed with schizophrenia or bipolar disorder and was associated with increased hospitalization and emergency room visits. During the 6 months following the policy change, increased payments for medical services largely offset reduced payments for olanzapine. PMID- 21294994 TI - Comorbidity patterns of anxiety and depressive disorders in a large cohort study: the Netherlands Study of Depression and Anxiety (NESDA). AB - BACKGROUND: Comorbidity of depressive and anxiety disorders is common and has been shown to be a consistent predictor of chronicity. Comorbidity patterns among specific depressive and anxiety disorders have not been extensively reported. This study examines comorbidity patterns and temporal sequencing of separate depressive and anxiety disorders using data from a large psychiatric cohort. METHOD: Baseline data (N = 1,783) of the Netherlands Study of Depression and Anxiety, collected between September 2004 and February 2007, were used. Current and lifetime comorbidity rates for depressive and anxiety disorders (DSM-IV-TR criteria) were calculated. Associations of comorbidity with sociodemographic, vulnerability, and clinical characteristics, and temporal sequencing of disorders were examined. RESULTS: Of those with a depressive disorder, 67% had a current and 75% had a lifetime comorbid anxiety disorder. Of persons with a current anxiety disorder, 63% had a current and 81% had a lifetime depressive disorder. Comorbidity of depressive and anxiety disorders was associated with more childhood trauma (OR = 1.19; 95% CI, 1.06-1.33), higher neuroticism (OR = 1.05; 95% CI, 1.02-1.08), earlier age at onset of first disorder (OR = 1.59; 95% CI, 1.22-2.07), longer duration of depressive and/or anxiety symptoms (OR = 1.01; 95% CI, 1.01-1.01), and higher symptom severity (ORs ranging from 1.01 to 1.03; all P values < .05). In 57% of comorbid cases, anxiety preceded depression, and in 18%, depression preceded anxiety. Comorbidity with preceding depression compared to preceding anxiety was associated with a shorter duration of symptoms of depressive and/or anxiety symptoms (OR = 0.99; 95% CI, 0.98-0.99), earlier age at first onset (OR = 0.46; 95% CI, 0.31-0.68), and fewer fear symptoms (OR = 0.98; 95% CI, 0.97-0.99). CONCLUSIONS: Comorbidity rates in anxiety and depressive disorders were very high, indicating that it is advisable to assess both disorders routinely regardless of the primary reason for consultation. This is especially important since comorbid patients showed a specific vulnerability pattern, with more childhood trauma, neuroticism, and higher severity and duration of symptoms. PMID- 21294995 TI - Binge drinking and Axis I psychiatric disorders in community-dwelling middle-aged and older adults: results from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). AB - OBJECTIVE: The aims of this study were to document the sociodemographic correlates of binge drinking in middle-aged and older adults and to test the association of binge drinking with the occurrence of DSM-IV mood, anxiety, and alcohol use disorders; smoking; and the use of illicit drugs independently of sociodemographic variables and lifetime diagnosis of the disorder in question. METHOD: We conducted secondary data analyses based on a subsample of a 3-year prospective, population-based study, the National Epidemiologic Survey on Alcohol and Related Conditions, which consisted of a nationally representative sample of 13,489 American community-dwelling adults aged 50 years and above, interviewed in both 2001-2002 and 2004-2005. This survey assessed the occurrence of 11 DSM-IV mood, anxiety, and alcohol use disorders; nicotine dependence; and the use of illicit drugs during the 3-year follow-up period by using the National Institute on Alcohol Abuse and Alcoholism's Alcohol Use Disorder and Associated Disabilities Interview Schedule-DSM-IV Version. RESULTS: We found that, among persons aged 50 years and above, 15.6% of men and 5.7% of women reported binge drinking in the year prior to baseline assessment in 2001-2002. After adjustment was made for covariates, both men who were occasional binge drinkers and men who were frequent binge drinkers were significantly more likely than current male drinkers without binge drinking to have alcohol abuse disorder (adjusted odds ratio [AOR] = 2.90 [95% CI, 1.82-4.62] and AOR = 5.68 [95% CI, 3.79-8.51], respectively) and alcohol dependence disorder (AOR = 3.69 [95% CI, 1.75-7.75] and AOR = 9.21 [95% CI, 5.59-15.18], respectively). Similarly, after adjustment was made for covariates, both women who were occasional binge drinkers and women who were frequent binge drinkers were significantly more likely than current female drinkers without binge drinking to have alcohol abuse disorder (AOR = 4.43 [95% CI, 1.85-10.60] and AOR = 3.49 [95% CI, 1.64-7.43], respectively) and alcohol dependence disorder (AOR = 5.20 [95% CI, 1.56-17.33] and AOR = 19.47 [95% CI, 7.59-49.98], respectively). In addition, in female subjects, occasional binge drinking was associated with an increased risk of panic disorder without agoraphobia (AOR = 2.23; 95% CI, 1.01-4.91) and posttraumatic stress disorder (AOR = 2.67; 95% CI, 1.05-6.84). CONCLUSIONS: Binge drinking is strongly associated with a higher risk of alcohol use disorder in middle-aged and older adults in the United States. Results provide valuable information on the risks associated with binge drinking and suggest targets for prevention strategies for mental health in middle and old age. PMID- 21294996 TI - Relationship between daily dose, plasma concentrations, dopamine receptor occupancy, and clinical response to quetiapine: a review. AB - OBJECTIVE: To assess the relationships among quetiapine blood concentration, daily dose, dopamine receptor occupancy, and clinical outcome in order, if possible, to define a target plasma level range in which therapeutic response is enhanced and adverse events are minimized. DATA SOURCES: A search of the database Embase from 1974 to March 2009 and the databases MEDLINE and PubMed from 1966 to March 2009 was conducted. The drug name quetiapine was searched with each of the terms plasma levels, plasma concentration, therapeutic drug monitoring, and dopamine occupancy. STUDY SELECTION: The search uncovered 42 relevant articles. All published reports of quetiapine plasma or serum concentration were considered for inclusion if reported in relation to a dose, clinical outcome, or dopamine occupancy. After application of exclusion criteria, 20 articles remained. DATA EXTRACTION: Trials designed primarily to investigate an interaction between quetiapine and another medication were excluded, as were those designed to compare methods of blood sample analysis. DATA SYNTHESIS: There was a weak correlation between quetiapine dose and measured plasma concentration (from trough samples). Quetiapine dose was correlated with central dopamine D(2) occupancy, although the relationship between plasma level and D(2) occupancy is less clear. CONCLUSIONS: The dose-response relationship for (immediate-release) quetiapine is established. Data on plasma concentration-response relationships are not sufficiently robust to allow determination of a therapeutic plasma level range for quetiapine. Therapeutic drug monitoring procedures are thus probably not routinely useful in optimizing quetiapine dose. Further examination of the relationship between peak quetiapine plasma concentration and clinical response is necessary. PMID- 21294997 TI - Efficacy and safety of loxapine for inhalation in the treatment of agitation in patients with schizophrenia: a randomized, double-blind, placebo-controlled trial. AB - OBJECTIVE: The objective of this study was to assess the efficacy and safety of inhaled loxapine in the treatment of agitation in patients with psychotic disorders. METHOD: In this randomized, double-blind, placebo-controlled study, 129 agitated patients with schizophrenia or schizoaffective disorder (DSM-IV criteria) were randomized to receive in a clinical or hospital setting a single inhalation of 5 or 10 mg of loxapine or placebo administered using the Staccato loxapine for inhalation device. The inhalation device delivered thermally generated drug aerosol to the deep lung for rapid absorption. The primary efficacy measure was change on the Positive and Negative Syndrome Scale-excited component (PANSS-EC) 2 hours following treatment. Secondary outcomes included the Clinical Global Impressions-Improvement scale (CGI-I), Behavioral Activity Rating Scale (BARS), and time to first rescue medication. The study was conducted between September 2006 and January 2007. RESULTS: Differences were statistically significant (P < .05) between placebo and both 5-mg and 10-mg doses on the CGI-I and the CGI-I responder analyses at 2 hours and in time to first rescue medication, and they were statistically significant (P < .05) between placebo and 10-mg loxapine on the PANSS-EC 20 minutes after administration continuing through 2 hours and in change from baseline BARS. Three serious adverse events occurred at least 6 days after treatment, but none were judged related to study treatment. The most common adverse events were sedation and dysgeusia (22% and 17%, respectively, in the 10-mg group, and 14% and 9%, respectively, in the placebo group). CONCLUSIONS: Inhaled loxapine was generally safe and well tolerated and produced rapid improvement in agitated patients with psychotic disorders. Statistically significant differences in efficacy were found for the 10-mg dose compared with placebo, with results suggesting 5 mg may be effective. The delivery of loxapine by inhalation may provide a rapid, well-tolerated option for treating acute psychotic agitation that allows patients to avoid the aversive effects and loss of autonomy often associated with use of intramuscular medications. Further investigation of this new loxapine formulation is warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00369577. PMID- 21294998 TI - Serum lipoproteins improve after successful pharmacologic antidepressant treatment: a randomized open-label prospective trial. AB - OBJECTIVE: Despite reports of lower plasma cholesterol in depressed patients, major depressive disorder has been shown to increase cardiovascular risk. Our objective was to study the composition of lipoproteins in depressed patients and controls and to examine the effects of pharmacologic treatment and treatment response on lipoprotein composition. METHOD: Lipoprotein composition was analyzed in 65 adult inpatients at a university psychiatric hospital in Germany with DSM IV major depressive disorder and 33 healthy controls (recruited via newspaper and radio ads) matched for age and sex. After the cross-sectional study phase, the patients were randomized in an open-label prospective trial to treatment with either mirtazapine or venlafaxine. Lipoproteins were reanalyzed after 4 weeks of treatment. Main outcome measures were total cholesterol, the low-density lipoprotein (LDL) to high-density lipoprotein (HDL) cholesterol ratio, and the LDL triglycerides to apolipoprotein B ratio. Secondary outcome measures were total triglycerides, HDL and LDL cholesterol levels, and apolipoproteins A1 and B levels. Comparisons were made between the 2 drug groups and between remitters and nonremitters as measured by the 21-item Hamilton Depression Rating Scale. The study was conducted from April 2003 through December 2007. RESULTS: Total cholesterol at baseline was lower in patients than in controls (mean +/- SD = 4.99 +/- 0.98 mmol/L vs 5.63 +/- 1.01 mmol/L; P = .003), with significantly lower HDL cholesterol (P < .001) and LDL cholesterol (P = .03) in patients. However, the ratio of LDL triglycerides to apolipoprotein B, an index of size and atherogenic potential of LDL particles, was higher in depressed subjects (mean +/ SD = 0.46 +/- 0.14 mmol/g vs 0.38 +/- 0.09 mmol/g; P = .002). Irrespective of treatment allocation, we found significant improvement of cardiovascular risk parameters in remitters but found deterioration in nonresponders. The LDL cholesterol mean change from baseline (remitters vs partial responders vs nonresponders) was -0.06 mmol/L versus +0.39 mmol/L versus +0.56 mmol/L (P = .014); the mean change in LDL/HDL cholesterol ratio was -0.50 versus +0.14 versus +0.80 (P = .002); and the mean change in the LDL triglycerides per apolipoprotein B ratio was -0.01 versus -0.01 versus +0.08 (P = .045). No drug-specific changes in lipid concentrations during treatment were observed except for total cholesterol (venlafaxine group mean = -0.02 mmol/L and mirtazapine group mean = +0.37 mmol/L; P = .033). CONCLUSIONS: In depressed patients, lipoprotein structure is changed toward LDL particles with a higher atherogenic potential. Remission from depression is associated with an improvement of the LDL/HDL cholesterol ratio, shifting lipoproteins toward a less atherogenic composition. Our findings should be confirmed in a larger study, as they have relevance for both researchers and clinicians. TRIAL REGISTRATION: German Clinical Trial Registry Identifier: DRKS00000008. PMID- 21294999 TI - The "doses" of initial, untreated hallucinations and delusions: a proof-of concept study of enhanced predictors of first-episode symptomatology and functioning relative to duration of untreated psychosis. AB - OBJECTIVE: A prominent limitation of literature on duration of untreated psychosis (DUP) is that researchers have studied only unidimensional duration as an early-course predictor, neglecting potential effects of frequency/severity of initial, untreated psychosis. This study demonstrates utility of the concept of "doses" of initial, untreated hallucinations and delusions-representing more complete measures of "exposure"-as enhanced predictors of symptomatology/functioning relative to DUP alone. METHOD: 109 first-episode patients with a psychotic disorder based on Structured Clinical Interview for DSM IV Axis I Disorders criteria were assessed at 3 public-sector psychiatric units serving an urban, socially disadvantaged, predominantly African American community between July 2004 and June 2008. Dependent variables included negative symptoms, general psychopathology, insight, and global functioning at initial hospitalization. RESULTS: When added to a baseline model (age, gender, and premorbid academic and social functioning), DUP predicted current negative symptoms (P = .02, model R(2) = 0.20), though dose of hallucinations and dose of delusions did not. However, regarding general psychopathology symptoms, DUP was not predictive, though dose of delusions was, when controlling for the other 5 variables (P = .02, model R(2) = 0.15). DUP was not a significant predictor of insight, though dose of hallucinations was, such that a greater dose of initial, untreated hallucinations was associated with better insight at initial hospitalization (P < .01, model R(2) = 0.20). DUP was associated with global functioning (P = .05), and dose of delusions added significantly to this prediction (P = .04; model R(2) = 0.13). CONCLUSIONS: Doses of initial, untreated hallucinations and delusions add substantively, though differentially, to the prediction of early-course symptomatology and functioning. Findings suggest a need for focused research on frequency/severity of pretreatment psychotic symptoms beyond duration measures. PMID- 21295000 TI - Measurement-based care in psychiatric practice: a policy framework for implementation. AB - This article describes the need for measurement-based care (MBC) in psychiatric practice and defines a policy framework for implementation. Although measurement in psychiatric treatment is not new, it is not standard clinical practice. Thus a gap exists between research and practice outcomes. The current standards of psychiatric clinical care are reviewed and illustrated by a case example, along with MBC improvements. Measurement-based care is defined for clinical practice along with limitations and recommendations. This article provides a policy top 10 list for implementing MBC into standard practice, including establishing clear expectations and guidelines, fostering practice-based implementation capacities, altering financial incentives, helping practicing doctors adapt to MBC, developing and expanding the MBC science base, and engaging consumers and their families. Measurement-based care as the standard of care could transform psychiatric practice, move psychiatry into the mainstream of medicine, and improve the quality of care for patients with psychiatric illness. PMID- 21295001 TI - The association between social isolation and DSM-IV mood, anxiety, and substance use disorders: wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions. AB - OBJECTIVE: The objective of this study is to document the prevalence of social isolation from close friends and religious group members and to test the association of having infrequently contacted close friends and members of religious groups with the current DSM-IV mood, anxiety, and substance use disorders. METHOD: We conducted a secondary data analysis based on a cross sectional, population-based study conducted in 2004-2005 that consists of a nationally representative sample of 34,653 American community-dwelling adults aged 18 years and older. Mood, anxiety, and substance use disorders were assessed using the Alcohol Use Disorder and Associated Disabilities Interview Schedule-DSM IV version. Due to missing values for social network characteristics, we focused on 33,368 subjects in this study. RESULTS: We found that many Americans lacked frequently contacted close friends (10.1%; 95% CI, 9.6%-10.6%) or religious group members (58.7%; 95% CI, 57.5%-59.9%) in their social network. After adjusting for sociodemographic variables, lifetime diagnosis of the disorder in question, and social isolation in terms of 10 other social ties, we found that the absence of close friends was associated (P < .01) with an increased risk of major depressive disorder, dysthymic disorder, social phobia, and generalized anxiety disorder; the absence of frequently contacted religious group members in a network was positively related (P < .01) to alcohol abuse and dependence, drug abuse, and nicotine dependence. CONCLUSIONS: These results suggest that social isolation is common in the United States and is associated with a higher risk of mental health problems. Results provide valuable information for prevention and treatment. PMID- 21295002 TI - Effectiveness and safety of vagus nerve stimulation for severe treatment resistant major depression in clinical practice after FDA approval: outcomes at 1 year. AB - OBJECTIVE: To describe the outcomes of a consecutive series of depressed patients treated with vagus nerve stimulation (VNS) following US Food and Drug Administration (FDA) approval of this intervention. METHOD: We implanted a VNS device in 15 consecutive outpatients with treatment-resistant major depressive episodes, including 10 with major depressive disorder and 5 with bipolar disorder (DSM-IV criteria), between November 2005 and August 2006. Existing antidepressant treatment remained fixed as far as clinically possible. The primary outcome was change from baseline in the Beck Depression Inventory (BDI) score. Outcomes were assessed at 6 and 12 months postimplant and compared to those of the VNS pivotal efficacy trial that led to FDA approval of VNS. RESULTS: The BDI score decreased significantly compared to baseline at 6 months (P < .05) and 12 months (P < .01), from a mean of 37.8 (SD = 7.8) before VNS activation to a mean of 24.6 (SD = 11.4) at 12 months. By 1 year, 28.6% (n = 4) of the sample responded to VNS and 7.1% (n = 1) remitted according to the BDI. Secondary outcomes on the Hamilton Depression Rating Scale 24-Item showed similar improvement at 1 year, with a 43% response rate (n = 6) and 14.3% remission rate (n = 2). No obvious predictors of response were detected. Side effects of VNS included hoarseness (73%), dyspnea (47%), nausea (40%), pain (33%), and anxiety (20%); no patient terminated treatment due to intolerable side effects. CONCLUSIONS: We found that a substantial minority of patients with extremely difficult-to-treat depressive disorders benefited from VNS in an ambulatory clinical practice, with outcomes comparable to those observed in previous VNS efficacy studies and with a similar side effect profile. PMID- 21295003 TI - A chemical compound for controlled expression of nmt1-driven gene in the fission yeast Schizosaccharomyces pombe. AB - The fission yeast Schizosaccharomyces pombe is a useful model organism for studying a variety of eukaryotic cellular events such as the cell cycle control mechanisms. For inducible expression of exogenous genes in S. pombe, vectors carrying the nmt1 (no message in thiamine 1) promoter are most commonly used. Although nmt1 is a potent promoter, its transcription activity is drastically repressed in the presence of a low concentration of thiamine. Therefore, a combination of thiamine and nmt1 promoter is convenient for regulating gene expression in an all-or-none fashion. However, it has been difficult to adjust the nmt1 promoter activity in a controlled manner. Here we describe a chemical compound, designated as YAM2, whose repressive activity on the nmt1 promoter has a wider linear range than thiamine. Expression of exogenous proteins, such as human immunodeficiency virus type 1 Vpr and jellyfish green fluorescent protein, driven by the nmt1 promoter is gradually repressed by YAM2 in a dose-dependent manner. YAM2 does not exhibit a detectable level of cytotoxicity at a concentration required to fully repress the nmt1 promoter. The compound may serve as a useful tool for controlled expression of the nmt1-driven gene in S. pombe. PMID- 21295004 TI - G-protein-coupled receptor prediction using pseudo-amino-acid composition and multiscale energy representation of different physiochemical properties. AB - G-protein-coupled receptors (GPCRs) are the largest family of cell surface receptors that, via trimetric guanine nucleotide-binding proteins (G-proteins), initiate some signaling pathways in the eukaryotic cell. Many diseases involve malfunction of GPCRs making their role evident in drug discovery. Thus, the automatic prediction of GPCRs can be very helpful in the pharmaceutical industry. However, prediction of GPCRs, their families, and their subfamilies is a challenging task. In this article, GPCRs are classified into families, subfamilies, and sub-subfamilies using pseudo-amino-acid composition and multiscale energy representation of different physiochemical properties of amino acids. The aim of the current research is to assess different feature extraction strategies and to develop a hybrid feature extraction strategy that can exploit the discrimination capability in both the spatial and transform domains for GPCR classification. Support vector machine, nearest neighbor, and probabilistic neural network are used for classification purposes. The overall performance of each classifier is computed individually for each feature extraction strategy. It is observed that using the jackknife test the proposed GPCR-hybrid method provides the best results reported so far. The GPCR-hybrid web predictor to help researchers working on GPCRs in the field of biochemistry and bioinformatics is available at http://111.68.99.218/GPCR. PMID- 21295005 TI - Studying G protein-coupled receptor activation using split-tobacco etch virus assays. AB - G protein-coupled receptors (GPCRs) constitute the largest receptor family in mammals and represent important drug targets. Signaling through GPCRs mediates physiological effects that are strongly dependent on the cellular context. Therefore, the availability of assays monitoring GPCR activation applicable in different cell types could help to better understand GPCR functions and to realize the potential of known substances as well as novel ones. Here we introduce a split-TEV (tobacco etch virus) assay to monitor GPCR activation through the stimulation-dependent recruitment of beta-arrestin 2. Inactive N- and C-terminal fragments of the TEV protease are coupled to a GPCR and beta-arrestin 2, respectively. Ligand-dependent interaction of the two fusion proteins leads to functional complementation of the TEV protease, followed by the cleavage of an artificial transcription factor and successive reporter gene activation. The presented split-TEV assay system is highly sensitive and was successfully applied in heterologous cell lines as well as in primary cultured neuronal and glial cells. We show that assay performance strongly depends on the endogenous properties of different cell types. The sensitivity and flexibility make split TEV assays a valuable tool to analyze GPCR activation in different cell types in a rapid and cost-effective way. PMID- 21295006 TI - Experimental conditions affecting functional comparison of highly active glutathione transferases. AB - Glutathione transferases (GSTs, EC 2.5.1.18) possess multiple functions and have potential applications in biotechnology. Direct evidence of underestimation of activity of human GST A3-3 and porcine GST A2-2 measured at submicromolar enzyme concentrations is reported here for the first time. The combination of time dependent and enzyme concentration-dependent loss of activity and the choice of the organic solvent for substrates were found to cause irreproducibility of activity measurements of GSTs. These effects contribute to high variability of activity values of porcine GST A2-2 and human Alpha-class GSTs reported in the literature. Adsorption of GSTs to surfaces was found to be the main explanation of the observed phenomena. Several approaches to improved functional comparison of highly active GSTs are proposed. PMID- 21295007 TI - Knockdown of connective tissue growth factor by plasmid-based short hairpin RNA prevented pulmonary vascular remodeling in cigarette smoke-exposed rats. AB - Cigarette smoking may contribute to pulmonary hypertension in chronic obstructive pulmonary disease by resulting in pulmonary vascular remodeling that involves pulmonary artery smooth muscle cell proliferation. Connective tissue growth factor (CTGF) is a cysteine-rich peptide implicated in several biological processes such as cell proliferation, survival, and migration. This study investigated the potential role of CTGF in pulmonary vascular remodeling. We constructed a plasmid-based short hairpin RNA (shRNA) to knock down the expression of CTGF in primary cultured rat pulmonary artery smooth muscle cells (rPASMCs) and in rat lung vessels. Rat PASMCs were challenged with cigarette smoke extract (CSE). Rats were exposed to cigarette smoke for 3 months in the absence or in the presence of plasmid-based short hairpin RNA against CTGF which was administrated by tail vein injection. CTGFshRNA significantly prevented CTGF and cyclin D1 expression, arrested cell cycle at G0/G1 phase and suppressed cell proliferation in rPASMCs exposed to CSE. CTGFshRNA administration ameliorated pulmonary vascular remodeling, inhibited cigarette smoke-induced CTGF elevation and reversed the cyclin D1 increase in pulmonary vessels in rats. Collectively, our data demonstrated that plasmid-based shRNA against CTGF attenuated pulmonary vascular remodeling in cigarette smoke-exposed rats. PMID- 21295008 TI - Inhibition by rapamycin of the lipoteichoic acid-induced granulocyte-colony stimulating factor expression in mouse macrophages. AB - Granulocyte-colony stimulating factor (G-CSF) is a cytokine which involves in anti-inflammation and inflammation as well. Rapamycin is an inhibitor of mTOR which also plays a role in innate immunity. This study investigated the effect of rapamycin on the lipoteichoic acid (LTA)-induced expression of G-CSF in macrophages and its underlying mechanism. Our data show that LTA induced G-CSF expression in RAW264.7 and bone marrow-derived macrophages and that this effect was inhibited by rapamycin. Analysis of the G-CSF 5' flanking sequence revealed that the -283 to +35 fragment, which contains CSF and octamer elements, was required for maximal promoter activity in response to LTA stimulation. Western blot analyses of proteins that bind to the CSF and octamer element show that LTA increased protein levels of NF-kappaB, C/EBPbeta and Oct-2, and that rapamycin inhibited the LTA-induced increase in Oct-2 protein levels, but not the others. Knockdown of Oct-2 by RNA interference resulted in a decrease in LTA-induced G CSF mRNA levels. Moreover, forced expression of Oct-2 by transfection with the pCG-Oct-2 plasmid overcame the inhibitory effect of rapamycin on the LTA-induced increase in G-CSF mRNA levels and promoter activity. This study demonstrates that rapamycin reduces G-CSF expression in LTA-treated macrophages by inhibiting Oct-2 expression. PMID- 21295009 TI - Crystal structure determination and dynamic studies of Mycobacterium tuberculosis Cytidine deaminase in complex with products. AB - Cytidine deaminase (CDA) is a key enzyme in the pyrimidine salvage pathway. It is involved in the hydrolytic deamination of cytidine or 2'-deoxycytidine to uridine or 2'-deoxyuridine, respectively. Here we report the crystal structures of Mycobacterium tuberculosis CDA (MtCDA) in complex with uridine (2.4 A resolution) and deoxyuridine (1.9 A resolution). Molecular dynamics (MD) simulation was performed to analyze the physically relevant motions involved in the protein ligand recognition process, showing that structural flexibility of some protein regions are important to product binding. In addition, MD simulations allowed the analysis of the stability of tetrameric MtCDA structure. These findings open-up the possibility to use MtCDA as a target in future studies aiming to the rational design of new inhibitor of MtCDA-catalyzed chemical reaction with potential anti proliferative activity on cell growth of M. tuberculosis, the major causative agent of tuberculosis. PMID- 21295010 TI - Mitochondrial localization of fission yeast manganese superoxide dismutase is required for its lysine acetylation and for cellular stress resistance and respiratory growth. AB - Manganese-dependent superoxide dismutase (MnSOD) is localized in the mitochondria and is important for oxidative stress resistance. Although transcriptional regulation of MnSOD has been relatively well studied, much less is known about the protein's posttranslational regulation. In budding yeast, MnSOD is activated after mitochondrial import by manganese ion incorporation. Here we characterize posttranslational modification of MnSOD in the fission yeast Schizosaccharomyces pombe. Fission yeast MnSOD is acetylated at the 25th lysine residue. This acetylation was diminished by deletion of N-terminal mitochondrial targeting sequence, suggesting that MnSOD is acetylated after import into mitochondria. Mitochondrial localization of MnSOD is not essential for the enzyme activity, but is crucial for oxidative stress resistance and growth under respiratory conditions of fission yeast. These results suggest that, unlike the situation in budding yeast, S. pombe MnSOD is already active even before mitochondrial localization; nonetheless, mitochondrial localization is critical to allow the cell to cope with reactive oxygen species generated inside or outside of mitochondria. PMID- 21295011 TI - PRSS14/Epithin is induced in macrophages by the IFN-gamma/JAK/STAT pathway and mediates transendothelial migration. AB - PRSS14/Epithin (also known as matriptase and ST14), a member of the type II transmembrane serine proteases, is primarily found in a subpopulation of normal epithelial cells and in epithelial cancers. Its known functions include maintaining the epithelial barrier, thymic development, and cancer progression. In this study, we show that several macrophage cell lines and activated bone marrow-derived macrophages also express PRSS14/Epithin. Surface expression, as well as cytoplasmic expression, was detectable upon activation by IFN-gamma, but not TNF-alpha or TGF-beta. Induction of the protein appeared to be restricted to macrophages. IFN-gamma showed a biphasic regulation in RAW264.7 cells, and upregulated expression was sustained for several days. This induction by IFN gamma was partially through the increase of PRSS14/Epithin mRNA production, which is downstream of the JAK pathway, shown by the inhibition by tyrphostin AG490. Using chromatin immunoprecipitation, we verified that two sites among six putative STAT1 binding sites in the PRSS14/Epithin promoter were occupied by STAT1 upon activation. Treatment with IFN-gamma enhanced the serum-triggered transendothelial migration of RAW264.7 cells, but not that of PRSS14/Epithin knock-down RAW264.7 cells, although they express multiple markers such as ICAM1, CD80, and CD40 at normal levels. These data strongly suggest that PRSS14/Epithin plays an important role in the transendothelial migration of activated macrophages in the inflammatory microenvironment, and the mode of action is similar to the events in cancer metastasis. PMID- 21295012 TI - Decoy receptor 3: a pleiotropic immunomodulator and biomarker for inflammatory diseases, autoimmune diseases and cancer. AB - Recently, several decoy molecules belonging to tumor necrosis factor receptor superfamily (TNFRSF) have been identified, including decoy receptor 1 (DcR1), decoy receptor 2 (DcR2), and decoy receptor 3 (DcR3). One of the tumor necrosis factor superfamily (TNFSF) members, TNF-related apoptosis-inducing ligand (TRAIL), binds to DcR1 and DcR2, which are membranous receptors with a truncated cytoplasmic domain, thus unable to transduce TRAIL-mediated signaling. In contrast to DcR1 and DcR2, DcR3 is a soluble receptor capable of neutralizing the biological effects of three other TNFSF members: Fas ligand (FasL/TNFSF6/CD95L), LIGHT (TNFSF14) and TNF-like molecule 1A (TL1A/TNFSF15). Since FasL is a potent apoptosis- and inflammation-inducing factor, LIGHT is involved in apoptosis and inflammation, and TL1A is a T cell costimulator and is involved in gut inflammation, DcR3 can be defined as an immunomodulator on the basis of its neutralizing effects on FasL, LIGHT, and TL1A. Initial studies demonstrated that DcR3 expression is elevated in tumors cells; however, later work showed that DcR3 expression is also upregulated in inflammatory diseases, where serum DcR3 levels correlate with disease progression. In addition to its neutralizing effect, DcR3 also acts as an effector molecule to modulate cell function via 'non-decoy' activities. This review focuses on the immunomodulatory effects of DcR3 via 'decoy' and 'non-decoy' functions, and discusses the potential of DcR3 as a biomarker to predict cancer invasion and inflammation progression. We also discuss the possible utility of recombinant DcR3 as a therapeutic agent to control autoimmune diseases, as well as the potential to attenuate tumor progression by inhibiting DcR3 expression. PMID- 21295013 TI - Quantification of neurological and other contributors to continence in female rats. AB - Smooth muscle, striated muscle, their central and peripheral innervations and control, and mucosal coaptation contribute to maintenance of continence. We used manual leak point pressure (mLPP) testing and electrical stimulation LPP (eLPP) testing in female rats to quantify the contribution of these factors to urethral resistance, a measure of continence. Abdominal muscles were electrically stimulated to induce leakage for eLPP. A Crede maneuver was applied for mLPP. These were repeated after complete T8 spinal cord injury (SCI) and/or bilateral pudendal nerve transection (PNT). After euthanasia, mLPP was repeated. MLPP was not significantly affected by opening the abdomen, suggesting that intra abdominal pressure transmission contributes little to continence during slow pressure changes. ELPP was significantly higher than mLPP in intact rats, after PNT, and after SCI+PNT, suggesting that abdominal pressure transmission contributes to continence during rapid increases in intra-abdominal pressure. MLPP decreased significantly after PNT, indicating that urethral striated muscles contribute significantly to continence. ELPP decreased significantly after PNT with and without SCI, suggesting that supraspinal control significantly affects continence during rapid pressure changes, but not during slow pressure changes. MLPP after euthanasia was significantly decreased compared to mLPP after SCI+PNT, suggesting that urethral mucosal seal coaptation and tissue elasticity also contribute to continence. The urethra is a complex organ that maintains continence via a highly organized and hierarchical system involving both the central and peripheral nervous systems. PMID- 21295014 TI - Fluctuations in central and peripheral temperatures induced by intravenous nicotine: central and peripheral contributions. AB - Nicotine (NIC) is a highly addictive substance that interacts with different subtypes of nicotinic acetylcholine receptors widely distributed in the central and peripheral nervous systems. While the direct action of NIC on central neurons appears to be essential for its reinforcing properties, the role of peripheral actions of this drug remains a matter of controversy. In this study, we examined changes in locomotor activity and temperature fluctuations in the brain (nucleus accumbens and ventral tegmental area), temporal muscle, and skin induced by intravenous (iv) NIC at low human-relevant doses (10 and 30MUg/kg) in freely moving rats. These effects were compared to those induced by social interaction, an arousing procedure that induces behavioral activation and temperature responses via pure neural mechanisms, and iv injections of a peripherally acting NIC analog, NIC pyrrolidine methiodide (NIC-PM) used at equimolar doses. We found that NIC at 30MUg/kg induces a modest locomotor activation, rapid and strong decrease in skin temperature, and weak increases in brain and muscle temperature. While these effects were qualitatively similar to those induced by social interaction, they were much weaker and showed a tendency to increase with repeated drug administrations. In contrast, NIC-PM did not affect locomotion and induced much weaker than NIC increases in brain and muscle temperatures and decreases in skin temperature; these effects showed a tendency to be weaker with repeated drug administrations. Our data indicate that NIC's actions in the brain are essential to induce locomotor activation and brain and body hyperthermic responses. However, rapid peripheral action of NIC on sensory afferents could be an important factor in triggering its central effects, contributing to neural and physiological activation following repeated drug use. PMID- 21295015 TI - Motor control of jaw movements: An fMRI study of parafunctional clench and grind behavior. AB - Jaw-clenching and tooth-grinding associated with bruxism can contribute to abnormal tooth wear and pain in the masticatory system. Clench and tooth-grinding jaw-movement tasks were evaluated in a block-design fMRI study comparing a dental control (DC) group with a tooth-grinding (TG) group. Group classification was made prior to imaging based upon self-reported parafunctional clench and grind behavior and clinical evidence of abnormal tooth wear. Group differences in brain activation patterns were found for each task compared to the resting baseline. The DC group showed a more widely distributed pattern; more extensive activity in the supplementary motor area (SMA) proper that extended into the pre-SMA; and, for clench, activity in the left inferior parietal lobule (IPL). The DC group activated more than the TG subjects the left IPL for clench, and pre-SMA for grind. Neither task elicited more activity in the TG than DC subjects. Our group findings suggest that jaw-movement tasks executed by the TG group elicited (1) more efficient brain activation pattern consistent with other studies that found less extensive activity with executing "over-learned" tasks; (2) "underactive" SMA activity that underlies reduced motor planning; (3) decreased inferior parietal activity that is associated with lesser motor-attentional demands. Thus orofacial parafunctional habits may influence brain circuits recruited for jaw movements, providing a possible basis for understanding involuntary jaw movements in bruxism and oral movement disorders in general. PMID- 21295016 TI - FLZ, a novel HSP27 and HSP70 inducer, protects SH-SY5Y cells from apoptosis caused by MPP(+). AB - Heat shock proteins (HSPs) play an essential role in various neurodegenerative diseases. Manipulation of upregulation of HSPs in cells has been demonstrated to provide a therapeutic strategy to counteract the misfolding and aggregation of proteins that resulted in neurodegenerative disease. Our previous studies have shown that FLZ, a synthetic novel derivative of squamosamide from a Chinese herb, had potent neuroprotective effect against several experimental Parkinson's disease (PD) models. However, the mechanism of its neuroprotective effect is still not clarified. The present study demonstrated that FLZ induced HSP27 and HSP70 proteins and mRNA expression in a time- and dose-dependent manner in SH SY5Y cells. Further studies showed that FLZ treatment stimulated the activation of heat shock factor 1 (HSF1) and its regulatory kinase Akt. Inactivation of Akt pathway by the PI3K inhibitor LY294002 blocked the expression of HSP27 and HSP70 induced by FLZ. Moreover, the inducing effects of FLZ on HSP27, HSP70, and HSF1 were all blocked by quercetin, an inhibitor of HSP biosynthesis. The cytoprotective effect of HSP27/HSP70 induced by FLZ against MPP(+) was assessed in SH-SY5Y cells. The pretreatment of FLZ significantly induced the accumulations of HSP27/HSP70 and suppressed the apoptosis caused by MPP(+) in SH-SY5Y cells. However, the protective effects of FLZ against MPP(+) were significantly blocked by quercetin, which indicated that the cytoprotective action of FLZ against MPP(+)-induced apoptosis is at least partially mediated by its induction of HSP27/HSP70. These results provide new evidence for elucidating the mechanism of the neuroprotective effect of FLZ against PD. PMID- 21295017 TI - Cortical mechanisms of auditory spatial attention in a target detection task. AB - The benefits of spatial attention on stimulus processing are thought to diminish with increased distance from the attended location, indicating an attention gradient. Evidence for attention gradients is provided by spatial attention effects on event-related potentials (ERPs) under conditions of rapid stimulus presentation from closely spaced locations. This study was motivated by ecological considerations which suggest that auditory attention is particularly useful for panoramic orienting to intermittent sounds. Auditory ERPs were recorded from a wide range of horizontal locations (180 degrees ) while subjects pressed a button to occasional targets at one attended location. Results showed that an ERP component associated with automatic orienting, the P3a, had linear amplitude increases to non-targets as a function of distance from the attended location. A component prior to the P3a with a latency of ~200ms, the P200, showed a similar pattern but only when subjects attended to the left hemifield. When attending to lateral targets frontal slow waves contralateral to the attended location followed the P3a and were attenuated at greater distances from the target location for at least 1s. Results suggest that auditory spatial attention under low cognitive loads modulates orienting responses as a function of distance from the attended location. The slow wave findings show that information about the relation between a stimulus and the attended location persists well beyond the time of initial sensory processing and may involve frontal regions important for maintaining online representations of task set. PMID- 21295018 TI - Hemodynamic responses to visual stimuli in cortex of adults and 3- to 4-year-old children. AB - In this study we used near-infrared spectroscopy (NIRS) to measure relative changes in cortical hemodynamics from 19 adult and 19 preschool children (aged 3 4 years old), while they watched epochs of static and motion pictures extracted from TV programs. The spatio-temporal characteristics of oxygenated and deoxygenated hemoglobin volumes (oxy- and deoxy-Hb) of both subject groups were described and compared where appropriate for five regions of interest (ROIs). These were striate, left and right middle temporal, and left and right temporo parietal areas. Over these areas, deoxy-Hb volumes did not differ between both groups. Preschool data showed significant increases in oxy-Hb over striate, middle temporal and temporo-parietal areas in response to visual motion stimuli. Static stimuli caused a significant oxy-Hb increase over striate and left middle temporal areas. Surprisingly, changes in adult oxy-Hb were not profound and did not show a significant oxy-Hb increase in striate and middle temporal areas in response to the motion stimuli, warranting further research. In spite of oxy-Hb volume differences, oxy-Hb recovery to baseline followed a similar pattern in both groups in response to both static and motion stimuli. Together, the results suggest that near-infrared spectroscopy is a viable method to investigate cortical development of preschool children by monitoring their hemodynamic response patterns. PMID- 21295019 TI - Neural processing of reward magnitude under varying attentional demands. AB - Central to the organization of behavior is the ability to represent the magnitude of a prospective reward and the costs related to obtaining it. Therein, reward related neural activations are discounted in dependence of the effort required to resolve a given task. Varying attentional demands of the task might however affect reward-related neural activations. Here we employed fMRI to investigate the neural representation of expected values during a monetary incentive delay task with varying attentional demands. Following a cue, indicating at the same time the difficulty (hard/easy) and the reward magnitude (high/low) of the upcoming trial, subjects performed an attention task and subsequently received feedback about their monetary reward. Consistent with previous results, activity in anterior-cingulate, insular/orbitofrontal and mesolimbic regions co-varied with the anticipated reward-magnitude, but also with the attentional requirements of the task. These activations occurred contingent on action-execution and resembled the response time pattern of the subjects. In contrast, cue-related activations, signaling the forthcoming task-requirements, were only observed within attentional control structures. These results suggest that anticipated reward-magnitude and task-related attentional demands are concurrently processed in partially overlapping neural networks of anterior-cingulate, insular/orbitofrontal, and mesolimbic regions. PMID- 21295020 TI - Effects of inverting contour and features on processing for static and dynamic face perception: an MEG study. AB - We investigated the effects of inverting facial contour (hair and chin) and features (eyes, nose and mouth) on processing for static and dynamic face perception using magnetoencephalography (MEG). We used apparent motion, in which the first stimulus (S1) was replaced by a second stimulus (S2) with no interstimulus interval and subjects perceived visual motion, and presented three conditions as follows: (1) U&U: Upright contour and Upright features, (2) U&I: Upright contour and Inverted features, and (3) I&I: Inverted contour and Inverted features. In static face perception (S1 onset), the peak latency of the fusiform area's activity, which was related to static face perception, was significantly longer for U&I and I&I than for U&U in the right hemisphere and for U&I than for U&U and I&I in the left. In dynamic face perception (S2 onset), the strength (moment) of the occipitotemporal area's activity, which was related to dynamic face perception, was significantly larger for I&I than for U&U and U&I in the right hemisphere, but not the left. These results can be summarized as follows: (1) in static face perception, the activity of the right fusiform area was more affected by the inversion of features while that of the left fusiform area was more affected by the disruption of the spatial relation between the contour and features, and (2) in dynamic face perception, the activity of the right occipitotemporal area was affected by the inversion of the facial contour. PMID- 21295021 TI - Oxidation of glycerolipids by maize 9-lipoxygenase and its A562G mutant. AB - Lipoxygenases (LOXs) are key enzymes in the biosynthesis of oxylipins, the diverse class of bioregulators involved into developmental processes, signalling and defence. This work was undertaken to better understand how LOXs control production of hydroperoxides with different positional and stereochemistry. A number of glycerolipids were tested as substrates for maize 9-LOX (ZmLOX) and its A562G mutant form. Both the wild type (WT) ZmLOX and A562G mutant were shown to dioxygenate monolinolenoylglycerol (MLG) and 2-linoleoyl-sn-glycero-3 phosphorylcholine (lysoPC). Both the WT ZmLOX and A562G mutant form oxidized the MLG predominantly into (9S)-hydroperoxide. The A562G mutation did not affect the relative yield of 13-hydroperoxide, but increased the proportion of (13R) enantiomer. LysoPC was a poor substrate for both wild type and A562G mutant form of ZmLOX. The oxidation of lysoPC exhibited the limited regio- and stereospecificity. Nevertheless, the WT ZmLOX produced some predominance of (13S) hydroperoxide. In contrast, the A562G mutant produced some excess of (9S) hydroperoxide of lysoPC. The bulky polar heads of glycerolipids like MLG and lysoPC cannot penetrate into the LOX active site. Thus, the obtained data indicate that both (9S)- and (13S)-hydroperoxides can be produced when substrate is arranged within LOX active site in the "methyl end first" orientation. PMID- 21295022 TI - Association between interleukin 23 receptor polymorphism and kidney transplant outcomes: a 10-year Taiwan cohort study. AB - OBJECTIVE: Interleukin 23 receptor (IL-23R) plays a role in the pathogenesis of multiple autoimmune processes. The relationship between allograft outcomes and the IL-23Rvariant genotypes has not been reported on previously. Therefore, we examined the relationship between this genetic polymorphism and kidney transplant outcomes. METHODS: This is an observational cohort study and 422 renal transplant recipients (RTRs) were enrolled. Polymerase chain reaction-restriction fragment length polymorphism was used for the measurement of IL-23R genetic polymorphisms. We used a composite end-point incorporating serum creatinine (SCr) doubling, graft failure and death as the primary outcome. Secondary outcomes included biopsy-proven acute rejection (BPAR), biopsy-proven interstitial fibrosis/tubular atrophy (IF/TA) and individual primary outcome. The risks of developing primary and secondary outcomes were compared between the different IL-23R genotypes and alleles. RESULTS: With a mean follow-up of 79.3+/-28.8 months, 26 patients in the IL-23R genotype AA group and 32 patients in the IL-23R genotype AC/CC group reached the primary outcome (p=0.061). RTRs who carried the IL-23R AC/CC genotype (aHR 1.78; 95% CI. 1.01-3.12; p=0.046) and C allele (aHR 1.48; 95% CI. 0.96-2.28; p=0.075) had a higher risk of developing primary outcome as compared to those with IL-23R AA genotype and A allele, respectively. Moreover, RTRs who carried the IL-23R AC/CC genotype and C allele had a higher risk of developing biopsy proven IF/TA (p=0.012; p=0.012) and SCr doubling (p=0.024; p=0.042) as compared to those with IL-23R AA genotype and A allele, respectively. The risk of BPAR, graft failure and death between the IL-23R genotypes and alleles were comparable. CONCLUSION: IL-23R polymorphism may have a potential immuno-modulating role in long-term allograft outcome. PMID- 21295023 TI - The genetic epidemiology of melanocortin 4 receptor variants. AB - While rare MC4R mutations are the commonest cause of monogenic forms of extreme, early-onset obesity, growing evidence shows that common MC4R variants contribute to obesity in the general population. Candidate gene studies have focussed on the V103I and I251L MC4R variants that both affect MC(4) receptor function in vitro. Individual association studies, which are typically small and underpowered, have found no association between V103I (frequency of 103I-allele: ~4%) or I251L (251L allele: ~2%) and the risk of obesity in the general population. However, large scale meta-analyses have confirmed that both variants reduce the risk of obesity by -21% in 103I-allele carriers (P<10(-4)) and by -50% in 251L-allele carriers (P<10(-4)). Recently, genome-wide association studies have identified a common variant (minor allele frequency: ~27%) at ~188kb downstream of MC4R showing robust association (P<5*10(-8)) with BMI and obesity in adults and children. Each additional minor allele increases BMI by 0.20kg/m(2), body weight by 700-1000g, and obesity risk by 14% in adults. Interestingly, this variant also showed association with increased height, consistent with the phenotype seen for rare MC4R mutations. Although MC4R is the nearest gene and phenotypic associations are consistent with those of MC4R mutations, it has not yet been established whether this variant indeed reflects MC(4) receptor function. Taken together, common MC4R variants contribute to variation in BMI and obesity risk in the general population. Of particular interest is the finding from genome-wide association studies that suggests that the region downstream of MC4R contributes to its regulation. PMID- 21295024 TI - Neurobiology of overeating and obesity: the role of melanocortins and beyond. AB - The alarming increase in the incidence of obesity and obesity-associated disorders makes the etiology of obesity a widely studied topic today. As opposed to 'homeostatic feeding', where food intake is restricted to satisfy one's biological needs, the term 'non-homeostatic' feeding refers to eating for pleasure or the trend to over-consume (palatable) food. Overconsumption is considered a crucial factor in the development of obesity. Exaggerated consumption of (palatable) food, coupled to a loss of control over food intake despite awareness of its negative consequences, suggests that overeating may be a form of addiction. At a molecular level, insulin and leptin resistance are hallmarks of obesity. In this review, we specifically address the question how leptin resistance contributes to enhanced craving for (palatable) food. Since dopamine is a key player in the motivation for food, the interconnection between dopamine, leptin and neuropeptides related to feeding will be discussed. Understanding the mechanisms by which these neuropeptidergic systems hijack the homeostatic feeding mechanisms, thus leading to overeating and obesity is the primary aim of this review. The melanocortin system, one of the crucial neuropeptidergic systems modulating feeding behavior will be extensively discussed. The inter-relationship between neuronal populations in the arcuate nucleus and other areas regulating energy homeostasis (lateral hypothalamus, paraventricular nucleus, ventromedial hypothalamus etc.) and reward circuitry (the ventral tegmental area and nucleus accumbens) will be evaluated and scrutinized. PMID- 21295025 TI - Let's shift lipid burden--from large to small adipocytes. AB - Adipose tissue mass in mammals expands by increasing both volume and total number of the adipocytes. The simultaneous existence of large and small adipocytes and their unsynchronized growth, even within the same adipose tissue depot, argues against simple filling-up of nascent small adipocytes with lipids and lipid droplets. Consequently, it is tempting to speculate about signals provoking shift of lipid loading from mature large to small adipocytes. Very recently, microvesicles have been shown (i) to harbor the glycosylphosphatidylinositol anchored (c)AMP-degrading phosphodiesterase Gce1 and the 5'-nuceotidase CD73, (ii) to be released (preferably) from large adipocytes, (iii) to interact (preferably) with small adipocytes and (iv) to transfer Gce1 and CD73 to plasma membranes and lipid droplets of the small adipocytes where they degrade (c)AMP. This sequence of events leads to upregulation of lipid storage in small adipocytes in response to the microvesicle-encoded "take-over" signal from large adipocytes. A model is proposed for the maturation of small adipocytes driven by large cells along a gradient of microvesicle-derived inter-adipocyte signals. Pharmacological modulation of the communication between adipocytes for their maturation may be useful for the therapy of metabolic diseases. PMID- 21295026 TI - Lesion of cholinergic neurons in nucleus basalis enhances response to general anesthetics. AB - Acetylcholine in the brain has been associated with consciousness and general anesthesia effects. We tested the hypothesis that the integrity of the nucleus basalis magnocellularis (NBM) affects the response to general anesthetics. Cholinergic neurons in NBM were selectively lesioned by bilateral infusion of 192IgG-saporin in adult, male Long-Evans rats, and control rats were infused with saline. Depletion of choline-acetyltransferase (ChAT)-immunoreactive cells in the NBM and decrease in optical density of acetylcholinesterase (AChE) staining in the frontal and visual cortices confirmed a significant decrease in NBM cholinergic neurons in lesioned as compared to control rats. AChE staining in the hippocampus and ChAT-positive neurons in the medial septum-vertical limb of the diagonal band were not different between lesioned and control rats. When a general anesthetic was administered, lesioned compared to control rats showed significantly longer duration of loss of righting reflex (LORR) after propofol (5 or 10mg/kg i.v.), pentobarbital (20 or 40 mg/kg i.p.) but not halothane (2%). However, the behavioral excitation, as indicated by horizontal movements, induced by halothane was reduced in lesioned as compared to control rats. Reversible inactivation of NBM with GABA(A) receptor agonist muscimol increased slow waves in the neocortex during awake immobility, and prolonged the duration of LORR and loss of tail-pinch response after propofol, pentobarbital and halothane. In summary, lesion of NBM cholinergic neurons or inactivation of the NBM prolonged the LORR response to general anesthetic drugs. PMID- 21295027 TI - Beta-lactam antibiotic offers neuroprotection in a spinal muscular atrophy model by multiple mechanisms. AB - Spinal muscular atrophy (SMA) is a devastating genetic motoneuron disease leading to infant death. No effective therapy is currently available. It has been suggested that beta-lactam antibiotics such as ceftriaxone may offer neuroprotection in motoneuron diseases. Here, we investigate the therapeutic effect of ceftriaxone in a murine model of SMA. Treated animals present a modest, but significant ameliorated neuromuscular phenotype and increased survival, which correlate with protection of neuromuscular units. Whole gene expression profiling in treated mice demonstrates modifications in several genes including those involved in RNA metabolism toward wild-type. The neuroprotective effect seems to be mediated by multiple mechanisms that encompass the increase of the glutamate transporter Glt1, the transcription factor Nrf2, as well as SMN protein. This study provides the first evidence of a potential positive effect of this class of molecules in SMA. Further investigation of analogs with increased and more specific therapeutic effects warrants the development of useful therapies for SMA. PMID- 21295028 TI - In vitro modelling of Alzheimer's disease: degeneration and cell death induced by viral delivery of amyloid and tau. AB - With increasing life expectancy, Alzheimer's disease (AD) and other dementias pose an increasing and as yet unresolved health problem. A variety of cellular models of AD has helped to decipher some key aspects of amyloid and tau related degeneration. The initial approach of extracellular applications of synthetic peptides has now been replaced by the introduction of amyloid precursor protein (APP) and tau genes. In the present study adenoviral transductions were exploited for gene delivery into primary rat hippocampal and dorsal root ganglion (DRG) cultures to enable comparative and mechanistic studies at the cellular level and subsequent drug testing. Time lapse experiments revealed a different pattern of cell death: apoptotic-like for APP whereas tau positive cells joined and formed clusters. Mutated human APP or tau expression caused accelerated neuronal damage and cell death (cf. EGFP: -50% for APP at 5 days; -40% for tau at 3 days). This reduction in viability was preceded by decreased excitability, monitored via responses to depolarising KCl-challenges in Ca(2+) imaging experiments. Additionally, both transgenes reduced neurite outgrowth in DRG neurones. Treatment studies confirmed that APP induced-damage can be ameliorated by beta- and gamma-secretase inhibitors (providing protection to 60-100% of control levels), clioquinol (80%) and lithium (100%); while anti-aggregation treatments were beneficial for tau-induced damage (60-90% recovery towards controls). Interestingly, caffeine was the most promising drug candidate for therapeutic intervention with high efficacy in both APP (77%) and tau-induced models (72% recovery). Overall, these cellular models offer advantages for mechanistic studies and target identification in AD and related disorders. PMID- 21295029 TI - In vitro antimalarial activity of ICL670: a further proof of the correlation between inhibition of beta-hematin formation and of peroxidative degradation of hemin. AB - Iron chelators such as deferiprone, deferoxamine (DFO) and ICL670 (deferasirox) have previously been shown to display in vitro and/or in vivo antimalarial activities. To gain further insight in their antimalarial mechanism of action, their activities on inhibition of beta-hematin formation and on both peroxidative and glutathione (GSH)-mediated degradation of hemin were investigated. Neither deferiprone nor DFO were able to inhibit beta-hematin formation while ICL670 activity nearly matched that of chloroquine (CQ). Peroxidative degradation of hemin was also only strongly inhibited by both CQ and ICL670, the latter being significantly more efficient at pH 5.2. All iron chelators displayed minor, if any, inhibitory activity on GSH-mediated degradation of hemin. Discrepancies in the results obtained for the three iron chelators show that iron chelation is not the main driving force behind interference with heme degradation. Deferiprone, DFO and ICL670 share little structural community but both ICL670 and antimalarial ursolic acid derivatives (previously shown to block beta-hematin formation and the peroxidative degradation of hemin) have hydrophobic groups and hydroxyphenyl moieties. These similarities in structures and activities further back up a possible two-step mechanism of action previously proposed for ursolic acid derivatives (Mullie et al., 2010) implying (1) stacking of an hydrophobic structure to hemin and (2) additive protection of hemin ferric iron from H(2)O(2) by hydroxyphenyl groups through steric hindrance and/or trapping of oxygen reactive species in the direct neighborhood of ferric iron. These peculiar antimalarial mechanisms of action for ICL670 warrant further investigations and development. PMID- 21295030 TI - Ancylostoma caninum: calibration and comparison of diagnostic accuracy of flotation in tube, McMaster and FLOTAC in faecal samples of dogs. AB - We performed a calibration of flotation in tube, McMaster and FLOTAC to determine the optimal flotation solution (FS) and the influence of faecal preservation for the diagnosis of Ancylostoma caninum in dogs, and compared the accuracy of the three copromicroscopic techniques. Among nine different FS, sodium chloride and sodium nitrate performed best for detection and quantification of A. caninum eggs. Faecal samples, either fresh or preserved in formalin 5%, resulted in higher A. caninum egg counts, compared to frozen samples or preserved in formalin 10% or sodium acetate-acetic acid-formalin. FLOTAC consistently resulted in higher A. caninum eggs per gram of faeces (EPG) and lower coefficient of variation (CV) than McMaster and flotation in tube. The best results in terms of mean faecal egg counts (highest value, i.e. 117.0EPG) and CV (lowest value, i.e. 4.8%) were obtained with FLOTAC using sodium chloride and faecal samples preserved in formalin 5%. Our findings suggest that the FLOTAC technique should be considered for the diagnosis of A. caninum in dogs. PMID- 21295031 TI - Tissue responses exhibited by Biomphalaria alexandrina snails from different Egyptian localities following Schistosoma mansoni exposure. AB - Snails' susceptibilities to infection with Schistosoma mansoni were determined through observation of infection rates, total cercarial production and tissue responses of the first generation (F1) of Biomphalaria alexandrina snails, originally collected from different Egyptian governorates (Giza, Fayoum, Kafr El Sheikh, Ismailia and Damietta) and responses were compared between groups. The emergence of cercariae for a 3-month period and the calculation of survival and infection rates, in control (Schistosome Biological Supply Center; SBSC) and infected snails were evaluated. SBSC and Giza snails showed greater susceptibilities to infection and lower mortality rates. In addition, at 6 and 72 h post-exposure to miracidia all the snail groups showed no difference in the anatomical locations of sporocysts. The larvae were found in the head-foot, the mantle collar and the tentacles of the snails. Sporocysts showed normal development with low tissue reactions in SBSC and Giza snail groups infected with S. mansoni miracidia (SBSC). However, in Fayoum, Kafr El-Sheikh, Ismailia and Damietta snail groups, variable tissue responses were observed in which numerous hemocytes made direct contact with S. mansoni larvae forming capsules. The results suggested that, different responses of B. alexandrina snail's hemocytes towards S. mansoni are related to the degree of susceptibility of these snails. So this is important in planning the strategy of schistosomiasis control. PMID- 21295032 TI - IQGAP1 in microbial pathogenesis: Targeting the actin cytoskeleton. AB - Microbial pathogens cause widespread morbidity and mortality. Central to the pathogens' virulence is manipulation of the host cell's cytoskeleton, which facilitates microbial invasion, multiplication, and avoidance of the innate immune response. IQGAP1 is a ubiquitously expressed scaffold protein that integrates diverse signaling cascades. Research has shown that IQGAP1 binds to and modulates the activity of multiple proteins that participate in bacterial invasion. Here, we review data that support a role for IQGAP1 in infectious disease via its ability to regulate the actin cytoskeleton. In addition, we explore other mechanisms by which IQGAP1 may be exploited by microbial pathogens. PMID- 21295033 TI - Nuclear receptors and microRNAs: Who regulates the regulators in neural stem cells? AB - In this mini-review, we focus on regulatory loops between nuclear receptors and microRNAs, an emerging class of small RNA regulators of gene expression. Evidence supporting interactions between microRNAs and nuclear receptors in the regulation of gene expression networks is discussed in relation to its possible role in neural stem cell self renewal and differentiation. Furthermore, we discuss possible disturbances of the regulatory loops between microRNAs and nuclear receptors in human neurodegenerative disease. Finally, we discuss the possible use of nuclear receptors as pharmacological entry points to regulate neural stem cell self-renewal and differentiation. PMID- 21295034 TI - Peroxisome proliferator-activated receptor gamma regulates angiotensin II-induced catalase downregulation in adventitial fibroblasts of rats. AB - Peroxisome proliferator-activated receptor (PPAR) gamma ligands oppose the effect induced by angiotensin II (Ang II) to reduce oxidative stress and improve antioxidant status. In this study, Ang II inhibited catalase (CAT) and peroxisome proliferator-activated receptor gamma (PPAR gamma) protein and mRNA expressions. Transfection with PPAR gamma small-interfering RNA (siRNA) led to a reduction in CAT expression. PPAR gamma ligands enhanced CAT expression and inhibited extracellular signal-regulated kinase 1/2 activation. We further reveal that Ang II type 1 receptor is not involved in the inhibitory effects of PPAR gamma ligands on Ang II stimulatory events. PMID- 21295036 TI - Repeatability of baseline and stress-induced corticosterone levels across early life stages in the Florida scrub-jay (Aphelocoma coerulescens). AB - Recent studies have posited that the pattern of glucocorticoid secretion within an individual represents a stable, fixed physiological trait. To test this hypothesis, we assessed the repeatability of baseline and stress-induced corticosterone (CORT) secretion across developmental stages and years in Florida scrub-jays. We sampled individuals from multiple cohorts repeatedly from the age of 11 days post-hatch up to 4 years of age. We found a significant degree of repeatability within individuals in stress-induced corticosterone levels, i.e., the amount of hormone secreted during a standardized stress protocol (corrected integrated corticosterone). However, baseline corticosterone levels were not statistically repeatable, although there was some indication that nestling levels predicted levels at 1 year of age. The results of this study indicate that stress induced CORT levels are consistent within individual scrub-jays, and the degree to which a young jay mounts an acute stress response appears to be somewhat "set" by the age of nutritional independence. Thus stress-induced corticosterone secretion appears to be a stable, repeatable trait within individuals and as such may be subject to natural selection. PMID- 21295035 TI - Effects of testosterone on spatial learning and memory in adult male rats. AB - A male advantage over females for spatial tasks has been well documented in both humans and rodents, but it remains unclear how the activational effects of testosterone influence spatial ability in males. In a series of experiments, we tested how injections of testosterone influenced the spatial working and reference memory of castrated male rats. In the eight-arm radial maze, testosterone injections (0.500 mg/rat) reduced the number of working memory errors during the early blocks of testing but had no effect on the number of reference memory errors relative to the castrated control group. In a reference memory version of the Morris water maze, injections of a wide range of testosterone doses (0.0625-1.000 mg/rat) reduced path lengths to the hidden platform, indicative of improved spatial learning. This improved learning was independent of testosterone dose, with all treatment groups showing better performance than the castrated control males. Furthermore, this effect was only observed when rats were given testosterone injections starting 7 days prior to water maze testing and not when injections were given only on the testing days. We also observed that certain doses of testosterone (0.250 and 1.000 mg/rat) increased perseverative behavior in a reversal-learning task. Finally, testosterone did not have a clear effect on spatial working memory in the Morris water maze, although intermediate doses seemed to optimize performance. Overall, the results indicate that testosterone can have positive activational effects on spatial learning and memory, but the duration of testosterone replacement and the nature of the spatial task modify these effects. PMID- 21295037 TI - Modelling the effect of temperature variation on the seasonal dynamics of Ixodes ricinus tick populations. AB - Seasonal variation in temperature is known to drive annual patterns of tick activity and can influence the dynamics of tick-borne diseases. An age-structured model of the dynamics of Ixodes ricinus populations was developed to explore how changes in average temperature and different levels of temperature variability affect seasonal patterns of tick activity and the transmission of tick-borne diseases. The model produced seasonal patterns of tick emergence that are consistent with those observed throughout Great Britain. Varying average temperature across a continuous spectrum produced a systematic pattern in the times of peak emergence of questing ticks which depends on cumulative temperature over the year. Examination of the effects of between-year stochastic temperature variation on this pattern indicated that peak emergence times are more strongly affected by temperature stochasticity at certain levels of average temperature. Finally the model was extended to give a simple representation of the dynamics of a tick-borne disease. A threshold level of annual cumulative temperature was identified at which disease persistence is sensitive to stochastic temperature variation. In conclusion, the effect of changing patterns of temperature variation on the dynamics of I. ricinus ticks and the diseases they transmit may depend on the cumulative temperature over the year and will therefore vary across different locations. The results also indicate that diapause mechanisms have an important influence on seasonal patterns of tick activity and require further study. PMID- 21295038 TI - Sensitive and viable quantification of inside-out signals for LFA-1 activation in human cytotoxic lymphocytes by flow cytometry. AB - An early step in immunosurveillance by cytotoxic lymphocytes is leukocyte functional antigen (LFA)-1-dependent adhesion to target cells, which is promoted by inside-out signals from receptors such as the T cell receptor and a variety of natural killer (NK) cell activating receptors. Inside-out signals induce a conformational change in LFA-1, resulting in an extension of the extracellular domain of the receptor. Here, we have evaluated several mAbs that specifically detect the extended conformation of LFA-1 and detail a protocol for flow cytometric quantification of beta2-integrin activation in human peripheral blood cytotoxic T cells and NK cells in response to target cell recognition. By comparison to the markers of degranulation and chemokine synthesis, e.g. surface CD107a expression and intracellular MIP-1beta expression, respectively, evaluation of LFA-1 conformational changes represent a sensitive and rapid parameter of primary cytotoxic lymphocyte activation that can facilitate isolation of viable cells. Potentially, combined with other read-outs of cytotoxic lymphocyte function, this technique is applicable to the assessment of various clinical conditions, including for the diagnosis of primary immunodeficiency syndromes and for evaluating the efficacy of tumor targeting by donor lymphocytes. PMID- 21295039 TI - Deciphering time measurement: the role of circadian 'clock' genes and formal experimentation in insect photoperiodism. AB - This review examines possible role(s) of circadian 'clock' genes in insect photoperiodism against a background of many decades of formal experimentation and model building. Since ovarian diapause in the genetic model organism Drosophila melanogaster has proved to be weak and variable, recent attention has been directed to species with more robust photoperiodic responses. However, no obvious consensus on the problem of time measurement in insect photoperiodism has yet to emerge and a variety of mechanisms are indicated. In some species, expression patterns of clock genes and formal experiments based on the canonical properties of the circadian system have suggested that a damped oscillator version of Pittendrigh's external coincidence model is appropriate to explain the measurement of seasonal changes in night length. In other species extreme dampening of constituent oscillators may give rise to apparently hourglass-like photoperiodic responses, and in still others there is evidence for dual oscillator (dawn and dusk) photoperiodic mechanisms of the internal coincidence type. Although the exact role of circadian rhythmicity and of clock genes in photoperiodism is yet to be settled, Bunning's general hypothesis (Bunning, 1936) remains the most persuasive unifying principle. Observed differences between photoperiodic clocks may be reflections of underlying differences in the clock genes in their circadian feedback loops. PMID- 21295040 TI - Genome analysis with distance to the nearest dissimilar nucleotide. AB - DNA may be represented by sequences of four symbols, but it is often useful to convert those symbols into real or complex numbers for further analysis. Several mapping schemes have been used in the past, but most of them seem to be unrelated to any intrinsic characteristic of DNA. The objective of this work was to study a mapping scheme that is directly related to DNA characteristics, and that could be useful in discriminating between different species. Recently, we have proposed a methodology based on the inter-nucleotide distance, which proved to contribute to the discrimination among species. In this paper, we introduce a new distance, the distance to the nearest dissimilar nucleotide, which is the distance of a nucleotide to first occurrence of a different nucleotide. This distance is related to the repetition structure of single nucleotides. Using the information resulting from the concatenation of the distance to the nearest dissimilar and the inter-nucleotide distance, we found that this new distance brings additional discriminative capabilities. This suggests that the distance to the nearest dissimilar nucleotide might contribute with useful information about the evolution of the species. PMID- 21295041 TI - The influence of the chloride currents on action potential firing and volume regulation of excitable cells studied by a kinetic model. AB - In excitable cells, the generation of an action potential (AP) is associated with transient changes of the intra- and extracellular concentrations of small ions such as Na(+), K(+) and Cl(-). If these changes cannot be fully reversed between successive APs cumulative changes of trans-membrane ion gradients will occur, impinging on the cell volume and the duration, amplitude and frequency of APs. Previous computational studies focused on effects associated with excitation induced changes of potassium and sodium. Here we present a model based study on the influence of chloride on the fidelity of AP firing and cellular volume regulation during excitation. Our simulations show that depending on the magnitude of the basal chloride permeability two complementary types of responsiveness and volume variability exist: (i) At high chloride permeability (typical for muscle cells), large excitatory stimuli are required to elicit APs; repetitive stimuli of equal strength result in almost identical spike train patterns (Markovian behavior), however, long excitation may lead to after discharges due to an outward directed current of intracellular chloride ions which accumulate during excitation; cell volume changes are large. (ii) At low chloride permeability (e.g., neurons), small excitatory stimuli are sufficient to elicit APs, repetitive stimuli of equal strength produce spike trains with progressively changing amplitude, frequency and duration (short-term memory effects or non-Markovian behavior); cell volume changes are small. We hypothesize that variation of the basal chloride permeability could be an important mechanism of neuronal cells to adapt their responsiveness to external stimuli during learning and memory processes. PMID- 21295042 TI - Rap1 GTPases: an emerging role in the cardiovasculature. AB - The Ras related GTPase Rap has been implicated in multiple cellular functions. A vital role for Rap GTPase in the cardiovasculature is emerging from recent studies. These small monomeric G proteins act as molecular switches, coupling extracellular stimulation to intracellular signaling through second messengers. This member of the Ras superfamily was once described as the transformation suppressor with the ability to ameliorate the Ras transformed phenotype; however, further studies uncovered a unique set of guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs) and effector proteins for Rap suggesting a more sophisticated role for this small GTPase. At least three different second messengers can activate Rap, namely cyclic AMP (cAMP), calcium and diacylglycerol. More recently, an investigation of Rap in the cardiovasculature has revealed multiple pathways of regulation involving Rap in this system. Two closely related isoforms of Rap1 exist, 1a and 1b. Murine genetic models exist for both and have been described. Although thought at first to be functionally redundant, these isoforms have differing roles in the cardiovasculature. The activation of Rap1a and 1b in various cell types of the cardiovasculature leads to alterations in cell attachment, migration and cell junction formation. This review will focus on the role of these Rap1 GTPases in hematopoietic, endothelial, smooth muscle, and cardiac myocyte function, and conclude with their potential role in human disease. PMID- 21295043 TI - Regulation of adipocytokine secretion and adipocyte hypertrophy by polymethoxyflavonoids, nobiletin and tangeretin. AB - AIMS: The polymethoxyflavonoids nobiletin and tangeretin possess several important biological properties such as neuroprotective, antimetastatic, anticancer, and anti-inflammatory properties. The present study was undertaken to examine whether nobiletin and tangeretin could modulate adipocytokine secretion and to evaluate the effects of these flavonoids on the hypertrophy of mature adipocytes. MAIN METHODS: All experiments were performed on the murine preadipocyte cell line 3T3-L1. We studied the formation of intracellular lipid droplets in adipocytes and the apoptosis-inducing activity to evaluate the effects of polymethoxyflavonoids on adipocyte differentiation and hypertrophy, respectively. The secretion of adipocytokines was measured using ELISA. KEY FINDINGS: We demonstrated that the combined treatment of differentiation reagents with nobiletin or tangeretin differentiated 3T3-L1 preadipocytes into adipocytes possessing less intracellular triglyceride as compared to vehicle-treated differentiated 3T3-L1 adipocytes. Both flavonoids increased the secretion of an insulin-sensitizing factor, adiponectin, but concomitantly decreased the secretion of an insulin-resistance factor, MCP-1, in 3T3-L1 adipocytes. Furthermore, nobiletin was found to decrease the secretion of resistin, which serves as an insulin-resistance factor. In mature 3T3-L1 adipocytes, nobiletin induced apoptosis; tangeretin, in contrast, did not induce apoptosis, but suppressed further triglyceride accumulation. SIGNIFICANCE: Our results suggest that nobiletin and tangeretin are promising therapeutic candidates for the prevention and treatment of insulin resistance by modulating the adipocytokine secretion balance. We also demonstrated the different effects of nobiletin and tangeretin on mature adipocytes. PMID- 21295044 TI - Pentadecapeptide BPC 157 and its effects on a NSAID toxicity model: diclofenac induced gastrointestinal, liver, and encephalopathy lesions. AB - AIMS: We attempted to fully antagonize the extensive toxicity caused by NSAIDs (using diclofenac as a prototype). MAIN METHODS: Herein, we used the stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, MW 1419), an anti-ulcer peptide shown to be efficient in inflammatory bowel disease clinical trials (PL 14736) and various wound treatments with no toxicity reported. This peptide was given to antagonize combined gastrointestinal, liver, and brain toxicity induced by diclofenac (12.5mg/kg intraperitoneally, once daily for 3 days) in rats. KEY FINDINGS: Already considered a drug that can reverse the toxic side effects of NSAIDs, BPC 157 (10 MUg/kg, 10 ng/kg) was strongly effective throughout the entire experiment when given (i) intraperitoneally immediately after diclofenac or (ii) per-orally in drinking water (0.16 MUg/mL, 0.16 ng/mL). Without BPC 157 treatment, at 3h following the last diclofenac challenge, we encountered a complex deleterious circuit of diclofenac toxicity characterized by severe gastric, intestinal and liver lesions, increased bilirubin, aspartate transaminase (AST), alanine transaminase (ALT) serum values, increased liver weight, prolonged sedation/unconsciousness (after any diclofenac challenge) and finally hepatic encephalopathy (brain edema particularly located in the cerebral cortex and cerebellum, more in white than in gray matter, damaged red neurons, particularly in the cerebral cortex and cerebellar nuclei, Purkinje cells and less commonly in the hippocampal neurons). SIGNIFICANCE: The very extensive antagonization of diclofenac toxicity achieved with BPC 157 (MUg-/ng-regimen, intraperitoneally, per-orally) may encourage its further use as a therapy to counteract diclofenac- and other NSAID-induced toxicity. PMID- 21295045 TI - Dopamine induces a GluN2A-dependent form of long-term depression of NMDA synaptic responses in the nucleus accumbens. AB - Natural rewards and addictive drugs are believed to exert their reinforcing actions by influencing synaptic plasticity in reward-related brain regions such as the nucleus accumbens (NAc). Long-lasting changes in the efficacy of excitatory synaptic transmission in the NAc are critically dependent on efficient interactions between the dopaminergic and the glutamatergic neurotransmitter systems. Potential targets to the actions of dopamine and of addictive drugs include the GluN2 subunits that compose the N-Methyl-D-Aspartate (NMDA) type of glutamate receptors. However, the ability of dopamine to induce synaptic plasticity by modulating specific subunits of the NMDA receptor has not been examined. The present study shows that in the mouse NAc, dopamine produces a long lasting depression of NMDA responses which occludes long-term depression (LTD) induced by high frequency stimulation (HFS) of glutamatergic fibers. LTD induced by dopamine or by HFS does not involve a change in the subunit composition of NMDA receptors. Although GluN2B contributes to synaptic responses in the NAc and is affected by dopamine, this subunit might not be a direct target to the actions of dopamine. The results, however, identify a critical role for GluN2A in dopamine-induced and HFS-induced synaptic plasticity. This study suggests a possible mechanism of action for dopamine in the regulation of reward-related behaviors. PMID- 21295046 TI - Contributions of the D-serine pathway to schizophrenia. AB - The glutamate neurotransmitter system is one of the major candidate pathways for the pathophysiology of schizophrenia, and increased understanding of the pharmacology, molecular biology and biochemistry of this system may lead to novel treatments. Glutamatergic hypofunction, particularly at the NMDA receptor, has been hypothesized to underlie many of the symptoms of schizophrenia, including psychosis, negative symptoms and cognitive impairment. This review will focus on D-serine, a co-agonist at the NMDA receptor that in combination with glutamate, is required for full activation of this ion channel receptor. Evidence implicating D-serine, NMDA receptors and related molecules, such as D-amino acid oxidase (DAO), G72 and serine racemase (SRR), in the etiology or pathophysiology of schizophrenia is discussed, including knowledge gained from mouse models with altered D-serine pathway genes and from preliminary clinical trials with D-serine itself or compounds modulating the D-serine pathway. Abnormalities in D-serine availability may underlie glutamatergic dysfunction in schizophrenia, and the development of new treatments acting through the D-serine pathway may significantly improve outcomes for many schizophrenia patients. PMID- 21295047 TI - Visual working memory as visual attention sustained internally over time. AB - Visual working memory and visual attention are intimately related, such that working memory encoding and maintenance reflects actively sustained attention to a limited number of visual objects and events important for ongoing cognition and action. Although attention is typically considered to operate over perceptual input, a recent taxonomy proposes to additionally consider how attention can be directed to internal perceptual representations in the absence of sensory input, as well as other internal memories, choices, and thoughts (Chun, Golomb, & Turk Browne, 2011). Such internal attention enables prolonged binding of features into integrated objects, along with enhancement of relevant sensory mechanisms. These processes are all limited in capacity, although different types of working memory and attention, such as spatial vs. object processing, operate independently with separate capacity. Overall, the success of maintenance depends on the ability to inhibit both external (perceptual) and internal (cognitive) distraction. Working memory is the interface by which attentional mechanisms select and actively maintain relevant perceptual information from the external world as internal representations within the mind. PMID- 21295048 TI - Chunking movements into sequence: the visual pre-selection of subsequent goals. AB - The chunking of individual movements into sequences has been studied extensively from a motor point of view. Here we approach the planning of sequential behavior from a perceptual perspective investigating the sensorimotor transformations that accompany visually guided sequential behavior. We show that visual attention pre selects subsequent goals only if two movements are planned to be carried out in rapid succession and therefore are integrated into one common action. This causes visual attention to select both intended goal locations in advance. In contrast, in more slowly executed motor sequences, the single movements are programmed one by-one and subsequent movement goals are only later visually prepared ('just in time'). The visual selection of a subsequent goal location crucially depends on the speed of the planned sequence: the longer the inter-reach delay, the less visual attention is deployed to the subsequent goal initially. PMID- 21295049 TI - Fto immunoreactivity is widespread in the rodent brain and abundant in feeding related sites, but the number of Fto-positive cells is not affected by changes in energy balance. AB - A single nucleotide polymorphism in the FTO gene is associated with obesity in humans. Evidence gathered in animals mainly relates energy homeostasis to the central FTO mRNA levels, but our knowledge of the Fto protein distribution and regulation is limited. Fto, a demethylase and transcriptional coactivator, is thought to regulate expression of other genes. Herein, we examined Fto immunoreactivity (IR) in the mouse and rat brain with emphasis on sites governing energy balance. We also studied whether energy status affects central Fto IR. We report that Fto IR, limited to nuclear profiles, is widespread in the brain, in- and outside feeding circuits; it shows a very similar distribution in feeding related sites in mice and rats. Several areas regulating energy homeostasis display enhanced intensity of Fto staining: the arcuate, paraventricular, supraoptic, dorsomedial, ventromedial nuclei, and dorsal vagal complex. Some regions mediating feeding reward, including the bed nucleus of the stria terminalis, have ample Fto IR. We found that differences in energy status between rats fed ad libitum, deprived or refed following deprivation, did not affect the number of Fto-positive nuclei in 10 sites governing consumption for energy or reward. We conclude that Fto IR, widespread in the rodent brain, is particularly abundant in feeding circuits, but the number of Fto-positive neurons is unaffected by changes in energy balance. PMID- 21295050 TI - 5-methoxy-N,N-di(iso)propyltryptamine hydrochloride (Foxy)-induced cognitive deficits in rat after exposure in adolescence. AB - Foxy or Methoxy Foxy (5-methoxy-N,N-di(iso)propyltryptamine hydrochloride; 5-MeO DIPT) is rapidly gaining popularity among recreational users as a hallucinogenic "designer drug." Unfortunately, much remain unknown about the consequences of its use on neuropsychological development or behavior. During one of two adolescent periods, the rats were given repeated injections of 5 mg/kg or 20 mg/kg of 5-MeO DIPT or a corresponding volume of isotonic saline. After the animals reached adulthood, they were trained and tested on a number of tasks designed to assess the impact of 5-MeO-DIPT, if any, on spatial memory, presumably involving declarative memory systems as well as a nonspatial task that is considered sensitive to disruptions in nondeclarative memory. Both the 5-MeO-DIPT- and saline-treated rats were able to master spatial navigation tests where the task included a single goal location and all groups performed comparably on these phases of training and testing. Regardless of exposure level during adolescence, the performance of the drug-treated rats was markedly inferior to that of the control animals on a task where the goal was moved to a new location and on a response learning task, suggesting a lack of flexibility in adapting their responses to changing task demands. Detected reductions in serotonin activity in the forebrain similar to the effects of extensively investigated compounds such as methylenedioxymethamphetamine (MDMA), suggest that 5-MeO-DIPT may produce its adverse effects by compromising serotonergic systems in the brain. PMID- 21295051 TI - Utilizing toxicogenomic data to understand chemical mechanism of action in risk assessment. AB - The predominant role of toxicogenomic data in risk assessment, thus far, has been one of augmentation of more traditional in vitro and in vivo toxicology data. This article focuses on the current available examples of instances where toxicogenomic data has been evaluated in human health risk assessment (e.g., acetochlor and arsenicals) which have been limited to the application of toxicogenomic data to inform mechanism of action. This article reviews the regulatory policy backdrop and highlights important efforts to ultimately achieve regulatory acceptance. A number of research efforts on specific chemicals that were designed for risk assessment purposes have employed mechanism or mode of action hypothesis testing and generating strategies. The strides made by large scale efforts to utilize toxicogenomic data in screening, testing, and risk assessment are also discussed. These efforts include both the refinement of methodologies for performing toxicogenomics studies and analysis of the resultant data sets. The current issues limiting the application of toxicogenomics to define mode or mechanism of action in risk assessment are discussed together with interrelated research needs. In summary, as chemical risk assessment moves away from a single mechanism of action approach toward a toxicity pathway-based paradigm, we envision that toxicogenomic data from multiple technologies (e.g., proteomics, metabolomics, transcriptomics, supportive RT-PCR studies) can be used in conjunction with one another to understand the complexities of multiple, and possibly interacting, pathways affected by chemicals which will impact human health risk assessment. PMID- 21295052 TI - Lithospermic acid B protects beta-cells from cytokine-induced apoptosis by alleviating apoptotic pathways and activating anti-apoptotic pathways of Nrf2-HO 1 and Sirt1. AB - Lithospermic acid B (LAB) has been reported to protect OLETF rats, an established type 2 diabetic animal model, from the development of diabetes-related vascular complications. We investigated whether magnesium lithospermate B (LAB) has a protective role under cytokine-induced apoptosis in INS-1 cells in vitro and whether it slows the development of diabetes in OLETF rats in vivo. Pretreatment with 50 MUM LAB significantly reduced the 1000 U/mL INF-gamma and 100 U/mL IL 1beta-induced INS-1 cell death. LAB significantly alleviated cytokine-induced phosphorylations of p38 and JNK in accordance with a decrease in cleaved caspase 3 activity in beta-cells. LAB also protected against the cytokine-induced caspase 3 apoptotic pathway via significant activation of Nrf2-HO (heme-oxygenase)-1 and Sirt1 expression. OLETF rats treated with 40 mg/kg/day LAB showed a significant improvement in glucose tolerance compared to untreated OLETF control rats in vivo. Our results suggest that the cytoprotective effects of LAB on pancreatic beta-cells are related with both alleviating apoptotic pathways and activating anti-apoptotic pathways of Nrf2-HO-1 and Sirt1. PMID- 21295053 TI - Visual search guidance is best after a short delay. AB - Search displays are typically presented immediately after a target cue, but in the real-world, delays often exist between target designation and search. Experiments 1 and 2 asked how search guidance changes with delay. Targets were cued using a picture or text label, each for 3000ms, followed by a delay up to 9000ms before the search display. Search stimuli were realistic objects, and guidance was quantified using multiple eye movement measures. Text-based cues showed a non-significant trend towards greater guidance following any delay relative to a no-delay condition. However, guidance from a pictorial cue increased sharply 300-600ms after preview offset. Experiment 3 replicated this guidance enhancement using shorter preview durations while equating the time from cue onset to search onset, demonstrating that the guidance benefit is linked to preview offset rather than a more complete encoding of the target. Experiment 4 showed that enhanced guidance persists even with a mask flashed at preview offset, suggesting an explanation other than visual priming. We interpret our findings as evidence for the rapid consolidation of target information into a guiding representation, which attains its maximum effectiveness shortly after preview offset. PMID- 21295054 TI - Neuronal adaptation to simulated and optically-induced astigmatic defocus. AB - PURPOSE: It is well established that spatial adaptation can improve visual acuity over time in the presence of spherical defocus. It is less well known how far adaptation to astigmatic defocus can enhance visual acuity. We adapted subjects to "simulated" and optically-induced "real" astigmatic defocus, and studied how much they adapt and how selective adaptation was for the axis of astigmatism. METHODS: Ten subjects with a mean age of 26.7+/-2.4years (range 23-30) were enrolled in the study, three of them myopic (average spherical equivalent (SE)+/ SD: -3.08+/-1.42D) and seven emmetropic (average SE+/-SD: -0.11+/-0.18D). All had a corrected minimum visual acuity (VA) of logVA 0.0. For adaptation, subjects watched a movie at 4m distance for 10min that was convolved frame-by-frame with an astigmatic point spread function, equivalent to +3D defocus, or they watched an unfiltered movie but with spectacle frames with a 0/+3D astigmatic trial lenses. Subsequently, visual acuity was determined at the same distance, using high contrast letter acuity charts. Four experiments were performed. In experiment (1), simulated astigmatic defocus was presented both for adaptation and testing, in experiment (2) optically-induced astigmatic defocus was presented both for adaptation and testing of visual acuity. In all these cases, the +3D power meridian was at 0 degrees . In experiments (3) and (4), the +3D power meridian was at 0 degrees during adaptation but rotated to 90 degrees during testing. Astigmatic defocus was simulated in experiment (3) but optically-induced in experiment (4). RESULTS: Experiments 1 and 2: adaptation to either simulated or real astigmatic defocus increased visual acuity in both test paradigms, simulated (change in VA 0.086+/-0.069 log units; p<0.01) and lens-induced astigmatic defocus (change in VA 0.068+/-0.031 log units; p<0.001). Experiments 3 and 4: when the axis was rotated, the improvement in visual acuity failed to reach significance, both for simulated (change in VA 0.042+/-0.079 log units; p=0.13) and lens-induced astigmatic defocus (change in VA 0.038+/-0.086 log units; p=0.19). CONCLUSIONS: Adaptation to astigmatic defocus occurs for both simulated and real defocus, and the effects of adaptation seem to be selective for the axis of astigmatism. These observations suggest that adaptation involves a re-adjustment of the spatial filters selectively for astigmatic meridians, although the underlying mechanism must be more complicated than just changes in shapes of the receptive fields of retinal or cortical neurons. PMID- 21295055 TI - Attenuating effect of adenosine receptor agonists on the development of behavioral sensitization induced by sporadic treatment with morphine. AB - The aim of the study is to investigate the effect of adenosine receptor agonists on the development of morphine-induced sensitization to the locomotor activity of mice. Selective A1 (N6-cyclopentyladenosine - CPA) and A2A (2-p-(2-carboxyethyl) phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride - CGS 21680) adenosine receptor agonists or non-selective A1/A2A (5'-N ethylcarboxamidoadenosine - NECA) adenosine agonists as representatives of adenosinergic drugs have been used in the experiment. Behavioral sensitization has been obtained by sporadic treatment with morphine (10.0mg/kg, i.p.). We have shown that adenosine receptor agonists co-administered with morphine significantly attenuates increase in the locomotor activity of mice evoked by challenge dose of morphine. These effects have been observed after stimulation of the selective A1 or A2A and non-selective A1/A2A adenosine receptors, namely both receptors were involved in morphine-induced sensitization. Thus, we have demonstrated that adenosine agonists are able to inhibit behavioral sensitization induced by sporadic applications of morphine. PMID- 21295056 TI - SB-334867-A, a selective orexin-1 receptor antagonist, enhances taste aversion learning and blocks taste preference learning in rats. AB - Lateral hypothalamus (LH) has been proposed as a possible center for the anatomical convergence of gustatory and postingestive information relevant to taste aversion learning (TAL) and conditioned flavor preference (CFP). Orexin, a neuropeptide that mainly originates in neurons in lateral hypothalamic areas, was recently related to learning and memory processes. The present study was designed to analyze a possible relationship between the orexinergic system and taste learning. We studied the effect of intracerebroventricular administration of three doses (3, 6, and 12 MUg/1 MUl) of the selective orexin-1 receptor antagonist SB-334867-A on the acquisition of TAL induced by a single administration of LiCl. Infusion of SB-334867-A did not block this learning and appeared to enhance TAL in a two-bottle test. However, SB-334867-A (6 MUg/1 MUl) blocked taste preference learning when a flavor associated with saccharin (CS+) was offered on alternate days against a different flavor without saccharin (CS-), during three acquisition sessions. These results offer evidence of a relationship between the orexinergic system and taste learning; they tentatively suggest the possibility that endogenous orexin and gustatory and postingestive (visceral and oral) signals converge in brain areas relevant to the acquisition of taste learning. PMID- 21295057 TI - Catecholamine influences on prefrontal cortical function: relevance to treatment of attention deficit/hyperactivity disorder and related disorders. AB - The primary symptoms of attention deficit/hyperactivity disorder (ADHD) include poor impulse control and impaired regulation of attention. Research has shown that the prefrontal cortex (PFC) is essential for the "top-down" regulation of attention, behavior, and emotion, and that this brain region is underactive in many patients with ADHD. The PFC is known to be especially sensitive to its neurochemical environment; relatively small changes in the levels of norepinephrine and dopamine can produce significant changes in its function. Therefore, alterations in the pathways mediating catecholamine transmission can impair PFC function, while medications that optimize catecholamine actions can improve PFC regulation of attention, behavior, and emotion. This article reviews studies in animals showing that norepinephrine and dopamine enhance PFC function through actions at postsynaptic alpha(2A)-adrenoceptors and dopamine D1 receptors, respectively. Stimulant medications and atomoxetine appear to enhance PFC function through increasing endogenous adrenergic and dopaminergic stimulation of alpha(2A)-receptors and D1-receptors. In contrast, guanfacine mimics the enhancing effects of norepinephrine at postsynaptic alpha(2A) receptors in the PFC, strengthening network connectivity. Stronger PFC regulation of attention, behavior, and emotion likely contributes to the therapeutic effects of these medications for the treatment of ADHD. PMID- 21295058 TI - Blockade of CRF1 and CCK2 receptors attenuated the elevated anxiety-like behavior induced by immobilization stress. AB - Two highly co-localized neurotransmitters: corticotropin-releasing factor (CRF) and cholecystokinin (CCK), have been implicated in the development of stress related anxiety disorders. This study was designed to examine the role of CRF1 and CCK2 receptors on the anxiety-like behavior induced by immobilization stress. Our results showed that 30-min immobilization enhanced the anxiety-like behavior in C57BL/6J mice examined in the elevated plus maze (EPM). The combined pretreatment of CR2945 (a CCK2 receptor antagonist) and antalarmin (a CRF1 receptor antagonist) fully blocked this elevated anxiety-like behavior, while the application of CR2945 or antalarmin alone showed only partial effects. The increased expression of CRF1 and CCK2 receptors at protein levels in three anxiety-related brain regions: cortex, hippocampus and hypothalamus, was detected by Western blot. The increased mRNA expression of CCK, CRF, CCK2 and CRF1 receptors was also examined by real-time RT-PCR. Our study demonstrated that the blockade of CRF1 and CCK2 receptors attenuated the elevated anxiety-like behavior induced by immobilization stress, suggestive of the CRF and CCK systems contributing to the development of stress-related anxiety behavior. PMID- 21295060 TI - About validity of conclusions based on multiple linear regression: a commentary on Kupelian et al. (2010). PMID- 21295061 TI - Factors associated with initial participation in a population-based screening for colorectal cancer in Catalonia, Spain: a mixed-methods study. AB - OBJECTIVE: To identify barriers and facilitators associated with participation in the first round of a population-based program for colorectal cancer (CRC) in Catalonia, Spain and to identify strategies for motivating and supporting behavioral change. MATERIAL AND METHODS: A two-part, mixed-methods design was used. In first place, a prospective study of individuals aged 50-69 years (n=1961) was conducted in 2006-2007. Secondly, focus groups were undertaken with participants and non-participants of the CRC screening, in 2008. RESULTS: Intention to participate was an important determinant of participation (82.9% vs 65.9%, OR=2.56, 95%CI:1.95-3.36) in addition to knowledge about CRC and its early detection. Respondents who reported that CRC may be asymptomatic in early stages enrolled in the screening program more frequently than those who thought CRC is always symptomatic (49.4% vs 44.8%, OR:1.82; 95%CI:1.3-2.6). Barriers for participation mentioned in focus groups were competing perceived for other health problems and other demands as well as misunderstanding about personal relevance of the screening. CONCLUSION: Individuals' perceptions of CRC are amenable to change through education-based interventions. Increasing public knowledge related to the burden of CRC and its preventive potential may be an effective way for improving participation in a population-based screening program. PMID- 21295059 TI - Cognitive enhancers for facilitating drug cue extinction: insights from animal models. AB - Given the success of cue exposure (extinction) therapy combined with a cognitive enhancer for reducing anxiety, it is anticipated that this approach will prove more efficacious than exposure therapy alone in preventing relapse in individuals with substance use disorders. Several factors may undermine the efficacy of exposure therapy for substance use disorders, but we suspect that neurocognitive impairments associated with chronic drug use are an important contributing factor. Numerous insights on these issues are gained from research using animal models of addiction. In this review, the relationship between brain sites whose learning, memory and executive functions are impaired by chronic drug use and brain sites that are important for effective drug cue extinction learning is explored first. This is followed by an overview of animal research showing improved treatment outcome for drug addiction (e.g. alcohol, amphetamine, cocaine, heroin) when explicit extinction training is conducted in combination with acute dosing of a cognitive-enhancing drug. The mechanism by which cognitive enhancers are thought to exert their benefits is by facilitating consolidation of drug cue extinction memory after activation of glutamatergic receptors. Based on the encouraging work in animals, factors that may be important for the treatment of drug addiction are considered. PMID- 21295063 TI - Accelerometer steps/day translation of moderate-to-vigorous activity. AB - Physical activity (PA) guidelines are typically communicated in terms of duration, frequency and intensity, e.g., 30 min/day of moderate-to-vigorous physical activity (MVPA) on at least 5 days/week. Step counters can be used to collect objective PA expressed as steps/day, however the association between steps/day and recommended PA levels is unclear. OBJECTIVE: We determined a direct steps/day translation of 30 min/day accumulated MVPA, using concurrently detected ActiGraph accelerometer-defined step and activity count data collected as part of the 2005-2006 National Health and Nutrition Examination Survey (NHANES). METHOD: We employed statistical models to analyze data from 3523 participants 20+years of age who wore the accelerometer for at least one valid day (i.e., at least 10/24h) over 7 days. RESULTS: 30 min/day of MVPA translated to approximately 7900 steps/day for males and 8300 steps/day for females. In a subsample of participants (n=1197) with valid data on all 7 days, we found 150 min/week of MVPA translated to approximately 7000 steps/day (or 49,000 steps/week). CONCLUSION: Accumulating approximately 8000 steps/day is a good proxy for 30 min of daily MVPA, while accumulating 7000 steps/day every day of the week is consistent with obtaining 150 min of weekly MVPA. PMID- 21295062 TI - Leisure-time physical activity and breast cancer risk defined by estrogen and progesterone receptor status--the Japan Public Health Center-based Prospective Study. AB - OBJECTIVE: The study aims to investigate the association between leisure-time physical activity and breast cancer risk in consideration of tumor estrogen receptor/progesterone-receptor status. METHODS: We conducted a population-based prospective cohort study among 53,578 women in the Japan Public Health Center based Prospective Study. Leisure-time physical activity was assessed by self reported questionnaires. A Cox proportional hazards regression model was used to derive relative risks and 95% confidence intervals. RESULTS: From 1990-1993 to the end of 2007, 652 cases were identified. The breast cancer rates (per 100,000 person-years) in the sedentary groups (<=3 days/month) was 84 in overall, 97 in premenopausal and 75 in postmenopausal women. We observed a statistically significant inverse association between leisure-time physical activity and breast cancer risk (relative risk(>=3 days/week vs. <=3 days/month)=0.73; 95% confidence interval 0.54-1.00; p(trend) 0.037), particularly in estrogen receptor+progesterone receptor+ (relative risk 0.43; 0.19-1.00; p(trend) 0.022), and this inverse trend was apparent among postmenopausal women (relative risk 0.25; 0.06-1.06; p(trend) 0.041). An inverse trend was also observed between daily total physical activity and postmenopausal estrogen receptor+progesterone receptor+ risk (p=0.046). Among body mass index >=25 kg/m(2) group, leisure-time physical activity was associated with decreased risk (relative risk(>=1 day/week vs. <=3 days/month)=0.65; 0.43-0.97; p(trend) 0.033). CONCLUSION: Active participation in leisure-time physical activity may contribute to a decrease in breast cancer risk, particularly for postmenopausal estrogen receptor+progesterone receptor+ tumors. PMID- 21295064 TI - Male circumcision as an HIV prevention intervention in the U.S.: Influence of health care providers and potential for risk compensation. AB - OBJECTIVE: The study aims to assess the acceptability of male circumcision as an HIV prevention intervention and the potential for risk compensation in the continental U.S. METHODS.: ConsumerStyles 2008 survey was used to identify correlates of 1) a "likely" or "very likely" response among uncircumcised men to "How likely are you to get circumcised if your health care provider told you that circumcision would reduce your chance of becoming HIV infected?" and 2) agreement or neutrality with a statement indicating that given the protective effects of circumcision for heterosexual men shown by research, men do not have to worry about risks like not wearing condoms during sex or having more sex partners (assessed potential for risk compensation). RESULTS: Response rate was 50.6% (10,108/19,996). Overall, 13.1% of uncircumcised men reported they would be likely to get circumcised if their health care provider told them it would reduce the risk of HIV infection through sex with infected women. Nearly 18% of all men responded in a way indicating a potential for risk compensation if circumcised. CONCLUSIONS: Tailored educational materials about the benefits and risks, including risk compensation, associated with male circumcision as an HIV prevention intervention should be made available to health care providers and specific groups. PMID- 21295065 TI - Poly(hydroxyethyl methacrylate) based affinity cryogel for plasmid DNA purification. AB - The aim of this study is to prepare supermacroporous pseudospecific cryogel which can be used for the purification of plasmid DNA (pDNA) from bacterial lysate. N methacryloyl-(l)-histidine methyl ester (MAH) was chosen as the pseudospecific ligand and/or comonomer. Poly(hydroxyethyl methacrylate-N-methacryloyl-(l) histidine methyl ester) [PHEMAH] cryogel was produced by free radical polymerization initiated by N,N,N',N'-tetramethylene diamine (TEMED) and ammonium persulfate (APS) pair in an ice bath. Compared with the PHEMA cryogel (50 MUg/g polymer), the pDNA adsorption capacity of the PHEMAH cryogel (13,350 MUg/g polymer) was improved significantly due to the MAH incorporation into the polymeric matrix. The amount of pDNA bound onto the PHEMAH cryogel disks first increased and then reached a saturation value (i.e., 13,350MUg/g) at around 300 MUg/ml pDNA concentration. pDNA adsorption amount decreased from 1137 MUg/g to 160 MUg/g with the increasing NaCl concentration. The maximum pDNA adsorption was achieved at 25 degrees C. The overall recovery of pDNA was calculated as 90%. The PHEMAH cryogel could be used 3 times without decreasing the pDNA adsorption capacity significantly. The results indicate that the PHEMAH cryogel disks promise high selectivity for pDNA. PMID- 21295066 TI - A family tree of vertebrate chemokine receptors for a unified nomenclature. AB - Chemokines receptors are involved in the recruitment of various cell types in inflammatory and physiological conditions. There are 23 known chemokine receptor genes in the human genome. However, it is still unclear how many chemokine receptors exist in the genomes of various vertebrate species other than human and mouse. Moreover, the orthologous relationships are often obscure between the genes of higher and lower vertebrates. In order to provide a basis for a unified nomenclature system of the vertebrate chemokine receptor gene family, we have analysed the chemokine receptor genes from the genomes of 16 vertebrate species, and classify them into 29 orthologous groups using phylogenetic and comparative genomic analyses. The results reveal a continuous gene birth and death process during the vertebrate evolution and an interesting evolutionary history of the chemokine receptor genes after the emergence in agnathans. PMID- 21295067 TI - Norepinephrine depresses the immunity and disease-resistance ability via alpha1- and beta1-adrenergic receptors of Macrobrachium rosenbergii. AB - In this study, we determined the effects of norepinephrine (NE) on immunity and the pathway of its function in the freshwater giant prawn, Macrobrachium rosenbergii. The total hemocyte count (THC), differential hemocyte count (DHC), phenoloxidase activity, respiratory bursts, superoxide dismutase (SOD) activity, phagocytic activity, and clearance efficiency in response to the pathogen, Lactococcus garvieae, were measured when the freshwater giant prawn, M. rosenbergii (16.2+/-2.1 g) was individually injected with saline or NE at 0.5, 5.0, and 50.0 pmol prawn(-1). Results showed that semi-granular cells, respiratory bursts and phagocytic activity at 2 h, PO activity and clearance efficiency from 2 to 4 h, THC at 8 h, and SOD activity from 4 to 8 h significantly decreased, but hyaline cells at 2 h, and respiratory bursts at 8 h had significantly increased after injection of NE at 50.0 pmol prawn(-1). In prawns that had received 5.0 pmol NE prawn(-1), the PO activity had decreased at 2 h, SOD activity at 8 h, and the clearance efficiency at 2 h. PO activity had decreased at 2 h after prawns had received 0.5 pmol NE prawn(-1). All of the immune parameters had returned to control values by 16 h after receiving NE. However, no significant differences were observed in the granular cells during the experimental period. An injection of NE also significantly increased the mortality of prawns challenged with L. garvieae, which appeared to be dose dependent. In another experiment, NE co-injected with prazosin, metoprolol, or propranolol significantly decreased the mortality of challenged prawns, especially when co-injected with prazosin and metoprolol. These results suggest that stress-inducing NE suppresses the immune system, which in turn promotes the susceptibility of M. rosenbergii to L. garvieae via both alpha1- and beta1 adrenergic receptors. PMID- 21295068 TI - Identification and functional characterization of an interferon regulatory factor 7-like (IRF7-like) gene from orange-spotted grouper, Epinephelus coioides. AB - Interferon regulatory factor (IRF) 7 plays a crucial role in modulating cellular responses to viral infection and cytokines, including interferons (IFNs). In the present study, a novel IRF7 gene (designated as EcIRF7) was cloned and characterized from orange-spotted grouper, Epinephelus coioides. The full-length EcIRF7 cDNA is composed of 2089 bp and encodes a polypeptide of 433 amino acids with 81% identity to IRF7 of Siniperca chuatsi, and the genomic DNA of EcIRF7 consists of 9 exons and 8 introns, with a length of approximately 5629 bp. EcIRF7 contains three conserved domains including a DNA-binding domain (DBD), an IRF associated domain (IAD) and a serine-rich domain, all of which are highly conserved across species. Recombinant EcIRF7 was expressed in Escherichia coli BL21 (DE3) and purified for mouse anti-EcIRF7 serum preparation. Realtime quantitative PCR (RT-qPCR) analysis revealed a broad expression of EcIRF7, with a relative strong expression in spleen, kidney, skin and intestine. The expression of EcIRF7 was differentially up-regulated after stimulation with Vibrio vulnificus, Staphylococcus aureus and Singapore grouper iridovirus (SGIV). EcIRF7 showed similar intracellular localization pattern to those of mammalian and chicken, and translocated into nucleus after SGIV infection. Further more, EcIRF7 was proved to be capable of activating zebrafish type I IFN promoter and inhibiting the replication of SGIV in grouper spleen (GS) cells. These results suggest that EcIRF7 is potentially involved in grouper immune responses to invasion of viral and bacterial pathogens. PMID- 21295069 TI - The C1q domain containing proteins of the Mediterranean mussel Mytilus galloprovincialis: a widespread and diverse family of immune-related molecules. AB - The key component of the classical complement pathway C1q is regarded as a major connecting link between innate and acquired immunity due to the highly adaptive binding properties of its trimeric globular domain gC1q. The gC1q domain also characterizes many non-complement proteins involved in a broad range of biological processes including apoptosis, inflammation, cell adhesion and cell differentiation. In molluscs and many other invertebrates lacking of adaptive immunity, C1q domain containing (C1qDC) proteins are abundant, they most probably emerged as lectins and subsequently evolved in a specialized class of pattern recognition molecules through the expanding interaction properties of gC1q. Here we report the identification of 168 C1qDC transcript sequences of Mytilus galloprovincialis. The remarkable abundance of C1qDC transcripts in the Mediterranean mussel suggests an evolutionary strategy of gene duplication, functional diversification and selection of many specific C1qDC variants. A comprehensive transcript sequence survey in Protostomia also revealed that the C1qDC family expansion observed in mussel could have occurred in some specific taxa independently from the events leading to the establishment of a large complement of C1qDC genes in the Chordates lineage. PMID- 21295070 TI - Host defense peptides in skin secretions of the Oregon spotted frog Rana pretiosa: implications for species resistance to chytridiomycosis. AB - Population declines due to chytridiomycosis among frogs belonging to the Amerana (Rana boylii) species group from western North America have been particularly severe. Norepinephrine-stimulated skin secretions from the Oregon spotted frog Rana pretiosa Baird and Girard, 1853 were collected from individuals that had been previously infected with the causative agent Batrachochytrium dendrobatidis but had proved resistant to developing chytridiomycosis. These secretions contained a more diverse array of antimicrobial peptides than found in other species from the Amerana group and 14 peptides were isolated in pure form. Determination of their primary structures identified the peptides as esculentin 2PRa and -2PRb; ranatuerin-2PRa, -2PRb, -2PRc, -2PRd, and -2PRe; brevinin-1PRa, 1PRb, -1PRc, and -1PRd; and temporin-PRa, -PRb, and -PRc. The strongly cationic ranatuerin-2PRd and the esculentin-2 peptides, which have not been identified in the secretions of other Amerana species except for the closely related R. luteiventris, showed the highest growth inhibitory potency against microorganisms. The strongly hydrophobic brevinin-1PRd was the most cytotoxic to erythrocytes. Although no clear correlation exists between production of dermal antimicrobial peptides by a species and its resistance to fatal chytridiomycosis, the diversity of these peptides in R. pretiosa may be pivotal in defending the species against environmental pathogens such as B. dendrobatidis. PMID- 21295071 TI - Aspirin resistance: effect of clinical, biochemical and genetic factors. AB - Aspirin is one of the cornerstones of treatment for cardiovascular disease. However, some patients may be 'resistant' to its effect: this is associated with adverse cardiovascular outcomes and increased mortality. Measuring response to aspirin is often difficult and there is no accepted definition of aspirin resistance. Many assays are available to test aspirin sensitivity but most are not specific to aspirin and the degree of agreement between different assays is poor. Each assay has its own advantages and disadvantages, and there is currently no one assay that can be recommended for routine clinical practise. There are also many potential modifiers of aspirin response including aspirin dose, non compliance, disease severity, genetic factors, inflammation, diabetes mellitus, hyperlipidaemia, smoking and interacting drugs. Treating the underlying cause may improve aspirin sensitivity but current data are contradictory with no large clinical trials that have addressed this. Further work is required in this area to determine whether and how aspirin resistance is important clinically, what the best measurement is phenotypically and how this should be used in clinical practise, and whether there are any genetic predisposing factors. This will require well designed prospective studies which take into account the numerous confounding factors that can modify aspirin resistance. PMID- 21295072 TI - The gut microbiome as therapeutic target. AB - Obesity, type-2 diabetes and low-grade inflammation are becoming worldwide epidemics. In this regard, the literature provides a novel concept that we call "MicrObesity" (Microbes and Obesity), which is devoted to deciphering the specific role of dysbiosis and its impact on host metabolism and energy storage. In the present review, we discuss novel findings that may partly explain how the microbial community participates in the development of the fat mass development, insulin resistance and low-grade inflammation that characterise obesity. In recent years, numerous mechanisms have been proposed and several proteins identified. Amongst the key players involved in the control of fat mass development, Fasting induced adipose factor, AMP-activated protein kinase, G protein coupled receptor 41 and G-protein coupled receptor 43 have been linked to gut microbiota. In addition, the discovery that low-grade inflammation might be directly linked to the gut microbiota through metabolic endotoxaemia (elevated plasma lipopolysaccharide levels) has led to the identification of novel mechanisms involved in the control of the gut barrier. Amongst these, the impacts of glucagon-like peptide-2, the endocannabinoid system and specific bacteria (e.g., Bifidobacterium spp.) have been investigated. Moreover, the advent of probiotic and prebiotic treatments appears to be a promising "pharmaco nutritional" approach to reversing the host metabolic alterations linked to the dysbiosis observed in obesity. Although novel powerful molecular system biology approaches have offered great insight into this "small world within", more studies are needed to unravel how specific changes in the gut microbial community might affect or counteract the development of obesity and related disorders. PMID- 21295073 TI - Carbon monoxide and the eye: Implications for glaucoma therapy. AB - In the late 1990s, the scientific community witnessed a very peculiar phenomenon: the transformation of nitric oxide (NO) from a noxious gas into a key chemical messenger. The importance of NO in biology and medicine was highlighted in 1998 when the Nobel Prize was awarded in Physiology and Medicine to Robert Furchgott, Louis Ignarro and Ferid Murad for their pioneering work on the role of NO in the nervous, cardiovascular and immune systems. In this same time period, carbon monoxide (CO), another gas usually associated with environmental pollution, air poisoning and suicidal behavior, was also undergoing a similar change in image, although not as closely followed. It had been known for several decades that the human body generated CO upon the decomposition of hemoglobin, which was determined by the discovery that heme oxygenase (HO) is the enzymatic source of CO. However, CO's role as an endogenous neurotransmitter was established only in the early 1990s. Since then, many biological activities of CO have been demonstrated in studies using different tools, such as the pharmacological induction of HO by hemin, the direct administration of CO or the use of pro-drugs that generate CO. This review focuses on CO as a fine modulator of intraocular pressure and on its potential implications in glaucoma. PMID- 21295075 TI - New opportunities in anti-hepatitis C virus drug discovery: targeting NS4B. AB - Current therapy for chronic hepatitis C virus (HCV) infection constitutes a combination of pegylated interferon alfa-2a or alpha-2b and ribavirin. Although successful for many patient populations, this regimen has numerous limitations, including non-response, relapse, poor tolerability and long duration of treatment. To address these shortcomings, new small molecule agents are advancing in clinical development. Most of the current clinical candidates act by directly inhibiting key enzymes in the viral life-cycle: the NS5B polymerase, or the NS3/4A protease. Less well-studied, the non-structural 4B (NS4B) protein has recently emerged as an alternative target for Direct-acting Antiviral Agents (DAAs). NS4B is a 27-kDa membrane protein that is primarily involved in the formation of membrane vesicles--also named membranous web--used as scaffold for the assembly of the HCV replication complex. In addition, NS4B contains NTPase and RNA binding activities, as well as anti-apoptotic properties. This review summarizes the current understanding of the structure and functions of NS4B, an essential component of the replication machinery of HCV. In this literature and patent review, we report the recent developments in anti-NS4B drug discovery. These advances open the possibility for future combination therapies with other DAAs. PMID- 21295076 TI - Conflict processing is modulated by positive emotion: ERP data from a flanker task. AB - Recent evidence shows that negative emotional stimuli speed up the resolution of conflict between opposing response tendencies. This mechanism ensures rapid reactions in potentially threatening situations. However, it is unclear whether positive emotion has a similar effect on conflict processing. We therefore presented positive emotional words in a version of the flanker conflict task, in which conflict is elicited by incongruent target and flanker stimuli. Response times to incongruent stimuli were shortened in positive words, indicating a speeding up of conflict resolution. We also observed an enlargement of the first conflict-sensitive event-related potential (ERP) of the electroencephalogram, the N200, in positive emotional trials. The data suggest that positive emotion already modulates first stages of conflict processing. The results demonstrate that positive, reward-predicting stimuli influence conflict processing in a similar manner to threat signals. Positive emotion thus reduces the time that an organism is unable to respond due to simultaneously present conflicting action tendencies. PMID- 21295074 TI - Is lipid signaling through cannabinoid 2 receptors part of a protective system? AB - The mammalian body has a highly developed immune system which guards against continuous invading protein attacks and aims at preventing, attenuating or repairing the inflicted damage. It is conceivable that through evolution analogous biological protective systems have been evolved against non-protein attacks. There is emerging evidence that lipid endocannabinoid signaling through cannabinoid 2 (CB2) receptors may represent an example/part of such a protective system/armamentarium. Inflammation/tissue injury triggers rapid elevations in local endocannabinoid levels, which in turn regulate signaling responses in immune and other cells modulating their critical functions. Changes in endocannabinoid levels and/or CB2 receptor expressions have been reported in almost all diseases affecting humans, ranging from cardiovascular, gastrointestinal, liver, kidney, neurodegenerative, psychiatric, bone, skin, autoimmune, lung disorders to pain and cancer, and modulating CB2 receptor activity holds tremendous therapeutic potential in these pathologies. While CB2 receptor activation in general mediates immunosuppressive effects, which limit inflammation and associated tissue injury in large number of pathological conditions, in some disease states activation of the CB2 receptor may enhance or even trigger tissue damage, which will also be discussed alongside the protective actions of the CB2 receptor stimulation with endocannabinoids or synthetic agonists, and the possible biological mechanisms involved in these effects. PMID- 21295077 TI - Social encounter with a novel partner in adolescent rats: activation of the central endocannabinoid system. AB - The endocannabinoid system is critically involved in the modulation of affect, motivation, and emotion. Here, we investigated the hypothesis that changes in the content of endocannabinoid levels might underlie adaptation to positive social conditions during adolescence. To this aim, separate pairs of adolescent (postnatal days 32-35) male Wistar rats were allowed to interact in a neutral cage under two different testing conditions, i.e. familiar (FAM) and non-familiar (NFAM) social partners. We found that adolescent rats that encountered a NFAM partner spent significantly more time Sniffing and Following the companion than subjects exposed to a FAM partner, whereas no changes in levels of rough-and tumble play were observed. Notably, the NFAM social encounter significantly increased striatal anandamide (AEA) levels compared to both non-social controls and animals that encountered a FAM partner. Changes in AEA levels appeared to be region-specific, since no changes were observed in the other brain regions analysed, neither were they observed in the activity of the AEA-hydrolase (FAAH) nor in the content of the other major endocannabinoid 2-arachidonylglycerol. In addition, animals that encountered a NFAM partner tended to explore less extensively the illuminated compartment of the light-dark box when compared to animals that had previously encountered a FAM companion. In conclusion, striatal AEA levels seem to participate in the emotional arousal resulting from a NFAM social encounter in adolescent rats, and to be particularly important for coping response to novel social contexts. PMID- 21295078 TI - Changes in phosphorylation of CREB, ERK, and c-fos induction in rat ventral tegmental area, hippocampus and prefrontal cortex after conditioned place preference induced by chemical stimulation of lateral hypothalamus. AB - Experimental evidence indicates that chemical stimulation of lateral hypothalamus (LH) by carbachol can produce conditioned place preference (CPP) in rats. Several lines of evidence have shown that cAMP-response element binding protein (CREB), extracellular signal-regulated kinase (ERK), and c-fos have pivotal role in CPP induced by drugs of abuse, such as morphine, cocaine, nicotine, and alcohol. Therefore, in the present study, we investigated the changes in phosphorylated CREB (p-CREB) and -ERK (p-ERK), and c-fos induction within ventral tegmental area (VTA), hippocampus and prefrontal cortex (PFC) after the acquisition of CPP induced by intra-LH administration of carbachol. Animals were unilaterally implanted by cannula into LH. For chemical stimulation of LH, carbachol (250 nmol/0.5 MUl saline) was microinjected once each day, during 3-day conditioning phase (acquisition period) of CPP paradigm. After the acquisition period, the brains were removed, and p-CREB and p-ERK, and c-fos induction in the ipsilateral VTA, hippocampus and PFC were measured by Western blot analysis. The results indicated a significant increase in level of phosphorylated CREB (P<0.01) in VTA, and PFC (P<0.05), during LH stimulation-induced CPP, while its level decreased in hippocampus (P<0.05). Also, in aforementioned regions, an increase in c-fos level was observed, but this enhancement in PFC was not significant. Moreover, p-ERK changed in these areas, but not significantly. Our findings suggest that studying the intracellular signals and their changes, such as phosphorylated-CREB, can elucidate a functional relationship between LH and other brain structures involved in reward processing in rats. PMID- 21295079 TI - Update on genetic markers of quinine resistance in Plasmodium falciparum. AB - The emergence and spread of antimalarial resistance remain burgeoning issues. Any strategy to slow down or overcome these problems requires an understanding of the genetic changes underlying this resistance. Quinine, the first antimalarial, has been central in the treatment of severe malaria, and has been proposed as second line treatment for uncomplicated malaria in many African countries. Some reports have indicated the emergence of quinine resistance in South East Asia and in Africa, however doubts have been raised about this quinine resistance in Africa. New and interesting data are emerging on the mechanism of quinine reduced susceptibility. In this report, we have reviewed work on the in vivo efficacy and in vitro activity of quinine, and discussed recent data on genetic markers of resistance to this drug. Overall, quinine still remains efficacious in Africa, and pfnhe, the sodium hydrogen exchanger, may be one of the genetic markers underlying quinine in vitro resistance. PMID- 21295081 TI - Abnormal actomyosin assembly in proliferating and differentiating myoblasts upon expression of a cytosolic DMPK isoform. AB - DMPK, the product of the mutated gene in myotonic dystrophy type 1, belongs to the subfamily of Rho-associated serine-threonine protein kinases, whose members play a role in actin-based cell morphodynamics. Not much is known about the physiological role of differentially localized individual DMPK splice isoforms. We report here that prominent stellar-shaped stress fibers are formed during early and late steps of differentiation in DMPK-deficient myoblast-myotubes upon complementation with the short cytosolic DMPK E isoform. Expression of DMPK E led to an increased phosphorylation status of MLC2. We found no such effects with vectors that encode a mutant DMPK E which was rendered enzymatically inactive or any of the long C-terminally anchored DMPK isoforms. Presence of stellar structures appears associated with changes in cell shape and motility and a delay in myogenesis. Our data strongly suggest that cytosolic DMPK participates in remodeling of the actomyosin cytoskeleton in developing skeletal muscle cells. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. PMID- 21295080 TI - Mitochondrial longevity pathways. AB - Average lifespan has increased over the last centuries, as a consequence of medical and environmental factors, but maximal life span remains unchanged. Better understanding of the underlying mechanisms of aging and determinants of life span will help to reduce age-related morbidity and facilitate healthy aging. Extension of maximal life span is currently possible in animal models with measures such as genetic manipulations and caloric restriction (CR). CR appears to prolong life by reducing oxidative damage. Reactive oxygen species (ROS) have been proposed to cause deleterious effects on DNA, proteins, and lipids, and generation of these highly reactive molecules takes place in the mitochondria. But ROS is positively implicated in cellular stress defense mechanisms and formation of ROS a highly regulated process controlled by a complex network of intracellular signaling pathways. There are endogenous anti-oxidant defense systems that have the potential to partially counteract ROS impact. In this review, we will describe pathways contributing to the regulation of the age related decline in mitochondrial function and their impact on longevity. This article is part of a Special Issue entitled Mitochondria: the deadly organelle. PMID- 21295082 TI - The TGF-beta co-receptor, CD109, promotes internalization and degradation of TGF beta receptors. AB - Transforming growth factor-beta (TGF-beta) is implicated in numerous pathological disorders, including cancer and mediates a broad range of biological responses by signaling through the type I and II TGF-beta receptors. Internalization of these receptors via the clathrin-coated pits pathway facilitates SMAD-mediated signaling, whereas internalization via the caveolae pathway is associated with receptor degradation. Thus, molecules that modulate receptor endocytosis are likely to play a critical role in regulating TGF-beta action. We previously identified CD109, a GPI-anchored protein, as a TGF-beta co-receptor and a negative regulator of TGF-beta signaling. Here, we demonstrate that CD109 associates with caveolin-1, a major component of the caveolae. Moreover, CD109 increases binding of TGF-beta to its receptors and enhances their internalization via the caveolae. In addition, CD109 promotes localization of the TGF-beta receptors into the caveolar compartment in the presence of ligand and facilitates TGF-beta-receptor degradation. Thus, CD109 regulates TGF-beta receptor endocytosis and degradation to inhibit TGF-beta signaling. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. PMID- 21295083 TI - Essential role of ERK activation in neurite outgrowth induced by alpha-lipoic acid. AB - BACKGROUND: Neurite outgrowth is an important aspect of neuronal plasticity and regeneration after neuronal injury. Alpha-lipoic acid (LA) has been used as a therapeutic approach for a variety of neural disorders. We recently reported that LA prevents local anesthetics-induced neurite loss. In this study, we hypothesized that LA administration promotes neurite outgrowth. METHODS: To test our hypothesis, we treated mouse neuroblastoma N2a cells and primary neurons with LA. Neurite outgrowth was evaluated by examination of morphological changes and by immunocytochemistry for beta-tubulin-3. ROS production was examined, as were the phosphorylation levels of ERK and Akt. In separate experiments, we determined the effects of the inhibition of ERK or PI3K/Akt as well as ROS production on LA induced neurite outgrowth. RESULTS: LA promoted significantly neurite outgrowth in a time- and concentration-dependent manner. LA stimulation significantly increased the phosphorylation levels of both Akt and ERK and transiently induced ROS production. PI3K/Akt inhibition did not affect LA-induced neurite outgrowth. However, the inhibition of ERK activation completely abolished LA-induced neurite outgrowth. Importantly, the prevention of ROS production by antioxidants attenuated LA-stimulated ERK activation and completely abolished LA-promoted neurite outgrowth. CONCLUSION: Our data suggest that LA stimulates neurite outgrowth through the activation of ERK signaling, an effect mediated through a ROS-dependent mechanism. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. PMID- 21295084 TI - Caspase-8 and bid: caught in the act between death receptors and mitochondria. AB - Mitochondria play a central role in maintaining cells alive, but are also important mediators of cell death. The main event in mitochondrial signalling and control of apoptosis is the permeabilisation of the outer mitochondrial membrane and the release of pro-apoptotic proteins into the cytosol from the mitochondrial intermembrane space. With respect to death receptor-mediated apoptosis, the activation of the mitochondrial pathway is required for apoptosis induction in cells which are described as "type II" cells whereas "type I" cells do not require it. In type I cells, activation of the extrinsic pathway is sufficient to induce apoptosis. This review deals with the events that enable cell death in type II cells, i.e., the signals that lead from death receptor stimulation to permeabilisation of the outer mitochondrial membrane. Caspase-8 and Bid are the known procurers of the death signal in this part of the apoptotic pathway. Currently many exciting new findings are emerging concerning the regulation of caspase-8 and Bid function and activation. We will take you on a journey through these new developments and point out what we consider the major unknowns in this field. We end our review on an up-to-date discussion of the determinants of the type I-type II cell distinction. This article is part of a Special Issue entitled Mitochondria: the deadly organelle. PMID- 21295085 TI - A combined theoretical and in vitro modeling approach for predicting the magnetic capture and retention of magnetic nanoparticles in vivo. AB - Magnetic nanoparticles (MNP) continue to draw considerable attention as potential diagnostic and therapeutic tools in the fight against cancer. Although many interacting forces present themselves during magnetic targeting of MNP to tumors, most theoretical considerations of this process ignore all except for the magnetic and drag forces. Our validation of a simple in vitro model against in vivo data, and subsequent reproduction of the in vitro results with a theoretical model indicated that these two forces do indeed dominate the magnetic capture of MNP. However, because nanoparticles can be subject to aggregation, and large MNP experience an increased magnetic force, the effects of surface forces on MNP stability cannot be ignored. We accounted for the aggregating surface forces simply by measuring the size of MNP retained from flow by magnetic fields, and utilized this size in the mathematical model. This presumably accounted for all particle-particle interactions, including those between magnetic dipoles. Thus, our "corrected" mathematical model provided a reasonable estimate of not only fractional MNP retention, but also predicted the regions of accumulation in a simulated capillary. Furthermore, the model was also utilized to calculate the effects of MNP size and spatial location, relative to the magnet, on targeting of MNPs to tumors. This combination of an in vitro model with a theoretical model could potentially assist with parametric evaluations of magnetic targeting, and enable rapid enhancement and optimization of magnetic targeting methodologies. PMID- 21295086 TI - Antibiotic-releasing porous polymethylmethacrylate/gelatin/antibiotic constructs for craniofacial tissue engineering. AB - An antibiotic-releasing porous polymethylmethacrylate (PMMA) construct was developed to maintain the bony space and prime the wound site in the initial step of a two-stage regenerative medicine approach toward reconstructing significant bony or composite craniofacial tissue defects. Porous PMMA constructs incorporating gelatin microparticles (GMPs) were fabricated by the sequential assembly of GMPs, the antibiotic colistin, and a clinically used bone cement formulation of PMMA powder and methylmethacrylate liquid. PMMA/gelatin/antibiotic constructs with varying gelatin incorporation and drug content were investigated to elucidate the relationship between material composition and construct properties (porosity and drug release kinetics). The porosity of PMMA/gelatin/antibiotic constructs ranged between 7.6+/-1.8% and 38.4+/-1.4% depending on the amount of gelatin incorporated and the drug solution added for gelatin swelling. The constructs released colistin over 10 or 14 days with an average release rate per day above 10 MUg/ml. The porosity and in vitro colistin release kinetics of PMMA/gelatin/antibiotic constructs were tuned by varying the material composition and fabrication parameters. This study demonstrates the potential of gelatin-incorporating PMMA constructs as a functional space maintainer for both promoting tissue healing/coverage and addressing local infections, enabling better long-term success of the definitive regenerated tissue construct. PMID- 21295087 TI - Glutathione-responsive nano-vehicles as a promising platform for targeted intracellular drug and gene delivery. AB - The past couple of years have witnessed a tremendous progress in the development of glutathione-responsive nano-vehicles for targeted intracellular drug and gene delivery, as driven by the facts that (i) many therapeutics (e.g. anti-cancer drugs, photosensitizers, and anti-oxidants) and biotherapeutics (e.g. peptide and protein drugs, and siRNA) exert therapeutical effects only inside cells like the cytosol and cell nucleus, and (ii) several intracellular compartments such as cytosol, mitochondria, and cell nucleus contain a high concentration of glutathione (GSH) tripeptides (about 2-10 mM), which is 100 to 1000 times higher than that in the extracellular fluids and circulation (about 2-20 MUM). Glutathione has been recognized as an ideal and ubiquitous internal stimulus for rapid destabilization of nano-carriers inside cells to accomplish efficient intracellular drug release. In this paper, we will review recent results on GSH responsive nano-vehicles in particular micelles, nanoparticles, capsules, polymersomes, nanogels, dendritic and macromolecular drug conjugates, and nano sized nucleic acid complexes for controlled delivery of anti-cancer drugs (e.g. doxorubicin and paclitaxel), photosensitizers, anti-oxidants, peptides, protein drugs, and nucleic acids (e.g. DNA, siRNA, and antisense oligodeoxynucleotide). The unique disulfide chemistry has enabled novel and versatile designs of multifunctional delivery systems addressing both intracellular and extracellular barriers. We are convinced that GSH-responsive nano-carrier systems have enormous potential in targeted cancer therapy. PMID- 21295088 TI - Prevention of metastasis in a 4T1 murine breast cancer model by doxorubicin carried by folate conjugated pH sensitive polymeric micelles. AB - This study primarily focused on the anti-metastatic activity of doxorubicin (DOX) loaded in a pH-sensitive mixed polymeric micelle formed from two block polymers: poly(L-lactide) (PLLA) (Mn 3000)-b-poly(ethylene glycol) (PEG) (Mn 2000)-folate and poly(L-histidine) (PHis) (Mn 4700)-b-PEG (Mn 2000). Tumor formation and metastasis in mice were examined using a murine mammary carcinoma cell of 4T1 which is one of the most aggressive metastatic cancer cell lines. The efficacy was evaluated by tumor size, body weight change, survival rate, dorsal skin fold window chamber model, and histological observation of the lung, heart, liver and spleen after treatment with various DOX formulations. When the tumor reached 50 100 mm3 in size, the mice were treated 4 times at a 3-day interval at a dose of 10 mg DOX/kg. The mixed micelle formulation resulted in retarded tumor growth, no weight loss, and no death for 4-5 weeks. In another set of the in vivo test for histological evaluation of the organs, the mice were similarly treated but the formulations were injected one day after 4T1 cell inoculation. The treatment by DOX loaded mixed micelle showed no apparent metastasis till 28 days. However, significant metastasis to the lung and heart was observed on Day 28 when the mice were treated with DOX carried by PBS, PLLA-b-PEG micelle and PHis-b-PEG micelle. PMID- 21295089 TI - Hyaluronic acid and fibrin hydrogels with concentrated DNA/PEI polyplexes for local gene delivery. AB - Local delivery of DNA through a hydrogel scaffold would increase the applicability of gene therapy in tissue regeneration and cancer therapy. However, the delivery of DNA/cationic polymer nanoparticles (polyplexes) using hydrogels is challenging due to the aggregation and inactivation of polyplexes during their incorporation into hydrogel scaffolds. We developed a novel process (termed caged nanoparticle encapsulation or CnE) to load concentrated and unaggregated non viral gene delivery nanoparticles into various hydrogels. Previously, we showed that PEG hydrogels loaded with DNA/PEI polyplexes through this process were able to deliver genes both in vitro and in vivo. In this study, we found that hyaluronic acid and fibrin hydrogels with concentrated and unaggregated polyplexes loaded through CnE were able to deliver genes in vivo as well, demonstrating the universality of the process. PMID- 21295090 TI - High-affinity peptide against MT1-MMP for in vivo tumor imaging. AB - Membrane type-1 matrix metalloproteinase (MT1-MMP) is a key member of the matrix metalloproteinase (MMP) family. It participates in pericellular proteolysis of extracellular matrix (ECM) macromolecules and is essential for many biological and pathological processes, such as tumor development, angiogenesis and metastasis. A ligand that specifically binds to MT1-MMP may facilitate the labeling of this molecule, allow imaging at the cellular and organism levels, and provide a means for targeted drug delivery specific to MT1-MMP. A non-substrate MT1-MMP binding peptide was identified by screening a Ph.D.-12TM phage display peptide library and conjugated with near-infrared fluorescent (NIRF) dye Cy5.5 for tumor imaging. Peptide HWKHLHNTKTFL (denoted as MT1-AF7p) showed high MT1-MMP binding affinity. Computer modeling verified that MT1-AF7p binds to the MT-loop region of MT1-MMP and interacts with MT1-MMP through hydrogen bonding and hydrophobic interactions. MDA-MB-435 xenografts with high MT1-MMP expression had significantly higher tumor accumulation and better tumor contrast than the low MT1-MMP expressing A549 xenografts after intravenous injection of Cy5.5-MT1-AF7p. Using NIRF imaging, we have demonstrated specific targeting of MT1-AF7p to MT1 MMP-expressing tumors. Thus, MT1-AF7p is an important tool for noninvasive monitoring of MT1-MMP expression in tumors, and it shows great potential as an imaging agent for MT1-MMP-positive tumors. PMID- 21295091 TI - FibroStic: a large confirmatory study for non-invasive biomarkers accuracy, if correctly interpreted. PMID- 21295094 TI - Tracheobronchial bio-engineering: biotechnology fulfilling unmet medical needs. AB - The development of substitutes for the human trachea or its bronchial tree represents a niche application in the rapidly advancing scientific field of Regenerative Medicine. Despite a comparatively small research foundation in the field of tracheo-bronchial bioengineering, four different approaches have already been translated into clinical settings and applied in patients. This can be attributed to the lack of established treatment options for a small group of patients with extensive major airway disease. In this review, the clinical background and tissue-specific basics of tracheo-bronchial bioengineering will be evaluated. Focusing on the clinical applications of bioengineered tracheal tissues, a "top-down" or "bedside-to-bench" analysis is performed in order to guide future basic and clinical research activities for airway bioengineering. PMID- 21295095 TI - Plasma kisspeptin levels are elevated in cord blood and present sexual dimorphism in the adult population: relation with leptin, gonadotropins and anthropometrical data. AB - Kisspeptin, the product of the hypothalamic KISS1 gene, is a main regulator of the hypothalamic-pituitary-gonadal axis and could be a link between metabolism and reproduction through its interaction with leptin. Kisspeptin could be involved in gonadotropin regulation and responsive to leptin levels from the first stages of life, exhibiting, as does leptin, sexual dimorphism. To test our hypothesis, we have analyzed plasma kisspeptin levels and their possible relationship with gonadotropins and leptin in a cohort composed of newborns (n = 86) and adults (n = 55). Plasma kisspeptin, gonadotropin and leptin levels were measured by RIA and multiplexed bead immunoassays, respectively. We have built a multivariate linear regression model (analyzing kisspeptin and LH separately as dependent variables) by stepwise analysis, incorporating the variables that had shown significant correlation in the univariate analysis. Cord blood samples exhibited high kisspeptin levels 127.01(113-141.02 pmol/l), but these were not sexually dimorphic. The adult population exhibited sexual dimorphism (3.72(2.95 4.49) vs. 1.77(1.23-2.31)pmol/l women vs. men, p<0.05). Leptin levels showed sexual dimorphism in cord blood samples and also in the adult population. Furthermore, there was a significant interaction between LH and kisspeptin levels and kisspeptin was negatively correlated with age. The high kisspeptin levels observed in cord blood, with no sexual dimorphism, suggest a placental source. The sexual dimorphism exhibited in adulthood supports the notion that there are different sources and/or differential kisspeptin regulation between men and women. PMID- 21295093 TI - Cancer cell invasion: treatment and monitoring opportunities in nanomedicine. AB - Cell invasion is an intrinsic cellular pathway whereby cells respond to extracellular stimuli to migrate through and modulate the structure of their extracellular matrix (ECM) in order to develop, repair, and protect the body's tissues. In cancer cells this process can become aberrantly regulated and lead to cancer metastasis. This cellular pathway contributes to the vast majority of cancer related fatalities, and therefore has been identified as a critical therapeutic target. Researchers have identified numerous potential molecular therapeutic targets of cancer cell invasion, yet delivery of therapies remains a major hurdle. Nanomedicine is a rapidly emerging technology which may offer a potential solution for tackling cancer metastasis by improving the specificity and potency of therapeutics delivered to invasive cancer cells. In this review we examine the biology of cancer cell invasion, its role in cancer progression and metastasis, molecular targets of cell invasion, and therapeutic inhibitors of cell invasion. We then discuss how the field of nanomedicine can be applied to monitor and treat cancer cell invasion. We aim to provide a perspective on how the advances in cancer biology and the field of nanomedicine can be combined to offer new solutions for treating cancer metastasis. PMID- 21295096 TI - Evaluation of reproductive/developmental and repeated dose (subchronic) toxicity and cytogenetic effects in rats of a roofing asphalt fume condensate by nose-only inhalation. AB - A Type III Built-up Roofing Asphalt (BURA) fume condensate was evaluated for subchronic systemic toxicity and reproductive/developmental toxicity screening in Wistar rats, by OECD protocol 422 and OECD cytogenetic protocol 474. Animals were exposed by nose-only inhalation to target concentrations of 30, 100 and 300 mg/m3 total hydrocarbons (actual concentrations, 30.0, 100.1 and 297.3 mg/m3). The study was performed to assess potential hazards from asphalt fumes to which humans could be exposed during application. No adverse effects were seen for spermology, reproductive or developmental parameters or early postnatal development of offspring from day 1 to 4 postpartum. BURA fume condensate did not induce any significant increases in micronucleus frequency in polychromatic erythrocytes of rat bone marrow nor was neurobehavioral toxicity observed at any dose. Systemic effects were slight and seen at doses above those measured at work sites. The systemic NOAEC of 100 mg/m3 for males was based on decreased body weight gain, food consumption and increased absolute and relative lung wet weight correlated with slight histological changes in the lung, primarily adaptive in nature at 300 mg/m3. The female NOAEC of 30 mg/m3 was based on a statistically significant increase in relative wet lung weight at higher doses, correlated with slight histopathologic effects in the lungs at the highest dose. However, no increase in relative lung weight was seen in breeding females at 100 mg/m3. PMID- 21295097 TI - The substitution principle. AB - According to the substitution principle, hazardous chemicals should be replaced by less hazardous alternatives. In this paper, the major issues concerning the more precise definition of the principle are analyzed, and a general purpose definition is proposed. It is claimed that the priority between reducing hazard, functionality and economical considerations in the application of the substitution principle is a matter for adjustment in each particular case that cannot be settled beforehand. None of these objectives can have absolute priority over the others, but the substitution principle is aimed at increasing the priority given to the reduction of hazards to human health and the environment. Major methods to promote and implement the principle are summarized, current legislative approaches are discussed, and proposals for efficient implementation are made. It is emphasized that the primary responsibility for avoiding hazardous substances and processes rests with industry. PMID- 21295098 TI - The impact of CYP2E1 genetic variability on risk assessment of VOC mixtures. AB - Humans are simultaneously exposed to multiple chemicals in the environment. Many of the chemicals use the same enzymes in their metabolic pathways. Competitive inhibition may occur as one of the possible interactions between the xenobiotics in human body. For example, many volatile organic compounds (VOCs) are metabolized using P450 enzymes, specifically CYP2E1. Inheritable gene alterations may result in changes of function of the enzymes in different human subpopulations. Variations in quantity and/or quality of particular isoenzymes may cause differences in the metabolism of VOCs. These variations may cause higher sensitivity in certain populations. Using examples of three different mixtures, this review paper outlines the variances in CYP2E1 isoenzymes, effect of exposure to such mixtures on sensitive populations, and approaches to mixtures risk assessment. PMID- 21295099 TI - Effectiveness of influenza vaccination of staff on morbidity, and mortality of residents of long term care facilities for the elderly. PMID- 21295100 TI - Effects of Taishan Pinus massoniana pollen polysaccharide on immune response of rabbit haemorrhagic disease tissue inactivated vaccine and on production performance of Rex rabbits. AB - Varied doses of Taishan Pinus massoniana pollen polysaccharide (TPPPS) and Astragalus polysaccharide (APS) extracted by hot water extraction and ethanol precipitation method were added to the vaccine in order to prepare polysaccharide rabbit haemorrhagic disease (RHD) tissue inactivated vaccine. The purpose was to study effects of TPPPS on immune response of RHD tissue inactivated vaccine and on production performance of Rex rabbits. Results showed that each index in groups I, II, III and IV was higher than that in group V, especially groups I, II and IV, the difference between which and group V was much more significant (P<0.05); each index in group I was extremely higher than that in group V (P<0.01); each index in group I was significantly higher than that in groups II, III (P<0.05), and generally no significant difference was observed between groups II and III. The overall level in group IV was slightly lower than that in group I. Each index in the polysaccharide groups reached its peak value later than that in the non-polysaccharide groups did. Results suggested that any dose of TPPPS can enhance immunologic function and production performance of rabbits, and the amount of 400mg per rabbit has the most obvious efficacy. Furthermore, it can extend the immune peak period of RHD tissue inactivated vaccine and the growing peak period of Rex rabbits. TPPPS has generally higher efficiency than APS. PMID- 21295101 TI - Peripheral administration of NR2 antagonists attenuates orofacial formalin induced nociceptive behavior in rats. AB - The present study investigated the role of the peripheral NR2 subunits of N methyl-d-aspartatic acid (NMDA) receptors in inflammatory orofacial pain. Experiments were carried out using adult male Sprague-Dawley rats weighing 220 to 280 g. Formalin (5%, 50 MUl) was applied subcutaneously to the vibrissa pad. For each animal, the number of noxious behavioral responses, including rubbing or scratching of the facial region proximal to the injection site, was recorded for 9 sequential 5 min intervals. NR2 subunit antagonists were injected subcutaneously at 20 min prior to formalin injection. The subcutaneous injection of 100 or 200 MUg of memantine significantly suppressed the number of scratches in the second phase of the behavioral responses to formalin. The subcutaneous injection of 0.25, 2.5, or 25 MUg of 5,7-dichlorokynurenic acid also produced significant antinociceptive effects in the second phase. The subcutaneous injection of AP-5 at high dose produced significant antinociceptive effects in the second phase. The subcutaneous injection of PPPA and Ro 25-6981 both significantly suppressed the number of scratches in the second phase. The antinociceptive doses of memantine (200 MUg), 5,7-dichlorokynurenic acid (25 MUg), AP-5 (20 MUg), PPPA (2.5 MUg), or Ro 25-6981 (50 MUg) injected into the contralateral hind paw did not affect the number of scratches in both the first and second phases. Moreover, the peripheral administration of NR2 subunit antagonists, including other NMDA receptor blockers, did not produce any motor dysfunction. These results indicate that a targeted blockade of peripheral NR2 receptors is a potentially important new method of treating inflammatory pain in the orofacial area. PMID- 21295102 TI - Curcumin potentiates doxorubicin-induced apoptosis in H9c2 cardiac muscle cells through generation of reactive oxygen species. AB - Doxorubicin (DOX) is a widely used chemotherapy agent. The major adverse effect of DOX treatment in cancer patients is the onset of cardiomyopathy and heart failure. Reactive oxygen species (ROS) are proposed to be responsible for DOX cardiotoxicity. Curcumin, a natural compound extracted from Curcuma Longa L., is known for its anti-oxidant properties. It has been identified as increased apoptosis in several cancer cell lines in combination with doxorubicin, but there are few studies about the effect of curcumin and doxorubicin on normal cardiac cells. Therefore, we evaluated the effects of curcumin on apoptosis induced by DOX in cardiac muscle cells. Pretreatment with curcumin significantly increased DOX-induced apoptosis of cardiac muscle cells through down regulation of Bcl-2, up-regulation of caspase-8 and caspase-9. The Bax/Bcl-2 ratio increased significantly after 1h pretreatment with curcumin. As well, curcumin increases ROS generation by DOX. In response to DOX, NF-kappaB was activated. However, curcumin was able to inhibit NF-kappaB activation. In conclusion, our results indicated that pretreatment with nontoxic concentrations of curcumin sensitized H9c2 cells to DOX-mediated apoptosis by generation of ROS. PMID- 21295103 TI - Inhibitory effects of wogonin on the invasion of human breast carcinoma cells by downregulating the expression and activity of matrix metalloproteinase-9. AB - Wogonin, a naturally occurring monoflavonoid extracted from Scutellariae radix, has been shown to possess tumor therapeutic potential in vitro and in vivo. However, the effects of wogonin on tumor cells invasion remains poorly understood. In this study, we performed in vitro experiments to investigate the anti-invasive and anti-metastatic activity of wogonin in MDA-MB-231 human breast carcinoma cells. Wogonin caused a concentration-dependent suppression of cell migration, adhesion and invasion. The mechanism revealed that wogonin significantly inhibited the expression and activity of both endogenous and phorbol-12-myristate-13-acetate (PMA)-induced matrix metalloproteinase-9 (MMP-9) potentially associating with the suppression of translocation of protein kinase C (PKC) delta and phosphorylation of extracellular signal-regulated kinase (ERK1/2). These results suggested that wogonin could inhibit the invasion of tumor cells by downregulating the expression and activity of MMP-9, the possible targets may be PKCdelta and ERK1/2. PMID- 21295104 TI - 2-Chloroethyl ethyl sulfide causes microvesication and inflammation-related histopathological changes in male hairless mouse skin. AB - Sulfur mustard (HD) is a vesicating agent that has been used as a chemical warfare agent in a number of conflicts, posing a major threat in both military conflict and chemical terrorism situations. Currently, we lack effective therapies to rescue skin injuries by HD, in part, due to the lack of appropriate animal models, which are required for conducting laboratory studies to evaluate the therapeutic efficacy of promising agents that could potentially be translated in to real HD-caused skin injury. To address this challenge, the present study was designed to assess whether microvesication could be achieved in mouse skin by an HD analog 2-chloroethyl ethyl sulfide (CEES) exposure; notably, microvesication is a key component of HD skin injury in humans. We found that skin exposure of male SKH-1 hairless mice to CEES caused epidermal-dermal separation indicating microvesication. In other studies, CEES exposure also caused an increase in skin bi-fold thickness, wet/dry weight ratio, epidermal thickness, apoptotic cell death, cell proliferation, and infiltration of macrophages, mast cells and neutrophils in male SKH-1 hairless mouse skin. Taken together, these results establish CEES-induced microvesication and inflammation related histopathological changes in mouse skin, providing a potentially relevant laboratory model for developing effective countermeasures against HD skin injury in humans. PMID- 21295105 TI - Concomitant apoptosis and regeneration of liver cells as a mechanism of liver tumor promotion by beta-naphthoflavone involving TNFalpha-signaling due to oxidative cellular stress in rats. AB - beta-naphthoflavone (BNF) is a strong inducer of cytochrome P450 1A enzymes, and exerts liver tumor-promoting activity through enhancement of oxidative stress responses in rats. This study investigated the role of the tissue environment surrounding hepatocellular preneoplastic lesions in the early tumor-promotion stage by BNF, using enzymatically modified isoquercitrin (EMIQ) as an anti oxidative chemopreventive agent. Male F344 rats were fed a diet containing BNF (0.5%) for 6 weeks, with or without EMIQ (0.2%) in the drinking water, 2 weeks after initiation with N-diethylnitrosamine, and were subjected to two-thirds partial hepatectomy 1 week after starting BNF-promotion. BNF-treatment increased concentrations of liver thiobarbituric acid-reactive substances, single liver cells expressing glutathione S-transferase placental form or heme oxygenase (HO) 1, and concomitant apoptosis and proliferation of liver cells. Transcript upregulation of anti-oxidative enzymes (Aldh1a1 and Nqo1), cell cycle-related molecules (Cdc20 and Cdkn2b) and inflammation-related molecules including proinflammatory cytokines (Ccl2, Col1a1, Il6, Nos2 and Serpine1) was also evident. Furthermore, BNF increased HO-1-expressing Kupffer cells and liver cells expressing tumor necrosis factor receptor 1 (TNFR1) and the TNFR1-associated death domain. Most of these BNF-induced fluctuations disappeared or were suppressed by EMIQ in conjunction with suppression of tumor-promotion. Tnf transcript levels with BNF were also suppressed by EMIQ. These results suggest that BNF-induced oxidative stress causes single liver cell toxicity, allowing subsequent concomitant apoptosis and regeneration involving inflammatory responses including TNFalpha-signaling, contributing to tumor promotion. Kupffer cells may act to protect against inflammatory stimuli induced as a result of oxidative cellular stress by BNF, causing proinflammatory cytokine level fluctuations. PMID- 21295106 TI - Cytotoxicity and accumulation of ergot alkaloids in human primary cells. AB - Ergot alkaloids are secondary metabolites produced by fungi of the species Claviceps. Toxic effects after consumption of contaminated grains are described since mediaeval times. Of the more than 40 known ergot alkaloids six are found predominantly. These are ergotamine, ergocornine, ergocryptine, ergocristine, ergosine and ergometrine, along with their corresponding isomeric forms (-inine forms). Toxic effects are known to be induced by an interaction of the ergot alkaloids as neurotransmitters, like dopamine or serotonin. Nevertheless data concerning cytotoxic effects are missing and therefore a screening of the six main ergot alkaloids was performed in human primary cells in order to evaluate the toxic potential. As it is well known that ergot alkaloids isomerize easily the stability was tested in the cell medium. Based on these results factors were calculated to correct the used concentration values to the biologically active lysergic (-ine) form. These factors range from 1.4 for the most stable compound ergometrine to 5.0 for the most unstable ergot alkaloid ergocristine. With these factors, reflecting the instability, several controverse literature data concerning the toxicity could be explained. To evaluate the cytotoxic effects of ergot alkaloids, human cells in primary culture were used. These cells remain unchanged in contrast to cell lines and the data allow a better comparison to the in vivo situation than using immortalized cell lines. To characterize the effects on primary cells, renal proximal tubule epithelial cells (RPTEC) and normal human astrocytes (NHA) were used. The parameters necrosis (LDH-release) and apoptosis (caspase-3-activation, DNA condensation and fragmentation) were distinguished. The results show that depending on the individual structure of the peptide ergot alkaloids the toxic properties change. While ergometrine as a lysergic acid amide did not show any effect, the peptide ergot alkaloids revealed a different toxic potential. Of all tested ergot alkaloids ergocristine was the most cytotoxic compound inducing apoptosis in human kidney cells starting at a concentration of 1MUM in RPTEC. Uptake studies underline the cytotoxic properties, with an accumulation of peptide ergot alkaloids and no uptake of ergometrine. The results represent a new description of effects of ergot alkaloids regarding cytotoxicity and accumulation in human primary cells. For the first time apoptosis has been identified besides well described receptor effects. This gives a hint for a more complex mode of action of ergot alkaloids than described in literature so far. PMID- 21295107 TI - Attenuation of LPS-induced apoptosis in NGF-differentiated PC12 cells via NF kappaB pathway and regulation of cellular redox status by an oxazine derivative. AB - Neuronal cell death due to apoptosis is a common characteristic of neurodegenerative diseases. In this study, we report protective effect of 2 ethoxy-4,5-diphenyl-1,3-oxazine-6-one (EDPOO) against lipopolysaccharide (LPS) induced cell death in rat pheochromocytoma (PC12) cells, as assessed by MTT test, acridine orange/ethidium bromide staining, determination of Bax, Bcl-2 and caspase-3 levels. We further show that this compound could increase heat shock proteins Hsp-70 and Hsp-32 levels. EDPOO also modulates nuclear levels of Nrf2 and NF-kappaB, transcription factors that are activated by intracellular reactive oxygen species and/or mediators generated due to chemical exposure of cells. Pretreatment of the cells with this oxazine derivative also increases gamma-GCS level, as well as antioxidant enzyme activities, in a dose-dependent manner. Protective effect of this compound could represent a promising approach for treatment of neurodegenerative diseases. PMID- 21295108 TI - Effects of competition on endurance performance and the underlying psychological and physiological mechanisms. AB - Competition can influence performance, however, the underlying psychological and physiological mechanisms are poorly understood. To address this issue we tested mechanisms underlying the competition-performance relationship. Measures of anxiety, effort, enjoyment, autonomic activity and muscle activity were obtained from 94 participants during a handgrip endurance task completed in individual and competition conditions. Competition improved endurance performance, increased anxiety, effort, enjoyment, heart rate and muscle activity, and decreased heart rate variability, R-wave to pulse interval and pulse amplitude. Enjoyment fully mediated whereas effort and heart rate variability partially mediated the effects of competition on performance. In addition, anxiety moderated the competition performance relationship; those with lower anxiety performed better in competition. We confirm that competition elicits effects on performance through psychological and physiological pathways, and identify mechanisms that underlie improved endurance performance during competition. PMID- 21295109 TI - Dissociated roles of the anterior cingulate cortex in reward and conflict processing as revealed by the feedback error-related negativity and N200. AB - The reinforcement learning theory of the error-related negativity (ERN) holds that the impact of reward signals carried by the midbrain dopamine system modulates activity of the anterior cingulate cortex (ACC), alternatively disinhibiting and inhibiting the ACC following unpredicted error and reward events, respectively. According to a recent formulation of the theory, activity that is intrinsic to the ACC produces a component of the event-related brain potential (ERP) called the N200, and following unpredicted rewards, the N200 is suppressed by extrinsically applied positive dopamine reward signals, resulting in an ERP component called the feedback-ERN (fERN). Here we demonstrate that, despite extensive spatial and temporal overlap between the two ERP components, the functional processes indexed by the N200 (conflict) and the fERN (reward) are dissociable. These results point toward avenues for future investigation. PMID- 21295110 TI - High expression of NPY receptors in the human testis. AB - NPY receptors represent novel molecular therapeutic targets in cancer and obesity. However, the extent of NPY receptor expression in normal human tissues is poorly investigated. Based on the role of NPY in reproductive functions, the NPY receptor expression was studied in 25 normal human testes and, additionally, 24 testicular tumors using NPY receptor autoradiography. In the normal testis, Leydig cells strongly expressed NPY receptor subtype Y2, and small arterial blood vessels Y1. Y2 receptors were found to be functional with agonist-stimulated [(35)S]GTPgammaS binding autoradiography. Full functional integrity of the NPY system was further suggested by the immunohistochemical detection of NPY peptide in nerve fibers directly adjacent to Leydig cells and arteries. Germ cell tumors expressed Y1 and Y2 on tumor cells in 33% and Y1 on intratumoral blood vessels in 50%. Based on its strong NPY receptor expression in Leydig cells and blood vessels, the normal human testis represents a potentially important physiological and pharmalogical NPY target. PMID- 21295111 TI - MicroRNA-223 expression in neutrophils in the early phase of secondary damage after spinal cord injury. AB - MicroRNA (miR)s are short non-coding RNAs that suppress the translation of target genes, and play an important role in gene regulation. Despite this prominence, there are few reports that refer to the expression of miRs after spinal cord injury (SCI). Previously, we reported on miR-223 expression after SCI in mice. The purpose of this study is to reveal the distribution of miR-223 and identify the cells that express miR-223 in the injured spinal cord. Quantitative polymerase chain reaction analysis revealed high expression of miR-223 at 12h after SCI. Double staining of in situ hybridization and immunohistochemistry showed that the signals of miR-223 merged with Gr-1 positive neutrophils. Our data indicate that miR-223 might regulate neutrophils in the early phase after SCI. PMID- 21295112 TI - Region-specific distribution of beta-amyloid peptide and cytokine expression in TgCRND8 mice. AB - Alzheimer's disease (AD) is a multifactorial disease that results in progressive neurodegeneration. Brain regions are differentially affected in AD. There is also an age-dependent effect on amyloid-beta peptide (Abeta) accumulation and neuroinflammation as disease progresses. In the TgCRND8 APP transgenic mouse model, levels of Abeta species and cytokines were examined as a function of brain region and age. A temporal sequence was observed whereby Abeta accumulation is followed by expression of IL-1beta and eventually, of CXCL1, in the hippocampus and olfactory bulb but not the cortex. We have shown for the first time, in an APP mouse model, age and regional differences in Abeta accumulation and cytokine expression. PMID- 21295113 TI - Sustained increase in the excitability of myelinated peripheral axons to depolarizing current is mediated by Nav1.6. AB - Changes in the excitability of peripheral myelinated axons in response to long lasting subthreshold depolarizing or hyperpolarizing currents (threshold electrotonus) are used as a complementary electrophysiological parameter in the study of peripheral nerve diseases in people. However, the contribution made by various axonal ion channels to specific components of threshold electrotonus remains incompletely understood. In this study, we have recorded threshold electrotonus responses from isolated nerve segments of sural nerve from control and Scn8amed mice, which lack functional Nav1.6 voltage-gated sodium channel. In med mice, the increase in axonal excitability produced by application of subthreshold depolarizing currents for 100-200ms was not sustained. In contrast, there was no difference in threshold electrotonus responses to subthreshold hyperpolarizing current application between Scn8amed and control mice. These data reveal the specific functional role of an identified subtype of voltage-gated sodium channel (Nav1.6) in mediating the depolarizing threshold electrotonus response of peripheral myelinated nerve fibers. PMID- 21295114 TI - Does caloric vestibular stimulation modulate tinnitus? AB - Caloric vestibular stimulation (CVS) has been demonstrated to transiently modulate a variety of cognitive functions. These effects are associated with the brain activation induced by CVS, involving the temporal-parietal cortex, anterior cingulate cortex and insular cortex, which are thought to form a multimodal vestibular cortical network. The present study investigated the effect of CVS upon tinnitus. Twenty patients undergoing vestibular function tests for symptoms of imbalance and who reported tinnitus were asked to rate their tinnitus using visual analogue measures of pitch and intensity immediately before and after CVS (H(2)O at 44 degrees C) in the ear ipsilateral to the tinnitus. One patient was excluded due to test findings indicative of a central vestibular abnormality. The mean VAS pitch (pre-post) changed from 5.65 to 5.28 (95% confidence interval ( 0.87, 0.12), p-value 0.13) and the mean change in intensity changed from 5.21 to 4.43 (95% confidence interval (-1.60, 0.04), p-value 0.06). The findings indicate that there is no consistent influence of CVS upon tinnitus, and we propose that perceived pitch and intensity of tinnitus are independent of the multimodal vestibular network that is activated by CVS. PMID- 21295115 TI - Relative telomere length and cognitive decline in the Nurses' Health Study. AB - Telomeres are short DNA repeats on the ends of mammalian chromosomes, which can undergo incomplete replication leading to gradual shortening with each cell cycle. Age and oxidative stress are contributors to telomere shortening; thus, telomere length may be a composite measure of biologic aging, and a potential predictor of health status in older adults. We evaluated whether relative telomere length (the proportion of telomere repeat copy number to single gene copy number, using a real-time PCR method) predicts cognitive decline measured ten years later among ~ 2000 older participants in the Nurses' Health Study (NHS). Mixed linear regression was used to evaluate mean differences in cognitive decline according to telomere length. After adjustment for potential confounders, we found that decreasing telomere length was associated with more cognitive decline, although associations were modest (e.g. for a global score, averaging all six tests in our cognitive battery, mean difference=0.03 standard units per SD increase in telomere length; p=0.04). The magnitude of these estimates was similar to the differences we find in this cohort for women one year apart in age (e.g. the differences that we observe between women who are 73 versus 74 years of age); thus, our results suggest that telomere length is not a particularly powerful marker of impending cognitive decline. PMID- 21295116 TI - AtoSC two-component system is involved in cPHB biosynthesis through fatty acid metabolism in E. coli. AB - BACKGROUND: We have shown previously that AtoSC two-component system regulates the biosynthesis of E. coli cPHB [complexed poly-(R)-3-hydroxybutyrate]. METHODS: The AtoSC involvement on fatty acids metabolism, towards cPHB synthesis, was studied using cPHB determination, gene expression, and fatty acid metabolic pathways inhibitors. RESULTS: Deletion of the atoDAEB operon from the E. coli genome resulted in a consistent reduction of cPHB accumulation. When in DeltaatoDAEB cells, the atoDAEB operon and the AtoSC system were introduced extrachromosomally, a significant enhancement of cPHB levels was observed. Moreover, the introduction of a plasmid with atoSC genes regulated positively cPHB biosynthesis. A lesser cPHB enhancement was triggered when plasmids carrying either atoS or atoC were introduced. The intracellular distribution of cPHB was regulated by AtoSC or AtoC according to the inducer (acetoacetate or spermidine). Blockage of beta-oxidation by acrylic acid reduced cPHB levels, suggesting the involvement of this pathway in cPHB synthesis; however, the overproduction of AtoSC or its constituents separately resulted in cPHB enhancement. Inhibition of fatty acid biosynthesis by cerulenin resulted to a major cPHB reduction, indicating the contribution of this pathway in cPHB production. Inhibition of both beta-oxidation and fatty acid biosynthesis reduced dramatically cPHB, suggesting the contribution of both pathways in cPHB biosynthesis. CONCLUSIONS: Short fatty acid catabolism (atoDAEB operon) and fatty acids metabolic pathways participate in cPHB synthesis through the involvement of AtoSC system. GENERAL SIGNIFICANCE: The involvement of the AtoSC system in the fatty acids metabolic pathways interplay towards cPHB biosynthesis provides additional perceptions of AtoSC role on E. coli regulatory biochemical processes. PMID- 21295117 TI - Abnormal subcellular localization of AQP5 and downregulated AQP5 protein in parotid glands of streptozotocin-induced diabetic rats. AB - BACKGROUND: The mechanisms underlying diabetic xerostomia have not been clarified in relation with aquaporin-5 (AQP5) subcellular localization in salivary glands. METHODS: Western blotting, real-time PCR, and immunocytochemistry were used to analyse AQP5 protein levels and mRNA expression. AQP5 protein levels were measured in the apical plasma membrane (APM) and detergent-insoluble fraction prepared from streptozotocin-diabetic rat parotid glands. RESULTS: Despite an increase in AQP5 mRNA, AQP5 protein levels were decreased in diabetic parotid glands compared with controls. Immunohistochemical studies indicated that AQP5, under unstimulated conditions, colocalised with flotillin-2 and GM1 with a diffuse pattern in the apical cytoplasm of acinar and duct cells in both control and diabetic rats. Ten minutes after intravenous injection of muscarinic agonist cevimeline, AQP5 was dramatically increased together with flotillin-2 and GM1 in the APM of parotid acinar and duct cells of control but not diabetic rats. Sixty minutes after injection, AQP5 was located in a diffuse pattern in the apical cytoplasm in both rats. Treatment of the parotid tissues with cevimeline for 10min increased the Triton X-100 solubility of AQP5 in control but not diabetic rats. Administration of insulin to diabetic rats tended to restore the cevimeline induced translocation of AQP5. CONCLUSION: Lack of AQP5 translocation in the salivary gland in response to a muscarinic agonist and downregulation of AQP5 protein might lead to diabetic xerostomia. GENERAL SIGNIFICANCE: Cevimeline is useful to cure diabetic xerostomia under insulin administration. PMID- 21295118 TI - Antidepressant-like effects of urocortin 3 fragments. AB - Urocortin 3 (Ucn 3) and various Ucn 3 fragments were tested with regard to antidepressive action in a modified forced swimming test following icv administration to mice. The fragment Ucn 3 (34-36) proved ineffective, whereas Ucn 3 (18-38), Ucn 3 (19-27), Ucn 3 (28-38), Ucn 3 (34-38), and Ucn 3 (36-38) demonstrated antidepressive-like action by shortening the immobility time and increasing the climbing and swimming times. The shortest molecule which elicited most of the antidepressive effects was the tripeptide Ucn 3 (36-38), H-Ala-Gln Ile-NH(2). The results indicate that the total sequence of Ucn 3 is not necessary for the antidepressive action of Ucn 3. Furthermore, the antidepressant actions of Unc3 (19-27) and Ucn 3 (36-38) can be blocked by the CRF2 receptor antagonist Astressin 2beta. Establishment of the smallest active sequence of the molecule may allow the synthesis of analogs or mimetics for antidepressive drugs. PMID- 21295119 TI - No male identity information loss during call propagation through dense vegetation: the case of the corncrake. AB - Individually specific acoustic signals in birds are used in territorial defence. These signals enable a reduction of energy expenditure due to individual recognition between rivals and the associated threat levels. Mechanisms and acoustic cues used for individual recognition seem to be versatile among birds. However, most studies so far have been conducted on oscine species. Few studies have focused on exactly how the potential for individual recognition changes with distance between the signaller and receiver. We studied a nocturnally active rail species, the corncrake, which utters a seemingly simple disyllabic call. The inner call structure, however, is quite complex and expressed as intervals between maximal amplitude peaks, called pulse-to-pulse durations (PPD). The inner call is characterized by very low within-individual variation and high between individuals difference. These variations and differences enable recognition of individuals. We conducted our propagation experiments in a natural corncrake habitat. We found that PPD was not affected by transmission. Correct individual identification was possible regardless of the distance and position of the microphone which was above the ground. The results for sounds from the extreme distance propagated through the vegetation compared to those transmitted above the vegetation were even better. These results support the idea that PPD structure has evolved under selection favouring individual recognition in a species signalling at night, in a dense environment and close to the ground. PMID- 21295120 TI - A behavioral-economic analysis of the essential value of brands. AB - Recently, Hursh and Silberberg (2008) have advanced a behavior-economic approach to measure the value of reinforcers, in which demand elasticity is measured relative to the point at which price is zero, a technique that allows for comparisons across reinforcers that show different consumption patterns or across different dosages or magnitudes of the same reinforcer. The authors have proposed an exponential model in which the elasticity coefficient measures the essential value of reinforcers. The application of the exponential model in various experiments has shown that it provided a good fit to the data and supplied different theoretically consistent results. Considering that this previous research has either been experimentally based or has involved nonhuman participants, the present work examined the application of the model to the analysis of changes in consumption of brands with changes in prices, employing data from actual consumers buying brands of food products in grocery shopping, differing in the level of informational (i.e., socially mediated) and utilitarian (i.e., product mediated) reinforcement they offered. Purchase information concerning two products was obtained from a consumer panel, which included data related to purchases of more than 1600 consumers during 52 weeks. The model, calculated for different brands, fitted the data only moderately, but its parameters showed good reliability across stores. The essential value of brands showed significant increases with increases in brand informational reinforcement. The results indicate the reliability of the measure of essential value as its application is extended from the closed setting of the laboratory to the open settings of the marketplace and to symbolic secondary reinforcers. PMID- 21295121 TI - Endpoint sensitivity in fish endocrine disruption assays: regulatory implications. AB - Identifying potential endocrine disrupting chemicals (EDCs) needs screening and testing for mode of action (MOA) and intrinsic toxicological properties. MOA is often indicated by biomarker endpoints, whereas toxicity by apical endpoints. Risk assessment is mainly based on apical but not on biomarker endpoints. The 21 day fish assay (OECD TG229) is considered a screening test. But it includes both biomarker and apical endpoints. This study explores the utility of results of the 21-day fish assay for risk assessment purposes. Endpoint sensitivity was analysed by compiling 142 data sets for 21-day fish assays and 38 data sets for the fish sexual development test (FSDT), encompassing 62 chemicals with different MOAs. Conclusions from this analysis include: (1) vitellogenin (VTG), fecundity and gonad histology are the most sensitive endpoints for fathead minnow, medaka and zebrafish in 21-day fish assays; secondary sex characteristics (SSC) are a less sensitive endpoint and is likely inadequate to detect all known MOAs. (2) Biomarker endpoints like VTG and apical endpoints like fecundity from the 21-day fish assay can be used for risk assessment. (3) Lowest observed effect concentrations (LOECs) of the most chemicals are comparable for the 21-day fish assay and for the FSDT, further supporting that results of 21-day fish assays can be used for risk assessment. However, a significant difference in LOECs was observed for some chemicals, suggesting that chemical specific effects should be taken into account. This paper emphasizes that a weight of evidence approach is important for interpretation of results of the 21-day fish assay. PMID- 21295122 TI - Sulfation of the 3,4-methylenedioxymethamphetamine (MDMA) metabolites 3,4 dihydroxymethamphetamine (DHMA) and 4-hydroxy-3-methoxymethamphetamine (HMMA) and their capability to inhibit human sulfotransferases. AB - 3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy) is excreted in human urine mainly as conjugates of its metabolites 3,4-dihydroxymethamphetamine (DHMA) and 4 hydroxy-3-methoxymethamphetamine (HMMA). The glucuronidation kinetics of HMMA showed high capacities, but also high K(m) values, unlikely to be reached after recreational user's doses. Therefore, the aim of the present work was to investigate the sulfation of DHMA and HMMA by human sulfotransferases (SULTs) in pooled human liver cytosol (pHLC). The kinetic data showed deviation from typical Michaelis-Menten kinetics. The overall efficiency for HMMA sulfation was calculated to be 2-10 times higher than for glucuronidation. As the sulfation of both MDMA metabolites showed substrate inhibition effects, their inhibitory potential towards typical sulfation reactions in pHLC was tested. The following substrates for typical sulfation reactions were used: nitrophenol, dopamine, estradiol, and dehydroepi androsten dione. Inhibition was observed towards dopamine sulfation by DHMA and HMMA, but not by MDMA. The 1/V vs. 1/S plots indicated a mixed-type or competitive inhibition model for DHMA and HMMA, respectively. In conclusion, the presented data indicated that sulfation of HMMA should be the major conjugation reaction observed in humans. Furthermore, both, DHMA and HMMA, were identified as inhibitors of dopamine sulfation. PMID- 21295123 TI - Distribution of thiolated mucoadhesive nanoparticles on intestinal mucosa. AB - It was the aim of the present study to evaluate and compare the distribution of thiolated mucoadhesive anionic poly(acrylic acid) (PAA) and cationic chitosan (CS) nanoparticles on intestinal mucosa. Modifications of these polymers were achieved by conjugation with cysteine (PAA-Cys) and 2-iminothiolane (CS-TBA). Nanoparticles (NP) were prepared by ionic gelation and labelled with the strong hydrophilic fluorescent dye Alexa Fluor 488 (AF 488) and hydrophobic fluorescein diacetate (FDA). Unmodified and modified CS and PAA NP were examined in vitro in terms of their mucoadhesive and mucus penetrating properties on the mucosa of rat small intestine. To investigate the transport of NP across the mucus layer, their diffusion behaviour through natural porcine intestinal mucus was studied through a new diffusion method developed by our group. Lyophilised particles displayed 526 MUmol/g (CS) and 513 MUmol/g (PAA) of free thiol groups and a zeta potential of 20 mV (CS) and -14 mV for PAA NP. Nanoparticle distribution on rat intestine suggested that mucoadhesion of thiolated NP is higher than the diffusion into the intestinal mucosa. Modified particles displayed more than a 6-fold increase in mucoadhesion compared to unmodified ones. The rank order with regard to mucoadhesion of all particles was: CS-TBA>PAA-Cys>CS>PAA, whereas CS-TBA showed 2 fold higher mucoadhesive properties compared to PAA-Cys NP. Diffusion through intestinal mucus was much higher for unmodified than for thiolated as well as for anionic compared to cationic particles. Overall, it was shown that thiolated particles of both anionic and cationic polymers have improved mucoadhesive properties and could be promising carriers for mucosal drug delivery. PMID- 21295124 TI - Preparation and in vitro/in vivo evaluation of revaprazan hydrochloride nanosuspension. AB - Revaprazan hydrochloride (RH) is a new reversible proton pump inhibitor. However, due to poor water solubility, oral bioavailability of the drug was relatively low. To investigate the particle size reduction effect of RH on dissolution and absorption, three suspensions that containing different sized particles were prepared by high pressure homogenization and in vitro/in vivo evaluations were carried out. DSC and powder X-ray diffraction were used to study crystalline state of freeze dried powder of RH suspensions and the results showed that particles of RH microsuspension and nanosuspension remained in the same crystalline state as coarse suspension, but had lower lattice energy. In the in vitro dissolution test, both microsuspension and nanosuspension showed increased dissolution rate. In the in vivo evaluation, compared to coarse suspension, RH nanosuspension exhibited significant increase in AUC(0-t), C(max) and decrease in T(max), MRT. Nevertheless, RH microsuspension did not display any significant differences in these pharmacokinetic parameters compared to the coarse suspension. The findings revealed that particle size reduction can influence RH absorption in gastrointestinal tract and nanosuspension can enhance oral bioavailability of RH in rats. PMID- 21295125 TI - The impact of material attributes and process parameters on the micronisation of lactose monohydrate. AB - Dry powder inhalers (DPIs), which are important medicines for drug delivery to the lungs, require drug particles in the respirable size range of 1-6 MUm for optimal lung deposition. Drugs administered by the oral route also derive benefit from particles in this size range owing to their large surface area to volume ratio, which provides potential for rapid dissolution. Micronisation used in the production of particles, however often leads to heterogeneous product containing mechanically activated surfaces with amorphous content. This study was therefore carried out to evaluate the effect of particle properties of three grades of lactose monohydrate, with sizes above and below the brittle-ductile transition (dcrit) and their interaction with process variables on the quality of micronised material. Following an experimental design, the impact of three factors (grinding pressure, injector pressure and feed rate) on the particulate attributes of micronised powders produced from the different size grades was assessed. Processing conditions were shown to be important determinants of powder properties only for the coarsest starting material. Ultrafine material was achieved by processing finer grade feed stock below dcrit. However the resultant product was more crystalline and transformed on heating to the anhydrous state with markedly reduced onset temperature with lower energy surfaces than powders produced from larger sized starting material. Thus the propensity for micronisation of lactose monohydrate can be altered through control of starting materials and optimal settings for process variables. PMID- 21295126 TI - A cocktail of metabolic probes demonstrates the relevance of primary human hepatocyte cultures in a microfluidic biochip for pharmaceutical drug screening. AB - In this paper, we compare the biotransformation capacities of cryopreserved primary human hepatocytes cultivated in a liver microfluidic biochip and in plates. The hepatocytes were exposed to the CIME cocktail (Carte d'Identite MEtabolique), a mixture of seven probes (acetaminophen, amodiaquine, caffeine, dextromethorphan, midazolam, omeprazole and tolbutamide) for key enzymes involved in the xenobiotic metabolism and pharmacokinetics. The purpose of the cocktail was to give an overview of the metabolic profile of the hepatocytes due to concomitant exposure and a simultaneous mass spectrometric detection method of the metabolites. The results showed a greater activity for CYP1A2, CYP2C9, CYP2C19 CYP2D6, CYP3A and UGT1A1 after 4 h of incubation in the microfluidic biochip when compared to the plate cultures. Furthermore, the metabolic ratio time-course measured at 1 h, 3 h and 4 h indicated that the enzymatic activity increased when the hepatocytes were cultivated in the microfluidic biochip, in contrast with their response in the plate cultures. These results illustrated the functional relevance of liver culture in the PDMS microfluidic biochip. The original method based on a microfluidic culture coupled with CIME cocktail analysis allowed the maintenance and the evaluation of the metabolic performances of the primary human hepatocytes through a new rapid assay. This metabolic analysis can thus become the reference situation when parallel studies of drug metabolism and toxicities are planned with functional hepatocytes in biochips. PMID- 21295127 TI - Roles of prostaglandin E2 in the cochlea. AB - Prostaglandins are one of the major groups of chemical mediators in the mammalian body. Among prostaglandins, prostaglandin E2 (PGE2) is the most abundant prostanoid in humans and involved in regulating many different fundamental biological functions. PGE2 signaling is mediated by four distinct E-prostanoid receptors (EPs) namely EP1-4. Recently, accumulating evidence indicates critical, but complex roles of EP signaling in the pathogenesis of neuronal diseases depending on the context of neuronal injury. Four distinct EPs are expressed in the stria vascularis, spiral ligament, spiral ganglion and organ of Corti, indicating an involvement of EP signaling in the cochlear function. Activation of EP4 in cochleae significantly attenuates noise-induced damage in cochleae, and activation of EP2 or EP4 induces the formation of vascular endothelial growth factor in cochleae. These findings strongly suggest that individual EP signaling may be involved in the maintenance of the cochlear sensory system similarly to the central nervous system. This review highlights recent findings on EP signaling in the central nervous system, and presents its possible roles in regulation of blood flow, protection of sensory cells and immune responses in cochleae. PMID- 21295128 TI - Chemical form of metals in traditional medicines underlines potential toxicity in cell cultures. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Mercury (Hg) and arsenic (As) are frequently found in traditional medicines as sulfides, such as cinnabar (HgS) and realgar (As(4)S(4)). There is a general perception that any medicinal use of such metal containing remedies is unacceptable. An opposing opinion is that different chemical forms of arsenic and mercury have different toxic potentials. AIM OF THE STUDY: To clarify this question, cinnabar, realgar, and cinnabar- and realgar containing traditional medicine An-Gong-Niu-HuangWan (AGNH), were compared to well-known mercurials (HgS, HgCl(2) and MeHg) and arsenicals (As(2)S(2), As(2)O(3), NaAsO(2), and Na(2)HAsO(4)) for their cytotoxicity in human and rodent cell lines. MATERIALS AND METHOD: Cultured cells derived from target organs such as brain (HAPI) and liver (Hep3B, HepG2 and TRL1215) were treated with chemicals for 48 h and cytotoxicity was determined by the MTS assay. RESULTS: MeHg was most toxic with LC(50) of 4-20MUM, followed by NaAsO(2) (LC(50), 25-250 MUM) and HgCl(2) (LC(50,) 50-100 MUM), Na(2)HAsO(4)(LC(50), 60-400MUM), As(2)O(3)(LC(50), 30-900 MUM), and As(2)S(2) (LC(50), 100-500 MUM). In comparison, the LC(50) of realgar ranged from 250 to1500 MUM; whereas cinnabar or HgS were approximately 20,000 MUM and the toxicity of AGNH was in the range of 1500-8000 MUM. Approximately 5000-fold differences exist between MeHg and HgS, and over 10-fold differences exist between NaAsO(2) and As(4)S(4). CONCLUSIONS: Chemical forms of metals are important factor in determining their toxicity in traditional medicines, both cinnabar and realgar are much less toxic than well-known mercurial and arsenicals. PMID- 21295129 TI - In vitro anti-inflammatory and anti-cancer activities of Cuscuta reflexa Roxb. AB - AIM OF THE STUDY: To determine anti-inflammatory and anti-cancer activities of Cuscuta reflexa in cell lines (in vitro). MATERIALS AND METHODS: Anti inflammatory activity of the water extract was analysed in vitro using lipopolysaccharide (LPS) induced inflammatory reactions in murine macrophage cell line RAW264.7. The expression of COX-2 and TNF-alpha genes involved in inflammation was analysed by SQ RT-PCR. EMSA was conducted to analyse the influence of the extract on NF-kappaB signalling. Anti-cancer activity was analysed on Hep3B cells by MTT assay, DAPI staining, annexin V staining and SQ-RT PCR analysis of BAX, Bcl-2, p53 and survivin. RESULTS: The extract down regulated LPS induced over expression of TNF-alpha and COX-2 in RAW264.7 cells; blocked NF kappaB binding to its motifs and induced apoptosis in Hep3B cells as evidenced from MTT, DAPI staining and annexin V staining assays. The extract up regulated pro-apoptotic factors BAX and p53, and down regulated anti-apoptotic factors Bcl 2 and survivin. CONCLUSIONS: The study showed that Cuscuta reflexa inhibits LPS induced inflammatory responses in RAW264.7 cells through interplay of TNF-alpha, COX-2 and NF-kappaB signalling. It induced apoptosis in Hep3B cells through the up regulation of p53, BAX and down regulation of Bcl-2 and survivin. PMID- 21295130 TI - "Plantas con madre": plants that teach and guide in the shamanic initiation process in the East-Central Peruvian Amazon. AB - AIM OF THE STUDY: We present and discuss a particular group of plants used by a diversity of healers in the initiation process and apprenticeship of traditional medicine, as practiced by Amazonian societies in East-Central Peru. Often, these plants are locally called plantas con madre (plants with a mother), and are thought to guide initiates in the process of seeking sacred knowledge, learning about plant usage, and understanding traditional medicine practices. We illustrate the diversity of plants used in the apprenticeship and practice of traditional medicine, and nurture the discussion to better understand the terminology used by Indigenous healers to describe plant uses and their practices. MATERIALS AND METHODS: The study was conducted between 2003 and 2008 with the participation of 29 curanderos (healers; 23 men, 6 women), 3 apprentices and 4 herbalists. The participants belonged to four ethnic groups: 17 Mestizos, 15 Shipibo-Konibo, 1 Ashaninka, and 1 Matsiguenga; a Spanish apprentice and an Italian herbalist were also included in the study. The field data were collected using semi-structured interviews, participant observation, and the witnessing of numerous healing sessions. Oral informed consent was obtained from each participant. RESULTS: We identified 55 plant species belonging to 26 botanical families, which are used in initiation processes and apprenticeships of traditional medicine. This group of plants is administered under strict conditions during training and healing sessions called dietas (shamanic diets), with the supervision of one or more maestros curanderos (master healers). We observed that during the shamanic diets, maestros curanderos administered plants depending on the teachings or tools he/she was passing on, and were based on a particular sequence during the initiation process: (I) purification and cleansing species; (II) sensitivity and intuition; (III) strengthening; and (IV) protection and defence. CONCLUSIONS: Traditional healers continue to be a primary source of health care for the majority of the population in the Amazon region. Our research suggests that the system of dietas and the plantas con madre are fundamental components of the everyday practice of traditional medicine, maintenance of cultural continuity and Indigenous cosmovisions in the Amazonian societies in East-Central Peru. This paper contributes to filling the gap in the understanding of the process of initiation among healers in this area of the world. The study offers evidence of the need to collaborate with Indigenous healers to improve the recognition of their medical practices, role in their societies, and the value of their tools and medicines. A respectful attitude and open exchange of ideas and information may contribute to a better understanding of the language used by traditional medical practitioners, their practice, and their worldviews. PMID- 21295131 TI - Computational dissection of Arabidopsis smRNAome leads to discovery of novel microRNAs and short interfering RNAs associated with transcription start sites. AB - The profiling of small RNAs by high-throughput sequencing (smRNA-Seq) has revealed the complexity of the RNA world. Here, we describe a computational scheme for dissecting the plant smRNAome by integrating smRNA-Seq datasets in Arabidopsis thaliana. Our analytical approach first defines ab initio the genomic loci that produce smRNAs as basic units, then utilizes principal component analysis (PCA) to predict novel miRNAs. Secondary structure prediction of candidates' putative precursors discovered a group of long hairpin double stranded RNAs (lh-dsRNAs) formed by inverted duplications of decayed coding genes. These gene remnants produce miRNA-like small RNAs which are predominantly 21- and 22-nt long, dependent of DCL1 but independent of RDR2 and DCL2/3/4, and associated with AGO1. Additionally, we found two classes of transcription start site associated (TSSa) RNAs located at sense (+) and antisense (-) approximately 100-200 bp downstream of TSSs, but are differentially incorporated into AGO1 and AGO4, respectively. PMID- 21295132 TI - Imatinib has deleterious effects on differentiating spermatogonia while sparing spermatogonial stem cell self renewal. AB - Imatinib mesylate is among a growing number of effective cancer drugs that provide molecularly targeted therapy; however, imatinib causes reproductive defects in rodents. The availability of an in vitro system for screening the effect of drugs on spermatogenesis would be beneficial. The imatinib targets, KIT and platelet derived growth factor receptor beta (PDGFRB), were shown here to be expressed in "germline stem" (GS) cell cultures that contain spermatogonia, including spermatogonial stem cells (SSCs). GS cell cultures were utilized to determine whether imatinib affects SSC self renewal or differentiation. GS cells grown in imatinib retained self renewal based on multiple assays, including transplantation. However, growth in imatinib led to decreased numbers of differentiated spermatogonia and reduced culture growth consistent with the known requirement for KIT in survival and proliferation of spermatogonia. These results build upon the in vivo studies and support the possibility of utilizing GS cell cultures for preclinical drug tests. PMID- 21295133 TI - MicroRNAs in Parkinson's disease. AB - MicroRNAs are small non-protein coding RNAs that regulate gene expression through post-transcriptional repression. Recent studies demonstrated the importance of microRNAs in the nervous system development, function and disease. Parkinson's disease is the second most prevalent neurodegenerative disease with only symptomatic treatment available. Recent success in using small RNAs as therapeutic targets hold a substantial promise for the Parkinson's disease field. Here we review recent work linking the microRNA pathway to Parkinson's disease. PMID- 21295134 TI - Differential effects of NADPH oxidase and xanthine oxidase inhibition on sympathetic reinnervation in postinfarct rat hearts. AB - Superoxide has been shown to play a major role in ventricular remodeling and arrhythmias after myocardial infarction. However, the source of increased myocardial superoxide production and the role of superoxide in sympathetic innervation remain to be further characterized. Male Wistar rats, after coronary artery ligation, were randomized to vehicle, allopurinol, or apocynin for 4weeks. To determine the role of peroxynitrite in sympathetic reinnervation, we also used 3-morpholinosydnonimine (a peroxynitrite generator). The postinfarction period was associated with increased oxidative stress, as measured by myocardial superoxide, nitrotyrosine, xanthine oxidase activity, NADPH oxidase activity, and dihydroethidium fluorescent staining. Measurement of myocardial norepinephrine levels revealed a significant elevation in vehicle-treated infarcted rats compared with sham. Sympathetic hyperinnervation was blunted after administration of allopurinol. Arrhythmic scores in the allopurinol-treated infarcted rats were significantly lower than those in vehicle. For similar levels of ventricular remodeling, apocynin had no beneficial effects on oxidative stress, sympathetic hyperinnervation, or arrhythmia vulnerability. Allopurinol-treated hearts had significantly decreased nerve growth factor expression, which was substantially increased after coadministration of 3-morpholinosydnonimine. These results indicate that xanthine oxidase but not NADPH oxidase largely mediates superoxide production after myocardial infarction. Xanthine oxidase inhibition ameliorates sympathetic innervation and arrhythmias possibly via inhibition of the peroxynitrite-mediated nerve growth factor pathway. PMID- 21295135 TI - Impaired CD200-CD200R-mediated microglia silencing enhances midbrain dopaminergic neurodegeneration: roles of aging, superoxide, NADPH oxidase, and p38 MAPK. AB - CD200-CD200R signaling holds microglia in a quiescent state. Parkinson disease (PD) neurodegeneration may be associated with impairment of CD200-CD200R-mediated microglia silencing in the substantia nigra (SN). In this study, an anti-CD200R blocking antibody (ACDR) selectively and significantly enhanced the susceptibility of dopaminergic neurons to neurotoxicity induced by rotenone (Rot) and iron (Ir) in mesencephalic neuron/glia cultures. Microglia were shown to mediate dopaminergic neurotoxicity induced by ACDR/Rot (combination of ACDR and Rot) and ACDR/Ir (combination of ACDR and Ir). ACDR significantly enhanced the microglial activation induced by Rot and Ir in neuron/glia cultures. NADPH oxidase-mediated superoxide generation was a key contributor to dopaminergic neurotoxicity induced by ACDR/Rot and ACDR/Ir. p38 MAPK contributed to NADPH oxidase activation induced by ACDR/Rot and ACDR/Ir. Interestingly, there were a decrease in CD200 expression (mRNA and protein) and an enhancement of microglial response (MHCII mRNA and ICAM-1 protein) in the rat SN with aging. ICAM-1 expression was significantly inversely correlated with CD200 expression. These results strongly indicate the participation of SN CD200-CD200R dysfunction in the etiopathogenesis of PD and provide a new insight into the molecular mechanisms underlying the involvement of aging in PD and help to elucidate the mechanisms of the combined involvement of immune/inflammatory factors, environmental substances, and aging in PD. PMID- 21295136 TI - Molecular cross-talk between the NRF2/KEAP1 signaling pathway, autophagy, and apoptosis. AB - Oxidative stress, perturbations in the cellular thiol level and redox balance, affects many cellular functions, including signaling pathways. This, in turn, may cause the induction of autophagy or apoptosis. The NRF2/KEAP1 signaling pathway is the main pathway responsible for cell defense against oxidative stress and maintaining the cellular redox balance at physiological levels. The relation between NRF2/KEAP1 signaling and regulation of apoptosis and autophagy is not well understood. In this hypothesis article we discuss how KEAP1 protein and its direct interactants (such as PGAM5, prothymosin alpha, FAC1 (BPTF), and p62) provide a molecular foundation for a possible cross-talk between NRF2/KEAP1, apoptosis, and autophagy pathways. We present a hypothesis for how NRF2/KEAP1 may interfere with the cellular apoptosis-regulatory machinery through activation of the ASK1 kinase by a KEAP1 binding partner-PGAM5. Based on very recent experimental evidence, new hypotheses for a cross-talk between NF-kappaB and the NRF2/KEAP1 pathway in the context of autophagy-related "molecular hub" protein p62 are also presented. The roles of KEAP1 molecular binding partners in apoptosis regulation during carcinogenesis and in neurodegenerative diseases are also discussed. PMID- 21295137 TI - In situ kinetic trapping reveals a fingerprint of reversible protein thiol oxidation in the mitochondrial matrix. AB - Reactive oxygen species (ROS) are released at the mitochondrial inner membrane by the electron transport chain (ETC). Increasing evidence suggests that mitochondrial H2O2 acts as a signaling molecule and participates in the (feedback) regulation of mitochondrial activity and turnover. It seems likely that key mitochondrial components contain redox-sensitive thiols that help to adapt protein function to changes in electron flow. However, the identity of most redox-regulated mitochondrial proteins remains to be defined. Thioredoxin 2 (Trx2) is the major protein-thiol-reducing oxidoreductase in the mitochondrial matrix. We used in situ mechanism-based kinetic trapping to identify disulfide exchange interactions of Trx2 within functional mitochondria of intact cells. Mass spectrometry successfully identified known and suspected Trx2 target proteins and, in addition, revealed a set of new candidate target proteins. Our results suggest that the mitochondrial protein biosynthesis machinery is a major target of ETC-derived ROS. In particular, we identified mitochondrial methionyl tRNA synthetase (mtMetRS) as one of the most prominent Trx2 target proteins. We show that an increase in ETC-derived oxidants leads to an increase in mtMetRS oxidation in intact cells. In conclusion, we find that in situ kinetic trapping provides starting points for future functional studies of intramitochondrial redox regulation. PMID- 21295138 TI - Nuclear receptor PXR, transcriptional circuits and metabolic relevance. AB - The pregnane X receptor (PXR, NR1I2) is a ligand activated transcription factor that belongs to the nuclear hormone receptor (NR) superfamily. PXR is highly expressed in the liver and intestine, but low levels of expression have also been found in many other tissues. PXR plays an integral role in xenobiotic and endobiotic metabolism by regulating the expression of drug-metabolizing enzymes and transporters, as well as genes implicated in the metabolism of endobiotics. PXR exerts its transcriptional regulation by binding to its DNA response elements as a heterodimer with the retinoid X receptor (RXR) and recruitment of a host of coactivators. The biological and physiological implications of PXR activation are broad, ranging from drug metabolism and drug-drug interactions to the homeostasis of numerous endobiotics, such as glucose, lipids, steroids, bile acids, bilirubin, retinoic acid, and bone minerals. The purpose of this article is to provide an overview on the transcriptional circuits and metabolic relevance controlled by PXR. This article is part of a Special Issue entitled: Translating Nuclear Receptors from Health to Disease. PMID- 21295139 TI - The interplay between SUCLA2, SUCLG2, and mitochondrial DNA depletion. AB - SUCLA2-related mitochondrial DNA (mtDNA) depletion syndrome is a result of mutations in the beta subunit of the ADP-dependent isoform of the Krebs cycle succinyl-CoA synthase (SCS). The mechanism of tissue specificity and mtDNA depletion is elusive but complementation by the GDP-dependent isoform encoded by SUCLG2, and the association with mitochondrial nucleoside diphosphate kinase (NDPK), is a plausible link. We have investigated this relationship by studying SUCLA2 deficient fibroblasts derived from patients and detected normal mtDNA content and normal NDPK activity. However, knockdown of SUCLG2 by shRNA in both patient and control fibroblasts resulted in a significant decrease in mtDNA amount, decreased NDPK and cytochrome c oxidase activities, and a marked growth impairment. This suggests that, SUCLG2, to a higher degree than SUCLA2, is crucial for mtDNA maintenance and that mitochondrial NDPK is involved. Although results pertain to a cell culture system, the findings might explain the pathomechanism and tissue specificity in mtDNA depletion caused by defective SUCLA2. PMID- 21295141 TI - An oral oligonucleotide delivery system based on a thiolated polymer: Development and in vitro evaluation. AB - The purpose of this study was to develop and evaluate an oral oligonucleotide delivery system based on a thiolated polymer/reduced glutathione (GSH) system providing a protective effect toward nucleases and permeation enhancement. A polycarbophil-cysteine conjugate (PCP-Cys) was synthesized. Enzymatic degradation of a model oligonucleotide by DNase I and within freshly collected intestinal fluid was investigated in the absence and presence of PCP-Cys. Permeation studies with PCP-Cys/GSH versus control were performed in vitro on Caco-2 cell monolayers and ex vivo on rat intestinal mucosa. PCP-Cys displayed 223 +/- 13.8 MUmol thiol groups per gram polymer. After 4h, 61% of the free oligonucleotides were degraded by DNase I and 80% within intestinal fluid. In contrast, less than 41% (DNase I) and 60% (intestinal fluid) were degraded in the presence of 0.02% (m/v) PCP-Cys. Permeation studies revealed an 8-fold (Caco-2) and 10-fold (intestinal mucosa) increase in apparent permeability compared to buffer control. Hence, this PCP Cys/GSH system might be a promising tool for the oral administration of oligonucleotides as it allows a significant protection toward degrading enzymes and facilitates their transport across intestinal membranes. PMID- 21295140 TI - Analysis of the mitochondrial proteome in multiple sclerosis cortex. AB - Mitochondrial dysfunction has been proposed to play a role in the neuropathology of multiple sclerosis (MS). Previously, we reported significant alterations in the transcription of nuclear-encoded electron transport chain genes in MS and confirmed translational alterations for components of Complexes I and III that resulted in reductions in their activity. To more thoroughly and efficiently elucidate potential alterations in the expression of mitochondrial and related proteins, we have characterized the mitochondrial proteome in postmortem MS and control cortex using Surface-Enhanced Laser Desorption Ionization Time of Flight Mass Spectrometry (SELDI-TOF-MS). Using principal component analysis (PCA) and hierarchical clustering techniques we were able to analyze the differential patterns of SELDI-TOF spectra to reveal clusters of peaks which distinguished MS from control samples. Four proteins in particular were responsible for distinguishing disease from control. Peptide fingerprint mapping unambiguously identified these differentially expressed proteins. Three proteins identified are involved in respiration including cytochrome c oxidase subunit 5b (COX5b), the brain specific isozyme of creatine kinase, and hemoglobin beta-chain. The fourth protein identified was myelin basic protein (MBP). We then investigated whether these alterations were consistent in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. We found that MBP was similarly altered in EAE but the respiratory proteins were not. These data indicate that while the EAE mouse model may mimic aspects of MS neuropathology which result from inflammatory demyelinating events, there is another distinct mechanism involved in mitochondrial dysfunction in gray matter in MS which is not modeled in EAE. PMID- 21295142 TI - Preparation and characterization of triclosan nanoparticles intended to be used for the treatment of acne. AB - This work focuses on the preparation and characterization of nanoparticles containing triclosan. Additionally, in vitro percutaneous permeation of triclosan through pig ear skin was performed, and comparisons were made with two commercial formulations: An o/w emulsion and a solution, intended for the treatment of acne. The nanoparticle suspensions were prepared by the emulsification-diffusion by solvent displacement method, using Eudragit(r) E 100 as polymer. All batches showed a size smaller than 300 nm and a positive Zeta potential, high enough (20 40 mV) to ensure a good physical stability. Differential scanning calorimetry (DSC), transmission electron microscopy (TEM), and scanning electron microscopy (SEM) studies suggested that triclosan was molecularly dispersed in the nanoparticle batches containing up to 31% of triclosan, with good encapsulation efficiency (95.9%). The results of the in vitro permeation studies showed the following order for the permeability coefficients: Solution>cream~nanoparticles; while for the amount retained in the skin, the order was as follows: cream>nanoparticles~solution. Nanoparticles, being free of surfactants or other potentially irritant agents, can be a good option for the delivery of triclosan to the skin, representing a good alternative for the treatment of acne. PMID- 21295143 TI - The circadian clock genes affect reproductive capacity in the desert locust Schistocerca gregaria. AB - The circadian clocks govern many metabolic and behavioral processes in an organism. In insects, these clocks and their molecular machinery have been found to influence reproduction in many different ways. Reproductive behavior including courtship, copulation and egg deposition, is under strong influence of the daily rhythm. At the molecular level, the individual clock components also have their role in normal progress of oogenesis and spermatogenesis. In this study on the desert locust Schistocerca gregaria, three circadian clock genes were identified and their expression profiles were determined. High expression was predominantly found in reproductive tissues. Similar daily expression profiles were found for period (per) and timeless (tim), while the clock (clk) mRNA level is higher 12h before the first per and tim peak. A knockdown of either per or tim resulted in a significant decrease in the progeny produced by dsRNA treated females confirming the role of clock genes in reproduction and providing evidence that both PER and TIM are needed in the ovaries for egg development. Since the knockdown of clk is lethal for the desert locust, its function remains yet to be elucidated. PMID- 21295144 TI - Rainbow trout surviving infections of viral haemorrhagic septicemia virus (VHSV) show lasting antibodies to recombinant G protein fragments. AB - Rainbow trout antibodies (Abs) binding to recombinant fragments (frgs) derived from the protein G of the viral haemorrhagic septicemia virus (VHSV)-07.71 strain, could be detected by ELISA (frg-ELISA) in sera from trout surviving laboratory-controlled infections. Abs were detected not only by using sera from trout infected with the homologous VHSV isolate but also with the VHSV-DK-201433 heterologous isolate, which had 13 amino acid changes. Sera from healthy trout and/or from trout surviving infectious haematopoietic necrosis virus (IHNV) infection, were used to calculate cut-off absorbances to differentiate negative from positive sera. Specific anti-VHSV Abs could then be detected by using any of the following frgs: frg11 (56-110), frg15 (65-250), frg16 (252-450) or G21-465. While high correlations were found among the ELISA values obtained with the different frgs, no correlations between any frg-ELISA and complement-dependent 50% plaque neutralization test (PNT) titres could be demonstrated. Between 4 and 10 weeks after VHSV infection, more trout sera were detected as positives by using heterologous frg-ELISA rather than homologous PNT. Furthermore, the percentage of positive sera detected by frg11-ELISA increased with time after infection to reach 100%, while those detected by complement-dependent PNT decreased to 29.4%, thus confirming that the lack of neutralizing Abs does not mean the lack of any anti-VHSV Abs in survivor trout sera. Preliminary results with sera from field samples suggest that further refinements of the frg-ELISA could allow detection of anti-VHSV trout Abs in natural outbreaks caused by different heterologous VHSV isolates. The homologous frg-ELISA method could be useful to follow G immunization attempts during vaccine development and/or to best understand the fish Ab response during VHSV infections. The viral frgs approach might also be used with other fish species and/or viruses. PMID- 21295145 TI - Mental number line training in children with developmental dyscalculia. AB - Developmental dyscalculia (DD) is a specific learning disability that affects the acquisition of mathematical skills in children with normal intelligence and age appropriate school education (prevalence 3-6%). One essential step in the development of mathematical understanding is the formation and automated access to a spatial representation of numbers. Many children with DD show a deficient development of such a mental number line. The present study aimed to develop a computer-based training program to improve the construction and access to the mental number line. Sixteen children with DD aged 8-10 years and 16 matched control children completed the 5-week computer training. All children played the game 15 min a day for 5 days a week. The efficiency of the training was evaluated by means of neuropsychological tests and functional magnetic resonance imaging (fMRI) during a number line task. In general, children with and without DD showed a benefit from the training indicated by (a) improved spatial representation of numbers and (b) the number of correctly solved arithmetical problems. Regarding group differences in brain activation, children with DD showed less activation in bilateral parietal regions, which reflects neuronal dysfunction in pivotal regions for number processing. Both groups showed reduced recruitment of relevant brain regions for number processing after the training which can be attributed to automatization of cognitive processes necessary for mathematical reasoning. Moreover, results point to a partial remediation of deficient brain activation in dyscalculics after consolidation of acquired and refined number representation. To conclude, the present study represents the first attempt to evaluate a custom designed training program in a group of dyscalculic children and results indicate that the training leads to an improved spatial representation of the mental number line and a modulation of neural activation, which both facilitate processing of numerical tasks. PMID- 21295146 TI - Expression of VGLUTs contributes to degeneration and acquisition of learning and memory. AB - Vesicular glutamate transporters (VGLUTs), which include VGLUT1, VGLUT2 and VGLUT3, are responsible for the uploading of L-glutamate into synaptic vesicles. The expression pattern of VGLUTs determines the level of synaptic vesicle filling (i.e., glutamate quantal size) and directly influences glutamate receptors and glutamatergic synaptic transmission; thus, VGLUTs may play a key role in learning and memory in the central nervous system. To determine whether VGLUTs contribute to the degeneration or acquisition of learning and memory, we used an animal model for the age-related impairment of learning and memory, senescence accelerated mouse/prone 8 (SAMP8). KM mice were divided into groups based on their learning and memory performance in a shuttle-box test. The expression of VGLUTs and synaptophysin (Syp) mRNA and protein in the cerebral cortex and hippocampus were investigated with real-time fluorescence quantitative PCR and western blot, respectively. Our results demonstrate that, in the cerebral cortex, protein expression of VGLUT1, VGLUT2, VGLUT3 and Syp was decreased in SAMP8 with age and increased in KM mice, which displayed an enhanced capacity for learning and memory. The protein expression of VGLUT2 and Syp was decreased in the hippocampus of SAMP8 with aging. The expression level of VGLUT1 and VGLUT2 proteins were highest in KM mouse group with a 76-100% avoidance score in the shuttle-box test. These data demonstrate that protein expression of VGLUT1, VGLUT2 and Syp decreases age-dependently in SAMP8 and increases in a learning- and memory-dependent manner in KM mice. Correlation analysis indicated the protein expression of VGLUT1, VGLUT2 and Syp has a positive correlation with the capacity of learning and memory. PMID- 21295147 TI - Total sleep deprivation impairs the encoding of trace-conditioned memory in the rat. AB - Sleep may help consolidate the information of certain memories, though its benefits in the consolidation of trace-conditioned memory still remain elusive. We investigated the effect of sleep deprivation on trace learning in male wistar rats. Rats were trained for trace conditioning and the number of head entries into liquid dispenser was accounted as an outcome measure of trace-learning. For training and testing, 75 presentations of conditioned stimulus (CS) (light) and unconditioned stimulus (US) (juice) were offered in five sessions (15 presentations/session; with 5 min inter-session gap). The duration of CS and US stimuli were 15 and 20s respectively, with 5s trace delay between stimuli and 20s condition delay between each presentation. The animals were divided randomly into three groups soon after training, sleep deprived (SD) (n=8), non-SD (NSD) (n=8) and stress control (n=5) groups. The animals of NSD and control groups were left undisturbed, while SD animals were sleep deprived for 6h after training. The learning of trace-conditioned task was examined on following days. We observed that SD rats poked approximately 63% less than NSD and control groups (p<0.001) to obtain juice on testing day. Also, the NSD rats exhibited significant positive correlation in number of head entries during the training and testing days; while the SD rats showed no significant correlation. The results demonstrate that SD animals had difficulties to associate CS with US and suggest that sleep deprivation soon after training impairs the encoding of trace memory. PMID- 21295148 TI - Acute psycho-social stress does not disrupt item-method directed forgetting, emotional stimulus content does. AB - It has been shown that stress affects episodic memory in general, but knowledge about stress effects on memory control processes such as directed forgetting is sparse. Whereas in previous studies item-method directed forgetting was found to be altered in post-traumatic stress disorder patients and abolished for highly arousing negative pictorial stimuli in students, no study so far has investigated the effects of experimentally induced psycho-social stress on this task or examined the role of positive picture stimuli. In the present study, 41 participants performed an item-method directed forgetting experiment while being exposed either to a psychosocial laboratory stressor, the Trier Social Stress Test (TSST), or a cognitively challenging but non-stressful control condition. Neutral and positive pictures were presented as stimuli. As predicted, salivary cortisol level as a biological marker of the human stress response increased only in the TSST group. Still, both groups showed directed forgetting. However, emotional content of the employed stimuli affected memory control: Directed forgetting was intact for neutral pictures whereas it was attenuated for positive ones. This attenuation was primarily due to selective rehearsal improving discrimination accuracy for neutral, but not positive, to-be-remembered items. Results suggest that acute experimentally induced stress does not alter item method directed forgetting while emotional stimulus content does. PMID- 21295150 TI - Carrefour Mme. Gras: a wild-isolated Neurospora crassa strain that suppresses meiotic silencing by unpaired DNA and uncovers a novel ascospore stability defect. AB - Ordinarily, RIP-induced erg-3 mutant Neurospora crassa ascospores and their erg(+) siblings do not differ in stability during long-term storage. Consequently, the frequency of RIP-induced erg-3 mutants remains about constant regardless of the time that has elapsed between ascospore harvest and germination. We found, however, that RIP-induced erg-3 mutants were apparently selectively lost with time from among the ascospores stored from a cross with the wild-isolated Carrefour Mme. Gras strain from Haiti. The Haitian strain was also found to exert a dominant suppression of meiotic silencing by unpaired DNA. Similar loss of RIP-induced erg-3 mutant ascospores was seen among the stored ascospores from a subset of crosses heterozygous for the semi-dominant Sad-1 or Sad-2 suppressors of meiotic silencing. Our results suggest that crosses suppressed in meiotic silencing can compromise the stability during storage of ascospores that inherit RIP-induced mutations. PMID- 21295149 TI - Behavioral analysis of NR2C knockout mouse reveals deficit in acquisition of conditioned fear and working memory. AB - N-methyl-D-aspartate (NMDA) receptors play an important role in excitatory neurotransmission and mediate synaptic plasticity associated with learning and memory. NMDA receptors are composed of two NR1 and two NR2 subunits and the identity of the NR2 subunit confers unique electrophysiologic and pharmacologic properties to the receptor. The precise role of NR2C-containing receptors in vivo is poorly understood. We have performed a battery of behavioral tests on NR2C knockout/nbeta-galactosidase knock-in mice and found no difference in spontaneous activity, basal anxiety, forced-swim immobility, novel object recognition, pain sensitivity and reference memory in comparison to wildtype counterparts. However, NR2C knockout mice were found to exhibit deficits in fear acquisition and working memory compared to wildtype mice. Deficit in fear acquisition correlated with lack of fear conditioning-induced plasticity at the thalamo-amygdala synapse. These findings suggest a unique role of NR2C-containing receptors in associative and executive learning representing a novel therapeutic target for deficits in cognition. PMID- 21295151 TI - Effects of linoleate on cell viability and lipid metabolic homeostasis in goose primary hepatocytes. AB - Studies have shown linoleate could not only promote cell viability but also affect lipid metabolism in mammals. However, to what degree these effects are mediated by steatosis in goose primary hepatocytes is unknown. In this study, the effect of linoleate on the lipid metabolic homeostasis pathway was determined. We measured the mRNA levels of genes involved in triglyceride synthesis, lipid deposition, beta-oxidation, and assembly and secretion of VLDL-TGs in goose (Anser cygnoides) primary hepatocytes. Linoleate significantly increased goose hepatocyte viability, and linoleate at 0.125 mM, 0.25 mM, 0.5 mM and 1.0 mM all showed a significant effect on TG accumulation. However, with increasing linoleate concentrations, the extracellular TG concentration and extracellular VLDL gradually decreased. DGAT1, DGAT2, PPARalpha, PPARgamma, FoxO1, MTP, PLIN and CPT-1 mRNA was detected by real-time PCR. With increasing linoleate concentrations, the changes in DGAT1, DGAT2, PPARalpha and CPT-1 gene expression, which regulates hepatic TG synthesis and fatty acid oxidation, first increased and then decreased. Additionally, FoxO1 and MTP gene expression was reduced with increasing linoleate concentrations, and the change in PLIN gene expression was increased at all concentrations, similar to the regulation of intracellular TG accumulation. In conclusion, linoleate regulated TG accumulation and increased hepatocyte viability. The data suggest that linoleate does promote goose hepatocyte viability and steatosis, which may up-regulate TG synthesis-relevant gene expression, suppress assembly and secretion of VLDL-TGs, and increase fatty acid oxidation properly to function of goose primary hepatocytes. PMID- 21295152 TI - The effects of radiation on sperm swimming behavior depend on plasma oxidative status in the barn swallow (Hirundo rustica). AB - Sperm are highly susceptible to reactive oxygen species (ROS) that can damage sperm DNA and structure, resulting in reduced fertilizing capacity. Exposure to radioactive contamination can also impair sperm swimming behavior and fertilizing ability, both through a reduction of sperm DNA integrity and via an increased generation of reactive oxygen species (ROS). However, the relationship between individual oxidative status and sperm swimming behavior has never been investigated in any wild population of animals exposed to radioactive contamination. We studied the motility of sperm collected from barn swallows, Hirundo rustica, breeding under different levels of radioactive contamination following the Chernobyl accident in 1986, in relation to individual oxidative status. We tested the hypothesis that the degree of impairment of sperm swimming behavior by radioactive contamination depended on plasma antioxidant capacity, the level of reactive oxygen metabolites (ROMs) and oxidative stress (sensu Costantini et al. 2006), a better oxidative status being associated with higher sperm motility. Sperm behavior parameters were subjected to principal component (PC) analysis, which extracted four PCs explaining 86% of the variance in sperm motility. PC2, representing sperm with high track velocity and ample lateral head displacement, was significantly predicted by the interaction between radiation level and either oxidative damage or oxidative stress. Contrary to our predictions, the highest values of PC2 were associated with relatively high radiation levels, particularly for high levels of either ROMs or oxidative stress. In addition, there was a tendency for values of PC3 (representing the percent of motile sperm) and PC4 (representing slow sperm with high beat cross frequency) to depend on the interaction between radiation level and total plasma antioxidant protection. Our results confirm the importance of oxidative status in determining the genetic and physiological outcome of exposure to radioactive contamination, complementing previous studies relating sperm abnormality to circulating levels of specific antioxidants. Our results also complement previous evidence that oxidative damage of sperm was negatively related to sperm motility, thus indicating a possible trade-off in quenching pro-oxidant compounds in the plasma and the seminal fluid. PMID- 21295154 TI - Oridonin: An active diterpenoid targeting cell cycle arrest, apoptotic and autophagic pathways for cancer therapeutics. AB - It is well-known that cell cycle arrest and/or death play a pivotal role in tumor progression, which has drawn a rising attention for cancer biologists due to their complex and intricate relationships. In this review, we demonstrate the recent research on oridonin, an active diterpenoid with remarkable anti proliferative activities, and then further explore its molecular mechanisms of cell cycle arrest, apoptosis, autophagy and their cross-talks in various cancer cells, which may provide a new perspective of oridonin as a candidate anti neoplastic drug for future cancer therapeutics. PMID- 21295153 TI - Immunity to seasonal and pandemic influenza A viruses. AB - The introduction of a new influenza strain into human circulation leads to rapid global spread. This review summarizes innate and adaptive immunity to influenza viruses, with an emphasis on T-cell responses that provide cross-protection between distinct subtypes and strains. We discuss antigenic variation within T cell immunogenic peptides and our understanding of pre-existing immunity towards the pandemic A(H1N1) 2009 strain. PMID- 21295155 TI - Mononuclear leukocyte DNA damage and oxidative stress: the association with smoking of hand-rolled and filter-cigarettes. AB - Cigarette smoking is a major cause of human cancer at various sites, although its carcinogenic mechanisms still remain unestablished. Based on the use of a filter, cigarette smoke can be divided into a gas phase and a tar phase. Both contain different concentrations of oxidants, free radicals and tobacco-specific carcinogens. To explore the effects of both filtered and non-filtered cigarette smoke on DNA damage and oxidative status, we measured the level of mononuclear leukocyte DNA damage by use of the single-cell gel electrophoresis (Comet) assay. We also determined malondialdehyde (MDA), protein carbonyl content (PC) and total antioxidative capacity (TAC) levels in blood plasma of smokers of manufactured filter-cigarettes and of hand-rolled cigarettes. Cotinine levels were also measured in plasma to estimate the degree of smoking. Mononuclear leukocyte DNA damage, plasma MDA, plasma PC and plasma cotinine levels were found significantly higher, while plasma TAC levels were found significantly lower in smokers of filter-cigarettes and smokers of hand-rolled cigarettes, compared with control subjects. TAC levels in hand-rolled and manufactured filter-cigarette smokers were not significantly different from each other. However, the levels of DNA damage, plasma MDA, plasma cotinine, and plasma protein oxidation were significantly higher in hand-rolled cigarette smokers than in filter-cigarette smokers. There was a significant positive correlation between MDA and DNA damage in both hand-rolled cigarette smokers and manufactured filter-cigarette smokers. This study indicates that smoking of hand-rolled cigarettes has stronger genotoxic and oxidative effects on the metabolism than smoking of manufactured filter-cigarettes. We propose that these harmful effects could be attributed to the higher level of oxidants. PMID- 21295156 TI - Is the tissue persistence of O(6)-methyl-2'-deoxyguanosine an indicator of tumour formation in the gastrointestinal tract? AB - Azoxymethane (AOM) is a methylating agent capable of inducing mutations in DNA by forming adducts with DNA bases. It has been used to understand the mechanisms involved in colon carcinogenesis. Of the adducts formed in response to AOM, O(6) methyl-2'-deoxy-guanosine (O(6)-mdGua) is the most mutagenic. Based on studies in rodents of the abundance and persistence of DNA adducts in various tissues after treatment with alkylating agents, previous results suggest, as a generalization, that the longer O(6)-mdGua adducts remain unrepaired in the cells of a tissue, the greater the risk for tumorigenesis. To test this hypothesis, we have built on these studies, expanding the number of tissues in which O(6)-mdGua abundance and persistence were examined and correlating these data with tumour distribution and abundance in rats maintained for 26 weeks after the treatment with AOM. Our study revealed firstly the existence of groups of tissues that developed relatively large amounts (proximal and distal colon, proximal small intestine (SI), liver and kidney) and relatively low levels (stomach, distal SI, bladder, spleen, blood and lung) of O(6)-mdGua after AOM exposure. Secondly, while all tissues showed an increase in adduct levels at 6h after mutagen treatment and most showed a significant drop in adduct levels between 6h and 48h (stomach, proximal and distal SI, liver, spleen, blood and lung), one group of tissues displayed O(6) mdGua levels that did not decrease at 48h (proximal and distal colon, kidney and bladder). Predictably, the colon displayed tumours 26 weeks after treatment. Interestingly, however, the proximal SI also displayed significant tumour formation at that time. Our findings demonstrate (1) a direct association between exposure to O(6)-mdGua and tumours of the distal colon and (2) a dissociation of the relationship between adduct clearance and tumorigenesis in the SI. This diversity of response in the gastrointestinal tract warrants further analysis. PMID- 21295157 TI - Hysteresis in thioredoxin-glutathione reductase (TGR) from the adult stage of the liver fluke Fasciola hepatica. AB - Thioredoxin-glutathione reductase (TGR) was purified from the adult stage of the liver fluke Fasciola hepatica. At 38 degrees C and pH 7.8, specific activity values were 10.2U mg(-1) and 64.5U mg(-1), with DTNB or GSSG as substrates, respectively. Under the same conditions, apparent Km values were 46+/-8 MUM (DTNB) and 30 +/- 5 MUM (GSSG). The enzyme was also able to catalyze thiol/disulfide exchange reactions. A subunit Mr of 61,000 was obtained. Like the homologous enzyme from the tapeworms, a lag time was observed in the enzyme assays at moderate or high concentrations of the substrate GSSG. The hysteretic behavior was reverted in the presence of GSH and was notably dependent on pH, such that the magnitude of the lag time increased with the acidity of the medium. These results strongly suggest that a hysteretic kinetic is a common feature of TGR from any parasitic flatworm. A sequence comparison revealed the structural cysteine residues proposed to be in the origin of the peculiar kinetic behavior of TGR are absent from the F. hepatica enzyme. Based on these observations, the model proposed recently to explain the GSSG-dependent hysteretic kinetic of TGR, which assumes the covalent modification of specific cysteine residues through glutathionylation [Bonilla M. et al. (2008) J Biol Chem 283: 17898] needs to be reevaluated. PMID- 21295158 TI - Content overlap in nurse and physician handoff artifacts and the potential role of electronic health records: a systematic review. AB - PURPOSE: The aims of this systematic review were: (1) to analyze the content overlap between nurse and physician hospital-based handoff documentation for the purpose of developing a list of interdisciplinary handoff information for use in the future development of shared and tailored computer-based handoff tools, and (2) to evaluate the utility of the Continuity of Care Document (CCD) standard as a framework for organizing hospital-based handoff information for use in electronic health records (EHRs). METHODS: We searched PubMed for studies published through July 2010 containing the indexed terms: handoff(s), hand-off, handover(s), shift-report, shift report, signout, and sign-out. Original, hospital-based studies of acute care nursing or physician handoff were included. Handoff information content was organized into lists of nursing, physician, and interdisciplinary handoff information elements. These information element lists were organized using CCD sections, with additional sections being added as needed. RESULTS: Analysis of 36 studies resulted in a total of 95 handoff information elements. Forty-six percent (44/95) of the information overlapped between the nurse and physician handoff lists. Thirty-six percent (34/95) were specific to the nursing list and 18% (17/95) were specific to the physician list. The CCD standard was useful for categorizing 80% of the terms in the lists and 12 category names were developed for the remaining 20%. CONCLUSION: Standardized interdisciplinary, nursing-specific, and physician-specific handoff information elements that are organized around the CCD standard and incorporated into EHRs in a structured narrative format may increase the consistency of data shared across all handoffs, facilitate the establishment of common ground, and increase interdisciplinary communication. PMID- 21295159 TI - Risk of sudden death among young individuals with J waves and early repolarization: putting the evidence into perspective. AB - The presence of J waves and ST-segment elevation on the electrocardiogram (ECG), jointly termed "the early repolarization pattern," has traditionally been considered a marker of "good health." However, recent case control series and long-term population studies have established a statistically significant association between this ECG pattern and an increased risk for arrhythmic death. This finding has raised concern among physicians, who now are asked to estimate the "arrhythmic risk" following the incidental discovery of J waves on routine ECG. Therefore, we review the literature linking early repolarization with arrhythmic risk to place this "fear of J waves" in the right perspective. We found five case control studies (involving 331 patients with idiopathic ventricular fibrillation [VF] and 8,649 controls). All of these studies showed that J waves, particularly of large amplitude and recorded in multiple leads, are more prevalent among patients with idiopathic VF. We also found three large population studies (involving >17,000 individuals) looking at the prognostic value of early repolarization. Two of these studies showed that the presence of J waves >2 mm in amplitude in asymptomatic adults is associated with a threefold increased of arrhythmic death during very long-term follow-up. Individuals with J waves do have some degree of increased dispersion of repolarization that places them at increased risk for arrhythmic death, but only in the presence of additional proarrhythmic factors or triggers. A sensible approach for the asymptomatic patient with J waves is proposed. PMID- 21295160 TI - Mutation rate of VNTR loci in Mycobacterium tuberculosis: response to Supply et al. PMID- 21295161 TI - Biometric approximation of diaphragmatic contractility during sustained hyperpnea. AB - Imposing load on respiratory muscles results in a loss of diaphragmatic contractility that develops early, is independent of task failure, and levels off following the initial decrease. This study assessed the progression of diaphragmatic contractility during sustained normocapnic hyperpnea and applied a biometric approximation (hypothesis: non-linear decay). Ten healthy subjects performed three consecutive hyperpnea bouts (I:6 min warm up/II:9 min/III:task failure 28.6 +/- 11.5 min; mean +/- SD) at maximal voluntary ventilation fractions (I:30-60%/II:70%/III:70%), followed by recovery periods (I:18 min/II:6 min/III:30 min). Twitch transdiaphragmatic pressure (TwPdi) was assessed throughout the protocol. Bouts II and III induced diaphragmatic fatigue (TwPdi baseline vs. Recovery -19 +/- 17% and -30 +/- 16%, both p < 0.05 RM-ANOVA) while bout I did not. During sustained hyperpnea (II/III), TwPdi followed an exponential decay (r(2) = 0.91). The reduction in diaphragmatic contractility closely follows a non-linear function with an early loss in diaphragmatic contractility during sustained hyperpnea, levels off thereafter, and is independent of task failure. Thus, reasons other than diaphragmatic fatigue are likely to be responsible for task failure during sustained hyperpnea. PMID- 21295162 TI - The reversal of diabetes in rat model using mouse insulin producing cells - a combination approach of tissue engineering and macroencapsulation. AB - Type 1 diabetes is a chronic disorder resulting from the autoimmune destruction of insulin-producing cells, a leading cause of morbidity and mortality all over the world. In this study a tissue engineering approach was compared with a macroencapsulation approach to reverse type 1 diabetes in a rat model, using mouse pancreatic progenitor cell (PPC)-derived islet-like clusters and mouse islets. For the tissue engineering approach the cells were cultured on gelatin scaffolds cross-linked with EDC in the presence of polyvinylpyrrolidone in vitro (GPE scaffolds), while for the macroencapsulation approach the cells were encapsulated in polyurethane-polyvinylpyrrolidone semi-interpenetrating networks. In the combination approach the cells cultured on GPE scaffolds were further encapsulated in a polyurethane-polyvinylpyrrolidone capsule. Real time PCR studies and the glucose challenge assay have shown that cells on GPE scaffolds could express and secrete insulin and glucagon in vitro. However, under in vivo conditions the animals treated by the tissue engineering approach died within 15 20 days and showed no reversal of their diabetes, due to infiltration of immune cells such as CD4 and CD8 cells and macrophages. In the macroencapsulation approach the animals showed euglycemia within 25 days, which was maintained for further 20 days, but after that the animals died. Interestingly, in the combination approach the animals showed reversal of hyperglycemia, and remained euglycemic for up to 3 months. The time needed to achieve initial euglycemia was different with different cell types, i.e. the combination approach with mouse islets achieved euglycemia within 15 days, whereas with PPC-derived islet-like clusters euglycemia was achieved within 25 days. This study confirmed that a combination of tissue engineering and macroencapsulation with mouse islets could reverse diabetes and maintain euglycemia in an experimental diabetes rat model for 90 days. PMID- 21295163 TI - Interdigitating biocalcite dendrites form a 3-D jigsaw structure in brachiopod shells. AB - We report a newly discovered dense microstructure of dendrite-like biocalcite that is formed by marine organisms. High spatial resolution electron backscatter diffraction (EBSD) was carried out under specific analytical conditions (15 and 10 kV) on the primary layer of the modern brachiopod Gryphus vitreus. The primary layer of modern brachiopods, previously termed nanocrystalline, is formed by an array of concave/convex calcite grains with interdigitated recesses and protrusions of abutting crystals without any cavities in or between the dendrites. The interface topology of this structure ranges from a few tens of nanometres to tens of micrometres, giving a nanoscale structure to the material fabric. The dendritic grains show a spread of crystallographic orientation of several degrees and can thus be referred to as mesocrystals. Individual dendritic mesocrystals reach sizes in one dimension larger than 20 MUm. The preferred crystallographic orientation is similar in the primary and adjacent fibrous shell layers, even though these two layers show completely different crystal morphologies and grain boundary topologies. This observation indicates that two separate control mechanisms are active when the primary and the fibrous shell layers are formed. We propose a growth model for the interdigitated dendritic calcite grain structure based on a precursor of vesicles filled with amorphous calcium carbonate (ACC). PMID- 21295164 TI - Characterization and dissolution of functionalized amorphous calcium phosphate biolayers using single-splat technology. AB - New processing routes and characterization techniques underpin further growth of biomaterials for improved performance and multifunctionality. This study investigates the characteristics and solubility of amorphous calcium phosphate (ACP) printed splats. Splats made from 20 to 60 MUm molten hydroxyapatite particles were classified for shape (rounded/splashed) and cracking. Recoil of the spread droplet created a bowl-shaped splat. This has previously not been observed and could be related to the longer solidification time associated with solidification to an ACP. A central depression was created from 20 MUm particles, but a bowl-shaped splat from 60 MUm particles. Cracking was more prevalent for splats that solidified with an edge discontinuity. Splats immersed in pH 7.3 tris buffer displayed dissolution followed by cracking. Cracking continued over a period of 15 min as dissolution induced more cracks. Further degradation occurred by delamination of splat segments. Delamination accelerated the process of splat removal. Applied to thermal spray coatings, this highlights topography and dissolution at the splat level. The use of separate splats can potentially be used as a biolayer where splats are separate, in a line or on top of each other. PMID- 21295165 TI - Synthesis and characterization of photocrosslinkable gelatin and silk fibroin interpenetrating polymer network hydrogels. AB - To effectively repair or replace damaged tissues, it is necessary to design scaffolds with tunable structural and biomechanical properties that closely mimic the host tissue. In this paper, we describe a newly synthesized photocrosslinkable interpenetrating polymer network (IPN) hydrogel based on gelatin methacrylate (GelMA) and silk fibroin (SF) formed by sequential polymerization, which possesses tunable structural and biological properties. Experimental results revealed that IPNs, where both the GelMA and SF were independently crosslinked in interpenetrating networks, demonstrated a lower swelling ratio, higher compressive modulus and lower degradation rate as compared to the GelMA and semi-IPN hydrogels, where only GelMA was crosslinked. These differences were likely caused by a higher degree of overall crosslinking due to the presence of crystallized SF in the IPN hydrogels. NIH-3T3 fibroblasts readily attached to, spread and proliferated on the surface of IPN hydrogels, as demonstrated by F-actin staining and analysis of mitochondrial activity (MTT). In addition, photolithography combined with lyophilization techniques was used to fabricate three-dimensional micropatterned and porous microscaffolds from GelMA SF IPN hydrogels, furthering their versatility for use in various microscale tissue engineering applications. Overall, this study introduces a class of photocrosslinkable, mechanically robust and tunable IPN hydrogels that could be useful for various tissue engineering and regenerative medicine applications. PMID- 21295166 TI - Osteoinduction of porous Ti implants with a channel structure fabricated by selective laser melting. AB - Many studies have shown that certain biomaterials with specific porous structures can induce bone formation in non-osseous sites without the need for osteoinductive biomolecules, however, the mechanisms responsible for this phenomenon (intrinsic osteoinduction of biomaterials) remain unclear. In particular, to our knowledge the type of pore structure suitable for osteoinduction has not been reported in detail. In the present study we investigated the effects of interconnective pore size on osteoinductivity and the bone formation processes during osteoinduction. Selective laser melting was employed to fabricate porous Ti implants (diameter 3.3mm, length 15 mm) with a channel structure comprising four longitudinal square channels, representing pores, of different diagonal widths, 500, 600, 900, and 1200 MUm (termed p500, p600, p900, and p1200, respectively). These were then subjected to chemical and heat treatments to induce bioactivity. Significant osteoinduction was observed in p500 and p600, with the highest observed osteoinduction occurring at 5mm from the end of the implants. A distance of 5mm probably provides a favorable balance between blood circulation and fluid movement. Thus, the simple architecture of the implants allowed effective investigation of the influence of the interconnective pore size on osteoinduction, as well as the relationship between bone quantity and its location for different pore sizes. PMID- 21295167 TI - New method for peptide desorption from abundant blood proteins for plasma/serum peptidome analyses by mass spectrometry. AB - This report describes a new method for desorption of low-molecular weight (LMW) peptides from abundant blood proteins for use in subsequent mass spectrometry analyses. Heating of diluted blood serum to 98 degrees C for 15min resulted in dissociation of LMW peptides from the most abundant blood proteins. Application of blood plasma/serum fractionation using magnetic beads with a functionalized surface followed by heating of the resultant fractions significantly increases the number of LMW peptides detected by MALDI-TOF MS, enhances the general reproducibility of mass spectrometry profiles and considerably increases the number of identified blood serum peptides by LC-MS/MS using an Agilent 6520 Accurate-Mass Q-TOF. PMID- 21295168 TI - "Proteomineering" or not? The debate on biomarker discovery in sera continues. AB - The performance of sera pre-treatments for biomarker discovery has been recently assessed as very poor not only for immuno-subtraction, in turn evaluated as a tool unable to look deep into the low-abundance proteome (LAP) and thus incapable to lead to any novel biomarker discovery (J Proteome Res 2010;9:4982-4991), but also for combinatorial peptide ligand libraries (CPLL) (Proteomics 2010;10:1416 1425). The performance of both tools has been given as enabling to barely detect a meagre 25% more as compared to control, untreated sera. Meanwhile, other studies indicated the extreme effectiveness of peptide libraries to enlarge the knowledge of proteome compositions. In this contradictory situation we are here re-evaluating some protocol aspects and report that indeed CPLL is an excellent tool, able to dig really deep into the low-abundance proteome. The problem is that in those reports under-optimized capture and elution protocols had been adopted. With the protocols here reported, namely (a) abandoning the step of adding 150mM salt to the sample; (b) capture at three different pH values (pH 4.0, 7.0 and 9.3) and (c), most importantly, eluting from CPLL beads in 4% boiling SDS in the presence of 25mM DTT, we can largely expand the windows of visibility. In particular, it is here shown that a common elution protocol adopted in several reports, in 4M urea and 1% CHAP, barely elutes about 15% of the captured species. Nevertheless if the CPLL beads thus treated are further eluted with boiling SDS-DTT, an additional 80% is recovered. PMID- 21295169 TI - Vitamin D inadequacy is associated with low-energy distal radius fractures: a case-control study. AB - INTRODUCTION: Vitamin D inadequacy is associated with hip fractures, but the relationship has not been explored for distal radius fractures. AIMS: To compare serum 25-hydroxyvitamin D (s-25(OH)D) status in low-energy distal radius fracture patients and a group of matched controls, and examine whether observed differences in s-25(OH)D between patients and controls would remain after adjusting for bone mineral density (BMD), body mass index (BMI), and smoking history. METHODS: A total of 575 female and 72 male low-energy distal radius fracture patients (50-90 years) and 534 female and 52 male matched controls were included. The primary measure was levels of vitamin D. Secondary measures were BMD assessed by dual energy X-ray absorptiometry, BMI and smoking history. RESULTS: Mean s-25(OH)D was 66.5nmol/L in female patients and 78.7nmol/L in controls (p<0.001). The corresponding figures in men were 64.5 and 77.0nmol/L (p=0.017). In adjusted conditional logistic regression analyzes, s-25(OH)D <50nmol/L (OR=2.32, 95% CI: 1.47-3.64, p<0.001), and 50-75 (OR=1.70, 95% CI: 1.17 2.47, p=0.005) were associated with distal radius fractures in women. s-25(OH)D <50nmol/L (OR=6.27, 95% CI: 1.17-33.66, p=0.032) was associated with distal radius fractures in men. CONCLUSIONS: Vitamin D inadequacy is associated with low energy distal radius fractures in both women and men. Differences in vitamin D levels are independent of BMD, BMI or smoking history. PMID- 21295170 TI - Effects of long-term vitamin K(1) (phylloquinone) or vitamin K(2) (menaquinone-4) supplementation on body composition and serum parameters in rats. AB - Vitamin K is a cofactor for gamma-glutamyl carboxylase, which is an essential enzyme for the gamma-carboxylation of vitamin K-dependent proteins such as osteocalcin and matrix Gla protein. Although it has been suggested that vitamin K plays an important role in the improvement of bone metabolism, the relationship between dietary vitamin K intake and bone metabolism has not been thoroughly investigated. Moreover, vitamin K is thought to have other actions beyond influencing the gamma-carboxylation status. In the present study, we examined the effects of the long-term addition of phylloquinone (PK) or menaquinone-4 (MK-4) to a control diet on bone mineral density, bone strength, body composition, and serum parameters in rats. A total of 23 female Sprague-Dawley strain rats (6 weeks old) were divided into three groups: basic control diet group, PK diet (PK: 600mg/kg diet) group, and MK diet (MK-4: 600mg/kg diet) group. Three months after starting the experimental diet, the addition of PK to the basic control diet significantly increased the bone mineral density (BMD) of the femur (p<0.05). In the MK group, there was no significant difference in the BMD of the femur. However, two types of bone strength parameter: the minimum cross-sectional moment of inertia and the polar moment of inertia, were significantly higher in the MK group than in the control (p<0.05, respectively). Furthermore, the femoral bone parameters (the width, dry weight and ash weight, and cortical, cancellous, trabecular, and total bone mineral contents) in the MK group were increased significantly compared with the control. Interestingly, the addition of PK or MK 4 significantly decreased the total fat accumulation (p<0.01 and p<0.05, respectively), and serum triglycerides were reduced by 48% in the PK group and 29% in the MK group compared with the control. There were no significant differences in the levels of serum calcium, phosphorus, alkaline phosphatase, growth hormone, insulin-like growth hormone-1, insulin-like growth hormone binding protein-3, and cross-linked N-teleopeptide of type I collagen among the three groups. This is the first study to demonstrate the effect of the long-term addition of PK or MK-4 to the control diet on body composition and serum parameters in an in vivo system using rats. Further studies on the mechanism of vitamin K supplementation in the regulation of bone metabolism would provide valuable data on the prevention of lifestyle-related disorders, including osteoporosis. PMID- 21295171 TI - Antioxidant and antiasthmatic effects of saucerneol D in a mouse model of airway inflammation. AB - Chronic airway inflammation is a hallmark of asthma, which is an immune-based disease. We evaluated the ability of saucerneol D, a tetrahydrofuran-type sesquilignan isolated from Saururus chinensis, to regulate airway inflammation in an ovalbumin (OVA)-induced airway inflammation model. Furthermore, we determined whether heme oxygenase (HO)-1 was required for the protective activity of saucerneol D. The airways of OVA-sensitized mice exposed to an OVA challenge developed eosinophilia and mucus hypersecretion and exhibited increased cytokine levels. Mice were administered saucerneol D orally at doses of 20 and 40mg/kg once daily on days 26-30. Saucerneol D administered orally significantly inhibited the number of OVA-induced inflammatory cells and the production of immunoglobulin E as well as Th2-type cytokines. Histopathology studies revealed a marked decrease in lung inflammation and goblet cell hyperplasia after saucerneol D treatment. In addition, saucerneol D induced HO-1 and led to a marked decrease in OVA-induced reactive oxygen species and malondialdehyde and an increase in superoxide dismutase and glutathione in lung tissues. These antioxidant effects were correlated with HO-1 induction. In our experiments, saucerneol D treatment reduced airway inflammation and suppressed oxidative stress in an OVA-induced asthma model. PMID- 21295173 TI - The risk of thromboembolism in heart failure: does it merit anticoagulation therapy? PMID- 21295172 TI - Characteristics of depression remission and its relation with cardiovascular outcome among patients with chronic heart failure (from the SADHART-CHF Study). AB - Depression is prevalent in patients with heart failure and is associated with a significant increase in hospitalizations and death. Primary results of the Sertraline Against Depression and Heart Disease in Chronic Heart Failure (SADHART CHF) trial revealed that sertraline and placebo had comparable effects on depression and cardiovascular outcomes. In this study, we explored whether remission from depression was associated with better survival and aimed to characterize participants who remitted during the trial. Based on depression response during the 12-week treatment phase, SADHART-CHF participants were divided into 2 groups: (1) remission, defined as participants whose last measured Hamilton Depression Rating Scale (HDRS) score was <8, and (2) nonremission, defined as participants whose last measured HDRS score was >=8. Patients who dropped out before having any repeat HDRS were not included. Baseline characteristics and survival differences up to 5 years were evaluated between the remission and nonremission groups. Of the 469 SADHART-CHF participants, 208 (44.3%) achieved remission, 194 (41.4%) remained depressed, and 67 (14.3%) dropped out or died without any repeat HDRS assessment. Patients in the remission group had significantly fewer cardiovascular events than those in the nonremission group (1.34 +/- 1.86 vs 1.93 +/- 2.71, adjusted p = 0.01). Men patients were more likely to remit than women patients (56.5 vs 44.8%, p = 0.02). The remission group had milder depressive symptoms at baseline compared to the nonremission group (HDRS 17.0 +/- 5.4 vs 19.6 +/- 5.5, Beck Depression Inventory scale 17.9 +/- 6.5 vs 20.3 +/- 7.2, p <0.001 for the 2 comparisons). In conclusion, this study indicates that remission from depression may improve the cardiovascular outcome of patients with heart failure. PMID- 21295174 TI - Effectiveness of serial increases in amino-terminal pro-B-type natriuretic peptide levels to indicate the need for mechanical circulatory support in children with acute decompensated heart failure. AB - We sought to determine prospectively whether serial assessment of the natriuretic peptide prohormone, amino-terminal pro-B-type natriuretic peptide (NT-pro-BNP), correlated with clinical severity and outcomes in children hospitalized for acute decompensated heart failure (ADHF). Patients (>1 month of age) admitted from 2005 to 2007 with ADHF requiring intravenous vasoactive/diuretic therapy for ADHF were eligible. Serum NT-pro-BNP levels were obtained within 24 hours of admission and at prespecified intervals, and clinical caregivers were blinded to these levels. End points included hospital discharge, death or cardiac transplantation, and care escalation including the need for mechanical circulatory support (MCS) was noted. Twenty-four patients were enrolled: 22 survived to hospital discharge and 2 died. Ten required MCS (of which 6 underwent cardiac transplantation). Two patients underwent transplantation without MCS. For the entire cohort, NT-pro-BNP levels peaked at days 2 to 3 after admission, with a subsequent gradual decrease until discharge. However, for those who did require MCS, NT-pro-BNP failed to decrease consistently until after MCS initiation. At discharge, NT-pro-BNP levels were significantly decreased from admission levels but remained well above normal for all patients. Single-point NT-pro-BNP levels on admission did not correlate with independently assessed clinical scores of heart failure severity or predict the need for MCS in this cohort. In conclusion, serial NT-pro-BNP levels demonstrated an incremental trend after 48 hours in patients who went on to require MCS but decreased in all other patients and may therefore assist the decision to initiate or avoid MCS after admission for pediatric ADHF. PMID- 21295175 TI - The editor's roundtable: Implantable cardioverter-defibrillators in primary prevention of sudden cardiac death and disparity-related barriers to implementation. PMID- 21295176 TI - Seeking optimal relation between oxygen saturation and hemoglobin concentration in adults with cyanosis from congenital heart disease. AB - In patients with cyanosis from congenital heart disease, erythropoiesis is governed by many factors that can alter the expected relation between the oxygen saturation (O(2sat)) and hemoglobin concentration. We sought to define the relation between the O(2sat) and hemoglobin in such patients and to predict an ideal hemoglobin concentration for a given O(2sat). Adults with congenital heart defects and cyanosis were studied prospectively using blood tests and exercise testing. Nonoptimal hemoglobin was defined as any evidence of inadequate erythropoiesis (i.e., iron, folate, or vitamin B(12) deficiency, increased erythropoietin, reticulocytosis, or a right-shifted oxygen-hemoglobin curve). For patients without these factors, a linear regression equation of hemoglobin versus O(2sat) was used to predict the optimal hemoglobin for all patients. Of the 65 patients studied, 21 met all the prestudy criteria for an optimal hemoglobin. For all patients, no correlation was found between O(2sat) and hemoglobin (r = 0.22). However, a strong linear correlation was found for those meeting the criteria for optimal hemoglobin (r = -0.865, p <0.001). The optimal hemoglobin regression equation was as follows: predicted hemoglobin = 57.5 - (0.444 * O(2sat)). A negative correlation was found between the hemoglobin difference (predicted minus measured) and exercise duration on cardiopulmonary exercise testing (r = -0.396, p = 0.005) and the 6-minute walk distance (r = -0.468, p <0.001). In conclusion, a strong relation between O(2sat) and hemoglobin concentration can be shown in stable cyanotic patients and used to predict an optimal hemoglobin. This relation might be useful in defining functional anemia in this group. PMID- 21295177 TI - Self-terminated ventricular fibrillation and recurrent syncope. AB - Ventricular fibrillation (VF) is a lethal arrhythmia that requires immediate cardioversion and is rarely self-terminating. Spontaneous termination is typically associated with more organized activation than sustained VF terminated by shock, but the precise mechanism is unclear. In the present case, we describe a patient with recurrent syncope and documented self-terminating VF, who ultimately underwent implantable cardioverter defibrillator insertion. Assessment of the rhythm strip revealed organization of a chaotic rhythm into monomorphic ventricular tachycardia before termination, in supportive of previous reports. In conclusion, self-terminating VF is a very rare condition that can cause syncope. PMID- 21295178 TI - Long-term follow up of atrioventricular block in transcatheter aortic valve implantation. PMID- 21295179 TI - Comparison of 600 versus 300-mg clopidogrel loading dose in patients with ST segment elevation myocardial infarction undergoing primary coronary angioplasty. PMID- 21295181 TI - Caring for the breast cancer survivor. PMID- 21295183 TI - Effect of annual colonoscopy volume and years in practice on polyp detection and removal. PMID- 21295185 TI - Tuberculous appendicitis. PMID- 21295186 TI - It is only the ignorant who despise education. PMID- 21295187 TI - How physicians can drive comparative-effectiveness research: lessons from New Zealand. PMID- 21295188 TI - Challenges and opportunities for cardiovascular disease prevention. AB - Cardiovascular diseases are highly preventable, yet they remain the most common cause of death in the world. The epidemic is receding in industrialized countries; however, many low-income and middle-income countries have experienced an increase in cardiovascular diseases and 80% of all cardiovascular diseases deaths occur there. In the last 20 years, the epidemiology and surveillance of cardiovascular diseases have laid the foundations for public health interventions that may reduce the burden of disease. Relevant population-specific local data are therefore needed to describe the trends and pattern of risk for atherosclerotic diseases. Once the basis for surveillance and epidemiological research has been laid, cardiovascular disease prevention will require approaches adapted for each individual and population. The existence of effective preventive interventions justifies the assertion that coronary heart disease and stroke could be virtually prevented and controlled. Our goal in this review is to summarize the current challenges and opportunities for cardiovascular medicine, focusing on the need for high-quality local surveillance systems that provide the appropriate data needed to develop sound national cardiovascular disease preventive policies. PMID- 21295189 TI - Aortic valve sclerosis and clinical outcomes: moving toward a definition. AB - The presence of aortic valve sclerosis has been suggested as a marker of increased cardiovascular risk, including increased mortality. However, it remains unclear whether aortic valve sclerosis is independently associated with risk or merely a marker of coexistent cardiovascular risk factors. Aortic valve sclerosis is usually diagnosed on transthoracic echocardiography, the most widely used imaging modality in observational and natural history studies of aortic valve disease. Defining aortic valve sclerosis has remained challenging due to the variable and qualitative nature of its description by ultrasound techniques. Importantly, artifacts common to ultrasound imaging and awareness of demographic and clinical history information may bias the diagnosis of aortic valve sclerosis. Because clinicians may alter treatment recommendations or follow-up based on echocardiographic reporting of aortic valve sclerosis, highlighting pitfalls of the subjective nature by which aortic valve sclerosis is identified and establishing diagnostic criteria are necessary. This review describes the diagnostic criteria for aortic valve sclerosis used in outcome studies, summarizes the epidemiological findings reporting the relationship between aortic valve sclerosis and clinical outcome, and proposes a definition of aortic valve sclerosis based on the literature. PMID- 21295190 TI - A "smart" heart failure sheet: using electronic medical records to guide clinical decision making. PMID- 21295191 TI - In the zone. PMID- 21295192 TI - Effect of renin-angiotensin system blockade on calcium channel blocker-associated peripheral edema. AB - BACKGROUND: Peripheral edema is a common adverse effect of calcium channel blockers. The addition of a renin-angiotensin system blocker, either an angiotensin-converting enzyme inhibitor or an ARB, has been shown to reduce peripheral edema in a dose-dependent way. METHODS: We performed a MEDLINE/COCHRANE search for all prospective randomized controlled trials in patients with hypertension, comparing calcium channel blocker monotherapy with calcium channel blocker/renin-angiotensin system blocker combination from 1980 to the present. Trials reporting the incidence of peripheral edema or withdrawal of patients because of edema and total sample size more than 100 were included in this analysis. RESULTS: We analyzed 25 randomized controlled trials with 17,206 patients (mean age 56 years, 55% were men) and a mean duration of 9.2 weeks. The incidence of peripheral edema with calcium channel blocker/renin-angiotensin system blocker combination was 38% lower than that with calcium channel blocker monotherapy (P<.00001) (relative risk [RR] 0.62; 95% confidence interval [CI], 0.53-0.74). Similarly, the risk of withdrawal due to peripheral edema was 62% lower with calcium channel blocker/renin-angiotensin system blocker combination compared with calcium channel blocker monotherapy (P=.002) (RR 0.38; 95% CI, 0.22 0.66). ACE inhibitors were significantly more efficacious than ARBs in reducing the incidence of peripheral edema (P<.0001) (ratio of RR 0.74; 95% CI, 0.64-0.84) (indirect comparison). CONCLUSION: In patients with hypertension, the calcium channel blocker/renin-angiotensin system blocker combination reduces the risk of calcium channel blocker-associated peripheral edema when compared with calcium channel blocker monotherapy. ACE inhibitor seems to be more efficacious than ARB in reducing calcium channel blocker-associated peripheral edema, but head-to-head comparison studies are needed to prove this. PMID- 21295193 TI - Trends in comorbidity, disability, and polypharmacy in heart failure. AB - BACKGROUND: Comorbidity, disability, and polypharmacy commonly complicate the care of patients with heart failure. These factors can change biological response to therapy, reduce patient ability to adhere to recommendations, and alter patient preference for treatment and outcome. Yet, a comprehensive understanding of the complexity of patients with heart failure is lacking. Our objective was to assess trends in demographics, comorbidity, physical function, and medication use in a nationally representative, community-based heart failure population. METHODS: Using data from the National Health and Nutrition Examination Survey, we analyzed trends across 3 survey periods (1988-1994, 1999-2002, 2003-2008). RESULTS: We identified 1395 participants with self-reported heart failure (n=581 in 1988-1994, n=280 in 1999-2002, n=534 in 2003-2008). The proportion of patients with heart failure who were >=80 years old increased from 13.3% in 1988-1994 to 22.4% in 2003-2008 (P <.01). The proportion of patients with heart failure who had 5 or more comorbid chronic conditions increased from 42.1% to 58.0% (P <.01). The mean number of prescription medications increased from 4.1 to 6.4 prescriptions (P <.01). The prevalence of disability did not increase but was substantial across all years. CONCLUSION: The phenotype of patients with heart failure changed substantially over the last 2 decades. Most notably, more recent patients have a higher percentage of very old individuals, and the number of comorbidities and medications increased markedly. Functional disability is prevalent, although it has not changed. These changes suggest a need for new research and practice strategies that accommodate the increasing complexity of this population. PMID- 21295194 TI - Smoking cessation reduces postoperative complications: a systematic review and meta-analysis. AB - OBJECTIVE: We aimed to review randomized trials and observational evidence to establish the effect of preoperative smoking cessation on postoperative complications and to determine if there is an optimal cessation period before surgery. METHODS: We conducted a systematic review of all randomized trials evaluating the effect of smoking cessation on postoperative complications and all observational studies evaluating the risk of complications among past smokers compared with current smokers. We searched independently, in duplicate, 10 electronic databases and the bibliographies of relevant reviews. We conducted a meta-analysis of randomized trials using a random effects model and performed a meta-regression to examine the impact of time, in weeks, on the magnitude of effect. For observational studies, we pooled proportions of past smokers in comparison with current smokers. RESULTS: We included 6 randomized trials and 15 observational studies. We pooled the 6 randomized trials and demonstrated a relative risk reduction of 41% (95% confidence interval [CI], 15-59, P = .01) for prevention of postoperative complications. We found that each week of cessation increases the magnitude of effect by 19%. Trials of at least 4 weeks' smoking cessation had a significantly larger treatment effect than shorter trials (P = .04). Observational studies demonstrated important effects of smoking cessation on decreasing total complications (relative risk [RR] 0.76, 95% CI, 0.69-0.84, P < .0001, I(2) = 15%). This also was observed for reduced wound healing complications (RR 0.73, 95% CI, 0.61-0.87, P = .0006, I(2) = 0%) and pulmonary complications (RR 0.81, 95% CI, 0.70-0.93, P = .003, I(2) = 7%). Observational studies examining duration of cessation demonstrated that longer periods of cessation, compared with shorter periods, had an average reduction in total complications of 20% (RR 0.80, 95% CI, 3-33, P = .02, I(2) = 68%). CONCLUSION: Longer periods of smoking cessation decrease the incidence of postoperative complications. PMID- 21295195 TI - Prevalence of contraindications and prescription of pharmacologic therapies for gout. AB - BACKGROUND: Patients with gout have comorbidities, but the impact of these comorbidities on treatment has not been studied. METHODS: A total of 575 patients with gout were stratified according to certainty of diagnosis according to International Classification of Diseases, 9th Revision, Clinical Modification code alone (cohort I), American College of Radiology criteria (cohort II), and crystal diagnosis (cohort III). Comorbid conditions were defined according to International Classification of Diseases, 9th Revision, Clinical Modification codes, and stratified as either moderate or severe. Drug contraindications were defined as moderate or strong, based on Food and Drug Administration criteria and severity of disease. RESULTS: The most common comorbidity was hypertension (prevalence 0.89). The presence of comorbidities resulted in a high frequency of contraindications to approved gout medications. More than 90% of patients had at least 1 contraindication to nonsteroidal anti-inflammatory drugs. Many patients demonstrated multiple contraindications to 1 or more gout medications. Frequently, patients were prescribed medications to which they harbored contraindications. The prevalence of patients prescribed colchicine despite having at least 1 strong contraindication was 30% (cohort I), 37% (cohort II), and 39.6% (cohort III). CONCLUSION: Patients with gout typically harbor multiple comorbidities that result in contraindications to many of the medications available to treat gout. Frequently, despite contraindications to gout therapies, patients are frequently prescribed these medications. PMID- 21295196 TI - Association between social isolation and left ventricular mass. AB - BACKGROUND: Social isolation is associated with progression of cardiovascular disease, with the most socially isolated patients being at increased risk. Increased left ventricular mass is a predictor of cardiovascular morbidity and mortality. It is not yet clear whether social isolation is a determinant of increased left ventricular mass. METHODS: We performed a cross-sectional study of Northern Manhattan Study participants who were free of clinical cardiovascular disease and had obtained transthoracic echocardiograms (n=2021) and a baseline questionnaire on social habits. Social isolation was defined as the lack of friendship networks (knowing fewer than 3 people well enough to visit within their homes). Echocardiographic left ventricular mass was indexed to height(2.7), analyzed as a continuous variable and compared between exposure groups. RESULTS: The prevalence of social isolation was 13.5%. The average left ventricular mass was significantly higher (50.2 gm/m(2.7)) in those who were, as compared with those who were not (47.6 gm/m(2.7)), socially isolated (P<.05). Higher prevalence of social isolation was found among those less educated, uninsured, or unemployed. There were no significant race-ethnic differences in the prevalence of social isolation. In multivariate analysis, there was a trend toward an association between social isolation and increased left ventricular mass in the total cohort (P=.09). Among Hispanics, social isolation was significantly associated with greater left ventricular mass. Hispanics who were socially isolated averaged 3.9 gm/ht(2.7) higher left ventricular mass compared with those not socially isolated (P=.002). This relationship was not present among non Hispanic blacks or whites. CONCLUSION: In this urban tri-ethnic cohort, social isolation was prevalent and associated with indices of low socioeconomic status. Hispanics who were socially isolated had a greater risk for increased left ventricular mass. PMID- 21295197 TI - Marked reduction in 30-day mortality among elderly patients with community acquired pneumonia. AB - BACKGROUND: Community-acquired pneumonia is the most common infectious cause of death in the US. Over the last 2 decades, patient characteristics and clinical care have changed. To understand the impact of these changes, we quantified incidence and mortality trends among elderly adults. METHODS: We used Medicare claims to identify episodes of pneumonia, based on a validated combination of diagnosis codes. Comorbidities were ascertained using the diagnosis codes located on a 1-year look back. Trends in patient characteristics and site of care were compared. The association between year of pneumonia episode and 30-day mortality was then evaluated by logistic regression, with adjustment for age, sex, and comorbidities. RESULTS: We identified 2,654,955 cases of pneumonia from 1987 2005. During this period, the proportion treated as inpatients decreased, the proportion aged >=80 years increased, and the frequency of many comorbidities rose. Adjusted incidence increased to 3096 episodes per 100,000 population in 1999, with some decrease thereafter. Age/sex-adjusted mortality decreased from 13.5% to 9.7%, a relative reduction of 28.1%. Compared with 1987, the risk of mortality decreased through 2005 (adjusted odds ratio, 0.46; 95% confidence interval, 0.44-0.47). This result was robust to a restriction on comorbid diagnoses assessing for the results' sensitivity to increased coding. CONCLUSIONS: These findings show a marked mortality reduction over time in community-acquired pneumonia patients. We hypothesize that increased pneumococcal and influenza vaccination rates as well as wider use of guideline-concordant antibiotics explain a large portion of this trend. PMID- 21295198 TI - Randomized trial of a warfarin communication protocol for nursing homes: an SBAR based approach. AB - BACKGROUND: More than 1.6 million Americans currently reside in nursing homes. As many as 12% of them receive long-term anticoagulant therapy with warfarin. Prior research has demonstrated compelling evidence of safety problems with warfarin therapy in this setting, often associated with suboptimal communication between nursing home staff and prescribing physicians. METHODS: We conducted a randomized trial of a warfarin management protocol using facilitated telephone communication between nurses and physicians in 26 nursing homes in Connecticut in 2007-2008. Intervention facilities received a warfarin management communication protocol using the approach "Situation, Background, Assessment, and Recommendation" (SBAR). The protocol included an SBAR template to standardize telephone communication about residents on warfarin by requiring information about the situation triggering the call, the background, the nurse's assessment, and recommendations. RESULTS: There were 435 residents who received warfarin therapy during the study period for 55,167 resident days in the intervention homes and 53,601 in control homes. In intervention homes, residents' international normalized ratio (INR) values were in the therapeutic range a statistically significant 4.50% more time than in control homes (95% confidence interval [CI], 0.31%-8.69%). There was no difference in obtaining a follow-up INR within 3 days after an INR value >=4.5 (odds ratio 1.02; 95% CI, 0.44-2.4). Rates of preventable adverse warfarin-related events were lower in intervention homes, although this result was not statistically significant: the incident rate ratio for any preventable adverse warfarin-related event was .87 (95% CI, .54-1.4). CONCLUSION: Facilitated telephone communication between nurses and physicians using the SBAR approach modestly improves the quality of warfarin management for nursing home residents. PMID- 21295199 TI - Maintenance of certification: 20 years later. PMID- 21295200 TI - Imaging spectrum of sudden athlete cardiac death. AB - Sudden athlete death (SAD) is a widely publicized and increasingly reported phenomenon. For many, the athlete population epitomize human physical endeavour and achievement and their unexpected death comes with a significant emotional impact on the public. Sudden deaths within this group are often without prior warning. Preceding symptoms of exertional syncope and chest pain do, however, occur and warrant investigation. Similarly, a positive family history of sudden death in a young person or a known family history of a condition associated with SAD necessitates further tests. Screening programmes aimed at detecting those at risk individuals also exist with the aim of reducing fatalities. In this paper we review the topic of SAD and discuss the epidemiology, aetiology, and clinical presentations. We then proceed to discuss each underlying cause, in turn discussing the pathophysiology of each condition. This is followed by a discussion of useful imaging methods with an emphasis on cardiac magnetic resonance and cardiac computed tomography and how these address the various issues raised by the pathophysiology of each entity. We conclude by proposing imaging algorithms for the investigation of patients considered at risk for these conditions and discuss the various issues raised in screening. PMID- 21295201 TI - Multimethod imaging, staging, and spectrum of manifestations of metastatic melanoma. AB - The incidence of melanoma has been steadily increasing. Imaging plays an important role in tumour assessment as metastatic melanoma can involve multiple organs. Computed tomography (CT) is currently the most widely used technique for tumour staging, surveillance and assessment of therapeutic response, but ultrasound, magnetic resonance imaging (MRI) and positron-emission tomography (PET)-CT also play important roles in the imaging of this tumour. In this article, we review the pathways of spread, staging according to the recently updated TNM classification, pathology, typical and atypical imaging features at common and uncommon sites, and treatment of metastatic melanoma. PMID- 21295202 TI - Manganese-enhanced MRI predicts the histological grade of hepatocellular carcinoma in potential surgical candidates. AB - AIM: To evaluate the role of manganese-enhanced magnetic resonance (Mn-MRI) in predicting tumour differentiation prior to liver transplant or resection for hepatocellular carcinoma (HCC). MATERIALS AND METHODS: The inclusion criteria were patients with HCC who underwent Mn-MRI prior to transplantation or resection from 2001-2008. T1-weighted MRI images were acquired at 0 and 24h after manganese dipyridoxal diphosphate (MnDPDP) intravenous contrast medium and reviewed prospectively. Manganese retention at 24h was correlated with tumour differentiation and disease-free survival. RESULTS: Eighty-six patients underwent Mn-MRI (transplantation 60, resection 26); 114/125 lesions (91%) that were arterialised as evidenced at computed tomography (CT) and had manganese uptake on MRI were HCC. There were 11 false positives (9%) that were regenerative nodules. Ten of fourteen non-manganese-retaining HCC (71%) were poorly differentiated, compared with only 13/114 manganese-retaining HCC (11%) (p<0.0001). Sensitivity, specificity, positive and negative predictive values of non-retention of MnDPDP in predicting poorly differentiated tumours were 0.43, 0.96, 0.71 and 0.88. Median disease-free survival of patients with non-manganese-retaining HCC was less than for patients with manganese-retaining HCC (14+/-5 months versus 39+/-3 months, log rank p=0.025). CONCLUSION: Non-manganese-retaining HCCs are likely to be poorly differentiated and have a poor prognosis. Manganese-enhanced MRI appears to have a role in preoperative assessment of HCC and warrants further evaluation. PMID- 21295203 TI - The role of dual time point FDG PET imaging in the evaluation of solitary pulmonary nodules with an initial standard uptake value less than 2.5. AB - AIM: To evaluate the accuracy of dual time point 2-[(18)F]-fluoro-2-deoxy-d glucose (FDG) positron-emission tomography (PET) imaging in the evaluation of the mildly metabolic solitary pulmonary nodule (SPN) and to assess whether accuracy could be improved by delaying second image acquisition to 180 minutes. MATERIALS AND METHODS: Fifty-four patients were included in the study. Thirty-six had an SUV(max) <2.5 at 60 min. For these patients, two methods of interpreting the subsequent delayed FDG PET imaging at 180 min were investigated. The first method analysed the SUV(max) of SPNs on delayed imaging, in which an SUV(max) of 2.5 or more was regarded as a criterion for malignancy. The second method was retention index (RI) analysis, in which an increase of 10% or more in SUV(max) between the initial and delayed images, was regarded as an indication of malignancy. RESULTS: For the group as a whole (n=54), the sensitivity, specificity and accuracy of using an SUV(max) of 2.5 or more as an indication of malignancy at the time of initial image acquisition (60 min) was 58, 89, and 74%, respectively. For SPNs that had an initial SUV(max) <2.5 (n=36), the sensitivity, specificity, and accuracy of using an SUV(max) of 2.5 or more as a criterion for malignancy on the delayed image acquisition (180 min), was 36, 96, and 78% respectively. However, if an RI of >10% was used as a criterion for malignancy between the initial and delayed images, the sensitivity, specificity, and accuracy was 73, 80, and 78%, respectively. These results are similar to a recent paper, where image acquisition occurred at 60 and 120 min post-tracer injection. CONCLUSION: Dual time point FDG PET imaging with RI analysis, is a useful technique in evaluating SPN with an initial SUV(max) <2.5. Prolonging second image acquisition from 120 to 180 min does not appear to improve the accuracy of this technique. However, given that maximal FDG uptake by lung carcinomas is thought to be in the region of 5h, it may be that improving the accuracy of dual time point FDG PET imaging requires a more significant delay in second image acquisition in this specific subgroup. PMID- 21295204 TI - A prospective evaluation of conventional cystography for detection of urine leakage at the vesicourethral anastomosis site after radical prostatectomy based on computed tomography. AB - AIM: To evaluate the diagnostic accuracy of conventional cystography for the detection of urine leakage at the vesicourethral anastomosis (VUA) site after radical prostatectomy based on computed tomography (CT) cystography. MATERIALS AND METHODS: Patients who underwent radical prostatectomies at a single tertiary cancer centre were prospectively enrolled. Conventional cystography was routinely performed on postoperative day 7. Non-enhanced pelvic CT images were obtained after retrograde instillation of the same contrast material for a reference standard of urine leakage at the VUA site. Urine leakage was classified as follows: none; a plication abnormality; mild; moderate; and excessive. RESULTS: One hundred and twenty consecutive patients were enrolled. Conventional cystography detected 14 urine leakages, but CT cystography detected 40 urine leakages, which consisted of 28 mild and 12 moderate urine leakages. When using CT cystography as the standard measurement, conventional cystography showed a diagnostic accuracy of 17.8% (5/28) for mild urine leakage and 75% (9/12) for moderate leakage. Of nine patients diagnosed with mild leakage on conventional cystography, four (44.4%) had complicated moderate urine leakages based on CT cystography, requiring prolonged catheterization. The sensitivity, specificity, positive and negative predictive values, and accuracy of conventional cystography were 35, 100, 100, 75.4, and 78.3%, respectively. CONCLUSIONS: Conventional cystography is less accurate than CT cystography for diagnosing urine leakage at the VUA site after a radical prostatectomy. The present results suggest that CT cystography is a good choice for diagnostic imaging of urine leakage after radical prostatectomy. PMID- 21295205 TI - Chest radiography patterns in 75 adolescents with vertically-acquired human immunodeficiency virus (HIV) infection. AB - AIM: To evaluate lung disease on chest radiography (CR), the relative frequency of CR abnormalities, and their clinical correlates in adolescents with vertically acquired human immunodeficiency virus (HIV) infection. MATERIALS AND METHODS: CRs of 75 patients [59 inpatients (33 males; mean age 13.7+/-2.3 years) and 16 outpatients (eight males; mean age 14.1+/-2.1 years)] were retrospectively reviewed by three independent observers. The overall extent of disease (to the nearest 5%), its distribution, and the proportional extents (totalling 100%) of different radiographic patterns (including ring/tramline opacities and consolidation) were quantified. CR features and clinical data were compared. RESULTS: CRs were abnormal in 51/75 (68%) with "extensive" disease in 38/51 (74%). Ring/tramline opacities and consolidation predominated (i.e., proportional extent >50%) in 26 and 21 patients, respectively. Consolidation was significantly more common in patients hospitalized primarily for a respiratory illness than patients hospitalized for a non-respiratory illness or in outpatients (p<0.005, chi(2) for trend); by contrast, ring/tramline opacities did not differ in prevalence across the groups. On stepwise logistic regression, predominant consolidation was associated with progressive dyspnoea [odds ratio (OR) 5.60; 95% confidence intervals (CI): 1.60, 20.1; p<0.01] and was associated with a primary respiratory cause for hospital admission (OR: 22.0; CI: 2.7, 181.1; p<0.005). Ring/tramline opacities were equally prevalent in patients with and without chronic symptoms and in those admitted to hospital with respiratory and non respiratory illness. CONCLUSION: In HIV-infected adolescents, evaluated in secondary practice, CR abnormalities are prevalent. The presence of ring/tramline opacities, believed to reflect chronic airway disease, is not linked chronic respiratory symptoms. PMID- 21295206 TI - FDG PET/CT features of ovarian metastasis. AB - AIM: To assess the characteristics of [(18)F]-fluoro-2-deoxy-d-glucose (FDG) uptake in cases of ovarian metastasis using positron-emission tomography/computed tomography (PET/CT). MATERIALS AND METHODS: Twelve patients with 16 ovarian metastases arising from colon cancer (n=6), breast cancer (n=4), gastric cancer (n=3), and pancreatic cancer (n=3) who underwent FDG-PET/CT examination were included in this study. The effect of lesion size and morphological pattern (predominantly solid or cystic) on FDG uptake was evaluated using the quantitative standardized uptake value (SUV). RESULTS: The mean maximum SUV for the 16 lesions was 4.6+/-2.4 (range 1.8~9.9). The Pearson correlation coefficient test showed no significant correlation between maximum SUV and lesion size (r=0.21, p=0.42). The maximum SUV of solid (n=5) and cystic (n=11) lesions was 5.5+/-2.7 and 4.3+/-2.2, respectively, and the difference was not significant (p=0.43). Breast cancer showed the highest maximum SUV (6.4+/-3.6), followed by colon cancer (5.3+/-1.4), gastric cancer (3.3+/-0.5), and pancreatic cancer (2.2+/-0.6). CONCLUSION: Ovarian metastases show a variable maximum SUV with mild to intense FDG uptake. PMID- 21295207 TI - Longitudinal split of the posterior cruciate ligament: description of a new MR finding and evaluation of its potential clinical significance. AB - AIM: To evaluate the clinical significance of the intra-substance longitudinal split of the posterior cruciate ligament (LS-PCL) and to evaluate its potential clinical significance on MRI. MATERIALS AND METHODS: The databases of two centres were searched for LS-PCL, 6917 knee magnetic resonance imaging (MRI) examinations undertaken were retrospectively reviewed. LS-PCL was defined as increased signal intensity in a PCL in the longitudinal direction, but with an intact ligament outer surface on MRI. Twelve patients were enrolled in this study. Available arthroscopic results, degree of posterior knee instability, and changes in MRI findings, or the degree of instability during follow-up (FU), were reviewed from the patients medical records and via their MRI images. MRI images were reviewed by two musculoskeletal radiologists in consensus for presence and location of LS PCL and any combined injuries: menisci lesions, ligament injuries, and bone marrow changes. RESULTS: Seven of 12 patients (58.3%) had morphological or functional evidence of PCL injury or insufficiency according to the change of posterior instability on FU stress testing (n=3), insufficiency during arthroscopy (n=2), or decreased extent and altered shape of the PCL split on the FU MRI (n=3). One patient revealed both change of posterior instability on FU stress testing and insufficiency during arthroscopy. Combined injuries were revealed in seven patients. Five patients had isolated LS-PCL: two patients underwent arthroscopic PCL reconstructions; and another three patients revealed knee instability on stress testing. CONCLUSION: Although LS-PCL has not been described before, it can be a type of partial tear of the PCL, which causes PCL insufficiency. PMID- 21295208 TI - 3 T MR cholangiopancreatography appearances of biliary ascariasis. AB - AIM: To evaluate the 3 T MR cholangiopancreatography (MRCP) appearances of biliary ascariasis. MATERIALS AND METHODS: Nine patients with a MRCP diagnosis of biliary ascariasis were reviewed. All patients had endoscopic retrograde cholangiopancreatography (ERCP) or surgical confirmation of the disease. RESULTS: On thin-slab MRCP imaging, Ascaris worms are clearly demarcated within the biliary tree. All the identified worms demonstrated a characteristic three parallel-lines appearance. The middle high-signal intensity line is sandwiched between two low-signal intensity lines and they are in turn surrounded by high signal bile. On thick-slab MRCP the worms also show the three-line sign but with less clarity. However, thick-slab MRCP has the advantage of providing three dimensional ERCP-like images of the pancreaticobiliary system. CONCLUSION: The "three-line" sign appears to be a characteristic sign of biliary ascariasis on 3 T MRCP. PMID- 21295209 TI - Magnetic resonance imaging of epilepsy at 3 Tesla. AB - Patients with epilepsy often have a structural cause for their seizures and may benefit from surgical resection. As recommended in the National Institute of Health and Clinical Excellence (NICE) guidelines, magnetic resonance imaging (MRI) is used to screen for structural abnormalities in these patients and there is increasing evidence that 3T MRI has better sensitivity and specificity than 1.5T. This article reviews the imaging findings of many of the common diseases that can cause epilepsy. PMID- 21295210 TI - Misleading unilateral V/Q and CTPA abnormality following previous cardiac surgery for tricuspid atresia. PMID- 21295211 TI - Remission of haematuria with radiofrequency ablation in a patient with colon cancer recurrence. PMID- 21295212 TI - Re: provisional reporting of polytrauma CT by on-call radiology registrars. Is it safe? PMID- 21295215 TI - Re: provisional reporting of polytrauma CT by on-call radiology registrars. Is it safe? PMID- 21295216 TI - Intermittent explosive disorder: development of integrated research criteria for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. AB - This study was designed to develop a revised diagnostic criteria set for intermittent explosive disorder (IED) for consideration for inclusion in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V). This revised criteria set was developed by integrating previous research criteria with elements from the current DSM-IV set of diagnostic criteria. Evidence supporting the reliability and validity of IED-IR ("IED Integrated Criteria") in a new and well-characterized group of subjects with personality disorder is presented. Clinical, phenomenologic, and diagnostic data from 201 individuals with personality disorder were reviewed. All IED diagnoses were assigned using a best-estimate process (eg, kappa for IED-IR >0.85). In addition, subjects meeting IED-IR criteria had higher scores on dimensional measures of aggression and had lower global functioning scores than non-IED-IR subjects, even when related variables were controlled. The IED-IR criteria were more sensitive than the DSM IV criteria only in identifying subjects with significant impulsive-aggressive behavior by a factor of 16. We conclude that the IED-IR criteria can be reliably applied and have sufficient validity to warrant consideration as DSM-V criteria for IED. PMID- 21295217 TI - Diagnostic and prognostic significance of Schneiderian first-rank symptoms: a 20 year longitudinal study of schizophrenia and bipolar disorder. AB - OBJECTIVE: This research addresses the following questions: what is the prevalence and severity of first-rank symptoms (FRS) during an extended period of time in patients with schizophrenia and bipolar disorder with psychosis? Are the specific FRS listed in Diagnostic and Statistical Manual of Mental Disorders DSM, Third Edition, Revised/Fourth Edition Criterion A for schizophrenia diagnosis (a voice keeping a running commentary or voices conversing) more prevalent and severe in patients with schizophrenia than bipolar disorder with psychosis? Lastly, do FRS at index hospitalization in patients with schizophrenia predict the absence of later recovery? METHODS: This research follows a sample of patients with psychotic disorders who were evaluated at index hospitalization and then prospectively followed-up at 6 evaluations during next 20 years (n = 86). All patients were evaluated as part of a prospective research study designed to measure multiple factors of phenomenology, severity of illness, course of illness, prognosis, and global outcome. RESULTS: First-rank symptoms are not exclusive to schizophrenia; they also occur in some bipolar patients. However, they are more frequent and more severe in patients with schizophrenia than bipolar disorder. Schizophrenia patients with FRS during the acute phase are more likely to have poorer long-term outcome than schizophrenia patients who do not have FRS during the acute phase. CONCLUSIONS: Our results indicate FRS at the acute phase are not a clinicopathologic correlate specific to schizophrenia. However, the presence and severity of any FRS and specifically of the 2 FRS associated with Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised/Fourth Edition Criterion A are more prevalent and more severe in patients with schizophrenia than patients with bipolar disorder. PMID- 21295218 TI - Recognizing mania in children and adolescents-age does not matter, but decreased need for sleep does. AB - BACKGROUND: The diagnosis of pediatric bipolar disorders is a controversial topic. If this is mainly due to a bias against a diagnosis in younger children, then just changing the information about the age of a patient should influence the likelihood of a diagnosis despite otherwise identical symptoms. Therefore, we designed a study to test if the age of a patient will influence diagnostic decisions. We further attempted to replicate an earlier result with regard to "decreased need for sleep" as a salient symptom for mania. METHODS: We randomly sent 1 of 4 case vignettes describing a person with current mania to child/adolescents psychiatrists in Germany. This vignette was systematically varied with respect to age of the patient (6 vs 16 years) and the presence/absence of decreased need for sleep but always included sufficient criteria to diagnose a mania. RESULTS: One hundred sixteen responded and, overall, 63.8% of the respondents diagnosed a bipolar disorder in the person described in the vignette. Although age did not affect the likelihood of a bipolar diagnosis, the presence of decreased need for sleep did increase its likelihood. Furthermore, the number of core symptoms identified by the clinicians was closely linked to the likelihood of assigning a bipolar diagnosis. CONCLUSION: Certain symptoms such as the decreased need for sleep, and also elated mood and grandiosity, seem to be salient for some clinicians and influence their diagnoses. Biological age of the patient, however, does not seem to cause a systematic bias against a diagnosis of bipolar disorder in children. PMID- 21295219 TI - Neuromotor abnormalities in neuroleptic-naive psychotic patients: antecedents, clinical correlates, and prediction of treatment response. AB - BACKGROUND: Primary neuromotor abnormalities are thought to be a manifestation of the brain pathology underlying the psychotic illness; however, their causes and consequences are poorly understood. The study's aim was to examine the prevalence and correlates of neuromotor abnormalities in a sample of neuroleptic-naive psychotic patients. METHOD: One hundred psychotic inpatients were rated for parkinsonism, catatonia, dyskinesia, and akathisia at the neuroleptic-naive state; and their association with demographic, antecedent, clinical, and treatment response variables was examined. RESULTS: Neurological syndromes tended to co-vary, and 34 of the patients had at least one categorically defined neurological syndrome. Higher ratings of parkinsonism, catatonia, and dyskinesia were associated with obstetric complications, poorer premorbid adjustment, more severe negative symptoms, higher prevalence of the deficit syndrome, and poorer response to antipsychotic drugs. Patients with schizophrenia had higher parkinsonism and dyskinesia ratings than those with other psychotic disorders. CONCLUSIONS: Neuromotor abnormalities represent both an integral part of the disease process not influenced by chronicity or antipsychotic drugs and a severity marker of the psychotic illness. PMID- 21295220 TI - Impact of obesity on the psychometric properties of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for major depressive disorder. AB - Obesity is associated with several symptoms that are components of the diagnostic criteria for major depressive disorder (MDD). Compared with nonobese individuals, obese individuals report more fatigue, sleep disturbance, and overeating. Obesity might, therefore, impact the psychometric properties of the MDD criteria. The goal of the present report from the Rhode Island Hospital Methods to Improve Diagnostic Assessment and Services project was to examine the impact of obesity on the psychometric characteristics of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition symptom criteria for major depression. Two thousand four hundred forty-eight psychiatric outpatients were administered a semistructured diagnostic interview. We inquired about all symptoms of depression for all patients. The mean sensitivity of the 9 criteria in the nonobese and obese patients was nearly identical (74.6% vs 74.3%). The mean specificity was slightly higher in the nonobese patients (82.0% vs 79.5%). No symptom was more specific in the obese than the nonobese patients, whereas the specificity of increased appetite, increased weight, and fatigue was more than 5% lower in the obese patients. Increased appetite, increased weight, hypersomnia, and fatigue had a higher sensitivity in the obese than the nonobese patients, whereas decreased appetite, weight loss, and diminished concentration had a higher sensitivity in the nonobese than the obese patients. Thus, although there were small differences between obese and nonobese patients in the operating characteristics of some symptoms, the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for MDD generally performed equally well for obese and nonobese patients. PMID- 21295221 TI - Examining the role of race and ethnicity in relapse rates of major depressive disorder. AB - OBJECTIVE: We test the hypothesis that racial or ethnic differences exist in relapse rates to fluoxetine discontinuation in major depressive disorder (MDD). METHOD: Data are from a prospective study examining the relapse rates secondary to fluoxetine discontinuation in MDD. Subjects in the discontinuation phase consisted of 255 adults aged 18 to 65: 214 subjects who self-identified as white, 22 as African American, 13 as Latino American, and 6 as Asian American. RESULTS: In both the fluoxetine and placebo groups, no statistically significant differences emerged when comparing time to relapse for minority groups as compared to the white population. Adjusting for statistically significant predictors of relapse (symptom severity, neurovegetative symptom pattern, sex) and for educational level did not change the outcome of the survival analyses. CONCLUSIONS: Although the size of minority groups in this sample was modest, in a randomized, controlled trial setting, minority and white patients may have similar rates of relapse in MDD. This finding reinforces the importance of maintenance treatment in relapse for both minority as well as white patients with MDD. Given the self-selecting nature of clinical trials, future studies are needed to further examine the potential influence of underlying cultural factors on clinical outcomes in minority populations. PMID- 21295222 TI - Neurocognitive functioning and suicidality in schizophrenia spectrum disorders. AB - OBJECTIVE: The aim of this study was to investigate whether suicide attempters had higher IQ, better executive functioning, or were more impulsive as measured by neuropsychological tests than non-attempters in a group of patients with schizophrenia spectrum disorders. METHOD: One hundred seventy-four patients with schizophrenia spectrum disorders were assessed with a clinical interview for diagnosis, suicidality, symptoms and function, and underwent an extensive neurocognitive test battery. RESULTS: There were no statistically significant differences in any neurocognitive domains between lifetime suicide attempters and non-attempters, or between patients with different rates of suicide attempts. Currently suicidal patients were significantly more impulsive (had poorer inhibitory control) than currently non-suicidal patients, but this difference was mediated by positive psychotic symptoms. CONCLUSION: The findings indicate that among patients with schizophrenia spectrum disorders, there are no significant differences in IQ or neurocognitive functioning between suicide attempters and non-attempters. PMID- 21295223 TI - The association among interpersonal problems, binge behaviors, and self-esteem, in the assessment of obese individuals. AB - OBJECTIVES: Although disordered eating has been assumed to be associated with interpersonal problems, there is a lack of research regarding the relationship between interpersonal problems and obesity. This study explored associations among self-esteem, binge behaviors, and interpersonal problems in obese individuals, by contrasting obese persons with overweight persons, and to investigate whether body mass index (BMI), binge behaviors, and self-esteem predict interpersonal problems in obese individuals. METHODS: A group of nonobese overweight people (n = 65; BMI range, 25-29.9 kg/m2) and a group of obese people (n = 78; BMI >35 kg/m2) were selected from 224 people attending a mental health care service specializing in eating disorders in Palermo (Italy). Seventy-eight percent of participants were female. All participants filled in the following measures: the Inventory of Interpersonal problems-short version, the Binge Eating Scale, and the Rosenberg Self-esteem Scale. RESULTS: The findings showed that 4 domains of interpersonal problems were associated with binge behaviors and self esteem in obese participants. Moreover, the relationship between binge behaviors and interpersonal problems was partially mediated by self-esteem. CONCLUSIONS: Given the poor prognosis for the long-term management of obesity, it could be important for clinicians to carefully assess patients' interpersonal functioning and its relationship to self-esteem and binge behaviors, especially with respect to treatment-seeking obese patients. PMID- 21295224 TI - Subjective quality of life in patients with chronic schizophrenia: relationships between psychosocial and clinical characteristics. AB - BACKGROUND: Using the theoretical framework of quality of life (QOL), many studies have demonstrated that the beliefs individuals hold about their QOL are important in predicting health outcomes. This study tested the Taiwanese version of the World Health Organization Quality of Life-Brief (WHOQOL-BREF) assessment in schizophrenia patients. The WHOQOL-BREF is a cross-cultural and widely used measure for assessing health-related QOL. This brief version of the questionnaire derived from the concepts included in the 100-item WHOQOL questionnaire was adapted for use in Taiwan. METHODS: In the current cross-sectional study, 104 patients who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for schizophrenia or schizoaffective disorder according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria were recruited and independently interviewed using the Taiwanese version of the WHOQOL-BREF. Patients were also examined using various other scales assessing insight, symptom severity, general psychopathology, and antipsychotic-induced side effects. In addition, we analyzed demographic data, clinical variables, and several self-rating scales as correlates of the Taiwanese version of the WHOQOL BREF. RESULTS: As predicted, age, onset of illness, insight measures, symptom severity, general psychopathology, and antipsychotic-induced side effects were all significantly related to the QOL scores. Multiple regression analyses revealed that depressive symptoms, antipsychotic-induced parkinsonism side effects, hopelessness, and age at illness onset were the 4 strongest predictors of subjective QOL in schizophrenia patients. These variables accounted for 39.2% of the total variance of this QOL model. CONCLUSIONS: The results suggest that the WHOQOL-BREF is a promising model for mental assessing health problems in schizophrenia patients. Furthermore, the present findings highlight the importance of understanding the complex nature of the concept of QOL. Our study also supports the belief that different domains of QOL are likely to have different predictors. PMID- 21295225 TI - Investigating SAPAP3 variants in the etiology of obsessive-compulsive disorder and trichotillomania in the South African white population. AB - BACKGROUND: Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder characterized by repeated obsessions and compulsions. Trichotillomania (TTM), a psychiatric disorder characterized by repetitive hairpulling, is presently classified as an impulse control disorder, but has also been viewed as an obsessive-compulsive spectrum disorder. Both conditions are complex disorders, with evidence from family and twin studies indicating that their etiology includes a genetic component. Results from a recent knockout animal model suggest that SAP90/PSD95-associated protein 3 (SAPAP3) may be involved in the pathophysiology of both disorders. METHODS: Seven polymorphic variants distributed across the gene encoding SAPAP3 were genotyped in South African white OCD (n = 172), TTM (n = 45), and control (n = 153) subjects. Single-locus and haplotype analyses were conducted to determine association between genetic variants and subjects with OCD, TTM, and controls. RESULTS: Although single-locus analysis revealed a significant association between rs11583978 in SAPAP3 and TTM, this association was nonsignificant after correction for multiple testing. In the OCD group, a significant association was observed between earlier age at onset and the A-T-A-T (rs11583978-rs7541937-rs6662980-rs4652867) haplotype compared with the C-G-G-G haplotype. CONCLUSIONS: This study generated preliminary evidence to link SAPAP3 variants to the development of earlier onset OCD. Future studies should concentrate on locating the susceptibility variant(s) by focusing on functional polymorphisms within SAPAP3. PMID- 21295226 TI - Monoamine oxidase A regulates antisocial personality in whites with no history of physical abuse. AB - OBJECTIVE: Preclinical and human family studies clearly link monoamine oxidase A (MAOA) to aggression and antisocial personality (ASP). The 30-base pair variable number tandem repeat in the MAOA promoter regulates MAOA levels, but its effects on ASP in humans are unclear. METHODS: We evaluated the association of the variable number tandem repeat of the MAOA promoter with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, ASP disorder (ASPD) traits in a community sample of 435 participants from the Hopkins Epidemiology of Personality Disorders Study. RESULTS: We did not find an association between the activity of the MAOA allele and ASPD traits; however, among whites, when subjects with a history of childhood physical abuse were excluded, the remaining subjects with low-activity alleles had ASPD trait counts that were 41% greater than those with high-activity alleles (P < .05). CONCLUSION: The high-activity MAOA allele is protective against ASP among whites with no history of physical abuse, lending support to a link between MAOA expression and antisocial behavior. PMID- 21295227 TI - Sex difference in the rates and co-occurring conditions of psychiatric symptoms in incoming college students in Taiwan. AB - OBJECTIVE: The authors investigated the sex difference in the rates and co occurring patterns in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-referenced psychiatric symptoms among incoming first-year college students in Taiwan. METHODS: This was a college-based questionnaire survey. The participants included 2731 incoming first-year college students (male, 52.4%; mean age, 19.3 +/- 2.6 years). The participants completed the Chinese version of the Adult Self Report Inventory-4 for the assessment of a wide range of psychiatric symptoms according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition symptom criteria. The participant rate was 74.1%. RESULTS: There were 55% of the participants having at least one psychiatric symptom. Symptoms of agoraphobia, body dysmorphic, and gender identity disorder were more prevalent in women; those of obsession-compulsion, tics, conduct problems, schizoid personality, and kleptomania were more prevalent in men. The magnitude of symptom correlations between compulsion and gender identity disorder, dysthymia, and antisocial personality, and between gender identity disorder and schizophrenia was significantly greater in male participants, whereas that between conduct problems and obsession and motor tics was significantly greater in female participants. CONCLUSIONS: The Chinese version of the Adult Self Report Inventory-4 identified similar sex difference in psychiatric symptoms as Western studies. The sex difference in co-occurring psychiatric conditions warrants further investigation. PMID- 21295228 TI - Assessing pain in depression: what do ratings on unidimensional pain scales really mean? AB - OBJECTIVE: The study aims to determine which dimensions of pain-somatosensory, affective, or evaluative-would predict unidimensional pain scores in patients with major depressive disorder (MDD); compare the results with findings in cancer and chronic musculoskeletal pain patients; and examine the relationship between pain complaints and psychopathology. METHODS: This is a 3-month prospective, observational study. Ninety-one Chinese patients were enrolled during an acute episode of MDD. Multidimensional Affect and Pain Survey (MAPS) was used to assess the multidimensional aspects of pain. Unidimensional pain intensity was evaluated using verbal rating scale (VRS) and visual analog scale (VAS). Hamilton Rating Scale for Depression and Hospital Anxiety and Depression Scale were used to assess depressive and anxiety symptoms. RESULTS: The VRS and VAS pain scores were more highly correlated with MAPS somatosensory supercluster than with Hamilton Rating Scale for Depression, Hospital Anxiety and Depression Scale, and MAPS emotional and well-being superclusters. Hierarchical regression analyses showed that unidimensional pain scores were predicted better by MAPS somatosensory than by emotional clusters. The explained variance of VRS and VAS scores could be improved by 9% to 16% by adding somatosensory clusters after controlling for emotional clusters, whereas 1% to 4% of the variance was improved by adding emotional clusters after controlling for somatosensory clusters. Pain intensity was more closely related to anxiety symptoms than to depressive symptoms cross sectionally and longitudinally. CONCLUSION: Our data suggest that pain and emotional symptoms in MDD are not entirely related. In cases in which pain symptoms are severe or remain persistent despite treatment of depression, specific strategy targeting pain may be needed. PMID- 21295229 TI - Factor structure and psychometric properties of the Connor-Davidson Resilience Scale among Chinese adolescents. AB - OBJECTIVES: Resilience refers to psychological characteristics that promote effective coping and positive adaptation in adversity. This study investigated the factor structure and psychometric properties of the Chinese version of the Connor-Davidson Resilience Scale (CD-RISC) among adolescents. METHODS: A total of 2914 Chinese adolescents living in Chengdu, Sichuan, completed the CD-RISC 1 month after the 2008 Sichuan earthquake. They also self-administered the Multidimensional Scale of Perceived Social Support, the Children's Depression Inventory, and the Screen for Child Anxiety Related Emotional Disorders. With confirmatory factor analysis, various factor structures of the CD-RISC reported in previous studies (eg, the 5- and 3-factor models) were examined at the first order level; and a single factor of resilience was investigated at the second order level in this sample. The internal consistency and concurrent validity were investigated. Sex and age differences were also examined. RESULTS: Confirmatory factor analysis results showed that the 5-factor model originally derived among US community adults was replicated in our sample, and these 5 factors also loaded on a higher-order "resilience" factor. The Cronbach alpha coefficient was 0.89. The resilience scores demonstrated expected positive correlation with social support (r = 0.44) and negative correlations with depression (r = -0.38) and anxiety (r = -0.25) (Ps < .001). Male participants reported higher resilience scores than female participants, and younger participants also reported higher resilience scores than older participants. CONCLUSIONS: The Chinese version of the CD-RISC was demonstrated to be a reliable and valid measurement in assessing resilience among Chinese adolescents. PMID- 21295230 TI - The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Defensive Functioning Scale: a validity study. AB - OBJECTIVE: We assess the convergent and predictive validity of the Defensive Functioning Scale (DFS) with measures of life events, including childhood abuse and adult partner victimization; dimensions of psychopathology, including axis I (depressive) and axis II (borderline personality disorder) symptoms; and quality of object relations. METHOD: One hundred and ten women from a university-based urban primary care clinic completed a research interview from which defense mechanisms were assessed. The quality of object relations was also assessed from interview data. The women completed self-report measures assessing depression, borderline personality disorder symptoms, childhood physical and sexual abuse, and adult partner physical and sexual victimization. RESULTS: Inter-rater reliability of the scoring of the DFS levels was good. High adaptive defenses were positively correlated with the quality of object relations and pathological defenses were positively correlated with childhood and adult victimization and symptom measures. Although major image distorting defenses were infrequently used, they were robustly correlated with all study variables. In a stepwise multiple regression analysis, major image distorting defenses, depressive symptoms, and minor image distorting defenses significantly predict childhood victimization, accounting for 37% of the variance. In a second stepwise multiple regression analysis, borderline personality disorder symptoms and disavowal defenses combined to significantly predict adult victimization, accounting for 16% of the variance. CONCLUSIONS: The DFS demonstrates good convergent validity with axis I and axis II symptoms, as well as with measures of childhood and adult victimization and object relations. The DFS levels add nonredundant information to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition beyond axis I and axis II. PMID- 21295232 TI - Guest editorial. PMID- 21295233 TI - Validation of the comprehensive ICF core set for osteoarthritis: the perspective of physical therapists. AB - BACKGROUND AND PURPOSE: Osteoarthritis is a common chronic disease associated with functional impairments and activity limitations, as well as participation restrictions. The Comprehensive International Classification of Functioning, Disability and Health (ICF) Core Set for Osteoarthritis is an application of the ICF and represents the typical spectrum of problems in functioning of patients with osteoarthritis. OBJECTIVE: To validate the Comprehensive ICF Core Set for Osteoarthritis from the perspective of physical therapists. METHODS: Physical therapists experienced in the treatment of patients with osteoarthritis were asked about patients' problems, resources and aspects of the environmental factors treated by physical therapists in patients with osteoarthritis in a three round, electronic-mail survey using the Delphi technique. Responses were linked to the ICF. RESULTS: Seventy-two experts from 22 countries named 744 meaningful concepts that covered all ICF components. One hundred and fifty-two ICF categories were linked to these answers, 32 concepts were linked to the not-yet developed personal factors component, and 14 issues were not covered by a single ICF category. Twelve ICF categories were not represented in the Comprehensive ICF Core Set for Osteoarthritis, although at least 75% of the participants rated them as important. DISCUSSION AND CONCLUSION: The content validity of the ICF was widely supported by the physical therapists. However, several issues were raised that were not covered and need to be investigated further. PMID- 21295234 TI - HIV/AIDS: use of the ICF in Brazil and South Africa--comparative data from four cross-sectional studies. AB - INTRODUCTION: Human immunodeficiency virus (HIV) is a serious disease which can be associated with various activity limitations and participation restrictions. The aim of this paper was to describe how HIV affects the functioning and health of people within different environmental contexts, particularly with regard to access to medication. METHOD: Four cross-sectional studies, three in South Africa and one in Brazil, had applied the International Classification of Functioning, Disability and Health (ICF) as a classification instrument to participants living with HIV. Each group was at a different stage of the disease. Only two groups had had continuing access to antiretroviral therapy. The existence of these descriptive sets enabled comparison of the disability experienced by people living with HIV at different stages of the disease and with differing access to antiretroviral therapy. RESULTS: Common problems experienced in all groups related to weight maintenance, with two-thirds of the sample reporting problems in this area. Mental functions presented the most problems in all groups, with sleep (50%, 92/185), energy and drive (45%, 83/185), and emotional functions (49%, 90/185) being the most affected. In those on long-term therapy, body image affected 93% (39/42) and was a major problem. The other groups reported pain as a problem, and those with limited access to treatment also reported mobility problems. Cardiopulmonary functions were affected in all groups. CONCLUSION: Functional problems occurred in the areas of impairment and activity limitation in people at advanced stages of HIV, and more limitations occurred in the area of participation for those on antiretroviral treatment. The ICF provided a useful framework within which to describe the functioning of those with HIV and the impact of the environment. Given the wide spectrum of problems found, consideration could be given to a number of ICF core sets that are relevant to the different stages of HIV disease. PMID- 21295235 TI - ICF participation restriction is common in frail, community-dwelling older people: an observational cross-sectional study. AB - OBJECTIVES: To determine the extent of participation restriction in a sample of frail older people, and to identify the domains of participation that are most restricted. A secondary aim was to determine which health and demographic factors were associated with participation restriction. DESIGN: An observational cross sectional study. SETTING: Adults recently discharged from an aged care and rehabilitation service in Australia who were enrolled in a clinical trial. PARTICIPANTS: One hundred and eighty-one community-dwelling adults aged over 70 years (mean age 84, standard deviation 5.7) who met the Cardiovascular Health Study criteria for frailty, had a Mini Mental State Examination score over 18 and a predicted life expectancy exceeding 12 months. MAIN OUTCOME MEASURES: Participation restriction was evaluated using the Reintegration to Normal Living Index. RESULTS: Eighty percent of subjects reported participation restriction in at least one aspect of their life. Restricted participation was most prevalent in the areas of work in the home or community (114/181, 63%) and community mobility (92/181, 51%), and least common with regard to interpersonal relationships (9/181, 5%). Multivariate regression analysis showed that grip strength, mood, number of medical conditions and mobility were independently and significantly (P<0.05) associated with participation restriction, and explained 29% of the variance in participation restriction. Cognition and living alone were not significantly associated with participation restriction. CONCLUSIONS: Participation restriction was common in this sample of frail, community-dwelling older people. It was associated with factors from multiple levels of the International Classification of Functioning, Disability and Health. Further research is suggested to investigate the causes and treatment of participation restriction. PMID- 21295236 TI - Does the Comprehensive International Classification of Functioning, Disability and Health (ICF) Core Set for Breast Cancer capture the problems in functioning treated by physiotherapists in women with breast cancer? AB - OBJECTIVE: The Comprehensive International Classification of Functioning, Disability and Health (ICF) Core Set for Breast Cancer is an application of the ICF, and represents the typical spectrum of problems in functioning and contextual factors that may influence functioning of patients with breast cancer. The objective of this study was to examine the content validity of this ICF core set from the perspective of physiotherapists. DESIGN: Physiotherapists from around the world experienced in the treatment of patients with breast cancer were interviewed about patients' problems, patients' resources and environmental aspects that physiotherapists take care of in a three-round survey using the Delphi technique. The responses were linked to the ICF. The degree of agreement was calculated by means of the Kappa statistic. PARTICIPANTS: Physiotherapists experienced in breast cancer treatment. RESULTS: Fifty-nine physiotherapists from 19 countries named 769 problems treated by physiotherapists in patients with breast cancer. One hundred and sixty-six ICF categories were linked to these answers. Nineteen ICF categories reached >75% agreement among the physiotherapists but are not represented in the Comprehensive ICF Core Set for Breast Cancer. Ten concepts were linked to the not-yet-classified personal factors component. Eleven concepts are not covered by the ICF. The Kappa coefficient for the agreement between the two persons who performed the linking was 0.66 (95% bootstrapped confidence interval 0.63 to 0.68). CONCLUSIONS: The content validity of the Comprehensive ICF Core Set for Breast Cancer was largely supported by the physiotherapists. However, several issues were raised which were not covered and these need to be investigated further. PMID- 21295237 TI - Impact of using the ICF framework as an assessment tool for students in paediatric physiotherapy: a preliminary study. AB - OBJECTIVE: To determine if clinical assessment of children with neurological conditions by physiotherapy students was improved through the overt use of the International Classification of Functioning, Disability and Health (ICF). DESIGN AND PARTICIPANTS: A retrospective, pragmatic audit of practice using written patient assessments completed by third-year physiotherapy students. Assessments completed by third-year students in 2008 were compared with assessments completed by third-year students in 2009. The assessment format used in 2008 was very loosely based on the ICF model, while the 2009 assessments made rigorous use of the ICF approach. SETTING: Two schools for children with special needs to which physiotherapy students from the Department of Health and Rehabilitation Sciences, Faculty of Health Sciences, Division of Physiotherapy, University of Cape Town are sent for clinical exposure. METHOD: A score sheet was drawn up to evaluate specific criteria in each assessment, using a five-point marking scheme. The mark sheet was tested for reliability. All assessments were evaluated independently using the score sheet by two external physiotherapists who were blind to the purpose of the exercise. RESULTS: There was a significant difference between the scores obtained on the score sheet for the 2008 group and the 2009 group. The 2009 group obtained a median score of 60, compared with a median score of 50 for the 2008 group (median difference between groups 9.2, 95% confidence interval 4.2 to 14.1). The overall impression mark given to the 2009 group was also higher than that given to the 2008 group, with a median difference between the groups of 5.9 (95% confidence interval 3.2 to 12.7). It would appear that the 2009 students, using the ICF framework for assessing patients, were able to include more function-related information in their assessments, resulting in a more holistic assessment. CONCLUSION: Teaching students to use the ICF framework when assessing paediatric patients encourages clinical reasoning and an improved holistic approach to identifying the patient's problems in context. This, in turn, enables the student to plan a more appropriate intervention treatment, to the patient's benefit. PMID- 21295238 TI - Introducing the ICF: the development of an online resource to support learning, teaching and curriculum design. AB - The International Classification of Functioning, Disability and Health (ICF) was adopted as one of the key models to support early health professional learning across a suite of new preregistration health science courses. It was decided that an online resource should be developed to enable students, course designers and teaching staff, across all disciplines, to have access to the same definitions, government policies and other supporting information on disability. As part of the comprehensive curriculum review, enquiry-based learning was adopted as the educational approach. Enquiry-based learning promotes deeper learning by encouraging students to engage in authentic challenges. As such, it was important that the online resource was not merely a site for accessing content, but enabled students to make decisions about where else to explore for credible information about the ICF. The selection of a host location that all students and staff could access meant that the resource could not be located in the existing online learning management system. Construction using software being trialled by the library at La Trobe University allowed for the required access, as well as alignment with an enquiry-based learning approach. Consultation for the content of the online resource included formal and informal working groups on curriculum review. The published version included resources from the World Health Organization, examples of research completed within different disciplines, a test of knowledge and a preformatted search page. The format of the online resource allows for updating of information, and feedback on the utilisation of the software has been used to enhance the student experience. The key issues for the development of this online resource were accessibility for students and staff, alignment with the adopted educational approach, consultation with all disciplines, and ease of modification of information and format once published. PMID- 21295239 TI - Reliability and diagnostic validity of the slump knee bend neurodynamic test for upper/mid lumbar nerve root compression: a pilot study. AB - OBJECTIVES: It has been proposed that neurodynamic examination can assist differential diagnosis of upper/mid lumbar nerve root compression; however, the diagnostic validity of many of these tests has yet to be established. This pilot study aimed to establish the diagnostic validity of the slump knee bend neurodynamic test for upper/mid lumbar nerve root compression in subjects with suspected lumbosacral radicular pain. DESIGN: Two independent examiners performed the slump knee bend test on subjects with radicular leg pain. Inter-tester reliability was calculated using the kappa coefficient. Slump knee bend test results were compared with magnetic resonance imaging findings, and diagnostic accuracy measures were calculated including sensitivity, specificity, predictive values and likelihood ratios. SETTING: Orthopaedic spinal clinic, secondary care. PARTICIPANTS: Sixteen patients with radicular leg pain. RESULTS: All four subjects with mid lumbar nerve root compression on magnetic resonance imaging were correctly identified with the slump knee bend test; however, it was falsely positive in two individuals without the condition. Inter-tester reliability for the slump knee bend test using the kappa coefficient was 0.71 (95% confidence interval 0.33 to 1.0). Diagnostic validity calculations for the slump knee bend test (95% confidence intervals) were: sensitivity, 100% (40 to 100%); specificity, 83% (52 to 98%); positive predictive value, 67% (22 to 96%); negative predictive value, 100% (69 to 100%); positive likelihood ratio, 6.0 (1.58 to 19.4); and negative likelihood ratio, 0 (0 to 0.6). CONCLUSIONS: Results indicate good inter-tester reliability and suggest that the slump knee bend test has potential to be a useful clinical test for identifying patients with mid lumbar nerve root compression. Further investigation is needed on larger numbers of patients to confirm these findings. PMID- 21295240 TI - Ankle positioning and knee perturbation affect temporal recruitment of the vasti muscles in people with patellofemoral pain. AB - OBJECTIVES: To compare the temporal recruitment of the vastus medialis obliquus (VMO) and vastus lateralis (VL) during voluntary ankle movements and perturbed standing in people with patellofemoral pain, and to determine the effects of different reflex and voluntary postural exercise tasks on VMO facilitation. DESIGN: Repeated-measures design. PARTICIPANTS: Twenty-three subjects with patellofemoral pain. INTERVENTIONS: Quadriceps reflex contraction in response to postero-anterior knee perturbations was measured with three crural muscle contraction conditions and three postural exercises (semi-squatting, tip-toeing and heel standing). MAIN OUTCOME MEASURES: The electromyographic (EMG) onset time of the VMO and VL during each task was measured and compared across the different tasks. RESULTS: The mean EMG onset time of the VMO was later than that of the VL in the voluntary tasks such as tip-toeing (VMO 95.3ms vs VL 36.4ms, mean difference 58.9ms, 95% confidence interval -33.7 to 151.5ms), whereas earlier VMO activation was found in the perturbation tests such as toe standing (VMO 17.6ms vs VL 22.9ms, mean difference -5.3ms, 95% confidence interval -25.3 to 14.7ms). CONCLUSION: These findings suggest the potential benefits of unexpected perturbation activities for facilitating VMO activation. The clinical applications of perturbation tasks in rehabilitation exercise programmes and the underlying mechanisms warrant further investigation. PMID- 21295241 TI - Discrete-event computer simulation methods in the optimisation of a physiotherapy clinic. AB - OBJECTIVE: To develop a computer model to analyse the performance of a standard physiotherapy clinic in the city of Rio de Janeiro, Brazil. DESIGN AND SETTING: The clinic receives an average of 80 patients/day and offers 10 treatment modalities. Details of patient procedures and treatment routines were obtained from direct interviews with clinic staff. Additional data (e.g. arrival time, treatment duration, length of stay) were obtained for 2000 patients from the clinic's computerised records from November 2005 to February 2006. METHODS AND MAIN OUTCOME MEASURES: A discrete-event model was used to simulate the clinic's operational routine. The initial model was built to reproduce the actual configuration of the clinic, and five simulation strategies were subsequently implemented, representing changes in the number of patients, human resources of the clinic and the scheduling of patient arrivals. RESULTS: Findings indicated that the actual clinic configuration could accept up to 89 patients/day, with an average length of stay of 119minutes and an average patient waiting time of 3minutes. When the scheduling of patient arrivals was increased to an interval of 6.5minutes, maximum attendance increased to 114 patients/day. For the actual clinic configuration, optimal staffing consisted of three physiotherapists and 12 students. According to the simulation, the same 89 patients could be attended when the infrastructure was decreased to five kinesiotherapy rooms, two cardiotherapy rooms and three global postural reeducation rooms. CONCLUSIONS: The model was able to evaluate the capacity of the actual clinic configuration, and additional simulation strategies indicated how the operation of the clinic depended on the main study variables. PMID- 21295242 TI - The evidence for and against 'PhysioDirect' telephone assessment and advice services. AB - Patients have experienced inadequate access to physiotherapy since the inception of the National Health Service (NHS). Over the last 50 years, many initiatives have been introduced to address this problem, the most recent being a new patient management pathway known as 'PhysioDirect'. Within these services, physiotherapists offer initial assessment and advice by telephone, sometimes supported by computerised algorithms, and patients are sent written self management and exercise advice by post. For some patients, face-to-face physiotherapy care will be offered where this is considered to be more appropriate. Although several such services have been developed across the UK, there is no robust evidence about clinical and cost-effectiveness, nor the acceptability of PhysioDirect to patients, physiotherapists or primary care organisations. This debate article summarises models of PhysioDirect, the links to other healthcare developments and relevant evidence to date about this type of service. By providing a summary of the arguments for, and key concerns about, PhysioDirect, this article stresses the need for more definitive evidence from high-quality randomised controlled trials before widespread roll-out across the NHS. PMID- 21295243 TI - Measuring quality of life in Parkinson's disease: selection of-an-appropriate health-related quality of life instrument. AB - There is growing awareness of the need to measure quality of life (QOL) in people with Parkinson's disease during routine physiotherapy assessment. This paper highlights why it is important for clinicians to focus particularly on health related QOL (HRQOL) when assessing people with this disabling and progressive neurological condition, and provides a guide for selection of the most appropriate instruments for measuring HRQOL. Using measures of health utility, health status and wellbeing, physiotherapists can better understand the social, physical and emotional consequences of Parkinson's disease. PMID- 21295244 TI - Editorial comment. PMID- 21295245 TI - Editorial comment. PMID- 21295246 TI - Numbers and types of nonbladder syndromes as risk factors for interstitial cystitis/painful bladder syndrome. AB - OBJECTIVES: To examine the interaction of types and numbers of antecedent nonbladder syndromes (NBSs) to seek clues to the pathogenesis of interstitial cystitis/painful bladder syndrome (IC/PBS). Numerous case series have shown IC/PBS to be associated with several syndromes that do not include bladder symptoms. In a previously reported case-control study, we confirmed these findings and found that such nonbladder syndromes often preceded the onset of IC/PBS. METHODS: Incident female IC/PBS cases (n = 312) and matched controls were compared for 11 antecedent NBSs. The odds ratios (ORs) for IC/PBS according to the number of antecedent NBSs per person were calculated. From this model, each NBS was serially removed, and the calculations for the ORs were repeated using the remaining 10 NBSs. We assessed the types of NBSs included in each subgroup formed by the number of NBSs. RESULTS: The ORs for IC/PBS increased with the increasing number of antecedent NBSs. The types of NBSs were interchangeable in calculating these ORs. The distribution of the types of NBSs was skewed, with allergy overrepresented in those with few NBSs, and the classic functional somatic syndromes of fibromyalgia, chronic fatigue syndrome, and irritable bowel syndrome overrepresented in those with many NBSs. CONCLUSIONS: Two main hypotheses were generated. One was that the incidence of a NBS initiated a process that contributed to the emergence of other NBSs and IC/PBS. The second was that each NBS and IC/PBS was a manifestation of a common, shared pathogenesis. It is likely that a well-designed prospective study will be necessary to distinguish between these 2 hypotheses. PMID- 21295247 TI - Editorial comment. PMID- 21295250 TI - Editorial comment. PMID- 21295251 TI - Editorial comment. PMID- 21295253 TI - Editorial comment. PMID- 21295255 TI - Editorial comment. PMID- 21295257 TI - Editorial comment. PMID- 21295258 TI - Editorial comment. PMID- 21295259 TI - Re: Bag et al.: One week of nitrofurantoin before percutaneous nephrolithotomy significantly reduces upper tract infection and urosepsis: a prospective controlled study (Urology 2010;77:45-49). PMID- 21295261 TI - Re: Feifer et al.: Utility of urine cytology in workup of asymptomatic microscopic hematuria in low-risk patients (Urology 2010;75:1278-1282). PMID- 21295262 TI - Reply by the authors to a letter by Chueh et al. (Urology 2010;77:253-254). PMID- 21295264 TI - An epigenetic Tet a Tet with pluripotency. AB - DNA and chromatin-modifying enzymes establish an ESC/iPSC-specific epigenomic landscape that is linked to a network of pluripotency genes and influences differentiation potential. In this issue of Cell Stem Cell, Koh et al. (2011) highlight Tet1 and Tet2 as key players in this network of coordinated genetic and epigenetic control. PMID- 21295265 TI - A comprehensive transcriptional landscape of human hematopoiesis. AB - Recently in Cell, Novershtern et al. (2011) reported a comprehensive transcriptome analysis of human hematopoiesis, combined with sophisticated bioinformatics analysis and high-throughput DNA binding data for multiple transcription factors. The resulting map of regulatory interactions controlling stem cell differentiation provides a valuable resource for identification of novel hematopoietic regulators. PMID- 21295266 TI - What your heart doth know. AB - Combining embryological insight with careful analysis of early stage cardiomyocyte differentiation, Kattman et al. (2011) in this issue of Cell Stem Cell have defined minimal culture conditions to efficiently produce cardiomyocytes from hESCs and hiPSCs. The lessons learned are applicable to the derivation of other organotypic cell types. PMID- 21295267 TI - A twist of cell fate. AB - Individuals carrying deleterious BRCA1 mutations typically develop basal-like rather than luminal breast cancers. In this issue of Cell Stem Cell, Proia et al. (2011) study breast tissue from women with heterozygous BRCA1 mutations and identify molecular mechanisms that regulate mammary progenitor cell differentiation and bias toward subsequent basal-like tumor formation. PMID- 21295268 TI - Unraveling epigenetic landscapes: the enigma of enhancers. AB - In recent publications in Nature and PNAS, Rada-Iglesias et al. (2010) and Creyghton et al. (2010) have uncovered unique chromatin signatures of developmental enhancers marking active, primed, or silent genes in human and mouse embryonic stem cells. PMID- 21295269 TI - An electrifying iPSC disease model: long QT syndrome type 2 and heart cells in a dish. AB - In a recent Nature paper, Itzhaki et al. (2011) generate induced pluripotent stem cells (iPSCs) from patients with a potentially fatal inherited arrhythmia, long QT syndrome type 2. Cardiomyocytes differentiated from the patient-derived iPSCs exhibit the hallmark cardiac electrical signatures of the disease, which can be reversed by pharmacological intervention. PMID- 21295270 TI - Policy uncertainty and the conduct of stem cell research. AB - A survey of U.S. stem cell scientists shows that uncertainty following the legal challenge to the Obama Administration's hESC research policy has negative scientific and economic impacts and affects a range of stem cell scientists, not just those working with hESCs. The international implications of these results are also discussed. PMID- 21295271 TI - Critical appraisal of the side population assay in stem cell and cancer stem cell research. AB - The "Side Population" (SP) discrimination assay is a flow cytometry method used to detect stem cells based on the dye efflux properties of ABC transporters. We discuss the SP assay and its applications in stem cell biology, with an emphasis on the technical challenges related to sample preparation, data acquisition, analysis, and interpretation. We highlight the value of multicolor phenotyping, the impact of DNA ploidy, and the importance of distinguishing graft versus host cells for an appropriate SP discrimination. To improve the consistency and reliability of data between laboratories, we propose a set of recommendations for SP assay data reporting. PMID- 21295272 TI - Genetic predisposition directs breast cancer phenotype by dictating progenitor cell fate. AB - Women with inherited mutations in the BRCA1 gene have increased risk of developing breast cancer but also exhibit a predisposition for the development of aggressive basal-like breast tumors. We report here that breast epithelial cells derived from patients harboring deleterious mutations in BRCA1 (BRCA1(mut /+) give rise to tumors with increased basal differentiation relative to cells from BRCA1+/+ patients. Molecular analysis of disease-free breast tissues from BRCA1(mut /+) patients revealed defects in progenitor cell lineage commitment even before cancer incidence. Moreover, we discovered that the transcriptional repressor Slug is an important functional suppressor of human breast progenitor cell lineage commitment and differentiation and that it is aberrantly expressed in BRCA1(mut /+) tissues. Slug expression is necessary for increased basal-like phenotypes prior to and after neoplastic transformation. These findings demonstrate that the genetic background of patient populations, in addition to affecting incidence rates, significantly impacts progenitor cell fate commitment and, therefore, tumor phenotype. PMID- 21295273 TI - DeltaNp63alpha is an oncogene that targets chromatin remodeler Lsh to drive skin stem cell proliferation and tumorigenesis. AB - The p53 homolog p63 is essential for development, yet its role in cancer is not clear. We discovered that p63 deficiency evokes the tumor-suppressive mechanism of cellular senescence, causing a striking absence of stratified epithelia such as the skin. Here we identify the predominant p63 isoform, DeltaNp63alpha, as a protein that bypasses oncogene-induced senescence to drive tumorigenesis in vivo. Interestingly, bypass of senescence promotes stem-like proliferation and maintains survival of the keratin 15-positive stem cell population. Furthermore, we identify the chromatin-remodeling protein Lsh as a new target of DeltaNp63alpha that is an essential mediator of senescence bypass. These findings indicate that DeltaNp63alpha is an oncogene that cooperates with Ras to promote tumor-initiating stem-like proliferation and suggest that Lsh-mediated chromatin remodeling events are critical to this process. PMID- 21295274 TI - Hair follicle stem cells provide a functional niche for melanocyte stem cells. AB - In most stem cell systems, the organization of the stem cell niche and the anchoring matrix required for stem cell maintenance are largely unknown. We report here that collagen XVII (COL17A1/BP180/BPAG2), a hemidesmosomal transmembrane collagen, is highly expressed in hair follicle stem cells (HFSCs) and is required for the maintenance not only of HFSCs but also of melanocyte stem cells (MSCs), which do not express Col17a1 but directly adhere to HFSCs. Mice lacking Col17a1 show premature hair graying and hair loss. Analysis of Col17a1 null mice revealed that COL17A1 is critical for the self-renewal of HFSCs through maintaining their quiescence and immaturity, potentially explaining the mechanism underlying hair loss in human COL17A1 deficiency. Moreover, forced expression of COL17A1 in basal keratinocytes, including HFSCs, in Col17a1-null mice rescues MSCs from premature differentiation and restores TGF-beta signaling, demonstrating that HFSCs function as a critical regulatory component of the MSC niche. PMID- 21295275 TI - Redox regulation by Keap1 and Nrf2 controls intestinal stem cell proliferation in Drosophila. AB - In Drosophila, intestinal stem cells (ISCs) respond to oxidative challenges and inflammation by increasing proliferation rates. This phenotype is part of a regenerative response, but can lead to hyperproliferation and epithelial degeneration in the aging animal. Here we show that Nrf2, a master regulator of the cellular redox state, specifically controls the proliferative activity of ISCs, promoting intestinal homeostasis. We find that Nrf2 is constitutively active in ISCs and that repression of Nrf2 by its negative regulator Keap1 is required for ISC proliferation. We further show that Nrf2 and Keap1 exert this function in ISCs by regulating the intracellular redox balance. Accordingly, loss of Nrf2 in ISCs causes accumulation of reactive oxygen species and accelerates age-related degeneration of the intestinal epithelium. Our findings establish Keap1 and Nrf2 as a critical redox management system that regulates stem cell function in high-turnover tissues. PMID- 21295276 TI - Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells. AB - TET family enzymes convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in DNA. Here, we show that Tet1 and Tet2 are Oct4-regulated enzymes that together sustain 5hmC in mouse embryonic stem cells (ESCs) and are induced concomitantly with 5hmC during reprogramming of fibroblasts to induced pluripotent stem cells. ESCs depleted of Tet1 by RNAi show diminished expression of the Nodal antagonist Lefty1 and display hyperactive Nodal signaling and skewed differentiation into the endoderm-mesoderm lineage in embryoid bodies in vitro. In Fgf4- and heparin-supplemented culture conditions, Tet1-depleted ESCs activate the trophoblast stem cell lineage determinant Elf5 and can colonize the placenta in midgestation embryo chimeras. Consistent with these findings, Tet1-depleted ESCs form aggressive hemorrhagic teratomas with increased endoderm, reduced neuroectoderm, and ectopic appearance of trophoblastic giant cells. Thus, 5hmC is an epigenetic modification associated with the pluripotent state, and Tet1 functions to regulate the lineage differentiation potential of ESCs. PMID- 21295277 TI - beta-catenin enhances Oct-4 activity and reinforces pluripotency through a TCF independent mechanism. AB - Understanding the mechanisms regulating pluripotency in embryonic and induced pluripotent stem cells is required to ensure their safe use in clinical applications. Glycogen synthase kinase-3 (GSK-3) has emerged as an important regulator of pluripotency, based primarily on studies with small-molecule GSK-3 inhibitors. Here, we use mouse embryonic stem cells (ESCs) lacking GSK-3 to demonstrate that a single GSK-3 substrate, beta-catenin, controls the ability of ESCs to exit the pluripotent state and to differentiate into neurectoderm. Unexpectedly, the effects of beta-catenin on pluripotency do not appear to be dependent on TCF-mediated signaling, based on experiments utilizing a beta catenin C-terminal truncation mutant or highly efficient dominant-negative TCF strategies. Alternatively, we find that stabilized beta-catenin forms a complex with and enhances the activity of Oct-4, a core component of the transcriptional network regulating pluripotency. Collectively, our data suggest previously underappreciated, divergent TCF-dependent and TCF-independent roles for beta catenin in ESCs. PMID- 21295278 TI - Stage-specific optimization of activin/nodal and BMP signaling promotes cardiac differentiation of mouse and human pluripotent stem cell lines. AB - Efficient differentiation of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) to a variety of lineages requires step-wise approaches replicating the key commitment stages found during embryonic development. Here we show that expression of PdgfR-alpha segregates mouse ESC-derived Flk-1 mesoderm into Flk-1(+)PdgfR-alpha(+) cardiac and Flk-1(+)PdgfR-alpha(-) hematopoietic subpopulations. By monitoring Flk-1 and PdgfR-alpha expression, we found that specification of cardiac mesoderm and cardiomyocytes is determined by remarkably small changes in levels of Activin/Nodal and BMP signaling. Translation to human ESCs and iPSCs revealed that the emergence of cardiac mesoderm could also be monitored by coexpression of KDR and PDGFR-alpha and that this process was similarly dependent on optimal levels of Activin/Nodal and BMP signaling. Importantly, we found that individual mouse and human pluripotent stem cell lines require optimization of these signaling pathways for efficient cardiac differentiation, illustrating a principle that may well apply in other contexts. PMID- 21295279 TI - Functional screening of Alzheimer pathology genome-wide association signals in Drosophila. AB - We have leveraged a Drosophila model relevant to Alzheimer disease (AD) for functional screening of findings from a genome-wide scan for loci associated with a quantitative measure of AD pathology in humans. In six of the 15 genomic regions evaluated, we successfully identified a causal gene for the association, on the basis of in vivo interactions with the neurotoxicity of Tau, which forms neurofibrillary tangles in AD. Among the top results, rs10845990 within SLC2A14, encoding a glucose transporter, showed evidence of replication for association with AD pathology, and gain and loss of function in glut1, the Drosophila ortholog, was associated with suppression and enhancement of Tau toxicity, respectively. Our strategy of coupling genome-wide association in humans with functional screening in a model organism is likely to be a powerful approach for gene discovery in AD and other complex genetic disorders. PMID- 21295280 TI - FAF1, a gene that is disrupted in cleft palate and has conserved function in zebrafish. AB - Cranial neural crest (CNC) is a multipotent migratory cell population that gives rise to most of the craniofacial bones. An intricate network mediates CNC formation, epithelial-mesenchymal transition, migration along distinct paths, and differentiation. Errors in these processes lead to craniofacial abnormalities, including cleft lip and palate. Clefts are the most common congenital craniofacial defects. Patients have complications with feeding, speech, hearing, and dental and psychological development. Affected by both genetic predisposition and environmental factors, the complex etiology of clefts remains largely unknown. Here we show that Fas-associated factor-1 (FAF1) is disrupted and that its expression is decreased in a Pierre Robin family with an inherited translocation. Furthermore, the locus is strongly associated with cleft palate and shows an increased relative risk. Expression studies show that faf1 is highly expressed in zebrafish cartilages during embryogenesis. Knockdown of zebrafish faf1 leads to pharyngeal cartilage defects and jaw abnormality as a result of a failure of CNC to differentiate into and express cartilage-specific markers, such as sox9a and col2a1. Administration of faf1 mRNA rescues this phenotype. Our findings therefore identify FAF1 as a regulator of CNC differentiation and show that it predisposes humans to cleft palate and is necessary for lower jaw development in zebrafish. PMID- 21295281 TI - Ancient voyaging and Polynesian origins. AB - The "Polynesian motif" defines a lineage of human mtDNA that is restricted to Austronesian-speaking populations and is almost fixed in Polynesians. It is widely thought to support a rapid dispersal of maternal lineages from Taiwan ~4000 years ago (4 ka), but the chronological resolution of existing control region data is poor, and an East Indonesian origin has also been proposed. By analyzing 157 complete mtDNA genomes, we show that the motif itself most likely originated >6 ka in the vicinity of the Bismarck Archipelago, and its immediate ancestor is >8 ka old and virtually restricted to Near Oceania. This indicates that Polynesian maternal lineages from Island Southeast Asia gained a foothold in Near Oceania much earlier than dispersal from either Taiwan or Indonesia 3-4 ka would predict. However, we find evidence in minor lineages for more recent two way maternal gene flow between Island Southeast Asia and Near Oceania, likely reflecting movements along a "voyaging corridor" between them, as previously proposed on archaeological grounds. Small-scale mid-Holocene movements from Island Southeast Asia likely transmitted Austronesian languages to the long established Southeast Asian colonies in the Bismarcks carrying the Polynesian motif, perhaps also providing the impetus for the expansion into Polynesia. PMID- 21295282 TI - A missense mutation in DHDDS, encoding dehydrodolichyl diphosphate synthase, is associated with autosomal-recessive retinitis pigmentosa in Ashkenazi Jews. AB - Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal degenerations caused by mutations in at least 50 genes. Using homozygosity mapping in Ashkenazi Jewish (AJ) patients with autosomal-recessive RP (arRP), we identified a shared 1.7 Mb homozygous region on chromosome 1p36.11. Sequence analysis revealed a founder homozygous missense mutation, c.124A>G (p.Lys42Glu), in the dehydrodolichyl diphosphate synthase gene (DHDDS) in 20 AJ patients with RP of 15 unrelated families. The mutation was not identified in an additional set of 109 AJ patients with RP, in 20 AJ patients with other inherited retinal diseases, or in 70 patients with retinal degeneration of other ethnic origins. The mutation was found heterozygously in 1 out of 322 ethnically matched normal control individuals. RT-PCR analysis in 21 human tissues revealed ubiquitous expression of DHDDS. Immunohistochemical analysis of the human retina with anti DHDDS antibodies revealed intense labeling of the cone and rod photoreceptor inner segments. Clinical manifestations of patients who are homozygous for the c.124A>G mutation were within the spectrum associated with arRP. Most patients had symptoms of night and peripheral vision loss, nondetectable electroretinographic responses, constriction of visual fields, and funduscopic hallmarks of retinal degeneration. DHDDS is a key enzyme in the pathway of dolichol, which plays an important role in N-glycosylation of many glycoproteins, including rhodopsin. Our results support a pivotal role of DHDDS in retinal function and may allow for new therapeutic interventions for RP. PMID- 21295283 TI - Whole-exome sequencing links a variant in DHDDS to retinitis pigmentosa. AB - Increasingly, mutations in genes causing Mendelian disease will be supported by individual and small families only; however, exome sequencing studies have thus far focused on syndromic phenotypes characterized by low locus heterogeneity. In contrast, retinitis pigmentosa (RP) is caused by >50 known genes, which still explain only half of the clinical cases. In a single, one-generation, nonsyndromic RP family, we have identified a gene, dehydrodolichol diphosphate synthase (DHDDS), demonstrating the power of combining whole-exome sequencing with rapid in vivo studies. DHDDS is a highly conserved essential enzyme for dolichol synthesis, permitting global N-linked glycosylation. Zebrafish studies showed virtually identical photoreceptor defects as observed with N-linked glycosylation-interfering mutations in the light-sensing protein rhodopsin. The identified Lys42Glu variant likely arose from an ancestral founder, because eight of the nine identified alleles in 27,174 control chromosomes were of confirmed Ashkenazi Jewish ethnicity. These findings demonstrate the power of exome sequencing linked to functional studies when faced with challenging study designs and, importantly, link RP to the pathways of N-linked glycosylation, which promise new avenues for therapeutic interventions. PMID- 21295284 TI - Utilization of minimally invasive breast biopsy for the evaluation of suspicious breast lesions. AB - BACKGROUND: Percutaneous needle biopsy, also known as minimally invasive breast biopsy (MIBB), has become the gold standard for the initial assessment of suspicious breast lesions. The purpose of this study is to determine modern rates of MIBB and open breast biopsy. METHODS: The Florida Agency for Health Care Administration outpatient surgery and procedure database was queried for patients undergoing open surgical biopsy and MIBB between 2003 and 2008. RESULTS: Although there was an increase in the use of MIBB, the overall rate of open surgical biopsy remained high (~30%). A reduction in the open biopsy rate from 30% to 10% could be associated with a charge reduction of >$37.2 million per year. CONCLUSIONS: The current rate of open surgical breast biopsy remains high. Interventions and quality initiatives are warranted, which could lead to a reduction in unnecessary operations for women, improved patient care, and a reduction in breast health care costs. PMID- 21295285 TI - Torsade de pointes induced by citalopram and amiodarone. AB - Long QT syndrome (LQTS) is a disorder of myocardial repolarization characterized by a prolonged QT interval on the electrocardiogram (ECG). This disorder is associated with an increased risk of torsade de pointes (TdP). We report a case of TdP induced by citalopram, a selective serotonin reuptake inhibitor (SSRI), taken in conjunction with amiodarone. PMID- 21295286 TI - A double-blind randomized placebo-controlled pilot study of neuropsychiatric adverse events in abstinent smokers treated with varenicline or placebo. AB - BACKGROUND: Varenicline is an alpha4beta2 partial nicotinic agonist approved for smoking cessation. There have been spontaneous postmarketing reports of neuropsychiatric adverse events (NPAEs) in smokers without a history of psychiatric illness quitting with varenicline. METHODS: One hundred ten smokers without history of psychiatric illness (screened by Structured Clinical Interview for DSM-IV) were randomized to 12 weeks of varenicline 1 mg twice daily (n = 55) or placebo. Adverse events were solicited systematically. Depressive symptoms, anxiety, aggression, and irritability were measured at baseline and weekly using the Montgomery-Asberg Depression Rating Scale (MADRS), the Hamilton Anxiety Scale (HAM-A), and the Overt Aggression Scale-Modified (OAS-M). The Profile of Mood States (POMS) was administered daily. Mixed-model analysis of repeated measures was conducted to compare mean changes in scores between groups across study periods. RESULTS: Participants' mean baseline characteristics were 33 years of age, 22 cigarettes/day and Fagerstrom Test for Nicotine Dependence score > 7. Reported NPAEs were similar between groups. No suicidal events were reported. There were no significant differences between groups for the MADRS (treatment difference vs. placebo = .03, 95% confidence interval [CI] -.68-.73; NS), HAM-A (treatment difference [TD] = .14, 95% CI -.62-.90; NS), OAS-M Aggression subscale (TD = .5, 95% CI -1.18-2.18; NS), OAS-M Irritability subscale (TD = .08, 95% CI .17-.34; NS), and the POMS total scores (TD = .5, 95% CI -.52-1.53; NS). CONCLUSIONS: There were no significant differences between groups on measures of depressive symptoms, anxiety, or aggression/hostility. Systematically solicited NPAEs were similar between the varenicline and placebo groups. PMID- 21295287 TI - Perinatal supplementation with thymoquinone improves diabetic complications and T cell immune responses in rat offspring. AB - BACKGROUND: Epidemiological studies have shown that the offspring of mothers who experience diabetes mellitus during pregnancy are seven times more likely to develop health complications later in life compared to offspring born to nondiabetic mothers. AIM OF THE STUDY: We investigated whether supplementation with a natural antioxidant (thymoquinone; TQ) in female rats with streptozotocin (STZ)-induced gestational diabetes (GD) improved diabetic complications and T cell immune responses in their offspring. METHODS: Three groups of female rats were tested: nondiabetics, diabetics treated with TQ during pregnancy and lactation periods and diabetics that were not treated with TQ (n=10 female rats in each group). RESULTS: Our data demonstrated a significant decrease in the numbers of neonates born to diabetic rats compared with those born to control rats. GD led to macrosomic pups with several postpartum complications, such as a significant increase in plasma levels of the pro-inflammatory cytokines IL-1beta, IL-6, and TNF-alpha (but not of IL-10); a marked decrease in the plasma level of IL-2; a marked reduction in the proliferative capacity of superantigen (SEB) stimulated T-lymphocytes; and an obvious reduction in the number of circulating and thymus homing T cells. TQ supplementation of diabetic mothers during pregnancy and lactation periods had an obvious and significant effect on the number and mean body weight of neonates. Furthermore, TQ significantly restored the IL-2 level and T cell proliferation and subsequently rescued both circulating and thymus homing T cells in the offspring. CONCLUSIONS: Our data suggest that nutritional supplementation of GD mothers with the natural antioxidant TQ during pregnancy and lactation periods improves diabetic complications and maintains an efficient T cell immune response in their offspring, providing a protective effect in later life. PMID- 21295288 TI - VPAC1 (vasoactive intestinal peptide (VIP) receptor type 1) G protein-coupled receptor mediation of VIP enhancement of murine experimental colitis. AB - Distinct roles of the two T cell G protein-coupled receptors for vasoactive intestinal peptide (VIP), termed VPAC1 and VPAC2, in VIP regulation of autoimmune diseases were investigated in the dextran sodium sulfate (DSS)-induced murine acute colitis model for human inflammatory bowel diseases. In mice lacking VPAC2 (VPAC2-KO), DSS-induced colitis appeared more rapidly with greater weight loss and severe histopathology than in wild-type mice. In contrast, DSS-induced colitis in VPAC1-KO mice was milder than in wild-type mice and VPAC2-KO mice. Tissues affected by colitis showed significantly higher levels of myeloperoxidase, IL-6, IL-1beta and MMP-9 in VPAC2-KO mice than wild-type mice, but there were no differences for IL-17, IFN-gamma, IL-4, or CCR6. Suppression of VPAC1 signals in VPAC2-KO mice by PKA inhibitors reduced the clinical and histological severity of DSS-induced colitis, as well as tissue levels of IL-6, IL-1beta and MMP-9. Thus VIP enhancement of the severity of DSS-induced colitis is mediated solely by VPAC1 receptors. PMID- 21295289 TI - The future of recruitment and selection in radiology. Is there a role for assessment of basic visuospatial skills? PMID- 21295290 TI - Early recognition of upper limb motor tasks through accelerometers: real-time implementation of a DTW-based algorithm. AB - A new real-time implementation of a Dynamic Time Warping (DTW)-based classification scheme is presented here, and its performance evaluated on experimental data. Nine young adults were requested to perform instances of eight different purposeful movements described in the Wolf Motor Function Test, while wearing a three-axis accelerometer sensor placed on the inner forearm. Results include the correct recognition percentage, as compared to a classification scheme based on the traditional DTW measure, and the recognition percentage as a function of the time elapsed from the beginning of the performed movements. The Real-Time DTW basically performs with the same accuracy of the traditional DTW based classification scheme (91.5% of correct recognition percentage), a figure that increases to 96.5% if the multidimensional scheme is adopted. Moreover, more than 60% of movements are correctly recognized before their end, thus setting the way for applications in rehabilitation and assistive technologies, where a real time control scheme is able to interact with the user while the movement is being performed. PMID- 21295291 TI - Shivering heat production and body fat protect the core from cooling during body immersion, but not during head submersion: a structural equation model. AB - Previous studies showed that core cooling rates are similar when only the head or only the body is cooled. Structural equation modeling was used on data from two cold water studies involving body-only, or whole body (including head) cooling. Exposure of both the body and head increased core cooling, while only body cooling elicited shivering. Body fat attenuates shivering and core cooling. It is postulated that this protection occurs mainly during body cooling where fat acts as insulation against cold. This explains why head cooling increases surface heat loss with only 11% while increasing core cooling by 39%. PMID- 21295292 TI - Heritable pollution tolerance in a marine invader. AB - The global spread of fouling invasive species is continuing despite the use of antifouling biocides. Furthermore, previous evidence suggests that non-indigenous species introduced via hull fouling may be capable of adapting to metal-polluted environments. Using a laboratory based toxicity assay, we investigated tolerance to copper in the non-indigenous bryozoan Watersipora subtorquata from four source populations. Individual colonies were collected from four sites within Port Hacking (Sydney, Australia) and their offspring exposed to a range of copper concentrations. This approach, using a full-sib, split-family design, tests for a genotype by environment (G*E) interaction. Settlement and complete metamorphosis (recruitment) were measured as ecologically relevant endpoints. Larval sizes were also measured for each colony. Successful recruitment was significantly reduced by the highest copper concentration of 80MUgL(-1). While there was no difference in pollution tolerance between sites, there was a significant G*E interaction, with large variation in the response of colony offspring within sites. Larval size differed significantly both between sites and between colonies and was positively correlated with tolerance. The high level of variation in copper tolerance between colonies suggests that there is considerable potential within populations to adapt to elevated copper levels, as tolerance is a heritable trait. Also, colonies that produce large larvae are more tolerant to copper, suggesting that tolerance may be a direct consequence of larger size. PMID- 21295293 TI - Metal pollution indirectly increases oxidative stress in great tit (Parus major) nestlings. AB - Metals can cause oxidative stress by increasing the formation of reactive oxygen species (ROS), when there are insufficient amount of antioxidants to defend against the growing amount of free radicals. We aimed to find out the most reliable biomarkers to detect pollution-related oxidative stress in wild birds by comparing oxidative stress status in great tit (Parus major) nestlings at populations in polluted and unpolluted areas. We also studied with experimental manipulations whether dietary carotenoid levels have any role in great tits' antioxidant defence and whether their carotenoid-based plumage colour was connected to an oxidative stress status. We used antioxidants (GSH, carotenoids) and several antioxidant enzymes (GP, GR, GST, SOD, and CAT) as indicators of the oxidative stress. We found no direct connections between dietary metal exposure and antioxidant or antioxidant enzyme levels. The activity of GP was, however, slightly higher in the polluted environment. This was due to poorer condition and subsequently higher level of oxidative stress in the nestlings in the polluted area. We also found a positive association between GP and an ambient temperature during the nestling period, which may be due to higher metabolic activity of partly poikilothermic nestlings in warm weather. The activity of GST was positively related to the number of nestlings at the sampling time. Fledging success was better in an unpolluted area, where also the nestling body mass was higher. Carotenoid treatment increased the plasma carotenoid concentrations 2.1 fold in carotenoid-supplemented birds, but was not associated with the oxidative stress biomarkers or metal levels. The yellow plumage colour was associated with dietary carotenoid levels in both study areas, but not with the metal exposure or the oxidative stress status. Our results suggest that at the exposure levels found in our study area, the enzyme activities do not indicate metal-related oxidative stress. Instead, GP can be used as an indicator of growth related oxidative stress, which is greater in the polluted area. The activity of this enzyme was, however, not directly related to metal exposure, but more likely to some secondary pollution-related change in the nestling condition. PMID- 21295294 TI - Inhibition of transcription, expression, and secretion of the vascular epithelial growth factor in human epithelial endometriotic cells by romidepsin. AB - OBJECTIVE: To investigate whether the histone deacetylase (HDAC) inhibitor romidepsin down-regulates VEGF (vascular endothelial growth factor) gene expression and abrogates VEGF protein secretion in human epithelial endometriotic cells. DESIGN: In vitro study with human immortalized epithelial endometriotic cells. SETTING: University hospital. PATIENT(S): Not applicable. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Real-time reverse-transcriptase polymerase chain reaction to evaluate VEGF gene expression, immunoblot analysis to evaluate protein expression, and enzyme-linked immunosorbent assay to evaluate VEGF protein secretion into the culture medium. RESULT(S): Treatment of 11z human endometriotic cells with romidepsin statistically significantly inhibited VEGF gene transcription and down-regulated VEGF protein expression. Moreover, romidepsin abrogated the secretion of VEGF protein into the culture medium. Romidepsin also reduced the expression of hypoxia-inducible factor-1alpha (HIF 1alpha), which is implicated in the transcription of the VEGF gene, in cobalt chloride-pretreated (to mimic hypoxic conditions) 11z cultures. CONCLUSION(S): Romidepsin targets VEGF at the transcriptional level, which subsequently leads to the reduction of secreted VEGF (the "active" form of VEGF). Therefore, romidepsin may be a potential therapeutic candidate against angiogenesis in endometriosis. PMID- 21295295 TI - Organ-preserving management of ovarian pregnancies by laparoscopic approach. AB - This article discusses the possible etiology and the preoperative, operative, and postoperative management of five ovarian pregnancies based on the initial nonspecific signs and symptoms and the high risk of hemoperitoneum and/or hypovolemic shock of a ruptured ovarian pregnancy with the associated diagnostic problems. The advances made in transvaginal ultrasonography and monitoring of serum beta-hCG levels in blood samples, as well as the substantial progress made in diagnostic pelviscopy and operative laparoscopy, have led to an early minimal invasive surgical management with the main emphasis on an organ-preserving procedure, i.e., a simple enucleation of the gestational sac with the utmost protection of the surrounding ovarian tissue. PMID- 21295296 TI - Klinefelter syndrome: does it confer a bad prognosis in treatment of nonobstructive azoospermia? AB - OBJECTIVE: To determine the effectiveness of microsurgical testicular sperm extraction (micro-TESE) and intracytoplasmic sperm injection (ICSI) for men with Klinefelter syndrome (KS). DESIGN: Retrospective clinical study. SETTING: Private IVF center. PATIENT(S): Men with nonmosaic KS (n = 106), and men with nonobstructive azoospermia (NOA) and normal karyotypes (n = 379). INTERVENTION(S): Micro-TESE on the day of oocyte retrieval. MAIN OUTCOME MEASURE(S): Sperm recovery, fertilization, pregnancy, and spontaneous abortion rates. RESULT(S): Sperm was successfully recovered in 50 of 106 (47%) men in the KS group and 188 of 379 (50%) in the NOA group. The fertilization rate was higher in the NOA group than the KS group (65% vs. 57%, respectively); however, pregnancy (55% vs. 53%) and abortion rates (12% vs. 11.5%) did not differ statistically significantly between groups. In the KS group, 23 pregnancies resulted in 29 live births; the 21 children who underwent genetic evaluation had normal karyotypes. CONCLUSION(S): Sperm recovery rates in men with KS were similar to those of men with NOA and normal karyotypes. The fertilization rate was statistically significantly lower for men with KS than men with NOA, but pregnancy and abortion rates were similar. We observed good sperm recovery and ICSI outcomes for patients with KS. PMID- 21295297 TI - Postoperative inflammation in the abdominal cavity increases adhesion formation in a laparoscopic mouse model. AB - OBJECTIVE: To investigate acute inflammation in the peritoneal cavity in adhesion formation. DESIGN: Prospective randomized, controlled trial. SETTING: University laboratory research center. ANIMAL(S): 9- to 10-week-old BALB/c female mice. INTERVENTION(S): In a laparoscopic mouse model, acute inflammation in the peritoneal cavity evaluated in CO(2) pneumoperitoneum enhanced adhesions, by CO(2) pneumoperitoneum plus manipulation, and in the latter group plus dexamethasone. MAIN OUTCOME MEASURE(S): Qualitative and quantitative adhesion scores and an acute inflammation score (neoangiogenesis, diapedesis, and leukocyte accumulation). RESULT(S): Adhesions at the lesion site were enhanced by the CO(2) pneumoperitoneum, further enhanced by manipulation, and decreased by the administration of dexamethasone. The acute inflammation scores (total, neoangiogenesis, diapedesis, and leukocyte accumulation) strongly correlated with the total adhesion score. Inflammation scores were similar at both the surgical lesion and the parietal peritoneum. CONCLUSION(S): Acute inflammation of the entire peritoneum cavity is an important mechanism involved in adhesion formation and enhances adhesion formation at the lesion site. PMID- 21295298 TI - Involvement of anticentromere antibody in interference with oocyte meiosis and embryo cleavage. AB - The aim of this study was to investigate the clinical significance of anticentromere antibody (ACA) among types of antinuclear antibody (ANA) in the properties of oocytes retrieved from infertile women. The rate of metaphase II oocytes or embryo cleavage was significantly decreased in patients with positive ACA compared with patients with negative ACA, suggesting that ACA is an essential marker for flawed oocytes in infertile women with any type of ANA. PMID- 21295299 TI - Epidermoid carcinoma complicating esophageal lichen planus without cutaneous or oral involvement. PMID- 21295300 TI - Stents for proximal esophageal cancer: a case-control study. AB - BACKGROUND: Self-expandable metal stents (SEMSs) are an established palliative therapy for esophageal cancer. SEMS placement for cancers near the upper esophageal sphincter (UES) is controversial because of a perceived increased risk of complications. OBJECTIVE: To compare outcomes after patients stented for proximal esophageal cancer (PC) and distal esophageal cancer (DC). DESIGN: Matched case-control study from a prospective database. SETTING: Tertiary referral center, Tenwek Hospital, Bomet, Kenya. PATIENTS: All patients with PC located within 6 cm of the UES were matched with randomly selected controls with DC. INTERVENTIONS: Outcomes of PC cases were compared with those of DC controls. MAIN OUTCOME MEASUREMENTS: Dysphagia score, complications, median survival. RESULTS: A total of 151 patients with PC were identified and were randomly matched with DC controls. Ninety-three case-control pairs had adequate follow-up information available. Mean dysphagia scores (scale 0-4) improved from 3.4 and 3.3 before stenting for PC and DC, respectively, to 1.5 after stenting for both groups (P = .93). Early complications occurred in 6.5% of PC cases and 9.7% of DC controls (P = .44). Late complications occurred in 20.4% of PC cases and 15.1% of DC controls (P = .25). Median survival was 210 days for PC cases and 272 days for DC controls (P = .25). Outcomes were similar for the subgroup of PC cases whose cancer extended to within 2 cm of the UES. LIMITATION: An important limitation is the absence of adequate follow-up data for 58 of the 151 case-control pairs. CONCLUSIONS: SEMSs effectively palliate dysphagia in PC cases, whereas complication and survival rates are not statistically different from those of DC controls. PMID- 21295301 TI - Active opening and closing movements of the orifices of esophageal intramural pseudodiverticulosis. PMID- 21295302 TI - Role of ERCP in the management of non-iatrogenic traumatic bile duct injuries in the pediatric population. PMID- 21295303 TI - Severe weather warnings predict fracture epidemics. AB - Winter epidemics of fractures have been described that greatly exceed normal seasonal variations and overwhelm resources. We investigated the relationship between severe weather warnings, the frequency of fractures, and fracture related workload. There was a significant increase in fractures with cold and inclement weather, mostly low-energy fractures treated with day-case surgery or in fracture clinics. The number of patients treated as inpatients for fractures did not increase. Hip fractures were not associated with weather. Severe weather warnings for icy roads were predictive of fracture epidemics (p<0.01) with an associated 40% (95% confidence limits 20-52%) increase in fractures. Meteorological Office issued severe weather warnings can provide a trigger to plan for an increased workload of low-energy fractures, with opportunities for anticipatory public health measures. PMID- 21295304 TI - Calpain-mediated cleavage negatively regulates the expression level of ABCG1. AB - OBJECTIVE: The ATP-binding cassette transporter ABCG1 mediates cholesterol efflux from macrophages, and prevents the progression of macrophage foam-cell formation. Much less is known about the regulatory mechanism of ABCG1, although its physiological importance is becoming clearer. Here, we show the role of calpain in ABCG1 degradation. METHODS AND RESULTS: Purified MU-calpain cleaved ABCG1 in crude membrane fractions prepared from human ABCG1-expressing HEK293 (ABCG1-HEK) cells. In ABCG1-HEK cells, calpeptin treatment, a calpain inhibitor, inhibited ABCG1 degradation, and thereby increased the expression and cholesterol efflux function of ABCG1. Biotinylation study demonstrated greater ABCG1 induction with calpeptin treatment in cell surface than that in whole cell lysates. Together with the result that increased ABCG1 expression with calpeptin treatment was observed under clathrin heavy-chain (CHC) knockdown conditions, where ABCG1 internalization was prevented, calpain is considered to catalyze ABCG1 cleavage on the plasma membrane. In mouse peritoneal macrophages as well as in ABCG1-HEK cells, calpeptin treatment inhibited ABCG1 degradation and enhanced ABCG1 expression, even under CHC-depleted conditions. CONCLUSION: These observations indicate that calpain promotes ABCG1 degradation by cleaving cell surface resident ABCG1, and consequently reduces the expression and cholesterol efflux function of ABCG1. Inhibition of ABCG1 cleavage by calpain could be a novel approach to suppress the progression of atherosclerosis. PMID- 21295305 TI - Wide-range dynamic magnetic resonance elastography. AB - Tissue mechanical parameters have been shown to be highly sensitive to disease by elastography. Magnetic resonance elastography (MRE) in the human body relies on the low-dynamic range of tissue mechanics <100 Hz. In contrast, MRE suited for investigations of mice or small tissue samples requires vibration frequencies 10 20 times higher than those used in human MRE. The dispersion of the complex shear modulus (G(*)) prevents direct comparison of elastography data at different frequency bands and, consequently, frequency-independent viscoelastic models that fit to G(*) over a wide dynamic range have to be employed. This study presents data of G(*) of samples of agarose gel, liver, brain, and muscle measured by high resolution MRE in a 7T-animal scanner at 200-800 Hz vibration frequency. Material constants MU and alpha according to the springpot model and related to shear elasticity and slope of the G(*)-dispersion were determined. Both MU and alpha of calf brain and bovine liver were found to be similar, while a sample of fibrotic human liver (METAVIR score of 3) displayed about fifteen times higher shear elasticity, similar to MU of bovine muscle measured in muscle fiber direction. alpha was the highest in fibrotic liver, followed by normal brain and liver, while muscle had the lowest alpha-values of all biological samples investigated in this study. As expected, the least G(*)-dispersion was seen in soft gel. The proposed technique of wide-range dynamic MRE can provide baseline data for both human MRE and high-dynamic MRE for better understanding tissue mechanics of different tissue structures. PMID- 21295306 TI - Efficient computational method for assessing the effects of implant positioning in cementless total hip replacements. AB - The present work describes a statistical investigation into the effects of implant positioning on the initial stability of a cementless total hip replacement (THR). Mesh morphing was combined with design of computer experiments to automatically construct Finite Element (FE) meshes for a range of pre-defined femur-implant configurations and to predict implant micromotions under joint contact and muscle loading. Computed micromotions, in turn, are postprocessed using a Bayesian approach to: (a) compute the main effects of implant orientation angles, (b) predict the sensitivities of the considered implant performance metrics with respect to implant ante-retroversion, varus-valgus and antero posterior orientation angles and (c) identify implant positions that maximise and minimise each metric. It is found that the percentage of implant area with micromotion greater than 50 MUm, average and maximum micromotions are all more sensitive to antero-posterior orientation than ante-retroversion and varus-valgus orientation. Sensitivities, combined with the main effect results, suggest that bone is less likely to grow if the implant is increasingly moved from the neutral position towards the anterior part of the femur, where the highest micromotions occur. The computed implant best position leads to a percentage of implant area with micromotion greater than 50 MUm of 1.14 when using this metric compared to 14.6 and 5.95 in the worst and neutrally positioned implant cases. In contrast, when the implant average/maximum micromotion is used to assess the THR performance, the implant best position corresponds to average/maximum micromotion of 9 MUm/59 MUm, compared to 20 MUm/114 MUm and 13 MUm/71 MUm in the worst and neutral positions, respectively. The proposed computational framework can be extended further to study the effects of uncertainty and variability in anatomy, bone mechanical properties, loading or bone-implant interface contact conditions. PMID- 21295307 TI - Level of subject-specific detail in musculoskeletal models affects hip moment arm length calculation during gait in pediatric subjects with increased femoral anteversion. AB - Biomechanical parameters of gait such as muscle's moment arm length (MAL) and muscle-tendon length are known to be sensitive to anatomical variability. Nevertheless, most studies rely on rescaled generic models (RGMo) constructed from averaged data of cadaveric measurements in a healthy adult population. As an alternative, deformable generic models (DGMo) have been proposed. These models integrate a higher level of subject-specific detail by applying characteristic deformations to the musculoskeletal geometry. In contrast, musculoskeletal models based on magnetic resonance (MR) images (MRMo) reflect the involved subject's characteristics in every level of the model. This study investigated the effect of the varying levels of subject-specific detail in these three model types on the calculated hip MAL during gait in a pediatric population of seven cerebral palsy subjects presenting aberrant femoral geometry. Our results show large percentage differences in calculated MAL between RGMo and MRMo. Furthermore, the use of DGMo did not uniformly reduce inter-model differences in calculated MAL. The magnitude of these percentage differences stresses the need to take these effects into account when selecting the level of subject-specific detail one wants to integrate in musculoskeletal. Furthermore, the variability of these differences between subjects and between muscles makes it very difficult to a priori estimate their importance for a biomechanical analysis of a certain muscle in a given subject. PMID- 21295308 TI - New method for development of carbon clad silica phases for liquid chromatography: Part I. Preparation of carbon phases. AB - Owing to its combination of unique selectivity and mechanical strength, commercial carbon clad zirconia (C/ZrO2) has been widely used for many applications, including fast two-dimensional liquid chromatography (2DLC). However, the low surface area available (only 20-30 m2/g for commercial porous ZrO2) limits its retentivity. We have recently addressed this limitation by developing a carbon phase coated on the high surface area of HPLC grade alumina (C/Al2O3). This material provides higher retentivity and comparable selectivity, but its use is still limited by how few HPLC quality types of alumina particles (e.g., particle size, surface area, and pore size) are available. In this work, we have developed useful carbon phases on silica particles, which are available in various particle sizes, pore sizes and forms of HPLC grade. To make the carbon phase on silica, we first treat the silica surface with a monolayer or less of metal cations that bind to deprotonated silanols to provide catalytic sites for carbon deposition. After Al (III) treatment, a carbon phase is formed on the silica surface by chemical vapor deposition at 700 degrees C using hexane as the carbon source. The amount of Al (III) on the surface was varied to assess its effect on carbon deposition, and the carbon loading was varied at different Al (III) levels to assess its effect on the chromatographic properties of the various carbon adsorbents. We observed that use of a concentration of Al (III) corresponding to a full monolayer leads to the most uniform carbon coating. A carbon coating sufficient to cover all the Al (III) sites, required about 4-5 monolayers in this work, provided the best chromatographic performance. The resulting carbon phases behave as reversed phases with reasonable efficiency (50,000-79,000 plates/m) for non-aromatic test species. PMID- 21295309 TI - Approaches to estimate the time and height at the peak maximum in liquid chromatography based on a modified Gaussian model. AB - The time and height at the peak maximum are key parameters to describe a chromatographic peak with prediction or optimization purposes, or in the qualitative/quantitative analysis of samples. Three different approaches to estimate these parameters, using the experimental points in the peak maximum region, are here described and compared. The approaches are based on the reliable description of the peak profile using a modified Gaussian model with a parabolic variance (PVMG). In the first approach, non-linear fitting of the chromatographic data to the PVMG model is carried out to obtain the time and height at the peak maximum (Approach I). In the other two approaches, the PVMG model is linearized to carry out a linear fitting. In each case, the optimal number of processed points was assessed. The three approaches yielded highly satisfactory results, being Approach I the best in terms of accuracy and robustness. The assessment of the accuracy in the estimations was carried out using simulated peaks. These peaks were built with the parameters obtained from real peaks for several probe compounds eluted under reversed-phase liquid chromatographic (RPLC) conditions, to which noise was added. PMID- 21295310 TI - High-performance liquid chromatographic enantioseparation of 1-(phenylethylamino) or 1-(naphthylethylamino)methyl-2-naphthol analogs and a temperature-induced inversion of the elution sequence on polysaccharide-based chiral stationary phases. AB - The stereoisomers of five 1-(phenylethylamino)methyl-2-naphthol analogs or 1 (naphthylethylamino)methyl-2-naphthol analogs containing two chiral centers were directly separated on chiral stationary phases containing the chiral selectors cellulose tris-(3,5-dimethylphenyl) carbamate (Lux Cellulose-1), cellulose tris (3-chloro-4-methylphenyl) carbamate (Lux Cellulose-2) and amylose tris-(5-chloro 2-methylphenyl) carbamate (Lux Amylose-2). Experiments were performed in normal phase mode in a wide temperature range -5 to 70 degrees C. Thermodynamic parameters and T(iso) values were calculated from plots of lnk or lnalpha vs. 1/T. -Delta(DeltaH degrees ) ranged from 1.0 to 4.7 kJ mol(-1), -Delta(DeltaS degrees ) from 1.6 to 11.0 J mol(-1) K(-1) and -Delta(DeltaG degrees ) from 0.1 to 1.5 kJ mol(-1). The sequence of elution of the stereoisomers was determined in all cases and in one case a temperature-induced inversion of the elution sequence was observed. PMID- 21295311 TI - Development of a dispersive liquid-liquid microextraction method for the simultaneous determination of the main compounds causing cork taint and Brett character in wines using gas chromatography-tandem mass spectrometry. AB - A novel dispersive liquid-liquid microextraction (DLLME) method, coupled to gas chromatography-tandem mass spectrometry (GC-MS/MS), was developed for simultaneously determining the main compounds responsible for cork taint (2,4,6 trichloranisole (TCA), 2,3,4,6-tetrachloroanisole (TeCA), 2,4,6-tribromoanisole (TBA) and pentachloranisole (PCA)) and Brett character (4-ethylguaiacol (EG), 4 ethylphenol (EP), 4-vinylguaiacol (VG) and 4-vinylphenol (VP)) in wines. Optimisation of DLLME procedure was performed by evaluating the type of disperser and extraction solvents and the temperature and salt addition effects. The volumes of disperser and extraction solvents were also optimised by means of a central composite design combined with desirability functions. Under optimum conditions, 5 mL of wine were extracted with an extraction mixture consisting of 1.43 mL of acetone, and 173 MUL of chloroform at room temperature. The analytical characteristics of the method were evaluated. Satisfactory linearity (with correlation coefficients over 0.992), repeatability (below 11.6%) and between days precision (below 11.0%) were obtained for all target analytes. Detection limits attained were at similar levels or even lower than the olfactory threshold of the studied compounds. Finally, the developed method was successfully applied to the analysis of wine samples. To our knowledge, this is the first time that DLLME has been applied to simultaneously determine the compounds responsible for cork taint and Brett character in wine. PMID- 21295312 TI - Temperature-assisted photochemical construction of CdS-based ordered porous films with photocatalytic activities on solution surfaces. AB - Taking a colloidal monolayer floating on the surface of a precursor solution as template, free-standing CdS/Cd composites and pure CdS (CdS-based) ordered porous films had been prepared by a temperature-assisted photochemical strategy. After irradiation with UV-light and heat treatment, the films formed hemi-spherical pores due to the preferable deposition of CdS and Cd onto the PS spheres during the photochemical and interfacial reactions. When the temperature increased from 15 to 60 degrees C, the air/water interface gradually changed into a vapor/water interface on the surface of the solution, resulting in variations of the final compositions. The optical properties of the films were hence changed. Because of the free-standing characteristic, the ordered porous films were first transferred on surface of polluted solutions as photocatalysts, which was a new mode in application of photocatalysts. The photocatalytic activities of films showed regular variations with the compositions in photodegradation of Rhodamine B. This method provides a simple route for tuning the properties of porous films through control of its composition and a flexible application of films on any surface. PMID- 21295313 TI - The stability of the ST segment estimation of myocardial area at risk between the prehospital and hospital electrocardiograms in patients with ST elevation myocardial infarction. AB - PURPOSE: Several ST segment deviation scores have been developed to estimate the myocardial area at risk (AAR) during acute myocardial infarction (AMI), which can be used to measure the effectiveness of reperfusion therapy. The purpose of this study was to assess whether one of these ST segment deviation scores (the Aldrich score) is sufficiently stable between the electrocardiogram (ECG) recorded in the ambulance (ECG 1) and the ECG recorded at the time of admission to the hospital (ECG 2) to be used as a baseline estimation of the AAR. METHODS: The Aldrich scores were compared between ECG 1 and ECG 2 in 77 patients who met the criteria for ST elevation myocardial infarction. The ECGs had a time interval of at least 5 minutes and were recorded before reperfusion therapy. Sufficiently stable was defined as 95% of the patients did not show a temporal change of the Aldrich score of more than 4.5%. RESULTS: The mean time interval between ECG 1 and ECG 2 was 20 +/- 9 minutes. Forty-three percent of the total study population showed an "unstable Aldrich score" between ECG 1 and ECG 2. Fifty-seven percent showed a "stable Aldrich score", which means that the 95% standard for sufficiently stable was not fulfilled. By dividing the population based on infarct location, the group with inferior AMI (n = 43) showed more stability (67%) than the group with anterior AMI (n = 34) (44%) (P < .05). However, this remains less than the 95% stability standard. CONCLUSION: For both inferior and anterior AMI locations, the Aldrich score was not sufficiently stable to be used as a reliable baseline estimation of the AAR in AMI. PMID- 21295314 TI - Sutureless mitral valve replacement with bioprostheses and Nitinol attachment rings: feasibility in acute pig experiments. AB - OBJECTIVE: There is a need for fast, minimally invasive sutureless replacement of mitral valves. METHODS: Unchanged FDA-approved biological valve prostheses were sutured to Nitinol attachment rings (Endosmart, Stutensee, Germany) that were covered with textile (devices). The lower flange of the device was stretched in ice water and maintained in a stretched position with stretching sutures. In 9 acute pig experiments through a limited left thoracotomy, a single suture was placed around the mitral annulus, the device was positioned, the annular suture tied, the stretching sutures retracted, and the device activated by warm saline. Position of the device, heart and valve function, coronary arteries, left ventricular outflow tract, and surrounding structures were observed with transoesophageal echocardiography, left ventricular and coronary angiograms, and pathologic examination at autopsy. RESULTS: The devices could be easily navigated to the mitral valve annulus and actuated within seconds. Three devices were placed with warm blood in the operative field and were tilted or dislocated at autopsy. In the other 6 devices, transesophageal echocardiography and left ventricular and coronary angiography demonstrated normal prosthetic valve and heart function, without valvular or para-device leakage, and with normal aortic valve and coronary arteries. At autopsy in these 6 cases, the devices were strongly fixed at the anatomic mitral valve annulus, without abnormalities of the device, heart valve prosthesis, left ventricular outflow tract, or aortic valve ostium. CONCLUSIONS: Nitinol attachments rings combined with unchanged biological valve prostheses can make fast and strong sutureless replacement of the mitral valve feasible in acute pig experiments. Applicators that constrain and release the device mechanically need to be developed. PMID- 21295315 TI - Potential risk of harmful algae transport by ballast waters: the case of Bilbao Harbour. AB - Ballast water exchange was measured for the first time in Bilbao Harbour, one of the most active of northern Spain. Between 1997 and 2006, 41,900,980.34 ballast water tn were loaded and 13,272,709 tn were discharged. Bilbao Harbour appears to be mainly a source of ballast water, 90% of which would be discharged in European harbours. We estimated that vessels carrying liquid and solid bulk have higher probabilities of exporting ballast water, whereas those with liquid bulk and containers are more likely to introduce it. From 30 potentially harmful phytoplankton species identified to date near harbour facilities, there would be a high risk of exporting at least Alexandrium minutum, Dinophysis sp., Heterosigma akashiwo, Karlodinium sp., Ostreopsis cf. siamensis, Pfiesteria-like and Prorocentrum minimum. Invasion risk by ballast water was tested by analyzing the response of six strains of H. akashiwo from different geographic areas to varying salinity. Results show that successful growth of foreign strains would be possible. PMID- 21295316 TI - Estimation of nearshore groundwater discharge and its potential effects on a fringing coral reef. AB - Radon (222Rn) measurements were conducted in Shiraho Reef (Okinawa, Japan) to investigate nearshore submarine groundwater discharge (SGD(nearshore)) dynamics. Estimated average groundwater flux was 2-3 cm/h (maximum 7-8 cm/h). End-member radon concentration and gas transfer coefficient were identified as major factors influencing flux estimation accuracy. For the 7-km long reef, SGD(nearshore) was 0.39-0.58 m3/s, less than 30% of Todoroki River's baseflow discharge. SGD(nearshore) was spatially and temporally variable, reflecting the strong influence of subsurface geology, tidal pumping, groundwater recharge, and hydraulic gradient. SGD(nearshore) elevated nearshore nitrate concentrations (0.8 2.2 mg/l) to half of Todoroki River's baseflow NO3--N (2-4 mg/L). This increased nearshore Chl-alpha from 0.5-2 MUg/l compared to the typically low Chl-alpha (< 0.1-0.4 MUg/l) in the moat. Diatoms and cyanobacteria concentrations exhibited an increasing trend. However, the percentage contributions of diatoms and cyanobacteria significantly decreased and increased, respectively. SGD may significantly induce the proliferation of cyanobacteria in nearshore reef areas. PMID- 21295317 TI - Occurrence of priority pollutants in WWTP effluents and Mediterranean coastal waters of Spain. AB - A comprehensive study aimed at evaluating the occurrence, significance of concentrations and spatial distribution of priority pollutants (PPs) along the Comunidad Valenciana coastal waters (Spain) was carried out in order to fulfil the European Water Framework Directive (WFD). Additionally, PP concentrations were also analysed in the effluent of 28 WWTPs distributed along the studied area. In coastal waters 36 organic pollutants of the 71 analysed, including 26 PPs were detected although many of them with low frequency of occurrence. Only 13 compounds, which belong to four different classes (VOCs, organochlorinated pesticides, phthalates and tributyltin compounds (TBT)) showed a frequency of occurrence above 20% in coastal waters. In the results obtained until now, octylphenol, pentachlorobenzene, DEHP and TBT exceeded the annual average concentration (EQS-AAC), and only TBT surpassed the maximum allowable concentration (EQS-MAC). The most frequent contaminants determined in coastal waters were also present in WWTP effluents. PMID- 21295318 TI - Field comparison of passive sampling and biological approaches for measuring exposure to PAH and alkylphenols from offshore produced water discharges. AB - Polycyclic aromatic hydrocarbons (PAH) and alkylphenols (AP) that are present in routine discharges of produced water (PW) from the offshore industry continue to cause concern. The suitability of biological methods and chemical based passive samplers to determine exposure to these compounds was tested by deploying them around an oil installation and at reference locations in the North Sea. PAH and AP were analysed either as parent compounds in passive samplers and mussel tissue or as metabolites in fish bile. Generally the pattern of exposure relative to proximity to the discharge was represented by mussels, SPMDs and fish for PAH. Fish and SPMDs showed good correlation for PAH accumulations, whereas some differences were apparent between mussels and SPMDs. POCIS was the only technique tested that could accurately measure the most abundant AP in PW. The advantages of biologically independent measures of exposure for inclusion in discharge monitoring studies are outlined. PMID- 21295319 TI - Secondary metabolites from the leaves of Neolitsea hiiranensis and the anti inflammatory activity of some of them. AB - Seven sesquiterpenoids, hiiranlactones A-D (1-4), (-)-ent-6alpha-methoxyeudesm 4(15)-en-1beta-ol (5), (+)-villosine (6), hiiranepoxide (7), and one triterpenoid, hiiranterpenone (8), together with 22 known compounds, were isolated from the leaves of Neolitsea hiiranensis (Lauraceae). Their structures were elucidated by spectroscopic analysis and single crystal X-ray diffraction. Among the isolates, hiiranlactone B (2) and hiiranlactone D (4) exhibited inhibitory activity against fMLP-induced superoxide production by human neutrophils with IC(50) values of 21.86+/-3.97 and 25.78+/-4.77MUM, respectively. PMID- 21295320 TI - [Cephalometric study of the velocardiofacial syndrome: Impact of dysmorphosis on phonation]. AB - INTRODUCTION: Velopharyngeal insufficiency is a frequent sign of the velocardiofacial syndrome (VCFS) but its origins are not well-documented. Our aim was to establish a correlation between this functional disorder and regional morphological anomalies. PATIENTS AND METHODS: Twenty-seven of 36 patients presenting with VCFS could be included retrospectively. We measured cavum depth and velum length on lateral orthodontic X-rays, and assessed the relationship between these two measures. We compared these measures to those of reference populations. Postoperative phonation was assessed with an aerophonoscope. RESULTS: The patients presented with a short velum and a deep cavum. Cranium base and upper cervical spine were malformed in 22 of the 27 patients. Seventeen of the 23 assessed patients (66%) improved their phonation after surgery. DISCUSSION: Our data suggests that velopharyngeal insufficiency in VCFS could be the result of a more global craniospinal growth disorder the functional consequences of which remain unclear. The frequent association of morphological anomalies with mental retardation is probably responsible for the failure to normalize phonation. PMID- 21295321 TI - [Bronchogenic cervical cyst in a child]. AB - INTRODUCTION: The bronchogenic cyst is a rare congenital malformation of the tracheobronchial tree. Ectopic bronchogenic cysts are extremely rare; they usually develop at the cervical level. This cyst is characterized by the presence of respiratory epithelium. OBSERVATION: A 5-year-old child was referred to maxillofacial surgery consultation because a right bronchial cyst was suspected. The radiological assessment suggested a thyroglossal tract cyst. The anatomopathological examination confirmed the cyst and lead to the final diagnosis of a dysembryoplastic bronchogenic cyst. DISCUSSION: A bronchogenic cyst is rarely found at the cervical level. When this is the case, its embryological origin and management may be discussed. The preoperative diagnosis may be complex with no clinical or non-specific symptomatology. A complete excision of the lesion must be performed to reduce the risk of recurrence and malignant transformation. PMID- 21295322 TI - Controlling the transmission of ultrahigh frequency bulk acoustic waves in silicon by 45 degrees mirrors. AB - In this paper, we present a feasible microsystem in which the direction of localized ultrahigh frequency (~1GHz) bulk acoustic wave can be controlled in a silicon wafer. Deep etching technology on the silicon wafer makes it possible to achieve high aspect ratio etching patterns which can be used to control bulk acoustic wave to transmit in the directions parallel to the surface of the silicon wafer. Passive 45 degrees mirror planes obtained by wet chemical etching were employed to reflect the bulk acoustic wave. Zinc oxide (ZnO) thin film transducers were deposited by radio frequency sputtering with a thickness of about 1MUm on the other side of the wafer, which act as emitter/receptor after aligned with the mirrors. Two opponent vertical mirrors were inserted between the 45 degrees mirrors to guide the transmission of the acoustic waves. The propagation of the bulk acoustic wave was studied with simulations and the characterization of S(21) scattering parameters, indicating that the mirrors were efficient to guide bulk acoustic waves in the silicon wafer. PMID- 21295323 TI - Emerging picture of host chaperone and cyclophilin roles in RNA virus replication. AB - Many plus-strand (+)RNA viruses co-opt protein chaperones from the host cell to assist the synthesis, localization and folding of abundant viral proteins, to regulate viral replication via activation of replication proteins and to interfere with host antiviral responses. The most frequently subverted host chaperones are heat shock protein 70 (Hsp70), Hsp90 and the J-domain co chaperones. The various roles of these host chaperones in RNA virus replication are presented to illustrate the astonishing repertoire of host chaperone functions that are subverted by RNA viruses. This review also discusses the emerging roles of cyclophilins, which are peptidyl-prolyl isomerases with chaperone functions, in replication of selected (+)RNA viruses. PMID- 21295324 TI - Minute virus of mice (MVMp) infection and NS1 expression induce p53 independent apoptosis in transformed rat fibroblast cells. AB - Parvoviruses infect and kill tumor cells in vivo and in vitro more efficiently than normal cells. Infection of transformed cells by the parvovirus minute virus of mice (MVM) results in high expression of the major non-structural cytolytic viral protein NS1, which induces a cell death modulated by cellular factors. In this work, we show that MVMp infection and/or NS1 protein expression in permissive transformed rat fibroblast cells leads to apoptosis in wild type and p53(-/-) cells. Apoptotic cell morphology correlates with mitochondrial membrane permeabilization and activation of caspases 9 and 3 but not caspase 8. Thus, further characterization of the antitumor activity of MVMp and its NS1 protein may contribute to the eradication of tumors, including those lacking p53. PMID- 21295325 TI - Exposure to PCBs, through inhalation, dermal contact and dust ingestion at Taizhou, China--a major site for recycling transformers. AB - Air samples containing gaseous and particulate phases were collected from e-waste workplaces and residential areas of an intensive e-waste recycling area and compared with a reference site. The highest total concentration of PCBs was detected at transformer recycling workshops (17.6 ng m(-3)), followed by the residential area (3.37 ng m(-3)) at Taizhou, and the lowest was obtained at the residential area of the reference site, Lin'an (0.46 ng m(-3)). The same trend was also observed with regards to PCB levels in dust samples. The highest average PCBs level of 2824 ng g(-1) (dry wt) was found in the transformer recycling workshops, and was significantly higher than that of residential areas of Taizhou (572 ng g(-1) dry wt) and Lin'an (42.4 ng g(-1) dry wt). WHO-PCB-TEQ level in the workshops of Taizhou was 2216 pg TEQ(1998)g(-1) dry wt or 2159 pg TEQ(2005)g(-1) dry wt, due to the high abundance of PCB 126 (21.5 ng g(-1) dry wt), which contributed 97% or 99% of WHO-PCB-TEQs. The estimated intake of PCBs via dust ingestion and dermal absorption by transformer recycling workers were 77.5*10(-5) and 36.0*10(-5) pg WHO-PCB-TEQ(1998)kg(-1)d(-1), and 67.3*10(-5) and 31.3*10(-5) pg WHO-PCB-TEQ(2005)kg(-1)d(-1), respectively. PMID- 21295326 TI - Fate of bisphenol A during treatment with the litter-decomposing fungi Stropharia rugosoannulata and Stropharia coronilla. AB - Bisphenol A is an endocrine disrupting compound, which is ubiquitous in the environment due to its wide use in plastic and resin production. Seven day old cultures of the litter-decomposing fungus Stropharia coronilla removed the estrogenic activity of bisphenol A (BPA) rapidly and enduringly. Treatment of BPA with purified neutral manganese peroxidase (MnP) from this fungus also resulted in 100% reduction of estrogenic activity, as analyzed using a bioluminescent yeast assay, and in the formation of polymeric compounds. In cultures of Stropharia rugosoannulata, estrogenic activity also quickly disappeared but temporarily re-emerged in the further course of cultivation. LC-MS analysis of the extracted estrogenic culture liquid revealed [M-H](-) ions with m/z values of 219 and 235. We hypothesize that these compounds are ring fission products of BPA, which still exhibit one intact hydroxyphenyl group to interact with estrogen receptors displayed by the yeast. PMID- 21295327 TI - A sporadic multiple gastrointestinal stromal tumor with unique clinical and molecular features. AB - Most sporadic gastrointestinal stromal tumors occur as solitary lesions, whereas a multicentric appearance involving the stomach, the small intestine, or both sites is suspicious for lesions developed in the setting of hereditary or idiopathic tumor syndromes or metastatic disease. The rare occurrence of multiple sporadic gastrointestinal stromal tumors has been recently reported in the literature. Here, we report a case of multiple sporadic gastrointestinal stromal tumors affecting the small intestine in a 61-year-old man, unique with regard to the number of lesions (>30) and the molecular profile. Four different mutations of KIT involving exons 11, 13, and 17 were present among 4 of 10 excised tumors. In addition, BRAF p.V600E mutation was detected in 5 tumors and was mutually exclusive with KIT mutations. To our knowledge, this is the first time a case of a synchronic multisporadic gastrointestinal stromal tumor outstanding for the high number of lesions, which are of independent origin, is reported. PMID- 21295328 TI - Nickel levels in convenience and fast foods: in vitro study of the dialyzable fraction. AB - Nickel presence was determined in 170 samples of 43 different convenience and fast foods widely consumed in Spain. Electrothermal atomic absorption spectrometry was used as analytical technique. Reliability of the procedure was checked. Ni levels ranged from 18.50 to 95.00 ng g(-1) (fresh weight of edible portion). The most elevated Ni concentrations were found in egg- and pork-based foods and in sauces but there is a high variability inside of each one of these foods. Ni content increases in products that contain spices and aromatic herbs, whole cereals, dry fruits, cheese and mushrooms. Mean Ni dialyzable fraction estimated by in vitro assays ranged from 4.50 to 7.75%. This study shows that the probability of exposure to health risks from these foods is overall small. However, the present findings are of potential use in food composition tables and to estimate the Ni dietary intake and tolerable intake levels in accordance with the current dietary habits. PMID- 21295329 TI - Total blood mercury, plasma homocysteine, methylmalonic acid and folate in US children aged 3-5 years, NHANES 1999-2004. AB - BACKGROUND: Mercury is a known neurotoxicant; however, the relationship between childhood exposures and neurodevelopmental outcomes is uncertain, and may be modified by nutrition-related susceptibilities. In vitro studies found that mercury inhibited methionine synthase, an enzyme that interacts with vitamin B-12 and folate to regenerate the amino acid methionine from homocysteine, and inhibition of methionine synthase diverted homocysteine to cysteine and glutathione synthesis. The relationships between mercury, homocysteine, B-12, and folate have not been examined in children. OBJECTIVE: This study aimed to evaluate associations between Hg and homocysteine in male and female children differentiated by higher and lower methylmalonic acid (MMA, an indicator of vitamin B-12 deficiency) and folate status. DESIGN: Cross-sectional data on total blood mercury (Hg), plasma homocysteine, MMA, and serum folate were obtained from the 1999-2004 National Health and Nutrition Examination Surveys for children aged 3-5 years (n=1005). We used multiple linear regression to evaluate relationships between homocysteine and Hg quartiles, stratified by sex, MMA >= and folate < sample medians, adjusted for demographic, anthropometric, and environmental factors. RESULTS: In boys with higher MMA and lower folate (n=135), but not in other children, we observed inverse associations between homocysteine and Hg. Children with Hg >3.49 MUmol/L showed 1.14 MUmol/L lower homocysteine (p<0.001) relative to the lowest quartile (<= 0.70 MUmol/L) {p-value for trend<0.001}. Compared to other subsamples, this subsample had significantly higher homocysteine levels. CONCLUSION: Hg was inversely correlated with plasma homocysteine in young boys, but not girls, with higher MMA and lower folate. Additional studies are merited to evaluate Hg and amino acid metabolism in susceptible children. PMID- 21295330 TI - High-dose cyclophosphamide without stem cell rescue for the treatment of refractory Behcet's disease. AB - OBJECTIVE: Behcet's disease (BD) is a systemic inflammatory disorder characterized by recurrent mucocutaneous ulcerations, ocular inflammation, and numerous severe systemic inflammatory manifestations. While most patients respond to standard immunosuppressive therapies, a subset will develop refractory disease. In this report, the use of a novel therapy for the treatment of BD is described. METHODS: Two patients with severe refractory BD who were treated with nonmyeloablative high-dose cyclophosphamide therapy without stem cell rescue. RESULTS: After treatment, both patients were completely weaned off immunosuppressive therapy and entered disease-free remissions of 18 and 24 months, respectively. CONCLUSIONS: These data suggest high-dose cyclophosphamide therapy without stem cell rescue as an alternative for the treatment of refractory BD. PMID- 21295331 TI - Imaging of synovitis in osteoarthritis: current status and outlook. AB - OBJECTIVES: This review article provides an overview of the current state of imaging of synovitis in osteoarthritis (OA), looking at recent advances and controversies and focusing particularly on the application of ultrasound and magnetic resonance imaging (MRI) in the assessment of the hand and knee joint. Computed tomography and nuclear medicine including positron emission tomography are also briefly discussed. METHODS: PubMed and MEDLINE search for articles published up to 2010, using the keywords synovitis, osteoarthritis, rheumatoid arthritis, pathogenesis, imaging, radiography, computed tomography, nuclear medicine, magnetic resonance imaging, ultrasound, and pain. RESULTS: Synovitis is defined as inflammation of the synovial membrane. Modern imaging techniques have demonstrated that synovial pathology is common in the early and late stages of OA and may be associated with pain. The current standard for OA imaging in clinical practice is conventional radiography but it does not allow direct visualization of synovitis. MRI without contrast administration, although widely used in clinical studies, cannot assess synovitis directly. Contrast-enhanced MRI and ultrasound, however, both allow direct visualization of synovitis including early inflammatory changes. They are regularly used to image synovitis in rheumatoid arthritis and increasingly in OA. CONCLUSIONS: Synovitis is increasingly recognized as an important feature of the pathophysiology of OA, although there is conflicting evidence with respect to its association with disease severity and clinical parameters. Contrast-enhanced MRI and ultrasound are the most important methods for assessing synovitis associated with OA. PMID- 21295332 TI - The proper use of multimodality treatment in locally advanced cervical cancer. PMID- 21295333 TI - Paraganglioma of the uterus. A case report and review of literature. PMID- 21295334 TI - Celiac lymph node resection and porta hepatis disease resection in advanced or recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancer. AB - INTRODUCTION: Prognostic value of complete macroscopic resection of primary disease has been reported and confirmed in several publications. Published data indicate that extensive upper abdominal disease involving the hepatic pedicle and celiac trunk is associated with an abortion of the surgical procedure or with suboptimal residual disease. METHODS: All patients who had disease at the porta hepatis or celiac lymph node resection as part of cytoreductive surgery were included. Medical and operative records with particular emphasis on extent and distribution of disease spread, number of peritonectomy procedures, visceral resections, and lymphadenectomy procedures were examined. RESULTS: A total of 28 patients who underwent some kind of celiac lymph node resection or resection of metastatic involvement of the porta hepatis were included. Median preoperative serum Ca-125 level was 78U/ml (range, 30-2950U/ml), and median ascites volume was 1900ml (range, 0-10,000ml). Of the 28 patients, 23 underwent supra-radical surgery for diffuse peritoneal carcinomatosis. Median operative time was 252minutes (range, 100-540minutes). Complete cytoreduction to CCO was achieved in all except one case, who was cytoreduced to millimetric residue. Fifteen patients had positive celiac nodes and nineteen patients had peritoneal disease in the porta hepatis region. DISCUSSION: Resection of enlarged nodes and metastatic disease to the porta hepatis is feasible with an acceptable morbidity. The decision to undergo an aggressive cytoreductive surgery is based on appropriate patient selection depending on the extension of surgical procedure, on medical comorbidities, and on the potential to tolerate an extensive procedure, rather than on specific anatomic locations. PMID- 21295335 TI - Insulin-like growth factor-I receptor inhibition by specific tyrosine kinase inhibitor NVP-AEW541 in endometrioid and serous papillary endometrial cancer cell lines. AB - PURPOSE: The role of the insulin-like growth factor (IGF) system in endometrial cancer has been well established. The IGF-I receptor (IGF-IR) emerged as a promising therapeutic target in a number of cancers. NVP-AEW541 (Novartis Pharma) is a pyrrolo(2,3-d)pyrimidine derivative with specific IGF-IR tyrosine kinase inhibitory activity. NVP-AEW541 has been shown to abrogate IGF-I-mediated IGF-IR autophosphorylation and to reduce activation of the IGF-IR signaling pathways. The aim of the present study was to investigate the anti-proliferative activity of NVP-AEW541 in Type I (endometrioid) and Type II (uterine serous papillary endometrial carcinoma, USPC) endometrial cancer cell lines. METHODS: Type I (ECC 1, Ishikawa) and Type II (USPC-1, USPC-2) endometrial cancer cell lines were treated with NVP-AEW541 in the presence of IGF-I, and the following parameters were measured: IGF-IR, AKT and ERK phosphorylation, apoptosis, proliferation, cell cycle progression and IGF-IR internalization. RESULTS: Results obtained showed that NVP-AEW541 abolished the IGF-I stimulated IGF-IR phosphorylation in all of the cell lines investigated, whereas it abolished AKT and ERK phosphorylation preferentially in ECC-1 and USPC-1 cells. Furthermore, the inhibitor prevented from IGF-I from exerting its antiapoptotic effect in ECC-1, USPC-1 and USPC-2 cells. In addition, proliferation assays showed that NVP-AEW541 caused a decrease in proliferation rate in all of the cell lines. NVP-AEW541 had no major effect on the insulin receptor. CONCLUSION: Our results suggest that specific IGF-IR inhibition by NVP-AEW541 might be a promising therapeutic tool in endometrial cancer. PMID- 21295336 TI - The effect of operative hysteroscopy conducted before progestin treatment in early stage endometrial cancer from the view of fertility. PMID- 21295337 TI - IL-7 engages multiple mechanisms to overcome chronic viral infection and limit organ pathology. AB - Understanding the factors that impede immune responses to persistent viruses is essential in designing therapies for HIV infection. Mice infected with LCMV clone 13 have persistent high-level viremia and a dysfunctional immune response. Interleukin-7, a cytokine that is critical for immune development and homeostasis, was used here to promote immunity toward clone-13, enabling elucidation of the inhibitory pathways underlying impaired antiviral immune response. Mechanistically, IL-7 downregulated a critical repressor of cytokine signaling, Socs3, resulting in amplified cytokine production, increased T cell effector function and numbers, and viral clearance. IL-7 enhanced thymic output to expand the naive T cell pool, including T cells that were not LCMV specific. Additionally, IL-7 promoted production of cytoprotective IL-22 that abrogated liver pathology. The IL-7-mediated effects were dependent on endogenous IL-6. These attributes of IL-7 have profound implications for its use as a therapeutic in the treatment of chronic viral diseases. PMID- 21295338 TI - Adolescent academic outcomes in school context: network effects reexamined. AB - This study examines the role of racial/ethnic segregation and peer effects in shaping educational achievement and attainment, using multi-level modeling on a nationally representative sample of adolescents. As in many prior studies, school socioeconomic composition was a significant predictor of achievement and attainment for students of all racial/ethnic groups. Educational attainment was negatively affected by the concentration of low-income students. However, for some racial/ethnic groups educational attainment increased with higher concentrations of minority students. Furthermore, peer social capital, measured as the average achievement of a peer network, was a significant predictor of both educational achievement and attainment for all racial/ethnic groups. In addition, and counter to some earlier studies, results revealed that segregated peer networks among African-Americans may lead to better academic achievement and attainment than school settings with more integrated friendship networks. PMID- 21295339 TI - Detection of prion infection in variant Creutzfeldt-Jakob disease: a blood-based assay. AB - BACKGROUND: Variant Creutzfeldt-Jakob disease (vCJD) is a fatal neurodegenerative disorder originating from exposure to bovine-spongiform-encephalopathy-like prions. Prion infections are associated with long and clinically silent incubations. The number of asymptomatic individuals with vCJD prion infection is unknown, posing risk to others via blood transfusion, blood products, organ or tissue grafts, and contaminated medical instruments. We aimed to establish the sensitivity and specificity of a blood-based assay for detection of vCJD prion infection. METHODS: We developed a solid-state binding matrix to capture and concentrate disease-associated prion proteins and coupled this method to direct immunodetection of surface-bound material. Quantitative assay sensitivity was assessed with a serial dilution series of 10-7 to 10-10 of vCJD prion-infected brain homogenate into whole human blood, with a baseline control of normal human brain homogenate in whole blood (10-6). To establish the sensitivity and specificity of the assay for detection of endogenous vCJD, we analysed a masked panel of 190 whole blood samples from 21 patients with vCJD, 27 with sporadic CJD, 42 with other neurological diseases, and 100 normal controls. Samples were masked and numbered by individuals independent of the assay and analysis. Each sample was tested twice in independent assay runs; only samples that were reactive in both runs were scored as positive overall. FINDINGS: We were able to distinguish a 10-10 dilution of exogenous vCJD prion-infected brain from a 10-6 dilution of normal brain (mean chemiluminescent signal, 1.3*105 [SD 1.1*104] for vCJD vs 9.9*104 [4.5*103] for normal brain; p<0.0001)-an assay sensitivity that was orders of magnitude higher than any previously reported. 15 samples in the masked panel were scored as positive. All 15 samples were from patients with vCJD, showing an assay sensitivity for vCJD of 71.4% (95% CI 47.8-88.7) and a specificity of 100% (95% CIs between 97.8% and 100%). INTERPRETATION: These initial studies provide a prototype blood test for diagnosis of vCJD in symptomatic individuals, which could allow development of large-scale screening tests for asymptomatic vCJD prion infection. FUNDING: UK Medical Research Council. PMID- 21295340 TI - A prototype assay to detect vCJD-infected blood. PMID- 21295341 TI - Toxicity of ammonia to surf clam (Spisula solidissima) larvae in saltwater and sediment elutriates. AB - Ammonia is a natural component of sediments and has been identified as a common contributor to toxicity in marine sediment, elutriate and porewater testing. In our study, the role of ammonia as a possible toxicant in sediment toxicity tests was evaluated using larvae of the surf clam, Spisula solidissima. Elutriates were prepared and tested using six baseline sediment samples. Ammonia was then purged from aliquots of the baseline sediment samples prior to elutriate preparation. Finally, ammonia was spiked into aliquots of the purged elutriates to mimic ammonia concentrations measured in the baseline elutriates. Toxicity was present in all of the baseline samples and was removed in the ammonia purged samples. In most cases, toxicity was comparable in the ammonia spiked samples to levels measured in the baseline samples. Water only toxicity tests revealed that larvae of the surf clam are one of the more ammonia sensitive marine species. The LC50 for survival was 10.6 mg/L total ammonia (.53 mg/L unionized ammonia) and the EC50 for shell development was 2.35 mg/L total ammonia (.12 mg/L unionized ammonia). Toxicity endpoints calculated from the water only ammonia toxicity test were good predictors of effects observed in the sediment elutriate tests. PMID- 21295342 TI - Self-organization, interfacial interaction and photophysical properties of gold nanoparticle complexes derived from resilin-mimetic fluorescent protein rec1 resilin. AB - In this investigation we report the synthesis of optically coupled hybrid architectures based on a new biomimetic fluorescent protein rec1-resilin and nanometer-scale gold nanoparticles (AuNPs) in a one-step method using a non covalent mode of binding protocol. The presence of uniformly distributed fluorophore sequences, -Ser(Thr)-Tyr-Gly- along the molecular structure of rec1 resilin provides significant opportunity to synthesize fluorophore-modified AuNPs bioconjugates with unique photophysical properties. The detailed analyses of the AuNP-bioconjugates, synthesized under different experimental conditions using spectroscopic, microscopic and scattering techniques demonstrate the organizational pathways and the electronic and photophysical properties of the developed AuNP-rec1-resilin bioconjugates. The calculation of the bimolecular quenching constant using the Stern-Volmer equation confirms that the dominant mechanism involved in quenching of fluorescence of rec1-resilin in the presence of AuNP is static. Photoacoustic infrared spectroscopy was employed to understand the nature of the interfacial interaction between the AuNP and rec1-resilin and its evolution with pH. In such bioconjugates the quenched emission of fluorescence by AuNP on the fluorophore moiety of rec1-resilin in the immediate vicinity of the AuNP has significant potential for fluorescence-based detection schemes, sensors and also can be incorporated into nanoparticle-based devices. PMID- 21295343 TI - The prevention of biofilm colonization by multidrug-resistant pathogens that cause ventilator-associated pneumonia with antimicrobial-coated endotracheal tubes. AB - Ventilator-associated pneumonia (VAP) continues to be the nosocomial infection associated with the highest mortality in critically ill patients. Since silver coated endotracheal tubes (ETT) was shown in a multicenter prospective randomized trials to decrease the risk of VAP, we compared the efficacy of two antiseptic agents such as gardine- and gendine-coated ETTs with that of silver-coated ETTs in preventing biofilm. The ETTs were tested for their ability to prevent the biofilm formation of methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Enterobacter cloacae, and Candida albicans. Scanning electron microscopy studies revealed a heavy biofilm on uncoated and silver-coated ETT but not on the gardine coated ETT. The gardine and gendine ETTs completely inhibited the formation of biofilms by all organisms tested and were more effective in preventing biofilm growth than the silver ETTs (p < 0.001). The gardine- and gendine-coated ETTs were more durable against MRSA than either the silver-coated or uncoated ETTs for up to 2 weeks (p < 0.0001). We have therefore shown that gardine- and gendine coated ETTs are superior to silver-coated ETTs in preventing biofilm. Future animal and clinical studies are warranted to determine whether the gardine- and gendine-coated ETTs can significantly reduce the risk of VAP. PMID- 21295344 TI - In vivo magnetic resonance imaging of cell tropism, trafficking mechanism, and therapeutic impact of human mesenchymal stem cells in a murine glioma model. AB - Stem cells have offered much promise as delivery vehicles for brain tumor therapy, with the development of modalities to track the tumor tropism of stem cells receiving intense focus. Cellular magnetic resonance imaging (MRI) allows serial high-resolution in vivo detection of transplanted stem cells' tropism toward gliomas in the mouse brain once these cells are internally labeled with iron oxide particles, but has been impeded by low labeling efficiencies. In this study, we describe the use of ferucarbotran and protamine (Fer-Pro) complexes for labeling human mesenchymal stem cells (hMSCs) for MRI tracking of glioma tropism in vivo. We found that Fer-Pro was not toxic and was highly efficient for labeling in vitro. Cell labeling with Fer-Pro promoted the migration of hMSCs toward glioma U87MG cells in vitro, which was mediated by stromal-derived factor 1/CXCR4 (SDF-1/CXCR4) signaling. Fer-Pro-labeled hMSCs could migrate specifically toward gliomas in vivo, which was observed with a clinical 1.5-T MRI system. The efficient labeling of Fer-Pro also allowed a tropic mechanism mediated by SDF 1/CXCR4 signaling to be detected by MRI in vivo. Additionally, the potential intrinsic inhibitory effect of hMSCs on glioma progression was estimated simultaneously. This is the first report to have used a clinical MRI modality to simultaneously study the migration, the therapeutic impact on tumors, and above all the trafficking mechanism of bone marrow-derived mesenchymal stem cells from human in a murine glioma xenograft model. The use of Fer-Pro for stem cell labeling may have potential clinical applications in stem cell guided therapy. PMID- 21295345 TI - Fluorine-18 labeled rare-earth nanoparticles for positron emission tomography (PET) imaging of sentinel lymph node. AB - Rare-earth-based nanoparticles have attracted increasing attention for their unique optical and magnetic properties. However, their application in bioimaging has been limited to photoluminescence bioimaging and magnetic resonance imaging. To facilitate their use in other bioimaging techniques, we developed a simple, rapid, efficient and general synthesis strategy for (18)F-labeled rare-earth nanoparticles through a facile inorganic reaction between rare-earth cations and fluoride ions. The (18)F-labeling process based on rare-earth elements was achieved efficiently in water at room temperature with an (18)F-labeling yield of >90% and completed within 5 min, with only simple purification by aqueous washing and centrifugation, and without the use of organic agents. The effectiveness of (18)F-labeled rare-earth nanoparticles was further evaluated by positron emission tomography (PET) imaging of their in vivo distribution and application in lymph monitoring. In addition, this strategy is proposed for the creation of a dual model bioimaging technique, combining upconversion luminescence bioimaging and PET imaging. PMID- 21295346 TI - Fetal and postnatal pulmonary circulation in the Alto Andino. AB - Lowland mammals at high altitude constrict the pulmonary vessels, augmenting vascular resistance and developing pulmonary arterial hypertension. In contrast, highland mammals, like the llama, do not present pulmonary arterial hypertension. Using wire myography, we studied the sensitivity to norepinephrine (NE) and NO of small pulmonary arteries of fetal llamas and sheep at high altitudes. The sensitivity of the contractile responses to NE was decreased whereas the relaxation sensitivity to NO was augmented in the llama fetus compared to the sheep fetus. Altogether these data show that the fetal llama has a lower sensitivity to a vasoconstrictor (NE) and a higher sensitivity to a vasodilator (NO), than the fetal sheep, consistent with a lower pulmonary arterial pressure found in the neonatal llama in the Andean altiplano. Additionally, we investigated carbon monoxide (CO) in the pulmonary circulation in lowland and highland newborn sheep and llamas. Pulmonary arterial pressure was augmented in neonatal sheep but not in llamas. These sheep had reduced soluble guanylate cyclase and heme oxygenase expression and CO production than at lowland. In contrast, neonatal llamas increased markedly pulmonary CO production and HO expression at high altitude. Thus, enhanced pulmonary CO protects against pulmonary hypertension in the highland neonate. Further, we compared pulmonary vascular responses to acute hypoxia in the adult llama versus the adult sheep. The rise in pulmonary arterial pressure was more marked in the sheep than in the llama. The llama pulmonary dilator strategy may provide insights into new treatments for pulmonary arterial hypertension of the neonate and adult. PMID- 21295347 TI - L-type calcium channel auto-regulation of transcription. AB - L-type calcium channels (LTCC) impact the function of nearly all excitable cells. The classical LTCC function is to mediate trans-sarcolemmal Ca(2+) flux. This review focuses on the contribution of a mobile segment of the LTCC that regulates ion channel function, and also serves as a regulator of transcription in the nucleus. Specifically we highlight recent work demonstrating an auto-feedback regulatory pathway whereby the LTCC transcription factor regulates the LTCC. Also discussed is acute and long-term regulation of function by the LTCC-transcription regulator. PMID- 21295348 TI - 4-Methlycatechol prevents NGF/p75(NTR)-mediated apoptosis via NGF/TrkA system in pancreatic beta cells. AB - In this study, it was aimed to investigate whether 4-methylcatechol (4-MC) could serve as an autocrine antiapoptotic agent by increasing nerve growth factor (NGF) in beta cells of hyperglycemic rats. Rats were divided into four groups: the first group was given citrate buffer and saline, the second group was administered 4-MC, the third group received streptozotocin (STZ), and the fourth group was given both 4-MC and STZ. 4-MC (10 MUg/kg) was administered by daily intraperitoneal injection for 10 days before the animals were rendered hyperglycemic by administration of STZ (75 mg/kg). With 4-MC pretreatment on hyperglycemic rats the following results were noted: (i) Increase in plasma glucose, beta cell apoptosis and caspase-8 activation was prevented. (ii) Reduction of NGF+ and tyrosine receptor kinase A (TrkA)+ beta cell number was blocked. (iii) p75 neurotrophin receptor (p75(NTR))+ beta cell number was increased. These data suggest that 4-MC might exert its antiapoptotic actions through NGF/TrkA system which may block NGF/p75(NTR) activation in pancreatic beta cells of hyperglycemic rats. PMID- 21295349 TI - Genetic association between BDNF gene polymorphisms and phobic disorders: a case control study among mainland Han Chinese. AB - INTRODUCTION: Phobic disorders are a common group of syndromes comprising persistently recurring, irrational severe anxiety of specific objects, activities, or situations with avoidance behavior of the phobic stimulus. The present study investigated the association between whole region polymorphisms, (including the Val66Met variant), in the BDNF gene and phobic disorders among Han Chinese young adults. METHODS: We conducted a case-control study to investigate the genetic association between BDNF polymorphisms and phobic disorders among mainland Chinese. One hundred and twenty young adults with phobic disorders and 267 matched controls were recruited. Three tag SNPs of BDNF were successfully genotyped by using PCR-based ligase detection reaction (PCR-LDR). RESULTS: We found significant differences in allele distributions of SNP rs10835210 (P<0.001) between the experimental and the control groups. In the haplotype analysis based on linkage-disequilibrium across this gene locus, we demonstrated significant association between phobic disorders and BDNF haplotype CAC (P=0.004). Association was significant after 10(4) permutation tests (P<0.001). CONCLUSION: To the best of our knowledge, this is the first study showing that the BDNF gene may play a significant role in the etiology of phobic disorders in the Han Chinese population. PMID- 21295350 TI - Risk indicators for post-traumatic stress disorder in adolescents exposed to the 5.12 Wenchuan earthquake in China. AB - In Chinese adolescents exposed to the Wenchuan earthquake, we used the Children's Revised Impact of Event Scale (CRIES) as the screening tool, and Post-traumatic Cognitions Inventory (PTCI) and the Social Support Rating Scale (SSRS) were used to assess the cognitive status and their social supports, to evaluate the prevalence and the predictors variables of post-traumatic stress disorder (PTSD) after the Wenchuan earthquake in China, which occurred on 12 May 2008. Subjects with a CRIES score greater than 30 were interviewed and assessed using the DSM-IV criteria for PTSD diagnosis by a trained psychiatrist with the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children Lifetime version (Kiddie-SADS-L). We found the overall prevalence of PTSD was 2.5% in 3208 adolescents from the surrounding areas of the epicentre 6months after the earthquake. Risk factors for post-traumatic stress symptoms are as follows: being female, being buried/injured during the earthquake, having parents who were severely injured, having classmate(s) who died, having a house destroyed, and witnessing someone buried/wounded/dying during the earthquake. Individuals with better social support had significantly lower scores on the CRIES. There were significant differences in cognitive style between individuals at low risk for PTSD (CRIES<30) and those at high risk for PTSD (CRIES>=30). Post-traumatic cognition emerged as an important factor that was associated with PTSD reactions in children. Social support can lessen the impact of a natural disaster by affecting post-traumatic cognition. PMID- 21295351 TI - Differential effects of childhood abuse and neglect: mediation by posttraumatic distress in neurotic disorder and negative symptoms in schizophrenia? AB - Dissociation, though understood as a response to trauma, lacks a proven etiology. The assumption of a dose-response relationship between trauma, dissociation and Schneiderian symptoms led to the proposal of a dissociative subtype of schizophrenia characterized by severe child maltreatment, dissociation and psychosis. Child maltreatment and dissociation are common features of neurotic disorders as well, and the link between trauma, dissociation, and hallucinations is not specific for schizophrenia. This study compares childhood abuse and neglect, posttraumatic distress and adult dissociation in patients with psychotic vs. non-psychotic disorder. Thirty-five participants with non-psychotic disorder and twenty-five with schizophrenia were analyzed using the Scale for the Assessment of Positive Symptoms (SAPS), the Scale for the Assessment of Negative Symptoms (SANS), the Montgomery-Asberg Depression Rating Scale (MADRS), the Posttraumatic Stress Diagnostic Scale PDS (PDS), the Childhood Trauma Questionnaire (CTO) and the Arbeitsgemeinschaft Methodik und Dokumentation in der Psychiatrie (AMDP)-module on dissociation. Trauma and clinical syndromes were compared by means of T-testing and logistic regression between 1) the diagnoses and 2) groups with and without post-traumatic stress disorder (PTSD), marked dissociation and psychotic symptoms. While non-psychotic disorder was related to abuse, schizophrenia showed an association with neglect. Childhood trauma predicted posttraumatic symptomatology and negative symptoms. Childhood abuse and neglect may effectuate different outcomes in neurotic and psychotic disorder. The underlying mechanisms, including dissociation, dovetail with cognitive, emotional and behavioural changes involved in depression, posttraumatic distress and chronic schizophrenia symptoms rather than being directly linked to trauma. PMID- 21295352 TI - Proportion of circulating chicken heterophils and CXCLi2 expression in response to Salmonella enteritidis are affected by genetic line and immune modulating diet. AB - Genetic line and diet affect chicken heterophil activity and gene expression, and the combination of these factors can enhance disease resistance. This study evaluated the effects of immune modulating diets on heterophil/lymphocyte (H/L) ratio and heterophil chemokine expression in distinct genetic lines. Fayoumi and Leghorn chickens were fed a basal diet or immune modulating diets enhanced with beta-glucans, ascorbic acid, or corticosterone. H/L ratios and heterophil gene expression in response to in vitro stimulation with Salmonella enteritidis (SE) were evaluated on days 1, 3, 7, and 21 of diet treatment. The stress-mimicking corticosterone diet influenced H/L ratio in the Leghorn line, but not the Fayoumi line, suggesting resistance to stress-induced immunosuppression in the Fayoumi line. Leghorn line H/L ratios were increased on days 1 and 3 of corticosterone diet treatment, but not days 7 or 21. Expression of CXCLi2 by SE stimulated heterophils was higher in the Leghorn line, suggesting that Leghorns rely more heavily on inflammatory response than do Fayoumis. Corticosterone diet was associated with reduced CXCLi2 expression in heterophils from both lines. Dietary beta-glucan or ascorbic acid did not affect H/L ratio or CXCLi2 expression, suggesting that benefits of these immunomodulators may not be evident in healthy birds. PMID- 21295353 TI - A comparison of audiometric and objective methods in hearing screening of school children. A preliminary study. AB - OBJECTIVE: In newborn hearing screening, one exclusively applies objective hearing testing methods--based on evoked potentials and/or on otoacoustic emissions. However, when testing school children, one can consider both audiometric and electrophysiological methods. The choice of methods is determined by the aims of the program. If one wants to detect conductive hearing losses, impedance audiometry seems to be the method of choice. METHODS: The aim of this study was to compare test performance measures from audiometric and objective methods (OAEs and impedance audiometry), in the hearing screening of school children. Screening protocols were applied on a group of 190 children of about 12 years of age (6th grade of primary school). RESULTS: For a single application of a screening procedure, the best performance was observed in the automated four tone audiometry, followed by the tympanometry and the TEOAE-based procedures. Screening performance was enhanced using a combination of automated and impedance audiometry. A four-tone audiometry test combined with tympanometry gives a sensitivity of 65%, and the PPV of 46%, which are reasonable values, acceptable for practical use. The use of a TEOAE protocol degrades the overall performance of screening. CONCLUSIONS: Screening of school children is feasible with a combination of automated audiometry and tympanometry with time requirements equal to 3 min per subject. PMID- 21295354 TI - A new measurement tool for speech development based on Ling's stages of speech acquisition in pediatric cochlear implant recipients. AB - OBJECTIVES: With the rapid increase of pediatric cochlear implantation (CI), there exists a need for a standardized assessment tool regarding speech and communication skills in children with CI. However, the current testing tools are not appropriate for the longitudinal evaluation of young children after CI. The aims of this study were to describe a progressive testing tool developed for the evaluation of speech acquisition and production in young children who have undergone CI and to examine its validity. METHODS: Sixty children younger than six years of age with CI participated in this study. A Korean version of Ling's stages (K-Ling) was developed based on the Ling speech teaching model to longitudinally assess phonologic and phonetic developments in young children after CI. The K-Ling, the Categories of Auditory Performance (CAP), and the Sequenced Language Scale for Infants (SELSI) were performed in the children with CI preoperatively and three, six, and 12 months postoperatively. Correlations among these three testing tools were analyzed. RESULTS: Auditory, language, and speech skills assessed using the CAP, SELSI, and K-Ling improved continuously for 12 months in young children following CI. Strong correlations were obtained among K-Ling's level, CAP scores, and the equivalent age of SELSI; correlation indices ranged from 0.540 to 0.800. CONCLUSIONS: The K-Ling was a valid evaluation tool regarding speech development in young children who are using CI and who are in the early stages of speech development. Longitudinal assessments of phonetic and phonologic developments may be attainable in young children using the K-Ling. PMID- 21295355 TI - Ear, nose and throat foreign bodies in children: a search for socio-demographic correlates. AB - OBJECTIVE: Ear nose and throat foreign bodies in children are one of the most common emergencies faced by otorhinolaryngologists. Our objective in the study conducted in the otolaryngology department of R.G. Kar Medical College & Hospital was to find out the socio-demographic correlates of self inflicted foreign body insertion in ear-nose-throat in children presenting in out patient department and emergency. METHODS: A cross sectional descriptive study was conducted from October 2009 to March 2010 in the out patient department and emergency of otolaryngology. Using a predesigned and pretested questionnaire, socio demographic data was collected prospectively on every alternate day by examining clinically all new pediatric patients attending with self-inflicted foreign body and interviewing their caregivers after removal of foreign body. The data collected from 288 children was analyzed by using simple proportion, odds ratio with 95% confidence interval, chi(2), t-test and analysis of one way variance (ANOVA) test. Epi info 3.4.3 version (CDC, Atlanta, retrieved from WHO website, on 01.11.09) and SPSS 17.0 were used for statistical calculations. RESULTS: Analysis showed male preponderance (59.72%) of cases from urban area (63.9%), predominance of 0-5 years age group with 5.19 +/- 3.02 (mean +/- standard deviation) years average age, nasal foreign body was on the top (44.4%), majority from low income (58.33%) joint family (65.3%) with housewives (75.0%) as primary care giver, majority of whom reported to have nil or low literacy (61.1%). 19.4% subjects having local pathology showed significant association with urban residence, joint family, low socio-economic status and two or less than two children of the mother of the participant children. Past history of similar incidence was found in 22.2% of study subjects and significantly associated with nasal foreign body insertion and higher among the children of housewives. CONCLUSIONS: Increasing awareness of the prime caregivers by the routine grass root level health workers may be tried to reduce incidence of this risky health event and capacity building of the Primary level physicians to handle foreign body insertion cases can lessen the stress of the victim children and their parents. PMID- 21295356 TI - Predicting the need of formal care in Taiwan: analysis of a national random sample. AB - The study aimed to examine the determinants of needing formal care and the factors impacting care arrangements in elderly Taiwanese by analyzing the 1999 and 2003 data of "The Survey of Health and Living Status of the Elderly in Taiwan", a prospective cohort study of older Taiwanese. For the purpose of this study, only participants 70 years or older were analyzed. The association of sociodemographic, lifestyle and health-related variables with care need and care arrangements at baseline and four years later were analyzed. Results showed that the major predictors of needing formal care in elderly Taiwanese were old age, cognitive impairment and functional disability. Self-perceived poor health and prior nursing-home admission were marginally significant. Results also showed that the traditional culture dictated care arrangement. Most elderly Taiwanese preferred to have private home carers (usually from neighboring countries) over institutionalization. The ratio of private care vs. institutionalization increased from 1:3 in 1999 to 1:1 in 2003 as the government allowed introducing more foreign carers. Results suggest that the major determinants of needing formal care in elderly Taiwanese are old age, and cognitive and functional impairments, similar to that observed in Western countries. However, culture and public policy impact care options. PMID- 21295357 TI - Acute myocardial infarction late following stent implantation: Incidence, mechanisms and clinical presentation. AB - Acute myocardial infarction (AMI) can occur late following stent implantation with an incidence up to >6% at 3-4 years, with no difference between DES and BMS. AMI can originate either from the stented site or from disease progression at nonstented sites. Restenosis, against previous thoughts, can lead to AMI. Stent thrombosis occurs with similar overall frequency following DES and BMS implantations, although a higher very late stent thrombosis with DES has been observed. Dissimilar mechanisms between BMS and DES thrombosis are very likely, with impaired neointimal healing being the rule for DES but the exemption for BMS. The use of invasive imaging techniques is useful in elucidating the involved mechanism. Disease progression is a particularly important cause of AMI late post stenting. The angiographic study depicted stent failure and disease progression equally implicated in the AMI late post stenting. When the AMI underlying mechanism is stent thrombosis, it usually occurs earlier and more frequently presented as STEMI compared to the other causes of AMI. The AMI caused by restenosis is more often presented as nonSTEMI, while disease progression leads to AMI later than the other causes. Further research should address equally not only the stent related inadequacies but also disease progression as causes of the future AMI. Angiographic follow-up and intracoronary imaging seem the most appropriate methods to define the exact pathophysiologic mechanism responsible for the AMI post stenting. PMID- 21295358 TI - Diabetes epidemic in China and its economic impact. PMID- 21295359 TI - Central pulse pressure and augmentation index in asymptomatic bicuspid aortic valve disease. PMID- 21295360 TI - Vitamin D deficiency is associated with significant coronary stenoses in asymptomatic African American chronic cocaine users. AB - BACKGROUND: Chronic cocaine use may lead to premature atherosclerosis, however, the prevalence of and risk factors for coronary artery disease in asymptomatic cocaine users have not been reported. METHODS: Between August 2007 and June 2010, 385 African American chronic cocaine users aged 25 to 54 years were consecutively enrolled in a study to investigate the prevalence of CT angiographically-defined significant (>= 50%) coronary stenosis and related risk factors. Sociodemographic, drug-use behavior, medical history and medication data were obtained by interview and confirmed by medical chart review. Clinical examinations were performed as well as extensive laboratory tests including those for fasting lipid profiles, HIV, high sensitivity C-reactive protein, and vitamin D. Contrast-enhanced coronary CT angiography was performed. RESULTS: Significant coronary stenosis was detected in 52 of 385 participants (13.5%). The prevalences were 12% and 30% in those with low risk and with middle-high risk Framingham score, respectively. In those with low risk scores, the prevalences of significant stenosis were 10% and 18% in those without and with vitamin D deficiency, defined as serum 25-(OH) vitamin D< 10 ng/mL (p=0.08). Multiple logistic regression analysis revealed that vitamin D deficiency (adjusted OR=2.18, 95% CI: 1.07-4.43) is independently associated with the presence of significant coronary stenosis after controlling for traditional risk factors. CONCLUSIONS: The study indicates that the prevalence of significant coronary stenoses is high in asymptomatic young and middle-aged African American chronic cocaine users. These findings emphasize the importance of aggressive reduction of risk factors, including vitamin D deficiency in this population. PMID- 21295361 TI - Evidence for non-ischemic scarring in patients with ventricular ectopy. PMID- 21295362 TI - Myocarditis and cardiac channelopathies: a deadly association? PMID- 21295363 TI - Rosuvastatin combined with ramipril significantly reduced atheroma volume by anti inflammatory mechanism: comparative analysis with rosuvastatin alone by intravascular ultrasound. AB - BACKGROUND: We tested the effects of rosuvastatin combined with ramipril on atheroma volume and its mechanism in de novo, intermediate coronary artery disease. METHODS: Subjects were randomly assigned to 2 treatment groups (rosuvastatin alone group; 20mg/day, combined group; rosuvastatin 20mg/day and ramipril 10mg/day). Total atheroma volume per 10mm segment (TAV/10mm), percent atheroma volume per 10mm segment (PAV/10mm) in entire indexed segments and TAV(most10), PAV(most10) in a 10mm subsegment with the greatest disease by intravascular ultrasound, and lipids, metabolic parameters (adiponectin, insulin sensitivity), biomarkers (hsCRP, matrix metalloproteinase-9) were analyzed at baseline and at 9-12 months follow-up. RESULTS: A total of 40 patients (rosuvastatin group; 21, combined group; 19), 46 lesions (rosuvastatin group; 24, combined group; 22) were finally analyzed. Rosuvastatin alone significantly reduced TAV/10mm (-7.8 +/- 17.4%, p<0.001) but did not change PAV/10mm, TAV(most10), PAV(most10) after therapy. In combined group, TAV/10mm, TAV(most10), PAV(most10) were significantly reduced after therapy (-10.7 +/- 11.5%, -13.4 +/- 14.5%, -2.7 +/- 5.8%, p<0.001, <0.001 and p=0.04) but PAV/10mm did not change. The magnitude of changes of all IVUS derived parameters did not differ significantly between 2 groups. Of interest, the most important factor for the changes of PAV(most10) was the percent changes of LDL cholesterol (beta=0.23, 95% CI [0.07-0.39], p=0.007) in rosuvastatin alone group and the changes in hsCRP (beta=1.89, 95% CI [0.63-3.14], p=0.005) and baseline fasting blood glucose (beta=0.06, 95% CI [0.01-0.11], p=0.02) in combined group by multivariate analysis. CONCLUSIONS: Rosuvastatin combined ramipril therapy significantly reduced atheroma volume that was related with anti-inflammatory effects. PMID- 21295364 TI - Determinants of long-term care spending: age, time to death or disability? AB - In view of population aging, better understanding of what drives long-term care expenditure (LTCE) is warranted. Time-to-death (TTD) has commonly been used to project LTCE because it was a better predictor than age. We reconsider the roles of age and TTD by controlling for disability and co-residence and illustrate their relevance for projecting LTCE. We analyze spending on institutional and homecare for the entire Dutch 55+ population, conditioning on age, sex, TTD, cause-of-death and co-residence. We further examined homecare expenditures for a sample of non-institutionalized conditioning additionally on disability. Those living alone or deceased from diabetes, mental illness, stroke, respiratory or digestive disease have higher LTCE, while a cancer death is associated with lower expenditures. TTD no longer determines homecare expenditures when disability is controlled for. This suggests that TTD largely approximates disability. Nonetheless, further standardization of disability measurement is required before disability could replace TTD in LTCE projections models. PMID- 21295365 TI - Pricing behaviour of nonprofit insurers in a weakly competitive social health insurance market. AB - In this paper we examine the pricing behaviour of nonprofit health insurers in the Dutch social health insurance market. Since for-profit insurers were not allowed in this market, potential spillover effects from the presence of for profit insurers on the behaviour of nonprofit insurers were absent. Using a panel data set for all health insurers operating in the Dutch social health insurance market over the period 1996-2004, we estimate a premium model to determine which factors explain the price setting behaviour of nonprofit health insurers. We find that financial stability rather than profit maximisation offers the best explanation for health plan pricing behaviour. In the presence of weak price competition, health insurers did not set premiums to maximize profits. Nevertheless, our findings suggest that regulations on financial reserves are needed to restrict premiums. PMID- 21295367 TI - Effect of acid tolerance response (ATR) on attachment of Listeria monocytogenes Scott A to stainless steel under extended exposure to acid or/and salt stress and resistance of sessile cells to subsequent strong acid challenge. AB - The aim of this study was to investigate the potential effect of adaptive stationary phase acid tolerance response (ATR) of Listeria monocytogenes Scott A cells on their attachment to stainless steel (SS) under low pH or/and high salt conditions and on the subsequent resistance of sessile cells to strong acid challenge. Nonadapted or acid-adapted stationary-phase L. monocytogenes cells were used to inoculate (ca. 108 CFU/ml) Brain Heart (BH) broth (pH 7.4, 0.5% w/v NaCl) in test tubes containing vertically placed SS coupons (used as abiotic substrates for bacterial attachment). Incubation was carried out at 16 degrees C for up to 15 days, without any nutrient refreshment. L. monocytogenes cells, prepared as described above, were also exposed to low pH (4.5; adjusted with HCl) or/and high salt (5.5% w/v NaCl) stresses, during attachment. On the 5th, 10th and 15th day of incubation, cells attached to SS coupons were detached (through bead vortexing) and enumerated (by agar plating). Results revealed that ATR significantly (p<0.05) affected bacterial attachment, when the latter took place under moderate acidic conditions (pH 4.5, 0.5 or 5.5% w/v NaCl), with the acid adapted cells adhering slightly more than the nonadapted ones. Regardless of acidity/salinity conditions during attachment, ATR also enhanced the resistance of sessile cells to subsequent lethal acid challenge (exposure to pH 2 for 6 min; pH adjusted with either hydrochloric or lactic acid). The trend observed with viable count data agreed well with conductance measurements, used to indirectly quantify remaining attached bacteria (following the strong acid challenge) via their metabolic activity. To sum, this study demonstrates that acid adaptation of L. monocytogenes cells during their planktonic growth enhances their subsequent attachment to SS under extended exposure (at 16 degrees C for up to 15 days) to mild acidic conditions (pH 4.5), while it also improves the resistance of sessile cells to extreme acid treatment (pH 2). Therefore, the ATR of bacterial cells should be carefully considered when applying acidic decontamination strategies to eradicate L. monocytogenes attached to food processing equipment. PMID- 21295366 TI - Computational design of protein-ligand interfaces: potential in therapeutic development. AB - Computational design of protein-ligand interfaces finds optimal amino acid sequences within a small-molecule binding site of a protein for tight binding of a specific small molecule. It requires a search algorithm that can rapidly sample the vast sequence and conformational space, and a scoring function that can identify low energy designs. This review focuses on recent advances in computational design methods and their application to protein-small molecule binding sites. Strategies for increasing affinity, altering specificity, creating broad-spectrum binding, and building novel enzymes from scratch are described. Future prospects for applications in drug development are discussed, including limitations that will need to be overcome to achieve computational design of protein therapeutics with novel modes of action. PMID- 21295368 TI - Prevalence of potentially neuropathic Campylobacter jejuni strains on commercial broiler chicken products. AB - Campylobacteriosis is the most common antecedent infection leading to the development of inflammatory neuropathies including Guillain Barre syndrome (GBS) and Miller Fisher syndrome (MFS), with alterations in surface proteins and genetic polymorphisms conferring increased risk. Poultry is the most common source of C. jejuni infection in industrialized countries, including the US. There are no data on the prevalence on consumer poultry products of various strains of C. jejuni, including those hypothesized to be associated with neuropathy. To study this, C. jejuni was isolated from fresh broiler chicken products purchased from grocery stores in the Baltimore area. LOS subtypes and specific genetic polymorphisms were determined by PCR and DNA sequencing. The observed relative proportions of LOS subtypes and genetic polymorphisms in the cstII gene (encoding bacterial sialyltransferases involved in LOS synthesis in C. jejuni) were characterized and compared to those reported in published studies of patients with GBS, MFS and uncomplicated enteritis. Commercial poultry products carry a relatively high prevalence of C. jejuni strains that have been associated with neuropathic sequelae. The relative proportions of LOS classes in poultry isolates were similar to those reported in isolates from human enteritis cases, and in some instances also similar to isolates from patients diagnosed with neuropathic disease. In terms of cstII polymorphisms, there were also similarities between isolates from poultry and those from patients with GBS and MFS. PMID- 21295369 TI - Genome-wide transcription factor binding: beyond direct target regulation. AB - The binding of transcription factors to specific DNA target sequences is the fundamental basis of gene regulatory networks. Chromatin immunoprecipitation combined with DNA tiling arrays or high-throughput sequencing (ChIP-chip and ChIP seq, respectively) has been used in many recent studies that detail the binding sites of various transcription factors. Surprisingly, data from a variety of model organisms and tissues have demonstrated that transcription factors vary greatly in their number of genomic binding sites, and that binding events can significantly exceed the number of known or possible direct gene targets. Thus, current understanding of transcription factor function must expand to encompass what role, if any, binding might have outside of direct transcriptional target regulation. In this review, we discuss the biological significance of genome-wide binding of transcription factors and present models that can account for this phenomenon. PMID- 21295370 TI - Four opportunities for studies of ecological succession. AB - Lessons learned from the study of ecological succession have much to offer contemporary environmental problem solving but these lessons are being underutilized. As anthropogenic disturbances increase, succession is more relevant than ever. In this review, we suggest that succession is particularly suitable to address concerns about biodiversity loss, climate change, invasive species, and ecological restoration. By incorporating modern experimental techniques and linking results across environmental gradients with meta-analyses, studies of succession can substantially improve our understanding of other ecological phenomena. Succession can help predict changes in biodiversity and ecosystem services impacted by invasive species and climate change and guide manipulative responses to these disruptions by informing restoration efforts. Succession is still a critical, integrative concept that is central to ecology. PMID- 21295371 TI - Scavenging: how carnivores and carrion structure communities. AB - Recent advances in the ecology of food webs underscore the importance of detritus and indirect predator-prey effects. However, most research considers detritus as an invariable pool and predation as the only interaction between carnivores and prey. Carrion consumption, scavenging, is a type of detrital feeding that should have widespread consequences for the structure and stability of food webs. Providing access to high-quality resources, facultative scavenging is a ubiquitous and phylogenetically widespread strategy. In this review, we argue that scavenging is underestimated by 16-fold in food-web research, producing inflated predation rates and underestimated indirect effects. Furthermore, more energy is generally transferred per link via scavenging than predation. Thus, future food-web research should consider scavenging, especially in light of how major global changes can affect scavengers. PMID- 21295372 TI - Molecular pathways of platelet factor 4/CXCL4 signaling. AB - The platelet-derived chemokine CXCL4 takes a specific and unique position within the family of chemotactic cytokines. Today, much attention is directed to CXCL4's capacity to inhibit angiogenesis and to promote innate immune responses, which makes this chemokine an interesting tool and target for potential intervention in tumor growth and inflammation. However, such attempts demand a comprehensive knowledge on the molecular mechanisms and pathways underlying the corresponding cellular functions. At least two structurally different receptors, CXCR3-B and a chondroitin sulfate proteoglycan, are capable of binding CXCL4 and to induce a specific intracellular signaling machinery. While signaling mediated by CXCR3-B involves Gs proteins, elevated cAMP levels, and p38 MAP kinase, signaling via proteoglycans appears to be more complicated and varies strongly between the cell types analyzed. In CXCL4-activated neutrophils and monocytes, tyrosine kinases of the Src family and Syk as well as monomeric GTPases and members of the MAP kinase family have been identified as essential intracellular signals. Most intriguingly, signaling does not proceed in a linear sequence of events but in a repeated activation of certain transducing elements like Rac2 or sphingosine kinase 1. Depending on the downstream targets, such biphasic kinetics either leads to a redundant and prolonged activation of a single pathway or to a timely separated initiation of disparate signals and functions. Results of the studies reviewed here help to understand the molecular basis of CXCL4's functional diversity and provide insights into integrated signaling processes in general. PMID- 21295373 TI - Endogenous RNA interference of chalcone synthase genes in soybean: formation of double-stranded RNA of GmIRCHS transcripts and structure of the 5' and 3' ends of short interfering RNAs. AB - In yellow soybean, seed coat pigmentation is inhibited via endogenous RNA interference (RNAi) of the chalcone synthase (CHS) genes. Genetic studies have shown that a single dominant gene, named the I gene, inhibits pigmentation over the entire seed coat in soybean. We previously isolated a candidate for the I gene from the yellow soybean genome with the I/I genotype, and designated it GmIRCHS. A structural feature of GmIRCHS is a perfect inverted repeat of the pseudoCHS gene lacking 5'-coding region. This suggests that the double-stranded RNA (dsRNA) structure of the pseudoCHS gene may be formed in the GmIRCHS transcript. RNAi is triggered by the dsRNA for a target gene, so the GmIRCHS transcript is likely to be a trigger for RNAi of CHS genes. In this study, we identified a 1087-bp dsRNA, including pseudoCHS region ranging from most of exon 2 to 3'-UTR, in the GmIRCHS transcript. Interestingly, this dsRNA was detected not only in the seed coat but also in the cotyledon and leaf tissues. Previously, CHS RNAi has been shown to be restricted to the seed coat, and we reported that endogenous short interfering RNAs of CHS genes (CHS siRNAs) are detected only in the seed coat and not in the cotyledon and leaf tissues. Taken together with these previous reports, our result suggests that seed-coat specificity of CHS RNAi may be determined in the amplification step of CHS siRNAs rather than dsRNA formation in the GmIRCHS transcript. Our studies further revealed that CHS siRNAs are modified at the 3' ends and bear 5' monophosphorylated ends, suggesting that CHS siRNA duplexes are generated by Dicer-like enzyme from CHS dsRNA and subsequently modified at the 3' ends for stabilizing CHS siRNAs. PMID- 21295374 TI - Adverse effects of ultraviolet radiation from the use of indoor tanning equipment: time to ban the tan. AB - The incidence of melanoma skin cancer is increasing rapidly, particularly among young women in the United States. Numerous studies have documented an association between the use of indoor tanning devices and an increased risk of skin cancer, especially in young women. Studies have shown that ultraviolet exposure, even in the absence of erythema or burn, results in DNA damage. Countries and regulatory bodies worldwide have recognized the health risks associated with indoor tanning. In the United States, 32 states have passed legislation to regulate the indoor tanning industry, but there is an urgent need to restrict the use of indoor tanning devices at the federal level. The Food and Drug Administration is currently reviewing the classification of these devices. For all of these reasons, the Food and Drug Administration should prohibit the use of tanning devices by minors and reclassify tanning devices to at least class II to protect the public from the preventable cancers and other adverse effects caused by ultraviolet radiation from indoor tanning. PMID- 21295375 TI - Scientific developments in indoor tanning and melanoma. PMID- 21295376 TI - Public access defibrillation: time to access the public. AB - STUDY OBJECTIVE: Public accessible automated external defibrillators (AEDs) are increasingly made available in highly frequented places, allowing coincidental bystanders to defibrillate with minimal delay if necessary. Although the public, as the largest and most readily available group of potential rescuers, is assigned a key role in this concept of "public" access defibrillation, it is unknown whether bystanders are actually sufficiently prepared. We therefore investigate knowledge and attitudes toward AEDs among the public. METHODS: Standardized interviews were conducted at the Central Railway Station of Amsterdam, the Netherlands, a highly frequented and AED-equipped public place with a high number of travelers and visitors from all over the world. RESULTS: Surveys from 1,018 participants from a total of 38 nations were analyzed, revealing a considerable lack of knowledge among the public. Less than half of participants (47%) would be willing to use an AED, and more than half (53%) were unable to recognize an AED. Overall, only a minority of individuals have sufficient knowledge and would be willing to use an AED. Differences between subgroups were identified, which may aid to tailor public information campaigns to specific target audiences. CONCLUSION: Only a minority of individuals demonstrate sufficient knowledge and willingness to operate an AED, suggesting that the public is not yet sufficiently prepared for the role it is destined for. Wide-scale public information campaigns are an important next step to exploit the lifesaving potential of public access defibrillation. PMID- 21295377 TI - Compound heterozygosity of 2 novel MAPT mutations in frontotemporal dementia. AB - Intronic MAPT mutations altering exon 10 splicing lead mainly to an increase of 4Rtau. The objective of this study is to report clinical, genetic, and neuropathological data of an apparently sporadic early onset frontotemporal dementia (FTD) case associated with 2 novel intronic MAPT gene mutations IVS10+4A > C and IVS9-15T > C that increase 3Rtau. Methods and subjects used are clinical, neuroradiological, and neuropathological examination; molecular genetics of MAPT, PGRN, and other relevant genes. Exon 10 splicing tested with minigene constructs. Tau deposits detected by immunohistochemistry. Sarkosyl-insoluble and soluble tau investigated by immunoblotting. Two novel MAPT mutations IVS10+4A > C and the IVS9-15T > C transmitted by the unaffected parents were identified. Semiquantitative reverse transcription polymerase chain reaction (RT-PCR) analyses on minigenes and in brain tissue showed that both mutations cause an increase of tau mRNA (messenger ribonucleic acid) transcripts lacking exon 10 only in the patient. Immunohistochemistry and immunoblotting of the patient's brain revealed tau deposits composed mostly of 3Rtau isoforms with a predominance of the shorter 3Rtau isoforms. The compound heterozygosity of the patient increasing 3Rtau seems to be responsible for the disease and furthermore suggests that sporadic cases can be caused by genetic mutations. PMID- 21295378 TI - Replication analysis of SNPs on 9p21.2 and 19p13.3 with amyotrophic lateral sclerosis in East Asians. AB - We performed a replication study of the 2 genetic variants, rs2814707 on 9p21.2 and rs12608932 on 19p13.3 that are recently reported to be most significantly associated with sporadic amyotrophic lateral sclerosis (ALS) in Caucasians. Both rs12608932 and rs2814707 showed no evidence of association in Japanese and Chinese (rs12608932, combined p = 0.58, odds ratio [OR] = 1.03, 95% confidence interval [CI] 0.93-1.13; rs2814707, combined p = 0.88, OR = 1.10, 95% CI 0.93 1.30). The association of these loci with susceptibility to sporadic ALS is considered negative in East Asians. PMID- 21295379 TI - Antibodies against beta-fibrin synthetic peptides: a study of their association with the immunogenetic background and disease course of rheumatoid arthritis patients. AB - Preliminary studies have shown the potential application for the diagnosis of Rheumatoid Arthritis (RA) patients with a severe disease course of an epitopic domain of beta-fibrin. The aim of the present work was the analysis of the presence of antibodies against several beta-fibrin synthetic peptides in relation to the immunogenetic background and disease course in a clinically well-defined RA patient cohort. Our results indicated that positive patients against anti-beta fibrin synthetic peptides have a higher percentage of HLA-DRB1 shared epitope (SE) than negative patients. We also observed that the presence of SE alleles was significantly associated with a higher level of anti-[Cit(376)]betafib(365-383) antibodies. When analyzing the effect of different SE alleles, we found a significant positive association between carriers of QRRAA allele and [Cit(376)]betafib(365-383) (Odds ratio 3.77; CI95%: 1.41-10.08). These results suggest that the anti-beta-fibrin status is associated with the immunogenetic background of RA patients. PMID- 21295380 TI - Exploration of (S)-3-aminopyrrolidine as a potentially interesting scaffold for discovery of novel Abl and PI3K dual inhibitors. AB - Based on the literature-reported compensatory effect of PI3K on Abl inhibition and the improved preclinical effect of drug combination of Abl and PI3K inhibitors, a series of compounds bearing novel scaffold of (S)-3 aminopyrrolidine was identified as Abl and PI3K dual inhibitors through support vector machine screening tool, which were subsequently synthesized and tested. Most compounds demonstrated promising cytoxicity against a CML leukemia cell-line K562 and moderate inhibition against Abl and PI3K kinases. These compounds induced no apoptosis in K562 cell-line, suggesting that their cytotoxic activities are unlikely duo to other known anti-CML mechanisms. Molecular docking study further showed that the compound 5k could bind with both Abl and PI3K, but the weaker binding with Abl compared to Imatinib is consistent with its low kinase inhibitory rates. These plus literature-reported evidences suggest that the promising cytotoxic effect of our novel compounds might be due to the collective effect of Abl and PI3K inhibition. PMID- 21295381 TI - Investigations on cytotoxicity and anti-inflammatory potency of licofelone derivatives. AB - A series of C5-substituted licofelone ([2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl 2,3-dihydro-1H-pyrrolizin-5-yl]acetic acid) derivatives were developed by a parallel synthesis approach and investigated for cytotoxicity against MCF-7 and MDA-MB-231 cells as well as for anti-inflammatory potency in vitro and in vivo. Dependent on the C5-substituent, the compounds showed high selectivity for MCF-7 cells. Especially 2-oxoethyl benzoate derivatives were inactive at the MDA-MB-231 cell line and as active as 5-FU at MCF-7 cells. C5-acetyl (8a), -2-oxoethyl formiate (8e), -2-oxoethyl acetate (8f) and -2-oxoethyl propionate (8g) derivatives showed growth inhibition at both cell lines, comparable with cisplatin. Modifications significantly reduced the inhibitory potency at COX-1 and COX-2 in vitro and in the xylene-induced ear swelling assay in mice. Only compound 8a was equipotent to licofelone, ibuprofen and celecoxibe in vivo. PMID- 21295382 TI - The development of evidence based guidelines for clinical practice portfolios. AB - AIMS: Although the use of portfolios is widespread within healthcare education, agreement on their purpose, content, assessment and value is still debated. The objective of this study was to achieve consensus on quality criteria for clinical practice portfolios that would act as guidance for students and lecturers. METHODS: A Delphi survey was undertaken to seek consensus on the opinions of 23 'expert participants' through a series of rounds of structured questionnaires. The Delphi tool was produced as an on-line survey questionnaire and panel experts were invited to score statements using a discrete 7 point visual analogue scale. The statements were written as quality criteria relating to portfolio development which had been identified from the literature and by the research team. The survey employed three rounds of feedback and consensus was measured as 80% agreement for each quality criteria scoring 5 and above. RESULTS: Consensus was reached on 31 quality criteria which were categorised into 4 areas: structured collection of labelled evidence; nature of evidence; critical reflection; and assessment and judgement. Mean scores for the final wording of the quality criteria ranged from 5.3 to 6.8 with the standard deviation for all of the mean scores being below 1.5. There was consensus that these quality criteria were relevant to health and social care professionals involved in developing clinical practice portfolios. CONCLUSIONS: The Delphi process facilitated exchange of ideas amongst panel 'experts' about the content and evaluation of clinical practice portfolios, with most debate relating to judgement of competence and rewarding originality and creativity. These issues illustrate the tensions between educational values and professional constraints. The Delphi process proved to be an effective method for achieving consensus on quality criteria for clinical practice portfolios and enabled the development of validated guidelines. PMID- 21295383 TI - Time-dependent effects of safflower oil to improve glycemia, inflammation and blood lipids in obese, post-menopausal women with type 2 diabetes: a randomized, double-masked, crossover study. AB - BACKGROUND & AIMS: Metabolic effects of dietary fat quality in people with type 2 diabetes are not well-understood. The study objective was to evaluate effects of conjugated linoleic acid (CLA) and safflower (SAF) oils on glycemia, blood lipids, and inflammation. The hypothesis we tested is that dietary oils improve glycemia, lipids, and inflammatory markers in a time-dependent way that follows accumulation of linoleic acid and CLA isomers in serum of subjects supplemented with dietary oils. METHODS: Fifty-five post-menopausal, obese women with type 2 diabetes enrolled, and 35 completed this randomized, double-masked crossover study. Treatments were 8 g daily of CLA and SAF for 16 weeks each. We used a multiple testing procedure with pre-determined steps analysis to determine the earliest time that a significant effect was detected. RESULTS: CLA did not alter measured metabolic parameters. SAF decreased HbA1c (-0.64 +/- 0.18%, p = 0.0007) and C-reactive protein (-13.6 +/- 8.2 mg/L, p = 0.0472), increased QUICKI (0.0077 +/- 0.0035, p = 0.0146) with a minimum time to effect observed 16 weeks after treatment. SAF increased HDL cholesterol (0.12 +/- 0.05 mmol/L, p = 0.0228) with the minimum time to detect an effect of SAF at 12 weeks. The minimum time to detect an increase of c9t11-CLA, t10c12-CLA, and linoleic acid in serum of women supplemented CLA or SAF, respectively, was four weeks. CONCLUSIONS: We conclude that 8 g of SAF daily improved glycemia, inflammation, and blood lipids, indicating that small changes in dietary fat quality may augment diabetes treatments to improve risk factors for diabetes-related complications. PMID- 21295384 TI - A review of facial protective equipment use in sport and the impact on injury incidence. AB - Sporting activities have an inherent risk of facial injury from traumatic impacts from fellow competitors, projectiles, and collisions with posts or the ground. This retrospective review systematically describes the interplay between the type of sport (including the level at which specific sports are played), the sex of the players and their musculoskeletal characteristics, the technology behind the materials used, the protective devices commonly used, the anatomical site, and the regularity of incidence of fractures. We describe how variations in sporting activities induce different orofacial fracture patterns, and critically consider the methods used to test protective headgear against more contemporary techniques. Facial injuries can have a profound psychological effect on those injured, can take a long time to heal, and have been known to end promising careers. Use of properly fitted protective head or facial equipment could reduce the number of facial fractures commonly seen in sports. We recommend that individual sports should have full risk assessments, and that mandatory standards should be agreed about protective devices that would be appropriate. PMID- 21295385 TI - Re: Valand K, McLoughlin PM. Encapsuloma: a case report. PMID- 21295386 TI - Midwives' and doctors' attitudes towards the use of the cardiotocograph machine. AB - The appropriate use of the cardiotocograph (CTG) machine in the clinical setting is an issue of concern for midwives and doctors. OBJECTIVE: To examine midwives and doctors attitudes towards the use of the CTG machine in labour ward practice. BACKGROUND: this small study provides new insight into the attitudes of doctor and midwives towards the use of CTG. DESIGN: An exploratory descriptive design that used a combination of qualitative and quantitative approaches. A valid and reliable tool designed by Sinclair (2001) was used to measure the attitudes of doctors and midwives towards CTG usage. In addition, follow-up semi-structured interviews with doctors and midwives were conducted. SETTING: A maternity unit in Northern Ireland. PARTICIPANTS: Participants selected had worked in the labour ward within the last year (n = 56 midwives; n = 19 doctors). Six midwives and two doctors were randomly selected to participate in the interviews. FINDINGS: The study demonstrated a favourable disposition towards the use of CTG machines with 72.5% (n = 29) of respondents indicating that they viewed CTG technology positively and 87.5% (n = 25) indicating they were confident about their skill in interpreting CTG tracings. The majority of the respondents (60.0%, n = 24) felt that their training adequately prepared them for using CTGs. The illustrative accounts provided by the respondents demonstrated a predominant belief that CTG technology continues to have a role in monitoring and detecting abnormalities in the fetal heart rate but this role is limited by how well the CTG is used and interpreted. The interviews confirmed the data obtained from the questionnaires and revealed a number of professional needs and concerns relating to CTG usage. IMPLICATIONS FOR PRACTICE: The implication of this study may be focused on addressing the training needs of students, newly qualified staff and regular updates for employed staff. There was some concern that this technology may be deskilling staff and therefore there is a need to improve confidence levels in using alternatives to this type of fetal monitoring. PMID- 21295387 TI - Management of older patients with multiple myeloma. AB - For many years, the oral combination melphalan-prednisone (MP) has been considered the standard of care for patients with multiple myeloma (MM) not eligible for autologous stem cell transplantation. In the era of novel agents, the introduction of immunomodulatory drugs and proteasome inhibitors has challenged the role of MP and led to new standards of care for this disease. Five randomized phase III studies compared the traditional MP with the MP plus thalidomide (MPT). All these studies showed a prolonged time to progression (TTP) with the 3-drug combination. However, in only two of these trials this advantage translated into an improvement in overall survival (OS). In another randomized trial, MP plus bortezomib (VMP) was correlated with an increase in both TTP and OS compared with MP. Preliminary data showed the superiority of the association of VMP plus thalidomide followed by bortezomib-thalidomide maintenance (VMPT-VT) vs VMP and melphalan-prednisone-lenalidomide followed by lenalidomide maintenance (MPR-R) compared to MP. Promising results have also been reported with the combination of lenalidomide plus low-dose dexamethasone. The availability of different efficacious regimens provided clinicians with the opportunity of tailoring the proper and specific approach for each patient. The choice should be based on patients' comorbidities and biologic age, while taking into account the expected toxicity profiles of each treatment regimen. Moreover, an accurate management of therapy-related adverse events and a gentler approach, particularly for patients older than 75 years, with appropriate age-adjusted dose reductions, should be considered to further improve outcome. PMID- 21295388 TI - Plasma cell leukemia. AB - Plasma cell leukemia (PCL) is a rare, yet aggressive plasma cell (PC) neoplasm, variant of multiple myeloma (MM), characterized by high levels of PCs circulating in the peripheral blood. PCL can either originate de novo (primary PCL) or as a secondary leukemic transformation of MM (secondary PCL). Presenting signs and symptoms are similar to those seen in MM such as renal insufficiency, hypercalcemia, lytic bone lesions, anemia, and thrombocytopenia, but can also include hepatomegaly and splenomegaly. The diagnostic evaluation of a patient with suspected PCL should include a review of the peripheral blood smear, bone marrow aspiration and biopsy, serum protein electrophoresis (SPEP) with immunofixation, and protein electrophoresis of an aliquot from a 24h urine collection (UPEP). The diagnosis is made when a monoclonal population of PCs is present in the peripheral blood with an absolute PC count exceeding 2000/MUL and PC comprising 20% or more of the peripheral blood white cells. The prognosis of PCL is poor with a median survival of 7 to 11 months. Survival is even shorter (2 to 7 months) when PCL occurs in the context of refractory or relapsing MM. There have been no prospective randomized trials investigating the treatment of PCL. Recommendations are primarily based upon data from small retrospective series, case reports, and extrapolation of data from patients with MM. In general, patients are treated with induction therapy followed by hematopoietic cell transplantation (HCT) in those who are appropriate candidates for this approach. The best induction regimen for PCL is not known and there is great variability in clinical practice. Newer agents that are being incorporated into frontline and salvage therapy for MM have also demonstrated activity in PCL such as Immunomodulatory agents and the use of bortezomib with different combinations. PMID- 21295389 TI - Urban and rural mortality rates during heat waves in Berlin and Brandenburg, Germany. AB - In large cities such as Berlin, human mortality rates increase during intense heat waves. Analysis of relevant data from north-eastern Germany revealed that, during the heat waves that occurred between 1990 and 2006, health risks were higher for older people in both rural and urban areas, but that, during the two main heat waves within that 17-year period of time, the highest mortality rates were from the city of Berlin, and in particular from its most densely built-up districts. Adaptation measures will need to be developed, particularly within urban areas, in order to cope with the expected future intensification of heat waves due to global climate change. PMID- 21295390 TI - Spatial and seasonal variations of polycyclic aromatic hydrocarbons in Haihe Plain, China. AB - A dynamic fugacity model was developed to simulate the spatial and seasonal variations of PAHs in Haihe Plain, China. The calculated and measured concentrations exhibited good consistency in magnitude with deviations within a factor of 4 in air and 2 in soil. The spatial distributions of PAHs in air were mainly controlled by emission while the seasonal variations were dominated by emission and gas-particle partition. In soil, the spatial distributions of PAHs were controlled by the soil organic carbon content while the seasonal variations were insignificant. The severest soil contamination was observed in Shanxi and followed by the southwest of Hebei province. Transfer fluxes of total PAHs between air and soil were calculated. The spatial distribution of air-to-soil flux was closely related to the landcover while the soil-to-air flux changed with soil organic matter content. Monte Carlo simulation was done to evaluate the uncertainty of the estimated results in air. PMID- 21295391 TI - Polychlorinated biphenyls in freshwater salmonids from the Kerguelen Islands in the Southern Ocean. AB - The Subantarctic Kerguelen Islands (49 degrees S, 70 degrees E) contain freshwater ecosystems among the most isolated in the world. Concentrations of polychlorinated biphenyls (PCBs) were assessed in the muscle of 48 brook trout and 38 brown trout caught during summer and spring 2006 in the rivers, lakes and ponds of Kerguelen. The sum of 29 PCBs averaged 404 and 358 ng g(-1) lipid, and dioxin-like PCB was 19 and 69 ng g(-1) lipid, in brook and brown trout, respectively. The values showed a high variability and some fish accumulated PCBs at levels similar to those of fish from impacted areas. While inter-sex differences were limited, the season and the morphotype appeared to have the most influence. Fish captured in summer had muscle PCB concentrations about three times higher than those caught in spring and the 'river' morphotype of brook trout showed the highest PCB levels. PMID- 21295392 TI - Accumulation of 14C-trinitrotoluene and related nonextractable (bound) residues in Eisenia fetida. AB - To determine if trinitrotoluene (TNT) forms nonextractable residues in earthworms and to measure the relative degree of accumulation as compared to TNT and its deaminated metabolites, Eisenia fetida was exposed to 14C-TNT using dermal contact to filter paper or exposure to soil. Nonextractable residues made up 32 68% of total body burden depending on exposure media and depuration time. Parent TNT accounted for less than 3% of radioactivity, while ADNTs accounted for 7-38%. Elimination half-lives were 61-120 h for TNT, ADNTs, and DANTs, which was significantly lower than the half-lives found for nonextractable residues, 201 240 h. However, over 80% of the nonextractable residue was solubilized using weak acid (pH 2). Based on our findings that TNT accumulation occurs primarily as nonextractable residues, which have a longer half-life, and that nonextractable residues can be solubilized, we propose that nonextractable residues could be used as a selective biomarker for assessing TNT contamination. PMID- 21295393 TI - Sequencing of two-jaw surgery: the case for operating on the maxilla first. PMID- 21295395 TI - Pilot study of comparative placental morphometry in pre-eclamptic and normotensive pregnancies suggests possible maladaptations of the fetal component of the placenta. AB - OBJECTIVE: Adequate maternal, intervillous and fetal blood flow are all necessary for fetal well-being. Compromise to any part of this exchange would be detrimental to pregnancy outcome. Pre-eclampsia is associated with reduced maternal spiral artery flow, resulting in reduced placental perfusion. This in turn creates an ischaemic environment, which may predispose to morphological changes in placental villi. This pilot study sought to assess whether there were morphological alterations in the fetal component of the placenta which could be detrimental to exchange and therefore pregnancy outcome. STUDY DESIGN: This study utilized morphometric image analysis to examine some features of the fetal component of the placenta in normotensive (NT) and pre-eclamptic (PE) groups. The features examined included: density of placental villi (expressed as percentage of field area occupied by placental tissue); stem vessel carrying capacity (expressed as percentage of stem villus area occupied by vessel lumina); the thickness of the stem arterial walls relative to artery size (expressed as percentage of artery area occupied by arterial wall) and the extent of fibrosis associated with villi (expressed as percentage of field area occupied by fibrosis). RESULTS: There were significant differences between NT and PE placentae in density of placental villus arrangement NT: 51.89 +/- 6.19, PE: 64.78 +/- 6.93 (P<0.001); carrying capacity of stem villi NT: 17.20 +/- 11.78, PE: 8.67 +/- 8.51 (P<0.001); relative thickness of stem villi arterial walls NT: 74.08 +/- 12.92, PE: 86.85 +/- 10.55 (P<0.001); and extent of fibrosis NT: 0.727 +/- 0.310, PE: 1.582 +/- 0.707 (P<0.001). CONCLUSION: These significant differences between normotensive and pre-eclamptic placentae suggest possible fetal maladaptations in response to the intervillous ischaemia, compounding the existing maternal compromise to materno-fetal exchange. Further investigations would, however, be necessary in order to make more conclusive deductions. PMID- 21295394 TI - Young adult female fragile X premutation carriers show age- and genetically modulated cognitive impairments. AB - The high frequency of the fragile X premutation in the general population and its emerging neurocognitive implications highlight the need to investigate the effects of the premutation on lifespan cognitive development. Until recently, cognitive function in fragile X premutation carriers (fXPCs) was presumed to be unaffected by the mutation. Here we show that young adult female fXPCs show subtle, yet significant, age- and FMR1 gene mutation-modulated cognitive impairments as tested by a quantitative magnitude comparison task. Our results begin to define the neurocognitive endophenotype associated with the premutation in adults, who are at risk for developing a neurodegenerative disorder associated with the fragile X premutation. Results from the present study may potentially be applied toward the design of early interventions wherein we might be able to target premutation carriers most at risk for degeneration for preventive treatment. PMID- 21295396 TI - Akt/protein B and estradiol receptor alpha expressions in postmenopausal endometrium. AB - OBJECTIVE: Estrogen receptor interacts in several types of cells with phosphatidyl-inositol 3-kinase/Akt pathway regulating cell survival and apoptosis. No data are available of the Akt/PKB signaling and its role in the endometrial homeostasis of the postmenopausal uterus. The aim of the present investigation was to study the Akt/protein kinase B signaling in tissue samples retrieved from postmenopausal endometrium of the human uterus with parallel observation of the changes of the expression and phosphorylation of ERalpha. STUDY DESIGN: Sixty disease-free postmenopausal women were enrolled in the study. Endometrial tissue samples were obtained from diagnostic curettage or direct from the uterus after hysterectomy done for benign uterine lesions other than endometrial disease. For comparison, the studied parameters were also analyzed in endometrial samples of women with regular menstrual cycles (n=16). In each individual tissue sample the expression and phosphorylation of ERalpha, Akt, and cyclin D1 was analyzed by Western blotting. RESULTS: The level of Akt protein did not show significant change, however, the activation of Akt proteins and the expression of ERalpha increased parallel with serum estrogen (E2) levels, suggesting the role of E2 in Akt activation and ERalpha expression. The level of pERalpha(Ser167) changed parallel with pAkt(Ser473) levels. Significant correlation was found between the changes of pERalpha and ERalpha (r=0.650399, p<0.005), and in that of pERalpha and pAkt (r=0.639643, p<0.007), respectively. The expression of cyclin D1 was increased in samples with elevated pAkt levels. CONCLUSION: The results are indicating that the postmenopausal endometrium responds to E2 by both genomic and nongenomic mechanism. The interaction between ERalpha and Akt plays crucial role in the regulation of proliferative activity in postmenopausal endometrium. PMID- 21295397 TI - Stabilizing effect of polyols is sensitive to inherent stability of protein. AB - In studies on polyol-mediated protein stabilization, the polyols are the preferred variable and less importance is given to the intrinsic properties of the protein used. We investigated the stabilizing effects of glycerol on three in vitro evolved lipase mutants with varying stabilities and also in a broad pH range of 3.3-12.1. Significant linear negative correlation between increment in stability due to glycerol and prior stability suggests that stabilizing effects of glycerol depend on the prior stability of the protein. Polar/nonpolar surface area and charge do not have a bearing on the stabilizing effects of glycerol. PMID- 21295398 TI - The dark side of targeted therapy. PMID- 21295399 TI - Polygenic risk score improves prostate cancer risk prediction: results from the Stockholm-1 cohort study. AB - BACKGROUND: More than 1 million prostate biopsies are conducted yearly in the United States. The low specificity of prostate-specific antigen (PSA) results in diagnostic biopsies in men without prostate cancer (PCa). Additional information, such as genetic markers, could be used to avoid unnecessary biopsies. OBJECTIVE: To determine whether single nucleotide polymorphisms (SNPs) associated with PCa can be used to determine whether biopsy of the prostate is necessary. DESIGN, SETTINGS, AND PARTICIPANTS: The Stockholm-1 cohort (n = 5241) consisted of men who underwent a prostate biopsy during 2005 to 2007. PSA levels were retrieved from databases and family histories were obtained using a questionnaire. Thirty five validated SNPs were analysed and converted into a genetic risk score that was implemented in a risk-prediction model. RESULTS AND LIMITATIONS: When comparing the nongenetic model (based on age, PSA, free-to-total PSA, and family history) with the genetic model and using a fixed number of detected PCa cases, it was found that the genetic model required significantly fewer biopsies than the nongenetic model, with 480 biopsies (22.7%) avoided, at a cost of missing a PCa diagnosis in 3% of patients characterised as having an aggressive disease. However, the overall genetic model does not discriminate between aggressive and nonaggressive cases. CONCLUSION: Although the genetic model reduced the number of biopsies more than the nongenetic model, the clinical significance of this finding requires further evaluation. PMID- 21295400 TI - Sequestration of cadmium ions using titanate nanotube. AB - In this manuscript, titanate (Na(2)Ti(3)O(7)) nanotubes synthesized from alkali hydrothermal route, with high BET surface area (206 m(2)/g), were used as an effective sorbent to remove cadmium ions from water. Sorption capacity (q(m,Langmuir) = 1.1 mmol/g at pH 7) was higher than other sorbents. X-ray photoelectron spectroscopy (XPS) analyses performed on fresh and cadmium-sorbed samples reveal intensities of Na 1s peak decreased after sorption indicating ion exchanging between cadmium and sodium ions occurred at interlayer of nanotubes. However kinetic study did not show a stoichiometrically equivalent amount of Na(+) being released suggesting Cd uptake was not due solely to ion-exchange mechanism. Batch tests also showed that cadmium uptake was not significantly affected by variation in ionic strength, signifying cadmium ions form an inner sphere complexation with surface hydroxyl groups. Finally, surface complexation modeling was performed based on charge distribution multisite ion complexation (CDMUSIC) model. It was found that CDMUSIC was able to fit the experimental data best when inner-sphere complexation and ion-exchange were applied together. PMID- 21295401 TI - Bioelectricity generation and microcystins removal in a blue-green algae powered microbial fuel cell. AB - Bioelectricity production from blue-green algae was examined in a single chamber tubular microbial fuel cell (MFC). The blue-green algae powered MFC produced a maximum power density of 11 4 mW/m(2) at a current density of 0.55 mA/m(2). Coupled with the bioenergy generation, high removal efficiencies of chemical oxygen demand (COD) and nitrogen were also achieved in MFCs. Over 78.9% of total chemical oxygen demand (TCOD), 80.0% of soluble chemical oxygen demand (SCOD), 91.0% of total nitrogen (total-N) and 96.8% ammonium-nitrogen (NH(3)-N) were removed under closed circuit conditions in 12 days, which were much more effective than those under open circuit and anaerobic reactor conditions. Most importantly, the MFC showed great ability to remove microcystins released from blue-green algae. Over 90.7% of MC-RR and 91.1% of MC-LR were removed under closed circuit conditions (500Omega). This study showed that the MFC could provide a potential means for electricity production from blue-green algae coupling algae toxins removal. PMID- 21295402 TI - Application of Box-Wilson experimental design method for 2,4-dinitrotoluene treatment in a sequential anaerobic migrating blanket reactor (AMBR)/aerobic completely stirred tank reactor (CSTR) system. AB - A sequential aerobic completely stirred tank reactor (CSTR) following the anaerobic migrating blanket reactor (AMBR) was used to treat a synthetic wastewater containing 2,4-dinitrotoluene (2,4-DNT). A Box-Wilson statistical experiment design was used to determine the effects of 2,4-DNT and the hydraulic retention times (HRTs) on 2,4-DNT and COD removal efficiencies in the AMBR reactor. The 2,4-DNT concentrations in the feed (0-280 mg/L) and the HRT (0.5-10 days) were considered as the independent variables while the 2,4-DNT and chemical oxygen demand (COD) removal efficiencies, total and methane gas productions, methane gas percentage, pH, total volatile fatty acid (TVFA) and total volatile fatty acid/bicarbonate alkalinity (TVFA/Bic.Alk.) ratio were considered as the objective functions in the Box-Wilson statistical experiment design in the AMBR. The predicted data for the parameters given above were determined from the response functions by regression analysis of the experimental data and exhibited excellent agreement with the experimental results. The optimum HRT which gave the maximum COD (97.00%) and 2,4-DNT removal (99.90%) efficiencies was between 5 and 10 days at influent 2,4-DNT concentrations 1-280 mg/L in the AMBR. The aerobic CSTR was used for removals of residual COD remaining from the AMBR, and for metabolites of 2,4-DNT. The maximum COD removal efficiency was 99% at an HRT of 1.89 days at a 2,4-DNT concentration of 239 mg/L in the aerobic CSTR. It was found that 280 mg/L 2,4-DNT transformed to 2,4-diaminotoluene (2,4-DAT) via 2 amino-4-nitrotoluene (2-A-4-NT) and 4-amino-2-nitrotoluene (4-A-2-NT) in the AMBR. The maximum 2,4-DAT removal was 82% at an HRT of 8.61 days in the aerobic CSTR. The maximum total COD and 2,4-DNT removal efficiencies were 99.00% and 99.99%, respectively, at an influent 2,4-DNT concentration of 239 mg/L and at 1.89 days of HRT in the sequential AMBR/CSTR. PMID- 21295403 TI - Health risk characterisation for environmental pollutants with a new concept of overall risk probability. AB - In health risk assessment, risk is commonly characterised by calculating a simple hazard quotient (HQ), which cannot reflect the actual distribution of exposure and health effect values. This study aimed to develop a new risk characterisation method, the overall risk probability (ORP) method based on probabilistic techniques. Exposure exceedence values were calculated to obtain an exposure exceedence curve (EEC). The area under the EEC was calculated as the ORP value to represent the risk. This method was demonstrated by a case study for two steroidal EDCs, 17beta-estradiol (E2) and 17alpha-ethinylestradiol (EE2) for fish in surface water. It was found that the risk probability of fish exposed to E2 (ORP, 8.1%) and EE2 (ORP, 27%) were both above the reference value of 2.5%, which was consistent with the results of HQ method. Assuming independent action of individual EDCs, a combined risk probability of 33% was obtained for the mixture effects of E2 and EE2. Our results implicated that the adverse health effects imposed by E2 and EE2 were significant for fish in surface water worldwide. PMID- 21295404 TI - Factors related to seeking health care among adolescents with musculoskeletal pain. AB - Musculoskeletal pain is common among adolescents, but little is known about the factors that affect seeking health care for the problem. We examined the care seeking pattern among adolescents reporting musculoskeletal pain. The study consisted of adolescents aged 16 years from the 1986 Northern Finland Birth Cohort who responded to a mailed questionnaire in 2001 and reported musculoskeletal pain over the preceding 6 months (n=5052). Logistic regression analyses were performed to assess whether enabling resources, need factors, personal health habits, and psychological problems were associated with seeking health care for musculoskeletal pain. Musculoskeletal pain during the preceding 6 months was reported by 68% of boys and 83% of girls in the study population. Only 16% of boys and 20% of girls reporting pain had sought medical care. Among both boys and girls, care-seeking was associated with being a member of a sports club (boys, odds ratio [OR] 2.1; girls, OR 1.5) and having one (boys, OR 2.1; girls, OR 1.8) or at least 2 (boys, OR 2.2; girls, OR 2.1) other health disorders. In addition, it was associated with a high physical activity level (OR 1.5) and low self-rated (OR 1.5) health among girls. Reporting pain in other anatomical areas decreased the likelihood of seeking care for pain among both genders. In conclusion, relatively few adolescents with musculoskeletal pain had consulted a health professional for the problem. Being physically active (trauma), participating in organized sport (accessibility of care), and having other health problems may explain why an adolescent seeks care for musculoskeletal pain. PMID- 21295405 TI - Increased hippocampal glycine uptake and cognitive dysfunction after peripheral nerve injury. AB - Patients with chronic pain often have accompanying cognitive deficiency, which may reduce their quality of life and hamper efficient medical treatment. Alteration of extracellular glycine concentration may affect cognitive function and spinal pain signaling. In the present study, we assessed recognition memory by novel-object recognition and found that mice developing mechanical hypersensitivity after peripheral nerve injury exhibited impaired recognition ability for novelty, which was never observed in mice provided the selective glycine transporter 1 (GlyT1) inhibitor N-[3-(4'-fluorophenyl)-3-(4' phenylphenoxy)propyl]sarcosine (NFPS) systemically. Although systemic NFPS generated analgesia via inhibitory effects of glycine in the spinal cord, the cognitive impairment in neuropathic mice was not restored upon relief of pain alone by intrathecal injection of NFPS. Whole-cell recordings were then made from hippocampal CA1 pyramidal neurons, and the effect of exogenously applied glycine or its endogenous increase by blockade of GlyT1 with NFPS on N-methyl-D-aspartate receptor-mediated excitatory postsynaptic currents (NMDA-EPSCs) was investigated in slices prepared from neuropathic mice and mice subjected to sham treatment. In slices from neuropathic mice, NMDA-EPSCs were less potentiated by glycine, whereas they were augmented by NFPS even at lower concentrations. After treating the slices with either NFPS or the glial-selective metabolic blocker fluoroacetate, glycine potentiated NMDA-EPSCs equally in slices from neuropathic and sham-treated mice. These findings imply that chronic pain has a crucial influence on hippocampal plasticity related to cognitive function, and strongly suggest that increasing the extracellular level of glycine via blockade of GlyT1 is a potential therapeutic approach for chronic pain with memory impairment. Chronic pain crucially influences hippocampal plasticity related to cognitive function. Increasing the extracellular level of glycine via blockade of GlyT1 is a potential therapeutic approach for chronic pain with memory impairment. PMID- 21295406 TI - Changes in synaptic transmission of substantia gelatinosa neurons in a rat model of lumbar radicular pain revealed by in vivo patch-clamp recording. AB - Little is known about the pathophysiological mechanisms of radicular pain. We investigated changes in synaptic transmission of substantia gelatinosa (SG) neurons after an injury to the L5 nerve root using in vivo patch-clamp recording. A total of 141 SG neurons were recorded at L4 and L5 segmental levels of the spinal cord in root constriction rats and sham-operated control rats. At L4 and L5 segmental levels, SG neurons without a receptive field were observed only in root constriction rats, and the frequencies of spontaneous action potential firings in SG neurons were higher in the root constriction group than in the control group. At the L5 segmental level, the frequencies and amplitudes of spontaneous excitatory postsynaptic currents (EPSCs) as well as the proportion of multireceptive neurons among SG neurons was higher in the root constriction group than in the control group. At the L4 segmental level, the frequencies and amplitudes of spontaneous EPSCs were increased in the root constriction group, but the proportions of cell types did not change. The mean amplitudes of EPSCs evoked by mechanical stimuli at L4 and L5 segmental levels were larger in the root constriction group than in the control group. The results indicated that injuring the nerve root led to characteristic excitatory synaptic transmission in SG neurons at each segmental level and changed sensory processing in SG neurons at the segment to which the injured nerve projected. These changes could lead to spontaneous pain, mechanical allodynia, and hyperalgesia contributing to the pathogenesis of radicular pain. PMID- 21295407 TI - Genetic ablation of delta opioid receptors in nociceptive sensory neurons increases chronic pain and abolishes opioid analgesia. AB - Opioid receptors are major actors in pain control and are broadly distributed throughout the nervous system. A major challenge in pain research is the identification of key opioid receptor populations within nociceptive pathways, which control physiological and pathological pain. In particular, the respective contribution of peripheral vs. central receptors remains unclear, and it has not been addressed by genetic approaches. To investigate the contribution of peripheral delta opioid receptors in pain control, we created conditional knockout mice where delta receptors are deleted specifically in peripheral Na(V)1.8-positive primary nociceptive neurons. Mutant mice showed normal pain responses to acute heat and to mechanical and formalin stimuli. In contrast, mutant animals showed a remarkable increase of mechanical allodynia under both inflammatory pain induced by complete Freund adjuvant and neuropathic pain induced by partial sciatic nerve ligation. In these 2 models, heat hyperalgesia was virtually unchanged. SNC80, a delta agonist administered either systemically (complete Freund adjuvant and sciatic nerve ligation) or into a paw (sciatic nerve ligation), reduced thermal hyperalgesia and mechanical allodynia in control mice. However, these analgesic effects were absent in conditional mutant mice. In conclusion, this study reveals the existence of delta opioid receptor-mediated mechanisms, which operate at the level of Na(V)1.8-positive nociceptive neurons. Delta receptors in these neurons tonically inhibit mechanical hypersensitivity in both inflammatory and neuropathic pain, and they are essential to mediate delta opioid analgesia under conditions of persistent pain. This delta receptor population represents a feasible therapeutic target to alleviate chronic pain while avoiding adverse central effects. The conditional knockout of delta-opioid receptor in primary afferent Na(V)1.8 neurons augmented mechanical allodynia in persistent pain models and abolished delta opioid analgesia in these models. PMID- 21295409 TI - Comparative efficacy of four commercially available heartworm preventive products against the MP3 laboratory strain of Dirofilaria immitis. AB - A controlled laboratory study was conducted to evaluate the efficacy of four commercial products administered as a single treatment for the prevention of heartworm disease caused by Dirofilaria immitis in dogs. Forty-four commercially sourced Beagle dogs, 6-7 months of age, were received at the test site (Auburn University, Department of Pathobiology) on Study Day (SD) -72 to begin acclimation. On SD -30, each dog was inoculated subcutaneously with 100 infective, third-stage D. immitis larvae (MP3 strain, TRS Laboratories, Inc., Athens, GA). On SD -1, 40 dogs weighing 18.2-25.3 lbs were ranked by decreasing body weight and randomized to five groups of eight dogs each. On SD 0, the dogs assigned to Group 1 were treated orally with ivermectin/pyrantel pamoate chewable tablets, Group 2 dogs were treated orally with milbemycin oxime flavored tablets, Group 3 dogs were treated with selamectin topical solution, and Group 4 dogs were treated with imidacloprid/moxidectin topical solution. Group 5 dogs remained nontreated. Dosages for dogs in Groups 1-4 were based on the individual body weight of each dog and current labeled dose banding for each commercial product. All dogs were fasted overnight prior to treatment. Food was returned four hours after treatment. Animals were observed for abnormal clinical signs involving eyes, feces, respiration, behavioral attitude, locomotion/musculature, or skin conditions at prescribed intervals immediately after treatment and at twice daily intervals thereafter. On SD 90, whole blood was collected and tested for adult heartworm antigen. On SDs 119/120, the dogs were euthanized and subjected to necropsy examination for recovery of adult D. immitis and/or worm fragments. At necropsy, all 8 dogs in the nontreated group were infected with adult D. immitis (34-70 worms/dog, geometric mean (GM)=51.6 worms/dog). One or more adult D. immitis and/or worm fragments were recovered from 7 of 8 of the dogs each in Groups 1-3 (87.5% were heartworm positive). The respective GM worm burdens/dog for Groups 1-3 was 2.3, 2.4, and 2.3 which resulted in 95.6, 95.4 and 95.5% efficacy, respectively. No worms were recovered from any of the 8 dogs in Group 4 resulting in 100% efficacy. PMID- 21295410 TI - Cross-sectional and 35-year longitudinal assessment of salivary cortisol and cognitive functioning: the Vietnam Era twin study of aging. AB - High levels of cortisol, a sign of potential hypothalamic-pituitary-adrenal (HPA) axis dysregulation, have been associated with poor cognitive outcomes in older adults. Most cortisol research has focused on hippocampal-related abilities such as episodic memory; however, the presence of glucocorticoid receptors in the human prefrontal cortex suggests that cortisol regulation is likely to be associated with prefrontally-mediated executive function abilities. We hypothesized that elevated cortisol levels would be associated with poorer frontal-executive function in addition to episodic memory. We assessed cortisol from 15 saliva samples paralleling individual diurnal rhythms across three non consecutive days in a group of 778 middle-aged twin men ages 51-60. Cognitive domains created from 24 standard measures included: general cognitive ability, verbal and visual-spatial ability, verbal and visual-spatial memory, short term/immediate memory, working memory, executive function, verbal fluency, abstract reasoning, and psychomotor processing speed. Adjusting for general cognitive ability at age 20, age, race, and multiple health and lifestyle indicators, higher levels of average area-under-the-curve cortisol output across three days were significantly associated with poorer performance in three domains: executive (primarily set-shifting) measures, processing speed, and visual-spatial memory. In a 35-year longitudinal component of the study, we also found that general cognitive ability at age 20 was a significant predictor of midlife cortisol levels. These results possibly support the notion that glucocorticoid exposure is associated with cognitive functions that are mediated by frontal-striatal systems, and is not specific to hippocampal-dependent memory. The results also suggest that the direction of effect is complex. PMID- 21295411 TI - alpha-Amylase as a reliable and convenient measure of sympathetic activity: don't start salivating just yet! AB - Recent years have seen a growing interest in salivary alpha-amylase (sAA) as a non-invasive marker for sympathetic nervous system (SNS) activity. Saliva offers many advantages as a biomarker fluid and sAA is one of its most plentiful components. sAA is a digestive enzyme that breaks down starch, which provides a simple means of quantification by measuring its enzymatic activity. This commentary will address a number of common misconceptions and methodological issues that surround the use of sAA as a marker of SNS activity and limit its utility in biobehavioral research. The usefulness of sAA as an SNS marker is undermined by the fact that the parasympathetic nerves also play a significant role in sAA release. Local parasympathetic nerves regulate sAA activity via: (1) alpha-amylase release from glands that are solely or mainly parasympathetically innervated; (2) via synergistic sympathetic-parasympathetic effects on protein secretion (known as 'augmented secretion'); and (3) via effects on salivary flow rate. Regarding methodology, we discuss why it is problematic: (1) to ignore the contribution of salivary flow rate; (2) to use absorbent materials for saliva collection, and; (3) to stimulate saliva secretion by chewing. While these methodological problems can be addressed by using standardized and timed collection of unstimulated saliva, the physiological regulation of sAA secretion presents less resolvable issues. We conclude that at present there is insufficient support for the use and interpretation of sAA activity as a valid and reliable measure of SNS activity. PMID- 21295412 TI - [Quality of antibiotic (fluoroquinolons, aminosids and amoxicillin-clavulanic acid) prescription in a French teaching hospital]. AB - OBJECTIVES: To assess the quality of prescription of fluoroquinolons, aminosids and amoxicillin-clavulanic acids in medicine departments. METHODS: Data on target antibiotic prescription were collected on a given day and confronted to local recommendations and literature guidelines. Evaluation of antibiotic therapy was done by assessing molecule choice, administration conditions (dosages, route and administration schedule, treatment duration), reassessment of treatments 48-72 h later, dose adaptation of aminosids depending on serum monitoring. RESULTS: Sixty three patients were included and 67 "target" antibiotics were prescribed. Prevalence of antibiotic-treated patients was 24.4%, and 14.6% for "target" antibiotic-treated patients. Antibiotic choice was appropriate in 67% of prescriptions. Dosages were adequates in 94% of case and administration schedule in 97% of cases. The oral route administration as soon as possible was applied to half of patients. Treatment duration were respected for 94% of prescriptions. Reassessment of antibiotic therapy 48-72 h later was realized in 66% of cases. Dose adaptation of aminosids, when necessary, was realized on one third of cases. For all the quality criteria assessed, the overall frequency of prescription conformity was 44%. CONCLUSION: Large diffusion of protocols, systematic reassessment of treatments at 48-72 h, promotion of training sessions for new prescribers in the institution, reinforcing the function of medical correspondents in antibiotic therapy and infectiologists, periodic evaluation of antibiotic therapy, should improve the quality of antibiotic therapy. PMID- 21295413 TI - [Epidemiology of healthcare-associated infections due to MRSA in Brest University Hospital from 2004 to 2007. Impact of hydroalcoholic gel and antibiotics consumptions]. AB - The fight against healthcare-associated infections is based on preventive measures of multidrug resistant bacteria diffusion. Hand hygiene is the simplest and the most effective preventive measure to reduce cross-transmission of infectious agents. Hydroalcoholic solutions for hand hygiene was recently introduced in the University Hospital of Brest (France). The aims of the study were: to describe the epidemiology of healthcare-associated infections due to methicillin-resistant Staphylococcus aureus (MRSA); to determine the annual consumptions of antistaphylococcal antibiotics; and to discuss the relation between consumption of antiseptic products or antibiotics and the epidemiology of MRSA. METHODS: A retrospective epidemiological and pharmaco-epidemiological study was realized from January 2004 to December 2007 in the University Hospital of Brest (France). It allowed to bring to light the cases of healthcare-associated infections due to MRSA and to quantify the consumptions of hang hygiene products and antistaphylococcal antibiotics. RESULTS: this retrospective study showed a decrease of healthcare-associated infections due to MRSA and an increase of the consumption of hydroalcoholic solutions. Antistaphylococcal resistance rates also decreased in a context of fall of the global antibiotics consumption in the hospital. PMID- 21295414 TI - Risk factors for all-cause, overdose and early deaths after release from prison in Washington state. AB - BACKGROUND: High mortality rates after release from prison have been well documented, particularly from overdose. However, little is known about the risk factors for death after release from prison. Therefore, the objective of this study was to determine the demographic and incarceration-related risk factors for all-cause, overdose and early mortality after release from prison. METHODS: We conducted a retrospective cohort study of inmates released from a state prison system from 1999 through 2003. The cohort included 30,237 who had a total of 38,809 releases from prison. Potential risk factors included gender, race/ethnicity, age, length of incarceration, and community supervision. Cox proportional hazards regression was used to determine risk factors for all-cause, overdose and early (within 30 days of release) death after release from prison. RESULTS: Age over 50 was associated with an increased risk for all-cause mortality (hazard ratio [HR] 2.67 for each decade increase, 95% confidence interval [CI] 2.23, 3.20) but not for overdose deaths or early deaths. Latinos were at decreased risk of death compared to Whites only for all-cause mortality (HR 0.61, 95% CI 0.42, 0.87). Increasing years of incarceration were associated with a decreased risk of all-cause mortality (HR 0.95, 95% CI 0.91, 0.99) and overdose deaths (HR 0.80, 95% CI 0.68, 0.95), but not early deaths. Gender and type of release were not significantly associated with all-cause, overdose or early deaths. CONCLUSIONS: Age, ethnicity and length of incarceration were associated with mortality after release from prison. Interventions to reduce mortality among former inmates are needed. PMID- 21295415 TI - Intracellular Yersinia pestis expresses general stress response and tellurite resistance proteins in mouse macrophages. AB - Yersinia pestis inoculated subcutaneously via fleabite or experimental injection in natural rodent hosts multiply initially in macrophage phagolysosomes. Survival and multiplication of Y. pestis in this acidic low [Ca(2+)] and [Mg(2+)] environment likely necessitates compensatory mechanisms involving expression of specific proteins compared to those expressed during extracellular growth. A proteomics approach was used to identify these proteins using mouse macrophage RAW264.7 cells infected with Y. pestis strain KIM6-2053.1+ for 8h. Intracellular Y. pestis protein samples were prepared by detergent lysis of infected RAW264.7 cells, isolation of intracellular Y. pestis by differential centrifugation, and sonication of isolated Y. pestis. Protein samples were similarly prepared from Y. pestis grown extracellularly in tissue culture media. Two intracellular and extracellular Y. pestis protein samples were analyzed by two-dimensional polyacrylamide gel electrophoresis and compared in silico identifying 12 protein spots present in both intracellular samples but absent in extracellularly grown Y. pestis. Mass spectrometry analysis of these identified nine proteins at a high level of confidence in the Y. pestis genome: superoxide dismutase-A (sodA), inorganic pyrophosphatase, autonomous glycyl radical cofactor GrcA, molecular chaperone DnaK, serine endoprotease GsrA, global DNA-binding transcriptional dual regulator H-NS, urease subunit gamma UreA, and tellurite resistance proteins TerD and TerE. These results support the involvement of various general stress response regulators of Y. pestis during the intracellular parasitism of host macrophages as well as identification of UreA, TerD and TerE with as yet unknown roles in the process of intracellular survival of Y. pestis. PMID- 21295416 TI - The relationship between RSV bronchiolitis and recurrent wheeze: the chicken and the egg. AB - Respiratory syncytial virus bronchiolitis is the most frequent cause of infant hospitalization. RSV bronchiolitis is often followed by recurrent episodes of wheeze. Pathogenesis of RSV bronchiolitis as well as post-bronchiolitis wheeze are incompletely understood. The aim of this review is to provide a brief overview of our current understanding of the complex pathogenesis of RSV bronchiolitis and post-bronchiolitis wheeze. Two non-exclusive hypotheses exist, which are paraphrased for this review as "the chicken and the egg". First, we reviewed the pre-existent genetic, pulmonary and immunological mechanisms of RSV bronchiolitis and post-bronchiolitis wheeze. Second, RSV as the causative virus of long-term airway morbidity is reviewed. Clearly, RSV infection is capable of causing direct damage to the airways and/or inducing long-term inappropriate immune responses to respiratory viruses or aero-allergens. It is concluded that intervention trials aimed at preventing RSV infections are required to establish the relative contribution of both RSV-induced and pre-existent mechanisms to the development of long-term airway disease following RSV bronchiolitis. PMID- 21295417 TI - Cognitive function in 18-month-old term infants of the DIAMOND study: a randomized, controlled clinical trial with multiple dietary levels of docosahexaenoic acid. AB - BACKGROUND: Studies investigating cognitive outcomes following docosahexaenoic acid (DHA) supplementation of infant formula yield conflicting results, perhaps due to inadequate dietary concentrations. AIM: To determine the optimal DHA concentration in term formula to support cognitive maturation. DESIGN: This was a double-masked, randomized, controlled, prospective trial. A total of 181 infants were enrolled at 1-9 days of age and assigned randomly to receive one of four term infant formulas with one of four levels of docosahexaenoic acid: Control (0% DHA), 0.32% DHA, 0.64% DHA, or 0.96% DHA. All DHA-supplemented formulas contained 0.64% arachidonic acid (ARA). Infants were fed the assigned formulas until 12 months of age. One hundred forty-one children completed the 12-month feeding trial and were eligible for this study. Cognitive function was assessed in 131 children at 18 months of age using the Bayley Scales of Infant Development II (BSID II). RESULTS: There were no diet group differences on the Mental Development Index (MDI), the Psychomotor Development Index (PDI), or the Behavior Rating Scale (BRS) of the BSID II. However, when the scores of children who received any of the three DHA-supplemented formulas were combined and compared to control children, a significant difference emerged: the MDI scores of DHA supplemented children were higher (104.1 v. 98.4; p=0.02). CONCLUSIONS: These results suggest that dietary supplementation of DHA during the first year of life leads to enhanced cognitive development at 18 months of age. DHA concentration of 0.32% is adequate to improve cognitive function; higher concentrations did not confer additional benefit. PMID- 21295418 TI - Routine Lactobacillus rhamnosus GG administration in VLBW infants: a retrospective, 6-year cohort study. AB - BACKGROUND: In preterm neonates, use of probiotic mixtures is increasingly popular and is effective in preventing NEC, fungal colonization, and improving feeding tolerance. However, concerns exist about safety and tolerability of long lasting administration of living microrganisms to not-immunocompetent hosts. We report a 6-year, two-NICUs experience of routinary Lactobacillus rhamnosus GG (LGG) use in VLBW infants. METHODS: Clinical charts review, retrospective study of VLBW infants admitted to two Italian NICUs in the years 2003-2008. Standard protocol of LGG administration consisted of 3 x 109 CFU/day, in single oral dose, since 4th day-of-life, for 4-to-6-week courses. Nutritional policy relied on administration of fresh, expressed mother's milk, supplementation with preterm formula if needed. Data about LGG safety and tolerability, infections, feeding tolerance, microbiological clinical and surveillance cultures were retrieved and analysed. RESULTS: Complete data were obtained for 743 of 811 VLBW infants. Mean birth-weight was 1056 g; mean gestational age 29.5 weeks. A total of 17,108 LGG doses were administered (mean 23.1/infant). No adverse effects or intolerances putatively attributable to LGG occurred. Overall, 5350 clinical and surveillance cultures from 13 different sites/devices were performed (mean: 7.2 cultures from 6.5 different sites/infant). None ever grew LGG, or other Lactobacilli. No clinical sepsis episode was attributable to LGG. Full enteral feeding was achieved at 19.2 mean days-of-life; 73% of infants were exclusively/partially breastfed. Fourteen NEC cases occurred (=1.9%), with 5 (=0.7%) being>2b stage. CONCLUSIONS: Routinary supplementation of probiotic LGG in a large, 6-year VLBW infants Italian cohort proved microbiologically safe and clinically well tolerated. PMID- 21295419 TI - MALDI-TOF mass spectrometry as a simple tool to determine the phospholipid/glycolipid composition of sperm: pheasant spermatozoa as one selected example. AB - Cellular membranes are composed of highly variable lipid molecules, mainly cholesterol and phospholipids (PLs). The cholesterol moiety and the saturation degree of the fatty acyl residues of PL determine the fluidity of the membrane, which is particularly important for sperm because they have to undergo characteristic membrane-dependent processes (acrosomal exocytosis and fusion with the oocyte). Glycolipids are an essential part of the membrane surface acting as key mediators in the interactions of sperm with components of the female genital tract. Although the lipid composition of many mammalian spermatozoa has already been determined, the lipid composition of avian spermatozoa has scarcely been investigated. Using spermatozoa extracts of the ring-necked pheasant (Phasianus colchicus) as a selected example, this work demonstrates that matrix-assisted laser desorption and ionization time-of-flight mass spectrometry (MALDI-TOF MS) is a simple and fast method to determine spermatozoal lipid compositions. The lipid compositions of pheasant spermatozoa have not yet been investigated. In addition to common membrane (primarily diacyl) PL (sphingomyelin, phosphatidylcholine, phosphatidylinositol and phosphatidylethanolamine), remarkable variation of different sulfoglycolipids (sulfogalactocerebrosides) was identified. This is in strong contrast to all other animal species investigated so far which nearly exclusively contain the sulfoglycolipid seminolipid (sulfogalactoalkylacylglycerol). We emphasize that the MALDI MS approach allows the characterization of sulfoglycolipids of sperm within a few minutes without the necessity for previous chromatographic separation. PMID- 21295420 TI - Gender and ageing in the 21st century: special issue. PMID- 21295421 TI - Management of non-small-cell lung cancer in the older adult. AB - The treatment of older adults with non-small cell lung cancer (NSCLC) poses special challenges for the clinician. Older adults are more likely to have decreased functional reserve which might limit their ability to undergo surgery or receive chemotherapy. Additionally, age is associated with increased number of co-morbid medical conditions that could be exacerbated by treatment and could predispose to poor outcome. It is unclear how these propensities affect the efficacy and safety of therapy in older patients with NSCLC, as the elderly are an understudied population and there are limited data in older adults in most trials evaluating therapy in lung cancer. As the number of trials of older adults increases, however, it is becoming more evident that age alone cannot be used as a surrogate for poor outcome. Various studies have shown that older adults are able to benefit from surgery or chemotherapy when correct patient selection is used. Most chemotherapeutic regimens have similar efficacy in older and younger patients, and while some toxicity rates are higher in older patients, with appropriate prophylaxis and supportive care older adults are generally able to tolerate most chemotherapy regimens, even in combinations. Proper selection of candidates for aggressive therapy is important, and identification of issues that might limit ability to complete treatment or benefit from treatment is essential, and can be accomplished through the use of a comprehensive geriatric assessment. This article serves as a review of the available evidence in the evaluation, treatment, and support of the older adult with cancer. PMID- 21295422 TI - Sleep problems in midlife and beyond. AB - Good sleep quality is important for good health, both physical and mental, and indeed for quality of life, performance and productivity. Sleep problems increase with age in both sexes, but women are more susceptible to them at all ages. Although menopause is considered an important milestone (the decrease in both oestrogen and progesterone has been shown to reduce sleep quality), an increase in sleep problems is already evident in midlife, as there is an increased incidence of other diseases as well as mood symptoms, which may exert an effect on sleep quality either directly or via the side-effects of the associated medications. Weight changes at midlife and the menopause may also affect sleep quality. In addition to reductions in sleep quality, specific sleep disorders, like sleep-disordered breathing and restless legs syndrome, become more prevalent in midlife and especially after menopause. Because sleep problems are commonly present in association with other conditions, rather than as isolated, independent disorders, treatment is often complex and patients generally need multiprofessional appraisal. PMID- 21295423 TI - Body weight as an indicator of fat-free mass in active elderly women. AB - OBJECTIVE: Fat-free mass (FFM) reduction and the tendency for a reduction in surrounding fatty issue and increase in the middle are a natural consequence of growing old and should be studied in order to gain a better understanding of the aging process. This study set out to find the FFM differences between active elderly women in two age groups (60-69 and 70-80 years) and to determine which of the anthropometric measurements, body weight (BW), abdominal circumference (AC), or body mass index (BMI) are the best predictors of FFM variation within the group. METHODS: Eighty-one (n=81) active elderly women of the Third Age willingly signed up to participate in the research during the activities at the University of the Third Age (UTA) in Brazil. The research was approved by the Research Ethics Committee of the Faculty of Medical Sciences of the State University of Campinas (UNICAMP). Body weight (BW), height (H) and the BMI were measured according to the international standards. The AC was measured in centimetres at the H of the navel and body composition was ascertained using bioimpedance analysis. The SAS program was used to perform the statistical analysis of independent samples and parametric data. RESULTS: The results showed FFM values with significant differences between the two groups, with the lowest values occurring among the women who were over 70 years of age. In the analysis, the Pearson's Correlation Coefficient for each measured independent variable was ascertained, with the BW measurement showing the highest ratio (0.900). CONCLUSIONS: The BW measurement was regarded as reliable, low-cost and easy to use for monitoring FFM in elderly women who engage in physical activities. PMID- 21295424 TI - Sex assessment from the carpals bones: discriminant function analysis in a 20th century Spanish sample. AB - Sex assessment is one of the first essential steps in human identification, in both medico-legal cases and bio-archaeological contexts. Fragmentary human remains compromised by different types of inhumation or physical insults may frustrate the use of the traditional sex estimation methods, such as the analysis of the skull and pelvis. Currently, the application of discriminant functions to sex unidentified skeletal remains is steadily increasing. However, several studies have demonstrated that, due to variation in size and patterns of sexual dimorphism, discriminant function equations are population-specific [1,2,5,12,61]. In this study, in order to improve sex assessment from skeletal remains and to establish population-specific discriminant functions, the diagnostic values of the carpal bones were considered. A sample of 100 individuals (50 males and 50 females) of known sex and age was analyzed. They belong to a 20th century identified collection from the Municipal Cemetery of "San Jose", Granada (Spain) and housed in the Laboratory of Anthropology, Faculty of Medicine, University of Granada (Spain). The age of the individuals ranged between 22 and 85 years. Between four and nine measurements of each carpal bone were performed [41,59]. Discriminant function statistics showed a sex assessment accuracy as high as 97.8%. The results suggest that carpal bones can be used for assessing sex in both forensic and bio-archaeological identification procedures. PMID- 21295425 TI - [Rift Valley fever]. AB - Rift Valley Fever (RVF) is a zoonotic arbovirosis. Among animals, it mainly affects ruminants, causing abortions in gravid females and mortality among young animals. In humans, RVF virus infection is usually asymptomatic or characterized by a moderate fever. However, in 1 to 3% of cases, more severe forms of the disease (hepatitis, encephalitis, retinitis, hemorrhagic fever) can lead to the death of infected individuals or to major sequels. The RVF virus (Bunyaviridae, genus Phlebovirus) was identified for the first time in the 1930s in Kenya. It then spread over almost all African countries, sometimes causing major epizootics/epidemics. In 2000, the virus was carried out of Africa, in the Middle East Arabian Peninsula. In 2007-2008, Eastern-African countries, including Madagascar, reported significant episodes of RVF virus, this was also the case for the Comoros archipelago and the French island of Mayotte. This ability to spread associated with many vectors, including in Europe, and high viral loads in infected animals led the health authorities worldwide to warn about the potential emergence of RVF virus in areas with a temperate climate. The awareness has increased in recent years with climate changes, which may possibly modify the vector distribution and competence, and prompted many RVF virus-free countries to better prepare for a potential implantation of RVF. PMID- 21295426 TI - [Severe presentations of Rift Valley Fever in Madagascar]. AB - OBJECTIVE: The authors describe clinical and epidemiologic characteristics of severe presentations of Rift valley fever (RVF) during the 2008 epidemic in Madagascar. METHODOLOGY: The diagnosis was confirmed by RVF virus polymerase chain reaction (PCR), or detection of specifics antibodies by Elisa. RESULTS: Sixteen cases of severe RVF were recorded. The sex-ratio was 7/1 and median age was 32 years (20/59 years). The risk factors of infection were: contact with infected animals or their meat (n=8), and travelling to a risk area (n=2). Hemorrhagic, neurological, and ocular manifestations were observed respectively in 87.5%, 43.8% and 6.3% of cases. All patients who died (n=4) presented with a hemorrhagic form of the disease. CONCLUSION: The hemorrhagic form was the most frequent presentation of RVF and was responsible for a high level of mortality. Epidemiologic surveillance must be implemented. PMID- 21295427 TI - [Dengue fever in the Reunion Island and in South Western islands of the Indian Ocean]. AB - South Western islands of the Indian Ocean are permanently threatened by dengue fever outbreaks. On the Reunion Island, two dengue outbreaks were biologically documented (1977-1978 and 2004). And since July 2004 there has been an inter epidemic period for the island with sporadic cases and clusters. Between January 1, 2007 and October 5, 2009, the epidemiologic surveillance system detected five confirmed autochthonous cases, five confirmed imported cases (South-East Asia), and 71 probable cases. All the five autochthonous confirmed cases occurred in Saint-Louis during two consecutive clusters. In other South Western islands of the Indian Ocean, several dengue fever outbreaks have been reported. Importation of dengue virus from South-East Asia is a major risk for a new outbreak on the island. The introduction of a new serotype could lead to the emergence of new and severe clinical forms, including dengue hemorrhagic fever. PMID- 21295428 TI - Bacterial species identification from MALDI-TOF mass spectra through data analysis and machine learning. AB - At present, there is much variability between MALDI-TOF MS methodology for the characterization of bacteria through differences in e.g., sample preparation methods, matrix solutions, organic solvents, acquisition methods and data analysis methods. After evaluation of the existing methods, a standard protocol was developed to generate MALDI-TOF mass spectra obtained from a collection of reference strains belonging to the genera Leuconostoc, Fructobacillus and Lactococcus. Bacterial cells were harvested after 24h of growth at 28 degrees C on the media MRS or TSA. Mass spectra were generated, using the CHCA matrix combined with a 50:48:2 acetonitrile:water:trifluoroacetic acid matrix solution, and analyzed by the cell smear method and the cell extract method. After a data preprocessing step, the resulting high quality data set was used for PCA, distance calculation and multi-dimensional scaling. Using these analyses, species specific information in the MALDI-TOF mass spectra could be demonstrated. As a next step, the spectra, as well as the binary character set derived from these spectra, were successfully used for species identification within the genera Leuconostoc, Fructobacillus, and Lactococcus. Using MALDI-TOF MS identification libraries for Leuconostoc and Fructobacillus strains, 84% of the MALDI-TOF mass spectra were correctly identified at the species level. Similarly, the same analysis strategy within the genus Lactococcus resulted in 94% correct identifications, taking species and subspecies levels into consideration. Finally, two machine learning techniques were evaluated as alternative species identification tools. The two techniques, support vector machines and random forests, resulted in accuracies between 94% and 98% for the identification of Leuconostoc and Fructobacillus species, respectively. PMID- 21295429 TI - Bystander cardiopulmonary resuscitation-induced splenic laceration and hepatosplenic hematoma. PMID- 21295430 TI - Inhalant abuse of computer cleaner manifested as angioedema. AB - Inhalant abuse is the intentional inhalation of chemical vapors or volatile substance to achieve a euphoric effect. Although no statistical data are reported yet, inhalant abuse is potentially life-threatening and has resulted in a wide range of toxic effects such as central nervous system depression, seizures, aspiration, cardiac arrhythmia, asphyxiation, hypoxia, metabolic acidosis, and sudden death among others. We are reporting a 25-year-old white man who was brought to the emergency department after inhaling aerosolized computer-cleaning spray composed of difluoroethane. He was found to have marked upper and lower lip facial swelling consistent with angioedema. The patient also had a prolonged QT interval, mild inspiratory stridor, but no urticaria. In this case, we believe the difluoroethane-related angioedema represents either idiopathic or bradykinin induced angioedema. PMID- 21295431 TI - Acute myocardial infarction and multiple traumas: a dilemma of protocol. AB - Treatment of myocardial infarction is today governed by specific protocols. Angioplasty involves a therapeutical anticoagulation to prevent the risk of acute thrombosis. Acute myocardial infarction after a blunt trauma has been described, but there is no specific treatment recommendations extant, particularly weighing the risk of hemorrhage. In this report, we describe an adolescent boy who suffered from an acute myocardial infarction by dissection of the left anterior descending coronary after a car crash. He also presented with a subdural hemorrhage and a lung contusion, injuries, which both present a substantial risk of hemorrhage. After diagnosing the therapeutical problem, we describe our decisions regarding how we approached this case. We provide an algorithm of treatment coming from our experience of these cases with the hope it can help physicians in their future decisions. PMID- 21295432 TI - Therapeutic hypothermia after profound accidental hypothermia and cardiac arrest. PMID- 21295433 TI - Computerized self-monitoring and technology-assisted feedback for weight loss with and without an enhanced behavioral component. AB - OBJECTIVE: The purpose of this study was to develop and evaluate a 12-week weight management intervention involving computerized self-monitoring and technology assisted feedback with and without an enhanced behavioral component. METHODS: 120 overweight (30.5+/-2.6kg/m(2)) adults (45.0+/-10.3 years) were randomized to one of three groups: computerized self-monitoring with Basic feedback (n=45), Enhanced behavioral feedback (n=45), or wait-list control (n=30). Intervention participants used a computer software program to record dietary and physical activity information. Weekly e-mail feedback was based on computer-generated reports, and participants attended monthly measurement visits. RESULTS: The Basic and Enhanced groups experienced significant weight reduction (-2.7+/-3.3kg and 2.5+/-3.1kg) in comparison to the Control group (0.3+/-2.2; p<0.05). Waist circumference and systolic blood pressure also decreased in intervention groups compared to Control (p<0.01). CONCLUSIONS: A program using computerized self monitoring, technology-assisted feedback, and monthly measurement visits produced significant weight loss after 12 weeks. However, the addition of an enhanced behavioral component did not improve the effectiveness of the program. PRACTICE IMPLICATIONS: This study suggests that healthcare professionals can effectively deliver a weight management intervention using technology-assisted strategies in a format that may complement and reduce face-to-face sessions. PMID- 21295434 TI - Understanding responses to government health recommendations: public perceptions of government advice for managing the H1N1 (swine flu) influenza pandemic. AB - OBJECTIVE: To explore people's beliefs, perceptions, reasoning, and emotional and contextual factors that may influence responses to government recommendations for managing flu pandemics. METHODS: Eleven focus groups were conducted with a purposive sample of 48 participants. Participants were invited to discuss their perceptions of the H1N1 pandemic and government advice on recommended actions for managing the H1N1 pandemic. RESULTS: Thematic analysis showed that participants were skeptical about the feasibility and appropriateness of government recommendations for managing the H1N1 pandemic. They expressed doubts about self diagnosis and concerns regarding the perceived effectiveness and costs of recommendations to stay home if unwell and get vaccinated. CONCLUSIONS: Government advice is a specialized form of health communication with members of the public. People engage in an active process of evaluating government advice in terms of its credibility, feasibility and costs. To improve future pandemic preparedness, attempts should be made to elicit and address common doubts and concerns people have about following recommended advice. PRACTICAL IMPLICATIONS: This study provides preliminary information on potential concerns and issues that could be addressed in future pandemic communications. Further research is needed to elicit and address the public perspective so that the impact of future pandemics may be reduced. PMID- 21295435 TI - RETRACTED: Rosiglitazone and pioglitazone aggravate doxorubicin-induced cardiomyopathy in Wistar rats. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.biomag.2010.12.001 The duplicate article has therefore been withdrawn. PMID- 21295436 TI - [Hemolytic anemia in adults: Main causes and diagnostic procedure]. AB - Hemolytic anemia (HA) is not an exceptional situation in adults. While establishing the hemolytic mechanism of an anemia is usually rather easy, finding the etiology may be quite difficult as both some hereditary (corpuscular) and acquired causes of HA may occur during adulthood. The diagnosis of HA therefore requires a multiple step procedure taking into account both patient's and family history, a careful analysis of the blood smear and a direct antiglobulin test. Based on these first data, the diagnosis procedure may then require more specific tests whose indications are discussed in this review. PMID- 21295437 TI - [Survival, clinical and biological outcomes of HIV-infected children treated by antiretroviral therapy in Africa: systematic review, 2004-2009]. AB - BACKGROUND: With 2.1 million HIV-infected children in 2008 in the world, especially in sub-Saharan Africa, the paediatric HIV/AIDS care remains an important public health challenge and is principally based on cotrimoxazole prophylaxis and antiretroviral treatments. This paper aims to review the effectiveness of cotrimoxole prophylaxis and antiretroviral treatment in HIV infected children in Africa, specifically mortality and treatment outcomes. METHODS: In two times, we searched the online databases PubMedTM and ScopusTM for articles and abstracts published in English and French between January 2004 and November 2009, with the following terms : " HIV " and " Africa " and ["paediatric" or "children" or "child"] and ["mortality" or "survival"] and ["cotrimoxazole" or "prophylaxis"] at the first time, " HIV " and " Africa " and ["paediatric" or "children" or "child"] and ["mortality" or "survival"] and ["antiretroviral"] and ["treatment" or "therapy"] at the second time. Longitudinal studies on HIV-infected children under cotrimoxazole prophylaxis or antiretroviral treatment were selected when survival outcomes were reported. RESULTS: The probability of death was significantly reduced by 43% where children received cotrimoxazole prophylaxis compared to placebo. Compared to the survival without treatment, the benefit of antiretroviral therapy on HIV-infected children survival was evident in all publications but early mortality was observed within the six first months of antiretroviral treatment. Over fifty percent of deaths occurred in this period. Severe malnutrition, anaemia and lower CD4% were identified as mortality predicting factors in both children received cotrimoxazole prophylaxis or treated by antiretroviral therapy. DISCUSSION: Better knowledge of determinants of early mortality for these children are important to optimized their survival and improve their quality of care and life. Finally, the beneficial effect of cotrimoxazole prophylaxis when associated with antiretroviral treatment has not been reported and need to be exploring in detail for more information. PMID- 21295438 TI - Posttraumatic stress symptoms and postpartum depression in couples after childbirth: the role of partner support and attachment. AB - AIM: The roles of partner attachment and perceptions of partner support were explored in relation to symptoms of posttraumatic stress and postpartum depression in couples within the first three postnatal months. METHODS: Participants (n=372) were recruited within the first seven days postpartum, and completed questionnaire measures of trait anxiety, symptoms of acute posttraumatic stress, and perceptions of partner support. Postal questionnaires were completed at six weeks and three months, assessing attachment, perception of partner support, symptoms of posttraumatic stress, and postpartum depression. Two hundred and twelve couples completed all time-points. RESULTS: Results indicated that symptoms were significantly related within couples. Men's acute trauma symptoms predicted their partner's subsequent symptoms of posttraumatic stress. Less secure attachment and dissatisfaction with partner support were associated with higher levels of postpartum depression and posttraumatic stress. CONCLUSIONS: Men's and women's responses following childbirth appear to be strongly interlinked; services should target both members of the dyad. PMID- 21295439 TI - Outcome evaluation of active support training in Taiwan. AB - Active Support was implemented for the first time in Taiwan in March, 2009. This study aims to evaluate whether the supervisors and front line managers of residential services receiving Active Support Training (AST) caused a positive impact on their users with intellectual disabilities (ID) while comparing this with their counterparts with ID whose residential staff were not being involved in the training. The nonequivalent groups design was used for the evaluation; the participants included 49 residents of 12 community living homes as the experimental group and 19 residents of another 5 community living homes as the comparative group. The pretest evaluation was conducted before the AST and the post-test and follow-up evaluations were conducted following 4 months and 14 months after the pre-test respectively. The assessment package contained questionnaires relating to domestic engagement, community inclusion, choice, social network, mood scales, challenging behaviors, adaptive behavior and demographic questions among the residents with ID. Within the group, analyses showed that the residents whose staff received AST showed increased levels of choice and adaptive behavior and decreased levels of depression in the post-test and follow up in addition the residents' engagement in domestic activities improved in the follow up. The intervention did not affect the frequency of family contact, community inclusion and challenging behavior among the residents. The residents in the comparative group showed no significant change except the levels of depression decreased comparing follow-up test and post-test. Based on a cross groups comparison of the effect of the intervention among the residents, only a decreased level of depression was found in the post-test results of the both groups. This study suggests Active Support is practicable but only partially effective in Taiwan; thus, conducting an AST Package of Taiwan version is expectable. PMID- 21295440 TI - Development of the Little Developmental Coordination Disorder Questionnaire for preschoolers and preliminary evidence of its psychometric properties in Israel. AB - PURPOSE: The early identification of motor coordination challenges before school age may enable close monitoring of a child's development and perhaps ameliorate some of the social, psychological and behavioral sequela that often accompany unrecognized Developmental Coordination Disorder (DCD). The purpose of this study was to develop and assess the initial psychometric properties of a screening tool, the Little DCD Questionnaire (Little DCDQ), designed to identify DCD amongst preschoolers aged 3 and 4. METHODS: The suitability of the items of the DCDQ'07 for 3- and 4-year-old children was assessed. Four items were found to be suitable and new items were generated. Content validity was ensured using a Table of Specification and the items were categorized into three sub-categories (Control During Movement, Fine Motor and General Coordination). The Little DCDQ was administered to 146 children (91 boys) aged 3 and 4 (mean age=49.39+/-7.16 months). Ninety-one typically developing children were included (mean age=47.80+/ 7.05 months; 46 boys) while 55 children had been referred or were being treated for some form of developmental delay (mean age=52.02+/-6.60 months; 45 boys). Of this sample, 28 parents completed the questionnaire twice within a 2-week interval. RESULTS: Test-retest reliability was evidenced by moderate to good intraclass correlation coefficient values between scores on the two administrations for the total and the three sub-category scores. Evidence of internal consistency was provided by adequate to high Cronbach's alpha co efficients calculated for each item, each sub-category score and the total score for the total group, and separately for the control group and the clinically referred group. Validity evidence based on relations to other variables was provided by the finding of significant group differences (clinically referred and control) for the total and sub-category scores for both the age groups and the total group. CONCLUSIONS: Based on the preliminary psychometric evidence, it appears that the Little DCDQ meets many of the necessary standards for validity and reliability as a screening instrument, and shows promise as a useful clinical and research tool. PMID- 21295441 TI - Concurrent validity of Preschooler Gross Motor Quality Scale with Test of Gross Motor Development-2. AB - Preschooler Gross Motor Quality Scale (PGMQ) was recently developed to evaluate motor skill quality of preschoolers. The purpose of this study was to establish the concurrent validity of PGMQ using Test of Gross Motor Development-2 (TGMD-2) as the gold standard. One hundred and thirty five preschool children aged from three to six years were recruited from three kindergartens in central Taiwan. Two independent evaluators who were unaware of each other's results evaluated all the children separately in their kindergartens using standardized setting and procedures. Concurrent validity was examined using correlation analysis with Pearson-Production Moment correlation coefficient. The results show that the total scores (r = .86, p < .001) and subscale total scores (r = .82 for locomotion, r = .76 for object manipulation, p < .001) of the two tests correlated well. Analysis of similar items in the locomotion subscale found significant but weak correlations in the running, jumping and galloping items of the two tests (r = .23-.25, p < .001). There were moderate to high correlations in hopping, sliding and leaping between the two tests (r = .52-.70, p < .001). Low to moderate correlations (r = .37-.54, p < .001) were found between the similar items in the object manipulation subscale of PGMQ and TGMD-2. Total scores of TGMD-2 also showed a high relation between the sum of the locomotion and object manipulation scores of PGMQ (r = .83, p < .001). The total scores of similar items in the locomotion subscale of PGMQ and TGMD-2 showed a similar high relation (r = .79, p < .001) likewise in the object manipulation subscale (r = .75, p < .001) The PGMQ proved to have adequate concurrent validity with TGMD-2. PMID- 21295442 TI - The longitudinal relationship between behavior and emotional disturbance in young people with intellectual disability and maternal mental health. AB - Although elevated rates of parent psychosocial distress have been associated with child behavior and emotional problems, little is known about the nature of this relationship over time. This study followed an epidemiological cohort of children and adolescents over 11 years with 4 waves of data collection. Within this cohort, complete data were available on 238 mothers and their children. Behavior and emotional problems were assessed using the DBC, maternal mental health with the GHQ. Multivariate growth curve modelling was used to evaluate the commonality of individual change patterns. High levels of mental health problems were reported, which were stable over time. Higher scores on the DBC were associated with higher rates of mental health problems. Increases in child social relating problems were associated with increases mental health symptoms, particularly depression and anxiety. PMID- 21295443 TI - Convergence optimization of parametric MLEM reconstruction for estimation of Patlak plot parameters. AB - In dynamic positron emission tomography data many researchers have attempted to exploit kinetic models within reconstruction such that parametric images are estimated directly from measurements. This work studies a direct parametric maximum likelihood expectation maximization algorithm applied to [(18)F]DOPA data using reference-tissue input function. We use a modified version for direct reconstruction with a gradually descending scheme of subsets (i.e. 18-6-1) initialized with the FBP parametric image for faster convergence and higher accuracy. The results compared with analytic reconstructions show quantitative robustness (i.e. minimal bias) and clinical reproducibility within six human acquisitions in the region of clinical interest. Bland-Altman plots for all the studies showed sufficient quantitative agreement between the direct reconstructed parametric maps and the indirect FBP (--0.035x+0.48E--5). PMID- 21295444 TI - A 24-h recall does not provide a valid estimate of absolute nutrient intakes for rural women in southern Ethiopia. AB - OBJECTIVE: To investigate the relative validity of a multiple-pass interactive 24 h recall (24-HR) for assessing nutrient intakes of a group of rural Ethiopian women. METHODS: Dietary intakes from a 24-HR were compared with weighed record (WR) intakes collected on the same day for 58 women of child-bearing age from three subsistence farming communities in Sidama. The impact of memory lapses, use of average recipe data, and inaccurate portion size estimates on 24-HR intakes was also assessed. RESULTS: Median daily intakes of energy and most nutrients (except fat and phytate) were lower (P < 0.05) by the 24-HR versus the WR. Controlling for energy densities decreased the discrepancies to lower than +/-6%, except for vitamin C. No significant differences between the two methods existed for the contribution of six food groups to energy intakes (percentages). Fewer than 40% of 24-HR intakes were +/-10% of the WR. After classifying intakes (per day) into quartiles, Cohen's kappa values were poor (<4.0) for protein, iron, retinol, and dietary fiber and fair (>=0.40 to <=0.75) for energy and other nutrients; all values per megajoule were mostly fair. Bland-Altman plots confirmed a negative bias for daily energy and nutrient intakes with the 24-HR versus WRs. Discrepancies were attributed mainly to inaccurate portion size estimates. CONCLUSION: In this setting, the 24-HR cannot be substituted for the WR to assess absolute nutrient intakes for a group or the prevalence of inadequate intakes but could be used for energy-adjusted intakes. Prior training may improve the accuracy of the 24-HR. PMID- 21295445 TI - Moving on in Schizophrenia Research to the next decade. PMID- 21295446 TI - Presence of qnrVC3 gene cassette in SXT and class 1 integrons of Vibrio cholerae. PMID- 21295447 TI - In vitro antibacterial activity of ceftobiprole against clinical isolates from French teaching hospitals: proposition of zone diameter breakpoints. AB - The aims of this study were to determine the in vitro activity profile of ceftobiprole, a pyrrolidinone cephalosporin, against a large number of bacterial pathogens and to propose zone diameter breakpoints for clinical categorisation according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) minimum inhibitory concentration (MIC) breakpoints. MICs of ceftobiprole were determined by broth microdilution against 1548 clinical isolates collected in eight French hospitals. Disk diffusion testing was performed using 30 MUg disks according to the method of the Comite de l'Antibiogramme de la Societe Francaise de Microbiologie (CA-SFM). The in vitro activity of ceftobiprole, expressed by MIC(50/90) (MICs for 50% and 90% of the organisms, respectively) (mg/L), was as follows: meticillin-susceptible Staphylococcus aureus, 0.25/0.5; meticillin-resistant S. aureus (MRSA), 1/2; meticillin-susceptible coagulase negative staphylococci (CoNS), 0.12/0.5; meticillin-resistant CoNS, 1/2; penicillin-susceptible Streptococcus pneumoniae, <= 0.008/0.03; penicillin resistant S. pneumoniae, 0.12/0.5; viridans group streptococci, 0.03/0.12; beta haemolytic streptococci, <= 0.008/0.016; Enterococcus faecalis, 0.25/1; Enterococcus faecium, 64/128; Enterobacteriaceae, 0.06/32; Pseudomonas aeruginosa, 4/16; Acinetobacter baumannii, 0.5/64; Haemophilus influenzae, 0.03/0.12; and Moraxella catarrhalis, 0.25/0.5. According to the regression curve, zone diameter breakpoints could be 28, 26, 24 and 22 mm for MICs of 0.5, 1, 2 and 4 mg/L respectively. In conclusion, this study confirms the potent in vitro activity of ceftobiprole against many Gram-positive bacteria, including MRSA but not E. faecium, whilst maintaining a Gram-negative spectrum similar to the advanced-generation cephalosporins such as cefepime. Thus ceftobiprole appears to be well suited for the empirical treatment of a variety of healthcare associated infections. PMID- 21295448 TI - Adaptive resistance to cationic compounds in Pseudomonas aeruginosa. AB - Adaptive resistance is an autoregulated phenomenon characterised by induction of resistance in the presence of drug and reversal to the sensitive phenotype in its absence. This type of resistance is well documented for polycationic antibiotics, including aminoglycosides and polymyxins, in Pseudomonas aeruginosa and other aerobic Gram-negative bacilli. It is not caused by selection of resistant mutants but rather by phenotypic alterations in order to survive the lethal drug effect. Adaptive resistance to aminoglycosides is mainly mediated by the MexXY-OprM efflux pump that is rapidly upregulated in bacteria surviving the first exposure to aminoglycosides and is downregulated when bacteria are no longer in contact with the drug. A two-component regulatory system designated ParR-ParS plays a major role in adaptive resistance induced by cationic peptides. In the presence of cationic peptides, ParR-ParS activates the lipopolysaccharide modification operon (arnBCADTEF) leading to increased resistance in polymyxins and aminoglycosides. The bactericidal kinetics related to adaptive resistance have important clinical implications and provide a rationale for administering cationic antibiotics in larger initial and longer interval bolus dosing. A better understanding of this phenomenon and the molecular mechanisms responsible will be essential not only for optimum use of cationic antibiotics but also for developing new agents with ability to counteract the detrimental effects of adaptive resistance and thus enhance the therapeutic efficacy of polycationic compounds. PMID- 21295449 TI - Harmonisation of resistance monitoring programmes in veterinary medicine: an urgent need in the EU? AB - Antimicrobial surveillance systems in Denmark (DANMAP), The Netherlands (MARAN), Spain (VAV) and Sweden (SVARM) as well as the European Antimicrobial Susceptibility Surveillance in Animals (EASSA) were reviewed. Data have been considered for extended-spectrum cephalosporins, fluoroquinolones and macrolides against food-borne and commensal bacteria. The greatest challenge arises from the lack of agreement between programmes on what is meant by resistance through the use of different interpretive criteria. Indeed, it is shown here that the extent of the differences depends on the antibacterial compound being investigated, the methodology and the interpretive criteria used. This emphasises a need to agree a definition for resistance and for epidemiological cut-off values and to consider harmonising the antimicrobials used in surveillance. This analysis of the data highlights the usefulness of using both epidemiological cut-off values and clinical resistance breakpoints for the purpose of detection of decreased susceptibility and development of clinical resistance, respectively. It is concluded that harmonisation in resistance monitoring programmes is needed since there is potential for data to be appropriately used within risk analysis, providing the opportunity to implement appropriate risk management steps as a response to the public health issues arising from changes in antibiotic resistance in food-borne pathogens and commensal organisms. PMID- 21295450 TI - Metabolic and endocrine adverse effects of second-generation antipsychotics in children and adolescents: A systematic review of randomized, placebo controlled trials and guidelines for clinical practice. AB - Second-generation antipsychotics (SGA) are being used more often than ever before in children and adolescents with psychotic and a wide range of non-psychotic disorders. Several SGA have received regulatory approval for some paediatric indications in various countries, but off-label use is still frequent. The aim of this paper was to perform a systematic review and critically evaluate the literature on cardiometabolic and endocrine side-effects of SGA in children and adolescents through a Medline/Pubmed/Google Scholar search of randomized, placebo controlled trials of antipsychotics in children and adolescents (<18 years old) until February 2010. In total, 31 randomized, controlled studies including 3595 paediatric patients were identified. A review of these data confirmed that SGA are associated with relevant cardiometabolic and endocrine side-effects, and that children and adolescents have a high liability to experience antipsychotic induced hyperprolactinaemia, weight gain and associated metabolic disturbances. Only weight change data were sufficiently reported to conduct a formal meta analysis. In 24 trials of 3048 paediatric patients with varying ages and diagnoses, ziprasidone was associated with the lowest weight gain (-0.04kg, 95% confidence interval [CI]: -0.38 to +0.30), followed by aripiprazole (0.79kg, 95% CI: 0.54 to 1.04], quetiapine (1.43kg, 95% CI: 1.17 to 1.69) and risperidone (1.76kg, 95% CI: 1.27 to 2.25) were intermediate, and olanzapine was associated with weight gain the most (3.45kg, 95% CI: 2.93 to 3.97). Significant weight gain appeared to be more prevalent in patients with autistic disorder who were also younger and likely less exposed to antipsychotics previously. These data clearly suggest that close screening and monitoring of metabolic side effects is warranted and that the least cardiometabolically problematic agents should be used first whenever possible. A good collaboration between child- and adolescent psychiatrists, general practitioners and paediatricians is essential to maximize overall outcomes and to reduce the likelihood of premature cardiovascular morbidity and mortality. PMID- 21295451 TI - The adverse skeletal effects of selective serotonin reuptake inhibitors. AB - Selective serotonin reuptake inhibitors (SSRIs) are a widely used group of antidepressants (ADs) with reported potential detrimental effects on bone mineral density (BMD) and increased fracture risk. Here, a comprehensive review of the in vitro, in vivo and clinical studies to date was carried out using the medical search engines MEDLINE (1950 to September 2010) and EMBASE (1980 to September 2010). Serotonin (5-HT) receptors have been identified on osteoclast, osteoblast and osteocyte cell lines. The effect of SSRIs on bone formation and resorption appears to be governed by the activation of a number of 5-HT receptors on osteoblasts and osteoclasts via endocrine, autocrine/paracrine and neuronal pathways. In vitro, in vivo and clinical collective data appears to indicate that SSRIs have a negative effect on bone at the therapeutic dose levels widely used for the treatment of depression in current clinical practice. Caution may therefore have to be employed with the use of SSRIs in patients at an increased risk of falls and osteoporosis. Further studies are needed in order to fully elicit the role of SSRIs in bone formation and their effects in the low oestrogen state. PMID- 21295452 TI - Maximum-uncertainty linear discrimination analysis of first-episode schizophrenia subjects. AB - Recent techniques of image analysis brought the possibility to recognize subjects based on discriminative image features. We performed a magnetic resonance imaging (MRI)-based classification study to assess its usefulness for outcome prediction of first-episode schizophrenia patients (FES). We included 39 FES patients and 39 healthy controls (HC) and performed the maximum-uncertainty linear discrimination analysis (MLDA) of MRI brain intensity images. The classification accuracy index (CA) was correlated with the Positive and Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning scale (GAF) at 1-year follow-up. The rate of correct classifications of patients with poor and good outcomes was analyzed using chi-square tests. MLDA classification was significantly better than classification by chance. Leave-one-out accuracy was 72%. CA correlated significantly with PANSS and GAF scores at the 1-year follow-up. Moreover, significantly more patients with poor outcome than those with good outcome were classified correctly. MLDA of brain MR intensity features is, therefore, able to correctly classify a significant number of FES patients, and the discriminative features are clinically relevant for clinical presentation 1 year after the first episode of schizophrenia. The accuracy of the current approach is, however, insufficient to be used in clinical practice immediately. Several methodological issues need to be addressed to increase the usefulness of this classification approach. PMID- 21295453 TI - [An unusual etiology of neonatal renal insufficiency: the spontaneous rupture of the bladder]. AB - Postnatal urinary ascites is a rare occurrence compared with other causes of peritoneal effusion at this age and its frequency in prenatal diagnosis. Spontaneous rupture of the bladder was diagnosed in a premature male infant presenting with postnatal ascites and anuric renal insufficiency. Surgical repair was required. No predisposing factor was associated with this rare complication. The urinary origin of the ascites was diagnosed based on the biochemical composition, allowing us to understand its mechanism and to treat it. PMID- 21295454 TI - Impact of ellagic acid on adriamycin-induced testicular histopathological lesions, apoptosis, lipid peroxidation and sperm damages. AB - The aim of the present study was to investigate whether ellagic acid (EA) has protective effect on adriamycin (ADR)-induced testicular and spermatozoal toxicity associated with the oxidative stress in male rats. Thirthy-two healthy 8 week-old male Sprague-Dawley rats were equally divided into four groups. The first (EA) group was treated with EA (2 mg/kg/every other day) by gavage. The second (ADR) group received ADR (2 mg/kg/once a week) intraperitoneally, while the combination of ADR and EA was given to the third (ADR+EA) group. The forth (control) group was treated with placebo. At the end of the 8-week treatment period, reproductive organ weights, epididymal sperm parameters, histopathological changes and apoptosis via Bax and Bcl-2 proteins, testicular tissue lipid peroxidation, and antioxidant enzyme activities, were investigated. ADR administration was determined to cause significant decreases in reproductive organ weights, epididymal sperm concentration and motility, plasma testosterone concentration, diameter of seminiferous tubules, germinal cell layer thickness, Johnsen's testicular score and Bcl-2 positive antiapoptotic cell rate, wherease it caused significant increases in level of lipid peroxidation and glutathione, catalase activity, abnormal sperm rates and Bax positive apoptotic cell rates along with degeneration, necrosis, immature germ cells, congestion and atrophy in testicular tissue when compared with the control group. EA administration to ADR treated rats provided significant improvements in ADR-induced disturbed oxidant/antioxidant balance, decreased testosterone concentration, testicular apoptosis and mild improvements in the histopathological view of the testicular tissue. However, EA failed to improve decreased reproductive organ weights and deteriorated sperm parameters due to ADR administration. It is concluded that while ADR has direct or indirect (lipid peroxidation) negative effects on sperm structure and testicular apoptosis in rats, EA has protective effects on ADR induced testicular lipid peroxidation and apoptosis. PMID- 21295455 TI - Analysis of the promoter region of the gene LIP1 encoding triglyceride lipase from Fusarium graminearum. AB - Triglyceride lipases catalyze the reversible degradation of glycerol esters with long-chain fatty acids into fatty acids and glycerol. In silico analysis of 5' end flanking sequence of the gene LIP1 encoding a triglyceride lipase from the wheat head blight pathogen Fusarium graminearum revealed the presence of several cis-regulatory elements. To delineate the function of these regulatory elements, we constructed a series of deletion mutants in the LIP1 promoter region fused to the open reading frame of a green fluorescent protein (GFP) and assayed the promoter activity. Analysis of GFP expression levels in mutants indicated that a 563-bp promoter sequence was sufficient to drive the expression of LIP1 and regulatory elements responsible for the gene induction were located within the 563-372bp region. To further investigate the regulatory elements, putative cis acting elements spanned within the 563-372bp region were mutated using a targeted mutagenesis approach. A CCAAT box, a CreA binding site, and a fatty acid responsive element (FARE) were identified and confirmed to be required for the basal expression of LIP1, glucose suppression and fatty acid induction, respectively. PMID- 21295456 TI - Targeting of AID-mediated sequence diversification to immunoglobulin genes. AB - Activation-induced cytidine deaminase (AID) is a key enzyme for antibody-mediated immune responses. Antibodies are encoded by the immunoglobulin genes and AID acts as a transcription-dependent DNA mutator on these genes to improve antibody affinity and effector functions. An emerging theme in field is that many transcribed genes are potential targets of AID, presenting an obvious danger to genomic integrity. Thus there are mechanisms in place to ensure that mutagenic outcomes of AID activity are specifically restricted to the immunoglobulin loci. Cis-regulatory targeting elements mediate this effect and their mode of action is probably a combination of immunoglobulin gene specific activation of AID and a perversion of faithful DNA repair towards error-prone outcomes. PMID- 21295457 TI - Dyspnoea and the brain. AB - Chronic dyspnoea is a devastating symptom that debilitates millions of people worldwide. It causes a large burden on both patient and carer, and significant costs to society and health services. Treatment options are limited. Much effort has been directed at optimising lung function and improving exercise capacity, however, the brain mechanisms underlying dyspnoea perception have received less attention. In this review, we focus on cognitive and affective aspects of dyspnoea and discuss how novel neuroimaging methods can provide quantitative measures of these subjective sensations. We draw parallels with the more advanced field of chronic pain, and explain some of the challenges faced when imaging dyspnoea. To date, brain mechanisms of dyspnoea have been investigated in a handful of studies by a limited number of authors. These have found consistent activation in the insular cortex, the anterior cingulate cortex and the amygdala. Novel neuroimaging methods and an improved understanding of perceptual mechanisms underlying dyspnoea now position us to transform dyspnoea research. Future research should investigate how brain regions associated with dyspnoea interact, as well as accurately correlate this neuronal activation with reliable behavioural measures. A better understanding of the brain processes underlying dyspnoea perception will lead to new therapies that will improve quality of life for a very large group of patients. PMID- 21295458 TI - Role of calcineurin in neurodegeneration produced by misfolded proteins and endoplasmic reticulum stress. AB - A hallmark event in neurodegenerative diseases is the accumulation of misfolded aggregated proteins in the brain leading to neuronal dysfunction and disease. Compelling evidence suggests that misfolded proteins damage cells by inducing endoplasmic reticulum (ER) stress and alterations in calcium homeostasis. Changes in cytoplasmic calcium concentration lead to unbalances on several signaling pathways. Recent data suggest that calcium-mediated hyperactivation of calcineurin (CaN), a key phosphatase in the brain, triggers synaptic dysfunction and neuronal death, the two central events responsible for brain degeneration in neurodegenerative diseases. Therefore, blocking CaN hyper-activation might be a promising therapeutic strategy to prevent brain damage in neurodegenerative diseases. PMID- 21295459 TI - Enhancement of the recycling of waste Ni-Cd and Ni-MH batteries by mechanical treatment. AB - A serious environmental problem was presented by waste batteries resulting from lack of relevant regulations and effective recycling technologies in China. The present work considered the enhancement of waste Ni-Cd and Ni-MH batteries recycling by mechanical treatment. In the process of characterization, two types of waste batteries (Ni-Cd and Ni-MH batteries) were selected and their components were characterized in relation to their elemental chemical compositions. In the process of mechanical separation and recycling, waste Ni-Cd and Ni-MH batteries were processed by a recycling technology without a negative impact on the environment. The technology contained mechanical crushing, size classification, gravity separation, and magnetic separation. The results obtained demonstrated that: (1) Mechanical crushing was an effective process to strip the metallic parts from separators and pastes. High liberation efficiency of the metallic parts from separators and pastes was attained in the crushing process until the fractions reached particle sizes smaller than 2mm. (2) The classified materials mainly consisted of the fractions with the size of particles between 0.5 and 2mm after size classification. (3) The metallic concentrates of the samples were improved from around 75% to 90% by gravity separation. More than 90% of the metallic materials were separated into heavy fractions when the particle sizes were larger than 0.5mm. (4) The size of particles between 0.5 and 2mm and the rotational speed of the separator between 30 and 60 rpm were suitable for magnetic separation during industrial application, with the recycling efficiency exceeding 95%. PMID- 21295460 TI - Influence of RFID tags on recyclability of plastic packaging. AB - The use of Radio Frequency IDentification Technology (RFID) in the packaging sector is an important logistical improvement regarding the advantages offered by this technology in comparison with barcodes. Nevertheless, the presence of these devices in plastic packaging, and consequently in plastic waste, can cause several problems in the recycling plants due to the materials included in these devices. In this study, the mentioned recycling constraints have been experimentally identified in a pilot scale recycling study consisting in three recycling tests with an increasing presence of RFID tags. Differences in each test were evaluated. Furthermore, the quality of the recycled material of each test was studied through the injection and testing of tests probes. The results of the pilot scale recycling tests did not show a decrease in the quality of the recycled plastic due to the presence of RFID tags. Nevertheless, several operational problems during the recycling process were observed such as the obstruction of the screens, which lessened the process yield and created process interruptions, as well as the loss of extruded plastic during the process. These recycling constraints cannot be directly extrapolated to the industrial plants due to the different working scales. Nevertheless, technological solutions are proposed in order to avoid these recycling constraints if they appear. PMID- 21295461 TI - Improving the layout of recycling centres by use of lean production principles. AB - There has been increased focus on recycling in Sweden during recent years. This focus can be attributed to external environmental factors such as tougher legislation, but also to the potential gains for raw materials suppliers. Recycling centres are important components in the Swedish total recycling system. Recycling centres are manned facilities for waste collection where visitors can bring, sort and discard worn products as well as large-sized, hazardous, and electrical waste. The aim of this paper was to identify and describe the main flows and layout types at Swedish recycling centres. The aim was also to adapt and apply production theory for designing and managing recycling centre operations. More specifically, this means using lean production principles to help develop guidelines for recycling centre design and efficient control. Empirical data for this research was primarily collected through interviews and questionnaires among both visitors and employees at 16 Swedish recycling centres. Furthermore, adapted observation protocols have been used in order to explore visitor activities. There was also close collaboration with a local recycling centre company, which shared their layout experiences with the researchers in this project. The recycling centres studied had a variety of problems such as queues of visitors, overloading of material and improper sorting. The study shows that in order to decrease the problems, the recycling centres should be designed and managed according to lean production principles, i.e. through choosing more suitable layout choices with visible and linear flows, providing better visitor information, and providing suitable technical equipment. Improvements can be achieved through proper planning of the layout and control of the flow of vehicles, with the result of increased efficiency and capacity, shorter visits, and cleaner waste fractions. The benefits of a lean production mindset include increased visitor capacity, waste flexibility, improved sorting quality, shorter time for visits and improved working conditions. PMID- 21295462 TI - Hydration and leaching characteristics of cement pastes made from electroplating sludge. AB - The purpose of this study was to investigate the hydration and leaching characteristics of the pastes of belite-rich cements made from electroplating sludge. The compressive strength of the pastes cured for 1, 3, 7, 28, and 90 days was determined, and the condensation of silicate anions in hydrates was examined with the (29)Si nuclear magnetic resonance (NMR) technology. The leachabilities of the electroplating sludge and the hardened pastes were studied with the multiple toxicity characteristic leaching procedure (MTCLP) and the tank leaching test (NEN 7345), respectively. The results showed that the electroplating sludge continued to leach heavy metals, including nickel, copper, and zinc, and posed a serious threat to the environment. The belite-rich cement made from the electroplating sludge was abundant in hydraulic beta-dicalcium silicate, and it performed well with regard to compressive-strength development when properly blended with ordinary Portland cements. The blended cement containing up to 40% the belite-rich cement can still satisfy the compressive-strength requirements of ASTM standards, and the pastes cured for 90 days had comparable compressive strength to an ordinary Portland cement paste. It was also found that the later hydration reaction of the blended cements was relatively more active, and high fractions of belite-rich cement increased the chain length of silicate hydrates. In addition, by converting the sludge into belite-rich cements, the heavy metals became stable in the hardened cement pastes. This study thus indicates a viable alternative approach to dealing with heavy metal bearing wastes, and the resulting products show good compressive strength and heavy-metal stability. PMID- 21295463 TI - Arthroscopic ankle arthrodesis for hemophilic arthropathy: two cases report. AB - In the second decade of life, the ankle joint can be considered as the most common site for haemophilic arthropathy. To the best of our knowledge, no detailed reports have been published regarding arthroscopic ankle arthrodesis with haemophilic arthropathy. The aim of this paper is to report the outcomes of arthroscopic ankle arthrodesis in haemophilic arthropathy of the hindfoot. We performed three arthroscopic ankle arthrodeses in two patients. Case 1 was a 26 year-old man and case 2 was a 25-year-old man. The follow-up periods ranged from 2 year and 4 months to 6 years and one month. Union was obtained in all three ankles. All the arthroscopic ankle arthrodeses stopped or significantly reduced recurrent joint bleeding. With our procedure, we achieved pain relief and walking ability improvement. The mean American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot scale scores were 39 (range: 32-52) points preoperatively and 80 (range: 74-92) points postoperatively. Our cases achieved high satisfaction levels with pain relief and minimal complications for arthroscopic ankle arthrodesis, and case 2 who originally underwent arthroscopic arthrodesis of the left ankle demanded the same operation for his right ankle. We consider that arthroscopic ankle arthrodesis is an effective technique for haemophilic arthropathy. PMID- 21295464 TI - GluA2-lacking, calcium-permeable AMPA receptors--inducers of plasticity? AB - AMPA receptors (AMPARs) are heterotetromeric complexes composed of GluA1-4 subunits. They are glutamate-gated channels traditionally considered solely as ion carriers for postsynaptic depolarization. However, the existence and dynamic regulation of GluA2-lacking, calcium-permeable AMPARs (Cp-AMPARs) enable these special receptors to serve also as signaling molecules presumably via calcium influx. Recent studies have implicated Cp-AMPARs in several types of synaptic plasticity, including homeostatic synaptic regulation and Hebbian synaptic plasticity. Cp-AMPARs are usually expressed transiently at an early stage of synaptic plasticity, but are then replaced with normal GluA2-containing receptors, indicating a role for Cp-AMPARs in induction, rather than the maintenance, of synaptic plasticity. PMID- 21295465 TI - Process of inorganic nitrogen transformation and design of kinetics model in the biological aerated filter reactor. AB - As one of the plug-flow reactors, biological aerated filter (BAF) reactor was divided into four sampling sectors to understand the characteristics of elemental nitrogen transformation during the reaction process, and then the different characteristics of elemental nitrogen transformation caused by different NH(3)-N loadings, biological quantities and activities in each section were obtained. The results showed that the total transformation ratio in the nitrifying reactor was more than 90% in the absence of any organic carbon resource, at the same time, more than 65% NH(3)-N in the influent were nitrified at the filter height of 70 cm below under the conditions of the influent runoff 9-19 L/h, the gas-water ratio 4-5:1, the dissolved oxygen 3.0-5.8 mg/L and the NH(3)-N load 0.28-0.48 kg NH(3)-N/m(3) d. On the base of the Eckenfelder mode, the kinetics equation of the NH(3)-N transformation along the reactor was S(e)=S(0) exp(-0.0134D/L(1.2612)). PMID- 21295466 TI - P3 optimization of functional potency, in vivo efficacy and oral bioavailability in 3-aminopyrazinone thrombin inhibitors bearing non-charged groups at the P1 position. AB - Although the S3 pocket of the thrombin active site is lined with lipophilic amino acid residues, the accommodation of polarity within the lipophilic P3 moiety of small molecule inhibitors is possible provided that the polar functionality is capable of pointing away from the binding pocket outwards toward solvent while simultaneously allowing the lipophilic portion of the P3 ligand to interact with the S3 amino acid residues. Manipulation of this motif provided the means to effect optimization of functional potency, in vivo antithrombotic efficacy and oral bioavailability in a series of 3-aminopyrazinone thrombin inhibitors which contained non-charged groups at the P1 position. PMID- 21295467 TI - Design, synthesis and SAR of a series of 1,3,5-trisubstituted benzenes as thrombin inhibitors. AB - A novel 1,3,5-trisubstituted benzamide thrombin inhibitor template was designed via hybridization of a known aminopyridinoneacetamide and a known 1,3,5 trisubstituted phenyl ether. Optimization of this lead afforded a novel potent series of biaryl 1,3,5-trisubstituted benzenes with excellent functional anticoagulant potency. PMID- 21295468 TI - Discovery of novel positive allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5). AB - Novel in vitro mGlu(5) positive allosteric modulators with good potency, solubility, and low lipophilicity are described. Compounds were identified which did not rely on the phenylacetylene and carbonyl functionalities previously observed to be required for in vitro activity. Investigation of the allosteric binding requirements of a series of dihydroquinolinone analogs led to phenylacetylene azachromanone 4 (EC(50) 11.5 nM). Because of risks associated with potential metabolic and toxicological liabilities of the phenylacetylene, this moiety was successfully replaced with a phenoxymethyl group (27; EC(50) 156.3 nM). Derivation of a second-generation of mGlu(5) PAMs lacking a ketone carbonyl resulted in azaindoline (33), azabenzimidazole (36), and N-methyl 8 azaoxazine (39) phenylacetylenes. By scoping nitrogen substituents and phenylacetylene replacements in 39, we identified phenoxymethyl 8-azaoxazine 47 (EC(50) 50.1 nM) as a potent and soluble mGlu(5) PAM devoid of both undesirable phenylacetylene and carbonyl functionalities. PMID- 21295469 TI - 6-amino-4-(pyrimidin-4-yl)pyridones: novel glycogen synthase kinase-3beta inhibitors. AB - The synthesis and structure-activity relationships for a novel series of 6-amino 4-(pyrimidin-4-yl)pyridones derived from a high throughput screening hit are discussed. Optimization of lead matter afforded compounds with good potency, selectivity and central nervous system (CNS) exposure. PMID- 21295470 TI - Design of novel CXCR4 antagonists that are potent inhibitors of T-tropic (X4) HIV 1 replication. AB - A novel series of CXCR4 antagonists were identified based on the substantial redesign of AMD070. These compounds possessed potent anti-HIV-1 activity and showed excellent pharmacokinetics in rat and dog. PMID- 21295471 TI - A new structural alert for benzimidazoles: 2,6-dimethylphenyl substituents increase mutagenic potential and time-dependent CYP3A4 inhibition risk. AB - A series of 2-[(2,6)-dimethylphenyl]benzimidazole analogs displayed strong potential for mutagenicity following metabolic activation in either TA98 or TA100 Salmonella typhimurium strains. The number of revertants was significantly reduced by replacing the 2,6-dimethylphenyl group with a 2,6-dichlorophenyl moiety. Time-dependent CYP3A4 inhibition was also observed with a compound containing a 2-[(2,6)-dimethylphenyl] benzimidazole ring, implying risk for this scaffold to generate reactive metabolites. PMID- 21295472 TI - Design and synthesis of novel tetrahydronaphthyl azoles and related cyclohexyl azoles as antileishmanial agents. AB - A novel series of trans-2-aryloxy-1,2,3,4,-tetrahydronaphthyl azoles and related cyclohexyl azoles were synthesized and evaluated in vitro against Leishmania donovani. Compound 9 identified as most active analog with IC(50) value of 0.64 MUg/mL and SI value of 34.78 against amastigotes, and is several folds more potent than the reference drugs sodium stilbogluconate and paromomycin. It also exhibited significant in vivo inhibition of 83.33%, and provided a new structural scaffold for antileishmanials. PMID- 21295473 TI - Specific biotinylation of IMP dehydrogenase. AB - IMP dehydrogenase (IMPDH) catalyzes a critical step in guanine nucleotide biosynthesis. IMPDH also has biological roles that are distinct from its enzymatic function. We report a biotin-linked reagent that selectively labels IMPDH and is released by dithiothreitol. This reagent will be invaluable in elucidating the moonlighting functions of IMPDH. PMID- 21295474 TI - 3-amido-4-anilinocinnolines as a novel class of CSF-1R inhibitor. AB - 3-Amido-4-anilinocinnolines have been identified as potent and highly selective inhibitors of CSF-1R. The synthesis and SAR of these compounds is reported, along with some physical property, pharmacokinetic and kinase selectivity data. PMID- 21295475 TI - Discovery and evaluation of pyrazolo[1,5-a]pyrimidines as neuropeptide Y1 receptor antagonists. AB - A novel series of pyrazolo[1,5-a]pyrimidine derivatives was synthesized and evaluated as NPY Y1R antagonists. High binding affinity and selectivity were achieved with C3 trisubstituted aryl groups and C7 substituted 2-(tetrahydro-2H pyran-4-ylamino)ethylamine moieties. Efforts to find close analogs with low plasma clearance in the rat and minimal p-glycoprotein efflux in the mouse were unsuccessful. Compound 2f (CP-671906) inhibited NPY-induced increases in blood pressure and food intake after iv and icv administration, respectively, in Sprague-Dawley (SD) rat models. Oral administration of compound 2f resulted in a modest, but statistically significant, reduction in food intake in a Wistar rat model of feeding behavior. Small inhibitions of food intake were also observed in an overnight fasting/refeeding model in SD rats. These data suggest a potential role for Y1R in the regulation of food intake in rodents. PMID- 21295476 TI - Synthesis and in vitro screening of novel N-benzyl aplysinopsin analogs as potential anticancer agents. AB - A series of novel substituted (Z)-5-((1-benzyl-1H-indol-3 yl)methylene)imidazolidin-2,4-diones (3a-f) and (Z)-5-((1-benzyl-1H-indol-3 yl)methylene)-2-iminothiazolidin-4-ones (3g-o) have been synthesized utilizing microwave irradiation. These analogs were evaluated for in vitro cytotoxicity against a panel of 60 human tumor cell lines. Compound 3i exhibits potent growth inhibition against melanoma UACC-257 (GI(50)=13.3 nM) and OVCAR-8 ovarian (GI(50)=19.5 nM) cancer cells while possessing significant cytotoxicity (LC(50)=308 nM and LC(50)=851 nM, respectively) against the same cell lines within this series of compounds. A second analog, 3a, had GI(50) values of 307 and 557 nM against SK-MEL-2 melanoma and A498 renal cancer cell lines, and exhibited GI(50) values ranging from 0.30 to 6 MUM against 98% of all cancer cell lines in the 60-cell panel. Thus, (Z)-5-((5-chloro-1-(4-fluorobenzyl)-1H-indol-3 yl)methylene)-2-iminothiazolidin-4-one (3i) and (Z)-methyl 1-(4-cyanobenzyl)-3 ((2,5-dioxoimidazolidin-4-ylidene)methyl)-1H-indole-6-carboxylate (3a) can be regarded as useful lead compounds for further structural optimization as antitumor agents. PMID- 21295477 TI - Structure-activity relationship studies of sphingosine-1-phosphate receptor agonists with N-cinnamyl-beta-alanine moiety. AB - Structure-activity relationship of sphingosine-1-phosphate receptor agonist was examined. In terms of reducing the flexibility of molecule, hit compound 1 was modified to improve S1P(1) agonistic activity as well as selectivity over S1P(3) agonistic activity. Novel S1P agonists with cinnamyl scaffold or 1,2,5,6 tetrahydropyridine scaffold were identified. PMID- 21295478 TI - Discovery of INCB10820/PF-4178903, a potent, selective, and orally bioavailable dual CCR2 and CCR5 antagonist. AB - We report the discovery of a potent, selective, and orally bioavailable dual CCR2 and CCR5 antagonist (3S,4S)-N-[(1R,3S)-3-isopropyl-3-({4-[4 (trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]-3 methoxytetrahydro-2H-pyran-4-amine (19). After evaluation in 28-day toxicology studies, compound 19 (INCB10820/PF-4178903) was selected as a clinical candidate. PMID- 21295479 TI - The high performance of 3XFLAG for target purification of a bioactive metabolite: a tag combined with a highly effective linker structure. AB - Affinity purification using immunoprecipitation (IP) is an extremely useful method for target profiling of bioactive natural products. We examined IP purification of CMetE, which is a molecular target for potassium isolespedezate (1), a leaf-opening factor of Cassia plant. We studied IP efficiency using a panel of FLAG-connected molecular probes (2-8), including probes with varying structures and lengths of the linker moiety. The results suggest that not only the length, but the chemical nature of the linker moiety, strongly affect the IP efficiency. 3XFLAG, a tag combined with a linker moiety of charged amino acids, gave the best results and was most useful for IP purification of the molecular target. PMID- 21295480 TI - Acceptance and adherence to treatment among breast cancer patients in Eastern Nigeria. AB - This study reports on the acceptance and adherence behaviors of patients presenting with a clinical suspicion of breast cancer at a breast clinic in Nigeria during a 5-year period (2004-2008). Of the 275 study patients, 28.7% (79 patients) refused a biopsy needed for a definitive diagnosis. Of those who agreed to a biopsy, 10.2% (28 patients) did not return for a follow-up visit. Mastectomy was offered to 140 patients, 47.9% (67 patients) refused the surgery. Of the 53 patients diagnosed with locally advanced lesions offered neo-adjuvant chemotherapy, 28.3% (15 patients) completed the recommended therapy. Of the 44 patients offered adjuvant chemotherapy, 38.6% (17 patients) completed the recommended therapy. Only 23 of the patients advised to go for radiotherapy complied. Barriers to patient adherence to diagnostic and treatment recommendations included both patient barriers and system barriers. PMID- 21295481 TI - Noggin and noggin-like genes control dorsoventral axis regeneration in planarians. AB - Planarians regenerate a whole animal from a small body piece within a few days. Recent studies have shown that the bone morphogenetic protein (BMP) pathway is required to reestablish the dorsoventral (DV) axis. In vertebrates, the specification of the DV axis depends on the coordinated action of a dual organizer defined by BMP and antidorsalizing morphogenetic protein (ADMP) under the control of several factors, including the inhibitors chordin and noggin. Planarians have an expanded noggin family (up to ten members), which have been classified as canonical noggin (nog) and noggin-like (nlg) genes, the latter carrying an insertion within the noggin domain. Here we show that a BMP/ADMP organizer governs DV axis reestablishment during planarian regeneration, highlighting a greater-than-thought conservation of the mechanisms that establish this axis in protostomes and deuterostomes. Also, we report that whereas noggin genes function as canonical BMP inhibitors, the silencing of planarian nlg8 induces ectopic neurogenesis and enhances ventralizing bmp(RNAi) phenotypes. Finally, we show that noggin-like genes are conserved from cnidarian to vertebrates and that both planarian nlg8 and Xenopus nlg ventralize Xenopus embryos when overexpressed. Remarkably, this ventralization is not associated with an increase in SMAD1/5/8 phosphorylation. PMID- 21295482 TI - Control of local Rho GTPase crosstalk by Abr. AB - BACKGROUND: The Rho GTPases-Rho, Rac, and Cdc42-regulate the dynamics of F-actin (filamentous actin) and myosin-2 with considerable subcellular precision. Consistent with this ability, active Rho and Cdc42 occupy mutually exclusive zones during single-cell wound repair and asymmetric cytokinesis, suggesting the existence of mechanisms for local crosstalk, but how local Rho GTPase crosstalk is controlled is unknown. RESULTS: Using a candidate screen approach for Rho GTPase activators (guanine nucleotide exchange factors; GEFs) and Rho GTPase inactivators (GTPase-activating proteins; GAPs), we find that Abr, a protein with both GEF and GAP activity, regulates Rho and Cdc42 during single-cell wound repair. Abr is targeted to the Rho activity zone via active Rho. Within the Rho zone, Abr promotes local Rho activation via its GEF domain and controls local crosstalk via its GAP domain, which limits Cdc42 activity within the Rho zone. Depletion of Abr attenuates Rho activity and wound repair. CONCLUSIONS: Abr is the first identified Rho GTPase regulator of single-cell wound healing. Its novel mode of targeting by interaction with active Rho allows Abr to rapidly amplify local increases in Rho activity using its GEF domain while its ability to inactivate Cdc42 using its GAP domain results in sharp segregation of the Rho and Cdc42 zones. Similar mechanisms of local Rho GTPase activation and segregation enforcement may be employed in other processes that exhibit local Rho GTPase crosstalk. PMID- 21295483 TI - A Bmp/Admp regulatory circuit controls maintenance and regeneration of dorsal ventral polarity in planarians. AB - Animal embryos have diverse anatomy and vary greatly in size. It is therefore remarkable that a common signaling pathway, BMP signaling, controls development of the dorsoventral (DV) axis throughout the Bilateria. In vertebrates, spatially opposed expression of the BMP family proteins Bmp4 and Admp (antidorsalizing morphogenetic protein) can promote restoration of DV pattern following tissue removal. bmp4 orthologs have been identified in all three groups of the Bilateria (deuterostomes, ecdysozoans, and lophotrochozoans). By contrast, the absence of admp orthologs in ecdysozoans such as Drosophila and C. elegans has suggested that a regulatory circuit of oppositely expressed bmp4 and admp genes represents a deuterostome-specific innovation. Here we describe the existence of spatially opposed bmp and admp expression in a protostome. An admp ortholog (Smed-admp) is expressed ventrally and laterally in adult Schmidtea mediterranea planarians, opposing the dorsal-pole expression of Smed-bmp4. Smed-admp is required for regeneration following parasagittal amputation. Furthermore, Smed-admp promotes Smed-bmp4 expression and Smed-bmp4 inhibits Smed-admp expression, generating a regulatory circuit that buffers against perturbations of Bmp signaling. These results suggest that a Bmp/Admp regulatory circuit is a central feature of the Bilateria, used broadly for the establishment, maintenance, and regeneration of the DV axis. PMID- 21295484 TI - High spontaneous rate of gene duplication in Caenorhabditis elegans. AB - Gene and genome duplications are the primary source of new genes and novel functions and have played a pivotal role in the evolution of genomic and organismal complexity. The spontaneous rate of gene duplication is a critical parameter for understanding the evolutionary dynamics of gene duplicates; yet few direct empirical estimates exist and differ widely. The presence of a large population of recently derived gene duplicates in sequenced genomes suggests a high rate of spontaneous origin, also evidenced by population genomic studies reporting rampant copy-number polymorphism at the intraspecific level. An analysis of long-term mutation accumulation lines of Caenorhabditis elegans for gene copy-number changes with array comparative genomic hybridization yields the first direct estimate of the genome-wide rate of gene duplication in a multicellular eukaryote. The gene duplication rate in C. elegans is quite high, on the order of 10(-7) duplications/gene/generation. This rate is two orders of magnitude greater than the spontaneous rate of point mutation per nucleotide site in this species and also greatly exceeds an earlier estimate derived from the frequency distribution of extant gene duplicates in the sequenced C. elegans genome. PMID- 21295485 TI - Restraints in intensive care units--a mixed method study. AB - The use of mechanical restraints is a controversial practice internationally but is common in South African Intensive Care Units (ICUs). Their use was studied in the ICUs of an academic, public hospital in Johannesburg, South Africa. RESEARCH METHODOLOGY: Quantitative data were collected over two months by means of a checklist and analysed by means of descriptive statistics. The patients' length of stay, type of restraint used and duration thereof, the daily nurse patient ratios, as well as information regarding sedation and analgesia were detailed. Individual interviews with twenty medical and nursing ICU clinicians elicited their stated rationale for restraint, their experiences and perceptions of the practice and recommendations for restraint. FINDINGS: Of a total of 219 patients in the three ICUs, 106 (48.4%) were restrained. The average number of days restrained was nine with a range of days from 1 to 53 (in one case only). In only six cases were restraints other than wrist ties used. Forty seven of the restrained patients had sedation and analgesic medication prescribed and 59 not. All participants conceded a place for physical restraint in the ICU, primarily to ensure the safety of patients but were divided as to the reason for restraining patients and disputed the benefits of restraint. CONCLUSION: Poor communication between the team, patients and families and diminished collaboration within the multi-disciplinary team emerged as central concepts in this study and influenced care decisions and practises regarding the use of mechanical restraints in the clinical area. PMID- 21295486 TI - Crystal structure of a human cleavage factor CFI(m)25/CFI(m)68/RNA complex provides an insight into poly(A) site recognition and RNA looping. AB - Cleavage factor I(m) (CFI(m)) is a highly conserved component of the eukaryotic mRNA 3' processing machinery that functions in sequence-specific poly(A) site recognition through the collaboration of a 25 kDa subunit containing a Nudix domain and a larger subunit of 59, 68, or 72 kDa containing an RNA recognition motif (RRM). Our previous work demonstrated that CFI(m)25 is both necessary and sufficient for sequence-specific binding of the poly(A) site upstream element UGUA. Here, we report the crystal structure of CFI(m)25 complexed with the RRM domain of CFI(m)68 and RNA. The CFI(m)25 dimer is clasped on opposite sides by two CFI(m)68 RRM domains. Each CFI(m)25 subunit binds one UGUA element specifically. Biochemical analysis indicates that the CFI(m)68 RRMs serve to enhance RNA binding and facilitate RNA looping. The intrinsic ability of CFI(m) to direct RNA looping may provide a mechanism for its function in the regulation of alternative poly(A) site selection. PMID- 21295487 TI - Efficiency of Pm-147 direct charge radioisotope battery. AB - A theoretical analysis is presented here of the efficiency of direct charge radioisotope batteries based on the efficiency of the radioactive source, the system geometry, electrostatic repulsion of beta particles from the collector, the secondary electron emission, and backscattered beta particles from the collector. Efficiency of various design batteries using Pm-147 sources was experimentally measured and found to be in good agreement with calculations. The present approach can be used for predicting the efficiency for different designs of direct charge radioisotope batteries. PMID- 21295488 TI - Determinants of pericardial drainage for cardiac tamponade following cardiac surgery. AB - OBJECTIVE: We aimed to identify independent risk factors predisposing toward postoperative surgical or percutaneous pericardial drainage following cardiac surgery, and to assess late survival. METHODS: A retrospective review of preoperative, intra-operative and postoperative variables was conducted in 5818 patients, who underwent adult heart surgery in a 7-year time span (2002-2009). Pericardial drainage was performed in 117 patients (2%), of whom 52 (44%) were evacuated by surgical drainage and 65 (56%) by echocardiographic-guided pericardiocentesis. Patients were divided in two groups: patients with two dimensional (2D) echocardiographic evidence of cardiac tamponade, who underwent pericardial surgical or percutaneous drainage (group I: 117 patients); and patients without cardiac tamponade (group II: 5701 patients), who served as the control group. RESULTS: The two groups were compared with univariate analysis, and variables significantly (p <= 0.05) or possibly (p <= 0.2) associated with pericardial drainage were entered into multivariable logistic regression analysis models assessing the role of pre-, intra- and postoperative variables together or separately. Pericardial drainage was more likely to occur in patients undergoing combined procedures such as double/triple valves or surgery on ascending aorta, in patients with higher EuroSCORE (European System for Cardiac Operative Risk Evaluation) levels, whereas patients receiving aspirin treatment before surgery had a lower risk of this complication. In addition, postoperative blood product transfusion and the occurrence of renal failure after surgery increased the risk of this complication. CONCLUSIONS: Postoperative pericardial drainage is an uncommon complication after heart surgery, mainly managed percutaneously. Our study has identified different independent causative factors for cardiac tamponade requiring pericardiocentesis. The identification of preoperative and postoperative risk factors may be useful to adopt strategies to further reduce the incidence of pericardial tamponade requiring drainage. PMID- 21295489 TI - Systematic evaluation of the flexible and rigid annuloplasty ring after mitral valve repair for mitral regurgitation. AB - OBJECTIVES: Mitral annulus reconstruction is now a common surgical procedure for the treatment of mitral regurgitation. However, there are still controversies in the selection of materials for annuloplasty in the clinical controlled studies available. The purpose of the present systematic review of the literature is to address whether a flexible ring is superior to a rigid ring in terms of improvement in clinical and echocardiographic outcomes. METHODS: A systematic literature search was undertaken of all clinical control trials comparing the outcomes of mitral annuloplasty surgery with the flexible and rigid ring in MEDLINE, EMBASE, and the Cochrane Library. RESULTS: Overall, 12 published trials were identified as being eligible for overview and were included in the meta analysis study between 1966 and 2010: four prospective randomized and eight case control studies. Combined hazard ratios suggested that the flexible annuloplasty ring had no favorable impact on survival: the mean (95% confidence interval (CI)) was 1.24 (0.24-2.24). From the mortality data at maximum follow-up ranging 35-61 months, there was no significant difference on mortality, reoperation, and significant recurrent mitral regurgitation between the two rings. Also, we were not able to find an improvement by flexible rings on shortening fraction, left ventricular end-diastolic volume, end-systolic volume, and end-diastolic and end systolic diameter. There was a significantly higher ejection fraction in arms for flexible rings relative to rigid rings with pooled standardized mean deviation (SMD) 0.29, 95% CI: 0.06-0.52, p=0.015. Finally, compared to the rigid annuloplasty ring, patients implanted with flexible ones presented significantly a far better effect preserving the mitral valve area: SMD 0.54, 95% CI: 0.13 0.95, p=0.01, and less constrictive for blood flow across the mitral valve, with the pooled SMD of peak velocity (flexible vs rigid: -0.63, 95% CI: -1.12 to 0.13, p=0.013). CONCLUSIONS: Except for the improvement in ejection fraction and preserving the mitral valve area effects in the flexible cases, it remains comparable with regard to overall survival, mortality, reoperation, regurgitant recurrence, and left ventricular performance between the flexible and rigid ring. PMID- 21295491 TI - Harnessing dendritic cells in cancer. AB - Dendritic cells (DCs) are central to the initiation of tumor-specific immune responses. However, the tumor microenvironment generates immunosuppressive cells and soluble mediators that compromise DC functions and limit the success of DC based therapies. Progress in understanding DC metabolism in cancer is uncovering novel therapeutic targets that could restore DC capacity to prime T cells and trigger effective anticancer responses. Accumulating evidence also indicates that conventional chemo- and radiotherapy protocols can cause DC activation, enhance antigen cross-presentation, selectively eliminate immunosuppressive cells and revert the immunosuppression state caused by cancer, suggesting that relevant chemoimmunotherapy associations could fully exploit DC capacity to trigger anticancer responses. Here, we discuss recent strategies that harness DC against cancer. PMID- 21295490 TI - Harnessing dendritic cells in inflammatory skin diseases. AB - The skin immune system harbors a complex network of dendritic cells (DCs). Recent studies highlight a diverse functional specialization of skin DC subsets. In addition to generating cellular and humoral immunity against pathogens, skin DCs are involved in tolerogenic mechanisms to ensure the maintenance of immune homeostasis, as well as in pathogenesis of chronic inflammation in the skin when excessive immune responses are initiated and unrestrained. Harnessing DCs by directly targeting DC-derived molecules or selectively modulate DC subsets is a convincing strategy to tackle inflammatory skin diseases. In this review we discuss recent advances underlining the functional specialization of skin DCs and discuss the potential implication for future DC-based therapeutic strategies. PMID- 21295492 TI - Environmental influences on T regulatory cells in inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) is characterized by chronic, idiopathic inflammation of the intestine. The disease is thought to result from a combination of genetic and environmental factors which ultimately leads to a mucosal immune system that overreacts to normal constituents of the mucosal microbiota. The inflammation in IBD is primarily mediated by inappropriate production of proinflammatory cytokines by CD4(+) T effector cells, effects that are suppressed by CD4(+) T regulatory cells. Defects in both the function of T regulatory cells, and the ability of T effector cells to be suppressed, have been implicated in IBD. In this review we will discuss environmental factors, including cytokines, vitamins A and D, and commensal bacteria, which influence the phenotype and function of regulatory T cells and thereby alter the course of IBD. We will also discuss how these environmental signals can be manipulated therapeutically in order to improve the function of regulatory T cells and ultimately restore mucosal homeostasis in patients with IBD. PMID- 21295493 TI - Sarcoidosis presenting as transient ischemic attack status. AB - We report a patient who experienced multiple transient ischemic attacks (TIAs) over a 3-month period as the presenting clinical manifestation of sarcoidosis. This previously healthy 27-year-old man was admitted due to several daily episodes of usually left hemiparesis and dysarthria lasting between 15 seconds and 3 minutes. He did not respond to aggressive antithrombotic treatment. Extensive investigations were negative except for a computed tomography body scan showing several small right hilar lymphoadenopathies, which were confirmed by abnormal 67-gallium scintigraphy and 18F-fluorodeoxyglucose positron emission tomography uptakes. The TIA episodes disappeared after the initiation of prednisone therapy. The lymphadenopathy specimens were biopsied via mediastinoscopy, and histological study revealed noncaseating epithelioid granulomatous inflammation consistent with sarcoidosis. Sarcoidosis should be considered in the differential diagnosis of stroke of unknown origin in any young patient, even in the absence of other clinical or laboratory features of sarcoidosis. PMID- 21295494 TI - Enhancing recovery after acute ischemic stroke with donepezil as an adjuvant therapy to standard medical care: results of a phase IIA clinical trial. AB - BACKGROUND: Our aim was to assess the safety, tolerability, and efficacy signal of early donepezil administration with regard to enhancing recovery in a diverse acute ischemic stroke population. METHODS: This was a multicenter, single-arm, National Institute of Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator trial-controlled, modified 2-stage adaptive clinical trial set in 2 tertiary care hospitals in the United States. Adults with ischemic stroke treated within 24 hours after onset of symptoms were included. The intervention studied was donepezil 5 mg/day for 30 days, followed by an increase to 10 mg/day for 60 days. Our main outcome measures included treatment-related adverse events and side effects. The primary favorable outcome was a 90-day National Institutes of Health Stroke Scale (NIHSS) score <=1. Neurologic, cognitive, functional, and psychological outcomes were assessed longitudinally. RESULTS: Thirty-three adults (median age 66 years; 59% female; 39% received tissue plasminogen activator) initiated treatment with donepezil. There were no treatment-related serious adverse events. Three participants (9%) discontinued donepezil because of side effects and 3 participants (9%) required a reduction to 5 mg/day after titration to 10 mg/day. Fifteen participants (45%) had a favorable outcome (NIHSS score <=1 at day 90), and the study met prespecified criteria for continuing to a randomized trial (P < .10). Statistically significant improvements from baseline were observed with several secondary cognitive measures, including the Trail Making Tests and Mini-Mental State Exam (P < .01 for both). CONCLUSIONS: Adjuvant donepezil therapy initiated within 24 hours of acute ischemic stroke was safe and tolerated at 5 mg/day to 10 mg/day. The study met a priori criteria to move forward with a randomized clinical trial. PMID- 21295495 TI - Case 2--2011: Acute myocardial infarction in a pregnant patient requiring coronary artery bypass graft surgery. PMID- 21295496 TI - Biventricular support using implantable continuous-flow ventricular assist devices. AB - A 34-year-old woman with fulminant myocarditis underwent emergent implant with the Toyobo (Nipro, Osaka, Japan) paracorporeal biventricular assist device (BiVAD). The patient had been stable for 6 months, until she started to develop heart failure symptoms due to severe pulmonary insufficiency. Pulmonary valve closure and BiVAD conversion to implantable rotary pumps was performed. A DuraHeart centrifugal pump (Terumo Heart Inc., Ann Arbor, MI) was used for left ventricular assist, and a Jarvik 2000 axial-flow pump (Jarvik Heart Inc., New York, NY) was used for right ventricular assist. Although strict management was required to balance the flow rates of the two different types of devices, her postoperative course was uneventful and she was discharged home. PMID- 21295497 TI - Sense of agency, associative learning, and schizotypy. AB - Despite the fact that the role of learning is recognised in empirical and theoretical work on sense of agency (SoA), the nature of this learning has, rather surprisingly, received little attention. In the present study we consider the contribution of associative mechanisms to SoA. SoA can be measured quantitatively as a temporal linkage between voluntary actions and their external effects. Using an outcome blocking procedure, it was shown that training action outcome associations under conditions of increased surprise augmented this temporal linkage. Moreover, these effects of surprise were correlated with schizotypy scores, suggesting that individual differences in higher level experiences are related to associative learning and to its impact on SoA. These results are discussed in terms of models of SoA, and our understanding of disrupted SoA in certain disorders. PMID- 21295498 TI - Does ghrelin level change after epileptic seizure in rats? AB - AIM: Epilepsy is one of the most common neurologic problems worldwide. A relationship between epilepsy and hormones has been demonstrated. This study was designed to investigate the effect of seizure on blood ghrelin level. METHODS: Twenty male Wistar rats were divided into two groups. The control group received saline and the pentylenetetrazole (PTZ) group received a single convulsive dose (50mg/kg) of PTZ. Thirty minutes later blood samples were collected and acylated and unacylated ghrelin levels in the plasma were assayed. RESULTS: Acylated or active form of ghrelin decreased significantly (p<0.05) after a PTZ-induced seizure, but the reduction of unacylated and total blood ghrelin levels failed to reach statistical significance. CONCLUSION: These findings may reflect that PTZ induced epilepsy decreases AG of plasma. PMID- 21295499 TI - Protein kinase B controls transcriptional programs that direct cytotoxic T cell fate but is dispensable for T cell metabolism. AB - In cytotoxic T cells (CTL), Akt, also known as protein kinase B, is activated by the T cell antigen receptor (TCR) and the cytokine interleukin 2 (IL-2). Akt can control cell metabolism in many cell types but whether this role is important for CTL function has not been determined. Here we have shown that Akt does not mediate IL-2- or TCR-induced cell metabolic responses; rather, this role is assumed by other Akt-related kinases. There is, however, a nonredundant role for sustained and strong activation of Akt in CTL to coordinate the TCR- and IL-2 induced transcriptional programs that control expression of key cytolytic effector molecules, adhesion molecules, and cytokine and chemokine receptors that distinguish effector versus memory and naive T cells. Akt is thus dispensable for metabolism, but the strength and duration of Akt activity dictates the CTL transcriptional program and determines CTL fate. PMID- 21295500 TI - Best medical therapy or wishful thinking in carotid disease? A single-centre audit in Germany. AB - INTRODUCTION: The optimal treatment of asymptomatic carotid disease is being debated again. The conclusions of the large randomised controlled trials of the early 1980s and 1990s are increasingly being questioned due to advances in modern medical treatment. This study investigates how patients are actually managed medically related to general risk factors prior to carotid endarterectomy in a German health-care region. MATERIALS/METHODS: A prospective data bank including 95 consecutive patients was used. The effectiveness of lipid lowering and diabetes management were investigated as well as the use of anti-thrombotic and blood pressure medication. RESULTS: A total of 108 carotid endarterectomies in 95 patients were performed between January 2009 and March 2010. All 95 patients (70 male, 25 female; 39 symptomatic/56 asymptomatic) were included in the study. Nearly half (54%) of the patients were on statins; of these, 45% had low-density lipoprotein (LDL) levels >100 mg dl(-1). Of 32 patients with diabetes, one had glycohaemoglobin (HbA(1c)) <6.0. Overall, four patients were on clopidogrel. Three patients were severely hypertensive (systolic blood pressure >180 mmHg). CONCLUSIONS: The best medical therapy for carotid disease is not optimal in the part of the German health-care system observed in this study. We strongly advocate similar audits in other health-care areas and systems. PMID- 21295501 TI - Behavioural sleep treatments and night time crying in infants: challenging the status quo. AB - In Australia, as in many Westernised industrialised nations, the majority of families encourage infants to sleep alone or 'solo' from an early age. Sleeping solo can increase night time crying, which in turn disrupts sleep for both parent and infant. Night time waking and crying are frequently culturally constructed as behavioural sleep 'problems'. The pursuit of solo sleeping is thus achieved through 'behavioural sleep treatments' that teach an infant to sleep alone. Some behavioural extinction treatments necessitate a parent leaving an infant to cry for extended periods unattended, a practice reportedly difficult for parents. Despite parent's anxieties, and the potential (though little studied) stress to the infant, the pursuit of those behavioural sleep treatments are advocated by many psychologists and clinicians as acceptable and necessary interventions. This paper questions this necessity and critically reviews and debates these methods from biological, anthropological and cultural perspectives. Specifically, it considers Foucaultian, Leidloffian, attachment and behavioural perspectives. The central debate in this paper is if and why an infant's nocturnal cries should be ignored. It challenges the aetiology and acceptance of the status quo in the hope of revisiting the underlying belief that these methods are necessary. In doing so, the paper theorises the ways in which current sleep training techniques do or do not satisfy the needs of infants and their parents and questions the extent to which they can be reconciled. The paper posits an agenda for further research in the area that may facilitate the reconciliation of the needs of parents and those of their infants. PMID- 21295502 TI - Obesity hypoventilation syndrome: more than just severe sleep apnea. PMID- 21295503 TI - Functional somatic syndromes, anxiety disorders and the upper airway: a matter of paradigms. AB - The relationship between the functional somatic syndromes, anxiety disorders and the upper airway (particularly, sleep disordered breathing) remains ambiguous. This ambiguity, despite a growing body of research supporting a relationship, may result from the absence of a paradigm to explain how upper airway dysfunction can promote disorders commonly associated with one's mental health. This review models the functional somatic syndromes and anxiety disorders as consequences of chronically increased hypothalamic-pituitary-adrenal axis activity. It then examines the literature supporting a relationship between these disorders and upper airway dysfunction during wakefulness and sleep. Finally, building upon an existing paradigm of neural sensitization, sleep disordered breathing is linked to functional somatic syndromes and anxiety disorders through chronic activation of the hypothalamic-pituitary-adrenal axis. PMID- 21295504 TI - Differential expression of microRNA-206 in skeletal muscle of female Piedmontese and Friesian cattle. AB - The double-muscle phenotype is an inherited condition in Piedmontese cattle traced to a point mutation in the myostatin gene. To investigate the potential role of muscle-specific miRNAs in determining muscle development in cattle, this study examined the patterns of expression of microRNAs (miRNA-1) and miRNA-206 in Piedmontese and Friesian cattle according to phenotype and sex. There were no significant differences in miRNA-1 expression between different muscle phenotypes, sexes or breeds, whereas there was significantly higher expression of miRNA-206 in female Piedmontese compared with female Friesian cattle. PMID- 21295505 TI - Application of high-frequency ultrasound for the detection of surgical anatomy in the rodent abdomen. AB - Rats are used extensively in abdominal disease research. To monitor disease progress in vivo, high-frequency ultrasound (HFU) can be a powerful tool for obtaining high-resolution images of biological tissues. However, there is a paucity of data regarding the correlation between rat anatomy and corresponding HFU images. Twenty-four adult male Sprague-Dawley (SD) rats underwent abdominal scans using HFU (40 MHz) surgical procedures to identify abdominal organs and major vessels as well as in situ scanning to confirm the imaging results. The results were compared with those of human abdominal organs in ultrasonographic scans. The rat liver, paired kidneys, stomach, intestines, and major blood vessels were identified by HFU and the ultrasonic morphologies of the liver and kidneys showed clear differences between rats and humans. Clinically relevant anatomical structures were identified using HFU imaging of the rat abdomen, and these structures were compared with the corresponding structures in humans. Increased knowledge with regard to identifying the anatomy of rat abdominal organs by ultrasound will allow scientists to conduct more detailed intra abdominal research in rodents. PMID- 21295506 TI - Re: Honzik T, Adamovicova A, Smolka V, Magner M, Hruba E, Zeman J. Clinical presentation and metabolic consequences in 40 breastfed infants with nutritional vitamin B12 deficiency--what have we learned? Eur Jour Ped Neurol 14 (2010) 488 495. PMID- 21295507 TI - Favorable long-term effects of growth hormone replacement therapy on quality of life, bone metabolism, body composition and lipid levels in patients with adult onset growth hormone deficiency. AB - OBJECTIVE: The goal of growth hormone (GH) replacement is to improve quality of life (QoL) and prevent the long-term complications of GH deficiency (GHD). Thirty nine patients with adult-onset GH deficiency (AOGHD) who had originally participated in a randomized placebo-controlled crossover study involving treatment with either GH or placebo for nine months were enrolled in an open, 33 month follow-up study of the effects on QoL as well as bone and metabolic parameters. METHODS: GH replacement was dosed individually to obtain IGF-I concentrations that were within the upper part of the normal range for age (mean+1SD). The variables were assessed on five occasions during the study. RESULTS: QoL, as assessed by the sum scores of HSCL-58, AGHDA, physical activity (KIMS question 11) and the dimension vitality in SF-36, improved. Markers of bone formation and resorption remained increased throughout the study period. Bone mineral area (BMA), bone mineral content (BMC) and bone mineral density (BMD) increased in both the lumbar (L2-L4) spine and total body. BMC and BMD increased in the femur. Hypogonadal women however, showed reduced bone mass during the study period. The changes in body fat mass (BFM) and lean body mass (LBM) were sustained throughout the long-term treatment (BFM -2.18 (+/-4.87) kg LBM by 2.01(+/-3.25) kg). Low-density lipoprotein cholesterol (LDL-C) levels were reduced by 0.6 (+/-1.1) mmol/l, and high-density lipoprotein cholesterol (HDL-C) levels increased by 0.2 (+/-0.3) mmol/l. No changes were observed in body weight, fasting total cholesterol, triglycerides, HbA1c and plasma glucose. Mean fasting insulin levels increased significantly from 110 pmol/l to 159 pmol/l, p<0.02. CONCLUSION: Long-term replacement of growth hormone in patients with AOGHD induces favorable effects on QoL as well as bone and metabolic parameters. An increase in insulin levels is also noteworthy. PMID- 21295508 TI - Roles of circulating soluble interleukin (IL)-6 receptor and IL-6 receptor expression on CD4+ T cells in patients with chronic hepatitis B. AB - OBJECTIVES: The objective of this study was to investigate the potential clinical roles of circulating soluble interleukin (IL)-6 receptor (sIL-6R) and IL-6R expression on CD4+ T cells (CD4+ IL-6R+ T cells) in chronic hepatitis B (CHB) patients. METHODS: One hundred and thirty-three subjects, including 72 CHB patients, 27 asymptomatic carriers, eight acute hepatitis B (AHB) patients, and 26 healthy donors were included in this study. Plasma IL-6 and sIL-6R levels were measured by enzyme-linked immunosorbent assay (ELISA); the frequency of CD4+ IL 6R+ T cells was detected by flow cytometry analysis. RESULTS: Our data showed a significant increase in plasma sIL-6R levels and the frequency of CD4+ IL-6R+ T cells in peripheral blood in CHB patients compared to asymptomatic carriers and healthy controls (both p<0.05). The elevated prevalence of CD4+ IL-6R+ T cells was positively associated with increased serum alanine aminotransferase levels in CHB patients (r = 0.316, p = 0.007), but was not correlated with serum hepatitis B virus (HBV) DNA load. Moreover, CHB patients with an HBV DNA load >1.0 * 10(6) copies/ml had a lower level of plasma sIL-6R than those with an HBV DNA load <1.0 * 10(6) copies/ml. CONCLUSIONS: Circulating sIL-6R and CD4+ IL-6R+ T cells were increased in CHB patients. Elevated plasma sIL-6R is probably associated with HBV elimination, and CD4+ IL-6R+ T cells in peripheral blood might contribute to the pathogenesis of liver injury in CHB patients. PMID- 21295509 TI - Identification of novel markers for uncomplicated lower genital tract infections and upper genital tract pathology due to Chlamydia trachomatis. AB - BACKGROUND: Untreated Chlamydia trachomatis infections in women can result in disease sequelae such as salpingitis and pelvic inflammatory disease (PID), ultimately culminating in tubal occlusion and infertility. Whilst nucleic acid amplification tests can effectively diagnose uncomplicated lower genital tract (LGT) infections, they are not suitable for diagnosing upper genital tract (UGT) pathological sequelae. As a consequence, this study aimed to identify serological markers that can, with a high degree of sensitivity and specificity, discriminate between LGT infections and UGT pathology. METHODS: Plasma was collected from 73 women with a history of LGT infection, UGT pathology due to C. trachomatis, or no serological evidence of C. trachomatis infection. Western blotting was used to analyze antibody reactivity against extracted chlamydial proteins. Sensitivity and specificity of differential markers were also calculated. RESULTS: Four antigens (CT157, CT423, CT727 and CT396) were identified and found to be capable of discriminating between the infection and disease sequelae state. Sensitivity and specificity calculations showed that our assay for diagnosing LGT infection had a sensitivity of 75% and specificity of 76%, whilst the assay for identifying UGT pathology demonstrated 80% sensitivity and 86% specificity. CONCLUSIONS: The use of these assays could potentially facilitate earlier diagnoses in women suffering UGT pathology due to C. trachomatis. PMID- 21295510 TI - New-onset diabetes after transplantation: risk factors and clinical impact. AB - With improvements in patient and graft survival, increasing attention has been placed on complications that contribute to long-term patient morbidity and mortality. New-onset diabetes after transplantation (NODAT) is a common complication of solid-organ transplantation, and is a strong predictor of graft failure and cardiovascular mortality in the transplant population. Risk factors for NODAT in transplant recipients are similar to those in non-transplant patients, but transplant-specific risk factors such as hepatitis C (HCV) infection, corticosteroids and calcineurin inhibitors play a dominant role in NODAT pathogenesis. Management of NODAT is similar to type 2 diabetes management in the general population. However, adjusting the immunosuppressant regimen to improve glucose tolerance must be weighed against the risk of allograft rejection. Lifestyle modification is currently the strategy with the least risk and the most benefit. PMID- 21295511 TI - Does cervical kyphosis relate to symptoms following whiplash injury? AB - The mechanisms for developing long-lasting neck pain after whiplash injuries are still largely unrevealed. In the present study it was investigated whether a kyphotic deformity of the cervical spine, as opposed to a straight or a lordotic spine, was associated with the symptoms at baseline, and with the prognosis one year following a whiplash injury. MRI was performed in 171 subjects about 10 d after the accident, and 104 participated in the pain recording at 1-year follow up. It was demonstrated that postures as seen on MRI can be reliably categorized and that a straight spine is the most frequent appearance of the cervical spine in supine MRI. In relation to symptoms it was seen that a kyphotic deformity was associated with reporting the highest intensities of headache at baseline, but not with an increased risk of long-lasting neck pain or headache. In conclusion, a kyphotic deformity is not significantly associated with chronic whiplash associated pain. Moreover, it is a clear clinical implication that pain should not be ascribed to a straight spine on MRI. We suggest that future trials on cervical posture focus upon the presence of kyphotic deformity rather than just on the absence of lordosis. PMID- 21295512 TI - Molecular and structural aspects of clinically relevant mutations related to the approved non-nucleoside inhibitors of HIV-1 reverse transcriptase. AB - In recent years relevant progress has been made in the treatment of HIV-1 with a consequent decrease in mortality. The availability of potent antiretroviral drugs and the ability of viral load assays that accurately evaluate the true level of viral replication, have led to a better understanding of pathogenesis of the disease and how to obtain improved therapeutic profiles. The highly active antiretroviral therapy (HAART), based on a combination of three or more antiretroviral drugs, has radically changed the clinical outcome of HIV. In particular, reverse transcriptase non-nucleoside inhibitors (NNRTIs) play an essential role in most protocols and are often used in first line treatment. The high specificity of these inhibitors towards HIV-1 has increased the number of structural and molecular modeling studies of enzyme complexes and that have led to chemical syntheses of more selective second and third-generation NNRTIs. However, a considerable percentage of new HIV-1 infections are caused by the emergence of drug-resistant mutant viruses that complicate treatment strategies. In this review we discuss relevant clinical and structural aspects for the management of antiretroviral drug resistance, with detailed explanations of mechanisms and mutation patterns useful to better understand the relation between drug resistance and therapy failure. PMID- 21295513 TI - Spectroscopic analyses on interaction of o-Vanillin-D-Phenylalanine, o-Vanillin-L Tyrosine and o-Vanillin-L-Levodopa Schiff Bases with bovine serum albumin (BSA). AB - In this work, three o-Vanillin Schiff Bases (o-VSB: o-Vanillin-D-Phenylalanine (o VDP), o-Vanillin-L-Tyrosine (o-VLT) and o-Vanillin-L-Levodopa (o-VLL)) with alanine constituent were synthesized by direct reflux method in ethanol solution, and then were used to study the interaction to bovine serum albumin (BSA) molecules by fluorescence spectroscopy. Based on the fluorescence quenching calculation, the bimolecular quenching constant (K(q)), apparent quenching constant (K(sv)), effective binding constant (K(A)) and corresponding dissociation constant (K(D)) as well as binding site number (n) were obtained. In addition, the binding distance (r) was also calculated according to Foster's non radioactive energy transfer theory. The results show that these three o-VSB can efficiently bind to BSA molecules, but the binding array order is o-VDP-BSA>o-VLT BSA>o-VLL-BSA. Synchronous fluorescence spectroscopy indicates that the o-VDP is more accessibility to tryptophan (Trp) residues of BSA molecules than to tyrosine (Tyr) residues. Nevertheless, the o-VLT and o-VLL are more accessibility to Tyr residues than to Trp residues. PMID- 21295514 TI - Effect of surface modification on photoluminescence properties of Y3Al5O12:Ce3+, Gd3+ nano-phosphors. AB - In this study, a series of Y(3)Al(5)O(12):Ce(3+), Gd(3+) nano-phosphors were prepared using a simply wet chemical process with polyvinyl pyrrolidone as a modifier. The crystal and bonding structures of Y(3)Al(5)O(12):Ce(3+), Gd(3+) nano-phosphors prepared with different weight percentages of polyvinyl pyrrolidone were characterized by X-ray diffractometry and infrared spectrometry. The decomposition process of dried precursor gel with adding 1.37 wt% polyvinyl pyrrolidone was investigated by differential thermal and thermogravimetric analysis. The effect of surface modification on photoluminescence properties for the samples was studied. The results show that the steric hindrance effect of polyvinyl pyrrolidone leads to high dispersion and good crystallinity of Y(3)Al(5)O(12):Ce(3+), Gd(3+) nano-phosphors prepared with adding a proper weight percentages of polyvinyl pyrrolidone. Adding polyvinyl pyrrolidone is beneficial for the photoluminescence enhancement of the samples, which is attributed to the promotion of the incorporation of Ce(3+) and Gd(3+) into the Y(3)Al(5)O(12) nanocrystal and the surface passivation of the nano-particles by the polyvinyl pyrrolidone molecules. PMID- 21295515 TI - Electre Tri-C, a multiple criteria decision aiding sorting model applied to assisted reproduction. AB - OBJECTIVE: The aim of this paper is to apply an informatics tool for dealing with a medical decision aiding problem to help infertile couples to become parents, when using assisted reproduction. METHODS: A multiple criteria decision aiding method for sorting or ordinal classification problems, called Electre Tri-C, was chosen in order to assign each couple to an embryo-transfer category. The set of categories puts in evidence a way for increasing the single pregnancy rate, while minimizing multiple pregnancies. The decision aiding sorting model was co constructed through an interaction process between the decision aiding analysts and the medical experts. RESULTS: According to the sample used in this study, the Electre Tri-C method provides a unique category in 86% of the cases and it achieves a sorting accuracy of 61%. Retrospectively, the medical experts do agree that some of their judgments concerning the number of embryos to transfer back to the uterus of the woman could be different according to these results. The current ART methodology achieves a single pregnancy rate of 47% and a twin pregnancy rate of 14%. Thus, this informatics tools may play an important role for supporting ART medical decisions, aiming to increase the single pregnancy rate, while minimizing multiple pregnancies. LIMITATIONS: Building the set of criteria comprises a part of arbitrariness and imperfect knowledge, which require time and expertise to be refined. Among them, three criteria are modeled by means of a holistic classification procedure by the medical experts. PMID- 21295516 TI - Phenotypic diversity of cytomegalovirus DNA polymerase gene variants observed after antiviral therapy. AB - BACKGROUND: Cytomegalovirus UL54 DNA polymerase mutations observed in clinical specimens are of diagnostic significance if confirmed to affect antiviral drug susceptibility. OBJECTIVES: Validate an updated recombinant phenotyping method to determine the degree of drug resistance conferred by previously uncharacterized UL54 sequence variants, in comparison with known resistance-related mutations. STUDY DESIGN: Bacterial artificial chromosome clones of viral DNA were mutagenized by recombination, transfected to produce live virus and phenotyped by standardized reporter-based yield reduction assays. RESULTS: Sixteen recombinant viruses were constructed, representing baseline sequences, known resistance related mutations and amino acid changes of unproven significance from clinical specimens. Phenotypes of baseline strains and known mutants were comparable to results from prior methods and helped to resolve some published inconsistencies. Mutations F412L, F412S, L545W were newly confirmed to confer ganciclovir and cidofovir resistance, while Q578H conferred ganciclovir and foscarnet resistance with borderline cidofovir resistance. Some foscarnet-resistant mutants were appreciably growth-retarded. CONCLUSIONS: Results add to known exonuclease domain mutations that confer ganciclovir-cidofovir cross-resistance, polymerase domain mutations that confer foscarnet resistance with variably decreased ganciclovir/cidofovir susceptibility, and increase the list of sequence variants with no measurable impact on drug susceptibility. The phenotypic diversity of similar UL54 genotypic variants complicates the interpretation of genotypic resistance testing. Technical improvements are facilitating the phenotyping of remaining unknown sequence variants. PMID- 21295517 TI - Insights into the mechanisms underlying cortical plasticity following spinal cord injury. PMID- 21295518 TI - Short-interval intracortical inhibition with incomplete spinal cord injury. AB - OBJECTIVE: Short-interval intracortical inhibition (SICI) in leg and hand muscles was characterized in individuals with incomplete spinal cord injury (SCI) to understand how such inhibition limits corticospinal drive after spinal insult. METHODS: We compared SICI during a voluntary contraction in 16 SCI and 14 control subjects, the latter group tested over a larger range of conditioning and test stimulus (CS and TS) intensities to best match the SCI data. RESULTS: The average peak SICI in the tibialis anterior muscle was typically 3-4 times lower in the SCI subjects compared to controls. When matched for absolute TS intensity, in terms of maximum stimulator output, both U-shaped SICI recruitment curves were produced by similar CS intensities. SICI in the first dorsal interosseous muscle of the hand tended to be larger than in the ankle flexor. CONCLUSIONS: Incomplete SCI reduces SICI compared to controls, but the absolute CS intensities that produce the U-shaped SICI recruitment curves are unchanged. SIGNIFICANCE: These findings suggest that although the relative excitability profile of cortical SICI networks is unchanged after SCI, the effective inhibition of corticospinal tract output by these neurons is reduced. PMID- 21295519 TI - Novel cultured protists identify deep-branching environmental DNA clades of cercozoa: New Genera Tremula, Micrometopion, Minimassisteria, Nudifila, Peregrinia. AB - We describe three new orders of filosan Cercozoa, five new deep-branching genera, eight new species of Thaumatomonas, Reckertia, Spongomonas, Rhogostoma, Agitata, Neoheteromita and Paracercomonas, sequence their 18S rDNA, and construct 18S rDNA trees for 148 Cercozoa. Our phylogeny indicates that Filosa were ancestrally gliding flagellates; non-flagellate filose amoebae evolved from them five times independently. The new genera are more closely related to environmental DNA sequences than cultured organisms. Tremula longifila, a zooflagellate glider on both flagella (unlike other Cercozoa), is the most divergent filosan (Tremulida ord. n.). Micrometopion nutans is a eukaryote-eating gliding zooflagellate like Metopion and Metromonas. Minimassisteria diva is a widespread trimorphic marine amoeboflagellate granofilosan. Peregrinia clavideferens, a non-testate, scale bearing, filose amoeba, branches deeply in Thaumatomonadida, which are probably sisters to Spongomonadida. Nudifila producta is a filose amoeboflagellate related to Clautriavia and Marimonadida (ord. n., e.g. Pseudopirsonia, Auranticordis). We substantially revise Imbricatea, now including Spongomonadida, and Thecofilosea to include Phaeodaria. Thecofilosea and Imbricatea and Thecofilosea are sisters, both arguably ancestrally rigid gliding flagellates with ventral pseudopod emitting grooves. Scale-free Ovulinata parva is sister to Paulinella, so imbricate silica scales can be lost. Internal hollow silica skeletons evolved twice in Thecofilosea (Ebriida, Phaeodaria) or were multiply lost. Protaspa replaces preoccupied 'Protaspis'. PMID- 21295520 TI - Increased sampling reveals novel lineages of Entamoeba: consequences of genetic diversity and host specificity for taxonomy and molecular detection. AB - To expand the representation for phylogenetic analysis, ten additional complete Entamoeba small-subunit rRNA gene sequences were obtained from humans, non-human primates, cattle and a tortoise. For some novel sequences no corresponding morphological data were available, and we suggest that these organisms should be referred to as ribosomal lineages (RL) rather than being assigned species names at present. To investigate genetic diversity and host specificity of selected Entamoeba species, a total of 91 new partial small subunit rRNA gene sequences were obtained, including 49 from Entamoeba coli, 18 from Entamoeba polecki, and 17 from Entamoeba hartmanni. We propose a new nomenclature for significant variants within established Entamoeba species. Based on current data we propose that the uninucleated-cyst-producing Entamoeba infecting humans is called Entamoeba polecki and divided into four subtypes (ST1-ST4) and that Entamoeba coli is divided into two subtypes (ST1-ST2). New hosts for several species were detected and, while host specificity and genetic diversity of several species remain to be clarified, it is clear that previous reliance on cultivated material has given us a misleading and incomplete picture of variation within the genus Entamoeba. PMID- 21295521 TI - Reflections on the NETNEP 2010 conference--nursing education in a global community: Collaboration and networking for the future. PMID- 21295522 TI - Clinical heterogeneity and diagnostic delay of autoimmune polyendocrinopathy candidiasis-ectodermal dystrophy syndrome. AB - Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive organ-specific autoimmune disorder that is characterized by a variable combination of (i) chronic mucocutaneous candidiasis, (ii) polyendocrinopathy and/or hepatitis and (iii) dystrophy of the dental enamel and nails. We analyzed the AIRE (autoimmune regulator) gene in subjects who presented any symptom that has been associated with APECED, including candidiasis and autoimmune endocrinopathy. We observed that 83.3% of patients presented at least two of the three typical manifestations of APECED, while the remaining 16.7% of patients showed other signs of the disease. Analysis of the genetic diagnosis of these subjects revealed that a considerable delay occurs in the majority of patients between the appearance of symptoms and the diagnosis. Overall, the mean diagnostic delay in our patients was 10.2 years. These results suggest that molecular analysis of AIRE should be performed in patients with relapsing mucocutaneous candidiasis for early identification of APECED. PMID- 21295523 TI - Early relapse in ALL is identified by time to leukemia in NOD/SCID mice and is characterized by a gene signature involving survival pathways. AB - We investigated the engraftment properties and impact on patient outcome of 50 pediatric acute lymphoblastic leukemia (ALL) samples transplanted into NOD/SCID mice. Time to leukemia (TTL) was determined for each patient sample engrafted as weeks from transplant to overt leukemia. Short TTL was strongly associated with high risk for early relapse, identifying an independent prognostic factor. This high-risk phenotype is reflected by a gene signature that upon validation in an independent patient cohort (n = 197) identified a high-risk cluster of patients with early relapse. Furthermore, the signature points to independent pathways, including mTOR, involved in cell growth and apoptosis. The pathways identified can directly be targeted, thereby offering additional treatment approaches for these high-risk patients. PMID- 21295524 TI - Tumor-derived JAGGED1 promotes osteolytic bone metastasis of breast cancer by engaging notch signaling in bone cells. AB - Despite evidence supporting an oncogenic role in breast cancer, the Notch pathway's contribution to metastasis remains unknown. Here, we report that the Notch ligand Jagged1 is a clinically and functionally important mediator of bone metastasis by activating the Notch pathway in bone cells. Jagged1 promotes tumor growth by stimulating IL-6 release from osteoblasts and directly activates osteoclast differentiation. Furthermore, Jagged1 is a potent downstream mediator of the bone metastasis cytokine TGFbeta that is released during bone destruction. Importantly, gamma-secretase inhibitor treatment reduces Jagged1-mediated bone metastasis by disrupting the Notch pathway in stromal bone cells. These findings elucidate a stroma-dependent mechanism for Notch signaling in breast cancer and provide rationale for using gamma-secretase inhibitors for the treatment of bone metastasis. PMID- 21295525 TI - N-alpha-acetyltransferase 10 protein suppresses cancer cell metastasis by binding PIX proteins and inhibiting Cdc42/Rac1 activity. AB - N-alpha-acetyltransferase 10 protein, Naa10p, is an N-acetyltransferase known to be involved in cell cycle control. We found that Naa10p was expressed lower in varieties of malignancies with lymph node metastasis compared with non-lymph node metastasis. Higher Naa10p expression correlates the survival of lung cancer patients. Naa10p significantly suppressed migration, tumor growth, and metastasis independent of its enzymatic activity. Instead, Naa10p binds to the GIT-binding domain of PIX, thereby preventing the formation of the GIT-PIX-Paxillin complex, resulting in reduced intrinsic Cdc42/Rac1 activity and decreased cell migration. Forced expression of PIX in Naa10-transfected tumor cells restored the migration and metastasis ability. We suggest that Naa10p functions as a tumor metastasis suppressor by disrupting the migratory complex, PIX-GIT- Paxillin, in cancer cells. PMID- 21295526 TI - Positive response to binge eating intervention enhances postoperative weight loss. AB - BACKGROUND: Binge eating disorder has been suggested as a predictor of negative outcomes, including weight regain and poorer weight loss, particularly if the symptoms (e.g., loss of control eating) remain after surgery. Binge eating disorder has been viewed by some as a contraindication for weight loss surgery, and preoperative treatment has been recommended to help reduce binge eating behaviors. The objective of the present study was to evaluate whether the response to a preoperative binge eating intervention related to differential postoperative weight loss at an academic medical center. METHODS: A total of 128 bariatric surgery candidates completed a brief cognitive behavioral group treatment for binge eating behaviors. The patients were categorized as positive responders or nonresponders according to the postintervention outcomes, including binge eating symptoms and episodes. The percentage of excess body weight loss (%EBWL) was measured at 6 and 12 months after surgery. RESULTS: Across all bariatric procedures, the positive responders to the brief binge eating intervention had lost significantly more weight at 6 months (46% EBWL versus 38% EBWL) and 12 months (59% EBWL versus 50% EBWL) postoperatively. The results for a subsample of Roux-en-Y gastric bypass patients (n = 89) were also significant, with 53% EBWL for the responders and 42% EBWL for the nonresponders at 6 months and 68% EBWL versus 54% EBWL at 12 months postoperatively, respectively. CONCLUSION: The response to binge eating treatment could be an important predictor of postoperative weight loss. The results from the present study provide support for patients who respond to preoperative binge eating treatment having enhanced surgical outcomes. PMID- 21295527 TI - Laparoscopic excision of ovarian remnants: retrospective cohort study with long term follow-up. AB - STUDY OBJECTIVE: To review the clinical presentation, surgical and pathologic findings, and long-term outcomes after excision of ovarian remnants using a predominantly laparoscopic approach. DESIGN: Retrospective medical record review and long-term follow-up via telephone interview (Canadian Task Force classification II-3). SETTING: Large academic medical institution. PATIENTS: Thirty women who underwent excision of pathologically confirmed ovarian remnants by a single surgeon between 2001 and 2009. INTERVENTION: Excision of ovarian remnants, 29 at laparoscopy and 1 at laparotomy. MEASUREMENTS AND MAIN RESULTS: Of the 30 patients, 29 had pain and 1 had a persistent adnexal mass. Of the 29 patients who underwent preoperative ultrasonography, 26 (89.6%) had an adnexal mass on the side of previous salpingo-oophorectomy. Masses ranged in size from 0.8 to 7.4 cm in greatest diameter and most commonly contained debris-filled cysts. Intraoperatively, 29 excisions (96.7%) required retroperitoneal dissection, 27 (90.0%) required enterolysis, 28 (93.3%) required ureterolysis, and 20 (66.7%) required ligation of the uterine artery at its origin. All pathology reports confirmed ovarian tissue, often associated with endometriosis, corpus luteal cysts, and simple cysts. Four bowel injuries and 2 bladder injuries were laparoscopically repaired by the primary surgeon. Three patients required bowel resections by a general surgeon. Records from postoperative visits were available for 28 patients, of whom 17 (60.7%) reported resolution of pain, 9 (32.1%) reported improvement, and 2 (7.1%) reported persistent pain. Of the 18 women who returned written consent for the telephone interview, 11 (61.1%) reported resolution of pain, 5 (27.8%) reported improvement, and 2 (11.1%) reported persistent pain. CONCLUSION: While laparoscopic excision of ovarian remnants is feasible, the procedure almost always requires a retroperitoneal dissection and is associated with high risk of complications. Careful surgical planning and preparation are essential. PMID- 21295528 TI - Application of Patient-Reported Outcomes Measurement Information System to chronic pelvic pain. AB - STUDY OBJECTIVES: To apply the Patient-Reported Outcomes Measurement Information System (PROMIS) recently developed by the National Institutes of Health in patients with chronic pelvic pain. Secondary objectives included evaluation of individual pain categories and of the effect of the occurrence of myofascial abdominal wall and pelvic floor muscle pain. DESIGN: Retrospective study (Canadian Task Force classification III). SETTING: Chronic pelvic pain multidisciplinary referral center. PATIENTS: A total of 149 consecutive patients with chronic pelvic pain provided evaluable results. INTERVENTIONS: As part of a comprehensive evaluation, patients were assigned diagnoses based on standard criteria, and completed the 96-item short-form PROMIS. MEASUREMENTS AND MAIN RESULTS: Pain-related and global PROMIS scores were significantly worse than in the reference population (p <.05). The presence of myofascial pain was also associated with worse PROMIS scores. CONCLUSION: Chronic pelvic pain is associated with impaired quality of life regardless of the diagnosis, including myofascial pain. PMID- 21295529 TI - Cracking the chromatin code: precise rule of nucleosome positioning. AB - Various aspects of packaging DNA in eukaryotic cells are outlined in physical rather than biological terms. The informational and physical nature of packaging instructions encoded in DNA sequences is discussed with the emphasis on signal processing difficulties--very low signal-to-noise ratio and high degeneracy of the nucleosome positioning signal. As the author has been contributing to the field from its very onset in 1980, the review is mostly focused at the works of the author and his colleagues. The leading concept of the overview is the role of deformational properties of DNA in the nucleosome positioning. The target of the studies is to derive the DNA bendability matrix describing where along the DNA various dinucleotide elements should be positioned, to facilitate its bending in the nucleosome. Three different approaches are described leading to derivation of the DNA deformability sequence pattern, which is a simplified linear presentation of the bendability matrix. All three approaches converge to the same unique sequence motif CGRAAATTTYCG or, in binary form, YRRRRRYYYYYR, both representing the chromatin code. PMID- 21295530 TI - Chromatin in 1, 2 and 3 dimensions: comment on "Cracking the chromatin code: precise rule of nucleosome positioning" by E.N. Trifonov. PMID- 21295531 TI - The role of support person for Ngaanyatjarra women during pregnancy and birth. AB - BACKGROUND: This study took place in a remote community on the Ngaanyatjarra Lands, Western Australia. Ngaanyatjarra women's cultural practices have been subject to erosion during the past 70 years. Women are now expected to birth hundreds of kilometres from home and, due to financial barriers, without family support. Older women lament their lack of input into, and control of, contemporary birthing services. RESEARCH QUESTION: In order to provide culturally appropriate maternity services we asked: What issues would the Ngaanyatjarra women of the community like to see resolved in the area of antenatal and birthing services? PARTICIPANTS AND METHODS: Eligible participants were any Ngaanyatjarra women of the study community who had birthed at least once. We utilised a participatory research methodology. 36 women were interviewed. FINDINGS: This paper discusses one finding related to support for child-bearing women. The role is important in many ways. Ngaanyatjarra women did not traditionally have their support persons with them during labour and birth, nor do they necessarily expect them to be present in current times. Most women do, however, wish to have a support person with them during antenatal checkups and when they travel to town to await birth. CONCLUSION: Aboriginal women from remote communities should be able to have a support person with them when they access regional birthing services, but the nature of this role must not be assumed. A culturally appropriate service has input from the community, provides options and respects choices. PMID- 21295532 TI - A stochastic model of the processes in PCR based amplification of STR DNA in forensic applications. AB - In forensic DNA profiling use is made of the well-known technique of PCR. When the amount of DNA is high, generally unambiguous profiles can be obtained, but for low copy number DNA stochastic effects can play a major role. In order to shed light on these stochastic effects, we present a simple model for the amplification process. According to the model, three possible things can happen to an individual single DNA strand in each complete cycle: successful amplification, no amplification, or amplification with the introduction of stutter. The model is developed in mathematical terms using a recursive approach: given the numbers of chains at a given cycle, the numbers in the next can be described using a multinomial probability distribution. A full set of recursive relations is derived for the expectations and (co)variances of the number of amplicon chains with no, 1 or 2 stutters. The exact mathematical solutions of this set are given, revealing the development of the expectations and (co)variances as function of the cycle number. The equations reveal that the expected number of amplicon chains without stutter grows exponentially with the cycle number, but for the chains with stutter the relation is more complex. The relative standard deviation on the numbers of chains (coefficient of variation) is inversely proportional to the square root of the expected number of DNA strands entering the amplification. As such, for high copy number DNA the stochastic effects can be ignored, but they play an important role at low concentrations. For the allelic peak, the coefficient of variation rapidly stabilizes after a few cycles, but for the chains with stutter the decrease is more slowly. Further, the ratio of the expected intensity of the stutter peak over that of the allelic peak increases linearly with the number of cycles. Stochastic models, like the one developed in the current paper, can be important in further developing interpretation rules in a Bayesian context. PMID- 21295533 TI - Population data for 10 X-chromosome STRs from north-east of Spain. PMID- 21295534 TI - Forensic genetic data of 6 Y-STR loci: an expanded Korean population database. PMID- 21295535 TI - Perineal hernia: The ventral decubitus perineal approach. PMID- 21295536 TI - Evolution of age at diagnosis of congenital hearing impairment. AB - AIM OF THE STUDY: To show the evolution of age at diagnosis of bilateral congenital hearing impairment according to date of birth and severity of hearing loss assessed in the better ear. PATIENTS AND METHODS: Retrospective study of children with hearing aids, born or living in France and examined in the ENT department for diagnosis or follow-up of congenital hearing impairment. RESULTS: In profound deafness, median age at diagnosis fell from 50 months for children born between 1985 and 1989 to 12 months for children born between 2000 and 2004; in severe hearing impairment, from 38 to 30 months, respectively; and in moderate hearing impairment, from 85 to 40 months, respectively. DISCUSSION: In this as in other series, age at diagnosis of bilateral congenital hearing impairment is seen to be decreasing slowly. CONCLUSION: In this study of children born before 2005 (i.e., before the start of the universal neonatal hearing screening program in the Paris region of France), age at diagnosis of moderate, severe or profound bilateral congenital hearing impairment remains high for the last period studied, but has fallen significantly over the last 20 years. PMID- 21295539 TI - Impact of improved potassium accumulation on pH homeostasis, membrane potential adjustment and survival of Corynebacterium glutamicum. AB - Metal ion uptake is crucial for all living cells and an essential part of cellular bioenergetic homeostasis. In this study the uptake and the impact of the most abundant internal cation, potassium, were investigated in Actinobacteria, a group of high G+C Gram-positives with a number of prominent biotechnologically and medically important members. Genome analyses revealed a variety of different potassium uptake systems in this monophyletic group ranging from potassium channels common in virtually all Actinobacteria to different active carriers that were present predominantly in pathogenic members able to cope with various stress conditions. By applying Corynebacterium glutamicum as model system we provide experimental evidence that under optimal conditions a potassium channel is sufficient in bacteria for the maintenance of internal pH and membrane potential ensuring survival of cells under stress conditions. Under potassium limitation, however, viability of C. glutamicum was increased under acidic stress or during desiccation when a functional KtrAB potassium transporter from the pathogen Corynebacterium jeikeium was heterologously expressed. We provide experimental evidence that the KtrAB mediated enhanced potassium accumulation improved maintenance of internal pH and membrane potential. The results indicate that the occurrence of active potassium transport systems correlates with an improved potassium-dependent bioenergetic homeostasis and survival of bacterial cells under stress conditions. PMID- 21295540 TI - Yeast ornithine decarboxylase and antizyme form a 1:1 complex in vitro: purification and characterization of the inhibitory complex. AB - Saccharomyces cerevisiae antizyme (AZ) resembles mammalian AZ in its mode of synthesis by translational frameshifting and its ability to inhibit and facilitate the degradation of ornithine decarboxylase (ODC). Despite many studies on the interaction of AZ and ODC, the ODC:AZ complex has not been purified from any source and thus clear information about the stoichiometry of the complex is still lacking. In this study we have studied the yeast antizyme protein and the ODC:AZ complex. The far UV CD spectrum of the full-length antizyme shows that the yeast protein consists of 51% beta-sheet, 19% alpha-helix, and 24% coils. Surface plasmon resonance analyses show that the association constant (K(A)) between yeast AZ and yeast ODC is 6*10(7) (M(-1)). Using purified His-tagged AZ as a binding partner, we have purified the ODC:AZ inhibitory complex. The isolated complex has no ODC activity. The molecular weight of the complex is 90 kDa, which indicates a one to one stoichiometric binding of AZ and ODC in vitro. Comparison of the circular dichroism (CD) spectra of the two individual proteins and of the ODC:AZ complex shows a change in the secondary structure in the complex. PMID- 21295541 TI - Several cardiomyopathy causing mutations on tropomyosin either destabilize the active state of actomyosin or alter the binding properties of tropomyosin. AB - We examined the cardiomyopathy-causing tropomyosin mutations E180G, D175N, and V95A to determine their effects on actomyosin regulation. V95A reduced the ATPase rate when filaments were saturated with regulatory proteins both in the presence and absence of calcium, indicating either a stabilization of the inactive state or an inability to fully populate the active state. Effects of E180G and D175N were more complex. These two mutations increased ATPase rates at sub-saturating concentrations of troponin and tropomyosin as compared to wild type tropomyosin. At higher concentrations of regulatory proteins, ATPase rates became similar to wild type. Normal activation was achieved with the tight-binding myosin analog N ethylmaleimide-S1, at saturating regulatory protein concentrations. These results suggest that the E180G and D175N mutations reduce the affinity of tropomyosin for actin and also destabilize troponin binding to the actin thin filaments. PMID- 21295542 TI - CREB represses p53-dependent transactivation of MDM2 through the complex formation with p53 and contributes to p53-mediated apoptosis in response to glucose deprivation. AB - Recently, we have described that CREB (cAMP-responsive element-binding protein) has the ability to transactivate tumor suppressor p53 gene in response to glucose deprivation. In this study, we have found that CREB forms a complex with p53 and represses p53-mediated transactivation of MDM2 but not of p21(WAF1). Immunoprecipitation analysis revealed that CREB interacts with p53 in response to glucose deprivation. Forced expression of CREB significantly attenuated the up regulation of the endogenous MDM2 in response to p53. By contrast, the mutant form of CREB lacking DNA-binding domain (CREBDelta) had an undetectable effect on the expression level of the endogenous MDM2. During the glucose deprivation mediated apoptosis, there existed an inverse relationship between the expression levels of MDM2 and p53/CREB. Additionally, p53/CREB complex was dissociated from MDM2 promoter in response to glucose deprivation. Collectively, our present results suggest that CREB preferentially down-regulates MDM2 and thereby contributing to p53-mediated apoptosis in response to glucose deprivation. PMID- 21295543 TI - DNA methylation-dependent regulation of TrkA, TrkB, and TrkC genes in human hepatocellular carcinoma. AB - The tropomyosin-related kinase (Trk) family of neurotrophin receptors, TrkA, TrkB and TrkC, has been implicated in the growth and survival of human cancers. Here we report that Trks are frequently overexpressed in hepatocellular carcinoma (HCC) from patients and human liver cancer cell lines. To unravel the underlying molecular mechanism(s) for this phenomenon, DNA methylation patterns of CpG islands in TrkA, TrkB, and TrkC genes were examined in normal and cancer cell lines derived from liver. A good correlation was observed between promoter hypermethylation and lower expression of TrkA, TrkB, and TrkC genes, which was supported by the data that inhibiting DNA methylation with 5-azacytidine restored expression of those genes in normal liver cell lines. Furthermore, Trks promoted the proliferation of HepG2 and induced expression of the metastatic regulator, Twist. These results suggest that Trks may contribute to growth and metastasis of liver cancer. PMID- 21295544 TI - Modulation of the dopamine transporter by interaction with Secretory Carrier Membrane Protein 2. AB - The monoamine transporters for dopamine (DAT), norepinephrine (NET) and serotonin (SERT) facilitate the homeostatic balance of neurotransmitters in the synaptic cleft and thus, play a fundamental role in regulating neuronal activity. Despite the importance of these monoamine transporters in controlling brain function, only relatively little information is available regarding the cellular and molecular regulation of these proteins. The monoamine transporters have been found to associate with a number of different proteins that regulate the function and subcellular localization of the transporters. We recently reported a functional interaction between SERT and the Secretory Carrier Membrane Protein 2 (SCAMP2). Here, we demonstrate that SCAMP2 also plays a role in the functional regulation of DAT. DAT and SCAMP2 interaction is here verified by co immunoprecipitation and fluorescence resonance energy transfer (FRET) microscopy. Moreover, co-expression of DAT and SCAMP2 results in a decrease in DAT-mediated dopamine uptake caused by reduced levels of DAT molecules on the cell surface. Our finding that SCAMP2 interacts with and regulates the subcellular distribution of both DAT and SERT suggests that interaction with SCAMP2 may constitute an important mechanism for coordinating cell surface expression of monoamine transporters. PMID- 21295545 TI - Assessing the efficacy of vesicle fusion with planar membrane arrays using a mitochondrial porin as reporter. AB - Reconstitution of functionally active membrane protein into artificially made lipid bilayers is a challenge that must be overcome to create a membrane-based biomimetic sensor and separation device. In this study we address the efficacy of proteoliposome fusion with planar membrane arrays. We establish a protein incorporation efficacy assay using the major non-specific porin of Fusobacterium nucleatum (FomA) as reporter. We use electrical conductance measurements and fluorescence microscopy to characterize proteoliposome fusion with an array of planar membranes. We show that protein reconstitution in biomimetic membrane arrays may be quantified using the developed FomA assay. Specifically, we show that FomA vesicles are inherently fusigenic. Optimal FomA incorporation is obtained with a proteoliposome lipid-to-protein molar ratio (LPR)=50 more than 10(5) FomA proteins could be incorporated in a bilayer array with a total membrane area of 2mm(2) within 20 min. This novel assay for quantifying protein delivery into lipid bilayers may be a useful tool in developing biomimetic membrane applications. PMID- 21295546 TI - Evidence for involvement of the C-terminal domain in the dimerization of the CopY repressor protein from Enterococcus hirae. AB - Metal binding to the C-terminal region of the copper-responsive repressor protein CopY is responsible for homodimerization and the regulation of the copper homeostasis pathway in Enterococcus hirae. Specific involvement of the 38 C terminal residues of CopY in dimerization is indicated by zonal and frontal (large zone) size-exclusion chromatography studies. The studies demonstrate that the attachment of these CopY residues to the immunoglobulin-binding domain of streptococcal protein G (GB1) promotes dimerization of the monomeric protein. Although sensitivity of dimerization to removal of metal from the fusion protein is smaller than that found for CopY (as measured by ultracentrifugation studies), the demonstration that an unrelated protein (GB1) can be induced to dimerize by extending its sequence with the C-terminal portion of CopY confirms the involvement of this region in CopY homodimerization. PMID- 21295547 TI - Dye-filling of the amphid sheath glia: implications for the functional relationship between sensory neurons and glia in Caenorhabditis elegans. AB - The nervous system is composed of cells including neurons and glia. It has been believed that the former cells play central roles in various neural functions while the latter ones have only supportive functions for neurons. However, recent findings suggest that glial cells actively participate in neural activities, and the cooperation between neurons and glia is important for nervous system functions. In Caenorhabditis elegans, amphid sensory organs in the head also consist of sensory neurons and glia-like support cells (amphid socket and amphid sheath cells). Ciliary endings of some sensory neurons exposed to the environment detect various chemicals, molecules and signals, and the cilia of some neurons can also take up fluorescent dyes such as DiI. Here, we show that the amphid sheath glia are also stained with DiI and that its uptake by the amphid sheath cells correlates with DiI-filling of sensory neurons, suggesting that the amphid sheath glia might interact with sensory neurons. Furthermore, the localization of the amphid sheath cell reporter F52E1.2SP::YFP is abnormal in che-2 mutants, which have defective cilia. These findings imply that sensory neurons might affect amphid sheath glia functions in the amphid sensory organ of C. elegans. PMID- 21295548 TI - Unconventional actin conformations localize on intermediate filaments in mitosis. AB - Different structural conformations of actin have been identified in cells and shown to reside in distinct subcellular locations of cells. In this report, we describe the localization of actin on a cage-like structure in metaphase HEK 293T cells. Actin was detected with the anti-actin antibodies 1C7 and 2G2, but not with the anti-actin antibody C4. Actin contained in this structure is independent of microtubules and actin filaments, and colocalizes with vimentin. Taking advantage of intermediate filament collapse into a perinuclear dense mass of cables when microtubules are depolymerized, we were able to relocalize actin to such structures. We hypothesize that phosphorylation of intermediate filaments at mitosis entry triggers the recruitment of different actin conformations to mitotic intermediate filaments. Storage and partition of the nuclear actin and antiparallel "lower dimer" actin conformations between daughter cells possibly contribute to gene transcription and transient actin filament dynamics at G1 entry. PMID- 21295549 TI - Transport of Poly(n-butylcyano-acrylate) nanoparticles across the blood-brain barrier in vitro and their influence on barrier integrity. AB - In previous studies it was shown that polysorbate 80(PS80)-coated poly(n butylcyano-acrylate) nanoparticles (PBCA-NP) are able to cross the blood-brain barrier (BBB) in vitro and in vivo. In order to explore and extend the potential applications of PBCA-NP as drug carriers, it is important to ascertain their effect on the BBB. The objective of the present study was to determine the effect of PS80-coated PBCA-NP on the BBB integrity of a porcine in vitro model. This has been investigated by monitoring the development of the transendothelial electrical resistance (TEER) after the addition of PBCA-NP employing impedance spectroscopy. Additionally, the integrity of the BBB in vitro was verified by measuring the passage of the reference substances (14)C-sucrose and FITC-BSA after addition of PBCA-NP. In this study we will show that the application of PS80-coated PBCA-NP leads to a reversible disruption of the barrier after 4h. The observed disruption of the barrier could also be confirmed by (14)C-sucrose and FITC-BSA permeability studies. Comparing the TEER and permeability studies the lowest resistances and maximal values for permeabilities were both observed after 4h. These results indicate that PS80-coated PBCA-NP might be suitable for the use as drug carriers. The reversible disruption also offers the possibility to use these particles as specific opener of the BBB. Instead of incorporating the therapeutic agents into the NP, the drugs may cross the BBB after being applied simultaneously with the PBCA-NP. PMID- 21295550 TI - Head/tail interaction of vinculin influences cell mechanical behavior. AB - This study evaluates the influence of vinculin in closed conformation on the mechanical properties of cells. We demonstrate that MEFvin(-/-) cells transfected with the eGFP-vinculin mutant A50I (talin-binding-deficient-vinculin in a constitutively closed conformation) show 2-fold lower stiffness and focal adhesion density compared to MEFvin(+/+) and MEF(Rescue) cells. MEF(A50I) cells are as stiff as MEFvin(-/-) cells with similar focal adhesion density. Further, 2D traction microscopy indicates that MEF(A50I) and MEFvin(-/-) cells generate 3- to 4-fold less strain energy than MEFvin(+/+) and MEF(Rescue) cells. These results demonstrate that vinculin's mechano-coupling function is dependent on its conformational state. PMID- 21295551 TI - Expression of serum miR-221 in human hepatocellular carcinoma and its prognostic significance. AB - OBJECTIVE: To investigate whether the serum miR-221 expression correlates with clinicopathologic features and the prognosis of hepatocellular carcinoma (HCC) patients. METHODS: Four miRNAs (miR-221, miR-222, miR-21 and miR-224) related to HCC were selected in the present study. Serum miRNA expression was investigated in 46 HCC patients and 20 healthy normal controls by using real-time PCR technique, and then correlations between miR-221 expression and the clinicopathological features and prognosis of HCC patients were evaluated. RESULTS: The four miRNAs were found to be differentially overexpressed in HCC serum samples, and high level of miR-221 expression was correlated with tumor size (P<0.001), cirrhosis (P=0.003) and tumor stage (P=0.016). In addition, Kaplan-Meier survival analysis showed that the overall survival rate of the high miR-221 expression group (27.6%) was significantly lower than that of the low miR 221 expression group (62.3%, P<0.05). CONCLUSIONS: Serum miR-221, upregulated in HCC, can provide predictive significance for prognosis of HCC patients. PMID- 21295552 TI - Developing predictive CSF biomarkers-a challenge critical to success in Alzheimer's disease and neuropsychiatric translational medicine. AB - The need to develop effective treatments for Alzheimer's disease has been confounded by repeated clinical failures where promising new chemical entities that have been extensively characterized in preclinical models of Alzheimer's disease have failed to show efficacy in the human disease state. This has been attributed to: the selection of drug targets that have yet to be shown as causal to the disease as distinct from being the result of the disease process, a lack of congruence in the animal models of Alzheimer's disease, wild-type and transgenic, to the human disease, and the enrollment of patients in proof of concept clinical trials who are at too advanced a stage of the disease to respond to any therapeutic. The development of validated biomarkers that can be used for disease diagnosis and progression is anticipated to improve patient enrollment in clinical trials, to develop new animal models and to identify new disease targets for drug discovery. The present review assesses the status of current efforts in developing CSF biomarkers for Alzheimer's disease and briefly discusses the status of CSF biomarker efforts in schizophrenia, depression, Parkinson's disease and multiple sclerosis. PMID- 21295553 TI - Taurine suppresses doxorubicin-triggered oxidative stress and cardiac apoptosis in rat via up-regulation of PI3-K/Akt and inhibition of p53, p38-JNK. AB - The objective of the present study was to investigate the signaling mechanisms involved in the beneficial role of taurine against doxorubicin-induced cardiac oxidative stress. Male rats were administered doxorubicin. Hearts were collected 3 weeks after the last dose of doxorubicin and were analyzed. Doxorubicin administration retarded the growth of the body and the heart and caused injury in the cardiac tissue because of increased oxidative stress. Similar experiments with doxorubicin showed reduced cell viability, increased ROS generation, intracellular Ca(2+) and DNA fragmentation, disrupted mitochondrial membrane potential and apoptotic cell death in primary cultured neonatal rat cardiomyocytes. Signal transduction studies showed that doxorubicin increased p53, JNK, p38 and NFkappaB phosphorylation; decreased the levels of phospho ERK and Akt; disturbed the Bcl-2 family protein balance; activated caspase 12, caspase 9 and caspase 3; and induced cleavage of the PARP protein. However, taurine treatment or cardiomyocyte incubation with taurine suppressed all of the adverse effects of doxorubicin. Studies with several inhibitors, including PS 1145 (an IKK inhibitor), SP600125 (a JNK inhibitor), SB203580 (a p38 inhibitor) and LY294002 (a PI3-K/Akt inhibitor), demonstrated that the mechanism of taurine induced cardio protection involves activation of specific survival signals and PI3-K/Akt as well as the inhibition of p53, JNK, p38 and NFkappaB. These novel findings suggest that taurine might have clinical implications for the prevention of doxorubicin-induced cardiac oxidative stress. PMID- 21295555 TI - Riluzole-induced glial cell line-derived neurotrophic factor production is regulated through fibroblast growth factor receptor signaling in rat C6 glioma cells. AB - Riluzole is approved for the treatment of amyotrophic lateral sclerosis (ALS); however, recent accumulating evidence suggests that riluzole is also effective for the treatment of psychiatric disorders, such as mood disorders. Plastic change in the brain induced by neurotrophic factors/growth factors is thought to be involved in the mechanism of antidepressants. This study investigated the mechanism of riluzole-induced glial cell line-derived neurotrophic factor (GDNF) production in rat C6 glioma cells (C6 cells), a model of astrocytes. The study investigated the phosphorylation of cAMP response element binding protein (CREB), an important transcriptional factor of the gdnf gene, and found that riluzole increased CREB phosphorylation in a time-dependent manner, peaking at 40min after treatment. The riluzole-induced CREB phosphorylation was completely blocked by a mitogen-activated protein kinase kinase (MEK) inhibitor (U0126). Riluzole increased extracellular signal-regulated kinase (ERK) activation prior to CREB phosphorylation. These results suggest that riluzole rapidly activates the MEK/ERK/CREB pathway. Furthermore, two types of fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitors (SU5402 and PD173074) completely blocked riluzole-induced CREB phosphorylation. In addition, riluzole rapidly phosphorylated FGFR substrate 2alpha (FRS2alpha), a major adaptor protein of FGFR. These findings suggest that riluzole induces CREB phosphorylation through FGFR. In addition, PD173074 inhibited riluzole-induced GDNF production. In contrast, l-glutamate and a glutamate transporter inhibitor (t-PDC) did not yield any effects in either CREB phosphorylation or GDNF production. These findings suggest that riluzole rapidly activates a MEK/ERK/CREB pathway through FGFR in a glutamate transporter-independent manner, followed by GDNF expression in C6 cells. PMID- 21295554 TI - Increasing proportions of tyrosine hydroxylase-immunoreactive interneurons colocalize with choline acetyltransferase or vasoactive intestinal peptide in the developing rat cerebral cortex. AB - Cortical interneurons are critical for information processing, and their dysfunction has been implicated in neurological disorders. One subset of this diverse cell population expresses tyrosine hydroxylase (TH) during postnatal rat development. Cortical TH-immunoreactive neurons appear at postnatal day (P) 16. The number of TH cells sharply increases between P16 and P20 and subsequently decreases to adult values. The absence of apoptotic markers in these cells suggests that the reduction in cell number is not due to cell death but is due to a decline in TH production. Cortical TH cells lack all additional catecholaminergic enzymes, and many coexpress GABA and calretinin, but little else is known about their phenotype or function. Because interneurons containing choline acetyltransferase (ChAT) or vasoactive intestinal peptide (VIP) share characteristics with cortical TH neurons, the coexpression of TH with ChAT or VIP was examined throughout the neocortex at P16, P20, and P30. The proportions of TH cell profiles double-labeled for ChAT or VIP significantly increased between P16 and P30. Based on their proximity to blood vessels, intrinsic cholinergic and VIPergic cells have been hypothesized to regulate cortical microcirculation. Labeling with the gliovascular marker aquaporin-4 revealed that at least half of the TH cells were apposed to microvessels at these ages, and many of these cells contained ChAT or VIP. Cortical TH neurons did not coproduce nitric oxide synthase. These results suggest that increasing proportions of cortical TH neurons express ChAT or VIP developmentally and that a subset of these TH neurons may regulate local blood flow. PMID- 21295556 TI - Schwann-like mesenchymal stem cells within vein graft facilitate facial nerve regeneration and remyelination. AB - To compare the ability of bone marrow mesenchymal stem cells (MSCs) and transdifferentiated Schwann-like MSCs (tMSCs) in promoting transected facial nerve branches repair in a rabbit model of injury, rabbit tMSCs were induced from bone marrow MSCs, and Schwann cells markers were assessed by Western blot analysis. The left facial nerve buccal branch was transected to form a 1-cm gap in 54 rabbits, and the gaps were immediately bridged using autologous vein grafts. Animals were then randomly assigned to three groups: vein graft (VG); VG+MSCs, and VG+tMSCs (n=18/group). Saline, autologous MSCs, and Schwann-like tMSCs were injected into vein conduits. Rabbits were sacrificed at week 4, 8, and 16 post-surgery. Facial nerves regeneration and myelination were analyzed by functional, immunohistochemical, and morphological tests. In addition, myelin protein genes expression, including peripheral myelin protein 22 (PMP22), myelin protein zero (P0), and myelin basic protein (MBP), in transplanted cells in vivo were assayed using real time quantitative-reverse transcription-polymerase chain reaction (RT-PCR). Rabbit tMSCs expressed Schwann cells markers, and results demonstrated better facial nerve functional recovery in the VG+tMSCs group, with earlier horseradish peroxidase (HRP) positive neurons appearance and a greater number of MBP positive myelinated axons since 4weeks after transplantation. Moreover, RT-PCR analysis showed transplanted tMSCs in vivo expressed higher myelin proteins at mRNA level than those of MSCs during the first 8weeks of neural regeneration. This study suggests that rabbit transdifferentiated Schwann like MSCs within autogenous vein graft accelerate transected axons regeneration and achieve better remyelinization. PMID- 21295557 TI - Erythropoietin promotes neurovascular remodeling and long-term functional recovery in rats following traumatic brain injury. AB - Erythropoietin (EPO) improves functional recovery after traumatic brain injury (TBI). This study was designed to investigate long-term (3 months) effects of EPO on brain remodeling and functional recovery in rats after TBI. Young male Wistar rats were subjected to unilateral controlled cortical impact injury. TBI rats were divided into the following groups: (1) saline group (n=7); (2) EPO-6h group (n=8); and (3) EPO-24h group (n=8). EPO (5000 U/kg in saline) was administered intraperitoneally at 6h, and 1 and 2 days (EPO-6h group) or at 1, 2, and 3 days (EPO-24h group) postinjury. Neurological function was assessed using a modified neurological severity score, footfault and Morris water maze tests. Animals were sacrificed at 3 months after injury and brain sections were stained for immunohistochemical analyses. Compared to the saline, EPO-6h treatment significantly reduced cortical lesion volume, while EPO-24h therapy did not affect the lesion volume (P<0.05). Both the EPO-6h and EPO-24h treatments significantly reduced hippocampal cell loss (P<0.05), promoted angiogenesis (P<0.05) and increased endogenous cellular proliferation (BrdU-positive cells) in the injury boundary zone and hippocampus (P<0.05) compared to saline controls. Significantly enhanced neurogenesis (BrdU/NeuN-positive cells) was seen in the dentate gyrus of both EPO groups compared to the saline group. Both EPO treatments significantly improved long-term sensorimotor and cognitive functional recovery after TBI. In conclusion, the beneficial effects of posttraumatic EPO treatment on injured brain persisted for at least 3 months. The long-term improvement in functional outcome may in part be related to the neurovascular remodeling induced by EPO. PMID- 21295558 TI - Septal stimulation inhibits spinal cord dorsal horn neuronal activity. AB - Deep brain stimulation (DBS) has been used for relieving chronic pain in patients that have been through other existing options. The septum has been one of the targets for such treatment. The purpose of this study was to determine the inhibitory effect of electrical stimulation in the medial septum diagonal band of broca (MSDB) on neuronal activity in the spinal cord of rats anesthetized with sodium pentobarbital. While unilaterally stimulating the MSDB, wide dynamic range neurons in the lumbar region of the spinal cord were recorded in response to graded mechanical stimulation of the hind paws (brush, pressure, and pinch). Stimulation was at 1, 5, 10, and 20V, at 100Hz, and 0.1ms duration. Significant bilateral reduction was observed in response to pressure (ipsilaterally: 0.90+/ 0.05, 0.48+/-0.06*, 0.55+/-0.05*, 0.40+/-0.05*; and contralaterally: 0.70+/ 0.06*, 0.59+/-0.08*, 0.75+/-0.05*, 0.49+/-0.07*) and pinch (ipsilaterally: 0.89+/ 0.08, 0.46+/-0.05*, 0.54+/-0.04*, 0.50+/-0.05*; and contralaterally: 0.78+/-0.05, 0.61+/-0.07*, 0.64+/-0.04*, 0.53+/-0.06*). Data were expressed as a fraction of control. Significant changes were also found in responses to brush in certain groups (ipsilaterally: 1.08+/-0.08, 0.72+/-0.06*, 1.00+/-0.12, 0.65+/-0.06*; and contralaterally: 0.93+/-0.05, 0.77+/-0.07*, 0.98+/-0.05, 0.84+/-0.07). Further analysis suggested that 5V was adequate for achieving optimal inhibition. It is concluded that the MSDB can be used as alternative target for DBS in the treatment of pain. PMID- 21295559 TI - Extracellular DC electric fields induce nonuniform membrane polarization in rat hippocampal CA1 pyramidal neurons. AB - Non-synaptic interactions among neurons via extracellular electric fields may play functional roles in the CNS. Previously in a study using voltage-sensitive dye imaging, we reported characteristic membrane polarization profiles in the CA1 region of hippocampal slices during exposure to extracellular DC fields: slow monophasic polarization in somatic region and biphasic polarization (fast polarization and following slow repolarization) in mid-dendritic region. Here, using optical imaging and patch-clamp recordings, we showed that CA1 pyramidal neurons indeed show the characteristic polarization in response to DC fields, and investigated the mechanism underlying the profiles. Both the monophasic and biphasic polarization could be fitted with a double exponential function. The taus (ms) were 12.6+/-2.5 and 56.0+/-4.7 for the monophasic polarization, and 14.2+/-1.2 and 42.2+/-2.8 for the biphasic polarization. Based on our previous theoretical studies, we hypothesized that lower resistivity in the distal apical dendrites is responsible for generating the characteristic polarization profiles. We tested this hypothesis by removing the distal apical dendrites or by blocking ion channel-mediated conductance. Removal of distal dendrites caused drastic changes in the polarization profiles, e.g. biphasic polarization was damped. However, none of the blockers tested had a marked effect on the biphasic polarization. Our results demonstrate the importance of the apical dendrite for generating the characteristic polarization profiles, and suggest that voltage activated conductance, including HCN channel-mediated conductance, had only minor contributions to these profiles. These findings provide a better understanding of how neurons in the CNS respond to extracellular electric fields. PMID- 21295560 TI - Stability of diether C(25,25) liposomes from the hyperthermophilic archaeon Aeropyrum pernix K1. AB - Temperature and pH effects were studied for stability, structural organization, fluidity and permeability of vesicles from a polar lipid methanol fraction isolated from the Aeropyrum pernix. We determined the permeability of C(25,25) liposomes using fluorescence intensity of released calcein. At pH 7.0 and 9.0, and from 85 degrees C to 98 degrees C, only 10% of entrapped calcein was released. After 10 h at 90 degrees C, calcein release reached 27%, independent of pH. Fluorescence anisotropy measurements of hydrophobic probe 1,6-diphenyl-1,3,5 hexatriene revealed gradual changes up to 60 degrees C. At higher temperatures, the anisotropy did not change significantly. Fluorescence alone did not provide detailed and direct structural information about these C(25,25) liposomes, so we used electron paramagnetic resonance spectroscopy (EPR) and differential scanning calorimetry (DSC). From EPR spectra, mean membrane fluidity determined according to maximal hyperfine splitting and empirical correlation times showed continuous increases with temperature. Computer simulation of EPR spectra showed heterogeneous membranes of these C(25,25) liposomes: at low temperatures, they showed three types of membrane regions characterized by different motional modes. Above 65 degrees C, the membrane becomes homogeneous with only one fluid-like region. DSC thermograms of C(25,25) liposomes reveal a very broad and endothermic transition in the temperature range from 0 degrees C to 40 degrees C. PMID- 21295561 TI - Mesenchymal miR-21 regulates branching morphogenesis in murine submandibular gland in vitro. AB - Branching morphogenesis in murine submandibular glands (SMG) is regulated by growth factors, extracellular matrix (ECM) and many biological processes through interactions between the epithelium and the mesenchyme. MicroRNAs (miRNAs) are a set of small, non-protein-coding RNAs that regulate gene expression at the post transcriptional level. We hypothesized that branching morphogenesis is partly regulated by miRNAs. Forty-four miRNAs and novel miRNA candidates were detected in SMG at embryonic day 13 by a cloning method combined with Argonaute-2 immunoprecipitation. MicroRNA21 (miR-21) expression in the mesenchyme was up regulated and accelerated by epidermal growth factor, which is known to enhance branching morphogenesis in vitro. Down-regulation of miR-21 in the mesenchyme by locked nucleic acids was associated with a decrease in the number of epithelial buds. Relative quantification of candidates for target genes of miR-21 indicated that two messenger RNAs (for Reck and Pdcd4) were down-regulated in the mesenchyme, where miR-21 expression levels were up-regulated. These results suggest that branching morphogenesis is regulated by miR-21 through gene expression related to ECM degradation in the mesenchyme. PMID- 21295562 TI - Evolutionary implications of morphogenesis and molecular patterning of the blind gut in the planarian Schmidtea polychroa. AB - The formation of a through-gut was a key innovation in the evolution of metazoans. There is still controversy regarding the origin of the anus and how it may have been either gained or lost during evolution in different bilaterian taxa. Thus, the study of groups with a blind gut is of great importance for understanding the evolution of this organ system. Here, we describe the morphogenesis and molecular patterning of the blind gut in the sexual triclad Schmidtea polychroa. We identify and analyze the expression of goosecoid, commonly associated with the foregut, and the GATA, ParaHox and T-box genes, members of which commonly are associated with gut regionalization. We show that GATA456a is expressed in the blind gut of triclads, while GATA456b is localized in dorsal parenchymal cells. Goosecoid is expressed in the central nervous system, and the unique ParaHox gene identified, Xlox, is detected in association with the nervous system. We have not isolated any brachyury gene in the T-box complement of S. polychroa, which consists of one tbx1/10, three tbx2/3 and one tbx20. Furthermore, the absence of genes like brachyury and caudal is also present in other groups of Platyhelminthes. This study suggests that GATA456, in combination with foxA, is a gut-specific patterning mechanism conserved in the triclad S. polychroa, while the conserved gut-associated expression of foregut, midgut and hindgut markers is absent. Based on these data and the deviations in spiral cleavage found in more basal flatworms, we propose that the lack of an anus is an innovation of Platyhelminthes. This may be associated with loss of gut gene expression or even gene loss. PMID- 21295563 TI - Dorsal-ventral patterning: Crescent is a dorsally secreted Frizzled-related protein that competitively inhibits Tolloid proteases. AB - In Xenopus, dorsal-ventral (D-V) patterning can self-regulate after embryo bisection. This is mediated by an extracellular network of proteins secreted by the dorsal and ventral centers of the gastrula. Different proteins of similar activity can be secreted at these two poles, but under opposite transcriptional control. Here we show that Crescent, a dorsal protein, can compensate for the loss of Sizzled, a ventral protein. Crescent is a secreted Frizzled-Related Protein (sFRP) known to regulate Wnt8 and Wnt11 activity. We now find that Crescent also regulates the BMP pathway. Crescent expression was increased by the BMP antagonist Chordin and repressed by BMP4, while the opposite was true for Sizzled. Crescent knock-down increased the expression of BMP target genes, and synergized with Sizzled morpholinos. Thus, Crescent loss-of-function is compensated by increased expression of its ventral counterpart Sizzled. Crescent overexpression dorsalized whole embryos but not ventral half-embryos, indicating that Crescent requires a dorsal component to exert its anti-BMP activity. Crescent protein lost its dorsalizing activity in Chordin-depleted embryos. When co-injected, Crescent and Chordin proteins greatly synergized in the dorsalization of Xenopus embryos. The molecular mechanism of these phenotypes is explained by the ability of Crescent to inhibit Tolloid metalloproteinases, which normally degrade Chordin. Enzyme kinetic studies showed that Crescent was a competitive inhibitor of Tolloid activity, which bound to Tolloid/BMP1 with a K(D) of 11 nM. In sum, Crescent is a new component of the D-V pathway, which functions as the dorsal counterpart of Sizzled, through the regulation of chordinases of the Tolloid family. PMID- 21295564 TI - Siamois and Twin are redundant and essential in formation of the Spemann organizer. AB - The Spemann organizer is an essential signaling center in Xenopus germ layer patterning and axis formation. Organizer formation occurs in dorsal blastomeres receiving both maternal Wnt and zygotic Nodal signals. In response to stabilized betacatenin, dorsal blastomeres express the closely related transcriptional activators, Siamois (Sia) and Twin (Twn), members of the paired homeobox family. Sia and Twn induce organizer formation and expression of organizer-specific genes, including Goosecoid (Gsc). In spite of the similarity of Sia and Twn sequence and expression pattern, it is unclear whether these factors function equivalently in promoter binding and subsequent transcriptional activation, or if Sia and Twn are required for all aspects of organizer function. Here we report that Sia and Twn activate Gsc transcription by directly binding to a conserved P3 site within the Wnt-responsive proximal element of the Gsc promoter. Sia and Twn form homodimers and heterodimers by direct homeodomain interaction and dimer forms are indistinguishable in both DNA-binding and activation functions. Sequential chromatin immunoprecipitation reveals that the endogenous Gsc promoter can be occupied by either Sia or Twn homodimers or Sia-Twn heterodimers. Knockdown of Sia and Twn together, but not individually, results in a failure of organizer gene expression and a disruption of axis formation, consistent with a redundant role for Sia and Twn in organizer formation. Furthermore, simultaneous knockdown of Sia and Twn blocks axis induction in response to ectopic Wnt signaling, demonstrating an essential role for Sia and Twn in mediating the transcriptional response to the maternal Wnt pathway. The results demonstrate the functional redundancy of Sia and Twn and their essential role in direct transcriptional responses necessary for Spemann organizer formation. PMID- 21295565 TI - Calcium/NFAT signalling promotes early nephrogenesis. AB - A number of Wnt genes are expressed during, and are known to be essential for, early kidney development. It is typically assumed that their products will act through the canonical beta-catenin signalling pathway. We have found evidence that suggests canonical Wnt signalling is not active in the early nephrogenic metanephric mesenchyme, but instead provide expressional and functional evidence that implicates the non-canonical Calcium/NFAT Wnt signalling pathway in nephrogenesis. Members of the NFAT (Nuclear Factor Activated in T cells) transcription factor gene family are expressed throughout murine kidney morphogenesis and NFATc3 is localised to the developing nephrons. Treatment of kidney rudiments with Cyclosporin A (CSA), an inhibitor of Calcium/NFAT signalling, decreases nephron formation--a phenotype similar to that in Wnt4(-/-) embryos. Treatment of Wnt4(-/-) kidneys with Ionomycin, an activator of the pathway, partially rescues the phenotype. We propose that the non-canonical Calcium/NFAT Wnt signalling pathway plays an important role in early mammalian renal development and is required for complete MET during nephrogenesis, potentially acting downstream of Wnt4. PMID- 21295566 TI - Lineage analysis of micromere 4d, a super-phylotypic cell for Lophotrochozoa, in the leech Helobdella and the sludgeworm Tubifex. AB - The super-phylum Lophotrochozoa contains the plurality of extant animal phyla and exhibits a corresponding diversity of adult body plans. Moreover, in contrast to Ecdysozoa and Deuterostomia, most lophotrochozoans exhibit a conserved pattern of stereotyped early divisions called spiral cleavage. In particular, bilateral mesoderm in most lophotrochozoan species arises from the progeny of micromere 4d, which is assumed to be homologous with a similar cell in the embryo of the ancestral lophotrochozoan, more than 650 million years ago. Thus, distinguishing the conserved and diversified features of cell fates in the 4d lineage among modern spiralians is required to understand how lophotrochozoan diversity has evolved by changes in developmental processes. Here we analyze cell fates for the early progeny of the bilateral daughters (M teloblasts) of micromere 4d in the leech Helobdella sp. Austin, a clitellate annelid. We show that the first six progeny of the M teloblasts (em1-em6) contribute five different sets of progeny to non-segmental mesoderm, mainly in the head and in the lining of the digestive tract. The latter feature, associated with cells em1 and em2 in Helobdella, is seen with the M teloblast lineage in a second clitellate species, the sludgeworm Tubifex tubifex and, on the basis of previously published work, in the initial progeny of the M teloblast homologs in molluscan species, suggesting that it may be an ancestral feature of lophotrochozoan development. PMID- 21295567 TI - ENU-3 is a novel motor axon outgrowth and guidance protein in C. elegans. AB - During the development of the nervous system, the migration of many cells and axons is guided by extracellular molecules. These molecules bind to receptors at the tips of the growth cones of migrating axons and trigger intracellular signaling to steer the axons along the correct trajectories. We have identified a novel mutant, enu-3 (enhancer of Unc), that enhances the motor neuron axon outgrowth defects observed in strains of Caenorhabditis elegans that lack either the UNC-5 receptor or its ligand UNC-6/Netrin. Specifically, the double-mutant strains have enhanced axonal outgrowth defects mainly in DB4, DB5 and DB6 motor neurons. enu-3 single mutants have weak motor neuron axon migration defects. Both outgrowth defects of double mutants and axon migration defects of enu-3 mutants were rescued by expression of the H04D03.1 gene product. ENU-3/H04D03.1 encodes a novel predicted putative trans-membrane protein of 204 amino acids. It is a member of a family of highly homologous proteins of previously unknown function in the C. elegans genome. ENU-3 is expressed in the PVT interneuron and is weakly expressed in many cell bodies along the ventral cord, including those of the DA and DB motor neurons. We conclude that ENU-3 is a novel C. elegans protein that affects both motor axon outgrowth and guidance. PMID- 21295568 TI - JAK/STAT and the GATA factor Pannier control hemocyte maturation and differentiation in Drosophila. AB - The lymph gland is the major site of hematopoiesis in Drosophila. During late larval stages three types of hemocytes are produced, plasmatocytes, crystal cells, and lamellocytes, and their differentiation is tightly controlled by conserved factors and signaling pathways. JAK/STAT is one of these pathways which have essential roles in vertebrate and fly hematopoiesis. We show that Stat has opposing cell-autonomous and non-autonomous functions in hemocyte differentiation. Using a clonal approach we established that loss of Stat in a set of prohemocytes in the cortical zone induces plasmatocyte maturation in adjacent hemocytes. Hemocytes lacking Stat fail to differentiate into plasmatocytes, indicating that Stat positively and cell-autonomously controls plasmatocyte differentiation. We also identified the GATA factor pannier (pnr) as a downstream target of Stat. By analyzing the phenotypes resulting from clonal loss and over-expression of pnr in lymph glands, we find that Pnr is positively regulated by Stat and specifically required for the differentiation of plasmatocytes. Stat and Pnr represent two essential factors controlling blood cell maturation in the developing lymph gland and exert their functions both in a cell-autonomous and non-cell-autonomous manner. PMID- 21295569 TI - Retinotopy of visual projections to the optic tectum and pretectum in larval sea lamprey. AB - The sea lamprey has a complex life cycle with very different larval and adult stages. The eyes of larvae are subcutaneous, lack a differentiated lens and probably work only as an ocellus-like photoreceptor organ, while the well developed adult eyes are capable of forming images. The larval retina differs greatly from the adult retina and presents a central region with differentiated photoreceptors and a lateral, largely undifferentiated part that grows in the second half of larval life. In the present study, we examined the retinotopy of projections from larval ganglion cells to the optic tectum and pretectum in sea lamprey by using retrograde tract-tracing techniques. In most regions of the tectum, application of the tracer neurobiotin (NB) resulted in labelled ganglion cells in the lateral retina, mostly in the contralateral eye. Ganglion cells of the lateral retina showed a very simple dendritic tree, possibly because of the lack of differentiation of most retinal layers in this region. The retinotectal projection is already retinotopically organized in larvae and follows a pattern similar to that observed in adult lampreys and other vertebrates. Application of NB to the central region of the tectum also led to labelling of a few ganglion cells in the central retina, which were clearly more complex than those in the lateral region, as they had dendrites that branched both in the outer and inner plexiform layers. Application of NB to the medial pretectum led to labelling of ganglion cells in the contralateral central retina. Occasional cells were also labelled in the lateral retina. The differential organization of larval retinal projections to the pretectum and tectum suggests a different role for these projections, which is consistent with the different involvement of these centres in visual behaviour, as determined in adult lampreys. The observations in larvae also reveal very different developmental timetables for these putative functions. PMID- 21295570 TI - Phalloidin perturbs the interaction of human non-muscle myosin isoforms 2A and 2C1 with F-actin. AB - Phalloidin and fluorescently labeled phalloidin analogs are established reagents to stabilize and mark actin filaments for the investigation of acto-myosin interactions. In the present study, we employed transient and steady-state kinetic measurements as well as in vitro motility assays to show that phalloidin perturbs the productive interaction of human non-muscle myosin-2A and -2C1 with filamentous actin. Phalloidin binding to F-actin results in faster dissociation of the complex formed with non-muscle myosin-2A and -2C1, reduced actin-activated ATP turnover, and slower velocity of actin filaments in the in vitro motility assay. In contrast, phalloidin binding to F-actin does not affect the interaction with human non-muscle myosin isoform 2B and Dictyostelium myosin-2 and myosin-5b. PMID- 21295571 TI - Lipopolysaccharide inhibits transforming growth factor-beta1-stimulated Smad6 expression by inducing phosphorylation of the linker region of Smad3 through a TLR4-IRAK1-ERK1/2 pathway. AB - Smad6, one of the inhibitory Smads, plays an important role in transforming growth factor-beta1 (TGF-beta1)-mediated negative regulation of pro-inflammatory signaling. In this study, we found that bacterial endotoxin lipopolysaccharide (LPS) inhibits TGF-beta1-induced expression of Smad6 in RAW264.7 cells. This repression was accompanied by increased Smad3 linker phosphorylation at Thr-179 and Ser-208 and was dependent on ERK1/2 activity via the TLR4-IRAK1-linked signaling cascade. The expression of a mutant Smad3, that lacks the phosphorylation sites in the linker regions, significantly reversed the inhibitory effect of LPS on TGF-beta1-induced Smad6 expression and its anti inflammatory capacity. Collectively, our findings show how LPS pro-inflammatory signal antagonizes the anti-inflammatory activity of TGF-beta1. PMID- 21295572 TI - Ambient salinity modifies the action of triiodothyronine in the air-breathing fish Anabas testudineus Bloch: effects on mitochondria-rich cell distribution, osmotic and metabolic regulations. AB - The hydromineral and metabolic actions of thyroid hormone on osmotic acclimation in fish is less understood. We, therefore, studied the short-term action of triiodothyronine (T(3)), the potent thyroid hormone, on the distribution and the function of gill mitochondria-rich (MR) cells and on the whole body hydromineral and metabolic regulations of air-breathing fish (Anabas testudineus) adapted to either freshwater (FW) or acclimated to seawater (SA; 30 g L(-1)). As expected, 24 h T(3) injection (100 ng g(-1)) elevated (P<0.05) plasma T(3) but classically reduced (P<0.05) plasma T(4). The higher Na(+), K(+)-ATPase immunoreactivity and the varied distribution pattern of MR cells in the gills of T(3)-treated FW and SA fish, suggest an action of T(3) on gill MR cell migration, though the density of these cells remained unchanged after T(3) treatment. The ouabain-sensitive Na(+), K(+)-ATPase activity, a measure of hydromineral competence, showed increases (P<0.05) in the gills of both FW and SA fish after T(3) administration, but inhibited (P<0.05) in the kidney of the FW fish and not in the SA fish. Exogenous T(3) reduced glucose (P<0.05) and urea (P<0.05) in the plasma of FW fish, whereas these metabolites were elevated (P<0.05) in the SA fish, suggesting a modulatory effect of ambient salinity on the T(3)-driven metabolic actions. Our data identify gill MR cell as a target for T(3) action as it promotes the spatial distribution and the osmotic function of these cells in both fresh water and in seawater. The results besides confirming the metabolic and osmotic actions of T(3) in fish support the hypothesis that the differential actions of T(3) may be due to the direct influence of ambient salinity, a major environmental determinant that alters the osmotic and metabolic strategies of fish. PMID- 21295573 TI - Effects of crustacean cardioactive peptide on the hearts of two Orthopteran insects, and the demonstration of a Frank-Starling-like effect. AB - Like vertebrate cardiovascular systems, the dorsal vessel of the Orthopteran insects Baculum extradentatum and Locusta migratoria is under myogenic as well as neural control, through the action of neurotransmitters, neuromodulators and neurohormones. It was previously shown that the excitatory neuropeptide, crustacean cardioactive peptide (CCAP), triggers an increase in heart rate in B. extradentatum, and CCAP-like immunoreactivity is present in the innervation to the heart in many insects. In the present study, CCAP resulted in a dose dependent increase in heart rate and hemolymph flow velocity, or cardiac output, in B. extradentatum. In contrast, CCAP led to a significant increase in stroke volume and cardiac output in L. migratoria without modifying heart rate or aortic contraction frequency. Hemolymph flow through the excurrent ostia of L. migratoria, small openings or valves on the posterior aorta and anterior heart, was inhibited with increasing concentrations of CCAP, with complete inhibition seen at 10(-7) M CCAP. In the locust, CCAP increases the volume of hemolymph in the dorsal vessel by the synchronous closing of the excurrent ostia, resulting in more forceful heart contractions and increased stroke volume and cardiac output, without modifying heart rate through a physiological mechanism analogous to the Frank-Starling mechanism in vertebrates. Therefore, crustacean cardioactive peptide alters the contractile properties of cardiac tissue in both B. extradentatum and L. migratoria, allowing for an increase in blood flow and circulation. PMID- 21295574 TI - Hormonal response of nestlings to predator calls. AB - Chicks of altricial birds may perceive predation risk by acoustic cues produced by predators. This capacity involves changes to a less conspicuous behavior to avoid being detected and predated. However, little is known about the physiological mechanisms underlying this capacity. Potential mechanisms may involve corticosterone and testosterone, two hormones related to begging, an acoustic signal, which could be used by predators to locate and predate the nest. However, given the species-specificity of this relationship, it is difficult to make particular predictions. We manipulated perceived risk of nest predation in the common blackbird (Turdus merula) and analyzed nestlings' plasma levels of these hormones to look for nest predation risk effects. Our experimental manipulation showed hormonal changes in response to nest predation risk. Chicks under a high risk of nest predation reduced their corticosterone plasma levels but increased their testosterone levels in comparison with nestlings exposed to a low nest predation risk. We explain our results as mechanisms to reduce begging activity and discuss them within the framework of hormonal modifications in developing animals. These findings highlight the importance of studying nest predation from the unusually considered chick perspective and underlined the benefits from including physiological variables in the study of predator-prey interactions. PMID- 21295575 TI - Hormonal action of relaxin-like gonad-stimulating substance (GSS) on starfish ovaries in growing and fully grown states. AB - Gonad-stimulating substance (GSS) of starfish is the only known invertebrate peptide hormone responsible for final gamete maturation, rendering it functionally analogous to gonadotropins in vertebrates. Recently, we purified GSS from the radial nerves of the starfish Asterina pectinifera and identified the chemical structure as a relaxin-like peptide. This study examined the hormonal action of GSS on ovaries in the growing (stage IV) and fully grown states (stage V) of the starfish. The sensitivity of oocytes to 1-methyladenine (1-MeAde) as starfish maturation-inducing hormone was enhanced as oocytes enlarged in stage V. GSS-stimulated 1-MeAde production by ovarian follicle cells was also correlated with the size of oocytes. Although 1-MeAde production was observed in whole ovaries in stage V, GSS failed to induce 1-MeAde production in young ovaries (stage IV). This suggests that follicle cells in ovaries in a growing state (stage IV) are still unresponsive to the hormonal action of GSS. According to competitive experiments using radioiodinated and radioinert GSS, however, dissociation constant (K(d)) values and the number of binding sites for GSS were mostly constant in the ovaries from stages IV to V. These results strongly suggest that GSS receptors are expressed in follicle cells of ovaries in the growing state. The failure of GSS to induce 1-MeAde production in young ovaries may be due to the uncoupling of signal transduction from the receptor to 1-MeAde biosynthesis in follicle cells. PMID- 21295576 TI - Donepezil plus estradiol treatment enhances learning and delay-dependent memory performance by young ovariectomized rats with partial loss of septal cholinergic neurons. AB - Effects of estrogen therapy on cognitive performance appear to diminish with age and time following the loss of ovarian function. We hypothesize that this is due to a reduction in basal forebrain cholinergic function and that treatment with a cholinergic enhancer can reverse the effect. This study tested whether combining the cholinesterase inhibitor donepezil with estradiol treatment can enhance/restore estradiol effects on cognitive performance in young ovariectomized rats with selective lesions of septal cholinergic neurons. 192IgG saporin was injected directly into the medial septum to produce selective cholinergic lesions. Rats were then treated with donepezil (Don, daily injections of 3mg/kg/day, i.p.) or vehicle, and then with 17beta-estradiol (E2, administered by silastic capsule implanted s.c.) or an empty capsule. Rats were trained on a delayed matching-to-position (DMP) T-maze task which previous studies have shown is sensitive to ovariectomy and estrogen replacement. Results show that neither estradiol nor donepezil alone significantly enhanced acquisition of the DMP task in rats with cholinergic lesions. Combination therapy was effective, however, depending on the severity of the lesion. Don+E2 significantly enhanced acquisition of the task in rats with partial lesions (<50% loss of cholinergic neurons), but not in rats with severe lesions. This effect was due largely to a reduction in perseverative behavior. Don+E2 also improved working memory in rats with partial lesions, as evidenced by significantly better performance than controls during increased intertrial delays. These findings suggest that even partial loss of septal cholinergic neurons can reduce effects of estrogen therapy on cognitive performance, and demonstrate that combining a cholinesterase inhibitor with estrogen therapy can help to restore beneficial effects on performance. We propose that combination therapy may have similar beneficial effects in women, particularly in older women who have not used estrogen therapy for many years and are beginning to show signs of cognitive impairment or early Alzheimer's disease. PMID- 21295577 TI - Vasotocin neurons and septal V1a-like receptors potently modulate songbird flocking and responses to novelty. AB - Previous comparisons of territorial and gregarious finches (family Estrildidae) suggest the hypothesis that arginine vasotocin (VT) neurons in the medial bed nucleus of the stria terminalis (BSTm) and V(1a)-like receptors in the lateral septum (LS) promote flocking behavior. Consistent with this hypothesis, we now show that intraseptal infusions of a V(1a) antagonist in male zebra finches (Taeniopygia guttata) reduce gregariousness (preference for a group of 10 versus 2 conspecific males), but have no effect on the amount of time that subjects spend in close proximity to other birds ("contact time"). The antagonist also produces a profound increase in anxiety-like behavior, as exhibited by an increased latency to feed in a novelty-suppressed feeding test. Bilateral knockdown of VT production in the BSTm using LNA-modified antisense oligonucleotides likewise produces increases in anxiety-like behavior and a potent reduction in gregariousness, relative to subjects receiving scrambled oligonucleotides. The antisense oligonucleotides also produced a modest increase in contact time, irrespective of group size. Together, these combined experiments provide clear evidence that endogenous VT promotes preferences for larger flock sizes, and does so in a manner that is coupled to general anxiolysis. Given that homologous peptide circuitry of the BSTm-LS is found across all tetrapod vertebrate classes, these findings may be predictive for other highly gregarious species. PMID- 21295578 TI - The novel role of mast cells in the microenvironment of acute myocardial infarction. AB - Mast cells are multifunctional cells containing various mediators, such as cytokines, tryptase, and histamine, and they have been identified in infarct myocardium. Here, we elucidated the roles of mast cells in a myocardial infarction (MI) rat model. We studied the physiological and functional roles of mast cell granules (MCGs), isolated from rat peritoneal fluid, on endothelial cells, neonatal cardiomyocytes, and infarct heart (1-hour occlusion of left coronary artery followed by reperfusion). The number of mast cells had two peak time points of appearance in the infarct region at 1day and 21days after MI induction in rats (p<0.05 in each compared with sham-operated heart). Simultaneous injection of an optimal dose of MCGs modulated the microenvironment and resulted in the increased infiltration of macrophages and decreased apoptosis of cardiomyocytes without change in the mast cell number in infarct myocardium. Moreover, MCG injection attenuated the progression of MI through angiogenesis and preserved left ventricular function after MI. MCG-treated cardiomyocytes were more resistant to hypoxic injury through phosphorylation of Akt, and MCG-treated endothelial cells showed enhanced migration and tube formation. We have shown that MCGs have novel cardioprotective roles in MI via the prolonged survival of cardiomyocytes and the induction of angiogenesis. PMID- 21295579 TI - Affixin (beta-parvin) promotes cardioprotective signaling via STAT3 activation. AB - The focal adhesion protein affixin (beta-parvin) is highly expressed in the heart and is associated with the sarcomeric z-disc as well as the cell membrane. While affixin is known to be involved in cell adhesion and migration, its functional role in cardiomyocytes remains unclear. To gain insight into the function of affixin, we performed a yeast-two-hybrid-screen employing affixin as a bait. The signal transducer and activator of transcription 3 (STAT3) was detected as a binding partner of affixin. Overexpression of affixin in neonatal rat cardiomyocytes resulted in markedly enhanced STAT3 DNA binding activity and upregulation of STAT3-dependent genes. Moreover, upregulation of affixin led to cardiomyocyte hypertrophy with an increase in cell size and enhanced protein synthesis. Consistent with STAT3 activation, overexpression of affixin also protected cardiomyocytes from doxorubicin-induced apoptosis. Finally, HUVECs that were cultivated in medium from affixin-overexpressing cardiomyocytes responded with an increase in tubuli formation, in line with a proangiogenic effect of affixin. In conclusion, we demonstrate that affixin activates STAT3 in cardiomyocytes and promotes characteristic STAT3-related effects such as hypertrophy, protection against apoptosis, and angiogenesis. This novel pathway might therefore represent a target for cardioprotective strategies. PMID- 21295580 TI - Non-proteolytic functions of calpain-3 in sarcoplasmic reticulum in skeletal muscles. AB - Mutations in CAPN3/Capn3, which codes for skeletal muscle-specific calpain-3/p94 protease, are responsible for limb-girdle muscular dystrophy type 2A. Using "knock-in" (referred to as Capn3(CS/CS)) mice, in which the endogenous calpain-3 is replaced with a mutant calpain-3:C129S, which is a proteolytically inactive but structurally intact calpain-3, we demonstrated in our previous studies that loss of calpain-3 protease activity causes muscular dystrophy [Ojima, K. et al. (2010) J. Clin. Invest. 120, 2672-2683]. However, compared to Capn3-null (Capn3( /-)) mice, Capn3(CS/CS) mice showed less severe dystrophic symptoms. This suggests that calpain-3 also has a non-proteolytic function. This study aimed to elucidate the non-proteolytic functions of calpain-3 through comparison of Capn3(CS/CS) mice with Capn3(-/-) mice. We found that calpain-3 is a component of the sarcoplasmic reticulum (SR), and that calpain-3 interacts with, but does not proteolyze, typical SR components such as ryanodine receptor and calsequestrin. Furthermore, Capn3(CS/CS) mice showed that the nonenzymatic role of calpain-3 is required for proper Ca(2+) efflux from the SR to cytosol during muscle contraction. These results indicate that calpain-3 functions as a nonenzymatic element for the Ca(2+) efflux machinery in the SR, rather than as a protease. Thus, defects in the nonenzymatic function of calpain-3 must also be involved in the pathogenesis of limb-girdle muscular dystrophy type 2A. PMID- 21295581 TI - The N-terminal unstructured domain of yeast ODC functions as a transplantable and replaceable ubiquitin-independent degron. AB - Ornithine decarboxylase (ODC), a homodimeric enzyme with a rate-limiting function in polyamine biosynthesis, is subject to a feedback control involving its selective proteolysis. Targeting of ODC monomers to the proteasome is mediated by ODC antizyme (OAZ), the expression of which is induced by high levels of polyamines. Here, we report our analysis of the N-terminal degron in Saccharomyces cerevisiae ODC and the mechanism of its antizyme-dependent targeting. This ~45-residue domain of ODC [termed ODC degradation signal (ODS)] is essential for degradation of ODC. Extensive mutagenesis indicated that it is not a specific sequence within ODS that is important but, rather, its unstructured nature. Consistent with this conclusion, ODS could be functionally replaced by an unrelated unstructured domain. We show that increasing the distance of ODS to the rest of the ODC protein reduced the dependence on Oaz1 for targeting, indicating that exposure of ODS is critical for its function. Disruption of ODC dimers by introducing interface mutations, in contrast, was insufficient for targeting. Binding of Oaz1 to ODC monomers is thus required to activate ODS. Fusion of ODS to the N terminus of Ura3 was sufficient to convert it into a ubiquitin-independent substrate of the proteasome. By contrast, ODS failed to destabilize maltose-binding protein or dihydrofolate reductase, indicating that this degron only operates in an appropriate structural context that enables rapid unfolding. PMID- 21295582 TI - Features of Rhodobacter sphaeroides ChrR required for stimuli to promote the dissociation of sigma(E)/ChrR complexes. AB - In the photosynthetic bacterium Rhodobacter sphaeroides, a transcriptional response to the reactive oxygen species singlet oxygen ((1)O(2)) is mediated by ChrR, a zinc metalloprotein that binds to and inhibits the activity of the alternative sigma factor sigma(E). We provide evidence that (1)O(2) promotes the dissociation of sigma(E) from ChrR to activate transcription in vivo. To identify what is required for (1)O(2) to promote the dissociation of sigma(E)/ChrR complexes, we analyzed the in vivo properties of variant ChrR proteins with amino acid changes in conserved residues of the C-terminal cupin-like domain (ChrR CLD). We found that (1)O(2) was unable to promote the detectable dissociation of sigma(E)/ChrR complexes when the ChrR-CLD zinc ligands (His141, His143, Glu147, and His177) were substituted with alanine, even though individual substitutions caused a 2-fold to 10-fold decrease in zinc affinity for this domain relative to that for wild-type ChrR (K(d)~4.6*10(-)(10) M). We conclude that the side chains of these invariant residues play a crucial role in the response to (1)O(2). Additionally, we found that cells containing variant ChrR proteins with single amino acid substitutions at Cys187 or Cys189 exhibited sigma(E) activity similar to those containing wild-type ChrR when exposed to (1)O(2), suggesting that these thiol side chains are not required for (1)O(2) to induce sigma(E) activity in vivo. Finally, we found that the same aspects of R. sphaeroides ChrR needed for a response to (1)O(2) are required for the dissociation of sigma(E)/ChrR complexes in the presence of the organic hydroperoxide t-butyl hydroperoxide. PMID- 21295583 TI - Insights into substrate gating in H. influenzae rhomboid. AB - Rhomboids are a remarkable class of serine proteases that are embedded in lipid membranes. These membrane-bound enzymes play key roles in cellular signaling events, and disruptions in these events can result in numerous disease pathologies, including hereditary blindness, type 2 diabetes, Parkinson's disease, and epithelial cancers. Recent crystal structures of rhomboids from Escherichia coli have focused on how membrane-bound substrates gain access to a buried active site. In E. coli, it has been shown that movements of loop 5, with smaller movements in helix 5 and loop 4, act as substrate gate, facilitating inhibitor access to rhomboid catalytic residues. Herein we present a new structure of the Haemophilus influenzae rhomboid hiGlpG, which reveals disorder in loop 5, helix 5, and loop 4, indicating that, together, they represent mobile elements of the substrate gate. Substrate cleavage assays by hiGlpG with amino acid substitutions in these mobile regions demonstrate that the flexibilities of both loop 5 and helix 5 are important for access of the substrates to the catalytic residues. Mutagenesis indicates that less mobility by loop 4 is required for substrate cleavage. A reexamination of the reaction mechanism of rhomboid substrates, whereby cleavage of the scissile bond occurs on the si-face of the peptide bond, is discussed. PMID- 21295585 TI - The dinucleotide CG as a genomic signalling module. AB - The operon model proposed the existence of a category of proteins that control gene expression by interacting with specific DNA sequences. Since then, a large number of transcription factors recognizing a diversity of sequence motifs have been discovered. This article discusses an unusually short protein recognition sequence, 5'CG, which is read by multiple DNA binding proteins. CG exists in three distinct chemical states, two of which bind mutually exclusively to proteins that modulate chromatin structure. Non-methylated CG, which is highly concentrated at CpG island promoters, recruits enzymes that create the mark of promoter activity, trimethyl-lysine 4 of histone H3. Methylated CG, on the other hand, is a gene silencing mark and accordingly recruits enzymes that deacetylate histones. Thus, CG, despite its simplicity, has the properties of a genome-wide signalling module that adds a layer of positive or negative control over gene expression. PMID- 21295584 TI - HIV-1 integrase strand transfer inhibitors stabilize an integrase-single blunt ended DNA complex. AB - Integration of human immunodeficiency virus cDNA ends by integrase (IN) into host chromosomes involves a concerted integration mechanism. IN juxtaposes two DNA blunt ends to form the synaptic complex, which is the intermediate in the concerted integration pathway. The synaptic complex is inactivated by strand transfer inhibitors (STI) with IC(50) values of ~20 nM for inhibition of concerted integration. We detected a new nucleoprotein complex on a native agarose gel that was produced in the presence of >200 nM STI, termed the IN single DNA (ISD) complex. Two IN dimers appear to bind in a parallel fashion at the DNA terminus, producing an ~32-bp DNase I protective footprint. In the presence of raltegravir (RAL), MK-2048, and L-841,411, IN incorporated ~20-25% of the input blunt-ended DNA substrate into the stabilized ISD complex. Seven other STI also produced the ISD complex (<=5% of input DNA). The formation of the ISD complex was not dependent on 3'OH processing, and the DNA was predominantly blunt ended in the complex. The RAL-resistant IN mutant N155H weakly forms the ISD complex in the presence of RAL at ~25% level of wild-type IN. In contrast, MK 2048 and L-841,411 produced ~3-fold to 5-fold more ISD than RAL with N155H IN, which is susceptible to these two inhibitors. The results suggest that STI are slow-binding inhibitors and that the potency to form and stabilize the ISD complex is not always related to inhibition of concerted integration. Rather, the apparent binding and dissociation properties of each STI influenced the production of the ISD complex. PMID- 21295586 TI - Multiple barriers to recombination between divergent HIV-1 variants revealed by a dual-marker recombination assay. AB - Recombination is a major force for generating human immunodeficiency virus type 1 (HIV-1) diversity and produces numerous recombinants circulating in the human population. We previously established a cell-based system using green fluorescent protein gene (gfp) as a reporter to study the mechanisms of HIV-1 recombination. We now report an improved system capable of detecting recombination using authentic viral sequences. Frameshift mutations were introduced into the gag gene so that parental viruses do not express full-length Gag; however, recombination can generate a progeny virus that expresses a functional Gag. We demonstrate that this Gag reconstitution assay can be used to detect recombination between two group M HIV-1 variants of the same or of different subtypes. Using both gfp and gag assays, we found that, similar to group M viruses, group O viruses also recombine frequently. When recombination between a group M virus and a group O virus was examined, we found three distinct barriers for intergroup recombination. First, similar to recombination within group M viruses, intergroup recombination is affected by the identity of the dimerization initiation signal (DIS); variants with the same DIS recombined at a higher rate than those with different DIS. Second, using the gfp recombination assay, we showed that intergroup recombination occurs much less frequently than intragroup recombination, even though the gfp target sequence is identical in all viruses. Finally, Gag reconstitution between variants from different groups is further reduced compared with green fluorescent protein, indicating that sequence divergence interferes with recombination efficiency in the gag gene. Compared with identical sequences, we estimate that recombination rates are reduced by 3 fold and by 10- to 13-fold when the target regions in gag contain 91% and 72-73% sequence identities, respectively. These results show that there are at least three distinct mechanisms preventing exchange of genetic information between divergent HIV-1 variants from different groups. PMID- 21295587 TI - Structures of iron-dependent alcohol dehydrogenase 2 from Zymomonas mobilis ZM4 with and without NAD+ cofactor. AB - The ethanologenic bacterium Zymomonas mobilis ZM4 is of special interest because it has a high ethanol yield. This is made possible by the two alcohol dehydrogenases (ADHs) present in Z. mobilis ZM4 (zmADHs), which shift the equilibrium of the reaction toward the synthesis of ethanol. They are metal dependent enzymes: zinc for zmADH1 and iron for zmADH2. However, zmADH2 is inactivated by oxygen, thus implicating zmADH2 as the component of the cytosolic respiratory system in Z. mobilis. Here, we show crystal structures of zmADH2 in the form of an apo-enzyme and an NAD+-cofactor complex. The overall folding of the monomeric structure is very similar to those of other functionally related ADHs with structural variations around the probable substrate and NAD+ cofactor binding region. A dimeric structure is formed by the limited interactions between the two subunits with the bound NAD+ at the cleft formed along the domain interface. The catalytic iron ion binds near to the nicotinamide ring of NAD+, which is likely to restrict and locate the ethanol to the active site together with the oxidized Cys residue and several nonpolar bulky residues. The structures of the zmADH2 from the proficient ethanologenic bacterium Z. mobilis, with and without NAD+ cofactor, and modeling ethanol in the active site imply that there is a typical metal-dependent catalytic mechanism. PMID- 21295588 TI - Structural mechanism of ribonucleotide discrimination by a Y-family DNA polymerase. AB - The ability of DNA polymerases to differentiate between ribonucleotides and deoxribonucleotides is fundamental to the accurate replication and maintenance of an organism's genome. The active sites of Y-family DNA polymerases are highly solvent accessible, yet these enzymes still maintain a high selectivity towards deoxyribonucleotides. Here, we biochemically demonstrate that a single active site mutation (Y12A) in Dpo4, a model Y-family DNA polymerase, causes both a dramatic loss of ribonucleotide discrimination and a decrease in nucleotide incorporation efficiency. We also determined two ternary crystal structures of the Dpo4 Y12A mutant incorporating either dATP or ATP nucleotides opposite a template dT base. Interestingly, both dATP and ATP were hydrolyzed to dADP and ADP, respectively. In addition, the dADP and ADP molecules adopt a similar conformation and position at the polymerase active site to a ddADP molecule in the ternary crystal structure of wild-type Dpo4. The Y12A mutant loses stacking interactions with the deoxyribose of dNTP, which destabilizes the binding of incoming nucleotides. The mutation also opens a space to accommodate the 2'-OH group of the ribose of NTP in the polymerase active site. The structural change leads to the reduction in deoxynucleotide incorporation efficiency and allows ribonucleotide incorporation. PMID- 21295589 TI - Modeling the host response to inhalation anthrax. AB - Inhalation anthrax, an often fatal infection, is initiated by endospores of the bacterium Bacillus anthracis, which are introduced into the lung. To better understand the pathogenesis of an inhalation anthrax infection, we propose a two compartment mathematical model that takes into account the documented early events of such an infection. Anthrax spores, once inhaled, are readily taken up by alveolar phagocytes, which then migrate rather quickly out of the lung and into the thoracic/mediastinal lymph nodes. En route, these spores germinate to become vegetative bacteria. In the lymph nodes, the bacteria kill the host cells and are released into the extracellular environment where they can be disseminated into the blood stream and grow to a very high level, often resulting in the death of the infected person. Using this framework as the basis of our model, we explore the probability of survival of an infected individual. This is dependent on several factors, such as the rate of migration and germination events and treatment with antibiotics. PMID- 21295590 TI - The interaction energy of charged filaments in an electrolyte: Results for all filament spacings. AB - Electrically charged long-chain macromolecules in an electrolyte can form an ordered lattice whose spacing is greater than their diameter. If entropic effects are neglected, these nematic structures can be predicted from a balance of Coulomb repulsion and van-der-Waals attraction forces. To enhance the utility of such theories, this paper extends existing results for the interaction between charged filaments, and gives approximate formulae for the screened Coulomb and van-der-Waals potentials over the whole range of their centre-to-centre spacing d. The repulsive Coulomb potential is proportional to exp(-lambdad)/lambdad for all spacings when the Debye screening length 1/lambda is smaller than the sum of the filament radii. The attractive van-der-Waals potential is asymptotic to d-5 at large d. For smaller spacings, the potential is calculated by numerical integration and compared with published formulae: the series expansion of Brenner and McQuarrie converges too slowly, whereas the interpolation formula of Moisescu provides reasonable accuracy over the whole range of d. Combining these potentials shows that there is a finite range of charge densities for which a nematic crystal lattice is stable, but this conclusion ignores entropic effects associated with motile filaments. The role of electrostatic forces in aligning filaments and stabilizing a nematic liquid-crystal phase is discussed, in conjunction with other mechanisms such as motor proteins, crosslinkers or scaffolding structures. PMID- 21295591 TI - Shear induced adhesion: contact mechanics of biological spatula-like attachment devices. AB - Most biological hairy adhesive systems of insects, arachnids, and reptiles, involved in locomotion, rely not on flat punches on their tips, but rather on spatulate structures. Several hypotheses have been previously proposed to explain the functional importance of this particular contact geometry: (1) enhancement of adaptability to the rough substrate; (2) contact formation by shear force rather than by normal load; (3) increase in total peeling line due to the use of an array of multiple spatulae; (4) contact breakage by peeling off. In the present paper, we used numerical approach to study dynamics of spatulate tips during contact formation on rough substrates. The model clearly demonstrates that the contact area increases under applied shear force, especially when spatulae are misaligned prior to the contact formation. Applied shear force has an optimum describing the situation when maximal contact is formed but no slip occurs. At such equilibrium, maximal adhesion can be generated. This principle manifests the crucial role of spatulate terminal elements in biological fibrillar adhesion. PMID- 21295592 TI - Inferring the effect of therapy on tumors showing stochastic Gompertzian growth. AB - The present work deals with a Gompertz-type diffusion process, which includes in the drift term a time-dependent function C(t) representing the effect of a therapy able to modify the dynamics of the underlying process. However, in experimental studies is not immediate to deduce the functional form of C(t) from a treatment protocol. So a statistical approach is proposed in order to estimate this function when a control group and one or more treated groups are observed. In order to validate the proposed strategy a simulation study for several interesting functional forms of C(t) has been carried out. Finally, an application to infer the net effect of cisplatin and doxorubicin+cyclophosphamide in actual murine models is presented. PMID- 21295593 TI - The replicator dynamics with n players and population structure. AB - The well-known replicator dynamics is usually applied to 2-player games and random matching. Here we allow for games with n players, and for population structures other than random matching. This more general application leads to a version of the replicator dynamics of which the standard 2-player, well-mixed version is a special case, and which allows us to explore the dynamic implications of population structure. The replicator dynamics also allows for a reformulation of the central theorem in Van Veelen (2009), which claims that inclusive fitness gives the correct prediction for games with generalized equal gains from switching (or, in other words, when fitness effects are additive). If we furthermore also assume that relatedness is constant during selection - which is a reasonable assumption in a setting with kin recognition - then inclusive fitness even becomes a parameter that determines the speed as well as the direction of selection. For games with unequal gains from switching, inclusive fitness can give the wrong prediction. With equal gains however, not only the sign, but also even the value of inclusive fitness becomes meaningful. PMID- 21295594 TI - Stochastic continuous time neurite branching models with tree and segment dependent rates. AB - In this paper we introduce a continuous time stochastic neurite branching model closely related to the discrete time stochastic BES-model. The discrete time BES model is underlying current attempts to simulate cortical development, but is difficult to analyze. The new continuous time formulation facilitates analytical treatment thus allowing us to examine the structure of the model more closely. We derive explicit expressions for the time dependent probabilities p(gamma,t) for finding a tree gamma at time t, valid for arbitrary continuous time branching models with tree and segment dependent branching rates. We show, for the specific case of the continuous time BES-model, that as expected from our model formulation, the sums needed to evaluate expectation values of functions of the terminal segment number MU(f(n),t) do not depend on the distribution of the total branching probability over the terminal segments. In addition, we derive a system of differential equations for the probabilities p(n,t) of finding n terminal segments at time t. For the continuous BES-model, this system of differential equations gives direct numerical access to functions only depending on the number of terminal segments, and we use this to evaluate the development of the mean and standard deviation of the number of terminal segments at a time t. For comparison we discuss two cases where mean and variance of the number of terminal segments are exactly solvable. Then we discuss the numerical evaluation of the S dependence of the solutions for the continuous time BES-model. The numerical results show clearly that higher S values, i.e. values such that more proximal terminal segments have higher branching rates than more distal terminal segments, lead to more symmetrical trees as measured by three tree symmetry indicators. PMID- 21295595 TI - A powerful truncated tail strength method for testing multiple null hypotheses in one dataset. AB - In microarray analysis, medical imaging analysis and functional magnetic resonance imaging, we often need to test an overall null hypothesis involving a large number of single hypotheses (usually larger than 1000) in one dataset. A tail strength statistic (Taylor and Tibshirani, 2006) and Fisher's probability method are useful and can be applied to measure an overall significance for a large set of independent single hypothesis tests with the overall null hypothesis assuming that all single hypotheses are true. In this paper we propose a new method that improves the tail strength statistic by considering only the values whose corresponding p-values are less than some pre-specified cutoff. We call it truncated tail strength statistic. We illustrate our method using a simulation study and two genome-wide datasets by chromosome. Our method not only controls type one error rate quite well, but also has significantly higher power than the tail strength method and Fisher's method in most cases. PMID- 21295596 TI - A mathematical model on fractional Lotka-Volterra equations. AB - The article presents the solutions of Lotka-Volterra equations of fractional order time derivatives with the help of analytical method of nonlinear problem called the homotopy perturbation method (HPM). By using initial values, the explicit solutions of predator and prey populations for different particular cases have been derived. The numerical solutions show that only a few iterations are needed to obtain accurate approximate solutions. The method performs extremely well in terms of efficiency and simplicity to solve this historical biological model. PMID- 21295597 TI - On the dynamics of predation risk perception for a vigilant forager. AB - Foraging animals often raise their head to scan for predators. Scanning intervals have variable durations, and occur more or less frequently, depending on ecological conditions. Our study relies on the assumption that temporal patterns of vigilance depend on the speed with which information concerning the likelihood of a predator's presence in the neighbourhood is gathered when an animal is vigilant, and lost when it is not. Using an analytical model, we study how the perceived level of risk progressively decreases, when the individual is vigilant and detects no predator, then increases again, when it lowers its head to feed, thereby losing most of its detection abilities. The speed of these variations is affected by the likelihood of the presence of a predator in the whole environment, by the mobility of this predator, and by the detection capacities of the prey. We show how, combined with the range of risk levels tolerated by this animal, this dynamics determines the frequency and the duration of its scanning intervals. The dynamics of risk perception can also explain particular behavioural patterns, such as the progressive decrease of vigilance that may occur after the arrival into a novel environment, and the central tendency in the distribution of interscan durations reported by many studies. Next, we use the model to compute optimal vigilance strategies, taking into account the trade-off between feeding and limiting exposure to predators. The model predicts that a forager will scan more often, and for longer periods, when the likelihood of a predator's presence in the surrounding environment is increased. A similar response is expected when the mobility of the predator is increased. By contrast, when the detection capacities of the prey are reduced, it will increase its vigilance by scanning for longer periods, but scanning intervals will be separated by longer interscans. PMID- 21295598 TI - Calcium dynamics in dendritic spines: a link to structural plasticity. AB - Calcium signals evoked either by action potential or by synaptic activity play a crucial role for the synaptic plasticity within an individual spine. Because of the small size of spine and the indicators commonly used to measure spine calcium activity, calcium function can be severely disrupted. Therefore, it is very difficult to explain the exact relationship between spine geometry and spine calcium dynamics. Recently, it has been suggested that the medium range of calcium which induces long term potentiation leads to the structural stability stage of spines, while very low or very high amount of calcium leads to the long term depression stage which results in shortening and eventually pruning of spines. Here we propose a physiologically realistic computational model to examine the role of calcium and the mechanisms that govern its regulation in the spine morphology. Calcium enters into spine head through NMDA and AMPA channels and is regulated by internal stores. Contribution of this calcium in the induction of long term potentiation and long term depression is also discussed. Further it has also been predicted that the presence of internal stores depletes the total calcium accumulation in cytosol which is in agreement with the recent experimental and theoretical studies. PMID- 21295599 TI - Effects of arm-cranking exercise in cutaneous microcirculation in older, sedentary people. AB - OBJECTIVES: Microvascular integrity is compromised by several diseases and conditions as well as age. Exercise can reverse these effects but it is unclear whether these are systemic or localised, or which mechanisms are responsible for observed improvements Therefore, the primary objective of this study was to assess whether arm-cranking exercise had a systemic or localised cutaneous, microcirculatory effect in an older, healthy population and compare these findings with our previous work on patients with chronic venous disease. A secondary objective was to see if improvements were greater in the lower- or in the upper-limb. METHODS: Endothelial-dependent- and independent-vasodilation were assessed on the forearm and the perimalleolar region in 14 older (59+/-4.5years), sedentary, healthy participants using LDF and incremental doses of acetylcholine (ACh) and sodium nitroprusside (SNP), before and after a session of arm-cranking exercise. Cutaneous blood flux data were expressed as cutaneous vascular conductance (CVC). RESULTS: Endothelial-dependent vasodilation increased both in the upper- (p=0.04, d=0.59) and lower-limb (p=0.03, d=0.52), after exercise. Endothelial-independent vasodilation did not change either in the lower- and upper-limb (p>0.05 on both occasions). "Between-limbs" comparison showed that pre exercise differences between the forearm and the lower-leg (p=0.04, d=0.47) disappeared after ACh-induced vasodilation, following arm-cranking exercise (p>0.05). Conversely, SNP-induced did not change. CONCLUSION: Our results suggest that in a healthy, sedentary population (and in contrast to post-surgical varicose vein patients), acute arm-cranking exercise leads to an improvement of microvascular endothelial function in the extremities. PMID- 21295600 TI - A novel synthetic approach to (20R)- and (20S)-21-hydroxy steroids. Synthesis of a marine sterol 21-hydroxycholesterol. AB - A short and efficient synthesis of steroid synthons, di(tert-butyldimethylsilyl) ethers of 3,21-dihydroxy-24-nor-chol-5-en-23-al (8 and 10) and of ethyl 3,21 dihydroxy-25-homo-chola-5,23-dien-25-oate (9 and 11), having natural (20R) and unnatural (20S) configuration from 3beta-(tert-butyldimethylsilyloxy) 14alpha,20xi-card-5-enolide (2) is reported. Further elongation of the side chain of these synthons provides a new method for the synthesis of (20R) and (20S)-21 hydroxy steroids. The utility of the method was exemplified by the synthesis of a natural marine sterol - 21-hydroxycholesterol (18). PMID- 21295601 TI - Steroidogenic enzyme gene expression profiles in the testis of cattle treated with illicit growth promoters. AB - Recently, the effect of illicit growth promoters (GPs) upon the cattle transcriptome has drawn the increasing attention of the scientific community. In the present study, the pre-transcriptional effects of three different illicit protocols on a set of target genes, including steroidogenic enzymes and three related transcription factors, were estimated in cattle testis. Beef cattle were administered with dexamethasone (DEX) orally (group D(1)) or intramuscularly in experiment 1 (group DIM). In experiment 2, DEX was orally administered alone (group D(2)) or with 17beta-estradiol (group DE), and in experiment 3, dehydroepiandrosterone and boldione were orally administered alone (group DHEA and group ADD) or in combination (group DHAD). The GP effects were measured by quantitative real time RT-PCR. The results of our study were significant but not univocal. A GP-dependent effect on target gene mRNA levels was noticed for 3beta hydroxysteroid dehydrogenase type 1 (HSD3beta1,p<0.05 and p<0.01 for the D(2), DE and DHAD groups, respectively), the cytochrome P450 side chain cleavage (DHAD, p<0.05), the cytochrome P450 17A1 (DIM and D(2), p<0.05), HSD17beta3 (DE, p<0.05), aromatase (DHEA, p<0.05), the androgen receptor (DHAD, p<0.05) and the mineralocorticoid receptor-like (DIM, p<0.05). Our present results suggest that different GP schedules are likely to affect genes involved in steroid synthesis and regulation in cattle testis. Thus, this tissue might be considered a potential surrogate tissue that warrants further study into its usefulness in the screening of GP abuse. PMID- 21295602 TI - Altered methanol embryopathies in embryo culture with mutant catalase-deficient mice and transgenic mice expressing human catalase. AB - The mechanisms underlying the teratogenicity of methanol (MeOH) in rodents, unlike its acute toxicity in humans, are unclear, but may involve reactive oxygen species (ROS). Embryonic catalase, although expressed at about 5% of maternal activity, may protect the embryo by detoxifying ROS. This hypothesis was investigated in whole embryo culture to remove confounding maternal factors, including metabolism of MeOH by maternal catalase. C57BL/6 (C57) mouse embryos expressing human catalase (hCat) or their wild-type (C57 WT) controls, and C3Ga.Cg-Catb/J acatalasemic (aCat) mouse embryos or their wild-type C3HeB/FeJ (C3H WT) controls, were explanted on gestational day (GD) 9 (plug=GD 1), exposed for 24 h to 4 mg/ml MeOH or vehicle, and evaluated for functional and morphological changes. hCat and C57 WT vehicle-exposed embryos developed normally. MeOH was embryopathic in C57 WT embryos, evidenced by decreases in anterior neuropore closure, somites developed and turning, whereas hCat embryos were protected. Vehicle-exposed aCat mouse embryos had lower yolk sac diameters compared to C3H WT controls, suggesting that endogenous ROS are embryopathic. MeOH was more embryopathic in aCat embryos than WT controls, with reduced anterior neuropore closure and head length only in catalase-deficient embryos. These data suggest that ROS may be involved in the embryopathic mechanism of methanol, and that embryonic catalase activity may be a determinant of teratological risk. PMID- 21295603 TI - Mycobacterium tuberculosis mtrA merodiploid strains with point mutations in the signal-receiving domain of MtrA exhibit growth defects in nutrient broth. AB - The genetic and biochemical aspects of the essential Mycobacteriumtuberculosis MtrAB two-component regulatory signal transduction (2CRS) system have not been extensively investigated. We show by bacterial two-hybrid assay that the response regulator (RR) MtrA and the sensor kinase MtrB interact. We further demonstrate that divalent metal ions [Mg2+, Ca2+ or both] promote MtrB kinase autophosphorylation activity, but only Mg2+ promotes phosphotransfer to MtrA. Replacement of the conserved aspartic acid residues at positions 13 and 56 with alanine (D13A), glutamine (D56E) or asparagine (D56N) prevented MtrA phosphorylation, indicating that these residues are important for phosphorylation. The MtrA(D56E) and MtrA(D13A) proteins bound to the promoter of fbpB, the gene encoding antigen 85B protein, efficiently in the absence of phosphorylation, whereas MtrA(D56N) did not. We also show that M.tuberculosismtrA merodiploids overproducing MtrA(D13A), unlike cells overproducing wild-type MtrA, grow poorly in nutrient broth and show reduced expression of fbpB. These latter findings are reminiscent of a phenotype associated with MtrA overproduction during intramacrophage growth. Our results suggest that MtrA(D13A) behaves like a constitutively active response regulator and that further characterization of mtrA merodiploid strains will provide valuable clues to the MtrAB system. PMID- 21295604 TI - Effect of immunomodulatory therapies in patients with pandemic influenza A (H1N1) 2009 complicated by pneumonia. AB - OBJECTIVE: To determine the effect of immunomodulatory therapies on the development of severe disease in hospitalized adults with laboratory-confirmed pandemic influenza A (H1N1) 2009 complicated by pneumonia. METHODS: Observational, prospective cohort study at thirteen tertiary hospitals in Spain. The use of corticosteroids, macrolides and statins was recorded. The outcome of interest was severe disease, defined as the composite of intensive care unit admission or death after the first day of hospitalization. RESULTS: Of the 197 patients with pandemic influenza A (H1N1) 2009 complicated by pneumonia, 68 (34.5%) received some anti-inflammatory therapy since hospital admission (corticosteroids in 37, macrolides in 31 and statins in 12). Severe disease occurred in 29 (14.7%) patients. After adjustment for confounding factors, immunomodulatory therapies as a group were not associated with a lower risk for developing severe disease (odds ratio [OR] 0.64; 95% confidence interval [CI] 0.22-1.86). In a further a priori analysis, corticosteroids, macrolides and statins were included in a multivariate model. None of these therapies was found to be associated with a lower risk for developing severe disease. CONCLUSIONS: Immunomodulatory therapies use since hospital admission did not prevent the development of severe disease in adults with pandemic influenza A (H1N1) 2009 complicated by pneumonia. PMID- 21295605 TI - Validating the use of M4-BAC-GFP mice as tissue donors in cell replacement therapies in a rodent model of Huntington's disease. AB - Huntington's disease (HD) is a neurodegenerative disease with currently only symptomatic treatment. Cell-based therapy, aiming at replacing the lost medium spiny neurons (MSN) with primary fetal striatal cells, has had some success at modifying the symptoms both in experimental studies and clinical trials. Additional pre-clinical studies are required to optimise transplantation protocols and conditions, learn about the limits of circuit reconstruction and functional recovery, and test alternative cell sources. Transgenic mice with integrated bacterial artificial chromosome (BAC) expressing the green fluorescent protein (GFP) can be used to study specific neuronal projections. The BAC transgenic line used in this study, with the GFP expression under the control of the muscarinic receptor M4 promoter, selectively expressed the reporter gene in the direct efferent pathway of the MSN projecting from the striatum to the substantia nigra pars reticulata and the entopeduncular nucleus, the rodent equivalent of the internal segment of the globus pallidus. The current work was designed to validate the use of M4-BAC-GFP mice as tissue donors in cell-based therapy in a rodent model of HD by examining the effect of the transplantation procedure on the GFP expression; the feasibility of identifying the GFP expression in vivo after different time points; and the survival and integration of the transgenic striatal tissue transplant up to 6 months in the host. The data confirm that embryonic striatal tissue from the M4-BAC-GFP mice survives, stably expresses GFP, and thus represents a powerful novel way to study graft-host interaction in this animal model neurodegeneration. PMID- 21295606 TI - Development of optimal liquid based cytology sample processing methods for HPV testing: minimising the 'inadequate' test result. AB - Incorporation of HPV testing into cervical screening is anticipated and robust methods for DNA extraction from liquid based cytology (LBC) samples are required. This study compared QIAamp extraction with Proteinase K digestion and developed methods to address DNA extraction failure (beta-globin PCR negative) from clinical specimens. Proteinase K and QIAamp extraction methods in paired LBC samples were comparable with adequate DNA retrieved from 93.3% of clinical specimens. An HPV prevalence cohort (n=10,000) found 7% (n=676) LBC samples tested negative for beta-globin, and were classified as inadequate. This 'failure' rate is unsuitable for population screening, particularly as the sampling method is intrusive. 379/676 samples were assessed to determine the cause of test failure. Re-testing confirmed adequate DNA in 21.6% of the original extracts; re-extraction from stored material identified 56.2% samples contained adequate material; dilution to overcome sample inhibition (1:10) resolved 51.7% cases in original extracts and 28% in new extracts. A standardised approach to HPV testing with an optimal DNA concentration input rather than standard volume input is recommended. Samples failing initial DNA extraction should be repeat extracted and assessed for sample inhibition to reduce the 7% of HPV tests being reported as inadequate and reduce the need for retesting of those women to <1%. PMID- 21295607 TI - Evaluation of the RIDA((r))QUICK immunochromatographic norovirus detection assay using specimens from Australian gastroenteritis incidents. AB - A range of laboratory methods is now available for the detection of norovirus, a major cause of gastroenteritis. Recently, a commercial immunochromatographic assay for norovirus detection, the RIDA((r))QUICK assay, has become available, but there is still only limited information on its efficacy. This study examined the sensitivity and specificity of the RIDA((r))QUICK assay, using faecal material received for testing in a major diagnostic/reference laboratory in Australia. The sensitivity of the assay was found to be 83% and the specificity was 100%. No false positive norovirus results were found and the assay did not cross-react with common faecal viruses such as rotavirus, astrovirus, sapovirus and adenovirus. The assay was less reliable for genogroup I (GI) noroviruses than for genogroup II (GII) noroviruses. Genotypes detected by the assay included GII.1, GII.2, GII.3, GII.4, GII.6 and GII.7. The assay failed to detect any GI specimens in the test group. Genotypes not detected included GI.4 and GI.6. The assay was simple and quick to perform. It is valuable in a point-of-care situation or as a backup in a laboratory where a rapid initial norovirus result is required. PMID- 21295608 TI - PEG-modulated column chromatography for purification of recombinant adeno associated virus serotype 9. AB - Column chromatography has been described for purification of recombinant adeno associated viral vectors (rAAV) serotypes 1, 2, 5, 6 and 8. Some of these purification processes have been used in manufacturing pre-clinical grade and clinical grade rAAV vectors. Recently, recombinant AAV9 has been reported to be highly efficient in transducing cardiac muscle in animal models. Systemic or cardiac gene delivery and other applications may require large quantities of rAAV9 vectors, thus a scalable method supporting large scale purification of rAAV9 is needed for clinical development. However, column chromatography-based purification has not been reported to date for rAAV9. This study reports a polyethylene glycol (PEG) modulated chromatography process for purification of AAV9 vectors. Inclusion of PEG in chromatography buffers modulated rAAV9 elution profiles in a manner that resulted in significantly improved resin binding capacity, vector purity and yield. PEG-modulated methods were developed and optimized for hydroxyapatite and ion exchange chromatography, and shown to result in vectors of high purity and functional activity. PMID- 21295609 TI - Diagnostic performance and application of two commercial cell viability assays in foot-and-mouth disease research. AB - Cell-based assays are still used widely in foot-and-mouth disease (FMD) research, despite the existence of a wide variety of molecular techniques. The aim of this study was to validate an automated, quantitative spectrometric reading to replace the time-consuming and subjective microscopic (MIC) evaluation of the FMD virus induced cytopathic effect (CPE). Therefore, the diagnostic performance of two commercial cell viability assays (CellTiter 96((r)) AQueous One Solution Cell Proliferation Assay (MTS) and CellTiter-Blue((r)) Cell Viability Assay (CTB), both from Promega, Leiden, The Netherlands) was evaluated. Following optimization of the assay protocols and using the MIC results as a reference standard, the absorbance-read MTS assay, the fluorescence-read CTB assay and the absorbance read CTB (CTB(abs)) assay demonstrated similar high sensitivities (97%, 99% and 98%, respectively), specificities (100%, 98% and 99%, respectively), accuracy measures (0.99, 0.98 and 0.98, respectively), precision measures (1.00, 0.98 and 0.99, respectively) and Cohen kappa agreement indices (0.97, 0.97 and 0.96, respectively) for detecting CPE in cell cultures. Due to its performance, cost effectiveness and ease of use, the CTB(abs) assay was selected for further evaluation of its ability to detect virus neutralization and to screen antiviral compounds. The CTB(abs) assay had 99% sensitivity and 100% specificity for the detection of neutralizing antibodies in sera from cattle infected with FMDV and in sera from unvaccinated, uninfected cattle and resulted in a mean Z'-factor of 0.85 for antiviral compound test plates. The CTB(abs) assay is now used routinely in the Belgian FMD reference laboratory for serological testing and high throughput antiviral compound screening. PMID- 21295610 TI - Importance of the cutoff ratio for detecting antibodies against hepatitis A virus in oral fluids by enzyme immunoassay. AB - Multiple studies have examined the use of oral fluids in modified serum-based assays aiming to replace serum in antibody detection for hepatitis A. However, the reliable detection of HAV immunity in oral fluid requires an extremely sensitive assay; most immunoassays designed for serum antibody determination lack sufficient sensitivity for this purpose. Consequently, an "in-house" competitive enzyme immunoassay (EIA) designed specifically for use with oral samples collected using a ChemBio((r)) device was developed to detect total anti-HAV antibodies (IgG and IgM). This system was compared to an in-house competitive EIA and a commercial EIA considered to be the "gold standard" using corresponding serum samples (n=225) to determine the accuracy of the assay and to evaluate the importance of the cutoff ratio for the detection of anti-HAV antibodies in oral fluids. When the median serum cutoff and the optimal oral fluid cutoff (ROC analysis) obtained from the in-house competitive EIA were compared, the oral fluid cutoff was found to be 28.8% higher than the serum cutoff. When different oral fluid cutoff values were compared, a reduction of about 17% was shown to be essential to increase test accuracy. At an oral fluid cutoff value of 0.351, sensitivity and specificity were higher, reaching 91.7% and 86.2% (p<0.001, AUROC=0.915), respectively. The convenience, accuracy and non-invasive nature of the developed method make it a useful alternative to serum-based assays for discriminating between HAV-immune and non-immune individuals. PMID- 21295611 TI - Reverse genetics plasmid for cloning unstable influenza A virus gene segments. AB - Reverse genetics approaches that enable the generation of recombinant influenza A viruses entirely from plasmids are invaluable for studies on virus replication, morphogenesis, pathogenesis, or transmission. Furthermore, influenza virus reverse genetics is now critical for the development of new vaccines for this human and animal pathogen. Periodically, influenza gene segments are unstable within plasmids in bacteria. The PB2 gene segment of a highly pathogenic avian H5 influenza virus A/Turkey/Ontario/7732/1966 (Ty/Ont) was unstable in commonly available cloning plasmids (e.g., pcDNA3.1/V5-His-TOPO) and in standard influenza virus reverse genetics plasmids (e.g., pHH21), which contain high copy origins of replication. Thus, a low-copy influenza reverse genetics plasmid (pGJ3C3) was developed to enable rapid cloning of unstable influenza A virus genes using ligation-independent recombination-based cloning. The unstable Ty/Ont PB2 gene segment was efficiently cloned using the pGJ3C3 plasmid and this clone was used to rescue a recombinant Ty/Ont virus. This low copy reverse genetics plasmid will be useful for cloning other unstable segments of influenza A viruses in order to rescue recombinant viruses, which will facilitate basic studies and vaccine seed stock production. PMID- 21295612 TI - An oligonucleotide-based microarray for detection of plant RNA viruses. AB - Currently, some of the methods used most widely for diagnosis and detection of plant viruses are ELISA, PCR, bioassays and electron microscopy. These methods only target one or a few species in each assay or they are time consuming and require expertise. Microarray-based approaches offer an alternative to these methods as microarrays with virus-specific probes could be capable of detecting an almost unlimited number of virus species in one assay. In the present study, the feasibility of this strategy was studied by constructing a microarray with 150 probes potentially capable of detecting 52 viruses from a broad range of genera. The array was printed in 16 subarrays to allow testing of several samples on each slide. Hybridizations with cDNA from plants infected with 52 different virus species showed that out of the 52 species tested, 49 were positive and identified correctly to species level. This array represents the largest published microarray for plant virus detection in terms of the number of targeted species and is thus an important milestone towards the construction of a generic microarray able to detect most, if not all, plant RNA viruses. PMID- 21295613 TI - Distribution of Human papillomavirus load in clinical specimens. AB - The information about the range and distribution of Human papillomavirus load in clinical specimens is important for the design of accurate clinical tests. The amount of Human papillomavirus in cervical specimens was estimated using the digene HC2 HPV DNA Test((r)) (QIAGEN). This semi-quantitative assay is based on linear signal amplification with an analytical limit-of-detection of approximately 2500 virus copies per assay and 3-4 log dynamic range. The dynamic range of the assay was extended by a serial dilution strategy. Two large sets of positive specimens (n=501 and 569) were analyzed and 9-11% of specimens was estimated to contain more than 7 * 10(7) copies of virus. The viral load was also assessed for an assortment of specimens with known cytology diagnoses (n=9435) and histological diagnoses (n=2056). The percentage of specimens with more than 7 * 10(7) copies of virus was estimated to be 0.89 for normal cells, 4.2 for atypical cells (unknown significance), 14.31 for cells of low-grade lesions and 22.24 for cells of high-grade lesions. The viral load increased with disease severity, but its broad distribution may not support its use as a disease biomarker. This information is important for assay design and automation, where cross-reactivity and sample-to-sample contamination must be addressed rigorously. PMID- 21295614 TI - Detection, characterization and quantitation of coxsackievirus A16 using polyclonal antibodies against recombinant capsid subunit proteins. AB - Coxsackievirus A16 (CVA16), together with enterovirus type 71 (EV71), is responsible for most cases of hand, foot and mouth disease (HFMD) worldwide. Recent findings suggest that the recombination between CVA16 and EV71, and co circulation of these two viruses may have contributed to the increase of HFMD cases in China over the past few years. Thus, for CVA16, further understanding of its virology, epidemiology and development of diagnostic tests and vaccines are of importance. The present study aimed to develop reagents and protocols for the detection, characterization and quantitation of CVA16. Recombinant CVA16 capsid subunit proteins VP0, VP3 and truncated VP1, were produced in Escherichia coli and used to immunize guinea pigs to generate polyclonal antibodies. The resultant three antisera detected specifically CVA16 propagated in Vero cells by immunostaining, ELISA and Western blotting. The antisera was used to show that CVA16 capsids were composed of correctly processed VP0, VP1 and VP3 subunits, and were present in the form of efficiently assembled particles. A method for the quantitation of the yield of CVA16 in Vero cells was established based on a Western blotting protocol using the recombinant VP0 as a reference standard and anti-VP0 as the detection antibody. This study shows the development and validation of reagents and methods, for qualitative and quantitative determination of CVA16, which are essential for the development of vaccines. PMID- 21295615 TI - A non-invasive intranasal inoculation technique using isoflurane anesthesia to infect the brain of mice with rabies virus. AB - Methods for intranasal inoculation of viruses are often described poorly and the effects of variations in the technique on the outcome are unknown. Standardization of protocols is key to compare studies and minimize animal use. The clinical and virological outcome of infection with rabies virus (genotypes 1 and 5) upon administration of different inoculum volumes (25, 50 and 100MUl) and different anesthetic regimens were examined. Administration of 25MUl of virus as a drop on both nostrils under brief superficial isoflurane anesthesia (92MUl/dm(3), recovery after 85 +/- 1 0s) was the most effective to infect the brain and induced 100% lethal infection 9 days later. Increasing the inoculum volume reduced infectivity significantly, with decreased viral loads in the brain and only 40% mortality. Increasing the depth of isoflurane anesthesia (230MUl/dm(3)) improved the infectivity of the large-volume inoculum (90% mortality), probably because of suppression of swallow and sneeze reflexes. Compared to isoflurane anesthesia, xylazine-ketamine anesthesia reduced the infectivity of the inoculum significantly. Thus, administration of a small volume of virus on the nostrils under brief gas anesthesia is a safe and reproducible technique to induce infection of the brain. Since needles are not required, this helps to preserve the integrity of the physical barriers, animal welfare and the manipulator's safety. PMID- 21295616 TI - Acetylcholine: future research and perspectives. AB - Ever since the initial description of chemical transmission in the early part of the 20th century and the identification of acetylcholine (ACh) as the first such transmitter, interests grew to define the multiple facets of its functions. This multitude is only partially covered here, but even in the areas preselected for this special issue, research on the cholinergic system is still thriving. Notwithstanding an impressive amount of knowledge that has been accumulated, partly triggered by the cholinergic hypothesis of Alzheimer's disease (AD [1]), the different reviews in this issue not only summarise our current state of the art, they also highlight that this field has still large potential for future development. Taken from these reviews, we here pinpoint several topics fit for future attention. PMID- 21295617 TI - Apomorphine locomotor sensitization can be potentiated by environmental change: evidence for a non-Pavlovian associative behavioral contrast factor in sensitization expression. AB - We investigated environmental contrast effects on the expression of apomorphine locomotor sensitization by using two arena formats (round and square) that elicited differential levels of spontaneous locomotion. Eight groups of rats received 3 daily injections of apomorphine (APO) (2.0mg/kg) or vehicle (VEH) to induce locomotor sensitization: four groups in the square arena (2 APO and 2 VEH) and four in the round arena (2 APO and 2 VEH). Subsequently, the groups were retested with the same APO/VEH regimen for 3 days. One APO group and one VEH group originally tested in the square arena were re-tested in the square arena while the other square arena induction pair was re-tested in the round arena. A similar re-test protocol (same/different arena) was implemented for the round arena groups. The change from a square induction arena to a round test arena potentiated sensitization as compared to the sensitization observed in the round test arena following induction in the same round arena. In contrast, the change from a round induction arena to a square test arena attenuated sensitization compared to sensitization in the square test arena following induction in the square arena. This asymmetric sensitization profile is inconsistent with a Pavlovian response conditioning mediation of sensitization. We suggest that psycho-stimulant experience in low or high activity environments can evoke positive and negative behavioral contrast effects when the environments are switched. This behavioral plasticity in response to environmental change linked to prior drug environment experience implicates contrast effects in the expression of psychostimulant sensitization. PMID- 21295618 TI - Three-dimensional motion analysis of postural adjustments during over-ground locomotion in a rat model of Parkinson's disease. AB - Postural instability, a symptom of Parkinson's disease (PD) patients, leads to frequent falls and difficulty in forward motion during gait. These motor deficits are mainly caused by neurodegenerative processes in the brain leading to reduced levels of the neurotransmitter dopamine. Postural studies involving animal models of PD are mainly based on movement scores or descriptive approaches to discerning differences in behaviour or function. Our aim was to describe postural adjustments in a rat model of PD utilising a quantitative three dimensional motion analysis technique during gait to investigate the effects of unilateral dopamine depletion on rat locomotion while walking on beams of varying widths (wide, narrow and graduated). Tail orientation, limb positions on the beam, range of motion and kinematic waveforms of the Roll, Pitch and Yaw of male Lister Hooded rats were investigated using passive markers placed in locations that were representative of their body axis. Hemiparkinsonian rats moved on the wide beam with a significantly higher Roll range of motion coupled with a positively biased Roll kinematic waveform during one gait cycle. While walking on the narrow beam they displayed an increased use of the ledge and placed their tail towards the right. These results are brought about by the rats' inability to shift body posture using the impaired limb. Our data demonstrate that marker-based motion capture can provide an effective and simple approach to quantifying postural adjustments for rat models of PD. PMID- 21295619 TI - Resting frontal gamma power at 16, 24 and 36 months predicts individual differences in language and cognition at 4 and 5 years. AB - Gamma activity has been linked to a variety of different cognitive processes and exists in both transient and persistent forms. Across studies, different brain regions have been suggested to contribute to gamma activity. Multiple studies have shown that the function of gamma oscillations may be related to temporal binding of early sensory information to relevant top-down processes. Given this hypothesis, we expected gamma oscillations to subserve general brain mechanisms that contribute to the development of cognitive and linguistic systems. The present study aims to examine the predictive relations between resting-state cortical gamma power density at a critical point in language and cognitive acquisition (i.e. 16, 24 and 36 months), and cognitive and language output at ages 4 and 5 years. Our findings show that both 24- and 36-month gamma power are significantly correlated with later language scores, notably Non-Word Repetition. Further, 16-, 24- and 36-month gamma were all significantly correlated with 4 year PLS-3 and CELF-P sentence structure scores. Although associations reported here do not reflect a direct cause and effect of early resting gamma power on later language outcomes, capacity to generate higher power in the gamma range at crucial developmental periods may index better modulation of attention and allow easier access to working memory, thus providing an advantage for overall development, particularly in the linguistic domain. Moreover, measuring abilities at times when these abilities are still emergent may allow better prediction of later outcomes. PMID- 21295620 TI - Caloric excess or restriction mediated modulation of metabolic enzyme acetylation proposed effects on cardiac growth and function. AB - Caloric excess has been postulated to disrupt cardiac function via (i) the generation of toxic intermediates, (ii) via protein glycosylation and (iii) through the generation of reactive oxygen species. It is now increasingly being recognized that the nutrient intermediates themselves may modulate metabolic pathways through the post-translational modifications of metabolic enzymes. In light of the high energy demand of the heart, these nutrient mediated modulations in metabolic pathway functioning may play an important role in cardiac function and in the capacity of the heart to adapt to biomechanical stressors. In this review the role of protein acetylation and deacetylation in the control of metabolic programs is explored. Although not extensively investigated directly in the heart, the emerging data support that these nutrient mediated post translational regulatory events (i) modulate cardiac metabolic pathways, (ii) integrate nutrient flux mediated post-translational effects with cardiac function and (iii) may be important in the development of cardiac pathology. Areas of investigation that need to be explored are highlighted. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection. PMID- 21295621 TI - Atrial cardiomyocyte calcium signalling. AB - Whereas Ca(2+) signalling in ventricular cardiomyocytes is well described, much less is known regarding the Ca(2+) signals within atrial cells. This is surprising given that atrial cardiomyocytes make an important contribution to the refilling of ventricles with blood, which enhances the subsequent ejection of blood from the heart. The dependence of cardiac function on the contribution of atria becomes increasingly important with age and exercise. Disruption of the rhythmic beating of atrial cardiomyocytes can lead to life-threatening conditions such as atrial fibrillation. Atrial and ventricular myocytes have many structural and functional similarities. However, one key structural difference, the lack of transverse tubules ("T-tubules") in atrial myocytes, make these two cell types display vastly different calcium patterns in response to electrical excitation. The lack of T-tubules in atrial myocytes means that depolarisation provokes calcium signals that originate around the periphery of the cells. Under resting conditions, such Ca(2+) signals do not propagate towards the centre of the atrial cells and so do not fully engage the contractile machinery. Consequently, contraction of atrial myocytes under resting conditions is modest. However, when atrial myocytes are stimulated with a positive inotropic agonist, such as isoproterenol, the peripheral Ca(2+) signals trigger a global wave of Ca(2+) that propagates in a centripetal manner into the cells. Enhanced centripetal movement of Ca(2+) in atrial myocytes leads to increased contraction and a more substantial contribution to blood pumping. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. PMID- 21295622 TI - The mitochondrial permeability transition pore and cyclophilin D in cardioprotection. AB - Mitochondria play a central role in heart energy metabolism and Ca(2+) homeostasis and are involved in the pathogenesis of many forms of heart disease. The body of knowledge on mitochondrial pathophysiology in living cells and organs is increasing, and so is the interest in mitochondria as potential targets for cardioprotection. This critical review will focus on the permeability transition pore (PTP) and its regulation by cyclophilin (CyP) D as effectors of endogenous protective mechanisms and as potential drug targets. The complexity of the regulatory interactions underlying control of mitochondrial function in vivo is beginning to emerge, and although apparently contradictory findings still exist we believe that the network of regulatory protein interactions involving the PTP and CyPs in physiology and pathology will increase our repertoire for therapeutic interventions in heart disease. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection. PMID- 21295623 TI - Identification of blood microRNAs associated to Parkinsonis disease. AB - The present study demonstrates that blood samples can be used as a source of miRNA identification associated to Parkinson's disease (PD). A set of six differentially expressed microRNAs were identified. They form two groups according to their expression profile in control, non-treated, early-onset and treated Parkinson's disease subjects. While miR-1, miR-22* and miR-29 expression levels allowed to distinguish non-treated PD from healthy subjects, miR-16-2*, miR-26a2* and miR30a differentiated treated from untreated patients. This study is innovative in contributing to the development of effective PD biomarkers. PMID- 21295624 TI - Influence of reaction conditions on the enantioselectivity of biocatalyzed C-C bond formations under high pressure conditions. AB - Benzoylformate decarboxylase (BFD, EC 4.1.1.7) is a homotetrameric thiamine diphosphate (ThDP)-dependent enzyme which catalyzes the synthesis of chiral 2 hydroxyketones accepting a broad range of aldehydes as substrates. In this study the synthesis of 2-hydroxypropiophenone (2-HPP) from benzaldehyde and acetaldehyde was catalyzed by three BFD variants namely BFD F464I, BFD A460I and BFD A460I-F464I. This paper reports the effect of hydrostatic pressure up to 290 MPa when the reactions were carried out at different benzaldehyde concentrations (5-40 mM) as well as at different pH values (7.0-8.5). Acetaldehyde concentration was fixed at 400 mM in all biotransformations. Reactions performed at high benzaldehyde concentrations and at high hydrostatic pressures showed an increase in (R)-2-HPP formation catalyzed by all BFD variants. For BFD A460I-F464I we observed an increase in the ee of (R)-2-HPP up to 80%, whereas at atmospheric conditions this variant synthesizes (R)-2-HPP with an ee of only 50%. Alkaline conditions (up to pH 8.5) and high hydrostatic pressures resulted in an increase of (R)-2-HPP synthesis, especially in the case of BFD A460I and BFD F464I. PMID- 21295625 TI - Pyramided rice lines harbouring Allium sativum (asal) and Galanthus nivalis (gna) lectin genes impart enhanced resistance against major sap-sucking pests. AB - We have developed transgene pyramided rice lines, endowed with enhanced resistance to major sap-sucking insects, through sexual crosses made between two stable transgenic rice lines containing Allium sativum (asal) and Galanthus nivalis (gna) lectin genes. Presence and expression of asal and gna genes in pyramided lines were confirmed by PCR and western blot analyses. Segregation analysis of F2 progenies disclosed digenic (9:3:3:1) inheritance of the transgenes. Homozygous F3 plants carrying asal and gna genes were identified employing genetic and molecular methods besides insect bioassays. Pyramided lines, infested with brown planthopper (BPH), green leafhopper (GLH) and whitebacked planthopper (WBPH), proved more effective in reducing insect survival, fecundity, feeding ability besides delayed development of insects as compared to the parental transgenics. Under infested conditions, pyramided lines were found superior to the parental transgenics in their seed yield potential. This study represents first report on pyramiding of two lectin genes into rice exhibiting enhanced resistance against major sucking pests. The pyramided lines appear promising and might serve as a novel genetic resource in rice breeding aimed at durable and broad based resistance against hoppers. PMID- 21295626 TI - Binding and purification of plasmid DNA using multi-layered carbon nanotubes. AB - We propose a new method for the separation of nucleic acids using multi-layered carbon nanotubes (CNTs) as an adsorbent. According to agarose gel electrophoresis, oxidized water-stable CNTs adsorb certain forms of nucleic acids, such as high molecular weight RNA, chromosomal DNA, linear and denatured forms of plasmid DNA. However, CNTs do not adsorb supercoiled form of plasmid DNA. Nucleic acids bound to CNTs can be readily removed by centrifugation whereas supercoiled plasmid DNA remains in solution. Upon the addition of divalent metal ions supercoiled plasmid DNA forms relatively stable complexes with CNTs due to chelation. Thus, new details about association of nucleic acids with CNTs were revealed and stoichiometry of the complexes was estimated. Our results can be used for fine purification of supercoiled plasmid DNA for gene therapy applications as well as manipulation of nucleic acids for biosensor design. PMID- 21295627 TI - Age and experience predict accurate short-term energy compensation in adults. AB - Many factors thought to influence the control of food intake have been investigated independently, but the relative importance of each of these factors remains unknown. This study investigated the concurrent role of 21 factors in accurate compensation for energy consumed 60min previously. Energy compensation was assessed by measuring the difference in energy intake at an ad libitum test meal following two preloads of differing energy content, in 105 participants. Using regression, energy compensation was associated only with age (B=-2.39, beta=-0.345, p<0.01), and accuracy of energy compensation was associated only with age (B=1.81, beta=0.376, p<0.01) and order of preload presentation (B= 21.80, beta=-0.233, p=0.01). These findings suggest that our ability to detect and/or adjust for energy intake deteriorates with age, and that individuals adjust more easily for missing, as opposed to additional, energy. Notably however, only these predictors were associated with energy compensation and they account for only 11-18% of total variance. PMID- 21295628 TI - Health discourse in Swedish television food advertising during children's peak viewing times. AB - Food marketing influences children's food preferences and consumption and is important to consider in the prevention of child obesity. In this paper, health messages in commercials during children's peak viewing times were analysed by examining how food is articulated in the health discourse. In total, 82 food commercials from 66h of television recordings of the most popular commercial channels with children in Sweden (TV3, TV4 and Channel 5) were analysed with discourse theoretical tools according to Laclau and Mouffe and with a focus on rhetoric. Physical, mental and social health aspects were present in 71% of the commercials. Three health discourse types; a medical (food as protection and treatment), a hedonic (food as feeling good) and a social discourse type (food as caring) were discerned. In relation to these, the heart symbol, lifestyle associations and nature/the natural were elements that could be interpreted in different ways. Moreover, foods carrying unhealthy associations were promoted in the health discourse and presented as especially healthy by offensive rhetoric. The analysis raises awareness of the prevailing health messages in food marketing. Children and parents should be encouraged to develop their critical thinking about television food advertising and how it may influence social norms and dietary practices. PMID- 21295629 TI - Evaluation of Agaricus blazei in vivo for antigenotoxic, anticarcinogenic, phagocytic and immunomodulatory activities. AB - The development of various types of cancer results from the interaction among endogenous, environmental and hormonal factors, where the most notable of these factors is diet. The aim of the present study was to determine the antigenotoxic, anticarcinogenic, phagocytic and immunomodulatory activities of Agaricus blazei. The test antigenotoxicity (Comet Assay) and anticarcinogenic (Test of Aberrant Crypt Foci) assess changes in DNA and/or intestinal mucosa that correlate to cancer development. Tests of phagocytosis in the spleen and differential count in blood cells allow the inference of modulation of the immune system as well as to propose a way of eliminating cells with DNA damage. Supplementation with the mushroom was carried out under pre-treatment, simultaneous treatment, post treatment and pre-treatment+continuous conditions. Statistical analysis demonstrated that the mushroom did not have genotoxic activity but showed antigenotoxic activity. Supplementation caused an increase in the number of monocytes and in phagocytic activity, suggesting that supplementation increases a proliferation of monocytes, consequently increasing phagocytic capacity especially in the groups pre-treatment, simultaneous and pre treatment+continuous. The data suggest that A. blazei could act as a functional food capable of promoting immunomodulation which can account for the destruction of cells with DNA alterations that correlate with the development of cancer, since this mushroom was demonstrated to have a preventive effect against pre neoplastic colorectal lesions evaluated by the aberrant crypt foci assay. According to these results and the literature, it is believed that supplementation with A. blazei can be an efficient method for the prevention of cancer as well as possibly being an important coadjuvant treatment in chemotherapy. PMID- 21295630 TI - Regenerative medicine. Foreword. PMID- 21295631 TI - In brief: Regenerative medicine. PMID- 21295632 TI - Regenerative medicine. PMID- 21295633 TI - Advanced imaging in GI mucosal disease: do you see what I see? PMID- 21295634 TI - Making 1+1=3: improving sedation through drug synergy. PMID- 21295635 TI - Artificial neural networks accurately predict mortality in patients with nonvariceal upper GI bleeding. AB - BACKGROUND: Risk stratification systems that accurately identify patients with a high risk for bleeding through the use of clinical predictors of mortality before endoscopic examination are needed. Computerized (artificial) neural networks (ANNs) are adaptive tools that may improve prognostication. OBJECTIVE: To assess the capability of an ANN to predict mortality in patients with nonvariceal upper GI bleeding and compare the predictive performance of the ANN with that of the Rockall score. DESIGN: Prospective, multicenter study. SETTING: Academic and community hospitals. PATIENTS: This study involved 2380 patients with nonvariceal upper GI bleeding. INTERVENTION: Upper GI endoscopy. MAIN OUTCOME MEASUREMENTS: The primary outcome variable was 30-day mortality, defined as any death occurring within 30 days of the index bleeding episode. Other outcome variables were recurrent bleeding and need for surgery. RESULTS: We performed analysis of certified outcomes of 2380 patients with nonvariceal upper GI bleeding. The Rockall score was compared with a supervised ANN (TWIST system, Semeion), adopting the same result validation protocol with random allocation of the sample in training and testing subsets and subsequent crossover. Overall, death occurred in 112 cases (4.70%). Of 68 pre-endoscopic input variables, 17 were selected and used by the ANN versus 16 included in the Rockall score. The sensitivity of the ANN-based model was 83.8% (76.7-90.8) versus 71.4% (62.8-80.0) for the Rockall score. Specificity was 97.5 (96.8-98.2) and 52.0 (49.8 4.2), respectively. Accuracy was 96.8% (96.0-97.5) versus 52.9% (50.8-55.0) (P<.001). The predictive performance of the ANN-based model for prediction of mortality was significantly superior to that of the complete Rockall score (area under the curve 0.95 [0.92 0.98] vs 0.67 [0.65-0.69]; P<.001). LIMITATIONS: External validation on a subsequent independent population is needed, patients with variceal bleeding and obscure GI hemorrhage are excluded. CONCLUSION: In patients with nonvariceal upper GI bleeding, ANNs are significantly superior to the Rockall score in predicting the risk of death. PMID- 21295636 TI - Estimation of malignant potential of GI stromal tumors by contrast-enhanced harmonic EUS (with videos). AB - BACKGROUND: Contrast-enhanced harmonic EUS (CEH-EUS) is a new sonographic technique that uses US contrast agents and depicts intratumoral vessels in real time. OBJECTIVE: To evaluate whether assessment of tumor vascularity by CEH-EUS can predict the preoperative malignancy risk of GI stromal tumors (GISTs). DESIGN: Prospective study to observe GIST vascularity. SETTING: Kinki University School of Medicine. PATIENTS: Between June 2007 and September 2009, 76 consecutive patients suspected of having subepithelial lesions underwent CEH-EUS. INTERVENTION: CEH-EUS was performed by using a prototype echoendoscope in an extended pure harmonic detection mode. MAIN OUTCOME MEASUREMENTS: Resected GIST specimens in 29 patients who underwent surgical resection were divided into high grade (n=16) and low-grade (n=13) malignancy groups based on mitotic activity. The abilities of EUS-guided FNA and CEH-EUS to diagnose the malignant potential were compared. The sensitivities with which contrast-enhanced multidetector CT, power-Doppler EUS, and CEH-EUS detected intratumoral vessels in high-grade malignancy GISTs also were compared. RESULTS: CEH-EUS identified irregular vessels and thereby predicted GIST malignancies with a sensitivity, specificity, and accuracy of 100%, 63%, and 83%, respectively. Diagnosis of high-grade malignancy GISTs by EUS-guided FNA had a sensitivity, specificity, and accuracy of 63%, 92%, and 81%, respectively. Contrast-enhanced multidetector CT, power Doppler EUS, and CEH-EUS detected intratumoral vessels in high-grade malignancy GISTs with sensitivities of 31%, 63%, and 100%, respectively (P<.05). LIMITATIONS: A single center was involved in this study. CONCLUSIONS: CEH-EUS successfully visualized intratumoral vessels and may play an important role in predicting the malignancy risk of GISTs. PMID- 21295637 TI - An endoscopic strategy for management of anastomotic complications from bariatric surgery: a prospective study. AB - BACKGROUND: Treatment of anastomotic fistulas after bariatric surgery is difficult, and they are often associated with additional surgery, sepsis, and prolonged non-oral feeding. OBJECTIVE: To assess a new, totally endoscopic strategy to manage anastomotic fistulas. DESIGN: Prospective study. SETTING: Tertiary-care university hospital. PATIENTS: This study involved 27 consecutive patients from July 2007 to December 2009. INTERVENTION: This strategy involved successive procedures for endoscopic drainage of the residual cavity, diversion of the fistula with a stent, and then closure of the residual orifice with surgical clips or sealant. MAIN OUTCOME MEASUREMENTS: Technical success, mortality and morbidity, migration of the stent. RESULTS: Multiple or complex fistulas were present in 16 cases (59%). Endoscopic drainage (nasal-fistula drain or necrosectomy) was used in 19 cases (70%). Diversion by a covered colorectal stent was used in 22 patients (81%). To close the residual or initial opening, wound clips and glue (cyanoacrylate) were used in 15 cases (55%). Neither mortality nor severe morbidity occurred. Migration of the stent occurred in 13 cases (59%) and was treated by replacement with either a longer stent or with 2 nested stents. The mean time until resolution of fistula was 86 days from the start of endoscopic management, with a mean of 4.4 endoscopies per patient. LIMITATIONS: Moderate sample size, nonrandomized study. CONCLUSION: An entirely endoscopic approach to the management of anastomosing fistulas that develop after bariatric surgery--using sequential drainage, sutures, and diversion by stents- achieved resolution of the fistulas with minimal morbidity. PMID- 21295638 TI - Cholangiopancreatoscopy: risks and benefits. PMID- 21295639 TI - Patient-controlled sedation with propofol and remifentanil for ERCP: a randomized, controlled study. AB - BACKGROUND: Deep sedation with propofol and an opioid is commonly used for ERCP but is associated with increased risk and may require the presence of an anesthesiologist. Delivery of propofol and a short-acting, potent opioid analgesic remifentanil by patients to themselves (patient-controlled sedation, PCS) could be another option. Comparative studies with propofol PCS for ERCP are lacking. OBJECTIVE: To compare PCS with propofol/remifentanil to anesthesiologist managed propofol sedation. DESIGN: Prospective, randomized, controlled human trial. SETTING: University hospital. PATIENTS: This study involved 80 patients presenting for elective ERCP. INTERVENTION: Patients were randomized to PCS with propofol/remifentanil (PCS group) or anesthesiologist-managed propofol sedation (propofol infusion group). Sedation level was estimated every 5 minutes throughout the procedure by using Ramsay and Gillham sedation scores. The total amount of propofol was calculated at the end of the procedure. Endoscopist and patient satisfaction with the procedures was evaluated with a structured questionnaire. MAIN OUTCOME MEASUREMENTS: Patient vital signs, amount of consumed propofol, sedation levels, and degree of endoscopist and patient satisfaction. RESULTS: PCS was successful with 38 of 40 (95%) ERCP patients. In the PCS group, the mean (+/-standard deviation) level of sedation was markedly lighter and propofol consumption significantly smaller (175+/-98 mg) than in the propofol infusion group (249+/-138 mg) (P<.01). Degrees of patient and endoscopist satisfaction were equally high in both groups. All of the patients preferred the same sedation method should a repeat ERCP be required. LIMITATIONS: Single-center study. CONCLUSION: PCS with propofol/remifentanil is a suitable and well-accepted sedation method for ERCP. Anesthesiologist-managed propofol sedation with constant propofol infusion is associated with unnecessary deep sedation without any impact on the degree of patient or endoscopist satisfaction. Further larger scale studies are needed to assess the safety of PCS in ERCP patients. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT01079312.). PMID- 21295640 TI - EUS visualization and direct celiac ganglia neurolysis predicts better pain relief in patients with pancreatic malignancy (with video). AB - BACKGROUND: EUS-guided celiac plexus neurolysis (EUS-CPN) improves pain control in patients with pancreatic cancer. EUS allows visualization of the celiac ganglion. OBJECTIVE: To determine predictors of response to EUS-CPN in a cohort of 64 patients with pancreatic malignancy. DESIGN: Retrospective analysis of prospective database. SETTING: Academic medical center. PATIENTS: Sixty-four patients with pancreatic cancer referred for EUS between March 2008 and January 2010. INTERVENTIONS: EUS-CPN injected directly into celiac ganglia when visible by linear EUS or bilateral injection at the celiac vascular trunk. MAIN OUTCOME MEASUREMENTS: Predictors of pain improvement at week 1 by univariate and multivariate analysis. RESULTS: At week 1, 32 patients (50%) had a symptomatic response. In a multivariate model with 8 potential predictors, visualization of the ganglia was the best predictor of response; patients with visible ganglia were >15 times more likely to respond (odds ratio 15.7; P<.001). Tumors located outside the head of the pancreas and patients with a higher baseline pain level were weakly associated with a good response. LIMITATIONS: Retrospective design and lack of blinding. CONCLUSIONS: Visualization of celiac ganglia with direct injection is the best predictor of response to EUS-CPN in patients with pancreatic malignancy. PMID- 21295641 TI - Pancreatic stents for prophylaxis against post-ERCP pancreatitis: a meta-analysis and systematic review. AB - BACKGROUND: Acute pancreatitis is a common complication of ERCP. Several randomized, controlled trials (RCTs) have evaluated the use of pancreatic stents in the prevention of post-ERCP pancreatitis with varying results. OBJECTIVE: We conducted a meta-analysis and systematic review to assess the role of prophylactic pancreatic stents for prevention of post-ERCP pancreatitis. DESIGN: MEDLINE, Cochrane Central Register of Controlled Trials and Database of Systematic Reviews, PubMed, and recent abstracts from major conference proceedings were searched. RCTs and retrospective or prospective, nonrandomized studies comparing prophylactic stent with placebo or no stent for post-ERCP pancreatitis were included for the meta-analysis and systematic review. Standard forms were used to extract data by 2 independent reviewers. The effect of stents (for RCTs) was analyzed by calculating pooled estimates of post-ERCP pancreatitis, hyperamylasemia, and grade of pancreatitis. Separate analyses were performed for each outcome by using the odds ratio (OR) or weighted mean difference. Random- or fixed-effects models were used. Publication bias was assessed by funnel plots. Heterogeneity among studies was assessed by calculating I(2) measure of inconsistency. SETTING: Systematic review and meta-analysis of patients undergoing pancreatic stent placement for prophylaxis against post-ERCP pancreatitis. PATIENTS: Adult patients undergoing ERCP. INTERVENTIONS: Pancreatic stent placement for the prevention of post-ERCP pancreatitis. MAIN OUTCOME MEASUREMENTS: Post-ERCP pancreatitis, hyperamylasemia, and complications after pancreatic stent placement. RESULTS: Eight RCTs (656 subjects) and 10 nonrandomized studies met the inclusion criteria (4904 subjects). Meta-analysis of the RCTs showed that prophylactic pancreatic stents decreased the odds of post ERCP pancreatitis (odds ratio, 0.22; 95% CI, 0.12-0.38; P<.01). The absolute risk difference was 13.3% (95% CI, 8.8%-17.8%). The number needed to treat was 8 (95% CI, 6-11). Stents also decreased the level of hyperamylasemia (WMD, -309.22; 95% CI, -350.95 to -267.49; P<=.01). Similar findings were also noted from the nonrandomized studies. LIMITATIONS: Small sample size of some trials, different types of stents used, inclusion of low-risk patients in some studies, and lack of adequate study of long-term complications of pancreatic stent placement. CONCLUSIONS: Pancreatic stent placement decreases the risk of post-ERCP pancreatitis and hyperamylasemia in high-risk patients. PMID- 21295642 TI - Assessment of morbidity and mortality associated with EUS-guided FNA: a systematic review. AB - BACKGROUND: EUS-guided FNA (EUS-FNA) permits both morphologic and cytologic analysis of lesions within or adjacent to the GI tract. Although previous studies have evaluated the accuracy of EUS-FNA, little is known about the complications of EUS-FNA. Moreover, the frequency and severity of complications may vary from center to center and may be related to differences in individual experience. OBJECTIVE: To systematically review the morbidity and mortality associated with EUS-FNA. DESIGN: MEDLINE and EMBASE were searched to identify relevant English language articles. MAIN OUTCOME MEASUREMENTS: EUS-FNA-specific morbidity and mortality rates. RESULTS: We identified 51 articles with a total of 10,941 patients who met our inclusion and exclusion criteria; the overall rate of EUS FNA-specific morbidity was 0.98% (107/10,941). In the small proportion of patients with complications of any kind, the rates of pancreatitis (36/8246; 0.44%) and postprocedure pain (37/10,941; 0.34%) were 33.64% (36/107) and 34.58% (37/107), respectively. The mortality rate attributable to EUS-FNA-specific morbidity was 0.02% (2/10,941). Subgroup analysis showed that the morbidity rate was 2.44% in prospective studies compared with 0.35% in retrospective studies for pancreatic mass lesions (P=.000), whereas it was 2.33% versus 5.07% for pancreatic cysts (P=.036). LIMITATIONS: Few articles reported well-designed, prospective studies and few focused on overall complications after EUS-FNA. CONCLUSIONS: EUS-FNA-related morbidity and mortality rates are relatively low, and most associated events are mild to moderate in severity. PMID- 21295643 TI - Improved visibility of lesions of the small intestine via capsule endoscopy with computed virtual chromoendoscopy. AB - BACKGROUND: We can now enhance video capsule endoscopy (CE) images in real time by means of a flexible spectral imaging color enhancement (FICE) digital processing system. Reports on the clinical usefulness of this system are few. OBJECTIVE: To clarify whether visualization of lesions of the small intestine is improved by FICE image analysis. DESIGN: A retrospective study. SETTING: Academic medical center. METHODS: Five physicians compared FICE images with corresponding conventional images of 145 lesions obtained from 122 patients who underwent video CE at our hospital. The lesions were classified as angioectasia (n=23), erosion/ulceration (n=45), or tumor (n=75), and 3 different sets of FICE images were viewed (ie, at 3 different wavelength settings). Physicians rated the visibility of the lesions on FICE images as follows: +2 (improved visibility), +1 (somewhat improved visibility), 0 (visibility equivalent to that of conventional video CE visibility), -1 (somewhat decreased visibility), and -2 (decreased visibility). Scores for each lesion were totaled (per FICE setting) and evaluated. Intraobserver agreement was also examined. RESULTS: With FICE setting 1 (red 595 nm, green 540 nm, blue 535 nm), improvement was achieved for 87% (20/23) of angioectasia images, 53.3% (26/47) of erosion/ulceration images, and 25.3% (19/75) of tumor images. With setting 2 (red 420 nm, green, 520 nm, blue 530 nm), improvement was achieved for 87% (20/23), 25.5% (12/47), and 20.0% (15/75), respectively. With setting 3, only equivalence was achieved. Intraobserver agreement was good to satisfactory at 5.4 or higher. LIMITATIONS: Single-center study. CONCLUSIONS: CE-FICE improves visibility of small-bowel angioectasia, erosion/ulceration, and tumor. PMID- 21295644 TI - Colonoscopy and kinematics: what is your path length and tip angulation? PMID- 21295645 TI - How to avoid common pitfalls with bowel preparation agents. PMID- 21295646 TI - Endoscopic mucosal resection with the grasp-and-snare technique through a double channel endoscope in humans. AB - BACKGROUND: EMR is being used to manage premalignant lesions of the GI tract. Lifting of the lesion is required to perform EMR. Earlier biopsy or snare may cause scarring and preclude adequate lifting. OBJECTIVE: We report our experience with a novel grasp-and-snare EMR technique that can be used when a good lifting is not achieved or the location of the lesion is challenging for standard EMR, such as in a fold. DESIGN: Single-center case series. SETTING: Tertiary referral academic gastroenterology unit. PATIENTS: Patients referred for endoscopic treatment of flat gastrointestinal polyps. INTERVENTIONS: Single-session EMR performed with a grasp-and-snare technique through a double-channel gastroscope or colonoscope. MAIN OUTCOME MEASUREMENTS: Technical success, complication rates, and recurrence rates. RESULTS: Seventeen patients with flat gastrointestinal polyps were referred: mean age 70 years, 11 (65%) male, polyp size 0.8 to 6 cm; 13 colonic, 2 duodenal, 1 gastric, and 1 esophageal EMR performed with grasp-and snare technique in single sessions. Six polyps (35%) did not lift after injection of hydroxypropylmethylcellulose. Fourteen polyps (82%) were resected completely. Two complications occurred (12%): 1 bleeding treated medically and 1 perforation treated surgically. Residual disease at 1 year was 18%, but 8 patients (47%) had not yet had their 1-year follow-up. LIMITATIONS: Single-center, uncontrolled, not randomized. Limited follow-up. CONCLUSIONS: The grasp-and-snare technique can be used to perform EMR with good outcomes and low complication rates in areas where poor lifting and accessibility are problems. PMID- 21295647 TI - Zenker's diverticulitis secondary to alendronate ingestion: a rare cause of recurrent dysphagia. AB - OBJECTIVE: Acute dysphagia/odynophagia developed in a 79-year-old female patient secondary to what we believe was a caustic injury to a large Zenker's diverticulum (ZD) in the setting of long-term alendronate use. She reported severe dysphagia and odynophagia of 1-week duration. She had experienced a similar episode 10 months earlier that had resolved after stopping alendronate temporarily. Although she was able to handle secretions, she was unable to swallow solids or liquids. She was noted to be dehydrated. On endoscopy, a large and markedly inflamed ZD was identified. There was no visual esophageal mucosal injury within the esophagus. Alendronate therapy was discontinued, and parenteral nutrition and proton pump inhibitors were initiated. Her symptoms resolved within 1 week, and she was able to resume oral intake. DESIGN: Case report. SETTING: University Hospital. LIMITATIONS: Case report. DISCUSSION: Bisphosphonate therapy is commonly used to treat osteoporosis and is therefore an increasingly prevalent component of the medication list of elderly patients. These medications may cause significant caustic injury and are therefore administered with strong caution in the setting of dysphagia or known structural abnormalities of the esophagus. The fear is that tablets may become entrapped within a diverticulum and lead to intense acute inflammatory changes. CONCLUSIONS: Health care providers should be aware of potential complications with ulcerogenic medications in patients with ZD. These medications should be administered with caution in the setting of dysphagia or known structural abnormalities of the esophagus. When patients with history of dysphagia are evaluated for their suitability to receive oral bisphosphonate therapy, care should be taken to investigate the etiology of dysphagia. Evaluation should focus not only on the tubular esophagus, but also on excluding a Zenker's pharyngeal diverticulum with appropriate contrast imaging. PMID- 21295648 TI - Endoscopic diagnosis and treatment of gastric glomus tumors. AB - BACKGROUND: Although gastric glomus tumors are usually benign lesions, occasional malignant transformation has been reported. Thus, complete resection of the gastric glomus tumor is necessary. OBJECTIVE: To provide a better understanding of the endoscopic features of this rare entity with an emphasis on its diagnosis and treatment. DESIGN: Retrospective case series. SETTING: Academic medical center. PATIENTS: Six patients (2 men, 4 women; median age 48 years) received a diagnosis of gastric glomus tumor and were treated. INTERVENTIONS: Endoscopic diagnosis and resection. MAIN OUTCOME MEASUREMENTS: Endoscopic features, resection success, adverse events, and follow-up endoscopy. RESULTS: Gastric glomus tumors do not exhibit specific features on gastroscopy and EUS that distinguish them from other gastric submucosal tumors. Endoscopic submucosal enucleation was successful in 5 patients. In one patient, the operation had to be discontinued because of significant bleeding during the procedure. The mean tumor size was 19.8+/-6.2 mm (range 12-30 mm). Perforation occurred in 1 patient and was successfully managed with hemoclips. No local recurrence was observed during follow-up (mean duration 9+/-5.1 months, range 3-17 months). LIMITATIONS: Small number of patients (N=6), limited follow-up, retrospective study. CONCLUSIONS: Diagnosis of gastric glomus tumors is difficult when based only on features derived from gastroscopy and EUS. Endoscopic submucosal enucleation is a feasible and safe procedure with which to diagnose and treat this lesion. However, further investigation and comparative studies are required to confirm the safety and efficacy of this method. PMID- 21295649 TI - Therapeutic endoscopy for stenotic pancreatodigestive tract anastomosis after pancreatoduodenectomy (with videos). AB - BACKGROUND: Pancreatodigestive tract anastomotic site stenosis is a problematic complication after pancreatoduodenectomy. OBJECTIVE: We evaluated the feasibility and efficacy of endoscopic treatments for a stenotic pancreatodigestive tract anastomosis. DESIGN: Retrospective study. SETTING: Endoscopic units of a university-affiliated hospital and a general hospital. PATIENTS: Fourteen patients with recurrent pancreatitis (n=10) and pancreatic fluid fistula (n=4) after anatomy-altering surgery with pancreatodigestive tract anastomosis. INTERVENTIONS: The initial ERCP included obtaining a pancreatogram, introducing a 0.025-inch guidewire through the anastomosis, along which a 5F plastic stent or nasopancreatic drain was inserted. If initial ERCP failed, we attempted EUS guided rendezvous, with a guidewire passed antegrade from the main pancreatic duct across the stenotic anastomosis. MAIN OUTCOME MEASUREMENTS: Rates of successful intervention and clinical relief. RESULTS: The initial intervention was successfully achieved in 6 of 14 patients (38%). Of the 6 patients with successful therapeutic endoscopies, 4 (66.7%) and 2 (25.0%) had undergone a previous pancreatogastrostomy or pancreatojejunostomy, respectively. Eight patients with an initial unsuccessful intervention successfully underwent a second intervention using an EUS-guided or US-guided rendezvous method. Finally, stenosis was relieved in all patients with either the retrograde placement of a pancreatic duct stent across the stenosis of an anastomotic site or antegrade percutaneous bougienage of the stenotic anastomosis. LIMITATIONS: Small sample size and lack of control patients. CONCLUSIONS: Endoscopic treatment of stenotic pancreatodigestive tract anastomosis for transanastomotic pancreatic juice drainage is safe and feasible. PMID- 21295650 TI - Treatment of chronic radiation proctitis with cryoablation. AB - BACKGROUND: Chronic radiation proctitis (CRP) is a common problem in patients receiving pelvic radiation. Current therapies have the potential for deep tissue injury with ulcerations, perforation, and fistula formation. Cryospray ablation therapy offers superficial ablation of mucosa and is a potential method to endoscopically treat CRP safely and effectively. OBJECTIVE: To determine tolerability of and response to cryotherapy in patients with radiation proctitis. DESIGN: Prospective case-series pilot study. SETTING: Baylor College of Medicine, Michael E. DeBakey Medical Center, Houston, Texas. PATIENTS: Ten patients were prospectively recruited with chronic hemorrhagic radiation proctitis. INTERVENTIONS: Endoscopic cryoablation of CRP. MAIN OUTCOME MEASUREMENTS: Symptom severity of CRP was obtained by using the Radiation Proctitis Severity Assessment Scale (RPSAS). Endoscopic assessment was obtained using the rectal telangiectasia density grade. The primary endpoint of the study was endoscopic improvement of CRP based on the change in rectal telangiectasia density at 3-month follow-up. Secondary endpoints included symptomatic improvement based on RPSAS and adverse events at 3 months. RESULTS: Ten patients with hemorrhagic radiation proctitis were treated with endoscopic cryoablation. Endoscopic severity improved as measured by rectal telangiectasia density from 2.7 to 1.7 (P=.004). Overall subjective clinical scores improved as determined by the Radiation Proctitis Severity Assessment Scale from 27.7 to 13.6 (P=.003). Endoscopic improvement correlated with symptom improvement. LIMITATIONS: Nonpowered case series pilot study. CONCLUSIONS: Cryoablation improved clinical and endoscopic indices in CRP. Further controlled studies are needed to identify the safety and efficacy of cryoablation for CRP. PMID- 21295651 TI - Safe and effective dilatation in eosinophilic esophagitis: the tale of two subgroups. PMID- 21295653 TI - Direct endoscopic dilation in patients with eosinophilic esophagitis. PMID- 21295655 TI - Combined antegrade and retrograde approach for dilation of radiation-induced esophageal strictures can be accomplished by a single endoscopist. PMID- 21295657 TI - The war of the worlds: metaplastic versus nonmetaplastic atrophic gastritis. PMID- 21295659 TI - Immediate bleeding during endoscopic submucosal dissection: a predictor of delayed bleeding? PMID- 21295661 TI - Single-balloon or short double-balloon enteroscope for ERCP in patients with surgically altered anatomies. PMID- 21295662 TI - Radiation doses to ERCP patients are significantly lower with experienced endoscopists. PMID- 21295664 TI - Introduction: Adult congenital heart disease. PMID- 21295665 TI - From numbers to guidelines. AB - Advances in pediatric cardiology and cardiac surgery have resulted in a change in the mortality, prevalence, and age distribution of patients with congenital heart disease (CHD). In this chapter, we review the changing epidemiology of CHD and the impact of these trends on health services utilization and delivery in this population. We demonstrate not only that adult CHD (ACHD) patients have high utilization rates but also that care gaps exist where disease is expected to be lifelong. We outline the components of quality improvement for the care of ACHD patients. We review the newly published guidelines for the management of CHD conditions in adults, anchoring them to structure, process, and outcome indexes of quality of care. We highlight the manpower needs and the importance of an appropriately trained cardiology workforce to provide ACHD care. Finally, we review recommended health care systems ideally suited to deliver care to this population. PMID- 21295666 TI - The whole adult congenital heart disease patient. AB - Adults with congenital heart disease (CHD) have unique medical and psychosocial needs. They require lifelong cardiac surveillance from medical providers with training and expertise in the care of adults with CHD. Patients with CHD must recognize the importance of ongoing surveillance and must not be lost to care in childhood, adolescence, or adulthood. This can be accomplished with the implementation of a comprehensive transition program with the collaboration of patients, parents, and both pediatric and adult health care providers. Finally, consideration of the "whole" patient demands recognition of the unique medical and psychosocial challenges of adults with CHD. PMID- 21295667 TI - Adult congenital heart disease: surgical advances and options. AB - The number of adults with congenital heart disease (CHD) has steadily increased as medical and surgical treatment of congenital heart lesions--whether simple or complex--continues to improve. Over the past half century advances in surgical technique have continued with the evolution of traditional surgical repair and introduction of new surgical procedures for complex lesions previously considered to be irreparable. This article describes the rich history of surgical repair, important surgical considerations specific to the adult undergoing primary or reoperative cardiac repair or palliation, the most common types congenital heart lesions and associated cardiac procedures (including cardiac transplantation) performed in the adult population, as well as considerations regarding the optimal surgical environment and current surgical training and education. PMID- 21295668 TI - Advances in transcatheter interventions in adults with congenital heart disease. AB - Cardiac catheterization in the adult patient with congenital heart disease clearly is now its own field. The history of the field is closely tied to pediatric cardiac catheterization, in large part because of the individual histories of its patients, and as such, at least for the foreseeable future, these two fields appear inexorably linked. For both, the pace of progress has been swift. This chapter provides a broad review of the important advances in cardiac catheterization that have occurred over the past decade as they pertain to the adult with congenital heart disease, with an emphasis on recent interventional tools and techniques that have revolutionized this exciting field. PMID- 21295669 TI - Intensive care of the adult patient with congenital heart disease. AB - Prevalence of congenital heart disease in the adult population has increased out of proportion to that of the pediatric population as survival has improved, and adult congenital heart disease patients make up a growing percentage of pediatric and adult cardiac intensive care unit admissions. These patients often develop complex multiorgan system disease as a result of long-standing altered cardiac physiology, and many require reoperation during adulthood. Practitioners who care for these patients in the cardiac intensive care unit must have a strong working knowledge of the pathophysiology of complex congenital heart disease, and a full team of specialists must be available to assist in the care of these patients. This chapter will review some of the common multiorgan system effects of long standing congenital heart disease (eg, renal and hepatic dysfunction, coagulation abnormalities, arrhythmias) as well as some of the unique cardiopulmonary physiology of this patient population. PMID- 21295670 TI - Electrophysiology and adult congenital heart disease: advances and options. AB - Although "congenital heart disease" incorporates a broad and diverse spectrum of inborn cardiac disorders, one shared feature is the propensity for cardiac arrhythmias, albeit to varying degrees. The magnitude of this issue is underscored by its high prevalence, major impact on morbidity and disability, considerable consummation of healthcare resources, and loss of life at ages well below normative population values. Moreover, with changing demographics, arrhythmias increasingly afflict the aging and growing population of survivors with congenital heart disease. Nevertheless, the field of cardiac electrophysiology has, auspiciously, greatly matured over the past 2 decades. The fruits of this progress are largely applicable to adults with congenital heart disease. This review focuses on recent advances and emerging therapeutic options that are providing safer solutions and increasing the effectiveness with which arrhythmias may be managed in adults with congenital heart disease, spanning pharmacotherapy to innovative interventions. PMID- 21295671 TI - Advances in imaging: the impact on the care of the adult with congenital heart disease. AB - Recent advances in pediatric cardiology have dramatically changed the landscape of the field of congenital heart disease. This changing field is placing new demands on imaging to plan medical management as well as identify the need for, and timing of, reintervention. There are a number of imaging modalities available to the clinician when it comes to these evaluations, including echocardiography, computed tomography, and cardiac magnetic resonance imaging; each having their strengths and unique contributions. This article will discuss the advances in the aforementioned imaging modalities over the past decade and highlight how these tools can provide guidelines on the management of adults with congenital heart disease. PMID- 21295672 TI - Management of pregnancy in patients with congenital heart disease. AB - Congenital heart diseases are the most common birth defects in humans, affecting approximately 0.8% of all live births. In the past, many of the more severe defects resulted in profound disability and death during childhood, and adult survival was exceptional. The past 4 decades have seen dramatic improvements in the survival and quality of life of patients with the more severe defects. As a result of these improvements, the challenges of caring for adults with congenital heart disease are only now being realized. Most women with congenital heart disease are now expected to reach childbearing age and maternal cardiac disease is the major cause of maternal morbidity and mortality. As such, appropriate pre pregnancy counseling and management during pregnancy are fundamental components of the care of these patients. This article describes the circulatory changes that occur during normal pregnancy and delivery, addresses the risks posed during pregnancy by specific congenital lesions, and reviews the current data on pregnancy outcomes in patients with individual congenital defects. PMID- 21295673 TI - Transplantation in adults with congenital heart disease. AB - Considerable progress in pediatric cardiac surgery has led to more patients with congenital heart disease surviving into adulthood. However, progressive cardiopulmonary dysfunction often occurs late after palliative or corrective surgeries to the point where transplantation becomes the only treatment option. Adult congenital heart disease represents a growing population of patients being referred for heart, lung, and combined heart-lung transplantation. This group of patients presents multiple unique surgical and medical challenges to transplantation owing to their complex anatomy, multiple prior palliative and corrective procedures, frequently increased pulmonary vascular resistance, and often debilitated condition. Consequently, transplantation in adults with congenital heart disease is associated with a relatively high operative mortality secondary to increased bleeding, infection, and graft failure rates compared with noncongenital heart disease transplant recipients. However, those who survive of the first posttransplant year enjoy an excellent long-term prognosis. PMID- 21295674 TI - The future of adult congenital heart disease care in the United States. PMID- 21295675 TI - This first volume of 2011 brings with it five diverse and strong chapters. Preface. PMID- 21295676 TI - The many roads to parasitism: a tale of convergence. AB - Parasitic organisms account for a large portion of living species. They have arisen on multiple independent occasions in many phyla, and thus encompass a huge biological diversity. This review uses several lines of evidence to argue that this vast diversity can be reduced to a few evolutionary end points that transcend phylogenetic boundaries. These represent peaks in the adaptive landscape reached independently by different lineages undergoing convergent evolution. Among eukaryotic parasites living in or on animals, six basic parasitic strategies are identified based on the number of hosts used per parasite generation, the fitness loss incurred by the host, and the transmission routes used by the parasites. They are parasitoids, parasitic castrators, directly transmitted parasites, trophically transmitted parasites, vector transmitted parasites and micropredators. These show evidence of convergence in morphology, physiology, reproduction, life cycles and transmission patterns. Parasite-host body size ratios, and the relationship between virulence and intensity of infection, are also associated with the different parasitic strategies, but not consistently so. At the population level, patterns of parasite distribution among hosts are not uniform across all parasitic strategies, but are distinctly different for parasitoids and castrators than for other parasites. To demonstrate that the above six strategies defined for animal parasites are universal, comparisons are made with parasites of plants, in particular, plant-parasitic nematodes and parasitic angiosperms; these are shown to follow the same evolutionary trajectories seen among animal parasites, despite huge physiological and ecological differences between animals and plants. Beyond demonstrating the inevitable convergence of disparate lineages across biological hyperspace towards a limited set of adaptive strategies, this synthesis also provides a unifying framework for the study of parasitism. PMID- 21295678 TI - Cytogenetics and chromosomes of tapeworms (Platyhelminthes, Cestoda). AB - Tapeworms (Cestoda, Platyhelminthes) are a highly diversified group of parasites that can have significant veterinary importance as well as medical impact as disease agents of human alveococcosis, hydatidosis, taeniosis/cysticercosis/neurocysticercosis, hymenolepidosis or diphyllobothriasis. Because of their great diversity, there has been keen interest in their phylogenetic relationships to other obligate parasitic platyhelminthes, as well as within the group itself. Recent phylogenetic analyses of cestodes, however, have focused on morphological, molecular, life cycle, embryology and host-specificity features and conspicuously omitted inclusion of karyological data. Here we review the literature from 1907 to 2010 and the current status of knowledge of the chromosomes and cytogenetics within all of the cestode orders and place it within an evolutionary perspective. Karyological data are discussed and tabulated for 115 species from nine eucestode orders with ideograms of 46 species, and a comparison of cytogenetic patterns between acetabulate and bothriate cestode lineages is made. Attention is drawn to gaps in our knowledge for seven remaining orders and cestodarian groups Gyrocotylidea and Amphilinidea. Among the cytogenetic aspects covered are: chromosome number, triploidy, classical karyotype cytogenetics (banding patterns, karyotype asymmetry, secondary constrictions), as well as advanced karyotype techniques allowing location of genes on chromosomes by fluorescence in situ hybridization. We demonstrate that further progress in cestode karyosystematics rests with new molecular approaches and the application of advanced cytogenetic markers facilitating intimate karyotype analysis. PMID- 21295677 TI - Malaria distribution, prevalence, drug resistance and control in Indonesia. AB - Approximately 230 million people live in Indonesia. The country is also home to over 20 anopheline vectors of malaria which transmit all four of the species of Plasmodium that routinely infect humans. A complex mosaic of risk of infection across this 5000-km-long archipelago of thousands of islands and distinctive habitats seriously challenges efforts to control malaria. Social, economic and political dimensions contribute to these complexities. This chapter examines malaria and its control in Indonesia, from the earliest efforts by malariologists of the colonial Netherlands East Indies, through the Global Malaria Eradication Campaign of the 1950s, the tumult following the coup d'etat of 1965, the global resurgence of malaria through the 1980s and 1990s and finally through to the decentralization of government authority following the fall of the authoritarian Soeharto regime in 1998. We detail important methods of control and their impact in the context of the political systems that supported them. We examine prospects for malaria control in contemporary decentralized and democratized Indonesia with multidrug-resistant malaria and greatly diminished capacities for integrated malaria control management programs. PMID- 21295679 TI - Soil-transmitted helminths of humans in Southeast Asia--towards integrated control. AB - Soil-transmitted helminths (STHs) pose significant public health challenges in many countries of Southeast Asia (SEA). Overall, approximately one-third of the world's cases of ascariasis, trichuriasis, and hookworm disease occur in the 11 major SEA countries. Various countries are at different stages in their response to controlling these diseases. For instance, in Malaysia and Thailand, the major burden of disease is confined to rural/remote, indigenous and/or refugee populations. In countries, such as Cambodia, Lao People's Democratic Republic and Vietnam, the burden remains high, although extensive deworming programmes are underway and are yielding encouraging results. The present chapter reviews the current status of STH infections in SEA, identifies knowledge gaps and offers a perspective on the development of improved, integrated surveillance and control in this geographical region. It indicates that advances in our understanding of the epidemiology of these parasites, through the strategic use of molecular and predictive (e.g. geographical information systems (GIS) and remote sensing (RS)) technologies, could readily underpin future research and control programmes. It is hoped that the gradual move towards integrated treatment/control programmes will assist substantially in decreasing the chronic disease burden linked to STHs, thus increasing human health and welfare, and supporting socio-economic growth and development in SEA countries. PMID- 21295681 TI - Oncogenesis and the development of treatments. Preface. PMID- 21295680 TI - The applications of model-based geostatistics in helminth epidemiology and control. AB - Funding agencies are dedicating substantial resources to tackle helminth infections. Reliable maps of the distribution of helminth infection can assist these efforts by targeting control resources to areas of greatest need. The ability to define the distribution of infection at regional, national and subnational levels has been enhanced greatly by the increased availability of good quality survey data and the use of model-based geostatistics (MBG), enabling spatial prediction in unsampled locations. A major advantage of MBG risk mapping approaches is that they provide a flexible statistical platform for handling and representing different sources of uncertainty, providing plausible and robust information on the spatial distribution of infections to inform the design and implementation of control programmes. Focussing on schistosomiasis and soil transmitted helminthiasis, with additional examples for lymphatic filariasis and onchocerciasis, we review the progress made to date with the application of MBG tools in large-scale, real-world control programmes and propose a general framework for their application to inform integrative spatial planning of helminth disease control programmes. PMID- 21295682 TI - Childhood cancer and developmental biology a crucial partnership. AB - For many years, there were relatively few research efforts that bridged the fields of developmental biology and cancer genetics. However, in the past decade, we have witnessed a dramatic shift and now these two fields are intertwined. Part of the impetus for this transition came from the discovery that regulatory pathways that were previously thought to be uniquely important for developmental processes were also perturbed in cancer. In addition, the conceptual framework for understanding how cells self-renew or undergo unidirectional changes in competence during development has proven to be very useful in cancer biology as researchers explore tumor initiation and progression. Finally, a deeper understanding of the process of terminal differentiation and how that relates to cellular plasticity may have important implications for both cancer biology and developmental biology. Here we highlight some of the important connections between developmental neurobiology and cancer biology in retinoblastoma. By bridging these fields, important advances have been made in modeling retinoblastoma in mice, elucidating the cell-of-origin for retinoblastoma and identifying novel therapeutic approaches. PMID- 21295683 TI - Stem cells in brain tumor development. AB - Gliomas are highly infiltrative and aggressive brain tumors that are resistant to conventional therapies. Recent studies have implicated neural stem cells (NSCs) in brain tumor initiation and development. Subpopulations of stem-like cancer cells have also been isolated from brain tumors, and are purported to be important mediators of malignant behavior and therapeutic resistance. Similar signaling pathways may be operative in both neural and cancer stem cells, suggesting that neural developmental systems may provide important clues on brain tumorigenesis. Transcriptional regulators such as microRNAs may also contribute to NSC and brain tumor development. Understanding the biology of neural and cancer stem cells and their regulatory mechanisms may directly impact current efforts for more directed therapeutics against these highly aggressive tumors. PMID- 21295684 TI - MDM2 and MDMX in cancer and development. AB - The p53 tumor suppressor pathway is active in cells that are subjected to stress and/or damaged, where it promotes cell cycle arrest or apoptosis. In contrast, in normal cells that are not exposed to stress signals and in tumor cells p53 is tightly kept in check or completely silenced. In most, if not all, tumor cells p53 is indeed inactivated by mutations in the p53 locus or by alternative, yet unclear, mechanisms that impinge directly or indirectly on p53 function. Recent biochemical and genetic data indicate that tumor cells hijack and enforce some of the mechanisms used by normal cells to restrain p53 function. This is best illustrated by the aberrant expression in tumor cells of MDM2 and MDMX (or MDM4), two structurally related proteins that play a critical role in maintaining p53 in an OFF state under normal conditions, but in particular in embryonic and stem cells. These advances and their potential implications for the development of new cancer therapeutic strategies form the focus of this chapter. PMID- 21295687 TI - Genetic alterations targeting lymphoid development in acute lymphoblastic leukemia. AB - While more than 80% of children with acute lymphoblastic leukemia (ALL) are cured with current chemotherapeutic regimens, a significant proportion of this patient population is at high risk of relapse. Recent advances in genomic profiling have identified novel genetic alterations that target key growth and development pathways in ALL and that influence the risk of treatment outcome. Notably, deletions and sequence mutations of lymphoid transcription factors are central events in the pathogenesis of B-lymphoid leukemia. Here, we describe these modern molecular techniques and their application to leukemia research. We also discuss the genetic lesions identified from these studies and how novel therapeutics directed at these targets may improve survival of pediatric ALL patients at high risk for relapse. PMID- 21295685 TI - The connections between neural crest development and neuroblastoma. AB - Neuroblastoma (NB), the most common extracranial solid tumor in childhood, is an extremely heterogeneous disease both biologically and clinically. Although significant progress has been made in identifying molecular and genetic markers for NB, this disease remains an enigmatic challenge. Since NB is thought to be an embryonal tumor that is derived from precursor cells of the peripheral (sympathetic) nervous system, understanding the development of normal sympathetic nervous system may highlight abnormal events that contribute to NB initiation. Therefore, this review focuses on the development of the peripheral trunk neural crest, the current understanding of how developmental factors may contribute to NB and on recent advances in the identification of important genetic lesions and signaling pathways involved in NB tumorigenesis and metastasis. Finally, we discuss how future advances in identification of molecular alterations in NB may lead to more effective, less toxic therapies, and improve the prognosis for NB patients. PMID- 21295688 TI - Myogenesis and rhabdomyosarcoma the Jekyll and Hyde of skeletal muscle. AB - Rhabdomyosarcoma, a neoplasm composed of skeletal myoblast-like cells, represents the most common soft tissue sarcoma in children. The application of intensive chemotherapeutics and refined surgical and radiation therapy approaches have improved survival for children with localized disease over the past 3 decades; however, these approaches have not improved the dismal outcome for children with metastatic and recurrent rhabdomyosarcoma. Elegant studies have defined the molecular mechanisms driving skeletal muscle lineage commitment and differentiation, and the machinery that couples differentiation with irreversible cell proliferation arrest. Further, detailed molecular analyses indicate that rhabdomyosarcoma cells have lost the capacity to fully differentiate when challenged to do so in experimental models. We review the intersection of normal skeletal muscle developmental biology and the molecular genetic defects in rhabdomyosarcoma with the underlying premise that understanding how the differentiation process has gone awry will lead to new treatment strategies aimed at promoting myogenic differentiation and concomitant cell cycle arrest. PMID- 21295686 TI - RB1, development, and cancer. AB - The RB1 gene is the first tumor suppressor gene identified whose mutational inactivation is the cause of a human cancer, the pediatric cancer retinoblastoma. The 25 years of research since its discovery has not only illuminated a general role for RB1 in human cancer, but also its critical importance in normal development. Understanding the molecular function of the RB1 encoded protein, pRb, is a long-standing goal that promises to inform our understanding of cancer, its relationship to normal development, and possible therapeutic strategies to combat this disease. Achieving this goal has been difficult, complicated by the complexity of pRb and related proteins. The goal of this review is to explore the hypothesis that, at its core, the molecular function of pRb is to dynamically regulate the location-specific assembly or disassembly of protein complexes on the DNA in response to the output of various signaling pathways. These protein complexes participate in a variety of molecular processes relevant to DNA including gene transcription, DNA replication, DNA repair, and mitosis. Through regulation of these processes, RB1 plays a uniquely prominent role in normal development and cancer. PMID- 21295690 TI - Rethinking pediatric gliomas as developmental brain abnormalities. AB - The neurofibromatosis type 1 (NF1) tumor predisposition syndrome provides an illustrative example of brain tumor formation and growth in which a permissive microenvironment (stroma) is required for the expansion and maintenance of the neoplastic cells. In this chapter, we review the experimental evidence that supports the emerging concept that brain tumors are dynamic ecosystems where interactions between non-neoplastic and neoplastic cell types dictate where and when gliomas (astrocytomas) form and grow. The notion that brain tumors require a confluence of supportive stromal cell types and signals, susceptible preneoplastic/neoplastic cells, and genomic influences allows researchers and clinicians to develop strategies that effectively disrupt these critical relationships in a targeted and developmentally appropriate fashion. PMID- 21295689 TI - Cerebellum development and medulloblastoma. AB - In the last 20 years, it has become clear that developmental genes and their regulators, noncoding RNAs including microRNAs and long-noncoding RNAs, within signaling pathways play a critical role in the pathogenesis of cancer. Many of these pathways were first identified in genetic screens in Drosophila and other lower organisms. Mammalian orthologs were subsequently identified and genes within the pathways cloned and found to regulate cell growth. Genes and pathways expressed during embryonic development, including the Notch, Wnt/beta-Catenin, TGF-beta/BMP, Shh/Patched, and Hippo pathways are mutated, lost, or aberrantly regulated in a wide variety of human cancers, including skin, breast, blood, and brain cancers, including medulloblastoma. These biochemical pathways affect cell fate determination, axis formation, and patterning during development and regulate tissue homeostasis and regeneration in adults. Medulloblastoma, the most common malignant nervous system tumor in childhood, are thought to arise from disruptions in cerebellar development [reviewed by Marino, S. (2005)]. Defining the extracellular cues and intracellular signaling pathways that control cerebellar neurogenesis, especially granule cell progenitor (GCP) proliferation and differentiation has been useful for developing models to unravel the mechanisms underlying medulloblastoma formation and growth. In this chapter, we will review the development of the cerebellar cortex, highlighting signaling pathways of potential relevance to tumorigenesis. PMID- 21295691 TI - Tumor macrophages protective and pathogenic roles in cancer development. AB - Macrophage infiltration often occurs in cancer and has stimulated new efforts to define macrophage function within solid tumors. The macrophage, a myelophagocytic cell of the immune system, is at the front line of pathogen defense, wound healing, and maintaining homeostasis within the body. However, increased macrophage numbers during cancer generally correlates with poor prognosis. This chapter will focus on the function of myelophagocytic cells within solid tumors, their potential roles in tumor progression, and the possibilities of their manipulation as a component of cancer therapy. PMID- 21295692 TI - Cell migration: GSK3beta steers the cytoskeleton's tip. AB - Directed cell migration polarizes the cytoskeleton, allowing the cell to move toward migratory cues. In this issue, Wu et al. (2011) demonstrate that the glycogen synthase kinase 3beta (GSK3beta) controls microtubule architecture and polarized movement of skin stem cells during wound healing in mammals by regulating the microtubule crosslinking protein ACF7. PMID- 21295693 TI - A versatile sugar transferase makes the cut. AB - The nutrient sensor O-GlcNAc transferase modifies proteins with the O-GlcNAc moiety. In this issue, Capotosti et al. (2011) reveal that O-GlcNAc transferase not only glycosylates the cell-cycle regulator host cell factor 1 but activates it through proteolytic cleavage, providing a surprising link between metabolism and epigenetic regulation of the cell cycle. PMID- 21295694 TI - Need tension relief fast? Try caveolae. AB - Caveolae are protein-driven membrane invaginations that regulate both the physical and chemical composition of the plasma membrane. Sinha et al. (2011) now show that caveolae are membrane reservoirs that are used to rapidly buffer against changes in membrane tension. PMID- 21295695 TI - Getting cells and tissues into shape. AB - Cells of all shapes and sizes are able to calculate the location of their middles in order to divide into two during mitosis. Minc et al. (2011) and Gibson et al. (2011) now show that simple mechanical models accurately predict cleavage-plane positioning, and that geometrical interactions between neighboring cells are sufficient to generate ordered patterns of mitosis in growing epithelia. PMID- 21295696 TI - Functional and mechanistic diversity of distal transcription enhancers. AB - Biological differences among metazoans and between cell types in a given organism arise in large part due to differences in gene expression patterns. Gene-distal enhancers are key contributors to these expression patterns, exhibiting both sequence diversity and cell type specificity. Studies of long-range interactions indicate that enhancers are often important determinants of nuclear organization, contributing to a general model for enhancer function that involves direct enhancer-promoter contact. However, mechanisms for enhancer function are emerging that do not fit solely within such a model, suggesting that enhancers as a class of DNA regulatory element may be functionally and mechanistically diverse. PMID- 21295697 TI - Skin stem cells orchestrate directional migration by regulating microtubule-ACF7 connections through GSK3beta. AB - Homeostasis and wound healing rely on stem cells (SCs) whose activity and directed migration are often governed by Wnt signaling. In dissecting how this pathway integrates with the necessary downstream cytoskeletal dynamics, we discovered that GSK3beta, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3beta sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules. Phosphorylation-refractile ACF7 rescues overall microtubule architecture, but phosphorylation-constitutive mutants do not. Neither mutant rescues polarized movement, revealing that phospho-regulation must be dynamic. This circuitry is physiologically relevant and depends upon polarized GSK3beta inhibition at the migrating front of SCs/progeny streaming from HFs during wound repair. Moreover, only ACF7 and not GSKbeta-refractile-ACF7 restore polarized microtubule-growth and SC-migration to ACF7 null skin. Our findings provide insights into how this conserved spectraplakin integrates signaling, cytoskeletal dynamics, and polarized locomotion of somatic SCs. PMID- 21295698 TI - O-GlcNAc transferase catalyzes site-specific proteolysis of HCF-1. AB - The human epigenetic cell-cycle regulator HCF-1 undergoes an unusual proteolytic maturation process resulting in stably associated HCF-1(N) and HCF-1(C) subunits that regulate different aspects of the cell cycle. Proteolysis occurs at six centrally located HCF-1(PRO)-repeat sequences and is important for activation of HCF-1(C)-subunit functions in M phase progression. We show here that the HCF 1(PRO) repeat is recognized by O-linked beta-N-acetylglucosamine transferase (OGT), which both O-GlcNAcylates the HCF-1(N) subunit and directly cleaves the HCF-1(PRO) repeat. Replacement of the HCF-1(PRO) repeats by a heterologous proteolytic cleavage signal promotes HCF-1 proteolysis but fails to activate HCF 1(C)-subunit M phase functions. These results reveal an unexpected role of OGT in HCF-1 proteolytic maturation and an unforeseen nexus between OGT-directed O GlcNAcylation and proteolytic maturation in HCF-1 cell-cycle regulation. PMID- 21295699 TI - Osh proteins regulate phosphoinositide metabolism at ER-plasma membrane contact sites. AB - Sac1 phosphoinositide (PI) phosphatases are essential regulators of PI-signaling networks. Yeast Sac1, an integral endoplasmic reticulum (ER) membrane protein, controls PI4P levels at the ER, Golgi, and plasma membrane (PM). Whether Sac1 can act in trans and turn over PI4P at the Golgi and PM from the ER remains a paradox. We find that Sac1-mediated PI4P metabolism requires the oxysterol binding homology (Osh) proteins. The PH domain-containing family member, Osh3, localizes to PM/ER membrane contact sites dependent upon PM PI4P levels. We reconstitute Osh protein-stimulated Sac1 PI phosphatase activity in vitro. We also show that the ER membrane VAP proteins, Scs2/Scs22, control PM PI4P levels and Sac1 activity in vitro. We propose that Osh3 functions at ER/PM contact sites as both a sensor of PM PI4P and an activator of the ER Sac1 phosphatase. Our findings further suggest that the conserved Osh proteins control PI metabolism at additional membrane contact sites. PMID- 21295700 TI - Cells respond to mechanical stress by rapid disassembly of caveolae. AB - The functions of caveolae, the characteristic plasma membrane invaginations, remain debated. Their abundance in cells experiencing mechanical stress led us to investigate their role in membrane-mediated mechanical response. Acute mechanical stress induced by osmotic swelling or by uniaxial stretching results in a rapid disappearance of caveolae, in a reduced caveolin/Cavin1 interaction, and in an increase of free caveolins at the plasma membrane. Tether-pulling force measurements in cells and in plasma membrane spheres demonstrate that caveola flattening and disassembly is the primary actin- and ATP-independent cell response that buffers membrane tension surges during mechanical stress. Conversely, stress release leads to complete caveola reassembly in an actin- and ATP-dependent process. The absence of a functional caveola reservoir in myotubes from muscular dystrophic patients enhanced membrane fragility under mechanical stress. Our findings support a new role for caveolae as a physiological membrane reservoir that quickly accommodates sudden and acute mechanical stresses. PMID- 21295701 TI - Influence of cell geometry on division-plane positioning. AB - The spatial organization of cells depends on their ability to sense their own shape and size. Here, we investigate how cell shape affects the positioning of the nucleus, spindle and subsequent cell division plane. To manipulate geometrical parameters in a systematic manner, we place individual sea urchin eggs into microfabricated chambers of defined geometry (e.g., triangles, rectangles, and ellipses). In each shape, the nucleus is positioned at the center of mass and is stretched by microtubules along an axis maintained through mitosis and predictive of the future division plane. We develop a simple computational model that posits that microtubules sense cell geometry by probing cellular space and orient the nucleus by exerting pulling forces that scale to microtubule length. This model quantitatively predicts division-axis orientation probability for a wide variety of cell shapes, even in multicellular contexts, and estimates scaling exponents for length-dependent microtubule forces. PMID- 21295702 TI - Control of the mitotic cleavage plane by local epithelial topology. AB - For nearly 150 years, it has been recognized that cell shape strongly influences the orientation of the mitotic cleavage plane (e.g., Hofmeister, 1863). However, we still understand little about the complex interplay between cell shape and cleavage-plane orientation in epithelia, where polygonal cell geometries emerge from multiple factors, including cell packing, cell growth, and cell division itself. Here, using mechanical simulations, we show that the polygonal shapes of individual cells can systematically bias the long-axis orientations of their adjacent mitotic neighbors. Strikingly, analyses of both animal epithelia and plant epidermis confirm a robust and nearly identical correlation between local cell topology and cleavage-plane orientation in vivo. Using simple mathematics, we show that this effect derives from fundamental packing constraints. Our results suggest that local epithelial topology is a key determinant of cleavage plane orientation, and that cleavage-plane bias may be a widespread property of polygonal cell sheets in plants and animals. PMID- 21295703 TI - Reference Maps of human ES and iPS cell variation enable high-throughput characterization of pluripotent cell lines. AB - The developmental potential of human pluripotent stem cells suggests that they can produce disease-relevant cell types for biomedical research. However, substantial variation has been reported among pluripotent cell lines, which could affect their utility and clinical safety. Such cell-line-specific differences must be better understood before one can confidently use embryonic stem (ES) or induced pluripotent stem (iPS) cells in translational research. Toward this goal we have established genome-wide reference maps of DNA methylation and gene expression for 20 previously derived human ES lines and 12 human iPS cell lines, and we have measured the in vitro differentiation propensity of these cell lines. This resource enabled us to assess the epigenetic and transcriptional similarity of ES and iPS cells and to predict the differentiation efficiency of individual cell lines. The combination of assays yields a scorecard for quick and comprehensive characterization of pluripotent cell lines. PMID- 21295704 TI - SnapShot: Chromatin remodeling: ISWI. PMID- 21295705 TI - Saving lives. Why we do what we do. PMID- 21295706 TI - Triage to transport. A case for national field triage guidelines. PMID- 21295707 TI - A wild ride. PMID- 21295708 TI - Teaching 'restraint'. Improper technique risks injury and lawsuits. PMID- 21295709 TI - The road ahead. Anticipating signal changes. PMID- 21295710 TI - Hanging out in Vegas. Responding to complex trauma cases. PMID- 21295712 TI - Are we ready for the future? Where EMS stands now & where it's prepared to go. PMID- 21295713 TI - Training for success. Strategies & core components to improve airway management. PMID- 21295714 TI - Without warning. How to effectively treat patients with excited delirium. PMID- 21295715 TI - Collaborative and supervisory relationships between attending physicians and advanced practice nurses in long-term care facilities. AB - Recent years have seen an increased interest and use of advanced practice nurses (APN) in long-term care. Models of best practices of supervision and collaboration have been promulgated by many organizations, but none have specifically addressed how these interactions should occur in the nursing home setting. In order to better define the role of the attending physician and APN to provide optimal resident care, American Medical Directors Association formed a work group to address collaborative and supervisory relationships in long-term care facilities. PMID- 21295716 TI - Quetiapine not quiet-a-pine--not a sleeper. PMID- 21295717 TI - Little known but powerful approach to applied research: community-based participatory research. PMID- 21295718 TI - Veterinary laboratory medicine. Preface. PMID- 21295719 TI - Diagnostic cytology in veterinary medicine: a comparative and evidence-based approach. AB - Diagnostic cytology is a core veterinary pathology service involving specimens from domestic animals, laboratory animals, and exotic species. Evidence-based application of cytopathology involves management of preanalytical factors, and thorough evaluation of the diagnostic accuracy of the technique in each species and for all specimen types. Unique to veterinary medicine is the reliance on cytology as the basis for crucial medical decisions such as humane euthanasia, especially when the patient is critically ill or when financial considerations limit diagnostic and therapeutic options. This article reviews the cytologic criteria for the diagnosis of selected neoplastic and infectious diseases. PMID- 21295720 TI - The diagnostic assessment of canine lymphoma: implications for treatment. AB - Lymphoma in dogs is a heterogeneous cancer with highly variable prognosis. Many types of canine lymphoma have similar counterparts in the World Health Organization classification of human lymphoid tumors. The most common variant of canine lymphoma is diffuse large B-cell lymphoma, which, if treated with multiagent chemotherapy, has a survival time of approximately 12 months. T-cell lymphomas are more heterogeneous and high- and low-grade variants are common, which necessitates classification beyond B- versus T-cell lineage. PMID- 21295721 TI - Glucose monitoring in diabetic dogs and cats: adapting new technology for home and hospital care. AB - Glucose levels in dogs and cats with diabetes mellitus can be monitored using a variety of techniques. Selecting the best monitoring technique requires involvement of the pet owner, communication between the owner and veterinarian, and practicality of the method. Some of the techniques typically used in dogs and cats are identical to those used in human diabetic patients. The use of modern technology designed specifically for people is being used increasingly for the management of diabetes in dogs and cats and offers a new mechanism for monitoring glucose in diabetic animals. PMID- 21295722 TI - Assay validation and diagnostic applications of major acute-phase protein testing in companion animals. AB - The use of major acute-phase proteins (APPs) for assessment of health and disease in companion animals has increased within the last decade because of increased knowledge in the field and increased access to appropriate assay systems for detection of relevant APPs, which are highly species specific. Despite evidence being restricted almost solely to proven excellent overlap performance of these markers in detecting inflammatory activity, clinically relevant studies at higher evidence levels do exist. The available body of literature shows a clear, but seemingly untapped, potential for more extended routine clinical use of major APP testing in companion animal medicine. PMID- 21295723 TI - Infectious and zoonotic disease testing in pet birds. AB - Pet bird ownership and the veterinary diagnostic market for avian and exotic species testing have grown markedly during the past 20 years. Birds present with both unique infectious diseases and other diseases that are known to the human medical community, including aspergillosis, mycobacteriosis, chlamydophilosis, and bornavirus infection, some of which have clear zoonotic implications. Although diagnostic testing for these avian infectious diseases has grown considerably and includes the newer technology of polymerase chain reaction as well as traditional serologic testing, guidelines for the use and interpretation of these tests and standardization of tests among veterinary laboratories remains an unmet challenge. PMID- 21295724 TI - Diagnostic hematology of reptiles. AB - The hematologic evaluation of reptiles is an indispensable diagnostic tool in exotic veterinary practice. The diversity of reptile species, their characteristic physiologic features, and effects of intrinsic and extrinsic factors present unique challenges for accurate interpretation of the hemogram. Combining the clinical presentation with hematologic findings provides valuable information in the diagnosis and monitoring of disease and helps guide the clinician toward therapy and further diagnostic testing. This article outlines the normal and pathologic morphology of blood cells of reptile species. The specific comparative aspects of reptiles are emphasized, and structural and functional abnormalities in the reptilian hemogram are described. PMID- 21295725 TI - The regenerative medicine laboratory: facilitating stem cell therapy for equine disease. AB - This article focuses on the emerging field of equine regenerative medicine with an emphasis on the use of mesenchymal stem cells (MSCs) for orthopedic diseases. We detail laboratory procedures and protocols for tissue handling and MSC isolation, characterization, expansion, and cryopreservation from bone marrow, fat, and placental tissues. We provide an overview of current clinical uses for equine MSCs and how MSCs function to heal tissues. Current laboratory practices in equine regenerative medicine mirror those in the human field. However, the translational use of autologous and allogeneic MSCs for patient therapy far exceeds what is currently permitted in human medicine. PMID- 21295726 TI - The equine neonatal intensive care laboratory: point-of-care testing. AB - Rapid evaluation and intervention is a requirement and a characteristic of patient management in neonatal intensive care units, and this applies for equine neonates also. Appropriate interventions are based on solid knowledge of age, maturity, and species-specific differences in reference ranges. Point-of-care (POC) testing devices speedup decision making regarding treatments and interventions. However, there are potential limitations of these devices when applied to age groups and species beyond those they were specifically developed for. This article discusses the age-specific differences in the reference ranges and the potential limitations of POC devices currently used, which may affect delivery of care. PMID- 21295727 TI - Comparative hemostasis: animal models and new hemostasis tests. AB - This article provides an overview of animal model systems to include their strengths and limitations in the study of hemostasis. Specific examples of spontaneous and engineered animal models are described in the context of cell based hemostasis. The article concludes with a review of the comparative aspects of 3 laboratory assays of cell-based hemostasis: thromboelastography, thrombin generation, and flow cytometric assessment of platelet activation. PMID- 21295728 TI - Preclinical safety assessment: current gaps, challenges, and approaches in identifying translatable biomarkers of drug-induced liver injury. AB - Currently, no serum biomarkers, including the biochemical gold standard alanine aminotransferase, can differentiate drug-induced from non-drug-related liver injury, can differentiate liver injury mediated by a specific drug or mechanism, or can accurately predict the progression and outcome of hepatic injury. Efforts have been made by veterinary clinical pathologists, toxicologists, and other scientists to address the gaps in hepatic biomarkers faced during drug development; although there have been no breakthroughs, several novel biomarker candidates have been identified. Efforts to address the gaps in translatable hepatic biomarkers and the challenges and hurdles faced during this process are highlighted in this review. PMID- 21295729 TI - Protecting animal and human health and the nation's food supply through veterinary diagnostic laboratory testing. AB - The current detection system for animal diseases requires coordination between veterinarians; veterinary medical laboratories; and state, federal, and international agencies, as well as associated private sector industries. Veterinary clinical pathologists in clinical and governmental laboratories often have responsibilities and expertise in one or more laboratory disciplines involved in diagnosing zoonotic and/or emerging diseases and diseases exotic to the United States that are important to animal and human health and the nation's food supply. The knowledge and roles of all veterinary laboratory professionals are vital to detect, monitor, and confirm diseases and conditions that affect animal and human health and the nation's animal food supply. PMID- 21295730 TI - Toxicosis caused by melamine and cyanuric acid in dogs and cats: uncovering the mystery and subsequent global implications. AB - Several major pet-food and human-food safety incidents occurred worldwide between 2003 and 2008, causing illnesses and deaths in children, cats, dogs, and pigs. During the 2007 outbreak of renal failure in dogs and cats in the United States, veterinary diagnostic laboratories helped identify melamine and melamine analogues as contaminants in implicated food. In 2008, thousands of infants developed renal failure from exposure to melamine alone. Management of these outbreaks depends on the collaboration of veterinary and human laboratories and clinics, government agencies, academic institutions, and food industries, along with prompt communication and sharing of data. PMID- 21295731 TI - A novel educational tool for teaching diagnostic reasoning and laboratory data interpretation to veterinary (and medical) students. AB - The Diagnostic Pathfinder was designed to help students learn diagnostic problem solving by supporting them in explaining relationships among history and physical examination findings, data abnormalities, and the underlying mechanisms of disease. The Pathfinder has been used to teach diagnostic problem solving to veterinary students since 2001 and is currently in use at 10 colleges of veterinary medicine. This article describes how the Pathfinder works and summarizes results from studies exploring the effect of Pathfinder use on learning and satisfaction. Pathfinder characteristics are described in terms of their influence on cognitive load, and strategies are provided for effective implementation. PMID- 21295732 TI - MRI catheter guidance and steering of vascular procedures with a reduced heating risk. PMID- 21295733 TI - Semiautomated motion correction of tumors in lung CT-perfusion studies. AB - RATIONALE AND OBJECTIVES: To compare the relative performance of one-dimensional (1D) manual, rigid-translational, and nonrigid registration techniques to correct misalignment of lung tumor anatomy acquired from computed tomography perfusion (CTp) datasets. MATERIALS AND METHODS: Twenty-five datasets in patients with lung tumors who had undergone a CTp protocol were evaluated. Each dataset consisted of one reference CT image from an initial cine slab and six subsequent breathhold helical volumes (16-row multi-detector CT), acquired during intravenous contrast administration. Each helical volume was registered to the reference image using two semiautomated intensity-based registration methods (rigid-translational and nonrigid), and 1D manual registration (the only registration method available in the relevant application software). The performance of each technique to align tumor regions was assessed quantitatively (percent overlap and distance of center of mass), and by a visual validation study (using a 5-point scale). The registration methods were statistically compared using linear mixed and ordinal probit regression models. RESULTS: Quantitatively, tumor alignment with the nonrigid method compared to rigid-translation was borderline significant, which in turn was significantly better than the 1D manual method: average (+/- SD) percent overlap, 91.8 +/- 2.3%, 87.7 +/- 5.5%, and 77.6 +/- 5.9%, respectively; and average (+/- SD) DCOM, 0.41 +/- 0.16 mm, 1.08 +/- 1.13 mm, and 2.99 +/- 2.93 mm, respectively (all P < .0001). Visual validation confirmed these findings. CONCLUSION: Semiautomated registration methods achieved superior alignment of lung tumors compared to the 1D manual method. This will hopefully translate into more reliable CTp analyses. PMID- 21295734 TI - Computer-aided diagnosis of pulmonary infections using texture analysis and support vector machine classification. AB - RATIONALE AND OBJECTIVES: The purpose of this study was to develop and test a computer-assisted detection method for the identification and measurement of pulmonary abnormalities on chest computed tomographic (CT) imaging in cases of infection, such as novel H1N1 influenza. The method developed could be a potentially useful tool for classifying and quantifying pulmonary infectious disease on CT imaging. MATERIALS AND METHODS: Forty chest CT examinations were studied using texture analysis and support vector machine classification to differentiate normal from abnormal lung regions on CT imaging, including 10 patients with immunohistochemistry-proven infection, 10 normal controls, and 20 patients with fibrosis. RESULTS: Statistically significant differences in the receiver-operating characteristic curves for detecting abnormal regions in H1N1 infection were obtained between normal lung and regions of fibrosis, with significant differences in texture features of different infections. These differences enabled the quantification of abnormal lung volumes on CT imaging. CONCLUSION: Texture analysis and support vector machine classification can distinguish between areas of abnormality in acute infection and areas of chronic fibrosis, differentiate lesions having consolidative and ground-glass appearances, and quantify those texture features to increase the precision of CT scoring as a potential tool for measuring disease progression and severity. PMID- 21295735 TI - Quantification of aortic regurgitant fraction and volume with multi-detector computed tomography comparison with echocardiography. AB - RATIONALE AND OBJECTIVES: Evaluate quantification of the aortic regurgitant fraction and volume with computed tomography (CT). MATERIALS AND METHODS: Fifty three patients with aortic regurgitation (AR) and 29 controls were examined with 64-multi-detector CT coronary angiography and transthoracic echocardiography (TTE). A dedicated software algorithm employing three-dimensional segmentation of left ventricle (LV) and right ventricle (RV) volumes and LV mass was applied. AR volume and fraction was calculated based on RV and LV stroke volumes (SV) and compared with echocardiography. The aortic regurgitant orifice area (ROA) was measured by CT. RESULTS: A good correlation of the AR fraction and AR volume determined by CT compared to echocardiography was found for mild, moderate, and severe AR with 14.2% +/- 9, 28.8% +/- 8, and 57.9% +/- 9 (r = 0.95, P < .001) for AR fraction, and 15.7 mL +/- 11.33 mL +/- 14, and 98.9 mL +/- 36 for AR volume (r = 0.92, P < .0001), respectively. CT correctly classified severity of AR in 93% of patients based of AR-fraction, and in 89% based on AR volume. The sensitivity and specificity of CT were 98% and specificity 90.3%. The specificity improved to 97%, if the ROA by CT was added as diagnostic criterion. CONCLUSION: Aortic regurgitation fraction and volume can be accurately quantified from CT coronary angiography datasets. These parameters can assist clinical management, e.g. in case of pending cardiac surgery decision. PMID- 21295737 TI - Prevalence of significant coronary artery disease in symptomatic patients without coronary calcification (agatston score 0) and low-intermediate risk. PMID- 21295738 TI - Chronicles of small beer. Jim Youker. PMID- 21295739 TI - Osteoporosis update from the 2010 santa fe bone symposium. AB - The 11th Santa Fe Bone Symposium was held in Santa Fe, NM, USA, on August 6-7, 2010. This annual event addresses clinically relevant advances in the fields of osteoporosis and metabolic bone disease. The venue includes plenary presentations by internationally recognized experts, oral presentations of abstracts, and interactive panel discussions of challenging cases and controversial issues. Attendees are active participants throughout the symposium program. Topics for the 2010 symposium included potential applications of novel technologies for the assessment of skeletal health for research and clinical practice; new and emerging treatments for osteoporosis; appropriate use of pharmacological agents to prevent osteoporosis; controversies with bisphosphonate therapy; practical applications of the World Health Organization fracture risk assessment tool (FRAX; World Health Organization Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, UK); insights into the use of osteoanabolic agents to enhance fracture healing; and challenges in laboratory testing in the assessment of factors contributing to skeletal fragility. Concurrent sessions focused on critical thinking for technologists in the acquisition and analysis of data with dual-energy X-ray absorptiometry. The key messages from each presentation, including the best available medical evidence and potential current and future clinical applications, are provided here. PMID- 21295740 TI - Age-related differences of bone mass, geometry, and strength in treatment-naive postmenopausal women. A tibia pQCT study. AB - Most studies addressing the effects of aging on bone strength have focused mainly on (areal) bone mineral densities and bone mineral content (BMC) and less on bone geometry. We assessed age-related differences of bone mass (grams of bone mineral), geometry, and derived strength in 219 treatment-naive postmenopausal women using peripheral quantitative computed tomography of the load-bearing tibia. Subjects were separated in 3 age groups: A=48-59yr (N=80), B=60-69yr (N=84), C=70-80yr (N=55). Three slices were obtained for each individual, at the 4% (trabecular), 14% (subcortical and cortical), and 38% (cortical bone) of tibia length sites. Trabecular, subcortical, and cortical BMC (mg per 1-mm slice), volumetric bone mineral densities (mg/cm(3)), bone cross-sectional areas (mm(2)), periosteal (PERI_C, mm) and endosteal circumference (ENDO_C, mm), mean cortical thickness (CRT_THK, mm), and Stress Strain Indexes (SSIs, mm(3)) were studied. Trabecular and cortical BMC and volumetric densities were significantly lower in the elder subjects (group C) compared with younger subjects (groups A and B), p<0.0005. Cortical area and CRT_THK were significantly lower in group C (vs A and B, p<0.0005), whereas total cross-sectional area was higher in group C compared with A and B. ENDO_C was significantly higher in older subjects (group C vs A and B, p<0.0005), whereas PERI_C did not differ significantly between the age groups. SSIs were significantly lower in older subjects at the 14% site (group C vs A, p<0.0005 and C vs B, p<0.005), and at the 38% site (group C vs group A, p<0.01). Our results indicate that age-induced differences on bone strength entail significant alterations not only of bone mass, but also of bone geometry. PMID- 21295741 TI - Assessing the clinical utility of quantitative computed tomography with a routinely used diagnostic computed tomography scanner in a cancer center. AB - The purpose of this study was to characterize quantitative computed tomography (QCT) in our multi-detector computed tomography (MDCT) scanner with regard to the influence of the QCT phantom on dose and the influence of varying mA and CIRS phantom size on bone mineral density (BMD) measurements. We accomplish this by scanning a commercially available QCT phantom and a corresponding quality assurance phantom. To assess the feasibility of having the QCT phantom in place while patients are being scanned, we measured radiation dose difference in a CT body phantom with and without the QCT phantom on the CT table and also, with and without the use of dose modulation programs. We also analyzed reconstructed QCT phantom images with the manufacturer's software to measure BMD. Although patient characteristics may be different, leading to different mA values, the influence of the QCT phantom on the dose to patients was minimal when compared with doses measured without the phantom in place. Average BMD measurements were not significantly affected by varying mA, for a fixed-size phantom. The average BMD exhibited a weak dependence on computerized imaging reference systems (CIRS) torso phantom size, with a propensity for decreasing BMD with increasing size. Measurement precision was unaffected by varying CIRS size. Having the ability to measure bone density as part of the routine management of cancer patients, with no added cost, time, or radiation dose, will allow for the prospective evaluation of bone mineral changes. We believe that this ability will facilitate the detection of abnormal bone loss and will lead to better management of this loss and, thus, reduce the complications and associated morbidity in these cancer survivors. PMID- 21295743 TI - Birth weight a negative determinant of whole body bone mineral apparent density in a group of adolescent boys. AB - The aim of this study was to explore the relation between birth weight and bone mass in a group of adolescent boys. This study included 44 adolescent (aged 14 20yr) boys. Anthropometric characteristics (height and weight) were measured and birth weights were obtained from the obstetric records. Body composition was assessed by dual-energy X-ray absorptiometry (DXA). Bone mineral content (BMC) and bone mineral density (BMD) of the whole body (WB) and the lumbar spine (L2 L4) were also assessed by DXA. Calculations of the bone mineral apparent density (BMAD) were completed for the WB and at the lumbar spine (L2-L4). The expressions WB BMC/height and WB BMD/height were calculated to adjust for WB bone size. Birth weight was positively correlated to body weight (r=0.37; p<0.05), body mass index (r=0.38; p<0.01), body fat percentage (r=0.44; p<0.01), and negatively associated with WB BMAD (r=-0.46; p<0.01). In conclusion, this study suggests that birth weight is a positive determinant of body weight, body mass index, and body fat percent but a negative determinant of WB BMAD in adolescent boys. PMID- 21295742 TI - The soy isoflavones for reducing bone loss study: 3-yr effects on pQCT bone mineral density and strength measures in postmenopausal women. AB - Soy isoflavones exert inconsistent bone density-preserving effects, but the bone strength-preserving effects in humans are unknown. Our double-blind randomized controlled trial examined 2 soy isoflavone doses (80 or 120mg/d) vs placebo tablets on volumetric bone mineral density (vBMD) and strength (by means of peripheral quantitative computed tomography) in healthy postmenopausal women (46 63yr). We measured 3-yr changes in cortical BMD (CtBMD), cortical thickness (CtThk), periosteal circumference (PC), endosteal circumference (EC), and strength-strain index (SSI) at 1/3 midshaft femur (N=171), and trabecular BMD (TbBMD), PC, and SSI at 4% distal tibia (N=162). We found no treatment effect on femur CtThk, PC, or EC, or tibia TbBMD or PC. The strongest predictors (negative) of tibia TbBMD and SSI and femur CtBMD were timepoint and bone resorption; whole body fat mass was protective of SSI. As time since last menstrual period (TLMP) increased (p=0.012), 120-mg/d dose was protective of CtBMD. The strongest predictors of femur SSI were timepoint, bone resorption, and TLMP (protective). Isoflavone tablets were negative predictors of SSI, but 80-mg/d dose became protective as bone turnover increased (p=0.011). Soy isoflavone treatment for 3yr was modestly beneficial for midshaft femur vBMD as TLMP increased and for midshaft femur SSI as bone turnover increased. PMID- 21295744 TI - Spontaneous supracondylar femoral fracture in an HIV patient in lotus position. AB - Bone disorders have been described in patients chronically infected with human immunodeficiency virus (HIV). A case of spontaneous supracondylar femoral fracture that occurred in a 58-year-old monk during meditation is reported. His AIDS disease was controlled with combination antiretroviral therapy. Vitamin D and calcium had been added 3yr before since osteoporosis was detected by dual energy X-ray absorptiometry (DXA). At the time of the fracture, the patient was on treatment with 35mg every week of sodium risedronate, 1000mg of calcium, and 400IU of Vitamin D every day. Clinical use of DXA for HIV patients should be considered as a routine measure to help reducing risk for fractures. PMID- 21295745 TI - [A complete issue devoted entirely to hepatocellular carcinoma?]. PMID- 21295746 TI - [Nephrology and therapeutics. Editorial]. PMID- 21295748 TI - Preface. Finding the fourth branch-understanding quality-of-care in anesthesiology. PMID- 21295749 TI - Teamwork and communication in the operating room: relationship to discrete outcomes and research challenges. AB - The literature defining and addressing teamwork and communication is abundant; however, few studies have analyzed the relationship between measures of teamwork and communication and quantifiable outcomes. The objectives of this review are: (1) to identify studies addressing teamwork and communication in the operating room in relation to discrete measures of outcome, (2) to create a classification of studies of the relationship between teamwork and communication and outcomes, (3) to assess the implications of these studies, (4) to explore the methodological challenges of teamwork and communication studies in the perioperative setting, and (5) to suggest future research directions.studies in the perioperative setting, and (5) to suggest future research directions. PMID- 21295750 TI - Simulation and quality improvement in anesthesiology. AB - Simulation, a strategy for improving the quality and safety of patient care, is used for the training of technical and nontechnical skills and for training in teamwork and communication. This article reviews simulation-based research, with a focus on anesthesiology, at 3 different levels of outcome: (1) as measured in the simulation laboratory, (2) as measured in clinical performance, and (3) as measured in patient outcomes. It concludes with a discussion of some current uses of simulation, which include the identification of latent failures and the role of simulation in continuing professional practice assessment for anesthesiologists. PMID- 21295751 TI - Using information technology to improve quality in the OR. AB - This article summarizes the current state of technology as it pertains to quality in the operating room, ties the current state back to its evolutionary pathway to understand how the current capabilities and their limitations came to pass, and elucidates how the overlay of information technology (IT) as a wrapper around current monitoring and device technology provides a significant advance in the ability of anesthesiologists to use technology to improve quality along many axes. The authors posit that IT will enable all the information about patients, perioperative systems, system capacity, and readiness to follow a development trajectory of increasing usefulness. PMID- 21295752 TI - Using real-time clinical decision support to improve performance on perioperative quality and process measures. AB - Anesthesia information management systems (AIMS) are becoming more commonplace in operating rooms across the world and have the potential to help clinicians measure and improve perioperative quality. However, to realize the full potential of AIMS, clinicians must first understand their capabilities and limitations. This article reviews the literature on AIMS, focusing on areas where AIMS have been shown to have a meaningful impact on quality, safety, and operational efficiency. PMID- 21295753 TI - Outcomes research using quality improvement databases: evolving opportunities and challenges. AB - The challenges to prospective randomized controlled trials have necessitated the exploration of observational data sets that support research into the predictors and modulators of preoperative adverse events. The primary purpose and design of quality improvement databases is quality assessment and improvement at the local, regional, or national level. However, these data can also provide the opportunity to robustly study specific questions related to patient outcomes with no additional clinical risk to the patient. The virtual explosion of anesthesia related registries has opened seemingly limitless opportunities for outcomes research in addition to generating hypothesis for more rigorous prospective analysis. PMID- 21295754 TI - Preventing postoperative complications in the elderly. AB - Postoperative complications are directly related to poor surgical outcomes in the elderly. This review outlines evidence based quality initiatives focused on decreasing neurologic, cardiac, and pulmonary complications in the elderly surgical patient. Important anesthesia quality initiatives for prevention of delirium, the most common neurologic complication in elderly surgical patients, are outlined. There are few age-specific quality measures aimed at prevention of cardiac and pulmonary complications. However, some recommendations for adults can be applied to the geriatric surgical population. In the future, process measures may provide a more global assessment of quality in the elderly surgical population. PMID- 21295755 TI - Improving quality through multidisciplinary education. AB - Multidisciplinary education (MDE) is perceived as the next means of implementing major improvements in the quality and cost-effectiveness of patient care. In this article, the authors discuss various definitions of MDE, evaluate how MDE might be implemented in clinical arenas relevant to the anesthesiologist, and describe several implementations of MDE within their hospital and the anesthesiology department. PMID- 21295756 TI - Health care quality in end-of-life care: promoting palliative care in the intensive care unit. AB - Seminal articles published in the late 1990s instigated not only an intense interest in health care quality but also a new era of research into quality end of-life care, particularly in intensive care units (ICUs). ICUs can improve health care quality at the end of life by better using palliative care services and palliative care-related principles. This article details how the interest in health care quality has spurred a similar interest in end-of-life and palliative care in ICUs, defines palliative care and describes how it improves health care quality, and highlights barriers to the incorporation of palliative care in ICUs. PMID- 21295757 TI - Quality assurance and assessment in pain management. AB - Relief from pain is itself a marker of high-quality medical care. Quality assurance in the case of pain management could simply mean successful elimination of pain. Because the means of controlling pain are imperfect, it is essential to consider whether pain interventions actually achieve the primary goal of pain relief and also whether they are safe, cost-effective, and even capable of producing secondary benefits such as early recovery from surgery. Quality assurance and assessment in pain management therefore becomes a complex undertaking that must incorporate into its processes the often-conflicting goals of comfort versus safety versus patients' rights. PMID- 21295758 TI - Medication safety in the perioperative setting. AB - Drug administration errors are a major cause of morbidity and mortality in hospitalized patients. These errors result in major harm and incur dramatic costs to the delivery of health care. This article highlights this problem, especially as it deals with patients in the perioperative setting. PMID- 21295759 TI - Reduction of regulated medical waste using lean sigma results in financial gains for hospital. AB - This article describes how anesthesiologists can lead innovation and process improvement focused on regulated medical waste reduction and cost savings using a process improvement methodology known as Lean Sigma. PMID- 21295760 TI - An anesthesiology department leads culture change at a hospital system level to improve quality and patient safety. AB - At New York-Presbyterian Hospital, Weill Cornell Medical Center, an innovative approach to involving housestaff in quality and patient safety, policy and procedure creation, and culture change was led by the Department of Anesthesiology of the Weill Medical College of Cornell University. A Housestaff Quality Council was started in 2008 that has partnered with hospital leadership and clinical departments to engage the housestaff in quality and patient safety initiatives, resulting in measurable improvements in several patient care projects and enhanced working relationships among various clinical constituencies. Ultimately this attempt to change culture has found great success in fostering a relationship between the housestaff and the hospital in ways that have and will continue to improve patient care. PMID- 21295761 TI - [Superficial angiomyxoma of the parotid region and review of the literature]. AB - Superficial angiomyxoma (SA) is a rare benign cutaneous neoplasm first described by Allen et al in 1988. To the best of our knowledge, we report the first case of superficial angiomyxoma located in the parotid region. We also stress the importance of distinguishing this entity from other lesions that may be involved in this location such as cutaneous neoplasms, parotid tumours or cysts. We emphasise the need to rule out the Carney complex, which has been associated with these tumours. PMID- 21295762 TI - [Otoplasty: results after anterior versus posterior approach]. AB - INTRODUCTION AND OBJECTIVE: In otoplasty, an anterior approach with sutures is commonly used, because it is not aggressive with cartilage. The aim of this study on otoplasty was to evaluate the usefulness of the anterior approach, comparing it to the results obtained after the posterior approach. MATERIAL AND METHODS: Retrospective study on 25 otoplasties performed at a University Hospital during the period 2004-2008. Clinical records from 13 patients (25 otoplasties), between 7-41 years of age, were reviewed. In the anterior approach, the anterior surface of the auricular cartilage is scratched with a rasp. The antihelix shape is obtained and mattress sutures are placed through the anterior surface of the ear. RESULTS: Out of 25 otoplasties, 92% were bilateral and 8%, unilateral; 54% of the patients were children and 46%, adults; anaesthesia was local in 20% and general in 80%. We performed 11 anterior and 14 posterior approach otoplasties. After an anterior approach, complications were suture extrusion in 82%, foreign body reaction in 9%, and revision surgery was needed in 28% of 11 otoplasties performed. After a posterior approach, complications were suture extrusion in 21%, foreign body reaction in 7%, and revision surgery was needed in 7% of 14 otoplasties performed. A good aesthetic result was obtained in almost all the cases (85%). Extrusion rate was statistically more common after the anterior approach. CONCLUSIONS: In our opinion, otoplasty is a simple technique for treatment of prominent ears, with good aesthetic results. The most common complication is suture extrusion, more frequent after an anterior approach. PMID- 21295763 TI - Performance in haptic geometrical matching tasks depends on movement and position of the arms. AB - Previous research on the properties of haptic space has shown systematic deviations from Euclidean parallelity in haptic parallelity tasks. The mainstream explanation for these deviations is that, in order to perform the task, participants generate a spatial representation with a frame of reference that integrates egocentric and allocentric components. Several studies have shown that the amount and type of deviations are affected by the configurations with regard to the arms and the rods to be matched. The present study reports 4 experiments that further address the effects of task configurations and body movements. Experiments 1 and 2 replicate and extend previous results concerning haptic matching task and acoustic pointing tasks. The third experiment includes acoustic cues aligned differentially to the reference and test bars. The fourth experiment concerns a geometrical matching task performed in the rear peripersonal space. Results show that haptic deviations from the Euclidean space are modulated by the available cues and by the body configurations. This indicates the need for further analysis on the role of body, arm and shoulder positions, and movement effects in haptic space perception. PMID- 21295764 TI - Understanding protein adsorption phenomena at solid surfaces. AB - Protein adsorption at solid surfaces plays a key role in many natural processes and has therefore promoted a widespread interest in many research areas. Despite considerable progress in this field there are still widely differing and even contradictive opinions on how to explain the frequently observed phenomena such as structural rearrangements, cooperative adsorption, overshooting adsorption kinetics, or protein aggregation. In this review recent achievements and new perspectives on protein adsorption processes are comprehensively discussed. The main focus is put on commonly postulated mechanistic aspects and their translation into mathematical concepts and model descriptions. Relevant experimental and computational strategies to practically approach the field of protein adsorption mechanisms and their impact on current successes are outlined. PMID- 21295765 TI - Comparison of astigmatic keratotomy results in deep anterior lamellar keratoplasty and penetrating keratoplasty in keratoconus. AB - PURPOSE: To compare astigmatic keratotomy (AK) outcomes in high astigmatism after deep anterior lamellar keratoplasty (DALK) and after penetrating keratoplasty (PK) in keratoconus patients. DESIGN: Prospective, comparative, interventional case series. METHODS: This study comprised 20 eyes that underwent DALK and 24 eyes that underwent PK. After suture removal, all eyes had more than 5 diopters (D) of astigmatism and underwent standard manual 1-pair, 90-degree, and 90% corneal thickness AK incisions. The main outcome measures included preoperative and postoperative manifest refraction, uncorrected visual acuity, best spectacle corrected visual acuity, surgically induced astigmatism, Orbscan II (Bausch & Lomb) corneal topography results, keratometric astigmatism, and complications. RESULTS: All eyes completed 6 months of follow-up. The overcorrection rate was 35% and 41.6% in the DALK and PK groups, respectively (P=.75). At 6 months after AK, logarithm of the minimal angle of resolution uncorrected visual acuity improved from 0.88 +/- 0.20 to 0.54 +/- 0.26 and from 1.0 +/- 0.34 to 0.53 +/- 0.26 in the DALK and PK groups, respectively (P=.01 to P<.01). Best spectacle corrected visual acuity improved from 0.16 +/- 0.09 to 0.13 +/- 0.08 and from 0.16 +/- 0.12 to 0.11 +/- 0.08 in the DALK and PK groups, respectively (P=.13 to P=.01). The mean refractive cylinder was decreased 2.74 +/- 1.44 D in the DALK group and 3.18 +/- 2.96 D in the PK group (P=.35). Surgically induced astigmatism was 6.10 +/- 3.27 D in the DALK group and 7.15 +/- 2.98 D in the PK group (P=.36). CONCLUSIONS: The manual AK for the treatment of postkeratoplasty astigmatism after DALK and PK in keratoconus patients is a safe and effective surgical procedure, allowing similar refractive cylinder reduction and improvement in uncorrected visual acuity and best spectacle-corrected visual acuity. PMID- 21295766 TI - Subfoveal retinal and choroidal thickness after verteporfin photodynamic therapy for polypoidal choroidal vasculopathy. AB - PURPOSE: To evaluate the morphologic retinal and choroidal changes after verteporfin photodynamic therapy (PDT) with and without ranibizumab for polypoidal choroidal vasculopathy using spectral-domain optical coherence tomography. DESIGN: Retrospective, comparative series. METHODS: The enhanced depth imaging optical coherence tomography technique was used in this retrospective, comparative series to measure the subfoveal retinal and choroidal thicknesses before and after treatment. RESULTS: Twenty-seven eyes with polypoidal choroidal vasculopathy were examined retrospectively. Sixteen eyes were treated with PDT monotherapy (PDT group). Eleven eyes were treated with PDT after intravitreal ranibizumab injection (ranibizumab plus PDT group). The polypoidal lesions regressed in all cases at 3 months. The mean retinal thickness, including the retinal detachment, increased from 401 +/- 157 MUm before treatment to 506 +/- 182 MUm 2 days after PDT (P<.001) and decreased to 365 +/- 116 MUm by 1 week after treatment (P=.03) and 265 +/- 127 MUm by 6 months after treatment (P<.001). The mean choroidal thickness increased from 269 +/- 107 MUm before treatment to 336 +/- 96 MUm 2 days after PDT treatment (P < .001 compared with baseline) and decreased to 262 +/- 96 MUm by 1 week after treatment (P=.24) and 229 +/- 104 MUm by 6 months (P<.001). Although the choroidal thickness showed a similar trend with both therapies, the retinal thickness in the ranibizumab plus PDT group remained thinner than that in the PDT group until 6 months after treatment. CONCLUSIONS: PDT was associated with decreased retinal and choroidal thicknesses. Combination therapy reduced the transient exudation after PDT in some cases, and monthly intravitreal ranibizumab injections maintained retinal thinning and seemed to improve vision better than PDT monotherapy. PMID- 21295767 TI - Reduced ADHD symptoms in adults with ADHD after structured skills training group: results from a randomized controlled trial. AB - OBJECTIVE: Feasibility, acceptability, and efficacy of a Dialectical Behavioral Therapy (DBT) -based method developed in Germany were evaluated in a Swedish outpatient psychiatric context. METHOD: Fifty-one adults with ADHD on stable medical treatment or on no medication were randomized to the DBT-based skills training (n=26) or a parallel loosely structured discussion group (n=25). Self rating scales were administered before randomization and after the treatment. RESULTS: Feasibility and participant satisfaction were good in both groups while skills training was perceived as more logical and effective for ADHD-related problems. The analyses of the individuals who completed the treatment and remained stable with regard to medication (n=19 in skills training; n=18 in control group) showed a significant reduction in ADHD symptoms in the skills training group, but not in the control group. No reduction of comorbidity was observed in any of the groups. CONCLUSIONS: The treatment was feasible in an outpatient psychiatric context, well tolerated, and significantly reduced ADHD symptoms in on-treatment individuals who remained stable regarding medication status. PMID- 21295768 TI - Path analytic examination of a cognitive model of PTSD. AB - Ehlers and Clark (2000) developed a cognitive model of posttraumatic stress disorder (PTSD) symptom maintenance which implicated the role of posttraumatic cognitions and aspects of the trauma memory in maintaining symptoms via an increased sense of current threat. The aim of the current study was to empirically test a variant of this model using path analysis. Participants in the current study were 514 undergraduates at a midwestern university who reported experiencing at least one traumatic event. Path analyses examined various models of the possible relationships between one's posttraumatic cognitions and the centrality of the traumatic event to the sense of self (considered an aspect of memory integration) in predicting current level of PTSD symptoms. Results indicate that both event centrality and posttraumatic cognitions are unique and independent predictors of current symptom level. Overall, the results of this study support aspects of Ehlers and Clark's cognitive model of PTSD; cognitive appraisals of the self and centrality of the event were highly related to levels of distress. However, the current study suggests that overly integrated trauma memories may lead to greater distress and not poorly integrated ones as suggested by Ehlers and Clark. PMID- 21295769 TI - Viscosity-temperature behavior of chitin solutions using lithium chloride/DMA as solvent. AB - Solutions of chitin in Li(+)/N,N-dimethylacetamide systems were studied via viscometry, using LiCl concentrations of 3% and 5% (m/v) and chitin concentrations ranging from 0.075 to 0.375 gL(-1). The reduced viscosity number versus concentration plot showed a minimum that was related to the formation of Li(+)-OC complex moieties along chitin macromolecular chains. Viscosity behavior was affected by temperature according to the Eyring model: concentration dependence of flow enthalpy of activation was correlated to polymer-polymer interactions and flow entropy of activation to the stiffness of the complexed chitosan macromolecular chain. PMID- 21295770 TI - [Spontaneous expulsion of a gallstone through the abdominal wall in chronic cholecystitis]. PMID- 21295771 TI - Preparing for severe contrast media reactions in children - results of a national survey, a literature review and a suggested protocol. AB - AIM: To identify current practices within paediatric radiology in the UK with regard to the use of prophylactic medication, prior to administering intravenous (IV) radiocontrast medium (RCM). In addition, the pre-injection risk management strategies of the departments questioned was to be evaluated, and using consensus opinion, a protocol for managing patients identified as being at high risk for an adverse reaction to RCM was to be outlined. MATERIALS AND METHODS: An online survey of paediatric radiology consultants representing all geographic regions of the UK was carried out. The questions asked included an assessment of the risk factors for adverse reactions to RCM, and how such reactions are anticipated and managed. The questionnaire asked about the perceived indications for, and the use of prophylactic medication prior to RCM administration. RESULTS: A response rate of 51% was achieved. The majority of respondents felt that a history of previous RCM reaction was an indication to administer prophylactic drugs prior to a further dose of RCM. No other risk factor was believed to require prophylactic medication. CONCLUSION: Using information obtained from the survey, a literature search was performed to assess the evidence available in support of each practice. A protocol was devised to identify children at risk of an adverse reaction to RCM, and guide the use of prophylactic medication in this group of patients. The survey highlighted considerable variability in the risk-assessment and management practices within paediatric radiology in the UK. The derived protocol may guide radiologists' management of children at risk for an RCM reaction. PMID- 21295772 TI - Accuracy of hepatocellular carcinoma detection on multidetector CT in a transplant liver population with explant liver correlation. AB - AIM: To evaluate the diagnostic accuracy of multidetector computed tomography (MDCT) for hepatocellular carcinoma (HCC) in cirrhotic patients undergoing liver transplantation. Secondary aims were to examine the effect of radiologist experience and lesion size on diagnostic accuracy. MATERIALS AND METHODS: Thirty nine patients (72% male with a mean age of 56.5 years) underwent liver transplantation following preoperative triple-phase MDCT examination of the liver. MDCT examinations were retrospectively independently reviewed by three radiologists for the presence and location of suspected HCCs, with the diagnostic confidence recorded using a five-point confidence scale. MDCT examinations were compared with explant specimens for histopathological correlation. RESULTS: Histopathological results demonstrated 46 HCCs in 29 of the 39 patients. Analysis demonstrated a sensitivity of 65-75% and specificity of 47-88% for detection of HCC lesions. The sensitivity dropped to 48-57% for lesions of size <=20mm. As the diagnostic confidence increased, there was a further decrease in the sensitivity (4-26%). The radiologist with the greatest number of years experience was found to have a significantly higher accuracy of detection of HCC lesions compared with the least experienced radiologist. CONCLUSION: Larger lesion size of HCC and greater number of years experience of the radiologist resulted in significantly higher accuracy of HCC lesion detection. The overall sensitivity and specificity results for MDCT detection of HCC are comparable to previous helical CT imaging. PMID- 21295773 TI - Effects of practice on task architecture: combined evidence from interference experiments and random-walk models of decision making. AB - Does extensive practice reduce or eliminate central interference in dual-task processing? We explored the reorganization of task architecture with practice by combining interference analysis (delays in dual-task experiment) and random-walk models of decision making (measuring the decision and non-decision contributions to RT). The main delay observed in the Psychologically Refractory Period at short stimulus onset asynchronies (SOA) values was largely unaffected by training. However, the range of SOAs over which this interference regime held diminished with learning. This was consistent with an overall shift observed in single-task performance from a highly variable decision time to a reliable (non-decision time) contribution to response time. Executive components involved in coordinating dual-task performance decreased (and became more stable) after extensive practice. The results suggest that extensive practice reduces the duration of central decision stages, but that the qualitative property of central seriality remains a structural invariant. PMID- 21295774 TI - Effects of atypical antipsychotics on neurocognition in euthymic bipolar patients. AB - BACKGROUND: Different factors may influence cognitive functioning in bipolar disorder such as the effect of subsyndromal symptoms, the history of psychotic symptomatology or substance abuse, negative symptomatology, chronicity, sleep disturbances, and hormonal factors. The effect of pharmacologic treatment on cognition is still uncertain because of an insufficient number of studies examining this issue. OBJECTIVE: The aims of this study were to compare neuropsychologic performance of treated bipolar patients with that of controls, including unmedicated patients and healthy subjects, as well as to evaluate possible neurocognitive differences among 3 different atypical antipsychotics. RESEARCH DESIGN AND METHODS: A total of 119 subjects were included in the study. Of 79 Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition euthymic bipolar patients, 68 were treated with one atypical antipsychotic, quetiapine (n = 12), olanzapine (n = 26), or risperidone (n = 30). Sixteen patients were drug-free. The 4 groups were compared with a sample of drug-naive patients and a healthy control group (n = 35) on several clinical and neuropsychologic variables, especially on the domains of attention, verbal memory, and executive functions. Euthymia was defined by a score of 6 or less at the Young Mania Rating Scale and a score of 8 or less at the Hamilton Depression Rating Scale for at least 6 months. RESULTS: The 5 groups did not differ in age, years of education, sex distribution, or estimated premorbid IQ. The 4 patients groups did not differ in chronicity, age of onset, total number of episodes, and number of hospitalizations. No differences were found regarding antipsychotic dosages between the groups. Bipolar patients performed poorly on most neuropsychologic measures as compared with healthy controls. After controlling for Hamilton Depression Rating Scale symptoms, no significant change in the results was observed. Because many patients with antipsychotic treatment had a history of psychotic symptoms, we performed multivariate analysis of covariance controlling for this variable. Bipolar patients taking 1 of the 3 antipsychotics presented with dose-independent significant deficits in most cognitive tasks compared with healthy controls. After several head-to-head group comparisons, the patients receiving quetiapine showed a better performance in learning task, short term memory, and recognition task assessed with the California Verbal Learning Test and verbal fluency (P < .05). CONCLUSIONS: Our results confirm the findings of previous studies of cognitive deficits in bipolar disorder. Untreated euthymic patients showed better cognitive performance than did patients on atypical antipsychotics. Some iatrogenic-pharmacologic effect, therefore, cannot be excluded, but quetiapine seemed to be less associated with impairment in measures of verbal memory than olanzapine or risperidone. We suggest to use drugs in bipolar disorder with a lower risk of cognitive adverse effects. However, randomized controlled trials are urgently needed to give a definite answer to this critical problem. PMID- 21295775 TI - Substance abuse versus dependence and the structure of common mental disorders. AB - BACKGROUND: In 1999, using data from the National Comorbidity Survey (NCS), Krueger presented a model that gave a novel taxonomic approach to mental disorders and their core psychopathologies. He proposed that the relationships among 10 common mental disorders could be understood in a factor structure composed of higher-order "Internalizing" and "Externalizing" factors, with the Internalizing factor subdivided into an "Anxious-Misery" subfactor and a "Fear" subfactor. However, Krueger did not include all of the mental disorders assessed in the NCS. The objective of the current study was to examine how alcohol abuse and drug abuse compare to alcohol dependence and drug dependence in Krueger's model. METHOD: The sample for this research was the 8098 noninstitutionalized US civilians aged 15 to 54 years who participated in the NCS between 1990 and 1992. The data from the NCS were analyzed using confirmatory factor analyses. RESULTS: Alcohol abuse and drug abuse loaded on both the Anxious-Misery subfactor and the Externalizing factor and were distinct from alcohol dependence and drug dependence. CONCLUSIONS: Individuals with drug abuse and alcohol abuse constitute a different population than individuals with drug dependence and alcohol dependence and have a different pattern of comorbidities. This suggests that underlying etiologies may vary between these 2 groups, leading to different approaches for both research and treatment. PMID- 21295776 TI - Testing a maintenance model for eating disorders in a sample seeking treatment at a tertiary care center: a structural equation modeling approach. AB - Fairburn et al (Fairburn, CG, Cooper, Z, Shafran, R. Behav Res Ther 2003;41:509 528) proposed additional maintenance mechanisms (ie, interpersonal difficulties, mood intolerance, low self-esteem, and perfectionism) for some individuals with eating disorders in addition to core eating disorder psychopathology (ie, overevaluation of eating, weight, and shape and their control). This is the first study to both elaborate and test this maintenance model as a structural model. Adults seeking treatment of an eating disorder (N = 1451) at a specialized tertiary care center were included in this cross-sectional study. In the first part of the study, diagnostically heterogeneous participants (n = 406) were randomly selected to test a structural model based on the maintenance model. In the second part of the study, remaining participants (n = 1045) were grouped according to eating disorder diagnosis to test for invariance of the structural paths of the final model across diagnoses. Overall, the structural model with core and additional mechanisms fit the data well and, with 1 exception, represented maintenance processes for each of the diagnostic groups. Treatment models based on both core and additional maintenance factors for those seeking therapy at a specialized tertiary care center may result in improved treatment outcomes for these patients with eating disorders. PMID- 21295777 TI - Differential effects of a complex organochlorine mixture on the proliferation of breast cancer cell lines. AB - Organochlorine compounds (OCs) are a group of persistent chemicals that accumulate in fatty tissues with age. Although OCs has been tested individually for their capacity to induce breast cancer cell proliferation, few studies examined the effect of complex mixtures that comprise compounds frequently detected in the serum of women. We constituted such an OC mixture containing 15 different components in environmentally relevant proportions and assessed its proliferative effects in four breast cancer cell lines (MCF-7, T47D, CAMA-1, MDAMB231) and in non-cancerous CV-1 cells. We also determined the capacity of the mixture to modulate cell cycle stage of breast cancer cells and to induce estrogenic and antiandrogenic effects using gene reporter assays. We observed that low concentrations of the mixture (100 * 10(3) and 50 * 10(3) dilutions) stimulated the proliferation of MCF-7 cells while higher concentrations (10 * 10(3) and 5 * 10(3) dilutions) had the opposite effect. In contrast, the mixture inhibited the proliferation of non-hormone-dependent cell lines. The mixture significantly increased the number of MCF-7 cells entering the S phase, an effect that was blocked by the antiestrogen ICI 182,780. Low concentrations of the mixture also caused an increase in CAMA-1 cell proliferation but only in the presence estradiol and dihydrotestosterone (p<0.05 at the 50 * 10(3) dilution). DDT analogs and polychlorinated biphenyls all had the capacity to stimulate the proliferation of CAMA-1 cells in the presence of sex steroids. Reporter gene assays further revealed that the mixture and several of its constituents (DDT analogs, aldrin, dieldrin, beta-hexachlorocyclohexane, toxaphene) induced estrogenic effects, whereas the mixture and several components (DDT analogs, aldrin, dieldrin and PCBs) inhibited the androgen signaling pathway. Our results indicate that the complex OC mixture increases the proliferation of MCF-7 cells due to its estrogenic potential. The proliferative effect of the mixture on CAMA 1 cells in the presence of sex steroids appears mostly due to the antiandrogenic properties of p,p'-DDE, a major constituent of the mixture. Other mixtures of contaminants that include emerging compounds of interest such as brominated flame retardants and perfluoroalkyl compounds should be tested for their capacity to induce breast cancer cell proliferation. PMID- 21295778 TI - Computer-assisted virtual surgical procedure for acetabular fractures based on real CT data. AB - OBJECTIVE: To develop and evaluate a computer-assisted virtual surgical procedure for preoperative planning that simulates the reduction and plate fixation for acetabular fractures based on real computed tomography (CT) data using computer softwares on personal computers. METHODS: Virtual preoperative planning for reduction and plate fixation for seven acetabular fractures was performed. Three dimensional (3D) models of acetabular fractures based on real CT data in Dicom format were built to perform reduction first. Then fixation was undertaken after plate contouring. Virtual planning was compared with real surgery with respect to operative approach, plate length and screw count. Furthermore, the time required for virtual surgery was recorded. RESULTS: Virtual surgery was successfully achieved and identical to the real operation in all cases. The mean time required was 79 min. CONCLUSION: The virtual surgical procedure for acetabular fractures is feasible and useful clinically for surgeons to determine surgical planning. It may be a valuable tool for surgeons in learning about the nature of the fracture and in formulating an appropriate surgical plan. PMID- 21295779 TI - Agreement between information provided by stroke patients and their relatives on psychophysical and vascular risk factors. AB - BACKGROUND: In studies examining vascular risk factors and the effects of stress in stroke patients, information sometimes has to be provided by a close relative. OBJECTIVES: The present study was designed to assess agreement between the information provided by a stroke patient and his/her next-of-kin or other close relative on prior vascular risk factors and situations of psychophysical stress based on a standardized interview within 72 h after stroke. DESIGN: Case-control observational study. PARTICIPANTS AND SETTINGS: All patients with incident stroke aged 18-65 years admitted to our centre were enrolled as cases, and their coinhabiting relatives as controls. The study was conducted from January to June 2008. METHODS: A structured questionnaire about vascular risk factors and psychophysical stress factors were obtained from the participants within 72 h after stroke. Subjects were required to grade themselves or their relatives using validated Spanish versions of the Life Events Stress Scale of Holmes and Rahe, Goldberg's General Health Questionnaire GHQ-28 and the SF-12 Health Survey, as well as the Spanish Type A Behaviour Scale. The questionnaires were self administered. Cases and controls completed the same questionnaires and which were administered with a time difference of no longer than 24 h between the two groups of subjects. Risk factors were analyzed by determining kappa statistics and interclass correlation coefficients (ICC). Bland-Altman plots were used to examine the scores obtained in graded scales. RESULTS: 25 patients and 25 relatives were recruited. Agreement between cases and controls was good for reported atrial fibrillation, diabetes, alcohol consumption and smoking (range 0.83-1.0). ICC were low for the questionnaires Holmes-Rahe Life Events (0.26; 95%CI: 0.08-0.57), General Health GHQ-28 (0.39; 95%CI: 0.03-0.67) and SF12 Health Survey (0.52; 95%CI: 0.16-0.76 and 0.35; 95%CI: 0.06-0.66), and good for the Type A Behaviour Scale ERCTA (0.62; 95%CI: 0.32-0.81). CONCLUSIONS: The information obtained from family members on patient risk factors could be considered reliable, while that related to psychophysical aspects was not sufficiently reliable for research purposes. Agreement assessments could be useful to avoid misclassification biases. PMID- 21295780 TI - Biomechanical effect of rapid mucoperiosteal palatal tissue expansion with the use of osmotic expanders. AB - The comparative study was performed to investigate the biomechanical properties (maximum tangential stiffness, maximum tangential modulus and tensile strength) of expanded mucoperiosteal palatal tissue after rapid expansion regimen correlated with histological findings. Rabbit palatal model was used to correlate the non-operated control group, sham-operated control (subperiosteal tissue dissection) groups and 24- and 48-hour tissue expansion groups. There was no observed damage of tissue collagen network in both tissue expansion groups analyzed immediately after expansion, and biomechanical profile was not significantly different from the profile of control groups. However, rapid tissue expansion activates remodeling of mucoperiosteal tissue structure that revealed significant changes in mechanical properties during the 4-week follow-up. The 24 hour expansion induced transient increase of resilience observed 2 weeks after surgery in comparison to the control groups. As a result of maturation of newly created collagen fibers and mucoperiosteum rebuilding, there were no significant differences between any of the analyzed tensile parameters 4 weeks after the 24 hour expansion. Increased and elongated inflammatory response and connective matrix synthesis observed during healing of 48-hour expanded tissue led to a significant decrease of tensile strength value in comparison to the control groups. Even though 4 weeks after surgery, the resilience of 48-hour expanded tissue was similar to the control groups, tissue healing was not completed and limited scar formation might considerably change the final biomechanical tissue profile. These findings provide new information about tensile properties to rapid mucoperiosteal palatal tissue expansion with the use of osmotic expanders for cleft palate repair by tissue augmentation. PMID- 21295781 TI - Damage accumulation in vertebral trabecular bone depends on loading mode and direction. AB - Osteoporotic vertebral fractures constitute a major clinical problem in ageing societies. A third of all vertebral fractures is caused by falls, 15% by lifting heavy loads or traffic accidents and over 50% are not relatable to a traumatic event. In the latter case vertebrae show sinter processes which indicate the accumulation of damage and permanent deformation. Accumulated damage may not be visible on radiographs but increases the risk of fracture and could lead to vertebral collapse. Clear understanding of the accumulation of damage and residual strains and their dependence on loading mode and direction is important for understanding vertebral fractures. Altogether, 251 cylindrical samples (8*18 25mm) were obtained from 50 male and 54 female fresh frozen human vertebrae (T1 L3) of 65 (21-94) years. Vertebrae were randomly assigned to three groups cranial caudal, anterior-posterior and latero-lateral. Specimens were mechanically loaded in compression, tension or torsion in five load steps at a strain rate of 0.2%/s. Three conditioning cycles were driven per load step. Stress-strain curves were reconstructed from the force-displacement or from the moment-twist angle curves. Damage accumulated from 0 to 86% in compression, from 0 to 76% in tension and from 0 to 86% in torsion through the five load steps. Residual strains accumulated from 0 to -0.008mm/mm in compression, 0 to 0.006mm/mm in tension and 0 to 0.026rad/rad in torsion. Significantly less damage (p<0.05) but not residual strains accumulated in transverse directions. This study provides detailed experimental insights into the damage behaviour of vertebral trabecular bone under various loads occurring in vivo. Damage but not residual strain evolution seems to be anisotropic. Both seem to evolve differently under different loading modes. The results could be of importance in understanding vertebral fractures. PMID- 21295782 TI - The influence of component design, bearing clearance and axial load on the squeaking characteristics of ceramic hip articulations. AB - Squeaking of hip replacements with ceramic-on-ceramic bearings has put the use of this material into question despite its superior wear behavior. Squeaking has been related to implant design. The purpose of this study was to determine the influence of particular acetabular cup and femoral stem designs on the incidence of squeaking and its characteristics. The dynamic behavior of the stem, head and stem assembled with head was investigated by determining their eigenfrequencies using experimental and numerical modal analysis. Four different stem and three different cup designs were investigated. Operational system vibrations resulting in audible squeaking were reproduced in a hip simulator and related to the respective component eigenfrequencies. The applied joint load and bearing clearance were varied in the clinically relevant range. Stems with lower eigenfrequencies were related to lower squeaking frequencies and increased acoustic pressure (loudness), and therefore to a higher susceptibility to squeaking. Higher load increased the squeaking frequency, while the acoustic pressure remained unchanged. No influence of the clearance or the cup design was found. Stem design was found to have an important influence on squeaking characteristics and its incidence, confirming and explaining similar clinical observations. Cup design itself was found to have no major influence on the dynamic behavior of the system but plays an important indirect role in influencing the magnitude of friction: Squeaking only occurs if the friction in the joint articulation is sufficient to excite vibrations to audible magnitudes. If friction is low, no squeaking occurs with any of the designs investigated. PMID- 21295783 TI - Preparation of monoliths from single crosslinking monomers for reversed-phase capillary chromatography of small molecules. AB - Highly cross-linked networks resulting from single crosslinking monomers were found to enhance the concentrations of mesopores in, and the surface areas of, polymeric monoliths. Four crosslinking monomers, i.e., bisphenol A dimethacrylate (BADMA), bisphenol A ethoxylate diacrylate (BAEDA, EO/phenol=2 or 4) and pentaerythritol diacrylate monostearate (PDAM), were used to synthesize monolithic capillary columns for reversed phase liquid chromatography (RPLC) of small molecules. Tetrahydrofuran (THF) and decanol were chosen as good and poor porogenic solvents for BAEDA-2 and BAEDA-4 monoliths. For the formation of the BADMA monolith, THF was replaced with dimethylformamide (DMF) to improve the column reproducibility. Appropriate combinations of THF, isopropyl alcohol and an additional triblock poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) or PPO-PEO-PPO porogen were found to be effective in forming rigid PDAM monoliths with the desired porosities. Selection of porogens for the BADMA and PDAM monoliths was investigated in further detail to provide more insight into porogen selection. Isocratic elution of alkyl benzenes at a flow rate of 0.3 MUL/min was conducted for BADMA and PDAM monoliths. The peaks showed little tailing on both monoliths without addition of acid to the mobile phase. The column efficiency measured for pentylbenzene using the BADMA monolithic column was 60,208 plates/m (k=7.9). Gradient elution of alkyl benzenes and alkyl parabens was achieved with high resolution. Optimized monoliths synthesized from all four crosslinking monomers showed high permeability, and demonstrated little swelling or shrinking in different polarity solvents. Column preparation was highly reproducible; relative standard deviation (RSD) values were less than 1.2% and 7.5% based on retention times and peak areas, respectively, of alkyl benzenes. PMID- 21295784 TI - Purification of recombinant adenovirus type 3 dodecahedric virus-like particles for biomedical applications using short monolithic columns. AB - Adenovirus type 3 dodecahedric virus-like particles (Ad3 VLP) are an interesting delivery vector. They penetrate animal cells in culture very efficiently and up to 300,000 Ad3 VLP can be observed in one cell. The purification of such particles usually consists of several steps. In these work we describe the method development and optimization for the purification of Ad3 VLP using the Convective Interaction Media analytical columns (CIMac). Results obtained with the CIMac were compared to the already established two-step purification protocol for Ad3 VLP based on sucrose density gradient ultracentifugation and the Q-Sepharose ion exchange column. Pure, concentrated and bioactive VLP were obtained and characterized by several analytical methods. The recovery of the Ad3 VLP was more than 50% and the purified fraction was almost completely depleted of DNA; less than 1% of DNA was present. The purification protocol was shortened from five days to one day and remarkably high penetration efficacy of the CIMac-purified vector was retained. Additionally, CIMac QA analytical column has proven to be applicable for the final and in-process control of various Ad3 VLP samples. PMID- 21295785 TI - Micelle formation of nonionic surfactants in a room temperature ionic liquid, 1 butyl-3-methylimidazolium tetrafluoroborate: surfactant chain length dependence of the critical micelle concentration. AB - Micellization behavior was investigated for polyoxyethylene-type nonionic surfactants with varying chain length (C(n)E(m)) in a room temperature ionic liquid, 1-butyl-3-methylimidazolium tetrafluoroborate (bmimBF(4)). Critical micelle concentration (cmc) was determined from the variation of (1)H NMR chemical shift with the surfactant concentration. The logarithmic value of cmc decreased linearly with the number of carbon atoms in the surfactant hydrocarbon chain, similarly to the case observed in aqueous surfactant solutions. However, the slope of the straight line is much smaller in bmimBF(4) than in aqueous solution. Thermodynamic parameters for micelle formation estimated from the temperature dependence of cmc showed that the micellization in bmimBF(4) is an entropy-driven process around room temperature. This behavior is also similar to the case in aqueous solution. However, the magnitude of the entropic contribution to the overall micellization free energy in bmimBF(4) is much smaller compared with that in aqueous solution. These results suggest that the micellization in bmimBF(4) proceeds through a mechanism similar to the hydrophobic interaction in aqueous surfactant solutions, although the solvophobic effect in bmimBF(4) is much weaker than the hydrophobic effect. PMID- 21295786 TI - The effects of the addition of the polyelectrolyte, poly(ethyleneimine), on the adsorption of mixed surfactants of sodium dodecylsulfate and dodecyldimethylaminoacetate at the air-water interface. AB - The effects of the addition of the polyelectrolyte, poly(ethyleneimine), PEI, on the adsorption of the mixed surfactants of sodium dodecylsulfate, SDS, and dodecyldimethylaminoacetate, dodecyl betaine, at the air-water interface have been investigated using neutron reflectivity and surface tension. In the absence of PEI the SDS and dodecyl betaine surfactants strongly interact and exhibit synergistic adsorption at the air-water interface. The addition of PEI, at pH 7 and 10, results in a significant modification of the surface partitioning of the SDS/dodecyl betaine mixture. The strong surface interaction at high pH (pH 7 and 10) between the PEI and SDS dominates the surface behavior. For solution compositions in the range 20/80-80/20 mol ratio dodecyl betaine/SDS at pH 7 the surface composition is strongly biased towards the SDS. At pH 10 a similar behavior is observed for a solution composition of 50/50 mol ratio dodecyl betaine/SDS. This strong partitioning in favor of the SDS at high pH is attributed to the strong ion-dipole attraction between the SDS sulfate and the PEI imine groups. At pH 3, where the electrostatic interactions between the surfactant and the PEI are dominant, the dodecyl betaine more effectively competes with the SDS for the interface, and the surface composition is much closer to the solution composition. PMID- 21295787 TI - The role of electrolyte and polyelectrolyte on the adsorption of the anionic surfactant, sodium dodecylbenzenesulfonate, at the air-water interface. AB - The role of the polyelectrolyte, poly(ethyleneimine), PEI, and the electrolytes NaCl and CaCl(2), on the adsorption of the anionic surfactant, sodium dodecylbenzenesulfonate, LAS, at the air-water interface have been investigated by neutron reflectivity and surface tension. The surface tension data for the PEI/LAS mixtures are substantially affected by pH and the addition of electrolyte, and are consistent with a strong adsorption of surface polymer/surfactant complexes down to relatively low surfactant concentrations. The effects are most pronounced at high pH, and this is confirmed by the adsorption data obtained directly from neutron reflectivity. However, the effects of the addition of PEI and electrolyte on the LAS adsorption are not as pronounced as previously reported for PEI/SDS mixtures. This is attributed primarily to the steric hindrance of the LAS phenyl group resulting in a reduction in the ion-dipole attraction between the LAS sulfonate and amine groups that dominates the interaction at high pH. PMID- 21295788 TI - [Parkinsonism induced by sulpiride and veralipride: two different stories]. PMID- 21295789 TI - [Who should have the ankle-arm index measured?]. PMID- 21295790 TI - Type 1 autoimmune hepatitis in a patient with microscopic polyangiitis: challenges in diagnosis and treatment. AB - BACKGROUND AND OBJECTIVE: Autoimmune diseases/autoantibodies tend sometimes to cumulate in the same individual, probably as a consequence of defects in immune regulation with breakdown of self-tolerance. Autoimmune hepatitis and microscopic polyangiitis have been occasionally reported with other autoimmune diseases, but the particular association of these both disorders has not been previously reported in the English and Spanish medical literature. CASE REPORT: A 72 year old woman presented with symptoms suggesting giant cell arteritis and polymyalgia rheumatica. RESULTS: A temporal artery biopsy disclosed a spared temporal artery, with vasculitis involving surrounding small vessels. Anti-neutrophil cytoplasmic antibodies were positive, with myeloperoxidase specificity. Increased liver enzymes led to a wider autoantibody determination. Anti-nuclear antibodies and anti-smooth muscle cell antibodies with anti-f-actin specificity were also positive. A liver biopsy showed changes consistent with autoimmune hepatitis. CONCLUSIONS: Clues for the diagnosis of vasculitis and AIH in the context of this patient, challenges in its classification among systemic vasculitides, and difficulties in the choice of a suitable therapeutic management for this particular association are discussed. PMID- 21295791 TI - [Intrapulmonary solitary fibrous tumor]. PMID- 21295792 TI - [Efficacy of glucocorticoids and antiviral medication in the treatment of Bell's palsy]. PMID- 21295793 TI - [Angioedema due to losartan]. PMID- 21295794 TI - [Concentration of glycosilated hemoglobin (HbA1c) in the area of Talavera de la Reina (Toledo), Spain (2006-2008)]. PMID- 21295795 TI - [Ulcerated nodular lesion]. PMID- 21295796 TI - [Pseudomonas aeruginosa folliculitis after depilation]. PMID- 21295797 TI - [Hospital at home and palliative care]. PMID- 21295798 TI - [Central retinal artery thrombosis and mitral papillary fibroelastoma]. PMID- 21295799 TI - [Tricuspid valve endocarditis]. PMID- 21295800 TI - Thiol redox-sensitive seed proteome in dormant and non-dormant hybrid genotypes of wheat. AB - The thiol redox-sensitive and the total proteome in harvest-ripe grains of closely related genotypes of wheat (Triticum aestivum L.), with either a dormant or a non-dormant phenotype, were investigated using hybrid lines of spring wheat double haploid population segregating transgressively, to gain further insight into seed dormancy controlling events. Redox signalling by reactive oxygen species has been shown to play a role in seed dormancy alleviation. Thiol disulfide proteins are of particular importance in the context of redox-dependent regulation as a central and flexible mechanism to control metabolic and developmental activities of the cells. Here we describe functional proteomic profiling of reversible oxidoreductive changes and characterize in vivo intrinsic reactivity of cysteine residues using thiol-specific fluorescent labelling, solubility-based protein fractionation, two-dimensional electrophoresis, and mass spectrometry analysis in conjunction with wheat EST sequence libraries. Quantitative differences between genotypes were found for 106 spots containing 64 unique proteins. Forty seven unique proteins displayed distinctive abundance pattern, and among them 31 proteins contained 78 unique redox active cysteines. Seventeen unique proteins with 19 reactive modified cysteines were found to have differential post-translational thiol redox modification. The results provide an insight into the alteration of thiol-redox profiles in proteins that function in major processes in seeds and include groups of redox- and stress-responsive, genetic information processing and cell cycle control, transport and storage proteins, enzymes of carbohydrate metabolism, proteases and their inhibitors. PMID- 21295801 TI - Interventions to prevent dog fouling: a systematic review of the evidence. AB - OBJECTIVES: To undertake a systematic review of articles on the prevention of dog fouling. STUDY DESIGN: Systematic review. METHODS: Literature searches were conducted using six major electronic databases. Published and unpublished material was considered, with no restrictions on date or language. A total of 47 other databases and websites were interrogated. Articles were hand searched for references that had not been identified in the electronic search. Only controlled trials or observational studies assessing the impact of any intervention on the prevention of dog fouling were liable for inclusion in the systematic review. RESULTS: The search identified a total of 68 articles, none of which fulfilled the inclusion criteria. CONCLUSIONS: The review did not find any good-quality studies which have looked at interventions to prevent dog fouling. According to the Cochrane Collaboration, reviews that are unable to find any relevant studies are particularly useful because they highlight important gaps in our knowledge. It is recommended that research is commissioned to answer the important question of what interventions actually work to prevent dog fouling. Methods for performing this research are suggested. PMID- 21295802 TI - [Comparison of doxorubicin-eluting bead transarterial chemoembolization (DEB TACE) with conventional transarterial chemoembolization (TACE) for the treatment of hepatocellular carcinoma]. AB - OBJECTIVE: To compare conventional transarterial chemoembolization (TACE) with doxorubicin-eluting bead transarterial chemoembolization (DEB-TACE) for the treatment of hepatocellular carcinoma, evaluating the tumor response, complications after treatment, and survival. MATERIAL AND METHODS: We present 72 patients diagnosed with hepatocellular carcinoma treated consecutively between January 2000 and December 2009. We studied 25 patients treated with TACE (Group A) and 47 patients treated with DEB-TACE (Group B); adriamycin (doxorubicin) was the chemotherapy agent used in both groups. All patients had compensated cirrhosis of the liver classified on the Child-Pugh score. The results were analyzed according to the RECIST criteria. Statistical analyses consisted of ANOVA, chi-square tests, Student's t-tests, and Kaplan-Meier log-rank tests. RESULTS: Patient's age, tumor size, number of tumors, and hepatic reserve were similar in the two groups. The mean number of sessions per patient was 1.32 +/- 0.67 in Group A versus 2.13 +/- 0.95 in Group B. The mean dose of adriamycin per patient was 50.60 +/- 29.95 mg in Group A and 231.91 +/- 110.2mg in Group B. A complete response of the tumor to treatment was observed in 5.6% of the patients in Group A and in 13.9% of those in Group B. According to the RECIST criteria, no significant differences were found. DEB-TACE was better tolerated and had fewer immediate complications (p=0.001). No significant differences were found in the survival of patients in the two groups (Group A: mean 686.24 days, median 709 days; Group B: mean 765.32 days, median 672 days. CONCLUSION: In patients with unresectable hepatocellular carcinoma, DEB-TACE is safe and better tolerated than conventional TACE; moreover, it seems to lead to greater necrosis of the tumors. PMID- 21295803 TI - [Malignant degeneration in a urethral diverticulum: an uncommon complication in a common condition]. AB - Acquired urethral diverticula are relatively common in women. They are usually asymptomatic but they can lead to complications; infection and stones are the most common complications. Malignant degeneration with the development of a malignant tumor in the diverticulum is a rare complication that must be taken into account. Few cases of malignant tumors in urethral diverticula have been reported. We present the case of a woman diagnosed with a malignant tumor in a urethral diverticulum. We review the imaging findings for urethral diverticula and the complications that can arise in this condition. PMID- 21295804 TI - [Multiple calcified coronary aneurysms diagnosed by plain-film radiography]. PMID- 21295805 TI - [Extrahepatic vessels depending on the hepatic artery. Identification and management]. AB - Patients with malignant liver tumors, whether primary tumors or metastases, that are not candidates for surgical treatment can benefit from different endovascular treatments with proven efficacy in local control of the disease. Correct treatment requires a careful angiographic technique and precise knowledge about the vascular anatomy afferent to the lesion. Occasionally, lesions considered relapse are actually areas that were untreated because the afferent pedicle was not adequately detected. On the other hand, some of the complications of endovascular treatments are related with material passing into non-hepatic vessels. Knowing the hepatic vascular anatomy and correctly identifying all the extrahepatic vessels will make it possible to perform safer, more efficacious treatments. In this article, we present different representative examples of extrahepatic vessels that originate in the hepatic artery. PMID- 21295806 TI - Passive immunisation of post-weaned piglets using hyperimmune serum against experimental Haemophilus parasuis infection. AB - The protective role of hyperimmune serum in the prevention of Haemophilus parasuis infections in post-weaned piglets was assessed by experimental challenge. The hyperimmune serum was obtained from a pig vaccinated with a commercial vaccine against Glasser's disease. Thirty-eight weaned piglets were divided into four groups: three groups were immunised intramuscularly with 10 ml of hyperimmune serum and one group consisted of unimmunised control animals. All piglets were subsequently infected intraperitoneally with H. parasuis serotype 5 at different times after immunisation. The use of hyperimmune serum provided the piglets with partial protection against experimental infection. The levels of protection indirectly depend on time between serum inoculation and challenge infection. The best protection of piglets against experimental infection was obtained in the group immunised 1 week before inoculation; the same group in which the highest levels of antibodies were detected at the time of challenge. PMID- 21295807 TI - The ergonomics of natural orifice translumenal endoscopic surgery (NOTES) navigation in terms of performance, stress, and cognitive behavior. AB - BACKGROUND: The evolution toward minimally invasive surgery and subsequently to natural orifice translumenal endoscopic surgery (NOTES) poses challenges to the surgeon in terms of increased task complexity requiring greater visuospatial and navigational ability. Neuroergonomics is the study of the brain and behavior at work, and establishing the baseline cortical response for NOTES procedures will help to ascertain whether technological innovation such as navigational aids can alleviate the task-induced cognitive burden. The aims of the current study are to characterize the impact of navigation within a NOTES environment on the subject in terms of (1) performance, (2) stress, (3) prefrontal cortical activity, and (4) how this is influenced by expertise. METHODS: In all, 29 subjects were assessed for performance, stress response, and prefrontal cortical activity during a NOTES navigational task within a validated NOTES simulator. RESULTS: Experts performed significantly better than novices (P < .05). Expertise was not a predictor for overall changes in prefrontal cortical activity. The differences between experts and novices were modulated by the location of prefrontal cortical activity, with experts demonstrating more pronounced lateral prefrontal cortical activation compared with novices. Stress was not an independent predictor of changes in prefrontal cortical hemodynamics. CONCLUSION: This study is the first to characterize the performance, stress, and neurocognitive behavior associated with natural orifice translumenal endoscopic surgery navigation. The results indicate the relevance of visuospatial centers in successful task execution, and they serve as a baseline within the neuroergonomic paradigm for investigating performance-enhancing technology. PMID- 21295808 TI - Is minimally invasive, video-assisted thyroidectomy feasible in Graves' disease? AB - BACKGROUND: Although the safety and advantages of minimally invasive, video assisted thyroidectomy (MIVAT) are well documented in nodular thyroid disease, its role in Graves' disease is controversial. We compared the outcomes of patients undergoing MIVAT with those undergoing conventional thyroidectomy for Graves' disease. METHODS: Of the 497 patients with Graves' disease referred for surgery (1999-2009), 157 (31.6%) patients underwent the MIVAT procedure (video assisted group). As a control group, 340 patients undergoing conventional thyroidectomy (conventional thyroidectomy group) were included in the current analysis. MIVAT was proposed if the thyroid volume was <= 30 mL. The data were obtained through a prospectively maintained surgical database. RESULTS: Most patients in both groups underwent total thyroidectomy (98% in the MIVAT group and 96.5% in the conventional group). Three (1.9%) conversions to open surgery occurred in the video-assisted group. Hospital stay was significantly shorter (P = .008) in the video-assisted group (2.1 +/- 0.4 days) compared with the conventional thyroidectomy group (2.4 +/- 1.4 days). The mean operative time was shorter (84 +/- 29 min; range, 15-240) for the video-assisted group compared with the conventional thyroidectomy group (94 +/- 43 min; range, 20-360), although this difference was not statistically significant (P = .05). Postoperative transient hypocalcemia occurred in 14 (8.9%), transient recurrent laryngeal nerve palsy occurred in 2 (1.3%), and postoperative hematoma occurred in 5 (3.2%) patients in the video-assisted group compared with 23 (6.8%), 11 (3.2%), and 8 (2.3%) patients in the conventional thyroidectomy group, respectively (P = ns). CONCLUSION: In selected patients with Graves' disease, MIVAT is feasible and can be performed safely with results comparable with open surgery. PMID- 21295810 TI - New directions in simulation-based surgical education and training: validation and transfer of surgical skills, use of nonsurgeons as faculty, use of simulation to screen and select surgery residents, and long-term follow-up of learners. AB - The Consortium of American College of Surgeons-Accredited Education Institutes was created to explore new opportunities in simulation-based surgical education and training beyond the scope of individual accredited institutes. During the Third Annual Meeting of the Consortium of American College of Surgeons-Accredited Education Institutes Consortium, 4 work groups addressed the validation and transfer of surgical skills, the use of nonsurgeons as faculty, the use of simulation to screen and select surgery residents, and long-term follow-up of learners. The key elements from the deliberations and conclusions are summarized in this manuscript. PMID- 21295809 TI - Effects of glucagon-like peptide 1 on glycemia control and its metabolic consequence after severe thermal injury--studies in an animal model. AB - BACKGROUND: Hyperglycemia with insulin resistance is commonly seen in severely burned patients and tight glycemia control with insulin may be beneficial in this condition. The most potent insulinotropic hormone, glucagon-like peptide 1 (GLP 1), stimulates insulin secretion in a glucose-dependent manner. Because infusion of GLP-1 never reduces glucose levels to below ~70 mg/dL, the risk of hypoglycemia by using insulin is reduced. In this study we investigated the metabolic effects of GLP-1 infusion after burn injury in an animal model. METHODS: Male CD rats were divided in 3 groups: burn injury with saline, burn injury with GLP-1 treatment, and sham burn (SB). Burn injury was full thickness 40% total body surface area. The burn injury with GLP-1 treatment group received GLP-1 infusion via osmotic pump. Fasting blood glucose, plasma insulin, and plasma GLP-1 levels were measured during intraperitoneal glucose tolerance tests. Expressions of caspase 3 and bcl-2 were evaluated in pancreatic islets. In a subset of animals, protein metabolism and total energy expenditure were measured. RESULTS: Fasting GLP-1 was reduced in burn injury with saline compared to SB or burn injury with GLP-1 treatment. Burn injury with GLP-1 treatment showed reduced fasting blood glucose, improved intraperitoneal glucose tolerance test results, with increased plasma insulin and GLP-1 responses to glucose. GLP-1 reduced protein breakdown and total energy expenditure in burn injury with GLP-1 treatment versus burn injury with saline, with improved protein balance. Increased expression of caspase 3 and decreased expression of bcl-2 in islet cells by burn injury were ameliorated by GLP-1. CONCLUSION: Burn injury reduced plasma GLP-1 in association with insulin resistance. GLP-1 infusion improved glucose tolerance and showed anabolic effects on protein metabolism and reduced total energy expenditure after burn injury, possibly via insulinotropic and non insulinotropic mechanisms. PMID- 21295811 TI - Resident education in 2011: three key challenges on the road ahead. AB - Two important changes in the past decade have altered the landscape of graduate medical education (GME) in the U.S. The national restrictions on trainee duty hours mandated by the Accreditation Council for Graduate Medical Education (ACGME) were the most visible and generated much controversy. Equally important is the ACGME Outcome Project, which mandates competency-based training. Both of these changes have unique implications for surgery trainees, who traditionally spent long hours caring for patients in the hospital, and who must be assessed in 2 broad domains: their medical care of pre- and postoperative patients, and their technical skill with procedures in and out of the operating room. This article summarizes 3 key challenges that lie ahead for surgical educators. First, the changes in duty hours in the past 7 years are summarized, and the conversation about added restrictions planned for July 2011 is reviewed. Next, the current state of the assessment of competency among surgical trainees is reviewed, with an outline of the challenges that need to be overcome to achieve widespread, competency-based training in surgery. Finally, the article summarizes the problems caused by increased reliance on handoffs among trainees as they compensate for decreased time in the hospital, and suggests changes that need to be made to improve safety and efficiency, including how to use handoffs as part of our educational evaluation of residents. PMID- 21295813 TI - Fat malabsorption and increased intestinal oxalate absorption are common after Roux-en-Y gastric bypass surgery. AB - BACKGROUND: Hyperoxaluria and increased calcium oxalate stone formation occur after Roux-en-Y gastric bypass (RYGB) surgery for morbid obesity. The etiology of this hyperoxaluria is unknown. We hypothesized that after bariatric surgery, intestinal hyperabsorption of oxalate contributes to increases in plasma oxalate and urinary calcium oxalate supersaturation. METHODS: We prospectively examined oxalate metabolism in 11 morbidly obese subjects before and 6 and 12 months after RYGB (n = 9) and biliopancreatic diversion-duodenal switch (BPD-DS) (n = 2). We measured 24-hour urinary supersaturations for calcium oxalate, apatite, brushite, uric acid, and sodium urate; fasting plasma oxalate; 72-hour fecal fat; and increases in urine oxalate following an oral oxalate load. RESULTS: Six and 12 months after RYGB, plasma oxalate and urine calcium oxalate supersaturation increased significantly compared with similar measurements obtained before surgery (all P <= .02). Fecal fat excretion at 6 and 12 months was increased (P = .026 and .055, 0 vs 6 and 12 months). An increase in urine oxalate excretion after an oral dose of oxalate was observed at 6 and 12 months (all P <= .02). Therefore, after bariatric surgery, increases in fecal fat excretion, urinary oxalate excretion after an oral oxalate load, plasma oxalate, and urinary calcium oxalate supersaturation values were observed. CONCLUSION: Enteric hyperoxaluria is often present in patients after the operations of RYGB and BPD-DS that utilize an element of intestinal malabsorption as a mechanism for weight loss. PMID- 21295812 TI - Multiple treatment cycles of liposome-encapsulated adenoviral RIP-TK gene therapy effectively ablate human pancreatic cancer cells in SCID mice. AB - BACKGROUND: Adenoviral gene therapy has been applied widely for cancer therapy; however, transient gene expression as result of humoral immunoneutralization response to adenovirus limits its effect. The purpose of this study is to determine whether DOTAP:cholesterol liposome could shield adenovirus from neutralizing antibody and permit the use of multiple cycles of intravenous liposome encapsulated serotype 5 adenoviral rat insulin promoter directed thymidine kinase (L-A-5-RIP-TK) with ganciclovir (GCV) to enhance its effect. METHODS: The effect of multiple cycles of systemic L-A-5-RIP-TK/GCV therapy was evaluated in grouped PANC-1 SCID mice treated with different numbers of cycles. Humoral immune response to A-5-RIP-TK or L-A-5-RIP-TK was assessed using C57/B6J mice challenged with adenovirus or liposome adenovirus complex. RESULTS: The minimal residual tumor burden (3.2 +/- 0.6 mm(3)) and greatest survival time (153.0 +/- 6 days) were obtained in the mice receiving 4 and 3 cycles of therapy, respectively. Toxicity to islet cells associated with RIP-TK/GCV therapy was observed after 4 cycles. DOTAP:chol-encapsulated adenovectors were able to protect adenovectors from the neutralization of high titer of anti-adenoviral antibodies induced by itself. CONCLUSION: Multiple treatment cycles of L-A-5-RIP TK/GCV ablate human PANC-1 cells effectively in SCID mice; however, the mice become diabetic and have substantial mortality after the 4th cycle. Liposome encapsulated adenovirus is functionally resistant to the neutralizing effects of anti-adenoviral antibodies, suggesting feasibility of multiple cycles of therapy. Liposome encapsulation of the adenovirus may be a promising strategy for repeated delivery of systemic adenoviral gene therapy. PMID- 21295814 TI - Comparison of in vivo and in vitro evolution of CCR5 to CXCR4 coreceptor use of primary human immunodeficiency virus type 1 variants. AB - During the course of at least 50% of HIV-1 subtype B infections, CCR5-using (R5) viruses evolve towards a CXCR4-using phenotype. To gain insight in the transition from CCR5 to CXCR4 coreceptor use, we investigated whether acquisition of CXCR4 use in vitro of R5 viruses from four patients resembled this process in vivo. R5 variants from only one patient acquired CXCR4 use in vitro. These variants had envelopes with higher V3 charge and higher number of potential N-linked glycosylation sites when compared to R5 variants that failed to gain CXCR4 use in vitro. In this patient, acquisition of CXCR4 use in vitro and in vivo was associated with multiple mutational patterns not necessarily involving the V3 region. However, changes at specific V3 positions were prerequisite for persistence of CXCR4-using variants in vivo, suggesting that positive selection targeting the V3 loop is required for emergence of CXCR4-using variants during natural disease course. PMID- 21295815 TI - Impaired memory CD8 T cell responses against an immunodominant retroviral cryptic epitope. AB - The immunodominant cryptic epitope SYNTGRFPPL, encoded within open reading frame 2 of the LP-BM5 retroviral gag gene, is critical for protection against retroviral-induced pathogenesis. The goal of this study was to dissect the memory response against this unique immunodominant cryptic epitope. Unlike the protective acute effector population of SYNTGRFPPL-specific CD8 T cells, long lived SYNTGRFPPL-specific CD8 T cells lacked the ability to protect susceptible mice infected with LP-BM5 retrovirus. Compared to memory CD8 T cells against a conventional epitope with similar MHC-I specificity, primed and restimulated using similar conditions, long-lived SYNTGRFPPL-specific CD8 T cells were impaired in their ability to recall against antigen, with reduced cytolytic capabilities and cytokine production. Since similar priming and restimulation regimes were utilized to generate each effector CD8 T cell population, this study has potentially broad implications with regard to the selection criteria of potent, highly conserved cryptic epitopes for use in epitope-based vaccines. PMID- 21295816 TI - Interaction between the G3 and L5 proteins of the vaccinia virus entry-fusion complex. AB - The vaccinia virus entry-fusion complex (EFC) consists of 10 to 12 proteins that are embedded in the viral membrane and individually required for fusion with the cell and entry of the core into the cytoplasm. The architecture of the EFC is unknown except for information regarding two pair-wise interactions: A28 with H2 and A16 with G9. Here we used a technique to destabilize the EFC by repressing the expression of individual components and identified a third pair-wise interaction: G3 with L5. These two proteins remained associated under several different EFC destabilization conditions and in each case were immunopurified together as demonstrated by Western blotting. Further evidence for the specific interaction of G3 and L5 was obtained by mass spectrometry. This interaction also occurred when G3 and L5 were expressed in uninfected cells, indicating that no other viral proteins were required. Thus, the present study extends our knowledge of the protein interactions important for EFC assembly and stability. PMID- 21295817 TI - The microbiota of an unpolluted calcareous soil faces up chlorophenols: Evidences of resistant strains with potential for bioremediation. AB - To highlight the effects of a variety of chlorophenols (CP) in relation to the response of an indigenous bacterial community, an agricultural Mediterranean calcareous soil has been studied in microcosms incubated under controlled laboratory conditions. Soil samples were artificially polluted with 2 monochlorophenol (MCP), 2,4,6-trichlorophenol (TCP) and pentachlorophenol (PCP), at concentrations ranging from 0.1 up to 5000 mg kg(-1). Both activity and composition of the microbial community were assessed during several weeks, respectively, by respirometric methods and PCR-DGGE analysis of extracted DNA and RNA. Significant decreases in soil respirometric values and changes in the bacterial community composition were observed at concentrations above 1000 mg kg( 1) MCP and TCP, and above 100 mg kg(-1) PCP. However, the persistence of several active bacterial populations in soil microcosms contaminated with high concentration of CP, as indicated by DGGE fingerprints, suggested the capacity of these native bacteria to survive in the presence of the pollutants, even without a previous adaptation or contact with them. The isolation of potential CP degraders was attempted by culture plating from microcosms incubated with high CP concentrations. Twenty-three different isolates were screened for their resistance to TCP and PCP. The most resistant isolates were identified as Kocuria palustris, Lysobacter gummosus, Bacillus sp. and Pseudomonas putida, according to 16S rRNA gene homology. In addition, these four isolates also showed the capacity to reduce the concentration of TCP and PCP from 15% to 30% after 5d of incubation in laboratory assays (initial pollutant concentration of 50 mg L(-1)). Isolate ITP29, which could be a novel species of Bacillus, has been revealed as the first known member in this bacterial group with potential for CP bioremediation applications, usually wide-spread in the soil natural communities, which has not been reported to date as a CP degrader. PMID- 21295818 TI - Discovered on gastrointestinal stromal tumor 1 (DOG1) is expressed in pancreatic centroacinar cells and in solid-pseudopapillary neoplasms--novel evidence for a histogenetic relationship. AB - Solid-pseudopapillary neoplasms of the pancreas are tumors of low malignant potential whose histogenesis has been discussed controversially. In the series of 15 solid-pseudopapillary neoplasms presented here, we demonstrate that discovered on gastrointestinal stromal tumor 1 is expressed significantly by these tumors (diffuse expression in 8 cases, focal expression in 4 cases, and scarce expression in 3 cases). Similar to the high expression of CD117, this finding parallels the immunohistochemical findings in gastrointestinal stromal tumors. Using double immunohistochemistry and immunofluorescence, we furthermore show that centroacinar cells express discovered on gastrointestinal stromal tumors 1. Thus, our findings suggest that, similarly to CD10 or vimentin, the expression of discovered on gastrointestinal stromal tumors 1 may serve as a novel marker for centroacinar cells and for solid-pseudopapillary neoplasms, which is suggestive of a centroacinar origin of these neoplasms. PMID- 21295819 TI - Synovial sarcoma of nerve. AB - Tumors of peripheral nerve are largely neuroectodermal in nature and derived from 2 elements of nerve, Schwann or perineurial cells. In contrast, mesenchymal tumors affecting peripheral nerve are rare and are derived mainly from epineurial connective tissue. The spectrum of the latter is broad and includes lipoma, vascular neoplasms, hematopoietic tumors, and even meningioma. Of malignant peripheral nerve neoplasms, the vast majority are primary peripheral nerve sheath tumors. Malignancies of mesenchymal type are much less common. To date, only 12 cases of synovial sarcoma of nerve have been described. Whereas in the past, parallels were drawn between synovial sarcoma and malignant glandular schwannoma, an uncommon form of malignant peripheral nerve sheath tumor, molecular genetics have since clarified the distinction. Herein, we report 10 additional examples of molecularly confirmed synovial sarcoma, all arising within minor or major nerves. Affecting 7 female and 3 male patients, 4 tumors occurred in pediatric patients. Clinically and radiologically, most lesions were initially thought to be benign nerve sheath tumors. On reinterpretation of imaging, they were considered indeterminate in nature with some features suspicious for malignancy. Synovial sarcoma of nerve, albeit rare, seems to behave in a manner similar to its more common, soft tissue counterpart. Those affecting nerve have a variable prognosis. Definitive recommendations regarding surgery and adjuvant therapies await additional reports and long-term follow-up. The literature is reviewed and a meta analysis is performed with respect to clinicopathologic features versus outcome. PMID- 21295820 TI - Hepatic gene expression profile in brown trout (Salmo trutta) exposed to traffic related contaminants. AB - In recent decades there has been growing concern about highway runoff as a potential threat and a significant source of diffuse pollution to the aquatic environment. However, identifying ecotoxicological effects might be challenging, especially at sites where the traffic density is modest to low. Hence, there is a need for alternatives e.g. small-scale toxicity tests using conventional endpoints such as mortality and growth. The present paper presents result from a transcriptional (microarray) screening performed on liver from brown trout (Salmo trutta) acutely exposed (4h) to traffic-related contaminants during washing of a highway tunnel outside the city of Oslo, Norway. The results demonstrated that traffic-related contaminants caused a plethora of molecular changes that persisted several hours after the exposure (i.e. during recovery). Beside an evident transcriptional up-regulation of e.g. cytochrome P450 1A1 (CYP1A1), cytochrome P450 1B1 (CYP1B1), and cytosolic sulfotransferase (SULT) involved in xenobiotic biotransformation, the observed responses were predominantly associated with immunosuppression, oxidative damage, and endocrine modulation. The observed responses were likely caused by an interaction of several contaminants including trace metals and organic micro-pollutants such as PAHs. PMID- 21295821 TI - Real-world operation conditions and on-road emissions of Beijing diesel buses measured by using portable emission measurement system and electric low-pressure impactor. AB - On-road measurement is an effective method to investigate real-world emissions generated from vehicles and estimate the difference between engine certification cycles and real-world operating conditions. This study presents the results of on road measurements collected from urban buses which propelled by diesel engine in Beijing city. Two widely used Euro III emission level buses and two Euro IV emission level buses were chosen to perform on-road emission measurements using portable emission measurement system (PEMS) for gaseous pollutant and Electric Low Pressure Impactor (ELPI) for particulate matter (PM) number emissions. The results indicate that considerable discrepancies of engine operating conditions between real-world driving cycles and engine certification cycles have been observed. Under real-world operating conditions, carbon monoxide (CO) and hydrocarbon (HC) emissions can easily meet their respective regulations limits, while brake specification nitrogen oxide (bsNO(x)) emissions present a significant deviation from its corresponding limit. Compared with standard limits, the real-world bsNO(x) emission of the two Euro III emission level buses approximately increased by 60% and 120% respectively, and bsNO(x) of two Euro IV buses nearly twice standard limits because Selective Catalytic Reduction (SCR) system not active under low exhaust temperature. Particle mass were estimated via particle size distribution with the assumption that particle density and diameter is liner. The results demonstrate that nanometer size particulate matter make significant contribution to total particle number but play a minor role to total particle mass. It is suggested that specific certified cycle should be developed to regulate bus engines emissions on the test bench or use PEMS to control the bus emissions under real-world operating conditions. PMID- 21295822 TI - Treatment of early rheumatoid arthritis: concepts in management. AB - OBJECTIVES: The early diagnosis and treatment of rheumatoid arthritis (RA) are important goals for rheumatologists. This article provides a review of the literature describing evolving concepts in the treatment of early RA, studies that evaluate treatment strategies using a predefined target, and methods to identify patients who are at higher risk for progressive joint damage. METHODS: We conducted a PubMed search for randomized trials using the terms "early rheumatoid arthritis" and subsequently "tight control" to compare the outcomes of studies using early intervention with biologics and disease-modifying antirheumatic drugs (DMARDs) in early RA and also to compare outcomes of strategies of treatment using a predefined target. RESULTS: The study designs and outcomes of clinical trials of DMARDs and biologic agents in early RA are presented. Early, prompt therapy with combination DMARDs or biologics combined with methotrexate leads to improved outcomes for patients with early RA. In studies where treatment was targeted to a specific outcome, such as remission, the target was achieved more often with targeted treatment than when patients received routine care. Patients who are more likely to experience a rapid disease course that is associated with joint destruction can be identified based on clinical and laboratory variables shown to be predictors of rapid progression. CONCLUSIONS: Early assessment and close monitoring of patients with early RA, targeting remission where possible, are important to optimize long-term outcomes. Specific treatment can be selected from among the many proven therapies to obtain the best results for the individual patient. PMID- 21295823 TI - Sperm characteristics in plains (Bison bison bison) versus wood (Bison bison athabascae) bison. AB - The objective was to compare sperm characteristics between the two subspecies of North American bison, plains bison (Bison bison bison) and wood bison (Bison bison athabascae). Frozen-thawed ejaculated sperm from age-matched plains (n = 3) and wood (n = 2) bison were evaluated for morphometry, motility, viability, protein profile, and in vitro fertilization characteristics. Sperm morphometry and motility were assessed with computer-based systems, viability was assessed with SYBR-14 and propidium iodide, and fertilizing ability was determined using a heterologous in vitro fertilization system (using bovine oocytes). For plains versus wood bison, there were significant differences for head width (4.76 +/- 0.22 vs 4.71 +/- 0.19 MUm; mean +/- SD), head area (35.64 +/- 1.91 vs 34.72 +/- 2.64 MUm(2)), head perimeter (23.61 +/- 0.68 vs 23.31 +/- 0.98 MUm), midpiece length (14.58 +/- 0.4 vs 14.36 +/- 0.51 MUm), midpiece width (0.81 +/- 0.06 vs 0.79 +/- 0.07 MUm), and tail length (46.61 +/- 2.15 vs 45.98 +/- 2.08 MUm). However, there was no significant difference in head length (overall, 9.04 +/- 0.37 MUm), progressive motility (41.16 +/- 8.39%), or viability (41.58 +/- 5.58%). Based on two-dimensional gel electrophoresis, 93 out of 113 protein spots were similar in their expression patterns. Furthermore, we inferred that differences in sperm biometry between these subspecies did not affect in vitro fertilization percentage (overall, 82.62 +/- 12.13%). Based on these findings, we concluded that plains bison were an appropriate research model for developing reproductive technologies for wood bison. PMID- 21295824 TI - Expression and methylation status of imprinted genes in placentas of deceased and live cloned transgenic calves. AB - Placental deficiencies are linked with developmental abnormalities in cattle produced by somatic cell nuclear transfer (SCNT). To investigate whether the aberrant expression of imprinted genes in placenta was responsible for fetal overgrowth and placental hypertrophy, quantitative expression analysis of six imprinted genes (H19, XIST, IGF2R, SNRPN, PEG3, and IGF2) was conducted in placentas of: 1) deceased (died during perinatal period) transgenic calves (D group, n = 4); 2) live transgenic calves (L group, n = 15); and 3) conventionally produced (control) female calves (N group, n = 4). In this study, XIST, PEG3 and IGF2 were significantly over-expressed in the D group, whereas expression of H19 and IGF2R was significantly reduced in the D group compared to controls. The DNA methylation patterns in the differentially methylated region (DMR) from H19, XIST, and IGF2R were compared using Bisulfite Sequencing PCR (BSP) and Combined Bisulfite Restriction Analysis (COBRA). In the D group, H19 DMR was significantly hypermethylated, but XIST DMR and IGF2R ICR were significantly hypomethylated compared to controls. In contrast, there were no noticeable differences in the expression and DNA methylation status of imprinted genes (except DNA methylation level of XIST DMR) in the L group compared to controls. In conclusion, altered DNA methylation levels in the DMRs of imprinted genes in placentas of deceased transgenic calves, presumably due to aberrant epigenetic nuclear reprogramming during SCNT, may have been associated with abnormal expression of these genes; perhaps this caused developmental insufficiencies and ultimately death in cloned transgenic calves. PMID- 21295825 TI - Effect of dietary antioxidant supplementation on fresh semen quality in stallion. AB - In this study, the effect of dietary supplementation of organic selenium, vitamin E, and zinc on raw semen characteristics was evaluated. Ten stallions with normal fertility were divided into two groups: a control group (CG), in which standard diet was provided, and a treated group (TG), in which the standard diet was supplemented with 1500 mg of alpha-tocopherol acetate, 360 mg of zinc, and 2.5 mg of organic selenium on a daily basis. Semen parameters on fresh semen were evaluated three times in all stallions before antioxidant supplementation (T0) and 30 (T1), 60 (T2), and 90 (T3) d after supplementation. Dietary supplementation with experimental antioxidants resulted in a significant increase in average path velocity (121.9 +/- 3.1 MUm/sec in TG vs 118.9 +/- 4.3 MUm/sec in CG), straightness (86.2 +/- 2.4 % vs 82.6 +/- 3.9 % in TG and CG respectively), viability (75.6 +/- 10.2 % in TG vs 72.3 +/- 6.9 % in CG) and total seminal plasma antioxidants levels (2.7 +/- 0.5 mmol/l vs 1.9 +/- 0.4 mmol/l in TG and CG respectively) while progressive motility 69.7 +/- 11 % vs 62.2 +/- 9.3 % in TG and CG stallions respectively) and abnormal sperm morphology (8.2+/-1.5 % in TG vs 14.4+/-4 % in CG) significantly improved in treated stallions after 60 d of supplementation. In contrast with previously reported in other species, a negative effect of antioxidant supplementation on semen concentration was recorded in the TG. A positive correlation between progressive motility and total antioxidants in seminal plasma in both treated and control stallions suggested that motility is affected by oxidative-antioxidative status, and that dietary antioxidant supplementation could increase the ability of spermatozoa to contrast reactive oxygen species or the ability of seminal plasma to reduce the oxidative stress. The improvement of semen parameters after antioxidant supplementation was not linear, and after 30 d (or 60 d for some parameters), a further increase was not noted. This evidence suggested that in our standard conditions, dietary intake of these antioxidants could be slightly under the dietary requirement and further evaluation of the actual nutrition requirements of organic selenium, zinc, and vitamin E in the stallion are needed. PMID- 21295826 TI - Agreement between measures of total motility and membrane integrity in stallion sperm. AB - Increasing seminal plasma concentrations in extended stallion semen were utilized to model decreasing sperm motility over time. Level of agreement was determined between flow cytometric measurement of sperm membrane integrity, using a combination of SYBR-14 and propidium iodide, and computer-assisted analysis of sperm motility. Values for total sperm motility (TMOT;%) and membrane integrity (SMI;%) were similar (~80%) at Time 0 within all sperm treatments. However, TMOT was lower than SMI after 24 and 48 h of storage in treatments with >20% seminal plasma. At Time 0, agreement (bias and absolute difference) between TMOT and SMI was high (-0.7 and 5.6%, respectively), but decreased after 24 (10.8 and 15.1%, respectively) and 48 h (23.0 and 23.8%, respectively) of cooled storage as motility declined more rapidly than SMI. We concluded that TMOT and SMI measured separate aspects of sperm quality. PMID- 21295827 TI - Quality of frozen-thawed semen in brown bear is not affected by timing of glycerol addition. AB - We have tested several freezing protocols for brown bear semen, modifying the time when glycerol was added (before and after cooling to 5 degrees C). No differences were found among protocols, indicating a good tolerance of brown bear semen to glycerol. This finding indicates that freezing protocols for brown bear semen could be modified to fit practical solutions which would facilitate preparation of the seminal samples in the field with the addition of glycerol at ambient temperature. PMID- 21295828 TI - Nutritional restriction of pre-pubertal liveweight gain impairs ovarian follicle growth and oocyte developmental competence of replacement gilts. AB - The objective was to investigate the effects of moderate restriction of pre- and peri-pubertal liveweight gain on ovarian development and oocyte meiotic competence. At 70 d of age, and 27.7 +/- 0.4 kg liveweight (LW), 64 Large White/Landrace crossbred gilts were allocated to two treatment groups (n = 32 gilts/treatment); one group was fed to attain a LW of 70 kg at 161 d of age (LIGHT), while the other group was fed to reach 100 kg LW (HEAVY). At 161 d of age, half of the gilts in each group (n = 16) were fed to gain LW at 0.5 kg/d (LOW), while the remaining half (n = 16) were fed to gain LW at 1.0 kg/d (HIGH) between 161 and 175 d of age, at which point they were killed and ovaries collected. For each gilt, surface antral follicles were counted and aspirated according to three size categories: 1-2.9 mm (small); 3-6 mm (medium); and > 6 mm (large). Follicles were pooled for each size class and treatment. Cumulus-oocyte complexes (COC) recovered from small and medium follicles were matured in vitro (IVM) for 44 to 46 h, and meiotic maturation assessed. There was an effect of treatment (LIGHT versus HEAVY) on the number of medium sized follicles: 25.1 +/- 2.59 versus 34.3 +/- 2.60 (P < 0.05). The ovaries of LOW gilts had more small follicles and fewer medium follicles compared to those of HIGH gilts: 92.8 +/- 8.35 versus 59.8 +/- 5.24, and 25.1 +/- 2.59 versus 32.5 +/- 2.86 (P < 0.05). Target LW at 161 d did not affect meiotic progression of oocytes. However, LOW compared to HIGH LW gain between 161 and 175 d resulted in fewer oocytes reaching MII (0.40 versus 0.54; P < 0.05). In conclusion, moderately restricting feed intake impaired follicle growth beyond 3 mm and reduced oocyte meiotic competence. Further, although a carry-over effect of long-term feed restriction on follicle growth was evident, acute changes in feed intake during the 14 d prior to ovary collection had the greatest effect on oocyte nuclear maturation in vitro. PMID- 21295829 TI - Effect of season, month of parturition and lactation on estrus behavior and ovarian activity in Barki x Rahmani crossbred ewes under subtropical conditions. AB - The correlations between some meteorological parameters and fertility data were evaluated in Barki x Rahmani crossbred ewes using the records of five consecutive years (2003-2007). Additionally, estrus detection and ultrasonic evaluation were applied on eighteen mature dry ewes during breeding and non-breeding seasons. The effect of lactation was evaluated by monitoring estrus behavior in ninety four lactating ewes from 40 to 120 d after parturition. Moreover, ultrasonography was used to identify ovarian activity in six cyclic and six acyclic non-lactating ewes. Results revealed that relative estrus occurrence and fertile mating were positively correlated (P <0.05) with high temperature and long photoperiod (conditions of summer season), and were negatively correlated (P < 0.01) with rainfall (condition of winter season). During breeding season, estrus rate, serum progesterone concentration, and diameter of largest follicle were significantly (P < 0.05) higher than those observed during the non-breeding season. Furthermore, month of parturition had a significant effect (P < 0.05) on estrus rate of lactating ewes where ewes that lambed in August, September, and October recorded higher estrus rate than those lambed in November and December. However, the lactational strength did not exert any deleterious effect on the reproductive performance of lactating ewes. In conclusion, in Egypt under subtropical conditions, Barki x Rahmani crossbred ewes exerted optimum estrus behavior and fertile mating during summer season. The reduction in estrus activity during lactation was due to the seasonal effect rather than lactational stress. PMID- 21295830 TI - Questionnaire-based survey of parturition in the queen. AB - The lack of scientific data concerning whether parturition in the queen proceeds normally or not may prevent veterinarians and cat owners from recognizing parturition problems in time. A questionnaire-based study of parturition in 197 queens was performed to determine several parameters of parturition and their influence on its progress. The mean length of gestation was 65.3 days (range 57 to 72 days) and it decreased with increasing litter size (P = 0.02). The median litter size was 4.5 kittens (range 1 to 9), with more males (53%) than females (46%) (P = 0.05). Sixty-nine percent of the kittens were born in anterior presentation and 31% in posterior presentation, indicating that either can be considered normal in the cat. Males were born in posterior position (34%) more often than females (26%) (P = 0.03). The mean birth weight was 98 g (range of 35 to 167 g) and decreased with increasing litter size (P < 0.01). Mean birth weight was higher in males and kittens born in posterior presentation (P < 0.01). Forty four (5%) of the 887 kittens were stillborn. This was not correlated with the presentation at expulsion but stillborn kittens were more often female (P = 0.02) and weighed less than those born alive (P = 0.04). The median interkitten time was 30 min (range 2 to 343 min) and 95% were born within 100 min after expulsion of the preceding kitten. The interkitten time as a measure of the progress of parturition was not influenced by the kitten's gender, presentation at expulsion, birth weight, or stillbirth, or by the parity of the queen. The results of this study can be used to develop reference values for parturition parameters in the queen, both to determine whether a given parturition is abnormal and as the basis for a parturition protocol. PMID- 21295831 TI - Effect of sod (superoxide dismutase) protein supplementation in semen extenders on motility, viability, acrosome status and ERK (extracellular signal-regulated kinase) protein phosphorylation of chilled stallion spermatozoa. AB - New studies are underway to find new methods for supporting longer storage of cooled stallion semen. It is known that high concentrations of reactive oxygen species (ROS) cause sperm pathology. The metalloprotein superoxide dismutase (SOD) is responsible for H(2)O(2) and O(2) production, by dismutation of superoxide radicals. The aim of this study is to assess the quality of chilled stallion semen processed with extenders containing SOD at different concentrations as antioxidant additives. A total of 80 ejaculates collected from 5 standardbred stallions was divided into 5 aliquots treated as: native semen (control 1); native semen diluted 1:3 with Kenney semen extender (control 2); spermatozoa diluted after centrifugation in extender without (control 3) or with SOD at 25 IU/ml (experimental 1) or 50 IU/ml (experimental 2). Each sample was analyzed for motility, viability and acrosome status, immediately after semen preparation and again after storage at 5 degrees C for 24 h, 48 h and 7 2h. Acrosome integrity was evaluated by Chlortetracycline (CTC) and Fluorescent labeled peanut lectin agglutinin (PNA-FITC conjugated staining). A proteomic approach of quantifying extracellular signal regulated kinase (ERK) was also evaluated as an indirect indicator of oxidative stress. In all samples sperm progressive motility and sperm acrosomal integrity showed a significant reduction between fresh and cooled spermatozoa at 24 h, 48 h and 72 h. Quality parameters of sperm were significantly higher (Progressive Motility P < 0.01; Viability P < 0.001) in aliquots supplemented with SOD. ERK phosphorylation was statistically higher (P < 0.01) in aliquots without SOD. The Authors concluded that addition of SOD to semen extenders improves the quality of chilled equine semen and reduces ERK activation. PMID- 21295832 TI - PGF(2alpha), LH, testosterone, oestrone sulphate, and cortisol plasma concentrations around sexual stimulation in jackass. AB - Many hormones are involved in the regulation of male reproductive functions, controlling sexual behavior, and influencing sexual arousal, the onset of erection and ejaculation, and the post-ejaculatory detumescence. The aims of this study were to analyze the plasma concentrations of 15-ketodihydro-PGF(2alpha) (PGFM), LH, testosterone (T), oestrone sulphate (OS), and cortisol (C) in relation to sexual stimulation and to evaluate the possible correlations among circulating hormones and between hormones and semen characteristics in the donkey stallion. Thirteen sexually experienced Martina Franca jackass of proven fertility were enrolled and semen was collected through an artificial vagina. Plasma samples were collected at 12, 9, 6 and 3 min before oestrous jenny exposure, at the first erection in the mating arena in the presence of an oestrous jenny, during ejaculation, at dismounting, 3, 6, 9 and 12 min after ejaculation in box, and then every 10 min during the following 50 min. PGFM showed an increasing trend with significant differences between the pre ejaculatory and post-ejaculatory period, suggesting a role of this hormone in the control of ejaculation. LH showed a significantly higher concentration at ejaculation compared to last samples, while T showed significantly higher levels at erection, ejaculation and dismounting, probably for its influence on these processes and on sexual behavior. Finally, OS did not show any difference in the period of observation, while C presented a significant increase only 22 minutes after erection. The only hormonal correlation found was a positive one between LH and T at erection and dismounting, while T and OS were positively correlated with total and progressive motility, respectively. PMID- 21295833 TI - Supplementation of equine early spring transitional follicles with luteinizing hormone stimulates follicle growth but does not restore steroidogenic activity. AB - This study was conducted to test the hypothesis that supplementation of growing follicles with LH during the early spring transitional period would promote the development of steroidogenically active, dominant follicles with the ability to respond to an ovulatory dose of hCG. Mares during early transition were randomly assigned to receive a subovulatory dose of equine LH (in the form of a purified equine pituitary fraction) or saline (transitional control; n = 7 mares per group) following ablation of all follicles >15 mm. Treatments were administered intravenously every 12 h from the day the largest follicle of the post-ablation wave reached 20 mm until a follicle reached >32 mm, when an ovulatory dose of hCG (3000 IU) was given. Saline-treated mares during June and July were used as ovulatory controls. In a preliminary study, injection of this pituitary fraction (eLH) to anestrus mares was followed by an increase in circulating levels of LH (P < 0.01) but not FSH (P > 0.6). Administration of eLH during early transition stimulated the growth of the dominant follicle (Group x Day, P < 0.00001), which attained diameters similar to the dominant follicle in ovulatory controls (P > 0.1). In contrast, eLH had no effect on the diameter of the largest subordinate follicle or the number of follicles >10 mm during treatment (P > 0.3). The numbers of mares that ovulated in response to hCG in transitional control, transitional eLH and ovulatory control groups (2 of 2, 3 of 5 and 7 of 7, respectively) were not significantly different (P > 0.1). However, after hCG induced ovulation, all transitional mares returned to an anovulatory state. Circulating estradiol levels increased during the experimental period in ovulatory controls but not in transitional eLH or transitional control groups (Group x Day, P = 0.013). In addition, although progesterone levels increased after ovulation in transitional control and transitional eLH groups, levels in these two groups were lower than in the ovulatory control group after ovulation (Group, P = 0.045). In conclusion, although LH supplementation of early transitional waves beginning after the largest follicle reached 20 mm promoted growth of ovulatory-size follicles, these follicles were developmentally deficient as indicated by their reduced steroidogenic activity. PMID- 21295834 TI - Fibroblast growth factor requirements for in vitro development of bovine embryos. AB - The overall goal was to describe the importance of fibroblast growth factors (FGFs) during development of the bovine embryo. An inhibitor of FGF receptor kinase activity (SU5402) was used to examine whether FGF signaling is required for embryo development. Addition of 20 MUM SU5402 on Day 0 (Day of IVF) reduced (P = 0.04) the percentage of oocytes becoming blastocysts on Day 7 compared to controls (5.9 +/- 2.1 vs 16.9 +/- 2.4; average +/- SEM). Also, Day-8 blastocysts placed into individual culture drops of medium containing SU5402 tended to have decreased (P = 0.08) blastomere numbers at Day 11 (211.1 +/- 27.5 vs 297.8 +/- 25.0). A second series of studies determined if supplemental FGF2 enhances development in vitro. There was no effect of FGF2 on cleavage or blastocyst development rates when 5 or 100 ng/mL FGF2 was provided immediately after fertilization. Also, FGF2 supplementation beginning on Day 5 post-fertilization did not significantly affect blastocyst rates or the number of trophoblast and inner cell mass cells. However, addition of 500 ng/mL FGF2 at both Day 0 and Day 4 increased (P = 0.03) the percentage of oocytes that became blastocysts on Day 7 compared with controls (27.4 +/- 1.3 vs 19.7 +/- 1.3). In a final study, the thermal-protective ability of FGF2 was examined by adding FGF2 1 h before exposing Day 5 embryos to heat shock. Addition of FGF2 did not significantly influence embryo thermal-tolerance. In conclusion, FGF receptor activation was important for optimal blastocyst formation and FGF2 supplementation increased bovine blastocyst formation when provided at high concentrations. PMID- 21295835 TI - In vitro fertilization and development of cumulus oocytes complexes collected by ultrasound-guided follicle aspiration in superstimulated llamas. AB - The objective was to evaluate the developmental competence of cumulus-oocyte complexes (COC) collected by follicular aspiration in llamas treated with FSH or eCG. Llamas were assigned randomly to two groups (n = 16 per group) and treated, at the time of ovarian follicular wave emergence, with either: 1) 25 mg of FSH im, twice daily for 4 d; or 2) 1000 IU of eCG as a single i.m. dose. The start of gonadotropin treatment was considered Day 0. Both groups were given 5 mg of Armour Standard LH im on Day 6, and COC were collected by follicle aspiration on Day 7. Expanded COC collected from FSH- (n = 157) and eCG-treated llamas (n = 151) were fertilized in vitro using epididymal sperm, and presumptive zygotes were in vitro cultured in SOF medium for 8 d. The FSH and eCG treatment groups did not differ with respect to: the number of follicles >=7 mm (16.0 +/- 2.7 vs 14.0 +/- 1.9, respectively; P = 0.5); the number of COC collected (11.5 +/- 1.9 vs 9.7 +/- 1.2; P = 0.4); the number of expanded COC (9.8 +/- 1.4 vs 9.4 +/- 1.2; P = 0.8); or the percentage of presumptive zygotes which developed into 2 to 8 cell stage embryos (65.3 vs 63.1), morulas (46.2 vs 42.5), or blastocysts (23.1 vs 20.5; P > 0.05). In conclusion, FSH and eCG treatments were equally effective for recovery of a high number of expanded COC which were used directly for in vitro fertilization. Furthermore, rate of embryo development was not significantly affected by the gonadotropin treatment used. PMID- 21295836 TI - Effects of the 3beta-hydroxysteroid dehydrogenase inhibitor trilostane on luteal progesterone production in the dog. AB - Interference with the pregnancy-maintaining influence of progesterone is the basis of most methods for termination of unwanted pregnancy in dogs. The currently available methods are based on induction of luteolysis or blocking of the progesterone receptor. Inhibition of progesterone synthesis using a competitive inhibitor of 3beta-hydroxysteroid dehydrogenase (3beta-HSD) could be another strategy to terminate unwanted pregnancies. In this study we investigated the effects of the 3beta-HSD inhibitor trilostane on corpus luteum function in non-pregnant bitches. Trilostane was administered orally for seven consecutive days in either the pituitary-independent part of the luteal phase (PIP, start of treatment on D11 after ovulation, n = 6) or the pituitary-dependent part (PDP, start of treatment on D31 after ovulation, n = 6), in an oral dose of about 4.5 mg/kg bw, twice daily. Results were compared with those obtained in control bitches (n = 6). ACTH stimulation tests were performed to assess adrenocortical reserve capacity. Trilostane caused no apparent side effects and ACTH stimulation tests revealed good suppression of cortisol secretion. Trilostane also caused a significant decrease in plasma progesterone concentration. When it was stopped during PIP, progesterone secretion was completely restored and there was no difference in the length of the luteal phase between those dogs and control dogs (99 days, range 70-138 d and 99 d, range 60-112 d, respectively). When trilostane was stopped during PDP there was no post-treatment recovery of progesterone secretion and although the luteal phase tended to be shorter (66 d, range 41-101 d) the difference was not significant (P = 0.09). Plasma prolactin concentration did not increase after the trilostane-induced decrease in plasma progesterone. The interoestrous interval in dogs treated during PIP (234 d, range 175-269 d) or PDP (198 d, range 120-287 d) was not significantly shorter than the control interval (247 d, range 176-313 d). In conclusion, trilostane treatment was effective in decreasing plasma progesterone concentration in bitches during the luteal phase, but the dose regimen used in this study produced less clear-cut inhibition of ovarian steroidogenesis than have other strategies to decrease plasma progesterone concentration. Further studies are warranted to determine whether trilostane can be used to terminate unwanted pregnancy in the bitch without inducing adrenocortical insufficiency. PMID- 21295837 TI - Caffeine, dibutyryl cyclic-AMP and heparin affect the chemotactic and phagocytotic activities of neutrophils for boar sperm in vitro. AB - The objective was to examine the effects of caffeine, dibutyryl cyclic AMP, and heparin on the chemotaxis and/or phagocytosis of PMNs for porcine sperm. The chemotactic activity of PMNs, determined in a blind well chamber, increased (P < 0.05) when fresh serum was added to the medium (control containing BSA, 1109.5 cells/mm(2) vs serum, 1226.3 cells/mm(2)), regardless of the presence of sperm (control, 1121.1 cells/mm(2) vs serum, 1245.8 cells/mm(2)), whereas heat inactivated serum did not affect activity (without sperm, 1099.4 cells/mm(2) and with sperm, 1132.6 cells/mm(2)). Regardless of live and dead sperm and of the origin of PMNs (boars vs sows), the phagocytotic activity of PMNs, as determined by co-culture of PMNs with sperm for 60 min, increased (P < 0.05) in the presence of fresh serum containing active complement (46.7 and 43.0%, respectively), but stimulation was decreased (P < 0.05) when 1 mM or higher concentrations of caffeine was added to the medium (from 40.7 to 20.8-31.6%). The origin of PMNs (sows vs boars) did not significantly affect phagocytotic activity. The percentage of PMNs that phagocytized polystyrene latex beads decreased when 2 mM caffeine was added to the medium containing porcine serum (from 43.7 to 21.5%). Serum-stimulated chemotactic activity of PMNs (1089.9 cells/mm(2)) was also reduced (P < 0.05) with 2 mM caffeine (942.5 cells/mm(2)). Furthermore, dibutyryl cAMP at >= 0.1 mM or heparin at >= 100 MUg/mL decreased phagocytotic activity, in a concentration-dependent manner (P < 0.05). Supplementation of PMNs with heparin at 100 or 500 MUg/mL decreased (P < 0.05) chemotactic activity in the presence of serum (from 1137.1 cells/mm(2) to 1008.8-1026.3 cells/mm(2)). We inferred that opsonization in the presence of active complement stimulated phagocytotic and chemotactic activities of PMNs, whereas supplementation with caffeine and dibutyryl cAMP (which could be associated with the intracellular cAMP level of PMNs) or adding heparin decreased serum-stimulated phagocytotic and chemotactic activities. PMID- 21295838 TI - Zona pellucida glycoprotein 3 (pZP3) and integrin beta2 (ITGB2) mRNA and protein expression in porcine oocytes after single and double exposure to brilliant cresyl blue test. AB - Brilliant cresyl blues (BCB) staining test is a useful tool in assessing the competence of cumulus-oocyte-complexes (COCs) in several mammalian species. It is mostly used to select gametes after they are recovered from the ovary or before and after IVM to isolate those oocytes that reach developmental competency. However, there is evidence that double exposure to BCB test may lead to impaired fertilization or even have a toxic effect on cells. The aim of the present study was to investigate the expression pattern of sperm-egg interaction molecules in oocytes after single and double exposure to BCB test. Follicles were dissected from porcine ovaries after slaughter and aspirated COCs were cultured in standard porcine IVM culture medium (TCM 199) for 44 h. The BCB test was applied to COCs before and after IVM. In developmentally competent oocytes, assessed by determining the activity of glucose-6-phosphate dehydrogenase (G6PDH; BCB test), real-time quantitative PCR reaction methods, western blot and confocal microscopy analysis were applied to determine the transcript levels of porcine zona pellucida glycoprotein 3 (pZP3), and integrin beta 2 (ITGB2), as well as the levels of pZP3 and ITGB2 proteins. In the control group, assessment of the expression of the investigated genes was performed before and after IVM without BCB test. We observed a significantly higher level of pZP3 mRNA in oocytes after single exposure to BCB test compared to control before and after IVM (P < 0.001), and to double staining (P < 0.05). The level of ITGB2 mRNA was also increased in gametes after single exposure to BCB test as compared to control before and after IVM (P < 0.001, P < 0.01, respectively), and double staining (P < 0.05). Western blot analysis demonstrated a higher level of pZP3 protein in oocytes after single staining with BCB as compared to control both before and after IVM (P < 0.001, P < 0.05, respectively) and double staining (P < 0.05). Confocal microscopic observations have revealed the same pattern of increased level of pZP3 and ITGB2 expression after single exposure to BCB test. In both cases we detected specific cytoplasmic localization of both proteins. The ITGB2 protein has zona pellucida and membrane localization in control oocytes before IVM. After IVM and after single exposure to BCB, ITGB2 was also strongly detected in the cytoplasm. In both cases, after double exposure to BCB both proteins were detected only partially in the cytoplasm. Our results suggest that (i) single exposure to BCB increased the expression of sperm-oocyte interaction genes, (ii) double exposure to BCB leads to only partial expression of pZP3 and ITGB2 in oocyte cytoplasm, (iii) the BCB staining test itself may be a cause of specific pZP3 translocation from the zona pellucida to the cytoplasm, and that (iv) in vitro maturation of oocytes may increase ITGB2 expression and translocation from the zona pellucida to the cytoplasm. PMID- 21295839 TI - Prepubertal goat oocytes from large follicles result in similar blastocyst production and embryo ploidy than those from adult goats. AB - Developmental competence of oocytes from prepubertal females is lower than those from adult females. Oocyte development competence is positively related to follicular diameter. Most of the follicles of prepubertal goat ovaries are smaller than 3 mm. The aim of this study was to compare oocytes of two follicle sizes (< 3 mm and >= 3 mm) from prepubertal goats with oocytes from adult goats in relation to their in vitro production and quality of blastocysts. Oocytes from prepubertal goats were obtained from slaughterhouse ovaries and selected according to the follicle diameter whereas oocytes from adult goats were recovered in vivo by LOPU technique without prior selection of follicle size. COCs were IVM for 27 h, IVF at the conventional conditions with fresh semen and presumptive zygotes were cultured in SOF medium for 8 days. Blastocysts obtained were vitrified and after warming their blastocoele re-expansion and the ploidy by FISH technique were assessed. We found significant differences between blastocysts yield of oocytes recovered from follicles smaller than 3 mm of prepubertal goats compared to those from adult goats (5.45% vs 20. 83%, respectively) however, these differences disappear if oocytes were recovered form large follicles (18.07%). A total of 28 blastocysts were analysed and 96.43% showed mixoploidy. Age did not affect the number of embryos with abnormal ploidy or blastocyst re-expansion after warming. Furthermore, the percentage of diploid blastomeres per embryo was similar in the 3 groups studied, adult, prepubertal from follicles >= 3 mm and < 3 mm (68.6%, 80.8% and 73.6%, respectively). In conclusion, IVP of blastocysts coming from follicles larger than 3 mm of goats 45 days old were not different to the blastocysts produced from adult goats, both in terms of quantity and quality. PMID- 21295840 TI - Effects of a lecithin and catalase containing semen extender and a second dilution with different enhancing buffers on the quality of cold-stored canine spermatozoa. AB - In the present study, a diluent containing 0.8% lecithin (Minitube(r), Tiefenbach, G) for the cold storage of canine semen was compared to a Tris-egg yolk extender (TRIS-EY) containing 20% egg yolk. For this purpose, aliquots of 10 mixed ejaculates (main fractions) were either diluted with TRIS-EY or with three lecithin extenders containing 0.8% lecithin with or without catalase and tyrosine. All samples were examined by computer assisted sperm analysis (CASA), chlortetracycline assay (CTC) and flow cytometry, sperm chromatin structure assay (SCSA) and zona pellucida binding assay (ZBA). Samples were then cold stored for 8 d and examinations repeated at days 3 and 8. Measurement in the CASA were repeated daily and prior to measurement, each sample was diluted with each of 4 enhancers with or without acetylcarnitine. The use of an enhancer proved to be essential for all extenders and after 8 d of cooling, progressive motility (P) and viability (V) still averaged > 70% and > 80% with the lecithin extenders containing additives, whereas with TRIS-EY and without additives it was significantly lower (P < 0.05). The percentage of capacitated spermatozoa did not differ between extender groups and there was no significant increase in acrosome reactions (AR) within 3 d. The chromatin status of cells was not changed by cooling within 8 d. The ZBA showed that with additives, significantly more spermatozoa bound to oocytes when a lecithin extender with additives was used (P < 0.05). In conclusion, the 0.8% lecithin extender containing catalase, conserved P and V during 8 d of cold storage better than the TRIS-EY extender, however, only when an enhancer was used; addition of acetylcarnitine to the enhancer did not further improve semen quality. The here introduced lecithin extender / enhancer combination is a useful tool for prolonged storage of cooled semen with excellent longevity and binding ability; addition of tyrosine to the extender did not improve semen quality. PMID- 21295841 TI - Mechanical phenotyping of stem cells. AB - Elasticity and visco-elasticity are mechanical properties of cells which directly reflect cellular composition, internal structure (cytoskeleton), and external interactions (cell-cell and/or cell-surface). A variety of techniques involving probing, pulling, or deforming cells have been used to characterize these mechanical properties. With continuing advances in the technology, it may be possible to establish mechanical phenotypes that can be used to identify cells at specific points of differentiation and dedifferentiation with direct applications to regenerative medicine, therapeutics, and diagnostics. PMID- 21295842 TI - Administration of human chorionic gonadotropin at embryo transfer induced ovulation of a first wave dominant follicle, and increased progesterone and transfer pregnancy rates. AB - We hypothesized that administration of hCG to recipients at embryo transfer (ET) would induce accessory CL, increase serum progesterone concentrations, and reduce early embryonic loss (as measured by increased transfer pregnancy rates). At three locations, purebred and crossbred Angus, Simmental, and Hereford recipients (n = 719) were assigned alternately to receive i.m. 1,000 IU hCG or 1 mL saline (control) at ET. Fresh or frozen-thawed embryos were transferred to recipients with a palpable CL on Days 5.5 to 8.5 (median = Day 7) of the cycle (Locations 1 and 2), or on Day 7 after timed ovulation (Location 3). Pregnancy diagnoses (transrectal ultrasonography) were done 28 to 39 d (median = 35 d) and reconfirmed 58 to 77 d (median = 67 d) post-estrus. At Location 1 (n = 108), ovaries were examined at pregnancy diagnosis to enumerate CL. More (P < 0.001) pregnant hCG-treated cows (69.0%) had multiple CL than pregnant controls (0%). Serum progesterone (ng/mL) determined at Locations 1 and 2 (n = 471) at both pregnancy diagnoses in pregnant cows was greater (P <= 0.05) after hCG treatment than in controls (first: 8.1 +/- 0.9 vs 6.1 +/- 0.8; second: 8.8 +/- 0.9 vs 6.6 +/- 0.7), respectively. Unadjusted pregnancy rates at the first diagnosis were 61.8 and 53.9% for hCG and controls. At the second diagnosis, pregnancy rates were 58.6 and 51.3%, respectively. Treatment (P = 0.026), embryo type (P = 0.016), and BCS (P = 0.074) affected transfer pregnancy rates. Based on odds ratios, greater pregnancy rates occurred in recipients receiving hCG, a fresh embryo (66.3 vs 55.5%), and having BCS >5 (62.3 vs 55.3%). We concluded that giving hCG at ET increased incidence of accessory CL, serum progesterone in pregnant recipients, and transfer pregnancy rates. Furthermore, we inferred that increased progesterone resulting from hCG-induced ovulation reduced early embryonic losses after transfer of embryos to recipients. PMID- 21295843 TI - Effects of timing of induced luteolysis in embryo donor mares on reproductive performance and pregnancy rate in recipient mares. AB - The objective was to evaluate the effects of giving prostaglandin F2(alpha) (PGF) to donor mares 48 h prior to embryo collection. Non-lactating donor mares (n = 20 estrous cycles in 10 mares), ranging from 2.5 to 10 y of age and 400 to 500 kg of body weight were used from September 2004 to February 2005 in the southern hemisphere (Brazil). Donor mares were randomly assigned in a cross-over design study. During a Treated cycle, 7.5 mg PGF was given 48 h prior to embryo collection, whereas in the Control cycle, 7.5 mg PGF was given at embryo collection. In Treated Cycles, serum progesterone concentrations decreased between the day of PGF treatment and the day of embryo collection (13.9 +/- 5.4 and 0.5 +/- 0.3 ng/mL, respectively; P < 0.05). In Treated versus Control cycles, the interovulatory interval was shorter (14.9 +/- 0.9 vs 17.5 +/- 1.1 d, P < 0.05). However, there was no significant difference between these groups for the interval from PGF to ovulation (average, 9.8 d), embryo recovery rate (average, 75%), embryo quality, uterine protein concentration, and pregnancy rate in recipient mares (average, 87% at 15 d after ovulation, with no pregnancy loss detected by 60 d). In conclusion, giving donor mares PGF 48 h prior to embryo collection reduced the average interovulatory interval by approximately 2.5 d, thereby potentially increasing the numbers of embryos that could be collected during a breeding season, with no deleterious effects on embryo recovery rate, embryo quality, or pregnancy rate in recipient mares. PMID- 21295844 TI - National, regional, and global trends in systolic blood pressure since 1980: systematic analysis of health examination surveys and epidemiological studies with 786 country-years and 5.4 million participants. AB - BACKGROUND: Data for trends in blood pressure are needed to understand the effects of its dietary, lifestyle, and pharmacological determinants; set intervention priorities; and evaluate national programmes. However, few worldwide analyses of trends in blood pressure have been done. We estimated worldwide trends in population mean systolic blood pressure (SBP). METHODS: We estimated trends and their uncertainties in mean SBP for adults 25 years and older in 199 countries and territories. We obtained data from published and unpublished health examination surveys and epidemiological studies (786 country-years and 5.4 million participants). For each sex, we used a Bayesian hierarchical model to estimate mean SBP by age, country, and year, accounting for whether a study was nationally representative. FINDINGS: In 2008, age-standardised mean SBP worldwide was 128.1 mm Hg (95% uncertainty interval 126.7-129.4) in men and 124.4 mm Hg (123.0-125.9) in women. Globally, between 1980 and 2008, SBP decreased by 0.8 mm Hg per decade (-0.4 to 2.2, posterior probability of being a true decline=0.90) in men and 1.0 mm Hg per decade (-0.3 to 2.3, posterior probability=0.93) in women. Female SBP decreased by 3.5 mm Hg or more per decade in western Europe and Australasia (posterior probabilities >=0.999). Male SBP fell most in high-income North America, by 2.8 mm Hg per decade (1.3-4.5, posterior probability >0.999), followed by Australasia and western Europe where it decreased by more than 2.0 mm Hg per decade (posterior probabilities >0.98). SBP rose in Oceania, east Africa, and south and southeast Asia for both sexes, and in west Africa for women, with the increases ranging 0.8-1.6 mm Hg per decade in men (posterior probabilities 0.72-0.91) and 1.0-2.7 mm Hg per decade for women (posterior probabilities 0.75 0.98). Female SBP was highest in some east and west African countries, with means of 135 mm Hg or greater. Male SBP was highest in Baltic and east and west African countries, where mean SBP reached 138 mm Hg or more. Men and women in western Europe had the highest SBP in high-income regions. INTERPRETATION: On average, global population SBP decreased slightly since 1980, but trends varied significantly across regions and countries. SBP is currently highest in low income and middle-income countries. Effective population-based and personal interventions should be targeted towards low-income and middle-income countries. FUNDING: Funding Bill & Melinda Gates Foundation and WHO. PMID- 21295845 TI - Stemming the global tsunami of cardiovascular disease. PMID- 21295847 TI - National, regional, and global trends in serum total cholesterol since 1980: systematic analysis of health examination surveys and epidemiological studies with 321 country-years and 3.0 million participants. AB - BACKGROUND: Data for trends in serum cholesterol are needed to understand the effects of its dietary, lifestyle, and pharmacological determinants; set intervention priorities; and evaluate national programmes. Previous analyses of trends in serum cholesterol were limited to a few countries, with no consistent and comparable global analysis. We estimated worldwide trends in population mean serum total cholesterol. METHODS: We estimated trends and their uncertainties in mean serum total cholesterol for adults 25 years and older in 199 countries and territories. We obtained data from published and unpublished health examination surveys and epidemiological studies (321 country-years and 3.0 million participants). For each sex, we used a Bayesian hierarchical model to estimate mean total cholesterol by age, country, and year, accounting for whether a study was nationally representative. FINDINGS: In 2008, age-standardised mean total cholesterol worldwide was 4.64 mmol/L (95% uncertainty interval 4.51-4.76) for men and 4.76 mmol/L (4.62-4.91) for women. Globally, mean total cholesterol changed little between 1980 and 2008, falling by less than 0.1 mmol/L per decade in men and women. Total cholesterol fell in the high-income region consisting of Australasia, North America, and western Europe, and in central and eastern Europe; the regional declines were about 0.2 mmol/L per decade for both sexes, with posterior probabilities of these being true declines 0.99 or greater. Mean total cholesterol increased in east and southeast Asia and Pacific by 0.08 mmol/L per decade (-0.06 to 0.22, posterior probability=0.86) in men and 0.09 mmol/L per decade (-0.07 to 0.26, posterior probability=0.86) in women. Despite converging trends, serum total cholesterol in 2008 was highest in the high-income region consisting of Australasia, North America, and western Europe; the regional mean was 5.24 mmol/L (5.08-5.39) for men and 5.23 mmol/L (5.03-5.43) for women. It was lowest in sub-Saharan Africa at 4.08 mmol/L (3.82-4.34) for men and 4.27 mmol/L (3.99-4.56) for women. INTERPRETATION: Nutritional policies and pharmacological interventions should be used to accelerate improvements in total cholesterol in regions with decline and to curb or prevent the rise in Asian populations and elsewhere. Population-based surveillance of cholesterol needs to be improved in low-income and middle-income countries. FUNDING: Bill & Melinda Gates Foundation and WHO. PMID- 21295846 TI - National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants. AB - BACKGROUND: Excess bodyweight is a major public health concern. However, few worldwide comparative analyses of long-term trends of body-mass index (BMI) have been done, and none have used recent national health examination surveys. We estimated worldwide trends in population mean BMI. METHODS: We estimated trends and their uncertainties of mean BMI for adults 20 years and older in 199 countries and territories. We obtained data from published and unpublished health examination surveys and epidemiological studies (960 country-years and 9.1 million participants). For each sex, we used a Bayesian hierarchical model to estimate mean BMI by age, country, and year, accounting for whether a study was nationally representative. FINDINGS: Between 1980 and 2008, mean BMI worldwide increased by 0.4 kg/m(2) per decade (95% uncertainty interval 0.2-0.6, posterior probability of being a true increase >0.999) for men and 0.5 kg/m(2) per decade (0.3-0.7, posterior probability >0.999) for women. National BMI change for women ranged from non-significant decreases in 19 countries to increases of more than 2.0 kg/m(2) per decade (posterior probabilities >0.99) in nine countries in Oceania. Male BMI increased in all but eight countries, by more than 2 kg/m(2) per decade in Nauru and Cook Islands (posterior probabilities >0.999). Male and female BMIs in 2008 were highest in some Oceania countries, reaching 33.9 kg/m(2) (32.8-35.0) for men and 35.0 kg/m(2) (33.6-36.3) for women in Nauru. Female BMI was lowest in Bangladesh (20.5 kg/m(2), 19.8-21.3) and male BMI in Democratic Republic of the Congo 19.9 kg/m(2) (18.2-21.5), with BMI less than 21.5 kg/m(2) for both sexes in a few countries in sub-Saharan Africa, and east, south, and southeast Asia. The USA had the highest BMI of high-income countries. In 2008, an estimated 1.46 billion adults (1.41-1.51 billion) worldwide had BMI of 25 kg/m(2) or greater, of these 205 million men (193-217 million) and 297 million women (280 315 million) were obese. INTERPRETATION: Globally, mean BMI has increased since 1980. The trends since 1980, and mean population BMI in 2008, varied substantially between nations. Interventions and policies that can curb or reverse the increase, and mitigate the health effects of high BMI by targeting its metabolic mediators, are needed in most countries. FUNDING: Bill & Melinda Gates Foundation and WHO. PMID- 21295848 TI - A simplified genetic design for mammalian enamel. AB - A biomimetic replacement for tooth enamel is urgently needed because dental caries is the most prevalent infectious disease to affect man. Here, design specifications for an enamel replacement material inspired by Nature are deployed for testing in an animal model. Using genetic engineering we created a simplified enamel protein matrix precursor where only one, rather than dozens of amelogenin isoforms, contributed to enamel formation. Enamel function and architecture were unaltered, but the balance between the competing materials properties of hardness and toughness was modulated. While the other amelogenin isoforms make a modest contribution to optimal biomechanical design, the enamel made with only one amelogenin isoform served as a functional substitute. Where enamel has been lost to caries or trauma a suitable biomimetic replacement material could be fabricated using only one amelogenin isoform, thereby simplifying the protein matrix parameters by one order of magnitude. PMID- 21295849 TI - The effect of surface charge on in vivo biodistribution of PEG-oligocholic acid based micellar nanoparticles. AB - To systematically elucidate the effect of surface charge on the cellular uptake and in vivo fate of PEG-oligocholic acid based micellar nanoparticles (NPs), the distal PEG termini of monomeric PEG-oligocholic acid dendrimers (telodendrimers) are each derivatized with different number (n = 0, 1, 3 and 6) of anionic aspartic acids (negative charge) or cationic lysines (positive charge). Under aqueous condition, these telodendrimers self-assemble to form a series of micellar NPs with various surface charges, but with similar particle sizes. NPs with high surface charge, either positive or negative, were taken up more efficiently by RAW 264.7 murine macrophages after opsonization in fresh mouse serum. Mechanistic studies of cellular uptake of NPs indicated that several distinct endocytic pathways (e.g., clathrin-mediated endocytosis, caveolae mediated endocytosis, and macropinocytosis) were involved in the cellular uptake process. After their cellular uptake, the majority of NPs were found to localize in the lysosome. Positively charged NPs exhibited dose-dependent hemolytic activities and cytotoxicities against RAW 264.7 cells proportional to the positive surface charge densities; whereas negatively charged NPs did not show obvious hemolytic and cytotoxic properties. In vivo biodistribution studies demonstrated that undesirable liver uptake was very high for highly positively or negatively charged NPs, which is likely due to active phagocytosis by macrophages (Kupffer cells) in the liver. In contrast, liver uptake was very low but tumor uptake was very high when the surface charge of NPs was slightly negative. Based on these studies, we can conclude that slightly negative charge may be introduced to the NPs surface to reduce the undesirable clearance by the reticuloendothelial system (RES) such as liver, improve the blood compatibility, thus deliver the anti-cancer drugs more efficiently to the tumor sites. PMID- 21295850 TI - Placental volume and vascular flow assessed by 3D power Doppler and adverse pregnancy outcomes. AB - OBJECTIVE: To estimate the utility of first-trimester 3D-placental volume and vascular flow indices in the prediction of adverse pregnancy outcomes. METHODS: A prospective cohort study including women with singleton pregnancies seen between 11 and 14 weeks as part of a screening program for aneuploidy. Placental volume and vascularization indices were obtained using 3D power Doppler imaging and the VOCAL technique. Placental volume (PV), Vascularization Index (VI), Flow Index (FI) and Vascularization Flow Index (VFI) were calculated. The adverse pregnancy outcomes investigated include preeclampsia (PE), gestational hypertension (GH) and small for gestational age (SGA). The predictive ability of each variable was evaluated using receiver-operating characteristic (ROC) curves. RESULTS: Of 388 women included, PE was seen in 30 (7.7%), GH in 37 (9.0%) and SGA in 31 (8.0%). Placental volume was not significantly different between the pregnancies with adverse outcomes and those without. The mean values of the VI and VFI were significantly lower in the pregnancies that developed PE but not in GH or SGA. The area under the ROC curve for the prediction of PE was 0.71, 0.69 and 0.70 for VI, FI and VFI, respectively. CONCLUSION: The study confirms lower 3D power Doppler vascular flow indices in pregnancies that develop PE. The discriminatory ability of using these indices alone for predicting PE appears modest. PMID- 21295851 TI - Review: hCG, preeclampsia and regulatory T cells. AB - Human chorionic gonadotropin (hCG) is crucial for successful pregnancy. Its many functions include angiogenesis and immune regulation. Despite years of research, the etiology of preeclampsia remains unknown. Marked by insufficient trophoblast invasion and poor spiral artery remodeling, preeclampsia has also been linked to immune dysregulation. Here we discuss the roles of hCG in the context of endovascular cross-talk between trophoblasts and endothelial cells and immune tolerance. We propose that functional and glycosylation modifications of hCG may contribute to the pathogenesis of preeclampsia. PMID- 21295852 TI - Review: The angiogenic and vasodilatory utero-placental network. AB - The objective of this review is to propose addition of the kallikrein-kinin system (KKS) to the conventional angiogenic repertoire of gestation. This proposal is based on the improved revascularization induced by transfecting the human kallikrein gene; on the angiogenic, chemoattractant, promigratory, antiapoptotic, and antiaggregating effects of bradykinin; and on suppression of these effects by blockade of the bradykinin B2 receptor. In addition, both bradykinin and vascular endothelial growth factor (VEGF) stimulate nitric oxide (NO), and the VEGF and bradykinin receptors have multiple interactions that converge in the endothelial NO synthase (eNOS)-NO pathway. The work of others, and of our group, have demonstrated that eNOS and matrix metalloproteinases, the components of the VEGF and kallikrein-kinin systems, colocalize in specific cell types at human and guinea-pig utero-placental interfaces. Expression of the endothelial angiogenic/vasodilatory repertoire in the syncytiotrophoblast, and in trophoblasts replacing endothelial cells of the spiral arteries, supports the concept that the intervillous space and the transformed uterine arteries represent genuine new vascular structures that should be included in the analysis of pregnancy-induced neovascularization. We believe that the evidence presented provides support for further studies to test the functional significance of the KKS in placental development. PMID- 21295853 TI - In vitro and ex vivo autoradiography of the NK-1 antagonist [3H]-LY686017 in Guinea pig brain. AB - NK-1 receptor antagonists have shown potential for the clinical treatment of chemotherapy-induced nausea and vomiting, depression and alcoholism. In a recent study, we disclosed the potential for the NK-1 antagonist, LY686017, to treat alcoholism in a clinical population. To assess whether this compound could be utilized as a platform for a brain imaging ligand, we evaluated the binding of [3H]-LY686017 to sections of guinea pig in vitro. In these studies, [3H]-LY686017 bound with a distribution and pharmacology consistent with the NK-1 receptor. Using sections through the region of the caudate nucleus, we obtained a K(d) of 0.34 nM and a B(max) of 31.37 fmoles/mg tissue. Based on its high potency and low nonspecific binding in vitro, we initiated studies to evaluate the radioligand as a tool to measure in vivo receptor occupancy. In initial studies, 25 microCi of [3H]-LY686017 was administered via an indwelling jugular catheter and accumulation of radioactivity in the caudate (NK-1 containing tissue) and cerebellum (low NK-1 expression) were assessed. The ratios of caudate to cerebellum radioactivity were optimal 2 h after radioligand administration so this time point was used for subsequent studies. To assess the pharmacological specificity of the radioactivity accumulation, we administered various doses of Aprepitant, a potent NK-1 antagonists 1h prior to intravenous administration of [3H]-LY686017. Aprepitant produced a dose-dependent reduction in radioactivity in the caudate with an approximate 70% reduction at 10 mg/kg. To image NK-1 receptors, 100 microCi of [3H]-LY686017 was administered and the brains sectioned for autoradiography. In these studies, a characteristic distribution on NK-1 receptors was observed. Based on these results, LY686017 should serve as a suitable chemical platform for future imaging ligand development. PMID- 21295854 TI - Nontuberculous mycobacterium genital infection mimicking donovanosis in a patient with hairy cell leukemia. PMID- 21295855 TI - Specific killing of CCR9 high-expressing acute T lymphocytic leukemia cells by CCL25 fused with PE38 toxin. AB - We have previously demonstrated that CCR9 plays a pivotal role in drug resistance and invasion in human acute T-lymphocytic leukemia (T-ALL). In this study, we investigated whether the MOLT4 cells, which naturally express CCR9 at high levels, can be successfully killed by the specific ligand, CCL25 fused to Pseudomonas exotoxin 38 (PE38) toxin. Our results demonstrated that CCL25-PE38 was able to specifically kill MOLT4 cells via apoptosis induction, and suppress the growth of CCR9(+) tumors. This work shows that CCR9 high-expressing human T ALL cells can be successfully killed by delivering PE38 toxin fused to the ligand CCL25. PMID- 21295856 TI - Science, the South Pole, and the Japanese expedition of 1910-1912. AB - In November 1910, Shirase Nobu (1861-1946) sailed from Tokyo Bay aboard the Kainan Maru as part of an international race for the South Pole. The Japanese had no history of polar exploration and looked to British precedence to compensate for their lack of experience. Following the British example required that they include a scientific dimension to their venture. It is clear, however, that Shirase and his men had little scientific understanding. Nevertheless, on failing to reach the Pole, science became the central aim of the expedition and the primary means to declaring their efforts a success. PMID- 21295857 TI - Clinical and microbiological characteristics of fungal keratitis in the United States, 2001-2007: a multicenter study. AB - OBJECTIVE: To study the epidemiology, clinical observations, and microbiologic characteristics of fungal keratitis at tertiary eye care centers in the United States. DESIGN: Retrospective multicenter case series. PARTICIPANTS: Fungal keratitis cases presenting to participating tertiary eye care centers. METHODS: Charts were reviewed for all fungal keratitis cases confirmed by culture, histology, or confocal microscopy between January 1, 2001, and December 31, 2007, at 11 tertiary clinical sites in the United States. MAIN OUTCOME MEASURES: Frequency of potential predisposing factors and associations between these factors and fungal species. RESULTS: A total of 733 cases of fungal keratitis were identified. Most cases were confirmed by culture from corneal scraping (n = 693) or biopsies (n = 19); 16 cases were diagnosed by microscopic examination of corneal scraping alone; and 5 cases were diagnosed by confocal microscopy alone. Some 268 of 733 cases (37%) were associated with refractive contact lens wear, 180 of 733 cases (25%) were associated with ocular trauma, and 209 of 733 cases (29%) were associated with ocular surface disease. No predisposing factor was identified in 76 cases (10%). Filamentous fungi were identified in 141 of 180 ocular trauma cases (78%) and in 231 of 268 refractive contact lens-associated cases (86%). Yeast was the causative organism in 111 of 209 cases (53%) associated with ocular surface disease. Yeast accounted for few cases of fungal keratitis associated with refractive contact-lens wear (20 cases), therapeutic contact-lens wear (11 cases), or ocular trauma (21 cases). Surgical intervention was undertaken in 26% of cases and was most frequently performed for fungal keratitis associated with ocular surface disease (44%). Surgical intervention was more likely in cases associated with filamentous fungi (P = 0.03). Among contact lens wearers, delay in diagnosis of 2 or more weeks increased the likelihood of surgery (age-adjusted odds ratio = 2.2; 95% confidence interval, 1.2-4.2). CONCLUSIONS: Trauma, contact lens wear, and ocular surface disease predispose patients to developing fungal keratitis. Filamentous fungi are most frequently the causative organism for fungal keratitis associated with trauma or contact lens wear, whereas yeast is most frequently the causative organism in patients with ocular surface disease. Delay in diagnosis increases the likelihood of surgical intervention for contact lens-associated fungal keratitis. PMID- 21295858 TI - Age of onset, clinical characteristics, and 15-year course of anxiety disorders in a prospective, longitudinal, observational study. AB - BACKGROUND: Age of onset is rarely studied in the anxiety disorders literature. The current study examined age of onset as it relates to clinical characteristics and course of anxiety disorders using a prospective, longitudinal, observational design. METHODS: Fifteen-year follow-up data were examined for participants with panic disorder with (PDA) or without (PD) agoraphobia, social phobia (SP), and/or generalized anxiety disorder (GAD) at baseline. Logistic regression analyses were conducted to determine whether age of onset was associated with demographic or clinical variables at baseline. Cox regression analyses were conducted to examine longitudinal course (time to recurrence and recovery, respectively) for each diagnostic group. RESULTS: At baseline, PD participants with early onset (i.e., < age 20) were more likely to have comorbid MDD, GAD, and SP relative to late-onset participants (>= age 20). For PDA, early-onset participants were less likely to be married, and more likely to have both GAD and SP at baseline. With respect to longitudinal course, earlier onset was associated with an increased likelihood of recurrence in participants with PDA. No other models reached significance. LIMITATIONS: The sample sizes for some disorders were comparatively small in relation to PDA, and all participants were treatment-seeking, which may limit generalizability. CONCLUSIONS: For some anxiety disorders, earlier age of onset appears to be associated with greater severity and worse course, as evidenced by increased risk of recurrence over 15years of follow-up. Early interventions focused on children and adolescents may alleviate some of the public health burden associated with anxiety disorders. PMID- 21295859 TI - Co-occurring manic symptomatology as a dimension which may help explaining heterogeneity of depression. AB - BACKGROUND: The dichotomous distinction between unipolar and bipolar disorders may be challenged by heterogeneity within diagnoses and overlap between different diagnoses. A broad mood disorder category in which patients differ as a result of variation along separate manic and depressive mood dimensions can be proposed. To test this, it is hypothesized that heterogeneity in clinical and other features of subjects selected for unipolar depression can be partly explained by coexisting manic symptoms. METHODS: A cohort selected for unipolar depressive disorder was followed up for two years at which time co-occurring manic symptoms were assessed, yielding four groups with increasing manic symptomatology: i) pure unipolar depressive disorder (n=1598), ii) unipolar depressive disorder with subthreshold manic symptomatology (n=64), iii) bipolar II disorder (n=39), and iv) bipolar I disorder (n=86). Multivariate logistic regression and analyses of covariance controlled for depression severity were used to investigate whether patients with increasing manic symptomatology could be differentiated from patients with pure depressive disorder. RESULTS: Male gender, a lower age at first episode, a history of suicide attempts and increased aggressive cognitions were independently associated with an increase in manic symptoms. The additional presence of (hypo)mania was associated with greater depression severity and more disability than pure depressive disorder. LIMITATIONS: The groups with manic symptomatology (subthreshold, hypomania and mania) were considerably smaller compared to the pure depression group. CONCLUSIONS: The heterogeneity in depressive illness can be partly explained by the coexisting variation along the manic symptom dimension. Co-occurring manic symptoms should be taken into account in depression and a symptom dimensional approach of mood disorders may provide phenotypes that are more informative than current mood disorder categories. PMID- 21295860 TI - Anticipatory vs. consummatory pleasure: what is the nature of hedonic deficits in schizophrenia? AB - Recent research has distinguished between anticipatory and consummatory pleasure. In the current study, we examined the psychometric properties of the Temporal Experience of Pleasure Scale (TEPS) to determine whether reliability and validity findings reported in previous research replicate in an additional sample of schizophrenia patients. Participants included 86 individuals with schizophrenia and 59 demographically matched healthy controls. Inconsistent with previous research, patients differed from controls in their reports of consummatory (TEPS CON), but not anticipatory (TEPS-ANT) pleasure. We also failed to replicate some important correlational findings reported in previous research indicating relationships between the TEPS-ANT subscale and external validators. Analyses of the stability of the TEPS subscales were conducted in a sub-group of patients (n=19), and indicated excellent stability for the TEPS-CON (ICC (intraclass correlation coefficient)=0.93), but somewhat lower stability for the TEPS-ANT subscale (ICC=0.74). These findings suggest that additional studies are needed using the TEPS, as well as other measures, to determine the nature of anhedonia in individuals with schizophrenia. PMID- 21295861 TI - Helminths and multiple sclerosis: will old friends give us new treatments for MS? PMID- 21295862 TI - Glatiramer acetate attenuates neuropathic allodynia through modulation of adaptive immune cells. AB - Immune-neuronal interactions contribute to neuropathic pain. Thus, immune competent cells such as microglia may provide targets for pain relief, as may infiltrating lymphocytes. We evaluated the nature of the lymphocyte response in the spinal cord in association with the maintenance of neuropathic allodynia. We assessed T cell contribution to pain processing by targeting these cells with Glatiramer acetate (GA) which when administered systemically reversed neuropathic allodynia, inhibited microglia response and increased IL-10 and IL-4 expressing T cells in neuropathic dorsal horns. These studies advance understanding of lymphocyte contribution to chronic pain and reveal a new mechanism of T cell intervention. PMID- 21295863 TI - Spatial hearing of normally hearing and cochlear implanted children. AB - OBJECTIVE: Spatial hearing uses both monaural and binaural mechanisms that require sensitive hearing for normal function. Deaf children using either bilateral (BCI) or unilateral (UCI) cochlear implants would thus be expected to have poorer spatial hearing than normally hearing (NH) children. However, the relationship between spatial hearing in these various listener groups has not previously been extensively tested under ecologically valid conditions using a homogeneous group of children who are UCI users. We predicted that NH listeners would outperform BCI listeners who would, in turn, outperform UCI listeners. METHODS: We tested two methods of spatial hearing to provide norms for NH and UCI using children and preliminary data for BCI users. NH children (n=40) were age matched (6-15 years) to UCI (n=12) and BCI (n=6) listeners. Testing used a horizontal ring of loudspeakers within a booth in a hospital outpatient clinic. In a 'lateral release' task, single nouns were presented frontally, and masking noises were presented frontally, or 90 degrees left or right. In a 'localization' task, allowing head movements, nouns were presented from loudspeakers separated by 30 degrees , 60 degrees or 120 degrees about the midline. RESULTS: Normally hearing children improved with age in speech detection in noise, but not in quiet or in lateral release. Implant users performed more poorly on all tasks. For frontal signals and noise, UCI and BCI listeners did not differ. For lateral noise, BCI listeners performed better on both sides (within ~2 dB of NH), whereas UCI listeners benefited only when the noise was opposite the unimplanted ear. Both the BCI and, surprisingly, the UCI listeners performed better than chance at all loudspeaker separations on the ecologically valid, localization task. However, the BCI listeners performed about twice as well and, in two cases, approached the performance of NH children. CONCLUSION: Children using either UCI or BCI have useful spatial hearing. BCI listeners gain benefits on both sides, and localize better, but not as well as NH listeners. PMID- 21295864 TI - Antral lavage using the Luma transilluminaton wire and vortex irrigator--a safe and effective advance in treating pediatric sinusitis. AB - INTRODUCTION: While the treatment of pediatric sinusitis can be controversial, there is evidence that performing antral lavage in combination with adenoidectomy can improve treatment outcomes. We present an "over the wire" technique using new technology that can improve accuracy and reliability when performing antral lavage. METHODS: The LUMA fiberoptic light wire (Acclarent Inc.) and Vortex sinus irrigation catheter (Acclarent Inc.) were used to perform antral lavage as an adjunct in the treatment of pediatric sinusitis. DISCUSSION: We found this method to have multiple advantages over other techniques of lavage. These advantages include: 1) confirmation of position in the maxillary sinus by transillumination, 2) improvement of the safety and accuracy of the lavage, 3) ability to balloon dilate the natural ostium and ethmoid infundibulum or to obtain cultures at the time of lavage if clinically warranted or indicated by CT evidence, 4) avoidance of radiation from the use of fluoroscopy associated with other balloon sinuplasty equipment and techniques, and 5) no alteration of normal anatomy. CONCLUSION: We found this technique to give the surgeon a reliable, safe, versatile, and efficacious alternative before consideration of more invasive procedures in the pediatric population with chronic sinusitis. PMID- 21295865 TI - Racial/ethnic and socioeconomic disparities in the diagnosis and treatment of sleep-disordered breathing in children. AB - OBJECTIVE: Although racial/ethnic and socioeconomic healthcare disparities in pediatric primary care are widely documented, little is known regarding health disparities for common otolaryngic conditions. Pediatric sleep-disordered breathing (SDB) is highly prevalent, associated with significant physical and neurocognitive sequelae, and a common reason for pediatric otolaryngology referral. We sought to synthesize information from published findings related to racial/ethnic and socioeconomic disparities in children with SDB. METHODS: Qualitative systematic review of MEDLINE database for articles reporting on racial/ethnic or socioeconomic differences in prevalence, diagnosis or surgical treatment of SDB in children over 30 years. RESULTS: Of 210 abstracts identified, 33 met inclusion criteria. 24 articles directly addressed differences in race/ethnicity and socioeconomic status, and 10 had findings which identified a disparity. Differences were identified in prevalence, sleep patterns, and sequelae of pediatric SDB (24/33) and in access to care and utilization of adenotonsillectomy (10/33). Black children (12/33) and children with socioeconomic deprivation (17/33) were the most common minority groups studied. Although conclusions were broad, common study findings showed: (1) children in racial/ethnic and socioeconomic minorities may have higher prevalence and greater risk for SDB, and (2) In the U.S., white children or children with private insurance are more likely to undergo adenotonsillectomy. CONCLUSIONS: Racial/ethnic and socioeconomic disparities are prevalent among children with SDB. Disparities in multiracial populations and disparities in access to care, treatment, and utilization of services for pediatric SDB require more detailed investigation. Given the potential negative impact of SDB in children, as well as its economic consequences, the evaluation of disparities should be prioritized in health policy research. PMID- 21295866 TI - Direct monitoring of mitochondrial calcium levels in cultured cardiac myocytes using a novel fluorescent indicator protein, GCaMP2-mt. AB - BACKGROUND: An opening of the mitochondrial permeability transition pore (MPTP), which leads to loss of mitochondrial membrane potential (DeltaPsi(m)), is the earliest event that commits a cell to death. Mitochondrial matrix calcium ([Ca(2+)](m)) is considered to be a critical regulator of MPTP, but direct monitoring of [Ca(2+)](m) is difficult with previously-reported sensors. We developed a novel fluorescent indicator for [Ca(2+)](m), GCaMP2-mt, by adding a mitochondrial targeting sequence to a high signal-to-noise Ca(2+) sensor protein GCaMP2, and monitored dynamic changes in oxidant-induced cardiac myocyte death. METHODS AND RESULTS: GCaMP2-mt was transduced into neonatal rat cardiac myocytes using a recombinant adenovirus. We confirmed that GCaMP2-mt colocalized with tetramethylrhodamine ethyl-ester, a fluorescent indicator of DeltaPsi(m). We monitored oxidant-induced responses of [Ca(2+)](m) and DeltaPsi(m) using time lapse confocal microscopy. The response of [Ca(2+)](m) was synchronous with that of cytosolic calcium and was divided into three kinetically-distinct phases; the first phase, during which [Ca(2+)](m) maintained its baseline level; the second phase, during which [Ca(2+)](m) showed a rapid and sudden increase; and the third phase, during which [Ca(2+)](m) continued to increase at a slower rate until the collapse of DeltaPsi(m). The third phase was likely to be mediated through a mitochondrial Ca(2+) uniporter, because it was modulated by uniporter-acting drugs. Importantly, there was a remarkable cellular heterogeneity in the third phase, and DeltaPsi(m) loss occurred in an all-or-none manner depending on the cellular [Ca(2+)](m) level with a clear cut-off value. CONCLUSIONS: Direct monitoring of [Ca(2+)](m) using GCaMP2-mt provides deeper insight into the mechanism of cardiac myocyte death. PMID- 21295867 TI - Echocardiographic assessment of acute hemodynamic response during optimization of resynchronization pace-maker using different pacing modalities and atrioventricular delays. PMID- 21295868 TI - Left ventricular hypertrabeculation/noncompaction associated with severe anemia, delusion, and polyneuropathy. PMID- 21295869 TI - Effects of exercise and antioxidant supplementation on endothelial gene expression. AB - BACKGROUND: The molecular mechanisms of exercise training induced cardiovascular protection are poorly understood. There is growing evidence that reactive oxygen species may be involved in a number of these adaptations and that antioxidants may be used to investigate this effect. OBJECTIVE: To determine the effects of exercise training and/or antioxidant supplementation on myocardial endothelium and vascular endothelium gene expression. METHODS: Male Wistar rats were divided into four groups: i) control; ii) exercise trained (90 min of treadmill running 4d per week, 14 weeks); iii) antioxidant-supplemented (alpha-tocopherol 1000 IU kg(-1) diet and alpha-lipoic acid 1.6 g kg(-1) diet, mixed with rat chow) and iv) exercise trained and antioxidant-supplemented. RESULTS: cDNA microarray analysis showed diverse expression changes in both left ventricular and coronary artery endothelial cells. In particular, RT-PCR analysis showed that a gene involved in cardiovascular disease progression, Ras homolog gene family member A, was down regulated by exercise, and up-regulated by antioxidant supplementation in left ventricular endothelial cells. Furthermore, an important gene involved in inflammation, IL-6, was down-regulated by all treatments. CONCLUSIONS: Exercise training and/or antioxidant supplementation affects cardiac endothelial cell gene expression, and their effects on genes such as ras homolog gene family member A and IL-6 provides insight into the molecular mechanisms of their influences on cardiovascular diseases. PMID- 21295870 TI - Updated evidence on early statin therapy for acute coronary syndromes: meta analysis of 18 randomized trials involving over 14,000 patients. AB - BACKGROUND: The short-term effects of early statin therapy in acute coronary syndromes (ACS) on clinical outcomes remain unclear. Our objective was to update the evidence on patient relevant outcomes from all randomized trials comparing early statin therapy with placebo or usual care at 1 and 4 months following ACS. METHODS: We performed a systematic review and meta-analysis of randomized trials that compared statins to control, initiated within 14 days after onset of ACS and with minimal follow-up of 30 days. Data were extracted in duplicate and analyzed by a random effects model. Investigators from individual trials contributed additional data where needed. RESULTS: A total of 18 trials involving 14,303 patients with ACS were included in the meta-analysis. We found no evidence for further trials on the topic. Risk ratios for the combined endpoint of death, myocardial infarction, and stroke of early statin therapy compared to control were 0.93 (95% confidence interval [CI], 0.80-1.08; P=0.34) at 1 month and 0.93 (95% CI, 0.81-1.06; P=0.27) at 4 months following ACS. There were favorable trends related to statin use for all individual secondary endpoints but there was no statistically significant risk reduction except for unstable angina with a risk ratio of 0.76 (95% CI, 0.59-0.96; P=0.02) at 4 months following ACS. CONCLUSIONS: Initiation of statin therapy within 14 days following ACS results in directionally favorable but non-significant reduction in death, myocardial infarction, or stroke up to 4 months, and significant reduction in the occurrence of unstable angina at 4 months following ACS. PMID- 21295871 TI - Intrafractional prostate motion during online image guided intensity-modulated radiotherapy for prostate cancer. AB - INTRODUCTION: Intrafractional motion consists of two components: (1) the movement between the on-line repositioning procedure and the treatment start and (2) the movement during the treatment delivery. The goal of this study is to estimate this intrafractional movement of the prostate during prostate cancer radiotherapy. MATERIAL AND METHODS: Twenty-seven patients with prostate cancer and implanted fiducials underwent a marker match procedure before a five-field IMRT treatment. For all fields, in-treatment images were obtained and then processed to enable automatic marker detection. Combining the subsequent projection images, five positions of each marker were determined using the shortest path approach. The residual set-up error (RSE) after kV-MV based prostate localization, the prostate position as a function of time during a radiotherapy session and the required margins to account for intrafractional motion were determined. RESULTS: The mean RSE and standard deviation in the antero-posterior, cranio-caudal and left-right direction were 2.3+/-1.5 mm, 0.2+/ 1.1 mm and -0.1+/-1.1 mm, respectively. Almost all motions occurred in the posterior direction before the first treatment beam as the percentage of excursions>5 mm was reduced significantly when the RSE was not accounted for. The required margins for intrafractional motion increased with prolongation of the treatment. Application of a repositioning protocol after every beam could decrease the 1cm margin from CTV to PTV by 2 mm. CONCLUSIONS: The RSE is the main contributor to intrafractional motion. This RSE after on-line prostate localization and patient repositioning in the posterior direction emphasizes the need to speed up the marker match procedure. Also, a prostate IMRT treatment should be administered as fast as possible, to ensure that the pre-treatment repositioning efforts are not erased by intrafractional prostate motion. This warrants an optimized workflow with the use of faster treatment techniques. PMID- 21295872 TI - 18F-FLT-PET for detection of rectal cancer. AB - PURPOSE: This pilot study was undertaken to examine the ability of (18)F-3' fluoro-3'-deoxy-l-thymidine positron emission tomography ((18)F-FLT-PET)to detect rectal cancer, to identify pathologic lymph nodes and to determine the accuracy of tumour length estimation in comparison with computer tomography (CT). METHODS: Nine patients with biopsy proven rectal cancer underwent CT and (18)F-FLT-PET scanning prior to short-term pre-operative radiotherapy (5*5Gy). Within 10 days after the start of radiotherapy a surgical resection was performed. Tumour lengths and regional lymph node visualisation on both imaging modalities were compared with pathology findings. RESULTS: All tumours were visible on CT. (18)F FLT-PET visualised 7 out of 9 tumours (78%). The pathology-based tumours lengths correlated better with CT as compared to FLT-PET(r=0.91, p<0.01). (18)F-FLT-PET was not able to visualise pathologic lymph nodes. However, CT identified all patients with pathologic lymph nodes. CONCLUSION: Primary rectal cancer can be visualised by (18)F-FLT-PET in the majority of cases but not in all. However, (18)F-FLT-PET was not able to identify pathologic lymph nodes. Therefore, we conclude that (18)F-FLT-PET has limited value for the detection of pathologic lymph nodes and tumour delineation in rectal cancer. PMID- 21295873 TI - Does the planning dose-volume histogram represent treatment doses in image-guided prostate radiation therapy? Assessment with cone-beam computerised tomography scans. AB - PURPOSE: To assess the accuracy of the initial CT plan dose-volume histograms (DVH's) for prostate, rectum and bladder by comparison to delivered doses determined from cone beam CT (CBCT) scans acquired during image-guided treatment. MATERIALS AND METHODS: Twelve prostate patients were treated using daily implanted fiducial guidance and following local protocol for bladder and rectal preparation. CBCT scans were acquired twice weekly and contoured for prostate, rectum and bladder. The planned beams were applied to all CBCT scans to determine the delivered doses. Prostate dose coverage was assessed by the proportion of the CTV fully encompassed by the 95% and 98% isodose lines. Rectal and bladder volumes receiving 40 Gy, 60 Gy and 70 Gy at treatment were compared to the initial plan, with significance determined using the one-sample t-test. RESULTS: Four patients showed marginally compromised CTV coverage by the 95% isodose at all CBCT plans. For nine patients the initial plan rectal DVH was significantly outside the range of the treatment DVH's. CONCLUSIONS: Dose coverage of the prostate was not achieved for all patients. Observed rectal and bladder doses were higher than predicted. The initial treatment plan cannot be assumed to represent accurate normal tissue doses. PMID- 21295874 TI - FDG-PET provides the best correlation with the tumor specimen compared to MRI and CT in rectal cancer. AB - PURPOSE: To compare CT-, MR- and PET-CT based tumor length measurements in rectal cancer with pathology. PATIENTS AND METHODS: Twenty-six rectal cancer patients underwent both MR and PET-CT imaging followed by short-course radiotherapy (RT 5*5 Gy) and surgery within 3 days after RT. Tumor length was measured manually and independently by 2 observers on CT, MR and PET. PET-based tumor length measurements were also generated automatically using the signal-to-background ratio (SBR) method. All measurements were correlated with the tumor length on the pathological specimen. RESULTS: CT-based measurements did not show a valuable correlation with pathology. MR-based measurements correlated only weakly, but still significantly (Pearson correlation=0.55 resp. 0.57; p<0.001). Manual PET measurements reached a good correlation with pathology, but less strong (Pearson correlation 0.72 and 0.76 for the two different observers) than automatic PET-CT based measurements, which provided the best correlation with pathology (Pearson correlation of 0.91 (p<0.001)). Bland-Altman analysis demonstrated in general an overestimation of the tumor diameter using manual measurements, while the agreement of automatic contours and pathology was within acceptable ranges. A direct comparison of the different modalities revealed a significant better precision for PET-based auto-contours as compared to all other measurements. CONCLUSION: Automatically generated PET-CT based contours show the best correlation with the surgical specimen and thus provide a useful and powerful tool to accurately determine the largest tumor dimension in rectal cancer. This could be used as a quick and reliable tool for target delineation in radiotherapy. However, a 3D volume analysis is needed to confirm these results. PMID- 21295876 TI - In response to "The distribution of brain metastases in the perihippocampal region (regarding Gondi et al., Radiother. Oncol. 2010; 95: 327-331) by van Kesteren et al. PMID- 21295875 TI - Melanoma cells show a heterogeneous range of sensitivity to ionizing radiation and are radiosensitized by inhibition of B-RAF with PLX-4032. AB - PURPOSE: To assess the relative radiosensitivities of a large collection of melanoma cell lines and to determine whether pharmacologic inhibition of mutant B RAF with PLX-4032 can radiosensitize B-Raf+ melanoma cells. MATERIALS AND METHODS: A large collection of melanoma cell lines (n=37) were treated with 0-8Gy IR and clonogenic survival assays used to generate survival curves to rank relative radiosensitivities among the cell lines. The ability of a B-RAF inhibitor, PLX-4032, to radiosensitize highly radioresistant B-Raf+ cells was also assessed by clonogenic cell survival and spheroid invasion assays and the effects of treatment on the cell cycle assessed by FACS. RESULTS: Melanoma cell lines displayed a very large, heterogeneous range of SF2 values (1.002-0.053) with a mean of 0.51. Cell lines with surviving fractions of 0.29 or less at SF2 and SF4 were observed at a high frequency of 18.9% and 70.2%, respectively. Treatment of B-Raf+ cells with the B-RAF inhibitor PLX-4032 in combination with radiation provided enhanced inhibition of both colony formation and invasion, and radiosensitized cells through an increase in G(1) arrest. CONCLUSIONS: Our data suggest that melanomas are not uniformly radioresistant with a significant subset displaying inherent radiosensitivity. Pharmacologic inhibition of B-RAF with PLX 4032 effectively radiosensitized B-Raf+ melanoma cells suggesting that this combination approach could provide improved radiotherapeutic response in B-Raf+ melanoma patients. PMID- 21295877 TI - Increasing treatment accuracy for cervical cancer patients using correlations between bladder-filling change and cervix-uterus displacements: proof of principle. AB - PURPOSE: To investigate application of pre-treatment established correlations between bladder-filling changes and cervix-uterus displacements in adaptive therapy. MATERIALS AND METHODS: Thirteen cervical cancer patients participated in this prospective study. Pre-treatment, and after delivery of 40 Gy, a full bladder CT-scan was acquired, followed by voiding the bladder and acquisition of 4 other 3D scans in a 1h period with a naturally filling bladder (variable bladder filling CT-scans, VBF-scans). For the pre-treatment VBF-scans, linear correlations between bladder volume change and displacements of the tip of the uterus (ToU) and the center of mass (CoM) of markers implanted in the fornices of the vagina relative to the full bladder planning scan were established. Prediction accuracy of these correlation models was assessed by comparison with actual displacements in CT-scans, both pre-treatment and after 40 Gy. Inter fraction ToU and marker-CoM displacements were derived from the established correlations and twice-weekly performed in-room bladder volume measurements, using a 3D ultrasound scanner. RESULTS: Target displacement in VBF-scans ranged from up to 65 mm in a single direction to almost 0mm, depending on the patient. For pre-treatment VBF-scans, the linear correlation models predicted the mean 3D position change for the ToU of 26.1 mm+/-10.8 with a residual of only 2.2 mm+/ 1.7. For the marker-CoM, the 8.4 mm+/-5.3 mean positioning error was predicted with a residual of 0.9 mm+/-0.7. After 40Gy, the mean ToU displacement was 26.8 mm+/-15.8, while prediction based on the pre-treatment correlation models yielded a mean residual error of 9.0 mm+/-3.7. Target positioning errors in the fractioned treatments were very large, especially for the ToU (-18.5mm+/-11.2 for systematic errors in SI-direction). CONCLUSIONS: Pre-treatment acquired VBF-scans may be used to substantially enhance treatment precision of cervical cancer patients. Application in adaptive therapy is promising and warrants further investigation. For highly conformal (IMRT) treatments, the use of a full bladder drinking protocol results in unacceptably large systematic set-up errors. PMID- 21295878 TI - HDR monotherapy for prostate cancer: a simulation study to determine the effect of catheter displacement on target coverage and normal tissue irradiation. AB - PURPOSE: The aim of this study was to systematically analyse the effect of catheter displacements both on target coverage and normal tissue irradiation in fractionated high dose rate (HDR) prostate brachytherapy, using a simulation study, and to define tolerances for catheter displacement ensuring that both target coverage and normal tissue doses remain clinically acceptable. Besides the effect of total implant displacement, also displacements of catheters belonging to selected template rows only were evaluated in terms of target coverage and normal tissue dose, in order to analyse the change in dose distribution as a function of catheter dwell weight and catheter location. MATERIAL AND METHODS: Five representative implant geometries, with 17 catheters each, were selected. The clinical treatment plan was compared to treatment plans in which an entire implant displacement in caudal direction over 3, 5, 7 and 10 mm was simulated. Besides, treatment plans were simulated considering a displacement of either the central, most ventral or most dorsal catheter rows only, over 5 mm caudally. RESULTS: Due to displacement of the entire implant the target coverage drops below the tolerance of 93% for all displacements studied. The effect of displacement of the entire implant on organs at risk strongly depended on the patient anatomy; e.g., for 80% of the implant geometries the V(80) of the rectum exceeded its tolerance for all displacements. The effect of displacement of catheters belonging to selected template rows depended strongly on the relative weight of each catheter row when considering the target coverage and on its location when considering the dose in the organs at risk. CONCLUSION: This study supports the need for a check of the catheter locations before each fraction and correction of deviations of the catheter position exceeding 3mm. PMID- 21295879 TI - A practical approach to diode based in vivo dosimetry for intensity modulated radiotherapy. AB - A method for in vivo entrance dosimetry, using point detectors, in intensity modulated radiotherapy has been clinically evaluated. Diode dosimetry was performed for treatments of the head and neck and prostate regions. The results were good; 92.2% of the measurements showed deviations within +/-5% of the expected values. PMID- 21295880 TI - Two-year results from a Swedish study on conventional versus accelerated radiotherapy in head and neck squamous cell carcinoma--the ARTSCAN study. AB - BACKGROUND AND PURPOSE: Studies on accelerated fractionation (AF) in head and neck cancer have shown increased local control and survival compared with conventional fractionation (CF), while others have been non-conclusive. In 1998 a national Swedish group decided to perform a randomised controlled clinical study of AF. MATERIALS AND METHODS: Patients with verified squamous cell carcinoma of the oral cavity, oropharynx, larynx (except glottic T1-T2, N0) and hypopharynx were included. Patients with prior chemotherapy or surgery were excluded. Patients were randomised to either CF (2Gy/day, 5days/week for 7 weeks, total dose 68Gy) or to AF (1.1Gy+2.0Gy/day, 5days/week for 4.5weeks, total dose 68Gy). An extensive quality assurance protocol was followed throughout the study. The primary end point was loco-regional tumour control (LRC) at two years after treatment. RESULTS: The study was closed in 2006 when 750 patients had been randomised. Eighty-three percent of the patients had stages III-IV disease. Forty eight percent had oropharyngeal, 21% laryngeal, 17% hypopharyngeal and 14% oral cancers. There were no significant differences regarding overall survival (OS) or LRC between the two regimens. The OS at two years was 68% for AF and 67% for CF. The corresponding figures for LRC were 71% and 67%, respectively. There was a trend towards improved LRC for oral cancers treated (p=0.07) and for large tumours (T3-T4) (p=0.07) treated with AF. The AF group had significantly worse acute reactions, while there was no significant increase in late effects. CONCLUSION: Overall the AF regimen did not prove to be more efficacious than CF. However, the trend towards improved results in AF for oral cancers needs to be further investigated. PMID- 21295881 TI - Reirradiation of metastatic spinal cord compression: definitive results of two randomized trials. AB - PURPOSE: Incidence, outcome and prognostic factors of metastatic spinal cord compression (MSCC) patients reirradiated for in-field recurrence were analyzed. Radiation therapists' attitude in reirradiate spinal cord relapses, doses adopted and incidence of myelopathy were also examined. MATERIALS AND METHODS: Data deriving from 579 evaluable patients entered two randomized trials on radiotherapy (RT) for MSCC were revised. RESULTS: Twenty-four (4.15%) patients had an in-field recurrence and 12 (50%) were reirradiated. At the time of analysis all reirradiated patients had died. Median time from first and second RT was 5 months (range, 2-31). Six patients received an 8 Gy single-dose, 2 patients 5*3Gy and remaining four patients 2*8, 5*4, or a single dose of 7 and 4 Gy, respectively. The median cumulative Biologically Effective Dose (BED) calculated was 114.5 Gy(2) (range, 80-120 Gy(2)). Six of seven (85.7%) ambulant patients maintained walking ability, whereas none of five not ambulant patients recovered the function. Median duration of response was 4.5 months (range, 1-24). The effect of reirradiation on motor function was significantly associated with walking capacity before reirradiation. Myelopathy was never recorded. CONCLUSIONS: In MSCC reirradiation was safe and effective. Patient walking capacity before reirradiation was the strongest prognostic factor for functional outcome. Reirradiation was given in about one-half of patients with in-field recurrence and different doses and fractionations were used, even though cumulative BED was in all cases <=120 Gy(2). PMID- 21295882 TI - Comparative study of the inhibitory effects of wine polyphenols on the growth of enological lactic acid bacteria. AB - This paper reports a comparative study of the inhibitory potential of 18 phenolic compounds, including hydroxybenzoic acids and their derivatives, hydroxycinnamic acids, phenolic alcohols and other related compounds, stilbenes, flavan-3-ols and flavonols, on different lactic acid bacteria (LAB) strains of the species Oenococcus oeni, Lactobacillus hilgardii and Pediococcus pentosaceus isolated from wine. In general, flavonols and stilbenes showed the greatest inhibitory effects (lowest IC50 values) on the growth of the strains tested (0.160-0.854 for flavonols and 0.307-0.855 g/L for stilbenes). Hydroxycinnamic acids (IC50 > 0.470 g/L) and hydroxybenzoic acids and esters (IC50 >1 g/L) exhibited medium inhibitory effect, and phenolic alcohols (IC50 > 2 g/L) and flavanol-3-ols (negligible effect) showed the lowest effect on the growth of the LAB strains studied. In comparison to the antimicrobial additives used in winemaking, IC50 values of most phenolic compounds were higher than those of potassium metabisulphite for O. oeni strains (e.g., around 4-fold higher for quercetin than for potassium metabisulphite), but lower for L. hilgardii and P. pentosaceus strains (e.g., around 2-fold lower for quercetin). Lysozyme IC50 values were negligible for L. hilgardii and P. pentosaceus, and were higher than those corresponding to most of the phenolic compounds tested for O. oeni strains, indicating that lysozyme was less toxic for LAB than the phenolic compounds in wine. Scanning electron microscopy confirmed damage of the cell membrane integrity as a consequence of the incubation with antimicrobial agents. These results contribute to the understanding of the inhibitory action of wine phenolics on the progress of malolactic fermentation, and also to the development of new alternatives to the use of sulphites in enology. PMID- 21295883 TI - Influence of glycosylated hemoglobin on sight-threatening diabetic retinopathy: a population-based study. AB - AIM: To evaluate the role of glycosylated hemoglobin (HbA1c) on the occurrence of sight-threatening diabetic retinopathy (STDR) in urban Chennai, Tamil Nadu, India. METHODS: A total of 5999 individuals were enumerated from the Chennai metropolis. Of these, 1414 subjects with diabetes were included for data analysis in the study. STDR or non-STDR groups were classified based on the fundus photographs. HbA1c was measured (Bio-Rad DiaSTATTM HbA1c Reagent Kit) by the liquid chromatography technique. RESULTS: A statistically significant difference (p < 0.05) was noted in the duration of diabetes, gender, body mass index, HbA1c, micro- and macro-albuminuria between both non-STDR and STDR groups as compared to the no-diabetic retinopathy (DR) group. On multivariate analysis, HbA1c (non STDR: odd's ratio OR = 1.23; 95% confidence interval CI = 1.15-1.32; p < 0.0001; STDR: OR = 1.31 95% CI = 1.14-1.52; p < 0.0001) was found to be significantly associated with non-STDR and STDR when compared with the no-DR group. The Receiver Operating Characteristic analysis showed that the cut-off value of 8.0 had 75.6% sensitivity and 58.2% specificity with 64.9% maximum area under the curve. CONCLUSION: HbA1c value >8.0% was significantly related with STDR. In a screening programme, the cut-off value of HbA1c >8.0% provided a maximum yield of STDR. PMID- 21295884 TI - Genome organization in and around the nucleolus. AB - The nucleolus is the largest compartment of the cell nucleus and is where ribosomal RNAs (rRNAs) are synthesized, processed and assembled with ribosomal proteins. In addition to rRNA gene clusters that build the core of this subnuclear structure, nucleoli are associated with condensed chromatin. Although the higher order structures of rRNA genes and nucleolus-associated chromatin have been studied for decades, detailed molecular insights into the constituents and organization of the nucleolar genome are only beginning to emerge. Here, we summarize current views on the structural organization of nucleolar DNA and on the targeting and anchoring of chromatin domains to this subnuclear compartment. PMID- 21295885 TI - [Detection of abuse of the elderly in hospital emergency departments]. PMID- 21295886 TI - [Diabetes: cost, process and results in Spain. Quality with amputations]. PMID- 21295887 TI - Design, synthesis and evaluation of 3-methylene-substituted indolinones as antimalarials. AB - The design, synthesis and evaluation of 3-methylene-substituted indolinones as falcipain inhibitors and antiplasmodial agents are described. These compounds react readily with thiols via an addition-elimination mechanism, indicating their potential as cysteine protease inhibitors. Several indolinones containing a Leu-i amyl recognition moiety were found to be moderate inhibitors of the Plasmodium falciparum cysteine protease falcipain-2, but not of the related protease falcipain-3, and displayed antiplasmodial activity against the chloroquine resistant P. falciparum W2 strain in the low micromolar range. Coupling a 7 chloroquinoline moiety to the 3-methylene-substituted indolinone scaffold led to a significant improvement in antiplasmodial activity. PMID- 21295888 TI - Synthesis and anti-mycobacterial activity of novel amino alcohol derivatives. AB - Thirteen new hydroxyethylamines have been synthesized from reactions of (2S,3S)Boc-phenylalanine epoxide, piperonylamine and arenesulfonyl chlorides in good yields. These compounds were evaluated as antibacterial agents against Mycobacterium tuberculosis H37Rv using the Alamar Blue susceptibility test and their activity expressed as the minimum inhibitory concentration (MIC) in MUM. Two amino alcohols displayed significant activity when compared with first line drug ethambutol (EMB). Therefore this class of compounds could be a good starting point to develop new lead compounds in the treatment of tuberculosis. PMID- 21295889 TI - Synthesis and structure-activity relationship of N-(2-arylethyl) isoquinoline derivatives as human scavenger receptor CD36 antagonists. AB - By using human scavenger receptor CD36 as the target, twenty-five N-(2-arylethyl) isoquinoline derivatives were designed, synthesized and evaluated for their antagonistic activities for CD36-oxidatively low density lipoprotein (oxLDL) binding. The primary analysis of structure-activity relationship (SAR) indicated a methoxyl at the 7-position and a hydroxyl at the 6- or 8-position could afford good activities. Among these analogs, compounds 7e and 7t showed the potential CD36 antagonistic activities with IC(50) values of 0.2 and 0.8 MUg/mL, respectively. Furthermore, both of them could effectively inhibit oxLDL uptake in insect Sf9 cells overexpressing human CD36, and thus have been selected for further investigation. We consider N-(2-arylethyl) isoquinoline analogs to be a family of novel CD36 antagonists. PMID- 21295890 TI - alpha-D-mannose derivatives as models designed for selective inhibition of Golgi alpha-mannosidase II. AB - Human Golgi alpha-mannosidase II (hGM) is a pharmaceutical target for the design of inhibitors with anti-tumor activity. Nanomolar inhibitors of hGM exhibit unwanted co-inhibition of the human lysosomal alpha-mannosidase (hLM). Hence, improving specificity of the inhibitors directed toward hGM is desired in order to use them in cancer chemotherapy. We report on the rapid synthesis of D-mannose derivatives having one of the RS-, R(SO)- or R(SO(2))- groups at the alpha anomeric position. Inhibitory properties of thirteen synthesized alpha-D mannopyranosides were tested against the recombinant enzyme Drosophila melanogaster homolog of hGM (dGMIIb) and hLM (dLM408). Derivatives with the sulfonyl [R(SO(2))-] group exhibited inhibitory activities at the mM level toward both dGMIIb (IC(50) = 1.5-2.5 mM) and dLM408 (IC(50) = 1.0-2.0 mM). Among synthesized, only the benzylsulfonyl derivative showed selectivity toward dGMIIb. Its inhibitory activity was explained based on structural analysis of the built 3 D complexes of the enzyme with the docked compounds. PMID- 21295891 TI - Synthesis of 9-substituted derivatives of berberine as anti-HIV agents. AB - Naturally occurring protoberberine alkaloids, berberine and berberrubine along with 9-substituted derivatives of berberine were assessed for the anti-human immunodeficiency virus (HIV) activity. Berberine was found to be the most active compound with an EC(50) of 0.13 MUM against HIV-1 NL4.3 virus in CEM-GFP cell lines. Berberrubine and two other compounds were found to be less active than berberine, at the same time they were less toxic than berberine. Enzyme based assay suggested that the anti-HIV activity of berberine and its analogs might be due to RTase inhibitory activity and some additional mechanisms. PMID- 21295892 TI - Synthesis, DNA-binding and topoisomerase inhibitory activity of ruthenium(II) polypyridyl complexes. AB - Two ruthenium(II) complexes [Ru(bpy)(2)(bfipH)](2+) (1) and [Ru(phen)(2)(bfipH)](2+) (2) have been synthesized and characterized. The DNA binding behaviors of complexes were studied by using spectroscopic and viscosity measurements. Results suggested that the two complexes bind to DNA in an intercalative mode. Complexes 1 and 2 can efficiently photocleave pBR322 DNA in vitro under irradiation, singlet oxygen ((1)O(2)) was proved to contribute to the DNA photocleavage process. Topoisomerase inhibition and DNA strand passage assay confirmed that two Ru(II) complexes acted as efficient dual inhibitors of topoisomerases I and II. In MTT cytotoxicity studies, two Ru(II) complexes exhibited antitumor activity against BEL-7402, HeLa, MCF-7 tumor cells. The AO/EB staining assay indicated that Ru(II) complexes could induce the apoptosis of HeLa cells. PMID- 21295893 TI - CORAL: building up the model for bioconcentration factor and defining it's applicability domain. AB - CORAL (CORrelation And Logic) software can be used to build up the quantitative structure--property/activity relationships (QSPR/QSAR) with optimal descriptors calculated with the simplified molecular input line entry system (SMILES). We used CORAL to evaluate the applicability domain of the QSAR models, taking a model of bioconcentration factor (logBCF) as example. This model's based on a large training set of more than 1000 chemicals. To improve the model is predictivity and reliability on new compounds, we introduced a new function, which uses the Delta(obs) = logBCF(expr)--logBCF(calc) of the predictions on the chemicals in the training set. With this approach, outliers are eliminated from the phase of training. This proved useful and increased the model's predictivity. PMID- 21295894 TI - Development of an undergraduate nursing Clinical Evaluation Form (CEF). AB - A clinical placement evaluation form for undergraduate nursing students was developed to address the need for evaluating success in clinical teaching support and provide a feedback loop to the University, clinical educators and clinical venues. A 21-item, with five domains, (orientation, clinical educator/teacher, ward staff and environment, clinical hurdles, and university) Clinical Evaluation Form (CEF) was developed. The form was live tested with 178 year 1 and 2 undergraduate nursing students. The CEF scale was reliable (alpha=0.90) and has good face and content validity approved by an expert panel. Further research is recommended to validate the CEF for use multi-professionally and across all year levels. PMID- 21295895 TI - Plethora or paucity: a systematic search and bibliometric study of the application and design of qualitative methods in nursing research 2008-2010. AB - Qualitative methodology has increased in application and acceptability in all research disciplines. In nursing, it is appropriate that a plethora of qualitative methods can be found as nurses pose real-world questions to clinical, cultural and ethical issues of patient care (Johnson, 2007; Long and Johnson, 2007), yet the methods nurses readily use in pursuit of answers remains under intense scrutiny. One of the problems with qualitative methodology for nursing research is its place in the hierarchy of evidence (HOE); another is its comparison to the positivist constructs of what constitutes good research and the measurement of qualitative research against this. In order to position and strengthen its evidence base, nursing may well seek to distance itself from a qualitative perspective and utilise methods at the top of the HOE; yet given the relation of qualitative methods to nursing this would constrain rather than broaden the profession in search of answers and an evidence base. The comparison between qualitative and quantitative can be both mutually exclusive and rhetorical, by shifting the comparison this study takes a more reflexive position and critically appraises qualitative methods against the standards set by qualitative researchers. By comparing the design and application of qualitative methods in nursing over a two year period, the study examined how qualitative stands up to independent rather than comparative scrutiny. For the methods, a four-step mixed methods approach newly constructed by the first author was used to define the scope of the research question and develop inclusion criteria. 2. Synthesis tables were constructed to organise data, 3. Bibliometrics configured data. 4. Studies selected for inclusion in the review were critically appraised using a critical interpretive synthesis (Dixon-Woods et al., 2006). The paper outlines the research process as well as findings. Results showed of the 240 papers analysed, 27% used ad hoc or no references to qualitative; methodological terms such as thematic analysis or constant comparative methods were used inconsistently; qualitative was a catch-all panacea rather than a methodology with well-argued terms or contextual definition. PMID- 21295896 TI - Cognitive impairment in peritoneal dialysis patients. AB - BACKGROUND: The prevalence of moderate to severe cognitive impairment in hemodialysis patients is more than double the prevalence in the general population. This study describes cognitive impairment occurrence in a peritoneal dialysis cohort compared with a cohort without chronic kidney disease (CKD). STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: 51 English-speaking peritoneal dialysis patients from 2 urban dialysis units compared with 338 hemodialysis patients from 16 urban dialysis units and 101 voluntary controls without CKD from urban general medicine clinics. PREDICTOR: 45-minute battery of 9 validated neuropsychological tests (cognitive domains memory, executive function, and language). OUTCOMES: Mild, moderate, or severe cognitive impairment, classified according to a previously designed algorithm. RESULTS: Of the peritoneal dialysis cohort, 33.3% had no or mild, 35.3% had moderate, and 31.4% had severe cognitive impairment; corresponding values were 60.4%, 26.7%, and 12.9% of the non-CKD cohort and 26.6%, 36.4%, and 37.0% of the hemodialysis cohort. A logistic regression model including age, sex, race, education, hemoglobin level, diabetes, and stroke showed that only nonwhite race (P = 0.002) and low education (P = 0.002) were associated with moderate to severe cognitive impairment in the peritoneal dialysis cohort. Compared with hemodialysis patients, more peritoneal dialysis patients had moderate to severe memory impairment (58% vs 51%), but fewer had impaired executive function (one-third vs one-half). Peritoneal dialysis was associated with a more than 2.5-fold increased risk of moderate to severe global cognitive impairment compared with no CKD (OR, 2.58; 95% CI, 1.02-6.53), as was hemodialysis (OR, 3.16; 95% CI, 1.91-5.24), in an adjusted logistic regression model. LIMITATIONS: Small sample size, participation rate somewhat low. CONCLUSIONS: Similar to hemodialysis patients, two-thirds of peritoneal dialysis patients had moderate to severe cognitive impairment, enough to interfere with safely self-administering dialysis and adhering to complex medication regimens. These patients could benefit from cognitive assessment before and periodically after dialysis therapy initiation. PMID- 21295897 TI - Systemic and kidney toxicity of intraocular administration of vascular endothelial growth factor inhibitors. AB - Intravenous injection of angiogenesis-inhibitor drugs is used widely to treat cancers. Associated renal complications primarily involve proteinuria and hypertension, and thrombotic microangiopathies also have been described. Intravitreal anti-vascular endothelial growth factor (VEGF) therapy currently is used by ophthalmologists to treat neovascularization in age-related macular degeneration. However, there is some evidence that intravitreal anti-VEGF injections may result in systemic absorption, with the potential for injury in organs that are reliant on VEGF, such as the kidney. We report the first case to our knowledge of a patient who developed an acute decrease in kidney function, nonimmune microangiopathic hemolytic anemia with schistocytes, and thrombocytopenia after 4 intravitreal injections of ranibizumab. Light microscopy of a kidney biopsy specimen showed segmental duplications of glomerular basement membranes with endothelial swelling and several recanalized arteriolar thrombi. Because of the increasing use of intravitreal anti-VEGF agents, ophthalmologists and nephrologists should be aware of the associated risk of kidney disease. Early detection is crucial so that intravitreal injections can be stopped before severe kidney disease occurs. PMID- 21295898 TI - Diffuse infiltrative lymphocytosis syndrome presenting as reversible acute kidney injury associated with Gram-negative bacterial infection in patients with newly diagnosed HIV infection. AB - Diffuse infiltrative lymphocytosis syndrome (DILS) is believed to be an immunologic syndrome, most likely in response to human immunodeficiency virus (HIV) antigens, and can be accompanied by decreased kidney function. The spectrum of kidney involvement includes acute or chronic kidney disease, primarily tubular proteinuria; enlarged kidneys on imaging studies; and dense lymphocytic tubulointerstitial infiltrates predominantly composed of CD8(+) T cells on kidney biopsy. We describe 3 newly diagnosed HIV-positive patients of African descent with the histologic and clinical diagnosis of DILS who presented with acute kidney injury associated with Gram-negative bacterial infections. Solely with specific antibiotic therapy without antiviral and/or corticosteroid therapy, all patients recovered from acute kidney injury and had partial to complete resolution of proteinuria and enlarged kidney size. These observations led us to hypothesize that an altered immunologic and/or inflammatory response to the endotoxin derived from Gram-negative bacteria, rather than an immunologic response directed to HIV-related antigens, may be a pathogenetic mechanism for the kidney disease associated with DILS in a subset of HIV-positive patients, especially those of immunogenetically susceptible African descent. PMID- 21295899 TI - Timing hemodialysis initiation: a call for clinical judgment. PMID- 21295900 TI - Traumatic temporomandibular joint ankylosis: our classification and treatment experience. AB - OBJECTIVE: This article studies the classification of traumatic temporomandibular joint (TMJ) ankylosis based on coronal computed tomographic (CT) scan and presents our treatment experience in the TMJ division of Shanghai Ninth People's Hospital. PATIENTS AND METHODS: From 2001 to 2009, 130 patients diagnosed with TMJ ankylosis were treated in the TMJ division. Among them, 84 patients with 124 joint injuries caused by trauma were treated first by our group of surgeons and were included in this study. All of them had CT scans, especially coronal reconstruction through the TMJ area before and after surgery. A new classification based on the coronal CT scan was proposed: type A1 is fibrous ankylosis without bony fusion of the joint; type A2 is ankylosis with bony fusion on the lateral side of the joint, while the residual condyle fragment is bigger than 0.5 of the condylar head in the medial side; type A3 is similar to A2 but the residual condylar fragment is smaller than 0.5 of the condylar head; type A4 is ankylosis with complete bony fusion of the joint. Our treatment protocol for type A1 ankylosis is fibrous tissue release or condylar head resection with costochondral graft (CCG) and temporalis myofascial flap (TMF). For type A2 and A3 ankylosis, the lateral bony fusion is resected, while the intact residual condylar fragment, displaced medially, is retained. We call it "lateral arthroplasty" (LAP). TMF or masseter muscle flap (MMF) is used as a barrier in the lateral gap between the TMJ fossa and the stump of the mandibular ramus. If the medial condylar fragment in type A3 ankylosis is too small to bear the load, it is resected with the bony mass. The joint is then reconstructed with CCG and TMF or MMF. For type A4 ankylosis, the bony fusion is completely removed and the joint is reconstructed with CCG and TMF or MMF. The result of the treatment was evaluated by CT scan and clinical follow-up. RESULTS: Among the 124 ankylotic joints, there were 14 type A1 ankylosis (11.3%); 43 type A2 ankylosis (34.7%); 46 type A3 ankylosis (37.1%); and 21 type A4 ankylosis (16.9%). Part of type A1, and all of type A2 and A3 ankylosis had the residual condylar head displaced medially, which accounted for 75% (93/124) of the TMJ ankylosis. Eighty-two joints (66.1%) had LAP treatment; 33 joints (26.6%) had CCG joint reconstruction; and 3 joints (2.4%) had TMJ fibrous tissue release. In our case, 1 joint (0.8%) had condylectomy and TMF; 3 joints (2.4%) with fibrous ankylosis had mouth opening treatment; and 2 joints had gap arthroplasty (1.6%). Forty-eight patients with 68 joints had long follow-ups from 10 months to 4 years. Among them, 4 of 17 joints reconstructed with CCG had reankylosis (23.5%), and 7 of 48 joints treated with LAP had reankylosis (14.6%). CONCLUSIONS: The new classification of TMJ ankylosis based on coronal CT scan is valuable in guiding clinical treatment. LAP with TMF is a good way to treat traumatic TMJ ankylosis when the medially displaced condylar head and disc are intact. CCG with TMF has a good result for type A4 ankylosis. PMID- 21295901 TI - The visual hemifield asymmetry in the spatial blink during singleton search and feature search. AB - The present study examined a visual field asymmetry in the contingent capture of attention that was previously observed by Du and Abrams (2010). In our first experiment, color singleton distractors that matched the color of a to-be detected target produced a stronger capture of attention when they appeared in the left visual hemifield than in the right visual hemifield. This replicated Du and Abrams and also revealed a difference between hemifields in the time course of this effect. Our second experiment suggested that this asymmetry is moderated by the tuning of attentional control settings: when the target was easier to detect the asymmetry was attenuated. Our third experiment showed that this asymmetry is also present during singleton detection: a color singleton distractor produced a larger capture effect in the left hemifield than in the right hemifield. Finally, our fourth experiment suggested that this asymmetry is moderated by the salience of the attention-capturing distractor: when the distractor was not salient, the asymmetry was attenuated. These results suggest that there are boundary conditions in the observed hemifield asymmetry in the contingent capture of attention and several underlying brain systems might be involved. PMID- 21295902 TI - Tuberculosis with a residual fibrostenotic endobronchial lesion. PMID- 21295903 TI - Variability in the performing of spirometry and its consequences in the treatment of COPD in primary care. AB - BACKGROUND: Several studies have approached the use of spirometry in the treatment of chronic obstructive pulmonary disease (COPD) in Primary Care (PC), but few have analysed its impact on the treatment of the patient with COPD. OBJECTIVES: To evaluate the use of spirometry in the diagnosis and follow-up of COPD patients in PC, and its impact on treatment. To analyse the variation in the performing of spirometry between PC centres. METHODOLOGY: A multicentre, observational and cross-sectional study of COPD patients seen in PC in Catalonia (Spain) during 2004-2005. A multilevel logistic regression model was used to identify factors associated with having spirometry and to determine the variation between the different centres. RESULTS: Twenty-one centres which included 801 patients took part. Only 53.2% of them had a diagnostic spirometer available and the mean (standard deviation) FEV1(%) was 54.8% (18%). The registers of smoking habits, complementary tests and spirometry follow-up were more common among patients who had a diagnostic spirometry available compared to those who did not. No statistically significant differences were found as regards demographic, clinical, treatment and quality of life variables between patients with and without follow-up spirometry. Significant variation was observed in the percentage of diagnostic spirometries between different PC centres (variance=0.217; p<0.001). CONCLUSION: Spirometry is underused in PC and performing it during follow-up is not associated to the different treatments received, or with a more complete approach to the disease. There is significant variation in the performing of spirometry among PC centres. PMID- 21295904 TI - Biogasification of biowaste and sewage sludge--measurement of biogas quality. AB - Biogas quality, the presence of some trace components (siloxanes, sulfur compounds, volatile organic compounds, VOCs) in biogas, is in a decisive role when determining the biogas utilization and the purification requirements and equipments. In the present work, the effects of process changes related to reactor loading variations on the concentrations of selected trace compounds in biogas were studied. Source separated biowaste and sewage sludge were co-digested in a mesophilic pilot reactor (200 L) for four months during which the organic load was stepwise increased. The results showed that the process worked steadily up to the load of 8 kgVS m(-3)d(-1). Also the community composition of methanogenic archae stayed largely unaffected by the load increase, and was at all stages typical for a mesophilic biogasification process. Gaseous concentrations of siloxanes, hydrogen sulfide and most VOCs remained at a constant low level, showing no sensitivity to variations in the load and related process changes. However, the total siloxane concentration in the biogas was dependent on feed quality, and the detected concentrations require removal prior to use in turbines or fuel cells. Otherwise, after the removal of siloxanes, the biogas studied in this work is well applicable in various electricity production options, like in gas engines, turbines, microturbines and fuel cells. PMID- 21295905 TI - Effect of methyl parathion on nitrous oxide production: a laboratory study. AB - We investigated the diversity of a denitrifying gene (nirK) and the emission of CO(2) and N(2)O, in a "chinampa" soil contaminated with methyl parathion. Soil at 40% of water holding capacity was spiked with methyl parathion at four concentrations (i.e. 0, 0.7, 1.47 and 4.27 g kg(-1) dry soil), while emission of N(2)O and CO(2) and nirK diversity was determined after 0, 1, 14, 30, 60 and 90 days. The emission of N(2)O on a daily base and the cumulative emission of CO(2) was not affected by the different concentrations of methyl parathion applied to soil. The diversity of the nirK gene, determined by using temperature gradient gel electrophoresis (TGGE), decreased with increased methyl parathion application. It was found that methyl parathion had effect on the emissions of N(2)O and CO(2), and reduced the diversity of the nirK gene. Consequently, the reduced diversity of the nirK gene could affect the emission of N(2)O. PMID- 21295906 TI - Reducing visitors' group size increases the number of birds during educational activities: Implications for management of nature-based recreation. AB - Organized tours to watch wildlife are popular recreational and educational activities, in which the visitor expectative (to observe as many and as diverse animals as possible) runs parallel to conservation purposes. However, the presence of visitors may cause negative impacts on wildlife, which makes recreation difficult to manage. Thus, restricting visitor's load to minimize impacts on fauna may be advisable, but too much restriction may end up disappointing the public. We analysed how visitors' group size influences the number and variety of birds observed during an educational activity directed to scholars, in a forested area where public access is otherwise restricted. We observed fewer birds, but not fewer species, as the size of scholars' groups increased. Such effect was apparently mediated by a few species demonstrating reduced tolerance to increased group size. Our results support the idea that reducing the size of visitors' groups not only helps to minimize the negative impacts on wildlife derived from leisure activities, but also allows visitors to watch more wildlife. Therefore, organizing visitors in small numbers is recommended in the design of activities directed to groups of people visiting natural areas. PMID- 21295908 TI - Inaccuracy and misjudged factors of Glasgow Coma Scale scores when assessed by inexperienced physicians. AB - OBJECTIVES: Appropriate triage of a large number of patients with head injury is crucial in the emergency department (ED) as well as in the field. Traumatic brain injury (TBI) is primarily assessed using the Glasgow Coma Scale (GCS) to evaluate consciousness. However, GCS score assignment is far from sufficiently reliable for correct assessment, especially with inexperienced users. The purpose of this study was to reveal what factors are misjudged when assessed by inexperienced medical personnel. METHODS: We analyzed GCS eye, verbal, and motor response (EVM) scoring profiles conducted by postgraduate year 1 junior residents (n=94) before they began residency in specific departments. GCS assessment was tested using a video simulation that portrayed mock patients with eight different levels of consciousness that are frequently encountered in trauma patients. RESULTS: On average, 26+/-18% of examinees failed to provide the correct EVM profiles for the eight selected consciousness levels. Primary misjudged GCS factors belonged to two categories: the assessment of "confused conversation (V4)", and the assessment of "withdrawal motor response (M4)". CONCLUSION: Additional instruction regarding the specific misjudged factors identified in this study may help inexperienced medical personnel improve the reliability of GCS score assignment to casualties with TBI. PMID- 21295907 TI - Preoperative nutritional status is an important predictor of survival in patients undergoing surgery for renal cell carcinoma. AB - BACKGROUND: The role of malnutrition has not been well studied in patients undergoing surgery for renal cell carcinoma (RCC). OBJECTIVE: Our aim was to evaluate whether nutritional deficiency (ND) is an important determinant of survival following surgery for RCC. DESIGN, SETTING, AND PARTICIPANTS: A total of 369 consecutive patients underwent surgery for locoregional RCC from 2003 to 2008. ND was defined as meeting one of the following criteria: body mass index <18.5 kg/m(2), albumin <3.5 g/dl, or preoperative weight loss >= 5% of body weight. INTERVENTION: All patients underwent radical or partial nephrectomy. MEASUREMENTS: Primary outcomes were overall and disease-specific mortality. Covariates included age, Charlson comorbidity index (CCI), preoperative anemia, tumor stage, Fuhrman grade, and lymph node status. Multivariate analysis was performed using a Cox proportional hazards model. Mortality rates were estimated using the Kaplan-Meier product-limit method. RESULTS AND LIMITATIONS: Eighty-five patients (23%) were categorized as ND. Three-year overall and disease-specific survival were 58.5% and 80.4% in the ND cohort compared with 85.4% and 94.7% in controls, respectively (p<0.001). ND remained a significant predictor of overall mortality (hazard ratio [HR]: 2.41, 95% confidence interval [CI], 1.40-4.18) and disease-specific mortality (HR: 2.76; 95% CI, 1.17-6.50) after correcting for age, CCI, preoperative anemia, stage, grade, and nodal status. This study is limited by its retrospective nature. CONCLUSIONS: ND is associated with higher mortality in patients undergoing surgery for locoregional RCC, independent of key clinical and pathologic factors. Given this mortality risk, it may be important to address nutritional status preoperatively and counsel patients appropriately. PMID- 21295909 TI - Polyrhodanine modified anodic aluminum oxide membrane for heavy metal ions removal. AB - Polyrhodanine was immobilized onto the inner surface of anodic aluminum oxide (AAO) membrane via vapor deposition polymerization method. The polyrhodanine modified membrane was applied to remove heavy metal ions from aqueous solution because polyrhodanine could be coordinated with specific metal ions. Several parameters such as initial metal concentration, contact time and metal species were evaluated systematically for uptake efficiencies of the fabricated membrane under continuous flow condition. Adsorption isotherms of Hg(II) ion on the AAO polyrhodanine membrane were analyzed with Langmuir and Freundlich isotherm models. The adsorption rate of Hg(II) ion on the membrane was obeyed by a pseudo second order equation, indicating the chemical adsorption. The maximum removal capacity of Hg(II) ion onto the fabricated membrane was measured to be 4.2 mmol/g polymer. The AAO-polyrhodanine membrane had also remarkable uptake performance toward Ag(I) and Pb(II) ions. Furthermore, the polyrhodanine modified membrane could be recycled after recovery process. These results demonstrated that the polyrhodanine modified AAO membrane provided potential applications for removing the hazardous heavy metal ions from wastewater. PMID- 21295910 TI - Effect of aging period on the characteristics and coagulation behavior of polyferric chloride and polyferric chloride-polyamine composite coagulant for synthetic dying wastewater treatment. AB - In this paper, a new composite inorganic-organic coagulant (PFC-EPI-DMA) was prepared by polyferric chloride (PFC) and epichlorohydrin-dimethylamine (EPI-DMA) under a given EPI-DMA/Fe and OH/Fe molar ratio. In comparison with PFC, the Fe (III) species and zeta potential of PFC-EPI-DMA were measured. Then their coagulation performance and coagulation kinetics for treating synthetic reactive dying wastewater were investigated. The results showed that the content of Fe(a) and Fe(b) in PFC-EPI-DMA and PFC coagulants decreased with increasing aging period. Compared to PFC, PFC-EPI-DMA had higher content of Fe(a) but lower content of Fe(b) and Fe(c). The zeta potentials of two coagulants decreased with increasing aging period within all tested pH range. For the treatment of reactive red 24, the color removal efficiency treated by PFC-EPI-DMA decreased, while that treated by PFC remained almost constant with increasing aging period. However, the color removal efficiencies of reactive blue 14 treated by two coagulants both decreased with increasing aging period. The results of floc aggregation process confirmed that with increasing aging period, the orders of floc growth rate, ratio and TWV treated by two coagulants were complicated. PMID- 21295911 TI - Selective sorption of divalent cations using a high capacity sorbent. AB - This manuscript describes the application of a novel sorbent, sodium titanate nanotube (STN) on partitioning of various divalent cations. Seven divalent cations, from alkaline earth, transition and post-transition groups, were used to determine the capacity and selectivity of STN. At pH 3 +/- 0.02 and 0.1M ionic strength, STN displayed high capacity for Pb and Cd (1.27 and 0.39 mmol/g, correspondingly). The affinity of divalent cations was in the order Pb ? Cd>Cu>Zn>Ca>Sr>Ni. For six of the tested cations, their sorption capacity can be linearly correlated to its hydrolysis constant and electronegativity. STN has unusually low affinity for Ni and correlations of sorption capacity of Ni falls outside the 95% confidence intervals. Furthermore, it exhibited sorption behavior similar to alkaline earth cations, significant uptakes occurred only when pH>point of zero charge. In competitive sorption tests, STN preferentially sorb Cd over other metals (Zn, Ni, Ca and Sr) which coexist in industrial wastewater. As such STN is a potential novel sorbent useful for partitioning Cd from other metals in industrial wastewater. PMID- 21295912 TI - Are neuropathic pain screening tools useful for patients with spinal cord injury? PMID- 21295913 TI - Atom probe characterization of precipitation in an aged Cu-Ni-P alloy. AB - A temporal evolution of clusters associated with age hardening behavior in a Cu Ni-P alloy during ageing at 250 degrees C for up to 100 ks after solution treatment has been carried out. A three-dimensional atom probe (3DAP) analysis has showed that Ni-P clusters are present in the as-quenched condition, and that the cluster density increases as the ageing time increases. The clusters have a wide range of Ni/P ratios when they are relatively small, whereas larger clusters exhibit a narrow distribution of the Ni/P ratio, approaching a ratio of approximately two. These results would indicate that the clusters with various Ni/P ratios form at the early stage of precipitation and the ratio approaches a value identical to that of the equilibrium phase at 250 degrees C as the clusters enlarge during ageing. PMID- 21295914 TI - Atom probe tomography of Ni-base superalloys Allvac 718Plus and Alloy 718. AB - Atom probe tomography (APT) allows near atomic scale compositional- and morphological studies of, e.g. matrix, precipitates and interfaces in a wide range of materials. In this work two Ni-base superalloys with similar compositions, Alloy 718 and its derivative Allvac 718Plus, are subject for investigation with special emphasis on the latter alloy. The structural and chemical nuances of these alloys are important for their properties. Of special interest are grain boundaries as their structure and chemistry are important for the materials' ability to resist rapid environmentally induced crack propagation. APT has proved to be suitable for analyses of these types of alloys using voltage pulsed APT. However, for investigations of specimens containing grain boundaries and other interfaces the risk for early specimen fracture is high. Analyses using laser pulsing impose lower electrical field on the specimen thereby significantly increasing the success rate of investigations. Here, the effect of laser pulsing was studied and the derived appropriate acquisition parameters were then applied for microstructural studies, from which initial results are shown. Furthermore, the influence of the higher evaporation field experienced by the hardening gamma' Ni(3)(Al,Nb) precipitates on the obtained results is discussed. PMID- 21295915 TI - Molecular identification of Eimeria species infecting market-age meat chickens in commercial flocks in Ontario. AB - A previously described multiplex PCR was evaluated for the identification and prevalence of Eimeria species in market-age commercial chicken flocks in Ontario. The multiplex PCR based on species-specific RAPD-SCAR markers was able to distinguish six available laboratory strains of Eimeria species (E. tenella, E. maxima, E. necatrix, E. mitis, E. acervulina, and E. brunetti) and E. tenella, E. maxima and E. acervulina in unknown field samples, including multiple infections in single reactions. No backyard (0/77) and 20/360 market-age commercial chickens were oocyst-positive using standard fecal flotation methods. PCR identified E. tenella alone (9/360, 2.5%), E. maxima alone (5/360, 1.38%), E. maxima plus E. tenella (5/360, 1.38%) and E. acervulina alone (1/360, 0.27%) in market-age commercial broilers. This is probably the first time the multiplex PCR has been evaluated in poultry establishments in Canada and illustrates the value of the tool in coccidiosis epidemiology on commercial farms. PMID- 21295916 TI - Detection of Leishmania (L.) chagasi in canine skin. AB - Canine visceral leishmaniasis (CVL) is caused by a protozoa parasite of the specie Leishmania (L.) chagasi endemic for humans and dogs in many regions of Brazil. The purpose of the present study was the detection of (L.) chagasi in canine skin tissues from three different groups of clinical signs: asymptomatic, oligosymptomatic and polysymptomatic Leishmania-infected dogs. Lesional or non lesional skin tissue samples from 34 naturally infected dogs were obtained and processed by histochemistry (HE) and immunohistochemistry (IMHC) for direct parasitological examination and the results were compared with a polymerase chain reaction (PCR) method. IMHC and HE methods detected intact Leishmania-amastigote parasites in lesional and no lesional skin, particularly in asymptomatic and oligosymptomatic dogs. 50% of skin samples collected from asymptomatic and 21.4% from oligosymptomatic dogs had parasites in their skins even though with mild inflammatory reaction or without any macroscopic dermatological alterations. On the other hand, 100% of polysymptomatic dogs showed several forms of clinical dermatological alterations and 91.7% had intact amastigotes with parasite load ranging from mild to intense. By PCR, DNA of Leishmania spp. was detected in 97.8% skin samples regardless clinical status of the dogs or IMHC/HE test results. PCR on skin was a sensitive procedure for CVL diagnosis, but direct observation of intact parasite in skin biopsies, particularly by IMHC, may be also considered to support the diagnosis. PMID- 21295917 TI - Adolescent computer use and alcohol use: what are the role of quantity and content of computer use? AB - The purpose of this study was to examine the relationship between computer use and alcohol use among adolescents. In particular, the goal of the research was to determine the role of lifetime drinking and past month drinking on quantity as measured by amount of time on the computer (for school work and excluding school work) and on content as measured by the frequency of a variety of activities on the internet (e.g., e-mail, searching for information, social networking, listen to/download music). Participants (aged 13-17 years and residing in the United States) were recruited via the internet to complete an anonymous survey online using a popular survey tool (N=270). Their average age was 16 and the sample was predominantly female (63% girls). A series of analyses was conducted with the computer use measures as dependent variables (hours on the computer per week for school work and excluding school work; various internet activities including e mail, searching for information, social networking, listen to/download music) controlling for gender, age, academic performance and age of first computer use. Based on the results, past month drinkers used the computer more hours per week excluding school work than those who did not. As expected, there were no differences in hours based on alcohol use for computer use for school work. Drinking also had relationships with more frequent social networking and listening to/downloading music. These findings suggest that both quantity and content of computer use were related to adolescent drinking. PMID- 21295918 TI - Understanding motivation for substance use treatment: the role of social pressure during the transition to adulthood. AB - Research has shown that social pressure is related to treatment motivation and plays an important role in treatment engagement in adults with problematic substance use. Despite the shifts in autonomy and decision-making in emerging adulthood, the factors affecting treatment motivation (e.g., readiness to comply with treatment) during this period have been largely ignored. In this cross sectional study, 134 youth (83 males and 51 females) presenting to an outpatient substance abuse program completed questionnaires regarding substance use history, mental health, social pressure to reduce use and enter treatment, and treatment motivation. Age was positively related to identification of internal reasons for seeking treatment and negatively related to external coercive social pressures as a motivator for treatment. Peer pressure accounted for significant variance in Identified (e.g., personal choice and commitment to the program) and Introjected (e.g., guilt about continued substance use) treatment motivation. Family pressure was related only to External treatment motivation when peer pressure was considered in the regression model. These results highlight the importance of emerging adult peers as motivators of youths' treatment seeking. Limitations, directions for future research and treatment implications are discussed. PMID- 21295919 TI - Using personalized feedback to reduce alcohol use among hazardous drinking college students: the moderating effect of alcohol-related negative consequences. AB - Web-based screening and brief interventions that include personalized feedback about their alcohol use have proven to be particularly promising for reducing hazardous drinking among university students. Despite the increasing use of these approaches, there is still relatively little known about how the content of these interventions may influence outcomes and who may benefit most from these approaches. The current study sought to address these issues by examining how individual differences in alcohol consequences influence outcomes of a laboratory based computerized intervention. METHODS: One-hundred and nineteen introductory psychology students who either had two episodes of heavy episodic drinking in the past month or scored >=8 on the AUDIT participated in this randomized controlled trial for course credit. Participants were assigned to 1 of 4 conditions in this 2 Intervention (Alcohol Feedback vs. Control)*2 Assessment (Motivational Assessment vs. No Motivational Assessment) between-subjects design. Quantity of alcohol consumed per week and heavy episodic drinking one month later were the primary dependent variables. RESULTS: Controlling for corresponding baseline alcohol measures, hierarchical linear regression analyses showed a significant interaction between intervention condition and baseline alcohol-related consequences. For those who reported more alcohol consequences at baseline, the alcohol intervention resulted in significantly less alcohol use and fewer heavy drinking episodes at follow-up, while no difference was observed between intervention conditions for those with few baseline consequences. Assessment did not moderate intervention effects. DISCUSSION: These findings suggest that a feedback-based computerized intervention that includes normative information about alcohol use and consequences may be more effective for hazardous drinking students who are experiencing higher levels of alcohol-related consequences. PMID- 21295920 TI - Effect of gender on meat quality in lamb from extensive and intensive grazing systems when slaughtered at the end of the growing season. AB - In Norway, most lambs are slaughtered at the end of the grazing season in September. An increased demand for fresh meat during the off-season may change this pattern. Castration of male lambs is not permitted, and off-season slaughtering may affect the acceptability of the meat. The objective of this study was to determine the effect of gender and the interaction between gender and diet on meat quality from Norwegian White Sheep lambs slaughtered in September. In two different experiments, 22 and 29 males compared with 22 and 46 female lambs, respectively, were used. Loin samples of M. Longissimus dorsi were analysed for sensory profile and fatty acid composition. Meat from male lambs in Experiment 2 had higher scores for cloying and rancid flavour, and lower scores for sour and sweet taste compared to meat from female lambs. It is concluded that even at the normal slaughtering time in September, significant differences between genders may occur. PMID- 21295921 TI - Oxidative stability of pork meat lipids as related to high-oleic sunflower oil and vitamin E diet supplementation and storage conditions. AB - The aim of this research work was to evaluate the oxidative stability of pork meat lipids as related to dietary supplementation with high-oleic sunflower oil (HOSO) and/or alpha-tocopheryl acetate (VE), as well as the influence of storage conditions. Four different diets (control; HOSO; VE; HOSO+VE), were fed to swines until slaughtering. Meat slices were packed in vessels with transparent shrink film and exposed to white fluorescent light for 3 days at 8 degrees C. HOSO supplementation increased oleic acid content of pork meat. The highest levels of peroxide value (PV) and cholesterol oxidation products (COPs) were detected in the control group, whereas HOSO-enriched diets displayed the highest thiobarbituric reactive substance (TBARs) content. After storage under light exposure, pork meat slices exhibited a decrease of PV, which resulted in an increasing trend of TBARs and COPs. Feeding enrichment with both HOSO and vitamin E can be, therefore, used as an appropriate supplementation strategy to produce pork meat with a suitable oxidative stability. PMID- 21295922 TI - Meat quality of "Galician Mountain" foals breed. Effect of sex, slaughter age and livestock production system. AB - The effects of sex, slaughter age (9 vs. 12 months) and livestock production system (freedom extensive system (FES) vs. semi extensive system (SES)) of "Galician Mountain" foals breed on meat quality from the Longissimus dorsi (LD) muscle were investigated. Forty-two foals had been used for this study, 19 (11 females and 8 males) were reared in a semi extensive system and weaned three months prior to slaughtering (8 and 11 were slaughtered at 9 and 12 months, respectively) while the other 23 (11 females and 12 males) were reared together with its mothers in a system in freedom and were slaughtered at the age of 9 months. The obtained results showed that there were no significant differences between the sexes and the slaughter age whereas the livestock production system was a significant variation source on intramuscular fat content and meat tenderness because SES foals showed 51.6% more of IMF and the improved meat tenderness achieved a shear force of <3 kg. In general, the meat from foals of the study at hand showed very lean meat (<0.3% in IMF) with a high protein content (>20.5%) and heme-iron (1.62 mg/100g meat) comparable to veal meat. Furthermore, the meat samples showed a higher luminosity (L*>40), a very good water holding capacity, measured by cooking losses (<18.3%), and a tenderness less than 4 kg. Thus, it can be classified as "very tender" meat. PMID- 21295923 TI - Very distal sensory nerve transfers in high median nerve lesions. AB - PURPOSE: We report on the results of reconstruction of fingertip sensation by very distal nerve transfer in 8 patients with high median nerve lesions. METHODS: Before surgery, patients underwent sensory testing of the hand using Semmes Weinstein monofilaments. All patients had surgery within 1 year of trauma. For sensory reconstruction, branches of the radial nerve on the proximal phalanx of the index and thumb were sutured to the ulnar proper digital nerve of the thumb and radial proper digital nerve of the index finger. Patients were followed up for 12 months. RESULTS: After median nerve lesions, zones of lost protective sensation were confined to the middle and index finger and the thumb. Sensation on the palm of the hand and proximal phalanx was preserved. Radial nerve transfer to palmar nerves restored protective or better sensation to the fingertips in all patients. Better results were observed for the thumb. Locognosia was acquired in all thumbs, and in 4 of 8 index fingers. Good results were detected even in patients who had undergone surgery later than 6 months after injury. CONCLUSIONS: Fingertip sensation can be restored by very distal nerve transfer of radial nerve branches to palmar nerves at the level of the proximal phalanx. This method of reconstruction appears useful in high median nerve lesions. In chronic lesions of the median nerve at the wrist and lesions in older patients, very distal nerve transfers might be adjunct to nerve grafting. PMID- 21295924 TI - Pollicization for congenital thumb aplasia using the second dorsal metacarpal artery as the vascular pedicle: case report. AB - The author presents the case of a child with bilateral thumb hypoplasia. Pollicization of the left index finger with grade 4 thumb hypoplasia was attempted and abandoned, apparently because of anomalous vascular anatomy. A secondary procedure identified a substantial second dorsal metacarpal artery that connected with a palmar-ulnar digital vessel at the level of the metacarpal neck. Successful pollicization was performed using the second dorsal metacarpal artery and its venae comitantes as the vascular pedicle. PMID- 21295925 TI - Cross-cultural adaptation, validation, and reliability process of the Michigan Hand Outcomes Questionnaire in a Turkish population. AB - PURPOSE: The Michigan Hand Outcomes Questionnaire (MHQ) is a domain-specific questionnaire that was developed to be used as a standardized instrument capable of measuring outcomes for patients with all types of hand disorders. The purpose of this study was to develop the Turkish version of the MHQ and to examine whether it is a valid and reliable tool for assessing the outcomes in hand disorders. METHODS: Translation and back-translation of the MHQ were performed, according to published guidelines. A total of 70 patients with hand complaints completed the final version of the MHQ and the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire Turkish version (DASH-T) twice, on their first visit and after an interval of 7 days. Visual analog scale (VAS) results for pain intensity and grip strength measurements of the individuals were also taken in both assessments consecutively. RESULTS: Translation and back-translation revealed no major difficulties. The Turkish version of the MHQ met set criteria of reliability and validity. The intraclass correlation coefficient of the test retest reliability for the 6 subscales ranged from 0.79 to 0.96. The internal consistency of the MHQ, estimated by Cronbach's alpha, ranged from 0.85 to 0.96 for all subscale scores. There were high to moderate correlations between MHQ and DASH scores and VAS and grip strength scores of the injured side. CONCLUSIONS: The Turkish version of the MHQ has excellent test-retest reliability and validity, and it is an adequate and useful instrument for measuring functional disability in hand disorders of Turkish-speaking patients. PMID- 21295926 TI - In vivo length and changes of ligaments stabilizing the thumb carpometacarpal joint. AB - PURPOSE: To investigate the lengths and changes of selected ligaments stabilizing the thumb carpometacarpal (CMC) joint during thumb motion in vivo. METHODS: We obtained serial computed tomography scans of the thumb CMC joints of 6 healthy volunteers during thumb flexion, abduction, and opposition. We reconstructed the 3-dimensional structures of the bones of the thumb CMC joint using customized software and modeled the paths of fibers of 5 principal ligaments--deep anterior oblique (beak), dorsoradial, posterior oblique, intermetacarpal, and dorsal intermetacarpal--at each of the CMC joint positions studied. We estimated the virtual lengths of these ligaments in neutral position, flexion, abduction, and opposition of the CMC joint by measuring the distances between the origin and the insertion of individual ligaments, and statistically analyzed the length changes. RESULTS: The estimated length of the CMC joint ligaments underwent significant changes during thumb motion in vivo. Thumb flexion led to the greatest changes in ligament lengths. During flexion, all the ligaments lengthened significantly (p < .05 or p < .01), except for the beak ligament, which shortened significantly (p < .001). The lengths of the ligaments changed similarly during thumb abduction and opposition, except for the dorsoradial ligament. In both motions, the posterior oblique and dorsal intermetacarpal ligaments lengthened and the beak ligament shortened significantly (p < .05 or p < .01). During the 3 thumb motions, the beak ligament underwent marked shortening, while the other measured ligaments lengthened to varied extent. CONCLUSIONS: The estimated lengths of principal ligaments stabilizing the CMC joint change substantially during thumb motions in vivo. Thumb flexion causes the greatest changes of the ligament lengths; abduction and opposition result in similar changes in the ligament lengths. The beak ligaments shorten while the other ligaments lengthen. This in vivo study suggests that thumb motions expose the CMC joint ligaments to different tensions at these thumb positions, and that the ligaments are under lower tension during thumb opposition and abduction than during flexion. PMID- 21295927 TI - Movements and postures of infants aged 3 to 5 months: to what extent is their optimality related to perinatal events and to the neurological outcome? AB - BACKGROUND: The quality of spontaneous general movements (GMs), assessed in the individual infant, has emerged as one of the most reliable and valid predictors especially of severe neurological impairments. AIMS: To implement a more detailed assessment of GMs and co-existing movements and postural patterns in a rehabilitation clinic, and to examine to what extend is the optimality of movements and postures of infants aged 3 to 5 months related to perinatal events and the neurological outcome. STUDY DESIGN: Prospective study of 41 infants (15 boys and 26 girls; 11 infants born preterm) admitted to the Department of Paediatric Neurology and Rehabilitation of the St. Joseph's Hospital in Kyoto (Japan). OUTCOME MEASURES: Clinical, neurological and psychological status at age 5. RESULTS: Motor optimality at age 3 to 5 months correlated positively with neonatal optimality (r=0.48, p<0.01), especially regarding factors associated with hypoxic events. A non-optimal motor performance (lowest possible scores) predicted cerebral palsy with 100% accuracy. Other adverse outcomes such as developmental delays, developmental coordination disorders, pervasive developmental disorder or attention deficit hyperactivity disorder turned out not to be associated with early motor performance. In 13% of cases absence of fidgety movements proved to be false positives, but their normal appearance along with a smooth concurrent motor performance was solely found in infants with a normal neurological development. CONCLUSION: Assessing the quality of motor performance at age 3 to 5 months considerably improves our ability to identify infants at risk for maldevelopment. PMID- 21295928 TI - Characterization of children's latent fingerprint residues by infrared microspectroscopy: forensic implications. AB - The chemistry of children's latent fingerprint residues was investigated as a function of time and temperature by non-destructive spectrochemical analysis. Latent fingerprints from children, ranging in age from 2 to 11 years, were deposited onto aluminum-coated glass slides and were analyzed by Fourier Transform Infrared Microspectroscopy. The results revealed that there are three major classes of compounds present in children's latent fingerprints: carboxylic acid salts, proteins, and esters. By studying the changes in the fingerprint residues as a function of time and at elevated temperatures, we discovered that the salts in the fingerprint residues are stable relative to the esters. These findings have relevant forensic implications; by targeting the acid salts instead of the esters or proteins, children's latent fingerprints may be recovered after extended periods of time have elapsed. PMID- 21295929 TI - Chemical signature of ecstasy volatiles by comprehensive two-dimensional gas chromatography. AB - A method for ecstasy volatiles 'signature' analysis based on two-dimensional gas chromatography separation and time-of-flight mass spectrometry detection (GC*GC TOFMS) is presented. Organic impurity volatiles were extracted by head space solid phase microextraction (HS-SPME). The final column phase choice of the four different column combinations tested was a low-polarity 5% phenyl polysilphenylene-siloxane coupled with a polyethylene glycol phase, which best displayed the complex impurity profile. Second dimension ((2)D) retention time reproducibility was found to be about 1% RSD, and area reproducibility of SPME sampling was just over 5% RSD for compounds with S/N ratio of about 100. High similarity of TOFMS spectra of impurities was obtained against commercial MS libraries. 16 components from the two-dimensional profiles were selected for comparison of the 24 ecstasy tablets, most of which proved to be benzodioxole derived compounds. All tablets were correctly classified in eight groups according to their post-tabletting characteristics, when appropriate data pre treatment was applied. Principal component analysis revealed clustering of samples according to the country of origin. Samples from Macedonia were elevated in N-formyl-MDMA and N-acetyl-MDMA while samples from Australia were elevated in 3,4-methylenedioxypropane and 3,4-methylenedioxyacetophenone. Furthermore, three components were found to be unique for one of the source countries. The additional separation of components on the (2)D column, increased response due to modulation, high acquisition rate with full mass spectra using TOFMS detection, and MS deconvolution extend the possibility of detecting additional markers and route-specific components, especially of low abundant, polar components. PMID- 21295930 TI - Evaluation of incidentally discovered adrenal masses with PET and PET/CT. AB - BACKGROUND AND PURPOSE: Incidentally discovered adrenal masses are commonly seen with high resolution diagnostic imaging performed for indications other than adrenal disease. Although the majority of these masses are benign and non secretory, their unexpected discovery prompts further biochemical and often repeated imaging evaluations, sufficient to identify hormonally active adrenal masses and/or primary or metastatic neoplasms to the adrenal(s). In the present paper we investigate the role of PET and PET/CT for the detection of adrenal incidentalomas in comparison with CT and MRI. MATERIALS AND METHODS: a systematic revision of the papers published in PubMed/Medline until September 2010 was done. RESULTS: The diagnostic imaging approach to incidentally discovered adrenal masses includes computed tomography (CT), magnetic resonance imaging (MRI) and more recently positron emission tomography (PET) with radiopharmaceuticals designed to exploit mechanisms of cellular metabolism, adrenal substrate precursor uptake, or receptor binding. CONCLUSION: The functional maps created by PET imaging agents and the anatomic information provided by near-simultaneously acquired, co-registered CT facilitates localization and diagnosis of adrenal dysfunction, distinguishes unilateral from bilateral disease, and aids in characterizing malignant primary and metastatic adrenal disease. PMID- 21295931 TI - Peripheral MRA with continuous table movement: imaging speed and robustness compared to a conventional stepping table technique. AB - PURPOSE: To investigate the potential of continuous table movement (CTM)-MRA for reduction of acquisition time and to evaluate the image quality in comparison to conventional stepping table (CST) MRA. MATERIALS AND METHODS: The data of 82 patients were included in this retrospective, IRB-approved study. All patients underwent peripheral MRA at our institution. 41 consecutive patients were examined with a CST-MRA at a 1.5 T MR system. 41 different consecutive patients were examined with a CTM-MRA at 3.0 T MR system. Image quality was assessed by two independent radiologists in consensus on a 4-point Likert-type scale. Descriptive statistics and t-tests were used to compare image acquisition time of CST-MRA to that of CTM-MRA with and without additional time-resolved imaging of the feet using the TWIST technique. Additionally, acquisition time was compared in a subgroup of the fastest 50%. RESULTS: The mean imaging time for the CTM-MRA was 34% less than with the CST-MRA (18.2 min vs. 27.5 min; p<0.0001). Even with inclusion of the TWIST sequence the combined CTM-/TWIST-MRA protocol was 26% faster (20.3 min vs. 27.5 min; p<0.0001). The image quality was slightly better with CTM-MRA (CTM-MRA mean score 3.3+/-0.5, mean score CST-MRA 2.9+/-0.6). Venous overlay was significantly lower using the CTM-MRA approach (CTM-MRA mean score 2.8+/-0.4; CST-MRA mean score 2.2+/-0.7; p<0.0001). CONCLUSION: CTM-MRA is on average 30% faster than a comparable CST-MRA protocol with equal image quality. Even when adding an additional time-resolved-MRA of the calf station the CTM-MRA protocol is still 26% faster. In conclusion, this study proves that CTM-MRA further improves MRA by reducing user interference and image acquisition times and hence allowing to increase the clinical throughput. PMID- 21295932 TI - Retrospective comparison of magnetic resonance imaging features and histopathology in Crohn's disease patients. AB - PURPOSE: To retrospectively compare histopathological findings of surgically resected bowel segments with magnetic resonance imaging (MRI) findings on Crohn's disease activity. MATERIALS AND METHODS: Patients who underwent a MR enterography or enteroclysis before surgery were included after informed consent. MRI features (T1-enhancement, T1 and T2 stratification, T2 signal intensity, bowel wall thickness, presence of ulcerations, comb sign, creeping fat, and disease activity) were assessed by three experienced abdominal radiologists. An acute inflammatory score based on histopathology (parameters: mucosal ulceration, edema, depth and degree of neutrophils) was calculated. Interobserver variability for subjective MRI features was also assessed. RESULTS: Thirty-nine segments in 25 patients (mean age 38 years) were included. Of the MRI features, disease activity per segment and bowel wall thickness had a positive association with the acute inflammatory score (p<0.05). T1-enhancement had a positive correlation with disease chronicity. All other MRI features did not have an association with the acute inflammatory score. Interobserver agreement between the three observers was weak to moderate. CONCLUSION: MR features bowel wall thickness and disease activity per-segment reflect disease activity in Crohn's disease patients. PMID- 21295933 TI - Development of a quantitative PCR assay for residual mouse DNA and comparison of four sample purification methods for DNA isolation. AB - Reliable and sensitive assays are required to determine whether a pharmaceutical product meets current regulatory guidelines for residual host cell DNA. In this study, the sensitivity of the qPCR assay was significantly improved by targeting the repetitive elements of mouse genome. This improved method allowed for sensitive and accurate quantitation of mouse genomic DNA in the range of 1 to 10(6)pg/mL. In addition, four sample purification methods for DNA isolation (Wako DNA extractor kit, MasterPureTM DNA purification kit, PrepSEQTM residual DNA sample preparation kit, and phenol-chloroform extraction method with addition of glycogen), each representing a different strategy for DNA isolation from proteinaceous solutions, were evaluated by isolating DNA from a mouse monoclonal IgG antibody. Among these methods, Wako DNA extractor kit and MasterPureTM DNA purification kit demonstrated superior DNA recovery, repeatability, and sensitivity, with quantitation limits of 1pg/mL. To further evaluate these two DNA isolation methods, six replicates of an unspiked mouse polyclonal IgG antibody sample were tested by both methods, and both methods demonstrated a good degree of precision. Therefore, the residual mouse DNA quantitation methods described here represented rapid, accurate, precise, and sensitive procedures that can be used in quality control testing for regulatory compliance in the pharmaceutical industry. PMID- 21295934 TI - Quantification of aesculin in rabbit plasma and ocular tissues by high performance liquid chromatography using fluorescent detection: application to a pharmacokinetic study. AB - A simple and sensitive high performance liquid chromatography method with fluorescence detection (HPLC-FD) was described for the determination of aesculin (AL) at low concentrations in rabbit plasma and ocular tissues. After deproteinization by methanol using pazufloxacin mesilate (PM) as an internal standard (I.S.), supernatants were evaporated to dryness at 40 degrees C under a gentle stream of nitrogen. The residue was reconstituted in mobile phase and a volume of 20MUL was injected into the HPLC for analysis. Analytes were separated on an Ultimate XB-C18 column (250mm * 4.6mm i.d., 5MUm particle size) and protected by a ODS guard column (10mm * 4.0mm i.d., 5MUm particle size), using acetonitrile-0.1% triethylamine in water (adjusted to pH 3.0 using phosphoric acid) (12:88, v/v) as mobile phase with a flow rate of 1.0mL/min. The wavelengths of fluorescence detector (FD) were set at 344nm for excitation and 466nm for emission. The lower limit of quantitation (LOQ) for AL was 0.80ng/mL for plasma and vitreous body, 1.59ng/mL for aqueous humor, and 6.55ng/g for iris and 1.66ng/g for retina. The method was used in the study of AL concentrations in plasma and ocular tissues after topical administration of AL eye drops. PMID- 21295935 TI - Mixture experiment methods in the development and optimization of microemulsion formulations. AB - Microemulsion formulations represent an interesting delivery vehicle for lipophilic drugs, allowing for improving their solubility and dissolution properties. This work developed effective microemulsion formulations using glyburide (a very poorly-water-soluble hypoglycaemic agent) as a model drug. First, the area of stable microemulsion (ME) formations was identified using a new approach based on mixture experiment methods. A 13-run mixture design was carried out in an experimental region defined by constraints on three components: aqueous, oil and surfactant/cosurfactant. The transmittance percentage (at 550 nm) of ME formulations (indicative of their transparency and thus of their stability) was chosen as the response variable. The results obtained using the mixture experiment approach corresponded well with those obtained using the traditional approach based on pseudo-ternary phase diagrams. However, the mixture experiment approach required far less experimental effort than the traditional approach. A subsequent 13-run mixture experiment, in the region of stable MEs, was then performed to identify the optimal formulation (i.e., having the best glyburide dissolution properties). Percent drug dissolved and dissolution efficiency were selected as the responses to be maximized. The ME formulation optimized via the mixture experiment approach consisted of 78% surfactant/cosurfacant (a mixture of Tween 20 and Transcutol, 1:1, v/v), 5% oil (Labrafac Hydro) and 17% aqueous phase (water). The stable region of MEs was identified using mixture experiment methods for the first time. PMID- 21295936 TI - Synthesis of qualitative linguistic research--a pilot review integrating and generalizing findings on doctor-patient interaction. AB - OBJECTIVE: There is a broad range qualitative linguistic research (sequential analysis) on doctor-patient interaction that had only a marginal impact on clinical research and practice. At least in parts this is due to the lack of qualitative research synthesis in the field. Available research summaries are not systematic in their methodology. This paper proposes a synthesis methodology for qualitative, sequential analytic research on doctor-patient interaction. METHODS: The presented methodology is not new but specifies standard methodology of qualitative research synthesis for sequential analytic research. RESULTS: This pilot review synthesizes twelve studies on German-speaking doctor-patient interactions, identifies 45 verbal actions of doctors and structures them in a systematics of eight interaction components. Three interaction components ("Listening", "Asking for information", and "Giving information") seem to be central and cover two thirds of the identified action types. CONCLUSIONS: This pilot review demonstrates that sequential analytic research can be synthesized in a consistent and meaningful way, thus providing a more comprehensive and unbiased integration of research. Future synthesis of qualitative research in the area of health communication research is very much needed. PRACTICE IMPLICATIONS: Qualitative research synthesis can support the development of quantitative research and of educational materials in medical training and patient training. PMID- 21295937 TI - Electrodermal activity in response to empathic statements in clinical interviews with fibromyalgia patients. AB - OBJECTIVE: To study patients' electrodermal response (1) to an interviewer's empathic statements vs. inattention to emotional concerns and (2) to the emotional content in clinical interviews. METHODS: Patients with fibromyalgia (n=48) were given a clinical interview in a randomized 2*2 design, in which interviewer empathic or inattentive behavior (scenario A) and the emotional or neutral content of the interview (scenario B) were manipulated. Electrodermal activity (EDA) was measured during the interview. The patients' affective state (PANAS) and patient satisfaction were also assessed. RESULTS: In scenario A a significant main effect of empathy was found, indicating an increased tonic EDA (skin conduction level, SCL) during the empathy condition (p<.05). In scenario B there was a main effect of empathy (p<.01) and a significant empathy*content interaction effect (p<.01). There was a strong positive association between empathy and patient satisfaction (p<.0001). CONCLUSIONS: Empathic statements by the interviewer were associated with increased SCL in patients, most so in interviews with emotional content. PRACTICE IMPLICATIONS: Psychophysiological variables such as EDA may be applied in clinical communication research on emotional communication, but the limitations of such measures should also be recognized. PMID- 21295938 TI - Reducing high-risk drinking in mandated college students: evaluation of two personalized normative feedback interventions. AB - This study evaluated the efficacy of two brief personalized normative feedback interventions aimed at reducing heavy drinking among mandated college students (N = 135). Students were randomly assigned to one of two conditions: Web-based assessment with self-guided personalized normative feedback (SWF) or Web-based assessment with counselor-guided personalized normative feedback (CWF). Results indicated that students in the CWF condition reported significantly greater reductions in weekly drinking quantity and binge drinking frequency than those in the SWF group at follow-up (M = 8 months). Students in the CWF group also reported significantly greater reductions in estimates of peer drinking from baseline to the follow-up assessment than students in the SWF group. In addition, changes in estimates of peer drinking partially mediated the effect of the intervention on changes in drinking. Results suggest that counselor-guided feedback may be more effective in reducing drinking among mandated students relative to self-guided feedback in the long term. PMID- 21295939 TI - Multimedia article. The rotator interval: pathology and management. AB - The rotator interval describes the anatomic space bounded by the subscapularis, supraspinatus, and coracoid. This space contains the coracohumeral and superior glenohumeral ligament, the biceps tendon, and anterior joint capsule. Although a definitive role of the rotator interval structures has not been established, it is apparent that they contribute to shoulder dysfunction. Contracture or scarring of rotator interval structures can manifest as adhesive capsulitis. It is typically managed nonsurgically with local injections and gentle shoulder therapy. Recalcitrant cases have been successfully managed with an arthroscopic interval release and manipulation. Conversely, laxity of rotator interval structures may contribute to glenohumeral instability. In some cases this can be managed with one of a number of arthroscopic interval closure techniques. Instability of the biceps tendon is often a direct result of damage to the rotator interval. Damage to the biceps pulley structures can lead to biceps tendon subluxation or dislocation depending on the structures injured. Although some authors describe reconstruction of this tissue sling, most recommend tenodesis or tenotomy if it is significantly damaged. Impingement between the coracoid and lesser humeral tuberosity is a relatively well-established, yet less common cause of anterior shoulder pain. It may also contribute to injury of the anterosuperior rotator cuff and rotator interval structures. Although radiographic indices are described, it appears intraoperative dynamic testing may be more helpful in substantiating the diagnosis. A high index of suspicion should be used in association with biceps pulley damage or anterosuperior rotator cuff tears. Coracoid impingement can be treated with either open or arthroscopic techniques. We review the anatomy and function of the rotator interval. The presentation, physical examination, imaging characteristics, and management strategies are discussed for various diagnoses attributable to the rotator interval. Our preferred methods for treatment of each lesion are also discussed. PMID- 21295940 TI - Meta-analysis and systematic review of clinical outcomes comparing mobile bearing and fixed bearing total knee arthroplasty. AB - Mobile bearing (MB) knee replacements were designed with the goal of increased conformity and decreased bearing wear. We conducted a meta-analysis and systematic review of randomized controlled trials comparing outcomes of MB and fixed bearing (FB) total knee arthroplasty (TKA). We identified 14 studies reporting our primary outcome of Knee Society Scores (KSS). We also pooled data for post-operative range of motion (ROM) and Hospital for Special Surgery scores (HSS). The standard difference in mean outcome scores for KSS and HSS demonstrated no difference between groups (P = .902, and P = .426 respectively). Similarly, the pooled data for ROM showed no difference between groups (P = .265). The results of this study found no significant differences between clinical outcomes of MB and FB TKA. PMID- 21295941 TI - Prospective, randomized study between Insall-Burstein II and NexGen legacy with a minimum 9-year follow-up. AB - A randomized, prospective, comparative study was performed in 2 related, adjacent generation posterior stabilized total knee prostheses, to evaluate whether the newer design improved the clinical and radiographic outcome for treatment of advanced osteoarthritis of the knee. Ninety one total knee arthroplasties in 84 patients (45 Insall-Burstein II and 46 NexGen Legacy posterior stabilized [both from Zimmer, Warsaw, Ind] prostheses) with an average of 10.3 years of follow-up (range, 9-11.8 years) were included. The preoperative diagnoses were primary osteoarthritis in all patients. At the latest evaluation, there were no significant differences detected in the mean clinical and functional knee scores, average postoperative active range of motion, and anterior knee pain between the Insall-Burstein II and the NexGen Legacy groups postoperatively. PMID- 21295942 TI - Traumatic events and obsessive compulsive disorder in children and adolescents: is there a link? AB - BACKGROUND: The extant literature supports an association between psychological trauma and development of OCD in adults, and this link is a plausible mediator for environment-gene interactions leading to phenotypic expression of OCD. OBJECTIVE: To explore the relationship between OCD and traumatic life events in children and adolescents. METHODS: We examined the prevalence of traumatic life events and PTSD in a large sample of systematically assessed children with OCD. OCD symptoms and severity were assessed using the Children's Yale Brown Obsessive Compulsive Scale (CY-BOCS) in those with and without concurrent PTSD. RESULTS: Rate of PTSD and trauma exposure was higher in children with OCD than in a comparable control group of non-OCD youth matched for age, gender and SES. Children with concurrent PTSD had more intrusive fears and distress and less control over their rituals than children with OCD but without PTSD. Total CY-BOCS scores were higher in those with concurrent PTSD. Specific type of OCD symptoms was not altered by a PTSD diagnosis. CONCLUSIONS: A history of psychologically traumatic events may be over-represented in children with OCD. Given the need to search for non-genetic factors that may lead to onset of OCD, better and more systematic methods to obtain and quantify psychologically traumatic life events are needed in clinical populations. PMID- 21295943 TI - Study healthy ageing and intellectual disabilities: recruitment and design. AB - Problems encountered in epidemiologic health research in older adults with intellectual disabilities (ID) are how to recruit a large-scale sample of participants and how to measure a range of health variables in such a group. This cross-sectional study into healthy ageing started with founding a consort of three large care providers with a total client population of 2322 clients of 50 years and over, and two academic institutes. This consort made formal agreements about a research infrastructure and research themes: (1) physical activity and fitness, (2) nutrition and nutritional state, and (3) mood and anxiety. Subsequently, preparation was started by carefully reviewing and selecting instruments to measure a wide set of health variables to answer the research questions. Specific demands of these instruments were that they could be executed efficiently and accurately on-site in a large sample of participants and that the burden of these measurements for participants as well as their caregivers was as minimal as possible. Then, preparation was continued by designing and executing a thorough communication plan for clients, legal representatives and staff of the care providers, preceding the informed consent procedure. In this plan, which had a top-down structure, specific attention was given to personally informing and motivating of key stakeholders: the professional care givers. This preparation led to a recruitment of 1050 participants (45.2%) and to high participation rates in key parts of the assessment. A detailed description is provided about the recruitment and organization and the selected instruments. PMID- 21295944 TI - Practicalities of nutrition support in the intensive care unit: the usefulness of gastric residual volume and prokinetic agents with enteral nutrition. AB - The provision of early nutrition therapy to critically ill patients is established as the standard of care in most intensive care units around the world. Despite the known benefits, tolerance of enteral nutrition in the critically ill varies and delivery is often interrupted. Observational research has demonstrated that clinicians deliver little more than half of the enteral nutrition they plan to provide. The main clinical tool for assessing gastric tolerance is gastric residual volume; however, its usefulness in this setting is debated. There are several strategies employed to improve the tolerance and hence adequacy of enteral nutrition delivery in the critically ill. One of the most widely used strategies is that of prokinetic drug administration, most commonly metoclopramide and erythromycin. Although there are new agents being investigated, none are ready for routine application in the critically ill and the benefits are still being established. This review investigates current practice and considers the literature on assessment of enteral tolerance and optimization of enteral nutrition in the critically ill. PMID- 21295945 TI - Effect of micellar lipids, dietary fiber and beta-carotene on lutein bioavailability in aged rats with lutein deficiency. AB - OBJECTIVE: To determine the effect of various dietary components on the intestinal uptake of lutein in aged rats. METHODS: This study determined the time course (2, 4, 6, 8 h) plasma and tissue responses of a pharmacologic dose of lutein (200 MUM) solubilized in mixed micelles with fat (3%, soybean oil), phosphatidylcholine (PC; 3 mM), lysophosphatidylcholine (lysoPC; 3 mM), dietary fiber (pectin, 1.25%), beta-carotene (200 MUM), or micelles with no dietary components (control) in aged rats with lutein deficiency. RESULTS: No lutein was detected in the plasma of rats at 0 h indicating the deficiency. After gavages of lutein, the mean percent area under the curve (picomoles per milliliter per 8 h) of plasma lutein in the fat (91.4), PC (218.0), and lysoPC (94.1) groups were higher (P > 0.05), whereas its level in the dietary fiber and beta-carotene groups was lower than the control group. The liver and eye lutein levels of the PC (95.4, 38.67%) and fat (18.2, 143%) groups were significantly higher, whereas the lysoPC (9.6, 27.2%), beta-carotene (19.2, 35.4%), and dietary fiber (3.1, 88.4%) groups were lower than the control group. CONCLUSION: Results indicate that soybean oil and soy phospholipids greatly sway lutein absorption in aged rats with lutein deficiency. The results also suggest that ingestion of lutein with pectin and beta-carotene suppresses lutein absorption. Hence, to improve the absorption of lutein in older adults with macular pigment deficiency, foods with sufficient fat with low dietary fiber and beta-carotene may be suggested. PMID- 21295946 TI - Nutritional compounds influence tissue factor expression and inflammation of chronic kidney disease patients in vitro. AB - OBJECTIVE: Nutritional compounds that potentially limit inflammation and tissue factor expression may decrease the progression of chronic kidney disease (CKD) and associated cardiovascular disease. This project aimed to determine the effect of curcumin, bovine colostrum, and fish oil on inflammatory cytokine and tissue factor procoagulant activity of peripheral blood mononuclear cells (PBMCs) from patients with CKD before dialysis. METHODS: Peripheral blood mononuclear cells from patients with CKD before dialysis (n = 13) and age- and sex-matched healthy controls (n = 12) were cultured alone and with low and high doses of the nutritional compounds for 24 h. Cells were cultured with and without lipopolysaccharide. Supernatants were analyzed for tumor necrosis factor-alpha, interleukin (IL)-6, IL-8, monocyte chemoattractant protein-1, IL-1beta, C reactive protein, and tissue factor procoagulant activity. RESULTS: The production of C-reactive protein, monocyte chemoattractant protein-1, IL-6, and IL-1beta by PBMCs was inhibited by low- and high-dose fish oil in the CKD group (P < 0.05). Curcumin decreased secretion of IL-6 (P = 0.015) and IL-1 beta (P = 0.016). Curcumin was more effective than colostrum at decreasing the procoagulant activity of PBMCs in the CKD and control groups (P < 0.019). CONCLUSION: Fish oil decreased inflammatory cytokine secretion from CKD PBMCs. In addition, the beneficial effects of curcumin were demonstrated in decreasing inflammation in vitro, often to a similar magnitude as fish oil. PMID- 21295947 TI - The comprehensive assessment of at-risk mental states: from mapping the onset to mapping the structure. AB - BACKGROUND: Improving the identification of clinical vulnerability to psychosis in help-seeking subjects is crucial for refining risk stratifications and implementing intervention strategies. AIMS: To define underlying dimensions of subclinical psychopathology in Ultra-High-Risk (UHR) subjects; to test their temporal stability and association with baseline clinical and functional features; and to evaluate their predictive value for subsequent transition to psychosis. METHOD: 223 subjects meeting the Personal Assessment and Crisis Evaluation (PACE) criteria for UHR were assessed with the Comprehensive Assessment of At-Risk Mental States (CAARMS) and monitored for a period of up to three years. Data were analysed via principal component analysis (PCA), Spearman correlation analysis and Cox regression. RESULTS: PCA of the CAARMS yielded three orthogonal symptom clusters (negative, disorganized and perceptual-affective instability) with substantial temporal stability over a one-month time span. These clusters were strongly related to global functioning, quality of life, baseline major psychopathology and duration of symptoms before referral. The severity of the CAARMS disorganized component was the strongest predictor of transition to frank psychosis at follow-up. CONCLUSIONS: A dimensional approach to CAARMS-measured symptoms may refine current early identification heuristics and provide an alternative way to characterize UHR profiles complementary to the current categorical one. PMID- 21295948 TI - A common variant of the cardiomyopathy associated 5 gene (CMYA5) is associated with schizophrenia in Chinese population. PMID- 21295949 TI - Prevalence and phenotypic characterisation of carbapenem resistance in Enterobacteriaceae bloodstream isolates in a tertiary care hospital in India. PMID- 21295950 TI - Class 1 integrons and virulence genes in Salmonella enterica isolates from pork and humans. AB - In this study, 183 Salmonella enterica isolates were characterised for integrons and virulence genes. Among the isolates, 46% were positive for intI1, but no isolates carried intI2 or intI3. Eighteen class 1 integrons (21%) contained resistance gene cassettes (i.e. dfrA1-orfC, dfrA12-aadA2, bla(PSE-1) and aadA2) and five class 1 integrons with the dfrA12-aadA2 array were conjugally transferable. Two Salmonella pork isolates of serotypes Albany and Kedougou possessed Salmonella genomic island 1 variants SGI1-G and SGI1-F, respectively. Four class 1 integrons contained an atypical 3'-CS linked to the qacH-sul3 domain, and three were not a sul type. Two novel GyrA mutations (Pro-45->Ser and Met-48->Ile) and three novel ParC mutations (Ser-5->Arg, Thr-31->Met and Leu-77 >Arg) were identified in ciprofloxacin-resistant isolates. At least 90% of the Salmonella isolates contained pagC, prgH, sitC, sipB or spaN, whereas all isolates harboured invA, msgA, spiA and tolC. PMID- 21295951 TI - Susceptibility patterns of coagulase-negative staphylococci to several newer antimicrobial agents in comparison with vancomycin and oxacillin. AB - Coagulase-negative staphylococci (CoNS) have emerged as important nosocomial pathogens. CoNS resistance to meticillin and other semisynthetic penicillins is now common. Elevated vancomycin minimal inhibitory concentrations (MICs) have been reported and are associated with worse treatment outcomes. Several newer antibiotics have recently become available for the treatment of Gram-positive infections. The purpose of this study was to assess the in vitro activity of telavancin, daptomycin, linezolid and tigecycline in comparison with oxacillin and vancomycin against 653 non-duplicate clinical isolates of CoNS by the agar dilution method. The greatest variability in MIC was observed for oxacillin. Presence of the mecA gene conferred higher MICs for oxacillin but did not influence MICs to all other antibiotics tested. Telavancin tended to have MICs that were 1-2 dilutions lower than vancomycin. Daptomycin had good activity against all isolates. Staphylococcus haemolyticus, Staphylococcus hominis subsp. novobiosepticus, Staphylococcus saprophyticus, Staphylococcus schleiferi and Staphylococcus simulans were the most daptomycin-susceptible CoNS species tested. The validity of the agar dilution method for daptomycin was confirmed, with >90% isolates having MICs that were within 1 dilution of parallel Etest results. Within-species MIC variation was most restricted for linezolid and tigecycline, with the exception of Staphylococcus epidermidis and Staphylococcus haemolyticus that demonstrated higher overall MICs to tigecycline. PMID- 21295952 TI - The ferritin-like protein Dps protects Salmonella enterica serotype Enteritidis from the Fenton-mediated killing mechanism of bactericidal antibiotics. AB - Dps is a ferritin-like protein with DNA-binding properties that is capable of affording protection during oxidative stress and during times of nutritional deprivation. Here we present evidence that in exponentially growing Salmonella enterica serotype Enteritidis, Dps is vital for protection against the common killing mechanism of bactericidal antibiotics, a mechanism manifested by hydroxyl radical production via the Fenton reaction. A dps deletion mutant ('dps mutant') was hypersensitive to the bactericidal antibiotics streptomycin, nalidixic acid, norfloxacin and rifampicin compared with its parental strain. However, the observed discrepancy in survivability between the dps mutant and the parental strain following exposure to bactericidal antibiotics was fully alleviated when drug-exposed cultures were treated with an iron chelator, confirming that Fenton mediated oxidative stress was a major factor in the reduced survival rate of the dps mutant. In addition, deletion of the DNA damage-induced repair protein RecA further intensified the killing capacity of bactericidal antibiotics in a Deltadps (i.e. dps deletion) background, implying that Dps and RecA may operate in a synergistic manner to protect against the common killing mechanism of bactericidal antibiotics. The relevance of this work is demonstrated by the need for new and increasingly effective bactericidal therapies. Targeting Dps may represent a means to increase the potency of bactericidal antibiotics in S. enterica and other bacterial pathogens alike. PMID- 21295953 TI - Dystrobrevin-binding protein 1 gene (DTNBP1) variants associated with cerebrospinal fluid homovanillic acid and 5-hydroxyindoleacetic acid concentrations in healthy volunteers. AB - The dystrobrevin binding protein-1 (DTNBP1) gene encodes dysbindin-1, a protein involved in neurodevelopmental and neurochemical processes related mainly to the monoamine dopamine. We investigated possible associations between eleven DTNBP1 polymorphisms and cerebrospinal fluid (CSF) concentrations of the major dopamine metabolite homovanillic acid (HVA), the major serotonin metabolite 5 hydroxyindoleacetic acid (5-HIAA), and the major noradrenaline metabolite 3 methoxy-4-hydroxyphenylglycol (MHPG) in healthy human subjects (n=132). Two polymorphisms, rs2619538 and rs760666, were nominally associated with CSF HVA and 5-HIAA concentrations, whereas a third polymorphism, rs909706, showed association only with HVA. After correction for multiple testing only the associations between rs2619538 and HVA and 5-HIAA concentrations remained significant. No significant association was found between any of the investigated DTNBP1 polymorphisms and CSF MHPG concentrations. The results suggest that genetic variation in DTNBP1 gene affects the regulation of dopamine and serotonin turnover in the central nervous system of healthy volunteers. PMID- 21295954 TI - Polymers of 2-methacryloyloxyethyl phosphorylcholine truly work as cell membrane mimic? AB - We have prepared several types of polymers derived from 2-methacryloyloxyethyl phosphorylcholine (MPC) to evaluate whether polymers of MPC work as cell membrane mimic or not. We firstly applied capturing test of target proteins of 4 carboxybenzenesulfonamide (Sul) or ibuprofen (Ibu) as a probe. As the results, the rather hydrophilic polymers based on MPC were able to suppress non-specific binding proteins as expected. Additionally, some of the MPC based polymeric surface was able to capture greater amount of carbonic anhydrase II than those of other polymers, when Sul was utilized as probe. In contrary, all the polymers having PC groups and Ibu probe were unable to capture Cyclooxygenase-1 (COX-1), its target protein. These results suggested that the position of PC groups realized hydrophilic polymer surface, while MPC based polymer was not able to supply the suitable environment for COX-1 to interact with Ibu. PMID- 21295955 TI - The complexation mode of metal ions with Langmuir monolayers of nitrogen containing flavonoid glycoside-based surfactants derived from rutin. AB - The molecular recognition activities of flavonoid derivatives toward other guest molecules have been the focus of interest recently. This study reports the metal complexation behavior of nitrogen-containing rutin (RuCn) in the organized Langmuir films. Three model compounds with different lipid chain lengths (n=8, 12 and 18) were designed and synthesized. The monolayer structures and metal-binding activities of RuCn were studied by the monolayer technology, FT-IR spectroscope and thermodynamic calculations (experimentally and theoretically). Results showed that hard Lewis acid-type metal cations, such as Na(I), K(I), Ca(II) and Fe(III), and soft metal cations, such as Cu(II), exhibited clearly different binding activities to RuCn monolayers. The sequence of the effects of metal ions on the monolayer properties and thermodynamic stability varies in the order: univalent ions < pure water < bivalent ions ~ tervalent ions. Importantly, the typical binding mode (including the binding site and coordination number) of Cu(II) and Fe(III) with RuCn at the interface was clarified. All evidences implied that two primary molecular configurations in the form of O-M-O and O-M-N linkage (M represents Cu or Fe) could account for the unusual structure-property relationship of RuCn monolayers at the air-electrolyte interfaces. These results provided a theoretical basis for the practical applications of such metal complexes as antimicrobials or anticancer drugs in the molecular level. PMID- 21295956 TI - Strategies to counteract MHC-I defects in tumors. AB - Defects in MHC-I antigen presentation represent a common feature of cancer and allow evasion from T cell recognition. Recent findings from immunotherapy in melanoma suggested that irreversible MHC-I defects enable escape from immune pressure. Although loss of antigen presentation is known for many years, strategies to counteract these defects are scarce and largely unexamined. Now that the first forms of T-cell-based immunotherapy show clinical efficacy and reach FDA approval, this issue deserves urgent awareness. Here we describe possible roads leading to corrections of MHC-I defects in tumors and describe a salvage pathway for CTL by targeting novel tumor antigens that we recently uncovered. PMID- 21295957 TI - Leukocytosis is a risk factor for lung function deterioration in children with sickle cell disease. AB - BACKGROUND: The decline in lung volumes associated with sickle cell disease (SCD) may begin in childhood. Risk factors for early restrictive lung disease may include SCD severity markers such as leukocytosis. OBJECTIVE: We examined the relationship between early alteration of lung function and extra-pulmonary markers of SCD severity. METHODS: We analyzed pulmonary function test results for 184 SCD children (mean age 12.6 y) enrolled in a pediatric cohort. MAIN RESULTS: Total lung capacity (TLC) and vital capacity (VC) were not associated with a history of acute chest syndrome. Lower TLC values were significantly associated with three independent factors: older age, previous acute episodes of anemia <6 g/dl, and higher baseline white blood cell counts. Only the baseline WBC count and age were independent risk factors for lower VC. Relative risks to have a TLC or a VC lower than the mediane value in our population were significantly associated to the baseline leukocytosis (per 10(9) G/L), after adjustment on age, sex, genotype, baseline Hb, and treatment (RR (95% CI) =1.16 (1.04-1.29) p<0.009, and 1.17 (1.06-1.29) p<0.002, respectively). The obstructive pattern, defined by FEV1/FVC ratio, was not significantly associated to biological parameters. CONCLUSIONS: Hemolysis and leukocytosis were independent risk factors for an early decline in lung volumes in this pediatric SCD cohort. PMID- 21295958 TI - Lower limit of normal or FEV1/FVC < 0.70 in diagnosing COPD: an evidence-based review. AB - AIM: To review the currently available literature comparing the FEV1/FVC 40 years. METHODS: A structured MEDLINE, EMBASE and Cochrane search of English-language literature was conducted. Studies comparing prevalence rates according to the LLN and a fixed value were included. Attention was paid to the choice of the reference test or gold standard used. RESULTS: Eighteen studies met the inclusion criteria. Sixteen studies compared the rates of subjects diagnosed with airflow obstruction by either definition of airflow obstruction without using a non-independent reference standard (level 4 studies). Using a fixed value of FEV1/FVC, an overall higher number of subjects were diagnosed with airflow obstruction that increased with age. Two studies included a follow-up phase comparing risks of either hospitalization or occurrence of respiratory symptoms and mortality (level 2b studies). Adjusted risks of hospitalization (HR 2.6) or mortality (HR 1.3) were significantly larger in subjects with an FEV1/FVC below 0.70 but above the LLN (in-between group) compared to subjects with normal lung function. CONCLUSION: The prevalence of spirometry-based COPD is greater when using the fixed value of FEV1/FVC in comparison to using the LLN. Based on one longitudinal study the in-between group appears to have a higher risk of hospitalization and mortality; therefore it seems that using the LLN of FEV1/FVC underestimates COPD. In absence of a gold standard of COPD longitudinal research will be necessary to determine which criterion is better and more clinically relevant. PMID- 21295959 TI - Proadipogenic effects of lactoferrin in human subcutaneous and visceral preadipocytes. AB - Lactoferrin has been associated with insulin sensitivity in vivo and in vitro studies. We aimed to test the effects of lactoferrin on human subcutaneous and visceral preadipocytes. Human subcutaneous and visceral preadipocytes were cultured with increasing lactoferrin (hLf, 0.1, 1, 10 MUM) under differentiation conditions. The effects of lactoferrin on adipogenesis were studied through the expression of different adipogenic and inflammatory markers, AMPK activation and Retinoblastoma 1 (RB1) activity. The response to insulin was evaluated through (Ser473)AKT phosphorylation. In both subcutaneous and visceral preadipocytes, lactoferrin (1 and 10 MUM) increased adipogenic gene expressions and protein levels (fatty acid synthase, PPARgamma, FABP4, ADIPOQ, ACC and STAMP2) and decreased inflammatory markers (IL8, IL6 and MCP1) dose-dependently in parallel to increased insulin-induced (Ser473)AKT phosphorylation. In addition to these adipogenic effects, lactoferrin decreased significantly AMPK activity (reducing (pThr172)AMPK and (pSer79)ACC) and RB1 activity (increasing the (pser807/811)RB1/RB1 ratio). In conclusion, these results suggest that lactoferrin promotes adipogenesis in human adipocytes by enhancing insulin signaling and inhibiting RB1 and AMPK activities. PMID- 21295960 TI - Resveratrol improves cognitive function in mice by increasing production of insulin-like growth factor-I in the hippocampus. AB - We examined whether resveratrol increases insulin-like growth factor-I (IGF-I) production in the hippocampus by stimulating sensory neurons in the gastrointestinal tract, thereby improving cognitive function in mice. Resveratrol increased calcitonin gene-related peptide (CGRP) release from dorsal root ganglion (DRG) neurons isolated from wild-type (WT) mice. Increases in tissue levels of CGRP, IGF-I, and IGF-I mRNA and immunohistochemical expression of IGF-I were observed in the hippocampus at 3 weeks after oral administration of resveratrol in WT mice. Significant enhancement of angiogenesis and neurogenesis was observed in the dentate gyrus of the hippocampus in these animals (P<.01). Improvement of spatial learning in the Morris water maze was observed in WT mice after administration of resveratrol. None of the effects of resveratrol observed in WT mice were seen after resveratrol administration in CGRP-knockout (CGRP(-/ )) mice. Although red wine containing 20 mg/L of resveratrol produced effects similar to those of resveratrol administrationl in WT mice, neither red wine containing 3.1 mg/L of resveratrol nor white wine exhibited such effects in WT mice. Resveratrol was undetectable in the hippocampus of WT mice administered resveratrol and red wine containing 20 mg/L of resveratrol. These observations strongly suggest that resveratrol increases hippocampal IGF-I production via sensory neuron stimulation in the gastrointestinal tract, thereby improving cognitive function in mice. PMID- 21295961 TI - Suppression of intestinal inflammation and inflammation-driven colon cancer in mice by dietary sphingomyelin: importance of peroxisome proliferator-activated receptor gamma expression. AB - Inflammation of the gastrointestinal tract increases the risk of developing colon cancer especially in younger adults. Dietary compounds are not only associated with the etiology of inflammation and colon cancer but also in their prevention. Sphingolipid metabolites have been shown to play a role in the initiation and perpetuation of inflammatory responses. In the present study, we investigated the suppression of dextran sodium sulfate-induced colitis and azoxymethane-induced colon cancer by dietary sphingomyelin (SM) in mice that lack functional peroxisome proliferator-activated receptor gamma (PPAR-gamma) in intestinal epithelial and immune cells. Dietary SM decreased disease activity and colonic inflammatory lesions in mice of both genotypes but more efficiently in mice expressing PPAR-gamma. The increased survival and suppression of tumor formation in the SM-fed mice appeared to be independent of PPAR-gamma expression in immune and epithelial cells. Using a real-time polymerase chain reaction array, we detected an up-regulation in genes involved in Th1 (interferon gamma) and Th17 (interleukin [IL]-17 and IL-23) responses despite the reduced inflammation scores. However, the genes involved in Th2 (IL-4, IL-13 and IL-13ra2) and Treg (IL-10rb) anti-inflammatory responses were up-regulated in a PPAR-gamma-dependent manner. In line with the PPAR-gamma dependency of our in vivo findings, treatment of RAW macrophages with sphingosine increased the PPAR-gamma reporter activity. In conclusion, dietary SM modulated inflammatory responses at the early stages of the disease by activating PPAR-gamma, but its anticarcinogenic effects followed a PPAR-gamma-independent pattern. PMID- 21295963 TI - An olfactory bulb slice-based biosensor for multi-site extracellular recording of neural networks. AB - Multi-site recording is the important component for studies of the neural networks. In order to investigate the electrophysiological properties of the olfactory bulb neural networks, we developed a novel slice-based biosensor for synchronous measurement with multi-sites. In the present study, the horizontal olfactory bulb slices with legible layered structures were prepared as the sensing element to construct a tissue-based biosensor with the microelectrode array. This olfactory bulb slice-based biosensor was used to simultaneously record the extracellular potentials from multi-positions. Spike detection and cross-correlation analysis were applied to evaluate the electrophysiological activities. The spontaneous potentials as well as the induced responses by glutamic acid took on different electrophysiological characteristics and firing patterns at the different sites of the olfactory bulb slice. This slice-based biosensor can realize multi-site synchronous monitoring and is advantageous for searching after the firing patterns and synaptic connections in the olfactory bulb neural networks. It is also helpful for further probing into olfactory information encoding of the olfactory neural networks. PMID- 21295964 TI - Recent progress and continuing challenges in bio-fuel cells. Part I: enzymatic cells. AB - Recent developments in bio-fuel cell technology are reviewed. A general introduction to bio-fuel cells, including their operating principles and applications, is provided. New materials and methods for the immobilisation of enzymes and mediators on electrodes, including the use of nanostructured electrodes are considered. Fuel, mediator and enzyme materials (anode and cathode), as well as cell configurations are discussed. A detailed summary of recently developed enzymatic fuel cell systems, including performance measurements, is conveniently provided in tabular form. The current scientific and engineering challenges involved in developing practical bio-fuel cell systems are described, with particular emphasis on a fundamental understanding of the reaction environment, the performance and stability requirements, modularity and scalability. In a companion review (Part II), new developments in microbial fuel cell technologies are reviewed in the context of fuel sources, electron transfer mechanisms, anode materials and enhanced O(2) reduction. PMID- 21295965 TI - Ultrasensitive biosensing on the zepto-molar level. AB - Detection of analytes on the zepto-molar (10(-21) M) level has been achieved using a field-effect bio-detector. By applying a gating voltage to enzymes immobilized on the working electrode of the detector, amplification of the biocatalytic current was observed. The amplification is attributed to the modification of the tunnel barrier between the enzyme and the electrode by the gating voltage-induced electric field which exists at the solution-electrode interface. The detection was demonstrated with the glucose oxidase (GOx)-glucose and alcohol dehydrogenase (ADH)-ethanol biocatalytic systems. Glucose at zepto molar level was detected with zepto-molar detection resolution. Equivalently, 30 glucose molecules present in the sample were detected and the detection system responded distinctively to the incremental change in the number of glucose molecules in unit of 30 molecules. The enzyme's biospecificity was also preserved in the presence of the applied field. We present possible processes that could give rise to the electrical charges required to produce the observed current level. PMID- 21295962 TI - Implications of cancer stem cell theory for cancer chemoprevention by natural dietary compounds. AB - The emergence of cancer stem cell theory has profound implications for cancer chemoprevention and therapy. Cancer stem cells give rise to the tumor bulk through continuous self-renewal and differentiation. Understanding the mechanisms that regulate self-renewal is of greatest importance for discovery of anticancer drugs targeting cancer stem cells. Naturally occurring dietary compounds have received increasing attention in cancer chemoprevention. The anticancer effects of many dietary components have been reported for both in vitro and in vivo studies. Recently, a number of studies have found that several dietary compounds can directly or indirectly affect cancer stem cell self-renewal pathways. Herein we review the current knowledge of most common natural dietary compounds for their impact on self-renewal pathways and potential effect against cancer stem cells. Three pathways (Wnt/beta-catenin, Hedgehog and Notch) are summarized for their functions in self-renewal of cancer stem cells. The dietary compounds, including curcumin, sulforaphane, soy isoflavone, epigallocatechin-3-gallate, resveratrol, lycopene, piperine and vitamin D(3), are discussed for their direct or indirect effect on these self-renewal pathways. Curcumin and piperine have been demonstrated to target breast cancer stem cells. Sulforaphane has been reported to inhibit pancreatic tumor-initiating cells and breast cancer stem cells. These studies provide a basis for preclinical and clinical evaluation of dietary compounds for chemoprevention of cancer stem cells. This may enable us to discover more preventive strategies for cancer management by reducing cancer resistance and recurrence and improving patient survival. PMID- 21295966 TI - Neuregulin signaling, cortical circuitry development and schizophrenia. AB - Neuregulin-1 (Nrg1) and its receptor ErbB4 are encoded by genes that have been repeatedly linked to schizophrenia. Both genes are thought to play important roles in the development of brain circuitry, but their precise contribution to the disease process remains unknown. In this review, we summarize novel findings on the biological function of Nrg1 and ErbB4 in mice, with a focus on the development of inhibitory circuits in the cerebral cortex. We will also discuss how this basic knowledge may help us to understand the etiology of schizophrenia, and eventually lead to the development of novel therapies for treating the disorder. PMID- 21295967 TI - Cost-effective production of Bacillus thuringiensis biopesticides by solid-state fermentation using wastewater sludge: effects of heavy metals. AB - This study demonstrated the feasibility to produce Bacillus thuringiensis subsp. kurstaki (Btk) based biopesticides using wastewater sludge as raw materials under solid-state fermentation (SSF). More than 10(10) CFU/g viable cells of Btk were obtained using sludge or its mixture with agricultural wastes. This study well considered the effect of heavy metals on Btk growth and their changes of chemical speciation caused by SSF. The IC(50) (concentration causing 50% inhibition in total cell biomass) for Pb(II), Cu(II), Cd(II) and Cr(III) on Btk were determined to be 227, 82, 15 and 263 mg/L, respectively. Exposure to 150 mg/L of Cu(II) severely reduced the amount and size of toxin crystals, which decreased the endotoxin synthesis and entomotoxicity potency of Btk cells. Using Tessier's sequential extraction procedure, the exchangeable heavy metals in sludge were shown to be transformed into residual fractions after SSF, and thus significantly reduced their bioavailability and potential environmental risks. PMID- 21295968 TI - Vertical tubular photobioreactor for semicontinuous culture of Cyanobium sp. AB - We evaluated the kinetic culture characteristics of the microalgae Cyanobium sp. grown in vertical tubular photobioreactor in semicontinuous mode. Cultivation was carried out in vertical tubular photobioreactor for 2 L, in 57 d, at 30 degrees C, 3200 Lux, and 12 h light/dark photoperiod. The maximum specific growth rate was found as 0.127 d(-1), when the culture had blend concentration of 1.0 g L( 1), renewal rate of 50%, and sodium bicarbonate concentration of 1.0 g L(-1). The maximum values of productivity (0.071 g L(-1) d(-1)) and number of cycles (10) were observed in blend concentration of 1.0 g L(-1), renewal rate of 30%, and bicarbonate concentration of 1.0 g L(-1). The results showed the potential of semicontinuous cultivation of Cyanobium sp. in closed tubular bioreactor, combining factors such as blend concentration, renewal rate, and sodium bicarbonate concentration. PMID- 21295969 TI - Power overshoot in two-chambered microbial fuel cell (MFC). AB - A two-chamber microbial fuel cell was started using iron-reducing strains as inoculum and acetate as carbon sources. The tested microbial fuel cell had an open-circuit voltage of 0.67 V, and reached 1045 mA m(-2) and a power density of 486 mW m(-2) at 0.46 V before power overshoot occurred. Anodic reactions were identified as the rate-determining steps. Stirring the anolyte insignificantly increased cell performance, suggesting a minimal external mass transfer resistance from the anolyte to the anodic biofilm. Data regression analysis indicates that charge transfer resistance at the biofilm-anode junction was negligible. The order of magnitude estimation of electrical conductance indicates that electron transfer resistance had an insignificant effect on microbial fuel cell performance. Resistance in electrogens for substrate utilization is proposed to induce microbial fuel cell power overshoot. PMID- 21295970 TI - The effect of calcium on the treatment of fresh leachate in an expanded granular sludge bed bioreactor. AB - This research investigated the calcium effect on the anaerobic treatment of fresh leachate in an expanded granular sludge bed (EGSB) bioreactor under mesophilic conditions. The observations show that the bioreactor, inoculated with anaerobic granular sludge, can be started up only in about 40 days for the treatment of calcium-containing fresh leachate with chemical oxygen demand (COD) removal efficiency above 90% and organic loading rate up to 72.84 kg COD/m(3) day. The calcium accumulation onto the granules was monotonically related to the calcium concentration, accounting for 17-18 wt.% of Ca in the suspended solid in the form of calcium carbonate, phosphates/phosphonates and carboxylates. The mineral formation significantly increased the granule settling velocity (by ~ 50%) and the suspended solid concentration (by ~ 100%). However, the effect of calcium precipitation on the specific methanogenic activity and the CH(4) production rate was complex, first positive during the start-up but later on negative. PMID- 21295971 TI - Assessments of critical flux in a pilot-scale membrane bioreactor. AB - In this study, the influence of various parameters such as determination methods and step height and length of incremental flux on critical flux values were investigated. Experiments were carried out on a pilot-scale membrane bioreactor (MBR) treated municipal wastewater. Three of the five critical flux determination methods, such as flux linearity, 90% permeability and flux cycling conducted in this study, indicated a decline in critical flux values as the step height of incremental flux increased. However, the hysteresis method and the two-third (2/3) flux limitation method showed an increase and independence of critical flux to the step height of incremental flux, respectively. On the other hand, the step length of incremental flux had no obvious effect on critical flux values evaluated by all critical flux determination methods. Like critical flux, sustainable flux has negative relationship with the increase of step height but no influence of step length was found in this study. PMID- 21295972 TI - Equilibrium of Cu(II) and Ni(II) biosorption by marine alga Sargassum filipendula in a dynamic system: competitiveness and selectivity. AB - The study focuses on the equilibrium of dynamic biosorption in single and binary systems containing Cu(II) and Ni(II) ions using Sargassum filipendula (a marine alga). The experiments were performed in fixed-bed columns with both single component and bi-component metal solutions (using different molar concentrations). Experimental data were fitted with different equilibrium models such as Langmuir, Langmuir with inhibition, Jain and Snowyink and Langmuir Freundlich equations. The biosorption of pure metal ions in solution presented adequate capacities both for Cu(II) and Ni(II). In binary solutions the preferential sorption of Cu(II) over Ni(II) was demonstrated by the displacement of Ni(II) (marked overshoot on the breakthrough curves). PMID- 21295973 TI - Nitrogen removal from wastewater with a low COD/N ratio at a low oxygen concentration. AB - The goal of the study was to determine the effectiveness of nitrification and denitrification and the kinetics of ammonia removal from a mixture of wastewater and anaerobic sludge digester supernatant in an SBR at limited oxygen concentration. In addition, the COD removal efficiency and sludge production were assessed. In the SBR cycle alternating aerobic and anaerobic phases occurred; in the aeration phase the dissolved oxygen (DO) concentration was below 0.7 mg O(2)/L. The low DO concentration did not inhibit ammonia oxidation-nitrification and the efficiency was ca. 96-98%. However, a relatively high COD concentration in the effluent was detected. The values of K(m) and V(max), calculated from the Michaelis-Menten equation, were 43 mg N-NH(4)/L and 15.64 mg N-NH(4)/L h, respectively. Activated sludge production was almost stable (0.62-0.66 g MLVSS/g COD). A high net biomass production resulted from a low specific biomass decay rate of 0.0015 d(-1). PMID- 21295974 TI - Depolymerization of steam-treated lignin for the production of green chemicals. AB - In this short communication, lignin produced by steam processing of agricultural (hemp) and forestry (softwood) was depolymerised via a base catalysis to produce a combination of monomers, dimers, trimers and residual char. The lignin broth produced directly after the base-catalysed steam treatment was treated under pressure (from 1300 to 1900 psi) at temperatures varying from 300 to 330 degrees C in a custom-made batch reactor. The lignin concentration in the aqueous base solution was 10 wt% whilst the NaOH concentration was 5 wt%. Identification of 26 compounds has been done: 17 compounds were common to the two feedstocks while the remaining 9 were specific to each feedstock used. PMID- 21295975 TI - Diversity of aromatic ring-hydroxylating dioxygenase gene in Citrobacter. AB - Genetic and functional diversity of Citrobacter spp. for their abilities to degrade aromatic compounds was evaluated to develop mixed cultures or a consortium for bioremediation technology. Thirty Citrobacter strains isolated from various effluent treatment plants were found to degrade a range of aromatic compounds: phenol, benzoate, hydroxy benzoic acid and biotransform mono chlorophenols and di-chlorophenol within 24 to 48 h of incubation at 30 degrees C. Sequence similarity and phylogeny of the ARHD gene transcripts (730 nucleotides) depicted their diversity within 9 Citrobacter strains: HPC255, HPC369, HPC560, HPC570, HPC784, HPC1196, HPC1216, HPC1276 and HPC1299. Here, the degree of associations varied up to 84% with (i) ARHD alpha-sub unit (SU), (ii) LSU of Phenylpropionate dioxygenase (PDO), (iii) Phenol hydroxylase alpha-SU, (iv) Benzoate 1,2-dioxygenase, alpha-SU, (v) Naphthalene dioxygenase LSU, etc. This study has provided basic information, which can be used to develop a consortium of bacteria with mutually beneficial characteristics. PMID- 21295976 TI - Catalytic hydrothermal processing of microalgae: decomposition and upgrading of lipids. AB - Hydrothermal processing of high lipid feedstock such as microalgae is an alternative method of oil extraction which has obvious benefits for high moisture containing biomass. A range of microalgae and lipids extracted from terrestrial oil seed have been processed at 350 degrees C, at pressures of 150-200 bar in water. Hydrothermal liquefaction is shown to convert the triglycerides to fatty acids and alkanes in the presence of certain heterogeneous catalysts. This investigation has compared the composition of lipids and free fatty acids from solvent extraction to those from hydrothermal processing. The initial decomposition products include free fatty acids and glycerol, and the potential for de-oxygenation using heterogeneous catalysts has been investigated. The results indicate that the bio-crude yields from the liquefaction of microalgae were increased slightly with the use of heterogeneous catalysts but the higher heating value (HHV) and the level of de-oxygenation increased, by up to 10%. PMID- 21295977 TI - Kinetic resolution of 2-hydroxybutanoate racemic mixtures by NAD-independent L lactate dehydrogenase. AB - Optically active D-2-hydroxybutanoate is an important building block intermediate for medicines and biodegradable poly(2-hydroxybutanoate). Kinetic resolution of racemic 2-hydroxybutanoate may be a green and desirable alternative for D-2 hydroxybutanoate production. In this work, D-2-hydroxybutanoate at a high concentration (0.197 M) and a high enantiomeric excess (99.1%) was produced by an NAD-independent L-lactate dehydrogenase (L-iLDH) containing biocatalyst. 2 Oxobutanoate, another important intermediate, was co-produced at a high concentration (0.193 M). Using a simple ion exchange process with the macroporous anion exchange resin D301, D-2-hydroxybutanoate was separated from the biotransformation system with a high recovery of 84.7%. PMID- 21295978 TI - Design and synthesis of substituted N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamides as positive allosteric modulators of the metabotropic glutamate receptor subtype 5. AB - Based on SAR in the alkyne class of mGlu5 receptor negative allosteric modulators and a set of amide-based positive allosteric modulators, optimized substitution of the aryl 'b' ring was used to create substituted N-(1,3-diphenyl-1H-pyrazol-5 yl)benzamides. Results from an mGlu5 receptor functional assay, using calcium fluorescence, revealed varying efficacies and potencies that provide evidence that subtle changes in compounds within a close structural class can have marked effects on functional activity including switches in modes of efficacy (i.e., negative to positive allosteric modulation). PMID- 21295979 TI - Trisubstituted ureas as potent and selective mPGES-1 inhibitors. AB - A novel series of trisubstituted ureas has been identified as potent and selective mPGES-1 inhibitors. These compounds are selective over other prostanoid enzymes such as PGF synthase and TX synthase. This series of inhibitors was developed by lead optimization of a hit from an internal HTS campaign. Lead compound 42 is potent in A549 cell assay (IC(50) of 0.34 MUM) and in human whole blood assay (IC(50) of 2.1 MUM). An efficient and versatile one-pot strategy for the formation of ureas, involving a reductive amination, was developed to generate these inhibitors. PMID- 21295980 TI - Synthesis and cytotoxicity of (-)-renieramycin G analogs. AB - (-)-Renieramycin G and fifteen C-22 analogs were prepared employing l-tyrosine as the chiral starting material. These analogs, along with (-)-renieramycin G itself, were evaluated in vitro for cytotoxicity against HCT-8, BEL-7402, A2780, MCF-7, A549, BGC-823, Ketr3, KB, Hela cells. The IC(50) values of most of these analogs were at the level of MUM. Among these analogs, 2-thiophenecarboxylate ester derivative 17 exhibited potent cytotoxic activity against KB cell line with the IC(50) of 20 nM. From this study, it could be concluded that the C-22 side chain played an important role in the cytotoxic potency and specificity of this class of (-)-renieramycin G derivatives. PMID- 21295981 TI - Mosaic caveolin-3 expression in acquired rippling muscle disease without evidence of myasthenia gravis or acetylcholine receptor autoantibodies. AB - Inherited rippling muscle disease is an autosomal dominant disorder usually associated with caveolin-3 mutations. Rare cases of acquired rippling muscle disease with abnormal caveolin-3 localisation have been reported, without primary caveolin-3 mutations and in association with myasthenia gravis and acetylcholine receptor autoantibodies, or thymoma. We present three new patients with electrically-silent muscle rippling and abnormal caveolin-3 localisation, but without acetylcholine receptor autoantibodies, or clinical or electrophysiological evidence of myasthenia gravis. An autoimmune basis for rippling muscle disease is supported by spontaneous recovery and normalisation of caveolin-3 staining in one patient and alleviation of symptoms in response to plasmapheresis and immunosuppression in another. These patients expand the autoimmune rippling muscle disease phenotype, and suggest that autoantibodies to additional unidentified muscle proteins result in autoimmune rippling muscle disease. PMID- 21295982 TI - Autologous fat transplantation in patients with breast cancer: "silencing" or "fueling" cancer recurrence? AB - Lipotransfer can be considered a technical revolution in plastic surgery and widely performed for esthetic surgery. Recently the lipofilling has been indicated in breast reconstruction and deformity correction after breast conservative treatment. However, there is lack of understanding concerning the interactions between the potential tumor beds and the lipoaspirates grafts. Current literature underlines the efficacy of the technique as well as its safety. Nevertheless, many experimental studies provide data on the endocrine, paracrine, and autocrine activities of the transplanted fat tissues. Adipocyte, pre-adipocyte and progenitor cell secretions can stimulate angiogenesis and cell growth. The "tumor-stroma interaction" can potentially induce cancer reappearance by "fueling" dormant breast cancer cells in tumor bed. There is lack of translational research that proves this concern in clinical aspect. No study on the effects of lipotransfer on human cancer breast cells in vivo is available. We provide direct and indirect effects of lipotransfer in breast cancer patients, highlighting pro and con related issues. To confirm the safety of lipotransfer in breast cancer patients we need clinical studies with control group based on long term follow up. PMID- 21295983 TI - Foot and ankle joint kinematics in rheumatoid arthritis cannot only be explained by alteration in walking speed. AB - Rheumatoid arthritis (RA) manifests itself in the foot and ankle of RA patients. The foot and ankle joint kinematics of these patients differ from that of healthy subjects. However, the factors that lead to these differences are not yet fully understood. The aim of this study was to analyse the effect of walking speed and the disease process on foot and ankle joint kinematics of RA subjects. Gait recordings of 23 RA and 14 age-matched healthy subjects were performed and their foot and ankle joint kinematics were analysed during the stance phase of the gait cycle. Stance phase characteristics of the group of RA subjects and of the group of healthy subjects were compared. The healthy subjects walked at 100% (Vc), 75% (V75) and 50% (V50) of their comfortable walking speed. In a multi-level linear model significant differences between the two groups due to the factors walking speed and the disease process were analysed. The ankle dorsi-flexion, medial arch and hallux abduction motion at single-stance and toe-off were only influenced by the walking speed. The hallux maximum flexion at toe-off and the midfoot supination at single-stance were influenced by both the walking speed and the disease process. The hindfoot eversion motion at single-stance was only influenced by the disease process. In conclusion, the reduction of walking speed of RA subjects compared to healthy subjects does not explain all of the observed foot and ankle kinematics differences. PMID- 21295984 TI - A markerless estimation of the ankle-foot complex 2D kinematics during stance. AB - A markerless technique is proposed and applied to estimate the two-dimensional joint kinematics of the shank and foot complex during the stance phase. Image sequences were acquired with a single camera from three healthy subjects while walking barefoot and with socks. Automatic segmentation of the shank and foot was performed to isolate the moving body from the background. A multi-rigid body model for the shank and foot complex, with the relevant segment anatomical axes, was defined and an image cross-correlation technique was applied to detect the anatomical axes locations throughout the movement. The proposed markerless technique was validated by acquiring the same trials also with a stereophotogrammetric marker-based system and a simple marker set. Differences in the joint kinematics estimates obtained with the two techniques fall in most cases within the intra-subject variability showing that, in selected applications, the markerless technique may replace more expensive and more experimental time demanding marker-based techniques. PMID- 21295985 TI - In situ method to determine depth distribution of buried activity. AB - A method is described to determine the depth distribution of buried activity offering an alternative to conventional soil sampling and laboratory analysis by in situ measurements with small detectors inserted into the ground. As a demonstration of the method small-scale variations in the distribution of (137)Cs in a riparian marsh in central-eastern Sweden are determined using lanthanum bromide detectors (LaBr3). The results show variations of the activity ranging between 400 and 2200 kBq/m2 over an area not exceeding 350 m2. The decrease of the average activity since 2003 coincides with the physical decay indicating that no net redistribution of activity into this part of the marsh has occurred during the intervening years. PMID- 21295986 TI - Acquisition of prompt gamma-ray spectra induced by 14 MeV neutrons and comparison with Monte Carlo simulations. AB - Gamma-ray spectra produced in carbon, nitrogen, oxygen, sodium, aluminium, silicon, chlorine, calcium, chromium, iron, nickel, copper, zinc, and lead by 14 MeV tagged neutrons have been collected with NaI(Tl) detectors of the EURITRACK system, which low-energy threshold has been reduced to 0.6 MeV to detect gamma rays of major elements like iron. The spectra have been compared with Monte Carlo simulations to check the tabulated gamma-ray production data. A quantitative approach to subtract the scattered neutron background is also reported. PMID- 21295987 TI - Determination of fast neutron flux distribution in irradiation sites of the Malaysian Nuclear Agency research reactor. AB - Determination of thermal to fast neutron flux ratio (f(fast)) and fast neutron flux (phi(fast)) is required for fast neutron reactions, fast neutron activation analysis, and for correcting interference reactions. The f(fast) and subsequently phi(fast) were determined using the absolute method. The f(fast) ranged from 48 to 155, and the phi(fast) was found in the range 1.03*10(10)-4.89*10(10) n cm(-2) s(-1). These values indicate an acceptable conformity and applicable for installation of the fast neutron facility at the MNA research reactor. PMID- 21295988 TI - Microarray analysis of ripening-regulated gene expression and its modulation by 1 MCP and hexanal. AB - Hexanal, an inhibitor of phospholipase D, has been successfully applied for the pre- and post-harvest treatment of fruits, vegetables and flowers. Changes in gene expression induced by hexanal and the ethylene antagonist 1-MCP, were analyzed by microarray using TOM2 tomato oligo-array containing approximately 12 000 unigenes. Mature green tomato fruits were treated with 1-MCP and hexanal, RNA isolated after 10 days of storage, and labeled cDNA synthesized for microarray analysis. A large variation in gene expression profile was observed in 1-MCP treated fruits. Genes for ethylene biosynthetic pathway enzymes such as ACC- synthase/oxidase, ethylene receptor and ethylene response factors were heavily down-regulated in 1-MCP-treated fruits. In addition, genes for key enzymes involved in cell wall degradation and carotenoid development pathways were down regulated. Hexanal treatment significantly down-regulated ACC-synthase, and to a lesser extent, other components of ethylene signal transduction. By contrast to MCP-treated fruits, hexanal-treated fruits gradually ripened and showed higher levels of lycopene and beta-carotene. GC-MS analysis of volatiles showed a higher level of major volatile components in hexanal-treated fruits. Similarities in the modulation of gene expression by hexanal and 1-MCP suggest that hexanal, in addition to being a PLD inhibitor, may also act as a weak ethylene inhibitor. PMID- 21295989 TI - Cd affects the translocation of some metals either Fe-like or Ca-like way in poplar. AB - In plants, Cd causes perturbation of root metal uptake and is known to interfere with the metal translocation to the shoot. The most significant effect is the strongly reduced transport of Fe. Fe accumulation in roots under Cd stress revealed that it is not the Fe acquisition but the Fe loading to xylem elements that is blocked by Cd, which can be a result of competition between Fe and Cd for the transporters. However, in animal cells as well as in plant stomata guard cells, Cd was shown to move through Ca channels. To clarify whether the perturbation of metal translocation/xylem loading caused by Cd show any regularity, translocation ability was tested by the determination of the metal content in leaves of hydroponically cultured (1/4 Hoagland nutrient solution, Fe source: 10 MUM Fe((III))-citrate) poplar plants grown for three weeks with or without 10 MUM Cd(NO3)2 treatment. Metals could be classified into two groups according to the behavior of their translocation under Cd treatment: alkaline earth metals (except Mg), Zn and Mn were influenced similarly to Ca, but other transition metals (together with alkali metals and Al) behaved like the Fe. Based on the translocation pattern, Cd seems to inhibit the transport of Ca-like metals competitively, but a different type of inhibition is exerted on the transition metal transport, with which Cd can share a common translocation system. The strongly decreased translocation of chelator-dependent transition metals may indicate Cd related disturbances in signalling pathways and gene expression of xylem transporters or chelators. PMID- 21295990 TI - Significance of the residual aortic obstruction in multistage repair of hypoplastic left heart syndrome. AB - OBJECTIVE: The population of children who received right ventricle-to-pulmonary artery shunt (RV-PA) at Norwood procedure (NP) is growing, but limited data are available regarding the long-term outcome. The aim of this study was to present operative outcomes and mid-term hemodynamics and to assess the impact of the residual aortic obstruction on the results in patients undergoing three-staged surgery with RV-PA application at NP. METHODS: Between June 2001 and June 2009, 229 children with hypoplastic left heart syndrome (HLHS) and variants underwent NP with RV-PA; 172 have proceeded to stage II and 95 to stage III. The medical records (clinical data, echocardiographic records, cardiac catheterization reports, electrocardiograms, and surgical notes) were retrospectively reviewed. RESULTS: The later era of NP was associated with significantly better outcome (2001-2004: 1- and 5-years' survival were 64.3% and 59.8%, respectively; 2005 2009: 1- and 4-years' survival were 93.1% and 86.9%, respectively) (p<0.001). There was no association between long-term survival and diagnosis (HLHS/HLHS variant) (p=0.39). The incidence of depressed ventricular function and moderate or severe systemic atrioventricular valve regurgitation among the children who required balloon aortoplasty (BA) before stage II surgery was significantly higher than in children without aortic arch obstruction (p=0.027, p=0.008, respectively). In midterm follow-up, BA had no significant influence on the actuarial survival (p=0.089). No ventricular arrhythmias were noticed at any stage. CONCLUSIONS: The RV-PA shunt is a safe technique that does not seem to impair systolic or electrical ventricular function; its outcomes continue to improve with growing experience. Combined cardiologic interventional and surgical procedures are required to optimize the outcomes. PMID- 21295991 TI - High-dose tranexamic acid is related to increased risk of generalized seizures after aortic valve replacement. AB - OBJECTIVE: To investigate the incidence of postoperative generalized seizures in patients undergoing aortic valve replacement (AVR) under extracorporeal circulation, who received either high-dose tranexamic acid (TXA) or epsilon aminocaproic acid (EACA) as an antifibrinolytic agent. METHODS: This retrospective analysis comprised 682 consecutive patients undergoing AVR with or without simultaneous coronary artery bypass surgery. Patients operated on before March 2008 were treated intra-operatively with TXA (100 mg kg-1; n = 341), patients operated on after March 2008 received EACA (50 mg kg-1 loading dose, followed by 25 mg kg-1 h-1, and an additional 5 g in the extracorporeal circuit; n = 341). RESULTS: Clinically diagnosed generalized seizures were observed within the first 24h postoperatively, more frequently in patients receiving TXA compared with EACA (6.4% vs 0.6%, p < 0.001, difference = 5.8%, 95% confidence interval 3.1-8.5%). Besides the antifibrinolytic agent, three other variables differed significantly between patients with and without postoperative seizures: age (mean (SD), 77.0 (5.9) years vs 73.2 (9.0) years, p = 0.039), preoperative creatinine clearance (55.4 (16.5)ml min-1 vs 72.6 (28.5)ml min-1, p = 0.002), and administration of recombinant activated factor VIIa (3 out of 24 patients (12.5%) vs 8 out of 658 patients (1.2%), p = 0.005). Logistic regression analysis demonstrated a significant impact of the antifibrinolytic drug, creatinine clearance, and the application of recombinant activated factor VIIa on the occurrence of generalized seizures. CONCLUSIONS: Our results indicate that high dose TXA is associated with an increased incidence of postoperative generalized seizures in patients undergoing AVR compared with EACA, especially when suffering from renal impairment. A possible association between recombinant activated factor VIIa and the occurrence of postoperative seizures needs further investigation. PMID- 21295992 TI - Transthoracic device closure of ventricular septal defects without cardiopulmonary bypass: experience in infants weighting less than 8 kg. AB - OBJECTIVE: Both surgical and percutaneous device closure of ventricular septal defect (VSD) have drawbacks and limitations in infants. We report our experiences and midterm results of transthoracic device closure of VSDs (TDCVs) without cardiopulmonary bypass (CPB) in infants. METHODS: Between September 2007 and September 2009, 32 patients, with a mean age of 7.2 +/- 4.7 months, body weight of 6.8 +/- 2.8 kg, underwent this procedure. The procedure was performed in the operating room. A small subxiphoid incision was made. A purse-string suture was placed on the right ventricular free wall. The free wall was punctured using a trocar, then a guide wire was inserted and advanced to cross the VSD into the left ventricle under transesophageal echocardiographic guidance. A modified delivery sheath was then introduced over the guide wire. The device was delivered and deployed in position along the sheath to close the defect. RESULTS: A total of 30 cases (94%) were successfully closed, and the remaining two cases (6%) were converted to open heart repair. No patients received transfusion. There was no perioperative mortality, or any major complication. The mean size of the devices was 7.6 +/- 3.4mm. The total operative time was less than 60 min, and the mean time for device implantation was 18.3 +/- 9.4 min. All patients were extubated within 2h, and were discharged within 5 days after operation. The follow-up period ranged from 6 to 31 months (18.3 +/- 9.6 months). There was no late major complication detected. CONCLUSION: Minimally invasive TDCV without CPB is a safe and effective alternative to the conventional operation in low-body-weight infants. PMID- 21295993 TI - On the relation between the Kautsky effect (chlorophyll a fluorescence induction) and Photosystem II: basics and applications of the OJIP fluorescence transient. AB - Chlorophyll a fluorescence is a highly sensitive, non-destructive, and reliable tool for measuring, rather quickly, photosynthetic efficiency, particularly of Photosystem II (PSII), the water-plastoquinone oxidoreductase. We briefly review here the connection between the fast (up to 2 s) chlorophyll fluorescence rise and PSII, as well as the empirical use of the fluorescence rise kinetics in understanding photosynthetic reactions, particularly of PSII. When dark-adapted photosynthetic samples are exposed to light, a fluorescence induction is observed, known as the Kautsky effect, after Hans Kautsky, the discoverer of the phenomenon showing the existence of variable fluorescence. The chlorophyll fluorescence intensity rises from a minimum level (the O level), in less than 1 s, to a maximum level (the P-level) via two intermediate steps labeled J and I. This is followed by a decline to a lower semi-steady state level, the S level, which is reached in about one minute. We provide here an educational review on how this phenomenon has been exploited through analysis of the fast OJIP fluorescence transient, by discussing basic assumptions, derivation of equations, as well as application to PSII-related questions. PMID- 21295994 TI - Creating an environment to implement and sustain evidence based practice: a developmental process. AB - BACKGROUND: Elements of evidence based practice (EBP) are well described in the literature and achievement of EBP is frequently being cited as an organisational goal. Despite this, the practical processes and resources for achieving EBP are often not readily apparent, available or successful. PURPOSE: To describe a multi dimensional EBP program designed to incorporate evidence into practice to lead to sustainable improvement in patient care and ultimately patient outcome. IMPLEMENTATION STRATEGIES: A multi-dimensional EBP program incorporating EBP champions and mentors, provision of resources, creation of a culture to foster EBP and use of practical EBP strategies was implemented in a 22-bed intensive care unit (ICU) in a public, tertiary hospital in Brisbane, Australia. The practical EBP strategies included workgroups, journal club and nursing rounds. ACHIEVEMENTS: The multi-dimensional EBP program has been successfully implemented over the past three years. EBP champions and mentors are now active and two EBP workgroups have investigated specific aspects of practice, with one of these resulting in development of an associated research project. Journal club is a routine component of the education days that all ICU nurses attend. Nursing rounds is now conducted twice a week, with between one and seven short-term issues identified for each patient reviewed in the first 12 months. CONCLUSIONS: A multi-dimensional program of practice change has been implemented in one setting and is providing a forum for discussion of practice-related issues and improvements. Adaptation of these strategies to multiple different health care settings is possible, with the potential for sustained practice change and improvement. PMID- 21295995 TI - Chronic kidney disease in patients with ischemic stroke. AB - To examine the significance of renal dysfunction in patients who have sustained ischemic stroke, we examined the relationship between the renal function evaluated in terms of estimated glomerular filtration rate (eGFR) and the subtype of brain infarction (BI) in patients with ischemic stroke. A total of 639 patients with BI were enrolled in this study, with 314 subjects without stroke or transient ischemic attack registered as age-matched controls. eGFR was calculated according to the equation 194 * Cr(-1.094) * Age(-0.287) (-0.739 if female), where Cr is serum creatinine concentration, and was classified into four stages: stage I, eGFR >= 90 mL/min/1.73 m(2); stage II, eGFR 60 ~ 89 mL/min/1.73 m(2); stage III, eGFR 30 ~ 59 mL/min/1.73 m(2); and stage IV, eGFR <29 mL/min/1.73 m(2). Stage III-IV was significantly more prevalent in the BI group (38%) than in the control group (22%; P < .001). The odds ratio for stage III-IV was significantly higher in the BI group (1.93; 95% confidence interval [CI], 1.35 2.76). Among the BI subgroups, the odds ratios of stage III-IV for the atherothrombotic type (1.81; 95% CI, 1.23-2.68) and the cardiogenic type (2.25; 95% CI, 1.32-3.83) were significantly higher than that of the control group, but that of stage III-IV for lacunar type was not (1.67; 95% CI, 0.98-2.84). Our results indicate that ischemic stroke is frequently associated with renal dysfunction. Chronic kidney disease might be independent risk factor for infarction, especially for cardiogenic and atherosclerotic types. PMID- 21295996 TI - Safety of thrombolytic therapy for acute ischemic stroke after recent transient ischemic attack. AB - BACKGROUND: The objective of this study was to assess the rate of symptomatic intracerebral hemorrhage (SICH) in patients given thrombolytic therapy for acute ischemic stroke (AIS) after recent transient ischemic attack (TIA). METHODS: This was a multicenter study of patients with confirmed TIA within 7 days before an AIS that was treated with intravenous (IV), intra-arterial (IA), or mechanical thrombolysis. A total of 23 cases were identified. RESULTS: The median time interval between index TIA and AIS was 9 hours. The median National Institutes of Health Stroke Scale score at the time of AIS was 12. The median time interval between stroke onset and thrombolytic treatment was 90 minutes. Thrombolytic therapies included IV thrombolysis (70%), IA thrombolysis (17%), IA and mechanical thrombolysis (9%), and IV followed by IA and mechanical thrombolysis (4%). The rate of postthrombolysis SICH in this group was 8.6% (2/23). CONCLUSIONS: The rate of SICH in our cohort appears similar to overall postthrombolysis hemorrhage rates. PMID- 21295997 TI - Comparison of MAX-ACT and K-ACT values when using bivalirudin anticoagulation during minimally invasive hybrid off-pump coronary artery bypass graft surgery. AB - OBJECTIVE: To compare the kaolin-activated coagulation time (K-ACT) to the MAX ACT for monitoring anticoagulation with bivalirudin in patients undergoing hybrid off-pump coronary artery revascularization procedures. DESIGN: A prospective, observational study. SETTING: A cardiac surgical operating room of a university affiliated hospital. PARTICIPANTS: Twelve patients undergoing off-pump coronary artery bypass graft surgery and percutaneous coronary intervention during the same procedure anticoagulated with bivalirudin to a target K-ACT of >300 seconds. INTERVENTION: At baseline and at frequent intervals during anticoagulation, K-ACT and MAX-ACT assays were run contemporaneously, and the pairs of results were analyzed with descriptive statistics, by correlation analysis, and with Bland Altman analysis. MEASUREMENTS AND MAIN RESULTS: The MAX-ACT and K-ACT assays were highly correlated, but the MAX-ACT assay consistently reported significantly lower ACT values compared with the K-ACT. The mean bias (K-ACT minus MAX-ACT) was 94 seconds (limits of agreement, 51-138 seconds). CONCLUSION: To maximize patient safety, centers using bivalirudin for anticoagulation during cardiac surgical procedures need to be aware of the different performance characteristics of ACT assay subtypes. PMID- 21295998 TI - Lung transplantation on extracorporeal membrane oxygenation with iatrogenic aortic dissection. PMID- 21295999 TI - Overheating and rupture of FMS 2000 rapid infuser. PMID- 21296000 TI - Myocardial dysfunction in severe sepsis and septic shock: more questions than answers? PMID- 21296001 TI - Iatrogenic thoracoscopic right ventricular laceration resulting in cardiovascular collapse treated with extracorporeal membrane oxygenation. PMID- 21296002 TI - CNS monitoring: the current weak state of the evidence. PMID- 21296003 TI - Intraoperative interaction between angiotensin-converting enzyme inhibitors and nitroglycerin in major surgical cases. PMID- 21296004 TI - Inductive parsimony and the Methodological Argument. AB - Studies on so-called Change Blindness and Inattentional Blindness have been taken to establish the claim that conscious perception of a stimulus requires the attentional processing of that stimulus. One might contend, against this claim, that the evidence only shows attention to be necessary for the subject to have access to the contents of conscious perception and not for conscious perception itself. This "Methodological Argument" is gaining ground among philosophers who work on attention and consciousness, such as Christopher Mole. I find that, without the supporting evidence of inaccessible consciousness, this argument collapses into an indefensible form of inductive parsimony. The Methodological Argument is thus shown to be unsuccessful when used against the claim that attention is required for conscious perception, though I suggest that it may be successful against the more ambitious claim that attention is necessary for all conscious experience. PMID- 21296005 TI - Bidirectional lexical-gustatory synesthesia. AB - In developmental lexical-gustatory synesthesia, specific words (inducers) can trigger taste perceptions (concurrents) and these synesthetic associations are generally stable. We describe a case of multilingual lexical-gustatory synesthesia for whom some synesthesias were bidirectional as some tastes also triggered auditory word associations. Evoked concurrents could be gustatory but also tactile sensations. In addition to words and pseudowords, many voices were effective inducers, suggesting increased connections between cortical taste areas and both voice-selective and language-selective areas. Lasting changes in some evoked tastes occurred during childhood suggesting that some plasticity can be present after the initial learning of associations. Inducers were often linked to taste concurrents phonologically or semantically, but also through identifiable childhood episodes (persons or events). Several inducers were phonologically linked to episodic inducers suggesting a process of secondary acquisition for many inducers. Implications of these observations are discussed. PMID- 21296006 TI - Mechanical function, glycolysis, and ultrastructure of perfused working mouse hearts following thoracic aortic constriction. AB - BACKGROUND: Glycolytic flux in the mouse heart during the progression of left ventricular hypertrophy (LVH) and mechanical dysfunction has not been described. METHODS: The main objectives of this study were to characterize the effects of thoracic aortic banding, of 3- and 6-week duration, on: (1) left ventricular (LV) systolic and diastolic function of perfused working hearts quantified by analysis of pressure-volume loops; (2) glycolytic flux in working hearts expressed as the rate of conversion of (3)H-glucose to (3)H(2)O, and (3) ultrastructure of LV biopsies assessed by quantitative and qualitative analysis of light and electron micrographs. RESULTS: Results revealed that (1) indexes of systolic function, including LV end-systolic pressure, cardiac output, and rate of LV pressure development and decline, were depressed to similar degrees at 3 and 6 weeks post banding; (2) diastolic dysfunction, represented by elevated LV end-diastolic pressure and volume, was more severe at 6 than at 3 weeks, consistent with a transition to failure; (3) a progressive decline in glycolytic flux that was roughly half the control rate by 6 weeks post-banding; and (4) structural derangements, manifested by increases in interstitial collagen content and myocyte Z-band disruption, that were more marked at 3 weeks than at 6 weeks. CONCLUSION: The results are consistent with the view that myocyte damage, fibrosis, and suppressed glycolytic flux represent maladaptive structural and metabolic remodeling that contribute to the development of failure in high pressure load-induced LVH in the mouse. PMID- 21296007 TI - Academic couples: implications for medical school faculty recruitment and retention. AB - BACKGROUND: Academic couples constitute 36% of the US professoriate. Universities are in the midst of a major transition in hiring practices to support these and other faculty with working partners. However, less is known about academic couples among medical school faculty and surgical specialties specifically. This study was designed to address this gap. STUDY DESIGN: In 2006-2007, the Michelle R Clayman Institute for Gender Research at Stanford University designed and administered the "Managing Academic Careers Survey" to nearly 30,000 full-time faculty across all academic fields at leading research universities nationwide. This study included 2,475 medical school faculty survey respondents at 12 participating institutions. Main outcomes measures were academic partner status; number of journal articles/chapters during career; and applications to other academic position(s) in last 5 years. RESULTS: A total of 73.3% of medical school faculty respondents were in dual-career partnerships (where both partners actively pursue employment) and 32.2% had an academic partner. Sixty-nine percent of academic partners were also in medical schools. Women faculty were more likely than men to have an academic partner. Among surgery faculty, 40% of women had an academic partner, as compared with 29.3% of men. In fully adjusted regression models, faculty with academic partners had higher publication counts than other faculty, and had higher odds of applying to other academic positions. CONCLUSIONS: Academic couples constitute one-third of all medical school faculty. They represent a productive and potentially mobile component of the medical faculty workforce. Because women had a higher rate of academic partnering, dual career academic hiring policies are especially important for recruitment and retention of female faculty in surgical specialties. PMID- 21296008 TI - Hand-assisted laparoscopic right colectomy: how does it compare to conventional laparoscopy? AB - BACKGROUND: There is sufficient evidence to support the use of hand-assisted laparoscopy for sigmoid, total, and proctocolectomy. As a result, the hand assisted technique has gained acceptance for these relatively complex types of colorectal surgery. For right colectomy, the use of conventional laparoscopy is supported by studies that have demonstrated its advantages over open surgery. Although the hand-assisted technique is also being used by some surgeons for right colectomy, there are few reported data to justify its use. With this deficiency in mind, we performed a study to compare the short-term outcomes of right colectomy performed by either the hand-assisted or conventional laparoscopic technique. STUDY DESIGN: A single-center retrospective analysis was performed. Patients who underwent hand-assisted or conventional laparoscopic right colectomy were identified from a prospectively maintained departmental database. Preoperative clinical information, details of the operation, lymph node count for cancer cases, postoperative morbidity, length of stay, and 30-day hospital readmissions were evaluated. RESULTS: From 2006 to 2009, 43 hand assisted and 84 conventional laparoscopic right colectomies were performed. Comparison of the hand-assisted and conventional laparoscopic groups revealed no differences in the preoperative clinical variables, including average body mass index (calculated as kg/m(2); 28 and 29), percent obese (33% and 34%), earlier abdominal surgery (30% and 39%), operative time (122 and 126 minutes), lymph nodes evaluated for cancer cases (22 and 21), postoperative morbidity (30%), length of stay (5 days), or 30-day hospital readmission (16% and 11%). CONCLUSIONS: Short-term outcomes of hand-assisted and conventional laparoscopic right colectomy are similar. The decision to perform hand-assisted or conventional laparoscopic right colectomy should be based on the surgeons' preference and not on the perception that one technique is preferable to the other. PMID- 21296009 TI - Risk factors for urinary tract infections in colorectal compared with vascular surgery: a need to review current present-on-admission policy? AB - BACKGROUND: To reduce cost, the Centers for Medicare and Medicaid Services adopted a nonpayment policy for "reasonably preventable events" including hospital acquired urinary tract infection (UTI). Type of operation a patient undergoes could be an inevitable nonmodifiable risk factor in the development of UTI. STUDY DESIGN: Using Participant User File for National Surgical Quality Improvement Program (NSQIP) data from 2005 to 2007, vascular and colorectal cases were identified using CPT codes and analyzed for UTI incidence and risk factors within each group. RESULTS: We identified 30,900 colorectal cases and 39,246 vascular cases with 1,289 (4.2%) colorectal and 952 (2.4%) vascular UTI cases. A multivariate analysis of the dataset revealed colorectal procedures as an independent risk factor for the development of UTI. Subset analysis revealed this significant relationship only for patients with low (<0.30) and intermediate (0.30 to 0.70) morbidity probability. Comparing only open intra-abdominal colorectal and vascular procedures revealed UTI rates of 3.9% versus 4.7%. Multivariate analysis revealed no significant difference in UTI rates in intraabdominal cases (all p values < 0.05). Subset analysis for the open cases revealed that colorectal procedures continued to be associated with UTI in low morbidity probability cases only. CONCLUSIONS: Current policy to reward higher quality fails to differentiate between UTI that may be preventable versus one likely due to nonmodifiable risk factors. Colorectal surgery is more likely to result in higher rates of UTI in comparison with vascular surgery, which may be related to type and complexity of a procedure. Further research needs to be done to change this policy to take into account this nonmodifiable risk factor. PMID- 21296010 TI - Morbidity and mortality as a televideoconference: a randomized prospective evaluation of learning and perceptions. AB - BACKGROUND: Central morbidity and mortality conferences ensure uniform content and more participants but consume work hours in commuting for programs with multiple teaching hospitals. Internet-based televideoconferencing (TVC) technology has the potential to eliminate commuting and expand participation and retain quality of instruction. STUDY DESIGN: A prospective, randomized pilot study compared a control (home, n = 43) group in a live morbidity and mortality conference with an experimental (remote, n = 35) group exposed to TVC. After the conference, 78 participants (11 faculty, 38 residents, and 29 medical students) completed a survey assessing learning (6 questions) and conference effectiveness and appeal (7 questions). RESULTS: Comparison of pooled scores on the 6 test items showed no difference by home versus remote group (4.9 versus 4.4; p = 0.47) or among faculty, residents, and students (4.5 versus 4.7 versus 4.7; p = 0.89), indicating that learning was not compromised by TVC. Overall perceptions of TVC were similar for home and remote sites (25.5 versus 23.4; p = 0.13); TVC was perceived as slightly less effective as attending a conference in person, but preferable to commuting. Perceptions of TVC grew proportionately more favorable as commuting distances increased. Students had a more positive perception of TVC than did residents, and faculty had the least positive perception (p = 0.048). Participants were comfortable giving a presentation via TVC, but less comfortable asking questions or participating in a discussion. CONCLUSIONS: This is the first study using televideoconferencing for morbidity and mortality. TVC did not hinder overall learning and was preferable to commuting between facilities. TVC can help maximize educational efficiency and opportunities in programs with multiple training sites. PMID- 21296011 TI - Defining perioperative mortality after open and endovascular aortic aneurysm repair in the US Medicare population. AB - BACKGROUND: Perioperative mortality is reported after abdominal aortic aneurysm (AAA) repair, but there is no agreed upon standard definition. Often, 30-day mortality is reported because in-hospital mortality may be biased in favor of endovascular repair given the shorter length of stay. However, the duration of increased risk of death after aneurysm repair is unknown. STUDY DESIGN: We used propensity score modeling to create matched cohorts of US Medicare beneficiaries undergoing endovascular (n = 22,830) and open (n = 22,830) AAA repair from 2001 to 2004. We calculated perioperative mortality using several definitions including in-hospital, 30-day, and combined 30-day and in-hospital mortality. We determined the relative risk (RR) of death after open compared with endovascular repair as well as the absolute mortality difference. To define the duration of increased risk we calculated biweekly interval death rates for 12 months. RESULTS: In-hospital, 30-day, and combined 30-day and in-hospital mortality for open and endovascular repair were 4.6% versus 1.1%, 4.8% versus 1.6%, and 5.3% versus 1.7%, respectively. The absolute differences in mortality were similar, at 3.5%, 3.2%, and 3.7%. The RRs of death (95% confidence interval) were 4.2 (3.6 to 4.8), 3.1 (2.7 to 3.4), and 3.2 (2.8 to 3.5). Biweekly interval death rates were highest during the first month after endovascular repair (0.6%) and during the first 2.5 months (0.5% to 2.1%) after open repair. After 2.5 months, rates were similar for both repairs (<0.5%) and stabilized after 3 months. The 90-day mortality rates for open and endovascular repair were 7.0% and 3.2%, respectively. CONCLUSIONS: In-hospital mortality comparisons overestimate the benefit of endovascular repair compared with 30-day or combined 30-day and in hospital mortality. The total mortality impact of AAA repair is not realized until 3 months after repair and the duration of highest mortality risk extends longer for open repair. PMID- 21296012 TI - MBD2 contributes to developmental silencing of the human epsilon-globin gene. AB - During erythroid development, the embryonic epsilon-globin gene becomes silenced as erythropoiesis shifts from the yolk sac to the fetal liver where gamma-globin gene expression predominates. Previous studies have shown that the epsilon-globin gene is autonomously silenced through promoter proximal cis-acting sequences in adult erythroid cells. We have shown a role for the methylcytosine binding domain protein 2 (MBD2) in the developmental silencing of the avian embryonic rho-globin and human fetal gamma-globin genes. To determine the roles of MBD2 and DNA methylation in human epsilon-globin gene silencing, transgenic mice containing all sequences extending from the 5' hypersensitive site 5 (HS5) of the beta globin locus LCR to the human gamma-globin gene promoter were generated. These mice show correct developmental expression and autonomous silencing of the transgene. Either the absence of MBD2 or treatment with the DNA methyltransferase inhibitor 5-azacytidine increases epsilon-globin transgene expression by 15-20 fold in adult mice. Adult mice containing the entire human beta-globin locus also show an increase in expression of both the epsilon-globin gene transgene and endogenous epsilon(Y) and beta(H1) genes in the absence of MBD2. These results indicate that the human epsilon-globin gene is subject to multilayered silencing mediated in part by MBD2. PMID- 21296013 TI - An epidemiological overview of swine trichinellosis in China. AB - Trichinellosis is a major food-borne zoonosis with health, social, and economic impacts. Epidemiological data on swine trichinellosis in China from 2005 to 2009 were obtained from seven Provinces/autonomous regions/Municipalities (P/A/M) and analyzed and sero-epidemiological data were acquired from five P/A. The seroprevalence ranged from 0.01% to 29.95% as determined by enzyme-linked immunosorbent assay or an immunochromatographic strip method. The prevalence of Trichinella infection in swine slaughtered at abattoirs varied from 0% to 5.75% in five P/A. Between 2005 and 2009, endemic areas of swine trichinellosis were located mainly in the Western (Guangxi and Qinghai), central (Henan and Hubei), and North-eastern parts (Heilongjiang) of China. Swine trichinellosis in China is transmitted mostly through garbage. Pigs infected with Trichinella are predominately from small backyard farms where animals are raised under poor hygienic conditions, and from rural and mountainous areas where they range freely at pasture. The prevalence of Trichinella in pork sold at the market was reported in four P/A, and varied from 0.06% to 5.6% as determined by trichinoscopy or the digestion method. From 2005 to 2009, 15 outbreaks of human trichinellosis, with 1387 cases and 4 deaths, were recorded in three P/A of South-western China. Twelve (85.71%) of these 15 outbreaks were caused by the eating of raw or undercooked pork, which remains the predominant source of trichinellosis in humans. Pig-rearing practices must be improved, and mandatory inspection of pork further strengthened in rural and mountainous areas in Western China for the control of the disease. PMID- 21296014 TI - Straightforward, effective calibration of SPINAL-64 decoupling results in the enhancement of sensitivity and resolution of biomolecular solid-state NMR. AB - We describe a simple yet highly effective optimization strategy for SPINAL-64 1H decoupling conditions for magic-angle spinning solid-state NMR. With adjustment of the phase angles in a coupled manner, the optimal conditions resulting from three parameter optimizations can be determined with adjustment of a single phase. Notably, echo T2 relaxation times for 13C and 15N show significant enhancement (up to 64%), relative to the previous described SPINAL-64 conditions, under the moderate 1H decoupling levels (60-100 kHz) and MAS rate (13.3 kHz) commonly employed for high-resolution SSNMR spectroscopy of proteins. Additionally, we also investigated the effect at higher spinning rate (33.3 kHz) and compared the results with other 1H decoupling schemes (TPPM, XiX), as well as SPINAL-64 with the originally reported optimal values. PMID- 21296015 TI - A Dynamic Nuclear Polarization spectrometer at 95 GHz/144 MHz with EPR and NMR excitation and detection capabilities. AB - A spectrometer specifically designed for systematic studies of the spin dynamics underlying Dynamic Nuclear Polarization (DNP) in solids at low temperatures is described. The spectrometer functions as a fully operational NMR spectrometer (144 MHz) and pulse EPR spectrometer (95 GHz) with a microwave (MW) power of up to 300 mW at the sample position, generating a MW B(1) field as high as 800 KHz. The combined NMR/EPR probe comprises of an open-structure horn-reflector configuration that functions as a low Q EPR cavity and an RF coil that can accommodate a 30-50 MUl sample tube. The performance of the spectrometer is demonstrated through some basic pulsed EPR experiments, such as echo-detected EPR, saturation recovery and nutation measurements, that enable quantification of the actual intensity of MW irradiation at the position of the sample. In addition, DNP enhanced NMR signals of samples containing TEMPO and trityl are followed as a function of the MW frequency. Buildup curves of the nuclear polarization are recorded as a function of the microwave irradiation time period at different temperatures and for different MW powers. PMID- 21296016 TI - Ergodicity and efficiency of cross-polarization in NMR of static solids. AB - Cross-polarization transfer is employed in virtually every solid-state NMR experiment to enhance magnetization of low-gamma spins. Theory and experiment is used to assess the magnitude of the final quasistationary magnetization amplitude. The many-body density matrix equation is solved for relatively large (up to N=14) spin systems without the spin-temperature assumption for the final spin states. Simulations show that about 13% of the thermodynamic limit is still retained within the proton bath. To test this theoretical prediction, a combination of a reverse cross-polarization experiment and multiple contacts is employed to show that the thermodynamic limit of magnetization cannot be transferred from high- to low-gamma nuclei in a single contact. Multiple contacts, however, fully transfer the maximum magnetization. A simple diffusion on a cone model shows that slow dynamics can affect the build up profile for the transferred magnetization. PMID- 21296017 TI - [Nursing care in the prevention of ventilator-associated pneumonia]. AB - INTRODUCTION: Certain nursing interventions reduce the incidence of ventilator associated pneumonia (VAP). OBJECTIVES: a) to analyze in patients with more than 24 hours of invasive mechanical ventilation how frequently oral hygiene, oropharyngeal suction, turning and evaluation of the tolerance of enteral nutrition were performed according to established protocols; b) to record in these same patients endotracheal tube cuff pressures and the degrees of elevation of the head of the bed (HOB); c) to determine over the three months of the study the incidence density of VAP. METHOD: This descriptive study was carried out in 26 patients. The nursing interventions of interest were recorded daily. Furthermore, endotracheal tube cuff pressures and the degrees of elevation of HOB were measured 3 times a day. Compliance with the established protocols was considered good when it reached >=80%. Cases of VAP were determined using CDC criteria. The incidence density was calculated including all the patients (122) with mechanical ventilation during the study period. RESULTS: Good compliance with the established protocols was achieved for oral hygiene in 23 patients, for oropharyngeal suction and for turning in 19 patients, and in all patients for the evaluation of the tolerance of enteral nutrition. In 214 measurements endotracheal tube cuff pressure was >= 20cm H20 and in 121 lower. In 79 measurements elevation of HOB was >=30 degrees and in 256 lower. The incidence density of VAP was 7.43/ 1.000 days of mechanical ventilation. CONCLUSIONS: : For these nurse interventions aimed at preventing VAP, levels of compliance with established protocols were satisfactory. The incidence density of VAP was low and well within internationally established ranges. Nevertheless, the incidence of VAP could be further reduced with a better control of cuff pressures and by elevating the HOB to between 30 degrees and 45 degrees . PMID- 21296018 TI - Near-infrared calibration transfer based on spectral regression. AB - A calibration transfer method for near-infrared (NIR) spectra based on spectral regression is proposed. Spectral regression method can reveal low dimensional manifold structure in high dimensional spectroscopic data and is suitable to transfer the NIR spectra of different instruments. A comparative study of the proposed method and piecewise direct standardization (PDS) for standardization on two benchmark NIR data sets is presented. Experimental results show that spectral regression method outperforms PDS and is quite competitive with PDS with background correction. When the standardization subset has sufficient samples, spectral regression method exhibits excellent performance. PMID- 21296019 TI - Single-trial detection of somatosensory evoked potentials by probabilistic independent component analysis and wavelet filtering. AB - OBJECTIVE: To develop an effective approach for enhancing the signal-to-noise ratio (SNR) and identifying single-trial short-latency somatosensory evoked potentials (SEPs) from multi-channel electroencephalography (EEG). METHODS: 128 channel SEPs elicited by electrical stimuli of the left posterior tibial nerve were recorded from 11 healthy subjects. Probabilistic independent component analysis (PICA) was used as a spatial filter to isolate SEP-related independent components (ICs), and wavelet filtering was used as a time-frequency filter to further enhance the SNR of single-trial SEPs. RESULTS: SEP-related ICs, identified using PICA, showed typical patterns of cortical SEP complex (P39-N50 P60) and scalp topography (centrally distributed with the spatial peak located near vertex). In addition, wavelet filtering significantly enhanced the SNR of single-trial SEPs (p=0.001). CONCLUSIONS: Combining PICA and wavelet filtering offers a space-time-frequency filter that can be used to enhance the SNR of single-trial SEPs greatly, thus providing a reliable estimation of single-trial SEPs. SIGNIFICANCE: This method can be used to detect single-trial SEPs and other types of evoked potentials (EPs) in various sensory modalities, thus facilitating the exploration of single-trial dynamics between EPs, behavioural variables (e.g., intensity of perception), as well as abnormalities in intraoperative neurophysiological monitoring. PMID- 21296020 TI - Magnetoencephalography in epilepsy: is it time for EMEG? PMID- 21296021 TI - Setting the stage for prevention of familial Alzheimer's disease. PMID- 21296022 TI - Pre-dementia clinical stages in presenilin 1 E280A familial early-onset Alzheimer's disease: a retrospective cohort study. AB - BACKGROUND: Mild cognitive impairment (MCI) and pre-MCI have been proposed as stages preceding Alzheimer's disease (AD) dementia. We assessed descendants of individuals with a mutation in presenilin 1 (PSEN1) that causes familial AD, with the aim of identifying distinct stages of clinical progression to AD dementia. METHODS: We retrospectively studied a cohort of descendants of carriers of the PSEN1 E280A mutation. Pre-dementia cognitive impairment was defined by a score 2 SD away from normal values in objective cognitive tests, and was subdivided as follows: asymptomatic pre-MCI was defined by an absence of memory complaints and no effect on activities of daily living; symptomatic pre-MCI was defined by a score on the subjective memory complaints checklist higher than the mean and no effect on activities of daily living; and MCI was defined by a score on the subjective memory complaints checklist higher than the mean, with no effect on basic activities of daily living and little or no effect on complex daily activities. Dementia was defined according to the diagnostic and statistical manual of mental disorders, fourth edition. Reference mean scores were those of participants who did not carry the PSEN1 E280A mutation. We used the Turnbull survival analysis method to identify ages at onset of each stage of the disease. We measured the time from birth until onset of the three pre-dementia stages, dementia, and death, and assessed decline in cognitive domains for each stage. FINDINGS: Follow-up was from Jan 1, 1995, to Jan 27, 2010. 1784 patients were initially identified, 449 of whom were PSEN1 E280A carriers who had complete clinical follow-up. Median age at onset was 35 years (95% CI 30-36) for asymptomatic pre-MCI, 38 years (37-40) for symptomatic pre-MCI, 44 years (43-45) for MCI, and 49 years (49-50) for dementia. The median age at death was 59 years (95% CI 58-61). The median time of progression from asymptomatic to symptomatic pre-MCI was 4 years (95% CI 2-8), from symptomatic pre-MCI to MCI was 6 years (4 7), from MCI to dementia was 5 years (4-6), and from dementia to death was 10 years (9-12). The cognitive profile was predominantly amnestic and was associated with multiple domains. Affected domains showed variability in initial stages, with some transient recovery in symptomatic pre-MCI followed by continuous decline. INTERPRETATION: Clinical deterioration can be detected as measurable cognitive impairment around two decades before dementia onset in PSEN1 E280A carriers. Onset and progression of pre-dementia stages should be considered in the investigation and use of therapeutic interventions for familial AD. FUNDING: Departamento Administrativo de Ciencia, Tecnologia e Innovacion, COLCIENCIAS, Republic of Colombia. PMID- 21296023 TI - Predictors of severity and treatment response in children with monosymptomatic nocturnal enuresis receiving behavioral therapy. AB - OBJECTIVE: To evaluate the role of bladder volume and bladder wall thickness measurement by ultrasound in assessing severity and predicting response to behavioral therapy in children with monosymptomatic nocturnal enuresis. METHODS: 122 children (68 boys and 54 girls) aged 5-9 years underwent ultrasound evaluation of bladder volume and bladder wall thickness, followed by calculation of the bladder volume wall thickness index (BVWI). They were treated using first line management (behavioral therapy) for 4 months. Correlation of severity and treatment response to ultrasound bladder measurements was investigated. RESULTS: Only 74 children completed the study: 16 showed complete response to treatment, 25 good response, 18 partial response, and 15 children showed no response. Age, gender and location of residence did not correlate to severity or to treatment response. Ultrasound measured bladder volume also did not correlate to either severity or response. Bladder wall thickness showed a strong correlation to both severity and response to treatment, as did BVWI. CONCLUSION: Ultrasound measured bladder wall thickness and BVWI are strongly associated with the severity of nocturnal enuresis and are highly predictive of treatment response to behavioral therapy. It is recommended that any child with monosymptomatic nocturnal enuresis should undergo an abdominal ultrasound examination before starting treatment. PMID- 21296024 TI - Food consumption patterns in Mediterranean adolescents: are there differences between overweight and normal-weight adolescents? AB - OBJECTIVE: To quantify food consumption (based on food group classification) during several time periods in a sample of adolescents and to identify potential differences in food patterns between normal-weight and overweight participants. DESIGN: Cross-sectional study. Participants were classified as normal weight and overweight/obese. Dietary intake was assessed by 3-day food records and analyzed at the food group level for 7 different time periods. To exploit the time dimension of the data and to further control for the influence of other covariates, the authors estimated a random effects regression model for panel data. PARTICIPANTS: One hundred twenty students. SETTING: Two high schools. RESULTS: In multivariate analysis, no statistically significant differences were found between normal-weight and overweight adolescents with regard to their consumption patterns throughout the day. However, compared to females, male participants had higher intake of all food groups with the exception of fruit, and adolescents engaging in vigorous exercise tended to consume more servings from all food groups during any given time period. CONCLUSIONS AND IMPLICATIONS: No preferential use of some food or food groups in specific day periods was found among overweight compared to normal-weight high school students. PMID- 21296025 TI - Beliefs about cancer and diet among those considering genetic testing for colon cancer. AB - OBJECTIVE: To assess beliefs about the role of diet in cancer prevention among individuals considering genetic testing for Lynch Syndrome. DESIGN: Family centered, cascade recruitment; baseline assessment of a longitudinal study. SETTING: Clinical research setting. PARTICIPANTS: Participants were 390 persons, ages 18 and older, including persons with a Lynch Syndrome-associated cancer and suspected of carrying a disease causing mutation, and relatives at risk for inheriting a previously identified mutation. MAIN OUTCOME MEASURES: Assess clustering of beliefs about the role of diet in cancer prevention and predictors of class membership. ANALYSIS: Confirmatory factor analysis; 2-class factor mixture model with binary indicators; multilevel regression analyses, individuals nested within families. RESULTS: Women endorsed a relationship between diet and cancer prevention more often than men (P < .01). A 2-class model was used where Class 1 indicated less likely to link cancer to diet, and Class 2 indicated more likely. Factors associated with increased odds of membership in Class 1 expressed belief that nothing can prevent cancer (P < .01) and fate attribution (P < .01); Class 2 mentioned personal cancer history (P < .05) and genetic knowledge (P < .01). CONCLUSIONS AND IMPLICATIONS: Identifying factors associated with a belief in cancer prevention through dietary behaviors can inform targeted interventions. PMID- 21296026 TI - Antibody and markers of T-cell activation illuminate the pathogenesis of HCV immune restoration disease in HIV/HCV co-infected patients commencing ART. AB - Some HIV/hepatitis C virus co-infected patients beginning ART experience Immune Restoration Disease (IRD) manifested as a rise in serum alanine transaminase. This was investigated in HIV/HCV co-infected individuals (n=50) commencing ART in Jakarta (Indonesia). Samples were collected at weeks 0, 4, 8, 12, 24 and at HCV IRD. Nine patients experienced HCV IRD (incidence=9.2 per 1000 person-weeks). These resolved without changing treatment. Markers of T-cell activation (sCD26, sCD30) and immune recruitment (CXCL10) increased in many HCV IRD cases, so T cells may mediate HCV IRD. Total anti-HCV antibody (core, NS3, NS4) remained lower in HCV IRD cases, but levels of antibody to core were not lower in HCV IRD cases. Rises in HCV RNA on ART were independent of HCV IRD, but there was a negative correlation between baseline HCV RNA and total anti-HCV antibody. High levels of antibody may protect against HCV IRD, via lower HCV antigen loads. PMID- 21296027 TI - Semantic association investigated with functional MRI and independent component analysis. AB - Semantic association, an essential element of human language, enables discourse and inference. Neuroimaging studies have revealed localization and lateralization of semantic circuitry, making substantial contributions to cognitive neuroscience. However, because of methodological limitations, these investigations have only identified individual functional components rather than capturing the behavior of the entire network. To overcome these limitations, we have implemented group independent component analysis (ICA) to investigate the cognitive modules used by healthy adults performing the fMRI semantic decision task. When compared with the results of a standard general linear modeling (GLM) analysis, ICA detected several additional brain regions subserving semantic decision. Eight task-related group ICA maps were identified, including left inferior frontal gyrus (BA44/45), middle posterior temporal gyrus (BA39/22), angular gyrus/inferior parietal lobule (BA39/40), posterior cingulate (BA30), bilateral lingual gyrus (BA18/23), inferior frontal gyrus (L>R, BA47), hippocampus with parahippocampal gyrus (L>R, BA35/36), and anterior cingulate (BA32/24). Although most of the components were represented bilaterally, we found a single, highly left-lateralized component that included the inferior frontal gyrus and the medial and superior temporal gyri, the angular and supramarginal gyri, and the inferior parietal cortex. The presence of these spatially independent ICA components implies functional connectivity and can be equated with their modularity. These results are analyzed and presented in the framework of a biologically plausible theoretical model in preparation for similar analyses in patients with right- or left-hemispheric epilepsies. PMID- 21296028 TI - Pharmacological management of persistent pain in older persons: focus on opioids and nonopioids. AB - Managing persistent pain is challenging, particularly in older adults who often have comorbidities and physiological changes that affect dosing and adverse effect profiles. The latest guideline issued by the American Geriatrics Society in 2009 is an important clinical resource on prescribing analgesics for older adults. This guideline helps form an evidence-based approach to treating persistent pain, along with other current endorsements, such as the relevant disease-specific recommendations by the American College of Rheumatology, the European League Against Rheumatism, and Osteoarthritis Research Society International, as well as opioid-specific guidelines issued by the American Pain Society, the American Academy of Pain Medicine, the Federation of State Medical Boards of the United States, and the American Society of Interventional Pain Physicians. Safety is of utmost concern, especially for older adults; these guidelines include key approaches for safe opioid prescribing. Combining analgesics that have multiple mechanisms of action with nonpharmaceutical approaches can be beneficial in providing pain relief. Nontraditional analgesics are also considered on a case-by-case basis, and a few of these options are weakly recommended. Therapies should be initiated at the lowest possible dose and slowly titrated to effect, while tailoring them to the therapeutic and side effect responses of the individual. PMID- 21296029 TI - Enhanced excitability and down-regulated voltage-gated potassium channels in colonic drg neurons from neonatal maternal separation rats. AB - Irritable bowel syndrome (IBS), characterized mainly by abdominal pain, is a functional bowel disorder. The present study aimed to examine changes in the excitability and the activity of the voltage-gated K(+) channel in dorsal root ganglia (DRG) neurons innervating the colon of rats subjected to neonatal maternal separation (NMS). Colonic DRG neurons from NMS rats as identified by FAST DiITM labeling showed an increased cell size compared with those from nonhandled (NH) rats. Whole cell current-clamp recordings showed that colonic DRG neurons from NMS rats displayed: 1) depolarized resting membrane potential; 2) increased input resistance; 3) a dramatic reduction in rheobase; and 4) a significant increase in the number of action potentials evoked at twice rheobase. Whole cell voltage-clamp recordings revealed that neurons from both groups exhibited transient A-type (I(A)) and delayed rectifier (I(K)) K(+) currents. Compared with NH rat neurons, the averaged density of I(K) was significantly reduced in NMS rat neurons. Furthermore, the Kv1.2 expression was significantly decreased in NMS rat colonic DRG neurons. These results suggest that NMS increases the excitability of colonic DRG neurons mainly by suppressing the I(K) current, which is likely accounted for by the downregulation of the Kv1.2 expression and somal hypertrophy. PERSPECTIVE: This study demonstrates the alteration of delayed rectifier K current and Kv1.2 expression in DRG neurons from IBS model rats, representing a molecular mechanism underlying visceral pain and sensitization in IBS, suggesting the potential of Kv1.2 as a therapeutic target for the treatment of IBS. PMID- 21296030 TI - Judgments about pain intensity and pain genuineness: the role of pain behavior and judgmental heuristics. AB - The primary objective of the present study was to examine the relative importance of pain behaviors and judgmental heuristics (eg, gender stereotypes) in observers' inferences about pain intensity and pain genuineness. Participants (n = 90) observed video depictions of chronic pain patients performing a physically challenging task and were asked to make inferences of pain intensity and pain genuineness. Analyses indicated that observers relied on judgmental heuristics and pain behaviors both when making inferences about pain intensity and when making inferences about pain genuineness. Follow-up analyses, however, revealed that judgmental heuristics (eg, gender stereotypes) were significantly less utilized when observers made inferences about pain genuineness than when observers made inferences about pain intensity. When observers made inferences about pain genuineness, analyses indicated that patients' facial pain behaviors became the most important source of information. Taken together, these findings suggest that observers who are asked to make inferences about the genuineness of others' pain are likely to reduce their reliance on judgmental heuristics in favor of more controlled and thoughtful inferential processes characterized by detailed processing of behavioral information, particularly others' facial pain behaviors. PERSPECTIVE: The current study provides new insights into the processes that are involved in observers' inferences about pain intensity and pain genuineness. These inferences play an important role in treatment decisions and advances in this domain could ultimately contribute to more effective management of the challenges facing patients with pain-related disorders. PMID- 21296031 TI - Impact of urinary catheterization on dosimetry after prostate implant brachytherapy with palladium-103 or iodine-125. AB - PURPOSE: Postoperative dosimetry is integral to quality assurance for prostate brachytherapy. Images on Day 0 are typically obtained with a contrast-filled urinary catheter in place for urethral dose calculations. However, expansion of the urethra and perhaps the prostate by the catheter may affect target coverage. We assessed the effect of urinary catheterization on target dosimetry after implantation with palladium-103 ((103)Pd) or iodine-125 ((125)I) seeds. METHODS AND MATERIALS: Patients were 29 consecutive men with postimplant dosimetry calculated with and without a urinary catheter after brachytherapy seed implantation; 19 patients received (103)Pd seeds and 10 patients received (125)I seeds. In each case, 14-French caude tip urinary catheters were placed before implantation, and axial CT slices of the pelvis were obtained before and after catheter removal for postimplant dosimetry. Dosimetric parameters were measured and compared with paired Student's t tests. Trends were assessed by linear regression with the Pearson correlation coefficient. RESULTS: Removal of the urinary catheter significantly improved V(100) and D(90) for (103)Pd implants (mean+/-standard deviation (SD), 2.7%+/-4.2%; range, -0.4% to 15%; p=0.011 and mean+/-SD, 4.0%+/-3.4%; range, -0.1% to 13.8%; p<0.01, respectively). For (125)I implants, catheter removal improved D(90) (mean+/-SD, 1.5%+/-1.8%; range, -1.3% to 4.2%; p=0.027). For the (103)Pd group, the magnitude of change in V(100) correlated with prostate size (R(2)=0.16) and source number (R(2)=0.15). CONCLUSIONS: Urinary catheterization can artificially reduce target coverage after prostate implant brachytherapy. The patients undergoing (103)Pd implantation with smaller (<30cm(3)) prostates and fewer (<90) sources are particularly susceptible to reduced D(90) and V(100) when a urinary catheter is present. PMID- 21296032 TI - Overview of brachytherapy resources in Latin America: a patterns-of-care survey. AB - PURPOSE: Relatively little is known about available resources and patterns of practice for brachytherapy (BT) in Latin America. To rectify this situation, we performed a patterns-of-care survey whose aim was to assess the human and material resources available for BT in Latin America and document current clinical practices. METHODS AND MATERIALS: A total of 392 radiotherapy (RT) centers located in 17 Latin American countries were asked to complete an online survey that included detailed questions about BT practices, facilities, and staffing. The study was coordinated through central offices located in Spain and Peru. National coordinators were appointed to manage the survey in each individual country. RESULTS: Overall, 77 of the 392 institutions (20%) completed the questionnaire. Of the 14 countries with at least one response, the participation rate was 35% (77 of 223 RT centers). The average number of patients (RT+BT) per center was 917. The mean number of BT patients per center increased by 46% (from 105 to 153 patients) from 2002 to 2007. Gynecologic localizations (endometrium, cervix, and vagina) accounted for 95% of treatments, and the uterine cervix was the most common tumor site (75% of all treatments). CONCLUSIONS: In Latin America, BT is most commonly used to treat gynecologic tumors, particularly of the cervix. Relatively few interventions were performed for breast and prostate. This was the first study of its kind in this region and should be repeated periodically. PMID- 21296033 TI - Surgical results of single-incision transumbilical laparoscopic Roux-en-Y gastric bypass. AB - BACKGROUND: Conventional laparoscopic Roux-en-Y gastric bypass (LRYGB) has been the reference standard for bariatric surgery but requires 5-7 trocar incisions. We have developed a new procedure-single-incision transumbilical LRYGB (SITU LRYGB)-that results in minimal scarring and is more cosmetically acceptable. To compare the surgical results and patient satisfaction between 5-port LRYGB and the novel SITU-LRYGB at a university hospital. METHODS: We performed 5-port or SITU-LRYGB on 140 morbidly obese patients; the patients chose the operation method. We used a novel liver traction method and omega-umbilicoplasty specifically designed for SITU-LRYGB. RESULTS: Before surgery, the patients in the 5-port surgery group were more obese than those in the SITU group (120.8 kg versus 108.9 kg, P = .013). The rate of hypertension was also greater in the former group. The operative time was longer for SITU-LRYGB (101.1 versus 81.1 min, P = .001) without increased intraoperative complications. The total morphine dose for the SITU group seemed to be greater but the difference was not statistically significant. No difference in complications was observed. Postoperatively, the percentage of excess body weight lost the SITU and 5-port surgery groups was 21.2% and 20.9%, 40.4% and 39.4%, 55.0% and 55.2%, 64.8% and 75.2%, and 75.4% and 78.2% at 1, 3, 6, 9, and 12 months, respectively. The SITU LRYGB patients reported greater satisfaction related to scarring than those who had undergone 5-port surgery (score 4.57 versus 3.96, respectively, P = .005). No patient died. CONCLUSION: Compared with conventional LRYGB, SITU-LRYGB resulted in acceptable complications, the same recovery, comparative weight loss, and better patient satisfaction related to scarring. PMID- 21296034 TI - Alcohol septal ablation in hypertrophic obstructive cardiomyopathy. PMID- 21296035 TI - Prevalence and histopathology of chronic polypoid sinusitis in pediatric patients with cystic fibrosis. AB - BACKGROUND: Chronic sinusitis is almost invariably a feature of cystic fibrosis. However, data on the endoscopically confirmed prevalence of chronic polypoid sinusitis (CPS) and its histological features are limited. METHODS: Single centre prospective observational study. Unselected pediatric CF patients (n=81; <= 18 years) were endoscopically assessed for the prevalence of CPS. Sixteen of these underwent sinus surgery. The surgically obtained sinus specimens were compared to sinus specimen of non-CF-patients undergoing sinus surgery (n=61), using conventional histology and immunohistochemistry. RESULTS: The prevalence of endoscopically confirmed CPS increased with age from 19% in infants younger than six years reaching 45% in adolescents. In CF patients, histology typically showed dilated glandular ducts and a predominance of mucous glands. The number of plasma cells and mast cells but not of eosinophils was significantly elevated compared to non-CF patients. CONCLUSION: Prevalence of CPS in pediatric CF patients increases with age. Our findings indicate that chronic bacterial infection rather than allergic mechanisms may forward this pathology. PMID- 21296036 TI - Distribution of CFTR mutations in Eastern Hungarians: relevance to genetic testing and to the introduction of newborn screening for cystic fibrosis. AB - BACKGROUND: The aim of this study was characterization of an updated distribution of CFTR mutations in a representative cohort of 40 CF patients with the classical form of the disease drawn from Eastern Hungary. Due to the homogeneity of the Hungarian population our data are generally applicable to other regions of the country, including the sizeable diaspora. METHODS: We utilized the recommended "cascade" CFTR mutation screening approach, initially using a commercial assay, followed by examination of the common "Slavic" deletion CFTRdele2,3(21kb). Subsequently, the entire CFTR coding region of the CFTR gene was sequenced in patients with yet unidentified mutations. RESULTS: The Elucigene CF29(Tm) v2 assay detected 81.25% of all CF causing mutations. An addition of the CFTRdele2,3(21kb) increased the mutation detection rate to 86.25%. DNA sequencing enabled us to identify mutations on 79/80 CF alleles. Mutations [CFTRdele2,3(21kb), p.Gln685ThrfsX4 (2184insA) were found at an unusually high frequency, each comprising 5.00% of all CF alleles. CONCLUSION: We have identified common CF causing mutations in the Hungarian population with the most common mutations (p.Phe508del, p.Asn1303Lys, CFTRdele2,3(21kb), 2184insA, p.Gly542X, and p.Leu101X), comprising over 93.75% of all CF alleles. Obtained data are applicable to the improvement of DNA diagnostics in Hungary and beyond, and are the necessary prerequisite for the introduction of a nationwide "two tier" CF newborn screening program. PMID- 21296037 TI - Quantification of triamcinolone acetonide in ocular tissues after intravitreal injection to rabbit using liquid chromatography-tandem mass spectrometry. AB - A sensitive and selective liquid chromatographic-tandem mass spectrometric method was developed for quantification of triamcinolone acetonide (TA) in rabbit ocular tissues. After a simple liquid-liquid extraction using tert-butyl methyl ether, TA and internal standard methylprednisolone were separated on a C18 column with a mobile phase of acetonitrile:water:formic acid (60:40:0.1, v/v/v) and quantified by the use of selected reaction monitoring mode with a total run time of 4 min. The method was validated in tissue homogenates with a daily working range of 1 1000 ng/mL with correlation coefficient of more than 0.99 and a sensitivity of 1 ng/mL as lower limit of quantification, respectively. The mean intra-day and inter-day precisions were less than 10% and accuracy values were higher than 90%. This method was fully validated for the accuracy, precision and stability studies. The method proved to be accurate and specific, and was applied to an in vivo biodistribution study of TA after intravitreal injection to rabbits. Values of mean residence time in vitreous humor, crystalline lens and aqueous humor were 27.7, 35.8 and 20.0 days, respectively. PMID- 21296038 TI - Hair analysis and self-report of methamphetamine use by methamphetamine dependent individuals. AB - The questions of whether the dose of drug that is consumed corresponds to drug concentration levels in hair and how results of hair analyses can be interpreted are still debated. The aim of this study was to investigate (1) whether there is a correlation between doses of Methamphetamine (MA) use and MA concentration levels in hair and (2) whether results of hair analyses can be used to estimate dose, frequency, and patterns of MA use. In this study, segmental hair analysis was performed through consecutive 1cm as well as 1-4 cm (=3 cm) segmental hair lengths. MA dependent individuals (n=9) provided information on doses (0.25-4 g/day) of MA use as well as the frequency of MA use. The concentrations of MA and its metabolite amphetamine (AP) in hair were determined using gas chromatography/mass spectrometry (GC/MS). One-way analysis of variance (ANOVA) test was performed to evaluate whether MA and AP concentrations in consecutive 1cm length segmental hair were consistent with the history of MA use. The cumulative doses of MA use calculated from the daily dose and the frequency during 1-4 months were well correlated to the concentrations of MA and AP in 1-4 cm segmental hair length (correlation coefficient, r=0.87 for MA and r=0.77 for AP). The results from this study show the patterns and histories of MA use from MA dependent individuals and could assist in the interpretation of hair results in forensic toxicology as well as in rehabilitation and treatment programs. PMID- 21296039 TI - Sequence determinants of histone-DNA binding preferences: comment on "Cracking the chromatin code: precise rule of nucleosome positioning" by Edward N. Trifonov. PMID- 21296040 TI - [Gastroduodenal invagination and Peutz-Jeghers syndrome]. PMID- 21296041 TI - Venous congestion in abdominal flap breast reconstructions--a simple treatment for a temporary problem. PMID- 21296042 TI - The effect of protease inhibition on the temporal stability of NT-proBNP in feline plasma at room temperature. AB - OBJECTIVES: To evaluate whether the addition of a protease inhibitor (PI) to feline plasma improves the temporal stability of N-terminal pro-B-type natriuretic peptide (NT-proBNP). ANIMALS, MATERIALS AND METHODS: Forty-four EDTA blood samples were collected from 42 cats with cardiac disease or hyperthyroidism. Samples were separated within 15 min of collection and the plasma stored at -80 degrees C. Samples were thawed and each separated into 2 aliquots, one of which was mixed with PI. Each was subdivided into 5 aliquots, which remained at room temperature (RT) for zero, 24, 48, 96 or 120 h before being returned to storage at -80 degrees C. NT-proBNP was measured using a commercially-available ELISA. RESULTS: There was no difference in NT-proBNP measurements between plain and PI samples at time zero (P = 0.836) or 24 h (P = 0.293). At subsequent time-points NT-proBNP was higher in the PI than the plain samples (P < 0.05). An overall effect of time at RT was detected for plain (P < 0.001) and PI samples (P < 0.001). CONCLUSIONS: The addition of PI to feline plasma significantly reduces, but does not eliminate, degradation of NT-proBNP at RT. This degradation occurs over a time course comparable to postal transportation of samples for laboratory analysis and may alter the clinical interpretation of results. PMID- 21296043 TI - Health care services and the transition to young adulthood: challenges and opportunities. AB - OBJECTIVE: The aim of this study was to examine the potential role of the health care system in the successful transition to young adulthood for all adolescents, with emphasis on adolescents with special health care needs (ASHCN), and to evaluate the system's status in filling that role. METHOD: Research and conceptual frameworks addressing successful transitions and functioning were reviewed. A framework describing a role for health care services in the transition was presented. The health care system's status in promoting healthy transitions was evaluated, including National Survey of Children with Special Health Care Needs 2005-2006 analyses of key outcomes for ASHCN. RESULTS: Although most national efforts to define skills needed for the transition have focused on career/vocational skills, a few frameworks integrate broader issues such as health, psychosocial development, and civic engagement. Adolescent transitional issues have generally received little attention; however, these have been articulated for ASHCN. Nevertheless, only 2 in 5 ASHCN receive transitional care, and ASHCN fare poorly on other core outcomes. ASHCN with mental health conditions fare worse on outcomes than those with physical health conditions. Our framework for healthy transitions includes the following: 1) adolescents can access a comprehensive health care system, 2) preventable problems are avoided, and 3) chronic problems are managed. The present health care system falls short of accomplishing these. CONCLUSIONS: Health care services can potentially play a role in facilitating a healthy transition to young adulthood; however, many gaps exist. Although the health care reform act addresses some gaps, efforts that integrate adolescents' developmental needs and address mental health issues are needed. PMID- 21296044 TI - Assessing family-provider partnerships and satisfaction with care among US children with special health care needs. AB - OBJECTIVES: Family-provider partnerships and satisfaction with services together are one of the Health Resources and Services Administration's (HRSA) Maternal and Child Health Bureau's (MCHB) 6 core outcomes for children with special health care needs (CSHCN) and are tracked using the 2005-2006 National Survey of Children with Special Health Care Needs. Our objectives were to examine demographic, health, and other correlates/associations, with the perception of family-provider partnership and satisfaction with care; determine the associations between these perceptions and other child/family outcomes; and evaluate differences in the perception of partnership and satisfaction between the families of CSHCN and other children. METHODS: We analyzed data for 40,723 CSHCN from the 2005-2006 National Survey of CSHCN and assessed the prevalence of family-provider partnerships and satisfaction with care and their association with other family-child outcomes. The partnership/satisfaction core outcome results were compared with a referent group of children without special needs included in the 2005-2006 survey. RESULTS: The proportion of CSHCN attaining the core outcome was 57.4% and was lower for households with no health insurance, minority ethnic status, non-English speakers, nontraditional family structure, lower income, and lower functioning CSHCN. Lower rates of satisfaction and partnership were associated with poorer child and family outcomes. Disparities in attainment rates were noted for CSHCN versus other children. CONCLUSIONS: Although parent perceptions of family-provider partnership were relatively high, satisfaction with care contributed to an overall lower attainment rate for the partnership/satisfaction core outcome. Providers, families, government, and advocates need to work together to increase attainment of family-provider partnerships and satisfactory care experiences. PMID- 21296045 TI - Children with special health care needs and changing policy. PMID- 21296046 TI - Videoendoscopic measurement of food bolus formation for quantitative evaluation of masticatory function. AB - PURPOSE: In the field of prosthodontics, many methods for evaluating the masticatory function involve ejection of the food bolus from the mouth. In addition, these methods could not evaluate mastication and swallowing function comprehensively. The present study aimed to quantitatively evaluate masticatory functions during a series of masticatory and swallowing movements by using videoendoscopy. METHODS: Subjects are ten healthy dentulous adults without dysphagia. The test foods used were 2-colored (green and white) molded rice and uirou (rice cake). The test foods were consumed under the restriction on the number of mastication (10, 15, 20, and 30), and under the instruction to "chew normally" or "chew well". The masticatory function was evaluated by observing the food bolus in the oropharynx with a videoendoscope. The bolus formation index (BFI), in terms of the degree of mixing of the green and white parts, was quantitatively determined using an image measurement software. RESULTS: The BFI of the rice and uirou increased significantly with increase in the number of mastication times (p<0.01). A significantly correlation coefficient was observed between the BFI and the number of mastication (0.84 for rice and 0.89 for uirou). The BFI obtained by "chewing well" was significantly higher than that obtained by "chewing normally" (p<0.01). CONCLUSIONS: The results of this study confirm that the endoscopic measurement of food bolus formation by mastication in terms of the color tones of 2-colored test foods enables quantitative evaluation of the masticatory function during a series of masticatory and swallowing movements. PMID- 21296047 TI - On understanding proton transfer to the biocatalytic [Fe-Fe](H) sub-cluster in [Fe-Fe]H(2)ases: QM/MM MD simulations. AB - Proton transfer to the [Fe-Fe](H) sub-cluster in the Desulfovibrio desulfuricans (DdH) and Clostridium pasteurianum (CpI) [Fe-Fe] hydrogenases was investigated by a combination of first principles and empirical molecular dynamics simulations. Pathways that can be inferred from the X-ray crystal structures of DdH and CpI, i.e., (Glu159->Ser198->Glu156->water460->Cys178->DTMA([Fe-Fe](H)) and (Glu282 >Ser319->Glu279->water612->Cys299), respectively, were considered. Proton transfer from Cys178 to DTMA in the [Fe-Fe](H) sub-cluster in DdH was readily observed in our results, specifically when [Fe-Fe](H) was in the reduced state ([Fe(I)-Fe(I)]) or in the mixed valence state for the protonated distal iron Fe(d) ([Fe(I)-Fe(II)-H(-)](H)). A concerted mechanism is proposed, where proton transfer in DdH from Glu159 to Glu156 via Ser198 and Glu156 to Cys178 via water460 readily occurred, as well as from Glu282 to Glu279 via Ser319 and Glu279 to Cys299 via water612 in CpI. The theoretical prediction of the proton transfer characteristics is consistent with the assumed biocatalytic mechanism of the [Fe Fe] hydrogenases in which the proton binds at Fe(d), providing confirmation that has not been explored so far. The computational results were qualitatively validated by the agreement with experimental hydrogen production activity data for mutated CpI enzymes, relative to the wild-type protein. Finally, the insight provided by the simulations, combined, in part, with experimental validation, are important for establishing an approach in future exploration of proton transfer to the active site in this class of enzymes, and possibly also for biomimetic analogs. PMID- 21296048 TI - Electron transfer to the active site of the bacterial nitric oxide reductase is controlled by ligand binding to heme b3. AB - The active site of the bacterial nitric oxide reductase from Paracoccus denitrificans contains a dinuclear centre comprising heme b3 and non heme iron (Fe(B)). These metal centres are shown to be at isopotential with midpoint reduction potentials of E(m) ~ +80 mV. The midpoint reduction potentials of the other two metal centres in the enzyme, heme c and heme b, are greater than the dinuclear centre suggesting that they act as an electron receiving/storage module. Reduction of the low-spin heme b causes structural changes at the dinuclear centre which allow access to substrate molecules. In the presence of the substrate analogue, CO, the midpoint reduction potential of heme b3 is raised to a region similar to that of heme c and heme b. This leads us to suggest that reduction of the electron transfer hemes leads to an opening of the active site which allows substrate to bind and in turn raises the reduction potential of the active site such that electrons are only delivered to the active site following substrate binding. PMID- 21296049 TI - Mitochondria-cytoskeleton interaction: distribution of beta-tubulins in cardiomyocytes and HL-1 cells. AB - Mitochondria-cytoskeleton interactions were analyzed in adult rat cardiomyocytes and in cancerous non-beating HL-1 cells of cardiac phenotype. We show that in adult cardiomyocytes betaII-tubulin is associated with mitochondrial outer membrane (MOM). betaI-tubulin demonstrates diffused intracellular distribution, betaIII-tubulin is colocalized with Z-lines and betaIV-tubulin forms microtubular network. HL-1 cells are characterized by the absence of betaII-tubulin, by the presence of bundles of filamentous betaIV-tubulin and diffusely distributed betaI and betaIII-tubulins. Mitochondrial isoform of creatine kinase (MtCK), highly expressed in cardiomyocytes, is absent in HL-1 cells. Our results show that high apparent K(m) for exogenous ADP in regulation of respiration and high expression of MtCK both correlate with the expression of betaII-tubulin. The absence of betaII-tubulin isotype in isolated mitochondria and in HL-1 cells results in increased apparent affinity of oxidative phosphorylation for exogenous ADP. This observation is consistent with the assumption that the binding of betaII-tubulin to mitochondria limits ADP/ATP diffusion through voltage-dependent anion channel of MOM and thus shifts energy transfer via the phosphocreatine pathway. On the other hand, absence of both betaII-tubulin and MtCK in HL-1 cells can be associated with their more glycolysis-dependent energy metabolism which is typical for cancer cells (Warburg effect). PMID- 21296050 TI - A patch clamp study on the electro-permeabilization of higher plant cells: Supra physiological voltages induce a high-conductance, K+ selective state of the plasma membrane. AB - Permeabilization of biological membranes by pulsed electric fields ("electroporation") is frequently used as a tool in biotechnology. However, the electrical properties of cellular membranes at supra-physiological voltages are still a topic of intensive research efforts. Here, the patch clamp technique in the whole cell and the outside out configuration was employed to monitor current voltage relations of protoplasts derived from the tobacco culture cell line "Bright yellow-2". Cells were exposed to a sequence of voltage pulses including supra-physiological voltages. A transition from a low-conductance (~0.1 nS/pF) to a high-conductance state (~5 nS/pF) was observed when the membrane was either hyperpolarized or depolarized beyond threshold values of around -250 to -300 mV and +200 to +250 mV, respectively. Current-voltage curves obtained with ramp protocols revealed that the electro-permeabilized membrane was 5-10 times more permeable to K+ than to gluconate. The K+ channel blocker tetraethylammonium (25 mM) did not affect currents elicited by 10 ms-pulses, suggesting that the electro permeabilization was not caused by a non-physiological activation of K+ channels. Supra-physiological voltage pulses even reduced "regular" K+ channel activity, probably due to an increase of cytosolic Ca2+ that is known to inhibit outward rectifying K+ channels in Bright yellow-2 cells. Our data are consistent with a reversible formation of aqueous membrane pores at supra-physiological voltages. PMID- 21296051 TI - Sex differences in expression and subcellular localization of heart rhythm determinant proteins. AB - To evaluate sex differences in protein expression in the heart, we performed Western blot studies on a subset of Heart Rhythm Determinant (HRD) proteins. We examined key components of a variety of types of mechanical and electrical junctions including, connexin43, plakophilin-2, N-cadherin and plakoglobin, ankyrin-2 and actin. We describe novel findings in sex differences in cardiac protein expression and membrane localization. For most proteins examined, sex differences were significantly more pronounced in the membrane compartment than in overall expression. These studies extend our previous findings in microarray studies to demonstrate that sex differences in gene expression are likely to confer distinct functional properties on male and female myocardium. PMID- 21296052 TI - Irbesartan increased PPARgamma activity in vivo in white adipose tissue of atherosclerotic mice and improved adipose tissue dysfunction. AB - The effect of the PPARgamma agonistic action of an AT(1) receptor blocker, irbesartan, on adipose tissue dysfunction was explored using atherosclerotic model mice. Adult male apolipoprotein E-deficient (ApoEKO) mice at 9 weeks of age were treated with a high-cholesterol diet (HCD) with or without irbesartan at a dose of 50mg/kg/day for 4 weeks. The weight of epididymal and retroperitoneal adipose tissue was decreased by irbesartan without changing food intake or body weight. Treatment with irbesartan increased the expression of PPARgamma in white adipose tissue and the DNA-binding activity of PPARgamma in nuclear extract prepared from adipose tissue. The expression of adiponectin, leptin and insulin receptor was also increased by irbesartan. These results suggest that irbesartan induced activation of PPARgamma and improved adipose tissue dysfunction including insulin resistance. PMID- 21296053 TI - Fluctuations in nuclear envelope's potential mediate synchronization of early neural activity. AB - Neural progenitor cells and developing neurons show periodic, synchronous Ca(2+) rises even before synapse formation, and the origin of the synchronous activity remains unknown. Here, fluorescence measurement revealed that the membrane potential of the nuclear envelope, which forms an intracellular Ca(2+) store, changed with a release of Ca(2+) and generated spontaneous, periodic bursts of fluctuations in potential. Furthermore, changes in the nuclear envelope's potential underlay spike burst generations. These results support the model that voltage fluctuations of the nuclear envelope synchronize Ca(2+) release between cells and also function as a current noise generator to cause synchronous burst discharges. PMID- 21296054 TI - O2-mediated oxidation of ferrous nitrosylated human serum heme-albumin is limited by nitrogen monoxide dissociation. AB - Human serum heme-albumin (HSA-heme-Fe) displays globin-like properties. Here, kinetics of O(2)-mediated oxidation of ferrous nitrosylated HSA-heme-Fe (HSA-heme Fe(II)-NO) is reported. Values of the first-order rate constants for O(2) mediated oxidation of HSA-heme-Fe(II)-NO (i.e., for ferric HSA-heme-Fe formation) and for NO dissociation from HSA-heme-Fe(II)-NO (i.e., for NO replacement by CO) are k=9.8 * 10(-5) and 8.3 * 10(-4) s(-1), and h=1.3 * 10(-4) and 8.5 * 10(-4) s( 1), in the absence and presence of rifampicin, respectively, at pH=7.0 and T=20.0 degrees C. The coincidence of values of k and h indicates that NO dissociation represents the rate limiting step of O(2)-mediated oxidation of HSA-heme-Fe(II) NO. Mixing HSA-heme-Fe(II)-NO with O(2) does not lead to the formation of the transient adduct(s), but leads to the final ferric HSA-heme-Fe derivative. These results reflect the fast O(2)-mediated oxidation of ferrous HSA-heme-Fe and highlight the role of drugs in modulating allosterically the heme-Fe-atom reactivity. PMID- 21296055 TI - Translational medicine special issue. PMID- 21296056 TI - Catalytic reduction of carbonyl groups in oxidized PAPC by Kvbeta2 (AKR6). AB - The beta-subunits of the voltage-gated potassium channel (Kvbeta) belong to the aldo-keto reductase superfamily. The Kvbeta-subunits dock with the pore-forming Kv alpha-subunits and impart or accelerate the rate of inactivation in Kv channels. Inactivation of Kv currents by Kvbeta is differentially regulated by oxidized and reduced pyridine nucleotides. In mammals, AKR6 family is comprised of 3 different genes Kvbeta1-3. We have shown previously that Kvbeta2 catalyzes the reduction of a broad range of carbonyls including aromatic carbonyls, electrophilic aldehydes and prostaglandins. However, the endogenous substrates for Kvbeta have not been identified. To determine whether products of lipid oxidation are substrates of Kvbetas, we tested the enzymatic activity of Kvbeta2 with oxidized phospholipids generated during the oxidation of 1-palmitoyl-2 arachidonoyl-sn-glycero-3-phosphocholine (PAPC). Electrospray ionization mass spectrometric analysis showed that Kvbeta2 catalyzed the NADPH-dependent reduction of several products of oxPAPC, including 1-palmitoyl-2-(5-oxovaleroyl) sn-glycero-3-phosphorylcholine (POVPC), 1-palmitoyl-2-(epoxycyclopentenone)-sn glycero-3-phosphorylcholine (PECPC), 1-palmitoyl-2-(5,6)- epoxyisoprostane E2-sn glycero-3-phosphocholine (PEIPC). These results were validated using high resolution mass spectrometric analysis. Time course analysis revealed that the reduced products reached significant levels for ions at m/z 594/596 (POVPC/PHVPC), 810/812 (PECPC/2H-PECPC) and 828/830 (PEIPC/2H-PEIPC) in the oxPAPC+Kvbeta2 mixture (p<0.01). These results suggest that Kvbeta could serve as a sensor of lipid oxidation via its catalytic activity and thereby alter Kv currents under conditions of oxidative stress. PMID- 21296057 TI - Comparative studies of vertebrate aldehyde dehydrogenase 3: sequences, structures, phylogeny and evolution. Evidence for a mammalian origin for the ALDH3A1 gene. AB - Mammalian ALDH3 genes (ALDH3A1, ALDH3A2, ALDH3B1 and ALDH3B2) encode enzymes of peroxidic and fatty aldehyde metabolism. ALDH3A1 also plays a major role in anterior eye tissue UV-filtration. BLAT and BLAST analyses were undertaken of several vertebrate genomes using rat, chicken and zebrafish ALDH3-like amino acid sequences. Predicted vertebrate ALDH3 sequences and structures were highly conserved, including residues involved in catalysis, coenzyme binding and enzyme structure as reported by Liu et al. [27] for rat ALDH3A1. Phylogeny studies of human, rat, opossum, platypus, chicken, xenopus and zebrafish ALDH3-like sequences supported three hypotheses: (1) the mammalian ALDH3A1 gene was generated by a tandem duplication event of an ancestral vertebrate ALDH3A2 gene; (2) multiple mammalian and chicken ALDH3B-like genes were generated by tandem duplication events within genomes of related species; and (3) vertebrate ALDH3A and ALDH3B genes were generated prior to the appearance of bony fish more than 500 million years ago. PMID- 21296058 TI - Inactivation of porcine kidney betaine aldehyde dehydrogenase by hydrogen peroxide. AB - Concentrated urine formation in the kidney is accompanied by conditions that favor the accumulation of reactive oxygen species (ROS). Under hyperosmotic conditions, medulla cells accumulate glycine betaine, which is an osmolyte synthesized by betaine aldehyde dehydrogenase (BADH, EC 1.2.1.8). All BADHs identified to date have a highly reactive cysteine residue at the active site, and this cysteine is susceptible to oxidation by hydrogen peroxide. Porcine kidney BADH incubated with H(2)O(2) (0-500 MUM) lost 25% of its activity. However, pkBADH inactivation by hydrogen peroxide was limited, even after 120 min of incubation. The presence of coenzyme NAD(+) (10-50 MUM) increased the extent of inactivation (60%) at 120 min of reaction, but the ligands betaine aldehyde (50 and 500 MUM) and glycine betaine (100 mM) did not change the rate or extent of inactivation as compared to the reaction without ligand. 2-Mercaptoethanol and dithiothreitol, but not reduced glutathione, were able to restore enzyme activity. Mass spectrometry analysis of hydrogen peroxide inactivated BADH revealed oxidation of M278, M243, M241 and H335 in the absence and oxidation of M94, M327 and M278 in the presence of NAD(+). Molecular modeling of BADH revealed that the oxidized methionine and histidine residues are near the NAD(+) binding site. In the presence of the coenzyme, these oxidized residues are proximal to the betaine aldehyde binding site. None of the oxidized amino acid residues participates directly in catalysis. We suggest that pkBADH inactivation by hydrogen peroxide occurs via disulfide bond formation between vicinal catalytic cysteines (C288 and C289). PMID- 21296059 TI - Optimizing preclinical study design in oncology research. AB - The current drug development pathway in oncology research has led to a large attrition rate for new drugs, in part due to a general lack of appropriate preclinical studies that are capable of accurately predicting efficacy and/or toxicity in the target population. Because of an obvious need for novel therapeutics in many types of cancer, new compounds are being investigated in human Phase I and Phase II clinical trials before a complete understanding of their toxicity and efficacy profiles is obtained. In fact, for newer targeted molecular agents that are often cytostatic in nature, the conventional preclinical evaluation used for traditional cytotoxic chemotherapies utilizing primary tumor shrinkage as an endpoint may not be appropriate. By utilizing an integrated pharmacokinetic/pharmacodynamic approach, along with proper selection of a model system, the drug development process in oncology research may be improved leading to a better understanding of the determinants of efficacy and toxicity, and ultimately fewer drugs that fail once they reach human clinical trials. PMID- 21296060 TI - Drosophila lacking a homologue of mammalian ALDH2 have multiple fitness defects. AB - Little is known about the roles of aldehyde dehydrogenases in non-vertebrate animals. We recently showed that in Drosophila melanogaster, an enzyme with ~70% amino acid identity to mammalian ALDH2 is necessary for detoxification of dietary ethanol. To investigate other functions of this enzyme, DmALDH, encoded by the gene Aldh, we compared two strains homozygous for Aldh-null mutations to two closely related wild type strains in measures of fitness and stress resistance in the absence of ethanol. Aldh-null strains have lower total reproductive rate, pre adult viability, resistance to starvation, and possibly longevity than wild-type strains. When maintained under hyperoxia, Aldh nulls die more quickly and accumulate higher levels of protein carbonyls than wild-types, thereby providing evidence that DmALDH is important for detoxifying reactive aldehydes generated by lipid peroxidation. However no effect of Aldh was seen on protein carbonyl levels in flies maintained under normoxia. It is possible that Aldh nulls experience elevated rates of protein carbonylation under normoxia, but this is compensated (at a fitness cost) by increased rates of degradation of the defective proteins. Alternatively, the fitness defects of Aldh nulls under normoxia may result from the absence of one or more other functions of DmALDH, unrelated to protection against protein carbonylation. PMID- 21296061 TI - NF-kappaB-mediated anti-inflammatory activity of the sesquiterpene lactone 7 hydroxyfrullanolide. AB - Microarray technology can be used to study the molecular mechanisms of new chemical entities with the aim to develop effective therapeutics. 7 Hydroxyfrullanolide (7HF) is a sesquiterpene lactone that was found to be efficacious in multiple animal models of inflammation by suppression of pro inflammatory cytokines; however, its molecular mechanism of action remains unclear. We investigated the effects of 7HF on lipopolysaccharide (LPS) stimulated human peripheral blood mononuclear cells using microarray-based gene expression studies and explored the molecular targets affected. Gene expression profiles and pathway analysis revealed that 7HF potently suppressed multiple inflammatory pathways induced by LPS. More importantly, 7HF was found to inhibit NF-kappaB related transcripts. These transcripts were further validated using freshly isolated synovial cells from rheumatoid arthritis patients, thus clinically validating our findings. Cell-based imaging and subsequent Western blot analysis demonstrated that 7HF inhibited the translocation of NF-kappaB into the nucleus by directly inhibiting the phosphorylation of IKK-beta. Since the transcription of adhesion molecules is regulated by NF-kappaB, further investigation showed that 7HF dose-dependently suppressed ICAM-1, VCAM-1 and E selectin expression on LPS-stimulated endothelial cells as well as inhibited the adhesion of monocytes to LPS-stimulated endothelial cells. Taken together, our results reveal that 7HF possesses NF-kappaB inhibitory potential and suggest a likely molecular mechanism of its anti-inflammatory activity. PMID- 21296062 TI - Blocking TNF-alpha by combination of TNF-alpha- and TNFR-binding cyclic peptide ameliorates the severity of TNBS-induced colitis in rats. AB - Tumor necrosis factor alpha (TNF-alpha) has been implicated in the pathogenesis of Crohn's disease. TNF antagonists are effectively used to treat these patients, although the efficiency of different antagonists varies. In the present study we combined TNF-alpha binding cyclic peptide (TBCP) and TNFR1 binding cyclic peptide (TRBCP) to treat TNBS-induced colitis in rats for one week. The symptoms of colitis including bloody diarrhea, rectal prolapse, and a profound and sustained weight loss were significantly ameliorated and the colon inflammatory damage, both macroscopic and histological scores, MPO activity, and NO production were markedly decreased in rats by neutralization of TNF-alpha and blocking TNFR1, as compared with those in rats treated with irrelevant peptide or normal saline (P<0.05). The transcripts of IL-1beta and IL-8, and the protein expression of TNF alpha in rats treated with both TBCP and TRBCP were also down-regulated (P<0.05), while these proinflammatory cytokines remained unchanged in rats treated with irrelevant peptide or normal saline. These findings suggest that the combination of TNF-alpha- and TNFR1-binding peptide effectively improves the symptoms of TNBS induced colitis and alleviates colonic pathological damages in rats. This combination may be a potent candidate for clinical treatment of the inflammatory bowel disease. PMID- 21296063 TI - beta-receptor antagonist treatment prevents activation of cell death signaling in the diabetic heart independent of its metabolic actions. AB - We have previously shown that metoprolol improves function in the diabetic heart, associated with inhibition of fatty acid oxidation and a shift towards protein kinase B signaling. The aim of this study was to determine the relative importance of these metabolic and signaling effects to the prevention of cellular damage. Diabetes was induced in male Wistar rats by a single IV injection of 60mg/kg streptozotocin, and treated groups received 15mg/kg/day metoprolol delivered subcutaneously by osmotic pumps. Echocardiography was performed 6weeks after streptozotocin injection, and the hearts immediately excised for histological and biochemical measurements of lipotoxicity, apoptosis, signaling and caveolin/caspase interactions. Metoprolol improved stroke volume and cardiac output, associated with attenuation of TUNEL staining and a more modest attenuation of caspase-3; however, the positive TUNEL staining was not associated with an increase in apoptosis or cell regeneration markers. Metoprolol inhibited CPT-1 without affecting CD36 translocation, associated with increased accumulation of triglycerides and long chain acyl CoA in the cytoplasm, and no effect on oxidative stress. Metoprolol induced a shift from protein kinase A to protein kinase B-mediated signaling, associated with a shift in the phosphorylation patterns of BCl-2 and Bad which favored BCl-2 action. Metoprolol also increased the interaction of activated caspase-3 with caveolins 1 and 3 outside caveolae. The actions of metoprolol on fatty acid oxidation do not prevent lipotoxicity; its beneficial effect is more likely to be due to pro survival signaling and sequestration of activated caspase-3 by caveolins. PMID- 21296064 TI - Sac-0601 prevents retinal vascular leakage in a mouse model of diabetic retinopathy. AB - Endothelium integrity is important for the normal functioning of vessels, the disruption of which can lead to disease. The blood-retinal barrier required for normal retinal function is compromised in diabetic retinopathy, causing retinal vascular leakage. Previously, we demonstrated the ability of Sac-0601[((2R,3S)-3 acetoxy-6-((3S,10R,13R,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl) 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3 yloxy)-3,6-dihydro-2H-pyran-2-yl)methyl acetate], a pseudo-sugar derivative of cholesterol, to increase survival of retinal endothelial cells. In the present study, we evaluated the ability of Sac-0601 to prevent retinal vascular leakages in vitro and in vivo. Sac-0601 treatment blocked VEGF-induced formation of actin stress fibers and stabilized the cortical actin ring in retinal endothelial cells. It also inhibited degradation of occludin, an important tight junction protein, and blocked VEGF-induced disruption of its linear pattern at the cell border. The [(14)C] sucrose permeability assay demonstrated that Sac-0601 was able to prevent VEGF-induced retinal endothelial permeability. The compound inhibited the vascular leakage in retina of mice intravitreally injected with VEGF. And it also significantly reduced the leakage in retina of diabetic retinopathy mice model. Taken together, our findings suggest the potential therapeutic usefulness of Sac-0601 for retinal vascular permeability diseases. PMID- 21296065 TI - Development of a high throughput screen for allosteric modulators of melanocortin 4 receptor signaling using a real time cAMP assay. AB - The melanocortin MC(4) receptor is a potential target for the development of drugs for both obesity and cachexia. Melanocortin MC(4) receptor ligands known thus far are orthosteric agonists or antagonists, however the agonists, in particular, have generally exhibited unwanted side effects. For some receptors, allosteric modulators are expected to reduce side-effect profiles. To identify allosteric modulators of the melanocortin MC(4) receptor, we created HEK293 cell lines coexpressing the human melanocortin MC(4) receptor and a modified luciferase-based cAMP sensor. Monitoring luminescence as a readout of real-time intracellular cAMP concentration, we demonstrate that this cell line is able to report melanocortin agonist responses, as well as inverse agonist response to the physiological AgRP peptide. Based on the MC4R-GLO cell line, we developed an assay that was shown to meet HTS standards (Z'=0.50). A pilot screen run on the Microsource Spectrum compound library (n=2000) successfully identified 62 positive modulators. This screen identified predicted families of compounds: beta(2)AR agonists - the beta(2)AR being endogenously expressed in HEK293 cells, an adenylyl cyclase activator and finally a distribution of phosphodiesterase (PDE) inhibitors well characterized or recently identified. In this last category, we identified a structural family of coumarin-derived compounds (imperatorin, osthol and prenyletin), along with deracoxib, a drug in veterinary use for its COX2 inhibitory properties. This latter finding unveiled a new off target mechanism of action for deracoxib as a PDE inhibitor. Overall, these data are the first report of a HTS for allosteric modulators for a Gs protein coupled receptor. PMID- 21296066 TI - Recombinant human erythropoietin ameliorated endothelial dysfunction and macrophage infiltration by increasing nitric oxide in hypertensive 5/6 nephrectomized rat aorta. AB - Recombinant human erythropoietin (rHuEPO), used clinically for renal anemia, reportedly exhibits pleiotropic properties in various tissues. To test whether it ameliorates vascular injury, rHuEPO (75U/kg) was administered subcutaneously every 3days for 10days to 5/6 nephrectomized hypertensive rats (5/6Nx) treated with 1% NaCl. rHuEPO had no effect on increased systolic blood pressure or decreased hematocrit values, but normalized levels of proteinuria and creatinine clearance. Vasodilation in response to acetylcholine in the aortic ring was impaired in the 5/6Nx, and improved by treatment with rHuEPO. Immunohistochemical analysis revealed that the infiltration of adventitial areas by macrophages and expression of osteopontin were enhanced in the 5/6Nx aorta and the overexpression was suppressed by rHuEPO. rHuEPO also attenuated medial hyperplasia. Akt signaling was activated by the increased expression of phosphorylated Akt and GSK 3beta in aorta from rHuEPO-treated 5/6Nx. rHuEPO restored plasma NOx (NO(2)( )+NO(3)(-)) levels and endothelial nitric oxide synthase (eNOS) content in the 5/6Nx aorta. Treatment with an eNOS substrate, l-arginine, which caused a similar increase in plasma NOx levels as the rHuEPO treatment, resulted in a normalization of endothelial dysfunction and vascular inflammation. These results suggest that a low dose of rHuEPO exerted vasoprotective effects in rats with hypertensive renal failure. PMID- 21296067 TI - Down-regulation of ICBP90 contributes to doxorubicin resistance. AB - Acquired resistance to doxorubicin has become a serious obstacle in breast cancer treatment. The underlying mechanism responsible for this has not been completely elucidated. In this study, a doxorubicin-resistant MCF-7/Dox cell was developed to mimic the occurrence of acquired doxorubicin resistance. We next contrasted the expression profiles of ICBP90 and Topo IIalpha and tumor cell growth of different breast cancer cell lines to doxorubicin. Decreased expression levels of ICBP90 and Topo IIalpha were found in doxorubicin-resistant cells. To examine its function in chemoresistance, RNA interference (RNAi) and forskolin stimulation experiments further demonstrated that ICBP90 and Topo IIalpha were involved in the proliferation of cells that had acquired doxorubicin resistance. In MCF-7/Dox and ICBP90-siRNA cells, the cell growth wasn't inhibited by doxorubicin and preferentially arrested in G1 phase. However, after forskolin increased the Topo IIalpha expression, these breast cancer cells were again found to be inhibited by doxorubicin. Further, immunohistochemical assay breast cancer patients accepted EFC regimen showed ICBP90 was significantly associated with tumor cell proliferation, locally advanced disease and Topo IIalpha expression. In conclusion, down-regulation of ICBP90 induced the descended expression of Topo IIalpha protein which is the target enzyme of doxorubicin. PMID- 21296068 TI - Geranylgeraniol and 6alpha,7beta-dihydroxyvouacapan-17beta-oate methyl ester isolated from Pterodon pubescens Benth.: Further investigation on the antinociceptive mechanisms of action. AB - The crude alcoholic extracts obtained from Pterodon pubescens Benth. seeds are widely used in Brazilian folk medicine as anti-inflammatory, analgesic, anti rheumatic tonics and depurative preparations. We previously demonstrated the antinociceptive activity on writhing capsaicin, glutamate, and hot-plate tests of two compounds isolated from P. pubescens: geranylgeraniol (C1) and 6alpha,7beta dihydroxyvouacapan-17beta-oate methyl ester (C2). This work is a continuation of the previous study investigating the possible mechanisms of action for compounds C1 and C2, and the differences between them. The present study demonstrated that when administered intraperitoneally (i.p.): i), compounds C1 and C2 produced significant anti-allodynic activity during the acute phase of the Complete Freund's Adjuvant (CFA)-induced persistent pain model; ii) compound C1 produced significant anti-hypernociception activity in the carrageenan-induced pain model; iii) compound C2 presented a significant loss of activity after p chlorophenylalanine methyl ester hydrochloride (PCPA) [5-HT synthesis inhibitor] treatment, suggesting that the mechanisms of action could be related to either the synthesis or release of serotonin; iv) compound C1 presented a significant loss of activity after ondansetron (5-HT(3) receptor antagonist) treatment suggesting activity upon 5-HT(3) serotonin receptors; v) compound C1 presented a significant loss of activity after efaroxan (mixed I(1) imidazoline/alpha(2) adrenoceptor antagonist) treatment suggesting the participation of this compound upon imidazoline I(1) receptors; and vi) both compounds C1 and C2 did not appear to exert their activity via 5-HT(1A), 5-HT(2A), imidazoline I(2), alpha(2) adrenoceptor, nitric oxide, GABA(A), acetylcholine muscarinic, and nicotinic receptors when evaluated in acetic acid-induced nociception. PMID- 21296069 TI - 5-HT induces enhanced phrenic nerve activity via 5-HT(2A) receptor/PKC mechanism in anesthetized rats. AB - Respiratory behavior expresses diverse forms of plasticity by altering breathing patterns. Failure of respiratory neuroplasticity often leads to malfunctions. Long-term facilitation (LTF), the most frequently studied model induced by episodic hypoxia to produce long-lasting enhancement of phrenic motor output, is thought to be serotonin 2A (5-HT(2A)) receptor-dependent. Previous studies have described 5-HT-induced prompt apnea in intact animals. However, the role of exogenous 5-HT in mediating respiratory neuroplasticity is less attended in vivo study. We hypothesized that an in vivo 5-HT challenge contributes to respiratory neuroplasticity. Here, we found that systemic bolus administration of 5-HT exerted an initial transient inhibition followed by marked facilitation, forming a biphasic pattern of phrenic nerve activity in artificially ventilated, midcervically vagotomized, and anesthetized adult rats. The facilitatory phase corresponded to the enhanced phrenic nerve activity that lasted for at least one hour after drug exposure, characterized as phrenic LTF (pLTF). The 5-HT-induced biphasic pattern and pLTF were 5-HT(2A) receptor-dependent and coupled to protein kinase C (PKC) activation. The initial inhibition of phrenic nerve activity was found to be nodose ganglion-associated, whereas the subsequent facilitation was carotid body-associated, establishing a peripheral inhibitory-facilitatory afferent balance. Immunoreactive expressions of 5-HT/5-HT(2A) receptors and phospho-PKC isoforms/PKC substrate provide morphological evidence of existence of a 5-HT/5-HT(2A) receptor/PKC mechanism in the nodose ganglion and the carotid body. We speculate that 5-HT challenge in vivo may contribute to respiratory neuroplasticity, to yield pLTF or augmented pLTF in animals with reduced or absent peripheral inhibitory inputs. PMID- 21296070 TI - ATP induces contraction mediated by the P2Y(2) receptor in rat intestinal subepithelial myofibroblasts. AB - Intestinal subepithelial myofibroblasts (IMFs) exist just under the epithelial membrane directly facing the mucosal microvascular capillary surface distributed in the lamina propria. In the gastrointestinal tract, ATP is released from epithelial and endothelial cells in response to mechanical stimuli. Although it has been reported that mechanical stimuli evoke synchronized Ca(2+) waves in cultured IMFs, the contractile responses by ATP stimulation have not been examined. The aim of this study was to clarify the mechanism of the contraction of IMFs in response to ATP. ATP (1-30MUM) induced contraction in a concentration dependent manner. These contractions were inhibited by LaCl(3) (100-300MUM) and by Ca(2+)-free solution (0.5mM EGTA). Fura-2/Ca(2+) signals indicated that ATP (1 10MUM) elicited transient increases in intracellular Ca(2+) concentration ([Ca(2+)](i)). In addition, alphabeta-methylene-ATP (10, 30 and 300MUM), a broad spectrum P2X agonist at a concentration higher than 100MUM, induced neither contraction nor [Ca(2+)](i) rise. UTP (1-30MUM), a selective P2Y(2) and P2Y(4) agonist in rodent, induced concentration-dependent contractions and [Ca(2+)](i) increases, whereas ADP and UDP (10MUM) did not induce contractions. Pretreatment with suramin (30-100MUM), a relatively selective P2Y(2) antagonist, strongly inhibited ATP- and UTP-induced contractions and [Ca(2+)](i) increases. However, pyridoxal-phosphate-6-azophenyl-2',4'-disulfonate (PPADS: 10-30MUM), a receptor antagonist for several P2X and P2Y but less effective to P2Y(2) receptor, failed to inhibit ATP- and UTP-induced contractions and [Ca(2+)](i) increases. By RT PCR, mRNA expressions of the P2Y(1) and P2Y(2) receptors, but not P2Y(4) or P2Y(6), were detected in IMFs. These results suggest that ATP induces [Ca(2+)](i) dependent contraction in IMFs, which is mediated through the P2Y(2) receptor. PMID- 21296071 TI - The galactosylation of N(omega)-nitro-L-arginine enhances its anti-nocifensive or anti-allodynic effects by targeting glia in healthy and neuropathic mice. AB - This study has investigated whether the galactosyl ester prodrug of N(omega) nitro-L-arginine (NAGAL), shows enhanced analgesic efficacy in healthy mice and in models of visceral and neuropathic pain: the writhing test and the spared nerve injury (SNI), respectively. NAGAL was compared to methyl ester pro-drug of N(omega)-nitro-l-arginine (L-NAME), a widely exploited non-specific nitric oxide synthase (NOS) inhibitor, for analgesic potential. The writhing test revealed that the ED(50) value, along with the 95% confidence limit (CL) was 3.82 (1.77 6.04) mg/kg for NAGAL and, 36.75 (20.07-68.37) mg/kg for L-NAME. Notably, NAGAL elicited a greater anti-allodynic effect than L-NAME did in neuropathic mice. Biomolecular and morphological studies revealed that spared nerve injury increased the expressions of pro-inflammatory enzymes (caspase-1) and two glial cell biomarkers: integrin alpha M (ITGAM) and glial fibrillary acidic protein (GFAP) in the spinal cord. Finally, GLUT-3, an isoform of the hexose transporters capable to bind NAGAL and inducible NOS (iNOS), were found to be over-expressed in the activated astrocytes of the spinal cord of neuropathic mice. NAGAL administration normalized expression levels of these biomarkers. NAGAL showed a greater efficacy in inhibiting visceral pain and allodynia than L-NAME possibly by a greater cell permeation through the hexose transporter which is highly over expressed by activated glia. PMID- 21296072 TI - Hypoxic preconditioning with cobalt ameliorates hypobaric hypoxia induced pulmonary edema in rat. AB - Exposure to high altitude results in hypobaric hypoxia which is considered as an acute physiological stress and often leads to high altitude maladies such as high altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE). The best way to prevent high altitude injuries is hypoxic preconditioning which has potential clinical usefulness and can be mimicked by cobalt chloride. Preconditioning with cobalt has been reported to provide protection in various tissues against ischemic injury. However, the effect of preconditioning with cobalt against high altitude induced pulmonary edema has not been investigated in vivo. Therefore, in the present study, rats pretreated with saline or cobalt (12.5mg/kg body weight) for 7days were exposed to hypobaric hypoxia of 9142m for 5h at 24 degrees C. Formation of pulmonary edema was assessed by measuring transvascular leakage of sodium fluorescein dye and lung water content. Total protein content, albumin content, vascular endothelial growth factor (VEGF) and cytokine levels were measured in bronchoalveolar lavage fluid. Expression of HO 1, MT, NF-kappaB DNA binding activity and lung tissue pathology were evaluated to determine the effect of preconditioning on HAPE. Hypobaric hypoxia induced increase in transvascular leakage of sodium fluorescein dye, lung water content, lavage total protein, albumin, VEGF levels, pro-inflammatory cytokine levels, tissue expression of cell adhesion molecules and NF-kappaB DNA binding activity were reduced significantly after hypoxic preconditioning with cobalt. Expression of anti-inflammatory protein HO-1, MT, TGF-beta and IL-6 were increased after hypoxic preconditioning. These data suggest that hypoxic preconditioning with cobalt has protective effect against HAPE. PMID- 21296073 TI - Direct inhibition of the transient voltage-gated K(+) currents mediates the excitability of tetrodotoxin-resistant neonatal rat nodose ganglion neurons after ouabain application. AB - The purpose of the present study was to determine the relationship between the responses of transient and sustained K(+) currents, and action potentials to ouabain, and to compare the immunoreactive expression of alpha Na(+)-K(+)-ATPase isoforms (alpha(1), alpha(2) and alpha(3)) in neonatal rat small-diameter nodose ganglion neurons. We used perforated patch-clamp techniques. We first confirmed that the neurons (n=20) were insensitive to 0.5 MUM tetrodotoxin (TTX). Application of 1 MUM ouabain 1) decreased the transient K(+) currents in 60% of neurons and the sustained K(+) currents in 20%, 2) increased voltage-gated transient and sustained K(+) currents in 20% of neurons, and 3) had no effect on transient K(+) currents in 20% of neurons and on sustained K(+) currents in 60%. Thirteen of the neurons were of a rapidly adapting type, and the remaining 7 were of a slowly adapting type. In 6 rapidly adapting type neurons (46%), their activity was not significantly altered by ouabain application, but in 4 rapidly adapting type neurons, the activity increased. In the remaining 3 rapidly adapting type neurons, ouabain application hyperpolarized the resting membrane potential. The slowly adapting type 7 neurons each showed increased activity after 1 MUM ouabain application. The alpha(1) isoform of Na(+)-K(+)-ATPase was identified as the predominant immunoreactive isoforms in small-diameter nodose ganglion neurons. These results suggest that the increased activity of small diameter nodose ganglion neurons seen after application of 1 MUM ouabain is mediated by direct inhibition of the transient K(+) current. PMID- 21296074 TI - Identification of angular naphthopyrones from the Philippine echinoderm Comanthus species as inhibitors of the NF-kappaB signaling pathway. AB - The redox-sensitive nuclear factor kappa-B (NF-kappaB) signaling pathway is an important cellular pathway often misregulated in various cancer cells. Therefore, blockade of NF-kappaB signaling in cancer cells presents a promising strategy and enormous effort has been invested to identify potent and specific inhibitors. The aim of this study was the identification of new compounds derived from marine organisms that act as NF-kappaB inhibitors and to identify their mechanism of action. In the present work a bioassay-guided investigation of a Philippine specimen of the marine echinoderm Comanthus sp. yielded ten compounds evenly divided into anthraquinones and naphthopyrones. From these compounds only two naphthopyrones, comaparvin and 6-methoxycomaparvin exhibited noteworthy inhibitory activity against tumor necrosis factor-alpha (TNF-alpha) induced NF kappaB activation in rat hepatoma cells and human breast cancer cells. Comaparvin at concentrations between 50MUM and 100MUM reduces chymotrypsin-like proteasomal activity, blocks nuclear translocation of NF-kappaB and effectively inhibits TNF alpha induced IkappaB phosphorylation suggesting a role of this compound in targeting IkappaB kinase (IKK). Furthermore, comaparvin sensitized cancer cells to apoptotic effects mediated by the pro-inflammatory cytokine TNF-alpha. These results correlate with downregulation of TNF-alpha induced expression of protective NF-kappaB target genes like MnSOD, XIAP or A20. In conclusion we identified the naphthopyrone comaparvin isolated from the marine echinoderm Comanthus sp. as a new inhibitor of the NF-kappaB signaling pathway acting by targeting both proteasome function and IkappaB phosphorylation likely by direct inhibitory effect on IKKbeta activity. PMID- 21296075 TI - The effect of interleukin-10 on apoptosis in macrophages stimulated by oxLDL. AB - Marked anti-atheromatous effects of the anti-inflammatory cytokine interleukin-10 (IL-10) were observed in several lipid-driven animal models of arteriosclerosis. We have previously demonstrated that IL-10 significantly inhibited lipid uptake in macrophages induced by oxLDL (Wang et al., 2008; Yang et al., 2008b). In this study, we investigated whether IL-10 affects the apoptosis related gene BCL2L11 and BMF expression in macrophages treated with oxLDL from THP-1 cells, which served as macrophage models. Cell apoptosis assays were performed by flow cytometry. Expression of the apoptosis related genes BCL2L11 and BMF mRNA was quantified by real-time RT-PCR (mRNA expression) and Western blotting (protein expression). IL-10 markedly blocked oxLDL induced cells undergoing early stage apoptosis. In the foam cell group, as compared with the macrophage group, the percentage of apoptosis increased by 100%. Here the expression of BCL2L11 was 45% (mRNA) and 41% (protein) elevated, while the expression of BMF was 54% (mRNA) and 44% (protein) elevated. When macrophages were co-stimulated by 100mg/l oxLDL and 20 MUg/l IL-10 for 24h, compared with the foam cell group, the percentage of the apoptosis decreased by 21%, the expression of apoptosis related gene BMF was inhibited, the expression of mRNA and protein was both depressed by 23% and 20%, respectively, but the BCL2L11 expression was unchanged. These results may explain why decrement of early stage apoptosis cells was observed during co-stimulation and raise the possibility that IL-10 reduces foam cell undergoing apoptosis partly through down-regulating the expression of BMF, which demonstrates a critical role of IL-10 in anti-atherogenesis. PMID- 21296076 TI - Involvement of the CD200 receptor complex in microglia activation in experimental glaucoma. AB - The interaction of the myeloid restricted molecule CD200R with its widely expressed ligand CD200 is involved in the down-regulation of microglia activation. In the present study, we examined the involvement of CD200R in microglia activation in experimental ocular hypertension to determine the role of microglia activation in retinal ganglion cell (RGC) death, the key pathological event in glaucoma. Experimental glaucoma was induced in adult Brown Norway rats by sclerosis of the episcleral veins with the injection of hypertonic saline. Immunohistochemical methods were used to determine the involvement of microglia using GFAP, CD45, OX42 and OX41 and the involvement of CD200 and CD200R in the optic nerve head. Our data demonstrate the increased presence of microglia within the optic nerve head during ocular hypertension, identified by positive staining with OX42 and OX41. The peak of microglia correlates with peak in RGC death at days 20-27 (T3) post OHT induction. In addition, CD200 and CD200R positive cells were increased in ocular hypertensive eyes. Increased expression of CD200 was detected in the early phase (days 1-7; T1) of OHT and decreased over time, whilst the expression of CD200R was detected in the middle phase (days 20-27; T3) of OHT, correlating with the increase in microglia markers. Changes in the expression of CD200R/CD200 occur early in experimental glaucoma and precede the peak in microglia infiltration and RGC death, suggesting that CD200R-positive microglia play an important role in the initiation of RGC death during OHT, indicating a potential area for therapeutic intervention in treating glaucoma. PMID- 21296077 TI - Toxoplasma gondii RH Ankara: production of evolving tachyzoites using a novel cell culture method. AB - Toxoplasma gondii is one of the most researched parasite due to its easy growth both in vitro and in vivo. Tachyzoites, derived from mouse or rat peritoneum encounters ethical and economical problems when used for research or diagnostic purposes. Currently, research has focused on determining the most suitable cell culture environment to reach highest amount of viable tachyzoites with least host cell contamination. However, gene expression changes that take place throughout the adaptation of evolving T. gondii strains to continuous cell cultures appear as a problem. The present study aimed to determine a novel cell culture strategy for T. gondii RH Ankara strain tachyzoites to harvest abundant tachyzoites with least host cell contamination and minimal antigenic variation at predetermined dates to use as an antigen source in serological assays that will facilitate reduction in animal use. To achieve this purpose, T. gondii RH Ankara strain tachyzoites were incubated with HeLa cell at different ratios for two or three days. In all flasks incubated for two days, viability rate reached to 100% and HeLa cell contamination decreased to levels between 0.12-0.5*10(6)/ml. In the flasks with HeLa-tachyzoite ratio 1/8, the tachyzoite yield and viability ratio were 3*10(6)/ml and 100%, respectively, with accompanying 10 fold decrease (0.12*10(6)/ml) in HeLa contamination. During continuous production, highest tachyzoite yield was obtained from the first passage (3.55*10(6)/ml) and until the end of third subculture viability rates and HeLa cell contaminations were between 98.2-99.4% and 0.31-0.37*10(6)/ml, respectively. ELISA, IFA and Western blot analyses showed that the quality, specificity and sensitivity of the antigen harvested from the first passage of cell culture performed at two days intervals were comparable to the antigen harvested from mice and decreased in the following subcultures. Overall, these results demonstrated that T. gondii RH Ankara strain is still evolving to adapt to cell culture environment and therefore such strains continuously produced in cell cultures should be avoided for serological assays. However, the two day short interval cell culture method described herein offers a chance to reduce the animal use intended for the preparation of serological assays' antigen from local evolving strains. PMID- 21296078 TI - Evaluation of the co-agglutination test in diagnosis of experimental microsporidiosis. AB - Microsporidiosis is an emerging and opportunistic infection associated with wide range of clinical syndromes in humans. Confirmation of the presence of microsporidia in different samples is laborious, costly and often difficult. The present study was designed to evaluate the utility of the Co-agglutination test (Co-A test) for detection of urinary, fecal and circulating microsporidial antigens in experimentally infected mice. One hundred and twenty male Swiss albino mice were divided into non infected control and infected experimental groups which were further subdivided into two equal subgroups; immunosuppressed and immunocompetent. Microsporidial spores were isolated from human stools and identified to be Encephalitozoon intestinalis by the molecular methods. They were used to infect each subgroup of mice, then their urine, stools and sera were collected at the 1st, 3rd, 5th, 7th and 9th days post-infection (PI). Co-A test, using prepared hyperimmune serum, was used to detect antigens in all samples collected. The cross reactivity of microsporidial hyperimmune sera with antigens of Cyclospora cyatenensis and Cryptosporidium parvum was investigated by Co-A test. The results showed that Co-A test was effective in detecting microsporidial antigen in stool of immunosuppressed infected mice from the 1st day PI, and in urine and serum from the 3rd day PI till the end of the study. In the immunocompetent subgroup, Co-A test detected microsporidial antigens in stool, serum and urine of mice from the 1st day, 3rd day and the 5th day PI, respectively till the end of the study, without cross reactivity with C. cyatenensis or C. parvum in both subgroups. Co-A test proved to be simple and suitable tool for detecting microsporidial antigen in different specimens and did not need sophisticated equipment. It is very practical under field or rural conditions and in poorly equipped clinical laboratories. PMID- 21296079 TI - Evaluation of the role of angiogenic factors in the pathogenesis of schistosomiasis. AB - Schistosomiasis is one disease produced by helminths, which affect many people in tropical areas. Granuloma formation is the main mechanism involved in the pathogenesis of this disease. Experimental studies have demonstrated angiogenesis (blood vessels formation from pre-existing vessels) in the initial phase of granuloma formation. In the present work, VEGF (vascular endothelial growth factor) levels were analyzed in sera from people diagnosed with different helminthic infections. Patients with schistosomiasis and filariasis had significantly high VEGF levels in compared with healthy people and patients diagnosed with hookworms. In addition, the effects of angiogenesis inhibition using anti-angiogenic factors (endostatin) were evaluated in a schistosomiasis murine model. A lesion decrease was observed in mice infected with Schistosoma mansoni and treated with endostatin. Finally, mechanisms of angiogenesis induction were studied and observed that cercariae antigens stimulated the angiogenic factors by host alveolar macrophages. PMID- 21296080 TI - The Zbeta domain of human DAI binds to Z-DNA via a novel B-Z transition pathway. AB - The human DNA-dependent activator of IFN-regulatory factor (DAI) protein, which activates the innate immune response in response to DNA, contains two tandem Z DNA binding domains (Zalpha and Zbeta) at the NH(2) terminus. The hZbeta(DAI) structure is similar to other Z-DNA binding proteins, although it demonstrates an unusual Z-DNA recognition. We performed NMR experiments on complexes of hZbeta(DAI) with DNA duplex, d(CGCGCG)(2), at a variety of protein-to-DNA molar ratios. The results suggest that hZbeta(DAI) binds to Z-DNA via an active-di B-Z transition mechanism, where two hZbeta(DAI) proteins bind to B-DNA to form the hZbeta(DAI)-B-DNA complex; the B-DNA is subsequently converted to left-handed Z DNA. This novel mechanism of DNA binding and B-Z conversion is distinct from Z DNA binding of the human ADAR1 protein. PMID- 21296081 TI - The reduction of food web robustness by parasitism: fact and artefact. AB - A robust food web is one which suffers few secondary extinctions after primary species losses. While recent research has shown that a food web with parasitism is less robust than one without, it still remains unclear whether the reduction in robustness is due to changes in network complexity or unique characteristics associated with parasitism. Here, using several published food webs, simulation experiments with different food web models and extinction scenarios were conducted to elucidate how such reduction can be achieved. Our results show that, regardless of changes in network complexity and preferential parasitism, the reduction in food web robustness is mainly due to the life cycle constraint of parasites. Our findings further demonstrate that parasites are prone to secondary extinctions and that their extinctions occur earlier than those involving free living species. These findings suggest that the vulnerable nature of parasites to species loss makes them highly sensitive indicators of food web integrity. PMID- 21296082 TI - Membrane trafficking and organelle biogenesis in Giardia lamblia: use it or lose it. AB - The secretory transport capacity of Giardia trophozoites is perfectly adapted to the changing environment in the small intestine of the host and is able to deploy essential protective surface coats as well as molecules which act on epithelia. These lumen-dwelling parasites take up nutrients by bulk endocytosis through peripheral vesicles or by receptor-mediated transport. The environmentally resistant cyst form is quiescent but poised for activation following stomach passage. Its versatility and fidelity notwithstanding, the giardial trafficking systems appear to be the product of a general secondary reduction process geared towards minimization of all components and machineries identified to date. Since membrane transport is directly linked to organelle biogenesis and maintenance, less complexity also means loss of organelle structures and functions. A case in point is the Golgi apparatus which is missing as a steady-state organelle system. Only a few basic Golgi functions have been experimentally demonstrated in trophozoites undergoing encystation. Similarly, mitochondrial remnants have reached a terminally minimized state and appear to be functionally restricted to essential iron-sulfur protein maturation processes. Giardia's minimized organization combined with its genetic tractability provides unique opportunities to study basic principles of secretory transport in an uncluttered cellular environment. Not surprisingly, Giardia is gaining increasing attention as a model for the investigation of gene regulation, organelle biogenesis, and export of simple but highly protective cell wall biopolymers, a hallmark of all perorally transmitted protozoan and metazoan parasites. PMID- 21296084 TI - Metabolic scaling in insects supports the predictions of the WBE model. AB - The functional association between body size and metabolic rate (BS-MR) is one of the most intriguing issues in ecological physiology. An average scaling exponent of 3/4 is broadly observed across animal and plant taxa. The numerical value of 3/4 is theoretically predicted under the optimized version of West, Brown, and Enquist's vascular resource supply network model. Insects, however, have recently been proposed to express a numerically different scaling exponent and thus application of the WBE network model to insects has been rejected. Here, we re analyze whether such variation is indeed supported by a global deviation across all insect taxa at the order and family levels to assess if specific taxa influence insect metabolic scaling. We show that a previous reported deviation is largely due to the effect of a single insect family (Termitidae). We conclude that the BS-MR relationship in insects broadly supports the core predictions of the WBE model. We suggest that the deviation observed within the termites warrants further investigation and may be due to either difficulty in accurately measuring termite metabolism and/or particularities of their life history. Future work on allometric scaling should assess the nature of variation around the central tendencies in scaling exponents in order to test if this variation is consistent with core assumptions and predictions of the WBE model that stem by relaxing its secondary optimizing assumptions that lead to the 3/4 exponent. PMID- 21296083 TI - Methodology and application of flow cytometry for investigation of human malaria parasites. AB - Historically, examinations of the inhibition of malaria parasite growth/invasion, whether using drugs or antibodies, have relied on the use of microscopy or radioactive hypoxanthine uptake. These are considered gold standards for measuring the effectiveness of antimalarial treatments, however, these methods have well known shortcomings. With the advent of flow cytometry coupled with the use of fluorescent DNA stains allowed for increased speed, reproducibility, and qualitative estimates of the effectiveness of antibodies and drugs to limit malaria parasite growth which addresses the challenges of traditional techniques. Because materials and machines available to research facilities are so varied, different methods have been developed to investigate malaria parasites by flow cytometry. This review is intended to serve as a reference guide for advanced users and importantly, as a primer for new users, to support expanded use and improvements to malaria flow cytometry, particularly in endemic countries. PMID- 21296085 TI - Association of the disordered C-terminus of CDC34 with a catalytically bound ubiquitin. AB - Cell division cycle protein 34 (CDC34) is a key E2 ubiquitin (Ub)-conjugating enzyme responsible for the polyubiquitination of proteins controlling the G1/S stages of cell division. The acidic C-terminus of the enzyme is required for this function, although there is little structural information providing details for a mechanism. One logical time point involving the C-terminus is the CDC34-Ub thiolester complex that precedes Ub transfer to a substrate. To examine this, we used a CDC34-Ub disulfide complex that structurally mimics the thiolester intermediate. NMR spectroscopy was used to show that the CDC34 C-terminus is disordered but can intramolecularly interact with the catalytically bound Ub. Using chemical shift perturbation analysis, we mapped two interacting regions on the surface of Ub in the CDC34-Ub complex. The first site comprises a hydrophobic patch (typical of other Ub complexes) that associates with the CDC34 catalytic domain. A novel second site, dependent on the C-terminus of CDC34, comprises a lysine-rich surface (K6, K11, K29, and K33) on the opposite face of Ub. Further, NMR experiments show that this interaction is described by two slowly exchanging states-a compact conformation where the C-terminus of CDC34 interacts with bound Ub and an extended structure where the C-terminus is released. This work provides the first structural details that show how the C-terminus of CDC34 might direct a thiolester-bound Ub to control polyubiquitin chain formation. PMID- 21296086 TI - Effects of the known pathogenic mutations on the aggregation pathway of the amyloidogenic peptide of apolipoprotein A-I. AB - The 93-residue N-terminal fragment of apolipoprotein A-I (ApoA-I) is the major constituent of fibrils isolated from patients affected by the amyloidosis caused by ApoA-I mutations. We have prepared eight polypeptides corresponding to all the currently known amyloidogenic variants of the N-terminal region of ApoA-I, other than a truncation mutation, and investigated their aggregation kinetics and the associated structural modifications. All the variants adopted a monomeric highly disordered structure in solution at neutral pH, whereas acidification of the solution induced an unstable alpha-helical conformation and the subsequent aggregation into the cross-beta structure aggregate. Two mutations (Delta70-72 and L90P) almost abrogated the lag phase of the aggregation process, three mutations (Delta60-71, L75P, and W50R) significantly accelerated the aggregation rate by 2- to 3-fold, while the remaining three variants (L64P, L60R, and G26R) were not significantly different from the wild type. Therefore, an increase in aggregation propensity cannot explain per se the mechanism of the disease for all the variants. Prediction of the protection factors for hydrogen exchange in the native state of full-length protein reveals, in almost all the variants, an expansion of the conformational fluctuations that could favour the proteolytic cleavage and the release of the amyloidogenic peptide. Such an event seems to be a necessary prerequisite for ApoA-I fibrillogenesis in vivo, but the observed increased aggregation propensity of certain variants can have a strong influence on the severity of the disease, such as an earlier onset and a faster progression. PMID- 21296087 TI - Detection and characterization of the in vitro e3 ligase activity of the human MID1 protein. AB - Human MID1 (midline-1) is a microtubule-associated protein that is postulated to target the catalytic subunit of protein phosphatase 2A for degradation. It binds alpha4 that then recruits the catalytic subunit of protein phosphatase 2A. As a member of the TRIM (tripartite motif) family, MID1 has three consecutive zinc binding domains-RING (really interesting new gene), Bbox1, and Bbox2-that have similar betabetaalpha-folds. Here, we describe the in vitro characterization of these domains individually and in tandem. We observed that the RING domain exhibited greater ubiquitin (Ub) E3 ligase activity compared to the Bbox domains. The amount of autopolyubiquitinated products with RING-Bbox1 and RING-Bbox1-Bbox2 domains in tandem was significantly greater than those of the individual domains. However, no polyubiquitinated products were observed for the Bbox1-Bbox domains in tandem. Using mutants of Ub, we observed that these MID1 domain constructs facilitate Ub chain elongation via Lys63 of Ub. In addition, we observed that the high-molecular-weight protein products were primarily due to polyubiquitination at one site (Lys154) on the Bbox1 domain of the RING-Bbox1 and RING-Bbox1-Bbox2 constructs. We observed that MID1 E3 domains could interact with multiple E2 conjugating enzymes. Lastly, a 45-amino-acid peptide derived from the C-terminus of alpha4 that binds tightly to Bbox1 was observed to be monoubiquitinated in the assay and appears to down-regulate the amount of polyubiquitinated products formed. These studies shed light on MID1 E3 ligase activity and show how its three zinc-binding domains can contribute to MID1's overall function. PMID- 21296088 TI - Application of density similarities to predict membrane protein types based on pseudo-amino acid composition. AB - Cell membranes provide integrity of living cells. Although the stability of biological membrane is maintained by the lipid bilayer, membrane proteins perform most of the specific functions such as signal transduction, transmembrane transport, etc. Then it is plausible membrane proteins being attractive drug targets. In this article, based on the concept of using the pseudo-amino acid composition to define a protein, three different density similarities are developed for predicting the membrane protein type. The predicted results showed that the proposed approach can remarkably improve the accuracy, and might become a useful tool for predicting the other attributes of proteins as well. PMID- 21296089 TI - Building stable chains with motile agents: Insights into the morphology of enteric neural crest cell migration. AB - A defining characteristic of the normal development of the enteric nervous system (ENS) is the existence of an enteric neural crest (ENC) cell colonization wave, where the ENC cells form stable chains often associated with axons and near the vascular network. However, within this evolving neural network, the individual ENC cell elements constantly move, change direction and appear to act independently of neighbors. Three possible hypotheses are investigated. The simplest of these postulates that the ENS follows the vascular network as a template. We present evidence which does not support this hypothesis. Two viable alternatives are either that (i) the axons muster the ENC cells, providing the pattern for the chain migration or (ii) ENC cells form chains and the axons follow these paths. These two hypotheses are explored by developing a stochastic cellular automata model, where ENC agents follow simple rules, which reflect the underlying biology of movement, proliferation and differentiation. By simulating ENC precursors and the associated neurons and axons, two models with different fundamental mechanisms are developed. From local rules, a mesoscale network pattern with lacunae emerges, which can be analyzed quantitatively. Simulation and analysis establishes the parameters that affect the morphology of the resulting network. This investigation into the axon/ENC and ENC/ENC interplay suggests possible explanations for observations in mouse and avian embryos in normal and abnormal ENS development, as well as further experimentation. PMID- 21296091 TI - Existence of excitation waves for a collection of cardiomyocytes electrically coupled to fibroblasts. AB - We consider mathematical models of a collection of cardiomyocytes (myocardial tissue) coupled to a varying number of fibroblasts. Our aim is to understand how conductivity (delta) and fibroblast density (eta) affect the stability of the collection. We provide mathematical and computational arguments indicating that there is a region of instability in the eta-delta space. Mathematical arguments, based on a simplified model of the coupled myocyte-fibroblast system, show that for certain parameter choices, a stationary solution cannot exist. Numerical experiments (1D,2D) are based on a recently developed model of electro-chemical coupling between a human atrial myocyte and a number of associated atrial fibroblasts. The numerical experiments demonstrate that there is a region of instability of the form observed in the simplified model analysis. PMID- 21296090 TI - Current issues with acetaminophen hepatotoxicity--a clinically relevant model to test the efficacy of natural products. AB - There is a significant need to evaluate the therapeutic potential of natural products and other compounds purported to be hepatoprotective. Acetaminophen induced liver injury, especially in mice, is an attractive and widely used model for this purpose because it is both clinically relevant and experimentally convenient. However, the pathophysiology of liver injury after acetaminophen overdose is complex. This review describes the multiple steps and signaling pathways involved in acetaminophen-mediated cell death. The toxicity is initiated by the formation of a reactive metabolite, which depletes glutathione and binds to cellular proteins, especially in mitochondria. The resulting mitochondrial oxidant stress and peroxynitrite formation, in part through amplification by c jun-N-terminal kinase activation, leads to mitochondrial DNA damage and opening of the mitochondrial permeability transition pore. Endonucleases from the mitochondrial intermembrane space and lysosomes are responsible for nuclear DNA fragmentation. Despite the oxidant stress, lipid peroxidation is not a relevant mechanism of injury. The mitochondrial dysfunction and nuclear DNA damage ultimately cause oncotic necrotic cell death with release of damage-associated molecular patterns that trigger a sterile inflammatory response. Current evidence supports the hypothesis that innate immune cells do not contribute to injury but are involved in cell debris removal and regeneration. This review discusses the latest mechanistic aspects of acetaminophen hepatotoxicity and demonstrates ways to assess the mechanisms of drug action and design experiments needed to avoid pitfalls and incorrect conclusions. This review should assist investigators in the optimal use of this model to test the efficacy of natural compounds and obtain reliable mechanistic information. PMID- 21296092 TI - Effect of media-induced social distancing on disease transmission in a two patch setting. AB - We formulate an SIS epidemic model on two patches. In each patch, media coverage about the cases present in the local population leads individuals to limit the number of contacts they have with others, inducing a reduction in the rate of transmission of the infection. A global qualitative analysis is carried out, showing that the typical threshold behavior holds, with solutions either tending to an equilibrium without disease, or the system being persistent and solutions converging to an endemic equilibrium. Numerical analysis is employed to gain insight in both the analytically tractable and intractable cases; these simulations indicate that media coverage can reduce the burden of the epidemic and shorten the duration of the disease outbreak. PMID- 21296093 TI - Gene-dose dependent effects of methamphetamine on interval timing in dopamine transporter knockout mice. AB - The dopamine transporter (DAT) is the major regulator of the spatial and temporal resolution of dopaminergic neurotransmission in the brain. Hyperdopaminergic mice with DAT gene deletions were evaluated for their ability to perform duration discriminations in the seconds-to-minutes range. DAT -/- mice were unable to demonstrate temporal control of behavior in either fixed-interval or peak interval timing procedures, whereas DAT +/- mice were similar to DAT +/+ mice under normal conditions. Low to moderate-dose methamphetamine (MAP) challenges indicated that DAT +/- mice were less sensitive to the clock-speed enhancing effects of MAP compared with DAT +/+ mice. In contrast, DAT +/- mice were more vulnerable than DAT +/+ mice to the disruptive effects of MAP at high doses as revealed by the elevation of response rate in the right hand tail of the Gaussian shaped timing functions. Moreover, this treatment made DAT +/- mice functionally equivalent to DAT -/- mice in terms of the loss of temporal control. Taken together, these results demonstrate the importance of dopaminergic control of interval timing in cortico-striatal circuits and the potential link of timing dysfunctions to schizophrenia and drug abuse. PMID- 21296094 TI - Interneurons go plastic. PMID- 21296095 TI - Importance sampling for Lambda-coalescents in the infinitely many sites model. AB - We present and discuss new importance sampling schemes for the approximate computation of the sample probability of observed genetic types in the infinitely many sites model from population genetics. More specifically, we extend the 'classical framework', where genealogies are assumed to be governed by Kingman's coalescent, to the more general class of Lambda-coalescents and develop further Hobolth et al.'s (2008) idea of deriving importance sampling schemes based on 'compressed genetrees'. The resulting schemes extend earlier work by Griffiths and Tavare (1994), Stephens and Donnelly (2000), Birkner and Blath (2008) and Hobolth et al. (2008). We conclude with a performance comparison of classical and new schemes for Beta- and Kingman coalescents. PMID- 21296097 TI - Oxidative stress and oxidative damage in chemical carcinogenesis. AB - Reactive oxygen species (ROS) are induced through a variety of endogenous and exogenous sources. Overwhelming of antioxidant and DNA repair mechanisms in the cell by ROS may result in oxidative stress and oxidative damage to the cell. This resulting oxidative stress can damage critical cellular macromolecules and/or modulate gene expression pathways. Cancer induction by chemical and physical agents involves a multi-step process. This process includes multiple molecular and cellular events to transform a normal cell to a malignant neoplastic cell. Oxidative damage resulting from ROS generation can participate in all stages of the cancer process. An association of ROS generation and human cancer induction has been shown. It appears that oxidative stress may both cause as well as modify the cancer process. Recently association between polymorphisms in oxidative DNA repair genes and antioxidant genes (single nucleotide polymorphisms) and human cancer susceptibility has been shown. PMID- 21296096 TI - Current concepts on oxidative/carbonyl stress, inflammation and epigenetics in pathogenesis of chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is a global health problem. The current therapies for COPD are poorly effective and the mainstays of pharmacotherapy are bronchodilators. A better understanding of the pathobiology of COPD is critical for the development of novel therapies. In the present review, we have discussed the roles of oxidative/aldehyde stress, inflammation/immunity, and chromatin remodeling in the pathogenesis of COPD. An imbalance of oxidants/antioxidants caused by cigarette smoke and other pollutants/biomass fuels plays an important role in the pathogenesis of COPD by regulating redox-sensitive transcription factors (e.g., NF-kappaB), autophagy and unfolded protein response leading to chronic lung inflammatory response. Cigarette smoke also activates canonical/alternative NF-kappaB pathways and their upstream kinases leading to sustained inflammatory response in lungs. Recently, epigenetic regulation has been shown to be critical for the development of COPD because the expression/activity of enzymes that regulate these epigenetic modifications have been reported to be abnormal in airways of COPD patients. Hence, the significant advances made in understanding the pathophysiology of COPD as described herein will identify novel therapeutic targets for intervention in COPD. PMID- 21296098 TI - Identification of developmentally toxic drinking water disinfection byproducts and evaluation of data relevant to mode of action. AB - Reactions between chemicals used to disinfect drinking water and compounds present in source waters produce chemical mixtures containing hundreds of disinfection byproducts (DBPs). Although the results have been somewhat inconsistent, some epidemiological studies suggest associations may exist between DBP exposures and adverse developmental outcomes. The potencies of individual DBPs in rodent and rabbit developmental bioassays suggest that no individual DBP can account for the relative risk estimates reported in the positive epidemiologic studies, leading to the hypothesis that these outcomes could result from the toxicity of DBP mixtures. As a first step in a mixtures risk assessment for DBP developmental effects, this paper identifies developmentally toxic DBPs and examines data relevant to the mode of action (MOA) for DBP developmental toxicity. We identified 24 developmentally toxic DBPs and four adverse developmental outcomes associated with human DBP exposures: spontaneous abortion, cardiovascular defects, neural tube defects, and low birth weight infancy. A plausible MOA, involving hormonal disruption of pregnancy, is delineated for spontaneous abortion, which some epidemiologic studies associate with total trihalomethane and bromodichloromethane exposures. The DBP data for the other three outcomes were inadequate to define key MOA steps. PMID- 21296099 TI - Regulation of Bach2 by the aryl hydrocarbon receptor as a mechanism for suppression of B-cell differentiation by 2,3,7,8-tetrachlorodibenzo-p-dioxin. AB - Exposure to the aryl hydrocarbon receptor (AHR) agonist, 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) alters B-cell differentiation and suppresses antibody production. Previous genomic studies in mouse B cells identified Bach2 as a direct target of the AHR. Bach2 is known to repress expression of Prdm1, a key transcription factor involved in B-cell differentiation, by binding to Maf elements (MAREs) in the regulatory regions of the gene. Chromatin immunoprecipitation followed by quantitative PCR in TCDD-treated lipopolysaccharide (LPS)-activated B cells showed increased binding of the AHR within the first intron in the Bach2 gene. The binding was further confirmed by electrophoretic mobility shift assay (EMSA). TCDD also induced expression of Bach2 in activated as well as resting B cells from 2 to 24h post-treatment in a time- and concentration-dependent manner. Expression of Prdm1 was decreased by TCDD at 24h and was consistent with repression by Bach2. Increased DNA binding activity to the intron 5 MARE with increasing TCDD concentrations was observed by EMSA. Supershifts identified the presence of Bach2 in the DNA binding complex associated with the intron 5 MARE of Prdm1. Functional validation of the role of Bach2 in the suppression of B-cell differentiation by TCDD was performed using RNA interference (RNAi). Knockdown of Bach2 showed approximately 40% reversal in the TCDD-induced suppression of IgM secretion when compared to controls. The results suggest that the transcriptional regulation of Bach2 by the AHR is one of the mechanisms involved in the suppression of B-cell differentiation by TCDD. PMID- 21296100 TI - The potential reproductive, neurobehavioral and systemic effects of soluble sodium tungstate exposure in Sprague-Dawley rats. AB - The debate on tungsten (W) is fostered by its continuous usage in military munitions. Reports demonstrate W solubilizes in soil and can migrate into drinking water supplies and, therefore, is a potential health risk to humans. This study evaluated the reproductive, systemic and neurobehavioral effects of sodium tungstate (NaW) in rats following 70 days of daily pre-and postnatal exposure via oral gavage to 5, 62.5 and 125 mg/kg/day of NaW through mating, gestation and weaning (PND 0-20). Daily administration of NaW produced no overt evidence of toxicity and had no apparent effect on mating success or offspring physical development. Distress vocalizations were elevated in F(1) offspring from the high dose group, whereas righting reflex showed unexpected sex differences where males demonstrated faster righting than females; however, the effects were not dose-dependent. Locomotor activity was affected in both low and high-dose groups of F(1) females. Low-dose group showed increased distance traveled, more time in ambulatory movements and less time in stereotypic behavior than controls or high dose animals. The high-dose group had more time in stereotypical movements than controls, and less time resting than controls and the lowest exposure group. Maternal retrieval was not affected by NaW exposure. Tungsten analysis showed a systemic distribution of NaW in both parents and offspring, with preferential uptake within the immune organs, including the femur, spleen and thymus. Histopathological evidence suggested no severe chronic injury or loss of function in these organs. However, the heart showed histological lesions, histiocytic inflammation from minimal to mild with cardiomyocyte degeneration and necrosis in several P(0) animals of 125 mg NaW dose group. The result of this study suggests that pre and postnatal exposure to NaW may produce subtle neurobehavioral effects in offspring related to motor activity and emotionality. PMID- 21296101 TI - Past, present and emerging toxicity issues for jet fuel. AB - The US Air Force wrote the specification for the first official hydrocarbon-based jet fuel, JP-4, in 1951. This paper will briefly review the toxicity of the current fuel, JP-8, as compared to JP-4. JP-8 has been found to have low acute toxicity with the adverse effects being slight dermal irritation and weak dermal sensitization in animals. JP-4 also has low acute toxicity with slight dermal irritation as the adverse effect. Respiratory tract sensory irritation was greater in JP-8 than in JP-4. Recent data suggest exposure to jet fuel may contribute to hearing loss. Subchronic studies for 90 days with JP-8 and JP-4 showed little toxicity with the primary effect being male rat specific hydrocarbon nephropathy. A 1-year study was conducted for JP-4. The only tumors seen were associated with the male rat specific hydrocarbon nephropathy. A number of immunosuppressive effects have been seen after exposure to JP-8. Limited neurobehavioral effects have been associated with JP-8. JP-8 is not a developmental toxicant and has little reproductive toxicity. JP-4 has not been tested for immune, neurobehavioral or reproductive endpoints. JP-8 and JP-4 were negative in mutagenicity tests but JP-4 showed an increase in unscheduled DNA synthesis. Currently, JP-8 is being used as the standard for comparison of future fuels, including alternative fuels. Emerging issues of concern with jet fuels include naphthalene content, immunotoxicity and inhalation exposure characterization and modeling of complex mixtures such as jet fuels. PMID- 21296102 TI - Dynamical systems modeling of Continuous Flash Suppression. AB - Continuous Flash Suppression (CFS) is a technique in which a stationary image in one eye can be reliably suppressed by rapid presentation of different flashing images in the other. In this paper we address why flashing stimuli modulate the visibility of the stimuli. We determine, in particular, which type of neural network is sufficient for the modulation of the dominance duration, assuming that elemental units are endowed with reciprocal inhibition and adaptation. We show that the model introduced by Wilson (2007) reproduces flash suppression, which is considered to be involved in CFS, but does not reproduce CFS. We then extend the model by including a stimulus feature dimension. With this extension, we found that the model accounts for the modulation of visibility observed in CFS. In addition, this model captured some defining characteristics of CFS such as dependence on flash interval and the depth of suppression. Our findings suggest that a network with inhibition and adaptation including feature dimension provides a crucial mechanism for the modulation of the dominance duration in CFS. PMID- 21296103 TI - A lumpers versus splitters approach to sexual differentiation of the brain. AB - Over 50 years of rigorous empirical attention to the study of sexual differentiation of the brain has produced sufficient data to reveal fundamental guiding principles, but has also required the generation of new hypotheses to explain non-conforming observations. An early emphasis on the powerful impact and essential role of gonadal steroids is now complemented by an appreciation for genetic contributions to sex differences in the brain. The organizing effects of early steroid hormones on reproductively relevant brain regions and endpoints are largely dependent upon neuronal aromatization of androgens to estrogens. The effect of estradiol is mediated via estrogen receptors (ER). The presence or absence of ER can restrict hormone action to select cells and either prevent or invoke cell death. Alternatively, ER activation can initiate signaling cascades that induce cell-to-cell communication and thereby transduce organizational steroid effects to large numbers of cells. However, the specific details by which cell death and cell-to-cell communication are achieved appear to be locally, even cellularly, unique and specific to that particular subpopulation. As the field moves forward the increasingly specific and detailed elucidation of mechanism challenges us to generate new guiding principles in order to gain a holistic understanding of how the brain develops in males and females. PMID- 21296104 TI - Phosphodiesterase 4 inhibitors enhance sexual pleasure-seeking activity in rodents. AB - Pleasure-seeking deficits, including lack of libido, are a core feature of depression. Animal and preliminary clinical studies both suggest that phosphodiesterase 4 (PDE4) is a target for developing novel antidepressants. This study examined the potential involvement of PDE4 in the pathology of depression in both animal models and human postmortem brains. In humans, PDE4B and PDE4D levels were elevated in cingulate cortical tissue from individuals with major depressive disorder (MDD) compared to controls. Using the female urine smelling test (FUST), a recently refined method for monitoring sexual pleasure-seeking activity in mice, we found that icv infusion of selective potent PDE4 inhibitors enhanced sexual pleasure-seeking activity in male mice that underwent the learned helplessness or serotonin depletion paradigms. The infusion also increased sexual pleasure-seeking activity in naive male mice. The results suggest that PDE4 may be a plausible contributor to the sexual pleasure-seeking deficits seen in depressed patients; inhibiting PDE4 may restore these deficits. PMID- 21296105 TI - Fentanyl-trazodone-paracetamol triple drug combination: multimodal analgesia in a mouse model of visceral pain. AB - Multimodal or balanced analgesia is commonly used in the management of acute and chronic pain in humans, in order to achieve the best analgesic/safety profile. Here, by using a model of visceral acute tonic pain, the acetic acid-induced writhing test of mice, we show a synergistic interaction between fentanyl, trazodone and paracetamol on the inhibition of nociception. First of all, once assessed that all drugs induced dose-related antinociceptive effects, they were mixed in fixed ratio (1:1) combinations and a synergistic drug-drug interaction was obtained in all circumstances. Thereafter, we assayed the effects of the triple combination of fentanyl-trazodone-paracetamol and it was demonstrated that they displayed a potent synergistic interaction on the inhibition of acetic acid mediated nociception. Interestingly, drug dosage reduction permitted to reduce the incidence of possible adverse effects, namely exploratory activity and motor coordination, thus it was demonstrated that it improved the benefit/risk profile of such treatment. Afterwards, we attempted to elucidate the mechanism of action of such interaction, by means of the non-selective opioid receptor antagonist naloxone. Interestingly, naloxone completely antagonized the antinociceptive effects of fentanyl, and it also partially reversed paracetamol and trazodone mediated analgesia. Furthermore, when naloxone was co-administered with the triple-drug treatment it blocked the previously observed enhanced antinociceptive effects of the combination. Thus, these results indicated that the endogenous opioid system played a main role in the present drug-drug interaction. Overall, the triple combination of fentanyl-trazodone-paracetamol induced a potent synergistic antinociceptive effect, which could be of interest for optimal multimodal clinical analgesia. PMID- 21296107 TI - Influenza vaccination among chiropractic patients and other users of complementary and alternative medicine: are chiropractic patients really different? AB - OBJECTIVE: Previous studies suggest a possible association between using chiropractic care and lower influenza vaccination rates. We examined adult influenza vaccination rates for chiropractic patients to determine if they are different than those for users of other complementary and alternative medicine (CAM). METHOD: We used the 2007 National Health Interview Survey to examine influenza vaccination rates among adult respondents who were considered high priority for the influenza vaccine (n=12,164). We separated respondents into clinically meaningful categories according to age and whether or not they had recently used chiropractic care, some other type of CAM, or neither. We used adjusted logistic regression to determine whether user status predicted influenza vaccination. RESULTS: Only 33% of younger and 64% of older high priority Chiropractic Users were vaccinated in 2007; these rates approximated those of Non CAM Users. However, younger Non-Chiropractic CAM Users were more likely than Non CAM Users to have been vaccinated (p-value=0.05). In adjusted logistic regressions, we found statistically insignificant differences when comparing Chiropractic Users to Non-CAM Users for younger adults (OR=0.93(95% CI:0.76 1.13), or for older adults OR=0.90 (95% CI:0.64-1.20). CONCLUSION: Chiropractic Users appear no less likely to be vaccinated for influenza; whereas, younger Non chiropractic CAM Users are more likely than Non-CAM Users to be vaccinated. PMID- 21296106 TI - Serotonergic lesions of the periaqueductal gray, a primary source of serotonin to the nucleus paragigantocellularis, facilitate sexual behavior in male rats. AB - While selective serotonin reuptake inhibitors (SSRIs) are widely used to treat anxiety and depression, they also produce profound disruptions of sexual function including delayed orgasm/ejaculation. The nucleus paragigantocellularis (nPGi), a primary source of inhibition of ejaculation in male rats, contains receptors for serotonin (5-HT). The ventrolateral periaqueductal gray (vlPAG) provides serotonin to this region, thus providing an anatomical and neurochemical basis for serotonergic regulation of the nPGi. We hypothesize that 5-HT acting at the nPGi could underlie the SSRI-induced inhibition of ejaculation in rodents. To this end, we produced 5-HT lesions of the source of 5-HT to the nPGi (the vlPAG) and examined sexual behavior. Removing the source of 5-HT to the nPGi facilitated genital reflexes, but not other aspects of sexual behavior, consistent with our hypothesis. Namely, 5-HT lesions produced a significant increase in the mean number of ejaculations and a significant decrease in ejaculation latency as compared to sham lesioned animals, while latency to mating and the post ejaculatory interval did not differ. These data suggest that the serotonergic vlPAG-nPGi pathway is an important regulatory mechanism for the inhibition of ejaculation in rats and supports the hypothesis that this circuit contributes to SSRI-induced inhibition of ejaculation. PMID- 21296108 TI - Discrepancy between data and interpretation. PMID- 21296109 TI - The pro- and anti-inflammatory properties of the cytokine interleukin-6. AB - Interleukin-6 is a cytokine not only involved in inflammation and infection responses but also in the regulation of metabolic, regenerative, and neural processes. In classic signaling, interleukin-6 stimulates target cells via a membrane bound interleukin-6 receptor, which upon ligand binding associates with the signaling receptor protein gp130. Gp130 dimerizes, leading to the activation of Janus kinases and subsequent phosphorylation of tyrosine residues within the cytoplasmic portion of gp130. This leads to the engagement of phosphatase Src homology domains containing tyrosin phosphatase-2 (SHP-2) and activation of the ras/raf/Mitogen-activated protein (MAP) kinase (MAPK) pathway. In addition, signal transducer and activator of transcription factors are recruited, which are phosphorylated, and consequently dimerize whereupon they translocate into the nucleus and activate target genes. Interestingly, only few cells express membrane bound interleukin-6 receptor whereas all cells display gp130 on the cell surface. While cells, which only express gp130, are not responsive to interleukin-6 alone, they can respond to a complex of interleukin-6 bound to a naturally occurring soluble form of the interleukin-6 receptor. Therefore, the generation of soluble form of the interleukin-6 receptor dramatically enlarges the spectrum of interleukin-6 target cells. This process has been named trans-signaling. Here, we review the involvement of both signaling modes in the biology of interleukin-6. It turns out that regenerative or anti-inflammatory activities of interleukin-6 are mediated by classic signaling whereas pro-inflammatory responses of interleukin-6 are rather mediated by trans-signaling. This is important since therapeutic blockade of interleukin-6 by the neutralizing anti-interleukin-6 receptor monoclonal antibody tocilizumab has recently been approved for the treatment of inflammatory diseases. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. PMID- 21296110 TI - The role and therapeutic potential of prohibitin in disease. AB - Prohibitin 1 (PHB1), a pleiotropic protein in the cell, has been implicated in the regulation of proliferation, apoptosis, transcription, mitochondrial protein folding, and as a cell-surface receptor. This diverse array of functions of PHB1 is attributed to the cell type studied and its subcellular localization. This review discusses recent data that indicate a diverse role of PHB1 in disease pathogenesis and suggest that targeting PHB1 may be a potential therapeutic option for treatment of diseases including cancer, inflammatory bowel disease, insulin resistance/type 2 diabetes, and obesity. These diseases are associated with increased oxidative stress and mitochondrial dysfunction and therefore, the role of PHB1 in both responses will also be discussed. PMID- 21296111 TI - A detailed comparative analysis on the overall codon usage patterns in hepatitis A virus. AB - Hepatitis A virus (HAV) is a hepatotropic member of the family Picornaviridae. HAV has several unique biological characteristics that distinguish it from other members of this family. Recent and previous studies revealed that codon usage plays a key role in HAV replication and evolution. In this study, the patterns of synonymous codon usage in HAV have been studied through multivariate statistical methods on 30 complete open reading frames (ORFs) from the available 30 full length HAV sequences. Effective number of codons (ENC) indicates that the overall extent of codon usage bias in HAV genomes is significant. The relative dinucleotide abundances suggest that codon usage in HAV can also be strongly influenced by underlying biases in dinucleotide frequencies. These factors strongly correlated with the first major axis of correspondence analysis (COA) on relative synonymous codon usage (RSCU). The distribution of the HAV ORFs along the plane defined by the first two major axes in COA showed that different genotypes are located at different places in the plane, suggesting that HAV codon usage is also reflecting an evolutionary process. It has been very recently described that fine-tuning translation kinetics selection also contributes to codon usage bias of HAV. The results of these studies suggest that HAV genomic biases are the result of the co-evolution of genome composition, controlled translation kinetics and probably the ability to escape the antiviral cell responses. PMID- 21296112 TI - Focus. PMID- 21296113 TI - Surveillance for hepatocellular carcinoma in cirrhotic patients: from official recommendations to the real life. PMID- 21296115 TI - Candy or apple? How self-control resources and motives impact dietary healthiness in women. AB - People can choose between a virtually endless array of food items rising the question, which factors determine healthy or unhealthy food choice. The present study examines the impact of two contrasting motives for food choice (affect regulation and body weight control) and self-regulatory competences on healthy eating within a sample of women (N=761). The data show that a relative lack of self-regulatory resources combined with a high tendency to regulate negative affect through comfort eating was associated with an unfavorable dietary pattern. Accordingly, a healthy dietary pattern requires not only self-regulatory capacities but also a facilitating motive structure. PMID- 21296116 TI - Towards validated assays for key immunological outcomes in malaria vaccine development. PMID- 21296117 TI - Are Kenyan healthcare workers willing to receive the pandemic influenza vaccine? Results from a cross-sectional survey of healthcare workers in Kenya about knowledge, attitudes and practices concerning infection with and vaccination against 2009 pandemic influenza A (H1N1), 2010. AB - Over 1200 cases of 2009 pandemic influenza A H1N1 (pH1N1) have been identified in Kenya since the first case in June 2009. In April 2010 the Kenyan government launched a program to immunize high-risk groups and healthcare workers (HCWs) with pH1N1 vaccines donated by the World Health Organization. To characterize HCWs' knowledge, attitudes and practices regarding pH1N1 vaccination, we conducted a quantitative and qualitative survey in 20 healthcare facilities across Kenya between January 11 and 26, 2010. Of 659 HCWs interviewed, 55% thought there was a vaccine against pH1N1, and 89% indicated that they would receive pH1N1 vaccine if it became available. In focus group discussions, many HCWs said that pH1N1 virus infection did not cause severe disease in Kenyans and questioned the need for vaccination. However, most were willing to accept vaccination if they had adequate information on safety and efficacy. In order for the influenza vaccination campaign to be successful, HCWs must understand that pH1N1 can cause severe disease in Kenyans, that pH1N1 vaccination can prevent HCWs from transmitting influenza to their patients, and that the vaccine has been widely used globally with few recognized adverse events. PMID- 21296118 TI - Immunogenicity and safety of CRM197 conjugated 9-valent pneumococcal and meningococcal C combination vaccine in healthy infants. AB - Streptococcus pneumoniae and Neisseria meningitidis cause invasive disease in children aged <2 years. While individual conjugate vaccines are available to protect this age group against these pathogens, availability of a vaccine combining these antigens into a single injection is desirable. This study randomized 467 healthy infants to receive 4 doses of combination 9-valent pneumococcal and meningococcal serogroup C conjugate vaccine (9vPnC-MnCC) or 9 valent pneumococcal conjugate vaccine (9vPnC). Percentages of subjects achieving immunoglobulin G (IgG) antibody concentrations >=0.35MUg/mL and geometric mean IgG concentrations for each pneumococcal serotype in the 9vPnC-MnCC group were noninferior compared to the 9vPnC group. Both vaccines were well-tolerated. PMID- 21296119 TI - Renal histopathology in toxicity and carcinogenicity studies with tert-butyl alcohol administered in drinking water to F344 rats: a pathology working group review and re-evaluation. AB - An independent Pathology Working Group (PWG) re-evaluated the kidney changes in National Toxicology Program (NTP) toxicology/carcinogenicity studies of tert butyl alcohol (TBA) in F344/N rats to determine possible mode(s) of action underlying renal tubule tumors in male rats at 2-years. In the 13-week study, the PWG confirmed that the normal pattern of round hyaline droplets in proximal convoluted tubules was replaced by angular droplet accumulation, and identified precursors of granular casts in the outer medulla, changes typical of alpha(2u) globulin (alpha(2u)-g) nephropathy. In the 2-year study, the PWG confirmed the NTP observation of increased renal tubule tumors in treated male groups. Linear papillary mineralization, another hallmark of the alpha(2u)-g pathway was present only in treated male rats. Chronic progressive nephropathy (CPN) was exacerbated in high-dose males and females, with a relationship between advanced grades of CPN and renal tumor occurrence. Hyperplasia of the papilla lining was a component of CPN in both sexes, but there was no pelvic urothelial hyperplasia. High-dose females showed no TBA-related nephrotoxicity. The PWG concluded that both alpha(2u)-g nephropathy and exacerbated CPN modes of action were operative in TBA renal tumorigenicity in male rats, neither of which has relevance for human cancer risk. PMID- 21296120 TI - Major depressive disorder skews the recognition of emotional prosody. AB - OBJECTIVE: Major depressive disorder (MDD) is associated with abnormalities in the recognition of emotional stimuli. MDD patients ascribe more negative emotion but also less positive emotion to facial expressions, suggesting blunted responsiveness to positive emotional stimuli. To ascertain whether these emotional biases are modality-specific, we examined the effects of MDD on the recognition of emotions from voices using a paradigm designed to capture subtle effects of biases. METHODS: Twenty-one MDD patients and 21 healthy controls (HC) underwent clinical and neuropsychological assessments, followed by a paradigm featuring pseudowords spoken by actors in five types of emotional prosody, rated on continuous scales. RESULTS: Overall, MDD patients performed more poorly than HC, displaying significantly impaired recognition of fear, happiness and sadness. Compared with HC, they rated fear significantly more highly when listening to anger stimuli. They also displayed a bias toward surprise, rating it far higher when they heard sad or fearful utterances. Furthermore, for happiness stimuli, MDD patients gave higher ratings for negative emotions (fear and sadness). A multiple regression model on recognition of emotional prosody in MDD patients showed that the best fit was achieved using the executive functioning (categorical fluency, number of errors in the MCST, and TMT B-A) and the total score of the Montgomery-Asberg Depression Rating Scale. CONCLUSIONS: Impaired recognition of emotions would appear not to be specific to the visual modality but to be present also when emotions are expressed vocally, this impairment being related to depression severity and dysexecutive syndrome. MDD seems to skew the recognition of emotional prosody toward negative emotional stimuli and the blunting of positive emotion appears not to be restricted to the visual modality. PMID- 21296121 TI - Dioxin exposure of human CD34+ hemopoietic cells induces gene expression modulation that recapitulates its in vivo clinical and biological effects. AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has a large number of biological effects, including skin, cardiovascular, neurologic diseases, diabetes, infertility, cancers and immunotoxicity. We analysed the in vitro TCDD effects on human CD34+ cells and tested the gene expression modulation by means of microarray analyses before and after TCDD exposure. We identified 257 differentially modulated probe sets, identifying 221 well characterized genes. A large part of these resulted associated to cell adhesion and/or angiogenesis and to transcription regulation. Synaptic transmission and visual perception functions, with the particular involvement of the GABAergic pathway were also significantly modulated. Numerous transcripts involved in cell cycle or cell proliferation, immune response, signal transduction, ion channel activity or calcium ion binding, tissue development and differentiation, female or male fertility or in several metabolic pathways were also affected after dioxin exposure. The transcriptional profile induced by TCDD treatment on human CD34+ cells strikingly reproduces the clinical and biological effects observed in individuals exposed to dioxin and in biological experimental systems. Our data support a role of dioxin in the neoplastic transformation of hemopoietic stem cells and in immune modulation processes after in vivo exposure, as indicated by the epidemiologic data in dioxin accidentally exposed populations, providing a molecular basis for it. In addition, TCDD alters genes associated to glucidic and lipidic metabolisms, to GABAergic transmission or involved in male and female fertility, thus providing a possible explanation of the diabetogenic, dyslipidemic, neurologic and fertility effects induced by TCDD in vivo exposure. PMID- 21296122 TI - Modulation of steroidogenic gene expression and hormone synthesis in H295R cells exposed to PCP and TCP. AB - Chlorophenols (CPs) have been suspected to disrupt the endocrine system and thus affect human and wildlife reproduction but less is known about the underlying mechanism. In this study, we investigated the effects of pentachlorophenol (PCP) and 2,4,6-trichlorophenol (TCP) on human adrenocortical carcinoma cell line (H295R). The H295R cells were exposed to environmentally relevant concentration (0.0, 0.4, 1.1, 3.4MUM) of PCP and TCP for 48h, and expression of specific genes involved in steroidogenesis, including cytochrome P450 (CYP11A, CYP17, CYP19), 3betaHSD2, 17betaHSD4 and StAR was quantitatively measured using real-time polymerase chain reaction. The selected gene expressions were significantly down regulated compared with those in the control group. Exposure to PCP and TCP significantly decreased production of both testosterone (T) and 17beta-estradiol (E2). Furthermore, a dose-dependent decrease of cellular cAMP was observed in H295R cells exposed to both PCP and TCP. A time-course study revealed that the observed selected steroidogenic gene expressions and protein abundance (StAR) are consistent with reduced cellular cAMP concentrations. The results showed that PCP and TCP may inhibit steroidogenesis by disrupting cAMP signaling. The research indicates that H295R cells can be used as an in vitro model for endocrine disruption assay for chlorophenols and the mechanism involvement of disturbing cAMP signaling. PMID- 21296123 TI - A toxicogenomic approach for identifying biomarkers for myelosuppressive anemia in rats. AB - Myelosuppressive anemia is a serious side effect associated with several drugs. Thus, there is an increasing demand for sensitive biomarkers for the early detection of myelosuppressive anemia during toxicological studies. We applied a toxicogenomic approach to identify useful biomarker genes reflecting myelosuppressive anemia in the rat liver. Expression of the hemoglobin beta chain complex (Hbb), aminolevulinic acid synthase 2 (Alas2), and cell division cycle 25 homolog B (Cdc25b) genes changed as a result of anemia induced by the myelosuppressive agents linezolid, cisplatin, and carboplatin, suggesting that these genes may be suitable biomarkers. Moreover, evaluation of perfused and unperfused livers indicated that changes in the expression of these genes originate in circulating reticulocytes in the liver. Erythroid differentiation associated changes in expression of the Hbb, Alas2, and Cdc25b genes were confirmed in vitro using Friend leukemia cells. In conclusion, our current research provides novel evidence that gene expression in circulating reticulocytes contained in the liver changes dramatically under myelosuppressive conditions. While further large-scale validation studies are needed, our results indicate that the genes we identified might be useful biomarkers for the sensitive detection of myelosuppressive anemia in rats. PMID- 21296124 TI - A human thymic epithelial cell culture system for the promotion of lymphopoiesis from hematopoietic stem cells. AB - OBJECTIVE: A human thymic epithelial cell (TEC) line expressing human leukocyte antigen-ABC and human leukocyte antigen-DR was engineered to overexpress murine Delta-like 1 (TEC-Dl1) for the purpose of establishing a human culture system that supports T lymphopoiesis from hematopoietic progenitor cells (HPCs). MATERIALS AND METHODS: Cord blood or bone marrow HPCs were co-cultured with either the parental TEC line expressing low levels of the Notch ligands, Delta like 1 and Delta-like 4, or with TEC-Dl1 to determine if these cell lines support human lymphopoiesis. RESULTS: In co-cultures with cord blood or bone marrow HPCs, TEC-Dl1 cells promote de novo generation of CD7(pos)CD1a(pos) T-lineage committed cells. Most CD7(pos)CD1a(hi) cells are CD4(pos)CD8(pos) double-positive (DP). We found that TEC-Dl1 cells are insufficient to generate mature CD3(hi) CD4(pos) or CD3(hi) CD8(pos) single-positive (SP) T cells from the CD4(pos)CD8(pos) DP T cells; however, we detected CD3(lo) cells within the DP and SP CD4 and CD8 populations. The CD3(lo) SP cells expressed lower levels of interleukin-2Ralpha and interleukin-7Ralpha compared to CD3(lo) DP cells. In contrast to the TEC-Dl1 line, the parental TEC-84 line expressing low levels of human Notch ligands permits HPC differentiation to the B-cell lineage. CONCLUSIONS: We report for the first time a human TEC line that supports lymphopoiesis from cord blood and bone marrow HPC. The TEC cell lines described herein provide a novel human thymic stroma model to study the contribution of human leukocyte antigen molecules and Notch ligands to T-cell commitment and maturation and could be utilized to promote lymphopoiesis for immune cell therapy. PMID- 21296125 TI - Side differences of the age-related changes in the white matter and the myelinated nerve fibers in the white matter of female rats. AB - The present study tested if there were side differences of the white matter and the myelinated fibers in the white matter of female rats, and if there were side differences in the age-related changes of the white matter and the myelinated fibers in the white matter of female rats. Five young, five middle-aged and five aged female Long-Evans rats were quantitatively investigated using electron microscopic technique and stereological methods. We found no side differences of the white matter volume, the total volume, total length and mean diameter of the myelinated fibers in the white matter of young, middle-aged, and aged female rats. When compared to middle-aged female rats, the total length of the myelinated fibers in the white matter of the left hemisphere in aged female rats was decreased significantly, but the total length of the myelinated fibers in the white matter of the right hemisphere in aged female rats was non-significantly decreased. Our data indicated that there were no significant side differences in the white matter and the myelinated fibers in the white matter in young, middle aged, and aged female rats. However, we demonstrated that the aged-related changes of the myelinated fibers in the white matter of the left hemisphere and right hemisphere were different. The results obtained in the present study will provide biological basis for the understanding of the asymmetry of cerebral functions. PMID- 21296126 TI - Lauroylethanolamide and linoleoylethanolamide improve functional outcome in a rodent model for stroke. AB - Ischemic stroke is a significant health problem affecting over 6 million people in the United States alone. In addition to surgical and thrombolytic therapeutic strategies for stroke, neuroprotective therapies may offer additional benefit. N acylethanolamines (NAEs) are signaling lipids whose synthesis is upregulated in response to ischemia, suggesting that they may be neuroprotective. To date only three NAEs, arachidonylethanolamide (NAE 20:4), palmitoylethanolamide (NAE 16:0) and oleoylethanolamide (NAE 18:1) have shown to exert neuroprotective effect in animal models for stroke. Here, we describe neuroprotective effects of the hitherto uncharacterized NAEs, lauroylethanolamide (NAE 12:0) and linoleoylethanolamide (NAE 18:2) in a middle cerebral artery occlusion model of stroke. Pretreatment with NAE 18:2 prior to ischemia/reperfusion (I/R) injury resulted in both significantly reduced cortical infarct volume and improved functional outcome as determined using the neurological deficit score. NAE 12:0 improved neurological deficits without a significant reduction lesion size. Our results suggest that NAEs, as a whole, provide neuroprotection during I/R injury and may have therapeutic benefit when used as complementary treatment with other therapies to improve stroke outcome. PMID- 21296127 TI - Gabapentin, A GABA analogue, enhances cognitive performance in mice. AB - Gabapentin is one of the new antiepileptic drugs (AEDs) launched recently. The advantage of new AEDs includes newer mechanism of action, broad spectrum of antiseizure effects, lesser drug interactions and fewer side effects. Gabapentin (GBP) a GABA analogue, is efficacious in several neurological and psychiatric conditions and it is conventionally used in the treatment of partial epilepsies. In this study, we aimed to evaluate the effects of GBP on learning and memory processes of naive mice in Morris water maze (MWM), passive avoidance (PA) and modified elevated plus maze (mEPM) tests. GBP (5 and 10mg/kg, i.p.) was administered on the probe trial of MWM and on the acquisation session of PA and mEPM tests. In the MWM test, GBP (10mg/kg) significantly increased the time spent in target quadrant and GBP (5 and 10mg/kg) significantly decreased the distance to platform compared to control group. In the mEPM test, GBP (5 and 10mg/kg) significantly decreased the transfer latency compared to control group on the second day and in the PA test, GBP (5 and 10mg/kg) significantly prolonged retention latency compared to control group. Our results indicate that GBP has improving effects on spatial and emotional cognitive performance of naive mice in MWM, PA and mEPM tasks. PMID- 21296128 TI - Genetic and environmental influences on structural variability of the brain in pediatric twin: deformation based morphometry. AB - Twin studies are one of the most powerful study designs for estimating the relative contribution of genetic and environmental influences on phenotypic variation inhuman brain morphology. In this study, we applied deformation based morphometry, a technique that provides a voxel-wise index of local tissue growth or atrophy relative to a template brain, combined with univariate ACE model, to investigate the genetic and environmental effects on the human brain structural variations in a cohort of homogeneously aged healthy pediatric twins. In addition, anatomical regions of interest (ROIs) were defined in order to explore global and regional genetic effects. ROI results showed that the influence of genetic factors on cerebrum (h(2)=0.70), total gray matter (0.67), and total white matter (0.73) volumes were significant. In particular, structural variability of left-side lobar volumes showed a significant heritability. Several subcortical structures such as putamen (h(ROI)(2)=0.79/0.77(L/R),h(MAX)(2)=0.82/0.79) and globus pallidus (0.81/0.76, 0.88/0.82) were also significantly heritable in both voxel-wise and ROI-based results. In the voxel-wise results, lateral parts of right cerebellum (c(2)=0.68) and the posterior portion of the corpus callosum (0.63) were rather environmentally determined, but it failed to reach statistical significance. Pediatric twin studies are important because they can discriminate several influences on developmental brain trajectories and identify relationships between gene and behavior. Several brain structures showed significant genetic effects and might therefore serve as biological markers for inherited traits, or as targets for genetic linkage and association studies. PMID- 21296129 TI - In vitro electrophysiological investigations of the acute effects of linezolid and novel oxazolidinones on central nervous system neurons. AB - Oxazolidinones are a novel class of antibacterial agents with demonstrated activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and enterococci. Prolonged clinical use of linezolid, the prototypical oxazolidinone, results in peripheral, central and optic neuropathies. The cellular mechanism by which it may alter neuronal function to produce these effects is not known. This study examined the in vitro effects of clinically relevant concentrations of linezolid and four selected potent antibacterial oxazolidinones on neuronal responses to determine if they are neuroactive and their possible neurotoxic mechanism(s). Using in vitro slice preparations of the rat nucleus accumbens (NAc) and hippocampus, we examined the effects of linezolid and the potent antibacterial triazolyl oxazolidinones, PH027, PH036, PH084 and PH108 on synaptic transmission and neuronal excitability recorded in voltage or current clamp mode. PH027 and PH084 generally depressed all excitatory and inhibitory postsynaptic currents. Linezolid, at the highest concentration tested, depressed NMDA receptor-mediated currents while PH036 and PH108 had no significant effect on any of these responses. The synaptic depression by PH084 was without effect on the resting membrane conductance at resting or relatively hyperpolarized voltage and could be blocked by GABA(B), dopamine D1-like and alpha-adrenergic receptor antagonists but not by an adenosine A1 receptor antagonist. Finally, PH084 decreased action potential firing frequency of NAc and hippocampal cells elicited at depolarized potentials. Our data indicate that, while oxazolidinones containing both the morpholine and triazole functional groups, as in PH027 and PH084, have neuroactivity, those containing morpholine and acetamide (linezolid) or piperazine and triazolyl (PH036 and PH108) functional groups have minimal acute neuroactivity and therefore may be safer antibacterial agents. PMID- 21296130 TI - Synaptic plasticity deficits in an experimental model of rett syndrome: long-term potentiation saturation and its pharmacological reversal. AB - Rett syndrome (RTT), a disorder caused almost exclusively by mutations in the X linked gene, MECP2, has a phenotype thought to be primarily of neurological origin. Disruption of Mecp2 in mice results in a prominent RTT-like phenotype. One of the consequences of MeCP2 absence in the brain is altered functional and structural plasticity. We aimed to characterize synaptic effects related to plasticity in the hippocampus further and establish whether plasticity defects are amenable to pharmacological reversal. Using male mice in which Mecp2 expression was prevented by a stop cassette, we assessed synaptic plasticity in area CA1 at different phenotypic stages, scoring the mice weekly for overt RTT like signs. Strongly symptomatic Mecp2(stop/y) mice displayed reduced long-term potentiation (LTP, 40.2+/-1.6% of wild-type), post-tetanic potentiation (PTP, 45+/-18.8% of wild-type) and paired-pulse facilitation (PPF, 78+/-0.1% of wild type) (all P<0.05), the impairment increasing with symptom severity score. These plasticity impairments were absent in presymptomatic mice. Repeated high frequency stimulation revealed pronounced LTP saturation in symptomatic Mecp2(stop/y) mice, suggesting an LTP 'ceiling' effect. Bath application of the weak NMDA receptor blocker memantine (1 MUM) resulted in partial restoration of a short-term plasticity component. These data support that idea that progressive functional synaptic impairment is a key feature in the RTT brain and demonstrate the potential for the pharmacological restoration of plasticity function. PMID- 21296131 TI - New pregnane saponins from Ecdysanthera rosea and their cytotoxicity. AB - Two new pregnane saponins elucidated as ecdysantheroside A (1) and ecdysantheroside B (2) and six known compounds (3-8) based on spectral data (MS, IR, 1D and 2D NMR) were isolated from the stem bark of Ecdysanthera rosea. The cytotoxicity against six cell lines of these compounds was tested by MTT assay. The results revealed that compounds 5 and 7 showed cytotoxicity against all the cell lines. Compound 2 showed cytotoxicity against cells A549, MDA435, HepG2, and HUVEC, while compound 4 showed cytotoxicity against cells A549, CEM, and HUVEC. Compound 6 had cytotoxicity against the others except cell HepG2. PMID- 21296132 TI - T-2 toxin induces apoptosis in ovarian granulosa cells of rats through reactive oxygen species-mediated mitochondrial pathway. AB - OBJECTIVE: To investigate the reproductive toxicity and cytotoxicity of T-2 toxin, which is a mycotoxin, and to explore its potential apoptotic induction mechanism. METHODS: Ovarian granulosa cells of rats were treated with T-2 toxin (1-100nM) for 24h. The cytotoxicity was assessed with MTT bioassay; apoptotic cells were identified microscopically by chromatin condensation and nuclear fragmentation with Hoechst 33258; mitochondrial membrane potential with hodamine 123 and reactive reactive oxygen species (ROS) with 2',7' dichlorofluoresceinacetate (DCFH-DA) was analyzed by fluorometry; p53 and other apoptosis-related proteins such as Bax, Bcl-2, caspase-3, caspase-9 were determined by Western blot analysis, and related mRNA expressions were determined by reverse transcriptase-polymerase chain reaction (RT-PCR). The caspase activity was measured by cleavage of the caspase substrate (Ac-DEVD-pNA for caspase-3, Ac LEHD- pNA for caspase-9). RESULTS: T-2 toxin inhibited the growth of granulosa cells in a concentration-dependent way. The result of Hoechst 33258 staining indicated that T-2 toxin induces granulosa cells apoptosis based on the typical apoptotic morphological changes. Subsequently, we found that T-2 toxin treatment induced ROS accumulation in granulosa cells, resulting in reduction of mitochondrial transmembrane potential. The induction of cell apoptosis was caused by the upregulation of p53, Bax, Bcl-2, Bax/Bcl-2 ration, and the activation of the caspases pathways. T-2 toxin-induced apoptotic granulosa cells significantly decreased through the use of antioxidant Trolox. CONCLUSION: These data suggest a possible underlying molecular mechanism for T-2 toxin that induces the apoptosis signaling pathway in rat granulosa cells by regulation of ROS-mediated mitochondrial pathway. PMID- 21296133 TI - Akt/GSK3beta signaling is involved in fipronil-induced apoptotic cell death of human neuroblastoma SH-SY5Y cells. AB - Fipronil (FPN) is a phenylpyrazole insecticide acted on insect gamma-aminobutyric acid (GABA) receptors. Although action of FPN is restricted on insect neuronal or muscular transmitter system, a few studies have assessed the effects of this neurotoxicant on neuronal cell death. To determine the mechanisms underlying FPN induced neuronal cell death, we investigated whether reactive oxygen species (ROS) plays a role in FPN-induced apoptosis, using an in vitro model of human dopaminergic SH-SY5Y cells. FPN was cytotoxic to these cells and its cytotoxicity showed a concentration-dependent manner. Additionally, FPN treatment significantly decreased the tyrosine hydroxylase (TH) expression without change of glutamic acid decarboxylase 65 (GAD65) expression. FPN-induced dopaminergic cell death involved in increase of ROS generation since pretreatment with N acetyl cysteine (NAC), an anti-oxidant, reduced cell death. After FPN treatment, dopamine (DA) levels decreased significantly in both cell and culture media, and oxidative effects of DA were blocked by NAC pretreatment. We showed that cell death in response to FPN was due to apoptosis since FPN increased cytochrome c release into the cytosol and activated caspase-3. It also led to nuclear accumulation of p53 and reduced the level of Bcl-2 protein in a concentration dependent manner. Additionally, FPN altered the level of Akt/glycogen synthase kinase-3 (GSK3beta) phosphorylation. FPN reduced the Akt phosphorylation on Ser473, and in parallel with the inactivation of Akt, phosphorylation of GSK3beta on Ser9 which inactivates GSK3beta, decreased after treatment with FPN. Furthermore, inhibition of the GSK3beta signal protected the cell against FPN induced cell death. These results suggest that regulation of GSK3beta activity may control the apoptosis induced by FPN-induced oxidative stress associated with neuronal cell death. PMID- 21296134 TI - Aflatoxin B1--a potential endocrine disruptor--up-regulates CYP19A1 in JEG-3 cells. AB - Previous studies have indicated that aromatase (CYP19A1) is involved in the metabolism of aflatoxin B1 (AFB1). We hypothesized that exposure to AFB1 contaminated food during pregnancy could disrupt the normal production of steroid hormones in placenta. We examined the capability of AFB1 exposure to disrupt CYP19A1 expression as a putative endocrine disrupter, and to investigate the metabolism of AFB1 by CYP19A1. JEG-3 cells, as model for placental cells, were exposed alone and in combination to AFB1 and estrogen receptor ligands for 24-96 h. AFB1 (0.3-1.0 MUM) induced the expression of CYP19A1 by 163%-339% compared to control at the 96 h time point, although no induction was observed at 24 h. AFB1 concentrations higher than 1 MUM were cytotoxic to JEG-3 cells, and the cytotoxicity was inhibited by the aromatase inhibitor, finrozole. AFB1 was metabolized to aflatoxicol (AFL) by JEG-3 cells and CYP19A1 recombinant protein. AFL formation was partially inhibited by addition of tamoxifen and finrozole to the JEG-3 cells. AFB1 had no effect on the expression of CYP1A2 and CYP3A4 in JEG 3 cells. These results reveal that AFB1 can affect the expression of aromatase enzyme, indicating that chronic exposure to AFB1 may cause endocrine disruption in the foetoplacental unit. PMID- 21296135 TI - Preparation and characterization of polymeric pH-sensitive STEALTH(r) nanoparticles for tumor delivery of a lipophilic prodrug of paclitaxel. AB - Paclitaxel is an effective and widely used anti-cancer agent. However, the drug is difficult to formulate for parenteral administration because of its low water solubility and Cremophor EL, the expient used for its formulation, has been shown to cause serious side effects. The present study reports an alternative administration vehicle involving a lipophilic paclitaxel prodrug, paclitaxel oleate, incorporated in the core of a nanoparticle-based dosage form. A hydrophobic poly (beta-amino ester) (PbAE) was used to formulate the nanoparticles, which were stabilized with a mixture of phosphatidylcholine, Synperonic(r) F 108, and poly(ethylene glycol)-dipalmitoyl phosphatidyl ethanolamine. PbAE undergoes rapid dissolution when the pH of the medium is less than 6.5 and is expected to rapidly release its content within the acidic tumor microenvironment and endo/lysosome compartments of cancer cells. PbAE nanoparticles were prepared by an ultrasonication method and characterized for particle size and physical stability. The nanoparticles obtained had a diameter of about 70 nm and a good physical stability when stored at 4 degrees C. In vitro cellular uptake and release of paclitaxel oleate PbAE nanoparticles were studied in Jurkat acute lymphoblastic leukemia cells. The results were compared with pclitaxel oleate in poly(E-caprolactone) (PCL) particles, that do not display pH-sensitive release behavior, and paclitaxel in PbAE particles. Both uptake and release of the prodrug were faster when administered in PbAE than in PCL, but much slower than those of the free drug in PbAE. Cytotoxicity assay was performed on the formulations at different doses. Paclitaxel and paclitaxel oleate showed almost identical activity, IC50 123 and 128 nM, respectively, while that of the prodrug in PCL was much lower with IC50 at 2.5 MUM. Thus, PbAE nanoparticles with the incorporated paclitaxel prodrug paclitaxel oleate may prove useful for replacement of the toxic Cremophor EL and also by improving the distribution of the drug to the tumor. PMID- 21296136 TI - Age differences in the purr call distinguished by units in the adult guinea pig primary auditory cortex. AB - Many communication calls contain information about the physical characteristics of the calling animal. During maturation of the guinea pig purr call the pitch becomes lower as the fundamental frequency progressively decreases from 476 to 261 Hz on average. Neurons in the primary auditory cortex (AI) often respond strongly to the purr and we postulated that some of them are capable of distinguishing between purr calls of different pitch. Consequently four pitch shifted versions of a single call were used as stimuli. Many units in AI (79/182) responded to the purr call either with an onset response or with multiple bursts of firing that were time-locked to the phrases of the call. All had a characteristic frequency <=5 kHz. Both types of unit altered their firing rate in response to pitch-shifted versions of the call. Of the responsive units, 41% (32/79) had a firing rate locked to the stimulus envelope that was at least 50% higher for one version of the call than any other. Some (14/32) had a preference that could be predicted from their frequency response area while others (18/32) were not predictable. We conclude that about 18% of stimulus-driven cells at the low-frequency end of AI are very sensitive to age-related changes in the purr call. PMID- 21296137 TI - Modified Si-Miao-San extract inhibits inflammatory response and modulates insulin sensitivity in hepatocytes through an IKKbeta/IRS-1/Akt-dependent pathway. AB - AIM OF THE STUDY: Modified Si-Miao-San (mSMS) has showed anti-inflammatory potency and has been used in the clinic to treat metabolic disorders such as obesity and diabetes, but whether its anti-inflammatory activity contributes to improving insulin resistance remains to be determined. This study aims to investigate the mechanistic relationship between its anti-inflammatory activity and modulation of insulin sensitivity in free fatty acid-stimulated HepG2 cells. MATERIALS AND METHODS: HepG2 cells were stimulated with palmitate (PA) and the effect of mSMS on insulin mediated-glycogen synthesis and triglyceride secretion was observed. The inhibition of mSMS on gene expression of proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and inhibitor of NF-kappaB kinase-beta (IKKbeta) activation was investigated. In addition, the effects of mSMS on insulin signaling transduction along insulin receptor substrates-1 (IRS-1)/Akt pathway were also evaluated. Furthermore, the effect of mSMS on glucose intolerance induced by conditioned-medium derived from activated macrophages was also assessed in normoglycemic mice. RESULTS: Treatment of hepatocytes with PA reduced insulin sensitivity and mSMS effectively increased insulin-mediated glycogen synthesis and restored insulin inhibition of triglyceride secretion. mSMS suppressed IKKbeta activation and down-regulated TNF alpha and IL-6 gene over-expression, demonstrating its anti-inflammatory activity in hepatocytes. PA-evoked inflammation impaired insulin signaling cascades and mSMS improved insulin signaling transduction by modification of Ser/Thr phosphorylation of IRS-1 and downstream Akt (T308), thereby improved insulin sensitivity in hepatocytes. mSMS also improved glucose intolerance induced by inflammatory cytokines in normoglycemic mice, which further demonstrated its modulation toward insulin sensitivity in vivo. CONCLUSIONS: The results suggest that mSMS inhibited inflammatory response and improved insulin sensitivity in hepatocytes via an IKKbeta/IRS-1/Akt-dependent pathway. PMID- 21296138 TI - The optimal therapeutic timing and mechanism of puerarin treatment of spinal cord ischemia-reperfusion injury in rats. AB - AIM OF THE STUDY: The purpose of this study was to explore the optimal therapeutic timing and mechanism of puerarin treatment of spinal cord ischemia reperfusion injury. MATERIALS AND METHODS: The spinal ischemia-reperfusion injury was conducted in male Sprague-Dawley rats, and 50mg/kg of puerarin was injected intraperitoneally at 1, 2, 4 and 6h after the injury. Motor function was measured 48 h after reperfusion started. Thioredoxin expression and apoptosis indices were determined. RESULTS: Improvement of motor function at 1, 2, and 4h was demonstrated in the animals with puerarin treatment. Ischemia-reperfusion injury resulted in a decrease in the expression of thioredoxin, while puerarin administration elevated the expression of thioredoxin-1/thioredoxin-2 mRNA. Apoptosis indices were significantly reduced by puerarin administration. CONCLUSIONS: We conclude that administration of puerarin within 4h of spinal ischemia-reperfusion injury reduces ischemic reperfusion damage, and that the neuroprotective effect of puerarin involves an increase in the transcription of thioredoxin and a reduction of apoptosis. PMID- 21296139 TI - Anti-ulcerogenic properties of Quassia amara L. (Simaroubaceae) standardized extracts in rodent models. AB - AIM OF THE STUDY: Quassia amara L. is commonly used in Costarican folk medicine. It has been used for the treatment of a broad range of gastrointestinal symptoms such as dyspepsia, gastritis and constipation. In this study, the gastroprotective activity of two standardized extracts of Quassia amara L., Lipro((r)) and Ligas((r)), was evaluated. MATERIALS AND METHODS: Anti-ulcerogenic properties were evaluated in female rats under acute ulcer-induction models (ethanol, indomethacin and hypotermic restraint). To get a deeper insight in the anti-ulcerogenic properties of the extracts, Ligas((r)) was evaluated in the Shay rat model. Five parameters were estimated with this model: gastric mucus barrier, non-protein sulfhydril groups (NPSG) in the gastric mucosa, and pH, total acidity and peptic activity of the gastric juice. RESULTS: Induction of ulcers by 95% ethanol (0.5 mL per os), indomethacin (100 mg/kgs.c.) and stress (2h in hypothermic restraint) was inhibited significantly with administration of Lipro((r)) (p<0.05), in a dosage range from 4.9 mg/kg/d to 48.9 mg/kg/d. Treatment was given for one week. The extract Ligas((r)) showed a significant augmentation of NPSG (p<0.05) in a dosage range from 4.0 to 39.7 mg/kg. Ligas((r)) did not produce a significant change (p>0.05) in the other indicators. CONCLUSIONS: Quassia amara L. standardized extracts, Lipro((r)) and Ligas((r)), showed an important anti-ulcerogenic effect in acute ulcer induction models. Their effect was related to an increase in gastric barrier mucus and non-protein sulfhydril groups. PMID- 21296140 TI - Bridging the "two cultures" in ethnopharmacology: barriers against interdisciplinarity in postgraduate education. AB - As significant contributors to the generation, dissemination and publication of scientific knowledge, graduate students have considerable leverage on publication trends and the future direction of ethnopharmacology. The rigid discipline oriented framework of academia is often cited as responsible for impeding interdisciplinarity, particularly for fields such as ethnopharmacology which span both the natural and social science domains. Funding opportunities, funding eligibility periods, time-to-degree patterns and departmental expectations and requirements for graduate students enrolled in the natural sciences are considerably different than for those in the social sciences. Consequently, adequate acquisition of ethnographic data is often compromised. Encouraging students to think across disciplines, cross-disciplinary collaboration, and flexibility in regards to the time and financial constraints imposed by departments and funding agencies would increase the likelihood of contextualizing bioscientific data with adequate traditional empirical knowledge, and ultimately embrace the core objectives on which the JEP was conceived. PMID- 21296141 TI - Adjuvant effects of Astragalus saponins macrophyllosaponin B and astragaloside VII. AB - AIM OF THE STUDY: The present study was undertaken to evaluate the hemolytic activities of two immunomodulator Astragalus saponins [Macrophyllosaponin B (MacB) from Astragalus oleifolius DC. and Astragaloside VII (Ast VII) from Astragalus trojanus Stev.], and their adjuvant potentials on the cellular and humoral immune responses of Swiss albino mice against BSA. MATERIALS AND METHODS: The hemolytic activity of Mac B and Ast VII was determined using 0.5% rabbit red blood cell. For adjuvant activity, Swiss albino mice were immunized subcutaneously with BSA 100 MUg alone or with BSA 100 MUg dissolved in saline containing Ast VII (30, 60, 120 and 240 MUg), Mac B (30, 60, 90 and 120 MUg) or Freund's adjuvant on Days 1 and 15. Sera and splenocytes were collected 2 weeks after the last immunization for concanavalin A (Con A)-, lipopolysaccharide (LPS) and BSA-stimulated splenocyte proliferation assay and measurement of BSA specific antibodies in serum. RESULTS: Mac B and Ast VII showed a slight hemolytic effect, with 0.42% and 0.54% values, respectively, at the highest concentration of 500 MUg/ml. Mac B and Ast VII significantly enhanced the Con A-, LPS-, and BSA-induced splenocyte proliferation in the BSA-immunized mice especially at 120 and 240 MUg (P<0.001), and 60, 90 and 120 MUg (P<0.05, P<0.01 or P<0.001) doses, respectively. BSA-specific IgG, IgG1 and IgG2b antibody titers in serum were also significantly enhanced by Ast VII (120 MUg), Mac B (90 MUg) and Freund's as compared to the control group (P<0.01 or P<0.001). Moreover, the IFN-gamma and IL-4 levels in the sera were detected using ELISA two weeks after the last immunization. Ast VII and Mac B were also found to stimulate IFN-gamma production such as Freund's, two weeks after the last immunization at doses of 120 MUg and 90 MUg, respectively, as compared to the control. CONCLUSION: Results show that Ast VII and Mac B generate important specific antibody and cellular response against BSA in mice, proving their potentials as a new class saponin adjuvant. PMID- 21296142 TI - Neuroprotective effect of oral S/B remedy (Scutellaria baicalensis Georgi and Bupleurum scorzonerifolfium Willd) on iron-induced neurodegeneration in the nigrostriatal dopaminergic system of rat brain. AB - AIM OF THE STUDY: S/B remedy prepared from Scutellaria baicalensis Georgi and Bupleurum scorzonerifolfium Willd, two herbals of Xiao-Tsai-Hu-Tang or Sho-Saiko To (TJ-9), contains active flavonoids. In this study, the protective effect of S/B remedy on iron-induced neurodegeneration was investigated in the nigrostriatal dopaminergic system of rat brain. MATERIALS AND METHODS: The antioxidative activity of S/B remedy was studied using brain homogenates incubated with ferrous citrate (iron, 1M), S/B remedy, Trolox and melatonin. Furthermore, a Parkinsonian animal model by an intranigral infusion of iron in the anesthetized rats was employed to investigate the protective effect of S/B remedy in the nigrostriatal dopaminergic system. RESULTS: Our in vitro studies showed that S/B remedy was more potent than melatonin and equal to trolox in inhibiting iron-induced lipid peroxidation of brain homogenates. Our in vivo studies found that oral administration of S/B remedy dose-dependently attenuated iron-elevated lipid peroxidation in the infused substantia nigra (SN) and iron depleted dopamine levels in the ipsilateral striatum. Furthermore, iron-induced reductions in glutathione (GSH) content and increases in GSSG (oxidized GSH)/GSH ratio in the infused SN were inhibited in S/B remedy-treated rats. Systemic S/B remedy attenuated the iron-induced increases in heme-oxygenase-1 levels and alpha synuclein aggregation in the infused SN. Moreover, S/B remedy reduced iron induced apoptosis via attenuating mitochondrial and endoplasmic reticulum stress. In addition, S/B remedy was anti-inflammatory as indicated by the attenuation of iron-induced elevations in inducible nitric oxide synthase and cyclo-oxygenase II levels as well as glial fibrillary acidic protein (a biological marker of astrocytes) and ED-1 (a protein indicative of activated microglia) levels in the infused SN of S/B remedy-treated rats. CONCLUSIONS: These findings suggest that oral administration of S/B remedy is protective against iron-induced neurodegeneration in the nigrostriatal dopaminergic system of rat brain. Therefore, S/B remedy may be therapeutically useful for the treatment of CNS neurodegenerative diseases. PMID- 21296143 TI - Antibacterial and anti-inflammatory effects of extracts and fractions from Polygonum capitatum. AB - AIM OF THE STUDY: This study was designed to investigate the antibacterial and anti-inflammatory activities of the extracts and the structure-based fractions from P. capitatum so as to provide the evidence for the traditional use of this plant in the treatment of urinary tract infections and to clarify the structural types that were responsible for the clinical use of the plant. MATERIALS AND METHODS: The dry whole plant of P. capitatum was extracted with water and 70% aqueous ethanol and then separated, respectively, into a fraction enriched in polysaccharides and proteins (PP) and four other fractions enriched in gallic acid and its analogues (GAA), flavonoids (FV), tannins (TN), and triterpenoids and steroids (TS). UV spectral or chemical methods were used for the confirmation of the five fractions. The in vitro antibacterial activities of the aqueous (AE) and 70% aqueous ethanol (70EE) extracts as well as the fractions against gram positive and gram-negative bacteria were initially evaluated by a disc diffusion test. The anti-bacterial potencies of the active extracts or fractions were then assessed in vitro by determining the MICs and MBCs. The anti-inflammatory activity was evaluated employing the xylene-induced mouse ear edema model. RESULTS: Except for fraction PP, AE, 70EE, and the four fractions (GAA, FV, TN, and TS) exhibited varying degrees of antibacterial and anti-inflammatory activities. The results of the minimal inhibition concentration (MIC) and minimal bactericidal concentration (MBC) indicated that the crude extracts or fractions FV and TN all possess bacteriostatic and bactericidal properties. Fractions FV and TS showed significantly anti-inflammatory activity (P<0.01) with the inhibition rates of 86.15 and 73.71% at 0.6g/kg, respectively, as compared to 76.93% of the positive control dexamethasone. CONCLUSIONS: The overall results suggested that the traditional use of this plant for the treatment of urinary tract infections were attributed to the presence of antibacterial and anti inflammatory agents. The results also provided evidence that the studied plant extracts, as well as some of the fractions obtained from this plant might be potential sources for antimicrobial and anti-inflammatory drug development. PMID- 21296144 TI - Anti-inflammatory effects of Huang-Lian-Jie-Du decoction, its two fractions and four typical compounds. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Huang-Lian-Jie-Du decoction (HLJDD) (Oren-gedoku to in Japanese) as a famous traditional Chinese recipe is composed of Rhizoma coptidis, Radix scutellariae, Cortex phellodendri and Fructus gardeniae. It has been used to treat inflammation for nearly two thousand years. AIM OF THE STUDY: To explore the material base for the anti-inflammatory activity of formula HLJDD, its extract was fractionated on D101 macroporous resin to afford two fractions, HLJDD-1 and HLJDD-2. The whole formula, HLJDD-1 and HLJDD-2, and four typical component compounds were then evaluated for their effects on inflammation-related parameters using lipopolysaccharide (LPS)-induced RAW264.7 cells as a model system. MATERIALS AND METHODS: The effect of HLJDD on carrageenan-induced mice paw edema was first evaluated. A series of inflammation-related parameters including malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), prostaglandin E(2) (PGE2), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-10 (IL-10) were then measured in LPS-induced RAW264.7 cells treated with HLJDD, its two fractions, and four typical component compounds (geniposide, baicalin, berberine and baicalein). RESULTS: With the help of principal component analysis (PCA) technique, the data obtained revealed that the two fractions and the major group of compounds in HLJDD (iridoids, flavonoids and alkaloids) complement each other with particular emphasis to synergistically exert anti-inflammatory effects. CONCLUSIONS: This study demonstrated that HLJDD exhibited anti-inflammatory effect as a "whole", which justified the combined use of the four component herbs forming the compound prescription and suggested quality control of HLJDD based on its three types of components. PMID- 21296146 TI - How cytokines leave their mark: the role of the placenta in developmental programming of brain and behavior. PMID- 21296145 TI - Association between adolescent emotional problems and metabolic syndrome: the modifying effect of C-reactive protein gene (CRP) polymorphisms. AB - Depression is associated with the development of the metabolic syndrome, and both depression and metabolic syndrome are associated with markers of systemic inflammation, such as C-reactive protein (CRP). We examined associations between affective status in adolescence and adulthood, and the metabolic syndrome at age 53 years in a large representative British birth cohort. We also investigated whether two CRP gene polymorphisms (rs1205 and rs3093068) were associated with affective status and the metabolic syndrome, and whether the association between affective status and the metabolic syndrome was modified by these CRP polymorphisms. Women, but not men, with emotional problems in adolescence were more likely to have the metabolic syndrome (OR=1.53, 95% CI: 1.04, 2.26), although this sex difference was not statistically significant (p=0.22). The CRP SNPs were not associated with affective status or the metabolic syndrome, but the association of adolescent emotional problems with the metabolic syndrome was stronger in those who were homozygous for the major allele (C) of rs1205 (OR=1.83, 95% CI: 1.17, 2.86) than in carriers of the T allele (OR=1.01, 95% CI: 0.66, 1.55) (p=0.05 for gene by affective status interaction). This interaction was stronger when considering adolescent emotional problems as a continuous variable (p=0.003). Adolescent emotional problems play an important role in the development of the metabolic syndrome later in life, particularly in those homozygous for the major allele of CRP rs1205. These findings may highlight new ways of identifying people with emotional problems at high risk of developing the metabolic syndrome, which is of great importance for the management of the physical health of these patients. PMID- 21296147 TI - Depression, inflammation and therapy: which way is right? PMID- 21296148 TI - Liposomes radiolabeled with 159Gd-DTPA-BMA: preparation, physicochemical characterization, release profile and in vitro cytotoxic evaluation. AB - The present work describes the preparation, labeling, physicochemical characterization, and in vitro cytotoxic evaluation of long circulating pH sensitive liposomes containing (159)Gd-DTPA-BMA. These liposomes were successfully obtained and submitted to neutron irradiation for gadolinium labeling. Their size, distribution, and homogeneity were determined by photon correlation spectroscopy, while their zeta potential was determined by laser Doppler anemometry. The morphology and structural organization were evaluated by atomic force microscopy. The stability and release profiles of Gd-DTPA-BMA in the liposomes were determined in vitro in Dubelco's Modified Eagle's Medium and rat serum at 70%. The results showed that liposomes remained physically stable after 8 h of irradiation and presented a low release profile of its content in two different biological mediums. The formulation of liposomes containing (159)Gd and its respective controls were evaluated by in vitro cytotoxicity against tumor cells RT2. The results showed increased cytotoxic activity of approximately 1170 fold in relation to free Gd-DTPA-BMA. PMID- 21296149 TI - Standardization of fluorine-18 manufacturing processes: new scientific challenges for PET. AB - In [(18)F]fluoride chemistry, the minute amounts of radioactivity taking part in a radiolabeling reaction are easily outnumbered by other reactants. Surface areas become comparably larger and more influential than in standard fluorine chemistry, while leachables, extractables, and other components that normally are considered small impurities can have a considerable influence on the efficiency of the reaction. A number of techniques exist to give sufficient (18)F-tracer for a study in a pre-clinical or clinical system, but the chemical and pharmaceutical understanding has significant gaps when it comes to scaling up or making the reaction more efficient. Automation and standardization of [(18)F]fluoride PET tracers is a prerequisite for reproducible manufacturing across multiple PET centers. So far, large-scale, multi-site manufacture has been established only for [(18)F]FDG, but several new tracers are emerging. In general terms, this transition from small- to large-scale production has disclosed several scientific challenges that need to be addressed. There are still areas of limited knowledge in the fundamental [(18)F]fluoride chemistry. The role of pharmaceutical factors that could influence the (18)F-radiosynthesis and the gaps in precise chemistry knowledge are discussed in this review based on a normal synthesis pattern. PMID- 21296150 TI - Enhanced physical stability of human calcitonin after methionine oxidation. AB - Calcitonin is a blood-calcium-lowering peptide, present in different species, which inhibits the resorption of bone by osteoclasts. Human calcitonin (hCT) is one of the few calcitonin peptides, which contains a methionine residue; this residue is in position 8. Methionines are known to be readily oxidized to sulfoxides both in vivo and in vitro. The current work describes the effect of methionine oxidation on the physical stability of hCT. Aggregation kinetics of human calcitonin were studied at different pH values by intrinsic fluorescence spectroscopy, turbidity at 350 nm, microscopy analyses, Nile Red, and 1,8-ANS fluorescence emission. In all the experiments, methionine oxidation reduced the aggregation rate of human calcitonin. The effect of methionine oxidation was independent of pH. Fluorescence lifetime data also showed that the conformation of hCT in the aggregated state can be influenced by methionine oxidation. A hypothesis for the enhanced physical stability of oxidized hCT is presented and discussed. PMID- 21296151 TI - HL005--a new selective PPARgamma antagonist specifically inhibits the proliferation of MCF-7. AB - Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear transcription factor which is involved in many diseases, such as diabetes, inflammation, dyslipidemia, hypertension, and cancer. Recently, there are many reports showing that PPARgamma agonists have preclinical and clinical anticancer activity, with relatively few reports on anticancer effects of PPARgamma antagonists. From our compound library, a novel 3-thiazolinone-modified benzoic acid derivative HL005 is found as PPARgamma selective ligand through SPR analysis (K(D)=0.21 MUM), yeast two-hybrid results suggest that HL005 antagonize the potent PPARgamma agonist rosiglitazone-induced recruitment of the coactivator for PPARgamma (IC(50)=7.97 MUM). Different from the most reported PPARgamma antagonist, HL005 can inhibit the proliferation of MCF-7 cell line in a concentration-dependent manner and induce cell cycle arrest at G2/M phase, other than interference with cell adhesion. In order to study the binding mode of this compound, three derivatives are synthesized to get more detail about the structure-activity relationship, molecular docking and the NMR spectra indicate that similar to most PPARgamma ligand, the carboxylic acid group is an important moiety for HL005 and contributes strong interaction with PPARgamma. PMID- 21296152 TI - Comparison of the humoral and cellular immune responses between body and head lice following bacterial challenge. AB - The differences in the immune response between body lice, Pediculus humanus humanus, and head lice, Pediculus humanus capitis, were investigated initially by measuring the proliferation rates of two model bacteria, a Gram-positive Staphylococcus aureus and a Gram-negative Escherichia coli, following challenge by injection. Body lice showed a significantly reduced immune response compared to head lice particularly to E. coli at the early stage of the immune challenge. Annotation of the body louse genome identified substantially fewer immune-related genes compared with other insects. Nevertheless, all required genetic components of the major immune pathways, except for the immune deficiency (Imd) pathway, are still retained in the body louse genome. Transcriptional profiling of representative genes involved in the humoral immune response, following bacterial challenge, revealed that both body and head lice, regardless of their developmental stages, exhibited an increased immune response to S. aureus but little to E. coli. Head lice, however, exhibited a significantly higher phagocytotic activity against E. coli than body lice, whereas the phagocytosis against S. aureus differed only slightly between body and head lice. These findings suggest that the greater immune response in head lice against E. coli is largely due to enhanced phagocytosis and not due to differences in the humoral immune response. The reduced phagocytotic activity in body lice could be responsible, in part, for their increased vector competence. PMID- 21296153 TI - Fruitless RNAi knockdown in males interferes with copulation success in Schistocerca gregaria. AB - In Drosophila melanogaster, the male-specific splice isoform of the fruitless gene (Fru(M)) codes for a set of transcription factors that are involved in the regulation of male courtship and copulation. Fru(M) is expressed in an interconnected neuronal circuit containing central and sensory neurons as well as motor neurons. A partial sequence from the Schistocerca gregaria fru-gene from an EST database allowed quantitative real time analysis of fru-expression in adult locusts, and revealed the highest expression in the testes, accessory glands as well as the brain (and optic lobes). Starting fru specific RNAi knockdown in the third and fourth nymphal stage resulted in a significantly lower cumulative copulation frequency of the RNAi-treated animals compared to controls after 3 h of observation. In addition, the testes of RNAi-treated males weigh less. Analysis of the egg pods resulting from a successful copulation event revealed that egg pods from females that mated with an RNAi-treated male were smaller and contained less fertilized eggs compared to egg pods from females who mated with control males. Starting injections in the fifth nymphal stage showed the complete opposite for the cumulative copulation frequency and testes weight. We conclude that already in the early nymphal phases of male desert locusts, fruitless starts to play an important role in the regulation of successful copulation in the adult. The RNAi treatment in the male has also its effects on fertility and fecundity. It remains unknown whether this effect is coming from aberrant courtship behaviour or from an altered composition of the sperm or seminal fluids. PMID- 21296154 TI - Identification and characterization of the fusion transcript, composed of the apterous homolog and a putative protein phosphatase gene, generated by 1.5-Mb interstitial deletion in the vestigial (Vg) mutant of Bombyx mori. AB - The vestigial (Vg) mutant is a Z-linked mutant that causes vestigial wings in the silkworm, Bombyx mori. We have previously reported a 1.5-Mb interstitial deletion on the Z chromosome bearing the Vg mutation (Z(Vg) chromosome). In this study, we found that exons 3-8 of a gene named Bmptp-Z encoding a putative tyrosine specific protein phosphatase are deleted by the 1.5-Mb interstitial deletion. We found that a gene encoding the Bombyx homolog of Drosophila Apterous (BmAp-A) protein is located 4.5 kb downstream of the distal breakpoint of the 1.5-Mb interstitial deletion. Moreover, an in-frame fusion transcript composed of the 5' part of Bmptp-Z and the 3' part of Bmap-A is generated specific to the Z(Vg) chromosome. Effects of the in-frame fusion transcript on the vestigial phenotype are discussed. PMID- 21296155 TI - Recognition of microbial molecular patterns and stimulation of prophenoloxidase activation by a beta-1,3-glucanase-related protein in Manduca sexta larval plasma. AB - Detection of pathogenic invaders is the essential first step of a successful defense response in multicellular organisms. In this study, we have identified a new member of the beta-1,3-glucanase-related protein superfamily from the tobacco hornworm Manduca sexta. This protein, designated microbe binding protein (MBP), is 61% identical in sequence to Bombyx mori Gram-negative bacteria binding protein, but only 34-36% identical to M. sexta beta-1,3-glucan recognition protein-1 and 2. Its mRNA levels were strongly up-regulated in hemocytes and fat body of immune challenged larvae, along with an increase in concentration of the plasma protein. We expressed M. sexta MBP in a baculovirus-insect cell system. The purified protein associated with intact bacteria and fungi. It specifically bound to lipoteichoic acid, lipopolysaccharide, diaminopimelic acid-type peptidoglycans (DAP-PGs) from Escherichia coli and Bacillus subtilis, but less so to laminarin or Lys-type PG from Staphylococcus aureus. The complex binding pattern was influenced by other plasma factors and additional microbial surface molecules. After different amounts of MBP had been incubated with larval plasma on ice, a concentration-dependent increase in phenoloxidase (PO) activity occurred in the absence of any microbial elicitor. The activity increase was also observed in the mixture of plasma and a bacterial or fungal cell wall component. The prophenoloxidase (proPO) activation became more prominent when DAP-PGs, Micrococcus luteus Lys-PG, or lipoteichoic acid was included in the mixture of MBP and plasma. Statistic analysis suggested that a synergistic enhancement of proPO activation was caused by an interaction between MBP and these elicitors, but not S. aureus Lys-PG, lipopolysaccharide, curdlan, or laminarin. These data indicate that M. sexta MBP is a component of the surveillance mechanism and, by working together with other pattern recognition molecules and serine proteinases, triggers the proPO activation system. PMID- 21296156 TI - Novel nicotinic action of the sulfoximine insecticide sulfoxaflor. AB - The novel sulfoximine insecticide sulfoxaflor is as potent or more effective than the neonicotinoids for toxicity to green peach aphids (GPA, Myzus persicae). The action of sulfoxaflor was characterized at insect nicotinic acetylcholine receptors (nAChRs) using electrophysiological and radioligand binding techniques. When tested for agonist properties on Drosophila melanogaster Dalpha2 nAChR subunit co-expressed in Xenopus laevis oocytes with the chicken beta2 subunit, sulfoxaflor elicited very high amplitude (efficacy) currents. Sulfoximine analogs of sulfoxaflor were also agonists on Dalpha2/beta2 nAChRs, but none produced maximal currents equivalent to sulfoxaflor nor were any as toxic to GPAs. Additionally, except for clothianidin, none of the neonicotinoids produced maximal currents as large as those produced by sulfoxaflor. These data suggest that the potent insecticidal activity of sulfoxaflor may be due to its very high efficacy at nAChRs. In contrast, sulfoxaflor displaced [(3)H]imidacloprid (IMI) from GPA nAChR membrane preparations with weak affinity compared to most of the neonicotinoids examined. The nature of the interaction of sulfoxaflor with nAChRs apparently differs from that of IMI and other neonicotinoids, and when coupled with other known characteristics (novel chemical structure, lack of cross resistance, and metabolic stability), indicate that sulfoxaflor represents a significant new insecticide option for the control of sap-feeding insects. PMID- 21296157 TI - Role of endothelin in the cardiovascular system. AB - The endothelin (ET) system consists of three peptide ligands (ET-1, ET-2 and ET 3) and two G-protein-coupled receptors, ET(A) and ET(B). In the cardiovascular system, ETs, particularly ET-1, are expressed in smooth muscle cells, cardiomyocytes, fibroblasts, and notably in vascular endothelial cells. Intense research over the last 10 years has changed the original view of ET-1 as mainly a vasoconstrictor regulating blood pressure, into a biological factor regulating processes such as vascular remodeling, angiogenesis or extracellular matrix synthesis. The advent of specific (and type-selective) ET receptor antagonists has greatly fostered our knowledge of the biological function of ET-1, and has offered a potential therapeutic approach for numerous diseases including hypertension, atherosclerosis or fibrosis. In this article, we review the regulation of the expression of vascular ET-1, as well as the contribution of ET 1 to endothelial, smooth muscle and fibroblast cell function, with particular interest in the role of ET-1 in the development of cardiovascular diseases. PMID- 21296158 TI - Improvement of translation efficiency in an Escherichia coli cell-free protein system using cysteine. AB - Cell-free protein synthesis systems are powerful tools for protein expression, and allow large amounts of specific proteins to be obtained even if these proteins are detrimental to cell survival. In this report we describe the effect of cysteine on cell-free protein synthesis. The addition of cysteine caused a 2.7 fold increase in the level of synthesized glutathione S-transferase (GST). Moreover, the levels of sulfhydryl group reductants, including reduced glutathione and dithiothreitol (DTT), were increased 1.9- and 1.7-fold, respectively, whereas levels of the disulfide dimers, cystine and oxidized glutathione, were suppressed 87% and 66%, respectively. These trends were also observed for green fluorescent protein (GFP) expression. The addition of cysteine competitively reversed the inhibitory effect of cystine on protein expression. These results suggest that the sulfhydryl group in cysteine plays a crucial role in enhancing protein synthesis, and that the addition of excess cysteine could be a convenient and useful method for improving protein expression. PMID- 21296159 TI - Efficient overexpression and purification of active full-length human transcription factor Yin Yang 1 in Escherichia coli. AB - The Yin Yang 1 protein is a zinc finger transcription factor involved in the regulation of diverse cellular processes through DNA and protein-protein interactions. Here we present an improved method for the expression and purification of the human full-length YY1 protein from Escherichia coli. The protein was first purified using denaturing conditions, refolded using optimized conditions and then purified using a DNA-affinity column to >= 95% purity; this process provided a high final yield and highly active protein. The protein was active in EMSA and the fluorescence anisotropy assays. The protein retained its full activity and its initial concentration for several months when stored at -80 degrees C. Thus, we have obtained YY1 protein with levels of activity and concentration that are suitable for spectroscopic and other biochemical studies. PMID- 21296160 TI - Structural basis for pH dependent monomer-dimer transition of 3,4-dihydroxy 2 butanone-4-phosphate synthase domain from Mycobacterium tuberculosis. AB - 3,4-dihydroxy 2-butanone 4-phosphate synthase (DHBPS) and GTP cyclohydrolase-II (GTPCH-II) are the two initial enzymes involved in riboflavin biosynthesis pathway, which has been shown to be essential for the pathogens. In Mycobacterium tuberculosis (Mtb), the ribA2 gene (Rv1415) encodes for the bi-functional enzyme with DHBPS and GTPCH-II domains at N- and C-termini, respectively. We have determined three crystal structures of Mtb-DHBPS domain in complex with phosphate and glycerol at pH 6.0, with sulphate at pH 4.0 and with zinc and sulphate at pH 4.0 at 1.8, 2.06 and 2.06 A resolution, respectively. The hydrodynamic volume and enzyme activity studies revealed that the Mtb-DHBPS domain forms a functional homo-dimer between the pH 6.0 and 9.0, however, at pH 5.0 and below, it forms a stable inactive monomer in solution. Furthermore, the functional activity of Mtb DHBPS and its dimeric state could be restored by increasing the pH between 6.0 and 9.0. The comparison of crystal structures determined at different pH revealed that the overall three-dimensional structure of Mtb-DHBPS monomer remains the same. However, the length of the alpha6-helix at pH 6.0 has increased from 15 to 22 A in pH 4.0 by increasing the number of amino acids contributing to the alpha6 helix from 11 to 15, achieving a higher structural stability at pH 4.0. Taken together our experiments strongly suggest that the Mtb-DHBPS domain can transit between inactive monomer to active dimer depending upon its pH values, both in solution as well in crystal structure. PMID- 21296161 TI - Scoring functions for cryoEM density fitting. AB - In fitting atomic structures into cryoEM density maps of macromolecular assemblies, the cross-correlation function (CCF) is the most prevalent method of scoring the goodness-of-fit. However, there are still many possible, less studied ways of scoring fits. In this paper, we introduce four scores new to cryoEM fitting and compare their performance to three known scores. Our benchmark consists of (a) 4 protein assemblies with simulated maps at 5-20 A resolution, including the heptameric ring of GroEL; and (b) 4 experimental maps of GroEL at ~6-23 A resolution with corresponding fitted atomic models. We perturb each fit 1000 times and assess each new fit with each score. The correlation between a score and the Calpha RMSD of each fit from the "correctly" fitted structure shows that the CCF is one of the best scores, but in certain situations could be augmented or even replaced by other scores. For instance, our implementation of a score based on mutual information outperforms or is comparable to the CCF in almost all test cases, and our new "envelope score" works as well as the CCF at sub-nanometer resolution but is an order of magnitude faster to calculate. The results also suggest that the width of the Gaussian function used to blur the atomic structure into a density map can significantly affect the fitting process. Finally, we show that our score-testing method, when combined with the Laplacian CCF or the mutual information scores, can be used as a statistical tool for improving cryoEM density fitting. PMID- 21296162 TI - Modeling protein structure at near atomic resolutions with Gorgon. AB - Electron cryo-microscopy (cryo-EM) has played an increasingly important role in elucidating the structure and function of macromolecular assemblies in near native solution conditions. Typically, however, only non-atomic resolution reconstructions have been obtained for these large complexes, necessitating computational tools for integrating and extracting structural details. With recent advances in cryo-EM, maps at near-atomic resolutions have been achieved for several macromolecular assemblies from which models have been manually constructed. In this work, we describe a new interactive modeling toolkit called Gorgon targeted at intermediate to near-atomic resolution density maps (10-3.5 A), particularly from cryo-EM. Gorgon's de novo modeling procedure couples sequence-based secondary structure prediction with feature detection and geometric modeling techniques to generate initial protein backbone models. Beyond model building, Gorgon is an extensible interactive visualization platform with a variety of computational tools for annotating a wide variety of 3D volumes. Examples from cryo-EM maps of Rotavirus and Rice Dwarf Virus are used to demonstrate its applicability to modeling protein structure. PMID- 21296163 TI - Mapping elasticity moduli of atherosclerotic plaque in situ via atomic force microscopy. AB - Several studies have suggested that evolving mechanical stresses and strains drive atherosclerotic plaque development and vulnerability. Especially, stress distribution in the plaque fibrous capsule is an important determinant for the risk of vulnerable plaque rupture. Knowledge of the stiffness of atherosclerotic plaque components is therefore of critical importance. In this work, force mapping experiments using atomic force microscopy (AFM) were conducted in apolipoprotein E-deficient (ApoE(-/-)) mouse, which represents the most widely used experimental model for studying mechanisms underlying the development of atherosclerotic lesions. To obtain the elastic material properties of fibrous caps and lipidic cores of atherosclerotic plaques, serial cross-sections of aortic arch lesions were probed at different sites. Atherosclerotic plaque sub structures were subdivided into cellular fibrotic, hypocellular fibrotic and lipidic rich areas according to histological staining. Hertz's contact mechanics were used to determine elasticity (Young's) moduli that were related to the underlying histological plaque structure. Cellular fibrotic regions exhibit a mean Young modulus of 10.4+/-5.7kPa. Hypocellular fibrous caps were almost six times stiffer, with average modulus value of 59.4+/-47.4kPa, locally rising up to ~250kPa. Lipid rich areas exhibit a rather large range of Young's moduli, with average value of 5.5+/-3.5kPa. Such precise quantification of plaque stiffness heterogeneity will allow investigators to have prospectively a better monitoring of atherosclerotic disease evolution, including arterial wall remodeling and plaque rupture, in response to mechanical constraints imposed by vascular shear stress and blood pressure. PMID- 21296164 TI - Designed ankyrin repeat protein binders for the crystallization of AcrB: plasticity of the dominant interface. AB - The formation of well-diffracting crystals is a major bottleneck in structural analysis of membrane proteins by X-ray crystallography. One approach to improve crystal quality is the use of DARPins as crystallization chaperones. Here, we present a detailed analysis of the interaction between DARPins and the integral membrane protein AcrB. We find that binders selected in vitro by ribosome display share a common epitope. The comparative analysis of three crystal structures of AcrB-DARPin complexes allowed us to study the plasticity of the interaction with this dominant binding site. Seemingly redundant AcrB-DARPin crystals show substantially different diffraction quality as a result of subtle differences in the binding geometry. This work exemplifies the importance to screen a number of crystallization chaperones to obtain optimal diffraction data. Crystallographic analysis is complemented by biophysical characterization of nine AcrB binders. We observe that small variations in the interface can lead to differing behavior of the DARPins with regards to affinity, stoichiometry of the complexes and specificity for their target. PMID- 21296166 TI - Optimal weights for local multi-atlas fusion using supervised learning and dynamic information (SuperDyn): validation on hippocampus segmentation. AB - We developed a novel method for spatially-local selection of atlas-weights in multi-atlas segmentation that combines supervised learning on a training set and dynamic information in the form of local registration accuracy estimates (SuperDyn). Supervised learning was applied using a jackknife learning approach and the methods were evaluated using leave-N-out cross-validation. We applied our segmentation method to hippocampal segmentation in 1.5T and 3T MRI from two datasets: 69 healthy middle-aged subjects (aged 44-49) and 37 healthy and cognitively-impaired elderly subjects (aged 72-84). Mean Dice overlap scores (left hippocampus, right hippocampus) of (83.3, 83.2) and (85.1, 85.3) from the respective datasets were found to be significantly higher than those obtained via equally-weighted fusion, STAPLE, and dynamic fusion. In addition to global surface distance and volume metrics, we also investigated accuracy at a spatially local scale using a surface-based segmentation performance assessment method (SurfSPA), which generates cohort-specific maps of segmentation accuracy quantified by inward or outward displacement relative to the manual segmentations. These measurements indicated greater agreement with manual segmentation and lower variability for the proposed segmentation method, as compared to equally-weighted fusion. PMID- 21296165 TI - Extracting information from functional connectivity maps via function-on-scalar regression. AB - Functional connectivity of an individual human brain is often studied by acquiring a resting state functional magnetic resonance imaging scan, and mapping the correlation of each voxel's BOLD time series with that of a seed region. As large collections of such maps become available, including multisite data sets, there is an increasing need for ways to distill the information in these maps in a readily visualized form. Here we propose a two-step analytic strategy. First, we construct connectivity-distance profiles, which summarize the connectivity of each voxel in the brain as a function of distance from the seed, a functional relationship that has attracted much recent interest. Next, these profile functions are regressed on predictors of interest, whether categorical (e.g., acquisition site or diagnostic group) or continuous (e.g., age). This procedure can provide insight into the roles of multiple sources of variation, and detect large-scale patterns not easily available from conventional analyses. We illustrate the proposed methods with a resting state data set pooled across four imaging sites. PMID- 21296167 TI - Anatomical correlates for category-specific naming of living and non-living things. AB - INTRODUCTION: Selective naming categories impairments for living and non-living things are widely reported in brain damaged patients. Electrostimulation mapping was used to study the possible anatomical segregation of living/non-living categories in a prospective series of patients operated on for tumor removal. MATERIALS AND METHODS: Fifty brain mappings (patients with no language impairment; range: 14-80 years; mean: 48 years; 26 males; 5 left handed) were performed in 46 left and 4 right hemispheres using two linguistically controlled tasks (naming for living and non-living things) during an awake surgery procedure. Fifteen regions and four macro cortical areas were designed to analyze the distribution of the interference sites. RESULTS: Over 761 sites stimulated in the lateral hemispheres, 130 naming interferences sites were detected in small cortical areas (<1cm(2)). High individual variability was observed for living/non living word retrieval localization and organization with a majority (62%) of shared living/non-living interferences. Specific living (12%) or non-living (26%) interferences were found too. In group analysis, no statistical significant anatomical localization was observed for living items in left lateral hemispheric cortex. A statistical significant representation of interference sites for non living objects was found (Generalized Estimating Equation methodology, z test=2.28, p=0.027) in the left posterolateral temporoparietal cortex. No influence of histopathology, gender and age on anatomical localization of naming categories was detected. CONCLUSION: The existence of dedicated neural structures for naming non-living things in the left posterolateral temporoparietal cortex is supported by this study although high individual differences exist in the organization of word categories retrieval. PMID- 21296168 TI - Algorithms, atrophy and Alzheimer's disease: cautionary tales for clinical trials. AB - Thompson and Holland (2010) highlight a biologically implausible deceleration of atrophy in results previously published in this journal (Hua et al., 2010); the results were derived using tensor based morphometry on images from the Alzheimer's Disease Neuroimaging Initiative. They speculate that bias may have been introduced due to asymmetric interpolation in global image registration, and/or to the use of a statistically defined region of interest. In their reply, Hua et al. (this issue) acknowledge the presence of a bias, but show that it stems largely from an asymmetry in the local image registration algorithm (an asymmetry common to methods in many published studies using nonlinear registration). Hua et al. demonstrate that the bias can largely be removed using a revised symmetric algorithm. This correspondence raises important issues relating to the lack of ground truth against which image analysis methodologies designed to determine atrophy patterns and rates can be assessed; and the increasing importance of striving to avoid potential biases as these techniques become utilised in clinical trials. In the absence of a "gold standard", we discuss a number of steps against which methodologies designed to quantify atrophy from serial scans can be assessed. PMID- 21296169 TI - Convergent evidence of the contribution of TP53 genetic variation (Pro72Arg) to metabolic activity and white matter volume in the frontal lobe in schizophrenia patients. AB - Abnormalities in white matter (WM) volumes and integrity in schizophrenia, together with post-mortem studies showing reduced expression of oligodendrocyte/myelination genes and apoptotic processes taking place in oligodendrocytes, suggest the interest of major regulators of apoptosis as candidate genes for some features related to myelin integrity in schizophrenia. Protein p53, encoded by TP53 gene, has a central role in the control of apoptosis and is involved in oligodendrocyte development. TP53 gene polymorphisms may account for variability in WM features, metabolic activity and biochemical markers of neuronal integrity and membrane turnover. Pro72Arg and Ins16bp polymorphisms at TP53 gene were analyzed in 20 DSM-IV schizophrenia patients. T1/T2-weighted sequences of these patients were acquired using a 1.5T Philips Gyroscan system. Scans were transformed into Talairach space and segmented into gray matter (GM), WM and cerebrospinal fluid (CSF) using Statistical Parametric Mapping under a ROI approach. Likewise dorsolateral prefrontal cortex (DLPFC) metabolic activity was measured using a procedure based on MRI/PET image fusion. In 13 of these patients proton magnetic resonance spectroscopy was used to examine N-acetylaspartate (NAA), creatine (Cr) and choline (Cho) levels in dorsolateral-medial prefrontal cortex (DLMPFC). MRI data were adjusted for age and brain volume using regression parameters from a healthy control group (n=45). Patients Pro/Arg heterozygous (Pro72Arg polymorphism) showed a generalized deficit in whole-brain WM that was especially prominent in frontal lobe and a lower metabolic activity in the DLPFC as compared to Pro/Pro homozygous. Pro/Arg subjects also showed decreased NAA/Cho and increased Cho/Cr ratios in right DLMPFC. TP53 genetic variability influences WM volumes in frontal lobes and it seems to modulate the metabolic activity in this region. Our results suggest that TP53 might influence aspects of myelin and white matter integrity which may account for some of the frontal dysfunction features commonly described in these patients. PMID- 21296170 TI - Specialization for written words over objects in the visual cortex. AB - The Visual Word Form Area (VWFA) is part of the left ventral visual stream that underlies the invariant identification of visual words. It remains debated whether this region is truly selective for words relative to common objects; why this particular part of the visual system is reproducibly engaged in reading; and whether reading expertise also relies on perceptual learning within earlier visual areas. In this fMRI study we matched written words and line-drawings of objects in luminance, contour length and number of features. We then compared them to control images made by scrambling procedures that kept local features intact. Greater responses to written words than to objects were found not only in the VWFA, but also in areas V1/V2 and V3v/V4. Furthermore, by contrasting stimuli reduced either to line junctions (vertices) or to line midsegments, we showed that the VWFA partially overlaps with regions of ventral visual cortex particularly sensitive to the presence of line junctions that are useful for object recognition. Our results indicate that preferential processing of written words can be observed at multiple levels of the visual system. It is possible that responses in early visual areas might be due to some remaining differences between words and controls not eliminated in the present stimuli. However, our results concur with recent comparisons of literates and illiterates and suggest that these early visual activations reflect the effects of perceptual learning under pressure for fast, parallel processing that is more prominent in reading than other visual cognitive processes. PMID- 21296171 TI - A regularization algorithm for decoding perceptual temporal profiles from fMRI data. AB - In several biomedical fields, researchers are faced with regression problems that can be stated as Statistical Learning problems. One example is given by decoding brain states from functional magnetic resonance imaging (fMRI) data. Recently, it has been shown that the general Statistical Learning problem can be restated as a linear inverse problem. Hence, new algorithms were proposed to solve this inverse problem in the context of Reproducing Kernel Hilbert Spaces. In this paper, we detail one iterative learning algorithm belonging to this class, called nu method, and test its effectiveness in a between-subjects regression framework. Specifically, our goal was to predict the perceived pain intensity based on fMRI signals, during an experimental model of acute prolonged noxious stimulation. We found that, using a linear kernel, the psychophysical time profile was well reconstructed, while pain intensity was in some cases significantly over/underestimated. No substantial differences in terms of accuracy were found between the proposed approach and one of the state-of-the-art learning methods, the Support Vector Machines. Nonetheless, adopting the nu-method yielded a significant reduction in computational time, an advantage that became more evident when a relevant feature selection procedure was implemented. The nu method can be easily extended and included in typical approaches for binary or multiple classification problems, and therefore it seems well-suited to build effective brain activity estimators. PMID- 21296172 TI - New perspectives on the evolutionary history of hepatitis B virus genotype F. AB - Hepatitis B virus (HBV) is a globally distributed human pathogen. The aim of this work was to analyze the evolutionary history of HBV genotype F, emphasizing on the study of subgenotypes prevalent in the Southern area of South America. Complete genomes of HBV genotype F from 36 samples from Argentina and Chile were sequenced and analyzed by phylogenetic and Bayesian coalescent methods along with sequences obtained from GenBank database. The phylogeography separated not only Central American from South American isolates but also revealed that different subgenotypes are distributed in constrained although not exclusive areas of the continent. The result obtained with time-stamped complete genomes failed to explain the wide geographical distribution and the clustering observed in this genotype. Conversely, the use of Bayesian coalescent analyses with substitution rates as priors, instead of the co-estimation of tMRCA and substitution rate, allowed us to propose a far origin for the HBV genotype F based on the phylogeographical and epidemiological data. PMID- 21296173 TI - Glacial survival east and west of the 'Mekong-Salween Divide' in the Himalaya Hengduan Mountains region as revealed by AFLPs and cpDNA sequence variation in Sinopodophyllum hexandrum (Berberidaceae). AB - Molecular phylogeographic studies have recently begun to elucidate how plant species from the Qinghai-Tibetan Plateau (QTP) and adjacent regions responded to the Quaternary climatic oscillations. In this regard, however, far less attention has been paid to the southern and south-eastern declivities of the QTP, i.e. the Himalaya-Hengduan Mountains (HHM) region. Here, we report a survey of amplified fragment length polymorphisms (AFLPs) and chloroplast DNA (cpDNA) sequence variation in the HHM endemic Sinopodophyllum hexandrum, a highly selfing alpine perennial herb with mainly gravity-dispersed berries (105 individuals, 19 localities). We specifically aimed to test a vicariant evolutionary hypothesis across the 'Mekong-Salween Divide', a known biogeographic and phytogeographic boundary of north-to-south trending river valleys separating the East Himalayas and Hengduan Mts. Both cpDNA and AFLPs identified two divergent phylogroups largely congruent with these mountain ranges. There was no genetic depauperation in the more strongly glaciated East Himalayas (AFLPs: H(E)=0.031; cpDNA: h(S)=0.133) compared to the mainly ice-free Hengduan Mts. (AFLPs: H(E)=0.037; cpDNA: h(S)=0.082), while population differentiation was consistently higher in the former region (AFLPs: Phi(ST)=0.522 vs. 0.312; cpDNA: Phi(ST)=0.785 vs. 0.417). Our results suggest that East Himalayan and Hengduan populations of S. hexandrum were once fragmented, persisted in situ during glacials in both areas, and have not merged again, except for a major instance of inter-lineage chloroplast capture identified at the MSD boundary. Our coalescent time estimate for all cpDNA haplotypes (c. 0.37-0.48 mya), together with paleogeological evidence, strongly rejects paleo-drainage formation as a mechanism underlying allopatric fragmentation, whereas mountain glaciers following the ridges of the MSD during glacials (and possible interglacials) could have been responsible. This study thus indicates an important role for mountain glaciers in driving (incipient) allopatric speciation across the MSD in the HHM region by causing vicariant lineage divergence and acting as barriers to post-divergence gene flow. PMID- 21296175 TI - Long-term outcome of human herpesvirus-6 encephalitis after allogeneic stem cell transplantation. AB - Human herpesvirus-6 (HHV-6) encephalitis is recognized as a relatively rare, but sometimes lethal, complication of allogeneic hematopoietic stem cell transplantation (HSCT). Although the development of new diagnostic techniques and antiviral therapy has improved, the prognosis of encephalitis is still unclear. We surveyed 197 patients who underwent allogeneic HSCT between January 2004 and March 2008 at our institution, and 8 (4.0%) were diagnosed as having HHV-6 encephalitis. Five were male and 3 were female, with a median age of 40.5 years. The median onset of HHV-6 encephalitis was 18 days after HSCT, and the median duration of antiviral therapy was 41 days. The median survival time from the onset of encephalitis was 23.1 months (range: 2.7-66.7), and 3 patients died of unrelated causes (sepsis in 2 and gastrointestinal tract bleeding in 1). Cord blood transplantation was identified as the only independent risk factor (relative risk [RR] = 4.98; P = .049) by multivariate analysis. There was no statistical significance of survival after HSCT between the patients with HHV-6 encephalitis and those without HHV-6 encephalitis (the 2-year survival rate was 60% and 52.6%, respectively; P = .617). Four of the 5 surviving patients were unable to return to society because of neuropsychological disorders, including anterograde amnesia and seizures with prominent hippocampal atrophy. Although HHV 6 encephalitis occurring after HSCT is now becoming a curable complication, its sequelae, such as neuropsychological disorders, have a marked influence on the quality of life of long-term survivors. Accordingly, it is necessary to identify risk factors for HHV-6 encephalitis and establish methods for prevention of this complication. PMID- 21296174 TI - Effects of pharmacological manipulations of NMDA-receptors on deliberation in the Multiple-T task. AB - Both humans and non-human animals have the ability to navigate and make decisions within complex environments. This ability is largely dependent upon learning and memory processes, many of which are known to depend on NMDA-sensitive receptors. When humans come to difficult decisions they often pause to deliberate over their choices. Similarly, rats pause at difficult choice points. This behavior, known as vicarious trial and error (VTE), is hippocampally dependent and entails neurophysiological representations of expectations of future outcomes in hippocampus and downstream structures. In order to determine the dependence of VTE behaviors on NMDA-sensitive receptors, we tested rats on a Multiple-T choice task with a reward-delivery reversal known to elicit VTE. Rats under the influence of NMDA-receptor antagonists (CPP) showed a significant reduction in VTE, particularly at the reward reversal, implying a role for NMDA-sensitive receptors in the generation of vicarious trial and error behaviors. PMID- 21296176 TI - Predictions in the face of clinical reality: HistoCheck versus high-risk HLA allele mismatch combinations responsible for severe acute graft-versus-host disease. AB - HLA polymorphism remains a major hurdle for hematopoietic stem cell transplantation (HSCT). In 2004, Elsner et al. proposed the HistoCheck Web-based tool to estimate the allogeneic potential between HLA-mismatched stem cell donor/recipient pairs expressed as a sequence similarity matching (SSM). SSM is based on the structure of HLA molecules and the functional similarity of amino acids. According to this algorithm, a high SSM score represents high dissimilarity between MHC molecules, resulting in a potentially more deleterious impact on stem cell transplant outcomes. We investigated the potential of SSM to predict high-risk HLA allele mismatch combinations responsible for severe acute graft-versus-host disease (aGVHD grades III and IV) published by Kawase et al., by comparing SSM in low- and high-risk combinations. SSM was calculated for allele mismatch combinations using the HistoCheck tool available on the Web (www.histocheck.org). We compared ranges and means of SSM among high-risk (15 combinations observed in 722 donor/recipient pairs) versus low-risk allele combinations (94 combinations in 3490 pairs). Simulation scenarios were created where the recipient's HLA allele was involved in multiple allele mismatch combinations with at least 1 high-risk and 1 low-risk mismatch combination. SSM values were then compared. The mean SSM for high- versus low-risk combinations were 2.39 and 2.90 at A, 1.06 and 2.53 at B, 16.60 and 14.99 at C, 4.02 and 3.81 at DRB1, and 7.47 and 6.94 at DPB1 loci, respectively. In simulation scenarios, no predictable SSM association with high- or low-risk combinations could be distinguished. No DQB1 combinations met the statistical criteria for our study. In conclusion, our analysis demonstrates that mean SSM scores were not significantly different, and SSM distributions were overlapping among high- and low-risk allele combinations within loci HLA-A, B, C, DRB1, and DPB1. This analysis does not support selecting donors for HSCT recipients based on low HistoCheck SSM scores. PMID- 21296177 TI - Detection of peroxynitrite accumulation in Arabidopsis thaliana during the hypersensitive defense response. AB - Nitric oxide (NO) is synthesized in plants in response to stress, and its role in signaling is well-documented. In contrast, very little is known about the physiological role of its derivate peroxynitrite (ONOO(-)), which forms when NO reacts with O(2)(-) and induces protein modification by tyrosine nitration. Infection with an avirulent pathogen triggers the simultaneous production of NO and reactive oxygen species, as well as an increase in tyrosine nitration, so peroxynitrite could be physiologically relevant during this process. To gain insight into the role of peroxynitrite in plants, we measured its accumulation during the hypersensitive response in Arabidopsis thaliana using the specific peroxynitrite-sensitive fluorescent dye HKGreen-2 in a leaf disc assay. The avirulent pathogen Pseudomonas syringae pv. tomato, carrying the AvrB gene (Pst AvrB), induced a strong increase in fluorescence 3-4 h post-infiltration (hpi) which peaked 7-8 hpi. The increase in HKGreen-2 fluorescence was inhibited by co injecting the peroxynitrite-scavenger urate together with the pathogen, and was almost completely eliminated by co-infiltrating urate with HKGreen-2, confirming that HKGreen-2 fluorescence in planta is induced specifically by peroxynitrite. This establishes a link between peroxynitrite synthesis and tyrosine nitration, and we therefore propose that peroxynitrite transduces the NO signal by modifying protein functions. PMID- 21296178 TI - Cytochrome P450 BM3, NO binding and real-time NO detection. AB - Nitric oxide is known to coordinate to ferrous heme proteins very tightly, following which it is susceptible to reaction with molecular oxygen or free NO. Its coordination to ferric heme is generally weaker but the resultant complexes are more stable in the presence of oxygen. Here we report determination of the binding constants of Cytochrome P450 BM3 for nitric oxide in the ferric state in the presence and absence of substrate. Compared to other 5-coordinate heme proteins, the K(d) values are particularly low at 16 and 40 nM in the presence and absence of substrate respectively. This most likely reflects the high hydrophobicity of the active site of this enzyme. The binding of NO is tight enough to enable P450 BM3 oxygenase domain to be used to determine NO concentrations and in real-time NO detection assays, which would be particularly useful under conditions of low oxygen concentration, where current methods break down. PMID- 21296179 TI - Regulation of growth performance and lipid metabolism by dietary n-3 highly unsaturated fatty acids in juvenile grass carp, Ctenopharyngodon idellus. AB - To determine the effects of n-3 highly unsaturated fatty acids (HUFAs) in grass carp (Ctenopharyngodon idellus), a 75-day feeding experiment was conducted using five isonitrogenous and isoenergetic semi-purified diets containing 0% (control), 0.26%, 0.52%, 0.83% or 1.13% n-3 HUFAs. Weight gain, specific growth rate, feed efficiency and protein efficiency increased by increasing the dietary HUFAs content from 0% to 0.52%, and declined thereafter. Intraperitoneal fat content and the hepatopancreatic lipid levels were lowest in the 0.52% group. The tissue fatty acid level was well correlated with dietary HUFAs content. Hepatic lipoprotein lipase (LPL) activity was significantly higher in the 0.52% group, while that of malate dehydrogenase (MDH) was stable in the 0-0.52% groups, and was significantly lower in the 1.13% group. Superoxide dismutase (SOD) activity increased significantly with increasing dietary HUFAs content, consistent with the level of malondialdehyde (MDA). Hepatic mRNA expression of peroxisome proliferator-activated receptor-alpha (PPAR-alpha) was greatest in the 0.83% group and that of the LPL gene increased with increasing dietary HUFAs content up to 0.83%. These results indicate that adequate dietary HUFAs supplementation significantly promotes growth performance and lipid metabolism in freshwater fish grass carp. However, excess HUFAs fortification may exert adverse effects, which might be due to oxidative stress. PMID- 21296180 TI - The kinetic properties of the glutamate dehydrogenase of Teladorsagia circumcincta and their significance for the lifestyle of the parasite. AB - Like other nematodes, both L(3) and adult Teladosagia circumcincta secrete or excrete NH(3)/NH(4)(+), but the reactions involved in the production are unclear. Glutamate dehydrogenase is a significant source NH(3)/NH(4)(+) in some species, but previous reports indicate that the enzyme is absent from L(3)Haemonchus contortus. We show that glutamate dehydrogenase was active in both L(3) and adult T. circumcincta. The apparent K(m)s of the L(3) enzyme differed from those of the adult enzyme, the most significant of these being the increase in the K(m) for NH(4)(+) from 18mM in L(3) to 49mM in adults. The apparent V(max) of the oxidative deamination reaction was greater than that of the reductive reaction in L(3), but this was reversed in adults. The activity of the oxidative reaction of the L(3) enzyme was not affected by adenine nucleotides, but that of the reductive reaction was stimulated significantly by either ADP or ATP. The L(3) enzyme was more active with NAD(+) than it was with NADP(+), although the activities supported by NADH and NADPH were similar at saturating concentrations. While the activity of the oxidative reaction was sufficient to account for the NH(3)/NH(4)(+) efflux we have previously reported, the reductive amination reaction was likely to be more active. PMID- 21296181 TI - Towards a quantitative prediction of the fluxome from the proteome. AB - The promise of proteomics and fluxomics is limited by our current inability to integrate these two levels of cellular organization. Here we present the derivation, experimental parameterization, and appraisal of flux functions that enable the quantitative prediction of changes in metabolic fluxes from changes in enzyme levels. We based our derivation on the hypothesis that, in the determination of steady-state flux changes, the direct proportionality between enzyme concentrations and reaction rates is principal, whereas the complexity of enzyme-metabolite interactions is secondary and can be described using an approximate kinetic format. The quality of the agreement between predicted and experimental fluxes in Lactococcus lactis, supports our hypothesis and demonstrates the need and usefulness of approximative descriptions in the study of complex biological systems. Importantly, these flux functions are scalable to genome-wide networks, and thus drastically expand the capabilities of flux prediction for metabolic engineering efforts beyond those conferred by the currently used constraints-based models. PMID- 21296182 TI - Metabolic engineering of geranic acid in maize to achieve fungal resistance is compromised by novel glycosylation patterns. AB - Many terpenoids are known to have antifungal properties and overexpression of these compounds in crops is a potential tool in disease control. In this study, 15 different mono- and sesquiterpenoids were tested in vitro against two major pathogenic fungi of maize (Zea mays), Colletotrichum graminicola and Fusarium graminearum. Among all tested terpenoids, geranic acid showed very strong inhibitory activity against both fungi (MIC<46 MUM). To evaluate the possibility of enhancing fungal resistance in maize by overexpressing geranic acid, we generated transgenic plants with the geraniol synthase gene cloned from Lippia dulcis under the control of a ubiquitin promoter. The volatile and non-volatile metabolite profiles of leaves from transgenic and control lines were compared. The headspaces collected from intact seedlings of transgenic and control plants were not significantly different, although detached leaves of transgenic plants emitted 5-fold more geranyl acetate compared to control plants. Non-targeted LC MS profiling and LC-MS-MS identification of extracts from maize leaves revealed that the major significantly different non-volatile compounds were 2 geranic acid derivatives, a geraniol dihexose and 4 different types of hydroxyl-geranic acid hexoses. A geranic acid glycoside was the most abundant, and identified by NMR as geranoyl-6-O-malonyl-beta-d-glucopyranoside with an average concentration of 45MUM. Fungal bioassays with C. graminicola and F. graminearum did not reveal an effect of these changes in secondary metabolite composition on plant resistance to either fungus. The results demonstrate that metabolic engineering of geraniol into geranic acid can rely on the existing default pathway, but branching glycosylation pathways must be controlled to achieve accumulation of the aglycones. PMID- 21296183 TI - Engineering the robustness of Clostridium acetobutylicum by introducing glutathione biosynthetic capability. AB - To improve the aero- and solvent tolerance of the solvent-producing Clostridium acetobutylicum, glutathione biosynthetic capability was introduced into C. acetobutylicum DSM1731 by cloning and over-expressing the gshAB genes from Escherichia coli. Strain DSM1731(pITAB) produces glutathione, and shows a significantly improved survival upon aeration and butanol challenge, as compared with the control. In addition, strain DSM1731(pITAB) exhibited an improved butanol tolerance and an increased butanol production capability, as compared with the recombinant strains with only gshA or gshB gene. These results illustrated that introducing glutathione biosynthetic pathway, which is redundant for the metabolism of C. acetobutylicum, can increase the robustness of the host to achieve a better solvent production. PMID- 21296184 TI - Nutritional influences on visual development and function. AB - Experiments conducted on many different species reveal a fundamental paradox about the vertebrate eye; it is damaged by its own operation. This vulnerability stems from the need to respond to visible light, often actinic, but also from the intrinsic metabolic and structural state of the eye's internal structures. Photoreceptor outer segments, for instance, have high concentrations of diet derived long-chain polyunsaturated fatty acids and these membrane lipids are highly prone to peroxidation due to the high oxygen tension of the outer retina. Such a high diathesis for damage would be catastrophic if it were not balanced by an equally impressive system for responding to such stressors. The retina (and to a lesser extent the crystalline lens), for instance, is especially rich in dietary antioxidants such as vitamin E, vitamin C and the macular carotenoids (lutein and zeaxanthin) putatively to retard light-induced oxidative damage. The nutrients that support both essential function (e.g., retinal, the vitamin form of vitamin A, in photopigment) and protection operate in a highly integrated manner. For instance, Vitamin E is a lipophillic chain-breaking anti-oxidant (protecting DHA-rich outer segment membranes) that regenerates itself through reaction with vitamin C (a primary anti-oxidant against aqueous radicals) and is spatially distributed in complement with the carotenoids lutein and zeaxanthin. Nor are these interactions relegated to simply providing protection and the basic elements needed for transduction. Macular lutein and zeaxanthin, for example, improve visual performance (e.g., reduce glare disability and discomfort, speed photostress recovery, and enhance chromatic contrast) through purely optical means (by absorbing short-wave light anterior to the foveal cones). The vulnerability of the eye to exogenous insult, and the sensitivity of the eye to dietary components, is not static: infants have more vulnerable retinas due to clearer lenses and higher metabolic activity; the elderly are more vulnerable due to such factors as increased inflammatory stress and a higher content of photosensitizers (such as lipofuscin) creating cascading oxidative effects. Hence, optimal dietary prophylaxis changes as the eye ages. The eye, perhaps more than most other biological structures, has evolved an exquisite and shifting sensitivity to dietary intake throughout the lifespan, not just for its basic operation (e.g., Vitamin A for transduction), but also for its very preservation. PMID- 21296185 TI - Cytotoxic and genotoxic effects of multi-wall carbon nanotubes on human umbilical vein endothelial cells in vitro. AB - Carbon nanomaterials have multiple applications in various areas. However, it has been suggested that exposure to nanoparticles may be a risk for the development of vascular diseases due to injury and dysfunction of the vascular endothelium. Therefore, in the present study, the cytotoxic and genotoxic effects of multi wall carbon nanotubes (MWCNTs) on human umbilical vein endothelial cells (HUVECs) were evaluated. Optical and transmission electronic microscopy (TEM) study showed that MWCNTs were able to enter cells rapidly, distribute in the cytoplasm and intracellular vesicles and induce morphological changes. Exposure to MWCNTs reduced the viability of HUVECs, and induced apoptosis in HUVECs. Furthermore, MWCNTs could cause DNA damage as indicated by the formation of gammaH2AX foci. MWCNTs also affected cellular redox status, e.g., increasing intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) levels, as well as altering superoxide dismutase (SOD) activity and glutathione peroxidase (GSH-Px) levels. On the other hand, the free radical scavenger N-acetyl-l-cysteine (NAC) preincubation can inhibit the cytotoxic and genotoxic effects of MWCNTs. Taken together, these results demonstrated that MWCNTs could induce cytotoxic and genotoxic effects in HUVECs, probably through oxidative damage pathways. PMID- 21296187 TI - Risk of nonmelanoma skin cancer in patients with inflammatory bowel disease who use thiopurines is not increased. PMID- 21296186 TI - Expression of the human atypical kinase ADCK3 rescues coenzyme Q biosynthesis and phosphorylation of Coq polypeptides in yeast coq8 mutants. AB - Coenzyme Q (ubiquinone or Q) is a lipid electron and proton carrier in the electron transport chain. In yeast Saccharomyces cerevisiae eleven genes, designated COQ1 through COQ9, YAH1 and ARH1, have been identified as being required for Q biosynthesis. One of these genes, COQ8 (ABC1), encodes an atypical protein kinase, containing six (I, II, III, VIB, VII, and VIII) of the twelve motifs characteristically present in canonical protein kinases. Here we characterize seven distinct Q-less coq8 yeast mutants and show that unlike the coq8 null mutant, each maintained normal steady-state levels of the Coq8 polypeptide. The phosphorylation states of Coq polypeptides were determined with two-dimensional gel analyses. Coq3p, Coq5p, and Coq7p were phosphorylated in a Coq8p-dependent manner. Expression of a human homolog of Coq8p, ADCK3(CABC1) bearing an amino-terminal yeast mitochondrial leader sequence, rescued growth of yeast coq8 mutants on medium containing a nonfermentable carbon source and partially restored biosynthesis of Q(6). The phosphorylation state of several of the yeast Coq polypeptides was also rescued, indicating a profound conservation of yeast Coq8p and human ADCK3 protein kinase function in Q biosynthesis. PMID- 21296188 TI - Necrotizing pancreatitis complicated by fistula and upper gastrointestinal hemorrhage. PMID- 21296190 TI - The dual nature of Ets-1: focus to the pathogenesis of systemic lupus erythematosus. AB - E26 transformation-specific-1 (Ets-1) belongs to the Ets family of transcription factors which share a common 85-amino-acid DNA-binding domain. Ets-1 is essential to regulation of the immune system including immune cell proliferation and differentiation. Past data demonstrated Ets-1 play a role in negative regulation of Th17 cells and B cells differentiation. Recently, association of genetic variation in Ets-1 with susceptibility to systemic lupus erythematosus (SLE) have been independently identified by two Genome-wide association studies (GWAS), and decreased Ets-1mRNA level in peripheral blood mononuclear cells (PBMCs) of SLE patients has been reported. All these findings suggest that the transcription factor is broadly linked to the pathogenesis of this disease. However, aberrant control of other immune cells and effector molecules illuminated the complexities of Ets-1 biology. In this review article, we will focus on the dual nature of Ets 1 and discuss its regulatory capability. Hopefully the information obtained will lead to a better understanding of the pathogenesis and development of novel therapeutic strategies for SLE. PMID- 21296189 TI - The multiple functions of cytochrome c and their regulation in life and death decisions of the mammalian cell: From respiration to apoptosis. AB - Cytochrome c (Cytc) is essential in mitochondrial electron transport and intrinsic type II apoptosis. Mammalian Cytc also scavenges reactive oxygen species (ROS) under healthy conditions, produces ROS with the co-factor p66(Shc), and oxidizes cardiolipin during apoptosis. The recent finding that Cytc is phosphorylated in vivo underpins a model for the pivotal role of Cytc regulation in making life and death decisions. An apoptotic sequence of events is proposed involving changes in Cytc phosphorylation, increased ROS via increased mitochondrial membrane potentials or the p66(Shc) pathway, and oxidation of cardiolipin by Cytc followed by its release from the mitochondria. Cytc regulation in respiration and cell death is discussed in a human disease context including neurodegenerative and cardiovascular diseases, cancer, and sepsis. PMID- 21296191 TI - Pernicious anemia - genetic insights. AB - Pernicious anemia (PA) is a complex, autoimmune, multi-factorial disease. Rapid progress has been made in the understanding of susceptibility to a spectrum of other autoimmune diseases through genome wide association studies (GWAS). However, PA has been conspicuous by its absence from this work. Here, we examine the evidence that PA has a significant heritable component through epidemiological evidence and its co-occurrence with other autoimmune diseases. Further, we consider how knowledge of the genetic susceptibility to other autoimmune diseases may provide insight into the etiology of PA. PMID- 21296192 TI - What is the role of HLA-B27 in spondyloarthropathies? AB - HLA-B27 (Human Leukocyte Antigen-B27) accounts approximately for the one third of the overall genetic susceptibility to spondylorthropathies (SpAs). Up to 70 HLA B27 subtypes have been reported all over the world with a decreasing north-south gradient of its frequency, which is reverse to that of endemic malaria. In an attempt to explain the possible role of HLA-B27 in SpAs pathogenesis, several theories have been suggested [1. Arthritogenic peptide, 2. Misfolding, 3. Cell surface HLA-B27 homodimers, 4. beta2m (beta2-microglobulin) deposition, 5. beta2m free/peptide free heavy chains of HLA-I, 6. Enhanced survival of some microbes in HLA-B27 cells, 7. ERAP1/ERAP2 (endoplasmic reticulum aminopeptidases 1 and 2) and Tapasin function, 8. beta2m over-expression] each of which contributes up to a point to our understanding of HLA-B27 subtypes' role in SpAs manifestation. However, reviewing all the suggested hypotheses it seems logical to pass from a puzzle of distinct hypotheses to a global theory. This review summarizes the current knowledge of HLA-B27 aiming to understand its potential use in clinical practice of SpAs diagnosis and to direct its future studies. PMID- 21296193 TI - Does polymorphysm of genes coding for pro-inflammatory mediators predict the clinical response to tnf alpha blocking agents? A review analysis of the literature. AB - Tumor necrosis factor-alpha (TNF-alpha) has a key role in the pathogenesis of rheumatoid arthritis (RA) and the introduction of anti-TNFalpha biological therapies has dramatically altered the treatment of RA. Anti-TNFalpha agents display good clinical efficacy in patients resistant to traditional disease modifying antirheumatic drugs and superior efficacy in the suppression of erosive joint damage, even if a significant non-response rate has been reported (30-40%). Because anti-TNFalpha therapy is associated with expensive treatment costs, leading to restrictions in the numbers of patients who may be treated, the identification of predictors of treatment outcome may improve the cost effectiveness of anti-TNFalpha therapies. Several candidate gene studies have addressed this topic, but they have had limited success in identifying predictors. It is not clear whether the response to anti-TNFalpha treatment will be conferred through a number of genes, each with a small effect size, or whether genes may predict the outcome of the treatment. PMID- 21296194 TI - Effects of chronic aspirations on breathing pattern and ventilatory drive in vagatomized rats. AB - The aim of this study was to test the hypothesis that aspirations induced by unilateral vagotomy destabilise ventilatory pattern during swallowing. The study was carried out on 15 Wistar rats (2-3 months, 290-350 g) using whole-body plethysmography and video recordings, before and after unilateral vagotomy. The rats were given water ad libitum via a baby bottle fitted with a nipple. The experiment was continued until rest ventilation and swallowing periods were identified on the video recordings. Following the sectioning of the right vagus nerve, all the rats presented bronchial aspirations and unilateral vocal cord paralysis in the aperture position. After the vagotomy there were no changes at rest of the ventilatory variables compared to healthy controls. In healthy animals during swallowing, we observed a decrease in total ventilatory time (TTOT), a decrease in inspiratory time (TI) (p < 0.001), a decrease in expiratory time (TE) (p < 0.001), no change in tidal volume (VT) and an increase in mean inspiratory time (VT/TI) (p < 0.001) compared to the rest period. Animals with chronic aspiration presented during swallowing an increase in TTOT (p < 0.001), TI (p < 0.01), and TE (p < 0.001), no change in VT and a decrease of VT/TI (p < 0.001) and a modification of ventilatory pattern. In conclusion, our results confirmed that swallowing modifies ventilation in healthy animals and that chronic aspiration decreases ventilatory drive and modifies ventilatory pattern during swallowing. PMID- 21296195 TI - Mechanics of longitudinal cracks in tooth enamel. AB - A study is made of longitudinal "channel" cracking in tooth enamel from axial compressive loading. The cracks simulate those generated in the molar and premolar teeth of humans and animals by natural tooth function. Contact loading tests are made on extracted human molars with hard and soft indenting plates to determine the evolution of such cracks with increasing load. Fracture is largely stable, with initial slow growth followed by acceleration as the cracks approach completion around an enamel side wall. A simple power law relation expresses the critical load for full fracture in terms of characteristic tooth dimensions-base radius and enamel thickness-as well as enamel toughness. Extended three dimensional finite element modeling with provision for growth of embedded cracks is used to validate this relation. The cracks leave "fingerprints" that offer valuable clues to dietary habits, and provide a basis for a priori prediction of bite forces for different animals from measured tooth dimensions. PMID- 21296196 TI - Proteome profiling of Epstein-Barr virus infected nasopharyngeal carcinoma cell line: identification of potential biomarkers by comparative iTRAQ-coupled 2D LC/MS-MS analysis. AB - Epstein-Barr virus (EBV) has been implicated in the development of nasopharyngeal carcinoma (NPC), a squamous cell carcinoma with high-occurrence in Southeast Asia and southern China. However, the underlying relationship of EBV and NPC squamous cell remains obscure. In this study, we employ a comparative iTRAQ-coupled 2D LC MS/MS system to analyze the protein profile of NPC cell line upon EBV infection. Based on the proteome data and Western blot validation, 12 proteins were found to be significantly up-regulated and associated with signal transduction, cytoskeleton formation, metabolic pathways and DNA bindings. The interactions among NPC and EBV proteins were further analyzed and protein networks were established. Based on the functions of differentially expressed proteins, a metabolic pathway was proposed to elucidate their relationship in cytoskeleton formation, cell proliferation and apoptosis. Our results suggested a new proteome platform to analyze EBV's role in NPC squamous cell line. And these differentially expressed proteins may hold the promise as potential biomarkers for NPC diagnostics and treatment. PMID- 21296197 TI - Endogenous lectins shape the function of dendritic cells and tailor adaptive immunity: mechanisms and biomedical applications. AB - In spite of their central role in orchestrating immunity, dendritic cells (DCs) can also limit harmful reactions and promote immune tolerance by inducing T cell anergy or favoring the differentiation of T regulatory (T(reg)) cells. Several factors may influence the 'decision' of DCs to become immunogenic or tolerogenic including the nature of antigenic challenge, the engagement of selective pathogen recognition receptors (PRRs) and the balance of cytokines and growth factors. In addition, mounting evidence indicates a key role of endogenous lectins including C-type lectins, siglecs and galectins in shaping DC immunogenicity and tailoring adaptive immune responses, through recognition of specific 'glycan signatures' on invading pathogens or host cells. While galectins are in general secreted proteins that act in a paracrine or autocrine manner, all known siglecs and most C-type lectins are membrane-bound receptors that convey glycan-containing information into DC differentiation or maturation programs. Yet, some of the signaling pathways triggered by endogenous lectins converge in similar functional outcomes regardless of divergences in their structure, homology or glycan-binding specificity. To gain a more complete understanding on the role of protein-glycan interactions in DC biology, here we will integrate scattered information on these structurally-divergent but functionally-related lectins and their potential biomedical applications. PMID- 21296198 TI - Comparing hemodynamics, blood gas analyses and proinflammatory cytokines in endotoxemic and severely septic rats. AB - Lipopolysaccharide (LPS) is often used in short-term models of inflammation. Since endotoxemia and sepsis are different entities we have recently established a short-term sepsis model in rats induced by cecal ligation and incision (CLI). This retrospective study was conducted in order to identify similarities and differences between both experimental approaches. 32 anesthetized/ventilated male rats from the following four groups were analysed (each n=8): CTRL-group (0.9% NaCl i.v.); LPS-group (5mg/kg i.v.); SHAM-group (laparotomy); CLI-group (1.5 cm blade incision). Mean arterial blood pressure (MAP) and blood gas parameters (arterial base excess (BE) and pH) were continuously recorded. Total observation time was 300 min. Plasma samples were obtained afterwards. LPS and CLI induced significant arterial hypotension and metabolic acidosis compared to CTRL- or SHAM group, respectively. Yet, between the LPS- and CLI-groups, there were no differences in MAP, BE and pH. LPS significantly induced IL-1beta, IL-6 and TNF alpha in the plasma. In contrast, CLI showed a clear tendency towards increased IL-1beta and IL-6 plasma levels and did not affect TNF-alpha. Our results indicate that the CLI sepsis model is suitable for short-term investigations on hemodynamic alterations and blood gas analyses during sepsis. 300 min after the proinflammatory insult, plasma concentrations of IL-1beta and IL-6 in the plasma remain considerably lower after CLI compared to endotoxemia. Low TNF-alpha concentrations 300 min after sepsis induction could be interpreted as considerable immunosuppression during CLI sepsis. PMID- 21296199 TI - Farnesoid X receptor suppresses constitutive androstane receptor activity at the multidrug resistance protein-4 promoter. AB - Multidrug resistance protein-4 (MRP4) is a member of the multidrug resistance associated gene family that is expressed on the basolateral membrane of hepatocytes and undergoes adaptive up-regulation in response to cholestatic injury or bile acid feeding. In this study we demonstrate that farnesoid X receptor (FXR) regulates MRP4 in vivo and in vitro. In vivo deletion of FXR induces MRP4 gene expression. In vitro treatment of HepG2 cells with FXR ligands, chenodeoxycholic acid (CDCA), cholic acid (CA) and the synthetic ligand GW-4064 suppresses basal mRNA level of the MRP4 gene as well as the co-treatment with CDCA and 6-(4-Chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4 dichlorobenzyl)oxime (CITCO), an activator of constitutive androstane receptor (CAR). We found in the human MRP4 promoter a CAR responsive element (CARE) embedded within an FXR responsive element (FXRE). We cloned this region and found that FXR suppresses CAR activity in luciferase assay. Finally, we demonstrated that FXR competes with CAR for binding to this overlapping binding site. Our results support the view that FXR activation in obstructive cholestasis might worsen liver injury by hijacking a protective mechanism regulated by CAR and provides a new molecular explanation to the pathophysiology of cholestasis. PMID- 21296200 TI - Development of an improved method to perform single particle analysis by TIMS for nuclear safeguards. AB - A method is described that allows measuring the isotopic composition of small uranium oxide particles (less than 1MUm in diameter) for nuclear safeguards purposes. In support to the development of reliable tools for the identification of uranium and plutonium signatures in trace amounts of nuclear materials, improvements in scanning electron microscopy (SEM) and thermal ionization mass spectrometry (TIMS) in combination with filament carburization and multiple ion counting (MIC) detection were investigated. The method that has been set up enables the analysis of single particles by a combination of analytical tools, thus yielding morphological, elemental and isotopic information. Hereby individual particles of certified reference materials (CRMs) containing uranium at femtogram levels were analysed. The results showed that the combination of techniques proposed in this work is suitable for the accurate determination of uranium isotope ratios in single particles with improved capabilities for the minor abundant isotopes. PMID- 21296201 TI - Recent developments in electrochemical flow detections--a review part II. Liquid chromatography. AB - This article is a review of the progress in application of electrochemical detections in liquid chromatography in recent 15-20 years. Based on 238 references, mostly to original research papers, it presents applications of amperometric and voltammetric detections, as well as coulometric, conductimetric and potentiometric ones. In case of those which have reached already the stage of routinely employed detections with commercially available instrumentation (amperometry, coulometry, conductometry) especially novel and original applications are presented. In case of voltammetric and potentiometric detections a ways of their improvements are showed, directed towards obtaining competitive results with other detection methods. PMID- 21296202 TI - A new atomization cell for trace metal determinations by tungsten coil atomic spectrometry. AB - A new metallic atomization cell is used for trace metal determinations by tungsten coil atomic absorption spectrometry and tungsten coil atomic emission spectrometry. Different protecting gas mixtures are evaluated to improve atomic emission signals. Ar, N(2), CO(2) and He are used as solvents, and H(2) and C(2)H(2) as solutes. A H(2)/Ar mixture provided the best results. Parameters such as protecting gas flow rate and atomization current are also optimized. The optimal conditions are used to determine the figures of merit for both methods and the results are compared with values found in the literature. The new cell provides a better control of the radiation reaching the detector and a small, more isothermal environment around the atomizer. A more concentrated atomic cloud and a smaller background signal result in lower limits of detection using both methods. Cu (324.7 nm), Cd (228.8 nm) and Sn (286.3 nm) determined by tungsten coil atomic absorption spectrometry presented limits of detection as low as 0.6, 0.1, and 2.2 MUg L(-1), respectively. For Cr (425.4 nm), Eu (459.4 nm) and Sr (460.7 nm) determined by tungsten coil atomic emission spectrometry, limits of detection of 4.5, 2.5, and 0.1 MUg L(-1) were calculated. The method is used to determine Cu, Cd, Cr and Sr in a water standard reference material. Results for Cu, Cd and Cr presented no significant difference from reported values in a 95% confidence level. For Sr, a 113% recovery was obtained. PMID- 21296203 TI - Construction of a carbon nanocomposite electrode based on amino acids functionalized gold nanoparticles for trace electrochemical detection of mercury. AB - A simple, highly sensitive and selective carbon nanocomposite electrode has been developed for the electrochemical trace determination of mercury. This mercury nanocomposite sensor was designed by incorporation of thiolated amino acids capped AuNps into the carbon ionic liquid electrode (CILE) which provides remarkably improved sensitivity and selectivity for the electrochemical stripping assay of Hg(II). Mercury ions are expected to interact with amino acids through cooperative metal-ligand interaction to form a stable complex which provides a sensitive approach for electrochemical detection of Hg(II) in the presence of other metal ions. The detection limit was found to be 2.3 nM (S/N = 3) that is lower than the permitted value of Hg(II) reported by the Environmental Protection Agency (EPA) limit of Hg(II) for drinkable water. The proposed nanocomposite electrode exhibits good applicability for monitoring Hg(II) in tap and waste water. PMID- 21296204 TI - Horseradish peroxidase-screen printed biosensors for determination of Ochratoxin A. AB - This work summarizes the manufacturing procedure of Horseradish peroxidase (HRP) based biosensors for the determination of the mycotoxin Ochratoxin A (OTA). The biosensors have been fabricated using the single technology of screen-printing. That is to say, an HRP containing ink has been directly screen-printed onto carbon electrodes, which offers a higher rapidity and simplicity in the manufacturing process of biosensors for OTA determination. The formal redox potential of the Fe(III/II) moiety of HRP has been used to demonstrate the effective loading of enzyme into the ink. The chronoamperometric oxidation current registered has been successfully related to the concentration of OTA in solution from different samples, including beer ones. Under the optimum conditions of the experimental variables, precision in terms of reproducibility and repeatability has been calculated in the concentration range from 23.85 to 203.28 nM. A relative standard deviation for the slopes of 10% (n = 4) was obtained for reproducibility. In the case of repeatability, the biosensor retained a 30% of the initial sensitivity after the third calibration. The average capability of detection for 0.05% probabilities of false positive and negative was 26.77 +/- 3.61 nM (alpha = 0.05 and beta=0.05, n = 3). PMID- 21296205 TI - Novel determination of the total phenolic content in crude plant extracts by the use of 1H NMR of the -OH spectral region. AB - A novel method for the determination of the total phenolic content using (1)H NMR spectroscopy in the -OH spectral region is presented. The use of DMSO-d(6), which is an aprotic and strongly hydrogen bonding solvent, allows the "appearance" of the relative sharp resonances of phenolic hydroxyl protons in the region of 8-14 ppm. The determination of the total phenolic -OH content requires three steps: (i) a 1D (1)H NMR spectrum is obtained in DMSO-d(6); (ii) a subsequent 1D (1)H NMR spectrum is recorded with irradiation of the residual water signal which results in the elimination or reduction of the phenolic -OH groups, due to proton exchange; and (iii) 1D (1)H NMR spectra are recorded with the addition of a progressively increased amount of salt, NaHCO(3), which results in extensive linebroadening of the COOH resonances thus allowing the discrimination of the phenolic from the carboxylic acid signals. Integration, with respect to the internal standard TSP-d(4), of the signal resonances between 14 and 8 ppm in spectrum (i) which are either eliminated or reduced in intensity in steps (ii) and (iii) allows the quantitation of the total phenolic content. The method was applied to model compounds, a mixture of them and several extracts of natural products. The results of the proposed (1)H NMR method were compared to the Folin Ciocalteu (FC) reagent method. Additionally, since (1)H NMR refers to the total phenolic hydroxyl protons, a reaction factor, A(e), is proposed that corresponds to the hydroxyl reactivity. The (1)H NMR method is rapid and accurate bearing the inherent advantages of the NMR spectroscopy and can be applied directly in complex extracts. Furthermore, it can be applied in a wide range of matrixes from crude plant extracts and food products to biological samples. PMID- 21296206 TI - On the performance of bioanalytical fluorescence correlation spectroscopy measurements in a multiparameter photon-counting microscope. AB - Fluorescence correlation spectroscopy (FCS) data acquisition and analysis routines were developed and implemented in a home-built, multiparameter photon counting microscope. Laser excitation conditions were investigated for two representative fluorescent probes, Rhodamine110 and enhanced green fluorescent protein (EGFP). Reliable local concentrations and diffusion constants were obtained by fitting measured FCS curves, provided that the excitation intensity did not exceed 20% of the saturation level for each fluorophore. Accurate results were obtained from FCS measurements for sample concentrations varying from pM to MUM range, as well as for conditions of high background signals. These experimental constraints were found to be determined by characteristics of the detection system and by the saturation behavior of the fluorescent probes. These factors actually limit the average number of photons that can be collected from a single fluorophore passing through the detection volume. The versatility of our setup and the data analysis capabilities were tested by measuring the mobility of EGFP in the nucleus of Drosophila cells under conditions of high concentration and molecular crowding. As a bioanalytical application, we studied by FCS the binding affinity of a novel peptide-based drug to the cancer-regulating STAT3 protein and corroborated the results with fluorescence polarization analysis derived from the same photon data. PMID- 21296207 TI - Direct introduction of a hydrazide group into a quartz crystal microbalance surface with dodecanoic hydrazide embedded in a hybrid bilayer membrane. AB - Hydrazide group has a potential of immobilizing an antibody on a sensor surface in a way that ensures an optimal orientation and efficiency of the antibody. However, a multi-step chemical process, required for the preparation of a hydrazide group, is a barrier to its extensive application. This paper describes a new method to introduce a hydrazide group to a sensor surface by a one-step process using dodecanoic hydrazide. The method is based on an ability of the dodecanoic hydrazide to be incorporated into a hybrid bilayer membrane (HBM) layer, thereby presenting its hydrazide group to the surface. Liposome containing dodecanoic hydrazide was added to a hydrophobic self-assembled monolayer surface of a quartz crystal microbalance for the formation of a HBM. Then, the hydrazide group, presented in the surface of the HBM layer, was utilized for the oriented immobilization of an antibody via its carbohydrate moiety which was partially oxidized prior to the conjugation reaction. Activity and stable status of the incorporated dodecanoic hydrazide was revealed by the efficiency and reproducibility of the resulting immunosensor chip. PMID- 21296208 TI - Tea-industry waste activated carbon, as a novel adsorbent, for separation, preconcentration and speciation of chromium. AB - Activated carbon was produced from tea-industry wastes (TIWAC) and employed as a low cost and effective solid phase material for the separation, preconcentration and speciation of chromium species without using a complexing agent, prior to determination by flame atomic absorption spectrometry (FAAS). The characterization of TIWAC was performed by utilizing several techniques such as Fourier Transform Infrared (FTIR) Spectroscopy, Scanning Electron Microscopy (SEM), and elemental analysis. The adsorption experiments were conducted in a batch adsorption technique. Under the experimental conditions, Cr(VI) adsorption amount was nearly equal to zero, however the adsorption percentage of Cr(III) was in the range of 95-100%. Therefore total chromium was determined after the reduction of Cr(VI) to Cr(III) and Cr(VI) was calculated by subtracting Cr(III) concentration from total chromium concentration. The suitable conditions for adsorption and speciation processes were evaluated in terms of pH, eluent type and volume, TIWAC concentration, adsorption and desorption contact time, etc. Adsorption capacity of TIWAC was found to be 61.0 mg g(-1). The detection limit for Cr(III) was found to be 0.27 MUg L(-1) and the preconcentration factor was 50 for 200mL of sample volume. The procedure was applied to the determination and speciation of chromium in stream, tap and sea water. Also, the proposed method was applied to total chromium preconcentration in microwave digested tobacco and dried eggplant samples with satisfactory results. The method was validated by analyzing certified reference materials (CRM-TMDW-500 Drinking Water and CRM-SA-C Sandy Soil C) and the results were in good agreement with the certified values. PMID- 21296209 TI - An indirect competitive enzyme-linked immunosorbent assay for determination of norfloxacin in waters using a specific polyclonal antibody. AB - A specific polyclonal anti-norfloxacin antibody was obtained, and a sensitive indirect competitive enzyme-linked immunosorbent assay (icELISA) was developed for determining trace amounts of norfloxacin in various waters. Good linearity was achieved in the range from 0.1 to 10 MUg L(-1). The average IC(50) value was determined to be 2.2 MUg L(-1) and the limit of detection was 0.016 MUg L(-1) at a signal-to-noise ratio of 3 in phosphate-buffered saline buffer. Recoveries of norfloxacin at various spiking levels ranged from 74 to 105% in groundwater, surface water, treated and untreated wastewater samples, with relative standard deviations of 3-5%. The assay was applied for determining norfloxacin in municipal wastewater, surface water, and groundwater collected in a metropolis of China. Raw wastewater samples were only submitted to filtration and pH adjustment while the other water samples were pre-concentrated by solid phase extraction prior to the icELISA assay. Good agreement of the results obtained by the icELISA and liquid chromatography tandem mass spectrometry further confirmed the reliability and accuracy of the icELISA for rapid detection of norfloxacin in waters. PMID- 21296210 TI - Optimizing size-exclusion chromatographic conditions using a composite objective function and chemometric tools: application to natural organic matter profiling. AB - A novel strategy is suggested for developing a size-exclusion chromatography (SEC) method in order to assess the molecular size distribution of natural organic matter (NOM). This strategy is based on the use of a chromatographic response function (CRF) and a response surface based on a central composite experimental design. The CRF qualifies the resolution degree attained under different SEC conditions with respect to global resolution of the chromatogram, number of distinguishable peaks, and analysis time. Based on a SEC study with a mixture of known organic compounds, predictive polynomial and linear models were developed according to the practice of design of experiments. Additionally, a chromatographic response surface was used, describing the effect of pH, amount of organic solvent, and salt concentration of the mobile phase on the values of the CRF. This new strategy predicted a single linear effect of salt concentration over the quality of the chromatographic separation, and the influence of this experimental variable on the quality of size-exclusion separations of various NOM samples was further discussed. For the analysis of NOM, the optimum settings for the mobile phase composition were as follows: pH 8.5, 11% of acetonitrile, and 15 mM of sodium chloride. Under such analytical conditions, the measured molecular size distributions of water-soluble organic matter from atmospheric particles and aquatic fulvic acids compare reasonably well with the published molecular weight data. The newly developed strategy is a reliable alternative for accomplishing an accurate description of the size-exclusion profiles of NOM from different environments. PMID- 21296211 TI - [Importance of the metabolic oxidation of drugs and other xenobiotics: recent developments]. PMID- 21296212 TI - [Molecular basis of red blood cell adhesion to endothelium]. AB - The extent of red blood cell adhesion is correlated with the incidence of vascular complications and the severity of the disease. Patients with sickle cell anemia (HbSS) experience vasoocclusive episodes. The adhesion of RBCs from HbSS patients is increased and related to VLA-4 exposure, which binds to vascular cell adhesion molecule (VCAM-1). Inter Cellular Adhesion Molecule (ICAM-1), CD31, CD36 and glycans are potential receptors for PfEMP1 of RBCs parasited by plasmodium falciparum. The incidence of vascular complications is very high in patients with diabetes mellitus. RBC adhesion is increased and statistically correlated with the severity of the angiopathy. Glycation of RBC membrane proteins is responsible for binding to the receptor for advanced glycation end products (RAGE). Polycythemia Vera (PV) is the most frequent myeloproliferative disorder and characterized by a high occurrence of thrombosis of mesenteric and cerebral vessels. PV is due to a mutation of the Janus kinase 2 (JAK2 V617F). This mutation stimulates erythropoiesis and is the cause of Lu/BCAM (CD239) phosphorylation, which potentiated the interaction with laminin alpha 5. The couple laminin alpha 5 endothelial and phosphorylated Lu/BCAM explained the increased adhesion of RBCs from patients PV to endothelium. PMID- 21296213 TI - [Study of meta-trajectories of CD4 cells count from taxonomy in the antiretroviral response of efavirenz-based regimen with naive symptomatic patients in Abidjan]. AB - INTRODUCTION: Sub-Saharan Africa remains the most affected region in the global AIDS epidemic. Cote d'Ivoire is one of the most affected countries by this epidemic. The collective search for deleterious determinants of the evolution of immunological markers (CD4 cells count) may help to optimize the therapeutic efficiency in this resource-limited country. PATIENTS AND METHODS: We are interested in studying the antiretroviral response of efavirenz-based regimen (treatment of choice in first line) by the nonhierarchical-descendant model by taxonomy of CD4 cells count trajectories. From 87 CD4 cells count trajectories of symptomatic naive patients, classes of similar profiles grouped by the model have formed typical profiles of evolution as meta-trajectories. The analysis of these meta-trajectories was used to study the determinants of CD4 cells count evolution by classes of patients. RESULTS: Four classes have been determined for an optimal taxonomy with a partition score of 0.72: P1 (n=27), P2 (n=15), P3 (n=24), P4 (n=21). Our model showed a variation between groups of CD4 cells count trajectories linked to explanatory factors by highlighting the predictive role of certain characteristics on antiretroviral response in Cote d'Ivoire (CD4 cells count baseline [P<0.01], CD4 percentage baseline [P<0.05], adherence [P<0.05]). The multiple correspondence analysis revealed other characteristics that influence the immune response such as the presence of opportunistic infections, bloodless status and weight at the initiation of treatment. CONCLUSION: The factors influencing the profile of meta-trajectories of CD4 cells count during efavirenz-based antiretroviral regimen should be considered at the initiation of treatment to optimize performance in the therapeutic monitoring of patients in Abidjan. The model of biomedical indicators meta-trajectories provides a therapeutic decision support provided prior to capitalize sufficient expertise for a better interpretation. PMID- 21296214 TI - [Handiness and acceptability of the new Abak bottle in chronically treated patients. A cross-sectional, retrospective and multicentre study]. AB - BACKGROUND: Difficulty of use of eyedrops is a factor associated with poor patient compliance that reduces treatment efficacy. The aim of this study was to evaluate the handiness and global acceptability of the new Abak timolol bottle (multidose preservative-free eyedrops) in comparison with that of other administration systems (classical multidose eyedrops or single-doses) in patients treated for glaucoma or ocular hypertension. METHODS: Cross-sectional, retrospective and multicentre study involving 41 ophthalmologists in France. Selected patients were those who had been treated with the new Abak bottle since at least two months, as a replacement for other beta-blocker eyedrops. Handiness and acceptability of the new Abak bottle in comparison with other delivery systems were evaluated using a questionnaire filled by the investigator. RESULTS: Almost all the patients were unanimous regarding the handiness of the new Abak bottle: easy to open for 96.5% of them, easy to handle for 96.0%, and easy to get drops for 91.1%. For all these criteria and in a general manner, patients preferred the new Abak bottle in comparison with the previous eyedrop container. These results were confirmed in the oldest patients. CONCLUSION: The new Abak bottle had a greater acceptability compared to preserved multidose eyedrops or to single-doses. Its handiness and the absence of preservative which may improve local tolerance are in favor of a greater compliance in chronically treated patients. PMID- 21296215 TI - Centralized intravenous additive services (CIVAS): the state of the art in 2010. AB - In hospitals, the major part of the drugs is administered by intravenous way and the majority of the reconstitution of injectable drugs are carried out right before the administration to the patient by the nursing staff. The risks and errors related to the preparation and the administration of the injectable drugs are numerous. The standardization then the centralization of the preparations and reconstitution by the hospital pharmacy make it possible to reduce these various risks and errors. In addition to the preparation of the mixtures of parenteral nutrition as well as doses of anticancer chemotherapy, many other treatments can be taken in charge, such as antibiotics, antiemetics and pain treatments. Consequent equipment is necessary but the realization of these treatments proves non-overdrawn insofar as a certain quantity of production is reached. The reconstitution of the intravenous treatments by a centralized intravenous admixture service guarantees the chemical stability and the microbiological quality of the ready-to-use injectable drugs and contributes to the quality and the total management of the care of the patient. PMID- 21296216 TI - [Accuracy, precision and speed of parenteral nutrition admixture bags manufacturing: comparison between automated and manual methods]. AB - INTRODUCTION: The parenteral nutrition admixture (PNA) manufacturing in hospital pharmacy is realized by aseptic transfer (AT) or sterilizing filtration (SF). The development of filling systems for PNA manufacturing requires, without standard, an evaluation comparing to traditional methods of SF. MATERIALS AND METHODS: The filling accuracy of automated AT and SF was evaluated by mass and physical chemistry tests in repeatability conditions (identical composition of PNA; n=five bags) and reproducibility conditions (different composition of PNA; n=57 bags). For each manufacturing method, the filling precision and the average time for PNA bags manufacturing were evaluated starting from an identical composition and volume PNA (n=five trials). RESULTS: Both manufacturing methods did not show significant difference of accuracy. Precision of both methods was lower than limits generally admitted for acceptability of mass and physical-chemistry tests. However, the manufacturing time for SF was superior (five different binary admixtures in five bags) or inferior (one identical binary admixture in five bags) to time recorded for automated AT. DISCUSSION AND CONCLUSIONS: We show that serial manufacturing of PNA bags by SF with identical composition is faster than automated AT. Nevertheless, automated AT is faster than SF in variable composition of PNA. The manufacturing method choice will be motivate by the nature (i. e., variable composition or not) of the manufactured bags. PMID- 21296217 TI - FAD-dependent enzymes involved in the metabolic oxidation of xenobiotics. AB - Although the majority of oxidative metabolic reactions are mediated by the CYP superfamily of enzymes, non-CYP-mediated oxidative reactions can play an important role in the metabolism of xenobiotics. Among the major oxidative enzymes, other than CYPs, involved in the oxidative metabolism of drugs and other xenobiotics, the flavin-containing monooxygenases (FMOs), the molybdenum hydroxylases [aldehyde oxidase (AO) and xanthine oxidase (XO)] and the FAD dependent amine oxidases [monoamine oxidases (MAOs) and polyamine oxidases (PAOs)] are discussed in this minireview. In a similar manner to CYPs, these oxidative enzymes can also produce therapeutically active metabolites and reactive/toxic metabolites, modulate the efficacy of therapeutically active drugs or contribute to detoxification. Many of them have been shown to be important in endobiotic metabolism (e.g. XO, MAOs), and, consequently, interactions between drugs and endogenous compounds might occur when they are involved in drug metabolism. In general, most non-CYP oxidative enzymes (e.g. FMOs, MAOs) appear to be noninducible or much less inducible than the CYP system. Some of these oxidative enzymes exhibit polymorphic expression, as do some CYPs (e.g. FMO3). It is possible that the contribution of non-CYP oxidative enzymes to the overall metabolism of xenobiotics is underestimated, as most investigations of drug metabolism have been performed using experimental conditions optimised for CYP activity, although in some cases the involvement of non-CYP oxidative enzymes in xenobiotic metabolism has been inferred from not sufficient experimental evidence. PMID- 21296218 TI - Amine oxidases of the quinoproteins family: their implication in the metabolic oxidation of xenobiotics. AB - Copper amine oxidases (CuAOs) are ubiquitous enzymes, which play a vital role in the physiology and pathology of mammals in controlling the metabolism of various primary monoamines, diamines and polyamines of endogenous or xenobiotic origin. CuAOs, which belong to the quinoproteins family, possess two cofactors: tightly bound Cu(II) and a quinone residue, which catalyzes the oxidative deamination of primary amines with concomitant production of aldehyde, ammonia and hydrogen peroxide through a "ping-pong" mechanism. Interest in human enzymes of the CuAOs class has increased in recent years driven by the discovery that the human vascular adhesion protein-1 (VAP-1), which regulates leucocyte trafficking and glucose transport, is a CuAO enzyme. The activities of CuAOs are increased in various human disorders such as diabetes, Alzheimer's disease and many inflammation-associated diseases leading to the overproduction of toxic metabolites, especially hydrogen peroxide and aldehyde compounds. As most consequences are pathological, effective and selective inhibitors of CuAOs should be of great interest as therapeutic agents. Nevertheless, the utilization of CuAOs to generate enzymatic toxic products into cancer cells for selective in situ killing, deserves to be considered in cancer therapy. This paper briefly highlights recent progress in the study of physiological, pathological and molecular aspects of CuAOs in mammals. Furthermore, a small molecule, that mimics the metabolic activity of CuAOs toward endogenous and exogenous amines, is described because it could be used as a surrogate of enzymes for a preliminary screening of potential inhibitors of CuAO enzymes. PMID- 21296219 TI - Brief historical overview and recent progress on cytochromes P450: adaptation of aerobic organisms to their chemical environment and new mechanisms of prodrug bioactivation. AB - The present brief overview of the history of the development of our knowledge on cytochromes P450 (P450s) illustrates the spectacular progress that have been made on P450 mechanisms and structures especially during these last 20 years. Recently published structures of mammalian P450-substrate complexes have shown the great diversity of size, shape, and binding modes that are offered by the conformationally flexible substrate binding sites of xenobiotic-metabolizing P450s. They have also shown that these binding sites can adapt themselves to the great structural diversity of xenobiotics, to facilitate their oxidation and elimination. Our present detailed knowledge of the mechanisms and chemistry of P450s allows us to understand, at the molecular level, the origin of the various consequences of P450-dependent metabolism of drugs in pharmacology and toxicology. This is here illustrated by recent data on the detailed mechanism of bioactivation of the anti-thrombotic prodrugs ticlopidine, clopidogrel, and prasugrel. PMID- 21296220 TI - A novel preparation of methyl-beta-cyclodextrin from dimethyl carbonate and beta cyclodextrin. AB - A novel green synthesis process about methyl-beta-cyclodextrin has been investigated through the reaction between beta-cyclodextrin and dimethyl carbonate by anhydrous potassium carbonate as catalyst in DMF. The influence of experimental factors including the molar ratio of dimethyl carbonate to beta cyclodextrin, reaction temperature, and reaction time on the average degree of substitution of methyl-beta-cyclodextrin was studied. The results show that the average degree of substitution of methyl-beta-cyclodextrin can be dependent on the reaction temperature and the molar ratio of raw material primarily. The structures of methyl-beta-cyclodextrin were characterized by TLC, IR, MS, (1)H NMR, and (13)C NMR. PMID- 21296221 TI - Natural disasters-taking a longer term view. PMID- 21296222 TI - Supporting the Global Fund to fight fraud. PMID- 21296223 TI - Looking forward to new hypertension guidelines. PMID- 21296224 TI - Restricted elimination diet for ADHD: the INCA study. PMID- 21296226 TI - Dagfinn Hoybraten-new Board Chair of GAVI Alliance. PMID- 21296227 TI - Health and societal effects of alcohol. PMID- 21296228 TI - Stronger guidance needed on lifelong care for chronic diseases. PMID- 21296229 TI - Putting teeth into chronic diseases. PMID- 21296230 TI - Anticoagulation: improve care quality or use new alternatives? PMID- 21296231 TI - Phenotyping and treatment of phenylketonuria. PMID- 21296234 TI - Founding of the MDG-15 Young Professionals Forum. PMID- 21296235 TI - Requests for euthanasia and palliative care in France. PMID- 21296236 TI - Empowering whom? Neuroethics at its limits. PMID- 21296237 TI - Effects of a restricted elimination diet on the behaviour of children with attention-deficit hyperactivity disorder (INCA study): a randomised controlled trial. AB - BACKGROUND: The effects of a restricted elimination diet in children with attention-deficit hyperactivity disorder (ADHD) have mainly been investigated in selected subgroups of patients. We aimed to investigate whether there is a connection between diet and behaviour in an unselected group of children. METHODS: The Impact of Nutrition on Children with ADHD (INCA) study was a randomised controlled trial that consisted of an open-label phase with masked measurements followed by a double-blind crossover phase. Patients in the Netherlands and Belgium were enrolled via announcements in medical health centres and through media announcements. Randomisation in both phases was individually done by random sampling. In the open-label phase (first phase), children aged 4-8 years who were diagnosed with ADHD were randomly assigned to 5 weeks of a restricted elimination diet (diet group) or to instructions for a healthy diet (control group). Thereafter, the clinical responders (those with an improvement of at least 40% on the ADHD rating scale [ARS]) from the diet group proceeded with a 4-week double-blind crossover food challenge phase (second phase), in which high-IgG or low-IgG foods (classified on the basis of every child's individual IgG blood test results) were added to the diet. During the first phase, only the assessing paediatrician was masked to group allocation. During the second phase (challenge phase), all persons involved were masked to challenge allocation. Primary endpoints were the change in ARS score between baseline and the end of the first phase (masked paediatrician) and between the end of the first phase and the second phase (double-blind), and the abbreviated Conners' scale (ACS) score (unmasked) between the same timepoints. Secondary endpoints included food-specific IgG levels at baseline related to the behaviour of the diet group responders after IgG-based food challenges. The primary analyses were intention to treat for the first phase and per protocol for the second phase. INCA is registered as an International Standard Randomised Controlled Trial, number ISRCTN 76063113. FINDINGS: Between Nov 4, 2008, and Sept 29, 2009, 100 children were enrolled and randomly assigned to the control group (n=50) or the diet group (n=50). Between baseline and the end of the first phase, the difference between the diet group and the control group in the mean ARS total score was 23.7 (95% CI 18.6-28.8; p<0.0001) according to the masked ratings. The difference between groups in the mean ACS score between the same timepoints was 11.8 (95% CI 9.2-14.5; p<0.0001). The ARS total score increased in clinical responders after the challenge by 20.8 (95% CI 14.3-27.3; p<0.0001) and the ACS score increased by 11.6 (7.7-15.4; p<0.0001). In the challenge phase, after challenges with either high-IgG or low-IgG foods, relapse of ADHD symptoms occurred in 19 of 30 (63%) children, independent of the IgG blood levels. There were no harms or adverse events reported in both phases. INTERPRETATION: A strictly supervised restricted elimination diet is a valuable instrument to assess whether ADHD is induced by food. The prescription of diets on the basis of IgG blood tests should be discouraged. FUNDING: Foundation of Child and Behaviour, Foundation Nuts Ohra, Foundation for Children's Welfare Stamps Netherlands, and the KF Hein Foundation. PMID- 21296238 TI - Mind the gap! An unusual metabolic acidosis. PMID- 21296240 TI - Off-label use of antibiotics in intensive care unit: the multidrug-resistant pathogens challenge. PMID- 21296242 TI - A meta-analysis on the clinical effectiveness of transversus abdominis plane block. AB - STUDY OBJECTIVE: To study the efficacy of the transversus abdominal plane (TAP) block. DESIGN: Meta-analysis. SETTING: District general hospital. PATIENTS: 86 patients in the TAP block group and 88 in the non-TAP block group. MEASUREMENTS: Statistical analyses were performed using Microsoft Excel 2007 for Windows XP. Hedges g statistic was used for the calculation of standardized mean differences (SMD). Binary data (nausea) were summarized as risk ratios (RR). MAIN RESULTS: Patients with TAP block required less morphine after 24 hours than those who did not have the block (random effects model: SMD -4.81, 95% CI [-7.45, -2.17], z = 3.57, P < 0.001). There was less time to first request of morphine in the non-TAP block group (random effects model: SMD 4.80, 95% CI [2.16, 7.43], z = 3.57, P < 0.001). Patients in the TAP block group had less pain up to 24 hours postoperatively. No statistical differences were found with respect to nausea. CONCLUSIONS: TAP block reduces the need for postoperative opioid use, it increases the time first request for further analgesia, it provides more effective pain relief, and it reduces opioid-associated side effects. PMID- 21296243 TI - A survey of airway training among U.S. and Canadian anesthesiology residency programs. AB - STUDY OBJECTIVE: To determine the current trends in airway education in academic programs. DESIGN: Survey instrument. SETTING: American academic medical center. SUBJECTS: 147 directors of American and Canadian anesthesiology residency programs. MEASUREMENTS: An invitation to complete an online questionnaire was sent. Non-responding institutions were contacted repeatedly by email and telephone to ensure a reasonable response rate. MAIN RESULTS: 88 of the 147 (60%) programs completed the survey. Forty-three respondents (49%) reported that they had formal airway rotations, and 39 respondents said that a designated titled faculty member was responsible for airway training. Didactic lecture and manikin instruction were used by more than two thirds of the programs. Documentation of supervised airway experience was recorded in 71 (82%) programs. The majority of the programs (81%) had videolaryngoscopes. A fiberoptic bronchoscope was nearly universally available, and approximately one third (34%) of graduating residents were estimated to have performed more than 25 awake fiberoptic intubations. For most techniques, the estimates of the required number of procedures to ensure competence varied widely. CONCLUSIONS: The number of programs with a formal airway management program continues to increase, and programs are incorporating newer intubation techniques. The criteria for competence have not been established. PMID- 21296244 TI - Evaluation of the Bullard, GlideScope, Viewmax, and Macintosh laryngoscopes using a cadaver model to simulate the difficult airway. AB - STUDY OBJECTIVE: To assess the performance and cervical (C)-spine movement associated with laryngoscopy using the Bullard laryngoscope (BL), GlideScope videolaryngoscope (GVL), Viewmax, and Macintosh laryngoscopes during conditions of a) unrestricted and b) restricted C-spine and temporomandibular joint (TMJ) mobility. DESIGN: Prospective, controlled, randomized, crossover study. SETTING: University teaching hospital. SUBJECTS: 21 cadavers with intact C-spine anatomy. INTERVENTIONS: Each cadaver underwent to total of 8 intubation attempts to complete the intubation protocol using all four devices under unrestricted and restricted C-spine and TMJ mobility. MEASUREMENTS: Laryngoscopic view was graded using the modified Cormack-Lehane system. Time to best laryngoscopic view and total time to intubation were recorded. C-spine movement was measured between McGregor's line and each vertebra from radiographs taken at baseline and at best laryngoscopic view. MAIN RESULTS: During both intubating conditions, the BL achieved the highest number of modified Cormack-Lehane grade 1 and 2A laryngoscopic views as compared to the other three devices (P < 0.05) and had fewer intubation failures than the Viewmax or Macintosh laryngoscopes (P < 0.05). The GVL had superior laryngoscopic performance as compared to the Viewmax and Macintosh laryngoscopes (P < 0.05) and had fewer intubation failures than those two devices (P < 0.05). All devices except the Macintosh laryngoscope in restricted mobility achieved median times to intubation in less than 30 seconds. For both conditions, BL showed the least total absolute movement between Occiput/C1 and C3/C4 of all the devices (all P < 0.05). Most of the difference was seen at C1/C2. CONCLUSIONS: In cadavers with unrestricted and restricted C spine mobility, the BL provided superior laryngoscopic views, comparable intubating times, and less C-spine movement than the GVL, Viewmax, or Macintosh laryngoscopes. PMID- 21296245 TI - Ergonomic task analysis of ultrasound-guided femoral nerve block: a pilot study. AB - STUDY OBJECTIVE: To apply ergonomic task analysis to the performance of ultrasound-guided (US-guided) femoral nerve block (FNB) in an acute hospital setting. DESIGN: Pilot prospective observational study. SETTING: Orthopedic operating room of a regional trauma hospital. SUBJECTS: 15 anesthesiologists of various levels of experience in US-guided FNB (estimated minimum experience < 10 procedures; maximum about 50 procedures, and from basic trainees to consultants); and 15 patients (5 men and 10 women), aged 77 +/- 15 (mean +/- SD yrs) years. MEASUREMENTS/OBSERVATIONS: A data capture "tool", which was modified from one previously developed for ergonomic study of spinal anesthesia, was studied. Patient, operator, and heterogeneous environmental factors related to ergonomic performance of US-guided FNB were identified. The observation period started immediately before commencement of positioning the patient and ended on completion of perineural injection. Data were acquired using direct observations, photography, and application of a questionnaire. MAIN RESULTS: The quality of ergonomic performance was generally suboptimal and varied greatly among operators. Eight (experience < 10 procedures) of 15 operators excessively rotated their head, neck, and/or back to visualize the image on the ultrasound machine. Eight operators (experience < 10 procedures) performed the procedure with excessive thoracolumbar flexion. CONCLUSION: Performance of US-guided FNB presents ergonomic challenges and was suboptimal during most of the procedures observed. Formal training in US-guided peripheral nerve blockade should include reference to ergonomic factors. PMID- 21296246 TI - Is replacement of albumin in major abdominal surgery useful? AB - STUDY OBJECTIVE: To evaluate retrospectively serum albumin concentrations as well as morbidity and mortality of abdominal surgical patients who--if hypoalbuminemic -did not receive human albumin solutions versus those who did receive such solutions. DESIGN: Retrospective observational study. SETTING: Academic community hospital. MEASUREMENTS: The records of 76 consecutive patients who had undergone elective abdominal surgery were reviewed. Preoperative and postoperative serum albumin concentrations up to the seventh day after surgery were recorded. Morbidity and mortality were followed until the time of discharge from the hospital. RESULTS: 38 patients who received albumin replacement if they were hypoalbuminemic versus 38 patients who did not receive albumin replacement showed no significant difference in cumulative (P < 0.52) or individual postoperative complications (infections P < 0.35, cardiovascular complications P < 1.0, organ failure P < 0.67, thromboembolic incidents P < 0.26), and mortality (P < 0.47). CONCLUSIONS: Postoperative serum albumin concentration had no correlation with postoperative morbidity. There is no justification for perioperative albumin replacement in abdominal cancer surgical patients. PMID- 21296247 TI - Passive smoke exposure is associated with perioperative adverse effects in children. AB - STUDY OBJECTIVE: To evaluate the frequency of respiratory adverse events during general anesthesia in children passively exposed to cigarette smoke (PSE). DESIGN: Prospective, double blinded, observational study. SETTING: Operating room and recovery room of a university hospital. MEASUREMENTS: Data were collected from 385 children who underwent elective surgery during general anesthesia from June to November, 2008. PSE was identified by using the child's caregivers' information. Respiratory adverse events were recorded during anesthesia and post anesthesia. MAIN RESULTS: Technique of anesthesia induction and management, distribution of patients' age, gender, surgical procedures, and perioperative analgesic methods were similar in the PSE and non-PSE groups. Respiratory adverse events were reported in 58 patients (15.1%): 50 patients (21.4%) were in the PSE and 8 patients (5.3%) were in the non-PSE group (P = 0.00). The frequency of laryngospasm during anesthesia (P = 0.03) and hypersecretions in the recovery room (P = 0.00) were significantly increased in the PSE group. CONCLUSIONS: Children who are exposed to environmental tobacco smoke and who undergo general anesthesia seem to have an increased risk of respiratory complications in the recovery period rather than during anesthesia. PMID- 21296248 TI - The efficacy of intravenous paracetamol versus tramadol for postoperative analgesia after adenotonsillectomy in children. AB - STUDY OBJECTIVE: To evaluate the efficacy and the quality of recovery with intravenous (IV) paracetamol versus tramadol for postoperative analgesia after adenotonsillectomy in children. DESIGN: Prospective, randomized, double-blinded clinical trial. SETTING: Operating room and Postanesthesia Care Unit (PACU) of a university-affiliated hospital. PATIENTS: 64 ASA physical status I and II children, aged 6 to 16 years, scheduled for adenotonsillectomy. INTERVENTIONS: All patients were premedicated with oral midazolam 0.5 mg/kg 30 minutes before surgery. Patients were randomized to two groups following induction of general anesthesia. The paracetamol group (n = 32) received 15 mg/kg of IV paracetamol and the tramadol group (n = 32) received 1.0 mg/kg of IV tramadol. MEASUREMENTS: Modified Hannallah pain scores, emergence agitation, Aldrete scores, sedation scores, time to first administration of analgesic, heart rate, and mean arterial blood pressure were recorded for each patient. Data were recorded every 5 minutes for the first 30 minutes and every 10 minutes for the remaining 30 minutes in the PACU, then at 2, 3, 4, 5, 6, 8, 12, and 24 hours in the ward. The frequency of postoperative nausea and vomiting also was noted. Satisfaction of parents and nurses was determined on a 4-point scale at the end of the study. MAIN RESULTS: No significant demographic differences between groups were noted. No statistically significant difference was found in postoperative pain scores in either group. Agitation scores, Aldrete scores, sedation scores, and number of patients who received rescue analgesia and time to administration of rescue analgesia were similar in both groups. CONCLUSIONS: The IV formulation of paracetamol was associated with similar analgesic properties and early recovery to that of IV tramadol after adenotonsillectomy in children. PMID- 21296249 TI - A case of adjustable pressure-limiting (APL) valve failure. AB - The adjustable pressure-limiting (APL) valve controls airway pressure during manual ventilation. Failure of the APL valve during induction of anesthesia may occur, and the anesthesiologist must be aware of solutions for this occurrence. PMID- 21296250 TI - Reversal of hypercoagulability with hydroxyethyl starch during transplantation: a case series. AB - During transplant surgery, clot formation resulting in life-threatening thromboembolic phenomena or graft loss may be a consequence unless close monitoring of coagulation and anticoagulation treatment is instituted in a timely manner. Three cases with a hypercoagulable state, as determined by thrombelastography at the time of surgery, but whose hypercoagulation was gradually attenuated with hydroxyethyl starch infusion during transplantation, are presented. PMID- 21296251 TI - The diagnostic challenge of a tracheal tear with a double-lumen endobronchial tube: massive air leak developing from the mouth during mechanical ventilation. AB - The case of a 78 year-old woman who underwent a right lower lobectomy using a 35 French, left-sided, double-lumen endobronchial tube (DLET) is presented. Multiple adjustments were needed for the DLET's proper placement. At the end of surgery, sudden loss of tidal volume with a large air leak from the patient's mouth was noted. Fiberoptic bronchoscopic examination through the DLET was negative. Rupture of the tracheal cuff was suspected, and the DLET was replaced with a single-lumen tube. In the intensive care unit, the massive air leak from the mouth recurred during mechanical ventilation. Nasal fiberoptic bronchoscopic examination showed a longitudinal laceration of the membranous portion of the trachea extending from the subglottic area to the orifice of the right bronchus. Surgical repair of the tear was performed. PMID- 21296252 TI - Intravascular balloon to minimize blood loss during total hip replacement in a Jehovah's Witness. AB - Intermittent intravascular occlusive balloons are commonly used to minimize bleeding in cases where massive blood loss is anticipated. However, the efficiency and safety of balloon occlusion remains unclear for elective procedures, and several cases of distal thrombosis have been reported. A case of intra-arterial occlusive balloon that was selectively placed preoperatively to minimize bleeding in a patient during total hip replacement is presented. Use of an external tourniquet was not feasible for this patient. The balloon was inflated to a minimum volume to achieve intravascular occlusion and was periodically deflated to minimize the risk of postoperative complications. A surgical field with minimal blood loss was created. PMID- 21296253 TI - Three-limb compartment syndrome and rhabdomyolysis after robotic cystoprostatectomy. AB - The case of a 53 year-old, ASA physical status III man who underwent laparoscopy assisted cystoprostatectomy, then subsequently developed three-limb compartment syndrome and rhabdomyolysis, is presented. He recovered baseline renal function and the use of his limbs. Well-limb compartment syndrome (WLCS) has a multifactorial etiology and is prevented and managed by avoidance of known risks. PMID- 21296254 TI - General anesthesia is not defined by a BIS level. PMID- 21296255 TI - Spinal anesthesia-induced sedation may obviously facilitate general anesthesia. PMID- 21296257 TI - Use of the GlideScope for placement of a recurrent laryngeal nerve monitoring endotracheal tube. PMID- 21296258 TI - Continuous epidural blockade for treatment of drug-induced priapism. PMID- 21296259 TI - The 'bubble technique': an innovative technique for confirming correct nasogastric tube placement. PMID- 21296260 TI - Trial registration in CAM. PMID- 21296261 TI - Tai chi Qigong improves lung functions and activity tolerance in COPD clients: a single blind, randomized controlled trial. AB - OBJECTIVE: To evaluate the effectiveness of a Tai chi Qigong (TCQ) program in enhancing respiratory functions and activity tolerance in clients with chronic obstructive pulmonary disease (COPD). DESIGN: A single-blind, randomized controlled trial. SETTING: Five general outpatient clinics in Hong Kong. INTERVENTION: In total, 206 COPD clients were randomly assigned into one of the three groups, namely, TCQ, exercise, and control group. Subjects in the TCQ group received a TCQ program consisting of two 60-min sessions each week for three months. Subjects in the exercise group were taught to practice breathing techniques combined with walking as an exercise. Subjects in the control group were instructed to maintain their usual activities. Data collection was performed at baseline and at the 6-week and 3-month marks. OUTCOMES: Lung functions, 6-min walk test, and COPD exacerbation rate. RESULTS: Results of repeated measures of analysis of covariance demonstrated that there were significant interaction effects between time and group in forced vital capacity (p=.002, eta(2)=.06), forced expiratory volume in 1s (p<.001, eta(2)=.02), walking distance (p<.001), and exacerbation rate (p=.006, eta(2)=.06) at 3 months. Improvements were noted in the TCQ group. No changes were observed in the exercise group, while a decline in lung functions was noticed in the control group. CONCLUSION: Tai chi Qigong was able to improve respiratory functions and activity tolerance level in COPD clients. The breathing and walking exercise helped maintain lung functions and slow down disease progression. PMID- 21296262 TI - Touching ethics: assessing the applicability of ethical rules for safe touch in CAM--outcomes of a CAM (complementary and alternative medicine) practitioner survey in Israel. AB - INTRODUCTION: Recently, ethical guidelines regarding safe touch in CAM were developed in Israel. Publishing ethical codes does not imply that they will actually help practitioners to meet ethical care standards. The effectiveness of ethical rules depends on familiarity with the code and its content. In addition, critical self-examination of the code by individual members of the profession is required to reflect on the moral commitments encompassed in the code. METHODS: For the purpose of dynamic self-appraisal, we devised a survey to assess how CAM practitioners view the suggested ethical guidelines for safe touch. We surveyed 781 CAM practitioners regarding their perspectives on the safe-touch code. RESULTS: There was a high level of agreement with general statements regarding ethics pertaining to safe touch with a mean rate of agreement of 4.61 out of a maximum of 5. Practitioners concurred substantially with practice guidelines for appropriate touch with a mean rate of agreement of 4.16 out of a maximum of 5. Attitudes toward the necessity to touch intimate areas for treatment purposes varied with 78.6% of respondents strongly disagreeing with any notion of need to touch intimate areas during treatment. 7.9% neither disagreed nor agreed, 7.9% slightly agreed, and 7.6% strongly agreed with the need for touching intimate areas during treatment. There was a direct correlation between disagreement with touching intimate areas for therapeutic purposes and agreement with general statements regarding ethics of safe touch (Spearman r=0.177, p<0.0001), and practice guidelines for appropriate touch (r=0.092, p=0.012). CONCLUSION: A substantial number of practitioners agreed with the code, although some findings regarding the need to touch intimate area during treatments were disturbing. Our findings can serve as a basis for ethical code development and implementation, as well as for educating CAM practitioners on the ethics of touch. PMID- 21296263 TI - Comparison between the effects of trigger point mesotherapy versus acupuncture points mesotherapy in the treatment of chronic low back pain: a short term randomized controlled trial. AB - OBJECTIVE: The goal of this study was to compare the effects of trigger point (TRP) mesotherapy and acupuncture (ACP) mesotherapy in the treatment of patients with chronic low back pain. DESIGN: Short term randomized controlled trial. SETTING: 62 subjects with chronic low back pain were recruited at outpatients Physical Medicine and Rehabilitation Clinic at the University of Rome "La Sapienza" in the period between July 2006 and May 2008. INTERVENTION: Study subjects were assigned to receive 4 weeks treatments with either trigger point mesotherapy (TRP mesotherapy, n=29) or acupoints mesotherapy (ACP mesotherapy, n=33). MAIN OUTCOME MEASURES: Pain intensity with a pain visual analogic scale (VAS) and verbal rating scale (VRS) and pain disability with McGill Pain Questionnaire Short Form (SFMPQ), Roland Morris Disability Questionnaire (RMQ) and Oswestry Low Back Pain Disability Questionaire (ODQ). RESULTS: ACP mesotherapy shows a more effective results in VRS and VAS measures in the follow up (p(VRS)=<.001 and p(VAS)=<.001). The SF-MPQ measure shows a better results for ACP instead of TRP with statistically significant differences between groups and time (p=.035). Participants reported a slight discomfort at the time of the inoculation, and 15% reported slight neck pain in ACP mesotherapy group. CONCLUSIONS: Our results suggest that the response to ACP mesotherapy may be greater than the response to TRP mesotherapy in the short term follow-up. This technique could be nevertheless a viable option as an adjunct treatment in an overall treatment planning of CLBP. PMID- 21296264 TI - Acupuncture in urological practice--a survey of urologists in England. AB - OBJECTIVE: To determine the feasibility of obtaining cooperation from urologists in carrying out large-scale studies on the efficacy of acupuncture for the treatment of urological conditions, based on urologists' general views and knowledge of acupuncture. METHODS: A questionnaire was distributed to 145 urologists within three training deaneries within England. RESULTS: A response rate of 70% (n=102) was achieved. The majority of urologists rated their knowledge of acupuncture as low (46%, n=46) and their general attitude towards acupuncture was neutral (54%, n=55). The majority of responding urologists (95%) thought that acupuncture may be of value in urological conditions, and acupuncture was suggested to patients by 30 urologists (29%). The urologists most likely to suggest acupuncture to their patients were typically over 40 years of age, more experienced, not in a training post, and since starting their urological career had changed their attitude towards acupuncture. In a multivariate analysis, a change of view regarding the efficacy of acupuncture was found to be the only variable significantly associated with a recommendation of acupuncture to patients. CONCLUSIONS: Although overall knowledge about acupuncture was poor, most responding urologists thought acupuncture may be useful for urological conditions. Those who had changed their views were most likely to suggest acupuncture to their patients. Acupuncture for urological conditions warrants further investigation and, as this study has shown high interest within the urological community large clinical trials involving multicentres may be feasible. PMID- 21296265 TI - Concurrent herb-prescription medication use and health care provider disclosure among university students. AB - OBJECTIVES: To determine the extent to which college students are intermixing mood-altering herbs with prescription medications and whether they are disclosing this information to their health care providers. DESIGN AND SETTING: A nonrandom sample was drawn from the student body of a Northwestern state university (n=305). METHODS: In November 2008 participants completed an online survey detailing herb use, disclosure to health care providers and herb/medicinal intermixing. RESULTS: There were no demographic differences between herb users and non-users. Most herb usage was self-prescribed (60%) and undisclosed to healthcare providers (only 25% of herb users disclosed to a healthcare provider). 34% of herb users used them to treat a mood disorder. Of herb users, 13% had simultaneously used herbs and prescription medication in the last year. In addition, herb users who intermixed herbs with prescription medications had higher depression and anxiety scores than those who did not intermix. CONCLUSIONS: College student herb use is primarily self prescribed and undisclosed to healthcare professionals, who may prescribe pharmaceuticals that interact negatively with herbals. Physician awareness and query is invaluable for the prevention of adverse herb and drug interactions. PMID- 21296266 TI - Lowering LDL cholesterol with margarine containing plant stanol/sterol esters: is it still relevant in 2011? AB - Recommendations about the use of plant stanol/sterol esters have not been updated since 2001. There have been many developments in medicines for lipid-lowering since 2001. In this review, the use of margarines containing stanol or sterol esters, to lower LDL cholesterol is considered in the 2011 setting. Firstly, there is a brief overview of the effects of the stanols/sterols on LDL cholesterol, which shows that these agents have a modest ability to lower LDL cholesterol, and are not effective in all conditions. Secondly, the relevance of the stanols/sterols in 2010/1 is questioned, given they have not been shown to reduce clinical endpoints, and have no effects on HDL cholesterol or triglyceride levels. Finally, there is a section comparing the stanols/sterols with the present day prescription lipid lowering medicines. Prescription drugs (statins, ezetimibe, and niacin) have a much greater ability to lower LDL cholesterol than the stanol/sterol esters, and also increase levels of HDL cholesterol and decrease levels of triglycerides. The statins and niacin have been shown to reduce cardiovascular clinical endpoints. Except in borderline normo/hypercholesterolemia, prescription drugs should be preferred to stanol/sterol esters for lowering LDL cholesterol in 2011. PMID- 21296267 TI - Efficacy of Clinacanthus nutans extracts in patients with herpes infection: systematic review and meta-analysis of randomised clinical trials. AB - OBJECTIVE: To examine the efficacy of Clinacanthus nutans extracts in treatment of Herpes genitalis and Herpes zoster from randomised clinical trials (RCTs). METHODS: Bibliographic databases, including MEDLINE, EMBASE, CINAHL, Cochrane CENTRAL, AMED, WHO trial registry, http://www.clinicaltrial.gov, Thai Index Medicus, and Index Medicus Siriraj library, were searched from their inception dates to February 2010 without language restrictions. Methodological quality of included trials was assessed using Jadad's quality scale and Cochrane's risk of bias. RESULTS: Four RCTs (n=286) met our inclusion criteria which include two studies on H. genitalis and the other two on H. zoster; in these studies, a total of 151 patients were assigned to the C. nutans group of H. genitalis trials, a pooled relative risk of C. nutans preparations against placebo for a 3 day-full crusting was 6.62 (95% C.I. 3.83-11.47) and of a 7-day complete healing was 3.77 (95% C.I. 2.46-5.78). In H. zoster, the relative risk for a 3 day-full crusting was 3.21 (IQR 0.97-10.58). CONCLUSIONS: This meta-analysis and systematic review suggests some beneficial effects of C. nutans preparations on treatments of H. genitalis and H. zoster. However, more robustly designed trials are needed to substantiate the benefit of these plants, specifically on their active purified compounds, and their potencies and benefits on treatment outcome of H. genitalis and H. zoster. PMID- 21296268 TI - How to treat a patient with chronic low back pain - methodology and results of the first international case conference of integrative medicine. AB - BACKGROUND AND OBJECTIVE: Complementary and alternative medicine (CAM) is frequently used in patients in industrialised countries. Despite this popularity, there remains a considerable deficit of discourse and cooperation between physicians practicing CAM and conventional medicine. The aim is to present the methodology and results of the first international case conference on integrative medicine (IM) dealing with a patient with low back pain. In this paper the methodological tool "case conference on IM" is also described. METHODS: The interactive case conference took place on November 20th, 2009 as part of the "2nd European Congress of IM" in Berlin, Germany. An experienced expert panel from both conventional medicine and CAM developed integrative medical diagnoses and therapeutic strategies using as their starting point an individual patient case on chronic low back pain (LBP). The case was selected because LBP is a common diagnosis with considerable economic impact and a problem which is often treated with CAM. RESULTS: In this case conference, the expert panel agreed on a diagnosis of "chronic non-specific LBP with somatic and psychological factors" and proposed multi-modal short- and long-term treatment including of CAM. The importance of the patient-physician-relationship and the consultation process with appropriate consultation time for treatment success was highlighted. There was consensus that the diagnostic process and resulting treatment plan should be individualised and focussed on the patient as a complete person, identifying the significance the disease has for the patient and not just on the disease for itself. Considerable differences were found amongst the experts regarding the first steps of treatment and each expert saw possibilities of "effective and adequate treatment" being met by their own individual treatment method. CONCLUSION: The case conference on integrative medicine stimulated an intensive exchange between the approaches used by conventional medicine and CAM clarifying different treatment possibilities for low back pain. Therefore, case conferences on integrative medicine could serve as a model for evaluating similar activities in academic hospitals and establishing such approaches in routine medical care. This strategy has the potential to improve patient centred care. PMID- 21296270 TI - Perceptions of contraceptive responsibility among female college students: an exploratory study. AB - PURPOSE: An important, although understudied, area related to contraceptive use is perceptions of contraceptive responsibility. The purpose of this exploratory study was to investigate these perceptions among female college students. METHODS: Web-based or mailed questionnaires were completed by 326 students from 2006-2007. Logistic regression was used to obtain odds ratios and 95% confidence intervals (CI) to model the associations between select demographic and lifestyle characteristics and contraceptive responsibility (shared vs. individual responsibility). RESULTS: Although 89.1% of women felt that contraceptive responsibility should be shared, only 51.8% indicated that responsibility is actually shared in their relationships. After adjustment for age, race/ethnicity, marital status, and year of study, women using "other" methods of contraception (i.e. withdrawal, rhythm, sterilization, etc.) had 3.25 times the odds of stating that contraceptive responsibility is actually shared as compared to hormonal users (95% CI: 1.20, 8.80). CONCLUSIONS: For college women, there is a disconnect between who they feel should be responsible for contraception and who actually is responsible. Insight into perceptions of contraceptive responsibility in the university setting may help guide health educators and clinicians in designing pregnancy and sexually transmitted infection prevention programming. PMID- 21296269 TI - Recreational physical activity and ovarian cancer risk and survival. AB - PURPOSE: Physical activity may influence ovarian cancer risk and outcomes through effects on ovulation, inflammatory markers, and other processes. We examined associations between self-reported physical activity and ovarian cancer risk and survival in a population-based, case-control study in North Carolina. METHODS: The analyses involved 638 epithelial ovarian cancer cases and 683 controls recruited between 1999-2008. Logistic regression analyses were used to assess ovarian cancer risk in relation to reported average physical activity at various time periods. Kaplan-Meier analyses and proportional hazards modeling were used to assess associations between physical activity and survival among ovarian cancer cases. RESULTS: Modestly reduced risks for ovarian cancer were observed in some categories of physical activity, but there were no consistent patterns of greater reductions in risk with higher activity levels. Physical activity before diagnosis was not significantly related to ovarian cancer survival overall, but survival was better for women who reported greater than 2 hours of activity/week as compared to those reporting less than 1 hour/week among women who were non obese (multivariable Hazard ratio = 0.69, 95% confidence interval: 0.47-1.00). CONCLUSIONS: Our data provide weak evidence in support of beneficial effects of physical activity on ovarian cancer risk and survival, but results should be interpreted cautiously because of the lack of a clear dose response relation with higher levels of exercise and the likely misclassification of self-reported activity. PMID- 21296271 TI - Frequency of human papillomavirus infection, coinfection, and association with different risk factors in Colombia. AB - PURPOSE: The aims of this study were to provide new insights into infection patterns of six high-risk human papillomaviruses (HR-HPV-16, -18, -31, -33, -45, and -58) and two low-risk HPV types (LR-HPV-6 and -11), their association with risk factors and coinfection. METHODS: Cervical samples of 2110 women were tested for the presence of HPV-DNA by polymerase chain reaction. Statistical analyses were performed to determine viral-type frequencies in single and multiple infections and association between infection and different risk factors. RESULTS: HPV-16 was the most prevalent type among the studied population, followed by HPV 31. This last viral type showed a variable distribution between the different cities evaluated. The results showed distinct type-specific distributions among regions and a high association between absence of pregnancies, cities as Girardot and Leticia, the indigenous ethnicity, and coinfection. CONCLUSIONS: The results showed a variable distribution of HPV types according to the geographical region analyzed. In addition, data suggest that some sociodemographic-factors such as ethnicity, number of pregnancies, lifetime number of sexual partners, and geographic region were significantly associated, and our results showed little differences between single and multiple infections by HPV with regard to risk factors. Furthermore, these results provide relevant information that will allow assessing in further studies the impact that vaccination programs on these populations and the selective pressure would have on the distribution of HPV types. PMID- 21296272 TI - Health behaviors of victims and related factors in Wenchuan earthquake resettlement sites. AB - PURPOSE: The purpose of this study was to describe the health behaviors of earthquake victims related to gastrointestinal and respiratory infectious diseases in the centralized transitional earthquake resettlement sites in Wenchuan, China; and to identify key factors related to health behaviors that may inform local infectious diseases prevention and control strategies. METHODS: Data were collected using a questionnaire that included questions about socio demographic characteristics and health beliefs and behaviors. In total, 1411 participants were included through a two-stage random sampling strategy. A bivariate multilevel model was used to explore the related factors. RESULTS: Approximately 67% of the participants wash their hands after going to lavatories every time, and 87% felt uncomfortable spitting on the ground. The more the participants perceived their susceptibility to and the severity of infectious diseases, the better their health-related behaviors (P < 0.05). Both health related behaviors were influenced by communication modes of health education (P = 0.01) and socio-demographic characteristics. There was heterogeneity of health related behaviors among different resettlement sites (P < 0.01). CONCLUSIONS: Health education intervention, based on the Health Belief Model, is one of the main preventative strategies that should be implemented to inspire self-efficacy and to enhance better health-related behaviors among earthquake victims. Appropriate health education communication modes should be considered among different resettlement sites. PMID- 21296273 TI - [Flexible ureteroscopy and mini percutaneous nephrolithotomy in the treatment of renal lithiasis less or equal to 2 cm]. AB - PURPOSE: Compare, in a retrospective study, the indications, the efficiency and the morbidity of the flexible ureteroscopy (URS) and the mini percutaneous nephrolithotomy (mini-perc) for the treatment of the renal lithiasis less or equal to 2 cm. MATERIALS AND METHODS: One hundred and forty-four operated patients: 101 by "mini-perc" and 43 by URS. Pre-, per- and post-operative data prospectively entered in a computerized database. RESULTS: URS and "mini-perc" groups were comparable in terms of age (49.2+/-14 years versus 51.7+/-16 years; P=0.37) and of size of the lithiasis (8.5+/-3.2 mm versus 8.9+/-2.7 mm, P=0.4). However, the number of lithiasis was more important in URS group (2.7+/-141.6 versus 1.3+/-0.38; P<0.05). The operating time was 59+/-32.6 min in URS and 48+/ 28.3 min "mini-perc" group (P=0.05). The peroperating complication rate was 2% for URS (a false passage during the introduction of the access girdle) and null in the "mini-perc" group. The hospitalization was 1.49+/-11.4 days after URS and of 4.1+/-1.2 days after "mini-perc" (P<0.05). The duration of ureter drainage by stent was respectively 13.8+/-11.5 and 2.6+/-1.2 days (P<0.05). One month later, the treatment was effective in 88% of cases in the URS group whereas 93% in "mini perc" group (P=0.17). Six patients (14%) need complementary treatment for residual lithiasis in the URS group and four (3.9%) in the "mini-perc" group. CONCLUSION: The "mini-perc" and the URS are two effective techniques for the treatment of the renal lithiasies less or equal to 2 cm. For the two groups, the complication rates were low and the length of hospital stay was short. PMID- 21296274 TI - [Photodynamic therapy and prostate cancer]. AB - PURPOSE: Photodynamic therapy (PDT) is an innovative therapeutic modality in urologic oncology. MATERIAL AND METHODS: We reviewed the current literature on principles and modalities of PDT in prostatic oncology. RESULTS: Focal therapy of prostate cancer is an application field of PDT. Clinical phase II studies are ongoing to determine PDT efficacy and safety in this indication. PDT as salvage treatment after prostatic radiotherapy has been tested. Carcinologic results were promising but important side effects were reported. Individual dosimetric planification is necessary to avoid this toxicity. CONCLUSION: PDT first clinical experience for prostate cancer has showed its technical feasibility. Several research ways are currently in study to improve carcinologic efficacy and to limit potential side effects. PMID- 21296275 TI - [Vaginal prolapse. What dynamic pelvic MRI adds to clinical examination?]. AB - OBJECTIVE: We wanted to study the role of dynamic pelvic MRI (D-MRI) in the surgical management of patients with genito-urinary prolapse. PATIENTS: A routine D-MRI examination before and after laparoscopic double promontofixation was performed in 15 cases with symptomatic vaginal prolapse in need of surgical treatment. The review included also three self-administered questionnaires of symptoms and quality of life. We compared the preoperative clinical evaluation of the studied cases with D-MRI data. Changes after the surgical treatment were also studied. RESULTS: The D-MRI provides an accurate diagnostic evaluation of the pelvis, which is both objective and reproducible. The correlation between clinical scores and radiological magnetic resonance was 53.3% only. In cases with absence of previous pelvic surgery, there was a radio-clinical discrepancy of 40% of cases, while in cases with history of a previous pelvic surgery we found a discrepancy of 60% of cases. This was due to clinical difficulty in differentiating between peritoneocele and rectocele, or due to under-diagnosis of complex prolapse. The sensitivity of MRI in the diagnosis of cystocele, hysterocele and rectocele were respectively 100, 100 and 83%. The gain in sensitivity provided by the MRI was significant for the diagnosis of peritoneocele: 100% against 33%. The specificity was 100%. Static images allowed a detailed study of damaged connective tissues and pelvic muscles. CONCLUSION: The D-MRI seems an appropriate tool in pre-operative assessment of cases with vaginal prolapse. It will help in focusing our surgical strategy, especially in cases that present post-hysterectomy and in cases with residual or recurrent prolapse. PMID- 21296276 TI - [Multiple sclerosis and urolithiasis]. AB - OBJECTIVE: The aim of our study was to determine the nature of urinary stones and the main lithogenic process in patients with multiple sclerosis who developed secondary urolithiasis. PATIENTS AND METHOD: This is a retrospective study of 60 urinary stones from 49 patients with lithiasis including 30 women and 19 men. The stones have been analyzed by optical microscopy and infrared spectroscopy. RESULTS: Our study clearly showed the net preponderance of phosphatic stones. Urinary stones were mainly located in the upper urinary tract (2/3 of cases). A particularly high frequency of struvite was observed among these stones (65% of cases in women and 45% of cases in men), thus suggesting the main lithogenic mechanism in multiple sclerosis patients was a urinary tract infection by urea splitting-bacteria. The second lithogenic process among these patients was metabolic. The high frequency of weddellite and brushite, especially in men, suggested that mainly hypercalciuria was involved in these metabolic stones. CONCLUSION: Urolithiasis in multiple sclerosis was mainly due to urinary tract infection, especially in women. Urinary tract infection related to bladder and sphincter disorders is extremely frequent and polymorphic in multiple sclerosis. Hence the importance of providing appropriate care to prevent complications of urinary tract infections and, especially, the ascending migration of microorganisms and the risk of pyelonephritis and of infectious kidney stones. PMID- 21296277 TI - [Horseshoe kidney stones: benefit of flexible ureterorenoscopy with holmium laser]. AB - OBJECTIVES: We aim to assess the outcome of the flexible ureterorenoscopy (F-URS) with holmium laser in treating horseshoe kidney (HSK) stones. PATIENTS AND METHODS: We reviewed retrospectively the records of 18 patients with HSK stone (18 renal units) who underwent F-URS using holmium laser from December 2004 to October 2009. The mean age was 37.7+/-6.9 years. The F-URS used after the extracorporeal shock wave lithotripsy (ESWL) failure in eight patients (44.4%) and four patients (22.2%) had PCNL failure. The follow up visit range were between 4 and 6 weeks with plain radiograph (KUB) and renal ultrasound or non contrast computed tomography scan (NCCT). Success rate was defined as stone free or residual fragment less than 3 mm. Use of auxiliary procedures like ESWL were considered as treatment failure. RESULTS: Eighteen patients, three females and 15 males with mean age was 37.7+/-6.9 years with HSK calculi underwent ureteroscopic management. The presenting symptoms were renal colic, urinary tract infection or hematuria. We found different HSK stone location (11 mixed calyceal, three mixed pelvic and calyceal and four pelvic). The average stone burden was 15.5+/-7.3 mm and the mean operative time was 112+/-9.4 minutes. All over procedures were 27, with mean average of 1.5 procedures per patient. The success rate was 89%. CONCLUSION: The F-URS with holmium laser is an efficient minimal invasive procedure in treating HSK stones. PMID- 21296278 TI - [Active surveillance for prostate cancer: usefulness of endorectal MR at 1.5 Tesla with pelvic phased array coil in detecting significant tumors]. AB - PURPOSE: To describe and assess MRI signs of significant tumor in a series of patients who all underwent radical prostatectomy and also fulfilled criteria to choose active surveillance according to French "SurAcaP" protocol. PATIENTS AND METHODS: The clinical reports of 681 consecutive patients operated on for prostate cancer between 2002 and 2007 were reviewed retrospectively. All patients had endorectal MR (1.5 Tesla) with pelvic phased array coil. (1.5 T erMR PPA). Sixty-one patients (8.9%) fulfilled "SurAcaP" protocol criteria. Preoperative data (MR+core biopsy) were assessed by comparison to whole-mount step section pathology. RESULTS: 85.3% of the 61 patients entering SurAcaP protocol had significant tumor at pathology. (Non Organ Confined Disease (Non OCD)=8.2%, Gleason sum score>6=39.2%). A new exclusion criterion has been assessed: T3MRI+/ NPS>1 as a predictor tool of significant tumor. ("T3MRI+/-NPS>1"=Non OCD at MR+/ number of positive sextants involved in tumor at MR and/or Core Biopsy > to 1). Sensitivity, specificity, PPV, NPV of the criterion "T3MRI+/-NPS>1" in predicting significant tumor were, respectively: 77%, 33%, 86%, 20%. Adding this criterion to other criteria of the "SurAcaP" protocol could allow the exclusion of all Non OCD, and a decrease in Gleason sum Score>6 rates (20%). CONCLUSION: Endorectal MR at 1.5 Tesla with pelvic-phased array coil should be considered when selecting patients for active surveillance in the management of prostate cancer. A criterion based upon MR and core biopsy findings, called "T3MR+/-NSP>1" may represent an exclusion citeria due to its ability to predict significant tumor. PMID- 21296279 TI - [Total cystectomies for cancers locally advanced of bladder about 12 cases in the service of urology of the general hospital of Grand-Yoff]. AB - OBJECTIVE: The goals of the study is to evaluate the feasability of the total cystectomy for cancer infiltrating locally advanced of bladder and to evaluate perioperatitive morbidity and short-term results. PATIENTS AND METHODS: We made a retrospective study concerning 12 first patients having profited from a total cystectomy for cancer infiltrating of the bladder in our hospital over one period of 1 year. The parameters of study were: the age at the time of the diagnosis, circumstances of the diagnosis, antecedents of the patient, the histological type and stage TNM before and after intervention, the type of derivation associated, duration of the intervention, the anesthesia, complications and morbidity per- and postoperational. We carried out calculations of average and frequency for the data analysis. RESULTS: The mean age was 51 years (extreme: 32; 83). They were nine men and three women. The circumstances of diagnosis were dominated by the total hematuria and in less frequency by the bladder irritative symptoms. The antecedents of the patients were dominated by the schistosomia (five cases) and the tobacco addiction (two cases). The histological type obtained in preoperative after biopsy or trans urethral resection of bladder found, seven cases of squamous cell carcinoma, four cases of transitional cell carcinoma and one case of adenocarcinoma. Into preoperative, three patients were at the stage pT2, eight patients pT3, one pT4. Four patients had a replacement of bladder: three by a bladder in Z and a patient had Camey II. They were the three patients pT2 preoperative and a patient pT3. Two patients had a standard ureterosigmoidostomy type coffey: the patient pT4 and a patient pT3. The six other patients had Bricker. All the patients profited from a blood transfusion peroperational (two units on average). We did not record any operational mortality. The complications and morbidity are represented by the suppurations of wall (three cases), the vesicocutaneous fistula (one case), the infections urinary and the anemia which was constant. CONCLUSION: The management of bladder cancer poses a real problem in our countries because of the diagnosis at advanced stage. PMID- 21296280 TI - [Oncological surgery and development: to refuse fate and search for prevention]. PMID- 21296281 TI - [Management of erectile dysfunction by general practitioners and endocrinologists in diabetes: a survey of 130 patients]. AB - OBJECTIVES: To assess the prevalence, the severity and expectations regarding erectile dysfunction (ED) in diabetic patients, then to investigate how general practitioners (GP) and endocrinologists manage this disorder. PATIENTS AND METHODS: A questionnaire was given during 5 weeks to every diabetic patient addressed to the endocrinology department in order to assess erectile function (IIEF5), patient's bother and expectations to be treated, and the management of ED by GP and endocrinologists and differences in management between male and female doctors. RESULTS: One hundred and thirty questionnaires were available. Mean age was 57.5 and the mean IIEF5 score was 13.6. Twenty-two patients (16.9%) reported an IIEF5 score less than 5 and 75 patients (57,6%) reported an IIEF5 between 5 and 20. Eighty-six patients declared ED (66.2%). In these patients, 76 (88.4%) sought for a medical treatment and 11 (12.8%) received a treatment for ED. Endocrinologists were more active than GP in the screening of ED (59.5% vs 19.4%, P=0.001) but prescribed a treatment less often (14.3% vs 45.2%, P=0.008). Female doctors seemed less active in ED management (29.3% vs 13.3%, NS). CONCLUSIONS: This study highlighted the lack of ED management by GT and endocrinologists in diabetic patients in spite of ED's frequency and patients' expectations. PMID- 21296282 TI - [Initial results of a novel technique for sperm retrieval in male infertility due to refractory retrograde ejaculation]. AB - AIMS: To describe and evaluate a novel technique of spermatozoa retrieval from patients suffering from infertility secondary to refractory retrograde ejaculation. METHOD: Prospective study to compare mobility and vitality of spermatozoa obtained from urine (U) after oral modification of chemical parameter (PH, Osmolarity) versus from endovesical instillation of sterile spermatozoa culture medium before ejaculation (F). Patients were their own controls. Twelve month prospective follow-up was achieved to document the results of assisted procreation. RESULTS: Eight patients were included and mobility and vitality were improved in all patients after F technique was compared to U technique. With U technique, eight patients on eight had negative defrost test; after F technique, seven patients on eight had a positive defrost test and could therefore have access to assisted reproduction techniques. Four couples had five ICSI and obtained three pregnancies leading to five births. CONCLUSION: Endovesical instillation of sterile spermatozoa culture medium before ejaculation was a safe and effective technique to improve spermatozoa quality in male infertility related to refractory retrograde ejaculation. PMID- 21296283 TI - [Training and future of urologist residents and chief residents in France: results from a national survey among 154 urologists in training]. AB - PURPOSE: To raise an appraisal of French urologist resident and chief resident's demographic characteristics, activity, post-residency project, career desires and factors associated with obtaining a fellowship. METHODS: An electronic questionnaire was sent by email between June 2009 and January 2010 to the 288 French urologists currently in training. Items analysed included demographics, achievement of academic works and post-residency projects. RESULTS: Overall, we obtained 156 answers (response rate of 54%). Our population was composed by 47 (27%) fellows and 114 (73%) residents. They work 68.1 hours per week and 31 (20%) leave the hospital after an on-call night. Thirty-two (20.5%) have validated a master 2. Among the resident, 54 (47.3%) are certain to have the opportunity to be a chief resident. Regarding residents, factors significantly associated with the fact to obtain a fellowship in multivariate analysis were: to gain a master 2, working more than 65 hours per week and achieving academics works. Installation in a general hospital, a university hospital and a private clinic was considered by respectively 21.7%, 41.6% and 67.3% of young urologists. CONCLUSION: French urologist resident and chief resident's work an average 68 hours per week. The determining factors in obtaining a fellowship are the realization of a master 2, a workweek exceeding 68 hours and the achievement of academic work. After completing their academic training, a majority of young urologists are attracted by private practice. PMID- 21296284 TI - [Urinothorax: rare complication of neonatal sectioned posterior urethral valve]. AB - We report a newborn aged 19 days, carrying a posterior urethral valve antenatal screening in which developed 7 days after the entire section of the valve, a compressive urinothorax in connection with a perirenal urinoma. Pleural and bladder drainage has a surrender of effusions and a healing of the renal parenchyma. The thoracic urine effusion is a very rare complication of a posterior urethral valve with perirenal urinoma. This probably results from a rupture of a fornix dysplastic by hypertension of the urinary tract. The authors emphasize the unusual discovery of this disease by breathing problems and his delayed character after resection of the obstruction in the neonatal period. PMID- 21296285 TI - [Bladder necrosis after an immediate post-operative mitomycin C instillation]. AB - Administration of intravesical chemotherapy by mitomycin C decreases the risk of recurrence in non-muscle-invasive bladder tumours. We report the case of a man, who presented a full bladder necrosis after an immediate adjuvant mitomycin C instillation. The failure of resection of the necrotic area led us to perform a total cystectomy with an intestinal reconstruction. A review of the literature showed four other cases of necrosis of the bladder or of lower urinary tract. In all cases the rules of early instillation were observed. PMID- 21296286 TI - [Toward a new border]. PMID- 21296287 TI - A rare case of anterior thoracic myelomeningocele with scoliosis--case report and review of the literature. AB - BACKGROUND CONTEXT: Spinal deformities associated with spinal dysraphism are a challenging problem. Myelomeningocele has been reported in the lumbar spine. However, it is rare in the thoracic spine. PURPOSE: The purpose of the report was to heighten the awareness of the rare presentation of the myelomeningocele in the thoracic spine and the ability to correct the scoliosis without debulking the lesion. STUDY DESIGN: This is a clinical case report and literature review. METHODS: We report a 13-year-old girl presented with complaints of back pain, difficulty in breathing, and easy fatigability. On examination, she had a thoracolumbar scoliosis, weakness of the right ankle dorsiflexors, and impaired sensation over the L5 dermatome of the right lower limb. Radiographic examination revealed a 128 degrees thoracolumbar scoliosis with congenital hemivertebra at T6-T9, block vertebrae of T4 and T5, and intrathoracic myelomeningocele. She underwent an anterior closing wedge osteotomy and posterior correction of scoliosis without removal of the sac. RESULTS: Four-year postoperative follow-up is uneventful. To date, our patient is the first patient who had scoliosis correction surgery for the rare presentation of a myelomeningocele in the thoracic spine without removal of the sac. CONCLUSIONS: To the best of our knowledge, this is the only case of anterior thoracic myelomeningocele with scoliosis in the literature who had undergone a surgical correction of the scoliosis with osteotomy without removal of the sac. Although rare, these curves are well amenable to surgical correction of scoliosis, thereby improving endurance and functional lung capacity. PMID- 21296288 TI - Epidural block-induced ligamentum flavum hematoma mimicking epidural hematoma in the lumbar spine: a case report. AB - BACKGROUND CONTEXT: The ligamentum flavum may undergo various pathologic changes, including hypertrophy, calcification, ossification, and cyst formation. Ligamentum flavum hematoma (LFH) is a rare cause of spinal nerve root or cord compression and usually occurs in the lumbar spine. We report a 66-year-old woman with LFH occurring after an epidural block, mimicking epidural hematoma on lumbar spine magnetic resonance imaging (MRI). PURPOSE: To document MRI findings of epidural block-induced LFH mimicking epidural hematoma. STUDY DESIGN/SETTING: A case report. METHODS: A 66-year-old woman presented with a 6-month history of pain in the left buttock and suffered abrupt weakness and numbness in her left leg after an epidural block procedure without any other trauma history. Lumbar spine MRI with enhancement showed a hematoma-like mass in the posterior epidural space at L3-L4 level. RESULTS: The patient underwent a left hemilaminectomy at the L3 level, and a surgeon found a small hematoma between inner and outer walls of ligamentum flavum instead of an epidural hematoma and performed the removal of the hypertrophied ligamentum flavum including the intraligamentary lesion. Histopathologic examination confirmed the lesion as hematoma in the left ligamentum flavum. After surgery, the patient recovered without significant neurologic deficit. CONCLUSIONS: Epidural block-induced LFH can mimic posterior epidural hematoma on MRI. Careful evaluation of hematoma, location, and imaging findings is required for accurate diagnosis. PMID- 21296289 TI - A rare calcified thrombosis of the dilated epidural venous plexus presenting with lumbar radiculopathy: a case report. AB - BACKGROUND CONTEXT: Lumbar radiculopathies may occur in the course of many diseases but are rarely caused by abnormalities or pathologic changes in the epidural venous plexus. We describe a patient with lumbar radiculopathy attributable to a thrombolith of the epidural venous plexus, as diagnosed by computed tomography (CT) and magnetic resonance imaging (MRI), and who was treated by hemilaminectomy and removal of the thrombolith. PURPOSE: To document the first report of thrombolith in the dilated vertebral epidural venous plexus presenting as a lumbar radiculopathy. STUDY DESIGN/SETTING: A case report and literature review. METHODS: A 72-year-old woman presented with a 2-year history of back pain radiating to the left buttock without a history of any trauma. Lumbar spinal CT and MRI showed a calcified lesion in the left epidural space at the L1 level. RESULTS: The patient was treated by hemilaminectomy at the T12-L1 level and left epidural mass excision. Histopathology confirmed a thrombolith in the left epidural malformed venous plexus. CONCLUSIONS: A thrombolith causing a lumbar radiculopathy in the dilated epidural venous plexus is a rare condition. If CT or MRI shows a vertebral epidural calcified lesion, an epidural venous thrombolith may be included in the differential diagnosis. PMID- 21296290 TI - Aberrant right subclavian artery encountered during debridement of T2 osteomyelitis and associated phlegmon. AB - BACKGROUND CONTEXT: An aberrant right subclavian artery is a rare congenital abnormality of the aortic arch. The anomalous origin for the right subclavian artery arises as the last branch of the thoracic aorta. In the most common anomalous form, the right subclavian artery passes posterior to both the esophagus and trachea as it crosses midline to supply the right upper extremity. The aberrant right subclavian artery is often not symptomatic, but it can cause dysphagia. PURPOSE: To describe a case of an aberrant right subclavian artery discovered during debridement of T2 osteomyelitis. STUDY DESIGN: Case report. METHODS: A 49-year-old woman with diabetes was transferred to our institution with bilateral lower extremity weakness and incontinence of bowel and bladder function. Examination revealed no motor function in quadriceps, hamstrings, tibialis anterior, extensor hallucis longus, or gastrocsoleus complex of her bilateral lower extremities. RESULTS: Spinal computed tomography scan showed pathologic collapse of the T2 vertebra. Magnetic resonance (MR) demonstrated an abscess and a phlegmon anterior to T2. Magnetic resonance also demonstrated spinal cord compression at the T2 vertebral level, and T2-weighted MR demonstrated the presence of spinal cord signal changes. CONCLUSIONS: We report a rare case where an aberrant right subclavian artery was associated with a T2 osteomyelitis and paravertebral abscess. The intraoperative injury to this aberrant artery led to the eventual death of the patient. When planning an anterior approach to the upper thoracic region, surgeons should be aware of this anatomic variant of the subclavian artery and its associated aberrant recurrent laryngeal nerve. PMID- 21296291 TI - Intradiscal treatment of back pain. PMID- 21296292 TI - Something is amiss. AB - Commentary on: Cao P, Jiang L, Zhuang C, et al. Intradiscal injection therapy for degenerative chronic discogenic low back pain with end plate Modic changes. Spine J 2011:11:100-106 (in this issue). PMID- 21296293 TI - Modic changes and intradiscal steroids. AB - Commentary on: Cao P, Jiang L, Zhuang C, et al. Intradiscal injection therapy for degenerative chronic discogenic low back pain with end plate Modic changes. Spine J 2011;11:100-106 (in this issue). PMID- 21296294 TI - A "simple" option in the surgical treatment of congenital scoliosis. AB - Commentary on: Li X-F, Liu Z-D, Hu G-Y, et al. Posterior unilateral pedicle subtraction osteotomy of hemivertebra for correction of the adolescent congenital spinal deformity. Spine J 2011;11:111-118 (in this issue). PMID- 21296295 TI - An evaluation of the learning curve for a complex surgical technique: the full endoscopic interlaminar approach for lumbar disc herniations. AB - BACKGROUND CONTEXT: Compared with conventional microsurgical technique, the full endoscopic (FE) interlaminar approach is a more minimally invasive technique for the surgical treatment of lumbar disc herniations. Its efficacy and safety have been confirmed by numerous studies. However, a steep learning curve with the use of such a complex technique is a major concern for the initial adoption of this technique. PURPOSE: To evaluate the learning curve of using an FE interlaminar technique for the surgical treatment of lumbar disc herniation. STUDY DESIGN: A prospective study of patients with lumbar disc herniation who underwent discectomy via interlaminar approach assisted by FE instruments. PATIENT SAMPLE: Thirty patients with lumbar disc herniation underwent discectomy using an interlaminar endoscopic-only approach between 2008 and 2009. METHODS: The patients were divided into three groups of 10 sequential cases each. Group A consisted of the first 10 cases, Group B the subsequent 10 cases, and Group C the last 10 cases. The clinical evaluation data included operative time, length of hospital stay, visual analog scale (VAS) leg and back pain scores, complications, and rate of conversion to an open. RESULTS: All patients were observed prospectively for 1.61 +/- 0.22 years (range, 1.2-2.0 years). There was no measurable intraoperative bleeding and postoperative infections in the three groups. Compared with Group A, the operative time in Group B was significantly decreased (p < .001). The patients in Group C had much less operative time than in Group B (p = .002). There was no significant difference with length of hospital stay in the three groups (p = .897). The improvement of VAS leg and back pain scores in each group was similar: there was a significant improvement (p < .01) at 3 months after surgery when compared with preoperative scores, but there was no statistical difference (p > .05) in the VAS leg and back pain scores between 3 months after surgery and final follow-up. The complication rate was 12.5% for Group A, 10% for Group B, and 0% for Group C. The need for conversion to an open procedure for Group A was 20% compared with zero cases in both Groups B and C. There were no symptomatic recurrences in our study. CONCLUSIONS: Excellent clinical and minimally invasive outcomes can be obtained in the surgical treatment of lumbar disc herniation via the interlaminar approach assisted by FE technique. However, attention must be paid to the steep learning curve by using this complex technique. Imprecise anatomic orientation and manipulation inside the spinal canal are key factors in the steep learning curve. Obtaining microsurgical experience, attending workshops, and suitable patient selection can help shorten the learning curve and decrease the complications. PMID- 21296296 TI - A steep learning curve is a good thing! AB - Commentary on: Wang B, Lu G, Patel AA, et al. An evaluation of the learning curve for a complex surgical technique: the full endoscopic interlaminar approach for lumbar disc herniations. Spine J 2011:11:122-130 (in this issue). PMID- 21296297 TI - Direct repair of spondylolysis presenting after correction of adolescent idiopathic scoliosis. AB - BACKGROUND CONTEXT: Although spondylolysis is found in 6% of idiopathic scoliosis patients, very little was reported on management of pars defects in this group. These patients with painful spondylolysis are most eligible for direct repair of the defect rather than lumbosacral fusion in an attempt to save motion segments. PURPOSE: The aim of this work was to analyze the clinical and radiologic outcome of pars repair in a group of adolescents who presented after surgical correction of their idiopathic scoliosis. STUDY DESIGN: A prospective nonrandomized study. PATIENT SAMPLE: Ten consecutive patients with spondylolysis presenting after an average of 3 months (range, 2-7 months) from correction of their idiopathic scoliosis with low back pain not responding to conservative therapy and interfering with everyday activities. The mean age at operation was 16 years (range, 14-19 years). OUTCOME MEASURES: Total blood loss, operative time, and hospital stay were recorded. Clinical outcome was assessed by the Oswestry Disability Index (ODI), visual analog scale (VAS), and Scoliosis Research Society (SRS)-22 questionnaire. Fusion of the pars interarticularis was assessed using plain, lateral, and oblique radiographs and a computed tomography (CT) scan. METHODS: The surgical technique consisted of thorough debridement of the defect, impacting the gap created with a tricortical iliac crest graft, and rigid fixation by either pedicle screws and a V-shaped rod (five patients) or a cable screw construct (five patients). RESULTS: Patients were followed up for an average of 4.5 years (range, 2-7 years). Nine patients had a good-to-excellent result, returned to normal everyday life, and participated in sports when desired. The mean ODI, VAS, and SRS total scores were 11 (range, 0-34), 1.1 (range, 0-2), and 92 (range, 61-108), respectively. Follow-up radiographs and CT scans revealed healing of all defects in nine cases, no signs of disc degeneration in any, and no implant-related complications. CONCLUSIONS: The results of direct repair of spondylolysis in idiopathic scoliosis patients were very satisfactory both clinically and radiologically. Direct repair appears to be a logical alternative to spinal fusion; lumbar spine mobility was preserved, and precocious motion segments were saved with a relatively simple operation. PMID- 21296298 TI - Bupivacaine decreases cell viability and matrix protein synthesis in an intervertebral disc organ model system. AB - BACKGROUND CONTEXT: Bupivacaine is a local anesthetic commonly used for back pain management in interventional procedures. Cytotoxic effects of bupivacaine have been reported in articular cartilage and, recently, in intervertebral disc cell culture. However, the relevance of these effects to discs in vivo remains unclear. This study examines the effect of bupivacaine on disc cell metabolism using an organotypic culture model system that mimics the in vivo environment. PURPOSE: To assess the effect of bupivacaine on disc cell viability and matrix protein synthesis using an organotypic model system and to determine whether this anesthetic has toxic effects. STUDY DESIGN: Mouse intervertebral discs were isolated and maintained ex vivo in an organotypic culture then exposed to clinically relevant concentrations of bupivacaine, and the impact on disc cell viability and matrix proteoglycan (PG) and collagen syntheses were measured in the presence and absence of the drug. SUBJECTS: Mouse functional spine units (FSUs) were isolated from the lumbar spines of 10-week-old mice. OUTCOME MEASURES: Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. Total PG and collagen syntheses were determined by measuring the incorporation of radioactive (35)S-sulfate and (3)H-l proline into PG and collagen, respectively. METHODS: Organotypic cultures of mouse FSUs were exposed to different concentrations (0%-0.5%) of bupivacaine for variable amounts of time (0-2 hours). Cell viability within disc tissue was quantified by MTT staining and histologic assay. Matrix protein synthesis was measured by incorporation of radioactive (35)S-sulfate (for PG synthesis) and (3)H-l-proline (for collagen synthesis). RESULTS: Untreated mouse disc organs were maintained in culture for up to 1 month with minimal changes in tissue histology, cell viability, and matrix protein synthesis. Exposure to bupivacaine decreased cell viability in a dose- and time-dependent manner. Exposure to bupivacaine at concentrations less than or equal to 0.25% did not significantly affect matrix protein synthesis. However, at 0.5% bupivacaine, collagen synthesis was reduced by fourfold and PG synthesis by threefold. CONCLUSIONS: Mouse discs can be successfully maintained ex vivo for upward of 4 weeks with little cell death, change in histologic structure, or matrix protein synthesis. This organotypic model system closely mimics the in vivo environment of the disc. Exposure of these cultures to bupivacaine dramatically decreased cell viability and matrix protein synthesis in a dose- and time-dependent manner. These findings corroborate those previously reported by Lee et al. using disc cell culture and demonstrate that this anesthetic at clinically relevant doses is toxic to intervertebral discs in both cell culture and disc organ models representative of the native architectural context. PMID- 21296299 TI - The effect of methylene blue on peridural fibrosis formation after laminectomy in rats: an experimental novel study. AB - BACKGROUND CONTEXT: Despite progress in surgical techniques, some patients still face postoperative recurrence of pain, although the rate of successful outcomes is estimated to be approximately 70% and 86% after primary decompression spinal surgery. Recently, attention has been focused on peridural fibrosis (PF), which may be responsible for recurrent pain after laminectomy or discectomy. Methylene blue (MB) has been shown to prevent fibrosis formation in various tissues. PURPOSE: The aims of this study were to investigate the effects of MB and assess the effects of different doses on the prevention of postlaminectomy fibrosis formation in a rat model. This preclinical model is a potential platform for future clinical trials to identify an effective agent for the prevention of clinically important epidural scar formation. STUDY DESIGN: An established bilateral L5-L6 rat laminectomy model was used to evaluate postlaminectomy PF with macroscopic and microscopic analyses. PATIENT SAMPLE: Seventy-five male adult white Sprague-Dawley rats that underwent laminectomy at the L5-L6 levels were divided into five groups of 15 rats each. OUTCOME MEASURES: Dissected specimens were evaluated macroscopically and microscopically by examiners who were unaware of the group assignment to record the presence or absence of PF formation. METHODS: Groups A and B served as controls and Groups C, D, and E received treatment. Group A (sham) underwent laminectomy, and Group B was treated with normal saline at the laminectomy site. Rats in Groups C, D, and E received 0.1 mL MB at concentrations of 0.5%, 1%, and 2%, respectively, at the laminectomy site. All rats were killed 4 weeks after laminectomy. The results were compared statistically with the nonparametric Kruskal-Wallis test and Poisson regression. RESULTS: Peridural fibrosis was found in five rats (33%) in control Groups A and B and in two rats (10%) in MB-treated laminectomy Groups C and D. The difference between control and MB groups was not statistically significant (p = .27). The preventive effect of MB on PF was not seen at the highest dose of MB (2%) in Group E. Severity of fibrosis was lower in Groups C (MB 0.5%) and D (MB 1%) than in Group E (MB 2%) (p < .01). Wound healing was not affected, and there was no cerebrospinal fluid leakage. No neurological deficits were seen. CONCLUSION: Low doses of MB may be an effective agent in preventing PF formation after lumbar laminectomy in rats. Clinical significance and safety in human use are currently undetermined. PMID- 21296300 TI - Traumatic pneumorrhachis: etiology, pathomechanism, diagnosis, and treatment. AB - BACKGROUND CONTEXT: Traumatic pneumorrhachis (PR) is a rare entity, consisting of air within the spinal canal. It can be classified as epidural or subarachnoid, identifying the anatomical space where the air is located, and is associated with different etiologies, pathology, and treatments. PURPOSE: To conduct a systematic review of the scientific literature focused on the etiology, pathomechanism, diagnosis, and treatment of PR, and to report a case of an asymptomatic epidural type. STUDY DESIGN: International medical literature has been reviewed systematically for the term "traumatic pneumorrhachis" and appropriate related subject headings, such as traumatic intraspinal air, traumatic intraspinal pneumocele, traumatic spinal pneumatosis, traumatic spinal emphysema, traumatic aerorachia, traumatic pneumosaccus, and traumatic air myelogram. All cases that were identified were evaluated concerning their etiology, pathomechanism, and possible complications. SAMPLES: Studies that included one of the aforementioned terms in their titles. METHODS: A systematic review was performed to identify, evaluate, and summarize the literature related to the term "traumatic pneumorrhachis" and related headings. Furthermore, we report a rare case of an asymptomatic epidural PR extending to the cervical and thoracic spinal canal. We present the current data regarding the etiology, pathomechanism, diagnosis, and treatment modalities of patients with PR. RESULTS: The literature review included 37 related articles that reported 44 cases of traumatic PR. Only isolated case reports and series of no more than three cases were found. In 21 cases, the air was located in the epidural space, and in 23 cases, it was in the subarachnoid space. Most of the cases were localized to a specific spinal region. However, eight cases extending to more than one spinal region have been reported. CONCLUSIONS: Traumatic PR is an asymptomatic rare clinical entity and often is underdiagnosed. It usually resolves by itself without specific treatment. We stress the significance of this information to trauma specialists, so that they may better differentiate between epidural and subarachnoid PR. This is of great significance because subarachnoid PR is a marker of severe injury. The management of traumatic PR has to be individualized and frequently requires multidisciplinary treatment, involving head, chest, and/or abdomen intervention. PMID- 21296301 TI - Low back pain: we cannot afford ignoring work. PMID- 21296303 TI - Letter to the editor regarding: Dua K, Kepler CK, Huang RC, Marchenko A. Vertebral body fracture after anterolateral instrumentation and interbody fusion in two osteoporotic patients. Spine J 2010;10:e11-5. PMID- 21296304 TI - Could chronic host inflammatory response be responsible for delayed onset of retrograde ejaculation after the labeled use of recombinant human bone morphogenetic protein-2? PMID- 21296306 TI - Hyperfunctional parathyroid carcinoma with mediastinal extension. AB - Parathyroid carcinoma (PC) is an extremely rare malignancy, 0.005% of all tumours and between 0.5% and 5% of all parathyroid neoplasms. Preoperative diagnosis is often difficult and is almost always obtained only after post-surgical histopathology. The prognosis is related to the local extent of disease and to complete surgical resection of the tumour. We report an uncommon case of hyperfunctional PC with mediastinal extension, emphasising the diagnostic difficulties, histopathological features and treatment strategies. The most recent data in the literature is analysed as well. PMID- 21296307 TI - Response-repetition effects in task switching - dissociating effects of anatomical and spatial response discriminability. AB - In task switching, response repetitions typically lead to performance benefits for task repetitions but costs for task switches. We examined whether this cost benefit pattern is affected by response discriminability (RD), varying (a) the anatomical response separation (within-hand vs. between-hand responses) and (b) the spatial separation (close vs. far response keys). We assumed that anatomical RD increases response competition generally, whereas spatial RD increases the salience of left-right coding and thus facilitates response selection. In two experiments, we found that spatial RD increased the response-repetition costs in task switches but similarly decreased the response-repetition benefit in task repetitions. The effect of spatial RD was response-specific but did not interact with task switching. This data pattern is consistent with a recent account that proposed that facilitated response selection increases response "self-inhibition" after response execution. In contrast, the influence of anatomical RD primarily consisted of an overall increase of reaction-time level in all conditions, whereas error rates decreased, suggesting a general shift in response criterion. Taken together, the data suggest that a self-inhibition mechanism on the level of motor response codes contributes to response-repetition effects in task switching, which is possibly independent of task-specific mechanisms of strengthening of associations. PMID- 21296308 TI - Visual search and visual world: interactions among visual attention, language, and working memory (introduction to the special issue). PMID- 21296309 TI - [Bluish papules on the forehead]. PMID- 21296310 TI - [Rosacea triggered by a vitamin B complex supplement]. PMID- 21296311 TI - [Contact dermatitis in children - a review of current opinions]. AB - In the not so distant past, in the United States contact dermatitis was considered to be a condition that affected mainly adults. The diagnosis was certainly less often rendered in pediatrics, mainly because it was believed that a child's immune system was immature and that children were generally exposed to fewer allergens. With this in mind, we can attribute the low prevalence formerly reported for this disease partly to the fact that most affected children were not (and are still not) evaluated using appropriate skin tests. Patch testing in children requires certain modifications, but the international literature of the last decade and US data published in the past year indicate that contact dermatitis is a common condition in the pediatric population and that the prevalence is similar in children and adults. PMID- 21296312 TI - ? PMID- 21296313 TI - Charge heterogeneity of surfaces: mapping and effects on surface forces. AB - The DLVO theory treats the total interaction force between two surfaces in a liquid medium as an arithmetic sum of two components: Lifshitz-van der Waals and electric double layer forces. Despite the success of the DLVO model developed for homogeneous surfaces, a vast majority of surfaces of particles and materials in technological systems are of a heterogeneous nature with a mosaic structure composed of microscopic and sub-microscopic domains of different surface characteristics. In such systems, the heterogeneity of the surface can be more important than the average surface character. Attractions can be stronger, by orders of magnitude, than would be expected from the classical mean-field DLVO model when area-averaged surface charge or potential is employed. Heterogeneity also introduces anisotropy of interactions into colloidal systems, vastly ignored in the past. To detect surface heterogeneities, analytical tools which provide accurate and spatially resolved information about material surface chemistry and potential - particularly at microscopic and sub-microscopic resolutions - are needed. Atomic force microscopy (AFM) offers the opportunity to locally probe not only changes in material surface characteristic but also charges of heterogeneous surfaces through measurements of force-distance curves in electrolyte solutions. Both diffuse-layer charge densities and potentials can be calculated by fitting the experimental data with a DLVO theoretical model. The surface charge characteristics of the heterogeneous substrate as recorded by AFM allow the charge variation to be mapped. Based on the obtained information, computer modeling and simulation can be performed to study the interactions among an ensemble of heterogeneous particles and their collective motions. In this paper, the diffuse-layer charge mapping by the AFM technique is briefly reviewed, and a new Diffuse Interface Field Approach to colloid modeling and simulation is briefly discussed. PMID- 21296314 TI - Clouding behaviour in surfactant systems. AB - A study on the phenomenon of clouding and the applications of cloud point technology has been thoroughly discussed. The phase behaviour of clouding and various methods adopted for the determination of cloud point of various surfactant systems have been elucidated. The systems containing anionic, cationic, nonionic surfactants as well as microemulsions have been reviewed with respect to their clouding phenomena and the effects of structural variation in the surfactant systems have been incorporated. Additives of various natures control the clouding of surfactants. Electrolytes, nonelectrolytes, organic substances as well as ionic surfactants, when present in the surfactant solutions, play a major role in the clouding phenomena. The review includes the morphological study of clouds and their applications in the extraction of trace inorganic, organic materials as well as pesticides and protein substrates from different sources. PMID- 21296315 TI - Comparison of inhaled nitric oxide versus oxygen on hemodynamics in patients with mitral stenosis and severe pulmonary hypertension after mitral valve surgery. AB - Pulmonary hypertension represents an important cause of morbidity and mortality in patients with mitral stenosis who undergo cardiac surgery, especially in the postoperative period. The aim of this study was to test the hypothesis that inhaled nitric oxide (iNO) would improve the hemodynamic effects and short-term clinical outcomes of patients with mitral stenosis and severe pulmonary hypertension who undergo cardiac surgery in a randomized, controlled study. Twenty-nine patients (4 men, 25 women; mean age 46 +/- 2 years) were randomly allocated to receive iNO (n = 14) or oxygen (n = 15) for 48 hours immediately after surgery. Hemodynamic data, the use of vasoactive drugs, duration of stay, and short-term complications were assessed. No differences in baseline characteristics were observed between the groups. After 24 and 48 hours, patients receiving iNO had a significantly greater increase in cardiac index compared to patients receiving oxygen (p <0.0001). Pulmonary vascular resistance was also more significantly reduced in patients receiving iNO versus oxygen (-117 dyne/s/cm(5), 95% confidence interval -34 to -200, vs 40 dyne/s/cm(5), 95% confidence interval -34 to 100, p = 0.005) at 48 hours. Patients in the iNO group used fewer systemic vasoactive drugs (mean 2.1 +/- 0.14 vs 2.6 +/- 0.16, p = 0.046) and had a shorter intensive care unit stay (median 2 days, interquartile range 0.25, vs median 3 days, interquartile range 7, p = 0.02). In conclusion, iNO immediately after surgery in patients with mitral stenosis and severe pulmonary hypertension improves hemodynamics and may have short-term clinical benefits. PMID- 21296316 TI - Effectiveness of the relative lymphocyte count to predict one-year mortality in patients with acute heart failure. AB - Several works have endorsed a significant role of the immune system and inflammation in the pathogenesis of heart failure. As indirect evidence, an association between a low relative lymphocyte count (RLC%) and worse outcomes found in this population has been suggested. Nevertheless, the role of RLC% for risk stratification in a large and nonselected population of patients with acute heart failure (AHF) has not yet been determined. Thus, the aim of this study was to determine the association between low RLC% and 1-year mortality in patients with AHF and consequently to define whether it has any role for early risk stratification. A total of 1,192 consecutive patients admitted for AHF were analyzed. Total white blood cell and differential counts were measured on admission. RLC% (calculated as absolute lymphocyte count/total white blood cell count) was categorized in quintiles and its association with all-cause mortality at 1 year assessed using Cox regression. At 1 year, 286 deaths (24%) were identified. A negative trend was observed between 1-year mortality rates and quintiles of RLC%: 31.5%, 27.2%, 23.1%, 23%, and 15.5% in quintiles 1 to 5, respectively (p for trend <0.001). After thorough covariate adjustment, only patients in the lowest quintile (<9.7%) showed an increased risk for mortality (hazard ratio 1.76, 95% confidence interval 1.17 to 2.65, p = 0.006). When RLC% was modeled with restricted cubic splines, a stepped increase in risk was observed patients in quintile 1: those with RLC% values <7.5% and <5% showed 1.95 and 2.66-fold increased risk for death compared to those in the top quintile. In conclusion, in patients with AHF, RLC% is a simple, widely available, and inexpensive biomarker, with potential for identifying patients at increased risk for 1-year mortality. PMID- 21296317 TI - Comparison of dual drug-eluting Cilotax stent and paclitaxel-eluting Taxus Liberte stent in native coronary artery lesions. AB - Cilotax stent is a new type of drug-eluting stent (DES) designed to increase the antirestenotic performance of the paclitaxel-eluting stent and decrease the risk of stent thrombosis by the incorporation of cilostazol. Therefore, we investigated the safety and efficacy of Cilotax dual DESs and compared their performance to that of paclitaxel-eluting Taxus Liberte. Patients undergoing percutaneous coronary intervention for de novo coronary artery lesions at 2 centers in Korea were randomized to receive Cilotax (n = 55) or Taxus Liberte (n = 56) stents. The primary end point was in-segment late loss at 8 months. The 2 groups had similar baseline characteristics. Cilotax stent was not inferior to Taxus Liberte stent as determined by in-segment late loss (0.28 +/- 0.30 vs 0.42 +/- 0.45 mm, difference -0.14, 95% confidence interval -0.27 to -0.01, 1-sided p = 0.028 for noninferiority). In-stent late loss was significantly lower in the Cilotax than in the Taxus Liberte group (0.22 +/- 0.31 vs 0.50 +/- 0.55 mm, p = 0.002). Although in-segment restenosis rate did not differ significantly between the 2 groups (3.8% vs 10.9%, respectively, p = 0.271), in-stent restenosis rate was significantly lower in the Cilotax stent group (0% vs 10.9%, p = 0.027). There was no stent thrombosis at 8 months in either group. Rates of death, myocardial infarction, and any target lesion revascularization at 8 months were 0%, 0%, and 1.9%, respectively, in the Cilotax group and 1.8%, 0% and 3.6%, respectively, in the Taxus Liberte group. In conclusion, the Cilotax stent was safe and effective in decreasing late loss, indicating that this stent represents a promising new type of DES system. PMID- 21296318 TI - Relation between high-density lipoprotein cholesterol and survival to age 85 years in men (from the VA normative aging study). AB - No previous researchers have sought to determine whether high-density lipoprotein (HDL) cholesterol levels are associated with survival to 85 years of age in a prospective cohort of aging men. We selected 652 men (mean age 65 years) enrolled in the VA Normative Aging Study who had >= 1 HDL cholesterol level documented during the study and who were old enough on the date of HDL cholesterol measurement to reach 85 years of age by the end of follow-up (July 1, 2008). We categorized initial HDL cholesterol into < 40 mg/dl (reference group), 40 to 49 mg/dl, or >= 50 mg/dl. Information on co-morbidities, lifestyle factors, measured lipid parameters, and medications were collected during triennial visits. We used proportional hazards to determine hazard ratios (HRs) for mortality before age 85 years for each category of initial HDL cholesterol compared to the reference adjusting for co-morbidities, calculated low-density lipoprotein cholesterol, medications, smoking, body mass index, and alcohol consumption. Treating HDL cholesterol as a continuous predictor, we also determined the HR for each 10 mg/dl increment in HDL cholesterol. Fully adjusted HR (95% confidence interval) for survival to 85 years of age for participants with an initial HDL cholesterol level >= 50 mg/dl compared to the reference was 0.72 (0.53 to 0.98). Each 10 mg/dl increment in HDL cholesterol was associated with a 14% (HR 0.86, 0.78 to 0.96) decrease in risk of mortality before 85 years of age. In conclusion, after adjusting for other factors associated with longevity, higher HDL cholesterol levels were significantly associated with survival to 85 years of age. PMID- 21296319 TI - Relation of baseline systolic blood pressure and long-term outcomes in ambulatory patients with chronic mild to moderate heart failure. AB - We studied the impact of baseline systolic blood pressure (SBP) on outcomes in patients with mild to moderate chronic systolic and diastolic heart failure (HF) in the Digitalis Investigation Group trial using a propensity-matched design. Of 7,788 patients, 7,785 had baseline SBP data and 3,538 had SBP <= 120 mm Hg. Propensity scores for SBP <= 120 mm Hg, calculated for each of the 7,785 patients, were used to assemble a matched cohort of 3,738 patients with SBP <= 120 and >120 mm Hg who were well-balanced in 32 baseline characteristics. All cause mortality occurred in 35% and 32% of matched patients with SBPs <= 120 and >120 mm Hg respectively, during 5 years of follow-up (hazard ratio [HR] when SBP <= 120 was compared to >120 mm Hg 1.10, 95% confidence interval [CI] 0.99 to 1.23, p = 0.088). HRs for cardiovascular and HF mortalities associated with SBP <= 120 mm Hg were 1.15 (95% CI 1.01 to 1.30, p = 0.031) and 1.30 (95% CI 1.08 to 1.57, p = 0.006). Cardiovascular hospitalization occurred in 53% and 49% of matched patients with SBPs <= 120 and > 120 mm Hg, respectively (HR 1.13, 95% CI 1.03 to 1.24, p = 0.008). HRs for all-cause and HF hospitalizations associated with SBP <= 120 mm Hg were 1.10 (95% CI 1.02 to 1.194, p = 0.017) and 1.21 (95% CI 1.07 to 1.36, p = 0.002). In conclusion, in patients with mild to moderate long-term systolic and diastolic HF, baseline SBP <= 120 mm Hg was associated with increased cardiovascular and HF mortalities and all-cause, cardiovascular, and HF hospitalizations that was independent of other baseline characteristics. PMID- 21296320 TI - G protein-coupled receptor kinase 2 in patients with acute myocardial infarction. AB - Lymphocyte G protein-coupled receptor kinase 2 (GRK2) levels are increased in patients with chronic heart failure, and in this condition, they correlate with cardiac function. The aim of this study was to assess the prognostic role of GRK2 during acute cardiac dysfunction in humans. A study was designed to investigate the role of GRK2 levels in patients with acute coronary syndromes. Lymphocyte GRK2 levels were examined at admission and after 24 and 48 hours in 42 patients with acute coronary syndromes, 32 with ST-segment elevation myocardial infarction and 10 with unstable angina as a control group. Echocardiographic parameters of systolic and diastolic function and left ventricular remodeling were evaluated at admission and after 2 years. GRK2 levels increased during ST-segment elevation myocardial infarction and were associated with worse systolic and diastolic function. This association held at 2-year follow-up, when GRK2 was correlated with the ejection fraction and end-systolic volume, indicating a prognostic value for GRK2 levels during acute ST-segment elevation myocardial infarction. In conclusion, lymphocyte GRK2 levels increase during acute myocardial infarction and are associated with worse cardiac function. Taken together, these data indicate that GRK2 could be predictive of ventricular remodeling after myocardial infarction and could facilitate the tailoring of appropriate therapy for high risk patients. PMID- 21296321 TI - Usefulness of red cell distribution width to predict mortality in patients with peripheral artery disease. AB - Increased red blood cell distribution width (RDW), a marker of anisocytosis, has been associated with adverse outcomes in multiple settings. Whether RDW is predictive of mortality in patients with peripheral artery disease (PAD) is unknown. We studied 13,039 consecutive outpatients (69.5 +/- 12.0 years of age, 60.9% men, 97.6% white) with PAD identified by noninvasive lower-extremity arterial testing at the Mayo Clinic from January 1997 through December 2007, with follow-up through September 2009. We defined PAD as a low (<= 0.9) or high (>= 1.4) ankle-brachial index (ABI). Cardiovascular risk factors and co-morbidities were ascertained using electronic medical record-based algorithms. RDW was obtained from the complete blood cell count drawn around the time of arterial evaluation. Mortality was ascertained using the Mayo electronic medical record and Accurint databases. Association of RDW with all-cause mortality was analyzed by multivariable Cox proportional hazards regression. During a median follow-up of 5.5 years, 4,039 (31.0%) deaths occurred (28.7% in low and 38.9% in high ABI subsets). After adjustment for age, gender, cardiovascular risk factors, and co morbidities, patients in the highest quartile of RDW (> 14.5%) had a 66% greater risk of mortality compared to the lowest quartile (< 12.8%, p < 0.0001); a 1% increment in RDW was associated with a 10% greater risk of all-cause mortality (hazard ratio 1.10, 95% confidence interval 1.08 to 1.12, p < 0.0001). The adjusted hazard ratio was similar in the low (1.10, 1.08 to 1.12) and high (1.09, 1.06 to 1.12) ABI subsets. In conclusion, RDW, a routinely available measurement, is an independent prognostic marker in patients with PAD. PMID- 21296322 TI - Acute changes in N-terminal pro-B-type natriuretic peptide during hospitalization and risk of readmission and mortality in patients with heart failure. AB - The level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a predictor of adverse events in patients with heart failure. We examined the relation between acute changes in NT-proBNP during a single hospitalization and subsequent mortality and readmission. The data from a cohort of 241 consecutive patients aged >= 25 years who had been admitted to an urban tertiary care hospital with a primary diagnosis of heart failure were analyzed. Creatinine and NT-proBNP were measured at admission and at discharge of the first admission. The patient demographics, co-morbidities, and length of stay were collected. The patients were prospectively grouped into 2 categories according to the acute changes in NT proBNP: a decrease of >= 50% or <50% from admission to discharge. The primary composite outcome was readmission or death within 1 year of the first hospital admission. The unadjusted hazard ratio of readmission/death was 1.40 (95% confidence interval 0.97 to 2.01; p = 0.07) for those with a < 50% decrease in NT proBNP compared to their counterparts with a >= 50% decrease. After adjustment for age, gender, race, and admission creatinine and NT-proBNP, the risk of readmission/death was 57% greater for those with a < 50% decrease (hazard ratio 1.57, 95% confidence interval 1.08 to 2.28; p = 0.02). An adjustment for co morbidity, length of stay, and left ventricular ejection fraction did not significantly change this relation. Reductions in NT-proBNP of < 50% during an acute hospitalization for heart failure might be associated with an increased hazard of readmission/death, independent of age, gender, race, creatinine, admission NT-proBNP, co-morbidities, left ventricular ejection fraction, and length of stay. In conclusion, patients with a < 50% reduction in NT-proBNP might benefit from more intensive medical treatment, monitoring, and follow-up. PMID- 21296323 TI - Ethical and legal views regarding deactivation of cardiac implantable electrical devices in patients with hypertrophic cardiomyopathy. AB - Little is known about patients' views surrounding the ethical and legal aspects of managing pacemakers (PMs) and implantable cardioverter-defibrillators (ICDs) near the end of life. Patients with hypertrophic cardiomyopathy (HC) are at heightened risk of sudden cardiac death and are common recipients of such devices. Patients with HC recruited from the membership of the Hypertrophic Cardiomyopathy Association were surveyed about their clinical histories, advance care planning, legal knowledge, and ethical beliefs relating to the withdrawal of PM and ICD therapy. The mean age of the 546 patients was 49.1 years, 47% were women, and 57% had ICDs. Only 46% of the respondents had completed an advance directive, only 51% had a healthcare proxy, and cardiac implantable electrical devices (CIEDs) were commonly not addressed in either (92% and 58%, respectively). Many patients characterized deactivating PMs or ICDs as euthanasia or physician-assisted suicide (29% for PMs and 17% for ICDs), and >50% expressed uncertainty regarding the legality of device deactivation. Patients viewed deactivation of ICDs and PMs as morally different from other life-sustaining therapies such as mechanical ventilation and dialysis, and these views varied substantially according to the CIED type (p <0.0001). The respondents expressed concerns regarding clinical conflicts related to religion, ethical and legal uncertainty, and informed consent. In conclusion, patients who have, or are eligible to receive, CIEDs might require improved advance care planning and education regarding the ethical and legal options for managing CIEDs at the end of life. PMID- 21296324 TI - Relation between heart rate and left ventricular mechanical dyssynchrony in patients with end-stage renal disease. AB - The effect of heart rate (HR) on left ventricular (LV) mechanical dyssynchrony has not been studied by phase analysis of myocardial perfusion imaging and has yielded conflicting results by echocardiography. We measured indexes of LV dyssynchrony by automated analysis of gated single-photon emission computed tomography in 140 patients with end-stage renal disease (ESRD) and 133 subjects with normal renal function (control group). Patients with abnormal perfusion pattern or QRS duration >120 ms were excluded. HR at time of acquisition of gated images was recorded. LV ejection fraction (EF), volumes, mass, and 2 indexes of dyssynchrony, phase SD and bandwidth, were derived. Almost 50% of patients in each group had an abnormal LVEF (<50%). HR at rest ranged from 48 to 113 beats/min (75 +/- 13). Patients with abnormal LVEF had a higher phase SD (30 +/- 13 degrees vs 22 +/- 11 degrees and 28 +/- 16 degrees vs 15 +/- 6 degrees for the ESRD and control groups, respectively, p <0.001 each) and higher histographic bandwidth (88 +/- 44 degrees vs 62 +/- 33 degrees and 80 +/- 49 degrees vs 43 +/- 14 degrees for the ESRD and control groups, p <0.001 each). Patients with ESRD and normal LVEF had higher SD and bandwidth than the control group (22 +/- 11 degrees vs 15 +/- 6 degrees and 62 +/- 33 degrees vs 43 +/- 14 degrees , respectively, p <0.001 each). The control and ESRD groups were divided into tertiles based on HR. The phase SD and bandwidth were similar in the first (slowest HR) and third (highest HR) tertiles in every group (p = NS). There were no significant correlations between phase SD or bandwidth and HR in either group. In conclusion, within the HR range examined in this cross-sectional study, there was no relation between HR at rest and LV dyssynchrony. PMID- 21296325 TI - Clinical profile, prognostic implication, and response to treatment of pulmonary hypertension in patients with severe aortic stenosis. AB - The incidence, correlates, and prognostic implications of pulmonary hypertension (PH) are unclear in patients with severe aortic stenosis (AS). We studied 509 patients with severe AS evaluated for transcatheter aortic valve implantation (TAVI). Patients were divided into groups based on pulmonary artery systolic pressure (PASP): group I, 161 (31.6%) with PASP <40 mm Hg; group II, 175 (34.3%) with PASP 40 to 59 mm Hg; and group III, 173 (33.9%) with PASP >= 60 mm Hg. Group III patients were more symptomatic and had higher creatinine levels and higher left ventricular end-diastolic pressure. Transpulmonary gradient was >12 mm Hg in 17 patients (10.5%), 31 patients (17.7%), and 80 patients (46.2%) in groups I through III, respectively. In a median follow-up of 202 days (73 to 446) mortality rates were 35 (21.7%), 69 (39.3%), and 85 (49.1%) in groups I through III, respectively (p <0.001). Immediately after TAVI, in patients with PASP >40 mm Hg there was significant decrease in PASP (63.1 +/- 16.2 to 48.8 +/- 12.4 mm Hg, p <0.0001), which remained at 1 year (50.1 +/- 13.1 mm Hg, p = 0.04). After surgical aortic valve replacement there was a significant immediate decrease in PASP (66.1 +/- 16.3 to 44.7 +/- 14.2 mm Hg, p <0.0001), which persisted at 3 to 12 months (44.8 +/- 20.1 mm Hg, p <0.001). In patients who underwent balloon aortic valvuloplasty, PASP decreased immediately after the procedure (63.2 +/- 14.8 to 51.8 +/- 17.1 mm Hg, p <0.0001), yet at 3 to 12 months pressure returned to baseline levels (57.4 +/- 17.0 mm Hg, p = 0.29). In conclusion, patients with severe AS have a high prevalence of PH, and in patients with severe AS increased PASP is associated with increased mortality. Surgical aortic valve replacement and TAVI are effective treatments for these patients and result in a significant PASP decrease. PMID- 21296326 TI - Comparison of three-year clinical outcomes after sirolimus-eluting stent implantation among insulin-treated diabetic, non-insulin-treated diabetic, and non-diabetic patients from j-Cypher registry. AB - The purpose of the present study was to evaluate the 3-year clinical outcomes after percutaneous coronary intervention with sirolimus-eluting stents in patients with insulin-treated diabetes mellitus (DM-insulin) and those with non insulin-treated DM (DM-non-insulin) compared to patients without DM. Of 10,778 consecutive patients treated exclusively with sirolimus-eluting stents in the j Cypher registry, we identified 996 patients with DM-insulin, 3,404 with DM-non insulin, and 6,378 without DM. Compared to the non-DM group, the adjusted risk of a serious cardiovascular event (composite of all-cause death, myocardial infarction, and stroke) was significantly greater in the DM-insulin group (hazard ratio 1.12, 95% confidence interval [CI] 1.03 to 1.23; p = 0.01), but not in the DM-non-insulin group (hazard ratio 1.02, 95% CI 0.96 to 1.09; p = 0.47). The adjusted risk of target lesion revascularization was significantly greater in both the DM-insulin group (odds ratio 1.52, 95% CI 1.19 to 1.92; p = 0.0006) and the DM-non-insulin group (odds ratio 1.24, 95% CI 1.05 to 1.45; p = 0.009). In conclusion, a diabetes-associated excess risk of target lesion revascularization was found, regardless of insulin use in this large, real-world study of Japanese patients with sirolimus-eluting stent implantation. However, regarding serious cardiovascular events, an excess risk was seen only in the DM-insulin group. The risk of serious cardiovascular events was similar between the DM-non-insulin and non-DM groups. PMID- 21296327 TI - Utility of left bundle branch block as a diagnostic criterion for acute myocardial infarction. AB - The clinical utility of new or "presumably new" left bundle branch block (LBBB) as an electrocardiographic criterion equivalent to ST-segment elevation myocardial infarction in contemporary practice is not well established. The aim of this study was to investigate the hypothesis that new or presumably new LBBB in symptomatic patients frequently leads to an overdiagnosis of acute myocardial infarction (AMI). A retrospective analysis of data from consecutive patients in the Mayo Clinic's ST-segment elevation myocardial infarction network from July 2004 to August 2009 was conducted among 892 patients, 36 (4%) of whom had new LBBB. The frequency, clinical characteristics, serum troponin levels, coronary angiographic findings, and outcomes of patients with new LBBB suspected of having AMI were evaluated. Compared with patients without LBBB (n = 856), those with new LBBB were older (64.5 vs 72.9 years, p < 0.001), had higher Thrombolysis In Myocardial Infarction (TIMI) risk scores (22.7 vs 31.0, p < 0.005), were less likely to undergo primary percutaneous coronary intervention (86% vs 22%, p < 0.001), and had longer door-to-balloon times. Only 14 patients (39%) had final diagnoses of acute coronary syndromes, of which 12 were AMI, while 13 (36%) had cardiac diagnoses other than acute coronary syndrome and 9 (25%) had noncardiac diagnoses. Of the patients with AMI, 5 had occluded culprit arteries, of which 2 involved the left anterior descending coronary artery. A Sgarbossa score >= 5 had low sensitivity (14%) but 100% specificity in diagnosing AMI in the presence of new LBBB. In conclusion, new or presumably new LBBB in patients suspected of having AMI identifies a high-risk subgroup, but only a small number have AMI. Two thirds of these patients are discharged from the hospital with alternative diagnoses. The Sgarbossa criteria appear to have limited utility in clinical practice because of their low sensitivity. PMID- 21296328 TI - Effect of left ventricular reverse remodeling on long-term prognosis after therapy with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers and beta blockers in patients with idiopathic dilated cardiomyopathy. AB - It remains unknown whether left ventricular (LV) reverse remodeling (LVRR) after therapy with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers and beta blockers is correlated with prognosis in patients with idiopathic dilated cardiomyopathy. Forty-two patients with idiopathic dilated cardiomyopathy treated with the therapy were studied. Complete left ventricular reverse remodeling was defined as LV end-diastolic dimension <= 55 mm and fractional shortening >= 25% at the last echocardiographic assessment. The incidence of complete LVRR was significantly higher in patients who survived than in those who died or underwent heart transplantation. Patients were divided into 3 groups: death or transplantation, alive with complete LVRR, and alive without complete LVRR. Although patients who died or underwent transplantation did not show any LV improvements, those with complete LVRR showed significant improvements at 1 to 6 months after starting the therapy. Patients without complete LVRR also showed small but significant improvements at 1 to 6 months. The decrease in LV end-systolic dimension from the initial value to that at 1 to 6 months was an independent determinant of future cardiac death or transplantation. In conclusion, complete LVRR is related to favorable prognosis in patients with idiopathic dilated cardiomyopathy. The extent of left ventricular reverse remodeling at 1 to 6 months after starting the therapy is predictive of long-term prognosis. PMID- 21296329 TI - Risk factors for the development and progression of carcinoid heart disease. AB - The development of valvular heart disease in patients with carcinoid syndrome is thought to be related to the secretion of vasoactive substances by a tumor. We sought to identify modifiable risk factors for the development of carcinoid heart disease because this may help define strategies to attenuate the disease process. Two hundred fifty-two patients with carcinoid syndrome were prospectively followed with serial echocardiograms at 6-month intervals. Clinical characteristics, biochemical markers, and radiologic markers were measured at set intervals. An echocardiographic scoring system was applied. Patients were defined as having progression of carcinoid heart disease if the echocardiographic score increased by >=25%. After a median follow-up of 29 months, 44 patients developed carcinoid heart disease or had progression of existing valvular dysfunction. At time of progression of carcinoid heart disease compared to the previous 6 months, there was a significant increase in median levels of 5-hydroxyindoleacetic acid (5-HIAA; 791 vs 460.5 MUmol/24 hours) and flushing episodes (4.5 vs 2 episodes per day). Independent predictors of the development or progression of carcinoid heart disease were a 5-HIAA level >= 300 MUmol/24 hours and >= 3 episodes of flushing per day. 5-HIAA levels of >= 300 to 599, 600 to 899, and > 900 MUmol/24 hours conferred 2.74, 3.16, and 3.40 times the risk of progression of carcinoid heart disease, respectively. In conclusion, a 5-HIAA level >= 300 MUmol/24 hours and >= 3 flushing episodes per day are predictors of the development or progression of carcinoid heart disease. PMID- 21296330 TI - Relation of myocardial mechanics in severe aortic stenosis to left ventricular ejection fraction and response to aortic valve replacement. AB - Decreased left ventricular (LV) longitudinal strain and increased circumferential LV strain have been demonstrated in patients with severe aortic stenosis (AS) and normal LV ejection fraction (LVEF). Biplane myocardial mechanics normalize after aortic valve replacement (AVR). This study objective was to examine LV mechanics before and soon after AVR in patients with AS and LV systolic dysfunction. Paired echocardiographic studies before and soon (7 +/- 3 days) after AVR were analyzed in 64 patients with severe AS: 32 with normal LVEF (>= 50%), 16 with mild to moderate LV dysfunction (LVEF <36% to 50%), and 16 with severe LV dysfunction (LVEF <= 35%). Longitudinal myocardial function was assessed from 3 apical views (average of 18 segments) and circumferential function was assessed at mid-LV and apical levels (average of 6 segments per view). Strain, strain rate, and mid-LV and apical rotations were measured using 2-dimensional velocity vector imaging. Before AVR (1) longitudinal strain was low in all patients and correlated with LVEF (rho = 0.74, p <0.001), (2) mid-LV circumferential strain was supranormal in patients with normal LVEF and low in patients with low LVEF (rho = 0.88, p <0.001), and (3) apical rotation was highest in patients with mild to moderate LV dysfunction. After AVR, LVEF increased in patients with LV dysfunction and myocardial mechanics partly normalized. In conclusion, compensatory mechanisms (high circumferential strain in patients with preserved LVEF and increased apical rotation in patients with mild to moderate LV dysfunction) were observed in patients with severe AS. Compensatory mechanics were lost in patients with severe LV dysfunction. AVR partly reversed these changes in patients with LV dysfunction. PMID- 21296331 TI - Significance of electrocardiographic right bundle branch block in trained athletes. AB - We sought to determine the clinical and physiologic significance of electrocardiographic complete right bundle branch block (CRBBB) and incomplete right bundle branch block (IRBBB) in trained athletes. The 12-lead electrocardiographic and echocardiographic data from 510 competitive athletes were analyzed. Compared to the 51 age-, sport type-, and gender-matched athletes with normal 12-lead electrocardiographic QRS complex duration, the 44 athletes with IRBBB (9%) and 13 with CRBBB (3%) had larger right ventricular (RV) dimensions, as measured by the basal RV end-diastolic diameter (CRBBB 43 +/- 3 mm, IRBBB 38 +/- 6 mm, normal QRS complex 35 +/- 4 mm, p <0.001) and RV end diastolic area (CRBBB 33 +/- 5, IRBBB 27 +/- 7, and normal QRS complex 23 +/- 3 cm(2); p <0.001). Athletes with CRBBB also had a relative reduction in the RV systolic function at rest as assessed by the RV fractional area change and peak systolic tissue velocity. Finally, QRS prolongation was associated with parallel increases in interventricular dyssynchrony (basal RV to basal lateral left ventricular peak systolic tissue velocity time difference: CRBBB 112 +/- 15, IRBBB 73 +/- 33, normal QRS complex 43 +/- 39 ms, p <0.001). Despite these findings, no athlete with CRBBB or IRBBB was found to have pathologic structural cardiac disease. In conclusion, among trained athletes, CRBBB and IRBBB appear to be markers of a structural and physiological cardiac remodeling triad characterized by RV dilation, a relative reduction in the RV systolic function at rest, and interventricular dyssynchrony. PMID- 21296332 TI - Meta-analysis of usefulness of d-dimer to diagnose acute aortic dissection. AB - Numerous studies have examined whether plasma D-dimer (DD) can be used to identify patients with acute aortic dissection (AAD). These studies have been inconclusive because of their limited sample sizes and the different cut-off values employed. We aimed to conduct a systematic review and meta-analysis to examine the utility of plasma DD as a screening tool for AAD. We systematically searched EMBASE and MEDLINE and hand-searched relevant articles to identify studies investigating plasma DD as a screening tool for AAD. A value of 500 ng/ml was defined as the threshold for a positive plasma DD finding because it is widely used for ruling out pulmonary emboli. Using DerSimonian-Laird random effects models we pooled data across studies to estimate sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios (LRs). We identified 7 studies involving 298 subjects with AAD and 436 without. When data were pooled across studies, sensitivity (0.97, 95% confidence interval [CI] 0.94 to 0.99) and negative predictive value (0.96, 95% CI 0.93 to 0.98) were high. Specificity (0.56, 95% CI 0.51 to 0.60) and positive predictive value (0.60, 95% CI 0.55 to 0.66) were low. Negative LR showed an excellent discriminative ability (0.06, 95% CI 0.03 to 0.12), whereas positive LR did not (2.43, 95% CI 1.89 to 3.12). In conclusion, our meta-analysis suggests that plasma DD <500 ng/ml is a useful screening tool to identify patients who do not have AAD. Plasma DD may thus be used to identify subjects who are unlikely to benefit from further aortic imaging. PMID- 21296333 TI - Rhythm- and rate-controlling effects of dronedarone in patients with atrial fibrillation (from the ATHENA trial). AB - Dronedarone is a multi-channel-blocking drug for the treatment of patients with atrial fibrillation (AF) or atrial flutter (AFL) with rate- and rhythm controlling properties. A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg b.i.d. for the Prevention of Cardiovascular Hospitalization or Death from Any Cause in Patients With Atrial Fibrillation/Atrial Flutter (ATHENA) demonstrated that dronedarone reduced the risk for first cardiovascular hospitalization or death from any cause. The aim of this post hoc analysis was to evaluate the rhythm- and rate-controlling properties of dronedarone in the ATHENA trial. Patients were randomized to dronedarone 400 mg twice daily (n = 2,301) or placebo (n = 2,327). Electrocardiographic tracings were classified for AF or AFL or sinus rhythm. Patients with AF or AFL on every postbaseline electrocardiogram were classified as having permanent AF or AFL. All electrical cardioversions were documented. The use of rate-controlling medications was equally distributed in the 2 treatment groups. The median time to first AF or AFL recurrence of patients in sinus rhythm at baseline was 498 days in placebo patients and 737 days in dronedarone patients (hazard ratio 0.749, 95% confidence interval 0.681 to 0.824, p <0.001). In the dronedarone group, 339 patients (15%) had >=1 electrical cardioversion, compared to 481 (21%) in the placebo group (hazard ratio 0.684, 95% confidence interval 0.596 to 0.786, p <0.001). The likelihood of permanent AF or AFL was lower with dronedarone (178 patients [7.6%]) compared to placebo (295 patients [12.8%]) (p <0.001). At the time of first AF or AFL recurrence, the mean heart rates were 85.3 and 95.5 beats/min in the dronedarone and placebo groups, respectively (p <0.001). In conclusion, dronedarone demonstrated both rhythm- and rate controlling properties in ATHENA. These effects are likely to contribute to the reduction of important clinical outcomes observed in this trial. PMID- 21296334 TI - Choriodecidua and amnion exhibit selective leukocyte chemotaxis during term human labor. AB - OBJECTIVE: The purpose of this study was to compare the chemotactic activity of the choriodecidua and amnion, and to identify the phenotype of the leukocytes chemoattracted by each tissue. STUDY DESIGN: Amnion, choriodecidua and whole fetal membranes extracts were obtained from women at term (>37 weeks of gestation) with or without labor (n = 5 each). Extracts were assayed for leukocyte chemotactic activity, and the number and phenotype of the chemoattracted leukocytes were characterized by flow cytometry. RESULTS: Although all of the extracts exhibited chemotactic activity, more leukocytes were chemoattracted by the choriodecidua and the whole fetal membranes during labor compared with no labor (P = .010, .008). During labor the choriodecidua is responsible for granulocyte, T-lymphocyte, monocyte, and natural killer-cell chemoattraction, and the amnion is responsible for B-lymphocyte chemoattraction. CONCLUSION: Choriodecidua and amnion exhibit chemotactic activity for selective leukocytes and thus, each fetal membrane differentially regulates leukocyte chemotactic activity during labor. PMID- 21296335 TI - Physiological and subjective evaluation of a human-robot object hand-over task. AB - In the context of task sharing between a robot companion and its human partners, the notions of safe and compliant hardware are not enough. It is necessary to guarantee ergonomic robot motions. Therefore, we have developed Human Aware Manipulation Planner (Sisbot et al., 2010), a motion planner specifically designed for human-robot object transfer by explicitly taking into account the legibility, the safety and the physical comfort of robot motions. The main objective of this research was to define precise subjective metrics to assess our planner when a human interacts with a robot in an object hand-over task. A second objective was to obtain quantitative data to evaluate the effect of this interaction. Given the short duration, the "relative ease" of the object hand over task and its qualitative component, classical behavioral measures based on accuracy or reaction time were unsuitable to compare our gestures. In this perspective, we selected three measurements based on the galvanic skin conductance response, the deltoid muscle activity and the ocular activity. To test our assumptions and validate our planner, an experimental set-up involving Jido, a mobile manipulator robot, and a seated human was proposed. For the purpose of the experiment, we have defined three motions that combine different levels of legibility, safety and physical comfort values. After each robot gesture the participants were asked to rate them on a three dimensional subjective scale. It has appeared that the subjective data were in favor of our reference motion. Eventually the three motions elicited different physiological and ocular responses that could be used to partially discriminate them. PMID- 21296336 TI - The effect of viewing angle on wrist posture estimation from photographic images using novice raters. AB - Observational assessment of wrist posture using photographic methods is theoretically affected by camera view angle. A study was conducted to investigate whether wrist flexion/extension and radial/ulnar deviation postures were estimated differently by raters depending on the viewing angle and compared to predictions using a quantitative 2D model of parallax. Novice raters (n=26) estimated joint angles from images of wrist postures photographed from ten different viewing angles. Results indicated that ideal views, orthogonal to the plane of motion, produced more accurate estimates of posture compared to non ideal views. The neutral (0 degrees ) posture was estimated the most accurately even at different viewing angles. Raters were more accurate than model predictions. Findings demonstrate a need for more systematic methods for collecting and analyzing photographic data for observational studies of posture. Renewed caution in interpreting existing studies of wrist posture where viewing angle was not controlled is advised. PMID- 21296337 TI - The interaction between skill, postures, forces and back pain in wool handling. AB - Wool handling is an important rural occupation where workers process 200 or more fleeces daily, separating them into various quality components. Loads and postures they experience carry substantial risk of low back pain (LBP). Although a formal skill training structure exists, interaction with loads and LBP is unknown. We examined whether skill and LBP influenced trunk postures and loads of 60 wool handlers representing 3 skill levels. LBP prevalence ranged from 20% for junior (lowest skill) to 45% for open class (highest skill) wool handlers. Open class wool handlers demonstrated increased lateral bend and more axially twisted postures, generating greater medio-lateral shear forces and lateral bend and axial twist moments. LBP was associated with open class wool handlers spending more time in severe axially twisted postures. These findings suggest that skill based training needs to be reviewed to reduce the quantity of axially twisted posture which may help reduce the prevalence of LBP in this workforce. PMID- 21296338 TI - Prevention of depression among Icelandic adolescents: a 12-month follow-up. AB - This paper reports the 12-month follow-up results regarding a program designed to prevent the initial episode of depression and/or dysthymia among Icelandic adolescents. This indicated prevention program was implemented in school settings for 14-15 year-old students judged to be "at risk" for depression because of the presence of some depressive symptoms and/or a negative attributional style. We previously reported (Arnarson & Craighead, 2009) that this program, when compared to treatment-as-usual, was effective in preventing the first episode of depression and/or dysthymia at 6-months following completion of the program. Survival analyses of the 12-month follow-up data indicated that the preventive effects were sustained at the end of 1 year following the completion of the prevention program with only 2 of the prevention program participants reporting an initial episode of MDD/DYS versus 13 of the TAU participants (chi(2)=5.02, p=.025). Using logistic regression, we also found that initial level of depressive symptoms significantly (p=.0330) predicted the first episode of depression and/or dysthymia among TAU subjects. The limitations of the study were noted, and future directions of research regarding prevention of depression were discussed. PMID- 21296339 TI - B cells from common variable immunodeficiency patients fail to differentiate to antibody secreting cells in response to TLR9 ligand (CpG-ODN) or anti-CD40+IL21. AB - Common variable immunodeficiency (CVID) is a primary immunodeficiency characterised by hypogammaglobulinaemia and antibody deficiency to T dependent and independent antigens. Patients suffer from recurrent respiratory infections and poor response to vaccination. Although the underlying molecular defect is unknown, most CVID patients show impaired late B cell differentiation. We investigated B cell differentiation and immunoglobulin secretion induced by two different stimuli: TLR9 specific ligand (CpG-ODN) and anti-CD40 combined with IL21. The contribution of BCR signalling (anti-IgM stimulation) was also evaluated. B cells from CVID patients produced low levels of IgG and IgA in response to both kinds of stimuli that was not restored by anti-IgM. Production of IgM was conserved when cells were stimulated with anti-CD40 and IL21. These results point to a wide signalling defect in B lymphocytes from CVID patients that may be related to their hypogammaglobulinaemia and poor response to vaccination. PMID- 21296340 TI - [Porcelain gallbladder: a clinical case and a review of the literature]. AB - Porcelain bladder is defined as calcification of the gallbladder wall. It is a rare condition and is seen in 0.06% to 0.8% of cholecystectomies. It origin is still unknown. We report two cases of patients with a porcelain gallbladder. One case is a 60 year-old male patient who was seen due to having biliary symptoms. The diagnosis was made by ultrasound and computed tomography, and he was surgically intervened by performing a partial cholecystectomy. The histopathology reported a gallbladder wall with sclerohyalinosis and dystrophic calcification foci. The other case is a 98 year-old female patient, whose form of presentation was incidental given that she suffered from symptoms of an intestinal obstruction. A cholecystectomy was performed with a good post-surgical outcome. A series published in between 1950 and 1960 show that the porcelain bladder can be frequently observed in patients with cancer of the gallbladder, although this relationship is currently being rejected. The reason why these cases are being presented is because of their low incidence and the controversy over what treatment to use, due to its association with gallbladder cancer. PMID- 21296341 TI - [Prolonged survival after resection of liver metastasis of a pancreatic neuroendocrine tumour]. PMID- 21296342 TI - Re.: Cardiac drugs used in cross-sectional cardiac imaging: what the radiologist needs to know. PMID- 21296343 TI - Comparative yield of positive brain computed tomography after implementing the NICE or SIGN head injury guidelines in two equivalent urban populations. AB - AIMS: To compare the yield of positive computed tomography (CT) brain examinations after the implementation of the National Institute for Clinical Excellence (NICE) or the Scottish Intercollegiate Guidance Network (SIGN) guidelines, in comparable urban populations in two teaching hospitals in England and Scotland. MATERIALS AND METHODS: Four hundred consecutive patients presenting at each location following a head injury who underwent a CT examination of the head according to the locally implemented guidelines were compared. Similar matched populations were compared for indication and yield. Yield was measured according to (1) positive CT findings of the sequelae of trauma and (2) intervention required with anaesthetic or intensive care unit (ICU) support, or neurosurgery. RESULTS: The mean ages of patients at the English and Scottish centres were 49.9 and 49.2 years, respectively. Sex distribution was 64.1% male and 66.4% male respectively. Comparative yield was 23.8 and 26.5% for positive brain scans, 3 and 2.75% for anaesthetic support, and 3.75 and 2.5% for neurosurgical intervention. Glasgow Coma Score (GCS) <13 (NICE) and GCS <= 12 and radiological or clinical evidence of skull fracture (SIGN) demonstrated the greatest statistical association with a positive CT examination. CONCLUSION: In a teaching hospital setting, there is no significant difference in the yield between the NICE and SIGN guidelines. Both meet the SIGN standard of >10% yield of positive scans. The choice of guideline to follow should be at the discretion of the local institution. The indications GCS <13 and clinical or radiological evidence of a skull fracture are highly predictive of intracranial pathology, and their presence should be an absolute indicator for fast-tracking the management of the patient. PMID- 21296345 TI - Relationship of symptomatic remission with quality of life and functionality in patients with schizophrenia. AB - OBJECTIVE: The aim of this study was to investigate the relationship between remission and quality of life (QoL) of patients with schizophrenia. METHOD: Quality of life was investigated with the Quality-of-Life Scale, the Personal and Social Performance Scale (PSP), and the Evaluation of Functional Remission Scale in 102 outpatients with schizophrenia. Positive and Negative Syndrome Scale and Calgary Depression Scale for Schizophrenia (CDSS) were used to assess symptom severity. Remission was defined based on the Andreasen et al criteria (2005). RESULTS: The remission group had higher levels of QoL and functionality as measured by the Quality-of-Life Scale (P = .001), PSP (P = .001), and Evaluation of Functional Remission Scale (P = .001). The remission group also had higher employment rates, lower smoking rates, and less depressive symptoms. We found that negative (P = .001) and positive symptoms of the Positive and Negative Syndrome Scale (P = .05) and CDSS score (P = .005) independently contributed to PSP score in a linear regression analysis. Years of education and positive symptoms were related to CDSS score. All of the 3 scales that we used to assess QoL and functionality were highly correlated with each other. In addition, the opinions of patients or relatives/partners about functionality of the patient was highly correlated with all of the scales. CONCLUSION: We found significant differences between patients with schizophrenia with and without remission for QoL and functionality. Relative/partner's evaluation of functional status provides a reliable measure of QoL as well. PMID- 21296344 TI - Parental substance use history of overweight men and women with binge eating disorder is associated with distinct developmental trajectories and comorbid mood disorder. AB - OBJECTIVE: To examine the significance of parental histories of substance use disorders (SUDs) in the expression of binge eating disorder (BED) and associated functioning. METHOD: Participants were 127 overweight patients with BED assessed using diagnostic interviews. Participants were administered a structured psychiatric history interview about their parents (N = 250) and completed a battery of questionnaires assessing current and historical eating and weight variables and associated psychological functioning (depression and self-esteem). RESULTS: Patients with BED with a parental history of SUD were significantly more likely to start binge eating before dieting, had a significantly earlier age at BED onset, and reported less time between binge eating onset and meeting diagnostic criteria for BED than did patients without a parental history of SUD. For psychiatric comorbidity, patients with BED with a parental history of SUD were significantly more likely to meet the criteria for a mood disorder. A parental history of SUD was not significantly associated with variability in current levels of binge eating, eating disorder psychopathology, or psychological functioning. DISCUSSION: Our findings suggest that a parental history of SUD is associated with certain distinct trajectories in the development of binge eating (earlier binge onset predating dieting onset) and with elevated rates of comorbidity with mood disorders in patients with BED. PMID- 21296346 TI - Self-perceived cognitive functioning does not correlate with objective measures of cognition in schizophrenia. AB - BACKGROUND: Growing interest in the study of self-perceived cognitive deficits in schizophrenia has been recently observed. The authors validated in a previous study the Subjective Scale To Investigate Cognition into Schizophrenia Tunisian Arabic Version (SSTICS_tun_arab), a self-questionnaire established to collect cognitive complaints in patients with schizophrenia. OBJECTIVE: The aim of the present study was to explore the relationship between the SSTICS_tun_arab scores and objective cognitive performances. METHODS: One hundred four patients with schizophrenia spectrum disorders were administered measures of the Positive and Negative Syndrome Scale, the Global Assessment Functioning Scale, and the Calgary Depression Scale as well as measures of the SSTICS_tun_arab and a cognitive battery. RESULTS: No correlations were found between objective neuropsychologic performances and scores of the SSTICS_tun_arab. CONCLUSIONS: Our findings support the hypothesis of independence of self-perceived cognitive functioning from objective neuropsychologic deficits in schizophrenia. They also suggest that insight of mental illness seems to be not a unitary concept but more likely to be divided in different aspects including cognitive insight. PMID- 21296347 TI - Acute effects of air pollution on pediatric asthma exacerbation: evidence of association and effect modification. AB - We investigated the short-term effects of particulate matter with aerodynamic diameter <10 MUg/m(3) (PM(10)), sulfur dioxide (SO(2)), nitrogen dioxide (NO(2)) and ozone (O(3)) on pediatric asthma emergency admissions in Athens, Greece over the period 2001-2004. We explored effect modification patterns by season, sex, age and by the presence of desert dust transported mainly from the Sahara area. We used daily time-series data provided by the children's hospitals and the fixed monitoring stations. The associations were investigated using Poisson regression models controlling for seasonality, weather, influenza episodes, day of the week and holiday effects. A 10 MUg/m(3) increase in PM(10) was associated with a 2.54% increase (95% confidence interval (CI): 0.06%, 5.08%) in the number of pediatric asthma hospital admissions, while the same increase in SO(2) was associated with a 5.98% (95% CI: 0.88%, 11.33%) increase. O(3) was associated with a statistically significant increase in asthma admissions among older children in the summer. Our findings provide limited evidence of an association between NO(2) exposure and asthma exacerbation. Statistically significant PM(10) effects were higher during winter and during desert dust days, while SO(2) effects occurred mainly during spring. Our study confirms previously reported PM(10) effects on emergency hospital admissions for pediatric asthma and further provides evidence of stronger effects during desert dust days. We additionally report severe effects of SO(2), even at today's low concentration levels. PMID- 21296348 TI - Procedure time of endoscopic submucosal dissection according to the size and location of early gastric cancers: analysis of 916 dissections performed by 4 experts. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) is curative treatment for patients with early gastric cancer (EGC). Because of the technical difficulties, however, these procedures may take a long time, which can increase the rate of procedure-related complications. OBJECTIVE: To investigate the procedure time of ESD performed by 4 experts according to the location and size of the EGC. DESIGN: Retrospectively analyzed study of prospectively collected data. SETTING: Tertiary care, academic medical center. PATIENTS: Complete ESDs were performed by 4 experts, primarily using an insulated-tip knife, for 916 EGCs. INTERVENTION: ESD. MAIN OUTCOME MEASUREMENT: Procedure time relative to the location and size of tumors was analyzed along with other predictive factors. RESULTS: ESD procedure time was increased as tumor size increased and for tumors in the middle and lower thirds of the stomach. Univariate analysis showed that tumor size, location, depth, submucosal fibrosis, and perforation during the procedure were significant predictors of procedure time. Multivariate analysis showed that proximal location, tumor size greater than 20 mm, submucosal fibrosis, and perforation during the procedure were independent predictors of a longer procedure time. LIMITATION: Single-center, retrospective study design. CONCLUSIONS: Procedure time became longer as tumor location became higher and as tumor size increased, except for tumors in the upper third of the stomach. These findings suggest that tumor size and location may be useful in predicting the time required to perform ESD. PMID- 21296349 TI - Autofluorescence imaging. PMID- 21296350 TI - Stress-induced cardiovascular reactivity and atherogenesis in adolescents. AB - OBJECTIVE: To examine the association between cardiovascular reactivity to a set of psychological stressors and carotid artery intima-media thickness, a marker of subclinical cardiovascular disease in healthy adolescents. METHODS: Participants were 25 boys and 23 girls age 14.2 +/- 0.9 years who were measured for heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressure reactivity to mirror tracing, reaction time, speech preparation and ad lib speech tasks and for common carotid artery intima-media thickness. Sequential regression analyses were used to establish the incremental increase in R(2)(R(inc)(2)) for the prediction of intima-media thickness due to cardiovascular reactivity independent of age, BMI percentile, sex, socioeconomic status, and resting HR or BP. RESULTS: SBP reactivity while preparing (beta=0.0019, R(inc)(2)=0.09) and giving the speech (beta=0.0014, R(inc)(2)=0.10) and an aggregate reactivity score based on all 4 tasks (beta=0.0026, R(inc)(2)=0.11) independently predicted (p <= 0.05) mean carotid artery intima-media thickness. Neither DBP reactivity nor HR reactivity during any task were independent predictors of intima-media thickness. CONCLUSION: Stress-induced cardiovascular reactivity, and especially SBP reactivity, is associated with carotid intima-media thickness and the early pathogenesis of cardiovascular disease. The use of an aggregate stress reactivity index provides a more reliable reflection of trait SBP reactivity to psychological stress and increases the confidence that youth with greater cardiovascular stress reactivity may indeed have greater progression of subclinical cardiovascular disease. PMID- 21296351 TI - Musashi-1 expression in atherosclerotic arteries and its relevance to the origin of arterial smooth muscle cells: histopathological findings and speculations. AB - The origin of smooth muscle cells in developing atherosclerotic lesions is a controversial topic with accumulating evidence indicating that at least some arterial smooth muscle cells might originate from bone marrow-derived smooth muscle cell precursors circulating in the blood. The stem cell markers currently used for the identification of stem cells in the arterial intima can be expressed by a number of different cell types residing in the arterial wall, such as mast cells, endothelial cells and dendritic cells, which can make interpretation of the data obtained somewhat ambiguous. In the present study we examined whether the putative intestinal stem cell marker Musashi-1 is expressed in the arterial wall. Using a multiplexed tandem polymerase chain reaction method (MT-PCR) and immunohistochemistry, Musashi-1 expression was revealed in human coronary arterial wall tissue segments, and this finding was followed by the demonstration of significantly higher expression levels of Musashi-1 in atherosclerotic plaques compared with those in undiseased intimal sites. Double immunohistochemistry demonstrated that in the arterial wall Musashi-1 positive cells either did not display any specific markers of cells that are known to reside in the arterial intima or Musashi-1 was co-expressed by smooth muscle alpha-actin positive cells. Some Musashi-1 positive cells were found along the luminal surface of arteries as well as within microvessels formed in atherosclerotic plaques by neovascularization, which supports the possibility that Musashi-1 positive cells might intrude into the arterial wall from the blood and might even represent circulating smooth muscle cell precursors. PMID- 21296352 TI - Effects of soft tissue artifacts on the calculated kinematics and kinetics of the knee during stair-ascent. AB - Biomechanics of the knee during stair-ascent has mostly been studied using skin marker-based motion analysis techniques, but no study has reported a complete assessment of the soft tissue artifacts (STA) and their effects on the calculated joint center translation, angles and moments at the knee in normal subjects during this activity. This study aimed to bridge the gap. Twelve young adults walked up a three-step stair while data were acquired simultaneously from a three dimensional motion capture system, a force plate and a dynamic fluoroscopy system. The "gold standards" of poses of the knee were obtained using a 3D fluoroscopy method. The STA of the markers on the thigh and shank were then calculated, together with their effects on the calculated joint center translations, angles and moments at the knee. The STA of the thigh markers were greater than those on the shank, leading to significantly underestimated flexion and extensor moments, but overestimated joint center translations during the first half of the stance phase. The results will be useful for a better understanding of the normal biomechanics of the knee during stair-ascent, as a baseline for future clinical applications and for developing a compensation method to correct for the effects of STA. PMID- 21296353 TI - In vitro indentation to determine the mechanical properties of epidermis. AB - The lack of understanding of the mechanical behavior of the human skin layers makes the development of drug delivery using microneedles or microjets a challenging task. In particular, the key mechanical properties of the epidermis composed of stratum corneum and viable epidermis should be better understood. Micro-indentation experiments were applied, using a spherical tip with a large diameter to the sample thickness ratio. The Young's moduli were derived via an analytical and a numerical method. The tests showed that the analytical method was not appropriate to assess the Young's moduli. That is why a numerical model was used to obtain the correct stiffness. When loaded perpendicularly, the stiffness of both the epidermis and stratum corneum vary between 1 and 2MPa. No significant differences in stiffness between the stratum corneum and viable epidermis were observed. PMID- 21296354 TI - Comparative diagnostic accuracy of knee adduction moments in knee osteoarthritis: a case for not normalizing to body size. AB - Previous authors have questioned the practice of normalizing the external knee adduction moment during gait to body size when investigating dynamic joint loading in knee osteoarthritis (OA). The purpose of this study was to compare the abilities of non-normalized and normalized external knee adduction moments during gait in discriminating between patients with least and greatest severity of radiographic medial compartment knee OA. Subjects with mild (n=118) and severe (n=115) medial compartment knee OA underwent three-dimensional gait analysis. The peak external knee adduction moment was calculated and kept in its original units (Nm), normalized to body mass (Nm/kg) and normalized to body weight and height (%BW * Ht). Receiver Operating Characteristic (ROC) curve analysis indicated that non-normalized values better discriminated between patients with mild and severe knee OA. The area under the ROC curve for non-normalized peak knee adduction moments (0.63) was significantly (p<0.05) greater than when normalized to body mass (0.58), or to body weight times height (0.57). Post-hoc analysis of covariance indicated the mean difference in peak knee adduction moment between OA severity groups (7.23 Nm, p=0.003) was reduced by approximately 50% (3.60 Nm, p=0.09) when adjusted for mass. These findings are consistent with the suggestion that non-normalized values are more sensitive to radiographic disease progression. We suggest including knee adduction moment values that are not normalized to body size when investigating knee OA. PMID- 21296355 TI - Scalable Technology for the Extraction of Pharmaceutics (STEP): the transition from academic knowhow to industrial reality. AB - This paper addresses the technological readiness of counter-current chromatography (CCC) instruments to become platform technology for the pharmaceutical industry. It charts the development of the prototype technology since its inception in 1966, through conceptual improvements in the 1980s that led to higher speed separations in hours as opposed to days. It then describes the engineering improvements that have led to the development of high performance counter-current chromatography with the potential for scale-up to process scale for manufacturing products in industry with separation times in minutes rather than hours. A new UK Technology Strategy Board high value manufacturing L1.5 m research programme to take CCC through to technology readiness level 8 (i.e. as platform technology for continuous 24 * 7 operation by industry) is introduced. Four case studies are given as examples of successes from its expanding applications portfolio, which is mainly confidential. Finally, the hurdles for the uptake of new technology by industry are highlighted and the following potential solutions given: rapid method development, automation, continuous processing and instrument reliability and robustness. The future challenge for the CCC community will be to address these development needs urgently if CCC is to become the platform technology it deserves to be. PMID- 21296356 TI - Fast separation of antiviral nucleoside phosphoramidate and H-phosphonate diastereoisomers by reversed-phase liquid chromatography. AB - The nucleoside-based antiviral phosphoramidates and H-phosphonates were synthesized and separated using reversed-phase liquid chromatography on bridged ethane hybrid (BEH) C18 column packed with 1.7 MUm particles of non-chiral stationary phase. The influences of the composition of mobile phase and column temperature have been investigated to optimize the diastereoisomeric separation. Complete separations of the phosphoramidate and H-phosphonate prodrugs with good resolution (R(S)=1.99-2.77) were achieved within a short time (5-9 min). The validation study of the optimized method including linearity, accuracy, repeatability and detection limit has revealed it is better performance versus conventional HPLC method. In addition, HPLC was combined with high resolution electrospray ionization time-of-flight mass spectrometry (ESI-TOF MS), which enabled the exact mass measurement and high sensitivity. Using MS as detection, the limits of detection and limits of quantification of the studied pronucleotide diastereoisomers were determined in the range of several nmol L-1 level. PMID- 21296357 TI - Fast and sensitive detection of genetically modified yeasts in wine. AB - In this work, a novel screening methodology based on the combined use of multiplex polymerase chain reaction (PCR) and capillary gel electrophoresis with laser induced fluorescence (CGE-LIF) is developed for the fast and sensitive detection of genetically modified yeasts in wine. As model, a recombinant EKD-13 Saccaromyces cerevisiae strain was selected and different wines were prepared using either recombinant or conventional yeasts. Special emphasis is put on the yeast DNA extraction step, exploring different commercial and non-commercial methods, in order to overcome the important difficulty of obtaining amplifiable DNA from wine samples. To unequivocally detect the transgenic yeast, two specific segments of the transgenic construction were amplified. In addition, a third primer pair was used as amplification control to confirm the quality of the yeast DNA obtained from the extraction step. CGE-LIF provides high sensitivity, good analysis speed and impressive resolution of DNA fragments, making this technique very convenient to optimize multiplex PCR parameters and to analyze the amplified DNA fragments. Thus, the CGE-LIF method provided %RSD values for DNA migration times lower than 0.82% (n=10) with the same capillary and lower than 1.92% (n=15) with three different capillaries, allowing the adequate size determination of the PCR products with an error lower than 4% compared to the theoretically expected. The whole method developed in this work requires less than one working day and grants the sensitive detection of transgenic yeasts in wine samples. PMID- 21296358 TI - Development of an improved method to extract pesticide residues in foods using acetonitrile with magnesium sulfate and chloroform. AB - A multiresidue method was developed based on extraction of 10 g sample with 10 mL acetonitrile and subsequent liquid-liquid partitioning formed by adding 4 g MgSO4 plus 1 mL chloroform. During the partitioning process, the extraction recoveries of polar analytes were found to be essentially determined by the acetonitrile content in the aqueous phase. The use of MgSO4 gave the least acetonitrile left in the aqueous phase (lower than 5%) and thus promoting complete partitioning of analytes into the organic phase. At the same time, removal of water from the acetonitrile phase was achieved by adding only a small amount of chloroform with no influence on the acetonitrile content in the aqueous phase, thus leading to decreasing the co-extraction of polar matrix components. The most complete mutual separation of acetonitrile and water was achieved by the joint use of MgSO4 and chloroform and thus the optimal extraction recovery and analytical selectivity were obtained simultaneously. The new method, with higher recoveries of polar analytes, better analytical selectivity and simpler manipulation, is a claimed improvement to the original QuEChERS method. The proposed method was finally validated by the determination of 20 pesticides in a mixed food matrix by using liquid chromatography tandem mass spectrum (LC-MS/MS). Acceptable linearity, sensitivity, recovery, precision and selectivity results were obtained. PMID- 21296359 TI - Evaluation of automated sample preparation, retention time locked gas chromatography-mass spectrometry and data analysis methods for the metabolomic study of Arabidopsis species. AB - In this paper, automated sample preparation, retention time locked gas chromatography-mass spectrometry (GC-MS) and data analysis methods for the metabolomics study were evaluated. A miniaturized and automated derivatisation method using sequential oximation and silylation was applied to a polar extract of 4 types (2 types*2 ages) of Arabidopsis thaliana, a popular model organism often used in plant sciences and genetics. Automation of the derivatisation process offers excellent repeatability, and the time between sample preparation and analysis was short and constant, reducing artifact formation. Retention time locked (RTL) gas chromatography-mass spectrometry was used, resulting in reproducible retention times and GC-MS profiles. Two approaches were used for data analysis. XCMS followed by principal component analysis (approach 1) and AMDIS deconvolution combined with a commercially available program (Mass Profiler Professional) followed by principal component analysis (approach 2) were compared. Several features that were up- or down-regulated in the different types were detected. PMID- 21296360 TI - Spontaneous formation of dye-functionalized gold nanoparticles using reverse micellar systems. AB - Detailed exploratory and mechanistic investigations on spontaneous formation of dye-functionalized gold nanoparticles (GNPs) using dye-based reverse micellar systems are described in this publication. The accumulated results from spectroscopic and microscopic investigations demonstrated that water molecules confined within nanoscopic enclosure of the self-assembled reverse micelles played critical role in the redox processes of aurate ions to produce GNPs, which are assumed to have approximately constant size distributions. The resulting dye functionalized GNPs were found to offer their absorption and fluorescence emission tunability by changing the medium polarity as well as to exhibit excellent film-forming properties to give optically homogeneous polystyrene thin films. These key findings in addition to broad applicability of the self assembling process with a variety of dye analogues have led to a conclusion that the protocol presented here serves as a versatile synthetic method to provide a potential convenience for future development of new organic-inorganic hybrid nanomaterials. PMID- 21296362 TI - Systemic sclerosis in aquaporin-4 antibody-positive longitudinally extensive transverse myelitis. AB - We report on the first patient with a relapsing, anti-aquaporin-4 (AQP-4) antibody-positive, longitudinally extensive transverse myelitis (LETM) who developed systemic sclerosis (SSc). A 62-year-old woman, who presented with bilateral, distal lower limb and perineal numbness, developed clinical manifestations and paraclinical features of SSc. Spinal cord imaging revealed lesions that were consistent with LETM. Patient's serum was positive for neuromyelitis optica (NMO)-IgG/AQP-4 antibodies. High-dose intravenous corticosteroids improved the neurological symptoms. The present case expands the list of autoimmune systemic diseases that occur in neuromyelitis optica spectrum disorders associated with NMO-IgG/AQP-4 antibodies. PMID- 21296361 TI - Medial temporal structures and memory functions in adolescents with heavy cannabis use. AB - Converging lines of evidence suggest an adverse effect of heavy cannabis use on adolescent brain development, particularly on the hippocampus. In this preliminary study, we compared hippocampal morphology in 14 "treatment-seeking" adolescents (aged 18-20) with a history of prior heavy cannabis use (5.8 joints/day) after an average of 6.7 months of drug abstinence, and 14 demographically matched normal controls. Participants underwent a high-resolution 3D MRI as well as cognitive testing including the California Verbal Learning Test (CVLT). Heavy-cannabis users showed significantly smaller volumes of the right (p < 0.04) and left (p < 0.02) hippocampus, but no significant differences in the amygdala region compared to controls. In controls, larger hippocampus volumes were observed to be significantly correlated with higher CVLT verbal learning and memory scores, but these relationships were not observed in cannabis users. In cannabis users, a smaller right hippocampus volume was correlated with a higher amount of cannabis use (r = -0.57, p < 0.03). These data support a hypothesis that heavy cannabis use may have an adverse effect on hippocampus development. These findings, after an average 6.7 month of supervised abstinence, lend support to a theory that cannabis use may impart long-term structural and functional damage. Alternatively, the observed hippocampal volumetric abnormalities may represent a risk factor for cannabis dependence. These data have potential significance for understanding the observed relationship between early cannabis exposure during adolescence and subsequent development of adult psychopathology reported in the literature for schizophrenia and related psychotic disorders. PMID- 21296363 TI - [Chemotherapy at the end of life. Is it compassive?]. PMID- 21296364 TI - [Incorporation of researchers to hospitals and research centres of the Spanish National Health System. Monitoring and evaluating the Miguel Servet Program of postdoctoral contracts]. PMID- 21296366 TI - [Severe hyponatremia in postoperatory of papillary thyroid carcinoma as a manifestation of acute intermittent porphyria]. PMID- 21296365 TI - [Visfatin in obese patients, relation with cardiovascular risk factors, a cross sectional study]. AB - BACKGROUND AND OBJECTIVE: Obesity and insulin resistance are associated with cardiovascular risk factors. The aim of the present study was to explore the relation of visfatin with insulin resistance, cardiovascular risk factors and anthropometry in obese patients without comorbidities. PATIENTS AND METHOD: A population of 270 obese patients was analyzed in a prospective way. In all patients we performed a biochemical analysis (lipid profile, insulin, HOMA and visfatina), and a nutritional evaluation (dietary intake, conventional anthropometry and bioimpedance). RESULTS: Patients were divided in two groups by median visfatin value (8,32 ng/ml), group I (patients with the low values, average value 7,11 (0,7) ng/ml) and group II (patients with the high values, average value 13,5 (10,1) ng/ml). Patients in the group I had higher weight, body mass index, waist circumference, and waist to hip ratio than patients in group II. Patients in group I had lower LDL-cholesterol and C reactive protein than patients in group II. Correlation analysis showed a positive correlation between visfatin levels and LDL cholesterol (r=0.194; p<0.05) and C reactive protein (r=0.266; p<0.05) and a negative corelation with weight (r=-0.162; p<0.05). In the logistic analysis with age-, sex- and dietary intake- adjusted basal visfatin concentration as a dependent variable, the next variables remained in the model; weight with an odds ratio (OR) 0,97 (IC95% 0,95-0,99), LDL cholesterol 1,012(1,010-1.023) and C reactive protein 1,15 (1.03-1.3). CONCLUSION: LDL cholesterol and c reactive protein levels are positively correlated with visfatin levels. Weight is negatively correlated with visfatin levels, in an independent way and adjusted by age, sex and dietary intake. PMID- 21296367 TI - [The mature minor's decisions' in health]. PMID- 21296368 TI - [Use of illicit drugs over gestation and their neonatal impact. Comparison between periods 1982-1988 and 2002-2008]. AB - BACKGROUND AND OBJECTIVE: The use of illicit drugs during pregnancy becomes a high risk situation. Our objective is to determine the currently prevalence, pregnancy, delivery and newborn's characteristics of mothers who use illicit drugs. PATIENTS AND METHODS: Retrospective study of children exposed prenatally to illicit drugs in the Neonatology's Unit of the Hospital del Mar during 2002 2008 and comparison with 1982-1988 data. RESULTS: Heroin use is lower currently and it is always associated with other drugs, mainly inhaled or smoked. There is an increase of the maternal age (28.4 years), an improved gestational control (60.5%) and more newborns are attended in shelters (13.1%). Methadone programs provide better overall results. Human immunodeficiency virus (HIV) (25%) and hepatitis B (BHV) (2.5%) infections have decreased. Placental abruption rate in cocaine users is very high (11%). By comparing both periods, there were statistically significant differences in maternal age, gestational control, delivery way, neonatal withdrawal syndrome treatment and newborn destination. CONCLUSIONS: Drug abuse remains prevalent in native pregnants. Heroin use has decreased. At present, there is a better gestational control and less HIV and HBV infections. The gestational age and somatometric parameters have not changed over the years. Methadone programs improve the deleterious aspects of opioid use. Placental abruption in pregnancy and neurobehavioral disorders in newborn are common in cocaine users. PMID- 21296369 TI - Association between excessive body fat and eating-disorder risk in adolescents: the AFINOS Study. AB - BACKGROUND AND OBJECTIVE: Overweight and obesity, together with eating disorders, are important public health concerns in adolescence. The aim of this study was to assess the association between excessive body fat and the risk of eating disorders. SUBJECTS AND METHOD: The sample consisted of 195 adolescents (97 girls) aged 13 to 18 years. Eating-disorder risk was evaluated by applying the SCOFF questionnaire. Body mass index, sum of 6 skinfolds, waist and hip circumferences and waist-hip and waist-height ratios were used to assess body fat. RESULTS: 24.7% of girls and 17.3% of boys were at risk of eating disorders, and 31.6% of boys and 21.6% of girls presented overweight (including obesity) according to Cole's cut-off points. Those adolescents classified above the 85th percentile on all the anthropometric measurements, as well as overweight adolescents, were at increased risk of developing an eating disorder (OR: 2.8 4.30, all p < 0.01). CONCLUSION: Regardless of the anthropometric measurements used, adolescents with excessive body fat showed a higher risk of having eating disorders than those with normal weight. PMID- 21296370 TI - [Iron and cardiovascular risk in HIV-infected patients]. PMID- 21296371 TI - [Paroxysmal nocturnal hemoglobinuria therapy with eculizumab: Spanish experience]. AB - BACKGROUND AND OBJECTIVES: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired clonal disease characterized by complement-mediated hemolysis, bone marrow failure and thrombosis. Eculizumab is a humanized monoclonal antibody that blocks the cytolytic component of the complement system by binding to complement C5. MATERIAL AND METHODS: We report the results of eculizumab treatment in 25 PNH patients from different centers in Spain. Statistical analysis was perfomed with a SPSS v15.0 software. RESULTS: Fifty-eight per cent of the patients achieved transfusional independence after a median of 14 months. Transfusion requirements were reduced in 60% of the remaining cases. Fatigue resolved in 96% of the patients and smooth muscle dystony-related symptoms in all cases. A single case of treatment-related infection was observed. CONCLUSIONS: Eculizumab controls effectively hemolysis and greatly improves clinical symptoms. The drug is safe and well tolerated, without significant adverse effects except meningococcal infection. Patients with suboptimal response to treatment must be assessed for bone marrow insufficiency and extravascular haemolysis. PMID- 21296372 TI - [Cerebrospinal fluid shunt infections. Risk factors, controversies, management and future perspectives]. PMID- 21296373 TI - Combining proteomics of root and shoot mitochondria and transcript analysis to define constitutive and variable components in plant mitochondria. AB - Mitochondria undertake respiration in plant cells, but through metabolic plasticity utilize differ proportions of substrates and deliver different proportions of products to cellular metabolic and biosynthetic pathways. In Arabidopsis the mitochondrial proteome from shoots and cell culture have been reported, but there has been little information on mitochondria in roots. We compare the root mitochondrial proteome with mitochondria isolated from photosynthetic shoots to define the role of protein abundance in these differences. The major differences observed were in the abundance and/or activities of enzymes in the TCA cycle and the mitochondrial enzymes involved in photorespiration. Metabolic pathways linked to TCA cycle and photorespiration were also altered, namely cysteine, formate and one-carbon metabolism, as well as amino acid metabolism focused on 2-oxoglutarate generation. Comparisons to microarray analysis of these same tissues showed a positive correlation between mRNA and mitochondrial protein abundance, but still ample evidence for the role of post-transcriptional processes in defining mitochondrial composition. Broader comparisons of transcript abundances for mitochondrial components across Arabidopsis tissues provided additional evidence for specialization of plant mitochondria, and clustering of these data in functional groups showed the constitutive vs variably expressed components of plant mitochondria. PMID- 21296374 TI - [Intrapulmonary solitary fibrous tumor associated with hemoptysis: a case report]. AB - Intrapulmonary solitary fibrous tumor is an extremely rare mesenchymal neoplasm about which very few references can be found in the literature. We present the case of a young woman with hemoptysis in whom plain-film chest radiographs showed a pulmonary mass. Contrast-enhanced MDCT showed a solid lung tumor with well defined margins and heterogeneous enhancement. Histological study after surgical resection of the lesion revealed an intrapulmonary solitary fibrous tumor with an area of myxoid degeneration. We describe the clinical, radiological, and histological findings for this rare entity and review the relevant literature. PMID- 21296375 TI - Hepatitis C virus-induced furin and thrombospondin-1 activate TGF-beta1: role of TGF-beta1 in HCV replication. AB - In this study, we demonstrated the molecular mechanisms of TGF-beta1 induction as well as proteolytic activation in HCV (JFH-1)-infected cells. Our studies showed the synthesis and secretion of TGF-beta1 in HCV-infected cells which was reduced in the presence of Ca(2+) chelators, an inhibitor of mitochondrial Ca(2+) uptake, and antioxidants. We also showed that the expression of HCV NS proteins NS3/4A, and NS5A can induce TGF-beta1 by cell-based luciferase assay. Furthermore, mutational analysis revealed that the functionally active protease domain of NS3 and N-terminus domain of NS5A are required for TGF-beta1 activity. Using siRNA approach we demonstrated that HCV-induced furin and thrombospondin-1 (TSP-1) are involved in the proteolytic activation of TGF-beta1. Our results also suggest that TGF-beta1 positively regulates HCV RNA replication. Collectively, these observations provide insight into the mechanism of TGF-beta1 activation, which likely manifest in liver fibrosis associated with hepatitis C infection. PMID- 21296376 TI - Structure-related distribution of PCDD/Fs, PCBs and HCB in a river-sea system. AB - Water concentrations of PCDD/Fs, HCB, and non-ortho, mono-ortho, and non-dioxin like PCBs were measured four times during 1 year in a coastal area of the Baltic Sea, to investigate background levels and distribution behaviour. Sampling sites included two rivers, an estuary, and the sea. Particulate and apparently dissolved concentrations were determined using active sampling (filters+PUFs), while freely dissolved concentrations were determined using passive sampling (POM samplers). The distribution between particulate+colloidal and freely dissolved phases, in the form of TOC-normalized distribution ratios (K(TOC)), was found to be near or at equilibrium. The observed K(TOC) were not significantly different between sampling sites or seasons. For PCDD/Fs, the concentrations were significantly correlated to suspended particulate matter (SPM), while no correlation to organic carbon (TOC) was observed. In the estuary and the sea, PCB concentrations were correlated to TOC. The sorption of various congeners to SPM and TOC appeared to be related to both hydrophobicity and 3D-structure. The PCDD/F concentration in the sea decreased to one third in May, likely connected to the increased vertical flux of particles during the spring bloom. PMID- 21296377 TI - Effects of phenanthrene on the mortality, growth, and anti-oxidant system of earthworms (Eisenia fetida) under laboratory conditions. AB - To assess the toxic effects of phenanthrene on earthworms, we exposed Eisenia fetida to artificial soils supplemented with different concentrations (0.5, 2.5, 12.5, mgkg(-1) soil) of phenanthrene. The residual phenanthrene in the soil, the bioaccumulation of phenanthrene in earthworms, and the subsequent effects of phenanthrene on growth, anti-oxidant enzyme activities, and lipid peroxidation (LPO) were determined. The degradation rate of low concentrations of phenanthrene was faster than it was for higher concentrations, and the degradation half-life was 7.3d (0.5 mgkg(-1)). Bioaccumulation of phenanthrene in the earthworms decreased the phenanthrene concentration in soils, and phenanthrene content in the earthworms significantly increased with increasing initial soil concentrations. Phenanthrene had a significant effect on E. fetida growth, and the 14-d LC(50) was calculated as 40.67 mgkg(-1). Statistical analysis of the growth inhibition rate showed that the concentration and duration of exposure had significant effects on growth inhibition (p<0.001). Superoxide dismutase (SOD) activity increased at the beginning (2 and 7d) and decreased in the end (14 and 28 d). Catalase (CAT) activity in all treatments was inhibited from 1 to 14 d of exposure. However, no significant perturbations in malondialdehyde (MDA) content were noted between control and phenanthrene-treated earthworms except after 2d of exposure. These results revealed that bioaccumulation of phenanthrene in E. fetida caused concentration-dependent, sub-lethal toxicity. Growth and superoxide dismutase activity can be regarded as sensitive parameters for evaluating the toxicity of phenanthrene to earthworms. PMID- 21296378 TI - Removal mechanisms and fate of insecticides in constructed wetlands. AB - Constructed wetlands (CWs), along with other vegetative systems, are increasingly being promoted as a mitigation practice to treat non-point source runoff to reduce contaminants such as pesticides. However, studies so far have mostly focused on demonstrating contaminant removal efficiency. In this study, using two operational CWs located in the Central Valley of California, we explored the mechanisms underlying the removal of pyrethroids and chlorpyrifos from agricultural runoff water, and further evaluated the likelihood for the retained pesticides to accumulate within the CWs over time. In the runoff water passing through the CWs, pyrethroids were associated overwhelmingly with suspended solids >0.7 MUm, and the sorbed fraction accounted for 38-100% of the total concentrations. The derived K(d) values for the suspended solids were in the order of 10(4)-10(5), substantially greater than those reported for bulk soils and sediments. Distribution of pyrethroids in the wetland sediments was found to mimic organic carbon distribution, and was enriched in large particles that were partially decomposed plant materials, and clay-size particles (<2 MUm). Retention of suspended particles, especially the very large particles (>250 MUm) and the very fine particles, is thus essential in removing pyrethroids and chlorpyrifos in CWs. Under flooded and anaerobic conditions, most pyrethroids and chlorpyrifos showed moderate persistence, with DT(50) values between 106-353 d. However, the retained pyrethroids were very stable in dry and aerobic sediments between irrigation seasons, suggesting a possibility for accumulation over time. Therefore, the long-term ecological risks of CWs should be further understood before their wide adoption. PMID- 21296379 TI - Transport of chlorinated dioxins and furans in soil columns: modeling pentachlorophenol pole-treating oil influence. AB - Column experiments were conducted to validate a screening model predicting the influence of pentachlorophenol (PCP) pole-treating oil on the vertical migration of its impurities, chlorinated dioxins and furans (PCDD/Fs). PCP pole-treating oil (15 mL d(-1)) and water (20 mL d(-1)) were added daily to the top of sand and organic soil columns during 35d. Column soil samples were analyzed to determine concentrations of hydrocarbons and PCDD/Fs at several depths in the columns (0 30cm) and their evolution in time (7, 14, 21 and 35d). The model predicted a significant vertical migration of PCDD/Fs due to the presence of oil as a free phase and PCDD/Fs were found in the different column layers at concentrations consistent with model predictions (same order of magnitude). Measured PCDD/Fs concentrations are in total disagreement with literature data and with model prediction in the absence of oil free phase, which implies PCDD/F properties alone cannot be used to predict their fate in the current context: the influence of PCP pole-treating oil must be accounted for to properly explain their migration. PMID- 21296380 TI - Evaluation of wastewater nitrogen transformation in a natural wetland (Ulaanbaatar, Mongolia) using dual-isotope analysis of nitrate. AB - The Tuul River, which provides water for the daily needs of many residents of Ulaanbaatar, Mongolia, has been increasingly polluted by wastewater from the city's sewage treatment plant. Information on water movement and the transformation of water-borne materials is required to alleviate the deterioration of water quality. We conducted a synoptic survey of general water movement, water quality including inorganic nitrogen concentrations, and isotopic composition of nitrogen (delta(15)N-NO(3)(-), delta(18)O-NO(3)(-), and delta(15)N NH(4)(+)) and water (delta(18)O-H(2)O) in a wetland area that receives wastewater before it enters the Tuul River. We sampled surface water, groundwater, and spring water along the two major water routes in the wetland that flow from the drain of the sewage treatment plant to the Tuul River: a continuous tributary and a discontinuous tributary. The continuous tributary had high ammonium (NH(4)(+)) concentrations and nearly stable delta(15)N-NH(4)(+), delta(15)N-NO(3)(-), and delta(18)O-NO(3)(-) concentrations throughout its length, indicating that nitrogen transformation (i.e., nitrification and denitrification) during transit was small. In contrast, NH(4)(+) concentrations decreased along the discontinuous tributary and nitrate (NO(3)(-)) concentrations were low at many points. Values of delta(15)N-NH(4)(+), delta(15)N-NO(3)(-), and delta(18)O-NO(3)(-) increased with flow along the discontinuous route. Our results indicate that nitrification and denitrification contribute to nitrogen removal in the wetland area along the discontinuous tributary with slow water transport. Differences in hydrological pathways and the velocity of wastewater transport through the wetland area greatly affect the extent of nitrogen removal. PMID- 21296381 TI - Organic compounds of PM2.5 in Mexico Valley: spatial and temporal patterns, behavior and sources. AB - A longitudinal study on spatial and temporal behavior of particles less than 2.5 MUm (PM(2.5)), solvent extracted organic matter (SEOM), polycyclic aromatic hydrocarbons (PAH), n-alkanes and nitro-PAH was carried out for a full year in 2006, at five sites simultaneously around the Metropolitan Zone of Mexico Valley (MZMV). There is rather uniform distribution of PM(2.5) and SEOM in the MZMV regarding gravimetric mass concentration, while some specific organic chemical components showed mass heterogeneity. The highest mass concentrations of target compounds occurred in the dry seasons with respect to the rainy season. Bonfires and fireworks are probably responsible for extreme values of PM(2.5), SEOM and PAH (>= 228 gmol(-1)). Benzo[ghi]perylene was the most abundant PAH, with C(24) C(26) the most abundant n-alkanes and 2-nitrofluoranthene and 9-nitroanthracene the most abundant nitro-PAH. The northeast zone was the area with the greatest presence of sources of incomplete diesel combustion, while the central for gasoline combustion. In the southwest, the biogenic sources were more abundant over the anthropogenic sources. This was opposite to the other sites. Factor analysis allowed us to relate different compounds to emitting sources. Three main factors were associated with combustion, pyrolysis and biogenic primary sources while the other factors were associated with secondary organic aerosol formation and industry. Correlation analyses indicated that SEOM originates from different primary emission sources or is formed by different processes than the other variables, except in southwest. Associations among variables suggest that PM(2.5) in the northwest and in the southeast originated mainly from primary emissions or consisted of primary organic compounds. PM(2.5) in the northeast, central and southwest contains a greater proportion of secondary organic compounds, with the less oxidized organic aerosols in the northeast and the most aged organic aerosol in the southwest. This follows the trends in the prevailing wind directions in MZMV during 2006. PMID- 21296382 TI - Effects of nano-scale TiO2, ZnO and their bulk counterparts on zebrafish: acute toxicity, oxidative stress and oxidative damage. AB - The acute toxicity and oxidative effects of nano-scale titanium dioxide, zinc oxide and their bulk counterparts in zebrafish were studied. It was found that although the size distribution of nanoparticles (NPs) was similar to that of the bulk particles in suspension, the acute toxicity of the TiO(2) NPs (96-h LC(50) of 124.5mg/L) to zebrafish was greater than that of the bulk TiO(2), which was essentially non-toxic. The acute toxicities observed for ZnO NPs, a bulk ZnO suspension, and a Zn(2+) solution were quite similar to each other (96-h LC(50) of 4.92, 3.31 and 8.06 mg/L, respectively). In order to explore the underlying toxicity mechanisms of NPs, .OH radicals generated by NPs in suspensions and five biomarkers of oxidative effects, i.e. superoxide dismutase, catalase activities, malondialdehyde, reduced glutathione and protein carbonyl were investigated. Results showed that after the illumination for 96 h, the quantities of .OH in the NP suspensions were much higher than ones in the bulk particles suspensions. The malondialdehyde content of zebrafish gills exposed to either illumination or dark were 217.2% and 174.3% of controls, respectively. This discrepancy indicates the occurrence of lipid peroxidation which is partly due to the generation of .OH. In contrast, exposure to 5mg/L ZnO NPs and bulk ZnO suspension induced oxidative stress in the gills without oxidative damage. Oxidative effects were more severe in the livers, where the protein carbonyl content, in the light and dark groups exposed to 50mg/L TiO(2) NPs, was 178.1% and 139.7% of controls, respectively. The malondialdehyde levels in the liver of fish exposed to 5mg/L ZnO NPs and bulk ZnO were elevated (204.2% and 286.9% of controls, respectively). Additionally, gut tissues exhibited oxidative effects after exposure to NP suspensions. These results highlight the importance of a systematic assessment of metal oxide NP toxicity mechanisms. PMID- 21296383 TI - The Ribble/Wyre observatory: major, minor and trace elements in rivers draining from rural headwaters to the heartlands of the NW England historic industrial base. AB - Information on a new observatory study of the water quality of two major river basins in northwestern England (the Ribble and Wyre) is presented. It covers upland, intermediate and lowland environments of contrasting pollution history with sufficient detail to examine transitional gradients. The upland rivers drain acidic soils subjected to long-term acidic deposition. Nonetheless, the acidic runoff from the soils is largely neutralised by high alkalinity groundwaters, although the rivers retain, perhaps as colloids, elements such as Al and Fe that are mobilised under acid conditions. The lowland rivers are contaminated and have variable water quality due to variable urban/industrial point and diffuse inputs reflecting local and regional differences in historic and contemporary sources. For most determinands, pollutant concentrations are not a major cause for concern although phosphate levels remain high. Set against earlier studies for other regions, there may be a general decline in pollutant levels and this is most clearly observed for boron where effluent inputs have declined significantly due to reductions in household products that are flushed down the drain. High concentrations of sodium and chloride occurred briefly after a severe cold spell due to flushing of road salts. A major inventory for water quality within rural, urban, industrial and agricultural typologies is provided within data summary attachments for over 50 water quality determinands. Within the next year, the full dataset will be made available from the CEH website. This, with ongoing monitoring, represents a platform for water quality studies across a wide range of catchment typologies pertinent to environmental management of clean and impacted systems within the UK. The study provides a base of research "from source to sea" including extensions to the estuary and open sea for a semi confined basin, the Irish Sea, where there are many issues of pollution inputs and contamination. PMID- 21296384 TI - Tumor necrosis factor-alpha G-308A gene polymorphism and coronary heart disease susceptibility: an updated meta-analysis. AB - PURPOSE: Several studies have reported apparently conflicting findings for the effects of tumor necrosis factor-alpha (TNF-alpha) G-308A polymorphism on coronary heart disease (CHD) susceptibility. We undertook a systematic review and meta-analysis to investigate the association between this gene variant and CHD predisposition. METHODS: We systematically searched electronic databases (Medline, EMbase, Chinese BioMedical, BIOSIS, Global Health, PsycINFO, Allied and Complementary Medicine Database, Cochrane Library, HuGE Navigator, and British Nursing) for relevant studies published between 1947 and October, 2010. Summarized estimation of odds ratio (OR) and 95% confidence interval (CI) were calculated. Publication bias and heterogeneity among studies were explored. RESULTS: We identified 24 studies providing data for 9 921 cases and 7 944 controls. Pooled analysis based on ORs adjusted by CHD risk factors showed that carrying the TNF-alpha gene A variant conferred a 1.5-fold increased risk of developing CHD (AG+AA vs. GG, OR = 1.50, 95% CI: 1.23-1.77) in Caucasian population. No significant association between the gene polymorphism and CHD risk could be found in other ethnic groups. CONCLUSIONS: It is probable that carrying the A variant is associated with CHD risk in Caucasians but not in Asians, Indians, or Africans. Further studies are merited to assess the association in greater details, especially in Asians, Indians and Africans. PMID- 21296385 TI - Outpatient management of acute deep vein thrombosis: results from the OTIS-DVT registry. AB - OBJECTIVES: We aimed to investigate clinical practice patterns for the outpatient management of acute deep vein thrombosis (DVT). METHODS: In the prospective Outpatient Treatment of Deep Vein Thrombosis in Switzerland (OTIS-DVT) registry, 534 consecutive outpatients with acute DVT (49% proximal, 24% recurrent, and 12% cancer-associated) were enrolled: 41% patients were managed in private angiology practice, 34% in an outpatient hospital department, and 25% in private general or internal medicine practice. RESULTS: For diagnosis, ultrasound was used in 95% and D-dimer testing in 53%. Low-molecular-weight heparin (LMWH) was prescribed for a median (IQR) duration of 7 (5-12) days in 83% of patients, and vitamin K antagonists for 163 (92-183) days in 81%. Mechanical measures to prevent post thrombotic syndrome were prescribed in 83%; compression stockings or bandages for a median (IQR) duration of 364 (101-730) days from hospital physicians, and 92 (45-183) days from private practice physicians (p < 0.001). Among patients with symptomatic proximal DVT, mechanical measures were prescribed for at least 2 years in 24% patients; 55% in hospital, and 6% in private practice (p < 0.001). Among patients with cancer-associated DVT, the median (IQR) duration of LMWH therapy was 16 (8-45) days, and 35% received LMWH for less than 90 days. CONCLUSIONS: The OTIS-DVT registry provides representative information on clinical practice patterns for outpatients with acute DVT managed by hospital or private practice physicians. The use of mechanical measures in patients with symptomatic proximal DVT and the administration of LMWH for a long-term therapy of cancer-associated DVT require improvement to comply with current guidelines. PMID- 21296386 TI - Vitamin E inhibition on platelet procoagulant activity: involvement of aminophospholipid translocase activity. AB - BACKGROUND: Activated platelets provide an important procoagulant surface, because exposed negatively charged phosphatidylserine (PS) is an important cofactor of the coagulation cascade. Aminophospholipid translocase (APLT) can transport PS from the outer to the inner membrane leaflet. Although vitamin E has been investigated for its anti-aggregating effect on platelets, its effect on platelet procoagulant activity has not been reported. METHODS: Phorbol 12 myristate 13-acetate (PMA), a well-known PKC activator, and thrombin were used to induce PS exposure on platelet surface. The expression of PS was measured by annexin A5 binding with flow cytometry. Platelet procoagulant activity was measured by a prothrombinase assay. APLT activity was measured by flow cytometry by determining the percent of 1-palmitoyl-2-[6-[(7-nitro-2-1,3-benzoxadiazol-4 yl)amino]caproyl]-sn-glycero-3-phosphatidylserine (NBD-PS) translocated from the outer to the inner membrane leaflet. Inhibition effects of vitamin E on platelet aggregation were simultaneously measured by a Multiplate aggregometer, a Chrono log aggregometer, and a PFA-100 system. RESULTS: Vitamin E significantly attenuated PMA-induced conformational change of glycoprotein IIb/IIIa and P selectin expression. Vitamin E significantly inhibited PMA and thrombin-induced PS externalization and reduced prothrombinase activity on platelet surfaces both in vitro and ex vivo. APLT activity was increased by vitamin E in a dose dependent manner, indicating that reduced procoagulant activity may be attributed, at least in part, to this increased APLT activity. Vitamin E inhibited platelet aggregation induced by combined chemokine SDF-1 and low-dose ADP as well as by usual doses of ADP or collagen when measured by the Multiplate and Chrono-log aggregometers but not when measured by PFA-100. CONCLUSIONS: These in vitro and ex vivo results showed that vitamin E inhibited platelet PS exposure and procoagulant activity partly by increasing APLT activity. These actions of vitamin E on platelet function provide new insights into the anticoagulation properties of vitamin E. PMID- 21296387 TI - Male mice have increased thrombotic potential: sex differences in a mouse model of venous thrombosis. AB - INTRODUCTION: Our objectives were to characterize sex differences during venous thrombosis, using the electrolytic inferior vena cava model of the disease. MATERIALS AND METHODS: Male and female C57BL/6 mice (6-8 weeks) underwent inferior vena cava thrombosis. Time points included 6 hours, day 2, day 6, and day 14 post surgery, along with surgically naive true controls and surgical shams. Analyses included thrombus weight, vein wall morphometrics, vein wall protein and gene expression for P-selectin, interleukin-1beta, and tumor necrosis factor-alpha; hematology, soluble P-selectin, and plasma microparticle tissue factor activity assays. RESULTS: Male venous thrombi were significantly larger than females at days 2 (13.1 +/- 1.0 vs. 6.8 +/- 0.5 * 10(-3) grams, p < 0.01), 6 (10.4 +/- 0.8 vs. 5.4 +/- 0.5 * 10(-3) grams, p < 0.01) and 14 (6.3 +/- 0.5 vs. 4.1 +/- 0.3 * 10(-3) grams, p < 0.01). Both male and female mice exhibited significantly increased vein wall P-selectin at 6 hours, vs. true controls (p < 0.05). Males had increased vein wall interleukin-1beta, versus females, at 6 hours (180.926 +/- 24.596 vs. 60.417 +/- 10.478 pg/mL, p < 0.05) and day 6 (76.966 +/- 13.081 vs. 33.834 +/- 4.198 pg/mL, p < 0.01). Males showed decreased tumor necrosis factor-alpha expression (-66 %) at 6 hours. Females had increased tumor necrosis factor-alpha expression at 6 hours (+541%) and day 6 (+539%). Both sexes demonstrated decreased peripheral platelets at 6 hours (p < 0.05), coinciding with thrombogenesis. Plasma P-selectin increased in both sexes, versus controls, through day 6 (p < 0.05). CONCLUSIONS: Males had significantly larger venous thrombi than females. Sex differences in vascular anatomy and response to inflammation may influence thrombus formation in our mouse thrombosis model. PMID- 21296388 TI - Clinical utility of fluorescence in situ hybridization for prediction of residual tumor after transurethral resection of bladder urothelial carcinoma. AB - OBJECTIVES: To evaluate the use of a multiprobe fluorescence in situ hybridization (FISH) assay for predicting the residual tumor load after transurethral resection (TUR) of bladder urothelial carcinoma (UC). METHODS: Voided urine specimens were collected from 125 consecutive patients with suspected UC who had been admitted for TUR. Of the 125 patients, 89 with UC diagnosed underwent a second procedure (repeated TUR or cystectomy) 4-6 weeks after the initial TUR and were included in the present study. Using the pathologic findings from the second procedure, the patients were divided into those with (n = 38) and those without (n = 51) residual tumor. Urine samples were taken both before and after the initial TUR. The multiprobe FISH assay was performed to detect aneuploidy of chromosomes 3, 7, and 17 and the loss of the 9p21 locus. RESULTS: Before the first TUR, no significant difference was found in the FISH-positive percentage between those with and without residual tumor. After the first TUR, the FISH-positive percentage in those with residual tumor was significantly greater than in those without residual tumor (42.2% vs 17.6%, P = .003). Moreover, before and after the initial TUR, the percentage of conversion from FISH positive to FISH negative in those with residual tumor was significantly lower than in those without residual tumor (28.9% vs 58.9%, P < .001). No patients were observed with a FISH result of conversion from negative to positive in those with and without residual tumor after the initial TUR. CONCLUSIONS: FISH appears to be useful for the prediction of the presence of the residual tumor load after TUR of bladder UC. PMID- 21296389 TI - Designing and usage of a low-cost penile model for male medical circumcision skills training in Rakai, Uganda. AB - OBJECTIVE: To describe the designing and usage of a locally made low-cost penile model used for male medical circumcision (MMC) skills training. MATERIAL AND METHODS: The Rakai MMC training team has experienced a number of challenges during conduct of MMC skills training, one of which was the lack of a model to use for MMC skills training. To address this challenge, the Rakai MMC skills training team has designed and developed a low-cost penile model for use in MMC skills training. RESULTS: The model has been successfully used to demonstrate external penile anatomy, to describe the biological mechanisms through which male circumcision (MC) prevents HIV acquisition, and for demonstration and practice of the MMC procedures. CONCLUSIONS: With an initial cost of only $10 and a recurrent cost of $5, this is a cost-efficient and useful penile model that provides a simulation of normal penile anatomy for use in MC training in resource-limited settings. It has also been used as a visual aid in preoperative education of patients before receiving male circumcision. The model can be improved and scaled up to develop cheaper commercial penile models. PMID- 21296390 TI - Quantification of preoperative stone burden for ureteroscopy and shock wave lithotripsy: current state and future recommendations. AB - OBJECTIVES: To determine which preprocedure imaging modality was used and how the stone burden quantification was assessed before shock wave lithotripsy (SWL) and ureteroscopy (URS) in published studies. MATERIAL AND METHODS: References were searched in the MEDLINE database using the terms "shock wave lithotripsy" and "ureteroscopy," excluding "percutaneous nephrolithotomy" from January 2007 to January 2009. The inclusion criteria for our study included clinical trials published in English with >20 patients and measurement of pretreatment stone size. RESULTS: Of the 198 studies in our initial MEDLINE search, 101 met the inclusion criteria. Of the 101 studies, 61 had evaluated SWL and 40 had evaluated URS. Also, 78 studies (77%) had quantified the stone burden in 1 dimension, 19 (19%) in 2 dimensions, and 4 (4%) in 3 dimensions. For SWL, the imaging modalities used to assess the stone burden included 24 mixed (40%), 10 noncontrast-enhanced computed tomography (16%), 12 plain abdominal film (20%), and 5 intravenous urography (8%); 10 studies (16%) did not mention the imaging modality used. For URS, the imaging modalities used to assess the stone burden included 15 mixed (38%), 8 noncontrast-enhanced computed tomography (20%), and 3 plain abdominal film (7%); 14 studies (35%) did not mention the imaging modality used. CONCLUSIONS: Heterogeneity exists in the published data regarding the imaging modality used both before URS and SWL. Up to one third of all studies for both URS and SWL did not mention the imaging modality used to quantify the stone burden. Standardization of preprocedure imaging and its reporting in published studies is needed to better assess the pretreatment stone burden and compare the treatments of stone disease. PMID- 21296391 TI - Prospective comparative study of endoscopic management of bladder lithiasis: is prostate surgery a necessary adjunct? AB - OBJECTIVES: To present the results of a prospective study comparing transurethral cystolithotripsy and simultaneous transurethral resection of the prostate (TURP), with transurethral cystolithotripsy and medical treatment of benign prostatic hyperplasia. The traditional dogma that bladder lithiasis constitutes an absolute indication for prostatic surgery has recently been questioned. METHODS: A total of 64 patients with bladder calculi were included in the present study. In all patients, stone clearance was achieved transurethrally. The patients in group 1 (n=32) underwent TURP during the same session, and the patients in group 2 (n=32) underwent medical therapy for benign prostatic hyperplasia (tamsulosin plus finasteride). RESULTS: The mean follow-up was 28.23+/-8.84 months. No statistically significant differences were found between the 2 groups regarding the preoperative parameters (age, International Prostate Symptom Score, prostatic volume, peak urinary flow rate, postvoid residual urine volume, prostate-specific antigen level, and bladder stone characteristics). Both groups experienced statistically significant postoperative improvements in the International Prostate Symptom Score, peak urinary flow rate, and postvoid residual urine volume. However, patients in group 1 experienced a more pronounced improvement in the International Prostate Symptom Score (P=.02) and peak urinary flow rate (P=.001). In total, 11 patients in group 2 underwent TURP during follow-up, with medical management considered to have failed. Multivariate logistic regression analysis revealed the postvoid residual urine volume as an independent risk factor that predicted the need for TURP in group 2 patients (odds ratio 1.033, 95% CI for odds ratio 1.007-1.060, P=.014). CONCLUSIONS: The findings of the present study have provided useful information on the natural history of bladder lithiasis, particularly in the context of improved patient consultation. PMID- 21296392 TI - GPR39, a putative receptor of Zn2+, is region specifically localized in different lobes of the mouse prostate. AB - OBJECTIVES: To define the expression pattern of the putative zinc receptor GPR39 at different regions of the mouse prostate. METHODS: We used a mouse strain harboring a LacZ reporter at 1 allele of gpr39 (gpr39(+/LacZ)). LacZ staining of adult prostate was performed by whole-mount staining followed by tissue section. The expression results were also confirmed at protein level by immunohistochemistry staining using GPR39 antibody in adult male mice. RESULTS: Whole-mount LacZ staining and tissue sections clearly revealed that GPR39 mRNA is intensely expressed at the epithelial cells of dorsal and anterior prostates, with lower intensity at the lateral prostate and very low or no expression in the ventral prostate. Immunohistochemistry staining results were consistent with those for LacZ staining. CONCLUSIONS: These data demonstrate that the putative zinc receptor GPR39 is spatially expressed at different regions of the mouse prostate with various intensities, suggesting that GPR39 might play an important role in mediating zinc function for normal prostate health in a region-specific manner. GPR39 expression in human prostate under normal and pathologic conditions is an interesting issue that warrants further investigation. PMID- 21296393 TI - Angiotensin II type 1 receptor expression and microvessel density in human bladder cancer. AB - OBJECTIVES: To determine whether angiotensin II type 1 receptor (AT1R) expression and tumor angiogenesis in human bladder cancer (BCa) specimens acquired by transurethral resection (TUR). It has recently been reported that AT1R is expressed in several tumors and is involved in tumor angiogenesis. However, no study has investigated AT1R expression in association with angiogenesis in clinical specimens of bladder cancer. METHODS: Surgical specimens were obtained from 108 patients who had undergone TUR for bladder cancer. All specimens were pathologically diagnosed as urothelial carcinoma. AT1R expression and microvessel density (MVD) were determined by immunostaining. The clinical and pathologic characteristics were retrospectively reviewed. RESULTS: The MVD was greater in muscle-invasive BCa (MIBC; 29 cases, 34.4 +/- 4.1/0.25 mm(2)) than in non-MIBC (NMIBC; 79 cases, 17.4 +/- 1.1/0.25 mm(2), P < .0001). AT1R expression was greater in the MIBC (P = .0004) and high-grade (P = .0063) specimens than in the NMIBC and low-grade specimens. In addition, the greater expression of AT1R was significantly associated with MVD (P < .05). In NMIBC, the factors significantly affecting recurrence-free survival on univariate analysis were AT1R (P = .02), MVD (P < .0001), tumor multiplicity (P = .0007), and bacille Calmette-Guerin intravesical instillation after TUR (P = .0026). Multivariate analysis revealed that tumor multiplicity and no BCG intravesical instillation after TUR were independent predictors of 5-year recurrence-free survival, and AT1R and MVD were independent predictors of 1-year recurrence-free survival (P < .01). CONCLUSIONS: AT1R expression and MVD were related to early intravesical recurrence in NMIBC. The results suggest that AT1R could become a new molecular target and a prognostic factor for NMIBC. PMID- 21296394 TI - Intact and internally cleaved free prostate-specific antigen in patients with prostate cancer with different pathologic stages and grades. AB - OBJECTIVES: To measure the concentration levels of free prostate-specific antigen (PSA) isoforms in patients with prostate cancer selected for curative treatment using radical prostatectomy and to study the association between the isoforms and the pathologic cancer stage and grade. METHODS: Preoperative plasma samples were obtained from 309 consecutive patients scheduled to undergo radical prostatectomy at Turku University Hospital. The pathologic TNM stage, Gleason score, and World Health Organization grade of the tumors were recorded. The total, free, and intact PSA (tPSA, fPSA, and fPSA-I, respectively) concentrations of the archived samples were measured with in-house immunoassays, and the nicked PSA (fPSA-N) concentrations (fPSA minus fPSA-I) and ratios of different PSA forms were calculated. These were compared with the prostate cancer stage, Gleason score, and World Health Organization grade. RESULTS: The median fPSA-I and fPSA-N concentrations in the patients with prostate cancer was 0.42 and 0.28 ng/mL, constituting an average of 60% and 40% of fPSA, respectively. The nicked/total PSA and free/total PSA ratios had the strongest negative correlations with a higher pathologic stage, Gleason score, and World Health Organization grade (Spearman rho -0.205 to -0.262, P < .05). Within a patient subgroup with tPSA <10 ng/mL, fPSA-N as a single marker had a negative correlation with a higher Gleason score (rho -0.160, P = .021). CONCLUSIONS: Lower proportions of fPSA-I and fPSA-N to total PSA were associated with a more advanced cancer stage and grade. A long term follow-up study and a comparison with currently used clinical methods are needed to evaluate the usefulness of the analytes as prognostic markers for cancer aggressiveness in individual patients. PMID- 21296395 TI - Laparoscopic nephrectomy for pelvic multicystic dysplastic kidney. AB - The management of multicystic dysplastic kidney (MCDK) is controversial. There has been a shift from routine surgical removal to nonoperative management. However, recently, an argument has emerged with regard to the management of MCDK, with several studies recommending surgical removal. We report a case of pelvic MCDK that was diagnosed and subsequently removed by a laparoscopic procedure. A laparoscopic approach to the renal and pelvic areas is a minimally invasive, safe, and effective procedure to diagnose and treat MCDK. We believe that laparoscopic nephrectomy should be offered as a management option to the families of children with unilateral MCDK. PMID- 21296396 TI - Persistent cloaca and partial caudal duplication: a case report. AB - Persistent cloaca and caudal duplication are 2 rare anomalies of embryogenesis that can present with a wide variety of pelvic malformations. Here we present the rare case of a female born with both abnormalities. The infant was born with a single introitus, an imperforate anus, a didelphys uterus, a duplicated cervix and vagina, and accessory limb and coccyx. Multiple surgeries were performed to correct for the anomalies that would have otherwise had important health and lifestyle consequences for the child. PMID- 21296397 TI - Robotic ureterolysis for relief of ureteral obstruction from retroperitoneal fibrosis. AB - OBJECTIVE: To review our experience with robotic surgery for the management of retroperitoneal fibrosis (RPF) with ureteral obstruction. Ureteral obstruction is common in retroperitoneal fibrosis RPF. METHODS: Since April 2006, 21 patients have presented to our institution with ureteral obstruction, apparently from RPF. All underwent robotic biopsy. If frozen pathology reveals malignancy, is equivocal, and/or the fibrotic reaction is extensive, we stent the obstructed side(s) and await final pathology. If RPF is confirmed, medical therapy is initiated to relieve obstruction; failures receive salvage ureterolysis. Lymphomas are referred to medical oncology. If frozen pathology demonstrates RPF, immediate ureterolysis is performed, if technically feasible. Ureterolysis is not performed for uninvolved contralateral systems. We reviewed data with institutional review board approval. RESULTS: Of 21 patients, 3 were diagnosed with lymphoma and 18 with RPF. Seventeen patients (21 renal units) with RPF received robotic ureterolysis (11 primary, 6 salvage); the other patient died of trauma before intervention. The only perioperative complication, an enterocutaneous fistula, required bowel resection. Three patients required a secondary procedure to relieve obstruction. At a mean follow-up of 20.5 months, no renal unit has evidence of obstruction, and all patients have improved or resolved symptoms. Furthermore, none of the 13 patients who underwent a unilateral ureterolysis have had disease progression to the contralateral side. CONCLUSIONS: Robotic ureterolysis can be performed with minimal morbidity and provides durable success rates for relief of symptoms and obstruction in RPF. Biopsy remains integral to ruling out lymphoma. Empiric contralateral ureterolysis may not be necessary. PMID- 21296398 TI - Logistic regression model for predicting stone-free rate after minimally invasive percutaneous nephrolithotomy. AB - OBJECTIVES: To investigate the prognostic factors associated with the treatment efficacy of minimally invasive percutaneous nephrolithotomy (MPCNL) and develop a preoperative logistic regression model for predicting the stone-free rate after the initial procedure. METHODS: We retrospectively analyzed the records of 865 patients who had undergone MPCNL in our department from January 2006 to September 2009. Patient age, sex, body mass index, degree of hydronephrosis, and stone side, number, size, and location were the investigated variables. According to the treatment outcome, the patients were divided into 2 groups, those who became stone free and those who did not. Student's t test, chi-square test, and multiple logistic regression analysis were performed to determine the statistically significant variables and to develop a predictive mathematical model. RESULTS: The stone-free rate after primary MPCNL was 80.1% (693 of 865). On univariate analysis, the stone number, size, and location and degree of hydronephrosis were identified as significant factors between the 2 groups. On multivariate analysis, they were also independent predictors of the surgical outcome. Next, a logistic regression model was developed using these variables to estimate the stone-free rate after MPCNL. CONCLUSIONS: The results of our study have demonstrated that an increased stone number and size, location in a calix, staghorn calculus, and moderate to severe hydronephrosis were associated with decreased stone-free rates after MPCNL. We have developed a mathematical model for predicting the stone-free rate that will be helpful for patient counseling and surgeon decision-making regarding the management of upper urinary tract calculi. PMID- 21296399 TI - Neoadjuvant systemic therapy or early cystectomy? Single-center analysis of outcomes after therapy for patients with clinically localized micropapillary urothelial carcinoma of the bladder. AB - OBJECTIVES: To analyze the treatment outcomes of patients with micropapillary bladder cancer (MPBC). MPBC is a rare variant of urothelial carcinoma with aggressive clinical behavior. Radical cystectomy is considered the standard approach for treatment of patients with localized disease; however, the role of perioperative systemic therapy has been poorly defined. MATERIAL AND METHODS: A retrospective review identified 38 consecutive patients who had been treated at our institution for MPBC from 2000 to 2010. The patient data were analyzed for the pre- and postoperative clinicopathologic features, treatment course, and cancer-specific survival. RESULTS: The median follow-up of surviving patients after cystectomy was 17 months (range 2-75). At the initial transurethral biopsy, 28 patients (74%) had clinical Stage T2N0 or less. In this group, 26 (93%) of 28 were upstaged to nonorgan-confined and/or lymph node-positive disease. Overall, 32 patients (86%) had evidence of lymph node metastasis on the final pathologic examination. All patients with cTis-T1 who had undergone initial bladder-sparing therapy with bacille Calmette-Guerin had pathologically advanced disease at cystectomy. All 15 patients who had received perioperative cisplatin-based chemotherapy died of metastatic disease. The 5-year overall survival rate was 40% (95% confidence interval 16-64). CONCLUSIONS: MPBC is an aggressive disease with a high likelihood of regional lymph node metastasis at the initial presentation. Although radical cystectomy plays a critical role in treatment, systemic neoadjuvant chemotherapy might be a more appropriate strategy than immediate cystectomy. Because of the poor response to current chemotherapy agents, the development of new and effective drugs for this subset of patients could be needed. PMID- 21296400 TI - Management of rectal injury during robotic radical prostatectomy. AB - OBJECTIVES: To review the incidence and management of rectal injury in 4400 consecutive cases of robotic radical prostatectomy at a single institution. MATERIAL AND METHODS: From September 2001 to September 2009, 4400 patients underwent robotic radical prostatectomy. We reviewed the intraoperative and postoperative data from patients with rectal injuries. Once recognized, the rectal injuries were closed in 2 layers. Clear liquids were started the day after surgery. Healing of the vesicourethral anastomosis was confirmed by cystography 5 14 days postoperatively. RESULTS: Rectal injuries were identified in 10 patients (0.2%). The mean patient age was 58.6 years (range 44-68), and the mean body mass index was 25.8 kg/m(2) (range 22-29). The mean prostate-specific antigen level was 7.1 ng/mL (range 0.9-14.8), and the mean prostate weight was 58.9 g (range 22 102). The clinical stage was T1c, T2a, and T2c in 7, 2, and 1 patient, respectively. The preoperative Gleason score was 6, 7, and 8 in 3, 3, and 4 patients, respectively. All rectal injuries were diagnosed and repaired intraoperatively. Of the 10 patients, 9 had an uneventful postoperative course. The average urethral catheterization time for these patients was 14 days (range 6 21). One patient had gross fecal spillage and developed a rectourethral fistula requiring a delayed diverting colostomy. No perioperative mortality occurred. CONCLUSIONS: We found a low incidence of rectal injury during robotic radical prostatectomy. We have also demonstrated that rectal injuries can be managed primarily with meticulous closure with minimal morbidity. PMID- 21296401 TI - Relational and social-cognitive correlates of early adolescents' forgiveness of parents. AB - This study examined how mother and father-child relationship quality and marital forgiveness were related to early adolescents' forgiveness of mothers and fathers. Adolescents' social-cognitive skills (empathy and emotional regulation) and parents' forgiveness of child were examined as mediators. Mother, father, and child self-reported questionnaires and observational data were taken from Time 1 and Time 3 (two years later) of the Flourishing Families Project, and included 334 two-parent families with an early adolescent (M age at Time 1 = 11.24; 51% male; 76% Caucasian). Using path analyses via structure equation modeling, mother child relationship quality and adolescents' own social-cognitive skills were salient correlates of adolescents' forgiveness toward parents. The unique contributions of mothers and fathers, differences by reporter, and the importance of studying forgiveness within the parent-child relationship are discussed. PMID- 21296402 TI - The end of the National Health Service? PMID- 21296403 TI - Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. AB - BACKGROUND: Systemic lupus erythematosus is a heterogeneous autoimmune disease that is associated with B-cell hyperactivity, autoantibodies, and increased concentrations of B-lymphocyte stimulator (BLyS). The efficacy and safety of the fully human monoclonal antibody belimumab (BLyS-specific inhibitor) was assessed in patients with active systemic lupus erythematosus. METHODS: Patients (aged >=18 years) who were seropositive with scores of at least 6 on the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) were enrolled in a multicentre phase 3 study, which was done in Latin America, Asia-Pacific, and eastern Europe. Patients were randomly assigned by use of a central interactive voice response system in a 1:1:1 ratio to belimumab 1 mg/kg or 10 mg/kg, or placebo by intravenous infusion in 1 h on days 0, 14, and 28, and then every 28 days until 48 weeks, with standard of care. Patients, investigators, study coordinators, and sponsors were masked to treatment assignment. Primary efficacy endpoint was improvement in the Systemic Lupus Erythematosus Responder Index (SRI) at week 52 (reduction >=4 points in SELENA-SLEDAI score; no new British Isles Lupus Assessment Group [BILAG] A organ domain score and no more than 1 new B organ domain score; and no worsening [<0.3 increase] in Physician's Global Assessment [PGA] score) versus baseline. Method of analysis was by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00424476. FINDINGS: 867 patients were randomly assigned to belimumab 1 mg/kg (n=289) or 10 mg/kg (n=290), or placebo (n=288). 865 were treated and analysed in the belimumab (1 mg/kg, n=288; 10 mg/kg, n=290) and placebo groups (n=287). Significantly higher SRI rates were noted with belimumab 1 mg/kg (148 [51%], odds ratio 1.55 [95% CI 1.10-2.19]; p=0.0129) and 10 mg/kg (167 [58%], 1.83 [1.30-2.59]; p=0.0006) than with placebo (125 [44%]) at week 52. More patients had their SELENA-SLEDAI score reduced by at least 4 points during 52 weeks with belimumab 1 mg/kg (153 [53%], 1.51 [1.07-2.14]; p=0.0189) and 10 mg/kg (169 [58%], 1.71 [1.21 2.41]; p=0.0024) than with placebo (132 [46%]). More patients given belimumab 1 mg/kg (226 [78%], 1.38 [0.93-2.04]; p=0.1064) and 10 mg/kg (236 [81%], 1.62 [1.09 2.42]; p=0.0181) had no new BILAG A or no more than 1 new B flare than did those in the placebo group (210 [73%]). No worsening in PGA score was noted in more patients with belimumab 1 mg/kg (227 [79%], 1.68 [1.15-2.47]; p=0.0078) and 10 mg/kg (231 [80%], 1.74 [1.18-2.55]; p=0.0048) than with placebo (199 [69%]). Rates of adverse events were similar in the groups given belimumab 1 mg/kg and 10 mg/kg, and placebo: serious infection was reported in 22 (8%), 13 (4%), and 17 (6%) patients, respectively, and severe or serious hypersensitivity reactions on an infusion day were reported in two (<1%), two (<1%), and no patients, respectively. No malignant diseases were reported. INTERPRETATION: Belimumab has the potential to be the first targeted biological treatment that is approved specifically for systemic lupus erythematosus, providing a new option for the management of this important prototypic autoimmune disease. FUNDING: Human Genome Sciences and GlaxoSmithKline. PMID- 21296404 TI - BLISS! Lupus learns its lessons. PMID- 21296405 TI - Amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is an idiopathic, fatal neurodegenerative disease of the human motor system. In this Seminar, we summarise current concepts about the origin of the disease, what predisposes patients to develop the disorder, and discuss why all cases of ALS are not the same. In the 150 years since Charcot originally described ALS, painfully slow progress has been made towards answering these questions. We focus on what is known about ALS and where research is heading-from the small steps of extending longevity, improving therapies, undertaking clinical trials, and compiling population registries to the overarching goals of establishing the measures that guard against onset and finding the triggers for this neurodegenerative disorder. PMID- 21296406 TI - The promotion of siRNA delivery to breast cancer overexpressing epidermal growth factor receptor through anti-EGFR antibody conjugation by immunoliposomes. AB - The LPD (liposome-polycation-DNA complex) is an effective nanovector for systemically small interfering RNA (siRNA) delivery which was well characterized previously. However, little effort was spend on the development of targeted LPD conjugated with tumor specific antibody (TLPD) which would be potent in promoting siRNA delivery in tumor. Here, we prepared TLPD through a self-assembling process followed by anti-EGFR antibody conjugation. The effect of antibody type, conjugation strategy and amount on the physicochemical and biological properties of TLPD was investigated. We obtained optimized TLPD conjugated with anti-EGFR Fab' by conventional conjugation (TLPD-FCC), which possessed a small size around 150nm and superior in vitro stability. Compared with nontargeted LPD (NTLPD), TLPD-FCC showed significantly enhanced binding affinity and luciferase gene silencing activity in EGFR overexpressing MDA-MB-231 breast cancer cells in vitro. Moreover, the in vivo accumulation of TLPD-FCC was obviously higher than that of NTLPD in MDA-MB-231 tumor 24h post intravenous injection. The promoted uptake of TLPD-FCC in MDA-MB-231 tumor was further confirmed by confocal microscopy. Notably, three intravenous injections of siRNA in TLPD-FCC significantly silenced luciferase expression by ~20%, whereas NTLPD showed little effect. All these results suggested that our TLPD-FCC have a great potential in delivering siRNA to EGFR overexpressing breast cancers. PMID- 21296407 TI - Cell affinity for bFGF immobilized heparin-containing poly(lactide-co-glycolide) scaffolds. AB - In order to effectively and uniformly immobilize basic fibroblast growth factor (bFGF) to thick PLGA scaffold, the heparin-conjugated PLGA (H-PLGA) was synthesized at the first by reaction between heparin and a low molecular weight PLGA. Then heparin-containing PLGA (H-PLGA/PLGA) scaffold was fabricated by blending the H-PLGA with a high molecular weight PLGA. Finally, bFGF was immobilized on the H-PLGA/PLGA scaffold mainly by static electricity action between them. The effect of H-PLGA content on bFGF binding efficiency of the H PLGA/PLGA scaffolds was investigated. It was found that bFGF binding efficiency increased with increasing H-PLGA content. The bound bFGF can release in vitro slowly from the H-PLGA/PLGA scaffolds and last over two weeks. The released bFGF has still preserved its bioactivity. The attachment and growth of mouse 3T3 fibroblasts on the H-PLGA/PLGA scaffolds were better than that on the PLGA scaffold, however bFGF immobilized H-PLGA/PLGA scaffolds showed much better cell affinity. Therefore, the method to use the H-PLGA/PLGA scaffold for immobilizing bFGF is not only effective for slow delivering bFGF with bioactivity, but also can be used for fabricating thick scaffold where bFGF could be combined and uniformly distributed. PMID- 21296408 TI - Transparent, tough collagen laminates prepared by oriented flow casting, multi cyclic vitrification and chemical cross-linking. AB - The lamellar architecture found in many natural fibrous tissues has a significant bearing on their specific functions. However, current engineered tissues have simultaneously no realistic structures and no adequate functions. This study demonstrates a two-step process for obtaining structurally mimicking laminates in natural fibrous tissues with good optical and mechanical characters from purified clinically-safe collagen molecules. Stacked lamella structures can be created by repeating flow casting, with the controlling parallel/orthogonal directionalities of each thin single-layer (2-5 MUm in thickness). The transparency of laminates is successfully improved by a unique multi-cyclic vitrification with chemical cross-linking. The directionalities of optical and mechanical functions in laminates are strongly related with the preferential collagen alignments in the laminates. The tensile strength of laminates is extremely higher than any other engineered materials as well as native cornea, which exhibit an orthogonal laminated collagen structure and a good optical transmission. PMID- 21296409 TI - Hierarchical nanoengineered surfaces for enhanced cytoadhesion and drug delivery. AB - Delivering therapeutics to mucosal tissues such as the nasal and gastrointestinal tracts is highly desirable due to ease of access and dense vasculature. However, the mucus layer effectively captures and removes most therapeutic macromolecules and devices. In previous work, we have shown that nanoengineered microparticles (NEMPs) adhere through the mucus layer, exhibiting up to 1000 times the pull-off force of an unmodified microsphere, and showing greater adhesion than some chemical targeting means. In this paper, we demonstrate that nanotopography improves device adhesion in vivo, increasing retention time up to ten-fold over unmodified devices. Moreover, we observe considerable adhesion in several cell lines using an in vitro shear flow model, indicating that this approach is promising for numerous tissues. We then demonstrate that nanowire-mediated adhesion is highly robust to variation in nanowire surface charge and cellular structure and function, and we characterize particle loading and elution. We present a form of cytoadhesion that utilizes the physical interaction of nanoengineered surfaces with subcellular structures to produce a robust and versatile cytoadhesive for drug delivery. These nanoscale adhesive mechanisms are also relevant to fields such as tissue engineering and wound healing because they likely affect stem cell differentiation, cell remodeling, migration, etc. PMID- 21296410 TI - An overview of tissue and whole organ decellularization processes. AB - Biologic scaffold materials composed of extracellular matrix (ECM) are typically derived by processes that involve decellularization of tissues or organs. Preservation of the complex composition and three-dimensional ultrastructure of the ECM is highly desirable but it is recognized that all methods of decellularization result in disruption of the architecture and potential loss of surface structure and composition. Physical methods and chemical and biologic agents are used in combination to lyse cells, followed by rinsing to remove cell remnants. Effective decellularization methodology is dictated by factors such as tissue density and organization, geometric and biologic properties desired for the end product, and the targeted clinical application. Tissue decellularization with preservation of ECM integrity and bioactivity can be optimized by making educated decisions regarding the agents and techniques utilized during processing. An overview of decellularization methods, their effect upon resulting ECM structure and composition, and recently described perfusion techniques for whole organ decellularization techniques are presented herein. PMID- 21296411 TI - Engineering fibrinogen-binding VSV-G envelope for spatially- and cell-controlled lentivirus delivery through fibrin hydrogels. AB - We recently demonstrated that fibrin hydrogels can be used as vehicles for efficient lentivirus gene delivery. Gene transfer in fibrin gels was strongly dependent on matrix degradation by target cells but a fraction of lentiviral particles diffused out of the gels over time compromising spatial control of gene transfer. To overcome this challenge, we engineered lentiviral particles that bind covalently to fibrin during polymerization. To this end, we fused into the viral envelope glycoprotein (VSV-G) peptide domains that are recognized by factor XIII and protease cleavage sites that are recognized by plasmin. Lentivirus pseudotyped with the modified envelopes bound to fibrinogen in a factor XIII dose dependent manner and was released upon plasmin treatment. The peptide/VSV-G fusion envelope variants did not compromise the transduction efficiency of the resulting virus except when lacking any flexible linkers separating the peptide from the VSV-G envelope. Diffusion of virus from the gels decreased dramatically, especially at high concentrations of FXIII, even for fibrin gels with low fibrinogen concentration that were loaded with high titer virus. Lentivirus arrays prepared with fibrin-conjugated lentivirus yielded highly efficient gene transfer that was confined to virus-containing fibrin spots. As a result, signal/noise ratio increased and cross-contamination between neighboring sites was minimal. Finally, in addition to lentivirus microarrays this strategy may be used to achieve spatially-controlled gene transfer for therapeutic applications. PMID- 21296412 TI - A self-assembling hydrophobically modified chitosan capable of reversible hemostatic action. AB - Blood loss at the site of a wound in mammals is curtailed by the rapid formation of a hemostatic plug, i.e., a self-assembled network of the protein, fibrin that locally transforms liquid blood into a gelled clot. Here, we report an amphiphilic biopolymer that exhibits a similar ability to rapidly gel blood; moreover, the self-assembly underlying the gelation readily allows for reversibility back into the liquid state via introduction of a sugar-based supramolecule. The biopolymer is a hydrophobically modified (hm) derivative of the polysaccharide, chitosan. When hm-chitosan is contacted with heparinized human blood, it rapidly transforms the liquid into an elastic gel. In contrast, the native chitosan (without hydrophobes) does not gel blood. Gelation occurs because the hydrophobes on hm-chitosan insert into the membranes of blood cells and thereby connect the cells into a sample-spanning network. Gelation is reversed by the addition of alpha-cyclodextrin, a supramolecule having an inner hydrophobic pocket: polymer hydrophobes unbind from blood cells and embed within the cyclodextrins, thereby disrupting the cell network. We believe that hm chitosan has the potential to serve as an effective, yet low-cost hemostatic dressing for use by trauma centers and the military. Preliminary tests with small and large animal injury models show its increased efficacy at achieving hemostasis - e.g., a 90% reduction in bleeding time over controls for femoral vein transections in a rat model. PMID- 21296413 TI - Differentiation of cardiosphere-derived cells into a mature cardiac lineage using biodegradable poly(N-isopropylacrylamide) hydrogels. AB - A family of injectable and thermosensitive hydrogels suitable for myocardial injection was developed to deliver cardiosphere-derived cells (CDCs), an emerging and promising cell type for cardiac cell therapy. The hydrogels were based on polycaprolactone, N-isopropylacrylamide, 2-hydroxyethyl methacrylate and dimethyl gamma-butyrolactone acrylate. Atom transfer radical polymerization was used to synthesize hydrogels with a well-defined structure and well-controlled properties. The hydrogel solutions possessed thermal transition temperatures around room temperature and exhibited injectability suitable for myocardial injection. At 37 degrees C, the hydrogel solutions were capable of forming solid gels within 5s. This would allow the hydrogels to largely retain in the heart during injection. The hydrogels were highly flexible at body temperature with moduli matching those of the rat and human myocardium, and breaking strains higher than those of the myocardium, enabling them to respond synchronically with heart motion. The well-controlled polymer structure allowed for precisely controlling and decoupling water content and stiffness that affect cell differentiation. DNA assay demonstrated that CDCs proliferated in the 3D hydrogels during a 2-week culture period. CDCs maintained their colony formation capability in the hydrogel. Interestingly, hydrogels directed CDCs differentiation into mature cardiac lineage. At mRNA level, the mature cardiac specific transcript factors cardiac troponin T (cTnT) and cardiac myosin heavy chain (MYH6) were up-regulated, while the pre-mature cardiac marker GATA4 was down-regulated even after 1 day of encapsulation. CDC differentiation was interplayed by hydrogel stiffness and collagen in the hydrogel. Hydrogel with modulus ~31 kPa was found to more significantly up-regulate cardiac expression than that with modulus ~5 or ~63 kPa. cTnT expression was largely regulated by both stiffness and collagen while MYH6 was mainly regulated by stiffness. Immunohistochemistry study showed that CDCs expressed cardiac troponin I and MYH6 proteins after 2 weeks of culture. These results demonstrate that the thermosensitive hydrogels not only possess physical properties suitable for myocardial injection, but also promote CDC proliferation and cardiac differentiation. These hydrogels represent potential candidates for delivery of CDCs into infarcted hearts. PMID- 21296414 TI - Regulation of stem cell signaling by nanoparticle-mediated intracellular protein delivery. AB - Intracellular delivery of specific proteins and peptides may be used to influence signaling pathways and manipulate cell function, including stem cell fate. Herein, we describe the delivery of proteins attached to hydrophobically modified 15-nm silica nanoparticles to manipulate specifically targeted cell signaling proteins. We designed a chimeric protein, GFP-FRATtide, wherein GFP acts as a biomarker for fluorescence detection, and FRATtide binds to and blocks the active site of glycogen synthase kinase-3beta (GSK-3beta) - a protein kinase involved in Wnt signaling. The SiNP-chimeric protein conjugates were efficiently delivered to the cytosol of human embryonic kidney cells and rat neural stem cells, presumably via endocytosis. This uptake impacted the Wnt signaling cascade, resulting in an elevation of beta-catenin levels due to GSK-3beta inhibition. Accumulation of beta-catenin led to increased transcription of Wnt target genes, such as c-MYC, which instruct the cell to actively proliferate and remain in an undifferentiated state. The results presented here suggest that functional proteins can be delivered intracellularly in vitro using nanoparticles and used to target key signaling proteins and regulate cell signaling pathways. This ability is critical for the design of in vitro screens for gain/loss of pathway function, and may also prove to be useful for in vivo delivery applications. PMID- 21296415 TI - Inhibition of human brain malignant glioblastoma cells using carmustine-loaded catanionic solid lipid nanoparticles with surface anti-epithelial growth factor receptor. AB - Innovated catanionic solid lipid nanoparticles (CASLNs) carrying carmustine (BCNU) (BCNU-CASLNs) were grafted with anti-epithelial growth factor receptor (EGFR) (anti-EGFR/BCNU-CASLNs) and applied to inhibiting the propagation of human brain malignant glioblastomas cells. U87MG cells were treated with anti-EGFR/BCNU CASLNs and stained for the expression of EGFR. The minimal average diameter of BCNU-CASLNs and maximal entrapment efficiency of BCNU emerged when the concentration of catanionic surfactants was 1 mm. An increase in the weight percentage of cacao butter (CB) reduced the zeta potential, enhanced the viability of human brain microvasscular endothelial cells (HBMECs), and decreased the expression of tumor necrosis factor-alpha by HBMECs. The dissolution rate of BCNU and inhibition against the multiplication of U87MG cells using anti EGFR/BCNU-CASLNs followed the order: 100% CB > 0% CB > 50% CB. Anti-EGFR/BCNU CASLNs demonstrated the properties including an effective delivery to U87MG cells and antiproliferative efficacy against the growth of malignant brain tumors. PMID- 21296416 TI - BRCA1 suppresses the expression of survivin and promotes sensitivity to paclitaxel through the calcium sensing receptor (CaSR) in human breast cancer cells. AB - Both BRCA1 and CaSR have been shown to suppress the expression of survivin and promote sensitivity to paclitaxel in human breast cancer cells. In this study we determined the functional linkage, if any, between BRCA1 and CaSR. We found that mutant cells (harboring mutant BRCA1 with loss of BRCA1 expression) had a significant reduction in the expression of CaSR with a concurrent up-regulated expression of survivin and were resistant to paclitaxel by comparison to wild type cells (harboring wild type BRCA1 and expressing BRCA1). Knocking down the expression of BRCA1 in wild type cells resulted in a reduction in CaSR expression with a concurrent up-regulated expression of survivin and reduction in sensitivity to paclitaxel. Re-expression of BRCA1 in BRCA1 knocked-down wild type cells restored CaSR expression with a concurrent down-regulated expression of survivin and restoration of sensitivity to paclitaxel. Corollary, ectopic expression of BRCA1 in mutant cells induced CaSR expression, suppressed the expression of survivin and restored sensitivity to paclitaxel. These results suggest that BRCA1 action is linked to that of CaSR. In a final series of experiments, we show that ectopic expression of CaSR in either the BRCA1 knocked down wild type or mutant cells suppressed the expression of survivin and promoted sensitivity to paclitaxel. Thus, CaSR can rescue BRCA1 defective cells from the deleterious effects of loss of BRCA1 function. CaSR expression, however, had no effect on the expression of BRCA1. BRCA1 could stimulate the transcriptional activities of the CaSR gene and shRNA targeting CaSR circumvented the action of BRCA1. We conclude, and report for the first time, that BRCA1 regulates the expression of CaSR and that it functions through CaSR in suppressing the expression of survivin and promoting sensitivity to paclitaxel. PMID- 21296417 TI - Neuromedin U(2) receptor signaling mediates alteration of sleep-wake architecture in rats. AB - Growing evidence indicates that neuromedin U (NmU) neuropeptide system plays an integral role in mediating the stress response through the corticotrophin releasing factor (CRF) pathways. Stress is often associated with alteration in sleep-wake architecture both in human and laboratory animals. Here, we investigated whether activation of the NmU2 receptor, a major high affinity receptor for NmU predominantly expressed in the brain, affects sleep behavior in rats. Effects of single (acute) intracebroventricular (icv) infusion of 2.5 nmol of the full agonists porcine NmU8 and rat NmU23 were assessed on sleep-wake architecture in freely moving rats, which were chronically implanted with EEG and EMG electrodes. In addition, repeated once daily administration of NmU8 at 2.5 nmol during 8 consecutive days (sub-chronic) was studied. Acute icv infusion of NmU23 elicited a robust alteration in sleep-wake architecture, namely enhanced wakefulness and suppressed sleep during the first 4h after administration. Acute infusion NmU8 had no effect on spontaneous sleep-wake architecture. However, sub chronic icv infusion of NmU8 increased the amount of rapid eye movement (REM) sleep and intermediate stage (IS), while decreased light sleep. Additionally, NmU8 increased transitions from sleep states towards wakefulness suggesting a disruption in sleep continuity. The present results show that central-activation of NmU2 receptor markedly reduced sleep duration and disrupted the mechanisms underlying NREM-REM sleep transitions. Given that sleep-wakefulness cycle is strongly influenced by stress and the role of NmU/NmU2 receptor signaling in stress response, the disruption in sleep pattern associated with peptides species may support at least some signs of stress. PMID- 21296418 TI - Bone marrow fibrosis in myeloproliferative neoplasms-associated myelofibrosis: deconstructing a myth? AB - The dominant pathophysiological and clinical features of myeloproliferative neoplasm (MPN)-associated myelofibrosis are caused by bone marrow fibrosis. It is widely believed this fibrosis is a reaction to the MPN-clone implying the cells causing fibrosis are polyclonal and genetically unrelated to the MPN-clone. We cite recent data illustrating the complexity of cell types comprising the bone marrow micro-environment and showing that at least some of the cells responsible for bone marrow fibrosis are clonal and genetically related to the MPN-clone. PMID- 21296419 TI - RAD51 and XRCC3 polymorphisms: impact on the risk and treatment outcomes of de novo inv(16) or t(16;16)/CBFbeta-MYH11(+) acute myeloid leukemia. AB - DNA double-strand break repair via homologous recombination (HR) is essential in maintaining genetic integrity, and may modulate susceptibility to the development of acute myeloid leukemia (AML) and influence outcomes of AML. This study was designed to evaluate the effects of polymorphisms in HR repair genes RAD51 and XRCC3 on the risk and treatment outcomes of inv(16)/t(16;16)/CBFbeta-MYH11(+) AML. The distribution of polymorphisms in RAD51-G135C and XRCC3-Thr241Met were studied by PCR-RFLP analysis in 625 cases of de novo AML, including 105 cases with inv(16)/t(16;16)/CBFbeta-MYH11, 806 family controls and 704 volunteer controls. It was found that the XRCC3-241Met variant significantly increased the risk of the development of the AML with inv(16)/t(16;16) as compared with both the volunteer control (OR=7.22; 95% CI, 4.37-11.91) and the family control (OR=7.99; 95% CI, 5.03-12.69). A retrospective study conducted in 103 inv(16)/t(16;16) AML patients. In multivariate analysis for the potential prognostic factors, the XRCC3-241Met variant significantly reduced disease-free survival (DFS) in complete remission (CR) achieved patients (HR=2.34, 95% CI, 1.32-4.16). These data indicate that the XRCC3-241Met variant may not be only a susceptibility factor to the AML with inv(16)/t(16;16), but also an independent poor-prognostic factor for this AML subtype. PMID- 21296420 TI - Effect of cadmium on the ovarian development in the freshwater prawn Macrobrachium rosenbergii (De Man). AB - In this investigation, effect of cadmium chloride (25 MUg/l) on oogenesis of freshwater prawn, Macrobrachium rosenbergii was studied. In vivo experiments were performed with both intact and eyestalk ablated prawns. The intact, cadmium exposed prawns exhibited decrease in Gonado Somatic Index (GSI) and ovarian development compared to controls. Whereas, ablated treated ovary showed reduction of yolk material and oocyte membrane thickness at the end of 15 days exposure. Interestingly, the control prawn showed normal cellular architecture of gills, hepatopancreas and ovary with mature oocytes. But, the gills of treated prawns showed lamellar hypertrophy, cuticular dystrophy and irregular arrangement of epithelial cells. Hepatopancreas showed reduction in both tubular diameter and basement membrane thickness. Conspicuously, ovary showed hypertrophied primary oocytes with more vacuoles in intact-treated group. Cadmium had increased gonad inhibiting hormone (GIH) secretion and decreased gonad stimulating hormone (GSH) release as evident with the retardation of gonadal maturation in the intact prawns. PMID- 21296421 TI - Mercury concentrations are low in commercial fish species of Lake Ziway, Ethiopia, but stable isotope data indicated biomagnification. AB - Stable isotope ratios of nitrogen (delta(15)N) and carbon (delta(13)C), complemented by stomach content data, were used to assess the food web structure and trophic transfer of mercury (Hg) in four commercial fish species of Lake Ziway, Ethiopia: Nile tilapia (Oreochromis niloticus), catfish (Clarias gariepinus), Tilapia zillii, and golden carp (Carassius auratus). Total mercury (THg in mg kg(-1), ww) concentrations were low, with mean values of 0.033, 0.034, 0.025, and 0.011, in C. gariepinus, T. zillii, C. auratus, and O. niloticus, respectively. The relationships between mercury concentrations against total length (TL) and total weight (TW) were positive and significant in T. zillii, C. auratus, and C. gariepinus (P<0.01), but not in O. niloticus, which even showed a decreasing tendency with increase in TL and TW. Regression of log THg vs. delta(15)N among all fish species showed a significant correlation, indicating that mercury is biomagnifying along the food web of Lake Ziway. Isotope ratios indicated that C. gariepinus occupied the highest trophic level of the food web of Lake Ziway; but contained similar THg concentrations as T. zillii, which is located at a lower trophic level, probably due to a faster growth rate of C. gariepinus, and thus an example of biodilution. PMID- 21296422 TI - Suitability of lysosomal membrane stability in Eisenia fetida as biomarker of soil copper contamination. AB - Accumulated metals in soils negatively affect dwelling organisms. Earthworms, which are widespread and perform various essential functions, are able to accumulate metals that can damage the coelomic cells. The aim of this work was to evaluate the effect on Eisenia fetida lysosomal membrane stability both during and after copper exposure, and finally to link this to internal concentrations. E. fetida specimens were exposed to a reference soil and two Cu-spiked soils (35 and 350 mg kg(-1) d.w.) for 14 days (uptake period) and then transferred into the reference soil for other 18 days (elimination period). After 3 days of uptake, internal Cu concentrations increased and were higher in the specimens exposed to soils spiked with 350 mg Cu kg(-1) d.w. After 2 days of elimination, a strong decrease of internal Cu concentrations was always observed. The lysosomal membrane stability, measured as neutral red retention-times, was approximately 50 min for the earthworms exposed to the reference soils, whereas it decreased, at the end of the uptake period, to 21 and 13 min, respectively, for the organisms exposed to soils spiked with 35 and 350 mg Cu kg(-1) d.w. A full recovery of the lysosomal membrane stability was reached after 14 and 18 days of the elimination period, respectively, for the organisms exposed to soils spiked with 35 and 350 mg Cu kg(-1) d.w. The neutral-red assay would seem a good biomarker since the lysosomal membrane stability of E. fetida appeared to respond rapidly and strongly to soil copper contamination. PMID- 21296423 TI - A literature review on the safety assessment of genetically modified plants. AB - In recent years, there has been a notable concern on the safety of genetically modified (GM) foods/plants, an important and complex area of research, which demands rigorous standards. Diverse groups including consumers and environmental Non Governmental Organizations (NGO) have suggested that all GM foods/plants should be subjected to long-term animal feeding studies before approval for human consumption. In 2000 and 2006, we reviewed the information published in international scientific journals, noting that the number of references concerning human and animal toxicological/health risks studies on GM foods/plants was very limited. The main goal of the present review was to assess the current state-of-the-art regarding the potential adverse effects/safety assessment of GM plants for human consumption. The number of citations found in databases (PubMed and Scopus) has dramatically increased since 2006. However, new information on products such as potatoes, cucumber, peas or tomatoes, among others was not available. Corn/maize, rice, and soybeans were included in the present review. An equilibrium in the number research groups suggesting, on the basis of their studies, that a number of varieties of GM products (mainly maize and soybeans) are as safe and nutritious as the respective conventional non-GM plant, and those raising still serious concerns, was currently observed. Nevertheless, it should be noted that most of these studies have been conducted by biotechnology companies responsible of commercializing these GM plants. These findings suggest a notable advance in comparison with the lack of studies published in recent years in scientific journals by those companies. All this recent information is herein critically reviewed. PMID- 21296424 TI - Crossing, grading, and keeping pure: animal breeding and exchange around 1860. AB - During the first half of the nineteenth century, breeders of livestock in the United States and Germany began to approach animal husbandry in a more systematic manner. Responding to changes in ideas about heredity and economic pressures, they imported large numbers of animals from abroad, especially from Great Britain. With these imported breeds they set out to transform their native specimens to better meet the needs of an industrializing nation. Their strategies for animal improvement, which included grading, crossing, and pure breeding, constituted practical experiments into heredity that ran parallel to the work of naturalists. By 1860, the modern system of breeding, with its attention to public registries of pedigrees, gained increasing influence in both contexts. PMID- 21296425 TI - Involvement of caveolin-1 in the Jak-Stat signaling pathway and infectious spleen and kidney necrosis virus infection in mandarin fish (Siniperca chuatsi). AB - Caveolae, the major source of caveolin-1 protein, are specialized invaginated microdomains of the plasma membrane that act as organizing centers for signaling molecules in the immune system. In the present study, we report the cloning and characterization of caveolin-1 (mCav-1) from mandarin fish (Siniperca chuatsi) and study on the roles of mCav-1 in the fish Jak-Stat signaling pathway and in virus infection. The cDNA sequence of mCav-1 was 707bp in size, encoding a protein of 181 amino acids, which was different from the mammalian protein (178 amino acids). The deduced amino acid sequence of mCav-1 shared similar architecture with vertebrate caveolin-1 proteins, but mCav-1 lacked a phosphorylation site (y14). The major subcellular location of mCav-1 was in the caveolae, where the protein appeared to have major functions. Real-time PCR revealed that the expression of the mandarin fish Mx, IRF-1, SOCS1, and SOCS3 genes involved in the poly(I:C)-induced Jak-Stat signaling pathway was impaired by the mCav-1 scaffolding domain peptide (mSDP). In mandarin fish fry (MFF-1) cells, the protein levels of mCav-1 were markedly up-regulated at 12 and 24h post infection with ISKNV (infectious spleen and kidney necrosis virus). In addition, ISKNV entry into MFF-1 cells was significantly inhibited by mSDP, and the inhibition was dose-dependent. Thus, ISKNV infection was apparently associated with mCav-1 protein and may utilize the caveolae-related endocytosis pathway. The findings reported here further our understanding of the function of caveolin-1 in the complex signal transduction network in fish immune systems and in the cellular entry mechanism of iridoviruses. PMID- 21296426 TI - School performance and risk of suicide in early adulthood: follow-up of two national cohorts of Swedish schoolchildren. AB - BACKGROUND: Poor school performance and low IQ are associated with an increased risk of suicide in males; it is uncertain whether cognitive performance is a risk factor for suicide in females and whether severe mental illness influences these associations. METHOD: Record linkage study of Swedish education, population and census data with mortality and inpatient registers. Data were available for 95,497 males and 91,311 females born in 1972 and 1977 and followed up until 31 December 2005. RESULTS: 230 males and 90 females died from suicide over the follow-up period. There were strong inverse associations between school performance at age 16 and subsequent suicide risk in males (fully adjusted hazard ratio (HR) per SD increase in school performance score: 0.6 (95% CI 0.6 to 0.7; p < 0.001)) but not females: adjusted HR. 1.1 (CI 0.9 to 1.4 p = 0.50). In males there were almost four fold differences in suicide risk between children in the top and bottom fifths of the range of school grade scores. Similar associations were seen with upper secondary school performance (age 18/19 years). There was no strong evidence that deterioration in school performance between ages 16 and 18 was associated with increased suicide risk. Amongst men who developed severe psychiatric illness school performance was not associated with suicide risk. LIMITATIONS: We had limited information on the prevalence of minor psychiatric disorder in cohort members and no data on IQ for the cohort as a whole. CONCLUSIONS: Good performance in secondary (age 16) and upper secondary (age 18) school is associated with a reduced risk of suicide in men but not women. This protective effect is not seen amongst those who develop severe psychiatric illness. These differences indicate that the aetiology of suicide differs in males and females and in those with and without severe mental illness. PMID- 21296427 TI - Increased prevalence of sexually transmitted viral infections in women: the role of female sex hormones in regulating susceptibility and immune responses. AB - Sexually transmitted infections (STIs) caused by viruses, including HSV-2, HIV-1, HPV, are among the most prevalent infectious diseases worldwide and a major cause of morbidity and mortality. Despite decades of effort, the attempts to develop efficacious vaccines against viral STIs have failed repeatedly, with the exception of the recent HPV vaccine. Given the higher prevalence rates of STIs in women, it is becoming clear that a better understanding of gender-specific differences in STIs may be critical for the development of preventative strategies for these diseases. In order to gain this insight, it is important to examine the distinct microenvironment of the female reproductive tract, the site of primary infection, since it can significantly influence the outcome of infection. An important biological factor in the female reproductive tract is the presence of female sex hormones, estrogen and progesterone, which are produced endogenously primarily by the ovaries and commonly provided exogenously via the use of hormonal contraceptives. Here we review our current knowledge of the role played by the female sex hormones in regulating susceptibility and immune responses to viral sexually transmitted infections and whether this could contribute to higher prevalence of STIs in women. Manipulating the microenvironment of the female genital tract with sex hormones may contribute to the development of improved immunization strategies against sexually transmitted infections. PMID- 21296428 TI - Change in visa status amongst Mandaean refugees: relationship to psychological symptoms and living difficulties. AB - Policies of deterrence, including the use of detention and temporary visas, have been widely implemented to dissuade asylum seekers from seeking protection in Western countries. The present study examined the impact of visa status change on the mental health of 97 Mandaean refugees resettled in Australia. At the time of the first survey (2004), 68 (70%) participants held temporary protection visas (TPVs) and 29 (30%) held permanent residency (PR) status, whereas by the second survey (2007), 97 (100%) participants held PR status. We tested a meditational model to determine whether the relationship between change in visa status and change in psychological symptoms was mediated by change in living difficulties associated with the visa categories. The conversion of visa status from TPV to PR status was associated with significant improvements in PTSD and depression symptoms, and increases in mental health-related quality of life (MHR-QOL). The relationship between change in visa status and reduced PTSD and depression symptoms was mediated by reductions in living difficulties. In contrast, the relationship between change in visa status and increased MHR-QOL was not mediated by changes in living difficulties. These results suggest that restriction of rights and access to services related to visa status negatively affect the mental health of refugees. Implications for government policies regarding refugees are discussed. PMID- 21296429 TI - Measuring communicative performance with the German version of the FAPCI instrument: normative data and longitudinal results. AB - OBJECTIVE: The German version of the Functioning after Paediatric Cochlear Implantation (FAPCI) inventory was designed to capture the communicative performance of cochlear implanted children. In order to be able to compare cochlear-implanted children to their normal hearing peers, normative growth curves were designed. Furthermore it was of interest how the communicative performance develops over time and whether it is influenced by age at implantation. METHOD: A polynomial regression curve was fit to the data of 133 normal hearing children. This normative curve was compared to individual growth curves of 90 cochlear implanted children. The cochlear-implanted study sample was split up into four groups depending on the age at implantation. RESULTS: The normative growth curve increases from 1 year of age until saturation is reached with 3 years of age. The individual FAPCI trajectories of cochlear implanted children are heterogeneous, but in general they are delayed in comparison to the normative growth curve. "Early implanted children" follow the development of their normal hearing peers more closely than "later-implanted children". CONCLUSION: The German version of the FAPCI parental questionnaire constitutes an additional instrument in monitoring the communicative performance development of cochlear implanted children and allows for comparison to normal hearing peers. PMID- 21296430 TI - Colchicine prolongs patency of myringotomy in an animal model. AB - OBJECTIVE: Chronic otitis media with effusion (COME) is a frequently observed condition in childhood. The most common and effective surgical therapy for COME is myringotomy with insertion of a ventilation tube (VT). Our aims were to investigate the combined effect of myringotomy and the topical application of Colchicine solution to the external ear canal for the prolongation of patency in the treatment of patients with COME and to evaluate the ototoxicity of Colchicine applied directly to the middle ear. METHODS: A prospective study on 47 ears in 26 fat sand rats was fashioned. In the first phase, solutions of different concentrations of Colchicine were applied to the middle ear cavity in order to determine the drug's ototoxicity, assessing inner ear function with ABR. In the second phase myringotomy was performed and a non ototoxic concentration of Colchicine applied to 12 external ear canals, while saline was applied to nine. RESULTS: In the first phase, Colchicine concentration of 0.1% and higher applied to the middle ear cavity caused an ABR threshold elevation. In the second phase, the mean closure time after 0.01% Colchicine application was prolonged to >2.14 weeks (P<0.05). CONCLUSION: Colchicine has a proven potential for prolongation of myringotomy patency when applied as a solution to the external ear as a 0.01% solution. Further investigations are required to validate these results in humans and to study the potential effect of repetitive Colchicine application on the duration of myringotomy patency for the treatment of COME. PMID- 21296431 TI - Histopathologic investigation of the dimensions of the cochlear nerve canal in normal temporal bones. AB - OBJECTIVE: Establish normative histopathologic data on the dimensions of the cochlear nerve canal (CNC). BACKGROUND: Evidence suggests that when the CNC is stenotic, the cochlear nerve may be hypoplastic. There is clear agreement in the literature that an internal auditory canal less than 2 mm in diameter is a relative contraindication to cochlear implantation in children. However, there has only been recent recognition in research that a narrowed CNC may lead to diminished ability to interpolate and use auditory information delivered through a cochlear implant. However, there is no consensus in the literature on the normal diameter of the CNC and what parameters should be used to determine stenosis. In addition, no normative histopathologic data is available for CNCs. METHODS: This study evaluated histopathologic axial sections from normal human temporal bones to measure the cochlear nerve canal in 110 individuals, aged 0-100 years. The maximum CNC diameter in each normal patient was identified and measured. RESULTS: The mean CNC diameter was 2.26 mm with a standard deviation of 0.25 mm. There were no differences in the CNC diameters between males and females or with increasing age. CONCLUSION: These measurements should provide a normative reference for comparison in histopathologic and radiographic assessment of any patient with suspected cochlear nerve canal stenosis. PMID- 21296432 TI - Measuring communicative performance with the FAPCI instrument: preliminary results from normal hearing and cochlear implanted children. AB - OBJECTIVE: To develop preliminary "growth curves" of Functioning after Pediatric Cochlear Implantation (FAPCI) scores using a cross-sectional sample of normal hearing children and to compare these curves to trajectories of FAPCI scores in children receiving cochlear implants. METHODS: Quantile regression was used to develop growth curves from the FAPCI scores of a cross-sectional sample of 82 normal hearing children (age range 7 months-5 years). Trajectories of FAPCI scores from a longitudinal cohort of 75 children with cochlear implants (age range 1-5 years) were compared to these growth curves. RESULTS: FAPCI scores were positively associated with increasing age in normal hearing children with a rapid increase in scores observed at earlier ages followed by a plateau at age 3 years. FAPCI trajectories for cochlear-implanted children varied with age at implantation and did not reach a plateau until age 5-6 years. CONCLUSION: Normal hearing children demonstrated increasing FAPCI scores with age, and these preliminary growth curves allow for the interpretation of a cochlear-implanted child's FAPCI scores in comparison to normal hearing children. Additional research using a larger, longitudinal cohort of normal hearing children will be needed to develop definitive normative FAPCI trajectories. PMID- 21296433 TI - Malondialdehyde-modified LDL to HDL-cholesterol ratio reflects endothelial damage. PMID- 21296434 TI - Azathioprine in isolated recurrent pericarditis: a single centre experience. PMID- 21296435 TI - Multiple myocardial crypts on cardiac CT angiography in a symptomatic patient with troponin elevation. PMID- 21296436 TI - Bosentan improves systemic sclerosis-related peripheral circulation insufficiency. PMID- 21296437 TI - Association between acute infections and risk of acute coronary syndrome: a meta analysis. PMID- 21296438 TI - Heme oxygenase 1 regulates the maturation process and inflammatory response in oxLDL-stimulated dendritic cells. PMID- 21296439 TI - Recurrent focal cardio-myocyte necrosis in severe aortic regurgitation. PMID- 21296440 TI - Repeated linac-based radiosurgery in high-grade cerebral arteriovenous malformations (AVM) Spetzler-Martin grade III to IV previously treated with radiosurgery. AB - BACKGROUND: Aim was to access outcome and toxicity of repeated linac-based radiosurgery in incompletely obliterated cerebral AVM. PATIENTS AND METHODS: Between 1998 and 2008, 11 patients were treated with repeated radiosurgery. The median dose to the 80%-isodose was 15 Gy (range, 12-18 Gy). During initial radiosurgery the median dose was 18 Gy (range, 9-22 Gy). RESULTS: The median time interval between initial radiosurgery and re-treatment was 9 years (range, 4-16 years). The median follow-up was 26 months (range, 2-115 months). Treatment response was seen in 8 patients (89%). Complete (partial) obliteration was achieved in 5 (3) patients (56%, 33%, respectively).The median time to complete obliteration was 26 months (range, 5-45 months). Pre-existing neurological symptoms improved in 2 patients (18%), were stable in 7 patients (64%) and worsened in 2 patients (18%). Prevalence of intracranial hemorrhage was 9% (1/11). Post-re-treatment intracranial hemorrhage rate was 2.7% (1/38 years at risk). During follow-up, no secondary malignancies or toxicity>grade III were observed. CONCLUSION: Repeated linac-based radiosurgery in incompletely obliterated cerebral AVM is an effective treatment option with a high rate of treatment response and an acceptable risk for side effects. Marginal doses above 15 Gy might further improve the rate of complete obliterations. PMID- 21296441 TI - Large breast size as a risk factor for late adverse effects of breast radiotherapy: is residual dose inhomogeneity, despite 3D treatment planning and delivery, the main explanation? AB - BACKGROUND AND PURPOSE: Large breast size is associated with an increased risk of late adverse effects after breast conservation surgery and radiotherapy, even when 3D dosimetry is used. The purpose of this study is to test the hypothesis that residual dose inhomogeneity is sufficient to explain the association. METHODS: Patients previously treated after breast conservation surgery with whole breast radiotherapy using 3D dosimetry and followed up in the UK FAST hypofractionation trial were selected for this analysis. The residual level of dose inhomogeneity across the whole breast treatment volume was used to test for association between residual dosimetry and post-treatment change in breast appearance at 2 years post-radiotherapy. RESULTS: At 2 years, 201/279 (72%) of women had no change in photographic breast appearance, 61 (22%) had mild change and 17 (6%) had marked change. Breast size and dosimetry were both significantly associated with late effects in univariate analyses, but only breast size remained an independent significant risk factor for change in breast appearance when included in a multiple regression model together with other prognostic factors (p=0.006 for trend). CONCLUSION: Large-breasted women are more likely to suffer change in breast size and shape after whole breast radiotherapy delivered using 3D dosimetry, but residual dose inhomogeneity is insufficient to explain the association. PMID- 21296442 TI - Tyrosine positron emission tomography and protein synthesis rate in pituitary adenoma: different effects of surgery and radiation therapy. AB - INTRODUCTION: Positron emission tomography (PET) using amino acid tracers is able to establish biochemical tumour characterization in vivo. The use of PET in the follow-up of non-functioning pituitary adenomas (NFA) and growth hormone producing pituitary adenomas (GHA) after surgery and radiation treatment is not yet clear. METHODS: To determine the value of PET before and after transsphenoidal neurosurgery in NFA and GHA, we investigated 12 patients with pituitary adenoma (9 NFA and 3 GHA) before and 4 months after surgery with magnetic resonance imaging (MRI) and tyrosine PET (TYR-PET). Three years after radiation therapy TYR-PET was used to document residual activity in 6 of these patients (4 NFA- and 2 GHA). Tumour size was quantified by computerized MRI measurements. In TYR-PET, tumour activity was assessed by computerized measurements of the hot spot and by determination of protein synthesis rate (PSR). RESULTS: In response to surgery, MRI showed a median tumour volume reduction of 58% (P<0.01). TYR-PET demonstrated 62% volume reduction (P<0.02), but no change in PSR (P>0.30). After radiation therapy the MRI-volumes of the residual pituitary adenomas did not change but the volume of the hot spot on TYR PET-imaging was reduced by 58% (P=0.02), and PSR decreased in 5 of 6 patients (P=0.12). CONCLUSION: Amino acid PET tumour activity is reduced parallel with MRI volume changes after surgery. The decrease in TYR-PET activity after radiation therapy, despite unaltered MRI tumour volume, supports the concept that it is possible to follow biological tumour activity with this technique. The diagnostic merit of this tracer technique, predicting pituitary adenoma re-growth, needs to be validated in a large prospective study. PMID- 21296443 TI - Evaluation of the SUV values calculation and 4D PET integration in the radiotherapy treatment planning system. AB - BACKGROUND AND PURPOSE: To evaluate the SUV calculation and integration of the gated (4D) PET in the iPlan 4.0 treatment planning software (BrainLAB). MATERIALS AND METHODS: Phantom and patient data for different tracers were used. Two comparisons were performed for each patient: for the delineated VOI, the maximum value of SUV in iPlan was compared with the results from TrueD software. For 10 patients lesion volumes were defined in both systems for a given SUV threshold and differences were calculated. For four patients examined with respiratory gated PET, SUV(max) and volume analysis was performed in each phase of the breathing cycle in the gated and the ungated PET. RESULTS: Maximum differences of 6% and 10% were found for phantom and patient measurements of SUV(max). For patient data, maximal differences in delineated volume of 10% for ungated and up to 27% for gated PET were found in both systems. CONCLUSION: This study suggests that for the safe implementation of PET data and delineation algorithms in the radiotherapy planning system, one has to be aware of the differences in SUVs and volumes found in the two systems. PMID- 21296444 TI - Results of high dose-rate brachytherapy boost before 2D or 3D external beam irradiation for prostate cancer. AB - BACKGROUND AND PURPOSE: To evaluate biochemical control and treatment related toxicity of patients with localized adenocarcinoma of the prostate treated with high dose-rate brachytherapy (HDRB) combined with conventional 2D or 3D-conformal external beam irradiation (EBI). MATERIAL AND METHODS: Four-hundred and three patients treated between December 2000 and March 2004. HDRB was delivered with three fractions of 5.5-7 Gy with a single implant, followed by 45 Gy delivered with 2D or 3D conformal EBI. RESULTS: The median follow-up was 48.4 months. Biochemical failure (BF) occurred in 9.6% according to both ASTRO and Phoenix consensus criteria. Mean time to relapse was 13 and 26 months, respectively. The 5-year BF free survival using the ASTRO criteria was 94.3%, 86.9% and 86.6% for the low, intermediate and high risk groups, respectively; using Phoenix criteria, 92.4%, 88.0% and 85.3%, respectively. The only predictive factor of BF in the multivariate analysis by both ASTRO and Phoenix criteria was the presence of prostate nodules detected by digital palpation, and patients younger than 60 years presented a higher chance of failure using Phoenix criteria only. CONCLUSIONS: Treatment scheme is feasible and safe with good efficacy. PMID- 21296446 TI - Impact of Bifidobacterium animalis subsp. lactis BB-12 and, Lactobacillus acidophilus LA-5-containing yoghurt, on fecal bacterial counts of healthy adults. AB - This randomized, placebo-controlled, double blind, parallel dose-response study investigated the impact of 4-week commercial yoghurt consumption supplemented with Bifidobacterium animalis subsp. lactis (BB-12) and Lactobacillus acidophilus (LA-5) on fecal bacterial counts of healthy adults. Fifty-eight volunteers were randomly assigned to three different groups: 1. placebo (no probiotic, no starter and no green tea extract); 2. Yoptimal (10(9)cfu/100g of BB-12 and LA-5 and 40mg of green tea extract) and 3. Yoptimal-10 (10(10)cfu/100g of BB-12, 10(9)cfu/100g of LA-5 and 40mg of green tea extract). These yoghurt products also contained Lactobacillus delbrueckii subsp. bulgaricus (10(7)cfu/100g) and Streptococcus thermophilus (10(10)cfu/100g). The quantitative PCR (qPCR) results showed that there were significant increases (P=0.02) in bifidobacteria counts with the Yoptimal treatment as compared to baseline. The fecal numbers of B. animalis subsp. lactis and LA-5 significantly increased in the two probiotic treatments compared to the placebo treatment. Viable counts of fecal lactobacilli were significantly higher (P=0.05) and those of enterococci were significantly lower (P=0.04) after the intervention when compared to placebo. No significant difference was observed between treatments in volunteers' weight, waist girth, blood pressure, fasting plasma triglyceride and HDL-C concentrations, as well as cholesterol/HDL-cholesterol ratio. However, a significant increase in plasma cholesterol levels was observed in the placebo group (P=0.0018) but the levels remained stable in the two probiotic yoghurt groups. These results show that probiotic strains supplemented in the form of yoghurt remain active during gut transit and are associated with an increase in beneficial bacteria and a reduction in potentially pathogenic bacteria. This trial was registered at clinicaltrials.gov as NCT00730626. PMID- 21296447 TI - Novel PCR-based identification of Weissella confusa using an AFLP-derived marker. AB - An extensive use of Weissella (W.) confusa is currently being made for the production of a variety of fermented foods and beverages although some strains of this species have emerged as opportunistic pathogens for humans and animals. Nevertheless, no rapid methods are available for the reliable identification of W. confusa. We developed a novel PCR using AFLP (Amplified Fragment Length Polymorphism)-derived primers for the rapid and unequivocal identification of W. confusa. Fluorescent AFLP of 30 strains of W. confusa, Leuconostoc citreum, Lactobacillus (Lb.) brevis, Lb. rossiae, Lb. plantarum and Lb. buchneri allowed us to detect, purify and sequence several W. confusa specific AFLP fragments. The homology search in BLAST of a 303 bp nucleotide sequence revealed a <= 77% identity of the purified fragment with the lepA gene of several lactic acid bacteria. A PCR assay targeting 225 bp of this fragment was developed and tested against the DNA of 109 strains, including 34 foodborne and clinical W. confusa and 75 strains of 47 phylogenetically closely and distantly related species, resulting in 100% specificity with a detection limit of 16 pg. Being the first species-specific PCR to date developed for the rapid and unambiguous identification of W. confusa, this novel assay could be a reliable and efficient tool for detecting W. confusa not only in food and beverages, but also in clinical specimens, thus contributing to clarify its real significance in human and animal infections. PMID- 21296448 TI - Platinum-based doublet chemotherapy in pre-treated malignant pleural mesothelioma (MPM) patients: a mono-institutional experience. AB - BACKGROUND: The major clinical problems of MPM management are the short duration of response and the early relapse. Currently, after the first-line standard pemetrexed/platinum combination there is not a defined regimen for the second line treatment of MPM, and the clinical benefits in fit patients are uncertain. We analyzed the feasibility of gemcitabine/platinum chemotherapy in pretreated MPM patients. METHODS: Eligible patients should have relapsed after first-line chemotherapy with pemetrexed plus cisplatin (24%) or carboplatin (76%); 53% of the patients had previously received trimodality treatment, 18% neoadjuvant chemotherapy followed by pleurectomy/decortication, 29% were inoperable. Patients had to have PS=0-2, adequate organ function, measurable disease. Chemotherapy was gemcitabine 1000 mg/m(2) days 1, 8 associated to the alternative platinum compound respect to 1st line, i.e. cisplatin 75 mg/m(2) or carboplatin AUC 5 day 1 every 3 weeks, for 3-6 cycles. Baseline staging and reassessment after cycles 3 and 6 were performed with CT-scan. RESULTS: Since 2006 17 relapsed MPM patients were referred to our centre. Patients were 12 males and 5 females; median age: 61 years (range 47-74); histology: 12 epithelial, 4 sarcomatoid and 1 biphasic. PS 1 2 (15:2). The combination of gemcitabine with carboplatin/cisplatin was administered as second line treatment in 13 (76%) patients, as third line in 4 (24%) patients. Two patients were lost to follow-up without re-evaluation, therefore radiologic and clinical response was assessable in 15 (88%) patients. Among evaluable patients 10 (67%) showed stable disease and 5 (33%) progressive disease. Symptoms improved in 8 (53%) cases. In the intent-to-treat population median survival was 28 weeks (range 13-168) and median time-to-treatment failure 15 weeks (range 3-75). Toxicity profile showed 2 (13%) grade 4 and 6 (40%) grade 3 thrombocytopenia, 4 (27%) grade 3 leucopenia, 3 (20%) grade 3 anaemia and 6 (40%) of grade 3 neutropenia. Grade 3 non haematological toxicities were nausea (14%) and asthenia (21%). CONCLUSION: Gemcitabine-platinum regimens are able to control symptoms and disease progression with a modest toxicity profile. The present results from a small series of patients should be confirmed by a prospective trial in a larger cohort of patients. PMID- 21296449 TI - Randomised phase II trial of 4 dose levels of single agent docetaxel in performance status (PS) 2 patients with advanced non-small cell lung cancer (NSCLC): DOC PS2 trial. Manchester lung cancer group. AB - BACKGROUND: The role of chemotherapy for advanced NSCLC patients and ECOG PS2 remains controversial. We evaluated 4 doses of 3-weekly docetaxel to identify a less toxic, clinically effective dose. METHODS: Seventy-three patients with stage III (22%) (unsuitable for radical surgery/radiotherapy) and IV (78%) NSCLC were randomized to receive 4 doses of 3-weekly docetaxel, for 4 cycles: arm (A) 40 mg/m(2) (n=17), arm (B) 50 mg/m(2) (n=17), arm (C) 60 mg/m(2) (n=19), arm (D) 50 mg/m(2) escalated by 10 mg/m(2) to a maximum of 70 mg/m(2) (n=19). Primary endpoints: maximum tolerated dose, RR, duration of response, symptom improvement, toxicity and QoL. Secondary endpoint: overall survival (OS). Patients and disease characteristics were well balanced. Median age was 67 (range 45-81), there were 32 male and 41 female, histology subtype: squamous/adenocarcinoma/mixed/NOS=42%/49%/4%/5%. RESULTS: Seven patients did not receive any treatment because of deterioration in PS or death. 50% of patients in arm D, who received more than one cycle, received dose escalation. There was no statistical difference in the number of cycles administered (arms A, B and D: median 2 cycles and arm C: median 3 cycles) and no difference in RR: arm A=6%, arm B=6%, arm C=10%, and arm D=0%. There was no statistically significant difference in grade 3/4 neutropenia and thrombocytopenia between the four arms. No difference was observed in hospitalization rate, blood transfusions, antibiotics administration and non-haematological toxicity. QoL: no difference in total scores between baseline and cycles 1-4. There was a significant decrease in pain scores from baseline to post cycles 2 and 3 (p=0.025 and p=0.002, respectively). There was no difference in OS (p=0.992). Median survival and 6 month survival were 61, 86, 88 and 97 days and 29%, 33%, 21% and 26% for arms A, B, C, and D, respectively. CONCLUSIONS: Clinical efficacy of docetaxel was observed at all dose levels. Higher dose levels were not associated with increased toxicities, use of IV antibiotics or hospitalization rates. However, the median survival observed is shorter than historical data and do not support further evaluation of these doses of single agent docetaxel in this population. PMID- 21296450 TI - The costs of describing the entire animal kingdom. PMID- 21296452 TI - Plectin interacts with the rod domain of type III intermediate filament proteins desmin and vimentin. AB - Plectin is a versatile cytolinker protein critically involved in the organization of the cytoskeletal filamentous system. The muscle-specific intermediate filament (IF) protein desmin, which progressively replaces vimentin during differentiation of myoblasts, is one of the important binding partners of plectin in mature muscle. Defects of either plectin or desmin cause muscular dystrophies. By cell transfection studies, yeast two-hybrid, overlay and pull-down assays for binding analysis, we have characterized the functionally important sequences for the interaction of plectin with desmin and vimentin. The association of plectin with both desmin and vimentin predominantly depended on its fifth plakin repeat domain and downstream linker region. Conversely, the interaction of desmin and vimentin with plectin required sequences contained within the segments 1A-2A of their central coiled-coil rod domain. This study furthers our knowledge of the interaction between plectin and IF proteins important for maintenance of cytoarchitecture in skeletal muscle. Moreover, binding of plectin to the conserved rod domain of IF proteins could well explain its broad interaction with most types of IFs. PMID- 21296451 TI - Peto's Paradox: evolution's prescription for cancer prevention. AB - The evolution of multicellularity required the suppression of cancer. If every cell has some chance of becoming cancerous, large, long-lived organisms should have an increased risk of developing cancer compared with small, short-lived organisms. The lack of correlation between body size and cancer risk is known as Peto's paradox. Animals with 1000 times more cells than humans do not exhibit an increased cancer risk, suggesting that natural mechanisms can suppress cancer 1000 times more effectively than is done in human cells. Because cancer has proven difficult to cure, attention has turned to cancer prevention. In this review, similar to pharmaceutical companies mining natural products, we seek to understand how evolution has suppressed cancer to develop ultimately improved cancer prevention in humans. PMID- 21296453 TI - [Reconstruction of the glans with free-skin graft applying the Bracka technique]. AB - INTRODUCTION: We analyse our experience in the conservative surgical management of penile cancer and/or penile skin pathologies at our institution. MATERIAL AND METHODS: We have retrospectively reviewed all the skin grafting procedures performed in penile surgery in the last eight years. We show the indications and results of these surgical procedures and the detailed surgical technique originally described by Bracka. RESULTS: Ten patients had several types of partial penile removal surgery followed by free-skin graft resurfacing, creating a neoglans. There were no relevant or major complications; two patients suffered partial necrosis of the skin graft. There was no local recurrence. 6 Patients returned to normal sexual activity after complete healing. CONCLUSIONS: There is a significant number of patients with penile cancer and/or other penile skin pathologies who can undergo definitive and non-mutilating surgery with excellent oncologic, cosmetic and functional results with skin grafting. PMID- 21296454 TI - [Assessment of reasons for overactive bladder treatment change]. AB - OBJECTIVES: although efficacious, some patients do not respond optimally to overactive bladder (OAB) treatment. The objective of this study was to identify the reasons why some patients do not respond and to look for reasons for changes in treatment and patient satisfaction with the new treatment. MATERIALS AND METHODS: epidemiological, cross-sectional, non-interventional study to determine the reasons for OAB treatment switching and satisfaction with such OAB treatment switch. OAB patients (OAB-V8>=8), 18 years or more, who had modified their treatment during the previous 3-4 months, were recruited. Demographic data, symptoms, previous, current and concomitant treatments, reasons for treatment switch, clinical global impression (CGI) on disease severity and symptom improvement, Morinsky Green questionnaire, satisfaction with treatment, treatment preference and treatment benefit scale (TBS) were compared. RESULTS: out of 3,365 successive patients, 2,038 (61%) were eligible (61.1+/-11.2 years; 77% women). The physician decided to switch in 69% of the cases and 31% of patients asked for a change in treatment. Reasons for switching were lack of clinical benefit (60%), side effects (24%), patients' request (8%), non-compliance (6%) and other (2%). 52% of patients complied with new treatment. According to the CGI, 65.4% showed improvement with respect to their previous treatment. 60% were quite/very satisfied with current treatment, 91% preferred it to their previous treatment and 93% reported that their symptoms had improved. CONCLUSIONS: the lack of clinical benefit is the main reason for changing OAB treatment. Most of the patients that switched prefer their new treatment. PMID- 21296455 TI - [Effectiveness of levetiracetam in the treatment of two cases of hypoxic encephalopathy with myoclonic status]. PMID- 21296456 TI - [Intensive medicine in Europe: a need]. PMID- 21296457 TI - [Urinary incontinence: multiple causes, different treatments and different professionals]. PMID- 21296458 TI - [Neuropsychiatric assessment in patients over 75 years-old admitted to an emergency department observation unit]. PMID- 21296459 TI - [Utilization of an emergency department by elderly people in a university hospital in Santiago de Chile]. AB - INTRODUCTION: An increase in visits to Emergency Departments by older adults has been reported, but there are no data available on this in countries in the early phases of demographic and epidemiological transition. This paper describes the characteristics of people over 60 years-old (AM) who visited the Emergency Department of the Hospital Clinico Universitario de la Pontificia Universidad Catolica, Chile (SU-PUC), compared to those less than 60 years-old (AJ). MATERIAL AND METHODS: Demographic data and reasons for admission and re-admission were collected retrospectively from the SU-PUC monthly statistics report. Obstetrics, paediatrics and "scheduled admissions" were excluded. The frequencies were compared using Chi-squared (significance: P < .05). RESULTS: A total of 37,660 visits to the SU-PUC were recorded (81% AJ; 19% AM; with 8% being older than 75 years). No statistical differences were found in the visit time (70% daytime), or by season between the groups. A total of 7,414 (19.6%) of those who visited were hospitalised, with differences being detected between groups (AM: 48.9% vs 12.9% AJ; P < .001), particularly in those over 75 years (59%). The primary cause of admission was cardiopulmonary in AM (22%) and gastrointestinal in AJ (31%). Re admissions were 10% in AM and 6% in AJ (P < .001). CONCLUSION: The use of SU by AM and some characteristics of their care process (hospitalisation) are similar to those found in countries in more advanced phases of demographic transition. PMID- 21296460 TI - [Splenic lymphoma presenting as acute pancreatitis in an 84 year-old patient. A case report]. AB - A case is presented of an 84 year-old woman who was admitted to the Emergency Department due to an episode of non-calculous acute pancreatitis. In the aetiological study, the presence of a splenic lymphoma was documented, which had a compressive effect on the pancreas. After resolving the symptoms, she was scheduled for a splenectomy with a good technical result. At six months after admission the patient was in an excellent clinical and functional condition. This case highlights the unusual clinical presentation of this haematological disease, and the need to evaluate all the available therapeutic options in selected elderly patients. PMID- 21296461 TI - [To achieve impact factor: the common task]. PMID- 21296462 TI - [Primary pulmonary non-Hodgkin lymphoma with myocardial infiltration]. AB - A case of primary pulmonary non-Hodgkin's lymphoma is presented. On this occasion, the lymphoma invaded the myocardium, an event which has not previously been reported in the literature. These neoplasms spread by proximity, and invasion of the pericardium, thoracic wall and oesophagus have been described. Our patient died from heart failure. Tumour myocardial infiltration may well have been the determinant cause through various mechanisms, including a decrease in myocardial contractility. Spread into the myocardium may be facilitated by bulky tumour infiltrates in the pleural space. PMID- 21296463 TI - [Unexplained anaemia in the elderly: towards a multifactorial approach]. PMID- 21296464 TI - [Drugs in the rubbish bin. Lots of blame and few solutions]. PMID- 21296465 TI - The Spanish version of the "STarT Back Screening Tool" (SBST) in different subgroups. AB - OBJECTIVE: The aim of this study was to translate and culturally adapt the original version of the STarT Back Screening Tool (SBST) to Spanish for different population subgroups. DESIGN: Translation and cultural adaptation of a questionnaire. SETTING: Primary care settings. METHOD: Thirty-eight people distributed by: gender; adults and elderly; and with or without pain. Phases: a) Forward translation (English-Spanish); b) Evaluation of the clarity, the acceptability and the familiarity of the content of the obtained Spanish version by means of cognitive interviews to participants, and c) Translation of the final Spanish version of the questionnaire back into the original language. RESULTS: The participants interviewed indicated that most of the items of the questionnaire were clear and comprehensible, showing greater difficulty in understanding in the dimensions of disability and anxiety. Furthermore, the questionnaire was more difficult to understand by the elderly and patients with a previous non-specific low back pain episode. CONCLUSION: The Spanish version of the SBST questionnaire was obtained, which was shown to be comprehensible and adapted to the general population in Spain. Due to being short and easy to use, it is a potentially useful tool for use in primary care. PMID- 21296466 TI - Design, synthesis and biological activity of pyrazolo[1,5-a]pyrimidin-7(4H)-ones as novel Kv7/KCNQ potassium channel activators. AB - Voltage-gated Kv7/KCNQ/M-potassium channels play a pivotal role in controlling neuronal excitability. Genetic reduction of KCNQ channel activity as a result of mutations causes various human diseases such as epilepsy and arrhythmia. Therefore, discovery of small molecules that activate KCNQ channels is an important strategy for clinical intervention of membrane excitability related disorders. In this study, a series of pyrazolo[1,5-a]pyrimidin-7(4H)-ones (PPOs) have been found to be novel activators (openers) of KCNQ2/3 potassium channels through high-throughput screening by using atomic absorption rubidium efflux assay. Based on structure-activity relationship (SAR), the substituted PPOs have been optimized. The 5-(2,6-dichloro-5-fluoropyridin-3-yl)-3-phenyl-2 (trifluoromethyl) pyrazolo[1,5-a]pyrimidin-7(4H)-one (17) was identified as a novel, potent, and selective KCNQ2/3 potassium channel opener by patch-clamp recording assay. PMID- 21296467 TI - Identification, structural properties and chelating capacity of miltipolone as a broad-spectrum inhibitor to cancer cells. AB - Miltipolone (1) was discovered as a good and broad-spectrum inhibitor against the growth of cancer cells from "Danshen" based on the activity-driven screening of TCMs. The structural features make 1 easily tautomerize between different forms and 1 is linked and stabilized by intermolecular O-H?O hydrogen bonds in the crystal structure. The interaction of 1 in ddH(2)O solution with Co(2+), Mn(2+), Zn(2+), Fe(2+) or Fe(3+) changed UV absorption values; the chelation of 1 with Fe(2+) or Fe(3+) also altered the characteristic UV absorption peaks. However, only did Fe(2+) reverse 1's inhibition against the growth of cancer cells; therefore, we concluded that 1 possibly acts as a Fe(2+) chelator to conduct its inhibitory activity. PMID- 21296468 TI - [Abdominal pain in a pregnant 34-year-old woman]. PMID- 21296469 TI - Increase of 210Po levels in human semen fluid after mussel ingestion. AB - Polonium-210 ((210)Po) radioactive concentrations were determined in human semen fluid of vasectomized non-smoker volunteers. The (210)Po levels ranged from 0.10 to 0.39 mBq g(-1) (mean: 0.23 +/- 0.08 mBq g(-1)). This value decreased to 0.10 +/- 0.02 mBq g(-1) (range from 0.07 to 0.13 mBq g(-1)) after two weeks of a controlled diet, excluding fish and seafood. Then, volunteers ate during a single meal 200 g of the cooked mussel Perna perna L., and (210)Po levels were determined again, during ten days, in semen fluid samples collected every morning. Volunteers continued with the controlled diet and maintained sexual abstinence through the period of the experiment. A 300% increase of (210)Po level was observed the day following mussel consumption, with a later reduction, such that the level returned to near baseline by day 4. PMID- 21296470 TI - Expression of mtc in Folsomia candida indicative of metal pollution in soil. AB - The soil-living springtail Folsomia candida is frequently used in reproduction bioassays to assess soil contamination. Alternatively, the response of genes to contamination is assessed. In this study the expression of F. candida's gene encoding the deduced metallothionein-like motif containing protein (MTC) was assessed, using quantitative PCR, in response to six different metals, each at two concentrations in soil. The expression of mtc was induced after exposure to all metals, except for one chromium concentration. Exposure to soil originating from metal-contaminated field sites also induced mtc, while the expression did not change in response to a polycyclic aromatic hydrocarbon. Since this transcript is induced by most of the tested metals, it may potentially be a good indicator of metal contamination. The presented gene expression assay might become a useful tool to screen potentially polluted sites, in order to identify the ones that need further ecotoxicological investigation. PMID- 21296471 TI - Distribution, availability, and sources of trace metals in different particle size fractions of urban soils in Hong Kong: Implications for assessing the risk to human health. AB - The concentration and loading distribution of trace metals (Cu, Zn, Pb, Co, Ni, Cr, and Mn) and major elements (Al, Ca, Fe, and Mg) in different particle size fractions (2000-280, 280-100, 100-50, 50-10, 10-2, and <2 MUm) of surface soils from highly urbanized areas in Hong Kong were studied. The enrichment of Pb, Cu, and Zn in the urban soils was strongly influenced by anthropogenic activities, and Pb accumulated in fine particles was mainly derived from past vehicular emissions as shown by Pb isotopic signatures. Trace metals primarily accumulated in clay, fine silt, and very fine sand fractions, and might pose potential health risks via the inhalation of resuspended soil particles in the air (PM10 or PM2.5), and ingestion of adhered soils through the hand-to-mouth pathway. The mobility, bioavailability, and human bioaccessibility of Pb and Zn in bulk soils correlated significantly with metal concentrations in fine silt and/or very fine sand fractions. PMID- 21296472 TI - Sensitivity analysis for models of greenhouse gas emissions at farm level. Case study of N(2)O emissions simulated by the CERES-EGC model. AB - Modelling complex systems such as farms often requires quantification of a large number of input factors. Sensitivity analyses are useful to reduce the number of input factors that are required to be measured or estimated accurately. Three methods of sensitivity analysis (the Morris method, the rank regression and correlation method and the Extended Fourier Amplitude Sensitivity Test method) were compared in the case of the CERES-EGC model applied to crops of a dairy farm. The qualitative Morris method provided a screening of the input factors. The two other quantitative methods were used to investigate more thoroughly the effects of input factors on output variables. Despite differences in terms of concepts and assumptions, the three methods provided similar results. Among the 44 factors under study, N(2)O emissions were mainly sensitive to the fraction of N(2)O emitted during denitrification, the maximum rate of nitrification, the soil bulk density and the cropland area. PMID- 21296474 TI - [Treatment of hand ischemia with arterialization of the venous system of the hand: report of three cases]. AB - INTRODUCTION: Hand ischemia is a rare phenomenom of various etiologies among which can be found Raynaud's phenomenon and autoimmune arteritis. The limitations of symptomatic medical treatment and the frequent plurisegmental and distal affection of arteries make the management of chronic hand ischemia difficult. The arterialization of the superficial venous system, which consists in redirecting the arterial flow to the fingertip through the dorsal venous system, could be an interesting alternative to the disappointing results of medical therapy and surgical sympathectomy. The authors present here the preliminary results of this technique. PATIENTS AND METHOD: We carried out a retrospective study analyzing the indications, the operative technique and results of three hands operated on two patients. An arteriography was carried out on each patient prior to perform the arterialization of the superficial venous system, in order to make sure that none of the patients was eligible for a technique of direct re-vascularization. RESULTS: Postoperatively, for each patient, the following points were evaluated: pain reduction, ulcer healing, and then we tried to obtain a more objective assessment by performing angio-MRI. CONCLUSION: This last resort technique in management of critical ischemia of the fingers led to an immediate and lasting improvement of symptoms in all the patients treated. This technique seems reliable and reproducible in selected cases aiming to re-vascularize hands that have reached the stage of critical ischemia. This treatment option should be known by hand surgeons, and distributed to internists who usually manage these patients. PMID- 21296473 TI - Cystatin C and albuminuria as risk factors for development of CKD stage 3: the Multi-Ethnic Study of Atherosclerosis (MESA). AB - BACKGROUND: The growing burden and morbidity of chronic kidney disease (CKD) warrant effective strategies for identifying those at increased risk. We examined the association of cystatin C level and albuminuria with the development of CKD stage 3. STUDY DESIGN: Prospective observational study. SETTING & PARTICIPANTS: 5,422 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) with estimated glomerular filtration rate (eGFR) >=60 mL/min/1.73 m(2). PREDICTOR: Participants were categorized into 4 mutually exclusive groups: the presence or absence of microalbuminuria (albumin-creatinine ratio >17 and >25 MUg/mg in men and women, respectively) in those with or without cystatin C level >=1.0 mg/L. OUTCOMES & MEASUREMENTS: Incident CKD stage 3 was defined as eGFR <60 mL/min/1.73 m(2) at the third or fourth visit and an annual decrease >1 mL/min/1.73 m(2). Poisson regression was used to evaluate incident rate ratios in unadjusted and adjusted analyses that include baseline eGFR. RESULTS: Mean age was 61 years, 49% were men, 38% were white, 11% had diabetes, 13.7% had cystatin C level >=1 mg/L, 8.4% had microalbuminuria, and 2.7% had cystatin C level >=1 mg/L with microalbuminuria. 554 (10%) participants developed CKD stage 3 during a median follow-up of 4.7 years, and adjusted incidence rate ratios were 1.57 (95% CI, 1.19-2.07), 1.37 (95% CI, 1.13-1.66), and 2.12 (95% CI, 1.61-2.80) in those with microalbuminuria, cystatin C level >=1 mg/L, and both, respectively, compared with those with neither. LIMITATIONS: Relatively short follow-up and absence of measured GFR. CONCLUSIONS: Cystatin C level and microalbuminuria are independent risk factors for incident CKD stage 3 and could be useful as screening tools to identify those at increased risk. PMID- 21296475 TI - Identity crisis of a Mullins Balloon. Is it a balloon-in-balloon catheter? PMID- 21296476 TI - Long-term pacemaker lead malposition. Role of echocardiography. PMID- 21296477 TI - Acute myocardial infarction probably related to severe coronary vasospasm during pheochromocytoma crisis. PMID- 21296478 TI - Survival after 48 min submersion and 107 min cardiopulmonary resuscitation. PMID- 21296479 TI - Embryonic stem cells in non-human primates: An overview of neural differentiation potential. AB - Non-human primate (NHP) embryonic stem (ES) cells show unlimited proliferative capacities and a great potential to generate multiple cell lineages. These properties make them an ideal resource both for investigating early developmental processes and for assessing their therapeutic potential in numerous models of degenerative diseases. They share the same markers and the same properties with human ES cells, and thus provide an invaluable transitional model that can be used to address the safety issues related to the clinical use of human ES cells. Here, we review the available information on the derivation and the specific features of monkey ES cells. We comment on the capacity of primate ES cells to differentiate into neural lineages and the current protocols to generate self renewing neural stem cells. We also highlight the signalling pathways involved in the maintenance of these neural cell types. Finally, we discuss the potential of monkey ES cells for neuronal differentiation. PMID- 21296480 TI - Extra-framework cation release from heulandite-type rich tuffs on exchange with NH(4)(+). AB - The outgoing cations of Greek heulandite-rich tuff samples (heulandite type-III, 91wt.%, mica 4wt.%, feldspar 5wt. %, CEC 2.22meq/g) were analysed upon exchange with ammonium acetate using atomic absorption spectrometry (AAS). The kinetic curves of each cation were investigated over a total time of contact of 720h with sampling at frequent intervals. The materials were examined by powder X-ray diffraction, SEM-EDS, and AAS. The sorption ability was measured using the ammonium acetate saturation method. It was found that Ca(2+) presents an unexpected extra-framework release and a surprisingly high degree of exchange (90%). The exchange of Mg (57%) is also worthy of note whereas the behavior of K(+) showed an expected rapid initial release. The behavior of Na(+) must be similar. However, its lower concentration in the zeolitic material minimizes its overall significance somewhat. On the other hand, Ca(2+) and Mg(2+) release is kinetically much slower, compared to that of alkali metal ions, and this phenomenon indicates that different exchange energies are needed till final equilibrium. PMID- 21296481 TI - A prospective randomised trial comparing the modified HM3 with the MODULITH(r) SLX-F2 lithotripter. AB - BACKGROUND: The relative efficacy of first- versus last-generation lithotripters is unknown. OBJECTIVES: To compare the clinical effectiveness and complications of the modified Dornier HM3 lithotripter (Dornier MedTech, Wessling, Germany) to the MODULITH((r)) SLX-F2 lithotripter (Storz Medical AG, Tagerwilen, Switzerland) for extracorporeal shock wave lithotripsy (ESWL). DESIGN, SETTING AND PARTICIPANTS: We conducted a prospective, randomised, single-institution trial that included elective and emergency patients. INTERVENTIONS: Shock wave treatments were performed under anaesthesia. MEASUREMENTS: Stone disintegration, residual fragments, collecting system dilatation, colic pain, and possible kidney haematoma were evaluated 1 d and 3 mo after ESWL. Complications, ESWL retreatments, and adjuvant procedures were documented. RESULTS AND LIMITATIONS: Patients treated with the HM3 lithotripter (n=405) required fewer shock waves and shorter fluoroscopy times than patients treated with the MODULITH((r)) SLX-F2 lithotripter (n=415). For solitary kidney stones, the HM3 lithotripter produced a slightly higher stone-free rate (p=0.06) on day 1; stone-free rates were not significantly different at 3 mo (HM3: 74% vs MODULITH((r)) SLX-F2: 67%; p=0.36). For solitary ureteral stones, the stone-free rate was higher at 3 mo with the HM3 lithotripter (HM3: 90% vs MODULITH((r)) SLX-F2: 81%; p=0.05). For solitary lower calyx stones, stone-free rates were equal at 3 mo (63%). In patients with multiple stones, the HM3 lithotripter's stone-free rate was higher at 3 mo (HM3: 64% vs MODULITH((r)) SLX-F2: 44%; p=0.003). Overall, HM3 lithotripter led to fewer secondary treatments (HM3: 11% vs MODULITH((r)) SLX-F2: 19%; p=0.001) and fewer kidney haematomas (HM3: 1% vs. MODULITH((r)) SLX-F2: 3%; p=0.02). CONCLUSIONS: The modified HM3 lithotripter required fewer shock waves and shorter fluoroscopy times, showed higher stone-free rates for solitary ureteral stones and multiple stones, and led to fewer kidney haematomas and fewer secondary treatments than the MODULITH((r)) SLX-F2 lithotripter. In patients with a solitary kidney and solitary lower calyx stones, results were comparable for both lithotripters. PMID- 21296482 TI - Pentafecta: a new concept for reporting outcomes of robot-assisted laparoscopic radical prostatectomy. AB - BACKGROUND: Widespread use of prostate-specific antigen screening has resulted in younger and healthier men being diagnosed with prostate cancer. Their demands and expectations of surgical intervention are much higher and cannot be adequately addressed with the classic trifecta outcome measures. OBJECTIVE: A new and more comprehensive method for reporting outcomes after radical prostatectomy, the pentafecta, is proposed. DESIGN, SETTING, AND PARTICIPANTS: From January 2008 through September 2009, details of 1111 consecutive patients who underwent robot assisted radical prostatectomy performed by a single surgeon were retrospectively analyzed. Of 626 potent men, 332 who underwent bilateral nerve sparing and who had 1 yr of follow-up were included in the study group. MEASUREMENTS: In addition to the traditional trifecta outcomes, two perioperative variables were included in the pentafecta: no postoperative complications and negative surgical margins. Patients who attained the trifecta and concurrently the two additional outcomes were considered as having achieved the pentafecta. A logistic regression model was created to evaluate independent factors for achieving the pentafecta. RESULTS AND LIMITATIONS: Continence, potency, biochemical recurrence-free survival, and trifecta rates at 12 mo were 96.4%, 89.8%, 96.4%, and 83.1%, respectively. With regard to the perioperative outcomes, 93.4% had no postoperative complication and 90.7% had negative surgical margins. The pentafecta rate at 12 mo was 70.8%. On multivariable analysis, patient age (p=0.001) was confirmed as the only factor independently associated with the pentafecta. CONCLUSIONS: A more comprehensive approach for reporting prostate surgery outcomes, the pentafecta, is being proposed. We believe that pentafecta outcomes more accurately represent patients' expectations after minimally invasive surgery for prostate cancer. This approach may be beneficial and may be used when counseling patients with clinically localized disease. PMID- 21296483 TI - Re: Firas Abdollah, Maxine Sun, Rodolphe Thuret, et al. A competing-risks analysis of survival after alternative treatment modalities for prostate cancer patients: 1988-2006. Eur Urol 2011;59:88-95. PMID- 21296484 TI - MicroRNA in prostate, bladder, and kidney cancer: a systematic review. AB - CONTEXT: MicroRNAs (miRNA) are noncoding RNAs that post-transcriptionally regulate gene expression. Their altered expression and function have been observed in most urologic cancers. MiRNAs represent potential disease biomarkers and novel therapeutic targets. OBJECTIVE: To review and evaluate the evidence implicating miRNAs in the pathogenesis of prostate cancer (PCa), bladder cancer (BCa), and renal cancer. EVIDENCE ACQUISITION: A systematic review was performed using PubMed and Embase to search for reports using strings for microRNA, non coding RNA, cancer, prostate, bladder, and renal cancer. Identified manuscripts were retrieved and references searched. Selected studies were required to concentrate on the role of miRNA in these urologic cancers. EVIDENCE SYNTHESIS: We reviewed articles that focus on this topic. More than 40 miRNAs have been implicated in urologic cancer and many target common carcinogenic pathways. In particular, apoptosis avoidance, cell proliferation, epithelial-to-mesenchymal transition, angiogenic signalling, and the generation of androgen independence are targeted or facilitated by more than one miRNA. Little work has been done to evaluate the translational applications for this knowledge to date. Novel therapeutic strategies have been developed and are under investigation to selectively modulate miRNAs; such work would potentially enable personalised tumour therapy. CONCLUSIONS: MiRNAs appear to be important modulators of urologic cancer. Their expression is frequently altered in these tumours, and many are functionally implicated in their pathogenesis. They require evaluation to determine the translational role and therapeutic potential for this knowledge. PMID- 21296486 TI - Molecular profiling of renal cancer: the journey to clinical application. PMID- 21296487 TI - From active surveillance to the concept of secondary prevention. PMID- 21296488 TI - Lymph node density affects cancer-specific survival in patients with lymph node positive urothelial bladder cancer following radical cystectomy. AB - BACKGROUND: The prognosis for patients with lymph node (LN)-positive bladder cancer (BCa) is likely affected by the extent of lymphadenectomy in radical cystectomy (RC) cases. Specifically, the prognostic significance of the LN density (ratio of positive LNs to the total number removed) has been demonstrated. OBJECTIVE: To evaluate the prognostic signature of lymphadenectomy variables, including the LN density, for a large, multicentre cohort of RC patients with LN-positive BCa. DESIGN, SETTING, AND PARTICIPANTS: The clinical and histopathologic data from 477 patients with LN-positive urothelial BCa (pN1 2) were analysed. The median follow-up period for all living patients was 28 mo. MEASUREMENTS: Multivariable Cox regression analysis was used to test the effect of various pelvic lymph node dissection (PLND) variables on cancer-specific survival (CSS) based on colinearity in various models. RESULTS AND LIMITATIONS: The median number of LNs removed was 12 (range: 1-66), and the median number of positive LNs was 2 (range: 1-25). Two hundred ninety (60.8%) of the patients presented with stage pN2 disease. The median and mean LN density was 17.6% and 29% (range: 2.3-100), respectively, where 268 (56.2%) and 209 (43.8%) patients exhibited am LN density of <=20% and >20%, respectively. In separate multivariable Cox regression models adjusted for age, sex, pTN stage, grade, associated Tis, and adjuvant chemotherapy, the interval-scaled LN density (hazard ratio [HR]: 1.01; p=0.002) and the LN density, ordinal-scaled by 20% (HR: 1.65; p<0.001) exhibit independent effects on CSS. In addition, an independent contribution appears from the pT but not the pN stage. Limitations include surgeon selection bias when determining the extent of lymphadenectomy. CONCLUSIONS: Our results support the prognostic relevance of LN density in patients with LN-positive BCa, where a threshold value of 20% stratifies the population into two prognostically distinct groups. Before LN density is integrated into the clinical decision-making process, these results should be validated by prospective studies with defined LN templates and standardised histopathologic methods. PMID- 21296489 TI - Re: Mireia Musquera, Lluis L. Peri, Ricardo Alvarez-Vijande, et al. Orthotopic kidney transplantation: an alternative surgical technique in selected patients. Eur Urol 2010;58:927-33. PMID- 21296490 TI - Hypoglossal palsy and coeliac disease: an uncommon presentation for a common disease? PMID- 21296491 TI - The TSP motif in AP180 inhibits phospholipase D1 activity resulting in increased efficacy of anticancer drug via its direct binding to carboxyl terminal of phospholipase D1. AB - Phospholipase D (PLD) has two isoforms, PLD1 and PLD2. Both isoforms are possible candidates for the development of anticancer drugs, since PLDs in several cancer cells act as survival factors. The aim of this study was to elucidate the inhibitory mechanism of PLD1 by AP180 in human cancer cells. Transfection of the human AP180 (hAP180) gene markedly inhibited phobol-12-myristate 13-acetate induced PLD activity resulting in exacerbation of anticancer drug-induced cell death. Experiments using deletion mutants of hAP180 showed that three amino acids (Thr312-Pro314) are critical for inhibition of PLD1 activity by binding directly to PLD1, and, of these, Ser313 was the most important residue for both binding to and inhibiting PLD1. However, this inhibitory relationship did not exist between hAP180 and PLD2. In addition, the C-terminal region of PLD1 is important for the interaction with hAP180. These results indicated that Thr312-Pro314 (especially Ser313 as a phosphorylation residue) of hAP180 can regulate hPLD1 activity through binding with the C-terminal region of PLD1. PMID- 21296492 TI - Dechlorination of polychlorinated biphenyls using magnesium and acidified alcohols. AB - Polychlorinated biphenyls (PCBs) were widely used in industry until their regulation in the 1970s. However, due to their inherent stability, they are still a widespread environmental contaminant. A novel method of degradation of PCBs (via hydrodehalogenation) has been observed using magnesium powder, a carboxylic acid, and alcohol solvents and is described in this paper. The rates of degradation were determined while varying the type of acid (formic, acetic, propionic, butyric, valeric, benzoic, ascorbic, and phosphoric), the amount of magnesium from 0.05 to 0.25 g, the amount of acetic acid from 0.5 to 50 MUL and the concentration of PCB-151 from 0.1 to 50 MUg/mL, as well as the alcohol solvent (methanol, ethanol, propanol, butanol, octanol, and decanol). The results of these studies indicate that the most rapid PCB dechlorination is achieved using a matrix consisting of at least 0.02 g Mg/mL ethanol, and 10 MUL acetic acid/mL ethanol in which case 50 ng/MUL of PCB-151 is dechlorinated in approximately 40 min. PMID- 21296493 TI - A bacterial consortium isolated from an Icelandic fumarole displays exceptionally high levels of sulfate reduction and metals resistance. AB - The soils of three fumaroles and one mining site, all with high metal content, were surveyed for the presence of metal-resistant sulfate-reducing bacteria and their potential application in the bioremediation of acid mine drainages. By means of selective soil enrichments a bacterial consortium was isolated from an Icelandic fumarole that displayed very high sulfate reduction in the presence of a mixture of 0.75 g/L of Fe, 0.20 g/L of Zn and 0.080 g/L of Cu. Under these conditions the bacterial consortium reduced 91% of the added 3.9 g/L of sulfate after 28 days, precipitating 100% of the Fe, 96% of the Zn and 97% of the Cu during the same time. Both total bacterial numbers and numbers of culturable sulfate-reducing bacteria remained unchanged when grown in media containing metals, suggesting low or absent inhibitory effects of the metals on the bacterial consortium. PCR-DGGE profiles of the sulfate reducing bacterial communities obtained from the Icelandic fumarole sample showed that bacterial diversity decreased significantly after metal addition: from the original 12 ribotypes only two were detected in the metal-tolerant culture. Phylogenetic analysis of 16S ribosomal RNA gene sequences revealed that these two ribotypes were affiliated with the genera Clostridium and Desulfovibrio, with C. subterminale, C. pascui, C. mesophilum and C. peptidovorans and D. desulfuricans identified as their closest relatives. PMID- 21296494 TI - Vaporization of zinc during thermal treatment of ZnO with tetrabromobisphenol A (TBBPA). AB - In the present work we investigate the vaporization of zinc or its compounds during thermal treatment of ZnO with tetrabromobisphenol A. Samples of 2g of ZnO:TBBPA (3.34:1) were isothermally heated in a laboratory-scale furnace at temperatures from 490 degrees C to 950 degrees C, and the solid, condensed and gaseous products formed were analyzed by X-ray diffraction analysis, electron probe microanalysis, inductively coupled plasma analysis, ion chromatography, and gas chromatography coupled with mass spectrometry. The results obtained indicate that the vaporization of ZnBr(2) formed strongly depends on heating time and temperature, yet is restrained by char, if formed with sufficient yield (above 15 wt%). Starting from 850 degrees C, this char commences carbothermic reduction of any remaining ZnO, which from then begins to evaporate as zinc metal vapor. Volatilization of zinc is completed at 950 degrees C. The presence of 5 vol.% of oxygen has no significant effect on the vaporization of formed ZnBr(2), the carbothermic reduction or the volatilization of metallic zinc. Strongly oxidizing conditions (20 vol.% of oxygen), however, boost the oxidation of char and thus the vaporization of ZnBr(2), but prevent carbothermic reduction of any un-reacted ZnO by depleting this char. PMID- 21296495 TI - Toxic pollutants emitted from thermal decomposition of phthalimide compounds. AB - Phthalimide (PI) and tetrahydrophthalimide (THPI) are two structurally similar compounds extensively used as intermediates for the synthesis of variety of industrial chemicals. This paper investigates the thermal decomposition of PI and THPI under oxygen rich to oxygen lean conditions, quantifying the production of toxicants and explaining their formation pathways. The experiments involved a plug flow reactor followed by silica cartridges, activated charcoal trap and a condenser, with the decomposition products identified and quantified by Fourier transform infrared spectroscopy (FTIR), gas chromatography-mass spectrometry (GC MS) and micro gas chromatography (MUGC). The density functional theory (DFT) calculations served to obtain dissociation energies and reaction pathways, to elucidate the reaction mechanism. The oxidation of PI and THPI produced several toxic nitrogen-containing gases and volatile organic compounds, including hydrogen cyanide, isocyanic acid, nitrogen oxides, benzonitrile, maleimide and tentatively identified benzenemethanimine. The detection of dibenzo-p-dioxin (DD) and dibenzofuran (DF) suggests potential formation of the toxic persistent organic pollutants (POPs) in fires involving PI and THPI, in presence of a chlorine source. The oxidation of THPI produced 2-cyclohexen-1-one, a toxic unsaturated ketone. The results of the present study provide the data for quantitative risk assessments of emissions of toxicants in combustion processes involving PI and THPI. PMID- 21296496 TI - Characterisation and management of ash produced in the hospital waste incinerator of Athens, Greece. AB - Bottom and fly ash samples (BASH and FASH) from the APOTEFROTIRAS S.A. medical waste incinerator (Athens, Greece) were investigated. Powder-XRD data and geochemical diagrams showed BASH to be an amorphous material, analogous to basaltic glass, and FASH consisting of crystalline compounds (mainly CaClOH). Bulk analyses by ICP-MS and point analyses by SEM-EDS indicated a high content of heavy metals, such as Fe, Cu and Cr, in both samples. However, BASH was highly enriched in Ni while FASH was additionally enriched in Zn and Pb. Gamma-ray measurements showed that the radioactivity of both ash samples, due to natural and artificial radionuclides ((137)Cs, (57)Co), was within the permissible levels recommended by IAEA. According to EN-type leaching tests, BASH was practically inert with regard to the mobility of the hazardous elements in aqueous media. FASH, however, showed a relatively high EN (and TCLP) leachability with regard to Pb and Zn. Finally, the stabilisation method, suggested for the treatment of FASH, included compression of the powder into briquettes using an appropriate machine and embedding the briquettes into pozzolanic cement blocks. After this treatment, TCLP and EN-type tests showed minimal release of Pb and Zn, thereby demonstrating a reliable management of ash waste. PMID- 21296497 TI - Temporal dissociation in the brain processing of pain and anger faces with different intensities of emotional expression. AB - Facial expression is one of the most relevant nonverbal behaviors in the communication of pain. However, little is known about brain processing of pain expressions in comparison with other affective facial expressions. The present experiment aimed to examine the effects of pain expression intensity on affective ratings and brain dynamics by recording electroencephalography (EEG) from 20 female healthy volunteers 18-24 years of age. Participants were asked to rate the affective characteristics of 144 stimuli depicting facial expressions of pain and anger with 3 level of intensities (high, mild, and low), as well as neutral faces. Results indicated that pain faces were judged as more unpleasant and arousing than anger and neutral faces for all intensity levels. EEG results further showed that facial expressions of pain elicited more enhanced amplitudes of the visual evoked potentials than anger and neutral faces in the latency between 350 and 550 milliseconds after stimulus onset; whereas anger faces elicited greater P200 amplitudes than pain and neutral faces. In addition, more increased theta activity in the latency of 200 to 400 milliseconds after stimulus onset was observed to high-intense as compared with low-intense facial expressions. These findings indicate that brain activity elicited by affective faces is modulated by the intensity of facial expressions and suggest the involvement of different brain mechanisms during the processing and recognition of facial expressions of pain and anger in healthy volunteers. PMID- 21296498 TI - Time-scheduled vs. pain-contingent opioid dosing in chronic opioid therapy. AB - Some expert guidelines recommend time-scheduled opioid dosing over pain contingent dosing for patients receiving chronic opioid therapy (COT). The premise is that time-scheduled dosing results in more stable opioid blood levels and better pain relief, fewer adverse effects, less reinforcement of pain behaviors, and lower addiction risk. We report results of a survey of 1781 patients receiving COT for chronic noncancer pain, in which 967 reported time scheduled opioid dosing only and 325 reported pain-contingent opioid dosing only. Opioid-related problems and concerns were assessed with the Prescribed Opioids Difficulties Scale. We hypothesized that respondents using time-scheduled opioid dosing would report significantly fewer problems and concerns than those using pain-contingent dosing. Patients receiving time-scheduled dosing received substantially higher average daily opioid doses than those using pain-contingent dosing (97.2 vs. 37.2mg average daily dose morphine equivalents, P < .0001). Contrary to expectation, time-scheduled opioid dosing was associated with higher levels of patient opioid control concerns than pain-contingent dosing (6.2 vs. 4.8, P=.008), after adjusting for patient and drug regimen differences. Opioid related psychosocial problems were somewhat greater among patients using time scheduled dosing, but this difference was nonsignificant after controlling for patient and drug regimen differences (5.9 vs. 5.0, P=.14). Time-scheduled dosing typically involved higher dosage levels and was associated with higher levels of patient concerns about opioid use. Controlled comparative effectiveness research is needed to assess benefits and risks of time-scheduled opioid dosing relative to pain-contingent opioid dosing among COT patients in ambulatory care. Patients with time-scheduled dosing received higher opioid dosage than patients with pain contingent dosing. Time-scheduled dosing was associated with greater opioid control concerns than pain-contingent dosing. PMID- 21296499 TI - Peripheral sensitization caused by insulin-like growth factor 1 contributes to pain hypersensitivity after tissue injury. AB - Sensitization of primary afferent neurons is one of the most important components of pain hypersensitivity after tissue injury. Insulin-like growth factor 1 (IGF 1), involved in wound repair in injured tissue, also plays an important role in maintaining neuronal function. In the present study, we investigated the effect of tissue IGF-1 on nociceptive sensitivity of primary afferent neurons. Local administration of IGF-1 induced thermal and mechanical pain hypersensitivity in a dose-dependent manner, and was attenuated by IGF-1 receptor (IGF1R) inhibition. Tissue but not plasma IGF-1 levels, as determined by enzyme-linked immunosorbent assay, significantly increased after plantar incision. Immunohistochemistry revealed that IGF1R was predominantly expressed in neurons as well as in satellite glial cells in the dorsal root ganglion (DRG). Double-labeling immunohistochemistry showed that IGF1R expression colocalized with peripherin and TRPV1, but not with NF200 in DRG neurons. The IGF1R inhibitor successfully alleviated mechanical allodynia, heat hyperalgesia, and spontaneous pain behavior observed after plantar incision. Expression of phosphorylated Akt in DRG neurons significantly increased after plantar incision and was suppressed by IGF1R inhibition. These results demonstrate that increased tissue IGF-1 production sensitizes primary afferent neurons via the IGF1R/Akt pathway to facilitate pain hypersensitivity after tissue damage. PMID- 21296501 TI - Pain is associated with regional grey matter reduction in the general population. AB - Regional decreases in grey matter volume as detected by magnetic resonance imaging-based volumetry have been reported in several clinical chronic pain cohorts. Here, we used voxel-based morphometry in a nonclinical cohort to investigate whether grey matter alterations also occur in older individuals (aged 40-85 years) from the general population. Based on self-report of pain, we identified 31 pain-free controls, 45 subjects with ongoing pain (low back pain, headache, or lower extremity joint pain) who had at least moderate pain on more than 3 days/month, and 29 individuals with past pain (stopped for >12 months). Relative to controls, the ongoing pain group showed regional grey matter volume decreases, predominantly in cingulate, prefrontal, and motor/premotor regions. No grey matter volume decreases were found in the group with pain that had stopped for >12 months. These results show that pain-related grey matter volume decreases are present in individuals from the general population. The lack of morphometric anomalies in subjects with past pain supports recent evidence suggesting that pain-related grey matter changes are reversible after cessation of pain. PMID- 21296500 TI - Reactive oxygen species contribute to neuropathic pain by reducing spinal GABA release. AB - Although both a loss of spinal inhibitory neurotransmission and the involvement of oxidative stress have been regarded as important mechanisms in the pathogenesis of pain, the relationship between these 2 mechanisms has not been studied. To determine whether reactive oxygen species (ROS) involvement in pain mechanisms is related to the diminished inhibitory transmission in the substantia gelatinosa (SG) of the spinal dorsal horn, behavioral studies and whole-cell recordings were performed in FVB/NJ mice. Neuropathic pain was induced by a tight ligation of the L5 spinal nerve (SNL). Pain behaviors in the affected foot were assessed by behavioral testing for mechanical hyperalgesia. Pain behaviors developed by 3 days and lasted more than 8 weeks. Both systemic and intrathecal administration of an ROS scavenger, phenyl-N-tert-butylnitrone (PBN), temporarily reversed mechanical hyperalgesia up to 2 hours, 1 week after SNL. In nonligated mice, an intrathecal injection of an ROS donor, tert-butyl hydroperoxide (t BOOH), dose-dependently induced mechanical hyperalgesia for 1.5 hours. In whole cell voltage clamp recordings of SG neurons, perfusion with t-BOOH significantly decreased the frequency of mIPSCs, and this effect was reversed by PBN. Furthermore, t-BOOH decreased the frequency of GABA(A) receptor-mediated mIPSCs without altering their amplitudes but did not affect glycine receptor-mediated mIPSCs. In SNL mice, mIPSC frequency in SG neurons was significantly reduced as compared with that of normal mice, which was restored by PBN. The antihyperalgesic effect of PBN on mechanical hyperalgesia was attenuated by intrathecal bicuculline, a GABA(A) receptor blocker. Our results indicate that the increased ROS in spinal cord may induce pain by reducing GABA inhibitory influence on SG neurons that are involved in pain transmission. PMID- 21296502 TI - Characteristics of a high brightness gaseous field ion source employing tungsten carbon doped NiAl needles. AB - We report on the characterization of a high brightness gaseous field ion source using an emitter made of a NiAl needle containing tiny spherical tungsten-carbon precipitates. By field evaporation of such a multiphase alloy, a surface protrusion is formed out of a precipitate, which can act as a small source size field ion emitter. The emission current-voltage characteristics of this emitter were recorded for a variety of parameters. The results obtained suggest that its application as a stable ion source is possible even on long term operation. PMID- 21296503 TI - First reports of Trichinella pseudospiralis in wild boars (Sus scrofa) of Italy. AB - Trichinella pseudospiralis is a non-encapsulated species infecting both mammals and birds. In Italy, this parasite was reported only in two night-birds of prey of Central Italy. In January 2010, Trichinella larvae were detected in three wild boars (Sus scrofa) of two regions of Northern Italy by enzymatic digestion. The parasites were identified as T. pseudospiralis by multiplex-PCR. The first infected wild boar was hunted in the Emilia Romagna region and the other two infected wild boars were bred outdoors in a small family farm of the Friuli Venezia Giulia region. These new epidemiological data reinforce the role of the wild boar as the main reservoir of T. pseudospiralis in Europe. PMID- 21296504 TI - Perceived risk associated with ecstasy use: a latent class analysis approach. AB - This study aims to define categories of perceived health problems among ecstasy users based on observed clustering of their perceptions of ecstasy-related health problems. Data from a community sample of ecstasy users (n=402) aged 18 to 30, in Ohio, was used in this study. Data was analyzed via Latent Class Analysis (LCA) and Regression. This study identified five different subgroups of ecstasy users based on their perceptions of health problems they associated with their ecstasy use. Almost one third of the sample (28.9%) belonged to a class with "low level of perceived problems" (Class 4). About one fourth (25.6%) of the sample (Class 2), had high probabilities of "perceiving problems on sexual-related items", but generally low or moderate probabilities of perceiving problems in other areas. Roughly one-fifth of the sample (21.1%, Class 1) had moderate probabilities of perceiving ecstasy health-related problems in all areas. A small proportion of respondents (11.9%, Class 5) had high probabilities of reporting "perceived memory and cognitive problems", and of perceiving "ecstasy-related problems in all areas" (12.4%, Class 3). A large proportion of ecstasy users perceive either low or moderate risk associated with their ecstasy use. It is important to further investigate whether lower levels of risk perception are associated with persistence of ecstasy use. PMID- 21296505 TI - The mediating effect of depressive symptoms on the relationship between traumatic childhood experiences and drug use initiation. AB - Stressful experiences such as childhood trauma and depressive symptoms have both been implicated in the initiation of drug use; however, longitudinal designs have not yet been used to elucidate their respective roles to better understand the causal sequence. In the present study, a sensitivity analysis was conducted using two mediation strategies to examine how this sequence may differ by various levels of statistical control, including (1) the standard mediational model in which the effect of lifetime traumatic stressors (Year 1) on the onset of drug use (Years 3 and 4) is mediated by levels of depressive symptoms (Year 2); and (2) a stronger test of causality such that the effect of lifetime traumatic stressors (Year 1) on the onset of drug use (Years 3 and 4) was mediated by changes in depressive symptoms (Year 1 to 2), measured by a residualized change score that controlled for levels in Year 1. Two types of trauma were studied in a community-based study of 489 Hispanic preadolescents (aged 10-12): (a) the number of lifetime traumatic stressors and (b) seven specific lifetime stressors. We also controlled for new onset traumatic stressors occurring between Years 1 and 2. Primary findings indicate that drug use initiation during early adolescence (e.g., ages 14-16) may not be tied to immediate proximal perturbations in risk factors, such as traumatic experiences and depressive symptoms. Rather, the effects of trauma on depression in this sample appear to be established earlier in childhood (ages 10-14 or younger) and persist in a relatively stable manner into middle adolescence when the risk for drug use may be heightened. PMID- 21296506 TI - Calcium pentosan polysulfate and sodium pentosan polysulfate may be used to treat intervertebral disc degeneration. AB - Intervertebral disc degeneration (IDD) is a major health problem world-wide, and several spinal disorders are closely associated with it. Although people have invested a great deal of time and effort, how to prevent and reverse the IDD for the researchers is still a difficult and hot issue. Intervertebral disc belongs to cartilage tissue, and IDD also is the cartilage degeneration disease. A large quantity of studies have shown that Calcium pentosan polysulfate (CaPPS) and sodium pentosan polysulfate (NaPPS) possess chondroprotective activities and play an important role in maintaining cartilage integrity. We reasonably hypothesize that NaPPS and CaPPS may be used to treat IDD. The possible mechanism may include that: (1) the significant effects of NaPPS and CaPPS in improving capillary blood flow could maintain nutritional supply to intervertebral disc, and preserve intervertebral disc tissue against degeneration; (2) CaPPS and NaPPS preserve cartilage integrity, proteoglycan synthesis, and improve cartilage biomechanical properties; (3) as the multifaceted exosite inhibitors of proteinases NaPPS and CaPPS strongly impede the activity and production of proteinases; (4) promotion of the balance between proteinases and TIMPs also may be involved in treating IDD; (5) NaPPS and CaPPS exhibit potent anti-inflammatory effects, and then reduce inflammation-induced IDD. If the hypothesis were conformed, the symptoms caused by IDD and its related diseases would be a corresponding alleviation or even disappearance, which could greatly alleviate the suffering of patients from disc degeneration diseases. Certainly, many roles of CaPPS and NaPPS, such as effectiveness, safety and side effects, need to be tested, and further works such as animal model and clinical trial, need to be done to prove this hypothesis. PMID- 21296507 TI - Cigarette smoking status in pathological gamblers: association with impulsivity and cognitive flexibility. AB - BACKGROUND: While the majority of pathological gamblers are current cigarette smokers (CS), some have quit smoking (former smokers, FS) while others never smoked (never smokers, NS). The reasons for elevated smoking rates in pathological gambling are not known, but gamblers may use nicotine as a putative cognitive enhancer. This study evaluated impulsivity and cognitive flexibility in a sample of pathological gamblers with differing smoking status. METHODS: Fifty five subjects with pathological gambling (CS, n=34; FS, n=10; NS, n=11) underwent cognitive assessments using the Stop-Signal (SST) and Intradimensional/Extra dimensional (ID/ED) set-shift tasks. RESULTS: CS reported less severe gambling problems than either FS or NS on the Yale Brown Obsessive Compulsive Scale modified for Pathological Gambling, and CS was associated with significantly fewer directional errors on the SST task, compared to NS. In addition, in CS, higher daily cigarette consumption was associated with fewer total errors on the ID/ED task. CONCLUSIONS: The potential role of nicotine as a cognitive enhancer was supported by objective tests of impulsivity and cognitive flexibility. Human laboratory studies using nicotine challenges in pathological gambling will shed further light on this relationship. PMID- 21296508 TI - Sleep disturbance and the effects of extended-release zolpidem during cannabis withdrawal. AB - BACKGROUND: Sleep difficulty is a common symptom of cannabis withdrawal, but little research has objectively measured sleep or explored the effects of hypnotic medication on sleep during cannabis withdrawal. METHODS: Twenty daily cannabis users completed a within-subject crossover study. Participants alternated between periods of ad libitum cannabis use and short-term cannabis abstinence (3 days). Placebo was administered at bedtime during one abstinence period (withdrawal test) and extended-release zolpidem, a non-benzodiazepine GABA(A) receptor agonist, was administered during the other. Polysomnographic (PSG) sleep architecture measures, subjective ratings, and cognitive performance effects were assessed each day. RESULTS: During the placebo-abstinence period, participants had decreased sleep efficiency, total sleep time, percent time spent in Stage 1 and Stage 2 sleep, REM latency and subjective sleep quality, as well as increased sleep latency and time spent in REM sleep compared with when they were using cannabis. Zolpidem attenuated the effects of abstinence on sleep architecture and normalized sleep efficiency scores, but had no effect on sleep latency. Zolpidem was not associated with any significant side effects or next day cognitive performance impairments. CONCLUSIONS: These data extend prior research that indicates abrupt abstinence from cannabis can lead to clinically significant sleep disruption in daily users. The findings also indicate that sleep disruption associated with cannabis withdrawal can be attenuated by zolpidem, suggesting that hypnotic medications might be useful adjunct pharmacotherapies in the treatment of cannabis use disorders. PMID- 21296509 TI - A cross-national study on Mexico-US migration, substance use and substance use disorders. AB - BACKGROUND: Epidemiologic research has consistently found lower prevalence of alcohol and drug use disorders among Hispanic immigrants to the US than among US born Hispanics. Recent research has begun to examine how this change occurs in the process of assimilation in the US. We aimed to study immigration, US nativity, and return migration as risk factors for alcohol and drug use among people of Mexican origin in both the US and Mexico. METHODS: Data come from nationally representative surveys in the United States (2001-2003; n=1208) and Mexico (2001-2002; n=5782). We used discrete time event history models to account for time-varying and time-invariant characteristics. RESULTS: We found no evidence that current Mexican immigrants in the US have higher risk for alcohol or alcohol use disorders than Mexicans living in Mexico, but current immigrants were at higher risk for drug use and drug use disorders. Current Mexican immigrants were at lower risk for drug use and drug disorders than US-born Mexican-Americans. US nativity, regardless of parent nativity, is the main factor associated with increasing use of alcohol and drugs. Among families of migrants and among return migrants we found increased risk for alcohol use, drug use and alcohol and drug use disorders. Evidence of selective migration and return of immigrants with disorders was found regarding alcohol use disorders only. CONCLUSIONS: Research efforts that combine populations from sending and receiving countries are needed. This effort will require much more complex research designs that will call for true international collaboration. PMID- 21296510 TI - Occurrence and associated lesions of Pasteurella multocida in porcine bronchopneumonia. AB - With the aim to extend the present knowledge on possible systemic spreading of Pasteurella multocida in pigs with bronchopneumonia, the occurrence and associated lesions of P. multocida were described by comparing cultural detection, pathological evaluation and in situ hybridization of P. multocida in lungs, hearts and kidneys from cases of porcine bronchopneumonia. P. multocida was cultivated from the lung lesions in 114 out of a total of 148 cases of porcine bronchopneumonia. Among the 114 cases, P. multocida was also cultivated from the pericardial sacs of 40 pigs and the kidneys of seven pigs. Gross lesions and histological findings included a variety of type and stages of bronchopneumonia in connection to the isolation of P. multocida. Furthermore, chronic fibrous pericarditis, interstitial nephritis and a high proportion of lympho-histocytic nephritis were observed. In situ hybridization identified P. multocida in the majority of the lungs, none of the hearts and in half of the kidneys examined. The results show a possible low rate of systemic spreading of P. multocida from lung lesions in pigs with bronchopneumonia. PMID- 21296511 TI - [Calicivirus gastroenteritis in children hospitalized in Dakar]. PMID- 21296512 TI - Postmortem abdominal CT: assessing normal cadaveric modifications and pathological processes. AB - PURPOSE: To investigate the interest of postmortem non-enhanced computer tomography (CT) for abdominal lesions in a forensic context of suspicions death and to list the different radiological cadaveric modifications occurring normally at abdominal stage, which must be known by non forensic radiologists in case of any postmortem exam. MATERIALS AND METHODS: 30 cadavers have been submitted to a body CT-scan without injection of contrast material. CT exams were reviewed by two independent radiologists and radiological findings were compared with forensic autopsy data. RESULTS: False positive CT findings included physiological postmortem transudates misdiagnosed with intra-abdominal bleedings, and putrefaction gas misdiagnosed with gas embolism, aeroporty, aerobily, digestive parietal pneumatosis. Incidentalomas without any role in death process were also reported. False negative CT findings included small contusions, vascular thromboses, acute infarcts foci, non radio-opaque foreign bodies. Normal cadaveric modifications were due to livor mortis and putrefaction, and are seen quickly (some hours) after death. CONCLUSION: The non forensic radiologist should be familiar with the normal abdominal postmortem features in order to avoid misdiagnoses, and detect informative lesions which can help and guide the forensic practitioner or the clinical physician. PMID- 21296513 TI - MRI morphological classification of ductal carcinoma in situ (DCIS) correlating with different biological behavior. AB - OBJECTIVE: To investigate morphological appearance of ductal carcinoma in situ of breast on MRI and to correlate the appearances with some factors. METHODS AND MATERIALS: MRI feature of 41 DCISs were analyzed retrospectively according to ACR BI-RADS, twenty-three of the 41 were pure DCIS and 18 were DCIS with microinvasion (DCIS-MI). The shape was categorized as mass lesion and non-mass like lesion. The shape was correlated with histological grade, ER status and expression of e-erbB2 as well as pure DCIS or DCIS-MI. RESULTS: Percentage of high grade in non-mass-like lesion was higher than that in mass type group, Average size of tumor in group of high grade, negative ER status and positive c erbB2 expression were larger than that in non-high grade, positive ER status and negative c-erbB2 expression. Comparing pure DCIS and DCIS-MI, high grade in DCIS MI was significantly higher than that in pure DCIS, Average size of DCIS-MI was larger than that in pure DCIS. Percentage of non-mass-like lesion was higher in DCIS-IM than that in pure DCIS, the difference was marginally significant. CONCLUSION: DCIS can be classified as mass type and non-mass-like type morphologically on MRI. The two types reflect different biological behavior. PMID- 21296514 TI - Comparison of three different injection methods for arterial phase of Gd-EOB-DTPA enhanced MR imaging of the liver. AB - OBJECTIVE: To compare three different injection methods for optimizing hepatic arterial phase of gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd EOB-DTPA) enhanced MR imaging. METHODS: Arterial phase images were obtained after the injection of contrast agent at a rate of 3 mL/s with diluted Gd-EOB-DTPA (dilution method) in 27 patients, 3 mL/s with undiluted Gd-EOB-DTPA (3 mL method) in 26 patients and 1 mL/s with undiluted Gd-EOB-DTPA (1 mL method) in 28 patients. In the quantitative evaluation, signal-to-phantom ratios (SPR) of the liver parenchyma, pancreas, renal cortex, portal vein and aorta were evaluated. In the qualitative evaluation, the seven items for image quality of hepatic arterial phase were assessed, and the total score of all items in each subject was calculated. RESULTS: The score of enhancement of abdominal aorta and total score of seven items in 1 mL method were significantly higher than those in 3 mL method. The SPR of the liver parenchyma in 3 mL method was significantly higher than that in 1 mL method, suggesting substantial hepatic inflow from portal venous return. CONCLUSION: For the optimal arterial phase imaging, injection rate of 1 mL/s with undiluted Gd-EOB-DTPA is convenient and preferable, compared with other two methods, based on our qualitative analysis. PMID- 21296515 TI - The effect of nuchal cord on nuchal fold thickness measured in the second trimester. AB - PURPOSE: To find out whether nuchal cord causes an effect on the nuchal skin fold thickness (NFT) measurements, or not. PATIENTS AND METHODS: A total of 242 fetuses with normal outcomes that had undergone detailed second trimester US scan between 18 and 24 weeks of gestation were included in the study. NFT measurements were made on axial cranial US images passing through the cerebellum and cavum septi pellucidum. To detect nuchal cord, color Doppler imaging was performed on the axial views of the fetal neck. To investigate the differences in NFT measurements of the fetuses with or without nuchal cord, statistical analysis was performed using Mann-Whitney test. P < 0.05 was considered statistically significant. RESULTS: The study group was divided into two groups: nuchal cord (+) (n: 26) and nuchal cord (-) (n: 216) fetuses. Mean NFT measurements were 4.66 +/- 0.64 mm and 4.36 +/- 0.79 mm for nuchal cord (+) and nuchal cord (-) fetuses, respectively. Median NFT measurement for nuchal cord (+) fetuses was 4.6mm, whereas it was 4.4mm for nuchal cord (-) fetuses. Statistically significant difference was denoted between two groups, in terms of NFT measurements (P = 0.049). CONCLUSION: NFT measurements of fetuses with nuchal cord are higher than the NFT measurements of fetuses without nuchal cord. One can conclude that the nuchal cord (+) fetuses with no other anomalies but increased NFT should be re scanned to see if the increased NFT resolves in the absence of nuchal cord. PMID- 21296516 TI - Usefulness of administration of SPIO prior to RF ablation for evaluation of the therapeutic effect: an experimental study using miniature pigs. AB - OBJECTIVES: To evaluate the usefulness of administration of superparamagnetic iron oxide (SPIO) and magnetic resonance (MR) imaging for assessing the efficacy of radiofrequency (RF) liver ablation. MATERIAL AND METHODS: Using a protocol approved by the animal research committee of our university, nine RF liver ablations were performed in three miniature pigs. Six ablations were performed after administration of SPIO in two pigs (group A). Three ablations were performed in the other pig without administration of SPIO (group B). All pigs were sacrificed 4 days after the procedure. Harvested livers were scanned with a 1.5T MR system before and after fixation with 10% buffered formalin, and MR images were precisely compared with histological specimens. RESULTS: There were no histological differences between the two groups. All ablated liver lesions showed coagulation necrosis at the external layer. There were no viable cells inside the coagulation necrosis. All ablated lesions had a hypointense rim on fast low angle shot (FLASH) images. The rims of group A were thicker than those of group B. The rims of group B corresponded histologically to congestion and hemorrhagic necrosis area. The rims of the group A corresponded to hemorrhagic necrosis and coagulation necrosis areas. In group A, the hypointense rim reflected necrotic Kupffer cells that took up SPIO before RF liver ablation. CONCLUSION: Administration of SPIO made it possible to precisely evaluate ablated liver parenchyma by hypointense rim on FLASH images. This method is helpful for the evaluation of safety margin after RF ablation for liver tumors. PMID- 21296517 TI - Relationship of apparent diffusion coefficient to survival for patients with unresectable primary hepatocellular carcinoma after chemoembolization. AB - OBJECTIVES: to evaluate the prognostic value of apparent diffusion coefficient (ADC) values from MR diffusion-weighted imaging of unresectable hepatocellular carcinoma after chemoembolization. METHODS: our study was proved by our institute and informed consent was obtained from all patients before commencement of the study. Twenty-three patients with unresectable hepatocellular carcinoma were scanned immediately before and after chemoembolization within 24h using conventional anatomical MR imaging and diffusion-weighted imaging, from which ADC values in the lesions were measured. The changes in ADC values after chemoembolization were calculated. The relationship between the lesion ADC and the survival time was analyzed by correlation analysis. The overall cumulative survival was analyzed by the Kaplan-Meier method, and survival curves were compared by the log-rank test. RESULTS: the mean overall survival period was (25.0+/-8.7) months. The pre-chemoembolization lesion ADC value was (1.36+/ 0.249)*10(-3) mm2/s; the change in ADC values post-chemoembolization was (0.377+/ 0.332)*10(-3) mm2/s. There were significant linear regression relation between the survival time and pre-chemoembolization lesion ADC values (r=-0.698, P<0.001) or the changes in ADC value post-chemoembolization (r=0.702, P<0.001). And Log rank test showed that pre-chemoembolization ADC values (chi2=7.339, P=0.007) or the changes in ADC value post-chemoembolization (chi2=9.820, P=0.002) significantly influenced the overall cumulative survival. CONCLUSION: Pre treatment ADC values as well as changes in ADC values after treatment may provide useful information for predicting survival for patients with unresectable hepatocellular carcinoma. PMID- 21296518 TI - Effectiveness of rosiglitazone on bleomycin-induced lung fibrosis: Assessed by micro-computed tomography and pathologic scores. AB - Peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists exhibit potent anti-fibrotic effects in the lung and other tissues. Recently, micro computed tomography (CT) has been a useful tool for the investigation of lung diseases in small animals and is now increasingly applied to visualize and quantify the pulmonary structures. However, there is little information on the assessment for therapeutic effects of PPARgamma agonists on the pulmonary fibrosis in mice using micro-CT. This study was aimed to determine the capability of micro-CT in examining the effects of rosiglitazone on pulmonary fibrosis. We used a murine model of bleomycin-induced lung fibrosis to evaluate the feasibility of micro-CT in evaluating the therapeutic potential of rosiglitazone on pulmonary fibrosis, comparing with pathologic scores. On micro-CT findings, ground glass opacity (80%) and consolidation (20%) were observed predominantly at 3 weeks after the instillation of bleomycin, and the radiologic features became more complex at 6 weeks. In bleomycin-instilled mice treated with rosiglitazone, the majority (80%) showed normal lung features on micro-CT. Radiological pathologic correlation analyses revealed that ground glass opacity and consolidation were correlated closely with acute inflammation, while reticular opacity was well correlated with histological honeycomb appearance. These results demonstrate that rosiglitazone displays a protective effect on pulmonary fibrosis in mice and that the visualization of bleomycin-induced pulmonary fibrosis using micro-CT is satisfactory to assess the effects of rosiglitazone. It implies that micro-CT can be applied to evaluate therapeutic efficacies of a variety of candidate drugs for lung diseases. PMID- 21296519 TI - Simultaneous determination of ciclesonide and its active metabolite desisobutyryl ciclesonide in human plasma by LC-APCI-MS/MS: application to pharmacokinetic study in healthy Chinese volunteers. AB - A sensitive and highly selective liquid chromatography tandem mass spectrometric (LC/MS/MS) method was developed and validated for the determination of ciclesonide (CIC) and its active metabolite, desisobutyryl-ciclesonide (des-CIC), in human plasma. Plasma samples were extracted using methyl tert-butyl ether with mifepristone as an internal standard (IS). Separation was carried out on a C(18) column using a mixture of 0.1% formic acid solution and methanol as the mobile phase with linear gradient elution. The detection was operated with positive atmospheric pressure chemical ionization (APCI) by selective multiple reaction monitoring (SRM). The chief benefit of the present method was the high sensitivity, with the lower limit of quantification (LLOQ) as low as 10pg/mL and the linearity ranging from 10 to 10,000pg/mL for both CIC and des-CIC. The method was fully validated and successfully applied to determine CIC and des-CIC simultaneously in human plasma and proved to be suitable for phase I clinical pharmacokinetic study of inhaled ciclesonide in healthy Chinese volunteers. PMID- 21296520 TI - Delayed diagnosis of injuries in pediatric trauma: the role of radiographic ordering practices. AB - OBJECTIVES: We sought to describe the use of radiographic studies in pediatric major trauma patients and determine the extent to which a selective, clinically guided use of imaging contributes to delayed diagnosis of injury (DDI). METHODS: We conducted a retrospective chart review of 324 consecutive pediatric major trauma patients at our level 1 trauma center. One radiologist reviewed all imaging. Delayed diagnosis of injury was defined as detection after more than 12 hours. Equivalency testing was performed to compare radiology use in patients with and without DDI. RESULTS: Twenty-six (8%) of 324 patients had 36 DDI; 27 (75%) of 36 were orthopedic injuries. Median time to DDI detection was 20.5 hours (interquartile range, 15-60.5). During initial evaluation, DDI patients had similar numbers of plain radiographs (3.5 vs 3, P = .54) but more computed tomographic (CT) scans (4 vs 3, P = .03) compared with patients without DDI. Sixteen percent of all patients received CT thorax; 55%, CT cervical spine; and 56%, CT abdomen. Only 1 clinically important DDI was detected solely on the basis of a later CT scan (0.3%; 95% confidence interval, 0-1.5). No cervical spine, intrathoracic, or intraabdominal DDI was attributable to failure to obtain a CT during initial evaluation. Patients with DDI had higher injury severity scores, intubation rates, and pediatric intensive care unit admission rates than those without DDI. CONCLUSIONS: Patients with DDI had similar initial plain x-ray evaluations to patients without DDI, despite DDI patients being more severely injured. Delayed diagnosis of injury was not attributable to inadequate CT use. Most DDIs were orthopedic, highlighting the importance of a tertiary survey and a low threshold for skeletal radiographs. PMID- 21296521 TI - Fetal loss in symptomatic first-trimester pregnancy with documented yolk sac intrauterine pregnancy. AB - BACKGROUND: The possibility of spontaneous miscarriage is a common concern among pregnant women in the emergency department (ED). OBJECTIVE: This study sought to determine fetal outcomes for women following ED evaluation for first-trimester abdominopelvic pain or vaginal bleeding who had an intrauterine pregnancy (IUP) on ultrasound before a visible fetal pole ("yolk sac IUP"). METHODS: A retrospective chart review of consecutive ED charts from December 2005 to September 2006 identified patients with a yolk sac IUP. Demographic data, obstetric/gynecologic history, and presenting symptoms were obtained. Outcomes were determined via computerized records. Fetal loss was diagnosed by falling beta-human chorionic gonadotropin or pathology specimen. Live birth was diagnosed by viable fetus at 20-week ultrasound or delivery. RESULTS: A total of 131 patients were enrolled in this study. Of these, 14 were lost to follow-up (12%), leaving 117 patient encounters. Of the 117 women, 82 carried their pregnancies to at least 20-week gestation. Thirty-five patients miscarried. Fetal loss rate by chief complaint were as follows: 8 of 46 patients presenting with pain only, 14 of 34 presenting with vaginal bleeding only, and 13 of 37 with both vaginal bleeding and pain. CONCLUSION: Seventy percent of women diagnosed with a yolk sac IUP in the ED carried their pregnancy to at least 20 weeks. The remaining women (30%) experienced fetal loss. Vaginal bleeding (with or without pain) increased the rate of fetal loss compared with women with pain only. These data will assist the emergency physician in counseling women with symptomatic first-trimester pregnancies. PMID- 21296522 TI - Rapture of the large intestine caused by severe oral glyphosate-surfactant intoxication. PMID- 21296523 TI - Prochlorperazine in children with migraine: a look at its effectiveness and rate of akathisia. AB - OBJECTIVE: The objective of this study is to evaluate the effectiveness of prochlorperazine and the rate of akathisia in children with severe migraine. METHODS: The study is a prospective cohort of a convenient sample of patients younger than 18 years old diagnosed with migraine and treated with intravenous prochlorperazine in adjunction with diphenhydramine in the emergency department. The evaluation of pain and akathisia was performed before the treatment and was repeated 60 minutes later and before discharge. A telephone follow-up was completed to assess relapse in pain and presence of akathisia. The effectiveness of prochlorperazine was determined using different outcomes: 50% reduction of pain, pain-free patients, treatment failure, and relapse of pain. RESULTS: Of the 79 patients included in the study for 25 months, 64 (81%) either met the International Headache Society criteria or had a diagnosis of migraine confirmed by a neurologist at follow-up. Among these patients, 47 (100%) of 47 had a 50% reduction of pain, and 24 (50%) of 48 were pain free at discharge. Only 14 (22%) of 64 patients had a treatment failure. However, 43 (68%) of 63 patients had a relapse of their headache within the first week after discharge. Overall, among the 79 patients, 4 (5%) had a definitive diagnosis of akathisia, but 27 (34%) other patients presented symptoms suggesting a possible diagnosis of akathisia. CONCLUSION: Prochlorperazine seems very effective to decrease pain on a short term basis in children. However, more than two thirds of the patients, overall, had a relapse of their migraine at home in the first week. Despite the use of diphenhydramine, akathisia remains a concern. PMID- 21296524 TI - Acute kidney injury associated with tumor lysis syndrome: a paradigm shift. PMID- 21296525 TI - Relation of signal in mononuclear cell with endotoxin response and clinical outcome after trauma. AB - BACKGROUND: We investigated the correlation of proinflammatory transcript nuclear factor kappaB (NF-kappaB) and antioxidative gene transcript nuclear factor erythroid 2-related factor 2 (Nrf2) expressions in peripheral blood mononuclear cells (PBMCs) with the tumor necrosis factor alpha (TNF-alpha) response after endotoxin stimulation and the clinical outcome of severely injured patients. METHODS: Thirty-two severe blunt trauma patients (injury severity score>16) with systemic inflammatory response syndrome were enrolled. Age- and sex-matched healthy persons were the controls. Patients' blood samples were obtained at 24 and 72 hours after injury. Peripheral blood mononuclear cells were isolated, and measurements for NF-kappaB p65 translocation, Nrf2 and phosphorylated inhibitory kappaB-alpha expressions, and TNF-alpha levels were assayed after endotoxin stimulation. RESULTS: In the trauma patients, TNF-alpha hyporesponse, depressed NF-kappaB p65 translocation, and phosphorylated inhibitory kappaB-alpha expression in PBMCs were found at 24 and 72 hours after injury; the Nrf2 expressions in PBMCs were not significantly different between patients and controls. The TNF-alpha levels had significant correlation with the NF-kappaB translocation and the trend of negative correlation with Nrf2 expression. Fifteen patients had critical injury (injury severity score>=25). Patients with critical injury had a lower NF-kappaB signal and a lower TNF-alpha response than did the counter group. Twelve patients developed organ failure; their Nrf2 expressions were significantly lower than those of patients without organ failure. CONCLUSIONS: The endotoxin hyporesponse associated with NF-kappaB and Nrf2 signal alternations in PBMCs of injured patients develops early after injury. The hyporesponse of PBMCs with a lower TNF-alpha level correlates with a lower NF kappaB signal and is associated with critical injury, whereas a depressed Nrf2 expression in PBMCs is associated with later organ failure in trauma patients. PMID- 21296526 TI - The use of bedside ultrasonography in the evaluation of a neck mass. PMID- 21296527 TI - Implication of cardiac marker elevation in patients who resuscitated from out-of hospital cardiac arrest. AB - OBJECTIVES: It is often difficult to diagnose acute myocardial infarction (AMI) in patients who resuscitated after out-of-hospital cardiac arrest (OHCA) and had a delayed elevation in cardiac marker. This study explored whether elevations in cardiac marker were due to coronary artery occlusion or resulted from other causes. METHODS: The study included 19 non-ST-segment elevation patients who resuscitated after OHCA and underwent delayed coronary angiography. We checked patients' serial creatine kinase-myocardial band (CK-MB) and troponin I (cTnI) levels on arrival and 6, 12, 24, 48, 72, and 96 hours postarrest. Based on the association of elevated cTnI and the results of their delayed angiographies, the patients were retrospectively divided into 2 groups: an AMI group (n=5) and a non AMI group (n=14). We then analyzed the serial cardiac marker measurements in each group. RESULTS: Peak marker levels were significantly higher in the AMI group than in the non-AMI group (CK-MB, 177.0+/-112.7 vs 66.4+/-85.2 ng/mL; P=.033 and cTnI, 40.4+/-14.5 vs 10.6+/-13.5 ng/mL; P=.005). After adjusting for covariates, the peak and 6-, 12-, and 24-hour cTnI and 6-hour CK-MB were significantly different between the 2 groups (P=.005, P=.004, P=.005, P=.020, and P=.007). In the non-AMI group, 3 patients had cTnI values that were within the reference range at all of the evaluated times. Most patients had only low cTnI elevations that rapidly fell back to normal. CONCLUSION: The resuscitation of patients who experience sudden OHCA but do not have an AMI may lead to elevations of cardiac markers. However, these elevations are low and normalize early. PMID- 21296528 TI - Impact of trauma activation on the ED length of stay for nontraumatic patients. AB - INTRODUCTION: Trauma activation prioritizes hospital resources for the assessment and treatment of trauma patient over all patients in the emergency department (ED). We hypothesized that length of stay (LOS) is longer for nontrauma patients during a trauma activation. METHODS: A retrospective, case-control chart review was conducted in a level I trauma center. Cases consist of patients who present 1 hour before and after the presentation of the trauma activation. Controls were patients presenting to the ED during the same period exactly 1 week before and after the cases. Confounding variables measured included sex, age, arrivals, and census for the 3 areas. RESULTS: Two hundred ninety-four trauma events occurred from January 1 until September 30, 2009. A significant difference was found between LOS of patients seen during a trauma activation with an average increase of 10.7 minutes in LOS (P =.0082; 95% confidence interval [CI], 2.8-18.7). This difference is attributable to the middle acuity area of the ED, in which the average increase in LOS was 20.3 minutes (P = .0004; 95% CI, 9.1-31.5). Significant LOS difference was not found when a trauma activation had an LOS of less than 60 minutes (P = .30; 95% CI, -7.1-61.7 for trauma LOS <60 minutes vs P = .02; 95% CI, 1.6-18.0 for trauma LOS >=60 minutes). CONCLUSION: This retrospective case-control chart review identified an increase in ED LOS for patient presenting during trauma activations. Resource prioritization should be accounted for during times when these critical patients enter the ED. PMID- 21296529 TI - Supracondylar radial nerve block for treatment of distal radius fractures in the emergency department. AB - BACKGROUND: Patients with acute distal radius fractures are frequently treated in the emergency department (ED) with closed reduction and splinting. Many of the anesthesia methods frequently employed may either lack efficacy or require additional monitoring and resources. CASE REPORT: An 18-year-old woman presented to the ED with a dorsally angulated distal radius fracture (Colles fracture). As an alternative to procedural sedation, an ultrasound-guided block of the radial nerve proximal to its bifurcation into the deep and superficial branches was performed. The resulting anesthesia was adequate to reduce and splint the fracture with minimal discomfort for the patient. CONCLUSION: Ultrasound-guided supracondylar block of the radial nerve proximal to the origin of the deep and superficial branches provides safe and efficacious anesthesia for distal radius fracture reduction in the ED. PMID- 21296530 TI - Identification of portal venous air with bedside ultrasound in the emergency department. PMID- 21296531 TI - Ectopic glandular breast tissue in a lactating young woman. AB - BACKGROUND: Ectopic breast tissue is a rare occurrence in pregnant women and should not be confused with abscess or other causes. Ectopic breast tissue is present at birth but often only diagnosed after puberty, pregnancy, or lactation. OBJECTIVE: Misdiagnosis is of concern due to the fact that ectopic breast tissue may undergo pathological changes with increased risk of malignancy. Therefore, it is vital for emergency physicians to be able to recognize this process and ensure proper follow-up care. CASE REPORT: We present a case of ectopic breast tissue in a 19-year-old primigravida. CONCLUSION: Surgical removal for the purpose of prophylaxis of malignant changes is not currently recommended. Definitive diagnosis is established by fine-needle aspiration and excisional biopsy. PMID- 21296532 TI - The "Superhero Cape Burrito": a simple and comfortable method of short-term procedural restraint. AB - BACKGROUND: Restraint is sometimes necessary to successfully perform procedures on pediatric patients in the emergency department. A papoose may be intimidating and uncomfortable, and a wrapped sheet may not keep the child's arms from wiggling free. DISCUSSION: We present an adaptation of the wrapped sheet (burrito) technique, using a pillowcase to better immobilize the child's arms. The arms are inserted in the pillowcase behind the child's back, and then the child is placed supine over a horizontally placed sheet and turned to each side so the sheet is tucked behind the back. The child is thereby easily and comfortably restrained. CONCLUSIONS: We believe this technique more successfully restrains the child than the wrapped sheet alone, and is easier to execute than other wrapped sheet techniques aimed at improving arm immobilization. PMID- 21296533 TI - Posterior papillary muscle rupture complicating an ST-segment myocardial infarction. PMID- 21296534 TI - Persistent neck pain after motor vehicle collision. PMID- 21296535 TI - Measuring pathways towards a healthier lifestyle in the Hoorn Prevention Study: the Determinants of Lifestyle Behavior Questionnaire (DLBQ). AB - OBJECTIVE: We developed the Determinants of Lifestyle Behavior Questionnaire (DLBQ) to measure determinants of lifestyle behavioral change according to the Theory of Planned Behavior (TPB) in adults at high risk of diabetes type 2 (T2DM) and cardiovascular diseases (CVD). The aim of the current study was to test the validity of the DLBQ. METHODS: From February to September 2008, a cross-sectional survey was conducted in the region West-Friesland (The Netherlands) among 622 adults, aged 30-50 years at high risk of T2DM or CVD participating in a lifestyle intervention trial. Structural equation modeling techniques were used for confirmatory factor analysis and to test correlations between the TPB constructs. RESULTS: The results demonstrate the factorial validity of the DLBQ in this population. The theoretical factor structure of the DLBQ is supported, and 41-56% of the variance in intentions to improve lifestyle behaviors is explained. CONCLUSIONS: The DLBQ proves to be a valid instrument for measuring important determinants of the intention to change three lifestyle behaviors in adults at high risk of T2DM and CVD. PRACTICE IMPLICATIONS: The identified 'key determinants' of the TPB that seem to contribute to an increased intention to change behavior could be of value in designing future lifestyle interventions. PMID- 21296536 TI - Methodological pluralism in health communication research. PMID- 21296537 TI - Open surgery versus endovascular repair of ruptured thoracic aortic aneurysms. AB - BACKGROUND: Ruptured descending thoracic aortic aneurysm (rDTAA) is a cardiovascular catastrophe, associated with high morbidity and mortality, which can be managed either by open surgery or thoracic endovascular aortic repair (TEVAR). The purpose of this study is to retrospectively compare the mortality, stroke, and paraplegia rates after open surgery and TEVAR for the management of rDTAA. METHODS: Patients with rDTAA treated with TEVAR or open surgery between 1995 and 2010 at seven institutions were identified and included for analysis. The outcomes between both treatment groups were compared; the primary end point of the study was a composite end point of death, permanent paraplegia, and/or stroke within 30 days after the intervention. Multivariate logistic regression analysis was used to identify risk factors for the primary end point. RESULTS: A total of 161 patients with rDTAA were included, of which 92 were treated with TEVAR and 69 with open surgery. The composite outcome of death, stroke, or permanent paraplegia occurred in 36.2% of the open repair group, compared with 21.7% of the TEVAR group (odds ratio [OR], 0.49; 95% confidence interval [CI], .24-.97; P = .044). The 30-day mortality was 24.6% after open surgery compared with 17.4% after TEVAR (OR, 0.64; 95% CI, .30-1.39; P = .260). Risk factors for the composite end point of death, permanent paraplegia, and/or stroke in multivariate analysis were increasing age (OR, 1.04; 95% CI, 1.01-1.08; P = .036) and hypovolemic shock (OR, 2.47; 95% CI, 1.09-5.60; P = .030), while TEVAR was associated with a significantly lower risk of the composite end point (OR, 0.44; 95% CI, .20-.95; P = .039). The aneurysm-related survival of patients treated with open repair was 64.3% at 4 years, compared with 75.2% for patients treated with TEVAR (P = .191). CONCLUSIONS: Endovascular repair of rDTAA is associated with a lower risk of a composite of death, stroke, and paraplegia, compared with traditional open surgery. In rDTAA patients, endovascular management appears the preferred treatment when this method is feasible. PMID- 21296538 TI - Haptoglobin phenotypes and plasma haptoglobin levels in patients with abdominal aortic aneurysm. AB - OBJECTIVE: Inflammation is associated with the disruption of the aortic media and appears to play a fundamental role in the progression and development of abdominal aortic aneurysm (AAA). Haptoglobin (Hp) is a genetically determined acute phase protein, the synthesis of which is increased during inflammation. This study was designed to investigate both phenotype and plasma levels of Hp in patients with AAA. METHODS: Patients with documented AAA who were admitted for elective open repair operation or endograft stent implantation, and non-AAA subjects admitted for coronary arteriography, but found to have normal or insignificant coronary artery disease, were included in the study. Plasma Hp levels were determined using a standard specific enzyme-linked immunosorbent assay, while Hp phenotype was determined by native polyacrylamide gel electrophoresis. Total cholesterol, high density lipoprotein, low density lipoprotein, and triglyceride levels were analyzed enzymatically, and C-reactive protein was analyzed by immunochemistry. RESULTS: Forty-five patients with AAA and 49 non-AAA subjects were included. The Hp 2-2 phenotype was more predominant in AAA patients compared with non-AAA subjects, but this difference was not significant (67% vs 47%; P = .141), while plasma Hp concentrations were significantly higher in AAA patients (237 +/- 144 vs 163 +/- 86 ng/mL; P = .024). Further analysis revealed that plasma Hp concentrations were significantly higher in AAA patients with the 2-2 phenotype compared with corresponding non-AAA subjects (238 +/- 144 vs 163 +/- 86 ng/mL;P = .024). CONCLUSIONS: Our findings suggest that plasma Hp concentrations are elevated in patients with AAA, particularly those with the Hp 2-2 phenotype. PMID- 21296539 TI - Pan-aortic hybrid treatment of mega-aorta syndrome. AB - Hybrid procedures combining traditional open and newer endovascular techniques are increasingly used to treat complex aortic disease. We present a novel approach for total aortic replacement, including hybrid repair of the arch and thoracoabdominal aorta, in a patient with "mega-aorta syndrome." A two-stage approach using a valve-sparing aortic root replacement, total arch replacement (stage I elephant trunk), and left carotid-axillary bypass was used to treat the root, proximal-mid arch, and left subclavian aneurysmal pathology. This was followed by a hybrid distal arch/Extent II thoracoabdominal aneurysm repair 3 months later. After 15 months follow-up, the patient remains asymptomatic with an intact repair, no endoleak, and normal ventricular and aortic valve function. This case demonstrates a novel "pan-aortic" hybrid approach for repair of extensive thoracic aortic disease. PMID- 21296540 TI - Coil embolization of persistent false lumen after stent graft repair of type B aortic dissection. AB - Patent false lumen after endovascular stent graft treatment of type B aortic dissection is a predictor for late death and retreatment. Between June 2008 and March 2010, five men with patent false lumen, due to a type B dissection previously treated with thoracic stent graft, underwent endovascular coiling treatment. Within a 30-day period, there were no deaths or major complications. The follow-up duration ranged from 1 to 22 months (mean 10.6 +/- 8.5). Endovascular coiling of patent false lumen after endovascular stent graft treatment for type B aortic dissection avoided the risk of rupture or death due to secondary aneurysm formation. PMID- 21296541 TI - The upside down Gore Excluder contralateral leg without extracorporeal predeployment for aortic or iliac aneurysm exclusion. AB - Endovascular techniques, including branched devices to preserve the internal iliac artery are evolving rapidly, but in cases in which the diameter of the proximal sealing zone is larger than that of the distal sealing zone, a reversed tapered device is needed. We describe the off label use of the Gore Excluder contralateral leg endoprosthesis in an upside down configuration to accommodate this diameter mismatch. The preinsertion technical steps of stent graft preparation, which do not require extracorporeal predeployment, are described in detail. As such, an aneurysm of the internal iliac artery and a saccular abdominal aortic aneurysm were successfully excluded. PMID- 21296542 TI - The relationship between morbidity after axillary surgery and long-term quality of life in breast cancer patients: the role of anxiety. AB - AIMS: Although arm/shoulder morbidity after sentinel lymph node biopsy (SLNB) and/or axillary lymph node dissection (ALND) has been studied before, information is lacking concerning self-imposed restrictions in activities and long-term consequences of both surgical procedures in relationship to quality of life (QoL) and anxiety. METHODS: Eighty-nine disease-free breast cancer survivors completed a set of questionnaires assessing arm/shoulder symptoms, limitations in daily life, anxiety and QoL. Also, the ipsi- and contra lateral arm circumference and the range of shoulder motion were measured. RESULTS: Fifty-one women had SLNB, 25 had SLNB followed by ALND and 13 had ALND. Although ALND patients experienced more shoulder symptoms, limitations in daily life and imposed more restrictions on themselves than SLNB patients, no significant differences during physical examination were found. A decreased range of motion and a higher score on trait anxiety resulted in a lower QoL. Trait anxiety and perceived limitations in daily life predicted long-term quality of life. CONCLUSIONS: There is a discrepancy between experienced and measured limitations in range of shoulder motion. Anxiety and self-imposed restrictions play an important role in predicting long-term QoL and should get the necessary attention when addressing shoulder symptoms in breast cancer patients. PMID- 21296543 TI - Variability in the quality of rectal cancer care in public hospitals in Catalonia (Spain): clinical audit as a basis for action. AB - AIM: Clinical practice guidelines in cancer are a relevant component of Catalonian Cancer Strategy aimed at promoting equity of access to therapy and quality of cancer care. The colorectal cancer (CRC) guideline was first published in 2003 and subsequently updated in 2008. This study examined the quality of therapy administered to patients with rectal cancer in public hospitals in Catalonia (Spain) in 2005 and 2007, according to CRC guideline recommendations. METHODS: We conducted a multicentre retrospective cohort study of patients who underwent curative-intent surgery for primary rectal cancer at Catalonian public hospitals in 2005 and 2007. Data were drawn from clinical records. RESULTS: The study covered 1831 patients with rectal cancer. Performance of total mesorectal excision (TME) was poorly reported by surgeons (46.4%) and pathologists (36.2%). Pre-operative radiotherapy was performed on 52% of stage-II and -III patients. Compared to high-caseload hospitals, those with a low caseload (<=11 cases/year) registered more Hartman's procedures, worse TME quality, a higher rate of post operative complications and lower adherence to recommended pre-operative radio chemotherapy. CONCLUSIONS: Reporting quality of care is essential for ascertaining current performance status and opportunities for improvement. In our case, there is a need for the quality of the information included in clinical records to be improved, and variability in adherence to guideline recommendations to be reduced. In view of the fact that heterogeneity in the quality of the health care process was linked to hospital caseload, the health authorities have decided to reorganise the provision of rectal cancer care. PMID- 21296544 TI - Do antibacterial-coated sutures reduce wound infection in head and neck cancer reconstruction? AB - BACKGROUND: Surgical wound infection is a common complication, which increases the hospital stay and costs after surgery for head and neck cancer. In this study, we evaluated the effect of Triclosan-coated sutures on surgical wounds and analyzed the risk factors for wound infections in head and neck cancer surgery. PATIENTS AND METHODS: From January 2007 to December 2009, 253 consecutive patients underwent wide excision of a head or neck cancer and reconstructive procedures. All patient data were collected prospectively. Of these, 241 patients were included in this study, divided into two groups. The Triclosan group contained 112 patients, whose surgical wounds were closed with Triclosan-coated sutures (Vicryl Plus). The control group included the remaining 129 patients, whose surgical wounds were closed with conventional Vicryl sutures. We conducted a retrospective, multivariate analysis to determine independent risk factors for the cervical wound infection. RESULTS: The cervical wound infection rate was 14.9% (17/112) in the Triclosan group and 14.7% (19/129) in the control group, and these rates were not significantly different. Tumour stage and delayed intra oral flap healing were independent risk factors for cervical wound infection. CONCLUSIONS: In this preliminary study, Triclosan-coated Vicryl sutures did not reduce the infection rate of cervical wounds after head or neck cancer surgery. The effectiveness of this suture material in head and neck cancer surgery should be considered with caution. PMID- 21296545 TI - Multimedia article. The arthroscopic management of partial-thickness rotator cuff tears: a systematic review of the literature. AB - PURPOSE: There is currently limited information available in the orthopaedic surgery literature regarding the appropriate management of symptomatic partial thickness rotator cuff tears. METHODS: A systematic search was performed in PubMed, EMBASE, CINAHL (Cumulative Index to Nursing and Allied Health Literature), and the Cochrane Central Register of Controlled Trials of all published literature pertaining to the arthroscopic management of partial thickness rotator cuff tears. Inclusion criteria were all studies that reported clinical outcomes after arthroscopic treatment of both articular-sided and bursal sided lesions using a validated outcome scoring system and a minimum of 12 months of follow-up. Data abstracted from the selected studies included tear type and location (articular v bursal sided), treatment approach, postoperative rehabilitation protocol, outcome scores, patient satisfaction, and postoperative imaging results. RESULTS: Sixteen studies met the inclusion criteria and were included for the final analysis. Seven of the studies treated partial-thickness rotator cuff tears with debridement with or without an associated subacromial decompression, 3 performed a takedown and repair, 5 used a transtendon repair technique, and 1 used a transosseous repair method. Among the 16 studies reviewed, excellent postoperative outcomes were reported in 28.7% to 93% of patients treated. In all 12 studies with available preoperative baseline data, treatment resulted in significant improvement in shoulder symptoms and function. For high-grade lesions, the data support arthroscopic takedown and repair, transtendon repairs, and transosseous repairs, with all 3 techniques providing a high percentage of excellent results. Debridement of partial-thickness tears of less than 50% of the tendon's thickness with or without a concomitant acromioplasty also results in good to excellent surgical outcomes; however, a 6.5% to 34.6% incidence of progression to full-thickness tears is present. CONCLUSIONS: This systematic review of 16 clinical studies showed that significant variation is present in the results obtained after the arthroscopic management of partial-thickness rotator cuff tears. What can be supported by the available data is that tears that involve less than 50% of the tendon can be treated with good results by debridement of the tendon with or without a formal acromioplasty, although subsequent tear progression may occur. When the tear is greater than 50%, surgical intervention focusing on repair has been successful. There is no evidence to suggest a differential in outcome for tear completion and repair versus transtendon repair of these lesions because both methods have been shown to result in favorable outcomes. LEVEL OF EVIDENCE: Level IV, systematic review of Level IV studies. PMID- 21296546 TI - [Occupational lipid pneumonia induced by cutting fluids exposition]. PMID- 21296547 TI - [Antiepileptic drugs]. AB - Currently available antiepileptic drugs aim to avoid recurrence of the epileptic seizures. They act by different mechanisms, at the level of the synaptic transmission and the membrane excitability. There is a large choice of antiepileptic drugs. The prescription of an antiepileptic drug relies on strict rules: it is first necessary to determine the epileptic syndrome, because some molecules may be inefficient or may worsen an epileptic syndrome, whereas they can be highly efficient in another epileptic syndrome. Among the antiepileptic drugs, known to be efficient in a specific epileptic syndrome, the choice of one molecule is done according to the suspected tolerance and therefore mainly depends on the characteristics of the patient. Rules for the initiation and adaptation of antiepileptic drugs are presented. Additional molecules, with new targets, must be developed in the future to take care of 25% of the patients with an epilepsy resistant to adapted and well-conducted treatments. PMID- 21296548 TI - A biomechanical evaluation of press-fit stem constructs for tumor endoprosthetic reconstruction of the distal femur. AB - This study was designed to assess the biomechanical parameters of the older Kotz Modular Femur Tibia Reconstruction (Stryker Inc, Mahwah, NJ) stem and the newer Restoration and the unfluted Global Modular Replacement System (Stryker Inc, Mahwah, NJ) uncemented stems for use with tumor endoprostheses as well as to assess the optimal reaming technique for insertion of these stems. Fresh-frozen adult femora or composite distal femora were implanted with the uncemented stems. Separate experiments were performed to compare reaming technique and bone resection level. All constructs were mechanically tested for axial compression, lateral bending, and torsional stiffness and torque to failure. Results showed that the biomechanical performance of all the stems were similar with respect to each parameter. Cylindrical reaming was associated with a significantly higher torque to failure than flexible reaming in the diaphysis (P = .006). Newer uncemented stems provide adequate initial biomechanical stability for implantation in the distal femur. PMID- 21296549 TI - Revision total knee arthroplasty: clinical outcome comparison with and without the use of femoral head structural allograft. AB - The use of femoral head structural allograft (FHSA) for the management of massive bony defects during revision total knee arthroplasty (TKA) is well documented in the literature. The purpose of this study was to compare the clinical outcomes of patients undergoing revision (TKA) with FHSA to those without. All patients undergoing revision TKA between January 2000 and August 2005 were reviewed. Two cohorts were generated: a study cohort--revision TKA using FHSA (n = 24)--and control cohort--revision TKA without FHSA (n = 48). The 2 study cohorts groups were comparable. All patients completed validated outcome questionnaires. The FHSA cohort was found to have significantly better outcome scores. This study demonstrates improved clinical outcomes for patients undergoing revision TKA using a structural allograft compared with those without. PMID- 21296550 TI - A 17-year follow-up of modified "Harrington" reconstruction after acetabular resection. AB - Acetabular reconstruction after resection of advanced periacetabular metastatic lesion is a complex undertaking. Harrington (J Bone Joint Surg [Am]. 1981;63-653) described a reconstructive technique in class III- and IV-type resections using threaded Steinmann pins and acrylic cement. This technique, although effective for pain relief and restoration of function, is traditionally considered when patient's life expectancy is short because of its questionable durability. A 17 year follow-up of our patient with plasma cell cytoma of the ilium and acetabulum, treated with a modification of the above technique after intralesional curettage, showed no mechanical failure or loosening. This suggests that the construct can be durable where there is no recurrence of disease and can also be a valuable asset in selected nontumor cases in adjunct to contemporary techniques. PMID- 21296551 TI - Acetabular component positioning in total hip arthroplasty: an evidence-based analysis. AB - Advocates for navigated (NAV) total hip arthroplasty (THA) emphasize the potential for improved component placement. We reviewed published literature to investigate the claim of increased precision of acetabular component placement in navigated THA compared to conventional (N-NAV) THA. Major medical and publishers' databases were searched, making no restrictions for study type, yet restricting results to English-language sources. Nine studies of varying methodological quality involving 1479 THA with a mean age of 59.10 years were included. There was no statistically significant difference in mean acetabular component abduction and anteversion angles between the NAV and N-NAV groups. There was a statistically significant difference in the incidence of acetabular component placement in the "safe zone," with NAV having significantly more "safe placements" than N-NAV, regardless of the chosen safe zone. In addition, NAV had significantly fewer dislocations than N-NAV. These outcomes demonstrate the possible patient benefit from navigation and resulting tighter control of component position. PMID- 21296552 TI - Use of an anatomical acetabular component for treatment of iliopsoas impingement. AB - Iliopsoas impingement is a known cause of pain after total hip arthroplasty. The author reports on a patient with iliopsoas impingement due to prominence of the anterior aspect of her acetabular hip arthroplasty component successfully treated with revision to an anatomically designed acetabular implant. Use of such an anatomically designed acetabular implant may prove to be beneficial in selected patients with iliopsoas impingement. PMID- 21296553 TI - Pharmacological treatment of sleep disturbance in developmental disabilities: a review of the literature. AB - Sleep disturbance is a common problem in children with developmental disabilities. Effective pharmacologic interventions are needed to ameliorate sleep problems that persist when behavior therapy alone is insufficient. The aim of the present study was to provide an overview of the quantity and quality of pharmacologic research targeting sleep in children with developmental disabilities. Efficacy studies of medications most likely to be prescribed to children are reviewed in detail. Medline and PsychInfo searches were performed to identify relevant clinical trials and case reports, published between 1975 and 2009. Key search terms included sleep, children, antihistamines, alpha adrenergic agonists, antidepressants, antipsychotics, melatonin, ramelteon, benzodiazepines, and nonbenzodiazepines. The literature search identified 58 articles that met the inclusion criteria. Well-controlled studies employing both objective polysomnography and subjective sleep measures are needed to determine the efficacy and safety of currently prescribed pediatric sleep medicines. Melatonin appears to be the most widely assessed agent and safest choice for children with developmental disabilities. Trazodone, mirtazapine, and ramelteon hold promise but require further study. PMID- 21296554 TI - Self-injurious behavior in people with profound intellectual disabilities: a meta analysis of single-case studies. AB - The limitations people with profound intellectual disabilities experience in functioning contribute to a vulnerability to self-injurious behavior. Since this problem behavior has important negative consequences for people concerned, examining the effectiveness of treatments is important. In the current meta analysis, single-case studies investigating non-aversive, non-intrusive forms of reinforcement were combined using hierarchical linear models. This analysis revealed that the average effect of treatment was relatively large and statistically significant. Further, significant variance was observed between both studies and participants. In addition, some evidence was found for a moderator effect of sensory impairment. Finally, no statistically significant moderator effects of medication, motor impairment, setting, age, gender, matching of treatment with behavioral function and contingency were found. PMID- 21296555 TI - Measurement invariance in the assessment of people with an intellectual disability. AB - Intellectual assessment is central to the process of diagnosing an intellectual disability and the assessment process needs to be valid and reliable. One fundamental aspect of validity is that of measurement invariance, i.e. that the assessment measures the same thing in different populations. There are reasons to believe that measurement invariance of the Wechsler scales may not hold for people with an intellectual disability. Many of the issues which may influence factorial invariance are common to all versions of the scales. The present study, therefore, explored the factorial validity of the WAIS-III as used with people with an intellectual disability. Confirmatory factor analysis was used to assess goodness of fit of the proposed four factor model using 13 and 11 subtests. None of the indices used suggested a good fit for the model, indicating a lack of factorial validity and suggesting a lack of measurement invariance of the assessment with people with an intellectual disability. Several explanations for this and implications for other intellectual assessments were discussed. PMID- 21296556 TI - Current biochemistry, molecular biology, and clinical relevance of natriuretic peptides. AB - The mammalian natriuretic peptide family consists of atrial (ANP), brain [B-type; BNP] and C-type natriuretic peptide (CNP) and three receptors, natriuretic receptors-A (NPR-A), -B (NPR-B) and -C (NPR-C). Both ANP and BNP are abundantly expressed in the heart and are secreted mainly from the atria and ventricles, respectively. By contrast, CNP is mainly expressed in the central nervous system, bone and vasculature. Plasma concentrations of both ANP and BNP are elevated in patients with cardiovascular disease, though the magnitude of the increase in BNP is usually greater than the increase in ANP. This makes BNP is a clinically useful diagnostic marker for several pathophysiological conditions, including heart failure, ventricular remodeling and pulmonary hypertension, among others. Recent studies have shown that in addition to BNP-32, proBNP-108 also circulates in human plasma and that levels of both forms are increased in heart failure. Furthermore, proBNP-108 is O-glycosylated and circulates at higher levels in patients with severe heart failure. In this review we discuss recent progress in our understanding of the biochemistry, molecular biology and clinical relevance of the natriuretic peptide system. PMID- 21296557 TI - Stenotrophomonas maltophilia resistance to trimethoprim/sulfamethoxazole mediated by acquisition of sul and dfrA genes in a plasmid-mediated class 1 integron. AB - Stenotrophomonas maltophilia is becoming a more and more common cause of infections. In this study, the minimal inhibitory concentrations of trimethoprim/sulfamethoxazole (SXT), ceftazidime, minocycline, levofloxacin, chloramphenicol and ticarcillin/clavulanic acid were determined and the distribution of integrons and sul1, sul2 and dfrA genes was investigated in 102 S. maltophilia isolates collected from patients treated in 31 hospitals in Anhui, China, in the month of September in 2006-2008. The rate of resistance to SXT was up to 30.4%, and 64.7% of isolates were class 1 integron-positive. Sequencing data revealed the following novel gene cassettes embedded in class 1 integrons: dfrA17-aadA5; dfrA12-aadA2; aacA4-catB8-aadA1; aadB-aac(6')-II-bla(CARB-8); and arr-3-aacA4. This is the first report of the gene cassettes dfrA17-aadA5 and dfrA12-aadA2 and of sul2 genes in SXT-resistant S. maltophilia isolates in China. None of the SXT-susceptible S. maltophilia isolates were positive for sul2 or dfrA gene products by polymerase chain reaction (PCR), but PCR products for sul1 were detected in 27 SXT-susceptible and 25 SXT-resistant isolates. The findings from this study indicate that the sul1 gene, in combination with dfrA17 and dfrA12 gene cassettes and sul2 genes located within a 7.3kb plasmid, lead to a high rate of SXT resistance and also confirm the need for ongoing resistance surveillance. PMID- 21296558 TI - Perceived negative attitude of others predicts transition to psychosis in patients at risk of psychosis. AB - AIM: Our previous study (Salokangas et al., 2009) suggested that the subjective experience of negative attitude of others (NAO) towards oneself is an early indicator of psychotic development. The aim of this prospective follow-up study was to test this hypothesis. METHODS: A total of 55 young psychiatric outpatients assessed as being at current risk of psychosis (CROP) were followed for up to 60 months and rates of transition to psychosis (TTP) identified. CROP was assessed employing the Bonn Scale for assessment of basic symptoms (Schultze-Lutter and Klosterkotter, 2002) and the Structured Interview for prodromal symptoms (Miller et al., 2002). TTP was defined by a psychotic episode lasting for more than one week. Associations between NAO at baseline and TTP were analyzed by a Cox regression survival analysis. RESULTS: Eight (14.5%) TTP were identified: four (57.1%) within seven NAO patients and four (8.7%) within forty-six non-NAO patients. In the multivariate Cox regression analysis, NAO at baseline significantly (P=0.007) predicted TTP. CONCLUSION: The prospective follow-up results support our hypothesis that subjective experience of NAO is an early indicator of psychotic in development. PMID- 21296559 TI - Use of psychiatric inpatient services by heavy users: findings from a national survey in Italy. AB - PURPOSE: To analyze factors associated with a patient's probability of being a Heavy User (HU) of inpatient psychiatric services and to compare the HU inpatient population with Non-Heavy Users (NHUs). PATIENTS AND METHODS: The survey was conducted among inpatients enrolled in the PROGRES-Acute-project, an Italian nationwide survey of public and private inpatient facilities. Patients with three or more admissions over the last 12 months were considered HUs, and patients who had undergone one or two admissions during the same period made up the NHU group. RESULTS: Four hundred and thirty-five (40.5%) were HUs, and 640 (59.5%) NHUs. HUs were younger, more frequently unmarried, unemployed, receiving a disability pension, and either homeless or living in a residential facility. HUs were more likely to have experienced conflicts with their partners or family members during the week prior to admission. A logistic regression analysis revealed that age, age at first admission, number of life-time admissions, and having been the victim of violence were the most important predictive factors for the HU phenomenon. CONCLUSION: Our study suggests that specific attention should be given to patients' family context, due to its crucial role in daily informal care and in the triggering of events leading to rehospitalization. PMID- 21296560 TI - Variation in use of coercive measures in psychiatric hospitals. AB - PURPOSE: The use of coercive measures in psychiatry is still poorly understood. Most empirical research has been limited to compulsory admission and to risk factors on an individual patient level. This study addresses three coercive measures and the role of predictive factors at both patient and institutional levels. METHODS: Using the central psychiatric register that covers all psychiatric hospitals in Canton Zurich (1.3 million people), Switzerland, we traced all inpatients in 2007 aged 18-70 (n = 9698). We used GEE models to analyse variation in rates between psychiatric hospitals. RESULTS: Overall, we found quotas of 24.8% involuntary admissions, 6.4% seclusion/restraint and 4.2% coerced medication. Results suggest that the kind and severity of mental illness are the most important risk factors for being subjected to any form of coercion. Variation across the six psychiatric hospitals was high, even after accounting for risk factors on the patient level suggesting that centre effects are an important source of variability. However, effects of the hospital characteristics 'size of the hospital', 'length of inpatient stay', and 'work load of the nursing staff' were only weak ('bed occupancy rate' was not statistically significant). CONCLUSION: The significant variation in use of coercive measures across psychiatric hospitals needs further study. PMID- 21296561 TI - Psychometric properties of the Spanish version of the diagnostic interview for depressive personality. AB - The aim of this study was to evaluate the reliability and validity of the Spanish language version of the diagnostic interview for depressive personality (DIDP). The DIDP was administered to 328 consecutive outpatients and the test-retest and inter-rater reliability were assessed. Factor analysis was used in search of factors capable of explaining the scale and a cutoff point was established. The DIDP scales showed adequate Cronbach's alpha values and acceptable test-retest and inter-rater reliability coefficients. Convergent and discriminant validity were explored, the latter with respect to avoidant and borderline personality disorders. The results of the factor analysis were consistent with the four factor structure of the DIDP scales. The receiver operating characteristic (ROC) analysis revealed the area under the curve to be 0.848. We found 30 to be a good cutoff point, with a sensitivity of 74.5% and a specificity of 78.5%. The DIDP proved to be a reliable and valid instrument for assessing depressive personality disorder, at least among our outpatients. The psychometric properties of the DIDP support its clinical usefulness in assessing depressive personality. PMID- 21296562 TI - Preparation, characterization and in vitro release study of carvacrol-loaded chitosan nanoparticles. AB - The fabrication of carvacrol-loaded chitosan nanoparticles was achieved by a two step method, i.e., oil-in-water emulsion and ionic gelation of chitosan with pentasodium tripolyphosphate. The obtained particles possessed encapsulation efficiency (EE) and loading capacity (LC) in the ranges of 14-31% and 3-21%, respectively, when the initial carvacrol content was 0.25-1.25 g/g of chitosan. The individual particles exhibited a spherical shape with an average diameter of 40-80 nm, and a positively charged surface with a zeta potential value of 25-29 mV. The increment of initial carvacrol content caused a reduction of surface charge. Carvacrol-loaded chitosan nanoparticles showed antimicrobial activity against Staphylococcus aureus, Bacillus cereus and Escherichia coli with an MIC of 0.257 mg/mL. The release of carvacrol from chitosan nanoparticles reached plateau level on day 30, with release amounts of 53% in acetate buffer solution with pH of 3, and 23% and 33% in phosphate buffer solutions with pH of 7 and 11, respectively. The release mechanism followed a Fickian behavior. The release rate was superior in an acidic medium to either alkaline or neutral media, respectively. PMID- 21296563 TI - The unexpected burden of hypomagnesaemia in gynae-oncology chemotherapy clinics. PMID- 21296564 TI - Medical exposure to radiation and thyroid cancer. AB - In 2008, the worldwide estimated age-standardised incidence rates for thyroid cancer incidence were 4.7 and 1.5 per 100,000 women and men, respectively. Thyroid cancer's overall contribution to the worldwide cancer burden is relatively small, but incidence rates have increased over the last three decades throughout the world. This trend has been hypothesised to reflect a combination of technological advances enabling increased detection, but also changes in environmental factors, including population exposure to ionising radiation from fallout, diagnostic tests and treatment for benign and malignant conditions. Studies of the atomic bomb survivors and populations treated with radiotherapy have established radiation as a risk factor for thyroid cancer, particularly from early life exposure. About 0.62 mSv (20%) of the global annual per caput effective radiation dose comes from diagnostic medical and dental radiation for the period of 1997-2007, increased from 0.4 mSv for the years 1991-1996. This international trend of increasing population exposure to medical diagnostic sources of radiation, attributed in large part to the growing use of computed tomography scans, but also interventional radiology procedures, has raised concerns about exposure to radiosensitive organs such as the thyroid. Worldwide, medical and dental X-rays constitute the most common type of diagnostic medical exposures, but their contribution to the cumulative effective dose is relatively low, whereas computed tomography scans account for 7.9% of diagnostic radiology examinations but 47% of the collective effective dose from diagnostic radiation procedures in parts of the world. Although the radiation exposure from computed tomography scans is substantially lower than that from radiotherapy, multiple computed tomography scans could result in non-trivial cumulative doses to the thyroid. Studies are currently underway to assess the incidence of cancer in large cohorts of children who received computed tomography scans. National and international efforts have been developed to raise awareness and to standardise procedures for use of computed tomography and interventional radiology procedures in paediatric and general populations. PMID- 21296565 TI - Experimental mycotoxic nephropathy in pigs provoked by a mouldy diet containing ochratoxin A and fumonisin B1. AB - Mycotoxic nephropathy was induced in eighteen young pigs by mouldy diets containing 0.5 ppm ochratoxin A (OTA) and/or 10 ppm fumonisin B1 (FB1) for three months. While the most obvious damages provoked by OTA were seen in the kidneys as expressed by the strong degenerative changes in proximal tubules and fibrosis in kidneys, FB1 was found to induce an increase in permeability of vessels mainly in lung, brain, cerebellum or kidneys and slight to moderate degenerative changes in kidneys. Pathomorphological damages in pigs exposed to both mycotoxins simultaneously present a combination of the main lesions provoked by each mycotoxin alone being stronger in their expression. Biochemical investigations as expressed by the increase of serum creatinine, urea and enzyme activity of ASAT/ALAT and by the decrease of serum cholesterol, total protein, albumin and glucose were strongest in pigs exposed to both mycotoxins simultaneously as can be anticipated form the strongest lesions in the kidneys. Both mycotoxins and their combination were found to disturb powerfully humoral immune response in all experimental pigs as expressed by the strong decrease in antibody titer against Morbus Aujesky at days 21 and 35 after vaccination. Having in mind that the feed levels of the both mycotoxins as well as the exposure time and the pathological findings corresponded to those in some spontaneous cases of porcine nephropathy in Bulgaria and South Africa, it can be concluded that the same mycotoxins are involved in the observed field cases of that nephropathy. PMID- 21296566 TI - Nuclear pore complex-a coat specifically tailored for the nuclear envelope. AB - Nuclear pore complexes (NPCs) are highly selective transport gates that enable the bi-directional traffic of macromolecules across the nuclear envelope (NE). NPCs are located at the fusion pores between the inner and outer membranes of the NE and are built from a common set of ~30 different proteins, nucleoporins. Remarkably, recent proteomic, bioinformatic, and structural studies have provided firm evidence that key structural nucleoporins share common ancestry with elements of coated vesicles, indicating an evolutionary link between these structures. This has provided novel insight into the origin of NPCs and may help us to better functionally characterize these fundamental components of eukaryotic cells. PMID- 21296567 TI - Simultaneous detection of guanine, adenine, thymine and cytosine at choline monolayer supported multiwalled carbon nanotubes film. AB - A rapid, convenient and accurate method for the simultaneous detection of guanine (G), adenine (A), thymine (T) and cytosine (C) was developed at a multiwalled carbon nanotube (MWCNT)/choline (Ch) monolayer-modified glassy carbon electrode (GCE). X-ray photoelectron spectroscopy data demonstrated that Ch was covalently immobilised on the surface of GCE through oxygen atom. The Ch monolayer provides a positively charged surface with -N(+)(CH(3))(3) polar groups, so that it can attract negatively charged MWCNTs to the surface. Consequently, the MWCNT/Ch film exhibited remarkable electrocatalytic activities towards the oxidation of G, A, T and C due to the advantages of high electrode activity, large surface area, prominent antifouling property, and high electron transfer kinetics. All purine and pyrimidine bases showed well-defined catalytic oxidation peaks at MWCNT/Ch/GCE. The peak separations between G and A, A and T, and T and C are 270, 200, and 190 mV, respectively, which are sufficiently large for their potential recognition and simultaneous detection in mixture. Under the optimum conditions, the designed MWCNT/Ch/GCE exhibited low detection limit, high sensitivity and wide linear range for simultaneous detection of G, A, T and C. Moreover, the proposed method was successfully applied to the assessment of G, A, T and C contents in a herring sperm DNA sample with satisfactory results. PMID- 21296568 TI - Curiouser and curiouser: genetic disorders of cortical specialization. AB - The processes by which cortical areas become specialized for high-level cognitive functions may be revealed by the study of familial developmental disorders such as dyslexia, dyscalculia, prosopagnosia, color agnosia and amusia. These disorders are characterised by the inability to integrate information across multiple areas and the consequent failure to develop representations of the knowledge of some category based on its associated attributes. In contrast, synesthesia may be seen as a hyper-associative condition, possibly due to a failure to properly segregate areas into distinct networks. Here, I consider recent advances in our understanding of the genetic and neurobiological bases of these conditions and the developmental mechanisms underlying the specialization of cortical areas and networks. PMID- 21296570 TI - Randomised controlled trials in oncology closed early for benefit: trends in methodology, results, and interpretation. AB - PURPOSE: To assess methodology, results and interpretation of oncology randomised controlled trials closed early for benefit (RCTCEB). METHODS: Structured literature search (1950-2008) to identify all published oncology RCTCEB. We then searched for related follow-up articles and conference abstracts to evaluate whether study results and conclusions changed with longer follow-up. A standardised data abstraction process captured information related to statistical methodology, details of interim analyses, results and conclusions. Original articles and follow-up reports were compared for results of primary end-point and author conclusions. RESULTS: We identified 71 RCTCEB. In 16 articles (23%) the study primary end-point was not explicitly stated. Most trials were open to accrual (47/71, 66%) at the time of closure. Formal interim analysis was performed in 65 (92%) trials of which 72% (47/65) was reported as planned; 82% (53/65) reported stopping rules. Trials on average accrued 75% of the planned sample size. Amongst the 23 (32%) RCTCEB with follow-up reports, in only one case did the study results or conclusions change substantially. CONCLUSIONS: While the majority of oncology RCTCEB follows rigourous methodological principles, an important percentage includes limitations in design and/or analysis. Amongst the 23 studies with subsequent follow-up reports, initial results were confirmed in 22 (96%). PMID- 21296569 TI - Working model for the structural basis for KCNE1 modulation of the KCNQ1 potassium channel. AB - The voltage-gated potassium channel KCNQ1 (Kv7.1) is modulated by KCNE1 (minK) to generate the I(Ks) current crucial to heartbeat. Defects in either protein result in serious cardiac arrhythmias. Recently developed structural models of the open and closed state KCNQ1/KCNE1 complexes offer a compelling explanation for how KCNE1 slows channel opening and provides a platform from which to refine and test hypotheses for other aspects of KCNE1 modulation. These working models were developed using an integrative approach based on results from nuclear magnetic resonance spectroscopy, electrophysiology, biochemistry, and computational methods-an approach that can be applied iteratively for model testing and revision. We present a critical review of these structural models, illustrating the strengths and challenges of the integrative approach. PMID- 21296571 TI - Development of chemically defined media supporting high cell density growth of Ketogulonicigenium vulgare and Bacillus megaterium. AB - The immediate precursor of L-ascorbic acid, or vitamin C, is 2-keto-L-gulonic acid (2-KLG). This is commonly produced commercially by Ketogulonicigenium vulgare and Bacillus megaterium, using corn steep liquor powder (CSLP) as an organic nitrogen source. In this study, the effects of the individual CSLP components (amino acids, vitamins, and metal elements) on 2-KLG production were evaluated, with the aim of developing a complete, chemically defined medium for 2 KLG production. Forty components of CSLP were analyzed, and key components were correlated to biomass, 2-KLG productivity, and consumption rate of L-sorbose. Glycine had the greatest effect, followed by serine, biotin, proline, nicotinic acid, and threonine. The combination of 0.28 g L(-1) serine, 0.36 g L(-1) glycine, 0.18 g L(-1) threonine, 0.28 g L(-1) proline, 0.19 g L(-1) nicotinic acid, and 0.62 mg L(-1)biotin in a chemically defined medium produced the highest maximum biomass concentration (4.2 * 10(9) cfu mL(-1)), 2-KLG concentration (58 g L(-1)), and yield (0.76 g g(-1)) after culturing for 28 h. PMID- 21296572 TI - Glycerol extracting dealcoholization for the biodiesel separation process. AB - By means of utilizing sunflower oil and Jatropha oil as raw oil respectively, the biodiesel transesterification production and the multi-stage extracting separation were carried out experimentally. Results indicate that dealcoholized crude glycerol can be utilized as the extracting agent to achieve effective separation of methanol from the methyl ester phase, and the glycerol content in the dealcoholized methyl esters is as low as 0.02 wt.%. For the biodiesel separation process utilizing glycerol extracting dealcoholization, its technical and equipment information were acquired through the rigorous process simulation in contrast to the traditional biodiesel distillation separation process, and results show that its energy consumption decrease about 35% in contrast to that of the distillation separation process. The glycerol extracting dealcoholization has sufficient feasibility and superiority for the biodiesel separation process. PMID- 21296573 TI - Substrate-controlled chemoselective synthesis and potent cytotoxic activity of novel 5,6,7-triarylpyrido[2,3-d]pyrimidin-4-one derivatives. AB - The substrate-controlled chemoselective synthesis of novel 5,6,7 triarylpyrido[2,3-d]pyrimidin-4-one derivatives has been successfully achieved via microwave-assisted three-component reactions of 2,6-diaminopyrimidin-4(3H) one, aromatic aldehydes and 1,2-diphenylethanone. This approach has the prominent features of chemoselectivity, diasteroselectivity, atom economy, short reaction time, high yield as well as operational simplicity. Moreover, these novel compounds were subject to the test of in vitro cytotoxicity to carcinoma SW1116 and SGC7901 cells. Most of the tested compounds showed significant cytotoxicity to SW1116 cells and compound 4b exhibited more potent and efficacious cytotoxicity to SGC7901 cells than doxorubicin hydrochloride as positive control. PMID- 21296574 TI - Delayed presentation of invasive thymoma in myasthenia gravis: a case report. AB - Current practice favors imaging of people with myasthenia gravis (MG) at the time of diagnosis to look for evidence of thymoma or thymic hyperplasia. However, there is no evidence to allow any recommendation about repeat imaging in people with normal scans at presentation, and there is little evidence to recommend surgical exploration in such cases. We present a patient with a delayed presentation of invasive thymoma 11 years after a normal thoracic computerized tomography. PMID- 21296575 TI - Cecal ligation and puncture: the gold standard model for polymicrobial sepsis? AB - Sepsis is a serious medical condition characterized by dysregulated systemic inflammatory responses followed by immunosuppression. To study the pathophysiology of sepsis, diverse animal models have been developed. Polymicrobial sepsis induced by cecal ligation and puncture (CLP) is the most frequently used model because it closely resembles the progression and characteristics of human sepsis. Here we summarize the role of several immune components in the pathogenesis of sepsis induced by CLP. However, several therapies proposed on the basis of promising results obtained by CLP could not be translated to the clinic. This demonstrates that experimental sepsis models do not completely mimic human sepsis. We propose several strategies to narrow the gap between experimental sepsis models and clinical sepsis, including targeting factors that contribute to the immunosuppressive phase of sepsis, and reproducing the heterogeneity of human patients. PMID- 21296576 TI - Metastatic pleomorphic xanthoastrocytoma in the scalp. AB - We present a 27-year-old Chinese male with a rare pleomorphic xanthoastrocytoma (PXA) that underwent transformation with metastasis to the scalp. To our knowledge this is the first report of a PXA undergoing malignant transformation and metastasizing to the scalp and provides further evidence that PXA may not be as benign as previously believed. PMID- 21296577 TI - Asian patients with limb girdle muscular dystrophy 2I (LGMD2I). AB - Limb girdle muscular dystrophy type 2I (LGMD2I) is caused by defects in the fukutin-related protein (FKRP) gene. In most Caucasian patients with LGMD2I, the condition is associated with a missense mutation - c.826C>A (p.Leu276Ile). We describe two Chinese brothers with progressive shoulder and pelvic muscle weakness. They had muscle stiffness and myalgia after exercise, but lacked obvious hypertrophy of the calves. Muscle biopsy showed dystrophic features with many rimmed vacuoles in the fibers. Immunohistochemistry and immunoblot analyses revealed reductions of alpha-(alpha)-dystroglycan (VIA4-1) and laminin-alpha2 (80 kDa C-terminal and 300-kDaN-terminal). Two novel heterozygous mutations (c.208T>A and c.1030G>T) in the FKRP gene were identified in these patients. In addition, we summarise the clinical features of patients with LGMD2I in the Asian region. Our findings might indicate that the pathogenic FKRP mutations in Asian patients with LGMD2I are sporadic compound heterozygous mutations rather than the hot-spot c.826C>A mutation seen in Caucasian populations. PMID- 21296578 TI - The effect of age and body mass index on cost of spinal surgery. AB - Complex shifts in demography combined with drastic advancements in spinal surgery have led to a steep increase in often expensive spinal interventions in older and obese patients. A cost analysis, based on hospital charges, was performed retrospectively on the spinal surgery of 787 randomly selected patients who were operated at The Medical Center of Central Georgia, a large urban hospital in Central Georgia. The types of surgery included anterior cervical decompression and fusion (ACDF), lumbar decompression and fusion (LDF), and lumbar microdiscectomy (LMD). The distribution of patient age followed a Gaussian form. The peak age for patients was 50-59 years (28.8%), and there was no statistical difference in age between men and women. The body mass index (BMI) differed (p<0.01) between males (28.86 kg/m(2); range: 18-47 kg/m(2)) and females (30.69 kg/m(2); range: 17-58 kg/m(2)). The BMI data did not follow a Gaussian distribution for either gender. The hospital cost for spinal surgery increased with age except for male patients who underwent ACDF. For male patients who underwent LDF, the increase in hospital cost was statistically significant between the 40-49-year and the >= 70-year age groups. Univariate analysis with type of surgery as a covariate showed that age was a significant determinant of hospital cost (p=0.000), and BMI was not (p=0.110); however, the interaction between age and BMI was significant (p=0.000). Older patients undergoing spinal surgery had lower BMI, more so in males (r=-0.047, p=0.426) than in females (r= 0.038, p=0.485). There were linear trends in all gender-spinal surgery categories between age, BMI and hospital cost. Older female patients who underwent LDF tended to have a lower BMI but higher hospital cost, confirming that age was more important than BMI in determining hospital cost in these patients. The increments in cost of spinal surgery in relation to age especially and BMI were, nevertheless, small. We believe that spinal surgery in the elderly should be viewed as a public investment, as the modern concept of retirement involves people working intermittently up to their 80s. Thus, where clinical research on medical costs is to be conducted, cost analysis needs to be expanded to include returns to government in the form of taxes. PMID- 21296579 TI - Antitumor agents 283. Further elaboration of desmosdumotin C analogs as potent antitumor agents: activation of spindle assembly checkpoint as possible mode of action. AB - In our ongoing study of the desmosdumotin C (1) series, twelve new analogues, 21 32, mainly with structural modifications in ring-A, were prepared and evaluated for in vitro antiproliferative activity against several human tumor cell lines. Among them, the 4'-iodo-3,3,5-tripropyl-4-methoxy analogue (31) showed significant antiproliferative activity against multiple human tumor cell lines with ED(50) values of 1.1-2.8 MUM. Elongation of the C-3 and C-5 carbon chains reduced activity relative to propyl substituted analogues; however, activity was still better than that of natural compound 1. Among analogues with various ether groups on C-4, compounds with methyl (2) and propyl (26) ethers inhibited cell growth of multiple tumor cells lines, while 28 with an isobutyl ether showed selective antiproliferative activity against lung cancer A549 cells (ED(50) 1.7 MUM). The gene expression profiles showed that 3 may modulate the spindle assembly checkpoint (SAC) and chromosome separation, and thus, arrest cells at the G2/M-phase. PMID- 21296580 TI - Structure-activity relationships in glycosylated 2-phenyl-indoles, 2-phenyl benzo[b]thiophenes and 2-phenyl-benzo[b]furans as DNA binding and potential antitumor agents. AB - In earlier investigations we have described the synthesis and biological evaluation of a panel of novel glycosylated heteroaromatics (1-12). It was found that these compounds can bind to DNA in vitro and are cytotoxic against several cancer cell lines at low micromolar concentration. We report here structure activity studies of these molecules with respect to DNA binding and cytotoxicity. In particular the structure of the linker moiety between the carbohydrate and the intercalator, the stereochemistry at the anomeric position, and the substituents and stereochemistry at C-4 in one of the carbohydrate residues (4-amino-2,3,4,6 tetradeoxy-alpha-L-threo-hexopyranose) are investigated. All these structural features were identified to have a clear influence on DNA binding; however, only the substituents at C-4 in the carbohydrate residue exhibited an obvious impact on cytotoxicity. It was found that the amino group at C-4 was favored over all other substituents with regard to both DNA binding and cytotoxicity. The information gathered from these structure-activity investigations suggested that future work on the preparation of additional analogues should focus on molecules containing an amino sugar moiety. PMID- 21296581 TI - Using 137 Cs measurements to investigate the influence of erosion and soil redistribution on soil properties. AB - Information on the interaction between soil erosion and soil properties is an important requirement for sustainable management of the soil resource. The relationship between soil properties and the soil redistribution rate, reflecting both erosion and deposition, is an important indicator of this interaction. This relationship is difficult to investigate using traditional approaches to documenting soil redistribution rates involving erosion plots and predictive models. However, the use of the fallout radionuclide (137)Cs to document medium term soil redistribution rates offers a means of overcoming many of the limitations associated with traditional approaches. The study reported sought to demonstrate the potential for using (137)Cs measurements to assess the influence of soil erosion and redistribution on soil properties (particle size composition, total C, macronutrients N, P, K and Mg, micronutrients Mn, Mo, Fe, Cu and Zn and other elements, including Ti and As). (137)Cs measurements undertaken on 52 soil cores collected within a 7 ha cultivated field located near Colebrooke in Devon, UK were used to establish the magnitude and spatial pattern of medium-term soil redistribution rates within the field. The soil redistribution rates documented for the individual sampling points within the field ranged from an erosion rate of -12.9 t ha(-1) yr(-1) to a deposition rate of 19.2 t ha(-1) yr(-1). Composite samples of surface soil (0-5 cm) were collected immediately adjacent to each coring point and these samples were analysed for a range of soil properties. Individual soil properties associated with these samples showed significant variability, with CV values generally lying in the range 10-30%. The relationships between the surface soil properties and the soil redistribution rate were analysed. This analysis demonstrated statistically significant relationships between some soil properties (total phosphorus, % clay, Ti and As) and the soil redistribution rate, but for most properties there was no significant relationship. This suggests that other factors, in addition to soil erosion and soil redistribution, are also important in causing spatial variability in soil properties, or that, because of the relatively deep soils, soil properties are relatively insensitive to soil redistribution processes. The importance of the erosional history of the field was explored using a simple model to predict changes in soil properties in response to the magnitude of the erosion or deposition rate and the length of the period during which the field had been subject to soil erosion and soil redistribution. PMID- 21296582 TI - Thermoluminescence and optically stimulated luminescence properties of the 0.5P2O5-xBaO-(0.5-x)Li2O glass systems. AB - Thermoluminescence and optically stimulated luminescence properties of phosphate glasses doped with BaO and Li(2)O at various concentrations were studied. Lithium doped glasses show a broad TL peak in the 200-300 degrees C region with poor dosimetric characteristics. Barium-doped glasses feature at least two TL peaks, approximately at 200 and 400 degrees C, which were attributed to Ba(2+) ions. They also produce a fast-decaying OSL signal correlated with the lower temperature TL peak. Responses of both TL emissions to radiation doses up to 100 Gy are linear (R2 >0.99). Due to its encouraging characteristics such as acceptable batch homogeneity, good measurement reproducibility and weak signal fading, the P2O5-xBaO glass can be considered as a candidate material for dosimetry in the high-dose range (>10 Gy). PMID- 21296583 TI - The drought response displayed by a DRE-binding protein from Triticum dicoccoides. AB - Drought is one of the major causes of dramatic yield loss in crop plants. Knowledge of how to alleviate this loss is still limited due to the complexity of both the stress condition and plant responses. Wild emmer wheat (Triticum turgidum ssp. dicoccoides) is a potential source of important drought-resistance genes for its cultivated relatives. The gene for an emmer DRE-binding protein, TdicDRF1, was cloned and shown to be drought-responsive with orthologs in other plants. This is the first report of the cloning of TdicDRF1, and its expression was further characterized by RT-PCR in both drought-sensitive and drought resistant accessions of Triticum dicoccoides. Analysis of the AP2/ERF DNA-binding domain of TdicDRF1 as a GST-fusion protein and its binding to DRE by electrophoretic mobility shift assay (EMSA) indicate functional differences between wheat DREBs and those characterized in Arabidopsis thaliana. DREB expression increased in drought-stressed roots, correlating with the RT-PCR results, but not in leaf, showing that tissue-specific regulation occurs at the protein level. Hence, the DREB-DRE interaction undergoes subtle multi-level regulation. PMID- 21296584 TI - Elicitin-membrane interaction is driven by a positive charge on the protein surface: role of Lys13 residue in lipids loading and resistance induction. AB - Elicitins are family of small proteins secreted by species of the pathogenic fungus Phytophthora inducing a defence reaction in plants. They contain a hydrophobic cavity capable of binding sterols and fatty acids, and on the basis of their pI they are classified as either alpha-elicitins or more necrotising beta-elicitins. The residue Lys13 was previously identified as a key determinant of the necrotising activity of basic elicitins. In the present study we describe changes in the ability of cryptogein, a beta-elicitin inducing a hypersensitive response in tobacco, to transfer sterols and fatty acids between micelles and liposomes upon Lys13Val mutation. We propose that the change in activity is influenced by the elimination of positive charge on the surface of cryptogein, which is significant for correct positioning of the protein during lipid loading, without adversely affecting the binding of sterol to the cavity of the protein. Compared to wild type cryptogein, mutation Lys13Val resulted in lowered expression of defence-related genes and compromised resistance to Phytophthora parasitica. Furthermore, resistance induced by Lys13Val mutant was similar to that induced by acidic elicitin capsicein containing at amino position 13 valine Determined results sustained a crucial role of positive lysine residues on the surface of basic elicitins and suggested their significant role in correct protein-membrane interaction and thus on their biological activity. PMID- 21296585 TI - A stress-associated protein containing A20/AN1 zing-finger domains expressed in Medicago truncatula seeds. AB - MtSAP1 (Medicago truncatula stress-associated protein 1) was revealed as a down regulated gene by suppressive subtractive hybridization between two mRNA populations of embryo axes harvested before and after radicle emergence. MtSAP1 is the first gene encoding a SAP with A20 and AN1 zinc-finger domains characterized in M. truncatula. MtSAP1 protein shares 54% and 62% homology with AtSAP7 (Arabidopsis thaliana) and OsiSAP8 (Oryza sativa) respectively, with in particular a strong homology in the A20 and AN1 conserved domains. MtSAP1 gene expression increased in the embryos during the acquisition of tolerance to desiccation, reached its maximum in dry seed and decreased dramatically during the first hours of imbibition. Abiotic stresses (cold and hypoxia), abscisic acid and desiccation treatments induced MtSAP1 gene expression and protein accumulation in embryo axis, while mild drought stress did not affect significantly its expression. This profile of expression along with the presence of anaerobic response elements and ABRE sequences in the upstream region of the gene is consistent with a role of MtSAP1 in the tolerance of low oxygen availability and desiccation during late stages of seed maturation. Silencing of MtSAP1 by RNA interference (RNAi) showed that the function of the encoded protein is required for adequate accumulation of storage globulin proteins, vicilin and legumin, and for the development of embryos able to achieve successful germination. PMID- 21296586 TI - Additive manufacturing for microvascular reconstruction of the mandible in 20 patients. AB - OBJECTIVES: The aim of this study was to evaluate the use of model mandibles made preoperatively by additive manufacturing, which were used to prebend reconstruction plates prior to mandibular resection and reconstruction with microvascular bony flaps. MATERIALS AND METHODS: Computer Tomography (CT) or Cone Beam Tomography (CBT) scans acquired preoperatively were used to obtain DICOM data sets to produce a model of the mandible using rapid prototyping. This model was used as a template to prebend and then sterilize a 2.3 or 2.7 reconstruction plate, which was used to reconstruct the mandible with a microvascular bony flap. This technique was used in 20 consecutive patients who required mandibular resection and reconstruction because of a tumour or osteoradionecrosis. RESULTS: The prebent plate was used in all patients intraoperatively without the need for any further bending. The average time to bend a plate on a nonsterile model was 0.42 h (range 0.25-0.68 h). This is felt to represent the minimum amount of time saved during the operation. Additive manufacture of the mandible prior to resection and reconstruction with a microvascular flap is a useful technique which reduces the operating time. PMID- 21296587 TI - Unusually rapid growth of brown tumour in the mandible after parathyroidectomy associated with the presence of a supernumerary parathyroid gland. AB - The aim of this study is to report the case of a quick growing brown tumour in the jaw after a parathyroidectomy due to the presence of a rare fifth parathyroid gland. The patient had chronic renal disease and the diagnosis was tertiary hyperparathyroidism. Thirty days after the parathyroidectomy, the patient returned with a significant increase in the tumour size. The suspicion of a supernumerary gland was confirmed by parathyroid scintigraphy. The treatment of brown tumour is dependent on the treatment of the hyperparathyroidism. However, curettage should be considered if a large lesion is disturbing mastication. In conclusion, this case should attract the attention of general practitioner dentists, since they may be the first professionals who have contact with the patient with a brown tumour in the jaws. Likewise, this case emphasises the importance of knowing the type of hyperparathyroidism involved to allow for effective treatment planning. PMID- 21296588 TI - Anterolateral thigh flap harvested from paralytic lower extremity in a patient with late polio sequel. AB - Free flap reconstruction is the treatment of choice after extensive head and neck tumour resection. When treating a patient with a previous disability, such as lower extremity paralysis secondary to poliomyelitis, it is important to offer the best reconstruction whilst preserving healthy extremities. We report the case of a 51-year-old man with a squamous cell carcinoma (SCC) of the right tongue and a left lower extremity paralysis secondary to an acute poliomyelitis during childhood in which reconstruction was successfully achieved with a left anterolateral thigh (ALT) free flap. PMID- 21296589 TI - Influence of temperature and UVR on photosynthesis and morphology of four species of cyanobacteria. AB - During the late austral spring of 2009 we carried out experiments (4days of duration) with four cyanobacteria species, Anabaena sp., Nostoc sp., Arthrospira platensis and Microcystis sp., to assess the combined effects of temperature and solar radiation on photosynthesis performance and morphology. Two experimental temperatures (18 degrees C and 23 degrees C, simulating a 5 degrees C increase under a scenario of climate change) and three radiation treatments (by using different filters/materials) were implemented: (i) P (PAR, 400-700nm), (ii) PA (PAR+UV-A, 320-700nm) and, (iii) PAB (PAR+UV-A+UV-B, 280-700nm). In general, samples under the P treatment had less decrease/higher recovery rates of effective photochemical quantum yield (Y) than those receiving UV-A or UV-A+UV-B. The effects of increased temperature were species-specific: At the end of the experiments, it was seen that increased temperature benefited photosynthetic performance of Anabaena sp. and Nostoc sp. but not of Microcystis sp. and A. platensis. Higher temperature was also associated to an increase in the chain area of Anabaena sp., and to bigger trichomes in A. platensis; however, no morphological effects were observed in Microcystis sp. In addition, in Nostoc sp. the increase in temperature counteracted the UVR impact on the reduction of the chain area. How these effects and mechanisms will affect the trophodynamics and production of aquatic ecosystems is still uncertain, but the specificity of the responses suggests that not all cyanobacteria would be equally benefited by temperature increases therefore affecting the balance and interaction among species in the water column. PMID- 21296590 TI - High mobility group box 1 protein suppresses T cell-mediated immunity via CD11c(low)CD45RB(high) dendritic cell differentiation. AB - AIM: High mobility group box 1 protein (HMGB1) has been identified as a late proinflammatory cytokine and plays a key role in immune regulation. However, it is not yet clear whether HMGB1 can induce the activation and differentiation of dendritic cell (DC) subsets and subsequently modulate immune function of T cells. This study was performed to investigate the effect of HMGB1 on the differentiation of splenic DCs and its influence on T cell-mediated immunity in terms of DC subsets CD11c(low)CD45RB(high) DCs and CD11c(high)CD45RB(low) DCs in male BALB/c mice spleens in vitro. RESULTS: MACS microbeads were used to isolate splenic DCs, CD11c(low)CD45RB(high) DCs, CD11c(high)CD45RB(low) DCs and CD4(+) T cells. The percentage of CD11c(low)CD45RB(high) DCs was significantly increased after treatment with HMGB1 compared to their counterparts (CD11c(high)CD45RB(low) DCs). It was found that unlike the gradually increasing interleukin (IL)-12 secretion of CD11c(high)CD45RB(low) DCs induced by HMGB1, CD11c(low)CD45RB(high) DCs showed a obvious dose-dependent response between IL-10 production and HMGB1 stimulation. In order to verify whether the alteration of CD4(+) T cells was mainly associated with the differentiation of splenic DCs mediated by HMGB1 to CD11c(low)CD45RB(high) DCs, anti-IL-12 receptor (IL-12R) or anti-IL-10R monoclonal antibody was used to inhibit the effect of CD11c(high)CD45RB(low) DCs or CD11c(low)CD45RB(high) DCs in CD4(+) T cells mixed lymphocyte reaction culture. After treatment with anti-IL-12R or anti-IL-10 monoclonal antibody in CD4(+) T cells+CD11c(high)CD45RB(low) DCs or CD11c(low)CD45RB(high) DCs mixed lymphocyte reaction, the induction of these DCs on T cells was inhibited dramatically. CONCLUSION: These data demonstrated that HMGB1 might induce the differentiation of splenic DCs to CD11c(low)CD45RB(high) DCs followed by shifting of Th1 to Th2 with enhancement of T lymphocyte immune function in vitro. Also, the effect of HMGB1 on T cell differentiation to Th2 was not associated with the inhibition of IL-12 production in CD11c(high)CD45RB(low) DCs. PMID- 21296591 TI - TNF-alpha system and lung function impairment in obesity. AB - A potential interaction between pulmonary function, abnormal adipose tissue activity, and systemic inflammation has been suggested. This study explores the relationship between circulating soluble TNF-alpha receptors (sTNF-R1 and sTNF R2) and respiratory function parameters in obese subjects. Thirty-one non diabetic morbidly obese women with a history of non-smoking and without prior cardiovascular or respiratory disease were prospectively recruited in the outpatient Obesity Unit of a referral center. Pulmonary function test included a forced spirometry, static pulmonary volume measurements, non-attended respiratory polygraphy, and arterial gas blood sampling. Circulating levels of sTNFR-R1, sTNF R2, interleukine 6 and adiponectin were determined using ELISA. Statistical analysis included a multivariate regression analysis taking into account the potential confounders. sTNF-R1 positively correlated with BMI (r=0.571, p=0.001) and arterial carbon dioxide pressure (PaCO(2), r=0.381, p=0.038), but negatively with forced expiratory volume in 1s (FEV(1), r=-0.437, p=0.012), maximum midexpiratory flow (FEF(25-75), r=-0.370, p=0.040) and forced vital capacity (FVC, r=-0.483, p=0.005). However, no correlation between sTNF-R2 and BMI and either pulmonary function tests or arterial blood samples was observed. Multiple linear regression analysis showed that sTNF-R1 independently predicted FEV(1) (beta=-0.437, p=0.012) and FVC (beta=-0.483, p=0.005). Thus, circulating levels of sTNF-R1, but not sTNF-R2, are related to reduced lung volumes and airflow limitation in morbidly obese patients prior to the development of a clinically recognized respiratory disease. Therefore, studies addressed to evaluating the potential beneficial effect of anti-TNF-alpha agents on pulmonary function tests in obese subjects seem warranted. PMID- 21296592 TI - Infectious triggers protect from autoimmunity. AB - While some infectious agents have been linked to onset of autoimmune disease there is also other evidence suggesting that certain infectious agents might inhibit autoimmune pathology. This review focuses on the ways in which infectious agents or their products might intervene in an autoimmune response. PMID- 21296593 TI - Advanced glycation end products increase permeability of brain microvascular endothelial cells through reactive oxygen species-induced vascular endothelial growth factor expression. AB - BACKGROUND: Advanced glycation end products (AGEs) have been implicated as important factors in the pathogenesis of diabetic vascular complication. The aim of this study is to reveal the effect of AGEs on permeability of brain microvascular endothelial cells (BMECs) in order to assess its role in diabetic vascular complications. METHODS: Permeability was determined by the flux of fluorescein isothiocyanate (FITC)-labeled dextran (4-kDa molecular weight) through endothelial cell monolayers on a transwell system and was compared between bovine BMECs (BBMECs) and bovine aortic endothelial cells (BAECs). The effect of AGEs on permeability was investigated in terms of the role of vascular endothelial growth factor (VEGF) and reactive oxygen species (ROS). RESULTS: Permeability and VEGF expression were significantly increased by the addition of 100 MUg/mL of glycer-AGEs in BBMECs. They also tended to be increased in BAECs, but not enough to make a significant difference. Simultaneous treatment with an anti-VEGF antibody suppressed the AGE-enhanced permeability. Furthermore, simultaneous treatment with a free radical scavenger, edaravone, also suppressed the AGE-enhanced permeability and the increase in VEGF mRNA levels and AGE induced intracellular ROS overproduction. CONCLUSIONS: These results suggest that BMECs are more susceptible than aortic endothelial cells to AGE-enhanced permeability and that AGE-enhanced permeability is dependent on VEGF expression induced by ROS over production. PMID- 21296594 TI - Association between genetic polymorphisms and sites of cervicocerebral artery atherosclerosis. AB - Ischemic stroke is a multifactorial disease with strong genetic elements. The purpose of this case-control study was to find relationships between apolipoprotein E (APOE), angiotensin-converting enzyme (ACE), and methylenetetrahydrofolate reductase (MTHFR) genotypes and atherosclerosis of the extracranial internal carotid and intracranial arteries in the Thai population. Patients aged >45 years with significant intracranial stenosis (IC group) or extracranial carotid artery stenosis (EC group) diagnosed by duplex ultrasound and/or computed tomography angiography (CTA) or magnetic resonance angiography (MRA) were studied. The control group comprised volunteers with no history of stroke and no evidence of significant cervicocerebral artery stenosis by ultrasound. Genomic DNA was extracted and genotyped for APOE isoforms, ACE insertion/deletion (I/D) polymorphism, and MTHFR C677T polymorphisms. There were 141 cases (83 in the IC group and 58 in the EC group) and 167 controls. The APOE epsilon3/epsilon4 genotype and APOE epsilon4 allele were significantly associated with extracranial carotid artery stenosis (odds ratio, 2.55; 95% confidence interval, 1.07-6.05 and odds ratio, 2.85; 95% confidence interval, 1.35-5.99, respectively). These associations were not observed in patients with intracranial atherosclerosis. There was no significant association between ACE and MTHFR polymorphisms and stenosis at any site. In a multivariate model, sex, diabetes mellitus, hypertension, ischemic heart disease, and APOE epsilon4 allele remained predictive of extracranial atherosclerosis. In our Thai population, the epsilon4 allele in the APOE gene contributes to the genetic susceptibility of extracranial internal carotid atherosclerosis. The low prevalence of extracranial carotid stenosis in this population might result from low frequencies of the APOE epsilon4 allele. PMID- 21296595 TI - Sense of agency over thought: external misattribution of thought in a memory task and proneness to auditory hallucination. AB - Previous studies have suggested that auditory hallucination is closely related to thought insertion. In this study, we investigated the relationship between the external misattribution of thought and auditory hallucination-like experiences. We used the AHES-17, which measures auditory hallucination-like experiences in normal, healthy people, and the Deese-Roediger-McDermott paradigm, in which false alarms of critical lure are regarded as spontaneous external misattribution of thought. We found that critical lures elicited increased the number of false alarms as AHES-17 scores increased and that scores of AHES-17 predicted the rate of false memory of critical lures. Furthermore, we revealed that the relationship between AHES-17 scores and the rates of false alarms to critical lures was strictly linear. Therefore, it might be said that individual differences in auditory hallucination-like experiences are highly related to the external misattribution of thought. We discussed these results from the perspective of the sense of agency over thought. PMID- 21296596 TI - Proteinase inhibitor 9 is reduced in human atherosclerotic lesion development. AB - BACKGROUND: Granzyme B, a proapoptotic serine protease, is abundant in advanced, unstable atherosclerotic plaques, and it is suggested to contribute to plaque instability by inducing vascular smooth muscle cells apoptosis and by degrading plaque extracellular matrix. Proteinase inhibitor 9, the only known endogenous inhibitor of granzyme B in humans, confers protection against granzyme-B-induced apoptosis. However, the role of proteinase inhibitor 9 in atherosclerotic lesion development has yet to be determined. We hypothesized that atherosclerotic lesions have lower proteinase inhibitor 9 expression levels that will increase their susceptibility to granzyme-B-induced apoptosis. METHODS: Serial sections of human coronary arteries exhibiting different stages of lesion development were assessed by immunohistochemistry for proteinase inhibitor 9, alpha-smooth muscle cells actin, granzyme B, CD8, and active caspase-3. Frozen samples were analyzed by Western blot to evaluate total proteinase inhibitor 9 levels. RESULTS: Vascular smooth muscle cells express less proteinase inhibitor 9 as disease severity increases, and a significant difference in proteinase inhibitor 9 expression is observed between medial and intimal smooth muscle cells. High granzyme B levels colocalize with CD8+ cells and foam cells in the shoulder region and necrotic core area of advanced lesions. In advanced lesions, increased expression of activated caspase-3 in intimal SMC was associated with reduced proteinase inhibitor 9 expression in the presence of granzyme B. CONCLUSION: Reduced proteinase inhibitor 9 expression in human vascular smooth muscle cells is associated with atherosclerotic disease progression and is inversely related to the extent of apoptosis within the intima. Reduced proteinase inhibitor 9 expression may contribute to increased smooth muscle cell susceptibility to granzyme-B-induced apoptosis within the plaque. PMID- 21296597 TI - A simulation program for teaching obstetrics and gynecology residents the pediatric gynecology examination and procedures. AB - STUDY OBJECTIVE: To assess the use of a pelvic simulation curriculum to teach obstetrics and gynecologic residents the pediatric gynecology examination and procedures. DESIGN: Residents in obstetrics and gynecology participated in a simulation curriculum using a modified pelvic hemimodel to simulate a pediatric pelvis. PARTICIPANTS: 19 obstetrics and gynecology residents completed the study protocol. INTERVENTIONS: Digitally recorded encounters with a standardized patient scenario using the simulator were utilized. After the initial encounter the trainees participated in a formal lecture and demonstration using the model. The trainees were then reassessed at least four weeks after the initial encounter; results were reviewed by a blinded evaluator. Scores were analyzed using the two-sided t-test and Wilcoxon signed-rank test. MAIN OUTCOME MEASURES: Scores from before to after the simulation training. RESULTS: A total of 19 residents completed the study protocol and demonstrated significant improvement in scores from before to after the simulation training. Scores improved from a pre-training mean of 6.1 to post-training mean of 16.7 (P = 0.0001). Improvement was seen at all levels of residency training. Specific skill sets included in the Council for Resident Education in Obstetrics and Gynecology (CREOG) Educational objectives (1) were improved including: pediatric gynecologic examination, collection of microbial cultures, vaginal lavage and vaginoscopy. CONCLUSIONS: This teaching program using a simulation model was found to be an effective tool to improve resident knowledge and performance of the skills needed to accomplish the pediatric gynecology examination. PMID- 21296598 TI - EPR, optical absorption and superposition model study of Fe3(+) doped strontium nitrate single crystals. AB - Electron paramagnetic resonance (EPR) study of Fe3(+) ions doped strontium nitrate (SN) single crystals is performed at liquid nitrogen temperature and at X band frequency. The spin Hamiltonian (SH) parameters are determined from the resonance lines observed at different angular rotations. The crystal field parameters (CFPs) are evaluated using superposition model of Newman. The Zeeman g factor and zero-field splitting parameters (ZFSPs) of Fe3(+) ion in SN (truncated SH considered) are: g=1.9989 +/- 0.002 and ?D?=(338 +/- 5) * 10-4 cm-1, ?E?=(10 +/- 5)* 10-4 cm-1, a=(458 +/- 5)* 10-4 cm-1, respectively. The Fe3(+) ion enters the lattice substitutionally replacing the Sr2(+) sites of cubic symmetry. The local site symmetry of Fe3(+) ion in the crystal is orthorhombic (lower than that of the host). The optical absorption study of the crystal is also done at room temperature in the wavelength range 195-925 nm. The energy values of different orbital levels are determined. The observed bands are assigned as transitions from the (6)A1(g)(S) ground state to various excited states of Fe3(+) ion in a cubic crystal field approximation. The observed band positions are fitted with four parameters, the Racah interelectronic repulsion parameters (B and C), the cubic crystal field splitting parameter (Dq) and the Trees correction (alpha) yielding: B=934, C=2059, Dq=1450, and alpha=90 (in cm-1). On the basis of EPR and optical data, the nature of metal-ligand bonding in this crystal is discussed. The ZFSPs are also determined theoretically using microscopic SH theory based on perturbation theory and CFPs, B(kq) obtained from superposition model. The values of ZFSPs thus obtained are ?D?=(340 +/- 5) * 10-4 cm-1 and ?E?=(15 +/- 5) * 10-4 cm-1. PMID- 21296599 TI - How valuable are multiple treatment comparison methods in evidence-based health care evaluation? AB - OBJECTIVES: To compare the use of pair-wise meta-analysis methods to multiple treatment comparison (MTC) methods for evidence-based health-care evaluation to estimate the effectiveness and cost-effectiveness of alternative health-care interventions based on the available evidence. METHODS: Pair-wise meta-analysis and more complex evidence syntheses, incorporating an MTC component, are applied to three examples: 1) clinical effectiveness of interventions for preventing strokes in people with atrial fibrillation; 2) clinical and cost-effectiveness of using drug-eluting stents in percutaneous coronary intervention in patients with coronary artery disease; and 3) clinical and cost-effectiveness of using neuraminidase inhibitors in the treatment of influenza. We compare the two synthesis approaches with respect to the assumptions made, empirical estimates produced, and conclusions drawn. RESULTS: The difference between point estimates of effectiveness produced by the pair-wise and MTC approaches was generally unpredictable-sometimes agreeing closely whereas in other instances differing considerably. In all three examples, the MTC approach allowed the inclusion of randomized controlled trial evidence ignored in the pair-wise meta-analysis approach. This generally increased the precision of the effectiveness estimates from the MTC model. CONCLUSIONS: The MTC approach to synthesis allows the evidence base on clinical effectiveness to be treated as a coherent whole, include more data, and sometimes relax the assumptions made in the pair-wise approaches. However, MTC models are necessarily more complex than those developed for pair-wise meta-analysis and thus could be seen as less transparent. Therefore, it is important that model details and the assumptions made are carefully reported alongside the results. PMID- 21296600 TI - Cost-effectiveness of transdermal nitroglycerin use for preterm labor. AB - OBJECTIVE: The objective of this study was to determine the cost-effectiveness of using transdermal nitroglycerin (GTN) for cases of preterm labor. METHODS: The study included 153 women with clinical preterm labor, who were randomly allocated to either a GTN or placebo arm. All randomized cases were included in the final economic analysis. Differences between the two arms in gestational age at delivery, neonatal intensive care unit (NICU) admission, length of NICU stay, and NICU cost were assessed. Costs for non-NICU cases were calculated using Ottawa Hospital data through the Ontario Case Costing Initiative (OCCI). Cost effectiveness and sensitivity analyses using a hospital perspective were both conducted. RESULTS: In the 153 randomized cases, 55 babies were admitted to NICU (GTN = 24; placebo = 31). We found no significant differences between the two arms in gestational age at delivery, NICU admission rate (32.4% vs. 39.2%), NICU length of stay (42.7 days vs. 52.8 days), or NICU cost (CAN $34,306 vs. CAN $44,326). Overall, (based on all randomized cases) the cost-effectiveness analyses showed that the GTN arm was the dominant strategy, with both lower cost (CAN $13,397 vs. CAN $18,427) and higher NICU admission avoided rate (67.6% vs. 60.8%) compared to the placebo arm. This dominance persisted in all sensitivity analyses. CONCLUSION: The use of GTN patch for preterm labor could reduce NICU costs, while improving important neonatal outcomes. PMID- 21296601 TI - Cost-effective psychotherapy for personality disorders in the Netherlands: the value of further research and active implementation. AB - OBJECTIVE: In a budget-constrained health care system, decisions regarding resource allocation towards research and implementation are critical and can be informed by cost-effectiveness analysis. The objective of this study was to assess the societal value of conducting further research to inform reimbursement decisions and implementation of cost-effective psychotherapy for clusters B and C personality disorders (PDs). METHODS: Value of information and value of implementation analyses were conducted using previously developed cost effectiveness models for clusters B and C PDs to evaluate the parameters that contribute to most of the decision uncertainty, and to calculate the population expected values of perfect information (pEVPI) and perfect implementation (pEVPIM). RESULTS: The pEVPI was estimated to be ?425 million for cluster B PDs and ?315 million for cluster C PDs, indicating that gathering additional evidence is expected to be cost-effective. The categories of parameters for which reduction of uncertainty would be most valuable were transition probabilities and health state costs. The pEVPIM was estimated to be ?595 million for cluster B PDs and ?1,372 million for cluster C PDs, suggesting that investing in implementation of cost-effective psychotherapy is likely to be worthwhile. CONCLUSIONS: The societal value of additional research on psychotherapy for clusters B and C PDs is substantial, especially when prioritizing information on transition probabilities and health state costs. Active implementation of cost-effective treatment strategies into clinical practice is likely to improve the efficiency of health care provision in The Netherlands. PMID- 21296602 TI - Imputing QALYs from single time point health state descriptions on the EQ-5D and the SF-6D: a comparison of methods for hepatitis a patients. AB - OBJECTIVES: To explore the impact of applying different non-standardized analytical choices for quality of life measurement to obtain quality-adjusted life years (QALYs). In addition to more widely discussed issues such as the choice of instrument (e.g. EQ-5D or SF-6D?) researchers must also choose between different recall periods, scoring algorithms and interpolations between points of measurement. METHODS: A prospective survey was made among 114 Belgian patients with acute hepatitis A illness. Using non-parametric tests and generalized linear models (GLM's), we compared four different methods to estimate QALY losses, two based on the EQ-5D (administered during the period of illness without recall period) and two based on the SF-6D (administered after illness with 4 weeks recall period). RESULTS: We found statistically significant differences between all methods, with the non-parametric SF-6D-based method yielding the highest median QALY impact (0.032 QALYs). This is more than five times as high as the EQ 5D-based method with linear health improvement, which yields the lowest median QALY impact (0.006 QALYs). CONCLUSIONS: Economic evaluations of health care technologies predominantly use QALYs to quantify health benefits. Non standardised analytical choices can have a decision-changing impact on cost effectiveness results, particularly if morbidity takes up a substantial part of the total QALY loss. Yet these choices are rarely subjected to sensitivity analysis. Researchers and decision makers should be aware of the influence of these somewhat arbitrary choices on their results. PMID- 21296603 TI - Improvements in participation in usual daily activities in patients with rheumatoid arthritis treated with abatacept. AB - OBJECTIVE: To examine changes in activity participation following abatacept treatment for rheumatoid arthritis (RA), and which factors contributed to such changes. METHODS: Data were analyzed from the Abatacept in Inadequate responders to Methotrexate (AIM) and Abatacept Trial in Treatment of Anti-TNF INadequate responders (ATTAIN) clinical trials of abatacept in patients with RA. Activity participation was evaluated by the validated Activity Participation Questionnaire (APaQ), along with measures of clinical response and health-related quality of life. Changes in the APaQ during the two study periods were compared between treatment groups. Multiple regression analyses were performed to investigate the determinants of change in activity participation. The relationship between clinical efficacy measures (including low disease activity state [LDAS], Disease Activity Score 28-defined remission, and European League Against Rheumatism [EULAR] responses) and changes in activity participation were investigated. RESULTS: Statistically significant, substantive improvements in activity participation were observed over the entire study period in patients treated with abatacept. Abatacept-treated patients showed improvements from baseline of 8.4 and 7.3 days in activity participation, compared with 4.5 and 1.4 days in the placebo group (P < 0.005 vs. placebo in both trials), at the end of AIM and ATTAIN, respectively. The Short Form-36 physical and mental component scores, patient global assessment, and the Health Assessment Questionnaire-Disability Index score were found to be the strongest determinants of changes in activity participation. Patients who achieved LDAS, disease remission and good EULAR responses experienced greater improvements in activity participation measures. CONCLUSIONS: Abatacept treatment substantively and significantly improved patients' ability to participate in their usual activities. The gain in activity was closely related to improvements in clinical status, physical function and quality of life. PMID- 21296604 TI - [Impact of the induced prescription on the doctor-patient relationship]. PMID- 21296605 TI - [Patients' perception on attention received from Health Centres non-sanitary staff]. AB - AIMS: To know patients' perceptions about relational aspects and technical procedures when they are attended by the administrative staff in Health Centres. To assess the utility of two ways for measuring satisfaction. MATERIAL AND METHODS: Cross-sectional study carried out in people attending the administrative sections of Health Centres for diverse reasons. Just after the interaction with the administrative they were interviewed using two different questions for assessing their opinions and satisfaction with communicational and technical aspects related with their demands. Descriptive analysis. Significant differences among mean was explored by chi(2) test. Open-ended questions were grouped in categories in a process involving three researchers independently. RESULTS: Over than 90% (360) of the attendees declared to be satisfied or very satisfied with the service received from the staff personal. Nevertheless, among 18-36% gave suggestions for improving the service after their consultation. Independently the domain explored, people suggested the communicational, personal capability, quality and quantity of explanations and waiting time as the main aspects to be improved. CONCLUSIONS: Surveys with open-ended questions are more useful to assess the quality of the attention the citizens receive from no-sanitary staff in Health Centres. These type of questions are also more useful for detecting problems and planning new interventions. Relational and informative issues seem to be the most prioritary areas to improve in this section of Health Centres. PMID- 21296606 TI - Botulinum toxin type A for the treatment of gastroparesis in Parkinson's disease patients. AB - Gastroparesis is a very common non-motor feature in Parkinson's disease (PD) patients. However, treatment options are limited and difficult. We present 2 cases of PD patients with excellent response to botulinum toxin type A as treatment for PD-related gastroparesis. PMID- 21296607 TI - "Sense of community belonging" in health surveys: what social capital is it measuring? AB - Canadian national health surveys regularly ask respondents to rate their sense of belonging to their local community. Health studies commonly use this question as a social capital indicator, but what social capital domains community belonging is measuring remains unclear. Analyzing Canadian General Social Survey data, we evaluate the validity of this measure with respect to network-based social capital and health. Results indicate that sense of community belonging is associated positively with several network-based social capital measures. Neighborhood network-based social capital most substantially reduced associations between sense of community belonging and health measures, but results differed by urban and rural settings. These findings indicate the need for public health surveys to include specific measures of respondents' networks. PMID- 21296608 TI - Songs to syntax: the linguistics of birdsong. AB - Unlike our primate cousins, many species of bird share with humans a capacity for vocal learning, a crucial factor in speech acquisition. There are striking behavioural, neural and genetic similarities between auditory-vocal learning in birds and human infants. Recently, the linguistic parallels between birdsong and spoken language have begun to be investigated. Although both birdsong and human language are hierarchically organized according to particular syntactic constraints, birdsong structure is best characterized as 'phonological syntax', resembling aspects of human sound structure. Crucially, birdsong lacks semantics and words. Formal language and linguistic analysis remains essential for the proper characterization of birdsong as a model system for human speech and language, and for the study of the brain and cognition evolution. PMID- 21296609 TI - Ferritin protein nanocages use ion channels, catalytic sites, and nucleation channels to manage iron/oxygen chemistry. AB - The ferritin superfamily is composed of ancient, nanocage proteins with an internal cavity, 60% of total volume, that reversibly synthesize solid minerals of hydrated ferric oxide; the minerals are iron concentrates for cell nutrition as well as antioxidants due to ferrous and oxygen consumption during mineralization. The cages have multiple iron entry/exit channels, oxidoreductase enzyme sites, and, in eukaryotes, Fe(III)O nucleation channels with clustered exits that extend protein activity to include facilitated mineral growth. Ferritin protein cage differences include size, amino acid sequence, and location of the active sites, oxidant substrate and crystallinity of the iron mineral. Genetic regulation depends on iron and oxygen signals, which in animals includes direct ferrous signaling to RNA to release and to ubiquitin-ligases to degrade the protein repressors. Ferritin biosynthesis forms, with DNA, mRNA and the protein product, a feedback loop where the genetic signals are also protein substrates. The ferritin protein nanocages, which are required for normal iron homeostasis and are finding current use in the delivery of nanodrugs, novel nanomaterials, and nanocatalysts, are likely contributors to survival and success during the transition from anaerobic to aerobic life. PMID- 21296610 TI - Analytical Raman spectroscopic discrimination between yellow pigments of the Renaissance. AB - The Renaissance represented a major advance in painting techniques, subject matter, artistic style and the use of pigments and pigment mixtures. However, most pigments in general use were still mineral-based as most organic dyes were believed to be fugitive; the historical study of artists' palettes and recipes has assumed importance for the attribution of art works to the Renaissance period. Although the application of diagnostic elemental and molecular spectroscopic techniques play vital and complementary roles in the analysis of art works, elemental techniques alone cannot definitively provide the data needed for pigment identification. The advantages and limitations of Raman spectroscopy for the definitive diagnostic characterisation of yellow pigments that were in use during the Renaissance is demonstrated here in consideration of heavy metal oxides and sulphides; these data will be compared with those obtained from analyses of synthetic yellow pigments that were available during the eighteenth and nineteenth Centuries which could have been used in unrecorded restorations of Renaissance paintings. PMID- 21296611 TI - Evaluation of portable Raman instrumentation for identification of beta-carotene and mellitic acid in two-component mixtures with halite. AB - Recently, portable Raman instrumentation has been in demand for geosciences and for future planetary exploration for the identification of both organic and inorganic compounds in situ on Earth and on other planetary bodies, especially on Mars. Here we present the results of the analysis of halite/beta-carotene and halite/mellitic acid mixtures, performed by miniaturized Raman instrumentation equipped with 785 and 1064 nm excitation. Various proportions of organics in the halite matrix were examined. The lowest concentration of beta-carotene detected using the 785 nm laser was 1 mg kg(-1), with slightly better signals observed with shorter exposure times compared with the bench instrument using the same excitation wavelength. Mellitic acid was identified at the concentration level 10 g kg(-1). The 1064 nm excitation provided a lower sensitivity towards low concentration when compared with the 785 nm excitation. PMID- 21296612 TI - Universal human papillomavirus genotyping by the digene HPV Genotyping RH and LQ Tests. AB - BACKGROUND: High-risk (hr)HPV testing plays an important role in primary cervical cancer screening. Subsequent hrHPV genotyping might contribute to better risk stratification. The majority of hrHPV tests do not include identification of individual hrHPV genotypes. OBJECTIVES: The digene HPV Genotyping RH Test (strip based) and LQ Test (xMAP-based) allow genotyping of GP5+/6+ amplimers, but their probes target a region in the L1 ORF, which is also amplified by other broad spectrum hrHPV assays, e.g., the Roche Amplicor HPV Test (Amplicor) and the Roche Linear Array. The goal was to test whether the RH Test and LQ Test can be used as an universal hrHPV genotyping test. STUDY DESIGN: Self-collected cervico-vaginal specimens (n=416) from an epidemiologic study were analyzed with Amplicor. The amplimers obtained were also tested with the RH Test and LQ Test for identification of 18 HPV types, including the 13 hrHPVs targeted by Amplicor. RESULTS: 197 specimens were positive by Amplicor, in which the RH Test and LQ Test identified one of the 13 hrHPVs in 94.4% and 98.0%, respectively. In 219 specimens remaining negative by Amplicor, the RH Test and LQ Test, performed on the Amplicor amplification products, still detected one of the 13 hrHPVs in 3.7% and 5.5%, respectively, and include identification of HPV53, 66, and 82. Overall, the RH and LQ Tests demonstrated high concordance with Amplicor for hrHPV detection (kappa=0.908 and kappa=0.923, respectively). CONCLUSIONS: The digene HPV Genotyping RH and LQ Tests can be directly used for amplimers generated by the Amplicor HPV Test. PMID- 21296613 TI - Altered cardio-respiratory response to spontaneous cortical arousals in children with upper airway obstruction. AB - OBJECTIVE: Upper airway obstruction (UAO) during childhood is associated with cardiovascular morbidity. The aim of this study was to investigate the cardio respiratory response to cortical arousal during sleep in children with UAO. METHODS: Standard paediatric overnight polysomnography (PSG) was conducted in 40 children with UAO (25M, 7.5+/-2.7yrs) prior to and 6 months following adenotonsillectomy. For comparison a control group of 40 normal, sex and age matched children (21M, 7.5+/-2.6yrs) underwent two PSGs without intervention at the same time points. RESULTS: Heart rate and respiratory rate were measured during spontaneous and respiratory arousals in stage 2 and REM sleep 15s prior to and 15s immediately following cortical arousal onset. Cortical arousal was associated with a significant increase in heart and respiratory rate in both groups of children. UAO children, however, showed a significantly higher heart rate response in stage 2 sleep (-17.5+/-6.0 vs. -14.4+/-4.8%; p<0.05), a lower pre-arousal baseline respiratory rate (stage 2: 17.1+/-1.4 vs. 18.2+/-1.7 BPM; p<0.01) and a prolonged increase in respiratory rate compared to control children. Cardiac and respiratory arousal responses were not significantly different from controls following adenotonsillectomy in the UAO children. CONCLUSIONS: UAO in children is associated with an altered cardiorespiratory response to spontaneous arousal from sleep, which may indicate early signs of autonomic dysfunction. Surgical treatment of UAO appears to reverse these outcomes. PMID- 21296614 TI - The midpoint of sleep is associated with dietary intake and dietary behavior among young Japanese women. AB - OBJECTIVES: How human chronotype is correlated to nutrient and food-group intakes and dietary behavior remains to be elucidated. We cross-sectionally examined the association between the midpoint of sleep and these dietary variables in young Japanese women. A calculated halfway point between bedtime and rise time was used as midpoint of sleep. METHODS: The subjects were 3304 female Japanese dietetics students aged 18-20years from 53 institutions in Japan. Dietary intake during the previous month was assessed by a validated, self-administered diet history questionnaire. The midpoint of sleep was calculated using self-reported bedtimes and rise times. RESULTS: Late midpoint of sleep was significantly negatively associated with the percentage of energy from protein and carbohydrates, and the energy-adjusted intake of cholesterol, potassium, calcium, magnesium, iron, zinc, vitamin A, vitamin D, thiamin, riboflavin, vitamin B(6), folate, rice, vegetables, pulses, eggs, and milk and milk products. It was also significantly positively associated with the percentage of energy from alcohol and fat, and the energy-adjusted intake of noodles, confections, fat and oil, and meat. Furthermore, subjects with a later midpoint of sleep tended to begin meals later, eat for a longer time, skip meals more frequently, and watch TV at meals, not only at breakfast but also at lunch and dinner. CONCLUSIONS: The midpoint of sleep is significantly associated with dietary intake of certain nutrients and foods and other dietary behaviors in young Japanese women. This finding may contribute to consider the relationships between chronotype and dietary intakes and behaviors. PMID- 21296615 TI - Definition and classification of cancer cachexia: an international consensus. AB - To develop a framework for the definition and classification of cancer cachexia a panel of experts participated in a formal consensus process, including focus groups and two Delphi rounds. Cancer cachexia was defined as a multifactorial syndrome defined by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment. Its pathophysiology is characterised by a negative protein and energy balance driven by a variable combination of reduced food intake and abnormal metabolism. The agreed diagnostic criterion for cachexia was weight loss greater than 5%, or weight loss greater than 2% in individuals already showing depletion according to current bodyweight and height (body-mass index [BMI] <20 kg/m(2)) or skeletal muscle mass (sarcopenia). An agreement was made that the cachexia syndrome can develop progressively through various stages--precachexia to cachexia to refractory cachexia. Severity can be classified according to degree of depletion of energy stores and body protein (BMI) in combination with degree of ongoing weight loss. Assessment for classification and clinical management should include the following domains: anorexia or reduced food intake, catabolic drive, muscle mass and strength, functional and psychosocial impairment. Consensus exists on a framework for the definition and classification of cancer cachexia. After validation, this should aid clinical trial design, development of practice guidelines, and, eventually, routine clinical management. PMID- 21296616 TI - Effects of the renin angiotensin system on vasculogenesis-related progenitor cells. AB - The current concept is that there are both cells that integrate into the vasculature, true endothelial progenitor cells (EPC), and cells with hematopoietic markers that support neovascularisation. As identification of the EPC is controversial and studies refer cells that might fall into either pools, we will use the term, vasculogenesis-related progenitor cells (VRPC), for this review. VRPC are considered to be an important target for the treatment of cardiovascular diseases (CVD). Angiotensin II is known to be an important player in neovascularisation and the modulation of renin angiotensin system (RAS) is one of the major pharmacotherapeutic strategies for the treatment of CVD. We will review the effects of different components of the RAS on such VRPC under physiological conditions and in CVD. The reviewed research strongly supports a critical role of the RAS in vasculogenesis and vascular regeneration. Therefore, pharmacological intervention on the components of the RAS does not only target directly end-organ remodelling and blood pressure but also influence tissue healing and/or regeneration by influencing specific progenitor cells. Thus, the interrogation of RAS effects on VRPC will be important in the optimisation of RAS intervention or regenerative therapy. PMID- 21296617 TI - Segmental multicystic dysplastic kidney: a rare situation. AB - Segmental multicystic dysplastic kidney is a rare subtype, found in only about 4% of children diagnosed with MCDK. To the best of our knowledge, we describe the 36th reported case of segmental multicystic kidney disease. PMID- 21296618 TI - Prenatal ultrasound: a critical look. PMID- 21296619 TI - RE: Papparella A, et al. The value of laparoscopy in the management of non palpable testis. J Pediatr Urol 2010;6: 550-4. PMID- 21296620 TI - Long-term results of pyeloplasty in poorly functioning kidneys in the pediatric age group. AB - OBJECTIVE: To determine the efficacy and long-term outcome of pyeloplasty in poorly functioning kidneys in the pediatric age group. METHOD: Retrospective data analysis was performed on patients who underwent pyeloplasty in 2000-2008. The parameter analyzed was postoperative outcome. Success was defined on the basis of either improvement in symptoms or better drainage on postoperative Tc-99m DTPA renography done after 3 months and yearly thereafter. RESULTS: A total of 39 patients with a mean age of 8.6 years (4 months to 13 years), and male to female ratio of 3:1, with poor function on isotope renogram (<30%) were included in the study. Left to right side ratio was 1.3:1. Dismembered pyeloplasty was done in all patients. Laparoscopic pyeloplasty was done in 27 (66.7%) and open in 12 (33.3%) patients. Follow-up renograms were available for 35 patients: 31 showed improvement in drainage and no further deterioration in renal function and 4 showed an obstructed pattern; of these, two patients had significant deterioration in split function and the other two underwent redo pyeloplasty by open technique. At a mean follow up of 41.6 months (8-75), overall success rate was 90%. CONCLUSION: Pyeloplasty gives good intermediate-term results in poorly functioning kidneys in the pediatric age group. PMID- 21296621 TI - Changes in extrafrontal integrity and cognition in frontal lobe epilepsy: a diffusion tensor imaging study. AB - We used diffusion tensor imaging to characterize microstructural changes and their associations with cognition in Chinese patients with frontal lobe epilepsy (FLE). We examined 18 adult patients with FLE and 20 healthy controls. Compared with normal controls, patients with FLE had increased mean diffusivity (MD) in the right frontal lobe and decreased fractional anisotropy (FA) in both thalami. Patients with FLE also had decreased FA in the right frontal lobe that correlated with patient age at seizure onset and increased MD in the left thalamus that correlated with duration of epilepsy. Patients with FLE performed significantly worse on nearly all cognitive tasks, and there was a positive correlation between Mini-Mental Status Examination scores and FA in the left frontal lobe and the left thalamus. Our results suggest that the thalamus might be an important extrafrontal structure involved in FLE and that a longer duration of epilepsy might result in more abnormalities in the thalamus. Our results also support the hypothesis that the left frontal lobe white matter and the thalamus contribute to cognitive impairment in patients with FLE. PMID- 21296622 TI - Efficacy of vagus nerve stimulation over time: review of 65 consecutive patients with treatment-resistant epilepsy treated with VNS > 10 years. AB - OBJECTIVE: Studies have reported improved seizure control with increased duration of vagus nerve stimulation (VNS) but are prone to methodological biases. We analyzed the efficacy of VNS over time in patients with treatment-resistant epilepsy (TRE) who underwent VNS therapy 10 or more years. METHODS: We retrospectively reviewed 65 consecutive patients (29 females) who underwent VNS therapy >= 10 years. The mean age at VNS insertion was 30.0 years. Forty-four adults (>= 18 years; 67.7%) and 21 children (32.3%) were included. Seizure frequency and antiepileptic drug (AED) regimens were recorded prior to VNS and, following VNS insertion, at 6 months, 1 year, 2 years, and every 2 years thereafter. RESULTS: The mean duration of VNS therapy for this group was 10.4 years, and the mean decrease in seizure frequency at last follow-up was 76.3%. The mean reduction in seizures at 6 months and years 1, 2, 4, 6, 8, and 10 years was 35.7, 52.1, 58.3, 60.4, 65.7, 75.5, and 75.5%, respectively. Seizure frequency was significantly reduced from baseline at each of the recorded intervals (P<0.001). There was a trend toward increased AED burden in the latter years of the follow-up period. CONCLUSION: Following a "ramp-up" and accommodation period throughout the initial 24 months after VNS implantation, seizure control improved slightly over the subsequent years of therapy and eventually stabilized. Variation in seizure frequency, however, was common, and frequent changes in AED regimens or stimulation parameters were likely an important and possibly synergistic component of seizure control. PMID- 21296623 TI - The overshoot phenomenon as a function of internal resistance in microbial fuel cells. AB - A method for assessing the performance of microbial fuel cells (MFCs) is the polarisation sweep where different external resistances are applied at set intervals (sample rates). The resulting power curves often exhibit an overshoot where both power and current decrease concomitantly. To investigate these phenomena, small-scale (1 mL volume) MFCs operated in continuous flow were subjected to polarisation sweeps under various conditions. At shorter sample rates the overshoot was more exaggerated and power generation was overestimated; sampling at 30 s produced 23% higher maximum power than at 3 min. MFCs with an immature anodic biofilm (5 days) exhibited a double overshoot effect, which disappeared after a sufficient adjustment period (5 weeks). Mature MFCs were subject to overshoot when the anode was fed weak (1 mM acetate) feedstock with low conductivity (<100 MUS) but not when fed with a higher concentration (20 mM acetate) feedstock with high conductivity (>1500 MUS). MFCs developed in a pH neutral environment produced overshoot after the anode had been exposed to acidic (pH 3) conditions for 24 h. In contrast, changes to the cathode both in terms of pH and varying catholyte conductivity, although affecting power output did not result in overshoot suggesting that this is an anodic phenomenon. PMID- 21296625 TI - Quantification of CPT13 in rat plasma using LC-MS/MS for a pharmacokinetic study. AB - A new, simple, sensitive and specific reversed-phase high performance liquid chromatographic (HPLC) method using tandem mass spectrometry detection was initially developed and validated for the analysis of 10-(2-pyrazolyl-ethoxy) (20S)-camptothecin (CPT13) in rat plasma. Pretreatment of the sample obtained from plasma involved a single protein precipitation step with using acetonitrile containing 0.1% formic acid. An aliquot of 20 MUl was injected into a C-18 column. The chromatographic separation was achieved using the mobile phase consisting of acetonitrile:water (35:65) at a flow rate of 1.0 mL/min. The total run time for each sample was 10 min, and camptothecin (CPT, IS) and CPT13 were well separated with retention times of 5.1 min and 5.6 min, respectively. Detection was performed using a triple quadrupole tandem mass spectrometer in multiple reaction monitoring (MRM) mode via an electrospray ionization (ESI) source. The calibration curve was linear (r2 = 0.9998) over the concentration range of 1-1000 ng/mL, with a LLOQ of 1 ng/mL for CPT13. The inter- and intra-day precision (%R.S.D.) were <2.58% and 6.28%, respectively, and the accuracies (%) were within the range of 97.34-110.67%. CPT13 in rat plasma was stable when stored at -20 degrees C or 4 degrees C for three freeze-thaw cycles, The method was employed for the first time during pharmacokinetic studies of CPT13 in rats following a single intravenous dose (0.1 mg/kg) and three different oral doses (50 mg/kg, 30 mg/kg, and 10 mg/kg). This fully validated method was successfully applied to a pharmacokinetic study of CPT13 in rats. PMID- 21296624 TI - An analysis of single nucleotide polymorphisms of 125 DNA repair genes in the Texas genome-wide association study of lung cancer with a replication for the XRCC4 SNPs. AB - DNA repair genes are important for maintaining genomic stability and limiting carcinogenesis. We analyzed all single nucleotide polymorphisms (SNPs) of 125 DNA repair genes covered by the Illumina HumanHap300 (v1.1) BeadChips in a previously conducted genome-wide association study (GWAS) of 1154 lung cancer cases and 1137 controls and replicated the top-hits of XRCC4 SNPs in an independent set of 597 cases and 611 controls in Texas populations. We found that six of 20 XRCC4 SNPs were associated with a decreased risk of lung cancer with a P-value of 0.01 or lower in the discovery dataset, of which the most significant SNP was rs10040363 (P for allelic test=4.89 x 10-4). Moreover, the data in this region allowed us to impute a potentially functional SNP rs2075685 (imputed P for allelic test=1.3 x 10-3). A luciferase reporter assay demonstrated that the rs2075685G>T change in the XRCC4 promoter increased expression of the gene. In the replication study of rs10040363, rs1478486, rs9293329, and rs2075685, however, only rs10040363 achieved a borderline association with a decreased risk of lung cancer in a dominant model (adjusted OR=0.80, 95% CI=0.62-1.03 and P=0.079). In the final combined analysis of both the Texas GWAS discovery and replication datasets, the strength of the association was increased for rs10040363 (adjusted OR=0.77, 95% CI=0.66-0.89, P(dominant)=5 x 10-4 and P for trend=5 x 10-4) and rs1478486 (adjusted OR=0.82, 95% CI=0.71-0.94, P(dominant)=6 x 10-3 and P for trend=3.5 x 10-3). Finally, we conducted a meta-analysis of these XRCC4 SNPs with available data from published GWA studies of lung cancer with a total of 12,312 cases and 47,921 controls, in which none of these XRCC4 SNPs was associated with lung cancer risk. It appeared that rs2075685, although associated with increased expression of a reporter gene and lung cancer risk in the Texas populations, did not have an effect on lung cancer risk in other populations. This study underscores the importance of replication using published data in larger populations. PMID- 21296626 TI - [Tumour in the fibula with aggressive radiological characteristics in an infant]. PMID- 21296627 TI - [Suspected sexual abuse. Perineal groove]. PMID- 21296628 TI - [Successful treatment of postoperative mediastinitis using a new portable vacuum assisted device]. PMID- 21296629 TI - [7p14.1 microdeletion and Greig cephalopolysyndactyly syndrome]. AB - Greig cephalopolysyndactyly is a rare autosomic dominant syndrome caused by mutations in GLI3 gene located on cytoband 7p14.1 and characterized by the clinical triad of polysyndactyly, macrocephaly and hypertelorism. In approximately 20% of the cases a deletion of variable size is detected. If deletion is large and affects other genes as well as GLI3, a more severe phenotype is expected. Thus, Greig cephalopolysyndactyly contiguous gene syndrome is a multiple malformation syndrome caused by haploinsufficiency of GLI3 and adjacent genes. We describe the case of a newborn female with polysyndactyly, hypertelorism and microcephaly and a 1.5 Mb 7p14.1 microdeletion of paternal origin diagnosed by array-CGH. PMID- 21296630 TI - [Prenatal diagnosis and novel mutation in X-linked chronic granulomatous disease]. AB - BACKGROUND: Chronic Granulomatous Disease (CGD) is a rare primary immunodeficiency caused by the alteration of the enzyme complex NADPH oxidase, which affects the phagocytic function. CGD patients are susceptible to recurrent infections mainly caused by bacteria and/or fungi. METHODS: We studied a 6 year old boy with suspicion of CGD. The diagnosis was confirmed based on the functional study of NADPH oxidase. Simultaneously, the second pregnancy of the mother was reported and genetic counselling was requested. RESULTS: We identified a new disease-causing mutation by direct sequencing of the CYBB gene (X-linked CGD). The prenatal study resulted in the identification of the same mutation in the foetus. COMMENTS: Molecular genetics characterisation of CGD is needed to obtain an accurate diagnosis of the disease and to offer prenatal diagnosis and genetic counselling in future pregnancies. PMID- 21296631 TI - [Kawasaki disease in 76 patients. Risk factors for coronary artery aneurysms]. AB - INTRODUCTION: Kawasaki disease is an acute systemic vasculitis of childhood, of unknown origin, and is considered the leading cause of acquired heart disease in children. Therefore, it is important to know clinical manifestations and complications in children with Kawasaki disease in our environment and to look for risk factors for the development of cardiac complications. MATERIAL AND METHODS: Retrospective review of 76 children with Kawasaki disease evaluated from January 1997 to May 2008. RESULTS: Of the patients studied, 64.5% were males. The mean age was 3 years and 4 months. The main clinical findings were fever (mean of 8.13 days), rash, bilateral non-exudative conjunctivitis, changes in lips and oral cavity, changes in the extremities, cervical lymphadenopathy and arthralgias. The most important laboratory findings were leucocytosis, thrombocytosis, elevated C-reactive protein and erythrocyte sedimentation rate, hypoalbuminaemia, hyperbilirubinaemia, elevated serum transaminases and sterile pyuria. Twelve of the patients (15.7%) developed coronary artery aneurysms, two patients had a mild mitral insufficiency and one patient with a mild pericardial effusion. There was one case of cholestatic hepatitis. All the complications were resolved without sequelae. Male sex (OR = 1.24), an urticarial exanthem (OR = 10.53) and a C-reactive protein > 10mg/dl (OR = 4.20) were identified as risk factors for coronary aneurysms. CONCLUSIONS: Our patients had the typical clinical and laboratory findings of Kawasaki disease. Mild coronary artery complications were observed in 15.7% of the patients. Male sex, an urticarial exanthem and an elevated C-reactive protein are risk factors for coronary aneurysms. PMID- 21296632 TI - Management of chyle leak post neck dissection: a case report and literature review. AB - Chyle leakage post head-and-neck resection is a rare but potentially life threatening complication. Management may be problematic and prolonged. Recently, thoracoscopic ligation of the thoracic duct has emerged as a promising technique to definitively treat this difficult problem. We present a recent case of a hemimandibulectomy, radical modified neck dissection and osseocutaneous fibular free-flap complicated by a chyle leakage. The chyle leak was successfully treated with thoracoscopic ligation of the thoracic duct. In the light of our clinical experience and following a thorough literature review, we have proposed that complicated or high-output chyle leaks (>1000 ml day(-1)) should be treated with early thoracoscopic thoracic duct ligation. PMID- 21296633 TI - [Atypical obstruction during a hemodialysis catheter replacement]. AB - We followed a 60-year-old woman in our department for a vascular chronic kidney disease. The peritoneal dialysis was stopped because of a Candida albicans catheter infection. As the patient refused the arterio-venous fistula creation, we have placed a central venous catheter (Medcomp 32cm). Because the instability of the cuff, we decided to remove and change it by another one (Quinton 40cm). The discovery of an important cylindrical calcification has complicated the manipulation requiring tranquility and agility. The finding of a massive calcification is uncommon and confirms the major risk of calcification in chronic kidney disease patients. PMID- 21296634 TI - The association between the survivin -31G/C promoter polymorphism and hepatocellular carcinoma risk in a Turkish population. AB - BACKGROUND: Survivin, a member of the inhibitor of apoptosis protein family, functions as a key regulator of apoptosis and cell cycle regulation. A common single nucleotide polymorphism (-31G>C) at the survivin promoter has been extensively studied in various cancers and reported to influence survivin expression, but its association with hepatocellular carinoma (HCC) has yet to be investigated. The aim of the present study was to investigate whether this polymorphism could be involved in the risk of HCC susceptibilty. METHODS: The genotype frequency of survivin -31G>C polymorphism was determined by using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in 160 subjects with HCC and 241 cancer-free control subjects matched on age, gender, smoking and alcohol status. RESULTS: No statistically significant differences were found in the genotype distributions of the survivin -31G>C polymorphism among HCC and cancer-free control subjects (p=0.28). CONCLUSION: Our results demonstrate for the first time that the survivin -31G/C polymorphism have not been any major role in genetic susceptibilty to hepatocellular carcinogenesis, at least in the population studied here. PMID- 21296635 TI - Clinical value of (18)F-FDG PET/CT in postoperative monitoring for patients with colorectal carcinoma. AB - OBJECTIVE: To evaluate the clinical value of (18)F-FDG PET/CT in postoperative monitoring for patients with colorectal carcinoma. METHODS: 66 postoperative patients with colorectal carcinoma underwent whole-body FDG PET/CT. The final histopathological and formal clinical follow-up findings were used as gold standard to determine the sensitivity and specificity of FDG PET/CT and enhanced CT of the same periods. RESULTS: The sensitivity and specificity of FDG PET/CT in detecting recurrence are 96.30%, 94.87% (while enhanced CT are 70.37% and 87.18% respectively). The sensitivity and specificity in detecting metastasis are 95.35%, 82.61% (enhanced CT are 61.90%, 75.00%). SUVmax was significantly higher in malignant lesions [range 4.16-22.00, mean+/-standard deviation (x+/-s) 8.06+/ 4.30] than in benign ones (range 1.18-6.25, x+/-s 2.82+/-1.02). CONCLUSION: At present, whole-body (18)F-FDG PET/CT is an advanced diagnostic imaging technique in detecting loco-regional recurrence and metastasis in postoperative patients with colorectal carcinoma for its higher sensitivity and specificity. PMID- 21296636 TI - Colorectal juvenile polyposis in an adult with ulcerative colitis. AB - Juvenile polyposis is a rare disorder. We report an unusual case of juvenile polyposis in a 22-yr-old woman with ulcerative colitis, apparently one of the first cases reported in the literature. PMID- 21296637 TI - Immediate implant loading following computer-guided surgery. AB - PURPOSE: The aim of this study was to develop and apply a new method for easy intraoperative adjustment of a provisional fixed full-arch restoration, in order to allow immediate implant loading following computer-guided surgery, regardless of any implant positioning errors compared to the virtual planning. METHODS: In accordance with the NobelGuideTM protocol, a provisional restoration for immediate loading of six maxillary implants was prepared prior to surgery. Because small shifts between the planned and the actual implant positions were to be expected, the provisional restoration was not fabricated directly on temporary cylinders as a conventional one-piece superstructure, but was divided into two portions: six custom made abutments and a long span fixed restoration which were left unconnected. After implantation, the custom abutments were attached to the six implants to be immediately loaded, and the superstructure was cemented simultaneously to all abutments using dual cure resin cement. After the excess cement was cleaned and polished, the superstructure was then reseated. Passive fit was achieved between implants and the superstructure. CONCLUSION: The superstructure described in this article can be easily seated and adjusted to accommodate any possible shifts in implant positioning occurring during computer guided surgery. Through this method uneventful immediate implant loading can be achieved in a reasonable operative time. PMID- 21296638 TI - No effect of conscious clenching on simple arithmetic task in healthy participants. AB - PURPOSE: This study aimed to investigate whether clenching aids performance in a task requiring mental concentration in healthy participants. MATERIALS AND METHODS: Twenty healthy participants (an average of 26.8 +/- 2.0 years, nine females and 11 males) were recruited from our department. Participants performed four sets of hundred-square calculations as a mental arithmetic task. Among these sets, the third and the fourth sets were randomly divided into two conditions: one condition where participants made an effort to not allow their teeth to touch ('no tooth-contact' condition), and another where they made a conscious effort to rhythmically clench their teeth ('clenching' condition) during the task. Surface EMG was recorded from the left masseter muscle. Arithmetic performance was compared between the tooth-contact and clenching conditions using paired t-tests. In addition, we computed Pearson product-moment coefficients of the correlations between the difference in EMG activity and arithmetic performance in the two conditions. RESULTS: No significant change in arithmetic score was found between the no tooth-contact (68.8 +/- 12.2) and clenching conditions (66.5 +/- 12.7; P=0.27). No significant correlation was found between the difference in EMG activity and changes in arithmetic performance (r=0.32, P=0.17). CONCLUSION: In healthy participants, conscious clenching was not associated with any benefit in arithmetic performance. Although our study was limited by only measuring the short-term effects of clenching on a simple arithmetic task, the results indicate that it may not be harmful for clinicians to encourage their patients to refrain from clenching their teeth. PMID- 21296639 TI - Clinical evaluation of a dental color analysis system: the Crystaleye Spectrophotometer(r). AB - PURPOSE: To evaluate the clinical performance of the Crystaleye Spectrophotometer((r)), a dental color analysis system. METHODS: Three color measuring devices (Crystaleye Spectrophotometer((r)), CAS-ID1, MSC-2000) were tested and the differences in color measurements among them were evaluated using Scheffe's F-test. Color measurements with the Crystaleye Spectrophotometer((r)) were repeated 10 times by the same operator. The color difference (DeltaE) between the first and tenth measurements was calculated. The Crystaleye Spectrophotometer((r)) was used to measure the color of the maxillary left central incisor under two conditions (light and dark) and the effect of exterior lighting was analyzed to assess the accuracy of measurements. Furthermore, five different operators performed color measurements, and DeltaE among the three devices was calculated. The DeltaE between the target tooth and the crown of a single maxillary central incisor crown fabricated using data from the Crystaleye Spectrophotmeter((r)) was calculated. Color differences between prebleaching and postbleaching were also analyzed with the Crystaleye Spectrophotometer((r)) using the parameters DeltaE, DeltaL*, Deltaa*, and Deltab*. RESULTS: The data from the three spectrophotometers were not significantly different. The DeltaE during repeated color measurements by the same operator was 0.6. The DeltaE between light and dark conditions was 0.9. The data from the five operators were not significantly different. The mean DeltaE value between the target tooth and the fabricated crown was 1.2 +/- 0.4, and the mean DeltaE value between prebleaching and postbleaching was 3.7 +/- 1.0. CONCLUSIONS: The Crystaleye Spectrophotometer((r)) is an easy-to-use color analysis system producing accurate color measurements under clinical conditions. PMID- 21296640 TI - DNA amplification using phi29 DNA polymerase validates gene polymorphism analysis from buccal mucosa samples. AB - Venous blood is currently the most common source of DNA for gene polymorphism screening; however, blood sampling is invasive and difficult to perform in general dental treatment. Buccal mucosa samples provide an alternative source of DNA, but it is frequently difficult to effectively amplify the DNA owing to the small amounts of sample material obtained. This study was performed to establish a method for performing total genomic DNA amplification from buccal mucosa samples using phi29 DNA polymerase. Total genomic DNA was isolated from buccal mucosa samples obtained from healthy subjects and was amplified using phi29 DNA polymerase. To determine the suitability of the extracted DNA for genotyping, polymerase chain reaction and restriction fragment length polymorphism analyses were performed for the IL-1 gene polymorphism. Genotyping of the IL-1 polymorphism was successful using the amplified DNA from a buccal mucosa, but genotyping was unsuccessful using the unamplified control because of low DNA purity. The method of extracting DNA from a buccal mucosa is painless, simple, minimally invasive, and rapid. Genomic DNA from a buccal mucosa can be amplified by phi29 DNA polymerase in sufficient quantity and quality to conduct gene polymorphism analyses. PMID- 21296641 TI - Clenching occurring during the day is influenced by psychological factors. AB - PURPOSE: We investigated the relationship between clenching occurring during the day under natural conditions and psychological attributes. METHOD: Subjects were 37 dentistry students and staff (14 women, 23 men; mean age 27.4+/-4.7 years). A portable EMG recording device was used to record muscle activity in the temporal muscles for a continuous 5-h period under subjects' natural conditions, including having lunch. Clenching was identified by electromyography, and subjects were categorized into clenching and non-clenching groups. Psychological testing was performed during the same period using the Modified Taylor Manifest Anxiety Scale (MAS), the Self-rating Depression Scale (SDS), and the Cornell Medical Index (CMI), and the psychological attributes of clenching and non-clenching groups were compared. RESULTS: Of the 37 subjects, 23 were assigned to the clenching group and 14 to the non-clenching group. Thirteen of the 23 subjects of the clenching group and none of the 14 subjects of the non-clenching group were determined to have psychological problems according to the MAS, with a significant difference observed between the clenching and non-clenching groups in terms of anxious tendency (p<0.001; Fisher's exact test). Total muscle activity in the clenching group, excluding eating and talking, was 3.5 times greater compared with the non-clenching group, and a significant difference between the groups was observed (p<0.05; Mann-Whitney U-test). CONCLUSIONS: Daytime clenching was shown to be associated with anxious tendency. Total muscle activity in the clenching group was 3.5 times greater compared with the non-clenching group. PMID- 21296643 TI - Beauvericin induced erythrocyte cell membrane scrambling. AB - Beauvericin is a mycotoxin with antiviral, antibacterial, nematicidal, insecticidal, cytotoxic, and apoptotic activity. Similar to nucleated cells erythrocytes may undergo suicidal death or eryptosis, which is characterized by cell shrinkage and phosphatidylserine exposure at the erythrocyte surface. Eryptosis may be triggered by energy depletion leading to increase of cytosolic Ca2+ activity. The present study thus explored whether beauvericin is able to trigger eryptosis and influence eryptosis following energy depletion. Cell membrane scrambling was estimated from binding of annexin V to phosphatidylserine at the erythrocyte surface, cell volume from forward scatter in FACS analysis, cytosolic Ca2+ concentration from Fluo3 fluorescence, cytosolic ATP concentration from a luciferase-assay and ion channel activity with whole cell patch clamp. Exposure to beauvericin (>= 5 MUM) significantly decreased erythrocyte ATP concentration and increased cytosolic Ca2+ concentration as well as annexin V binding. The effect of beauvericin on annexin V binding was significantly blunted by removal of extracellular Ca2+. Glucose depletion (48 h) was followed by, increase of Fluo3 fluorescence, decrease of forward scatter and increase of annexin V-binding. Beauvericin (>= 1 MUM) augmented the effect of glucose withdrawal on Fluo3 fluorescence and annexin V-binding, but significantly blunted the effect of glucose withdrawal on forward scatter, an effect paralleled by inhibition of Ca2+ activated K+ channels. The present observations disclose novel effects of beauvericin, i.e. stimulation of Ca2+ entry with subsequent cell membrane scrambling and inhibition of Ca2+ activated K+ channels with blunting of cell shrinkage. PMID- 21296644 TI - alpha1-Antichymotrypsin inactivates staphylococcal cysteine protease in cross class inhibition. AB - Staphylococcal cysteine proteases are implicated as virulence factors in human and avian infections. Human strains of Staphylococcus aureus secrete two cysteine proteases (staphopains A and B), whereas avian strains express staphopain C (ScpA2), which is distinct from both human homologues. Here, we describe probable reasons why the horizontal transfer of a plasmid encoding staphopain C between avian and human strains has never been observed. The human plasma serine protease inhibitor alpha(1)-antichymotrypsin (ACHT) inhibits ScpA2. Together with the lack of ScpA2 inhibition by chicken plasma, these data may explain the exclusively avian occurrence of ScpA2. We also clarify the mechanistic details of this unusual cross-class inhibition. Analysis of mutated ACHT variants revealed that the cleavage of the Leu383-Ser384 peptide bond results in ScpA2 inhibition, whereas hydrolysis of the preceding peptide bond leads to ACHT inactivation. This evidence is consistent with the suicide-substrate-like mechanism of inhibition. PMID- 21296645 TI - Sex differences in the contribution of ATP-sensitive K+ channels in trigeminal ganglia under an acute muscle pain condition. AB - In this study, we examined whether functional subunits of the ATP-dependent K+ channel (KATP) are expressed in trigeminal ganglia (TG), which contains sensory neurons that innervate oral and facial structures. We also investigated whether direct activation of the KATP effectively attenuates mechanical hypersensitivity in the context of an acute orofacial muscle pain condition. The KATP expression in TG and behavioral studies were conducted in age matched male and female Sprague-Dawley rats. RT-PCR experiments showed that the mRNAs for the inwardly rectifying pore-forming subunits, Kir6.1 and Kir6.2, as well as the regulatory sulfonylurea subunits, SUR1 and SUR2, were reliably detected in TG. Subsequent western blot analysis confirmed that proteins for all four subunits are expressed in TG, and showed that Kir6.2 is expressed at a significantly higher level in male TG compared to that of female rats. This observation was confirmed by the immunohistochemical demonstration of higher percentages of Kir6 positive masseter afferents in female rats. Masseteric injection of capsaicin evokes a time dependent increase in masseter sensitivity to noxious mechanical stimulation. A specific KATP agonist, pinacidil, dose-dependently attenuated the capsaicin induced mechanical hypersensitivity in male rats. The dose of pinacidil (20 MUg) that completely blocked the capsaicin responses in male rats was ineffective in female rats regardless of their estrus phases. Only at the highest dose (300 MUg) we used, pinacidil was partially effective in female rats. Similarly, another KATP agonist, diazoxide which targets different KATP subunits also showed sex specific responses in attenuating capsaicin-induced masseter hypersensitivity. These data suggested that sex differences in functional KATP expression in TG may underlie sex specific responses to KATP agonists. The present study provided novel information on sex differences in KATP expression in TG and its contribution under an orofacial muscle pain condition. PMID- 21296646 TI - Traditional uses, phytochemistry and pharmacology of Ficus religiosa: a review. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ficus religiosa L. (Moraceae) has been extensively used in traditional medicine for a wide range of ailments of the central nervous system, endocrine system, gastrointestinal tract, reproductive system, respiratory system and infectious disorders. AIM OF THE REVIEW: To comprehend the fragmented information available on the botany, traditional uses, phytochemistry, pharmacology and toxicology of F. religiosa to explore its therapeutic potential and future research opportunities. MATERIALS AND METHODS: All the available information on F. religiosa was collected via electronic search (using Pubmed, SciFinder, Scirus, Google Scholar, Agricola and Web of Science) and a library search. RESULTS: Ethnomedical uses of F. religiosa are recorded throughout South Asia, where it has been used for about 50 types of disorders. Phytochemical research had led to the isolation of phytosterols, amino acids, furanocoumarins, phenolic components, hydrocarbons, aliphatic alcohols, volatile components and few other classes of secondary metabolites from F. religiosa. Fresh plant materials, crude extracts and isolated components of F. religiosa showed a wide spectrum of in vitro and in vivo pharmacological activities like, antidiabetic, cognitive enhancer, wound healing, anticonvulsant, anti inflammatory, analgesic, antimicrobial, antiviral, hypolipidemic, antioxidant, immunomodulatory, antiasthmatic, parasympathetic modulatory, esterogenic, antitumor, antiulcer, antianxiety, antihelmintic, endotheilin receptor antagonistic, apoptosis inducer and hypotensive. CONCLUSIONS: F. religiosa emerged as a good source of traditional medicine for the treatment of asthma, diabetes, diarrhea, epilepsy, gastric problems, inflammatory disorders, infectious disorders and sexual disorders. Although many of the experimental studies validated its traditional medicinal uses, but employed uncharacterized crude extracts. Thus, it is difficult to reproduce the results and pinpoint the bioactive metabolite. Hence, there is a need of phytochemical standardization and bioactivity-guided identification of bioactive metabolites. The results of few pharmacological studies and bioactive metabolites already reported in F. religiosa warrant detailed investigation for its potential against cancer, cardiovascular disorders, neuroinflammatory disorders, neuropsychiatric disorders, oxidative stress related disorders and parasitic infections. The outcome of these studies will further expand the existing therapeutic potential of F. religiosa and provide a convincing support to its future clinical use in modern medicine. PMID- 21296647 TI - Prokinetic and laxative activities of Lepidium sativum seed extract with species and tissue selective gut stimulatory actions. AB - AIM OF THE STUDY: To provide ethnopharmacological basis for the medicinal use of Lepidium sativum seeds in indigestion and constipation. MATERIALS AND METHODS: The in vivo studies were conducted in mice, while isolated tissues of mouse, guinea-pig and rabbit were suspended in tissue bath to measure isotonic contractions. RESULTS: The aqueous-methanolic extract of Lepidium sativum seeds (Ls.Cr) at 30 and 100mg/kg showed atropine-sensitive prokinetic and laxative activities in mice, which were partially sensitive to atropine. In isolated gut preparations of mouse and guinea-pig, Ls.Cr (0.1-1mg/mL) caused a concentration dependent stimulatory effects both in jejunum and ileum, which was blocked in the presence of atropine. In rabbit jejunum, the stimulant effect of Ls.Cr remained unchanged in the presence of atropine, pyrilamine or SB203186, while in rabbit ileum, the stimulatory effect was partially blocked by atropine. The Ls.Cr was more efficacious in gut preparations of rabbit than in guinea-pig or mouse. The phytochemical analysis of the plant extract detected alkaloids, saponins and anthraquinones as plant constituents. CONCLUSION: This study showed the prokinetic and laxative effects of Lepidium sativum in mice, which were partially mediated through a cholinergic pathway. The in vitro spasmodic effect of the plant extract mediated through a similar mechanism with species and tissue selectivity, provides a rationale for the medicinal use of the seeds of Lepidium sativum in indigestion and constipation, and suggests studying the plant extracts on more than one species to get the wider picture. PMID- 21296648 TI - The garlic constituent diallyl trisulfide increases the lifespan of C. elegans via skn-1 activation. AB - Medicinal benefits of Allium vegetables, such as garlic, have been noted throughout recorded history, including protection against cancer and cardiovascular disease. We now demonstrate that garlic constituent diallyl trisulfide (DATS) increases longevity of Caenorhabditis elegans by affecting the skn-1 pathway. Treatment of worms with 5-10 MUM DATS increased worm mean lifespan even when treatment is started during young adulthood. To explore the mechanisms involved in the DATS-mediated increase in longevity, we treated daf-2, daf-16, and eat-2 mutants and found that DATS increased the lifespan of daf-2 and daf-16 mutants, but not the eat-2 mutants. Microarray experiments demonstrated that a number of genes regulated by oxidative stress and the skn-1 transcription factor were also changed by DATS treatment. Consistently, DATS treatment leads to the induction of the skn-1 target gene gst-4, and this induction was dependent on skn 1. We also found that the effects of DATS on worm lifespan depend on skn-1 activity in both in the intestine and ASI neurons. Together our data suggest that DATS is able to increase worm lifespan by enhancing the function of the pro longevity transcription factor skn-1. PMID- 21296649 TI - Aging effects on the control of grip force magnitude: an fMRI study. AB - Functional neuroimaging techniques have allowed for investigations into the mechanisms of age-related deterioration in motor control. This study used functional Magnetic Resonance Imaging (fMRI) to investigate age related differences in the control of grip force magnitude. Using an event-related design, fMRI scans were completed on 13 older adults, and 13 gender matched younger adults, while using their dominant hand to squeeze a rubber bulb for 4s at 10%, 40% or 70% of their maximum voluntary contraction. Both groups were able to match the relative force targets, however the older adults produced significantly lower levels of absolute force. fMRI analysis consisted of a 1) region of interest (ROI) approach to detect differences in selected motor areas within brain and 2) a voxel-wise whole brain comparison to find areas of differential activation that were not defined a priori between the older and younger group. The ROI analysis revealed that despite producing lower levels of absolute force, the older adults showed higher levels of activity predominantly in subcortical structures (putamen, thalamus and cerebellum) when compared to the younger group. The older adults also showed higher levels of activity in the ipsilateral ventral premotor cortex. A total of 19 of the 22 ROIs analyzed showed a significant main effect of the required force-level. In the majority of the ROIs that showed a significant force effect there were no significant differences in the magnitude of the blood-oxygen-level-dependent (BOLD) signal between the 10% and 40% conditions but a significantly higher BOLD signal in the 70% condition, suggesting that the modulation of brain activation with grip force may not be controlled in a linear fashion. It was also found that the older adult group demonstrate higher levels of activation in 7 areas during a force production task at higher force levels using a voxel-wise analysis. The 7 clusters that showed significant differences tended to be areas that are involved in visual-spatial and executive processing. The results of this study revealed that older adults require significantly higher activation of several areas to perform the same motor task as younger adults. Higher magnitudes of the BOLD signal in older adults may represent a compensatory pattern to counter age related deterioration in motor control systems. PMID- 21296650 TI - Protein chimeras containing the Mycoplasma bovis GAPDH protein and bovine host defence peptides retain the properties of the individual components. AB - Besides the well characterized role in glycolysis, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has been implicated in virulence of pathogenic micro organisms and because of its cell surface location, it has been shown to act as an adhesin for colonization of tissue surfaces both for pathogenic and non pathogenic normal microflora. These novel properties of GAPDH make this protein a target for studies in pathogenesis and a candidate for vaccine development against several diseases. Previously, we have isolated the GAPDH protein of Mycoplasma bovis and we are currently using this protein as a test antigen to develop a vaccine to protect feedlot animals from M. bovis-related diseases. As part of our vaccine studies, we are testing several novel immune modulators, some of which are host-defence peptides (HDP). HDP are small protein molecules that are part of the innate immune system of the host possess antimicrobial activities and can act as adjuvants. These novel compounds have been used as part of chimeric proteins composed of viral antigens fused to HDP and these chimeras were found to promote immune responses. The first step in the use of the M. bovis GAPDH protein and HDP as components of a vaccine was to construct M. bovis GAPDH HDP chimeric proteins. The three M. bovis GAPDH-HDP chimeric proteins constructed here: GAPDH-BMAP28 (sGap-M), GAPDH-indolicidin (sGap-I), and GAPDH-TAP (Gap-T) retained properties associated with the individual components, namely GAPDH enzymatic and HDP antimicrobial activities. PMID- 21296651 TI - Properties of cells with increased resistance to some picornaviruses. AB - The resistance to picornaviral infection cells of susceptible lines has similar changes in the phenotype. They have decreased number of nucleoli and increased percentage of euploidy. Also the percentage of euploid cells those were resistant to the picornaviral infection increased in all highly transformed cultures. In resistant cells of all cultures has been found reduction of DNA. RNA amount also decreased both in nucleus and in cytoplasm. All these data correlated with the increased euploidy of the resistant population. The resistant cells had a less transformed phenotype, and decreased proliferative activity. Decreased nucleolar status became apparent by reduction of absolute and relative nucleolar indices. Consequently the reduction of viral titer (viral titters reduction) in resistant cells could be the direct result of diminished activity of the RNA synthesis machinery. It is important to note that the cells lose resistance while another type of virus, even from the same family, infects the culture once. PMID- 21296652 TI - Paracoccidioidomycosis: cells expressing IL17 and Foxp3 in cutaneous and mucosal lesions. AB - We demonstrated and quantified by immunohistochemistry the population of cells expressing IL17 and Foxp3 in cutaneous and mucosal paracoccidioidomycosis lesions, associating these populations of cells with different presentations of granulomatous response. For this purpose, 61 skin biopsies and 55 oral mucosal biopsies were evaluated. Cells expressing IL17 were distributed in the inflammatory infiltrate in both groups of lesions and were found in the vessels' wall too. Foxp3+ expression was limited to the nuclei of lymphocytes in the inflammatory infiltrate. The distribution of IL17 was similar among the groups; however, Foxp3+ cells were increased in mucosal lesions that displayed compact granulomas. The results suggest that IL17 seems to play a role in paracoccidioidomycosis cutaneous and mucosal lesions, probably as secondary cells in the clearance of the fungal antigens. The presence of Foxp3+ cells both in skin and mucosa corroborates some previous researches that suggest the role of this group of cells in the modulation of local immune response. PMID- 21296653 TI - Peptide aptamer mimicking RAD51-binding domain of BRCA2 inhibits DNA damage repair and survival in Trypanosoma brucei. AB - The eukaryotic DNA recombination repair protein BRCA2 is functional in the parasitic protozoan Trypanosoma brucei. The mechanism of the involvement of BRCA2 in homologous recombination includes its interaction with the DNA recombinase proteins of the RAD51 family. BRCA2 is known to interact with RAD51 through its unique and essential BRC sequence motifs. T. brucei BRCA2 homolog (TbBRCA2) has fifteen repeating BRC motifs as compared to mammalian BRCA2 that has only eight. We report here our yeast 2-hybrid analysis studies on the interactions of TbBRCA2 BRC motifs with five different RAD51 paralogues of T. brucei. Our study revealed that a single BRC motif is sufficient to bind to these RAD51 paralogues. To test the possibility whether a single 44 amino acid long repeating unit of the TbBRCA2 BRC motif may be exploited as an inhibitor of T. brucei growth, we ectopically expressed this peptide segment in the procyclic form of the parasite and evaluated its effects on cell survival as well as the sensitivity of these cells to the DNA damaging agent methyl methane sulfonate (MMS). Expression of a single BRC motif led to MMS sensitivity and inhibited cellular proliferation in T. brucei. PMID- 21296654 TI - Evaluation of tissue engineered models of the oral mucosa to investigate oral candidiasis. AB - Candida albicans is a commensal organism that can be isolated from the majority of healthy individuals. However, in certain susceptible individuals C. albicans can become pathogenic leading to the mucocutaneous infection; oral candidiasis. Murine models and in vitro monolayer cultures have generated some data on the likely virulence and host factors that contribute to oral candidiasis but these models have limitations. Recently, tissue engineered oral mucosal models have been developed to mimic the normal oral mucosa but little information is available on their true representation. In this study, we assessed the histological features of three different tissue engineered oral mucosal models compared to the normal oral mucosa and analysed both cell damage and cytokine release following infection with C. albicans. Models comprised of normal oral keratinocytes and a fibroblast-containing matrix displayed more similar immunohistological and proliferation characteristics to normal mucosa, compared to models composed of an oral carcinoma cell line. Although all models were invaded and damaged by C. albicans in a similar manner, the cytokine response was much more pronounced in models containing normal keratinocytes. These data suggest that models based on normal keratinocytes atop a fibroblast-containing connective tissue will significantly aid in dissecting the molecular pathogenesis of oral candidiasis. PMID- 21296655 TI - DNA methylation in repetitive elements and Alzheimer disease. AB - Epigenetics is believed to play a role in Alzheimer's disease (AD). DNA methylation, the most investigated epigenetic hallmark, is a reversible mechanism that modifies genome function and chromosomal stability through the addition of methyl groups to cytosine located in CpG dinucleotides to form 5 methylcytosine (5mC). Methylation status of repetitive elements (i.e. Alu, LINE-1 and SAT-alpha) is a major contributor of global DNA methylation patterns and has been investigated in relation to a variety of human diseases. However, the role of methylation of repetitive elements in blood of AD patients has never been investigated so far. In the present study, a quantitative bisulfite-PCR pyrosequencing method was used to evaluate methylation of Alu, LINE-1 and SAT alpha sequences in 43 AD patients and 38 healthy donors. In multivariate analysis adjusting for age and gender, LINE-1 was increased in AD patients compared with healthy volunteers (ADs: 83.6%5mC, volunteers: 83.1%5mC, p-value: 0.05). The group with best performances in mini mental state examination (MMSE) showed higher levels of LINE-1 methylation compared to the group with worst performances (MMSE>22: 83.9%5mC; MMSE<=22: 83.2%5mC; p=0.05). Our data suggest that LINE-1 methylation may lead to a better understanding of AD pathogenesis and course, and may contribute to identify novel markers useful to assess risk stratification. Further prospective investigations are warranted to evaluate the dynamics of DNA methylation from early-stage AD to advanced phases of the disease. PMID- 21296656 TI - Exposure and effects of perfluoroalkyl compounds on tree swallows nesting at Lake Johanna in east central Minnesota, USA. AB - Tree swallow (Tachycineta bicolor) samples were collected at a reference lake and a nearby lake (Lake Johanna) in east central Minnesota, USA contaminated with perfluorinated carboxylic and sulfonic acids. Tissues were analyzed for a suite of 13 perfluoroalkyl compounds (PFCs) to quantify exposure and to determine if there was an association between egg concentrations of PFCs and reproductive success of tree swallows. Concentrations of perfluoroocatane sulfonate (PFOS) were elevated in all tree swallow tissues from Lake Johanna compared to tissues collected at the reference lake. Other PFCs, except for two, were elevated in blood plasma at Lake Johanna compared to the reference lake. PFOS was the dominant PFC (>75%) at Lake Johanna, but accounted for <50% of total PFCs at the reference lake. There was a negative association between concentrations of PFOS in eggs and hatching success. Reduced hatching success was associated with PFOS levels as low as 150ng/g wet weight. PMID- 21296657 TI - Polychlorinated biphenyl (PCB) exposure in mothers and time to pregnancy in daughters. AB - Developmental exposure to polychlorinated biphenyls (PCBs) disrupts reproduction in animals. Human data are lacking. We measured PCBs in preserved mothers' serum samples collected during 1960-1963, 1-3 days after their daughters' birth. We recorded time to pregnancy (TTP) in 289 daughters 28-31 years later. PCB congeners 187, 156, and 99 in mother's serum were associated with longer TTP in their daughters while PCB congeners 105, 138 and 183 were associated shorter TTP. Probability of pregnancy fell by 38% (95% CI 17-53%) and infertility was higher (30% not pregnant after 13 cycles versus 11% not pregnant after 13 cycles) among women whose mothers had a higher proportion of PCB congeners associated with longer TTP (75th percentile versus 25th percentile). This study demonstrates, for the first time, that developmental exposure to PCBs may disrupt pregnancy in humans. PMID- 21296658 TI - Differential accumulation of HCBz and PeCBz in porcine ovarian follicles and their opposing actions on steroid secretion and CYP11, CYP17, 17beta-HSD and CYP19 protein expression. A tissue culture approach. AB - In the current study, we determined in vitro accumulation of hexachlorobenzene (HCBz) and pentachlorobenzene (PeCBz) in porcine ovarian follicles, the effect on steroidogenesis and the expression of enzymes responsible for steroid synthesis. Sixty percent of the HCBz and almost 100% of the PeCBz that was added to the culture medium accumulated in ovarian tissue, and only 1% of each was found in the medium. An inhibitory HCBz effect and stimulatory PeCBz effect on testosterone and estradiol secretion were noted. Immunoblot analyses showed an inhibitory effect of HCBz on CYP17, 17beta-HSD and CYP19, a stimulatory effect of PeCBz on CYP17 and CYP19 and no effect on 17beta-HSD protein expression. In conclusion, the greater exposure to an estrogenic action of PeCBz than anti estrogenic HCBz would be a consequence of the preferential accumulation of PeCBz in the ovarian follicles. As one of the mechanisms of action, we propose modulation of steroidogenic enzymes expression. PMID- 21296659 TI - Mouse embryonic stem cell adherent cell differentiation and cytotoxicity (ACDC) assay. AB - An adherent cell differentiation and cytotoxicity (ACDC) assay was developed using pluripotent J1 mouse embryonic stem cells (mESCs). Adherent mESCs were used to evaluate chemical-induced effects on both stem cell viability and differentiation using an in-cell western technique after a 9-day culture. DRAQ5/Sapphire700 stains were used to quantify cell number. Myosin heavy chain protein was used as a marker of cardiomyocyte differentiation and was corrected for cell number, thereby separating cytotoxicity and effects on differentiation. Acetic acid, 5-fluorouracil and bromochloroacetic acid were evaluated using the embryonic stem cell test and ACDC assay. Both systems distinguish the relative potencies of these compounds. TaqMan low-density arrays were used to characterize the time course of differentiation and effects of chemical exposure on multiple differentiation gene markers. The ACDC assay is a technique that can be used to evaluate the effects of xenobiotics on mESC differentiation and cell number using a single assay. PMID- 21296660 TI - Clinical and molecular characterization of five patients with succinyl-CoA:3 ketoacid CoA transferase (SCOT) deficiency. AB - Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency is an inborn error of ketone body metabolism and causes episodic ketoacidosis. We report clinical and molecular analyses of 5 patients with SCOT deficiency. Patients GS07, GS13, and GS14 are homozygotes of S405P, L327P, and R468C, respectively. GS17 and GS18 are compound heterozygotes for S226N and A215V, and V404F and E273X, respectively. These mutations have not been reported previously. Missense mutations were further characterized by transient expression analysis of mutant cDNAs. Among 6 missense mutations, mutants L327P, R468C, and A215V retained some residual activities and their mutant proteins were detected in immunoblot analysis following expression at 37 degrees C. They were more stable at 30 degrees C than 37 degrees C, indicating their temperature sensitive character. The R468C mutant is a distinct temperature sensitive mutant which retained 12% and 51% of wild type residual activities at 37 and 30 degrees C, respectively. The S226N mutant protein was detected but retained no residual activity. Effects of missense mutations were predicted from the tertiary structure of the SCOT molecule. Main effects of these mutations were destabilization of SCOT molecules, and some of them also affected catalytic activity. Among 5 patients, GS07 and GS18 had null mutations in both alleles and the other three patients retained some residual SCOT activities. All 5 developed a first severe ketoacidotic crisis with blood gas pH <7.1, and experienced multiple ketoacidotic decompensations (two of them had seven such episodes). In general, the outcome was good even following multiple ketoacidotic events. Permanent ketosis or ketonuria is considered a pathognomonic feature of SCOT deficiency. However, this condition depends not only on residual activity but also on environmental factors. PMID- 21296661 TI - Ethanol exposure modulates hepatic S-adenosylmethionine and S adenosylhomocysteine levels in the isolated perfused rat liver through changes in the redox state of the NADH/NAD(+) system. AB - Methionine metabolism is disrupted in patients with alcoholic liver disease, resulting in altered hepatic concentrations of S-adenosylmethionine (SAM), S adenosylhomocysteine (SAH), and other metabolites. The present study tested the hypothesis that reductive stress mediates the effects of ethanol on liver methionine metabolism. Isolated rat livers were perfused with ethanol or propanol to induce a reductive stress by increasing the NADH/NAD(+) ratio, and the concentrations of SAM and SAH in the liver tissue were determined by high performance liquid chromatography. The increase in the NADH/NAD(+) ratio induced by ethanol or propanol was associated with a marked decrease in SAM and an increase in SAH liver content. 4-Methylpyrazole, an inhibitor the NAD(+) dependent enzyme alcohol dehydrogenase, blocked the increase in the NADH/NAD(+) ratio and prevented the alterations in SAM and SAH. Similarly, co-infusion of pyruvate, which is metabolized by the NADH-dependent enzyme lactate dehydrogenase, restored the NADH/NAD(+) ratio and normalized SAM and SAH levels. The data establish an initial link between the effects of ethanol on the NADH/NAD(+) redox couple and the effects of ethanol on methionine metabolism in the liver. PMID- 21296662 TI - Human growth hormone: new delivery systems, alternative routes of administration, and their pharmacological relevance. AB - The availability of recombinant human growth hormone (GH) has broadened its range of clinical applications. Approved indications for GH therapy include treatment of growth hormone deficiency (in children and in adults), Turner syndrome, Prader Willi syndrome, chronic renal insufficiency and more recently, idiopathic short stature in children, AIDS-related wasting and fat accumulation associated with lipodystrophy in adults. Therapy with GH usually begins at a low dose and is gradually titrated to obtain optimal efficacy while minimizing side effects. It is usually administered on a daily basis by subcutaneous injection, since this was considered to impact upon patient compliance, extended-release GH preparations were developed and new delivery platforms - e.g., auto-injectors and needle-free devices - were introduced in order to improve not only compliance and convenience but also dosing accuracy. In addition, alternative less invasive modes of administration such as the nasal, pulmonary and transdermal routes have also been investigated. Here, we provide an overview of the different technologies and routes of GH administration and discuss the principles, limitations and pharmacological profiles for each approach. PMID- 21296663 TI - Gonadotropin-releasing hormone modulates cholesterol synthesis and steroidogenesis in SH-SY5Y cells. AB - Neurosteroids are involved in Central Nervous System development, brain functionality and neuroprotection but little is known about regulators of their biosynthesis. Recently gonadotropins, Gonadotropin-releasing Hormone (GnRH) and their receptors have been localized in different brain regions, such as hippocampus and cortex. Using human neuronal-like cells we found that GnRH up regulates the expression of key genes of cholesterol and steroid synthesis when used in a narrow range around 1.0 nM. The expression of Hydroxysterol D24 reductase (seladin-1/DHCR24), that catalyzes the last step of cholesterol biosynthesis, is increased by 50% after 90 min of incubation with GnRH. StAR protein and P450 side chain cleavage (P450scc) are up-regulated by 3.3 times after 90 min and by 3.5 times after 3 h, respectively. GnRH action is mediated by LH and 1.0 nM GnRH enhances the expression of LHbeta as well. A two fold increase of cell cholesterol is induced after 90 min of GnRH incubation and 17beta estradiol (E2) production is increased after 24, 48 and 72 h. These data indicate for the first time that GnRH regulates both cholesterol and steroid biosynthesis in human neuronal-like cells and suggest a new physiological role for GnRH in the brain. PMID- 21296664 TI - The scavenger receptor CD36 contributes to the neurotoxicity of bone marrow derived monocytes through peroxynitrite production. AB - CD36, a class B scavenger receptor present in microglia, endothelium and leukocytes, plays a key role in ischemic brain injury by promoting the expression of inflammatory genes and production of reactive oxygen species (ROS). However, it is not known whether ischemic brain damage is mediated by CD36 activation in resident brain cells, i.e., microglia, or by blood-borne cells that infiltrate the brain. To address this question, we studied oxygen-glucose deprivation (OGD) in hippocampal slice cultures, a model of ischemic injury that does not involve cells extrinsic to the brain. We found that CD36 gene knockout does not afford protection of hippocampal slices to OGD-induced cytotoxicity. In contrast, immunoactivated bone marrow-derived monocytes-macrophages (BMM) from wild type (WT) mice trigger hippocampal damage when incubated with brain slices via a mechanism that is prevented in CD36-/- BMM. The neurotoxic activity of CD36+/+ BMM was attributed to reactive oxygen species (ROS) since it was concomitant with increased ROS production and could be prevented by treatment with a selective ROS scavenger, MnTBAP, or a peroxynitrite decomposition catalyst, FeTPPS. Importantly, ROS production and accumulation 3-nitrotyrosine in hippocampal proteins (a hallmark of peroxynitrite production) was significantly dampened in immunoactivated CD36-/- BMM, whereas production of NO-derived metabolites (nitrite and nitrate) was unaltered. We conclude that CD36 signaling may not contribute to injury induced by OGD in the brain itself but is involved in the neurotoxicity mediated by activated BMM. These findings are consistent with the hypothesis that CD36 in infiltrating inflammatory cells drives peroxynitrite mediated ischemic brain damage. Accordingly, targeting CD36 in the vascular compartment may protect against neurotoxicity in the ischemic brain. PMID- 21296665 TI - Alterations of white matter integrity related to motor activity in schizophrenia. AB - Altered structural connectivity is a key finding in schizophrenia, but the meaning of white matter alterations for behavior is rarely studied. In healthy subjects, motor activity correlated with white matter integrity in motor tracts. To explore the relation of motor activity and fractional anisotropy (FA) in schizophrenia, we investigated 19 schizophrenia patients and 24 healthy control subjects using Diffusion Tensor Imaging (DTI) and actigraphy on the same day. Schizophrenia patients had lower activity levels (AL). In both groups linear relations of AL and FA were detected in several brain regions. Schizophrenia patients had lower FA values in prefrontal and left temporal clusters. Furthermore, using a general linear model, we found linear negative associations of FA and AL underneath the right supplemental motor area (SMA), the right precentral gyrus and posterior cingulum in patients. This effect within the SMA was not seen in controls. This association in schizophrenia patients may contribute to the well known dysfunctions of motor control. Thus, structural disconnectivity could lead to disturbed motor behavior in schizophrenia. PMID- 21296666 TI - Calcium dysregulation, mitochondrial pathology and protein aggregation in a culture model of amyotrophic lateral sclerosis: mechanistic relationship and differential sensitivity to intervention. AB - The combination of Ca(2+) influx during neurotransmission and low cytosolic Ca(2+) buffering contributes to the preferential vulnerability of motor neurons in amyotrophic lateral sclerosis (ALS). This study investigated the relationship among Ca(2+) accumulation in intracellular compartments, mitochondrial abnormalities, and protein aggregation in a model of familial ALS (fALS1). Human SOD1, wild type (SOD1(WT)) or with the ALS-causing mutation G93A (SOD1(G93A)), was expressed in motor neurons of dissociated murine spinal cord-dorsal root ganglia (DRG) cultures. Elevation of mitochondrial Ca(2+) ([Ca(2+)](m)), decreased mitochondrial membrane potential (Deltapsi) and rounding of mitochondria occurred early, followed by increased endoplasmic reticular Ca(2+) ([Ca(2+)](ER)), elevated cytosolic Ca(2+) ([Ca(2+)](c)), and subsequent appearance of SOD1(G93A) inclusions (a consequence of protein aggregation). [Ca(2+)](c) was elevated to a greater extent in neurons with inclusions than in those with diffusely distributed SOD1(G93A) and promoted aggregation of mutant protein, not vice versa: both [Ca(2+)](c) and the percentage of neurons with SOD1(G93A) inclusions were reduced by co-expressing the cytosolic Ca(2+) buffering protein, calbindin D-28K; treatment with the heat shock protein inducer, geldanamycin, prevented inclusions but not the increase in [Ca(2+)](c), [Ca(2+)](m) or loss of Deltapsi, and inhibiting proteasome activity with epoxomicin, known to promote aggregation of disease-causing mutant proteins including SOD1(G93A), had no effect on Ca(2+) levels. Both expression of SOD1(G93A) and epoxomicin-induced inhibition of proteasome activity caused mitochondrial rounding, independent of Ca(2+) dysregulation and reduced Deltapsi. That geldanamycin prevented inclusions and mitochondrial rounding, but not Ca(2+) dysregulation or loss of Deltapsi indicates that chaperone-based therapies to prevent protein aggregation may require co-therapy to address these other underlying mechanisms of toxicity. PMID- 21296667 TI - Forebrain CRHR1 deficiency attenuates chronic stress-induced cognitive deficits and dendritic remodeling. AB - Chronic stress evokes profound structural and molecular changes in the hippocampus, which may underlie spatial memory deficits. Corticotropin-releasing hormone (CRH) and CRH receptor 1 (CRHR1) mediate some of the rapid effects of stress on dendritic spine morphology and modulate learning and memory, thus providing a potential molecular basis for impaired synaptic plasticity and spatial memory by repeated stress exposure. Using adult male mice with CRHR1 conditionally inactivated in the forebrain regions, we investigated the role of CRH-CRHR1 signaling in the effects of chronic social defeat stress on spatial memory, the dendritic morphology of hippocampal CA3 pyramidal neurons, and the hippocampal expression of nectin-3, a synaptic cell adhesion molecule important in synaptic remodeling. In chronically stressed wild-type mice, spatial memory was disrupted, and the complexity of apical dendrites of CA3 neurons reduced. In contrast, stressed mice with forebrain CRHR1 deficiency exhibited normal dendritic morphology of CA3 neurons and mild impairments in spatial memory. Additionally, we showed that the expression of nectin-3 in the CA3 area was regulated by chronic stress in a CRHR1-dependent fashion and associated with spatial memory and dendritic complexity. Moreover, forebrain CRHR1 deficiency prevented the down-regulation of hippocampal glucocorticoid receptor expression by chronic stress but induced increased body weight gain during persistent stress exposure. These findings underscore the important role of forebrain CRH-CRHR1 signaling in modulating chronic stress-induced cognitive, structural and molecular adaptations, with implications for stress-related psychiatric disorders. PMID- 21296668 TI - Autophagy failure in Alzheimer's disease--locating the primary defect. AB - Autophagy, the major degradative pathway for organelles and long-lived proteins, is essential for the survival of neurons. Mounting evidence has implicated defective autophagy in the pathogenesis of several major neurodegenerative diseases, particularly Alzheimer's disease (AD). A continuum of abnormalities of the lysosomal system has been identified in neurons of the AD brain, including pathological endocytic pathway responses at the very earliest disease stage and a progressive disruption of autophagy leading to the massive buildup of incompletely digested substrates within dystrophic axons and dendrites. In this review, we examine research on autophagy in AD and evaluate evidence addressing the specific step or steps along the autophagy pathway that may be defective. Current evidence strongly points to disruption of substrate proteolysis within autolysosomes for the principal mechanism underlying autophagy failure in AD. In the most common form of familial early onset AD, mutant presenilin 1 disrupts autophagy directly by impeding lysosomal proteolysis while, in other forms of AD, autophagy impairments may involve different genetic or environmental factors. Attempts to restore more normal lysosomal proteolysis and autophagy efficiency in mouse models of AD pathology have yielded promising therapeutic effects on neuronal function and cognitive performance, demonstrating the relevance of autophagy failure to the pathogenesis of AD and the potential of autophagy modulation as a therapeutic strategy. This article is part of a Special Issue entitled "Autophagy and protein degradation in neurological diseases." PMID- 21296669 TI - High frequency stimulation of the subthalamic nucleus impacts adult neurogenesis in a rat model of Parkinson's disease. AB - Chronic high frequency stimulation of the subthalamic nucleus (STN-HFS) efficiently alleviates motor symptoms of advanced Parkinson's disease (PD). Here, we looked for possible STN-HFS-induced changes on adult brain neurogenesis in the hippocampus and olfactory bulb that may be related to non-motor deficits associated to PD, such as mood disorders and olfaction deficits. Cell proliferation (Ki-67 immuno-positive-cells) and survival (bromodeoxyuridine (BrdU)-immuno-positive cells) were assessed in the subventricular zone-olfactory bulb continuum and the dentate gyrus of the hippocampus of hemiparkinsonian rats with or without continuous STN-HFS for 8 days. Dopamine lesion impaired cell proliferation and survival through different mechanisms, the effect on proliferation being correlated to the level of dopamine depletion whereas the effect on survival was not. Prolonged STN-HFS did not affect cell proliferation, but increased cell survival bilaterally. In these regions of constitutive neurogenesis, the percentage of new neuroblasts (BrdU-doublecortin-positive cells) was unchanged, suggesting that STN-HFS can lead to a net increase in newly formed neurons later on. STN-HFS also increased new cell survival in the striatum and promoted dopamine system recovery detected by tyrosine hydroxylase immunostaining. These data provide the first evidence that prolonged STN-HFS has a neurorestorative action and support the view that the action of this neurosurgical treatment can bypass the cortico-basal ganglia-thalamocortical loop circuits and largely impinge neuroplasticity and brain function. PMID- 21296670 TI - Molecular signature of hepatocellular carcinoma, hope or hype in prognosis and therapy. PMID- 21296671 TI - Solution NMR structure and dynamics of human apo-S100A1 protein. AB - S100A1 belongs to the EF-hand superfamily of calcium binding proteins. It is a representative of the S100 protein family based on amino acid sequence, three dimensional structure, and biological function as a calcium signal transmitter. It is a homodimer of noncovalently bound subunits. S100A1, like most of other members of the S100 protein family, is a multifunctional, regulatory protein involved in a large variety of biological processes and closely associated with several human diseases. The three-dimensional structure of human apo-(i.e. calcium free)-S100A1 protein was determined by NMR spectroscopy (PDB 2L0P) and its backbone dynamics established by 15N magnetic relaxation. Comparison of these results with the structure and backbone dynamics previously determined for bovine apo-S100A1 protein modified by disulfide formation with beta-mercaptoethanol at Cys 85 revealed that the secondary structure of both these proteins was almost identical, whereas the global structure of the latter was much more mobile than that of human apo-S100 protein. Differences between the structures of human and rat apo-S100A1 are also discussed. PMID- 21296672 TI - Dietary administration of beta-mercapto-ethanol treated Saccharomyces cerevisiae enhanced the growth, innate immune response and disease resistance of the rainbow trout, Oncorhynchus mykiss. AB - The effects of dietary whole cell yeast (Saccharomyces cerevisiae), n-3 HUFA enriched yeast and treated yeast cells with beta-mercapto-ethanol (2ME) on immunity, growth performance and disease resistance to Yersinia ruckeri were investigated in Oncorhynchus mykiss. During 30 days, juvenile rainbow trout were fed diets supplemented with different forms of yeast at 5 * 10(7) CFU g(-1) or a control diet. After the feeding trial, remaining fish of each treatment were challenged by pathogenic Yersinia ruckeri and kept under observation for 14 days to record clinical signs and daily mortality rate. Yeast supplementation in all treatment groups significantly promoted the growth performance compared to control group. A significantly increase was also observed in immune responses in juvenile fish fed 2ME-treated yeast diet. More ever, the lowest fish mortality was obtained in this treatment group. The present results show that a diet supplemented with 2ME-treated yeast stimulates the immune system and growth of juvenile rainbow trout thus enhancing their resistance against Y. ruckeri. PMID- 21296673 TI - Mitochondrial DNA diversification, molecular phylogeny, and biogeography of the primitive rhacophorid genus Buergeria in East Asia. AB - In this study we sought to clarify the evolutionary relationships and biogeographic history of the bell-ring frog, Buergeria buergeri (family Rhacophoridae), and two congeneric species Buergeria japonica and Buergeria robusta, by analyzing three mitochondrial (mt) genes: 12S rRNA, Cytb, and ND5. Phylogenetic analyses based on gene data showed the mt clades corresponding to the Buergeria species and three major haplogroups within B. buergeri. Each haplogroup corresponded clearly to the area in which it was distributed, namely eastern Japan (excluding Hokkaido; Hg I), central Japan (Hg II), and western Japan (including the Shikoku and Kyushu regions; Hg III). The estimated divergence time suggested that the lineage splits of the Buergeria species occurred before the formation of the island of Taiwan and the Japan Archipelago (including the Ryukyu islands). The differentiation among the genealogical lineages of B. buergeri seems to have begun in the Late Miocene (approx. 7-5Mya), and the formation of their present distribution pattern might have been influenced by climatic changes and geographical events such as the formation of a wide peneplane and expansions of certain basins. PMID- 21296674 TI - Mammalian intermediate-term memory: new findings in neonate rat. AB - The ability of anisomycin, a translation inhibitor, and actinomycin, a transcription inhibitor to disrupt a cAMP/PKA-dependent odor preference memory in neonate rat was examined. Previous reports in invertebrates had described a novel translation-dependent intermediate-term memory dissected with these inhibitors, but similar effects have not been reported in mammalian memory systems. When anisomycin was infused into the olfactory bulb after the pairing of peppermint odor and the beta-adrenoceptor agonist isoproterenol (2mg/kg), short-term memory (1 or 3h) was intact, but intermediate (5h) and long-term (24h) memory was disrupted. When actinomycin was infused, only long-term memory was disrupted. This pattern of results is consistent with that reported in invertebrates for intermediate-term memory and led us to try a lower level of the unconditioned stimulus (isoproterenol) to isolate intermediate-term memory from long-term memory. Pups given a dose of 1.5mg/kg isoproterenol paired with peppermint odor showed memory for peppermint 5h, but not 24h, after training. These observations in the rat pup olfactory system parallel short-, intermediate- and long-term memory characteristics previously described in invertebrates. Odor preference memory in neonate rodents offers a tool to increase our understanding of the properties and mechanisms of multi-phasic memory in mammals. PMID- 21296676 TI - Patterns of cough in the clinic. AB - Current guidelines for the management of cough highlight the value of a taking a careful history to establish specific features of the cough in particular its duration, typical triggers or aggravants and associated symptoms. Unfortunately the diagnostic yield from a history alone is poor and there is a need to understand the pattern of clinical cough in a more precise way. As the technology to record cough in ambulatory settings becomes more sophisticated so the possibility that precise measurement of the cough frequency, intensity and acoustic characteristics may offer diagnostically valuable information in individual patients becomes a reality. In this article the current knowledge of the clinical patterns of cough is discussed and the potential for new technology to record cough patterns in a meaningful way is considered. PMID- 21296675 TI - Reduced-intensity allogeneic transplantation provides high event-free and overall survival in patients with advanced indolent B cell malignancies: CALGB 109901. AB - Cancer and Leukemia Group B conducted a phase II study to evaluate the safety and efficacy of a reduced-intensity conditioning regimen with allogeneic transplantation to treat patients with recurrent low-grade B cell malignancies. Patients over age 18 with a diagnosis of relapsed, chemotherapy-sensitive disease underwent transplantation with a matched sibling donor, and conditioning with cyclophosphamide (1 g/m(2)/day * 3) and fludarabine phosphate (25 mg/m(2)/day * 5). Graft-versus-host prophylaxis included cyclosporine or tacrolimus plus low dose methotrexate. Forty-four evaluable patients with a median age of 53 and median of 2 prior regimens were accrued. Sixteen patients had follicular non Hodgkin lymphoma and 28 had histologies including 7 indolent B cell lymphomas, 4 mantle cell, 15 chronic lymphocytic leukemia (CLL), and 2 prolymphocytic leukemia (PLL) patients. The 6-month treatment-related mortality (TRM) was 2.4% and 3-year TRM was 9%. Three-year event-free and overall survival were 0.75 and 0.81 for the follicular patients, 0.59 and 0.71 for the CLL/PLL patients, and 0.55 and 0.64 for the other histologies. The incidence of grade II-IV acute graft-versus-host disease (GVHD) was 29%, and extensive chronic GVHD was 18%. This report demonstrates that allogeneic sibling transplantation with a reduced-intensity conditioning regimen is safe and efficacious for patients with advanced indolent B cell malignancies enrolled on a Cooperative Group study. PMID- 21296677 TI - Heat shock protein 104 inhibited the fibrillization of prion peptide 106-126 and disassembled prion peptide 106-126 fibrils in vitro. AB - Amyloid-like fibrils have been associated with the pathogenesis of human prion diseases. Prion peptide of aa 106-126 (PrP106-126) exhibits many PrP(Sc)-like biochemical features, forming amyloid-like fibrils in vitro. Here, we found that the recombinant yeast-derived molecular chaperon Hsp104 inhibited significantly the fibril assembly of the synthetic PrP106-126 peptide by dynamic ThT assays in vitro. EM assays revealed almost no fibril-like structure after incubation of the synthetic PrP106-126 peptides with Hsp104 for 12h. Circular dichroism assays identified that treatment of Hsp104 shifted the secondary structure of PrP106-126 fibrils from beta-sheet to a random coil. MTT tests confirmed that interaction of PrP106-126 with Hsp104 maintained the toxicity of PrP106-126 on human neuroblastoma cell line SK-N-SH. Additionally, Hsp104 was able to disassemble the mature PrP106-126 fibrils in vitro, leading to recovering the cytotoxicity of PrP106-126 on SK-N-SH cells. Our study provides the molecular evidences that the yeast-derived Hsp104 can interfere in the fibril assembly and disassembly of human PrP106-126 segment. PMID- 21296678 TI - Regulation of CXCL12 expression by canonical Wnt signaling in bone marrow stromal cells. AB - CXCL12 (stromal cell-derived factor-1, SDF-1), produced by stromal and endothelial cells including cells of the bone marrow, binds to its receptor CXCR4 and this axis regulates hematopoietic cell trafficking. Recently, osteoclast precursor cells were found to express CXCR4 and a potential role for the CXCL12 CXCR4 axis during osteoclast precursor cell recruitment/retention and development was proposed as a regulator of bone resorption. We examined the role of canonical Wnt signaling in regulating the expression of CXCL12 in bone marrow stromal cells. In mouse stromal ST2 cells, CXCL12 mRNA was expressed, while its expression was reduced in Wnt3a over-expressing ST2 (Wnt3a-ST2) cells or by treatment with lithium chloride (LiCl). Wnt3a decreased CXCL12 levels in culture supernatants from mouse bone marrow stromal cells. The culture supernatant from Wnt3a-ST2 cells also reduced migratory activity of bone marrow-derived cells in a Transwell migration assay. Silencing of glycogen synthase kinase-3beta decreased CXCL12 expression, suggesting that the canonical Wnt signaling pathway regulates CXCL12 expression. In a transfection assay, LiCl down-regulated the activity of a reporter gene, a 1.8kb fragment of the 5'-flanking region of the CXCL12 gene. These results show that canonical Wnt signaling regulates CXCL12 gene expression at the transcriptional level, and this is the first study linking chemokine expression to canonical Wnt signaling. PMID- 21296679 TI - Considerations on photochemical genotoxicity. II: report of the 2009 International Workshop on Genotoxicity Testing Working Group. AB - A workshop to reappraise the previous IWGT recommendations for photogenotoxicity testing [E. Gocke, L. Muller, P.J. Guzzie, S. Brendler-Schwaab, S. Bulera, C.F. Chignell, L.M. Henderson, A. Jacobs, H. Murli, R.D. Snyder, N. Tanaka, Considerations on photochemical genotoxicity: report of the International Workshop on Genotoxicity Test Procedures working group, Environ. Mol. Mutagen., 35 (2000) 173-184] was recently held as part of the 5th International Workshop on Genotoxicity Testing (IWGT) meeting in Basel, Switzerland (August 17-19, 2009). An Expert Panel was convened from regulatory, academic and industrial scientists (with several members serving on the original panel) and chaired by Dr Peter Kasper (BfArM, Germany). The aim of the workshop was to review progress made in photo(geno)toxicity testing over the past decade; a period which saw the introduction of several regulatory photosafety guidances in particular in Europe and the USA. Based on current regulatory guidelines a substantial proportion of compounds trigger the requirements for photosafety testing. Moreover, there has been growing concern within industry about the performance of the in vitro photosafety tests in the "real world" of compound development. Therefore, the expert group reviewed the status of the current regulatory guidance's and the impact these have had on compound development in the context of the various triggers for photosafety testing. In addition, the performance of photogenotoxicity assays (old and new) was discussed, particularly in view of reports of pseudophotoclastogencity. The Expert Panel finished with an assessment of the positioning of photogenotoxicity testing within a photosafety testing strategy. The most significant conclusion made by the Expert Panel was that photogenotoxicity testing should no longer be recommended as part of the standard photosafety testing strategy. In addition, progress was made on the refinement of triggers for photosafety testing. For example, there was support for harmonisation of methods to determine the Molar Extinction Coefficient (MEC) and a consensus agreement that there should be no requirement for testing of compounds with a MEC<1000Lmol(-1)cm(-1). PMID- 21296680 TI - Variability in intron sequences of housekeeping and antigen-coding genes among Schistosoma japonicum isolates in mainland China. AB - The accurate characterization of Schistosoma japonicum has important implications for analyzing genetic variation and would provide basic data for disease control. Previous studies using proteins, coding sequences, and especially antigen-coding genes showed lower genetic variation among S. japonicum isolates from mainland China. Therefore, the present study focused on variations in intron sequences of housekeeping and antigen-coding genes, which may be more informative for genetic analysis. We compared sequence variation between introns of two housekeeping genes and two antigen-coding genes. All 4 genes were polymorphic among all the S. japonicum isolates in mainland China, with 103, 158, 47, and 19 polymorphic (segregating) sites per kilobase in intron sequences of Actin, FBPA, 22.6kDa antigen and GST-26, respectively. Introns of housekeeping genes were slightly more polymorphic than coding and non-coding regions of antigen-coding genes examined in the present study within or among lake/marshland and mountainous types. Phylogenetic analysis based on sequences of single gene or combined sequences of multiple genes showed no specific clustering comprising parasites from single geographical or endemic regions. These results demonstrated that introns of housekeeping and antigen-coding genes were polymorphic, but the intron sequences examined in the present study were not suitable markers for examining genetic relationship among different isolates from endemic regions in mainland China. PMID- 21296681 TI - Overexpression of apolipoprotein O does not impact on plasma HDL levels or functionality in human apolipoprotein A-I transgenic mice. AB - Apolipoprotein (apo) O is a newly discovered apolipoprotein preferentially contained within HDL; however, currently, no data are available on the (patho)physiological effects of apoO. Therefore, the present study assessed the impact of apoO overexpression on (i) plasma lipids and lipoproteins as well as on (ii) HDL functionality. Human apoO was overexpressed by means of recombinant adenovirus (AdhapoO) in human apoA-I transgenic mice, a humanized mouse model of HDL metabolism. AdhapoO substantially increased apoO in plasma and within HDL. However, plasma triglycerides, phospholipids, total cholesterol and HDL cholesterol did not change. HDL size distribution, lipid composition and the apoA I and the apoO distribution over the different HDL fractions separated by FPLC remained unaltered. Furthermore, enrichment of HDL with apoO did not impact on HDL functionality assessed in four independent ways, namely (i) stimulation of cholesterol efflux from macrophage foam cells, (ii) protection against LDL oxidation, (iii) anti-inflammatory activity on endothelial cells, and (iv) induction of vasodilation in isolated aortic rings ex vivo as a measure of stimulating vascular NO production. These results demonstrate that although overexpression of apoO results in a substantial enrichment of HDL particles with this novel apolipoprotein, apoO does not impact the plasma lipoprotein profile or HDL functionality. PMID- 21296682 TI - Content-based histopathology image retrieval using a kernel-based semantic annotation framework. AB - Large amounts of histology images are captured and archived in pathology departments due to the ever expanding use of digital microscopy. The ability to manage and access these collections of digital images is regarded as a key component of next generation medical imaging systems. This paper addresses the problem of retrieving histopathology images from a large collection using an example image as query. The proposed approach automatically annotates the images in the collection, as well as the query images, with high-level semantic concepts. This semantic representation delivers an improved retrieval performance providing more meaningful results. We model the problem of automatic image annotation using kernel methods, resulting in a unified framework that includes: (1) multiple features for image representation, (2) a feature integration and selection mechanism (3) and an automatic semantic image annotation strategy. An extensive experimental evaluation demonstrated the effectiveness of the proposed framework to build meaningful image representations for learning and useful semantic annotations for image retrieval. PMID- 21296683 TI - Clinical utility of a novel wireless implantable loop recorder in the evaluation of patients with unexplained syncope. AB - BACKGROUND: The implantable loop recorder (ILR) is particularly useful for monitoring patients with syncope, given the episodic nature and unpredictable pattern of recurrent episodes. Current practice guidelines advocate ILR implantation in select patients with unexplained syncope. OBJECTIVE: The purpose of this study was to evaluate the clinical utility and potential advantages of a novel wireless ILR in a consecutive cohort of patients with unexplained syncope. METHODS: Patients with unexplained syncope despite a comprehensive evaluation who underwent implantation of a Transoma Medical Sleuth ILR were examined. ILR implantation was considered in these patients if left ventricular function was >= 40% and if syncope was recurrent, associated with trauma, and/or associated with an abnormal ECG (e.g., bifascicular block). RESULTS: The Sleuth ILR was implanted in 50 patients. During mean follow-up 293 +/- 211 days, 16 (32%) patients had recurrent near-syncope or syncope. Only half of the patients self-activated the ILR; in the other half, a diagnosis was established based on autoactivation initiated storage of a significant arrhythmia event. Overall, there were 5 patients with complete heart block, 3 with sinus node dysfunction, 3 with supraventricular tachycardia, 2 with neurally mediated syncope, and 3 with a nonarrhythmic cause of syncope. The median time from an event to physician notification was 150 minutes (interquartile range 99, 297 min). Median time from ILR implantation to final diagnosis was 71 days (interquartile range 24, 143 days; range 3-683 days). CONCLUSION: A diagnosis of syncope was ultimately made in nearly one third of patients with unexplained syncope. Patients frequently did not activate their ILR at the time of recurrent syncope. However, the wireless ILR automatically transferred ECG data to a central monitoring station within minutes to hours of the arrhythmic event, virtually eliminating the possibility of data loss, thus greatly facilitating clinical decision making. PMID- 21296684 TI - Toward specific cardiac I(K1) modulators for in vivo application: old drugs point the way. PMID- 21296685 TI - A wide QRS tachycardia in a left univentricular pacing system: what is the mechanism? PMID- 21296686 TI - Characteristics of multidrug-resistant Mycobacterium tuberculosis in Taiwan: a population-based study. AB - A population-based study was performed to characterize the genotype and drug resistant patterns of multidrug-resistant tuberculosis (MDR-TB) in Taiwan. From 2007 to 2008, we analyzed 494 MDR Mycobacterium tuberculosis complex isolates using spacer oligonucleotide typing and drug susceptibility testing. The majority of cases occurred in the age groups of 45-54 (24.3%) and >=65 (23.1%). Of the 494 MDR isolates, 25.1% were resistant to ethambutol, 15.6% were resistant to streptomycin, 27.1% were resistant to all four first-line anti-tuberculosis drugs, 28.9% were resistant to ofloxacin, and 8.7% were extensively drug resistant (XDR). Compared with the SpolDB4, 86 spoligotypes were identified in 492 isolates. We observed 427 (86.8%) isolates belonging to 49 known spoligotypes and 65 isolates (13.2%) in 37 undesignated spoligotypes. Beijing lineages (50.0%) were the predominant genotype, followed by Haarlem (18.2%) and East-African Indian (EAI) (5.7%). Geographically, Beijing lineages were predominant in all regions, whereas Haarlem lineages were predominant only in the east (28.1%) and EAI (11.3%) only in the south. Beijing lineages are statistically associated with MDR in younger age groups and eastern Taiwan. Furthermore, we found that Beijing ST1 (46.1%), Haarlem3 ST50 (7.1%) and ST742 (4.7%), and EAI2_MANILA ST19 (3.9%) were the prevalent groups. Thus, continuous surveillance with more thorough genotyping and epidemiological investigation is crucial for the prevention of further dissemination, the determination of the temporal and spatial trends of multi-drug resistance, and the emergence of XDR-TB in Taiwan. PMID- 21296687 TI - Mitochondrial dysfunction and genetic heterogeneity in chronic periodontitis. AB - We performed an extensive study on mitochondrial dysfunction in chronic periodontitis (CP). Electron microscopic analysis of gingival cells revealed abnormal mitochondria in 60% of the patients. Mitochondrial membrane potential and oxygen consumption of gingival cells were reduced by 4 fold and 5.8 fold, respectively; whereas ROS production was increased by 18%. The genetic analysis by complete mitochondrial DNA sequencing revealed the identification of 14 novel mutations only in periodontal tissues but not in the blood, suggesting a role of oxidative stress on periodontal tissues. Thus, our functional and genetic analysis provided an evidence for the mitochondrial dysfunction in CP. PMID- 21296688 TI - The embryonic brain and development of vagal pathways. AB - To regulate the autonomic function, the vagus nerve transfers various sensory information from peripheral organs, and appropriate motor reflexes are produced in the neural circuit. The functional development of the vagal pathway during the early phase of embryonic development has long been unclear. Optical recording with voltage-sensitive dyes has provided a new approach to the analysis of the functional development of the embryonic central nervous system. In this review, we present recent progress in optical studies on the vagal pathway in the embryonic chick and rat brainstems. The topics include how neural excitability is initially expressed in the motor and sensory nuclei [e.g. the dorsal motor nucleus of the vagus nerve (DMNV) and the nucleus of the tractus solitarius (NTS)] and how synapse networks are formed in the primary and higher-ordered sensory nuclei [e.g. the parabrachial nucleus (PBN)]. We also refer to the functional development of the glossopharyngeal nuclei and compare the developmental steps with those of the vagal nuclei. PMID- 21296689 TI - Commentary on: 'Predictors of length of stay in patients having elective colorectal surgery within an enhanced recovery protocol' Int J Surg 2010; 8: 628 32. PMID- 21296690 TI - Commentary on: Risk factors predictive of severe diverticular hemorrhage. International Journal of Surgery, in press. PMID- 21296691 TI - Epigenetic control of Agrobacterium T-DNA integration. AB - To genetically transform plants, Agrobacterium transfers its T-DNA into the host cell and integrates it into the plant genome, resulting in neoplastic growths. Over the past 2 decades, a great deal has been learned about the molecular mechanism by which Agrobacterium produces T-DNA and transports it into the host nucleus. However, T-DNA integration, which is the limiting, hence, the most critical step of the transformation process, largely remains an enigma. Increasing evidence suggests that Agrobacterium utilizes the host DNA repair machinery to facilitate T-DNA integration. Meanwhile, it is well known that chromatin modifications, including the phosphorylation of histone H2AX, play an important role in DNA repair. Thus, by implication, such epigenetic codes in chromatin may also have a considerable impact on T-DNA integration, although the direct evidence to demonstrate this hypothesis is still lacking. In this review, we summarize the recent advances in our understanding of Agrobacterium T-DNA integration and discuss the potential link between this process and the epigenetic information in the host chromatin. This article is part of a Special Issue entitled: Epigenetic Control of cellular and developmental processes in plants. PMID- 21296692 TI - Transcription factor Sp1 regulates basal transcription of the human DRG2 gene. AB - Developmentally regulated GTP-binding protein 2 (DRG2) is an evolutionarily conserved GTP-binding protein. DRG2 mRNA expression has been confirmed in many animal and human tissues. DRG2 is thought to play an essential role in the control of cell growth and differentiation. However, transcriptional regulation of DRG2 is largely unknown. To investigate the mechanisms controlling DRG2 expression, we cloned 1509bp of the 5'-flanking sequence of this gene. Deletion analysis showed that the region between -113 and -70 is essential for the basal level expression of the DRG2 gene in K562 human erythroleukemic cells. Mutation of a putative stimulating protein 1 (Sp1) regulatory site located at position 108 resulted in a significant decline in DRG2 promoter activity. Electrophoretic mobility shift assay and chromatin immunoprecipitation analysis revealed that Sp1 binds to this site. Knockdown of Sp1 expression using siRNA inhibited the promoter activation as well as the endogenous DRG2 transcriptional level. Taken together, these results demonstrate that basal expression level of DRG2 is regulated by the Sp1 transcription factor. PMID- 21296693 TI - Adverse events following pandemic influenza vaccine Pandemrix(r) reported in the French military forces--2009-2010. AB - BACKGROUND: In the face of the A(H1N1) 2009 influenza pandemic, in October 2009 the French military health service (SSA) initiated a large vaccination campaign with Pandemrix((r)) vaccine in the military forces. The aim of this study was to describe vaccine adverse events (VAE) reported during this campaign. METHODS: VAE and the number of people vaccinated were surveyed by the SSA Epidemiological network across all military forces during the campaign, from October 2009 to April 2010. For each case, a notification form was completed, providing patient and clinical information. Three types of VAE were considered: non-serious, serious and unexpected. RESULTS: There were 315.4 reported VAE per 100,000 vaccinations. Vaccination and VAE incidence rate peaks coincided with influenza epidemic peak in early December. The number of injected doses was 49,138, corresponding to a 14.5% vaccination coverage among military personnel, and 155 VAE were reported, including 5 serious VAE (1 Guillain-Barre syndrome, 2 malaises and 1 convulsive episode). Most VAE were non-serious (97.1%). Among these, 6 cases of local, rapidly regressive paresthesia were observed. DISCUSSION: The military VAE surveillance system constitutes the only observatory on benign VAE in France. The reporting rate was much higher after the pandemic vaccine than after the seasonal vaccine, which may be a reflection of stimulated reporting. This report provides a useful description of VAE among military personnel during a mass emergency vaccination program, showing that the tolerance of the pandemic vaccine appeared acceptable. PMID- 21296694 TI - Safety and immunogenicity of two freeze-dried Vero cell rabies vaccines for human use in post-exposure prophylaxis. AB - To provide basis for human rabies vaccination in China, the safety and immunogenicity of two freeze-dried Vero cell rabies vaccines for human use were assessed. A total of 250 volunteers were enrolled and divided into two groups: volunteers in Group A (n=200) were vaccinated five doses of Speeda Vero cell rabies vaccine manufactured by Liaoning Chengda Biotechnology Co. Ltd. on day 0, 3, 7, 14, 28 after exposure. Volunteers in Group B (n=50) were treated with Verorab Vero cell rabies vaccine manufactured by Sanofi Pasteur on the same schedule. The local and systematic adverse reactions were observed. Serum neutralizing antibody levels of 80 individuals in Group A and 50 individuals in Group B were tested with RFFIT on day 7, 14, 45, 180, 360 after the first dose. The seroconversion rates in Groups A and B were 40.3% and 37.0% on day 7 after the first dose, 95.5% and 97.7% on day 14, 100% and 100% on day 45, 100% and 100% on day 180, 89.1% and 89.5% on day 360 respectively, indicating no significant differences between the two groups. And no significant differences were found between the neutralizing antibody geometric mean titers (GMTs) of the two groups on day 7, 14, 45, 180 and 360 after the first dose, with the GMTs of day 14, 45, 180 and 360 all higher than 0.5IU/ml. Antibody levels of the two groups peaked around 2 weeks after the full vaccination program, followed by a 55% decrease up to day 180 and another 76% decrease up to day 360. Both groups experienced occasions of transient fever, rash, edema, and scleroma after vaccination. Neither group had any severe adverse reactions. It was concluded that both vaccines showed satisfactory safety and immunogenicity. Booster vaccination is recommended following another exposure after six months since the full vaccination program. PMID- 21296695 TI - Embelin ameliorates dextran sodium sulfate-induced colitis in mice. AB - Embelin has been used to treat fever, inflammatory diseases, and a variety of gastrointestinal ailments for thousands of years. Although reports indicate that embelin has anti-inflammatory and anti-tumor effects, its effects on ulcerative colitis have not been previously explored. The purpose of the present work was to evaluate the anti-inflammatory effect of embelin on dextran sulfate sodium (DSS) induced colitis. Experimental colitis was induced in BALB/c mice by dissolving 5% DSS in their drinking water for 7days. Embelin (10, 30 or 50mg/kg body weight) was administrated daily per oral route for 7days. Embelin significantly attenuated DSS-induced DAI scores and tissue MPO accumulation, which implied that it suppressed weight loss, diarrhea, gross bleeding, and the infiltrations of immune cells. Embelin administration also effectively and dose-dependently prevented shortening of colon length and enlargement of spleen size. Histological examinations indicated that embelin suppressed edema, mucosal damage, and the loss of crypts induced by DSS. Furthermore, embelin inhibited the abnormal secretions and mRNA expressions of pro-inflammatory cytokines, such as, TNF alpha, IL-1beta, and IL-6. These results suggest that embelin has an anti inflammatory effect at colorectal sites that is due to the down-regulations of the productions and expressions of inflammatory mediators, and that it may have therapeutic value in the setting of inflammatory bowel disease (IBD). PMID- 21296696 TI - Costunolide stimulates the function of osteoblastic MC3T3-E1 cells. AB - The effect of costunolide on the function of osteoblastic MC3T3-E1 cells was studied. Costunolide significantly increased the growth of MC3T3-E1 cells and caused a significant elevation of alkaline phosphatase (ALP) activity, collagen content, and mineralization in the cells (P<0.05). The effect of costunolide in increasing cell growth was completely prevented by the presence of ICI182780, LY294002, PD98059, rotlerin, or glibenclamide, suggesting that the effect of costunolide might be partly mediated from estrogen receptor (ER), PI3K, ERK, protein kinase C (PKC) and mitochondrial ATP-sensitive K(+) channel. The effect of costunolide in increasing ALP activity was prevented by the presence of ICI182780, PD98059, SB203580, or rotrelin, suggesting that the effect of costunolide on ALP activity might be mediated from ER, ERK, p38, and PKC. The effect of costunolide in increasing collagen content was prevented by the presence of LY294002, PD98059, SB203580, SP600125, or rotrelin, suggesting that the effect of costunolide on collagen synthesis might be mediated from PI3K, ERK, p38, JNK, and PKC. Moreover, cotreatment of ICI182780 or LY294002 inhibited costunolide-mediated upregulation of mineralization, suggesting that the induction of mineralization by costunolide is associated with increased activation of ER and PI3K. Our data indicate that the enhancement of osteoblast function by costunolide may result in the prevention for osteoporosis. PMID- 21296697 TI - Toll-like receptor 3 ligand polyinosinic:polycytidylic acid enhances autoimmune disease in a retinal autoimmunity model. AB - Viral components can trigger autoimmunity, but the involved mechanisms remain to be elucidated. Toll-like receptor 3 (TLR3) recognizes viral double-stranded RNA (dsRNA) and appears to play an important role in this context. Our previous studies showed that signaling of TLR2, TLR3, TLR4 and TLR9 is highly redundant in the adjuvant effect needed to induce experimental autoimmune uveitis (EAU), an animal model of human autoimmune eye disease. In this study, we analyzed the effects of systemic delivery of polyinosinic:polycytidylic acid (poly(I:C)), a mimic of viral dsRNA, in the induction of EAU. We found that TLR3 agonist poly(I:C) enhanced EAU scores, DTH responses and Ag-specific T cell proliferation. In addition, Ag-specific Interleukin 17 (IL-17) and interferon gamma (IFN-gamma) production by draining lymph node cells was markedly increased in the poly(I:C)-treated group. Our results suggest that activation of innate immune system mediated by TLR3 signaling pathway is of importance in the pathogenesis of virus-induced autoimmune diseases. PMID- 21296698 TI - Mobilized progenitor cells as a bridging therapy for radiation casualties: a brief review of tocopherol succinate-based approaches. AB - Nuclear detonation through either military or terrorist action would most likely lead to a mass-casualty scenario involving victims with varying degrees of exposure to ionizing radiation. As a result of radiation injury to the hematopoietic system, victims would suffer from a lack of red blood cells that deliver oxygen, immune cells that detect and eliminate infectious agents, and blood platelets that promote blood clot formation. In part, these symptoms are generally referred to as acute radiation syndrome (ARS). While some victims of moderate to high levels of radiation will be beyond saving, most will have received enough radiation to injure but not kill their bone marrow cells completely. Such people will recover from their injuries but face a 30-60day period during which they cannot fully fight infections and are prone to uncontrolled bleeding and anemia. To keep them alive until their hematopoietic system recovers, they must receive supportive care. Recently, using experimental animal models of ARS, transfusion of myeloid progenitor cells have been tried as a bridging therapy for radiation-exposed animals. Such cells have been shown to be effective in protecting animals exposed to lethal doses of radiation. These myeloid progenitors (along with of other hematopoietic progenitor cell types) can be mobilized out of the bone marrow into the blood for the reconstitution of hematopoiesis. This review discusses various approaches to the mobilization of progenitors using different mobilizing agents, and their utility as a bridging therapy for radiation casualties. We suggest that alpha-tocopherol succinate (TS) is an optimal mobilizing agent for progenitors. The extent of progenitor mobilization TS elicits in experimental mice is comparable to clinically used drugs such as recombinant granulocyte-colony stimulating factor rhG CSF/Neupogen(r) and the bicyclam AMD3100 (plerixafor/Mozobil); therefore, we propose that TS be considered for further translational development and, ultimately for use in humans. PMID- 21296699 TI - Treatment with N-methyl-D-aspartate receptor antagonist (MK-801) protects against oxidative stress in lipopolysaccharide-induced acute lung injury in the rat. AB - Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) are common syndromes that affect both clinical and surgical patients. This study describes the effects of a potent and specific N-methyl-d-aspartate receptor antagonist (MK-801) against oxidative stress in acute lung injury induced by intratracheal lipopolysaccharide (LPS) injection. This study was performed using male Wistar rats weighing 200-250g. Rats were randomly divided into four groups: control with isotonic saline instillation (n=6); LPS (100MUg/100g of body weight) treated with saline (n=6); LPS treated with MK-801 (0.3mg/kg, intraperitoneally; n=6); LPS treated with MK-801 (0.3mg/kg, intratracheally; n=6). Twelve hours after the LPS instillation, rats were anesthetized and a bronchoalveolar lavage (BAL) was performed in order to determine the alveolar-capillary membrane alterations and the inflammatory infiltrate level. Blood and lung samples were isolated and assayed for oxidative stress variables and histopathologic analysis. The use of MK-801 decreased bronchoalveolar lavage fluid protein, LDH activity and inflammatory cells. Indeed, the treatment with MK-801 significantly attenuated lung oxidative damage and histopathologic alterations after LPS instillation. Our data provide the first experimental demonstration that MK-801 decreases oxidative stress and limits inflammatory response and alveolar disarray in lipopolysaccharide-induced acute lung injury. PMID- 21296700 TI - Remote sensing of heart rate and patterns of respiration on a stationary subject using 94-GHz millimeter-wave interferometry. AB - Using continuous wave, 94-GHz millimeter-wave interferometry, a signal representing chest wall motion can be obtained that contains both the heart rate and respiration patterns of a human subject. These components have to be separated from each other in the received signal. Our method was to use the quadrature and in-phase components of the signal, after removing the mean of each, to find the phase, unwrap it, and convert it to a displacement measurement. Using this, the power spectrum was examined for peaks, which corresponded to the heart rate and respiration rate. The displacement waveform of the chest was also analyzed for discrete heartbeats using a novel wavelet decomposition technique. PMID- 21296701 TI - Open- and closed-loop multiobjective optimal strategies for HIV therapy using NSGA-II. AB - In this paper, multiobjective open- and closed-loop optimal treatment strategies for HIV/AIDS are presented. It is assumed that highly active antiretroviral therapy is available for treatment of HIV infection. Amount of drug usage and the quality of treatment are defined as two objectives of a biobjective optimization problem, and Nondominated Sorting Genetic Algorithm II is used to solve this problem. Open- and closed-loop control strategies are used to produce optimal control inputs, and the Pareto frontiers obtained from these two strategies are compared. Pareto frontier, resulted from the optimization process, suggests a set of treatment strategies, which all are optimal from a perspective, and can be used in different medical and economic conditions. Robustness of closed-loop system in the presence of measurement noises is analyzed, assuming various levels of noise. PMID- 21296702 TI - Identification and control for automated regulation of hemodynamic variables during hemodialysis. AB - This paper proposes a novel model-based control methodology for a computer controlled hemodialysis system, designed to maintain the hemodynamic stability of end-stage renal failure patients undergoing fluid removal during hemodialysis. The first objective of this paper is to introduce a linear parameter varying system to model the hemodynamic response of patients during hemodialysis. Ultrafiltration rate (UFR) and dialysate sodium concentration (DSC) are imposed as the inputs, and the model computes the relative blood volume (RBV), percentage change in heart rate ( ?HR), and systolic blood pressure (SBP) during the course of hemodialysis. The model parameters were estimated based on data collected from 12 patients undergoing 4 profiled hemodialysis sessions. The modeling results demonstrated that the proposed model could be useful for estimating the individual patient's hemodynamic behavior during hemodialysis. Based on the model, the second objective is to implement a computer-controlled hemodialysis system for the regulation of RBV and HR during hemodialysis while maintaining SBP within stable range. The proposed controller is based on a model predictive control approach utilizing pre-defined constraints on the control inputs (UFR and DSC) as well as the output (SBP). The designed control system was experimentally verified on four patients. The results demonstrated that the proposed computer controlled hemodialysis system regulated the RBV and HR of the patients according to individual reference profiles with an average mean square error of 0.24% and 2.6%, respectively, and thus can be potentially useful for ensuring the stability of patients undergoing hemodialysis by avoiding sudden changes in hemodynamic variables. PMID- 21296703 TI - Computerized classification of intraductal breast lesions using histopathological images. AB - In the diagnosis of preinvasive breast cancer, some of the intraductal proliferations pose a special challenge. The continuum of intraductal breast lesions includes the usual ductal hyperplasia (UDH), atypical ductal hyperplasia (ADH), and ductal carcinoma in situ (DCIS). The current standard of care is to perform percutaneous needle biopsies for diagnosis of palpable and image-detected breast abnormalities. UDH is considered benign and patients diagnosed UDH undergo routine follow-up, whereas ADH and DCIS are considered actionable and patients diagnosed with these two subtypes get additional surgical procedures. About 250,000 new cases of intraductal breast lesions are diagnosed every year. A conservative estimate would suggest that at least 50% of these patients are needlessly undergoing unnecessary surgeries. Thus, improvement in the diagnostic reproducibility and accuracy is critically important for effective clinical management of these patients. In this study, a prototype system for automatically classifying breast microscopic tissues to distinguish between UDH and actionable subtypes (ADH and DCIS) is introduced. This system automatically evaluates digitized slides of tissues for certain cytological criteria and classifies the tissues based on the quantitative features derived from the images. The system is trained using a total of 327 regions of interest (ROIs) collected across 62 patient cases and tested with a sequestered set of 149 ROIs collected across 33 patient cases. An overall accuracy of 87.9% is achieved on the entire test data. The test accuracy of 84.6% is obtained with borderline cases (26 of the 33 test cases) only, when compared against the diagnostic accuracies of nine pathologists on the same set (81.2% average), indicates that the system is highly competitive with the expert pathologists as a stand-alone diagnostic tool and has a great potential in improving diagnostic accuracy and reproducibility when used as a "second reader" in conjunction with the pathologists. PMID- 21296704 TI - Enhanced functional brain imaging by using adaptive filtering and a depth compensation algorithm in diffuse optical tomography. AB - Reflectance diffuse optical tomography (rDOT) of brain function is limited by its high sensitivity to the superficial tissues (i.e., the scalp and skull) and by its severe decrease in measurement sensitivity with increased depth. Significant interference in rDOT results from spontaneous fluctuations that are embedded in both the superficial tissues and brain, such as arterial pulsation and vasomotion. In this study, first we investigate coherence and phase shift of the spontaneous fluctuations in the resting state, within the superficial tissues and at various depths of the brain, respectively. We demonstrate that the spontaneous fluctuations originating from arterial pulsations ( ~ 1 Hz) are spatially global and temporally coherent, while the fluctuations originating from vasomotion ( ~ 0.1 Hz) tend to have less coherence with increased depth. Second, adaptive cancellation of spontaneous fluctuations with a frequency-specific strategy is utilized and validated in both resting and activation (evoked by a finger-tapping task) states. Third, improved depth localization of motor activation in reconstructed rDOT images is achieved by combining adaptive cancellation with a depth compensation algorithm that we recently reported. PMID- 21296705 TI - Perception-based visualization of manifold-valued medical images using distance preserving dimensionality reduction. AB - A method for visualizing manifold-valued medical image data is proposed. The method operates on images in which each pixel is assumed to be sampled from an underlying manifold. For example, each pixel may contain a high dimensional vector, such as the time activity curve (TAC) in a dynamic positron emission tomography (dPET) or a dynamic single photon emission computed tomography (dSPECT) image, or the positive semi-definite tensor in a diffusion tensor magnetic resonance image (DTMRI). A nonlinear mapping reduces the dimensionality of the pixel data to achieve two goals: distance preservation and embedding into a perceptual color space. We use multidimensional scaling distance-preserving mapping to render similar pixels (e.g., DT or TAC pixels) with perceptually similar colors. The 3D CIELAB perceptual color space is adopted as the range of the distance preserving mapping, with a final similarity transform mapping colors to a maximum gamut size. Similarity between pixels is either determined analytically as geodesics on the manifold of pixels or is approximated using manifold learning techniques. In particular, dissimilarity between DTMRI pixels is evaluated via a Log-Euclidean Riemannian metric respecting the manifold of the rank 3, second-order positive semi-definite DTs, whereas the dissimilarity between TACs is approximated via ISOMAP. We demonstrate our approach via artificial high-dimensional, manifold-valued data, as well as case studies of normal and pathological clinical brain and heart DTMRI, dPET, and dSPECT images. Our results demonstrate the effectiveness of our approach in capturing, in a perceptually meaningful way, important features in the data. PMID- 21296706 TI - Aligning scan acquisition circles in optical coherence tomography images of the retinal nerve fibre layer. AB - Optical coherence tomography (OCT) is widely used in the assessment of retinal nerve fibre layer thickness (RNFLT) in glaucoma. Images are typically acquired with a circular scan around the optic nerve head. Accurate registration of OCT scans is essential for measurement reproducibility and longitudinal examination. This study developed and evaluated a special image registration algorithm to align the location of the OCT scan circles to the vessel features in the retina using probabilistic modelling that was optimised by an expectation-maximization algorithm. Evaluation of the method on 18 patients undergoing large number of scans indicated improved data acquisition and better reproducibility of measured RNFLT when scanning circles were closely matched. The proposed method enables clinicians to consider the RNFLT measurement and its scan circle location on the retina in tandem, reducing RNFLT measurement variability and assisting detection of real change of RNFLT in the longitudinal assessment of glaucoma. PMID- 21296707 TI - Voxel-based adaptive spatio-temporal modelling of perfusion cardiovascular MRI. AB - Contrast enhanced myocardial perfusion magnetic resonance imaging (MRI) is a promising technique, providing insight into how reduced coronary flow affects the myocardial tissue. Stenosis in a coronary vessel leads to reduced myocardial blood flow, but collaterals may secure the blood supply of the myocardium, with altered tracer kinetics. Due to a low signal-to-noise ratio, quantitative analysis of the signal is typically difficult to achieve at the voxel level. Hence, analysis is often performed on measurements that are aggregated in predefined myocardial segments, that ignore the variability in blood flow in each segment. The approach presented in this paper uses local spatial information that enables one to perform a robust analysis at the voxel level. The spatial dependencies between local response curves are modelled via a hierarchical Bayesian model. In the proposed framework, all local systems are analyzed simultaneously along with their dependencies, producing a more robust context driven estimation of local kinetics. Detailed validation on both simulated and patient data is provided. PMID- 21296708 TI - Video time encoding machines. AB - We investigate architectures for time encoding and time decoding of visual stimuli such as natural and synthetic video streams (movies, animation). The architecture for time encoding is akin to models of the early visual system. It consists of a bank of filters in cascade with single-input multi-output neural circuits. Neuron firing is based on either a threshold-and-fire or an integrate and-fire spiking mechanism with feedback. We show that analog information is represented by the neural circuits as projections on a set of band-limited functions determined by the spike sequence. Under Nyquist-type and frame conditions, the encoded signal can be recovered from these projections with arbitrary precision. For the video time encoding machine architecture, we demonstrate that band-limited video streams of finite energy can be faithfully recovered from the spike trains and provide a stable algorithm for perfect recovery. The key condition for recovery calls for the number of neurons in the population to be above a threshold value. PMID- 21296709 TI - m-SNE: Multiview Stochastic Neighbor Embedding. AB - Dimension reduction has been widely used in real-world applications such as image retrieval and document classification. In many scenarios, different features (or multiview data) can be obtained, and how to duly utilize them is a challenge. It is not appropriate for the conventional concatenating strategy to arrange features of different views into a long vector. That is because each view has its specific statistical property and physical interpretation. Even worse, the performance of the concatenating strategy will deteriorate if some views are corrupted by noise. In this paper, we propose a multiview stochastic neighbor embedding (m-SNE) that systematically integrates heterogeneous features into a unified representation for subsequent processing based on a probabilistic framework. Compared with conventional strategies, our approach can automatically learn a combination coefficient for each view adapted to its contribution to the data embedding. This combination coefficient plays an important role in utilizing the complementary information in multiview data. Also, our algorithm for learning the combination coefficient converges at a rate of O(1/k(2)), which is the optimal rate for smooth problems. Experiments on synthetic and real data sets suggest the effectiveness and robustness of m-SNE for data visualization, image retrieval, object categorization, and scene recognition. PMID- 21296710 TI - A Deep-Cutting-Plane Technique for Reverse Convex Optimization. AB - A large number of problems in engineering design and in many areas of social and physical sciences and technology lend themselves to particular instances of problems studied in this paper. Cutting-plane methods have traditionally been used as an effective tool in devising exact algorithms for solving convex and large-scale combinatorial optimization problems. Its utilization in nonconvex optimization has been also promising. A cutting plane, essentially a hyperplane defined by a linear inequality, can be used to effectively reduce the computational efforts in search of a global solution. Each cut is generated in order to eliminate a large portion of the search domain. Thus, a deep cut is intuitively superior in which it will exclude a larger set of extraneous points from consideration. This paper is concerned with the development of deep-cutting plane techniques applied to reverse-convex programs. An upper bound and a lower bound for the optimal value are found, updated, and improved at each iteration. The algorithm terminates when the two bounds collapse or all the generated subdivisions have been fathomed. Finally, computational considerations and numerical results on a set of test problems are discussed. An illustrative example, walking through the steps of the algorithm and explaining the computational process, is presented. PMID- 21296711 TI - A Validity Index for Prototype-Based Clustering of Data Sets With Complex Cluster Structures. AB - Evaluation of how well the extracted clusters fit the true partitions of a data set is one of the fundamental challenges in unsupervised clustering because the data structure and the number of clusters are unknown a priori. Cluster validity indices are commonly used to select the best partitioning from different clustering results; however, they are often inadequate unless clusters are well separated or have parametrical shapes. Prototype-based clustering (finding of clusters by grouping the prototypes obtained by vector quantization of the data), which is becoming increasingly important for its effectiveness in the analysis of large high-dimensional data sets, adds another dimension to this challenge. For validity assessment of prototype-based clusterings, previously proposed indexes mostly devised for the evaluation of point-based clusterings-usually perform poorly. The poor performance is made worse when the validity indexes are applied to large data sets with complicated cluster structure. In this paper, we propose a new index, Conn_Index, which can be applied to data sets with a wide variety of clusters of different shapes, sizes, densities, or overlaps. We construct Conn_Index based on inter- and intra-cluster connectivities of prototypes. Connectivities are defined through a "connectivity matrix", which is a weighted Delaunay graph where the weights indicate the local data distribution. Experiments on synthetic and real data indicate that Conn_Index outperforms existing validity indices, used in this paper, for the evaluation of prototype based clustering results. PMID- 21296712 TI - Occupational solvent exposure and brain function: an fMRI study. AB - BACKGROUND: Deficits in cognitive function have been demonstrated among workers chronically exposed to solvents, but the neural basis for these deficits has not been shown. OBJECTIVES: We used functional magnetic resonance imaging (fMRI) to compare pathophysiological changes in brain function between solvent-exposed and control workers. METHODS: Painters, drywall tapers, and carpenters were recruited from the International Union of Painters and Allied Trades, District Council 9 in New York City and District Council 21 in Philadelphia, Pennsylvania, and from the Carpenters Union in New Jersey. Twenty-seven solvent-exposed and 27 control subjects of similar age, education, and occupational status completed the N-Back working memory test during fMRI. After controlling for confounders (age; lifetime marijuana, cocaine, and alcohol use; blood lead; symptoms of depression; verbal intelligence), voxelwise group analysis and regional activation levels were compared and then correlated with an index of lifetime solvent exposure. RESULTS: Solvent-exposed workers' performance on the N-Back was significantly worse than that of controls. Activation of the anterior cingulate, prefrontal, and parietal cortices--areas serving working memory function and attention--was also significantly lower for solvent-exposed workers relative to controls. After controlling for confounders, we observed a negative correlation between lifetime solvent exposure and activation in these same regions among the solvent-exposed workers. CONCLUSIONS: This study is one of the few to document neural structures affected by exposure to solvents. Our findings provide a biological mechanism for the neurobehavioral deficits in working memory and attention that have previously been reported by other groups studying the effects of chronic exposure to solvents. These imaging markers, which are consistent with the neurobehavioral measures in our subject population, are consistent with altered brain pathology caused by prolonged exposure to solvent mixtures during construction work. PMID- 21296713 TI - [Prevalence of malnutrition in institutionalized intellectually disabled patients]. AB - As patients with intellectual and developmental disability (ID) may be more exposed to unfavorable factors, they are at higher risk of suffering nutritional alterations. Our objective was to determine prevalence of malnutrition in institutionalized patients with ID. An evaluation of the nutritional status through determination of transversal anthropometric parameters of weight (kg) and height (cm) was made on 614 individuals (352 men and 262 women) institutionalized at Colonia Nacional Montes de Oca, Buenos Aires Province, Argentina. Body mass index and prevalence of underweight, overweight and obesity cases by sex and ID type: mild, moderate and severe intellectual disability were determined. Regardless of sex, prevalence of underweight, overweight and obesity were of 2.9%, 30% and 27.7%, respectively. Regardless of degree of ID, greater prevalence of obesity (41.2%) was found amongst women, while overweight (34.7%) was more frequent amongst men. Taking the degree of ID and regardless of sex, greater prevalence of underweight was observed in severe ID, and overweight and obesity amongst mild ID. No any of the patients with mild ID presented underweight. Taking into account sex and ID, higher prevalence of underweight and overweight were observed amongst men with mild ID, (7% and 38.4%, respectively) and of obesity in women with moderate ID (44%). Results obtained would indicate the importance of caloric intake and energy consumption control in adults with ID, paying particular attention to life conditions and alimentary disorders in terms of the degree of ID and their multiple associated disabilities. PMID- 21296714 TI - [Optimizing iron therapy in hemodialysis: a prospective long term clinical study]. AB - The usefulness of intravenous iron therapy in hemodialysis is evidence-based. However, controversy still arises about the most suitable iron marker to optimize this treatment in the long term. We aimed to determine the most suitable marker with a prospective, cohort study, designed to comprise a basal period (BP) and two consecutive experimental periods (PI, PII). Low molecular weight iron dextran was infused at 100, 150 and 200 mg/month respectively, on a biweekly basis, during 6 months. At the end of each period, the following were determined: transferrin saturation (TSAT), ferritin (FERR), percentage of hypochromic eritrocytes (HYPO) and haemoglobin content in reticulocytes (HCr). During the study, albumin increased significantly, whereas no significant changes in hemoglobin, EPO doses and C-reactive protein were observed. Changes in HYPO and FERR were unspecific. Only TSAT (from 21.4 +/- 6 in PB to 34 +/- 7.1% in PII, p < 0.01) and HCr (from 27.5 +/- 1.3 in PB to 29.3 +/- 1.7 pg in PII, P < 0.05 ) responded specifically to changes in Fe doses, but change of TSAT was 65% (CI 95% 22), whereas change of HCr was just 6% (CI 95% 2.3; p = 0.0002). The difference was observed in all patients. Results suggest that 200 mg/FeIV/month is effective and that, of the markers tested in this study, TSAT would be the most suitable one to the practicing nephrologist to optimize intravenous iron in the long term. PMID- 21296715 TI - Breast cancer and the stromal factor. The "prometastatic healing process" hypothesis. AB - The correlation between axillary status and several histological features of breast carcinomas has been well established, however stromal changes have rarely been analyzed. Detailed clinicopathological review of 1803 patients with infiltrating breast carcinoma was performed. Stromal myxoid changes (SMC), size (T2-T3: > 2 cm, T1c: 1-2 cm, T1 a-b: < 1cm), fibrotic focus, age, lymphovascular embolizations, tumor infiltrating lymphocytes (TIL), multifocality, histological grade (G), estrogen receptors (ER), progesterone receptors (PR) and HER2 were semi-quantitated in two or three grades and correlated to axillary status. SMC3 followed by T2-T3, G3, fibrotic focus, T1c, embolizations, SMC2, TIL2, G2 and multifocality were strongly associated with positive axillary nodes; an inverse association was found with ER+++ and PR+++. Our findings support a critical role of the peritumoral stroma in the development of metastases. These stromal alterations should be remarked in routine pathology reports as they can be easily assessed and provide important information about tumor biology and aggressiveness. They could also become, in a future, the target of novel therapeutics. PMID- 21296716 TI - [Distribution of Lutzomyia longipalpis in the Argentine Mesopotamia, 2010]. AB - The first case of visceral leishmaniasis (VL) in Argentina was reported in 2006 in Posadas, Misiones. During the summer 2008-2009 Lutzomyia longipalpis, the VL vector, and canine VL cases were already spread along the province of Corrientes. In order to know the distribution of VL risk, systematic captures of the vector were performed between February and March 2010, in 18 areas of the provinces of Entre Rios and Corrientes, and the city of Puerto Iguazu, Misiones, with a total of 313 traps/night. We confirmed the presence of Lu. longipalpis, for the first time in Chajari (Entre Rios), Alvear, La Cruz, Curuzu Cuatia and Bella Vista (Corrientes), and Puerto Iguazu (Misiones). In Santo Tome and Monte Caseros (Corrientes), where the vector had been previously reported, traps with more samples were obtained with 830 and 126 Lu. Longipalpis trap/site/night respectively. These results show that the vector of urban VL continues spreading in the Argentine territory. Simultaneously, the spread of the parasite and the resulting human VL cases are associated with the dispersion of reservoirs, infected dogs, with or without clinical symptoms or signs, due to human transit. PMID- 21296717 TI - [Mechanical ventilation. Influence of the age in the outcome]. AB - There is not consensus about the true influence of age on mortality associated to mechanical ventilation (MV). We performed a prospective study in order to determine if age is an independent factor to predict mortality in patients under MV. Two hundred patients requiring MV at the intensive care unit were included and clinical variables at admission, co-morbidities, complications and outcome at the hospital and after 6 months were registered. Patients were divided in 2 groups: Group 1 (n = 164) under 80 year old and Group 2 (n = 36) 80 year or older. There were no differences in intensive care unit or hospital mortality between the two groups (55.56% vs. 41.46% and 58.33% vs. 42.68%). Six-month survival were significantly lower in patients over 80 year-old (22.22% vs. 48.17%, p = 0.0051). Multivariate analysis showed that only an APACHE II score > 20 (p = 0.0077) or the absence of an autonomous life (p = 0.0028) were independent predictive factors of mortality. Elderly patients under mechanical ventilation do not show a higher mortality because of the advance age in itself. Restriction of mechanical ventilation and invasive care does not seem to be justified based on the advanced age. PMID- 21296718 TI - [RAC3 overexpression is a transforming and proliferative signal that contributes to tumoral development]. AB - RAC3 has been firstly characterized as a nuclear receptor coactivator that is found in limited amounts in normal cells, but is over-expressed in tumors and is also an NF-kB coactivator. Although the mechanisms involved in its over expression are not clear, it is well known that it enhances resistance to apoptosis. In this work, we investigated if there are any additional mechanisms by which RAC3 may contribute to tumor development and if TNF-a, an inflammatory cytokine that is found at high levels in cancer could increase RAC3 levels. We found that enhancement of RAC3 levels by transfection of HEK293 cells with a RAC3 expression vector induces a significant increase of cell proliferation not only in the presence, but also in the absence of serum growth factors. Moreover, the cells were transformed showing an anchorage independent growth, similar to that observed in tumoral cells. The treatment of HEK293 cells with TNF-a induced an increase in the protein levels of RAC3 and this was blocked by an NF-kB specific inhibitor, suggesting that this transcription factor is involved in the cytokine effect. We conclude that RAC3, in addition to is anti-apoptotic action, is a transforming factor that promotes the proliferation and growth independent of anchorage, and that its levels could be elevated by the action of inflammatory cytokines that are involved in the anti-tumoral response. PMID- 21296719 TI - [A case of melioidosis in Argentina]. AB - We describe a case of 17-year- old man native of Dominican Republic, with Hodgkin's lymphoma, who presented soft espontaneous draining nodules. In the clinical samples grew Burkholderia pseudomallei; the etiological agent of melioidosis. He received antimicrobial treatment with imipenem and amoxicillin/clavulanic with very good clinical evolution of the infectious process. Melioidosis diagnosis could be underestimated due to the low incidence of Burkholderia pseudomallei in our continent. The definitive diagnosis depends of the isolation and identification in the clinical sample. PMID- 21296720 TI - [Otomastoiditis as an initial clinical manifestation of Wegener's granulomatosis]. AB - Wegener's granulomatosis (WG) forms part of a group of primary vasculitis of the small and medium-sized blood vessels, associated with antineutrophil cytoplasmic antibodies (ANCA). This disease may affect any body organ, especially the upper and lower airways and the kidneys. Hardly ever is otomastoiditis the first and only clinical manifestation of generalized Wegener's granulomatosis. We present the case of a patient whose disease started with the inflammation of the middle ear, which was unresponsive to the usual treatment. Later he developed nasal, pulmonary and renal compromise. The determination of ANCA and a transbronchial biopsy confirmed the diagnosis of WG. We report this case to express the view that otomastoiditis in adults, which is refractory to the usual treatment, may seldom be the first and only clinical manifestation of WG. PMID- 21296721 TI - [Hypothyroidism, dilated cardiomyopathy and nephrotic syndrome during pregnancy]. AB - Hypothyroidism during pregnancy is infrequent, but its presence is associated with maternal and fetal complications. We present the case of a young pregnant woman with no previous history of cardiovascular disease, who consulted for orthopnea, chest pain and edema in both legs. Laboratory tests demonstrated a hypothyroid condition and a nephrotic syndrome with renal failure. The echo Doppler exam showed a four chamber dilatation with systolic dysfunction. Treatment with intravenous levothyroxine improved her medical condition. We analyze the effects of thyroid hormone on the heart and vascular system and discuss the pathophysiologic mechanisms of heart failure during pregnancy. PMID- 21296722 TI - [Quadrilateral space syndrome with compromise of the teres minor muscle]. PMID- 21296723 TI - [Tree-in-bud sign]. PMID- 21296724 TI - [Biomedicine philately]. AB - Biomedicine is a vast field in philately or stamp collecting. It opens the topic the image of the goddess Hygeia, issued in a stamp from Nevis Island dated 1861. The first physicians to appear printed in stamps, in 1869, were three American constitutionalists, but only in 1937 there appear Dutch physicians as an acknowledgement of their contribution to public health. In Argentina the first stamp officially related to the topic was issued in 1944, to raise funds for the victims of the San Juan earthquake. Florentino Ameghino was the first scientist included in 1954, and in 1967 a stamp was issued in honour of Dr. Cecilia Grierson. Afterwards, Argentinean philately has recognized several of our scientists and physicians, congresses, universities, health campaigns, dentistry topics, chemistry, and nursery, among others, promoting a large amount of philatelic material in acknowledgement of the social value that Argentinean biomedical science has gained locally and abroad. Probably, it is a scientist, Dr. Bernardo Houssay, the Argentinean who has more often appeared in international philately. PMID- 21296725 TI - [Organ transplants in HIV infected patients. Update and recommendations]. AB - Until few years ago, HIV infection was an absolute contraindication to consider organ transplants. Since HAART introduction, patient survival increased dramatically, but high mortality due to liver and kidney diseases became evident. For these reasons, this group of patients is now reconsidered for organ transplantation. In 2008, the Argentine Society of Transplants (SAT) and the Argentine Infectious Diseases Society (SADI), encouraged by the increasing published experience on kidney and liver transplants in this population, decided to form a Working Group, to prepare an update on this issue and elaborate practical recommendations for the better management of these patients. The first meeting was held on December 4th 2008. The most important conclusion was that HIV infection did not contraindicate a solid organ transplant. Later on, taking into account the accumulated experience and the available literature, the current document was prepared. HIV infected patients must fulfill certain clinical, immunological, virological and psychosocial criteria to be considered for solid organ transplants. HIV infected recipients of kidney and liver transplants currently show similar short and middle term survival to non HIV infected patients. There is not yet enough data on intrathoracic transplants in these patients in order to include them on a waiting list for these organs-transplants. Interactions between immunosupressors and antiretroviral drugs (specially protease inhibitors) are very important, and require a strict monitoring of immunosupressor levels. PMID- 21296726 TI - ["Malnutrition-inflammation complex syndrome" in chronic hemodialysis]. AB - Protein-energy wasting (PEW) and inflammation are usually common and concurrent conditions in maintenance dialysis patients and associated with poor prognosis. Low appetite and hypercatabolic states are common features. In dialysis patients, the former has been suggested to be secondary to inflammation; however, the evidence is not conclusive. Hence, the term malnutrition-inflammation complex syndrome (MICS) was coined to include this clinical entity, regardless the original causes. Possible causes of MICS include comorbid illnesses, oxidative stress, nutrient loss through dialysis, hyporexia, uremic toxins, decreased clearance of inflammatory cytokines, volume overload, increased blood phosphate and dialysis-related factors. MICS is believed to be the main cause of erythropoietin hypo-responsiveness, cardiovascular atherosclerotic disease, decreased quality of life, hospitalization and increased mortality in dialysis patients. Because MICS leads to a low body mass index, hypocholesterolemia, decrease in muscle mass, hypocreatininemia and hypohomocysteinemia, a "reverse epidemiology" phenomenon of cardiovascular risk factors can occur in dialysis patients. Therefore, obesity, hypercholesterolemia, and increased blood levels of creatinine and homocysteine, within certain limits, appear to be protective and paradoxically associated with a better outcome. There is no consensus about how to determine the degree of severity of MICS or how to manage it. Several diagnostic tools and treatment modalities are discussed in this paper. The correct management of MICS may diminish the cardiovascular disease, main cause of death in this population. PMID- 21296727 TI - [Prophylactic treatment with antiepileptic drugs in neurological conditions]. AB - Prophylactic use of antiepileptic drugs in neurological conditions such as ischemic and hemorrhagic stroke, subarachnoid hemorrhage, head injury, and brain tumors has been matter of debate for many years. These drugs are used for reducing secondary neurological damage caused by epileptic seizures. However, the evidence supporting this indication is scarce. Potential drug interactions, side effects, and even neurotoxicity related to these drugs have raised concern about this therapeutic approach. In this review, we examine the evidence on the prophylactic use of antiepileptic drugs in the neurological disorders above mentioned. PMID- 21296728 TI - [Safety standards for the use of magnetic resonance in patients with cardiovascular devices]. AB - We conducted a meeting of experts to establish rules for the management of patients with cardiovascular devices when they require a magnetic resonance imaging (MRI) study in the most common clinical scenarios, defining whether the study is safe, unsafe or conditional. PMID- 21296729 TI - [Rabies in the river plate]. PMID- 21296730 TI - [The great tradition. Houssay, Braun Menendez, Leloir, De Robertis, Milstein]. PMID- 21296731 TI - [Generational rupture. On Alfredo Lanari's centenary]. PMID- 21296732 TI - [Eurotransplant--new possibility for the Hungarian transplantation]. AB - The year 2010 was a milestone in the history of transplantation in Hungary. The State Secretary for Health Issues announced a program in order to solve the serious problems of organ transplantation: 1) to increase waiting lists, 2) to raise donor numbers, 3) to establish a lung transplant program in the country, 4) to promote education and increase the knowledge base regarding transplantation for the public and the medical profession, and finally, 5) to begin negotiations for Hungary to join Eurotransplant. Joining Eurotransplant has been a priority of the transplant community. Finally, this year saw the Budapest Transplant Center perform 20% of their kidney transplants from living donors, up from a 5% frequency historically, an operation which is available in all four centers from this year. PMID- 21296733 TI - [Leprosy--a stigma in the 21st century]. AB - For the initiation of the French journalist Raoul Follereau in 1954 the UNO inaugurated the Leprosy Day (Martyr's Day) that is celebrated on the last Sunday of January every year. Although the bacterium that causes leprosy was isolated by the Norwegian scientist Gerhard Henrik Armauer Hansen in 1873 and from 1982 this disease can be cured with a special pharmaceutical complex, still 219.826 new leprous are detected on Earth every year, according to the data published in August, 2010 by WHO-experts. Ancient Chinese and Hindu source-strings from 600 B. C. are referring to leprosy, however, the disease was imported by the army of Alexander the Great from India around 327-326 B. C. Even the Old and the New Testament from the Holy Bible are mentioning leprosy in several details. During the Middle Ages the Military and Hospitaller Order of St. Lazarus of Jerusalem, established in the Holy Land in 72 A. D., did pioneer work in nursing leprous. In the process of time the medical attendance concerning leprous was organized in special hospitals called "leprosoriums" built on river-banks. Special office and even services were organized for the treatment and isolation of the people infected. Although medical science has prevailed against leprosy, and almost simultaneously even jurisprudence defended the patients' rights via legislation, still mankind can regrettably not get rid of this disease that stigmatizes seriously. PMID- 21296734 TI - [Empirical antibiotic therapy of complicated skin and soft tissue infections in dermatological practice]. AB - Erysipelas is an acute bacterial infection of the skin predominantly caused by Streptococcus pyogenes. According to the international classification complicated erysipelas belongs to the complicated skin and soft tissue infections. Complicated infections are defined as severe skin involvement or when the infection occurs in compromised hosts. These infections frequently involve Gram negative bacilli and anaerobic bacteria. AIMS: The aim of this study was to compare the efficacy of the empirical antibiotic therapy for the patients who were admitted to the Department of Dermatology and Allergology, University of Szeged. METHODS: The empirical therapy was started according to a previously determined protocol. The data of 158 patients with complicated skin and soft tissue infections were analyzed and the microbiology culture specimens and the isolates were also examined. RESULTS AND CONCLUSIONS: The results show that penicillin is the first choice for the treatment of erysipelas. However, the complicated skin and soft tissue infections require broad-spectrum antibiotics. PMID- 21296735 TI - [Restless legs syndrome: the most prevalent "unknown" disorder]. AB - Sleep disorders are also considered as significant chronic disorders, as their physiological and psycho-social consequences are well documented. Restless legs syndrome has high prevalence, as it occurs in 5-10 % of the general population. Since clinical presentation is not well appreciated by many of the health care professionals, only a small proportion of the patients with restless legs syndrome is diagnosed and treated. The consequences of disease, however, are not negligible. The majority of the patients suffer from insomnia, impaired daytime functioning and quality of life. Although, restless legs syndrome is frequently characterized as a sleep disorder, it does not only influence sleep but also the daytime functioning of the patients. Additionally, restless legs syndrome causes not only subjective complaints and sleep disruption, but it is also associated with cardiovascular disorders. PMID- 21296736 TI - [Multiple hepatic abscesses due to actinomycosis: difficulties of diagnosis]. AB - Authors present the case of a 65 year-old man without any remarkable previous illness, hospitalized because of having prolonged fever caused probably by an infection due to a tick bite. Tularaemia and bartonellosis based on serological results as well as neoplasm of the sigma with multiple metastases to the liver raised by ultrasonography and abdominal CT could be excluded with detailed investigations. Multiple abscesses of the liver were diagnosed, followed by a percutaneuos ultrasonography directed aspiration of one of the abscesses which resulted in 150 ml buffy pus. Microbiological examination evaluated the presence of Actinomyces meyeri. Instead of neoplasm, diverticulosis and diverticulitis of the sigma could be clarified with perforation of one of the diverticuli causing peridiverticulitis, retroperitoneal abscess and probably abscesses in the liver by haematogenous dissemination. Surgical intervention, resection of the liver and the sigma resulted in recovery of the patient. Difficulties of diagnosis are discussed in the article pointing out the importance of interdisciplinary collaboration, involving also infectologist. Diverticulosis of the sigma as presumably origin of hepatic actinomycosis is a literary curiosity. This was the cause of the case presentation. PMID- 21296741 TI - Ancestry-informative markers on chromosomes 2, 8 and 15 are associated with insulin-related traits in a racially diverse sample of children. AB - Type 2 diabetes represents an increasing health burden. Its prevalence is rising among younger age groups and differs among racial/ethnic groups. Little is known about its genetic basis, including whether there is a genetic basis for racial/ethnic disparities. We examined a multi-ethnic sample of 253 healthy children to evaluate associations between insulin-related phenotypes and 142 ancestry-informative markers (AIMs), while adjusting for sex, age, Tanner stage, genetic admixture, total body fat, height and socio-economic status. We also evaluated the effect of measurement errors in the estimation of the individual ancestry proportions on the regression results. We found that European genetic admixture is positively associated with insulin sensitivity (S I ), and negatively associated with the acute insulin response to glucose, fasting insulin levels and the homeostasis model assessment of insulin resistance. Our analysis revealed associations between individual AIMs on chromosomes 2, 8 and 15 and these phenotypes. Most notably, marker rs3287 at chromosome 2p21 was found to be associated with S I ( p = 5.8 * 10(-5)). This marker may be in admixture linkage disequilibrium with nearby loci ( THADA and BCL11A ) that previously have been reported to be associated with diabetes and diabetes-related phenotypes in several genome-wide association and linkage studies. Our results provide further evidence that variation in the 2p21 region containing THADA and BCL11A is associated with type 2 diabetes. Importantly, we have implicated this region in the early development of diabetes-related phenotypes, and in the genetic aetiology of population differences in these phenotypes. PMID- 21296742 TI - Naming 'junk': human non-protein coding RNA (ncRNA) gene nomenclature. AB - Previously, the majority of the human genome was thought to be 'junk' DNA with no functional purpose. Over the past decade, the field of RNA research has rapidly expanded, with a concomitant increase in the number of non-protein coding RNA (ncRNA) genes identified in this 'junk'. Many of the encoded ncRNAs have already been shown to be essential for a variety of vital functions, and this wealth of annotated human ncRNAs requires standardised naming in order to aid effective communication. The HUGO Gene Nomenclature Committee (HGNC) is the only organisation authorised to assign standardised nomenclature to human genes. Of the 30,000 approved gene symbols currently listed in the HGNC database (http://www.genenames.org/search), the majority represent protein-coding genes; however, they also include pseudogenes, phenotypic loci and some genomic features. In recent years the list has also increased to include almost 3,000 named human ncRNA genes. HGNC is actively engaging with the RNA research community in order to provide unique symbols and names for each sequence that encodes an ncRNA. Most of the classical small ncRNA genes have now been provided with a unique nomenclature, and work on naming the long (>200 nucleotides) non coding RNAs (lncRNAs) is ongoing. PMID- 21296743 TI - Exploring the potential relevance of human-specific genes to complex disease. AB - Although human disease genes generally tend to be evolutionarily more ancient than non-disease genes, complex disease genes appear to be represented more frequently than Mendelian disease genes among genes of more recent evolutionary origin. It is therefore proposed that the analysis of human-specific genes might provide new insights into the genetics of complex disease. Cross-comparison with the Human Gene Mutation Database (http://www.hgmd.org) revealed a number of examples of disease-causing and disease-associated mutations in putatively human specific genes. A sizeable proportion of these were missense polymorphisms associated with complex disease. Since both human-specific genes and genes associated with complex disease have often experienced particularly rapid rates of evolutionary change, either due to weaker purifying selection or positive selection, it is proposed that a significant number of human-specific genes may play a role in complex disease. PMID- 21296744 TI - Transient receptor potential (TRP) gene superfamily encoding cation channels. AB - Transient receptor potential (TRP) non-selective cation channels constitute a superfamily, which contains 28 different genes. In mammals, this superfamily is divided into six subfamilies based on differences in amino acid sequence homology between the different gene products. Proteins within a subfamily aggregate to form heteromeric or homomeric tetrameric configurations. These different groupings have very variable permeability ratios for calcium versus sodium ions. TRP expression is widely distributed in neuronal tissues, as well as a host of other tissues, including epithelial and endothelial cells. They are activated by environmental stresses that include tissue injury, changes in temperature, pH and osmolarity, as well as volatile chemicals, cytokines and plant compounds. Their activation induces, via intracellular calcium signalling, a host of responses, including stimulation of cell proliferation, migration, regulatory volume behaviour and the release of a host of cytokines. Their activation is greatly potentiated by phospholipase C (PLC) activation mediated by coupled GTP-binding proteins and tyrosine receptors. In addition to their importance in maintaining tissue homeostasis, some of these responses may involve various underlying diseases. Given the wealth of literature describing the multiple roles of TRP in physiology in a very wide range of different mammalian tissues, this review limits itself to the literature describing the multiple roles of TRP channels in different ocular tissues. Accordingly, their importance to the corneal, trabecular meshwork, lens, ciliary muscle, retinal, microglial and retinal pigment epithelial physiology and pathology is reviewed. PMID- 21296745 TI - A short survey of computational analysis methods in analysing ChIP-seq data. AB - Chromatin immunoprecipitation followed by massively parallel next-generation sequencing (ChIP-seq) is a valuable experimental strategy for assaying protein DNA interaction over the whole genome. Many computational tools have been designed to find the peaks of the signals corresponding to protein binding sites. In this paper, three computational methods, ChIP-seq processing pipeline (spp), PeakSeq and CisGenome, used in ChIP-seq data analysis are reviewed. There is also a comparison of how they agree and disagree on finding peaks using the publically available Signal Transducers and Activators of Transcription protein 1 (STAT1) and RNA polymerase II (PolII) datasets with corresponding negative controls. PMID- 21296746 TI - RGD: a comparative genomics platform. AB - The Rat Genome Database (RGD) (http://rgd.mcw.edu) provides a comprehensive platform for comparative genomics and genetics research. RGD houses gene, QTL and polymorphic marker data for rat, mouse and human and provides easy access to data through sophisticated searches, disease portals, interactive pathway diagrams and rat and human genome browsers. PMID- 21296748 TI - Gobe: an interactive, web-based tool for comparative genomic visualization. AB - Gobe is a web-based tool for viewing comparative genomic data. It supports viewing multiple genomic regions simultaneously. Its simple text format and flash based rendering make it an interactive, exploratory research tool. Gobe can be used without installation through our web service, or downloaded and customized with stylesheets and javascript callback functions. AVAILABILITY: Gobe is a flash application that runs in all modern web-browsers. The full source-code, including that for the online web application is available under the MIT license at: http://github.com/brentp/gobe. Sample applications are hosted at http://try gobe.appspot.com/ and http://synteny.cnr.berkeley.edu/gobe-app/. PMID- 21296749 TI - LSPR: an integrated periodicity detection algorithm for unevenly sampled temporal microarray data. AB - We propose a three-step periodicity detection algorithm named LSPR. Our method first preprocesses the raw time-series by removing the linear trend and filtering noise. In the second step, LSPR employs a Lomb-Scargle periodogram to estimate the periodicity in the time-series. Finally, harmonic regression is applied to model the cyclic components. Inferred periodic transcripts are selected by a false discovery rate procedure. We have applied LSPR to unevenly sampled synthetic data and two Arabidopsis diurnal expression datasets, and compared its performance with the existing well-established algorithms. Results show that LSPR is capable of identifying periodic transcripts more accurately than existing algorithms. AVAILABILITY: LSPR algorithm is implemented as MATLAB software and is available at http://bioinformatics.cau.edu.cn/LSPR. PMID- 21296750 TI - SIMA: simultaneous multiple alignment of LC/MS peak lists. AB - MOTIVATION: Alignment of multiple liquid chromatography/mass spectrometry (LC/MS) experiments is a necessity today, which arises from the need for biological and technical repeats. Due to limits in sampling frequency and poor reproducibility of retention times, current LC systems suffer from missing observations and non linear distortions of the retention times across runs. Existing approaches for peak correspondence estimation focus almost exclusively on solving the pairwise alignment problem, yielding straightforward but suboptimal results for multiple alignment problems. RESULTS: We propose SIMA, a novel automated procedure for alignment of peak lists from multiple LC/MS runs. SIMA combines hierarchical pairwise correspondence estimation with simultaneous alignment and global retention time correction. It employs a tailored multidimensional kernel function and a procedure based on maximum likelihood estimation to find the retention time distortion function that best fits the observed data. SIMA does not require a dedicated reference spectrum, is robust with regard to outliers, needs only two intuitive parameters and naturally incorporates incomplete correspondence information. In a comparison with seven alternative methods on four different datasets, we show that SIMA yields competitive and superior performance on real world data. AVAILABILITY: A C++ implementation of the SIMA algorithm is available from http://hci.iwr.uni-heidelberg.de/MIP/Software. PMID- 21296751 TI - GOSSIP: a method for fast and accurate global alignment of protein structures. AB - MOTIVATION: The database of known protein structures (PDB) is increasing rapidly. This results in a growing need for methods that can cope with the vast amount of structural data. To analyze the accumulating data, it is important to have a fast tool for identifying similar structures and clustering them by structural resemblance. Several excellent tools have been developed for the comparison of protein structures. These usually address the task of local structure alignment, an important yet computationally intensive problem due to its complexity. It is difficult to use such tools for comparing a large number of structures to each other at a reasonable time. RESULTS: Here we present GOSSIP, a novel method for a global all-against-all alignment of any set of protein structures. The method detects similarities between structures down to a certain cutoff (a parameter of the program), hence allowing it to detect similar structures at a much higher speed than local structure alignment methods. GOSSIP compares many structures in times which are several orders of magnitude faster than well-known available structure alignment servers, and it is also faster than a database scanning method. We evaluate GOSSIP both on a dataset of short structural fragments and on two large sequence-diverse structural benchmarks. Our conclusions are that for a threshold of 0.6 and above, the speed of GOSSIP is obtained with no compromise of the accuracy of the alignments or of the number of detected global similarities. AVAILABILITY: A server, as well as an executable for download, are available at http://bioinfo3d.cs.tau.ac.il/gossip/. PMID- 21296752 TI - DDN: a caBIG(r) analytical tool for differential network analysis. AB - Differential dependency network (DDN) is a caBIG(r) (cancer Biomedical Informatics Grid) analytical tool for detecting and visualizing statistically significant topological changes in transcriptional networks representing two biological conditions. Developed under caBIG(r)'s In Silico Research Centers of Excellence (ISRCE) Program, DDN enables differential network analysis and provides an alternative way for defining network biomarkers predictive of phenotypes. DDN also serves as a useful systems biology tool for users across biomedical research communities to infer how genetic, epigenetic or environment variables may affect biological networks and clinical phenotypes. Besides the standalone Java application, we have also developed a Cytoscape plug-in, CytoDDN, to integrate network analysis and visualization seamlessly. AVAILABILITY: The Java and MATLAB source code can be downloaded at the authors' web site http://www.cbil.ece.vt.edu/software.htm. PMID- 21296753 TI - Model annotation for synthetic biology: automating model to nucleotide sequence conversion. AB - MOTIVATION: The need for the automated computational design of genetic circuits is becoming increasingly apparent with the advent of ever more complex and ambitious synthetic biology projects. Currently, most circuits are designed through the assembly of models of individual parts such as promoters, ribosome binding sites and coding sequences. These low level models are combined to produce a dynamic model of a larger device that exhibits a desired behaviour. The larger model then acts as a blueprint for physical implementation at the DNA level. However, the conversion of models of complex genetic circuits into DNA sequences is a non-trivial undertaking due to the complexity of mapping the model parts to their physical manifestation. Automating this process is further hampered by the lack of computationally tractable information in most models. RESULTS: We describe a method for automatically generating DNA sequences from dynamic models implemented in CellML and Systems Biology Markup Language (SBML). We also identify the metadata needed to annotate models to facilitate automated conversion, and propose and demonstrate a method for the markup of these models using RDF. Our algorithm has been implemented in a software tool called MoSeC. AVAILABILITY: The software is available from the authors' web site http://research.ncl.ac.uk/synthetic_biology/downloads.html. PMID- 21296754 TI - SpaCEM3: a software for biological module detection when data is incomplete, high dimensional and dependent. AB - SUMMARY: Among classical methods for module detection, SpaCEM(3) provides ad hoc algorithms that were shown to be particularly well adapted to specific features of biological data: high-dimensionality, interactions between components (genes) and integrated treatment of missingness in observations. The software, currently in its version 2.0, is developed in C++ and can be used either via command line or with the GUI under Linux and Windows environments. AVAILABILITY: The SpaCEM(3) software, a documentation and datasets are available from http://spacem3.gforge.inria.fr/. PMID- 21296755 TI - The MobM relaxase domain of plasmid pMV158: thermal stability and activity upon Mn2+ and specific DNA binding. AB - Protein MobM, the relaxase involved in conjugative transfer of the streptococcal plasmid pMV158, is the prototype of the MOB(V) superfamily of relaxases. To characterize the DNA-binding and nicking domain of MobM, a truncated version of the protein (MobMN199) encompassing its N-terminal region was designed and the protein was purified. MobMN199 was monomeric in contrast to the dimeric form of the full-length protein, but it kept its nicking activity on pMV158 DNA. The optimal relaxase activity was dependent on Mn(2+) or Mg(2+) cations in a dosage dependent manner. However, whereas Mn(2+) strongly stabilized MobMN199 against thermal denaturation, no protective effect was observed for Mg(2+). Furthermore, MobMN199 exhibited a high affinity binding for Mn(2+) but not for Mg(2+). We also examined the binding-specificity and affinity of MobMN199 for several substrates of single-stranded DNA encompassing the pMV158 origin of transfer (oriT). The minimal oriT was delimited to a stretch of 26 nt which included an inverted repeat located eight bases upstream of the nick site. The structure of MobMN199 was strongly stabilized by binding to the defined target DNA, indicating the formation of a tight protein-DNA complex. We demonstrate that the oriT recognition by MobMN199 was highly specific and suggest that this protein most probably employs Mn(2+) during pMV158 transfer. PMID- 21296756 TI - NSrp70 is a novel nuclear speckle-related protein that modulates alternative pre mRNA splicing in vivo. AB - Nuclear speckles are known to be the storage sites of mRNA splicing regulators. We report here the identification and characterization of a novel speckle protein, referred to as NSrp70, based on its subcellular localization and apparent molecular weight. This protein was first identified as CCDC55 by the National Institutes of Health Mammalian Gene Collection, although its function has not been assigned. NSrp70 was colocalized and physically interacted with SC35 and ASF/SF2 in speckles. NSrp70 has a putative RNA recognition motif, the RS-like region, and two coiled-coil domains, suggesting a role in RNA processing. Accordingly, using CD44, Tra2beta1 and Fas constructs as splicing reporter minigenes, we found that NSrp70 modulated alternative splice site selection in vivo. The C-terminal 10 amino acids (531-540), including (536)RD(537), were identified as a novel nuclear localization signal, and the region spanning 290 471 amino acids was critical for speckle localization and binding to SC35 and ASF/SF2. The N-terminal region (107-161) was essential for the pre-mRNA splicing activity. Finally, we found that knockout of NSrp70 gene in mice led to a lack of progeny, including fetal embryos. Collectively, we demonstrate that NSrp70 is a novel splicing regulator and essentially required early stage of embryonic development. PMID- 21296757 TI - Cyclodipeptide synthases, a family of class-I aminoacyl-tRNA synthetase-like enzymes involved in non-ribosomal peptide synthesis. AB - Cyclodipeptide synthases (CDPSs) belong to a newly defined family of enzymes that use aminoacyl-tRNAs (aa-tRNAs) as substrates to synthesize the two peptide bonds of various cyclodipeptides, which are the precursors of many natural products with noteworthy biological activities. Here, we describe the crystal structure of AlbC, a CDPS from Streptomyces noursei. The AlbC structure consists of a monomer containing a Rossmann-fold domain. Strikingly, it is highly similar to the catalytic domain of class-I aminoacyl-tRNA synthetases (aaRSs), especially class Ic TyrRSs and TrpRSs. AlbC contains a deep pocket, highly conserved among CDPSs. Site-directed mutagenesis studies indicate that this pocket accommodates the aminoacyl moiety of the aa-tRNA substrate in a way similar to that used by TyrRSs to recognize their tyrosine substrates. These studies also suggest that the tRNA moiety of the aa-tRNA interacts with AlbC via at least one patch of basic residues, which is conserved among CDPSs but not present in class-Ic aaRSs. AlbC catalyses its two-substrate reaction via a ping-pong mechanism with a covalent intermediate in which L-Phe is shown to be transferred from Phe-tRNA(Phe) to an active serine. These findings provide insight into the molecular bases of the interactions between CDPSs and their aa-tRNAs substrates, and the catalytic mechanism used by CDPSs to achieve the non-ribosomal synthesis of cyclodipeptides. PMID- 21296758 TI - Artificial trans-encoded small non-coding RNAs specifically silence the selected gene expression in bacteria. AB - Recently, many small non-coding RNAs (sRNAs) with important regulatory roles have been identified in bacteria. As their eukaryotic counterparts, a major class of bacterial trans-encoded sRNAs acts by basepairing with target mRNAs, resulting in changes in translation and stability of the mRNA. RNA interference (RNAi) has become a powerful gene silencing tool in eukaryotes. However, such an effective RNA silencing tool remains to be developed for prokaryotes. In this study, we described first the use of artificial trans-encoded sRNAs (atsRNAs) for specific gene silencing in bacteria. Based on the common structural characteristics of natural sRNAs in Gram-negative bacteria, we developed the designing principle of atsRNA. Most of the atsRNAs effectively suppressed the expression of exogenous EGFP gene and endogenous uidA gene in Escherichia coli. Further studies demonstrated that the mRNA base pairing region and AU rich Hfq binding site were crucial for the activity of atsRNA. The atsRNA-mediated gene silencing was Hfq dependent. The atsRNAs led to gene silencing and RNase E dependent degradation of target mRNA. We also designed a series of atsRNAs which targeted the toxic genes in Staphyloccocus aureus, but found no significant interfering effect. We established an effective method for specific gene silencing in Gram-negative bacteria. PMID- 21296759 TI - The histone H3K36 demethylase Rph1/KDM4 regulates the expression of the photoreactivation gene PHR1. AB - The dynamics of histone methylation have emerged as an important issue since the identification of histone demethylases. We studied the regulatory function of Rph1/KDM4 (lysine demethylase), a histone H3K36 demethylase, on transcription in Saccharomyces cerevisiae. Overexpression of Rph1 reduced the expression of PHR1 and increased UV sensitivity. The catalytically deficient mutant (H235A) of Rph1 diminished the repressive transcriptional effect on PHR1 expression, which indicates that histone demethylase activity contributes to transcriptional repression. Chromatin immunoprecipitation analysis demonstrated that Rph1 was associated at the upstream repression sequence of PHR1 through zinc-finger domains and was dissociated after UV irradiation. Notably, overexpression of Rph1 and H3K36A mutant reduced histone acetylation at the URS, which implies a crosstalk between histone demethylation and acetylation at the PHR1 promoter. In addition, the crucial checkpoint protein Rad53 acted as an upstream regulator of Rph1 and dominated the phosphorylation of Rph1 that was required for efficient PHR1 expression and the dissociation of Rph1. The release of Rph1 from chromatin also required the phosphorylation at S652. Our study demonstrates that the histone demethylase Rph1 is associated with a specific chromatin locus and modulates histone modifications to repress a DNA damage responsive gene under control of damage checkpoint signaling. PMID- 21296760 TI - Explaining the varied glycosidic conformational, G-tract length and sequence preferences for anti-parallel G-quadruplexes. AB - Guanine-rich DNA sequences tend to form four-stranded G-quadruplex structures. Characteristic glycosidic conformational patterns along the G-strands, such as the 5'-syn-anti-syn-anti pattern observed with the Oxytricha nova telomeric G quadruplexes, have been well documented. However, an explanation for these featured glycosidic patterns has not emerged. This work presents MD simulation and free energetic analyses for simplified two-quartet [d(GG)](4) models and suggests that the four base pair step patterns show quite different relative stabilities: syn-anti > anti-anti > anti-syn > syn-syn. This suggests the following rule: when folding, anti-parallel G-quadruplexes tend to maximize the number of syn-anti steps and avoid the unfavorable anti-syn and syn-syn steps. This rule is consistent with most of the anti-parallel G-quadruplex structures in the Protein Databank (PDB). Structural polymorphisms of G-quadruplexes relate to these glycosidic conformational patterns and the lengths of the G-tracts. The folding topologies of G2- and G4-tracts are not very polymorphic because each strand tends to populate the stable syn-anti repeat. G3-tracts, on the other hand, cannot present this repeating pattern on each G-tract. This leads to smaller energy differences between different geometries and helps explain the extreme structural polymorphism of the human telomeric G-quadruplexes. PMID- 21296761 TI - Zn2+ selectively stabilizes FdU-substituted DNA through a unique major groove binding motif. AB - We report, based on semi-empirical calculations, that Zn(2+) binds duplex DNA containing consecutive FdU-dA base pairs in the major groove with distorted trigonal bipyramidal geometry. In this previously uncharacterized binding motif, O4 and F5 on consecutive FdU are axial ligands while three water molecules complete the coordination sphere. NMR spectroscopy confirmed Zn(2+) complexation occurred with maintenance of base pairing while a slight hypsochromic shift in circular dichroism (CD) spectra indicated moderate structural distortion relative to B-form DNA. Zn(2+) complexation inhibited ethidium bromide (EtBr) intercalation and stabilized FdU-substituted duplex DNA (DeltaT(m) > 15 degrees C). Mg(2+) neither inhibited EtBr complexation nor had as strong of a stabilizing effect. DNA sequences that did not contain consecutive FdU were not stabilized by Zn(2+). A lipofectamine preparation of the Zn(2+)-DNA complex displayed enhanced cytotoxicity toward prostate cancer cells relative to the individual components prepared as lipofectamine complexes indicating the potential utility of Zn(2+) DNA complexes for cancer treatment. PMID- 21296762 TI - Specific regulation of pyrethrin biosynthesis in Chrysanthemum cinerariaefolium by a blend of volatiles emitted from artificially damaged conspecific plants. AB - Plants emit specific blends of volatile organic compounds (VOCs) in response to mechanical wounding. Such induced VOCs have been shown to mediate in plant and interplant communication, yet little is known about the time- and dose-response relationships in VOC-mediated communications. Here, we employed young seedlings of Chrysanthemum cinerariaefolium to examine the effects of volatiles emitted by artificially damaged seedlings on the biosynthesis of the natural insecticides pyrethrins in intact conspecific plants. Wounded leaves emitted (Z)-3-hexenal, (E)-2-hexenal, (Z)-3-hexen-1-ol, (Z)-3-hexen-1-yl acetate and (E)-beta-farnesene as dominant wound-induced VOCs. Exposing intact seedlings to a mixture of these VOCs at concentrations mimicking those emitted from wounded seedlings, as well as placing the intact seedlings next to the wounded seedlings, resulted in enhanced pyrethrin contents in the intact seedlings. Thus we quantified mRNA transcripts of 1-deoxy-D-xylulose 5-phosphate synthase (DXS), chrysanthemyl diphosphate synthase (CPPase), 13-lipoxygenase (13-LOX) and allene oxide synthase (AOS) genes in intact seedlings exposed to the VOC mixture to show that DXS and 13-LOX gene expression reached a maximum at 3 h, whereas CPPase and AOS reached it at 6 h. Interestingly, both increasing and decreasing the VOC mixture concentrations from those observed on injury reduced the expression of DXS, CPPase and AOS genes to the control level. Also, separating the VOC mixture into individual components eliminated the ability to enhance the expression of all the biosynthetic genes examined. This is the first study showing that the wound-induced VOCs function as a blend to control the biosynthesis of second metabolites at specific concentrations. PMID- 21296763 TI - Double loss-of-function mutation in EARLY FLOWERING 3 and CRYPTOCHROME 2 genes delays flowering under continuous light but accelerates it under long days and short days: an important role for Arabidopsis CRY2 to accelerate flowering time in continuous light. AB - The photoperiodic response is one of the adaptation mechanisms to seasonal changes of lengths of day and night. The circadian clock plays pivotal roles in this process. In Arabidopsis, LHY, CCA1, ELF3, and other clock proteins play major roles in maintaining circadian rhythms. lhy;cca1 double mutants with severe defects in circadian rhythms showed accelerated flowering under short days (SDs), but delayed flowering under continuous light (LL). The protein level of the floral repressor SVP increased in lhy;cca1 mutants under LL, and the late flowering phenotype of lhy;cca1 mutants was partially suppressed by svp, flc, or elf3. ELF3 interacted with both CCA1 and SVP, and elf3 suppressed the SVP accumulation in lhy;cca1 under LL. These results suggest that the unique mechanism of the inversion of the flowering response of lhy;cca1 under LL may involve both the ELF3-SVP/FLC-dependent and -independent pathways. In this work, elf3-1 seeds were mutagenized with heavy-ion beams and used to identify mutation(s) that delayed flowering under LL but not long days (LDs) or SDs even without ELF3. In this screening, seven candidate lines named suppressor of elf3 1 (self1), sel3, sel5, sel7, sel14, sel15, and sel20 were identified. Genetic analysis indicated that sel20 was a new deletion allele of a mutation in the blue light receptor, CRY2. A late-flowering phenotype and decrease of FT expression in the elf3;sel20 double mutant was obvious under LL but not under SDs or LDs. These results indicated that the late-flowering phenotype in the double mutant elf3;sel20 as well as in lhy;cca1 was affected by the presence of darkness. The results suggest that CRY2 may play more essential roles in the acceleration of flowering under LL than LDs or SDs. PMID- 21296764 TI - Identification and characterization of genomic regions on chromosomes 4 and 8 that control the rate of photosynthesis in rice leaves. AB - DNA marker-assisted selection appears to be a promising strategy for improving rates of leaf photosynthesis in rice. The rate of leaf photosynthesis was significantly higher in a high-yielding indica variety, Habataki, than in the most popular Japanese variety, Koshihikari, at the full heading stage as a result of the higher level of leaf nitrogen at the same rate of application of nitrogen and the higher stomatal conductance even when the respective levels of leaf nitrogen were the same. The higher leaf nitrogen content of Habataki was caused by the greater accumulation of nitrogen by plants. The higher stomatal conductance of Habataki was caused by the higher hydraulic conductance. Using progeny populations and selected lines derived from a cross between Koshihikari and Habataki, it was possible to identify the genomic regions responsible for the rate of photosynthesis within a 2.1 Mb region between RM17459 and RM17552 and within a 1.2 Mb region between RM6999 and RM22529 on the long arm of chromosome 4 and on the short arm of chromosome 8, respectively. The designated region on chromosome 4 of Habataki was responsible for both the increase in the nitrogen content of leaves and hydraulic conductance in the plant by increasing the root surface area. The designated region on chromosome 8 of Habataki was responsible for the increase in hydraulic conductance by increasing the root hydraulic conductivity. The results suggest that it may be possible to improve photosynthesis in rice leaves by marker-assisted selection that focuses on these regions of chromosomes 4 and 8. PMID- 21296765 TI - Genome size and transposable element content as determined by high-throughput sequencing in maize and Zea luxurians. AB - The genome of maize (Zea mays ssp. mays) consists mostly of transposable elements (TEs) and varies in size among lines. This variation extends to other species in the genus Zea: although maize and Zea luxurians diverged only ~140,000 years ago, their genomes differ in size by ~50%. We used paired-end Illumina sequencing to evaluate the potential contribution of TEs to the genome size difference between these two species. We aligned the reads both to a filtered gene set and to an exemplar database of unique repeats representing 1,514 TE families; ~85% of reads mapped against TE repeats in both species. The relative contribution of TE families to the B73 genome was highly correlated with previous estimates, suggesting that reliable estimates of TE content can be obtained from short high throughput sequencing reads, even at low coverage. Because we used paired-end reads, we could assess whether a TE was near a gene by determining if one paired read mapped to a TE and the second read mapped to a gene. Using this method, Class 2 DNA elements were found significantly more often in genic regions than Class 1 RNA elements, but Class 1 elements were found more often near other TEs. Overall, we found that both Class 1 and 2 TE families account for ~70% of the genome size difference between B73 and luxurians. Interestingly, the relative abundance of TE families was conserved between species (r = 0.97), suggesting genome-wide control of TE content rather than family-specific effects. PMID- 21296766 TI - COX-2 contributes to P-glycoprotein-mediated multidrug resistance via phosphorylation of c-Jun at Ser63/73 in colorectal cancer. AB - Cross-drug resistance in multidrug-resistant (MDR) cells, which overexpress P glycoprotein (P-gp) encoded by the MDR1 gene, is a major impediment to successful chemotherapy for colorectal cancer. In the present study, drug-sensitive HCT8 and multidrug-resistant (vincristine, VCR) HCT8/V colorectal cancer cell lines were used to examine the role of c-Jun NH2-Terminal Kinase- (JNK) signaling pathway in P-gp-mediated MDR associated with Cyclo-oxygenase-2 (COX-2). The results showed that SP600125, a JNK inhibitor, and NS-398, a COX-2 inhibitor, significantly reduced the degree of MDR in HCT8/V cells. This was accompanied by a significant decrease in gene level of MDR1 and protein level of P-gp in HCT8/V cells. Notably, addition of a JNK inhibitor had no significant effect on the expression of COX-2 in both HCT8 and HCT8/V cells. Interestingly, inhibition of COX-2 activity by a chemical inhibitor or its silence by small interfering RNA significantly decreased the level of phosphorylated c-Jun at Ser63/73 in HCT8/V cells. In contrast, upregulation of COX-2 significantly increased the levels of P gp and p-c-Jun at Ser63/73 in HCT8 cells, but not in HCT8/V cells. Moreover, the intracellular vincristine accumulation in HCT8/V cells significantly increased after inhibiting COX-2 and JNK activity. Taken together, our study has provided the first direct evidence that COX-2 contributes to P-gp-mediated multidrug resistance via phosphorylation of c-Jun at Ser63/73 in colorectal cancer cells. PMID- 21296767 TI - Performance of electroencephalogram-derived parameters in prediction of depth of anaesthesia in a rabbit model. AB - BACKGROUND: The index of consciousness (IoC), the permutation entropy (PE), and the approximate entropy are recent EEG-derived indices of anaesthetic depth. In this study, a rabbit model under fentanyl and isoflurane anaesthesia was used to compare the performance of these indices and also the classic median and spectral edge frequency 95%. METHODS: EEG recordings were obtained from six rabbits. Animals received fentanyl for premedication, followed by induction with propofol and maintenance with isoflurane. Anaesthetic depth was evaluated according to a clinical scale from 1 (awake) to 4 (surgical anaesthesia). Animals were submitted to surgical implantation of a small device in the lumbar muscles. A correction factor for the EEG suppression ratio was applied to the spectral parameters and to the PE. The correlation of the indices with the clinical scale of anaesthesia was analysed using prediction probability. Repeated-measures analysis of variance or its non-parametric equivalent was used to analyse the indices values at the study times and to compare their variability. RESULTS: The IoC showed the best mean prediction probability value [0.94 (0.01)] followed by burst suppression corrected PE [0.91(0.03)]. Both parameters also showed less variability than the others. CONCLUSIONS: The IoC and PE are promising indices for anaesthetic depth monitoring. The PE might benefit from the application of a burst suppression correction at deeper stages of anaesthesia. The rabbit is useful as a translational research animal model for the validation of clinical indices. PMID- 21296768 TI - Analgesia and pulmonary function after lung surgery: is a single intercostal nerve block plus patient-controlled intravenous morphine as effective as patient controlled epidural anaesthesia? A randomized non-inferiority clinical trial. AB - BACKGROUND: Thoracic epidural anaesthesia (EDA) is regarded as the 'gold standard' for postoperative pain control and restoration of pulmonary function after lung surgery. Easier, less time-consuming, and, perhaps, safer is intercostal nerve block performed under direct vision by the surgeon before closure of the thoracotomy combined with postoperative i.v. patient-controlled analgesia with morphine. We hypothesized that this technique is as effective as thoracic EDA. METHODS: The study was designed as a single-centre, open labelled, randomized non-inferiority trial. A total of 92 patients undergoing elective lung surgery were randomly assigned to the epidural (n=47) or intercostal group (n=45), and 83 patients completed the study. Pain scores, inspiratory vital capacity, forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), and peak expiratory flow rate (PEFR) were assessed during the first four postoperative days. RESULTS: Median treatment differences regarding pain scores at rest failed to demonstrate non-inferiority of the intercostal nerve block at the first postoperative day. Patients of the intercostal group reported significantly higher pain scores on coughing during the first and second postoperative days. The epidural group had a significantly higher median FVC, FEV1, and PEFR values on the second postoperative day. No difference was found in pulmonary complications, length of hospital stay, or in-hospital deaths. CONCLUSIONS: In patients undergoing lung surgery, single intercostal nerve block plus i.v. patient-controlled analgesia with morphine is not as effective as patient-controlled EDA with respect to pain control and restoration of pulmonary function. PMID- 21296769 TI - Revisiting black medical school extinctions in the Flexner era. AB - Abraham Flexner's 1910 expose on medical education recommended that only two of the seven extant medical schools for blacks be preserved and that they should train their students to "serve their people humbly" as "sanitarians." Addressing charges of racism, this article traces the roots of the recommendation that blacks serve a limited professional role to the schools themselves and presents evidence that, in endorsing the continuance of Howard's and Meharry's medical programs, Flexner exhibited greater leniency than he had toward comparable schools for white students. Whether his recommendations to eliminate the other five schools were key factors in their extinction is addressed here by examining 1901-30 enrollment patterns. Those patterns suggest that actions of the American Medical Association and state licensing boards, combined with the broader problem of limited premedical educational opportunities for blacks, were more consequential than was the Flexner report both for the extinction of the schools and for the curtailed production of black doctors. PMID- 21296770 TI - Breast cancer risk after radiation treatment at infancy: potential consequences of radiation-induced genomic instability. AB - Swedish hemangioma patients were treated in infancy mainly by external application of radium-226 starting from 1920. This work analysed the radiation risk among 17,158 women with a total of 678 breast cancer incidence cases with models of carcinogenesis and empirical excess relative risk models. Models incorporating effects of genomic instability were developed and applied to the hemangioma cohort. The description of the radiation risk was significantly improved with a model of genomic instability at an early stage of carcinogenesis. PMID- 21296771 TI - A comparative study of the responses of lithium borate and calcium sulphate phosphors in a TL personal dosemeter. AB - This work summarises the results of a series of experiences made on Panasonic UD 802AS, a multi-element dosemeter that is currently used in Caorso Nuclear Power Plant for personnel external monitoring. Two main topics have been considered: energy response and the influence of working place dose rate on relative readings of the elements at the end of the monitoring period. The presence of four elements of different materials and filtrations gives the possibility of evaluating radiation energy by a simple algorithm, so that an accurate estimate of the personal dose equivalent can be provided; the good results of the participation of Caorso Individual Monitoring Service (IMS) to 'EURADOS 2008 intercomparison on whole-body dosemeters' account for the reliability of the method. A study on the response in low-dose rate fields is also reported, giving in practice interesting information about operational conditions. PMID- 21296772 TI - Implantable cardioverter-defibrillator utilization. PMID- 21296773 TI - Right atrial perforation at the end of an atrial fibrillation ablation procedure. AB - A 74-year-old man with chronic atrial fibrillation underwent ablation under conscious sedation. After sheath removal from the left atrium, the patient flexed his thighs, resulting in a 'foetal position' developing tamponade due to an right atrial (RA) appendage perforation from sheath migration. This illustrates the importance of close monitoring during sedation weaning, recommending removal of all sheaths prior to sedation withdrawal. PMID- 21296774 TI - The infarct characteristics on magnetic resonance imaging and ventricular tachycardia: do we see what we need to see? PMID- 21296775 TI - Left ventricular apical akinetic aneurysmatic area associated with permanent right ventricular apical pacing for advanced atrioventricular block: clinical characteristics and long-term outcome. AB - BACKGROUND: Right ventricular apical (RVA) pacing can induce left ventricular (LV) dyssynchrony and dysfunction. In this article, we describe the prevalence, clinical characteristics, and outcome in a subset of patients with unrecognized LV apical akinetic aneurysmatic area associated with permanent RVA pacing as potential causes of heart failure (HF) and/or ventricular tachyarrhythmias (VT). METHODS AND RESULTS: We retrospectively studied 220 patients with permanent RVA pacing and no pre-existing structural heart disease in our follow-up clinic for high-degree atrioventricular block. Patients who presented with new-onset HF, chest pain, or VT following RVA pacing were evaluated by echocardiogram and cardiac catheterization. RVA pacing-induced LV apical akinetic aneurysmatic area was diagnosed in the absence of significant coronary artery disease by left ventriculogram. After a mean 8.8 +/- 6.3 years, eight patients (3.6%) had LV apical akinetic aneurysmatic area. Of those with LV apical akinetic aneurysmatic area, four patients presented with or died of VT. There was no evidence of LV apical akinetic aneurysmatic area on echocardiogram or left ventriculogram in the remaining 212 patients. The four patients with LV apical akinetic aneurysmatic area and HF underwent cardiac resynchronization therapy: in all cases LV ejection fraction improved (from 33 +/- 6 to 47 +/- 10%, P = 0.03), and LV apical akinetic aneurysmatic area resolved in two. CONCLUSION: Permanent RVA pacing for high degree atrioventricular block is associated with LV apical akinetic aneurysmatic area. This condition was associated with a high incidence of VT and cardiovascular complication, but was possibly reversible with cardiac resynchronization therapy. PMID- 21296776 TI - Efficacy and safety of different antitachycardia pacing sites in the termination of ventricular tachycardia in patients with biventricular implantable cardioverter-defibrillator. AB - AIMS: We sought to evaluate the efficacy and safety of different antitachycardia pacing (ATP) sites in heart failure (HF) patients with a biventricular implantable cardioverter-defibrillator (ICD). METHODS AND RESULTS: Between January 2003 and December 2008, 89 consecutive patients with biventricular (BiV) ICDs (Medtronic Inc., St Paul, Minnesota, USA) were enrolled. In these patients, stored electrograms of the true spontaneous ventricular tachycardia (VT) episodes with at least one ATP therapy were analysed. Out of the 89 patients, 46 experienced 259 VT episodes. When we considered all VT forms, both left ventricular (LV)-ATP (91%) and BiV-ATP (89%) were significantly better than right ventricular (RV)-ATP (72%) in terminating VTs (P = 0.03 and 0.04, respectively). In the fastVT zone, there was a trend for higher efficacy of BiV-ATP compared with RV-ATP and LV-ATP (75 vs. 60 vs. 60%, P = 0.10). Fast VT acceleration occurred to a similar extent in all ATP groups (20% in RV-ATP vs. 20% in LV-ATP vs. 20% in BiV-ATP, P = NS). In the slow VT zone, RV-ATP was significantly less effective than LV-ATP (74 vs. 100%, P = 0.001) and BiV-ATP (74 vs. 100%, P = 0.014). Incidence of acceleration was lower with LV-ATP and BiV-ATP than RV-ATP (0 vs. 0 vs. 9%, P = 0.03) in the slow VT zone. CONCLUSIONS: In HF patients treated with BiV ICD, overall ATP efficacy is higher when delivered from LV or BiV than from RV. Biventricular-ATP and LV-ATP are also safer than RV-ATP in the slow VT zone. PMID- 21296777 TI - Cardiovascular hospitalization as a surrogate endpoint for mortality in studies of atrial fibrillation: report from the Stockholm Cohort Study of Atrial Fibrillation. AB - AIMS: Cardiovascular (CV)-related hospitalization has been used as a surrogate endpoint for mortality in recent treatment studies on atrial fibrillation (AF), but our understanding of the relationship between CV-related hospitalization and death is incomplete. We aimed to investigate whether CV-related hospitalization is an independent risk factor and suitable as a surrogate endpoint for death in clinical studies of patients with AF. METHOD AND RESULTS: All 2912 patients with a diagnosis of AF in 2002 at one of Sweden's largest hospitals were studied for 6.5 years using information about medication from the local medical records. In a sub-study of the last 2.5 years of the study period, we used detailed information about medication from the new National Prescription Register. Information about diagnoses, hospitalizations, and deaths was obtained from national registries. Patients who were re-admitted to hospital with a CV diagnosis within the first 3 months had higher mortality than those who were not (15.6 vs. 9.3 deaths per 100 patient-years at risk, P < 0.0001). Those who spent >2% of their time-at-risk in hospital with a CV diagnosis had higher mortality than those who had spent less time in hospital (36.0 vs. 8.2 deaths per 100 patient years, P < 0.0001). After adjustment for co-factors, mortality was still higher for patients who had been re-hospitalized for CV disease within 3 months than for those who had not [hazard ratio (HR) = 1.36; 95% confidence interval (CI) = 1.18-1.57]. When analyses were performed on patients who had survived for 3 years since inclusion, and with the use of detailed information about the exposure to medication, the association between CV-related hospitalization and death was highly significant (HR 2.69, CI 1.96-3.68). These results were virtually unchanged after propensity score matching, which was done in order to adjust further for residual unidentified confounding. CONCLUSION: CV-related hospitalization is a marker for patients who are at increased risk of death, and may be used as a valid surrogate endpoint in studies of AF. PMID- 21296778 TI - Incidence, risk factors, and consequences of new-onset atrial fibrillation following epicardial ablation for ventricular tachycardia. AB - INTRODUCTION: We sought to determine the incidence, predictors, and consequences of new-onset atrial fibrillation (AF) following epicardial ventricular tachycardia (VT) ablation. METHODS AND RESULTS: A total of 41 patients with no prior history of AF underwent epicardial VT ablation via a percutaneous subxiphoid approach. All patients were monitored continuously for 3 days following ablation and then via implantable cardiac defibrillator (ICD) or Holter monitoring. Mean age was 70.0 +/- 11.3 years and mean ejection fraction was 30.3 +/- 16.6%. In seven (17%) patients, the right ventricle (RV) was punctured during access with subsequent needle withdrawal without requiring surgical repair. Thirty patients (73%) were treated with amiodarone following ablation. Post ablation, eight (19.5%) patients had documented new-onset AF within 7 days. All AF patients had clinical symptoms of pericarditis. One patient with AF was maintained on amiodarone post-procedure. Complications of AF included three patients who received inappropriate ICD shocks and one patient who developed a large, left atrial appendage clot. Acutely, all patients responded to short-term medical therapy or electrical cardioversion. At 18.0 +/- 9.0 months of follow-up, no patient had recurrence of AF, and all were off antiarrhythmic drugs. One patient had typical atrial flutter requiring catheter ablation. Risk factors for AF included lack of amiodarone immediately after ablation (12.5 vs. 87.9%, P < 0.001), RV puncture (50.0 vs. 9.1%, P = 0.02), and epicardial ablation time >10 min (62.5 vs. 3.0%, P < 0.001). CONCLUSIONS: Atrial fibrillation after epicardial ablation is common and can lead to ICD shocks and atrial thrombus formation. Short-term antiarrhythmic drug therapy and ICD reprogramming should be considered after epicardial VT ablation. PMID- 21296779 TI - Dissociated pulmonary vein potentials following antral pulmonary vein isolation for atrial fibrillation: impact on long-term outcome. AB - BACKGROUND: Pulmonary vein (PV) reconnection is the Achilles heel of pulmonary vein isolation (PVI) for atrial fibrillation (AF). Dissociated pulmonary vein potentials (dPVP) may reflect abnormal PV automaticity, indicate more extensive PV muscular sleeve or may simply be an epiphenomenon. OBJECTIVE: This study sought to determine the incidence, characteristics and prognostic significance of dPVP following PVI for AF. METHODS: 89 consecutive patients (mean age 58.2 +/- 8.4 years, 75% male, 74% paroxysmal, 26% persistent AF) underwent antral PVI using three-dimensional mapping systems with image integration with the endpoint of bidirectional PV block. Following PV electrical isolation the presence and characteristics of dPVP were recorded. Holter monitoring was performed at 3, 6 and 12 months. Acute PV reconnection was assessed over a 30-min waiting period. RESULTS: Electrical isolation was achieved in all 372 PV targeted for ablation. 69 of 372 isolated PV (19%) demonstrated dPVP after acute electrical isolation. Sites of dPVP origin were the left superior in 36%, left inferior in 20%, right superior in 31% and right inferior in 12%. All 69 dPVP demonstrated slow activity (cycle length >1500 ms) with only four persisting more than 30 min after acute isolation. There was no difference in the clinical characteristics between dPVP positive vs dPVP-negative patients. At a mean follow-up of 21 +/- 8 months the single procedure success was 25/33 (76%) in dPVP-positive versus 39/60 (64%) in dPVP-negative patients (p = -0.3). In the eight dPVP-positive patients who underwent a second procedure, 11 of the 14 (79%) veins with initial dPVP demonstrated PV-left atrial reconnection. CONCLUSION: dPVP are present in 19% of PV following acute antral electrical isolation. The presence of dPVP did not predict recurrent AF following PVI. PMID- 21296780 TI - Candesartan versus imidapril in hypertension: a randomised study to assess effects of anti-AT1 receptor autoantibodies. AB - BACKGROUND: Anti-angiotensin II receptor subtype 1 (AT1 receptor) autoantibodies have previously been shown in sera of hypertensive patients. This study assessed whether anti-AT1-receptor autoantibody in serum is correlated with the efficacy of an AT1-receptor blocker (ARB; candesartan)-based regimen in hypertensive patients after 8 weeks of treatment. DESIGN: The Study of Optimal Treatment in Hypertensive Patients with Anti-AT1-Receptor Autoantibodies is a multicentre, randomised, blinded endpoint, open-label, parallel-group comparison clinical trial conducted in five centres in Wuhan, China. Treatment is designed as stepwise added-on therapy to reduce blood pressure (BP) < 140/90 mm Hg. 512 patients with moderate to severe primary hypertension were randomly assigned to an 8-week treatment with either ARB (candesartan)-based regimen (n=257) or ACE inhibitor (imidapril)-based regimen (n=255). RESULTS: Systolic and diastolic BP was reduced significantly in both treatment groups. The candesartan-based regimen achieved a significantly greater systolic BP reduction than imdapril (30.8 +/- 10.3 vs 28.8 +/- 10.3 mm Hg, p = 0.023). In those anti-AT1 receptor autoantibody positive hypertensive patients, the mean systolic BP at baseline was higher than in the anti-AT1 receptor autoantibody-negative group (160.5 +/- 16.5 vs 156.2 +/- 17.7 mm Hg; p = 0.006). The mean BP reduction was greater in the candesartan based regimen than the imidapril-based regimen (-35.4 +/- 9.8/16.9 +/- 6.9 vs 29.4 +/- 9.8/14.2 +/- 6.9 mm Hg; p = 0.000 and 0.002, respectively), and more patients on imidapril required add-on medications to achieve BP control (94% vs 86%; p=0.03). No correlation was observed between the titre of anti-AT1 receptor autoantibody and the efficacy of candesartan-based therapy. In those anti-AT1 receptor autoantibody-negative patients similar BP lowering was reached in the candesartan and the imidapril-based regimens. CONCLUSIONS: An ARB-based regimen is more effective in BP lowering than an ACE inhibitor-based regimen in the presence of anti-AT1 receptor autoantibodies. Trial registration number This trial has been registered at http://www.register.clinicaltrials.gov/ (identifier: NCT00360763). PMID- 21296781 TI - Triglycerides and atherogenic dyslipidaemia: extending treatment beyond statins in the high-risk cardiovascular patient. AB - Although statins significantly decrease the incidence of cardiovascular disease (CVD), residual CVD risk remains high. This may partly be due to uncorrected atherogenic dyslipidaemia. The driving force behind atherogenic dyslipidaemia is hypertriglyceridaemia, which results from hepatic oversecretion and/or hypocatabolism of triglyceride-rich lipoproteins, and is typical of type 2 diabetes and metabolic syndrome. Persistent atherogenic dyslipidaemia in patients treated with a statin according to low-density lipoprotein-cholesterol goals may be corrected with niacin, fibrates or n-3 fatty acids. Clinical trial evidence to inform best practice is limited, but new data support adding fenofibrate to a statin. A consistent feature of fibrate clinical trials is the specific benefit of these agents in dyslipidaemic patients and the improvement in diabetic retinopathy with fenofibrate. Ongoing clinical trials may provide good evidence for adding niacin to a statin. Low-dose n-3 fatty acids could be used routinely after a myocardial infarction, but the value of higher doses of n-3 fatty acids in reducing CVD risk remains to be demonstrated. PMID- 21296782 TI - Quantification of myocardial iron deposition by two-dimensional speckle tracking in patients with beta-thalassaemia major and Blackfan-Diamond anaemia. AB - BACKGROUND: Cardiac disease related to transfusional iron overload is the leading cause of death in patients with beta-thalassaemia major. Early myocardial iron deposition predates decreased left ventricular dysfunction and currently is best assessed by cardiac magnetic resonance. METHODS: Echocardiographic speckle tracking-derived myocardial mechanics were compared with cardiac MRI T2 star (T2*) calculations in 45 chronically transfused patients with beta-thalassaemia major or Diamond-Blackfan anaemia (26 retrospectively and an additional 19 for validation). Two groups were studied: patients with presumed cardiac iron overload and interventricular T2* value <=20 ms (low T2*) and patients with >20 ms (normal T2*). They were compared with a normal control group of 18 age- and gender-matched patients. RESULTS: Patients with low T2* had a uniform decrease in longitudinal and circumferential strain compared with normal controls (-16+/-3% vs -20+/-3% and -20+/-4% vs -23+/-5%, respectively; p<0.0005). Peak twist and peak apical rotation were lower in patients with low T2* than in those with normal T2* or normal control patients. Conversely, no significant difference was observed between patients with normal T2* and controls. There was a strong and direct logarithmic correlation between average global longitudinal strain and T2* values (r=-0.68, p=0.0007). Using a cut-off of <=-17%, global longitudinal strain predicted a T2* value of <20 ms with a sensitivity of 76% and a specificity of 88%. CONCLUSION: Myocardial mechanics offers a simple alternative to cardiac MRI for assessing significant myocardial iron deposition. PMID- 21296783 TI - Efficacy of percutaneous closure of patent foramen ovale: comparison among three commonly used occluders. AB - BACKGROUND: Percutaneous closure of patent foramen ovale (PFO) is standard treatment for patients with paradoxical embolism but studies examining the efficacy of the various occluders are lacking. OBJECTIVE: To evaluate short- and medium-term closure rates of three common occluders. METHODS: One hundred and sixty-six adults (47+/-12 (18-81 years)) were evaluated with transthoracic bubble echocardiography before and after PFO closure. Only patients with large PFOs were included (>30 bubbles in the left heart after Valsalva). RESULTS: Three occluders were used: Amplatzer (AGA Medical Corporation) (n=80, 48%), Gore Helex (n=48, 29%) and Premere TM (St Jude Medical) (n=38, 23%). One (0.6%) neurological event occurred during follow-up. At 6 months significant residual shunting after Valsalva was highest in the group that received the Helex (58.3%), and lower for Premere (39.5%) and Amplatzer (32.5%). At final follow-up residual shunting remained higher in patients with the Helex (33.3%) than in Premere (18.5%) and Amplatzer (11%). Amplatzer had a significantly lower residual shunt rate than Helex (p<0.05 at 6 months and final follow-up). The Premere had an intermediate residual shunt rate. Septal aneurysm also predicted residual shunting (RR=24.7, 95% CI: 8.2 to 74.4, p<0.0001). CONCLUSIONS: Percutaneous PFO closure is an efficacious progressive treatment but closure rates also depend on the presence of aneurysm and differ between occluders. PMID- 21296784 TI - The diagnosis and management of chronic heart failure: review following the publication of the NICE guidelines. PMID- 21296785 TI - Cardiac CT beyond coronary angiography: current and emerging non-coronary cardiac applications. PMID- 21296786 TI - The challenges of transvenous lead extraction. PMID- 21296787 TI - Diagnosis of heart failure in primary care: the syndrome and the spectrum. PMID- 21296788 TI - The microbiota-gut-brain axis: learning from intestinal bacteria? PMID- 21296789 TI - The issue is tissue. PMID- 21296791 TI - Strategies for antiviral stockpiling for future influenza pandemics: a global epidemic-economic perspective. AB - Influenza pandemics present a global threat owing to their potential mortality and substantial economic impacts. Stockpiling antiviral drugs to manage a pandemic is an effective strategy to offset their negative impacts; however, little is known about the long-term optimal size of the stockpile under uncertainty and the characteristics of different countries. Using an epidemic economic model we studied the effect on total mortality and costs of antiviral stockpile sizes for Brazil, China, Guatemala, India, Indonesia, New Zealand, Singapore, the UK, the USA and Zimbabwe. In the model, antivirals stockpiling considerably reduced mortality. There was greater potential avoidance of expected costs in the higher resourced countries (e.g. from $55 billion to $27 billion over a 30 year time horizon for the USA) and large avoidance of fatalities in those less resourced (e.g. from 11.4 to 2.3 million in Indonesia). Under perfect allocation, higher resourced countries should aim to store antiviral stockpiles able to cover at least 15 per cent of their population, rising to 25 per cent with 30 per cent misallocation, to minimize fatalities and economic costs. Stockpiling is estimated not to be cost-effective for two-thirds of the world's population under current antivirals pricing. Lower prices and international cooperation are necessary to make the life-saving potential of antivirals cost effective in resource-limited countries. PMID- 21296792 TI - A simple DNA gate motif for synthesizing large-scale circuits. AB - The prospects of programming molecular systems to perform complex autonomous tasks have motivated research into the design of synthetic biochemical circuits. Of particular interest to us are cell-free nucleic acid systems that exploit non covalent hybridization and strand displacement reactions to create cascades that implement digital and analogue circuits. To date, circuits involving at most tens of gates have been demonstrated experimentally. Here, we propose a simple DNA gate architecture that appears suitable for practical synthesis of large-scale circuits involving possibly thousands of gates. PMID- 21296793 TI - Do reducing regimens of fluorometholone for paediatric ocular surface disease cause glaucoma? AB - BACKGROUND/AIMS: Although fluorometholone (FML) is considered a steroid of minimal ocular penetration, reports in children have shown dose-dependent intraocular pressure (IOP) rise. The authors aimed to assess whether reducing regimens of FML for paediatric ocular surface disease have sustained clinically significant ocular hypertensive effects. METHODS: Retrospective case-note review. Glaucoma was defined as an IOP of >= 21 mm Hg on at least two occasions or, in young children, moderate/firm digital IOP with one of the following: myopic shift, increased cup:disc ratio or corneal oedema. Exclusion criteria were other concurrent steroids or pre-existing optic nerve disease. RESULTS: 107 cases were included. The median age was 6 years (range 3 months to 17 years). The commonest indication for FML was blepharo-kerato-conjunctivitis. The maximal frequency prescribed was four times a day, gradually reduced to once weekly in cases of long-term treatment. The mean total number of eye-drop applications was 228 over a mean time span of 9 months. Post-FML IOP was formally documented in 51/107 casenotes (median age 6.85 years, range 4 months to 16 years) and it was <19 mm Hg in all cases. 56 cases did not allow IOP measurement (median age 5.9 years, range 3 months to 17 years), but none met the glaucoma definition. CONCLUSIONS: In this cohort, reducing regimens of FML proved to be a safe anti-inflammatory treatment in terms of avoiding steroid-induced glaucoma. PMID- 21296794 TI - Pitfalls in obtaining and interpreting bone marrow aspirates: to err is human. AB - Pitfalls relating to bone marrow aspirates and their interpretation start even before the aspirate is obtained. There can be failure to perform an aspiration that is clinically indicated or, conversely, an aspiration may be done that is not actually necessary. Once an aspirate is obtained it may be unhelpful because it is a blood tap or very dilute, or because of the sampling error that is intrinsic to the procedure. Even if an adequate aspirate is obtained, it may be misinterpreted. Megaloblastic marrows and children's marrows with increased haematogones or marked reactive changes are particularly prone to misinterpretation. A constant awareness of potential pitfalls and an assessment of the aspirate in the appropriate clinical context will help to reduce errors. PMID- 21296795 TI - Loss of cellular polarity/cohesiveness in the invasive front of papillary thyroid carcinoma, a novel predictor for lymph node metastasis; possible morphological indicator of epithelial mesenchymal transition. AB - BACKGROUND: Loss of cellular polarity/cohesiveness (LOP/C) in the invasive front of papillary thyroid carcinoma (PTC) results in a high recurrence risk of PTC. AIMS: To investigate the immunohistochemical features of LOP/C in PTC and to show that this feature is linked to a high association of lymph node metastasis (LNM) at surgery and tumour recurrence. METHODS: The degree of LOP/C of the PTCs was evaluated histologically using a cut-off value of 20% and the immunohistochemical features of LOP/C were analysed using immunohistochemical staining for E cadherin, beta-catenin and vimentin. The relationship between the LOP/C and the other clinicopathological parameters was analysed. RESULTS: 43 cases of PTC with LOP/C (>=20%) were selected and 27 cases with LOP/C (<20%) were included as control tumours. 11/44 cases (25%) were observed to develop recurrence, LNM or distant metastasis at an average follow-up of 31 months. Less expression of E cadherin and aberrant localisation of beta-catenin and vimentin were observed in PTC tumour cells with LOP/C. LOP/C (>=20%) was significantly correlated with extrathyroid invasion (r=0.336, p=0.003), advanced tumour stage (r=0.275, p=0.017), LNM (r=0.389, p<0.001) and recurrence after surgery (r=0.302, p=0.036). Both extrathyroid invasion and LOP/C were independent significant predictors of LNM. CONCLUSIONS: LOP/C may be a useful morphological feature of epithelial mesenchymal transition under H&E observation, and it is an important indicator of lymph node metastasis and aggressive clinical behaviour of PTC. PMID- 21296796 TI - Short message service reminder intervention doubles sexually transmitted infection/HIV re-testing rates among men who have sex with men. AB - OBJECTIVES: To evaluate the impact of a short message service (SMS) reminder system on HIV/sexually transmitted infection (STI) re-testing rates among men who have sex with men (MSM). METHODS: The SMS reminder programme started in late 2008 at a large Australian sexual health clinic. SMS reminders were recommended 3-6 monthly for MSM considered high-risk based on self-reported sexual behaviour. The evaluation compared HIV negative MSM who had a HIV/STI test between 1 January and 31 August 2010 and received a SMS reminder (SMS group) with those tested in the same time period (comparison group) and pre-SMS period (pre-SMS group, 1 January 2008 and 31 August 2008) who did not receive the SMS. HIV/STI re-testing rates were measured within 9 months for each group. Baseline characteristics were compared between study groups and multivariate logistic regression used to assess the association between SMS and re-testing and control for any imbalances in the study groups. RESULTS: There were 714 HIV negative MSM in the SMS group, 1084 in the comparison group and 1753 in the pre-SMS group. In the SMS group, 64% were re tested within 9 months compared to 30% in the comparison group (p<0.001) and 31% in the pre-SMS group (p<0.001). After adjusting for baseline differences, re testing was 4.4 times more likely (95% CI 3.5 to 5.5) in the SMS group than the comparison group and 3.1 times more likely (95% CI 2.5 to 3.8) than the pre-SMS group. CONCLUSION: SMS reminders increased HIV/STI re-testing among HIV negative MSM. SMS offers a cheap, efficient system to increase HIV/STI re-testing in a busy clinical setting. PMID- 21296797 TI - Hypoglycaemia: current management and controversies. AB - Hypoglycaemia is a major burden on patients and society and is often a barrier to the achievement of tight glycaemic control. Intact awareness of hypoglycaemia is crucial to recognising and treating hypoglycaemia before it becomes severe enough to impair consciousness. Repeated hypoglycaemia can lead to impaired awareness increasing the risk of severe hypoglycaemia up to sixfold. Hypoglycaemia is much less common in those with type 2 diabetes, the incidence increasing with longer duration of treatment with insulin, associated comorbidities, and in the elderly. Alcohol, advancing age and exercise may predispose to hypoglycaemia. Newer agents acting via the incretin axis are associated with low rates of hypoglycaemia. Intensification of therapy to achieve tight glucose control can increase the risk of hypoglycaemia in the outpatient as well as critical care setting. In some studies this has also been associated with increased mortality, although causality has not been proven. Insulin treated patients are currently restricted from driving heavy goods vehicles or public service vehicles, although it is unclear if those with diabetes have any higher rates of accidents than those without diabetes. Surveys show that professionals are poor at emphasising the Driver and Vehicle Licensing Agency recommendations for drivers with diabetes in the UK. At every visit, patients with diabetes on hypoglycaemic agents should be assessed for frequency, severity, and awareness of hypoglycaemia. The main therapeutic strategies for reducing hypoglycaemia are structured patient education, use of modern insulin analogues, insulin pumps, and continuous glucose monitoring. Transplantation of islets or whole pancreas is indicated in those with recurrent disabling hypoglycaemia. PMID- 21296798 TI - Determinants of tetanus and sepsis among the last neonatal deaths at household level in a peri-urban area of India. AB - BACKGROUND: India contributes to one quarter of the total number of newborn deaths in the world. Less explored are the causes of these deaths, and household factors and decision makers for antenatal and postnatal care and their association with neonatal mortality. OBJECTIVE: This study estimated neonatal mortality rate due to tetanus and sepsis (TS) and tried to identify the risk factors for TS in a peri-urban area of India characterised by a high level of infant and neonatal mortality rate. METHODS: An intensive cross-sectional study was conducted during January to March 2008. A structured interview schedule was developed, after reviewing major demographic and health studies done in India, to collect data from all women selected in the sample villages, situated at a distance of 3-5 km from a primary health centre. RESULTS: Of the 894 married women (<50 years of age), 109 reported their last pregnancy outcome as neonatal death, and 84 cases of TS were noted. Using forward conditional stepwise logistic regression the risk factors of TS identified were women's age, socioeconomic score, antenatal care, pregnancy complications, and treatment after delivery during the neonatal period. CONCLUSIONS: Independent of social class there is high prevalence of neonatal mortality. There is a close association between utilisation of health care services during pregnancy, postnatal period and neonatal deaths due to TS. It is argued that there is a need for a two pronged approach to reduce neonatal mortality due to TS: (1) to train traditional birth attendants, and expand the reach of existing antenatal care and childbirth facilities; and (2) to empower women to increase their awareness to take decisions about seeking proper medical assistance during pregnancy and childbirth. PMID- 21296799 TI - Poisoning hospitalisations among reproductive-aged women in the USA, 1998-2006. AB - OBJECTIVE: To describe poisoning hospitalisations among reproductive-aged women from 1998 to 2006. METHODS: 1998-2006 data from the Nationwide Inpatient Sample of the Healthcare Cost and Utilisation Project were used to identify hospitalisations for poisonings among US women aged 15-44 years. Differences in hospitalisation characteristics were compared by intent using chi(2) statistics. Trends in poisoning hospitalisation rates were calculated overall and by subgroup. RESULTS: There were approximately 636,000 poisoning hospitalisations in women aged 15-44 years during 1998-2006. Hospitalisations for intentionally self inflicted poisonings had a higher proportion of women aged 15-24 years and privately insured women than did unintentional poisonings (p<0.001). Poisoning hospitalisations in rural areas and those that resulted in death were more likely to be of undetermined intent than those for which intent was specified (p<0.001). Co-diagnoses of substance abuse (34.5%) or mental disorders (66.5%) were high. The rate of poisoning hospitalisations overall and unintentional poisoning hospitalisations increased 6% and 22%, respectively, during this period (p<0.001). The most frequently diagnosed poisoning agent was acetaminophen. Poisonings attributable to acetaminophen, opioids, central nervous system stimulants and benzodiazepines increased, while poisonings attributable to antidepressants decreased (p<0.05). CONCLUSIONS: The increase in unintentional poisoning hospitalisations among women aged 15-44 years and the changing profile of poisoning agents should inform the healthcare community's poisoning prevention strategies. Poisoning prevention strategies should include a component to address substance abuse and mental health disorders among reproductive-age women. PMID- 21296800 TI - Injuries and deaths due to victim-activated improvised explosive devices, landmines and other explosive remnants of war in Nepal. AB - BACKGROUND: Following more than a decade of civil conflict, Nepal is among the countries affected by landmines, victim-activated improvised explosive devices (IED) and other explosive remnants of war (ERW). OBJECTIVES: To assess the magnitude of injuries due to landmines, victim-activated IED and other ERW in Nepal and to describe epidemiological patterns and risk factors for these events. METHODS: Analysis of surveillance data on civilian injuries due to landmines, victim-activated IED and other ERW between July 2006 and June 2010. Data were collected through active community-based prospective surveillance. RESULTS: Of 307 total casualties, 94 (31%) were female and 169 (55%) were children under 18 years of age. The case-fatality ratio was 14%. The highest number of casualties was in the age group 10-14 years. 233 (76%) injuries were caused by victim activated IED, 13 (4%) by landmines and 44 (14%) by other ERW. Two types of IED, sutali and socket bombs, caused the majority of injuries (28% and 31%, respectively). 117 (38%) of all injuries occurred in victims' homes and 152 (50%) occurred while victims were tampering with explosive devices. CONCLUSIONS: Substantial numbers of civilians, including women and children, were injured and killed following implementation of the Comprehensive Peace Agreement in 2006. The government of Nepal and humanitarian organisations should continue their efforts to reach communities at highest risk through targeted interventions and nationwide media campaigns to convey the risks of tampering with explosive devices or suspicious objects. PMID- 21296801 TI - Booster seat legislation: does it work for all children? AB - OBJECTIVE: To assess the impact of a booster seat law in Wisconsin on booster seat use in relation to race, ethnicity and socioeconomic status. METHODS: A longitudinal study in Milwaukee County, Wisconsin, involving repeated direct observational assessments of booster seat use rates by child passengers aged 4-7 years over five time periods, before and after legislation mandating booster seat use. RESULTS: Overall, booster seat use increased from 24% to 43%, whereas proper restraint use increased pre to post-legislation from 21% to 28%. Proper use increased after legislation in white, but not in black or Latino children. White individuals had a proper booster use increase from 48% to 68% over the time period of the study. Black children's proper use dropped from 18% to 7% over the study period and Latino children's proper use rates were stable at 10%. Driver reported household income had a significant impact on overall use, but not on proper use. CONCLUSIONS: Racial/ethnic minority groups and those of lower socioeconomic status have significantly lower use and proper use of booster seats. Legislation may increase the total use of booster seats but not necessarily the correct use of the restraint, particularly in racial/ethnic minorities. PMID- 21296802 TI - Haplotype analysis of chemokine CXCL12 polymorphisms and susceptibility to premature ovarian failure in Chinese women. AB - BACKGROUND Chemokine (C-X-C motif) ligand 12 (CXCL12/stromal cell-derived factor 1) has been suggested to play an essential role in primordial germ cell migration, colonization and survival, and in the primordial to primary follicle transition. This study was performed to investigate an association of polymorphisms in CXCL12 with the risk of premature ovarian failure (POF) in Chinese patients. METHODS Tagging single nucleotide polymorphisms (SNPs) were selected using the Chinese HapMap database. Five SNPs (rs4948878, rs1801157, rs266087, rs266093 and rs1029153) were genotyped by direct sequencing in 111 patients with POF and 183 healthy controls recruited from the First Affiliated Hospital, Anhui Medical University, China. RESULTS Compared with controls, there were significantly higher frequencies of the rs1801157 A allele and haplotype C-T A-T-T in cases with POF [P = 6.38E-07, odds ratio (OR) = 3.10, 95% confidence interval (CI) 1.955-4.890 by allele; P = 7.0E-04, OR = 2.39, 95% CI 1.43-3.97 by haplotype]. No differences were observed for the other four SNPs between POF cases and controls. CONCLUSIONS A strong association between a CXCL12 polymorphism and POF was established in Chinese patients, suggesting that CXCL12 might be a new candidate gene involved in POF. The A allele of CXCL12 polymorphism rs1801157 is a possible risk factor for developing POF. However, further independent studies are necessary to confirm our findings. PMID- 21296803 TI - Does cessation of progesterone supplementation during early pregnancy in patients treated with recFSH/GnRH antagonist affect ongoing pregnancy rates? A randomized controlled trial. AB - BACKGROUND: The aim of this study was to assess whether the cessation of progesterone (P) supplementation during early pregnancy after GnRH antagonist cycles is not inferior to its continuation in terms of pregnancy rates beyond 12 weeks of gestation METHODS: There were 200 patients, with a positive beta-hCG test (followed by a doubling in beta-hCG levels 48 h later) after a fixed recombinant FSH (recFSH)/GnRH antagonist protocol for IVF/ICSI and a Day-3 fresh embryo transfer (ET), participated in this randomized controlled study. All patients received luteal support, with 200 mg vaginal P being administered three times daily for 14 days, beginning on the day of ET until the second beta-hCG test, 16 days post-ET. In the control group (n = 100) the administration of P was continued until 7 weeks of gestation. In the study group (n = 100), vaginal P was discontinued on the 16th day post-ET RESULTS: The ongoing pregnancy rate beyond 12 weeks, the primary outcome measure, did not differ between the study and control groups (82 versus 73%, P = 0.175; difference 9%, 95% CI: -2.6 to 20.3). There were also no significant differences observed between the study and control group in terms of abortion before or after 7 weeks of gestation [(9 versus 12%, P = 0.645) and (8 versus 10%, P = 0.806), respectively]. The same was true for bleeding episodes (14 versus 19%, P = 0.446). CONCLUSIONS: After recFSH/GnRH antagonist cycles, the withdrawal of P supplementation in early pregnancy, with normally increasing beta-hCG levels on the 16th day post-ET, had no significant clinical impact in terms of ongoing pregnancy rates beyond 12 weeks. PMID- 21296804 TI - Editorial commentary: is it time to abandon progesterone supplementation of early pregnancy after IVF? PMID- 21296805 TI - Headache and sleep: the missing links. PMID- 21296806 TI - Nummular headache: two simultaneous areas of pain in the same patient. PMID- 21296807 TI - Endothelium-dependent vasodilatation in migraine patients. AB - BACKGROUND: Endothelial dysfunction could be involved in the pathophysiology of migraine. The results obtained from a few studies on endothelial dysfunction in migraine are controversial. We investigated brachial flow-mediated dilatation (FMD), which reflects systemic endothelial dysfunction, in migraine patients without comorbidities. By employing strict inclusion criteria we avoided the possible changes to FMD from confounding factors. METHODS: Forty migraine patients without comorbidities (20 with and 20 without aura) and 20 healthy subjects were included. FMD of brachial arteries and carotid intima-media thickness were measured by using standard procedures. RESULTS: We did not find any difference in FMD between migraine patients and healthy subjects (p = .96). Also, no differences were found among healthy subjects, migraine patients with aura and without aura (p = .99). CONCLUSION: Our study showed that systemic endothelial function is not impaired in migraine patients without comorbidities, neither in those with or without aura. Considering these findings, the investigation of cerebral endothelial function would be useful in a further investigation of the role of endothelial (dys)function in migraine pathophysiology. PMID- 21296808 TI - Hierarchical encoding in visual working memory: ensemble statistics bias memory for individual items. AB - Influential models of visual working memory treat each item to be stored as an independent unit and assume that there are no interactions between items. However, real-world displays have structure that provides higher-order constraints on the items to be remembered. Even in the case of a display of simple colored circles, observers can compute statistics, such as mean circle size, to obtain an overall summary of the display. We examined the influence of such an ensemble statistic on visual working memory. We report evidence that the remembered size of each individual item in a display is biased toward the mean size of the set of items in the same color and the mean size of all items in the display. This suggests that visual working memory is constructive, encoding displays at multiple levels of abstraction and integrating across these levels, rather than maintaining a veridical representation of each item independently. PMID- 21296809 TI - Effect of topical azithromycin on corneal innate immune responses. AB - PURPOSE: To determine the effect of azithromycin (AZM) in a murine model of corneal inflammation. METHODS: The effect of topical AZM was studied in murine corneal inflammation. Corneal inflammation was induced by thermal cautery in BALB/c mice. Leukocyte infiltration at different time points was analyzed by flow cytometry. At set time points, real-time polymerase chain reaction was performed to quantify the expression of different inflammatory cytokine transcript in the cornea. Corneal samples were analyzed immunohistochemically for the expression of intercellular adhesion molecule-1 (ICAM-1). Corneal neovascularization (CNV) was induced by micropellet (VEGF-A) placement. Mice were then treated topically with either AZM or vehicle. CNV was evaluated morphometrically. RESULTS: Eyes receiving AZM showed a significant decrease in corneal infiltration compared with the vehicle-treated group. AZM also significantly decreased messenger RNA expression levels of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha) and ICAM-1 in the cornea. There was no significant difference in CNV between the AZM- and vehicle-treated groups. CONCLUSIONS: After an inflammatory insult, topical AZM significantly reduced leukocyte infiltration into the cornea. This was further supported by an associated decrease in expression of IL-1beta, TNF-alpha, and ICAM-1 in the cornea, indicating AZM may have a potential anti inflammatory effect on corneal inflammation. PMID- 21296810 TI - Oscillatory eye movements resembling pendular nystagmus in normal juvenile macaques. AB - PURPOSE: Juvenile monkeys being trained on smooth-pursuit tasks exhibit ocular oscillations resembling pendular nystagmus. The purpose of this study was to analyze these oscillations, the effects of gabapentin on them, and responses of cerebellar floccular neurons to understand possible neuronal mechanisms. METHODS: Four monkeys were trained for horizontal and vertical smooth pursuit; in two, saccades were also tested. Frequency, peak-to-peak eye velocity, and amplitude of the ocular oscillations were measured. In one monkey, the effect of gabapentin on the oscillations was measured, and oscillation-related neuronal discharge was recorded in the cerebellar floccular region. RESULTS: Ocular oscillations, with features of pendular nystagmus, appeared early during training of both horizontal and vertical pursuit in all four monkeys. Although these oscillations were observed both in the direction of pursuit and orthogonally, the velocity and amplitude of oscillation were larger in the direction of pursuit, implicating pursuit mechanisms in their generation. Corrective saccades were often superimposed on the oscillations during pursuit and fixation. Gabapentin suppressed oscillations in the monkey tested. Recordings in the floccular region revealed a subset of neurons discharged during both the oscillations and corrective saccades. Many of them exhibited burst-tonic discharge during visually guided saccades, similar to discharge of brain stem burst-tonic neurons, suggesting contributions of the neural integrator to the oscillations. CONCLUSIONS: The developmentally transient ocular oscillations occurring in monkeys during pursuit training has properties resembling pendular nystagmus. Both smooth pursuit and a neural integrator may contribute to these ocular oscillations. Analysis using an efference-copy pursuit model supports the interpretation herein. PMID- 21296811 TI - Morphometric analysis of optic nerves and retina from an end-stage retinitis pigmentosa patient with an implanted active epiretinal array. AB - PURPOSE: To characterize optic nerve and retinal changes in a patient with end stage retinitis pigmentosa (RP) with an implanted active epiretinal array. METHODS: A 74-year-old man with end-stage X-linked RP underwent implantation of an epiretinal array over the macula in the right eye and subsequent stimulation until his death at 5 years and 3 months after implantation. The optic nerves from this study patient, as well as those from two age-matched normal patients and two age-matched RP patients, were morphometrically analyzed against two different sets of criteria and compared. The retina underlying the array in the study patient was also morphometrically analyzed and compared with corresponding regions of the retina in the age-matched RP patients. RESULTS: Optic nerve total axon counts were significantly lower in the study patient and RP patients than in normal patients. However, there was no significant difference when comparing total axon counts from the optic nerve corresponding to the patient's implanted right eye versus the optic nerves from the RP patients (P = 0.59 and P = 0.61 using the two different criteria). Degenerated axon data quantified damage and did not show increased damage in the optic nerve quadrant that retinotopically corresponded to the site of epiretinal array implantation and stimulation. Except for the tack site, there was no significant difference when comparing the retina underlying the array and the corresponding perimacular regions of two RP patients. CONCLUSIONS: Long-term implantation and electrical stimulation with an epiretinal array did not result in damage that could be appreciated in a morphometric analysis of the optic nerve and retina. PMID- 21296812 TI - Three-dimensional magnetic resonance imaging of the phakic crystalline lens during accommodation. AB - PURPOSE: To quantify changes in crystalline lens curvature, thickness, equatorial diameter, surface area, and volume during accommodation using a novel two dimensional magnetic resonance imaging (MRI) paradigm to generate a complete three-dimensional crystalline lens surface model. METHODS: Nineteen volunteers, aged 19 to 30 years, were recruited. T(2)-weighted MRIs, optimized to show fluid filled chambers of the eye, were acquired using an eight-channel radio frequency head coil. Twenty-four oblique-axial slices of 0.8 mm thickness, with no interslice gaps, were acquired to visualize the crystalline lens. Three Maltese cross-type accommodative stimuli (at 0.17, 4.0, and 8.0 D) were presented randomly to the subjects in the MRI to examine lenticular changes with accommodation. MRIs were analyzed to generate a three-dimensional surface model. RESULTS: During accommodation, mean crystalline lens thickness increased (F = 33.39, P < 0.001), whereas lens equatorial diameter (F = 24.00, P < 0.001) and surface radii both decreased (anterior surface, F = 21.78, P < 0.001; posterior surface, F = 13.81, P < 0.001). Over the same stimulus range, mean crystalline lens surface area decreased (F = 7.04, P < 0.005) with a corresponding increase in lens volume (F = 6.06, P = 0.005). These biometric changes represent a 1.82% decrease and 2.30% increase in crystalline lens surface area and volume, respectively. CONCLUSIONS; The results indicate that the capsular bag undergoes elastic deformation during accommodation, causing reduced surface area, and the observed volumetric changes oppose the theory that the lens is incompressible. PMID- 21296813 TI - NOD2 deficiency results in increased susceptibility to peptidoglycan-induced uveitis in mice. AB - PURPOSE: The innate immune receptor NOD2 is a genetic cause of uveitis (Blau syndrome). Intriguingly, in the intestine where polymorphisms of NOD2 predispose to Crohn's disease, NOD2 reportedly suppresses inflammation triggered by the bacterial cell wall component, peptidoglycan (PGN). Whether NOD2 exerts a similar capacity in the regulation of ocular inflammation to PGN has not been explored. METHODS: NOD2, NOD1, or MyD88 knockout (KO) mice and their wild-type (WT) controls were administered an intravitreal injection of PGN (a metabolite of which is the NOD2 agonist, muramyl dipeptide), or synthetic TLR2/1 and TLR2/6 agonists, Pam3CSK4 and FSL-1. Ocular inflammation was assessed by intravital microscopy and histopathology. Cytokine production in eye tissue homogenates was measured by ELISA. RESULTS: PGN triggered uveitis in mice. This inflammation was abolished in the absence of the TLR signaling mediator MyD88. NOD2 exerted a negative regulatory role because PGN-triggered eye inflammation was exacerbated in NOD2 KO mice. Increased intravascular response coincided with enhanced leukocytes within the aqueous and vitreous humors. The enhanced susceptibility of NOD2 KO mice to PGN uveitis coincided with increased cytokine production of IL 12p40, IL-17, and IL-23 but not IL-12p70, TNFalpha, or IFNgamma. NOD1 deficiency did not result in the same sensitivity to PGN. Ocular inflammation induced by synthetic TLR2 agonists required MyD88 but not NOD2 or NOD1. CONCLUSIONS: NOD2 may serve differential roles in the eye to promote inflammation while also tempering cell responses to PGN akin to what has been reported in colitis. PMID- 21296814 TI - Prevalence and risk factors for refractive errors in Indians: the Singapore Indian Eye Study (SINDI). AB - PURPOSE: To determine the prevalence and risk factors for refractive errors in middle-aged to elderly Singaporeans of Indian ethnicity. METHODS: A population based, cross-sectional study of Indians aged over 40 years of age residing in Southwestern Singapore was conducted. An age-stratified (10-year age group) random sampling procedure was performed to select participants. Refraction was determined by autorefraction followed by subjective refraction. Myopia was defined as spherical equivalent (SE) < -0.50 diopters (D), high myopia as SE < 5.00 D, astigmatism as cylinder < -0.50 D, hyperopia as SE > 0.50 D, and anisometropia as SE difference > 1.00 D. Prevalence was adjusted to the 2000 Singapore census. RESULTS: Of the 4497 persons eligible to participate, 3400 (75.6%) were examined. Complete data were available for 2805 adults with right eye refractive error and no prior cataract surgery. The age-adjusted prevalence was 28.0% (95% confidence interval [CI], 25.8-30.2) for myopia and 4.1% (95% CI, 3.3-5.0) for high myopia. There was a U-shaped relationship between myopia and increasing age. The age-adjusted prevalence was 54.9% (95% CI, 52.0-57.9) for astigmatism, 35.9% (95% CI, 33.7-38.3) for hyperopia, and 9.8% (95% CI, 8.6-11.1) for anisometropia. In a multiple logistic regression model, adults who were female, younger, taller, spent more time reading and writing per day, or had astigmatism were more likely to be myopic. Adults who were older or had myopia or diabetes mellitus had higher risk of astigmatism. CONCLUSIONS: In Singapore, the prevalence of myopia in Indian adults is similar to those in Malays, but lower than those in Chinese. Risk factors for myopia are similar across the three ethnic groups in Singapore. PMID- 21296815 TI - Hyperosmotic stress-induced corneal epithelial cell death through activation of Polo-like kinase 3 and c-Jun. AB - PURPOSE: Hyperosmotic stress causes cell shrinkage, perturbs cell function, and damages DNA, resulting in cell cycle arrest and apoptosis. In the present study, the authors explore the mechanism involving hyperosmotic stress-induced activation of c-Jun/AP-1 through a novel Plk3 pathway in human corneal epithelial cells. METHODS: Human primary corneal epithelial cells and cell line were cultured in a serum-free keratinocyte medium and DMEM/F12 medium containing 10% FBS in a 37 degrees C incubator supplied with 5% CO(2), respectively. Western blot analysis was used to determine protein expression and phosphorylation levels. Protein kinase activities were measured by immunocomplex kinase assay. Cell viability and apoptosis were determined by MTT assay and caspase-3 (DEVDase) activity. RESULTS: It was found that hyperosmotic stress-induced increases in the phosphorylation of c-Jun, resulting in apoptosis through the activation of Plk3 in human corneal epithelial cells. Plk3 was activated by extracellular hyperosmotic stress to directly phosphorylate c-Jun in the serine 63 and 73 residues. Hyperosmotic stress-induced c-Jun phosphorylation was enhanced by overexpression of constitutively positive Plk3 mutants and suppressed by the knockdown of Plk3 mRNA with Plk3-specific siRNA. Further studies indicated that the phosphorylation of c-Jun by Plk3 was responsible for hyperosmotic stress induced apoptosis, which was independent from activation of the JNK signaling pathway in human corneal epithelial cells. CONCLUSIONS: These results, for the first time, provide a novel and alternative signaling mechanism that involves hyperosmotic stress-induced activation of the Plk3 pathway in addition to JNK/p38 MAPK pathways to regulate the c-Jun/AP-1 transcriptional complex and human corneal epithelial cell fate. PMID- 21296816 TI - Determinants of macular pigment optical density and its relation to age-related maculopathy: results from the Muenster Aging and Retina Study (MARS). AB - PURPOSE: The controversial protective effect of macular pigment (MP), consisting of lutein (L) and zeaxantin (Z), in age-related maculopathy (ARM) and its late stage, age-related macular degeneration (AMD) is discussed. Determinants of MP optical density (MPOD) and its relation to ARM were investigated. METHODS: MPOD was accessed at eccentricities of 0.5 degrees and 2.0 degrees from the fovea in 369 participants in the 2.6-year follow-up examination of the prospective Muenster Aging and Retina Study using dual-wavelength analysis of autofluorescence images. ARM was graded from standardized fundus photographs according to the International Classification System. RESULTS: MPOD at 0.5 degrees and 2.0 degrees between pairs and within single eyes was strongly correlated (P < 0.001). Smoking and body mass index showed moderately inverse associations with MPOD at 2.0 degrees , and age was positively related to MPOD at both eccentricities. Serum L, measured at the baseline examination, was significantly associated with MPOD measured at follow-up. Likewise, use of L/Z containing supplements raised MPOD. Crude mean MPOD increased with ascending stage of ARM. However, adjustment for influential factors and exclusion of L supplement users removed differences of mean MPOD between ARM stages. Considering further the accompanying eye, study eyes with ARM had significantly higher MPOD when the contralateral eye had AMD. CONCLUSIONS: MPOD levels showed a high degree of intraindividual concordance and interindividual variability. Long-standing serum L levels, and in particular L supplementation, were the strongest determinants of MPOD. The hypothetical inverse association between MPOD and ARM stage was not confirmed. PMID- 21296817 TI - Effect of bilateral macular scotomas from age-related macular degeneration on reach-to-grasp hand movement. AB - PURPOSE: Vision plays a critical role in reaching and grasping objects. Consequently, bilateral macular scotomas from age-related macular degeneration (AMD) may affect reach-to-grasp movements. The purpose of this work was to investigate changes in reach-to-grasp movement dynamics and to relate those changes to the characteristics of subjects' preferred retinal loci (PRL), scotomas, and visual acuities. METHODS: Three-dimensional positions of the index finger and thumb were recorded while subjects with bilateral scotomas and subjects with normal vision reached for and grasped blocks of three widths at two distances under binocular and monocular viewing conditions. Reach-dynamic parameters and the grip aperture (thumb-index finger distance) were calculated. Retinal locations and sizes of subjects' scotomas and PRLs were mapped with a scanning laser ophthalmoscope. RESULTS: Scotoma subjects' hand trajectories had longer movement durations, lower maximum velocities, and longer visual reaction times than those of control subjects. With monocular viewing, maximum grip aperture (MGA) increased as a function of block width at a significantly higher rate for scotoma subjects than for control subjects. MGA decreased with increasing PRL bivariate normal ellipse area, and visual reaction time increased with decreasing acuity of the eye tested. CONCLUSIONS: Compared with normally sighted subjects, subjects with bilateral macular scotomas from AMD have reach-to grasp movements with longer trajectories, longer visual reaction times, lower velocities, and altered MGA-block width scaling. Visual reaction time and MGA are directly related to PRL characteristics. Deficits in reach-to-grasp movement caused by macular scotomas are greater in degree than those reported by others for real or artificial peripheral scotomas. PMID- 21296818 TI - Mesenchymal stem cells ameliorate experimental autoimmune uveoretinitis by comprehensive modulation of systemic autoimmunity. AB - PURPOSE: The authors studied the therapeutic effect of rat mesenchymal stem cells (MSCs) on experimental autoimmune uveoretinitis (EAU) induced in rats by peptide 1169-1191 of the interphotoreceptor retinoid-binding protein (IRBP). METHODS: The authors intravenously injected syngeneic (isolated from Lewis rats) or allogeneic (isolated from Wistar rats) MSCs into IRBP-induced EAU Lewis rats, either before disease onset (simultaneous with immunization, preventive protocol) or at different time points after disease onset (therapeutic protocol). T-cell response to IRBP 1169-1191 from MSC-treated rats was evaluated, Th1/Th2/Th17 cytokines produced by lymphocytes were measured, and CD4(+)CD25(+) regulatory T cells (Treg) were detected. RESULTS: MSC administration before disease onset not only strikingly reduced the severity of EAU, it also delayed the onset of the disease. MSC administration was also effective after disease onset and at the peak of disease, but not after disease stabilization. Clinical efficacy for all treatments was consistent with reduced cellular infiltrates and milder uveal and retinal impairment. T-cell response to IRBP 1169-1191 from MSC-treated rats was inhibited. MSCs significantly decreased the production of IFN-gamma and IL-17 and increased the production of IL-10 of T lymphocytes from EAU rats either in vivo or in vitro. Allogeneic and syngeneic MSCs showed a similar immunosuppression potential with regard to clinical effect, T cell proliferation, and cytokine secretion, and MSC therapy upregulated Treg cells. CONCLUSIONS: These data suggest that the immunoregulatory properties of MSCs effectively interfere with the autoimmune attack in the course of EAU through the comprehensive modulation of systemic autoimmunity. PMID- 21296819 TI - Macular pigment and visual performance in glare: benefits for photostress recovery, disability glare, and visual discomfort. AB - PURPOSE: One theory of macular pigment's (MP) presence in the fovea is to improve visual performance in glare. This study sought to determine the effect of MP level on three aspects of visual performance in glare: photostress recovery, disability glare, and visual discomfort. METHODS: Twenty-six subjects participated in the study. Spatial profiles of MP optical density were assessed with heterochromatic flicker photometry. Glare was delivered via high-bright white LEDs. For the disability glare and photostress recovery portions of the experiment, the visual task consisted of correct identification of a 1 degrees Gabor patch's orientation. Visual discomfort during the glare presentation was assessed with a visual discomfort rating scale. Pupil diameter was monitored with an infrared (IR) camera. RESULTS: MP level correlated significantly with all the outcome measures. Higher MP optical densities (MPODs) resulted in faster photostress recovery times (average P < 0.003), lower disability glare contrast thresholds (average P < 0.004), and lower visual discomfort (P = 0.002). Smaller pupil diameter during glare presentation significantly correlated with higher visual discomfort ratings (P = 0.037). CONCLUSIONS: MP correlates with three aspects of visual performance in glare. Unlike previous studies of MP and glare, the present study used free-viewing conditions, in which effects of iris pigmentation and pupil size could be accounted for. The effects described, therefore, can be extended more confidently to real-world, practical visual performance benefits. Greater iris constriction resulted (paradoxically) in greater visual discomfort. This finding may be attributable to the neurobiologic mechanism that mediates the pain elicited by light. PMID- 21296820 TI - In vivo evaluation of laser-induced choroidal neovascularization using spectral domain optical coherence tomography. AB - PURPOSE: To describe the in vivo evolution of laser-induced choroidal neovascularization (CNV) in mice using spectral domain optical coherence tomography (SD-OCT). METHODS: Laser photocoagulation was applied to the mouse fundus using a 532-nm diode laser (100, 150, and 200 mW; 100-MUm diameter, 0.1 second duration). SD-OCT examination was performed immediately after laser application and at days 3, 5, 7, 14, 21, and 28 after laser. Fluorescein angiography (FA) was performed at day 5, 7, 14, and 28. Acquired SD-OCT images were analyzed to describe morphologic features, measure CNV size and retinal thickness, and assess the frequency of lesions resulting in fluid accumulation. Finally, SD-OCT images were compared to fluorescein angiograms and histologic sections with immunostaining at similar time points. RESULTS: SD-OCT allowed visualization of the initial laser damage and the subsequent stages of the injury response. CNV formation reached its maximum size at day 5. By day 7, significant size reduction was observed (P < 0.001), continuing through days 14 and 28. Exudation signs, such as fluid accumulation and increase in retinal thickness, followed the same time course, with a peak at day 5 and a decrease by day 7. Delivery of higher laser energy levels to the RPE/choroid complex resulted in a significant percentage of lesions demonstrating excessive chorioretinal damage without CNV formation. CONCLUSIONS: SD-OCT is a fast and reliable tool for the in vivo evaluation of laser-induced CNV, allowing quantification of lesion size and exudation parameters. Moreover, it provides morphologic information that correlates with histologic findings. PMID- 21296821 TI - The impact of retardance pattern variability on nerve fiber layer measurements over time using GDx with variable and enhanced corneal compensation. AB - PURPOSE: To examine the impact of retardance pattern variability on retinal nerve fiber layer (RNFL) measurements over time using scanning laser polarimetry with variable (GDxVCC) and enhanced corneal compensation (GDxECC; both by Carl Zeiss Meditec, Inc., Dublin, CA). METHODS: Glaucoma suspect and glaucomatous eyes with 4 years of follow-up participating in the Advanced Imaging in Glaucoma Study were prospectively enrolled. All eyes underwent standard automated perimetry (SAP), GDxVCC, and GDxECC imaging every 6 months. SAP progression was determined with point-wise linear regression analysis of SAP sensitivity values. Typical scan score (TSS) values were extracted as a measure of retardance image quality; an atypical retardation pattern (ARP) was defined as TSS < 80. TSS fluctuation over time was measured using three parameters: change in TSS from baseline, absolute difference (maximum minus minimum TSS value), and TSS variance. Linear mixed effects models that accommodated the association between the two eyes were constructed to evaluate the relationship between change in TSS and RNFL thickness over time. RESULTS: Eighty-six eyes (51 suspected glaucoma, 35 glaucomatous) of 45 patients were enrolled. Twenty (23.3%) eyes demonstrated SAP progression. There was significantly greater fluctuation in TSS over time with GDxVCC compared with GDxECC as measured by absolute difference (18.40 +/- 15.35 units vs. 2.50 +/ 4.69 units; P < 0.001), TSS variance (59.63 +/- 87.27 units vs. 3.82 +/- 9.63 units, P < 0.001), and change in TSS from baseline (-0.83 +/- 11.2 vs. 0.25 +/- 2.9, P = 0.01). The change in TSS over time significantly (P = 0.006) influenced the TSNIT average RNFL thickness when measured by GDxVCC but not by GDxECC. CONCLUSIONS: Longitudinal images obtained with GDxECC have significantly less variability in TSS and retardance patterns and have reduced bias produced by ARP on RNFL progression assessment. PMID- 21296822 TI - The effect of lens-induced anisometropia on accommodation and vergence during human visual development. AB - PURPOSE: Clear and single binocular vision, a prerequisite for normal human visual development, is achieved through accommodation and vergence. Anisometropia is associated with abnormal visual development, but its impact on accommodation and vergence, and therefore on the individual's visual experience, is not known. This study determined the impact of transiently induced anisometropia on accommodative and vergence performance of the typically developing human visual system. METHODS: One hundred eighteen subjects (age range, 2.9 months to 41.1 years) watched a cartoon movie that moved between 80 and 33 cm under six different viewing conditions: binocular and monocular, and with +/-2 diopters (D) and +/-4 D of lens-induced anisometropia. Twenty-one subjects (age range, 3.1 months to 12.1 years) also watched the movie with 11% induced aniseikonia. Accommodation and vergence were recorded in both eyes using a videoretinoscope (25 Hz). RESULTS: The main effect of viewing condition was statistically significant for both accommodation and vergence (both P < 0.001), with monocular accommodative and vergence gains statistically significantly smaller than the binocular and four induced anisometropia conditions (P < 0.001 for both accommodation and vergence). The main effect of age approached significance for accommodation (P = 0.06) and was not significant for vergence (P = 0.32). Accommodative and vergence gains with induced aniseikonia were not statistically significantly different from the binocular condition (both P > 0.5). CONCLUSIONS: Accommodative and vergence gains of the typically developing visual system deteriorated marginally (accommodation more than vergence) with transiently induced anisometropia (up to +/-4 D) and did not deteriorate significantly with induced aniseikonia of 11%. Some binocular cues remained with +/-4 D of induced anisometropia and 11% induced aniseikonia, as indicated by the accommodative and vergence gains being higher than in monocular viewing. PMID- 21296823 TI - Activated gammadelta T cells promote the activation of uveitogenic T cells and exacerbate EAU development. AB - PURPOSE: To determine how the activation of gammadelta T cells affects the generation of uveitogenic alphabeta T cells and the development of experimental autoimmune uveitis (EAU). METHODS: gammadelta T cells were isolated from B6 mice immunized with the uveitogenic peptide IRBP(1-20) and alphabeta T cells from immunized TCR-delta(-/-) mice. Resting gammadelta T cells were prepared by culture of separated gammadelta T cells in cytokine-free medium for 3 to 5 days, when they showed downregulation of CD69 expression. Activated gammadelta T cells were prepared by incubating resting gammadelta T cells with anti-gammadelta TCR (GL3) for 2 days. Responder alphabeta T cells were cocultured with immunizing antigen and antigen-presenting cells. The numbers of antigen-specific T cells expressing IL-17 or IFN-gamma were determined by intracellular staining followed by FACS analysis after stimulation, with or without the addition of purified gammadelta T cells. The cytokines in the culture medium were measured by ELISA. RESULTS: Highly enriched gammadelta T cells exert widely different effects on autoreactive alphabeta T cells in EAU, depending on the activation status of the gammadelta T cells. Whereas nonactivated gammadelta T cells had little effect on the activation of interphotoreceptor retinoid-binding protein-specific alphabeta T cells in vitro and in vivo, activated gammadelta T cells promoted the generation of uveitogenic T cells and exacerbated the development of EAU. CONCLUSIONS: The functional ability of gammadelta T cells is greatly influenced by their activation status. Activated gammadelta T cells exacerbate EAU through increased activation of uveitogenic T cells. PMID- 21296824 TI - Reading rehabilitation of individuals with AMD: relative effectiveness of training approaches. AB - PURPOSE: To quantify the effects of three vision rehabilitation training approaches on improvements in reading performance. METHODS: Thirty subjects with AMD participated in the training portion of the study. The median age of the subjects was 79 years (range, 54-89 years). The three training modules were: Visual Awareness and Eccentric Viewing (module 1), Control of Reading Eye Movements (module 2), and Reading Practice with Sequential Presentation of Lexical Information (module 3). Subjects were trained for 6 weekly sessions on each module, and the order of training was counterbalanced. All subjects underwent four assessments: at baseline and at three 6-week intervals. Reading performance was measured before and after each training module. A separate group of 6 subjects was randomly assigned to a control condition in which there was no training. These subjects underwent repeated assessments separated by 6 weeks. RESULTS: Reading speeds decreased by an average of 8.4 words per minute (wpm) after training on module 1, increased by 27.3 wpm after module 2, and decreased by 9.8 wpm after module 3. Only the increase in reading speed after module 2 was significantly different from zero. Sentence reading speeds for the control group, who had no reading rehabilitation intervention, was essentially unchanged over the 18 weeks (0.96 +/- 1.3 wpm). CONCLUSIONS: A training curriculum that concentrates on eye movement control increased reading speed in subjects with AMD. This finding does not suggest that the other rehabilitation modules have no value; it suggests that they are simply not the most effective for reading rehabilitation. PMID- 21296825 TI - Cone photoreceptor abnormalities correlate with vision loss in patients with Stargardt disease. AB - PURPOSE. To study the relationship between macular cone structure, fundus autofluorescence (AF), and visual function in patients with Stargardt disease (STGD). METHODS. High-resolution images of the macula were obtained with adaptive optics scanning laser ophthalmoscopy (AOSLO) and spectral domain optical coherence tomography in 12 patients with STGD and 27 age-matched healthy subjects. Measures of retinal structure and AF were correlated with visual function, including best-corrected visual acuity, color vision, kinetic and static perimetry, fundus-guided microperimetry, and full-field electroretinography. Mutation analysis of the ABCA4 gene was completed in all patients. RESULTS. Patients were 15 to 55 years old, and visual acuity ranged from 20/25-20/320. Central scotomas were present in all patients, although the fovea was spared in three patients. The earliest cone spacing abnormalities were observed in regions of homogeneous AF, normal visual function, and normal outer retinal structure. Outer retinal structure and AF were most normal near the optic disc. Longitudinal studies showed progressive increases in AF followed by reduced AF associated with losses of visual sensitivity, outer retinal layers, and cones. At least one disease-causing mutation in the ABCA4 gene was identified in 11 of 12 patients studied; 1 of 12 patients showed no disease-causing ABCA4 mutations. CONCLUSIONS. AOSLO imaging demonstrated abnormal cone spacing in regions of abnormal fundus AF and reduced visual function. These findings provide support for a model of disease progression in which lipofuscin accumulation results in homogeneously increased AF with cone spacing abnormalities, followed by heterogeneously increased AF with cone loss, then reduced AF with cone and RPE cell death. PMID- 21296826 TI - Comparison of the in vitro tolerance and in vivo efficacy of traditional timolol maleate eye drops versus new formulations with bioadhesive polymers. AB - PURPOSE: To assess the in vitro tolerance and in vivo efficacy of new unpreserved formulations of timolol maleate (TM) in aqueous solutions of bioadhesive polymers used for dry eye treatment and to compare them with three traditional TM formulations: unpreserved Timabak (Thea, Madrid, Spain), benzalkonium chloride (BAK)-preserved Timoftol (Frosst Laboratories, Madrid, Spain), and BAK-preserved Timolol Sandoz (Frosst Laboratories). METHODS: New formulations were composed of TM (0.5%) and carboxymethyl cellulose (0.5%), hyaluronic acid (0.2%), or hydroxypropylmethyl cellulose (0.3% or 0.5%). In vitro tolerance was determined in human corneal-limbal epithelial cells and normal human conjunctival cells. The ocular hypotensive effect was evaluated measuring IOP in rabbit eyes for 8 hours. RESULTS: In all cases, cell survival after exposure to the formulations was greater in the new unpreserved TM formulations than in the traditional TM solutions (BAK-preserved and unpreserved). In addition, the new formulations were demonstrated to maintain the hypotensive effect of TM in different magnitudes. The maximum hypotensive effect was reached by TM 0.5% in carboxymethyl cellulose 0.5% (32.37%). CONCLUSIONS: The results demonstrated that new unpreserved formulations of TM with bioadhesive polymers decreased IOP in rabbits and reached values closer to those reached by traditional solutions. Furthermore, new formulations presented a significantly higher in vitro tolerance than the same compound in traditional formulations. Although unpreserved formulations are usually more expensive, preservative-free antiglaucoma eye drops should improve compliance and adherence in the medical treatment of glaucoma. Bioadhesive polymers could be part of antiglaucoma formulations to reduce ocular toxicity, improve drug efficacy, and protect the ocular surface in long-term therapies. PMID- 21296827 TI - Comparing corneal variables in healthy subjects and patients with primary open angle glaucoma. AB - PURPOSE: This study was designed to identify possible differences between healthy subjects and patients with primary open-angle glaucoma (POAG) in keratometry, central corneal thickness, overall corneal thickness, mean thickness of a circular zone centered at the corneal apex of 1-mm radius (zone I), and mean thickness of several concentric rings also centered at the apex of 1-mm width (zones II to VI, respectively). METHODS: These variables were recorded in 126 healthy subjects and 130 patients with POAG. Corneal thicknesses and the power of the flattest and steepest axes were compared between the two populations using a t-test and the position of the flattest axis using a Mann-Whitney U test. A binary logistic regression procedure was used to determine the diagnostic capacity of the corneal variables using the area under the receiver operator characteristic curve (AUC) to select the best regression equation. RESULTS: Significant differences between subjects and patients were detected in mean corneal thickness and in mean thicknesses of zones I to VI. The logistic regression model included as predictors the mean corneal thickness and the mean thicknesses of zones IV and VI; for this model, the AUC was 0.711, sensitivity was 67.7%, and specificity was 65.5%. CONCLUSIONS: Healthy subjects and glaucoma patients differ significantly in terms of mean overall corneal thickness and thicknesses of the corneal zones I to VI defined here. The variables mean corneal thickness and mean thicknesses of zones IV and VI are able to discriminate between subjects with or without glaucoma. PMID- 21296828 TI - Low-luminance contrast stimulation is optimal for early detection of glaucoma using multifocal visual evoked potentials. AB - PURPOSE: The blue-on-yellow multifocal visual evoked potential (BonY mfVEP) stimulus is more sensitive than the conventional black-and-white pattern-reversal stimulus in identifying early glaucoma. BonY employs pattern-onset stimulation and lower luminance contrast (40%) in addition to color. This study was conducted to elucidate the mechanism responsible for the enhanced performance of the BonY stimulus. METHODS: Multifocal pattern-onset VEPs were recorded in response to BonY, high-luminance contrast achromatic (HLA) and low-luminance contrast achromatic (LLA) stimulations in 30 normal subjects (to construct normative databases) and 23 patients with early glaucoma (mean deviation [MD] < 6 dB). In addition, the specificity of BonY and LLA stimulation was examined in a subset of 25 normal subjects. RESULTS: In normal subjects, LLA mfVEPs had significantly lower amplitudes than did BonY and HLA mfVEPs (P < 0.001), which were not significantly different from each other. In glaucomatous eyes, all three stimuli demonstrated significantly reduced amplitudes in comparison with those of normal eyes. Although the sensitivities of both BonY and LLA in identifying subjective visual field defects were similarly high (93% and 89.7%, respectively), HLA showed only a 79.3% detection rate. BonY and LLA demonstrated significantly higher defect severity scores than did HLA (P < 0.05 for both). Specificities for BonY and LLA were similar (96%). CONCLUSIONS: BonY and LLA mfVEPs performed comparably, and both were significantly better than the HLA mfVEP in identifying early glaucoma. Enhanced performance of BonY stimulation is most likely due to its low-luminance contrast component rather than the pattern-onset mode of presentation or its chromatic properties. PMID- 21296829 TI - Suppression of choroidal neovascularization and quantitative and qualitative inhibition of VEGF and CCL2 by heparin. AB - PURPOSE: To study the effect of heparin on the development of laser-induced choroidal neovascularization (CNV) and to assess the underlying molecular mechanisms. METHODS: Bone marrow transplantation (BMT) was conducted by intravenous injection of green fluorescence protein (GFP)-labeled bone marrow cells (1 * 10(7) cells) into irradiated (9 Gy) C57BL/6J mice. Laser photocoagulation was applied to induce CNV; subsequently, unfractionated heparin or phosphate-buffered saline was injected into mice that did or did not undergo BMT. The area of CNV, distribution of injected heparin, and quantities of infiltrating cells positive for Griffonia simplicifolia (GS) and GFP inside and outside the CNV were evaluated. Effects of heparin on the secretion of VEGF, CCL2, and TNF-alpha by ARPE19 cells and on the binding of VEGF, CCL2, TNF-alpha, and their receptors were analyzed in vitro. RESULTS: Intravitreal injection of heparin at higher doses reduced the size of the CNV. Heparin localized at the vascular structures and photoreceptor layers adjacent to the laser scar. Only GS positive cells infiltrating outside the CNV were reduced significantly, but not those inside the CNV or those expressing GFP. Relative decreases in VEGF and CCL2 levels were observed in media of ARPE19 cells at higher heparin concentrations. In vitro binding assays revealed that heparin and porcine ocular fluid, respectively, suppressed the binding of VEGF to VEGFR2 and CCL2 to CCR2. CONCLUSIONS: Intravitreal heparin injection inhibited CNV development. Reduced VEGF and CCL2 secretion by RPE cells and suppression of VEGF-VEGFR2 and CCL2-CCR2 interactions at the laser site mediated by heparin may contribute to the pharmacologic effect. PMID- 21296830 TI - Validation of a mutant of the pore-forming toxin sticholysin-I for the construction of proteinase-activated immunotoxins. AB - The use of pore-forming toxins from sea anemones (actinoporins) in the construction of immunotoxins (ITs) against tumour cells is an alternative for cancer therapy. However, the main disadvantage of actinoporin-based ITs obtained so far has been the poor cellular specificity associated with the toxin's ability to bind and exert its activity in almost any cell membrane. Our final goal is the construction of tumour proteinase-activated ITs using a cysteine mutant at the membrane binding region of sticholysin-I (StI), a cytolysin isolated from the sea anemone Stichodactyla helianthus. The mutant and the ligand moiety would be linked by proteinase-sensitive peptides through the StI cysteine residue blocking the toxin binding region and hence the IT non-specific killing activity. To accomplish this objective the first step was to obtain the mutant StI W111C, and to evaluate the impact of mutating tryptophan 111 by cysteine on the toxin pore forming capacity. After proteolysis of the cleavage sequence, a short peptide would remain attached to the toxin. The next step was to evaluate whether this mutant is able to form pores even with a residual peptide linked to cysteine 111. In this work we demonstrated that (i) StI W111C shows pore-forming capacity in a nanomolar range, although it is 8-fold less active than the wild-type recombinant StI, corroborating the previously reported importance of residue 111 for the binding of StI to membranes, and (ii) the mutant is able to form pores even with a residual seven-residue peptide linked to cysteine 111. In addition, it was demonstrated that binding of a large molecule to cysteine 111 renders an inactive toxin that is no longer able to bind to the membrane. These results validate the mutant StI W111C for its use in the construction of tumour proteinase-activated ITs. PMID- 21296831 TI - Meta-analysis of bone marrow transplantation treatment studies: mixing 'apples and oranges'. PMID- 21296832 TI - Effects of selected South African plant extracts on haemolysis and coagulation. AB - The use of herbal preparations for staunching blood flow and reducing the risk of vascular thrombosis is common worldwide. In this study, aqueous and methanolic extracts of plants used to treat blood-associated complaints were investigated to determine their effects on red blood cell haemolysis and coagulation. The extent of haemolysis was determined spectrophotometrically. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) as indicators of coagulation rate were determined using a coagulatometer. All of the plant extracts tested had a significant effect on coagulation time, prolonging the aPTT. Cassia petersiana had the greatest prolonging effect on PT compared to the control, phosphate buffered saline (PBS). As all of the herbal extracts tested had a delaying effect on coagulation, patients using herbal/plant therapies should be cautioned to stop their medication before surgery. PMID- 21296833 TI - Neuroprotection by estradiol: some important considerations. PMID- 21296834 TI - Decreased paraoxonase 1 activity and increased oxidative stress in low lead exposed workers. AB - Paraoxonase 1 (PON1) has been proposed as an antioxidant enzyme. Although lead inhibited PON1 activity has been demonstrated mostly based on in vitro experiments, it is uncertain whether this phenomenon is relevant in pathogenesis of lead-induced oxidative stress in the lead exposure. We examined associations of blood lead levels (BLL) and PON1 activity along with oxidative stress parameters in lead exposure workers. We determined malondialdehyde (MDA), conjugated diene (CD), total peroxides (TP), total antioxidant status (TAS), the oxidative stress index (OSI), and PON1 activity in earthenware factory workers (n = 60) and control subjects (n = 65). The lead-exposed group significantly increased lipid peroxidation parameters and OSI compared to the control group (p < 0.001). The lead-exposed group had significantly decreased PON1 activity and TAS levels compared to the control group (p < 0.001). Multiple linear regression analysis revealed that BLL were significantly correlated with decreased TAS (r = 0.496) and PON1 activity (r = -0.434), but with increased CD (r = 0.694), TP (r = 0.614), MDA (r = 0.788), and OSI (r = 0.722). Interestingly, BLL at 10 ug/dL significantly decreased PON1 activity and increased oxidative stress parameters with insignificant changes in other biochemical and hematological parameters. Altogether, the reduction of PON1 activity may associate in an imbalance in pro oxidants and antioxidants, leading to oxidative damage in lead-exposed workers even at low BLL. PMID- 21296835 TI - Audiovisual feedback and quality of CPR. PMID- 21296836 TI - Does home oxygen benefit people with chronic heart failure? PMID- 21296837 TI - Research to decrease areas of clinical uncertainty. PMID- 21296838 TI - Effect of real-time feedback during cardiopulmonary resuscitation outside hospital: prospective, cluster-randomised trial. AB - OBJECTIVE: To investigate whether real-time audio and visual feedback during cardiopulmonary resuscitation outside hospital increases the proportion of subjects who achieved prehospital return of spontaneous circulation. DESIGN: A cluster-randomised trial. SUBJECTS: 1586 people having cardiac arrest outside hospital in whom resuscitation was attempted by emergency medical services (771 procedures without feedback, 815 with feedback). SETTING: Emergency medical services from three sites within the Resuscitation Outcomes Consortium in the United States and Canada. INTERVENTION: Real-time audio and visual feedback on cardiopulmonary resuscitation (CPR) provided by the monitor-defibrillator. MAIN OUTCOME MEASURE: Prehospital return of spontaneous circulation after CPR. RESULTS: Baseline patient and emergency medical service characteristics did not differ between groups. Emergency medical services muted the audible feedback in 14% of cases during the period with feedback. Compared with CPR clusters lacking feedback, clusters assigned to feedback were associated with increased proportion of time in which chest compressions were provided (64% v 66%, cluster-adjusted difference 1.9 (95% CI 0.4 to 3.4)), increased compression depth (38 v 40 mm, adjusted difference 1.6 (0.5 to 2.7)), and decreased proportion of compressions with incomplete release (15% v 10%, adjusted difference -3.4 (-5.2 to -1.5)). However, frequency of prehospital return of spontaneous circulation did not differ according to feedback status (45% v 44%, adjusted difference 0.1% (-4.4% to 4.6%)), nor did the presence of a pulse at hospital arrival (32% v 32%, adjusted difference -0.8 (-4.9 to 3.4)), survival to discharge (12% v 11%, adjusted difference -1.5 (-3.9 to 0.9)), or awake at hospital discharge (10% v 10%, adjusted difference -0.2 (-2.5 to 2.1)). CONCLUSIONS: Real-time visual and audible feedback during CPR altered performance to more closely conform with guidelines. However, these changes in CPR performance were not associated with improvements in return of spontaneous circulation or other clinical outcomes. Trial Registration Clinical Trials NCT00539539. PMID- 21296839 TI - Pfizer closes Kent plant as it trims research spending by $1bn a year. PMID- 21296843 TI - Number of UK women who will get breast cancer has risen to one in eight. PMID- 21296844 TI - Home exercise equipment-related injuries among children in the United States. AB - This study investigated home exercise equipment-related injuries to children in the United States. Data from the National Electronic Injury Surveillance System were analyzed for children 18 years old and younger. An estimated 241 573 children with home exercise equipment-related injuries were treated in US hospital emergency departments from 1990 through 2008, averaging 12 714 children per year. There was a statistically significant increase in the annual number (41.9%) and rate of home exercise equipment-related injuries during the study period. Children younger than 10 years accounted for 71.4% of these injuries. Laceration (37.2%) was the leading injury diagnosis, and the most commonly injured body regions were the head (28.6%), finger/hand (22.0%), and foot (10.9%). The majority of injuries were associated with stationary bicycles (26.5%), treadmills (25.3%), and jump ropes (21.5%). The increasing number and rate of home exercise equipment-related injuries to US children underscores the need for increased efforts to prevent these injuries. PMID- 21296845 TI - A semiquantitative way to measure MUAC in anaesthesia. AB - As anaesthetists we have to learn to recognize malnourished children. The implications for fluid management, cardiac function, weaning and nutrition are important. Mid-upper arm circumference (MUAC) is the most useful anthropometric parameter for severely debilitated patients. We observed that the measuring tape is frequently missing or out of stock. In order to overcome this challenge we searched for an always available, easy to understand method with acceptable accuracy which is free. We conducted a study of 262 volunteers in four professional groups. In a deliberately short training session of 5-10 min we provided them with gauze bandages and asked them to measure the circumference with their own fingers, nails and interphalangeal crests. Later we showed them bandages (substitutes for upper arms) of different sizes and asked them to determine whether these were bigger or smaller than the original or the same size. Of the 1048 decisions, 91.2% were taken correctly and 97.2% were acceptable for the identification of a malnourished patient. Two hundred and thirty-five of the 262 participants (89.7%) would have been able to identify a severely malnourished child. The best subgroup recognized all children in danger and even the non-medical subgroup diagnosed 80.6%. The child who was not in need of special resources was recognized by all 262 participants (100%). Only two (0.76%) made decisions which were contradictory. A semiquantitative measurement of MUAC is possible. Our method is sufficiently exact, needs minimal training, alerts the anaesthetist and is free. We should train all professionals working in developing countries with malnourished children in the 'one grip' measurement of MUAC. PMID- 21296846 TI - Human ocular angiostrongyliasis: a literature review. AB - Human ocular angiostrongyliasis caused by Angiostrongylus cantonensis infection in the eye is a very rare condition. Until now, there has been no comprehensive analysis of this disease. We searched and analysed the references found on the Internet that refer to human ocular angiostrongyliasis and reviewed the aetiology, clinical manifestations, diagnosis, epidemiology and treatment of the condition. Twenty-six references were found reporting 35 patients from 10 countries that were diagnosed with human ocular angiostrongyliasis. People are usually infected by eating raw or undercooked intermediate hosts of the parasite such as snails or contaminated vegetables. The most common symptom was visual loss. Although several treatments have been used, ocular angiostrongyliasis can still result in permanent visual impairment and may even cause blindness. As the eye is the site of infection and direct visualization is possible, ocular examination is crucial for diagnosis. The therapeutic success depended on early and complete surgical removal. PMID- 21296847 TI - Applying WHO's 'workforce indicators of staffing need' (WISN) method to calculate the health worker requirements for India's maternal and child health service guarantees in Orissa State. AB - OBJECTIVE: In one district of Orissa state, we used the World Health Organization's Workforce Indicators of Staffing Need (WISN) method to calculate the number of health workers required to achieve the maternal and child health 'service guarantees' of India's National Rural Health Mission (NRHM). We measured the difference between this ideal number and current staffing levels. METHODS: We collected census data, routine health information data and government reports to calculate demand for maternal and child health services. By conducting 54 interviews with physicians and midwives, and six focus groups, we were able to calculate the time required to perform necessary health care tasks. We also interviewed 10 new mothers to cross-check these estimates at a global level and get assessments of quality of care. FINDINGS: For 18 service centres of Ganjam District, we found 357 health workers in our six cadre categories, to serve a population of 1.02 million. Total demand for the MCH services guaranteed under India's NRHM outpaced supply for every category of health worker but one. To properly serve the study population, the health workforce supply should be enhanced by 43 additional physicians, 15 nurses and 80 nurse midwives. Those numbers probably under-estimate the need, as they assume away geographic barriers. CONCLUSIONS: Our study established time standards in minutes for each MCH activity promised by the NRHM, which could be applied elsewhere in India by government planners and civil society advocates. Our calculations indicate significant numbers of new health workers are required to deliver the services promised by the NRHM. PMID- 21296848 TI - Basal sympathetic activity generated in neonatal mouse brainstem-spinal cord preparation requires T-type calcium channel subunit 1H. AB - The T-type calcium channel (T-channel) is a low-voltage-activated channel. Whether T-channels are involved in sympathetic nerve discharge (SND), with subunits alpha1G and alpha1H differentially regulating SND genesis, was explored using in vitro brainstem-spinal cord-splanchnic sympathetic nerve preparations of wild-type and genetically modified B6 mice. Applications of 10-80 MUm NNC 55-0396 to block T-channels in wild-type mice reduced SND in a concentration-dependent manner. Amounts of SND were measured in units of signal-to-noise ratio for objective comparisons between mouse groups. Comparable amounts of SND were observed in wild-type and alpha1G(-/-) mice. However, only ~40% of the amount of SND of that in wild-type or alpha1G(-/-) mice was observed in alpha1H(-/-) mice. Whether a diminished excitatory drive originating in the brainstem could explain a low SND in alpha1H(-/-) mice was evaluated by cervical cord transections. Isolated spinal cord preparations of mice with different genetic backgrounds produced comparable amounts of SND. Excitability of the spinal circuitry was further explored by bath applications of 5 mm glutamate. Glutamate applications produced a prominent SND rise in all mouse groups. The ratios of glutamate induced SND rise were similar between wild-type and alpha1H(-/-) mice, but significantly higher in alpha1G(-/-) mice. Taken together, these results suggest that alpha1H in mouse brainstem is essential for the genesis of presympathetic drive, whereas alpha1G in mouse spinal cord is functionally inhibitory for SND genesis. We conclude that alpha1H and alpha1G T-channel subunits may differentially regulate mouse SND genesis at different levels of the neuraxis. PMID- 21296849 TI - A Japanese case of familial Mediterranean fever presenting diffuse bone marrow uptake of FDG-PET and high levels of neutrophil membrane CD64 expression. PMID- 21296850 TI - FCGR3B copy number variation is associated with systemic lupus erythematosus risk in Afro-Caribbeans. AB - OBJECTIVES: To evaluate FCGR3B copy number variation (CNV) in African and European populations and to determine if FCGR3B copy number is associated with SLE and SLE nephritis risk in Afro-Caribbeans, adjusting for African genetic ancestry. METHODS: We estimated FCGR3B to determine if there were ethnic variations in CNV (unrelated unadmixed Europeans and Africans). We then examined CNV at FCGR3B in relation to SLE and SLE nephritis within a case-control collection of 134 cases of SLE (37 with SLE nephritis) and 589 population controls of mainly Afro-Caribbean descent resident in Trinidad. RESULTS: We found a significant difference in copy number FCGR3B distribution between unadmixed African and European UK cohorts, with 27 (29%) vs 3 (5%) for those with low (0 or 1) copy FCGR3B, respectively, P = 0.002. In a Trinidadian SLE case-control study, low FCGR3B CNV was associated with SLE risk 1.7 (95% CI 1.1, 2.8), P = 0.02, which remained after adjustment for African genetic ancestry; odds ratios (ORs) 1.7 (95% CI 1.0, 2.8), P = 0.04. CONCLUSION: Our studies suggest that FCGR3B low copy number is associated with SLE risk in Afro-Caribbean populations independently of CNV due to African ancestry. PMID- 21296851 TI - Commentary: Fatherhood status and prostate cancer risk--the jury is still out. PMID- 21296852 TI - Cohort description: the Northern Ireland Longitudinal Study (NILS). PMID- 21296853 TI - Trends in malnutrition and mortality in Darfur, Sudan, between 2004 and 2008: a meta-analysis of publicly available surveys. AB - BACKGROUND: The humanitarian response to the crisis in Darfur is the largest humanitarian operation in the world. To investigate the evolution of the conditions of the affected population, we analysed trends in malnutrition and mortality, the most widely accepted indicators for assessing the degree of severity of a crisis. METHODS: We did a meta-analysis of 164 publicly available surveys taking into account changes in the contextual situation and humanitarian aid; type of population [residents and internally displaced persons (IDPs)]; and seasonal variations. Data on global acute malnutrition (GAM), severe acute malnutrition (SAM), crude death rate (CDR) and under-five death rate (U5DR) were analysed using a random effect model. RESULTS: GAM and SAM decreased by 16% and 28%, respectively, in 2004-05, whereas CDR dropped by 44-75% per year depending on state and type of population and U5DR decreased by an overall 50% yearly. Both security and the humanitarian contexts became increasingly complex after 2005, but levels of malnutrition stabilized in North and South Darfur. In West Darfur, GAM remained stable but SAM tended to increase for IDPs, although mortality rates remained constant. Mortality increased slightly for residents in South Darfur after 2005, even though nutritional status was stable. GAM, SAM, CDR and U5DR fluctuated markedly with seasons. CONCLUSION: A meta-analysis of myriads of surveys permitted us to draw an overall picture of the situation in Darfur and to identify some of its influencing factors. The large humanitarian operation, which gained momentum through 2004-05, was able to contain the crisis despite huge difficulties, but did not compensate for seasonal variations. The situation has remained fragile with some negative patterns tending to emerge. It is crucial that the humanitarian situation continues to be closely monitored. PMID- 21296854 TI - Avoidable cancer deaths globally. PMID- 21296855 TI - Global cancer statistics. AB - The global burden of cancer continues to increase largely because of the aging and growth of the world population alongside an increasing adoption of cancer causing behaviors, particularly smoking, in economically developing countries. Based on the GLOBOCAN 2008 estimates, about 12.7 million cancer cases and 7.6 million cancer deaths are estimated to have occurred in 2008; of these, 56% of the cases and 64% of the deaths occurred in the economically developing world. Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among females, accounting for 23% of the total cancer cases and 14% of the cancer deaths. Lung cancer is the leading cancer site in males, comprising 17% of the total new cancer cases and 23% of the total cancer deaths. Breast cancer is now also the leading cause of cancer death among females in economically developing countries, a shift from the previous decade during which the most common cause of cancer death was cervical cancer. Further, the mortality burden for lung cancer among females in developing countries is as high as the burden for cervical cancer, with each accounting for 11% of the total female cancer deaths. Although overall cancer incidence rates in the developing world are half those seen in the developed world in both sexes, the overall cancer mortality rates are generally similar. Cancer survival tends to be poorer in developing countries, most likely because of a combination of a late stage at diagnosis and limited access to timely and standard treatment. A substantial proportion of the worldwide burden of cancer could be prevented through the application of existing cancer control knowledge and by implementing programs for tobacco control, vaccination (for liver and cervical cancers), and early detection and treatment, as well as public health campaigns promoting physical activity and a healthier dietary intake. Clinicians, public health professionals, and policy makers can play an active role in accelerating the application of such interventions globally. PMID- 21296856 TI - Shadow of doubt. PMID- 21296857 TI - Biomedical research in Germany: the role of ethics committee and state medical association. PMID- 21296858 TI - Research oversight in Germany: safeguards and shortcomings. PMID- 21296859 TI - Hydroxyethyl starches: what do we still know? PMID- 21296860 TI - Batf promotes growth arrest and terminal differentiation of mouse myeloid leukemia cells. AB - Batf is a basic leucine zipper transcription factor belonging to the activator protein-1 superfamily. Batf expression is regulated following stimulation of both lymphoid and myeloid cells. When treated with leukemia inhibitory factor, mouse M1 myeloid leukemia cells commit to a macrophage differentiation program that is dependent on Stat3 and involves the induction of Batf gene transcription via the binding of Stat3 to the Batf promoter. RNA interference was employed to block Batf induction in this system and the cells failed to growth arrest or to terminally differentiate. Restoring Batf expression not only reversed the differentiation-defective phenotype but also caused the cells to display signs of spontaneous differentiation in the absence of stimulation. Efforts to define genetic targets of the Batf transcription factor in M1 cells led to the identification of c-myb, a proto-oncogene known to promote blood cell proliferation and to inhibit the differentiation of M1 cells. These results provide strong evidence that Batf mediates the differentiation-inducing effects of Stat3 signaling in M1 cells and suggest that Batf may play a similar role in other blood cell lineages where alterations to the Jak-Stat pathway are hallmarks of disrupted development and disease. PMID- 21296861 TI - Targeting cell spreading: a method of sensitizing metastatic tumor cells to TRAIL induced apoptosis. AB - TNF-related apoptosis-inducing ligand (TRAIL) is a current focus for the development of new cancer therapies, because of its selective induction of apoptosis in cancer cells. TRAIL has previously been shown to be important for tumor cell clearance from the liver; however, many cancer cell lines show some resistance toward TRAIL, posing a problem for the future use of TRAIL therapies. In this study, we show that interfering with a cell's ability to attach and spread onto a matrix can sensitize tumor cells to TRAIL-induced apoptosis in vitro. We targeted different members of the integrin signaling pathway using siRNA or inhibitors, including beta-integrins, talin, Src, and downstream survival pathways PI3K and MAPK. Targeting any of these molecules could sensitize both MDA-MB-231 human breast cancer cells and TRAIL-resistant 1205Lu melanoma cells to TRAIL-induced apoptosis in vitro. Transcriptionally targeting the cytoskeleton, using myocardin-related transcription factor depletion to disrupt the transcription of cytoskeletal proteins, also caused TRAIL sensitization in MDA-MB-231 cells. We showed that this sensitivity to TRAIL correlated with increased activation of the intrinsic pathway of apoptosis. Manipulation of cell spreading therefore presents a potential method by which disseminated tumor cells could be sensitized to TRAIL therapies in vivo. PMID- 21296862 TI - Recombinant human granulocyte colony-stimulating factor in preterm neonates with sepsis and relative neutropenia: a randomized, single-blind, non-placebo controlled trial. AB - We performed a prospective, randomized, single-blind, non-placebo-controlled trial on preterm (<37 weeks) neonates (birth weight <2000g) with sepsis and absolute neutrophil counts (ANC) <5000 cells mm(-3) to study the effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on all-cause neonatal mortality and hematological parameters (total leucocyte (TLC, ANC, absolute monocyte and absolute platelet counts). The rhG-CSF group (n = 20) received 10 ug/kg/day of intravenous infusion of rhG-CSF once daily for 5 days along with conventional therapy, and the control group (n = 20) received conventional therapy alone. Hematological parameters on Days 0, 1, 3, 5, 7 and 14 of study entry and all-cause mortality rates at discharge were recorded. Baseline characteristics between the rhG-CSF and control group including mean birth weight (1395 +/- 289 vs. 1500 +/- 231g), mean gestational age (31.5 +/- 2.68 vs. 32.6 +/ 2.23 weeks), initial neonatal complaints and maternal characteristics were comparable. Mortality rates were significantly less among the rhG-CSF group (3/20 (15%) vs. 7/20 (35%), p < 0.05). By Day 5 (for TLC) and Day 3 (for ANC) of start of the intervention, rhG-CSF group had significantly higher TLC (8189 +/- 1570 vs. 6936 +/- 1128 cells mm(-3), p < 0.05) and ANC (4756 +/- 1089 vs. 4213 +/- 354 cells mm(-3), p < 0.05) compared to controls. ANC levels recovered to levels >5000 cells mm(-3) faster in the rhG-CSF group, with 80% babies having ANC >5000 cells mm(-3) by Day 7 of study entry compared with 35% in the control group (p < 0.05). Preterm neonates with sepsis and neutropenia treated with rhG-CSF adjunctive therapy have decreased all-cause mortality at discharge and a quicker recovery of their total leucocyte and ANC. PMID- 21296863 TI - Long-term consequences of the early treatment of children with congenital hypothyroidism detected by neonatal screening in Nanjing, China: a 12-year follow up study. AB - This study was performed to investigate the prevalence of congenital hypothyroidism (CH) in neonates in Nanjing, China and the long-term consequences of early treatment. A total of 442 454 neonates were screened for CH and 183 neonates were confirmed, with a prevalence of 1 in 2418. Of these, 163 neonates completed the follow-up process and 163 healthy children were recruited as the control group. The height, weight and body mass index (BMI) of the children with CH from 0.5 to 6 years were not significantly different from the control group (p > 0.05). The children with CH had a significantly increased risk for being overweight or obese between 0.5 and 6 years (p < 0.05). The children with CH showed a significantly lower developmental quotient (DQ) than the control group in all four areas of the Gesell test (p < 0.05). The results suggest that children with CH that has been identified by newborn screening and early treatment have normal growth and neuromotor development. PMID- 21296864 TI - Emotional and cognitive stimuli differentially engage the default network during inductive reasoning. AB - The brain's default network (DN) is comprised of several cortical regions demonstrating robust intrinsic connectivity at rest. The authors sought to examine the differential effects of emotional reasoning and reasoning under certainty upon the DN through the employment of an event-related fMRI design in healthy participants. Participants were presented with syllogistic arguments which were organized into a 2 * 2 factorial design in which the first factor was emotional salience and the second factor was certainty/uncertainty. We demonstrate that regions of the DN were activated both during reasoning that is emotionally salient and during reasoning which is more certain, suggesting that these processes are neurally instantiated on a network level. In addition, we present evidence that emotional reasoning preferentially activates the dorsomedial (dMPFC) subsystem of the DN, whereas reasoning in the context of certainty activates areas specific to the DN's medial temporal (MTL) subsystem. We postulate that emotional reasoning mobilizes the dMPFC subsystem of the DN because this type of reasoning relies upon the recruitment of introspective and self-relevant data such as personal bias and temperament. In contrast, activation of the MTL subsystem during certainty argues that this form of reasoning involves the recruitment of mnemonic and semantic associations to derive conclusions. PMID- 21296865 TI - Bottom-up and top-down emotion generation: implications for emotion regulation. AB - Emotion regulation plays a crucial role in adaptive functioning and mounting evidence suggests that some emotion regulation strategies are often more effective than others. However, little attention has been paid to the different ways emotions can be generated: from the 'bottom-up' (in response to inherently emotional perceptual properties of the stimulus) or 'top-down' (in response to cognitive evaluations). Based on a process priming principle, we hypothesized that mode of emotion generation would interact with subsequent emotion regulation. Specifically, we predicted that top-down emotions would be more successfully regulated by a top-down regulation strategy than bottom-up emotions. To test this hypothesis, we induced bottom-up and top-down emotions, and asked participants to decrease the negative impact of these emotions using cognitive reappraisal. We observed the predicted interaction between generation and regulation in two measures of emotional responding. As measured by self-reported affect, cognitive reappraisal was more successful on top-down generated emotions than bottom-up generated emotions. Neurally, reappraisal of bottom-up generated emotions resulted in a paradoxical increase of amygdala activity. This interaction between mode of emotion generation and subsequent regulation should be taken into account when comparing of the efficacy of different types of emotion regulation, as well as when reappraisal is used to treat different types of clinical disorders. PMID- 21296866 TI - The zebrafish dag1 mutant: a novel genetic model for dystroglycanopathies. AB - In a forward genetic approach to identify novel genes for congenital muscle diseases, a zebrafish mutant, designated patchytail, was identified that exhibits degenerating muscle fibers with impaired motility behavior. Genetic mapping identified a genomic locus containing the zebrafish ortholog of the dystroglycan gene (DAG1). Patchytail fish contain a point mutation (c.1700T>A) in dag1, resulting in a missense change p.V567D. This change is associated with reduced transcripts and a complete absence of protein. The absence of alpha-dystroglycan and beta-dystroglycan caused destabilization of dystroglycan complex, resulting in membrane damages. Membrane damage was localized on the extracellular matrix at myosepta as well as basement membrane between adjacent myofibers. These studies also identified structural abnormalities in triads at 3 days post fertilization (dpf) of dystroglycan-deficient muscles, significantly preceding sarcolemmal damage that becomes evident at 7 dpf. Immunofluorescence studies identified a subpopulation of dystroglycan that is expressed at t-tubules in normal skeletal muscles. In dag1-mutated fish, smaller and irregular-shaped t-tubule vesicles, as well as highly disorganized terminal cisternae of sarcoplasmic reticulum, were common. In addition to skeletal muscle defects, dag1-mutated fish have brain abnormalities and ocular defects in posterior as well as anterior chambers. These phenotypes of dystroglycan-deficient fish are highly reminiscent of the phenotypes observed in the human conditions muscle-eye-brain disease and Walker Warburg syndrome. This animal model will provide unique opportunities in the understanding of biological functions of dystroglycan in a wide range of dystroglycanopathies, as disruption of this gene in higher vertebrates results in early embryonic lethality. PMID- 21296867 TI - Maternal methyl-donor supplementation induces prolonged murine offspring colitis susceptibility in association with mucosal epigenetic and microbiomic changes. AB - Developmental epigenetic changes, such as DNA methylation, have been recognized as potential pathogenic factors in inflammatory bowel diseases, the hallmark of which is an exaggerated immune response against luminal microbes. A methyl-donor (MD) diet can modify DNA methylation at select murine genomic loci during early development. The components of the MDs are routinely incorporated into prenatal human supplements. Therefore, we studied the effects of maternal MD supplementation on offspring colitis susceptibility and colonic mucosal DNA methylation and gene expression changes in mice as a model. Additionally, we investigated the offspring mucosal microbiomic response to the maternal dietary supplementation. Colitis was induced by dextran sulfate sodium. Colonic mucosa from offspring of MD-supplemented mothers following reversal to control diet at weaning was interrogated by methylation-specific microarrays and pyrosequencing at postnatal days 30 (P30) and P90. Transcriptomic changes were analyzed by microarray profiling and real-time reverse transcription polymerase chain reaction. The mucosal microbiome was studied by high throughput pyrosequencing of 16S rRNA. Maternal MD supplementation induced a striking susceptibility to colitis in offspring. This phenotype was associated with colonic mucosal DNA methylation and expression changes. Metagenomic analyses did not reveal consistent bacteriomic differences between P30 and P90, but showed a prolonged effect of the diet on the offspring mucosal microbiome. In conclusion, maternal MD supplementation increases offspring colitis susceptibility that associates with persistent epigenetic and prolonged microbiomic changes. These findings underscore that epigenomic reprogramming relevant to mammalian colitis can occur during early development in response to maternal dietary modifications. PMID- 21296868 TI - Neutral mitochondrial heteroplasmy and the influence of aging. AB - The development and maintenance of mitochondrial heteroplasmy has important consequences for both health and heredity. Previous studies using pathogenic mutations have shown considerable variability between maternally related individuals and studies of several D-loop polymorphisms have suggested a relationship between heteroplasmy and somatic aging. To broadly explore the variation of human heteroplasmy and to clarify the dynamics of somatic heteroplasmy over the course of lifespan, we analyzed mitochondrial sequence variation across a range of ages. We utilized array-generated single-nucleotide polymorphism data that were well correlated with independent measures of heteroplasmy. Significant levels of heteroplasmy were identified at 0.24% of sites evaluated. By examining mother-child pairs, we found that heteroplasmy was inherited (30%) but could occur de novo in offspring or, conversely, be present in mothers but eliminated in their children (70%). Cumulatively, mitochondrial heteroplasmy across the genome increased significantly with advanced age (r = 0.224, P =8 * 10(-30)). Surprisingly, changes in heteroplasmy were not uniform with some sites demonstrating a loss of variation (increased homoplasmy) with aging. These data suggest that both mutation and selective pressure affect blood mitochondrial DNA sequence over the course of the human lifespan and reveal the unexpectedly dynamic nature of human heteroplasmy. PMID- 21296869 TI - Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy. AB - Parkin, an E3 ubiquitin ligase implicated in Parkinson's disease, promotes degradation of dysfunctional mitochondria by autophagy. Using proteomic and cellular approaches, we show that upon translocation to mitochondria, Parkin activates the ubiquitin-proteasome system (UPS) for widespread degradation of outer membrane proteins. This is evidenced by an increase in K48-linked polyubiquitin on mitochondria, recruitment of the 26S proteasome and rapid degradation of multiple outer membrane proteins. The degradation of proteins by the UPS occurs independently of the autophagy pathway, and inhibition of the 26S proteasome completely abrogates Parkin-mediated mitophagy in HeLa, SH-SY5Y and mouse cells. Although the mitofusins Mfn1 and Mfn2 are rapid degradation targets of Parkin, we find that degradation of additional targets is essential for mitophagy. These results indicate that remodeling of the mitochondrial outer membrane proteome is important for mitophagy, and reveal a causal link between the UPS and autophagy, the major pathways for degradation of intracellular substrates. PMID- 21296870 TI - For better and for worse: the relationship between future expectations and functioning in the second half of life. AB - OBJECTIVES: To examine age group differences in the relationship between future expectations about standards of living and physical, mental, and cognitive functioning in the second half of life. METHOD: Data from the Survey of Health, Ageing, and Retirement in Europe (N=27,687, mean age=64.44). RESULTS: First, with increasing age, the expectation to improve (ETI) and the expectation to worsen (ETW) in standards of living became more independent of each other. Second, with increasing age, ETI was less strongly correlated with functioning whereas ETW was more strongly correlated with it. Third, with increasing age, the relationship between ETI and functioning was more strongly moderated by ETW, so that adaptive functioning was associated with expectations that no major change is to occur and with expectations for both growth and decline. DISCUSSION: Late-life positive and negative expectancies are less interdependent than they are in younger age, probably due to their stronger interaction when associating with functioning. Expectancies interact either to reflect an attempt to preserve the functional status quo (low expectancy to improve and to decline) or may signal a highly complex mental organization (high expectancy to improve and to decline). PMID- 21296871 TI - Coordinated cancer germline antigen promoter and global DNA hypomethylation in ovarian cancer: association with the BORIS/CTCF expression ratio and advanced stage. AB - PURPOSE: Cancer germline (CG) antigens are frequently expressed and hypomethylated in epithelial ovarian cancer (EOC), but the relationship of this phenomenon to global DNA hypomethylation is unknown. In addition, the potential mechanisms leading to DNA hypomethylation, and its clinicopathologic significance in EOC, have not been determined. EXPERIMENTAL DESIGN: We used quantitative mRNA expression and DNA methylation analyses to determine the relationship between expression and methylation of X-linked (MAGE-A1, NY-ESO-1, XAGE-1) and autosomal (BORIS, SOHLH2) CG genes, global DNA methylation (5mdC levels, LINE-1, Alu, and Sat-alpha methylation), and clinicopathology, using 75 EOC samples. In addition, we examined the association between these parameters and a number of mechanisms proposed to contribute to DNA hypomethylation in cancer. RESULTS: CG genes were coordinately expressed in EOC and this was associated with promoter DNA hypomethylation. Hypomethylation of CG promoters was highly correlated and strongly associated with LINE-1 and Alu methylation, moderately with 5mdC levels, and rarely with Sat-alpha methylation. BORIS and LINE-1 hypomethylation, and BORIS expression, were associated with advanced stage. GADD45A expression, MTHFR genotype, DNMT3B isoform expression, and BORIS mRNA expression did not associate with methylation parameters. In contrast, the BORIS/CTCF expression ratio was associated with DNA hypomethylation, and furthermore correlated with advanced stage and decreased survival. CONCLUSIONS: DNA hypomethylation coordinately affects CG antigen gene promoters and specific repetitive DNA elements in EOC, and correlates with advanced stage disease. The BORIS/CTCF mRNA expression ratio is closely associated with DNA hypomethylation and confers poor prognosis in EOC. PMID- 21296872 TI - Lysate microarrays enable high-throughput, quantitative investigations of cellular signaling. AB - Lysate microarrays (reverse-phase protein arrays) hold great promise as a tool for systems-level investigations of signaling and multiplexed analyses of disease biomarkers. To date, however, widespread use of this technology has been limited by questions concerning data quality and the specificity of detection reagents. To address these concerns, we developed a strategy to identify high-quality reagents for use with lysate microarrays. In total, we tested 383 antibodies for their ability to quantify changes in protein abundance or modification in 20 biological contexts across 17 cell lines. Antibodies yielding significant differences in signal were further evaluated by immunoblotting and 82 passed our rigorous criteria. The large-scale data set from our screen revealed that cell fate decisions are encoded not just by the identities of proteins that are activated, but by differences in their signaling dynamics as well. Overall, our list of validated antibodies and associated protocols establish lysate microarrays as a robust tool for systems biology. PMID- 21296873 TI - A unified view of cystic fibrosis transmembrane conductance regulator (CFTR) gating: combining the allosterism of a ligand-gated channel with the enzymatic activity of an ATP-binding cassette (ABC) transporter. AB - The cystic fibrosis transmembrane conductance regulator (CFTR) is a unique ion channel in that its gating is coupled to an intrinsic enzymatic activity (ATP hydrolysis). This enzymatic activity derives from the evolutionary origin of CFTR as an ATP-binding cassette transporter. CFTR gating is distinct from that of a typical ligand-gated channel because its ligand (ATP) is usually consumed during the gating cycle. However, recent findings indicate that CFTR gating exhibits allosteric properties that are common to conventional ligand-gated channels (e.g. unliganded openings and constitutive mutations). Here, we provide a unified view of CFTR gating that combines the allosterism of a ligand-gated channel with its unique enzymatic activity. PMID- 21296874 TI - Genetic and molecular basis of inflammasome-mediated disease. PMID- 21296875 TI - Regulation of fatty acid metabolism by cell autonomous circadian clocks: time to fatten up on information? AB - Molecular, cellular, and animal-based studies have recently exposed circadian clocks as critical regulators of energy balance. Invariably, mouse models of genetically manipulated circadian clock components display features indicative of altered lipid/fatty acid metabolism, including differential adiposity and circulating lipids. The purpose of this minireview is to provide a comprehensive summary of current knowledge regarding the regulation of fatty acid metabolism by distinct cell autonomous circadian clocks. The implications of these recent findings for cardiometabolic disease and human health are discussed. PMID- 21296876 TI - CK2 phosphorylation of an acidic Ser/Thr di-isoleucine motif in the Na+/H+ exchanger NHE5 isoform promotes association with beta-arrestin2 and endocytosis. AB - Internalization of the Na(+)/H(+) exchanger NHE5 into recycling endosomes is enhanced by the endocytic adaptor proteins beta-arrestin1 and -2, best known for their preferential recognition of ligand-activated G protein-coupled receptors (GPCRs). However, the mechanism underlying their atypical association with non GPCRs, such as NHE5, is unknown. In this study, we identified a highly acidic, serine/threonine-rich, di-isoleucine motif (amino acids 697-723) in the cytoplasmic C terminus of NHE5 that is recognized by beta-arrestin2. Gross deletions of this site decreased the state of phosphorylation of NHE5 as well as its binding and responsiveness to beta-arrestin2 in intact cells. More refined in vitro analyses showed that this site was robustly phosphorylated by the acidotropic protein kinase CK2, whereas other kinases, such as CK1 or the GPCR kinase GRK2, were considerably less potent. Simultaneous mutation of five Ser/Thr residues within 702-714 to Ala ((702)ST/AA(714)) abolished phosphorylation and binding of beta-arrestin2. In transfected cells, the CK2 catalytic alpha subunit formed a complex with NHE5 and decreased wild-type but not (702)ST/AA(714) NHE5 activity, further supporting a regulatory role for this kinase. The rate of internalization of (702)ST/AA(714) was also diminished and relatively insensitive to overexpression of beta-arrestin2. However, unlike in vitro, this mutant retained its ability to form a complex with beta-arrestin2 despite its lack of responsiveness. Additional mutations of two di-isoleucine-based motifs (I697A/L698A and I722A/I723A) that immediately flank the acidic cluster, either separately or together, were required to disrupt their association. These data demonstrate that discrete elements of an elaborate sorting signal in NHE5 contribute to beta-arrestin2 binding and trafficking along the recycling endosomal pathway. PMID- 21296877 TI - A distinct role for Pin1 in the induction and maintenance of pluripotency. AB - The prominent characteristics of pluripotent stem cells are their unique capacity to self-renew and pluripotency. Although pluripotent stem cell proliferation is maintained by specific intracellular phosphorylation signaling events, it has not been well characterized how the resulting phosphorylated proteins are subsequently regulated. We here report that the peptidylprolyl isomerase Pin1 is indispensable for the self-renewal and maintenance of pluripotent stem cells via the regulation of phosphorylated Oct4 and other substrates. Pin1 expression was found to be up-regulated upon the induction of induced pluripotent stem (iPS) cells, and the forced expression of Pin1 with defined reprogramming factors was observed to further enhance the frequency of iPS cell generation. The inhibition of Pin1 activity significantly suppressed colony formation and induced the aberrant differentiation of human iPS cells as well as murine ES cells. We further found that Pin1 interacts with the phosphorylated Ser(12)-Pro motif of Oct4 and that this in turn facilitates the stability and transcriptional activity functions of Oct4. Our current findings thus uncover an atypical role for Pin1 as a putative regulator of the induction and maintenance of pluripotency via the control of phosphorylation signaling. These data suggest that the manipulation of Pin1 function could be a potential strategy for the stable induction and proliferation of human iPS cells. PMID- 21296878 TI - Involvement of oxygen-regulated protein 150 in AMP-activated protein kinase mediated alleviation of lipid-induced endoplasmic reticulum stress. AB - Hepatocytes show endoplasmic reticulum (ER) stress when exposed to lipotoxic stimuli such as hyperlipidemia. Recent work has revealed that AMP- activated protein kinase (AMPK) can mitigate ER stress. In this study we investigated the impact of AMPK on lipid-induced ER stress in hepatocytes and its underlying molecular mechanism. Treatment with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an AMPK agonist, or overexpression of a constitutively active AMPK significantly suppressed lipid-mediated ER stress, leading to marked protection against lipotoxic death. Incubation with AICAR and constitutively active AMPK overexpression induced the expression of an ER-associated chaperone, 150-kDa oxygen-regulated protein (ORP150), at both the mRNA and protein levels in hepatocytes. Forkhead box O1 (FOXO1) was identified as the critical transcription factor regulating ORP150 expression because silencing FOXO1 expression prevented the induction of ORP150 expression by AMPK. In contrast, overexpression of FOXO1 ADA promoted ORP150 expression in hepatocytes. FOXO1 bound directly to the ORP150 promoter, which was enhanced in the presence of AICAR. AMPK acts to activate FOXO1 by increasing its deacetylation and transcriptional activity via silent mating type information regulation 2 homolog 1 (SIRT1). Furthermore, AICAR infusion enhanced ORP150 expression, resulting in the marked amelioration of hepatic ER stress and apoptosis in C57BL/6J mice fed a high fat diet. Our results reveal a novel mechanism by which AMPK regulates ER homeostasis in hepatocytes and suggest that AMPK has a protective role against hypercholesterolemia-related liver damage. PMID- 21296879 TI - Immunoinhibitory adapter protein Src homology domain 3 lymphocyte protein 2 (SLy2) regulates actin dynamics and B cell spreading. AB - Appropriate B cell activation is essential for adaptive immunity. In contrast to the molecular mechanisms that regulate positive signaling in immune responses, the counterbalancing negative regulatory pathways remain insufficiently understood. The Src homology domain 3 (SH3)-containing adapter protein SH3 lymphocyte protein 2 (SLy2, also known as hematopoietic adapter-containing SH3 and sterile alpha-motif (SAM) domains 1; HACS1) is strongly up-regulated upon B cell activation and functions as an endogenous immunoinhibitor in vivo, but the underlying molecular mechanisms of SLy2 function have been elusive. We have generated transgenic mice overexpressing SLy2 in B and T cells and have studied the biological effects of elevated SLy2 levels in Jurkat and HeLa cells. Our results demonstrate that SLy2 induces Rac1-dependent membrane ruffle formation and regulates cell spreading and polarization and that the SLy2 SH3 domain is essential for these effects. Using immunoprecipitation and confocal microscopy, we provide evidence that the actin nucleation-promoting factor cortactin is an SH3 domain-directed interaction partner of SLy2. Consistent with an important role of SLy2 for actin cytoskeletal reorganization, we further show that SLy2 transgenic B cells are severely defective in cell spreading. Together, our findings extend our mechanistic understanding of the immunoinhibitory roles of SLy2 in vivo and suggest that the physiological up-regulation of SLy2 observed upon B cell activation functions to counteract excessive B cell spreading. PMID- 21296880 TI - Plant D-2-hydroxyglutarate dehydrogenase participates in the catabolism of lysine especially during senescence. AB - D-2-Hydroxyglutarate dehydrogenase (D-2HGDH) catalyzes the specific and efficient oxidation of D-2-hydroxyglutarate (D-2HG) to 2-oxoglutarate using FAD as a cofactor. In this work, we demonstrate that D-2HGDH localizes to plant mitochondria and that its expression increases gradually during developmental and dark-induced senescence in Arabidopsis thaliana, indicating an enhanced demand of respiration of alternative substrates through this enzymatic system under these conditions. Using loss-of-function mutants in D-2HGDH (d2hgdh1) and stable isotope dilution LC-MS/MS, we found that the D-isomer of 2HG accumulated in leaves of d2hgdh1 during both forms of carbon starvation. In addition to this, d2hgdh1 presented enhanced levels of most TCA cycle intermediates and free amino acids. In contrast to the deleterious effects caused by a deficiency in D-2HGDH in humans, d2hgdh1 and overexpressing lines of D-2HGDH showed normal developmental and senescence phenotypes, indicating a mild role of D-2HGDH in the tested conditions. Moreover, metabolic fingerprinting of leaves of plants grown in media supplemented with putative precursors indicated that D-2HG most probably originates during the catabolism of lysine. Finally, the L-isomer of 2HG was also detected in leaf extracts, indicating that both chiral forms of 2HG participate in plant metabolism. PMID- 21296881 TI - Two novel classes of enzymes are required for the biosynthesis of aurofusarin in Fusarium graminearum. AB - Previous studies have reported the functional characterization of 9 out of 11 genes found in the gene cluster responsible for biosynthesis of the polyketide pigment aurofusarin in Fusarium graminearum. Here we reanalyze the function of a putative aurofusarin pump (AurT) and the two remaining orphan genes, aurZ and aurS. Targeted gene replacement of aurZ resulted in the discovery that the compound YWA1, rather than nor-rubrofusarin, is the primary product of F. graminearum polyketide synthase 12 (FgPKS12). AurZ is the first representative of a novel class of dehydratases that act on hydroxylated gamma-pyrones. Replacement of the aurS gene resulted in accumulation of rubrofusarin, an intermediate that also accumulates when the GIP1, aurF, or aurO genes in the aurofusarin cluster are deleted. Based on the shared phenotype and predicted subcellular localization, we propose that AurS is a member of an extracellular enzyme complex (GIP1-AurF-AurO-AurS) responsible for converting rubrofusarin into aurofusarin. This implies that rubrofusarin, rather than aurofusarin, is pumped across the plasma membrane. Replacement of the putative aurofusarin pump aurT increased the rubrofusarin-to- aurofusarin ratio, supporting that rubrofusarin is normally pumped across the plasma membrane. These results provide functional information on two novel classes of proteins and their contribution to polyketide pigment biosynthesis. PMID- 21296882 TI - Cellular hypoxia of pancreatic beta-cells due to high levels of oxygen consumption for insulin secretion in vitro. AB - Cellular oxygen consumption is a determinant of intracellular oxygen levels. Because of the high demand of mitochondrial respiration during insulin secretion, pancreatic beta-cells consume large amounts of oxygen in a short time period. We examined the effect of insulin secretion on cellular oxygen tension in vitro. We confirmed that Western blotting of pimonidazole adduct was more sensitive than immunostaining for detection of cellular hypoxia in vitro and in vivo. The islets of the diabetic mice but not those of normal mice were hypoxic, especially when a high dose of glucose was loaded. In MIN6 cells, a pancreatic beta-cell line, pimonidazole adduct formation and stabilization of hypoxia-inducible factor 1alpha (HIF-1alpha) were detected under mildly hypoxic conditions. Inhibition of respiration rescued the cells from becoming hypoxic. Glucose stimulation decreased cellular oxygen levels in parallel with increased insulin secretion and mitochondrial respiration. The cellular hypoxia by glucose stimulation was also observed in the isolated islets from mice. The MIN6 cells overexpressing HIF 1alpha were resistant to becoming hypoxic after glucose stimulation. Thus, glucose-stimulated beta-cells can become hypoxic by oxygen consumption, especially when the oxygen supply is impaired. PMID- 21296883 TI - Iron mediates N-methyl-D-aspartate receptor-dependent stimulation of calcium induced pathways and hippocampal synaptic plasticity. AB - Iron deficiency hinders hippocampus-dependent learning processes and impairs cognitive performance, but current knowledge on the molecular mechanisms underlying the unique role of iron in neuronal function is sparse. Here, we investigated the participation of iron on calcium signal generation and ERK1/2 stimulation induced by the glutamate agonist N-methyl-D-aspartate (NMDA), and the effects of iron addition/chelation on hippocampal basal synaptic transmission and long-term potentiation (LTP). Addition of NMDA to primary hippocampal cultures elicited persistent calcium signals that required functional NMDA receptors and were independent of calcium influx through L-type calcium channels or alpha-amino 3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors; NMDA also promoted ERK1/2 phosphorylation and nuclear translocation. Iron chelation with desferrioxamine or inhibition of ryanodine receptor (RyR)-mediated calcium release with ryanodine reduced calcium signal duration and prevented NMDA-induced ERK1/2 activation. Iron addition to hippocampal neurons readily increased the intracellular labile iron pool and stimulated reactive oxygen species production; the antioxidant N acetylcysteine or the hydroxyl radical trapper MCI-186 prevented these responses. Iron addition to primary hippocampal cultures kept in calcium-free medium elicited calcium signals and stimulated ERK1/2 phosphorylation; RyR inhibition abolished these effects. Iron chelation decreased basal synaptic transmission in hippocampal slices, inhibited iron-induced synaptic stimulation, and impaired sustained LTP in hippocampal CA1 neurons induced by strong stimulation. In contrast, iron addition facilitated sustained LTP induction after suboptimal tetanic stimulation. Together, these results suggest that hippocampal neurons require iron to generate RyR-mediated calcium signals after NMDA receptor stimulation, which in turn promotes ERK1/2 activation, an essential step of sustained LTP. PMID- 21296884 TI - Functional and topological analysis of Pen-2, the fourth subunit of the gamma secretase complex. AB - The gamma-secretase complex is a member of the family of intramembrane cleaving proteases, involved in the generation of the Abeta peptides in Alzheimer disease. One of the four subunits of the complex, presenilin, harbors the catalytic site, although the role of the other three subunits is less well understood. Here, we studied the role of the smallest subunit, Pen-2, in vivo and in vitro. We found a profound Notch-deficiency phenotype in Pen-2-/- embryos confirming the essential role of Pen-2 in the gamma-secretase complex. We used Pen-2-/- fibroblasts to investigate the structure-function relation of Pen-2 by the scanning cysteine accessibility method. We showed that glycine 22 and proline 27 in hydrophobic domain 1 of Pen-2 are essential for complex formation and stability of gamma secretase. We also demonstrated that hydrophobic domain 1 and the loop domain of Pen-2 are located in a water-containing cavity and are in short proximity to the presenilin C-terminal fragment. We finally demonstrated the essential role of Pen 2 for the proteolytic activity of the complex. Our study supports the hypothesis that Pen-2 is more than a structural component of the gamma-secretase complex and may contribute to the catalytic mechanism of the enzyme. PMID- 21296885 TI - Studies on the mechanism of ring hydrolysis in phenylacetate degradation: a metabolic branching point. AB - The widespread, long sought-after bacterial aerobic phenylalanine/phenylacetate catabolic pathway has recently been elucidated. It proceeds via coenzyme A (CoA) thioesters and involves the epoxidation of the aromatic ring of phenylacetyl-CoA, subsequent isomerization to an uncommon seven-membered C-O-heterocycle (oxepin CoA), and non-oxygenolytic ring cleavage. Here we characterize the hydrolytic oxepin-CoA ring cleavage catalyzed by the bifunctional fusion protein PaaZ. The enzyme consists of a C-terminal (R)-specific enoyl-CoA hydratase domain (formerly MaoC) that cleaves the ring and produces a highly reactive aldehyde and an N terminal NADP(+)-dependent aldehyde dehydrogenase domain that oxidizes the aldehyde to 3-oxo-5,6-dehydrosuberyl-CoA. In many phenylacetate-utilizing bacteria, the genes for the pathway exist in a cluster that contains an NAD(+) dependent aldehyde dehydrogenase in place of PaaZ, whereas the aldehyde-producing hydratase is encoded outside of the cluster. If not oxidized immediately, the reactive aldehyde condenses intramolecularly to a stable cyclic derivative that is largely prevented by PaaZ fusion in vivo. Interestingly, the derivative likely serves as the starting material for the synthesis of antibiotics (e.g. tropodithietic acid) and other tropone/tropolone related compounds as well as for omega-cycloheptyl fatty acids. Apparently, bacteria made a virtue out of the necessity of disposing the dead-end product with ring hydrolysis as a metabolic branching point. PMID- 21296886 TI - Inactivation of the mitochondrial carrier SLC25A25 (ATP-Mg2+/Pi transporter) reduces physical endurance and metabolic efficiency in mice. AB - An ATP-Mg(2+/)P(i) inner mitochondrial membrane solute transporter (SLC25A25), which is induced during adaptation to cold stress in the skeletal muscle of mice with defective UCP1/brown adipose tissue thermogenesis, has been evaluated for its role in metabolic efficiency. SLC25A25 is thought to control ATP homeostasis by functioning as a Ca(2+)-regulated shuttle of ATP-Mg(2+) and P(i) across the inner mitochondrial membrane. Mice with an inactivated Slc25a25 gene have reduced metabolic efficiency as evidenced by enhanced resistance to diet-induced obesity and impaired exercise performance on a treadmill. Mouse embryo fibroblasts from Slc25a25(-/-) mice have reduced Ca(2+) flux across the endoplasmic reticulum, basal mitochondrial respiration, and ATP content. Although Slc25a25(-/-) mice are metabolically inefficient, the source of the inefficiency is not from a primary function in thermogenesis, because Slc25a25(-/-) mice maintain body temperature upon acute exposure to the cold (4 degrees C). Rather, the role of SLC25A25 in metabolic efficiency is most likely linked to muscle function as evidenced from the physical endurance test of mutant mice on a treadmill. Consequently, in the absence of SLC25A25 the efficiency of ATP production required for skeletal muscle function is diminished with secondary effects on adiposity. However, in the absence of UCP1-based thermogenesis, induction of Slc25a25 in mice with an intact gene may contribute to an alternative thermogenic pathway for the maintenance of body temperature during cold stress. PMID- 21296887 TI - Structure-guided antigen engineering yields pneumolysin mutants suitable for vaccination against pneumococcal disease. AB - Pneumolysin (PLY) is a cholesterol-binding, pore-forming protein toxin. It is an important virulence factor of Streptococcus pneumoniae and a key vaccine target against pneumococcal disease. We report a systematic structure-driven approach that solves a long-standing problem for vaccine development in this field: detoxification of PLY with retention of its antigenic integrity. Using three conformational restraint techniques, we rationally designed variants of PLY that lack hemolytic activity and yet induce neutralizing antibodies against the wild type toxin. These results represent a key milestone toward a broad-spectrum protein-based pneumococcal vaccine and illustrate the value of structural knowledge in formulating effective strategies for antigen optimization. PMID- 21296888 TI - The CC' and DE loops in Ig domains 1 and 2 of MAdCAM-1 play different roles in MAdCAM-1 binding to low- and high-affinity integrin alpha4beta7. AB - Lymphocyte homing is regulated by the dynamic interaction between integrins and their ligands. Integrin alpha4beta7 mediates both rolling and firm adhesion of lymphocytes by modulating its affinity to the ligand, mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Although previous studies have revealed some mechanisms of alpha4beta7-MAdCAM-1 binding, little is known about the different molecular bases of the low- and high-affinity alpha4beta7-MAdCAM-1 interactions, which mediate rolling and firm adhesion of lymphocytes, respectively. Here, we found that two loops in immunoglobulin domains 1 and 2 (D1 and D2) of MAdCAM-1 played different roles in MAdCAM-1 binding to low-affinity (inactive) and high affinity (activated) alpha4beta7. The Asp-42 in the CC' loop of D1 was indispensable for MAdCAM-1 binding to both low-affinity and high-affinity alpha4beta7. The other CC' loop residues except for Arg-39 and Ser-44 were essential for MAdCAM-1 binding to both inactive alpha4beta7 and alpha4beta7 activated by SDF-1alpha or talin, but not required for MAdCAM-1 binding to Mn2+ activated alpha4beta7. Single amino acid substitution of the DE loop residues mildly decreased MAdCAM-1 binding to both inactive and activated alpha4beta7. Notably, removal of the DE loop greatly impaired MAdCAM-1 binding to inactive and SDF-1alpha- or talin-activated alpha4beta7, but only decreased 60% of MAdCAM-1 binding to Mn2+-activated alpha4beta7. Moreover, DE loop residues were important for stabilizing the low-affinity alpha4beta7-MAdCAM-1 interaction. Thus, our findings demonstrate the distinct roles of the CC' and DE loops in the recognition of MAdCAM-1 by low- and high-affinity alpha4beta7 and suggest that the inactive alpha4beta7 and alpha4beta7 activated by different stimuli have distinct conformations with different structural requirements for MAdCAM-1 binding. PMID- 21296889 TI - Characterization of the Interaction between hantavirus nucleocapsid protein (N) and ribosomal protein S19 (RPS19). AB - Hantaviruses, members of the Bunyaviridae family, are negative-stranded emerging RNA viruses and category A pathogens that cause serious illness when transmitted to humans through aerosolized excreta of infected rodent hosts. Hantaviruses have evolved a novel translation initiation mechanism, operated by nucleocapsid protein (N), which preferentially facilitates the translation of viral mRNAs. N binds to the ribosomal protein S19 (RPS19), a structural component of the 40 S ribosomal subunit. In addition, N also binds to both the viral mRNA 5' cap and a highly conserved triplet repeat sequence of the viral mRNA 5' UTR. The simultaneous binding of N at both the terminal cap and the 5' UTR favors ribosome loading on viral transcripts during translation initiation. We characterized the binding between N and RPS19 and demonstrate the role of the N-RPS19 interaction in N-mediated translation initiation mechanism. We show that N specifically binds to RPS19 with high affinity and a binding stoichiometry of 1:1. The N-RPS19 interaction is an enthalpy-driven process. RPS19 undergoes a conformational change after binding to N. Using T7 RNA polymerase, we synthesized the hantavirus S segment mRNA, which matches the transcript generated by the viral RNA-dependent RNA polymerase in cells. We show that the N-RPS19 interaction plays a critical role in the translation of this mRNA both in cells and rabbit reticulocyte lysates. Our results demonstrate that the N-mediated translation initiation mechanism, which lures the host translation machinery for the preferential translation of viral transcripts, primarily depends on the N-RPS19 interaction. We suggest that the N-RPS19 interaction is a novel target to shut down the N mediated translation strategy and hence virus replication in cells. PMID- 21296890 TI - Alpha-synuclein sequesters Dnmt1 from the nucleus: a novel mechanism for epigenetic alterations in Lewy body diseases. AB - DNA methylation is a major epigenetic modification that regulates gene expression. Dnmt1, the maintenance DNA methylation enzyme, is abundantly expressed in the adult brain and is mainly located in the nuclear compartment, where it has access to chromatin. Hypomethylation of CpG islands at intron 1 of the SNCA gene has recently been reported to result in overexpression of alpha synuclein in Parkinson disease (PD) and related disorders. We therefore investigated the mechanisms underlying altered DNA methylation in PD and dementia with Lewy bodies (DLB). We present evidence of reduction of nuclear Dnmt1 levels in human postmortem brain samples from PD and DLB patients as well as in the brains of alpha-synuclein transgenic mice models. Furthermore, sequestration of Dnmt1 in the cytoplasm results in global DNA hypomethylation in human and mouse brains, involving CpG islands upstream of SNCA, SEPW1, and PRKAR2A genes. We report that association of Dnmt1 and alpha-synuclein might mediate aberrant subcellular localization of Dnmt1. Nuclear Dnmt1 levels were partially rescued by overexpression of Dnmt1 in neuronal cell cultures and in alpha-synuclein transgenic mice brains. Our results underscore a novel mechanism for epigenetic dysregulation in Lewy body diseases, which might underlie the decrease in DNA methylation reported for PD and DLB. PMID- 21296891 TI - Human neuroglobin functions as a redox-regulated nitrite reductase. AB - Neuroglobin is a highly conserved hemoprotein of uncertain physiological function that evolved from a common ancestor to hemoglobin and myoglobin. It possesses a six-coordinate heme geometry with proximal and distal histidines directly bound to the heme iron, although coordination of the sixth ligand is reversible. We show that deoxygenated human neuroglobin reacts with nitrite to form nitric oxide (NO). This reaction is regulated by redox-sensitive surface thiols, cysteine 55 and 46, which regulate the fraction of the five-coordinated heme, nitrite binding, and NO formation. Replacement of the distal histidine by leucine or glutamine leads to a stable five-coordinated geometry; these neuroglobin mutants reduce nitrite to NO ~2000 times faster than the wild type, whereas mutation of either Cys-55 or Cys-46 to alanine stabilizes the six-coordinate structure and slows the reaction. Using lentivirus expression systems, we show that the nitrite reductase activity of neuroglobin inhibits cellular respiration via NO binding to cytochrome c oxidase and confirm that the six-to-five-coordinate status of neuroglobin regulates intracellular hypoxic NO-signaling pathways. These studies suggest that neuroglobin may function as a physiological oxidative stress sensor and a post-translationally redox-regulated nitrite reductase that generates NO under six-to-five-coordinate heme pocket control. We hypothesize that the six coordinate heme globin superfamily may subserve a function as primordial hypoxic and redox-regulated NO-signaling proteins. PMID- 21296892 TI - Using imputed genotypes for relative risk estimation in case-parent studies. AB - Meta-analyses of genome-wide association studies are often based on imputed single nucleotide polymorphism (SNP) data, because component studies were genotyped using different platforms. One would like to include case-parent triad studies along with case-control studies in such meta-analyses. However, there are no published methods for estimating relative risks from imputed data for case parent triad studies. The authors propose a method for estimating the relative risk for a variant SNP allele based on a log-additive model. Their simulations first confirm that the proposed method performs well with genotyped SNP data. As an empirical test of the method's behavior with imputed SNPs, the authors then apply it to chromosome 22 data from the Mexico City Childhood Asthma Study (1998 2003). For chromosome 22, the authors had data on 7,293 SNPs that were both genotyped and imputed using the software MACH, which relies on linkage disequilibrium with nearby SNPs. Correlation between estimated relative risks based on the actual genotypes and those based on the imputed genotypes was remarkably high (r(2) = 0.95), validating this method of relative risk estimation for the case-parent study design. This method should be useful to investigators who wish to conduct meta-analyses using imputed SNP data from both case-parent triad and case-control studies. PMID- 21296893 TI - Matrix metalloproteinases: all the RAGE in the acute respiratory distress syndrome. PMID- 21296894 TI - Alternaria alternata serine proteases induce lung inflammation and airway epithelial cell activation via PAR2. AB - Allergens are diverse proteins from mammals, birds, arthropods, plants, and fungi. Allergens associated with asthma (asthmagens) share a common protease activity that may directly impact respiratory epithelial biology and lead to symptoms of asthma. Alternaria alternata is a strong asthmagen in semiarid regions. We examined the impact of proteases from A. alternata on lung inflammation in vivo and on cleaving protease-activated receptor-2 (PAR(2)) in vitro. A. alternata filtrate applied to the airway in nonsensitized Balb/c mice induced a protease-dependent lung inflammation. Moreover, A. alternata filtrate applied to human bronchial epithelial cells (16HBE14o-) induced changes in intracellular Ca(2+) concentration ([Ca(2+)](i)), consistent with PAR(2) activation. These effects were blocked by heat inactivation or by serine protease inhibition of A. alternata filtrates, and mimicked by PAR(2) specific ligands SLIGRL-NH(2) or 2-furoyl-LIGRLO-NH(2), but not the PAR(1)-specific ligand TFLLR NH(2). Desensitization of PAR(2) in 16HBE14o- cells with 2-furoyl-LIGRLO-NH(2) or trypsin prevented A. alternata-induced [Ca(2+)](i) changes while desensitization of PAR(1), PAR(3), and PAR(4) with thrombin had no effect on A. alternata-induced Ca(2+) responses. Furthermore, the Ca(2+) response to A. alternata filtrates was dependent on PAR(2) expression in stably transfected HeLa cell models. These data demonstrate that A. alternata proteases act through PAR(2) to induce rapid increases in human airway epithelial [Ca(2+)](i) in vitro and cell recruitment in vivo. These responses are likely critical early steps in the development of allergic asthma. PMID- 21296895 TI - Genetic evidence for NAD(P)H:quinone oxidoreductase 1-catalyzed quinone reduction on passage through the mouse pulmonary circulation. AB - The quinones duroquinone (DQ) and coenzyme Q(1) (CoQ(1)) and quinone reductase inhibitors have been used to identify reductases involved in quinone reduction on passage through the pulmonary circulation. In perfused rat lung, NAD(P)H:quinone oxidoreductase 1 (NQO1) was identified as the predominant DQ reductase and NQO1 and mitochondrial complex I as the CoQ(1) reductases. Since inhibitors have nonspecific effects, the goal was to use Nqo1-null (NQO1(-)/(-)) mice to evaluate DQ as an NQO1 probe in the lung. Lung homogenate cytosol NQO1 activities were 97 +/- 11, 54 +/- 6, and 5 +/- 1 (SE) nmol dichlorophenolindophenol reduced.min( 1).mg protein(-1) for NQO1(+/+), NQO1(+/-), and NQO1(-/-) lungs, respectively. Intact lung quinone reduction was evaluated by infusion of DQ (50 MUM) or CoQ(1) (60 MUM) into the pulmonary arterial inflow of the isolated perfused lung and measurement of pulmonary venous effluent hydroquinone (DQH(2) or CoQ(1)H(2)). DQH(2) efflux rates for NQO1(+/+), NQO1(+/-), and NQO1(-/-) lungs were 0.65 +/- 0.08, 0.45 +/- 0.04, and 0.13 +/- 0.05 (SE) MUmol.min(-1).g dry lung(-1), respectively. DQ reduction in NQO1(+/+) lungs was inhibited by 90 +/- 4% with dicumarol; there was no inhibition in NQO1(-/-) lungs. There was no significant difference in CoQ(1)H(2) efflux rates for NQO1(+/+) and NQO1(-/-) lungs. Differences in DQ reduction were not due to differences in lung dry weights, wet to-dry weight ratios, perfusion pressures, perfused surface areas, or total DQ recoveries. The data provide genetic evidence implicating DQ as a specific NQO1 probe in the perfused rodent lung. PMID- 21296896 TI - Dale J. Benos, Ph.D. (1950-2010). PMID- 21296897 TI - New insights into the molecular basis of atrial fibrillation: mechanistic and therapeutic implications. PMID- 21296898 TI - Psychotherapy in dizziness: a systematic review. AB - BACKGROUND: About 30-50% of complex dizziness disorders are organically not sufficiently explained or related to a psychiatric disorder. Of patients with such dizziness disorders, 80% are severely impaired by dizziness in their daily and working lives; nevertheless, they are often not diagnosed or treated adequately. OBJECTIVES: This review aims to give a systematic overview of psychotherapeutic approaches and their efficacy regarding the treatment of dizziness that is medically not sufficiently explained or related to a psychiatric disorder. METHODS: A systematic literature search was conducted in Medline, PSYNDEX and PsycINFO. Included in this systematic review were (randomised) controlled trials ((R)CTs) concerning psychotherapy in patients with dizziness, medically not sufficiently explained or associated with a psychiatric disorder. If possible, Hedges' g was used to express the effect sizes (ES) of the treatment. Heterogeneity was assessed using the Q statistic. In addition, the quality of the studies was rated. RESULTS: Three (R)CTs were included. All studies used cognitive-behavioural treatment methods in combination with relaxation techniques or vestibular rehabilitation. All studies suggested that psychotherapy may provide improvement. The mean ES in the treatment groups was 0.46 (95% CI 0.05 to 0.88) for dizziness related outcome, 0.10 (-0.44 to 0.64) for anxiety and 0.17 (-0.24 to 0.58) for depression whereas in the control groups the mean dizziness related ES was -0.04 (-0.44 to 0.37), anxiety related ES was 0.03 (-0.43 to 0.38) and depression related ES was -0.02 (-0.42 to 0.38). The quality of the studies was average. Sample sizes were small, however, and there was a lack of long term studies. CONCLUSION: This systematic review provides some preliminary evidence that psychotherapy may be effective in patients with dizziness that is medically not sufficiently explained or due to a psychiatric disorder. The results should be replicated in larger samples and follow-up RCTs. PMID- 21296899 TI - The perfect crime? CCSVI not leaving a trace in MS. AB - BACKGROUND: Multiple sclerosis (MS) is a chronic, inflammatory demyelinating disease of the central nervous system, believed to be triggered by an autoimmune reaction to myelin. Recently, a fundamentally different pathomechanism termed 'chronic cerebrospinal venous insufficiency' (CCSVI) was proposed, provoking significant attention in the media and scientific community. METHODS: Twenty MS patients (mean age 42.2 +/- 13.3 years; median Extended Disability Status Scale 3.0, range 0-6.5) were compared with 20 healthy controls. Extra- and intracranial venous flow direction was assessed by colour-coded duplex sonography, and extracranial venous cross-sectional area (VCSA) of the internal jugular and vertebral veins (IJV/VV) was measured in B-mode to assess the five previously proposed CCSVI criteria. IJV-VCSA <= 0.3 cm(2) indicated 'stenosis,' and IJV-VCSA decrease from supine to upright position 'reverted postural control.' The sonographer, data analyser and statistician were blinded to the patient/control status of the participants. RESULTS: No participant showed retrograde flow of cervical or intracranial veins. IJV-VCSA <= 0.3 cm(2) was found in 13 MS patients versus 16 controls (p=0.48). A decrease in IJV-VCSA from supine to upright position was observed in all participants, but this denotes a physiological finding. No MS patient and one control had undetectable IJV flow despite deep inspiration (p=0.49). Only one healthy control and no MS patients fulfilled at least two criteria for CCSVI. CONCLUSIONS: This triple-blinded extra- and transcranial duplex sonographic assessment of cervical and cerebral veins does not provide supportive evidence for the presence of CCSVI in MS patients. The findings cast serious doubt on the concept of CCSVI in MS. PMID- 21296900 TI - Usefulness of measurement of fibrinogen, D-dimer, D-dimer/fibrinogen ratio, C reactive protein and erythrocyte sedimentation rate to assess the pathophysiology and mechanism of ischaemic stroke. AB - BACKGROUND: Classification defined in the Trial of Org10172 in Acute Ischaemic Stroke (TOAST) is widely used in trials and practice. Previous studies on pathophysiology suggest a role for endothelial inflammation in atherothrombotic strokes and intracardiac thrombosis in cardioembolic strokes. Data on lacunar and undetermined strokes are limited. The aim of the study was to assess non-specific inflammatory and thrombogenic parameters in patients with ischaemic stroke. METHODS: This was a prospective controlled clinical study involving 200 patients with ischaemic stroke and 50 controls. Patients were classified following the TOAST criteria. Plasma levels of fibrinogen, D-dimer, C reactive protein and values for D-dimer/fibrinogen ratio and erythrocyte sedimentation rate were assessed over 48 h after admission. Clinical severity was measured using the National Institutes of Health Stroke Scale and the Oxfordshire Community Stroke Project classification. Patients with severe systemic disorders were excluded. RESULTS: The assessed parameters were significantly higher in patients versus controls. Cardioembolic stroke patients showed increased D-dimer, fibrinogen and D-dimer/fibrinogen ratio. Patients with atherothrombotic stroke showed raised fibrinogen and erythrocyte sedimentation rate. Patients with lacunar and undetermined stroke showed intermediate values of markers. Total anterior cerebral infarction syndrome was related to D-dimer. DISCUSSION: Patients showed analytical modifications during the acute phase of stroke, both related to acute response and mechanism. The results suggest that the biochemical profile may be prothrombotic in patients with cardioembolism and inflammatory in those with atherothrombotic stroke. Patients with lacunar and undetermined stroke showed intermediate profiles. Assessment of the studied parameters is not expensive, widely available and may proportionate information about pathophysiology in stroke patients without severe systemic conditions. PMID- 21296901 TI - Endocrine and immune substrates of depressive symptoms and fatigue in multiple sclerosis patients with comorbid major depression. AB - OBJECTIVE: Depression and fatigue are among the most common symptoms of multiple sclerosis (MS). These symptoms frequently co-occur and partially overlap in MS but their underlying biological substrates are unclear. In this study, the relative role of cytokines and hypothalamic-pituitary-adrenal (HPA) axis activity in depression and fatigue were examined in patients with relapsing-remitting MS (RRMS). METHODS: HPA axis function and frequency of stimulated cytokine (interferon gamma (IFNgamma) and tumour necrosis factor alpha (TNFalpha)) producing T cells was measured cross sectionally in 44 female patients with RRMS. All subjects completed a neurological examination, the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) and self-report questionnaires. RESULTS: 10 patients met diagnostic criteria for major depressive disorder (MDD). MS patients with comorbid MDD showed normal morning but elevated evening salivary cortisol levels, resulting in a flattened slope. While a higher frequency of cytokine producing CD8+ T cells was also seen in MS patients with MDD, these markers were more closely associated with fatigue than depression. CONCLUSIONS: This study supports a role for HPA axis hyperactivity in major depression in MS. In addition, inflammatory and neuroendocrine factors may differentially mediate fatigue and depressive symptoms. PMID- 21296902 TI - Childhood and adulthood socioeconomic position and the hospital-based incidence of hip fractures after 13 years of follow-up: the role of health behaviours. AB - BACKGROUND: To investigate the association between childhood and adulthood socioeconomic position and the hospital-based incidence of hip fractures, and the contribution of health behaviours to these socioeconomic disparities. METHODS: Baseline (1991) information about socioeconomic position in childhood and adulthood, behavioural factors (alcohol consumption, smoking, physical inactivity, coffee consumption) and body height of 25-74-year-old participants (n=18 810) were linked to hospital admissions for hip fractures (ICD9 code 820 821) over a follow-up period of almost 13 years. RESULTS: During follow-up 192 hip fractures resulted in hospital admission. Childhood socioeconomic position was not associated with the incidence of hip fractures. Adjusted for body height, a lower educational level and being in a lower income proxy group were associated with an increased probability of hip fractures (HR=1.88, 95% CI 1.00 to 3.53 in the lowest education group; HR=2.39, 95% 1.46 to 3.92 in the lowest income group). Very excessive alcohol consumption, smoking and physical inactivity were associated with an increased probability of hip fractures, and contributed (10-31%) to socioeconomic disparities in hip fractures. CONCLUSIONS: The higher prevalence of unhealthy behaviour in lower socioeconomic groups in adulthood contributes moderately to socioeconomic disparities in incidence of hip fractures later in life. PMID- 21296903 TI - Do effects of price discounts and nutrition education on food purchases vary by ethnicity, income and education? Results from a randomised, controlled trial. AB - BACKGROUND: Reducing health inequalities requires interventions that work as well, if not better, among disadvantaged populations. The aim of this study was to determine if the effects of price discounts and tailored nutrition education on supermarket food purchases (percentage energy from saturated fat and healthy foods purchased) vary by ethnicity, household income and education. METHOD: A 2*2 factorial trial of 1104 New Zealand shoppers randomised to receive a 12.5% discount on healthier foods and/or tailored nutrition education (or no intervention) for 6 months. RESULTS: There was no overall association of price discounts or nutrition education with percentage energy from saturated fat, or nutrition education with healthy food purchasing. There was an association of price discounts with healthy food purchasing (0.79 kg/week increase; 95% CI 0.43 to 1.16) that varied by ethnicity (p=0.04): European/other 1.02 kg/week (n=755; 95% CI 0.60 to 1.43); Pacific 1.20 kg/week (n=101; 95% CI 0.06 to 2.34); Maori 0.15 kg/week (n=248; 95% CI -1.10 to 0.80). This association of price discounts with healthy food purchasing did not vary by household income or education. CONCLUSIONS: While a statistically significant variation by ethnicity in the effect of price discounts on food purchasing was found, the authors caution against a causal interpretation due to likely biases (eg, attrition) that differentially affected Maori and Pacific people. The study highlights the challenges in generating valid evidence by social groups for public health interventions. The null findings for tailored nutritional education across all social groups suggest that structural interventions (such as price) may be more effective. PMID- 21296904 TI - Growing up in a domestic violence environment: relationship with developmental trajectories of body mass index during adolescence into young adulthood. AB - BACKGROUND: This study investigated the relationship between growing up in a violent home and developmental trajectories of body mass index (BMI) in a cohort of adolescents followed longitudinally from 1996 to 2003-4. METHODS: 6043 girls and 4934 boys aged 9-14 years in 1996 who reported height and weight at least two times and whose mothers completed intimate partner violence (IPV) questions at the 2001 Nurses' Health Study. Main exposure was experiencing the first family violence during early (0-5 years) or later (6-11 years) childhood, based on mother's year-specific exposure of IPV and the birth year of each participant. Mother's report of IPV was ascertained by the abuse assessment screen. Four distinct BMI trajectory groups were estimated from age-specific BMI (age 12-20 years), using general growth mixture modelling. RESULTS: Four distinct BMI trajectories were identified separately for girls and boys: healthy growth; healthy to obese; steady overweight and consistently obese. Compared with boys not exposed to violence at home, boys raised in violent homes before 5 years were at increased risk of being in the consistently obese (OR =2.0; 95% CI 1.2 to 3.5) and steady overweight (OR 1.4; 95% CI 1.1 to 1.9) groups after adjusting for confounders. Girls raised in violent homes were more likely to be in the steady overweight group, but associations did not maintain statistical significance after adjusting for confounding. CONCLUSION: These data link children's exposure to domestic violence to a risk of unhealthy weight trajectories during adolescence in boys. Detrimental effects of exposure to a domestic violence environment may take root in the first few years of development for boys. PMID- 21296905 TI - Wet cooling systems as a source of sporadic Legionnaires' disease: a geographical analysis of data for England and Wales, 1996-2006. AB - BACKGROUND: The source of infection for most sporadic cases of Legionnaires' disease remains unknown. This study aims quantify the relationship between cases and wet cooling systems (WCS), a potential source of aerosolised legionella bacteria. METHODS: The study analysed data on 1163 sporadic, community-acquired cases of Legionnaires' disease in England and Wales with onset between 1996 and 2006, and 11630 postcode controls randomly sampled in proportion to population size and matched on region, age group and sex. The relationship between risk of Legionnaires' disease and distance from a WCS was analysed by conditional logistic regression. RESULTS: Cases and controls had a mean age of 56.3 years; 79.3% were male. Cases lived appreciably closer to WCS than their controls (mean distance of cases=2.11 km, controls=2.58 km; mean difference 0.47 km (95% CI 0.28 to 0.65)). The OR for disease within 1 km of a WCS compared with over 6 km (a distance taken to reflect background rates of Legionnaires' disease) was 1.59 (95% CI 1.26 to 2.01) when adjusted for socio-economic deprivation, and 1.33 (95% CI 1.04 to 1.71) when additionally adjusted for population density. The results suggest that residential proximity to a WCS may account for 19.6% of sporadic community-acquired cases. CONCLUSIONS: WCS may be an important source of sporadic, community-acquired cases of Legionnaires' disease, an observation that has important implications for health protection, especially given the likely increase in such systems as a component of strategies to improve energy efficiency in buildings. PMID- 21296906 TI - Health-promoting and health-damaging neighbourhood resources and coronary heart disease: a follow-up study of 2 165 000 people. AB - BACKGROUND: It has been hypothesised that the presence of health-damaging factors and lack of health-promoting factors lie in the causal pathway between neighbourhood deprivation and coronary heart disease (CHD). This study is the first to examine the associations between individual-level CHD risk and neighbourhood availability of fast-food restaurants, bars/pubs, physical activity facilities and healthcare resources. METHODS: Multilevel logistic regression models were used for the follow-up of 1 065 000 men and 1 100 000 women (aged 35 80 years) between 1 December 2005 and 31 December 2007, for individual-level CHD events (both morbidity and mortality). RESULTS: The relatively weak associations between neighbourhood availability of potentially health-damaging and health promoting goods, services and resources, and CHD incidence no longer remained significant after adjustment for neighbourhood-level deprivation and individual level age and income. CONCLUSIONS: The presence of potentially health-damaging factors and lack of potentially health-promoting factors do not seem to contribute significantly to the development of CHD. Other features of deprived neighbourhoods appear to play a greater role. PMID- 21296907 TI - A comparison of green space indicators for epidemiological research. AB - BACKGROUND: The potential for natural environments to be salutogenic has received growing interest from epidemiologists, but there has been no critical examination of the extent to which associations between green space and health might vary according to the indicator of green space coverage used. METHODS: Three different indicators of green space coverage were derived for a set of 268 small areas in four cities within Britain. The indicators had different origins and provided a spectrum of sensitivity from larger spaces only, through to ambient greenery. Two indicators reproducible for anywhere in Europe were included. Agreement between the indicators on the quantity of green space in a small area, and their independent association with measures of mortality and self-reported morbidity, were compared. RESULTS: Overall, the indicators showed relatively close overall agreement (all r(2)>0.89, p<0.001). However, agreement varied by level of area socioeconomic deprivation (p<0.001). The indicator that detected larger spaces only found less green space in areas of socioeconomic deprivation than the other two. Despite this difference, all indicators showed similar protective associations with the risk of mortality and self-reported morbidity suggesting that larger green spaces may be more important for health effects than smaller spaces. CONCLUSIONS: Associations between green space indicator and health were not sensitive to indicator origin and type. This raises the possibility of trans European epidemiological studies. Larger green spaces may be the most important for health effects, but may also be less prevalent in more deprived areas. PMID- 21296908 TI - Aging effects on regional brain structural changes in schizophrenia. AB - BACKGROUND: Although mostly conceptualized as a neurodevelopmental disorder, there is an increasing interest in progressive changes of cognitive deficits and brain structure and function in schizophrenia across the life span. METHODS: In this study, we investigated age-related changes in regional gray matter using voxel-based morphometry in a sample of 99 patients (age range 18-65 years) with Diagnostic and Statistical Manual of Mental Disorders-IV schizophrenia and 113 healthy controls (age range 19-59 years) using a cross-sectional design. RESULTS: We found steeper age-related decline in gray matter in patients in a cluster comprising the left superior temporal cortex and adjacent inferior parietal lobule. We then divided the schizophrenia sample in 3 subgroups based on a 3 factor model of psychopathology ratings. Age-related changes were markedly different in each of the 3 subgroups (compared with healthy controls). While patients with predominantly paranoid symptoms showed stronger age-related progression in the left superior temporal cortex and right inferior frontal gyrus, those of the disorganized subgroup had stronger gray matter loss in the left lateral cerebellum, while the predominantly negative subgroup showed minor effects in the left superior temporal gyrus. CONCLUSIONS: Our findings show that differences in brain structural changes associated with aging diverge between schizophrenia patients and healthy subjects and that different subgroups within a patient sample might be at higher risk of age-related regional gray matter loss. PMID- 21296910 TI - Theory and policy innovation for health: where has the creativity and fun gone? PMID- 21296909 TI - Bayesian estimation of substitution rates from ancient DNA sequences with low information content. PMID- 21296911 TI - Public health policy research: making the case for a political science approach. AB - The past few years have seen the emergence of claims that the political determinants of health do not get due consideration and a growing demand for better insights into public policy analysis in the health research field. Several public health and health promotion researchers are calling for better training and a stronger research culture in health policy. The development of these studies tends to be more advanced in health promotion than in other areas of public health research, but researchers are still commonly caught in a naive, idealistic and narrow view of public policy. This article argues that the political science discipline has developed a specific approach to public policy analysis that can help to open up unexplored levers of influence for public health research and practice and that can contribute to a better understanding of public policy as a determinant of health. It describes and critiques the public health model of policy analysis, analyzes political science's specific approach to public policy analysis, and discusses how the politics of research provides opportunities and barriers to the integration of political science's distinctive contributions to policy analysis in health promotion. PMID- 21296913 TI - Immunolocalization of an alternative respiratory chain in Antonospora (Paranosema) locustae spores: mitosomes retain their role in microsporidial energy metabolism. AB - Microsporidia are a group of fungus-related intracellular parasites with severely reduced metabolic machinery. They lack canonical mitochondria, a Krebs cycle, and a respiratory chain but possess genes encoding glycolysis enzymes, a glycerol phosphate shuttle, and ATP/ADP carriers to import host ATP. The recent finding of alternative oxidase genes in two clades suggests that microsporidial mitosomes may retain an alternative respiratory pathway. We expressed the fragments of mitochondrial chaperone Hsp70 (mitHsp70), mitochondrial glycerol-3-phosphate dehydrogenase (mitG3PDH), and alternative oxidase (AOX) from the microsporidium Antonospora (Paranosema) locustae in Escherichia coli. Immunoblotting with antibodies against recombinant polypeptides demonstrated specific accumulation of both metabolic enzymes in A. locustae spores. At the same time comparable amounts of mitochondrial Hsp70 were found in spores and in stages of intracellular development as well. Immunoelectron microscopy of ultrathin cryosections of spores confirmed mitosomal localization of the studied proteins. Small amounts of enzymes of an alternative respiratory chain in merogonial and early sporogonial stages, alongside their accumulation in mature spores, suggest conspicuous changes in components and functions of mitosomes during the life cycle of microsporidia and the important role of these organelles in parasite energy metabolism, at least at the final stages of sporogenesis. PMID- 21296914 TI - Traffic of chitin synthase 1 (CHS-1) to the Spitzenkorper and developing septa in hyphae of Neurospora crassa: actin dependence and evidence of distinct microvesicle populations. AB - We describe the subcellular location of chitin synthase 1 (CHS-1), one of seven chitin synthases in Neurospora crassa. Laser scanning confocal microscopy of growing hyphae showed CHS-1-green fluorescent protein (GFP) localized conspicuously in regions of active wall synthesis, namely, the core of the Spitzenkorper (Spk), the apical cell surface, and developing septa. It was also present in numerous fine particles throughout the cytoplasm plus some large vacuoles in distal hyphal regions. Although the same general subcellular distribution was observed previously for CHS-3 and CHS-6, they did not fully colocalize. Dual labeling showed that the three different chitin synthases were contained in different vesicular compartments, suggesting the existence of a different subpopulation of chitosomes for each CHS. CHS-1-GFP persisted in the Spk during hyphal elongation but disappeared from the septum after its development was completed. Wide-field fluorescence microscopy and total internal reflection fluorescence microscopy revealed subapical clouds of particles, suggestive of chitosomes moving continuously toward the Spk. Benomyl had no effect on CHS-1-GFP localization, indicating that microtubules are not strictly required for CHS trafficking to the hyphal apex. Conversely, actin inhibitors caused severe mislocalization of CHS-1-GFP, indicating that actin plays a major role in the orderly traffic and localization of CHS-1 at the apex. PMID- 21296915 TI - Role of carnitine acetyltransferases in acetyl coenzyme A metabolism in Aspergillus nidulans. AB - The flow of carbon metabolites between cellular compartments is an essential feature of fungal metabolism. During growth on ethanol, acetate, or fatty acids, acetyl units must enter the mitochondrion for metabolism via the tricarboxylic acid cycle, and acetyl coenzyme A (acetyl-CoA) in the cytoplasm is essential for the biosynthetic reactions and for protein acetylation. Acetyl-CoA is produced in the cytoplasm by acetyl-CoA synthetase during growth on acetate and ethanol while beta-oxidation of fatty acids generates acetyl-CoA in peroxisomes. The acetyl carnitine shuttle in which acetyl-CoA is reversibly converted to acetyl-carnitine by carnitine acetyltransferase (CAT) enzymes is important for intracellular transport of acetyl units. In the filamentous ascomycete Aspergillus nidulans, a cytoplasmic CAT, encoded by facC, is essential for growth on sources of cytoplasmic acetyl-CoA while a second CAT, encoded by the acuJ gene, is essential for growth on fatty acids as well as acetate. We have shown that AcuJ contains an N-terminal mitochondrial targeting sequence and a C-terminal peroxisomal targeting sequence (PTS) and is localized to both peroxisomes and mitochondria, independent of the carbon source. Mislocalization of AcuJ to the cytoplasm does not result in loss of growth on acetate but prevents growth on fatty acids. Therefore, while mitochondrial AcuJ is essential for the transfer of acetyl units to mitochondria, peroxisomal localization is required only for transfer from peroxisomes to mitochondria. Peroxisomal AcuJ was not required for the import of acetyl-CoA into peroxisomes for conversion to malate by malate synthase (MLS), and export of acetyl-CoA from peroxisomes to the cytoplasm was found to be independent of FacC when MLS was mislocalized to the cytoplasm. PMID- 21296916 TI - Cell signals, cell contacts, and the organization of yeast communities. AB - Even relatively simple species have evolved mechanisms to organize individual organisms into communities, such that the fitness of the group is greater than the fitness of isolated individuals. Within the fungal kingdom, the ability of many yeast species to organize into communities is crucial for their growth and survival, and this property has important impacts both on the economy and on human health. Over the last few years, studies of Saccharomyces cerevisiae have revealed several fundamental properties of yeast communities. First, strain-to strain variation in the structures of these groups is attributable in part to variability in the expression and functions of adhesin proteins. Second, the extracellular matrix surrounding these communities can protect them from environmental stress and may also be important in cell signaling. Finally, diffusible signals between cells contribute to community organization so that different regions of a community express different genes and adopt different cell fates. These findings provide an arena in which to view fundamental mechanisms by which contacts and signals between individual organisms allow them to assemble into functional communities. PMID- 21296922 TI - Reduced appetite and body mass index with delayed puberty in a mother and son: association with a rare novel sequence variant in the leptin gene. AB - INTRODUCTION: Leptin deficiency caused by mutations within the leptin gene (LEP) results in severe early onset obesity, hypogonadism, pubertal delay and immune system abnormalities. Constitutional delay in growth and puberty (CDGP) is a common condition seen in paediatric clinics, in which children present with delayed growth and puberty but usually also have a slim body habitus. We hypothesized that LEP variants may play a role in the phenotype seen in CDGP. AIM: To screen a group of children with CDGP for pathogenic sequence variants in LEP. PATIENTS AND METHODS: Denaturing HPLC was used to screen for LEP sequence variants in DNA samples from 78 children with CDGP (predominantly white males) and 112 control subjects. DNA fragments with a WAVE pattern deviant from wild type were directly sequenced. A STAT3 luciferase reporter assay in human embryonic kidney (HEK293) cells transiently transfected with the leptin receptor was used to test activity of mutant leptin. RESULTS: One child with CDGP was identified to be heterozygous for a novel missense variant (c.68C>G), which results in a proline to arginine substitution (p.P23R). This sequence variant was not identified in any of the other control subjects, but was identified in his mother who shared a similar phenotype of slim body habitus, reduced appetite and pubertal delay (menarche aged 15 years). The leptin variant showed similar stability in serum compared with wild type and did not demonstrate increased activity in an in vitro reporter gene assay. CONCLUSIONS: This is the first report of a sequence variant within the LEP gene associated with reduced body mass index rather than obesity. We hypothesize that this variant has increased bioactivity in vivo. PMID- 21296923 TI - Marinobacter daqiaonensis sp. nov., a moderate halophile isolated from a Yellow Sea salt pond. AB - A Gram-negative, oxidase- and catalase-positive, moderately halophilic strain, designated YCSA40(T), was isolated from sediment of Daqiao saltern in Qingdao, on the east coast of China. Growth occurred at 10-45 degrees C, at pH 5-9 and with 1-15% NaCl. Strain YCSA40(T) showed the highest 16S rRNA gene sequence similarity to Marinobacter segnicrescens SS011B1-4(T) (97%) and M. gudaonensis SL014B61A(T) (96.9%) and 16S rRNA gene sequence phylogenetic analysis assigned the isolate to the genus Marinobacter. Strain YCSA40(T) contained C(18:1)omega9c (34.8%), C(16:0) (11.6%), C(19:0) cyclo omega10c/C(19:1)omega6c (10.5%), C(16:1)omega9c (8.4%), C(17:0) (6.3%) and C(12:0) 3-OH (5.8%) as the predominant fatty acids. The DNA G+C content was 60.8 mol% and the major ubiquinone was Q-9. These chemotaxonomic characters were all consistent with membership of the genus Marinobacter. DNA-DNA relatedness between the isolate and M. segnicrescens CGMCC 1.6489(T), M. gudaonensis CGMCC 1.6294(T) and other type strains of species of the genus Marinobacter was <=30%. On the basis of the aforementioned data, it was concluded that strain YCSA40(T) represents a novel species of the genus Marinobacter, for which the name Marinobacter daqiaonensis sp. nov. is proposed. The type strain is YCSA40(T) (=CGMCC 1.9167(T) =NCCB 100308(T) =LMG 25365(T)). PMID- 21296924 TI - A multilocus sequence analysis approach to the phylogeny and taxonomy of the Halobacteriales. AB - Members of the order Halobacteriales are obligate extreme halophiles that belong to the domain Archaea. The classification of the Halobacteriales currently relies on a polyphasic approach, which integrates phenotypic, genotypic and chemotaxonomic characterization. However, the most utilized genetic marker for phylogeny, the 16S rRNA gene, has multiple drawbacks for use with the Halobacteriales: the species of many genera exhibit large intragenic differences between multiple ribosomal RNA operons, the gene is too conserved to discriminate reliably at the species level and it appears to be the most frequently recombined gene between closely related species. Moreover, the Halobacteriales is a rapidly expanding group due to recent successes at cultivating novel strains from a diverse set of hypersaline environments; a fast, reliable, inexpensive, portable molecular method for discriminating species is required for their investigation. Recently, multilocus sequence analysis (MLSA) has been shown to be an effective tool for strain identification and taxonomic designation, even for those taxa that experience frequent lateral gene transfer and homologous recombination. In this study, MLSA was utilized for evolutionary and taxonomic investigation of the Halobacteriales. Efficacy of the MLSA approach was tested across a hierarchical gradient using 52 halobacterial strains, representing 33 species (including names without standing in nomenclature) and 14 genera. A subset of 21 strains from the genus Haloarcula was analysed separately to test the sensitivity and relevance of the MLSA approach among closely related strains and species. The results demonstrated that MLSA differentiated individual strains, reliably grouped strains into species and species into genera and identified potential novel species and also family-like relationships. This study demonstrates that MLSA is a rapid and informative molecular method that will probably accommodate strain analysis at any taxonomic level within the Halobacteriales. PMID- 21296925 TI - Alkalibacterium subtropicum sp. nov., a slightly halophilic and alkaliphilic marine lactic acid bacterium isolated from decaying marine algae. AB - Two novel strains of marine lactic acid bacteria, isolated from decaying marine algae collected from a subtropical area of Japan, are described. The isolates, designated O24-2(T) and O25-2, were Gram-positive, non-sporulating and non motile. They lacked catalase and quinones. Under anaerobic cultivation conditions, lactate was produced from glucose with the production of formate, acetate and ethanol in a molar ratio of approximately 2:1:1. Under aerobic cultivation conditions, acetate and lactate were produced from carbohydrates and related compounds. The isolates were slightly halophilic, highly halotolerant and alkaliphilic. They were able to grow in 0-17.0% (w/v) NaCl, with optimum growth of strains O24-2(T) and O25-2 at 1.0-3.0 and 1.0-2.0% (w/v) NaCl, respectively. Growth of strain O24-2(T) was observed at pH 7.5-9.5, with optimum growth at pH 8.0-8.5. Comparative 16S rRNA gene sequence analysis revealed that the isolates occupied a phylogenetic position within the genus Alkalibacterium, showing highest similarity (99.6%) to Alkalibacterium putridalgicola T129-2-1(T). Although sequence similarity was high, the DNA-DNA relatedness value between strain O24-2(T) and A. putridalgicola T129-2-1(T) was 27%, indicating that they are members of distinct species. The DNA G+C contents of O24-2(T) and O25-2 were 43.7 and 44.4 mol%, respectively, and DNA-DNA relatedness between the isolates was 89%. The cell-wall peptidoglycan was type A4beta, Orn-d-Asp. The major cellular fatty acid components were C(14:0), C(16:0) and C(16:1)omega9c. Based on phenotypic characteristics and genetic distinctiveness, the isolates were classified as representatives of a novel species within the genus Alkalibacterium, for which the name Alkalibacterium subtropicum sp. nov. is proposed; the type strain is O24-2(T) (=DSM 23664(T)=NBRC 107172(T)). PMID- 21296926 TI - Reclassification of Paralactobacillus selangorensis Leisner et al. 2000 as Lactobacillus selangorensis comb. nov. AB - The taxonomic status of Paralactobacillus selangorensis is described and, based on evidence presented, transfer of the species to the genus Lactobacillus with the name Lactobacillus selangorensis comb. nov. is proposed. This reclassification is supported by multilocus sequence analysis of the 16S rRNA gene and portions of the cpn60, pheS and rpoA genes. Mode of cell division and existing phenotypic information also show that P. selangorensis cannot be differentiated from the genus Lactobacillus. The type strain of Lactobacillus selangorensis comb. nov. is ATCC BAA-66(T) (=LMG 17710(T) =CIP 106482(T)). PMID- 21296927 TI - Frondihabitans cladoniiphilus sp. nov., an actinobacterium of the family Microbacteriaceae isolated from lichen, and emended description of the genus Frondihabitans. AB - A novel actinobacterium, designated strain CafT13(T), was isolated from the thallus of the reindeer lichen Cladonia arbuscula sampled in the Austrian Alps (Koralpe). The organism was aerobic, with rod- to irregular-shaped cells (often forming dense clusters of cells when grown in liquid medium), Gram-stain positive, oxidase-negative, catalase-positive and non-motile. It was able to grow at 1 degrees C and at low to neutral pH, but not above 30 degrees C or at high pH. The peptidoglycan type was B2beta with ornithine as the diagnostic diamino acid. The menaquinones were MK-7 and MK-8. The polar lipid profile comprised diphosphatidylglycerol, phosphatidylglycerol, three unidentified phospholipids, three unidentified glycolipids and one unidentified aminolipid. The predominant fatty acids were C(18:1), C(14:0) 2-OH, C(17:1)omega9c, C(16:0) and anteiso C(15:0). The mean DNA G+C content of strain CafT13(T) was 69.0+/-0.17 mol%. 16S rRNA gene sequence analysis showed that strain CafT13(T) belongs to the family Microbacteriaceae, within the genus Frondihabitans. The mean level of DNA-DNA relatedness between strain CafT13(T) and the type strain of Frondihabitans australicus was 35.2+/-5.23%. The enzyme spectrum of strain CafT13(T) differentiated it from recognized species of the genus Frondihabitans. Based on molecular, chemotaxonomic and physiological data, strain CafT13(T) is considered to represent a novel species of the genus Frondihabitans, for which the name Frondihabitans cladoniiphilus sp. nov. is proposed; the type strain is CafT13(T) (=DSM 23273(T)=LMG 25550(T)). PMID- 21296928 TI - Proposal of Bisgaardia hudsonensis gen. nov., sp. nov. and an additional genomospecies, isolated from seals, as new members of the family Pasteurellaceae. AB - Phenotypic and phylogenetic studies were performed on eight Gram-negative staining, rod-shaped bacteria isolated from seals. Biochemical and physiological studies showed identical profiles for all of the isolates and indicated that they were related to the family Pasteurellaceae. 16S rRNA gene sequencing demonstrated that the organism represented a distinct cluster with two sublines within the family Pasteurellaceae with <96% sequence similarity to any recognized species. Multilocus sequence analysis (MLSA) including rpoB, infB and recN genes further confirmed these findings with the eight isolates forming a genus-like cluster with two branches. Genome relatedness as deduced from recN gene sequences suggested that the isolates represented a new genus with two species. On the basis of the results of the phylogenetic analysis and phenotypic criteria, it is proposed that these bacteria from seals are classified as Bisgaardia hudsonensis gen. nov., sp. nov. (the type species) and Bisgaardia genomospecies 1. The G+C content of the DNA was 39.5 mol%. The type strain of Bisgaardia hudsonensis gen. nov., sp. nov. is M327/99/2(T) (=CCUG 43067(T)=NCTC 13475(T)=98-D-690B(T)) and the reference strain of Bisgaardia genomospecies 1 is M1765/96/5 (=CCUG 59551=NCTC 13474). PMID- 21296929 TI - Rhodanobacter panaciterrae sp. nov., a bacterium with ginsenoside-converting activity isolated from soil of a ginseng field. AB - A novel gammaproteobacterium, designated LnR5-47(T), was isolated from soil of a ginseng field in Liaoning province, China. The isolate was a Gram-negative, aerobic, non-motile, non-spore-forming rod. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain LnR5-47(T) belonged to the genus Rhodanobacter. The isolate was most closely related to Rhodanobacter ginsengisoli GR17-7(T), Rhodanobacter terrae GP18-1(T), Dyella ginsengisoli Gsoil 3046(T), Rhodanobacter soli DCY45(T), Dyella soli JS12-10(T) and Dyella japonica IAM 15069(T) (98.0, 97.9, 97.7, 97.3, 97.2 and 97.1% 16S rRNA gene sequence similarity, respectively). Chemotaxonomic data (Q-8 as the predominant ubiquinone, and iso-C(16:0), iso-C(17:1)omega9c and iso-C(15:0) as the major fatty acids) also supported the affiliation of strain LnR5-47(T) with the genus Rhodanobacter. However, DNA-DNA relatedness between strain LnR5-47(T) and its closest phylogenetic neighbours was <25.8%. Moreover, physiological and biochemical tests phenotypically differentiated the isolate from other members of the genus Rhodanobacter. Therefore, strain LnR5-47(T) represents a novel species, for which the name Rhodanobacter panaciterrae sp. nov. is proposed; the type strain is LnR5-47(T) (=KACC 12826(T)=KCTC 22232(T)=LMG 24460(T)). PMID- 21296930 TI - The genus Listonella MacDonell and Colwell 1986 is a later heterotypic synonym of the genus Vibrio Pacini 1854 (Approved Lists 1980)--a taxonomic opinion. AB - We analysed the taxonomic position of the genus Listonella based on phylogenetic, genomic and phenotypic data. The species of the genus Listonella were nested within the genus Vibrio according to the 16S rRNA gene sequence-based phylogenetic tree. The closest neighbour of Vibrio (Listonella) anguillarum strains LMG 4437(T) and ATCC 68554 (=strain 775) was Vibrio ordalii LMG 13544(T), with more than 99.5% 16S rRNA gene sequence similarity. Furthermore, Vibrio (Listonella) pelagius is highly related to Vibrio splendidus. According to average amino acid identity (AAI), multilocus sequence analysis (MLSA) and Karlin genome signature, the closest neighbour of L. anguillarum ATCC 68554 is V. ordalii LMG 13544(T), with 95% AAI, 98% MLSA and 5 in Karlin. V. anguillarum ATCC 68554 and Vibrio cholerae N16961 had 77% similarity in AAI, 85% in MLSA and 14 in the Karlin signature. Phenotypic analyses of previously published data for V. (L.) anguillarum and V. (L.) pelagius revealed that the genus Listonella is extremely similar to the genus Vibrio. V. ordalii and L. anguillarum strains yielded up to 67% DNA-DNA hybridization. There are only a few phenotypic features that might be used to discriminate these two species: L. anguillarum is positive for the Voges-Proskauer reaction, citrate utilization, starch hydrolysis, lipase activity and acid production from glycerol, sorbitol and trehalose, whereas V. ordalii is negative for these traits. We suggest that the genus Listonella is a later heterotypic synonym of the genus Vibrio and propose to use the names Vibrio anguillarum and Vibrio pelagius in place of Listonella anguillarum and Listonella pelagia, respectively. PMID- 21296931 TI - Vibrio variabilis sp. nov. and Vibrio maritimus sp. nov., isolated from Palythoa caribaeorum. AB - Two novel vibrio isolates (R-40492(T) and R-40493(T)) originating from the zoanthid Palythoa caribaeorum in Brazil in 2005 were taxonomically characterized by means of a polyphasic approach comprising multilocus sequence analysis (MLSA), DNA-DNA hybridization (DDH), DeltaT(m) analysis and phenotypic characterization. Phylogenetic analysis based on 16S rRNA gene sequences showed that R-40492(T) and R-40493(T) fell within the genus Vibrio and were most closely related to each other with 99% similarity; similarities of these two novel isolates towards Vibrio neptunius LMG 20536(T), Vibrio coralliilyticus LMG 20984(T), Vibrio nigripulchritudo LMG 3896(T), Vibrio sinaloensis LMG 25238(T) and Vibrio brasiliensis LMG 20546(T) varied between 97.1 and 98.5%. DDH experiments showed that the two isolates had less than 15% relatedness to the phylogenetically most closely related Vibrio species. R-40492(T) and R-40493(T) had 55-57% relatedness to each other. The DeltaT(m) between R-40492(T) and R-40493(T) was 6.12 degrees C. In addition, MLSA of concatenated sequences (16S rRNA, ftsZ, gyrB, recA, rpoA, topA, pyrH and mreB; 6035 bp in length) showed that the two novel isolates formed a separate branch with less than 92% concatenated gene sequence similarity towards known species of vibrios. Two novel species are proposed to accommodate these novel isolates, namely Vibrio variabilis sp. nov. (type strain, R 40492(T)=LMG 25438(T)=CAIM 1454(T)) and Vibrio maritimus sp. nov. (type strain, R 40493(T)=LMG 25439(T)=CAIM 1455(T)). PMID- 21296932 TI - Mutacins from Streptococcus mutans UA159 are active against multiple streptococcal species. AB - Streptococcus mutans UA159, whose genome is completely sequenced, produces two nonlantibiotic mutacins, mutacin IV (encoded by nlmAB) and mutacin V (encoded by nlmC). In this study, we investigated the contribution of nlmA and nlmB to mutacin IV activity and demonstrated by performing genetic studies as well as by using semipurified molecules that, in contrast to a previous report, both of these genes are required for optimum mutacin IV activity. We also showed that mutacin IV is active against multiple Streptococcus species. In contrast, mutacin V displayed a narrower inhibitory range than mutacin IV. Our results suggest that mutacin IV and mutacin V may act synergistically to inhibit various organisms. PMID- 21296933 TI - Altering the composition of caseicins A and B as a means of determining the contribution of specific residues to antimicrobial activity. AB - Caseicin A (IKHQGLPQE) and caseicin B (VLNENLLR) are antimicrobial peptides generated through the bacterial fermentation of sodium caseinate, and on the basis of this and previous studies, they are active against many Gram-negative pathogens (Cronobacter sakazakii, Cronobacter muytjensii, Salmonella enterica serovar Typhimurium, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas fluorescens) as well as the Gram-positive organism Staphylococcus aureus. Here we describe further studies with the aim of establishing the importance of specific (charged and nonpolar aliphatic) residues within the caseicin peptides and the effects that they have on the bacteria listed above. In order to achieve our objective, we created four derivatives of each caseicin (A1 to A4 and B1 to B4) in which specific residues were altered, and results obtained with these derivatives were compared to wild-type caseicin activity. Although conversion of cationic residues to alanine in caseicins B1 (R8A change), A1 (K2A), A2 (H3A), and A3 (K2A-H3A) generally resulted in their activity against microbial targets being reduced or unaltered, C. sakazakii DPC6440 was unusual in that it displayed enhanced sensitivity to three peptides (caseicins A1, A3, and B2) in which positively charged residues had been eliminated. While the replacement of leucine with alanine in selected variants (B3 and B4) resulted in reduced activity against a number of strains of Cronobacter and, in some cases, S. Typhimurium, these changes enhanced the activities of these peptides against DPC6440 and a number of S. aureus strains. It is thus apparent that the importance of specific residues within the caseicin peptides is dependent on the strain being targeted. PMID- 21296934 TI - Development of an O-antigen serotyping scheme for Cronobacter sakazakii. AB - Cronobacter sakazakii is an opportunistic pathogen that can cause severe infections. Serotyping provides a basis for the categorization of bacterial strains and is an important tool for epidemiological and surveillance purposes. In this study, of the 135 Cronobacter strains tested initially, 119 were identified as C. sakazakii and used. A serotyping scheme for C. sakazakii that classifies strains based on their different O antigens was developed. Seven antisera that exhibited high agglutinin titers (>640) were produced. O2 and O6 antisera were specific for their homologous strains, O4 and O7 antisera gave heterologous titers with O1 and O6 antigens, respectively, and O1, O3, and O5 antisera cross-reacted with each other and require preabsorption with the other two antigens. All of these 119 C. sakazakii strains were clearly assigned to these seven serotypes. O1 and O2 are the dominant serotypes, comprising 69.7% of the isolates. We also characterized the O-antigen gene clusters using restriction fragment length polymorphism (RFLP). The grouping of C. sakazakii strains based on their RFLP banding patterns correlated well with the grouping of strains based on our serotyping scheme. The serotype scheme presented here could prove to be a useful tool for serotyping C. sakazakii isolates. PMID- 21296935 TI - Antibacterial activity and mechanism of action of zinc oxide nanoparticles against Campylobacter jejuni. AB - The antibacterial effect of zinc oxide (ZnO) nanoparticles on Campylobacter jejuni was investigated for inhibition and inactivation of cell growth. The results showed that C. jejuni was extremely sensitive to treatment with ZnO nanoparticles. The MIC of ZnO nanoparticles for C. jejuni was determined to be 0.05 to 0.025 mg/ml, which is 8- to 16-fold lower than that for Salmonella enterica serovar Enteritidis and Escherichia coli O157:H7 (0.4 mg/ml). The action of ZnO nanoparticles against C. jejuni was determined to be bactericidal, not bacteriostatic. Scanning electron microscopy examination revealed that the majority of the cells transformed from spiral shapes into coccoid forms after exposure to 0.5 mg/ml of ZnO nanoparticles for 16 h, which is consistent with the morphological changes of C. jejuni under other stress conditions. These coccoid cells were found by ethidium monoazide-quantitative PCR (EMA-qPCR) to have a certain level of membrane leakage. To address the molecular basis of ZnO nanoparticle action, a large set of genes involved in cell stress response, motility, pathogenesis, and toxin production were selected for a gene expression study. Reverse transcription-quantitative PCR (RT-qPCR) showed that in response to treatment with ZnO nanoparticles, the expression levels of two oxidative stress genes (katA and ahpC) and a general stress response gene (dnaK) were increased 52-, 7-, and 17-fold, respectively. These results suggest that the antibacterial mechanism of ZnO nanoparticles is most likely due to disruption of the cell membrane and oxidative stress in Campylobacter. PMID- 21296936 TI - Suitability of Vader for transposon-mediated mutagenesis in Aspergillus niger. AB - The filamentous fungus Aspergillus niger is widely used in biotechnological applications. Strain CBS513.88 is known to harbor 21 copies of the nonautonomous transposon Vader. Upon selection of chlorate-resistant A. niger colonies, one Vader copy was found integrated in the nirA gene. This copy was used for vector construction and development of a transposon-tagging method. Vader showed an excision frequency of about 1 in 2.2 * 10(5) conidiospores. A total of 95 of 97 colonies analyzed exhibited an excision event at the DNA level, and Vader footprints were found. By employing thermal asymmetric interlaced (TAIL)-PCR, the reintegration sites of 21 independent excision events were determined. All reintegration events occurred within or very close to genes. Therefore, this method can be used for transposon mutagenesis in A. niger. PMID- 21296937 TI - Shuttle vector system for Methanococcus maripaludis with improved transformation efficiency. AB - We have identified an open reading frame and DNA element that are sufficient to maintain shuttle vectors in Methanococcus maripaludis. Strain S0001, containing ORF1 from pURB500 integrated into the M. maripaludis genome, supports a significantly smaller shuttle vector, pAW42, and a 7,000-fold increase in transformation efficiency for pURB500-based vectors. PMID- 21296938 TI - Versatile metabolic adaptations of Ralstonia eutropha H16 to a loss of PdhL, the E3 component of the pyruvate dehydrogenase complex. AB - A previous study reported that the Tn5-induced poly(3-hydroxybutyric acid) (PHB) leaky mutant Ralstonia eutropha H1482 showed a reduced PHB synthesis rate and significantly lower dihydrolipoamide dehydrogenase (DHLDH) activity than the wild type R. eutropha H16 but similar growth behavior. Insertion of Tn5 was localized in the pdhL gene encoding the DHLDH (E3 component) of the pyruvate dehydrogenase complex (PDHC). Taking advantage of the available genome sequence of R. eutropha H16, observations were verified and further detailed analyses and experiments were done. In silico genome analysis revealed that R. eutropha possesses all five known types of 2-oxoacid multienzyme complexes and five DHLDH-coding genes. Of these DHLDHs, only PdhL harbors an amino-terminal lipoyl domain. Furthermore, insertion of Tn5 in pdhL of mutant H1482 disrupted the carboxy-terminal dimerization domain, thereby causing synthesis of a truncated PdhL lacking this essential region, obviously leading to an inactive enzyme. The defined DeltapdhL deletion mutant of R. eutropha exhibited the same phenotype as the Tn5 mutant H1482; this excludes polar effects as the cause of the phenotype of the Tn5 mutant H1482. However, insertion of Tn5 or deletion of pdhL decreases DHLDH activity, probably negatively affecting PDHC activity, causing the mutant phenotype. Moreover, complementation experiments showed that different plasmid encoded E3 components of R. eutropha H16 or of other bacteria, like Burkholderia cepacia, were able to restore the wild-type phenotype at least partially. Interestingly, the E3 component of B. cepacia possesses an amino-terminal lipoyl domain, like the wild-type H16. A comparison of the proteomes of the wild-type H16 and of the mutant H1482 revealed striking differences and allowed us to reconstruct at least partially the impressive adaptations of R. eutropha H1482 to the loss of PdhL on the cellular level. PMID- 21296939 TI - Molecular risk assessment and epidemiological typing of Shiga toxin-producing Escherichia coli by using a novel PCR binary typing system. AB - Shiga toxin-producing Escherichia coli (STEC) is a zoonotic pathogen that causes diarrheal disease in humans and is of public health concern because of its ability to cause outbreaks and severe disease such as hemorrhagic colitis or hemolytic-uremic syndrome. More than 400 serotypes of STEC have been implicated in outbreaks and sporadic human disease. The aim of this study was to develop a PCR binary typing (P-BIT) system that could be used to aid in risk assessment and epidemiological studies of STEC by using gene targets that would represent a broad range of STEC virulence genes. We investigated the distribution of 41 gene targets in 75 O157 and non-O157 STEC isolates and found that P-BIT provided 100% typeability for isolates, gave a diversity index of 97.33% (compared with 99.28% for XbaI pulsed-field gel electrophoresis [PFGE] typing), and produced 100% discrimination for non-O157 STEC isolates. We identified 24 gene targets that conferred the same level of discrimination and produced the same cluster dendrogram as the 41 gene targets initially examined. P-BIT clustering identified O157 from non-O157 isolates and identified seropathotypes associated with outbreaks and severe disease. Numerical analysis of the P-BIT data identified several genes associated with human or nonhuman sources as well as high-risk seropathotypes. We conclude that P-BIT is a useful approach for subtyping, offering the advantage of speed, low cost, and potential for strain risk assessment that can be used in tandem with current molecular typing schema for STEC. PMID- 21296940 TI - Effect of spatial differences in microbial activity, pH, and substrate levels on methanogenesis initiation in refuse. AB - The initiation of methanogenesis in refuse occurs under high volatile fatty acid (VFA) concentration and low pH (5.5 to 6.25), which generally are reported to inhibit methanogenic Archaea. One hypothesized mechanism for the initiation of methanogenesis in refuse decomposition is the presence of pH-neutral niches within the refuse that act as methanogenesis initiation centers. To provide experimental support for this mechanism, laboratory-scale landfill reactors were operated and destructively sampled when methanogenesis initiation was observed. The active bacterial and archaeal populations were evaluated using RNA clone libraries, RNA terminal restriction fragment length polymorphism (T-RFLP), and reverse transcription-quantitative PCR (RT-qPCR). Measurements from 81 core samples from vertical and horizontal sections of each reactor showed large spatial differences in refuse pH, moisture content, and VFA concentrations. No pH neutral niches were observed prior to methanogenesis. RNA clone library results showed that active bacterial populations belonged mostly to Clostridiales, and that methanogenic Archaea activity at low pH was attributable to Methanosarcina barkeri. After methanogenesis began, pH-neutral conditions developed in high moisture-content areas containing substantial populations of M. barkeri. These areas expanded with increasing methane production, forming a reaction front that advanced to low-pH areas. Despite low-pH conditions in >50% of the samples within the reactors, the leachate pH was neutral, indicating that it is not an accurate indicator of landfill microbial conditions. In the absence of pH-neutral niches, this study suggests that methanogens tolerant to low pH, such as M. barkeri, are required to overcome the low-pH, high-VFA conditions present during the anaerobic acid phase of refuse decomposition. PMID- 21296941 TI - Proximity-dependent inhibition in Escherichia coli isolates from cattle. AB - We describe a novel proximity-dependent inhibition phenotype of Escherichia coli that is expressed when strains are cocultured in defined minimal media. When cocultures of "inhibitor" and "target" strains approached a transition between logarithmic and stationary growth, target strain populations rapidly declined >4 log CFU per ml over a 2-h period. Inhibited strains were not affected by exposure to conditioned media from inhibitor and target strain cocultures or when the inhibitor and target strains were incubated in shared media but physically separated by a 0.4-MUm-pore-size membrane. There was no evidence of lytic phage or extracellular bacteriocin involvement, unless the latter was only present at effective concentrations within immediate proximity of the inhibited cells. The inhibitory activity observed in this study was effective against a diversity of E. coli strains, including enterohemorrhagic E. coli serotype O157:H7, enterotoxigenic E. coli expressing F5 (K99) and F4 (K88) fimbriae, multidrug resistant E. coli, and commensal E. coli. The decline in counts of target strains in coculture averaged 4.8 log CFU/ml (95% confidence interval, 4.0 to 5.5) compared to their monoculture counts. Coculture of two inhibitor strains showed mutual immunity to inhibition. These results suggest that proximity-dependent inhibition can be used by bacteria to gain a numerical advantage when populations are entering stationary phase, thus setting the stage for a competitive advantage when growth conditions improve. PMID- 21296942 TI - Accumulation of sulfonamide resistance genes in arable soils due to repeated application of manure containing sulfadiazine. AB - Two soils were amended three times with pig manure. The abundance of sulfonamide resistance genes was determined by quantitative PCR 2 months after each application. In both soils treated with sulfadiazine-containing manure, the numbers of copies of sul1 and sul2 significantly increased compared to numbers after treatments with antibiotic-free manure or a control and accumulated with repeated applications. PMID- 21296943 TI - Significant shift in median guinea pig infectious dose shown by an outbreak associated Listeria monocytogenes epidemic clone strain and a strain carrying a premature stop codon mutation in inlA. AB - Listeria monocytogenes contains (i) epidemic clone (EC) strains, which have been linked to the majority of listeriosis outbreaks worldwide and are overrepresented among sporadic cases in the United States, and (ii) strains commonly isolated from ready-to-eat foods that carry a mutation leading to a premature stop codon (PMSC) in inlA, which encodes the key virulence factor internalin A (InlA). Internalin A binds certain isoforms of the cellular receptor E-cadherin to facilitate crossing the intestinal barrier during the initial stages of an L. monocytogenes infection. Juvenile guinea pigs, which express the human isoform of E-cadherin that binds InlA, were intragastrically challenged with a range of doses of (i) an EC strain associated with a listeriosis outbreak or (ii) a strain carrying a PMSC mutation in inlA. Recovery of L. monocytogenes from tissues (i.e., liver, spleen, mesenteric lymph nodes, and ileum) was used to develop strain-specific dose-response curves on the basis of individual and combined organ data. Modeling of individual and combined organ data revealed an approximate 1.2 to 1.3 log(10) increase in the median infectious dose for the strain carrying a PMSC in inlA relative to that for the EC strain. Inclusion of the strain parameter significantly improved the goodness of fit for individual and combined organ models, indicating a significant shift in median infectious dose for guinea pigs challenged with an inlA PMSC strain compared to that for guinea pigs challenged with an EC strain. Results from this work provide evidence that the L. monocytogenes dose-response relationship is strain specific and will provide critical data for enhancement of current risk assessments and development of future risk assessments. PMID- 21296944 TI - Internalization of murine norovirus 1 by Lactuca sativa during irrigation. AB - Romaine lettuce (Lactuca sativa) was grown hydroponically or in soil and challenged with murine norovirus 1 (MNV) under two conditions: one mimicking a severe one-time contamination event and another mimicking a lower level of contamination occurring over time. In each condition, lettuce was challenged with MNV delivered at the roots. In the first case, contamination occurred on day one with 5 * 10(8) reverse transcriptase quantitative PCR (RT-qPCR) U/ml MNV in nutrient buffer, and irrigation water was replaced with virus-free buffer every day for another 4 days. In the second case, contamination with 5 * 10(5) RT-qPCR U/ml MNV (freshly prepared) occurred every day for 5 days. Virus had a tendency to adsorb to soil particles, with a small portion suspended in nutrient buffer; e.g., ~8 log RT-qPCR U/g MNV was detected in soil during 5 days of challenge with virus inoculums of 5 * 10(8) RT-qPCR U/ml at day one, but <6 log was found in nutrient buffer on days 3 and 5. For hydroponically grown lettuce, ~3.4 log RT qPCR U of viral RNA/50 mg of plant tissue was detected in some lettuce leaf samples after 5 days at high MNV inoculums, significantly higher than the internalized virus concentration (~2.6 log) at low inoculums (P < 0.05). For lettuce grown in soil, approximately 2 log RT-qPCR U of viral RNA/50 mg of plant tissue was detected in lettuce with both high and low inoculums, showing no significant difference. For viral infectivity, infectious MNV was found in lettuce samples challenged with high virus inoculums grown hydroponically and in soil but not in lettuce grown with low virus inoculums. Lettuce grown hydroponically was further incubated in 99% and 70% relative humidities (RH) to evaluate plant transpiration relative to virus uptake. More lettuce samples were found positive for MNV at a significantly higher transpiration rate at 70% RH, indicating that transpiration might play an important role in virus internalization into L. sativa. PMID- 21296945 TI - Parameters affecting spore recovery from wipes used in biological surface sampling. AB - The need for the precise and reliable collection of potential biothreat contaminants has motivated research in developing a better understanding of the variability in biological surface sampling methods. In this context, the objective of this work was to determine parameters affecting the efficiency of extracting Bacillus anthracis Sterne spores from commonly used wipe sampling materials and to describe performance using the interfacial energy concept. In addition, surface thermodynamics was applied to understand and predict surface sampling performance. Wipe materials were directly inoculated with known concentrations of B. anthracis spores and placed into extraction solutions, followed by sonication or vortexing. Experimental factors investigated included wipe material (polyester, cotton, and polyester-rayon), extraction solution (sterile deionized water [H(2)O], deionized water with 0.04% Tween 80 [H(2)O-T], phosphate-buffered saline [PBS], and PBS with 0.04% Tween 80 [PBST]), and physical dissociation method (vortexing or sonication). The most efficient extraction from wipes was observed for solutions containing the nonionic surfactant Tween 80. The increase in extraction efficiency due to surfactant addition was attributed to an attractive interfacial energy between Tween 80 and the centrifuge tube wall, which prevented spore adhesion. Extraction solution significantly impacted the extraction efficiency, as determined by statistical analysis (P < 0.05). Moreover, the extraction solution was the most important factor in extraction performance, followed by the wipe material. Polyester-rayon was the most efficient wipe material for releasing spores into solution by rank; however, no statistically significant difference between polyester-rayon and cotton was observed (P > 0.05). Vortexing provided higher spore recovery in H(2)O and H(2)O-T than sonication, when all three wipe materials and the reference control were considered (P < 0.05). PMID- 21296946 TI - Transcriptome, proteome, and metabolite analyses of a lactate dehydrogenase negative mutant of Enterococcus faecalis V583. AB - A constructed lactate dehydrogenase (LDH)-negative mutant of Enterococcus faecalis V583 grows at the same rate as the wild type but ferments glucose to ethanol, formate, and acetoin. Microarray analysis showed that LDH deficiency had profound transcriptional effects: 43 genes in the mutant were found to be upregulated, and 45 were found to be downregulated. Most of the upregulated genes encode enzymes of energy metabolism or transport. By two-dimensional (2D) gel analysis, 45 differentially expressed proteins were identified. A comparison of transcriptomic and proteomic data suggested that for several proteins the level of expression is regulated beyond the level of transcription. Pyruvate catabolic genes, including the truncated ldh gene, showed highly increased transcription in the mutant. These genes, along with a number of other differentially expressed genes, are preceded by sequences with homology to binding sites for the global redox-sensing repressor, Rex, of Staphylococcus aureus. The data indicate that the genes are transcriptionally regulated by the NADH/NAD ratio and that this ratio plays an important role in the regulatory network controlling energy metabolism in E. faecalis. PMID- 21296947 TI - Diversity of and selection acting on cylindrospermopsin cyrB gene adenylation domain sequences in Florida. AB - Aphanizomenon ovalisporum is the only confirmed cylindrospermopsin producer identified in the United States to date. On the other hand, Cylindrospermopsis raciborskii is a prominent feature of many lakes in Florida and other regions of the United States. To see the variation in cylindrospermopsin cyrB gene adenylation domain sequences and possibly discover new cylindrospermopsin producers, we collected water samples for a 3-year period from 17 different systems in Florida. Positive amplicons were cloned and sequenced, revealing that approximately 92% of sequences were A. ovalisporum-like (>99% identity). Interestingly, 6% of sequences were very similar (>99% identity) to cyrB sequences of C. raciborskii from Australia and of Aphanizomenon sp. from Germany. Neutrality tests suggest that A. ovalisporum-like cyrB adenylation domain sequences are under purifying selection, with abundant low-frequency polymorphisms within the population. On the other hand, when compared between species by codon-based methods, amino acids of CyrB also seem to be under purifying selection, in accordance with the one proposed amino acid thought to be activated by the CyrB adenylation domain. PMID- 21296948 TI - Phylogeny of replication initiator protein TrfA reveals a highly divergent clade of incompatibility group P1 plasmids. AB - Incompatibility group P1 (IncP-1) plasmid diversity was evaluated based on replication initiator protein (TrfA) phylogeny. A new and highly divergent clade was identified. Replication assays indicated that TrfA of recently discovered IncP-1 plasmids from Xylella fastidiosa and Verminephrobacter eiseniae initiated plasmid replication using cognate or heterologous origins of replication. PMID- 21296949 TI - Characterization of Actinoplanes missouriensis spore flagella. AB - Actinoplanes missouriensis spores swim with a tuft of flagella. Flagella of newborn spores are wrapped with a membranous sheath. When the sheath is unwrapped, spores start swimming. Flagellar length is kept short, at around 1.9 MUm, which covers half the circumference of the spore. PMID- 21296950 TI - Enhancing isoprene production by genetic modification of the 1-deoxy-d-xylulose-5 phosphate pathway in Bacillus subtilis. AB - To enhance the production of isoprene, a volatile 5-carbon hydrocarbon, in the Gram-positive spore-forming rod-shaped bacterium Bacillus subtilis, 1-deoxy-d xylulose-5-phosphate synthase (Dxs) and 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr) were overexpressed in B. subtilis DSM 10. For the strain that overexpresses Dxs, the yield of isoprene was increased 40% over that by the wild-type strain. In the Dxr overexpression strain, the level of isoprene production was unchanged. Overexpression of Dxr together with Dxs showed an isoprene production level similar to that of the Dxs overproduction strain. The effects of external factors, such as stress factors including heat (48 degrees C), salt (0.3 M NaCl), ethanol (1%), and oxidative (0.005% H(2)O(2)) stress, on isoprene production were further examined. Heat, salt, and H(2)O(2) induced isoprene production; ethanol inhibited isoprene production. In addition, induction and repression effects are independent of SigB, which is the general stress-responsive alternative sigma factor of Gram-positive bacteria. PMID- 21296951 TI - Validation of a Clostridium endospore viability assay and analysis of Greenland ices and Atacama Desert soils. AB - A microscopy-based endospore viability assay (micro-EVA) capable of enumerating germinable Clostridium endospores (GCEs) in less than 30 min has been validated and employed to determine GCE concentrations in Greenland ices and Atacama Desert soils. Inoculation onto agarose doped with Tb(3+) and d-alanine triggers Clostridium spore germination and the concomitant release of ~10(8) molecules of dipicolinic acid (DPA) per endospore, which, under pulsed UV excitation, enables enumeration of resultant green Tb(3+)-DPA luminescent spots as GCEs with time gated luminescence microscopy. The intensity time courses of the luminescent spots were characteristic of stage I Clostridium spore germination dynamics. Micro-EVA was validated against traditional CFU cultivation from 0 to 1,000 total endospores/ml (i.e., phase-bright bodies/ml), yielding 56.4% +/- 1.5% GCEs and 43.0% +/- 1.0% CFU. We also show that d-alanine serves as a Clostridium-specific germinant (three species tested) that inhibits Bacillus germination of spores (five species tested) in that endospore concentration regime. Finally, GCE concentrations in Greenland ice cores and Atacama Desert soils were determined with micro-EVA, yielding 1 to 2 GCEs/ml of Greenland ice (versus <1 CFU/ml after 6 months of incubation) and 66 to 157 GCEs/g of Atacama Desert soil (versus 40 CFU/g soil). PMID- 21296952 TI - The centromere site of the segregation cassette of broad-host-range plasmid RA3 is located at the border of the maintenance and conjugative transfer modules. AB - RA3 is a low-copy-number, broad-host-range (BHR) conjugative plasmid of the IncU incompatibility group isolated originally from Aeromonas spp. A 4.9-kb fragment of RA3 is sufficient to stabilize an otherwise unstable replicon in Escherichia coli. This fragment specifies the korA-incC-korB-orf11 operon coding for an active partition system related to the central control operon of IncP-1 plasmids and found also in BHR environmental plasmids recently classified as the PromA group. All four genes in the cassette are necessary for segregation. IncC and KorB of RA3 belong to the ParA and ParB families of partitioning proteins, respectively. In contrast with IncP-1 plasmids, neither KorB nor IncC are involved in transcriptional autoregulation. Instead, KorA exerts transcriptional control of the operon by binding to a palindromic sequence that overlaps the putative -35 promoter motif of the cassette. The Orf11 protein is not required for regulation, but its absence decreases the stabilization potential of the segregation module. A region discontiguous from the cassette harbors a set of unrelated repeat motifs distributed over ~300 bp. Dissection of this region identified the centromere sequence that is vital for partitioning. The ~300-bp fragment also encompasses the origin of conjugative transfer, oriT, and the promoter that drives transcription of the conjugative transfer operon. A similar set of cis-acting motifs are evident in the PromA group of environmental plasmids, highlighting a common evolutionary origin of segregation and conjugative transfer modules in these plasmids and members of the IncU group. PMID- 21296953 TI - Efficient generation of unmarked deletions in Legionella pneumophila. AB - Unmarked gene deletions facilitate studies of Legionella pneumophila multicomponent processes, such as motility and exonuclease activity. For this purpose, FRT-flanked alleles constructed in Escherichia coli using lambda-Red recombinase were transferred to L. pneumophila by natural transformation. Resistance cassettes were then efficiently excised using the Flp site-specific recombinase encoded on a plasmid that is readily lost. PMID- 21296954 TI - Multiple approaches to enhance the cultivability of bacteria associated with the marine sponge Haliclona (gellius) sp. AB - Three methods were examined to cultivate bacteria associated with the marine sponge Haliclona (gellius) sp.: agar plate cultures, liquid cultures, and floating filter cultures. A variety of oligotrophic media were employed, including media with aqueous and organic sponge extracts, bacterial signal molecules, and siderophores. More than 3,900 isolates were analyzed, and 205 operational taxonomic units (OTUs) were identified. Media containing low concentrations of mucin or a mixture of peptone and starch were most successful for the isolation of diversity, while the commonly used marine broth did not result in a high diversity among isolates. The addition of antibiotics generally led to a reduced diversity on plates but yielded different bacteria than other media. In addition, diversity patterns of isolates from agar plates, liquid cultures, and floating filters were significantly different. Almost 89% of all isolates were Alphaproteobacteria; however, members of phyla that are less commonly encountered in cultivation studies, such as Planctomycetes, Verrucomicrobia, and Deltaproteobacteria, were isolated as well. The sponge associated bacteria were categorized into three different groups. The first group represented OTUs that were also obtained in a clone library from previously analyzed sponge tissue (group 1). Furthermore, we distinguished OTUs that were obtained from sponge tissue (in a previous study) but not from sponge isolates (group 2), and there were also OTUs that were not obtained from sponge tissue but were obtained from sponge isolates (group 3). The 17 OTUs categorized into group 1 represented 10 to 14% of all bacterial OTUs that were present in a large clone library previously generated from Haliclona (gellius) sp. sponge tissue, which is higher than previously reported cultivability scores for sponge-associated bacteria. Six of these 17 OTUs were not obtained from agar plates, which underlines that the use of multiple cultivation methods is worthwhile to increase the diversity of the cultivable microorganisms from sponges. PMID- 21296955 TI - Hypoxia upregulates PGI-synthase and increases PGI2 release in human vascular cells exposed to inflammatory stimuli. AB - Hypoxia affects vascular function and cell metabolism, survival, growth, and motility; these processes are partially regulated by prostanoids. We analyzed the effect of hypoxia and inflammation on key enzymes involved in prostanoid biosynthesis in human vascular cells. In human vascular smooth muscle cells (VSMC), hypoxia and interleukin (IL)-1beta synergistically increased prostaglandin (PG)I2 but not PGE2 release, thereby increasing the PGI2/PGE2 ratio. Concomitantly, these stimuli upregulated cyclooxygenase-2 (COX-2) expression (mRNA and protein) and COX activity. Interestingly, hypoxia enhanced PGI-synthase (PGIS) expression and activity in VSMC and human endothelial cells. Hypoxia did not significantly modify the inducible microsomal-PGE-synthase (mPGES)-1. Hypoxia-inducible factor (HIF)-1alpha-silencing abrogated hypoxia induced PGIS upregulation. PGIS transcriptional activity was enhanced by hypoxia; however, the minimal PGIS promoter responsive to hypoxia (-131 bp) did not contain any putative hypoxia response element (HRE), suggesting that HIF-1 does not directly drive PGIS transcription. Serial deletion and site-directed mutagenesis studies suggested several transcription factors participate cooperatively. Plasma levels of the stable metabolite of PGI2 and PGIS expression in several tissues were also upregulated in mice exposed to hypoxia. These data suggest that PGIS upregulation is part of the adaptive response of vascular cells to hypoxic stress and could play a role in counteracting the deleterious effect of inflammatory stimuli. PMID- 21296956 TI - Small-molecule inhibitors of FABP4/5 ameliorate dyslipidemia but not insulin resistance in mice with diet-induced obesity. AB - Fatty acid binding protein-4 (FABP4) and FABP5 are two closely related FA binding proteins expressed primarily in adipose tissue and/or macrophages. The small molecule FABP4 inhibitor BMS309403 was previously reported to improve insulin sensitivity in leptin-deficient Lep(ob)/Lep(ob) (ob/ob) mice. However, this compound was not extensively characterized in the more physiologically relevant animal model of mice with diet-induced obesity (DIO). Here, we report the discovery and characterization of a novel series of FABP4/5 dual inhibitors represented by Compounds 1-3. Compared with BMS309403, the compounds had significant in vitro potency toward both FABP4 and FABP5. In cell-based assays, Compounds 2 and 3 were more potent than BMS309403 to inhibit lipolysis in 3T3-L1 adipocytes and in primary human adipocytes. They also inhibited MCP-1 release from THP-1 macrophages as well as from primary human macrophages. When chronically administered to DIO mice, BMS309403 and Compound 3 reduced plasma triglyceride and free FA levels. Compound 3 reduced plasma free FAs at a lower dose level than BMS309403. However, no significant change was observed in insulin, glucose, or glucose tolerance. Our results indicate that the FABP4/5 inhibitors ameliorate dyslipidemia but not insulin resistance in DIO mice. PMID- 21296957 TI - ALOX5 gene variants affect eicosanoid production and response to fish oil supplementation. AB - The objective of this study was to determine whether 5-lipoxygenase (ALOX5) gene variants associated with cardiovascular disease affect eicosanoid production by monocytes. The study was a randomized, double-masked, parallel intervention trial with fish oil (5.0 g of fish oil daily, containing 2.0 g of eicosapentaenoic acid [EPA] and 1.0 g of docosahexaenoic acid [DHA]) or placebo oil (5.0 g of corn/soy mixture). A total of 116 subjects (68% female, 20-59 years old) of African American ancestry enrolled, and 98 subjects completed the study. Neither ALOX5 protein nor arachidonic acid-derived LTB4, LTD4, and LTE4 varied by genotype, but 5-hydroxyeicosatetraenoate (5-HETE), 6-trans-LTB4, 5-oxo-ETE, 15-HETE, and 5,15 diHETE levels were higher in subjects homozygous for the ALOX5 promoter allele containing five Sp1 element tandem repeats ("55" genotype) than in subjects with one deletion (d) (three or four repeats) and one common ("d5" genotype) allele or with two deletion ("dd") alleles. The EPA-derived metabolites 5-HEPE and 15-HEPE and the DHA-derived metabolite 17-HDoHE had similar associations with genotype and increased with supplementation; 5-HEPE and 15-HEPE increased, and 5-oxo-ETE decreased to a greater degree in the 55 than in the other genotypes. This differential eicosanoid response is consistent with the previously observed interaction of these variants with dietary intake of omega-3 fatty acids in predicting cardiovascular disease risk. PMID- 21296958 TI - Autoregulatory characteristics of a Bacillus anthracis serine/threonine kinase. AB - BA-Stk1 is a serine/threonine kinase (STK) expressed by Bacillus anthracis. In previous studies, we found that BA-Stk1 activity is modulated through dephosphorylation by a partner phosphatase, BA-Stp1. In this study, we identified critical phosphorylation regions of BA-Stk1 and determined the contributions of these phosphodomains to autophosphorylation and substrate phosphorylation. The data indicate that BA-Stk1 undergoes trans-autophosphorylation within a regulatory domain, referred to as the activation loop, which carries eight putative regulatory serine and threonine residues. We identified activation loop mutants that impacted kinase activity in three different manners: regulation of autophosphorylation (T162), regulation of substrate phosphorylation (T159 and S169), and regulation of overall kinase activity (T163). Tandem mass spectrometry (MS/MS) analysis of the phosphorylation profile of each mutant revealed a second site of phosphorylation on the kinase that was influenced by the phosphorylation status of the activation loop. This second region of the kinase contained a single phosphorylation residue, S214. Previous work has shown S214 to be necessary for downstream substrate phosphorylation, and we have shown that this residue is subject to dephosphorylation by BA-Stp1. These findings indicate a connection between the phosphorylation status of the activation loop and phosphorylation of S214, and this suggests a previously undescribed model for how a bacterial STK shifts from a state of autophosphorylation to targeting downstream substrates. PMID- 21296959 TI - ZouA, a putative relaxase, is essential for dna amplification in Streptomyces kanamyceticus. AB - Previously, we showed that a 145-kb DNA region, including the entire kanamycin biosynthetic gene cluster (with two kanamycin resistance genes), was tandemly amplified up to 36-fold in an industrial strain of Streptomyces kanamyceticus. Strain improvement had included the use of increased kanamycin resistance as an initial potential indicator of higher kanamycin productivity. We were able to recapitulate the DNA amplification by cultivating S. kanamyceticus under selection for kanamycin resistance. To identify the genes required for amplification, various chromosome deletions were constructed, and the DNA amplification was shown to depend on orf1082 (zouA), present in a putative mobile genetic element. ZouA consists of 1,481 amino acids and is homologous to the products of traA-like genes of some conjugative plasmids. These genes encode relaxases that initiate DNA transfer during conjugation by single-strand nicking at oriT. As in the original high-producing strain, DNA amplification occurred between 16-nucleotide (nt) sites (RsA and RsB) containing 14 identical nucleotides. Interestingly, RsA lies just 80 bp upstream of the initiation codon of zouA and is partially contained in an inverted repeat structure similar to those found in plasmid oriT sequences, suggesting that it might function in a manner similar to that of oriT. We therefore propose that DNA amplification in S. kanamyceticus is initiated by relaxase-mediated recombination between oriT related sequences. PMID- 21296960 TI - Mycobacterium tuberculosis can utilize heme as an iron source. AB - Most iron in mammals is found within the heme prosthetic group. Consequently, many bacterial pathogens possess heme acquisition systems to utilize iron from the host. Here, we demonstrate that Mycobacterium tuberculosis can utilize heme as an iron source, suggesting that M. tuberculosis possesses a yet-unknown heme acquisition system. PMID- 21296961 TI - Lactate dehydrogenase A promotes communication between carbohydrate catabolism and virulence in Bacillus cereus. AB - The diarrheal potential of a Bacillus cereus strain is essentially dictated by the amount of secreted nonhemolytic enterotoxin (Nhe). Expression of genes encoding Nhe is regulated by several factors, including the metabolic state of the cells. To identify metabolic sensors that could promote communication between central metabolism and nhe expression, we compared four strains of the B. cereus group in terms of metabolic and nhe expression capacities. We performed growth performance measurements, metabolite analysis, and mRNA measurements of strains F4430/73, F4810/72, F837/76, and PA cultured under anoxic and fully oxic conditions. The results showed that expression levels of nhe and ldhA, which encodes lactate dehydrogenase A (LdhA), were correlated in both aerobically and anaerobically grown cells. We examined the role of LdhA in the F4430/73 strain by constructing an ldhA mutant. The ldhA mutation was more deleterious to anaerobically grown cells than to aerobically grown cells, causing growth limitation and strong deregulation of key fermentative genes. More importantly, the ldhA mutation downregulated enterotoxin gene expression under both anaerobiosis and aerobiosis, with a more pronounced effect under anaerobiosis. Therefore, LdhA was found to exert a major control on both fermentative growth and enterotoxin expression, and it is concluded that there is a direct link between fermentative metabolism and virulence in B. cereus. The data presented also provide evidence that LdhA-dependent regulation of enterotoxin gene expression is oxygen independent. This study is the first report to describe a role of a fermentative enzyme in virulence in B. cereus. PMID- 21296962 TI - An experimentally validated genome-scale metabolic reconstruction of Klebsiella pneumoniae MGH 78578, iYL1228. AB - Klebsiella pneumoniae is a Gram-negative bacterium of the family Enterobacteriaceae that possesses diverse metabolic capabilities: many strains are leading causes of hospital-acquired infections that are often refractory to multiple antibiotics, yet other strains are metabolically engineered and used for production of commercially valuable chemicals. To study its metabolism, we constructed a genome-scale metabolic model (iYL1228) for strain MGH 78578, experimentally determined its biomass composition, experimentally determined its ability to grow on a broad range of carbon, nitrogen, phosphorus and sulfur sources, and assessed the ability of the model to accurately simulate growth versus no growth on these substrates. The model contains 1,228 genes encoding 1,188 enzymes that catalyze 1,970 reactions and accurately simulates growth on 84% of the substrates tested. Furthermore, quantitative comparison of growth rates between the model and experimental data for nine of the substrates also showed good agreement. The genome-scale metabolic reconstruction for K. pneumoniae presented here thus provides an experimentally validated in silico platform for further studies of this important industrial and biomedical organism. PMID- 21296963 TI - Complete genome sequence of Yersinia enterocolitica subsp. palearctica serogroup O:3. AB - We report here the first finished and annotated genome sequence of a representative of the most epidemiologically successful Yersinia group, Y. enterocolitica subsp. palearctica strain Y11, serotype O:3, biotype 4. This strain is a certified type strain of the German DSMZ collection (DSM no. 13030; Yersinia enterocolitica subsp. palearctica) that was isolated from the stool of a human patient (H. Neubauer, S. Aleksic, A. Hensel, E. J. Finke, and H. Meyer. Int. J. Med. Microbiol. 290:61-64, 2000). PMID- 21296964 TI - Genome of a European fresh-vegetable food safety outbreak strain of Salmonella enterica subsp. enterica serovar weltevreden. AB - The genome of Salmonella enterica subsp. enterica serovar Weltevreden strain 2007 60-3289-1 was sequenced. The genome sequence of this fresh-vegetable isolate from Scandinavia will be useful for the elucidation of plant host factors in comparison to other serovars of S. enterica subsp. enterica. PMID- 21296965 TI - Whole-genome sequence of the transformable Neisseria meningitidis serogroup A strain WUE2594. AB - Serogroup A meningococci are a leading cause of bacterial meningitis in children and young adults worldwide. However, the genetic basis of serogroup A strains' virulence and their epidemiological properties remain poorly understood. Therefore, we sequenced the complete genome of the transformable Neisseria meningitidis serogroup A strain WUE2594. PMID- 21296966 TI - Indole transport across Escherichia coli membranes. AB - Indole has many, diverse roles in bacterial signaling. It regulates the transition from exponential to stationary phase, it is involved in the control of plasmid stability, and it influences biofilm formation, virulence, and stress responses (including antibiotic resistance). Its role is not restricted to bacteria, and recently it has been shown to include mutually beneficial signaling between enteric bacteria and their mammalian hosts. In many respects indole behaves like the signaling component of a quorum-sensing system. Indole synthesized within the producer bacterium is exported into the surroundings where its accumulation is detected by sensitive cells. A view often repeated in the literature is that in Escherichia coli the AcrEF-TolC and Mtr transporter proteins are involved in the export and import, respectively, of indole. However, the evidence for their involvement is indirect, and it has been known for a long time that indole can pass directly through a lipid bilayer. We have combined in vivo and in vitro approaches to examine the relative importance of protein mediated transport and direct passage across the E. coli membrane. We conclude that the movement of indole across the E. coli membrane under normal physiological conditions is independent of AcrEF-TolC and Mtr. Furthermore, direct observation of individual liposomes shows that indole can rapidly cross an E. coli lipid membrane without the aid of any proteinaceous transporter. These observations not only enhance our understanding of indole signaling in bacteria but also provide a simple explanation for the ability of indole to signal between biological kingdoms. PMID- 21296967 TI - Role of the periplasmic chaperones Skp, SurA, and DegQ in outer membrane protein biogenesis in Neisseria meningitidis. AB - The periplasmic chaperones Skp, SurA, and DegP are implicated in the biogenesis of outer membrane proteins (OMPs) in Escherichia coli. Here, we investigated whether these chaperones exert similar functions in Neisseria meningitidis. Although N. meningitidis does not contain a homolog of the protease/chaperone DegP, it does possess a homolog of another E. coli protein, DegQ, which can functionally replace DegP when overproduced. Hence, we examined whether in N. meningitidis, DegQ acts as a functional homolog of DegP. Single skp, surA, and degQ mutants were easily obtained, showing that none of these chaperones is essential in N. meningitidis. Furthermore, all combinations of double mutants were generated and no synthetic lethality was observed. The absence of SurA or DegQ did not affect OMP biogenesis. In contrast, the absence of Skp resulted in severely lower levels of the porins PorA and PorB but not of other OMPs. These decreased levels were not due to proteolytic activity of DegQ, since porin levels remained low in a skp degQ double mutant, indicating that neisserial DegQ is not a functional homolog of E. coli DegP. The absence of Skp resulted in lower expression of the porB gene, as shown by using a P(porB)-lacZ fusion. We found no cross-species complementation when Skp of E. coli or N. meningitidis was heterologously expressed in skp mutants, indicating that Skp functions in a species-specific manner. Our results demonstrate an important role for Skp but not for SurA or DegQ in OMP biogenesis in N. meningitidis. PMID- 21296968 TI - Effects of modified Phycobilin biosynthesis in the Cyanobacterium Synechococcus sp. Strain PCC 7002. AB - The pathway for phycocyanobilin biosynthesis in Synechococcus sp. strain PCC 7002 comprises two enzymes: heme oxygenase and phycocyanobilin synthase (PcyA). The phycobilin content of cells can be modified by overexpressing genes encoding alternative enzymes for biliverdin reduction. Overexpression of the pebAB and HY2 genes, encoding alternative ferredoxin-dependent biliverdin reductases, caused unique effects due to the overproduction of phycoerythrobilin and phytochromobilin, respectively. Colonies overexpressing pebAB became reddish brown and visually resembled strains that naturally produce phycoerythrin. This was almost exclusively due to the replacement of phycocyanobilin by phycoerythrobilin on the phycocyanin alpha-subunit. This phenotype was unstable, and such strains rapidly reverted to the wild-type appearance, presumably due to strong selective pressure to inactivate pebAB expression. Overproduction of phytochromobilin, synthesized by the Arabidopsis thaliana HY2 product, was tolerated much better. Cells overexpressing HY2 were only slightly less pigmented and blue-green than the wild type. Although the pcyA gene could not be inactivated in the wild type, pcyA was easily inactivated when cells expressed HY2. These results indicate that phytochromobilin can functionally substitute for phycocyanobilin in Synechococcus sp. strain PCC 7002. Although functional phycobilisomes were assembled in this strain, the overall phycobiliprotein content of cells was lower, the efficiency of energy transfer by these phycobilisomes was lower than for wild-type phycobilisomes, and the absorption cross-section of the cells was reduced relative to that of the wild type because of an increased spectral overlap of the modified phycobiliproteins with chlorophyll a. As a result, the strain producing phycobiliproteins carrying phytochromobilin grew much more slowly at low light intensity. PMID- 21296969 TI - Protection of Bacillus subtilis against cold stress via compatible-solute acquisition. AB - Accumulation of compatible solutes is a strategy widely employed by bacteria to achieve cellular protection against high osmolarity. These compounds are also used in some microorganisms as thermostress protectants. We found that Bacillus subtilis uses the compatible solute glycine betaine as an effective cold stress protectant. Glycine betaine strongly stimulated growth at 15 degrees C and permitted cell proliferation at the growth-inhibiting temperature of 13 degrees C. Initial uptake of glycine betaine at 15 degrees C was low but led eventually to the buildup of an intracellular pool whose size was double that found in cells grown at 35 degrees C. Each of the three glycine betaine transporters (OpuA, OpuC, and OpuD) contributed to glycine betaine accumulation in the cold. Protection against cold stress was also accomplished when glycine betaine was synthesized from its precursor choline. Growth of a mutant defective in the osmoadaptive biosynthesis for the compatible solute proline was not impaired at low temperature (15 degrees C). In addition to glycine betaine, the compatible solutes and osmoprotectants l-carnitine, crotonobetaine, butyrobetaine, homobetaine, dimethylsulfonioactetate, and proline betaine all served as cold stress protectants as well and were accumulated via known Opu transport systems. In contrast, the compatible solutes and osmoprotectants choline-O-sulfate, ectoine, proline, and glutamate were not cold protective. Our data highlight an underappreciated facet of the acclimatization of B. subtilis to cold environments and allow a comparison of the characteristics of compatible solutes with respect to their osmotic, heat, and cold stress-protective properties for B. subtilis cells. PMID- 21296970 TI - I feel like I know you: sharing negative attitudes of others promotes feelings of familiarity. AB - Holding similar negative-versus positive-attitudes toward a third party has been shown to predict increased closeness to a stranger. Here, the authors examined whether this effect is mediated by the heightened feelings of familiarity engendered by shared negative attitudes. In Study 1, participants who shared with a (bogus) stranger a negative attitude of a professor subsequently reported knowing more about the stranger than those who shared a positive attitude, but only when they did not feel strongly about the attitude. In Study 2, a familiarity manipulation produced high levels of closeness among participants who believed they had a lot of information about a stranger. Among those who believed they knew little about the stranger, closeness was facilitated by sharing a weakly held, negative attitude of a professor. Discussion considers the relevance of these findings to the interpersonal attraction literature. PMID- 21296971 TI - Detection of circulating endothelial cells via a microfluidic disk. AB - BACKGROUND: Circulating endothelial cells (CECs) in the blood are rare but have been shown to be associated with various diseases. With the ratio of CECs to peripheral blood mononuclear cells (PBMCs) less than 1 part per thousand, their separation from PBMCs and detection are challenging. We present a means of detecting CECs from PBMCs via an economical microfluidic disk with a model cell system [human umbilical vein endothelial cells (HUVECs) in PBMCs], along with demonstration of its efficacy clinically. METHODS: To enrich these rare cells, we used immunomagnetic beads and a tailor-made magnet on the disk. CEC-simulating HUVECs, as target cells, were stained with primary anti-CD146-phycoerythrin antibody and bound with secondary antibody on antiphycoerythrin magnetic beads. PBMCs served as nontarget cells and were labeled with anti-CD45-FITC antibody. RESULTS: When hundreds of HUVECs were mixed in 10(6) PBMCs, 95% of spiked HUVECs were detected. This yield also held for 60 HUVEC in <10(4) PBMCs. We compared data from flow cytometry with that from the disk: CEC counts in 50 MUL blood from patients with systemic lupus erythematosus were 61.1 (21.5), significantly higher (P < 0.01) than those of healthy donors, 31.2 (13.3). CONCLUSIONS: The count of CECs is a suitable marker for symptoms of systemic lupus erythematosus. The microfluidic disk system should be a viable platform for detection of CECs. PMID- 21296972 TI - Short-term treadmill running as a model for studying cell-free DNA kinetics in vivo. AB - BACKGROUND: Increased plasma concentrations of cell-free DNA (cf-DNA) are considered a hallmark of various clinical conditions. Despite intensive research in this field, limited data are available concerning the time course of release and clearance of cf-DNA in vivo. METHODS: We extracted cf-DNA from plasma samples taken before and immediately after a 10-km cross-country run, and from samples taken before, immediately after, and 30 min after exhaustive short-term treadmill exercise. The contribution of nuclear (nDNA) and mitochondrial DNA (mtDNA) was measured by quantitative real-time PCR. The incremental treadmill exercise setup was exploited to delineate the precise sequencing and timing of cf-nDNA, lactate, and high-mobility group box 1 protein (HMGB1) release during the exercise and recovery phases. RESULTS: Postexercise plasma cf-nDNA concentrations in cross country and treadmill runners were significantly increased, by 7.6-fold and 9.9 fold, respectively (P < 0.001). cf-nDNA concentrations were not correlated with age, sex, or body mass index. Plasma concentrations of cf-nDNA and HMGB1 in postexercise samples of treadmill runners were significantly correlated (r = 0.84; P = 0.004). cf-mtDNA concentrations were not affected by treadmill exercise. Time-course analyses demonstrated that cf-nDNA is released within minutes after the onset of exercise and is rapidly cleared from the circulation after the cessation of exercise. Nearly congruent kinetics for cf-nDNA, lactate, and HMGB1 were observed during the exercise phase. CONCLUSIONS: A single bout of exhaustive short-term treadmill exercise constitutes a versatile model system suitable for addressing basic questions about cf-DNA biology. PMID- 21296973 TI - Estimates of insulin secretory function in apparently healthy volunteers vary as a function of how the relevant variables are quantified. AB - BACKGROUND: Several surrogate estimates have been used to define relationships between insulin action and pancreatic beta-cell function in healthy individuals. Because it is unclear how conclusions about insulin secretory function depend on specific estimates used, we evaluated the effect of different approaches to measurement of insulin action and secretion on observations of pancreatic beta cell function in individuals whose fasting plasma glucose (FPG) was <7.0 mmol/L (126 mg/dL). METHODS: We determined 2 indices of insulin secretion [homeostasis model assessment of beta-cell function (HOMA-beta) and daylong insulin response to mixed meals], insulin action [homeostasis model assessment of insulin resistance (HOMA-IR) and steady-state plasma glucose (SSPG) concentration during the insulin suppression test], and degree of glycemia [fasting plasma glucose (FPG) and daylong glucose response to mixed meals] in 285 individuals with FPG <7.0 mmol/L. We compared the relationship between the 2 measures of insulin secretion as a function of the measures of insulin action and degree of glycemia. RESULTS: Assessment of insulin secretion varied dramatically as a function of which of the 2 methods was used and which measure of insulin resistance or glycemia served as the independent variable. For example, the correlation between insulin secretion (HOMA-beta) and insulin resistance varied from an r value of 0.74 (when HOMA-IR was used) to 0.22 (when SSPG concentration was used). CONCLUSIONS: Conclusions about beta-cell function in nondiabetic individuals depend on the measurements used to assess insulin action and insulin secretion. Viewing estimates of insulin secretion in relationship to measures of insulin resistance and/or degree of glycemia does not mean that an unequivocal measure of pancreatic beta-cell function has been obtained. PMID- 21296974 TI - Measurement of hemoglobin A1c from filter papers for population-based studies. AB - BACKGROUND: Stability and transport challenges make hemoglobin (Hb) A(1c) measurement from EDTA whole blood (WB) inconvenient and costly for large-scale population studies. This study investigated Hb A(1c) measurement from WB blotted on filter paper (FP) in a Level I National Glycohemoglobin Standardization Program (NGSP)-accredited laboratory. METHODS: Three Bio-Rad VariantTM II HPLC instruments and WB and FP specimens were used. Precision, accuracy, linearity, and readable total area of the 6.5-min (beta-thalassemia method) Variant II HbA(2)/HbA(1c) Dual Program were assessed. Hb A(1c) stability was measured using in-house FP QC samples. The INTERHEART (a study of the effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries) and CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) studies provided chromatographs for morphometric analyses and interoperator variability experiments. Statistical analyses were performed to assess long-term sample stability, WB vs FP agreement, and significance of Hb A(1c) peak integration. RESULTS: Intra- and interassay CVs were <=2.00%. Total area counts between 0.8 and 5.5 * 10(6) MUV/s produced accurate Hb A(1c) results. The regression equation for agreement between WB(x) and FP(y) was as follows: y = 0.933x + 0.4 (n = 85). FP QC samples stored at -70 degrees C and tested over approximately 3 years yielded CVs of 1.72%-2.73% and regression equations with slopes of -1.08 * 10(-4) to 7.81 * 10(-4). The CURE study, with better preanalytical preparation, achieved a 97% reportable rate, and the reportable rate of the INTERHEART study was 85%. CONCLUSIONS: The FP collection method described provided accurate, robust, and reproducible measurement of Hb A(1c) using the Bio-Rad Variant II HPLC autoanalyzer when FP specimens were prepared according to standardized protocols, and analyses were performed in an NGSP-certified laboratory, supporting the use of FP collection cards in large multinational studies. PMID- 21296975 TI - Immune evasion by Helicobacter pylori is mediated by induction of macrophage arginase II. AB - Helicobacter pylori infection persists for the life of the host due to the failure of the immune response to eradicate the bacterium. Determining how H. pylori escapes the immune response in its gastric niche is clinically important. We have demonstrated in vitro that macrophage NO production can kill H. pylori, but induction of macrophage arginase II (Arg2) inhibits inducible NO synthase (iNOS) translation, causes apoptosis, and restricts bacterial killing. Using a chronic H. pylori infection model, we determined whether Arg2 impairs host defense in vivo. In C57BL/6 mice, expression of Arg2, but not arginase I, was abundant and localized to gastric macrophages. Arg2(-/-) mice had increased histologic gastritis and decreased bacterial colonization compared with wild-type (WT) mice. Increased gastritis scores correlated with decreased colonization in individual Arg2(-/-) mice but not in WT mice. When mice infected with H. pylori were compared, Arg2(-/-) mice had more gastric macrophages, more of these cells were iNOS(+), and these cells expressed higher levels of iNOS protein, as determined by flow cytometry and immunofluorescence microscopy. There was enhanced nitrotyrosine staining in infected Arg2(-/-) versus WT mice, indicating increased NO generation. Infected Arg2(-/-) mice exhibited decreased macrophage apoptosis, as well as enhanced IFN-gamma, IL-17a, and IL-12p40 expression, and reduced IL-10 levels consistent with a more vigorous Th1/Th17 response. These studies demonstrate that Arg2 contributes to the immune evasion of H. pylori by limiting macrophage iNOS protein expression and NO production, mediating macrophage apoptosis, and restraining proinflammatory cytokine responses. PMID- 21296976 TI - Mechanism of action of type II, glycoengineered, anti-CD20 monoclonal antibody GA101 in B-chronic lymphocytic leukemia whole blood assays in comparison with rituximab and alemtuzumab. AB - We analyzed in B-chronic lymphocytic leukemia (B-CLL) whole blood assays the activity of therapeutic mAbs alemtuzumab, rituximab, and type II glycoengineered anti-CD20 mAb GA101. Whole blood samples were treated with Abs, and death of CD19(+) B-CLL was measured by flow cytometry. Alemtuzumab efficiently lysed B-CLL targets with maximal lysis at 1-4 h (62%). In contrast, rituximab induced a more limited cell death (21%) that was maximal only at 24 h. GA101 killed B-CLL targets to a similar extent but more rapidly than rituximab, with 19.2 and 23.5% cell death at 4 and 24 h, respectively, compared with 7.9 and 21.4% for rituximab. Lysis by both rituximab and GA101 correlated directly with CD20 expression levels (r(2) = 0.88 and 0.85, respectively). Interestingly, lysis by all three Abs at high concentrations was mostly complement dependent, because it was blocked by the anti-C5 Ab eculizumab by 90% in the case of alemtuzumab and rituximab and by 64% in the case of GA101. Although GA101 caused homotypic adhesion, it induced only limited (3%) direct cell death of purified B-CLL cells. Both rituximab and GA101 showed the same efficiency in phagocytosis assays, but phagocytosis was not significant in whole blood due to excess Igs. Finally, GA101 at 1-100 MUg/ml induced 2- to 3-fold more efficient NK cell degranulation than rituximab in isolated B-CLL or normal PBMCs. GA101, but not rituximab, also mediated significant NK cell degranulation in whole blood samples. Thus, complement and Ab-dependent cellular cytotoxicity are believed to be the major effector mechanisms of GA101 in whole blood assays. PMID- 21296977 TI - The role of heat shock protein 70 in mediating age-dependent mortality in sepsis. AB - Sepsis is primarily a disease of the aged, with increased incidence and mortality occurring in aged hosts. Heat shock protein (HSP) 70 plays an important role in both healthy aging and the stress response to injury. The purpose of this study was to determine the role of HSP70 in mediating mortality and the host inflammatory response in aged septic hosts. Sepsis was induced in both young (6- to 12-wk-old) and aged (16- to 17-mo-old) HSP70(-/-) and wild-type (WT) mice to determine whether HSP70 modulated outcome in an age-dependent fashion. Young HSP70(-/-) and WT mice subjected to cecal ligation and puncture, Pseudomonas aeruginosa pneumonia, or Streptococcus pneumoniae pneumonia had no differences in mortality, suggesting HSP70 does not mediate survival in young septic hosts. In contrast, mortality was higher in aged HSP70(-/-) mice than aged WT mice subjected to cecal ligation and puncture (p = 0.01), suggesting HSP70 mediates mortality in sepsis in an age-dependent fashion. Compared with WT mice, aged septic HSP70(-/-) mice had increased gut epithelial apoptosis and pulmonary inflammation. In addition, HSP70(-/-) mice had increased systemic levels of TNF alpha, IL-6, IL-10, and IL-1beta compared with WT mice. These data demonstrate that HSP70 is a key determinant of mortality in aged, but not young hosts in sepsis. HSP70 may play a protective role in an age-dependent response to sepsis by preventing excessive gut apoptosis and both pulmonary and systemic inflammation. PMID- 21296978 TI - Immunization with live and dead Chlamydia muridarum induces different levels of protective immunity in a murine genital tract model: correlation with MHC class II peptide presentation and multifunctional Th1 cells. AB - Mice that were intranasally vaccinated with live or dead Chlamydia muridarum with or without CpG-containing oligodeoxynucleotide 1862 elicited widely disparate levels of protective immunity to genital tract challenge. We found that the frequency of multifunctional T cells coexpressing IFN-gamma and TNF-alpha with or without IL-2 induced by live C. muridarum most accurately correlated with the pattern of protection against C. muridarum genital tract infection, suggesting that IFN-gamma(+)-producing CD4(+) T cells that highly coexpress TNF-alpha may be the optimal effector cells for protective immunity. We also used an immunoproteomic approach to analyze MHC class II-bound peptides eluted from dendritic cells (DCs) that were pulsed with live or dead C. muridarum elementary bodies (EBs). We found that DCs pulsed with live EBs presented 45 MHC class II C. muridarum peptides mapping to 13 proteins. In contrast, DCs pulsed with dead EBs presented only six MHC class II C. muridarum peptides mapping to three proteins. Only two epitopes were shared in common between the live and dead EB-pulsed groups. This study provides insights into the role of Ag presentation and cytokine secretion patterns of CD4(+) T effector cells that correlate with protective immunity elicited by live and dead C. muridarum. These insights should prove useful for improving vaccine design for Chlamydia trachomatis. PMID- 21296979 TI - Involvement of CD226+ NK cells in immunopathogenesis of systemic lupus erythematosus. AB - Dysfunction of immune systems, including innate and adaptive immunity, is responsible for the immunopathogenesis of systemic lupus erythematosus (SLE). NK cells are a major part of the innate immune system, and diminished populations of NK cells have been reported in SLE patients. However, the mechanisms behind this decrease and the role of NK cells in SLE pathogenesis remain poorly understood. In this study, we found that a deficiency of NK cells, especially CD226(+) NK cells, is prominent in patients with active SLE. Meanwhile, expression of the CD226 ligands CD112 and CD155 on plasmacytoid dendritic cells is observed in SLE patients; thus, activation of CD226(+) NK cells may be induced by CD226-ligand interactions. Furthermore, IFN-alpha, which is mainly produced by plasmacytoid dendritic cells, can mediate the activation-induced cell death of NK cells. Therefore, these processes likely contribute to the loss of NK cells in patients with active SLE. Despite the impaired cytotoxicity of peripheral NK cells in human SLE patients and mouse SLE models, we provide evidence that CD226(+) NK cells infiltrate the kidneys of predisease MRL-lpr/lpr mice. Kidney-infiltrating NK cells displayed an activated phenotype and a marked ability to produce cytotoxic granules. These results suggest that, before apoptosis, activated NK cells can infiltrate tissues and, to some extent, mediate tissue injury by producing cytotoxic granules and immunoregulatory cytokines. PMID- 21296980 TI - CCR7 essentially contributes to the homing of plasmacytoid dendritic cells to lymph nodes under steady-state as well as inflammatory conditions. AB - The chemokine receptor CCR7 represents an important determinant for circulating lymphocytes to enter lymph nodes (LN) via high endothelial venules. High endothelial venules also represent the major site of entry for plasmacytoid dendritic cells (pDC). In the steady-state, murine pDC have been suggested to home to LN engaging the chemokine receptors CXCR3, CXCR4, and CCR5, whereas responsiveness to CCR7 ligands is thought to be acquired only upon activation. In this study, we show that already resting pDC express minute amounts of CCR7 that suffice to trigger migration to CCL19/CCL21 in vitro. Upon activation with TLR ligands, CCR7 levels on pDC are strongly increased. Notably, CCR7-deficient mice display substantially reduced pDC counts in LN but not in bone marrow and spleen. Adoptive cell transfer experiments revealed that under both steady-state as well as inflammatory conditions, the homing of CCR7-deficient pDC is severely impaired, indicating that the reduced cell counts of naive pDC observed in CCR7( /-) mice reflect an intrinsic homing defect of pDC. Together, these observations provide strong evidence that similar to naive lymphocytes, nonstimulated pDC exploit CCR7 to gain entry into LN. This adds to the repertoire of chemokine receptors permitting them to enter diverse tissues. PMID- 21296981 TI - Granulysin delivered by cytotoxic cells damages endoplasmic reticulum and activates caspase-7 in target cells. AB - Granulysin is a human cytolytic molecule present in cytotoxic granules with perforin and granzymes. Recombinant 9-kDa granulysin kills a variety of microbes, including bacteria, yeast, fungi, and parasites, and induces apoptosis in tumor cells by causing intracellular calcium overload, mitochondrial damage, and activation of downstream caspases. Reasoning that granulysin delivered by cytotoxic cells may work in concert with other molecules, we crossed granulysin transgenic (GNLY(+/-)) mice onto perforin (perf)- or granzyme B (gzmb)-deficient mice to examine granulysin-mediated killing in a more physiologic whole-cell system. Splenocytes from these animals were activated in vitro with IL-15 to generate cytolytic T cells and NK cells. Cytotoxic cells expressing granulysin require perforin, but not granzyme B, to cause apoptosis of targets. Whereas granzyme B induces mitochondrial damage and activates caspases-3 and -9 in targets, cytotoxic cell-delivered granulysin induces endoplasmic reticulum stress and activates caspase-7 with no effect on mitochondria or caspases-3 and -9. In addition, recombinant granulysin and cell-delivered granulysin activate distinct apoptotic pathways in target cells. These findings suggest that cytotoxic cells have evolved multiple nonredundant cell death pathways, enabling host defense to counteract escape mechanisms employed by pathogens or tumor cells. PMID- 21296982 TI - Murine syngeneic graft-versus-host disease is responsive to broad-spectrum antibiotic therapy. AB - Murine syngeneic graft-versus-host disease (SGVHD) initiates colon and liver inflammation following lethal irradiation, reconstitution with syngeneic bone marrow transplantation, and therapy with the immunosuppressive agent cyclosporine A. Previous studies have demonstrated that the inducible disease is mediated by CD4(+) T cells with increased reactivity of peripheral and liver-associated lymphocytes against intestinal microbial Ags. In the current report, studies were performed to analyze the specificity of the CD4(+) T cell response of T cells isolated from diseased animals and to determine the in vivo role of the microbiota to the development of SGVHD. Increased major histocompatibility Ag (MHC) class II-restricted responsiveness of SGVHD CD4(+) T cells against microbial Ags isolated from the ceca of normal animals was observed. The enhanced proliferative response was observed in the CD62L(-) memory population of CD4(+) T cells. To determine the role of the bacterial microbiota in the development of murine SGVHD, control and CsA-treated bone marrow transplantation animals were treated with broad-spectrum antibiotics (metronidazole, ciprofloxacin) after transplantation. Cyclosporine A-treated animals that were given antibiotic therapy failed to develop clinical symptoms and pathological lesions in the target tissues characteristic of SGVHD. Furthermore, the reduction in intestinal bacteria resulted in the elimination of the enhanced antimicrobial CD4(+) T cell response and significantly reduced levels of the inflammatory cytokines, IFN gamma, IL-17, and TNF-alpha. The elimination of the disease-associated inflammatory immune responses and pathology by treatment with broad-spectrum antibiotics definitively links the role of the microbiota and microbial-specific immunity to the development of murine SGVHD. PMID- 21296983 TI - EBV protein BNLF2a exploits host tail-anchored protein integration machinery to inhibit TAP. AB - EBV, the prototypic human gamma(1)-herpesvirus, persists for life in infected individuals, despite the presence of vigorous antiviral immunity. CTLs play an important role in the protection against viral infections, which they detect through recognition of virus-encoded peptides presented in the context of HLA class I molecules at the cell surface. The viral peptides are generated in the cytosol and are transported into the endoplasmic reticulum (ER) by TAP. The EBV encoded lytic-phase protein BNLF2a acts as a powerful inhibitor of TAP. Consequently, loading of antigenic peptides onto HLA class I molecules is hampered, and recognition of BNLF2a-expressing cells by cytotoxic T cells is avoided. In this study, we characterize BNLF2a as a tail-anchored (TA) protein and elucidate its mode of action. Its hydrophilic N-terminal domain is located in the cytosol, whereas its hydrophobic C-terminal domain is inserted into membranes posttranslationally. TAP has no role in membrane insertion of BNLF2a. Instead, Asna1 (also named TRC40), a cellular protein involved in posttranslational membrane insertion of TA proteins, is responsible for integration of BNLF2a into the ER membrane. Asna1 is thereby required for efficient BNLF2a-mediated HLA class I downregulation. To optimally accomplish immune evasion, BNLF2a is composed of two specialized domains: its C-terminal tail anchor ensures membrane integration and ER retention, whereas its cytosolic N terminus accomplishes inhibition of TAP function. These results illustrate how EBV exploits a cellular pathway for TA protein biogenesis to achieve immune evasion, and they highlight the exquisite adaptation of this virus to its host. PMID- 21296988 TI - Patient guide to hyperprolactinemia diagnosis and treatment. PMID- 21296989 TI - Update in hormone therapy use in menopause. AB - The original report from the Women's Health Initiative (WHI) changed our understanding of the benefits and risks of hormone therapy. Since that time, reanalysis of the WHI and additional data from other studies have further refined these concepts. Here we provide an update on recent advances in the field. Menopausal hormone therapy continues to have a clinical role in the management of vasomotor symptoms. However, our understanding of the role of hormones in cardiovascular disease and breast cancer continues to evolve. Further analyses of the effect of age and proximity to menopause at the time of initiation of therapy, duration of treatment, dose, route of administration, and the persistence of risks and benefits after stopping hormone therapy are described. In addition, recent data have emerged suggesting that there may be a link between hormone therapy and cancers of the lung and ovary. Finally, we discuss new advances in hormone therapy that will likely lead to a more favorable benefit-to risk ratio, enabling safer effective menopausal symptom relief. PMID- 21296990 TI - Approach to the pregnant patient with thyroid cancer. AB - Thyroid cancer, the most common endocrine malignancy, increased progressively from 1972 through 2002 largely as the result of an increasing incidence of small papillary thyroid cancers, the majority of which are less than 2 cm and which increased almost 3-fold during the 30-yr study. During this time, thyroid cancer was found to affect women more often than men by a ratio of almost 3 to 1. Moreover, papillary thyroid cancer was found to be the most common form of differentiated thyroid cancer among women of childbearing age, 10% of whom were either pregnant or in the early postpartum period when thyroid cancer was diagnosed. Although the prevalence of thyroid cancer in pregnant women remains high, most are first identified after delivery. Nonetheless, the management of thyroid cancer during pregnancy poses serious diagnostic and therapeutic challenges to both the patient and fetus. The thyroid gland may secrete more thyroid hormone than usual during early pregnancy, which may not only be the cause of this problem but also may be responsible for the higher rate of differentiated thyroid cancer during pregnancy. There is concern about therapy for thyroid cancer during this period, including the timing of surgery, the use of levothyroxine, and the assessment of follow-up during gestation. PMID- 21296991 TI - Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. AB - OBJECTIVE: The aim was to formulate practice guidelines for the diagnosis and treatment of hyperprolactinemia. PARTICIPANTS: The Task Force consisted of Endocrine Society-appointed experts, a methodologist, and a medical writer. EVIDENCE: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. CONSENSUS PROCESS: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of The Endocrine Society, The European Society of Endocrinology, and The Pituitary Society reviewed and commented on preliminary drafts of these guidelines. CONCLUSIONS: Practice guidelines are presented for diagnosis and treatment of patients with elevated prolactin levels. These include evidence-based approaches to assessing the cause of hyperprolactinemia, treating drug-induced hyperprolactinemia, and managing prolactinomas in nonpregnant and pregnant subjects. Indications and side effects of therapeutic agents for treating prolactinomas are also presented. PMID- 21296992 TI - Sonoelastography in de Quervain thyroiditis. PMID- 21296993 TI - Thyroid and obesity: not a one-way interaction. PMID- 21296994 TI - Emerging therapies in sight for the fight against dedifferentiated thyroid cancer. PMID- 21296995 TI - Docetaxel treatment in castration-resistant prostate cancer: the triad gene-drug disease. PMID- 21296996 TI - Efficient generation of transgene-free induced pluripotent stem cells from normal and neoplastic bone marrow and cord blood mononuclear cells. AB - Reprogramming blood cells to induced pluripotent stem cells (iPSCs) provides a novel tool for modeling blood diseases in vitro. However, the well-known limitations of current reprogramming technologies include low efficiency, slow kinetics, and transgene integration and residual expression. In the present study, we have demonstrated that iPSCs free of transgene and vector sequences could be generated from human BM and CB mononuclear cells using non-integrating episomal vectors. The reprogramming described here is up to 100 times more efficient, occurs 1-3 weeks faster compared with the reprogramming of fibroblasts, and does not require isolation of progenitors or multiple rounds of transfection. Blood-derived iPSC lines lacked rearrangements of IGH and TCR, indicating that their origin is non-B- or non-T-lymphoid cells. When cocultured on OP9, blood-derived iPSCs could be differentiated back to the blood cells, albeit with lower efficiency compared to fibroblast-derived iPSCs. We also generated transgene-free iPSCs from the BM of a patient with chronic myeloid leukemia (CML). CML iPSCs showed a unique complex chromosomal translocation identified in marrow sample while displaying typical embryonic stem cell phenotype and pluripotent differentiation potential. This approach provides an opportunity to explore banked normal and diseased CB and BM samples without the limitations associated with virus-based methods. PMID- 21296997 TI - MYB transcriptionally regulates the miR-155 host gene in chronic lymphocytic leukemia. AB - Elevated levels of microRNA miR-155 represent a candidate pathogenic factor in chronic B-lymphocytic leukemia (B-CLL). In this study, we present evidence that MYB (v-myb myeloblastosis viral oncogene homolog) is overexpressed in a subset of B-CLL patients. MYB physically associates with the promoter of miR-155 host gene (MIR155HG, also known as BIC, B-cell integration cluster) and stimulates its transcription. This coincides with the hypermethylated histone H3K4 residue and spread hyperacetylation of H3K9 at MIR155HG promoter. Our data provide evidence of oncogenic activities of MYB in B-CLL that include its stimulatory role in MIR155HG transcription. PMID- 21296998 TI - An anti-PR1/HLA-A2 T-cell receptor-like antibody mediates complement-dependent cytotoxicity against acute myeloid leukemia progenitor cells. AB - PR1 (VLQELNVTV) is a human leukocyte antigen-A2 (HLA-A2)-restricted leukemia associated peptide from proteinase 3 (P3) and neutrophil elastase (NE) that is recognized by PR1-specific cytotoxic T lymphocytes that contribute to cytogenetic remission of acute myeloid leukemia (AML). We report a novel T-cell receptor (TCR)-like immunoglobulin G2a (IgG2a) antibody (8F4) with high specific binding affinity (dissociation constant [K(D)] = 9.9nM) for a combined epitope of the PR1/HLA-A2 complex. Flow cytometry and confocal microscopy of 8F4-labeled cells showed significantly higher PR1/HLA-A2 expression on AML blasts compared with normal leukocytes (P = .046). 8F4 mediated complement-dependent cytolysis of AML blasts and Lin(-)CD34(+)CD38(-) leukemia stem cells (LSCs) but not normal leukocytes (P < .005). Although PR1 expression was similar on LSCs and hematopoietic stem cells, 8F4 inhibited AML progenitor cell growth, but not normal colony-forming units from healthy donors (P < .05). This study shows that 8F4, a novel TCR-like antibody, binds to a conformational epitope of the PR1/HLA A2 complex on the cell surface and mediates specific lysis of AML, including LSCs. Therefore, this antibody warrants further study as a novel approach to targeting leukemia-initiating cells in patients with AML. PMID- 21296999 TI - Regulation of dectin-1-mediated dendritic cell activation by peroxisome proliferator-activated receptor-gamma ligand troglitazone. AB - Dectin-1 is the major receptor for fungal beta-glucans. The activation of Dectin 1 leads to the up-regulation of surface molecules on dendritic cells (DCs) and cytokine secretion. Furthermore, Dectin-1 is important for the recruitment of leukocytes and the production of inflammatory mediators. Peroxisome proliferator activated receptor-gamma (PPAR-gamma) and its ligands, cyclopentenone prostaglandins or thiazolidinediones, have modulatory effects on B-cell, T-cell, and DC function. In the present study, we analyzed the effects of troglitazone (TGZ), a high-affinity synthetic PPAR-gamma ligand, on the Dectin-1-mediated activation of monocyte-derived human DCs. Dectin-1-mediated activation of DCs was inhibited by TGZ, as shown by down-regulation of costimulatory molecules and reduced secretion of cytokines and chemokines involved in T-lymphocyte activation. Furthermore, TGZ inhibited the T-cell-stimulatory capacity of DCs. These effects were not due to a diminished expression of Dectin-1 or to a reduced phosphorylation of spleen tyrosine kinase; they were mediated by the inhibition of downstream signaling molecules such as mitogen-activated protein kinases and nuclear factor-kappaB. Furthermore, curdlan-mediated accumulation of caspase recruitment domain 9 (CARD9) in the cytosol was inhibited by TGZ. Our data demonstrate that the PPAR-gamma ligand TGZ inhibits Dectin-1-mediated activation by interfering with CARD9, mitogen-activated protein kinase, and nuclear factor kappaB signaling pathways. This confirms their important role as negative feedback regulators of potentially harmful inflammatory responses. PMID- 21297000 TI - Murine prolylcarboxypeptidase depletion induces vascular dysfunction with hypertension and faster arterial thrombosis. AB - Prolylcarboxypeptidase (PRCP) activates prekallikrein to plasma kallikrein, leading to bradykinin liberation, and degrades angiotensin II. We now identify PRCP as a regulator of blood vessel homeostasis. beta-Galactosidase staining in PRCP(gt/gt) mice reveals expression in kidney and vasculature. Invasive telemetric monitorings show that PRCP(gt/gt) mice have significantly elevated blood pressure. PRCP(gt/gt) mice demonstrate shorter carotid artery occlusion times in 2 models, and their plasmas have increased thrombin generation times. Pharmacologic inhibition of PRCP with Z-Pro-Prolinal or plasma kallikrein with soybean trypsin inhibitor, Pro-Phe-Arg-chloromethylketone or PKSI 527 also shortens carotid artery occlusion times. Aortic and renal tissues have uncoupled eNOS and increased reactive oxygen species (ROS) in PRCP(gt/gt) mice as detected by dihydroethidium or Amplex Red fluorescence or lucigenin luminescence. The importance of ROS is evidenced by the fact that treatment of PRCP(gt/gt) mice with antioxidants (mitoTEMPO, apocynin, Tempol) abrogates the hypertensive, prothrombotic phenotype. Mechanistically, our studies reveal that PRCP(gt/gt) aortas express reduced levels of Kruppel-like factors 2 and 4, thrombomodulin, and eNOS mRNA, suggesting endothelial cell dysfunction. Further, PRCP siRNA treatment of endothelial cells shows increased ROS and uncoupled eNOS and decreased protein C activation because of thrombomodulin inactivation. Collectively, our studies identify PRCP as a novel regulator of vascular ROS and homeostasis. PMID- 21297001 TI - Telomerase reverse transcriptase protects ATM-deficient hematopoietic stem cells from ROS-induced apoptosis through a telomere-independent mechanism. AB - Telomerase reverse transcriptase (TERT) contributes to the prevention of aging by a largely unknown mechanism that is unrelated to telomere lengthening. The current study used ataxia-telangiectasia mutated (ATM) and TERT doubly deficient mice to evaluate the contributions of 2 aging-regulating molecules, TERT and ATM, to the aging process. ATM and TERT doubly deficient mice demonstrated increased progression of aging and had shorter lifespans than ATM-null mice, while TERT alone was insufficient to affect lifespan. ATM-TERT doubly null mice show in vivo senescence, especially in hematopoietic tissues, that was dependent on p16(INK4a) and p19(ARF), but not on p21. As their HSCs show decreased stem cell activities, accelerated aging seen in these mice has been attributed to impaired stem cell function. TERT-deficient HSCs are characterized by reactive oxygen species (ROS) fragility, which has been suggested to cause stem cell impairment during aging, and apoptotic HSCs are markedly increased in these mice. p38MAPK activation was indicated to be partially involved in ROS-induced apoptosis in TERT-null HSCs, and BCL-2 is suggested to provide a part of the protective mechanisms of HSCs by TERT. The current study demonstrates that TERT mitigates aging by protecting HSCs under stressful conditions through telomere length-independent mechanisms. PMID- 21297002 TI - A novel mechanism for egress of malarial parasites from red blood cells. AB - The culminating step of the intraerythrocytic development of Plasmodium falciparum, the causative agent of malaria, is the spectacular release of multiple invasive merozoites on rupture of the infected erythrocyte membrane. This work reports for the first time that the whole process, taking place in time scales as short as 400 milliseconds, is the result of an elastic instability of the infected erythrocyte membrane. Using high-speed differential interference contrast (DIC) video microscopy and epifluorescence, we demonstrate that the release occurs in 3 main steps after osmotic swelling of the infected erythrocyte: a pore opens in ~ 100 milliseconds, ejecting 1-2 merozoites, an outward curling of the erythrocyte membrane is then observed, ending with a fast eversion of the infected erythrocyte membrane, pushing the parasites forward. It is noteworthy that this last step shows slight differences when infected erythrocytes are adhering. We rationalize our observations by considering that during the parasite development, the infected erythrocyte membrane acquires a spontaneous curvature and we present a subsequent model describing the dynamics of the curling rim. Our results show that sequential erythrocyte membrane curling and eversion is necessary for the parasite efficient angular dispersion and might be biologically essential for fast and numerous invasions of new erythrocytes. PMID- 21297003 TI - Programming of marginal zone B-cell fate by basic Kruppel-like factor (BKLF/KLF3). AB - Splenic marginal zone (MZ) B cells are a lineage distinct from follicular and peritoneal B1 B cells. They are located next to the marginal sinus where blood is released. Here they pick up antigens and shuttle the load onto follicular dendritic cells inside the follicle. On activation, MZ B cells rapidly differentiate into plasmablasts secreting antibodies, thereby mediating humoral immune responses against blood-borne type 2 T-independent antigens. As Kruppel like factors are implicated in cell differentiation/function in various tissues, we studied the function of basic Kruppel-like factor (BKLF/KLF3) in B cells. Whereas B-cell development in the bone marrow of KLF3-transgenic mice was unaffected, MZ B-cell numbers in spleen were increased considerably. As revealed in chimeric mice, this occurred cell autonomously, increasing both MZ and peritoneal B1 B-cell subsets. Comparing KLF3-transgenic and nontransgenic follicular B cells by RNA-microarray revealed that KLF3 regulates a subset of genes that was similarly up-regulated/down-regulated on normal MZ B-cell differentiation. Indeed, KLF3 expression overcame the lack of MZ B cells caused by different genetic alterations, such as CD19-deficiency or blockade of B-cell activating factor-receptor signaling, indicating that KLF3 may complement alternative nuclear factor-kappaB signaling. Thus, KLF3 is a driving force toward MZ B-cell maturation. PMID- 21297004 TI - Lyn and PECAM-1 function as interdependent inhibitors of platelet aggregation. AB - Inhibition of platelet responsiveness is important to control pathologic thrombus formation. Platelet-endothelial cell adhesion molecule-1 (PECAM-1) and the Src family kinase Lyn inhibit platelet activation by the glycoprotein VI (GPVI) collagen receptor; however, it is not known whether PECAM-1 and Lyn function in the same or different inhibitory pathways. In these studies, we found that, relative to wild-type platelets, platelets derived from PECAM-1-deficient, Lyn deficient, or PECAM-1/Lyn double-deficient mice were equally hyperresponsive to stimulation with a GPVI-specific agonist, indicating that PECAM-1 and Lyn participate in the same inhibitory pathway. Lyn was required for PECAM-1 tyrosine phosphorylation and subsequent binding of the Src homology 2 domain-containing phosphatase-2, SHP-2. These results support a model in which PECAM-1/SHP-2 complexes, formed in a Lyn-dependent manner, suppress GPVI signaling. PMID- 21297005 TI - Prospective long-term outcomes of the medial collagen meniscus implant versus partial medial meniscectomy: a minimum 10-year follow-up study. AB - BACKGROUND: Loss of meniscal tissue can be responsible for increased pain and decreased function. HYPOTHESIS: At a minimum 10-year follow-up, patients receiving a medial collagen meniscus implant (MCMI) would show better clinical, radiological, and magnetic resonance imaging (MRI) outcomes than patients treated with partial medial meniscectomy (PMM). STUDY DESIGN: Cohort study; Level of evidence 2. METHODS: Thirty-three nonconsecutive patients (men; mean age, 40 years) with meniscal injuries were enrolled in the study to receive MCMI or to serve as a control patient treated with PMM. The choice of treatment was decided by the patient. All patients were clinically evaluated at time 0 and at 5 years and a minimum of 10 years after surgery (mean follow-up, 133 months) by Lysholm, visual analog scale (VAS) for pain, objective International Knee Documentation Committee (IKDC) knee form, and Tegner activity level scores. The SF-36 score was performed preoperatively and at final follow-up. Bilateral weightbearing radiographs were completed before the index surgery and at final follow-up. Minimum 10-year follow-up MRI images were compared with preoperative MRI images by means of the Yulish score. The Genovese score was also used to evalute MCMI MRI survivorship. RESULTS: The MCMI group, compared with the PMM one, showed significantly lower VAS for pain (1.2 +/- 0.9 vs 3.3 +/- 1.8; P = .004) and higher objective IKDC (7A and 10B for MCMI, 4B and 12C for PMM; P = .0001), Teger index (75 +/- 27.5 vs 50 +/- 11.67; P = .026), and SF-36 (53.9 +/- 4.0 vs 44.1 +/ 9.2; P = .026 for Physical Health Index; 54.7 +/- 3.8 vs 43.8 +/- 6.5; P = .004 for Mental Health Index) scores. Radiographic evaluation showed significantly less medial joint space narrowing in the MCMI group than in the PMM group (0.48 +/- 0.63 mm vs 2.13 +/- 0.79 mm; P = .0003). No significant differences between groups were reported regarding Lysholm (P = .062) and Yulish (P = .122) scores. Genovese score remained constant between 5 and 10 years after surgery (P = .5). The MRI evaluation of the MCMI patients revealed 11 cases of myxoid degeneration signal: 4 had a normal signal with reduced size, and 2 had no recognizable implant. CONCLUSION: Pain, activity level, and radiological outcomes are significantly improved with use of the MCMI at a minimum 10-year follow-up compared with PMM alone. Randomized controlled trials on a larger population are necessary to confirm MCMI benefits at long term. PMID- 21297006 TI - Knee injuries and the use of prophylactic knee bracing in off-road motorcycling: results of a large-scale epidemiological study. AB - BACKGROUND: The effectiveness of prophylactic knee bracing in preventing knee injuries during sports has been evaluated; however, because of the variability in study conclusions, the topic remains controversial. Despite a paucity of data, the authors believe that prophylactic knee bracing is frequently used in off-road motorcycling. HYPOTHESIS: No statistically significant difference exists in the frequency and types of knee injuries incurred between braced and nonbraced riders using commercially available knee braces in off-road motorcycling. STUDY DESIGN: Descriptive epidemiology study. METHODS: Data from 2115 off-road motorcycle riders was obtained using an Internet-based survey over a 1-year period. Participants were grouped by use or nonuse of prophylactic knee bracing, and an incidence rate ratio was used for injury rate comparison. RESULTS: Participants recorded 39 611 riding hours over the study period. A total of 57 riders (2.7%) sustained at least 1 knee injury, for a total of 89 injuries. The most common injuries involved the anterior cruciate ligament, menisci, and medial collateral ligament. There was a significantly higher rate of overall injuries in the nonbraced group versus the braced group (3.675 vs 1.587 per 1000 rider hours, P < .001). Significantly higher incidence rates of anterior cruciate ligament rupture (1.518 vs 0.701 per 1000 rider hours, P = .0274) and medial collateral ligament injury (0.799 vs 0.111 per 1000 rider hours, P = .002) were found among nonbraced riders compared with braced riders. CONCLUSION: The most common knee injuries in off-road motorcycling involve the anterior cruciate ligament, menisci, and medial collateral ligament. The use of prophylactic knee bracing appears to have a beneficial effect in preventing medial collateral ligament and anterior cruciate ligament injuries as well as overall knee injury occurrence. These findings may be applicable to other sports that involve similar forces and mechanics. PMID- 21297007 TI - Chronic skin lesions from a patient with Bruton's X-linked agammaglobulinemia. PMID- 21297009 TI - Administration of alpha-galactosylceramide impairs the survival of dendritic cell subpopulations in vivo. AB - In this study, we examine whether recognition of alpha-GalCer presented on CD1d expressing DCs and B cells in vivo elicits the cytotoxic activity of iNKT cells and elimination of alpha-GalCer-presenting cells. We report that i.v. injection of alpha-GalCer induced a decrease in the percentage and number of splenic CD8(+)Langerin(+) DCs, while CD8(-) DCs were not affected. The decline in CD8(+) DC numbers was clearly detectable by 15 h after alpha-GalCer injection, was maximal at 24-48 h, returned to normal by day 7, and was accompanied by a reduced cross-presentation of OVA protein given i.v. to specific CD8(+) T cells in vitro. The decrease in the numbers of CD8(+) DCs required iNKT cells but was independent of perforin, Fas, or IFN-gamma, as it was observed in mice deficient in each of these molecules. In contrast, treatment with a TNF-alpha-neutralizing antibody was effective at reducing the decline in CD8(+) DC numbers and DC activation. Treatment with immunostimulatory CpG ODN also resulted in DC activation and a decreased number of CD8(+) DCs; however, the decline in DC number was a result of down-regulation of CD11c and CD8 and did not require iNKT cells or TNF-alpha. Although CD8(+)Langerin(+) DCs appeared to be selectively affected by alpha GalCer treatment, they were not required for early iNKT cell responses, as their prior depletion did not prevent the increase in serum TNF-alpha and IL-4 observed after alpha-GalCer treatment. Thus, iNKT cells regulate the survival of CD8(+) DCs through a mechanism that does not appear to involve direct cell killing. PMID- 21297010 TI - Ihh signaling regulates mandibular symphysis development and growth. AB - Symphyseal secondary cartilage is important for mandibular development, but the molecular mechanisms underlying its formation remain largely unknown. Here we asked whether Indian hedgehog (Ihh) regulates symphyseal cartilage development and growth. By embryonic days 16.5 to 18.5, Sox9-expressing chondrocytes formed within condensed Tgfbeta-1/Runx2-expressing mesenchymal cells at the prospective symphyseal joint site, and established a growth-plate-like structure with distinct Ihh, collagen X, and osteopontin expression patterns. In post-natal life, mesenchymal cells expressing the Ihh receptor Patched1 were present anterior to the Ihh-expressing secondary cartilage, proliferated, differentiated into chondrocytes, and contributed to anterior growth of alveolar bone. In Ihh null mice, however, symphyseal development was defective, mainly because of enhanced chondrocyte maturation and reduced proliferation of chondroprogenitor cells. Proliferation was partially restored in dual Ihh;Gli3 mutants, suggesting that Gli3 is normally a negative regulator of symphyseal development. Thus, Ihh signaling is essential for symphyseal cartilage development and anterior mandibular growth. PMID- 21297011 TI - DMP1 processing is essential to dentin and jaw formation. AB - Dentin matrix protein 1 (DMP1), an acidic protein that is essential to the mineralization of bone and dentin, exists as proteolytically processed fragments in the mineralized tissues. In this study, we characterized the tooth and jaw phenotypes in transgenic mice containing no wild-type DMP1, but expressing a mutant DMP1 in which Asp(213), a residue at one cleavage site, was replaced by Ala(213) (named "Dmp1-KO/D213A-Tg" mice). The teeth and mandible of Dmp1-KO/D213A Tg mice were compared with those of wild-type, Dmp1-knockout (Dmp1-KO), and Dmp1 KO mice expressing the normal Dmp1 transgene. The results showed that D213A-DMP1 was not cleaved in dentin, and the expression of D213A-DMP1 failed to rescue the defects in the dentin, cementum, and alveolar bones in the Dmp1-KO mice. These findings indicate that the proteolytic processing of DMP1 is essential to the formation and mineralization of dentin, cementum, and jaw bones. PMID- 21297012 TI - Cell differentiation and matrix organization in engineered teeth. AB - Embryonic dental cells were used to check a series of criteria to be achieved for tooth engineering. Implantation of cultured cell-cell re-associations led to crown morphogenesis, epithelial histogenesis, organ vascularization, and root and periodontium development. The present work aimed to investigate the organization of predentin/dentin, enamel, and cementum which formed and mineralized after implantation. These implants were processed for histology, transmission electron microscopy, x-ray microanalysis, and electron diffraction. After two weeks of implantation, the re-associations showed gradients of differentiating odontoblasts. There were ciliated, polarized, and extended cell processes in predentin/dentin. Ameloblasts became functional. Enamel crystals showed a typical oriented arrangement in the inner and outer enamel. In the developing root, odontoblasts differentiated, cementogenesis occurred, and periodontal ligament fibroblasts interacted with the root surface and newly formed bone. The implantation of cultured dental cell re-associations allows for reproduction of complete functional differentiation at the cell, matrix, and mineral levels. PMID- 21297013 TI - Effect of reacted acidic monomer with calcium on bonding performance. AB - We determined the number of reacted and unreacted 10-methacryloyloxydecyl dihydrogen phosphate (10-MDP) molecules with calcium during the demineralization process of hydroxyapatite or dentin by 10-MDP-based one-step (Clearfil Tri-S Bond, TS) or two-step self-etch adhesive (Clearfil SE Bond Primer, SE). We then examined the effects of the number of reacted and/or unreacted 10-MDP molecules on the initial bond strength and bond durability of the resultant adhesive layer. The null hypotheses were that (1) the etching efficacy of tooth apatite by 10-MDP used in TS was the same as that in SE, and (2) the unreacted 10-MDP polymer included within the adhesive layer does not affect bond durability. Addition of hydroxyapatite or dentin to the TS and SE resulted in decreases in the NMR peak intensities for 10-MDP. The peak intensity for 10-MDP showed a greater reduction in SE than in TS, consistent with the observation that SE provided significantly higher initial mean bond strengths than TS. Further, the unreacted 10-MDP polymer within the adhesive layer did not decrease the mean bond strength, despite the application of 20,000x thermo-cycling. PMID- 21297014 TI - Msx1 mutations: how do they cause tooth agenesis? AB - Mutations in the transcription factors PAX9 and MSX1 cause selective tooth agenesis in humans. In tooth bud mesenchyme of mice, both proteins are required for the expression of Bmp4, which is the key signaling factor for progression to the next step of tooth development. We have previously shown that Pax9 can transactivate a 2.4-kb Bmp4 promoter construct, and that most tooth-agenesis causing PAX9 mutations impair DNA binding and Bmp4 promoter activation. We also found that Msx1 by itself represses transcription from this proximal Bmp4 promoter, and that, in combination with Pax9, it acts as a potentiator of Pax9 induced Bmp4 transactivation. This synergism of Msx1 with Pax9 is significant, because it is currently the only documented mechanism for Msx1-mediated activation of Bmp4. In this study, we investigated whether the 5 known tooth agenesis-causing MSX1 missense mutations disrupt this Pax9-potentiation effect, or if they lead to deficiencies in protein stability, protein-protein interactions, nuclear translocation, and DNA-binding. We found that none of the studied molecular mechanisms yielded a satisfactory explanation for the pathogenic effects of the Msx1 mutations, calling for an entirely different approach to the investigation of this step of odontogenesis on the molecular level. PMID- 21297015 TI - rEnolase maternal immunization confers caries protection on offspring. AB - Therapeutic vaccination with Streptococcus sobrinus recombinant enolase (rEnolase) protects rats from dental caries. Here, we investigated the effect that maternal rEnolase vaccination before pregnancy had on the offspring's immune response to S. sobrinus oral infection and dental caries progression. Female Wistar rats were immunized by intranasal and subcutaneous routes with rEnolase adsorbed onto aluminum hydroxide as adjuvant or similarly treated with the adjuvant alone (sham-immunized). Ten days after the last administration, the immunized females were paired with a male rat. The oral immune responses to S. sobrinus infection and dental caries in the offspring were evaluated. The results showed that pups born from rEnolase-immunized mothers had higher levels of rEnolase-specific salivary IgA and IgG antibodies (indicating a placental antibody transfer) and lower sulcal and proximal enamel caries scores than rats born from sham-immunized mothers. In conclusion, rEnolase maternal immunization before pregnancy provides offspring with protection against S. sobrinus-induced dental caries. PMID- 21297016 TI - Genetic diversity of plaque mutans streptococci with rep-PCR. AB - Mutans streptococci (MS) are key organisms associated with the etiology of dental caries. Using probabilities that were tested by oversampling, we designed this study to determine the minimal number of MS isolates from an individual required to evaluate diversity of genotypes. MS isolates were genotyped by repetitive extragenic palindromic-polymerase chain-reaction (rep-PCR). Analysis of 20 isolates from individuals resulted in a mean of 1.6 and 2.4 genotypes in children (N = 12) and adults (N = 10), respectively. In a follow-up study, reducing the number of isolates to 7-10 resulted in a theoretical probability of up to 78% for detecting up to 4 genotypes. A mean of 1.5 genotypes was found in 35 children and 10 adults. These findings provide evidence for the design of studies of MS genotyping that can serve as a model for the analysis of genotypes within individuals. PMID- 21297017 TI - Cell therapy for salivary gland regeneration. AB - There are still no effective therapies for hyposalivation caused by irradiation. In our previous study, bone marrow stem cells can be transdifferentiated into acinar-like cells in vitro. Therefore, we hypothesized that transplantation with bone marrow stem cells or acinar-like cells may help functional regeneration of salivary glands. Bone marrow stem cells were labeled with nanoparticles and directly co-cultured with acinar cells to obtain labeled acinar-like cells. In total, 140 severely combined immune-deficiency mice were divided into 4 groups for cell therapy experiments: (1) normal mice, (2) mice receiving irradiation around their head-and-neck areas; (3) mice receiving irradiation and intra-gland transplantation with labeled stem cells; and (4) mice receiving irradiation and intra-gland transplantation with labeled acinar-like cells. Our results showed that salivary glands damaged due to irradiation can be rescued by cell therapy with either bone marrow stem cells or acinar-like cells for recovery of saliva production, body weight, and gland weight. Transdifferentiation of bone marrow stem cells into acinar-like cells in vivo was also noted. This study demonstrated that cell therapy with bone marrow stem cells or acinar-like cells can help functional regeneration of salivary glands, and that acinar-like cells showed better therapeutic potentials than those of bone marrow stem cells. PMID- 21297018 TI - Titanium topography controls FoxO/beta-catenin signaling. AB - Little is known about how surface topography can modulate mesenchymal cell responses to oxygen-related stress occurring with age, or during the early phases of wound healing or inflammation. To antagonize Reactive Oxygen Species (ROS), cells resort to defense mechanisms, relying on beta-catenin, a molecular switch between a TCF-mediated pathway, which promotes cells proliferation and commitment, and an alternative one controlled by FoxO, which induces quiescence and defenses against ROS. In the present study, we show that mesenchymal C2C12 cells are protected from H2O2-induced oxidative stress when they grow on rough (SLA) titanium surfaces. The expression of anti-ROS genes and FoxO/beta-catenin signaling, as measured by a reporter assay, were increased on SLA surfaces. We also show that TCF-mediated transcription was inhibited by ROS in cells growing on either smooth or SLA titanium. Our results demonstrate that surface topography modulates cell resistance to ROS and the balance between the molecular pathways regulating cell growth and cell defense against oxidative stress. PMID- 21297019 TI - Contribution of 6p24 to non-syndromic cleft lip and palate in a Malay population: association of variants in OFC1. AB - Non-syndromic cleft lip, with or without cleft palate, is a heterogeneous, complex disease with a high incidence in the Asian population. Several association studies have been done on cleft candidate genes, but no reports have been published thus far on the Orofacial Cleft 1 (OFC1) genomic region in an Asian population. This study investigated the association between the OFC1 genomic region and non-syndromic cleft lip with or without cleft palate in 90 Malay father-mother-offspring trios. Results showed a preferential over transmission of a 101-bp allele of marker D6S470 in the allele- and haplotype based transmission disequilibrium test (TDT), as well as an excess of maternal transmission. However, no significant p-value was found for a maternal genotype effect in a log-linear model, although single and double doses of the 101-bp allele showed a slightly increased cleft risk (RR = 1.37, 95% CI, 0.527-3.4, p value = 0.516). Carrying two copies of the 101-bp allele was significantly associated with an increased cleft risk (RR = 2.53, 95% CI, 1.06-6.12, p-value = 0.035). In conclusion, we report evidence of the contribution of the OFC1 genomic region to the etiology of clefts in a Malay population. PMID- 21297020 TI - Impaired Ca2+ handling in penile arteries from prediabetic Zucker rats: involvement of Rho kinase. AB - Diabetes is associated with an increased vascular tone usually involved in the pathogenesis of diabetic cardiovascular complications such as hypertension, stroke, coronary artery disease, or erectile dysfunction (ED). Enhanced contractility of penile erectile tissue has been associated with augmented activity of the RhoA/Rho kinase (RhoK) pathway in models of diabetes-associated ED. The present study assessed whether abnormal vasoconstriction in penile arteries from prediabetic obese Zucker rats (OZRs) is due to changes in the intracellular Ca(2+) concentration ([Ca(2+)](i)) and/or in myofilament Ca(2+) sensitivity. Penile arteries from OZRs and lean Zucker rats (LZRs) were mounted on microvascular myographs for simultaneous measurements of [Ca(2+)](i) and tension. The relationships between [Ca(2+)](i) and contraction for the alpha(1) adrenergic vasoconstrictor phenylephrine (PE) were left shifted and steeper in OZRs compared with LZRs, although the magnitude of the contraction was similar in both groups. In contrast, the vasoconstriction induced by the thromboxane A(2) receptor agonist U-46619 was augmented in arteries from OZRs, and this increase was associated with an increase in both the sensitivity and maximum responses to Ca(2+). The RhoK inhibitor Y-27632 (10 MUM) reduced the vasoconstriction induced by PE to a greater extent in OZRs than in LZRs, without altering Ca(2+). Y-27632 inhibited with a greater potency the contraction elicited by high KCl in arteries from OZRs compared with LZRs without changing [Ca(2+)](i). RhoK-II expression was augmented in arteries from OZRs. These results suggest receptor-specific changes in the Ca(2+) handling of penile arteries under conditions of metabolic syndrome. Whereas augmented vasoconstriction upon activation of the thromboxane A(2) receptor is coupled to enhanced Ca(2+) entry, a RhoK-mediated enhancement of myofilament Ca(2+) sensitivity is coupled with the alpha(1)-adrenergic vasoconstriction in penile arteries from OZRs. PMID- 21297021 TI - Endotoxemia decreases matching of regional blood flow and O2 delivery to O2 uptake in the porcine left ventricle. AB - Heterogeneity of regional coronary blood flow is caused in part by heterogeneity in O(2) demand in the normal heart. We investigated whether myocardial O(2) supply/demand mismatching is associated with the myocardial depression of sepsis. Regional blood flow (microspheres) and O(2) uptake ([(13)C]acetate infusion and analysis of resultant NMR spectra) were measured in about nine contiguous tissue samples from the left ventricle (LV) in each heart. Endotoxemic pigs (n = 9) showed hypotension at unchanged cardiac output with a fall in LV stroke work and first derivative of LV pressure relative to controls (n = 4). Global coronary blood flow and O(2) delivery were maintained. Lactate accumulated in arterial blood, but net lactate extraction across the coronary bed was unchanged during endotoxemia. When LV O(2) uptake based on blood gas versus NMR data were compared, the correlation was 0.73 (P = 0.007). While stable over time in controls, regional blood flows were strongly redistributed during endotoxin shock, with overall flow heterogeneity unchanged. A stronger redistribution of blood flow with endotoxin was associated with a larger fall in LV function parameters. Moreover, the correlation of regional O(2) delivery to uptake fell from r = 0.73 (P < 0.001) in control to r = 0.18 (P = 0.25, P = 0.009 vs. control) in endotoxemic hearts. The results suggest a redistribution of LV regional coronary blood flow during endotoxin shock in pigs, with regional O(2) delivery mismatched to O(2) demand. Mismatching may underlie, at least in part, the myocardial depression of sepsis. PMID- 21297022 TI - Secretoneurin facilitates endothelium-dependent relaxations in porcine coronary arteries. AB - Secretoneurin enhances the adhesion and transendothelial migration properties of monocytes and is a part of the peptide family encoded by the secretogranin II gene. The expression of the secretogranin II gene is upregulated in senescent endothelium. The present study was designed to examine the effects of secretoneurin on endothelium-dependent responsiveness. Isometric tension was measured in rings (with or without endothelium) of porcine coronary arteries. Secretoneurin did not induce contraction of quiescent or contracted rings. In preparations contracted by U-46619, relaxation was observed with high concentrations of the peptide. This relaxation was endothelium dependent and reduced by the nitric oxide synthase inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME). It was abolished when the preparations were incubated with l-NAME in combination with the cyclooxygenase inhibitor indomethacin. The relaxation was not affected by the combination of 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34) and 6,12,19,20,25,26-hexahydro-5,27:13,18:21,24-trietheno-11,7-etheno 7H-dibenzo[b,m][1,5,12,16]tetraazacyclotricosine-5,13-diiumditrifluoroacetate hydrate (UCL 1684), which abrogates endothelium-dependent hyperpolarizations. These results indicate that secretoneurin acutely induces relaxation through the activation of endothelial nitric oxide synthase (eNOS) and cyclooxygenase, with nitric oxide playing the dominant role. Prolonged (24 h) incubation with physiological concentrations of secretoneurin enhanced the relaxations to bradykinin and to the calcium ionophore A-23187, but this difference was not observed in preparations incubated with l-NAME or the calmodulin antagonist calmidazolium. Under these conditions, the relaxation to sodium nitroprusside remained unchanged. Incubation with secretoneurin significantly augmented the expression of eNOS and calmodulin as well as the dimerization of eNOS in cultures of porcine coronary arterial endothelial cells. These observations suggest that secretoneurin not only acutely causes but also, upon prolonged exposure, enhances endothelium-dependent relaxations. PMID- 21297023 TI - Silencing of cardiac mitochondrial NHE1 prevents mitochondrial permeability transition pore opening. AB - Inhibition of Na(+)/H(+) exchanger 1 (NHE1) reduces cardiac ischemia-reperfusion (I/R) injury and also cardiac hypertrophy and failure. Although the mechanisms underlying these NHE1-mediated effects suggest delay of mitochondrial permeability transition pore (MPTP) opening, and reduction of mitochondrial derived superoxide production, the possibility of NHE1 blockade targeting mitochondria has been incompletely explored. A short-hairpin RNA sequence mediating specific knock down of NHE1 expression was incorporated into a lentiviral vector (shRNA-NHE1) and transduced in the rat myocardium. NHE1 expression of mitochondrial lysates revealed that shRNA-NHE1 transductions reduced mitochondrial NHE1 (mNHE1) by ~60%, supporting the expression of NHE1 in mitochondria membranes. Electron microscopy studies corroborate the presence of NHE1 in heart mitochondria. Immunostaining of rat cardiomyocytes also suggests colocalization of NHE1 with the mitochondrial marker cytochrome c oxidase. To examine the functional role of mNHE1, mitochondrial suspensions were exposed to increasing concentrations of CaCl(2) to induce MPTP opening and consequently mitochondrial swelling. shRNA-NHE1 transduction reduced CaCl(2)-induced mitochondrial swelling by 64 +/- 4%. Whereas the NHE1 inhibitor HOE-642 (10 MUM) decreased mitochondrial Ca(2+)-induced swelling in rats transduced with nonsilencing RNAi (37 +/- 6%), no additional HOE-642 effects were detected in mitochondria from rats transduced with shRNA-NHE1. We have characterized the expression and function of NHE1 in rat heart mitochondria. Because mitochondria from rats injected with shRNA-NHE1 present a high threshold for MPTP formation, the beneficial effects of NHE1 inhibition in I/R resulting from mitochondrial targeting should be considered. PMID- 21297024 TI - Arginase inhibition restores in vivo coronary microvascular function in type 2 diabetic rats. AB - Nitric oxide (NO) is crucial for maintaining normal endothelial function and vascular integrity. Increased arginase activity in diabetes might compete with NO synthase (NOS) for their common substrate arginine, resulting in diminished production of NO. The aim of this study was to evaluate coronary microvascular function in type 2 diabetic Goto-Kakizaki (GK) rats using in vivo coronary flow velocity reserve (CFVR) and the effect of arginase inhibition to restore vascular function. Different groups of GK and Wistar rats were given vehicle, the arginase inhibitor N(omega)-hydroxy-nor-l-arginine (nor-NOHA), l-arginine, and the NOS inhibitor N(G)-monomethyl -l-arginine (l-NMMA). GK rats had impaired CFVR compared with Wistar rats (1.31 +/- 0.09 vs. 1.87 +/- 0.05, P < 0.001). CFVR was restored by nor-NOHA treatment compared with vehicle in GK rats (1.71 +/- 0.13 vs. 1.23 +/- 0.12, P < 0.05) but remained unchanged in Wistar rats (1.88 +/- 0.10 vs. 1.79 +/- 0.16). The beneficial effect of nor-NOHA in GK rats was abolished after NOS inhibition. CFVR was not affected by arginine compared with vehicle. Arginase II expression was increased in the aorta and myocardium from GK rats compared with Wistar rats. Citrulline-to-ornithine and citrulline-to-arginine ratios measured in plasma increased significantly more in GK rats than in Wistar rats after nor-NOHA treatment, suggesting a shift of arginine utilization from arginase to NOS. In conclusion, coronary artery microvascular function is impaired in the type 2 diabetic GK rat. Treatment with nor-NOHA restores the microvascular function by a mechanism related to increased utilization of arginine by NOS and increased NO availability. PMID- 21297025 TI - Ventricular pacing-induced loss of contractile function and development of epicardial inflammation. AB - Perturbations in the normal sequence of ventricular activation can create regions of early and late activation, leading to dysynchronous contraction and areas of dyskinesis. Dyskinesis occurs across the left ventricular (LV) wall, and its presence may have important consequences on cardiac structure and function in normal and failing hearts. Acutely, dyskinesis can trigger inflammation and, in the long term (6 wk and above), leads to LV remodeling. The mechanisms that trigger these changes are unknown. To gain further insight, we used a canine model to evaluate transumural changes in myocardial function and inflammation induced by epicardial LV pacing. The results indicate that 4 h of LV suprathreshold pacing resulted in a 30% local loss of endocardial thickening. Assessment of neutrophil infiltration showed a significant approximately fivefold increase in myeloperoxidase activity in the epicardium versus the midwall/endocardium. Matrix metalloproteinase-9 activity increased ~2 fold in the epicardium and ROS generation increased ~2.5-fold compared with the midwall/endocardium. To determine the effects that electrical current alone has on these end points, a group of animals was subjected to subthreshold pacing. Significant increases were observed only in epicardial myeloperoxidase levels. Thus, the results indicate that transmural dyskinesis induced by suprathreshold epicardial LV activation triggers a localized epicardial inflammatory response, whereas subthreshold stimulation appears to solely induce the trapping of leucocytes. Suprathreshold pacing also induces a loss of endocardial function. These results may have important implications as to the nature of the mechanisms that trigger the inflammatory response and possibly long-term remodeling in the setting of dysynchrony. PMID- 21297026 TI - Caveolin-1 deficiency exacerbates cardiac dysfunction and reduces survival in mice with myocardial infarction. AB - Caveolin (Cav)-1 has been involved in the pathogenesis of ischemic injuries. For instance, modulations of Cav-1 expression have been reported in animal models of myocardial infarction and cerebral ischemia-reperfusion. Furthermore, ablation of the Cav-1 gene in mice has been shown to increase the extent of ischemic injury in models of cerebral and hindlimb ischemia. Cav-1 has also been suggested to play a role in myocardial ischemic preconditioning. However, the role of Cav-1 in myocardial ischemia (MI)-induced cardiac dysfunction still remains to be determined. We determined the outcome of a permanent left anterior descending coronary artery (LAD) ligation in Cav-1 knockout (KO) mice. Wild-type (WT) and Cav-1 KO mice were subjected to permanent LAD ligation for 24 h. The progression of ischemic injury was monitored by echocardiography, hemodynamic measurements, 2,3,5-triphenyltetrazolium chloride staining, beta-binding analysis, cAMP level measurements, and Western blot analyses. Cav-1 KO mice subjected to LAD ligation display reduced survival compared with WT mice. Despite similar infarct sizes, Cav-1 KO mice subjected to MI showed reduced left ventricular (LV) ejection fraction and fractional shortening as well as increased LV end-diastolic pressures compared with their WT counterparts. Mechanistically, Cav-1 KO mice subjected to MI exhibit reduced beta-adrenergic receptor density at the plasma membrane as well as decreased cAMP levels and PKA phosphorylation. In conclusion, ablation of the Cav-1 gene exacerbates cardiac dysfunction and reduces survival in mice subjected to MI. Mechanistically, Cav-1 KO mice subjected to LAD ligation display abnormalities in beta-adrenergic signaling. PMID- 21297027 TI - Central command does not decrease cardiac parasympathetic efferent nerve activity during spontaneous fictive motor activity in decerebrate cats. AB - To examine whether withdrawal of cardiac vagal efferent nerve activity (CVNA) predominantly controls the tachycardia at the start of exercise, the responses of CVNA and cardiac sympathetic efferent nerve activity (CSNA) were directly assessed during fictive motor activity that occurred spontaneously in unanesthetized, decerebrate cats. CSNA abruptly increased by 71 +/- 12% at the onset of the motor activity, preceding the tachycardia response. The increase in CSNA lasted for 4-5 s and returned to the baseline, even though the motor activity was not ended. The increase of 6 +/- 1 beats/min in heart rate appeared with the same time course of the increase in CSNA. In contrast, CVNA never decreased but increased throughout the motor activity, in parallel with a rise in mean arterial blood pressure (MAP). The peak increase in CVNA was 37 +/- 9% at 5 s after the motor onset. The rise in MAP gradually developed to 21 +/- 2 mmHg and was sustained throughout the spontaneous motor activity. Partial sinoaortic denervation (SAD) blunted the baroreflex sensitivity of the MAP-CSNA and MAP-CVNA relationship to 22-33% of the control. Although partial SAD blunted the initial increase in CSNA to 53% of the control, the increase in CSNA was sustained throughout the motor activity. In contrast, partial SAD almost abolished the increase in CVNA during the motor activity, despite the augmented elevation of 31 +/- 1 mmHg in MAP. Because afferent inputs from both muscle receptors and arterial baroreceptors were absent or greatly attenuated in the partial SAD condition, only central command was operating during spontaneous fictive motor activity in decerebrate cats. Therefore, it is likely that central command causes activation of cardiac sympathetic outflow but does not produce withdrawal of cardiac parasympathetic outflow during spontaneous motor activity. PMID- 21297028 TI - Ca2+ sensitization and PKC contribute to exercise training-enhanced contractility in porcine collateral-dependent coronary arteries. AB - Exercise training enhances endothelium-dependent coronary vasodilatation, improving perfusion and contractile function of collateral-dependent myocardium. Paradoxically, studies from our laboratory have revealed increased Ca(2+) dependent basal active tone in collateral-dependent arteries of exercise-trained pigs. In this study, we tested the hypothesis that exercise training enhances agonist-mediated contractile responses of collateral-dependent arteries by promoting Ca(2+) sensitization. Ameroid constrictors were surgically placed around the proximal left circumflex coronary (LCX) artery of female Yucatan miniature pigs. Eight weeks postoperatively, pigs were randomized into sedentary (pen confined) or exercise-training (treadmill run; 5 days/wk; 14 wk) groups. Arteries (~150 MUm luminal diameter) were isolated from the collateral-dependent and nonoccluded (left anterior descending artery supplied) myocardial regions, and measures of contractile tension or simultaneous tension and intracellular free Ca(2+) concentration levels (fura-2) were completed. Exercise training enhanced contractile responses to endothelin-1 in collateral-dependent compared with nonoccluded arteries, an effect that was more pronounced in the presence of nitric oxide synthase inhibition (N(omega)-nitro-l-arginine methyl ester; 100 MUM). Contractile responses to endothelin-1 were not altered by coronary occlusion alone. Exercise training produced increased tension at comparable levels of intracellular free Ca(2+) concentration in collateral-dependent compared with nonoccluded arteries, indicative of exercise training-enhanced Ca(2+) sensitization. Inhibition of PKC (calphostin C; 1 MUM), but not Rho-kinase (Y-27632, 10 MUM; or hydroxyfasudil, 30 MUM), abolished the training-enhanced endothelin-1-mediated contractile response. Exercise training also increased sensitivity to the PKC activator phorbol 12,13-dibutyrate in collateral-dependent compared with nonoccluded arteries. Taken together, these data reveal that exercise training enhances endothelin-1-mediated contractile responses in collateral-dependent coronary arteries likely via increased PKC-mediated Ca(2+) sensitization. PMID- 21297029 TI - CC chemokine receptor 5 deletion impairs macrophage activation and induces adverse remodeling following myocardial infarction. AB - Post-myocardial infarction (MI), chemokine homing of inflammatory cells into the injured left ventricle (LV) regulates ventricular remodeling, in part by stimulating the extracellular matrix response. The CC chemokine receptor 5 (CCR5) is a key chemokine receptor expressed on macrophages, and CCR5 ligands are highly upregulated post-MI. We hypothesized that deletion of CCR5 would attenuate adverse remodeling by decreasing inflammatory cell recruitment. Accordingly, we examined LV function, macrophage recruitment and activation, and collagen content in wild-type (WT, n = 25) and CCR5 null (n = 33) mice at 7 days post-MI. Both groups had similar infarct sizes (44 +/- 2% in WT and 42 +/- 2% in CCR5 null; P = 0.37). However, the LV remodeling index (end diastolic volume/LV mass) increased to a larger extent in CCR5 null (1.28 +/- 0.08 MUl/mg for CCR5 null and 1.02 +/- 0.06 MUl/mg for WT; P < 0.05). Although numbers of infiltrated macrophages were similar in WT and CCR5 null mice, CCR5-deficient macrophages isolated from the infarct zone displayed >50% decrease in gene expression levels of proinflammatory activation markers (interleukin-1beta, interleukin-6, and tumor necrosis factor alpha), as well as anti-inflammatory activation markers (arginase 1, CD163, mannose receptor, and transforming growth factor-beta1) compared with WT (all P < 0.05). Concomitant with the reduced macrophage activation, heat shock protein-47 and collagen type I precursor levels in the infarct region decreased in the CCR5 null (1.2 +/- 0.3 units in the CCR5 null and 2.3 +/- 0.4 units in the WT; P < 0.05), while collagen fragments increased (88.3 +/- 5.9 units in the CCR5 null and 32.7 +/- 8.5 units in the WT; P < 0.05). We conclude that CCR5 deletion impairs LV remodeling by hindering macrophage activation, which stimulates an imbalance in collagen metabolism and increases the remodeling index. PMID- 21297030 TI - Wall stress of the cervical carotid artery in patients with carotid dissection: a case-control study. AB - Spontaneous internal carotid artery (ICA) dissection (sICAD) results from an intimal tear located around the distal carotid sinus. The mechanisms causing the tear are unknown. This case-control study tested the hypotheses that head movements increase the wall stress in the cervical ICA and that the stress increase is greater in patients with sICAD than in controls. Five patients with unilateral, recanalized, left sICAD and five matched controls were investigated before and after maximal head rotation to the left and neck hyperextension after 45 degrees head rotation to the left. The anatomy of the extracranial carotid arteries was assessed by magnetic resonance imaging and used to create finite element models of the right ICA. Wall stress increased after head movements. Increases above the 80th and 90th percentile were located at the intimal side of the artery wall from 7.4 mm below to 10 mm above the cranial edge of the carotid sinus, i.e., at the same location as histologically confirmed tears in patients with sICAD. Wall stress increase did not differ between patients and controls. The present findings suggest that wall stress increases at the intimal side of the artery wall surrounding the distal edge of the carotid bulb after head movements may be important for the development of carotid dissection. The lack of wall stress difference between the two groups indicates that the carotid arteries of patients with carotid dissection have either distinct functional or anatomical properties or endured unusually heavy wall stresses to initiate dissection. PMID- 21297031 TI - TGF-beta2 treatment enhances cytoprotective factors released from embryonic stem cells and inhibits apoptosis in infarcted myocardium. AB - We investigated whether factors released from mouse embryonic stem (ES) cells primed with and without transforming growth factor (TGF)-beta2 inhibit iodoacetic acid (IAA)- and H(2)O(2)-induced apoptosis in the cell culture system as well as after transplantation in the infarcted heart. We generated conditioned media (CMs) from ES cells primed with and without TGF-beta2 and determined their effects on IAA- and H(2)O(2)-induced apoptosis in H9c2 cells. We also transplanted both ES-CMs in the infarcted heart to determine the effects on apoptosis and cardiac function after myocardial infarction (MI) at day (D)1 and D14. Terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) staining, apoptotic ELISA, and cell viability data demonstrated significantly (P < 0.05) reduced apoptosis with ES-CM compared with controls in both cell culture models. Moreover, TGF-beta2-primed ES-CM (T-ES-CM) demonstrated enhanced beneficial effects, with further reduced (P < 0.05) apoptosis compared with ES CM, suggesting the a presence of additional cytoprotective released factors after TGF-beta2 treatment. Next, our in vivo apoptosis data suggested significant decrease in apoptosis with both ES-CMs compared with MI alone at D1 and D14. Notably, T-ES-CM demonstrated significant (P < 0.05) inhibition of apoptosis and fibrosis with improved cardiac function compared with ES-CM at D14, whereas no such effects were observed at D1. Next, we confirmed that apoptosis is mediated through a prosurvival Akt pathway. Moreover, we determined that after TGF-beta2 treatment there was a two- to fivefold increase in cytoprotective released factors (interleukin-10, stem cell factor, tissue inhibitor of matrix metalloproteinase-1, and VEGF) with T-ES-CM compared with ES-CM. In conclusion, we suggest that factors released from ES cells with and without TGF-beta2 treatment contain antiapoptotic factors that inhibit apoptosis in vitro and in vivo. We also suggest that T-ES-CM demonstrates additional beneficial effects that provide useful information for future therapeutic applications in regenerative medicine. PMID- 21297032 TI - Molecular regulation of NADPH oxidase 5 via the MAPK pathway. AB - The mechanisms controlling the activity of NADPH oxidase 5 (Nox5) are unique in that they are independent of the protein: protein interactions that coordinate the activation of other Nox isoforms. Instead, the primary driving force for Nox5 activity is calcium. However, in a previous study we reported that the protein kinase C (PKC)-agonist PMA could induce a sustained activation of Nox5 that was independent of calcium changes. This apparent calcium-independent activation was found to be mediated by the PKC-dependent phosphorylation of specific serine and threonine residues on Nox5 which increased the calcium sensitivity of the enzyme and enabled activation at resting levels of calcium. However, the specific kinase(s) mediating the phosphorylation and activation of Nox5 are not known. As PKC can activate the MEK/ERK1/2 signaling pathway, we hypothesized that Nox5 is activated by the coordinated phosphorylation of both MAPK and PKC pathways. The inhibition of MEK1 using PD-98059 and U-0126 significantly reduced the phosphorylation and activity of Nox5 in response to PMA but not to the calcium mobilizing stimulus ionomycin. Dominant negative MEK1 and knockdown of endogenous MEK1/2 using a specific small interfering RNA also inhibited Nox5 activity in response to PMA. The mutation of S498 to a nonphosphorylatable residue and to a lesser degree T494 blocked the ability of ERK to stimulate Nox5 activity. However, a constitutively active form of MEK1 failed to increase Nox5 activity in the absence of PMA stimulation. These results suggest that the MEK/ERK1/2 pathway is necessary but not sufficient to regulate the PMA-dependent activation of Nox5. PMID- 21297033 TI - Standoff spectroscopy via remote generation of a backward-propagating laser beam. AB - In an earlier publication we demonstrated that by using pairs of pulses of different colors (e.g., red and blue) it is possible to excite a dilute ensemble of molecules such that lasing and/or gain-swept superradiance is realized in a direction toward the observer. This approach is a conceptual step toward spectroscopic probing at a distance, also known as standoff spectroscopy. In the present paper, we propose a related but simpler approach on the basis of the backward-directed lasing in optically excited dominant constituents of plain air, N(2) and O(2). This technique relies on the remote generation of a weakly ionized plasma channel through filamentation of an ultraintense femtosecond laser pulse. Subsequent application of an energetic nanosecond pulse or series of pulses boosts the plasma density in the seed channel via avalanche ionization. Depending on the spectral and temporal content of the driving pulses, a transient population inversion is established in either nitrogen- or oxygen-ionized molecules, thus enabling a transient gain for an optical field propagating toward the observer. This technique results in the generation of a strong, coherent, counterpropagating optical probe pulse. Such a probe, combined with a wavelength tunable laser signal(s) propagating in the forward direction, provides a tool for various remote-sensing applications. The proposed technique can be enhanced by combining it with the gain-swept excitation approach as well as with beam shaping and adaptive optics techniques. PMID- 21297034 TI - Sortase-catalyzed transformations that improve the properties of cytokines. AB - Recombinant protein therapeutics often suffer from short circulating half-life and poor stability, necessitating multiple injections and resulting in limited shelf-life. Conjugation to polyethylene glycol chains (PEG) extends the circulatory half-life of many proteins, but the methods for attachment often lack specificity, resulting in loss of biological activity. Using four-helix bundle cytokines as an example, we present a general platform that uses sortase-mediated transpeptidation to facilitate site-specific attachment of PEG to extend cytokine half-life with full retention of biological activity. Covalently joining the N and C termini of proteins to obtain circular polypeptides, again executed using sortase, increases thermal stability. We combined both PEGylation and circularization by exploiting two distinct sortase enzymes and the use of a molecular suture that allows both site-specific PEGylation and covalent closure. The method developed is general, uses a set of easily accessible reagents, and should be applicable to a wide variety of proteins, provided that their termini are not involved in receptor binding or function. PMID- 21297035 TI - The vulnerable developing brain. PMID- 21297036 TI - Rice MADS3 regulates ROS homeostasis during late anther development. AB - The rice (Oryza sativa) floral homeotic C-class gene, MADS3, was previously shown to be required for stamen identity determination during early flower development. Here, we describe a role for MADS3 in regulating late anther development and pollen formation. Consistent with this role, MADS3 is highly expressed in the tapetum and microspores during late anther development, and a newly identified MADS3 mutant allele, mads3-4, displays defective anther walls, aborted microspores, and complete male sterility. During late anther development, mads3-4 exhibits oxidative stress-related phenotypes. Microarray analysis revealed expression level changes in many genes in mads3-4 anthers. Some of these genes encode proteins involved in reactive oxygen species (ROS) homeostasis; among them is MT-1-4b, which encodes a type 1 small Cys-rich and metal binding protein. In vivo and in vitro assays showed that MADS3 is associated with the promoter of MT 1-4b, and recombinant MT-1-4b has superoxide anion and hydroxyl radical scavenging activity. Reducing the expression of MT-1-4b causes decreased pollen fertility and an increased level of superoxide anion in transgenic plants. Our findings suggest that MADS3 is a key transcriptional regulator that functions in rice male reproductive development, at least in part, by modulating ROS levels through MT-1-4b. PMID- 21297037 TI - An Arabidopsis dual-localized pentatricopeptide repeat protein interacts with nuclear proteins involved in gene expression regulation. AB - Following the endosymbiotic acquisition of mitochondria by eukaryotic cells, most of the genes in this organelle were transferred to the nucleus. To maintain mitochondrial biogenesis and function, nuclear and mitochondrial genomes require regulated and coordinated expression. In plant organelles, nuclear-encoded proteins targeted to the organelles control posttranscriptional and posttranslational mechanisms. Pentatricopeptide repeat (PPR) proteins are good candidates to play such regulatory roles. Here, we identify PNM1 (for PPR protein localized to the nucleus and mitochondria 1), a novel PPR protein that is dual localized to mitochondria and nuclei in Arabidopsis thaliana, as observed by green fluorescent protein fusions and immunodetection on subcellular fractions and on histological sections. Genetic complementation showed that loss of PNM1 function in mitochondria, but not in nuclei, is lethal for the embryo. In mitochondria, it is associated with polysomes and may play a role in translation. A genetic screen in yeast identified protein partners of PNM1. These partners, the nucleosome assembly protein NAP1, and the transcription factor TCP8 interact with PNM1 in the nucleus in planta. Furthermore, TCP8 can bind the promoter of PNM1. This suggests that PNM1 might be involved in the regulation of its own gene expression in the nucleus and could thus play a role in gene expression adjustments between mitochondria and the nucleus. PMID- 21297038 TI - Association between levels of C-reactive protein and leukocytes and cancer: three repeated measurements in the Swedish AMORIS study. AB - OBJECTIVE: To study levels of C-reactive protein (CRP) and leukocytes, as inflammatory markers, in the context of cancer risk. METHODS: From the Apolipoprotein MOrtality RISk (AMORIS) study, we selected 102,749 persons with one measurement and 9,273 persons with three repeated measurements of CRP and leukocytes. Multivariate Cox proportional hazards regression was applied to categories of CRP (<10, 10-15, 15-25, 25-50, >50 g/L) and quartiles of leukocytes. An inflammation-based predictive score (IPS) indicated whether someone had CRP levels of more than 10 mg/L combined with leukocytes of more than 10*10(9)/L. Reverse causality was assessed by excluding those with less than 3, 5, or 7 years of follow-up. To analyze repeated measurements of CRP and leukocytes, the repeated IPS (IPSr) was calculated by adding the IPS of each measurement. RESULTS: In the cohort with one measurement, there was a positive trend between CRP and risk of developing cancer, with the lowest category being the 0.99 (0.92-1.06), 1.28 (1.11-1.47), 1.27 (1.09-1.49), and 1.22 (1.01-1.48) for the second to fifth categories, respectively. This association disappeared when excluding those with follow-up of less than 3, 5, or 7 years. The association between leukocytes and cancer was slightly stronger. In the cohort with repeated measurements, the IPSr was strongly associated with cancer risk: 1.87 (1.33-2.63), 1.51 (0.56-4.06), and 4.46 (1.43-13.87) for IPSr=1, 2, and 3 compared with IPSr=0. The association remained after excluding those with follow up of less than 1 year. CONCLUSIONS AND IMPACT: Our large, prospective cohort study adds evidence for a link between inflammatory markers and cancer risk by using repeated measurements and ascertaining reverse causality. PMID- 21297039 TI - The analysis of depression and subsequent cancer risk in Taiwan. AB - BACKGROUND: Patients with depression are suggestive of having a tendency toward a marginally significant association with the subsequent cancer risk. The aim of this study was to evaluate the possible relationship between depression and cancer risk in Taiwan. METHODS: We used the data of the National Health Insurance system of Taiwan to assess this issue. The Cox proportional hazard regression analysis was conducted to estimate the effects of depression on the cancer risk. RESULTS: In patients with depression, there was no significant change in the risk of developing overall cancer or for the site-specific cancer and all showed the same direction (positive) except for colorectal cancer, which had a negative direction. CONCLUSIONS: This population-based study did not find Taiwanese patients with depression to have a higher risk to develop overall cancer or site specific cancer. IMPACT: Depression does not increase cancer risk. PMID- 21297040 TI - BD-ProExC as adjunct molecular marker for improved detection of CIN2+ after HPV primary screening. AB - BACKGROUND AND METHODS: We investigated the efficacy of 8 cervical cancer screening strategies relative to cytology with emphasis on immunocytochemical detection of high-risk human papillomavirus (hrHPV)-induced cell transformation (BD-ProExC) as a tool of triage following primary cytology or hrHPV testing. 3,126 women were tested with BD-SurePath liquid-based cytology, hrHPV PCR genotyping and BD-ProExC immunostaining, and colposcopy verification to calculate sensitivity and positive predictive value (PPV) in detecting cervical intraepithelial neoplasia (CIN2(+)). RESULTS: Compared to cytology screening, double testing with cytology and hrHPV resulted in the same sensitivity with a significant increase in the PPV (relative PPV: 1.83). However, twice as many tests were needed. Cytology with atypical squamous cells of undetermined significance (ASC-US) triage and hrHPV testing showed comparative results to double testing requiring only a small increase in number of tests. Screening for hrHPV subtypes 16/18, and ASC-US triage with hrHPV16/18 resulted in significant reductions in sensitivity (ratio: 0.74 and 0.96, respectively). Primary hrHPV/BD ProExC screening was significantly more sensitive (ratio: 1.63/1.33), but had a significantly lower PPV (ratio: 0.64/0.88). ASC-US triage by BD-ProExC increased the PPV (ratio: 1.90) but decreased the sensitivity (ratio: 0.96). Primary hrHPV screening followed by BD-ProExC triage, led to significant increases in sensitivity (ratio: 1.30) and PPV (ratio: 2.89), and resulted in 55% fewer referrals for colposcopy. CONCLUSIONS: From the investigated screening strategies, primary hrHPV DNA-based screening followed by BD-ProExC triage was determined to be the best screening strategy. IMPACT: Immunocytological triage could be used to perfect hrHPV primary screening. PMID- 21297041 TI - Ultraviolet exposure and mortality among women in Sweden. AB - BACKGROUND: Ecological studies have reported possible effects of sunlight on the risk of several diseases. Little evidence is available on the association between mortality and solar and artificial UV exposure by individual level from prospective studies. METHODS: The Swedish Women's Lifestyle and Health cohort study included women aged 30 to 49 years in 1991-1992. Participants completed a questionnaire and were followed-up through linkages to national registries until the end of 2006. Cox models were used to estimate adjusted HRs and 95% CIs for all-cause mortality and for cancer and cardiovascular disease (CVD) mortality. RESULTS: During 15 years of follow-up, among the 38,472 women included in the present study, 754 deaths occurred: 457 due to cancer and 100 due to CVD. When combining the information on sun exposure from age 10 to 39 years, women who got sunburned twice or more per year during adolescence had a reduced all-cause mortality, compared with women who had been sunburned once or less. A reduced risk for all-cause and CVD mortality was observed in women who went on sunbathing vacations more than once a year over three decades. Solarium use once or more per month for at least one decade increased the risk of all-cause mortality, when compared with women who never used a solarium. CONCLUSIONS: Solar UV exposure was associated with reduced overall and CVD mortality, whereas artificial UV exposure was associated with increased overall and cancer mortality among Swedish women. IMPACT: Moderate sun exposure may protect against cause-specific mortality. PMID- 21297042 TI - Plasma coenzyme Q10 levels and prostate cancer risk: the multiethnic cohort study. AB - BACKGROUND: Coenzyme Q10 (CoQ10) is considered to be a potential anticancer agent, but epidemiologic evidence regarding CoQ10 and prostate cancer risk is lacking. We examined the association of circulating CoQ10 levels with prostate cancer risk, using prediagnostic blood samples. METHODS: Each of the 307 cases was individually matched to approximately 2 controls, for a total of 596 controls, on age, ethnicity, geographic location, date/time of specimen collection, and hours of fasting. Logistic regression was used to compute ORs and 95% CIs. RESULTS: There was no overall statistically significant association of plasma CoQ10 levels with prostate cancer risk (P(trend) = 0.50). However, after matched sets in which controls who had possible undiagnosed prostate cancer (prostate specific antigen value >4.0) were excluded, the ORs for quintiles 2 to 5 were all less than 1.0. CONCLUSIONS: The results suggest the possibility that moderate levels of circulating CoQ10 may be optimal for the reduction of prostate cancer risk; however, the findings were weak and not statistically significant. Because this is the first epidemiologic study of the association between CoQ10 and prostate cancer, further research on this topic is needed. IMPACT: If a nutritional factor such as CoQ10 were determined to reduce prostate cancer risk, it would have considerable public health significance because of the very high incidence of this cancer. PMID- 21297043 TI - Thinning of the cerebral cortex during development: a dimension of ADHD. PMID- 21297044 TI - Toward neurotrophin-based therapeutics. PMID- 21297045 TI - What can large simple trials do for psychiatry? PMID- 21297046 TI - Thought, feeling, and action in real time--monitoring of drug use in schizophrenia. PMID- 21297047 TI - The Yale Child Study Center centennial: 1911-2011. PMID- 21297048 TI - The importance of responding to negative affect in psychotherapies. PMID- 21297049 TI - Clozapine-induced lymphocytic alveolitis. PMID- 21297050 TI - Propofol addiction initiated by anesthetic use. PMID- 21297051 TI - Aripiprazole adjunctive to antidepressant therapy. PMID- 21297052 TI - Fatal hepatotoxicity in an elderly patient receiving low-dose quetiapine. PMID- 21297054 TI - Retinal image recognition for verifying the identity of fattening and replacement lambs. AB - With the objective of verifying the presumed identity of sheep in a traceability study based on visual ear tags and electronic boluses, retinal image recognition was used as an auditing biomarker on 152 lambs of 2 dairy breeds (Manchega, n=82; Lacaune, n=70). Lambs were identified with temporary ear tags (birth to weaning), and with official ear tags and electronic mini-boluses (weaning to yearling). At 3 mo of age, 58 lambs were recruited for flock replacement, and the rest were transported to a slaughterhouse. Retinal images (RI) and capturing times (CT) were recorded from the left and right eyes of each lamb in duplicate and by the same operator using an OptiReader device (Optibrand, Fort Collins, CO) at 3, 6, and 12 mo of age in 152, 58, and 58 lambs, respectively. The 3-mo RI were used as reference images and to assess operator training and accuracy of the technique. Intra- and inter-age comparisons were made to obtain the matching score (MS; 0 to 100) of pairs of RI from the same eye, using Optibrand's software. Operator skill improved with training sessions, but MS reached a plateau after the sixth session (264 images; MS=93.2 +/- 1.5). Values of CT also decreased in trained compared with untrained operators (63 +/- 5 vs. 144 +/- 15 s, respectively; P < 0.001). Training data were eliminated from further analysis. Matching exclusion criteria were estimated from trained operator images at random (804 images) using a nonparametric receiver operating characteristic curve analysis for MS=70. No breed, eye, or age effects were detected in the MS intra-age comparisons at 3-, 6 , and 12-mo periods, which averaged 96.3 +/- 0.3. Capturing time was longer in Lacaune than in Manchega lambs (P < 0.01) and decreased by age (34 +/- 4 and 21 +/- 2 s, for 6- and 12-mo periods, respectively; P < 0.001). Regarding lamb traceability, 2.8% temporary ear tags were lost from birth to weaning (traceability, 97.2%), but no official ear tag or mini-bolus losses were reported from weaning to yearling (traceability, 100%). Inter-age MS comparison, used as the biomarker for traceability auditing, did not vary by age or breed, on average being 92.6 +/- 0.5. Using the 3-mo RI as reference, all 6- and 12-mo RI showed MS >70, which supported 100% lamb traceability. In conclusion, retinal imaging was an accurate technique for auditing the identity of living lambs from weaning to yearling. PMID- 21297055 TI - Within-herd biosecurity and Salmonella seroprevalence in slaughter pigs: a simulation study. AB - In Europe, on-farm biosecurity measures, involving a strict all-in/all-out batch management system and decontamination of the rearing rooms between consecutive batches, are recommended to control Salmonella infection in growing pigs. However, implementation of these measures is often relaxed under common farming conditions. Therefore, this study was conducted to assess the relative contributions of batch-management system and room decontamination efficacy on Salmonella seroprevalence for different growing rates and subsequent slaughter ages of pigs. Because the impact of these factors cannot be easily evaluated by an observational approach in commercial farms, a stochastic simulation model representing the population dynamics, herd management, and Salmonella infection within a farrow-to-finish pig herd was used. Realistic levels were set for each factor under study (3 for batch-management system and slaughter age; 4 for room decontamination) to generate 54 simulation scenarios. Salmonella shedding prevalence in groups of slaughter pigs was then compared. A sensitivity analysis was performed to rank the impacts of the 3 factors on output. Batch-management system had little effect. In contrast, room decontamination efficacy had the greatest impact on Salmonella prevalence in pigs at slaughter. A drop in decontamination efficacy from 100 to 50%, with a strict all-in/all-out batch management system and for all slaughter ages tested, noticeably increased (P<0.001) the prevalence and almost doubled it for the reference slaughter age. Our results suggest that the control of Salmonella in pig herds should primarily focus on room decontamination efficacy. Provided that a good level of room decontamination is ensured, some flexibility in batch management, in terms of pig mixing, would be acceptable to limit the number of underweight pigs delivered to the slaughterhouse. PMID- 21297056 TI - Relationships between chewing behavior, digestibility, and digesta passage kinetics in steers fed oat hay at restricted and ad libitum intakes. AB - The objective of this study was to evaluate the relationships between chewing behavior, digestibility, and digesta passage kinetics in steers fed oat hay at restricted and ad libitum intakes. Four Hereford steers, with an initial average BW of 136 kg, were used in an experiment conducted as a balanced 4 * 4 Latin square with 4 treatments (levels of intake) and 4 periods. Animals were fed lopsided oat hay (Avena strigosa Schreb.) at 4 levels of intake (as a percentage of BW): 1.5, 2.0, 2.5, and ad libitum. Digestibility, chewing behavior, and digesta passage kinetic measurements were recorded during the experimental period. Chewing rates during eating and ruminating [(chews*min(-1))/g of DMI*kg( 1) of BW*d(-1)] decreased (P = 0.018 and P = 0.032, respectively) with increased DMI (g*kg(-1) of BW*d(-1)), whereas total chewing and total time spent on each chewing activity increased. Calculated total energy expended by the chewing activity was 4.2, 4.4, 5.2, and 5.3% of ME intake for DMI of 1.5, 2.0, and 2.5% of BW and ad libitum, respectively, indicating that adjustments in animal chewing behavior may be a mechanism of reducing energy expenditure when forages are fed at restricted intake. Hay digestibility decreased (P < 0.001) with increased DMI (r = -0.865). Digesta mean retention time (h) was strongly correlated with DMI (r = -0.868) and OM digestibility (r = 0.844). At reduced intake, hay digestibility was enhanced (P < 0.001) by extending digesta retention time and by increasing chewing efficiency, highlighting the relationship between chewing behavior and the digestive process. Fractional outflow rate of particulate matter from the reticulorumen (k(1)) was positively correlated with total chews, emphasizing that the decrease in particle size caused by chewing facilitates particle flow through the digestive tract. Increased hay intake also increased (P < 0.001) k(1), whereas passage rate of the liquid phase, transit time, and rumen fill were not affected (P > 0.05). The latter was correlated with rumen volume (r = 0.803). In conclusion, the results of this study indicate that animals fed at restricted intake increased chewing rate when eating and ruminating, which, along with a longer digesta retention time, contributed to enhance feed digestibility. PMID- 21297057 TI - Characterization of bovine pyruvate carboxylase promoter 1 responsiveness to serum from control and feed-restricted cows. AB - Pyruvate carboxylase (PC; EC 6.4.1.1) is critical in gluconeogenesis from lactate and maintenance of tricarboxylic acid cycle intermediates. Whereas increases in PC mRNA have been observed during feed restriction, the mechanism of regulation is unknown; however, coinciding increases in circulating NEFA concentrations suggests that fatty acids may contribute to regulation of gene expression during feed restriction. The objective of this study was to examine the direct effect of exposure to serum from full-fed control cows with serum from cows that were restricted to 50% of ad libitum intake for 5 d on PC expression in vitro. Rat hepatoma (H4IIE) cells were transiently transfected with bovine promoter luciferase constructs containing bovine PC promoter 1 and treated with serum from control cows, serum from feed-restricted cows, or modified serum. Modified serum pools were generated by supplemented serum from control cows with C14:0, C16:0, C18:0, C18:1n-9 cis, C18:2n-6 cis, and C18:3n-3 cis to match the total NEFA in serum from feed-restricted cows (1.3 mM) in the relative proportion found in serum from control or feed-restricted cows. Exposure of cells to serum from feed restricted cows increased (P < 0.05) PC promoter 1 activity 2.2-fold compared with cells exposed to control cow serum. Exposure to serum from control cows with fatty acids added to a NEFA concentration of 1.3 mM to reflect the fatty acid profile of control and feed-restricted cows increased (P < 0.05) promoter 1 activity 2.1- and 2.5-fold, respectively, compared with cells incubated with control cow serum. There was no difference (P >= 0.05) in promoter 1 activity in cells treated with modified serum compared with serum from feed-restricted cows. These data indicate that promoter 1 is activated by fatty acids found in serum of feed-restricted cows. These data suggest a role of NEFA to regulate expression of bovine PC mRNA through specific activation of PC promoter 1. PMID- 21297058 TI - A vascular contractility bioassay using bovine right ruminal artery and vein. AB - Endophyte-infected (Neotyphodium coenophialum) tall fescue (Lolium arundinaceum) produces ergot alkaloids that are associated with peripheral vasoconstriction in grazing animals, and ingestion of these alkaloids may affect splanchnic vasculature. Peripheral effects of ergot alkaloids have been well documented previously in cattle using a lateral saphenous vein bioassay. Because of significant differences in morphological and functional characteristics between vasculature supporting digestive and peripheral tissues, the bovine foregut vascular model required validation. Experiments were conducted, using dose responses to norepinephrine and serotonin that were normalized to either 0.12 M KCl, or 0.1 mM norepinephrine or serotonin, to compare responses of vessels equilibrated at different tensions on the day of collection or the day after collection. Segments of a branch of right ruminal artery and vein were collected from the ventral coronary groove of healthy cattle of mixed breed, age, and sex (n = 20) at local abattoirs. Cross-sections of the artery and vein were suspended on luminal supports in a chamber of a multimyograph containing continuously oxygenated Krebs-Henseleit buffer (95% O(2)/5% CO(2), pH 7.4; 37 degrees C). Vessels were allowed to equilibrate at either 0.5 or 1.0 g of tension for 1.5 h before exposure to a reference compound. Increasing concentrations of each biogenic amine were administered in 15-min intervals after buffer replacement. Data were normalized as a percentage of the contractile response induced by the reference compound for each tension and day of analysis. The ruminal artery and vein were both more responsive to KCl as a reference compound (P < 0.05) than to norepinephrine or serotonin and did not differ between days when normalized with KCl. Ruminal arteries had greater contractile responses (P < 0.05) when tension was set to 1.0 g, compared with 0.5 g, during equilibration. The ruminal vein response had a more stable maintenance of baseline tension in vessels equilibrated at 0.5 g of resting tension. Development of this bioassay allows separation of the effects tall fescue alkaloids exert on both the right ruminal artery and vein as representative vessels that service tissues functioning in nutrient absorption. PMID- 21297059 TI - Evaluation of the nutritional value of glycerol for nursery pigs. AB - In Exp. 1, a total of 144 pigs (BW, 6.68 +/- 0.17 kg) were weaned at 21 d, blocked by BW, and allocated to 48 pens with 3 pigs per pen. Pens were randomly assigned to 1 of 6 dietary treatments (0, 2.5, 5, 7.5, and 10% glycerol supplemented to replace up to 10% lactose in a basal starter 1 diet containing 20% total lactose, which was fed for 2 wk), and a negative control diet with 10% lactose and 0% glycerol. A common starter diet was fed for the next 2 wk. In Exp. 2, a total of 126 pigs (BW, 6.91 +/- 0.18 kg) were weaned at 21 d of age, blocked by BW, and allocated to 42 pens with 3 pigs per pen. Pigs were assigned to 1 of 6 treatments in a 2 * 3 factorial arrangement in a randomized complete block design with factors being 1) glycerol inclusion in replacement of lactose in starter 1 diets (0 or 5%) fed for 2 wk, and 2) glycerol inclusion in starter 2 diets (0, 5, or 10%) fed for 3 wk. In Exp. 1, glycerol supplementation at 10% improved (P=0.01) ADG (266 vs. 191 g/d) and G:F (871 vs. 679 g/kg) during the starter 1 period when compared with the negative control. Incremental amounts of glycerol linearly (P<0.05) increased ADG and ADFI, but did not affect G:F during starter 1. There was no effect of feeding glycerol during the starter 1 phase on subsequent performance during the starter 2 phase or overall. Serum glycerol concentrations increased linearly (P=0.003) with increasing dietary glycerol, and serum creatinine (P=0.004) and bilirubin (P=0.03) concentrations decreased with increasing glycerol. In Exp. 2, glycerol did not affect performance during starter 1, but it linearly increased (P<=0.01) ADG and ADFI during starter 2 (464, 509, and 542 and 726, 822, and 832 g/d, respectively) and overall (368, 396, and 411 and 546, 601, and 609 g/d, respectively). At the end of the study, pigs were 1.0 and 1.5 kg heavier when fed 5 and 10% glycerol, respectively (linear, P<0.01). Serum glycerol concentrations increased linearly during starter 2 (P<0.001), but were not affected during starter 1. Glycerol supplementation increased serum urea N quadratically (P<0.001) and decreased creatinine linearly (P<0.05) in the starter 2 phase. Overall, data indicate that glycerol can be added to nursery pig diets at 10%, while improving growth performance. PMID- 21297060 TI - Effects of feeding diets containing bacitracin methylene disalicylate to heat stressed finishing pigs. AB - The objective of this study was to evaluate the effects of heat stress and dietary bacitracin methylene disalicylate (BMD) on growth performance, carcass characteristics, and immunological responses in finishing pigs. Four groups of 32 finishing pigs (n = 128) with initial BW between 80 to 90 kg were used. Pigs were fed a corn-soybean meal-distillers grains-based control or BMD (31.5 mg/kg) diet for a 14-d adaptation period at the thermal neutral temperature (23 degrees C), and continued to be fed their respective diets when exposed to a constant temperature (23 degrees C) or a cyclical heat stress environment (37 degrees C from 1000 to 1900 h and 27 degrees C from 1900 to 1000 h) for a 28-d experimental period. Each group of pigs was housed in 4 rooms, with 2 pens/room and 4 pigs/pen. Saliva samples from each pig were collected on d -1 (initial baseline), 1, 13, and 27 for cortisol analysis. Concentrations of haptoglobin, IL-1beta, and tumor necrosis factor-alpha were determined in serum samples on d -1, 1, 13, and 27. Pigs exposed to heat stress had 31% less ADG (P < 0.001), 23% less ADFI (P < 0.001), 9% less G:F (P < 0.001), and 34% greater average daily water intake (P = 0.03) than those in the non-heat-stress conditions. Dietary BMD tended to reduce ADG (P < 0.07) compared with the control (0.66 vs. 0.73 kg/d, respectively). Heat stress increased (P < 0.05) saliva cortisol on d 1, but no effects were observed on subsequent days. Serum haptoglobin concentrations were greater (P < 0.05) in heat-stressed pigs on d 1, and concentrations tended to remain greater (P < 0.1) on d 13. Pigs fed the BMD diet tended to have a longer villus height (P = 0.07) in the duodenum and greater crypt depths in the duodenum (P = 0.09) and jejunum (P = 0.07). Heat-stressed pigs tended to have a decreased proportion of propionate (P = 0.08), greater acetate:propionate (P = 0.08), and a reduced proportion of valerate (P = 0.02) in the cecum. These results indicate that BMD did not counteract the negative effects of heat stress on growth performance, but BMD appears to increase villus height and crypt depth in the duodenum. Furthermore, heat stress appears to alter VFA production in finishing pigs. PMID- 21297061 TI - Evidence of heterogeneity within bovine satellite cells isolated from young and adult animals. AB - Satellite cells are a heterogeneous population of myogenic precursors responsible for muscle growth and repair in mammals. The objectives of the experiment were to examine the growth rates and degree of heterogeneity within bovine satellite cells (BSC) isolated from young and adult animals. The BSC were harvested from the semimembranosus of young (4.3 +/- 0.5 d) and adult (estimated 24 to 27 mo) cattle and cultured en masse. Young animal BSC re-enter the cell cycle sooner and reach maximal 5-ethynyl-2'-deoxyuridine (EdU) incorporation earlier (P < 0.05) than adult contemporaries. Adult BSC contain fewer (P < 0.05) MyoD and myogenin immunopositive nuclei than BSC isolated from young animals after 3, 4, and 5 d in culture. These results indicate that BSC from young animals activate, proliferate, and differentiate sooner than isolates from adult animals. Lineage heterogeneity within BSC was examined using antibodies specific for Pax7 and Myf5, lineage markers of satellite cells, and myoblasts. Immunocytochemistry revealed the majority of Pax7-expressing BSC also express Myf5; a minor population (~5%) fails to exhibit Myf5 immunoreactivity. The percentage of Pax7:Myf5 BSC from young animals decreases sooner (P < 0.05) in culture than adult BSC, indicating a more rapid rate of muscle fiber formation. A subpopulation immunopositive for Myf5 only was identified in both ages of BSC isolates. The growth kinetics and heterogeneity of young BSC was further evaluated by clonal analysis. Single cell clones were established and analyzed after 10 d. Colonies segregated into 2 groups based upon population doubling time. Immunostaining of the slow-growing colonies (population doubling time >= 3 d) revealed that a portion exhibited asymmetric distribution of the lineage markers Pax7 and Myf5, similar to self-renewable mouse muscle stem cells. In summary, these results offer insight into the heterogeneity of BSC and provide evidence for subtle differences between rodent and bovine myogenic precursors. PMID- 21297062 TI - Partial-genome evaluation of postweaning feed intake and efficiency of crossbred beef cattle. AB - The effects of individual SNP and the variation explained by sets of SNP associated with DMI, metabolic midtest BW, BW gain, and feed efficiency, expressed as phenotypic and genetic residual feed intake, were estimated from BW and the individual feed intake of 1,159 steers on dry lot offered a 3.0 Mcal/kg ration for at least 119 d before slaughter. Parents of these F(1) * F(1) (F(1)(2)) steers were AI-sired F(1) progeny of Angus, Charolais, Gelbvieh, Hereford, Limousin, Red Angus, and Simmental bulls mated to US Meat Animal Research Center Angus, Hereford, and MARC III composite females. Steers were genotyped with the BovineSNP50 BeadChip assay (Illumina Inc., San Diego, CA). Effects of 44,163 SNP having minor allele frequencies >0.05 in the F(1)(2) generation were estimated with a mixed model that included genotype, breed composition, heterosis, age of dam, and slaughter date contemporary groups as fixed effects, and a random additive genetic effect with recorded pedigree relationships among animals. Variance in this population attributable to sets of SNP was estimated with models that partitioned the additive genetic effect into a polygenic component attributable to pedigree relationships and a genotypic component attributable to genotypic relationships. The sets of SNP evaluated were the full set of 44,163 SNP and subsets containing 6 to 40,000 SNP selected according to association with phenotype. Ninety SNP were strongly associated (P < 0.0001) with at least 1 efficiency or component trait; these 90 accounted for 28 to 46% of the total additive genetic variance of each trait. Trait-specific sets containing 96 SNP having the strongest associations with each trait explained 50 to 87% of additive variance for that trait. Expected accuracy of steer breeding values predicted with pedigree and genotypic relationships exceeded the accuracy of their sires predicted without genotypic information, although gains in accuracy were not sufficient to encourage that performance testing be replaced by genotyping and genomic evaluations. PMID- 21297063 TI - Detection of chromosome segments of zebu and taurine origin and their effect on beef production and growth. AB - Cattle in breeds formed by recent crossing of Bos taurus (Bt) and Bos indicus (Bi) subspecies should contain chromosomes that are a composite of Bt and Bt segments. Using data from a 50K SNP chip, we were able to identify whether a chromosome segment of 11 SNP in a composite animal descended from a Bt or a Bi ancestor. When the method was tested in purebred Bt or Brahman cattle, about 94% of segments were assigned correctly. About 10% of the genome in Australian Brahman cattle appears to be of Bt origin, as might be expected from their history. We then examined the effect of the origin of each chromosome segment on BW in a population of 515 Bt * Bi composite cattle and found 67 chromosome segments with a significant (P<0.01) effect. We confirmed these effects by examining these 67 segments in a population of Brahman cattle and in a population of mixed breeds including composite breeds such as Santa Gertrudis and Brahman cattle. About 66% of the 67 segments had an effect in the same direction in the confirmation analyses as in the discovery population. However, the effect on BW and other traits of chromosome segment origin is small, indicating that we had low power to detect these effects with the number of animals available. Consequently, when chromosome segment origin was used in genomic selection to predict BW, the accuracy was low (0.08). Chromosome segments that had a positive effect on BW tend to be at greater frequency in composite breeds than chromosome segments with a negative effect on BW. PMID- 21297064 TI - Neopterin and biopterin as biomarkers of immune system activation associated with castration in piglets. AB - Recent reports have shown that stressful situations may affect the production of unconjugated pterins (neopterin and biopterin). The aim of the study was to investigate the effect of castration on neopterin and biopterin plasma concentrations in piglets, using 2 groups of 12 piglets allocated to castrated and uncastrated (control) groups. Pterin concentrations were determined by HPLC with fluorescence detection. Blood samples were also analzyed for leukocyte profiles and plasma cortisol concentrations. A time * treatment interaction (P < 0.05) was detected for neopterin concentrations, such that neopterin was greater (P < 0.01) at 1 h after surgery in castrated piglets compared with precastration concentrations, and neopterin was greater (P = 0.05) in castrated than in control piglets at 1 h. Castration had no effect on biopterin concentration (P > 0.1). Time effects (P < 0.05) for neutrophil and lymphocyte concentrations and neutrophil-to-lymphocyte ratios were found. A time * treatment interaction (P < 0.01) was detected for plasma cortisol concentrations, such that cortisol was greater (P < 0.01) at 1 and 24 h after surgery in castrated piglets compared with precastration concentrations and was greater (P < 0.01) in castrated than in control piglets at 1 and 24 h. This study showed that castration activated the immune system of piglets as demonstrated by an increase in plasma neopterin concentrations. PMID- 21297065 TI - A meta-analysis of the effects of high ambient temperature on growth performance of growing-finishing pigs. AB - High ambient temperature (T) is one of the most important climatic factors influencing pig performance. Increased T occurs sporadically during summer heat waves in temperate climates and year round in tropical climates. Results of published experiments assessing the effects of high T on pig performance are surprisingly variable. Thus, a meta-analysis was performed to aggregate our knowledge and attempt to explain differences in the results across studies on the effect of increased T on ADFI and ADG in growing-finishing pigs. Data for ADFI and ADG were extracted from 86 and 80 trials, respectively, from articles published in scientific journals indexed in PubMed, Science Direct, and from proceedings of scientific meetings through November 2009. Data on ADFI and ADG were analyzed using a linear mixed model that included the linear and the quadratic effects of T and BW, and their interactions as continuous, fixed effects variables, and the trial as a random effect factor (i.e., block). In addition, the effects of housing type (2 levels: individual and group housing) and the year of publication (3 levels: 1970 to 1989, 1990 to 1999, and 2000 to 2009) on the intercept and the linear regression term for T (i.e., the slope) were also tested. Results showed that high T had a curvilinear effect on ADFI and ADG and that this effect was more pronounced in heavier pigs. Across T, ADFI was less when pigs were group-housed. The intercept and the regression coefficient (slope) for T were significantly affected by the year of publication. The effect of increased T was greater in more contemporary works, suggesting that modern genotypes could be more sensitive to heat stress than older genotypes of lesser growth potential. In conclusion, pig performance decreases at an accelerating rate as T is increased. The large between-study variability on the effects of high T on pig performance is partially explained by differences in pig BW and to a lesser extent by the year the study was published. PMID- 21297066 TI - Quantification of melamine absorption, distribution to tissues, and excretion by sheep. AB - Eight Dohne Merino rams were used to quantify apparent absorption, distribution to tissues, and excretion of dietary melamine in sheep. Two batches of concentrate pellets were made; one (CON) contained corn gluten meal with no detectable melamine and the other (MEL) contained corn gluten meal that was previously found to be highly contaminated with melamine at 15,117 mg/kg. The MEL pellets contained 1,149 mg/kg of melamine. During a 10-d adaptation period, all the animals received a forage-based diet supplemented with 600 g/d of the CON pellets. This was followed by an 8-d collection period during which 6 of the animals received MEL pellets and 2 received CON pellets. Melamine intake of sheep that received MEL pellets was 0.69 g/d. Blood samples were taken before first ingestion of MEL pellets on d 1 and again on d 3, 6, and 8 of the collection period for melamine and serum creatinine analyses. Feces and urine were collected quantitatively over the 8 d for proximate and melamine analyses. All the animals were slaughtered at the end of the trial, and samples of the LM, liver, kidneys, and abdominal fat were taken for melamine analysis. Data of the 2 sheep that received CON pellets for the duration of the trial confirmed that no melamine was detected in any of the samples, and no statistical analyses were performed on these data. The apparent digestibility or efficiency of absorption of ingested melamine was 76.7%. Melamine was detected in the urine, blood, muscle (LM), and fat tissue of all the sheep that received MEL pellets. Serum melamine concentrations reached 5.4 mg/kg on d 8 of the collection period, and the meat (LM) contained 9.6 mg/kg of melamine. Calculations on the partitioning of ingested melamine suggested that urine is the major excretion route accounting for 53.2%, whereas feces accounted for 23.3% of ingested melamine. Approximately 3.5% of the ingested melamine was detected in muscle. It was concluded that ingested melamine is highly absorbable from the small intestine and that a pathway exists for the distribution of dietary melamine to meat. PMID- 21297067 TI - Best practices for clinical pathology testing in carcinogenicity studies. AB - The Society of Toxicologic Pathology (STP) and American Society for Veterinary Clinical Pathology (ASCVP) convened a Clinical Pathology in Carcinogenicity Studies Working Group to recommend best practices for inclusion of clinical pathology testing in carcinogenicity studies. Regulatory guidance documents and literature were reviewed, and veterinary pathologists from North America, Japan, and Europe were surveyed regarding current practices, perceived value, and recommendations for clinical pathology testing in carcinogenicity studies. For two-year rodent carcinogenicity studies, the Working Group recommends that clinical pathology testing be limited to collection of blood smears at scheduled and unscheduled sacrifices to be examined only if indicated to aid in the diagnosis of possible hematopoietic neoplasia following histopathologic evaluation. Additional clinical pathology testing is most appropriately used to address specific issues from prior toxicity studies or known test article-related class effects. Inadequate data were available to make a recommendation concerning clinical pathology testing for alternative six-month carcinogenicity assays using genetically modified mice, although the Working Group suggests that it may be appropriate to use the same approach as for two-year carcinogenicity studies since the study goal is the same. PMID- 21297068 TI - Asthma and chronic obstructive pulmonary disease: common genes, common environments? AB - Asthma and chronic obstructive pulmonary disease (COPD) show similarities and substantial differences. The Dutch hypothesis stipulated that asthma and COPD have common genetic and environmental risk factors (allergens, infections, smoking), which ultimately lead to clinical disease depending on the timing and type of environmental exposures (Postma and Boezen, Chest 2004;126:96S-104S). Thus, a particular group of shared genetic factors may lead to asthma when combined with specific environmental factors that are met at a certain stage in life, whereas combination with other environmental factors, or similar environmental factors at a different stage in life, will lead toward COPD. Multiple genes have been found for asthma and COPD. In addition to genes unique to these diseases, some shared genetic risk factors exist. Moreover, there are both common host risk factors and environmental risk factors for asthma and COPD. Here we put forward, based on the data available, that genes that affect lung development in utero and lung growth in early childhood in interaction with environmental detrimental stimuli, such as smoking and air pollution, are contributing to asthma in childhood and the ultimate development of COPD. Additional genes and environmental factors then drive specific immunological mechanisms underlying asthma, and others may contribute to the ultimate development of specific subtypes of COPD (i.e., airway disease with mucous hypersecretion, small airway disease, and emphysema). The genetic predisposition to the derailment of certain pathways may further help to define subgroups of asthma and COPD. In the end this may lead to stratification of patients by their genetic make-up and open new therapeutic prospects. PMID- 21297069 TI - Lung stress and strain during mechanical ventilation: any safe threshold? AB - RATIONALE: Unphysiologic strain (the ratio between tidal volume and functional residual capacity) and stress (the transpulmonary pressure) can cause ventilator induced lung damage. OBJECTIVES: To identify a strain-stress threshold (if any) above which ventilator-induced lung damage can occur. METHODS: Twenty-nine healthy pigs were mechanically ventilated for 54 hours with a tidal volume producing a strain between 0.45 and 3.30. Ventilator-induced lung damage was defined as net increase in lung weight. MEASUREMENTS AND MAIN RESULTS: Initial lung weight and functional residual capacity were measured with computed tomography. Final lung weight was measured using a balance. After setting tidal volume, data collection included respiratory system mechanics, gas exchange and hemodynamics (every 6 h); cytokine levels in serum (every 12 h) and bronchoalveolar lavage fluid (end of the experiment); and blood laboratory examination (start and end of the experiment). Two clusters of animals could be clearly identified: animals that increased their lung weight (n = 14) and those that did not (n = 15). Tidal volume was 38 +/- 9 ml/kg in the former and 22 +/- 8 ml/kg in the latter group, corresponding to a strain of 2.16 +/- 0.58 and 1.29 +/ 0.57 and a stress of 13 +/- 5 and 8 +/- 3 cm H(2)O, respectively. Lung weight gain was associated with deterioration in respiratory system mechanics, gas exchange, and hemodynamics, pulmonary and systemic inflammation and multiple organ dysfunction. CONCLUSIONS: In healthy pigs, ventilator-induced lung damage develops only when a strain greater than 1.5-2 is reached or overcome. Because of differences in intrinsic lung properties, caution is warranted in translating these findings to humans. PMID- 21297070 TI - Vitamin D deficiency causes deficits in lung function and alters lung structure. AB - RATIONALE: The prevalence of vitamin D deficiency is increasing and has been linked to obstructive lung diseases including asthma and chronic obstructive pulmonary disease. Recent studies suggest that vitamin D deficiency is associated with reduced lung function. The relationship between vitamin D deficiency and lung function is confounded by the association between physical activity levels and vitamin D status. Thus, causal data confirming a relationship between vitamin D and lung function are lacking. OBJECTIVES: To determine if vitamin D deficiency alters lung structure and function. METHODS: A physiologically relevant BALB/c mouse model of vitamin D deficiency was developed by dietary manipulation. Offspring from deficient and replete colonies of mice were studied for somatic growth, lung function, and lung structure at 2 weeks of age. MEASUREMENTS AND MAIN RESULTS: Lung volume and function were measured by plethysmography and the forced oscillation technique, respectively. Lung structure was assessed histologically. Vitamin D deficiency did not alter somatic growth but decreased lung volume. There were corresponding deficits in lung function that could not be entirely explained by lung volume. The volume dependence of lung mechanics was altered by deficiency suggesting altered tissue structure. However, the primary histologic difference between groups was lung size rather than an alteration in architecture. CONCLUSIONS: Vitamin D deficiency causes deficits in lung function that are primarily explained by differences in lung volume. This study is the first to provide direct mechanistic evidence linking vitamin D deficiency and lung development, which may explain the association between obstructive lung disease and vitamin D status. PMID- 21297071 TI - Rapid diagnosis of tuberculosis and multidrug resistance by the microscopic observation drug-susceptibility assay. AB - RATIONALE: Mortality is exceedingly high and rapid among patients infected with HIV and tuberculosis (TB), in part because of limited access to appropriate TB diagnostics. The microscopic observation drug-susceptibility (MODS) assay is a simple, rapid, low-cost test for TB and multidrug-resistant (MDR) TB, but data in individuals infected with HIV and in Africa are limited. OBJECTIVES: To evaluate the MODS assay in a high-HIV-prevalence setting. METHODS: We performed a prospective diagnostic accuracy study of consecutive adults suspected to have TB from outpatient and inpatient settings at a district hospital in rural South Africa. Sputum was tested by concentrated smear microscopy; agar (Middlebrook 7H11) and liquid (mycobacterial growth indicator tube) culture; and the MODS assay. Drug-susceptibility testing (DST) was by indirect 1% proportion method and MODS. Reference standard for Mycobacterium tuberculosis detection was growth on Middlebrook or mycobacterial growth indicator tube culture; 1% proportion was the reference standard for isoniazid and rifampin DST. MEASUREMENTS AND MAIN RESULTS: Among 534 adults enrolled, 388 (73%) were HIV-positive, with a median CD4 count of 161 cells/mm(3) (interquartile range [IQR]: 72-307). TB was diagnosed by the reference standard culture in 113 (21%). MODS sensitivity was 85% (95% confidence interval [CI], 78-92%), and specificity was 97% (CI, 95-99%). MODS test performance did not differ by patients' HIV status (sensitivity 88% vs. 90%, specificity 97% vs. 100% for HIV-positive versus HIV-negative, respectively). For MDR-TB diagnosis (n = 11), sensitivity was 100% (one-sided CI, 68-100%) and specificity was 94% (CI, 82-98%). Median turnaround time for MDR-TB diagnosis was 7 days (IQR: 6-9) with MODS versus 70 days (IQR: 49-96) with indirect proportion method (P < 0.001). CONCLUSIONS: Among adult TB suspects predominantly infected with HIV, MODS provided high sensitivity and specificity for rapid diagnosis of TB and MDR-TB. Given the high mortality from TB and MDR-TB and prolonged opportunity for TB transmission before diagnosis, the MODS assay warrants serious consideration for use in similar high-HIV-prevalence, resource-limited settings. PMID- 21297072 TI - Pseudomonas aeruginosa population diversity and turnover in cystic fibrosis chronic infections. AB - RATIONALE: Pseudomonas aeruginosa isolates from chronic cystic fibrosis lung infections display multiple phenotypes indicating extensive population diversity. OBJECTIVES: We aimed to examine how such diversity is distributed within and between patients, and to study the dynamics of single-strain phenotypic diversity in multiple patients through time. METHODS: Sets of 40 P. aeruginosa isolates per sputum samples were analyzed for a series of phenotypic and genotypic characteristics. Population differentiation between patients, between samples within patients, and between isolates within samples was analyzed. MEASUREMENTS AND MAIN RESULTS: We characterized 15 traits for a total of 1,720 isolates of an important and widely disseminated epidemic strain of P. aeruginosa from 10 chronically infected patients with cystic fibrosis multiply sampled during 2009. Overall, 43 sputum samples were analyzed and 398 haplotypes of the Liverpool Epidemic Strain were identified. The majority of phenotypic diversity occurred within patients. Such diversity is highly dynamic, displaying rapid turnover of haplotypes through time. P. aeruginosa populations within each individual sputum sample harbored extensive diversity. Although we observed major changes in the haplotype composition within patients between samples taken at intervals of several months, the compositions varied much less during exacerbation periods, despite the use of intravenous antibiotics. Our data also highlight a correlation between periods of pulmonary exacerbation and the overproduction of pyocyanin, a quorum sensing-controlled virulence factor. CONCLUSIONS: These results significantly advance our understanding of the within-host population biology of P. aeruginosa during infection of patients with cystic fibrosis, and provide in vivo evidence for a link between pyocyanin production and patient morbidity. PMID- 21297073 TI - Dual Role of IL-22 in allergic airway inflammation and its cross-talk with IL 17A. AB - RATIONALE: IL-22 has both proinflammatory and antiinflammatory properties. Its role in allergic lung inflammation has not been explored. OBJECTIVES: To investigate the expression and roles of IL-22 in the onset and resolution of experimental allergic asthma and its cross-talk with IL-17A. METHODS: IL-22 expression was assessed in patient samples and in the lung of mice immunized and challenged with ovalbumin. IL-22 functions in allergic airway inflammation were evaluated using mice deficient in IL-22 or anti-IL-22 neutralizing antibodies. Moreover, the effects of recombinant IL-22 and IL-17A neutralizing antibodies were investigated. MEASUREMENTS AND MAIN RESULTS: Increased pulmonary IL-22 expression is found in the serum of patients with asthma and mice immunized and challenged with ovalbumin. Allergic lung inflammation is IL-22 dependent because eosinophil recruitment, Th2 cytokine including IL-13 and IL-33, chemokine production, airway hyperreactivity, and mucus production are drastically reduced in mice deficient in IL-22 or by IL-22 antibody neutralization during immunization of wild-type mice. By contrast, IL-22 neutralization during antigen challenge enhanced allergic lung inflammation with increased Th2 cytokines. Consistent with this, recombinant IL-22 given with allergen challenge protects mice from lung inflammation. Finally, IL-22 may regulate the expression and proinflammatory properties of IL-17A in allergic lung inflammation. CONCLUSIONS: IL-22 is required for the onset of allergic asthma, but functions as a negative regulator of established allergic inflammation. Our study reveals that IL-22 contributes to the proinflammatory properties of IL-17A in experimental allergic asthma. PMID- 21297075 TI - Suppression of histone deacetylases worsens right ventricular dysfunction after pulmonary artery banding in rats. AB - RATIONALE: Inhibitors of histone deacetylases (HDACs) reduce pressure-overload induced left ventricular hypertrophy and dysfunction, but their effects on right ventricular (RV) adaptation to pressure overload are unknown. OBJECTIVES: Determine the effect of the broad-spectrum HDAC inhibitors trichostatin A (TSA) and valproic acid (VPA) on RV function and remodeling after pulmonary artery banding (PAB) in rats. METHODS: Chronic progressive RV pressure-overload was induced in rats by PAB. After establishment of adaptive RV hypertrophy 4 weeks after surgery, rats were treated for 2 weeks with vehicle, TSA, or VPA. RV function and remodeling were determined using echocardiography, invasive hemodynamic measurements, immunohistochemistry, and molecular analyses after 2 weeks of HDAC inhibition. The effects of TSA were determined on the expression of proangiogenic and prohypertrophic genes in human myocardial fibroblasts and microvascular endothelial cells. MEASUREMENTS AND MAIN RESULTS: TSA treatment did not prevent the development of RV hypertrophy and was associated with RV dysfunction, capillary rarefaction, fibrosis, and increased rates of myocardial cell death. Similar results were obtained with the structurally unrelated HDAC inhibitor VPA. With TSA treatment, a reduction was found in expression of vascular endothelial growth factor and angiopoietin-1, which proteins are involved in vascular adaptation to pressure-overload. TSA dose-dependently suppressed vascular endothelial growth factor, endothelial nitric oxide synthase, and angiopoietin-1 expression in cultured myocardial endothelial cells, which effects were mimicked by selective gene silencing of several class I and II HDACs. CONCLUSIONS: HDAC inhibition is associated with dysfunction and worsened remodeling of the pressure-overloaded RV. The detrimental effects of HDAC inhibition on the pressure-overloaded RV may come about via antiangiogenic or proapoptotic effects. PMID- 21297074 TI - Recombinant tissue factor pathway inhibitor in severe community-acquired pneumonia: a randomized trial. AB - RATIONALE: Severe community-acquired pneumonia (sCAP) is a leading cause of death worldwide. Adjunctive therapies for sCAP are needed to further improve outcome. A systemic inhibitor of coagulation, tifacogin (recombinant human tissue factor pathway inhibitor) seemed to provide mortality benefit in the sCAP subgroup of a previous sepsis trial. OBJECTIVES: Evaluate the impact of adjunctive tifacogin on mortality in patients with sCAP. METHODS: A multicenter, randomized, placebo controlled, double-blind, three-arm study was conducted from July 2005 to June 2008 at 188 centers in North and South America, Europe, South Africa, Asia, Australia, and New Zealand. Adults with sCAP were randomized to receive a continuous intravenous infusion of tifacogin 0.025 mg/kg/h, tifacogin 0.075 mg/kg/h, or matching placebo over 96 hours. MEASUREMENTS AND MAIN RESULTS: Severity-adjusted 28-day all-cause mortality. Of 2,138 randomized patients, 946, 238, and 918 received tifacogin 0.025 mg/kg/h, tifacogin 0.075 mg/kg/h, and placebo, respectively. Tifacogin 0.075 mg/kg/h was discontinued after the first interim analysis according to prespecified futility criterion. The 28-day all cause mortality rates were similar between the 0.025 mg/kg/h (18%) and placebo groups (17.9%) (P = 0.56). Greater reduction in prothrombin fragment 1+2 and thrombin antithrombin complexes levels relative to baseline throughout the first 96 hours was found with tifacogin 0.025 mg/kg/h than with placebo. The incidence of adverse events and serious adverse events were comparable between the tifacogin 0.025 mg/kg/h and placebo groups. CONCLUSIONS: Tifacogin showed no mortality benefit in patients with sCAP despite evidence of biologic activity. PMID- 21297076 TI - Haplotype association mapping of acute lung injury in mice implicates activin a receptor, type 1. AB - RATIONALE: Because acute lung injury is a sporadic disease produced by heterogeneous precipitating factors, previous genetic analyses are mainly limited to candidate gene case-control studies. OBJECTIVES: To develop a genome-wide strategy in which single nucleotide polymorphism associations are assessed for functional consequences to survival during acute lung injury in mice. METHODS: To identify genes associated with acute lung injury, 40 inbred strains were exposed to acrolein and haplotype association mapping, microarray, and DNA-protein binding were assessed. MEASUREMENTS AND MAIN RESULTS: The mean survival time varied among mouse strains with polar strains differing approximately 2.5-fold. Associations were identified on chromosomes 1, 2, 4, 11, and 12. Seven genes (Acvr1, Cacnb4, Ccdc148, Galnt13, Rfwd2, Rpap2, and Tgfbr3) had single nucleotide polymorphism (SNP) associations within the gene. Because SNP associations may encompass "blocks" of associated variants, functional assessment was performed in 91 genes within +/- 1 Mbp of each SNP association. Using 10% or greater allelic frequency and 10% or greater phenotype explained as threshold criteria, 16 genes were assessed by microarray and reverse real-time polymerase chain reaction. Microarray revealed several enriched pathways including transforming growth factor-beta signaling. Transcripts for Acvr1, Arhgap15, Cacybp, Rfwd2, and Tgfbr3 differed between the strains with exposure and contained SNPs that could eliminate putative transcriptional factor recognition sites. Ccdc148, Fancl, and Tnn had sequence differences that could produce an amino acid substitution. Mycn and Mgat4a had a promoter SNP or 3'untranslated region SNPs, respectively. Several genes were related and encoded receptors (ACVR1, TGFBR3), transcription factors (MYCN, possibly CCDC148), and ubiquitin-proteasome (RFWD2, FANCL, CACYBP) proteins that can modulate cell signaling. An Acvr1 SNP eliminated a putative ELK1 binding site and diminished DNA-protein binding. CONCLUSIONS: Assessment of genetic associations can be strengthened using a genetic/genomic approach. This approach identified several candidate genes, including Acvr1, associated with increased susceptibility to acute lung injury in mice. PMID- 21297077 TI - Allergic lung inflammation is mediated by soluble tumor necrosis factor (TNF) and attenuated by dominant-negative TNF biologics. AB - Tumor Necrosis Factor (TNF) is a pleiotropic cytokine consisting of soluble and transmembrane forms, with distinct roles in inflammation and immunity. TNF is an important factor in allergic airway inflammation. However, the disparate functions of soluble (sol) and transmembrane (tm) TNF in lung pathology are not well understood. Our aim was to assess the activities of solTNF and tmTNF in murine models of allergic airway disease, and to evaluate the efficacy of solTNF selective inhibition. We used ovalbumin sensitization and challenge of TNF knockout, tmTNF knockin, and wild-type C57BL/6 mice to distinguish differences in airway inflammation and hyperreactivity mediated by solTNF and tmTNF. Functions of solTNF and tmTNF in hyperresponsive, wild-type Balb/c mice were assessed by comparing dominant-negative anti-TNF biologics, which antagonize solTNF yet spare tmTNF, to etanercept, a nonselective inhibitor of both TNF forms. Responses in transgenic C57BL/6 mice demonstrated that solTNF, and not tmTNF, is necessary to drive airway inflammation. In Balb/c mice, dominant-negative TNF biologics administered during immunization decreased the recruitment of eosinophils and lymphocytes into the bronchoalveolar space and lung parenchyma, reduced specific serum IgE, goblet-cell hyperplasia, and eosinophilic inflammation, and suppressed methacholine-induced airway hyperreactivity. Concentrations of IL-5, CCL5/RANTES, CCL11/eotaxin, and CCL17/TARC were also reduced in bronchoalveolar lavage. Dominant-negative TNFs reduced lung eosinophilia, even when given only during antigen challenge. The selective inhibition of soluble TNF suppresses inflammation, hyperreactivity, and remodeling in transgenic and wild-type murine models of allergic airway disease, and may offer safety advantages in therapies that preserve the immunoprotective functions of transmembrane TNF. PMID- 21297079 TI - Interleukin-6 promotes pulmonary emphysema associated with apoptosis in mice. AB - The IL-6 cytokine family, which signals via the shared gp130 coreceptor, is linked with the pathogenesis of emphysema. However, the definitive mechanisms by which these cytokines cause emphysema remain ill-defined. We took an in vivo genetic complementation approach to identify the specific IL-6 cytokine family members and gp130-regulated cellular processes that cause emphysema. We used gp130(F/F) mice homozygous for a subtle knock-in mutation in gp130 that deregulates intracellular signaling by the IL-6 cytokine family. The gp130(F/F) mice spontaneously develop emphysema by age 6 months. Within the IL-6 cytokine family, only IL-6 was significantly up-regulated in the lungs of gp130(F/F) mice, and the genetic targeting of IL-6 in gp130(F/F) mice (gp130(F/F):IL-6(-/-)) prevented emphysema. By contrast, the genetic ablation of receptor signaling via IL-11, which like IL-6 signals via a gp130 homodimer and uses the same signaling machinery, failed to ameliorate emphysema in gp130(F/F) mice. Among the disease associated processes examined, emphysema strongly correlated with elevated alveolar cell apoptosis. Acute (4-day) exposure to cigarette smoke (CS) further augmented the expression of IL-6 in lungs of gp130(F/F) mice, and subchronic (6 week) exposure to CS exacerbated emphysematous and apoptotic changes in the lungs of gp130(F/F) but not gp130(F/F): IL-6(-/-) mice. IL-6 is the main causative agent of IL-6 cytokine family-induced emphysema, and operates to induce apoptosis in the lung. We propose that the discrete targeting of IL-6 signaling may provide an effective therapeutic strategy against human lung disease. PMID- 21297078 TI - Do cell junction protein mutations cause an airway phenotype in mice or humans? AB - Cell junction proteins connect epithelial cells to each other and to the basement membrane. Genetic mutations of these proteins can cause alterations in some epithelia leading to varied phenotypes such as deafness, renal disease, skin disorders, and cancer. This review examines if genetic mutations in these proteins affect the function of lung airway epithelia. We review cell junction proteins with examples of disease mutation phenotypes in humans and in mouse knockout models. We also review which of these genes are expressed in airway epithelium by microarray expression profiling and immunocytochemistry. Last, we present a comprehensive literature review to find the lung phenotype when cell junction and adhesion genes are mutated or subject to targeted deletion. We found that in murine models, targeted deletion of cell junction and adhesion genes rarely result in a lung phenotype. Moreover, mutations in these genes in humans have no obvious lung phenotype. Our research suggests that simply because a cell junction or adhesion protein is expressed in an organ does not imply that it will exhibit a drastic phenotype when mutated. One explanation is that because a functioning lung is critical to survival, redundancy in the system is expected. Therefore mutations in a single gene might be compensated by a related function of a similar gene product. Further studies in human and animal models will help us understand the overlap in the function of cell junction gene products. Finally, it is possible that the human lung phenotype is subtle and has not yet been described. PMID- 21297080 TI - Hydrogen sulfide inhibits proliferation and release of IL-8 from human airway smooth muscle cells. AB - Hydrogen sulfide (H(2)S) is synthesized intracellularly by the enzymes cystathionine-gamma-lyase and cystathionine-beta-synthase (CBS), and is proposed to be a gasotransmitter with effects in modulating inflammation and cellular proliferation. We determined a role of H(2)S in airway smooth muscle (ASM) function. ASM were removed from resection or transplant donor lungs and were placed in culture. Proliferation of ASM was induced by FCS and the proinflammatory cytokine, IL-1beta. Proliferation of ASM and IL-8 release were measured by bromodeoxyuridine incorporation and ELISA, respectively. Exposure of ASM to H(2)S "donors" inhibited this proliferation and IL-8 release. Methemoglobin, a scavenger of endogenous H(2)S, increased DNA synthesis induced by FCS and IL-1beta. In addition, methemoglobin increased IL-8 release induced by FCS, but not by IL-1beta, indicating a role for endogenous H(2)S in these systems. Inhibition of CBS, but not cystathionine-gamma-lyase, reversed the inhibitory effect of H(2)S on proliferation and IL-8 release, indicating that this is dependent on CBS. CBS mRNA and protein expression were inhibited by H(2)S donors, and were increased by methemoglobin, indicating that CBS is the main enzyme responsible for endogenous H(2)S production. Finally, we found that exogenous H(2)S inhibited the phosphorylation of extracellular signal-regulated kinase-1/2 and p38, which could represent a mechanism by which H(2)S inhibited cellular proliferation and IL-8 release. In summary, H(2)S production provides a novel mechanism for regulation of ASM proliferation and IL-8 release. Therefore, regulation of H(2)S may represent a novel approach to controlling ASM proliferation and cytokine release that is found in patients with asthma. PMID- 21297081 TI - Interleukin-1 receptor-associated kinase 3 gene associates with susceptibility to acute lung injury. AB - Sepsis is the most common cause of acute lung injury (ALI), leading to organ dysfunction and death in critically ill patients. Previous studies associated variants of interleukin-1 receptor-associated kinase genes (IRAKs) with differential immune responses to pathogens and with outcomes during sepsis, and revealed that increased expression levels of the IRAK3 gene were correlated with poor outcomes during sepsis. Here we explored whether common variants of the IRAK3 gene were associated with susceptibility to, and outcomes of, severe sepsis. After our discovery of polymorphism, we genotyped a subset of seven single-nucleotide polymorphisms (SNPs) in 336 population-based control subjects and 214 patients with severe sepsis, collected as part of a prospective study of adults from a Spanish network of intensive care units. Whereas IRAK3 SNPs were not associated with susceptibility to severe sepsis, rs10506481 showed a significant association with the development of ALI among patients with sepsis (P = 0.007). The association remained significant after adjusting for multiple comparisons, population stratification, and clinical variables (odds ratio, 2.50; 95% confidence interval, 1.15-5.47; P = 0.021). By imputation, we revealed three additional SNPs independently associated with ALI (P < 0.01). One of these (rs1732887) predicted the disruption of a putative human-mouse conserved transcription factor binding site, and demonstrated functional effects in vitro (P = 0.017). Despite the need for replication in independent studies, our data suggest that common SNPs in the IRAK3 gene may be determinants of sepsis-induced ALI. PMID- 21297082 TI - Bronchial epithelium-derived IL-8 and RANTES increased bronchial smooth muscle cell migration and proliferation by Kruppel-like factor 5 in areca nut-mediated airway remodeling. AB - This study is first to analyze the inflammatory cytokines, produced by the bronchial epithelium after exposure to areca nut extract (ANE), which contribute to airway remodeling by increasing human bronchial smooth muscle cells (BSMC) migration and proliferation. We treated human bronchial epithelial cell lines BEAS-2B and HBE135-E6E7 (HBE) with ANE, saliva-reacted ANE (sANE), and the areca alkaloids arecoline and then harvested the conditioned medium (CM) that was added to BSMC. Exposure of BEAS-2B and HBE to ANE, sANE, and arecoline increased interleukin 8 (IL-8) and Regulated upon Activation, Normal T-cell Expressed, and Secreted (RANTES) production. Cultures of BSMC with ANE-, sANE-, and arecoline BEAS-2B-CM and -HBE-CM increased BSMC proliferation and migration. Induction of BSMC proliferation and migration by sANE-BEAS-2B-CM and -HBE-CM was associated with increased phosphorylation of Raf, MEK1/2, and extracellular signal regulated kinase (ERK)1/2 and the upregulation of kruppel-like factor 5 (KLF5), cyclin D, and integrin-linked kinase. Blocking ERK1/2 by a specific inhibitor significantly decreased BSMC proliferation and migration by inhibiting KLF5 enhancement. KLF5 knockdown also decreased sANE-BEAS-2B-CM, sANE-HBE-CM, and recombinant human interleukin 8/recombinant human RANTES-mediated BSMC proliferation and migration, suggesting that KLF5 was involved in the regulation of BSMC proliferation and migration. Our study suggests that inhibition of IL-8 and RANTES or IL-8/RANTES mediated mitogen-activated protein kinase/KLF5 signaling is an attractive therapeutic target for areca nut-induced asthma. PMID- 21297084 TI - A cross-sectional study of risk factors for HIV among pregnant women in Guatemala City, Guatemala: lessons for prevention. AB - Although the Central American HIV epidemic is concentrated in high-risk groups, HIV incidence is increasing in young women. From 2005 to 2007, we conducted a cross-sectional study of pregnant women in a large public hospital and an HIV clinic in Guatemala City to describe risk factors for HIV infection and inform prevention strategies. For 4629 consenting patients, HIV status was laboratory confirmed and participant characteristics were assessed by interviewer administered questionnaires. Lifetime number of sexual partners ranged from 1 to 99, with a median (interquartile range) of 1 (1, 2). 2.6% (120) reported exchanging sex for benefits; 0.1% (3) were sex workers, 2.3% (106) had used illegal drugs, 31.1% (1421) planned their pregnancy and 31.8% (1455) experienced abuse. In logistic regression analyses, HIV status was predicted by one variable describing women's behaviour (lifetime sexual partners) and three variables describing partner risks (partner HIV+, migrant worker or suspected unfaithful). Women in our sample exhibited few behavioural risks for HIV but significant vulnerability via partner behaviours. To stem feminization of the epidemic, health authorities should complement existing prevention interventions in high risk populations with directed efforts towards bridging populations such as migrant workers. We identify four locally adapted HIV prevention strategies. PMID- 21297085 TI - Use of modern and traditional products to self-treat symptoms of sexually transmitted infections in South African women. AB - The objective of the study is to investigate products used by women self-treating symptoms of reproductive tract infections (RTIs), including sexually transmitted infections (STIs), and their methods of administration. A household survey using a multi-stage cluster sample design was undertaken in KwaZulu-Natal, South Africa. Women aged 18-60 years were interviewed (n = 867) and information was collected on demographics, reproductive health and sexual behaviours. A fifth of women reported having RTI/STI symptoms (20.5%), of whom 41.9% were treating these symptoms (mostly discharge [79.1%], ulcers [6.8%] and itching [7.7%]). Only three women were using medication prescribed by a health provider, while the remainder were self-treating using traditional medicines and modern products, including antiseptics, soaps, petroleum jelly, menthol creams and alum. Products were administered in various ways. Although RTI/STI treatment is widely available and free in public health facilities, many women are still self-treating. Potential harm of products for self-treatment requires further investigation and efforts should be made to improve STI service uptake. PMID- 21297083 TI - The implications of DNA methylation for toxicology: toward toxicomethylomics, the toxicology of DNA methylation. AB - Identifying agents that have long-term deleterious impact on health but exhibit no immediate toxicity is of prime importance. It is well established that long term toxicity of chemicals could be caused by their ability to generate changes in the DNA sequence through the process of mutagenesis. Several assays including the Ames test and its different modifications were developed to assess the mutagenic potential of chemicals (Ames, B. N., Durston, W. E., Yamasaki, E., and Lee, F. D. (1973a). Carcinogens are mutagens: a simple test system combining liver homogenates for activation and bacteria for detection. Proc. Natl. Acad. Sci. U.S.A. 70, 2281-2285; Ames, B. N., Lee, F. D., and Durston, W. E. (1973b). An improved bacterial test system for the detection and classification of mutagens and carcinogens. Proc. Natl. Acad. Sci. U.S.A. 70, 782-786). These tests have also been employed for assessing the carcinogenic potential of compounds. However, the DNA molecule contains within its chemical structure two layers of information. The DNA sequence that bears the ancestral genetic information and the pattern of distribution of covalently bound methyl groups on cytosines in DNA. DNA methylation patterns are generated by an innate program during gestation but are attuned to the environment in utero and throughout life including physical and social exposures. DNA function and health could be stably altered by exposure to environmental agents without changing the sequence, just by changing the state of DNA methylation. Our current screening tests do not detect agents that have long-range impact on the phenotype without altering the genotype. The realization that long-range damage could be caused without changing the DNA sequence has important implications on the way we assess the safety of chemicals, drugs, and food and broadens the scope of definition of toxic agents. PMID- 21297086 TI - Risk factors for delayed HIV diagnosis at the Hospital of Tropical Diseases in Ho Chi Minh City, Vietnam. AB - The objective was to identify factors associated with delayed diagnosis of HIV infection in Vietnam, defined as having a CD4 cell count of <200/mm(3) at the time of the first positive test. Data were collected retrospectively from the medical records of HIV-infected outpatients who received their initial care at the Hospital for Tropical Diseases in Ho Chi Minh City between July 2004 and August 2005. Among the 204 included patients, 58.3% had a delayed diagnosis. Independent factors associated with a delayed diagnosis were male gender (adjusted odds ratio [AOR] = 2.10; 95% confidence interval [CI] = 1.03-4.41) and having an opportunistic infection at the time of the first positive HIV test (AOR = 3.07; 95% CI = 1.71-5.53). Counselling for early HIV screening is important in populations at risk of infection. Facilitating access to care should be reinforced for symptomatic patients. PMID- 21297087 TI - Jarisch-Herxheimer reaction among syphilis patients in Rio de Janeiro, Brazil. AB - The Jarisch-Herxheimer reaction (JHR) is a syndrome observed after antimicrobial treatment of some infectious diseases. The syndrome has clinical characteristics of an inflammatory reaction to antibiotic treatment. A prospective study of patients with a clinical and laboratory diagnosis of syphilis was conducted at a sexually transmitted diseases clinic in Rio de Janeiro, Brazil. Patients were treated with benzathine penicillin and observed for the JHR. A total of 115 patients were included in this study. Fifty-one patients (44%) had secondary syphilis; 37 (32%), primary; 26 (23%), latent; and one (1%), tertiary syphilis. Ten patients (9%) developed the JHR. All JHRs occurred in patients with secondary and latent syphilis. No patients experienced an allergic reaction to penicillin. The JHR occurred less frequently than in previous studies. It is important that health-care professionals recognize the clinical characteristics of the JHR so that it is not misinterpreted as an allergic reaction to penicillin. PMID- 21297088 TI - Minimum effective plasma concentration of efavirenz in treatment-naive Chinese HIV-infected patients. AB - To assess the relationship between mean efavirenz (EFV) plasma concentration and clinical effect during the first 48 weeks of combination antiretroviral therapy (cART), the baseline CD4 cell count was recorded and plasma EFV concentration and CD4 cell count were measured every 12 weeks. HIV-RNA viral load was determined in the 48th week of cART. In total, 42 subjects were recruited and grouped according to their mean concentration of EFV during the study period: groups A, B and C with EFV concentrations (mean) <2 mg/L (1.8 mg/L), 2-4 mg/L (2.9 mg/L) and >4 mg/L (5.5 mg/L), respectively. The CD4 cell counts in group C increased more quickly than in groups B and A, although this was not statistically significant (211 +/- 176/MUL versus 151 +/- 145/MUL and 172 +/- 105/MUL, respectively; P = 0.799). Groups B and C had higher rates of HIV viral load suppression than group A (P = 0.017). For treatment-naive Chinese HIV-infected patients, EFV plasma concentrations above 2 mg/L appear to suppress HIV replication more effectively than concentrations below 2 mg/L. PMID- 21297089 TI - Assessment of cardiac diastolic dysfunction in HIV-infected people without cardiovascular symptoms in China. AB - This study assessed cardiac diastolic dysfunction (DD) in HIV-infected subjects without cardiovascular symptoms in China. Eighty-four HIV-infected patients without cardiovascular symptoms were recruited and compared with 30 HIV-negative control subjects. Cardiac DD was evaluated using echocardiography including tissue Doppler imaging. DD was detected in 47.6% of AIDS patients and 42.8% of HIV-positive patients, which was significantly higher than in HIV-negative controls. After logistic regression analysis, HIV infection was independently correlated with cardiac DD (P < 0.05). Among HIV-positive subjects, logistic regression analysis showed that zidovudine exposure was associated with higher prevalence of DD (P < 0.05). Asymptomatic cardiac DD was observed frequently in HIV-infected subjects. HIV infection itself and zidovudine exposure were correlated with a higher prevalence of cardiac DD. PMID- 21297090 TI - Rectal infections with chlamydia and gonorrhoea in women attending a multiethnic sexually transmitted diseases urban clinic. AB - Sexually transmitted rectal infections with Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC) have been well documented in men who have sex with men (MSM). Few studies have described infections in women who engage in anal intercourse. We performed testing for rectal infections in women who reported ano receptive intercourse at the Miami Dade Health Department Sexually Transmitted Diseases (STD) clinic and report the prevalence and characteristics of women with rectal CT or GC infections. Our results revealed a prevalence of 17.5% for rectal chlamydia and 13.4% for rectal gonorrhoea. Urine-based screening alone would have missed 6% of rectal chlamydia infections and 35% of rectal gonorrhoea infections. Anal symptoms were reported in 12.5% of women with rectal chlamydia infections. The only associated factor identified was an age less than 28 years. We conclude that rectal screening for CT and GC should be included in STD prevention strategies, especially in the younger population. PMID- 21297091 TI - Ethnic diversity and patterns of infection of a UK HIV-positive patient population outwith major conurbations. AB - We surveyed the HIV-positive population attending a major teaching hospital sited outwith a major conurbation. Eighty-five percent of homosexually acquired infections were contracted within the UK and 91% of heterosexually acquired infections were contracted outside of the UK. A strikingly wide range of nationalities (45) and countries of origin of infection were represented within a relatively small patient population. Most patients were non-UK-born immigrants. A high proportion of illegal immigrants were identified within which there was a high proportion lost to follow-up. This degree of ethnic diversity and domiciliary instability is rarely a feature of non-HIV populations in this setting and imposes additional demands on delivery of care and health-care planning. PMID- 21297092 TI - Post-coital bleeding in young women: the role of genitourinary medicine. AB - Recently published Department of Health (DoH) guidelines and National Health Service Cervical Screening Programme guidelines recommend referral to a genitourinary (GU) medicine or sexual health clinic as part of the management pathway for young women with post-coital bleeding (PCB). The objectives of this questionnaire study were to ascertain whether GU medicine practitioners agreed with these recommendations and to assess which skills were considered necessary regarding the diagnosis and management of cervical pathology in departments of GU medicine and sexual health and also, therefore, in training in the specialty. The majority of respondents considered it important to check for cervical infection in determining the cause of PCB, but few GU medicine practitioners now perform colposcopy and many consider themselves insufficiently trained to assess the cervix in more detail. Since the colposcope is the optimal tool for examining the anogenital tract, we suggest that colposcopy, in its broadest sense, should be reconsidered as an essential part of GU medicine training. PMID- 21297093 TI - Prevalence and factors associated with idiopathic hypercalciuria in HIV patients on combination antiretroviral therapy. AB - Idiopathic hypercalciuria may lead to bone loss via three pathogenic mechanisms described in HIV-negative patients: intestinal hyperabsorption, kidney loss and bone hyperabsorption. We conducted a cross-sectional study in a cohort of 217 HIV positive antiretroviral-experienced patients, identifying hypercalciuria in 67 patients: the prevalence was 30.9% (95% confidence interval 27.4-37.0). The occurrence of hypercalciuria in subjects with normal values of parathormone may indicate an absorptive form of hypercalciuria. In this sample, other bone turnover markers and T-scores were not related to the condition. The results of this study show a high prevalence of idiopathic hypercalciuria in a group of antiretroviral-experienced patients. The consequences and the exact causes of this metabolic complication are not yet known and further investigation is needed. PMID- 21297094 TI - Self-reported psychological distress associated with steroid therapy for HIV. AB - Anabolic androgenic steroid (AAS) replacement therapy is standard care for patients with low testosterone, including HIV-related conditions. These medications have been associated with development of aggressiveness, anxiety disorders, and depression, but only in short-term clinical trials. We conducted an anonymous street survey at a gay and lesbian community event and a survey in a clinic-based setting to study the wider prevalence of psychiatric side-effects associated with androgenic steroids. In the street-based survey, almost half of those prescribed AAS reported psychological side-effects, most commonly aggression (29%) followed by depression (21%). In the clinic survey of mostly HIV+ male patients, changes in sex drive were the most commonly reported effect of treatment while impulsive aggression, anxiety and depression were reported at levels similar to those in the street fair survey. These findings suggest that AAS therapy may be more frequently associated with distress than has been reported in the clinical literature. PMID- 21297095 TI - Cervical screening uptake in immunocompromised women in Waikato, New Zealand. AB - A one-year retrospective case study was undertaken of cervical cytology in two cohorts of immunocompromised women: those with HIV infection or renal transplants in the Waikato region of New Zealand. Uptake of cervical screening in the two groups was compared with national guidelines. The results showed that HIV patients' uptake was close to the national recommendation for annual cytology (84% had a smear in 18 months); they were more likely to have cytology performed in an HIV-related care setting. Renal transplant patients had lower uptake (56% in 18 months), a finding similar to internationally reported data. Local discussions of these results identified potential influencing factors, which included inadequate dissemination of updated guidelines and inadequate documentation of immunocompromised health status on the national cervical screening programme database. This audit supports including cervical cytology as part of an annual review in all immunocompromised patients. PMID- 21297096 TI - A review of HIV postexposure prophylaxis provision at a genitourinary medicine department. AB - We undertook a retrospective case-note audit of all patients who presented to the Edinburgh genitourinary (GU) medicine department following a potential exposure to HIV infection during the period 1 January 2006 to 31 December 2008. Over the audit period, 81 individuals attended the department, in relation to 85 exposure events. Twenty-three (27%) exposures had occurred in a health-care occupational setting and 50 (59%) in a sexual context. Baseline HIV testing was only performed in 38 (45%) of the 85 exposures. Postexposure prophylaxis (PEP) was initiated in 65 (76%) cases: 61 (94%) received the first dose within the recommended 72 hours. In 68 (80%) of the 85 exposures, the PEP initiation decision tallied with guideline recommendations. Fifty-six of the 65 individuals started on PEP continued beyond 72 hours; 53 of them were reviewed at least once during the course of PEP and had routine blood monitoring performed. Documentation regarding adherence was poor, with only 31 having this recorded in notes. Thirty-seven (66%) individuals who continued on PEP attended for follow-up HIV testing at three months. In summary, the department performed well in some aspects of PEP provision. However, baseline HIV testing and documentation regarding adherence are unsatisfactory and we suggest recommendations to improve this. PMID- 21297097 TI - Emergence of raltegravir-resistant HIV-1 in the central nervous system. AB - Integrase inhibitor-resistant HIV-1 was detected in the cerebrospinal fluid, but not in the plasma of a 42-year-old man with HIV encephalopathy treated with a raltegravir (RAL)-containing regimen. Raltegravir resistance may develop in the central nervous system when the virus is already multi-drug resistant because of different penetration into cerebrospinal fluid of individual antiretroviral agents. PMID- 21297098 TI - Eosinophilic oesophagitis: an unsuspected aetiology for dysphagia in an HIV positive patient. AB - Patients with HIV/AIDS are often afflicted with oesophageal disorders. Opportunistic infections such as candidiasis, herpes simplex, cytomegalovirus, mycobacterial infections, Kaposi sarcoma or lymphoma involving the oesophagus, motility disorders and reflux oesophagitis are the usual culprits. Eosinophilic oesophagitis (EE), a recently recognized entity, is an important cause of dysphagia, food impaction and chest discomfort. We report the case of an HIV infected man who had persistent dysphagia for six months despite treatment with proton pump inhibitor. He was diagnosed with EE after having endoscopic evaluation and biopsy of his oesophagus and was successfully treated with swallowed fluticasone. This case represents the first reported case of EE in an HIV-infected individual. PMID- 21297099 TI - HIV and systemic lupus erythematosus: the clinical and diagnostic dilemmas of having dual diagnosis. AB - We present the case of a young black African woman living in the UK who presented with systemic lupus erythematosus (SLE) and HIV. The reported coexistence of HIV and SLE is unusual with fewer than 30 published cases. We discuss some of the clinical and diagnostic challenges that face clinicians when a patient presents with both conditions. In particular, we discuss the overlap in symptoms, signs and laboratory findings, and the difficulties that this may pose in terms of making a diagnosis. The implications that having a dual diagnosis may have for treating each condition are also discussed. With increased HIV testing in a variety of clinical settings there is likely to be an increase in detection of similar cases. This case emphasizes the need for careful diagnostic testing and judicious interpretation of the validity of laboratory results in order to reach an accurate diagnosis in such patients. PMID- 21297100 TI - BASHH CEG guidelines: which guidelines are popular? PMID- 21297101 TI - RE: Sampling for Chlamydia trachomatis infection. PMID- 21297102 TI - 3D models of epithelial-mesenchymal transition in breast cancer metastasis: high throughput screening assay development, validation, and pilot screen. AB - Despite advancements in therapies developed for the treatment of cancer, patient prognosis and mortality rates have improved minimally, and metastasis remains the primary cause of cancer mortality worldwide. An underlying mechanism promoting metastasis in many types of cancer is epithelial-mesenchymal transition (EMT). Here the authors report a novel 3D model of EMT and metastatic breast cancer suitable for high-throughput screening (HTS) drug discovery. The primary assay incorporates the expression of the prognostic biomarker vimentin, as a luciferase reporter of EMT, in basil-like/triple-negative MDA-MB-231 breast carcinoma spheroids. Using this model, the authors developed a number of known antitumor agents as control modulators of EMT. U0126, PKC412, PF2341066, dasatinib, and axitinib downregulated vimentin expression by 70% to 90% as compared to untreated spheroids. Counterassays were developed to measure spheroid viability and the invasive potential of MDA-MB-231 spheroids after small-molecule treatment and used to confirm hits from primary screening. Finally, the authors conducted a pilot screen to validate this model for HTS using a purified library of marine secondary metabolites. From 230 compounds screened, they obtained a Z' score of 0.64, indicative of an excellent assay, and confirmed 4 hits, including isonaamidine B, papuamine, mycalolide E, and jaspamide. This HTS model demonstrates the potential to identify small-molecule modulators of EMT that could be used to discover novel antimetastatic agents for the treatment of cancer. PMID- 21297103 TI - A quantitative, facile, and high-throughput image-based cell migration method is a robust alternative to the scratch assay. AB - Cell migration is a key phenotype for a number of therapeutically important biological responses, including angiogenesis. A commonly used method to assess cell migration is the scratch assay, which measures the movement of cells into a wound made by physically scoring a confluent cell monolayer to create an area devoid of cells. Although this method has been adequate for qualitative characterization of migration inhibitors, it does not provide the highly reproducible results required for quantitative compound structure-activity relationship evaluation because of the inconsistent size and placement of the wound area within the microplate well. The OrisTM Cell Migration Assay presents a superior alternative to the scratch assay, permitting formation of precisely placed and homogeneously sized cell-free areas into which migration can occur without releasing factors from wounded or dead cells or damaging the underlying extracellular matrix. Herein the authors compare results from the scratch and OrisTM cell migration assays using an endothelial progenitor cell line and the Src kinase inhibitor dasatinib. They find that using the AcumenTM Explorer laser microplate cytometer in combination with the OrisTM Cell Migration Assay plate provides a robust, efficient, and cost-effective cell migration assay exhibiting excellent signal to noise, plate uniformity, and statistical validation metrics. PMID- 21297104 TI - Comparison of 2 cell-based phosphoprotein assays to support screening and development of an ALK inhibitor. AB - Anaplastic lymphoma kinase (ALK) when expressed as a fusion protein with nucleophosmin (NPM) has been implicated as a driving oncogene in a subset of lymphomas. Recent reports of ALK expression in a number of other cancers have raised the possibility that an ALK inhibitor may benefit patients with these diseases as well. In a campaign to identify and develop a selective ALK inhibitor, 2 assays were devised to measure the phosphorylation of tyrosine residue 1604 of ALK (pY(1604) ALK). Amplified Luminescent Proximity Homogeneous Assay (AlphaScreen((r))) and phosflow platforms were used to detect modulation of pY(1604) ALK to determine the relative potency of a set of small-molecule inhibitors. Prior to making use of these assays in diverse settings, the authors attempted to ensure their equivalence with a direct comparison of their performance. The pY(1604) ALK assays correlated well both with each other and with assays of ALK enzyme activity or ALK-dependent cell proliferation. The AlphaScreen((r)) assay was amenable to automation and enabled rapid, high throughput compound assessment in an NPM-ALK-driven cell line, whereas the phosflow assay enabled the authors to characterize the activity of compounds with respect to their impact on targeted enzymes and pathways. Results show that both AlphaScreen((r)) and phosflow ALK assays exhibited diverse characteristics that made them desirable for different applications but were determined to be equally sensitive and robust in the detection of inhibition of pY(1604) ALK. PMID- 21297105 TI - Development of an HTS-compatible assay for discovery of RORalpha modulators using AlphaScreen(r) technology. AB - The retinoid acid receptor-related orphan receptors (RORs) represent important targets for the treatment of metabolic and immune disorders. Here the authors describe the application of AlphaScreen((r)) technology to develop a high throughput screening (HTS)-compatible assay to facilitate the discovery of RORalpha modulators. Using the ligand binding domain (LBD) of RORalpha and a peptide derived from the NR1 box of the nuclear receptor coactivator PGC-1alpha, a 384-well format assay was developed exhibiting high sensitivity, requiring only low nanomolar concentration of reagents. Recently, it was shown that oxysterols such as 7alpha-hydroxycholesterol (7alpha-OHC) function as modulators of the RORs. In this assay, 7alpha-OHC produced a concentration-response curve with an EC(50) of 162 nM, a Z' factor of 0.6, and a signal-to-background (S/B) ratio of 4.2, demonstrating that the assay is HTS compatible. Validation of the assay was afforded by screening against the Sigma LOPAC1280TM library in a 384-well format. In summary, the results presented here demonstrate that this assay can be used to screen large chemical libraries to discover novel modulators of RORalpha. PMID- 21297106 TI - An AlphaScreen(r)-based assay for high-throughput screening for specific inhibitors of nuclear import. AB - Specific viral proteins enter the nucleus of infected cells to perform essential functions, as part of the viral life cycle. The integrase (IN) molecule of human immunodeficiency virus (HIV)-1 is of particular interest in this context due to its integral role in integrating the HIV genome into that of the infected host cell. Most IN-based antiviral compounds target the IN/DNA interaction, but since IN must first enter the nucleus before it can perform these critical functions, nuclear transport of IN is also an attractive target for therapeutic intervention. Here the authors describe a novel high-throughput screening assay for identifying inhibitors of nuclear import, particularly IN, based on amplified luminescent proximity homogeneous assay (AlphaScreen((r))) technology, which is high throughput, requires low amounts of material, and is efficient and cost effective. The authors use the assay to screen for specific inhibitors of the interaction between IN and its nuclear transport receptor importin alpha/beta, successfully identifying several inhibitors of the IN/importin alpha/beta interaction. Importantly, they demonstrate that one of the identified compounds, mifepristone, is effective in preventing active nuclear transport of IN in transfected cells and hence may represent a useful anti-HIV therapeutic. The screen also identified broad-spectrum importin alpha/beta inhibitors such as ivermectin, which may represent useful tools for nuclear transport research in the future. The authors validate the activity and specificity of mifepristone and ivermectin in inhibiting nuclear protein import in living cells, underlining the utility of the screening approach. PMID- 21297107 TI - Optimized high-throughput screen for hepatitis C virus translation inhibitors. AB - Hepatitis C virus (HCV) is a considerable global health problem for which new classes of therapeutics are needed. The authors developed a high-throughput assay to identify compounds that selectively block translation initiation from the HCV internal ribosome entry site (HCV IRES). Rabbit reticulocyte lysate conditions were optimized to faithfully report on authentic HCV IRES-dependent translation relative to a 5' capped mRNA control. The authors screened a library of ~430,000 small molecules for IRES inhibition, leading to ~1700 initial hits. After secondary counterscreening, the vast majority of hits proved to be luciferase and general translation inhibitors. Despite well-optimized in vitro translation conditions, in the end, the authors found no selective HCV IRES inhibitors but did discover a new scaffold of general translation inhibitor. The analysis of these molecules, as well we the finding that a large fraction of false positives resulted from off-target effects, highlights the challenges inherent in screens for RNA-specific inhibitors. PMID- 21297108 TI - A novel enzyme-linked immunosorbent assay for screening HIV-1 fusion inhibitors targeting HIV-1 Gp41 core structure. AB - The gp41 subunit of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein mediates the fusion of viral and host cell membranes. As the HIV-1 enters the host cells, the 2 helical regions, HR1 and HR2, in the ectodomain of gp41 can form a 6-helix bundle, which brings the viral and target cell membranes to close proximity and serves as an attractive target for developing HIV-1 fusion inhibitors. Now, there are several cell- and molecule-based assays to identify potential HIV-1 fusion inhibitors targeting gp41. However, these assays cannot be used universally because they are time-consuming, inconvenient, and expensive. In the present study, the authors expressed and purified GST-HR121 and C43-30a proteins that were derived from the HIV-1 gp41 ectodomain region. GST-HR121 has a function similar to the HR1 peptide of gp41, whereas C43-30a is an HR2-derived peptide that added 50 amino acid residues (aa) in the N-terminal of C43. Further research found they could interact with each other, and a potential HIV-1 fusion inhibitor could inhibit this interaction. On the basis of this fact, a novel, rapid, and economic enzyme-linked immunosorbent assay was established, which can be developed for high-throughput screening of HIV-1 fusion inhibitors. PMID- 21297109 TI - Application of a fluorescence-based continuous-flow bioassay to screen for diversity of cytochrome P450 BM3 mutant libraries. AB - A fluorescence-based continuous-flow enzyme affinity detection (EAD) setup was used to screen cytochrome P450 BM3 mutants on-line for diversity. The flow injection screening assay is based on the BM3-mediated O-dealkylation of alkoxyresorufins forming the highly fluorescent product resorufin, and can be used in different configurations, namely injection of ligands, enzymes and substrates. Screening conditions were optimized and the activity of a library of 32 BM3 mutants towards the recently synthesized new probe substrate allyloxyresorufin was measured in flow-injection analysis (FIA) mode and it was shown that large activity differences between the mutants existed. Next, six BM3 mutants containing mutations at different positions in the active site were selected for which on-line enzyme kinetics were determined. Subsequently, for these six BM3 mutants affinity towards a set of 30 xenobiotics was determined in FIA EAD mode. It was demonstrated that significant differences existed for the affinity profiles of the mutants tested and that these differences correlated to alterations in the BM3 mutant-generated metabolic profiles of the drug buspirone. In conclusion, the developed FIA EAD approach is suitable to screen for diversity within BM3 mutants and this alternative screening technology offers new perspectives for rapid and sensitive screening of compound libraries towards BM3 mutants. PMID- 21297110 TI - High-throughput screening assay for sphingosine kinase inhibitors in whole blood using RapidFire(r) mass spectrometry. AB - To facilitate discovery of compounds modulating sphingosine-1-phosphate (S1P) signaling, the authors used high-throughput mass spectrometry technology to measure S1P formation in human whole blood. Since blood contains endogenous sphingosine (SPH) and S1P, mass spectrometry was chosen to detect the conversion of an exogenously added 17-carbon-long variant of sphingosine, C17SPH, into C17S1P. The authors developed procedures to achieve homogeneous mixing of whole blood in 384-well plates and for a method requiring minimal manipulations to extract S1P from blood in 96- and 384-well plates prior to analyses using the RapidFire((r)) mass spectrometry system. PMID- 21297112 TI - LOH and copy neutral LOH (cnLOH) act as alternative mechanism in sporadic colorectal cancers with chromosomal and microsatellite instability. AB - BACKGROUND AND AIMS: Tumor suppressor genes are often located in frequently deleted chromosomal regions of colorectal cancers (CRCs). In contrast to microsatellite stable (MSS) tumors, only few loss of heterozygosity (LOH) studies were performed in microsatellite instable (MSI) tumors, because MSI carcinomas are generally considered to be chromosomally stable and classical LOH studies are not feasible due to MSI. The single nucleotide polymorphism (SNP) array technique enables LOH studies also in MSI CRC. The aim of our study was to analyse tissue from MSI and MSS CRC for the existence of (frequently) deleted chromosomal regions and tumor suppressor genes located therein. METHODS AND RESULTS: We analyzed tissues from 32 sporadic CRCs and their corresponding normal mucosa (16 MSS and 16 MSI tumors) by means of 50K SNP array analysis. MSS tumors displayed chromosomal instability that resulted in multiple deleted (LOH) and amplified regions and led to the identification of MTUS1 (8p22) as a candidate tumor suppressor gene in this region. Although the MSI tumors were chromosomally stable, we found several copy neutral LOHs (cnLOH) in the MSI tumors; these appear to be instrumental in the inactivation of the tumor suppressor gene hMLH1 and a gene located in chromosomal region 6pter-p22. DISCUSSION: Our results suggest that in addition to classical LOH, cnLOH is an important mutational event in relation to the carcinogenesis of MSS and MSI tumors, causing the inactivation of a tumor suppressor gene without copy number alteration of the respective region; this is crucial for the development of MSI tumors and for some chromosomal regions in MSS tumors. PMID- 21297111 TI - Signaling via macrophage G2A enhances efferocytosis of dying neutrophils by augmentation of Rac activity. AB - Phosphatidylserine (PS) and oxidized PS species have been identified as key ligands on apoptotic cells important for their recognition and removal (efferocytosis) by phagocytes, a requisite step for resolution of inflammation. We have recently demonstrated that lysophosphatidylserine (lyso-PS) generated and retained on neutrophils following short term activation of the NADPH oxidase in vitro and in vivo enhanced their clearance via signaling through the macrophage G protein-coupled receptor G2A. Here, we investigated the signaling pathway downstream of G2A. Lyso-PS, either made endogenously in apoptosing neutrophils or supplied exogenously in liposomes along with lyso-PS(neg) apoptotic cells, signaled to macrophages in a G2A-dependent manner for their enhanced production of prostaglandin E2 (PGE2) via a calcium-dependent cytosolic phospholipase A2/cyclooxygenase-mediated mechanism. Subsequent signaling by PGE2 via EP2 receptors activated macrophage adenylyl cyclase and protein kinase A. These events, in turn, culminated in enhanced activity of Rac1, resulting in an increase in both the numbers of macrophages efferocytosing apoptotic cells and the numbers of cells ingested per macrophage. These data were surprising in light of previous reports demonstrating that signaling by PGE2 and adenylyl cyclase activation are associated with macrophage deactivation and inhibition of apoptotic cell uptake. Further investigation revealed that the impact of this pathway, either the enhancement or inhibition of efferocytosis, was exquisitely sensitive to concentration effects of these intermediaries. Together, these data support the hypothesis that lyso-PS presented on the surface of activated and dying neutrophils provides a tightly controlled, proresolution signal for high capacity clearance of neutrophils in acute inflammation. PMID- 21297113 TI - Change in abdominal obesity and risk of coronary calcification. AB - BACKGROUND: A prospective follow-up study was conducted to examine the relationship between 9 year change in abdominal obesity and risk of coronary artery calcification (CAC). METHODS: Data on coronary risk factors for 573 postmenopausal women were collected at baseline (1993-1997) and follow-up (2002-2004). At follow-up, the women underwent a multidetector CT to assess coronary calcium using the Agatston score. Markers of abdominal obesity were waist and hip circumference, waist-to-hip ratio (WHR) and body mass index. RESULTS: Compared to subjects whose waist circumference remained below the median at both occasions, those with a waist above the median had a 1.5-fold (95% CI 1.0 to 2.3) increased risk of CAC. Women whose waist rose over the 9 year period had a 2.2-fold (95% CI 1.1 to 4.2) increased risk of CAC, whereas women whose WHR became lower had a non-significant 1.5-fold increased risk of CAC (95% CI 0.7 to 3.0). In contrast, change in body mass index or hip circumference was not related to risk of CAC. CONCLUSION: This study supports the existing evidence that persistent abdominal obesity, as well as an increase in abdominal fat, relates to an increased risk of coronary atherosclerosis. PMID- 21297114 TI - Molecular breeding of polymerases for resistance to environmental inhibitors. AB - Potent inhibitors limit the use of PCR assays in a wide spectrum of specimens. Here, we describe the engineering of polymerases with a broad resistance to complex environmental inhibitors using molecular breeding of eight different polymerase orthologues from the genus Thermus and directed evolution by CSR in the presence of inhibitors. Selecting for resistance to the inhibitory effects of Neomylodon bone powder, we isolated 2D9, a chimeric polymerase comprising sequence elements derived from DNA polymerases from Thermus aquaticus, Thermus oshimai, Thermus thermophilus and Thermus brockianus. 2D9 displayed a striking resistance to a broad spectrum of complex inhibitors of highly divergent composition including humic acid, bone dust, coprolite, peat extract, clay-rich soil, cave sediment and tar. The selected polymerase promises to have utility in PCR-based applications in a wide range of fields including palaeobiology, archaeology, conservation biology, forensic and historic medicine. PMID- 21297115 TI - Thermophoretic melting curves quantify the conformation and stability of RNA and DNA. AB - Measuring parameters such as stability and conformation of biomolecules, especially of nucleic acids, is important in the field of biology, medical diagnostics and biotechnology. We present a thermophoretic method to analyse the conformation and thermal stability of nucleic acids. It relies on the directed movement of molecules in a temperature gradient that depends on surface characteristics of the molecule, such as size, charge and hydrophobicity. By measuring thermophoresis of nucleic acids over temperature, we find clear melting transitions and resolve intermediate conformational states. These intermediate states are indicated by an additional peak in the thermophoretic signal preceding most melting transitions. We analysed single nucleotide polymorphisms, DNA modifications, conformational states of DNA hairpins and microRNA duplexes. The method is validated successfully against calculated melting temperatures and UV absorbance measurements. Interestingly, the methylation of DNA is detected by the thermophoretic amplitude even if it does not affect the melting temperature. In the described setup, thermophoresis is measured all-optical in a simple setup using a reproducible capillary format with only 250 nl probe consumption. The thermophoretic analysis of nucleic acids shows the technique's versatility for the investigation of nucleic acids relevant in cellular processes like RNA interference or gene silencing. PMID- 21297116 TI - Towards more robust methods of alien gene detection. AB - Because the properties of horizontally-transferred genes will reflect the mutational proclivities of their donor genomes, they often show atypical compositional properties relative to native genes. Parametric methods use these discrepancies to identify bacterial genes recently acquired by horizontal transfer. However, compositional patterns of native genes vary stochastically, leaving no clear boundary between typical and atypical genes. As a result, while strongly atypical genes are readily identified as alien, genes of ambiguous character are poorly classified when a single threshold separates typical and atypical genes. This limitation affects all parametric methods that examine genes independently, and escaping it requires the use of additional genomic information. We propose that the performance of all parametric methods can be improved by using a multiple-threshold approach. First, strongly atypical alien genes and strongly typical native genes would be identified using conservative thresholds. Genes with ambiguous compositional features would then be classified by examining gene context, including the class (native or alien) of flanking genes. By including additional genomic information in a multiple-threshold framework, we observed a remarkable improvement in the performance of several popular, but algorithmically distinct, methods for alien gene detection. PMID- 21297117 TI - The RNA annealing mechanism of the HIV-1 Tat peptide: conversion of the RNA into an annealing-competent conformation. AB - The annealing of nucleic acids to (partly) complementary RNA or DNA strands is involved in important cellular processes. A variety of proteins have been shown to accelerate RNA/RNA annealing but their mode of action is still mainly uncertain. In order to study the mechanism of protein-facilitated acceleration of annealing we selected a short peptide, HIV-1 Tat(44-61), which accelerates the reaction efficiently. The activity of the peptide is strongly regulated by mono- and divalent cations which hints at the importance of electrostatic interactions between RNA and peptide. Mutagenesis of the peptide illustrated the dominant role of positively charged amino acids in RNA annealing--both the overall charge of the molecule and a precise distribution of basic amino acids within the peptide are important. Additionally, we found that Tat(44-61) drives the RNA annealing reaction via entropic rather than enthalpic terms. One-dimensional-NMR data suggest that the peptide changes the population distribution of possible RNA structures to favor an annealing-prone RNA conformation, thereby increasing the fraction of colliding RNA molecules that successfully anneal. PMID- 21297118 TI - Purification and characterization of a novel and unique ginsenoside Rg1 hydrolyzing beta-D-glucosidase from Penicillium sclerotiorum. AB - In this paper, a novel and unique ginsenoside Rg(1)-hydrolyzing beta-D glucosidase from Penicillium sclerotiorum was isolated, characterized, and generally described. The beta-glucosidase is an ~180 kDa glycoprotein with pI 6.5, and consists of four identical subunits of ~40 kDa. The beta-glucosidase was active in a narrow pH range (4-5) and at relatively high temperature (60-70 degrees C). The optimal activity against p-nitrophenyl-beta-D-glucopyranoside (pNPG) was as follows: pH 4.5 and temperature 65 degrees C. Under these conditions, the K(m) of the enzyme was 0.715 mM with a V(max) of 0.243 mmol nitrophenol/min mg. Metal ions such as Ba(2+), K(+), Fe(3+), and Co(2+) significantly promoted the enzymatic activity, while Ca(2+), Mg(2+), and Ag(+) inhibited its activity. Of the tested substrates, only ginsenoside Rg(1) could be specifically hydrolyzed by the beta-glucosidase at the C6-glucoside to form the rare ginsenoside F(1). These properties were novel and different from those of other previously described glycosidases. PMID- 21297119 TI - Isolation, functional, and partial biochemical characterization of galatrox, an acidic lectin from Bothrops atrox snake venom. AB - Snake venom lectins have been studied in regard to their chemical structure and biological functions. However, little is known about lectins isolated from Bothrops atrox snake venom. We report here the isolation and partial functional and biochemical characterization of an acidic glycan-binding protein called galatrox from this venom. This lectin was purified by affinity chromatography using a lactosyl-sepharose column, and its homogeneity and molecular mass were evaluated by high-performance liquid chromatography, sodium dodecyl sulfate polyacrylamide gel electrophoresis, and matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry. The purified galatrox was homogeneous and characterized as an acidic protein (pI 5.2) with a monomeric and dimeric molecular mass of 16.2 and 32.5 kDa, respectively. Alignment of N terminal and internal amino acid sequences of galatrox indicated that this protein exhibits high homology to other C-type snake venom lectins. Galatrox showed optimal hemagglutinating activity at a concentration of 100 MUg/ml and this effect was drastically inhibited by lactose, ethylenediaminetetraacetic acid, and heating, which confirmed galatrox's lectin activity. While galatrox failed to induce the same level of paw edema or mast cell degranulation as B. atrox crude venom, galatrox did alter cellular viability, which suggested that galatrox might contribute to venom toxicity by directly inducing cell death. PMID- 21297120 TI - Clinicopathological outcomes of clinical T1a renal cell carcinoma by tumor size. AB - OBJECTIVE: We performed a retrospective review of clinical T1a renal cell carcinoma patients treated in our institution. The clinicopathological findings and patients' prognoses were analyzed according to tumor size, and risk factors for tumor recurrence were elucidated. METHODS: A total of 140 cases of sporadic renal cell carcinoma with a diameter of 4 cm or less on computed tomography findings for preoperative evaluation were treated as clinical T1a. Patients underwent radical nephrectomy or nephron-sparing surgery, and were evaluated postoperatively every 3-6 months to screen for metastatic disease. Patients' medical records were reviewed retrospectively and the status of each patient was assessed. RESULTS: There were four cases of clinically metastatic disease at diagnosis. There were no correlations between tumor size and pathological stage, Fuhrman nuclear grade or histological type. The rate of cases with microvascular invasion on pathological findings increased according to tumor diameter. Disease recurrence occurred in six patients (5.7%) during a mean postoperative follow-up of 41.7 months. There was a significant difference in the recurrence-free rate between pT1a patients with a tumor diameter of 31 mm or more and other patient groups. In terms of microvascular invasion on histological findings, the probability of non-recurrence at 7 years was 0% for patients with and 92.9% for those without microvascular invasion. CONCLUSIONS: Among T1a renal cell carcinoma, tumors over 30 mm in diameter may have aggressive biological potential, possibly due to microvascular invasion. Long-term follow-up is needed for these tumors. PMID- 21297121 TI - A study using ifosfamide and etoposide in patients with cisplatin-refractory recurrent or metastatic head and neck squamous cell carcinoma. AB - OBJECTIVE: To investigate the efficacy and safety of combination therapy with ifosfamide and etoposide in cisplatin-refractory recurrent/metastatic squamous cell carcinoma of the head and neck. METHODS: Thirty patients with cisplatin refractory recurrent/metastatic squamous cell carcinoma of the head and neck were treated with ifosfamide (1000 mg/m(2)/day) as a continuous 24 h infusion for 3 days and etoposide (100 mg/m(2)/day) as a bolus 1 h infusion on the same 3 days. The treatment was repeated every 4 weeks until disease progression. RESULTS: The overall rate of response was 27% (8/30), and 20% (6/30) of the patients achieved stable disease status. Median overall survival was 7.7 months. Subgroup analysis demonstrated significant improvement in overall survival in the group that achieved control of disease. Thirteen (43.3%) patients developed grade 3-4 neutropenia, and five (16.6%) developed grade 3-4 non-hematologic mucositis. CONCLUSIONS: This combination chemotherapy had an effective and safe profile and improved survival in patients with cisplatin-refractory recurrent/metastatic squamous cell carcinoma of the head and neck who achieved disease control. PMID- 21297122 TI - The effects of androgen deprivation therapy on lipid metabolism and body composition in Japanese patients with prostate cancer. AB - OBJECTIVE: In Japan, androgen deprivation therapy is employed as the primary therapy for prostate cancer in more than 50% of patients, which is a percentage larger than that in the USA. The adverse effects of androgen deprivation therapy on body composition and lipid profile associated with metabolic syndrome have been reported mainly in Caucasian populations, and few studies have been performed in East Asian populations, including Japanese. METHODS: This study enrolled 39 Japanese patients who were starting to receive androgen deprivation therapy for prostate cancer. Subjects were evaluated at baseline and at 3, 6, 9 and 12 months. Body composition and lipid profiles were measured by bioelectrical impedance analysis and using blood samples, respectively. RESULTS: The volume of fat and visceral fat was significantly increased 6 months after the treatment and continued to increase until 12 months. On the other hand, skeletal muscle was significantly decreased during the same period. The serum concentration of total cholesterol and low-density lipoprotein cholesterol increased significantly over the same period. CONCLUSIONS: Androgen deprivation therapy changed the body composition and lipid profile of men with prostate cancer. It was demonstrated that even Japanese patients with prostate cancer who are treated with androgen deprivation therapy have the risk of developing metabolic syndrome. PMID- 21297123 TI - Nitric oxide delays atrial tachycardia-induced electrical remodelling in a sheep model. AB - AIMS: Rapid atrial pacing for 1 week leads to decreased expression of endocardial nitric oxide (NO)-synthase and decreased NO concentrations. We hypothesized that increasing NO bioavailability may reduce electrical remodelling induced by atrial tachycardia. METHODS AND RESULTS: We examined the effect of molsidomine, a NO donor, and N(omega)-nitro-l-arginine methylester (l-NAME), a NO-synthase inhibitor, on electrical remodelling occurring during 4 h of rapid atrial pacing in sheep. Haemodynamic and electrophysiological parameters were measured at baseline, 1 h after the start of the infusion and before the start of pacing, and 2 and 4 h after pacing. We measured the effect of molsidomine on atrial monophasic action potentials (MAPs) in non-instrumented sheep and on l-type Ca(2+) currents and intracellular Ca(2+) concentration ([Ca(2+)](i)) transients in right atrial cells, isolated from control sheep. In control sheep, rapid atrial pacing shortened the atrial effective refractory period (AERP) by 12 +/- 0.18% after 4 h, an effect that was unaffected by l-NAME. Infusion of molsidomine increased AERP at baseline (+13.4 +/- 1.04%) and transiently attenuated pacing induced AERP shortening (13.6 +/- 0.1% at 2 h). Molsidomine tended to increase MAP duration by 20.7 +/- 13.4 ms. Incubation of isolated atrial myocytes with NO donor 3-morpholino-sydnonimine (SIN-1) increased significantly l-type Ca(2+) current and [Ca(2+)](i) transients. CONCLUSION: Infusion of molsidomine, a NO donor, delayed shortening of the action potential during short-term rapid atrial pacing, by increasing [Ca(2+)](i). Whereas the former could be protective against repetitive short episodes of atrial fibrillation, the latter might be detrimental in the long term. PMID- 21297124 TI - Catecholamine-dependent wide QRS complex tachycardia in a 71-year-old male 'super athlete'. AB - Recent studies have suggested an association between increased athletic activity and atrial arrhythmias; however, the mechanism remains unclear. Presented herein is a 71-year-old man with atrial flutter with 1:1 atrioventricular (AV) conduction triggered by high-intensity exercise as well as administration of isoproterenol, suggesting that arrhythmia is autonomically mediated. PMID- 21297125 TI - MR diffusion tensor and perfusion-weighted imaging in preoperative grading of supratentorial nonenhancing gliomas. AB - We evaluate the value of MR diffusion tensor imaging (DTI) and dynamic susceptibility-weighted contrast material-enhanced perfusion-weighted imaging (PWI) in preoperative grading of supratentorial nonenhancing gliomas. This institutional review board-approved, Health Insurance Portability and Accountability Act-compliant retrospective study involved 52 patients: 37 with low-grade gliomas (LGGs) and 15 with high-grade gliomas (HGGs). The mean trace apparent diffusion coefficient (ADC), minimal ADC, mean fractional anisotropy (FA), maximal FA, and maximal relative cerebral blood volume (rCBV) ratio of the lesions were measured and compared between LGG and HGG. The efficacy of the above parameters in grading supratentorial nonenhancing gliomas was evaluated. There was no significant difference in rCBV ratio, minimal ADC, and mean ADC between LGG and HGG (p > 0.05). The mean and maximal FA values of LGG were significantly lower than the values of HGG (p < 0.001). The receiver operating characteristic analysis showed that the mean FA with a cutoff value of 0.129 and the maximal FA with a cutoff value of 0.219 could differentiate between LGG and HGG with specificity of 69.2% and 76.9%, respectively, and sensitivity of 93.3% and 100.0%, respectively. The combination of mean FA and maximal FA based on the linear discriminant analysis improved the diagnostic accuracy with specificity of 92.3% and sensitivity of 86.7%. These findings were better than maximal rCBV ratio, mean ADC, and minimum ADC. The mean FA and maximal FA, used individually or combined, may be useful in preoperative grading of supratentorial nonenhancing gliomas. PMID- 21297126 TI - MRI as a central component of clinical trials analysis in brainstem glioma: a report from the Pediatric Brain Tumor Consortium (PBTC). AB - We report MRI findings from 2 pediatric clinical trials of diffuse intrinsic brainstem glioma (BSG) incorporating concurrent radiation therapy (RT) with molecularly targeted agents (gefitinib and tipifarnib). We determined associations of MRI variables with progression-free survival and overall survival and investigated effects of treatment on these variables. MRI (including diffusion and perfusion) was done before treatment, every 8 weeks (first year), every 12 weeks (thereafter), and at the end of treatment or disease progression. Reduced tumor volume (P < .0001) and tumor diffusion values (P <.0001) were apparent on the first post-RT/drug studies. Decreases in tumor volume correlated with pre-RT volume (P < .0001) and pre-RT diffusion values (P < .0001); larger decreases were noted for tumors with higher volumes and diffusion values. Patients with larger pre-RT tumors had longer progression-free survival (P < .0001). Patients with >= 25% decrease in tumor volume and diffusion values after RT had longer progression-free survival (P = .028) and overall survival (P = .0009). Enhancement at baseline and over time was significantly associated with shorter survival. Tumor diffusion values with baseline enhancement were significantly lower than those without (P = .0002). RT of BSG is associated with decreased tumor volume and intralesional diffusion values; patients with >= 25% decrease in values post-RT had relatively longer survival intervals, apparently providing an early imaging-based surrogate for relative outcomes. Patients with larger tumors and greater decreases in tumor volume and diffusion values had longer survival intervals. Tumor enhancement was associated with shorter survival, lower tumor diffusion values (increased cellularity), and a smaller drop in diffusion values after RT (P = .006). These associations justify continued investigation in other large clinical trials of brainstem glioma patients. PMID- 21297127 TI - A phase II study evaluating the efficacy and safety of AMG 102 (rilotumumab) in patients with recurrent glioblastoma. AB - This phase II study evaluated the efficacy and safety of AMG 102 (rilotumumab), a fully human monoclonal antibody against hepatocyte growth factor/scatter factor (HGF/SF), in patients with recurrent glioblastoma (GBM). Patients with histologically confirmed, measurable recurrent GBM or gliosarcoma (World Health Organization grade 4) and <=3 relapses or prior systemic therapies received AMG 102 (10 or 20 mg/kg) by infusion every 2 weeks. The primary endpoint was best confirmed objective response rate (central assessment) per Macdonald criteria. Of the 61 patients who enrolled, 60 received AMG 102. Twenty-nine patients (48%) had previously received bevacizumab. There were no objective responses per central assessment, but 1 patient had an objective response per investigator assessment. Median overall survival (95% CI) in the 10- and 20-mg/kg cohorts was 6.5 months (4.1-9.8) and 5.4 months (3.4-11.4), respectively, and progression-free survival (PFS) per central assessment was 4.1 weeks (4.0-4.1) and 4.3 weeks (4.1-8.1), respectively. PFS was similar among patients who had previously received bevacizumab compared with bevacizumab-naive patients. The most common adverse events were fatigue (38%), headache (33%), and peripheral edema (23%). AMG 102 serum concentrations increased approximately dose-proportionally with 2-fold accumulation at steady state. Plasma total HGF/SF and soluble c-Met concentrations increased 12.05- and 1.12-fold, respectively, from baseline during AMG 102 treatment. AMG 102 monotherapy at doses up to 20 mg/kg was not associated with significant antitumor activity in heavily pretreated patients with recurrent GBM. PMID- 21297128 TI - Serial analysis of imaging parameters in patients with newly diagnosed glioblastoma multiforme. AB - The objective of this study was to test the predictive value of serial MRI data in relation to clinical outcome for patients with glioblastoma multiforme (GBM). Sixty-four patients with newly diagnosed GBM underwent conventional MRI and diffusion-weighted and perfusion-weighted imaging postsurgery and prior to radiation/chemotherapy (pre-RT), immediately after RT (post-RT), and every 1-2 months thereafter until tumor progression, up to a maximum of 1 year. Tumor volumes and perfusion and diffusion parameters were calculated and subject to time-independent and time-dependent Cox proportional hazards models that were adjusted for age and MR scanner field strength. Larger volumes of the T2 hyperintensity lesion (T2ALL) and nonenhancing lesion (NEL) at pre-RT, as well as increased anatomic volumes at post-RT, were associated with worse overall survival (OS). Higher normalized cerebral blood volumes (nCBVs), normalized peak height (nPH) and normalized recirculation factors (nRF) at pre-RT, and nCBV at post-RT, in the T2ALL and NEL, were associated with shorter progression-free survival (PFS). From pre- to post-RT, there was a reduction in nCBV and nPH and an increase in apparent diffusion coefficient (ADC). Patients with lower nRF values at pre-RT, or a larger increase in nRF from pre-RT to post-RT, had significantly longer PFS. Time-dependent analysis showed that patterns of changes in ADC and anatomic volumes were associated with OS, while changes in nCBV, nPH, and the contrast-enhancing volume were associated with PFS. Our studies suggest that quantitative MRI variables derived from anatomic and physiological MRI provide useful information for predicting outcome in patients with GBM. PMID- 21297129 TI - Myocardial ischaemia and viability: the pivotal role of echocardiography. AB - Echocardiography has a central role for the diagnosis and management of patients with known or suspected coronary artery disease. Besides the fact that it provides an essential role in the differential diagnosis of patients presenting with chest pain in the emergency department, echocardiography provides a comprehensive non-invasive haemodynamic and functional assessment of those patients. Stress echocardiography in many institutions is now the preferred stress modality associated with imaging as it is cost-effective and does not use ionizing radiation. It is used for assessing patients with known or suspected coronary artery disease, risk stratification and for assessing myocardial viability. The recent introductions of ultrasound contrast agents as well as deformation imaging techniques have eliminated the last limitations of stress echocardiography such as image quality and quantification, respectively. PMID- 21297130 TI - Locus coeruleus damage and noradrenaline reductions in multiple sclerosis and experimental autoimmune encephalomyelitis. AB - The endogenous neurotransmitter noradrenaline exerts anti-inflammatory and neuroprotective effects in vitro and in vivo. Several studies report that noradrenaline levels are altered in the central nervous system of patients with multiple sclerosis and rodents with experimental autoimmune encephalomyelitis, which could contribute to pathology. Since the major source of noradrenaline are neurons in the locus coeruleus, we hypothesized that alterations in noradrenaline levels are a consequence of stress or damage to locus coeruleus neurons. In C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein peptide 35-55 to develop chronic disease, cortical and spinal cord levels of noradrenaline were significantly reduced versus control mice. Immunohistochemical staining revealed increased astrocyte activation in the ventral portion of the locus coeruleus in immunized mice. The immunized mice showed neuronal damage in the locus coeruleus detected by a reduction of average cell size of tyrosine hydroxylase stained neurons. Analysis of the locus coeruleus of multiple sclerosis and control brains showed a significant increase in astrocyte activation, a reduction in noradrenaline levels, and neuronal stress indicated by hypertrophy of tyrosine hydroxylase stained cell bodies. However, the magnitude of these changes was not correlated with extent of demyelination or of cellular infiltrates. Together these findings demonstrate the presence of inflammation and neuronal stress in multiple sclerosis as well as in experimental autoimmune encephalomyelitis. Since reduced noradrenaline levels could be permissive for increased inflammation and neuronal damage, these results suggest that methods to raise noradrenaline levels or increase locus coeruleus function may be of benefit in treating multiple sclerosis. PMID- 21297131 TI - Blood flow measurements within optic nerve head during on-pump cardiovascular operations. A window to the brain? AB - This observational study is conducted to demonstrate optic nerve head (ONH) blood flow alterations during extracorporeal circulation (ECC) in routine on-pump cardiovascular operations in order to evaluate the perfusion status of important autoregulatory tissue vascular beds during moderate hypothermia. Twenty-one patients free from eye disease were prospectively enrolled in our database. Perioperative ONH blood flow measurements were performed using a hand-held portable ocular laser Doppler flowmeter just after administration of general anesthesia and during cardiopulmonary bypass (CPB) upon the lowest temperature point of moderate hypothermia. Important operative flow variables were correlated to optic nerve blood flow during surgical phases. Statistical analysis showed significant reduction of 32.1 +/- 14.5% of mean ONH blood flow in phase 2 (P < 0.0001) compared to the reference flow values of phase 1. A negative univariate association between ECC time and ONH blood flow in phase 2 (P = 0.031) is noted. This angiokinetic approach can detect changes of flow within autoregulatory vascular tissue beds like ONH, thus creating a 'window' on cerebral microvasculature. ONH blood flow is reduced during CPB. Our data suggest that it is of paramount importance to avoid extracorporeal prolongation even in moderate hypothermic cardiovascular operations. PMID- 21297132 TI - Should double lung transplant be performed with or without cardiopulmonary bypass? AB - A best evidence topic in cardiothoracic surgery was written according to a structured protocol. The question addressed was whether double lung transplantation should be performed with or without cardiopulmonary bypass (CPB) in order to improve postoperative clinical outcomes. Altogether 386 papers were found using the reported search, of which 14 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. All 14 papers assessed a range of postoperative outcomes and broadly speaking, six papers found significantly worse outcomes with CPB use, six found no difference and two found a mixture of both depending on the specific outcomes assessed. Dalibon et al. [J Cardiothorac Vasc Anesth 2006;20:668-672] found that mortality was significantly worse in the CPB group at 48 h, one month and one year [P = 0.001, odds ratio (OR) = 246.1; P = 0.083, OR = 2.6; P = 0.001, OR = 5.3, respectively]. Other papers revealed poor outcomes in the CPB group in a range of measures including diffuse alveolar damage (P = 0.009), chest radiograph infiltrate score (P = 0.005), longer intubation time (P = 0.002), longer intensive care unit stay (P = 0.05), and greater incidence of pulmonary reimplantation response (P = 0.03). However, Myles et al. [J Cardiothorac Vasc Anesth 1997;11:177-183] found that only acute postoperative outcomes were significantly worse in their CPB group (P < 0.001); medium- and long-term survival outcomes were not significantly different (P = 0.055). de Boer et al. [Transplantation 2002;73:1621-1627] even found that there was an improved one-year survival rate with CPB use (OR = 0.25, P = 0.038) and that the number of human leukocyte antigen DR (HLA-DR) mismatches influenced this effect. Those papers suggesting no deleterious effects of CPB generally measured similar postoperative outcomes to those mentioned above, with one study also assessing incidence of primary graft failure, which was not significantly different (P = 0.37). We conclude that CPB should continue to be used where clinically indicated for a specific reason (for example, where there is pulmonary hypertension or a requirement for concomitant cardiac repair). However, given that the evidence for using CPB for all elective cases is relatively weak, and the fact that there are strong arguments in the literature for both methods, either approach would be clinically acceptable. PMID- 21297133 TI - Mediastinal hibernoma presenting with hoarseness. AB - Hibernoma is an unusual benign soft tissue tumor derived from a specialized form of brown fat. A case of a 52-year-old female who was admitted with a slowly worsening hoarseness is presented. Further investigation revealed a left upper mediastinal mass next to the aortic arch. Upon surgical exploration a soft encapsulated mass was identified. Pathology was consistent with hibernoma. Despite their benign behavior, some variants of hibernoma can be confused histologically with liposarcoma. Therefore, long-term follow-up is advisable. PMID- 21297134 TI - Migrating foreign body in mediastinum--intravascular Steinman pin. AB - We report a case of migration of a Steinman pin to the innominate vein. A pin was used to fix a shoulder separation but a broken piece was left unattended at the time of removal of the pin. How this piece made its way in to innominate vein is puzzling. To our knowledge migration of fixation wires to the innominate vein has not been reported previously. PMID- 21297135 TI - Validation of pN2 sub-classifications in patients with pathological stage IIIA N2 non-small cell lung cancer. AB - Optimal surgical treatment for patients with stage IIIA N2 non-small cell lung cancer (NSCLC) remains a matter of debate, because of the outcomes. The outcomes may be affected from variations in patterns of lymph node metastasis. As the patterns of lymph node sub-classifications, multiple station metastases of mediastinal lymph nodes (MN2), highest metastasis of the mediastinal lymph nodes (HM), distribution of metastatic nodes (skip N2 or non-skip N2), and clinical (c ) N factor have been cited. We investigated these factors for patients with pathological stage IIIA (pIIIA) N2 NSCLC. We reviewed 121 consecutive patients with pIIIA N2 who underwent complete resection. Age, gender, tumor laterality, histology, lobe location of the tumor, c-T factor, pathological (p-) T factor, c N factor, MN2, HM and skip N2 condition were used as prognostic variables. Overall five-year survival rate was 41.8%. Based on log-rank testing, c-T factor (P = 0.022), p-T factor (P = 0.0002), c-N factor (P = 0.009), HM (P = 0.019) and skip N2 (P = 0.030) were identified as significantly prognostic. Using these variables, p-T factor, c-N factor and skip N2 showed significance and independence on Cox multivariate analysis. The sub-classification of lymph node metastasis in patients with p-stage IIIA N2 NSCLC has clinical implications for the prognosis. PMID- 21297136 TI - Novel approach for talc pleurodesis by dedicated catheter through flexi-rigid thoracoscope under local anesthesia. AB - For pleurodesis, talc administered by poudrage is usually insufflated blindly from a single port of entry using the standard method with a small-diameter rigid thoracoscope. In order to visually perform talc poudrage from a single port, we introduced a catheter technique through a flexi-rigid thoracoscope. Patients with uncontrolled and symptomatic pleural effusion requiring pleurodesis underwent flexi-rigid thoracoscopy under local anesthesia for talc poudrage. A dedicated catheter with 2.1-mm inner diameter was connected to a talc atomizer and inserted through the working channel of the flexi-rigid thoracoscope to insufflate talc into the pleural cavity under visualization. Nine patients were included in this study. Three patients were >75 years old, and two were Karnofsky performance status 50. Three patients received propofol for sedation and six were not sedated. Mean operative time was 30.8 min for all patients, and 21.3 min for cases without sedation. All procedures were performed easily under clear visualization with no major complications or catheter obstructions. This novel approach for talc pleurodesis using a catheter was well-tolerated and seems feasible for patients with uncontrolled pleural effusion. We consider this technique useful even for difficult cases, such as elderly patients or those with relatively low performance status. PMID- 21297137 TI - Surgical treatment of non-small cell lung cancer in octogenarians. AB - As the European population ages, surgeons are regularly faced with octogenarians with resectable early stage non-small cell lung cancer (NSCLC). We compared our experience with those reported in the literature to comprehend the feasibility, outcomes and lessons learned regarding surgical treatment. We reviewed octogenarians who underwent lung resection for NSCLC in the past nine years in our Department. The purpose of this paper is to retrospectively analyse postoperative surgical and oncological outcomes of our series, trying to find possible correlations between mortality, morbidity, survival and preoperative oncological and functional assessment, surgical approach and extent of resection. Eighty-two patients (M/F = 63/19), with a mean age 81.0 years (range 80-87 years) underwent lung resection for NSCLC: 63 lobectomies, one inferior bilobectomy, three segmentectomies, and 15 wedge resections. There were two perioperative deaths (2.4%). The overall complication rate was 30.0%, with a major complication rate of 2.5%. Actuarial cancer-related survival rates at one, three and five years were 90%, 44% and 36%, respectively, with a statistically-significant correlation with pathological stage. Octogenarians may benefit from surgical treatment of NSCLC with an acceptable morbidity and mortality rate, if an accurate preoperative selection is pursued. PMID- 21297138 TI - Serum markers are not reliable measures of renal function in conjunction with cardiopulmonary bypass. AB - The present study explored the influence of haemodilution on estimates of the glomerular filtration rate (GFR) in conjunction with cardiopulmonary bypass (CPB) and cardiac surgery. Ninety-eight patients (n = 98) undergoing coronary artery bypass grafting with the aid of CPB were examined. The serum concentration of cystatin C and creatinine was analysed prior to surgery, after completion of CPB and in the intensive care the day after surgery. The estimated GFR was calculated using standard equations based on the serum concentration of cystatin C and creatinine. It was found that haemodilution induced by CPB had significant effects on the estimated GFR. For cystatin C, the GFR increased by 50.5 +/- 2.5 ml/min (P = 0.000) and for creatinine based GFR with 22.5 +/- 0.9 ml/min (P = 0.000) using the 4-variable modification of diet renal disease formula and with 22.1 +/- 0.93 ml/min (P = 0.000) for the Cockcroft-Gault formula, respectively. Similar effects of haemodilution on GFR were also detected postoperatively. Haemodilution induced by CPB may therefore significantly overestimate the renal function as indicated by GFR based on serum markers. PMID- 21297139 TI - Stenting of the descending thoracic aorta: a six-year single-center experience. AB - OBJECTIVES: The aim of this study was to review the six-year results of the endovascular repair of descending thoracic aortic pathologies, reporting the early perioperative outcomes as well as the mid-term follow-up of the treated patients. METHODS: Fifty-five consecutive patients who underwent endovascular repair for thoracic aortic pathology (32 aneurysms, 17 acute thoracic aortic syndromes, and six traumatic aortic ruptures) during a six-year period were retrospectively reviewed. From these patients, 30 (54.5%) were treated electively and 25 (45.5%) on an emergency basis. In eight cases (14.5%) there was a need for left subclavian artery orifice overstenting. In seven patients (12.7%) an abdominal aortic lesion was simultaneously treated, while three more patients (5.5%) had previously had their abdominal aortic aneurysm repaired. RESULTS: The primary technical success was 92.7%. Seven patients (12.7%) underwent some operation related complication, while postoperative complications occurred in five patients (9.1%), namely four myocardial infarctions, one acute respiratory distress syndrome and two delayed parapareses resulting in an overall incidence of neurological complications of 3.6%. The combined 30-day and in-hospital mortality was 9.1%, exclusively related to patients treated emergently (P = 0.01). In a mean follow-up period of 34 months there were six deaths, and the overall cumulative survival at four years was estimated at 72.6%. Only one type II endoleak was observed one month after the procedure and it spontaneously disappeared 18 months later. CONCLUSIONS: The endovascular repair of descending thoracic aortic pathologies seems to be a well-established method, with favorable morbidity and mortality rates, at least for 30 days and in the mid-term. Taking into account the potential of a wide application of the endovascular technique in many vascular centers, stenting of the thoracic aorta might offer an overall better solution for patients suffering from these devastating pathologies. PMID- 21297140 TI - A more conservative technique for anterior mediastinal tracheostomy after sub total resection of the trachea. AB - Anterior mediastinal tracheostomy (AMT) is a rare but challenging operation associated with a high morbidity and mortality rate mainly related to the invasiveness of the procedure. In order to provide a more conservative technique with a lower risk of major postoperative complications, we proposed: (1) to reduce the extent of chest wall resection to only a trapezoidal segment of the manubrium; (2) to use a simple pedicle pectoralis major flap instead of myocutaneous or omental flaps; and (3) to perform a simple relocation of the residual trachea (RT) below the brachiocephalic artery instead of artery ligation, percutaneous stent placement or replacement by cadaveric allograft. This technique was used in a patient with cancer recurrence at the cervical stoma after total laryngectomy. Despite a short 2.5-cm RT, it was possible to perform AMT without any tension at the mediastinal stoma. Postoperative course showed only regressive minor complications. There was no late complication related to the procedure with a one-year follow-up. This more conservative technique for AMT could be used as an alternative to previously described procedures in order to reduce postoperative complications and mortality rate after sub-total resection of the trachea. PMID- 21297141 TI - Rib chondrosarcoma with intramedullary progression completely resected by magnetic resonance imaging: useful short inversion time inversion recovery sequence. AB - Chondrosarcoma is the second most common bone sarcoma, for which complete resection is the only effective treatment. Herein, we report a case of completely resected rib chondrosarcoma protruding through the bone marrow. An intramedullary lesion was revealed with magnetic resonance imaging using short inversion time inversion recovery sequence (STIR-MRI), but was not depicted by computed tomography. STIR-MRI is highly sensitive for the detection of bone tumors due to the suppression of peritumoral soft tissue signals, and is critical for radical resection of chondrosarcoma. PMID- 21297142 TI - Three-dimensional transesophageal echocardiography: diagnosing intraoperative pulmonary artery thrombus. AB - A 61-year-old patient with the diagnosis of acute heart failure based on severe mitral valve insufficiency due to chordae rupture was scheduled for surgery. Intraoperatively, a standard two-dimensional transesophageal echocardiogram (2D TEE) examination, revealed severe mitral valve regurgitation due to a prolaps with chordal rupture and an echo dense structure in the pulmonary artery (PA). Because it was not possible to visualize this echo dense structure fully with 2D TEE we performed a three-dimensional transesophageal echocardiogram (3D-TEE). On the basis of the clear demonstration on 3D-TEE of an at least 6-cm thrombus in the PA we decided to remove the thrombus prior to proceeding with the mitral valve repair. We conclude that 3D-TEE can alter surgical management and provide more valuable information on PA thrombus than that obtained by 2D-TEE. PMID- 21297143 TI - An intra-parenchymal pulmonary lipoma with a high activity on positron emission tomography scan. AB - Benign pulmonary tumours are a less frequent differential diagnosis of the more common malignant pulmonary tumours. They usually present in the younger age groups and are almost invariably inactive on positron emission tomography (PET) studies. We report a unique case of peripheral pulmonary lipoma in an 81-year-old female which showed increased activity on PET. PMID- 21297144 TI - Preoperative B-type natriuretic peptide, and not the inflammation status, predicts an adverse outcome for patients undergoing heart surgery. AB - OBJECTIVES: B-type natriuretic peptide (BNP) and inflammatory markers are implicated in the pathophysiology of both ischemic cardiomyopathy and complications after cardiac surgery with cardiopulmonary bypass (CPB). The purpose of this study was to assess preoperative and postoperative levels of BNP, interleukin-6 (IL-6), interleukin-8 (IL-8), P-selectin, intercellular adhesion molecule (ICAM), C-reactive protein (CRP) in patients undergoing cardiac surgery with CPB and investigate their variation and ability to correlate with immediate outcome. METHODS: Plasma levels of these markers were measured preoperatively, 6 and 24 h after CBP in 62 patients. Main endpoints were requirements for intra aortic balloon pump, intensive care unit (ICU) stay longer than five days, ventilator dependence >24 h, requirement for dobutamine, hospital stay >10 days, clinical complications (infection, myocardial infarction, renal failure, stroke and ventricular arrhythmias) and in-hospital mortality. RESULTS: Preoperative BNP levels correlate with longer ICU stay (P = 0.003), longer ventilator use (P = 0.018) and duration of dobutamine use (P < 0.001). The receiver-operating characteristic curve demonstrated BNP levels >190 pg/ml as predictor of ICU >5 days and BNP levels >20.5 pg/ml correlated with dobutamine use, with areas under the curve of 0.712 and 0.842, respectively. Preoperative levels of ICAM-1 were associated with in-hospital mortality (P = 0.042). In the postoperative period, was found association between CRP, IL-6 and P-selectin with ventilation duration (P = 0.013, P = 0.006, P < 0.001, respectively) and P-selectin with ICU stay (P = 0.009). CONCLUSIONS: BNP correlates with clinical endpoints more than inflammatory markers and can be used as a predictor of early outcome after heart surgery. PMID- 21297145 TI - Robotic total endoscopic coronary artery bypass hybrid revascularization procedure in a patient with a preoperative tracheostoma. AB - Preoperative tracheostoma presents a significant risk of sternal wound complications, mediastinitis, stoma necrosis and tracheal injury in patients requiring cardiac surgery. Several approaches have been described to limit these risks. Robotic totally endoscopic coronary artery bypass grafting in patients with a tracheostoma has not been reported. We describe a case of completely endoscopic coronary surgery using the daVinci((r)) SiTM system in a patient with a tracheostoma. Single left internal mammary artery grafting to the left coronary artery system was carried out successfully as the first stage of a hybrid revascularization and followed by percutaneous coronary intervention to the circumflex coronary artery. We regard this technique as the most minimally invasive method of surgical coronary revascularization with a significant potential to reduce the risk of mediastinitis in patients with a tracheostoma. PMID- 21297146 TI - Double-patch sandwich repair for left ventricular free wall rupture. AB - We present a case of a patient with left ventricular free wall rupture who successfully underwent emergency surgical repair using the double-patch sandwich technique. This technique has already been used for the treatment of left ventricular aneurysm and retains the proper shape and size of the left ventricle. Multislice computed tomography was fast and non-invasive in the detection of a ventricular rupture. PMID- 21297147 TI - Relapse of giant cell myocarditis supported with veno-arterial extracorporeal membrane oxygenation. AB - Giant cell myocarditis (GCM) is a fatal form of myocarditis that often presents with acute heart failure. An inflammatory infiltrate with giant cells and myocardial necrosis is characteristic. During the acute presentation, mechanical circulatory support may be necessary for hemodynamic support while immunosuppression is initiated. We report a case of GCM relapse which was supported with veno-arterial membrane oxygenation until recovery. The patient is doing well one year after explantation. PMID- 21297148 TI - The use of cell salvage in routine cardiac surgery is ineffective and not cost effective and should be reserved for selected cases. AB - The reported benefits of intraoperative cell salvage are decreased requirement for blood transfusion and cost-effectiveness. This study was designed to challenge this hypothesis. We assessed intraoperative blood loss and the use of cell saver in our institution. In <7% of cases the volume of blood loss was sufficient enough to be washed and returned. We conclude that the routine use of cell savers in all cardiac operations affords no benefit and consumes additional revenue. We recommend that the system only be considered in selected high-risk cases or complex procedures. PMID- 21297149 TI - Early pericalcarine atrophy in acute optic neuritis is associated with conversion to multiple sclerosis. AB - BACKGROUND: Previous work showed that pericalcarine cortical volume loss is evident early after presentation with acute clinically isolated optic neuritis (ON). The aims of this study were: (1) to determine whether pericalcarine atrophy in patients with ON is associated with conversion to multiple sclerosis (MS); (2) to investigate whether regional atrophy preferentially affects pericalcarine cortex; and (3) to investigate potential causes of early pericalcarine atrophy using MRI. METHODS: 28 patients with acute ON and 10 controls underwent structural MRI (brain and optic nerves) and were followed-up over 12 months. Associations between the development of MS, optic nerve, optic radiation and pericalcarine cortical damage measures were investigated using multiple linear regression models. Regional cortical volumetric differences between patients and controls were calculated using t tests. RESULTS: The development of MS at 12 months was associated with greater whole brain and optic radiation lesion loads, shorter acute optic nerve lesions and smaller pericalcarine cortical volume at baseline. Regional atrophy was not evident in other sampled cortical regions. Pericalcarine atrophy was not directly associated with whole brain lesion load, optic radiation measures or optic nerve lesion length. However, the association between pericalcarine atrophy and MS was not independent of these parameters. CONCLUSIONS: Reduced pericalcarine cortical volumes in patients with early clinically isolated ON were associated with the development of MS but volumes of other cortical regions were not. Hence pericalcarine cortical regions appear particularly susceptible to early damage. These findings could be explained by a combination of pathological effects to visual grey and white matter in patients with ON. PMID- 21297150 TI - Palliative care in amyotrophic lateral sclerosis: a review of current international guidelines and initiatives. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative condition. Optimal management requires a palliative approach from diagnosis with emphasis on patient autonomy, dignity and quality of life. OBJECTIVE: To conduct a systematic analysis of the type, level and timing of specialist palliative care intervention in ALS. RESULTS: Despite an international consensus that ALS management should adopt a multidisciplinary approach, integration of palliative care into ALS management varies considerably across health care systems. Late referral to palliative services in ALS is not uncommon and may impact negatively on the quality of life of ALS patients and their caregivers. However, common themes and principles of engagement can be identified across different jurisdictions, and measurement systems have been established that can assess the impact of palliative care intervention. CONCLUSIONS: There is considerable evidence that palliative care intervention improves quality of life in patients and carers. International consensus guidelines would assist in the development of a framework for active palliative care engagement in ALS and other neurodegenerative diseases. PMID- 21297151 TI - Unexplained iron deficiency in idiopathic and heritable pulmonary arterial hypertension. AB - BACKGROUND: Anaemia is common in left heart failure and is associated with a poorer outcome. Many patients with pulmonary arterial hypertension (PAH) are anaemic or iron-deficient. This study was performed to investigate the prevalence of iron deficiency in PAH and to identify possible causes. METHODS: All patients with idiopathic or heritable PAH diagnosed in 1995-2008 were identified. Controls were selected from patients with chronic thromboembolic pulmonary hypertension (CTEPH). Full blood counts were examined and any abnormality was investigated. Patients were excluded if they had a cause for iron deficiency. The prevalence study was based on 85 patients with idiopathic PAH and 120 with CTEPH. A separate group of 20 patients with idiopathic PAH and 24 with CTEPH with matching haemodynamics were prospectively investigated for serum factors affecting iron metabolism. RESULTS: The prevalence study identified a point prevalence of unexplained iron deficiency of 50% in premenopausal women with idiopathic PAH compared with 8% in premenopausal women with CTEPH (p=0.002); 14% in postmenopausal women with idiopathic PAH compared with 6% in postmenopausal women with CTEPH (p=0.16); 28% in men with idiopathic PAH men compared with 2% in men with CTEPH (p=0.002); and 60% in patients with heritable PAH. The serum study showed that patients with idiopathic PAH had lower serum iron and transferrin saturations than those with CTEPH. Interleukin-6 levels correlated with iron levels (r=-0.6, p=0.006) and transferrin saturations (r=-0.68, p=0.001) in idiopathic PAH but not in CTEPH. CONCLUSIONS: The prevalence of unexplained iron deficiency is significantly higher in idiopathic PAH than in CTEPH. This may be linked to interleukin-6. PMID- 21297152 TI - Respiratory health and lung function in Chinese restaurant kitchen workers. AB - OBJECTIVES: To measure air pollutant concentrations in Chinese restaurant kitchens using different stove types and assess their influence on workers' respiratory health. METHODS: 393 kitchen workers from 53 Chinese restaurants were surveyed over 16 months: 115 workers from 21 restaurants using only electric stoves and 278 workers from 32 restaurants using only gas stoves. Workers were interviewed about their respiratory symptoms and had their lung function tested. Concentrations of nitric oxide (NO), nitrogen dioxide (NO(2)), carbon monoxide (CO), carbon dioxide (CO(2)), methane (CH(4)), non-methane hydrocarbons (NMHC), total volatile organic compounds (TVOC) and fine particulate matter (PM(2.5)) were measured using portable monitors and air-bag sampling. Temperature and noise levels were assessed. RESULTS: Median concentrations of NO, NO(2) and CO were 7.4, 1.5 and 1.6 times higher in gas-fuelled kitchens than in electric ones and average concentrations of PM(2.5) and TVOC were 81% and 78% higher, respectively. Differences were smaller for CH(4) and NMHC. Electricity-run kitchens were 4.5 degrees C cooler and 9 dBA less noisy than gas-fuelled ones. Workers using electric cookers had significantly better lung function than their gas-using counterparts and their mean FEV(1) and FVC values were 5.4% and 3.8% higher, respectively, after adjustment for confounders. Wheeze, phlegm, cough and sore throat were more prevalent in workers using gas. The adjusted OR for having phlegm regularly was significantly higher. CONCLUSIONS: The poorer lung function and higher prevalence of respiratory symptoms among workers in gas-fuelled kitchens compared to those in electricity-powered kitchens may be associated with exposure to higher concentrations of toxic air pollutants generated during gas cooking. PMID- 21297153 TI - A cross-shift study of lung function, exhaled nitric oxide and inflammatory markers in blood in Norwegian cement production workers. AB - OBJECTIVES: To study possible effects of aerosol exposure on lung function, fractional exhaled nitric oxide (FeNO) and inflammatory markers in blood from Norwegian cement production workers across one work shift (0 to 8 h) and again 32 h after the non-exposed baseline registration. METHODS: 95 workers from two cement plants in Norway were included. Assessment of lung function included spirometry and gas diffusion pre- and post-shift (0 and 8 h). FeNO concentrations were measured and blood samples collected at 0, 8 and 32 h. Blood analysis included cell counts of leucocytes and mediators of inflammation. RESULTS: The median respirable aerosol level was 0.3 mg/m(3) (range 0.02-6.2 mg/m(3)). FEV(1), FEF(25-75%) and DL(CO) decreased by 37 ml (p=0.04), 170 ml/s (p<0.001) and 0.17 mmol/min/kPa (p=0.02), respectively, across the shift. A 2 ppm reduction in FeNO between 0 and 32 h was detected (p=0.01). The number of leucocytes increased by 0.6*10(9) cells/l (p<0.001) across the shift, while fibrinogen levels increased by 0.02 g/l (p<0.001) from 0 to 32 h. TNF-alpha level increased and IL-10 decreased across the shift. Baseline levels of fibrinogen were associated with the highest level of respirable dust, and increased by 0.39 g/l (95% CI 0.06 to 0.72). CONCLUSIONS: We observed small cross-shift changes in lung function and inflammatory markers among cement production workers, indicating that inflammatory effects may occur at exposure levels well below 1 mg/m(3). However, because the associations between these acute changes and personal exposure measurements were weak and as the long-term consequences are unknown, these findings should be tested in a follow-up study. PMID- 21297154 TI - Reduced lung function among sisal processors. AB - OBJECTIVES: The objective of this study was to examine lung function and chronic respiratory symptoms among sisal workers in Tanzania and compare the results with a control group. METHODS: A cross-sectional study on chronic respiratory symptoms and lung function was conducted in 2006 among male Tanzanian sisal processing workers from six sisal estates. Participants included 86 workers in decortication departments, 68 workers in brushing departments and 30 low exposed security guards. The response rate was 97%. Chronic respiratory symptoms and background information were obtained by structured interview. Forced ventilatory capacity (FVC) and forced expiratory volume in 1 s (FEV(1)) were estimated before and after a work shift, and FEV(1)/FVC ratio calculated. RESULTS: Workers were aged 19-85, with the oldest in the brushing and security departments. Chronic cough and chest tightness were experienced by 38% and 68% of workers in brushing departments, 20% and 6% of workers in decortication and 7% and 0% of security workers, respectively. A reduced FEV(1)/FVC ratio related to years of work was found among workers in brushing departments when adjusting for age, smoking, previous respiratory illnesses and body mass index, using regression analyses. Work in decortication departments was not related to reduced lung function parameters. The prevalence of FEV(1)/FVC<70 was above 50 for all three groups. Lung function parameters were similar before and after work shifts, except that peak expiratory flow increased among workers in brushing departments after work shifts. CONCLUSIONS: The results indicate a relationship between work in sisal brushing departments and the development of obstructive lung disorders. PMID- 21297155 TI - The nuclear mitotic apparatus (NuMA) protein: localization and dynamics in human oocytes, fertilization and early embryos. AB - The oocyte's meiotic spindle is a dynamic structure that relies on microtubule organization and regulation by centrosomes. Disorganization of centrosomal proteins, including the nuclear mitotic apparatus (NuMA) protein and the molecular motor complex dynein/dynactin, can lead to chromosomal instability and developmental abnormalities. The present study reports the distribution and function of these proteins in human oocytes, zygotes and early embryos. A total of 239 oocytes, 90 zygotes and discarded embryos were fixed and analyzed with confocal microscopy for NuMA and dynactin distribution together with microtubules and chromatin. Microtubule-associated dynein-dependent transport functions were explored by inhibiting phosphatase and ATPase activity with sodium-orthovanadate (SOV). At germinal vesicle (GV) stages, NuMA was dispersed across the nucleoplasm. After GV breaks down, NuMA became cytoplasmic before localizing at the spindle poles in metaphase I and II oocytes. Aberrant NuMA localization patterns were found during oocyte in vitro maturation. After fertilization, normal and abnormal pronuclear stage zygotes and embryos displayed translocation of NuMA to interphase nuclei. SOV treatment for up to 2 h induced lower maturation rates with chromosomal scattering and ectopic localization of NuMA. Accurate distribution of NuMA is important for oocyte maturation, zygote and embryo development in humans. Proper assembly of NuMA is likely necessary for bipolar spindle organization and human oocyte developmental competence. PMID- 21297156 TI - Phylogenomic analyses of the BARREN STALK1/LAX PANICLE1 (BA1/LAX1) genes and evidence for their roles during axillary meristem development. AB - The diversity of plant architectural form is largely determined by the extent and duration of axillary meristem (AM) derived lateral growth. The orthologous basic helix-loop-helix (bHLH) proteins maize BARREN STALK1 (BA1) and rice LAX PANICLE1 (LAX1) are essential for the formation of AMs during vegetative development and all lateral structures during inflorescence development, but whether BA1/LAX1 co orthologs exist outside of the grass family is unclear. Here, we present Bayesian phylogenetic evidence of a well-supported BA1/LAX1 clade comprised monocots and eudicots, estimating an origin for the lineage at least near the base of flowering plants. Genomic analyses in Arabidopsis, papaya, medicago, rice, sorghum, and maize indicate that BA1/LAX1 genes reside in syntenic regions, although there has also been a complex pattern of gene duplication and loss during the diversification of the angiosperm clade. BA1/LAX1 mRNA expression coincided with the initiation of leaves and associated AMs in the vegetative meristems of broccoli, medicago, and papaya implicating a role for the lineage in the formation of AMs in eudicots as well as monocots. Expression on the adaxial surface of lateral inflorescence structures was conserved in all sampled flowering plants, whereas mRNA expression in leaves of Arabidopsis, broccoli, and papaya also links BA1/LAX1 co-orthologs with roles in regulating leaf development, possibly as a downstream target of auxin regulating genes. Together these data point to roles for BA1/LAX1 genes during AM formation, leaf, and inflorescence development in diverse flowering plants and lend support to the hypothesis that the same genetic mechanisms regulate the development of different AM types. PMID- 21297157 TI - A large palindrome with interchromosomal gene duplications in the pericentromeric region of the D. melanogaster Y chromosome. AB - The non-recombining Y chromosome is expected to degenerate over evolutionary time, however, gene gain is a common feature of Y chromosomes of mammals and Drosophila. Here, we report that a large palindrome containing interchromosomal segmental duplications is located in the vicinity of the first amplicon detected in the Y chromosome of D. melanogaster. The recent appearance of such amplicons suggests that duplications to the Y chromosome, followed by the amplification of the segmental duplications, are a mechanism for the continuing evolution of Drosophila Y chromosomes. PMID- 21297158 TI - Evolution of nuclear retinoic acid receptor alpha (RARalpha) phosphorylation sites. Serine gain provides fine-tuned regulation. AB - The human nuclear retinoic acid (RA) receptor alpha (hRARalpha) is a ligand dependent transcriptional regulator, which is controlled by a phosphorylation cascade. The cascade starts with the RA-induced phosphorylation of a serine residue located in the ligand-binding domain, S(LBD), allowing the recruitment of the cdk7/cyclin H/MAT1 subcomplex of TFIIH through the docking of cyclin H. It ends by the subsequent phosphorylation by cdk7 of an other serine located in the N-terminal domain, S(NTD). Here, we show that this cascade relies on an increase in the flexibility of the domain involved in cyclin H binding, subsequently to the phosphorylation of S(LBD). Owing to the functional importance of RARalpha in several vertebrate species, we investigated whether the phosphorylation cascade was conserved in zebrafish (Danio rerio), which expresses two RARalpha genes: RARalpha-A and RARalpha-B. We found that in zebrafish RARalphas, S(LBD) is absent, whereas S(NTD) is conserved and phosphorylated. Therefore, we analyzed the pattern of conservation of the phosphorylation sites and traced back their evolution. We found that S(LBD) is most often absent outside mammalian RARalpha and appears late during vertebrate evolution. In contrast, S(NTD) is conserved, indicating that the phosphorylation of this functional site has been under ancient high selection constraint. This suggests that, during evolution, different regulatory circuits control RARalpha activity. PMID- 21297159 TI - Estimating the acute health effects of coarse particulate matter accounting for exposure measurement error. AB - In air pollution epidemiology, there is a growing interest in estimating the health effects of coarse particulate matter (PM) with aerodynamic diameter between 2.5 and 10 MUm. Coarse PM concentrations can exhibit considerable spatial heterogeneity because the particles travel shorter distances and do not remain suspended in the atmosphere for an extended period of time. In this paper, we develop a modeling approach for estimating the short-term effects of air pollution in time series analysis when the ambient concentrations vary spatially within the study region. Specifically, our approach quantifies the error in the exposure variable by characterizing, on any given day, the disagreement in ambient concentrations measured across monitoring stations. This is accomplished by viewing monitor-level measurements as error-prone repeated measurements of the unobserved population average exposure. Inference is carried out in a Bayesian framework to fully account for uncertainty in the estimation of model parameters. Finally, by using different exposure indicators, we investigate the sensitivity of the association between coarse PM and daily hospital admissions based on a recent national multisite time series analysis. Among Medicare enrollees from 59 US counties between the period 1999 and 2005, we find a consistent positive association between coarse PM and same-day admission for cardiovascular diseases. PMID- 21297160 TI - Molecular cloning and catalytic mechanism of a novel glycosphingolipid-degrading beta-N-acetylgalactosaminidase from Paenibacillus sp. TS12. AB - We report here the molecular cloning, characterization, and catalytic mechanism of a novel glycosphingolipid-degrading beta-N-acetylgalactosaminidase (beta-NGA) from Paenibacillus sp. TS12 (NgaP). Consisting of 1034 putative amino acid residues, NgaP shares no sequence similarity with known proteins. Recombinant NgaP, expressed in Escherichia coli, cleaved the nonreducing terminal beta-GalNAc residues of gangliotriaosylceramide and globotetraosylceramide. The enzyme hydrolyzed para-nitrophenyl-beta-N-acetylgalactosaminide ~100 times faster than para-nitrophenyl-beta-N-acetylglucosaminide. GalNAc thiazoline, an analog of the oxazolinium intermediate and potent inhibitor for enzymes adopting substrate assisted catalysis, competitively inhibited the enzyme. The K(i) of the enzyme for GalNAc thiazoline was 1.3 nM, whereas that for GlcNAc thiazoline was 46.8 MUM. Comparison of the secondary structure with those of known enzymes exhibiting substrate-assisted catalysis and point mutation analysis indicated that NgaP adopts substrate-assisted catalysis in which Glu-608 and Asp-607 could function as a proton donor and a stabilizer of the 2-acetamide group of the beta-GalNAc at the active site, respectively. These results clearly indicate that NgaP is a beta NGA showing substrate-assisted catalysis. This is the first report describing the molecular cloning of a beta-NGA adopting substrate-assisted catalysis. PMID- 21297161 TI - Structure and biochemical activities of Escherichia coli MgsA. AB - Bacterial "maintenance of genome stability protein A" (MgsA) and related eukaryotic enzymes play important roles in cellular responses to stalled DNA replication processes. Sequence information identifies MgsA enzymes as members of the clamp loader clade of AAA+ proteins, but structural information defining the family has been limited. Here, the x-ray crystal structure of Escherichia coli MgsA is described, revealing a homotetrameric arrangement for the protein that distinguishes it from other clamp loader clade AAA+ proteins. Each MgsA protomer is composed of three elements as follows: ATP-binding and helical lid domains (conserved among AAA+ proteins) and a tetramerization domain. Although the tetramerization domains bury the greatest amount of surface area in the MgsA oligomer, each of the domains participates in oligomerization to form a highly intertwined quaternary structure. Phosphate is bound at each AAA+ ATP-binding site, but the active sites do not appear to be in a catalytically competent conformation due to displacement of Arg finger residues. E. coli MgsA is also shown to form a complex with the single-stranded DNA-binding protein through co purification and biochemical studies. MgsA DNA-dependent ATPase activity is inhibited by single-stranded DNA-binding protein. Together, these structural and biochemical observations provide insights into the mechanisms of MgsA family AAA+ proteins. PMID- 21297162 TI - Hepatitis C virus NS5A protein interacts with phosphatidylinositol 4-kinase type IIIalpha and regulates viral propagation. AB - Hepatitis C Virus (HCV) nonstructural 5A (NS5A) is a pleiotropic protein involved in viral RNA replication and modulation of the cellular physiology in HCV infected cells. To elucidate the mechanisms of the HCV life cycle, we identified cellular factors interacting with the NS5A protein in HCV-infected cells. Huh7.5 cells were electroporated with HCV Jc1 RNA. Cellular factors associated with HCV NS5A were identified by immunoprecipitation with Dynabead-conjugated NS5A antibody and LC-MS/MS. Phosphatidylinositol 4-kinase type IIIalpha (PI4KIIIalpha) was identified as a binding partner for the NS5A protein. NS5A derived from both genotypes 1b and 2a interacted with PI4KIIIalpha. NS5A interacted with PI4KIIIalpha through amino acids 401-600 of PI4KIIIalpha and domain I of NS5A. Interference of the protein interaction between NS5A and PI4KIIIalpha decreased HCV propagation. Knockdown of PI4KIIIalpha significantly reduced HCV replication in Huh7 cells harboring the subgenomic replicon and in Huh7.5 cells infected with cell culture grown virus (HCVcc). Silencing of PI4KIIIalpha further inhibited HCV release into the tissue culture medium. NS5A may recruit PI4KIIIalpha to the HCV RNA replication complex. These data suggest that PI4KIIIalpha is an essential host factor that supports HCV proliferation and therefore PI4KIIIalpha may be a legitimate target for anti-HCV therapy. PMID- 21297163 TI - Structural variations within the transferrin binding site on transferrin-binding protein B, TbpB. AB - Pathogenic bacteria acquire the essential element iron through specialized uptake pathways that are necessary in the iron-limiting environments of the host. Members of the Gram-negative Neisseriaceae and Pasteurellaceae families have adapted to acquire iron from the host iron binding glycoprotein, transferrin (Tf), through a receptor complex comprised of transferring-binding protein (Tbp) A and B. Because of the critical role they play in the host, these surface exposed proteins are invariably present in clinical isolates and thus are considered prime vaccine targets. The specific interactions between TbpB and Tf are essential and ultimately might be exploited to create a broad-spectrum vaccine. In this study, we report the structure of TbpBs from two porcine pathogens, Actinobacillus pleuropneumoniae and suis. Paradoxically, despite a common Tf target, these swine related TbpBs show substantial sequence variation in their Tf-binding site. The TbpB structures, supported by docking simulations, surface plasmon resonance and hydrogen/deuterium exchange experiments with wild type and mutant TbpBs, explain why there are structurally conserved elements within TbpB homologs despite major sequence variation that are required for binding Tf. PMID- 21297164 TI - Structural and biochemical studies of serine acetyltransferase reveal why the parasite Entamoeba histolytica cannot form a cysteine synthase complex. AB - Cysteine (Cys) plays a major role in growth and survival of the human parasite Entamoeba histolytica. We report here the crystal structure of serine acetyltransferase (SAT) isoform 1, a cysteine biosynthetic pathway enzyme from E. histolytica (EhSAT1) at 1.77 A, in complex with its substrate serine (Ser) at 1.59 A and inhibitor Cys at 1.78 A resolution. EhSAT1 exists as a trimer both in solution as well as in crystal structure, unlike hexamers formed by other known SATs. The difference in oligomeric state is due to the N-terminal region of the EhSAT1, which has very low sequence similarity to known structures, also differs in orientation and charge distribution. The Ser and Cys bind to the same site, confirming that Cys is a competitive inhibitor of Ser. The disordered C-terminal region and the loop near the active site are responsible for solvent-accessible acetyl-CoA binding site and, thus, lose inhibition to acetyl-CoA by the feedback inhibitor Cys. Docking and fluorescence studies show that EhSAT1 C-terminal mimicking peptides can bind to O-acetyl serine sulfhydrylase (EhOASS), whereas native C-terminal peptide does not show any binding. To test further, C-terminal end of EhSAT1 was mutated and found that it inhibits EhOASS, confirming modified EhSAT1 can bind to EhOASS. The apparent inability of EhSAT1 to form a hexamer and differences in the C-terminal region are likely to be the major reasons for the lack of formation of the large cysteine synthase complex and loss of a complex regulatory mechanism in E. histolytica. PMID- 21297165 TI - Structure and interactions of myosin-binding protein C domain C0: cardiac specific regulation of myosin at its neck? AB - Myosin-binding protein C (MyBP-C) is a multidomain protein present in the thick filaments of striated muscles and is involved in both sarcomere formation and contraction regulation. The latter function is believed to be located at the N terminus, which is close to the motor domain of myosin. The cardiac isoform of MyBP-C is linked to hypertrophic cardiomyopathy. Here, we use NMR spectroscopy and biophysical and biochemical assays to study the three-dimensional structure and interactions of the cardiac-specific Ig-like domain C0, a part of cardiac MyBP-C of which little is known. The structure confirmed that C0 is a member of the IgI class of proteins, showing many of the characteristic features of this fold. Moreover, we identify a novel interaction between C0 and the regulatory light chain of myosin, thus placing the N terminus of the protein in proximity to the motor domain of myosin. This novel interaction is disrupted by several cardiomyopathy-linked mutations in the MYBPC3 gene. These results provide new insights into how cardiac MyBP-C incorporates in the sarcomere and how it can contribute to the regulation of muscle contraction. PMID- 21297167 TI - How well do children who are internationally adopted acquire language? A meta analysis. AB - PURPOSE: In this article, the authors present the results of a systematic and meta-analytic examination of the language outcomes of children who are internationally adopted. The study examined the questions of whether the early life experiences of children who are internationally adopted and the language switch that occurs after adoption hinder the acquisition of language skills. METHOD: The authors selected available studies on the language acquisition of internationally adopted children using search strategies from both a comprehensive set of databases and manual searching of selected studies. Study eligibility criteria included (a) participants clearly identified as being internationally adopted, (b) measurable language outcomes were reported, (c) a control group or normative measure was used in the design of the study, and (d) effect size was reported, or data were provided to calculate effect size. RESULTS: The meta-analysis found that as a group, the children expressed great variability in their language skills. Overall, they were more likely to have poorer language outcomes than comparison children, but several moderating variables were found. CONCLUSIONS: The results of the meta-analysis have direct clinical application regarding the assessment and treatment of language skills of internationally adopted children. The study also has implications for future studies of the language development of internationally adopted children. PMID- 21297166 TI - Deoxyribonucleotide metabolism in cycling and resting human fibroblasts with a missense mutation in p53R2, a subunit of ribonucleotide reductase. AB - Ribonucleotide reduction provides deoxynucleotides for nuclear and mitochondrial (mt) DNA replication and DNA repair. In cycling mammalian cells the reaction is catalyzed by two proteins, R1 and R2. A third protein, p53R2, with the same function as R2, occurs in minute amounts. In quiescent cells, p53R2 replaces the absent R2. In humans, genetic inactivation of p53R2 causes early death with mtDNA depletion, especially in muscle. We found that cycling fibroblasts from a patient with a lethal mutation in p53R2 contained a normal amount of mtDNA and showed normal growth, ribonucleotide reduction, and deoxynucleoside triphosphate (dNTP) pools. However, when made quiescent by prolonged serum starvation the mutant cells strongly down-regulated ribonucleotide reduction, decreased their dCTP and dGTP pools, and virtually abolished the catabolism of dCTP in substrate cycles. mtDNA was not affected. Also, nuclear DNA synthesis and the cell cycle-regulated enzymes R2 and thymidine kinase 1 decreased strongly, but the mutant cell populations retained unexpectedly larger amounts of the two enzymes than the controls. This difference was probably due to their slightly larger fraction of S phase cells and therefore not induced by the absence of p53R2 activity. We conclude that loss of p53R2 affects ribonucleotide reduction only in resting cells and leads to a decrease of dNTP catabolism by substrate cycles that counterweigh the loss of anabolic activity. We speculate that this compensatory mechanism suffices to maintain mtDNA in fibroblasts but not in muscle cells with a larger content of mtDNA necessary for their high energy requirements. PMID- 21297168 TI - Vowel identification by listeners with hearing impairment in response to variation in formant frequencies. AB - PURPOSE: This study examined the influence of presentation level and mild-to moderate hearing loss on the identification of a set of vowel tokens systematically varying in the frequency locations of their second and third formants. METHOD: Five listeners with normal hearing (NH listeners) and five listeners with hearing impairment (HI listeners) identified synthesized vowels that represented both highly identifiable and ambiguous examples of /i/, /[Please see symbol]/, and /[Please see symbol]/. RESULTS: Response patterns of NH listeners showed significant changes, with an increase in presentation level from 75 dB SPL to 95 dB SPL, including increased category overlap. HI listeners, listening only at the higher level, showed greater category overlap than normal and overall identification patterns that differed significantly from those of NH listeners. Excitation patterns based on estimates of auditory filters suggested smoothing of the internal representations, resulting in impaired formant resolution. CONCLUSIONS: Both increased presentation level for NH listeners and the presence of hearing loss produced a significant change in vowel identification for this stimulus set. Major differences were observed between NH listeners and HI listeners in vowel category overlap and in the sharpness of boundaries between vowel tokens. It is likely that these findings reflect imprecise internal spectral representations due to reduced frequency selectivity. PMID- 21297169 TI - Evidence for preserved novel word learning in Down syndrome suggests multiple routes to vocabulary acquisition. AB - PURPOSE: Three studies investigated novel word learning, some requiring phonological production, each involving between 11 and 17 individuals with Down syndrome, and between 15 and 24 typically developing individuals matched for receptive vocabulary. The effect of stimuli wordlikeness and incidental procedure based memory demands were examined to see whether these may account for an apparent impairment in word learning in Down syndrome demonstrated in earlier research. METHOD: Paired associate word and nonword learning tasks were presented, requiring participants to learn the names of novel characters. The nonword stimuli varied in the degree of wordlikeness in 2 studies. A third study investigated extraneous task demand. RESULTS: Across 3 studies, there was no suggestion of a word learning deficit associated with Down syndrome (eta(2)(p) for the main effect of group of .03, .11, and .03, respectively), despite the level of phonological representation required. There was evidence that novel word learning by participants with Down syndrome exceeded that which their verbal short-term memory capacity would predict. CONCLUSIONS: Vocabulary acquisition in Down syndrome may not rely on verbal short-term memory to the same extent as in typically developing children, lending support to the suggestion that new word learning may be underpinned by an additional memory process. PMID- 21297170 TI - The unsettled baby: how complexity science helps. PMID- 21297171 TI - Osteoarthritis in football: FIFA/F-MARC approach. PMID- 21297172 TI - Meniscal tears, repairs and replacement: their relevance to osteoarthritis of the knee. AB - The menisci of the knee are important load sharers and shock absorbers in the joint. Meniscal tears are common, and whenever possible meniscal tears should be surgically repaired. Meniscectomy leads to a significant increased risk of osteoarthritis, and various options now exist for replacing missing menisci, including the use of meniscal scaffolds or the replacement of the entire meniscus by meniscal allograft transplantation. The field of meniscal surgery continues to develop apace, and the future may lie in growing new menisci by tissue engineering techniques. PMID- 21297173 TI - Imaging abnormalities that correlate with joint pain. AB - This article summarises evidence on structural pathology in the joint that causes joint pain. Evidence, mostly from studies using MRI scans in persons with and without joint pain has suggested that pain often originates in bone or synovium. PMID- 21297174 TI - Lower extremity osteoarthritis management needs a paradigm shift. AB - The current pre-eminent focus in osteoarthritis research and clinical practice is on persons with established radiographic disease. This is the very end-stage of disease genesis and modern therapies are thus largely palliative. A major shift in the focus of osteoarthritis research and clinical practice is critically needed if an impact is to be made for the millions living with the chronic pain and disability of osteoarthritis. The disease management paradigm needs to be revolutionised to focus on persons at high risk of developing or with early disease in which structural changes may be preventable or reversible. Similarly, current palliation should shift towards coordinated conservative management with reorganisation of the delivery of health services. PMID- 21297175 TI - Acupuncture for cancer-induced bone pain: a pilot study. PMID- 21297176 TI - A 3-year lifestyle intervention for adults at moderate to high risk of cardiovascular disease is cost effective when added to standard care and improves physical health-related quality of life. PMID- 21297177 TI - Plasma apolipoprotein C-III metabolism in patients with chronic kidney disease. AB - Moderate chronic kidney disease (CKD) (defined by an estimated glomerular filtration rate of 30-60 ml/min) is associated with mild hypertriglyceridemia related to delayed catabolism of triglyceride-rich lipoprotein particles. Altered apolipoprotein C-III (apoC-III) metabolism may contribute to dyslipidemia in CKD. To further characterize the dyslipidemia of CKD, we investigated the kinetics of plasma apoC-III in 7 nonobese, nondiabetic, non-nephrotic CKD subjects and 7 age- and sex-matched healthy controls, using deuterated leucine ([5, 5, 5, 2H3]leucine), gas chromatography-mass spectrometry, and multicompartmental modeling. Compared with controls, CKD subjects had higher concentrations of plasma and VLDL triglycerides and plasma and VLDL apoC-III (P < 0.05). The increased plasma apoC-III concentration was associated with a decreased apoC-III fractional catabolic rate (FCR) (1.21 +/- 0.15 vs. 0.74 +/- 0.12 pools/day, P = 0.03). There were no differences between apoC-III production rates of controls and those of CKD subjects. In CKD subjects, plasma apoC-III concentration was significantly and negatively correlated with apoC-III FCR (r = -0.749, P = 0.05) but not with apoC-III production rate. Plasma apoC-III concentration was positively correlated with plasma and VLDL triglycerides and VLDL apoB concentrations and negatively correlated with VLDL apoB FCR (P < 0.05 for all). ApoC-III FCR was negatively correlated with plasma and VLDL triglycerides and VLDL apoB concentration and positively correlated with VLDL apoB FCR (P < 0.05 for all). Altered plasma apoC-III metabolism is a feature of dyslipidemia in moderate CKD. Modification of apoC-III catabolism may be an important therapeutic target for reducing cardiovascular disease risk in moderate CKD. PMID- 21297178 TI - Contraction-induced skeletal muscle FAT/CD36 trafficking and FA uptake is AMPK independent. AB - The aim of this study was to investigate the molecular mechanisms regulating FA translocase CD36 (FAT/CD36) translocation and FA uptake in skeletal muscle during contractions. In one model, wild-type (WT) and AMP-dependent protein kinase kinase dead (AMPK KD) mice were exercised or extensor digitorum longus (EDL) and soleus (SOL) muscles were contracted, ex vivo. In separate studies, FAT/CD36 translocation and FA uptake in response to muscle contractions were investigated in the perfused rat hindlimb. Exercise induced a similar increase in skeletal muscle cell surface membrane FAT/CD36 content in WT (+34%) and AMPK KD (+37%) mice. In contrast, 5-aminoimidazole-4-carboxamide ribonucleoside only induced an increase in cell surface FAT/CD36 content in WT (+29%) mice. Furthermore, in the perfused rat hindlimb, muscle contraction induced a rapid (1 min, +15%) and sustained (10 min, +24%) FAT/CD36 relocation to cell surface membranes. The increase in cell surface FAT/CD36 protein content with muscle contractions was associated with increased FA uptake, both in EDL and SOL muscle from WT and AMPK KD mice and in the perfused rat hindlimb. This suggests that AMPK is not essential in regulation of FAT/CD36 translocation and FA uptake in skeletal muscle during contractions. However, AMPK could be important in regulation of FAT/CD36 distribution in other physiological situations. PMID- 21297179 TI - Gender and income associations in physical activity and blood pressure among older adults. AB - OBJECTIVES: To examine physical activity (PA) in multiple contexts (household, walking, and leisure-time PA) and blood pressure (BP) across gender and income among older adults living independently. METHODS: A convenience sample of 372 older adults completed 2 BP measurements and PA questionnaires. RESULTS: Older adults with high incomes (>=$30,000) engaged in less household activity, more leisure time PA and better controlled their BP than those with low incomes (<$30,000). Men walked more than women. Older women in the low-income group had less controlled BP than those women in the high-income group. Participants with normal or controlled BP were engaged in more household and walking activities than those with uncontrolled BP. CONCLUSION: Findings suggest that older men and women at high or low-income levels have different mode of PA and BP management that should be considered for intervention strategies. PMID- 21297180 TI - The association between meeting physical activity guidelines and chronic diseases among Canadian adults. AB - BACKGROUND: Physical activity is associated with a reduced risk of chronic disease. This study describes the relationship between meeting the guidelines for physical activity described in Canada's Physical Activity Guide and heart disease, type 2 diabetes, hypertension, obesity, and low levels of general health. METHODS: Leisure-time energy expenditure (LTEE) was calculated from leisure-time physical activities reported by adults who participated in the 2007 Canadian Community Health Survey. Respondents were classified as meeting the guidelines for physical activity or not, and were stratified by sex into quartiles of LTEE. Logistic regression was used to determine the odds for all conditions associated with not meeting the guidelines and by quartile of LTEE, adjusting for covariates. RESULTS: The odds of type 2 diabetes, obesity, and fair/poor health were significantly higher among those not meeting the guidelines for both sexes and for high blood pressure among women. Significantly higher odds were seen between the lowest and highest quartiles of LTEE for type 2 diabetes and high blood pressure and across all quartiles for obesity and fair/poor health for both sexes. CONCLUSIONS: Canadian adults meeting the physical activity guidelines have lower odds of chronic diseases and fair/poor health than those not meeting the guidelines. PMID- 21297181 TI - Fitness and adiposity as predictors of functional limitation in adults. AB - BACKGROUND: This study examined the associations of body mass index (BMI), waist circumference (WC), and cardiorespiratory fitness (CRF) with incident functional limitation (IFL) in adults. METHODS: Patients (n = 2400), 30+ years [mean age, 45.2 (SD, 8.3); 12% women], completed a baseline health examination during 1979 to 1995. CRF was quantified by age-and sex-specific thirds for maximal treadmill exercise test duration. Adiposity was assessed by BMI and WC (grouped for analysis according to clinical guidelines). Incident IFL was identified from mail back surveys during 1995, 1999, and 2004. RESULTS: After adjusting for potential confounders and either BMI or WC, CRF was inversely related to IFL (P trend < .001). The association between BMI and IFL was significant after adjusting for all confounders (P trend = .002), but not after additional adjustment for CRF (P trend = .23). After controlling for all confounders and CRF, high WC was associated with greater odds of IFL in those aged 30 to 49; normal WC was associated with greater odds of IFL in those aged 50+. CONCLUSIONS: CRF was a significant predictor of IFL in middle aged and older adults, independent of overall or abdominal adiposity. Clinicians should consider the importance of preserving functional capacity by recommending regular physical activity for normal-weight and overweight individuals. PMID- 21297182 TI - Physical activity in Iran: results of the third national surveillance of risk factors of non-communicable diseases (SuRFNCD-2007). AB - BACKGROUND: Physical inactivity is a modifiable risk factor for obesity, diabetes, cardiovascular diseases, and certain types of cancer. This study aimed to investigate the patterns and demographic correlates of physical activity in Iran. METHODS: The data collected through the third national surveillance of risk factors of noncommunicable diseases (SuRFNCD-2007) on 4120 adults were studied. Physical activity was assessed by the global physical activity questionnaire (GPAQ) in domains of work, commuting and recreation. Participants were categorized into low, moderate and high activity categories. Total physical activity (TPA) was calculated using metabolic equivalents (MET). RESULTS: 40% of Iranian adults (31.6% of men and 48.6% of women) belonged to the low physical activity category. The median value of TPA was 206 (342 in men and 129 in women) MET-minutes/day. Physical activity at work, commuting and recreation contributed to 71%, 20% and 9% of TPA, respectively. Approximately 15% of Iranian adults (4.7 million people) do not have any physical activity in any of the 3 studied domains. CONCLUSIONS: Physical inactivity is common in Iran, particularly in females and in the older age groups. Preventing a rapid growth of conditions such as diabetes and cardiovascular diseases requires health programs with more focus on physical activity. PMID- 21297183 TI - Summer to winter variability in the step counts of normal weight and overweight adults living in the UK. AB - BACKGROUND: This study investigated whether pedometer-determined activity varies between summer and winter in normal-weight and overweight adults. METHODS: Forty five normal-weight (58% female, age = 39.1 +/- 12.4 years, BMI = 22.2 +/- 2.1 kg/m2) and 51 overweight (49% female, age = 42.1 +/- 12.5 years, BMI = 29.3 +/- 4.5 kg/m2) participants completed a within-subject biseasonal pedometer study. All participants completed 2 4-week monitoring periods; 1 period in the summer and 1 period the following winter. Changes in step counts across seasons were calculated and compared for the 2 BMI groups. RESULTS: Both BMI groups reported significant summer to winter reductions in step counts, with the magnitude of change being significantly greater in the normal-weight group (-1737 +/- 2201 versus -781 +/- 1673 steps/day, P = .02). Winter step counts did not differ significantly between the 2 groups (9250 +/- 2845 versus 8974 +/- 2709 steps/day, P = .63), whereas the normal-weight group reported a significantly higher mean daily step count in the summer (10986 +/- 2858 versus 9755 +/- 2874 steps/day, P = .04). CONCLUSION: Both normal-weight and overweight individuals experienced a reduction in step counts between summer and winter; however, normal-weight individuals appear more susceptible to winter decreases in ambulatory activity, with the greatest seasonal change occurring on Sundays. Effective physical activity policies should be seasonally tailored to provide opportunities to encourage individuals to be more active during the winter, particularly on weekends. PMID- 21297184 TI - Determination of step rate thresholds corresponding to physical activity intensity classifications in adults. AB - BACKGROUND: Current recommendations call for adults to be physically active at moderate and/or vigorous intensities. Given the popularity of walking and running, the use of step rates may provide a practical and inexpensive means to evaluate ambulatory intensity. Thus, the purpose of this study was to identify step rate thresholds that correspond to various intensity classifications. METHODS: Oxygen consumption was measured at rest and during 10 minute treadmill walking and running trials at 6 standardized speeds (54, 80, 107, 134, 161, and 188 m.min-1) in 9 men and 10 women (28.8 +/- 6.8 yrs). Two observers counted the participants' steps at each treadmill speed. Linear and nonlinear regression analyses were used to develop prediction equations to ascertain step rate thresholds at various intensities. RESULTS: Nonlinear regression analysis of the metabolic cost versus step rates across all treadmill speeds yielded the highest R2 values for men (R2 = .91) and women (R2 = .79). For men, the nonlinear analysis yielded 94 and 125 step.min-1 for moderate and vigorous intensities, respectively. For women, 99 and 135 step.min-1 corresponded with moderate and vigorous intensities, respectively. CONCLUSIONS: Promoting a step rate of 100 step.min-1 may serve as a practical public health recommendation to exercise at moderate intensity. PMID- 21297185 TI - Using pedometers to estimate ambulatory physical activity in Vietnam. AB - BACKGROUND: Pedometer measurement of physical activity (PA) has been shown to be reliable and valid in industrialized populations, but its applicability in economically developing Vietnam remains untested. This study assessed the feasibility, stability and validity of pedometer estimates of PA in Vietnam. METHODS: 250 adults from a population-based survey were randomly selected to wear Yamax pedometers and record activities for 7 consecutive days. Stability and concurrent validity were assessed using intraclass correlation coefficients (ICC) and Spearman correlation coefficients. RESULTS: Overall, 97.6% of participants provided at least 1 day of usable recordings, and 76.2% wore pedometers for all 7 days. Only 5.2% of the sample participants were involved in work activities not measurable by pedometer. The number of steps increased with hours of wear. There was no significant difference between weekday and weekend in number of steps, and at least 3 days of recordings were required (ICC of the 3 days of recordings: men 0.96, women 0.97). Steps per hour were moderately correlated (men r = .42, women r = .26) with record estimates of total PA. CONCLUSIONS: It is feasible to use pedometers to estimate PA in Vietnam. The measure should involve at least 3 days of recording irrespective of day of the week. PMID- 21297186 TI - Self-report vs. objectively assessed physical activity: which is right for public health? AB - BACKGROUND: To examine the agreement between self-reported and objectively assessed physical activity (PA) according to current public health recommendations. METHODS: One-hundred and fourteen British University students wore a combined accelerometer and heart rate monitor (Actiheart; AHR) to estimate 24-hour energy expenditure over 7 consecutive days. Data were extracted based on population-based MET-levels recommended to improve and maintain health. On day 8, participants were randomly assigned to complete either the short-form International Physical Activity Questionnaire (IPAQ) or the Leisure-Time Exercise Questionnaire (LTEQ). Estimates of duration (IPAQ; N = 46) and frequency (LTEQ; N = 41) of PA were compared with those recorded by the AHR. RESULTS: Bland-Altman analysis showed the mean bias between the IPAQ and AHR to be small for moderate intensity and total PA, however the 95% limits of agreement (LOA) were wide. The mean number of moderate bouts of PA estimated by the LTEQ was similar to those derived by the AHR but the 95% LOA between the 2 measures were large. CONCLUSIONS: Although self-report questionnaires may provide an approximation of PA at a population level, they may not determine whether an individual is participating in the type, intensity, and amount of PA advocated in current public health recommendations. PMID- 21297187 TI - Estimating minutes of physical activity from the previous day physical activity recall: validation of a prediction equation. AB - BACKGROUND: This study was designed to develop a prediction algorithm that would allow the Previous Day Physical Activity Recall (PDPAR) to be equated with temporally matched data from an accelerometer. METHODS: Participants (n = 121) from a large, school-based intervention wore a validated accelerometer and completed the PDPAR for 3 consecutive days. Physical activity estimates were obtained from PDPAR by totaling 30-minute bouts of activity coded as >=4 METS. A regression equation was developed in a calibration sample (n = 91) to predict accelerometer minutes of moderate to vigorous physical activity (MVPA) from PDPAR bouts. The regression equation was then applied to a separate, holdout sample (n = 30) to evaluate the utility of the prediction algorithm. RESULTS: Gender and PDPAR bouts accounted for 36.6% of the variance in accelerometer MVPA. The regression model showed that on average boys obtain 9.0 min of MVPA for each reported PDPAR bout, while girls obtain 4.8 min of MVPA per bout. When applied to the holdout sample, predicted minutes of MVPA from the models showed good agreement with accelerometer minutes (r = .81). CONCLUSIONS: The prediction equation provides a valid and useful metric to aid in the interpretation of PDPAR results. PMID- 21297188 TI - The association of physical activity and work-related characteristics among Latino adults. AB - BACKGROUND: Studies have examined the association between work-related characteristics and physical activity participation; however few studies include U.S. Latinos. METHODS: Six hundred and seventy two Latino adults of San Diego County were randomly sampled and surveyed to assess their health behaviors in the fall of 2006. Analyses were conducted with 633 respondents with physical activity data (94% of sample), examining the extent to which job category and hours worked per week were associated with 4 domains of physical activity defined by MET minutes per week using the long IPAQ. RESULTS: Multivariate analysis of variance models were computed. After adjusting for covariates, occupational MET-minutes per week were associated with job category and hours worked per week, such that blue collar workers expended more MET-minutes per week than white collar or nonworkers, and those who worked 20 hours a week or less expended less occupational physical activity compared with those who worked more than 20 hours per week. In addition, nonworkers reported expending more household MET-minutes per week than blue collar or white collar workers. CONCLUSIONS: Efforts are needed to increase the physical activity levels of Mexican immigrants/Mexican Americans, with interventions designed in consideration of the individual's work status. PMID- 21297189 TI - Who participates in physical activity intervention trials? AB - BACKGROUND: Taking a representative snapshot of physical activity intervention trial findings published between 1996 and 2006, we empirically evaluated participant characteristics, response and retention rates, and their associations with intervention settings. METHODS: A structured database search identified 5 representative health behavior journals, from which 32 research reports of physical activity intervention trials were reviewed. Interventions settings were categorized as workplace, healthcare, home- or community-based. Information on participant and intervention characteristics was extracted and reviewed. RESULTS: The majority of participants were Caucasian (86%), women (66%), healthy but sedentary (63%), and middle-aged (mean age = 51 years). Intervention response rates ranged from 20% to 89%, with the greatest response rate for healthcare and home-based interventions. Compared with nonparticipants, study participants tended to be women, Caucasian, tertiary-educated, and middle-class. Participants in workplace interventions were younger, more educated, and healthier; in community-based interventions, participants were older and more ethnically diverse. Reporting on education and income was inconsistent. The mean retention rate was 78%, with minimal differences between intervention settings. CONCLUSIONS: These results emphasize the need for physical activity interventions to target men, socioeconomically disadvantaged, and ethnic minority populations. Consistent reporting of response rate and retention may enhance the understanding of which intervention settings best recruit and retain large, representative samples. PMID- 21297190 TI - Factors predicting adherence to 9 months of supervised exercise in healthy older women. AB - BACKGROUND: Little is known about factors affecting adherence to highly structured and supervised exercise programs in older people. METHODS: Healthy, inactive older (>=65 y) women (N = 30) were randomized into a 1) higher- (ATH-80% VO2peak); 2) moderate- (ATM-65% VO2peak) intensity aerobic; or 3) lower-intensity resistance (RTL; 50% VO2peak) group. All 3 groups exercised 4 days.week-1 for an average of 45 to 70 min.session-1 over 9 months. Adherence (%) was defined as the proportion of prescribed sessions (N = 144) in which subjects achieved their 1) prescribed heart rate (intensity adherence) and 2) their prescribed duration (duration adherence). Primary determinants of adherence included prescribed intensity (METs) and prescribed duration (min), as well as age, body composition, VO2peak, and exercise self-efficacy score. RESULTS: Intensity adherence was nearly 100% for all 3 groups, while duration adherence was 95%, 91%, and 85% in the RTL, ATH, and ATM groups, respectively. Prescribed exercise duration was the strongest determinant of duration adherence (r = -0.72; P < .0001), independent of prescribed METs, age, VO2peak, and body composition. CONCLUSIONS: Due to competing lifestyle demands, exercise intensity may be less of a factor in adherence among older women than is exercise duration. PMID- 21297191 TI - Adherence to a strength training intervention in adult women. AB - BACKGROUND: The factors influencing exercise adherence are not well characterized in women in their premenopausal years. METHODS: The purpose of this report is to provide an analysis of demographic factors contributing to women's adherence to a 2-year twice-weekly weight training intervention. Overweight and obese premenopausal women were randomized to a control or intervention group. RESULTS: During the supervised period of the intervention (months 1 to 4), adherence was significantly lower among those with a higher level of education and among unmarried women with children aged 6 to 12 compared with married women without children (F = 4.83, P = .004). Overall adherence during the supervised and unsupervised periods was 95.4% and 64.5%, respectively (unadjusted mean). During year 1, white women were significantly more adherent to the intervention (70.3%) than women of color (48.6%). Non-married women with children 13 years or older were significantly less adherent than married women with children 5 years or younger (36.3% versus 75.4%, respectively, P < .007). Overall adherence was 51.4% in year 2. CONCLUSIONS: Interventions and public health recommendations need to further consider how to engage communities to provide effective support for long term adherence to fitness center based exercise of all women, regardless of demographics. PMID- 21297192 TI - The effect of active workstation use on measures of cognition, attention, and motor skill. AB - BACKGROUND: The purpose of this study was to assess participants' ability to perform tasks requiring attention, short term memory, and simple motor skill while sitting, standing or walking at an active workstation. METHODS: Fifty participants completed the Stroop Color Word test (SCWT), Auditory Consonant Trigram test (ACTT), and Digital Finger Tapping test (DFTT) while sitting, standing and walking 1.6 km/h at an active workstation. RESULTS: A significant difference was found for DFTT, but no differences across conditions were found on ACTT or SCWT. Examination of the linear contrasts and post hoc means comparison tests revealed significant differences in DFTT scores between sitting and walking (t = 2.39 (49) P < .02) and standing and walking (t = 2.28 (49) P < .03). These results indicate that adding the walking task to the ACTT and SCWT conditions results in no decrement in performance on these tasks. Conversely, adding the walking task to the DFTT condition results in reduced performance on the DFTT task. CONCLUSIONS: These results further support the potential of active workstations to increase physical activity in the workplace without compromising cognitive capabilities. PMID- 21297193 TI - Barriers to physical activity among Brazilian elderly women from different socioeconomic status: a focus-group study. AB - BACKGROUND: The aim of this study was to identify barriers to physical activity among elderly Brazilian women of different socioeconomic status (SES). METHODS: A focus-group approach was employed. Subjects were aged, on average, 69.9 years (+/ 6.9; n = 25). SES was measured based on a structured interview and women were grouped according to SES classification. Content analysis was used to categorize mentions of barriers to physical activities followed by descriptive analysis of absolute and relative frequencies of similar reports. RESULTS: Most common barriers among high-SES elderly women were those within "psychological, cognitive, and emotional" dimensions (33.8%) and "environmental" (29.2%). Among women from lower SES, barriers were inversely ranked, the highest prevalence was verified for environmental (33.8%) and "psychological, cognitive, and emotional" dimensions (25%). CONCLUSIONS: The results highlight that barriers perception varies according to women's SES, indicating that physical activity promotion strategies must address such differences. PMID- 21297194 TI - Individual, social, and physical environmental correlates of physical activity among young women at risk of depression. AB - BACKGROUND: A number of factors have been identified as important correlates of physical activity (PA) among young women. Young women at risk of depression have a greater likelihood of being physically inactive and it is unknown whether correlates differ for women at risk and not at risk of depression. METHODS: A sample of 451 women aged 18 to 35 years self-reported leisure-time PA, enjoyment of and self-efficacy for walking and vigorous PA, barriers, social support, access to sporting/leisure facilities, and access to sporting equipment in the home. Depression risk was assessed using the General Health Questionnaire (cut point >=5). Logistic regression analyses examined differences in PA correlates among women at risk and not at risk of depression. RESULTS: Self-efficacy for vigorous PA was statistically different between groups in predicting odds for meeting PA recommendations but odds ratios were similar across groups. No other significant interactions between correlates and depressive symptoms were identified. CONCLUSIONS: The findings suggest few differences in the individual, social, and physical environmental correlates of PA among young women who are and are not at risk of depression. Further research is needed to confirm the existence of any PA correlates specific to this high-risk target group. PMID- 21297195 TI - Errors in MET estimates of physical activities using 3.5 ml.kg-1.min-1 as the baseline oxygen consumption. PMID- 21297198 TI - Outcome of non-cardiac surgery after stent implantation in the DES era: results of the Surgery After Stent (SAS) registry. AB - BACKGROUND: Optimal management of patients needing non-cardiac surgery after coronary stenting has not been established. Objective. To assess the perioperative outcome of patients undergoing non-cardiac surgery after coronary bare-metal stent (BMS) or drug-eluting stent (DES) implantation. METHODS: We enrolled consecutive patients undergoing non-cardiac surgery (up to 2008) after coronary stenting in a single-center registry, prospectively registering clinical and procedural data about revascularization and retrospectively recording surgical details, perioperative therapy and in-hospital outcome after surgery. At our institution, we implant BMS for planned surgery at time of revascularization, and use antiplatelet therapy for surgery required within 1 month of BMS or within 12 months of DES implantation. The primary endpoint was defined as perioperative occurrence of major adverse events, both cardiovascular (death, myocardial infarction, stent thrombosis and repeated revascularization) and hemorrhagic (bleeding requiring transfusions or surgical hemostasis). RESULTS: We enrolled 101 patients: 70 treated with BMS (group 1) and 31 with DES (group 2). The mean interval between stenting and surgery was 288 days. The average number of antiplatelet drugs used during the operative period was higher in group 2 than group 1 (p = 0.02). Fifteen patients (15%) experienced major adverse events (5.9% had non-ST elevation myocardial infarction, 12% received blood transfusions), without a significant difference between the two groups (p = 0.72). At multivariate analysis, the predictor of primary endpoint was time interval between stenting and surgery (p = 0.022). CONCLUSION: We found similar outcomes for non-cardiac surgery after coronary stenting when BMS were selected for planned surgery and dual antiplatelet therapy was used, if indicated, during the operative period. PMID- 21297199 TI - Procedural and clinical evaluation of the novel zotarolimus-eluting resolute stent in patients with unselected bifurcated coronary stenosis treated by provisional approach: a multicenter registry. AB - AIMS: As data on the use of the latest-generation drugeluting stents (DES) in bifurcation interventions are lacking, we realized a multicenter registry to assess the procedural and clinical results obtained in patients with unselected bifurcated lesions treated with the novel zotarolimus-eluting Resolute stent (ZRS). METHODS AND RESULTS: Three Italian centers participated in the study. Consecutive patients with significant stenosis of bifurcated lesions undergoing DES implantation were treated with ZRS. The recommended technique was the "provisional TAP approach" [main-vessel (MV) stent implantation eventually followed by kissing balloon and sidebranch (SB) stenting according to TAP technique]. Clinical characteristics, procedural details and clinical follow-up data were prospectively recorded. Procedural success was defined as post percutaneous coronary intervention visual stenosis > 20% on MV and TIMI 3 flow on both MV and SB. Primary endpoint was major adverse coronary events (cardiac death, myocardial infarction and target vessel revascularization) at 9-month follow up. A total of 180 patients were enrolled. The target lesion was located in the distal left main in 16% and in the left anterior descending artery in 52%. All but 3 cases were treated according to the provisional TAP approach (kissing balloon rate, 69%; overall SB stenting rate, 10.6%). Procedural success was obtained in 98.3% (3 failures due to final SB TIMI flow < 3). At 9-month follow up, the survival free from MACE was 97.8% (1 cardiac death and 3 repeat revascularizations). CONCLUSION: The use of the latest-generation ZRS in unselected bifurcated lesions treated by a provisional approach is associated with excellent procedural results and with promising clinical outcomes. PMID- 21297200 TI - ResoluteTM drug-eluting stent: a resolution for bifurcation lesions? PMID- 21297201 TI - Angiographic and clinical characteristics of patients with acetylcholine-induced coronary vasospasm on follow-up coronary angiography following drug-eluting stent implantation. AB - Recent studies have shown that drug-eluting stents (DES) induce vascular endothelial dysfunction in both Cypher and Taxus stents. These studies evaluated coronary vasomotion in the peristent coronary segment for 1 lesion with 1 DES. The angiographic and clinical characteristics of real-world patients with coronary spasm following DES implantation have not been well documented. METHODS AND RESULTS: All patients at our hospital who underwent coronary angiography at follow up after DES deployment (Cypher and Taxus stents) between July 2007 and March 2009 were included. We performed an acetylcholine (ACh) provocation test for diagnosing coronary vasospasm in 3 vessels, except in patients with significant stenosis or contraindications to ACh administration. ACh provocation test was positive in 36/55 of the coronary arteries (65.4%) and in 30/42 of the patients with DES (71.4%). There was no difference in the positive rate between patients with and without symptoms. A total of 13/20 asymptomatic patients (65.0%) also showed positive results. In patients with positive results in the ACh provocation test, vasoconstriction at segments distal to the stent was exaggerated compared with corresponding segments in non-stented vessels (0.46 +/- 0.27 versus 0.31 +/- 0.20, respectively; p = 0.008). Vessels with positive results had a longer stent length compared with those with negative results (31.6 +/- 13.6 mm versus 24.2 +/- 11.2 mm, respectively; p = 0.049). CONCLUSION: Coronary vasoconstriction was exaggerated at distal segments in DES-implanted vessels compared to non-stented vessel segments and stent length was longer in the ACh provocation test positive group. PMID- 21297202 TI - Relationship between the angiographically derived SYNTAX score and outcomes in high-risk patients undergoing percutaneous coronary intervention. AB - Numerous risk scores have been designed to predict the outcome of percutaneous coronary intervention (PCI). The Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) score has been shown to predict outcome in patients with severe coronary artery disease (CAD) randomized to PCI or bypass surgery, but its utility in patients with less severe CAD is less well established. METHODS: We calculated the SYNTAX score in 482 patients with diabetes mellitus or chronic kidney disease (serum creatinine > 1.5 mg/ml) undergoing non-emergency PCI. The study endpoint was 3-year all-cause mortality or repeat revascularization. RESULTS: The mean age was 69 +/- 11 years, 44% were women, 82% had diabetes and they had 1.82 +/- 0.78 diseased vessels. The mean creatinine clearance was 67.3 +/- 37.2 ml/min. The mean SYNTAX score was 11 +/- 8, median of 9 (5-15), tertiles < 7, 7-12 and > 12. There was good interobserver concordance (0.784 and 0.816, p < 0.01, respectively among two pairs of observers). The 3-year estimated survival rate was 0.85 (95% confidence interval [CI] 0.82-0.88). By multivariable analysis, creatinine clearance (hazard ratio [HR] 0.82 per 10 ml/min, p < 0.001), ejection fraction (HR 0.82 per 10%, p = 0.004) and prior infarction (HR 1.7, p = 0.03) were the only predictors of death. The SYNTAX score did not predict mortality. The incidence of repeat PCI by increasing tertiles of SYNTAX score was 19.2%, 32.2% and 33.2%, respectively, p < 0.001. CONCLUSION: In patients at high risk for ischemic events without severe CAD, the SYNTAX score is not associated with mortality at 3 years. PMID- 21297203 TI - Risk scoring systems for PCI: does one size fit all? PMID- 21297204 TI - Effect of chronic angiotensin converting enzyme inhibitor therapy on myocardial injury in patients undergoing percutaneous coronary interventions. AB - BACKGROUND: Procedural MI is a frequent complication of percutaneous coronary intervention (PCI). Angiotensin converting enzyme inhibitors (ACE-I) have been shown to reduce ischemic events in the setting of acute myocardial infarction (MI) and heart failure. OBJECTIVE: We sought to evaluate whether chronic ACE-I treatment prior to PCI reduces the incidence of procedural MI. METHODS: The study cohort included consecutive patients from January 2003 to August 2004 undergoing PCI with normal baseline serum creatinine kinase (CK) and cardiac CK isoform (CK MB) (n = 265). Procedural MI was defined as CK-MB elevation >= 3 times the upper limit of normal. RESULTS: Patients on chronic ACE-I had a higher baseline prevalence of adverse prognostic features including diabetes (p = 0.02) and a trend towards a lower incidence of drug-eluting stent use (p = 0.07). Using multiple logistic regression, patients on chronic ACE-I therapy (n = 138) had a 64% reduction in procedural MI compared with those not on ACE-I (n = 127; odds ratio = 0.36; 95% confidence intervals 0.13-0.99; p = 0.05). Long-term outcomes, including death and major adverse cardiac events (MACE) (combined total of death, MI and target lesion revascularization were similar in the two groups. Procedural MI was, however, associated with increased MACE during follow up (60% vs. 35.4%; p = 0.035). CONCLUSION: Chronic ACE-I therapy before PCI may reduce the incidence of procedural MI. PMID- 21297205 TI - Spontaneous coronary artery dissection: case series with extended follow up. AB - Spontaneous coronary artery dissection (SCAD) is atherosclerotic or non atherosclerotic in origin. Eosinophilic infiltrate is identified in coronary artery adventitia in non-atherosclerotic SCAD. We postulate that a systemic inflammatory state causes SCAD in younger women who do not have significant coronary artery disease risk factors. We report a case series of 13 patients presenting with SCAD from ages 26-48 with follow up from 1 month to 13 years. Most patients did not have conventional risk factors for coronary artery disease (CAD). Approximately 50% of the patients developed recurrent dissection within the first 2 weeks of an index event, but < 25% were symptomatic during follow up. All patients were alive at follow up. Systemic inflammatory state was observed in 80% of patients who developed early recurrent dissection. SCAD should be strongly suspected in younger women presenting with acute coronary syndrome without CAD risk factors. Coronary dissection may recur within first 2 weeks, but patients have good long-term survival without new episodes of dissection. Broad rheumatologic and connective tissue disease work-up should be considered in young females presenting with SCAD. PMID- 21297206 TI - Percutaneous site-specific pharmacomechanical thrombolysis- thrombectomy system for bilateral acute limb ischemia. AB - Acute limb ischemia (ALI) remains a life-threatening condition. Studies with catheter-directed thrombolysis and percutaneous mechanical thrombectomy systems show modest improvements in mortality compared to surgery but with pitfalls of major bleeding, distal embolization, recurrent thrombosis, prolonged thrombolytic infusion and increased overall cost. We present a unique and therapeutically challenging case of bilateral acute lower limb ischemia that was managed percutaneously in one setting by a novel technique using site-specific (isolated) pharmaco-mechanical thrombolysis-thrombectomy (IPMT) system. PMID- 21297207 TI - Successful fenestration using a chronic total occlusion-dedicated guidewire in a patient with catheter-induced dissection of the right coronary artery. AB - Guiding catheter-induced coronary artery dissection is a rare, but hazardous complication of percutaneous coronary intervention (PCI) and is associated with the potential risk of impairment of coronary blood flow. Therefore, occurrence of this complication mandates a prompt revascularization procedure. A 68-year-old female patient with acute myocardial infarction caused by total occlusion of the proximal right coronary artery (RCA) underwent PCI. After revascularization by thrombus aspiration, catheter-induced dissection of the ostium of the right coronary artery (RCA) occurred when the guiding catheter and guidewire were accidentally removed. An attempt to engage the guiding catheter and guidewire into the true lumen failed because of total occlusion of the right coronary ostium. A chronic total occlusion (CTO)-dedicated guidewire was then used to create a fenestration of the intimal flap, and after it penetrated into the distal true lumen, a low-profile balloon catheter was dilated, and coronary flow from the false to the true lumen was established. After balloon dilatation, stents were deployed at both the dissection site and in the distal lesion. The final angiogram revealed restoration of coronary blood flow. We propose that application of a CTO-dedicated guidewire to create a fenestration of the intimal flap in the region of the coronary dissection is a feasible and effective alternative to conventional procedures. PMID- 21297208 TI - Coronary acute syndrome due to a large occlusive thrombus in an aortosaphenous vein graft. PMID- 21297209 TI - Recurrent coronary artery thrombus formation in the setting of diabetic ketoacidosis. AB - A 34-year-old male with insulin-dependent type II diabetes mellitus developed recurrent ST-elevation myocardial infarction in the setting of diabetic ketoacidosis. In both circumstances, coronary angiography revealed a large thrombus without angiographically evident coronary atherosclerosis. To our knowledge, this is the first report of diabetic ketoacidosis associated with coronary thrombosis in the absence of underlying atherosclerotic disease, inherited hypercoagulable disorders or previous personal or family history of thromboembolism. PMID- 21297210 TI - Coronary fistulas can develop collateral vessels: angiographic follow-up of an embolized giant right coronary artery-superior vena cava fistula in a patient with variant angina. AB - A 54-year-old man was transferred to our emergency department because of acute inferior myocardial infarction. However, ST-segment elevation resolved after intravenous nitrate administration on admission and coronary angiography revealed a nonobstructive atherosclerotic plaque at the mid-portion of the circumflex artery and a giant tortuous fistula from the right sinus of Valsalva to the superior vena cava. The patient was diagnosed with variant angina and coronary arteriovenous fistula after vasodilator treatment and maximal treadmill stress test. After effective medical treatment of variant angina and successful percutaneous coil embolization of the fistula, the patient had not experienced any angina episodes for 1 year. However, control coronary angiography revealed partial persistence of fistula flow because of new collateral vessels, bridging distal and proximal parts of the occluded segment. We present the first coexistence of coronary to superior vena cava fistula and variant angina in the literature. This report also shows the ability of coronary fistulas to develop collateral vessels, like coronary arteries. PMID- 21297211 TI - Recurrent myocardial infarction due to one subacute and two very late thrombotic events of drug-eluting stent associated with clopidogrel resistance. AB - Although drug-eluting stent (DES) thrombosis is a recognized complication of coronary intervention, recurrent late stent thrombosis is rarely reported. Clopidogrel resistance or low-responsiveness may be associated with recurrent late stent thrombosis after DES implantation. We present a diabetic patient with hypertension, obesity and heavy smoking history, who suffered 3 recurrent attacks of acute anterior ST-segment elevation myocardial infarction over 6 years due to recurrent thromboses of DES despite prolonged and regular triple antiplatelet therapy. Laboratory evaluation of hypercoagulability yielded negative results, but low responsiveness for clopidogrel was revealed by the VerifyNow P2Y12 assay. PMID- 21297212 TI - Simultaneous aortic and mitral metallic paravalvular leaks repaired through one delivery sheath. AB - Paravalvular leaks (PVL) are a well-known complication after prosthetic valve surgery. Effective non-surgical repair techniques are being developed using several off-label transcatheter occlusive devices given that there is no unique technique applicable to repair each paravalvular leak. We describe a technique used to simultaneously repair several PVL percutaneously, in a patient with double mechanical prosthesis using a single delivery system, by taking advantage of specific anatomical factors and selecting the best applicable devices. PMID- 21297213 TI - Sudden cardiac death due to large coronary aneurysm successfully treated with a covered stent and ChromaFlo guidance. AB - We present the case of a gentleman who presented to our hospital with recurrent episodes of sudden cardiac death treated initially with cardioversion. Immediate coronary angiography revealed a 7 mm aneurysm in the proximal left coronary artery. Using intravascular ultrasound and ChromaFlo technology, the aneurysm was successfully treated with a polytetrafluoroethylene-covered stent and the patient had no further episodes of sudden cardiac death. PMID- 21297214 TI - Intra-aortic balloon pump prior to noncardiac surgery: a forgotten remedy? AB - High-risk cardiac patients, especially those with severe coronary artery disease, are prone to ischemic, arrhythmic and heart failure complications during urgent or emergent noncardiac surgery. The American and European guidelines endorse selective revascularization by either coronary artery bypass grafting or percutaneous coronary intervention in symptomatic ischemic patients prior to major elective surgery. However, conventional revascularization may not be suitable for certain patients requiring emergent or urgent surgery. Reported are two representative cases in which severely ischemic patients were bridged uneventfully through moderate-risk surgery by using prophylactic intra-aortic balloon pump (IABP). Prophylactic IABP should be considered for the support of ischemic patients who are severely symptomatic or hemodynamically unstable undergoing moderate-high risk surgery, who are not suitable for preoperative revascularization. This therapeutic option should be acknowledged in the relevant guidelines. PMID- 21297215 TI - Coronary vasospasm in a postpartum woman. AB - Acute myocardial infarction during pregnancy or the postpartum period is rare. We report a case of a 40-year-old postpartum woman who developed ST-elevation myocardial infarction due to severe diffuse coronary vasospasm. To our knowledge, this is the first case of angiographically evidenced coronary vasospasm in a postpartum woman, in the absence of vasoconstrictive medications. PMID- 21297216 TI - Tortuous aorta in kyphoscoliosis. AB - We present a rare case of a tortuous aorta in a patient with kyphoscoliosis and the advantages of using radial angiography in this case. PMID- 21297217 TI - Acute stent thrombosis associated with heparin-induced thrombocytopenia and abciximab-induced profound thrombocytopenia. AB - Heparin-induced thrombocytopenia (HIT) is a wellknown complication after exposure to heparin products. Profound thrombocytopenia has also been reported with the use of abciximab, a glycoprotein IIb/IIIa receptor antagonist, which is used during percutaneous coronary intervention. Acute stent thrombosis is a rare but serious complication of HIT. We report an unusual case of acute stent thrombosis with concomitant heparin- and abciximab-induced profound thrombocytopenia and discuss the subsequent treatment strategies. Prompt identification and management of this disorder is critically important to avoid devastating complications. PMID- 21297218 TI - Left main thrombus as a complication of thrombectomy during primary percutaneous coronary intervention. AB - Small randomized trials in patients with ST-elevation myocardial infarction have shown that aspiration thrombectomy improves angiographic outcomes and may improve clinical outcomes. However, there remains a lack of reports on device-related complications. We report a case of a device complication involving the left main coronary artery where a large burden of thrombus was brought back into the left main coronary artery from the circumflex during aspiration thrombectomy. PMID- 21297219 TI - Chromosome organizaton in simple and complex unicellular organisms. AB - The genomes of unicellular organisms form complex 3-dimensional structures. This spatial organization is hypothesized to have a significant role in genomic function. Spatial organization is not limited solely to the three-dimensional folding of the chromosome(s) in genomes but also includes genome positioning, and the folding and compartmentalization of any additional genetic material (e.g. episomes) present within complex genomes. In this comment, I will highlight similarities in the spatial organization of eukaryotic and prokaryotic unicellular genomes. PMID- 21297220 TI - Cell cycle arrest is not senescence. AB - DNA damaging agents and radiation, cytotoxins and anti-cancer drugs, telomere erosion and cytokines, culture shock and mitogenic stimuli, oncogenes and tumor suppressors can induce both cell cycle arrest and cellular senescence. Due to this semi-coincidence, senescence is confused with cell cycle arrest, or even more misleadingly, with growth inhibition. With such misconceptions, cellular senescence cannot be linked to organismal aging. Also, the relation between cancer and senescence is distorted. Here I discuss why the link between arrest and senescence is semi-coincidental and how senescence is related to aging and cancer. PMID- 21297221 TI - Tumor-associated oncogenes go on (phage) display. PMID- 21297222 TI - Myc on my mind: a transcription factor family's essential role in brain development. PMID- 21297223 TI - Interleukin-9 (IL-9) and NPM-ALK each generate mast cell hyperplasia as single 'hit' and cooperate in producing a mastocytosis-like disease in mice. AB - Mast cell neoplasms are characterized by abnormal growth and focal accumulation of mast cells (MC) in one or more organs. Although several cytokines, including stem cell factor (SCF) and interleukin-9 (IL-9) have been implicated in growth of normal MC, little is known about pro-oncogenic molecules and conditions triggering differentiation and growth of MC far enough to lead to the histopathological picture of overt mastocytosis. The anaplastic lymphoma kinase (ALK) has recently been implicated in growth of neoplastic cells in malignant lymphomas. Here, we describe that transplantation of NPM-ALK-transplanted mouse bone marrow progenitors into lethally irradiated IL-9 transgenic mice not only results in lymphoma-formation, but also in the development of a neoplastic disease exhibiting histopathological features of systemic mastocytosis, including multifocal dense MC-infiltrates, occasionally with devastating growth in visceral organs. Transplantation of NPM-ALK-transduced progenitors into normal mice or maintenance of IL-9-transgenic mice without NPM-ALK each resulted in MC hyperplasia, but not in mastocytosis. Neoplastic MC in mice not only displayed IL 9, but also the IL-9 receptor, and the same was found to hold true for human neoplastic MC. Together, our data show that neoplastic MC express IL-9 receptors, that IL-9 and NPM-ALK upregulate MC-production in vivo, and that both'hits' act in concert to induce a mastocytosis-like disease in mice. These data may have pathogenetic and clinical implications and fit well with the observation that neoplastic MC in advanced SM strongly express NPM and multiple "lymphoid" antigens including CD25 and CD30. PMID- 21297224 TI - Breast carcinomatous tumoral emboli can result from encircling lymphovasculogenesis rather than lymphovascular invasion. AB - The canonical view of the origin of tumor lymphovascular emboli is that they usually originate from lymphovascular invasion as part of a multistep metastatic process. Recent experimental evidence has suggested that metastasis can occur earlier than previously thought and we found evidence that tumor emboli formation can result from the short-circuiting step of encircling lymphovasculogenesis. Experimentally, we used a xenograft of human inflammatory breast cancer (MARY-X), a model that exhibited florid tumor emboli, to generate tumoral spheroids in vitro. In observational studies, we chose human breast carcinoma cases where there appeared to be a possible transition of in situ carcinoma to lymphovascular emboli without intervening stromal invasion. These cases were studied by morphometry as well as IHC with tumor proliferation (Ki-67) and adhesion (E cadherin) markers, myoepithelial (p63), as well as endothelial (podoplanin [D2 40], CD31, VEGFR-3, Prox-1) markers. Unlabelled spheroids coinjected with either GFP or RFP-human myoepithelial cells or murine embryonal fibroblasts (MEFs) gave rise to tumors which exhibited GFP/RFP immunoreactivity within the cells lining the emboli-containing lymphovascular channels. In vitro studies demonstrated that the tumoral spheroids induced endothelial differentiation of cocultured myoepithelial cells and MEFs, measured by real time PCR and immunofluorescence. In humans, the in situ clusters exhibited similar proliferation, E-cadherin immunoreactivity and size as the tumor emboli (p =.5), suggesting the possibility that the latter originated from the former. The in situclusters exhibited a loss (50%-100%) of p63 myoepithelial immunoreactivity but not E-cadherin epithelial immunoreactivity. The tumor emboli were mainly present within lymphatic channels whose dual p63/CD31, p63/D2-40 and p63/VEGFR-3 and overall weak patterns of D2 40/CD31/VEGFR-3 immunoreactivities suggested that they represented immature and newly created vasculature derived from originally myoepithelial-lined ducts. Collectively both experimental as well as observational studies suggested the possibility that these breast cancer emboli resulted from encircling lymphovasculogenesis rather than conventional lymphovascular invasion. PMID- 21297226 TI - Identification of protein-coding regions using Modified Gabor-Wavelet Transform with Signal Boosting Technique. AB - Modified Gabor-Wavelet Transform (MGWT) has been previously used for identification of protein coding regions. This method does not significantly suppress the non-coding regions which may result incorrect identification. To enhance the discrimination between the coding and non-coding regions of the DNA sequence, Signal Boosting Technique (SBT) is applied on the projection coefficients which are obtained by applying MGWT. The performance of the proposed Modified Gabor-Wavelet Transform with Signal Boosting Technique (MGWT-SBT) is compared with other existing methods such as MGWT, Short-Time Discrete Fourier Transform (ST-DFT), anti-notch filter and multi-stage filter. Results show that the proposed method gives better identification accuracy as compared to other methods. PMID- 21297225 TI - Role of Pten in leukemia stem cells. AB - Chronic myeloid leukemia (CML) is initiated from the BCR-ABL-expressing leukemia stem cells (LSCs). These LSCs are highly resistant to BCR-ABL kinase inhibitors, imatinib, dasantinib and nilotinib, and methods for eradication of LSCs are still not available. It is critical to identify genes that play roles in survival and proliferation of LSCs. We recently discovered that the tumor suppressor gene Pten is downregulated in LSCs of CML mice. By genetic deletion or overexpression of Pten, we confirmed that Pten functions as a tumor suppressor in LSCs of CML, consistent with the role of Pten in LSCs of acute myeloid leukemia (AML) and progenitor cells of T-ALL progenitors. Functional enhancement of the Pten pathway provides a therapeutic strategy for targeting LSCs. PMID- 21297227 TI - A systematic bioinformatics approach for selection of target and screening of ligand for malignant tumours suppressing APG4A gene on Xq22.1. AB - Autophagy is a biological process involved in the intracellular destruction of endogenous proteins and has been suggested to be essential for cell homeostasis as well as for cell remodelling. Autophagy selectively eradicates damaged cytoplasmic components like injured mitochondria, which increases mutation rates and promote tumour initiation and progression. In addition, autophagy inhibits necrosis, which promotes progression by inducing angiogenesis and metastasis. This study aims to find autophagy-related cysteine endopeptidase A (APG4A) which has a significant role in suppressing various cancers. This bioinformatics research with a suitable target for inducing autophagy through APG4A would be a real breakthrough in cancer therapy. PMID- 21297228 TI - Digital tomosynthesis parallel imaging computational analysis with shift and add and back projection reconstruction algorithms. AB - Digital tomosynthesis is a novel technology that has been developed for various clinical applications. Parallel imaging configuration is utilised in a few tomosynthesis imaging areas such as digital chest tomosynthesis. Recently, parallel imaging configuration for breast tomosynthesis began to appear too. In this paper, we present the investigation on computational analysis of impulse response characterisation as the start point of our important research efforts to optimise the parallel imaging configurations. Results suggest that impulse response computational analysis is an effective method to compare and optimise imaging configurations. PMID- 21297229 TI - Assessing gene length biases in gene set analysis of Genome-Wide Association Studies. AB - Genome-Wide Association Studies (GWAS) have rapidly become a major genetics approach to studying complex diseases. Although many susceptibility variants and genes have been uncovered by single marker analysis, gene set based analysis is emerging as a very promising approach aiming to detect joint association of a set of genes with disease. In the available gene set based methods, it is often the smallest P value of the Single Nucleotide Polymorphisms (SNPs) in a gene region is used to represent the gene-level association signal. This approach may introduce strong bias of association signal towards long genes. In this study, we propose a resampling strategy by randomly generating genomic intervals across the accessible genomic region to estimate the background distribution of P values at the gene level. Comparing with the gene-wise P value in real data, the proportion of random intervals could be used to assess the bias that might be introduced by gene length and in turn to help the investigators choose the appropriate gene set analysis algorithms in their GWAS datasets. Our method uses only summarised GWAS data with no need of permutation, thus, it is computationally efficient. A computer program is freely available for the users. PMID- 21297230 TI - Fuzzy-adaptive-thresholding-based exon prediction. AB - Thresholding is always critical and decisive in many bioinformatics problems. In this paper, we propose and apply a fuzzy-logic-based adaptive thresholding approach to a well-known solution for the exon prediction problem, which uses a threshold on the frequency component at f = 1/3 in the nucleotide sequence. The proposed approach allows the thresholds to vary along the data set based on the local statistical properties. Experiments and results on the nucleotide data of Saccharomyces cerevisiae (Bakers yeast) illustrate the advantage of our approach. A user-friendly GUI in MATLAB is freely available for academic use at www.cs.iastate.edu/~ankitag/FATBEP.html. PMID- 21297231 TI - Structural assessment of the effects of amino acid substitutions on protein stability and protein protein interaction. AB - A structure-based approach is described for predicting the effects of amino acid substitutions on protein function. Structures were predicted using a homology modelling method. Folding and binding energy differences between wild-type and mutant structures were computed to quantitatively assess the effects of amino acid substitutions on protein stability and protein protein interaction, respectively. We demonstrated that pathogenic mutations at the interaction interface could affect binding energy and destabilise protein complex, whereas mutations at the non-interface might reduce folding energy and destabilise monomer structure. The results suggest that the structure-based analysis can provide useful information for understanding the molecular mechanisms of diseases. PMID- 21297232 TI - Room temperature synthesis of 2D CuO nanoleaves in aqueous solution. AB - A simple room temperature method was reported for the synthesis of CuO nanocrystals in aqueous solution through the sequence of Cu(2+) -> Cu(OA)2 -> Cu(OH)2 -> Cu(OH)(2-)4 -> CuO. Sodium oleate (SOA) was used as the surfactant and shape controller. The as-prepared samples were characterized by x-ray diffraction (XRD), scanning electron microscopy (SEM), UV-visible absorption spectroscopy (UV vis) and differential thermal analysis (DTA). It can be seen that 1D Cu(OH)(2) nanowires were first obtained from Cu(OA)(2) and, at room temperature, converted into 2D CuO nanoleaves (CuO NLs) in a short time under a weakly basic environment. On prolonging the reaction time, the top part of these 2D nanoleaves branched and separated along the long axis to form 1D rod-like nano-CuO because of the assistance of SOA. A possible transformation mechanism of Cu(OH)(2) to CuO nanostructures at room temperature in aqueous solution is discussed. The transformation velocity can be controlled by changing the pH value of the system. The prepared CuO NLs were used to construct an enzyme-free glucose sensor. The detecting results showed that the designed sensor exhibited good amperometric responses towards glucose with good anti-interferent ability. PMID- 21297233 TI - Formation of magnetic aluminium oxyhydroxide nanorods and use for hyperthermal effects. AB - In the present work, we show that a porous alumina template can easily be filled with magnetic nanoparticles and then be sealed by a hot water treatment (by forming an aluminium oxyhydroxide (AlOOH) sealant layer). The porous layer then can be separated from the substrate by an etch to form free magnetic AlOOH nano capsules. The process allows for a straightforward and highly defined size control of the magnetic units and can easily be scaled up. Furthermore, as AlOOH is biocompatible and has been used as a drug adjuvant for human use, the nanorod shaped capsules are highly promising for biomedical applications such as hyperthermal effects (heating in alternating magnetic fields). PMID- 21297234 TI - Light harvesting with multiwall carbon nanotube/silicon heterojunctions. AB - We report on a significant photocurrent generation from a planar device obtained by coating a bare n doped silicon substrate with a random network of multiwall carbon nanotubes (MWCNTs). This MWCNT/n-Si hybrid device exhibits an incident photon to current efficiency reaching up to 34% at 670 nm. We also show that MWCNTs covering a quartz substrate still exhibit photocurrent, though well below than that of the MWCNTs coating the silicon substrate. These results suggest that MWCNTs are able to generate photocurrent and that the silicon substrate plays a fundamental role in our planar device. The former effect is particularly interesting because MWCNTs are generally known to mimic the electronic properties of graphite, which does not present any photocurrent generation. On the basis of theoretical calculations revealing a weak metallic character for MWCNTs, we suggest that both metallic and semiconducting nanotubes are able to generate e-h pairs upon illumination. This can be ascribed to the presence of van Hove singularities in the density of states of each single wall carbon nanotube constituting the MWCNT and to the low density of electrons at the Fermi level. Finally, we suggest that though both MWCNTs and Si substrate are involved in the photocurrent generation process, MWCNT film mainly acts as a semitransparent electrode in our silicon-based device. PMID- 21297235 TI - In situ observation of reversible rippling in multi-walled boron nitride nanotubes. AB - The recent observation of high flexibility in buckled boron nitride nanotubes (BNNTs) contradicts the pre-existing belief about BN nanotube brittleness due to the partially ionic character of bonding between the B and N atoms. However, the underlying mechanisms and relationships within the nanotube remained unexplored. This study reports for the first time the buckling mechanism in multi-walled BNNTs upon severe mechanical deformation. Individual BNNTs were deformed inside a transmission electron microscope (TEM) equipped with an in situ atomic force microscopy holder. High-resolution TEM images revealed that bent BNNTs form multiple rippling upon buckling. The critical strain to form the first ripple was measured as 4.1% and the buckling process was reversible up to 26% strain. As opposed to carbon nanotubes, the BNNTs buckled into V-shaped ripples rather than smooth wavy shapes. The rippling wavelength was quantified in terms of the outer diameter and thickness of the nanotubes. The BNNTs showed a larger rippling wavelength compared to that of CNTs with the same number of walls. This difference was explained by the tendency of BN structures to reduce the number of thermodynamically unfavorable B-B and N-N bonds at the sharp corners in the rippling regions. The BNNTs' structure also exhibited a higher fracture strain compared to their counterpart. PMID- 21297236 TI - Amazing ageing property and in situ comparative study of field emission from tungsten oxide nanowires. AB - In this work, needle-shaping of tungsten oxide nanowires occurred during field emission characterization. Compared with nanowires with a flat apex, needle shaped emitters showed a lower threshold field of 11.9 V um(-1) for 1 mA cm(-2) and a higher emission current of 1120 uA at 16.2 V um(-1). Most notably, the measured ageing current dramatically increased by more than four times until it slightly decreased, tending towards stability. In addition, the samples showed striking difference in their nonlinear Fowler-Nordheim plot before and after ageing tests. Selected area diffraction and transmission electron microscope characterizations were used to further study these amazing results. PMID- 21297237 TI - Probing the photoresponse of individual Nb2O5 nanowires with global and localized laser beam irradiation. AB - Photoresponse of isolated Nb(2)O(5) nanowires (NW) padded with platinum (Pt) at both ends were studied with global irradiation by a laser beam and localized irradiation using a focused laser beam. Global laser irradiation on individual NW in ambient and vacuum conditions revealed photocurrent contributions with different time characteristics (rapid and slowly varying components) arising from defect level excitations, thermal heating effect, surface states and NW-Pt contacts. With a spot size of < 1 um, localized irradiation highlighted the fact that the measured photocurrent in this single NW device (with and without applied bias) depended sensitively on the photoresponse at the NW-Pt contacts. At applied bias, unidirectional photocurrent was observed and higher photocurrent was achieved with localized laser irradiation at reverse-biased NW-Pt contacts. At zero bias, the opposite polarity of photocurrents was detected when the two NW-Pt contacts were subjected to focused laser beam irradiation. A reduced Schottky barrier/width resulting from an increase in charge carriers and thermoelectric effects arising from the localized thermal heating due to focused laser beam irradiation were proposed as the mechanisms dictating the photocurrent at the NW Pt interface. Comparison of photocurrents generated upon global and localized laser irradiation showed that the main contribution to the photocurrent was largely due to the photoresponse of the NW-Pt contacts. PMID- 21297238 TI - Fabrication of surface magnetic nanoclusters using low energy ion implantation and electron beam annealing. AB - Magnetic nanoclusters have novel applications as magnetic sensors, spintronic and biomedical devices, as well as applications in more traditional materials such as high-density magnetic storage media and high performance permanent magnets. We describe a new synthesis protocol which combines the advantages of ion implantation and electron beam annealing (EBA) to produce surface iron nanoclusters. We compare the structure, composition and magnetic properties of iron nanoclusters fabricated by low dose 15 keV Fe implantation into SiO(2) followed by 1000 degrees C EBA or furnace annealing. Atomic force microscopy (AFM) and high resolution transmission electron microscopy (HRTEM) images together with superconducting quantum interference device (SQUID) magnetometry measurements show that only EBA leads to the rapid formation of surface crystalline Fe spherical nanoclusters, showing magnetic moments per Fe atom comparable to that of bulk bcc Fe and superparamagnetic properties. We propose a fabrication mechanism which includes e-beam enhanced desorption of SiO(2). This method has potential for fabricating nanoscale magnetic sensors integrated in microelectronic devices. PMID- 21297239 TI - Transparent liquid-crystal-based microlens array using vertically aligned carbon nanofiber electrodes on quartz substrates. AB - A novel transparent liquid-crystal-based microlens array has been fabricated using an array of vertically aligned multi-wall carbon nanofibers (MWCNFs) on a quartz substrate and its optical characteristics investigated. Electron beam lithography was used for the catalyst patterning on a quartz substrate to grow the MWCNF array of electrodes. The structure of the electrode array was determined through simulation to achieve the best optical performance. Both the patterned catalyst and growth parameters were optimized for optimal MWCNF properties. We report an in-depth optical characterization of these reconfigurable hybrid liquid crystal and nanofiber microlens arrays. PMID- 21297240 TI - Dose uncertainty in radiotherapy of patients with head and neck cancer measured by in vivo ESR/alanine dosimetry using a mouthpiece. AB - In order (i) to evaluate the dose uncertainty of the mouthpiece in daily use during intensity-modulated radiotherapy of patients with head and neck cancer, and (ii) to present a system for in vivo dosimetry of the oral mucosa, we equipped the mouthpiece with alanine dosimeter probes for in vivo dosimetry. The aim was to determine the dose uncertainty caused by the daily positioning of the mouthpiece during dynamic treatment techniques. During IMRT radiotherapy of patients with head and neck cancer, the doses accumulated next to the mucosa were measured in five patients and compared to the dose calculated by the treatment planning system. The comparison of the applied and measured dose for each measurement point showed in six of the eight alanine probe positions a good agreement within the given relative combined standard uncertainty of less than 4.5% for a accumulated dose of 30 Gy and less than 4.6% for an accumulated dose of 8 Gy, respectively. In two of the eight alanine probe positions the applied and measured doses differed by 7.7% and 8.2% from each other. The dominant contribution to the overall uncertainty for the in vivo measurements was the positioning of the dosimeter probes in the patient's body and their corresponding localization in the CT data as well as the inaccuracy of the available algorithm for dose distribution calculation at the low-density material/soft tissue interface between the mouthpiece and the mucosa. Regarding our results, we refrain from the use of a mouthpiece during dynamic treatments such as IMRT. PMID- 21297241 TI - Spatio-temporal (2D+T) non-rigid registration of real-time 3D echocardiography and cardiovascular MR image sequences. AB - In this paper we describe a method to non-rigidly co-register a 2D slice sequence from real-time 3D echocardiography with a 2D cardiovascular MR image sequence. This is challenging because the imaging modalities have different spatial and temporal resolution. Non-rigid registration is required for accurate alignment due to imprecision of cardiac gating and natural motion variations between cardiac cycles. In our approach the deformation field between the imaging modalities is decoupled into temporal and spatial components. First, temporal alignment is performed to establish temporal correspondence between a real-time 3D echocardiography frame and a cardiovascular MR frame. Spatial alignment is then performed using an adaptive non-rigid registration algorithm based on local phase mutual information on each temporally aligned image pair. Experiments on seven volunteer datasets are reported. Evaluation of registration errors based on expert-identified landmarks shows that the spatio-temporal registration algorithm gives a mean registration error of 3.56 +/- 0.49 and 3.54 +/- 0.27 mm for the short and long axis sequences, respectively. PMID- 21297242 TI - Modeling of beam customization devices in the pencil-beam splitting algorithm for heavy charged particle radiotherapy. AB - A broad-beam-delivery system for radiotherapy with protons or ions often employs multiple collimators and a range-compensating filter, which offer complex and potentially useful beam customization. It is however difficult for conventional pencil-beam algorithms to deal with fine structures of these devices due to beam size growth during transport. This study aims to avoid the difficulty with a novel computational model. The pencil beams are initially defined at the range compensating filter with angular-acceptance correction for upstream collimation followed by stopping and scattering. They are individually transported with possible splitting near the aperture edge of a downstream collimator to form a sharp field edge. The dose distribution for a carbon-ion beam was calculated and compared with existing experimental data. The penumbra sizes of various collimator edges agreed between them to a submillimeter level. This beam customization model will be used in the greater framework of the pencil-beam splitting algorithm for accurate and efficient patient dose calculation. PMID- 21297243 TI - GPU-based fast pencil beam algorithm for proton therapy. AB - Performance of a treatment planning system is an essential factor in making sophisticated plans. The dose calculation is a major time-consuming process in planning operations. The standard algorithm for proton dose calculations is the pencil beam algorithm which produces relatively accurate results, but is time consuming. In order to shorten the computational time, we have developed a GPU (graphics processing unit)-based pencil beam algorithm. We have implemented this algorithm and calculated dose distributions in the case of a water phantom. The results were compared to those obtained by a traditional method with respect to the computational time and discrepancy between the two methods. The new algorithm shows 5-20 times faster performance using the NVIDIA GeForce GTX 480 card in comparison with the Intel Core-i7 920 processor. The maximum discrepancy of the dose distribution is within 0.2%. Our results show that GPUs are effective for proton dose calculations. PMID- 21297244 TI - Modelling millimetre wave propagation and absorption in a high resolution skin model: the effect of sweat glands. AB - The aim of this work was to investigate the potential effect of sweat gland ducts (SGD) on specific absorption rate (SAR) and temperature distributions during mm wave irradiation. High resolution electromagnetic and bio-heat transfer models of human skin with SGD were developed using a commercially available simulation software package (SEMCAD XTM). The skin model consisted of a 30 um stratum corneum, 350 um epidermis and papillary dermis (EPD) and 1000 um dermis. Five SGD of 60 um radius and 300 um height were embedded linearly with 370 um separation. A WR-10 waveguide positioned 20 um from the skin surface and delivering 94 GHz electromagnetic radiation was included in the model. Saline conductivity was assigned inside SGD. SAR and temperatures were computed with and without SGD. Despite their small scale, SAR was significantly higher within SGD than in the EPD without SGD. Without SGD, SAR and temperature maxima were in the dermis near EPD. With SGD, SAR maximum was inside SGD while temperature maximum moved to the EPD/stratum-corneum junction. Since the EPD participates actively in perception, the effect of SGD should be taken into account in nociceptive studies involving mm-waves. This research represents a significant step towards higher spatial resolution numerical modelling of the skin and shows that microstructures can play a significant role in mm-wave absorption and induced temperature distributions. PMID- 21297245 TI - Intensity-modulated arc therapy: principles, technologies and clinical implementation. AB - Intensity-modulated arc therapy (IMAT) was proposed by Yu (1995 Phys. Med. Biol. 40 1435-49) as an alternative to tomotherapy. Over more than a decade, much progress has been made. The advantages and limitations of the IMAT technique have also been better understood. In recent years, single-arc forms of IMAT have emerged and become commercially adopted. The leading example is the volumetric modulated arc therapy (VMAT), a single-arc form of IMAT that delivers apertures of varying weights with a single-arc rotation that uses dose-rate variation of the treatment machine. With commercial implementation of VMAT, wide clinical adoption has quickly taken root. However, there remains a lack of general understanding for the planning of such arc treatments, as well as what delivery limitations and compromises are made. Commercial promotion and competition add further confusion for the end users. It is therefore necessary to provide a summary of this technology and some guidelines on its clinical implementation. The purpose of this review is to provide a summary of the works from the radiotherapy community that led to wide clinical adoption, and point out the issues that still remain, providing some perspective on its further developments. Because there has been vast experience in IMRT using multiple intensity-modulated fields, comparisons between IMAT and IMRT are also made in the review within the areas of planning, delivery and quality assurance. PMID- 21297246 TI - Are transient environmental agents involved in the aetiology of primary biliary cirrhosis? PMID- 21297247 TI - Infectious agents in the pathogenesis of primary biliary cirrhosis. AB - Primary biliary cirrhosis (PBC) is a chronic progressive cholestatic liver disease which is characterized by the breakdown of self-tolerance to the highly conserved pyruvate dehydrogenase complex, specially the pyruvate dehydrogenase E2 complex (PDC-E2). The breakdown of the tolerance to such antigens leads to an autoimmune process characterized by portal inflammation and immune-mediated destruction of the intrahepatic bile ducts. Epidemiological studies have suggested that infections agents can trigger or even exacerbate the disease. Among other gram negative bacteria, Escherichia Coli, and Nosphingobium aromaticivorans are the most associated agents reported hitherto. Epidemiological and molecular evidence points towards molecular mimicry between some components of these microorganisms and specific amino-acid sequences that are present in proteins on normal cells of the biliary tract. In this review, we revisit all reports suggesting that infectious agents might be associated with the autoimmune pathogenesis of PBC. We also retrieve the immune molecular mimicry mechanisms that are likely involved with the autoimmune process in PBC. PMID- 21297248 TI - Infectious agents and xenobiotics in the etiology of primary biliary cirrhosis. AB - Primary biliary cirrhosis (PBC)is a chronic autoimmune cholestatic liver disease that manifests a latitudinal gradient in prevalence and incidence. The mechanisms leading to the initiation and perpetuation of PBC remain largely enigmatic, although it is established that a combination of genetic predisposition and environmental stimulation is required. PBC is also characterized by a high concordance rate in monozygotic twins and is considered a model autoimmune disease because of several features common to other conditions and the relatively homogeneous serological and biochemical features. From a diagnostic standpoint, PBC is characterized by the highest specificity of serum autoantibodies directed at mitochondrial proteins. Several risk factors have been suggested to be associated with PBC, including exposure to infectious agents and chemical xenobiotics that will be critically discussed in the present review article. PMID- 21297249 TI - The role of E. coli infection in the pathogenesis of primary biliary cirrhosis. AB - Among various infectious agents possibly involved in the pathogenesis of primary biliary cirrhosis (PBC), Escherichia Coli (E. coli) has received special attention because of epidemiological and experimental evidence linking this bacterium with the disease's development. This review discusses early and more recent epidemiological studies associating recurrent urinary tract infections with E. coli and the development of PBC. We also critically review data provided over the years demonstrating disease-specific humoral and cellular immune responses against E. coli antigens in patients with PBC. Finally, we assess the relevance of experimental findings reporting cross-reactive immunity between mimicking sequences of E. coli and the major PBC mitochondrial antigens in the pathogenesis of the PBC. We also address the extent to which molecular mimicry and immunological cross-reactivity can be considered as a critical pathogenic process linking infection with self destruction. PMID- 21297250 TI - Infection as a risk factor in the pathogenesis of primary biliary cirrhosis: pros and cons. AB - Primary biliary cirrhosis (PBC) is a chronic and slowly progressive cholestatic liver disease of autoimmune etiology, characterized by injury of the intrahepatic bile ducts that may eventually lead to cirrhosis and liver failure. Evidence suggests cardinal roles for both environmental factors and genetic susceptibility. Nevertheless, the absolute etiology of PBC is unclear, despite recent well-designed case-control studies that reported environmental risk factors, including infectious agents, for PBC. Of the reported infectious agents, some of them are not reproducible and remain controversial. However, infection is no doubt one of the major risks among the environmental factors. This is supported by the fact that infectious agents in autoimmune diseases express antigens resulting in molecular mimicry and xenobiotics that play a role in breaking tolerance. Taken together, recent findings from genome wide assays as well as novel animal models may enable us to better understand the mechanism of pathogenesis responsible for this disease. PMID- 21297251 TI - Primary biliary cirrhosis: environmental risk factors. AB - Primary biliary cirrhosis (PBC) is an autoimmune disease of unclear etiology. It is a chronic, progressive condition that causes intrahepatic ductal destruction ultimately leading to symptoms of cholestasis, cirrhosis and liver failure. The disease predominantly affects middle aged Caucasian women. It has a predilection to certain regions and is found in higher incidences in North America and Northern Europe. It also has a genetic predisposition with a concordance rate of 60% among monozygotic twins. Combinations of genetic and environmental factors are proposed in the pathogenesis of this disease with a compelling body of evidence that suggests a role for both these factors. This review will elucidate data on the proposed environmental agents involved the disease's pathogenesis including xenobiotic and microbial exposure and present some of the supporting epidemiologic data. PMID- 21297252 TI - Environmental agents involved in the cause of primary biliary cirrhosis. AB - Primary biliary cirrhosis (PBC) is an immune mediated chronic cholestatic liver disease with a slowly progressive course It is a universal disease with a reported latitudinal gradient in prevalence and incidence. The aetiology of primary biliary cirrhosis is still unknown. It is characterized by a 60% concordance in monozygotic twins and is considered an autoimmune disease because of several features common to other autoimmune conditions and the relatively homogeneous serological and biochemical features. However geoepidemiological and clinical studies strongly imply that environmental factors also play an important role. It is accepted that the disease is clearly the result of a combination of genetic and environmental factors. Several risk factors have been suggested to be associated with PBC, including exposure to infectious agents and chemical xenobiotics. This review will attempt to place such factors in perspective. PMID- 21297253 TI - PBC triggers in water reservoirs, coal mining areas and waste disposal sites: from Newcastle to New York. AB - Various environmental factors have been proposed as triggers of primary biliary cirrhosis (PBC), a progressive autoimmune cholestatic liver disease which is characterised by the destruction of the small intrahepatic bile ducts. Support for their pathogenic role in PBC is provided by epidemiological studies reporting familial clustering and clusters of the disease within a given geographical area. The seminal study by Triger reporting that the great majority of PBC cases in the English city of Sheffield drank water from a specific water reservoir, has been followed by studies reporting disease 'hot spots' within a restricted geographic region of the former coal mining area of Newcastle. The New York study reporting an increased risk and significant clustering of PBC cases near toxic federal waste disposal sites has added strength to the notion that environmental factors, possibly in the form of infectious agents or toxic/chemical environmental factors in areas of contaminated land, water or polluted air may play a key role in the development of the disease. This review discusses the findings of reports investigating environmental factors which may contribute to the cause of primary biliary cirrhosis. PMID- 21297254 TI - Upregulation of brain renin angiotensin system by 27-hydroxycholesterol in Alzheimer's disease. AB - In spite of the fact that cholesterol does not pass the blood-brain barrier, hypercholesterolemia has been linked to increase Alzheimer's disease (AD) risk. Hypertension is another risk factor and angiotensin converting enzyme (ACE) activity is known to be increased in AD. Furthermore, a lower incidence of AD has been reported in patients taking anti-hypertensive drugs. Here we show that the levels of angiotensinogen (AGT) and ACE are increased in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment and AD. Moreover, we show ACE activity in the CSF to be positively correlated with both plasma and CSF levels of 27-hydroxycholesterol (27-OH), an oxysterol known to pass through the BBB and taken up from the circulation by the brain. In addition, treatment of rat primary neurons, astrocytes, and human neuroblastoma cells with 27-OH resulted in increased production of AGT. Our results demonstrate that upregulation of renin angiotensin system (RAS) in AD brains occurs not only at the enzymatic level (ACE) but also at the substrate level (AGT). The possibility that 27-OH is part of a mechanism linking hypercholesterolemia with increased brain RAS activity and increased AD risk is discussed. PMID- 21297255 TI - Amyloid-beta-induced amyloid-beta secretion: a possible feed-forward mechanism in Alzheimer's Disease. AB - Amyloid-beta (Abeta) peptides, 36-43 amino acids in length, are produced from beta- and gamma-secretase cleavage of the amyloid-beta protein precursor (AbetaPP), and are one of the causative agents of Alzheimer's disease (AD). Here we show that an ELISA can detect total rodent Abeta without interference from physiological concentrations of human Abeta. In cultured dissociated rat cortical neurons and rat and mouse hippocampal organotypic slices, we apply the assay to measure the production of Abeta in response to treatment with hydrogen peroxide, a known stimulator of Abeta secretion, or human Abeta dimer/trimer (Abetad/t), fractionated from the culture medium of 7PA2 cells. Peroxide increases Abeta secretion by about 2 fold, similar to results from previous reports that used a different assay. Of greater significance is that physiologically relevant concentrations (~250 pM) of human Abetad/t increase rodent Abeta secretion from cultured rat cortical neurons by >3 fold over 4 days. Surprisingly, neither treatment with peroxide nor human Abetad/t leads to accumulation of intracellular Abeta. Human Abetad/t increased >2 fold the Abeta secreted by organotypic hippocampal slices from tau knock-out mice whether or not they expressed a human tau transgene, suggesting tau plays no role in enhanced Abeta secretion. Together, these results support an Abeta-mediated feed-forward mechanism in AD progression. PMID- 21297256 TI - Age-related macular degeneration (AMD): Alzheimer's disease in the eye? AB - Age-related macular degeneration (AMD) is a late-onset, neurodegenerative retinal disease that shares several clinical and pathological features with Alzheimer's disease (AD), including stress stimuli such as oxidative stress and inflammation. In both diseases, the detrimental intra- and extracellular deposits have many similarities. Aging, hypercholesterolaemia, hypertension, obesity, arteriosclerosis, and smoking are risk factors to develop AMD and AD. Cellular aging processes have similar organelle and signaling association in the retina and brain tissues. However, it seems that these diseases have a different genetic background. In this review, differences and similarities of AMD and AD are thoroughly discussed. PMID- 21297257 TI - Physical exercise protects against Alzheimer's disease in 3xTg-AD mice. AB - Physical exercise is considered to exert a positive neurophysiological effect that helps to maintain normal brain activity in the elderly. Expectations that it could help to fight Alzheimer's disease (AD) were recently raised. This study analyzed the effects of different patterns of physical exercise on the 3xTg-AD mouse. Male and female 3xTg-AD mice at an early pathological stage (4-month-old) have had free access to a running wheel for 1 month, whereas mice at a moderate pathological stage(7-month-old) have had access either during 1 or 6 months. The non-transgenic mouse strain was used as a control. Parallel animal groups were housed in conventional conditions. Cognitive loss and behavioral and psychological symptoms of dementia (BPSD)-like behaviors were present in the 3xTg AD mice along with alteration in synaptic function and ong-term potentiation impairment in vivo. Brain tissue showed AD-pathology and oxidative-related changes. Disturbances were more severe at the older age tested. Oxidative stress was higher in males but other changes were similar or higher in females. Exercise treatment ameliorated cognitive deterioration and BPSD-like behaviors such as anxiety and the startle response. Synaptic changes were partially protected by exercise. Oxidative stress was reduced. The best neuroprotection was generally obtained after 6 months of exercise in 7-month-old 3xTg-AD mice. Improved sensorimotor function and brain tissue antioxidant defence were induced in both 3xTg-AD and NonTg mice. Therefore, the benefits of aerobic physical exercise on synapse, redox homeostasis, and general brain function demonstrated in the 3xTg AD mouse further support the value of this healthy life-style against neurodegeneration. PMID- 21297259 TI - Structural and functional network connectivity breakdown in Alzheimer's disease studied with magnetic resonance imaging techniques. AB - Patients with Alzheimer's disease (AD) experience a brain network breakdown, reflecting disconnection at both the structural and functional system level. Resting-state (RS) functional MRI (fMRI) studies demonstrated that the regional coherence of the fMRI signal is significantly altered in patients with AD and amnestic mild cognitive impairment. Diffusion tensor (DT) MRI has made it possible to track fiber bundle projections across the brain, revealing a substantially abnormal interplay of "critical" white matter tracts in these conditions. The observed agreement between the results of RS fMRI and DT MRI tractography studies in healthy individuals is encouraging and offers interesting hypotheses to be tested in patients with AD, a MCI, and other dementias in order to improve our understanding of their pathobiology in vivo. In this review,we describe the major findings obtained in AD using RS fMRI and DT MRI tractography, and discuss how the relationship between structure and function of the brain networks in AD may be better understood through the application of MR-based technology. This research endeavor holds a great promise in clarifying the mechanisms of cognitive decline in complex chronic neurodegenerative disorders. PMID- 21297258 TI - A multi-center study of ACE and the risk of late-onset Alzheimer's disease. AB - A key pathological feature of late-onset Alzheimer's disease (LOAD) is the abnormal extracellular accumulation of the amyloid-beta (Abeta) peptide. Thus, altered Abeta degradation could be a major contributor to the development of LOAD. Variants in the gene encoding the Abeta-degrading enzyme, angiotensin-1 converting enzyme (ACE) therefore represent plausible candidates for association with LOAD pathology and risk. Following Alzgene meta-analyses of all published case-control studies, the ACE variants rs4291 and rs1800764 showed significant association with LOAD risk. Furthermore ACE haplotypes are associated with both plasma ACE levels and LOAD risk. We tested three ACE variants (rs4291, rs4343, and rs1800764) for association with LOAD in ten Caucasian case-control populations (n = 8,212). No association was found using multiple logistic models (all p > 0.09). We found no population heterogeneity (all p > 0.38) or evidence for association with LOAD risk following meta-analysis of the ten populations for rs4343 (OR = 1.00), rs4291 (OR = 0.97), or rs1800764 (OR = 0.99). Although we found no haplotypic association in our complete dataset (p = 0.51), a significant global haplotypic p-value was observed in one population (p = 0.007) due to an association of the H3 haplotype (OR = 0.72, p = 0.02) and a trend towards an association of H4 (OR = 1.38, p = 0.09) and H7 (OR = 2.07, p = 0.08) although these did not survive Bonferroni correction. Previously reported associations of ACE variants with LOAD will be diminished following this study. At best, ACE variants have modest effect sizes, which are likely part of a complex interaction between genetic, phenotypic and pharmacological effects that would be undetected in traditional case-control studies. PMID- 21297260 TI - Anti-amnesic and neuroprotective actions of the sigma-1 receptor agonist (-)-MR22 in rats with selective cholinergic lesion and amyloid infusion. AB - Sigma-1 receptor agonists have recently attracted much attention as potential therapeutic drugs for cognitive and affective disorders, however, it is still unclear whether they act via modulation of transmitter release or activation of sigma-1 receptors in memory-related brain regions. In the present study,we have investigated the anti-amnesic and neuroprotective actions of the compound (-) methyl (1S,2R)-2-{[1-adamantyl(methyl)amino]methyl}-1-phenylcyclopropane carboxylate) [(-)-MR22],a selective sigma-1 receptor agonist able to protect cultured cortical neurons from amyloid toxicity. To this aim, cognitive deficits, cholinergic loss, and amyloid peptide accumulation were obtained in the rat by simultaneous injections of a selective immunotoxin and pre-aggregated amyloid peptide into the basal forebrain and the hippocampus, respectively. At about five six weeks post-lesion, the double-lesioned animals exhibited dramatic deficits in spatial learning and memory, whereas animals with single injections of either compound were not or only marginally affected, in spite of equally severe cholinergic loss oramyloid deposition. Administration of (-)-MR22 appeared to reverse cognitive impairments in double lesioned animals, whereas pre-treatment with the selective sigma-1 antagonist BD1047 abolished this effect. Moreover, (-) MR22 normalized the levels of cell-associated amyloid-beta protein precursor (AbetaPP) in the neocortex and hippocampus, thus sustaining a non-amyloidogenic AbetaPP processing. By contrast, treatment with (-)-MR22 produced no effects whatsoever in intact animals. Thus, sigma-1 receptor agonists such as (-)-MR22 may ameliorate perturbed cognitive abilities and exert a protective action onto target neurons, holding promises as viable tools for memory enhancement and neuroprotection. PMID- 21297261 TI - Socioeconomic status during lifetime and cognitive impairment no-dementia in late life: the population-based aging in the Chianti Area (InCHIANTI) Study. AB - Thousand and twelve dementia-free elderly (60-98 years old) enrolled in the InChianti Study (Italy) were evaluated at baseline (1998-2000) and at 3-year follow-up (2001-2003) with the aim of analyzing the association of lifetime socioeconomic status (SES) with prevalent and incident cognitive impairment no dementia (CIND). SES was defined from information on formal education, longest held occupation, and financial conditions through life. CIND was defined as age adjusted Mini-Mental State Examination score one standard deviation below the baseline mean score of participants without dementia. Logistic regression and Cox proportional-hazards models were used to estimate the association of SES with CIND. Demographics,occupation characteristics (i.e., job stress and physical demand), cardiovascular diseases, diabetes, apolipoprotein E (APOE)genotype, smoking, alcohol consumption, depressive symptoms, and C-reactive protein were considered potential confounders.Prevalence of CIND was 17.7%. In the fully adjusted model, low education (OR = 2.1; 95% confidence intervals, CI = 1.4 to 3.2)was associated with prevalent CIND. Incidence rate of CIND was 66.0 per 1000 person-years. Low education (HR = 1.7; 95% CI = 1.04 to 2.6) and manual occupation (HR = 1.9; 95% CI = 1.0 to 3.6) were associated with incident CIND. Among covariates,high job-related physical demand was associated with both prevalent and incident CIND (OR = 1.6; 95% CI = 1.1 to 2.4 and HR= 1.5; 95% CI = 1.0 to 2.3). After stratification for education, manual occupation was still associated with CIND among participants with high education (HR = 2.2; 95% CI = 1.2 to 4.3 versus HR= 1.4; 95% CI = 0.2 to 10.4 among those with low education). Proxy markers of lifetime SES (low education, manual occupation and high physical demand) are cross-sectional correlates of CIND and predict incident CIND over a three-year follow-up. PMID- 21297262 TI - Cerebrospinal fluid biomarkers for Alzheimer's disease: diagnostic performance in a homogeneous mono-center population. AB - The cerebrospinal fluid (CSF) biomarkers amyloid-beta (Abeta)(1-42), T-tau, and P tau have good diagnostic accuracy for clinically diagnosed Alzheimer's disease (AD). However, in multi-center studies, the predictive values of the CSF biomarkers have been lower, possibly due to differences in procedures for lumbar puncture and CSF handling and storage, and to differences in patient populations, clinical evaluations, and diagnostic procedures. Here we investigate the diagnostic accuracy of CSF biomarkers in a well defined homogeneous mono-center population. We also evaluate an extended panel of amyloid related biomarkers. Sixty consecutive patients admitted for cognitive impairment to a memory clinic were recruited. The participants included patients with AD or mild cognitive impairment (MCI) diagnosed with AD upon follow-up (n = 32), patients with stable MCI (n = 13), patients with other dementias diagnosed at primary evaluation or upon follow-up (n = 15), and healthy controls(n = 20). CSF was analyzed for Abeta(1-42), T-tau, and P-tau, and PA(X-38), Abeta(X-40), Abeta(X-42), sAbetaPPalpha, and sAbetaPPbeta. In multivariate analysis, thecore biomarkers Abeta(1-42), T-tau, and P-tau demonstrated a high ability to diagnose AD versus the combined groups of controls and stable MCI, with an area under the receiver operating characteristic curve (AUROC) of 0.97 (95% CI 0.93-1.00, p < 0.0001). The additional biomarkers only marginally increased AUROC to 0.98 (95% CI 0.95 1.00, p < 0.0001), this increase mainly mediated by Abeta(X-42). In conclusion, CSF biomarkers Abeta(1-42), T-tau, and P-tau have very high diagnostic accuracy in a well defined cohort of untreated patients, demonstrating the excellent potency of CSF biomarkers to identify pathological processes in AD when astringent analytical protocol is used. PMID- 21297263 TI - Genetic association of sequence variants near AGER/NOTCH4 and dementia. AB - We performed a survey of sequence variation in a series of 20 genes involved in inflammation-related pathways for association with dementia risk in twin and unrelated case-control samples consisting in total of 1462 Swedish dementia casesand 1929 controls. For a total of 218 tested genetic markers, strong evidence was obtained implicating a region near AGER and NOTCH4 on chromosome 6p with replication across both samples and maximum combined significance at marker rs1800625 (OR = 1.37, 95% CI 1.19-1.56, p = 1.36*10(-6)). Imputation of the associated genomic interval provided an improved signal atrs8365, near the 3UTR of AGER (p = 7.34*10(-7)). The associated region extends 120 kb encompassing 11 candidate genes.While AGER encodes a key receptor for amyloid-beta protein, an analysis of network context based upon genes now confirmed to contribute to dementia risk (AbetaPP, PSEN1, PSEN2, CR1, CLU, PICALM, and APOE) suggested strong functional coupling to NOTCH4, with no significant coupling to the remaining candidates. The implicated region occurs in the broad HLA locus on chromosome 6p, but associated markers were not in strong LD with known variants that regulate HLA gene function, suggesting that this may represent a signal distinct from immune-system pathways. PMID- 21297264 TI - PSEN1 and PRNP gene mutations: co-occurrence makes onset very early in a family with FTD phenotype. AB - Prion protein (PRNP) gene mutations have recently been associated with clinical pictures resembling Frontotemporal dementia (FTD). We describe a novel seven extra-repeat insertional mutation in the PRNP gene in a family affected by early onset autosomal dominant FTD previously reported as caused by a PSEN1 mutation in which there was inconsistency between clinical picture and genotype. Both mutations were pathogenic and showed a variable penetrance when present separately; when occurring together, the onset was very early, within the third decade of life. Genetic screening of the PRNP gene becomes of major importance in early onset autosomal dominant dementia. PMID- 21297265 TI - Synaptic loss in the inferior temporal gyrus in mild cognitive impairment and Alzheimer's disease. AB - Alzheimer's disease (AD) is a slowly progressing form of dementia characterized in its earliest stages as a loss of memory. Individuals with amnestic mild cognitive impairment (aMCI) may be in the earliest stages of the disease and represent an opportunity to identify pathological changes related to the progression of AD. Synaptic loss is one of the hallmarks of AD and associated with cognitive impairment. The inferior temporal gyrus plays an important role in verbal fluency, a cognitive function affected early in the onset of AD. Unbiased stereology coupled with electron microscopy was used to quantify total synaptic numbers in lamina 3 of the inferior temporal gyrus from short postmortem autopsy tissue harvested from subjects who died at different cognitive stages during the progression of AD. Individuals with aMCI had significantly fewer synapses (36%) compared to individuals with no cognitive impairment. Individuals with AD showed a loss of synapses very similar to the aMCI cohort. Synaptic numbers correlated highly with Mini Mental State Examination scores and a test of category verbal fluency. These results demonstrate that the inferior temporal gyrus is affected during the prodromal stage of the disease and may underlie some of the early AD related clinical dysfunctions. PMID- 21297266 TI - Implication of a genetic variant at PICALM in Alzheimer's disease patients and centenarians. AB - A common polymorphism (rs3851179) in the PICALM (phosphatidylinositol-binding clathrin assembly protein) gene has been recently associated with reduced risk of developing late-onset Alzheimer's disease (LOAD). We analyzed the genotype and allele distributions of the PICALM polymorphism in 813 Italian subjects, including LOAD patients and centenarians. The segregation of the PICALM rs3851179 showed no statistically significant difference between LOAD cases and controls. The implication of a genetic variant at PICALM is confirmed for the first time, in centenarians, thus suggesting a possible role in longevity. PMID- 21297267 TI - Berberine attenuates calyculin A-induced cytotoxicity and Tau hyperphosphorylation in HEK293 cells. AB - The Chinese herb berberine has versatile health effects. Recent reports indicate that berberine has the potential to prevent and treat Alzheimer's disease (AD). In the present study, we employed tau-expressing HEK293 cells (HEK293/tau) treated with calyculin-A as a cellular model to investigate the roles of berberine in cell viability, tau phosphorylation, and oxidative stress. We found a significant reduction of calyculin A-induced tau hyperphosphorylation at Ser198/199/202, Ser396, Ser404, Thr205, and Thr231 24 h after treatment with 20 MUg/ml berberine. Berberine also restored protein phosphates 2A activity and reversed glycogen synthase kinase-3beta (GSK-3beta) activation, as determined by phosphatase activity assay and GSK-3beta phosphorylation at Tyr216 and Ser9, respectively. Furthermore, berberine reversed both the increase of malondialdehyde and the decrease of superoxide dismutase activity induced by calyculin A, indicating its role in anti-oxidative stress. Our findings suggest that berberine may be a potential therapeutic drug for AD. PMID- 21297268 TI - CDR state transition probabilities in Alzheimer's disease with and without cholinesterase inhibitor intervention in an observational cohort. AB - Cholinesterase inhibitors and memantine are medications used in the treatment of Alzheimer's disease (AD). These agents have been shown to reduce the rate of AD progression in randomized trials. The objective of this study is to evaluate the association between treatment with cholinesterase inhibitors or memantine and the probability of transitioning to a more severe Clinical Dementia Rating (CDR) state. Analysis was limited to possible or probable AD patients from NACC-UDS with three or more observations, baseline CDR score of 0.5 or 1, and without reported use AD drugs at enrollment. Use of an AD drug at any observation after baseline was classified as treatment. Odds of CDR stage were calculated by multinomial logistic regression controlling for baseline age, baseline MMSE score, education, marital status, race, gender, place of residence, and time since last measure. The resulting coefficients from logistic regression were used to calculate transitional probabilities. A total of 1,114 patients were included. No differences were observed in the probability of transitioning to more severe CDR states based on treatment, but treated patients had lower odds of death, OR 0.49 (95% CI 0.31 to 0.79) compared to untreated. Ultimately, this study failed to detect a difference in the probability of progressing to a more severe AD state as a result of treatment in an observational cohort of AD patients, but is limited by non-randomized treatment selection and small dataset. The NACC-UDS dataset is ongoing and this analysis may be improved if repeated when more data is available. PMID- 21297269 TI - Disturbed choline plasmalogen and phospholipid fatty acid concentrations in Alzheimer's disease prefrontal cortex. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by brain deposition of senile (neuritic) plaques containing amyloid beta, neurofibrillary tangles, synaptic loss, neuroinflammation, and overexpression of arachidonic acid (AA, 20:4n-6) metabolizing enzymes. Lipid concentration changes have been reported in different brain regions, but often partially or as a percent of the total concentration. In this study, we measured absolute concentrations (per gram wet weight) of a wide range of lipids in postmortem prefrontal cortex (Brodmann area 9) from 10 AD patients and 9 non-AD controls. Mean total brain lipid, phospholipid, cholesterol, and triglyceride concentrations did not differ significantly between AD and controls. There was a significant 73% decrease in plasmalogen choline, but no difference in other measured phospholipids. Fatty acid concentrations in total phospholipid did not differ from control. However, docosahexaenoic acid (DHA, 22:6n-3) was reduced in ethanolamine glycerophospholipid and choline glycerophospholipid, but increased in phosphatidylinositol. AA was reduced in choline glycerophospholipid, but increased in phosphatidylinositol, while docosatetraenoic acid (22:4n-6), an AA elongation product, was reduced in total brain lipid, cholesteryl ester and triglyceride. These lipid changes, which suggest extensive membrane remodeling, may contribute to membrane instability and synaptic loss in AD and reflect neuroinflammation. PMID- 21297270 TI - The flavonoid apigenin protects brain neurovascular coupling against amyloid beta25-35-induced toxicity in mice. AB - Apigenin, one of the most common flavonoids, has demonstrated anti-inflammatory, anticarcinogenic, and free radical-scavenging activities. Recent studies revealed its protective effects against amyloid-beta (Abeta)-induced neurotoxicity, but the mechanism was unclear. In the present study, we aimed to explore the anti amnesic and protective effects of apigenin against Abeta25-35-induced toxicity and the underlying mechanisms in the cerebral cortex in mice. The learning and memory impairments, changes in morphology of major components of neurovascular unit, ultrastructural changes and oxidative stress of cerebral cortex, cerebrovascular dysfunction, and neuronal changes were detected after oral administration of apigenin continuously for 8 days. Our results demonstrate that oral administration of apigenin for Abeta25-35-induced amnesic mice conferred robust neurovascular coupling protection, involving improvement of the learning and memory capabilities, maintenance of neurovascular unit integrity, modulation of microvascular function, reduction of neurovascular oxidative damage, increase of regional cerebral blood flow, improvement of cholinergic system involving the inhibition of AChE activity and elevation of ACh level, and modification of BNDF, TrkB, and phospho-CREB levels. PMID- 21297271 TI - Region- and age-specific changes in glutamate transport in the AbetaPP23 mouse model for Alzheimer's disease. AB - Using 8- and 18-month-old AbetaPP23 mice, we investigated the involvement of high affinity glutamate transporters (GLAST, GLT-1, EAAC1), vesicular glutamate transporters (VGLUT1-3) and xCT, the specific subunit of system x(c)-, in Alzheimer's disease (AD) pathogenesis. Transporter expression was studied in cortical and hippocampal tissue and linked to extracellular glutamate and glutamate reuptake activity as measured using in vivo microdialysis. In 8-month old animals, we could not observe plaque formation or gliosis. Yet, in hippocampus as well as cortex GLAST and GLT-1 expression was decreased. Whereas in cortex this was accompanied by upregulated VGLUT1 expression, extracellular glutamate concentrations were decreased. Surprisingly, inhibiting glutamate reuptake with TBOA revealed increased glutamate reuptake activity in cortex of AbetaPP23 mice, despite decreased GLAST and GLT-1 expression, and resulted in status epilepticus in all AbetaPP23 mice, contrary to wildtype littermates. In hippocampus of 8-month-old AbetaPP23 mice, we observed increased EAAC1 expression besides the decrease in GLAST and GLT-1. Yet, glutamate reuptake activity was drastically decreased according to the decreased GLAST and GLT-1 expression. In 18-month-old AbetaPP23 mice, plaque formation and gliosis in cortex and hippocampus were accompanied by decreased GLT-1 expression. We also showed, for the first time, increased cortical expression of VGLUT3 and xCT together with a strong tendency towards increased cortical extracellular glutamate levels. VGLUT2 expression remained unaltered in all conditions. The present findings support the hypothesis that alterations in transport of glutamate, and more particular via GLT-1, may be involved in AD pathogenesis. PMID- 21297272 TI - Time course of glucose metabolism in relation to cognitive performance and postmortem neuropathology in Met146Val PSEN1 mutation carriers. AB - Studies in carriers of mutations that cause early-onset familial Alzheimer's disease (eoFAD) are of significant interest.We showed previously that regional glucose hypometabolism could be detected many years before disease onset in presenilin 1(PSEN1) mutation carriers. Here we studied four members of a family with a Met146Val PSEN1 mutation, two symptomatic carriers and two non-carriers, longitudinally with 18F-FDG PET over a period of about two and four years, respectively. The two mutation carriers showed global cortical glucose hypometabolism over time with the most distinct decline occurring in the posterior cingulate, the parietal and parietotemporal cortex, which was also observed when compared with a group of 23 healthy controls and a group of 27 sporadic Alzheimer's disease (sAD) patients. This decline correlated with cognitive deterioration overtime as measured by neuropsychological tests. Postmortem examination of brain tissue revealed substantially elevated levels of AD type neuropathology in terms of neuritic plaques and neurofibrillary tangles in the two mutation carriers compared with a reference group of 249 sAD patients. In the mutation carriers, the amount of neuritic plaques but not neurofibrillary tangles correlated hereby significantly with regional glucose metabolism as measured by 18F-FDG on the last scanning occasions, which were performed four and approximately five years before death, respectively. We here show that FDG PET can depict in vivo the aggressive disease progression in eoFAD mutation carriers in relationship to neuropathology. PMID- 21297273 TI - APOE epsilon4 allele status in korean dementia patients with severe white matter hyperintensities. AB - Few studies have investigated the apolipoprotein E (APOE) epsilon4 allele status of dementia patients with severe white matter hyperintensities (WMH). In this study, we aimed to characterize the APOE epsivlon genotypes and clinical features of dementia patients with severe WMH. Four hundred and thirty nine patients with dementia and 152 subjects with normal cognition (NC) were recruited from multiple centers in Korea, known as the Clinical Research Center for Dementia of South Korea (CREDOS), since November 2005. The WMH were rated using the scale that had been developed by the CREDOS study. Dementia patients with minimal WMH were considered to have Alzheimer's disease (AD) without WMH (AD-WMH: 325), and those with severe WMH were considered to have Subcortical Ischemic Vascular Dementia (SIVD: 50) or AD with severe WMH (AD+WMH: 64). Comparisons of APOE epsilon4 allelic prevalence were performed using chi-square analysis. The APOE epsilon4 allele was more prevalent in those with AD than in those with SIVD and NC (p < 0.001). It was not more prevalent in those with SIVD than in those with NC (p = 0.169). APOE epsilon4 allele status in AD+WMH did not differ from that in AD-WMH (p = 0.625). The APOE epsilon4 allele was more prevalent in those with AD than in those with SIVD. APOE epsilon4 may not be associated with SIVD although it is one of the vascular risk factors. PMID- 21297274 TI - CSF amyloid-beta peptides in neuropathologically diagnosed dementia with Lewy bodies and Alzheimer's disease. AB - Appropriate treatment of dementia requires biomarkers that provide an exact and differential diagnosis. We recently presented differentially expressed amyloid beta (Abeta) peptide patterns in cerebrospinal fluid (CSF) as biomarker candidates for neurochemical diagnosis of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). The objective of the present study was to investigate CSF Abeta peptide patterns in both neuropathologically and clinically defined diagnostic groups of AD and DLB. Using the quantitative Abeta-SDS PAGE/immunoblot, we analyzed CSF samples of neuropathologically defined patients with AD (definite AD, dAD; n = 11) and DLB (definite, dDLB; n = 12). We compared absolute and relative quantities of CSF Abeta-peptides with a larger cohort of clinically diagnosed patients with probable AD (pAD; n = 71), probable DLB (pDLB; n = 32), and non-demented controls (NDC; n = 71). Each neuropathologically and clinically defined diagnostic group showed a similar relative distribution of CSF Abeta-peptides (Abeta(1-X%)). Abeta(1-42%) was lowered in dAD compared to NDC (p = 1.6 * 10-7, but did not differ between dAD and pAD. Abeta(1-40ox%) was elevated in dDLB as compared to NDC (p = 1.8 * 10-5, but did not differ between dDLB and pDLB. Thus, we were able to confirm previous results on Abeta peptide patterns in neuropathologically characterized patients with AD and DLB. Our results underline the usefulness of the CSF Abeta(1-42%) and Abeta(1-40ox%) as diagnostic biomarkers for AD and DLB, respectively. PMID- 21297275 TI - Validation analysis of the Attention Questionnaire Scale. AB - Screening tests that briefly measure early signs of cognitive dysfunction in Alzheimer's disease (AD) are lacking. We devised a new scale focused on early detecting cognitive dysfunction: the Attention Questionnaire Scale (AQS). We prospectively studied the AQS in 268 subjects with varying degrees of cognitive dysfunction and compared it with the Mini-Mental Status Examination (MMSE), digit span test, trail making test part B, letter cancellation test, Instrumental ADL, Geriatric Depression Scale, and Clinical Dementia Rating Scale. The internal consistency was excellent with the AQS (Cronbach's alpha = 0.945). There were significant differences in the overall AQS scores across varying degree of cognitive dysfunction (26.80 +/- 3.43 in normal elderly, 20.78 +/- 4.83 in patients with mild cognitive impairment (MCI), 19.01 +/- 4.49 in early AD, 16.00 +/- 5.03 in mild AD, and 12.02 +/- 6.28 in moderate AD), and subjects with the early stage of cognitive dysfunction could be further distinguished using the AQS than MMSE. The area under the receiver operating characteristic curve was estimated to be 0.93 (95% confidence interval 0.89-0.97) in screening for normal elderly versus patients with MCI or various stages of AD. The AQS provides greater screening ability for early stage cognitive dysfunction, used not only as a screening tool but also an appropriate simple questionnaire. PMID- 21297276 TI - Incidence of dementia is increased in type 2 diabetes and reduced by the use of sulfonylureas and metformin. AB - To determine incidence of dementia in type 2 diabetic (T2DM) patients, and whether there are adverse or favorable effects of oral agents (OA) in DM, we obtained a representative cohort of 800,000 from Taiwan's National Health Insurance database. Those who, as of on January 1, 2000, were 50 years or older and dementia free (n = 127,209) were followed until December 31, 2007, in relation to absence (n = 101,816) or presence (n = 25,393) of T2DM, and whether any OA was used. Dementia was ascertained by ICD9-CM or A-code. Dementia incidence densities (DID) and fully adjusted Cox proportional hazard models were used to estimate association between dementia, DM, and OA. Notably, DID (per 10,000 person-years)was markedly increased with DM (without medication), compared to DM free subjects (119 versus 46). Using non-DM as reference, the adjusted hazard ratios (HRs) (95% confidence interval) for DM without and with OA were 2.41 (2.17-2.66) and 1.62 (1.49-1.77), respectively. For T2DM, compared with no medication, sulfonylureas alone reduced the HR from 1 to 0.85 (0.71-1.01), metformin alone to 0.76 (0.58-0.98), while with combined oral therapy the HR was 0.65 (0.56-0.74). Adjustments included cerebrovascular diseases so that non stroke related dementias were found to be decreased in DM with sulfonylurea and metformin therapy. T2DM increases the risk of dementia more than 2-fold. On the other hand, sulfonylureas may decrease the risk of dementia, as does metformin; together, these 2 OAs decrease the risk of dementia in T2DM patients by 35% over 8 years. PMID- 21297278 TI - Work injury prevention and rehabilitation. PMID- 21297277 TI - Administration of amyloid-beta42 oligomer-specific monoclonal antibody improved memory performance in SAMP8 mice. AB - Amyloid-beta peptide (Abeta) is recognized by many as the leading cause of Alzheimer's disease (AD), and Abeta oligomers play a major role in the early onset form of AD. Recently, the application of passive immunization targeting Abeta has been investigated as a potential method of AD immunotherapy. We used a strain of monoclonal antibody against Abeta42 oligomers, designated A8, as an Abeta inhibitor to suppress Abeta aggregation and Abeta-derived cell toxicity in vitro, and as a passive immunotherapy approach to treat SAMP8 (senescence accelerated mouse sub-line P8) mice, an animal model of AD, in vivo. First, our results showed that pre-incubation of A8 with Abeta oligomers inhibited both the maturation of Abeta fiber and Abeta oligomer toxicity on SH-SY5Y cells. Second, learning and memory was improved through intraperitoneal administration of A8 in SAMP8 mice. Third, Abeta pathology was ameliorated with decreased Abeta oligomers and phospho-tau levels in SAMP8 mice. Our data suggest that our monoclonal antibody A8 may be a candidate as a potential immunotherapeutic agent in AD. PMID- 21297279 TI - Does Saudi school furniture meet ergonomics requirements? AB - OBJECTIVE: The goal of this research was to study the effect of adjustable imported desk and chair combinations available in the market on student performance. METHODS: Six sets of chairs and tables within three different activities (reading, writing, and looking to the blackboard) were the independent variables. Evaluation of back force at 5th lumbar vertebrae and the 1st sacrum (L5/S1), subjective measures of discomfort, and the mismatch between student body dimension and classroom furniture analysis were measured. PARTICIPANTS: A total of 124 young male students (first through sixth-grade) participated in this experiment. RESULTS: The results revealed too low or too high chair and table heights relative to the students' body dimensions increased the stresses acting at L5/S1 as well as discomfort ratings. CONCLUSIONS: This study indicated there was a high level of body mismatch in desk-chair combinations even with the adjustable imported furniture available in the local market. Anthropometric data of Saudi students should be collected from different regions in the Kingdom and then design and development of desk-chair combinations could follow the development of a standard procedure to adapt to the needs of Saudi school children. PMID- 21297280 TI - Do managers experience more stress than employees? Results from the Intervention Project on Absence and Well-being (IPAW) study among Danish managers and their employees. AB - OBJECTIVE: To examine whether managers' perceived stress and work strain is higher than perceived stress and work strain among employees. METHODS AND PARTICIPANTS: The study is based on questionnaire responses from 2052 respondents (128 managers and 1924 employees) at 48 worksites. Bi-variate and multivariate analyses were used to explain possible differences in stress levels and related mediators. RESULTS: Managers experienced higher demands, higher level of conflicts, and lower degree of social support from peers. They tended to experience significantly lower emotional stress, whereas this trend was insignificant with regards to behavioural, somatic and cognitive stress. The difference was partly explained by higher scores in the psychosocial work environment factors; job satisfaction, perceived management quality from their managers, influence, degrees of freedom at work, possibilities for development and meaning of work. For behavioural stress, 41% of the difference was explained by the preventive factors, 20% for somatic stress, 39% for emotional stress and 56% for cognitive stress. CONCLUSIONS: This study indicates that the preventive psychosocial factors explain parts of the managers' lower stress level. These results contradict the lay perception of managers being under higher pressure and experiencing more stress than employees. Interventions aiming at reducing employee stress levels, especially regarding behavioural and cognitive stress, could benefit from focussing on psychosocial work environment exposures such as skill discretion, meaning of work, psychological demands, information flow and management quality. PMID- 21297281 TI - Loading and recovery behavior of the human lumbar spine under static flexion. AB - OBJECTIVE: In this study, the effect of prolonged forward flexion on the recovery process of the reflexive muscle activity of the lumbar musculature to its original state is studied using human participants. METHODS: The behavior of the lower back erector spinae muscle during 20 minutes of forward bending and three hours of recovery was evaluated experimentally using electromyography (EMG) and mathematical modeling. PARTICIPANTS: Ten healthy males participated in this study. The EMG of erector-spinae muscle from two different lumbar levels was recorded and expressed as normalized integrated EMG (NIEMG). RESULTS: In general, the average NIEMG values of the erector spinae muscles demonstrated an exponential decrease during the 20-minute loading period. The biexoponential structure, derived from the animal model, did not completely explain the muscle behavior during recovery period. Inclusion of the "intrinsic loading factor" to the biexoponential structure improved the fit of the recovery model to 100%. CONCLUSIONS: Most of the recovery (almost 50%) of the reflexive activity of erector spinae muscle was observed in the initial 30 minutes; yet by the end of three hours, complete recovery was not observed. PMID- 21297282 TI - Depressive state and subsequent weight gain in workers: A 4-year follow-up study. AB - OBJECTIVE: It has been suggested that the presence of a depressive state is a predictor of increase of the body weight. However, to precisely understand the nature of this relationship, the data should be controlled for other factors that can also be associated with weight gain. METHODS AND PARTICIPANTS: To test the hypothesis that the presence of a depressive state is associated with future weight gain, a 4-year prospective occupation-based cohort study was conducted in male adult workers (N=1730) at a railway company. Following the initial screening, follow-up information was obtained via a legally required annual health examination. The presence of a depressive state was identified using the Zung Self-Rating Depression Scale (SDS). The weight of each participant was measured to the nearest kilogram. Multiple logistic regression analysis was used to test the association between the depressive state and a weight gain of 4 kg or more over the 4-year study period after controlling for potentially confounding variables such as the age, smoking status, alcohol intake status, and physical activity. RESULTS: A weight gain of 4 kg or more over the 4-year study period was significantly associated with the depressive state, even after controlling for confounding variables (p< 0.05). Short-term longitudinal analysis also revealed an association between the depressive state and subsequent increase of the body weight. CONCLUSION: Since the depressive state was demonstrated to be an important risk factor for increase of the body weight, further research on depression should be conducted with a view to providing effective health education. PMID- 21297283 TI - Job functions of Swedish public and private rehabilitation workers; their perceived level of importance and related knowledge. AB - OBJECTIVE: To investigate and gather knowledge of how important the various functions of Swedish rehabilitation workers are and whether this knowledge is equivalent to the demands of the vocational rehabilitation process. PARTICIPANTS: Swedish rehabilitation workers from both public and private sectors. METHODS: A questionnaire comprising 89 work task items was used to identify the major dimensions of the Swedish rehabilitation workers job in the rehabilitation process. A principle component factor analysis was performed on the 89 job-task items from the Swedish Task Inventory. RESULTS: The number of factors/dimensions that could be formed was only three, which is judged to be limited both in scope and depth. The level of perceived knowledge reported varied from limited to having the required competence. The results also reveal that the workers perceive their work tasks and the dimensions that make up their role function as being of moderate to low importance. Their perceived level of knowledge for the similar work task items and dimensions were rated moderate to low. Differences between the groups of rehabilitation workers were mixed. CONCLUSIONS: The vocational rehabilitation process offered in Sweden is limited. It appears that the level of knowledge within the area can and should be increased and that better education is needed in order to improve the quality of the vocational rehabilitation process and for further development to take place. PMID- 21297284 TI - Assessment of standing in Functional Capacity Evaluations: An exploration of methods used by a sample of occupational therapists. AB - OBJECTIVE: The primary aim of the study was to explore the current practice of occupational therapists when assessing standing performance during Functional Capacity Evaluations (FCEs). METHODS: A semi-structured interview was conducted with occupational therapists and the participants were interviewed using both open and closed questions. PARTICIPANTS: A sample of occupational therapists (n=20) from Queensland, Australia were involved in a survey. They were all experienced in conducting FCEs. RESULTS: Ninety percent of the respondents used a distracting task during the assessment of standing with standardised and non standardised nuts and bolts assembly tasks the most commonly used. Respondents reported using a mix of biophysical, physiological and psychophysical clinical observations to assess standing. The nuts and bolts assembly activities used by the respondents were rated to be of low interest in terms of engaging the client. CONCLUSIONS: It was identified there are minimal guidelines in the literature which focuses on assessment of standing in FCEs. Questions were raised regarding the adequacy of the use of nuts and bolts activities as a suitably distracting task in FCEs and further research is required on assessing standing in functional capacity evaluation including the use of suitably distracting activities. PMID- 21297285 TI - Sheltered Employment Centers: Characteristics and users' perception. AB - OBJECTIVE: To know the situation of Sheltered Employment Centers (CEE) in the Autonomous Community of Madrid. METHOD: A quantitative approach was developed by using a questionnaire which was sent to all the CEE. With this questionnaire we got information about the performance level of CEE. A qualitative approach was developed too by using an interview applied to a representative sample of users. With the interview we got information about users' perception and satisfaction. PARTICIPANTS: 73 centers from 175 (41.71%) participated in the quantitative approach. For the qualitative approach, 60 workers were selected from 1,899 (3.16%) in a randomized and stratified sample by age and gender. RESULTS: Users of CEE have most of them physical (38.41%) or intellectual (26.88%) disabilities, between 25 and 44 years old (65.44%) with permanent and full-time contract (64.17%). Satisfaction is very high (93.33%), mainly with the task (41.76%) and their coworkers (30.00%), and emphasizing that money is the least attractive feature (35.59%). CONCLUSIONS: CEE need to give careful thought to some of the key aspects of their makeup and practices. We would point out the need to make clear use of the personal and social adaptation services, act as routes for the transition to normalized employment. PMID- 21297286 TI - Monitoring of the sleep patterns of shift workers in the automotive industry. AB - OBJECTIVE: The effect of shift schedules on the amount of sleep that workers receive is an important factor in workplace health and safety as well as the employees' overall quality of life. The objective of this study is to compare sleep period among workers engaging in each of the three-shift work. METHODS AND PARTICIPANTS: The amount of sleep (sleep period) that male workers with rotating shift schedules received was measured using accelerometers. The mean age of the 16 male workers enrolled in this study was 54.3 years (one standard deviation, 6.7 years). Thirteen participants ranged in age from 51 to 60 years of age, and the other three participants were 32, 48, and 50 years old. Work shifts were rotated on a weekly basis and were categorized into three periods: shift-1 (8:00 to 17:00), shift-2 (15:00 to 23:50), and shift-3 (23:30 to 8:15). Each work week consisted of 5 days. RESULTS: No significant differences were observed in the mean sleep period for each of the three shifts. However, the sleep periods during shift-1 or shift-2 tended to be longer than that obtained during shift-3. No effect of age on the length of the sleep period was observed. CONCLUSIONS: Rotating shift-work did not affect the amount of sleep that workers obtained. However, a comparison with previous study results suggests that morning shifts (starting at 6 AM) and day shifts (starting at 8 AM) may have different effects on sleep time. PMID- 21297287 TI - Shoulder functional assessments in persons with chronic neck/shoulder pain and healthy subjects: Reliability and effects of movement repetition. AB - OBJECTIVE: Obtaining reliable functional capacity measures from injured workers is an essential part of the return to work (RTW) process. The present study compares shoulder functional outcomes between healthy individuals and others with neck/shoulder pain, assesses reliability and examines the influence of repetitive movements on shoulder function. METHODS: Subjects performed trials of flexion and abduction active range of motion (ROM), and cumulative power output (PO) in a pushing/pulling task on the Baltimore Therapeutic Equipment Simulator II in two consecutive sessions. Tasks were assessed before and after performing a repetitive arm task, during which heart rate (HR) was recorded, until scoring 8 on the Borg CR-10 scale or on a 11-point numeric rating scale (NRS) for pain. PARTICIPANTS: Persons with chronic neck/shoulder pain (intensity >= 3/10 for > 3 months) (n = 16) and an age- and sex-matched control group (n = 16). RESULTS: Functional shoulder measures demonstrated strong inter-session reliability, except PO in the pain group. Average repetitive task duration was shorter in the pain group (4 min vs. 7 min). CONCLUSIONS: The protocol detected both pain- and time-related impairments, with HR and PO being sensitive to movement duration and ROM to pain. PMID- 21297288 TI - Job burnout and job wornout as risk factors for long-term sickness absence. AB - OBJECTIVE: Contingent self-esteem has been assumed to be a risk for burnout related disorders, and a contingent self-worth notion of job burnout was applied to study the prospective relationship between job burnout and registered episodes of sickness absence of >= 60 consecutive days. METHODS: Job burnout was defined as being in the high quartiles on the Maslach Burnout Inventory - General Survey (MBI-GS) scales of exhaustion and cynicism and, in addition, as being above the median on a scale for performance-based self-esteem. Another high exhaustion cynicism group, a "job wornout" group, was defined as being high on the same MBI GS scales but having performance-based self-esteem scores below the median. Data were analyzed by a multivariate, logistic regression approach. PARTICIPANTS: 4,109 public employees in Sweden. RESULTS: The job burnout group showed an over risk of long-term sickness absence incidence, both compared with a low exhaustion cynicism reference group and with the job wornout group after adjustment for several potential confounders. No association with incidence of long-term sickness absence was found for the job wornout group. CONCLUSIONS: The differential vulnerability to long-term sickness absence among high exhaustion cynicism groups suggests that a self-worth perspective of job burnout can be advantageous for prevention of the costly long-term sickness absences. PMID- 21297289 TI - Should FCE be used to identify validity of effort? PMID- 21297291 TI - Analysis of molecular interactions in solid dosage forms; challenge to molecular pharmaceutics. AB - The molecular states of active pharmaceutical ingredients (APIs) in pharmaceutical dosage forms strongly affect the properties and quality of a drug. Various important fundamental physicochemical studies were reviewed from the standpoint of molecular pharmaceutics. Mechanochemical effects were evaluated in mixtures of APIs and pharmaceutical additives. Amorphization, complex formation and nanoparticle formation are observed after grinding process depending on the combination of APIs and pharmaceutical additives. Sealed-heating method and mesoporous materials have been used to investigate drug molecular interactions in dosage forms. Molecular states have been investigated using powder X-ray diffraction, thermal analysis, IR, solid state fluorometry, and NMR. PMID- 21297292 TI - Floating and sustained-release characteristics of effervescent tablets prepared with a mixed matrix of Eudragit L-100-55 and Eudragit E PO. AB - The aim of this study was to evaluate the influence of Na-bicarbonate as an effervescent agent on the floating and sustained-release characteristics in 0.1 M HCl of tablets made of Eudragit E PO (EE) and/or Eudragit L-100-55 (EL) as matrix formers at different EE:EL weight ratios: 0:100, 25:75, 50:50, 75:25, and 100:0. The tablets were made by direct compression utilizing metronidazole as a model drug. Effervescent tablets with 50EE/50EL (w/w) showed the best floating and sustained drug release properties in the dissolution medium. The corresponding noneffervescent tablets were nonfloating and showed significantly faster drug release. Effervescent tablets with single polymers showed an immediate drug release pattern. These results were explained by Fourier-transform infrared spectroscopy and elemental analysis, which showed strong evidence of interpolyelectrolyte complexation between EE and EL when they were exposed to 0.1 M HCl as an effervescent hybrid matrix, but not as a noneffervescent hybrid matrix. The role of Na-bicarbonate in allowing EE-EL complexation during dissolution was explained as due to raising the pH around EL particles for sufficient polymer ionization and ionic-interaction with the ionized EE. PMID- 21297293 TI - Inhibitory activities on mammalian central nervous system receptors and computational studies of three sesquiterpene lactones from Coriaria ruscifolia subsp. ruscifolia. AB - The electrophysiological characterization of sesquiterpene lactones from Coriaria ruscifolia subsp. ruscifolia has been tested on hippocampal neurons. The results for glycinergic rat hippocampal transmission and native gamma-aminobutyric acid (GABA)ergic transmission on neurons (13DIV) are remarkably different for tutin, coriamyrtin, and dihydrotutin, being tutin the most potent inhibitor and dihydrotutin the least potent one. To understand the applied mechanism of action, we discuss the structural and electronic requirements for inhibitory activity by these sesquiterpene lactones when modulating receptors of the central nervous system. The structural and electrostatic properties of these compounds were compared to those of more active metabolites like picrotoxins. The minimal energy level of these structures was calculated and then optimized at the ab initio B3LYP/DGDZVP level of theory using Gaussian 03W software. This allowed calculation of the corresponding vibrational circular dichroism spectrum of coriamyrtin which rendered the molecular absolute configuration after comparison with an experimental spectrum. These results are consistent with those from studies of other models that provide the basis for the activity on the presence of the lactone at carbons 3 and 5, the presence of the hydroxyl group at position 6, and the different electronic distributions observed in tutin and coriamyrtin. The latter has an isopropenyl moiety at carbon 4 in contrast to the dihydrotutin isopropyl group at the same position, which could explain the difference in activity between dihydrotutin and tutin or coriamyrtin. The presence of the hydroxyl group at carbon 2 is not decisive since this functionality is present in tutin, the most active compound, and in dihydrotutin, the less active one. PMID- 21297294 TI - Synthesis, characterization and biological evaluation of mononuclear Co(II), Ni(II), Cu(II) and Pd(II) complexes with new N2O2 Schiff base ligands. AB - New tetradentate N(2)O(2) donor Schiff bases and their mononuclear Co(II), Ni(II), Cu(II), and Pd(II) complexes were synthesized and characterized extensively by IR, (1)H-, (13)C-NMR, mass, ESR, conductivity measurements, elemental and thermal analysis. Specifically the magnetic and electronic spectral measurements demonstrate the octahedral structures of cobalt(II), nickel(II) complexes and square planar geometries of copper(II), palladium(II) complexes. All the ligands and complexes were screened for their in vitro antibacterial activity against two gram-positive bacteria (Bacillus subtilis, Staphylococcus aureus) and two gram-negative bacteria (Escherichia coli, Klebsiella pneumonia). In this study, Pd(II) complexes exhibited potent antibacterial activity against B. subtilis, S. aureus whereas other metal complexes also exerted good activity towards all tested strains even than standard drugs streptomycin and ampicillin. PMID- 21297295 TI - Development and characterization of eucalyptol microemulsions for topic delivery of curcumin. AB - Microemulsions have received great attention for applications in transdermal drug delivery. The use of curcumin for treating various skin diseases like scleroderma, psoriasis, and skin cancer was extensively reported. The solubility of curcumin in various oils, surfactants, and cosurfactants was studied herein in order to find the optimal components for a transdermal delivery vehicle. Microemulsion systems composed of eucalyptol, polysorbate 80, ethanol, and water were developed as transdermal delivery vehicles for curcumin. Effects of the microemulsion composition on transdermal curcumin delivery were studied using Franz diffusion cells. The transdermal curcumin flux, permeability coefficient, and enhancement ratio were analyzed to evaluate the effects of eucalyptol/water ratios in the microemulsions. Pseudo-ternary phase diagrams of the eucalyptol microemulsions with various surfactant/cosurfactant ratios (1:1-1:3) were constructed to investigate their phase behaviors. Conductivity, interfacial tension, size, and viscosity data of the microemulsions were used to characterize the physicochemical properties of transdermal vehicles. The influence of the microemulsions on skin histology and on the delivery route was analyzed using hematoxylin/eosin staining and confocal laser scanning microscopy. In conclusion, microemulsions were successfully developed for transdermal curcumin delivery after screening various components and adjusting the oil/water ratios. The curcumin permeation rate of the microemulsion developed was 15.7-fold higher than that of the control (eucalyptol only). These results indicate that an eucalyptol microemulsion system is a promising tool for the percutaneous delivery of curcumin. PMID- 21297296 TI - Effect of substitution on the antimycobacterial activity of 2-(substituted benzyl)sulfanyl benzimidazoles, benzoxazoles, and benzothiazoles--a quantitative structure-activity relationship study. AB - A set of 1160 minimum inhibitory concentration (MIC) values evaluating effect of substitution on the antimycobacterial activity of the previously published 2 (substituted benzyl)sulfanyl benzimidazoles, benzoxazoles, and benzothiazoles has been analyzed by the methods of multidimensional analysis (exploratory analysis, 2D-nonlinear mapping (NLM), principal component analysis (PCA), factor analysis (FA), multiple linear regression (MLR)). The antimycobacterial activity of 2 (subst. benzyl)sulfanyl derivatives of benzimidazole (BIM), 5-methylbenzimidazole (5-Me-BIM), benzoxazole (BOZ), and benzothiazole (BTZ) increased in the order of BTZ70%, because no effective treatment has been established. We evaluated the effectiveness of combination therapy of tacrolimus and methylprednisolone for AE-IPF. METHODS: Patients of AE-IPF treated with methylprednisolone pulse therapy with or without tacrolimus (targeting 20 ng/mL) during the period between January 2001 and April 2010 were retrospectively reviewed. The primary endpoints were survival rate and duration. We also observed lactate dehydrogenase levels, partial pressure of arterial oxygen/fraction of inspired oxygen ratio (P/F ratio), KL-6, occurrence of re-exacerbation, and computed tomography score. RESULTS: Fifteen Japanese patients [tacrolimus group aged 74.2+/-6.0 years old (n=5), non-tacrolimus group aged 75.1+/-12.8 years old (n=10)] were identified. Pre-treatment clinical parameters were not significantly different between the two groups. Four of 5 tacrolimus group patients and 1 of 10 non-tacrolimus group patients survived (p<0.05). The median survival durations were >92 days (tacrolimus group) and 38 days (non-tacrolimus group) (p<0.05). Lactate dehydrogenase levels and the P/F ratio were also significantly favorable in the tacrolimus group. KL-6 and CT score were not significantly different in both groups. Four re-acute exacerbations were observed only in the non-tacrolimus group. CONCLUSION: Combined tacrolimus and methylprednisolone pulse therapy mitigates AE-IPF, prevents re-acute exacerbation, and contributes to a better prognosis. PMID- 21297320 TI - Factors associated with functional outcomes of patients with cerebral embolism due to nonvalvular atrial fibrillation. AB - OBJECTIVE: This study aimed to identify factors associated with the functional outcomes of patients with cerebral embolism due to nonvalvular atrial fibrillation. METHODS: We retrospectively investigated the short-term functional outcomes of 134 patients diagnosed with cardiogenic cerebral embolism due to nonvalvular atrial fibrillation during the period of May 2006 to August 2008. Functional state was evaluated using the modified Rankin Scale (mRS) on admission and at discharge. RESULTS: A good functional outcome (mRS <=2) at discharge was significantly associated with low mRS on admission (OR: 0.07; CI: 0.03-0.18; p<0.001), and a low C-reactive protein (CRP) level (OR: 0.19; CI: 0.04-0.89; p<0.05). Functional improvement during admission was positively associated with the presence of dyslipidemia (OR: 2.74; CI: 1.11-6.76; p<0.05), whereas high diastolic blood pressure (OR: 0.95; CI: 0.90-0.99; p<0.05) and a high blood sugar level (OR: 0.98; CI: 0.97-0.99; p<0.05) on admission were inversely associated with functional improvement. Furthermore, no relationship existed between mRS on admission and functional improvement during hospitalization. CONCLUSION: The results suggest that a good functional state at discharge was associated with a good functional state on admission as well as a low serum CRP level. On the other hand, functional improvement was associated with the presence of dyslipidemia, low diastolic blood pressure, and low blood sugar level on admission. PMID- 21297318 TI - Safety and efficacy of long-term maintenance therapy with oral dose of rabeprazole 10 mg once daily in Japanese patients with reflux esophagitis. AB - OBJECTIVE: The aim of this prospective clinical study was to evaluate the efficacy and safety of long-term proton pump inhibitor (PPI) treatment for two years in Japanese patients with reflux esophagitis (RE). METHODS: The efficacy and safety of two-year (104-week) treatment with rabeprazole (RPZ) 10 mg were studied in patients confirmed to have been cured of RE by PPI and who required long-term maintenance therapy with PPI. We performed serial endoscopy, checked gastroesophageal reflux disease (GERD) symptoms, adverse events, laboratory values and serum gastrin. We also monitored gastric mucosal histology, atrophy and polyps. RESULTS: The endoscopic non-relapse rate for RE was 87.3% for the 104 week period. GERD symptoms improved based on the fact that the mean change from baseline in GERD symptom score after treatment was a negative value. Treatment was safe; and atrophy was found to have developed in virtually no cases. A few new benign fundic gland or hyperplastic polyps developed throughout the study, but no ECL carcinoids were found to have developed. Serum gastrin levels tended to increase up to 24 weeks, but there were no subsequent changes thereafter up to 104 weeks. CONCLUSION: The results confirmed oral RPZ 10 mg to be effective for maintenance therapy in Japanese patients with RE. Although effects on the gastric mucosa were not ruled out, long-term use of RPZ was confirmed to be safe overall. PMID- 21297321 TI - Study of folate status among Egyptian asthmatics. AB - OBJECTIVE: To compare serum folate levels between atopic asthmatics, non-atopic asthmatics, and healthy controls. METHODS: This case-control study included 60 asthmatics with at least one positive skin prick test (SPT) reaction (atopic asthma group), 60 asthmatics with negative SPT reactions (non-atopic asthma group), and 60 healthy controls with no history of asthma or other allergic diseases, and with negative SPT reactions. Serum folate and total IgE levels were measured in all subjects. In addition, lung functions were assessed by spirometry. RESULTS: Serum folate levels were significantly lower among the atopic asthma group [9.1 (4.9, 12.1) ng/mL] as compared to the non-atopic asthma group [11.3 (7.5, 14.8) ng/mL] and the control group [12.0 (8.3, 15.1) ng/mL], p= 0.001. Among atopic asthmatics, serum folate levels were inversely correlated with total serum IgE levels (r=-0.483, p<0.001), and the number of positive SPT reactions (r=-0.442, p<0.001). Atopic asthmatics with a total serum IgE <=200 IU/mL had significantly higher levels of serum folate than those with a total serum IgE >200 IU/mL. Regression analysis showed that higher folate levels independently predicted lower total serum IgE levels. Folate was not found to be an independent predictor of asthma. No association was observed between serum folate levels and values of forced expiratory volume in 1s. CONCLUSION: Among asthmatics, serum folate levels are significantly lower among atopics, and correlate inversely with the degree of atopy. PMID- 21297322 TI - Diagnostic usefulness of Carnett's test in psychogenic abdominal pain. AB - OBJECTIVE: Carnett's test is a simple clinical test in which abdominal tenderness is evaluated while the patient tenses the abdominal muscles. It is useful for differentiating abdominal wall pain from intra-abdominal pain. However, no study has reported its association with psychogenic abdominal pain. We evaluated its diagnostic usefulness in psychogenic abdominal pain. METHODS: Two physicians performed Carnett's test on each patient, but only one received the medical history. The other physician only conducted the test. Based on the final diagnosis, patients were categorized into 3 groups: psychogenic pain, abdominal wall pain, or intra-abdominal pain. Each group was analyzed in association with the results of Carnett's test conducted by the blinded physician. PATIENTS: A total of 130 outpatients with the chief complaint of abdominal pain who had abdominal tenderness. RESULTS: There were 22 patients with psychogenic abdominal pain, 19 with abdominal wall pain and 62 with intra-abdominal pain. In patients with psychogenic pain or abdominal wall pain, Carnett's test was usually positive, whereas the test was usually negative in patients with intra-abdominal pain (p<0.001, respectively). The positive likelihood ratio of Carnett's test for psychogenic abdominal pain was 2.91 (95% confidence interval [CI], 2.71-3.13), while the negative likelihood ratio was 0.19 (95% CI, 0.11-0.34). The corresponding values for abdominal wall pain were 2.62 (95% CI, 2.45-2.81) and 0.23 (95% CI, 0.13-0.41), respectively. CONCLUSION: Carnett's test may be useful for ruling in and ruling out psychogenic abdominal pain in addition to distinguishing between abdominal wall pain and intra-abdominal pain. PMID- 21297323 TI - Intestinal involvement in Wegener's granulomatosis diagnosed and followed up by double balloon enteroscopy. AB - Wegener's granulomatosis (WG) is a multisystemic disease of unknown etiology characterized by necrotizing vasculitis and granulomatous inflammation (1-3). The disease typically involves the upper airways, lungs and kidneys, and gastrointestinal involvement is uncommon. Described here is a 33-year-old man who presented at the hospital with abdominal pain. Colonoscopy revealed multiple ulcers, including round ulcers, throughout the large intestine. Small bowel ulcers were detected by double balloon enteroscopy (DBE). Further study confirmed that these ulcers were caused by gastrointestinal complications of WG. The patient was administered prednisolone and cyclophosphamide and remains in remission. This case indicates the importance of considering a gastrointestinal complication of WG as the potential cause of abdominal symptoms among WG patients as well as the use of DBE in detecting such a complication. PMID- 21297324 TI - PFAPA syndrome in a young adult with a history of tonsillectomy. AB - Since its clinical definition in 1987, the syndrome called, "periodic fever, aphtous stomatitis, pharyngitis and cervical adenitis" syndrome (PFAPA) has been considered peculiar to pediatric age. In the recent literature there are a few case reports of PFAPA in adults. We describe a case of a 21-year-old female affected by PFAPA who presented a history of tonsillectomy at the age of four. To our knowledge this is the fourth case described with a diagnosis of PFAPA in an adult with a history of tonsillectomy during childhood. Although the role of tonsillectomy in the treatment of PFAPA is still controversial, due to the lack of definitive data in literature, this case suggests that fever episodes may relapse several years after surgery. PMID- 21297325 TI - A rare case of ACTH-independent macronodular adrenal hyperplasia associated with aldosterone-producing adenoma. AB - A 52-year-old man was evaluated for incidentally discovered bilateral adrenal masses. He had drug-resistant hypertension but lacked Cushingoid features. Endocrinological tests revealed autonomous secretion of cortisol and aldosterone with suppressed plasma ACTH and renin activity. A selective adrenal venous sampling demonstrated aldosterone hypersecretion from the left adrenal vein. The clinical diagnosis of subclinical Cushing's syndrome due to ACTH-independent macronodular adrenal hyperplasia (AIMAH) associated with primary aldosteronism was made, and he underwent left adrenalectomy; the resected adrenal lesion was consistent with the pathological diagnosis of AIMAH coexistent with aldosterone producing adenoma (APA). This is a very rare case of AIMAH with concomitant unilateral APA, whose hypertension improved after surgery. PMID- 21297326 TI - A case of membranous nephropathy with primary biliary cirrhosis and cyclosporine induced remission. AB - We report a case of membranous nephropathy with primary biliary cirrhosis (PBC). A 76-year-old Japanese man had been treated for PBC and was referred to our department because of acute severe proteinuria (10 g/day). Renal biopsy was performed and was compatible with a diagnosis of membranous nephropathy. The patient was treated with cyclosporine A (CsA; Neoral(r)), which was followed by normalization of liver function and partial remission of proteinuria (0.68 g/day) within six months without any significant side effects. This case suggests that CsA monotherapy is effective for the treatment of both liver dysfunction and membranous nephropathy associated with PBC. PMID- 21297327 TI - Right coronary artery fistula to left ventricle complicated with huge coronary artery aneurysm. AB - Congenital coronary artery fistula (CAF) with huge coronary artery aneurysm is a very rare condition. In this paper, we describe a 26-year-old asymptomatic male patient with right coronary artery (RCA) to the left ventricle fistula with a huge coronary artery aneurysm which was diagnosed by multidetector computed tomography and coronary angiography. The patient received surgical treatment for coronary artery after diagnosis. Both RCA and a giant aneurysm were excised; surgical closure of CAF and coronary artery bypass grafting were performed on this patient. Two months after surgery, the enlarged left ventricle returned to normal as evaluated by echocardiography. PMID- 21297328 TI - A rare lung nodule consisting of adenocarcinoma and amyloid deposition in a patient with primary systemic AL amyloidosis. AB - A 60-year-old woman was found to have proteinuria and a lung nodule. The surgically resected left upper lobe contained a nodule, in which the adenocarcinoma was surrounded by a heavy deposition of amyloid. Subsequent renal and gastric biopsies demonstrated amyloid deposition with Alambda immunoreactivity. She was treated with 2 courses of VAD (vincristine, doxorubicin and dexamethasone), resulting in the disappearance of Bence Jones proteinuria. Her nephrotic syndrome has been improving during the subsequent 3 years. The rare lung nodule consisting of adenocarcinoma and amyloid deposition was a diagnostic clue in this primary systemic AL amyloidosis patient. PMID- 21297329 TI - A case of adult onset Still's disease complicated with cryptogenic organizing pneumonia. AB - Only a few pathologic reports exist describing adult onset Still's disease (AOSD) with pulmonary involvement. We report this very rare case of AOSD complicated with cryptogenic organizing pneumonia (COP). A 32-year-old woman was referred with high spiking fever, salmon-pink rash in her arms and legs, and polyarthralgia. The laboratory data showed marked increases in white blood cell count, an erythrocyte sedimentation rate, and C reactive protein, ferritin, and liver dysfunction. All cultures remained negative, as were autoantibodies and rheumatoid factor. The patient was strongly suspected of AOSD according to specific diagnostic criteria. However, chest X ray disclosed an infiltrative shadow accompanied by air bronchogram in the upper lobe of the right lung and therapy with antibiotics was initiated. As the patient did not respond to antibiotics and a remittent fever of over 38 degrees C, a flexible bronchoscopy was performed. Organizing pneumonia was diagnosed by transbronchial lung biopsy (TBLB) histology and radiologically, and the lesions were thought to be due to pulmonary involvement of AOSD. Therefore, she was diagnosed with AOSD complicated with COP. Oral treatment with prednisolone (30 mg/day) resulted in rapid disappearance of the infiltrative shadow. Symptoms and markers of inflammation also improved. Clinicians should be aware that COP can be a complication of AOSD. PMID- 21297330 TI - Minimal-change nephrotic syndrome associated with isoniazid in anti-tuberculosis chemoprophylaxis for a patient with rheumatoid arthritis. AB - A 66-year-old woman with seropositive rheumatoid arthritis (RA) and latent tuberculosis infection developed minimal-change nephrotic syndrome following the initiation of anti-tuberculosis chemoprophylaxis with isoniazid. This is the first reported case of an isoniazid-induced nephrotic syndrome. Isoniazid as a single-drug intervention is widely accepted as a safe and effective means of anti tuberculosis chemoprophylaxis, particularly for RA patients with latent tuberculosis infection; the present case, however, demonstrates that isoniazid has the potential to induce minimal-change nephrotic syndrome, even when used as a single-drug intervention. PMID- 21297331 TI - Herpes labialis in multiple sclerosis with a trigeminal lesion. PMID- 21297332 TI - Ossification of the cervical anterior longitudinal ligament presenting dysphagia. PMID- 21297333 TI - Right atrium thrombus and pulmonary artery aneurysm in a man with Behcet's disease. PMID- 21297335 TI - The mechanism of improvement of gas exchange by noninvasive ventilation (NIV) therapy for the post-operative state of liver cirrhosis patients. PMID- 21297336 TI - Protein disulfide isomerase knockdown-induced cell death is cell-line-dependent and involves apoptosis in MCF-7 cells. AB - Protein disulfide isomerase (PDI) is a multifunctional protein that catalyzes disulfide bond formation and assists protein folding, as well as being a structural subunit of microsomal triglyceride transfer protein (MTP) and prolyl 4 hydroxylase (P4HD), and an estrogen and thyroid hormone-binding protein. Previous reports indicate that some endocrine-disrupting chemicals (EDCs) bind to PDI and disturb its functions, and we executed PDI-knockdown to examine the effects of dysfunction of PDI. In this study, the effects of PDI-knockdown were compared among three cell lines: MCF-7, SH-SY5Y and HeLa. PDI-knockdown induced different levels of cytotoxicity among these cell lines. In MCF-7 cells, PDI-knockdown activated apoptotic signaling, causing cytochrome c release from mitochondria and activation of caspase-9, caspase-6, caspase-7 and poly[ADP-ribose]polymerase-1, and the cytotoxicity induced by PDI-knockdown was suppressed by a pan-caspase inhibitor, z-VAD-fmk. These data suggest that cell death induced by PDI-knockdown is caspase-dependent apoptosis in MCF-7 cells. PMID- 21297337 TI - Sex and circadian modulatory effects on rat liver as assessed by transcriptome analyses. AB - The present study was designed to fully uncover sex and circadian modulatory effects on rat liver. Hepatic transcriptome analyses were performed at 4 hr intervals of a day-night cycle using young adult male and female rats. Sexually dimorphic genes, which were identified by a cross-sex comparison of time series data, included representative sex-predominant genes such as male- or female predominant cytochrome P450 subfamilies (Cyp2c11, Cyp2c12, Cyp2c13, and Cyp3a2), sulfotransferases, and glutathione S-transferase Yc2. The identified sexually dimorphic genes were over-represented in the metabolism of retinols, xenobiotics, linoleic acids, or androgen and estrogen, or bile acid biosynthesis. Furthermore, transcription factor targets modeling suggested that transcription factors SP1, hepatocyte nuclear factor 4-alpha (HNF4-alpha), and signal transducer and activator of transcription 5b (STAT5b) serve as core nodes in the regulatory networks. On the other hand, Fourier transform analyses extracted universal circadian-regulated genes in both sexes. The circadian-regulated genes included clock or clock-controlled genes such as aryl hydrocarbon receptor nuclear translocator-like (Arntl), period homolog 2 (Per2), and D site albumin promoter binding protein (Dbp). The extracted cyclic genes were over-represented in major tissue activities, e.g. the urea cycle and the metabolism of amino acids, fatty acids, or glucose, indicating that the major liver functions are under circadian control. The transcription factor targets modeling suggested that transcription factors SP1, HNF4-alpha, and c-Myc proto-oncogene protein (c-MYC) serve as major hubs in the circadian-regulatory gene networks. Interestingly, transcription factors SP1 and HNF4-alpha are likely to orchestrate not only sexually dimorphic, but also circadian-regulated genes even though each criterion was rather mutually exclusive. This suggests the cross-talk between those regulations. Sexual dimorphism is likely to interact with circadian rhythmicity via overlapping gene regulatory networks on rat liver. PMID- 21297338 TI - Solid gastric emptying mediated by the serotonin (5-HT)3 receptor in mice is a simple marker to predict emesis. AB - Nausea and emesis are often observed as side effects with many medicines and may lead to poor treatment compliance. In the present study, we aimed to establish simple methods for predicting nausea and/or emesis in mice, which do not vomit, using drugs and chemicals known to evoke nausea and/or emesis. The gastrointestinal transit test, the liquid gastric emptying by phenol red solution (Phenol red method) and the solid gastric emptying by resin beads (Beads method) were used and the effects of antispasmogenics (atropine, 0.1-3 mg/kg i.p.; salmon calcitonin, 1-30 units/kg i.m.), nauseants (copper sulfate, 1-30 mg/kg p.o.; apomorphine, 0.01-0.3 mg/kg s.c.) and chemotherapeutics (cisplatin, 0.3-10 mg/kg i.v.; doxorubicin, 0.3-10 mg/kg i.v.) were evaluated. In addition, the effects of ondansetron, a serotonin (5-HT)(3) receptor antagonist, on the inhibition of solid gastric emptying induced by salmon calcitonin, copper sulfate, cisplatin and doxorubicin were also assessed. Only the solid gastric emptying method could detect changes of gastric emptying by all drugs and chemicals. We also found that the inhibition of solid gastric emptying induced by cisplatin and doxorubicin was dose-dependently antagonized by ondansetron. However, ondansetron failed to antagonize the salmon calcitonin-induced delay, but exerted only very weak effects with copper sulfate. Solid gastric emptying may be more suitable than gastrointestinal intestinal transit or liquid gastric emptying in mice to predict nausea and/or emesis. Our results also suggest that chemotherapeutic-induced delay of solid gastric emptying mediated via 5-HT(3) receptors in mice could also be useful for prediction purposes. PMID- 21297339 TI - Depression-related anhedonic behaviors caused by immobilization stress: a comparison with nicotine-induced depression-like behavioral alterations and effects of nicotine and/or "antidepressant" drugs. AB - Anhedonia, an affective symptom related to the inability to experience pleasure, is one of the representative symptoms observed in depression. In the present study, considering that repeated nicotine (NC) also causes "depressive" symptoms, the depression-related anhedonic behavioral alterations caused by a typical depression-inducing stressor, immobilization stress (IM), combined with or without NC administration, were examined in mice and compared with the depression like behavioral alterations caused by NC. In the repeated IM (10 min, 4 days) group, as well as the repeated NC (0.3 mg/kg, s.c., 4 days) group, depression related behavioral despair was observed in both forced swimming and tail suspension tests. Depression-related anhedonic behavioral alterations, as judged in the sucrose test, were observed only in the IM group. In the group treated with IM plus NC (IM-NC group), NC antagonized the IM-induced anhedonic attenuation of sucrose consumption in the sucrose test. Furthermore, in the IM-NC group, NC attenuated the effects of antidepressants which inhibit the reuptake of monoamines in the forced swimming test. Against the IM-induced anhedonia in the sucrose test, the cannabinoid agonists anandamide and CP 55940, in addition to the antidepressants previously reported, restored the preference for sucrose to control levels, with or without NC co-treatment. The absence of anhedonic behavioral alterations, the antidepressant-like anti-anhedonic effects against IM, and the effects against some antidepressant drugs all seemed to be characteristic of the effects of NC. Neural mechanisms other than those involved in the depression-like effects of NC seemed to contribute to the IM-induced anhedonic component of depression. PMID- 21297340 TI - Endocrine disrupting effects of low dose 17 beta-estradiol (E2) on the Japanese quail (Coturnix japonica) were detected by modified one-generation reproduction study. AB - Previously, we investigated endocrine disrupting effects of 17 beta-estradiol (E(2)) on Japanese quail (Coturnix japonica) in the avian reproduction test according to the testing guidelines, in which new endpoints such as blood vitellogenin (VTG) concentration in parent quails and pathology of F(1) chicks were added, and consequently these additional endpoints suggested to be sensitive markers for detecting any impacts of endocrine disrupting effects (Shibuya et al., 2005b). In the present study, to investigate low dose effects of estrogenic endocrine disrupting chemicals in birds, the avian reproduction study of E(2) at low dose levels was conducted using Japanese quail with additional endpoints such as observations of F(1) chicks until 10 weeks of age, histopathology of F(1) chicks at 14 days and 10 weeks of age and blood VTG concentration in parent quails. Sixteen pairs of 10-week-old quails were fed a low phytoestrogen diet containing E(2) at 0 (control), 0.3, 3, and 30 ppm for 6 weeks, and parent quails, eggs and offspring were examined. F(1) chicks were maintained up to 14 days or 10 weeks of age. Serum E(2) and VTG concentrations in males of the E(2) 3 and 30-ppm groups and in females of the E(2) 30-ppm groups were significantly elevated. In the E(2) 30-ppm group, two parent females died, and toxic changes such as suppression of body weight gain, decrease in food consumption and atrophic and degenerative changes of the reproductive organs were observed in parent quails. In the same group, the number of eggs laid and the fertility rate of eggs were significantly decreased. In addition, the viability of F(1) chicks in the E(2) 30-ppm group were significantly decreased at 10 weeks of age. On the other hand, no abnormalities described above were observed in any parent quails, eggs and F(1) chicks in the E(2) 3- and 0.3-ppm groups, although the fertility rates of eggs in both groups were decreased and the body weight gain of F(1) females in the E(2) 3-ppm group was significantly suppressed. In the histopathological examination of F(1) chicks maintained up to 10 weeks of age, persistent right oviduct and atrophy of the oviduct gland were observed in females of E(2)-treatment groups with significantly high incidences. Moreover, cystic dilatation and tubular degeneration of the seminiferous tubules and atrophy of the cloacal gland were also observed in males of the E(2)-treatment groups. Thus, the dietary treatment of low dose E(2) (even 0.3 ppm) to parent quails resulted in decreased viability and induction of abnormalities in the oviduct, testis and cloacal gland in F(1) chicks maintained up to 10 weeks of age. These results suggest that additional endpoints such as observations of F(1) chicks until 10 weeks of age, histopathology of F(1) chicks at 14 days and 10 weeks of age and blood VTG concentration in parent quails would be useful and sensitive endpoints for evaluating estrogenic endocrine disrupting effects in the avian reproduction study. PMID- 21297341 TI - Ultrasonic-induced tonic convulsion in rats after subchronic exposure to perfluorooctane sulfonate (PFOS). AB - Perfluorooctane sulfonate (PFOS) is one of the persistent organic pollutants distributed widely in the global environment. We have found that a single oral administration of PFOS induced tonic convulsion in mice and rats when a brief ultrasonic stimulus was applied to the animals. The aim of this study is to examine whether the neurotoxicity is caused by subchronic dietary exposure to PFOS. Rats were treated with dietary PFOS at 0, 2, 8, 32 and 128 ppm for 13 weeks. Animals were carefully observed for pharmacotoxic signs and responses to the ultrasonic stimulus applied biweekly. PFOS increased liver weight and decreased food consumption and body weight. PFOS concentrations in the serum, brain, liver and kidney were increased almost proportional to its total dose, although the ratios of PFOS concentrations in tissues to total doses in the group treated with the highest concentration were a little lower. The ranges of relative concentrations in the brain, liver and kidney to serum concentration were 0.13 to 0.24, 2.7 to 6.3 and 0.82 to 1.6, respectively. PFOS alone did not cause any neurotoxic symptoms; however, 5 rats out of 6 showed tonic convulsion in the 6th week when ultrasonic stimulus was applied to the 128 ppm rats with the total PFOS dose of 338 mg/kg. The ultrasonic stimulus did not cause convulsion in the other groups. Histopathological examination including electron microscopic examination could not detect any abnormality in the brain. Because the acute oral dose of PFOS causing the convulsion was 250 mg/kg (Sato et al., 2009), the convulsion induced by PFOS seemed to depend on its total dose regardless of treatment schedule. PMID- 21297342 TI - Influence of coefficient of variation in determining significant difference of quantitative values obtained from 28-day repeated-dose toxicity studies in rats. AB - In order to understand the influence of coefficient of variation (CV) in determining significant difference of quantitative values of 28-day repeated-dose toxicity studies, we examined 59 parameters of 153 studies conducted in accordance with Chemical Substance Control Law in 12 test facilities. Sex difference was observed in 12 parameters and 10 parameters showed large CV in females. The minimum CV was 0.74% for sodium. CV of electrolytes was comparatively small, whereas enzymes had large CV. Large differences in CV were observed for major parameters among 7-8 test facilities. The changes in CV were grossly classified into 11. Our study revealed that a statistical significant difference is usually detected if there is a difference of 7% in mean values between the groups and the groups have a CV of about 7%. A parameter with a CV as high as 30% may be significantly different, if the difference of the mean between the groups is 30%. It would be ideal to use median value to assess the treatment related effect, rather than mean, when the CV is very high. We recommend using CV of the body weight as a standard to judge the adverse effect level. PMID- 21297343 TI - Neurobehavioral effects of combined prenatal exposure to low-level mercury vapor and methylmercury. AB - We evaluated the effects of prenatal exposure to low-level mercury (Hg(0)) or methylmercury (MeHg) as well as combined exposure (Hg(0) + MeHg exposure) on the neurobehavioral function of mice. The Hg(0) exposure group was exposed to Hg(0) at a mean concentration of 0.030 mg/m(3) for 6 hr/day during gestation period. The MeHg exposure was supplied with food containing 5 ppm of MeHg from gestational day 1 to postnatal day 10. The combined exposure group was exposed to both Hg(0) vapor and MeHg according to above described procedure. After delivery, when their offspring reached the age of 8 weeks, behavioral analysis was performed. Open field (OPF) tests of the offspring showed an increase and decrease in voluntary activity in male and female mice, respectively, in the MeHg exposure group. In addition, the rate of central entries was significantly higher in this group than in the control group. The results of OPF tests in the Hg(0) + MeHg exposure group were similar to those in the MeHg exposure group in both males and females. The results in the Hg(0) exposure group did not significantly differ from those in the control group in males or females. Passive avoidance response (PA) tests revealed no significant differences in avoidance latency in the retention trial between the Hg(0), MeHg, or Hg(0) + MeHg exposure group and the control group in males or females. Morris water maze tests showed a delay in the latency to reach the platform in the MeHg and Hg(0) + MeHg exposure groups compared with the control group in males but no significant differences between the Hg(0), MeHg, or Hg(0) + MeHg exposure group and the control group in females. The results of OPF tests revealed only slight effects of prenatal low-level Hg(0) exposure (0.03 mg/m(3)), close to the no-observable-effect level (NOEL) stated by the WHO (0.025 mg/m(3)), on the subsequent neurobehavioral function. However, prenatal exposure to 5 ppm of MeHg affected exploratory activity in the OPF test, and, in particular, male mice were highly sensitive to MeHg. The MeHg and Hg(0) + MeHg exposure groups showed similar neurobehavioral effects. Concerning the effects of prenatal mercury exposure under the conditions of this study, the effects of MeHg exposure may be more marked than those of Hg(0) exposure. PMID- 21297344 TI - A multigeneration reproductive and developmental safety evaluation of authentic Morinda citrifolia (noni) juice. AB - The impact of Morinda citrifolia (noni) juice on fertility and offspring health in three generations of ICR mice was evaluated. The authenticity of the source of noni juice in this study was determined by chemical analysis of known marker compounds. Mice were supplied with 5% noni juice at gestation (day 0) until weaning (21 days postpartum). This procedure was followed through three generations of offspring. Three generations of control mice were also evaluated. There were no intergroup differences in gestation and fertility indices or malformation rates. However, litter sizes of the noni group in the first (F1), second (F2), and third (F3) generations were, respectively, 29.3% (P < 0.01), 19.8% (P < 0.01) and 19.6% (P < 0.01) larger than corresponding controls. Despite larger litter sizes, there were no decreases in fetal weight in any generation of the noni group. Further, maternal health and offspring viability in the noni groups were equal to or greater than the controls. The results of this study suggest that authentic noni juice has no adverse effect on fertility and fetal development, consistent with previous two-generation studies of noni fruit from French Polynesia, Indonesia, and Hainan , China. On the contrary, noni juice appears to facilitate pregnancy and fetal development. PMID- 21297345 TI - Genotoxicity detection of five medicinal plants in Nigeria. AB - This study was performed to investigate the safety of Alchornea cordifolia, Cnestis ferruginea, Lonchocarpus sericeus, Trema orientalis, and Senna alata in respect to genotoxicity. These five medicinal plants are widely distributed in Africa. They are used as a traditional medicine in many African counties for the treatment of microbial, inflammatory, and stress-related diseases. To evaluate the bacterial reverse mutation of these five medicinal plants, the in vitro Ames test using Salmonella typhimurium TA98, TA100, TA1535, and TA1537, and Escherichia coli WP2uvrA, with or without the addition of S9 mixture was performed. Concentrations used for this test were 625, 2,500, and 5,000 ug per plate. A. cordifolia, C. ferruginea, L. sericeus, and T. orientalis showed negative results in the bacterial reverse mutation test, suggesting that it is potentially safe for these plants to be used in medicinal plants supplements at high doses. However, our experiments suggest that S. alata is a potent mutagen. Therefore, further studies are needed to evaluate the carcinogenicity of S. alata in order to adequately assess the risks for human health. PMID- 21297346 TI - Effects of coating materials and size of titanium dioxide particles on their cytotoxicity and penetration into the cellular membrane. AB - In order to estimate the effects of the size and surface treatment (coating or non-coating) of titanium dioxide particles on their cytotoxicity and penetration into the cellular membrane, two types of non-treated titanium dioxide (TiO(2)) particles of 20 nm (LU175) and 250 nm (LU205) were exposed to CHO cells, RBL-2H3 cells, A431 cells, B16 melanoma, NHEK(F), and NHSF, and six types of surface treated or non-treated TiO(2) particles of 35 nm were exposed to RBL-2H3 cells and NHSF. The order of half-maximal inhibitory concentrations (IC50s) of LU175 was NHSF < CHO, RBL-2H3 < A431 < B16 melanoma, NHEK(F). On the other hand, LU205 showed no cytotoxicity against any cells. Surface-treated TiO(2) showed much less cytotoxicity against RBL-2H3 cells than non-treated TiO(2). Then, between 0.5 and 10 mg of LU175 or LU205 was exposed to CHO cells. After 24 hr, the amount of LU175 in cellular cytosol increased dose-dependently. On the other hand, the amount of LU205 in cellular cytosol was much less than that of LU175. The proportion of surface-treated TiO(2) in the cellular cytosol of RBL-2H3 cells differed for each coating material. These results suggested that TiO(2) has different cytotoxicities among cell lines, and that of surface-treated TiO(2) was weaker than that of non-treated TiO(2). TiO(2) located in cytosol might be the main cause of cytotoxicity. PMID- 21297347 TI - Dietary zinc-deficiency and its recovery responses in rat liver cytosolic alcohol dehydrogenase activities. AB - The purpose of the present study was to elucidate the effects of dietary zinc deficient feeding and its recovery on liver cytosolic alcohol dehydrogenase (ADH; alcohol: NAD(+) oxidoreductase, EC1.1.1.1) activities and plasma zinc levels in rats. The weaned male Sprague Dawley rats were randomly divided into the zinc deficient diet (ZDF: 1.9 mg zinc/kg diet) group and the control diet (53.5 mg zinc/kg diet) group, and were fed for 4 weeks. In the recovery periods, the rats of two groups were fed with the control diet for 3 weeks. Liver cytosolic protein content per body weight in the zinc-deficiency and its recovery period showed no significant changes between both groups. However, zinc-deficiency decreased significantly liver cytosolic ADH specific activity, total liver cytosolic ADH activity and total liver cytosolic ADH activity/body weight by 50%, 76% and 53%, respectively, as compared with the control diet group. Zinc-deficiency also decreased significantly plasma zinc concentration by 84%, as compared with the control diet group. On the contrary, no significant changes in liver cytosolic ADH specific activity, total liver cytosolic ADH activity and total liver cytosolic ADH activity/body weight in the recovery period were observed between both groups. Plasma zinc concentration in the recovery period was almost recovered to the control level. These results suggest that rat liver cytosolic ADH activity was clearly related to dietary zinc intake levels. PMID- 21297348 TI - Capsaicinoids-induced changes of plasma glucose, free fatty acid and glycerol concentrations in rats. AB - Red peppers are used as a spice for enhancing the palatability of foods. Two major capsaicinoids, dihydrocapsaicin (DHC) and capsaicin (CAP) are responsible for up to 90% of the total pungency of pepper fruits. These capsaicinoids are known to enhance energy metabolism and thermogenesis. However, there is a little information on the effects of capsaicinoids on the lipolysis and carbohydrate metabolism. We studied the effects of DHC and CAP on plasma glucose, free fatty acid (FFA) and glycerol concentrations in rats. Male six-week-old Sprague Dawley rats were divided into the DHC, CAP and control groups. Each capsaicinoid (dose = 3 mg/kg BW/day) was subcutaneously administered to rats for 10 days. DHC increased markedly plasma glucose, FFA and glycerol concentrations on day 1-10 by 14-35%, 61-103% and 108-174%, respectively, as compared with those of the control group. CAP increased relatively plasma glucose concentrations on day 1-3 by 15 17%, as compared with the control group. However, there were no significant differences in plasma glucose concentrations on day 7-10 among three groups. On the contrary, CAP did not change plasma FFA and glycerol concentrations on day 1 3. However, CAP increased markedly plasma FFA and glycerol concentrations on day 7-10 by 54-89% and 92-98%, respectively, as compared with the control group. DHC and CAP did not change the weights of white (perirenal and periepididymal) and brown (interscapular) adipose tissues. In conclusion, the effects of capsaicinoids on plasma glucose, FFA and glycerol concentrations were relatively higher in the DHC than in the CAP, and capsaicinoids did not change the weight of white and brown adipose tissues. PMID- 21297349 TI - Bfr1p is responsible for tributyltin resistance in Schizosaccharomyces pombe. AB - ATP-binding cassette (ABC) transporter plays an important role for resistance against xenobiotics. There are eleven ABC transporter genes in the genome of fission yeast Schizosaccharomyces pombe. We examined the role of ABC transporter against the toxicity of tributyltin chloride (TBT), a widespread environmental pollutant, in cell growth. Among individual ABC transporter mutants, the growth of a mutant deficient in Bfr1p, a plasma membrane-embedded transporter, was extremely sensitive to TBT. The lethal TBT concentration inducing 50% of cell death (LC(50)) was 25 uM for the parent strain and 10.2 uM for the bfr1? mutant. Thus, Bfr1p was responsible for TBT resistance in S. pombe. PMID- 21297350 TI - Enhanced elimination of tissue methylmercury in Parachlorella beijerinckii-fed mice. AB - To investigate the influence of Chlorella (Parachlorella beijerinckii) on the excretion and tissue accumulation of methylmercury (MeHg), we orally administered 5 mg/kg of MeHg chloride (4 mg Hg/kg) to female C57BL/6N mice (aged 10 weeks). The mice were housed in metabolism cages to collect urine and feces for 3 weeks with diets containing 0%, 5%, or 10% P. beijerinckii powder (BP) in a basal diet (CE-2). The lowered blood Hg levels in the 5% and 10% BP groups became significant compared to those of the control group (0% BP) as early as day 7. During the 21 days of testing, significant increases in the cumulative Hg eliminations into urine (5% BP) and feces (5% and 10% BP) were found in the BP groups. Twenty-one days after administration, the organ Hg levels in both BP groups tended to decrease compared to that of the control group. The reduction of Hg levels in the kidney and brain were significant, whereas that in the liver was not. Although tissue Hg levels are known to be closely related to glutathione (GSH) metabolism, no difference was found in GSH levels in the blood or organs between the control group and the 10% BP group. These results suggest that continuous BP intake accelerates the excretion of MeHg and subsequently decreases tissue Hg levels in mice, with no alteration of GSH metabolism. We should conduct further research to elucidate details regarding the mechanism of BP-induced enhancement of MeHg excretion. PMID- 21297351 TI - DNA microarray analysis of normal rat kidney epithelial cells treated with cadmium. AB - In order to elucidate the transcriptional response of kidney epithelial cells to cadmium, the gene expression pattern was examined in normal rat kidney epithelial cells (NRK-52E cells) exposed to 50 uM cadmium for 4 hr using DNA microarray. Cadmium was found to increase the expression of 73 genes and decrease the expression of 42 genes in NRK-52E cells before the development of cytotoxicity. PMID- 21297352 TI - Proteomic analysis for neuronal vacuolation induced by MK-801 in rat retrosplenial cortex. AB - Proteomic analysis was carried out for neuronal vacuolation in rat retrosplenial cortex (RSC) induced by MK-801, a N-methyl-D-aspartate (NMDA) receptor antagonist. Female rats were given a single subcutaneous (sc) injection of either MK-801 (9 mg/kg in saline) or saline. Comparison of changes in proteins in the RSC region between MK-801- and saline-treated groups revealed that MK-801 induced changes in six proteins involved in vesicular transport (vesicle-fusing ATPase) and glycolysis (fructose-bisphosphate aldolase C, triosephosphate isomerase, and glyceraldehyde-3-phosphate dehydrogenase). PMID- 21297353 TI - Chronic exposure to arsenite induces S100A8 and S100A9 expression in rat RBL-2H3 mast cells. AB - To investigate the effects of chronic exposure to arsenite on the gene expression profiles of mast cells, microarray analysis was performed on rat basophilic leukemia RBL-2H3 cells exposed to arsenite for 28 days. Upregulated genes include calcium-binding S100 proteins such as S100A9, S100A10, S100A6, and S100A13, and granzymes B and C. Among S100 proteins, S100A9 showed the highest expression (8.62-fold of untreated cells) after 4-weeks of exposure to arsenite. As S100A8 and S100A9 comprise a heterodimer called calprotectin, and are implicated in the development of atherosclerosis and cancer, mRNA levels of both S100A8 and S100A9 were analyzed. The results demonstrated that exposure of RBL-2H3 cells to arsenite for a few weeks induces marked increases in mRNA levels of S100A8 and S100A9. PMID- 21297354 TI - DNA microarray analysis of human coronary artery endothelial cells exposed to cadmium. AB - Cadmium (Cd) is a toxic heavy metal that has been shown to induce vascular diseases, such as atherosclerosis. We used DNA microarray to monitor the transcriptional response of human coronary artery endothelial cells (HCAEC) to a non-lethal dose of Cd (10 uM). Out of 35,035 human genes, Cd enhanced the expression of 3 metallothionein (MT)-I subisoform genes, including MT1E, MT1H and MT1B, and reduced the expression of 12 genes, including ISG20 and TK1, 2-fold or greater. PMID- 21297355 TI - [Clinical findings of the patients with sick building syndrome and the results of environmental measurement]. AB - OBJECTIVES: Although many survey reports on sick house syndrome have been published, few clinical studies have reported sick building syndrome (SBS) in Japan. We examined patients with SBS-like complaints by clinical observation and made environment measurements. METHODS: The subjects of our study were 11 office workers (2 men and 9 women) who visited our hospital because of poor physical condition after the construction and painting of a fireproof vault in their office. We performed a medical interview, biochemical examinations of blood, immunological tests, pulmonary function tests, and psychological tests. The environment in the office was evaluated 3 times at 27, 55, and 132 days after the cessation of vault construction. A questionnaire survey was distributed to the workers who did not visit our hospital. RESULTS: The workers resumed work 9 days after the end of construction: Shortly after the resumption of work, most of the workers smelled a bad odor, and complained of headache, malaise, disturbed concentration, and eye irritation. Acrylic resin paint was used for painting the vault, and the concentrations of toluene, xylene, and total volatile organic compounds (T-VOC) on day 27 after painting were 2,972, 2,610, and 7,100 MUg/m3, respectively. One hundred and thirty-two days after painting, the concentrations of toluene, xylene, and T-VOC decreased to unscented levels of 78, 113, and 261 MUg/m3, respectively. CONCLUSION: Seven females among the eleven patients were diagnosed as having SBS on the basis of the time of the onset of the symptoms, negative results of allergy and other organic diseases, and the results of the environment measurements. From the responses of the other workers (22 men and 1 woman) to the survey questionnaire, the development and the disappearance of complaints, such as bad odor and unpleasantness, agreed with change of the level of toluene in the vault, which confirmed the validity of the SBS diagnosis. PMID- 21297356 TI - [New development of histamine research on the inflammation. Foreword]. PMID- 21297357 TI - [Histamine H1 receptor gene as an allergic diseases-sensitive gene and its impact on therapeutics for allergic diseases]. AB - Therapeutics targeting disease-sensitive genes are required for the therapy of multifactorial diseases. There is no clinical report on therapeutics for allergic disease-sensitive genes. We are focusing on the histamine H1 receptor (H1R) as a sensitive gene. H1R mediates allergy histamine signals. H1R is a rate-limiting molecule of the H1R signal because the signal is increased with elevated receptor expression level. We discovered that the stimulation of H1R induced H1R gene expression through PKCdelta activation, resulting in receptor upregulation. The mechanism of H1R gene expression was revealed to play a key role in the receptor expression level in studies using cultured HeLa cells and allergic rhinitis model rats. Preseasonal prophylactic treatment with antihistamines is recommended for the therapy of pollinosis. However, the mechanism of the therapy remains to be elucidated. We demonstrated that repeated pretreatment treatment with antihistamines in the allergic rhinitis model rats resulted not only in improvement of symptoms but also in suppressed elevation of H1R mRNA levels in the nasal mucosa. A clinical trial was then initiated. When symptoms and H1R mRNA levels in the nasal mucosa of pollinosis patients with or without preseasonal prophylactic treatment with antihistamines were examined, both symptoms and high levels of H1R mRNA were significantly improved in treated compared with untreated patients. These results strongly suggest that H1R is an allergic disease sensitive gene. PMID- 21297358 TI - [Roles of histamine in the exacerbated allergic dermatitis]. AB - We established a novel dermatitis model in mice earlobes and analyzed the roles of histamine using specific antagonists for histamine receptors. After sensitization with picryl chloride (PiCl) by painting it on the earlobes of cyclophosphamide-treated mice, 12-O-tetradecanoylphorbol 13-acetate (TPA) was painted twice at the same site, and then allergic inflammation was induced by painting with PiCl. Histamine antagonists and cyclosporin A were administered i.v. The application of TPA shifted the PiCl-induced allergic inflammation from a delayed-type response to a biphasic response and increased the infiltration of eosinophils and mast cells at the inflammatory site. In this model, the PiCl induced increase in the thickness of the earlobe in the immediate phase was suppressed by the histamine H1 antagonist pyrilamine. In contrast, the increase in the swelling in the late phase and the infiltration of eosinophils were suppressed by the H3/H4 antagonist thioperamide. The inhibitory effect of the combined treatment with pyrilamine and thioperamide on TPA-modified contact dermatitis was as potent as that of cyclosporin A. Histamine plays significant roles in early-phase swelling via H1 receptors and in late-phase swelling via H3/H4 receptors in this TPA-modified allergic dermatitis model. PMID- 21297359 TI - [Roles of histamine in the pathogenesis of bronchial asthma and reevaluation of the clinical usefulness of antihistamines]. AB - Histamine has been reported to play an important role in pathogenesis of bronchial asthma. However, H1-blockers are not recommended as the first drug for asthma therapy in the guidelines. Histamine may play various roles in allergic airway inflammation through the H1 receptor (H1R), H2R, and H4R in immune cells including T lymphocytes and dendritic cells. We therefore evaluated its role in allergic airway inflammation with the use of histamine-deficient mice. The results suggested that histamine plays a role in the prevention of goblet cell hyperplasia. Organic cation transporter-3 (OCT-3) is thought to be a transporter of histamine. Polymorphism of OCT-3 {R120R (T/C)} was associated with the severity of asthma. Recently, it has been proposed that both asthma and allergic rhinitis should be treated as a single airway disease. Comorbidity of asthma and allergic rhinitis is very high (70-80%) and they share similar allergic inflammation. H1-blockers are recommended as first-line drugs to treat allergic rhinitis in the guidelines. Therefore H1-blockers are strongly recommended for patients with both asthma and allergic rhinitis. PMID- 21297360 TI - [Recent topics of nanotox studies for their safety. Foreword]. PMID- 21297361 TI - [Importance of researches on chronic effects by manufactured nanomaterials]. AB - Manufactured nanomaterials are the most important substances for the nanotechnology. The nanomaterials possess different physico-chemical properties from bulk materials. The new properties may lead to biologically beneficial effects and/or adverse effects. However, there are no standardized evaluation methods at present. Some domestic research projects and international OECD programs are ongoing, in order to share the health impact information of nanomaterials or to standardize the evaluation methods. From 2005, our institutes have been conducting the research on the establishment of health risk assessment methodology of manufactured nanomaterials. In the course of the research project, we revealed that the nanomaterials were competent to cause chronic effects, by analyzing the intraperitoneal administration studies and carcinogenic promotion studies. These studies suggested that even aggregated nanomaterials were crumbled into nanosized particles inside the body during the long-term, and the particles were transferred to other organs. Also investigations of the toxicokinetic properties of nanomaterials after exposure are important to predict the chronically targeted tissues. The long lasting particles/fibers in the particular tissues may cause chronic adverse effects. Therefore, focusing on the toxicological characterization of chronic effects was considered to be most appropriate approach for establishing the risk assessment methods of nanomaterials. PMID- 21297362 TI - [Transdermal penetration and biodistribution of nanomaterials and their acute toxicity in vivo]. AB - Recently, the number of applications of nanomaterials in medicine, cosmetics and food to which we are directly exposed has been expanding rapidly. The safety of such nanomaterials has not been well assessed, because nanomaterials have been considered as safe as common larger sized materials which are known not to be absorbed by the body. Therefore, WHO and OECD are collecting safety information on nanomaterials with a view to regulation of their use. Although assessment of in vivo behaviors of nanomaterials, (i.e., absorption and distribution, and correlation analysis with hazard information) is urgently needed, such research has not yet been undertaken. In this regard, using amorphous silica particles as model nanomaterials, we are starting to study safety, in vivo behavior and their correlation; silica particles are often used in cosmetics and foods and also, downsized particles are rapidly becoming available. In our study, we have found that silica particles below 100 nm in diameter show significantly different characteristics in in vivo behavior and biological effects i.e., penetration through skin and distribution to brain. Here, I addressed the importance of studies in physicochemical characteristics, kinetic behaviors, and biological effects of nanomaterials below 100 nm in size, to ensure their safety. PMID- 21297363 TI - [Development of nanosafety forecasting system from the viewpoint of nanomaterial protein interaction]. AB - With recent developments in nanotechnology, nanomaterials have been successfully employed in various industrial applications such as medicine and cosmetics. Nanomaterials demonstrate useful properties such as electronic reactivity and tissue permeability that are absent in micromaterials. Thus, it is anticipated that nanomaterials will be developed as innovative materials in medicine and the cosmetics industry. However, these innovative properties may be accompanied by unknown biological responses that could not have been detected by conventional toxicity assays. To promote industrial development and to establish an affluent society that enjoys only the benefits of nanomaterials, we urgently need to gather information on the properties and biological effects of nanomaterials, and to establish appropriate standard safety evaluation methods. We are therefore analyzing the association of nanomaterial interactions with macromolecules (proteins, DNA etc.) and biodistribution using nanosilicas (nSP) as a standard nanomaterial. The results of this study are useful for extrapolation to other nanomaterials and to establish practicable strategies for the development of prediction methods for nanomaterials. PMID- 21297364 TI - [Safety studies of nanomaterials about intracellular distribution and genotoxicity]. AB - Recently, nanomaterials (NMs) showing useful properties such as controlled release and tissue permeability have been developed for practical use as medicine and cosmetics. On the other hand, because NMs possess innovative properties, kinetics, and biological effects distinct from those of micro size bulk materials, the potential harmful effects of NMs on humans are raising concerns about their safety. Therefore, there is an urgent need for risk assessment of NMs. To achieve this, it is most important to analyze the relationship between physicochemical properties such as particle size and surface characteristics, cellular distribution and biological effects, allowing prediction and avoidance of risk in using NMs. However there is little information about association of nanomaterial properties with kinetics (exposure, absorption, distribution, and excretion). In this respect, we have not only collected hazard information on NMs but have also analyzed the linkage between silica particle size and their hazards. We have demonstrated that NM with a diameter of under 100 nm can penetrate the stratum corneum of mouse skin and are taken up by living cells such as keratinocytes and Langerhans cells. Additionally, NM taken up by cells entered the nucleus, indicating the risk of genotoxicity. In this review, we would like to discuss the relationship between particle size, intracellular distribution, and hazard effect. PMID- 21297365 TI - [Nanosafety studies of nanomaterials about biodistribution and immunotoxicity]. AB - A diverse array of nanomaterials such as nanosilicas and carbon nanotubes are in widespread use due to the development of nanotechnology. Nanomaterials are already being applied in universal fields such as electronics, sunscreens, cosmetics, and medicine, because they have unique physicochemical properties such as high conductivity, strength, durability, and chemical reactivity. The advent of nanomaterials has also provided extraordinary opportunities for biomedical applications. However, the increasing use of nanomaterials has raised public concern about their potential risks to human health. In particular, recent reports have indicated that carbon nanotubes induced exaggerated inflammation and mesothelioma-like lesions in mice. However, few studies have examined the immunotoxicity of nanomaterials and it is essential to progress studies on the immunotoxicity of nanomaterials to ensure their safety. In this regard, we have attempted to elucidate the pharmacodynamics and immunotoxicity of nanomaterials, in order to develop novel safe nanomaterials and to establish scientifically based regulations. In this review, we would like to introduce our data on the immunotoxicity of nanosilicas, especially the relationship between physical properties (primary grain size, configuration and surface charge), pharmacodynamics of these materials, and their immunotoxicity. We consider that our study will improve the quality of human life by safely using nanomaterials, which can benefit society in general. PMID- 21297366 TI - [Biodistribution of nanosilica particles in pregnant mice and the potential risk on the reproductive development]. AB - Nanomaterials acquire revolutionary functions such as anti-inflammatory and anti viral effects by increasing surface area per unit weight, due to the reduction to nanosize. Such nanomaterials are rapidly put to practical use without safety evaluation. This is because it is widely assumed that nanomaterials are merely of the same molecular composition as existing materials of more than submicron size, and that nanomaterials cannot be absorbed from the digestive tract or skin as is the case with existing materials of more than submicron size. On the other hand, as was the case with thalidomide, evidence shows that fetuses and infants are affected more than adults by a variety of environmental toxins, because of physiological immaturity. Thus, placental or breast milk-mediated exposure to nanomaterials may possibly induce unexpected biological effects. To our knowledge, however, no studies have examined effects of pregnant animal exposure to nanomaterials on transitivity to placenta or infants, or on maintenance of pregnancy. Therefore, using nanosilica particles (nSPs) employed as additives in cosmetics and foods, we will report on the efficiency of transitivity of nSPs of various diameters to the circulation through the placental barrier after nanomaterial exposure and the risks of nSP exposure to pregnant mice. In this review, I will discuss the development of safety in nanomaterials and the maintenance of good health. PMID- 21297367 TI - [Health effects of nanomaterials on next generation]. AB - In order to discuss the health effects of nanomaterials, we cannot disregard the research on the health effects of airborne particulates. It is said that many of the fine or ultrafine particles in airborne particulates originate from diesel vehicles in metropolitan areas. The results of not only animal experiments but many epidemiologic surveys and volunteer intervention experiments in humans are reported on the health effects of particles. Although the health effects of the particulate matter particle sizes below 10 um (PM10) were investigated in the initial studies, recently even smaller particles have come to be regarded as questionable and research of the health effects of the minute particulate matter below 2.5 um (PM2.5) has been done. However, our recent study about maternal exposure to diesel exhaust suggests that health effect study of PM0.1, particles below 0.1 um (100 nm), namely nanoparticles, is necessary from now on. We are proceeding with the study of the health effects of various types of intentionally produced nanomaterials such as carbon black, carbon nanotube, fullerene and titanium dioxide, examining in particular their influence on next generation. Although there are differences in the sites affected and the seriousness of the damage, basically similar findings to DEPs mentioned above are being discovered in research on nanomaterials. Regardless of dosage and administration method, such as inhalation, endotracheal administration, nasal drip and subcutaneous administration, once nanomaterials enter the bloodstream of a pregnant mother mouse, they move to the offspring and have effects on them. The effects may appear as various symptoms in the process of growth after birth, and can sometimes lead to the onset and aggravation of serious diseases. PMID- 21297368 TI - [Pharmacogenomics study to avoid serious drug adverse reactions. Foreword]. PMID- 21297369 TI - [Pharmacogenomic research for avoiding adverse reactions by anti-cancer drugs]. AB - Anti-cancer drugs have relatively low effective rates and high frequencies of adverse reactions, occasionally leading to cessation of their treatments. Use of pharmacogenomic (PGx) information could be able to select the patients with high response and less-adverse reactions, resulting in increase of patients' QOL and proper use of drugs. We have been collaborating with National Cancer Center for PGx analysis of anti-cancer drugs including irinotecan and gemcitabine in Japanese cancer patients. Irinotecan, now used for treatments of many cancers, is metabolically activated to SN-38 and then inactivated to SN-38 glucuronide by a UDP-glucuronosyltransferase UGT1A1. In the UGT1A1 gene, two representative genetic polymorphisms, *28 and *6, were detected at 0.138 and 0.167, respectively in 177 Japanese cancer patients. When the patients were homozygotes of *28 or *6, or compound heterozygotes of them, statistically significant decreases were observed in the SN-38 glucuronidation activity and increases in the rate of severe neutropenia, compared to those in the patients without *28 or *6. Our results and papers were cited in the Japanese package inserts of irinotecan. Gemcitabine was inactivated by cytidine deaminase (CDA) into 2'-2' difluorodeoxyuridine. A CDA polymorphism 208G>A (Ala70Thr) was detected at 0.037 frequency in 256 Japanese cancer patients and associated with reduced gemcitabine clearance as well as increased frequency of severe neutropenia. In the 4 patients suffered from very severe bone marrow toxicities, 3 patients were homozygous CDA*3, suggesting that this polymorphism is exquisite for predicting severe adverse reactions by gemcitabine in Japanese. PMID- 21297370 TI - [Genetic marker of statin-induced rhabdomyolysis]. AB - This review summarizes genetic factors predisposed to statin-induced rhabdomyolysis. The first genetic risk factor of statin myopathy uncovered by genome-wide analysis of single nucleotide polymorphisms was the common variant of SLCO1B1 gene. Analysis of 30000 genetic markers in 85 patients with myopathy induced by high-dose simvastatin showed a strong association with 521T>C polymorphism of SLCO1B1. Another study also showed that this variant of SLCO1B1 has a significant association with myopathy in patients taking pravastatin or atorvastatin although the number of patients analyzed was limited. In addition to SLCO1B1, recent studies suggested that variants of genes encoding transporters (ABCG2 and ABCB1) and metabolic enzymes (CYP2C8 and UGT1A3) involved in the disposition of statins, and those involved in the metabolic muscle disease (glycogen storage disorders, carnitine palmitoyl-2 deficiency and myoadenylate deaminase deficiency) are also risk factors of statin-induced myopathy. These genetic factors may provide predisposition testing for statin-induced rhabdomyolysis. PMID- 21297371 TI - [Exploratory study on biomarkers associated with severe cutaneous adverse reactions]. AB - Most of adverse drug reactions (ADRs) occur as an extension of pharmacological effects. They occur dependently on their blood concentrations and can be potentially reduced by controlling their dose. On the other hand, ADRs categorized as Type B usually occur irrelevantly to their pharmacological effects at different organs from their target, and are often life-threatening and unpredictable. The incidences of Type B ADRs are very low. Severe cutaneous adverse reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are delayed allergic reactions in which T-cells are involved and categorized as Type B ADRs. Recent progress of pharmacogenomic studies has revealed that particular types of human leukocyte antigen (HLA) class I antigens have strong associations with severe cutaneous adverse reactions and that the associations are specific to causative drugs, phenotypes of adverse reactions and ethnic groups. We established a research group in 2006 with professionals of pharmacogenomics, dermatologists, ophthalmologists and psychiatrists to explore genetic biomarkers associated with Japanese SJS/TEN patients. To date, we have collected more than 100 Japanese SJS/TEN patients through participating institutes and a case-collecting system covering all over Japan constructed by us. No carriers of HLA-B*1502 which was reported to have extremely strong association with carbamazepine-induced SJS/TEN in Han Chinese and south Asians, although a moderate association between allopurinol-induced SJS/TEN and HLA B*5801 detected in Han Chinese was observed. PMID- 21297372 TI - [Current status of researches in genomic medicine and the guidelines for pharmacogenomics (PGx)]. AB - Since the whole human genome sequence has become available, the methods to search for genes of diseases or drugs responses (traits) have changed dramatically. The former approach designated as "candidate gene approach" is now dominated by "genome-wide approach". In the former approach, researchers search for the genes based on the functions using biochemistry and molecular biology; however, in the latter approach, the genes are searched for by the genetic and statistical methods. Initially, monogenic diseases were the targets of the researches; however, polygenic diseases and drug responses have become the targets. Parametric linkage analysis was quite useful for identifying responsible genes for monogenic diseases. Genome-wide association study (GWAS) has been introduced for the identification of the genes for polygenic diseases and drug responses. GWAS was first introduced from 2002 to 2004 in Center for Genomic Medicine, RIKEN but has expanded rapidly to other countries including US, Europe and Asian countries from 2005. In Nature Genetics journal, about half of the articles published recently include the data from GWAS studies. Both qualitative and quantitative traits have been analyzed by GWAS. Qualitative traits include diseases and drug responses and quantitative traits include physical measures and clinical laboratory test values. Recent reports about the association between drug responses and genes have clarified many important pharmacogenomic associations. For these data to be analyzed efficiently and used appropriately; however, guidelines for researches and clinical tests concerning pharmacogenomics (PGx) are necessary. "Guideline for pharmacogenomic test" was issued in 2009 and, in addition, an extended guideline covering various fields is now being discussed. PMID- 21297373 TI - [Natural products syntheses based on the biotransformation using biocatalyst]. AB - This review summarizes the chemoenzymatic synthesis of the biologically active natural products based on a combination of chemical diastereoselectivity and enzymatic enantioselectivity using biocatalyst. Asymmetric reduction of 2-methyl 3-keto ester with yeast gave the optically active syn-2-methyl-3-hydroxy ester, which was converted to natural product such as (-)-oudemansin B. Asymmetric hydrolysis of 3-acetoxy-2-methy esters possessing syn- or anti-structure afforded the optically active 3-hydroxy-2-methyl esters and 3-acetoxy-2-methy esters corresponding to the starting material. One of these optically active 3-hydroxy-2 methyl esters was converted to aglycone of macrolide, venturicidins A and B possessing 10 chiral centers. Both primary alcohols possessing a chiral center at beta-position of hydroxyl group and secondary alcohols were subjected to the lipase-assisted acylation in the presence of acyl donor to afford the optically active esters and the optically active alcohols corresponding to the starting material. These optically active compounds were converted to the biologically active natural products such as bisabolane type sesquiterpenes, decaline type diterpenes or triterpenes, nikkomycin B, (+)-asperlin, (-)-chuangxinmycin, (-) indolmycin, cystothiazoles melithiazols, myxothiazols and piericidins possessing antifungal and cytotoxicic activities, inhibition of NADH oxidation, etc. Reaction of primary alcohol and glucose using immobilized beta-glucosidase gave alkyl beta-glucosides in high yield. Pentaacetate of allyl beta-glucoside was subjected to Mizoroki-Heck type reaction with phenylboronic acid derivatives to give phenylpropenoid beta-D-glucopyranosid congeners. PMID- 21297374 TI - [Development of highly nuclease-resistant chemically-modified oligonucleotides]. AB - Chemical modification of therapeutic oligodeoxyribonucleotides (ODNs) is necessary to avoid not only degradation by endo- and exo-nucleases but also recognition by sensors such as an innate immune system. We have been developing modified nucleosides having an aminoalky linker at the pyrimidine nucleobase or sugar moiety. ODNs containing 5-N-(6-aminohexyl)carbamoyl-2'-deoxyuridine (7) were thermally stabilized about 3 degrees C per modification and were about 160 times more stable to hydrolysis by snake venom phosphodiesterase (a 3' exonuclease) than unmodified ODNs, but not by endonucleases. On the other hand, ODNs containing 4'-C-(aminoethyl)thymidine (14b), which was synthesized by a newly developed radical cyclization-ring-enlargement reaction by us, were 87 times more stable to hydrolysis by DNase I (an endonuclease) and 133 times more stable in 50% human serum than unmodified ODNs. The highly stereoselective synthesis of 4'-thioribonuclesides ((S)Ns) was also developed using a Pummerer reaction. Human thrombin RNA aptamer (CII-1-37) containing 4'-thiouridine and 4' thiocytidine was obtained by SELEX with a K(d) value of 4.7 nM, while a previously known RNA aptamer (RNA-24) has a K(d) value of 85 nM. Studies of the modification pattern-RNAi activity relationships by using (S)Ns have been carried out against luciferase genes. We found that siRNAs, which have 4 residues of (S)Ns on both ends of the sense strand and 4 residues on the 3'-end of the antisense strand, were the most effective. 4'-ThioRNA is about 1100 times more stable in 50% human plasma than unmodified RNA. However, oligoribonucleotides ((SM)ONs) containing 2'-O-methyl-4'-thioribonucleosides were 9800 times more stable in 50% human plasma than unmodified RNA. Since (SM)ON duplexes were thermally more stable than unmodified ON duplexes, therefore they would be quite suitable to use for oligonucleotide therapeutics. PMID- 21297375 TI - [Development of animal models of herpetic pain and postherpetic neuralgia and elucidation of the mechanisms of the onset and inhibition of allodynia]. AB - Herpes zoster characterized by clustered vesicles and severe pain is caused by reactivation of varicella-zoster virus in the sensory ganglion in humans. In some herpes zoster patients, pain persists long after healing of the skin lesions, which is postherpetic neuralgia. Patients with postherpetic neuralgia report various types of pain. In addition, a large proportion describes "allodynia", which is a painful sensation elicited by normally innocuous light mechanical stimulation. Once established, postherpetic neuralgia is particularly difficult to treat, and is often resistant to conventional analgesics. The mechanisms that underlie the induction and maintenance of herpetic pain and postherpetic neuralgia remain unclear. Therefore we attempted to establish animal models of herpetic pain and postherpetic neuralgia. This review summarizes our findings regarding the development of mouse models of herpetic pain and postherpetic neuralgia, pharmacological characterization of mouse models, mechanisms of allodynia and risk factors for postherpetic neuralgia. PMID- 21297376 TI - [Effects of sperminated pullulans on the pulmonary absorption of insulin]. AB - Sperminated pullulans (SP) having different molecular weights (MWs) were prepared, and the enhancing effect on the pulmonary absorption of insulin in rats was examined. SP acted as enhancers of insulin absorption when a 0.1% solution was applied with insulin simultaneously and their enhancing effects depended on the MW of the SP; the same solutions exhibited low toxicity in the in vivo LDH leaching test. In the in vitro experiments using Calu-3 cells, tight junction opening effects and a toxic effect of SP in the MTT assay were observed at lower concentrations compared with the in vivo experiments. A mucus layer might interfere with the interaction between SP and the cell surface and might suppress both these effects and toxicity. SP having a high MW will be useful for preparing safe and efficient formulations of peptide and protein drugs. The change in the localization of the tight junction proteins may be related to the permeation enhancing mechanism of SP. PMID- 21297377 TI - Protective effects of basic fibroblast growth factor in the development of emphysema induced by interferon-gamma. AB - Recent clinical evidence indicates that the non-eosinophilic subtype of severe asthma is characterized by fixed airway obstruction, which may be related to emphysema. Transgenic studies have demonstrated that high levels of IFN-gamma in the airways induce emphysema. Fibroblast growth factor 2 (FGF2), which is the downstream mediator of TGF-beta, is important in wound healing. We investigated the role of FGF2 in IFN-gamma-induced emphysema and the therapeutic effects of recombinant FGF2 in the prevention of emphysema in a severe non-eosinophilic asthma model. To evaluate the role of FGF2 in IFN-gamma-induced emphysema, lung targeted IFN-gamma transgenic mice were cross-bred with FGF2-deficient mice. A severe non-eosinophilic asthma model was generated by airway application of LPS containing allergens twice a week for 4 weeks. To evaluate protective effects of FGF2, recombinant FGF2 (10 MUg) was injected subcutaneously during allergen challenge in the severe asthma model. We found that non-eosinophilic inflammation and emphysema induced by transgenic overexpression of IFN-gamma in the airways were aggravated by the absence of FGF2. Airway challenge with LPS-containing allergens induced more inflammation in mice sensitized with LPS-containing allergens compared to challenge with allergens alone. In addition, LPS-induced lung inflammation and emphysema depended on IFN-gamma but not on IL-13. Interestingly, emphysema in the severe asthma model was significantly inhibited by treatment with recombinant FGF2 during allergen challenge, whereas lung inflammation was unaffected. Therefore, our present data suggest that FGF2 may help protect against IFN-gamma-induced emphysema, and that recombinant FGF2 may help lessen the severity of emphysema. PMID- 21297378 TI - 5-Formylhonokiol exerts anti-angiogenesis activity via inactivating the ERK signaling pathway. AB - Our previous report has demonstrated that 5-formylhonokiol (FH), a derivative of honokiol (HK), exerts more potent anti-proliferative activities than honokiol in several tumor cell lines. In present study, we first explored the antiangiogenic activities of 5-formylhonokiol on proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVECs) for the first time in vitro. Then we investigated the in vivo antiangiogenic effect of 5-formylhonokiol on zebrafish angiogenesis model. In order to clarify the underlying molecular mechanism of 5-formylhonokiol, we investigated the signaling pathway involved in controlling the angiogenesis process by western blotting assay. Wound-healing results showed that 5-formylhonokiol significantly and dose-dependently inhibited migration of cultured human umbilical vein enthothelial cells. The invasiveness of HUVEC cells was also effectively suppressed at a low concentration of 5 formylhonokiol in the transwell assay. Further F-actin imaging revealed that inhibitory effect of 5-formylhonokiol on invasion may partly contribute to the disruption of assembling stress fiber. Tube formation assay, which is associated with endothelial cells migration, further confirmed the anti-angiogenesis effect of 5-formylhonokiol. In in vivo zebrafish angiogenesis model, we found that 5 formylhonokiol dose-dependently inhibited angiogenesis. Furthermore, western blotting showed that 5-formylhonokiol significantly down-regulated extracellular signal-regulated kinase (ERK) expression and inhibited the phosphorylation of ERK but not affecting the total protein kinase B (Akt) expression and related phosphorylation, suggesting that 5-formylhonokiol might exert anti-angiogenesis capacity via down-regulation of the ERK signal pathway. Taken together, these data suggested that 5-formylhonokiol might be a viable drug candidate in antiangiogenesis and anticancer therapies. PMID- 21297379 TI - Bisphosphonate enhances TRAIL sensitivity to human osteosarcoma cells via death receptor 5 upregulation. AB - Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily of cytokines, is one of the most promising candidates for cancer therapeutics. However, many osteosarcomas are resistant to TRAIL. Bisphosphonates are very effective in the treatment of bone problems associated with malignancies; the antitumor effects are due to the inhibition of protein prenylation that is essential for cell function and survival. The purpose of this study was to determine the effects of bisphosphonates on TRAIL-resistant MG 63 human osteosarcoma cells. The cells showed no response to TRAIL alone; however, pre-treatment with bisphosphonates significantly increased TRAIL-mediated apoptosis and cellular activation of caspase-3. Bisphosphonates significantly induced mRNA and protein expression of the TRAIL receptor, DR5. Bisphosphonates induced protein unprenylation in MG 63 cells; in addition, co-treatment with TRAIL also significantly increased protein unprenylation. Blocking of protein unprenylation using geranylgeraniol attenuated the cellular responses, including cell apoptosis and protein unprenylation induced by bisphosphonates and TRAIL. This is the first study to demonstrate that bisphosphonates markedly enhanced TRAIL-induced apoptosis in human osteosarcoma cells. These findings suggest that bisphosphonates may be a new and effective anticancer treatment with TRAIL proteins for TRAIL-resistant cancer cells. PMID- 21297380 TI - New therapeutic algorithm of Type 2 diabetes: lights and shadows. PMID- 21297381 TI - Environmental triggers of thyroiditis: hepatitis C and interferon-alpha. AB - Autoimmune thyroid diseases (AITD) are postulated to develop as a result of a complex interplay between several genetic and environmental influences. The pathogenesis of AITD is still not clearly defined. However, among the implicated triggers (e.g. iodine, infections, medications), more recent data confirmed strong associations of AITD with the hepatitis C virus (HCV) infection and interferon-alpha (IFNalpha) therapy. Moreover, it is likely that HCV and IFN act in synergism to trigger AITD in patients. Indeed, approximately 40% of HCV patients develop either clinical or subclinical disease while receiving IFNalpha. Interferon induced thyroiditis (IIT) can manifest as non-autoimmune thyroiditis (presenting as destructive thyroiditis, or non-autoimmune hypothyroidism), or autoimmune thyroiditis [presenting with clinical features of Graves' disease (GD) or Hashimoto's thyroiditis (HT)]. Although not yet clearly understood, it is thought that IFNalpha can induce thyroiditis via both immune stimulatory and direct toxic effects on the thyroid. In view of the high frequency of IIT, routine screening and surveillance of HCV patients receiving IFNalpha is recommended to avoid the complications, such as cardiac arrhythmias, associated with thyrotoxicosis. In summary, IIT is a common clinical problem that can be readily diagnosed with routine thyroid function screening of HCV patients receiving IFN. The treatment of IIT consists of the standard therapy for differing clinical manifestations of IIT such as GD, HT, or destructive thyroiditis. However, anti-thyroid medications are not recommended in this setting since they can potentially be hepatotoxic. PMID- 21297382 TI - Acupuncture in clinical and experimental reproductive medicine: a review. AB - BACKGROUND: Acupuncture has been used as treatment for infertility for hundreds of years, and recently it has been studied in male and female infertility and in assisted reproductive technologies, although its role in reproductive medicine is still debated. AIM: To review studies on acupuncture in reproductive medicine, in experimental and clinical settings. METHODS: Papers were retrieved on PubMed and Google Scholar and were included in the review if at least the abstract was in English. RESULTS: There is evidence of benefit mainly when acupuncture is performed on the day of embryo transfer (ET) in the live birth rate. Benefit is also evident when acupuncture is performed for female infertility due to polycystic ovary syndrome (PCOS). There is some evidence of sperm quality improvement when acupuncture is performed on males affected by idiopathic infertility. Experimental studies suggest that acupuncture effects are mediated by changes in activity of the autonomic nervous system and stimulation of neuropeptides/neurotransmitters which may be involved in the pathogenesis of infertility. CONCLUSIONS: Acupuncture seems to have beneficial effects on live birth rate when performed on the day of ET, and to be useful also in PCOS as well as in male idiopathic infertility, with very low incidence of side effects. However, further studies are necessary to confirm the clinical results and to expand our knowledge of the mechanisms involved. PMID- 21297383 TI - Androgen regulation of prostate cancer: where are we now? AB - BACKGROUND: Androgens play an essential role in the development and differentiation of the prostate gland; their contribution to pathological conditions, such as benign prostatic hyperplasia and prostate cancer (PC), remains unclear. AIM: We reviewed relationships between androgens and the prostate both in physiological and pathological conditions. MATERIAL AND METHODS: A systematic search of published evidence was performed using Medline (1969 to September 2010). RESULTS: Androgen-dependency of prostate growth is evident only in the hypogonadal condition, but not in the eugonadal state (the "saturation hypothesis"). There is unequivocal evidence that reducing androgen signaling to the hypogonadal range can reduce PC growth and patient symptoms. At physiological testosterone concentration there is no link between androgen levels and PC risk. In addition, different strategies of androgen deprivation (ADT) for advanced PC are only palliative and rarely cure patients. Preliminary evidence indicates that a low androgen milieu is associated with tumor aggressiveness. Transition to androgen-independence is complex and involves both selection and outgrowth of preexisting androgen resistant clones, as well as adaptative upregulation of genes that help the cancer cells to survive and grow after ADT. Because androgens are essential for the regulation of fat distribution, insulin sensitivity, and lipid and bone metabolism, recent publications have highlighted the concept that ADT may also be involved with an increase in overall, as well as cardiovascular, morbidity and mortality. CONCLUSIONS: While ADT still represents a cornerstone for the palliative therapy of a small fraction of aggressive PC, a "misuse and/or abuse" of ADT should be avoided. PMID- 21297384 TI - Genetic defects of ovarian TGF-beta-like factors and premature ovarian failure. AB - Premature ovarian failure (POF) is an ovarian defect characterized by the premature depletion of ovarian follicles; POF affects approximately 1-2% of women under the age of 40 yr, thus representing one major cause of female infertility. POF relevance is continuously growing because women tend to conceive always more frequently beyond 30 yr. Frequently, POF is the end-stage of an occult process [primary ovarian insufficiency (POI)]. POI is a heterogeneous disease caused by a variety of mechanisms. Though the underlying cause remains unexplained in the majority of cases, several data indicate that POI has a strong genetic component. These data include the existence of several causal genetic defects in human, experimental, and natural models, as well as the frequent familiarity. The candidate genes are numerous, but POF remains unexplained in most of the cases. Several recent evidences have driven the attention of researchers on the possible involvement of various elements belonging to the transforming growth factor beta family, which includes bone morphogenetic proteins, growth/differentiation factors, and inhibins. These peptides are produced by either the oocyte or granulosa cells to constitute a complex paracrine network within the ovarian follicle. Here, we review the studies reporting the genetic alterations of these factors in human and animal defects of ovarian folliculogenesis which support the fundamental roles played by these signals in ovarian morphogenesis and function. PMID- 21297385 TI - Treatment of methicillin-resistant Staphylococcus aureus surgical site infections. PMID- 21297386 TI - Echocardiography: pictures worth 1000 words. PMID- 21297387 TI - Healthy work environment 101. PMID- 21297388 TI - Creating a culture to promote nursing specialty certification. Symposium introduction. PMID- 21297389 TI - The value of certification. AB - Certification is defined in the nursing literature in several ways; no one consistent definition of certification exists. Nursing specialty certification programs are intended for consumer protection. Certification protects the public by enabling consumers to identify competent people more readily. However, benefits for stakeholders other than patients and families are also described in the literature. This article describes the value of specialty certification from the perspective of the patient and family, nurse, and employer. PMID- 21297390 TI - Best practices in creating a culture of certification. AB - Certification is the criterion standard of professional practice, distinguishing excellence in nursing care, mastery of knowledge, skills, and abilities beyond the scope of professional licensure. It is the validation of an individual nurse's qualifications for practice in a defined area. Becoming certified is a personal and professional commitment that demonstrates the value that the individual nurse places on higher standards of practice and lifelong learning. The American Association of Critical-Care Nurses (AACN) Beacon Award for Excellence, Magnet Recognition Program, and Malcolm Baldrige National Quality Award all recognize certification as a key component of nursing excellence in specialty practice. Both the general public and nurse professionals increasingly recognize the need for practice on the basis of evidence to provide safe, quality patient care. In today's rapidly changing and complex health care delivery system, certification is becoming the standard by which bedside practice and the impact of nursing care on patient outcomes are measured. This article will provide a review of current best practices in creating a culture of certification, including the journey of 3 hospitals selected as the 2010 Best Practice Roundtable presentations at the AACN National Teaching Institute. PMID- 21297391 TI - APRN regulation: the licensure-certification interface. AB - This article describes the development of a new regulatory model for advanced practice nursing. The history of nursing licensure is detailed to provide a perspective of the differences in the way that advanced practice roles evolved as a result of external forces and patient needs without the direct control of regulators and the resulting variations in the interpretation and implementation of the roles nationwide. Key provisions of the new consensus model for regulation are detailed, along with implications for each of the main stakeholder groups: licensure, accreditation, certification, and education. PMID- 21297392 TI - Let's get certified: best practices for nurse leaders to create a culture of certification. AB - Certification benefits nurses, patients and their families, and hospitals. Nurses become certified for various reasons: personal challenge; self-improvement; advancement of knowledge and education; demonstration of mastery of skills, knowledge, and abilities; and commitment to lifelong learning and career growth. However, there are also barriers to certification. Fear of test taking or failure and lack of resources or organization recognition are reasons many nurses cite for not becoming certified. Nurse leaders play a pivotal role in supporting nurses to obtain and maintain specialty nursing certification. Nurse leaders may promote certification, support nurses who are on their certification journey, and reward and recognize those staff that become certified. This article will share practices to increase the number of specialty certified nurses in your unit or organization. PMID- 21297393 TI - Promoting certification: the chapter's role. AB - The mission of the American Association of Critical-Care Nurses focuses on providing nurses with expert knowledge to promote delivery of excellent, safe, quality care to acutely and critically ill patients and their families. Chapters consist of professional leaders in a community who carry on the mission work of the American Association of Critical-Care Nurses at the local level. Chapters can emphasize the value of certification and continuing education, because they offer a wide spectrum of opportunities to meet the learning and developmental needs of nurses as they advance in their professional careers. This article will highlight strategies that can be implemented by local chapters to facilitate and promote certification. PMID- 21297394 TI - Certifiably excellent. AB - The purpose of this article is to provide a road map for individuals and chapters to use in beginning a certification program. The Heart of the Piedmont Chapter used the mission, vision, and values of the American Association of Critical-Care Nurses to create an environment of safety and expert care for patients and their families. The journey began when our chapter realized that there were only a few certified nurses in our chapter and hospital. As a chapter, we decided to use a survey to determine interest in certification. We invited all interested nurses to attend a certification meeting. Eighty nurses attended. Collaborating with nursing administration, we held study groups, brought in a national speaker, and assisted with payment of the certification examination. This article describes how 1 chapter can make a positive difference in the lives of nurses and patients. Although our chapter's journey is ongoing, we hope to share our strategies for success with others. PMID- 21297395 TI - Qualitative research: using "soft" evidence to solve hard clinical problems. PMID- 21297396 TI - It started with Einthoven: the history of the ECG and cardiac monitoring. PMID- 21297397 TI - The Uniform Data System for Medical Rehabilitation: report of patients with hip fracture discharged from comprehensive medical programs in 2000-2007. AB - OBJECTIVE: The aim of this study was to provide benchmarking information for a large national sample of patients receiving inpatient rehabilitation because of a hip fracture. DESIGN: A secondary data analysis of records from 893 medical rehabilitation facilities located in the United States that contributed information to the Uniform Data System for Medical Rehabilitation from January 2000 through December 2007 was performed. Variables analyzed included demographic information (age, sex, marital status, race/ethnicity, prehospital living setting, and discharge setting), hospitalization information (length of stay, program interruptions, payer, onset date, rehabilitation impairment group, International Classification of Diseases, Ninth Revision, codes for admitting diagnosis, comorbidities), and Functional Status Information (FIM instrument ratings at admission and discharge, FIM efficiency, and FIM gain). RESULTS: Descriptive statistics from 303,594 patients showed length of stay decreasing from a mean (SD) of 14.5 (7.9) days to 13.3 (5.5) days over the 8-yr study period. FIM total admission and discharge ratings also decreased. Mean admission ratings decreased from 72.5 (14.5) to 59.9 (15.7). Mean discharge ratings decreased from 95.8 (18.1) to 86.0 (19.8). FIM change per day remained relatively stable; mean for the entire sample was 2.1 (1.6). The percentage of persons discharged to the community also decreased across the study period, ranging from 77.8% in 2000 to 70.0% in 2007. All results are likely influenced by various policy changes affecting classification and/or documentation processes. CONCLUSIONS: National rehabilitation data from persons with hip fracture in 2000 2007 indicate that patients are spending less time in inpatient rehabilitation care than in previous years and are experiencing improvements in functional independence during their stay. In addition, most patients are discharged to the community after inpatient rehabilitation. PMID- 21297398 TI - A pointing task to improve reaching performance in older adults. AB - OBJECTIVE: The objective of this study was to evaluate whether adding a pointing task would influence functional reach test performance in younger and older adults. DESIGN: While standing on a force plate, 20 older (73 +/- 8 yrs) and 20 younger (23 +/- 1 yrs) adults were randomly administered a modification of the functional reach test and the functional point test. Functional pointing involved reaching and pointing at the farthest possible target in a series of 1.27-cm colored craft pom-poms attached at 2.54-cm intervals on a yardstick. RESULTS: Both older adults (P = 0.001) and younger adults (P = 0.043) reached farther using the functional point test. Older adults also increased their anterior center of pressure displacement with this test (P = 0.037). CONCLUSIONS: The addition of a pointing task can make the original clinical test more functional and increase reaching distance in both older and younger adults. Further research is needed to determine whether functional pointing challenges subjects' stability limits more than the traditional test does and offers greater sensitivity in the evaluation of functional balance and fall risk. PMID- 21297399 TI - Acceleration-based motion analysis as a tool for rehabilitation: exploration in simulated functional knee limited walking conditions. AB - OBJECTIVE: The aim of this study was to investigate the ability of acceleration based gait analysis to differentiate between normal gait and different simulated functional knee limitations of increasing severity. DESIGN: Gait of 48 healthy subjects was measured under four different walking conditions. Gait parameters (e.g., speed and asymmetry) were derived from trunk accelerations. Subjects walked a 20-m distance under four conditions: normal, simulated limited knee extension, simulated limited knee flexion, and simulated arthrodesis. The functional knee limitations were simulated using an adjustable knee brace on the right leg. RESULTS: Acceleration-based gait analysis detected acute gait changes (i.e., speed, step length, step duration, cadence, vertical displacement, asymmetry, and irregularity) during the simulated functional knee limitations with high repeatability. The degree of change depended on the severity of the limitation, with the more severe limitations producing bigger changes in gait and the relative changes comparing well with literature values measured with laboratory-based motion analysis. CONCLUSIONS: Acceleration-based gait analysis is sensitive for different walking conditions. The easy and fast use, the production of objective gait characteristics, and the ability to differentiate functional knee limitations suggest its suitability for clinical rehabilitation. PMID- 21297400 TI - Specificity of needle electromyography for lumbar radiculopathy in 55- to 79-yr old subjects with low back pain and sciatica without stenosis. AB - OBJECTIVE: The aim of this study was to determine the specificity of needle electromyography for lumbar radiculopathy in subjects with low back pain and sciatica without stenosis. DESIGN: Subjects 55 yrs or older with diagnoses of low back pain and sciatica underwent a standardized monopolar needle evaluation by blinded electromyographers as part of a spinal stenosis study. The presence or absence of radiculopathy was determined using different electrodiagnostic criteria. RESULTS: Seventy-two subjects with a mean age of 64.6 years (SD, 7.0 yrs) were studied. When only positive sharp waves or fibrillations were considered abnormal, most of the diagnostic criteria--two limb muscles + associated lumbar paraspinal muscle abnormal, two limb muscles abnormal, or one limb muscle + associated lumbar paraspinal muscle abnormal--had 97%, 96%, and 92% specificity, respectively. When 30% or greater polyphasia in the limb muscles was also considered abnormal, the respective specificities were 90%, 81%, and 85%. When 20% or greater polyphasia in the limb muscles was also considered abnormal, the respective specificities were 90%, 74%, and 71% [corrected]. CONCLUSIONS: There is good specificity for lumbosacral radiculopathy when appropriate diagnostic criteria are used. PMID- 21297401 TI - Sympathetic storming in a patient with intracranial basal ganglia hemorrhage. AB - Neurologic deficits and medical complications are common sequelae after intracranial hemorrhage. Among the medical complications, sympathetic storming is relatively rare. We describe a case of a patient with an acute right basal ganglia hemorrhage. During the patient's hospital course, he developed tachypnea, diaphoresis, hypertension, hyperthermia, and tachycardia for three consecutive days. A complete laboratory work-up and imaging studies were unremarkable for infectious etiology, new intracranial hemorrhage, and deep vein thrombosis. The patient was diagnosed with sympathetic storming, a relatively uncommon cause of these symptoms. The storming was secondary to a kinked Foley catheter, and subsequent placement of a new catheter resulted in the resolution of his symptoms. PMID- 21297402 TI - Ensuring accountability in public health prevention research: evaluating the Prevention Research Centers Program at the Centers for Disease Control and Prevention. PMID- 21297403 TI - CrowdED: crowding metrics and data visualization in the emergency department. AB - OBJECTIVES: Emergency department (ED) crowding metrics were validated in our facility and a new technique of data visualization is proposed. DESIGN: A sequential cross-sectional study was conducted in our ED during October 2007. Data were collected every 2 hours by a research assistant and included patient arrivals and acuity levels, available inpatient and ED beds, ambulance diversion status, staff present, and patient reneging. The charge nurse and an attending physician also completed a single-question crowding instrument. Pearson correlation coefficients were calculated and logistic regression were performed to test the usefulness of the crowding score and test significance of the data visualization trends. SETTING/PARTICIPANTS: Our ED is an adult, level-III, veterans administration ED in urban southern California. It is open 24 hours per day, has 15 treatment beds with 4 cardiac monitors, and typically sees about 30 000 patients per year. MAIN OUTCOME MEASURE(S): The key outcome variables were patient reneging (number of patients who left before being seen by a physician) and ambulance diversion status. RESULTS: Average response rate was 72% (n = 227) of sampling times. Emergency Department Work Index, demand value, lack of inpatient beds, census, patients seen in alternate locations, and patient reneging correlated significantly (P < .01) with the crowding instrument. Staff workload ranks predicted patient reneging (odds ratio 6.0, 95% confidence interval 2.3-15.4). The data visualization focused on common ED overcrowding metrics and was supported by logistic regression modeling. CONCLUSIONS: The demand value, ED Work Index, and patient reneging are valid measures of crowding in the studied ED, with staff workload rank being an easy, 1-question response. Data visualization may provide the site-specific crowding component analysis needed to guide quality improvement projects to reduce ED crowding and its impact on patient outcome measures. PMID- 21297406 TI - Statewide applied epidemiology workforce capacity and competency assessment- Nebraska, 2008. PMID- 21297404 TI - Continued benefits of a technical assistance web site to local tobacco control coalitions during a state budget shortfall. AB - CONTEXT: A state budget shortfall defunded 10 local tobacco coalitions during a randomized trial but defunded coalitions continued to have access to 2 technical assistance Web sites. OBJECTIVE: To test the ability of Web-based technology to provide technical assistance to local tobacco control coalitions. DESIGN: Randomized 2-group trial with local tobacco control coalitions as the unit of randomization. SETTING: Local communities (ie, counties) within the State of Colorado. PARTICIPANTS: Leaders and members in 34 local tobacco control coalitions funded by the state health department in Colorado. INTERVENTION: Two technical assistance Web sites: A Basic Web site with text-based information and a multimedia Enhanced Web site containing learning modules, resources, and communication features. MAIN OUTCOME MEASURE(S): Use of the Web sites in minutes, pages, and session and evaluations of coalition functioning on coalition development, conflict resolution, leadership satisfaction, decision-making satisfaction, shared mission, personal involvement, and organization involvement in survey of leaders and members. RESULTS: Coalitions that were defunded but had access to the multimedia Enhanced Web site during the Fully Funded period and after defunding continued to use it (treatment group * funding status * period, F(3,714) = 3.18, P = .0234). Coalitions with access to the Basic Web site had low Web site use throughout and use by defunded coalitions was nearly zero when funding ceased. Members in defunded Basic Web site coalitions reported that their coalitions functioned worse than defunded Enhanced Web site coalitions (coalition development: group * status, F(1,360) = 4.81, P = .029; conflict resolution: group * status, F(1,306) = 5.69, P = .018; leadership satisfaction: group * status, F(1,342) = 5.69, P = .023). CONCLUSIONS: The Enhanced Web site may have had a protective effect on defunded coalitions. Defunded coalitions may have increased their capacity by using the Enhanced Web site when fully funded or by continuing to use the available online resources after defunding. Web-based technical assistance with online training and resources may be a good investment when future funding is not ensured. PMID- 21297407 TI - Data-driven management strategies in public health collaboratives. PMID- 21297408 TI - Disseminating evidence from research and practice: a model for selecting evidence to guide obesity prevention. PMID- 21297409 TI - School-based nutrition education intervention: effect on achieving a healthy weight among overweight ninth-grade students. PMID- 21297410 TI - Meeting the need of a rural state for primary care physicians: a health care reform challenge. PMID- 21297411 TI - Successful implementation in the public sector: lessons learned from Florida's Medicaid reform program. PMID- 21297412 TI - The Southeast Telehealth Network: using technology to overcome the barriers to rural public health practice. PMID- 21297413 TI - Race and ethnicity reporting in statewide hospital data: progress and future challenges in a key resource for local and state monitoring of health disparities. PMID- 21297414 TI - Improving collaboration for effective violence surveillance and health promotion. PMID- 21297415 TI - Local public health capacities to address the needs of culturally and linguistically diverse populations. PMID- 21297416 TI - The management moment: building conflict competence. PMID- 21297417 TI - News from NACCHO: Local health departments' response to the diabetes epidemic. PMID- 21297418 TI - Relative time to pregnancy among HIV-infected and uninfected women in the Women's Interagency HIV Study, 2002-2009. AB - OBJECTIVES: To determine the incidence rate of, and the relative time to pregnancy by HIV status in US women between 2002 and 2009. DESIGN: The Women's Interagency HIV Study (WIHS) is an ongoing, multicenter prospective cohort study of the natural and treated history of HIV infection and related outcomes among women with and without HIV. METHODS: Eligible participants were 45 years of age or less; sexually active with male partner(s) or reported a pregnancy outcome within the past year; and never reported hysterectomy, tubal ligation, or oopherectomy. Poisson regression was conducted to compare pregnancy incidence rates over time by HIV status. Relative time to pregnancy was ascertained via Kaplan-Meier plots and generalized gamma survival analysis. RESULTS: Adjusting for age, number of male sex partners, contraception, parity, exchanging sex, and alcohol use, HIV infection was associated with a 40% reduction in the incidence rate of pregnancy [incidence rate ratio = 0.60, 95% confidence interval (CI) 0.46 0.78]. The time for HIV-infected women to become pregnant was 73% longer relative to HIV-uninfected women (relative time = 1.73, 95% CI 1.35-2.36). In addition to HIV infection, decreased parity and older age were independent predictors of lower pregnancy incidence. CONCLUSIONS: Despite the beneficial effects of modern antiretroviral therapy on survival and prevention of maternal-to-child transmission, our findings suggest that pregnancy incidence remains lower among HIV-infected women. Whether this lower incidence is due to behavioral differences or reduced biologic fertility remains an area worthy of further study. PMID- 21297419 TI - Long-term outcomes for HIV-infected infants less than 6 months of age at initiation of lopinavir/ritonavir combination antiretroviral therapy. AB - OBJECTIVE: To investigate the longitudinal pharmacokinetics, safety and efficacy of lopinavir/ritonavir (LPV/r) in HIV-infected infants initiating combination antiretroviral therapy (cART) between 2 weeks and 6 months of age. METHOD: A prospective, open-label, multicenter Phase I/II study of LPV/r-based cART at a dose of 300/75 mg/m(2)/dose LPV/r twice daily. Intensive pharmacokinetic sampling at 12 months of age and quarterly predose LPV concentrations were collected and safety, virologic and immunologic responses were monitored every 4-12 weeks up to 252 weeks. RESULTS: Thirty-one HIV-infected infants enrolled into two age cohorts, 14 days to <6 weeks and 6 weeks to <6 months; 29 completed >=48 weeks of follow-up (median = 123 weeks, range 4-252). At 12 months of age, median LPV area under the curve was comparable for both age cohorts and similar to older children and adults. At week 48, 22 of 31 patients (71%) had HIV-1 RNA <400 copies/ml and 11 of 15 (73%) had <50 copies/ml; 29 of 31 achieved HIV-1 RNA <400 copies/ml on study treatment and 19 (66%) remained durably suppressed until the end of study; viral suppression correlated with a higher percentage of predose time points exceeding the LPV target of 1 MUg/ml (92 vs. 71%, P = 0.002). CONCLUSION: LPV/r at 300/75 mg/m(2)/dose as part of a cART regimen resulted in viral suppression through 96 weeks of treatment in >65% of young infants. Due to initially low LPV exposure in infants <6 weeks of age, frequent dose adjustment for weight gain is advisable and consideration should be given to studying a higher dose for very young infants. PMID- 21297420 TI - The impact of HIV drug resistance testing on changes to treatment. AB - BACKGROUND: We investigate changes made to therapy after a resistance test result and identify factors associated with switching regimen. METHODS: Patients receiving antiretroviral therapy (ART) who had a resistance test performed during 1998-2007 were included in the analysis. A switch was defined as starting at least two drugs/starting a drug from a class not previously experienced within 4 months of the resistance test result. Logistic regression was used to identify factors independently associated with switching regimen. RESULTS: Of the 5123 test results included in the analyses, 1874 (36.6%) were followed by a switch within 4 months of the test result. Independent factors associated with switching included genotypic sensitivity score (GSS) of the current regimen [odds ratio (OR) 4.86, 95% confidence interval (CI) 3.95, 5.97 for GSS less than 1 compared to GSS of at least 3] and a higher number of previous failures [1.12 (1.06, 1.18) per additional failed regimen]. Patients with fewer drug options were less likely to switch [0.36 (0.27, 0.48) comparing 0-3 drug options with >=10 drug options]. CONCLUSIONS: Only 37% of patients switched regimen within 4 months of the resistance test result. Whilst toxicity concerns of available drugs may somewhat explain this finding, it is also likely that there is a lack of treatment options available for patients who did not switch. PMID- 21297421 TI - Absence of reproducibly detectable low-level HIV viremia in highly exposed seronegative men and women. AB - OBJECTIVE: Transient HIV infections have been invoked to account for the cellular immune responses detected in highly virus-exposed individuals who have remained HIV-seronegative. We tested for very low levels of HIV RNA in 524 seronegative plasma samples from 311 highly exposed women and men from three longitudinal HIV cohorts. DESIGN: Two thousand and seventy-three transcription-mediated amplification (TMA) HIV RNA tests were performed for an average of 3.95 TMA assays per plasma sample. Quadruplicate TMA assays, analyzing a total of 2 ml of plasma, provided an estimated sensitivity of 3.5 HIV RNA copies/ml. RESULTS: Four samples from individuals who did not seroconvert within the following 6 months were positive for HIV RNA. For one sample, human polymorphism DNA analysis indicated a sample mix-up. Borderline HIV RNA detection signals were detected for the other three positive samples but further replicate TMA testing yielded no positive results. Nested PCR assays (n = 254) for HIV proviral DNA in peripheral blood mononuclear cells (PBMCs) from these three individuals were negative. CONCLUSION: Transient viremia was not reproducibly detected in highly HIV-exposed seronegative men and women. If transient infections do occur, plasma HIV RNA levels may remain below the detection limits of the sensitive assay used here, be of very short duration, or viral replication may be restricted to mucosal surfaces or their draining lymphoid tissues. PMID- 21297422 TI - Polymorphisms in interferon regulatory factor 7 reduce interferon-alpha responses of plasmacytoid dendritic cells to HIV-1. AB - Recognition of HIV-1 ssRNA by Toll-like receptor 7 induces the production of the pro-inflammatory cytokines that may contribute to the systemic immune activation associated with HIV-1 disease progression. Here, we describe a novel association between polymorphisms in interferon regulatory factor 7 (IRF7), a master regulator of interferon-alpha (IFN-alpha), and the ability of plasmacytoid dendritic cells to produce IFN-alpha in response to HIV-1. IRF7 polymorphisms may, therefore, affect the ability of individuals to respond to HIV-1 and modulate HIV-1 disease progression. PMID- 21297424 TI - Global trends in molecular epidemiology of HIV-1 during 2000-2007. AB - OBJECTIVE: To estimate the global and regional distribution of HIV-1 subtypes and recombinants between 2000 and 2007. DESIGN: Country-specific HIV-1 molecular epidemiology data were combined with estimates of the number of HIV-infected people in each country. METHODS: Cross-sectional HIV-1 subtyping data were collected from 65 913 samples in 109 countries between 2000 and 2007. The distribution of HIV-1 subtypes in individual countries was weighted according to the number of HIV-infected people in each country to generate estimates of regional and global HIV-1 subtype distribution for the periods 2000-2003 and 2004 2007. RESULTS: Analysis of the global distribution of HIV-1 subtypes and recombinants in the two periods indicated a broadly stable distribution of HIV-1 subtypes worldwide with a notable increase in the proportion of circulating recombinant forms (CRFs), a decrease in unique recombinant forms (URFs) and an overall increase in recombinants. In 2004-2007, subtype C accounted for nearly half (48%) of all global infections, followed by subtypes A (12%) and B (11%), CRF02_AG (8%), CRF01_AE (5%), subtype G (5%) and D (2%). Subtypes F, H, J and K together cause fewer than 1% of infections worldwide. Other CRFs and URFs are each responsible for 4% of global infections, bringing the combined total of worldwide CRFs to 16% and all recombinants (CRFs along with URFs) to 20%. CONCLUSION: The global and regional distributions of individual subtypes and recombinants are broadly stable, although CRFs may play an increasing role in the HIV pandemic. The global diversity of HIV-1 poses a formidable challenge to HIV vaccine development. PMID- 21297425 TI - Persistence of HIV-associated cognitive impairment, inflammation, and neuronal injury in era of highly active antiretroviral treatment. AB - OBJECTIVE: To determine whether cognitive impairment and brain injury as measured by proton magnetic resonance spectroscopy (MRS) persist in the setting of HAART. DESIGN: This study is an observational cohort study. METHODS: MRS was performed in 268 patients: HIV-negative controls (N = 28), HIV-positive neuroasymptomatic individuals (N = 124), and individuals with AIDS dementia complex (ADC; N = 50) on stable antiretroviral therapy (ART) with a mean duration of infection of 12 years and CD4 cell count of 309 cells/MUl. Four metabolites were measured over creatine: N-acetyl aspartate (NAA), marker of neuronal integrity; choline (Cho), myoinositol, markers of inflammation, and glutamate and glutamine (Glx) in the basal ganglia, frontal white matter (FWM), and mid-frontal cortex. Analyses included analysis of variance, analysis of covariance, linear, and nonparametric regression models. RESULTS: Cognitive impairment was found in 48% of HIV-infected individuals. Both HIV-positive groups showed significant increases in myoinositol/creatine or Cho/creatine in all brain regions when compared to controls; a significant decrease in Glx/creatine in the FWM was observed in the neuroasymptomatic group; and only individuals with ADC showed a significant reduction in NAA/creatine, although a significant trend for decreasing NAA/creatine in the basal ganglia was found across the groups. Effects related to aging and duration of infection, but not central nervous system penetration effectiveness were observed. CONCLUSION: Brain inflammatory changes remain ubiquitous among HIV-infected individuals, whereas neuronal injury occurs predominantly in those with cognitive impairment. Together these findings indicate that despite the widespread use of HAART, HIV-associated cognitive impairment and brain injury persist in the setting of chronic and stable disease. PMID- 21297426 TI - Using the WHOQOL-BREF in persons with dementia: a validation study. AB - Increasing evidence suggests that persons with early dementia can give reliable and valid assessments about their own quality of life (QOL), thereby improving accuracy, and reducing the need for proxy informants. The objective of this study was to examine QOL in persons diagnosed with dementia (Diagnostic and Statistical Manual of Mental Disorder-IV) using a battery of subjective assessments including the new World Health Organization Quality of Life (WHOQOL-BREF). Persons with mild-to-moderate dementia (n=104) were recruited and interviewed at 6 Spanish centers to obtain sociodemographic information, health perceptions, depressive symptoms (Geriatric Depression Scale 15-item version), functional ability (Barthel Index), generic QOL (WHOQOL-BREF), and specific QOL (DEMQOL-28). Analysis was performed using classical psychometric methods. Internal consistency reliability for the WHOQOL-BREF domains ranged from moderate (0.54 for social) to good (0.79 for psychological). Test-retest reliability (intraclass correlation) ranged from moderate (0.51 for psychological) to good (0.70 for physical). Associations were confirmed between WHOQOL-BREF domains with DEMQOL-28, Geriatric Depression Scale 15-item version, and Barthel dimensions. With regard to contrasting groups' differences, WHOQOL-BREF scores significantly differentiated between healthy and unhealthy and depressed and nondepressed participants. This study is the first to report on the use of the WHOQOL-BREF in persons with mild to-moderate dementia. These results indicate that it is a useful tool in assessing these groups, as it includes important dimensions commonly omitted from other dementia measures. PMID- 21297427 TI - Microcephaly genes and risk of late-onset Alzheimer disease. AB - Brain development in the early stages of life has been suggested to be one of the factors that may influence an individual's risk of Alzheimer disease (AD) later in life. Four microcephaly genes, which regulate brain development in utero and have been suggested to play a role in the evolution of the human brain, were selected as candidate genes that may modulate the risk of AD. We examined the association between single nucleotide polymorphisms tagging common sequence variations in these genes and risk of AD in two case-control samples. We found that the G allele of rs2442607 in microcephalin 1 was associated with an increased risk of AD (under an additive genetic model, P=0.01; odds ratio=3.41; confidence interval, 1.77-6.57). However, this association was not replicated using another case-control sample research participants from the Alzheimer Disease Neuroimaging Initiative. We conclude that the common variations we measured in the 4 microcephaly genes do not affect the risk of AD or that their effect size is small. PMID- 21297428 TI - Geographic distribution of dementia mortality: elevated mortality rates for black and white Americans by place of birth. AB - We hypothesized that patterns of elevated stroke mortality among those born in the United States Stroke Belt (SB) states also prevailed for mortality related to all-cause dementia or Alzheimer Disease. Cause-specific mortality (contributing cause of death, including underlying cause cases) rates in 2000 for United States born African Americans and whites aged 65 to 89 years were calculated by linking national mortality records with population data based on race, sex, age, and birth state or state of residence in 2000. Birth in a SB state (NC, SC, GA, TN, AR, MS, or AL) was cross-classified against SB residence at the 2000 Census. Compared with those who were not born in the SB, odds of all-cause dementia mortality were significantly elevated by 29% for African Americans and 19% for whites born in the SB. These patterns prevailed among individuals who no longer lived in the SB at death. Patterns were similar for Alzheimer Disease-related mortality. Some non-SB states were also associated with significant elevations in dementia-related mortality. Dementia mortality rates follow geographic patterns similar to stroke mortality, with elevated rates among those born in the SB. This suggests important roles for geographically patterned childhood exposures in establishing cognitive reserve. PMID- 21297429 TI - Recombinant human thyroid stimulating hormone in thyroid remnant ablation with 1.1 GBq 131iodine in low-risk patients. AB - OBJECTIVE: To evaluate the efficacy of recombinant human thyroid stimulating hormone [rhTSH (versus hypothyroidism)] in thyroid ablation with an activity of 1.1 GBq (30 mCi) (131)I. METHODS: A total of 102 patients with thyroid cancer who fulfilled the following criteria were studied: submitted to total thyroidectomy with complete tumor resection; tumor <=4 cm without extrathyroid invasion or lymph node metastases; negative anti-thyroglobulin (anti-Tg) antibodies. Thirty two patients (group A) received 0.9 mg of rhTSH for 2 consecutive days followed by (131)I administration and 70 patients (group B) were prepared by levothyroxine withdrawal for 4 weeks. The groups were similar in sex, age, and tumor characteristics. RESULTS: Ablation was successful (stimulated Tg<1 ng/mL and negative diagnostic whole-body scanning and neck ultrasonography 9 to 12 mo after ablation) in 27 patients of group A (84.3%) and in 58 of group B (83%). Considering patients with Tg greater than 1 ng/mL immediately before (131)I administration, the rates were 72.2% in group A and 75% in group B. In group A, the ablation rate was similar for patients who discontinued levothyroxine-T4 3 days before (131)I administration and those maintained on hormone therapy. The mean follow-up was 29.6 months in group A and 55 months in group B. Stimulated Tg (after rhTSH) was undetectable in 29 patients of group A (90.6%) and in 61 of group B (87%) and 1 patient of group B presented cervical metastases at the last assessment. CONCLUSIONS: Low (131)I activity after rhTSH is effective for remnant ablation in patients who are at low risk of recurrence. PMID- 21297430 TI - Prostate cancer, androgen deprivation therapy, obesity, the metabolic syndrome, type 2 diabetes, and cardiovascular disease: a review. AB - Prostate cancer is the most frequently diagnosed malignancy among UK men and accounts for 12% of male deaths. Androgen deprivation therapy (ADT) is commonly used as part of the treatment for prostate cancer. It is effective at suppressing prostate-specific antigen, stabilizing disease, alleviating symptoms in advanced disease, and potentially prolonging survival. However ADT, presumably at least in part owing to low testosterone levels is associated with insulin resistance, the development of metabolic syndrome plus increased overall and cardiovascular disease mortality. We have reviewed the relationship between prostate cancer, ADT, metabolic syndrome, type 2 diabetes, and cardiovascular disease. We have not reviewed other potential medical problems such as osteoporosis. We suggest that there should be a baseline assessment of patients' risk for cardiovascular disease before starting ADT. Consideration should be given to starting appropriate therapies including lifestyle advice, antihypertensive and lipid lowering agents, insulin sensitizer, plus possibly aspirin. Having started ADT, the patients should have a regular (possibly annual) assessment of their cardiovascular risk factors. PMID- 21297431 TI - Systemic therapy for squamous cell carcinoma of the skin in organ transplant recipients. AB - During the second half of the 20th century, organ transplantation saved thousands of lives. This, unfortunately, also led to unforeseen consequences that need to be addressed to help extend the lives of patients who require these life-saving procedures. Secondary malignancies have been recognized as a potential consequence for decades. One of these malignancies, squamous cell carcinoma of the skin, not only appears more frequently in organ transplant recipients than the general population, but also is more aggressive in organ transplant recipients. It also shows a high propensity to nodal spread and metastasis in transplant patients. Unfortunately, there are no clear guidelines for a chemotherapy in this population, who have an increased need for alternative therapies to surgery given the high recurrence and metastasis rate. In this review, we attempt to describe the characteristics of squamous cell carcinoma of the skin in transplant recipients and discuss what chemotherapeutic options can be used to treat this aggressive malignancy. PMID- 21297432 TI - Postoperative low pelvic radiotherapy and chemotherapy for stage II and III rectal cancer. AB - OBJECTIVES: To evaluate whether postoperative low pelvic radiotherapy (RT) combined with chemotherapy is an appropriate treatment for stage II and III rectal cancer. METHODS: Between November 1997 and May 2006, 104 patients with stage II and III rectal cancer underwent surgery as the primary treatment followed by postoperative RT combined with chemotherapy in our institute and were reviewed retrospectively. Sixty-nine patients received low pelvic RT only (upper margin at 1 cm above the low end of the sacroiliac joint; median dose 54 Gy) (low pelvic RT group) and the other 35 patients received whole pelvic RT (upper margin at the mid L5; median dose 43.2 Gy) and subsequently received a boost to the low pelvis (total median dose 54 Gy) (whole pelvic RT group). RESULTS: The 5-year overall survival rate, local control rate, and distant metastasis-free rate were 72% versus 63%, 86% versus 84%, and 66% versus 62% for low pelvic versus whole pelvic RT group. There were no statistical differences in these 2 groups. Two patients (2.9%) of the low pelvic RT group and 2 patients (5.7%) of the whole pelvic RT group developed upper pelvis relapse, which was out of the low pelvic field. The incidence of Grade 3 to 5 small bowel late complications of the low pelvic RT group was significantly less than that of the whole pelvic RT group (4.3% vs. 20%) (P=0.029). CONCLUSIONS: Low pelvic RT significantly reduces small bowel late complications and does not compromise the overall survival rate, local control rate, and distant metastasis-free rate. PMID- 21297433 TI - Palliative reirradiation for progressive diffuse intrinsic pontine glioma. AB - OBJECTIVE: Diffuse intrinsic pontine gliomas (DIPGs) are highly aggressive tumors and have a poor prognosis. Nearly all patients experience disease progression after definitive treatment, accompanied by severe neurologic deficits and morbidity. Here, we report a series of patients treated with reirradiation for palliation of symptoms. METHODS: Six patients received reirradiation for progressive DIPG at MD Anderson Cancer Center from 2007 to 2009. Progression after initial chemoradiation and salvage chemotherapy had been confirmed clinically and by magnetic resonance imaging. Each case was discussed at a multidisciplinary conference before reirradiation. RESULTS: Interval between the initial radiation therapy and reirradiation was 8 to 28 months. The initial radiation therapy dose was 54 to 55.8 Gy. Time to initial progression was 4 to 18 months. All of the patients had further progression on salvage chemotherapy. Reirradiation was given with concurrent chemotherapy to a dose of 20 Gy (n=4) or 18 Gy (n=1); 1 patient withdrew care after a single 2-Gy fraction. Four patients had substantial clinical improvement in symptoms, with improvement in speech (n=3), ataxia (n=3), and swallowing (n=2). Three patients showed renewed ability to ambulate after reirradiation. Four patients had decreased tumor size on posttreatment magnetic resonance imaging. The median clinical progression-free survival time was 5 months. Acute radiation-related toxicities were fatigue (n=2), alopecia (n=2), and decreased appetite (n=1). No grade 3 or 4 toxicities were reported. CONCLUSIONS: Reirradiation with chemotherapy may be feasible to improve symptoms and delay progression with minimal toxicity. Patients who are most likely to benefit may be those with prolonged response to initial therapy and a long interval since initial radiation. PMID- 21297434 TI - Neoadjuvant paclitaxel poliglumex, cisplatin, and radiation for esophageal cancer: a phase 2 trial. AB - PURPOSE: To evaluate the pathologic complete response (CR) rate and safety of paclitaxel poliglumex (PPX), cisplatin, and concurrent radiation for patients with esophageal cancer. PATIENTS AND METHODS: Patients with adenocarcinoma or squamous cell carcinoma of the esophagus or gastroesophageal junction with no evidence of distant metastasis received PPX (50 mg/m(2)/wk) and cisplatin (25 mg/m(2)/wk) for 6 weeks with 50.4 Gy concurrent radiation. Six to eight weeks after completion of chemoradiotherapy, patients underwent surgical resection. RESULTS: Forty patients were enrolled, 37 patients with adenocarcinoma and 3 patients with squamous cell cancer. The treatment-related grade 3 nonhematologic toxicities included esophagitis (7%), nausea (7%), and fatigue (5%). Three patients with clinical endoscopic CR (2 with squamous cell cancer) refused surgery. Twelve of the remaining 37 patients (32%) had a pathologic CR. The 12 patients with pathologic CR all had adenocarcinoma. CONCLUSION: PPX, cisplatin, and concurrent radiation are well tolerated, easily administered regimen for esophageal cancer with a low incidence of significant esophagitis and a high pathologic CR rate consistent with the preclinical data of PPX and radiation. PMID- 21297435 TI - The forensic radiographer: a new member in the medicolegal team. AB - Multidetector computed tomography is becoming more widespread in forensic medicine. In most services, autopsy assistants perform the radiological examination. We introduced professional radiographers into the legal medicine service and hypothesized they would also be able to take over duties currently reserved for other specialists. The aims of this study were to evaluate if radiographers could be trained as "forensic radiographers" by (1) integrating graduated medical radiographers into the legal medicine service, (2) investigating the advantages of this collaboration, and (3) defining the duties of the forensic radiographers.The study was performed prospectively on a group of 8 recruited radiographers who underwent a testing period with special training. They learned the basics of medicolegal case treatment, the autonomous execution of postmortem computed tomography angiography, and postprocessing of data. Seven of 8 radiographers finished the training and were integrated into our service. Although all radiographers were able to fulfill the duties demanded after the training period, some radiographers could not enter or complete the program because they were unable to work with dead bodies.Our study presents the advantages of integrating radiographers into the medicolegal team and proposes how to train the forensic radiographers. In addition, the duties and responsibilities of these new specialists are defined. PMID- 21297436 TI - Impact of identity theft on methods of identification. AB - Responsibility for confirming a decedent's identity commonly falls on the shoulders of the coroner or medical examiner. Misidentification of bodies results in emotional turmoil for the next-of-kin and can negatively impact the coroner's or medical examiner's career. To avoid such mishaps, the use of scientific methods to establish a positive identification is advocated. The use of scientific methods of identification may not be reliable in cases where the decedent had assumed the identity of another person. Case studies of erroneously identified bodies due to identity theft from the state medical examiner offices in Iowa and New Mexico are presented. This article discusses the scope and major concepts of identity theft and how identity theft prevents the guarantee of a positive identification. PMID- 21297437 TI - Neonatal freshwater drowning after birth in the bathroom. AB - The macroscopic and microscopic findings in neonatal freshwater drowning are demonstrated on the basis of 3 exemplary cases of birth in the bathroom after concealed pregnancy. If the newborn is expelled under water and remains there until death, the lungs cannot be ventilated with air. In case of incomplete or only temporary submersion, aeration of the lungs may develop in the immediate postpartum period. The morphologic criteria of separate existence are critically discussed with respect to the presented findings. PMID- 21297438 TI - Immunohistochemical staining for DNA mismatch repair proteins in intestinal tract carcinoma: how reliable are biopsy samples? AB - BACKGROUND: In recent years, immunohistochemistry has emerged as an efficient tool in the detection of DNA mismatch repair protein abnormality in colorectal cancers. Currently, the immunohistochemical test is mainly applied to cancer resection specimens. Detection of mismatch repair abnormality in biopsies carries obvious clinical importance, as it would allow informed decision about the extent of surgery (segmental resection vs total colectomy, prophylactic hysterectomy or not). Moreover, in the case of treated rectal carcinoma with no residual tumor, it provides a means to evaluate the mismatch repair proteins. However, whether biopsy samples can be reliably used for mismatch repair protein detection remains to be determined. MATERIALS AND METHODS: Paired biopsy and resection specimens of adenocarcinomas of the gastrointestinal tract, enriched for patients at increased risk for Lynch syndrome, were analyzed for immunohistochemical staining patterns for MLH1, MSH2, MSH6, and PMS2. Abnormal staining was defined as total loss of protein in the tumor with appropriate control. Cases with focal and weak staining, defined as staining of no more than moderate intensity present in <10% of the tumor cells, were recorded. Correlation analysis with germline mutation data was in a subset of cases. RESULTS: Among 70 gastrointestinal tract cancers (3 from the small bowel, 36 from the right colon, 15 from the left colon, and 16 from the anorectum), both the biopsy and resection specimens detected the same 29 cancers as having loss of staining for at least 1 protein, 14 affecting MLH1/PMS2 and 15 affecting MSH2/MSH6. Focal and weak staining was most commonly seen for MLH1 stain in biopsies (4 of 70, 6%), followed by MSH6 stain in biopsies (3 of 70, 4%). Concordant staining patterns between biopsies and resections were reached in all 70 cases for MSH2 and PMS2, whereas discordant patterns were identified in 3 cases (3 of 70, 4%) for MLH1 and in 2 cases (2 of 70, 3%) for MSH6. None of the discordant patterns affected the final interpretation of whether the immunohistochemistry test was normal or abnormal in either the biopsy or the resection. In 13 of the 13 cases that were known to have a pathogenic germline mutation (5 in MLH1 and 8 in MSH2), the stains were abnormal for the corresponding protein and/or its partner protein in both the biopsy and the resection specimens. CONCLUSIONS: This study provides data indicating that biopsy samples are as reliable as resections in the immunohistochemical detection of mismatch repair protein abnormality in intestinal cancers. Our study also shows that various staining variations can occur in both biopsies and resections. Awareness and further understanding of such variations will enhance the use of immunohistochemistry, a commonplace tool that is being increasingly used in the screening workup for Lynch syndrome. PMID- 21297439 TI - Prevalence and clinical significance of Kupffer cell hyperplasia with hemophagocytosis in liver biopsies. AB - Hemophagocytic syndrome (HS) is a rare life-threatening condition due to uncontrolled macrophagic activation. Liver involvement is constant in HS, characterized by Kupffer cell hyperplasia with hemophagocytosis. Conversely, the specificity, frequency, and clinical significance of this histologic lesion remain poorly investigated. We aimed to evaluate the prevalence of this elementary lesion in liver biopsies (LB) to attempt to identify its clinical significance and to investigate its potential association with perforin expression deficiency. Kupffer cell hyperplasia with hemophagocytosis has been systematically searched for in consecutive LBs in a 6-year period. In positive cases, clinical, biological, and outcome characteristics have been retrospectively recorded. The ratio of perforin to CD3(+) lymphocytes was assessed on immunostained LB sections. This histologic lesion was detected in LB of 69 of 5194 patients (1.3%). It was not associated with hepatotropic viral infection, alcohol-related chronic liver disease, or autoimmune chronic liver disease. Although only 36% of patients with this histologic lesion had a complete HS (association of fever, splenomegaly, bicytopenia, hypertriglyceridemia, hyperferritinemia, and/or hypofibrinogenemia), almost all patients had similar underlying diseases (human immunodeficiency virus infection, malignant hemopathy, and autoimmune disease) and/or acute ongoing infections (tuberculosis, cytomegalovirus, and Epstein-Barr virus). A decrease of the perforin to CD3(+) lymphocytes ratio was specifically associated with this lesion. Kupffer cell hyperplasia with hemophagocytosis in LB is a rare finding; although it does not necessarily denote a complete HS, it is associated with the same underlying disease and/or infection, with a decrease in intrahepatic perforin-positive lymphocytes. PMID- 21297440 TI - Myogenic differentiation in ewing sarcoma family of tumors. PMID- 21297441 TI - Inguinal smooth muscle tumors in women-a dichotomous group consisting of Mullerian-type leiomyomas and soft tissue leiomyosarcomas: an analysis of 55 cases. AB - Assessment of the biological potential of smooth muscle tumors can be difficult and depends primarily on tumor site, stage, and histologic parameters. In this study, we examined the clinicopathologic and immunohistochemical features of 55 noncutaneous inguinal smooth muscle tumors of women (age range, 20 to 82 y; median, 57 y). Histologically, 23 tumors were considered as leiomyomas. They showed low mitotic activity (range, 0 to 6 mitoses/10 high-power fields, without atypical mitotic figures), minimal cytologic atypia, and absence of coagulative necrosis. Fifteen of these tumors histologically resembled conventional uterine leiomyomas and 8 resembled their variants: lipoleiomyomas (n = 2) and epithelioid variants (n = 6). The mean size was 7.8 cm, and half of the tumors with specified location arose in association with the round ligament. Immunohistochemical expression of estrogen receptor (ER) and/or Wilms tumor protein (WT1) was detected in most cases (83%), supporting Mullerian derivation. Follow-up data (range, 10 to 29 y; median, 13 y) on 11 patients showed that all were alive without disease or death from unrelated causes. The second group, classified as leiomyosarcomas, consisted of 32 mitotically active smooth muscle tumors, almost invariably with atypical mitotic figures, and exhibiting significant cytologic atypia. These patients were older than those with leiomyomas, and their tumors were mostly subcutaneous with a mean tumor size of 5.4 cm. Two leiomyosarcomas showed a femoral vein origin, but none were associated with the round ligament. All but 3 leiomyosarcomas were negative for ER. Follow-up data on 13 patients (range, 2 mo to 30 y; median, 4.5 y) showed that 5 died of metastatic sarcoma. Six individuals were alive without disease (median, 16 y), and 2 died of unrelated causes. In conclusion, inguinal smooth muscle tumors in women are a dichotomous group. They consist of ER/WT1-positive Mullerian-type leiomyomas resembling uterine leiomyomas with an excellent prognosis and conventional LMSs that are usually ER/WT1-negative and show a variable malignant course. Separation of these 2 categories is important for prognostication and optimal patient management, and is aided by immunohistochemical studies for ER and WT1. PMID- 21297442 TI - Preoperative dexamethasone enhances quality of recovery after laparoscopic cholecystectomy: effect on in-hospital and postdischarge recovery outcomes. AB - BACKGROUND: The effect of dexamethasone on quality of recovery after discharge from the hospital after laparoscopic surgery has not been examined rigorously in previous investigations. We hypothesized that preoperative dexamethasone would enhance patient-perceived quality of recovery on postoperative day 1 in subjects undergoing laparoscopic cholecystectomy. METHODS: One hundred twenty patients undergoing outpatient laparoscopic cholecystectomy were randomized to receive either dexamethasone (8 mg) or placebo-saline. A 40-item quality-of-recovery scoring system (QoR-40) was administered preoperatively and on postoperative day 1 to all subjects. Nausea, vomiting, fatigue, and pain scores were recorded at the time of discharge from the postanesthesia care unit and ambulatory surgical unit. Hospital length of stay was also assessed. RESULTS: Global QoR-40 scores on postoperative day 1 were higher in the dexamethasone group (median [range], 178 [130-195]) compared with the control group (161 [113-194]) (median difference [99% CI], -18 [-26 to -8]; P < 0.0001). Postoperative QoR-40 scores in the dimensions of emotional state, physical comfort, and pain were all improved in the dexamethasone group compared with the control group (P < 0.001). Nausea, fatigue, and pain scores were all reduced in the dexamethasone group during the hospitalization, as were postoperative analgesic requirements (P < 0.05). Total hospital length of stay was also reduced in subjects administered steroids (P = 0.003). CONCLUSIONS: Among patients undergoing outpatient laparoscopic cholecystectomy surgery, the use of preoperative dexamethasone enhanced postdischarge quality of recovery and reduced nausea, pain, and fatigue in the early postoperative period. PMID- 21297443 TI - Hybrid schwannoma-perineurioma of the gastrointestinal tract: a clinicopathologic study of 2 cases and reappraisal of perineurial cells in gastrointestinal schwannomas. AB - Soft tissue neoplasms with features of both schwannoma and perineurioma (hybrid schwannoma-perineurioma) have been increasingly recognized in recent years. To date, only a single case of this entity has been documented in the gastrointestinal tract (sigmoid colon). We herein describe 2 new cases of this entity. For comparison, we reevaluated 12 classic gastrointestinal schwannomas for the perineurial cell component. The 2 hybrid schwannoma-perineuriomas were detected incidentally in the gastric antrum and the vermiform appendix in a 50 year-old woman and a 17-year-old man during surgery for gastric GIST and appendicitis-like symptoms, respectively. None of the patients had neurofibromatosis 1 or 2. Patients were alive with no evidence of recurrence or new tumors at 8 and 12 months, respectively. The tumors measured 1.2 cm and 1.5 cm in size. Histologically, they showed prominent storiform, lamellar, and fascicular patterns. Notably, both lacked peripheral lymphoid cuffs and the trabecular pattern of gastrointestinal schwannomas. Both tumors coexpressed protein S100 (>=80%), CD34 (80%), and the perineurial cell markers (20% to 40% of tumor cells). The perineurial cell component formed alternating fascicles with S100-positive cells throughout the neoplasm. Reevaluation of 12 classic gastrointestinal schwannomas showed isolated claudin-1/epithelial membrane antigen-positive cells. However, 4 schwannomas (33%) strongly expressed glucose transporter-1 in most of the tumor cells indicating its limited specificity in this setting. Compared with gastrointestinal schwannomas, CD34 expression was stronger and more diffuse in hybrid schwannoma-perineuriomas. We conclude that hybrid schwannoma-perineuriomas are distinct from gastrointestinal schwannoma, both histologically and immunohistochemically. PMID- 21297444 TI - Differential expression of transferrin receptor (TfR) in a spectrum of normal to malignant breast tissues: implications for in situ and invasive carcinoma. AB - Transferrin receptor (TfR), a type II transmembranous receptor involved in iron uptake, is highly expressed in some cancers. We evaluated the expression of TfR in a spectrum of normal to malignant breast tissues to test the hypothesis that overexpression is associated with malignant transformation. Expression of TfR was studied by immunohistochemistry (CD71-Antibody, Thermo Fisher Scientific, Fremont, CA) for percent positive cells (%) and intensity of staining (0 to 3 score) in normal (n=127), benign (n=172), potentially premalignant and in-situ carcinoma (n=65), and invasive carcinoma (n=38). Normal and benign lesions had significantly lower TfR expression compared with premalignant lesions (atypical hyperplasia and carcinoma in situ) and invasive carcinoma (median %: 0, 10, 50, and 80, respectively; P<0.0001). TfR expression was higher in high-grade ductal carcinoma in situ (DCIS) than in other grades of DCIS (median %: 95 vs 55; P=0.02) and in high-grade invasive carcinoma. Among the latter, medullary carcinoma had the highest expression and there was a trend for invasive lobular carcinoma to have a higher expression than invasive ductal carcinoma. In invasive carcinoma cases, the proportion (%) of cells staining for TfR was inversely correlated with the percentage of estrogen receptor-positive cells, with a decreasing slope on linear regression models. In comparison, the relationship with progesterone receptor was not as well defined and linear regression models revealed close to a flat line. These data show that there is a differential expression of TfR in breast tissues with the highest expression in in-situ and invasive carcinoma and with aggressive phenotypes (higher grade DCIS and lower estrogen receptor positivity in invasive carcinomas). Further studies are indicated to determine whether TfR is an independently significant prognostic marker that may have potential as a therapeutic target in in-situ and invasive breast carcinoma. PMID- 21297445 TI - Spindle cell foci in the thyroid gland: an immunohistochemical analysis. AB - Spindle cell proliferations of the thyroid gland are uncommon lesions that encompass a wide spectrum of reactive, hyperplastic, and neoplastic processes. Spindle cells may occur in subsets of papillary carcinomas and follicular adenomas where they are thought to represent metaplastic foci. The goals of the present study are to further characterize the metaplastic nature of spindle cell foci of the thyroid (SCFT), to define their immunohistochemical profiles and to review their differential diagnoses. The study group included: multinodular goiter (2), follicular adenoma (2), and minimally invasive follicular carcinoma (2). SCFTs were composed of elongate cells with thin or slightly plump nuclei with finely granular chromatin and inconspicuous nucleoli. Rare mitotic figures were present but there was no necrosis or inflammation. All cases were positive for thyroglobulin, thyroid transcription factor (TTF)-1, and TTF-2. TTF-1 and TTF 2 had a characteristic nuclear localization although the intensity of staining for TTF-1 was consistently greater than that of TTF-2. Each of the 6 cases was positive for vimentin whereas 5 of the 6 cases were positive for broad-spectrum cytokeratins. None of the cases was positive for high molecular weight cytokeratin, cytokeratin-19, smooth muscle actin, desmin, calcitonin, chromogranin, or synaptophysin. The proliferative rate was less than 1% in all cases. Staining for TTF-1 and TTF-2 provided high specificity for identification of SCFT since these markers were not subject to the same diffusion artifact inherent in thyroglobulin-stained sections. The results of this study further support the hypothesis that SCFT result from metaplastic transformation of follicular cells. PMID- 21297446 TI - Pdx1 expression in pancreatic precursor lesions and neoplasms. AB - Pancreatic and duodenal homeobox (Pdx1) is a homeobox transcription factor required for the embryonic development of the pancreas. Pdx1 expression has been earlier identified in pancreatic ductal adenocarcinomas and endocrine neoplasms. This study characterizes Pdx1 protein expression in pancreatic precursor lesions and neoplasms, including pancreatic intraepithelial neoplasia (PanIN, n=32), intraductal papillary mucinous neoplasm (IPMN, n=88), mucinous cystic neoplasm (MCN, n=3), acinar cell carcinoma (ACC, n=8), pancreatic endocrine neoplasm (PEN, n=44), pancreatoblastoma (PB, n=1), solid pseudopapillary neoplasm (n=8), invasive ductal adenocarcinoma (n=67), and nondysplastic ductal epithelium. A mouse monoclonal antibody for Pdx1 was used to examine archived surgical pathology cases and tissue microarrays containing >655 tissue cores from more than 250 pancreatic specimens. Immunohistochemical labeling for Pdx1 was performed using standard methods and scored for percentage and intensity of nuclear labeling. Among non-neoplastic pancreatic tissues, Pdx1 nuclear protein was expressed in islet cells, cells of the centroacinar cell compartment, and non neoplastic ductal epithelium. No expression of Pdx1 was seen in non-neoplastic acinar cells. Among pancreatic neoplasms, Pdx1 consistently labeled >50% of the tumor cells in 87.5% of ACC cases and 38.6% of PEN cases. Pdx1 expression was variable in invasive ductal adenocarcinoma and precursor lesions of ductal adenocarcinomas (PanIN, IPMN, and MCN). A single case of PB was examined and it showed Pdx1 in the acinar component, but no expression in squamoid nests. Solid pseudopapillary neoplasms did not express Pdx1. This study shows Pdx1 expression in precursor lesions of ductal adenocarcinomas, PEN, ACC, and a case of PB. In the immunohistochemical evaluation of neoplasms of the pancreas, Pdx1 expression is not a finding specific to PENs and ductal adenocarcinomas, but also occurs in precursor lesions (PanIN, IPMN, MCN) and other neoplasms of the pancreas. PMID- 21297447 TI - Proliferation (Ki-67 and phosphohistone H3) and oncotype DX recurrence score in estrogen receptor-positive breast cancer. AB - The Oncotype DX Recurrence Score (RS) is often used in lymph node-negative, estrogen receptor-positive breast cancer to refine prognosis and direct therapy. Its utility is limited by its cost, proprietary nature, and turnaround time. Markers of proliferation factor heavily into determination of RS. Our aim is to correlate expression of proliferation markers Ki-67 and phosphohistone H3 (PPH3) with RS and other prognostic indicators. Estrogen receptor-positive invasive breast carcinomas from 133 patients with Oncotype DX testing were selected. Representative tumor sections were stained with MIB1, a monoclonal antibody that reacts against Ki-67, and antibody to PPH3. Nuclear staining was quantitated through an automated imaging system. The percentage of positive cells was scored as low (<10%), intermediate (10% to 20%), or high (>20%) for Ki-67, and low (<2%), intermediate (2% to 5%), or high (>5%) for PPH3. Expression of both markers was compared with RS and clinicopathologic parameters including grade, tumor size, lymph node metastasis, and angiolymphatic invasion. Ki-67 and PPH3 expression were both significantly associated with RS (P=0.02 and P=0.027, respectively) and grade (P<0.001 and P=0.002, respectively). Ki-67 expression correlated with angiolymphatic invasion (P=0.01) but not with tumor size or lymph node metastasis; PPH3 expression showed no association with any of these 3 parameters. Expression of proliferation markers Ki-67 and PPH3 by immunohistochemistry is significantly correlated with RS and tumor grade. This observation suggests that immunohistochemical assessment of markers of proliferation may provide useful prognostic information, at lower cost than RS testing. PMID- 21297448 TI - Serum thrombin activatable fibrinolysis inhibitor levels in patients with newly diagnosed multiple myeloma. AB - Multiple myeloma has been associated with the development of thromboembolic events. Thrombin activatable fibrinolysis inhibitor (TAFI) is a carboxypeptidase B-like proenzyme, which potently inhibits fibrinolysis. The purpose of the present study was to assess the TAFI levels in patients with newly diagnosed multiple myeloma. Twenty-seven newly diagnosed multiple myeloma patients (16 women and 11 men) and 27 age-matched healthy individuals (14 women and 13 men) were included in the study. Serum TAFI levels were significantly increased in patients with multiple myeloma (46 +/- 13. 3 vs. 36. 6 +/- 9.7 MUg/ml) compared with healthy individuals. Serum TAFI levels were negatively correlated with serum albumin (CC: -0.453, P < 0.05) and hemoglobin levels (CC: -0.392, P < 0.05) and positively correlated with the beta-2 microglobulin levels (CC: 0.524, P < 0.05). In this study, we observed significantly elevated TAFI levels in patients with multiple myeloma and higher serum TAFI levels were suggested to be associated with higher disease stage. With these results, a possible role of elevated TAFI levels in thromboembolic manifestations in the course of multiple myeloma can be suggested. PMID- 21297449 TI - Melatonin stimulates release of tissue factor pathway inhibitor from the vascular endothelium. AB - We previously found an association between the circadian variation of free tissue factor pathway inhibitor (TFPI) and melatonin in able-bodied males and in men with complete cervical spinal cord injuries. We therefore examined whether melatonin modifies production and/or secretion of TFPI in endothelial cells. We sampled supernatants from cultures of primary human umbilical vein endothelial cells (HUVECs) and of human coronary artery endothelial cells (HCAECs), that had been exposed to varying doses (0-300 pg/ml) of melatonin for 0.5-24 h. We then measured the protein concentrations of free TFPI, tissue factor and plasminogen activator inhibitor type 1 (PAI-1). We also measured endothelial TFPI, tissue factor and PAI-1 transcripts using quantitative real-time PCR. Melatonin dose dependently increased free TFPI levels about 25-30-fold in supernatants of both HUVEC and HCAEC, and independent of incubation duration. In contrast, TF and PAI 1 remained unaltered upon increasing doses of melatonin. Neither TFPI mRNAs nor tissue factor mRNAs nor PAI-1-mRNAs were changed in cell cultures added melatonin. The ratio of free TFPI in cell supernatants to free TFPI in cell lysates about doubled upon addition of melatonin, indicating that melatonin increased release from intracellular storages of free TFPI or from membrane-bound free TFPI. Our data indicate that melatonin stimulates vascular endothelial cells to secrete TFPI without altering transcription of the TFPI gene. If melatonin increases TFPI release in a similar fashion in vivo as in vitro, this could have potential clinical implications in both prophylaxis and treatment of thromboembolic events. PMID- 21297450 TI - Protamine sulfate stimulates degradation of factor Xa and the factor Xa antithrombin complex. AB - The effect of protamine sulfate on factor Xa (FXa) and the factor Xa-antithrombin complex was studied via SDS-PAGE and Western blot analysis. Human factor Xa [(FXaalpha) ~52 kDa, FXabeta ~47 kDa] and human antithrombin (AT ~55 kDa) form a primary (1 degrees ) complex at 109 and 104 kDa, a secondary (2 degrees ) complex at 99 and 95 kDa, and a tertiary (3 degrees ) complex at 66 and 62 kDa, as detected with polyclonal anti-FXa and anti-AT antibodies. Addition of protamine sulfate stimulates a transformation from free FXaalpha to FXabeta and degradation thence to inactive FXagamma (~30 kDa), as well as transformation of FXaalpha-AT complexes to FXabeta-AT complexes. Additionally, protamine sulfate promotes digestive degradation from 1 degrees to 3 degrees complexes and FXagamma by the active enzyme. It further promotes reduction in total complex formation as a function of stimulation of hydrolysis of FXa moieties from the complex, thereby generating ATM. Protamine sulfate effects are proportional to the protamine sulfate concentration. PMID- 21297451 TI - A novel factor XII mutation, FXII R84P, causing factor XII deficiency in a patient with hereditary spastic paraplegia. AB - Hereditary factor XII (FXII) deficiency is a clinically asymptomatic, autosomal recessive disorder. We have experienced a rare case of FXII deficiency in a patient previously diagnosed with hereditary spastic paraplegia (HSP). The patient had no major bleeding episodes and presented with a prolonged activated partial thromboplastin time (APTT) at hospital administration. Sequencing of the FXII gene revealed a novel missense mutation at exon 4 that substitutes arginine 84 to proline (R84P). To elucidate the molecular mechanism of FXII deficiency, wild-type and R84P mutant FXII cDNA were transiently expressed in CHO cells. We found that secretion but not synthesis of R84P mutant protein was markedly reduced compared to wild type. These results indicated that R84P mutation might impair the intracellular transport or secretion of FXII protein of the cells and could be a useful tool for the analysis of structure-function relationship and intracellular protein transport of FXII protein in the future. PMID- 21297452 TI - Hemorrhagic manifestation of megaloblastic anemia: report of two cases and literature review. AB - Megaloblastic anemia is not uncommon in developing countries. Its presentation as thrombocytopenia and hemorrhagic manifestation are, however, rare. We describe the clinical scenario in two young patients who presented to the emergency room of Sir Ganga Ram Hospital, a tertiary care center in New Delhi, India, with pancytopenia and bleeding diathesis. Both patients improved after B12 supplementation. Reports of two cases and a brief review is presented. PMID- 21297453 TI - Influence of 8 and 24-h storage of whole blood at ambient temperature on prothrombin time, activated partial thromboplastin time, fibrinogen, thrombin time, antithrombin and D-dimer. AB - This study evaluates the effect of whole blood storage on common coagulation parameters in order to confirm or revise acceptable storage limits as defined by current guidelines and diverse study reports. Aliquots were taken from the citrated whole blood of inpatients and outpatients (n = 147) within 4 h after blood withdrawal and after extended storage of whole blood for 8 and 24 h at ambient temperature. Aliquots were centrifuged and analyzed for prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (Fbg), antithrombin (AT), thrombin time (TT) and D-dimer. For each parameter, samples from 33-56 patients were investigated covering a wide range of normal and pathological values. Samples from patients receiving heparin were excluded from analyses of APTT and TT. All assays were performed using reagents and an analyzer from Siemens Healthcare Diagnostics Products GmbH. The mean percentage change after 8 and 24-h storage was below 10% for all parameters. Considering the changes in individual samples, all parameters can be reliably tested after 8-h storage, since less than 15% of the samples demonstrated individual changes of above 10%. The acceptable storage time can be extended to 24 h for PT, TT and D dimer. Clinically relevant changes were detected after 24-h storage for APTT: 41% of the investigated samples demonstrated changes of above 10%. After 24-h storage, changes for Fbg and AT values were more than 15% in five out of 49 and in three out of 45 samples, respectively. This sporadic increase of values is clinically acceptable except for borderline samples. PMID- 21297454 TI - Molecular characterization of female hemophilia A by multiplex ligation-dependent probe amplification analysis and X-chromosome inactivation study. AB - Hemophilia A is an X-linked recessive bleeding disorder caused by mutations in the F8 gene. Hemophilia A typically occurs in male individuals, but female patients with hemophilia A have rarely been reported. Here we describe molecular characteristics of three unrelated female patients with severe hemophilia A of Korean descent. Patient 1 was a 5-year-old girl and was found to be compound heterozygous for intron 22 inversion inherited from her father with hemophilia A and a large deletion mutation from her mother. The large deletion detected by multiplex ligation-dependent probe amplification involved the whole F8 gene. Patient 2 was a 30-year-old woman and was heterozygous for small duplication mutation in exon 14 (c.3275dupA; p.Asn1092LysfsX26). Patient 3 was a 16-year-old girl and was heterozygous for intron 22 inversion. All three patients showed nonrandom X-chromosome inactivation status. The results underscore the need for a meticulous search for another mutation in the maternally derived X-chromosome such as large-dosage mutations. PMID- 21297455 TI - Functionality of fondaparinux (pentasaccharide) depends on clinical antithrombin levels. AB - Fondaparinux (Arixtra) is an antithrombin (AT)-dependent synthetic inhibitor of factor Xa (FXa). We undertook a study to determine the ramifications of varying levels of circulating AT on the pharmacologic activity of fondaparinux. AT deficient human plasma supplemented with 0.125-2.0 U/ml purified human AT and plasmas from liver disease patients (n = 20; 0.3 U/ml AT) were supplemented with fondaparinux (0.125-12.5 MUg/ml) then assayed by an amidolytic anti-FXa assay and the clot-based Heptest. A decrease in fondaparinux activity was observed with AT levels of 0.5 U/ml that became more pronounced with decreasing AT levels. For 0.2 1.5 MUg/ml fondaparinux (plasma concentrations achieved with dosages for prophylaxis and treatment of venous thromboembolism) and AT levels of 0.5 U/ml there was 20% loss of activity and with 0.25 U/ml AT there was a 45% loss of activity compared to 1 U/ml AT. Increasing AT levels to over 0.5 U/ml or increasing fondaparinux concentrations for AT levels between 0.5 and 1 U/ml achieved fondaparinux activity comparable to that obtained with 1 U/ml AT. With AT levels above 1.0 U/ml a greater inhibitory activity was achieved. The observed potency of fondaparinux in terms of anti-FXa activity was reduced approximately three-fold in patients with liver disease. These in-vitro findings were confirmed in a rabbit model of stasis thrombosis. With AT levels below 30% of normal induced by anti-AT antibodies, there was a 60% in-vivo reduction in the antithrombotic activity of fondaparinux (ED50 75 vs. 240 MUg/kg). In summary, the AT level is a rate-limiting factor for the antithrombotic activity of fondaparinux. PMID- 21297456 TI - A pharmacokinetic-pharmacodynamic model for duodenal levodopa infusion. AB - OBJECTIVE: The purpose of this work was to identify and estimate a population pharmacokinetic- pharmacodynamic model for duodenal infusion of a levodopa/carbidopa gel (Duodopa) to examine pharmacological properties of this treatment. METHODS: The modeling involved pooling data from 3 studies (on advanced Parkinson disease) and fixing some parameters to values found in literature. The first study involved 12 patients studied on 3 occasions each and was previously published. The second study involved 3 patients on 2 occasions. A bolus dose was given after a washout during night. Plasma samples and motor ratings (clinical assessment of motor function on a 7-point treatment response scale ranging from "very off" to "very hyperkinetic") were collected until the clinical effect returned to baseline. The third study involved 5 patients on 3 occasions receiving 5 different dose levels. Different structural models were evaluated using the nonlinear mixed-effects modeling program NONMEM VI. Population mean parameter values, and interindividual, interoccasion, and residual variabilities were estimated. RESULTS: Absorption of the levodopa/carbidopa gel can be adequately described with first-order absorption with bioavailability and lag time. Estimated population parameter values were a mean absorption time of 28.5 minutes, a lag time of 2.9 minutes, and a bioavailability of 88%. The pharmacodynamic model for motor ratings had the following population values: a half-life of effect delay of 21 minutes, a concentration at 50% effect of 1.55 mg/L, an Emax of 2.39 U on the treatment response scale, and a sigmoidicity of the Emax function of 11.6. CONCLUSIONS: For the typical unmedicated subject, it will take 51.4 minutes until the peak levodopa effect is reached after a bolus dose. This delay is, like the magnitude of the effect, highly variable in this patient group. The residual error magnitudes of 20% for levodopa concentrations and 0.92 U (SD) for motor ratings indicate that the models developed provide predictions of a relevant quality. The developed model may be a first step toward model-guided treatment individualization of duodenal infusion of levodopa. PMID- 21297457 TI - Platelet cytochrome c oxidase activity and quantity in septic patients. AB - OBJECTIVE: The cytopathic hypoxia theory proposes that there is an impaired cellular oxygen utilization during sepsis. Respiratory complex IV, or cytochrome c oxidase, was only previously studied in muscle biopsies of 16 surviving and 12 nonsurviving septic patients. We hypothesized that higher activities and quantities of this enzyme complex could be associated with septic patient survival. The objective was to evaluate the relationship between cytochrome c oxidase activities and quantities and 6-month survival in a larger series of septic patients using a less invasive method (circulating platelets). DESIGN: Prospective, multicenter, observational study. SETTING: The study was carried out in six Spanish intensive care units. PATIENTS: We included 96 septic patients. INTERVENTIONS: We determined the cytochrome c oxidase activity per citrate synthase activity ratio and cytochrome c oxidase quantity per citrate synthase activity ratio in circulating platelets at the time of diagnosis and related them to 6-month survival. The written informed consent from the family members was obtained. MEASUREMENTS AND MAIN RESULTS: Survivor patients (n = 54) showed higher cytochrome c oxidase activity per citrate synthase activity ratio (p = .04) and cytochrome c oxidase quantity per citrate synthase activity ratio (p = .006) than nonsurvivors (n = 42). Logistic regression analyses confirmed that the cytochrome c oxidase activity per citrate synthase activity ratio (p = .04) and cytochrome c oxidase quantity per citrate synthase activity ratio (p = .02) were independent predictors of 6-month survival. The area under the curve to predict 6-month survival was 0.62 (95% confidence interval 0.51-0.74; p = .04) for the cytochrome c oxidase activity per citrate synthase activity ratio and 0.67 (95% confidence interval 0.56-0.76; p = .003) for the cytochrome c oxidase quantity per citrate synthase activity ratio. A negative correlation was found between the cytochrome c oxidase quantity per citrate synthase activity ratio and Sepsis-Related Organ Failure Assessment score (p = .04). CONCLUSIONS: Platelet cytochrome c oxidase activity and quantity were independent predictors of 6-month survival and could be used as biomarkers of sepsis mortality. This is a rapid, easy, and less invasive protocol to assess mitochondrial function. Patients with lower cytochrome c oxidase activity and quantity could benefit from drugs that improve mitochondrial function. PMID- 21297458 TI - Critical care in resource-poor settings: lessons learned and future directions. AB - CONTEXT: Critical care faces the same challenges as other aspects of healthcare in the developing world. However, critical care faces an additional challenge in that it has often been deemed too costly or complicated for resource-poor settings. This lack of prioritization is not justified. Hospital care for the sickest patients affects overall mortality, and public health interventions depend on community confidence in healthcare to ensure participation and adherence. Some of the most effective critical care interventions, including rapid fluid resuscitation, early antibiotics, and patient monitoring, are relatively inexpensive. Although cost-effectiveness studies on critical care in resource-poor settings have not been done, evidence from the surgical literature suggests that even resource-intensive interventions can be cost effective in comparison to immunizations and human immunodeficiency virus care. In the developing world, where many critically ill patients are younger and have fewer comorbidities, critical care presents a remarkable opportunity to provide significant incremental benefit, arguably much more so than in the developed world. ESSENTIAL CONSIDERATIONS: Key areas of consideration in developing critical care in resource-poor settings include: Personnel and training, equipment and support services, ethics, and research. Strategies for training and retaining skilled labor include tying education to service commitment and developing protocols for even complex processes. Equipment and support services need to focus on technologies that are affordable and sustainable. Ethical decision making must be based on data when possible and on transparent articulated policies always. Research should be performed in resource-poor settings and focus on needs assessment, prognostication, and cost effectiveness. FUTURE DIRECTIONS: The development of critical care in resource-poor settings will rely on the stepwise introduction of service improvements, leveraging human resources through training, a focus on sustainable technology, ongoing analysis of cost effectiveness, and the sharing of context-specific best practices. Although prevention, public health, and disease-specific agendas dominate many current conversations in global health, this is nonetheless a time ripe for the development of critical care. Leaders in global health funding hope to improve quality and length of life. Critical care is an integral part of the continuum of care necessary to make that possible. PMID- 21297459 TI - Plasma erythromycin concentrations predict feeding outcomes in critically ill patients with feed intolerance. AB - OBJECTIVE: Motilin receptors are rapidly down-regulated by exposure to erythromycin, and its progressive loss of clinical prokinetic effect may relate to higher plasma drug concentrations. This study aimed to evaluate the relationship between plasma erythromycin concentrations and feeding outcomes in critically ill patients. DESIGN: Observational comparative study. SETTING: Tertiary critical care unit. PATIENTS: Twenty-nine feed-intolerant (gastric residual volume >250 mL) mechanically ventilated, medical critically ill patients. INTERVENTIONS: Patients received intravenous erythromycin 200 mg twice daily for feed intolerance. MEASUREMENTS: Plasma erythromycin concentrations were measured 1 and 7 hrs after drug administration on day 1. Success of enteral feeding, defined as 6-hourly gastric residual volume of <= 250 mL with a feeding rate >= 40 mL/h, was recorded over 7 days. RESULTS: At day 7, 38% (11 of 29) of patients were feed tolerant. Age, Acute Physiology and Chronic Health Evaluation scores, serum glucose concentrations, and creatinine clearance were comparable between successful and failed feeders. Both plasma erythromycin concentrations at 1 and 7 hrs after drug administration were significantly lower in successfully treated patients compared to treatment failures (1 hr: 3.7 +/- 0.8 mg/L vs. 7.0 +/- 1.0 mg/L, p = .02; and 7 hr: 0.7 +/- 0.3 mg/L vs. 2.8 +/- 0.6 mg/L, p = .01). There was a negative correlation between the number of days to failure of feeding and both the 1-hr (r = -.47, p = .049) and 7-hr (r = -.47, p = .050) plasma erythromycin concentrations. A 1-hr plasma concentration of >4.6 mg/L had 72% sensitivity and 72% specificity, and a 7-hr concentration of >= 0.5 mg/L had 83% sensitivity and 72% specificity in predicting loss of response to erythromycin. CONCLUSIONS: In critically ill feed-intolerant patients, there is an inverse relationship between plasma erythromycin concentrations and the time to loss of clinical motor effect. This suggests that erythromycin binding to motilin receptors contributes to variations in the duration of prokinetic response. The use of lower doses of erythromycin and tailoring the dose of erythromycin according to plasma concentrations may be useful strategies to reduce erythromycin tachyphylaxis. PMID- 21297460 TI - Assessing and improving safety climate in a large cohort of intensive care units. AB - OBJECTIVES: To evaluate the impact of a comprehensive unit-based safety program on safety climate in a large cohort of intensive care units participating in the Keystone intensive care unit project. DESIGN/SETTING: A prospective cohort collaborative study to improve quality of care and safety culture by implementing and evaluating patient safety interventions in intensive care units predominantly in the state of Michigan. INTERVENTIONS: The comprehensive unit-based safety program was the first intervention implemented by every intensive care unit participating in the collaborative. It is specifically designed to improve the various elements of a unit's safety culture, such as teamwork and safety climate. We administered the validated Safety Attitudes Questionnaire at baseline (2004) and after 2 yrs of exposure to the safety program (2006) to assess improvement. The safety climate domain on the survey includes seven items. MEASUREMENTS AND MAIN RESULTS: Post-safety climate scores for intensive care units. To interpret results, a score of <60% was in the "needs improvement" zone and a >=10-point discrepancy in pre-post scores was needed to describe a difference. Hospital bed size, teaching status, and faith-based status were included in our analyses. Seventy-one intensive care units returned surveys in 2004 and 2006 with 71% and 73% response rates, respectively. Overall mean safety climate scores significantly improved from 42.5% (2004) to 52.2% (2006), t = -6.21, p < .001, with scores higher in faith-based intensive care units and smaller-bed-size hospitals. In 2004, 87% of intensive care units were in the "needs improvement" range and in 2006, 47% were in this range or did not score >=10 points or higher. Five of seven safety climate items significantly improved from 2004 to 2006. CONCLUSIONS: A patient safety program designed to improve teamwork and culture was associated with significant improvements in overall mean safety climate scores in a large cohort of 71 intensive care units. Research linking improved climate scores and clinical outcomes is a critical next step. PMID- 21297461 TI - Is there a role for surgeons in transcatheter mitral valve procedures? AB - PURPOSE OF REVIEW: The rapid advancement in transcatheter therapies seeks to provide less invasive options compared with conventional surgery in the treatment of acquired valvular heart disease. A number of transcatheter mitral valve devices using a variety of approaches for the treatment of mitral regurgitation are under development or in early clinical application. Although yet to be clearly defined, there is no doubt that transcatheter mitral valve procedures will have a significant role alongside conventional surgery. The question is: will surgeons, who have led the treatment of mitral valve disease for the past 30 years, have a role in these procedures? RECENT FINDINGS: In order to answer this question, this review discusses key understanding of mitral valve anatomy, function and disorder required to perform transcatheter mitral valve interventions. It assesses the potential role of transcatheter therapies with particular reference to percutaneous edge-to-edge repair using the Mitraclip system (Abbott Vascular Devices, California, USA). The new era in collaboration between surgeons and cardiologists is discussed and the potential role of the surgeon in percutaneous mitral valve procedures is examined. SUMMARY: Transcatheter mitral valve procedures demand increasing collaboration between cardiologists and surgeons in order to achieve optimal outcomes. Interventional cardiologists will require dedicated training in the specialized field of transcatheter interventions in acquired structural heart diseases. As the delivery of such therapies brings the interface between interventional cardiology and cardiac surgery ever closer, there is the potential for a niche area in cardiac surgery to develop comprising minimally invasive surgical and transcatheter skills. PMID- 21297462 TI - Minimally invasive aortic valve replacement: how does this perform in high-risk patients? AB - PURPOSE OF REVIEW: Minimally invasive techniques are increasingly important in aortic valve surgery. The aim of this publication is to review our experience and recent literature to assess and present the current 'state-of-the-art'-role of minimally invasive aortic valve operations for high-risk patients. RECENT FINDINGS: Minimally invasive aortic valve operation for high-risk patients (e.g. patients with left ventricular dysfunction, reoperation, elderly, multimorbid patients, etc.) can be performed with an operative mortality similar to standard sternotomy approach. Less postoperative bleeding, fewer blood transfusions, better cosmesis, lower ICU and in-hospital stays as well as the absence of sternal wound infection are the main advantages of this technique. SUMMARY: Minimally invasive aortic valve surgery has evolved into a well tolerated, efficient surgical treatment option in experienced centers, providing greater patient satisfaction and lower complication rates in high-risk patients. PMID- 21297463 TI - Recent progress in the genetics of cardiomyopathy and its role in the clinical evaluation of patients with cardiomyopathy. AB - PURPOSE OF REVIEW: This review will provide an overview of the genetic basis of cardiomyopathy with an emphasis on the clinically relevant breakthroughs that have occurred recently and their role in the evaluation of patients with cardiomyopathy. RECENT FINDINGS: Recent developments that have occurred in genetic cardiomyopathy include the finding of a shared genetic basis of familial dilated cardiomyopathy in at least a subset of cases of peripartum cardiomyopathy; the increased yield for the diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) when genetic testing is incorporated into Task Force Criteria; and the value of testing a spectrum of implicated genes in hypertrophic cardiomyopathy and ARVC because of the severe phenotype associated with compound mutations. SUMMARY: Recent progress in genetic cardiomyopathy points to the potential value of genetic testing in shaping the clinician's ability to diagnose and understand the pathogenetic basis of the inherited cardiomyopathies. The rapid rate at which the field is progressing emphasizes the importance of referral of such patients to multidisciplinary teams equipped to address the complex biological, social and psychological issues that accompany the genetic diagnosis of inherited cardiomyopathy. PMID- 21297464 TI - Recent advances in cardiac imaging for patients with heart failure. AB - PURPOSE OF REVIEW: Transthoracic echocardiography (ECHO) and single-photon emission computed tomography (SPECT) are routine in many heart failure patients. Recently, other imaging tests have emerged in heart failure management: cardiovascular magnetic resonance (CMR), positron emission tomography (PET) and computed tomography (CT). This article reviews recent developments in heart failure imaging. RECENT FINDINGS: Longitudinal left ventricular systolic strain on ECHO speckle tracking imaging detects subclinical cardiomyopathy and predicts survival in symptomatic heart failure. Late gadolinium enhancement for myocardial scar is an independent predictor of death or transplantation in ischemic and nonischemic cardiomyopathy. In contrast to earlier reports, both ECHO and CMR contrast have a negligible risk of adverse outcomes. Stress perfusion imaging (SPECT or PET) and PET flow quantification have prognostic value in ischemic cardiomyopathy. F-2-fluoro-2-deoxyglucose (FDG) PET directed management can impact outcome. Abnormal myocardial neuronal activity on I metaiodobenzylguanidine (MIBG) imaging is associated with increased risk of ventricular arrhythmias and death. Cardiac CT potentially could assess heart failure etiology through coronary angiography and myocardial tissue characterization but its precise role remains undetermined. SUMMARY: There have been several exciting developments in all imaging modalities. Large multicenter trials such as IMAGE heart failure are required to standardize measures and establish benefit before widespread use in heart failure can be recommended. PMID- 21297465 TI - The concept of ventricular reserve in heart failure and pulmonary hypertension: an old metric that brings us one step closer in our quest for prediction. AB - PURPOSE OF REVIEW: Ventricular reserve is emerging a strong predictor of outcome in heart failure and cardiovascular disease. Ventricular reserve is the term used to describe the extent of increase or change in ventricular function that occurs during exercise or pharmacological stress (typically with dobutamine). RECENT FINDINGS: The interest in ventricular reserve lies in its ability to assess viability in coronary artery disease, to predict clinical outcome and response to therapy in patients with heart failure and to screen patients for early cardiovascular disease. SUMMARY: In this paper, we will review the emerging role of ventricular reserve in heart failure and pulmonary hypertension. We will also explore the mechanisms involved in the pathophysiology of impaired ventricular reserve and discuss future directions of research in the field. PMID- 21297466 TI - Dyslipidemia and lipid management in HIV-infected patients. AB - PURPOSE OF REVIEW: Dyslipidemia is highly prevalent among patients living with chronic HIV infection and may confer increased risk of cardiovascular disease in this patient population. This review summarizes recent data investigating lipid abnormalities and its management in HIV-infected patients. RECENT FINDINGS: Studies in the last year have evaluated the effects of various lipid-lowering therapies not previously investigated in the HIV patient population. Rosuvastatin is a potent statin that appears to be well tolerated and effective in HIV infected patients with hypercholesterolemia. SUMMARY: Dyslipidemia is common in HIV-infected individuals. Medical therapy of lipid disorders needs to take potential drug-drug interactions of lipid-lowering medications and antiretroviral agents into consideration. PMID- 21297467 TI - Obesity, insulin resistance and free fatty acids. AB - PURPOSE OF REVIEW: To describe the role of free fatty acid (FFA) as a cause for insulin resistance in obese people. RECENT FINDINGS: Elevated plasma FFA levels can account for a large part of insulin resistance in obese patients with type 2 diabetes. Insulin resistance is clinically important because it is closely associated with several diseases including type 2 diabetes, hypertension, dyslipidemia and abnormalities in blood coagulation and fibrinolysis. These disorders are all independent risk factors for cardiovascular disease (heart attacks, strokes and peripheral arterial disease). The mechanisms by which FFA can cause insulin resistance, although not completely known, include generation of lipid metabolites (diacylglycerol), proinflammatory cytokines (TNF-alpha, IL 1beta, IL-6, MCP1) and cellular stress including oxidative and endoplasmic reticulum stress. SUMMARY: Increased plasma FFA levels are an important cause of obesity-associated insulin resistance and cardiovascular disease. Therapeutic application of this knowledge is hampered by the lack of readily accessible methods to measure FFA and by the lack of medications to lower plasma FFA levels. PMID- 21297468 TI - Hypoglycemia complicating bariatric surgery: incidence and mechanisms. AB - PURPOSE OF REVIEW: To discuss the clinical scope and frequency of hypoglycemia following bariatric surgery, and possible mechanisms mediating this potentially life-threatening complication. RECENT FINDINGS: Consequent to the rise in severe obesity, bariatric surgery is being performed with ever increasing frequency. Although data continue to accumulate supporting the myriad metabolic and other health benefits of bariatric surgery, there are also concerns regarding the mounting reports of severe hypoglycemia. The problem is particularly significant following gastric bypass, with the first concerns raised in 2005 following a case series reported from the Mayo Clinic. A Swedish nationwide cohort study recently estimated the frequency of this complication suggesting it was less than 1%. Hypotheses regarding the mechanism(s) by which hypoglycemia arise following gastric bypass range from beta cell expansion to altered beta cell function as well as nonbeta cell factors. SUMMARY: Regardless of the incidence, the severity of hypoglycemia for select patients following gastric bypass necessitates that we strive to gain a better understanding of the underlying mechanisms. With such knowledge, those patients at greater risk for this complication might be identified preoperatively, and decisions regarding their surgical management optimized to reduce this risk. PMID- 21297469 TI - Farnesoid X receptor agonists for primary biliary cirrhosis. AB - PURPOSE OF REVIEW: This review will provide an overview of the role of nuclear receptors in bile acid homeostasis with a focus on the farnesoid X receptor (FXR) and its potential therapeutic use in cholestatic liver diseases. RECENT FINDINGS: Nuclear receptors have emerged as important mediators of a variety of metabolic and transport functions involving the liver. The role of FXR, in particular, has come to light because of its important role in bile acid homeostasis. The use of potent FXR ligands has recently been shown to offer potentially important therapeutic benefits in patients with primary biliary cirrhosis, an important cholestatic liver disease of adults. This recent finding has now opened the door for future therapeutic trials for use of FXR agonists such as obeticholic acid for the treatment of chronic cholestatic liver diseases. SUMMARY: Further understanding of the role of farnesoid X receptor agonists and the potential role of ligands in animal models of other forms of cholestasis will be important to set the stage for future applications to human disease. PMID- 21297470 TI - Cancer-associated fibroblasts in intrahepatic cholangiocarcinoma. AB - PURPOSE OF REVIEW: The aim of this brief review is to provide an up-to-date view of the role played by alpha-smooth muscle actin-positive cancer-associated fibroblastic cells in promoting intrahepatic cholangiocarcinoma progression. RECENT FINDINGS: An increase in alpha-smooth muscle actin-positive cancer associated fibroblastic cells in the stroma of intrahepatic cholangiocarcinoma has recently been demonstrated to accelerate cholangiocarcinoma progression. However, our understanding of the evolving cellular and molecular interactions between these stromal cells and cholangiocarcinoma cells in relation to promoting intrahepatic cholangiocarcinoma progression is only just beginning to be elucidated. Imbalances in multifactorial growth factor/cytokine signaling, activation of Hedgehog-GLI signaling and of proteases involved in extracellular matrix remodeling, and matricellular protein-protein and protein cholangiocarcinoma cell interactions, as well as hypoxia, all appear to factor into the complex and dynamic interactive mechanisms through which cancer associated fibroblastic cells crosstalk with cholangiocarcinoma cells to promote intrahepatic cholangiocarcinoma progression. Novel three-dimensional organotypic co-culture models are being developed to facilitate relevant studies of cancer associated fibroblastic cell/cholangiocarcinoma cell interactions that may more accurately mimic physiologically pertinent features of the tumor. SUMMARY: Increasing our understanding of critical interactive pathways by which cancer associated fibroblastic cells crosstalk with cholangiocarcinoma cells to promote tumor progression can lead to the development of novel multitargeting strategies for intrahepatic cholangiocarcinoma therapy. PMID- 21297471 TI - MRI of the small bowel in patients with Crohn's disease. AB - PURPOSE OF REVIEW: To highlight the advances in MRI of the small intestine in patients with Crohn's disease. MRI of the gut has become more feasible with improved spatial resolution and speed of the MR sequences allowing parallel evaluation for both disease activity and extra-enteric complications. RECENT FINDINGS: Recent literature highlights excellent diagnostic accuracy of MR enterography (MRE) that is comparable to computed tomography enterography (CTE). Compared to CTE the image quality is not quite as good, and there is slightly more interobserver variability in interpretation. Despite these performance characteristics, the overall diagnostic yield of MRE is comparable to CTE. The lack of radiation exposure related to MRE is a significant strength, especially in Crohn's population that by virtue of their younger age, body habitus and potential need for repeated imaging, is at highest risk of potential cancer from radiation exposure due to diagnostic imaging. MRE should not be viewed as a 'safer' version of a CTE. The physics of MRI allows the application of unique sequences that add novel insights not possible with other imaging modalities. SUMMARY: MRE is a highly effective technique for assessing Crohn's disease. We are only starting to explore new MRI sequences and the future of this technology is extremely exciting. PMID- 21297472 TI - Evolving applications of microarray analysis in prenatal diagnosis. AB - PURPOSE OF REVIEW: Evaluation of copy number variation by microarray analysis has significant advantages over standard metaphase karyotyping and is quickly becoming the primary means of postnatal genetic evaluation for neonates and infants with dysmorphic features or cognitive difficulties. Before this technology is routinely used for prenatal diagnosis, further evaluation of its value and the clinical dilemmas it may introduce requires further study. This article reviews the recent literature on array technology use in prenatal diagnosis. RECENT FINDINGS: The use of microarray analysis for routine prenatal diagnosis is still being investigated. Use in certain prenatal situations such as the fetus with structural anomalies or those who are stillborn appears to add important, clinically relevant information. There are a broad range of array designs available and recent research has focused on the appropriate design for prenatal testing. Patient counseling may occasionally be difficult because of the uncertain phenotype associated with some array findings. SUMMARY: We present a brief overview of microarray technology including benefits and limitations. Previous research regarding use of microarray in prenatal diagnosis including specific scenarios of anomalous fetuses and abnormal karyotype is reviewed. Current guidelines and the authors' recommendations are presented. PMID- 21297473 TI - Nonabortal pregnancy complications of chorionic villous sampling. AB - PURPOSE OF REVIEW: First trimester screening for genetic diseases has become the predominant tool for selecting higher risk women in developed countries. As a consequence, chorionic villous sampling (CVS) is considered the most effective method for early diagnosis. The purpose of this review is to report recent updates related to CVS complications. RECENT FINDINGS: The most recent data about CVS-related complications are more optimistic than in the past. These improved results are probably due to more advanced instruments used, more proper operator training and 30 years of medical experience of several centers. SUMMARY: Currently CVS is the gold standard method of first trimester prenatal diagnosis. Because it will likely be in higher demand in the next years, knowledge of the associated complications and their frequency is worth noting for both physicians and patients. Recent data have clarified some controversies and speculations but the magnitude of the association between CVS and fetal and obstetrical complications is still unclear. PMID- 21297474 TI - Contemporary approaches to hyperemesis during pregnancy. AB - PURPOSE OF REVIEW: Nausea and vomiting of pregnancy (NVP) affects 90% of pregnant women and its impact is often underappreciated. Hyperemesis gravidarum, the most severe end of the spectrum, affects 0.5-2% of pregnancies. The pathogenesis of this condition remains obscure and its management has largely been empirical. This review aims to provide an update on advances in pregnancy hyperemesis focusing on papers published within the past 2 years. RECENT FINDINGS: The cause of hyperemesis is continuing to be elaborated. Recent data attest to the effectiveness of the oral doxylamine-pyridoxine in NVP. Follow-up data of children exposed in early pregnancy to doxylamine-pyridoxine for NVP are reassuring. Evidence is increasing for ginger as an effective herbal remedy for NVP. Metoclopramide is effective in NVP and hyperemesis gravidarum, with a good balance of efficacy and tolerability. A recent large-scale study on first trimester exposure to metoclopramide is reassuring of its safety. Evidence is emerging for the treatment of acid reflux to ameliorate NVP. The role of corticosteroids for hyperemesis gravidarum remains controversial. Transpyloric feeding may be warranted for persistent weight loss, despite optimal antiemetic therapy. SUMMARY: Women with significant NVP should be identified so that they can be safely and effectively treated. PMID- 21297475 TI - Different therapeutic strategies in primary salivary gland-type nasopharyngeal carcinomas. AB - PURPOSE OF REVIEW: Primary salivary gland-type nasopharyngeal carcinoma (PSGT NPC) is an uncommon malignancy with aggressive behavior and poor prognosis. Its optimal treatment policy remains debated, even though recent evidence provides support for a multimodality approach. The aim of this study was to summarize the optimal management approaches and treatment outcomes of PSGT-NPCs. RECENT FINDINGS: As most of the PSGT-NPCs, such as adenoid cystic carcinoma, mucoepidermoid carcinoma and low-grade (well-differentiated) adenocarcinoma, have low sensitivity to radiation, combined surgical treatment and radiotherapy are still the main treatment approach for limited or resectable lesions. As a result of the fact that in well-differentiated PSGT-NPCs the occult neck metastasis rate is low (less than 20%), elective neck dissection is not recommended in patients with a node-negative neck. Since high-grade (poorly-differentiated) PSGT-NPCs are relatively sensitive to radiation, radiotherapy or chemoradiotherapy is currently considered as the main treatment policy for such patients. There is no evidence to indicate that chemotherapy would improve overall survival. Cranial nerve infiltration, residual tumor, and distant metastases are independent predictive factors of overall survival. SUMMARY: In most patients with PSGT-NPCs, especially for well-differentiated tumors, combined surgical treatment and radiotherapy should be recommended. For poorly-differentiated or unresectable tumors, radiotherapy or chemoradiotherapy is still considered the main treatment approach. Because of the rare incidence of PSGT-NPCs, the number of cases available for analysis is relatively small, and large multicentric studies should be conducted to further evaluate their optimal treatment policy. PMID- 21297476 TI - Minimizing complications in salvage head and neck oncological surgery following radiotherapy and chemo-radiotherapy. AB - PURPOSE OF REVIEW: The term salvage surgery denotes oncological surgery after failed radiotherapy or chemoradiotherapy (CRT). Salvage surgery is a high-risk endeavour as it carries a significant risk of complications. The purpose of this review is to assess the ways in which complications from salvage surgery can be prevented and minimized. This is a complex subject and complications are often multifactorial and interrelated. There are many aspects that can be discussed; however, to address each of them individually would be impossible and beyond the scope of this article. We will, therefore, focus this review on the most relevant aspects to current practice for head and neck surgeons. RECENT FINDINGS: Salvage surgery after failure of radiotherapy and CRT remains controversial and many aspects still lack evidence. Many patients with recurrent cancer are not suitable for salvage surgery due to severe co-morbidities or disease progression. Salvage surgery is best carried out in tertiary centres by experienced multidisciplinary teams. Preoperative assessment and evaluation is critical to success and to minimize complications. Surgical principles include single incisions, delicate tissue handling, use of frozen sections, adopting a critical approach to neck dissections and the use of flaps, secondary surgical voice restoration for laryngectomies and appropriate postoperative care. SUMMARY: This review emphasizes the importance of a multidisciplinary approach by experienced teams, the centralization of resources and teams, a structured and thorough patient assessment, surgical planning and a systematic attention to detail when addressing patients undergoing salvage surgery. PMID- 21297477 TI - Management of the neck in metastatic cutaneous squamous cell carcinoma of the head and neck. AB - PURPOSE OF REVIEW: This article reviews the predictors, prognosis, and treatment of nodal metastases in cutaneous squamous cell carcinoma of the head and neck. RECENT FINDINGS: There is a better understanding of the risk factors that predict metastatic disease in cutaneous squamous cell carcinoma. Recent data has simplified the relationship between the site of the primary tumour and nodal disease, allowing for a more selective approach to the neck, in terms of both surgery and radiotherapy. Newer staging systems that take into account the clinicopathological factors allow better prognostication, and their application has been discussed. There is ongoing research on concurrent chemoradiotherapy, sentinel node biopsy, and epidermal growth factor receptor overexpression. SUMMARY: The status of the parotid and level II/III nodes has important implications for the management of the neck, and therefore dissection of level I and level IV/V nodes is required in selected cases only. Prognostic stratification is needed to tailor treatment algorithms that intensify therapy in high-risk disease and minimize toxicity in selected low-risk patients. PMID- 21297479 TI - Persistently high prevalence and unrecognized HIV infection among men who have sex with men in Baltimore: the BESURE study. AB - BACKGROUND: Given high rates of HIV among Baltimore men who have sex with men (MSM), we examined characteristics associated with HIV prevalence and unrecognized HIV infection among Baltimore MSM at two time points. METHODS: Cross sectional behavioral surveys and HIV testing in 2004-2005 and 2008 using venue based sampling among adult Baltimore men at MSM-identified locations. MSM was defined as sex with a male partner in the past year. Bivariate and backward stepwise regression identified characteristics associated with HIV and unrecognized infection. RESULTS: HIV prevalence was 37.7% overall in 2004-2005 (n = 645) and 37.5% in 2008 (n = 448), 51.4% and 44.7% among black MSM and 12.9% and 18.3% among non-Hispanic white MSM. Compared with non-Hispanic white MSM, black MSM were 4.0 times (95% confidence interval, 2.3-7.0) more likely to be HIV positive in 2004-2005 and 2.5 times (95% confidence interval, 1.5-4.0) more likely in 2008. Prevalence of unrecognized HIV infection was 58.4% overall in 2004-2005 and 74.4% in 2008, 63.8% and 76.9% among black MSM and 15.4% and 47.4% among non-Hispanic white MSM. In adjusted models, unrecognized infection was significantly associated with minority race/ethnicity, younger age, and no prior year doctor visits in 2004-2005 and with younger age and no prior year doctor visits in 2008. CONCLUSION: High rates of HIV infection and substantial rates of unrecognized HIV infection among Baltimore MSM, particularly men of color and young men, require urgent public and private sector attention and increased prevention response. PMID- 21297480 TI - HIV prevalence and risk practices among men who have sex with men in two South African cities. AB - BACKGROUND: In South Africa, information on HIV among men who have sex with men (MSM) is limited, and HIV prevention programs for men MSM are not widely available, despite global evidence that MSM are at substantial risk for HIV infection. The Johannesburg/eThekwini Men's Study was conducted during 2008 to provide information on HIV among MSM in Johannesburg and Durban. METHODS: MSM aged 18 years or older were recruited using respondent-driven sampling. Participants completed a questionnaire and provided finger-prick blood specimens for anonymous HIV testing in a laboratory. RESULTS: From July to December 2008, 285 MSM were recruited in Johannesburg (n = 204) and Durban (n = 81). Participants had a median age of 22 years and were predominantly black Africans (88.3%). The HIV prevalence was 49.5% [95% confidence interval (CI): 42.5% to 56.5%] in Johannesburg and 27.5% [95% CI: 17.0% to 38.1%] in Durban. HIV infection was associated with gay identification [adjusted odds ratio (aOR): 8.4; 95% CI: 3.7 to 19]. Factors in the previous year that were associated with HIV infection included receptive unprotected anal intercourse [aOR 4.3; 95% CI: 2.4 to 7.6]; sex with a person known to be HIV positive [aOR: 2.3; 95% CI: 1.1 to 4.9]; and a sexually transmitted infection diagnosis [aOR 2.4; 95% CI: 1.1 to 5.2]. CONCLUSIONS: HIV prevalence among MSM in Johannesburg and Durban is considerably higher compared with men in the general population. There is an urgent need to establish national HIV surveillance among MSM and to expand the availability of HIV prevention programs for MSM. PMID- 21297482 TI - Extensively drug-resistant TB in Eastern Cape, South Africa: high mortality in HIV-negative and HIV-positive patients. AB - BACKGROUND: Tuberculosis is a leading cause of morbidity and mortality worldwide. Patients with extensively drug-resistant tuberculosis (XDR-TB) have had high mortality rates, especially when coinfected with HIV. METHODS: A retrospective cohort study of the first 206 patients treated for XDR-TB in Eastern Cape Province, South Africa, October 2006 to January 2008, a province that has treated multidrug-resistant tuberculosis since 2000. All 206 patients were hospitalized for treatment until monthly sputum specimens were culture negative. RESULTS: Sixty-five patients diagnosed with XDR-TB died before XDR-TB treatment start. Among 195 patients starting treatment with a known HIV status, 108 (55.4%) were HIV positive, and 86 patients (44.1%) died during the first year of treatment. HIV-positive patients receiving antiretroviral treatment (ARVs) fared and HIV negative patients, and more of both these groups survived than HIV-positive patients not on ARVs. However, HIV-negative patients experienced more serious adverse events requiring the withdrawal of medications than did HIV-positive patients, regardless of the use of ARVs. CONCLUSIONS: Experience in Eastern Cape Province, South Africa, suggests that patients can be treated for both XDR-TB and HIV. We have also shown that such combination therapy can be well tolerated by patients. PMID- 21297481 TI - Sexual behaviors over a 3-year period among individuals with advanced HIV/AIDS receiving antiretroviral therapy in an urban HIV clinic in Kampala, Uganda. AB - BACKGROUND: Few studies have prospectively examined sexual behaviors of HIV infected person on antiretroviral therapy (ART) in sub-Saharan Africa. METHODS: Between 2004 and 2005, 559 HIV-infected, ART-naive individuals initiating ART at an HIV clinic in Kampala, Uganda, were enrolled into a prospective study and followed to 2008. Clinical and sexual behavior information was assessed at enrollment and semiannually for 3 years after ART initiation. Using log-binomial regression models, we estimated prevalence ratios (PRs) to determine factors associated with being sexually active and having unprotected sex over 3 years after initiating ART. RESULTS: Five hundred fifty-nine adults contributed 2594 person-visits of follow-up. At the time of ART initiation, 323 (57.9%) were sexually active of which 176 (54.5%) had unprotected sex at last sexual intercourse. The majority (63.4%) of married individuals were unaware of their partner's HIV status. Female gender (PR, 2.97; 95% confidence interval, 1.85 4.79), being married (PR, 1.48; 95% confidence interval, 1.06-2.06), and reporting unprotected sex before ART (PR, 1.68; 95% confidence interval, 1.16 2.42) were among the factors independently associated with unprotected sex while on ART. Overall, 7.3% of visit intervals of unprotected sex, 1.0% of intervals of sexual activity, occurred when plasma viral load greater than 1500 copies/mL, representing periods of greater HIV transmission risk. CONCLUSIONS: Although unprotected sex reduced over time, women reported unprotected sex more often than men. Disclosure of HIV status was low. Integration of comprehensive prevention programs into HIV care is needed, particularly ones specific for women. PMID- 21297483 TI - Risk factors for HIV-1 infection in a longitudinal, prospective cohort of adults from the Mbeya Region, Tanzania. AB - BACKGROUND: To control the global HIV epidemic, targeted interventions to reduce the incidence of HIV infections are urgently needed until an effective HIV vaccine is available. This study describes HIV-1 incidence and associated risk factors in a general population cohort of adults from Mbeya region, Tanzania, who participated in a vaccine preparedness study. METHODS: We conducted a closed prospective cohort study with 6-monthly follow-up from 2002 to 2006 enrolling adults from the general population. HIV-1 incidence and risk factors for HIV-1 acquisition were analyzed using Cox regression. RESULTS: We observed 2578 seronegative participants for a mean period of 3.06 person years (PY) (7471 PY in total). Overall HIV-1 incidence was 1.35 per 100 PY (95% confidence interval [CI], 1.10-1.64/100 PY). The highest overall HIV-1 incidence was found in females from Itende village (1.55 per 100 PY; 95% CI, 0.99-2.30/100 PY); the highest age specific incidence was observed in semiurban males aged 30 to 34 years (2.75 per 100 PY; 95% CI, 0.75-7.04). HIV-1 acquisition was independently associated with female gender (hazard ratio [HR], 1.64; 95% CI, 1.05-2.57), younger age at enrollment (age 18-19 versus 35-39 years: HR, 0.29; 95% CI, 0.11-0.75), alcohol consumption (almost daily versus none: HR, 2.01; 95% CI, 1.00-4.07), education level (secondary school versus none: HR, 0.39; 95% CI, 0.17-0.89), and number of lifetime sex partners (more than five versus one: HR, 2.22; 95% CI, 1.13-4.36). CONCLUSIONS: A high incidence of HIV was observed in this cohort, and incident infection was strongly associated with young age, alcohol consumption, low school education level, and number of sex partners. Targeted interventions are needed to address the elevated risk associated with these factors. PMID- 21297485 TI - Atherosclerotic burden in coronary and peripheral arteries in patients with first clinical manifestation of coronary artery disease. AB - The aim of our study was to assess the atherosclerotic burden in patients with the first symptoms of coronary artery disease (CAD). The study population consisted of 100 consecutive patients (new-onset severe angina or myocardial infarction) and 70 age and sex matched asymptomatic volunteers. Functional and morphologic atherosclerotic markers were sought in carotid, brachial and femoral arteries of all individuals by means of high-resolution ultrasonography, whereas coronary arteriography was performed in the CAD patients only. A total of 347 coronary lesions [230 (66%) obstructive] were discovered in the CAD patients as well as 105 peripheral plaques [26 (25%) obstructive]. The mean percentage diameter stenosis of the culprit coronary lesion was 83.8 +/- 15.8%, the mean vessel score 1.7 (range 0-3), the mean stenosis score 19.8 (range 1.5-89.0), and the mean extent score 49.1% (range 10-65%). Endothelium-dependent vasodilation, as assessed by the brachial flow-mediated response (FMR), was reduced by 50% in the CAD patients (P < 0.001 vs. controls). Furthermore, endothelium-independent vasodilation was significantly impaired in all investigated peripheral arteries of the CAD patients (P < 0.05-0.001 vs. controls). Intima-media thickness (IMT) was increased in the carotid arteries of the CAD patients by 43%, in brachial arteries by 20% and in femoral arteries by 57% (P < 0.01-0.001 vs. controls). Decreased FMR or increased carotid IMT was found to be independent risk factors for the CAD, and they correlated with the coronary vessel and extent scores. In conclusion, the atherosclerotic process was quite advanced in coronary as well as peripheral arteries of our patients with the first clinical presentation of CAD. PMID- 21297484 TI - A cost-effectiveness analysis of alternative HIV retesting strategies in sub saharan Africa. AB - BACKGROUND: Guidelines in sub-Saharan Africa on when HIV-seronegative persons should retest range from never to annually for lower-risk populations and from annually to every 3 months for high-risk populations. METHODS: We designed a mathematical model to compare the cost-effectiveness of alternative HIV retesting frequencies. Cost of HIV counseling and testing, linkage to care, treatment costs, disease progression, and mortality, and HIV transmission are modeled for three hypothetical cohorts with posited annual HIV incidence of 0.8%, 1.3%, and 4.0%, respectively. The model compared costs, quality-adjusted life-years gained, and secondary infections averted from testing intervals ranging from 3 months to 30 years. Input parameters from sub-Saharan Africa were used and explored in sensitivity analyses. RESULTS: Accounting for secondary infections averted, the most cost-effective testing frequency was every 7.5 years for 0.8% incidence, every 5 years for 1.3% incidence, and every 2 years for 4.0% incidence. Optimal testing strategies and their relative cost-effectiveness were most sensitive to assumptions about HIV counseling and testing and treatment costs, rates of CD4 decline, rates of HIV transmission, and whether tertiary infections averted were taken into account. CONCLUSIONS: While higher risk populations merit more frequent HIV testing than low risk populations, regular retesting is beneficial even in low-risk populations. Our data demonstrate benefits of tailoring testing intervals to resource constraints and local HIV incidence rates. PMID- 21297486 TI - Downgrading mitral regurgitation in the echo laboratory: a case of rheumatic mitral restricted motion unmasked by emotional stress. AB - We report the case of a 76-year-old woman with mild-to-moderate mitral regurgitation due to rheumatic disease, severe dyspnoea, pulmonary hypertension and a recent episode of heart failure with paroxysmal atrial fibrillation. Transthoracic echocardiography at rest showed a mild-to-moderate mitral regurgitation, which was unable to justify the acute worsening of heart failure symptoms. During transesophageal echocardiography (TEE), deep anxiety induced sinus tachycardia and high SBP followed by pulmonary subedema. The TEE study ascertained a new-onset transient severe mitral regurgitation induced by stress and tachycardia. We speculate that the mechanism underlying the increasing of mitral regurgitation was related to the restricted motion of the posterior leaflet worsened by tachycardia. A further TEE, performed in the operating room under general anesthesia, thus without the emotional involvement of the patient, was not able to provoke a heart failure, even after dobutamine infusion, thus, downgrading the anatomical and functional mitral regurgitation severity. PMID- 21297487 TI - Multislice computed tomography in the diagnosis of coronary anomalies with superimposed coronary artery disease. AB - Multislice computed tomography (MSCT) is widely used to complement conventional angiography in the diagnosis and characterisation of coronary artery anomalies. MSCT adds relevant 3-dimensional information that relates the course of anomalous vessels to specific anatomical structures of the heart. The utility of MSCT in patients with coronary anomalies is exemplified in a patient with superimposed coronary artery disease. PMID- 21297488 TI - Congenital coronary anomalies: a complementary role of multimodality imaging. PMID- 21297489 TI - Expression of circulatory dendritic cells and regulatory T-cells in patients with different subsets of coronary artery disease. AB - BACKGROUND: Dendritic cells (DCs), regulators of innate and adaptive immunity, may play an important role in atherosclerosis. DC invasion was found in early atherosclerotic lesions. We aimed to characterize circulating DC gene expression in patients with different subsets of coronary artery disease (CAD). METHODS: Peripheral blood mononuclear cells were quantified using real-time polymerase chain reaction and fluorescence activated cell sorting in patients with acute coronary syndrome (ST-elevation myocardial infarction [STEMI], n = 35; non-ST elevation myocardial infarction [NSTEMI], n = 30) and stable CAD (6 months after stent implantation without progression, n = 15) compared with control subjects (n = 15). DCs and T-cells (TCs) were characterized using specific primers for CD1a (immature), CD86 (mature), CD123 (plasmacytoid), BDCA1 (myeloid), CD178 (activated TCs), and FOXP3 (regulatory TCs). To evaluate whether serum of patients with STEMI induces DC differentiation, incubation of patient serum was performed. RESULTS: CD86 was upregulated and CD1a downregulated in all patients with CAD (P < 0.05). Patients with STEMI and NSTEMI showed a downregulation of CD1a compared with patients with stable CAD (P <= 0.01). In contrast, stable patients with CAD had elevated CD178 levels compared with patients with STEMI and NSTEMI (P <= 0.04). In patients with STEMI, FOXP3 was downregulated compared with control subjects (P < 0.0001). Incubation of STEMI serum induced an upregulation of CD1a and CD86 in a human DC cell line. Coincubation with a blocking antibody for heat shock protein 60 inhibited this upregulation. CONCLUSIONS: DCs are differentially regulated in patients with different subsets of CAD. Mature DCs are upregulated and immature DCs are downregulated in patients with CAD. Patients with STEMI show a significant downregulation of regulatory TCs. Circulating shock protein 60 induces DC differentiation in patients with STEMI. PMID- 21297490 TI - Communication signals between cardiac fibroblasts and cardiac myocytes. AB - Interspersed between cardiac myocytes, cardiac fibroblasts serve mainly as a structural support during ventricular wall thickening from embryogenesis until adulthood. Cardiac fibroblasts, however, may also serve as a source of mitogens, extracellular matrix proteins, cytokines, and growth factors that could affect the phenotype of the cardiac myocyte. The crosstalk between cardiac fibroblasts and myocytes is important during cardiac development and remodeling in response to injury. The cell-to-cell communication involves paracrine signals (cytokines and growth factors), direct interactions (connexins and cadherins) as well as indirect interactions (integrin signaling through the extracellular matrix). In this review, known cardiac fibroblast-cardiac myocyte signaling pathways are briefly examined and their effect on the heart during disease progression is discussed. Furthermore, speculations are made regarding the possibility that vascular endothelial growth factor B can serve as an important signaling molecule between cardiac fibroblasts and cardiac myocytes and could promote cardiac function in compromised hearts. PMID- 21297491 TI - Effect of oral atorvastatin on CD4+CD25+ regulatory T cells, FoxP3 expression, and prognosis in patients with ST-segment elevated myocardial infarction before primary percutaneous coronary intervention. AB - OBJECTIVE: Our objective was to explore the effects of atorvastatin on changes of CD4+CD25+ regulatory T cells (Tregs), FoxP3 expression in the infarct-related coronary artery, and peripheral venous blood of patients with ST-segment elevation myocardial infarction. METHODS: We recorded 112 cases of patients with ST-segment elevation myocardial infarction who were randomly assigned to receive either atorvastatin 80 mg (n = 52) or placebo (n = 60) before primary percutaneous coronary intervention. Blood samples were obtained from the infarct related coronary artery and peripheral vein during percutaneous coronary intervention. The proportion of CD4+CD25+ Tregs, FoxP3 mRNA expression in blood and concentrations of transforming growth factor-beta and interferon-gamma in plasma of the samples were measured or detected by flow cytometry, real-time polymerase chain reaction, or enzyme-linked immunosorbent assay, respectively. RESULTS: In comparison with the control group, the proportions of CD4+CD25+ Tregs and the mRNA level of FoxP3 and transforming growth factor-beta significantly increased; however, interferon-gamma decreased with atorvastatin therapy. In the controls, the proportions of CD4+CD25+ Tregs and the mRNA level of FoxP3 and transforming growth factor-beta were significantly decreased, but the level of interferon-gamma increased more in the infarct-related coronary artery than in the peripheral vein. CONCLUSION: : The inhibition of CD4+CD25+ Tregs in patients with ST-segment elevation myocardial infarction could be regulated with atorvastatin given before percutaneous coronary intervention. PMID- 21297492 TI - The effect of ezetimibe and simvastatin on monocyte cytokine release in patients with isolated hypercholesterolemia. AB - Apart from reducing plasma lipids, ezetimibe may produce non-lipid-related pleiotropic effects. The aim of this article was to compare the effect of ezetimibe and simvastatin on monocyte cytokine release and systemic inflammation in isolated hypercholesterolemic patients. One hundred thirty-four subjects with isolated hypercholesterolemia were allocated to 1 of 4 treatment groups treated for 90 days with, respectively, ezetimibe, simvastatin, ezetimibe plus simvastatin, or placebo. Monocyte cytokine release was determined at baseline and after 30 and 90 days of treatment. Compared with placebo, all the remaining treatment options reduced-monocyte release of tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, and monocyte chemoattractant protein-1, which was accompanied by a reduction in plasma C-reactive protein levels. In subjects receiving both simvastatin and ezetimibe, posttreatment monocyte cytokine release and plasma C-reactive protein levels did not differ from those observed in 30 matched healthy subjects. Monocyte-suppressing and systemic-anti-inflammatory effects were more expressed in simvastatin- than in ezetimibe-treated patients and strongest when both the agents were administered together. The results obtained suggest that simvastatin may be a better treatment option than ezetimibe in isolated hypercholesterolemic patients and that hypercholesterolemic patients of high cardiovascular risk may benefit the most from combined treatment with simvastatin and ezetimibe. PMID- 21297493 TI - Fibroblasts and myofibroblasts: what are we talking about? AB - Cardiac myocytes, although large enough to make up most of the heart volume, are only a minority of cells within the heart with fibroblasts and blood vessel components (endothelial and smooth muscle cells) making up the remainder of the heart. In recent years, there has been increasing interest in the nonmyocyte population within the heart. This is attributable, in part, to our increasing understanding of the biology of the nonmyocyte cell types and additionally it is the result of our awakening realization that these cells are not static but rather that they are dynamic in nature indicating that they play a more active role in cardiac function than previously imagined. Studies now show that fibroblasts are involved in formation of the extracellular matrix and they control the size of the extracellular matrix. Additionally, they participate in the repair process by differentiating into myofibroblasts, which are cells involved in the inflammatory response to injury. Myofibroblasts migrate to the sites of injury where they produce cytokines, thus enhancing the inflammatory response. This review discusses both structural and functional differences between the two cell types and examines the different roles of these two different cell types in the heart. PMID- 21297494 TI - Effects of prescription omega-3-acid ethyl esters on fasting lipid profile in subjects with primary hypercholesterolemia. AB - This double-blind, randomized crossover study investigated the effects of 6 weeks of treatment with prescription omega-3-acid ethyl esters (POM3, 4 g/day) versus placebo (soy oil) on low-density lipoprotein cholesterol (LDL-C) and other aspects of the fasting lipid profile in 31 men and women with primary, isolated hypercholesterolemia (LDL-C 130-220 mg/dL and triglycerides less than 150 mg/dL while free of lipid-altering therapies). Mean +/- standard error of the mean baseline concentrations of total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C), very-low-density lipoprotein cholesterol, and triglycerides were 229 +/- 3, 146 +/- 3, 60 +/- 2, 23 +/- 2, and 113 +/- 8 mg/dL, respectively. POM3 produced a modest increase from baseline in LDL-C (3.4%) versus the placebo response (-0.7%, P = 0.010). Significant changes (P < 0.05) for POM3 (placebo corrected) were observed for very-low-density lipoprotein cholesterol (-18.8%), triglycerides (-18.7%), and HDL-C (3.3%). Nuclear magnetic resonance-determined very-low-density lipoprotein particle concentration and size and HDL particle concentration decreased significantly more with POM3 versus placebo, whereas LDL and HDL particle sizes increased significantly more with POM3 versus placebo. Total cholesterol, non-HDL-C, apolipoproteins A1 and B, and LDL particle concentration responses did not differ between treatments. These results did not confirm the hypothesis that POM3 treatment would lower LDL-C in primary, isolated hypercholesterolemia. Effects on other variables were consistent with prior results in mixed dyslipidemia. PMID- 21297495 TI - Concomitant angiotensin AT1 receptor antagonism and neprilysin inhibition produces omapatrilat-like antihypertensive effects without promoting tracheal plasma extravasation in the rat. AB - Dual inhibition of angiotensin-converting enzyme (ACE) and neprilysin (NEP) by drugs such as omapatrilat produces superior antihypertensive efficacy but cause high incidence of angioedema. We examined whether dual inhibition of angiotensin AT1 receptor (ARB) and NEP (ARB-NEPI, valsartan-candoxatril) provides similar efficacy to omapatrilat without the risk of angioedema. Activity of test compounds at the targets was assayed using fluorescence-based enzyme assays (ACE, NEP, aminopeptidase P) or competition binding assays (AT1). Target engagement in vivo (ACE, AT1, and NEP) was quantified by measuring inhibition of angiotensin pressor responses and potentiation of atrial natriuretic peptide-induced urinary cyclic guanosine monophosphate (cGMP) output in rats. Tracheal plasma extravasation (TPE) was used as a surrogate to assess propensity of compounds to promote upper airway angioedema. Antihypertensive efficacy in renin-dependent and -independent states was measured in spontaneously hypertensive rats and deoxycorticosterone acetate salt hypertensive rats, respectively. Administration of omapatrilat and coadministration of valsartan and candoxatril blocked angiotensin induced vasopressor responses and potentiated atrial natriuretic peptide-induced increase in urinary cGMP output. In spontaneously hypertensive rats, valsartan, omapatrilat, and valsartan-candoxatril combination all produced reduction in blood pressure to a similar extent, whereas candoxatril was ineffective. In deoxycorticosterone acetate rats, omapatrilat, candoxatril, and valsartan-candoxatril combination but not valsartan produced reduction in blood pressure. Antihypertensive doses of omapatrilat produced robust increases in TPE; by contrast, valsartan, candoxatril, or their combination did not increase TPE. Pretreatment with icatibant, a bradykinin B2 antagonist, abolished omapatrilat induced TPE but not its antihypertensive effects. On the background of NEP inhibition, suppression of the renin-angiotensin system through ARB and ACE inhibition shows a similar antihypertensive efficacy but exerts differential effects on bradykinin metabolism and TPE indicative of reduced risk of angioedema. Thus, dual AT1 receptor blockade and NEP inhibition is potentially an attractive approach to retain the excellent antihypertensive effects of omapatrilat but with a superior safety profile. PMID- 21297496 TI - Calcium-activated potassium channels in vasculature in response to ischemia reperfusion. AB - Based on the genetic relationship, single-channel conductance, and gating mechanisms, calcium-activated potassium (KCa) channels identified in vasculature can be divided into 3 groups including large-conductance KCa, small, and intermediate conductance KCa. KCa channels in smooth muscle and endothelial cells are essential for the regulation of vascular tone. Vascular dysfunction under ischemia-reperfusion (I-R) or hypoxia-reoxygenation (H-R) conditions is associated with modulations of KCa channels that are attributable to multiple mechanisms. Most studies in this regard relied on the change of relaxation components sensitive to certain channel blockers to indicate the alteration of KCa channels under I-R conditions, which however provided conflicting results for the effect of I-R. The possible mechanisms involved in KCa channel modulation under I-R/H-R include overproduction of reactive oxygen species such as superoxide anion, hydrogen peroxide, and peroxynitrite, increase of intracellular H ion, and lactate accumulation, etc. However, more studies are necessary to further understand the discrepancies in the sensitivity of KCa channels to I-R injury in different vascular beds. PMID- 21297497 TI - Obstructive sleep apnea-specific quality of life and behavioral problems in children with syndromic craniosynostosis. AB - OBJECTIVE: This study aimed at evaluating the impact of syndromic craniosynostosis on quality of life, assessing the association between the presence of craniosynostosis syndrome and prevalence of behavioral problems and assessing the impact of obstructive sleep apnea (OSA) in syndromic craniosynostosis compared with healthy controls. METHOD: A prospective study was carried out using the Obstructive Sleep Apnea-18 (OSA-18) survey and Child Behavior Checklist (CBCL) in 119 syndromic craniosynostosis patients and the OSA 18 survey in 459 controls. The craniosynostosis population underwent a polysomnography to diagnose OSA. RESULTS: The total OSA-18 score and scores on the domains sleep disturbance, physical suffering, and caregiver concerns were significantly higher in the craniosynostosis group than in controls. Subgroup analysis revealed behavioral problems in 67% and 50% of boys with Apert and Muenke syndrome, respectively. Correlations between obstructive apnea-hypopnea index and total OSA-18 and CBCL scores were significant. Mean scores for the domains sleep disturbance and physical suffering were significantly higher in moderate OSA. CONCLUSIONS: OSA is related with a lower quality of life in children with syndromic craniosynostosis. Behavioral problems were more common in boys with Apert and Muenke syndrome. OSA-18 and CBCL scores were correlated with OSA severity. PMID- 21297498 TI - Relationship of predominantly mild current smoking to out-of-office blood pressure in a community sample in Africa. AB - OBJECTIVES: As the impact of mild smoking on blood pressure (BP) is uncertain, we assessed the relationship between predominantly mild current smoking and out-of office BP and the effect of angiotensin-converting enzyme (ACE) genotype on this relationship in a community sample of black African ancestry. METHODS: In 689 participants randomly recruited from an urban, developing community of black African descent, we assessed smoking habits, out-of-office (24-h), and in-office conventional and central (applanation tonometry) BP, and ACE insertion (I)/deletion (D) variant genotype. RESULTS: A total of 14.5% (n=100) were current smokers, the majority being mild (72%, 7.4 +/- 4.6 cigarettes/day). Despite current smokers having only modest increases in in-office (P<0.05) and similar central aortic BP values as nonsmokers, current smokers had higher unadjusted (P<0.005-P<0.0005) and multivariate adjusted 24-h SBP/DBP (mmHg; smokers=123 +/- 15/76 +/- 10; nonsmokers=118 +/- 14/72 +/- 9; P<0.005-P<0.0005) than nonsmokers, effects that were DD genotype-dependent (P<0.005 for interaction) and replicated in sex-specific groups, nondrinkers, and in overweight and obese. Current smoking was second only to age in the quantitative impact on 24-h DBP. Smoking 4.6 cigarettes per day (one standard deviation) translated into increases in 24-h SBP (mmHg) of 2.12 [confidence interval (CI)=1.77-2.47] in all participants and 3.62 (CI=3.13-4.12) in participants with the DD genotype. The risk of uncontrolled 24 h BP was increased in smokers as compared to nonsmokers (adjusted odds ratio=1.87, CI=1.02-3.41, P<0.05), an effect that was enhanced in participants with the DD genotype (adjusted odds ratio=4.01, CI=1.59-10.09, P<0.005). CONCLUSION: Mild current smoking is independently associated with an appreciable proportion of out-of-office BP in a black African community, an effect that is ACE genotype-dependent. PMID- 21297499 TI - Reversal of subclinical left ventricular dysfunction by antihypertensive treatment: a prospective trial of nebivolol against metoprolol. AB - OBJECTIVES: To assess the effects of antihypertensive treatment on subclinical left ventricular dysfunction and to compare the effects of nebivolol with metoprolol. METHODS: This is a prospective, randomized, parallel, active controlled, PROBE design study (ClinicalTrials.org: NCT00942487) in 60 patients (53+/-9 years, 67% men) with arterial hypertension, left ventricular hypertrophy, normal ejection fraction, and no coronary heart disease, randomized to either a nebivolol-based or a metoprolol-based treatment, who had conventional and tissue Doppler echocardiography, at rest and during dobutamine stress, at baseline and after 6 months. RESULTS: SBP and DBP, and resting heart rate decreased by 13, 13, and 12%, respectively, on nebivolol, and by 11, 13, and 7%, respectively, on metoprolol (all, P<0.01). Mean longitudinal early diastolic velocity increased by 16% (P<0.05) on nebivolol compared with 9% (P=not significant) on metoprolol (P=not significant for intergroup differences), whereas flow propagation velocity increased by 34% on nebivolol (P<0.05) and did not change on metoprolol (P<0.01 for intergroup differences). Mean longitudinal displacement increased by 10% on nebivolol (P<0.05) and did not change on metoprolol (P<0.05 for intergroup differences), whereas ejection time increased by 5% on nebivolol (P<0.05) and did not change on metoprolol. All the other parameters of left ventricular function were not different between the two treatment arms. CONCLUSION: Patients with mild to-moderate hypertension have a beneficial effect from 6-month antihypertensive treatment on diastolic longitudinal left ventricular function; effects are significant with nebivolol, but not with metoprolol. PMID- 21297500 TI - Initial left-ventricular mass predicts probability of uncontrolled blood pressure in arterial hypertension. AB - BACKGROUND: Left-ventricular hypertrophy (LVH) is a marker of organ damage in hypertension and helps stratifying cardiovascular risk. Initial left-ventricular mass (LVM) is also a predictor of progression to hypertension, independently of initial blood pressure (BP) and other confounders. OBJECTIVES: To evaluate whether baseline LVM can influence BP control in treated hypertension. METHODS: We evaluated risk of uncontrolled BP (>140 or 90 mmHg under at least two medications), in relation to initial LVM in 4693 hypertensive outpatients (mean age 53+/-11 years, 43% women, 5% diabetic), without prevalent cardiovascular disease, from the Campania Salute Network. RESULTS: Uncontrolled BP was found in 2240 patients (48%). Participants with initial LVH were more often men, older, diabetic, had higher initial BP, fasting glucose, uric acid and triglycerides, and lower heart rate (HR), high-density lipoprotein-cholesterol and glomerular filtration rate than those without LVH (all P<0.05). Of 1440 patients with initial LVH, 803 (56%) were uncontrolled at follow-up compared to 44% without LVH (P<0.0001). In multivariate analyses, odds of uncontrolled BP increased with higher baseline systolic BP [odds ratio (OR)=1.13*5 mmHg, 95% confidence interval (CI) 1.10-1.15], HR (OR=1.04*5 beats/min, 95% CI 1.01-1.07), BMI (OR=1.03*kg/m, 95% CI 1.01-1.04), LVM index (OR=1.05*5 g/m, 95% CI 1.01-1.10) and prevalence of diabetes (OR=5.22, 95% CI 3.52-7.76; all P<0.05) independently of age, sex, metabolic parameters and number of antihypertensive meds (P>0.1). Among medication classes, only angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were associated with lower risk of uncontrolled BP (OR=0.83, 95% CI 0.71-0.96; P=0.01), independently of covariates. CONCLUSION: In a population of treated hypertensive patients, initial LVM is a significant predictor of uncontrolled BP, independently of major risk factors and antihypertensive therapy. PMID- 21297501 TI - New software analyses increase the reliability of measurements of retinal arterioles morphology by scanning laser Doppler flowmetry in humans. AB - OBJECTIVE: The investigation of the retinal arterioles offers the unique opportunity to analyze in vivo arteriolar remodeling in arterial hypertension in humans. We analyzed the reliability of assessing retinal arteriolar morphology with our new version of the software analyses for scanning laser Doppler flowmetry. METHOD: In the test-retest reliability study, 10 eyes of 10 healthy persons were measured during 5 days under routine laboratory conditions with the Heidelberg Retinal Flowmetry. In a second study, interobserver and intraobserver reliability was analyzed from retinal images of 18 patients with three types of arterial hypertension by three readers and the most experienced reader analyzed all images twice on two different days. Images were analyzed by the old and the newly developed software versions. To characterize the reliability, the coefficients of variation were calculated. RESULTS: The test-retest study analyzed with the new program showed that the variation coefficients of vessel and lumen diameter, wall thickness, wall/lumen ratio and new calculated parameter: lumen/vessel diameter ratio of retinal arterioles were significantly less than 10%, with the exception of the wall cross-sectional area (12.5%). The interobserver and intraobserver reliability showed in nearly all circumstances coefficients of variations of less than 10% and did not differ across various readers and patient groups. CONCLUSION: The new software 'SLDF version 4.0' clearly improved the reliability of assessing the structural parameters of the retinal arterioles. The application delivers reliable measurements of the retinal arteriolar structure in vivo in humans. PMID- 21297502 TI - Impact of atorvastatin among older and younger patients in the Anglo-Scandinavian Cardiac Outcomes Trial Lipid-Lowering Arm. AB - OBJECTIVE: Older patients experience higher rates of cardiovascular disease than younger patients, but may be undertreated with statins due to doubts about efficacy and safety. The Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial allowed an evaluation of the efficacy and safety of atorvastatin among older (>= 65 years) and younger (<65 years) patients with hypertension. METHODS: A total of 10 305 patients with hypertension, at least three other cardiovascular risk factors, total cholesterol concentrations of 251 mg/dl or less, and no known coronary heart disease (CHD) were randomized to receive atorvastatin 10 mg or placebo. The primary endpoint was a composite of nonfatal myocardial infarction and fatal CHD. RESULTS: There were 4445 patients in the older group (mean 71 years) and 5860 patients (mean 57 years) in the younger group. Among those taking placebo, the older group experienced a higher rate of primary endpoints than the younger group (11.7 vs. 7.6 events per 1000 patient years, respectively). After a median follow-up of 3.3 years, the primary endpoint was reduced by a similar proportion in both older and younger patients (37 vs. 33%, respectively). Although older patients reported more serious adverse events than younger patients, there were no significant differences between atorvastatin and placebo within each age group. CONCLUSION: Atorvastatin reduced the risk of major cardiovascular events to a similar relative extent in both older and younger patients with treated hypertension. However, given that event rates were higher in older patients, the absolute benefits of atorvastatin were greater for older than younger patients. PMID- 21297503 TI - Impact of amlodipine-based therapy among older and younger patients in the Anglo Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA). AB - OBJECTIVES: Older patients experience higher rates of cardiovascular disease than younger patients, but studies have suggested that relative risk reductions due to antihypertensive therapy are lower in older than younger patients. The Anglo Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA) allowed an evaluation of the efficacy and safety of an amlodipine versus an atenolol-based antihypertensive regimen among older (>= 65 years) and younger (<65 years) patients. METHODS: In ASCOT-BPLA 19 257 patients (8137 aged >= 65 years and 11 020 <65 years) were randomly assigned to receive amlodipine or atenolol-based antihypertensive therapy. The primary endpoint (nonfatal myocardial infarction and fatal coronary heart disease) and seven secondary endpoints were consistent with the original trial design. RESULTS: All cardiovascular endpoints evaluated favoured the amlodipine-based regimen, significantly so in seven of the 16 age-stratified endpoints. Compared with the atenolol-based regimen, the amlodipine-based regimen reduced the relative risk of cardiovascular events by 17% in older and 15% in younger patients (P < 0.01). Overall, older patients experienced more cardiovascular events [n = 1625 (20%)] than younger patients [n = 1339 (12%)]. Discontinuations due to serious adverse events were low in both age groups and less frequent in the amlodipine-based versus atenolol-based regimen: 0.6 versus 1.1% among older patients and 0.4 versus 0.8% among younger patients. CONCLUSIONS: The amlodipine-based regimen reduced the relative risk of cardiovascular events more effectively than the atenolol-based regimen in both older and younger patients. However, because event rates were higher among older patients, the absolute benefits were greater for older compared with younger patients. PMID- 21297504 TI - Colonic mass, colorectal adenocarcinoma. PMID- 21297505 TI - Compound heterozygote of a novel missense mutation (p.K402T) and a double missense mutation (p.[G71R;Y486D]) in type II Crigler-Najjar syndrome. PMID- 21297506 TI - Neonatal tracheobiliary fistula diagnosed by MR cholangiopancreatography. PMID- 21297507 TI - Pediatric inflammatory bowel disease and imaging-related radiation: are we increasing the likelihood of malignancy? AB - BACKGROUND AND AIMS: Increasing use of diagnostic radiography has led to concern about the malignant potential of ionizing radiation. We aimed to quantify the cumulative effective dose (CED) from diagnostic medical imaging in children with inflammatory bowel disease (IBD) and to identify which children are at greatest risk for high amounts of image-related radiation exposure. PATIENTS AND METHODS: A retrospective chart review of pediatric IBD patients seen between January 1 and May 30, 2008 was conducted. The effective dose of radiation received from all of the radiology tests performed during the course of each patient's treatment was estimated using typical effective doses and our institution's computed tomography dose index. A CED >=50 mSv was considered high. RESULTS: Complete records were available for 257 of 372 screened subjects. One hundred seventy-one had Crohn disease (CD) and 86 had ulcerative colitis (UC). The mean CED was 17.56 +/- 15.91 mSv and was greater for children with CD than for those with UC (20.5 +/- 17.5 vs 11.7 +/- 9.9 mSv, P < 0.0001). Fifteen children (5.8%) had a CED >=50 mSv, including 14 of 171 (8.2%) with CD and 1 of 86 (1.2%) with UC (P = 0.02). In children with CD, factors associated with high CED per multivariate analysis were any IBD-related surgery (odds ratio 42, 95% confidence interval 8-223, P < 0.0001) and platelet count (odds ratio 16, 95% confidence interval 1.5-175, P = 0.02). CONCLUSIONS: Although all doses of ionizing radiation have some malignancy inducing potential, a small but important percentage of children with IBD are exposed to particularly high doses of ionizing radiation from diagnostic tests and procedures. Physicians caring for such patients must seek to limit radiation exposure whenever possible to lessen the lifetime risk of malignancy. PMID- 21297508 TI - Patient and parent psychosocial factors associated with health-related quality of life in pediatric inflammatory bowel disease. AB - OBJECTIVES: The aim of the study was to examine the mediating role of youth depressive symptoms in the relation between parent distress and youth health related quality of life (HRQOL) in a sample of adolescents with inflammatory bowel disease (IBD). PATIENTS AND METHODS: Sixty-two adolescents, ages 13 to 17 years, with a confirmed diagnosis of IBD completed assessments of depressive symptoms and HRQOL. Each adolescent's primary caregiver completed a measure of parent stress related to his or her child's illness. Pediatric gastroenterologists provided data for disease severity assessments. RESULTS: Multiple regression analyses revealed that adolescent depressive symptoms fully mediated the relation between parent distress and several dimensions of HRQOL (ie, general well-being, emotional functioning, social functioning, and total HRQOL). Moreover, mediation was observed after statistically controlling for the effect of disease severity, IBD diagnosis, and significant demographic parameters on HRQOL. CONCLUSIONS: Findings suggest that adolescent depressive symptoms may serve as the mechanism through which parent distress is linked to poorer HRQOL in adolescents with IBD. Close monitoring of parent illness-related distress and adolescent depressive symptoms, as well as clinical interventions targeting these factors, is needed to promote optimal outcomes in adolescents with IBD. PMID- 21297509 TI - Abnormal Gastrointestinal Histopathology in Children With Autism Spectrum Disorders. AB - OBJECTIVES:: The significance of the association between many gastrointestinal (GI) pathologies and autism has yet to be discovered. The aim of the present study was to review available evidence documenting any link between autism and GI histopathology in children. MATERIALS AND METHODS:: In a systematic review, the following sources were searched: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1980-August week 2, 2009), EMBASE (1980-August week 2, 2009), PubMed (last 180 days), Web of Science, and Scopus, using the terms "autism" or "autistic spectrum disorder" and "intestinal" or "gastrointestinal" or "colitis." In addition, relevant studies were identified through browsing the reference lists of the included articles for relevant citations. All children younger than 18 years old with autistic spectrum disorder who were examined for abnormal GI histopathology were included. Cohort studies published in the English language, reporting GI histopathological examination findings in children with autism, were included. Two independent authors performed data extraction. The methodological quality of each trial was assessed. RESULTS:: Eight studies have reported the histopathological features of the GI tract in children with autism and fulfilled inclusion criteria. In general, none of these trials appeared to be of high quality. Apart from intestinal lymphonodular hyperplasia, the majority of these findings were not consistent. CONCLUSIONS:: GI pathological findings in children with autism have been inconsistent. The present available evidence does not support or refute a link between GI histopathology and autism in children. The significance of intestinal lymphonodular hyperplasia in these children is unknown. Large properly designed prospective controlled trials addressing this issue are required. PMID- 21297510 TI - Stroke, part 2: Respond aggressively to hemorrhagic stroke. PMID- 21297511 TI - Do swimming goggles limit microbial contamination of contact lenses? AB - PURPOSE: Wearing goggles over contact lenses while swimming is often recommended by eye care professionals. Limited data are available to assess this recommendation. The purpose of this study was to examine whether wearing goggles while swimming limits bacterial colonization on contact lenses and whether the type of lens worn affects contamination rates. METHODS: Twenty-three subjects underwent two swimming sessions at an ocean (salt water) pool (Maroubra beach Rock Pool, Sydney, Australia). Silicone hydrogel (Ciba Focus Night and Day) or hydrogel lenses (Ciba Focus Daily) were inserted into subjects' eyes before 30 min of swimming sessions, and subjects used modified goggles to mimic goggled and non-goggled conditions. At the end of each session, lenses were collected for microbial investigation. Viable bacterial colonies were classified as gram positive and gram negative and enumerated. The level of bacterial colonization on contact lenses between goggled and non-goggled conditions and between the two lens materials were compared. RESULTS: The range of colony forming units recovered from goggled lenses were 0 to 930 compared with 0 to 1210 on non goggled lenses. The majority of subjects (16/23) had more microorganisms in the non-goggled condition than when wearing goggles (p = 0.03). Gram negative organisms were found in three non-goggled lenses. No significant difference was shown in the number of bacteria isolated from silicone hydrogel and hydrogel lenses (p > 0.6) irrespective of wearing goggles. Water samples had consistently higher numbers of bacterial counts than those adhered to the lenses; however, no association was found between the number of bacteria in the water sample and those found on the contact lenses. CONCLUSIONS: Consistently, fewer bacterial colonies were found on the goggled contact lens, thus suggesting goggles offer some protection against bacterial colonization of contact lenses while swimming. These data would support the recommendation encouraging lens wearers to use goggles while swimming. PMID- 21297514 TI - Birth season, photoperiod, and infancy refraction. AB - PURPOSE: To investigate the association between birth month/photoperiod and refraction in infancy. METHODS: Seven hundred twenty-two children with refractions measured between 1 and 3 months were included in this analysis. Non cycloplegic near retinoscopy was performed by three experienced optometrists over a 32-year period. Photoperiod hours were calculated as the mean daylight hours 30 days after each infant's birth and then grouped into quartiles between 9.12 and 15.25 hours. Two classifications for birth season were considered: regular season (Spring: March-May, Summer: June-August, Fall: September-November, and Winter: December-February) and alternate season (Spring: February-April, Summer: May July, Fall: August-October, and Winter: November-January). RESULTS: The mean infant age was 2.11 +/- 0.55 months. The mean spherical equivalent refraction (SER) was 0.61 +/- 1.56 diopters (D). Children born in the photoperiod group with the most daylight hours had slightly lower refractions than those in the shortest photoperiod group (0.43 +/- 1.60 D vs. 0.87 +/- 1.43 D, p < 0.05). In the longest photoperiod group, the percentage of infants with SER <=-0.25 D was significantly higher (51/179 = 28.49%) than in the shortest photoperiod group (31/177 = 17.51%) (p = 0.02). Similar patterns were observed using the alternate season classification, with (1) lower mean SER in infants born in the summer vs. the winter and (2) a higher percentage of SER <=-0.25 D in infants born in the summer vs. the winter. However, by regular seasons, the mean SERs were similar between summer and winter. CONCLUSIONS: A small, statistically significant lower refraction was found in infants with the most vs. the least daylight soon after birth, suggesting that light might play a small role in the refractive error of newborns. PMID- 21297515 TI - Is there a difference in clinical outcomes, inflammation, and hypermetabolism between scald and flame burn? AB - OBJECTIVE: Severe thermal injury induces inflammatory and hypermetabolic responses that are associated with morbidity and mortality. However, it is not well-documented whether the causes of burns affect inflammation, hypermetabolism, and morbidity. The aim of the present study was to determine whether there is a difference in degree of inflammation, hypermetabolism, endocrine and acute-phase response, and clinical outcome between pediatric patients with scald and flame burns. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Children with burns requiring surgical intervention were enrolled in this cohort study and divided into two groups, scald or flame burn. In a second assignment, we analyzed the study populations in representative subgroups containing individuals with third degree burns of 40% to 60% total body surface area. We determined clinical outcomes, resting energy expenditures, cytokine profiles, acute-phase proteins, constitutive proteins, and hormone panels. Statistical analysis was evaluated by analysis of variance, Student's t test corrected with the Bonferroni post hoc test, and the propensity score. Statistical significance was set at p < .05. A total of 912 patients were identified. Six hundred seventy-four had a flame burn and 238 had a scald burn. There was a significant difference (p < .05) in burn size (flame, 48% +/- 23%; scald, 40% +/- 21%), third-degree burn (flame, 39% +/- 27%; scald 22% +/- 25%), age (flame, 8 +/- 5 yrs; scald, 3 +/- 3 yrs), and mortality between groups. Propensity analysis confirmed the type of burn as a significant risk factor for morbidity and mortality. Subanalysis conducted in a representative patient group suffering from 40% to 60% burn total body surface area revealed that flame burns lead to significantly increased hypermetabolic, inflammatory, and acute-phase responses when compared to scald burns (p < .05). The frequency of sepsis was 3% in the scald burn group, while it was 14% in the flame group (p < .001). Multiorgan failure occurred in 14% of the scald patients, while it occurred in 17% of flame patients. The mortality in patients suffering from a scald burn was 3% compared to 6% in the flame-burned group (p < .05). CONCLUSION: The type of burn affects hypermetabolism, inflammation, acute-phase responses, and mortality postburn. PMID- 21297516 TI - Inhaled nitric oxide improves systemic microcirculation in infants with hypoxemic respiratory failure. AB - OBJECTIVES: To investigate the effect of inhaled nitric oxide on the systemic microcirculation. We hypothesized that inhaled nitric oxide improves the systemic microcirculation. Inhaled nitric oxide improves outcome in infants with persistent pulmonary hypertension of the newborn diagnosed by improving pulmonary blood flow and oxygenation. It reduces pulmonary vascular resistance without decline in systemic blood pressure. Inhaled nitric oxide is also utilized in the treatment of acute hypoxemic respiratory failure in children and adults. It is thought to improve regional ventilation perfusion by regional selective pulmonary vasodilation. DESIGN: Pilot study. SETTING: Intensive care unit of a level III university children's hospital. PATIENTS: Consecutive ventilated patients who were treated with inhaled nitric oxide (20 ppm) were enrolled in this study. Eight patients (five boys, three girls) were included; five had congenital diaphragmatic hernia diagnosed, one had persistent pulmonary hypertension of the newborn diagnosed, one had acute respiratory distress syndrome diagnosed, and one had bronchiolitis diagnosed. The median age was 0 months (range, 0-38 months). INTERVENTIONS: Inhaled nitric oxide administration. MEASUREMENTS AND MAIN RESULTS: The microcirculation was assessed in the buccal mucosa within 1 hr before and within 1 hr after the start of inhaled nitric oxide using orthogonal polarization spectral imaging. The median functional capillary density before the inhaled nitric oxide was started was 4.0 cm/cm (range, 1.8-5.6 cm/cm) and improved to 4.9 cm/cm (range, 2.8-6.6 cm/cm; p = .017) after the start of inhaled nitric oxide. CONCLUSIONS: Inhaled nitric oxide improves the systemic microcirculation in children with hypoxemic respiratory failure. PMID- 21297517 TI - Informed consent for bedside procedures in the pediatric intensive care unit: a preliminary report. AB - OBJECTIVES: No uniform guidelines exist regarding informed consent for bedside procedures in the intensive care unit (ICU), and practice varies widely between institutions. Neither guidelines nor data exist to help pediatric ICU (PICU) directors craft procedural consent policies. We conducted an exploratory study to explore the impact on patients, parents, and healthcare providers of a requirement for informed consent for bedside procedures in the PICU and to describe parental and provider beliefs regarding procedural consent. DESIGN: Prospective, observational and survey-based exploratory study. SETTING: Single center, tertiary care, university-affiliated PICU. PATIENTS: Children admitted to the PICU and undergoing an invasive bedside procedure. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: During two 14-day periods, all bedside procedures conducted in the PICU were identified. Consent forms were reviewed, and parents and the healthcare providers who participated in the consent discussion were invited to complete a brief verbal questionnaire regarding the consent process. Quantitative data are presented using descriptive statistics and qualitative data were analyzed using thematic coding. During the study period, 50 bedside procedures were performed. Informed consent was not obtained for two emergent procedures. Only the first procedure on a child was included in the study, leaving 41 informed consent discussions for analysis. Consent was obtained in person in 33 cases (80%) and over the phone for the remainder. The median reported duration of the informed consent discussion was 5 mins. Ninety-six percent of parents correctly recalled what procedure had been performed, and 92% correctly recalled at least one reason for the procedure, but only 58% recalled at least one risk of the procedure. Parents viewed themselves as the primary decision makers, and many parents believed that their refusal of consent would be honored even if it would potentially harm the child. However, no parent refused or even significantly resisted giving consent for a procedure recommended by their child's healthcare provider. CONCLUSION: Parental consent for invasive bedside procedures in the PICU can be obtained reliably and without posing an undue time burden on healthcare providers. Most parents perceive a real decision making opportunity surrounding invasive procedures, but agree readily to the recommendations of their healthcare providers. PMID- 21297518 TI - Enteral potassium supplementation in a pediatric cardiac intensive care unit: evaluation of a practice change. AB - BACKGROUND: Potassium supplementation is a common practice in critically ill children, especially those with heart disease. Intravenous potassium supplementation is the standard route of administration in most intensive care units. Although the enteral route is safer and thus may be a reasonable alternative, data on the efficacy of enteral potassium administration are lacking. METHODS: A change of practice to encourage use of enteral potassium was instituted in the cardiac intensive care unit at Texas Children's Hospital, and a review of this practice change was undertaken. The primary outcome of interest was the comparable efficacy of enteral and intravenous potassium administration. Patient demographic data, including urine output, diuretic use, route of potassium administration, and adverse events were documented and analyzed. RESULTS: Seventy-six patients met inclusion criteria and received 399 bolus doses of potassium (166 intravenous and 233 enteral). No patients became hyperkalemic after either route of administration. The increase in serum potassium was similar in both groups of patients. Side effects of the two routes of administration were not different. CONCLUSIONS: The efficacy of enteral potassium is comparable to intravenous potassium for potassium replacement in pediatric patients after congenital heart surgery. PMID- 21297519 TI - A critical appraisal of Vlasselaers D, Milants I, Desmet L, et al: intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised controlled study. Lancet 2009; 373:547-556. AB - OBJECTIVE: To review findings and discuss implications of strict glycemic control in children. DESIGN: Critical appraisal of a randomized controlled trial. FINDINGS: This is the largest prospective randomized controlled trial to date, comparing intensive insulin therapy (glycemic targets: 50.4-79.2 mg/dL [2.8-4.4 mmol/L] and 70.2-99 mg/dL [3.9-5.5 mmol/L] [for infants and children, respectively]) and conventional insulin therapy (target: 180-215 mg/dl [10-11.9 mmol/L]) among critically ill children. Groups were similar at enrollment and had comparable forms of nutrition and glucose infusion rates. Steroid use and vasoactive-inotrope scores were not compared. Intensive insulin therapy reduced pediatric intensive care unit length of stay (primary outcome measure) and attenuated C-reactive protein concentrations >5 days. The effect of intensive insulin therapy on secondary outcome measures was precise in regards to significant reductions in secondary infection occurrence (absolute risk reduction = 7.6% [95% confidence interval: 0.6-14.4], number needed to treat = 14 [95% confidence interval: 7-179]) and need for vasoactive support beyond 2 days (absolute risk reduction = 10.4% [95% confidence interval: 3-17], number needed to treat = 10 [95% confidence interval: 6-30]). Mortality decreased with intensive insulin therapy (p = .038); however, this finding was imprecise (absolute risk reduction = 3.1% [95% confidence interval: 0.2-5.4], number needed to treat = 33 [95% confidence interval: 18.6-597.3]). The incidence of hypoglycemia was significantly higher with intensive insulin therapy (absolute risk increase = 23.5% [95% confidence interval: 20-25%], number needed to harm = 4 [95% confidence interval: 4-5]). Long-term effects on outcomes were not evaluated, and the authors recognize the need for such follow-up studies. This study demonstrated efficacy of intensive insulin therapy at the same institution where the original adult intensive insulin therapy trial was conducted, but it may not demonstrate effectiveness in populations other than postoperative cardiac patients, which composed the majority of patients enrolled or in institutions without a highly experienced nursing staff to manage intensive insulin therapy. CONCLUSIONS: This was a well-designed single-center trial that serves as proof of concept. The effects of intensive insulin therapy on mortality require further investigation, and its practice may need refinement to reduce the risk of hypoglycemia. In the meantime, targeting age-adjusted fasting glucose ranges cannot be routinely recommended in critically ill children. PMID- 21297520 TI - Routine inpatient human immunodeficiency virus testing system increases access to pediatric human immunodeficiency virus care in sub-Saharan Africa. AB - BACKGROUND: Routine Human Immunodeficiency Virus (HIV) testing, called provider initiated opt-out HIV testing and counseling (PITC), is recommended in African countries with high HIV prevalence. However, it is unknown whether PITC increases access to pediatric HIV care. In 2008, the Baylor International Pediatric AIDS Initiative implemented PITC (BIPAI-PITC) at a Malawian hospital. We sought to evaluate the influence of BIPAI-PITC, compared with nonroutine HIV testing (NRT), on pediatric HIV care access. METHODS: Retrospective data from 7077 pediatric inpatients were collected during sequential 4-month periods of NRT and BIPAI PITC. In-hospital and 1-year outcomes for 337 HIV-infected and HIV-exposed uninfected inpatients not previously enrolled in HIV care were analyzed to assess the clinical influence of each testing strategy. RESULTS: During BIPAI-PITC, a greater proportion of all hospitalized children received HIV testing (81.0% vs. 33.3%, P < 0.001), accessed inpatient HIV-trained care (7.5% vs. 2.4%, P < 0.001), enrolled into an outpatient HIV clinic after discharge (3.2% vs. 1.3%, P < 0.001), and initiated antiretroviral therapy (ART) after hospitalization (1.1% vs. 0.6%, P = 0.010) compared with NRT. Additionally, BIPAI-PITC increased the proportion of hospitalized HIV-infected and HIV-exposed uninfected children receiving DNA polymerase chain reaction testing (73.5% vs. 35.2%, P < 0.001), but did not improve outpatient enrollment or ART initiation of identified HIV infected patients. CONCLUSIONS: BIPAI-PITC increases access to inpatient and outpatient pediatric HIV care for hospitalized children, including DNA polymerase chain reaction testing and ART. Broader implementation of BIPAI-PITC or similar approaches, along with more pediatric HIV-trained clinicians and improved defaulter-tracking methods, would improve pediatric HIV service utilization globally. PMID- 21297521 TI - The impact of the heptavalent pneumococcal conjugate vaccine on the epidemiology of acute otitis media complicated by otorrhea. AB - BACKGROUND: The heptavalent pneumococcal conjugate vaccine (PCV7) has a considerable effect on the epidemiology of pneumococcal disease. The aim of this observational hospital-based study was to examine the effect of the PCV7 (introduced in our settings in 2004) on the epidemiology of spontaneously draining acute otitis media. METHODS: Results of all middle ear fluid cultures (n = 3446) obtained from children with acute otitis media complicated with otorrhea before the introduction of immunization (between 2000 and 2003) were compared with those (n = 2134) obtained during a similar post-PCV7 period (between 2005 and 2008). Results of cultures obtained between 2006 and 2008 were examined prospectively, whereas those obtained in previous years were retrospectively reviewed. RESULTS: Following PCV7 immunization, the rates of otorrhea visits per 10,000 emergency department visits decreased by 38% from 133 to 83 (95% confidence interval of the difference, 42-53; P < 0.001), mainly as a result of the decrease in the incidence of pneumococcal disease (48% decrease-25 vs. 13 per 10,000 emergency department visits; P < 0.001). Otorrhea due to Haemophilus influenzae decreased by 20% (20-16 per 10,000 visits; P < 0.001). Serotype 19A accounted for 1 of 47 (2%) pneumococcal strains in 2006, for 5 of 34 (15%) in 2007, and for 13 of 53 (25%) in 2008 (P for trend: 0.001). In the postvaccine years, penicillin-resistant pneumococcal strains (minimum inhibitory concentration >= 2 MUg/mL) increased from 4% to 13% (P < 0.001). However, the proportion of pneumococci resistant to macrolides decreased (44% vs. 35%; P = 0.01). CONCLUSIONS: After the introduction of immunization, otorrhea incidents decreased considerably, mainly because of the decrease in pneumococcal disease. H. influenzae is now the predominant organism. Serotype 19A has increased significantly and is the most common nonvaccine pneumococcal serotype. Penicillin resistance has increased in recent years. PMID- 21297522 TI - Drug-resistant tuberculosis: pediatric guidelines. AB - Drug-resistant Mycobacterium tuberculosis (TB) infection represents a serious and growing problem. For patients infected or suspected of being infected with multidrug or extensively drug-resistant TB, several medications have to be given simultaneously for prolonged periods. Here, we review the literature on treatment and monitoring of adverse effects of pediatric drug-resistant TB therapy in a high resource, low TB burden setting. PMID- 21297523 TI - Long-term response to GH therapy in short children with a delayed infancy childhood transition (DICT). AB - Transition of growth from infancy to childhood is associated with activation of the GH-IGF-I axis. Children with a delayed infancy-childhood transition (DICT) are short as adults. Thus, age at ICT may impact on growth response to GH. The objective was to investigate associations between growth response to GH treatment and ICT timing in children with idiopathic short stature (ISS) in a randomized, controlled, multicenter trial, TRN 88-080. A total of 147 prepubertal children (mean age, 11.5 +/- 1.4 y) were randomized to receive GH 33 MUg/kg/d (GH33, n = 43), GH 67 MUg/kg/d (GH67, n = 61), or no treatment (n = 43). Data on growth to final height (FH) were analyzed after categorization into those with normal (n = 76) or delayed ICT (n = 71). Within the GH33 group, significant height gain at FH was only observed in children with a DICT (p < 0.001), with each month of delay corresponding to gain of 0.13 SD score (SDS). For the GH67 group, the timing of the onset of the ICT had no impact on growth response. In conclusion, ISS children with a DICT responded to standard GH dose (better responsiveness), whereas those with a normal ICT required higher doses to attain a significant height gain to FH. PMID- 21297524 TI - The 1p13.3 LDL (C)-associated locus shows large effect sizes in young populations. AB - Genome-wide association studies (GWASs) have identified polymorphic loci associated with coronary artery disease (CAD) risk factors (i.e. serum lipids) in adult populations (42-69 y). We hypothesized that younger populations would show a greater relative genetic component due to fewer confounding variables. We examined the influence of 20 GWAS loci associated with serum lipids and insulin metabolism, in a university student cohort (n = 548; mean age = 24 y), and replicated statistically associated results in a second study cohort of primary school students (n = 810, mean age = 11.5 y). Nineteen loci showed no relationship with studied risk factors in young adults. However, the ancestral allele of the rs646776 (SORT1) locus was strongly associated with increased LDL (C) in young adults [TT: 97.6 +/- 1.0 mg/dL (n = 345) versus CT/CC: 87.3 +/- 1.0 mg/dL (n = 203); p = 3 * 10(x6)] and children [TT: 94.0 +/- 1.3 mg/dL (n = 551) versus CT/CC: 84.7 +/- 1.4 mg/dL (n = 259); p = 4 * 10(x6)]. This locus is responsible for 3.6% of population variance in young adults and 2.5% of population variance in children. The effect size of the SORT1 locus is considerably higher in young populations (2.5-4.1%) compared with older subjects (1%). PMID- 21297525 TI - Diagnosis of irritable bowel syndrome: what are we missing? PMID- 21297526 TI - Algorithm for the management of osteoporosis. PMID- 21297527 TI - Clinical characteristics and evaluation of patients with large hiatal hernia and Cameron lesions. AB - OBJECTIVES: Cameron lesions are located at the neck of large hiatal hernias, and are associated with anemia or overt gastrointestinal (GI) bleeding. The aim of this study was to investigate the clinical and endoscopic properties of patients with Cameron lesions. METHODS: Eighteen patients were diagnosed as having large hiatal hernia and Cameron lesions. Patients with Cameron lesions (n = 18) were compared to patients with large hiatal hernias without Cameron lesions (n = 26), by means of presenting symptoms and endoscopic findings. RESULTS: The mean age of patients with Cameron lesions was significantly higher than patients without Cameron lesions (71.1 +/- 11.63 vs 56.7 +/- 17.4 years, P = 0.005). The ratio of female patients with Cameron lesions was higher compared to patients with large hiatal hernia without Cameron lesions (14/18 [77.7%] vs 12/26 [46.1%], P = 0.00). While 12 of 18 patients with Cameron lesions had overt GI bleeding, none of the patients with large hiatal hernia without Cameron lesions had signs of GI bleeding. Fifteen of 18 patients had ulcers in the hernia sac and the others had linear erosions. There was no significant difference between patients with and without Cameron lesions by means of hemoglobin levels (11.1 +/- 2.20 vs 12.2 +/- 2.5 g/dL, P = 0.157). CONCLUSION: Most patients with large hiatal hernia and Cameron lesions presented with overt GI bleeding. Patients with Cameron lesions tend to be older females. In patients with anemia and GI bleeding, large hiatal hernia and Cameron erosions should also be considered. PMID- 21297528 TI - Polycystic ovary syndrome: focus on platelets and prothrombotic risk. AB - OBJECTIVES: Subjects with polycystic ovary syndrome (PCOS) were shown to carry an increased long-term cardiovascular risk. Systemic inflammation and reactive leukocytosis have also been described in PCOS. Recent research suggests the presence of an increased thrombotic risk in these patients. METHODS: We describe a cohort of PCOS patients presenting with persistent thrombocytosis. Our cohort included women aged 20-37 who also had moderate leukocytosis and neutrophilia. They showed normal mean platelet volume and platelet aggregation. We excluded any myeloproliferative conditions in all patients. RESULTS: The mean platelet count and standard deviation (SD) at presentation were 587 +/- 61 * 10/L (normal 140 440 * 10/L). Median C-reactive protein (CRP) was 1.66 (range 1.2-2.2, normal <1 mg/dL). The platelet counts did not correlate with the CRP levels in our patients (Pearson correlation coefficient 0.171 and 0.170, respectively, P = 0.08). CONCLUSION: While the inflammatory state of PCOS could play a role in triggering an increased platelet count, the persistent thrombocytosis in our patients did not correlate with the CRP levels. Therefore, from an etiological perspective, thrombocytosis appears to be at least partially independent from the classical pathways of systemic inflammation. The preexisting procoagulant state in PCOS due to coagulation cascade stimulation, platelet activation, and endothelial dysfunction may be further fueled by the presence of persistent thrombocytosis. We propose a unique model for cardiovascular risk assessment in women with PCOS to include not only the classic cardiovascular risk factors, but also the parameters related to the proinflammatory and procoagulant tendencies manifested in PCOS. PMID- 21297529 TI - Ischemic heart disease in women: a review for primary care physicians. AB - Ischemic heart disease (IHD) is the leading cause of death among women in the Western world, and its prevalence is growing. The pathophysiology of heart disease in women differs from that in men. Women with chest pain and abnormal stress tests are less likely than men to have critical stenosis of coronary arteries, a phenomenon attributed to endothelial dysfunction. Hypertension, intimal injury, and cholesterol are among the various factors that contribute to endothelial dysfunction. The presenting symptoms of IHD also differ in women. Women are more likely to describe neck and throat pain and to characterize the pain as intense, sharp, or burning. A history of coronary or other vascular disease, diabetes, or chronic kidney disease places patients at high risk for IHD. Risk factor modification can be tailored based on each patient's risk. Hormone replacement therapy, antioxidants, folic acid, and aspirin in healthy women under 65 years of age have recently been shown to be ineffective in the prevention of IHD. PMID- 21297531 TI - Cutaneous metastatic rectal carcinoma masquerading as herpes zoster. AB - A 78-year-old female with locally recurrent rectal carcinoma and hepatic metastases presented with new skin lesions. She had multiple painful skin lesions over her groin area initially treated as contact dermatitis. The lesions continued to spread to include the lower abdomen and developed a zosteriform appearance. She was referred to dermatology, where shave biopsies revealed metastatic rectal carcinoma. This case is unique as the patient had rapidly growing zosteriform cutaneous metastases from rectal carcinoma, which has rarely been reported. Physicians providing care to patients with a history of cancer should maintain a high clinical suspicion for cutaneous metastases in patients with new or evolving skin conditions. PMID- 21297532 TI - Hepatitis B vaccination coverage levels among nurses in Greece: need for improvement. AB - OBJECTIVES: : The aims of this study were to estimate the hepatitis B vaccination coverage levels among nurses and understand the reasons for receiving or not receiving the preventive vaccination. METHODS: : This cross-sectional study was based on a self-reported questionnaire, which was administered to 788 nurses working in 17 hospitals in Greece. RESULTS: : Overall, 606 out of 784 participants (77.3%) completed the survey. Of these, 63.2% nurses reported that they were fully vaccinated. The majority of immunized nurses (66%) were female (P = 0.008), and 72.6% of the fully-vaccinated nurses were working in Intensive Care Units (ICUs). CONCLUSIONS: : This study showed that almost 40% of nurses are not protected against hepatitis B infection. There is a need for a more aggressive approach to increase the vaccination coverage among nurses. PMID- 21297533 TI - Low-grade fibromyxoid sarcoma arising in the big toe. AB - Low-grade fibromyxoid sarcoma (LGFMS) is a rare neoplasm commonly affecting young adults and typically arising in the somatic soft tissue of the proximal extremities. Its occurrence within the big toe is exceedingly rare. A 43-year-old man had surgery on a mass located in the big toe, which was first noted 6 months previously. Histological examination revealed LGFMS. One year after surgery, the patient is alive with no evidence of disease. Low-grade fibromyxoid sarcoma is a rare neoplasm that should be considered in the differential diagnosis of spindle cell neoplasms of the foot. PMID- 21297534 TI - Diagnosing irritable bowel syndrome: a changing clinical paradigm. AB - Rather than being a diagnosis of exclusion, irritable bowel syndrome (IBS) is a diagnosis that can be identified by symptom-based criteria. The collection of these criteria by a meticulous history can be enhanced by using various tools. Once a positive diagnosis is made, using clinical criteria for diagnosis, one should look for alarm or warning symptoms or signs, and should characterize the type of bowel habit. Determining whether the condition is a diarrhea-predominant or a constipation-predominant IBS will direct further diagnostic evaluation and management. PMID- 21297535 TI - Platypnea-orthodeoxia: bilateral lower-lobe pulmonary emboli and review of associated pathophysiology and management. AB - Platypnea-orthodeoxia is a rare syndrome characterized by dyspnea and arterial deoxygenation, which is exacerbated in an upright position and relieved with recumbency. We report a case of platypnea-orthodeoxia in a 56-year-old male who was found to have bilateral lower-lobe pulmonary emboli. He did not have any evidence of an intracardiac shunt. A comprehensive review of the pathophysiology and management of platypnea-orthodeoxia is provided. PMID- 21297536 TI - Proximal intercessory prayer. PMID- 21297537 TI - Helicobacter pylori and beta-2 microglobulin levels. PMID- 21297538 TI - Bariatric surgery for diabetic nephropathy. PMID- 21297539 TI - Isolated abdominal pain: should colonic investigation be performed? PMID- 21297540 TI - Tuberous sclerosis and neurocysticercosis. PMID- 21297541 TI - Prolonged sinus pauses with hydromorphone in the absence of cardiac conduction disease. AB - A 49-year-old male had open sigmoid colectomy with colorectal anastomosis for sigmoid diverticulitis. The patient was given patient-controlled analgesia (PCA) hydromorphone and subsequently developed bradycardia with prolonged sinus pauses up to 7.1 seconds. The pauses resolved shortly after the hydromorphone was discontinued. This is the first case report to our knowledge of reversible prolonged sinus pauses associated with the use of hydromorphone. Animal studies support a role for opioid signaling at the sinoatrial (SA) node. Hydromorphone is a potential cause of prolonged sinus pauses and should be taken into consideration when monitoring a patient on hydromorphone for pain control. PMID- 21297542 TI - Lemierre syndrome caused by group C streptococci and associated with red cell aplasia and immune thrombocytopenia. PMID- 21297543 TI - Hydatid cyst disease: optimal management of complex liver involvement. AB - The most frequent location of hydatid cystic lesions is in the liver (up to 80% of cases), followed by the lung (about 20% of cases), and with lower reported incidence, virtually in any other organ or tissue in the body. Therefore, the case an American medical practitioner would most likely encounter, albeit still rare, is a large, symptomatic liver cyst, similar to the one presented in this report. Current techniques and reasoning concerning optimal treatment of liver hydatid cyst disease are revisited, and recommendations based on available literature regarding ideal management of such cases are presented. PMID- 21297544 TI - Safety of conscious sedation in patients with sleep apnea in a veteran population. AB - OBJECTIVES: Due to the presumed higher risk of cardiopulmonary complications in patients with obstructive sleep apnea (OSA), many endoscopy centers consider OSA a contraindication to using conscious sedation. We evaluated the safety of conscious sedation during endoscopy for patients with OSA in a veteran population, and compared this to patients without OSA. METHODS: Polysomnography studies were reviewed from 2004 to 2009 to identify 200 patients with OSA who had undergone endoscopy. Controls included the last 200 consecutive endoscopies in this institution for patients without OSA. Sixty-three upper endoscopies, 136 colonoscopies, and one enteroscopy were included in the OSA group. Sixty-five upper endoscopies, 133 colonoscopies, one sigmoidoscopy, and one endoscopic ultrasound comprised the control group. Data obtained included demographics, medications prescribed, and any complication noted in the procedure report. RESULTS: No complications occurred in the control group. In the OSA group, a patient experienced oxygen desaturation during an upper endoscopy and required oxygen supplementation. The procedure was completed and did not require an extended stay in the endoscopy suite. CONCLUSION: This study demonstrated that endoscopy can be safely done in OSA patients using conscious sedation, and the complication rate is not significantly different than patients without OSA. PMID- 21297545 TI - Current management of salicylate-induced pulmonary edema. AB - Salicylate-induced pulmonary edema (SIPE) can occur in both acute and chronic users of aspirin or salicylate products. The medical history, especially when it reveals the use of salicylates, is critical when considering this diagnosis. Unfortunately, the neurologic and systemic effects of salicylate toxicity may hinder the ability to obtain a reliable medical history. SIPE should be considered in patients who present with pulmonary edema and neurological changes, anion-gap metabolic acidosis, or possible sepsis. Some patients may be treated for "pseudosepsis" or other conditions, thereby delaying the diagnosis of salicylate intoxication. Misdiagnosis and possibly delayed diagnosis of SIPE can lead to a significant increase in morbidity and mortality. Serum and urine alkalinization by administration of intravenous sodium bicarbonate are commonly utilized therapeutic strategies. Finally, hemodialysis is a therapy which should be considered early in the course of treatment. The objective of this review was to emphasize the importance of rapid diagnosis and appropriate treatment in patients with SIPE, and summarize the current literature as it relates to the adult population. PMID- 21297546 TI - Systemic mastocytosis-associated leonine facies and eyebrow loss. AB - Leonine facies or loss of eyebrows, or both, occurring concurrently or in succession, can be associated with numerous etiologies. A 62-year-old woman with systemic mastocytosis who developed both leonine facies and eyebrow loss is described. The differential diagnosis of neoplasms that may present with leonine facies is summarized and conditions characterized by concurrent or sequential eyebrow loss and leonine facies are reviewed. PMID- 21297547 TI - Prophylaxis with ertapenem in patients with obstructive jaundice undergoing endoscopic retrograde cholangiopancreatography: safety, efficacy, and biliary penetration. AB - BACKGROUND: Cholangitis and biliary sepsis are rare but serious complications of endoscopic retrograde cholangiopancreatography (ERCP). The aim of this study is to investigate the safety, efficacy, and biliary penetration of ertapenem, a newer carbapenem with a long half-life and broad-spectrum antimicrobial activity, for ERCP prophylaxis. METHODS: Patients with obstructive jaundice without cholangitis received a single dose of ertapenem equal to 1 gram intravenously prior to ERCP. A 2-3 mL bile sample was collected after cannulation and prior to contrast injection. Patients were observed for 72 hours for cholangitis or drug related adverse events. Biliary ertapenem levels were measured using high performance liquid chromatography (HPLC). RESULTS: Twenty-eight patients (ages 18 87 years, M/F ratio 1:1) were enrolled. Seven had no cholestasis and were included to study ertapenem penetration in unobstructed biliary trees. Cannulation was achieved in all patients. One patient (3.6%) with persistent intrahepatic stones developed cholangitis. No drug-related adverse events were noted. The mean time from ertapenem administration to bile collection was 60 +/- 24 minutes. There was a significant negative correlation between serum bilirubin and biliary ertapenem levels (r = -0.542, P = 0.003) with the highest level (6.25 MUg/mL) noted in unobstructed biliary systems. CONCLUSION: Ertapenem appears to be a safe and effective prophylaxis in patients with obstructive jaundice undergoing ERCP despite a limited biliary penetration in patients with high-grade obstruction. PMID- 21297548 TI - Bloodstream infection with Anaerobiospirillum succiniciproducens: a potentially lethal infection. AB - Anaerobiospirillum succiniciproducens (A succiniciproducens), a spiral, Gram negative anaerobic rod which is part of the normal intestinal flora of cats and dogs, has rarely been reported as a cause of bacteremia and diarrhea in humans, particularly in immunocompromised hosts. Although it can be associated with significant mortality, the full extent of its pathogenicity, clinical spectrum, and optimal therapy remain to be determined. We review the available literature on microbiology, clinical manifestations, and treatment options for Anaerobiospirillum infection. PMID- 21297549 TI - Preferable colonic investigations for isolated abdominal pain. AB - OBJECTIVES: Isolated abdominal pain is seen as a poor indication for colonic investigations. The yield of serious pathology detected by optical colonoscopy (OC) has differed greatly in published series. This study aims to establish the yield of colonic investigations for isolated abdominal pain. METHODS: A retrospective analysis of the endoscopy database was undertaken on all OCs performed from 2000 to 2008. The yield of OCs for detection of pathology (polyps, cancers, and inflammatory bowel disease) was compared for the symptoms of abdominal pain, chronic diarrhea, or anemia. Data on computed tomographic colonographies (CTC), performed for isolated abdominal pain in 2008, were used to compare the yield of CTCs and OCs. RESULTS: Of the 8564 OCs and 525 CTCs performed, 5.4% and 8.2% were undertaken for isolated abdominal pain, respectively. The yield of OCs for overall pathology detection was not significantly different for abdominal pain (23.87%), compared to other indications (20.34-24.85%). The yield of pathology detection was not significantly different for CTC (20.93%) and OC. Colonic polyps were the most common pathology (OC 16.05%, CTC 18.6%). CONCLUSION: Colonic investigations undertaken for isolated abdominal pain had a high yield of incidental colonic pathology. The detection of polyps could be beneficial, but it does not explain the symptoms. CTC offers a less invasive way of detecting colonic pathology in such patients, while maintaining the same yield. If CTC is used as a first line of investigation, it could spare 75% of patients the colonoscopy procedure. PMID- 21297550 TI - Simultaneous quantification of levetiracetam and gabapentin in plasma by ultra pressure liquid chromatography coupled with tandem mass spectrometry detection. AB - INTRODUCTION: Gabapentin (Neurontin) and levetiracetam (Keppra) are anticonvulsants with novel structures and suggested therapeutic ranges of 2-10 mg/L and 6-20 mg/L, respectively. Gabapentin is also used extensively to manage neuropathic pain, and for this indication, wherein higher doses are prescribed, plasma concentrations of 15-30 mg/L are typical. OBJECTIVE: Here, we describe a simple rapid assay to support therapeutic drug monitoring of gabapentin and levetiracetam in plasma by ultra-pressure liquid chromatography couples to tandem mass spectrometry (UPLC-MS/MS) detection. METHODS: After the addition of internal standard and protein precipitation of patient plasma with methanol:acetonitrile in a 50:50 ratio, 1 MUL of supernatant sample is injected onto an Acquity UPLC HSS T3, 1.8 MUm, 2.1 * 50 mm (Waters) column. Elution occurs using a linear gradient of acetonitrile and water, each having 0.1% formic acid added. The column is eluted into a Waters Acquity UPLC TQD, operating in a positive mode to detect gabapentin at transition 172.18 > 154.11, levetiracetam at 171.11 > 126, and internal standard (3-amino-2-naphthoic acid) at 188.06 > 170. Secondary transitions for each analyte are also monitored for gabapentin at 172.18 > 137.06, levetiracetam at 171.11 > 154, and internal standard at 188.06 > 115. Runtime is 1.5 minutes per injection with baseline resolved chromatographic separation. RESULTS: The analytical measurement ranges were 1-150 mg/L for gabapentin and for levetiracetam. Intra-assay imprecision by the coefficient of variance (CV) was less than 8% and interassay CV was less than 5% for both analytes, at 4 different concentrations. Results obtained from patient samples were compared with results generated by established high-performance liquid chromatography-UV methods with the following regression statistics: y = 1.12x - 0.77, r = 0.996, Sy, x = 0.89, and n = 29 for gabapentin and y = 0.991x + 0.70, r = 0.997, Sy, x = 2.24, and n = 30 for levetiracetam. No analytical interferences were identified. CONCLUSION: : In summary, a simple reliable UPLC-MS/MS method was developed and validated for routine clinical monitoring of gabapentin and levetiracetam. PMID- 21297551 TI - How does auxiliary liver transplantation regulate alloreactivity in sensitized kidney transplant patients? PMID- 21297552 TI - The 5-year outcome of ABO-incompatible kidney transplantation with rituximab induction. AB - BACKGROUND: In 2002, we introduced the anti-CD20 chimeric antibody, rituximab, for ABO-incompatible kidney transplantation (ABO-IKT). Here, we report the 5-year outcome obtained using rituximab as part of the preoperative regimen for ABO-IKT. METHODS: Between January 2002 and December 2008, 408 patients underwent living related kidney transplantation at our department. The patients were divided into three groups: group A (n=280), ABO-compatible kidney transplantation (ABO-CKT); group B (n=63), ABO-IKT without rituximab induction; and group C (n=50), ABO-IKT with rituximab induction. Basic immunosuppression was the same in all three groups except for the use of rituximab, which was administered at 100 mg (n=6), 200 mg (n=26), and 500 to 1000 mg (n=18). RESULTS: The graft survival rates in groups A, B, and C were 99.2%, 96.8%, and 100% at 1 year, 93.8%, 94.9%, and 100% at 3 years, and 88.4%, 90.3%, and 100% at 5 years after transplantation, respectively. Serum creatinine levels in the three groups were not different at 1, 3, and 5 years after transplantation. The numbers of episodes of acute antibody-mediated rejection in groups A, B, and C were 7 (2.5%), 10 (15.9%), and 2 (4.0%), respectively (P=0.651), and acute cellular rejection was observed in 40 (14.3%), 6 (9.5%), and 2 (4.0%) patients, respectively (P=0.0957). There was no increased risk of cytomegalovirus infection in group C. CONCLUSIONS: In the long term, inclusion of rituximab in the preoperative regimen yielded an even better outcome than that of ABO-CKT and rituximab-untreated ABO-IKT, without any increase in the risk of infection. PMID- 21297553 TI - Safety and efficacy of intensified versus standard dosing regimens of enteric coated mycophenolate sodium in de novo renal transplant patients. AB - BACKGROUND: Efficacy and safety of an intensified dosing (ID) regimen of enteric coated mycophenolate sodium (EC-MPS), which achieves higher mycophenolic acid exposure early posttransplantation, were evaluated in comparison with a standard dosing (SD) regimen. METHODS: In total, 128 de novo kidney transplant recipients treated with basiliximab induction, cyclosporine A, and steroids were randomized (1:1) to receive EC-MPS as SD (1440 mg/day; n=65) or ID (days 0-14: 2880 mg/day; days 15-42: 2160 mg/day; followed by 1440 mg/day; n=63). Efficacy parameters, safety, and tolerability were assessed over a 6-month study period. The primary endpoint was mean time to first occurrence of treatment failure. RESULTS: Mean time to treatment failure was 130 days (95% confidence interval [CI]: 81-n/a) in the ID group versus 114 days (95% CI: 15-155) in the SD group (P=0.36). Similar percentages (ID 30.2%; SD 36.9%) experienced treatment failure. Biopsy-proven acute rejection occurred in 2 (3.2%) ID versus 11 (16.9%) SD patients (P<0.001). Three (2.3%) deaths (2 SD, 1 ID) and five (3.9%) graft losses (3 SD, 2 ID) occurred. Renal function, incidence of infection, and hematologic disorders were comparable in both study cohorts. Gastrointestinal disorders occurred in 51 (81.0%) ID and 49 (75.4%) SD patients with overall similar tolerability as assessed by the Gastrointestinal Symptom Rating Scale. CONCLUSION: In this exploratory study, the EC-MPS ID regimen reduced the incidence of rejection and showed a comparable safety and tolerability profile to SD. Further examination of this approach in a larger patient cohort is now warranted to confirm these findings. PMID- 21297554 TI - Rapamycin impairs proliferation of transplanted islet beta cells. AB - BACKGROUND: The cause for a progressive attrition of islet graft function observed over the years after islet transplantation is not well defined but may be in part the result of adverse effects of immunosuppressive agents. In this study, we examined the effect of rapamycin, a key component of the immunosuppressive regimen, on beta-cell replication of transplanted islets. METHODS: Mice transplanted with rat islets under kidney capsule received bromodeoxyuridine for 7 days. Mice were treated with rapamycin or appropriate vehicle. beta-cell replication was determined by double immunofluorescence staining for insulin and bromodeoxyuridine. For in vitro studies, apoptosis, glucose-stimulated insulin secretion, and proliferation were determined in islet cells incubated with EdU in the presence or absence of rapamycin. RESULTS: In our islet transplant model, rapamycin impaired glucose tolerance and beta-cell proliferation of transplanted and host islets. In vitro, rapamycin reduced glucose-stimulated insulin secretion and reversibly decreased beta-cell replication. The inhibitory effect of rapamycin on beta-cell proliferation was not due to the decrease in insulin release. Additionally, in islet cells, expression of cell cycle proteins was significantly modified by rapamycin, suggesting a blockade of cell cycle progression. Inhibition of p38MAPK partially reverted rapamycin effect on beta-cell proliferation. CONCLUSION: Rapamycin, at concentration usually used to prevent islet graft rejection, is able to reduce the rate of beta-cell proliferation in transplanted rat islets but also in host murine islets. These data suggest that the progressive islet graft dysfunction observed under immunosuppressive therapy may result in part from an impairment of beta-cell regeneration. PMID- 21297555 TI - Heart transplant patient outcomes: 5-year mean follow-up by coronary computed tomography angiography. AB - BACKGROUNDS: We evaluate the feasibility and safety of coronary computed tomography angiography (CCTA) as the first-line investigation in heart transplant patients and the rate of coronary allograft vasculopathy detected using CCTA. METHODS: From September 2003 to June 2009, we prospectively included 65 heart transplant recipients, retaining 62 who underwent yearly CCTA for coronary allograft vasculopathy detection (261 CCTAs). We used 16-slice, 64-slice, and 2*64-slice CT machines. Patients with coronary artery stenosis by CCTA had a confirmation and a further follow-up exclusively by conventional coronary angiography (CCA). RESULTS: No major coronary events occurred during the study. Of the 62 baseline CCTAs, 37 (60%) were normal, 18 (29%) showed wall thickening, and 7 (11%) known significant stenosis, confirmed by CCA. The mean follow-up duration was 5 years. At the last follow-up, 26 (70%) patients with normal baseline findings remained normal, 9 (24%) had wall thickening, and 2 (6%) significant stenoses. Time to stenosis was consistently greater than 3 years. Of the 18 patients with initially wall thickening, 14 (78%) had wall thickening and 4 (22%) significant stenosis at last follow-up. The mean interval without any coronary lesion was 9.46+/-3.98 years. The mean interval without de novo significant stenosis was 10.31+/-4 years. CONCLUSIONS: CCTA seems to be a safe noninvasive tool for monitoring heart transplant patients, and thus obviating the need for CCA. In patients with normal baseline CCTA, a 2-year interval between CCTAs may be safe. PMID- 21297556 TI - Pyomyositis after chemotherapy for endometrial cancer. AB - Pyomyositis is a rare complication of chemotherapy that is commonly seen in tropical climates and in patients with immunodeficiency states. Owing to its rarity and subacute presentation, its diagnosis is often delayed. It has been reported after intense chemotherapy for hematological cancers. We present a case of a 58-year-old woman with endometrial cancer who developed pyomyositis after the first cycle of carboplatin and paclitaxel with no prior predisposing factor except for cancer and premedication with corticosteroids. The patient improved once the diagnosis was established and managed with antibiotics and drainage of abscess. Full recovery was made with a protracted course of antibiotics.Early diagnosis of this entity with appropriate investigations and treatment prevents septicemia, which can often be life threatening. PMID- 21297557 TI - A review on strength exercise-induced muscle damage: applications, adaptation mechanisms and limitations. AB - This study aims to review the main aspects that induce muscle damage, and to discuss the adaptations of this phenomenon, applications and limitations of this study area. Damage induced by strength training has been utilized for two purposes: 1) verification of the recovery period required between training sessions, which has a direct influence on designing exercise programs; and 2) as indication for higher training intensity, mainly in studies on the "repeated bout effect". There is some speculation about the role of muscle damage in inducing hypertrophy. However, studies demonstrate that exercise-induced muscle damage may not be a consistent indicator of higher chronic hypertrophic response, because hypertrophy also occurs in training strategies with very low mechanical overloads. In addition, aerobic exercise, also induces muscle damage, exhibits no hypertrophic response after training. The remodeling process induced bay muscle damage promotes alterations to strength x length relationship for stretched positions, indicating an increased number of sarcomeres in series, due to strength exercises. Therefore, the study on strength exercise-induced damage seems to be adequate for implementing adequate rest periods to recovery from different sessions of strength training, and not to suggest chronic hypertrophy. PMID- 21297558 TI - Effect of acute caffeine ingestion on EPOC after intense resistance training. AB - AIM: This study investigated the effect of acute caffeine (CAF) intake on postexercise oxygen consumption (EPOC) after intense resistance training. METHODS: Fourteen strength-trained men (mean +/- SD age and mass =23.1 +/- 4.2 yr and 83.4 +/- 13.2 kg, respectively) who were caffeine users initially completed one-repetition maximum testing (1-RM) of four exercises: bench press, leg press, lat row, and shoulder press. On each of two days separated by one week, they completed four sets of each exercise to fatigue at 70-80% 1-RM, which was preceded by ingestion of CAF (6 mg/kg) or placebo. Pre-exercise, indirect calorimetry was used to assess energy expenditure for 35 min; this was repeated for 75 min postexercise while subjects remained seated in a quiet lab. Two-way analysis of variance with repeated measures was used to examine differences in gas exchange variables across time and treatment. RESULTS: Results revealed that EPOC was significantly higher (P<0.05) with CAF (26.7 +/- 4.1 L) compared to placebo (22.8 +/- 3.8 L). With CAF ingestion, oxygen uptake was significantly higher (P<0.05) from 10 min pre-exercise to 70 min postexercise. Respiratory exchange ratio was significantly different (P<0.05) with CAF versus placebo. Caffeine intake increased total energy expenditure by 15% (P<0.05), but the additional calories burned was minimal (+27 kcal). CONCLUSION: Caffeine ingestion in individuals regularly completing rigorous resistance training significantly increases EPOC and energy expenditure pre-and post-exercise, yet the magnitude of this effect is relatively small. PMID- 21297559 TI - Is repeated-sprint ability of soccer players predictable from field-based or laboratory physiological tests? AB - AIM: The aim of this study was to investigate multiple regression models with prediction equations that would enable a valid estimate of running repeated sprint ability (RSA) in soccer players from the variables measured in field and laboratory physiological tests. METHODS: Adolescent soccer players (N=33) performed five field performance tests and two laboratory tests for assessment of muscle strength of legs, sprint ability, anaerobic power and capacity, aerobic power and capacity, and running economy. These tests served as potential predictors of RSA. RSA was assessed by a intermittent anaerobic running test (IAnRT) consisted of ten 20 m sprints. RESULTS: Multiple regression analysis revealed that the mean speed in the 20 m sprint test and the 2 km endurance running test accounted for 89% of total variation in the mean running speed in the IAnRT (VIAnRT) as the indicator of capacity for multiple sprint work (R2=0.89, SEM=0.09 m.s-1). Using the variables from the laboratory tests, the best prediction of the VIAnRT was obtained from the running speed at the ventilatory threshold level (VVT) and anaerobic power (Pmax.kg-1) (R2=0.49, SEM=0.21 m.s-1). CONCLUSION: Performance in the multiple-sprint exercise as an indicator of RSA can be estimated by the regression equation with two predictors mean speed in the 20 m sprint and 2 km running test with an error of 4%. PMID- 21297560 TI - Relationship among maximal grip, throwing velocity and anthropometric parameters in elite water polo players. AB - AIM: As independent aspects, body size, body composition, and physiological performance of elite athletes have aroused the interest of sports scientists but, unfortunately, studies that combine these aspects are scarcely avalaible in water polo. The aim of the present study was to: 1) to develop an anthropometric profile of highly skilled male Water Polo players, and 2) to identify significant relationships between these features and overhead throwing velocity in highly skilled male water polo players. METHODS: Thirteen male water polo players, with a mean age of 26.10+/-4.82, were recruited from the Spanish Water Polo team and an anthropometric assessment on all of them was carried out. Throwing velocity was evaluated in three different situations from the 5 m-penalty line on the center of the water polo goal: A) throwing without a defender nor a goalkeeper; B) throwing with a goalkeeper only, and C) 3) armfuls running shot with goalkeeper. Maximal handgrip was also tested. RESULTS: Biacromial breadth shows a significative correlation with hand grip in water polo players (r=0.792; P=0.001) and also correlates with Throwing velocity (r=0.716; P<0.001). Biepicondylar femur breadth correlates significatively with hand grip (r=0.727; P<0.05) and also with throwing velocity in "throwing with goalkeeper" situation (r=0.664; P<0.05). Hand grip shows a significant correlation with throwing velocity in "throwing with goalkeeper" situation (r=0.603; P<0.05). CONCLUSION: In conclusion, body mass aspects are not related with throwing velocity in highly skilled Water Polo players. Maximal hand grip is related with throwing velocity in "throwing with goalkeeper" situation. More investigations about water polo are necessary. PMID- 21297561 TI - Validity and reliability of the single-trial line drill test of anaerobic power in basketball players. AB - AIM: This study evaluated the validity, reliability, and sensitivity of the single-trial line drill test (SLDT) for anaerobic power assessment. METHODS: Twenty-four volunteers were assigned to either a control (C, N.=12) or an experimental (BP, N.=12 basketball players) group. SLDT's (time-to-complete) concurrent validity was evaluated against the Wingate testing (WAnT: mean [MP] and peak power [PP]) and a 30-sec vertical jump testing test (VJT: mean height and MP). Blood lactate concentration was measured at rest and immediately post test. SLDT's reliability [test-retest intraclass correlation coefficients (ICC), coefficient of variation (CV), Bland-Altman plots] and sensitivity were determined (one-way ANOVA). RESULTS: Kendall's tau correlation analysis revealed correlations (P<0.05) between SLDT time and WAnT's PP (=0.78) and MP (=0.56) and VJT's MP (=0.85) and height (=0.90). SLDT lactate concentration was moderately (P<0.05) correlated with the respective lactate values of WAnT (=0.40) and VJT (=0.66). SLDT time in BP correlated (P<0.05) with VJT's MP (=0.80) and height (=0.90) but not with WAnT performance variables. SLDT lactate responses in BP were moderately (P<0.05) correlated with WAnT's PP (=0.54) and VJT MP (=0.68), height (=0.65), and lactate concentration (=0.65). ICCs for time and lactate were 0.92 and 0.93, respectively (P<0.05) although Bland-Altman plots and CV indicate that SLDT time demonstrated greater reliability than lactate responses. In all tests, BP demonstrated higher (P<0.05) performance levels compared to C indicating an adequate sensitivity for SLDT. CONCLUSION: Results suggest that the SLDT appears to be a valid, reliable, and sensitive field test of anaerobic capacity for basketball players. PMID- 21297562 TI - Reliability and validity of the lactate-minimum test. A revisit. AB - AIM: The Lactate-Minimum Test (LMT) is a high-resolution, physiologically elegant test for estimating the anaerobic threshold (AnT), or the Maximal Lactate Steady State (MLSS). Nevertheless, it has not gained the acceptance level of typical progressive lactate-response tests (PLRT). Aim of this study was to compare LMT's validity and reviewer reliability vs. a PLRT-type test and re-evaluate the justification for LMT's dismissal. METHODS: Sixteen male distance trained runners (37.1+/-11.6 yrs) were included in the study. MLSS, LMT, and PLRT tests were performed in separate sessions. Two reviewers, blind to the subjects' identity, independently determined LMT and PLRT's threshold velocities (VLMT, VPLRT) twice. Additionally, VLMT was determined objectively, using best-fit polynomial regressions (VLMTP). RESULTS: VPLRT, VLMT and VLMTP correlated well with VMLSS (r=0.92, 0.90, 0.93, resp.). VPLRT was identical to VMLSS (13.54 km.h-1), but VLMT and VLMTP were 0.33 and 0.46 km.h-1 lower, respectively. Inter-reviewer reliability was higher for VLMT than VPLRT (ICC=0.96 vs. 0.57, resp.). Intra reviewer reliability showed a similar pattern. CONCLUSION: LMT's underestimation of MLSS appears corrigible. The validity of corrected LMT appears comparable to that of PLRT, while its reliability, objectivity and resolution are superior. Although neither test is a perfect MLSS-substitute, the corrected LMT is not inferior to PLRT-type testing and cannot be dismissed. PMID- 21297563 TI - Effects of plyometric training on explosive strength, acceleration capacity and kicking speed in young elite soccer players. AB - AIM: The main aim of this study was to determine the effects of a 10-week plyometric training program on explosive strength, acceleration capacity and kicking speed in young elite soccer players. METHODS: Twenty-two players participated in the study: control group (CG), (N.=11; 18.2 +/- 0.9 years) and treatment group (TG) (N.=11; 18.4 +/- 1.1 years). Both groups performed technical and tactical training exercises and matches together. However, the CG players followed the regular physical conditioning program, which was replaced by a plyometric program for TG. Plyometric training took place three days a week and included jumps over hurdles, horizontal jumps and lateral jumps over hurdles. Jumping ability, 10 m sprint and kicking speed were measured on five separate occasions. RESULTS: Two-way analysis of variance (ANOVA) with repeated measures reflected that the TG demonstrated significant increases (P<0.05) in jumping ability and acceleration capacity after six weeks of training and in kicking speed with dominant and non-dominant leg after eight and ten weeks respectively. On the other hand there were no significant changes in CG players throughout the study. CONCLUSION: The main findings revealed that a 10-week plyometric program may be an effective training stimulus to improve explosive strength compared to a more conventional physical training program. The improvements in explosive strength can be transferred to acceleration capacity and kicking speed but players need time to transfer these increases. PMID- 21297564 TI - Evaluation of the relationship between the body positioning and the postural comfort of non-professional cyclists: a new approach. AB - AIM: Most biomechanical studies on bicycle ergonomics focused on racing efficiency and often neglected the investigation of cycling comfort, due to the difficulties related to the people's subjective feelings. This research work aims at analyzing the comfort on bicycle from an objective viewpoint; specifically, an attempt to relate subject's preferences, determined in a dynamic way, with his/her physical features, acquired by means of anthropometric measurements, was carried out. The validity of some existing and commonly used "rules of thumb" for bicycle fitting is discussed and investigated, and new indications are also proposed to achieve an optimal bike configuration. METHODS: A group of 120 volunteers was considered in this study; they were non-professional cyclists. First, the participants' anthropometric features were acquired; afterwards, the volunteers were asked to cycle on a bicycle fitting system (adjustable gym bike) and then to modify the simulator settings till the optimal subjective feelings of comfort are reached. The linear correlation coefficient between the measured anthropometric features and the geometrical preferences adopted on the cycling simulator was calculated. RESULTS: On one hand, the data analysis allows to propose new indications to achieve an optimal postural comfort on the basis of the physical features of the subject, but, on the other hand, the results confirm that the comfort on bicycles is highly related to personal preferences and, therefore, it is strongly subjective. CONCLUSION: The main conclusions and implications of this study can be summarized as follows: 1) the comfort on bicycle is strongly subjective as it is highly related to personal preferences; 2) an optimal bicycle setting can be achieved only by taking in to account the most relevant anthropometric features of every single cyclist; 3) a station for acquiring cyclists' anthropometric measurements and a bicycle simulator (adjustable gym bike) can act as very useful tools for designing optimal and custom-made bicycle configurations. PMID- 21297565 TI - Physiological and neuromuscular impact of beach-volleyball with reference to fatigue and recovery. AB - AIM: The aim of the present study was to analyze the physiological and neuromuscular impact of a one 3-set beach-volleyball match and to analyze the ability of the players to recover from fatigue. METHODS: Heart rate (HR) and blood lactate concentration (BLC) were measured in sixteen Portuguese male elite volleyball players during beach-volleyball matches. Vertical countermovement jump (CMJ), sprint (7.5 and 15m) ability and maximal isometric voluntary contraction (MIVC) were evaluated at baseline, immediately (0h) and 3 hours after each match. RESULTS: Mean HR during the match was 146 +/- 3 bpm (117 +/- 2-185 +/- 3 bpm) corresponding to about 75% of HRmax (61-90%HRmax). Players spent 34% of match time above 80% HRmax. BLC during the 3-sets increased from rest (0.95 +/- 0.23 vs. 2.10 +/- 0.66 [1st-set] vs. 2.41 +/- 0.15 [2nd-set] vs. 2.39 +/- 0.21mM [3rd set]). No changes in CMJ were observed at 0 and 3h. Knee extensor and flexor muscles MIVC decreased at 0h (~19 and 17%, respectively) and returned to baseline 3h after. Sprint performance was the only variable that was impaired both at 0h and 3h after the match (~3%). CONCLUSION: Beach-volleyball is performed intermittently at moderate-to-high intensity with brief bouts of high intensity exercise interspersed by long low intensity periods. Match induced a temporary reduction in lower limb strength and sprinting time but 3h after the match all variables with the exception of the sprinting time, that was only slightly reduced, were recovered. PMID- 21297566 TI - "Living high - training low" vs. "living high - training high": erythropoietic responses and performance of adolescent cross-country skiers. AB - AIM: To determine and compare the erythropoietic response and exercise performance of adolescent cross-country skiers, as a result of "living high training high" (HH) and "living high-training low" (HL). METHODS: Nine female and six male adolescent cross-country skiers volunteered to participate in separate trials. In the first trial (HH), the skiers lived and trained for 21 days at 1550 2050 m, while in the second trial (HL) they trained near sea level (450-500 m) but resided at 1550 m. All participants underwent maximal cycle ergometer tests for the determination of VO2max and cardiorespiratory parameters via an open circuit system at sea level before ascent to altitude, and 1-2 days after descent from altitude. Blood samples were drawn prior to and immediately after maximal cycle exercise testing, at sea level prior to ascent, on days 1 (D1) and 21 (D21) at altitude (1740 m), and 1-2 days post-altitude, for the determination of serum erythropoietin (EPO) concentration, haemoglobin (Hb), hematocrit (Ht), and red blood cell (RBC) volume. RESULTS: The results showed that both boys and girls cross-country skiers, significantly improved their sea level VO2max after 21 days of living at moderate altitude and training near sea level. CONCLUSION: The present study demonstrates that living at moderate altitude, 1550-2050 m and training low, near sea level (450-500 m) significantly increases VO2max and RBC mass for both boys and girls. Results indicate that applying the training concept "living high - training low" in adolescent athletes may improve their endurance performance. PMID- 21297567 TI - Branched-chain amino acids supplementation enhances exercise capacity and lipid oxidation during endurance exercise after muscle glycogen depletion. AB - AIM: It has been demonstrated that branched-chain amino acids (BCAA) transaminase activation occurs simultaneously with exercise-induced muscle glycogen reduction, suggesting that BCAA supplementation might play an energetic role in this condition. This study aimed to test whether BCAA supplementation enhances exercise capacity and lipid oxidation in glycogen-depleted subjects. METHODS: Using a double-blind cross-over design, volunteers (N.=7) were randomly assigned to either the BCAA (300 mg . kg . day -1) or the placebo (maltodextrine) for 3 days. On the second day, subjects were submitted to an exercise-induced glycogen depletion protocol. They then performed an exhaustive exercise test on the third day, after which time to exhaustion, respiratory exchange ratio (RER), plasma glucose, free fatty acids (FFA), blood ketones and lactate were determined. BCAA supplementation promoted a greater resistance to fatigue when compared to the placebo (+17.2%). Moreover, subjects supplemented with BCAA showed reduced RER and higher plasma glucose levels during the exhaustive exercise test. CONCLUSION: In conclusion, BCAA supplementation increases resistance to fatigue and enhances lipid oxidation during exercise in glycogen-depleted subjects. PMID- 21297568 TI - Changes in hydration status of soccer players competing in the 2008 European Championship. AB - AIM: Body composition is highly modifiable through exercise and may be changed by the physical stress of soccer training and competition. Especially body water as a constituent of body composition is assumed to be subjected to changes. It is speculated that during the most important soccer championship the combination of heat and the strenuous competitive program could lead to the development of a chronic state of hypohydration. However, no one tested this hypothesis. Therefore, the purpose of present work was to investigate the impact of the European Soccer Championship 2008 on players' body composition. METHODS: Participants were 14 players of one team, split into Starters (N.=7) and Non Starters (N.=7). Starters participated in the games, while Non-Starters served as substitutes, with marginal playing times. Body composition was examined by bioelectrical impedance analysis before the championship and 36 hours after the first and second game. RESULTS: After the first game, Starters and Non-Starters showed decreased extra-cellular mass (-3.3% and -5.5%) and body cell mass (-4.1% and -6.1%) compared to prechampionship measurements. The impedance vector graph showed a significant lengthening in both groups (Starters T2=30.5, P=0.000; Non Starters T2=39.0, P=0.000). After the second game, extra-cellular mass (-3.4%) and body weight (-1.1%) decreased in Starters only. ANOVA revealed a significant difference in extra-cellular mass between Starters and Non-Starters (P=0.027). The impedance vector graph was lengthened in the Starters only (T2=17.5, P=0.000). The distance covered during the games was correlated to the percent drop in extra-cellular mass between the end of games 1 and 2 (r=-0.602; P=0.023). CONCLUSION: Players competing in the European championship games experienced a decrease in extra-cellular mass and body weight. The impedance vector graph showed a lengthening, indicating fluid loss. Therefore, proper hydration of players requires diligent attention. PMID- 21297569 TI - Hazards of hydrodensitometry. AB - The limitations of the two-component model of body composition have been investigated extensively in the past resulting in a clear message of violation of basic assumptions underlying its use. This strong message may or may not be appropriate, since hydrodensitometry is still used, in particular in sports sciences. The combination of novel information with previously described indicators should allow to confirm or reject the pretended violation of basic assumptions underlying the use of hydrodensitometry. Water content of adipose tissue (AT) and of AT free mass as opposed to fat and fat free mass, and bone density of separate bones was obtained from the Brussels Cadaver Analysis Study collection. Analysis of different studies indicated anomalies up to -12% fat but also suggests that the borderline between chemical and morphological interpretations becomes vague and the ad hoc terminology does not reflect reality. Predicted % body fat using different methods on the same individual ranges between 9.6% up to 21% of AT. Total body water of separate tissues suggests intra-and intervariability within tissues. Whole skeleton density and the separate bone density cannot support the two-component constancy (1.164 g/mL to 1.570 g/mL). PMID- 21297570 TI - Anthropometric characteristics and technical skills of 12 and 14 year old basketball players. AB - AIM: The aims of this study were: a) to describe the anthropometric characteristics and technical skills in children aged 12 and 14 taking part in competitive basketball; b) to compare the mean scores between these two groups; and c) to detect the relationship between anthropometric characteristics and basketball skills. METHODS: At the sample of total of 118 young basketball players, 54 of 14 (+/- 0.5) year old and 64 of 12 (+/- 0.5) year old, 18 anthropometric variables were measured: five longitudinal measures, two transversal measures, body mass, four circumferences, six skinfolds and 3 derived variables: Body Mass Index (BMI), sitting height/stature ratio (SH/ST ratio) and sum of skinfolds (SUM SKF). Also, they did four basketball field tests: speed spot shooting, passing, control dribble and defensive movement. RESULTS: Values of most of anthropometric variables were significantly higher in 14 year old players as compared to 12 year old, except in SH/ST ratio and BMI which were similar. Only values of SUM SKF were significantly lower in 14 year old players. In variables: control dribble, passing and defensive movement 14 year old players have better scores then 12 year old players. CONCLUSION: The players presented a very high values of anthropometric dimensions, especially longitudinal and a very good technical skills. The correlation between certain field tests and some anthropometric parameters indicates that some anthropometric measures might have moderately negative influence on test results in technical skills in 14 year old players. PMID- 21297571 TI - Association of extracurricular sports participation with obesity in Greek children. AB - AIM: Childhood obesity has become a modern epidemic with escalating rates. The aim of our study was the assessment of the association between extracurricular sports participation with the obesity status among Greek schoolchildren aged 10 12 years. METHODS: Seven-hundred children (323 boys) aged 10-12 years were evaluated through a standardized questionnaire. Several lifestyle, dietary and physical activity attributes were recorded. Children according to the median hours of participation in after-school structured physical activity were classified as participating for more or less than 3 hours per week. Body height and mass were measured and body mass index was calculated in order to classify children as overweight or obese according to IOTF classification. Multiple logistic regression analysis was used in order to evaluate the association between the participation of more than 3 hours per week in structured physical activity after school with overweight or obesity. RESULTS: A total of 48.9% of the boys and 31.8% of the girls were participating for more than 3 hours per week (P<0.001) in extracurricular sport activities. Moreover, 33.9 % of the boys and 22.1 % of the girls were classified as overweight and 9.4% of the boys and 8.6% of the girls as obese (P=0.006). Girls who participated in excess of 3 hours in extracurricular sport activities were 59% less likely to be overweight or obese than their non participating counterparts, adjusted for several confounders (adjusted OR: 0.41, 95% CI: 0.20-0.83). CONCLUSION: Participation in extracurricular sports activity is inversely related to overweight or obesity in 10-12 years old Greek girls. PMID- 21297572 TI - Barriers to adolescent girls' participation in physical activity defined by physical activity levels. AB - AIM: Perceived barriers were the single most powerful predictors of a change in health behaviours and the most consistent negative correlate of children's actual physical activity (PA). The purpose of this study was to compare the perceived barriers of physical activity in 714 adolescent girls defined by physical activity levels. METHODS: The final sample consisted of 714 adolescent, student girls. The age of these students ranged from 12 to 15 years, with a mean age of 13.5 +/- 0.7 years. Perceived physical activity and perceived barriers to physical activity were measured using the Physical Self-Description Questionnaire and a Scale of Barriers that includes 17 units of barriers divided into two categories: intrapersonal barriers and environmental/contextual barriers. RESULTS: In our study, girls with a low activity level perceived a greater number of barriers than those with a high activity level, more specifically three intrapersonal barriers and two environmental/contextual barriers. Girls with a low activity level reported greater barriers to physical activity than high active girls for these barriers: don't like physical activity (F=23.405, p=0.001), not good at physical activity and sports (F=24.160, p=0.001), I'm too lazy to do physical activity (F=8.415, P=0.001), it is not safe to do physical activity outdoors (F=11.39, P<0.001) and there is no-one to do physical activity with (F=15.22 P<0.001). CONCLUSION: This study shows the need to learn and effectively use time management strategies that emphasize prioritising and better scheduling of physical activities. PMID- 21297573 TI - Load carrying walking test and its relationships to endurance and neuromuscular capabilities in women and men of different ages. AB - The aim of this study was to examine load carrying walking test (TMload) performance on the treadmill and its associations to endurance and neuromuscular capabilities in women and men of different ages. Sixty participants (aged 28 to 71 years) were divided into young, middle-aged and old groups of both genders. Clinical stress test was performed by stationary cycle ergometer (CEload). Peak oxygen uptake (VO2peak), heart rate and lactate concentration were measured using maximal TMload test. Isometric strength and EMG-activity of upper and lower extremities were measured before and after TMload. VO2peak of TMload correlated significantly with TMload exercise time (ET) in all other groups (r=0.67 to 0.91 and p <= 0.05 to p<0.001) except old men. Leg extension force decreased (p <= 0.05 to p<0.001) after TMload in all groups, grip force in young groups (p <= 0.05), while plantar flexion force and all EMGs remained unchanged. In men VO2peak explained 81% and in women VO2peak and age explained 87% of the total variation of the TMload ET. In conclusion, ET of TMload is associated with high VO2peak, but not with muscle strength or its changes during the loading. The present load carrying walking test may be used for testing workers with heavy loading in their occupation or in rehabilitation purposes. Further research is needed to examine in more detailed the loading model of the present study as well as the effects of different types of training on load carrying performance. PMID- 21297574 TI - Proxidant* antioxidant balance in supplemented elite female volleyball athletes during a six week training period. AB - AIM: The objectives of this study were: 1) to evaluate pro-oxidant-antioxidant balance (PAB) associations with the commonly measured parameters of oxidative stress and antioxidatve defence in elite female volleyball athletes; 2) to investigate changes in the parameters of oxidative stress during a period of intense training and dietary antioxidant supplementation. METHODS: Twenty-seven female volleyball players participated in this study. Blood samples were collected the day before the pre-competitive mesocycle training period began. After the first blood sample donation and during the next six weeks fourteen players (supplemented group) received a cocktail of antioxidants while thirteen of them (control group) received no dietary supplementation. The following parameters were measured: reactive oxygen metabolites (ROMs), superoxide anion (O2-), malondialdehyde (MDA), advanced oxidation protein products (AOPP), lipid hydroperoxides (LOOH), biological antioxidative potential (BAP), paraoxonase activity toward paraoxon (POase) and diazoxon (DZOase), superoxide dismutase (SOD), total sulphydryl group concentration (SH groups) and pro-oxidant antioxidant balance. RESULTS: Significant associations were observed between biomarkers of oxidative damage with PAB in multiple linear regression model in the supplemented and the control groups (82.3% vs. 83.1%) before training and in the control group (82.1%) after training. Significant associations between antioxidative defence parameters and PAB values were found in the supplemented group after six-weeks of training (57%). CONCLUSION: In the absence of antioxidant supplementation, PAB values were dependent on the association with biomarkers of oxidative damage before and after training. After a six-week training period and the applied antioxidant supplementation, PAB values were under the influence of non-enzymatic anti-oxidative defence. PMID- 21297575 TI - Performance and blood monitoring in sports: the artificial intelligence evoking target testing in antidoping (AR.I.E.T.T.A.) project. AB - AIM: Substances and methods used to increase oxygen blood transport and physical performance can be detected in the blood, but the screening of the athletes to be tested remains a critical issue for the International Federations. This project, AR.I.E.T.T.A., aimed to develop a software capable of analysing athletes' hematological and performance profiles to detect abnormal patterns. METHODS: One hundred eighty athletes belonging to the International Biathlon Union gave written informed consent to have their hematological data, previously collected according to anti-doping rules, used to develop the AR.I.E.T.T.A. software. RESULTS: Software was developed with the included sections: 1) log-in; 2) data entry: where data are loaded, stored and grouped; 3) analysis: where data are analysed, validated scores are calculated, and parameters are simultaneously displayed as statistics, tables and graphs, and individual or subpopulation profiles; 4) screening: where an immediate evaluation of the risk score of the present sample and/or the athlete under study is obtained. The sample risk score or AR.I.E.T.T.A. score is calculated by a simple computational system combining different parameters (absolute values and intra-individual variations) considered concurrently. The AR.I.E.T.T.A. score is obtained by the sum of the deviation units derived from each parameter, considering the shift of the present value from the reference values, based on the number of standard deviations. CONCLUSION: AR.I.E.T.T.A. enables a quick evaluation of blood results assisting surveillance programs and perform timely target testing controls on athletes by the International Federations. Future studies aiming to validate the AR.I.E.T.T.A. score and improve the diagnostic accuracy will improve the system. PMID- 21297576 TI - Basal plasma leptin levels in healthy elderly males are related to physical fitness without impact on bone metabolism. AB - AIM: Investigated the relationship between leptin levels or bone remodelling and physical fitness level in healthy elderly participants. METHODS: Twenty women and 18 men (mean age 72.7 years, range 59-90) performed a maximal incremental exercise test to evaluate their maximal oxygen uptake (VOmax). Basal blood concentrations of bone biochemical markers (BM) and leptin were analysed. RESULTS: Women presented higher values of leptin than men (+34.7%, P=0.024), but no difference related to gender was observed for the other biological parameters. Leptin levels were positively correlated with Body Mass Index (BMI) in both genders. Whether adjusted or not for BMI, leptin was negatively correlated with VOmax only in men (r=-0.55, P=0.02 and r=-0.57, P=0.01, respectively). No relationship between VOmax or leptin and BM was observed, except for leptin and osteocalcin in men (r=-0.66, P=0.015). CONCLUSION: Our data suggest that neither physical fitness nor leptin level seems to have a noticeable effect in the regulation of bone cell activity in healthy elderly participants. In this specific population, physical fitness plays a crucial role on leptin secretion, independently of BMI variation, and this action appears to be sex-dependent. PMID- 21297577 TI - Effects of resistance training on the lipid profile in obese women. AB - AIM: The aim of the present study was to analyze the effects of resistance training in groups (with music) on the lipid profile in obese women. METHODS: The sample was composed of 28 sedentary obese women. Of these, 13 were submitted to the resistance training in group program (GT) and 15 took part in a control group (GC). The training lasted for 9 weeks, with three weekly sessions. The classes emphasized resistance training through the performance of 10 localized exercises. The analysis evaluated the following variables: total cholesterol (TC), high density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG) and the TC/HDL ratio in the pre and post-training periods in both groups. The data was analyzed using Anova for repeated measures with one factor, adopting P<0.05. RESULTS: The study found significant differences for the training group between the pre- and post-training period in all the analyzed variables, except for the TG. In contrast, for the control group there was no significant difference between the pre and post-training period in any of the variables, except for the TG in which we found a statistically significant increase. The reductions were from 200.62 +/- 39.11 mg.dL-1 to 184.92 +/- 28.62 mg.dL-1 for TC; from 137.69 +/- 32.09 mg.dL-1 to 110.31 +/- 21.92 mg.dL-1 for LDL; from 4.48 +/- 1.00 to 3.70 +/- 0.90 for the TC/HDL ratio and the improvement in the HDL was from 46.23 +/- 12.04 mg.dL-1 to 53.15 +/- 16.83 mg.dL-1. CONCLUSION: Thus, it was concluded that the resistance training in groups with music was effective since it provided beneficial modifications to the lipid profile, which may result in lower risk of coronary arterial diseases in the obese female population. PMID- 21297578 TI - Drosophila Ras/MAPK signalling regulates innate immune responses in immune and intestinal stem cells. AB - Immune signalling pathways need to be tightly regulated as overactivation of these pathways can result in chronic inflammatory diseases and cancer. NF-kappaB signalling and associated innate immune pathways are crucial in the first line of defense against infection in all animals. In a genome-wide RNAi screen for modulators of Drosophila immune deficiency (IMD)/NF-kappaB signalling, we identified components of the Ras/MAPK pathway as essential for suppression of IMD pathway activity, even in the absence of an immune challenge. Downregulation of Ras/MAPK activity mimics the induction of innate immune responses by microbial patterns. Conversely, ectopic Ras/MAPK pathway activation results in the suppression of Drosophila IMD/NF-kappaB signalling. Mechanistically, we show that the Ras/MAPK pathway acts by inducing transcription of the IMD pathway inhibitor Pirk/Rudra/PIMS. Finally, in vivo experiments demonstrate a requirement for Ras/MAPK signalling in restricting innate immune responses in haemocytes, fat body and adult intestinal stem cells. Our observations provide an example of a pathway that promotes cell proliferation and has simultaneously been utilized to limit the immune response. PMID- 21297579 TI - Lgr5 intestinal stem cells have high telomerase activity and randomly segregate their chromosomes. AB - Somatic cells have been proposed to be limited in the number of cell divisions they can undergo. This is thought to be a mechanism by which stem cells retain their integrity preventing disease. However, we have recently discovered intestinal crypt stem cells that persist for the lifetime of a mouse, yet divide every day. We now demonstrate biochemically that primary isolated Lgr5+ve stem cells contain significant telomerase activity. Telomerase activity rapidly decreases in the undifferentiated progeny of these stem cells and is entirely lost in differentiated villus cells. Conversely, asymmetric segregation of chromosomes has been proposed as a mechanism for stem cells to protect their genomes against damage. We determined the average cell cycle length of Lgr5+ve stem cells at 21.5 h and find that Lgr5+ve intestinal stem cells randomly segregate newly synthesized DNA strands, opposing the 'immortal strand' hypothesis. PMID- 21297580 TI - Structure of a TCR with high affinity for self-antigen reveals basis for escape from negative selection. AB - The failure to eliminate self-reactive T cells during negative selection is a prerequisite for autoimmunity. To escape deletion, autoreactive T-cell receptors (TCRs) may form unstable complexes with self-peptide-MHC by adopting suboptimal binding topologies compared with anti-microbial TCRs. Alternatively, escape can occur by weak binding between self-peptides and MHC. We determined the structure of a human autoimmune TCR (MS2-3C8) bound to a self-peptide from myelin basic protein (MBP) and the multiple sclerosis-associated MHC molecule HLA-DR4. MBP is loosely accommodated in the HLA-DR4-binding groove, accounting for its low affinity. Conversely, MS2-3C8 binds MBP-DR4 as tightly as the most avid anti microbial TCRs. MS2-3C8 engages self-antigen via a docking mode that resembles the optimal topology of anti-foreign TCRs, but is distinct from that of other autoreactive TCRs. Combined with a unique CDR3beta conformation, this docking mode compensates for the weak binding of MBP to HLA-DR4 by maximizing interactions between MS2-3C8 and MBP. Thus, the MS2-3C8-MBP-DR4 complex reveals the basis for an alternative strategy whereby autoreactive T cells escape negative selection, yet retain the ability to initiate autoimmunity. PMID- 21297581 TI - L1CAM regulates DNA damage checkpoint response of glioblastoma stem cells through NBS1. AB - Glioblastomas (GBMs) are highly lethal brain tumours with current therapies limited to palliation due to therapeutic resistance. We previously demonstrated that GBM stem cells (GSCs) display a preferential activation of DNA damage checkpoint and are relatively resistant to radiation. However, the molecular mechanisms underlying the preferential checkpoint response in GSCs remain undefined. Here, we show that L1CAM (CD171) regulates DNA damage checkpoint responses and radiosensitivity of GSCs through nuclear translocation of L1CAM intracellular domain (L1-ICD). Targeting L1CAM by RNA interference attenuated DNA damage checkpoint activation and repair, and sensitized GSCs to radiation. L1CAM regulates expression of NBS1, a critical component of the MRE11-RAD50-NBS1 (MRN) complex that activates ataxia telangiectasia mutated (ATM) kinase and early checkpoint response. Ectopic expression of NBS1 in GSCs rescued the decreased checkpoint activation and radioresistance caused by L1CAM knockdown, demonstrating that L1CAM signals through NBS1 to regulate DNA damage checkpoint responses. Mechanistically, nuclear translocation of L1-ICD mediates NBS1 upregulation via c-Myc. These data demonstrate that L1CAM augments DNA damage checkpoint activation and radioresistance of GSCs through L1-ICD-mediated NBS1 upregulation and the enhanced MRN-ATM-Chk2 signalling. PMID- 21297582 TI - A TACC3/ch-TOG/clathrin complex stabilises kinetochore fibres by inter microtubule bridging. AB - Kinetochore fibres (K-fibres) of the spindle apparatus move chromosomes during mitosis. These fibres are discrete bundles of parallel microtubules (MTs) that are crosslinked by inter-MT 'bridges' that are thought to improve fibre stability during chromosomal movement. The identity of these bridges is unknown. Clathrin is a multimeric protein that has been shown to stabilise K-fibres during early mitosis by a mechanism independent of its role in membrane trafficking. In this study, we show that clathrin at the mitotic spindle is in a transforming acidic colied-coil protein 3 (TACC3)/colonic, hepatic tumour overexpressed gene (ch TOG)/clathrin complex. The complex is anchored to the spindle by TACC3 and ch TOG. Ultrastructural analysis of clathrin-depleted K-fibres revealed a selective loss of a population of short inter-MT bridges and a general loss of MTs. A similar loss of short inter-MT bridges was observed in TACC3-depleted K-fibres. Finally, immunogold labelling confirmed that inter-MT bridges in K-fibres contain clathrin. Our results suggest that the TACC3/ch-TOG/clathrin complex is an inter MT bridge that stabilises K-fibres by physical crosslinking and by reducing rates of MT catastrophe. PMID- 21297583 TI - RNA content in the nucleolus alters p53 acetylation via MYBBP1A. AB - A number of external and internal insults disrupt nucleolar structure, and the resulting nucleolar stress stabilizes and activates p53. We show here that nucleolar disruption induces acetylation and accumulation of p53 without phosphorylation. We identified three nucleolar proteins, MYBBP1A, RPL5, and RPL11, involved in p53 acetylation and accumulation. MYBBP1A was tethered to the nucleolus through nucleolar RNA. When rRNA transcription was suppressed by nucleolar stress, MYBBP1A translocated to the nucleoplasm and facilitated p53 p300 interaction to enhance p53 acetylation. We also found that RPL5 and RPL11 were required for rRNA export from the nucleolus. Depletion of RPL5 or RPL11 blocked rRNA export and counteracted reduction of nucleolar RNA levels caused by inhibition of rRNA transcription. As a result, RPL5 or RPL11 depletion inhibited MYBBP1A translocation and p53 activation. Our observations indicated that a dynamic equilibrium between RNA generation and export regulated nucleolar RNA content. Perturbation of this balance by nucleolar stress altered the nucleolar RNA content and modulated p53 activity. PMID- 21297584 TI - IgG4 plasma cells in inflammatory myofibroblastic tumor: inflammatory marker or pathogenic link? AB - Inflammatory myofibroblastic tumor is a rare mesenchymal neoplasm that harbors an anaplastic lymphoma kinase (ALK) gene rearrangement in the majority of cases. It is composed of fibroblastic-myofibroblastic cells with a characteristic inflammatory infiltrate that consists predominantly of plasma cells. In contrast, IgG4-related sclerosing disease is a recently described multisystem disorder with a histological appearance similar to inflammatory myofibroblastic tumor. The plasma cell infiltrate is characteristic in IgG4-related sclerosing disease and has been studied as a tool to render this diagnosis. Histologically, the two disorders overlap, although there are significant clinical differences. This study analyzes the histological appearance of 36 inflammatory myofibroblastic tumors, compares them with IgG4-related sclerosing disease, and assesses the plasma cell profile using immunohistochemistry to determine the range and proportion of IgG4 plasma cells. The majority of patients were children and young adults, mainly with solitary masses and no clinical manifestations of IgG4 related sclerosing disease. ALK-1 positivity was present in 23 cases (64%). None showed obliterative phlebitis or prominent lymphoid aggregates. Of 36 inflammatory myofibroblastic tumors, 15 cases showed an IgG4/IgG ratio >=0.10, a cutoff described in the literature as supportive of IgG4-related sclerosing disease and up to 33 IgG4-positive plasma cells per high-power field indicating a mild-to-moderate increase as compared with IgG4-related sclerosing disease. Currently, the diagnostic recognition of inflammatory myofibroblastic tumor is based on clinicopathological features and diagnostic adjuncts, such as ALK-1 reactivity and genetic tests. Although inflammatory myofibroblastic tumor and IgG4-related sclerosing disease are distinct entities, a subset of inflammatory myofibroblastic tumors exhibit an IgG4/IgG ratio that is within the range for IgG4-related sclerosing disease. Therefore, the ratio alone cannot be used as a reliable discriminator between these two entities and other clinical and pathologic features must always be taken into account. PMID- 21297585 TI - Differential gene expression profiles of neurothekeomas and nerve sheath myxomas by microarray analysis. AB - Neurothekeomas and dermal nerve sheath myxomas have previously been considered related cutaneous neoplasms of peripheral nerve sheath origin based on light microscopic similarities. However, recent immunohistochemical and ultrastructural data indicate nerve sheath myxomas exhibit true nerve sheath differentiation, whereas no such compelling evidence exists for neurothekeomas. Although neurothekeomas lack a specific immunohistochemical profile, similar antigen expression and histopathologic patterns suggest neurothekeomas may be categorized as fibrohistiocytic tumors. To date, no known molecular studies have examined the histogenetic relationship of these tumors. We report the first microarray-based gene expression profile study of these entities on formalin-fixed paraffin embedded tissues. Cases of dermal schwannomas, dermal nerve sheath myxomas, myxoid/mixed/cellular neurothekeomas, and cellular fibrous histiocytomas diagnosed in the past 3 years were identified in our database. Archival formalin fixed paraffin-embedded tissue from 28 patients was selected for microarray analysis (seven schwannomas, five nerve sheath myxomas, nine myxoid/mixed/cellular neurothekeomas and seven cellular fibrous histiocytomas). Following tumor RNA isolation, amplification and labeling using commercially available kits, labeled targets were hybridized to the Affymetrix GeneChip Human Genome U133 Plus 2.0 Array (Santa Clara, CA, USA). Acquisition of array images and data analyses was performed using appropriate software. Hierarchical clustering and principal component analysis demonstrated discrete groups, which correlated with histopathologically identified diagnoses. Dermal nerve sheath myxomas demonstrate very similar molecular genetic signatures to dermal schwannomas, whereas neurothekeomas of all subtypes more closely resemble cellular fibrous histiocytomas. We are the first to report distinct gene expression profiles for nerve sheath myxomas and neurothekeomas, which further substantiates the argument that these are separate entities. Our molecular data confirms that dermal nerve sheath myxomas are of peripheral nerve sheath origin, and suggests that neurothekeomas may actually be a variant of fibrous histiocytomas. PMID- 21297586 TI - Genetics and epigenetics of small bowel adenocarcinoma: the interactions of CIN, MSI, and CIMP. AB - Characterization of tumor genetics and epigenetics allows to stratify a tumor entity according to molecular pathways and may shed light on the interactions of different types of DNA alterations during tumorigenesis. Small intestinal adenocarcinoma is rare, and to date the interrelation of genomic instability and epigenetics has not been investigated in this tumor type. We therefore analyzed 37 primary small bowel carcinomas with known microsatellite instability and KRAS status for chromosomal instability using comparative genomic hybridization, for the presence of aberrant methylation (CpG island methylation phenotype) by methylation-specific polymerase chain reaction, and for BRAF mutations. Chromosomal instability was detected in 22 of 37 (59%) tumors (3 of 9 microsatellite instable, and 19 of 28 microsatellite stable carcinomas). Nine carcinomas (24%) were microsatellite and chromosomally stable. High-level DNA methylation was found in 16% of chromosomal instable tumors and in 44% of both microsatellite instable and microsatellite and chromosomally stable carcinomas. KRAS was mutated in 55, 0, and 10% of chromosomal instable, microsatellite instable, and microsatellite and chromosomally stable tumors, respectively whereas the frequencies of BRAF mutations were 6% for chromosomal instable and 22% for both microsatellite instable and microsatellite and chromosomally stable carcinomas. In conclusion, in this study we show that chromosomal instable carcinomas of the small intestine are distinguished from microsatellite instable and microsatellite and chromosomally stable tumors by a high frequency of KRAS mutations, low frequencies of CpG island methylation phenotype, and BRAF mutations. In microsatellite instable and microsatellite and chromosomally stable cancers, CpG island methylation phenotype and BRAF/KRAS mutations are similarly distributed, indicating common mechanisms of tumor initiation or progression in their molecular pathogenesis. PMID- 21297587 TI - The scientific social network. PMID- 21297588 TI - Are advance market commitments for drugs a real advance? PMID- 21297589 TI - Analysts see 'tale of two CEOs' unfolding at Pfizer and Merck. PMID- 21297590 TI - Action urged on foreign takeovers of Indian drugmakers. PMID- 21297591 TI - Transparency initiative moves ahead despite official's departure. PMID- 21297592 TI - Compromise is in sight for new embryo research rules in France. PMID- 21297593 TI - New regulations urged for UK health research. PMID- 21297595 TI - New initiative aims to grow UK life sciences. PMID- 21297594 TI - Animal instinct helps doctors ferret out disease. PMID- 21297596 TI - Drug scandal exposes French regulators to public ire. PMID- 21297597 TI - Genzyme, though unique, could be a bellwether for US biotech. PMID- 21297598 TI - Vaccines move forward against a range of addictions. PMID- 21297599 TI - Straight talk with...Jeremy Berg. Interview by Michelle Pflumm. PMID- 21297602 TI - Fecal matters. PMID- 21297603 TI - Review of classification rules represents an opportunity, even for medicine. PMID- 21297605 TI - Globular warming: how fat gets to the furnace. PMID- 21297606 TI - Tuberculosis vaccines--a new kid on the block. PMID- 21297607 TI - Sugar rush bleeds the brain. PMID- 21297608 TI - Stemming a tumor with a little miR. PMID- 21297609 TI - Linking the inflammasome to obesity-related disease. PMID- 21297610 TI - Cystic fibrosis: an-ion transport issue? PMID- 21297611 TI - A MRSA-terious enemy among us: boosting MRSA vaccines. PMID- 21297612 TI - A MRSA-terious enemy among us: end of the PVL controversy? PMID- 21297615 TI - DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration. AB - Geographic atrophy (GA), an untreatable advanced form of age-related macular degeneration, results from retinal pigmented epithelium (RPE) cell degeneration. Here we show that the microRNA (miRNA)-processing enzyme DICER1 is reduced in the RPE of humans with GA, and that conditional ablation of Dicer1, but not seven other miRNA-processing enzymes, induces RPE degeneration in mice. DICER1 knockdown induces accumulation of Alu RNA in human RPE cells and Alu-like B1 and B2 RNAs in mouse RPE. Alu RNA is increased in the RPE of humans with GA, and this pathogenic RNA induces human RPE cytotoxicity and RPE degeneration in mice. Antisense oligonucleotides targeting Alu/B1/B2 RNAs prevent DICER1 depletion induced RPE degeneration despite global miRNA downregulation. DICER1 degrades Alu RNA, and this digested Alu RNA cannot induce RPE degeneration in mice. These findings reveal a miRNA-independent cell survival function for DICER1 involving retrotransposon transcript degradation, show that Alu RNA can directly cause human pathology, and identify new targets for a major cause of blindness. PMID- 21297616 TI - Fluorescent peptides highlight peripheral nerves during surgery in mice. AB - Nerve preservation is an important goal during surgery because accidental transection or injury leads to significant morbidity, including numbness, pain, weakness or paralysis. Nerves are usually identified by their appearance and relationship to nearby structures or detected by local electrical stimulation (electromyography), but thin or buried nerves are sometimes overlooked. Here, we use phage display to select a peptide that binds preferentially to nerves. After systemic injection of a fluorescently labeled version of the peptide in mice, all peripheral nerves are clearly delineated within 2 h. Contrast between nerve and adjacent tissue is up to tenfold, and useful contrast lasts up to 8 h. No changes in behavior or activity are observed after treatment, indicating a lack of obvious toxicity. The fluorescent probe also labels nerves in human tissue samples. Fluorescence highlighting is independent of axonal integrity, suggesting that the probe could facilitate surgical repair of injured nerves and help prevent accidental transection. PMID- 21297617 TI - Kinase suppressor of Ras-1 protects against pulmonary Pseudomonas aeruginosa infections. AB - Pseudomonas aeruginosa is a Gram-negative pathogen that causes severe infections in immunocompromised individuals and individuals with cystic fibrosis or chronic obstructive pulmonary disease (COPD). Here we show that kinase suppressor of Ras 1 (Ksr1)-deficient mice are highly susceptible to pulmonary P. aeruginosa infection accompanied by uncontrolled pulmonary cytokine release, sepsis and death, whereas wild-type mice clear the infection. Ksr1 recruits and assembles inducible nitric oxide (NO) synthase (iNOS) and heat shock protein-90 (Hsp90) to enhance iNOS activity and to release NO upon infection. Ksr1 deficiency prevents lung alveolar macrophages and neutrophils from activating iNOS, producing NO and killing bacteria. Restoring NO production restores the bactericidal capability of Ksr1-deficient lung alveolar macrophages and neutrophils and rescues Ksr1 deficient mice from P. aeruginosa infection. Our findings suggest that Ksr1 functions as a previously unknown scaffold that enhances iNOS activity and is therefore crucial for the pulmonary response to P. aeruginosa infections. PMID- 21297618 TI - High-throughput single-molecule optofluidic analysis. AB - We describe a high-throughput, automated single-molecule measurement system, equipped with microfluidics. The microfluidic mixing device has integrated valves and pumps to accurately accomplish titration of biomolecules with picoliter resolution. We demonstrate that the approach enabled rapid sampling of biomolecule conformational landscape and of enzymatic activity, in the form of transcription by Escherichia coli RNA polymerase, as a function of the chemical environment. PMID- 21297619 TI - Flybow: genetic multicolor cell labeling for neural circuit analysis in Drosophila melanogaster. AB - To facilitate studies of neural network architecture and formation, we generated three Drosophila melanogaster variants of the mouse Brainbow-2 system, called Flybow. Sequences encoding different membrane-tethered fluorescent proteins were arranged in pairs within cassettes flanked by recombination sites. Flybow combines the Gal4-upstream activating sequence binary system to regulate transgene expression and an inducible modified Flp-FRT system to drive inversions and excisions of cassettes. This provides spatial and temporal control over the stochastic expression of one of two or four reporters within one sample. Using the visual system, the embryonic nervous system and the wing imaginal disc, we show that Flybow in conjunction with specific Gal4 drivers can be used to visualize cell morphology with high resolution. Finally, we demonstrate that this labeling approach is compatible with available Flp-FRT-based techniques, such as mosaic analysis with a repressible cell marker; this could further support the genetic analysis of neural circuit assembly and function. PMID- 21297620 TI - Visualizing a one-way protein encounter complex by ultrafast single-molecule mixing. AB - We combined rapid microfluidic mixing with single-molecule fluorescence resonance energy transfer to study the folding kinetics of the intrinsically disordered human protein alpha-synuclein. The time-resolution of 0.2 ms revealed initial collapse of the unfolded protein induced by binding with lipid mimics and subsequent rapid formation of transient structures in the encounter complex. The method also enabled analysis of rapid dissociation and unfolding of weakly bound complexes triggered by massive dilution. PMID- 21297621 TI - Drosophila Brainbow: a recombinase-based fluorescence labeling technique to subdivide neural expression patterns. AB - We developed a multicolor neuron labeling technique in Drosophila melanogaster that combines the power to specifically target different neural populations with the label diversity provided by stochastic color choice. This adaptation of vertebrate Brainbow uses recombination to select one of three epitope-tagged proteins detectable by immunofluorescence. Two copies of this construct yield six bright, separable colors. We used Drosophila Brainbow to study the innervation patterns of multiple antennal lobe projection neuron lineages in the same preparation and to observe the relative trajectories of individual aminergic neurons. Nerve bundles, and even individual neurites hundreds of micrometers long, can be followed with definitive color labeling. We traced motor neurons in the subesophageal ganglion and correlated them to neuromuscular junctions to identify their specific proboscis muscle targets. The ability to independently visualize multiple lineage or neuron projections in the same preparation greatly advances the goal of mapping how neurons connect into circuits. PMID- 21297622 TI - Orbital reflectometry of oxide heterostructures. AB - The occupation of d orbitals controls the magnitude and anisotropy of the inter atomic electron transfer in transition-metal oxides and hence exerts a key influence on their chemical bonding and physical properties. Atomic-scale modulations of the orbital occupation at surfaces and interfaces are believed to be responsible for massive variations of the magnetic and transport properties, but could not thus far be probed in a quantitative manner. Here we show that it is possible to derive quantitative, spatially resolved orbital polarization profiles from soft-X-ray reflectivity data, without resorting to model calculations. We demonstrate that the method is sensitive enough to resolve differences of ~3% in the occupation of Ni e(g) orbitals in adjacent atomic layers of a LaNiO(3)-LaAlO(3) superlattice, in good agreement with ab initio electronic-structure calculations. The possibility to quantitatively correlate theory and experiment on the atomic scale opens up many new perspectives for orbital physics in transition-metal oxides. PMID- 21297624 TI - The origins and limits of metal-graphene junction resistance. AB - A high-quality junction between graphene and metallic contacts is crucial in the creation of high-performance graphene transistors. In an ideal metal-graphene junction, the contact resistance is determined solely by the number of conduction modes in graphene. However, as yet, measurements of contact resistance have been inconsistent, and the factors that determine the contact resistance remain unclear. Here, we report that the contact resistance in a palladium-graphene junction exhibits an anomalous temperature dependence, dropping significantly as temperature decreases to a value of just 110 +/- 20 Omega um at 6 K, which is two to three times the minimum achievable resistance. Using a combination of experiment and theory we show that this behaviour results from carrier transport in graphene under the palladium contact. At low temperature, the carrier mean free path exceeds the palladium-graphene coupling length, leading to nearly ballistic transport with a transfer efficiency of ~75%. As the temperature increases, this carrier transport becomes less ballistic, resulting in a considerable reduction in efficiency. PMID- 21297625 TI - Flexible high-performance carbon nanotube integrated circuits. AB - Carbon nanotube thin-film transistors are expected to enable the fabrication of high-performance, flexible and transparent devices using relatively simple techniques. However, as-grown nanotube networks usually contain both metallic and semiconducting nanotubes, which leads to a trade-off between charge-carrier mobility (which increases with greater metallic tube content) and on/off ratio (which decreases). Many approaches to separating metallic nanotubes from semiconducting nanotubes have been investigated, but most lead to contamination and shortening of the nanotubes, thus reducing performance. Here, we report the fabrication of high-performance thin-film transistors and integrated circuits on flexible and transparent substrates using floating-catalyst chemical vapour deposition followed by a simple gas-phase filtration and transfer process. The resulting nanotube network has a well-controlled density and a unique morphology, consisting of long (~10 um) nanotubes connected by low-resistance Y-shaped junctions. The transistors simultaneously demonstrate a mobility of 35 cm(2) V( 1) s(-1) and an on/off ratio of 6 * 10(6). We also demonstrate flexible integrated circuits, including a 21-stage ring oscillator and master-slave delay flip-flops that are capable of sequential logic. Our fabrication procedure should prove to be scalable, for example, by using high-throughput printing techniques. PMID- 21297626 TI - Fast DNA sequencing with a graphene-based nanochannel device. AB - Devices in which a single strand of DNA is threaded through a nanopore could be used to efficiently sequence DNA. However, various issues will have to be resolved to make this approach practical, including controlling the DNA translocation rate, suppressing stochastic nucleobase motions, and resolving the signal overlap between different nucleobases. Here, we demonstrate theoretically the feasibility of DNA sequencing using a fluidic nanochannel functionalized with a graphene nanoribbon. This approach involves deciphering the changes that occur in the conductance of the nanoribbon as a result of its interactions with the nucleobases via pi-pi stacking. We show that as a DNA strand passes through the nanochannel, the distinct conductance characteristics of the nanoribbon (calculated using a method based on density functional theory coupled to non equilibrium Green function theory) allow the different nucleobases to be distinguished using a data-mining technique and a two-dimensional transient autocorrelation analysis. This fast and reliable DNA sequencing device should be experimentally feasible in the near future. PMID- 21297627 TI - Direct observation of stepwise movement of a synthetic molecular transporter. AB - Controlled motion at the nanoscale can be achieved by using Watson-Crick base pairing to direct the assembly and operation of a molecular transport system consisting of a track, a motor and fuel, all made from DNA. Here, we assemble a 100-nm-long DNA track on a two-dimensional scaffold, and show that a DNA motor loaded at one end of the track moves autonomously and at a constant average speed along the full length of the track, a journey comprising 16 consecutive steps for the motor. Real-time atomic force microscopy allows direct observation of individual steps of a single motor, revealing mechanistic details of its operation. This precisely controlled, long-range transport could lead to the development of systems that could be programmed and routed by instructions encoded in the nucleotide sequences of the track and motor. Such systems might be used to create molecular assembly lines modelled on the ribosome. PMID- 21297628 TI - The neural substrates of rapid-onset Dystonia-Parkinsonism. AB - Although dystonias are a common group of movement disorders, the mechanisms by which brain dysfunction results in dystonia are not understood. Rapid-onset Dystonia-Parkinsonism (RDP) is a hereditary dystonia caused by mutations in the ATP1A3 gene. Affected individuals can be free of symptoms for years, but rapidly develop persistent dystonia and Parkinsonism-like symptoms after a stressful experience. Using a mouse model, we found that an adverse interaction between the cerebellum and basal ganglia can account for the symptoms of these individuals. The primary instigator of dystonia was the cerebellum, whose aberrant activity altered basal ganglia function, which in turn caused dystonia. This adverse interaction between the cerebellum and basal ganglia was mediated through a di synaptic thalamic pathway that, when severed, alleviated dystonia. Our results provide a unifying hypothesis for the involvement of cerebellum and basal ganglia in the generation of dystonia and suggest therapeutic strategies for the treatment of RDP. PMID- 21297629 TI - Timing of neurogenesis is a determinant of olfactory circuitry. AB - An odorant receptor map in mammals that is constructed by the glomerular coalescence of sensory neuron axons in the olfactory bulb is essential for proper odor information processing. How this map is linked with olfactory cortex is unknown. Using a battery of methods, including various markers of cell division in combination with tracers of neuronal connections and time-lapse live imaging, we found that early- and late-generated mouse mitral cells became differentially distributed in the dorsal and ventral subdivisions of the odorant receptor map. In addition, the late-generated mitral cells extended substantially stronger projections to the olfactory tubercle than did the early-generated cells. Together, these data indicate that the odorant receptor map is developmentally linked to the olfactory cortices in part by the birthdate of mitral cells. Thus, different olfactory cortical regions become involved in processing information from distinct regions of the odorant receptor map. PMID- 21297630 TI - NR3A-containing NMDARs promote neurotransmitter release and spike timing dependent plasticity. AB - Recent evidence suggests that presynaptic-acting NMDA receptors (preNMDARs) are important for neocortical synaptic transmission and plasticity. We found that unique properties of the NR3A subunit enable preNMDARs to enhance spontaneous and evoked glutamate release and that NR3A is required for spike timing-dependent long-term depression in the juvenile mouse visual cortex. In the mature cortex, NR2B-containing preNMDARs enhanced neurotransmission in the absence of magnesium, indicating that presynaptic NMDARs may function under depolarizing conditions throughout life. Our findings indicate that NR3A relieves preNMDARs from the dual activation requirement of ligand-binding and depolarization; the developmental removal of NR3A limits preNMDAR functionality by restoring this associative property. PMID- 21297631 TI - Phosphorylation of SCG10/stathmin-2 determines multipolar stage exit and neuronal migration rate. AB - Cell migration is the consequence of the sum of positive and negative regulatory mechanisms. Although appropriate migration of neurons is a principal feature of brain development, the negative regulatory mechanisms remain obscure. We found that JNK1 was highly active in developing cortex and that selective inhibition of JNK in the cytoplasm markedly increased both the frequency of exit from the multipolar stage and radial migration rate and ultimately led to an ill-defined cellular organization. Moreover, regulation of multipolar-stage exit and radial migration in Jnk1(-/-) (also known as Mapk8) mice, resulted from consequential changes in phosphorylation of the microtubule regulator SCG10 (also called stathmin-2). Expression of an SCG10 mutant that mimics the JNK1-phosphorylated form restored normal migration in the brains of Jnk1(-/-) mouse embryos. These findings indicate that the phosphorylation of SCG10 by JNK1 is a fundamental mechanism that governs the transition from the multipolar stage and the rate of neuronal cell movement during cortical development. PMID- 21297632 TI - Ancestry and pharmacogenomics of relapse in acute lymphoblastic leukemia. AB - Although five-year survival rates for childhood acute lymphoblastic leukemia (ALL) are now over 80% in most industrialized countries, not all children have benefited equally from this progress. Ethnic differences in survival after childhood ALL have been reported in many clinical studies, with poorer survival observed among African Americans or those with Hispanic ethnicity when compared with European Americans or Asians. The causes of ethnic differences remain uncertain, although both genetic and non-genetic factors are likely important. Interrogating genome-wide germline SNP genotypes in an unselected large cohort of children with ALL, we observed that the component of genomic variation that co segregated with Native American ancestry was associated with risk of relapse (P = 0.0029) even after adjusting for known prognostic factors (P = 0.017). Ancestry related differences in relapse risk were abrogated by the addition of a single extra phase of chemotherapy, indicating that modifications to therapy can mitigate the ancestry-related risk of relapse. PMID- 21297633 TI - Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. AB - Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis. PMID- 21297634 TI - LIN-28 co-transcriptionally binds primary let-7 to regulate miRNA maturation in Caenorhabditis elegans. AB - The highly conserved let-7 microRNA (miRNA) regulates developmental pathways across animal phyla. Mis-expression of let-7 causes lethality in C. elegans and has been associated with several human diseases. We show that timing of let-7 expression in developing worms is under complex transcriptional and post transcriptional control. Expression of let-7 primary transcripts oscillates during each larval stage, but precursor and mature let-7 miRNAs do not accumulate until later in development after LIN-28 protein has diminished. We demonstrate that LIN-28 binds endogenous primary let-7 transcripts co-transcriptionally. We further show that LIN-28 binds endogenous primary let-7 transcripts in the nuclear compartment of human ES cells, suggesting that this LIN-28 activity is conserved across species. We conclude that co-transcriptional interaction of LIN 28 with let-7 primary transcripts blocks Drosha processing and, thus, precocious expression of mature let-7 during early development. PMID- 21297635 TI - Substrate-induced remodeling of the active site regulates human HTRA1 activity. AB - Crystal structures of active and inactive conformations of the human serine protease HTRA1 reveal that substrate binding to the active site is sufficient to stimulate proteolytic activity. HTRA1 attaches to liposomes, digests misfolded proteins into defined fragments and undergoes substrate-mediated oligomer conversion. In contrast to those of other serine proteases, the PDZ domain of HTRA1 is dispensable for activation or lipid attachment, indicative of different underlying mechanistic features. PMID- 21297637 TI - Structural insights into energy regulation of light-harvesting complex CP29 from spinach. AB - CP29, one of the minor light-harvesting complexes of higher-plant photosystem II, absorbs and transfers solar energy for photosynthesis and also has important roles in photoprotection. We have solved the crystal structure of spinach CP29 at 2.80-A resolution. Each CP29 monomer contains 13 chlorophyll and 3 carotenoid molecules, which differs considerably from the major light-harvesting complex LHCII and the previously proposed CP29 model. The 13 chlorophyll-binding sites are assigned as eight chlorophyll a sites, four chlorophyll b and one putative mixed site occupied by both chlorophylls a and b. Based on the present X-ray structure, an integrated pigment network in CP29 is constructed. Two special clusters of pigment molecules, namely a615-a611-a612-Lut and Vio(Zea)-a603-a609, have been identified and might function as potential energy-quenching centers and as the exit or entrance in energy-transfer pathways. PMID- 21297636 TI - Genome-wide mapping of Arabidopsis thaliana origins of DNA replication and their associated epigenetic marks. AB - Genome integrity requires faithful chromosome duplication. Origins of replication, the genomic sites at which DNA replication initiates, are scattered throughout the genome. Their mapping at a genomic scale in multicellular organisms has been challenging. In this study we profiled origins in Arabidopsis thaliana by high-throughput sequencing of newly synthesized DNA and identified ~1,500 putative origins genome-wide. This was supported by chromatin immunoprecipitation and microarray (ChIP-chip) experiments to identify ORC1- and CDC6-binding sites. We validated origin activity independently by measuring the abundance of nascent DNA strands. The midpoints of most A. thaliana origin regions are preferentially located within the 5' half of genes, enriched in G+C, histone H2A.Z, H3K4me2, H3K4me3 and H4K5ac, and depleted in H3K4me1 and H3K9me2. Our data help clarify the epigenetic specification of DNA replication origins in A. thaliana and have implications for other eukaryotes. PMID- 21297638 TI - Competition for XPO5 binding between Dicer mRNA, pre-miRNA and viral RNA regulates human Dicer levels. AB - MicroRNAs (miRNAs) are a class of small, noncoding RNAs that function by regulating gene expression post-transcriptionally. Alterations in miRNA expression can strongly influence cellular physiology. Here we demonstrated cross regulation between two components of the RNA interference (RNAi) machinery in human cells. Inhibition of exportin-5, the karyopherin responsible for pre-miRNA export, downregulated expression of Dicer, the RNase III required for pre-miRNA maturation. This effect was post-transcriptional and resulted from an increased nuclear localization of Dicer mRNA. In vitro assays and cellular RNA immunoprecipitation experiments showed that exportin-5 interacted directly with Dicer mRNA. Titration of exportin-5 by overexpression of either pre-miRNA or the adenoviral VA1 RNA resulted in loss of Dicer mRNA-exportin-5 interaction and reduction of Dicer level. This saturation also occurred during adenoviral infection and enhanced viral replication. Our study reveals an important cross regulatory mechanism between pre-miRNA or viral small RNAs and Dicer through exportin-5. PMID- 21297639 TI - Structural and biochemical studies of the 5'->3' exoribonuclease Xrn1. AB - The 5'->3' exoribonucleases (XRNs) have important functions in transcription, RNA metabolism and RNA interference. The structure of Rat1 (also known as Xrn2) showed that the two highly conserved regions of XRNs form a single, large domain that defines the active site of the enzyme. Xrn1 has a 510-residue segment after the conserved regions that is required for activity but is absent from Rat1/Xrn2. Here we report the crystal structures of Kluyveromyces lactis Xrn1 (residues 1 1,245, E178Q mutant), alone and in complex with a Mn(2+) ion in the active site. The 510-residue segment contains four domains (D1-D4), located far from the active site. Our mutagenesis and biochemical studies show that their functional importance results from their ability to stabilize the conformation of the N terminal segment of Xrn1. These domains might also constitute a platform that interacts with protein partners of Xrn1. PMID- 21297640 TI - Structural landscape of isolated agonist-binding domains from single AMPA receptors. AB - AMPA receptors mediate fast excitatory neurotransmission by converting chemical signals into electrical signals, and thus it is important to understand the relationship between their chemical biology and their function. We used single molecule fluorescence resonance energy transfer to examine the conformations explored by the agonist-binding domain of the AMPA receptor for wild-type and T686S mutant proteins. Each form of the agonist binding domain showed a dynamic, multistate sequential equilibrium, which could be identified only using wavelet shrinkage, a signal processing technique that removes experimental shot noise. These results illustrate that the extent of activation depends not on a rigid closed cleft but instead on the probability that a given subunit will occupy a closed-cleft conformation, which in turn is determined not only by the lowest energy state but also by the range of states that the protein explores. PMID- 21297641 TI - Rapid and efficient clathrin-mediated endocytosis revealed in genome-edited mammalian cells. AB - Clathrin-mediated endocytosis (CME) is the best-studied pathway by which cells selectively internalize molecules from the plasma membrane and surrounding environment. Previous live-cell imaging studies using ectopically overexpressed fluorescent fusions of endocytic proteins indicated that mammalian CME is a highly dynamic but inefficient and heterogeneous process. In contrast, studies of endocytosis in budding yeast using fluorescent protein fusions expressed at physiological levels from native genomic loci have revealed a process that is very regular and efficient. To analyse endocytic dynamics in mammalian cells in which endogenous protein stoichiometry is preserved, we targeted zinc finger nucleases (ZFNs) to the clathrin light chain A and dynamin-2 genomic loci and generated cell lines expressing fluorescent protein fusions from each locus. The genome-edited cells exhibited enhanced endocytic function, dynamics and efficiency when compared with previously studied cells, indicating that CME is highly sensitive to the levels of its protein components. Our study establishes that ZFN-mediated genome editing is a robust tool for expressing protein fusions at endogenous levels to faithfully report subcellular localization and dynamics. PMID- 21297642 TI - CD4+ T cell help and innate-derived IL-27 induce Blimp-1-dependent IL-10 production by antiviral CTLs. AB - Interleukin (IL)-10 is an important regulatory cytokine that can modulate excessive immune mediated injury. Several distinct cell types have been demonstrated to produce IL-10, including most recently CD8+ cytotoxic T lymphocytes (CTLs) responding to respiratory virus infection. Here we report that CD4+ T cell help in the form of IL-2 is required for IL-10 production by CTLs, but not for the induction of CTL effector cytokines. We show that IL-2 derived from CD4+ helper T cells cooperates with innate immune cell-derived IL-27 to amplify IL-10 production by CTLs through a Blimp-1-dependent mechanism. These findings reveal a previously unrecognized pathway that coordinates signals derived from innate and helper T cells to control the production of a regulatory cytokine by CTLs during acute viral infection. PMID- 21297643 TI - Control of the development of CD8alphaalpha+ intestinal intraepithelial lymphocytes by TGF-beta. AB - The molecular mechanisms that direct the development of TCRalphabeta+CD8alphaalpha+ intestinal intraepithelial lymphocytes (IELs) are not thoroughly understood. Here we show that transforming growth factor-beta (TGF beta) controls the development of TCRalphabeta+CD8alphaalpha+ IELs. Mice with either a null mutation in the gene encoding TGF-beta1 or T cell-specific deletion of TGF-beta receptor I lacked TCRalphabeta+CD8alphaalpha+ IELs, whereas mice with transgenic overexpression of TGF-beta1 had a larger population of TCRalphabeta+CD8alphaalpha+ IELs. We observed defective development of the TCRalphabeta+CD8alphaalpha+ IEL thymic precursors (CD4-CD8-TCRalphabeta+CD5+) in the absence of TGF-beta. In addition, we found that TGF-beta signaling induced CD8alpha expression in TCRalphabeta+CD8alphaalpha+ IEL thymic precursors and induced and maintained CD8alpha expression in peripheral populations of T cells. Our data demonstrate a previously unrecognized role for TGF-beta in the development of TCRalphabeta+CD8alphaalpha+ IELs and the expression of CD8alpha in T cells. PMID- 21297645 TI - Dementia in 2010: Paving the way for Alzheimer disease drug development. PMID- 21297646 TI - Headache in 2010: Progress in headache mechanisms and management. PMID- 21297647 TI - Stroke in 2010: Clearing the air on clearing the carotid. PMID- 21297648 TI - Movement disorders in 2010: Parkinson disease-symptoms and treatments. PMID- 21297649 TI - Epilepsy in 2010: Refinement of optimal medical and surgical treatments. PMID- 21297650 TI - Multiple sclerosis in 2010: Advances in monitoring and treatment of multiple sclerosis. PMID- 21297651 TI - Neuroscience insights improve neurorehabilitation of poststroke aphasia. AB - The treatment of aphasias-acquired language disorders-caused by stroke and other neurological conditions has benefitted from insights from neuroscience and neuropsychology. Hebbian mechanisms suggest that massed practice and exploitation of residual neurological capacities can aid neurorehabilitation of patients with poststroke aphasia, and progress in basic neuroscience research indicates that the language system of the human brain is functionally interwoven with perceptual and motor systems. Intensive speech and language therapies, including constraint induced aphasia therapy, that activate both the linguistic and concordant motor circuits utilize the knowledge gained from these advances in neuroscience research and can lead to surprisingly rapid improvements in language performance, even in patients with chronic aphasia. Drug-based therapies alone and in conjunction with behavioral language therapies also increase language performance in patients with aphasia. Furthermore, noninvasive transcranial magnetic stimulation and electrical stimulation techniques that target neuronal activity within perilesional areas might help patients with aphasia to regain lost language functions. Intensive language-action therapies that lead to rapid improvements in language skills might provide a new opportunity for investigating fast plastic neuronal changes in the areas of the brain associated with language processing. Here, we review progress in basic neuroscience research and its translational impact on the neurorehabilitation of language disorders after stroke. PMID- 21297652 TI - A potent chemotherapeutic strategy in prostate cancer: S-(methoxytrityl)-L cysteine, a novel Eg5 inhibitor. AB - Docetaxel-based combination chemotherapy remains the predominant treatment for castration-resistant prostate cancer. However, taxane-related drug resistance and neurotoxicity have prompted us to develop substitute treatment strategies. Eg5 (kinesin spindle protein), which is crucial for bipolar spindle formation and duplicated chromosome separation during the early phase of mitosis, has emerged as an attractive target for cancer chemotherapy. The aim of this study was to investigate the anticancer efficacy of S-(methoxytrityl)-L-cysteine (S(MeO)TLC), a novel Eg5 inhibitor in prostate cancer. Eg5 expression was examined in human prostate cancer cell lines and tissue microarrays were constructed from clinical specimens. Antiproliferative activity of S(MeO)TLC in prostate cancer cells was assessed by a cell viability assay. The anticancer effect and inhibitory mechanism of S(MeO)TLC in prostate cancer cells was further explored by Hoechst staining, flow cytometry and immunofluorescence. In addition, the antitumor effect of S(MeO)TLC on subcutaneous xenograft models was assessed. Eg5 expression was identified in PC3, DU145 and LNCaP cells. More than half of prostate cancer clinical specimens displayed Eg5 expression. S(MeO)TLC exhibited more powerful anticancer activity in prostate cancer cells compared with the other four Eg5 inhibitors tested. S(MeO)TLC induced cell death after arresting dividing cells at mitosis with distinct monopolar spindle formation. S(MeO)TLC exhibited its significant inhibitory activity (P<0.05) on subcutaneous xenograft models also through induction of mitotic arrest. We conclude that Eg5 is a good target for prostate cancer chemotherapy, and S(MeO)TLC is a potent promising anticancer agent in prostate cancer. PMID- 21297653 TI - Low-dose testosterone treatment decreases oxidative damage in TM3 Leydig cells. AB - Testosterone replacement therapy has benefits for aging men and those with hypogonadism. However, the effects of exogenous testosterone on Leydig cells are still unclear and need to be clarified. In this report, we demonstrate that testosterone supplementation can reduce oxidative damage in Leydig cells. The TM3 Leydig cell line was used as an in vitro cell model in this study. Cytoprotective effects were identified with 100-nmol l-1 testosterone treatment, but cytotoxic effects were found with >= 500-nmol l-1 testosterone supplementation. Significantly reduced reactive oxygen species (ROS) generation, lipid peroxide contents and hypoxia induction factor (HIF)-1alpha stabilization and activation were found with 100-nmol l-1 testosterone treatment. There was a 1.72-fold increase in ROS generation in the 500-nmol l-1 compared to the 100-nmol l-1 testosterone treatment. A 1.58-fold increase in steroidogenic acute regulatory protein (StAR) expression was found in 50-nmol l-1 testosterone-treated cells (P < 0.01). Chemically induced hypoxia was attenuated by testosterone supplementation. Leydig cells treated with low-dose testosterone supplementation showed cytoprotection by decreasing ROS and lipid peroxides, increasing StAR expression and relieving hypoxia stress as demonstrated by HIF-1alpha stabilization. Increased oxidative damage was found with >= 500-nmol l-1 testosterone manipulation. The mechanism governing the differential dose effects of testosterone on Leydig cells needs further investigation in order to shed light on testosterone replacement therapy. PMID- 21297654 TI - Meiotic recombination and male infertility: from basic science to clinical reality? AB - Infertility is a common problem that affects approximately 15% of the population. Although many advances have been made in the treatment of infertility, the molecular and genetic causes of male infertility remain largely elusive. This review will present a summary of our current knowledge on the genetic origin of male infertility and the key events of male meiosis. It focuses on chromosome synapsis and meiotic recombination and the problems that arise when errors in these processes occur, specifically meiotic arrest and chromosome aneuploidy, the leading cause of pregnancy loss in humans. In addition, meiosis-specific candidate genes will be discussed, including a discussion on why we have been largely unsuccessful at identifying disease-causing mutations in infertile men. Finally clinical applications of sperm aneuploidy screening will be touched upon along with future prospective clinical tests to better characterize male infertility in a move towards personalized medicine. PMID- 21297655 TI - PSA-based prostate cancer screening: the role of active surveillance and informed and shared decision making. AB - Since the first publication describing the identification of prostate-specific antigen (PSA) in the 1960s, much progress has been made. The PSA test changed from being initially a monitoring tool to being also used as a diagnostic tool. Over time, the test has been heavily debated due to its lack of sensitivity and specificity. However, up to now the PSA test is still the only biomarker for the detection and monitoring of prostate cancer. PSA-based screening for prostate cancer is associated with a high proportion of unnecessary testing and overdiagnosis with subsequent overtreatment. In the early years of screening for prostate cancer, high rates of uptake were very important. However, over time the opinion on PSA-based screening has shifted towards the notion of informed choice. Nowadays, it is thought to be unethical to screen men without them being aware of the pros and cons of PSA testing, as well as the fact that an informed choice is related to better patient outcomes. Now, as the results of three major screening studies have been presented and the downsides of screening are becoming better understood, informed choice is becoming more relevant. PMID- 21297656 TI - Single-centre study comparing standard apical dissection with a modified technique to facilitate vesico-urethral anastomosis during laparoscopic radical prostatectomy. AB - A modified apical dissection of the prostate to improve the efficiency of vesico urethral anastomosis (VUA) in laparoscopic radical prostatectomy (LRP) was reported. A total of 42 patients were randomly selected and enrolled in this study. A standard LRP was performed in 21 patients (group 1), whereas a novel, modified apical dissection of the prostate in LRP was performed in another 21 patients (group 2). Surgical data, total operative time, VUA time, extravasation rate, catheterisation time, occurrence of anastomotic strictures, and the early and late continence rates were analysed statistically. No differences in clinical or pathological characteristics were determined between the two groups. The total operative time, VUA time, blood loss and catheterisation time were lower in group 2, which received the novel, modified technique compared with group 1, which received the standard technique to dissect the apex of the prostate (P < 0.01 for each variable). Regarding the extravasation rate and the occurrence of anastomotic strictures, no significant differences were found between the two groups (P > 0.05 for each). After catheter removal, a statistically significant difference in the continence rates was present at 3 and 30 days post operation in the two groups (P < 0.01, respectively). At 90 days post operation, the difference, although still present, was no longer statistically significant (P > 0.05). The novel, modified apical dissection of the prostate facilitates the VUA and significantly improves the efficacy of the procedure and early restoration of continence. PMID- 21297657 TI - Is 37LRP cell surface receptor for PSP94? PMID- 21297658 TI - Plasmid-based Stat3 siRNA delivered by hydroxyapatite nanoparticles suppresses mouse prostate tumour growth in vivo. AB - DNA vector-based Stat3-specific RNA interference (si-Stat3) blocks Stat3 signalling and inhibits prostate tumour growth. However, the antitumour activity depends on the efficient delivery of si-Stat3. The effects on the growth of mouse prostate cancer cells of si-Stat3 delivered by hydroxyapatite were determined in this study. RM-1 tumour blocks were transplanted into C57BL/6 mice. CaCl2 modified hydroxyapatite carrying si-Stat3 plasmids were injected into tumours, and tumour growth and histology were determined. The expression levels of Stat3, pTyr-Stat3, Bcl-2, Bax, Caspase3, VEGF and cyclin D1 were measured by western blot analysis. Amounts of apoptosis in cancer cells were analysed with immunohistochemistry and the terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling (TUNEL) assay. The results showed that hydroxyapatite-delivered si-Stat3 significantly suppressed tumour growth up to 74% (P < 0.01). Stat3 expression was dramatically downregulated in the tumours. The immunohistochemistry and TUNEL results showed that si-Stat3-induced apoptosis (up to 42%, P < 0.01). The Stat3 downstream genes Bcl-2, VEGF and cyclin D1 were also strongly downregulated in the tumour tissues that also displayed significant increases in Bax expression and Caspase3 activity. These results suggest that hydroxyapatite can be used for the in vivo delivery of plasmid-based siRNAs into tumours. PMID- 21297660 TI - Loss of a single Hic1 allele accelerates polyp formation in Apc(Delta716) mice. AB - Adenomatous polyposis coli (APC) gene mutations have been implicated in familial and sporadic gastrointestinal (GI) cancers. APC mutations are associated with autosomal dominant inheritance of disease in humans. Similarly, mice that contain a single mutant APC gene encoding a protein truncated at residue 716 (Apc(Delta716)) develop multiple polyps throughout the GI tract as early as 4 weeks after birth. Inactivation of another tumor suppressor gene, Hypermethylated in Cancer 1 (HIC1), often occurs in human colon cancers, among others, via CpG island hypermethylation. Homozygous deletion of Hic1 in mice results in major developmental defects and embryonic lethality. Hic1 heterozygotes have previously been shown to develop tumors of a variety of tissue types. We now report that loss of a single Hic1 allele can promote crypt hyperplasia and neoplasia of the GI tract, and Hic1(+/-), Apc(+/Delta716) double heterozygotes (DH) develop increased numbers of polyps throughout the GI tract at 60 days. Hic1 expression is absent in polyps from DH mice, with concomitant increased expression of two transcriptional repression targets of Hic1, Sirt1 and Sox9. Together, our data suggest that loss of a gene frequently silenced via epigenetic mechanisms, Hic1, can cooperate with loss of a gene mutated in GI cancer, Apc, to promote tumorigenesis in an in vivo model of multiple intestinal neoplasia. PMID- 21297661 TI - MiniSOX9, a dominant-negative variant in colon cancer cells. AB - Inherited and acquired changes in pre-mRNA processing have significant roles in human diseases, especially cancer. Characterization of aberrantly spliced mRNAs may thus contribute to understand malignant transformation. We recently reported an anti-oncogenic potential for the SOX9 transcription factor in the colon. For instance, the Sox9 gene knock out in the mouse intestine results in an excess of proliferation with appearance of hyperplasia. SOX9 is expressed in colon cancer cells but its endogenous activity is weak. We looked for SOX9 variants that may impair SOX9 activity in colon cancer cells and we discovered MiniSOX9, a truncated version of SOX9 devoid of transactivation domain as a result of retention of the second intron. A significant overexpression of MiniSOX9 mRNA in human tumor samples compared with their matched normal tissues was observed by real-time reverse transcriptase-PCR. Immunohistochemistry revealed that MiniSOX9 is expressed at high levels in human colon cancer samples whereas it is undetectable in the surrounding healthy tissues. Finally, we discovered that MiniSOX9 behaves as a SOX9 inhibitor, inhibits protein kinase Calpha promoter activity and stimulates the canonical Wnt pathway. This potential oncogenic activity of the SOX9 locus gives new insights on its role in colon cancer. PMID- 21297662 TI - Homeodomain protein DLX4 counteracts key transcriptional control mechanisms of the TGF-beta cytostatic program and blocks the antiproliferative effect of TGF beta. AB - The antiproliferative activity of transforming growth factor-beta (TGF-beta) is essential for maintaining normal tissue homeostasis and is lost in many types of tumors. Gene responses that are central to the TGF-beta cytostatic program include activation of the cyclin-dependent kinase inhibitors, p15(Ink4B) and p21(WAF1/Cip1), and repression of c-myc. These gene responses are tightly regulated by a repertoire of transcription factors that include Smad proteins and Sp1. The DLX4 homeobox patterning gene encodes a transcription factor that is absent from most normal adult tissues, but is expressed in a wide variety of malignancies, including lung, breast, prostate and ovarian cancers. In this study, we demonstrate that DLX4 blocks the antiproliferative effect of TGF-beta. DLX4 inhibited TGF-beta-mediated induction of p15(Ink4B) and p21(WAF1/Cip1) expression. DLX4 bound and prevented Smad4 from forming complexes with Smad2 and Smad3, but not with Sp1. However, DLX4 also bound and inhibited DNA-binding activity of Sp1. In addition, DLX4 induced expression of c-myc independently of TGF-beta/Smad signaling. The ability of DLX4 to counteract key transcriptional control mechanisms of the TGF-beta cytostatic program could explain, in part, the resistance of tumors to the antiproliferative effect of TGF-beta. PMID- 21297663 TI - Myc overexpression brings out unexpected antiapoptotic effects of miR-34a. AB - Downregulation of microRNA-34a by Myc is known to be essential for tumorigenesis and improve tumor-cell survival. Conversely, upregulation of miR-34a by p53 is thought to enhance its acetylation and activity and contribute to the pro apoptotic effects of this tumor suppressor. We sought to determine whether restoration of miR-34a levels in B-lymphoid cells with Myc overexpression would aid therapeutic apoptosis. Unexpectedly, delivery of miR-34a, which doesn't target p53 directly, severely compromised steady-state p53 levels. This effect was preceded and mediated by direct targeting of Myc, which sustained p53 protein levels via the Arf-Hdm2 pathway. As a result, in the presence of Myc, miR-34a inhibited p53-dependent bortezomib-induced apoptosis as efficiently as anti-p53 small interfering RNA. Conversely, inhibition of miR-34a using antisense RNA sensitized lymphoma cells to therapeutic apoptosis. Thus, in tumors with deregulated Myc expression, miR-34a confers drug resistance and could be considered a therapeutic target. PMID- 21297664 TI - Heat shock protein Hsp72 plays an essential role in Her2-induced mammary tumorigenesis. AB - The major heat shock protein Hsp72 is expressed at elevated levels in many human cancers and its expression correlates with tumor progression. Here, we investigated the role of Hsp72 in Her2 oncogene-induced neoplastic transformation and tumorigenesis. Expression of Her2 in untransformed MCF10A mammary epithelial cells caused transformation, as judged by foci formation in culture and tumorigenesis in xenografts. However, expression of Her2 in Hsp72-depleted cells failed to induce transformation. The anti-tumorigenic effects of Hsp72 downregulation were associated with cellular senescence because of accumulation of p21 and depletion of survivin. Accordingly, either knockdown of p21 or expression of survivin reversed this senescence process. Further, we developed an animal model of Hsp72-dependent breast cancer associated with expression of Her2. Knockout (KO) of Hsp72 almost completely suppressed tumorigenesis in the MMTVneu breast cancer mouse model. In young Hsp72 KO mice, expression of Her2 instead of mammary tissue hyperplasia led to suppression of duct development and blocked alveolar budding. These effects were due to massive cell senescence in mammary tissue, which was associated with upregulation of p21 and downregulation of survivin. Therefore, Hsp72 has an essential role in Her2-induced tumorigenesis by regulating oncogene-induced senescence pathways. PMID- 21297665 TI - Bax inhibitor 1 in apoptosis and disease. AB - Bax inhibitor 1 (BI-1) was originally discovered as an inhibitor of Bax-induced apoptosis; this review highlights the fundamental importance of BI-1 in a wider context, including in tissue homeostasis and as a regulator of cellular stress. BI-1 has been shown to interact with a broad range of partners to inhibit many facets of apoptosis, such as reactive oxygen species production, cytosolic acidification and calcium levels as well as endoplasmic reticulum stress signalling pathways. BI-1's anti-apoptotic action initially enables the cell to adapt to stress, although if the stress is prolonged or severe the actions of BI 1 may promote apoptosis. This almost universal anti-apoptotic capacity has been shown to be manipulated during infection with enteropathogenic and enterohaemorrhagic Escherichia coli inhibiting host cell death through direct interaction between their effector NleH and BI-1. In addition, BI-1 activity is important in a large number of cancers, promoting metastasis by modulating actin dynamics, a process dependent upon the BI-1 C-terminus and BI-1:actin interaction. Manipulation of BI-1 therefore has the potential for significant therapeutic benefit in a wide range of human diseases. PMID- 21297666 TI - E-cadherin inhibits tumor cell growth by suppressing PI3K/Akt signaling via beta catenin-Egr1-mediated PTEN expression. AB - E-cadherin is a cell-cell adhesion protein and tumor suppressor that is silenced in many malignancies. E-cadherin is thought to suppress tumor cell growth by antagonizing beta-catenin signaling. However, the role of E-cadherin in ovarian cancer progression is still controversial. In this study, we showed that loss of E-cadherin induced ovarian cancer cell growth and constitutive activation of phosphoinositide 3-kinase (PI3K)/Akt signaling by the inhibition of phosphatase and tensin homolog (PTEN) transcription through the downregulation of early growth response gene 1 (Egr1). In addition, immunofluorescence microscopy and T cell factor promoter/luciferase reporter assays showed that E-cadherin loss was associated with enhanced nuclear beta-catenin signaling. Constitutive activation of PI3K/Akt signaling reinforced nuclear beta-catenin signaling by inactivating glycogen synthase kinase-3beta indicating cross-talk between the PI3K/Akt and beta-catenin signaling pathways. Finally, we found that E-cadherin negatively regulates tumor cell growth, in part, by positively regulating PTEN expression via beta-catenin-mediated Egr1 regulation, thus influencing PI3K/Akt signaling. In summary, endogenous E-cadherin inhibits PI3K/Akt signaling by antagonizing beta-catenin-Egr1-mediated repression of PTEN expression. Thus, the loss of E cadherin itself may contribute to dysregulated PI3K/Akt signaling through its effects on PTEN, or it may exacerbate the frequent activation of PI3K/Akt signaling that occurs as a result of overexpression, mutation and/or amplification. PMID- 21297667 TI - Targeting SET/I(2)PP2A oncoprotein functions as a multi-pathway strategy for cancer therapy. AB - The SET oncoprotein participates in cancer progression by affecting multiple cellular processes, inhibiting the tumor suppressor protein phosphatase 2A (PP2A), and inhibiting the metastasis suppressor nm23-H1. On the basis of these multiple activities, we hypothesized that targeted inhibition of SET would have multiple discrete and measurable effects on cancer cells. Here, the effects of inhibiting SET oncoprotein function on intracellular signaling and proliferation of human cancer cell lines was investigated. We observed the effects of COG112, a novel SET interacting peptide, on PP2A activity, Akt signaling, nm23-H1 activity and cellular migration/invasion in human U87 glioblastoma and MDA-MB-231 breast adenocarcinoma cancer cell lines. We found that COG112 interacted with SET protein and inhibited the association between SET and PP2A catalytic subunit (PP2A-c) and nm23-H1. The interaction between COG112 and SET caused PP2A phosphatase and nm23-H1 exonuclease activities to increase. COG112-mediated increases in PP2A activity resulted in the inhibition of Akt signaling and cellular proliferation. Additionally, COG112 inhibited SET association with Ras related C(3) botulinum toxin substrate 1 (Rac1), leading to decreased cellular migration and invasion. COG112 treatment releases the SET-mediated inhibition of the tumor suppressor PP2A, as well as the metastasis suppressor nm23-H1. These results establish SET as a novel molecular target and that the inhibition of SET may have beneficial effects in cancer chemotherapy. PMID- 21297668 TI - p16(Ink4a) overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors. AB - p16(Ink4a) is a protein involved in regulation of the cell cycle. Currently, p16(Ink4a) is considered a tumor suppressor protein because of its physiological role and downregulated expression in a large number of tumors. Intriguingly, overexpression of p16(Ink4a) has also been described in several tumors. This review attempts to elucidate when and why p16(Ink4a) overexpression occurs, and to suggest possible implications of p16(Ink4a) in the diagnosis, prognosis and treatment of cancer. PMID- 21297669 TI - Untapped potential: exploiting fungi in bioremediation of hazardous chemicals. AB - Fungi possess the biochemical and ecological capacity to degrade environmental organic chemicals and to decrease the risk associated with metals, metalloids and radionuclides, either by chemical modification or by influencing chemical bioavailability. Furthermore, the ability of these fungi to form extended mycelial networks, the low specificity of their catabolic enzymes and their independence from using pollutants as a growth substrate make these fungi well suited for bioremediation processes. However, despite dominating the living biomass in soil and being abundant in aqueous systems, fungi have not been exploited for the bioremediation of such environments. In this Review, we describe the metabolic and ecological features that make fungi suited for use in bioremediation and waste treatment processes, and discuss their potential for applications on the basis of these strengths. PMID- 21297670 TI - Are bloodstream leukocytes Trojan Horses for the metastasis of Staphylococcus aureus? AB - Staphylococcus aureus bacteraemia remains very difficult to treat, and a large proportion of cases result in potentially lethal metastatic infection. Unpredictable and persistent bacteraemia in the face of highly active, usually bactericidal antibiotics is the strongest predictor of death or disseminated disease. Although S. aureus has conventionally been considered an extracellular pathogen, much evidence demonstrates that it can survive intracellularly. In this Opinion article, we propose that phagocytes, and specifically neutrophils, represent a privileged site for S. aureus in the bloodstream, offering protection from most antibiotics and providing a mechanism by which the bacterium can travel to and infect distant sites. Furthermore, we suggest how this can be experimentally confirmed and how it may prompt a change in the current paradigm of S. aureus bacteraemia and identify better treatment options for improved clinical outcomes. PMID- 21297671 TI - Intensive chemotherapy for a relapsed ALL patient who received living-donor lobar lung transplantation. PMID- 21297672 TI - Combining allografting with mTOR inhibitors for metastatic renal cell cancer. PMID- 21297673 TI - Treosulfan-based preparative regimens for allo-HSCT in childhood hematological malignancies: a retrospective study on behalf of the EBMT pediatric diseases working party. AB - This retrospective analysis evaluated 51 children (0.7-17 years; median eight) with high-risk or advanced hematological malignancies, including 18 (35%) patients undergoing second/third hematopoietic SCT (allo-HSCT), not eligible for standard myeloablative regimens and transplanted from matched sibling (MSD) (n=24) or matched unrelated (MUD) (n=27) donors. Preparative regimens were based on treosulfan (TREO) i.v., a structural analog of BU, given at total dose of 30 g/m(2) (n=21) or 36-42 g/m(2) (n=30) in combination with, fludarabine, cyclophosphamide, melphalan and/or VP-16 according to diagnosis, and risk factors. Deaths due to early regimen-related toxicity (RRT) did not occur. Nonrelapse mortality was 8% at 1 year and 16% after 4 years. Myeloid engraftment was achieved in 94%, complete donor chimerism in 90% of patients. A 4-year incidence of relapse was 24%, and was significantly lower after MUD-HSCT (8%) than after MSD-HSCT (39%), but similar in children undergoing first (28%) or second/third HSCT (17%). A 4-year disease-free survival was 61%, but it was significantly better in myeloid (73%), than in lymphoid malignancies (41%). Thus, children with high-risk and advanced hematological malignancies and high-risk of life-threatening RRT can be transplanted effectively and safely using TREO-based regimens. Particularly favorable results were achieved in myeloid malignancies and in children undergoing second HSCT. PMID- 21297674 TI - WMDA guidelines for subsequent donations following initial BM or PBSCs. AB - Unrelated donor SCT activity is increasing, and in 5-10% of cases a subsequent donation of stem cells or donor lymphocytes may be requested. Second donations of stem cells are not associated with an increased chance of donor complications, but the yield of CD34+ cells may be lower in some donors. It is acceptable practice for any registry to request subsequent donations and it is recommended that donors should be counselled about this possibility before their first donation. Guidance is provided on the requirements for further medical assessment, the procedures used to agree requests, frequency and timing of donation and timing and duration of donor follow up. PMID- 21297675 TI - [Not Available]. PMID- 21297676 TI - [Not Available]. PMID- 21297677 TI - From Russia With WHO. PMID- 21297678 TI - In praise of the annual check-up. PMID- 21297679 TI - Fetal alcohol syndrome. PMID- 21297680 TI - The opted-out MD. PMID- 21297681 TI - Yet another ripper. PMID- 21297682 TI - Gee, thanks. PMID- 21297683 TI - As it happened: how important is a good history? AB - The problem in this case was not so much the diagnosis as the etiology and its possible consequences. I am sure we all agree that a good history is important, but are we practicing what we preach? Judge for yourself. PMID- 21297684 TI - [Not Available]. PMID- 21297685 TI - Immunization and the year of the child: an achievable goal. PMID- 21297686 TI - The nationalist view. PMID- 21297687 TI - Infant feeding problems. PMID- 21297688 TI - Device clears throat of foreign objects. PMID- 21297689 TI - Physiology of the immune response. AB - The established mechanisms of immune responsiveness to foreign or self components are reviewed, with particular reference to relevant clinical problems and current research. A multitiered immunological system of cellular and subcellular elements are involved when the body deals with perturbations from without or within. The concept exists that a delicate balance between positive ('helper') and negative ('suppressor') forces is essential to maintaining health. Brief discussion is given to diagnosis of immune abnormalities in the light of these facts. PMID- 21297690 TI - Controversies in viral immunization. AB - Immunization has contributed to an impressive reduction in morbidity and mortality of infectious diseases. As diseases are brought under control and public opinion desires ethical review of immunization and health delivery costs, accepted practices are questioned. Current controversies in viral immunization are raised and discussed in light of recent findings. PMID- 21297691 TI - The HBsAg-Positive Patient: Implications and a Guide to Management. AB - Following infection with hepatitis B virus (HBV), hepatitis B surface antigen (HBsAg) is detectable in the serum before liver function tests become abnormal and before development of clinical features of hepatitis; HBsAg tests usually become negative shortly after illness subsides. Screening individuals such as volunteer blood donors for HBsAg occasionally reveals apparently healthy people who are persistent carriers of HBsAg; the majority have no laboratory evidence of hepatitis whereas others have biochemical or histologic findings of chronic liver disease. PMID- 21297692 TI - Autoimmune bowel disease. AB - The gastrointestinal tract is one of the major lymphatic organs of the body. It is capable of many immunological responses and is exposed to more foreign antigens and pathogens than any other part of the body. Because of the complexity of the GI tract and the difficulty in studying normal responses, even the normal physiology of the immunological aspects of the bowel are not fully understood.Definite abnormalities in immunity are apparent in some GI diseases; the three most common are pernicious anemia, ulcerative colitis, and Crohn's disease. Many of the abnormal immune states seen in these diseases, the possibilities of autoimmunity, some of the extra-intestinal manifestations of these diseases and their possible relationship to an autoimmune state are discussed in this article. PMID- 21297693 TI - The immune response and the connective tissue diseases. AB - Immunological aberrations are recognizable in a number of the connective diseases such as SLE and RA. Some of these abnormalities are reviewed, in particular the variety of circulating auto-antibodies and their possible relationship to disease, as well as some evidence for involvement of circulating immune complexes. A number of these abnormalities have become the basis for essential tests in the diagnosis and management of these disorders and helping monitor their response to therapy. PMID- 21297694 TI - Self evaluation program. PMID- 21297695 TI - A brief update in psychopharmacology. AB - Recent developments in psychopharmacology have changed the thinking on prescription of several psychoactive drugs. Also, several known facts about administration of these drugs have been underemphasized. The current knowledge about each class of psychoactive drug is briefly reviewed in this article. PMID- 21297696 TI - The Family Doctor's Appointment System. AB - This two part article describes a study of appointment systems used in Alberta family practices, and ways in which appointment systems might be improved. Most respondents to the survey practiced in some form of expense-sharing system, most used three rooms in their practice, and urban physicians saw more patients per hour than did rural doctors. In setting up an appointment system, the physician's current practice should be studied and timed, then set up in blocks of eight visits, starting with two patients to allow for preparation time. PMID- 21297697 TI - Age is not a disease. PMID- 21297698 TI - Resuscitation and responsibility. PMID- 21297699 TI - [Not Available]. PMID- 21297700 TI - [Not Available]. PMID- 21297701 TI - Forced immunization. PMID- 21297702 TI - Productivity and women doctors. PMID- 21297704 TI - More than the price is wrong. PMID- 21297703 TI - Amnesty international. PMID- 21297705 TI - Who's on First? PMID- 21297706 TI - Electronic Monitor Controls IV Flow. PMID- 21297707 TI - Acquired bacterial infection in the newborn. AB - Sepsis in the neonatal period constitutes a major diagnostic and therapeutic challenge for the physician involved in the care of newborn infants. The paucity of definitive clinical symptoms and signs necessitates a comprehensive knowledge of the pathogenesis and clinical findings of septicemia. Early commencement of appropriate antimicrobial therapy is of utmost importance if inroads are to be made into the high morbidity and mortality rates of this disease entity. PMID- 21297708 TI - [Not Available]. PMID- 21297709 TI - The prenatal assessment of fetal health. AB - This article reviews the objectives, indications and methods currently used to assess fetal health in pregnancies at risk of fetoplacental dysfunction. The graphic display of clinical data encourages the physician to recognize deviations from the norm and assists in the selection of patients for assessment by the more sophisticated tests of fetoplacental function. PMID- 21297710 TI - The need for improved perinatal care in prevention of cerebral palsy. AB - Of 314 children assessed at the Ontario Crippled Children's Centre during 1975 77, 84% had cerebral palsy resulting from potentially preventable perinatal factors. The importance of risk scoring in pregnancy is stressed, as is the necessity for referral to a well equipped perinatal centre when problems are anticipated. The majority of children in this study were born in centres where these facilities were not available. PMID- 21297711 TI - Jaundice in the newborn. AB - In some centres, 20% of healthy new born infants have bilirubin greater than 12 mg/dl. Sorting out the sick infants, preventing kernicterus and encouraging breastfeeding may seem like conflicting goals. The family physician plays a critical role in preventing dangerous jaundice before birth and maintaining the calm afterwards. PMID- 21297712 TI - Helping families explore parenthood alternatives. AB - As many more couples are choosing childlessness as a lifestyle, physicians are more frequently being consulted about alternatives. Changing cultural values as well as changing attitudes to women have opened up these alternatives; the physician must ensure that he or she does not steer patients towards an alternative that may not be for them. Examples of six couples illustrate how childfree couples cope with the implications of their decision. PMID- 21297713 TI - The axial percussion test for fracture. AB - This article describes axial percussion as a helpful new sign in the clinical diagnosis of certain fractures. Tapping, or percussion, produces a force which is transmitted along the shaft of a bone and this, in turn, will cause pain at the site of a recent transverse fracture. Because no force is applied at the site of injury, there is usually good patient cooperation and compliance during the test. It is useful in diagnosing transverse fractures of long bones, prior to radiologic investigation, or at locations where X-ray facilities are not immediately available, such as the home or roadside. PMID- 21297714 TI - A non-academic commentary: doc looks at the 25th anniversary. PMID- 21297716 TI - [Not Available]. PMID- 21297715 TI - [Not Available]. PMID- 21297717 TI - Drugs or vitamins? PMID- 21297718 TI - Research neglected. PMID- 21297719 TI - [Not Available]. PMID- 21297720 TI - Licensure debate. PMID- 21297721 TI - CPS distribution. PMID- 21297722 TI - Child abuse legislation. PMID- 21297723 TI - The trouble with guarantees. PMID- 21297724 TI - Soft eartips improve acoustics of stethoscopes. PMID- 21297725 TI - The limping child. AB - The challenge of the limping child demands that the primary care physician identify those problems which are urgent, when neglect can harm the child, and to provide appropriate supportive care for those which are not. The approach to the limping child should consider the child's age, whether or not the limp is painful, and certain key physical findings. PMID- 21297726 TI - Recognition of orofacial fracture. AB - This is a guide for the emergency physician or family doctor to help in the assessment and management of facial fractures. Signs and symptoms, complications and diagnostic difficulties are dealt with in some detail. The importance of carefully examining the entire patient is stressed. Most facial fractures can wait for swelling to subside before they are treated. This ensures better diagnosis and allows time for more sophisticated treatment methods so that reductions and fixation can be perfect. PMID- 21297727 TI - [Not Available]. PMID- 21297728 TI - Diagnosis and management of involutional osteoporosis. AB - Of postmenopausal women, 20-30% will experience symptomatic involutional osteoporosis. Though the cause is still poorly defined, recent information gives the family physician several routes to treat effectively most patients who become symptomatic. Two other responsibilities exist, however: defining occult causes for the porotic process which may be of greater importance than the osteoporosis itself, and attempting to treat patients at risk for future osteoporosis prophylactically. The latter is a task where we have very effective modes of therapy, but we are only just beginning to develop means of defining that populace destined to suffer from future osteoporosis. PMID- 21297729 TI - Rehabilitation of the patient with a fractured hip. AB - Fracture of the hip is a common traumatic event in the elderly. Surgical repair is the treatment of choice for most patients, but represents only the first phase in the total rehabilitation of the patient. A comprehensive team approach, involving the patient, the family, the physician, nursing personnel and rehabilitation staff, is mandatory if the elderly person is to achieve maximal recovery and hopefully return to his normal lifestyle. Lack of a team approach leads to ineffectual therapy, with the likelihood that the patient will become unnecessarily institutionalized. However, some patients will be very poor candidates for rehabilitation if already at a non-ambulatory, heavy care level, with a variety of complicated medical conditions such as congestive heart failure, diabetes and obstructive lung disease. Realistic, individual goals must be set. PMID- 21297731 TI - Missionary doctor-in deepest toronto. PMID- 21297730 TI - A combination theory on the mechanism of acupuncture analgesia. AB - Pain relief is a puzzle in medicine. No possible single theory can give a satisfactory explanation of the mechanism of acupuncture analgesia. Various theories have been advanced but none is acceptable-even to the proponents themselves. In this paper a combination theory is used to try to explain the possible mechanism by using the 'specific receptors theory', 'gate-control theory', 'electro-interference theory' and the most recent 'endorphin-release theory'. PMID- 21297732 TI - Surgical Contraception: It's Anything But Free. PMID- 21297734 TI - College memories. PMID- 21297733 TI - [Not Available]. PMID- 21297735 TI - Uses for CPS. PMID- 21297737 TI - Answering device pages doctor for emergency calls. PMID- 21297736 TI - Accountability through records. PMID- 21297738 TI - Surgical reversal of tubal ligation. AB - An increasing number of women are requesting reversal of previous tubal sterilization. The potential for reversibility of the commonly performed sterilization procedures is discussed in connection with the emerging profile of the woman who is at risk of changing her mind. Prior to tubal reconstruction, an infertility screening process should be instituted. Details of this process are given. The current controversies about terminology, the role of splints and stents, the place of postoperative lavage, and the role of systemic or intraperitoneal anti-inflammatory agents are presented, together with the arguments for and against microsurgical procedures. PMID- 21297739 TI - [Not Available]. PMID- 21297740 TI - Tendon injuries: surgery or not? AB - Early recognition of major tendon disruption is within the clinical expertise of the family doctor. The treatment of most major tendon injuries is early surgical repair. PMID- 21297741 TI - Intraocular lens prostheses in cataract surgery. AB - The introduction of intraocular lens prostheses presents some real advantages for aphakic patients, but these must be balanced against practical and theoretical objections. Indications include the patient's advancing age, inability to use contact lenses and the presence of monocular cataract. Contraindications include the young patient, the one-eyed patient, and the presence of any ocular disease known to prejudice success. PMID- 21297742 TI - Should immunization schedules be legislated? PMID- 21297743 TI - Failure of intrauterine contraceptives: a review. AB - Accidental pregnancies with intrauterine devices may in part be attributed to inappropriate patient selection, lack of insertion expertise by physicians, and downward migration of IUDs from initial placement position. Available research on these factors is reviewed and a clinical protocol using ultrasound is proposed to detect and correct malpositioned devices. PMID- 21297744 TI - Cardiovascular effects of tricyclic and tetracyclic antidepressants. AB - This article reviews all available studies on the cardiovascular effects of tri- and tetracyclic antidepressants at therapeutic and toxic levels. There is growing evidence that tricyclics, even at therapeutic levels, can be cardiotoxic. Plasma TCA levels are too variable to define a safe therapeutic range. Any patient showing cardiovascular side effects should have an ECG before continuing medication. PMID- 21297745 TI - Academic commentary faculty development: some thoughts about the process and content. AB - Faculty development, particularly that aspect of it concerned with increasing the educational and teaching skills of faculty members, is currently a major issue for medicine in general-and family medicine in particular. This article presents the author's views about what might be aspects of the guiding philosophy and content of such a program of faculty development, where it is concerned with increasing teaching skills.These views have been distilled over several years of personal growth and development, whilst working in this area as an educator within the RACGP's family medicine program, as a participant and facilitator in international workshops examining related topics, and most recently as a visiting professor within the McGill Department of Family Medicine at Jewish General Hospital, Montreal. PMID- 21297746 TI - The future of family medicine. PMID- 21297747 TI - Times change-and so does canadian family physician. PMID- 21297748 TI - [Not Available]. PMID- 21297749 TI - More on flurazepam. PMID- 21297750 TI - Reader appeals for aid to boat people.. PMID- 21297751 TI - Pas en francais, s'il vous plait.. PMID- 21297752 TI - Cancer of the cervix: a 20 year follow up. AB - Twenty-nine cases of carcinoma in situ of the cervix were detected during less than ten years of private family practice, using routine Pap smears as a case finding technique. In 20 years' follow up of those patients, one patient developed recurrent invasive cancer and died. These results are in keeping with others from the recent literature. These patients should be followed closely because there is significant mortality from recurrence of carcinoma. The family physician is in an excellent position for case finding and early diagnosis because of the long natural history of cancer of the cervix. This approach, coupled with appropriate follow up, can prevent much human suffering. PMID- 21297753 TI - Epidemiology of the ten most common neoplasms. AB - Excluding skin cancer, the most prevalent cancers in Canada are those of lung, breast, colon and rectum, stomach, pancreas, uterus, ovary, prostate and bladder, besides leukemia and lymphomas. Those of the lung, and to a lesser extent pancreas and uterus and the lymphomas are increasing, while stomach, cervix and bladder in females are decreasing. The etiological factors believed relevant are discussed for each of these sites, but two are common to a number of sites: at least a third of cancer cases and 40% of cancer deaths are probably attributable to cigaret smoking and excess fat in the diet. PMID- 21297754 TI - Controversy in cancer of the breast. AB - Cancer of the breast is a capricious disease. Until we know the etiology and can accurately appraise its extent we cannot give accurate prognosis and our therapy is often palliative. There are still controversies over the incidence and whether any true change has been made in mortality from the disease. The place of xeromammography in detecting cancer of the breast is still unsettled. When there are so many unknowns it is not remarkable that the best treatment is so controversial. Each form of therapy has advantages and disadvantages; at present we are unable to predict with accuracy which patient will benefit most from which regimen. We need adequate numbers of patients in properly controlled studies to draw conclusions from reports on the course and therapy of such a variable disease. PMID- 21297755 TI - Acute leukemias in children. AB - With combination chemotherapy approximately 50% of children with lymphoblastic leukemia survive for five or more years and it is now realistic to hope for a cure. Development of sophisticated cytochemical and immunological techniques have enabled us to recognize the factors that predispose to treatment failures. The survival in acute non-lymphocytic leukemia continues to be poor despite the introduction of several innovative treatment regimens. Current research is focused on the manipulation of the host-tumor immune response to eradicate the disease by treatment modalities such as immunotherapy and bone marrow transplantation. Since the treatment regimens are becoming more complex, the initial diagnosis and treatment is best carried out at centres specialized in the management of childhood malignancies. PMID- 21297756 TI - Nutrition in cancer. AB - The treatment and control of malignant disease is one of the most serious problems facing family physicians. One of the more positive actions that can be taken to support these patients is the monitoring of the nutritional state prior to hospital admission and during the interval between treatments. This can be done both in hospital and at home. Counsel using behavior modification; symptomatically treat controllable side effects, and use either oral or tube feedings to attain a nutritional state which gives the patient the best opportunity to respond to therapy and resist complications. PMID- 21297757 TI - The role of alcohol as a co-carcinogen. AB - If cancer occurs because of what we eat, what we drink, what we smoke, and to some extent where we live and work, it follows that over 80% of cancers in human beings are related to environmental causes and therefore preventable.Since virtually every major chemical is under investigation for its carcinogenic effect, it is high time that the biological impact of alcohol received more than scant attention from the health professions as a lifestyle chemical which may be a factor in the commencement or promotion of modern man's most deadly disease.Clinical and epidemiological studies have implicated the excessive use of alcohol with the risk of developing certain cancers, especially when combined with heavy smoking. Other factors associated with drinking and increased risk of cancer consist of geographic, racial, sex and organ specificity, variations of which must be borne in mind in any study of potential environmental hazards.Research is currently under way to determine whether certain alcohol beverages may contain carcinogens, which may focus attention on the role of heavy drinking as one additional environmental factor in the spectrum of exogenous agents related to cancer production. PMID- 21297758 TI - Disease, disability & rehabilitation: considerations for patient care. AB - The traditional medical model is disease oriented. In contrast, the rehabilitation model is functionally oriented. Optimal function depends on the interaction of normal anatomy and physiology of the organism, psychological stability of the individual and the environment in which he must live. Rehabilitation requires the assessment and management of loss of function, i.e. disabilities resulting from multifactorial etiologies. Ability rather than disability is stressed, with the aim of maximizing the individual's capacity to manage his basic self care needs and to interact with society in a productive manner. Rehabilitation is the province of the physiatrist, but it must be the concern of all practitioners. PMID- 21297759 TI - Care of the dying adolescent. AB - This is a description of the obstacles encountered in the management of one 17 year old patient dying with malignant melanoma. Various areas are seen to contribute to the difficulties including the "health care system" (specifically the hospital environment), the patient himself, his family, his disease and its treatment, and his physician(s). An increased awareness of the difficulties would be helpful to those of us not frequently encountering the responsibility of caring for a dying adolescent.The details have been left vague or slightly changed in this real case to respect the privacy of those involved. PMID- 21297760 TI - Self evaluation program. PMID- 21297761 TI - H. Tristram engelhardt. PMID- 21297762 TI - Graduate training in family medicine: two years or three? AB - Graduate training in family medicine is a three year program in the United States and a two year program in Canada. For the majority of family practice residents the third year is required in order to consolidate the attitudes and skills related to continuing comprehensive health care and prevention. Without this consolidation, the application of these concepts to the practice of family health care is subject to the normal anxieties, frustrations and uncertanties which lead physicians to provide technologically oriented, episodic care. PMID- 21297763 TI - [Not Available]. PMID- 21297764 TI - Axial percussion test. PMID- 21297765 TI - Elective cesarean section. PMID- 21297766 TI - Examining rape victims. PMID- 21297767 TI - Compliance with immunization. PMID- 21297768 TI - Elective cesarean section. PMID- 21297770 TI - Elective cesarean section. PMID- 21297769 TI - Elective cesarean section. PMID- 21297771 TI - Elective cesarean section. PMID- 21297773 TI - Elective cesarean section. PMID- 21297772 TI - Elective cesarean section. PMID- 21297775 TI - Elective cesarean section. PMID- 21297774 TI - Elective cesarean section. PMID- 21297776 TI - Elective cesarean section. PMID- 21297777 TI - Elective cesarean section. PMID- 21297778 TI - Elective cesarean section. PMID- 21297779 TI - Elective cesarean section. PMID- 21297780 TI - Elective cesarean section. PMID- 21297781 TI - Elective cesarean section. PMID- 21297782 TI - A free ride-courtesy of the boat people. PMID- 21297783 TI - Some reflections on the doctor/patient relationship. PMID- 21297784 TI - [Not Available]. PMID- 21297786 TI - Helping 'boat people'.. PMID- 21297785 TI - [Not Available]. PMID- 21297787 TI - Decreasing anxiety. PMID- 21297788 TI - An apple a day.. PMID- 21297789 TI - What's in a name?.. PMID- 21297790 TI - Screening for hypertension: case finding. AB - A 13 year review of a Hamilton, Ontario, family practice resulted in the detection of 607 hypertensive patients through case finding. By using a series of simple strategies, the measurement and recording of patients' blood pressures increased from 41% in 1965 to 98% in 1977. Team members now consistently measure and record the blood pressures at virtually all encounters of patients at risk and are convinced that case finding is the only method of detection of hypertension which is at all logical, economical and practical. PMID- 21297791 TI - Lung cancer: an overview. AB - In this article the various presentations of lung cancer and the current status of its investigation and treatment are summarized. Since the incidence of lung cancer continues to increase, all physicians should be familiar with the various features of this disease. PMID- 21297792 TI - Respiratory tract infections in adults. AB - Most upper respiratory tract infections are caused by viruses, but recognition of the cause of a particular illness is impossible based on clinical findings alone. Epiglottitis caused by type B Hemophilus influenzae can occur in adults with the same threat to upper airway obstruction as in children. An approach to the diagnosis of pneumonia is outlined and pneumonias caused specifically by viruses, mycoplasma, and bacteria are described. PMID- 21297793 TI - Pragmatics of pulmonary function testing. AB - At present, there are a multitude of tests to assess respiratory function. The most reliable test of resting pulmonary function is simple spirometry. Using this, along with measurements of lung volume, one is able to make a useful assessment of a respiratory patient's pathophysiology. The where and how of these measurements, together with a discussion of other testing methods are described. PMID- 21297794 TI - Care for patients with severe chronic airflow obstruction and respiratory failure. AB - The successful care of patients with disorders causing chronic airflow obstruction (CAO) and potential chronic respiratory failure and pulmonary heart disease (cor pulmonale) requires the following:1. Recognize CAO as the cause of a patient's problem.2. Describe and measure airflow obstruction and the individual's response to it.3. Undertake therapeutic trials to maximize airflow.4. Teach patients monitoring skills and interventions in order to prevent acute respiratory failure and hospital admission.5. Maintain optimism and interest in the patient's chronic illness, appreciating its impact on the total person and his daily life. PMID- 21297795 TI - Medication et nutrition chez le coronarien. PMID- 21297796 TI - Assessment and treatment of asthma. AB - The objectives of treating asthma are to control symptoms by a minimum of medication, and to prevent severe attacks in the future. However, before these can be achieved the presence of asthma must be recognized, its severity determined, and the individual triggering factors identified. Full assessment is simple and practical: it involves history, measurement of airflow rates and allergy skin tests. Occasionally, if the diagnosis is not certain, trials of treatment and/or histamine (or methacholine) inhalation tests provide confirmation. Treatment involves not only avoidance or protection against triggering factors and trials of medication, but also patient education and modification of behavior to comply with treatment. For this the patient must have ready access to consistent medical advice to ensure and reinforce the correct response to asthmatic symptoms. PMID- 21297797 TI - Respiratory infections in children. AB - Respiratory tract infections are the commonest pediatric problem brought to primary care physicians for treatment. The following overview of these disorders focuses on practical questions and therapy. What is an excessive number of "colds"? Which cases of pharyngitis deserve antibiotic therapy, with or without culture? How do I differentiate croup from epiglottitis? Is there any way to help the child with recurrent acute or serous otitis media to prevent future morbidity? The answers to these questions and others are discussed below, as well as some of the potential advances in therapy that are under review. PMID- 21297798 TI - Basic life supports: community hospital management of respiratory failure. AB - Respiratory failure is often associated with multiple systems failure and must be suspected in a number of serious illnesses such as septic shock, major trauma and acute pancreatitis. It is a common presentation in patients with advanced obstructive or nonobstructive pulmonary disease or neuromuscular disorders leading to alveolar hypoventilation or severe hypoxemia. To determine the presence and severity of respiratory failure requires the ability to measure and interpret blood gases, understanding of important respiratory physiological concepts and facilities to implement and monitor appropriate therapy. Since the longterm management of such patients is complex, transfer to a major treatment centre is usually advisable once the acute phase of the problem has been controlled. PMID- 21297799 TI - Investigation and management of rhinitis. AB - The family physician is ideally situated to deal with most chronic-recurrent nasal problems. The physician is alerted to the real problem by the recognition that terms such as 'sinus' and 'colds' often camouflage the problem of chronic rhinitis and chronic nasal obstruction. Avoidance of offending substances, the use of medications, the occasional judicious use of allergen injection treatment and sometimes surgical intervention for nasal polyps provide different modalities of treatment which can have a major beneficial effect upon symptoms. Improved results are often achieved with a more analytic approach to the use of antihistimine and the availability of topical steroids and topical cromoglycate. The treatment method described embodies a systematic approach involving the sequential addition of modalities until specified objectives are achieved. PMID- 21297800 TI - Tips on psychotherapy. AB - Ten items to consider in providing psychotherapy can be useful to the family physician. These items include: respect both for oneself and for one's patients, determination of clear goals, the use of simple interventions first, development of specific methods, the development of therapist and patient congruence, the significance of repetition and practice, homework, the use of audiovisual and other aids, the importance of the concept of mastery, and the occurrence of negative effects. Understanding these points contributes to making therapy pleasurable for the physician and more useful for the patients. PMID- 21297802 TI - As it happened: the 'instinctive' diagnosis. AB - The "instinctive" diagnosis is often the first step in problem solving. This instinct, of course, is more than just an unfounded feeling; it is based on the physician's previous experience. The instinctive diagnosis must be confirmed, so the physician orders tests to prove his diagnosis. The trouble is that at times these tests are ambiguous and misleading. How instinct, evidence and truth can interplay is the subject of this presentation. PMID- 21297801 TI - The neurological presentation of sick sinus syndrome. AB - There is growing awareness of sick sinus syndrome (SSS) and related arrhythmias as treatable causes of epilepsy, syncope, dizziness, confusion and some psychoses, as well as non-neurological symptoms such as episodic congestive heart failure, pulmonary edema and palpitations. Six cases are presented which occurred in family practice in a period of 18 months; four required ventricular pacing, one declined and one is asymptomatic. PMID- 21297804 TI - What I wish my doctor had told me. PMID- 21297803 TI - The problems of treating the mentally retarded in the community. AB - There is an irreversible trend towards elimination of large institutions for the care of the mentally retarded. As the role of the institutions decreases, mentally retarded individuals are returning to the community. This trend is dictated not only by the fact that the large institutions have failed in their role, but also by recognition of the retarded person as a handicapped human being with civil rights supported by recent court decisions. The medical care of the mentally retarded requires special skills, considerations and preferably training. It is essential that medical schools place more emphasis in their curriculum on the care of the mentally retarded. PMID- 21297805 TI - [Not Available]. PMID- 21297806 TI - Son of ICHPPC. PMID- 21297807 TI - Holistic approach.. PMID- 21297808 TI - Parasuicide and the family physician. AB - Parasuicide (attempted suicide) was studied at Toronto General Hospital with the aim of relating the data to the physician in family practice. The problem is one of young people, especially young women. Drug ingestion was by far the most frequently used method of self-harm. Since prescription drugs, expecially psychotropics, were taken most often, the role of these drugs in family practice is examined. Guidelines for the recognition and management of parasuicide are offered. PMID- 21297809 TI - Attitudes towards mental retardation: implications for medical practice. AB - The cooperation of professionals is sought in the way in which they counsel parents with mentally retarded children. Problems have arisen from existing societal attitudes and prejudices which have had the effect of misguiding those who provide information and advice, such as the family physician. Scientific studies of attitudes have led to some understanding of attitude formation and change, offering some approaches to easing the problem. PMID- 21297810 TI - Care of the mentally retarded. AB - Mental retardation is a clinical syndrome, not an intellectual defect or brain disease per se. As such, physicians should not participate in the downgrading labelling of moron, idiot and imbecile. Such labelled people are difficult to relate to and this results in the concept of 'nil expectations' in which the whole of society participates.Maladaptation in this syndrome is more related to poor environmental input than to basic organic defect, and is a family problem. The family doctor is in an ideal situation to help the family handle the problems of anger, shame, guilt, rejection. If aware of his own feelings, he should also be the coordinator of the physical needs of the child and the alternatives available for maximal input. PMID- 21297811 TI - Organic brain syndromes: conditions of acquired intellectual deficit. AB - The term 'organic brain syndrome' covers a multitude of ills, many of which are treatable conditions. Diagnosis must concentrate on defining which syndrome is involved; this article presents a diagnostic schema with illustrative case histories. Clinical aspects of acquired mental deficit are also outlined. The approach to organic brain syndromes is the classic medical observation of signs and symptoms. PMID- 21297812 TI - The needs of the retarded adult. AB - This article deals primarily with the needs of people with a degree of mental retardation, from mild to moderately severe, who are able to live approximately normal lives with assistance by counselling, advice and family help.It has been found that they do much better living in the community, mixing with normal people, but also with access to the company of persons similarly affected. With adequate advice and counselling, they can become self-sustaining in a number of ways, such as self care, living in their own homes or in small groups, and working either in sheltered employment or in the labor force. Their needs, like those of all others, range from the material such as shelter, food, clothing, possessions, transportation, health care, through the pyschological such as self fulfillment, recreation and enjoyment, love, affection and sex, and social such as legal protection and responsibility. With appropriate arrangements, these needs can be better met in community living, probably at less cost than if they were living in the traditional large institutions. Continued training and rehabilitative measures can often improve their abilities to an astonishing degree. They are rarely unteachable. PMID- 21297813 TI - Maternal deprivation masking as mental retardation in children. AB - A child with delayed development and behavioral abnormalities presents a clinical challenge to the physician caring for children. Understanding of normal milestones and behavior, and the importance of the environment are necessary in making an accurate diagnosis and planning treatment. Maternal deprivation may produce a picture that initially suggests mild mental retardation. Differentiation is possible by a closer look at the child's developmental and behavioral characteristics and some associated specific physical features. PMID- 21297814 TI - The importance of immediate postnatal contact: its effect on breastfeeding. AB - Breastfeeding is said to be the ideal form of infant nutrition, but promoting it is thought to be difficult. The results of this study show that success is more likely when breastfeeding and skin-to-skin contact begin in the delivery room. The procedure is simple and the contact period need to be of only 15-20 minutes duration. The primiparas in this study seemed contented, happy or excited with the experience. Possibly it is most beneficial to those mothers who have not asked to hold their infants at birth. PMID- 21297815 TI - The 'shopping list' of doctors' services: who gets paid for what. PMID- 21297816 TI - Should CME Be Compulsory? PMID- 21297817 TI - The Place of Small General Hospitals in Canada's Health Care System. PMID- 21297818 TI - [Not Available]. PMID- 21297819 TI - [Not Available]. PMID- 21297820 TI - Iatrogenic IUD failure. PMID- 21297821 TI - Spermicidal agents and birth defects. PMID- 21297822 TI - SIDS monitoring. PMID- 21297823 TI - Tubal ligation. PMID- 21297824 TI - Safety of flurazepam. PMID- 21297825 TI - More on milk: breast and bottle. PMID- 21297826 TI - In search of the perfect chart. PMID- 21297827 TI - A team approach to psychotherapy in family practice. AB - Two London, Ontario, family physicians and a public health nurse attached to their practices developed a team approach to treat a patient's psychosocial problems. This paper describes how the team made the role of the family physician more effective and points out the advantages such an approach can have over more traditional ones in family practice. PMID- 21297829 TI - Family practice: a strategy for survival. PMID- 21297828 TI - Pediatrics and politics. PMID- 21297830 TI - [Not Available]. PMID- 21297831 TI - [Not Available]. PMID- 21297832 TI - St. John ambulance.. PMID- 21297834 TI - Oral decongestants.. PMID- 21297833 TI - BP Screening.. PMID- 21297835 TI - Tropical medicine.. PMID- 21297836 TI - Feingold diet.. PMID- 21297837 TI - Anxiety and diet.. PMID- 21297838 TI - L'examen complet.. PMID- 21297839 TI - French in CFP. PMID- 21297840 TI - The role of the family physician in hospital. AB - Five family doctors at St. Joseph's Hospital in Hamilton, Ontario, completed a comprehensive survey of 88 active, associate and senior members of the Department of Family Medicine, detailing their activities in hospital, their attitudes toward the hospital, their actual and desired roles and their Department of Family Medicine.The study illustrates the changing role in hospital from procedure-orientation to patient advocate, and the resulting problems. These problems were mainly lack of communication skills and feeling impotent in dealing with the hospital power structure. Implications for family medicine training programs, continuing medical education programs and teaching and community hospitals are discussed in a series of four papers. PMID- 21297841 TI - Acute tonsillopharyngitis in native and white families. AB - Native and white families in whom a diagnosis of tonsillopharyngitis had been documented during 1975 or 1976 were surveyed during 1978 whenever a family member presented to the Southwest Middlesex Health Centre. The relationship between smoking and allergic disorders within the family and the diagnosis of tonsillopharyngitis was determined. The presence of smoking family members and family members with allergic disorders was noted significantly more often in study than in control families. Similarly, families which had an average of two or more persons per bedroom were found significantly more frequently in study families with tonsillopharyngitis.Native patients were diagnosed as having tonsillopharyngitis significantly more frequently than white patients. In addition, native patients had a significantly greater number of positive bacterial throat cultures than did white patients. PMID- 21297842 TI - Rubella susceptibility: a solo family physician survey. AB - Of patients seen in the office during one month, 156 were screened for rubella hemagglutination antibody (HI) after a clinical history of susceptibility was obtained. Of these, 64 (42%) believed that they had had clinical rubella and 18 (seven percent) that they had been vaccinated. When tested, 95 (63%) were found to be immune and the remaining 55 (37%) were offered vaccination.The vaccination was given to 28 patients, 22 of whom returned after three months for a repeat HI titer. Half of these (11) required a second vaccination and five of these had the vaccination in the office. Of these five, all showed no change in immunity after the second vaccination. PMID- 21297843 TI - Nitrous oxide/oxygen analgesia in emergency care. AB - A method of analgesia relatively new to North American emergency care involves the use of a homogeneous gas composed of 50% nitrous oxide and 50% oxygen (Entonox). The gas is administered by the patient, who holds the Entonox apparatus mask to his face and triggers gas flow by exerting negative inspiratory pressure (-1 cm. H(2)O). Worthwhile analgesia (i.e. marked or partial pain relief) was achieved in 95% of 110 emergency department patients experiencing significant pain from various sources. PMID- 21297844 TI - Clinical application of serological tests for syphilis. AB - This article differentiates and describes the serological tests for syphilis- antitreponemal antibody tests (TPI, FTA-ABS, TPHA), non-treponemal antigen test (VDRL)-their clinical and serological correlation, the responses to therapy and the biologically false positive syndrome. PMID- 21297845 TI - Some simple facts about urinary incontinence in the elderly. AB - Incontinence can be caused by physiological changes, neurological disorders, trauma, certain drugs, and environmental factors. This article takes each of these causes step by step, suggesting methods of treatment and prevention. PMID- 21297846 TI - As it happened: false security. AB - Technical progress with its sophisticated new tools has changed the pattern of modern medicine. These tools should be used wisely, as adjuvant to and not as a replacement for sound clinical judgement. PMID- 21297847 TI - Self evaluation program. PMID- 21297848 TI - Differential diagnosis of common female genitourinary complaints. AB - The symptoms and diagnosis of the three most common female bladder-urethral dysfunctions (infection, stress incontinence, and irritable bladder syndrome) are examined so that the practitioner may better differentiate between these problems and some of their counterparts. Cystitis cystica, urethritis, and radiation cystitis are among the less common infections and are frequently missed. Other conditions can be mistaken for infections: urethral diverticulum, Hunner's ulcer, atrophic vaginitis, urethral stenosis. Stress urinary incontinence, arising from abnormal bladder-urethral unit physiology or from obesity, can benefit from Kegel's exercise to strengthen the external sphincter and pubococcygeus muscles. For irritable bladder syndrome, which is often misdiagnosed, a bladder drill with increasing voiding intervals is useful. Patient understanding of bladder function and the need for retraining is also important. PMID- 21297849 TI - Patient Profile: Inuvik General Hospital and Four Regional Nursing Stations, NWT. AB - A five year retrospective study of the inpatient caseload at Inuvik General Hospital (July 1, 1973-July 1, 1978) and the total caseload at four regional nursing stations (July 1, 1974-July 1, 1979) was undertaken. The 20 most common diagnoses and the 10 most common causes of medical evacuation for Fort Norman, Fort Franklin, Fort Good Hope and Norman Wells are presented. The 50 most common diagnoses in Inuvik are compared to figures for Alberta, 1975. Industrialization of the north causes an increase in the frequency and severity of physical trauma and in the amount of psychological morbidity treated by health professionals. PMID- 21297850 TI - Great wall to democracy wall: china enters the 80s. PMID- 21297851 TI - The evaluation of clinical competence. AB - During a workshop on the evaluation of clinical competence, the participants identified the process skills that comprise clinical competence and examined the techniques available for evaluating these skills. No single technique allows satisfactory evaluation of all the process skills; the most commonly used methods (chart review and case presentation) evaluate few process skills. An adequate performance profile in all the process skills requires a combination of evaluation techniques. Medical evaluators should strive to define clinical competence in measurable terms, based on the clinical skills to be mastered and the spectrum of clinical situations to be managed. PMID- 21297852 TI - Cryptic multiple hypotheses testing in linear models: overestimated effect sizes and the winner's curse. AB - Fitting generalised linear models (GLMs) with more than one predictor has become the standard method of analysis in evolutionary and behavioural research. Often, GLMs are used for exploratory data analysis, where one starts with a complex full model including interaction terms and then simplifies by removing non-significant terms. While this approach can be useful, it is problematic if significant effects are interpreted as if they arose from a single a priori hypothesis test. This is because model selection involves cryptic multiple hypothesis testing, a fact that has only rarely been acknowledged or quantified. We show that the probability of finding at least one 'significant' effect is high, even if all null hypotheses are true (e.g. 40% when starting with four predictors and their two-way interactions). This probability is close to theoretical expectations when the sample size (N) is large relative to the number of predictors including interactions (k). In contrast, type I error rates strongly exceed even those expectations when model simplification is applied to models that are over-fitted before simplification (low N/k ratio). The increase in false-positive results arises primarily from an overestimation of effect sizes among significant predictors, leading to upward-biased effect sizes that often cannot be reproduced in follow-up studies ('the winner's curse'). Despite having their own problems, full model tests and P value adjustments can be used as a guide to how frequently type I errors arise by sampling variation alone. We favour the presentation of full models, since they best reflect the range of predictors investigated and ensure a balanced representation also of non-significant results. PMID- 21297853 TI - Gender Socialization in Chinese Kindergartens: Teachers' Contributions. AB - Teacher-child interactions and peer exchanges were observed once a week for 10 months in four kindergartens in Hong Kong, China. A total of 206 anecdotes/scenes considered representative of the gender-related experiences of 109 4-year-old Chinese children in these kindergartens were analyzed. Descriptive codes, generated iteratively were clustered, categorized, integrated, recoded and recategorized and led to the identification of two major themes related to the socialization practices of teachers: Gendered Kindergarten Routines and Perpetuation of Gender Stereotypes. Findings indicated that these early years' educational contexts were not gender neutral. Teachers interacted with boys significantly more than girls. They also subtly conveyed traditional Chinese gender values through their repeated use of gendered routines in the kindergartens and their behaviors reflected gender stereotypes. PMID- 21297854 TI - Gender and the Communication of Emotion Via Touch. AB - We reanalyzed a data set consisting of a U.S. undergraduate sample (N = 212) from a previous study (Hertenstein et al. 2006a) that showed that touch communicates distinct emotions between humans. In the current reanalysis, we found that anger was communicated at greater-than-chance levels only when a male comprised at least one member of a communicating dyad. Sympathy was communicated at greater than-chance levels only when a female comprised at least one member of the dyad. Finally, happiness was communicated only if females comprised the entire dyad. The current analysis demonstrates gender asymmetries in the accuracy of communicating distinct emotions via touch between humans. PMID- 21297855 TI - Explicitly searching for useful inventions: dynamic relatedness and the costs of connecting versus synthesizing. AB - Inventions combine technological features. When features are barely related, burdensomely broad knowledge is required to identify the situations that they share. When features are overly related, burdensomely broad knowledge is required to identify the situations that distinguish them. Thus, according to my first hypothesis, when features are moderately related, the costs of connecting and costs of synthesizing are cumulatively minimized, and the most useful inventions emerge. I also hypothesize that continued experimentation with a specific set of features is likely to lead to the discovery of decreasingly useful inventions; the earlier-identified connections reflect the more common consumer situations. Covering data from all industries, the empirical analysis provides broad support for the first hypothesis. Regressions to test the second hypothesis are inconclusive when examining industry types individually. Yet, this study represents an exploratory investigation, and future research should test refined hypotheses with more sophisticated data, such as that found in literature-based discovery research. PMID- 21297856 TI - The end of the beginning: a reflection on the first five years of the HRI conference. AB - This study presents a historical overview of the International Conference on Human Robot Interaction (HRI). It summarizes its growth, internationalization and collaboration. Rankings for countries, organizations and authors are provided. Furthermore, an analysis of the military funding for HRI papers is performed. Approximately 20% of the papers are funded by the US Military. The proportion of papers from the US is around 65% and the dominant role of the US is only challenged by the strong position of Japan, in particular by the contributions by ATR. PMID- 21297857 TI - Searching for converging research using field to field citations. AB - We define converging research as the emergence of an interdisciplinary research area from fields that did not show interdisciplinary connections before. This paper presents a process to search for converging research using journal subject categories as a proxy for fields and citations to measure interdisciplinary connections, as well as an application of this search. The search consists of two phases: a quantitative phase in which pairs of citing and cited fields are located that show a significant change in number of citations, followed by a qualitative phase in which thematic focus is sought in publications associated with located pairs. Applying this search on publications from the Web of Science published between 1995 and 2005, 38 candidate converging pairs were located, 27 of which showed thematic focus, and 20 also showed a similar focus in the other, reciprocal pair. PMID- 21297858 TI - Cell-Matrix De-Adhesion Dynamics Reflect Contractile Mechanics. AB - Measurement of the mechanical properties of single cells is of increasing interest both from a fundamental cell biological perspective and in the context of disease diagnostics. In this study, we show that tracking cell shape dynamics during trypsin-induced de-adhesion can serve as a simple but extremely useful tool for probing the contractility of adherent cells. When treated with trypsin, both SW13(-/-) epithelial cells and U373 MG glioma cells exhibit a brief lag period followed by a concerted retraction to a rounded shape. The time-response of the normalized cell area can be fit to a sigmoidal curve with two characteristic time constants that rise and fall when cells are treated with blebbistatin and nocodazole, respectively. These differences can be attributed to actomyosin-based cytoskeletal remodeling, as evidenced by the prominent buildup of stress fibers in nocodazole-treated SW13(-/-) cells, which are also two-fold stiffer than untreated cells. Similar results observed in U373 MG cells highlights the direct association between cell stiffness and the de-adhesion response. Faster de-adhesion is obtained with higher trypsin concentration, with nocodazole treatment further expediting the process and blebbistatin treatment blunting the response. A simple finite element model confirms that faster contraction is achieved with increased stiffness. PMID- 21297859 TI - Imaging of Oxidation-Specific Epitopes in Atherosclerosis and Macrophage-Rich Vulnerable Plaques. AB - Oxidative stress, and in particular oxidation of lipoproteins, is a hallmark of atherosclerosis. Upon entry of lipoproteins into the vessel wall, a cascade of pro-atherogenic pathways is initiated whereby the reaction of reactive oxygen species with substrates amenable to oxidation, such as polyunsaturated fatty acids, generates a variety of oxidation-specific epitopes on lipoproteins, proteins in the vessel wall, and apoptotic macrophages. Several of these oxidation-specific epitopes have been well characterized and specific murine and fully human antibodies have been generated in our laboratory to detect them in the vessel wall. We have developed radionuclide, gadolinium and iron oxide based MRI techniques to noninvasively image oxidation-specific epitopes in atherosclerotic lesions. These approaches quantitate plaque burden and also allow detection of atherosclerosis regression and plaque stabilization. In particular, gadolinium micelles or lipid-coated ultrasmall superparamagnetic iron oxide particles containing oxidation-specific antibodies accumulate within macrophages in the artery wall, suggesting they may image the most unstable plaques. Translation of these approaches to humans may allow a sensitive technique to image and monitor high-risk atherosclerotic lesions and may guide optimal therapeutic interventions. PMID- 21297861 TI - Frugivory and spatial patterns of seed deposition by carnivorous mammals in anthropogenic landscapes: a multi-scale approach. AB - BACKGROUND: Knowledge about how frugivory and seed deposition are spatially distributed is valuable to understand the role of dispersers on the structure and dynamics of plant populations. This may be particularly important within anthropogenic areas, where either the patchy distribution of wild plants or the presence of cultivated fleshy-fruits may influence plant-disperser interactions. METHODOLOGY/PRINCIPAL FINDINGS: We investigated frugivory and spatial patterns of seed deposition by carnivorous mammals in anthropogenic landscapes considering two spatial scales: 'landscape' (~10 km(2)) and 'habitat type' (~1-2 km(2)). We sampled carnivore faeces and plant abundance at three contrasting habitats (chestnut woods, mosaics and scrublands), each replicated within three different landscapes. Sixty-five percent of faeces collected (n = 1077) contained seeds, among which wild and cultivated seeds appeared in similar proportions (58% and 53%) despite that cultivated fruiting plants were much less abundant. Seed deposition was spatially structured among both spatial scales being different between fruit types. Whereas the most important source of spatial variation in deposition of wild seeds was the landscape scale, it was the habitat scale for cultivated seeds. At the habitat scale, seeds of wild species were mostly deposited within mosaics while seeds of cultivated species were within chestnut woods and scrublands. Spatial concordance between seed deposition and plant abundance was found only for wild species. CONCLUSIONS/SIGNIFICANCE: Spatial patterns of seed deposition by carnivores differed between fruit types and seemed to be modulated by the fleshy-fruited plant assemblages and the behaviour of dispersers. Our results suggest that a strong preference for cultivated fruits by carnivores may influence their spatial foraging behaviour and lower their dispersal services to wild species. However, the high amount of seeds removed within and between habitats suggests that carnivores must play an important role- often overlooked--as 'restorers' and 'habitat shapers' in anthropogenic areas. PMID- 21297860 TI - PPARdelta activation acts cooperatively with 3-phosphoinositide-dependent protein kinase-1 to enhance mammary tumorigenesis. AB - Peroxisome proliferator-activated receptordelta (PPARdelta) is a transcription factor that is associated with metabolic gene regulation and inflammation. It has been implicated in tumor promotion and in the regulation of 3-phosphoinositide dependent kinase-1 (PDK1). PDK1 is a key regulator of the AGC protein kinase family, which includes the proto-oncogene AKT/PKB implicated in several malignancies, including breast cancer. To assess the role of PDK1 in mammary tumorigenesis and its interaction with PPARdelta, transgenic mice were generated in which PDK1 was expressed in mammary epithelium under the control of the MMTV enhancer/promoter region. Transgene expression increased pT308AKT and pS9GSK3beta, but did not alter phosphorylation of mTOR, 4EBP1, ribosomal protein S6 and PKCalpha. The transgenic mammary gland also expressed higher levels of PPARdelta and a gene expression profile resembling wild-type mice maintained on a diet containing the PPARdelta agonist, GW501516. Both wild-type and transgenic mice treated with GW501516 exhibited accelerated rates of tumor formation that were more pronounced in transgenic animals. GW501516 treatment was accompanied by a distinct metabolic gene expression and metabolomic signature that was not present in untreated animals. GW501516-treated transgenic mice expressed higher levels of fatty acid and phospholipid metabolites than treated wild-type mice, suggesting the involvement of PDK1 in enhancing PPARdelta-driven energy metabolism. These results reveal that PPARdelta activation elicits a distinct metabolic and metabolomic profile in tumors that is in part related to PDK1 and AKT signaling. PMID- 21297862 TI - High-resolution melting system to perform multilocus sequence typing of Campylobacter jejuni. AB - Multi-locus sequence typing (MLST) has emerged as the state-of-the-art method for resolving bacterial population genetics but it is expensive and time consuming. We evaluated the potential of high resolution melting (HRM) to identify known MLST alleles of Campylobacter jejuni at reduced cost and time. Each MLST locus was amplified in two or three sub fragments, which were analyzed by HRM. The approach was investigated using 47 C. jejuni isolates, previously characterized by classical MLST, representing isolates from diverse environmental, animal and clinical sources and including the six most prevalent sequence types (ST) and the most frequent alleles. HRM was then applied to a validation set of 84 additional C. jejuni isolates from chickens; 92% of the alleles were resolved in 35 hours of laboratory time and the cost of reagents per isolate was $20 compared with $100 for sequence-based typing. HRM has the potential to complement sequence-based methods for resolving SNPs and to facilitate a wide range of genotyping studies. PMID- 21297863 TI - Comparative and joint analysis of two metagenomic datasets from a biogas fermenter obtained by 454-pyrosequencing. AB - Biogas production from renewable resources is attracting increased attention as an alternative energy source due to the limited availability of traditional fossil fuels. Many countries are promoting the use of alternative energy sources for sustainable energy production. In this study, a metagenome from a production scale biogas fermenter was analysed employing Roche's GS FLX Titanium technology and compared to a previous dataset obtained from the same community DNA sample that was sequenced on the GS FLX platform. Taxonomic profiling based on 16S rRNA specific sequences and an Environmental Gene Tag (EGT) analysis employing CARMA demonstrated that both approaches benefit from the longer read lengths obtained on the Titanium platform. Results confirmed Clostridia as the most prevalent taxonomic class, whereas species of the order Methanomicrobiales are dominant among methanogenic Archaea. However, the analyses also identified additional taxa that were missed by the previous study, including members of the genera Streptococcus, Acetivibrio, Garciella, Tissierella, and Gelria, which might also play a role in the fermentation process leading to the formation of methane. Taking advantage of the CARMA feature to correlate taxonomic information of sequences with their assigned functions, it appeared that Firmicutes, followed by Bacteroidetes and Proteobacteria, dominate within the functional context of polysaccharide degradation whereas Methanomicrobiales represent the most abundant taxonomic group responsible for methane production. Clostridia is the most important class involved in the reductive CoA pathway (Wood-Ljungdahl pathway) that is characteristic for acetogenesis. Based on binning of 16S rRNA-specific sequences allocated to the dominant genus Methanoculleus, it could be shown that this genus is represented by several different species. Phylogenetic analysis of these sequences placed them in close proximity to the hydrogenotrophic methanogen Methanoculleus bourgensis. While rarefaction analyses still indicate incomplete coverage, examination of the GS FLX Titanium dataset resulted in the identification of additional genera and functional elements, providing a far more complete coverage of the community involved in anaerobic fermentative pathways leading to methane formation. PMID- 21297864 TI - Heterologous epitope-scaffold prime:boosting immuno-focuses B cell responses to the HIV-1 gp41 2F5 neutralization determinant. AB - The HIV-1 envelope glycoproteins (Env) gp120 and gp41 mediate entry and are the targets for neutralizing antibodies. Within gp41, a continuous epitope defined by the broadly neutralizing antibody 2F5, is one of the few conserved sites accessible to antibodies on the functional HIV Env spike. Recently, as an initial attempt at structure-guided design, we transplanted the 2F5 epitope onto several non-HIV acceptor scaffold proteins that we termed epitope scaffolds (ES). As immunogens, these ES proteins elicited antibodies with exquisite binding specificity matching that of the 2F5 antibody. These novel 2F5 epitope scaffolds presented us with the opportunity to test heterologous prime:boost immunization strategies to selectively boost antibody responses against the engrafted gp41 2F5 epitope. Such strategies might be employed to target conserved but poorly immunogenic sites on the HIV-1 Env, and, more generally, other structurally defined pathogen targets. Here, we assessed ES prime:boosting by measuring epitope specific serum antibody titers by ELISA and B cell responses by ELISpot analysis using both free 2F5 peptide and an unrelated ES protein as probes. We found that the heterologous ES prime:boosting immunization regimen elicits cross reactive humoral responses to the structurally constrained 2F5 epitope target, and that incorporating a promiscuous T cell helper epitope in the immunogens resulted in higher antibody titers against the 2F5 graft, but did not result in virus neutralization. Interestingly, two epitope scaffolds (ES1 and ES2), which did not elicit a detectable 2F5 epitope-specific response on their own, boosted such responses when primed with the ES5. Together, these results indicate that heterologous ES prime:boost immunization regimens effectively focus the humoral immune response on the structurally defined and immunogen-conserved HIV-1 2F5 epitope. PMID- 21297865 TI - Communicative interactions improve visual detection of biological motion. AB - BACKGROUND: In the context of interacting activities requiring close-body contact such as fighting or dancing, the actions of one agent can be used to predict the actions of the second agent. In the present study, we investigated whether interpersonal predictive coding extends to interactive activities--such as communicative interactions--in which no physical contingency is implied between the movements of the interacting individuals. METHODOLOGY/PRINCIPAL FINDINGS: Participants observed point-light displays of two agents (A and B) performing separate actions. In the communicative condition, the action performed by agent B responded to a communicative gesture performed by agent A. In the individual condition, agent A's communicative action was substituted with a non communicative action. Using a simultaneous masking detection task, we demonstrate that observing the communicative gesture performed by agent A enhanced visual discrimination of agent B. CONCLUSIONS/SIGNIFICANCE: Our finding complements and extends previous evidence for interpersonal predictive coding, suggesting that the communicative gestures of one agent can serve as a predictor for the expected actions of the respondent, even if no physical contact between agents is implied. PMID- 21297866 TI - Prioritizing conservation of ungulate calving resources in multiple-use landscapes. AB - BACKGROUND: Conserving animal populations in places where human activity is increasing is an ongoing challenge in many parts of the world. We investigated how human activity interacted with maternal status and individual variation in behavior to affect reliability of spatially-explicit models intended to guide conservation of critical ungulate calving resources. We studied Rocky Mountain elk (Cervus elaphus) that occupy a region where 2900 natural gas wells have been drilled. METHODOLOGY/PRINCIPAL FINDINGS: We present novel applications of generalized additive modeling to predict maternal status based on movement, and of random-effects resource selection models to provide population and individual based inference on the effects of maternal status and human activity. We used a 2*2 factorial design (treatment vs. control) that included elk that were either parturient or non-parturient and in areas either with or without industrial development. Generalized additive models predicted maternal status (parturiency) correctly 93% of the time based on movement. Human activity played a larger role than maternal status in shaping resource use; elk showed strong spatiotemporal patterns of selection or avoidance and marked individual variation in developed areas, but no such pattern in undeveloped areas. This difference had direct consequences for landscape-level conservation planning. When relative probability of use was calculated across the study area, there was disparity throughout 72 88% of the landscape in terms of where conservation intervention should be prioritized depending on whether models were based on behavior in developed areas or undeveloped areas. Model validation showed that models based on behavior in developed areas had poor predictive accuracy, whereas the model based on behavior in undeveloped areas had high predictive accuracy. CONCLUSIONS/SIGNIFICANCE: By directly testing for differences between developed and undeveloped areas, and by modeling resource selection in a random-effects framework that provided individual-based inference, we conclude that: 1) amplified selection or avoidance behavior and individual variation, as responses to increasing human activity, complicate conservation planning in multiple-use landscapes, and 2) resource selection behavior in places where human activity is predictable or less dynamic may provide a more reliable basis from which to prioritize conservation action. PMID- 21297867 TI - Proteasome inhibition represses unfolded protein response and Nox4, sensitizing vascular cells to endoplasmic reticulum stress-induced death. AB - BACKGROUND: Endoplasmic reticulum (ER) stress has pathophysiological relevance in vascular diseases and merges with proteasome function. Proteasome inhibition induces cell stress and may have therapeutic implications. However, whether proteasome inhibition potentiates ER stress-induced apoptosis and the possible mechanisms involved in this process are unclear. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that proteasome inhibition with MG132, per se at non-lethal levels, sensitized vascular smooth muscle cells to caspase-3 activation and cell death during ER stress induced by tunicamycin (Tn). This effect was accompanied by suppression of both proadaptive (KDEL chaperones) and proapoptotic (CHOP/GADD153) unfolded protein response markers, although, intriguingly, the splicing of XBP1 was markedly enhanced and sustained. In parallel, proteasome inhibition completely prevented ER stress-induced increase in NADPH oxidase activity, as well as increases in Nox4 isoform and protein disulfide isomerase mRNA expression. Increased Akt phosphorylation due to proteasome inhibition partially offset the proapoptotic effect of Tn or MG132. Although proteasome inhibition enhanced oxidative stress, reactive oxygen species scavenging had no net effect on sensitization to Tn or MG132-induced cell death. CONCLUSION/RELEVANCE: These data indicate unfolded protein response-independent pathways whereby proteasome inhibition sensitizes vascular smooth muscle to ER stress-mediated cell death. This may be relevant to understand the therapeutic potential of such compounds in vascular disease associated with increased neointimal hyperplasia. PMID- 21297869 TI - Dynamic approach to space and habitat use based on biased random bridges. AB - BACKGROUND: Although habitat use reflects a dynamic process, most studies assess habitat use statically as if an animal's successively recorded locations reflected a point rather than a movement process. By relying on the activity time between successive locations instead of the local density of individual locations, movement-based methods can substantially improve the biological relevance of utilization distribution (UD) estimates (i.e. the relative frequencies with which an animal uses the various areas of its home range, HR). One such method rests on Brownian bridges (BBs). Its theoretical foundation (purely and constantly diffusive movements) is paradoxically inconsistent with both HR settlement and habitat selection. An alternative involves movement-based kernel density estimation (MKDE) through location interpolation, which may be applied to various movement behaviours but lacks a sound theoretical basis. METHODOLOGY/PRINCIPAL FINDINGS: I introduce the concept of a biased random (advective-diffusive) bridge (BRB) and show that the MKDE method is a practical means to estimate UDs based on simplified (isotropically diffusive) BRBs. The equation governing BRBs is constrained by the maximum delay between successive relocations warranting constant within-bridge advection (allowed to vary between bridges) but remains otherwise similar to the BB equation. Despite its theoretical inconsistencies, the BB method can therefore be applied to animals that regularly reorientate within their HRs and adapt their movements to the habitats crossed, provided that they were relocated with a high enough frequency. CONCLUSIONS/SIGNIFICANCE: Biased random walks can approximate various movement types at short times from a given relocation. Their simplified form constitutes an effective trade-off between too simple, unrealistic movement models, such as Brownian motion, and more sophisticated and realistic ones, such as biased correlated random walks (BCRWs), which are too complex to yield functional bridges. Relying on simplified BRBs proves to be the most reliable and easily usable way to estimate UDs from serially correlated relocations and raw activity information. PMID- 21297868 TI - Childhood socioeconomic position and objectively measured physical capability levels in adulthood: a systematic review and meta-analysis. AB - BACKGROUND: Grip strength, walking speed, chair rising and standing balance time are objective measures of physical capability that characterise current health and predict survival in older populations. Socioeconomic position (SEP) in childhood may influence the peak level of physical capability achieved in early adulthood, thereby affecting levels in later adulthood. We have undertaken a systematic review with meta-analyses to test the hypothesis that adverse childhood SEP is associated with lower levels of objectively measured physical capability in adulthood. METHODS AND FINDINGS: Relevant studies published by May 2010 were identified through literature searches using EMBASE and MEDLINE. Unpublished results were obtained from study investigators. Results were provided by all study investigators in a standard format and pooled using random-effects meta-analyses. 19 studies were included in the review. Total sample sizes in meta analyses ranged from N = 17,215 for chair rise time to N = 1,061,855 for grip strength. Although heterogeneity was detected, there was consistent evidence in age adjusted models that lower childhood SEP was associated with modest reductions in physical capability levels in adulthood: comparing the lowest with the highest childhood SEP there was a reduction in grip strength of 0.13 standard deviations (95% CI: 0.06, 0.21), a reduction in mean walking speed of 0.07 m/s (0.05, 0.10), an increase in mean chair rise time of 6% (4%, 8%) and an odds ratio of an inability to balance for 5s of 1.26 (1.02, 1.55). Adjustment for the potential mediating factors, adult SEP and body size attenuated associations greatly. However, despite this attenuation, for walking speed and chair rise time, there was still evidence of moderate associations. CONCLUSIONS: Policies targeting socioeconomic inequalities in childhood may have additional benefits in promoting the maintenance of independence in later life. PMID- 21297870 TI - Synthesis of amphiphilic triblock copolymers as multidentate ligands for biocompatible coating of quantum dots. AB - One barrier to apply current tri-octylphosphine oxide (TOPO) based quantum dots (QDs) to biomedical imaging is that the TOPO on TOPO-QDs can be replaced by the proteins in living system, which may cause the degradation of QDs and/or deactivation of protein. In order to develop biocompatible optical imaging agents, a novel triblock copolymer, designed as a multidentate ligand, was synthesized to coat quantum dot nanocrystals (QDs). The copolymer consists of a polycarboxylic acid block at one end and a polythiol block at the other end with an intervening cross-linked poly(styrene-co-divinylbenzene) block bridging the ends. The multiple mercapto groups from the polythiol block act as multidentate ligands to stabilize QDs, while the polycarboxylic acid block improves the water solubility of QDs and offers reaction sites for surface modification or conjugation with bimolecules. The cross-linked poly(styrene-co-divinylbenzene) block provides a densely compacted hydrophobic shell. This shell will act as a barrier to inhibit the degradation of QDs by preventing the diffusion of ions and small molecules into the core of QDs. This new multidentate polymer coating facilitates the transfer of QDs from organic solvent into aqueous phase. The QDs directly bound to multidentate mercapto groups instead of TOPO are less likely to be affected by the mercapto or disulfide groups within proteins or other biomolecules. Therefore, this research will provide an alternative coating material instead of TOPO to produce QDs which could be more suitable for in vivo use under complex physiological conditions. PMID- 21297871 TI - Molecular mechanisms of sarcomere dysfunction in dilated and hypertrophic cardiomyopathy. AB - The sarcomeres form the molecular motor of the cardiomyocyte and consist of a complex multi-protein of thick and thin filaments which are anchored to the cytoskeleton. The thick filament, composed of myosin and associated proteins, and the thin filament composed of actin, tropomyosin and the troponins develop actinmyosin crossbridges which cycle in response to calcium resulting in sliding of the filaments and contraction. The thin filament in fixed to the cardiomyocyte cytoskeleton at the Z-disc, a complex of structural and regulatory proteins. A giant protein, titin, provides an external scaffold and regulates passive force in diastole. Both genetic disorders and acquired conditions may affect proteins of the sarcomere. Genetic disorders of the thick and thin filament proteins are the predominant cause of hypertrophic cardiomyopathy. These mutations lead to abnormal sarcomere function, often an enhanced sensitivity to calcium, and impaired relaxation. This may result in secondary changes in calcium cycling and amplification of hypertrophic signaling cascades. Correcting the abnormal function of the sarcomere as well as intervening in later stages of the pathophysiologic cascades may ameliorate disease. In dilated cardiomyopathy genetic abnormalities in the sarcomere, Z-disc, calcium regulatory and cytoskeletal proteins as well as the dystrophin complex may be causal for disease. In dilated cardiomyopathy, disturbances in post-translational modifications of the sarcomere my also play a prominent role. Experimental models indicate that altered phosphorylation of sarcomeric proteins may impair systolic and diastolic function as well as the response to heart rate and afterload. Thus correcting these post-translational changes are legitimate targets for future therapeutic strategies for dilated cardiomyopathy. PMID- 21297872 TI - F-FDG PET Imaging of Atherosclerosis-A New Approach to Detect Inflamed, High-Risk Coronary Plaques? PMID- 21297873 TI - Challenges in protein folding simulations: Timescale, representation, and analysis. AB - Experimental studies of protein folding processes are frequently hampered by the fact that only low resolution structural data can be obtained with sufficient temporal resolution. Molecular dynamics simulations offer a complementary approach, providing extremely high resolution spatial and temporal data on folding processes. The effectiveness of such simulations is currently hampered by continuing questions regarding the ability of molecular dynamics force fields to reproduce the true potential energy surfaces of proteins, and ongoing difficulties with obtaining sufficient sampling to meaningfully comment on folding mechanisms. We review recent progress in the simulation of three common model systems for protein folding, and discuss how recent advances in technology and theory are allowing protein folding simulations to address their current shortcomings. PMID- 21297874 TI - Environmental induction of the fetal epigenome. AB - The healthy adult is the result of successful interaction between the maternal environment and the developing fetal epigenome. The Barker hypothesis first suggested that in utero exposure to the maternal environment impacts adult health and disease. Since the origin of this theory, numerous studies have lent further support. Epigenomic alteration involves DNA methylation and histone modifications. Pregnancy, when the epigenome is typically actively programmed, is a vulnerable time, when exposures may have the most profound epigenetic effect. Recent advances have allowed an understanding of the extent and mechanism by which environmental exposures alter the epigenome of the fetus. Healthcare providers who treat and counsel reproductive-age women are in a unique position to protect against these epigenetic alterations and therefore prevent adverse impact on the developing fetus that may manifest throughout life. PMID- 21297875 TI - Deformation of stem cell nuclei by nanotopographical cues. AB - Cells sense cues in their surrounding microenvironment. These cues are converted into intracellular signals and transduced to the nucleus in order for the cell to respond and adapt its function. Within the nucleus, structural changes occur that ultimately lead to changes in the gene expression. In this study, we explore the structural changes of the nucleus of human mesenchymal stem cells as an effect of topographical cues. We use a controlled nanotopography to drive shape changes to the cell nucleus, and measure the changes with both fluorescence microscopy and a novel light scattering technique. The nucleus changes shape dramatically in response to the nanotopography, and in a manner dependent on the mechanical properties of the substrate. The kinetics of the nuclear deformation follows an unexpected trajectory. As opposed to a gradual shape change in response to the topography, once the cytoskeleton attains an aligned and elongation morphology on the time scale of several hours, the nucleus changes shape rapidly and intensely. PMID- 21297877 TI - Phonotactic constraints on infant word learning. AB - How do infants use their knowledge of native language sound patterns when learning words? There is ample evidence of infants' precocious acquisition of native language sound structure during the first years of life, but much less evidence concerning how they apply this knowledge to the task of associating sounds with meanings in word learning. To address this question, 18-month-olds were presented with two phonotactically legal object labels (containing sound sequences that occur frequently in English) or two phonotactically illegal object labels (containing sound sequences that never occur in English), paired with novel objects. Infants were then tested using a looking-while-listening measure. The results revealed that infants looked at the correct objects after hearing the legal labels, but not the illegal labels. Furthermore, vocabulary size was related to performance. Infants with larger receptive vocabularies displayed greater differences between learning of legal and illegal labels than infants with smaller vocabularies. These findings provide evidence that infants' knowledge of native language sound patterns influences their word learning. PMID- 21297876 TI - DEAD-box proteins as RNA helicases and chaperones. AB - DEAD-box proteins are ubiquitous in RNA-mediated processes and function by coupling cycles of ATP binding and hydrolysis to changes in affinity for single stranded RNA. Many DEAD-box proteins use this basic mechanism as the foundation for a version of RNA helicase activity, efficiently separating the strands of short RNA duplexes in a process that involves little or no translocation. This activity, coupled with mechanisms to direct different DEAD-box proteins to their physiological substrates, allows them to promote RNA folding steps and rearrangements and to accelerate remodeling of RNA-protein complexes. This review will describe the properties of DEAD-box proteins as RNA helicases and the current understanding of how the energy from ATPase activity is used to drive the separation of RNA duplex strands. It will then describe how the basic biochemical properties allow some DEAD-box proteins to function as chaperones by promoting RNA folding reactions, with a focus on the self-splicing group I and group II intron RNAs. PMID- 21297879 TI - An experimental and theoretical analysis of molecular separations by diffusion through ultrathin nanoporous membranes. AB - Diffusion based separations are essential for laboratory and clinical dialysis processes. New molecularly thin nanoporous membranes may improve the rate and quality of separations achievable by these processes. In this work we have performed protein and small molecule separations with 15 nm thick porous nanocrystalline silicon (pnc-Si) membranes and compared the results to 1- and 3- dimensional models of diffusion through ultrathin membranes. The models predict the amount of resistance contributed by the membrane by using pore characteristics obtained by direct inspection of pnc-Si membranes in transmission electron micrographs. The theoretical results indicate that molecularly thin membranes are expected to enable higher resolution separations at times before equilibrium compared to thicker membranes with the same pore diameters and porosities. We also explored the impact of experimental parameters such as porosity, pore distribution, diffusion time, and chamber size on the sieving characteristics. Experimental results are found to be in good agreement with the theory, and ultrathin membranes are shown to impart little overall resistance to the diffusion of molecules smaller than the physical pore size cutoff. The largest molecules tested experience more hindrance than expected from simulations indicating that factors not incorporated in the models, such as molecule shape, electrostatic repulsion, and adsorption to pore walls, are likely important. PMID- 21297878 TI - Current trends in targeting the hormonal regulation of appetite and energy balance to treat obesity. AB - With the eruption of the obesity pandemic over the past few decades, much research has been devoted to understanding the molecular mechanisms by which the human body regulates energy balance. These studies have revealed several mediators, including gut/pancreatic/adipose hormones and neuropeptides that control both short- and long-term energy balance by regulating appetite and/or metabolism. These endogenous mediators of energy balance have been the focus of many anti-obesity drug-development programs aimed at either amplifying endogenous anorexigenic/lipolytic signaling or blocking endogenous orexigenic/lipogenic signaling. Here, we discuss the efficacy and safety of targeting these pathways for the pharmacologic treatment of obesity. PMID- 21297880 TI - Benefits of "Observer Effects": Lessons from the Field. AB - This paper responds to the criticism that "observer effects" in ethnographic research necessarily bias and therefore invalidate research findings. Instead of aspiring to distance and detachment, some of the greatest strengths of ethnographic research lie in cultivating close ties with others and collaboratively shaping discourses and practices in the field. Informants' performances - however staged for or influenced by the observer - often reveal profound truths about social and/or cultural phenomena. To make this case, first we mobilize methodological insights from the field of science studies to illustrate the contingency and partiality of all knowledge and to challenge the notion that ethnography is less objective than other research methods. Second, we draw upon our ethnographic projects to illustrate the rich data that can be obtained from "staged performances" by informants. Finally, by detailing a few examples of questionable behavior on the part of informants, we challenge the fallacy that the presence of ethnographers will cause informants to self-censor. PMID- 21297881 TI - Estrogen regulation of X-box binding protein-1 and its role in estrogen induced growth of breast and endometrial cancer cells. AB - BACKGROUND: X-box binding protein 1 (XBP1), a transcription factor involved in unfolded protein response, is also an estrogen-regulated gene and strongly correlates with estrogen receptor alpha (ERalpha) expression in breast cancers. We investigated the functional role of XBP1 in estrogen responsive breast and endometrial cancer cells as its functions are not fully understood. MATERIALS AND METHODS: ERalpha positive breast (MCF7) and endometrial (ECC1) cancer cells were used to study XBP1 gene regulation by 17-beta-estradiol (E2) and to investigate the role of XBP1 in E2-mediated growth using short interfering RNA. Quantitative real-time PCR and Western blot were used to assess RNA and protein levels. Recruitment of ERalpha and other cofactors at the promoter and enhancer region of the XBP1 gene was investigated by chromatin immunoprecipitation. Estrogen responsive element (ERE)-mediated transcriptional activity was evaluated by a luciferase reporter assay. RESULTS: E2 induced the transcription of XBP1 in both MCF7 and ECC1 cells. E2-dependent recruitment of ERalpha, steroid receptor coactivator (SRC)-1 and SRC-3, and RNA polymerase II were observed at the promoter and/or enhancer region of the XBP1 gene. Depletion of XBP1 markedly inhibited the E2-induced growth in MCF7 and ECC1 cells. However, ERE-mediated transcription was not altered in XBP1-overexpressing or XBP1-depleted MCF7 cells. CONCLUSION: Our results confirm E2-induced transcription of XBP1 and demonstrate the crucial role of XBP1 in E2-induced growth of ERalpha positive breast and endometrial cancer cells without modulating the classical ERE-mediated transcription by ER. This knowledge creates new opportunities for therapeutic interventions. PMID- 21297883 TI - Genome-Targeted Drug Design: Understanding the Netropsin-DNA Interaction. AB - Knowledge of the sequence of the human genome has provided significant opportunities to exploit DNA as a target in the rational design of therapeutic agents. Among agents that target DNA, netropsin exhibits a strong preference for binding A/T rich regions. In order to investigate the key factors responsible for DNA recognition and binding by netropsin, molecular dynamics simulations were carried out on a DNA-netropsin complex in which two netropsin molecules are bound to each AATT site of the 16-mer d(CTTAATTCGAATTAAG)(2). In this complex, the two netropsins are bound to the DNA minor groove in a head-to-head orientation with the guanidinium-termini of both netropsins pointed toward the center of the DNA. Despite their identical environments, molecular dynamics simulations showed that the two netropsins exhibited differences in their respective RMS behaviors, binding energies, minor groove width fluctuations, and rotations of their structural planes. These observations suggest that DNA recognition and binding by small molecules may be governed by mechanism(s) that are much more complex than initially anticipated and may represent unexpected challenges in genome-targeted drug design. PMID- 21297884 TI - Statistics Online Computational Resource for Education. AB - The Statistics Online Computational Resource (www.SOCR.ucla.edu) provides one of the largest collections of free Internet-based resources for probability and statistics education. SOCR develops, validates and disseminates two core types of materials - instructional resources and computational libraries. PMID- 21297885 TI - The spread and density of the phonological neighborhood can strongly influence the verbal transformation illusion. AB - When a recorded verbal stimulus repeats over and over, adaptation occurs and listeners hear competing forms. Reports of these "verbal transformations" (VTs) were obtained for 36 consonant-vowel (CV) syllables that varied both in frequency weighted neighborhood density (ranging from 12.73 to 90.42) and in neighborhood spread [i.e., for 18 CVs, changes at either phoneme position could yield real words (spread = 2) while for the remaining 18 CVs, changes at only one position could yield words (spread = 1)]. The strength of the VT illusion, measured by the amount of time the stimuli were heard nonveridically during the 300-s repetition period, decreased substantially with both increasing neighborhood density [r= 0.74, F(1,34)=42.6, p<0.0001] and increasing spread [r=-0.75, F(1,34) = 44.1, p<0.0001]. Stepwise regression revealed that density and spread collectively accounted for approximately 70% of the variance in illusion strength [F(1,33)>=10.0, p<0.003 or better]. These effects are larger than, but generally consistent with, neighborhood effects obtained with other psycholinguistic tasks, and they suggest that VTs can provide a highly sensitive measure of lexical competition. [Work supported by NIH.]. PMID- 21297886 TI - Enhanced modelling of the glucose-insulin system and its applications in insulin therapies. AB - It is well known that Michaelis-Menten kinetics is suitable for the response function in chemical reaction, when the reaction rate does not increase indefinitely when an excess of resource is available. However, the existing models for insulin therapies assume that the response function of insulin clearance is proportional to the insulin concentration. In this paper, we propose a new model for insulin therapy for both type 1 and type 2 diabetes mellitus, in which the insulin degradation rate assumes Michaelis-Menten kinetics. Our analysis shows that it is possible to mimic pancreatic insulin secretion by exogenous insulin infusions, and our numerical simulations provide clinical strategies for insulin-administration practices. PMID- 21297887 TI - RTI models as alternatives to traditional views of learning disabilities: Response to the commentaries. AB - Two commentaries in this issue, one by Torgesen and one by Fuchs and Fuchs, are largely supportive of our views of the value of implementing response to intervention (RTI) models in schools. In contrast, Reynolds and Shaywitz's criticisms of RTI represent traditional and often nonempirical views of learning disabilities (LDs). The evidence base on RTI is not empty, and Reynolds and Shaywitz fail to provide research support for their views of either LDs or RTI. PMID- 21297889 TI - Newspaper Coverage of Intimate Partner Violence: Skewing Representations of Risk. AB - How media portray intimate partner violence (IPV) has implications for public perceptions and social policy. Therefore, to better understand these portrayals, this study content analyzes a nationally representative sample of newspaper coverage of IPV over a two-year-period and compares this coverage to epidemiological data in order to examine the implications of the discrepancies between coverage and social reality. Stratified media outlets across the country were used to obtain a representative sample of daily newspapers based on their designated market areas, resulting in 395 IPV-related articles. Results show that newspaper framing of IPV tends to be heavily skewed toward episodic framing. In addition, there are significant differences between our data and epidemiological estimates, particularly in the coverage of homicide and use of alcohol and illegal drugs, which may skew public perceptions of risk. Implications for public perceptions and social policy are discussed. PMID- 21297888 TI - Escherichia coli Shiga Toxin Mechanisms of Action in Renal Disease. AB - Shiga toxin-producing Escherichia coli is a contaminant of food and water that in humans causes a diarrheal prodrome followed by more severe disease of the kidneys and an array of symptoms of the central nervous system. The systemic disease is a complex referred to as diarrhea-associated hemolytic uremic syndrome (D(+)HUS). D(+)HUS is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. This review focuses on the renal aspects of D(+)HUS. Current knowledge of this renal disease is derived from a combination of human samples, animal models of D(+)HUS, and interaction of Shiga toxin with isolated renal cell types. Shiga toxin is a multi-subunit protein complex that binds to a glycosphingolipid receptor, Gb3, on select eukaryotic cell types. Location of Gb3 in the kidney is predictive of the sites of action of Shiga toxin. However, the toxin is cytotoxic to some, but not all cell types that express Gb3. It also can cause apoptosis or generate an inflammatory response in some cells. Together, this myriad of results is responsible for D(+)HUS disease. PMID- 21297890 TI - Addressing Health Literacy and Numeracy to Improve Diabetes Education and Care. PMID- 21297891 TI - Correlates of Correct Condom Use Among High-Risk African American Men Attending an Urban STD Clinic in the South. AB - The purpose of this cross-sectional study was to assess prevalence and correlates of correct condom use among high-risk African American men attending a publicly funded sexually transmitted disease (STD) clinic. Men 18 through 29 years of age and newly diagnosed with a sexually transmitted disease were further assessed for study eligibility. Of 296 meeting eligibility criteria, 271 agreed to participate thereby yielding a participation rate of 91.5%. Correct use, assessed by an index, was reported by 38%. Correct use was associated with having sex with 3 or fewer female sex partners (AOR=3.1), being in an exclusive relationship (AOR=3.2), not indicating problems with the fit or feel of condoms (AOR=2.9), and not being drunk/high while using condoms (AOR=2.6). The correct use of condoms among young African American men newly diagnosed with an STD may be a function of situational factors. These factors could potentially be addressed in the context of clinic-based behavioral intervention programs. PMID- 21297892 TI - Molecular mechanism of long-range synergetic color tuning between multiple amino acid residues in conger rhodopsin. AB - The synergetic effects of multiple rhodopsin mutations on color tuning need to be completely elucidated. Systematic genetic studies and spectroscopy have demonstrated an interesting example of synergetic color tuning between two amino acid residues in conger rhodopsin's ancestral pigment (p501): -a double mutation at one nearby and one distant residue led to a significant lambda(max) blue shift of 13 nm, whereas neither of the single mutations at these two sites led to meaningful shifts.To analyze the molecular mechanisms of this synergetic color tuning, we performed homology modeling, molecular simulations, and electronic state calculations. For the double mutant, N195A/A292S, in silico mutation analysis demonstrated conspicuous structural changes in the retinal chromophore, whereas that of the single mutant, A292S, was almost unchanged. Using statistical ensembles of QM/MM optimized structures, the excitation energy of retinal chromophore was evaluated for the three visual pigments. As a result, the lambda(max) shift of double mutant (DM) from p501 was -8 nm, while that of single mutant (SM) from p501 was +1 nm. Molecular dynamics simulation for DM demonstrated frequent isomerization between 6-s-cis and 6-s-trans conformers. Unexpectedly, however, the two conformers exhibited almost identical excitation energy, whereas principal component analysis (PCA) identified the retinal counterion cooperative change of BLA (bond length alternation) and retinal counterion interaction lead to the shift. PMID- 21297893 TI - The Relationship of Chronological Age, Age at Injury, and Duration of Injury to Employment Status in Individuals with Spinal Cord Injury. AB - Employment status following spinal cord injury (SCI) has important implications for financial and psychosocial well-being. Several age-related variables-in particular chronological age, duration of SCI, and age at SCI onset-have been identified as being associated with employment among individuals with SCI. Cross sectional investigations of this topic are complicated by methodological and statistical issues associated with aging and disability. The purpose of the current study was to examine the associations between three aging variables and employment status in individuals with SCI through a series of regression analyses. Six hundred twenty individuals with SCI completed a survey that included measures of demographic characteristics, pain, psychological functioning, physical functioning, fatigue, and sleep. The results indicated that chronological age and age at SCI onset were significant predictors of employment status. A significantly greater proportion of individuals aged 45-54 were employed compared to those aged 55-64 even after controlling for biopsychosocial variables. Additionally, there was a negative linear relationship between percent employed and age at SCI onset, and this relationship was not accounted for by the biopsychosocial variables. The analyses used in this study provide one method by which to disentangle the effects of different age-related variables on important SCI outcomes in cross-sectional research. Continued research in this area is needed to better understand age-related effects on employment status, which could be used to help maximize the quality of life in individuals with SCI. PMID- 21297894 TI - OpenPET: A Flexible Electronics System for Radiotracer Imaging. AB - We present the design for OpenPET, an electronics readout system designed for prototype radiotracer imaging instruments. The critical requirements are that it has sufficient performance, channel count, channel density, and power consumption to service a complete camera, and yet be simple, flexible, and customizable enough to be used with almost any detector or camera design. An important feature of this system is that each analog input is processed independently. Each input can be configured to accept signals of either polarity as well as either differential or ground referenced signals. Each signal is digitized by a continuously sampled ADC, which is processed by an FPGA to extract pulse height information. A leading edge discriminator creates a timing edge that is "time stamped" by a TDC implemented inside the FPGA. This digital information from each channel is sent to an FPGA that services 16 analog channels, and information from multiple channels is processed by this FPGA to perform logic for crystal lookup, DOI calculation, calibration, etc. As all of this processing is controlled by firmware and software, it can be modified / customized easily. The system is open source, meaning that all technical data (specifications, schematics and board layout files, source code, and instructions) will be publicly available. PMID- 21297895 TI - Interactive Image Analysis in Age-related Macular Degeneration (AMD) and Stargardt Disease (STGD). AB - The literature of the last three decades is replete with automatic methods for retinal image analysis. Acceptance has been limited due to post-processing or tuning requirements that may be just as time consuming as the original manual methods. The point of view herein is that by taking advantage of the human visual system and expert knowledge from the outset, the promised efficiencies of digital methods can be achieved in practice as well as in theory. Thus, simple labeling of regions of interest that is accepted and easily performed in a few moments by the human can provide enormous advantage to an already well-developed algorithm. Three examples are provided: drusen segmentation, image registration, and geographic atrophy segmentation, with applications to disease understanding. PMID- 21297896 TI - Neuroimmunomodulation and Aging. AB - Inflammation is by definition a protective phase of the immune response. The very first goal of inflammation is destroying and phagocytosing infected or damaged cells to avoid the spread of the pathogen or of the damage to neighboring, healthy, cells. However, we now know that during many chronic neurological disorders, inflammation and degeneration always coexist at certain time points. For example, inflammation comes first in multiple sclerosis, but degeneration follows, while in Alzheimer's or Parkinson's disease degeneration starts and inflammation is secondary. Either way these are the two pathological detectable problems. The central nervous system (CNS) has long been viewed as exempt from the effects of the immune system. The brain has physical barriers for protection, and it is now clear that cells in the nervous system respond to inflammation and injury in unique ways. In recent years, researchers have presented evidence supporting the idea that in the CNS there is an ongoing protective inflammatory mechanism, which involves macrophage, monocytes, T cells, regulatory T-cells, effector T cells and many others; these, in turn, promote repair mechanisms in the brain not only during inflammatory, and degenerative disorders but also in healthy people. This "repair mechanism" can be considered as an intrinsic part of the physiological activities of the brain. It is now well known that the microenvironment of the brain is a crucial player in determining the relative contribution of the two different outcomes. Failure of molecular and cellular mechanisms sustaining the "brain-repair programme" might be, at least in part, a cause of neurological disorders. Today, the neurotoxic and neuroprotective roles of the innate immune reactions in aging, brain injury, ischemia, autoimmune and neurodegenerative disorders of the CNS are widely investigated and highly debated research topics. Nevertheless, several issues remain to be elucidated, notably the earlier cellular events that initiate dysregulation of brain inflammatory pathways. If these inflammatory processes could be identified and harnessed, then cognitive function may be protected during aging and age-related neurodegenerative diseases through early interventions directed against the negative consequences of inflammation. This commentary highlights the major issues/opinions presented by experts on the involvement of the brain immune system in aging and age-related diseases in a special edition of the journal Aging and Disease. PMID- 21297897 TI - Progress in BazookaSPECT. AB - Recent progress on a high-resolution, photon-counting gamma-ray and x-ray imager called BazookaSPECT is presented. BazookaSPECT is an example of a new class of scintillation detectors based on integrating detectors such as CCD(charge-coupled device) or CMOS(complementary metal-oxide semiconductor) sensors. BazookaSPECT is unique in that it makes use of a scintillator in close proximity to a microchannel plate-based image intensifier for up-front optical amplification of scintillation light. We discuss progress made in bringing about compact BazookaSPECT modules and in real-time processing of event data using graphics processing units (GPUs). These advances are being implemented in the design of a high-resolution rodent brain imager called FastSPECT III. A key benefit of up front optical gain is that any CCD/CMOS sensor can now be utilized for photon counting. We discuss the benefits and feasibility of using CMOS sensors as photon counting detectors for digital radiography, with application in mammography and computed tomography (CT). We present as an appendix a formal method for comparing various photon-counting integrating detectors using objective statistical criteria. PMID- 21297898 TI - Human epithelial cell cultures from superficial limbal explants. AB - PURPOSE: To study the kinetics of growth and the phenotype of cells cultured from human limbal explants in a cholera toxin-free medium with no feeder cell layer. METHODS: Human organ-cultured corneas were used to prepare limbal explants (full thickness and superficial limbal explants) and corneal stromal explants. Cell growth kinetics and phenotypes were assessed by cultivating explants in cholera toxin-free Green medium. Epithelial and progenitor cell markers were assessed by immunocytochemistry, flow cytometry, and Reverse Transcription and Polymerase Chain Reaction (RT-PCR). RESULTS: The successful epithelial cell growth rates from full thickness limbal explant and superficial limbal explant tissues were 41 and 86%, respectively (p=0.0001). The mean cell area and the percentage of small cells in superficial and full-thickness explant cultures were, respectively, 317 um(2) and 429 um(2), and 8.9% and 1.7% (p<0.001). The percentage of positive cells in superficial and full-thickness limbal explant cultures as assessed by immunocytochemistry were the following: broad spectrum cytokeratins (cytokeratins 4, 5, 6, 8, 10, 13, and 18 [MNF116]), 82%/37% (p=0.01); cytokeratin 3 (CK3), 74%/25% (p=0.009); cytokeratin 19 (CK19), 46%/25% (p=0.19); vimentin, 56%/53% (p=0.48); delta N p63alpha, 54%/0% (p<0.001); and ABCG2, 5%/0% (p=0.1). Flow cytometry showed a higher percentage of small cells, a higher percentage of MNF116+ cells, and stronger expression of progenitor-associated markers in superficial than in full-thickness explant cultures. For superficial limbal explant cultures, analysis of the expression profiles for various mRNAs at the end of 21 days of culture showed high levels of expression of the mRNAs encoding CK3, vimentin, and CK19. The expression of mRNA of delta N p63alpha and ABCG2 was weaker. Cultures obtained from full-thickness limbal explants featured no expression of mRNA of CK19, delta N p63alpha, and ABCG2, whereas mRNAs encoding CK3 and vimentin were detected. Human corneal stromal explants cultured with the same medium featured late cell growth, large mean cell area (2,529 um(2)), no expression of cytokeratins, delta N p63alpha, and ABCG2, and high expression of vimentin. CONCLUSIONS: Superficial limbal explants appear to be superior to full thickness limbal explants for growing human limbal epithelial cells. Preparation of explants using surgical facilities (i.e., operating microscope and microsurgical blades) led to a dramatic increase in the percentage of successful cultures, higher epithelial cell growth, decreased fibroblast contamination, and better preservation of limbal epithelial progenitors. PMID- 21297899 TI - Effects of asymmetric dimethylarginine on bovine retinal capillary endothelial cell proliferation, reactive oxygen species production, permeability, intercellular adhesion molecule-1, and occludin expression. AB - PURPOSE: Asymmetric dimethylarginine (ADMA), an endogenous competitive inhibitor of nitric oxide synthase, is associated with impaired endothelial dysfunction, such as chronic heart failure, hypertension, diabetes, and pulmonary hypertension. The effects of ADMA on cell proliferation, reactive oxygen species (ROS) production, cell permeability, intercellular adhesion molecule-1 (ICAM-1), and tight-junction protein occludin levels in bovine retinal capillary endothelial cells (BRCECs) were investigated. METHODS: A cell proliferation assay was performed using the novel tetrazolium compound 3-(4,5-dimethylthiazol-2-yl)-5 (3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium and an electron coupling reagent. Intracellular ROS levels were determined using the fluorescent probe CM-H(2)DCFDA. Horseradish peroxidase was used for a permeability assay. ICAM-1 and tight-junction protein occludin were assessed by western blotting and quantitative real-time PCR. RESULTS: Cell proliferation was significantly inhibited by ADMA. ADMA increased intracellular ROS generation in BRCECs. The increased ROS production induced by ADMA was markedly inhibited by the angiotensin II receptor-blocker telmisartan, the angiotensin-converting enzyme inhibitor benazepril, the reduced form of nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase inhibitor diphenyliodonium (DPI), or the antioxidant and free-radical scavenger N-acetyl-L-cysteine (NAC). ADMA significantly increased horseradish peroxidase (HRP) permeability in BRCECs. Benazepril, telmisartan, DPI, and NAC downregulated cell permeability. ADMA markedly upregulated ICAM-1 expression in BRCECs, which were downregulated by telmisartan, DPI, and NAC. ADMA significantly downregulated occludin expression in BRCECs. Benazepril and telmisartan upregulated occludin expression in BRCECs exposed to ADMA. CONCLUSIONS: Our results provide the first reported evidence that ADMA has potent adverse effects on cell proliferation, intracellular ROS generation, cell permeability, levels of ICAM-1, and the tight-junction protein occludin. Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and antioxidants are effective inhibitors of the adverse effects of ADMA. PMID- 21297900 TI - Total Synthesis of (+/-)-Vibsanin E. PMID- 21297901 TI - Region of Interest (ROI) Computed Tomography. AB - High-resolution computed tomography (CT) reconstructions currently require either full field of view (FOV) exposure, resulting in high dose, or region of interest (ROI) exposure, resulting in artifacts. To obtain high-resolution 3D reconstruction of an ROI with minimal artifacts, we have developed a method involving a non-uniform ROI beam filter to reduce dose outside the ROI while acquiring the ROI at a higher dose. High-resolution, high-dose full-field projections of a phantom were obtained. ROIs in the images were selected and the low-dose data outside the ROI were simulated by adding various levels of noise to the projection data corresponding to a dose of 1/16 and 1/256 of the original dose. For an ROI of 30% FOV, artifacts in the reconstructed ROI were minimal for both dose reduction levels. For an ROI of 10% FOV, artifacts remained minimal only for the 1/16(th) dose case. The effect of the presence of a high contrast object outside the ROI was also studied. We found that the intensity of the artifacts increases with the contrast of the object, its size, and its distance from the axis of rotation. CT using an ROI filter provides a way to reconstruct an ROI with reduced integral dose and yet with minimal artifacts and improved spatial resolution. PMID- 21297903 TI - Enteric bacteria and cancer stem cells. AB - Intestinal bacteria can contribute to cell proliferation and cancer development, particularly in chronic infectious diseases in which bacteria and/or bacterial components might interfere with cell function. The number of microbial cells within the gut lumen is estimated to be 100 trillion, which is about 10-times larger than the number of eukaryotic cells in the human body. Because of the complexity of the gut flora, identifying the specific microbial agents related to human diseases remains challenging. Recent studies have demonstrated that the stemness of colon cancer cells is, in part, orchestrated by the microenvironment and is defined by high Wnt activity. In this review article, we will discuss recent progress with respect to intestinal stem cells, cancer stem cells, and the molecular mechanisms of enteric bacteria in the activation of the Wnt pathway. We will also discuss the roles of other pathways, including JAK-STAT, JNK, and Notch, in regulating stem cell niches during bacterial infections using Drosophila models. Insights gained from understanding how host-bacterial interaction during inflammation and cancer may serve as a paradigm for understanding the nature of self-renewal signals. PMID- 21297904 TI - New light-amplifier-based detector designs for high spatial resolution and high sensitivity CBCT mammography and fluoroscopy. AB - New cone-beam computed tomographic (CBCT) mammography system designs are presented where the detectors provide high spatial resolution, high sensitivity, low noise, wide dynamic range, negligible lag and high frame rates similar to features required for high performance fluoroscopy detectors. The x-ray detectors consist of a phosphor coupled by a fiber-optic taper to either a high gain image light amplifier (LA) then CCD camera or to an electron multiplying CCD. When a square-array of such detectors is used, a field-of-view (FOV) to 20 * 20 cm can be obtained where the images have pixel-resolution of 100 um or better. To achieve practical CBCT mammography scan-times, 30 fps may be acquired with quantum limited (noise free) performance below 0.2 uR detector exposure per frame. Because of the flexible voltage controlled gain of the LA's and EMCCDs, large detector dynamic range is also achievable. Features of such detector systems with arrays of either generation 2 (Gen 2) or 3 (Gen 3) LAs optically coupled to CCD cameras or arrays of EMCCDs coupled directly are compared. Quantum accounting analysis is done for a variety of such designs where either the lowest number of information carriers off the LA photo-cathode or electrons released in the EMCCDs per x-ray absorbed in the phosphor are large enough to imply no quantum sink for the design. These new LA- or EMCCD-based systems could lead to vastly improved CBCT mammography, ROI-CT, or fluoroscopy performance compared to systems using flat panels. PMID- 21297902 TI - Molecular mechanisms of mouse skin tumor promotion. AB - Multiple molecular mechanisms are involved in the promotion of skin carcinogenesis. Induction of sustained proliferation and epidermal hyperplasia by direct activation of mitotic signaling pathways or indirectly in response to chronic wounding and/or inflammation, or due to a block in terminal differentiation or resistance to apoptosis is necessary to allow clonal expansion of initiated cells with DNA mutations to form skin tumors. The mitotic pathways include activation of epidermal growth factor receptor and Ras/Raf/mitogen activated protein kinase signaling. Chronic inflammation results in inflammatory cell secretion of growth factors and cytokines such as tumor necrosis factor-a and interleukins, as well as production of reactive oxygen species, all of which can stimulate proliferation. Persistent activation of these pathways leads to tumor promotion. PMID- 21297905 TI - Do free radicals play causal role in atherosclerosis? Low density lipoprotein oxidation and vitamin E revisited. AB - Lipid peroxidation induced by free radicals has been implicated in the pathogenesis of various diseases. Numerous in vitro and animal studies show that oxidative modification of low density lipoprotein (LDL) is an important initial event of atherosclerosis. Vitamin E and other antioxidants inhibit low density lipoprotein oxidation efficiently in vitro, however, human clinical trials with vitamin E have not yielded positive results. The mixed results for vitamin E effect may be ascribed primarily to the two factors. Firstly low density lipoprotein oxidation proceeds by multiple pathways mediated not only by free radicals but also by other non-radical oxidants and vitamin E is effective only against free radical mediated oxidation. Secondly, in contrast to animal experiments, vitamin E is given at the latter stage where oxidation is no more important. Free radicals must play causal role in pathogenesis of atherosclerosis and vitamin E should be effective if given at right time to right subjects. PMID- 21297907 TI - Hypoxic regulation of glycosylation via the N-acetylglucosamine cycle. AB - Glucose is an energy substrate, as well as the primary source of nucleotide sugars, which are utilized as donor substrates in protein glycosylation. Appropriate glycosylation is necessary to maintain the stability of protein, and is also important in the localization and trafficking of proteins. The dysregulation of glycosylation results in the development of a variety of disorders, such as cancer, diabetes mellitus and emphysema. Glycosylation is kinetically regulated by dynamically changing the portfolio of glycosyltransferases, nucleotide sugars, and nucleotide sugar transporters, which together form a part of what is currently referred to as the "Glycan cycle". An excess or a deficiency in the expression of glycosyltransferases has been shown to alter the glycosylation pattern, which subsequently leads to the onset, progression and exacerbation of a number of diseases. Furthermore, alterations in intracellular nucleotide sugar levels can also modulate glycosylation patterns. It is observed that pathological hypoxic microenvironments frequently occur in solid cancers and inflammatory foci. Hypoxic conditions dramatically change gene expression profiles, by activating hypoxia-inducible factor-1, which mediates adaptive cellular responses. Hypoxia-induced glycosyltransferases and nucleotide sugar transporters have been shown to modulate glycosylation patterns that are part of the mechanism associated with cancer metastasis. Hypoxia-inducible factor 1 also induces the expression of glucose transporters and various types of glycolytic enzymes, leading to shifts in glucose metabolic patterns. This fact strongly suggests that hypoxic conditions are an important factor in modulating various nucleotide sugar biosynthetic pathways. This review discusses some of the current thinking of how hypoxia alters glucose metabolic fluxes that can modulate cellular glycosylation patterns and consequently modify cellular functions, particularly from the standpoint of the N-acetylglucosamine cycle, a part of the "Glycan cycle". PMID- 21297906 TI - Myeloperoxidase-derived oxidation: mechanisms of biological damage and its prevention. AB - There is considerable interest in the role that mammalian heme peroxidase enzymes, primarily myeloperoxidase, eosinophil peroxidase and lactoperoxidase, may play in a wide range of human pathologies. This has been sparked by rapid developments in our understanding of the basic biochemistry of these enzymes, a greater understanding of the basic chemistry and biochemistry of the oxidants formed by these species, the development of biomarkers that can be used damage induced by these oxidants in vivo, and the recent identification of a number of compounds that show promise as inhibitors of these enzymes. Such compounds offer the possibility of modulating damage in a number of human pathologies. This reviews recent developments in our understanding of the biochemistry of myeloperoxidase, the oxidants that this enzyme generates, and the use of inhibitors to inhibit such damage. PMID- 21297908 TI - Lipoic acid: energy metabolism and redox regulation of transcription and cell signaling. AB - The role of R-alpha-lipoic acid as a cofactor (lipoyllysine) in mitochondrial energy metabolism is well established. Lipoic acid non-covalently bound and exogenously administered to cells or supplemented in the diet is a potent modulator of the cell's redox status. The diversity of beneficial effects of lipoic acid in a variety of tissues can be mechanistically viewed in terms of thiol/disulfide exchange reactions that modulate the environment's redox and energy status. Lipoic acid-driven thiol/disulfide exchange reactions appear critical for the modulation of proteins involved in cell signaling and transcription factors. This review emphasizes the effects of lipoic acid on PI3K and AMPK signaling and related transcriptional pathways that are integrated by PGC-1alpha, a critical regulator of energy homoestasis. The effects of lipoic acid on the neuronal energy-redox axis are largely reviewed in terms of their outcomes for aging and age-related neurodegenerative diseases. PMID- 21297909 TI - Nucleotides function as endogenous chemical sensors for oxidative stress signaling. AB - Oxidized and nitrated nucleotides including 8-oxogunanine and 8-nitroguanine derivatives such as 8-nitroguanosine 3',5'-cyclic monophosphate were generated by reactive nitrogen oxides and reactive oxygen species in cultured cells and in tissues. 8-oxoguanine and 8-nitroguanine in DNA and RNA are potentially mutagenic, and the former also induces cell death. Some derivative, 8 nitroguanosine 3',5'-cyclic monophosphate a major nitrated guanine nucleotide, was identified as a novel second messenger. Surprisingly, the amount of 8 nitroguanosine 3',5'-cyclic monophosphate generated was found to be higher than that of guanosine 3',5'-cyclic monophosphate in cells expressing inducible nitric oxide synthase. More important, 8-nitroguanosine 3',5'-cyclic monophosphate is electrophilic and reacted efficiently with sulfhydryls of proteins to produce a novel posttranslational modification (named S-guanylation) via guanosine 3',5' cyclic monophosphate adduction. For example, 8-nitroguanosine 3',5'-cyclic monophosphate-induced S-guanylation of Kelch-like ECH-associated protein 1 led to NF-E2-related factor activation and induction of antioxidant enzymes. 8 nitroguanosine 3',5'-cyclic monophosphate may thus protect cells against oxidative stress-related cytotoxicity. Therefore, although chemically modified nucleotides produced via oxidative and nitrative stress are regarded simply as endogenous mutagens, the endogenous nucleotides stored in cells per se may serve functionally as a sensing mechanism for reactive nitrogen oxides and oxygen species to induce cellular adaptive responses to oxidative stress. PMID- 21297910 TI - High selenium intake and increased diabetes risk: experimental evidence for interplay between selenium and carbohydrate metabolism. AB - The essential trace element selenium has long been considered to exhibit anti diabetic and insulin-mimetic properties, but recent epidemiological studies indicated supranutritional selenium intake and high plasma selenium levels as possible risk factors for development of type 2 diabetes, pointing to adverse effects of selenium on carbohydrate metabolism in humans. However, increased plasma selenium levels might be both a consequence and a cause of diabetes. We summarize current evidence for an interference of selenium compounds with insulin regulated molecular pathways, most notably the phosphoinositide-3-kinase/protein kinase B signaling cascade, which may underlie some of the pro- and anti-diabetic actions of selenium. Furthermore, we discuss reports of hyperinsulinemia, hyperglycemia and insulin resistance in mice overexpressing the selenoenzyme glutathione peroxidase 1. The peroxisomal proliferator-activated receptor gamma coactivator 1alpha represents a key regulator for biosynthesis of the physiological selenium transporter, selenoprotein P, as well as for hepatic gluconeogenesis. As proliferator-activated receptor gamma coactivator 1alpha has been shown to be up-regulated in livers of diabetic animals and to promote insulin resistance, we hypothesize that dysregulated pathways in carbohydrate metabolism and a disturbance of selenium homeostasis are linked via proliferator activated receptor gamma coactivator 1alpha. PMID- 21297911 TI - Mysterious link between iron overload and CDKN2A/2B. AB - Persistent oxidative stress has been associated with carcinogenesis. Iron overload is considered one such condition that causes oxidative stress. Epidemiological studies support a close link between iron overload and carcinogenesis. Reportedly, regular semiannual phlebotomies reduced cancer risk in an otherwise normal population. More specifically, genetic hemochromatosis, chronic viral hepatitis, ovarian endometriosis and asbestosis induce iron overload, which can lead to hepatocellular carcinoma, ovarian carcinoma or mesothelioma in humans. Through a combination of animal experiments and microarray analyses, homozygous deletion of CDKN2A/2B has been recognized as one of the major target genes involved in iron overload-induced carcinogenesis. CDKN2A/2B are the second most frequently inactivated tumor suppressing genes in human cancers. Currently, when infection is becoming sufficiently controlled worldwide, iron regulation may be the next target for human longevity. PMID- 21297912 TI - Divergent roles of superoxide and nitric oxide in liver ischemia and reperfusion injury. AB - Liver ischemia and reperfusion-induced injury is a major clinical complication associated with hemorrhagic or endotoxin shock and thermal injury as well as liver transplantation and resectional surgery. Data obtained from several different studies suggest that an important initiating event in the pathophysiology of ischemia and reperfusion-induced tissue injury is enhanced production of superoxide concomitant with a decrease in the bioavailability of endothelial cell-derived nitric oxide. This review will summarize the evidence supporting the hypothesis that the redox imbalance induced by alterations in superoxide and nitric oxide generation creates a more oxidative environment within the different cells of the liver that enhances the nuclear transcription factor-kappaB-dependent expression of a variety of different cytokines and mediators that may promote as well as limit ischemia and reperfusion-induced hepatocellular injury. In addition, the evidence implicating endothelial cell nitric oxide synthase-dependent and -independent generation of nitric oxide as important regulatory pathways that act to limit ischemia and reperfusion-induced liver injury and inflammation is also presented. PMID- 21297913 TI - Singlet molecular oxygen-quenching activity of carotenoids: relevance to protection of the skin from photoaging. AB - Carotenoids are known to be potent quenchers of singlet molecular oxygen [O(2) ((1)Delta(g))]. Solar light-induced photooxidative stress causes skin photoaging by accelerating the generation of reactive oxygen species via photodynamic actions in which O(2) ((1)Delta(g)) can be generated by energy transfer from excited sensitizers. Thus, dietary carotenoids seem to participate in the prevention of photooxidative stress by accumulating as antioxidants in the skin. An in vivo study using hairless mice clarified that a O(2) ((1)Delta(g)) oxygenation-specific peroxidation product of cholesterol, cholesterol 5alpha hydroperoxide, accumulates in skin lipids due to ultraviolet-A exposure. Matrix metalloproteinase-9, a metalloproteinase family enzyme responsible for the formation of wrinkles and sagging, was enhanced in the skin of ultraviolet-A irradiated hairless mice. The activation of metalloproteinase-9 and the accumulation of 5alpha-hydroperoxide, as well as formation of wrinkles and sagging, were lowered in mice fed a beta-carotene diet. These results strongly suggest that dietary beta-carotene prevents the expression of metalloproteinase-9 (at least in part), by inhibiting the photodynamic action involving the formation of 5alpha-hydroperoxide in the skin. Intake of beta-Carotene therefore appears to be helpful in slowing down ultraviolet-A -induced photoaging in human skin by acting as a O(2) ((1)Delta(g)) quencher. PMID- 21297914 TI - Cocoa flavanols: effects on vascular nitric oxide and blood pressure. AB - Diets rich in fruits and vegetables have been associated with benefits for human health. Those effects have been partially ascribed to their content in flavonoids, compounds that are present in many edible plants and its derived foods. In humans, a significant number of studies has been developed analyzing the effect of foods and beverages rich in flavonoids on the presence and progression of risk factors associated to cardiovascular diseases, including hypertension. Cocoa derived products, rich in flavanols, have been thoroughly studied and demonstrated to be efficient improving endothelial function and decreasing blood pressure in humans and animals. However, the final chemical species and the mechanism/s responsible for these effects have not been completely defined. In this paper we present data supporting the hypothesis that flavanols could define superoxide anion production and then, establish optimal nitric oxide levels and blood pressure. PMID- 21297915 TI - Oxidative stress in cardiac and skeletal muscle dysfunction associated with diabetes mellitus. AB - Diabetes mellitus increases the risk of heart failure independently of underlying coronary artery disease. It also causes skeletal muscle dysfunction, which is responsible for reduced exercise capacity commonly seen in heart failure. The underlying pathogenesis is partially understood. Several factors may contribute to the development of cardiac and skeletal muscle dysfunction in heart failure and diabetes mellitus. Based on the findings in animal models, this review discusses the role of oxidative stress that may be involved in the development and progression of cardiac and skeletal dysfunction associated with diabetes. PMID- 21297916 TI - Clinical and experimental evidence for oxidative stress as an exacerbating factor of diabetes mellitus. AB - The involvement of reactive oxygen species in various diseases has been demonstrated almost in vitro or in animal studies and clinical studies supporting the involvement of reactive oxygen species are very few. Bilirubin has been recognized as an important antioxidant and also shown to have an inhibitory effect on the activity of NADPH oxidase, which may be an important source for superoxide production in various tissues. When the prevalence of vascular complcations was compared in diabetic patients with and without a congenital hyperbilirubinemia (Gilbert syndrome), the prevalence of retinopathy, macroalbuminuria and coronary artery disease in patients with Gilbert syndrome was about 20% of that in those without Gilbert syndrome. For study of lifestyle related diseases, the Fukuoka Cohort was constructed from 2003 to 2009 in Kyushu area in Japan, which contains a total of 12,949 persons. Cross-sectional study of the Fukuoka Cohort revealed an inverse relation between serum bilirubin level and the prevalence of type 2 diabetes mellitus. A precursor of bilirubin, biliverdin treated db/db mice exhibited less albuminuria and nephropathic changes. These effects were paralleled with normalization of oxidative stress markers and expression of NAD(P)H oxidase subunits in kidney. These results suggested that oxidative stress is an exacerbating factor of type 2 diabetes mellitus and that antioxidant therapies are of value to diabetic nephropathy. PMID- 21297917 TI - Extensive screening for herbal extracts with potent antioxidant properties. AB - This paper summarizes our research for herbal extracts with potent antioxidant activity obtained from a large scale screening based on superoxide radical (O(2) (*-)) scavenging activity followed by characterization of antioxidant properties. Firstly, scavenging activity against O(2) (*-) was extensively screened from ethanol extracts of approximately 1000 kinds of herbs by applying an electron spin resonance (ESR)-spin trapping method, and we chose four edible herbal extracts with prominently potent ability to scavenge O(2) (*-). They are the extracts from Punica granatum (Peel), Syzygium aromaticum (Bud), Mangifera indica (Kernel), and Phyllanthus emblica (Fruit). These extracts were further examined to determine if they also scavenge hydroxyl radical ((*)OH), by applying the ESR spin-trapping method, and if they have heat resistance as a desirable characteristic feature. Experiments with the Fenton reaction and photolysis of H(2)O(2) induced by UV irradiation demonstrated that all four extracts have potent ability to directly scavenge (*)OH. Furthermore, the scavenging activities against O(2) (*-) and (*)OH of the extracts of P. granatum (peel), M. indica (kernel) and P. emblica (fruit) proved to be heat-resistant.The results of the review might give useful information when choosing a potent antioxidant as a foodstuff. For instance, the four herbal extracts chosen from extensive screening possess desirable antioxidant properties. In particular, the extracts of the aforementioned three herbs are expected to be suitable for food processing in which thermal devices are used, because of their heat resistance. PMID- 21297918 TI - Anticancer property of gallic acid in A549, a human lung adenocarcinoma cell line, and possible mechanisms. AB - Gallic acid is widely distributed in plants, fruits and foods with a range of biological activities. In the present study the possible mechanisms of gallic acid anticancer properties were explored in A549, a human lung adenocarcinoma cell line. Our study shows that it inhibited the A549 cell growth and decreased cell viability monitored at 24 h. It also inhibited cell proliferation in dose- and time-dependent manner as measured by 3-[4,5-methylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay at 24 and 48 h. Morphological examination of the cells after gallic acid treatment showed the typical feature of cell death such as cell shrinkage and rounding up of the cells. Clonogenic assay indicated that gallic acid treatments inhibited the colony formation. DNA fragmentation assay indicated the disappearance of the genomic DNA in dose-dependent manner. To find out possible mechanisms, mitochondrial potential and intracellular reactive oxygen species were measured. It was observed that gallic acid treatment decreased mitochondrial membrane potential and increased intracellular reactive oxygen species. Further caspases activity was measured and it was found that gallic acid activated the caspase-3 but not caspase-8 indicating the involvement of intrinsic pathway of cell apoptosis. PMID- 21297919 TI - Lipid antioxidants: free radical scavenging versus regulation of enzymatic lipid peroxidation. AB - The essentiality of polyunsaturated lipids makes membranes susceptible to peroxidative modifications. One of the most contemporary examples includes selective peroxidation of cardiolipin in mitochondria of cells undergoing apoptosis. Cardiolipin peroxidation products are required for the mitochondrial membrane permeabilization, release of pro-apoptotic factors and completion of the cell death program. Therefore, search for effective inhibitors of cardiolipin peroxidation is critical to discovery and development of anti-apoptotic antioxidants. Mitochondria contain significant amounts of alpha-tocopherol, a well known scavenger of reactive free radicals. In the present study, we used an oxidative lipidomics approach to evaluate the effect of alpha-tocopherol and its homologues with different lengths of the side-chain such as 2,5,7,8,-tetramethyl 2(4-methylpentyl)-6-chromanol and 2,2,5,7,8-pentamethyl-6-chromanol, on oxidation of tetralinoleoyl cardiolipin induced by cytochrome c in the presence of hydrogen peroxide. Our data indicate that vitamin E homologues inhibit not only accumulation of tetralinoleoyl cardiolipin hydroperoxides but also hydroxy derivatives of tetralinoleoyl cardiolipin formed in the enzymatic peroxidase half reaction catalyzed by cytochrome c. This suggests that protective effects of vitamin E homologues against tetralinoleoyl cardiolipin peroxidation catalyzed by cytochrome c/hydrogen peroxide are realized largely due to their effects on the peroxidase activity of cytochrome c towards tetralinoleoyl cardiolipin rather than via their scavenging activity. PMID- 21297920 TI - Carbon monoxide stimulates global protein methylation via its inhibitory action on cystathionine beta-synthase. AB - Although carbon monoxide derived from heme oxygenase has been reported to exert diverse biological actions in mammals, macromolecules responsible for its direct reception and functional outcomes of the gas binding remain largely unknown. Based on our previous results in vivo suggesting carbon monoxide serves as an inhibitor of cystathionine beta-synthase that rate-limits transsulfuration pathway for generation of hydrogen sulfide, we have herein hypothesized that the gas might serve as a regulator of protein methylation through accelerating turnover of remethylation cycle residing at the upstream of the enzyme. Metabolomic analysis in human monoblastic leukemia U937 cells in culture revealed that application of carbon monoxide-releasing molecules caused increases in methionine and S-adenosylmethionine and a decrease in cystathionine in the cells, suggesting the cystathionine beta-synthase inhibition by carbon monoxide. Under these circumstances, the cells exhibited global protein arginine methylation: this event was also reproduced by the cell treatment with hemin, a heme oxygenase 1 inducer. The protein arginine methylation elicited by carbon monoxide was attenuated by knocking down cystathionine beta-synthase with its small interfering RNA or by blocking S-adenosylhomocysteine hydrolase with adenosine dialdehyde, suggesting remethylation cycling is necessary to trigger the methylation processing. Furthermore, proteins undergoing the carbon monoxide induced arginine methylation involved histone H3 proteins, suggesting chromatin modification by the gas. Collectively with our studies in vivo showing its inhibitory action on endogenous hydrogen sulfide production, the current results suggest that not only inhibition of transsulfuration pathway for H(2)S generation but also activation of protein methylation accounts for notable biological actions of carbon monoxide via the cystathionine beta-synthase inhibition. PMID- 21297921 TI - Inhibitory effects of Indigofera aspalathoides on 20-methylcholanthrene-induced chemical carcinogenesis in rats. AB - BACKGROUND: The anticancer and antioxidant effects of the aqueous extract of Indigofera aspalathoides on 20-methylcholanthrene (20-MCA) induced fibrosarcoma were investigated in male albino rats. MATERIALS AND METHODS: The rats were divided into four different groups, each group consisting of six animals. Group I animals were served as normal control, Group II animals were fibrosarcoma-bearing animals after the incubation period, Group III animals were fibrosarcoma-bearing animals, treated with aqueous extract of I. aspalathoides intraperitoneally at a dose of 250 mg/kg b.w. for 30 days and Group IV animals were administered with the aqueous extract of I. aspalathoides alone, at a dose of 250 mg/kg b.w. for 30 days, served as drug control animals. After the experimental period, all the rats were weighed and killed by cervical decapitation. The serum was separated from the blood for analysis. The weights of the liver and the kidneys were noted. The fibrosarcoma was proved by pathological examinations. The liver and kidney tissues were excised and then homogenized in an ice-cold buffer. These tissues were used for biochemical analysis. RESULTS: The activities of antioxidant enzymes, e.g. catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD), in blood serum, liver, and kidney of control and experimental animals, respectively, have been reported. CONCLUSION: The present observations suggested that the aqueous extract of I. aspalathoides treatment enhanced the recovery from 20-MCA-induced fibrosarcoma due to its antioxidants and antineoplastic properties. PMID- 21297922 TI - Zoledronic acid directly suppresses cell proliferation and induces apoptosis in highly tumorigenic prostate and breast cancers. AB - BACKGROUND: Bisphosphonates (BPs) were designed for the prevention of skeletal related events secondary to bone metastases. The purpose of this study was to show that zoledronic acid (ZA) directly eradicates highly tumorigenic and potentially metastatic cancer cells. MATERIALS AND METHODS: Human prostate and breast highly tumorigenic (PC3, MCF 7) and low- or non-tumorigenic (LNCaP, MCF 10a) cell lines, respectively, were exposed to different concentrations of ZA (0 10 MUM). Reverse transcriptase double quantitative polymerase chain reaction was used for quantitative gene expression analysis. Apoptosis and cell proliferation were determined using microscopic observation and MTS assays. Western blot was used to confirm the translational effects of apoptotic genes on protein expression. RESULTS: Human prostate and breast highly tumorigenic (PC3, MCF 7) and low- or non-tumorigenic (LNCaP, MCF 10a) cell lines, respectively, showed multiple genes demonstrating differential expressions, including TRAF, TRADD, BCL2, CASPASES and IAP families. Increasing ZA concentrations showed a greater concentration-time response on cell proliferation and apoptosis in the highly tumorigenic cells. These results were confirmed by both reversing and enhancing the effect of ZA on cell proliferation with caspase 3, 7 or survivin siRNA, respectively. Pro-apoptotic proteins bax and caspase 2, 3, 7 and 9 were up regulated, while the anti-apoptotic proteins bcl2, birc3 and survivin were down regulated only in the highly tumorigenic cells. CONCLUSIONS: This explains the ability of ZA to inhibit bony metastasis in highly tumorigenic cells compared with the low- or non-tumorigenic cells through a significant decrease in cell proliferation and increase in apoptosis through gene-regulated and translational mediated down-regulation of survivin coupled with the inhibition of caspase 3 or 7. This has significant implications toward understanding the pharmacophysiology of BPs in metastasis and supports the clinically observed effect of BPs when administered adjunctively with anticancer drugs such as cyclophosphamide/methotrexate/5-fluorouracil, epirubicin in combination with cyclophosphamide or docetaxel, and doxorubicin. PMID- 21297923 TI - Pott's disease in children. AB - BACKGROUND: The incidence of tuberculosis is increasing, and skeletal tuberculosis accounts for 10-20% of all extrapulmonary cases. Spinal tuberculosis occurs mostly in children and young adults. It causes bone destruction, spinal deformity and neural complications. MATERIALS AND METHODS: Our study includes 37 children (below 15 years of age) with spinal tuberculosis treated in our department in the last 6 years. The demographic data, clinical profile, surgical intervention and outcome of these children are reported. RESULTS: The mean age ranged from 4 to 15 years, with an average of 9.1 years, and the male/female ratio was 1.8. Thirty patients (81%) had progressive inflammatory rachialgia and only six patients (16.2%) had neurological symptoms. The lumbar spine was mostly affected (23 cases). All patients have benefited from antituberculous chemotherapy (Regimen 2SRHZ/10RH) associated with spinal immobilization during 3 months. The surgical treatment was indicated in seven patients because of the presence of large bilateral abscess of the psoas muscle in one patient and the presence of severe neurological symptoms in the six remaining patients. The evolution was favorable in all cases, including those with neurological symptoms. There was no case of death and the length of follow-up for these patients ranged between 1 and 4 years. CONCLUSION: Spinal tuberculosis is still a prevalent disease in developing countries, mainly occurring in children. Complications of the disease can be devastating because of its ability to cause bone destruction, spinal deformity and paraplegia. Therefore, an early diagnosis and establishment of treatment are necessary to expect a good outcome. PMID- 21297924 TI - From the bench to the bedside: Everolimus for subependymal giant cell astrocytomas in Tuberous sclerosis complex, optic nerve regeneration, targeted cytotoxins for gliomas. PMID- 21297925 TI - Abscess formation associated with pituitary adenoma: A case report: Changes in the MRI appearance of pituitary adenoma before and after abscess formation. AB - BACKGROUND: Pituitary abscess is an extremely rare finding. The abscess may arise as a primary pituitary lesion or be associated with parasellar pathology. It is important for pituitary abscess treatments to perform early diagnosis. In this report, we describe a case of pituitary adenoma in which MRI findings changed during the follow-up period and strongly suggested progression to pituitary abscess arising from adenoma. CASE DESCRIPTION: In a 73-year-old female, pituitary adenoma had been incidentally detected; MRI showed typical findings of pituitary adenoma, and we had followed up the pituitary lesion and clinical symptoms. Six months later, she had oculomotor nerve palsy and symptoms of hypopituitarism. Hematological examination revealed inflammation and hypopituitarism. MRI showed striking changes in the signal intensity of the pituitary lesion, and strongly suggested occurrence of sinusitis and pituitary abscess ascribed to pituitary adenoma. She was admitted and endoscopic transsphenoidal surgery was performed. The sellar floor was destroyed, and yellowish-white creamy pus was observed. A histopathological study using hematoxylin-eosin staining showed adenoma and inflammatory cells. Aerobic, anaerobic, and fungal cultures were negative. Antibiotics were administered and hormonal replacement was started. Neurological and general symptoms were improved, and postoperative MRI revealed complete evacuation of abscess and removal of tumor. CONCLUSIONS: Pituitary abscess within invasive pituitary adenoma is a rare entity, and shows high mortality. Early diagnosis of pituitary abscess is very important for the prompt surgery and initiation of treatment with antibiotics. In our case, changes in MRI findings were helpful to diagnose pituitary abscess, and endoscopic transsphenoidal surgery was an optimal surgical treatment. PMID- 21297926 TI - Craniofacial pain: A neurosurgical outlook. PMID- 21297927 TI - Cogito ergo sum: A commentary. PMID- 21297928 TI - Microvascular anastomosis at 30-50* magnifications (super-microvascular anastomosis) in neurosurgery. AB - BACKGROUND: We report a safe and precise technique of microvascular anastomosis at higher magnifications (30 - 50 *) in neurosurgery and evaluate our experiences to examine the utility of this method for cerebral revascularization in various situations. METHODS: A retrospective review was carried out of patients who underwent microvascular anastomosis using a high-magnified operating microscope. This method was performed in 30 patients with 35 microvascular anastomoses in various situations. This microscope has two optical systems, a standard zooming system and a newly developed high magnification system. High resolution and good depth of focus are achieved by a new lens design in the optical system, which makes the image of the object very clear at higher magnifications. In this operating microscope, the combination of a 10 * eyepiece and the 200, 250, and 300-mm objective lens enables a range of final magnifications from 2.9 * to 50.4 *. RESULTS: This method enabled one to pay attention to performing atraumatic manipulations of small vessels and correct suturing, intima-to-intima, of vessel walls. Microvascular anastomoses were performed safely and precisely at higher magnifications. All anastomoses were patent. CONCLUSION: It is obvious that practical final magnifications of more than 30 * in neurosurgery would be super magnified operative views. Microvascular anastomosis at 30 - 50 * magnifications (super-microvascular anastomosis) can help neurosurgeons to improve their skills, with good visualization, and to be safe and accurate when conducting cerebral revascularization in various situations. PMID- 21297929 TI - Trends in inpatient setting laminectomy for excision of herniated intervertebral disc: Population-based estimates from the US nationwide inpatient sample. AB - BACKGROUND: Herniated intervertebral discs can result in pain and neurological compromise. Treatment for this condition is categorized as surgical or non surgical. We sought to identify trends in inpatient surgical management of herniated intervertebral discs using a national database. METHODS: Patient discharges identified with a principal procedure relating to laminectomy for excision of herniated intervertebral disc were selected from the Nationwide Inpatient Sample (Healthcare Cost and Utilization Project - Agency for Healthcare Research and Quality, Rockville, MD), under the auspices of a data user agreement. These surgical patients did not undergo instrumented fusion. To account for the Nationwide Inpatient Sample weighting schema, design-adjusted analyses were used. The estimates of standard errors were calculated using SUDAAN software (Research Triangle International, NC, USA). This software is based on the International Classification of Diseases, 9(th) Revision, Clinical Modification (ICD-9-CM); a uniform and standardized coding system. RESULTS: Using International Classification of Disease 9(th) Revision clinical modifier (ICD-9 CM) procedure code 80.51, we were able to identify disc excision, in part or whole, by laminotomy or hemilaminectomy. The incidence of laminectomy for the excision of herniated intervertebral disc has decreased dramatically from 1993 where 266,152 cases were reported [CI = 22,342]. In 2007, only 123,398 cases were identified [CI = 12,438]. The average length of stay in 1993 was 4 days [CI = 0.17], and in 2007 it decreased to just 2 days [CI = 0.17]. Both these comparisons were significantly different at P < 0.001. The average inflation adjusted (2007 buying power) charge of the procedure in 1993 was 14,790.87 USD [CI = 916.85]. This value rose in 2007 to 24,639 USD [CI = 1,485.51]. This difference was significant at P < 0.001. CONCLUSIONS: National estimates indicate that the incidence of inpatient laminectomy for the excision of herniated intervertebral disc has decreased significantly. This trend is multifactorial and is likely related to developments in outcomes research, the growing popularity of alternative procedures (intervertebral instrumented fusion), and transition to an ambulatory setting of surgical care. PMID- 21297930 TI - Cilostazol improves symptomatic intracranial artery stenosis - Evaluation of cerebral blood flow with single photon emission computed tomography. AB - BACKGROUND: To evaluate the effectiveness of cilostazol in patients with intracranial arterial stenosis, we used magnetic resonance angiography (MRA). The drug's effect on the cerebral blood flow (CBF) was examined by single photon emission computed tomography (SPECT). METHODS: In this retrospective study, we evaluated the clinical outcomes of 20 patients with stenosis in the M1 segment of the middle cerebral artery (MCA) who had suffered ischemic stroke within 12 weeks or manifested asymptomatic stenosis exceeding 50%. All patients received cilostazol (100 mg twice daily). MRA and SPECT (at rest and after acetazolamide challenge) studies were performed before and 6 and 12 months after the start of cilostazol treatment. RESULTS: In 5 patients the stenotic lesion showed improvement on MRA. Mean stenosis before cilostazol therapy was 71.7 +/- 4.9%, which improved to 39.0 +/- 3.2% at 6 months and to 27.2 +/- 2.8% at 12 months. SPECT study showed that CBF was improved in 3 patients; in one there was improvement at rest and the other 2 manifested improvement upon acetazolamide challenge. CONCLUSIONS: Cilostazol had a remodeling effect on stenotic lesions due to arteriosclerotic changes and improved CBF in some patients. PMID- 21297931 TI - Efficacy and outcomes of dynamic-plated single-level anterior diskectomy/fusion with additional analysis of comparative costs. AB - BACKGROUND: Few studies focus on the fusion rates and outcomes for single-level anterior cervical diskectomy/fusion (1-ACDF) utilizing iliac autograft and dynamic plates. METHODS: Fusion rates and outcomes were prospectively evaluated in 60 consecutive patients undergoing 1-ACDF utilizing iliac autograft and dynamic plates (ABC; Aesculap, Tuttlingen, Germany). Eighteen patients had radiculopathy, while 42 were myelopathic (average Nurick Score 3.3). Pathology included single-level disc disease/spondylosis (38 patients) and/or ossification of the posterior longitudinal ligament (OPLL, 22 patients). Fusion was assessed at 3, 6, and up to 12 months postoperatively utilizing dynamic X-rays and 2D-CT scans. Outcomes were evaluated up to 24 months postoperatively utilizing Odom's Criteria, Nurick Grades, and Short-Form 36 (SF-36) outcome questionnaires. Patients were followed for an average of 4.8 postoperative years (minimum 2 years). RESULTS: Although dynamic X-rays/2D-CT studies documented 100% fusion an average of 3.8 months (range 2.5-8 months] postoperatively, 5 heavy smokers exhibited delayed fusions [6-8 months postoperatively]. Two years postoperatively, the average Nurick Score was 0.3 (mild radiculopathy), while Odom's Criteria revealed 52 excellent, 6 good, and 2 fair outcomes [the latter 8 patients were heavy smokers]). Utilizing SF-36 outcome questionnaires, patients markedly improved (>10.0 point gain) on 5 of 8 Health Scales within 6 months, 7 of 8 within 1 year, and all 8 within 2 postoperative years. CONCLUSIONS: For 60 patients undergoing 1-ACDF utilizing dynamic plates, ultimately a 100% fusion rate was achieved (5 heavy smokers exhibited delayed fusions). Two years postoperatively, Nurick Grades, Odom's Criteria, and SF-36 questionnaires revealed adequate outcomes. PMID- 21297932 TI - Pros, cons, and costs of INFUSE in spinal surgery. AB - BACKGROUND: INFUSE (recombinant human bone morphogenetic protein-2 [rh-BMP-2]; Medtronic, Memphis, TN, USA) is approved by the Federal Drug Administration (FDA) only for use with the lumbar tapered fusion device (LT Cage; Medtronic) to perform single-level anterior lumbar interbody fusions (ALIF: L2-S1 levels). INFUSE, however, is widely utilized in an "off-label" capacity for anterior and/or posterior cervical, thoracic, and lumbar surgery. Nevertheless, Medicare and other insurance companies, are now increasingly denying reimbursement (average cost of a "large" INFUSE to the hospital without overhead $5000-6000) to hospitals for INFUSE when utilized "off-label". METHODS: This commentary looks at several representative studies citing the cons associated with utilizing INFUSE in spinal surgery, contraindications, complications, and cost factors. RESULTS: There are multiple cons of utilizing INFUSE in an "off-label" capacity for spinal surgery. Direct contraindications include pregnancy, allergy to titanium, allergy to bovine type I collagen or rhBMP-2, infection, tumor, liver or kidney disease, immunosuppression (e.g., lupus, HIV/AIDS); contraindications are also seen in those receiving radiation, chemotherapy, or steroids. Reported complications include exuberant/ectopic bone formation, paralysis (cord, nerve damage), dural tears, bowel-bladder and sexual dysfunction, respiratory failure, inflammation of adjacent tissues, fetal developmental complications, scar, excessive bleeding, and even death. Complications are so prevalent in the anterior cervical spine, that many surgeons no longer use it in this region. Similarly, INFUSE complications and indications for posterior lumbar interbody fusions (PLIFs) and transforaminal interbody lumbar fusions (TLIFs) should also be reexamined. CONCLUSIONS: More surgeons need to question the safety, efficacy, and appropriate "off-label" use of INFUSE in all spine surgeries. PMID- 21297933 TI - Fluorotic cervical compressive myelopathy, 20 years after laminectomy: A rare event. AB - BACKGROUND: Spinal cord compression in flourosis is a common complication. These complications are mainly due to compression of the spinal cord by thickening and ossification of posterior longitudinal ligament and ligamentum flavum. Surgical decompression is the treatment of choice for fluorotic spinal cord compression. The recurrence of spinal cord compression after surgical decompression in flourosis is a rare event. CASE DESCRIPTION: We are presenting a case of a 63 year-old man who belonged to Kanpur, an endemic fluorosis region in India, with symptoms of cervical cord compression cranial to the operative site, 20 years after laminectomy for cervical fluorotic myelopathy. Urinary and serum fluoride levels were elevated. The patient underwent a skeletal survey: computed tomography and magnetic resonance imaging of the cervical spine showed a postoperative defect of laminectomy, osteosclerosis, osteophyte formation, calcification of the intraosseus membrane in the forearm, thickening and ossification of the posterior longitudinal ligament at C1, thickening and ossification of the residual ligamentum flavum at C1/C2, and dural calcification at the C2 vertebral level and compressive myelopathy. The patient refused surgical decompression and was managed with tizanidine HCl (an antispasticity medicine), a sublingual single night dose, 8 mg for symptomatic relief. CONCLUSION: The recurrence of spinal cord compression in the fluorotic spine 20 years after laminectomy is a very unusual event and hence the patient should be kept under observation for a long duration. This case report contributes to the literature associated with the management of fluorotic spine. PMID- 21297934 TI - Simultaneous Determination of Hydrochlorothiazide and Reserpine in Human Urine by LC with a Simple Pre-Treatment. AB - A simple, selective and sensitive reversed-phase high performance liquid chromatography method for simultaneous analysis of hydrochlorothiazide and reserpine in human urine was developed and subjected to primary pharmacokinetic study. After a simple protein precipitation using methanol and extraction with ethyl acetate, the analytes were separated on an Elite C(18) column at a flow rate of 0.8 mL min(-1). The mobile phase was composed of acetonitrile (A) and 0.2% ammonium chloride solution (B) for a gradient elution starting at A:B at 30:70, v/v for 0~6 min, linearly raising the percent of A from 30% to 50% (6~9 min) and ending at 50:50, v/v (9~25 min). The standard curves were linear over the range of 0.05-20 ug mL(-1) for hydrochlorothiazide and 0.02-5.0 ug mL(-1) for reserpine, respectively (r > 0.999). The limit of detection (LOD) and the limit of quantification (LOQ) were 5.5 ng mL(-1) and 18.2 ng mL(-1) for hydrochlorothiazide, and 7.1 ng mL(-1) and 23.6 ng mL(-1) for reserpine, respectively. The recoveries for both analytes were above 89.0+/-1.35%. The intra day and inter-day precision for hydrochlorothiazide were less than 1.91% and 1.38%, and those for reserpine were below 1.61% and 2.64%, respectively. The method indicated good performance in terms of specificity, linearity, detection and quantification limits, precision and accuracy, and it was employed successfully for the simultaneous determination of hydrochlorothiazide and reserpine in human urine samples. PMID- 21297935 TI - Fluorescent detection of (-)-epicatechin in microsamples from cacao seeds and cocoa products: Comparison with Folin-Ciocalteu method. AB - Polyphenolic compounds of the flavanoid family are abundantly present in cacao seed and its cocoa products. Results from studies using cocoa products indicate beneficial effects of flavanols on cardiovascular endpoints. Evidence indicates that (-)-epicatechin is the main cacao flavanol associated with cardiovascular effects, so the accurate quantification of its content in cacao seeds or cocoa products is important. Common methods for the quantification of phenolic content in cocoa products are based on the reaction of phenols with colorimetric reagents such as the Folin-Ciocalteu (FC) In this study, we compared the FC method of phenolic determinations using 2 different standards (gallic acid and (-) epicatechin) to construct calibration curves. We compare these results with those obtained from a simple fluorometric method (Ex(280)/Em(320) nm) used to determine catechin/(-)-epicatechin content in samples of cacao seeds and cocoa products. Values obtained from the FC method determination of polyphenols yield an overestimation of phenol (flavonoid) content when gallic acid is used as standard. Moreover, the epicatechin is a more reliable standard because of its abundance in cacao seeds and cocoa products. The use of fluorometric spectra yields a simple and highly quantitative means for a more precise and rapid quantification of cacao catechins. Fluorometric values are essentially in agreement with those reported using more cumbersome methods. In conclusion, the use of fluorescence emission spectra is a quick, practical and suitable means to quantifying catechins in cacao seeds and cocoa products. PMID- 21297936 TI - Interpersonal Violence and Mental Health Outcomes among Asian American and Native Hawaiian/Other Pacific Islander College Students. AB - In a cross-sectional survey of college students (N = 614) we studied interpersonal violence victimization, perpetration, and mental health outcomes in an ethnoracially diverse rural-based sample of Asian Americans (27%), and Native Hawaiian/Other Pacific Islanders (25%), two groups vastly underrepresented in trauma research. High rates of interpersonal violence (34%), violence perpetration (13%), and probable psychiatric diagnoses (77%), including posttraumatic stress disorder, were found. Exposure to physical violence, sexual violence, and life stress all were predictive of psychopathology. Female participants were associated with higher likelihood of sexual violence victimization compared to male participants, and Asian American status (especially among males) was associated with lower likelihood of physical and sexual violence compared with European Americans. These data enhance our understanding of interpersonal violence and mental health outcomes among previously understudied minority groups. PMID- 21297937 TI - Maternal genome-wide DNA methylation patterns and congenital heart defects. AB - The majority of congenital heart defects (CHDs) are thought to result from the interaction between multiple genetic, epigenetic, environmental, and lifestyle factors. Epigenetic mechanisms are attractive targets in the study of complex diseases because they may be altered by environmental factors and dietary interventions. We conducted a population based, case-control study of genome-wide maternal DNA methylation to determine if alterations in gene-specific methylation were associated with CHDs. Using the Illumina Infinium Human Methylation27 BeadChip, we assessed maternal gene-specific methylation in over 27,000 CpG sites from DNA isolated from peripheral blood lymphocytes. Our study sample included 180 mothers with non-syndromic CHD-affected pregnancies (cases) and 187 mothers with unaffected pregnancies (controls). Using a multi-factorial statistical model, we observed differential methylation between cases and controls at multiple CpG sites, although no CpG site reached the most stringent level of genome-wide statistical significance. The majority of differentially methylated CpG sites were hypermethylated in cases and located within CpG islands. Gene Set Enrichment Analysis (GSEA) revealed that the genes of interest were enriched in multiple biological processes involved in fetal development. Associations with canonical pathways previously shown to be involved in fetal organogenesis were also observed. We present preliminary evidence that alterations in maternal DNA methylation may be associated with CHDs. Our results suggest that further studies involving maternal epigenetic patterns and CHDs are warranted. Multiple candidate processes and pathways for future study have been identified. PMID- 21297938 TI - Improving rational treatment of malaria: perceptions and influence of RDTs on prescribing behaviour of health workers in southeast Nigeria. AB - INTRODUCTION: Developments in rapid diagnostic tests (RDTs) have opened new possibilities for improved remote malaria diagnosis that is independent of microscopic diagnosis. Studies in some settings have tried to assess the influence of RDTs on the prescribing behaviour of health workers, but such information is generally lacking in Nigeria and many parts of sub-Saharan Africa. This study analysed health workers' perceptions of RDTs and their potential influence on their prescribing and treatment practices after their introduction. METHODS: The study was conducted in four health centers in the Enugu East local government of Enugu State, Nigeria. All 32 health workers in the health centers where RDTs were deployed were interviewed by field workers. Information was sought on their perception of symptoms-based, RDT-based, and microscopy-based malaria diagnoses. In addition, prescription analysis was carried out on 400 prescriptions before and 12 months after RDT deployment. RESULTS: The majority of the health workers perceived RDTs to be more effective for malaria diagnosis than microscopy and clinical diagnosis. They also felt that the benefits of RDTs included increased use of RDTs in the facilities and the tendency to prescribe more Artemisinin-based combination therapies (ACTs) and less chloroquine and SP. Some of the health workers experienced some difficulties in the process of using RDT kits. ACTs were prescribed in 74% of RDT-negative results. CONCLUSIONS/SIGNIFICANCE: RDT-supported malaria diagnosis may have led to the overprescription of ACTs, with the drug being prescribed to people with RDT negative results. However, the prescription of other antimalarial drugs that are not first-line drugs has been reduced. Efforts should be made to encourage health workers to trust RDT results and prescribe ACTs only to those with positive RDT results. In-depth studies are needed to determine why health workers continue to prescribe ACTs in RDT-negative results. PMID- 21297939 TI - Amplification of the 20q chromosomal arm occurs early in tumorigenic transformation and may initiate cancer. AB - Duplication of chromosomal arm 20q occurs in prostate, cervical, colon, gastric, bladder, melanoma, pancreas and breast cancer, suggesting that 20q amplification may play a causal role in tumorigenesis. According to an alternative view, chromosomal imbalance is mainly a common side effect of cancer progression. To test whether a specific genomic aberration might serve as a cancer initiating event, we established an in vitro system that models the evolutionary process of early stages of prostate tumor formation; normal prostate cells were immortalized by the over-expression of human telomerase catalytic subunit hTERT, and cultured for 650 days till several transformation hallmarks were observed. Gene expression patterns were measured and chromosomal aberrations were monitored by spectral karyotype analysis at different times. Several chromosomal aberrations, in particular duplication of chromosomal arm 20q, occurred early in the process and were fixed in the cell populations, while other aberrations became extinct shortly after their appearance. A wide range of bioinformatic tools, applied to our data and to data from several cancer databases, revealed that spontaneous 20q amplification can promote cancer initiation. Our computational model suggests that 20q amplification induced deregulation of several specific cancer-related pathways including the MAPK pathway, the p53 pathway and Polycomb group factors. In addition, activation of Myc, AML, B-Catenin and the ETS family transcription factors was identified as an important step in cancer development driven by 20q amplification. Finally we identified 13 "cancer initiating genes", located on 20q13, which were significantly over-expressed in many tumors, with expression levels correlated with tumor grade and outcome suggesting that these genes induce the malignant process upon 20q amplification. PMID- 21297940 TI - Temporal associations between weather and headache: analysis by empirical mode decomposition. AB - BACKGROUND: Patients frequently report that weather changes trigger headache or worsen existing headache symptoms. Recently, the method of empirical mode decomposition (EMD) has been used to delineate temporal relationships in certain diseases, and we applied this technique to identify intrinsic weather components associated with headache incidence data derived from a large-scale epidemiological survey of headache in the Greater Taipei area. METHODOLOGY/PRINCIPAL FINDINGS: The study sample consisted of 52 randomly selected headache patients. The weather time-series parameters were detrended by the EMD method into a set of embedded oscillatory components, i.e. intrinsic mode functions (IMFs). Multiple linear regression models with forward stepwise methods were used to analyze the temporal associations between weather and headaches. We found no associations between the raw time series of weather variables and headache incidence. For decomposed intrinsic weather IMFs, temperature, sunshine duration, humidity, pressure, and maximal wind speed were associated with headache incidence during the cold period, whereas only maximal wind speed was associated during the warm period. In analyses examining all significant weather variables, IMFs derived from temperature and sunshine duration data accounted for up to 33.3% of the variance in headache incidence during the cold period. The association of headache incidence and weather IMFs in the cold period coincided with the cold fronts. CONCLUSIONS/SIGNIFICANCE: Using EMD analysis, we found a significant association between headache and intrinsic weather components, which was not detected by direct comparisons of raw weather data. Contributing weather parameters may vary in different geographic regions and different seasons. PMID- 21297941 TI - Regulation of human neurotropic JC virus replication by alternative splicing factor SF2/ASF in glial cells. AB - BACKGROUND: The human neurotropic virus, JC virus (JCV), is the etiologic agent of the fatal demyelinating disease of the central nervous system, Progressive Multifocal Leukoencephalopathy (PML) that is seen primarily in immunodeficient individuals. Productive infection of JCV occurs only in glial cells, and this restriction is, to a great extent, due to the activation of the viral promoter that has cell type-specific characteristics. Earlier studies led to the hypothesis that glial-specific activation of the JCV promoter is mediated through positive and negative transcription factors that control reactivation of the JCV genome under normal physiological conditions and suppress its activation in non glial cells. METHODOLOGY/PRINCIPAL FINDINGS: Using a variety of virological and molecular biological approaches, we demonstrate that the alternative splicing factor SF2/ASF has the capacity to exert a negative effect on transcription of the JCV promoter in glial cells through direct association with a specific DNA sequence within the viral enhancer/promoter region. Our results show that down regulation of SF2/ASF in fetal and adult glial cells increases the level of JCV gene expression and its replication indicating that negative regulation of the JCV promoter by SF2/ASF may control reactivation of JCV replication in brain. CONCLUSIONS/SIGNIFICANCE: Our results establish a new regulatory role for SF2/ASF in controlling gene expression at the transcriptional level. PMID- 21297942 TI - Eimeria species and genetic background influence the serum protein profile of broilers with coccidiosis. AB - BACKGROUND: Coccidiosis is an intestinal disease caused by protozoal parasites of the genus Eimeria. Despite the advent of anti-coccidial drugs and vaccines, the disease continues to result in substantial annual economic losses to the poultry industry. There is still much unknown about the host response to infection and to date there are no reports of protein profiles in the blood of Eimeria-infected animals. The objective of this study was to evaluate the serum proteome of two genetic lines of broiler chickens after infection with one of three species of Eimeria. METHODOLOGY/PRINCIPAL FINDINGS: Birds from lines A and B were either not infected or inoculated with sporulated oocysts from one of the three Eimeria strains at 15 d post-hatch. At 21 d (6 d post-infection), whole blood was collected and lesion scoring was performed. Serum was harvested and used for 2 dimensional gel electrophoresis. A total of 1,266 spots were quantitatively assessed by densitometry. Protein spots showing a significant effect of coccidia strain and/or broiler genetic line on density at P<0.05-0.01 (250 spots), P<0.01 0.001 (248 spots), and P<0.001 (314 spots) were excised and analyzed by matrix assisted laser desorption/ionization tandem time-of-flight mass spectrometry. Proteins were identified in 172 spots. A total of 46 different proteins were identified. Of the spots with a corresponding protein identification, 57 showed a main effect of coccidia infection and/or 2-way interaction of coccidia infection*broiler genetic line at P<0.001. CONCLUSIONS/SIGNIFICANCE: Several of the metabolic enzymes identified in this study are potential candidates for early diagnostic markers of E. acervulina infection including malate dehydrogenase 2, NADH dehydrogenase 1 alpha subcomplex 9, and an ATP synthase. These proteins were detected only in Line A birds that were inoculated with E. acervulina. Results from this study provide a basic framework for future research aimed at uncovering the complex biochemical mechanisms involved in host response to Eimeria infection and in identifying molecular targets for diagnostic screening and development of alternative preventative and therapeutic methods. PMID- 21297943 TI - Ablation of Akt2 induces autophagy through cell cycle arrest, the downregulation of p70S6K, and the deregulation of mitochondria in MDA-MB231 cells. AB - BACKGROUND: Akt/PKB is a promising anticancer therapeutic target, since abnormally elevated Akt activity is directly correlated to tumor development, progression, poor prognosis and resistance to cancer therapies. Currently, the unique role of each Akt isoform and their relevance to human breast cancer are poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: We previously found that Akt1, 2 and 3 are localized at specific subcellular compartments (the cytoplasm, mitochondria and nucleus, respectively), raising the possibility that each isoform may have unique functions and employ different regulation mechanisms. By systematically studying Akt-ablated MDA-MB231 breast cancer cells with isoform specific siRNA, we here show that Akt2 is the most relevant isoform to cell proliferation and survival in our cancer model. Prolonged ablation of Akt2 with siRNA resulted in cell-cycle arrest in G0/G1 by downregulating Cdk2 and cyclin D, and upregulating p27. The analysis of the Akt downstream signaling pathways suggested that Akt2 specifically targets and activates the p70S6K signaling pathway. We also found that Akt2 ablation initially resulted in an increase in the mitochondrial volume concomitantly with the upregulation of PGC-1alpha, a regulator of mitochondrial biogenesis. Prolonged ablation of Akt2, but not Akt1 or Akt3, eventually led to cell death by autophagy of the mitochondria (i.e., mitophagy). CONCLUSIONS/SIGNIFICANCE: Collectively, our data demonstrates that Akt2 augments cell proliferation by facilitating cell cycle progression through the upregulation of the cell cycle engine, and protects a cell from pathological autophagy by modulating mitochondrial homeostasis. Our data, thus, raises the possibility that Akt2 can be an effective anticancer target for the control of (breast) cancer. PMID- 21297944 TI - An enhanced probabilistic LDA for multi-class brain computer interface. AB - BACKGROUND: There is a growing interest in the study of signal processing and machine learning methods, which may make the brain computer interface (BCI) a new communication channel. A variety of classification methods have been utilized to convert the brain information into control commands. However, most of the methods only produce uncalibrated values and uncertain results. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we presented a probabilistic method "enhanced BLDA" (EBLDA) for multi-class motor imagery BCI, which utilized Bayesian linear discriminant analysis (BLDA) with probabilistic output to improve the classification performance. EBLDA builds a new classifier that enlarges training dataset by adding test samples with high probability. EBLDA is based on the hypothesis that unlabeled samples with high probability provide valuable information to enhance learning process and generate a classifier with refined decision boundaries. To investigate the performance of EBLDA, we first used carefully designed simulated datasets to study how EBLDA works. Then, we adopted a real BCI dataset for further evaluation. The current study shows that: 1) Probabilistic information can improve the performance of BCI for subjects with high kappa coefficient; 2) With supplementary training samples from the test samples of high probability, EBLDA is significantly better than BLDA in classification, especially for small training datasets, in which EBLDA can obtain a refined decision boundary by a shift of BLDA decision boundary with the support of the information from test samples. CONCLUSIONS/SIGNIFICANCE: The proposed EBLDA could potentially reduce training effort. Therefore, it is valuable for us to realize an effective online BCI system, especially for multi-class BCI systems. PMID- 21297945 TI - G = MAT: linking transcription factor expression and DNA binding data. AB - Transcription factors are proteins that bind to motifs on the DNA and thus affect gene expression regulation. The qualitative description of the corresponding processes is therefore important for a better understanding of essential biological mechanisms. However, wet lab experiments targeted at the discovery of the regulatory interplay between transcription factors and binding sites are expensive. We propose a new, purely computational method for finding putative associations between transcription factors and motifs. This method is based on a linear model that combines sequence information with expression data. We present various methods for model parameter estimation and show, via experiments on simulated data, that these methods are reliable. Finally, we examine the performance of this model on biological data and conclude that it can indeed be used to discover meaningful associations. The developed software is available as a web tool and Scilab source code at http://biit.cs.ut.ee/gmat/. PMID- 21297946 TI - Differences in reversion of resistance mutations to wild-type under structured treatment interruption and related increase in replication capacity. AB - BACKGROUND: The CPCRA 064 study examined the effect of structured treatment interruption (STI) of up to 4 months followed by salvage treatment in patients failing therapy with multi-drug resistant HIV. We examined the relationship between the reversion rate of major reverse transcriptase (RT) resistance associated mutations and change in viral replication capacity (RC). The dataset included 90 patients with RC and genotypic data from virus samples collected at 0 (baseline), 2 and 4 months of STI. PRINCIPAL FINDINGS: Rapid shift towards wild type RC was observed during the first 2 months of STI. Median RC increased from 47.5% at baseline to 86.0% at 2 months and to 97.5% at 4 months. Between baseline and 2 months of STI, T215F had the fastest rate of reversion (41%) and the reversion of E44D and T69D was associated with the largest changes in RC. Among the most prevalent RT mutations, M184V had the fastest rate of reversion from baseline to 2 months (40%), and its reversion was associated with the largest increase in RC. Most rates of reversion increased between 2 months and 4 months, but the change in RC was more limited as it was already close to 100%. The highest frequency of concurrent reversion was found for L100I and K103N. Mutagenesis tree models showed that M184V, when present, was overall the first mutation to revert among all the RT mutations reported in the study. CONCLUSION: Longitudinal analysis of combined phenotypic and genotypic data during STI showed a large amount of variability in prevalence and reversion rates to wild-type codons among the RT resistance-associated mutations. The rate of reversion of these mutations may depend on the extent of RC increase as well as the co occurring reversion of other mutations belonging to the same mutational pathway. PMID- 21297947 TI - Can preference for oviposition sites initiate reproductive isolation in Callosobruchus maculatus? AB - Theory has identified a variety of evolutionary processes that may lead to speciation. Our study includes selection experiments using different host plants and test key predictions concerning models of speciation based on host plant choice, such as the evolution of host use (preference and performance) and assortative mating. This study shows that after only ten generations of selection on different resources/hosts in allopatry, strains of the seed beetle Callosobruchus maculatus develop new resource preferences and show resource dependent assortative mating when given the possibility to choose mates and resources during secondary contact. The resulting reduced gene flow between the different strains remained for two generations after contact before being overrun by disassortative mating. We show that reduced gene flow can evolve in a population due to a link between host preference and assortative mating, although this result was not found in all lines. However, consistent with models of speciation, assortative mating alone is not sufficient to maintain reproductive isolation when individuals disperse freely between hosts. We conclude that the evolution of reproductive isolation in this system cannot proceed without selection against hybrids. Other possible factors facilitating the evolution of isolation would be longer periods of allopatry, the build up of local adaptation or reduced migration upon secondary contact. PMID- 21297948 TI - Apolipoprotein E: isoform specific differences in tertiary structure and interaction with amyloid-beta in human Alzheimer brain. AB - We applied a novel application of FLIM-FRET to in situ measurement and quantification of protein interactions to explore isoform specific differences in Abeta-ApoE interaction and ApoE tertiary conformation in senile plaques in human Alzheimer brain. ApoE3 interacts more closely with Abeta than ApoE4, but a greater proportion of Abeta molecules within plaques are decorated with ApoE4 than ApoE3, lending strong support to the hypothesis that isoform specific differences in ApoE are linked with Abeta deposition. We found an increased number of ApoE N-terminal fragments in ApoE4 plaques, consistent with the observation that ApoE4 is more easily cleaved than ApoE3. In addition, we measured a small but significant isoform specific difference in ApoE domain interaction. Based on our in situ data, supported by traditional biochemical data, we propose a pathway by which isoform specific conformational differences increase the level of cleavage at the hinge region of ApoE4, leading to a loss of ApoE function to mediate clearance of Abeta and thereby increase the risk of AD for carriers of the APOEepsilon4 allele. PMID- 21297949 TI - State of knowledge of coastal and marine biodiversity of Indian Ocean countries. AB - The Indian Ocean (IO) extends over 30% of the global ocean area and is rimmed by 36 littoral and 11 hinterland nations sustaining about 30% of the world's population. The landlocked character of the ocean along its northern boundary and the resultant seasonally reversing wind and sea surface circulation patterns are features unique to the IO. The IO also accounts for 30% of the global coral reef cover, 40,000 km2 of mangroves,some of the world's largest estuaries, and 9 large marine ecosystems. Numerous expeditions and institutional efforts in the last two centuries have contributed greatly to our knowledge of coastal and marine biodiversity within the IO. The current inventory, as seen from the Ocean Biogeographic Information System, stands at 34,989 species, but the status of knowledge is not uniform among countries. Lack of human, institutional, and technical capabilities in some IO countries is the main cause for the heterogeneous level of growth in our understanding of the biodiversity of the IO. The gaps in knowledge extend to several smaller taxa and to large parts of the shelf and deep-sea ecosystems, including seamounts. Habitat loss, uncontrolled developmental activities in the coastal zone, over extraction of resources, and coastal pollution are serious constraints on maintenance of highly diverse biota, especially in countries like those of the IO, where environmental regulations are weak. PMID- 21297950 TI - Gene expression meta-analysis identifies VDAC1 as a predictor of poor outcome in early stage non-small cell lung cancer. AB - BACKGROUND: The bioenergetic status of non-small cell lung cancer correlates with tumour aggressiveness. The voltage dependent anion channel type 1 (VDAC1) is a component of the mitochondrial permeability transition pore, regulates mitochondrial ATP/ADP exchange suggesting that its over-expression could be associated with energy dependent processes including increased proliferation and invasiveness. To test this hypothesis, we conducted an in vivo gene-expression meta-analysis of surgically resected non-small cell lung cancer (NSCLC) using 602 individual expression profiles, to examine the impact of VDAC1 on survival. METHODOLOGY/PRINCIPAL FINDINGS: High VDAC1 expression was associated with shorter overall survival with hazard ratio (HR) = 0.6639 (95% confidence interval (CI) 0.4528 to 0.9721), p = 0.035352 corresponding to 52 versus 101 months. VDAC1 predicted shorter time to recurrence and was shown to be an independent prognostic factor compared with histology, gender, age, nodal stage and tumour stage in a Cox multivariate analysis. Supervised analysis of all the datasets identified a 6-gene signature comprising HNRNPC, HSPA4, HSPA9, UBE2D2, CSNK1A1 and G3BP1 with overlapping functions involving regulation of protein turnover, RAS-RAF-MEK pathway and transcription. VDAC1 predicted survival in breast cancer and myeloma and an unsupervised analysis revealed enrichment of the VDAC1 signature in specific subsets. CONCLUSIONS: In summary, gene expression analysis identifies VDAC1 gene expression as a predictor of poor outcome in NSCLC and other cancers and is associated with dysregulation of a conserved set of biological pathways, which may be causally associated with aggressive tumour behaviour. PMID- 21297951 TI - Misrepresentation of neuroscience data might give rise to misleading conclusions in the media: the case of attention deficit hyperactivity disorder. AB - BACKGROUND: There is often a huge gap between neurobiological facts and firm conclusions stated by the media. Data misrepresentation in the conclusions and summaries of neuroscience articles might contribute to this gap. METHODOLOGY/PRINCIPAL FINDINGS: Using the case of attention deficit hyperactivity disorder (ADHD), we identified three types of misrepresentation. The first relies on prominent inconsistencies between results and claimed conclusions and was observed in two scientific reports dealing with ADHD. Only one out of the 61 media articles echoing both scientific reports adequately described the results and, thus questioned the claimed conclusion. The second type of misrepresentation consists in putting a firm conclusion in the summary while raw data that strongly limit the claim are only given in the results section. To quantify this misrepresentation we analyzed the summaries of all articles asserting that polymorphisms of the gene coding for the D4 dopaminergic receptor are associated with ADHD. Only 25 summaries out of 159 also mentioned that this association confers a small risk. This misrepresentation is also observed in most media articles reporting on ADHD and the D4 gene. The third misrepresentation consists in extrapolating basic and pre-clinical findings to new therapeutic prospects in inappropriate ways. Indeed, analysis of all ADHD-related studies in mice showed that 23% of the conclusions were overstated. The frequency of this overstatement was positively related with the impact factor of the journal. CONCLUSION/SIGNIFICANCE: Data misrepresentations are frequent in the scientific literature dealing with ADHD and may contribute to the appearance of misleading conclusions in the media. In synergy with citation distortions and publication biases they influence social representations and bias the scientific evidence in favor of the view that ADHD is primarily caused by biological factors. We discuss the social consequences and the causes of data misrepresentations and suggest a few corrective actions. PMID- 21297952 TI - CDK11(p58) is required for centriole duplication and Plk4 recruitment to mitotic centrosomes. AB - BACKGROUND: CDK11(p58) is a mitotic protein kinase, which has been shown to be required for different mitotic events such as centrosome maturation, chromatid cohesion and cytokinesis. METHODOLOGY/PRINCIPAL FINDINGS: In addition to these previously described roles, our study shows that CDK11(p58) inhibition induces a failure in the centriole duplication process in different human cell lines. We propose that this effect is mediated by the defective centrosomal recruitment of proteins at the onset of mitosis. Indeed, Plk4 protein kinase and the centrosomal protein Cep192, which are key components of the centriole duplication machinery, showed reduced levels at centrosomes of mitotic CDK11-depleted cells. CDK11(p58), which accumulates only in the vicinity of mitotic centrosomes, directly interacts with the centriole-associated protein kinase Plk4 that regulates centriole number in cells. In addition, we show that centriole from CDK11 defective cells are not able to be over duplicated following Plk4 overexpression. CONCLUSION/SIGNIFICANCE: We thus propose that CDK11 is required for centriole duplication by two non-mutually-exclusive mechanisms. On one hand, the observed duplication defect could be caused indirectly by a failure of the centrosome to fully maturate during mitosis. On the other hand, CDK11(p58) could also directly regulate key centriole components such as Plk4 during mitosis to trigger essential mitotic centriole modifications, required for centriole duplication during subsequent interphase. PMID- 21297953 TI - Renalase deficiency in heart failure model of rats--a potential mechanism underlying circulating norepinephrine accumulation. AB - BACKGROUND: Sympathetic overactivity and catecholamine accumulation are important characteristic findings in heart failure, which contribute to its pathophysiology. Here, we identify a potential mechanism underlying norepinephrine accumulation in a rat model of heart failure. METHODOLOGY/PRINCIPAL FINDINGS: Initially, we constructed a rat model of unilateral renal artery stenosis (n = 16) and found that the expression of renalase, a previously identified secreted amine oxidase, was markedly reduced in the ischemic compared to the non-ischemic kidney (protein: 0.295+/-0.085 versus 0.765+/-0.171, p<0.05). Subsequently, we utilized an isolated perfused rat kidney model to demonstrate that the clearance rate of norepinephrine decreased with reduction of perfusion flow. On the basis of these findings, we hypothesized the reduced renal blood supply which occurs in heart failure would result in impaired synthesis of renalase by the kidney and consequently reduced degradation of circulating norepinephrine. To verify this, we used a rat model of infarction induced heart failure (n = 12 per group). In these rats, the flow velocity of renal artery, when measured at four weeks, is obviously lower in the operation group. Renal expression of renalase was reduced (protein: 0.476+/-0.043 for control, 0.248+/-0.029 for operation versus 0.636+/-0.151 for sham-operation) and this was associated with an increase in circulating norepinephrine (0.168+/-0.016 ng/mL for control, 0.203+/-0.019 ng/mL for operation versus 0.138+/-0.008 ng/mL for sham-operation). CONCLUSIONS/SIGNIFICANCE: Renalase expression is influenced by renal blood flow and impaired synthesis of renalase by the kidney may represent a potential mechanism underlying circulating norepinephrine accumulation in heart failure. PMID- 21297954 TI - Effects of thioglycolic acid on parthenogenetic activation of Xenopus oocytes. AB - BACKGROUND: Existing in Permanent-wave solutions (PWS), thioglycolic acid (TGA) is widely used in hairdressing industry for its contribution to hair styling. However, the toxicity of TGA, especially its reproductive toxicity, gradually calls the attention of more and more researchers. METHOD: In this work, xenopus oocytes were pretreated with different concentration of TGA, and then activated by calcium ionophore A23187. During culture, the oocytes activation rates were taken note at different time after adding calcium ionophore A23187. At the end of the culture period, the nuclear status was detected under confocal microscope. In addition, some other samples were collected for Western-Blotting analysis. RESULT: TGA significantly inhibited the oocytes activation rate and pronuclear formation. It may be resulted from the inhibition of the degradation of p-ERK1, Mos and CyclinB2. CONCLUSION: TGA inhibits in vitro parthenogenetic activation of xenopus oocytes with inhibited the degradation of proteins involved in mitogenic activated protein kinase (MAPK) and maturation-promoting factor (MPF) pathways. PMID- 21297955 TI - Efficacy of fumaric acid esters in the R6/2 and YAC128 models of Huntington's disease. AB - Huntington's disease (HD) is an autosomal dominantly inherited progressive neurodegenerative disease. The exact sequel of events finally resulting in neurodegeneration is only partially understood and there is no established protective treatment so far. Some lines of evidence speak for the contribution of oxidative stress to neuronal tissue damage. The fumaric acid ester dimethylfumarate (DMF) is a new disease modifying therapy currently in phase III studies for relapsing-remitting multiple sclerosis. DMF potentially exerts neuroprotective effects via induction of the transcription factor "nuclear factor E2-related factor 2" (Nrf2) and detoxification pathways. Thus, we investigated here the therapeutic efficacy of DMF in R6/2 and YAC128 HD transgenic mice which mimic many aspects of HD and are characterized by an enhanced generation of free radicals in neurons. Treatment with DMF significantly prevented weight loss in R6/2 mice between postnatal days 80-90. At the same time, DMF treatment led to an attenuated motor impairment as measured by the clasping score. Average survival in the DMF group was 100.5 days vs. 94.0 days in the placebo group. In the histological analysis on day 80, DMF treatment resulted in a significant preservation of morphologically intact neurons in the striatum as well as in the motor cortex. DMF treatment resulted in an increased Nrf2 immunoreactivity in neuronal subpopulations, but not in astrocytes. These beneficial effects were corroborated in YAC128 mice which, after one year of DMF treatment, also displayed reduced dyskinesia as well as a preservation of neurons. In conclusion, DMF may exert beneficial effects in mouse models of HD. Given its excellent side effect profile, further studies with DMF as new therapeutic approach in HD and other neurodegenerative diseases are warranted. PMID- 21297956 TI - Increased prothrombin, apolipoprotein A-IV, and haptoglobin in the cerebrospinal fluid of patients with Huntington's disease. AB - Huntington's disease (HD) is a progressive neurodegenerative disease caused by an unstable CAG trinucleotide repeat expansion. The need for biomarkers of onset and progression in HD is imperative, since currently reliable outcome measures are lacking. We used two-dimensional electrophoresis and mass spectrometry to analyze the proteome profiles in cerebrospinal fluid (CSF) of 6 pairs of HD patients and controls. Prothrombin, apolipoprotein A-IV (Apo A-IV) and haptoglobin were elevated in CSF of the HD patients in comparison with the controls. We used western blot as a semi-quantified measurement for prothrombin and Apo A-IV, as well as enzyme linked immunosorbent assay (ELISA) for measurement of haptoglobin, in 9 HD patients and 9 controls. The albumin quotient (Qalb), a marker of blood brain barrier (BBB) function, was not different between the HD patients and the controls. The ratios of CSF prothrombin/albumin (prothrombin/Alb) and Apo A IV/albumin (Apo A-IV/Alb), and haptoglobin level were significantly elevated in HD. The ratio of CSF prothrombin/Alb significantly correlated with the disease severity assessed by Unified Huntington's Disease Rating Scale (UHDRS). The results implicate that increased CSF prothrombin, Apo A-IV, and haptoglobin may be involved in pathogenesis of HD and may serve as potential biomarkers for HD. PMID- 21297957 TI - Integrative identification of Arabidopsis mitochondrial proteome and its function exploitation through protein interaction network. AB - Mitochondria are major players on the production of energy, and host several key reactions involved in basic metabolism and biosynthesis of essential molecules. Currently, the majority of nucleus-encoded mitochondrial proteins are unknown even for model plant Arabidopsis. We reported a computational framework for predicting Arabidopsis mitochondrial proteins based on a probabilistic model, called Naive Bayesian Network, which integrates disparate genomic data generated from eight bioinformatics tools, multiple orthologous mappings, protein domain properties and co-expression patterns using 1,027 microarray profiles. Through this approach, we predicted 2,311 candidate mitochondrial proteins with 84.67% accuracy and 2.53% FPR performances. Together with those experimental confirmed proteins, 2,585 mitochondria proteins (named CoreMitoP) were identified, we explored those proteins with unknown functions based on protein-protein interaction network (PIN) and annotated novel functions for 26.65% CoreMitoP proteins. Moreover, we found newly predicted mitochondrial proteins embedded in particular subnetworks of the PIN, mainly functioning in response to diverse environmental stresses, like salt, draught, cold, and wound etc. Candidate mitochondrial proteins involved in those physiological acitivites provide useful targets for further investigation. Assigned functions also provide comprehensive information for Arabidopsis mitochondrial proteome. PMID- 21297958 TI - PDE 7 inhibitors: new potential drugs for the therapy of spinal cord injury. AB - BACKGROUND: Primary traumatic mechanical injury to the spinal cord (SCI) causes the death of a number of neurons that to date can neither be recovered nor regenerated. During the last years our group has been involved in the design, synthesis and evaluation of PDE7 inhibitors as new innovative drugs for several neurological disorders. Our working hypothesis is based on two different facts. Firstly, neuroinflammation is modulated by cAMP levels, thus the key role for phosphodiesterases (PDEs), which hydrolyze cAMP, is undoubtedly demonstrated. On the other hand, PDE7 is expressed simultaneously on leukocytes and on the brain, highlighting the potential crucial role of PDE7 as drug target for neuroinflammation. METHODOLOGY/PRINCIPAL FINDINGS: Here we present two chemically diverse families of PDE7 inhibitors, designed using computational techniques such as virtual screening and neuronal networks. We report their biological profile and their efficacy in an experimental SCI model induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy. We have selected two candidates, namely S14 and VP1.15, as PDE7 inhibitors. These compounds increase cAMP production both in macrophage and neuronal cell lines. Regarding drug-like properties, compounds were able to cross the blood brain barrier using parallel artificial membranes (PAMPA) methodology. SCI in mice resulted in severe trauma characterized by edema, neutrophil infiltration, and production of a range of inflammatory mediators, tissue damage, and apoptosis. Treatment of the mice with S14 and VP1.15, two PDE7 inhibitors, significantly reduced the degree of spinal cord inflammation, tissue injury (histological score), and TNF-alpha, IL-6, COX-2 and iNOS expression. CONCLUSIONS/SIGNIFICANCE: All these data together led us to propose PDE7 inhibitors, and specifically S14 and VP1.15, as potential drug candidates to be further studied for the treatment of SCI. PMID- 21297959 TI - Megafaunal community structure of Andaman seamounts including the Back-arc Basin- a quantitative exploration from the Indian Ocean. AB - Species rich benthic communities have been reported from some seamounts, predominantly from the Atlantic and Pacific Oceans, but the fauna and habitats on Indian Ocean seamounts are still poorly known. This study focuses on two seamounts, a submarine volcano (cratered seamount--CSM) and a non-volcano (SM2) in the Andaman Back-arc Basin (ABB), and the basin itself. The main purpose was to explore and generate regional biodiversity data from summit and flank (upper slope) of the Andaman seamounts for comparison with other seamounts worldwide. We also investigated how substratum types affect the megafaunal community structure along the ABB. Underwater video recordings from TeleVision guided Gripper (TVG) lowerings were used to describe the benthic community structure along the ABB and both seamounts. We found 13 varieties of substratum in the study area. The CSM has hard substratum, such as boulders and cobbles, whereas the SM2 was dominated by cobbles and fine sediment. The highest abundance of megabenthic communities was recorded on the flank of the CSM. Species richness and diversity were higher at the flank of the CSM than other are of ABB. Non-metric multi-dimensional scaling (nMDS) analysis of substratum types showed 50% similarity between the flanks of both seamounts, because both sites have a component of cobbles mixed with fine sediments in their substratum. Further, nMDS of faunal abundance revealed two groups, each restricted to one of the seamounts, suggesting faunal distinctness between them. The sessile fauna corals and poriferans showed a significant positive relation with cobbles and fine sediments substratum, while the mobile categories echinoderms and arthropods showed a significant positive relation with fine sediments only. PMID- 21297960 TI - Model of yield response of corn to plant population and absorption of solar energy. AB - Biomass yield of agronomic crops is influenced by a number of factors, including crop species, soil type, applied nutrients, water availability, and plant population. This article is focused on dependence of biomass yield (Mg ha(-1) and g plant(-1)) on plant population (plants m(-2)). Analysis includes data from the literature for three independent studies with the warm-season annual corn (Zea mays L.) grown in the United States. Data are analyzed with a simple exponential mathematical model which contains two parameters, viz. Y(m) (Mg ha(-1)) for maximum yield at high plant population and c (m(2) plant(-1)) for the population response coefficient. This analysis leads to a new parameter called characteristic plant population, x(c) = 1/c (plants m(-2)). The model is shown to describe the data rather well for the three field studies. In one study measurements were made of solar radiation at different positions in the plant canopy. The coefficient of absorption of solar energy was assumed to be the same as c and provided a physical basis for the exponential model. The three studies showed no definitive peak in yield with plant population, but generally exhibited asymptotic approach to maximum yield with increased plant population. Values of x(c) were very similar for the three field studies with the same crop species. PMID- 21297961 TI - The actin binding domain of betaI-spectrin regulates the morphological and functional dynamics of dendritic spines. AB - Actin microfilaments regulate the size, shape and mobility of dendritic spines and are in turn regulated by actin binding proteins and small GTPases. The betaI isoform of spectrin, a protein that links the actin cytoskeleton to membrane proteins, is present in spines. To understand its function, we expressed its actin-binding domain (ABD) in CA1 pyramidal neurons in hippocampal slice cultures. The ABD of betaI-spectrin bundled actin in principal dendrites and was concentrated in dendritic spines, where it significantly increased the size of the spine head. These effects were not observed after expression of homologous ABDs of utrophin, dystrophin, and alpha-actinin. Treatment of slice cultures with latrunculin-B significantly decreased spine head size and decreased actin-GFP fluorescence in cells expressing the ABD of alpha-actinin, but not the ABD of betaI-spectrin, suggesting that its presence inhibits actin depolymerization. We also observed an increase in the area of GFP-tagged PSD-95 in the spine head and an increase in the amplitude of mEPSCs at spines expressing the ABD of betaI spectrin. The effects of the betaI-spectrin ABD on spine size and mEPSC amplitude were mimicked by expressing wild-type Rac3, a small GTPase that co immunoprecipitates specifically with betaI-spectrin in extracts of cultured cortical neurons. Spine size was normal in cells co-expressing a dominant negative Rac3 construct with the betaI-spectrin ABD. We suggest that betaI spectrin is a synaptic protein that can modulate both the morphological and functional dynamics of dendritic spines, perhaps via interaction with actin and Rac3. PMID- 21297962 TI - Different neuroplasticity for task targets and distractors. AB - Adult learning-induced sensory cortex plasticity results in enhanced action potential rates in neurons that have the most relevant information for the task, or those that respond strongly to one sensory stimulus but weakly to its comparison stimulus. Current theories suggest this plasticity is caused when target stimulus evoked activity is enhanced by reward signals from neuromodulatory nuclei. Prior work has found evidence suggestive of nonselective enhancement of neural responses, and suppression of responses to task distractors, but the differences in these effects between detection and discrimination have not been directly tested. Using cortical implants, we defined physiological responses in macaque somatosensory cortex during serial, matched, detection and discrimination tasks. Nonselective increases in neural responsiveness were observed during detection learning. Suppression of responses to task distractors was observed during discrimination learning, and this suppression was specific to cortical locations that sampled responses to the task distractor before learning. Changes in receptive field size were measured as the area of skin that had a significant response to a constant magnitude stimulus, and these areal changes paralleled changes in responsiveness. From before detection learning until after discrimination learning, the enduring changes were selective suppression of cortical locations responsive to task distractors, and nonselective enhancement of responsiveness at cortical locations selective for target and control skin sites. A comparison of observations in prior studies with the observed plasticity effects suggests that the non-selective response enhancement and selective suppression suffice to explain known plasticity phenomena in simple spatial tasks. This work suggests that differential responsiveness to task targets and distractors in primary sensory cortex for a simple spatial detection and discrimination task arise from nonselective increases in response over a broad cortical locus that includes the representation of the task target, and selective suppression of responses to the task distractor within this locus. PMID- 21297963 TI - Automatic network fingerprinting through single-node motifs. AB - Complex networks have been characterised by their specific connectivity patterns (network motifs), but their building blocks can also be identified and described by node-motifs-a combination of local network features. One technique to identify single node-motifs has been presented by Costa et al. (L. D. F. Costa, F. A. Rodrigues, C. C. Hilgetag, and M. Kaiser, Europhys. Lett., 87, 1, 2009). Here, we first suggest improvements to the method including how its parameters can be determined automatically. Such automatic routines make high-throughput studies of many networks feasible. Second, the new routines are validated in different network-series. Third, we provide an example of how the method can be used to analyse network time-series. In conclusion, we provide a robust method for systematically discovering and classifying characteristic nodes of a network. In contrast to classical motif analysis, our approach can identify individual components (here: nodes) that are specific to a network. Such special nodes, as hubs before, might be found to play critical roles in real-world networks. PMID- 21297964 TI - Evidence for D1 dopamine receptor activation by a paracrine signal of dopamine in tick salivary glands. AB - Ticks that feed on vertebrate hosts use their salivary secretion, which contains various bioactive components, to manipulate the host's responses. The mechanisms controlling the tick salivary gland in this dynamic process are not well understood. We identified the tick D1 receptor activated by dopamine, a potent inducer of the salivary secretion of ticks. Temporal and spatial expression patterns examined by immunohistochemistry and reverse transcription polymerase chain reaction suggest that the dopamine produced in the basal cells of salivary gland acini is secreted into the lumen and activates the D1 receptors on the luminal surface of the cells lining the acini. Therefore, we propose a paracrine function of dopamine that is mediated by the D1 receptor in the salivary gland at an early phase of feeding. The molecular and pharmacological characterization of the D1 receptor in this study provides the foundation for understanding the functions of dopamine in the blood-feeding of ticks. PMID- 21297965 TI - Modulation of Mrp1 (ABCc1) and Pgp (ABCb1) by bilirubin at the blood-CSF and blood-brain barriers in the Gunn rat. AB - Accumulation of unconjugated bilirubin (UCB) in the brain causes bilirubin encephalopathy. Pgp (ABCb1) and Mrp1 (ABCc1), highly expressed in the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) respectively, may modulate the accumulation of UCB in brain. We examined the effect of prolonged exposure to elevated concentrations of UCB on expression of the two transporters in homozygous, jaundiced (jj) Gunn rats compared to heterozygous, not jaundiced (Jj) littermates at different developmental stages (2, 9, 17 and 60 days after birth). BBB Pgp protein expression was low in both jj and Jj pups at 9 days (about 16-27% of adult values), despite the up-regulation in jj animals (2 and 1.3 fold higher than age matched Jj animals at P9 and P17-P60, respectively); Mrp1 protein expression was barely detectable. Conversely, at the BCSFB Mrp1 protein expression was rather high (60-70% of the adult values) in both jj and Jj at P2, but was markedly (50%) down-regulated in jj pups starting at P9, particularly in the 4(th) ventricle choroid plexuses: Pgp was almost undetectable. The Mrp1 protein down regulation was accompanied by a modest up regulation of mRNA, suggesting a translational rather than a transcriptional inhibition. In vitro exposure of choroid plexus epithelial cells obtained from normal rats to UCB, also resulted in a down-regulation of Mrp1 protein. These data suggest that down-regulation of Mrp1 protein at the BSCFB, resulting from a direct effect of UCB on epithelial cells, may impact the Mrp1-mediated neuroprotective functions of the blood-cerebrospinal fluid barrier and actually potentiate UCB neurotoxicity. PMID- 21297966 TI - DEVELOPMENTAL SEX DIFFERENCES IN THE RELATION OF NEUROANATOMICAL CONNECTIVITY TO INTELLIGENCE. AB - Recent neuroimaging research has shown sex-related differences in the relationship between brain structure and cognitive function. Anatomical studies have shown a greater reliance for cognitive function on white matter structure in adult females, and a greater reliance on gray matter structure in adult males. Functional neuroimaging studies have also shown a greater correlation between brain connectivity and cognitive function in females. However, this relationship is not present in young childhood (5 years old) but appears during the developmental period. Here sex differences in structure-function relationships and their developmental trajectory are investigated using diffusion tensor imaging (DTI) on a large cohort of over 100 normal children ages 5-18. Significant sex-X-IQ interactions on fractional anisotropy (FA), a marker for white matter organization, were seen in the left frontal lobe, in fronto-parietal areas bilaterally, and in the arcuate fasciculus bilaterally, with girls showing positive correlations of FA with IQ, and boys showing a negative correlation. Significant sex-X-IQ-X-age interactions on FA were also seen in the left frontal lobe and in fronto-parietal areas bilaterally, showing a developmental effect. These results strongly corroborate previous findings regarding sex differences in structure-function relationships regarding intelligence. Results also indicate that a naive interpretation of "more is better" with respect to FA may not be accurate, especially in adult males. PMID- 21297967 TI - Label-free proteomics reveals decreased expression of CD18 and AKNA in peripheral CD4+ T cells from patients with Vogt-Koyanagi-Harada syndrome. AB - Vogt-Koyanagi-Harada (VKH) syndrome is a systemic autoimmune disease. CD4(+) T cells have been shown to be involved in autoimmune diseases including VKH syndrome. To screen aberrantly expressed membrane proteins in CD4(+) T cell from patients with active VKH syndrome, blood samples were taken from five patients with active VKH syndrome and five healthy individuals. A label-free quantitative proteomic strategy was used to identify the differently expressed proteins between the two groups. The results revealed that the expression of 102 peptides was significantly altered (p<0.05) between two groups and matched amino acid sequences of proteins deposited in the international protein index (ipi.HUMAN.v3.36.fasta). The identified peptides corresponded to 64 proteins, in which 30 showed more than a 1.5-fold difference between the two groups. The decreased expression of CD18 and AKNA transcription factor (AKNA), both being three-fold lower than controls in expression identified by the label-free method, was further confirmed in an additional group of five active VKH patients and six normal individuals using the Western blot technique. A significantly decreased expression of CD18 and AKNA suggests a role for both proteins in the pathogenesis of this syndrome. PMID- 21297968 TI - Behavioural dissociation between exogenous and endogenous temporal orienting of attention. AB - BACKGROUND: In the current study we compared the effects of temporal orienting of attention based on predictions carried by the intrinsic temporal structure of events (rhythm) and by instructive symbolic cues; and tested the degree of cognitive, strategic control that could be exerted over each type of temporal expectation. The experiments tested whether the distinction between exogenous and endogenous orienting made in spatial attention may extend to the temporal domain. TASK DESIGN AND MAIN RESULTS: In this task, a ball moved across the screen in discrete steps and disappeared temporarily under an occluding band. Participants were required to make a perceptual discrimination on the target upon its reappearance. The regularity of the speed (rhythmic cue) or colour (symbolic cue) of the moving stimulus could predict the exact time at which a target would reappear after a brief occlusion (valid trials) or provide no temporal information (neutral trials). The predictive nature of rhythmic and symbolic cues was manipulated factorially in a symmetrical and orthogonal fashion. To test for the effects of strategic control over temporal orienting based on rhythmic or symbolic cues, participants were instructed either to "attend-to-speed" (rhythm) or "attend-to-colour". Our results indicated that both rhythmic and symbolic (colour) cues speeded reaction times in an independent fashion. However, whilst the rhythmic cueing effects were impervious to instruction, the effects of symbolic cues were contingent on the instruction to attend to colour. FINAL CONCLUSIONS: Taken together, our results provide evidence for the existence of qualitatively separable types of temporal orienting of attention, akin to exogenous and endogenous mechanisms. PMID- 21297969 TI - Species recognition and cryptic species in the Tuber indicum complex. AB - Morphological delimitation of Asian black truffles, including Tuber himalayense, T. indicum, T. sinense, T. pseudohimalayense, T. formosanum and T. pseudoexcavatum, has remained problematic and even phylogenetic analyses have been controversial. In this study, we combined five years of field investigation in China with morphological study and DNA sequences analyses (ITS, LSU and beta tubulin) of 131 Tuber specimens to show that T. pseudohimalayense and T. pseudoexcavatum are the same species. T. formosanum is a separate species based on its host plants and geographic distribution, combined with minor morphological difference from T. indicum. T. sinense should be treated as a synonym of T. indicum. Our results demonstrate that the present T. indicum, a single described morphological species, should include at least two separate phylogenetic species. These findings are of high importance for truffle taxonomy and reveal and preserve the richness of truffle diversity. PMID- 21297970 TI - Aberrant promoter CpG methylation is a mechanism for impaired PHD3 expression in a diverse set of malignant cells. AB - BACKGROUND: The prolyl-hydroxylase domain family of enzymes (PHD1-3) plays an important role in the cellular response to hypoxia by negatively regulating HIF alpha proteins. Disruption of this process can lead to up-regulation of factors that promote tumorigenesis. We observed decreased basal expression of PHD3 in prostate cancer tissue and tumor cell lines representing diverse tissues of origin. Furthermore, some cancer lines displayed a failure of PHD3 mRNA induction when introduced to a hypoxic environment. This study explores the mechanism by which malignancies neither basally express PHD3 nor induce PHD3 under hypoxic conditions. METHODOLOGY/PRINCIPAL FINDINGS: Using bisulfite sequencing and methylated DNA enrichment procedures, we identified human PHD3 promoter hypermethylation in prostate, breast, melanoma and renal carcinoma cell lines. In contrast, non-transformed human prostate and breast epithelial cell lines contained PHD3 CpG islands that were unmethylated and responded normally to hypoxia by upregulating PHD3 mRNA. Only treatment of cells lines containing PHD3 promoter hypermethylation with the demethylating drug 5-aza-2'-deoxycytidine significantly increased the expression of PHD3. CONCLUSIONS/SIGNIFICANCE: We conclude that expression of PHD3 is silenced by aberrant CpG methylation of the PHD3 promoter in a subset of human carcinoma cell lines of diverse origin and that this aberrant cytosine methylation status is the mechanism by which these cancer cell lines fail to upregulate PHD3 mRNA. We further show that a loss of PHD3 expression does not correlate with an increase in HIF-1alpha protein levels or an increase in the transcriptional activity of HIF, suggesting that loss of PHD3 may convey a selective advantage in some cancers by affecting pathway(s) other than HIF. PMID- 21297971 TI - Sildenafil reduces insulin-resistance in human endothelial cells. AB - BACKGROUND: The efficacy of Phosphodiesterase 5 (PDE5) inhibitors to re-establish endothelial function is reduced in diabetic patients. Recent evidences suggest that therapy with PDE5 inhibitors, i.e. sildenafil, may increase the expression of nitric oxide synthase (NOS) proteins in the heart and cardiomyocytes. In this study we analyzed the effect of sildenafil on endothelial cells in insulin resistance conditions in vitro. METHODOLOGY/PRINCIPAL FINDINGS: Human umbilical vein endothelial cells (HUVECs) were treated with insulin in presence of glucose 30 mM (HG) and glucosamine 10 mM (Gluc-N) with or without sildenafil. Insulin increased the expression of PDE5 and eNOS mRNA assayed by Real time-PCR. Cytofluorimetric analysis showed that sildenafil significantly increased NO production in basal condition. This effect was partially inhibited by the PI3K inhibitor LY 294002 and completely inhibited by the NOS inhibitor L-NAME. Akt-1 and eNOS activation was reduced in conditions mimicking insulin resistance and completely restored by sildenafil treatment. Conversely sildenafil treatment can counteract this noxious effect by increasing NO production through eNOS activation and reducing oxidative stress induced by hyperglycaemia and glucosamine. CONCLUSIONS/SIGNIFICANCE: These data indicate that sildenafil might improve NOS activity of endothelial cells in insulin resistance conditions and suggest the potential therapeutic use of sildenafil for improving vascular function in diabetic patients. PMID- 21297972 TI - Computing the partition function for kinetically trapped RNA secondary structures. AB - An RNA secondary structure is locally optimal if there is no lower energy structure that can be obtained by the addition or removal of a single base pair, where energy is defined according to the widely accepted Turner nearest neighbor model. Locally optimal structures form kinetic traps, since any evolution away from a locally optimal structure must involve energetically unfavorable folding steps. Here, we present a novel, efficient algorithm to compute the partition function over all locally optimal secondary structures of a given RNA sequence. Our software, RNAlocopt runs in O(n3) time and O(n2) space. Additionally, RNAlocopt samples a user-specified number of structures from the Boltzmann subensemble of all locally optimal structures. We apply RNAlocopt to show that (1) the number of locally optimal structures is far fewer than the total number of structures--indeed, the number of locally optimal structures approximately equal to the square root of the number of all structures, (2) the structural diversity of this subensemble may be either similar to or quite different from the structural diversity of the entire Boltzmann ensemble, a situation that depends on the type of input RNA, (3) the (modified) maximum expected accuracy structure, computed by taking into account base pairing frequencies of locally optimal structures, is a more accurate prediction of the native structure than other current thermodynamics-based methods. The software RNAlocopt constitutes a technical breakthrough in our study of the folding landscape for RNA secondary structures. For the first time, locally optimal structures (kinetic traps in the Turner energy model) can be rapidly generated for long RNA sequences, previously impossible with methods that involved exhaustive enumeration. Use of locally optimal structure leads to state-of-the-art secondary structure prediction, as benchmarked against methods involving the computation of minimum free energy and of maximum expected accuracy. Web server and source code available at http://bioinformatics.bc.edu/clotelab/RNAlocopt/. PMID- 21297973 TI - Genome-wide analysis of transcriptional reprogramming in mouse models of acute myeloid leukaemia. AB - Acute leukaemias are commonly caused by mutations that corrupt the transcriptional circuitry of haematopoietic stem/progenitor cells. However, the mechanisms underlying large-scale transcriptional reprogramming remain largely unknown. Here we investigated transcriptional reprogramming at genome-scale in mouse retroviral transplant models of acute myeloid leukaemia (AML) using both gene-expression profiling and ChIP-sequencing. We identified several thousand candidate regulatory regions with altered levels of histone acetylation that were characterised by differential distribution of consensus motifs for key haematopoietic transcription factors including Gata2, Gfi1 and Sfpi1/Pu.1. In particular, downregulation of Gata2 expression was mirrored by abundant GATA motifs in regions of reduced histone acetylation suggesting an important role in leukaemogenic transcriptional reprogramming. Forced re-expression of Gata2 was not compatible with sustained growth of leukaemic cells thus suggesting a previously unrecognised role for Gata2 in downregulation during the development of AML. Additionally, large scale human AML datasets revealed significantly higher expression of GATA2 in CD34+ cells from healthy controls compared with AML blast cells. The integrated genome-scale analysis applied in this study represents a valuable and widely applicable approach to study the transcriptional control of both normal and aberrant haematopoiesis and to identify critical factors responsible for transcriptional reprogramming in human cancer. PMID- 21297974 TI - Down-regulation of miR-101 in endothelial cells promotes blood vessel formation through reduced repression of EZH2. AB - Angiogenesis is a balanced process controlled by pro- and anti-angiogenic molecules of which the regulation is not fully understood. Besides classical gene regulation, miRNAs have emerged as post-transcriptional regulators of angiogenesis. Furthermore, epigenetic changes caused by histone-modifying enzymes were shown to modulate angiogenesis as well. However, a possible interplay between miRNAs and histone-modulating enzymes during angiogenesis has not been described. Here we show that VEGF-mediated down-regulation of miR-101 caused pro angiogenic effects. We found that the pro-angiogenic effects are partly mediated through reduced repression by miR-101 of the histone-methyltransferase EZH2, a member of the Polycomb group family, thereby increasing methylation of histone H3 at lysine 27 and transcriptome alterations. In vitro, the sprouting and migratory properties of primary endothelial cell cultures were reduced by inhibiting EZH2 through up-regulation of miR-101, siRNA-mediated knockdown of EZH2, or treatment with 3-Deazaneplanocin-A (DZNep), a small molecule inhibitor of EZH2 methyltransferase activity. In addition, we found that systemic DZNep administration reduced the number of blood vessels in a subcutaneous glioblastoma mouse model, without showing adverse toxicities. Altogether, by identifying a pro angiogenic VEGF/miR-101/EZH2 axis in endothelial cells we provide evidence for a functional link between growth factor-mediated signaling, post-transcriptional silencing, and histone-methylation in the angiogenesis process. Inhibition of EZH2 may prove therapeutic in diseases in which aberrant vascularization plays a role. PMID- 21297975 TI - Noise-induced modulation of the relaxation kinetics around a non-equilibrium steady state of non-linear chemical reaction networks. AB - Stochastic effects from correlated noise non-trivially modulate the kinetics of non-linear chemical reaction networks. This is especially important in systems where reactions are confined to small volumes and reactants are delivered in bursts. We characterise how the two noise sources confinement and burst modulate the relaxation kinetics of a non-linear reaction network around a non-equilibrium steady state. We find that the lifetimes of species change with burst input and confinement. Confinement increases the lifetimes of all species that are involved in any non-linear reaction as a reactant. Burst monotonically increases or decreases lifetimes. Competition between burst-induced and confinement-induced modulation may hence lead to a non-monotonic modulation. We quantify lifetime as the integral of the time autocorrelation function (ACF) of concentration fluctuations around a non-equilibrium steady state of the reaction network. Furthermore, we look at the first and second derivatives of the ACF, each of which is affected in opposite ways by burst and confinement. This allows discriminating between these two noise sources. We analytically derive the ACF from the linear Fokker-Planck approximation of the chemical master equation in order to establish a baseline for the burst-induced modulation at low confinement. Effects of higher confinement are then studied using a partial propensity stochastic simulation algorithm. The results presented here may help understand the mechanisms that deviate stochastic kinetics from its deterministic counterpart. In addition, they may be instrumental when using fluorescence lifetime imaging microscopy (FLIM) or fluorescence-correlation spectroscopy (FCS) to measure confinement and burst in systems with known reaction rates, or, alternatively, to correct for the effects of confinement and burst when experimentally measuring reaction rates. PMID- 21297976 TI - Recursive filtering for zero offset correction of diving depth time series with GNU R package diveMove. AB - Zero offset correction of diving depth measured by time-depth recorders is required to remove artifacts arising from temporal changes in accuracy of pressure transducers. Currently used methods for this procedure are in the proprietary software domain, where researchers cannot study it in sufficient detail, so they have little or no control over how their data were changed. GNU R package diveMove implements a procedure in the Free Software domain that consists of recursively smoothing and filtering the input time series using moving quantiles. This paper describes, demonstrates, and evaluates the proposed method by using a "perfect" data set, which is subsequently corrupted to provide input for the proposed procedure. The method is evaluated by comparing the corrected time series to the original, uncorrupted, data set from an Antarctic fur seal (Arctocephalus gazella Peters, 1875). The Root Mean Square Error of the corrected data set, relative to the "perfect" data set, was nearly identical to the magnitude of noise introduced into the latter. The method, thus, provides a flexible, reliable, and efficient mechanism to perform zero offset correction for analyses of diving behaviour. We illustrate applications of the method to data sets from four species with large differences in diving behaviour, measured using different sampling protocols and instrument characteristics. PMID- 21297977 TI - Nonlinear analysis of motor activity shows differences between schizophrenia and depression: a study using Fourier analysis and sample entropy. AB - The purpose of this study has been to describe motor activity data obtained by using wrist-worn actigraphs in patients with schizophrenia and major depression by the use of linear and non-linear methods of analysis. Different time frames were investigated, i.e., activity counts measured every minute for up to five hours and activity counts made hourly for up to two weeks. The results show that motor activity was lower in the schizophrenic patients and in patients with major depression, compared to controls. Using one minute intervals the depressed patients had a higher standard deviation (SD) compared to both the schizophrenic patients and the controls. The ratio between the root mean square successive differences (RMSSD) and SD was higher in the schizophrenic patients compared to controls. The Fourier analysis of the activity counts measured every minute showed that the relation between variance in the low and the high frequency range was lower in the schizophrenic patients compared to the controls. The sample entropy was higher in the schizophrenic patients compared to controls in the time series from the activity counts made every minute. The main conclusions of the study are that schizophrenic and depressive patients have distinctly different profiles of motor activity and that the results differ according to period length analysed. PMID- 21297978 TI - Discovering conformational sub-states relevant to protein function. AB - BACKGROUND: Internal motions enable proteins to explore a range of conformations, even in the vicinity of native state. The role of conformational fluctuations in the designated function of a protein is widely debated. Emerging evidence suggests that sub-groups within the range of conformations (or sub-states) contain properties that may be functionally relevant. However, low populations in these sub-states and the transient nature of conformational transitions between these sub-states present significant challenges for their identification and characterization. METHODS AND FINDINGS: To overcome these challenges we have developed a new computational technique, quasi-anharmonic analysis (QAA). QAA utilizes higher-order statistics of protein motions to identify sub-states in the conformational landscape. Further, the focus on anharmonicity allows identification of conformational fluctuations that enable transitions between sub states. QAA applied to equilibrium simulations of human ubiquitin and T4 lysozyme reveals functionally relevant sub-states and protein motions involved in molecular recognition. In combination with a reaction pathway sampling method, QAA characterizes conformational sub-states associated with cis/trans peptidyl prolyl isomerization catalyzed by the enzyme cyclophilin A. In these three proteins, QAA allows identification of conformational sub-states, with critical structural and dynamical features relevant to protein function. CONCLUSIONS: Overall, QAA provides a novel framework to intuitively understand the biophysical basis of conformational diversity and its relevance to protein function. PMID- 21297979 TI - Abnormal kinetochore-generated pulling forces from expressing a N-terminally modified Hec1. AB - BACKGROUND: Highly Expressed in Cancer protein 1 (Hec1) is a constituent of the Ndc80 complex, a kinetochore component that has been shown to have a fundamental role in stable kinetochore-microtubule attachment, chromosome alignment and spindle checkpoint activation at mitosis. HEC1 RNA is found up-regulated in several cancer cells, suggesting a role for HEC1 deregulation in cancer. In light of this, we have investigated the consequences of experimentally-driven Hec1 expression on mitosis and chromosome segregation in an inducible expression system from human cells. METHODOLOGY/PRINCIPAL FINDINGS: Overexpression of Hec1 could never be obtained in HeLa clones inducibly expressing C-terminally tagged Hec1 or untagged Hec1, suggesting that Hec1 cellular levels are tightly controlled. On the contrary, a chimeric protein with an EGFP tag fused to the Hec1 N-terminus accumulated in cells and disrupted mitotic division. EGFP- Hec1 cells underwent altered chromosome segregation within multipolar spindles that originated from centriole splitting. We found that EGFP-Hec1 assembled a mutant Ndc80 complex that was unable to rescue the mitotic phenotypes of Hec1 depletion. Kinetochores harboring EGFP-Hec1 formed persisting lateral microtubule kinetochore interactions that recruited the plus-end depolymerase MCAK and the microtubule stabilizing protein HURP on K-fibers. In these conditions the plus end kinesin CENP-E was preferentially retained at kinetochores. RNAi-mediated CENP-E depletion further demonstrated that CENP-E function was required for multipolar spindle formation in EGFP-Hec1 expressing cells. CONCLUSIONS/SIGNIFICANCE: Our study suggests that modifications on Hec1 N terminal tail can alter kinetochore-microtubule attachment stability and influence Ndc80 complex function independently from the intracellular levels of the protein. N-terminally modified Hec1 promotes spindle pole fragmentation by CENP-E-mediated plus-end directed kinetochore pulling forces that disrupt the fine balance of kinetochore- and centrosome-associated forces regulating spindle bipolarity. Overall, our findings support a model in which centrosome integrity is influenced by the pathways regulating kinetochore-microtubule attachment stability. PMID- 21297980 TI - Comparative studies of genome-wide maps of nucleosomes between deletion mutants of elp3 and hos2 genes of Saccharomyces cerevisiae. AB - In order to elucidate the influence of histone acetylation upon nucleosomal DNA length and nucleosome position, we compared nucleosome maps of the following three yeast strains; strain BY4741 (control), the elp3 (one of histone acetyltransferase genes) deletion mutant, and the hos2 (one of histone deactylase genes) deletion mutant of Saccharomyces cerevisiae. We sequenced mononucleosomal DNA fragments after treatment with micrococcal nuclease. After mapping the DNA fragments to the genome, we identified the nucleosome positions. We showed that the distributions of the nucleosomal DNA lengths of the control and the hos2 disruptant were similar. On the other hand, the distribution of the nucleosomal DNA lengths of the elp3 disruptant shifted toward shorter than that of the control. It strongly suggests that inhibition of Elp3-induced histone acetylation causes the nucleosomal DNA length reduction. Next, we compared the profiles of nucleosome mapping numbers in gene promoter regions between the control and the disruptant. We detected 24 genes with low conservation level of nucleosome positions in promoters between the control and the elp3 disruptant as well as between the control and the hos2 disruptant. It indicates that both Elp3-induced acetylation and Hos2-induced deacetylation influence the nucleosome positions in the promoters of those 24 genes. Interestingly, in 19 of the 24 genes, the profiles of nucleosome mapping numbers were similar between the two disruptants. PMID- 21297981 TI - Phylogenetic comparison of F-Box (FBX) gene superfamily within the plant kingdom reveals divergent evolutionary histories indicative of genomic drift. AB - The emergence of multigene families has been hypothesized as a major contributor to the evolution of complex traits and speciation. To help understand how such multigene families arose and diverged during plant evolution, we examined the phylogenetic relationships of F-Box (FBX) genes, one of the largest and most polymorphic superfamilies known in the plant kingdom. FBX proteins comprise the target recognition subunit of SCF-type ubiquitin-protein ligases, where they individually recruit specific substrates for ubiquitylation. Through the extensive analysis of 10,811 FBX loci from 18 plant species, ranging from the alga Chlamydomonas reinhardtii to numerous monocots and eudicots, we discovered strikingly diverse evolutionary histories. The number of FBX loci varies widely and appears independent of the growth habit and life cycle of land plants, with a little as 198 predicted for Carica papaya to as many as 1350 predicted for Arabidopsis lyrata. This number differs substantially even among closely related species, with evidence for extensive gains/losses. Despite this extraordinary inter-species variation, one subset of FBX genes was conserved among most species examined. Together with evidence of strong purifying selection and expression, the ligases synthesized from these conserved loci likely direct essential ubiquitylation events. Another subset was much more lineage specific, showed more relaxed purifying selection, and was enriched in loci with little or no evidence of expression, suggesting that they either control more limited, species-specific processes or arose from genomic drift and thus may provide reservoirs for evolutionary innovation. Numerous FBX loci were also predicted to be pseudogenes with their numbers tightly correlated with the total number of FBX genes in each species. Taken together, it appears that the FBX superfamily has independently undergone substantial birth/death in many plant lineages, with its size and rapid evolution potentially reflecting a central role for ubiquitylation in driving plant fitness. PMID- 21297982 TI - Central angiotensin II stimulation promotes beta amyloid production in Sprague Dawley rats. AB - BACKGROUND: Stress and various stress hormones, including catecholamines and glucocorticoids, have recently been implicated in the pathogenesis of Alzheimer's disease (AD), which represents the greatest unresolved medical challenge in neurology. Angiotensin receptor blockers have shown benefits in AD and prone-to AD animals. However, the mechanisms responsible for their efficacy remain unknown, and no studies have directly addressed the role of central angiotensin II (Ang II), a fundamental stress hormone, in the pathogenesis of AD. The present study focused on the role of central Ang II in amyloidogenesis, the critical process in AD neuropathology, and aimed to provide direct evidence for the role of this stress hormone in the pathogenesis of AD. METHODOLOGY/PRINCIPAL FINDINGS: Increased central Ang II levels during stress response were modeled by intracerebroventricular (ICV) administration of graded doses of Ang II (6 ng/hr low dose, 60 ng/hr medium dose, and 600 ng/hr high dose, all delivered at a rate of 0.25 ul/hr) to male Sprague Dawley rats (280-310 g) via osmotic pumps. After 1 week of continuous Ang II infusion, the stimulation of Ang II type 1 receptors was accompanied by the modulation of amyloid precursor protein, alpha-, beta-and gamma-secretase, and increased beta amyloid production. These effects could be completely abolished by concomitant ICV infusion of losartan, indicating that central Ang II played a causative role in these alterations. CONCLUSIONS/SIGNIFICANCE: Central Ang II is essential to the stress response, and the results of this study suggest that increased central Ang II levels play an important role in amyloidogenesis during stress, and that central Ang II-directed stress prevention and treatment might represent a novel anti-AD strategy. PMID- 21297983 TI - Antamanide, a derivative of Amanita phalloides, is a novel inhibitor of the mitochondrial permeability transition pore. AB - Antamanide is a cyclic decapeptide derived from the fungus Amanita phalloides. Here we show that antamanide inhibits the mitochondrial permeability transition pore, a central effector of cell death induction, by targeting the pore regulator cyclophilin D. Indeed, (i) permeability transition pore inhibition by antamanide is not additive with the cyclophilin D-binding drug cyclosporin A, (ii) the inhibitory action of antamanide on the pore requires phosphate, as previously shown for cyclosporin A; (iii) antamanide is ineffective in mitochondria or cells derived from cyclophilin D null animals, and (iv) abolishes CyP-D peptidyl-prolyl cis-trans isomerase activity. Permeability transition pore inhibition by antamanide needs two critical residues in the peptide ring, Phe6 and Phe9, and is additive with ubiquinone 0, which acts on the pore in a cyclophilin D-independent fashion. Antamanide also abrogates mitochondrial depolarization and the ensuing cell death caused by two well-characterized pore inducers, clotrimazole and a hexokinase II N-terminal peptide. Our findings have implications for the comprehension of cyclophilin D activity on the permeability transition pore and for the development of novel pore-targeting drugs exploitable as cell death inhibitors. PMID- 21297984 TI - Human RSPO1/R-spondin1 is expressed during early ovary development and augments beta-catenin signaling. AB - Human testis development starts from around 42 days post conception with a transient wave of SRY expression followed by up-regulation of testis specific genes and a distinct set of morphological, paracrine and endocrine events. Although anatomical changes in the ovary are less marked, a distinct sub-set of ovary specific genes are also expressed during this time. The furin-domain containing peptide R-spondin1 (RSPO1) has recently emerged as an important regulator of ovary development through up-regulation of the WNT/beta-catenin pathway to oppose testis formation. Here, we show that RSPO1 is upregulated in the ovary but not in the testis during critical early stages of gonad development in humans (between 6-9 weeks post conception), whereas the expression of the related genes WNT4 and CTNNB1 (encoding beta catenin) is not significantly different between these tissues. Furthermore, reduced R-spondin1 function in the ovotestis of an individual (46,XX) with a RSPO1 mutation leads to reduced beta catenin protein and WNT4 mRNA levels, consistent with down regulation of ovarian pathways. Transfection of wild-type RSPO1 cDNA resulted in weak dose-dependent activation of a beta-catenin responsive TOPFLASH reporter (1.8 fold maximum), whereas co-transfection of CTNNB1 (encoding beta-catenin) with RSPO1 resulted in dose-dependent synergistic augmentation of this reporter (approximately 10 fold). Furthermore, R-spondin1 showed strong nuclear localization in several different cell lines. Taken together, these data show that R-spondin1 is upregulated during critical stages of early human ovary development and may function as a tissue specific amplifier of beta-catenin signaling to oppose testis determination. PMID- 21297985 TI - Ventilatory chaos is impaired in carotid atherosclerosis. AB - Ventilatory chaos is strongly linked to the activity of central pattern generators, alone or influenced by respiratory or cardiovascular afferents. We hypothesized that carotid atherosclerosis should alter ventilatory chaos through baroreflex and autonomic nervous system dysfunctions. Chaotic dynamics of inspiratory flow was prospectively evaluated in 75 subjects undergoing carotid ultrasonography: 27 with severe carotid stenosis (>70%), 23 with moderate stenosis (<70%), and 25 controls. Chaos was characterized by the noise titration method, the correlation dimension and the largest Lyapunov exponent. Baroreflex sensitivity was estimated in the frequency domain. In the control group, 92% of the time series exhibit nonlinear deterministic chaos with positive noise limit, whereas only 68% had a positive noise limit value in the stenoses groups. Ventilatory chaos was impaired in the groups with carotid stenoses, with significant parallel decrease in the noise limit value, correlation dimension and largest Lyapunov exponent, as compared to controls. In multiple regression models, the percentage of carotid stenosis was the best in predicting the correlation dimension (p<0.001, adjusted R(2): 0.35) and largest Lyapunov exponent (p<0.001, adjusted R(2): 0.6). Baroreflex sensitivity also predicted the correlation dimension values (p = 0.05), and the LLE (p = 0.08). Plaque removal after carotid surgery reversed the loss of ventilatory complexity. To conclude, ventilatory chaos is impaired in carotid atherosclerosis. These findings depend on the severity of the stenosis, its localization, plaque surface and morphology features, and is independently associated with baroreflex sensitivity reduction. These findings should help to understand the determinants of ventilatory complexity and breathing control in pathological conditions. PMID- 21297986 TI - Plasmodium vivax sub-patent infections after radical treatment are common in Peruvian patients: results of a 1-year prospective cohort study. AB - BACKGROUND: There is an increasing body of literature reporting treatment failure of the currently recommended radical treatment of Plasmodium vivax infections. As P. vivax is the main malaria species outside the African continent, emerging tolerance to its radical treatment regime could have major consequences in countries like Peru, where 80% of malaria cases are due to P. vivax. Here we describe the results of a 1-year longitudinal follow up of 51 confirmed P. vivax patients living around Iquitos, Peruvian Amazon, and treated according to the Peruvian national guidelines. METHODOLOGY: Each month a blood sample for microscopy and later genotyping was systematically collected. Recent exposure to infection was estimated by detecting antibodies against the P. vivax circumsporozoite protein (CSP) and all PCR confirmed P. vivax infections were genotyped with 16 polymorphic microsatellites. RESULTS: During a 1-year period, 84 recurrent infections, 22 positive also by microscopy, were identified, with a median survival time to first recurrent infection of 203 days. Most of them (71%) were asymptomatic; in 13 patients the infection persisted undetected by microscopy for several consecutive months. The genotype of mostly recurrent infections differed from that at day 0 while fewer differences were seen between the recurrent infections. The average expected heterozygosity was 0.56. There was strong linkage disequilibrium (I(A)(s) = 0.29, p<1.10(-4)) that remained also when analyzing only the unique haplotypes, suggesting common inbreeding. CONCLUSION: In Peru, the P. vivax recurrent infections were common and displayed a high turnover of parasite genotypes compared to day 0. Plasmodium vivax patients, even when treated according to the national guidelines, may still represent an important parasite reservoir that can maintain transmission. Any elimination effort should consider such a hidden reservoir. PMID- 21297987 TI - Boys and girls on the playground: sex differences in social development are not stable across early childhood. AB - Sex differences in human social behaviors and abilities have long been a question of public and scientific interest. Females are usually assumed to be more socially oriented and skillful than males. However, despite an extensive literature, the very existence of sex differences remains a matter of discussion while some studies found no sex differences whereas others reported differences that were either congruent or not with gender stereotypes. Moreover, the magnitude, consistency and stability across time of the differences remain an open question, especially during childhood. As play provides an excellent window into children's social development, we investigated whether and how sex differences change in social play across early childhood. Following a cross sectional design, 164 children aged from 2 to 6 years old, divided into four age groups, were observed during outdoor free play at nursery school. We showed that sex differences are not stable over time evidencing a developmental gap between girls and boys. Social and structured forms of play emerge systematically earlier in girls than in boys leading to subsequent sex differences in favor of girls at some ages, successively in associative play at 3-4 years, cooperative play at 4-5 years, and social interactions with peers at 5-6 years. Preschool boys also display more solitary play than preschool girls, especially when young. Nevertheless, while boys catch up and girls move on towards more complex play, sex differences in social play patterns are reversed in favor of boys at the following ages, such as in associative play at 4-5 years and cooperative play at 5-6 years. This developmental perspective contributes to resolve apparent discrepancies between single-snapshot studies. A better understanding of the dynamics of sex differences in typical social development should also provide insights into atypical social developments which exhibit sex differences in prevalence, such as autism. PMID- 21297988 TI - MCT expression and lactate influx/efflux in tanycytes involved in glia-neuron metabolic interaction. AB - Metabolic interaction via lactate between glial cells and neurons has been proposed as one of the mechanisms involved in hypothalamic glucosensing. We have postulated that hypothalamic glial cells, also known as tanycytes, produce lactate by glycolytic metabolism of glucose. Transfer of lactate to neighboring neurons stimulates ATP synthesis and thus contributes to their activation. Because destruction of third ventricle (III-V) tanycytes is sufficient to alter blood glucose levels and food intake in rats, it is hypothesized that tanycytes are involved in the hypothalamic glucose sensing mechanism. Here, we demonstrate the presence and function of monocarboxylate transporters (MCTs) in tanycytes. Specifically, MCT1 and MCT4 expression as well as their distribution were analyzed in Sprague Dawley rat brain, and we demonstrate that both transporters are expressed in tanycytes. Using primary tanycyte cultures, kinetic analyses and sensitivity to inhibitors were undertaken to confirm that MCT1 and MCT4 were functional for lactate influx. Additionally, physiological concentrations of glucose induced lactate efflux in cultured tanycytes, which was inhibited by classical MCT inhibitors. Because the expression of both MCT1 and MCT4 has been linked to lactate efflux, we propose that tanycytes participate in glucose sensing based on a metabolic interaction with neurons of the arcuate nucleus, which are stimulated by lactate released from MCT1 and MCT4-expressing tanycytes. PMID- 21297989 TI - Primary human mDC1, mDC2, and pDC dendritic cells are differentially infected and activated by respiratory syncytial virus. AB - Respiratory syncytial virus (RSV) causes recurrent infections throughout life. Vaccine development may depend upon understanding the molecular basis for induction of ineffective immunity. Because dendritic cells (DCs) are critically involved in early responses to infection, their interaction with RSV may determine the immunological outcome of RSV infection. Therefore, we investigated the ability of RSV to infect and activate primary mDCs and pDCs using recombinant RSV expressing green fluorescent protein (GFP). At a multiplicity of infection of 5, initial studies demonstrated ~6.8% of mDC1 and ~0.9% pDCs were infected. We extended these studies to include CD1c(-)CD141(+) mDC2, finding mDC2 infected at similar frequencies as mDC1. Both infected and uninfected cells upregulated phenotypic markers of maturation. Divalent cations were required for infection and maturation, but maturation did not require viral replication. There is evidence that attachment and entry/replication processes exert distinct effects on DC activation. Cell-specific patterns of RSV-induced maturation and cytokine production were detected in mDC1, mDC2, and pDC. We also demonstrate for the first time that RSV induces significant TIMP-2 production in all DC subsets. Defining the influence of RSV on the function of selected DC subsets may improve the likelihood of achieving protective vaccine-induced immunity. PMID- 21297990 TI - Interaction of TGFbeta and BMP signaling pathways during chondrogenesis. AB - TGFbeta and BMP signaling pathways exhibit antagonistic activities during the development of many tissues. Although the crosstalk between BMP and TGFbeta signaling pathways is well established in bone development, the relationship between these two pathways is less well defined during cartilage development and postnatal homeostasis. We generated hypomorphic mouse models of cartilage specific loss of BMP and TGFbeta signaling to assess the interaction of these pathways in postnatal growth plate homeostasis. We further used the chondrogenic ATDC5 cell line to test effects of BMP and TGFbeta signaling on each other's downstream targets. We found that conditional deletion of Smad1 in chondrocytes resulted in a shortening of the growth plate. The addition of Smad5 haploinsufficiency led to a more severe phenotype with shorter prehypertrophic and hypertrophic zones and decreased chondrocyte proliferation. The opposite growth plate phenotype was observed in a transgenic mouse model of decreased chondrocytic TGFbeta signaling that was generated by expressing a dominant negative form of the TGFbeta receptor I (DeltaTbetaRI) in cartilage. Histological analysis demonstrated elongated growth plates with enhanced Ihh expression, as well as an increased proliferation rate with altered production of extracellular matrix components. In contrast, in chondrogenic ATDC5 cells, TGFbeta was able to enhance BMP signaling, while BMP2 significantly reduces levels of TGF signaling. In summary, our data demonstrate that during endochondral ossification, BMP and TGFbeta signaling can have antagonistic effects on chondrocyte proliferation and differentiation in vivo. We also found evidence of direct interaction between the two signaling pathways in a cell model of chondrogenesis in vitro. PMID- 21297991 TI - Clinical relevance of tumor cells with stem-like properties in pediatric brain tumors. AB - BACKGROUND: Primitive brain tumors are the leading cause of cancer-related death in children. Tumor cells with stem-like properties (TSCs), thought to account for tumorigenesis and therapeutic resistance, have been isolated from high-grade gliomas in adults. Whether TSCs are a common component of pediatric brain tumors and are of clinical relevance remains to be determined. METHODOLOGY/PRINCIPAL FINDINGS: Tumor cells with self-renewal properties were isolated with cell biology techniques from a majority of 55 pediatric brain tumors samples, regardless of their histopathologies and grades of malignancy (57% of embryonal tumors, 57% of low-grade gliomas and neuro-glial tumors, 70% of ependymomas, 91% of high-grade gliomas). Most high-grade glioma-derived oncospheres (10/12) sustained long-term self-renewal akin to neural stem cells (>7 self-renewals), whereas cells with limited renewing abilities akin to neural progenitors dominated in all other tumors. Regardless of tumor entities, the young age group was associated with self-renewal properties akin to neural stem cells (P = 0.05, chi-square test). Survival analysis of the cohort showed an association between isolation of cells with long-term self-renewal abilities and a higher patient mortality rate (P = 0.013, log-rank test). Sampling of low- and high-grade glioma cultures showed that self-renewing cells forming oncospheres shared a molecular profile comprising embryonic and neural stem cell markers. Further characterization performed on subsets of high-grade gliomas and one low-grade glioma culture showed combination of this profile with mesenchymal markers, the radio-chemoresistance of the cells and the formation of aggressive tumors after intracerebral grafting. CONCLUSIONS/SIGNIFICANCE: In brain tumors affecting adult patients, TSCs have been isolated only from high-grade gliomas. In contrast, our data show that tumor cells with stem cell-like or progenitor-like properties can be isolated from a wide range of histological sub-types and grades of pediatric brain tumors. They suggest that cellular mechanisms fueling tumor development differ between adult and pediatric brain tumors. PMID- 21297992 TI - Differential in vitro effects of intravenous versus oral formulations of silibinin on the HCV life cycle and inflammation. AB - Silymarin prevents liver disease in many experimental rodent models, and is the most popular botanical medicine consumed by patients with hepatitis C. Silibinin is a major component of silymarin, consisting of the flavonolignans silybin A and silybin B, which are insoluble in aqueous solution. A chemically modified and soluble version of silibinin, SIL, has been shown to potently reduce hepatitis C virus (HCV) RNA levels in vivo when administered intravenously. Silymarin and silibinin inhibit HCV infection in cell culture by targeting multiple steps in the virus lifecycle. We tested the hepatoprotective profiles of SIL and silibinin in assays that measure antiviral and anti-inflammatory functions. Both mixtures inhibited fusion of HCV pseudoparticles (HCVpp) with fluorescent liposomes in a dose-dependent fashion. SIL inhibited 5 clinical genotype 1b isolates of NS5B RNA dependent RNA polymerase (RdRp) activity better than silibinin, with IC50 values of 40-85 uM. The enhanced activity of SIL may have been in part due to inhibition of NS5B binding to RNA templates. However, inhibition of the RdRps by both mixtures plateaued at 43-73%, suggesting that the products are poor overall inhibitors of RdRp. Silibinin did not inhibit HCV replication in subgenomic genotype 1b or 2a replicon cell lines, but it did inhibit JFH-1 infection. In contrast, SIL inhibited 1b but not 2a subgenomic replicons and also inhibited JFH 1 infection. Both mixtures inhibited production of progeny virus particles. Silibinin but not SIL inhibited NF-kappaB- and IFN-B-dependent transcription in Huh7 cells. However, both mixtures inhibited T cell proliferation to similar degrees. These data underscore the differences and similarities between the intravenous and oral formulations of silibinin, which could influence the clinical effects of this mixture on patients with chronic liver diseases. PMID- 21297993 TI - The p38/MK2/Hsp25 pathway is required for BMP-2-induced cell migration. AB - BACKGROUND: Bone morphogenetic proteins (BMPs) have been shown to participate in the patterning and specification of several tissues and organs during development and to regulate cell growth, differentiation and migration in different cell types. BMP-mediated cell migration requires activation of the small GTPase Cdc42 and LIMK1 activities. In our earlier report we showed that activation of LIMK1 also requires the activation of PAKs through Cdc42 and PI3K. However, the requirement of additional signaling is not clearly known. METHODOLOGY/PRINCIPAL FINDINGS: Activation of p38 MAPK has been shown to be relevant for a number of BMP-2's physiological effects. We report here that BMP-2 regulation of cell migration and actin cytoskeleton remodelling are dependent on p38 activity. BMP-2 treatment of mesenchymal cells results in activation of the p38/MK2/Hsp25 signaling pathway downstream from the BMP receptors. Moreover, chemical inhibition of p38 signaling or genetic ablation of either p38alpha or MK2 blocks the ability to activate the downstream effectors of the pathway and abolishes BMP 2-induction of cell migration. These signaling effects on p38/MK2/Hsp25 do not require the activity of either Cdc42 or PAK, whereas p38/MK2 activities do not significantly modify the BMP-2-dependent activation of LIMK1, measured by either kinase activity or with an antibody raised against phospho-threonine 508 at its activation loop. Finally, phosphorylated Hsp25 colocalizes with the BMP receptor complexes in lamellipodia and overexpression of a phosphorylation mutant form of Hsp25 is able to abolish the migration of cells in response to BMP-2. CONCLUSIONS: These results indicate that Cdc42/PAK/LIMK1 and p38/MK2/Hsp25 pathways, acting in parallel and modulating specific actin regulatory proteins, play a critical role in integrating responses during BMP-induced actin reorganization and cell migration. PMID- 21297994 TI - Profiling the HER3/PI3K pathway in breast tumors using proximity-directed assays identifies correlations between protein complexes and phosphoproteins. AB - BACKGROUND: The identification of patients for targeted antineoplastic therapies requires accurate measurement of therapeutic targets and associated signaling complexes. HER3 signaling through heterodimerization is an important growth promoting mechanism in several tumor types and may be a principal resistance mechanism by which EGFR and HER2 expressing tumors elude targeted therapies. Current methods that can study these interactions are inadequate for formalin fixed, paraffin-embedded (FFPE) tumor samples. METHODOLOGY AND PRINCIPAL FINDINGS: Herein, we describe a panel of proximity-directed assays capable of measuring protein-interactions and phosphorylation in FFPE samples in the HER3/PI3K/Akt pathway and examine the capability of these assays to inform on the functional state of the pathway. We used FFPE breast cancer cell line and tumor models for this study. In breast cancer cell lines we observe both ligand dependent and independent activation of the pathway and strong correlations between measured activation of key analytes. When selected cell lines are treated with HER2 inhibitors, we not only observe the expected molecular effects based on mechanism of action knowledge, but also novel effects of HER2 inhibition on key targets in the HER receptor pathway. Significantly, in a xenograft model of delayed tumor fixation, HER3 phosphorylation is unstable, while alternate measures of pathway activation, such as formation of the HER3PI3K complex is preserved. Measurements in breast tumor samples showed correlations between HER3 phosphorylation and receptor interactions, obviating the need to use phosphorylation as a surrogate for HER3 activation. SIGNIFICANCE: This assay system is capable of quantitatively measuring therapeutically relevant responses and enables molecular profiling of receptor networks in both preclinical and tumor models. PMID- 21297995 TI - Diabetes mellitus is associated with shortened activated partial thromboplastin time and increased fibrinogen values. AB - OBJECTIVE: This study was designed to examine the relationship between shortened activated partial thromboplastin time (APTT) and increased fibrinogen values with diabetes mellitus. METHODS: APTT, prothrombin time (PT), fibrinogen, fasting plasma glucose (FPG) and glycosylated hemoglobin A1c (HbA1c) levels were measured in 1,300 patients. Patients were divided into three groups according to their HbA1c and FPG levels. RESULTS: When participants were grouped according to their HbA1c levels, we found significantly shorter APTT values (26.9+/-5.6 s) and increased fibrinogen levels (3.1, 1.9-6.3 g/L) in the diabetes group when compared with the other two groups. When participants were grouped according to their FPG levels, we found significantly shorter APTT values (26.9+/-6.2 s) and increased fibrinogen levels (3.1, 1.8-6.2 g/L) in the diabetes group when compared with the euglycemic group. CONCLUSIONS: Shorter APTT and increased fibrinogen levels might be useful hemostatic markers in patients with diabetes and in patients at high risk for diabetes. PMID- 21297996 TI - Use of non-steroidal anti-inflammatory drugs and prostate cancer risk: a population-based nested case-control study. AB - BACKGROUND: Despite strong laboratory evidence that non-steroidal anti inflammatory drugs (NSAIDs) could prevent prostate cancer, epidemiological studies have so far reported conflicting results. Most studies were limited by lack of information on dosage and duration of use of the different classes of NSAIDs. METHODS: We conducted a nested case-control study using data from Saskatchewan Prescription Drug Plan (SPDP) and Cancer Registry to examine the effects of dose and duration of use of five classes of NSAIDs on prostate cancer risk. Cases (N = 9,007) were men aged >=40 years diagnosed with prostatic carcinoma between 1985 and 2000, and were matched to four controls on age and duration of SPDP membership. Detailed histories of exposure to prescription NSAIDs and other drugs were obtained from the SPDP. RESULTS: Any use of propionates (e.g., ibuprofen, naproxen) was associated with a modest reduction in prostate cancer risk (Odds ratio = 0.90; 95%CI 0.84-0.95), whereas use of other NSAIDs was not. In particular, we did not observe the hypothesized inverse association with aspirin use (1.01; 0.95-1.07). There was no clear evidence of dose-response or duration-response relationships for any of the examined NSAID classes. CONCLUSIONS: Our findings suggest modest benefits of at least some NSAIDs in reducing prostate cancer risk. PMID- 21297997 TI - Bulk segregant analysis using single nucleotide polymorphism microarrays. AB - Bulk segregant analysis (BSA) using microarrays, and extreme array mapping (XAM) have recently been used to rapidly identify genomic regions associated with phenotypes in multiple species. These experiments, however, require the identification of single feature polymorphisms (SFP) between the cross parents for each new combination of genotypes, which raises the cost of experiments. The availability of the genomic polymorphism data in Arabidopsis thaliana, coupled with the efficient designs of Single Nucleotide Polymorphism (SNP) genotyping arrays removes the requirement for SFP detection and lowers the per array cost, thereby lowering the overall cost per experiment. To demonstrate that these approaches would be functional on SNP arrays and determine confidence intervals, we analyzed hybridizations of natural accessions to the Arabidopsis ATSNPTILE array and simulated BSA or XAM given a variety of gene models, populations, and bulk selection parameters. Our results show a striking degree of correlation between the genotyping output of both methods, which suggests that the benefit of SFP genotyping in context of BSA can be had with the cheaper, more efficient SNP arrays. As a final proof of concept, we hybridized the DNA from bulks of an F2 mapping population of a Sulfur and Selenium ionomics mutant to both the Arabidopsis ATTILE1R and ATSNPTILE arrays, which produced almost identical results. We have produced R scripts that prompt the user for the required parameters and perform the BSA analysis using the ATSNPTILE1 array and have provided them as supplemental data files. PMID- 21297998 TI - Microbial dysbiosis in colorectal cancer (CRC) patients. AB - The composition of the human intestinal microbiota is linked to health status. The aim was to analyze the microbiota of normal and colon cancer patients in order to establish cancer-related dysbiosis. PATIENTS AND METHODS: Stool bacterial DNA was extracted prior to colonoscopy from 179 patients: 60 with colorectal cancer, and 119 with normal colonoscopy. Bacterial genes obtained by pyrosequencing of 12 stool samples (6 Normal and 6 Cancer) were subjected to a validated Principal Component Analysis (PCA) test. The dominant and subdominant bacterial population (C. leptum, C. coccoides, Bacteroides/Prevotella, Lactobacillus/Leuconostoc/Pediococcus groups, Bifidobacterium genus, and E. coli, and Faecalibacterium prausnitzii species) were quantified in all individuals using qPCR and specific IL17 producer cells in the intestinal mucosa were characterized using immunohistochemistry. FINDINGS: Pyrosequencing (Minimal sequence 200 nucleotide reads) revealed 80% of all sequences could be assigned to a total of 819 taxa based on default parameter of Classifier software. The phylogenetic core in Cancer individuals was different from that in Normal individuals according to the PCA analysis, with trends towards differences in the dominant and subdominant families of bacteria. Consequently, All-bacteria [log(10) (bacteria/g of stool)] in Normal, and Cancer individuals were similar [11.88+/-0.35, and 11.80+/-0.56, respectively, (P = 0.16)], according to qPCR values whereas among all dominant and subdominant species only those of Bacteroides/Prevotella were higher (All bacteria-specific bacterium; P = 0.009) in Cancer (-1.04+/-0.55) than in Normal (-1.40+/-0.83) individuals. IL17 immunoreactive cells were significantly expressed more in the normal mucosa of cancer patients than in those with normal colonoscopy. CONCLUSION: This is the first large series to demonstrate a composition change in the microbiota of colon cancer patients with possible impact on mucosal immune response. These data open new filed for mass screening and pathophysiology investigations. PMID- 21297999 TI - Defective molecular timer in the absence of nucleotides leads to inefficient caspase activation. AB - In the intrinsic death pathway, cytochrome C (CC) released from mitochondria to the cytosol triggers Apaf-1 apoptosome formation and subsequent caspase activation. This process can be recapitulated using recombinant Apaf-1 and CC in the presence of nucleotides ATP or dATP [(d)ATP] or using fresh cytosol and CC without the need of exogenous nucleotides. Surprisingly, we found that stored cytosols failed to support CC-initiated caspase activation. Storage of cytosols at different temperatures led to the loss of all (deoxy)nucleotides including (d)ATP. Addition of (d)ATP to such stored cytosols partially restored CC initiated caspase activation. Nevertheless, CC could not induce complete caspase 9/3 activation in stored cytosols, even with the addition of (d)ATP, despite robust Apaf-1 oligomerization. The Apaf-1 apoptosome, which functions as a proteolytic-based molecular timer appeared to be defective as auto-processing of recruited procaspase-9 was inhibited. Far Western analysis revealed that procaspase-9 directly interacted with Apaf-1 and this interaction was reduced in the presence of physiological levels of ATP. Co-incubation of recombinant Apaf-1 and procaspase-9 prior to CC and ATP addition inhibited CC-induced caspase activity. These findings suggest that in the absence of nucleotide such as ATP, direct association of procaspase-9 with Apaf-1 leads to defective molecular timer, and thus, inhibits apoptosome-mediated caspase activation. Altogether, our results provide novel insight on nucleotide regulation of apoptosome. PMID- 21298000 TI - Prostaglandin E2 reverses aberrant production of an inflammatory chemokine by microglia from Sandhoff disease model mice through the cAMP-PKA pathway. AB - BACKGROUND: Sandhoff disease (SD) is a neurodegenerative lysosomal beta hexosaminidase (Hex) deficiency involving excessive accumulation of undegraded substrates, including terminal GlcNAc-oligosaccharides and GM2 ganglioside. Microglia-mediated neuroinflammation contributes to the pathogenesis and progression of SD. Our previous study demonstrated that MIP-1alpha, a putative pathogenic factor for SD, is up-regulated in microglial cells derived from SD model mice (SD-Mg) through activation of Akt and JNK. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we first demonstrated that prostaglandin E2 (PGE2), which is one of the lipid mediators derived from arachidonic acid and is known to suppress activation of microglia, reduced the aberrant MIP-1alpha production by SD-Mg to the same level as by WT-Mg. PGE2 also attenuated the activation of Akt and JNK. The inhibition of MIP-1alpha production and the activation of Akt and JNK occurred through the EP2 and 4/cAMP/PKA signaling pathway in the murine microglia derived from SD model mice. CONCLUSIONS/SIGNIFICANCE: We propose that PGE2 plays a role as a negative regulator of MIP-1alpha production in the pathogenesis of SD, and that PGE2-EP2 and 4/cAMP/PKA signaling could be a target pathway for therapy for SD. PMID- 21298001 TI - Nucleic acid amplification tests for diagnosis of smear-negative TB in a high HIV prevalence setting: a prospective cohort study. AB - BACKGROUND: Nucleic acid amplification tests are sensitive for identifying Mycobacterium tuberculosis in populations with positive sputum smears for acid fast bacilli, but less sensitive in sputum-smear-negative populations. Few studies have evaluated the clinical impact of these tests in low-income countries with high burdens of TB and HIV. METHODS: We prospectively enrolled 211 consecutive adults with cough >=2 weeks and negative sputum smears at Mulago Hospital in Kampala, Uganda. We tested a single early-morning sputum specimen for Mycobacterium tuberculosis DNA using two nucleic acid amplification tests: a novel in-house polymerase chain reaction targeting the mycobacterial secA1 gene, and the commercial Amplified(r) Mycobacterium tuberculosis Direct (MTD) test (Gen Probe Inc, San Diego, CA). We calculated the diagnostic accuracy of these index tests in reference to a primary microbiologic gold standard (positive mycobacterial culture of sputum or bronchoalveolar lavage fluid), and measured their likely clinical impact on additional tuberculosis cases detected among those not prescribed initial TB treatment. RESULTS: Of 211 patients enrolled, 170 (81%) were HIV-seropositive, with median CD4+ T-cell count 78 cells/uL (interquartile range 29-203). Among HIV-seropositive patients, 94 (55%) reported taking co-trimoxazole prophylaxis and 29 (17%) reported taking antiretroviral therapy. Seventy-five patients (36%) had culture-confirmed TB. Sensitivity of MTD was 39% (95% CI 28-51) and that of secA1 was 24% (95% CI 15-35). Both tests had specificities of 95% (95% CI 90-98). The MTD test correctly identified 18 (24%) TB patients not treated at discharge and led to a 72% relative increase in the smear-negative case detection rate. CONCLUSIONS: The secA1 and MTD nucleic acid amplification tests had moderate sensitivity and high specificity for TB in a predominantly HIV-seropositive population with negative sputum smears. Although newer, more sensitive nucleic acid assays may enhance detection of Mycobacterium tuberculosis in sputum, even currently available tests can provide substantial clinical impact in smear-negative populations. PMID- 21298002 TI - Prostaglandin E2 synthesizing enzymes in rheumatoid arthritis B cells and the effects of B cell depleting therapy on enzyme expression. AB - INTRODUCTION: B cells may play an important role in promoting immune activation in the rheumatoid synovium and can produce prostaglandin E(2) (PGE(2)) when activated. In its turn, PGE(2) formed by cyclooxygenase (COX) and microsomal prostaglandin E(2) synthase 1 (MPGES1) contributes to the rheumatoid arthritis (RA) pathological process. Therapeutic depletion of B cells results in important improvement in controlling disease activity in rheumatoid patients. Therefore we investigated the expression of PGE(2) pathway enzymes in RA B cells and evaluated the effects of B cell depleting therapy on their expression in RA tissue. METHODS: B cells expressing MPGES1 and COX-2 were identified by flow cytometry in in vitro stimulated and control mononuclear cells isolated from synovial fluid and peripheral blood of RA patients. Synovial biopsies were obtained from 24 RA patients before and at two consecutive time points after rituximab therapy. Expression of MPGES1, COX-1 and COX-2, as well as interleukin (IL)-1beta and IL 6, known inducers of MPGES1, was quantified in immunostained biopsy sections using computerized image analysis. RESULTS: Expression of MPGES1 or COX-2 was significantly upregulated upon stimulation of B cells from blood and synovial fluid while control cells displayed no detectable enzymes. In synovial biopsy sections, the expression of MPGES1, COX-1 or COX-2 was resistant to rituximab therapy at 8 or 16 weeks after start of treatment. Furthermore expression of IL 1beta in the synovial tissue remained unchanged, while IL-6 tended to decrease after therapy. CONCLUSIONS: Therapy with B cell depleting agents, although efficient in achieving good clinical and radiographic response in RA patients, leaves important inflammatory pathways in the rheumatoid synovium essentially unaffected. PMID- 21298003 TI - The role of histone H4 biotinylation in the structure of nucleosomes. AB - BACKGROUND: Post-translational modifications of histones play important roles in regulating nucleosome structure and gene transcription. It has been shown that biotinylation of histone H4 at lysine-12 in histone H4 (K12Bio-H4) is associated with repression of a number of genes. We hypothesized that biotinylation modifies the physical structure of nucleosomes, and that biotin-induced conformational changes contribute to gene silencing associated with histone biotinylation. METHODOLOGY/PRINCIPAL FINDINGS: To test this hypothesis we used atomic force microscopy to directly analyze structures of nucleosomes formed with biotin modified and non-modified H4. The analysis of the AFM images revealed a 13% increase in the length of DNA wrapped around the histone core in nucleosomes with biotinylated H4. This statistically significant (p<0.001) difference between native and biotinylated nucleosomes corresponds to adding approximately 20 bp to the classical 147 bp length of nucleosomal DNA. CONCLUSIONS/SIGNIFICANCE: The increase in nucleosomal DNA length is predicted to stabilize the association of DNA with histones and therefore to prevent nucleosomes from unwrapping. This provides a mechanistic explanation for the gene silencing associated with K12Bio H4. The proposed single-molecule AFM approach will be instrumental for studying the effects of various epigenetic modifications of nucleosomes, in addition to biotinylation. PMID- 21298004 TI - Immunological and metabolomic impacts of administration of Cry1Ab protein and MON 810 maize in mouse. AB - We have investigated the immunological and metabolomic impacts of Cry1Ab administration to mice, either as a purified protein or as the Cry1Ab-expressing genetically modified (GM) MON810 maize. Humoral and cellular specific immune responses induced in BALB/cJ mice after intra-gastric (i.g.) or intra-peritoneal (i.p.) administration of purified Cry1Ab were analyzed and compared with those induced by proteins of various immunogenic and allergic potencies. Possible unintended effects of the genetic modification on the pattern of expression of maize natural allergens were studied using IgE-immunoblot and sera from maize allergic patients. Mice were experimentally sensitized (i.g. or i.p. route) with protein extracts from GM or non-GM maize, and then anti-maize proteins and anti Cry1Ab-induced immune responses were analyzed. In parallel, longitudinal metabolomic studies were performed on the urine of mice treated via the i.g. route. Weak immune responses were observed after i.g. administration of the different proteins. Using the i.p. route, a clear Th2 response was observed with the known allergenic proteins, whereas a mixed Th1/Th2 immune response was observed with immunogenic protein not known to be allergenic and with Cry1Ab. This then reflects protein immunogenicity in the BALB/c Th2-biased mouse strain rather than allergenicity. No difference in natural maize allergen profiles was evidenced between MON810 and its non-GM comparator. Immune responses against maize proteins were quantitatively equivalent in mice treated with MON810 vs the non-GM counterpart and no anti-Cry1Ab-specific immune response was detected in mice that received MON810. Metabolomic studies showed a slight "cultivar" effect, which represented less than 1% of the initial metabolic information. Our results confirm the immunogenicity of purified Cry1Ab without evidence of allergenic potential. Immunological and metabolomic studies revealed slight differences in mouse metabolic profiles after i.g. administration of MON810 vs its non-GM counterpart, but no significant unintended effect of the genetic modification on immune responses was seen. PMID- 21298005 TI - Neurotransmitter Transporter-Like: a male germline-specific SLC6 transporter required for Drosophila spermiogenesis. AB - The SLC6 class of membrane transporters, known primarily as neurotransmitter transporters, is increasingly appreciated for its roles in nutritional uptake of amino acids and other developmentally specific functions. A Drosophila SLC6 gene, Neurotransmitter transporter-like (Ntl), is expressed only in the male germline. Mobilization of a transposon inserted near the 3' end of the Ntl coding region yields male-sterile mutants defining a single complementation group. Germline transformation with Ntl cDNAs under control of male germline-specific control elements restores Ntl/Ntl homozygotes to normal fertility, indicating that Ntl is required only in the germ cells. In mutant males, sperm morphogenesis appears normal, with elongated, individualized and coiled spermiogenic cysts accumulating at the base of the testes. However, no sperm are transferred to the seminal vesicle. The level of polyglycylation of Ntl mutant sperm tubulin appears to be significantly lower than that of wild type controls. Glycine transporters are the most closely related SLC6 transporters to Ntl, suggesting that Ntl functions as a glycine transporter in developing sperm, where augmentation of the cytosolic pool of glycine may be required for the polyglycylation of the massive amounts of tubulin in the fly's giant sperm. The male-sterile phenotype of Ntl mutants may provide a powerful genetic system for studying the function of an SLC6 transporter family in a model organism. PMID- 21298006 TI - Secreted amyloid precursor protein beta and secreted amyloid precursor protein alpha induce axon outgrowth in vitro through Egr1 signaling pathway. AB - BACKGROUND: sAPPalpha released after alpha secretase cleavage of Amyloid Precursor Protein (APP) has several functions including the stimulation of neurite outgrowth although detailed morphometric analysis has not been done. Two domains involved in this function have been described and are present in sAPPbeta released at the first step of amyloid peptide cleavage, raising the possibility that sAPPbeta could also stimulate neurite outgrowth. We investigated the morphological effects of sAPPalpha and sAPPbeta on primary neurons and identified a key signaling event required for the changes observed. METHODOLOGY/PRINCIPAL FINDINGS: Final concentrations of 50 to 150 nM bacterial recombinant sAPPalpha or sAPPbeta added to primary neuronal cultures after 1 day in vitro decreased cell adhesion 24 hours later and primary dendrite length 96 hours later. 150 nM sAPPalpha and sAPPbeta induced a similar increase of axon outgrowth, although this increase was already significant at 100 nM sAPPalpha. These morphological changes induced by sAPPs were also observed when added to differentiated neurons at 5 days in vitro. Real time PCR and immunocytochemistry showed that sAPPalpha and sAPPbeta stimulated Egr1 expression downstream of MAPK/ERK activation. Furthermore, in primary neurons from Egr1 -/- mice, sAPPs affected dendritic length but did not induce any increase of axon length. CONCLUSION/SIGNIFICANCE: sAPPalpha and sAPPbeta decrease cell adhesion and increase axon elongation. These morphological changes are similar to what has been observed in response to heparan sulfate. The sAPPalpha/sAPPbeta stimulated increase in axon growth requires Egr1 signaling. These data suggest that sAPPbeta is not deleterious per se. Since sAPPbeta and sAPPalpha are present in the embryonic brain, these two APP metabolites might play a role in axon outgrowth during development and in response to brain damage. PMID- 21298007 TI - Molecular evolutionary analysis of ABCB5: the ancestral gene is a full transporter with potentially deleterious single nucleotide polymorphisms. AB - BACKGROUND: ABCB5 is a member of the ABC protein superfamily, which includes the transporters ABCB1, ABCC1 and ABCG2 responsible for causing drug resistance in cancer patients and also several other transporters that have been linked to human disease. The ABCB5 full transporter (ABCB5.ts) is expressed in human testis and its functional significance is presently unknown. Another variant of this transporter, ABCB5 beta possess a "half-transporter-like" structure and is expressed in melanoma stem cells, normal melanocytes, and other types of pigment cells. ABCB5 beta has important clinical implications, as it may be involved with multidrug resistance in melanoma stem cells, allowing these stem cells to survive chemotherapeutic regimes. METHODOLOGY/PRINCIPAL FINDINGS: We constructed and examined in detail topological structures of the human ABCB5 protein and determined in-silico the cSNPs (coding single nucleotide polymorphisms) that may affect its function. Evolutionary analysis of ABCB5 indicated that ABCB5, ABCB1, ABCB4, and ABCB11 share a common ancestor, which began duplicating early in the evolutionary history of chordates. This suggests that ABCB5 has evolved as a full transporter throughout its evolutionary history. CONCLUSIONS/SIGNIFICANCE: From our in-silco analysis of cSNPs we found that a large number of non-synonymous cSNPs map to important functional regions of the protein suggesting that these SNPs if present in human populations may play a role in diseases associated with ABCB5. From phylogenetic analyses, we have shown that ABCB5 evolved as a full transporter throughout its evolutionary history with an absence of any major shifts in selection between the various lineages suggesting that the function of ABCB5 has been maintained during mammalian evolution. This finding would suggest that ABCB5 beta may have evolved to play a specific role in human pigment cells and/or melanoma cells where it is predominantly expressed. PMID- 21298008 TI - MicroRNA profile predicts recurrence after resection in patients with hepatocellular carcinoma within the Milan Criteria. AB - OBJECTIVE: Hepatocellular carcinoma (HCC) is difficult to manage due to the high frequency of post-surgical recurrence. Early detection of the HCC recurrence after liver resection is important in making further therapeutic options, such as salvage liver transplantation. In this study, we utilized microRNA expression profiling to assess the risk of HCC recurrence after liver resection. METHODS: We examined microRNA expression profiling in paired tumor and non-tumor liver tissues from 73 HCC patients who satisfied the Milan Criteria. We constructed prediction models of recurrence-free survival using the Cox proportional hazard model and principal component analysis. The prediction efficiency was assessed by the leave-one-out cross-validation method, and the time-averaged area under the ROC curve (ta-AUROC). RESULTS: The univariate Cox analysis identified 13 and 56 recurrence-related microRNAs in the tumor and non-tumor tissues, such as miR-96. The number of recurrence-related microRNAs was significantly larger in the non tumor-derived microRNAs (N-miRs) than in the tumor-derived microRNAs (T-miRs, P<0.0001). The best ta-AUROC using the whole dataset, T-miRs, N-miRs, and clinicopathological dataset were 0.8281, 0.7530, 0.7152, and 0.6835, respectively. The recurrence-free survival curve of the low-risk group stratified by the best model was significantly better than that of the high-risk group (Log rank: P = 0.00029). The T-miRs tend to predict early recurrence better than late recurrence, whereas N-miRs tend to predict late recurrence better (P<0.0001). This finding supports the concept of early recurrence by the dissemination of primary tumor cells and multicentric late recurrence by the 'field effect'. CONCLUSION: MicroRNA profiling can predict HCC recurrence in Milan criteria cases. PMID- 21298009 TI - The substrate-driven transition to an inward-facing conformation in the functional mechanism of the dopamine transporter. AB - BACKGROUND: The dopamine transporter (DAT), a member of the neurotransmitter:Na(+) symporter (NSS) family, terminates dopaminergic neurotransmission and is a major molecular target for psychostimulants such as cocaine and amphetamine, and for the treatment of attention deficit disorder and depression. The crystal structures of the prokaryotic NSS homolog of DAT, the leucine transporter LeuT, have provided critical structural insights about the occluded and outward-facing conformations visited during the substrate transport, but only limited clues regarding mechanism. To understand the transport mechanism in DAT we have used a homology model based on the LeuT structure in a computational protocol validated previously for LeuT, in which steered molecular dynamics (SMD) simulations guide the substrate along a pathway leading from the extracellular end to the intracellular (cytoplasmic) end. METHODOLOGY/PRINCIPAL FINDINGS: Key findings are (1) a second substrate binding site in the extracellular vestibule, and (2) models of the conformational states identified as occluded, doubly occupied, and inward-facing. The transition between these states involve a spatially ordered sequence of interactions between the two substrate-binding sites, followed by rearrangements in structural elements located between the primary binding site and the cytoplasmic end. These rearrangements are facilitated by identified conserved hinge regions and a reorganization of interaction networks that had been identified as gates. CONCLUSIONS/SIGNIFICANCE: Computational simulations supported by information available from experiments in DAT and other NSS transporters have produced a detailed mechanistic proposal for the dynamic changes associated with substrate transport in DAT. This allosteric mechanism is triggered by the binding of substrate in the S2 site in the presence of the substrate in the S1 site. Specific structural elements involved in this mechanism, and their roles in the conformational transitions illuminated here describe, a specific substrate-driven allosteric mechanism that is directly amenable to experiment as shown previously for LeuT. PMID- 21298010 TI - Subnormal cytokine profile in the tear fluid of keratoconus patients. AB - Keratoconus, historically viewed as a non-inflammatory disease, is an ectatic corneal disorder associated with progressive thinning of the corneal stroma. Recently, a few inflammatory mediators have been reported to be elevated in the tear fluid of keratoconus patients. Consequently, we investigated a wide range of inflammation regulating cytokines in the tears and sera of keratoconus and control subjects. Interleukin (IL)-1beta, IL-4, IL-6, IL-10, IL-12, IL-13, IL-17, interferon (IFN)-gamma, chemokine C-C motif ligand 5 (CCL5) and tumor necrosis factor (TNF)-alpha were tested in tear samples and sera of keratoconus and control individuals by multiplex immuno-bead assays. Selected cytokines were further tested by standard ELISA on pooled tear samples. All cytokines in the sera were generally low, with no significant changes between keratoconus and control subjects. However, in tear fluids, clear differences were detected between the two groups. These differences include increased IL-6, and decreased IL-12, TNF-alpha, IFN-gamma, IL-4, IL-13 and CCL5 in keratoconus compared to control tear fluids. The decreases in IL-12, TNF-alpha and CCL5 were statistically significant, while the IL-13 decrease was statistically significant in the severe keratoconus group only. IL-17 could not be detected by multiplex immuno-bead assay, but showed an increase in keratoconus by conventional ELISA on a limited number of pooled tear samples. Our findings confirm increased IL-6, but dispute earlier reports of increased TNF-alpha, and suggest a cytokine imbalance in keratoconus disrupting corneal homeostasis. Moreover, an increase in IL-17 suggests tissue degenerative processes at work, contributing to the thinning and weakening of the corneal connective tissue in keratoconus. PMID- 21298011 TI - Characterization of dendritic cells subpopulations in skin and afferent lymph in the swine model. AB - Transcutaneous delivery of vaccines to specific skin dendritic cells (DC) subsets is foreseen as a promising strategy to induce strong and specific types of immune responses such as tolerance, cytotoxicity or humoral immunity. Because of striking histological similarities between human and pig skin, pig is recognized as the most suitable model to study the cutaneous delivery of medicine. Therefore improving the knowledge on swine skin DC subsets would be highly valuable to the skin vaccine field. In this study, we showed that pig skin DC comprise the classical epidermal langerhans cells (LC) and dermal DC (DDC) that could be divided in 3 subsets according to their phenotypes: (1) the CD163(neg)/CD172a(neg), (2) the CD163(high)CD172a(pos) and (3) the CD163(low)CD172a(pos) DDC. These subtypes have the capacity to migrate from skin to lymph node since we detected them in pseudo-afferent lymph. Extensive phenotyping with a set of markers suggested that the CD163(high) DDC resemble the antibody response-inducing human skin DC/macrophages whereas the CD163(neg)CD172(low) DDC share properties with the CD8(+) T cell response inducing murine skin CD103(pos) DC. This work, by showing similarities between human, mouse and swine skin DC, establishes pig as a model of choice for the development of transcutaneous immunisation strategies targeting DC. PMID- 21298012 TI - Pituitary stalk interruption syndrome: diagnostic delay and sensitivity of the auxological criteria of the growth hormone research society. AB - OBJECTIVES: To study the diagnostic delay for pituitary stalk interruption syndrome (PSIS) with growth hormone deficiency (GHD) and the sensitivity of the auxological criteria of the Growth Hormone Research Society (GHRS) consensus guidelines. METHODS: A single-center retrospective case-cohort study covering records from January 2000 through December 2007 evaluated the performance of each GHRS auxological criterion for patients with GHD and PSIS. Diagnostic delay was calculated as the difference between the age at which the earliest GHRS criterion could have been observed and the age at diagnosis of PSIS with GHD. A diagnostic delay exceeding one year was defined as late diagnosis. RESULTS: The study included 21 patients, 16 (76%) of whom had isolated GHD and 5 (24%) multiple pituitary hormone deficiencies. The median age at diagnosis was 3.6 years (interquartile range, IQR, 2.6-5.5). The median diagnostic delay was 2.3 years (range 0-12.6; IQR 1.5-3.6), with late diagnosis for 17 patients (81%). Height more than 1.5 SDS below target height was the most effective criterion: 90% of the patients met the criterion before diagnosis at a median age of 1 year, and it was the first criterion to be fulfilled for 84%. CONCLUSION: In our cohort, the delay for diagnosis of PSIS with GHD was long and could have been reduced by using the GHRS criteria, in particular, height more than 1.5 SDS below the target height. The specificity of such a strategy needs to be tested in healthy populations. PMID- 21298014 TI - Downregulation of cinnamyl-alcohol dehydrogenase in switchgrass by RNA silencing results in enhanced glucose release after cellulase treatment. AB - Cinnamyl alcohol dehydrogenase (CAD) catalyzes the last step in monolignol biosynthesis and genetic evidence indicates CAD deficiency in grasses both decreases overall lignin, alters lignin structure and increases enzymatic recovery of sugars. To ascertain the effect of CAD downregulation in switchgrass, RNA mediated silencing of CAD was induced through Agrobacterium mediated transformation of cv. "Alamo" with an inverted repeat construct containing a fragment derived from the coding sequence of PviCAD2. The resulting primary transformants accumulated less CAD RNA transcript and protein than control transformants and were demonstrated to be stably transformed with between 1 and 5 copies of the T-DNA. CAD activity against coniferaldehyde, and sinapaldehyde in stems of silenced lines was significantly reduced as was overall lignin and cutin. Glucose release from ground samples pretreated with ammonium hydroxide and digested with cellulases was greater than in control transformants. When stained with the lignin and cutin specific stain phloroglucinol-HCl the staining intensity of one line indicated greater incorporation of hydroxycinnamyl aldehydes in the lignin. PMID- 21298013 TI - Expanding the diversity of mycobacteriophages: insights into genome architecture and evolution. AB - Mycobacteriophages are viruses that infect mycobacterial hosts such as Mycobacterium smegmatis and Mycobacterium tuberculosis. All mycobacteriophages characterized to date are dsDNA tailed phages, and have either siphoviral or myoviral morphotypes. However, their genetic diversity is considerable, and although sixty-two genomes have been sequenced and comparatively analyzed, these likely represent only a small portion of the diversity of the mycobacteriophage population at large. Here we report the isolation, sequencing and comparative genomic analysis of 18 new mycobacteriophages isolated from geographically distinct locations within the United States. Although no clear correlation between location and genome type can be discerned, these genomes expand our knowledge of mycobacteriophage diversity and enhance our understanding of the roles of mobile elements in viral evolution. Expansion of the number of mycobacteriophages grouped within Cluster A provides insights into the basis of immune specificity in these temperate phages, and we also describe a novel example of apparent immunity theft. The isolation and genomic analysis of bacteriophages by freshman college students provides an example of an authentic research experience for novice scientists. PMID- 21298016 TI - Earthworm effects without earthworms: inoculation of raw organic matter with worm worked substrates alters microbial community functioning. AB - BACKGROUND: Earthworms are key organisms in organic matter decomposition because of the interactions they establish with soil microorganisms. They enhance decomposition rates through the joint action of direct effects (i.e. effects due to direct earthworm activity such as digestion, burrowing, etc) and indirect effects (i.e. effects derived from earthworm activities such as cast ageing). Here we test whether indirect earthworm effects affect microbial community functioning in the substrate, as when earthworms are present (i. e., direct effects). METHODOLOGY/PRINCIPAL FINDINGS: To address these questions we inoculated fresh organic matter (pig manure) with worm-worked substrates (vermicompost) produced by three different earthworm species. Two doses of each vermicompost were used (2.5 and 10%). We hypothesized that the presence of worm worked material in the fresh organic matter will result in an inoculum of different microorganisms and nutrients. This inoculum should interact with microbial communities in fresh organic matter, thus promoting modifications similar to those found when earthworms are present. Inoculation of worm-worked substrates provoked significant increases in microbial biomass and enzyme activities (beta-glucosidase, cellulase, phosphatase and protease). These indirect effects were similar to, although lower than, those obtained in pig manure with earthworms (direct and indirect earthworm effects). In general, the effects were not dose-dependent, suggesting the existence of a threshold at which they were triggered. CONCLUSION/SIGNIFICANCE: Our data reveal that the relationships between earthworms and microorganisms are far from being understood, and suggest the existence of several positive feedbacks during earthworm activity as a result of the interactions between direct and indirect effects, since their combination produces stronger modifications to microbial biomass and enzyme activity. PMID- 21298015 TI - Highly selective end-tagged antimicrobial peptides derived from PRELP. AB - BACKGROUND: Antimicrobial peptides (AMPs) are receiving increasing attention due to resistance development against conventional antibiotics. Pseudomonas aeruginosa and Staphylococcus aureus are two major pathogens involved in an array of infections such as ocular infections, cystic fibrosis, wound and post-surgery infections, and sepsis. The goal of the study was to design novel AMPs against these pathogens. METHODOLOGY AND PRINCIPAL FINDINGS: Antibacterial activity was determined by radial diffusion, viable count, and minimal inhibitory concentration assays, while toxicity was evaluated by hemolysis and effects on human epithelial cells. Liposome and fluorescence studies provided mechanistic information. Protease sensitivity was evaluated after subjection to human leukocyte elastase, staphylococcal aureolysin and V8 proteinase, as well as P. aeruginosa elastase. Highly active peptides were evaluated in ex vivo skin infection models. C-terminal end-tagging by W and F amino acid residues increased antimicrobial potency of the peptide sequences GRRPRPRPRP and RRPRPRPRP, derived from proline arginine-rich and leucine-rich repeat protein (PRELP). The optimized peptides were antimicrobial against a range of gram-positive S. aureus and gram negative P. aeruginosa clinical isolates, also in the presence of human plasma and blood. Simultaneously, they showed low toxicity against mammalian cells. Particularly W-tagged peptides displayed stability against P. aeruginosa elastase, and S. aureus V8 proteinase and aureolysin, and the peptide RRPRPRPRPWWWW-NH(2) was effective against various "superbugs" including vancomycin-resistant enterococci, multi-drug resistant P. aeruginosa, and methicillin-resistant S. aureus, as well as demonstrated efficiency in an ex vivo skin wound model of S. aureus and P. aeruginosa infection. CONCLUSIONS/SIGNIFICANCE: Hydrophobic C-terminal end-tagging of the cationic sequence RRPRPRPRP generates highly selective AMPs with potent activity against multiresistant bacteria and efficiency in ex vivo wound infection models. A precise "tuning" of toxicity and proteolytic stability may be achieved by changing tag-length and adding W- or F-amino acid tags. PMID- 21298017 TI - HNF4alpha dysfunction as a molecular rational for cyclosporine induced hypertension. AB - Induction of tolerance against grafted organs is achieved by the immunosuppressive agent cyclosporine, a prominent member of the calcineurin inhibitors. Unfortunately, its lifetime use is associated with hypertension and nephrotoxicity. Several mechanism for cyclosporine induced hypertension have been proposed, i.e. activation of the sympathetic nervous system, endothelin-mediated systemic vasoconstriction, impaired vasodilatation secondary to reduction in prostaglandin and nitric oxide, altered cytosolic calcium translocation, and activation of the renin-angiotensin system (RAS). In this regard the molecular basis for undue RAS activation and an increased signaling of the vasoactive oligopeptide angiotensin II (AngII) remain elusive. Notably, angiotensinogen (AGT) is the precursor of AngII and transcriptional regulation of AGT is controlled by the hepatic nuclear factor HNF4alpha. To better understand the molecular events associated with cyclosporine induced hypertension, we investigated the effect of cyclosporine on HNF4alpha expression and activity and searched for novel HNF4alpha target genes among members of the RAS cascade. Using bioinformatic algorithm and EMSA bandshift assays we identified angiotensin II receptor type 1 (AGTR1), angiotensin I converting enzyme (ACE), and angiotensin I converting enzyme 2 (ACE2) as genes targeted by HNF4alpha. Notably, cyclosporine represses HNF4alpha gene and protein expression and its DNA-binding activity at consensus sequences to AGT, AGTR1, ACE, and ACE2. Consequently, the gene expression of AGT, AGTR1, and ACE2 was significantly reduced as evidenced by quantitative real-time RT-PCR. While RAS is composed of a sophisticated interplay between multiple factors we propose a decrease of ACE2 to enforce AngII signaling via AGTR1 to ultimately result in vasoconstriction and hypertension. Taken collectively we demonstrate cyclosporine to repress HNF4alpha activity through calcineurin inhibitor mediated inhibition of nuclear factor of activation of T cells (NFAT) which in turn represses HNF4alpha that leads to a disturbed balance of RAS. PMID- 21298018 TI - Estimating the magnitude and direction of altered arbovirus transmission due to viral phenotype. AB - Vectorial capacity is a measure of the transmission potential of a vector borne pathogen within a susceptible population. Vector competence, a component of the vectorial capacity equation, is the ability of an arthropod to transmit an infectious agent following exposure to that agent. Comparisons of arbovirus strain-specific vector competence estimates have been used to support observed or hypothesized differences in transmission capability. Typically, such comparisons are made at a single time point during the extrinsic incubation period, the time in days it takes for the virus to replicate and disseminate to the salivary glands. However, vectorial capacity includes crucial parameters needed to effectively evaluate transmission capability, though often this is based on the discrete vector competence values. Utilization of the rate of change of vector competence over a range of days gives a more accurate measurement of the transmission potential. Accordingly, we investigated the rate of change in vector competence of dengue virus in Aedes aegypti mosquitoes and the resulting vectorial capacity curves. The areas under the curves represent the effective vector competence and the cumulative transmission potentials of arboviruses within a population of mosquitoes. We used the calculated area under the curve for each virus strain and the corresponding variance estimates to test for differences in cumulative transmission potentials between strains of dengue virus based on our dynamic model. To further characterize differences between dengue strains, we devised a displacement index interpreted as the capability of a newly introduced strain to displace the established, dominant circulating strain. The displacement index can be used to better understand the transmission dynamics in systems where multiple strains/serotypes circulate or even multiple arbovirus species. The use of a rate of a rate of change based model of vectorial capacity and the informative calculations of the displacement index will lead to better measurements of the differences in transmission potential of arboviruses. PMID- 21298019 TI - Geographic proximity not a prerequisite for invasion: Hawaii not the source of California invasion by light brown apple moth (Epiphyas postvittana). AB - BACKGROUND: The light brown apple moth (LBAM), Epiphyas postvittana (Walker), is native to Australia but invaded England, New Zealand, and Hawaii more than 100 years ago. In temperate climates, LBAM can be a major agricultural pest. In 2006 LBAM was discovered in California, instigating eradication efforts and quarantine against Hawaiian agriculture, the assumption being that Hawaii was the source of the California infestation. Genetic relationships among populations in Hawaii, California, and New Zealand are crucial to understanding LBAM invasion dynamics across the Pacific. METHODOLOGY/PRINCIPAL FINDINGS: We sequenced mitochondrial DNA (mtDNA) from 1293 LBAM individuals from California (695), Hawaii (448), New Zealand (147), and Australia (3) to examine haplotype diversity and structure among introduced populations, and evaluate the null hypothesis that invasive populations are from a single panmictic source. However, invasive populations in California and New Zealand harbor deep genetic diversity, whereas Hawaii shows low level, shallow diversity. CONCLUSIONS/SIGNIFICANCE: LBAM recently has established itself in California, but was in Hawaii and New Zealand for hundreds of generations, yet California and New Zealand show similar levels of genetic diversity relative to Hawaii. Thus, there is no clear relationship between duration of invasion and genetic structure. Demographic statistics suggest rapid expansion occurring in California and past expansions in New Zealand; multiple introductions of diverse, genetically fragmented lineages could contribute to these patterns. Hawaii and California share no haplotypes, therefore, Hawaii is not the source of the California introduction. Paradoxically, Hawaii and California share multiple haplotypes with New Zealand. New Zealand may be the source for the California and Hawaii infestations, but the introductions were independent, and Hawaii was invaded only once. This has significant implications for quarantine, and suggests that probability of invasion is not directly related to geographic distance. Surprisingly, Hawaiian LBAM populations have much lower genetic diversity than California, despite being older. PMID- 21298020 TI - Neisseria gonorrhoeae infection induces altered amphiregulin processing and release. AB - Adhesion of the human pathogen Neisseria gonorrhoeae has established effects on the host cell and evokes a variety of cellular events including growth factor activation. In the present study we report that infection with N. gonorrhoeae causes altered amphiregulin processing and release in human epithelial cells. Amphiregulin is a well-studied growth factor with functions in various cell processes and is upregulated in different forms cancer and proliferative diseases. The protein is prototypically cleaved on the cell surface in response to external stimuli. We demonstrate that upon infection, a massive upregulation of amphiregulin mRNA is seen. The protein changes its subcellular distribution and is also alternatively cleaved at the plasma membrane, which results in augmented release of an infection-specific 36 kDa amphiregulin product from the surface of human cervical epithelial cells. Further, using antibodies directed against different domains of the protein we could determine the impact of infection on pro-peptide processing. In summary, we present data showing that the infection of N. gonorrhoeae causes an alternative amphiregulin processing, subcellular distribution and release in human epithelial cervical cells that likely contribute to the predisposition cellular abnormalities and anti-apoptotic features of N. gonorrhoeae infections. PMID- 21298021 TI - Allelic diversity of the Plasmodium falciparum erythrocyte membrane protein 1 entails variant-specific red cell surface epitopes. AB - The clonally variant Plasmodium falciparum PfEMP1 adhesin is a virulence factor and a prime target of humoral immunity. It is encoded by a repertoire of functionally differentiated var genes, which display architectural diversity and allelic polymorphism. Their serological relationship is key to understanding the evolutionary constraints on this gene family and rational vaccine design. Here, we investigated the Palo Alto/VarO and IT4/R29 and 3D7/PF13_003 parasites lines. VarO and R29 form rosettes with uninfected erythrocytes, a phenotype associated with severe malaria. They express an allelic Cys2/group A NTS-DBL1alpha(1) PfEMP1 domain implicated in rosetting, whose 3D7 ortholog is encoded by PF13_0003. Using these three recombinant NTS-DBL1alpha(1) domains, we elicited antibodies in mice that were used to develop monovariant cultures by panning selection. The 3D7/PF13_0003 parasites formed rosettes, revealing a correlation between sequence identity and virulence phenotype. The antibodies cross-reacted with the allelic domains in ELISA but only minimally with the Cys4/group B/C PFL1955w NTS DBL1alpha. By contrast, they were variant-specific in surface seroreactivity of the monovariant-infected red cells by FACS analysis and in rosette-disruption assays. Thus, while ELISA can differentiate serogroups, surface reactivity assays define the more restrictive serotypes. Irrespective of cumulated exposure to infection, antibodies acquired by humans living in a malaria-endemic area also displayed a variant-specific surface reactivity. Although seroprevalence exceeded 90% for each rosetting line, the kinetics of acquisition of surface-reactive antibodies differed in the younger age groups. These data indicate that humans acquire an antibody repertoire to non-overlapping serotypes within a serogroup, consistent with an antibody-driven diversification pressure at the population level. In addition, the data provide important information for vaccine design, as production of a vaccine targeting rosetting PfEMP1 adhesins will require engineering to induce variant-transcending responses or combining multiple serotypes to elicit a broad spectrum of immunity. PMID- 21298022 TI - Liquid based material from fine needle aspirates from breast carcinomas offers the possibility of long-time storage without significant loss of immunoreactivity of estrogen and progesterone receptors. AB - BACKGROUND: Estrogen receptor (ER) status and progesterone receptor (PgR) status are strong prognostic and predictive markers in breast carcinomas. Steroid receptors are fragile and optimal handling of both cytological and histological material, including fixation, is crucial. Liquid based material offers the possibility to prepare a number of slides from one lesion and is increasingly being used for immunocytochemistry. It also offers the possibility to prepare several smears and to store these at different temperatures as well as storing residual material in the liquid. MATERIALS AND METHODS: The samples consisted of fine needle aspirate material from 53 breast carcinomas. Direct smears and liquid based preparations were used in parallel for immunocytochemical detection of ER and PgR receptor status. Slides from liquid suspensions were stored at -20 degrees C and -74 degrees C for 3 and 6 months, respectively. Direct smears were fixed primarily in 4% formalin. Liquid based specimens were post-fixed in 4% formalin. All specimens were subjected to microwave-stimulated epitope retrieval. Antibody concentrations were ER 1:150 and PgR 1:200 for both preparation methods. The immunostaining program was identical for both the methods. RESULTS: Liquid based specimens had a statistically non-significant higher percentage of positive cases compared to direct smears. Specimens prepared from liquid suspensions and stored at -20 degrees C and -74 degrees C for 3 and 6 months, respectively, showed a virtually unchanged ER and PgR reactivity (P = 0.002). CONCLUSIONS: Liquid suspensions and liquid based slide preparations seem to offer an optimal pre-fixation and preservation of ER/PgR in breast carcinoma cells. Post-fixation with 4% formalin followed by microwave-stimulated epitope retrieval before immunostaining is recommended. Long-time storage of liquid based specimens at -20 degrees C or -74 degrees C for at least 6 months without significant loss of immunoreactivity is feasible. They may be used as internal positive and negative controls. PMID- 21298024 TI - Cytomorphology of cervicovaginal melanoma: ThinPrep versus conventional Papanicolaou tests. AB - BACKGROUND: Primary cervicovaginal melanoma is a rare malignancy associated with a high risk of recurrence. Prior studies discussing the cytomorphology of cervicovaginal melanoma have been based primarily on review of conventional Papanicolaou (Pap) smears. The aim of this study was to evaluate cervicovaginal melanomas identified in liquid-based Pap tests, in comparison with features seen on conventional Pap smear preparation. MATERIALS AND METHODS: Cases of cervicovaginal melanoma identified on Pap tests with concurrent or subsequent histopathologic confirmation were collected from the Baystate Medical Center cytopathology files and personal archives of the authors over a total period of 34 years. All cytopathology (n = 6) and the available histology slides (n = 5) were reviewed. Cases were analyzed regarding clinical, histopathologic and cytomorphological findings. RESULTS: A total of six cases with invasive cervicovaginal melanoma diagnosed on Pap tests were identified. Most patients were postmenopausal with contact bleeding, correlating with surface ulceration (identified in biopsy/excision material in 5/5 cases). Most cases had deeply invasive tumors (5/5: modified Breslow's thickness > 5 mm and Chung's level of invasion IV/V). Pap tests included four ThinPrep and two conventional smears. Overall, ThinPrep Pap tests exhibited a higher ratio of tumor cells to background squamous cells. While all Pap tests were bloodstained, tumor diathesis was prominent only within conventional smears. Melanoma cells were present both as clusters and scattered single cells in each Pap test type. Both the preparations contained epithelioid tumor cells, whereas spindled tumor cells were seen in only two ThinPrep cases. Prominent nucleoli and binucleation of tumor cells were seen in both the preparations. Melanin pigment was identified in only ThinPrep (3/4) cases and nuclear pseudo-inclusions in one conventional Pap smear. Cell blocks were made in three ThinPrep cases and immunocytochemistry (S-100, HMB45, Melan-A) performed on additional vial material (one ThinPrep slide and one cell block) was immunoreactive in melanoma cells. CONCLUSION: Primary cervicovaginal melanoma, a rare malignancy seen predominantly in postmenopausal women, may be successfully diagnosed in either ThinPrep Pap tests or conventional Pap smears. While ThinPrep Pap tests did not demonstrate morphological advantage over conventional smears, liquid-based cytology specimens did provide additional material for cellblock preparation and immunocytochemical evaluation in a subset of cases. PMID- 21298025 TI - Rescue of foot-and-mouth disease viruses that are pathogenic for cattle from preserved viral RNA samples. AB - BACKGROUND: Foot and mouth disease is an economically important disease of cloven hoofed animals including cattle, sheep and pigs. It is caused by a picornavirus, foot-and-mouth disease virus (FMDV), which has a positive sense RNA genome which, when introduced into cells, can initiate virus replication. PRINCIPAL FINDINGS: A system has been developed to rescue infectious FMDV from RNA preparations generated from clinical samples obtained under experimental conditions and then applied to samples collected in the "field". Clinical samples from suspect cases of foot-and-mouth disease (FMD) were obtained from within Pakistan and Afghanistan. The samples were treated to preserve the RNA and then transported to National Veterinary Institute, Lindholm, Denmark. Following RNA extraction, FMDV RNA was quantified by real-time RT-PCR and samples containing significant levels of FMDV RNA were introduced into susceptible cells using electroporation. Progeny viruses were amplified in primary bovine thyroid cells and characterized using antigen ELISA and also by RT-PCR plus sequencing. FMD viruses of three different serotypes and multiple lineages have been successfully rescued from the RNA samples. Two of the rescued viruses (of serotype O and Asia 1) were inoculated into bull calves under high containment conditions. Acute clinical disease was observed in each case which spread rapidly from the inoculated calves to in contact animals. Thus the rescued viruses were highly pathogenic. The availability of the rescued viruses enabled serotyping by antigen ELISA and facilitated genome sequencing. CONCLUSIONS: The procedure described here should improve the characterization of FMDVs circulating in countries where the disease is endemic and thus enhance disease control globally. PMID- 21298026 TI - Pressure and volume limited ventilation for the ventilatory management of patients with acute lung injury: a systematic review and meta-analysis. AB - BACKGROUND: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life threatening clinical conditions seen in critically ill patients with diverse underlying illnesses. Lung injury may be perpetuated by ventilation strategies that do not limit lung volumes and airway pressures. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing pressure and volume-limited (PVL) ventilation strategies with more traditional mechanical ventilation in adults with ALI and ARDS. METHODS AND FINDINGS: We searched Medline, EMBASE, HEALTHSTAR and CENTRAL, related articles on PubMedTM, conference proceedings and bibliographies of identified articles for randomized trials comparing PVL ventilation with traditional approaches to ventilation in critically ill adults with ALI and ARDS. Two reviewers independently selected trials, assessed trial quality, and abstracted data. We identified ten trials (n = 1,749) meeting study inclusion criteria. Tidal volumes achieved in control groups were at the lower end of the traditional range of 10 15 mL/kg. We found a clinically important but borderline statistically significant reduction in hospital mortality with PVL [relative risk (RR) 0.84; 95% CI 0.70, 1.00; p = 0.05]. This reduction in risk was attenuated (RR 0.90; 95% CI 0.74, 1.09, p = 0.27) in a sensitivity analysis which excluded 2 trials that combined PVL with open-lung strategies and stopped early for benefit. We found no effect of PVL on barotrauma; however, use of paralytic agents increased significantly with PVL (RR 1.37; 95% CI, 1.04, 1.82; p = 0.03). CONCLUSIONS: This systematic review suggests that PVL strategies for mechanical ventilation in ALI and ARDS reduce mortality and are associated with increased use of paralytic agents. PMID- 21298027 TI - A meta-analysis of genome-wide association scans identifies IL18RAP, PTPN2, TAGAP, and PUS10 as shared risk loci for Crohn's disease and celiac disease. AB - Crohn's disease (CD) and celiac disease (CelD) are chronic intestinal inflammatory diseases, involving genetic and environmental factors in their pathogenesis. The two diseases can co-occur within families, and studies suggest that CelD patients have a higher risk to develop CD than the general population. These observations suggest that CD and CelD may share common genetic risk loci. Two such shared loci, IL18RAP and PTPN2, have already been identified independently in these two diseases. The aim of our study was to explicitly identify shared risk loci for these diseases by combining results from genome wide association study (GWAS) datasets of CD and CelD. Specifically, GWAS results from CelD (768 cases, 1,422 controls) and CD (3,230 cases, 4,829 controls) were combined in a meta-analysis. Nine independent regions had nominal association p value <1.0 x 10-5 in this meta-analysis and showed evidence of association to the individual diseases in the original scans (p-value < 1 x 10-2 in CelD and < 1 x 10-3 in CD). These include the two previously reported shared loci, IL18RAP and PTPN2, with p-values of 3.37 x 10-8 and 6.39 x 10-9, respectively, in the meta analysis. The other seven had not been reported as shared loci and thus were tested in additional CelD (3,149 cases and 4,714 controls) and CD (1,835 cases and 1,669 controls) cohorts. Two of these loci, TAGAP and PUS10, showed significant evidence of replication (Bonferroni corrected p-values <0.0071) in the combined CelD and CD replication cohorts and were firmly established as shared risk loci of genome-wide significance, with overall combined p-values of 1.55 x 10-10 and 1.38 x 10-11 respectively. Through a meta-analysis of GWAS data from CD and CelD, we have identified four shared risk loci: PTPN2, IL18RAP, TAGAP, and PUS10. The combined analysis of the two datasets provided the power, lacking in the individual GWAS for single diseases, to detect shared loci with a relatively small effect. PMID- 21298028 TI - Horizontal transfer, not duplication, drives the expansion of protein families in prokaryotes. AB - Gene duplication followed by neo- or sub-functionalization deeply impacts the evolution of protein families and is regarded as the main source of adaptive functional novelty in eukaryotes. While there is ample evidence of adaptive gene duplication in prokaryotes, it is not clear whether duplication outweighs the contribution of horizontal gene transfer in the expansion of protein families. We analyzed closely related prokaryote strains or species with small genomes (Helicobacter, Neisseria, Streptococcus, Sulfolobus), average-sized genomes (Bacillus, Enterobacteriaceae), and large genomes (Pseudomonas, Bradyrhizobiaceae) to untangle the effects of duplication and horizontal transfer. After removing the effects of transposable elements and phages, we show that the vast majority of expansions of protein families are due to transfer, even among large genomes. Transferred genes--xenologs--persist longer in prokaryotic lineages possibly due to a higher/longer adaptive role. On the other hand, duplicated genes--paralogs--are expressed more, and, when persistent, they evolve slower. This suggests that gene transfer and gene duplication have very different roles in shaping the evolution of biological systems: transfer allows the acquisition of new functions and duplication leads to higher gene dosage. Accordingly, we show that paralogs share most protein-protein interactions and genetic regulators, whereas xenologs share very few of them. Prokaryotes invented most of life's biochemical diversity. Therefore, the study of the evolution of biology systems should explicitly account for the predominant role of horizontal gene transfer in the diversification of protein families. PMID- 21298029 TI - Rnf12--a jack of all trades in X inactivation? PMID- 21298030 TI - A cardinal role for cathepsin d in co-ordinating the host-mediated apoptosis of macrophages and killing of pneumococci. AB - The bactericidal function of macrophages against pneumococci is enhanced by their apoptotic demise, which is controlled by the anti-apoptotic protein Mcl-1. Here, we show that lysosomal membrane permeabilization (LMP) and cytosolic translocation of activated cathepsin D occur prior to activation of a mitochondrial pathway of macrophage apoptosis. Pharmacological inhibition or knockout of cathepsin D during pneumococcal infection blocked macrophage apoptosis. As a result of cathepsin D activation, Mcl-1 interacted with its ubiquitin ligase Mule and expression declined. Inhibition of cathepsin D had no effect on early bacterial killing but inhibited the late phase of apoptosis associated killing of pneumococci in vitro. Mice bearing a cathepsin D(-/-) hematopoietic system demonstrated reduced macrophage apoptosis in vivo, with decreased clearance of pneumococci and enhanced recruitment of neutrophils to control pulmonary infection. These findings establish an unexpected role for a cathepsin D-mediated lysosomal pathway of apoptosis in pulmonary host defense and underscore the importance of apoptosis-associated microbial killing to macrophage function. PMID- 21298031 TI - The pel polysaccharide can serve a structural and protective role in the biofilm matrix of Pseudomonas aeruginosa. AB - Bacterial extracellular polysaccharides are a key constituent of the extracellular matrix material of biofilms. Pseudomonas aeruginosa is a model organism for biofilm studies and produces three extracellular polysaccharides that have been implicated in biofilm development, alginate, Psl and Pel. Significant work has been conducted on the roles of alginate and Psl in biofilm development, however we know little regarding Pel. In this study, we demonstrate that Pel can serve two functions in biofilms. Using a novel assay involving optical tweezers, we demonstrate that Pel is crucial for maintaining cell-to-cell interactions in a PA14 biofilm, serving as a primary structural scaffold for the community. Deletion of pelB resulted in a severe biofilm deficiency. Interestingly, this effect is strain-specific. Loss of Pel production in the laboratory strain PAO1 resulted in no difference in attachment or biofilm development; instead Psl proved to be the primary structural polysaccharide for biofilm maturity. Furthermore, we demonstrate that Pel plays a second role by enhancing resistance to aminoglycoside antibiotics. This protection occurs only in biofilm populations. We show that expression of the pel gene cluster and PelF protein levels are enhanced during biofilm growth compared to liquid cultures. Thus, we propose that Pel is capable of playing both a structural and a protective role in P. aeruginosa biofilms. PMID- 21298032 TI - Pathogenesis of the 1918 pandemic influenza virus. PMID- 21298033 TI - TNF-alpha contributes to caspase-3 independent apoptosis in neuroblastoma cells: role of NFAT. AB - There is increasing evidence that soluble factors in inflammatory central nervous system diseases not only regulate the inflammatory process but also directly influence electrophysiological membrane properties of neurons and astrocytes. In this context, the cytokine TNF-alpha (tumor necrosis factor-alpha) has complex injury promoting, as well as protective, effects on neuronal viability. Up regulated TNF-alpha expression has also been found in various neurodegenerative diseases such as cerebral malaria, AIDS dementia, Alzheimer's disease, multiple sclerosis, and stroke, suggesting a potential pathogenic role of TNF-alpha in these diseases as well. We used the neuroblastoma cells SK-N-MC. Transcriptional activity was measured using luciferase reporter gene assays by using lipofectin. We performed cotransfection experiments of NFAT (nuclear factor of activated T cells) promoter constructed with a dominant negative version of NFAT (dn-NFAT). Cell death was performed by MTT (3-(4,5-dimethylthiazol-2-yl)5,5 diphenyltetrazolium bromide) and TUNEL assays. NFAT translocation was confirmed by Western blot. Involvement of NFAT in cell death was assessed by using VIVIT. P53, Fas-L, caspase-3, and caspase-9 expressions were carried out by Western blot. The mechanisms involved in TNF-alpha-induced cell death were assessed by using microarray analysis. TNF-alpha causes neuronal cell death in the absence of glia. TNF-alpha treatment results in nuclear translocation of NFAT through activation of calcineurin in a Ca(2+) independent manner. We demonstrated the involvement of FasL/Fas, cytochrome c, and caspase-9 but the lack of caspase-3 activation. NB cell death was absolutely reverted in the presence of VIVIT, and partially diminished by anti-Fas treatment. These data demonstrate that TNF-alpha promotes FasL expression through NFAT activation in neuroblastoma cells and this event leads to increased apoptosis through independent caspase-3 activation. PMID- 21298034 TI - Familial associations of adiposity: findings from a cross-sectional study of 12,181 parental-offspring trios from Belarus. AB - BACKGROUND: It is suggested that maternal adiposity has a stronger association with offspring adiposity than does paternal adiposity. Furthermore, a recent small study reported gender assortment in parental-offspring adiposity associations. We aimed to examine these associations in one of the largest studies to date using data from a low-middle income country that has recently undergone a major political and economic transition. METHODS AND PRINCIPAL FINDINGS: In a cross-sectional study of 12,181 parental-offspring trios from Belarus (mean age (SD) of mothers 31.7 (4.9), fathers 34.1 (5.1) and children 6.6 (0.3) at time of assessment), we found positive graded associations of mother's and father's BMI with offspring adiposity. There was no evidence that these associations differed between mothers and fathers. For example, the odds ratio of offspring overweight or obesity (based on BMI) comparing obese and overweight mothers to normal weight mothers was 2.03 (95%CI 1.77, 2.31) in fully adjusted models; the equivalent result for father's overweight/obesity was 1.81 (1.58, 2.07). Equivalent results for offspring being in the top 10% waist circumference were 1.91 (1.67, 2.18) comparing obese/overweight to normal weight mothers and 1.72 (1.53, 1.95) comparing obese/overweight to normal weight fathers. Similarly, results for offspring being in the top 10% of percent fat mass were 1.58 (1.36, 1.84) and 1.76 (1.49, 2.07), for mother's and father's obese/overweight exposures respectively. There was no strong or consistent evidence of gender assortment- i.e. associations of maternal adiposity exposures with offspring outcomes were similar in magnitude for their daughters compared to equivalent associations in their sons and paternal associations were also similar in sons and daughters. CONCLUSIONS/SIGNIFICANCE: These findings suggest that genetic and/or shared familial environment explain family clustering of adiposity. Interventions aimed at changing overall family lifestyle are likely to be important for population level obesity prevention. PMID- 21298035 TI - Platelet activating factor blocks interkinetic nuclear migration in retinal progenitors through an arrest of the cell cycle at the S/G2 transition. AB - Nuclear migration is regulated by the LIS1 protein, which is the regulatory subunit of platelet activating factor (PAF) acetyl-hydrolase, an enzyme complex that inactivates the lipid mediator PAF. Among other functions, PAF modulates cell proliferation, but its effects upon mechanisms of the cell cycle are unknown. Here we show that PAF inhibited interkinetic nuclear migration (IKNM) in retinal proliferating progenitors. The lipid did not, however, affect the velocity of nuclear migration in cells that escaped IKNM blockade. The effect depended on the PAF receptor, Erk and p38 pathways and Chk1. PAF induced no cell death, nor a reduction in nucleotide incorporation, which rules out an intra-S checkpoint. Notwithstanding, the expected increase in cyclin B1 content during G2 phase was prevented in the proliferating cells. We conclude that PAF blocks interkinetic nuclear migration in retinal progenitor cells through an unusual arrest of the cell cycle at the transition from S to G2 phases. These data suggest the operation, in the developing retina, of a checkpoint that monitors the transition from S to G2 phases of the cell cycle. PMID- 21298036 TI - Epigenetics underpinning the regulation of the CXC (ELR+) chemokines in non-small cell lung cancer. AB - BACKGROUND: Angiogenesis may play a role in the pathogenesis of Non-Small Cell Lung cancer (NSCLC). The CXC (ELR(+)) chemokine family are powerful promoters of the angiogenic response. METHODS: The expression of the CXC (ELR(+)) family members (CXCL1-3/GROalpha-gamma, CXCL8/IL-8, CXCR1/2) was examined in a series of resected fresh frozen NSCLC tumours. Additionally, the expression and epigenetic regulation of these chemokines was examined in normal bronchial epithelial and NSCLC cell lines. RESULTS: Overall, expression of the chemokine ligands (CXCL1, 2, 8) and their receptors (CXCR1/2) were down regulated in tumour samples compared with normal, with the exception of CXCL3. CXCL8 and CXCR1/2 were found to be epigenetically regulated by histone post-translational modifications. Recombinant CXCL8 did not stimulate cell growth in either a normal bronchial epithelial or a squamous carcinoma cell line (SKMES-1). However, an increase was observed at 72 hours post treatment in an adenocarcinoma cell line. CONCLUSIONS: CXC (ELR(+)) chemokines are dysregulated in NSCLC. The balance of these chemokines may be critical in the tumour microenvironment and requires further elucidation. It remains to be seen if epigenetic targeting of these pathways is a viable therapeutic option in lung cancer treatment. PMID- 21298037 TI - Fatty-acid binding proteins modulate sleep and enhance long-term memory consolidation in Drosophila. AB - Sleep is thought to be important for memory consolidation, since sleep deprivation has been shown to interfere with memory processing. However, the effects of augmenting sleep on memory formation are not well known, and testing the role of sleep in memory enhancement has been limited to pharmacological and behavioral approaches. Here we test the effect of overexpressing the brain-type fatty acid binding protein (Fabp7) on sleep and long-term memory (LTM) formation in Drosophila melanogaster. Transgenic flies carrying the murine Fabp7 or the Drosophila homologue dFabp had reduced baseline sleep but normal LTM, while Fabp induction produced increases in both net sleep and LTM. We also define a post training consolidation "window" that is sufficient for the observed Fabp-mediated memory enhancement. Since Fabp overexpression increases consolidated daytime sleep bouts, these data support a role for longer naps in improving memory and provide a novel role for lipid-binding proteins in regulating memory consolidation concurrently with changes in behavioral state. PMID- 21298038 TI - Development of fearfulness in birds: genetic factors modulate non-genetic maternal influences. AB - The development of fearfulness and the capacity of animals to cope with stressful events are particularly sensitive to early experience with mothers in a wide range of species. However, intrinsic characteristics of young animals can modulate maternal influence. This study evaluated the effect of intrinsic fearfulness on non-genetic maternal influence. Quail chicks, divergently selected for either higher (LTI) or lower fearfulness (STI) and from a control line (C), were cross-fostered by LTI or STI mothers. Behavioural tests estimated the chicks' emotional profiles after separation from the mother. Whatever their genotype, the fearfulness of chicks adopted by LTI mothers was higher than that of chicks adopted by STI mothers. However, genetic background affected the strength of maternal effects: the least emotional chicks (STI) were the least affected by early experience with mothers. We demonstrated that young animal's intrinsic fearfulness affects strongly their sensitivity to non-genetic maternal influences. A young animal's behavioural characteristics play a fundamental role in its own behavioural development processes. PMID- 21298040 TI - Optimal homogenization of perfusion flows in microfluidic bio-reactors: a numerical study. AB - In recent years, the interest in small-scale bio-reactors has increased dramatically. To ensure homogeneous conditions within the complete area of perfused microfluidic bio-reactors, we develop a general design of a continually feed bio-reactor with uniform perfusion flow. This is achieved by introducing a specific type of perfusion inlet to the reaction area. The geometry of these inlets are found using the methods of topology optimization and shape optimization. The results are compared with two different analytic models, from which a general parametric description of the design is obtained and tested numerically. Such a parametric description will generally be beneficial for the design of a broad range of microfluidic bioreactors used for, e.g., cell culturing and analysis and in feeding bio-arrays. PMID- 21298039 TI - Microarray analysis on human neuroblastoma cells exposed to aluminum, beta(1-42) amyloid or the beta(1-42)-amyloid aluminum complex. AB - BACKGROUND: A typical pathological feature of Alzheimer's disease (AD) is the appearance in the brain of senile plaques made up of beta-amyloid (Abeta) and neurofibrillary tangles. AD is also associated with an abnormal accumulation of some metal ions, and we have recently shown that one of these, aluminum (Al), plays a relevant role in affecting Abeta aggregation and neurotoxicity. METHODOLOGY: In this study, employing a microarray analysis of 35,129 genes, we investigated the effects induced by the exposure to the Abeta(1-42)-Al (Abeta-Al) complex on the gene expression profile of the neuronal-like cell line, SH-SY5Y. PRINCIPAL FINDINGS: The microarray assay indicated that, compared to Abeta or Al alone, exposure to Abeta-Al complex produced selective changes in gene expression. Some of the genes selectively over or underexpressed are directly related to AD. A further evaluation performed with Ingenuity Pathway analysis revealed that these genes are nodes of networks and pathways that are involved in the modulation of Ca(2+) homeostasis as well as in the regulation of glutamatergic transmission and synaptic plasticity. CONCLUSIONS AND SIGNIFICANCE: Abeta-Al appears to be largely involved in the molecular machinery that regulates neuronal as well as synaptic dysfunction and loss. Abeta-Al seems critical in modulating key AD-related pathways such as glutamatergic transmission, Ca(2+) homeostasis, oxidative stress, inflammation, and neuronal apoptosis. PMID- 21298041 TI - Prognostic impact of lymphocytes in soft tissue sarcomas. AB - PURPOSE: The purpose of this study was to clarify the prognostic significance of lymphocyte infiltration in soft tissue sarcomas (STS). Prognostic markers in potentially curable STS should guide therapy after surgical resection. The immune status at the time of resection may be important, but the prognostic significance of tumor infiltrating lymphocytes is controversial as the immune system has conflicting roles during cancer development. EXPERIMENTAL DESIGN: Tissue microarrays from 249 patients with STS were constructed from duplicate cores of viable and representative neoplastic tumor areas. Immunohistochemistry was used to evaluate the CD3+, CD4+, CD8+, CD20+ and CD45+ lymphocytes in tumors. RESULTS: In univariate analyses, increased numbers of CD4+ (P = 0.008) and CD20+ (P = 0.006) lymphocytes in tumor correlated significantly with an improved disease specific survival (DSS) in patients with wide resection margins (n = 108). In patients with non-wide resection margins (n = 141) increased numbers of CD3+ (P = 0.028) lymphocytes in tumor correlated significantly with shorter DSS. In multivariate analyses, a high number of CD20+ lymphocytes (HR = 5.5, CI 95% = 1.6-18.6, P = 0.006) in the tumor was an independent positive prognostic factor for DSS in patients with wide resections margins. CONCLUSIONS: High density of CD20+ lymphocytes in STS with wide resection margins is an independent positive prognostic indicator for these patients. Further research is needed to define if CD20+ cells can modify tumors in a way that reduces disease progression and metastatic potential. PMID- 21298042 TI - Neisseria meningitidis has two independent modes of recognizing its human receptor CEACAM1. AB - BACKGROUND: Several human-restricted gram-negative bacteria exploit carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) for host colonization. For example, Neisseria meningitidis engages these human receptors via outer membrane proteins of the colony opacity-associated (Opa) protein family triggering internalization into non-phagocytic cells. PRINCIPAL FINDINGS: We report that a non-opaque strain of N. meningitidis selectively interacts with CEACAM1, but not other CEACAM family members. Using functional assays of bacterial adhesion and internalisation, microscopic analysis, and a panel of CEACAM1 deletion mutants we demonstrate that the engagement of CEACAM1 by non opaque meningococci occurs in a manner distinct from Opa protein-mediated association. In particular, the amino-terminal domain of CEACAM1 is necessary, but not sufficient for Opa protein-independent binding, which requires multiple extracellular domains of the human receptor in a cellular context. Knock-down of CEACAM1 interferes with binding to lung epithelial cells, whereas chemical or pharmacological disruption of host protein glycosylation does not abrogate CEACAM1 recognition by non-opaque meningococci. The previously characterized meningococcal invasins NadA or Opc do not operate in a CEACAM1-dependent manner. CONCLUSIONS: The results demonstrate a mechanistically distinct, Opa protein independent interaction between N. meningitidis and human CEACAM1. Our functional investigations suggest the presence of a second CEACAM1-binding invasin on the meningococcal surface that associates with the protein backbone and not the carbohydrate structures of CEACAM1. The redundancy in meningococcal CEACAM1 binding factors further highlights the important role of CEACAM recognition in the biology of this human-adapted pathogen. PMID- 21298043 TI - Evaluation of an adjustable epidemiologic information system. AB - BACKGROUND: In order to facilitate public health response and to achieve early control of infectious disease epidemics, an adjustable epidemiologic information system (AEIS) was established in the Taiwan public health network in February 2006. METHODOLOGY/PRINCIPAL FINDINGS: The performance of AEIS for the period 2006 through 2008 was evaluated based on a number of response times (RT) and the public health impact. After implementation of the system, the apparent overall shortened RT was mainly due to the shortening of personnel response time (PRT) and the time needed to draft a new questionnaire that incurred as personnel system interface (PSI); PRT dropped from a fluctuating range of 9.8 ~28.8 days in the first four months to <10 days in the following months and remained low till 2008 (0.88+/-1.52 days). The PSIs for newly emerged infectious diseases were 2.6 and 3.4 person-hours for H5N1 in 2007 and chikungunya in 2008, respectively, a much improvement from 1142.5 person-hours for SARS in 2003. The duration of each rubella epidemic cluster was evaluated as public health impact and showed a shortening trend (p = 0.019) that concurred with the shortening of PRT from 64.8+/-47.3 to 25.2+/-38.2 hours per cluster (p<0.0001). CONCLUSIONS/SIGNIFICANCE: The first evaluation of the novel instrument AEIS that had been used to assist Taiwan's multi-level government for infectious diseases control demonstrated that it was well integrated into the existing public health infrastructure. It provided flexible tools and computer algorithms with friendly interface for timely data collection, integration, and analysis; as a result, it shortened RTs, filled in gaps of personnel lacking sufficient experiences, created a more efficient flow of response, and identified asymptomatic/mild cases early to minimize further spreading. With further development, AEIS is anticipated to be useful in the application of other acute public health events needing immediate orchestrated data collection and public health actions. PMID- 21298044 TI - Genetic variation among major human geographic groups supports a peculiar evolutionary trend in PAX9. AB - A total of 172 persons from nine South Amerindian, three African and one Eskimo populations were studied in relation to the Paired box gene 9 (PAX9) exon 3 (138 base pairs) as well as its 5'and 3'flanking intronic segments (232 bp and 220 bp, respectively) and integrated with the information available for the same genetic region from individuals of different geographical origins. Nine mutations were scored in exon 3 and six in its flanking regions; four of them are new South American tribe-specific singletons. Exon3 nucleotide diversity is several orders of magnitude higher than its intronic regions. Additionally, a set of variants in the PAX9 and 101 other genes related with dentition can define at least some dental morphological differences between Sub-Saharan Africans and non-Africans, probably associated with adaptations after the modern human exodus from Africa. Exon 3 of PAX9 could be a good molecular example of how evolvability works. PMID- 21298045 TI - Single-beat noninvasive imaging of ventricular endocardial and epicardial activation in patients undergoing CRT. AB - BACKGROUND: Little is known about the effect of cardiac resynchronization therapy (CRT) on endo- and epicardial ventricular activation. Noninvasive imaging of cardiac electrophysiology (NICE) is a novel imaging tool for visualization of both epi- and endocardial ventricular electrical activation. METHODOLOGY/PRINCIPAL FINDINGS: NICE was performed in ten patients with congestive heart failure (CHF) undergoing CRT and in ten patients without structural heart disease (control group). NICE is a fusion of data from high resolution ECG mapping with a model of the patient's individual cardiothoracic anatomy created from magnetic resonance imaging. Beat-to-beat endocardial and epicardial ventricular activation sequences were computed during native rhythm as well as during ventricular pacing using a bidomain theory-based heart model to solve the related inverse problem. During right ventricular (RV) pacing control patients showed a deterioration of the ventricular activation sequence similar to the intrinsic activation pattern of CHF patients. Left ventricular propagation velocities were significantly decreased in CHF patients as compared to the control group (1.6+/-0.4 versus 2.1+/-0.5 m/sec; p<0.05). CHF patients showed right-to-left septal activation with the latest activation epicardially in the lateral wall of the left ventricle. Biventricular pacing resulted in a resynchronization of the ventricular activation sequence and in a marked decrease of total LV activation duration as compared to intrinsic conduction and RV pacing (129+/-16 versus 157+/-28 and 173+/-25 ms; both p<0.05). CONCLUSIONS/SIGNIFICANCE: Endocardial and epicardial ventricular activation can be visualized noninvasively by NICE. Identification of individual ventricular activation properties may help identify responders to CRT and to further improve response to CRT by facilitating a patient-specific lead placement and device programming. PMID- 21298046 TI - Stress resistance and longevity are not directly linked to levels of enzymatic antioxidants in the ponerine ant Harpegnathos saltator. AB - BACKGROUND: The molecular mechanisms of variations in individual longevity are not well understood, even though longevity can be increased substantially by means of diverse experimental manipulations. One of the factors supposed to be involved in the increase of longevity is a higher stress resistance. To test this hypothesis in a natural system, eusocial insects such as bees or ants are ideally suited. In contrast to most other eusocial insects, ponerine ants show a peculiar life history that comprises the possibility to switch during adult life from a normal worker to a reproductive gamergate, therewith increasing their life expectancy significantly. RESULTS: We show that increased resistance against major stressors, such as reactive oxygen species and infection accompanies the switch from a life-history trait with normal lifespan to one with a longer life expectancy. A short period of social isolation was sufficient to enhance stress resistance of workers from the ponerine ant species Harpegnathos saltator significantly. All ant groups with increased stress resistances (reproducing gamergates and socially isolated workers) have lower catalase activities and glutathione levels than normal workers. Therewith, these ants resemble the characteristics of the youngest ants in the colony. CONCLUSIONS: Social insects with their specific life history including a switch from normal workers to reproducing gamergates during adult life are well suited for ageing research. The regulation of stress resistance in gamergates seemed to be modified compared to foraging workers in an economic way. Interestingly, a switch towards more stress resistant animals can also be induced by a brief period of social isolation, which may already be associated with a shift to a reproductive trajectory. In Harpegnathos saltator, stress resistances are differently and potentially more economically regulated in reproductive individuals, highlighting the significance of reproduction for an increase in longevity in social insects. As already shown for other organisms with a long lifespan, this trait is not directly coupled to higher levels of enzymatic and non-enzymatic antioxidants. PMID- 21298047 TI - The nuclear transcription factor PKNOX2 is a candidate gene for substance dependence in European-origin women. AB - Substance dependence or addiction is a complex environmental and genetic disorder that results in serious health and socio-economic consequences. Multiple substance dependence categories together, rather than any one individual addiction outcome, may explain the genetic variability of such disorder. In our study, we defined a composite substance dependence phenotype derived from six individual diagnoses: addiction to nicotine, alcohol, marijuana, cocaine, opiates or other drugs as a whole. Using data from several genomewide case-control studies, we identified a strong (Odds ratio = 1.77) and significant (p-value = 7E-8) association signal with a novel gene, PBX/knotted 1 homeobox 2 (PKNOX2), on chromosome 11 with the composite phenotype in European-origin women. The association signal is not as significant when individual outcomes for addiction are considered, or in males or African-origin population. Our findings underscore the importance of considering multiple addiction types and the importance of considering population and gender stratification when analyzing data with heterogeneous population. PMID- 21298048 TI - Intersexual trophic niche partitioning in an ant-eating spider (Araneae: Zodariidae). AB - BACKGROUND: Divergence in trophic niche between the sexes may function to reduce competition between the sexes ("intersexual niche partitioning hypothesis"), or may be result from differential selection among the sexes on maximizing reproductive output ("sexual selection hypothesis"). The latter may lead to higher energy demands in females driven by fecundity selection, while males invest in mate searching. We tested predictions of the two hypotheses underlying intersexual trophic niche partitioning in a natural population of spiders. Zodarion jozefienae spiders specialize on Messor barbarus ants that are polymorphic in body size and hence comprise potential trophic niches for the spider, making this system well-suited to study intersexual trophic niche partitioning. METHODOLOGY/PRINCIPAL FINDINGS: Comparative analysis of trophic morphology (the chelicerae) and body size of males, females and juveniles demonstrated highly female biased SSD (Sexual Size Dimorphism) in body size, body weight, and in the size of chelicerae, the latter arising from sex-specific growth patterns in trophic morphology. In the field, female spiders actively selected ant sub-castes that were larger than the average prey size, and larger than ants captured by juveniles and males. Female fecundity was highly positively correlated with female body mass, which reflects foraging success during the adult stage. Females in laboratory experiments preferred the large ant sub-castes and displayed higher capture efficiency. In contrast, males occupied a different trophic niche and showed reduced foraging effort and reduced prey capture and feeding efficiency compared with females and juveniles. CONCLUSIONS/SIGNIFICANCE: Our data indicate that female-biased dimorphism in trophic morphology and body size correlate with sex-specific reproductive strategies. We propose that intersexual trophic niche partitioning is shaped primarily by fecundity selection in females, and results from sex-differences in the route to successful reproduction where females are selected to maximize energy intake and fecundity, while males switch from foraging to invest in mating effort. PMID- 21298049 TI - Human processing of behaviorally relevant and irrelevant absence of expected rewards: a high-resolution ERP study. AB - Acute lesions of the posterior medial orbitofrontal cortex (OFC) in humans may induce a state of reality confusion marked by confabulation, disorientation, and currently inappropriate actions. This clinical state is strongly associated with an inability to abandon previously valid anticipations, that is, extinction capacity. In healthy subjects, the filtering of memories according to their relation with ongoing reality is associated with activity in posterior medial OFC (area 13) and electrophysiologically expressed at 220-300 ms. These observations indicate that the human OFC also functions as a generic reality monitoring system. For this function, it is presumably more important for the OFC to evaluate the current behavioral appropriateness of anticipations rather than their hedonic value. In the present study, we put this hypothesis to the test. Participants performed a reversal learning task with intermittent absence of reward delivery. High-density evoked potential analysis showed that the omission of expected reward induced a specific electrocortical response in trials signaling the necessity to abandon the hitherto reward predicting choice, but not when omission of reward had no such connotation. This processing difference occurred at 200-300 ms. Source estimation using inverse solution analysis indicated that it emanated from the posterior medial OFC. We suggest that the human brain uses this signal from the OFC to keep thought and behavior in phase with reality. PMID- 21298050 TI - Inactivation of the Rcan2 gene in mice ameliorates the age- and diet-induced obesity by causing a reduction in food intake. AB - Obesity is a serious international health problem that increases the risk of several diet-related chronic diseases. The genetic factors predisposing to obesity are little understood. Rcan2 was originally identified as a thyroid hormone-responsive gene. In the mouse, two splicing variants that harbor distinct tissue-specific expression patterns have been identified: Rcan2-3 is expressed predominately in the brain, whereas Rcan2-1 is expressed in the brain and other tissues such as the heart and skeletal muscle. Here, we show that Rcan2 plays an important role in the development of age- and diet-induced obesity. We found that although the loss of Rcan2 function in mice slowed growth in the first few weeks after birth, it also significantly ameliorated age- and diet-induced obesity in the mice by causing a reduction in food intake rather than increased energy expenditure. Rcan2 expression was most prominent in the ventromedial, dorsomedial and paraventricular hypothalamic nuclei governing energy balance. Fasting and refeeding experiment showed that only Rcan2-3 mRNA expression is up-regulated in the hypothalamus by fasting, and loss of Rcan2 significantly attenuates the hyperphagic response to starvation. Using double-mutant (Lep(ob/ob) Rcan2(-/-)) mice, we were also able to demonstrate that Rcan2 and leptin regulate body weight through different pathways. Our findings indicate that there may be an Rcan2 dependent mechanism which regulates food intake and promotes weight gain through a leptin-independent pathway. This study provides novel information on the control of body weight in mice and should improve our understanding of the mechanisms of obesity in humans. PMID- 21298051 TI - Increased rate of CD4+ T-cell decline and faster time to antiretroviral therapy in HIV-1 subtype CRF01_AE infected seroconverters in Singapore. AB - BACKGROUND: It remains controversial as to whether HIV-1 subtypes influence disease progression. Singapore offers a unique opportunity to address this issue due to the presence of co-circulating subtypes. We compared subtype CRF01_AE and non-CRF01_AE infected patients, with regards to estimated annual rate of CD4+ T cell loss and time from estimated data of seroconversion (EDS) to antiretroviral therapy (ART). METHODS: We recruited ART-naive patients with known dates of seroconversion between October 2002 and December 2007 at the Singapore Communicable Disease Centre, the national reference treatment centre. Multilevel mixed-effects models were used to analyse the rate of CD4+ T-cell decline. Time from EDS to ART was analyzed with the Kaplan-Meier survival method and compared with Cox proportional hazards models. RESULTS: 54 patients with previously assigned HIV-1 subtypes (24 CRF01_AE, 17 B, 8 B', 1 CRF33_01B, 3 CRF34_01B and 1 G) were observed for 89 patient-years. Subtype CRF01_AE and non-CRF01_AE infected patients did not differ in age, gender, risk factor, rate of symptomatic seroconversion, baseline CD4+ T-cell count, log(10) viral load or haemoglobin concentration. The estimated annual rate of CD4+ T-cell loss was 58 cells/mm(3)/year (95% CI: 7 to 109; P = 0.027) greater in subtype CRF01_AE infected patients compared to non-CRF01_AE patients, after adjusting for age, baseline CD4+ T-cell count and baseline log(10) viral load. The median time from EDS to ART was 1.8 years faster comparing CRF01_AE to non-CRF01_AE infected patient with a 2.5 times (95% CI: 1.2-5.0; P = 0.013) higher hazard for ART initiation, after controlling for age, baseline CD4+ T-cell count and baseline log(10) viral load. CONCLUSIONS: Infecting subtype significantly impacted the rate of CD4+ T-cell loss and time to treatment in this cohort. Studies to understand the biological basis for this difference could further our understanding of HIV pathogenesis. PMID- 21298052 TI - Protein kinase D2 is an essential regulator of murine myoblast differentiation. AB - Muscle differentiation is a highly conserved process that occurs through the activation of quiescent satellite cells whose progeny proliferate, differentiate, and fuse to generate new myofibers. A defined pattern of myogenic transcription factors is orchestrated during this process and is regulated via distinct signaling cascades involving various intracellular signaling pathways, including members of the protein kinase C (PKC) family. The protein kinase D (PKD) isoenzymes PKD1, -2, and -3, are prominent downstream targets of PKCs and phospholipase D in various biological systems including mouse and could hence play a role in muscle differentiation. In the present study, we used a mouse myoblast cell line (C2C12) as an in vitro model to investigate the role of PKDs, in particular PKD2, in muscle stem cell differentiation. We show that C2C12 cells express all PKD isoforms with PKD2 being highly expressed. Furthermore, we demonstrate that PKD2 is specifically phosphorylated/activated during the initiation of mouse myoblast differentiation. Selective inhibition of PKCs or PKDs by pharmacological inhibitors blocked myotube formation. Depletion of PKD2 by shRNAs resulted in a marked inhibition of myoblast cell fusion. PKD2-depleted cells exhibit impaired regulation of muscle development-associated genes while the proliferative capacity remains unaltered. Vice versa forced expression of PKD2 increases myoblast differentiation. These findings were confirmed in primary mouse satellite cells where myotube fusion was also decreased upon inhibition of PKDs. Active PKD2 induced transcriptional activation of myocyte enhancer factor 2D and repression of Pax3 transcriptional activity. In conclusion, we identify PKDs, in particular PKD2, as a major mediator of muscle cell differentiation in vitro and thereby as a potential novel target for the modulation of muscle regeneration. PMID- 21298053 TI - The epidemiology of multiple sclerosis in Scotland: inferences from hospital admissions. AB - BACKGROUND: Multiple sclerosis (MS) is a neurological disorder with a highly characteristic disease distribution. Prevalence and incidence in general increase with increasing distance from the equator. Similarly the female to male sex ratio increases with increasing latitude. Multiple possible risk factors have been hypothesised for this epidemiological trend, including human leukocyte antigen allele frequencies, ultraviolet exposure and subsequent vitamin D levels, smoking and Epstein-Barr virus. In this study we undertook a study of medical records across Scotland on an NHS health board level of resolution to examine the epidemiology of MS in this region. METHODS AND RESULTS: We calculated the number and rate of patient-linked hospital admissions throughout Scotland between 1997 and 2009 from the Scottish Morbidity Records. We used weighted-regression to examine correlations between these measures of MS, and latitude and smoking prevalence. We found a highly significant relationship between MS patient-linked admissions and latitude (r weighted by standard error (r(sw)) = 0.75, p = 0.002). There was no significant relationship between smoking prevalence and MS patient linked admissions. DISCUSSION: There is a definite latitudinal effect on MS risk across Scotland, arising primarily from an excess of female MS patients at more Northerly latitudes. Whether this is a true gradient or whether a threshold effect may apply at particular latitude will be revealed only by further research. A number of genetic and environmental factors may underlie this effect. PMID- 21298054 TI - Assessing conservation values: biodiversity and endemicity in tropical land use systems. AB - Despite an increasing amount of data on the effects of tropical land use on continental forest fauna and flora, it is debatable whether the choice of the indicator variables allows for a proper evaluation of the role of modified habitats in mitigating the global biodiversity crisis. While many single-taxon studies have highlighted that species with narrow geographic ranges especially suffer from habitat modification, there is no multi-taxa study available which consistently focuses on geographic range composition of the studied indicator groups. We compiled geographic range data for 180 bird, 119 butterfly, 204 tree and 219 understorey plant species sampled along a gradient of habitat modification ranging from near-primary forest through young secondary forest and agroforestry systems to annual crops in the southwestern lowlands of Cameroon. We found very similar patterns of declining species richness with increasing habitat modification between taxon-specific groups of similar geographic range categories. At the 8 km(2) spatial level, estimated richness of endemic species declined in all groups by 21% (birds) to 91% (trees) from forests to annual crops, while estimated richness of widespread species increased by +101% (trees) to +275% (understorey plants), or remained stable (-2%, butterflies). Even traditional agroforestry systems lost estimated endemic species richness by -18% (birds) to -90% (understorey plants). Endemic species richness of one taxon explained between 37% and 57% of others (positive correlations) and taxon specific richness in widespread species explained up to 76% of variation in richness of endemic species (negative correlations). The key implication of this study is that the range size aspect is fundamental in assessments of conservation value via species inventory data from modified habitats. The study also suggests that even ecologically friendly agricultural matrices may be of much lower value for tropical conservation than indicated by mere biodiversity value. PMID- 21298055 TI - Familial CJD associated PrP mutants within transmembrane region induced Ctm-PrP retention in ER and triggered apoptosis by ER stress in SH-SY5Y cells. AB - BACKGROUND: Genetic prion diseases are linked to point and inserted mutations in the prion protein (PrP) gene that are presumed to favor conversion of the cellular isoform of PrP (PrP(C)) to the pathogenic one (PrP(Sc)). The pathogenic mechanisms and the subcellular sites of the conversion are not completely understood. Here we introduce several PRNP gene mutations (such as, PrP-KDEL, PrP 3AV, PrP-A117V, PrP-G114V, PrP-P102L and PrP-E200K) into the cultured cells in order to explore the pathogenic mechanism of familial prion disease. METHODOLOGY/PRINCIPAL FINDINGS: To address the roles of aberrant retention of PrP in endoplasmic reticulum (ER), the recombinant plasmids expressing full-length human PrP tailed with an ER signal peptide at the COOH-terminal (PrP-KDEL) and PrP with three amino acids exchange in transmembrane region (PrP-3AV) were constructed. In the preparations of transient transfections, 18-kD COOH-terminal proteolytic resistant fragments (Ctm-PrP) were detected in the cells expressing PrP-KDEL and PrP-3AV. Analyses of the cell viabilities in the presences of tunicamycin and brefeldin A revealed that expressions of PrP-KDEL and PrP-3AV sensitized the transfected cells to ER stress stimuli. Western blots and RT-PCR identified the clear alternations of ER stress associated events in the cells expressing PrP-KDEL and PrP-3AV that induced ER mediated apoptosis by CHOP and caspase-12 apoptosis pathway. Moreover, several familial CJD related PrP mutants were transiently introduced into the cultured cells. Only the mutants within the transmembrane region (G114V and A117V) induced the formation of Ctm-PrP and caused the ER stress, while the mutants outside the transmembrane region (P102L and E200K) failed. CONCLUSIONS/SIGNIFICANCE: The data indicate that the retention of PrP in ER through formation of Ctm-PrP results in ER stress and cell apoptosis. The cytopathic activities caused by different familial CJD associated PrP mutants may vary, among them the mutants within the transmembrane region undergo an ER-stress mediated cell apoptosis. PMID- 21298056 TI - High-dose enalapril treatment reverses myocardial fibrosis in experimental uremic cardiomyopathy. AB - AIMS: Patients with renal failure develop cardiovascular alterations which contribute to the higher rate of cardiac death. Blockade of the renin angiotensin system ameliorates the development of such changes. It is unclear, however, to what extent ACE-inhibitors can also reverse existing cardiovascular alterations. Therefore, we investigated the effect of high dose enalapril treatment on these alterations. METHODS: Male Sprague Dawley rats underwent subtotal nephrectomy (SNX, n = 34) or sham operation (sham, n = 39). Eight weeks after surgery, rats were sacrificed or allocated to treatment with either high-dose enalapril, combination of furosemide/dihydralazine or solvent for 4 weeks. Heart and aorta were evaluated using morphometry, stereological techniques and TaqMan PCR. RESULTS: After 8 and 12 weeks systolic blood pressure, albumin excretion, and left ventricular weight were significantly higher in untreated SNX compared to sham. Twelve weeks after SNX a significantly higher volume density of cardiac interstitial tissue (2.57+/-0.43% in SNX vs 1.50+/-0.43% in sham, p<0.05) and a significantly lower capillary length density (4532+/-355 mm/mm(3) in SNX vs 5023+/-624 mm/mm(3) in sham, p<0.05) were found. Treatment of SNX with enalapril from week 8-12 significantly improved myocardial fibrosis (1.63+/-0.25%, p<0.05), but not capillary reduction (3908+/-486 mm/mm(3)) or increased intercapillary distance. In contrast, alternative antihypertensive treatment showed no such effect. Significantly increased media thickness together with decreased vascular smooth muscles cell number and a disarray of elastic fibres were found in the aorta of SNX animals compared to sham. Both antihypertensive treatments failed to cause complete regression of these alterations. CONCLUSIONS: The study indicates that high dose ACE-I treatment causes partial, but not complete, reversal of cardiovascular changes in SNX. PMID- 21298057 TI - "Keep calm and carry on": structural correlates of expressive suppression of emotions. AB - There is a growing appreciation that individuals differ systematically in their use of particular emotion regulation strategies. Our aim was to examine the structural correlates of the habitual use of expressive suppression of emotions. Based on our previous research on the voluntary suppression of actions we expected this response-focused emotion regulation strategy to be associated with increased grey matter volume in the dorsomedial prefrontal cortex (dmPFC). On high-resolution MRI scans of 42 college-aged healthy adults we computed optimized voxel-based-morphometry (VBM) to explore the correlation between grey matter volume and inter-individual differences in the tendency to suppress the expression of emotions assessed by means of the Emotion Regulation Questionnaire (Gross & John, 2003). We found a positive correlation between the habitual use of expressive suppression as an emotion regulation strategy and grey matter volume in the dmPFC. No other brain area showed a significant positive or negative correlation with the Emotion Regulation Questionnaire scores. The association between the suppression of expression of emotions and volume in the dmPFC supports the behavioural stability and biological foundation of the concept of this particular emotion regulation strategy within an age-homogenous sample of adults. PMID- 21298058 TI - Hippocampal deletion of BDNF gene attenuates gamma oscillations in area CA1 by up regulating 5-HT3 receptor. AB - BACKGROUND: Pyramidal neurons in the hippocampal area CA3 express high levels of BDNF, but how this BDNF contributes to oscillatory properties of hippocampus is unknown. METHODOLOGY/PRINCIPAL FINDINGS: Here we examined carbachol-induced gamma oscillations in hippocampal slices lacking BDNF gene in the area CA3. The power of oscillations was reduced in the hippocampal area CA1, which coincided with increases in the expression and activity of 5-HT3 receptor. Pharmacological block of this receptor partially restored power of gamma oscillations in slices from KO mice, but had no effect in slices from WT mice. CONCLUSION/SIGNIFICANCE: These data suggest that BDNF facilitates gamma oscillations in the hippocampus by attenuating signaling through 5-HT3 receptor. Thus, BDNF modulates hippocampal oscillations through serotonergic system. PMID- 21298059 TI - Ensemble composition and activity levels of insectivorous bats in response to management intensification in coffee agroforestry systems. AB - Shade coffee plantations have received attention for their role in biodiversity conservation. Bats are among the most diverse mammalian taxa in these systems; however, previous studies of bats in coffee plantations have focused on the largely herbivorous leaf-nosed bats (Phyllostomidae). In contrast, we have virtually no information on how ensembles of aerial insectivorous bats--nearly half the Neotropical bat species--change in response to habitat modification. To evaluate the effects of agroecosystem management on insectivorous bats, we studied their diversity and activity in southern Chiapas, Mexico, a landscape dominated by coffee agroforestry. We used acoustic monitoring and live captures to characterize the insectivorous bat ensemble in forest fragments and coffee plantations differing in the structural and taxonomic complexity of shade trees. We captured bats of 12 non-phyllostomid species; acoustic monitoring revealed the presence of at least 12 more species of aerial insectivores. Richness of forest bats was the same across all land-use types; in contrast, species richness of open-space bats increased in low shade, intensively managed coffee plantations. Conversely, only forest bats demonstrated significant differences in ensemble structure (as measured by similarity indices) across land-use types. Both overall activity and feeding activity of forest bats declined significantly with increasing management intensity, while the overall activity, but not feeding activity, of open-space bats increased. We conclude that diverse shade coffee plantations in our study area serve as valuable foraging and commuting habitat for aerial insectivorous bats, and several species also commute through or forage in low shade coffee monocultures. PMID- 21298060 TI - Spinal cord injury causes sustained disruption of the blood-testis barrier in the rat. AB - There is a high incidence of infertility in males following traumatic spinal cord injury (SCI). Quality of semen is frequently poor in these patients, but the pathophysiological mechanism(s) causing this are not known. Blood-testis barrier (BTB) integrity following SCI has not previously been examined. The objective of this study was to characterize the effects of spinal contusion injury on the BTB in the rat. 63 adult, male Sprague Dawley rats received SCI (n = 28), laminectomy only (n = 7) or served as uninjured, age-matched controls (n = 28). Using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), BTB permeability to the vascular contrast agent gadopentate dimeglumine (Gd) was assessed at either 72 hours-, or 10 months post-SCI. DCE-MRI data revealed that BTB permeability to Gd was greater than controls at both 72 h and 10 mo post-SCI. Histological evaluation of testis tissue showed increased BTB permeability to immunoglobulin G at both 72 hours- and 10 months post-SCI, compared to age-matched sham-operated and uninjured controls. Tight junctional integrity within the seminiferous epithelium was assessed; at 72 hours post-SCI, decreased expression of the tight junction protein occludin was observed. Presence of inflammation in the testes was also examined. High expression of the proinflammatory cytokine interleukin-1 beta was detected in testis tissue. CD68(+) immune cell infiltrate and mast cells were also detected within the seminiferous epithelium of both acute and chronic SCI groups but not in controls. In addition, extensive germ cell apoptosis was observed at 72 h post-SCI. Based on these results, we conclude that SCI is followed by compromised BTB integrity by as early as 72 hours post-injury in rats and is accompanied by a substantial immune response within the testis. Furthermore, our results indicate that the BTB remains compromised and testis immune cell infiltration persists for months after the initial injury. PMID- 21298061 TI - The mitochondrial T16189C polymorphism is associated with coronary artery disease in Middle European populations. AB - BACKGROUND: The pivotal role of mitochondria in energy production and free radical generation suggests that the mitochondrial genome could have an important influence on the expression of multifactorial age related diseases. Substitution of T to C at nucleotide position 16189 in the hypervariable D-loop of the control region (CR) of mitochondrial DNA (mtDNA) has attracted research interest because of its suspected association with various multifactorial diseases. The aim of the present study was to compare the frequency of this polymorphism in the CR of mtDNA in patients with coronary artery disease (CAD, n = 482) and type 2 diabetes mellitus (T2DM, n = 505) from two study centers, with healthy individuals (n = 1481) of Middle European descent in Austria. METHODOLOGY AND PRINCIPAL FINDINGS: CR polymorphisms and the nine major European haplogroups were identified by DNA sequencing and primer extension analysis, respectively. Frequencies and Odds Ratios for the association between cases and controls were calculated. Compared to healthy controls, the prevalence of T16189C was significantly higher in patients with CAD (11.8% vs 21.6%), as well as in patients with T2DM (11.8% vs 19.4%). The association of CAD, but not the one of T2DM, with T16189C remained highly significant after correction for age, sex and body mass index (BMI) and was independent of the two study centers. CONCLUSIONS AND SIGNIFICANCE: Our results show for the first time a significant association of T16189C with CAD in a Middle European population. As reported in other studies, in patients with T2DM an association with T16189C in individuals of European decent remains questionable. PMID- 21298062 TI - Comparative proteomic analysis of lung lamellar bodies and lysosome-related organelles. AB - Pulmonary surfactant is a complex mixture of lipids and proteins that is essential for postnatal function. Surfactant is synthesized in alveolar type II cells and stored as multi-bilayer membranes in a specialized secretory lysosome related organelle (LRO), known as the lamellar body (LB), prior to secretion into the alveolar airspaces. Few LB proteins have been identified and the mechanisms regulating formation and trafficking of this organelle are poorly understood. Lamellar bodies were isolated from rat lungs, separated into limiting membrane and core populations, fractionated by SDS-PAGE and proteins identified by nanoLC tandem mass spectrometry. In total 562 proteins were identified, significantly extending a previous study that identified 44 proteins in rat lung LB. The lung LB proteome reflects the dynamic interaction of this organelle with the biosynthetic, secretory and endocytic pathways of the type II epithelial cell. Comparison with other LRO proteomes indicated that 60% of LB proteins were detected in one or more of 8 other proteomes, confirming classification of the LB as a LRO. Remarkably the LB shared 37.8% of its proteins with the melanosome but only 9.9% with lamellar bodies from the skin. Of the 229 proteins not detected in other LRO proteomes, a subset of 34 proteins was enriched in lung relative to other tissues. Proteins with lipid-related functions comprised a significant proportion of the LB unique subset, consistent with the major function of this organelle in the organization, storage and secretion of surfactant lipid. The lung LB proteome will facilitate identification of molecular pathways involved in LB biogenesis, surfactant homeostasis and disease pathogenesis. PMID- 21298063 TI - Age-related changes in the epithelial and stromal compartments of the mammary gland in normocalcemic mice lacking the vitamin D3 receptor. AB - The vitamin D(3) receptor (VDR) serves as a negative growth regulator during mammary gland development via suppression of branching morphogenesis during puberty and modulation of differentiation and apoptosis during pregnancy, lactation and involution. To assess the role of the VDR in the aging mammary gland, we utilized 12, 14, and 16 month old VDR knockout (KO) and wild type (WT) mice for assessment of integrity of the epithelial and stromal compartments, steroid hormone levels and signaling pathways. Our data indicate that VDR ablation is associated with ductal ectasia of the primary mammary ducts, loss of secondary and tertiary ductal branches and atrophy of the mammary fat pad. In association with loss of the white adipose tissue compartment, smooth muscle actin staining is increased in glands from VDR KO mice, suggesting a change in the stromal microenviroment. Activation of caspase-3 and increased Bax expression in mammary tissue of VDR KO mice suggests that enhanced apoptosis may contribute to loss of ductal branching. These morphological changes in the glands of VDR KO mice are associated with ovarian failure and reduced serum 17beta-estradiol. VDR KO mice also exhibit progressive loss of adipose tissue stores, hypoleptinemia and increased metabolic rate with age. These developmental studies indicate that, under normocalcemic conditions, loss of VDR signaling is associated with age related estrogen deficiency, disruption of epithelial ductal branching, abnormal energy expenditure and atrophy of the mammary adipose compartment. PMID- 21298064 TI - Reshaping of bulbar odor response by nasal flow rate in the rat. AB - BACKGROUND: The impact of respiratory dynamics on odor response has been poorly studied at the olfactory bulb level. However, it has been shown that sniffing in the behaving rodent is highly dynamic and varies both in frequency and flow rate. Bulbar odor response could vary with these sniffing parameter variations. Consequently, it is necessary to understand how nasal airflow can modify and shape odor response at the olfactory bulb level. METHODOLOGY AND PRINCIPAL FINDINGS: To assess this question, we used a double cannulation and simulated nasal airflow protocol on anesthetized rats to uncouple nasal airflow from animal respiration. Both mitral/tufted cell extracellular unit activity and local field potentials (LFPs) were recorded. We found that airflow changes in the normal range were sufficient to substantially reorganize the response of the olfactory bulb. In particular, cellular odor-evoked activities, LFP oscillations and spike phase-locking to LFPs were strongly modified by nasal flow rate. CONCLUSION: Our results indicate the importance of reconsidering the notion of odor coding as odor response at the bulbar level is ceaselessly modified by respiratory dynamics. PMID- 21298065 TI - Timed picture naming norms for Mandarin Chinese. AB - The present study reports timed norms for 435 object pictures in Mandarin Chinese. These data include naming latency, name agreement, concept agreement, word length, and age of acquisition (AoA) based on children's naming and adult ratings, and several other adult ratings of concept familiarity, subjective word frequency, image agreement, image variability, and visual complexity. Furthermore, we examined factors that influence the naming latencies of the pictures. The results show that concept familiarity, AoA, concept agreement, name agreement, and image agreement are significant predictors of naming latencies, whereas subjective word frequency is not a reliable determinant. These results are discussed in light of picture naming data in other languages. An item-based index for the norms is provided in the Table S1. PMID- 21298066 TI - A novel role for ATM in regulating proteasome-mediated protein degradation through suppression of the ISG15 conjugation pathway. AB - Ataxia Telangiectasia (A-T) is an inherited immunodeficiency disorder wherein mutation of the ATM kinase is responsible for the A-T pathogenesis. Although the precise role of ATM in A-T pathogenesis is still unclear, its function in responding to DNA damage has been well established. Here we demonstrate that in addition to its role in DNA repair, ATM also regulates proteasome-mediated protein turnover through suppression of the ISG15 pathway. This conclusion is based on three major pieces of evidence: First, we demonstrate that proteasome mediated protein degradation is impaired in A-T cells. Second, we show that the reduced protein turnover is causally linked to the elevated expression of the ubiquitin-like protein ISG15 in A-T cells. Third, we show that expression of the ISG15 is elevated in A-T cells derived from various A-T patients, as well as in brain tissues derived from the ATM knockout mice and A-T patients, suggesting that ATM negatively regulates the ISG15 pathway. Our current findings suggest for the first time that proteasome-mediated protein degradation is impaired in A-T cells due to elevated expression of the ISG15 conjugation pathway, which could contribute to progressive neurodegeneration in A-T patients. PMID- 21298067 TI - Delaying Gal4-driven gene expression in the zebrafish with morpholinos and Gal80. AB - The modular Gal4/UAS gene expression system has become an indispensable tool in modern biology. Several large-scale gene- and enhancer-trap screens in the zebrafish have generated hundreds of transgenic lines expressing Gal4 in unique patterns. However, the early embryonic expression of the Gal4 severely limits their use for studies on regeneration or behavior because UAS-driven effectors could disrupt normal organogenesis. To overcome this limitation, we explored the use of the Gal4 repressor Gal80 in transient assays and with stable transgenes to temporally control Gal4 activity. We also validated a strategy to delay Gal4 driven gene expression using a morpholino targeted to Gal4. The first approach is limited to transgenes expressing the native Gal4. The morphant approach can also be applied to transgenic lines expressing the Gal4-VP16 fusion protein. It promises to become a standard approach to delay Gal4-driven transgene expression and enhance the genetic toolkit for the zebrafish. PMID- 21298068 TI - Non-visual effects of light on melatonin, alertness and cognitive performance: can blue-enriched light keep us alert? AB - BACKGROUND: Light exposure can cascade numerous effects on the human circadian process via the non-imaging forming system, whose spectral relevance is highest in the short-wavelength range. Here we investigated if commercially available compact fluorescent lamps with different colour temperatures can impact on alertness and cognitive performance. METHODS: Sixteen healthy young men were studied in a balanced cross-over design with light exposure of 3 different light settings (compact fluorescent lamps with light of 40 lux at 6500K and at 2500K and incandescent lamps of 40 lux at 3000K) during 2 h in the evening. RESULTS: Exposure to light at 6500K induced greater melatonin suppression, together with enhanced subjective alertness, well-being and visual comfort. With respect to cognitive performance, light at 6500K led to significantly faster reaction times in tasks associated with sustained attention (Psychomotor Vigilance and GO/NOGO Task), but not in tasks associated with executive function (Paced Visual Serial Addition Task). This cognitive improvement was strongly related with attenuated salivary melatonin levels, particularly for the light condition at 6500K. CONCLUSIONS: Our findings suggest that the sensitivity of the human alerting and cognitive response to polychromatic light at levels as low as 40 lux, is blue shifted relative to the three-cone visual photopic system. Thus, the selection of commercially available compact fluorescent lights with different colour temperatures significantly impacts on circadian physiology and cognitive performance at home and in the workplace. PMID- 21298069 TI - A modified vaccinia Ankara virus (MVA) vaccine expressing African horse sickness virus (AHSV) VP2 protects against AHSV challenge in an IFNAR -/- mouse model. AB - African horse sickness (AHS) is a lethal viral disease of equids, which is transmitted by Culicoides midges that become infected after biting a viraemic host. The use of live attenuated vaccines has been vital for the control of this disease in endemic regions. However, there are safety concerns over their use in non-endemic countries. Research efforts over the last two decades have therefore focused on developing alternative vaccines based on recombinant baculovirus or live viral vectors expressing structural components of the AHS virion. However, ethical and financial considerations, relating to the use of infected horses in high biosecurity installations, have made progress very slow. We have therefore assessed the potential of an experimental mouse-model for AHSV infection for vaccine and immunology research. We initially characterised AHSV infection in this model, then tested the protective efficacy of a recombinant vaccine based on modified vaccinia Ankara expressing AHS-4 VP2 (MVA-VP2). PMID- 21298070 TI - Analysis of convergent gene transcripts in the obligate intracellular bacterium Rickettsia prowazekii. AB - Termination of transcription is an important component of bacterial gene expression. However, little is known concerning this process in the obligate intracellular pathogen and model for reductive evolution, Rickettsia prowazekii. To assess transcriptional termination in this bacterium, transcripts of convergent gene pairs, some containing predicted intrinsic terminators, were analyzed. These analyses revealed that, rather than terminating at a specific site within the intervening region between the convergent genes, most of the transcripts demonstrated either a lack of termination within this region, which generated antisense RNA, or a putative non-site-specific termination that occurred throughout the intervening sequence. Transcripts terminating at predicted intrinsic terminators, as well as at a putative Rho-dependant terminator, were also examined and found to vary based on the rickettsial host environment. These results suggest that transcriptional termination, or lack thereof, plays a role in rickettsial gene regulation. PMID- 21298071 TI - Extrasynaptic GABA(A) receptors and tonic inhibition in rat auditory thalamus. AB - BACKGROUND: Neural inhibition plays an important role in auditory processing and attentional gating. Extrasynaptic GABA(A) receptors (GABA(A)R), containing alpha(4)and delta GABA(A)R subunits, are thought to be activated by GABA spillover outside of the synapse following release resulting in a tonic inhibitory Cl(-) current which could account for up to 90% of total inhibition in visual and somatosensory thalamus. However, the presence of this unique type of inhibition has not been identified in auditory thalamus. METHODOLOGY/PRINCIPAL FINDINGS: The present study used gaboxadol, a partially selective potent agonist for delta-subunit containing GABA(A) receptor constructs to elucidate the presence of extrasynaptic GABA(A)Rs using both a quantitative receptor binding assay and patch-clamp electrophysiology in thalamic brain slices. Intense [(3)H]gaboxadol binding was found to be localized to the MGB while whole cell recordings from MGB neurons in the presence of gaboxadol demonstrated the expression of delta-subunit containing GABA(A)Rs capable of mediating a tonic inhibitory Cl(-) current. CONCLUSIONS/SIGNIFICANCE: Potent tonic inhibitory GABA(A)R responses mediated by extrasynaptic receptors may be important in understanding how acoustic information is processed by auditory thalamic neurons as it ascends to auditory cortex. In addition to affecting cellular behavior and possibly neurotransmission, functional extrasynaptic delta-subunit containing GABA(A)Rs may represent a novel pharmacological target for the treatment of auditory pathologies including temporal processing disorders or tinnitus. PMID- 21298072 TI - The dual impact of HIV-1 infection and aging on naive CD4 T-cells: additive and distinct patterns of impairment. AB - HIV-1-infected adults over the age of 50 years progress to AIDS more rapidly than adults in their twenties or thirties. In addition, HIV-1-infected individuals receiving antiretroviral therapy (ART) present with clinical diseases, such as various cancers and liver disease, more commonly seen in older uninfected adults. These observations suggest that HIV-1 infection in older persons can have detrimental immunological effects that are not completely reversed by ART. As naive T-cells are critically important in responses to neoantigens, we first analyzed two subsets (CD45RA(+)CD31(+) and CD45RA(+)CD31(-)) within the naive CD4(+) T-cell compartment in young (20-32 years old) and older (39-58 years old), ART-naive, HIV-1 seropositive individuals within 1-3 years of infection and in age-matched seronegative controls. HIV-1 infection in the young cohort was associated with lower absolute numbers of, and shorter telomere lengths within, both CD45RA(+)CD31(+)CD4(+) and CD45RA(+)CD31(-)CD4(+) T-cell subsets in comparison to age-matched seronegative controls, changes that resembled seronegative individuals who were decades older. Longitudinal analysis provided evidence of thymic emigration and reconstitution of CD45RA(+)CD31(+)CD4(+) T cells two years post-ART, but minimal reconstitution of the CD45RA(+)CD31( )CD4(+) subset, which could impair de novo immune responses. For both ART-naive and ART-treated HIV-1-infected adults, a renewable pool of thymic emigrants is necessary to maintain CD4(+) T-cell homeostasis. Overall, these results offer a partial explanation both for the faster disease progression of older adults and the observation that viral responders to ART present with clinical diseases associated with older adults. PMID- 21298073 TI - Endothelin-dependent vasoconstriction in human uterine artery: application to preeclampsia. AB - BACKGROUND: Reduced uteroplacental perfusion, the initiating event in preeclampsia, is associated with enhanced endothelin-1 (ET-1) production which feeds the vasoconstriction of uterine artery. Whether the treatments of preeclampsia were effective on ET-1 induced contraction and could reverse placental ischemia is the question addressed in this study. We investigated the effect of antihypertensive drugs used in preeclampsia and of ET receptor antagonists on the contractile response to ET-1 on human uterine arteries. METHODOLOGY/PRINCIPAL FINDINGS: Experiments were performed, ex vivo, on human uterine artery samples obtained after hysterectomy. We studied variations in isometric tension of arterial rings in response to the vasoconstrictor ET-1 and evaluated the effects of various vasodilators and ET-receptor antagonists on this response. Among antihypertensive drugs, only dihydropyridines were effective in blocking and reversing the ET-1 contractile response. Their efficiency, independent of the concentration of ET-1, was only partial. Hydralazine, alpha methyldopa and labetalol had no effect on ET-1 induced contraction which is mediated by both ET(A) and ET(B) receptors in uterine artery. ET receptors antagonists, BQ-123 and BQ-788, slightly reduced the amplitude of the response to ET-1. Combination of both antagonists was more efficient, but it was not possible to reverse the maximal ET-1-induced contraction with antagonists used alone or in combination. CONCLUSION: Pharmacological drugs currently used in the context of preeclampsia, do not reverse ET-1 induced contraction. Only dihydropyridines, which partially relax uterine artery previously contracted with ET-1, might offer interesting perspectives to improve placental perfusion. PMID- 21298074 TI - Abnormal brain default-mode network functional connectivity in drug addicts. AB - BACKGROUND: The default mode network (DMN) is a set of brain regions that exhibit synchronized low frequency oscillations at resting-state, and is believed to be relevant to attention and self-monitoring. As the anterior cingulate cortex and hippocampus are impaired in drug addiction and meanwhile are parts of the DMN, the present study examined addiction-related alteration of functional connectivity of the DMN. METHODOLOGY: Resting-state functional magnetic resonance imaging data of chronic heroin users (14 males, age: 30.1+/-5.3 years, range from 22 to 39 years) and non-addicted controls (13 males, age: 29.8+/-7.2 years, range from 20 to 39 years) were investigated with independent component analysis to address their functional connectivity of the DMN. PRINCIPAL FINDINGS: Compared with controls, heroin users showed increased functional connectivity in right hippocampus and decreased functional connectivity in right dorsal anterior cingulate cortex and left caudate in the DMN. CONCLUSIONS: These findings suggest drug addicts' abnormal functional organization of the DMN, and are discussed as addiction-related abnormally increased memory processing but diminished cognitive control related to attention and self-monitoring, which may underlie the hypersensitivity toward drug related cues but weakened strength of cognitive control in the state of addiction. PMID- 21298075 TI - Impaired auditory-vestibular functions and behavioral abnormalities of Slitrk6 deficient mice. AB - A recent study revealed that Slitrk6, a transmembrane protein containing a leucine-rich repeat domain, has a critical role in the development of the inner ear neural circuit. However, it is still unknown how the absence of Slitrk6 affects auditory and vestibular functions. In addition, the role of Slitrk6 in regions of the central nervous system, including the dorsal thalamus, has not been addressed. To understand the physiological role of Slitrk6, Slitrk6-knockout (KO) mice were subjected to systematic behavioral analyses including auditory and vestibular function tests. Compared to wild-type mice, the auditory brainstem response (ABR) of Slitrk6-KO mice indicated a mid-frequency range (8-16 kHz) hearing loss and reduction of the first ABR wave. The auditory startle response was also reduced. A vestibulo-ocular reflex (VOR) test showed decreased vertical (head movement-induced) VOR gains and normal horizontal VOR. In an open field test, locomotor activity was reduced; the tendency to be in the center region was increased, but only in the first 5 min of the test, indicating altered adaptive responses to a novel environment. Altered adaptive responses were also found in a hole-board test in which head-dip behavior was increased and advanced. Aside from these abnormalities, no clear abnormalities were noted in the mood, anxiety, learning, spatial memory, or fear memory-related behavioral tests. These results indicate that the Slitrk6-KO mouse can serve as a model of hereditary sensorineural deafness. Furthermore, the altered responses of Slitrk6-KO mice to the novel environment suggest a role of Slitrk6 in some cognitive functions. PMID- 21298076 TI - Impact of sarcoplasmic reticulum calcium release on calcium dynamics and action potential morphology in human atrial myocytes: a computational study. AB - Electrophysiological studies of the human heart face the fundamental challenge that experimental data can be acquired only from patients with underlying heart disease. Regarding human atria, there exist sizable gaps in the understanding of the functional role of cellular Ca2+ dynamics, which differ crucially from that of ventricular cells, in the modulation of excitation-contraction coupling. Accordingly, the objective of this study was to develop a mathematical model of the human atrial myocyte that, in addition to the sarcolemmal (SL) ion currents, accounts for the heterogeneity of intracellular Ca2+ dynamics emerging from a structurally detailed sarcoplasmic reticulum (SR). Based on the simulation results, our model convincingly reproduces the principal characteristics of Ca2+ dynamics: 1) the biphasic increment during the upstroke of the Ca2+ transient resulting from the delay between the peripheral and central SR Ca2+ release, and 2) the relative contribution of SL Ca2+ current and SR Ca2+ release to the Ca2+ transient. In line with experimental findings, the model also replicates the strong impact of intracellular Ca2+ dynamics on the shape of the action potential. The simulation results suggest that the peripheral SR Ca2+ release sites define the interface between Ca2+ and AP, whereas the central release sites are important for the fire-diffuse-fire propagation of Ca2+ diffusion. Furthermore, our analysis predicts that the modulation of the action potential duration due to increasing heart rate is largely mediated by changes in the intracellular Na+ concentration. Finally, the results indicate that the SR Ca2+ release is a strong modulator of AP duration and, consequently, myocyte refractoriness/excitability. We conclude that the developed model is robust and reproduces many fundamental aspects of the tight coupling between SL ion currents and intracellular Ca2+ signaling. Thus, the model provides a useful framework for future studies of excitation-contraction coupling in human atrial myocytes. PMID- 21298077 TI - A Review of 2010 for PLoS Computational Biology. PMID- 21298078 TI - Estimation of parent specific DNA copy number in tumors using high-density genotyping arrays. AB - Chromosomal gains and losses comprise an important type of genetic change in tumors, and can now be assayed using microarray hybridization-based experiments. Most current statistical models for DNA copy number estimate total copy number, which do not distinguish between the underlying quantities of the two inherited chromosomes. This latter information, sometimes called parent specific copy number, is important for identifying allele-specific amplifications and deletions, for quantifying normal cell contamination, and for giving a more complete molecular portrait of the tumor. We propose a stochastic segmentation model for parent-specific DNA copy number in tumor samples, and give an estimation procedure that is computationally efficient and can be applied to data from the current high density genotyping platforms. The proposed method does not require matched normal samples, and can estimate the unknown genotypes simultaneously with the parent specific copy number. The new method is used to analyze 223 glioblastoma samples from the Cancer Genome Atlas (TCGA) project, giving a more comprehensive summary of the copy number events in these samples. Detailed case studies on these samples reveal the additional insights that can be gained from an allele-specific copy number analysis, such as the quantification of fractional gains and losses, the identification of copy neutral loss of heterozygosity, and the characterization of regions of simultaneous changes of both inherited chromosomes. PMID- 21298079 TI - Protrusive push versus enveloping embrace: computational model of phagocytosis predicts key regulatory role of cytoskeletal membrane anchors. AB - Encounters between human neutrophils and zymosan elicit an initially protrusive cell response that is distinct from the thin lamella embracing antibody-coated targets. Recent experiments have led us to hypothesize that this behavior has its mechanistic roots in the modulation of interactions between membrane and cytoskeleton. To test and refine this hypothesis, we confront our experimental results with predictions of a computer model of leukocyte mechanical behavior, and establish the minimum set of mechanistic variations of this computational framework that reproduces the differences between zymosan and antibody phagocytosis. We confirm that the structural linkages between the cytoskeleton and the membrane patch adherent to a target form the "switchboard" that controls the target specificity of a neutrophil's mechanical response. These linkages are presumably actin-binding protein complexes associating with the cytoplasmic domains of cell-surface receptors that are engaged in adhesion to zymosan and Fc domains. PMID- 21298080 TI - The role of additive neurogenesis and synaptic plasticity in a hippocampal memory model with grid-cell like input. AB - Recently, we presented a study of adult neurogenesis in a simplified hippocampal memory model. The network was required to encode and decode memory patterns despite changing input statistics. We showed that additive neurogenesis was a more effective adaptation strategy compared to neuronal turnover and conventional synaptic plasticity as it allowed the network to respond to changes in the input statistics while preserving representations of earlier environments. Here we extend our model to include realistic, spatially driven input firing patterns in the form of grid cells in the entorhinal cortex. We compare network performance across a sequence of spatial environments using three distinct adaptation strategies: conventional synaptic plasticity, where the network is of fixed size but the connectivity is plastic; neuronal turnover, where the network is of fixed size but units in the network may die and be replaced; and additive neurogenesis, where the network starts out with fewer initial units but grows over time. We confirm that additive neurogenesis is a superior adaptation strategy when using realistic, spatially structured input patterns. We then show that a more biologically plausible neurogenesis rule that incorporates cell death and enhanced plasticity of new granule cells has an overall performance significantly better than any one of the three individual strategies operating alone. This adaptation rule can be tailored to maximise performance of the network when operating as either a short- or long-term memory store. We also examine the time course of adult neurogenesis over the lifetime of an animal raised under different hypothetical rearing conditions. These growth profiles have several distinct features that form a theoretical prediction that could be tested experimentally. Finally, we show that place cells can emerge and refine in a realistic manner in our model as a direct result of the sparsification performed by the dentate gyrus layer. PMID- 21298081 TI - Integrative features of the yeast phosphoproteome and protein-protein interaction map. AB - Following recent advances in high-throughput mass spectrometry (MS)-based proteomics, the numbers of identified phosphoproteins and their phosphosites have greatly increased in a wide variety of organisms. Although a critical role of phosphorylation is control of protein signaling, our understanding of the phosphoproteome remains limited. Here, we report unexpected, large-scale connections revealed between the phosphoproteome and protein interactome by integrative data-mining of yeast multi-omics data. First, new phosphoproteome data on yeast cells were obtained by MS-based proteomics and unified with publicly available yeast phosphoproteome data. This revealed that nearly 60% of ~6,000 yeast genes encode phosphoproteins. We mapped these unified phosphoproteome data on a yeast protein-protein interaction (PPI) network with other yeast multi-omics datasets containing information about proteome abundance, proteome disorders, literature-derived signaling reactomes, and in vitro substratomes of kinases. In the phospho-PPI, phosphoproteins had more interacting partners than nonphosphoproteins, implying that a large fraction of intracellular protein interaction patterns (including those of protein complex formation) is affected by reversible and alternative phosphorylation reactions. Although highly abundant or unstructured proteins have a high chance of both interacting with other proteins and being phosphorylated within cells, the difference between the number counts of interacting partners of phosphoproteins and nonphosphoproteins was significant independently of protein abundance and disorder level. Moreover, analysis of the phospho-PPI and yeast signaling reactome data suggested that co phosphorylation of interacting proteins by single kinases is common within cells. These multi-omics analyses illuminate how wide-ranging intracellular phosphorylation events and the diversity of physical protein interactions are largely affected by each other. PMID- 21298082 TI - Detecting remote evolutionary relationships among proteins by large-scale semantic embedding. AB - Virtually every molecular biologist has searched a protein or DNA sequence database to find sequences that are evolutionarily related to a given query. Pairwise sequence comparison methods--i.e., measures of similarity between query and target sequences--provide the engine for sequence database search and have been the subject of 30 years of computational research. For the difficult problem of detecting remote evolutionary relationships between protein sequences, the most successful pairwise comparison methods involve building local models (e.g., profile hidden Markov models) of protein sequences. However, recent work in massive data domains like web search and natural language processing demonstrate the advantage of exploiting the global structure of the data space. Motivated by this work, we present a large-scale algorithm called ProtEmbed, which learns an embedding of protein sequences into a low-dimensional "semantic space." Evolutionarily related proteins are embedded in close proximity, and additional pieces of evidence, such as 3D structural similarity or class labels, can be incorporated into the learning process. We find that ProtEmbed achieves superior accuracy to widely used pairwise sequence methods like PSI-BLAST and HHSearch for remote homology detection; it also outperforms our previous RankProp algorithm, which incorporates global structure in the form of a protein similarity network. Finally, the ProtEmbed embedding space can be visualized, both at the global level and local to a given query, yielding intuition about the structure of protein sequence space. PMID- 21298083 TI - Erratic flu vaccination emerges from short-sighted behavior in contact networks. AB - The effectiveness of seasonal influenza vaccination programs depends on individual-level compliance. Perceptions about risks associated with infection and vaccination can strongly influence vaccination decisions and thus the ultimate course of an epidemic. Here we investigate the interplay between contact patterns, influenza-related behavior, and disease dynamics by incorporating game theory into network models. When individuals make decisions based on past epidemics, we find that individuals with many contacts vaccinate, whereas individuals with few contacts do not. However, the threshold number of contacts above which to vaccinate is highly dependent on the overall network structure of the population and has the potential to oscillate more wildly than has been observed empirically. When we increase the number of prior seasons that individuals recall when making vaccination decisions, behavior and thus disease dynamics become less variable. For some networks, we also find that higher flu transmission rates may, counterintuitively, lead to lower (vaccine-mediated) disease prevalence. Our work demonstrates that rich and complex dynamics can result from the interaction between infectious diseases, human contact patterns, and behavior. PMID- 21298084 TI - Evolutionary conserved regulation of HIF-1beta by NF-kappaB. AB - Hypoxia Inducible Factor-1 (HIF-1) is essential for mammalian development and is the principal transcription factor activated by low oxygen tensions. HIF-alpha subunit quantities and their associated activity are regulated in a post translational manner, through the concerted action of a class of enzymes called Prolyl Hydroxylases (PHDs) and Factor Inhibiting HIF (FIH) respectively. However, alternative modes of HIF-alpha regulation such as translation or transcription are under-investigated, and their importance has not been firmly established. Here, we demonstrate that NF-kappaB regulates the HIF pathway in a significant and evolutionary conserved manner. We demonstrate that NF-kappaB directly regulates HIF-1beta mRNA and protein. In addition, we found that NF-kappaB mediated changes in HIF-1beta result in modulation of HIF-2alpha protein. HIF 1beta overexpression can rescue HIF-2alpha protein levels following NF-kappaB depletion. Significantly, NF-kappaB regulates HIF-1beta (tango) and HIF-alpha (sima) levels and activity (Hph/fatiga, ImpL3/ldha) in Drosophila, both in normoxia and hypoxia, indicating an evolutionary conserved mode of regulation. These results reveal a novel mechanism of HIF regulation, with impact in the development of novel therapeutic strategies for HIF-related pathologies including ageing, ischemia, and cancer. PMID- 21298085 TI - RNF12 activates Xist and is essential for X chromosome inactivation. AB - In somatic cells of female placental mammals, one of the two X chromosomes is transcriptionally silenced to accomplish an equal dose of X-encoded gene products in males and females. Initiation of random X chromosome inactivation (XCI) is thought to be regulated by X-encoded activators and autosomally encoded suppressors controlling Xist. Spreading of Xist RNA leads to silencing of the X chromosome in cis. Here, we demonstrate that the dose dependent X-encoded XCI activator RNF12/RLIM acts in trans and activates Xist. We did not find evidence for RNF12-mediated regulation of XCI through Tsix or the Xist intron 1 region, which are both known to be involved in inhibition of Xist. In addition, we found that Xist intron 1, which contains a pluripotency factor binding site, is not required for suppression of Xist in undifferentiated ES cells. Analysis of female Rnf12-/- knockout ES cells showed that RNF12 is essential for initiation of XCI and is mainly involved in the regulation of Xist. We conclude that RNF12 is an indispensable factor in up-regulation of Xist transcription, thereby leading to initiation of random XCI. PMID- 21298086 TI - Bub1-mediated adaptation of the spindle checkpoint. AB - During cell division, the spindle checkpoint ensures accurate chromosome segregation by monitoring the kinetochore-microtubule interaction and delaying the onset of anaphase until each pair of sister chromosomes is properly attached to microtubules. The spindle checkpoint is deactivated as chromosomes start moving toward the spindles in anaphase, but the mechanisms by which this deactivation and adaptation to prolonged mitotic arrest occur remain obscure. Our results strongly suggest that Cdc28-mediated phosphorylation of Bub1 at T566 plays an important role for the degradation of Bub1 in anaphase, and the phosphorylation is required for adaptation of the spindle checkpoint to prolonged mitotic arrest. PMID- 21298087 TI - A new sauropodomorph dinosaur from the Early Jurassic of Patagonia and the origin and evolution of the sauropod-type sacrum. AB - BACKGROUND: The origin of sauropod dinosaurs is one of the major landmarks of dinosaur evolution but is still poorly understood. This drastic transformation involved major skeletal modifications, including a shift from the small and gracile condition of primitive sauropodomorphs to the gigantic and quadrupedal condition of sauropods. Recent findings in the Late Triassic-Early Jurassic of Gondwana provide critical evidence to understand the origin and early evolution of sauropods. METHODOLOGY/PRINCIPAL FINDINGS: A new sauropodomorph dinosaur, Leonerasaurus taquetrensis gen. et sp. nov., is described from the Las Leoneras Formation of Central Patagonia (Argentina). The new taxon is diagnosed by the presence of anterior unserrated teeth with a low spoon-shaped crown, amphicoelous and acamerate vertebral centra, four sacral vertebrae, and humeral deltopectoral crest low and medially deflected along its distal half. The phylogenetic analysis depicts Leonerasaurus as one of the closest outgroups of Sauropoda, being the sister taxon of a clade of large bodied taxa composed of Melanorosaurus and Sauropoda. CONCLUSIONS/SIGNIFICANCE: The dental and postcranial anatomy of Leonerasaurus supports its close affinities with basal sauropods. Despite the small size and plesiomorphic skeletal anatomy of Leonerasaurus, the four vertebrae that compose its sacrum resemble that of the large-bodied primitive sauropods. This shows that the appearance of the sauropod-type of sacrum predated the marked increase in body size that characterizes the origins of sauropods, rejecting a causal explanation and evolutionary linkage between this sacral configuration and body size. Alternative phylogenetic placements of Leonerasaurus as a basal anchisaurian imply a convergent acquisition of the sauropod-type sacrum in the new small-bodied taxon, also rejecting an evolutionary dependence of sacral configuration and body size in sauropodomorphs. This and other recent discoveries are showing that the characteristic sauropod body plan evolved gradually, with a step-wise pattern of character appearance. PMID- 21298088 TI - A novel method for volumetric MRI response assessment of enhancing brain tumors. AB - Current radiographic response criteria for brain tumors have difficulty describing changes surrounding postoperative resection cavities. Volumetric techniques may offer improved assessment, however usually are time-consuming, subjective and require expert opinion and specialized magnetic resonance imaging (MRI) sequences. We describe the application of a novel volumetric software algorithm that is nearly fully automated and uses standard T1 pre- and post contrast MRI sequences. T1-weighted pre- and post-contrast images are automatically fused and normalized. The tumor region of interest is grossly outlined by the user. An atlas of the nasal mucosa is automatically detected and used to normalize levels of enhancement. The volume of enhancing tumor is then automatically calculated. We tested the ability of our method to calculate enhancing tumor volume with resection cavity collapse and when the enhancing tumor is obscured by subacute blood in a resection cavity. To determine variability in results, we compared narrowly-defined tumor regions with tumor regions that include adjacent meningeal enhancement and also compared different contrast enhancement threshold levels used for the automatic calculation of enhancing tumor volume. Our method quantified enhancing tumor volume despite resection cavity collapse. It detected tumor volume increase in the midst of blood products that incorrectly caused decreased measurements by other techniques. Similar trends in volume changes across scans were seen with inclusion or exclusion of meningeal enhancement and despite different automated thresholds for tissue enhancement. Our approach appears to overcome many of the challenges with response assessment of enhancing brain tumors and warrants further examination and validation. PMID- 21298089 TI - The relation between self-reported empathy and motor identification with imagined agents. AB - BACKGROUND: In a previous study, we found that when required to imagine another person performing an action, participants reported a higher correspondence between their own handedness and the hand used by the imagined person when the agent was seen from the back compared to when the agent was seen from the front. This result was explained as evidence of a greater involvement of motor areas in the back-view perspective, possibly indicating a greater proneness to put oneself in the agent's shoes in such a condition. In turn, the proneness to put oneself in another's shoes could also be considered as a cue of greater identification with the other, that is a form of empathy. If this is the case, the proportion of lateral matches vs mismatches should be different for subjects with high and low self-reported empathy. In the present study, we aimed at testing this hypothesis. METHODOLOGY/PRINCIPAL FINDINGS: Participants were required to imagine a person performing a single manual action in a back view and to indicate the hand used by the imagined person during movement execution. Consistent with our hypothesis, the proportion of matching between the handedness of participants and the handedness of agents imagined was higher for participants scoring high in a self report measure of empathy. Importantly, this relationship was specific for females. CONCLUSIONS/SIGNIFICANCE: At least for females, our data seem to corroborate the idea of a link between self-reported empathy and motor identification with imagined agents. This sex-specific result is consistent with neuroimaging studies indicating a stronger involvement of action representations during emotional and empathic processing in females than in males. In sum, our findings underline the possibility of employing behavioral research as a test-bed for theories deriving from functional studies suggesting a link between empathic processing and the activation of motor-related areas. PMID- 21298090 TI - Low dose organochlorine pesticides and polychlorinated biphenyls predict obesity, dyslipidemia, and insulin resistance among people free of diabetes. AB - BACKGROUND: There is emerging evidence that background exposure to persistent organic pollutants (POPs) are important in the development of conditions predisposing to diabetes as well as of type 2 diabetes itself. We recently reported that low dose POPs predicted incident type 2 diabetes in a nested case control study. The current study examined if low dose POPs predicted future adiposity, dyslipidemia, and insulin resistance among controls without diabetes in that study. METHODOLOGY/PRINCIPAL FINDINGS: The 90 controls were diabetes-free during 20 years follow-up. They were a stratified random sample, enriched with overweight and obese persons. POPs measured in 1987-88 (year 2) sera included 8 organochlorine (OC) pesticides, 22 polychlorinated biphenyls (PCBs), and 1 polybrominated biphenyl (PBB). Body mass index (BMI), triglycerides, HDL cholesterol, LDL-cholesterol, and homeostasis model assessment value for insulin resistance (HOMA-IR) were study outcomes at 2005-06 (year 20). The evolution of study outcomes during 18 years by categories of serum concentrations of POPs at year 2 was evaluated by adjusting for the baseline values of outcomes plus potential confounders. Parallel to prediction of type 2 diabetes, many statistically significant associations of POPs with dysmetabolic conditions appeared at low dose, forming inverted U-shaped dose-response relations. Among OC pesticides, p,p'-DDE most consistently predicted higher BMI, triglycerides, and HOMA-IR and lower HDL-cholesterol at year 20 after adjusting for baseline values. Oxychlordane, trans-nonachlor, and hexachlorobenzene also significantly predicted higher triglycerides. Persistent PCBs with >=7 chlorides predicted higher BMI, triglycerides, and HOMA-IR and lower HDL-cholesterol at year 20 with similar dose response curves. CONCLUSIONS/SIGNIFICANCE: Simultaneous exposure to various POPs in the general population may contribute to development of obesity, dyslipidemia, and insulin resistance, common precursors of type 2 diabetes and cardiovascular diseases. Although obesity is a primary cause of these metabolic abnormalities, POPs exposure may contribute to excess adiposity and other features of dysmetabolism. PMID- 21298091 TI - Abrogation of the twin arginine transport system in Salmonella enterica serovar Typhimurium leads to colonization defects during infection. AB - TatC (STM3975) is a highly conserved component of the Twin Arginine Transport (Tat) systems that is required for transport of folded proteins across the inner membrane in gram-negative bacteria. We previously identified a DeltatatC mutant as defective in competitive infections with wild type ATCC14028 during systemic infection of Salmonella-susceptible BALB/c mice. Here we confirm these results and show that the DeltatatC mutant is internalized poorly by cultured J774-A.1 mouse macrophages a phenotype that may be related to the systemic infection defect. This mutant is also defective for short-term intestinal and systemic colonization after oral infection of BALB/c mice and is shed in reduced numbers in feces from orally infected Salmonella-resistant (CBA/J) mice. We show that the DeltatatC mutant is highly sensitive to bile acids perhaps resulting in the defect in intestinal infection that we observe. Finally, the DeltatatC mutant has an unusual combination of motility phenotypes in Salmonella; it is severely defective for swimming motility but is able to swarm well. The DeltatatC mutant has a lower amount of flagellin on the bacterial surface during swimming motility but normal levels under swarming conditions. PMID- 21298092 TI - MR angiography of collateral arteries in a hind limb ischemia model: comparison between blood pool agent Gadomer and small contrast agent Gd-DTPA. AB - The objective of this study was to compare the blood pool agent Gadomer with a small contrast agent for the visualization of ultra-small, collateral arteries (diameter<1 mm) with high resolution steady-state MR angiography (SS-MRA) in a rabbit hind limb ischemia model. Ten rabbits underwent unilateral femoral artery ligation. On days 14 and 21, high resolution SS-MRA (voxel size 0.49*0.49*0.50 mm(3)) was performed on a 3 Tesla clinical system after administration of either Gadomer (dose: 0.10 mmol/kg) or a small contrast agent (gadopentetate dimeglumine (Gd-DTPA), dose: 0.20 mmol/kg). All animals received both contrast agents on separate days. Selective intra-arterial x-ray angiograms (XRAs) were obtained in the ligated limb as a reference. The number of collaterals was counted by two independent observers. Image quality was evaluated with the contrast-to-noise ratio (CNR) in the femoral artery and collateral arteries. CNR for Gadomer was higher in both the femoral artery (Gadomer: 73+/-5 (mean +/- SE); Gd-DTPA: 40+/ 3; p<0.01) and collateral arteries (Gadomer: 18+/-4; Gd-DTPA: 9+/-1; p = 0.04). Neither day of acquisition nor contrast agent used influenced the number of identified collateral arteries (p = 0.30 and p = 0.14, respectively). An average of 4.5+/-1.0 (day 14, mean +/- SD) and 5.3+/-1.2 (day 21) collaterals was found, which was comparable to XRA (5.6+/-1.7, averaged over days 14 and 21; p>0.10). Inter-observer variation was 24% and 18% for Gadomer and Gd-DTPA, respectively. In conclusion, blood pool agent Gadomer improved vessel conspicuity compared to Gd-DTPA. Steady-state MRA can be considered as an excellent non-invasive alternative to intra-arterial XRA for the visualization of ultra-small collateral arteries. PMID- 21298093 TI - Cause of death affects racial classification on death certificates. AB - Recent research suggests racial classification is responsive to social stereotypes, but how this affects racial classification in national vital statistics is unknown. This study examines whether cause of death influences racial classification on death certificates. We analyze the racial classifications from a nationally representative sample of death certificates and subsequent interviews with the decedents' next of kin and find notable discrepancies between the two racial classifications by cause of death. Cirrhosis decedents are more likely to be recorded as American Indian on their death certificates, and homicide victims are more likely to be recorded as Black; these results remain net of controls for followback survey racial classification, indicating that the relationship we reveal is not simply a restatement of the fact that these causes of death are more prevalent among certain groups. Our findings suggest that seemingly non-racial characteristics, such as cause of death, affect how people are racially perceived by others and thus shape U.S. official statistics. PMID- 21298094 TI - A unique human-fox burial from a pre-Natufian cemetery in the Levant (Jordan). AB - New human burials from northern Jordan provide important insights into the appearance of cemeteries and the nature of human-animal relationships within mortuary contexts during the Epipalaeolithic period (c. 23,000-11,600 cal BP) in the Levant, reinforcing a socio-ideological relationship that goes beyond predator-prey. Previous work suggests that archaeological features indicative of social complexity occur suddenly during the latest Epipalaeolithic phase, the Natufian (c. 14,500-11,600 cal BP). These features include sedentism, cemeteries, architecture, food production, including animal domestication, and burials with elaborate mortuary treatments. Our findings from the pre-Natufian (Middle Epipalaeolithic) cemetery of 'Uyun al-Hammam demonstrate that joint human-animal mortuary practices appear earlier in the Epipalaeolithic. We describe the earliest human-fox burial in the Near East, where the remains of dogs have been found associated with human burials at a number of Natufian sites. This is the first time that a fox has been documented in association with human interments pre-dating the Natufian and with a particular suite of grave goods. Analysis of the human and animal bones and their associated artefacts provides critical data on the nature and timing of these newly-developing relationships between people and animals prior to the appearance of domesticated dogs in the Natufian. PMID- 21298095 TI - Variance component analysis of a multi-site study for the reproducibility of multiple reaction monitoring measurements of peptides in human plasma. AB - BACKGROUND: In the Addona et al. paper (Nature Biotechnology 2009), a large-scale multi-site study was performed to quantify Multiple Reaction Monitoring (MRM) measurements of proteins spiked in human plasma. The unlabeled signature peptides derived from the seven target proteins were measured at nine different concentration levels, and their isotopic counterparts were served as the internal standards. METHODOLOGY/PRINCIPAL FINDINGS: In this paper, the sources of variation are analyzed by decomposing the variance into parts attributable to specific experimental factors: technical replicates, sites, peptides, transitions within each peptide, and higher-order interaction terms based on carefully built mixed effects models. The factors of peptides and transitions are shown to be major contributors to the variance of the measurements considering heavy (isotopic) peptides alone. For the light ((12)C) peptides alone, in addition to these factors, the factor of study*peptide also contributes significantly to the variance of the measurements. Heterogeneous peptide component models as well as influence analysis identify the outlier peptides in the study, which are then excluded from the analysis. Using a log-log scale transformation and subtracting the heavy/isotopic peptide [internal standard] measurement from the peptide measurements (i.e., taking the logarithm of the peak area ratio in the original scale establishes that), the MRM measurements are overall consistent across laboratories following the same standard operating procedures, and the variance components related to sites, transitions and higher-order interaction terms involving sites have greatly reduced impact. Thus the heavy peptides have been effective in reducing apparent inter-site variability. In addition, the estimates of intercepts and slopes of the calibration curves are calculated for the sub studies. CONCLUSIONS/SIGNIFICANCE: The MRM measurements are overall consistent across laboratories following the same standard operating procedures, and heavy peptides can be used as an effective internal standard for reducing apparent inter-site variability. Mixed effects modeling is a valuable tool in mass spectrometry-based proteomics research. PMID- 21298096 TI - Rare copy number deletions predict individual variation in intelligence. AB - Phenotypic variation in human intellectual functioning shows substantial heritability, as demonstrated by a long history of behavior genetic studies. Many recent molecular genetic studies have attempted to uncover specific genetic variations responsible for this heritability, but identified effects capture little variance and have proven difficult to replicate. The present study, motivated an interest in "mutation load" emerging from evolutionary perspectives, examined the importance of the number of rare (or infrequent) copy number variations (CNVs), and the total number of base pairs included in such deletions, for psychometric intelligence. Genetic data was collected using the Illumina 1MDuoBeadChip Array from a sample of 202 adult individuals with alcohol dependence, and a subset of these (N = 77) had been administered the Wechsler Abbreviated Scale of Intelligence (WASI). After removing CNV outliers, the impact of rare genetic deletions on psychometric intelligence was investigated in 74 individuals. The total length of the rare deletions significantly and negatively predicted intelligence (r = -.30, p = .01). As prior studies have indicated greater heritability in individuals with relatively higher parental socioeconomic status (SES), we also examined the impact of ethnicity (Anglo/White vs. Other), as a proxy measure of SES; these groups did not differ on any genetic variable. This categorical variable significantly moderated the effect of length of deletions on intelligence, with larger effects being noted in the Anglo/White group. Overall, these results suggest that rare deletions (between 5% and 1% population frequency or less) adversely affect intellectual functioning, and that pleotropic effects might partly account for the association of intelligence with health and mental health status. Significant limitations of this research, including issues of generalizability and CNV measurement, are discussed. PMID- 21298097 TI - Mammalian frataxin: an essential function for cellular viability through an interaction with a preformed ISCU/NFS1/ISD11 iron-sulfur assembly complex. AB - BACKGROUND: Frataxin, the mitochondrial protein deficient in Friedreich ataxia, a rare autosomal recessive neurodegenerative disorder, is thought to be involved in multiple iron-dependent mitochondrial pathways. In particular, frataxin plays an important role in the formation of iron-sulfur (Fe-S) clusters biogenesis. METHODOLOGY/PRINCIPAL FINDINGS: We present data providing new insights into the interactions of mammalian frataxin with the Fe-S assembly complex by combining in vitro and in vivo approaches. Through immunoprecipitation experiments, we show that the main endogenous interactors of a recombinant mature human frataxin are ISCU, NFS1 and ISD11, the components of the core Fe-S assembly complex. Furthermore, using a heterologous expression system, we demonstrate that mammalian frataxin interacts with the preformed core complex, rather than with the individual components. The quaternary complex can be isolated in a stable form and has a molecular mass of ~190 kDa. Finally, we demonstrate that the mature human FXN(81-210) form of frataxin is the essential functional form in vivo. CONCLUSIONS/SIGNIFICANCE: Our results suggest that the interaction of frataxin with the core ISCU/NFS1/ISD11 complex most likely defines the essential function of frataxin. Our results provide new elements important for further understanding the early steps of de novo Fe-S cluster biosynthesis. PMID- 21298098 TI - Tendon is covered by a basement membrane epithelium that is required for cell retention and the prevention of adhesion formation. AB - The ability of tendons to glide smoothly during muscle contraction is impaired after injury by fibrous adhesions that form between the damaged tendon surface and surrounding tissues. To understand how adhesions form we incubated excised tendons in fibrin gels (to mimic the homeostatic environment at the injury site) and assessed cell migration. We noticed cells exiting the tendon from only the cut ends. Furthermore, treatment of the tendon with trypsin resulted in cell extravagation from the shaft of the tendons. Electron microscopy and immunolocalisation studies showed that the tendons are covered by a novel cell layer in which a collagen type IV/laminin basement membrane (BM) overlies a keratinised epithelium. PCR and western blot analyses confirmed the expression of laminin beta1 in surface cells, only. To evaluate the cell retentive properties of the BM in vivo we examined the tendons of the Col4a1(+/Svc) mouse that is heterozygous for a G-to-A transition in the Col4a1 gene that produces a G1064D substitution in the alpha1(IV) chain of collagen IV. The flexor tendons had a discontinuous BM, developed fibrous adhesions with overlying tissues, and were acellular at sites of adhesion formation. In further experiments, tenotomy of wild-type mice resulted in expression of laminin throughout the adhesion. In conclusion, we show the existence of a novel tendon BM-epithelium that is required to prevent adhesion formation. The Col4a1(+/Svc) mouse is an effective animal model for studying adhesion formation because of the presence of a structurally-defective collagen type IV-containing BM. PMID- 21298099 TI - Stress strengthens memory of first impressions of others' positive personality traits. AB - Encounters with strangers bear potential for social conflict and stress, but also allow the formation of alliances. First impressions of other people play a critical role in the formation of alliances, since they provide a learned base to infer the other's future social attitude. Stress can facilitate emotional memories but it is unknown whether stress strengthens our memory for newly acquired impressions of other people's personality traits. To answer this question, we subjected 60 students (37 females, 23 males) to an impression formation task, viewing portraits together with brief positive vs. negative behavior descriptions, followed by a 3-min cold pressor stress test or a non stressful control procedure. The next day, novel and old portraits were paired with single trait adjectives, the old portraits with a trait adjective matching the previous day's behavior description. After a filler task, portraits were presented again and subjects were asked to recall the trait adjective. Cued recall was higher for old (previously implied) than the novel portraits' trait adjectives, indicating validity of the applied test procedures. Overall, recall rate of implied trait adjectives did not differ between the stress and the control group. However, while the control group showed a better memory performance for others' implied negative personality traits, the stress group showed enhanced recall for others' implied positive personality traits. This result indicates that post-learning stress affects consolidation of first impressions in a valence-specific manner. We propose that the stress-induced strengthening of memory of others' positive traits forms an important cue for the formation of alliances in stressful conditions. PMID- 21298100 TI - Lycium barbarum polysaccharides reduce neuronal damage, blood-retinal barrier disruption and oxidative stress in retinal ischemia/reperfusion injury. AB - Neuronal cell death, glial cell activation, retinal swelling and oxidative injury are complications in retinal ischemia/reperfusion (I/R) injuries. Lycium barbarum polysaccharides (LBP), extracts from the wolfberries, are good for "eye health" according to Chinese medicine. The aim of our present study is to explore the use of LBP in retinal I/R injury. Retinal I/R injury was induced by surgical occlusion of the internal carotid artery. Prior to induction of ischemia, mice were treated orally with either vehicle (PBS) or LBP (1 mg/kg) once a day for 1 week. Paraffin-embedded retinal sections were prepared. Viable cells were counted; apoptosis was assessed using TUNEL assay. Expression levels of glial fibrillary acidic protein (GFAP), aquaporin-4 (AQP4), poly(ADP-ribose) (PAR) and nitrotyrosine (NT) were investigated by immunohistochemistry. The integrity of blood-retinal barrier (BRB) was examined by IgG extravasations. Apoptosis and decreased viable cell count were found in the ganglion cell layer (GCL) and the inner nuclear layer (INL) of the vehicle-treated I/R retina. Additionally, increased retinal thickness, GFAP activation, AQP4 up-regulation, IgG extravasations and PAR expression levels were observed in the vehicle-treated I/R retina. Many of these changes were diminished or abolished in the LBP-treated I/R retina. Pre-treatment with LBP for 1 week effectively protected the retina from neuronal death, apoptosis, glial cell activation, aquaporin water channel up regulation, disruption of BRB and oxidative stress. The present study suggests that LBP may have a neuroprotective role to play in ocular diseases for which I/R is a feature. PMID- 21298101 TI - DISC1 and Huntington's disease--overlapping pathways of vulnerability to neurological disorder? AB - We re-annotated the interacting partners of the neuronal scaffold protein DISC1 using a knowledge-based approach that incorporated recent protein interaction data and published literature to. This revealed two highly connected networks. These networks feature cellular function and maintenance, and cell signaling. Of potentially greatest interest was the novel finding of a high degree of connectivity between the DISC1 scaffold protein, linked to psychiatric illness, and huntingtin, the protein which is mutated in Huntington's disease. The potential link between DISC1, huntingtin and their interacting partners may open new areas of research into the effects of pathway dysregulation in severe neurological disorders. PMID- 21298102 TI - A role for the RNA chaperone Hfq in controlling adherent-invasive Escherichia coli colonization and virulence. AB - Adherent-invasive Escherichia coli (AIEC) has been linked with the onset and perpetuation of inflammatory bowel diseases. The AIEC strain LF82 was originally isolated from an ileal biopsy from a patient with Crohn's disease. The pathogenesis of LF82 results from its abnormal adherence to and subsequent invasion of the intestinal epithelium coupled with its ability to survive phagocytosis by macrophages once it has crossed the intestinal barrier. To gain further insight into AIEC pathogenesis we employed the nematode Caenorhabditis elegans as an in vivo infection model. We demonstrate that AIEC strain LF82 forms a persistent infection in C. elegans, thereby reducing the host lifespan significantly. This host killing phenotype was associated with massive bacterial colonization of the nematode intestine and damage to the intestinal epithelial surface. C. elegans killing was independent of known LF82 virulence determinants but was abolished by deletion of the LF82 hfq gene, which encodes an RNA chaperone involved in mediating posttranscriptional gene regulation by small non coding RNAs. This finding reveals that important aspects of LF82 pathogenesis are controlled at the posttranscriptional level by riboregulation. The role of Hfq in LF82 virulence was independent of its function in regulating RpoS and RpoE activity. Further, LF82Deltahfq mutants were non-motile, impaired in cell invasion and highly sensitive to various chemical stress conditions, reinforcing the multifaceted function of Hfq in mediating bacterial adaptation. This study highlights the usefulness of simple non-mammalian infection systems for the identification and analysis of bacterial virulence factors. PMID- 21298103 TI - Malectin participates in a backup glycoprotein quality control pathway in the mammalian ER. AB - Malectin is a conserved, endoplasmic reticulum (ER)-resident lectin that recognizes high mannose oligosaccharides displaying terminal glucose residues. Here we show that Malectin is an ER stress-induced protein that selectively associates with glycopolypeptides without affecting their entry and their retention in the Calnexin chaperone system. Analysis of the obligate Calnexin client influenza virus hemagglutinin (HA) revealed that Calnexin and Malectin associated with different timing to different HA conformers and that Malectin associated with misfolded HA. Analysis of the facultative Calnexin clients NHK and alpha1-antitrypsin (alpha1AT) revealed that induction of Malectin expression to simulate conditions of ER stress resulted in persistent association between the ER lectin and the model cargo glycoproteins, interfered with processing of cargo-linked oligosaccharides and reduced cargo secretion. We propose that Malectin intervention is activated upon ER stress to inhibit secretion of defective gene products that might be generated under conditions of aberrant functioning of the ER quality control machinery. PMID- 21298104 TI - Visual stability and the motion aftereffect: a psychophysical study revealing spatial updating. AB - Eye movements create an ever-changing image of the world on the retina. In particular, frequent saccades call for a compensatory mechanism to transform the changing visual information into a stable percept. To this end, the brain presumably uses internal copies of motor commands. Electrophysiological recordings of visual neurons in the primate lateral intraparietal cortex, the frontal eye fields, and the superior colliculus suggest that the receptive fields (RFs) of special neurons shift towards their post-saccadic positions before the onset of a saccade. However, the perceptual consequences of these shifts remain controversial. We wanted to test in humans whether a remapping of motion adaptation occurs in visual perception.The motion aftereffect (MAE) occurs after viewing of a moving stimulus as an apparent movement to the opposite direction. We designed a saccade paradigm suitable for revealing pre-saccadic remapping of the MAE. Indeed, a transfer of motion adaptation from pre-saccadic to post saccadic position could be observed when subjects prepared saccades. In the remapping condition, the strength of the MAE was comparable to the effect measured in a control condition (33+/-7% vs. 27+/-4%). Contrary, after a saccade or without saccade planning, the MAE was weak or absent when adaptation and test stimulus were located at different retinal locations, i.e. the effect was clearly retinotopic. Regarding visual cognition, our study reveals for the first time predictive remapping of the MAE but no spatiotopic transfer across saccades. Since the cortical sites involved in motion adaptation in primates are most likely the primary visual cortex and the middle temporal area (MT/V5) corresponding to human MT, our results suggest that pre-saccadic remapping extends to these areas, which have been associated with strict retinotopy and therefore with classical RF organization. The pre-saccadic transfer of visual features demonstrated here may be a crucial determinant for a stable percept despite saccades. PMID- 21298105 TI - Detecting instability in animal social networks: genetic fragmentation is associated with social instability in rhesus macaques. AB - The persistence of biological systems requires evolved mechanisms which promote stability. Cohesive primate social groups are one example of stable biological systems, which persist in spite of regular conflict. We suggest that genetic relatedness and its associated kinship structure are a potential source of stability in primate social groups as kinship structure is an important organizing principle in many animal societies. We investigated the effect of average genetic relatedness per matrilineal family on the stability of matrilineal grooming and agonistic interactions in 48 matrilines from seven captive groups of rhesus macaques. Matrilines with low average genetic relatedness show increased family-level instability such as: more sub-grouping in their matrilineal groom network, more frequent fighting with kin, and higher rates of wounding. Family-level instability in multiple matrilines within a group is further associated with group-level instability such as increased wounding. Stability appears to arise from the presence of clear matrilineal structure in the rhesus macaque group hierarchy, which is derived from cohesion among kin in their affiliative and agonistic interactions with each other. We conclude that genetic relatedness and kinship structure are an important source of group stability in animal societies, particularly when dominance and/or affilative interactions are typically governed by kinship. PMID- 21298106 TI - Ablations of ghrelin and ghrelin receptor exhibit differential metabolic phenotypes and thermogenic capacity during aging. AB - BACKGROUND: Obesity is a hallmark of aging in many Western societies, and is a precursor to numerous serious age-related diseases. Ghrelin (Ghrl), via its receptor (growth hormone secretagogue receptor, GHS-R), is shown to stimulate GH secretion and appetite. Surprisingly, our previous studies showed that Ghrl(-/-) mice have impaired thermoregulatory responses to cold and fasting stresses, while Ghsr(-/-) mice are adaptive. METHODOLOGY/PRINCIPAL FINDINGS: To elucidate the mechanism, we analyzed the complete metabolic profiles of younger (3-4 months) and older (10-12 months) Ghrl(-/-) and Ghsr(-/-) mice. Food intake and locomotor activity were comparable for both null mice and their wild-type (WT) counterparts, regardless of age. There was also no difference in body composition between younger null mice and their WT counterparts. As the WT mice aged, as expected, the fat/lean ratio increased and energy expenditure (EE) decreased. Remarkably, however, older Ghsr(-/-) mice exhibited reduced fat/lean ratio and increased EE when compared to older WT mice, thus retaining a youthful lean and high EE phenotype; in comparison, there was no significant difference with EE in Ghrl(-/-) mice. In line with the EE data, the thermogenic regulator, uncoupling protein 1 (UCP1), was significantly up-regulated in brown adipose tissue (BAT) of Ghsr(-/-) mice, but not in Ghrl(-/-) mice. CONCLUSIONS: Our data therefore suggest that GHS-R ablation activates adaptive thermogenic function(s) in BAT and increases EE, thereby enabling the retention of a lean phenotype. This is the first direct evidence that the ghrelin signaling pathway regulates fat-burning BAT to affect energy balance during aging. This regulation is likely mediated through an as-yet-unidentified new ligand of GHS-R. PMID- 21298107 TI - The cryptic African wolf: Canis aureus lupaster is not a golden jackal and is not endemic to Egypt. AB - The Egyptian jackal (Canis aureus lupaster) has hitherto been considered a large, rare subspecies of the golden jackal (C. aureus). It has maintained its taxonomical status to date, despite studies demonstrating morphological similarities to the grey wolf (C. lupus). We have analyzed 2055 bp of mitochondrial DNA from C. a. lupaster and investigated the similarity to C. aureus and C. lupus. Through phylogenetic comparison with all wild wolf-like canids (based on 726 bp of the Cytochrome b gene) we conclusively (100% bootstrap support) place the Egyptian jackal within the grey wolf species complex, together with the Holarctic wolf, the Indian wolf and the Himalayan wolf. Like the two latter taxa, C. a. lupaster seems to represent an ancient wolf lineage which most likely colonized Africa prior to the northern hemisphere radiation. We thus refer to C. a. lupaster as the African wolf. Furthermore, we have detected C. a. lupaster individuals at two localities in the Ethiopian highlands, extending the distribution by at least 2,500 km southeast. The only grey wolf species to inhabit the African continent is a cryptic species for which the conservation status urgently needs assessment. PMID- 21298108 TI - Use of rbcL and trnL-F as a two-locus DNA barcode for identification of NW European ferns: an ecological perspective. AB - Although consensus has now been reached on a general two-locus DNA barcode for land plants, the selected combination of markers (rbcL + matK) is not applicable for ferns at the moment. Yet especially for ferns, DNA barcoding is potentially of great value since fern gametophytes--while playing an essential role in fern colonization and reproduction--generally lack the morphological complexity for morphology-based identification and have therefore been underappreciated in ecological studies. We evaluated the potential of a combination of rbcL with a noncoding plastid marker, trnL-F, to obtain DNA-identifications for fern species. A regional approach was adopted, by creating a reference database of trusted rbcL and trnL-F sequences for the wild-occurring homosporous ferns of NW-Europe. A combination of parsimony analyses and distance-based analyses was performed to evaluate the discriminatory power of the two-region barcode. DNA was successfully extracted from 86 tiny fern gametophytes and was used as a test case for the performance of DNA-based identification. Primer universality proved high for both markers. Based on the combined rbcL + trnL-F dataset, all genera as well as all species with non-equal chloroplast genomes formed their own well supported monophyletic clade, indicating a high discriminatory power. Interspecific distances were larger than intraspecific distances for all tested taxa. Identification tests on gametophytes showed a comparable result. All test samples could be identified to genus level, species identification was well possible unless they belonged to a pair of Dryopteris species with completely identical chloroplast genomes. Our results suggest a high potential of the combined use of rbcL and trnL-F as a two-locus cpDNA barcode for identification of fern species. A regional approach may be preferred for ecological tests. We here offer such a ready-to-use barcoding approach for ferns, which opens the way for answering a whole range of questions previously unaddressed in fern gametophyte ecology. PMID- 21298109 TI - Implant size and fixation mode strongly influence tissue reactions in the CNS. AB - The function of chronic brain machine interfaces depends on stable electrical contact between neurons and electrodes. A key step in the development of interfaces is therefore to identify implant configurations that minimize adverse long-term tissue reactions. To this end, we here characterized the separate and combined effects of implant size and fixation mode at 6 and 12 weeks post implantation in rat (n = 24) cerebral cortex. Neurons and activated microglia and astrocytes were visualized using NeuN, ED1 and GFAP immunofluorescence microscopy, respectively. The contributions of individual experimental variables to the tissue response were quantified. Implants tethered to the skull caused larger tissue reactions than un-tethered implants. Small diameter (50 um) implants elicited smaller tissue reactions and resulted in the survival of larger numbers of neurons than did large diameter (200 um) implants. In addition, tethering resulted in an oval-shaped cavity, with a cross-section area larger than that of the implant itself, and in marked changes in morphology and organization of neurons in the region closest to the tissue interface. Most importantly, for implants that were both large diameter and tethered, glia activation was still ongoing 12 weeks after implantation, as indicated by an increase in GFAP staining between week 6 and 12, while this pattern was not observed for un-tethered, small diameter implants. Our findings therefore clearly indicate that the combined small diameter, un-tethered implants cause the smallest tissue reactions. PMID- 21298110 TI - Overexpression of full-length ETV1 transcripts in clinical prostate cancer due to gene translocation. AB - ETV1 is overexpressed in a subset of clinical prostate cancers as a fusion transcript with many different partners. However, ETV1 can also be overexpressed as a full-length transcript. Full-length ETV1 protein functions differently from truncated ETV1 produced by fusion genes. In this study we describe the genetic background of full-length ETV1 overexpression and the biological properties of different full-length ETV1 isoforms in prostate cancer. Break-apart FISH showed in five out of six patient samples with overexpression of full-length ETV1 a genomic rearrangement of the gene, indicating frequent translocation. We were able to study the rearrangements in more detail in two tumors. In the first tumor 5'-RACE on cDNA showed linkage of the complete ETV1 transcript to the first exon of a prostate-specific two exon ncRNA gene that maps on chromosome 14 (EST14). This resulted in the expression of both full-length ETV1 transcripts and EST14 ETV1 fusion transcripts. In chromosome spreads of a xenograft derived from the second prostate cancer we observed a complex ETV1 translocation involving a chromosome 7 fragment that harbors ETV1 and fragments of chromosomes 4 and 10. Further studies revealed the overexpression of several different full-length transcripts, giving rise to four protein isoforms with different N-terminal regions. Even the shortest isoform synthesized by full-length ETV1 stimulated in vitro anchorage-independent growth of PNT2C2 prostate cells. This contrasts the lack of activity of even shorter N-truncated ETV1 produced by fusion transcripts. Our findings that in clinical prostate cancer overexpression of full-length ETV1 is due to genomic rearrangements involving different chromosomes and the identification of a shortened biologically active ETV1 isoform are highly relevant for understanding the mechanism of ETV1 function in prostate cancer. PMID- 21298111 TI - Visceral adipose inflammation in obesity is associated with critical alterations in tregulatory cell numbers. AB - BACKGROUND: The development of insulin resistance (IR) in mouse models of obesity and type 2 diabetes mellitus (DM) is characterized by progressive accumulation of inflammatory macrophages and subpopulations of T cells in the visceral adipose. Regulatory T cells (Tregs) may play a critical role in modulating tissue inflammation via their interactions with both adaptive and innate immune mechanisms. We hypothesized that an imbalance in Tregs is a critical determinant of adipose inflammation and investigated the role of Tregs in IR/obesity through coordinated studies in mice and humans. METHODS AND FINDINGS: Foxp3-green fluorescent protein (GFP) "knock-in" mice were randomized to a high-fat diet intervention for a duration of 12 weeks to induce DIO/IR. Morbidly obese humans without overt type 2 DM (n = 13) and lean controls (n = 7) were recruited prospectively for assessment of visceral adipose inflammation. DIO resulted in increased CD3(+)CD4(+), and CD3(+)CD8(+) cells in visceral adipose with a striking decrease in visceral adipose Tregs. Treg numbers in visceral adipose inversely correlated with CD11b(+)CD11c(+) adipose tissue macrophages (ATMs). Splenic Treg numbers were increased with up-regulation of homing receptors CXCR3 and CCR7 and marker of activation CD44. In-vitro differentiation assays showed an inhibition of Treg differentiation in response to conditioned media from inflammatory macrophages. Human visceral adipose in morbid obesity was characterized by an increase in CD11c(+) ATMs and a decrease in foxp3 expression. CONCLUSIONS: Our experiments indicate that obesity in mice and humans results in adipose Treg depletion. These changes appear to occur via reduced local differentiation rather than impaired homing. Our findings implicate a role for Tregs as determinants of adipose inflammation. PMID- 21298112 TI - Resident memory T cells (T(RM)) are abundant in human lung: diversity, function, and antigen specificity. AB - Recent studies have shown that tissue resident memory T cells (T(RM)) are critical to antiviral host defense in peripheral tissues. This new appreciation of T(RM) that reside in epithelial tissues and mediate host defense has been studied most extensively in skin: adult human skin contains large numbers of functional T(RM) that express skin specific markers. Indeed, more than twice as many T cells reside in skin as in peripheral blood. This T cell population has a diverse T cell receptor repertoire, and can produce a broad array of cytokines. More recently, we have begun to examine other epithelial tissues for the presence of resident T cells. In the present study, we asked whether analogous populations of resident T cells could be found in human lung. We were able to demonstrate abundant resident T cells in human lung-more than 10 billion T cells were present. Lung T cells were largely of the effector memory T cell (T(EM)) phenotype, though small numbers of central memory T cells (T(CM)) and T regulatory cells (T(reg)) could be identified. Lung T cells had a diverse T cell receptor repertoire and subsets produced IL-17, IL-4, IFNgamma, as well as TNFalpha. A significant number of lung T(RM) CD4+Th cells produced more than one cytokine, identifying them as "multifunctional" Th1 type cells. Finally, lung T(RM), but not T(RM) resident to skin or T cells from blood, proliferated in response to influenza virus. This work suggests that normal human lung contains large numbers of T(RM) cells, and these cells are poised to respond to recall antigens previously encountered through lung mucosa. This population of T cells may contribute to the pathogenesis of asthma and other T cell mediated lung diseases. PMID- 21298114 TI - Development and characterization of synthetic glucopyranosyl lipid adjuvant system as a vaccine adjuvant. AB - Innate immune responses to vaccine adjuvants based on lipopolysaccharide (LPS), a component of gram-negative bacterial cell walls, are driven by Toll-like receptor (TLR) 4 and adaptor proteins including MyD88 and TRIF, leading to the production of inflammatory cytokines, type I interferons, and chemokines. We report here on the characterization of a synthetic hexaacylated lipid A derivative, denoted as glucopyranosyl lipid adjuvant (GLA). We assessed the effects of GLA on murine and human dendritic cells (DC) by combining microarray, mRNA and protein multiplex assays and flow cytometry analyses. We demonstrate that GLA has multifunctional immunomodulatory activity similar to naturally-derived monophosphory lipid A (MPL) on murine DC, including the production of inflammatory cytokines, chemokines, DC maturation and antigen-presenting functions. In contrast, hexaacylated GLA was overall more potent on a molar basis than heterogeneous MPL when tested on human DC and peripheral blood mononuclear cells (PBMC). When administered in vivo, GLA enhanced the immunogenicity of co-administered recombinant antigens, producing strong cell-mediated immunity and a qualitative T(H)1 response. We conclude that the GLA adjuvant stimulates and directs innate and adaptive immune responses by inducing DC maturation and the concomitant release of pro-inflammatory cytokines and chemokines associated with immune cell trafficking, activities which have important implications for the development of future vaccine adjuvants. PMID- 21298113 TI - Sudden unexpected deaths and vaccinations during the first two years of life in Italy: a case series study. AB - BACKGROUND: The signal of an association between vaccination in the second year of life with a hexavalent vaccine and sudden unexpected deaths (SUD) in the two days following vaccination was reported in Germany in 2003. A study to establish whether the immunisation with hexavalent vaccines increased the short term risk of SUD in infants was conducted in Italy. METHODOLOGY/PRINCIPAL FINDINGS: The reference population comprises around 3 million infants vaccinated in Italy in the study period 1999-2004 (1.5 million received hexavalent vaccines). Events of SUD in infants aged 1-23 months were identified through the death certificates. Vaccination history was retrieved from immunisation registries. Association between immunisation and death was assessed adopting a case series design focusing on the risk periods 0-1, 0-7, and 0-14 days after immunisation. Among the 604 infants who died of SUD, 244 (40%) had received at least one vaccination. Four deaths occurred within two days from vaccination with the hexavalent vaccines (RR = 1.5; 95% CI 0.6 to 4.2). The RRs for the risk periods 0-7 and 0-14 were 2.0 (95% CI 1.2 to 3.5) and 1.5 (95% CI 0.9 to 2.4). The increased risk was limited to the first dose (RR = 2.2; 95% CI 1.1 to 4.4), whereas no increase was observed for the second and third doses combined. CONCLUSIONS: The RRs of SUD for any vaccines and any risk periods, even when greater than 1, were almost an order of magnitude lower than the estimates in Germany. The limited increase in RRs found in Italy appears confined to the first dose and may be partly explained by a residual uncontrolled confounding effect of age. PMID- 21298115 TI - Respiratory infections by HMPV and RSV are clinically indistinguishable but induce different host response in aged individuals. AB - BACKGROUND: Human metapneumovirus and respiratory syncytial virus can cause severe respiratory diseases, especially in infants, young children, and the elderly. So far it remains unclear why infections in the elderly become life threatening despite the presence of neutralizing antibodies in the serum, and to which extent double infections worsen the clinical course. METHODS: Young and aged BALB/c-mice were infected with RSV or/and HMPV. Appearance of the mice was observed during course of infection. On day 5 p.i. animals were dispatched by cervical dislocation and levels of TNF-alpha and NF-kappaB were determined. RESULTS: The observation of activity, weight and appearance of the different mice showed no differences among the tested groups. Despite this, the immunologic response depends on the animals' age and the virus they were infected with. In young animals, NF-kappaB levels were elevated if infected with HMPV and HMPV/RSV but remained low in RSV infections, whereas in aged animals the opposite was observed: solely RSV-infected animals showed elevated levels of NF-kappaB. TNF alpha was slightly elevated in HMPV-infected young and old animals, but only in young animals this elevation was significant. CONCLUSIONS: Contrary to other studies, no weight loss or change in activity despite productive lung infection with the different viruses were observed. This may be due to the weaker anaesthesia or the lesser volume of virus solution used, leading to less stress in the animals. The observed differences in TNF-alpha and NF-kappaB elevation lead to the assumption that young and old individuals have different mechanisms to react against the viruses. PMID- 21298117 TI - [The arduous time of our pioneers]. PMID- 21298116 TI - Dietary fat intake and the risk of depression: the SUN Project. AB - Emerging evidence relates some nutritional factors to depression risk. However, there is a scarcity of longitudinal assessments on this relationship. OBJECTIVE: To evaluate the association between fatty acid intake or the use of culinary fats and depression incidence in a Mediterranean population. MATERIAL AND METHODS: Prospective cohort study (1999-2010) of 12,059 Spanish university graduates (mean age: 37.5 years) initially free of depression with permanently open enrolment. At baseline, a 136-item validated food frequency questionnaire was used to estimate the intake of fatty acids (saturated fatty acids (SFA), polyunsaturated fatty acids (PUFA), trans unsaturated fatty acids (TFA) and monounsaturated fatty acids (MUFA) and culinary fats (olive oil, seed oils, butter and margarine) During follow-up participants were classified as incident cases of depression if they reported a new clinical diagnosis of depression by a physician and/or initiated the use of antidepressant drugs. Cox regression models were used to calculate Hazard Ratios (HR) of incident depression and their 95% confidence intervals (CI) for successive quintiles of fats. RESULTS: During follow-up (median: 6.1 years), 657 new cases of depression were identified. Multivariable-adjusted HR (95% CI) for depression incidence across successive quintiles of TFA intake were: 1 (ref), 1.08 (0.82-1.43), 1.17 (0.88-1.53), 1.28 (0.97-1.68), 1.42 (1.09-1.84) with a significant dose-response relationship (p for trend = 0.003). Results did not substantially change after adjusting for potential lifestyle or dietary confounders, including adherence to a Mediterranean Dietary Pattern. On the other hand, an inverse and significant dose-response relationship was obtained for MUFA (p for trend = 0.05) and PUFA (p for trend = 0.03) intake. CONCLUSIONS: A detrimental relationship was found between TFA intake and depression risk, whereas weak inverse associations were found for MUFA, PUFA and olive oil. These findings suggest that cardiovascular disease and depression may share some common nutritional determinants related to subtypes of fat intake. PMID- 21298118 TI - [Computed tomography in the evaluation of acute aortic dissection]. AB - Acute aortic dissection is the most frequent cause of aortic emergency, associated to high morbidity and mortality rates. It is important to quickly establish the diagnosis and properly characterize the findings in order to determine the appropriate treatment. Multidetector computed tomography is, in many centers, the initial imaging modality of choice, due to its diagnostic accuracy (with sensitivity and specificity indexes of nearly 100%), wide availability, examination speed and ease performance. It enables differentiation between classic aortic dissection, intramural hematoma and penetrating atherosclerotic ulcer, entities with a similar clinical presentation. Initial precontrast images are extremely important in the detection of an intramural hematoma. Regarding classic aortic dissection, the definitive diagnostic finding is the demonstration of two contrast-filled lumina separated by an intimal flap. Accurate differentiation between the true and the false lumen is often possible and has becoming particularly important for treatment planning. PMID- 21298119 TI - [Peri-operative stroke and carotid artery disease in cardiac surgery]. AB - Stroke still remains one of the most frequent and dreadful complications of contemporary cardiac surgery, due to the consequences and disabilities that can cause, often definite and irreversible. An intensive investigation has been dedicated to the search of their causes and pathogenic mechanisms, which are multiple and diverse, aimed at identification of risk factors and their adequate prevention. In this paper, the author makes an evaluation and critical review of this matter, giving particular emphasis to the participation and involvement of the carotid artery obstructive disease, its means and methods of diagnosis as well as indications for treatment, either by open conventional or endovascular management, performed previously or concomitantly with cardiac surgery. PMID- 21298120 TI - [Hybrid approach to structural cardiac disease: three clinical cases]. AB - Structural cardiac diseases can be successfully treated by a multidisciplinary team using a hybrid strategy. We report a small series of complex cases were the team effort of cardiologists, cardiac surgeons and anaesthesiologists allowed a favourable result. PMID- 21298121 TI - [Myocardial abscess of the right ventricle anterior wall]. AB - The authors report the clinical case of a 63 old male, with a previous history of aortic mechanical replacement valve, who was admitted with fever, neutrophilic leukocytosis and c-reactive protein elevation. During admission Escherichia coli was cultured from blood, and the patient underwent repeated transthoracic and transesophageal echocardiograms, that did not reveal any abnormalities. Three weeks after admission, a new transesophageal echocardiogram showed an image suggestive of an aortic annular abscess. The patient was transferred to the Cardiothoracic Department of Santa Maria Hospital, in order to be submitted to surgical treatment. During the procedure an abscess in the anterior wall of right ventricle was diagnosed. The microbiological cultures of pus were negative. It was assumed the diagnosis of E. coli myocardial abscess. The diagnostic approach to patients with febrile syndrome and mechanical replacement valve should consider the hypothesis of infectious endocarditis and myocardial abscess, despite the rarity of its occurrence. PMID- 21298122 TI - [Endovascular aortic procedures]. AB - The authors report a retrospective analysis of all the aortic endovascular procedures performed in the Department until November 2009. The series includes a total of 302 patients, 246 of them having an elective treatment of an abdominal aortic aneurysm; 33 underwent an emergency treatment of an abdominal aortic aneurysm; and the remainder 23 patients had an endovascular procedure of the thoracic aorta. The aim of the study was dedicated at the evaluation of the epidemiologic characteristics of the patients, including associated and co-morbid entities, as well as the evaluation of the results, especially the early 30 days post-operative mortality and major morbidity. PMID- 21298123 TI - [Hybrid treatment of an aortic arch aneurysm]. AB - Traditional open repair of aortic arch aneurysms is a complex and demanding surgery that requires cardiopulmonary bypass, hypothermia and circulatory arrest, being associated with considerable morbidity and mortality. Even with significant advances in pre-operative assessment and optimization, advanced anaesthetic techniques and intensive care, conventional aortic arch repairs remain amongst the highest risk of across all surgical specialties. Therefore, a hybrid approach with sequential transposition of the supra-aortic branches and endovascular stent graft placement is a less invasive alternative treatment that opens the indication for repair to more critical patients. We report our institution's first experience in the hybrid surgery of aortic arch aneurysms. PMID- 21298124 TI - [Upper extremity post-thrombotic syndrome and quality of life]. AB - PURPOSE: To assess the occurrence of post thrombotic syndrome and quality of life in patients with upper extremity deep venous thrombosis. MATERIAL AND METHODS: Twenty-seven patients with the previous diagnosis of upper extremity venous thrombosis, from January 2006 to March 2010, were recruited for clinical evaluation, ultrasonography studies and an interview utilizing the Modified scale and the SF-36 questionnaire RESULTS: Only II (40.7%) of the patients responded, there women and men, average age of 53.7 years. Ultrasonography revealed a residual thrombus in 18.2% of the cases, with repercussions in the venous flow. A clinical post-thrombotic syndrome was diagnosed in 36.4% of the patients, being light in 27.2% and moderate in 9.2%. Neoplasia and central venous catheter were not associated to the occurrence of the syndrome, but thrombophylia played a significant role in its occurrence. The quality of life questionnaire revealed 90.9% of patients with good functional capacity, but 54.5% of them complained of precarious state of health. Paradoxically, patients with neoplasia displayed a satisfactory health state. Certain emotional aspects related with the previous TVP, affected the quality of life of same patients. Patients with post-thrombotic syndrome have considered as precarious their health status. CONCLUSION: Deep venous thrombosis of upper extremity may cause a post-thrombotic syndrome of light intensity. The presence of a central venous catheter or neoplasia were not considered risk factors of its occurrence. Most of the patients displayed a satisfactory functional capacity, but around an half considered as having a precarious health state. Patients classified as having poor quality of life were those having recurrent DVT and post-thrombotic syndrome. PMID- 21298125 TI - [Intima-media thickness and hypertensive disorders of pregnancy: a prospective study]. AB - PURPOSE: To evaluate intima-media thickness (IMT) in hypertensive pregnant women and to ascertain if an increased IMTcorrelates with the development of preeclampsia. METHODS: A controlled, descriptive and prospective study was conducted in the Maternal-Fetal Medicine Unit (MFMU) of a level II hospital with perinatal assistance. Throughout six months randomly selected pregnant women were allocated in three branches (A - control group, n = 17; B - gestational hypertension group, n = 17; C - pregestational hypertension group, n = 14(. All of them were subjected to clinical interview, physical exam, obstetric ultrasound, laboratory and CTG evaluation and IMT measurement in the distal wall of both common carotid arteries at 1 cm. from bifurcation by the same operator from whom group classification was concealed. High resolution ultrasound and a linear 7.5 MHz transducer were used. Follow-up included obstetric and neonatal outcomes. RESULTS: Mean IMT was 0.43 mm with a standard deviation (sd) of 0.09 mm in group A; 0.52 (sd=0.11), p=0.034 in group B; 0.58 (sd=0.11), p=2,3*10-4 in group C. RESULTS were not significantly different in hypertensive women with or without preeclampsia (0.52 (sd=0.11) vs 0.57 (sd=0.11), p=0.20). CONCLUSIONS: Carotid IMT, a validated endothelial dysfunction surrogate endpoint, was increased in both groups B and C although there were no differences between hypertensive women with or without preeclampsia. PMID- 21298126 TI - Controlled side-by-side assembly of gold nanorods and dye molecules into polymer wrapped SERRS-active clusters. AB - The controlled side-by-side assembly of gold nanorods in solution together with Raman reporter dye molecules to create small SERRS-active clusters stabilised by a surrounding polymer layer is demonstrated. This promising new class of nanotags offers several advantages over spherical nanoparticles for bioimaging and is of potential importance for a wide range of plasmon-enhanced spectroscopies and can also serve as building blocks for more complex solution-phase nanostructures. PMID- 21298127 TI - Impact of in situ polymer coating on particle dispersion into solid laser generated nanocomposites. AB - The crucial step in the production of solid nanocomposites is the uniform embedding of nanoparticles into the polymer matrix, since the colloidal properties or specific physical properties are very sensitive to particle dispersion within the nanocomposite. Therefore, we studied a laser-based generation method of a nanocomposite which enables us to control the agglomeration of nanoparticles and to increase the single particle dispersion within polyurethane. For this purpose, we ablated targets of silver and copper inside a polymer-doped solution of tetrahydrofuran by a picosecond laser (using a pulse energy of 125 MUJ at 33.3 kHz repetition rate) and hardened the resulting colloids into solid polymers. Electron microscopy of these nanocomposites revealed that primary particle size, agglomerate size and particle dispersion strongly depend on concentration of the polyurethane added before laser ablation. 0.3 wt% polyurethane is the optimal polymer concentration to produce nanocomposites with improved particle dispersion and adequate productivity. Lower polyurethane concentration results in agglomeration whereas higher concentration reduces the production rate significantly. The following evaporation step did not change the distribution of the nanocomposite inside the polyurethane matrix. Hence, the in situ coating of nanoparticles with polyurethane during laser ablation enables simple integration into the structural analogue polymer matrix without additives. Furthermore, it was possible to injection mold these in situ stabilized nanocomposites without affecting particle dispersion. This clarifies that sufficient in situ stabilization during laser ablation in polymer solution is able to prevent agglomeration even in a hot polymer melt. PMID- 21298128 TI - Photocatalytic reduction of nitrobenzenes to aminobenzenes in aqueous suspensions of titanium(IV) oxide in the presence of hole scavengers under deaerated and aerated conditions. AB - Photocatalytic reduction of nitrobenzenes to corresponding aminobenzenes in aqueous suspensions of titanium(IV) oxide (TiO(2)) containing hole scavengers under various conditions was examined. In photocatalytic reduction of m nitrobenzenesulfonic acid (m-NBS) in the presence of formic acid (FA) under deaerated conditions, m-aminobenzenesulfonic acid (m-ABS) was produced almost quantitatively in acidic suspensions and high efficiency (>99%) in FA utilization as a hole scavenger was achieved. No re-oxidation of m-ABS occurred in acidic conditions both in the presence and absence of FA. The high yield of m-ABS was explained by strong ability of FA as a hole scavenger and possible repulsion of the reduced functional group (ammonium group, -NH(3)(+)) from the protonated, i.e., positively charged TiO(2) surface in acidic suspensions avoiding re oxidation of m-ABS. Using TiO(2) samples of various physical properties, which had been synthesized by a solvothermal method and post-calcination at various temperatures, effects of physical properties of the TiO(2) samples on m-ABS yield were also investigated. A linear correlation between the amount of m-NBS adsorbed and the m-ABS yield was observed, suggesting that ability of TiO(2) for m-NBS adsorption is one of the key factors for effective photocatalytic reduction of m NBS to m-ABS. This photocatalytic system can be applied for reduction of aminonitrobenzenes to corresponding diaminobenzenes (DAB) in the presence of oxalic acid as a hole scavenger. High yields of m-ABS and DAB were achieved even when the reactions were performed in the presence of oxygen. PMID- 21298129 TI - Diffusion-mediated in situ alginate encapsulation of cell spheroids using microscale concave well and nanoporous membrane. AB - Here, we present a novel and simple process of spheroid formation and in situ encapsulation of the formed spheroid without intervention. A hemispherical polydimethylsiloxane (PDMS) micromold was employed for the formation of uniform sized spheroids and two types of nano-porous membrane were used for the control of the crosslinking agent. We characterized the transport properties of the membrane, and the selection of alginate hydrogel as a function of gelation time, alginate concentration, and membrane type. Using the developed process and micromold, HepG2 cell spheroids were successfully formed and encapsulated in alginate without replating. This method allows spheroid encapsulation with minimal damage to the spheroid while maintaining high cell viability. We demonstrate the feasibility of this method in developing a bio-artificial liver (BAL) chip by evaluating viability and function of encapsulated HepG2 spheroids. This method may be applied to the encapsulation of several aggregating cell types, such as beta-cells for islet formation and stem cells for embryonic body preservation, or as a model for tumor cell growth and proliferation in a 3D hydrogel environment. PMID- 21298130 TI - The rotational excitation of the interstellar HNC by para- and ortho-H2. AB - Rotational excitation of the interstellar HNC due to collisions with H(2) is investigated. We present a new four dimensional (4D) potential energy surface for the HNC-H(2) collisional system. Both molecules were treated as rigid rotors. Interaction energy was obtained from the electronic structure calculations using a single and double-excitation coupled cluster method with perturbative contributions from connected triple excitations [CCSD(T)]. The five atoms were described using the aug-cc-pVTZ basis sets. Bond functions were placed at mid distance between the HNC center of mass and the center of mass of H(2) for a better description of the van der Waals interaction. Close coupling calculations of the inelastic integral cross sections of HNC in collisions with para-H(2) and ortho-H(2) were calculated for kinetic energies up to 800 cm(-1). After Boltzmann thermal averaging, rate coefficients were obtained for temperatures ranging from 5 to 100 K. Significant differences exist between para- and ortho-H(2) results. The strongest collision-induced rotational HNC transitions are the transitions with Deltaj = 1 for collisions with para-H(2) and with ortho-H(2). The new rate coefficients should induce important consequences on the determination of HNC abundance in the interstellar medium. In particular, we expect that they will help to solve the interstellar problem of relative abundance of the HCN and HNC isomers. PMID- 21298131 TI - Electrokinetic gated injection-based microfluidic system for quantitative analysis of hydrogen peroxide in individual HepG2 cells. AB - A microfluidic system to determine hydrogen peroxide (H(2)O(2)) in individual HepG2 cells based on the electrokinetic gated injection was developed for the first time. A home-synthesized fluorescent probe, bis(p methylbenzenesulfonate)dichlorofluorescein (FS), was employed to label intracellular H(2)O(2) in the intact cells. On a simple cross microchip, multiple single-cell operations, including single cell injection, cytolysis, electrophoresis separation and detection of H(2)O(2), were automatically carried out within 60 s using the electrokinetic gated injection and laser-induced fluorescence detection (LIFD). The performance of the method was evaluated under the optimal conditions. The linear calibration curve was over a range of 4.39-610 amol (R(2)=0.9994). The detection limit was 0.55 amol or 9.0*10(-10) M (S/N=3). The relative standard deviations (RSDs, n=6) of migration time and peak area were 1.4% and 4.8%, respectively. With the use of this method, the average content of H(2)O(2) in single HepG2 cells was found to be 16.09+/-9.84 amol (n=15). Separation efficiencies in excess of 17,000 theoretical plates for the cells were achieved. These results demonstrated that the efficient integration and automation of these single-cell operations enabled the sensitive, reproducible, and quantitative examination of intracellular H(2)O(2) at single-cell level. Owing to the advantages of simple microchip structure, controllable single-cell manipulation and ease in building, this platform provides a universal way to automatically determine other intracellular constituents within single cells. PMID- 21298132 TI - Resilience of protein-protein interaction networks as determined by their large scale topological features. AB - The relationship between the structure and function of biological networks constitutes a fundamental issue in systems biology. Particularly, the structure of protein-protein interaction networks is related to important biological functions. In this work, we investigated how such a resilience is determined by the large scale features of the respective networks. Four species are taken into account, namely yeast Saccharomyces cerevisiae, worm Caenorhabditis elegans, fly Drosophila melanogaster and Homo sapiens. We adopted two entropy-related measurements (degree entropy and dynamic entropy) in order to quantify the overall degree of robustness of these networks. We verified that while they exhibit similar structural variations under random node removal, they differ significantly when subjected to intentional attacks (hub removal). As a matter of fact, more complex species tended to exhibit more robust networks. More specifically, we quantified how six important measurements of the networks topology (namely clustering coefficient, average degree of neighbors, average shortest path length, diameter, assortativity coefficient, and slope of the power law degree distribution) correlated with the two entropy measurements. Our results revealed that the fraction of hubs and the average neighbor degree contribute significantly for the resilience of networks. In addition, the topological analysis of the removed hubs indicated that the presence of alternative paths between the proteins connected to hubs tend to reinforce resilience. The performed analysis helps to understand how resilience is underlain in networks and can be applied to the development of protein network models. PMID- 21298133 TI - Rare antibodies from combinatorial libraries suggests an S.O.S. component of the human immunological repertoire. AB - Convergence of observations from different sources is the norm in science. However, when convergence occurs in man for antibodies it is remarkable because the repertoire of possible immunoglobulin products is very large and diverse. Thus, one would not expect to see the same antibody twice from divergent populations unless there is special significance as to why the immune response is constrained. Now, broadly neutralizing antibodies isolated from combinatorial libraries from three separate populations have been shown to all use the same (V(H) 1-69) germ line gene and interact with the influenza virus in very similar ways. Here we discuss the reasons for this convergence in terms of how the immunological repertoire responds to emergency situations where time is short as occurs, for example, in potentially lethal infections. It is suggested that there is a first responder or S.O.S. component of the antibody repertoire that evolved to initiate rapid defense against infectious agents. The discovery of the homologies between these commonly produced antibodies may have significance for the design of novel vaccines. Finally, these convergent results may give much insight into why antibodies encoded by the V(H) 1-69 germ line gene are highly over represented in B-cell lymphomas. PMID- 21298134 TI - Localized and propagating surface plasmon co-enhanced Raman spectroscopy based on evanescent field excitation. AB - The localized and propagating surface plasmon co-enhanced Raman scattering of 4 mercaptopyridine was observed based on evanescent field excitation. The most effective coupling of the localized and propagating surface plasmons resulted in a >50 times enhanced signal relative to signals obtained on vacuum-deposited silver film. PMID- 21298135 TI - Sequencing transcriptomes in toto. AB - The development of next-generation sequencing technologies has enabled the transcriptome to be measured and characterized at a level which was previously unattainable. Shot gun sequencing of RNAs, or RNA-Seq as it is known, is providing the means to simultaneously survey locus activity, transcript-specific expression, sequence content of transcripts and transcriptome discovery. This article discusses the current state of RNA-Seq, its potential for redefining transcriptomics and some of the challenges associated with this revolutionary technology. PMID- 21298136 TI - Simple one-pot synthesis of Rh-Fe3O4 heterodimer nanocrystals and their applications to a magnetically recyclable catalyst for efficient and selective reduction of nitroarenes and alkenes. AB - A simple synthesis of Rh-Fe(3)O(4) heterodimer nanocrystals was achieved by controlled one-pot thermolysis. The nanocrystals exhibited excellent activities for the selective reduction of nitroarenes and alkenes. Furthermore the nanocrystal catalyst could be easily separated by a magnet, and recycled eight times without losing the catalytic activity. PMID- 21298137 TI - Growth of silver nanocrystals on graphene by simultaneous reduction of graphene oxide and silver ions with a rapid and efficient one-step approach. AB - A rapid and efficient one-step approach to prepare graphene-Ag nanocomposites by simultaneous reduction of graphene oxide (GO) and silver ions with formaldehyde as the reducing agent within several minutes was demonstrated. PMID- 21298138 TI - Restoring orbital thinking from real space descriptions: bonding in classical and non-classical transition metal carbonyls. AB - A combined strategy that unifies our interacting quantum atoms approach (IQA), a chemically intuitive energetic perspective within the quantum theory of atoms in molecules (QTAIM), the domain natural orbitals obtained by the diagonalization of the charge-weighted domain-averaged Fermi hole (DAFH), and the statistical analyses of chemical bonding provided by the electron number distribution functions (EDF) is presented. As shown, it allows for recovering traditional orbital images from the orbital invariant descriptions of QTAIM. It does also provide bonding indices (like bond orders) and bond energetics, all in a per orbital basis, still invariant manner, using a single unified framework. The procedure is applied to show how the Dewar, Chatt, and Ducanson model of bonding in simple transition metal carbonyls may be recovered in the real space. The balance between the number of sigma-donated and pi-backdonated electrons is negative in classical compounds and positive in non-classical ones. The energetic strength of backdonation is, however, smaller than that of donation. Our technique surpasses conventional orbital models by providing physically sound, quantitative energetics of chemical bonds (or interactions) together with effective one-electron pictures, all for arbitrary wavefunctions. PMID- 21298139 TI - Hydrothermal synthesis of TiO2(B) nanowires with ultrahigh surface area and their fast charging and discharging properties in Li-ion batteries. AB - We first report a facile hydrothermal route for preparing TiO(2)(B) nanowires with ultrahigh surface area, up to 210 m(2) g(-1). Due to the 1D structure, high BET surface area and shorter b-and c-axis channel across the nanowires, the obtained TiO(2)(B) nanowire was shown to be a good anode material for lithium-ion batteries, especially on the fast charging and discharging performance. PMID- 21298140 TI - Interplay between the diamine structure and absolute helicity in Ni-salen metallofoldamers. AB - The nature of internal chiral diamines can greatly influence the ratio of helical diastereomers for Ni-salen based metallofoldamers. The diastereomer ratio is small for metallofoldamers derived from (1R, 2R)-cyclohexanediamine, (11R, 12R) 9,10-dihydro-9,10-ethanoanthracene-11,12-diamine, or (1R, 2R) cyclopentanediamine. By contrast, the foldamer from (1S, 2S)-1,2 diphenylethylenediamine provides a relatively large bias (6 : 1) for the P helical diastereomer as evidenced by NMR studies, chiroptical data, and X-ray studies. A model is proposed to explain the origin of the helical bias. These findings underscore the need to consider helical diastereomers in models for asymmetric induction in metal-salen catalyzed reactions. PMID- 21298141 TI - Acetylide-bridged tetracene dimers. AB - Alkyne linked tetracene dimers were synthesized from naphthacenequinone and terminal acetylenes. The silylethynyl tetracene dimers exhibit good solubility, high photostability, and broad absorbance leading to photocurrent generation in an organic photovoltaic device. PMID- 21298142 TI - Lewis base character of the phosphorus atom in phosphanido-niobocene complexes. Synthesis of new early-early homo- and heterobimetallic entities. AB - The reaction of phosphanido complexes [Nb(eta(5)-C(5)H(4)SiMe(3))(2)(L)(PPh(2))] [L = CO (1), CNXylyl (2)] with early transition metal halides in high oxidation states has been carried out. New bimetallic niobocene complexes [{Nb(eta(5) C(5)H(4)SiMe(3))(2)(L)}(MU-PPh(2))(MCl(5))] [M = Nb, L = CO (3), L = CNXylyl (4); M = Ta, L = CO (5), L = CNXylyl (6)] have been successfully synthesized by the reaction with [MCl(5)](2) (M = Nb or Ta). In a similar way [{Nb(eta(5) C(5)H(4)SiMe(3))(2)(L)}(MU-PPh(2))(MCl(4))] [M = Ti, L = CO (13), CNXylyl (14); M = Zr, L = CO (15), CNXylyl (16)] were synthesized using MCl(4) (M = Ti or Zr). Solutions of complexes 4-6 in chloroform produced new ionic derivatives [Nb(eta(5)-C(5)H(4)SiMe(3))(2)(P(H)Ph(2))(L)] [MCl(6)] [M = Nb, L = CO (7), L = CNXylyl (8); M = Ta, L = CO (9), L = CNXylyl (10)]. Ionic complexes [Nb(eta(5) C(5)H(4)SiMe(3))(2)(P(Cl)Ph(2))(L)] [NbCl(4)O(thf)] [L = CO (11), CNXylyl (12)] were formed from solutions in thf - rapidly in the case of 3 but more slowly for 4. New heterometallic complexes [Nb(eta(5)-C(5)H(4)SiMe(3))(2)(L)(MU PPh(2)){(Ti(eta(5)-C(5)R(5))Cl(3)}] [R = H, L = CO (17), CNXylyl (18); R = CH(3), L = CO (19), CNXylyl (20)] were synthesized by the reaction of 1 or 2 with [Ti(eta(5)-C(5)R(5))Cl(3)] (R = H or CH(3)). All of these compounds were characterized by IR and multinuclear NMR spectroscopy, and the molecular structures of 9 and 12 were determined by single-crystal X-ray diffraction. PMID- 21298143 TI - Methylaluminium 8-quinolinolates: synthesis, characterization and use in ring opening polymerization (ROP) of epsilon-caprolactone. AB - The stoichiometric reactions of 2-(2,6-R-phenylimino)quinolin-8-ol (L1-L5, L1: R = Me, L2: R = Et, L3: R = (i)Pr, L4: R = Cl, L5: R = F) with Me(3)Al afforded the dimeric aluminium complexes [Me(2)AlL](2) (1-5) in good yields. By contrast, stoichiometric reactions of 2-(1-(2,6-R-phenylimino)propyl) quinolin-8-ol (L6 L10, L6: R = Me, L7: R = Et, L8: R = (i)Pr, L9: R = Cl, L10: R = F)) with Me(3)Al gave the mononuclear aluminium complexes Me(2)AlL (6-10) accompanied with by products of the form Me(2)AlL.Me(3)Al (11-15). All methylaluminium complexes were characterized by NMR spectroscopy, elemental analysis, and the molecular structures of complexes 3, 6 and 8 were determined by single-crystal X-ray diffraction. Aluminium compounds 1-5 possessed negligible activity towards the ring-opening polymerization of epsilon-caprolactone either in the presence or absence of BnOH. In contrast, in the presence of BnOH, the mononuclear aluminium compounds 6-10 could efficiently initiate the ring-opening polymerization of epsilon-caprolactone; the polymerization proceeded in a living manner. PMID- 21298144 TI - Synthesis, characterization, and photoresponsive properties of a series of Mo(IV) Cu(II) complexes. AB - Six Mo(IV)-Cu(II) complexes, [Cu(tpa)](2)[Mo(CN)(8)].15H(2)O (1, tpa = tris(2 pyridylmethyl)amine), [Cu(tren)](2)[Mo(CN)(8)].5.25H(2)O (2, tren = tris(2 aminoethyl)amine), [Cu(en)(2)][Cu(0.5)(en)][Cu(0.5)(en)(H(2)O)][Mo(CN)(8)].4H(2)O (3, en = ethylenediamine), [Cu(bapa)](3)[Mo(CN)(8)](1.5).12.5H(2)O (4, bapa = bis(3-aminopropyl)amine), [Cu(bapen)](2)[Mo(CN)(8)].4H(2)O (5, bapen = N,N'-bis(3 aminopropyl)ethylenediamine), and [Cu(pn)(2)][Cu(pn)][Mo(CN)(8)].3.5H(2)O (6, pn = 1,3-diaminopropane), were synthesized and characterized. Single-crystal X-ray diffraction analyses show that 1-6 have different structures varying from trinuclear clusters (1-2), a one-dimensional belt (3), two-dimensional grids (4 5), to a three-dimensional structure (6). Magnetic and ESR measurements suggest that 1-6 exhibit thermally reversible photoresponsive properties on UV light irradiation through a Mo(IV)-to-Cu(II) charge transfer mechanism. A trinuclear compound [Cu(II)(tpa)](2)[Mo(V)(CN)(8)](ClO(4)) (7) was synthesized as a model of the photoinduced intermediate. PMID- 21298145 TI - Kinetico-mechanistic studies of the acidolysis of Rh-C bonds in monocyclometallated dirhodium(II) acetato complexes; influence of electronic and steric effects. AB - The protonation/demetallation reaction, in CD(3)COOD, of phosphine monometallated triacetato-bridged dirhodium(ii) complexes of general formulae [Rh(2)(MU OOCCH(3))(3){(RC(5)CH(3))P(RC(6)H(4))(2)}(2)] has been studied from a kinetico mechanistic perspective. The process has been monitored via the disappearance of the nuclear magnetic resonance signals of the protons present in the non metallated ortho positions of the phosphine ligand and taking advantage of the relatively fast back metallation process that follows the acidolysis reaction, the sequence behaving as an overall equilibrium reaction. The process has a high associative character with important entropy demands, increasing both for the larger and the more electron withdrawing phosphine ligands. For the complexes with electron withdrawing CF(3) substituents on the cyclometallated phenyl ring, this demand is compensated by very low activation enthalpies. The data agree with an intimate mechanism that corresponds to the reverse of the electrophilic C-H bond activation, which has already been studied for this type of system, and requires the presence of a protonated acetato ligand in the axial position, close to the metallated Rh-C(aromatic) bond. The involvement of external solvent molecules, interacting via hydrogen bonds with the system, is also evident for systems which include CF(3) groups with the correct geometric arrangement. PMID- 21298146 TI - pH-sensitive fluorescent sensors based on europium(III) complexes. AB - New europium(III) complexes Eu(TTA)(2)-DSQ and Eu(TTA)(3)-DR1 were designed and synthesized as new fluorescent pH probes (where HDSQ = 5-(dimethylamino)-N-(4-(2 ((8-hydroxyquinolin-2-yl)methylene)hydrazinecarbonyl)phenyl)naphthalene-1 sulfonamide, DR1 = N(1)-(4-(dimethylamino)benzylidene)-N(2)-(rhodamine-6G) lactamethylene-diamine and TTA = thiophentrifluoroacetone). Eu(TTA)(2)-DSQ exhibited high sensitivity in monitoring pH changes in neutral aqueous solution with negligible background fluorescence. Eu(TTA)(3)-DR1 comprised a green light emitting Rhodamine 6G fluorophore and a Eu(III) moiety as the origin of red light. These pH-sensitive emitter components have pK(a) values of 5.0 and 7.2 respectively, and exhibit isolated protonated steps within one molecule. Luminescence titrations demonstrate that Eu(TTA)(3)-DR1 was able to detect pH values at both near neutral pH and acidic pH ranges, and was also able to detect pH in both cultured cells and in vivo. PMID- 21298147 TI - Comparison between alpha- and beta-carbonic anhydrases: can Zn(His)3(H2O) and Zn(His)(Cys)2(H2O) sites lead to equivalent enzymes? AB - Large models of alpha- and beta-carbonic anhydrases were compared using DFT calculations. They indicate similar acidity of the coordinated water molecule and zinc affinity. This explains their similar mechanism of action, despite the wide difference in their first coordination sphere. PMID- 21298148 TI - Subcellular spatial segregation of integrin subtypes by patterned multicomponent surfaces. AB - While it is well known that individual integrins are critical mediators of cell behavior, recent work has shown that when multiple types of integrins simultaneously engage the ECM, cell functions are enhanced. However, it is not known how integrins spatially coordinate to regulate cell adhesion because no reliable method exists to segregate integrins on the cell membrane. Here, we use a microcontact printing-based strategy to pattern multiple ECMs that bind distinct integrins in order to study how integrins might interact. In our technique, proteins are first adsorbed uniformly to a poly(dimethyl siloxane) stamp, and then selectively "de-inked." Our strategy overcomes several inherent limitations of conventional microcontact printing, including stamp collapse and limited functionality of the surface patterns. We show that integrins spatially segregate on surfaces patterned with multiple ECMs, as expected. Interestingly, despite spatial segregation of distinct integrins, cells could form adhesions and migrate across multicomponent surfaces as well as they do on single component surfaces. Together, our data indicate that although cells can segregate individual integrins on the cell surface to mediate ECM-specific binding, integrins function cooperatively to guide cell adhesion and migration. PMID- 21298149 TI - Highly stereoselective double (R)-phenylglycinol-induced cyclocondensation reactions of symmetric aryl bis(oxoacids). AB - The double cyclocondensation of symmetric pyridyl bis(oxoacids) 2b and 3b with (R)-phenylglycinol stereoselectively gave access to bis-phenylglycinol-derived oxazolopyrrolidine 9 and oxazolopiperidone 10, respectively. Application of the stereocontrolled cyclocondensation reaction to phenyl bis-gamma-oxoacid 4b provided 11, which was converted to the corresponding enantiopure di(pyrrolidinyl)benzene 22. The absolute configuration of the new stereogenic centers generated in the key cyclocondenstion step was unambiguously established by X-ray crystallographic analysis. PMID- 21298150 TI - On the cutting edge: protease-sensitive prodrugs for the delivery of photoactive compounds. AB - Most invasive diseases such as cancer or rheumatoid arthritis are characterized by the upregulation of diverse proteases. Since the early 1970s this phenomenon has been exploited for the selective delivery of a variety of drugs. However, only recently have we and others tried to translate this concept into photomedicine. After a short overview of proteases and the proteolytic imbalance in cancer, we will discuss strategies, their potential and limitations to exploit upregulation of proteases for the selective delivery of in vivo fluorescence reporters and photosensitizers. These strategies can be roughly divided into horizontal, i.e. peptide-based, and vertical, i.e. macromolecular approaches. In the former, a short peptide-based substrate is directly tagged to the photoactive compound or used as a linker between the photoactive compound and a substance that alters its photoactivity. In the latter, the protease sensitive sequence serves as linker between a polymeric carrier and the photoactive payload. Such a macromolecular approach may further benefit from passive targeting through the enhanced penetration and retention effect. PMID- 21298151 TI - Lower sensitivity of FHC fetal colon epithelial cells to photodynamic therapy compared to HT-29 colon adenocarcinoma cells despite higher intracellular accumulation of hypericin. AB - Preferential uptake of photosensitizer by tumour tissue is an elementary prerequisite of effective and successful photodynamic therapy (PDT). Therefore intracellular concentration of photosensitizer is one of the limiting factors affecting PDT efficiency. Hypericin (HY) has found applications in photodynamic diagnostics solely due to its high specificity for tumour cells and tissues. However, here we suggest that not only HY uptake, but importantly also the cell ability to manage oxidative stress induced by HY-PDT can be important decisive factors finally affecting the cell death response. We showed that despite the higher accumulation of HY in FHC human fetal colon epithelial cells compared to HT-29 colon adenocarcinoma cells, the cytotoxic effects of this photosensitizer were more pronounced in the latter cell line, and this was associated with enhanced accumulation of HY-PDT-induced reactive oxygen species (ROS). PMID- 21298152 TI - La2Sb, a layered superconductor with metal-metal bonds. AB - We found that La(2)Sb with a layered structure composed of alternate stacking of La square nets and LaSb layers exhibits bulk superconductivity with a critical temperature of 5.3 K. This suggests that the presence of the square net with strong La-La metal bonding is essential for the emergence of superconductivity. PMID- 21298153 TI - Observations on PVP-protected noble metallic nanoparticle deposits upon heating via in situ synchrotron radiation X-ray diffraction. AB - Through monitoring the evolution of the X-ray diffraction peaks, the phase transformation of PVP-protected Ag and Au nanoparticle deposits (NPDs) on electronic substrates of Cu and Ni upon heating in air was investigated via in situ synchrotron radiation X-ray diffraction. With an increasing temperature, the broad diffraction peak of nano-sized Ag and Au particles with the original average diameters of 4.2 nm and 9.6 nm, respectively, became sharp because of particle coarsening and coalescence. Complex phase transitions among Au, Cu, AuCu(3) and CuO(x) were observed, mainly due to the negative enthalpy of mixing between Au and Cu. The interactions between NPDs and the substrates affected the shift of diffraction peaks to lower angles, caused by thermal expansion and also the temperature for the oxide formation. Compared to Au, Ag NPDs did not form intermetallic compounds with Cu and the formation of copper oxides can also be retarded mainly due to the phase separation feature of the Ag-Cu system. PMID- 21298154 TI - Influence of particle size on solid solution formation and phase interfaces in Li0.5FePO4 revealed by 31P and 7Li solid state NMR spectroscopy. AB - Here we report the observation of electron delocalization in nano-dimension xLiFePO(4):(1 - x)FePO(4) (x = 0.5) using high temperature, static, (31)P solid state NMR. The (31)P paramagnetic shift in this material shows extreme sensitivity to the oxidation state of the Fe center. At room temperature two distinct (31)P resonances arising from FePO(4) and LiFePO(4) are observed at 5800 ppm and 3800 ppm, respectively. At temperatures near 400 degrees C these resonances coalesce into a single narrowed peak centered around 3200 ppm caused by the averaging of the electronic environments at the phosphate centers, resulting from the delocalization of the electrons among the iron centers. (7)Li MAS NMR spectra of nanometre sized xLiFePO(4):(1 - x)FePO(4) (x = 0.5) particles at ambient temperature reveal evidence of Li residing at the phase interface between the LiFePO(4) and FePO(4) domains. Moreover, a new broad resonance is resolved at 65 ppm, and is attributed to Li adjacent to the anti-site Fe defect. This information is considered in light of the (7)Li MAS spectrum of LiMnPO(4), which despite being iso-structural with LiFePO(4) yields a remarkably different (7)Li MAS spectrum due to the different electronic states of the paramagnetic centers. For LiMnPO(4) the higher (7)Li MAS paramagnetic shift (65 ppm) and narrowed isotropic resonance (FWHM ~ 500 Hz) is attributed to an additional unpaired electron in the t(2g) orbital as compared to LiFePO(4) which has delta(iso) = -11 ppm and a FWHM = 9500 Hz. Only the delithiated phase FePO(4) is iso-electronic and iso-structural with LiMnPO(4). This similarity is readily observed in the (7)Li MAS spectrum of xLiFePO(4):(1 - x)FePO(4) (x = 0.5) where Li sitting near Fe in the 3+ oxidation state takes on spectral features reminiscent of LiMnPO(4). Overall, these spectral features allow for better understanding of the chemical and electrochemical (de)lithiation mechanisms of LiFePO(4) and the Li-environments generated upon cycling. PMID- 21298155 TI - Gas-phase binding energies for non-covalent Abeta-40 peptide/small molecule complexes from CID mass spectrometry and RRKM theory. AB - The gas-phase binding of small molecules to the Amyloid beta-40 peptide generated by electrospray ionization has been explored with collision-induced dissociation mass spectrometry and kinetic rate theory. This study discusses a simple procedure used to theoretically model the experimental breakdown diagrams for the Abeta-40 peptide complexed with a series of aminosulfonate small molecules, namely homotaurine, 3-cyclohexylamino-2-hydroxy-1-propanesulfonic acid (CAPSO), 3 (1,3,4,9-tetrahydro-2H-beta-carbolin-2-yl)propane-1-sulfonic acid, 3-(1,3,4,9 tetrahydro-2H-beta-carbolin-2-yl)butane-1-sulfonic acid, and 3 (cyclohexylamino)propane-1-sulfonic acid. An alternative procedure employing an extrapolation procedure for k(E) is also discussed. PMID- 21298156 TI - Energy transfer of highly vibrationally excited phenanthrene and diphenylacetylene. AB - The energy transfer between Kr atoms and highly vibrationally excited, rotationally cold phenanthrene and diphenylacetylene in the triplet state was investigated using crossed-beam/time-of-flight mass spectrometer/time-sliced velocity map ion imaging techniques. Compared to the energy transfer between naphthalene and Kr, energy transfer between phenanthrene and Kr shows a larger cross-section for vibrational to translational (V -> T) energy transfer, a smaller cross-section for translational to vibrational and rotational (T -> VR) energy transfer, and more energy transferred from vibration to translation. These differences are further enlarged in the comparison between naphthalene and diphenylacetylene. In addition, less complex formation and significant increases in the large V -> T energy transfer probabilities, termed supercollisions in diphenylacetylene and Kr collisions were observed. The differences in the energy transfer between these highly vibrationally excited molecules are attributed to the low-frequency vibrational modes, especially those vibrations with rotation like wide-angle motions. PMID- 21298157 TI - Maximum directionality and systematic classification of molecular motors. AB - Track-walking molecular motors are widely used in living cells for transport purposes, and artificial mimics are being vigorously pursued in engineered molecular systems. The defining character for a motor is its intrinsic capability to utilize energy input to rectify a sustained directional motion out of stochastic thermal motion. The energy injection can be coupled to a motor's mechanical steps in different ways, leading to different motor mechanisms. We derive here a formulation for maximum motor performance in terms of a new quantity called directionality based on a general representation of the track walking motors. Compared to performance measures like velocity and processivity, directionality is a cleaner and more robust indicator of the rectification mechanism that amounts to a motor's inner design/working principles. Meaningful and distinctly different upper limits of directionality were found to exist for a wide variety of experimentally demonstrated and theoretically proposed motors and their biological counterparts. The maximum directionality provides a conceptual framework by which all of these different motors were quantitatively compared and systematically classified according to their mechanistic advancement. The results yield a series of guidelines for artificial motor development, and expose important evolutionary traits of biomotors. PMID- 21298158 TI - Boron-containing inhibitors of synthetases. AB - The use of boron in small-molecule pharmaceuticals is increasing. Boron's ubiquitous occurrence in nature and the recent success of a boronic acid drug (Velcade(r)) in the clinic have alleviated many concerns over its use in pharmaceuticals. In addition, the unique physicochemical properties of boronic acids make them an attractive addition to the medicinal chemists toolbox. This tutorial review will discuss these properties and potential benefits for anyone interested in finding novel enzyme inhibitors. An exceptional class of boronic acids, the oxaboroles, will be highlighted and their properties and uses will be discussed in detail. Finally, the current paradigm for the reaction of boronic acids with enzyme nucleophiles will be summarized. PMID- 21298159 TI - Continuous separation of breast cancer cells from blood samples using multi orifice flow fractionation (MOFF) and dielectrophoresis (DEP). AB - Circulating tumor cells (CTCs) are highly correlated with the invasive behavior of cancer, so their isolations and quantifications are important for biomedical applications such as cancer prognosis and measuring the responses to drug treatments. In this paper, we present the development of a microfluidic device for the separation of CTCs from blood cells based on the physical properties of cells. For use as a CTC model, we successfully separated human breast cancer cells (MCF-7) from a spiked blood cell sample by combining multi-orifice flow fractionation (MOFF) and dielectrophoretic (DEP) cell separation technique. Hydrodynamic separation takes advantage of the massive and high-throughput filtration of blood cells as it can accommodate a very high flow rate. DEP separation plays a role in precise post-processing to enhance the efficiency of the separation. The serial combination of these two different sorting techniques enabled high-speed continuous flow-through separation without labeling. We observed up to a 162-fold increase in MCF-7 cells at a 126 uL min(-1) flow rate. Red and white blood cells were efficiently removed with separation efficiencies of 99.24% and 94.23% respectively. Therefore, we suggest that our system could be used for separation and detection of CTCs from blood cells for biomedical applications. PMID- 21298160 TI - Controlling the contents of microdroplets by exploiting the permeability of PDMS. AB - A microfluidic device capable of exploiting the permeability of small molecules through polydimethylsiloxane (PDMS) has been fabricated in order to control the contents of microdroplets stored in storage wells. We demonstrate that protein precipitation and crystallization can be triggered by delivery of ethanol from a reservoir channel, thus controlling the protein solubility in microdroplets. Likewise quorum sensing in bacteria was triggered by delivery of the auto-inducer N-(3-oxododecanoyl)-l-homoserine lactone (OdDHL) through the PDMS membrane of the device. PMID- 21298161 TI - Role of metal dyshomeostasis in Alzheimer's disease. AB - Despite serving a crucial purpose in neurobiological function, transition metals play a sinister part in the aging brain, where the abnormal accumulation and distribution of reactive iron, copper, and zinc elicit oxidative stress and macromolecular damage that impedes cellular function. Alzheimer's disease (AD), an age-related neurodegenerative condition, presents marked accumulations of oxidative stress-induced damage, and increasing evidence points to aberrant transition metal homeostasis as a critical factor in its pathogenesis. Amyloid beta oligomerization and fibrillation, considered by many to be the precipitating factor underlying AD onset and development, is also induced by abnormal transition metal activity. We here elaborate on the roles of iron, copper, and zinc in AD and describe the therapeutic implications they present. PMID- 21298162 TI - Exploration of the 'cytochromome' of Desulfuromonas acetoxidans, a marine bacterium capable of powering microbial fuel cells. AB - Recent progress in bacterial genomic analysis has revealed a vast number of genes that encode c-type cytochromes that contain multiple heme cofactors. This high number of multiheme cytochromes in several bacteria has been correlated with their great respiratory flexibility, and in what concerns biotechnological applications, has been correlated with electricity production in Microbial Fuel Cells. Desulfuromonas acetoxidans, a member of the Geobactereaceae family, is one of these organisms for which the genome was recently made available, coding for 47 putative multiheme cytochromes. The growth of D. acetoxidans in different media allowed the identification of the cytochromes dominant in each condition. The triheme cytochrome c(7) is always present suggesting a key role in the bioenergetic metabolism of this organism, and a dodecaheme cytochrome of low homology with other proteins in the databases was also isolated. Different cytochromes are found for different growth conditions showing that their roles can be assigned to specific bioenergetic electron transfer routes. PMID- 21298163 TI - Intramolecular catalytic asymmetric carbon-hydrogen insertion reactions. Synthetic advantages in total synthesis in comparison with alternative approaches. AB - The synthetic potential of highly directional formal insertion of a carbene between carbon and hydrogen of a carbon-hydrogen bond has recently been developed for intramolecular reactions that lead to compounds of biological and medicinal interest. Stereoselective and regiocontrolled intramolecular processes from diazoacetate reactants, catalyzed by dirhodium(II) compounds with chiral carboxamidate ligands, provide efficient and selective access to compounds as diverse as enterolactone, baclofen, imperanene, xylolactone, and rolipram. A comparison of the C-H insertion methodology with alternative approaches is presented. PMID- 21298164 TI - Synthesis of functionalized arylpyridines and -pyrimidines by domino [4+2]/retro [4+2] cycloadditions of electron-rich dienes with alkynylpyridines and pyrimidines. AB - Aryl-substituted pyridines and pyrimidines were prepared by [4+2] cycloadditions of alkynyl-substituted pyridines and -pyrimidines with electron-rich dienes. The reactions proceed by formation of a bridged cycloadduct and subsequent thermal extrusion of ethylene. The pyridine moiety plays a crucial role for the success of the reaction. PMID- 21298165 TI - Function and structure of GFP-like proteins in the protein data bank. AB - The RCSB protein databank contains 266 crystal structures of green fluorescent proteins (GFP) and GFP-like proteins. This is the first systematic analysis of all the GFP-like structures in the pdb. We have used the pdb to examine the function of fluorescent proteins (FP) in nature, aspects of excited state proton transfer (ESPT) in FPs, deformation from planarity of the chromophore and chromophore maturation. The conclusions reached in this review are that (1) The lid residues are highly conserved, particularly those on the "top" of the beta barrel. They are important to the function of GFP-like proteins, perhaps in protecting the chromophore or in beta-barrel formation. (2) The primary/ancestral function of GFP-like proteins may well be to aid in light induced electron transfer. (3) The structural prerequisites for light activated proton pumps exist in many structures and it's possible that like bioluminescence, proton pumps are secondary functions of GFP-like proteins. (4) In most GFP-like proteins the protein matrix exerts a significant strain on planar chromophores forcing most GFP-like proteins to adopt non-planar chromophores. These chromophoric deviations from planarity play an important role in determining the fluorescence quantum yield. (5) The chemospatial characteristics of the chromophore cavity determine the isomerization state of the chromophore. The cavities of highlighter proteins that can undergo cis/trans isomerization have chemospatial properties that are common to both cis and trans GFP-like proteins. PMID- 21298166 TI - Ligand inducible assembly of a DNA tetrahedron. AB - Here we show that a small synthetic ligand can be used as a key building component for DNA nanofabrication. Using naphthyridinecarbamate dimer (NCD) as a molecular glue for DNA hybridization, we demonstrate NCD-triggered formation of a DNA tetrahedron. PMID- 21298167 TI - White light excitation of the near infrared Er3+ emission in exchanged zeolite sensitised by oxygen vacancies. AB - A new material based on Er(3+)-exchanged zeolite L crystals, in which oxygen vacancies have been generated, is proposed as an efficient emitter in the near infrared third telecommunication window. The rare earth ions photoluminescence is efficiently generated by energy transfer from the excited oxygen vacancies, which act as wide range light harvesters. The proposed material can be excited in the whole Near UV-VIS-NIR spectral range from 355 to 700 nm, thus representing the first step toward versatile, zeolite based NIR sources that can be excited with white light. PMID- 21298168 TI - Determination of differential cross sections and kinetic energy release of co products from central sliced images in photo-initiated dynamic processes. AB - For photo-initiated inelastic and reactive collisions, dynamic information can be extracted from central sliced images of state-selected Newton spheres of product species. An analysis framework has been established to determine differential cross sections and the kinetic energy release of co-products from experimental images. When one of the reactants exhibits a high recoil speed in a photo initiated dynamic process, the present theory can be employed to analyze central sliced images from ion imaging or three-dimensional sliced fluorescence imaging experiments. It is demonstrated that the differential cross section of a scattering process can be determined from the central sliced image by a double Legendre moment analysis, for either a fixed or continuously distributed recoil speeds in the center-of-mass reference frame. Simultaneous equations which lead to the determination of the kinetic energy release of co-products can be established from the second-order Legendre moment of the experimental image, as soon as the differential cross section is extracted. The intensity distribution of the central sliced image, along with its outer and inner ring sizes, provide all the clues to decipher the differential cross section and the kinetic energy release of co-products. PMID- 21298169 TI - Microporous magnets. AB - Combining porosity and magnetic ordering in a single material presents a significant challenge since magnetic exchange generally requires short bridges between the spin carriers, whereas porosity usually relies on the use of long diamagnetic connecting ligands. Despite this apparent incompatibility, notable successes have been achieved of late in generating truly microporous solids with high magnetic ordering temperatures. In this critical review, we give an overview of this emerging class of multifunctional materials, with particular emphasis on synthetic strategies and possible routes to new materials with improved properties (149 references). PMID- 21298170 TI - Titanium "constrained geometry" complexes with pendant arene groups. AB - The synthesis of the proligands C(5)Me(4)HSiMe(2)N(H)R) (R = CMe(2)Ph 1, 2 C(6)H(4)Ph 2) was accomplished via a straightforward salt metathesis reaction of the appropriate lithium amide and ClSiMe(2)(C(5)Me(5)H). Generation of the dilithio salt and reaction with TiCl(3).(THF)(3) followed by oxidation gave C(5)Me(4)SiMe(2)N(C(6)H(4)Ph)TiCl(2) (3) in low yield. In contrast, deprotonation of 1 and 2 and reaction with (Me(2)N)(2)TiCl(2) afforded C(5)Me(4)(SiMe(2)NR)Ti(NMe(2))(2) (R = CMe(2)Ph 4, 2-C(6)H(4)Ph 5), respectively, in good yields Treatment with MeI gave the analogs C(5)Me(4)(SiMe(2)NR)TiI(2) (R = CMe(2)Ph 6, 2-C(6)H(4)Ph 7). Reduction of 7 with potassium graphite afforded C(5)Me(4)(SiMe(2)NC(6)H(4)Ph)Ti 8. Treatment of 6 and 7 with MeMgBr afforded C(5)Me(4)(SiMe(2)NR)TiMe(2) (R = CMe(2)Ph 9, 2-C(6)H(4)Ph 10). Complexes 9 and 10 in combination with the activator [Ph(3)C][B(C(6)F(5))(4)] catalyzed the polymerization of styrene and ethylene. Copolymerization was also investigated. While the catalyst derived from 10 showed poor activity, compound 9 showed markedly higher activity than 10 and (C(5)Me(4))SiMe(2)(NtBu)]TiMe(2). PMID- 21298171 TI - Role of weakly polarized nanoparticles in electroporation. AB - In this study, we present a role for weakly polarized nanoparticles as engineered gene transporters that can enhance electromediated gene delivery. To validate this proof-of-concept, fluorescent poly(ethylene glycol) (PEG)-coated silica nanoparticles (SiNPs) with opposite polarities, SiNPs(RITC)-PEG/PTMA(+) and SiNPs(RITC)-PEG/PMP(-), are used. To investigate the electroporative uptake direction of the nanoparticles-gene complex, we employ microscale electroporation to generate more symmetric and uniform electric fields. The effect of the polarity of the nanoparticles on EGFP gene transfection efficiency in HeLa cells is measured by flow cytometry analysis. The results show that, compared to cationic nanoparticles, anionic nanoparticles have potential as electromediated gene transporters at a low gene concentration. Furthermore, we believe that this finding can be useful for developing a platform that enables electroporation based gene/drug delivery associated with functional nanoparticles. PMID- 21298173 TI - An straightforward entry to new pyrazolo-fused dibenzo[1,4]diazepines. AB - A series of novel pyrazolodibenzo[1,4]diazepines has been synthesized with good overall yields. The diarylpyrazole intermediates, with structure similarity to biologically relevant compounds such as currently marketed drugs like rimonabant or celecoxib, were prepared by a tandem sequence amine-exchange/heterocyclization starting from readily available enaminones and arylhydrazines. The key step of this efficient methodology was C(aryl)-N bond construction, accomplished by a palladium-catalyzed intramolecular N-arylation reaction, which was conducted in both homogeneous and polymer-supported versions. Reaction scope of such protocols and recycling of the heterogeneous catalyst were also examined. PMID- 21298172 TI - Rapid synthesis and zebrafish evaluation of a phenanthridine-based small molecule library. AB - A Heck cyclisation approach is described for the rapid synthesis of a library of natural product-like small molecules, based on the phenanthridine core. The synthesis of a range of substituted benzylamine building blocks and their incorporation into the library is reported, together with a highly selective cis dihydroxylation protocol that enables access to the target compounds in an efficient manner. Biological evaluation of the library using zebrafish phenotyping has led to the discovery of compound 20c, a novel inhibitor of early stage zebrafish embryo development. PMID- 21298174 TI - The first bridged lanthanide carbene complex formed through reduction of carbodiimide by diamine-bis(phenolate) ytterbium(II) complex and its reactivity to phenylisocyanate. AB - The reaction of YbL(THF)(2) (L = [-OC(6)H(2)(2,4-(t)Bu(2))(6 CH(2))](2)NCH(2)CH(2)NMe(2)) with (i)PrN=C=N(i)Pr led to the bridged carbene ytterbium complex (YbL)(2)(MU-N(i)PrCN(i)Pr) via a two-electron reduction process of carbodiimide, which reacted with PhNCO to afford a dinuclear ytterbium complex and a spiro derivative.